PMID- 28070647 TI - [Two children with intermediate uveitis and granuloma annulare from the same neighbourhood]. AB - Two children from the same neighbourhood presented with concomitant granuloma annulare (GA) and intermediate uveitis (IU) at an interval of 2 weeks. A coincidence seemed unlikely, as IU is very rare in children and even more so in connection with GA. Thorough diagnosis was performed to exclude other associated diseases. No systemic disease, no special features of vaccination or medication, no history of infection, and no toxic cause could be found. An association between GA and IU based on other, as yet undiagnosed factors, is still possible. Therefore, when evaluating patients with newly diagnosed IU, clinical work-up should also include medical history and examination to rule out GA. PMID- 28070648 TI - Deinbollia mosaic virus: a novel begomovirus infecting the sapindaceous weed Deinbollia borbonica in Kenya and Tanzania. AB - Four isolates of a bipartite begomovirus from naturally infected Deinbollia borbonica plants exhibiting yellow mosaic symptoms in Kenya and Tanzania were molecularly characterised. The DNA-A was most closely related to that of tomato leaf curl Mayotte virus (AM701764; 82%), while the DNA-B shared the highest nucleotide sequence identity with that of East African cassava mosaic virus (AJ704953) at 65%. Based on the current ICTV species demarcation criterion for the genus Begomovirus (>=91% sequence identity for the complete DNA-A), we report the full-length genome sequence of this novel bipartite begomovirus. The results reveal additional diversity and reservoir hosts of begomoviruses in East Africa. PMID- 28070649 TI - Bipolar cell gap junctions serve major signaling pathways in the human retina. AB - Connexin36 (Cx36) constituent gap junctions (GJ) throughout the brain connect neurons into functional syncytia. In the retina they underlie the transmission, averaging and correlation of signals prior conveying visual information to the brain. This is the first study that describes retinal bipolar cell (BC) GJs in the human inner retina, whose function is enigmatic even in the examined animal models. Furthermore, a number of unique features (e.g. fovea, trichromacy, midget system) necessitate a reexamination of the animal model results in the human retina. Well-preserved postmortem human samples of this study are allowed to identify Cx36 expressing BCs neurochemically. Results reveal that both rod and cone pathway interneurons display strong Cx36 expression. Rod BC inputs to AII amacrine cells (AC) appear in juxtaposition to AII GJs, thus suggesting a strategic AII cell targeting by rod BCs. Cone BCs serving midget, parasol or koniocellular signaling pathways display a wealth of Cx36 expression to form homologously coupled arrays. In addition, they also establish heterologous GJ contacts to serve an exchange of information between parallel signaling streams. Interestingly, a prominent Cx36 expression was exhibited by midget system BCs that appear to maintain intimate contacts with bistratified BCs serving other pathways. These findings suggest that BC GJs in parallel signaling streams serve both an intra- and inter-pathway exchange of signals in the human retina. PMID- 28070650 TI - Revision total knee arthroplasty due to bone cement and metal hypersensitivity. AB - INTRODUCTION: Hypersensitivity to implants is a rare complication of total knee arthroplasty (TKA). Metal and, less frequently, bone cement can produce allergic symptomatology that if unresponsive to conservative treatment could lead to revision. MATERIALS AND METHODS: We present the case of a patient with generalized pruritus and metal taste starting during the first postoperative month after TKA. Dermal allergy exams revealed that the patient had hypersensitivity to nickel sulphate and cobalt chloride and bone cement. Conservative treatment with antihistamine medication and corticosteroids failed to control the symptoms. The patient underwent revision TKA with a hypoallergic prosthesis 8 months after the primary procedure. RESULTS: Full disappearance of the symptoms occurred 3 months after revision. The latest follow-up evaluation (3 years post-revision) was unremarkable. CONCLUSIONS: In our opinion, an exhaustive medical history should be obtained from every candidate for total joint replacement and in cases of prior severe allergic reactions to metals, plastics or glues, patch testing of the components of the future prosthesis should be done. When an already implanted prosthesis causes symptoms like pain, edema, pruritus, erythema, limited range of motion and increase in joint's temperature, the possibility of allergy to metals and/or bone cement (in case of cemented prosthesis) should be checked after the exclusion of other reasons like infection. If symptoms cannot be controlled by conservative measures, revision should be decided and carried out with hypoallergic prosthesis. PMID- 28070651 TI - Inferior vena cava involvement in children with Wilms tumor. AB - OBJECTIVES: Retrospective review of children with WT thrombus involving the IVC. METHODS: We reviewed the charts of 123 patients with WT diagnosed between January 2006 and December 2015. Patients with caval tumor thrombus were identified, demographic data, radiological images, extent of thrombus, chemo- and radiotherapy, surgical approach, pathology reports and outcomes were analyzed. RESULTS: IVC involvement was identified in 11 patients (9%). Left-sided tumors were more common (55%). Sensitivity of CT scan in thrombus identification was 64%. Neoadjuvant chemotherapy was the primary mode of treatment with 19% reduction of primary tumor size, thrombus resolution in four and regression in six patients. No thrombus progression was observed. Delayed surgical treatment was either nephro-ureterectomy (nine patients) or partial nephrectomy in patients with bilateral WT (two patients). During surgery, thrombectomy and intimal stripping achieved local control in patients with persistent caval tumor. Cardiopulmonary bypass was not needed in patients with initial atrial involvement (five patients). Despite adherence and invasion of tumor thrombus to IVC wall, only one patient required segmental vein resection. All patients eventually achieved CR, none had local relapse. One patient had lung relapse treated to complete remission. The 3-year EFS is 85.7 +/- 13.2% and the 3-year OS is 100%. CONCLUSION: IVC tumor thrombus in patients with WT was managed successfully using preoperative chemotherapy followed by surgery with minimal aggressive approach. Luminal thrombus removal and intimal stripping supplanted by local radio boost when indicated seem to be adequate tools for local control with documented good overall outcomes. PMID- 28070652 TI - Similarities between parasternal intercostal nerve block and subpectoral interfascial plane block. PMID- 28070653 TI - Impact of acute changes in perfusion index and blood pressure on the accuracy of non-invasive continuous hemoglobin concentration measurements during induction of anesthesia. AB - PURPOSE: Several factors affect the accuracy of non-invasive continuous hemoglobin concentration (SpHb) measurements. We had previously shown an increase in the perfusion index (PI) following induction of anesthesia which was associated with an increase in the difference between SpHb and total hemoglobin (tHb) (SpHb-tHb). We hypothesized that blunting the increase in PI by maintaining blood pressure during induction of anesthesia would improve the agreement between SpHb and tHb measurements. METHODS: Twenty-nine adult patients were enrolled. Patients were randomly assigned by use of sequentially numbered, opaque sealed envelopes to a control (group C) or a phenylephrine group (group P). Anesthesia was induced and maintained with propofol, remifentanil, and ketamine. In group P, phenylephrine was infused at 0.5 ug/kg/min during induction of anesthesia. SpHb and PI were monitored with a Radical-7 Pulse CO-Oximeter. tHb and hematocrit were measured with the ABL800 blood gas analyzer. RESULTS: Following induction of anesthesia, PI increased significantly in both groups (p < 0.001 and p < 0.05 in groups C and P, respectively). However, the increase in PI was significantly smaller in group P than in group C (2.6 +/- 1.3 vs 0.8 +/- 1.4%, p < 0.001). Similarly, the change in SpHb-tHb was significantly smaller in group P than in group C (0.40 +/- 0.78 vs 0.97 +/- 0.70 g/dl, p < 0.05). Changes in SpHb-tHb are correlated with changes in PI (r = 0.46, p < 0.05). CONCLUSIONS: The findings suggest that blunting the increase in PI by maintaining arterial pressure during induction of anesthesia improves the agreement between SpHb and tHb values. PMID- 28070654 TI - Anesthesia management of cesarean section in parturient with anti-N-methyl-D aspartate receptor encephalitis: a case report. AB - A 24-year-old woman at 29 weeks' gestation, and with psychiatric symptoms, was admitted to hospital and diagnosed as having anti-N-methyl-D-aspartate receptor encephalitis. After 4 weeks of immunotherapy with little effect, an emergency cesarean section was performed at 33+4 weeks gestation under general anesthesia. The parturient was intubated after rapid sequence induction with etomidate, remifentanil and succinylcholine. Anesthesia was maintained with sevoflurane and remifentanil. Except for low weight, the infant was normal at birth. The surgery went uneventfully and teratoma or other masses were not found. The parturient was sent to ICU for further treatment without extubation after surgery. She was extubated on the 6th day after surgery and was transferred to the general ward of the neurology department to control her seizures. After the seizures were controlled, she was discharged home on the 80th postoperative day and her neurological symptoms had slowly improved half a year later. This case report presents the anesthetic considerations in patients with anti-NMDAR encephalitis undergoing cesarean section. PMID- 28070655 TI - Synthetic introns help identify sequences in the 5' UTR intron of the Glycine max polyubiquitin (Gmubi) promoter that give increased promoter activity. AB - MAIN CONCLUSION: Specific sequences within the leader intron of a soybean polyubiquitin gene stimulated gene expression when placed either within a synthetic intron or upstream of a core promoter. The intron in the 5' untranslated region of the soybean polyubiquitin promoter, Gmubi, seems to contribute to the high activity of this promoter. To identify the stimulatory sequences within the intron, ten different sequential intronic sequences of 40 nt were isolated, cloned as tetrameric repeats and placed upstream of a minimal cauliflower mosaic virus 35S (35S) core promoter, which was used to control expression of the green fluorescent protein. Intron fragment tetramers were also cloned within a modified, native intron, creating a Synthetic INtron Cassette (SINC), which was then placed downstream of Gmubi and 35S core promoters. Intron fragment tetramers and SINC constructs were evaluated using transient expression in lima bean cotyledons and stable expression in soybean hairy roots. Intron fragments, used as tetramers upstream of the 35S core promoter, yielded up to 80 times higher expression than the core promoter in transient expression analyses and ten times higher expression in stably transformed hairy roots. Tetrameric intronic fragments, cloned downstream of the Gmubi and 35S core promoters and within the synthetic intron, also yielded increased transient and stable GFP expression that was up to 4 times higher than Gmubi alone and up to 40 times higher than the 35S core promoter alone. These intron fragments contain sequences that seem to act as promoter regulatory elements and may contribute to the increased expression observed with this native strong promoter. Intron regulatory elements and synthetic introns may provide additional tools for increasing transgene expression in plants. PMID- 28070656 TI - Peri-procedural use of anticoagulants in radiology: an evidence-based review. AB - Peri-procedural anticoagulant management hinges on the balance of hemorrhagic and thrombotic complications. The radiologist is tasked with accurately assessing the hemorrhagic risk for patients undergoing procedures, taking into account procedural bleeding rates, underlying coagulopathy based on lab tests, and use of anticoagulants. The purpose of this article is to provide a contemporary review of commonly used anticoagulants and, incorporating published evidence, review their management related to image-guided procedures. PMID- 28070657 TI - "How to" incorporate dual-energy imaging into a high volume abdominal imaging practice. AB - Dual-energy CT imaging has many potential uses in abdominal imaging. It also has unique requirements for protocol creation depending on the dual-energy scanning technique that is being utilized. It also generates several new types of images which can increase the complexity of image creation and image interpretation. The purpose of this article is to review, for rapid switching and dual-source dual energy platforms, methods for creating dual-energy protocols, different approaches for efficiently creating dual-energy images, and an approach to navigating and using dual-energy images at the reading station all using the example of a pancreatic multiphasic protocol. It will also review the three most commonly used types of dual-energy images: "workhorse" 120kVp surrogate images (including blended polychromatic and 70 keV monochromatic), high contrast images (e.g., low energy monochromatic and iodine material decomposition images), and virtual unenhanced images. Recent developments, such as the ability to create automatically on the scanner the most common dual-energy images types, namely new "Mono+" images for the DSDECT (dual-source dual-energy CT) platform will also be addressed. Finally, an approach to image interpretation using automated "hanging protocols" will also be covered. Successful dual-energy implementation in a high volume practice requires careful attention to each of these steps of scanning, image creation, and image interpretation. PMID- 28070658 TI - Getting the GIST: a pictorial review of the various patterns of presentation of gastrointestinal stromal tumors on imaging. AB - Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, are a relatively recently described entity. Most exhibit a mutated tyrosine kinase receptor gene and in some capacity are treated by tyrosine kinase inhibitors. GISTs can occur across the age spectrum but are more common in patients older than 40 years. They exhibit a wide range of clinical presentations and imaging characteristics. All patterns of enhancement on contrast enhanced computed tomography (CECT) can be seen with GISTs, including hypoenhancing, isoenhancing, and hyperenhancing tumors. They can be large or small, endoluminal or exophytic. Clinical presentations include asymptomatic patients, nonspecific symptoms, obstruction, and bleeding. Bleeding can take the form of slow, intraluminal GI bleeding or massive intraperitoneal bleeding secondary to rupture and can be seen regardless of the enhancement pattern. Some can cavitate, ulcerate, rupture or cause fistulae. The radiologist's knowledge of the variety of combinations of presentations can narrow the differential diagnosis and ultimately lead to faster diagnosis and treatment. PMID- 28070659 TI - Diagnosis, treatment, and consequences of anastomotic leakage in colorectal surgery. AB - PURPOSE: The aim of this study was to explore the choice of modality for diagnosis, treatments, and consequences of anastomotic leakage. METHODS: This is a retrospective study of consecutive patients who underwent surgery that included a colorectal anastomosis due to colorectal cancer, diverticulitis, inflammatory bowel disease (IBD), or benign polyps. RESULTS: A total of 600 patients were included during 2010-2012, and 60 (10%) had an anastomotic leakage. It took in mean 8.8 days (range 2-42) until the anastomotic leakage was diagnosed. A total of 44/60 of the patients with a leakage had a CT scan of the abdomen; 11 (25%) were initially negative for anastomotic leakage. Among all leakages, the anastomosis was taken down in 45 patients (76.3%). All patients with a grade B leakage (n = 6) were treated with antibiotics, and two also received transanal drainage. The overall complication rate was also significantly higher in those with leakage (93.3 vs. 28.5%, p < 0.001), and it was more common with more than three complications (70 vs. 1.5%, p < 0.001). There was a higher mortality in the leakage group. CONCLUSION: This study demonstrated that one fourth of the CT scans that were executed were initially negative for leakage. Most patients with a grade C leakage will not have an intact anastomosis. An anastomotic leakage leads to significantly more severe postoperative complications, higher rate of reoperations, and higher mortality. An earlier relaparotomy instead of a CT scan and improved postoperative surveillance could possibly reduce the consequences of the anastomotic leakage. PMID- 28070660 TI - Treatment options for hyperemesis gravidarum. AB - Hyperemesis gravidarum (HG) is a severe and prolonged form of nausea and/or vomiting during pregnancy. HG affects 0.3-2% of pregnancies and is defined by dehydration, ketonuria, and more than 5% body weight loss. Initial pharmacologic treatment for HG includes a combination of doxylamine and pyridoxine. Additional interventions include ondansetron or dopamine antagonists such as metoclopramide or promethazine. The options are limited for women who are not adequately treated with these medications. We suggest that mirtazapine is a useful drug in this context and its efficacy has been described in case studies. Mirtazapine acts on noradrenergic, serotonergic, histaminergic, and muscarinic receptors to produce antidepressant, anxiolytic, antiemetic, sedative, and appetite-stimulating effects. Mirtazapine is not associated with an independent increased risk of birth defects. Further investigation of mirtazapine as a treatment for HG holds promise to expand treatment options for women suffering from HG. PMID- 28070661 TI - Voltage-gated sodium channels as targets for pyrethroid insecticides. AB - The pyrethroid insecticides are a very successful group of compounds that have been used extensively for the control of arthropod pests of agricultural crops and vectors of animal and human disease. Unfortunately, this has led to the development of resistance to the compounds in many species. The mode of action of pyrethroids is known to be via interactions with the voltage-gated sodium channel. Understanding how binding to the channel is affected by amino acid substitutions that give rise to resistance has helped to elucidate the mode of action of the compounds and the molecular basis of their selectivity for insects vs mammals and between insects and other arthropods. Modelling of the channel/pyrethroid interactions, coupled with the ability to express mutant channels in oocytes and study function, has led to knowledge of both how the channels function and potentially how to design novel insecticides with greater species selectivity. PMID- 28070662 TI - Investigation of the instability and low water kefir grain growth during an industrial water kefir fermentation process. AB - A poorly performing industrial water kefir production process consisting of a first fermentation process, a rest period at low temperature, and a second fermentation process was characterized to elucidate the causes of its low water kefir grain growth and instability. The frozen-stored water kefir grain inoculum was thawed and reactivated during three consecutive prefermentations before the water kefir production process was started. Freezing and thawing damaged the water kefir grains irreversibly, as their structure did not restore during the prefermentations nor the production process. The viable counts of the lactic acid bacteria and yeasts on the water kefir grains and in the liquors were as expected, whereas those of the acetic acid bacteria were high, due to the aerobic fermentation conditions. Nevertheless, the fermentations progressed slowly, which was caused by excessive substrate concentrations resulting in a high osmotic stress. Lactobacillus nagelii, Lactobacillus paracasei, Lactobacillus hilgardii, Leuconostoc mesenteroides, Bifidobacterium aquikefiri, Gluconobacter roseus/oxydans, Gluconobacter cerinus, Saccharomyces cerevisiae, and Zygotorulaspora florentina were the most prevalent microorganisms. Lb. hilgardii, the microorganism thought to be responsible for water kefir grain growth, was not found culture-dependently, which could explain the low water kefir grain growth of this industrial process. PMID- 28070663 TI - The pygidial gland secretion of the forest caterpillar hunter, Calosoma (Calosoma) sycophanta: the antimicrobial properties against human pathogens. AB - Recently, various insect secretions have been tested as possible antimicrobial agents. In beetles, these secretions are essentially products of various exocrine glands, of which particular emphasis is on pygidial glands that are common for the suborder Adephaga. The antimicrobial potential of the pygidial gland secretion isolated from the adults of Calosoma sycophanta against human pathogens has been tested and compared with the potential of other carabid species, particularly within the tribe Carabini. The antimicrobial assay includes a microdilution method which was applied in order to determine the minimal inhibitory, minimal fungicidal and minimal bactericidal concentrations. It has been tested the effect of the secretion against eight strains of fungal and eight strains of bacterial species. The secretion sample of the tested carabid species has shown statistically significant antifungal effect against all strains of treated micromycetes, the highest in comparison with previously tested carabids (Carabus spp., Laemostenus punctatus and Abax parallelepipedus). Aspergillus versicolor proved to be the most sensitive micromycete, while the remaining seven fungal strains have shown the same level of sensibility. In comparison with commercial mycotics ketoconazole and bifonazole, applied as positive controls, the tested secretion showed much higher antifungal activity for all fungal strains. Antibacterial effect has been manifested only against one bacterial strain (Escherichia coli), contrary to other previously studied carabid species. These observations might have a significant impact on the ecological domain and possible purpose in biomedical studies and applications in the future. Additionally, morpho-histology of the pygidial glands of C. sycophanta is investigated and discussed. PMID- 28070664 TI - Transcriptome and metabolome responses of Shewanella oneidensis MR-1 to methyl orange under microaerophilic and aerobic conditions. AB - Shewanella oneidensis MR-1 degrades various azo dyes under microaerophilic and anaerobic conditions, but this process is inhibited under aerobic conditions. The mechanisms underlying azo dye biodegradation and inhibition remain unknown. Therefore, we investigated metabolic and transcriptional changes in strain MR-1, which was cultured under different conditions, to elucidate these mechanisms. At the transcriptional level, genes involved in certain metabolic processes, particularly the tricarboxylic acid (TCA) cycle, amino acid biodegradation, and the electron transfer system, were significantly altered (M ? 2, p > 0.8 ) in the presence of methyl orange (MO). Moreover, a high concentration of dissolved oxygen heavily impacted the expression levels of genes involved in fatty acid biodegradation. Metabolome analysis revealed significant alteration (p < 0.05) in the concentrations of nine metabolites when strain MR-1 was cultured under aerobic conditions; the majority of these metabolites were closely associated with amino acid metabolism and DNA replication. Accordingly, we propose a possible pathway for MO biodegradation and discuss the most likely causes of biodegradation inhibition due to dissolved oxygen. PMID- 28070665 TI - Current state of purification, isolation and analysis of bacteriocins produced by lactic acid bacteria. AB - The scientific interest for the search of natural means of microbial inhibitors has not faded for several years. A search of natural antibiotics, so-called bacteriocins which are produced by lactic acid bacteria (LAB), gains a huge attention of the scientists in the last century, in order to reduce the usage of synthetic food additives. Pure bacteriocins with wide spectra of antibacterial activity are promising among the natural biopreservatives. The usage of bacteriocin(s) producing LAB as starter culture for the fermentation of some food products, in order to increase their shelf-life, when synthetic preservatives are not allowable, is also possible. There are a lot of studies focusing on the isolation of new bacteriocins from traditional fermented food, dairy products and other foods or sometimes even from unusual non-food matrices. Bacteriocins producing bacteria have been isolated from different sources with the different antibacterial activity against food-borne microorganisms. This review covers the classification of bacteriocins, diversity of sources of bacteriocin(s) producing LAB, antibacterial spectra of isolated bacteriocins and analytical methods for the bacteriocin purification and analysis within the last 15 years. PMID- 28070666 TI - Health-beneficial nutraceuticals-myth or reality? AB - The modern term nutraceutical sounds extremely promising to the health-conscious consumers and to the broad audience. But what are the scientific foundations of this hybrid between nutrient and pharmaceutical? Still, most compelling evidence for potential health-beneficial effects of nutraceuticals seem to derive from descriptive and correlative epidemiological data. Here, we will take an inventory of the general concepts of research to assess the current plethora of health claims that were made for nutraceutical products. Thereby, we will discuss the limitations of current experimental approaches to advance in establishing mechanistic or causal links to the possible benefits of bioactive dietary molecules. Finally, we aim to provide perspectives to generate potential scientific evidence for the beneficial effects of nutraceuticals on human physiology. PMID- 28070667 TI - Erratum to: Regional citrate anticoagulation for continuous renal replacement therapy in children. PMID- 28070668 TI - What happens to asymptomatic lower pole kidney stones smaller than 10 mm in children during watchful waiting? AB - BACKGROUND: The optimal management of lower pole kidney (LPK) stones in children is controversial. The aim of this study was to determine the outcomes of children with asymptomatic isolated LPK stones smaller than 10 mm during follow-up. METHODS: A total of 242 patients with 284 stones presenting at our institution between June 2004 and December 2014 with an asymptomatic, single LPK stone with a diameter of <10 mm were enrolled in the study. All children were assigned to receive first-line therapy and then categorized according to the need for medical intervention. Age, gender, stone laterality, stone size and type, associated urinary tract problems, and uncontrolled metabolic status were assessed as predictive factors of medical treatment for small (<10 mm) asymptomatic LPK stones. Stone-free rates were compared between interventions. RESULTS: The mean age and mean stone size were 9.4 +/- 1.9 years and 7.4 +/- 0.6 mm at admission, respectively. Stone progression rate was 61.2%, and the mean time for intervention was 19.2 +/- 4.6 months. Flexible ureterorenoscopy (n = 68) or micro percutaneous nephrolithotomy (n = 4) were performed for 72 stones (25.4%; group 1), and extracorporeal shock wave lithotripsy was performed for 102 stones (35.9%; group 2). The stone-free rates were 81.8 and 79.3% in group 1 and 2, respectively (p > 0.05). The remaining asymptomatic stones (110, 38.8%; group 3) were managed by continued observation, and at the end of the observation time (mean 40.8 +/- 20.8 months) the spontaneous passage rate was 9.1% in this group. In the multivariate analysis, stone size of >7 mm, concurrent renal anomalies, and stones composed of magnesium ammonium phosphate (struvite) and cystine were statistically significant predictors of the need for intervention. CONCLUSIONS: Children with stones larger than 7 mm, renal anomalies, or stones composed of metabolically active cystine or struvite are more likely to require intervention, and those with asymptomatic LPK stones smaller than 10 mm can be managed by continued observation. PMID- 28070669 TI - Prospective cohort study of cancer patients diagnosed with incidental venous thromboembolism on routine computed tomography scans. AB - PURPOSE: Venous thromboembolism (VTE) is a major complication of cancer with recent increasing reports of incidental VTE. The objectives are to estimate the prevalence of incidental VTE in cancer patients on staging CT scans, identify common symptoms, and determine VTE recurrence in a prospective study. PATIENTS AND METHODS: One thousand ninety patients were studied. Adult cancer patients scheduled for outpatient staging CT scans were eligible. VTE cases were followed for 6 months. Fisher's exact test for group comparisons of categorical variables and generalized linear modeling to estimate the prevalence of incidental VTE was used. RESULTS: The mean age was 58 years (range 18-87 years); 50% were male. The prevalence of incidental VTE was 1.8% (CI 1.15-2.87%). Significant symptoms in patients with VTE included fatigue (p = 0.004), stress (p = 0.0195), depression (p = 0.019), poorer quality of life (p = 0.0194), and poorer physical well-being (p = 0.0007). All the patients with VTE had at least one comorbidity (p = 0.03). No patient had recurrence within 6 months. CONCLUSION: The prevalence of incidental VTE on staging CT scans is lower than previously reported. Symptoms were associated with VTE; however, further work is needed to understand whether these are clinically relevant. No VTE recurrences were noted following 6 months. PMID- 28070670 TI - The impact of pneumococcal conjugate vaccine on community-acquired pneumonia hospitalizations in children with comorbidity. AB - : The burden of community-acquired pneumonia (CAP) in high-income countries is still significant. The introduction of pneumococcal conjugate vaccines (PCV) has reduced the overall need for hospitalization for CAP. However, it is not clear whether children with underlying disease also have benefitted from the PCV immunization programme. Children 0 to <5 years of age hospitalized with CAP and discharged with an ICD-10 code of J13-J18.9 between November 1, 2005, and April 30, 2007 (pre-vaccination period), and November 1, 2010, and April 30, 2012 (post vaccination period), were eligible for this study. Data on hospitalization and discharge diagnoses were retrieved from the Hospital Registry. In addition, chart review was performed in 50% of the patients. Our result confirmed a decrease in hospitalization rate for CAP in the PCV13 period. Chart review revealed that half of the patients had underlying comorbidity and these children had more severe symptoms and required longer hospital stay. Intensive care was provided to less than 10% of the children and mostly for children with an underlying neurological disease. CONCLUSIONS: We show that all children have benefitted from the reduction of CAP hospitalization after introduction of PCV. Our finding emphasizes the importance of children with chronic diseases receiving adequate vaccinations that may protect from lower respiratory diseases. What is known? * Community-acquired pneumonia is a leading infectious cause of hospitalizations and death among children <5 years of age globally * Pneumococcal conjugate vaccine reduces the hospitalizations of all-cause pneumonia What is new? * We show that also children with underlying comorbidities have benefitted from PCV immunization with a reduction of CAP hospitalization * We show that approximately half of all children hospitalized with CAP also have underlying comorbidities. PMID- 28070671 TI - Place of death of children with complex chronic conditions: cross-national study of 11 countries. AB - : Cross-national understanding of place of death is crucial for health service systems for their provision of efficient and equal access to paediatric palliative care. The objectives of this population-level study were to examine where children with complex chronic conditions (CCC) die and to investigate associations between places of death and sex, cause of death and country. The study used death certificate data of all deceased 1- to 17-year-old children (n = 40,624) who died in 2008, in 11 European and non-European countries. Multivariable logistic regression was performed to determine associations between place of death and other factors. Between 24.4 and 75.3% of all children 1-17 years in the countries died of CCC. Of these, between 6.7 and 42.4% died at home. In Belgium and the USA, all deaths caused by CCC other than malignancies were less likely to occur at home, whereas in Mexico and South Korea, deaths caused by neuromuscular diseases were more likely to occur at home than malignancies. In Mexico (OR = 0.91, 95% CI: 0.83-1.00) and Sweden (OR = 0.35, 95% CI: 0.15-0.83), girls had a significantly lower chance of dying at home than boys. CONCLUSION: This study shows large cross-national variations in place of death. These variations may relate to health system-related infrastructures and policies, and differences in cultural values related to place of death, although this needs further investigation. The patterns found in this study can inform the development of paediatric palliative care programs internationally. What is known: * There is a scarcity of population-level studies investigating where children with CCC die in different countries. * Cross-national understanding of place of death provides information to health care systems for providing efficient and equal access to paediatric palliative care. What is new : * There are large cross-national variations in the place of death of children with CCC, with few deathsoccuring at home in some countries whereas hospital deaths are generally most common. * In general, deaths caused by neuromuscular diseases and malignancies occur at home more often thanother CCC. PMID- 28070673 TI - [People and dementia : How do we meet the needs of the patients and their relatives?] PMID- 28070672 TI - Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network. AB - Progranulin (PGRN) is implicated in Alzheimer's disease (AD) as well as frontotemporal lobar degeneration. Genetic studies demonstrate an association of the common GRN rs5848 variant that results in reduced PGRN levels with increased risk for AD. However, the mechanisms by which PGRN reduction from the GRN AD risk variant or mutation exacerbates AD pathophysiology remain ill defined. Here, we show that the GRN AD risk variant has no significant effects on florbetapir positron emission tomographic amyloid imaging and cerebrospinal fluid (CSF) Abeta levels, whereas it is associated with increased CSF tau levels in human subjects of the Alzheimer's disease neuroimaging initiative studies. Consistent with the human data, subsequent analyses using the APPswe/PS1DeltaE9 (APP/PS1) mouse model of cerebral amyloidosis show that PGRN deficiency has no exacerbating effects on Abeta pathology. In contrast and unexpectedly, PGRN deficiency significantly reduces diffuse Abeta plaque growth in these APP/PS1 mice. This protective effect is due, at least in part, to enhanced microglial Abeta phagocytosis caused by PGRN deficiency-induced expression of TYROBP network genes (TNG) including an AD risk factor Trem2. PGRN-deficient APP/PS1 mice also exhibit less severe axonal dystrophy and partially improved behavior phenotypes. While PGRN deficiency reduces these amyloidosis-related phenotypes, other neuronal injury mechanisms are increased by loss of PGRN, revealing a multidimensional interaction of GRN with AD. For example, C1q complement deposition at synapses is enhanced in APP/PS1 mice lacking PGRN. Moreover, PGRN deficiency increases tau AT8 and AT180 pathologies in human P301L tau-expressing mice. These human and rodent data suggest that global PGRN reduction induces microglial TNG expression and increases AD risk by exacerbating neuronal injury and tau pathology, rather than by accelerating Abeta pathology. PMID- 28070674 TI - [Care of Korean elderly in need of care : Tendency to strengthen the role of integrated care for the elderly in communities]. AB - Since the introduction of long-term nursing care insurance in 2008, the Korean elderly in need of care are entitled to residential care or home based care services, as in the other welfare states. This article initially introduces the Korean nursing care insurance (PfV) for the elderly to give an overview of the healthcare system. Subsequently, the latest model project "Community based comprehensive care system" is introduced. The confusing care and social services should be networked and provided in a manner customized to the needs of the elderly, so that home based care before residential care can be realized. PMID- 28070675 TI - [Refeeding syndrome in geriatric patients : A frequently overlooked complication]. AB - The refeeding syndrome is a life-threatening complication that can occur after initiation of a nutrition therapy in malnourished patients. If the risk factors and pathophysiology are known, the refeeding syndrome can effectively be prevented and treated, if recognized early. A slow increase of food intake and the close monitoring of serum electrolyte levels play an important role. Because the refeeding syndrome is not well known and the symptoms may vary extremely, this complication is poorly recognized, especially against the background of geriatric multimorbidity. This overview is intended to increase the awareness of the refeeding syndrome in the risk group of geriatric patients. PMID- 28070676 TI - [Upper extremity fractures in the elderly]. AB - Upper extremity fractures in the elderly are very frequent and second only to hip fractures in the group of fragility fractures. Their impact on mobility and functional decline seems to be underestimated especially when they occur in combination with lower extremity fractures. Fractures of the proximal humerus and the distal radius can often be treated conservatively; however, the indications for operative treatment must not be based on fracture morphology alone and due consideration should be given to all concomitant circumstances affecting functional aspects of patients. Operative treatment of proximal humeral fractures may aim either at preserving the humeral head or at prosthetic replacement. There is broad agreement that this decision should depend on the condition of the humeral head fragment (degree of damage, perfusion). Fixation of distal radial fractures is commonly performed with angular volar stable plates. The more complex the fracture, the more likely conservative treatment will fail. PMID- 28070677 TI - Potential Activity of Subglacial Microbiota Transported to Anoxic River Delta Sediments. AB - The Watson River drains a portion of the SW Greenland ice sheet, transporting microbial communities from subglacial environments to a delta at the head of Sondre Stromfjord. This study investigates the potential activity and community shifts of glacial microbiota deposited and buried under layers of sediments within the river delta. A long-term (12-month) incubation experiment was established using Watson River delta sediment under anaerobic conditions, with and without CO2/H2 enrichment. Within CO2/H2-amended incubations, sulphate depletion and a shift in the microbial community to a 52% predominance of Desulfosporosinus meridiei by day 371 provides evidence for sulphate reduction. We found evidence of methanogenesis in CO2/H2-amended incubations within the first 5 months, with production rates of ~4 pmol g-1 d-1, which was likely performed by methanogenic Methanomicrobiales- and Methanosarcinales-related organisms. Later, a reduction in methane was observed to be paired with the depletion of sulphate, and we hypothesise that sulphate reduction out competed hydrogenotrophic methanogenesis. The structure and diversity of the original CO2/H2-amended incubation communities changed dramatically with a major shift in predominant community members and a decline in diversity and cell abundance. These results highlight the need for further investigations into the fate of subglacial microbiota within downstream environments. PMID- 28070678 TI - tRNA Misacylation with Methionine in the Mouse Gut Microbiome in Situ. AB - Global protein mistranslation with methionine has been shown to be a conserved biological process that affords distinct functional advantages in all three domains of life. In all instances, methionine mistranslation occurs through a regulated process where low-fidelity forms of methionyl-tRNA synthetase are conditionally induced to mischarge non-methionyl-tRNAs with methionine followed by the utilization of the misacylated tRNAs in translation. In mammals, methionine mistranslation contributes to oxidative stress response; in the hyperthermophilic archaeon Aeropyrum pernix, methionine mistranslation produces proteins that are better adapted to low temperature growth; in E. coli, methionine mistranslation increases resistance to antibiotics and chemical stressors. The phenotypic benefits conferred by tRNA mismethionylation suggest that it should be a widespread adaptational mechanism in diverse bacterial lineages, yet this response has only been described in E. coli. Furthermore, previous microbial investigations on this response have been confined to axenic laboratory cultures. It was unknown whether tRNA mismethionylation was relevant in a natural microbial habitat. Here we show that four abundant gut microbiotal genera belonging to the Firmicutes and Bacteroidetes phyla perform constitutive tRNA misacylation with methionine in the mouse cecum in situ. These results reveal the ubiquity of the tRNA mismethionylation process among bacteria and implicate the potential importance of this response for subsistence and adaptation in natural habitats. PMID- 28070679 TI - Diversity of Microbial Carbohydrate-Active enZYmes (CAZYmes) Associated with Freshwater and Soil Samples from Caatinga Biome. AB - Semi-arid and arid areas occupy about 33% of terrestrial ecosystems. However, little information is available about microbial diversity in the semi-arid Caatinga, which represents a unique biome that extends to about 11% of the Brazilian territory and is home to extraordinary diversity and high endemism level of species. In this study, we characterized the diversity of microbial genes associated with biomass conversion (carbohydrate-active enzymes, or so called CAZYmes) in soil and freshwater of the Caatinga. Our results showed distinct CAZYme profiles in the soil and freshwater samples. Glycoside hydrolases and glycosyltransferases were the most abundant CAZYme families, with glycoside hydrolases more dominant in soil (~44%) and glycosyltransferases more abundant in freshwater (~50%). The abundances of individual glycoside hydrolase, glycosyltransferase, and carbohydrate-binding module subfamilies varied widely between soil and water samples. A predominance of glycoside hydrolases was observed in soil, and a higher contribution of enzymes involved in carbohydrate biosynthesis was observed in freshwater. The main taxa associated with the CAZYme sequences were Planctomycetia (relative abundance in soil, 29%) and Alphaproteobacteria (relative abundance in freshwater, 27%). Approximately 5-7% of CAZYme sequences showed low similarity with sequences deposited in non redundant databases, suggesting putative homologues. Our findings represent a first attempt to describe specific microbial CAZYme profiles for environmental samples. Characterizing these enzyme groups associated with the conversion of carbohydrates in nature will improve our understanding of the significant roles of enzymes in the carbon cycle. We identified a CAZYme signature that can be used to discriminate between soil and freshwater samples, and this signature may be related to the microbial species adapted to the habitat. The data show the potential ecological roles of the CAZYme repertoire and associated biotechnological applications. PMID- 28070680 TI - A disturbance of intestinal epithelial cell population and kinetics in APC1638T mice. AB - The adenomatous polyposis coli (APC) is a multifunctional protein as well as a tumor suppressor. To determine the functions of the C-terminal domain of APC, we explored APC 1638T/1638T (APC1638T) mice that express a truncated APC lacking the C-terminal domain. The APC1638T mice were tumor free and exhibited growth retardation. In the present study, we compared small intestinal crypt-villus cells homeostasis in APC +/+ (WT) mice and APC1638T mice. The body weight of APC1638T mice was significantly smaller than that of WT mice at all ages. The length of small intestine of APC1638T mice was significantly shorter than that of WT mice. The crypt-villus axis was significantly elongated, and the number of intestinal epithelial cells also increased in APC1638T mice compared with those in WT mice. However, the number of intestinal epithelial cells per 100 um of villi was not different between WT and APC1638T mice. Migration and proliferation of intestinal epithelial cells in APC1638T mice were faster than that in WT mice. The population of Goblet cells, Paneth cells, and enteroendocrine cells was significantly altered in APC1638T mice. These results indicate that C-terminal domain of APC has a role in the regulation of intestinal epithelium homeostasis. PMID- 28070682 TI - Abstracts for GEER-Congress in Toledo, Spain, June 2016. PMID- 28070681 TI - Comparison of the 18-month outcome after the treatment of osteoporotic insufficiency fractures by means of balloon sacroplasty (BSP) and radiofrequency sacroplasty (RFS) in comparison: a prospective randomised study. AB - PURPOSE: The objective of this prospective, randomised study was to examine the feasibility and clinical outcome of balloon sacroplasty and radiofrequency sacroplasty. METHODS: In 40 patients with a total of 57 sacral fractures, CT guided cement augmentation was performed by means of BSP or RFS. For BSP, the balloon catheter was inflated and deflated in the fracture zone, and the hollow space, thus, created was then filled with PMMA cement. For RFS, the spongious space in the fracture zone was initially extended using a flexible osteotome, and the highly viscous PMMA cement, activated by radiofrequency, was then inserted into the prepared fracture zone. Pain intensity was determined on a VAS before the intervention, on the second day, and 6, 12 and 18 months after the intervention. The results were tested for significance by means of paired Wilcoxon rank-sum tests and Mann-Whitney U tests. RESULTS: BSP and RFS were technically fully feasible in all patients. An average of 6.3 ml cement per fracture was inserted in the BSP group and an average of 6.1 ml per fracture in the RFS group. Leakage could be ruled out for both procedures. The mean pain score on the VAS before the intervention was 8.6 +/- 0.55 in the BSP group and 8.8 +/- 0.58 in the RFS group. On the second postoperative day, a significant pain reduction was seen (p < 0.001), with an average value of 2.5 (BSP +/- 0.28, RFS +/- 0.38) for both groups. After 6 (12; 18) months, these values were stable for the BSP group at 2.3 +/- 0.27 (2.3 +/- 0.24; 2.0 +/- 0.34) and for the RFS group at 2.4 +/- 0.34 (2.2 +/- 0.26; 2.0 +/- 0.31). With regard to pain, exceedance probability values of p = 0.86 (6 months), p = 0.94 (12 months) and p = 1 (18 months) were seen, so that neither treatment method leads to differences in results. CONCLUSIONS: BSP and RFS are interventional, minimally invasive procedures that enable reliable cement augmentation and achieve equally good clinical outcomes in the medium term. PMID- 28070683 TI - Do we have the right PROMs for measuring outcomes in lumbar spinal surgery? AB - PURPOSE: Patient-reported outcome measures (PROMs) have become an important part of routine auditing of outcomes in spinal surgery in the UK. PROMs can be used to help assess the quality of care provided by surgical units by determining the comparative health status of patients, before and after surgery. This study was designed to review the PROMs used to assess outcomes in spinal surgery and to determine if they are fit for the purpose. METHODS: A systematic literature search was undertaken to identify studies that reported PROMs data following lumbar spinal surgery. The PROMs that were used in each study were recorded and a separate search was undertaken to determine the evidence regarding the validity of each measure. RESULTS: The initial search identified 1142 abstracts, which were reduced through de-duplication, filtering and review to 58 articles, which were retrieved and reviewed in full. The search identified that the majority of studies used either the Oswestry Disability Index (ODI), SF-36, Roland-Morris Disability Questionnaire (RMDQ) and EQ-5D along with visual analogue scales or numeric rating scales for back and leg pain. CONCLUSIONS: The consistent use of PROMs supports the comparison of outcomes from different studies, although there was minimal evidence regarding the specificity and sensitivity of these measures for use with lumbar spinal patients. Our review highlights the need to determine a consensus regarding the use and reporting of outcome measures within the lumbar spine literature. PMID- 28070684 TI - A pilot cadaveric study of temperature and adjacent tissue changes after exposure of magnetic-controlled growing rods to MRI. AB - PURPOSE: To test for possible thermal injury and tissue damage caused by magnetic controlled growing rods (MCGRs) during MRI scans. METHODS: Three fresh frozen cadavers were utilized. Four MRI scans were performed: baseline, after spinal hardware implantation, and twice after MCGR implantation. Cross connectors were placed at the proximal end and at the distal end of the construct, making a complete circuit hinged at those two points. Three points were identified as potential sites for significant heating: adjacent to the proximal and distal cross connectors and adjacent to the actuators. Data collected included tissue temperatures at baseline (R1), after screw insertion (R2), and twice after rod insertions (R3 and R4). Tissue samples were taken and stained for signs of heat damage. RESULTS: There was a slight change in tissue temperature in the regions next to the implants between baseline and after each scan. Average temperatures ( degrees C) increased by 0.94 (0.16-1.63) between R1 and R2, 1.6 (1.23-1.97) between R2 and R3, and 0.39 (0.03-0.83) between R3 and R4. Subsequent histological analysis revealed no signs of heat induced damage. CONCLUSION: Recurrent MRI scans of patients with MCGRs may be necessary over the course of treatment. When implanted into human cadaveric tissue, these rods appear to not be a risk to the patient with respect to heating or tissue damage. Further in vivo study is warranted. LEVEL OF EVIDENCE: N/A. PMID- 28070685 TI - Porcine spine finite element model: a complementary tool to experimental scoliosis fusionless instrumentation. AB - PURPOSE: Developing fusionless devices to treat pediatric scoliosis necessitates lengthy and expensive animal trials. The objective was to develop and validate a porcine spine numerical model as an alternative platform to assess fusionless devices. METHODS: A parametric finite element model (FEM) of an osseoligamentous porcine spine and rib cage, including the epiphyseal growth plates, was developed. A follower-type load replicated physiological and gravitational loads. Vertebral growth and its modulation were programmed based on the Hueter-Volkmann principle, stipulating growth reduction/promotion due to increased compressive/tensile stresses. Scoliosis induction via a posterior tether and 5 level rib tethering, was simulated over 10 weeks along with its subsequent correction via a contralateral anterior custom tether (20 weeks). Scoliosis induction was also simulated using two experimentally tested compression-based fusionless implants (hemi- and rigid staples) over 12- and 8-weeks growth, respectively. Resulting simulated Cobb and sagittal angles, apical vertebral wedging, and left/right height alterations were compared to reported studies. RESULTS: Simulated induced Cobb and vertebral wedging were 48.4 degrees and 7.6 degrees and corrected to 21 degrees and 5.4 degrees , respectively, with the contralateral anterior tether. Apical rotation (15.6 degrees ) was corrected to 7.4 degrees . With the hemi- and rigid staples, Cobb angle was 11.2 degrees and 11.8 degrees , respectively, with 3.7 degrees and 2.0 degrees vertebral wedging. Sagittal plane was within the published range. Convex/concave-side vertebral height difference was 3.1 mm with the induction posterior tether and reduced to 2.3 with the contralateral anterior tether, with 1.4 and 0.8 for the hemi- and rigid staples. CONCLUSIONS: The FEM represented growth-restraining effects and growth modulation with Cobb and vertebral wedging within 0.6 degrees and 1.9 degrees of experimental animal results, while it was within 5 degrees for the two simulated staples. Ultimately, the model would serve as a time- and cost-effective tool to assess the biomechanics and long-term effect of compression-based fusionless devices prior to animal trials, assisting the transfer towards treating scoliosis in the growing spine. PMID- 28070686 TI - Turn left where you felt unhappy: how affect influences landmark-based wayfinding. AB - The present work investigated the impact of affect in landmark-based wayfinding. We assumed that affect-laden landmarks improve wayfinding performance and have an impact on later landmark recognition. To investigate our hypotheses, we ran two experiments in a virtual maze. In Experiment 1, we investigated how affect-laden landmarks influence wayfinding and recognition in comparison with neutral landmarks. The aim of Experiment 2 was to focus on the affective valence of a landmark. The memory tasks of both experiments were repeated after 1 week in order to assess memory consolidation. Results showed that the best wayfinding and recognition performance occurs when negatively laden landmarks were used. In comparison with neutral and positively laden landmarks, recognition performance hardly decreased over time for the negatively laden landmarks. Our results not only support findings in the field of emotion research but also expand the concept of semantic landmark salience with respect to emotional responses. PMID- 28070687 TI - Predicting chromatin architecture from models of polymer physics. AB - We review the picture of chromatin large-scale 3D organization emerging from the analysis of Hi-C data and polymer modeling. In higher mammals, Hi-C contact maps reveal a complex higher-order organization, extending from the sub-Mb to chromosomal scales, hierarchically folded in a structure of domains-within domains (metaTADs). The domain folding hierarchy is partially conserved throughout differentiation, and deeply correlated to epigenomic features. Rearrangements in the metaTAD topology relate to gene expression modifications: in particular, in neuronal differentiation models, topologically associated domains (TADs) tend to have coherent expression changes within architecturally conserved metaTAD niches. To identify the nature of architectural domains and their molecular determinants within a principled approach, we discuss models based on polymer physics. We show that basic concepts of interacting polymer physics explain chromatin spatial organization across chromosomal scales and cell types. The 3D structure of genomic loci can be derived with high accuracy and its molecular determinants identified by crossing information with epigenomic databases. In particular, we illustrate the case of the Sox9 locus, linked to human congenital disorders. The model in-silico predictions on the effects of genomic rearrangements are confirmed by available 5C data. That can help establishing new diagnostic tools for diseases linked to chromatin mis-folding, such as congenital disorders and cancer. PMID- 28070688 TI - Pharmacists and patients feedback on empirically designed prescription warning labels: a qualitative study. AB - Background Recommendations call for the inclusion of both patient and provider input in the redesign of prescription labels. Pharmacist opinions on prescription warning labels are important because they are the health providers who would eventually distribute and explain the revised labels during medication counseling. They may be the first health provider to notice a patient's misunderstanding on how to safely use their prescription medications. Objectives To explore the perspectives of patients and pharmacists on five newly designed PWLs, and examine if there were similarities and differences between patients' and pharmacists' perspectives. Setting Private room in Wisconsin. Methods A descriptive study using semi-structured 60-min face-to-face individual interviews with patients and pharmacists explored patients and pharmacists' feedback on five newly designed PWLs. Patients who were 18 years and older, spoke English, and took a prescription medication and pharmacists who filled prescriptions in an ambulatory setting participated in the study. The patient and pharmacist perspectives on the words (content), picture and color (cosmetic appearance), and placement of warning instructions on the pill bottle (convenience) was based on a label redesign framework. Qualitative content analysis was done. Main outcome measure Patient and pharmacist perspectives on the newly designed PWLs. Results Twenty-one patients and eight pharmacists practicing in an academic medical center outpatient setting (n = 5) or retail pharmacy (n = 3) participated. All patients and pharmacists wanted the PWLs positioned on the front of the pill bottle but not the side of the bottle or warning instructions embedded into the main prescription label. Other similarities included participants preferring: (1) pictures closely depicting the instructions and (2) the use of yellow highlighting on the PWL to draw attention to it. There were differences in patient and pharmacist perspectives regarding the addition of 'Warning' to the instruction on the PWL with the patient preference to include the word 'Warning'. Pharmacists thought some PWL pictures had racial stereotypes, but this feedback was never mentioned by patients. Conclusions Patients and pharmacists had different preferences for PWL design changes to improve understandability. Pharmacist preferences did not always correspond with patient preferences. However, patients and pharmacists generally agreed on the preferred location of the PWL on the pill bottle and the use of color for drawing patients' attention. PMID- 28070689 TI - Redispensing of medicines unused by patients: a qualitative study among stakeholders. AB - Background Medication waste has undesirable economic and environmental consequences. This waste is partly unavoidable, but might be reduced by redispensing medicines unused by patients. However, there is little knowledge of stakeholders' views on the redispensing. Objective To identify the stakeholders' views on the redispensing of medicines unused by patients. Setting Dutch healthcare system. Method Semi-structured interviews were conducted with 19 Dutch stakeholders from September 2014 until April 2015. The interview guide included two themes: medication waste and redispensing of unused medicines. The latter included qualitative-, legal- and financial aspects and stakeholder involvement, with specific attention to the patient. Interview transcripts were subjected to thematic content analysis. Main outcome measure Requirements related to the redispensing of unused medicines. Results All stakeholders considered the redispensing of medicines desirable if the implementation is feasible and the requirements for the safe redispensing are met. All of them pointed out that the product quality of redispensed medicines should be guaranteed and that it should be clear who is responsible for the quality of redispensed medicines. The stakeholders stated that transparent communication to patients is essential to guarantee trust in the redispensing system and that patients should be willing to use redispensed medicines. Moreover, the redispensing system's benefits should outweigh the costs and a minimal economic value of medicines suitable for redispensing should be determined. Conclusion Redispensing unused medicines could decrease medication waste if several requirements are met. For successful implementation of a redispensing system, all relevant stakeholders should be involved and cooperate as a joint-force. PMID- 28070690 TI - Reconstruction of defects of the trachea. AB - The trachea has a complex anatomy to fulfill its tasks. Its unique fibro cartilaginous structure maintains an open conduit during respiration, and provides vertical elasticity for deglutition, mobility of the neck and speech. Blood vessels pierce the intercartilaginous ligaments to perfuse the ciliated epithelium, which ensures effective mucociliary clearance. Removal of a tracheal segment affected by benign or malignant disease requires airtight restoration of the continuity of the tube. When direct approximation of both tracheal ends is no longer feasible, a reconstruction is needed. This may occur in recurrent short segment defects in a scarred environment, or in defects comprising more than half the length of the trachea. The resulting gap must be filled with vascularized tissue that restores the mucosal lining and supports the semi-rigid, semi flexible framework of the trachea. For long-segment or circular defects, restoration of this unique biomechanical profile becomes even more important. Due to the inherent difficulty of creating such a tube, a tracheostomy or palliative stenting are often preferred over permanent reconstruction. To significantly improve and sustain quality of life of these patients, surgeons proposed innovative strategies for complex tracheal repair. In this review, we provide an overview of current clinical applications of tracheal repair using autologous and allogenic tissues. We look at recent advances in the field of tissue engineering, and the areas for improvement of these first human applications. Lastly, we highlight the focus of our research, in an effort to contribute to the development of optimized tracheal reconstructive techniques. PMID- 28070692 TI - Design considerations of an analytic intelligence for predicting the efficacy of tissue engineered composites. PMID- 28070691 TI - Biological characteristic effects of human dental pulp stem cells on poly-epsilon caprolactone-biphasic calcium phosphate fabricated scaffolds using modified melt stretching and multilayer deposition. AB - Craniofacial bone defects such as alveolar cleft affect the esthetics and functions that need bone reconstruction. The advanced techniques of biomaterials combined with stem cells have been a challenging role for maxillofacial surgeons and scientists. PCL-coated biphasic calcium phosphate (PCL-BCP) scaffolds were created with the modified melt stretching and multilayer deposition (mMSMD) technique and merged with human dental pulp stem cells (hDPSCs) to fulfill the component of tissue engineering for bone substitution. In the present study, the objective was to test the biocompatibility and biofunctionalities that included cell proliferation, cell viability, alkaline phosphatase activity, osteocalcin, alizarin red staining for mineralization, and histological analysis. The results showed that mMSMD PCL-BCP scaffolds were suitable for hDPSCs viability since the cells attached and spread onto the scaffold. Furthermore, the constructs of induced hDPSCs and scaffolds performed ALP activity and produced osteocalcin and mineralized nodules. The results indicated that mMSMD PCL-BCP scaffolds with hDPSCs showed promise in bone regeneration for treatment of osseous defects. PMID- 28070693 TI - microRNAs Expression as Novel Genetic Biomarker for Early Prediction and Continuous Monitoring in Pulmonary Cancer. AB - One of the main causes of death in the world is lung cancer. According to the World Health Organization, the annual incidence of lung cancer increases significantly. Moreover, lung cancer accounts for one of the highest mortality rates, mainly due to late detection. Numerous studies have been conducted in order to identify new biomarkers for early diagnosis and for monitoring and evaluation of lung cancer stages. An ideal biomarker candidate is represented by the analysis of microRNAs expression. In this paper, we want to summarize microRNAs expressions in lung cancer. We also want to present the expression of microRNAs depending on the evolution of lung cancer. For this study, we analyzed the studies available in scientific databases, such as PubMed and Scopus. The studies were selected using the search keywords "microRNAs expression," "lung cancer," and "genetic biomarkers." The most significant articles were selected for the study, following rigorous analysis. To evaluate and monitor lung cancer, the expression of microRNAs may be used successfully due to increased specificity and selectivity. However, further studies are needed on the assignment and validation of microRNAs for each type of lung cancer, respectively, for each stage of evolution. PMID- 28070694 TI - Early Evaluation and Monitoring of Critical Patients with Acute Respiratory Distress Syndrome (ARDS) Using Specific Genetic Polymorphisms. AB - A high percentage of critical patients are found to develop acute respiratory distress syndrome (ARDS). Several studies have reported high mortality rates in these cases which are most frequently associated with multiple organ dysfunctions syndrome. Lately, many efforts have been made to evaluate and monitor ARDS in critical patients. In this regard, the assessment of genetic polymorphisms responsible for developing ARDS present as a challenge and are considered future biomarkers. Early detection of the specific polymorphic gene responsible for ARDS in critically ill patients can prove to be a useful tool in the future, able to help decrease the mortality rates in these cases. Moreover, identifying the genetic polymorphism in these patients can help in the implementation of a personalized intensive therapy scheme for every type of patient, based on its genotype. PMID- 28070695 TI - Barth Syndrome: Connecting Cardiolipin to Cardiomyopathy. AB - The Barth syndrome (BTHS) is caused by an inborn error of metabolism that manifests characteristic phenotypic features including altered mitochondrial membrane phospholipids, lactic acidosis, organic acid-uria, skeletal muscle weakness and cardiomyopathy. The underlying cause of BTHS has been definitively traced to mutations in the tafazzin (TAZ) gene locus on chromosome X. TAZ encodes a phospholipid transacylase that promotes cardiolipin acyl chain remodeling. Absence of tafazzin activity results in cardiolipin molecular species heterogeneity, increased levels of monolysocardiolipin and lower cardiolipin abundance. In skeletal muscle and cardiac tissue mitochondria these alterations in cardiolipin perturb the inner membrane, compromising electron transport chain function and aerobic respiration. Decreased electron flow from fuel metabolism via NADH ubiquinone oxidoreductase activity leads to a buildup of NADH in the matrix space and product inhibition of key TCA cycle enzymes. As TCA cycle activity slows pyruvate generated by glycolysis is diverted to lactic acid. In turn, Cori cycle activity increases to supply muscle with glucose for continued ATP production. Acetyl CoA that is unable to enter the TCA cycle is diverted to organic acid waste products that are excreted in urine. Overall, reduced ATP production efficiency in BTHS is exacerbated under conditions of increased energy demand. Prolonged deficiency in ATP production capacity underlies cell and tissue pathology that ultimately is manifest as dilated cardiomyopathy. PMID- 28070696 TI - An ionic liquid based strain sensor for large displacement measurement. AB - A robust and low cost ionic liquid based strain sensor is fabricated for high strain measurements in biomedical applications (up to 40 % and higher). A tubular 5 mm long silicone microchannel with an inner diameter of 310 um and an outer diameter of 650 um is filled with an ionic liquid. Three ionic liquids have been investigated: 1-butyl-1-methylpyrrolidinium bis (trifluoromethylsulfonyl) imide, ethylammonium nitrate and cholinium ethanoate. When the channel is axially stretched, geometrical deformations change the electrical impedance of the liquid channel. The sensors display a linear response and low hysteresis with an average gauge factors of 1.99 for strains up to 40 %. Additionally, to fix the sensor by surgical stitching to soft biological tissue, a sensor with tube clamps consisting of photopatternable SU-8 epoxy-based resin is proposed. PMID- 28070697 TI - Development of a DsRed-expressing HepaRG cell line for real-time monitoring of hepatocyte-like cell differentiation by fluorescence imaging, with application in screening of novel geometric microstructured cell growth substrates. AB - The bipotent nature of the HepaRG cell line is a unique property among human hepatoma-derived cells. Cell treatment with specific differentiation inducers results in a mixture of hepatocyte- and biliary-like cells, accompanied by upregulation of liver-specific proteins, drug metabolizing enzymes, transcription regulators, membrane receptors or innate immune response effectors. These features make the HepaRG cells a suitable and handy replacement for primary hepatocytes, to study hepatic functions in vitro. However, cell differentiation is a long, variable process, requiring special culture conditions, while the resulting mixed cell populations is usually a major drawback. This process can potentially be controlled by interface characteristics, such as substrate topography. To screen for such novel substrates, we have first developed a new HepaRG cell line, designated as HepaRGDsRed, expressing the reporter gene DsRed. The fluorescent protein was expressed in hepatocyte- and not biliary-like cells, in a differentiation dependent-manner. We have further used replicated microstructured gradients of polydimethylsiloxane (PDMS) that allow three dimensional manipulation in vitro, to monitor HepaRGDsRed differentiation in real time. We demonstrate that this approach enables the controlled assembly of viable hepatocyte-like cells for functional studies, which can be maintained in culture without loss of differentiation. The regulated expression of the DsRed reporter proved a valuable tool not only for rapid screening of novel cell growth substrates favoring cell differentiation, but also, to enrich the hepatocyte-like cell population by fluorescence-activated cell sorting to investigate liver specific processes in vitro. PMID- 28070698 TI - Drug-coated microneedles for rapid and painless local anesthesia. AB - This study showed that drug-coated PLLA (Poly (L-lactide)) microneedle arrays can induce rapid and painless local anesthesia. Microneedle arrays were fabricated using a micro-molding technique, and the needle tips were coated with 290.6 +/- 45.9 MUg of lidocaine, the most widely used local anesthetic worldwide. A dip coating device was newly designed for the coating step using an optimized coating formulation. Lidocaine coated on the arrays was released rapidly into PBS within 2 min, and its stability in storage lasted 3 weeks at 4, 25, and 37 degrees C. Furthermore, the microneedle arrays showed consistent in vitro skin penetration and delivered 200.8 +/- 43.9, 224.2 +/- 39.3, and 244.1 +/- 19.6 MUg of lidocaine into the skin 1, 2, and 5 min after application with a high delivery efficiency of 69, 77, and 84%. Compared to a commercially available topical anesthetic EMLA(r) cream, a 22.0, 13.6, and 14.0-fold higher amount of lidocaine was delivered into the skin. Note, in vitro skin permeation of Lidocaine was also notably enhanced by a 2-min-application of the lidocaine-coated microneedle arrays. Altogether, these results suggest that the biocompatible lidocaine-coated PLLA microneedle arrays could provide significantly rapid local anesthesia in a painless manner without any of the issues from topical applications or hypodermic injections of local anesthetics. PMID- 28070699 TI - In situ soil COS exchange of a temperate mountain grassland under simulated drought. AB - During recent years, carbonyl sulfide (COS), a trace gas with a similar diffusion pathway into leaves as carbon dioxide (CO2), but with no known "respiration-like" leaf source, has been discussed as a promising new approach for partitioning net ecosystem-scale CO2 fluxes into photosynthesis and respiration. The utility of COS for flux partitioning at the ecosystem scale critically depends on the understanding of non-leaf sources and sinks of COS. This study assessed the contribution of the soil to ecosystem-scale COS fluxes under simulated drought conditions at temperate grassland in the Central Alps. We used transparent steady state flow-through chambers connected to a quantum cascade laser spectrometer to measure the COS and CO2 gas exchange between the soil surface and the atmosphere. Soils were a source of COS during the day, emissions being mainly driven by incoming solar radiation and to a lesser degree soil temperature. Soil water content had a negligible influence on soil COS exchange and thus the drought and control treatment were statistically not significantly different. Overall, daytime fluxes were large (12.5 +/- 13.8 pmol m-2 s-1) in their magnitude and consistently positive compared to the previous studies, which predominantly used dark chambers. Nighttime measurements revealed soil COS fluxes around zero, as did measurements with darkened soil chambers during daytime reinforcing the importance of incoming solar radiation. Our results suggest that abiotic drivers play a key role in controlling in situ soil COS fluxes of the investigated grassland. PMID- 28070700 TI - Clouds homogenize shoot temperatures, transpiration, and photosynthesis within crowns of Abies fraseri (Pursh.) Poiret. AB - Multiple studies have examined the effects of clouds on shoot and canopy-level microclimate and physiological processes; none have yet done so on the scale of individual plant crowns. We compared incident photosynthetically active radiation (PAR), leaf temperatures, chlorophyll fluorescence, and photosynthetic gas exchange of shoots in three different spatial locations of Abies fraseri crowns on sunny (clear to partly cloudy) versus overcast days. The field site was a Fraser fir farm (1038 m elevation) in the Appalachian mountains, USA. Ten saplings of the same age class were marked and revisited for all measurements. Sunny conditions corresponded with 5-10* greater sunlight incidence on south facing outer shoots compared to south-facing inner and north-facing outer shoots, which were shaded and received only indirect (diffuse) sunlight. Differences in spatial distribution of irradiance were mirrored in differences in shoot temperatures, photosynthesis, and transpiration, which were all greater in south facing outer shoots compared to more shaded crown locations. In contrast, overcast conditions corresponded with more homogeneous sunlight distribution between north and south-facing outer shoots, and similar shoot temperatures, chlorophyll fluorescence (PhiPSII), photosynthesis, and transpiration; these effects were observed in south-facing inner shoots as well, but to a lesser extent. There was no significant difference in conductance between different crown locations on sunny or overcast days, indicating spatial differences in transpiration under sunny conditions were likely driven by leaf temperature differences. We conclude that clouds can affect spatial distribution of sunlight and associated physiological parameters not only within forest communities, but within individual crowns as well. PMID- 28070701 TI - Use of a continual sweep motion to compare air polishing devices, powders and exposure time on unexposed root cementum. AB - Low abrasive air polishing powders are a viable method for subgingival biofilm removal. This in vitro study evaluated the effects of air polishing using a standard tip on cementum following clinically recommended protocols. Forty-eight teeth were randomly divided into eight groups with six teeth per group. Teeth were treated using either a Hu-Friedy EMS or DENTSPLY Cavitron(r) air polishing device. One of three glycine powders (Air-flow 25 um, Clinpro 45 MUm, Clinpro+TCP 45 MUm) or a sodium bicarbonate powder (NaHCO3 85 MUm) was sprayed on cementum using a clinically relevant sweeping motion. Volume and depth of cementum removed after 5 and 90 s exposures were calculated. Surface texture was evaluated using SEMs taken following the last exposure. After 5 s exposures, neither unit nor powder had a substantial effect on volume loss or defect depth. After 90 s exposures, differences between powders existed only for the DENTSPLY unit (p < 0.0001). Pairwise comparisons for this unit revealed mean volume loss and maximum defect depth were greater for NaHCO3 85 MUm than the glycine powders (p < 0.0001). The 90 s exposure produced greater mean volume loss and defect depth for all powders (p < 0.0001). SEM images revealed dentinal tubule exposure with all powders; however, exposed tubules were larger and more prevalent for NaHCO3 85 MUm. Root surface loss was similar for glycine powders evaluated in this study. Differences in powder performance between units may be related to tip apertures and spray patterns. Additional research is needed to determine if cementum loss is greater than what occurs with conventional biofilm removal methods, such as curets and ultrasonic scalers. PMID- 28070702 TI - Effects of tributylborane-activated adhesive and two silane agents on bonding computer-aided design and manufacturing (CAD/CAM) resin composite. AB - The present study was conducted to evaluate the effects of an experimental adhesive agent [methyl methacrylate-tributylborane liquid (MT)] and two adhesive agents containing silane on the bonding between a resin composite block of a computer-aided design and manufacturing (CAD/CAM) system and a light-curing resin composite veneering material. The surfaces of CAD/CAM resin composite specimens were ground with silicon-carbide paper, treated with phosphoric acid, and then primed with either one of the two silane agents [Scotchbond Universal Adhesive (SC) and GC Ceramic Primer II (GC)], no adhesive control (Cont), or one of three combinations (MT/SC, MT/GC, and MT/Cont). A light-curing resin composite was veneered on the primed CAD/CAM resin composite surface. The veneered specimens were subjected to thermocycling between 4 and 60 degrees C for 10,000 cycles, and the shear bond strengths were determined. All data were analyzed using analysis of variance and a post hoc Tukey-Kramer HSD test (alpha = 0.05, n = 8). MT/SC (38.7 MPa) exhibited the highest mean bond strengths, followed by MT/GC (30.4 MPa), SC (27.9 MPa), and MT/Cont (25.7 MPa), while Cont (12.9 MPa) and GC (12.3 MPa) resulted in the lowest bond strengths. The use of MT in conjunction with a silane agent significantly improved the bond strength. Surface treatment with appropriate adhesive agents was confirmed as a prerequisite for veneering CAD/CAM resin composite restorations. PMID- 28070703 TI - NMR-based metabolomics reveals brain region-specific metabolic alterations in streptozotocin-induced diabetic rats with cognitive dysfunction. AB - Diabetes mellitus (DM) can result in cognitive dysfunction, but its potential metabolic mechanisms remain unclear. In the present study, we analyzed the metabolite profiling in eight different brain regions of the normal rats and the streptozotocin (STZ)-induced diabetic rats accompanied by cognitive dysfunction using a 1H NMR-based metabolomic approach. A mixed linear model analysis was performed to assess the effects of DM, brain region and their interaction on metabolic changes. We found that different brain regions in rats displayed significant metabolic differences. In addition, the hippocampus was more susceptible to DM compared with other brain regions in rats. More interestingly, significant interaction effects of DM and brain region were observed on alanine, creatine/creatine-phosphate, lactate, succinate, aspartate, glutamate, glutamine, gamma-aminobutyric acid, glycine, choline, N-acetylaspartate, myo-inositol and taurine. Based on metabolic pathway analysis, we speculate that cognitive dysfunction in the STZ-induced diabetic rats may be associated with brain region specific metabolic alterations involving energy metabolism, neurotransmitters, membrane metabolism and osmoregulation. PMID- 28070704 TI - Sleep disturbances in patients of liver cirrhosis with minimal hepatic encephalopathy before and after lactulose therapy. AB - Sleep disturbances are common in patients of cirrhosis with minimal hepatic encephalopathy (MHE) and affect health related quality of life (HRQOL). No study has evaluated effect of lactulose on sleep disturbances and correlation with HRQOL in patients with MHE. We assessed sleep disturbances in cirrhosis with MHE and effect of lactulose on sleep disturbances and HRQOL. One hundred patients of cirrhosis [MHE; (n = 50, age 45.3 +/- 11.2 years, 45 males) no-MHE (n = 50, age 46.3 +/- 10.4 years, 44 males)] were included. MHE was diagnosed with psychometric hepatic encephalopathy score (PHES) <= -5. All patients underwent laboratory parameters including arterial ammonia and critical flicker frequency (CFF) Sleep disturbances were measured with Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and polysomnography. HRQOL was measured with SF-36(v2) questionnaire. Patients with MHE were given lactulose therapy for 3 months and all the parameters were repeated. Poor quality of sleep and excessive day time sleepiness were more common in patients with MHE, compared to without MHE. With lactulose therapy there was improvement in MHE in 21 patients and arterial ammonia levels (93.74 +/- 14.8 vs. 71.44 +/- 18.8 MUmol/L: p < 0.001), CFF (34.83 +/- 3.54 vs. 39.44 +/- 4.95 Hz: p < 0.001), PHES (-7.64 +/- 2.1 vs. -5.58 +/- 2.09: p < 0.001), PSQI (8.6 +/- 3.3 vs. 5.2 +/- 1.5: p < 0.001), ESS (12.52 +/- 3.01 vs. 9.24 +/- 2.27: p < 0.001) and HRQOL (p = 0.01). Excessive day time sleepiness and impaired sleep quality are common in patients with MHE and correlate with neuropsychiatric impairment. Improvement in MHE with lactulose also leads to improvement in sleep disturbances and HRQOL. PMID- 28070705 TI - Enzymatic activation of double-targeted 5'-O-L-valyl-decitabine prodrug by biphenyl hydrolase-like protein and its molecular design basis. AB - A primary focus of this research was to explore the activation process and mechanism of decitabine (5-aza-2'-deoxycytidine, DAC) prodrug. Recently, it has been reported that biphenyl hydrolase-like protein (BPHL) can play an important role in the activation of some amino acid nucleoside prodrugs with a general preference for hydrophobic amino acids and 5'-esters. Therefore, we put forward a bold hypothesis that this novel enzyme may be primarily responsible for the activation process of DAC prodrug as well. 5'-O-L-valyl-decitabine (L-val-DAC) was synthesized before and can be transported across biological membranes by the oligopeptide transporter (PEPT1), granting it much greater utility in vivo. In this report, L-val-DAC was found to be a good substrate of BPHL protein (K m 0.59 mM; k cat/K m 553.69 mM-1 s-1). After intestinal absorption, L-val-DAC was rapidly and almost completely hydrolyzed to DAC and L-valine. The catalysis was mainly mediated by the BPHL hydrolase and resulted in the intestinal first-pass effect of L-val-DAC after oral administration in Sprague-Dawley rats with cannulated jugular and portal veins. The structural insights using computational molecular docking showed that BPHL had a unique binding mode for L-val-DAC. As a fundamental basis, the simulation was employed to explain the catalytic mechanism in molecular level. In conclusion, BPHL was at least one of the primary candidate enzymes for L-val-DAC prodrug activation. This promising double-targeted prodrug approach have more advantages than the traditional targeted designs due to its higher transport and more predictable activation, thereby leading to a favorable property for oral delivery. PMID- 28070706 TI - Analysis of 12 X-STR loci in the population of south Croatia. AB - The aim of the study was to assess forensic pertinence of 12 short tandem repeats (STRs) on X-chromosome in south Croatia population. Investigator(r) Argus X-12 kit was used to co-amplify 12 STR loci belonging to four linkage groups (LGs) on X-chromosome in 99 male and 98 female DNA samples of unrelated donors. PCR products were analyzed by capillary electrophoresis. Population genetic and forensic parameters were calculated by the Arlequin and POPTREE2 software, and an on-line tool available at ChrX-STR.org. Hardy-Weinberg equilibrium was confirmed for all X-STR markers in female samples. Biallelic patterns at DXS10079 locus were detected in four male samples. Polymorphism information content for the most (DXS10135) and the least (DXS8378) informative markers was 0.9212 and 0.6347, respectively. In both male and female samples, combined power of discrimination exceeded 0.999999999. As confirmed by linkage disequilibrium test, significant association of marker pair DXS10074-DXS10079 (P = 0.0004) within LG2 and marker pair DXS10101-DXS10103 (P = 0.0003) within LG3 was found only in male samples. Number of observed haplotypes in our sample pool amounted 3.01, 7.53, 5 and 3.25% of the number of possible haplotypes for LG1, LG2, LG3 and LG4, respectively. According to haplotype diversity value of 0.9981, LG1 was the most informative. In comparison of south Croatia with 26 world populations, pair-wise [Formula: see text] values increase in parallel with geographical distance. Overall statistical assessment confirmed suitability of Investigator(r) Argus X-12 kit for forensic casework in both identification and familial testing in the population of south Croatia. PMID- 28070707 TI - Value-Based Assessment of Radiology Reporting Using Radiologist-Referring Physician Two-Way Feedback System-a Design Thinking-Based Approach. AB - In the era of value-based healthcare, many aspects of medical care are being measured and assessed to improve quality and reduce costs. Radiology adds enormously to health care costs and is under pressure to adopt a more efficient system that incorporates essential metrics to assess its value and impact on outcomes. Most current systems tie radiologists' incentives and evaluations to RVU-based productivity metrics and peer-review-based quality metrics. In a new potential model, a radiologist's performance will have to increasingly depend on a number of parameters that define "value," beginning with peer review metrics that include referrer satisfaction and feedback from radiologists to the referring physician that evaluates the potency and validity of clinical information provided for a given study. These new dimensions of value measurement will directly impact the cascade of further medical management. We share our continued experience with this project that had two components: RESP (Referrer Evaluation System Pilot) and FRACI (Feedback from Radiologist Addressing Confounding Issues), which were introduced to the clinical radiology workflow in order to capture referrer-based and radiologist-based feedback on radiology reporting. We also share our insight into the principles of design thinking as applied in its planning and execution. PMID- 28070708 TI - Delayed treatment of undescended testes may promote hypogonadism and infertility. AB - CONTEXT: Undescended testes at birth may be caused by testosterone deficiency during fetal development. It is unclear whether the process of failed descent contributes to permanent endocrine impairment. OBJECTIVES: To evaluate the impact of age at treatment of undescended testes on endocrine and spermatogenic testicular function in middle-aged men. PATIENTS AND METHODS: Reproductive hormone and semen data of 357 men with previously undescended testes were evaluated with respect to age at correction of testicular position and compared to those of 709 controls with eutopic testes at birth and normozoospermia. RESULTS: Men with undescended testes had higher mean Luteinizing Hormone levels (p < 0.0001) and lower mean testosterone levels (p = 0.003) compared to controls. They also had lower bi-testicular volumes, higher Follicle Stimulating Hormone levels, and lower sperm concentrations (all p < 0.0001). Lowest mean sperm concentrations were found in subjects with bilateral undescended testes. Normal sperm concentrations were found in 21 % of cases (in 27 % of men with unilateral and in 12 % with bilateral undescended testes), while oligozoospermia was diagnosed in 44 %, and azoospermia in 35 % (in 28 % with unilateral, 46 % with bilateral undescended testes). Subjects with reduced semen quality had higher gonadotropin levels than those with normozoospermia. Age at correction (median: 6 years (1-39)) was inversely correlated with bi-testicular volumes and sperm concentrations, and positively correlated with FSH and LH, but not with serum testosterone. CONCLUSION: Latent, rarely decompensated hypogonadism is a potential long-term consequence of undescended testes, besides infertility and testicular cancer, preferentially affecting subjects with delayed or unsuccessful correction of testicular position. Impaired Leydig cell function is likely to contribute to compromised fertility. These observations support correction of cryptorchidism during early infancy. PMID- 28070709 TI - Influence of resveratrol on endoplasmic reticulum stress and expression of adipokines in adipose tissues/adipocytes induced by high-calorie diet or palmitic acid. AB - PURPOSE: This study aimed to determine whether resveratrol treatment alleviates endoplasmic reticulum stress and changes the expression of adipokines in adipose tissues and cells. METHODS: 8-week-old male C57BL/6 mice were fed a high-calorie diet (HCD group) or high-calorie diet supplemented with resveratrol (high-calorie diet + resveratrol group) for 3 months. Insulin resistance, serum lipids and proinflammatory indices, the size and inflammatory cell infiltration in subcutaneous and visceral adipose tissues were analyzed. The gene expressions of endoplasmic reticulum stress, adipokines, and inflammatory cytokines were determined. The induced mature 3T3-L1 cells were pretreated with resveratrol and then palmitic acid, and the gene expressions of endoplasmic reticulum stress, adipokines, and inflammatory cytokines were determined. RESULTS: Subcutaneous and visceral adipose tissues in the high-calorie diet-fed mice exhibited adipocyte hypertrophy, inflammatory activation, and endoplasmic reticulum stress. Resveratrol alleviated high-calorie diet-induced insulin resistance and endoplasmic reticulum stress, increased expression of SIRT1, and reversed expression of adipokines in varying degrees in both subcutaneous and visceral adipose tissues. The effects of resveratrol on palmitic acid-treated adipocytes were similar to those shown in the tissues. CONCLUSIONS: Resveratrol treatment obviously reversed adipocyte hypertrophy and insulin resistance by attenuating endoplasmic reticulum stress and inflammation, thus increasing the expression of SIRT1 and inverting the expression of adipokines in vivo and in vitro. PMID- 28070710 TI - The accumulation of vitrified oocytes is a strategy to increase the number of euploid available blastocysts for transfer after preimplantation genetic testing. AB - PURPOSE: In a preimplantation genetic diagnosis for aneuploidy (PGD-A) program, the more embryos available for biopsy, consequently increases the chances of obtaining euploid embryos to transfer. The aim was to increase the number of viable euploid blastocysts in patients undergoing PGD-A using fresh oocytes together with previously accumulated vitrified oocytes. METHODS: Sixty-nine patients with normal ovarian reserve underwent PGD-A for repeated implantation failure or recurrent pregnancy loss indication. After several cycles of ovarian stimulation, 591 accumulated vitrified oocytes and 463 fresh oocytes were micro injected with the same partner's semen sample. PGD-A was completed on 134 blastocysts from vitrified/warmed oocytes and 130 blastocysts from fresh oocytes. RESULTS: A mean of 9.6% euploid blastocyst per micro-injected vitrified/warmed oocytes and 11.4% euploid blastocyst per micro-injected fresh oocyte were obtained (p > 0.05). The euploidy and aneuploidy rates were comparable in blastocysts obtained from micro-injected vitrified/warmed oocytes and fresh oocytes (42.5 versus 40.8% and 57.5 versus 59.2%, p > 0.05). Implantation rates of euploid blastocysts were comparable between the two sources of oocytes (56.0% from vitrified/warmed oocytes versus 60.9% from fresh oocytes, p > 0.05). CONCLUSIONS: Oocyte vitrification and warming do not generate aneuploidy in blastocysts. The number of viable euploid embryos for transfer can be increased by using accumulated vitrified oocytes together with fresh oocytes in ICSI. TRIAL REGISTRATION: NCT02820415 ClinicalTrials.gov. PMID- 28070711 TI - Immune Suppression During Preclinical Drug Development Mitigates Immunogenicity Mediated Impact on Therapeutic Exposure. AB - In the clinical setting, anti-drug antibodies (ADA) against biotherapeutics can influence patient safety and interfere with product efficacy. High immunogenicity has been addressed in clinic by concomitant immune suppression, such as co administration of methotrexate with enzyme replacement therapy (ERT) and combination tacrolimus/sirolimus treatment for prophylaxis against organ transplant rejection. This study investigates the use of such immune suppressants in mitigating ADA responses to a fully human monoclonal antibody (mAb1) in preclinical animal studies. Three groups of Sprague Dawley rats (n = 18) were treated with low (0.01 mg/kg), moderate (50 mg/kg), or high (300 mg/kg) doses of mAb1. Experimental groups also received either methotrexate or tacrolimus/sirolimus immune suppressive regimens. ELISA-based methods were utilized to measure and characterize ADA and mAb1 pharmacokinetics (PK). Results demonstrated a stepwise increase in immunogenicity with mAb1 dosage. Methotrexate significantly lowered incidence of anti-variable region antibodies at moderate mAb1 dose (P < 0.05), while tacrolimus/sirolimus did likewise at moderate and high doses (P < 0.01) of mAb1. Except for low-dose mAb1 + methotrexate, all immunosuppressed groups displayed more than a 70-fold decrease in ADA magnitude (P < 0.05). This abrogation in ADA response correlated with more mAb1 in circulation by week 4 for moderate- and high-dosed mAb1 groups. These data provide an approach to mitigate preclinical immunogenicity by the use of immunosuppressant regimens. Such preconditioning can support preclinical drug development of human therapeutics that are antigenic to animals. Similar approaches could be investigated for wider application to novel therapeutics. PMID- 28070712 TI - Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development. AB - Injuries to the central nervous system continue to be vast contributors to morbidity and mortality; specifically, traumatic brain injury (TBI) is the most common cause of death during the first four decades of life. Several modalities are used to monitor patients suffering from TBI in order to prevent detrimental secondary injuries. The microdialysis (MD) technique, introduced during the 1990s, presents the treating physician with a robust monitoring tool for brain chemistry in addition to conventional intracranial pressure monitoring. Nevertheless, some limitations remain, such as limited spatial resolution. Moreover, while there have been several attempts to develop new potential pharmacological therapies in TBI, there are currently no available drugs which have shown clinical efficacy that targets the underlying pathophysiology, despite various trials investigating a plethora of pharmaceuticals. Specifically in the brain, MD is able to demonstrate penetration of the drug through the blood-brain barrier into the brain extracellular space at potential site of action. In addition, the downstream effects of drug action can be monitored directly. In the future, clinical MD, together with other monitoring modalities, can identify specific pathological substrates which require tailored treatment strategies for patients suffering from TBI. PMID- 28070713 TI - Porous mannitol carrier for pulmonary delivery of cyclosporine A nanoparticles. AB - This study employed the ultrasonic spray-freeze-drying technique to prepare porous mannitol carriers that incorporated hydrophobic cyclosporine A (CsA) nanoparticles (NPs) for pulmonary delivery. Two nanosuspension stabilization systems, (1) a combination of lecithin and lactose system and (2) a D-alpha tocopheryl polyethylene glycol succinate (TPGS) system, were investigated. The ability of the lecithin and TPGS in anchoring the hydrophobic CsA NPs to the porous hydrophilic mannitol structure was first reported. Formulations stabilized by TPGS provided a much better dose uniformity, suggesting that TPGS is a better anchoring agent compared with lecithin. The effects of mannitol carrier density and CsA loading (4.9-27%) on aerosol performance and dissolution profiles were assessed. The fine particle fraction (FPF) increased from 44 to 63% as the mannitol concentration decreased from 1 to 5%. All formulations achieved full dissolution within an hour without significant influence from the mannitol content and CsA loading. The initial dissolution rates of the present formulations were almost double than that of the spray-dried counterpart, with 90% of the drug dissolved in 10 min. Overall, the CsA NPs were successfully incorporated into the porous mannitol which demonstrated good aerosol performance and enhanced dissolution profiles. These spray-freeze-drying (SFD) powders were stable after 2-year storage under desiccation at 20 +/- 3 degrees C. PMID- 28070714 TI - Influence of drug load and physical form of cinnarizine in new SNEDDS dosing regimens: in vivo and in vitro evaluations. AB - The aim of this work was to evaluate the influence of drug load and physical form of cinnarizine (CIN) in self-nanoemulsifying drug delivery systems (SNEDDS) on absorption in rats. Further, the predictivity of the dynamic in vitro lipolysis model was evaluated. The following dosing regimens were assessed: (1) CIN dissolved in SNEDDS at 80% of equilibrium solubility (Seq) (SNEDDS 80%); (2) supersaturated SNEDDS with CIN dissolved at 200% Seq (super-SNEDDS solution); (3) SNEDDS suspension with CIN added at 200% Seq (CIN partially dissolved and partially suspended) (super-SNEDDS suspension); (4) drug-free SNEDDS co-dosed with aqueous CIN suspension (Chasing principle), and (5) CIN aqueous suspension. The CIN dose was kept constant for all dosing regimens. Therefore, the super SNEDDS solution and super-SNEDDS suspension contained 2.5-fold less SNEDDS pre concentrate than SNEDDS 80% and the Chasing principle. In vivo, a higher AUC after dosing CIN in SNEDDS 80% and the Chasing principle was obtained when compared to the super-SNEDDS solution, super-SNEDDS suspension, and aqueous suspension. In vitro, a higher extent of CIN in the aqueous phase was observed for all SNEDDS-containing dosing regimens, compared to the aqueous suspension. Since the drug level in the aqueous phase is traditionally considered as the fraction available for absorption, a lack of in vitro-in vivo relation was observed. This study revealed that the physical form of CIN in the current SNEDDS does not affect CIN absorption and solubilization, whereas the drug load, or amount of co-dosed lipid, significantly influenced CIN bioavailability. PMID- 28070715 TI - An Integrated Assessment of the Effects of Immunogenicity on the Pharmacokinetics, Safety, and Efficacy of Elotuzumab. AB - Elotuzumab is a humanized, immunostimulatory anti-signaling lymphocytic activation molecule F7 (SLAMF7) IgG1 monoclonal antibody indicated in combination with lenalidomide and dexamethasone for patients with multiple myeloma (MM) who have received 1-3 prior therapies. We assessed the immunogenicity of elotuzumab as a monotherapy and in combination with bortezomib/dexamethasone and lenalidomide/dexamethasone in patients with MM in five clinical studies, including the pivotal ELOQUENT-2 trial (NCT01239797). Anti-drug antibody (ADA) prevalence was determined using a validated bridging assay. The prevalence of neutralizing antibodies (NAbs) was assessed in ADA-positive samples from ELOQUENT 2. Data from four trials of elotuzumab combined with lenalidomide/dexamethasone or bortezomib/dexamethasone (n = 390 evaluable patients) demonstrated that nine (2.3%) patients were ADA positive in baseline assays, 72 (18.5%) were ADA positive on-treatment or during follow-up, and two (0.5%) developed persistent ADAs. Patients treated with elotuzumab monotherapy had a higher incidence of elotuzumab ADAs than those on the combination therapy. In general, ADAs developed early and resolved after 2-4 months. Of 45 on-treatment ADA-positive patients in ELOQUENT-2, 19 had NAbs. Population pharmacokinetic modeling demonstrated an apparent increase in target-mediated elimination (higher V max, lower K M) in ADA positive versus ADA-negative patients. ADAs were associated with lower elotuzumab steady-state exposure; however, this result may have been confounded by differential myeloma protein levels. ADAs/NAbs were not associated with hypersensitivity, infusion reactions, or loss of elotuzumab efficacy. Using a novel visualization, we also demonstrate that there is no clear relationship between the occurrence and titer values of ADA/NAbs and progression-free survival and best overall response status in patients treated with elotuzumab. PMID- 28070716 TI - Pharmacokinetics and Saturable Absorption of Gabapentin in Nursing Home Elderly Patients. AB - Pharmacokinetic data of gabapentin (GBP) in community-dwelling elderly patients show a significant effect of advanced age on GBP pharmacokinetics due to altered renal function. However, there are no data in elderly nursing home (NH) patients to evaluate gabapentin absorption and elimination. Our objective was to characterize the pharmacokinetics of GBP in elderly nursing home patients maintained on GBP therapy. This was a prospective pharmacokinetic study in elderly nursing home patients (>=60 years) receiving GBP for the management of chronic pain or epilepsy from seven nursing homes. Pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling. A one-compartment model described the data and clearance (CL) was associated with estimated glomerular filtration rate (eGFR) (p < 0.0001). The GBP CL in elderly nursing home patients was 2.93 L/h. After adjusting for the effect of GFR, GBP CL was not affected by age, sex, body weight, or comorbidity scores. No significant effects of body size measures, age, and sex were detected on volume of distribution. Dose-dependent bioavailability of GBP was demonstrated, and the saturable absorption profile was described by a nonlinear hyperbolic function. Prediction-corrected visual predictive check (pc-VPC) suggests adequate fixed- and random-effects models that successfully simulated the mean trend and variability in gabapentin concentration time profiles. In this analysis, the parameters of the hyperbolic nonlinearity appear to be similar between elderly and younger adults. PMID- 28070717 TI - Identification of New Synthetic Cannabinoid ADB-CHMINACA (MAB-CHMINACA) Metabolites in Human Hepatocytes. AB - ADB-CHMINACA (MAB-CHMINACA) is a new synthetic cannabinoid with high potency and many reported adverse events and fatalities. The drug is currently scheduled in several countries in Europe and the USA. Analytical methods need to be developed to confirm ADB-CHMINACA intake for clinical and forensic programs. For many synthetic cannabinoids, parent compound is not detectable in biological samples after intake, making the detection of metabolites the only way to prove consumption. Therefore, detection of ADB-CHMINACA metabolites in biological specimens is critical. Since there are currently no published data on ADB CHMINACA metabolism, we aimed to identify its major metabolites. Cryopreserved human hepatocytes were incubated with 10 MUmol/L ADB-CHMINACA for 3 h. Incubations were analyzed with liquid chromatography on a biphenyl column, high resolution tandem mass spectrometry (orbitrap), and metabolite identification software. A reference standard of six commercially available potential metabolites was simultaneously analyzed under the same conditions to allow correct assignment of isomers. We detected ten major metabolites. Biotransformations mainly occurred at the cyclohexylmethyl tail of the compound, as also observed with structural analogs' metabolism. Minor reactions also occurred at the tert-butyl chain. Only two analytical standards of potential metabolites matched an actual metabolite detected in hepatocyte incubations. We recommend A9 (ADB-CHMINACA hydroxycyclohexylmethyl), A4 (ADB-CHMINACA 4" hydroxycyclohexyl), and A6 (ADB-CHMINACA hydroxycyclohexylmethyl) as metabolite targets to document ADB-CHMINACA intake in clinical and forensic cases. Additionally, these results will guide analytical standard manufacturers to better provide suitable references for further studies on ADB-CHMINACA metabolism. PMID- 28070718 TI - First-in-human trial of an anti-5T4 antibody-monomethylauristatin conjugate, PF 06263507, in patients with advanced solid tumors. AB - Background The antibody-drug conjugate PF-06263507 targets the cell-surface, tumor-associated antigen 5T4 and consists of a humanized IgG1 conjugated to the microtubule-disrupting agent monomethylauristatin-F by a non-cleavable maleimidocaproyl linker. In this first-in-human, dose-finding trial (NCT01891669), we evaluated safety, pharmacokinetics, and preliminary antitumor activity of PF-06263507 in pretreated patients with advanced solid tumors, unselected for 5T4 expression. starting at 0.05 mg/kg, with 25, 56, and 95% dose increments, depending on observed dose-limiting toxicities (DLTs), applying a modified continual reassessment method. Results Twenty-six patients received PF 06263507 at 0.05 to 6.5 mg/kg. The first DLT, grade 3 photophobia, occurred at 4.34 mg/kg and two additional DLTs, grade 2 keratitis and grade 1 limbal stem cell deficiency (> 2-week dosing delay), at 6.5 mg/kg. The most common adverse events (AEs) were fatigue (38.5%), photophobia (26.9%), and decreased appetite, dry eye, nausea, and thrombocytopenia (23.1% each). No treatment-related grade 4 5 AEs were reported. Systemic exposure of PF-06263507 increased in a dose-related manner. At the maximum tolerated dose (MTD, 4.34 mg/kg), mean terminal half-life for PF-06263507 and unconjugated payload were ~6 and 3 days, respectively. Payload serum concentrations were substantially lower compared with PF-06263507. No objective responses were observed. Conclusions The MTD and recommended phase II dose were determined to be 4.34 mg/kg. Ocular toxicities accounted for the DLTs observed, as previously reported with monomethylauristatin-F payloads. Further studies are warranted to investigate clinical activity of this agent in patients with 5T4-expressing tumors.Trial registration ID: NCT01891669. PMID- 28070719 TI - Sunitinib-paracetamol sex-divergent pharmacokinetics and tissue distribution drug drug interaction in mice. AB - The sex-divergent pharmacokinetics and interaction of tyrosine kinase inhibitor sunitinib with paracetamol was evaluated in male and female mice. Mice (control groups) were administered 60 mg/kg PO sunitinib alone or with 200 mg/kg PO paracetamol (study groups). Sunitinib concentration in plasma, brain, kidney and liver were determined and non-compartmental pharmacokinetic analysis performed. Female control mice showed 36% higher plasma sunitinib AUC0->infinity, 31% and 27% lower liver and kidney AUC0->infinity and 2.2-fold higher AUC0->infinity in brain (all p < 0.001) and had lower liver- and kidney-to-plasma AUC0->infinity ratios (p < 0.001) than male control mice. Paracetamol decreased 29% plasma AUC0 >infinity (p < 0.05) in male mice and remained unchanged in female mice. In male and female mice, it decreased liver (15%, 9%), kidney (15%, 20%) and brain (47%, 50%) AUC0->infinity (p < 0.001) respectively owing to 52% brain uptake efficiency reduction in female mice (p < 0.01). Sunitinib displayed sex-divergent pharmacokinetics, tissue distribution and DDI with potential clinical translatability for the treatment of brain tumor and RCC patients. PMID- 28070720 TI - Safety, tolerability and pharmacokinetics of the fibroblast growth factor receptor inhibitor AZD4547 in Japanese patients with advanced solid tumours: a Phase I study. AB - Background AZD4547 is a potent, oral, highly selective fibroblast growth factor receptor (FGFR) inhibitor in clinical development for treating tumours with a range of FGFR aberrations, including FGFR mutations, amplifications and fusions. Methods This open-label, Phase I, multicentre study (NCT01213160) evaluated the safety, pharmacokinetics, and preliminary antitumour efficacy (RECIST v1.1) of AZD4547 monotherapy in Japanese patients with advanced solid tumours. Part A was a dose-escalation part; Part B was a dose-expansion part in patients with FGFR amplified tumours, confirmed by fluorescence in situ hybridization. Results Thirty patients enrolled in Part A (dose range: 40 mg twice daily [bid] to 120 mg bid; 160 mg once daily [qd]), four in Part B (80 mg bid). No dose-limiting toxicities were observed and maximum tolerated dose was not determined. Most common adverse events (AEs; any grade) were: dysgeusia (50% of patients); stomatitis (41%); diarrhoea (38%); hyperphosphataemia (38%); dry mouth (35%). Common grade >=3 AEs were nausea (12% of patients) and neutropenia (9%). No complete or partial responses were observed: 21/30 patients had stable disease >=4 weeks in Part A, and 1/4 patients had stable disease >=10 weeks in Part B. Following single and multiple dosing, absorption rate appeared moderate; peak plasma concentrations generally occurred 3-4 h post-dose, then declined biphasically with terminal half-life ~30 h. Steady state was reached by day 8. Compared with single dosing, plasma concentrations were, on average, 2.4- and 3.3 to 5.4-fold higher after qd and bid dosing, respectively. Conclusions AZD4547 was well tolerated in Japanese patients, with best response of stable disease >=4 weeks. PMID- 28070721 TI - Enhanced xylose fermentation by engineered yeast expressing NADH oxidase through high cell density inoculums. AB - Accumulation of reduced byproducts such as glycerol and xylitol during xylose fermentation by engineered Saccharomyces cerevisiae hampers the economic production of biofuels and chemicals from cellulosic hydrolysates. In particular, engineered S. cerevisiae expressing NADPH-linked xylose reductase (XR) and NAD+ linked xylitol dehydrogenase (XDH) produces substantial amounts of the reduced byproducts under anaerobic conditions due to the cofactor difference of XR and XDH. While the additional expression of a water-forming NADH oxidase (NoxE) from Lactococcus lactis in engineered S. cerevisiae with the XR/XDH pathway led to reduced glycerol and xylitol production and increased ethanol yields from xylose, volumetric ethanol productivities by the engineered yeast decreased because of growth defects from the overexpression of noxE. In this study, we introduced noxE into an engineered yeast strain (SR8) exhibiting near-optimal xylose fermentation capacity. To overcome the growth defect caused by the overexpression of noxE, we used a high cell density inoculum for xylose fermentation by the SR8 expressing noxE. The resulting strain, SR8N, not only showed a higher ethanol yield and lower byproduct yields, but also exhibited a high ethanol productivity during xylose fermentation. As noxE overexpression elicits a negligible growth defect on glucose conditions, the beneficial effects of noxE overexpression were substantial when a mixture of glucose and xylose was used. Consumption of glucose led to rapid cell growth and therefore enhanced the subsequent xylose fermentation. As a result, the SR8N strain produced more ethanol and fewer byproducts from a mixture of glucose and xylose than the parental SR8 strain without noxE overexpression. Our results suggest that the growth defects from noxE overexpression can be overcome in the case of fermenting lignocellulose derived sugars such as glucose and xylose. PMID- 28070722 TI - Laparoscopic Adjustable Gastric Band and Type 2 Diabetes Mellitus. PMID- 28070723 TI - Anorectal malformations: definitive surgery during adulthood. AB - BACKGROUND: Anorectal malformations (ARMs) are rarely seen in adults, since majority of cases are corrected in infancy or childhood. The aim of this study was to describe the profile of patients who underwent definitive surgery to correct their ARM in adulthood, and to discuss the outcomes of surgery (morbidity, mortality, and function). METHODS: This retrospective study included patients 18 years old and above, managed surgically by the Division of Colorectal Surgery at the Philippine General Hospital, University of the Philippines, Manila, from January 1, 2004, to December 31, 2012. Data from the Integrated Surgical Information System and the patients' hospital records were used to fill out a Data Collection Form. Frequencies and percentages were then computed. RESULTS: Eight patients were included in the study. The most common reason for consult was recurrent urinary tract infection (UTI, 25%). One patient had an imperforate anus (IA) without a fistula, and 1 patient had IA with rectal atresia, and the 6 had an IA with a fistula. All but one (87.5%) of the patients had undergone a prior diversion in infancy or childhood. Definitive surgical procedures included posterior sagittal anorectoplasty (PSARP) in 3 patients, anal transposition in 2 patients, laparotomy with colocutaneous anastomosis in two patients, and laparotomy and PSARP in 1 patient. There were 3 cases (37.5%) of postoperative complications. These complications included ureteral injury, enterocutaneous fistula, anal stricture, rectal stricture, rectovesical fistula, and recurrent rectourethral fistula. There was no reported mortality. Five patients already had their stomas reversed at the time of this writing. CONCLUSION: Our results showed that the rarity of the disease, limited surgical experience, and a technically challenging anatomy make the management of ARMs that persist into adulthood a formidable undertaking. PMID- 28070725 TI - Type of Resection (Whipple vs. Distal) Does Not Affect the National Failure to Provide Post-resection Adjuvant Chemotherapy in Localized Pancreatic Cancer. AB - INTRODUCTION: Adjuvant chemotherapy improves survival after curative intent resection for localized pancreatic adenocarcinoma (PDAC). Given the differences in perioperative morbidity, we hypothesized that patients undergoing distal partial pancreatectomy (DPP) would receive adjuvant therapy more often those undergoing pancreatoduodenectomy (PD). METHODS: The National Cancer Data Base (2004-2012) identified patients with localized PDAC undergoing DPP and PD, excluding neoadjuvant cases, and factors associated with receipt of adjuvant therapy were identified. Overall survival (OS) was analyzed using multivariable Cox proportional hazards regression. RESULTS: Overall, 13,501 patients were included (DPP, n = 1933; PD, n = 11,568). Prognostic characteristics were similar, except DPP patients had fewer N1 lesions, less often positive margins, more minimally invasive resections, and shorter hospital stay. The proportion of patients not receiving adjuvant chemotherapy was equivalent (DPP 33.7%, PD 32.0%; p = 0.148). The type of procedure was not independently associated with adjuvant chemotherapy (hazard ratio 0.96, 95% confidence interval 0.90-1.02; p = 0.150), and patients receiving adjuvant chemotherapy had improved unadjusted and adjusted OS compared with surgery alone. The type of resection did not predict adjusted mortality (p = 0.870). CONCLUSION: Receipt of adjuvant chemotherapy did not vary by type of resection but improved survival independent of procedure performed. Factors other than type of resection appear to be driving the nationwide rates of post-resection adjuvant chemotherapy in localized PDAC. PMID- 28070724 TI - Identification of potential glutaminyl cyclase inhibitors from lead-like libraries by in silico and in vitro fragment-based screening. AB - A glutaminyl cyclase (QC) fragment library was in silico selected by disconnection of the structure of known QC inhibitors and by lead-like 2D virtual screening of the same set. The resulting fragment library (204 compounds) was acquired from commercial suppliers and pre-screened by differential scanning fluorimetry followed by functional in vitro assays. In this way, 10 fragment hits were identified ([Formula: see text]5 % hit rate, best inhibitory activity: 16 [Formula: see text]). The in vitro hits were then docked to the active site of QC, and the best scoring compounds were analyzed for binding interactions. Two fragments bound to different regions in a complementary manner, and thus, linking those fragments offered a rational strategy to generate novel QC inhibitors. Based on the structure of the virtual linked fragment, a 77-membered QC target focused library was selected from vendor databases and docked to the active site of QC. A PubChem search confirmed that the best scoring analogues are novel, potential QC inhibitors. PMID- 28070726 TI - Prognostic and Oncologic Significance of Perineural Invasion in Sporadic Colorectal Cancer. AB - BACKGROUND: The presence of perineural invasion (PNI) in colorectal cancer (CRC) indicates a more aggressive phenotype, resulting in a poor prognosis. The aims of this study were to evaluate the oncologic outcome of PNI+ tumors and to investigate whether PNI status affects patient survival. METHODS: The study retrospectively enrolled 3807 patients from a single institution who underwent surgery for colorectal adenocarcinoma between January 2006 and December 2010. The patients were classified into two groups based on PNI status: PNI+ and PNI-. RESULTS: The PNI+ group included 565 patients (14.8 %) and had significantly more involved circumferential resection margins (p = 0.001) and a more advanced TNM stage (p = 0.001) than the PNI- group. Compared with the PNI- group, the PNI+ group had worse 5-year overall survival (65 vs. 88 %; p = 0.001) and 5-year disease-free survival (63 vs. 85 %; p = 0.001). Among PNI+ patients with stage IIA disease, those who received adjuvant therapy had significantly greater 5-year overall survival than those who did not (89.3 vs. 50.8 %; p = 0.001). In multivariate analyses, PNI+ was an independent negative prognostic factor for 5 year overall survival (hazard ratio [HR] 1.518, 95 % confidence interval [CI] 1.175-1.961; p = 0.001) and 5-year disease-free survival (HR 1.495, 95 % CI 1.237 1.806; p = 0.001). CONCLUSIONS: PNI positivity is an independent predictor of aggressive behavior and unfavorable prognosis in CRC. Further evaluation is needed to confirm the impact of PNI status on survival in stage IIA CRC. PMID- 28070727 TI - Responses: Re: Csaba Berczi, Ben Thomas, Zsolt Bacso, Tibor Flasko. Bilateral renal cancers: oncological and functional outcomes. Int Urol Nephrol 2016 (Epub ahead of print). PMID- 28070728 TI - Sunitinib tolerance and efficacy in patients with metastatic renal cell carcinoma according to ethnic and geographic factors. PMID- 28070729 TI - Inhibiting autophagy with chloroquine enhances the anti-tumor effect of high-LET carbon ions via ER stress-related apoptosis. AB - Energetic carbon ions (CI) offer great advantages over conventional radiations such as X- or gamma-rays in cancer radiotherapy. High linear energy transfer (LET) CI can induce both endoplasmic reticulum (ER) stress and autophagy in tumor cells under certain circumstances. The molecular connection between ER stress and autophagy in tumor exposed to high-LET radiation and how these two pathways influence the therapeutic effect against tumor remain poorly understood. In this work, we studied the impact of autophagy and apoptosis induced by ER stress following high-LET CI radiation on the radiosensitivity of S180 cells both in vitro and in vivo. In the in vitro experiment, X-rays were also used as a reference radiation. Our results documented that the combination of CI radiation with chloroquine (CQ), a special autophagy inhibitor, produced more pronounced proliferation suppression in S180 cells and xenograft tumors. Co-treatment with CI radiation and CQ could block autophagy through the IRE1/JNK/Beclin-1 axis and enhance apoptotic cell death via the activation of C/EBP homologous protein (CHOP) by the IRE1 pathway rather than PERK in vitro and in vivo. Thus, our study indicates that inhibiting autophagy might be a promising therapeutic strategy in CI radiotherapy via aggravating the ER stress-related apoptosis. PMID- 28070730 TI - CADD medicine: design is the potion that can cure my disease. AB - The acronym "CADD" is often used interchangeably to refer to "Computer Aided Drug Discovery" and "Computer Aided Drug Design". While the former definition implies the use of a computer to impact one or more aspects of discovering a drug, in this paper we contend that computational chemists are most effective when they enable teams to apply true design principles as they strive to create medicines to treat human disease. We argue that teams must bring to bear multiple sub disciplines of computational chemistry in an integrated manner in order to utilize these principles to address the multi-objective nature of the drug discovery problem. Impact, resourcing principles, and future directions for the field are also discussed, including areas of future opportunity as well as a cautionary note about hype and hubris. PMID- 28070731 TI - Evaluation of two intraoperative gamma detectors for assessment of 177Lu activity concentration in vivo. AB - BACKGROUND: Patients with somatostatin receptor-expressing neuroendocrine tumours can be treated with intravenously administered 177Lu-octreotate. Few patients are cured with the present protocol due to the current dose limitation of normal organs at risk, such as the kidneys. By locally administering 177Lu-octreotate to the liver for the purpose of treating liver metastases, a substantially reduced absorbed dose to organs at risk could be achieved. The development of such a technique requires the capability of measuring the 177Lu activity concentration in tissues in vivo. The aim of this study was to evaluate different performance parameters of two commercially available intraoperative gamma detectors in order to investigate whether intraoperative gamma detector measurements could be used to determine 177Lu activity concentration in vivo. RESULTS: Measurements were made using different sources containing 177Lu. Response linearity, sensitivity, spatial resolution and its depth dependence, organ thickness dependence of the measured count rate and tumour detectability were assessed for two intraoperative gamma detectors. The two detectors (a scintillation and a semiconductor detector) showed differences in technical performance. For example, the sensitivity was higher for the scintillation detector, while the spatial resolution was better for the semiconductor detector. Regarding organ thickness dependence and tumour detectability, similar results were obtained for both detectors, and even relatively small simulated tumours of low tumour-to-background activity concentration ratios could be detected. CONCLUSIONS: Acceptable results were obtained for both detectors, although the semiconductor detector proved more advantageous for our purpose. The measurements demonstrated factors that must be corrected for, such as organ thickness or dead-time effects. Altogether, intraoperative gamma detector measurements could be used to determine 177Lu activity concentration in vivo. PMID- 28070732 TI - The clinical and laboratory spectrum of dedicator of cytokinesis 8 immunodeficiency syndrome in patients with a unique mutation. AB - Mutations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency usually diagnosed as autosomal recessive hyper IgE syndrome. We sought to reveal the varying manifestations in patients with a unique mutation in DOCK8 gene by a retrospective medical record review. Ten patients from five consanguineous families and three tribes were included. Seven patients were homozygous for the c.C5134A, p.S1711X mutation, and the remaining three patients were their siblings manifesting hyper IgE syndrome features without a genetic diagnosis. Prior to the genetic diagnosis, the clinical diagnosis was "hyper IgE syndrome" in six patients and "anti-pneumococcal antibody deficiency," "recurrent pneumonia with bronchiectasis," and "asthma with hypereosinophilic syndrome" each diagnosed once. One additional patient was diagnosed due to family history. The age of presentation varied from 1 to 16 months. Eczema was diagnosed in all patients, food allergies in three, and severe herpes keratitis or malignancy or autoimmunity in two patients. Elevated IgE was recorded in nine patients; however, in six patients, the initial serum IgE concentration was equal to or less than three times the normal concentration for age, and in these patients, the median age at IgE evaluation was 7.5 months compared with 21.5 months in patients with an initial IgE concentration above three times the normal concentration for age (P = 0.067). The spectrum of disease manifestations in patients with a unique mutation in DOCK8 is variable. The genotype-phenotype correlations may be modified by genetic and/or epigenetic modifiers beyond the monogenic effect. Younger patients tend to have lower IgE concentrations at the initial measurement of IgE. PMID- 28070733 TI - GLP-1 RA Treatment Patterns Among Type 2 Diabetes Patients in Five European Countries. AB - INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a relatively new class of injectable drugs used in the treatment of type 2 diabetes (T2D). This retrospective database study evaluated real-world treatment patterns of T2D patients initiating GLP-1 RAs in Belgium (BE), France (FR), Germany (DE), The Netherlands (NL) and Sweden (SE). METHODS: Adult T2D patients initiating exenatide twice daily (exBID), exenatide once weekly (exQW), liraglutide (LIRA) or lixisenatide (LIXI) during 2013 were identified using the QuintilesIMS (QuintilesIMS, Durham, NC, and Danbury, CT, USA) longitudinal retail pharmacy databases (LRx; BE/FR/DE/NL) and national health register data (SE). Therapy initiation date was termed 'index date.' Eligible patients had >=180-day pre- and variable follow-up (minimum >=360 days post-index). Baseline patient and treatment characteristics were assessed. Treatment modification and persistence were evaluated over the 1-year follow-up. Kaplan-Meier (KM) survival curves evaluated stopping of the index therapy (first of discontinuation or switch) over the available follow-up. RESULTS: A total of 4339 exBID, 1499 exQW, 20,955 LIRA and 1751 LIXI patients were included in the analysis (45.1-61.9% female; mean age range 57.1-62.9 years). Mean follow-up ranged from 17.7 to 30.7 months. Across countries/databases, the proportion experiencing a treatment modification at 1 year ranged from 84.1 to 93.8% for exBID, 53.3-73.4% for exQW and 59.5-80.5% for LIRA patients. The proportion of LIXI patients with treatment modification was 55.0% in Belgium (N = 20) and 96.9% in Germany (LIXI taken off the German market in April 2014). In KM analyses, LIRA patients had the lowest proportion stopping therapy, while exBID patients had the highest proportion stopping therapy, across databases, with the exception of LIXI patents. CONCLUSION: Treatment patterns varied among GLP-1 RA patients, and persistence was generally highest among LIRA and lowest among exBID across countries. Longer term data would be useful, given the recent approval of several GLP-1 RA therapies. FUNDING: Eli Lilly and Co., Indianapolis, IN, USA. PMID- 28070735 TI - Assessment of atherosclerotic plaque calcification using F18-NaF PET-CT. AB - BACKGROUND: The aim of the present study was to evaluate the uptake of F18-NaF by the arterial wall in patients with high cardiovascular (CV) risk profile. The tracer uptake was assessed in relation to gender and the number of CV risk factors. METHODS AND RESULTS: 25 patients without known CV disease were included and evaluated by PET-CT with F18-NaF: 14 (56%) men and 11 (44%) women. The mean target-to-background ratio (TBR: max SUV/mean blood-pool SUV) but not the corrected uptake per lesion (CUL: max SUV - mean blood-pool SUV) was higher in men than women (TBR: 1.8 +/- 0.6 vs 1.7 +/- 0.2; P = 0.04; CUL: 0.7 +/- 0.3 vs W 0.6 +/- 0.1; P = 0.4). Patients with >3 CV risk factors had higher CUL (0.8 +/- 0.1 vs 0.6 +/- 0.2; P = 0.01) but not TBR (1.8 +/- 0.2 vs 1.7 +/- 0.6; P = 0.7) than patients with <3 risk factors. CONCLUSIONS: The TBR but not CUL is higher in men than women while the CUL but not TBR is related to the number of CV risk factors. These results are hypothesis-generating and require validation in larger studies. PMID- 28070734 TI - Significant correlation between renal 123I-metaiodobenzylguanidine scintigraphy and muscle sympathetic nerve activity in patients with primary hypertension. AB - BACKGROUND: Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy is used as a noninvasive imaging method for assessing cardiac sympathetic nerve activity. We tested the hypothesis that renal 123I-MIBG imaging is correlated with muscle sympathetic nerve activity (MSNA) in patients with primary hypertension. METHODS: Thirty-one consecutive patients with primary hypertension were included. Multiunit MSNA was recorded from the peroneal nerve to evaluate direct efferent sympathetic nerve activity. Planar renal and cardiac 123I-MIBG images were acquired. Early and delayed kidney-to-mediastinum ratio (K/M), early and delayed heart-to-mediastinum ratio (H/M), and washout rates (WR) were calculated. RESULTS: In 27 of 31 patients, blood pressure was controlled on antihypertensive medication. Mean systolic and diastolic blood pressures were 118 +/- 18 and 67 +/ 15 mmHg, respectively. Although early and late K/M and H/M were not significantly correlated with MSNA, both cardiac and average renal WR were significantly correlated with MSNA (r = 0.45, P = .0035 and r = 0.68, P < .001, respectively). Right and left renal WR were similarly correlated with MSNA. Renal WR was significantly higher than cardiac WR (43.2% vs 25.8%, P < .001) in these patients with hypertension. CONCLUSIONS: Renal 123I-MIBG WR was significantly associated with multiunit MSNA. Renal 123I-MIBG imaging offers a noninvasive clinical methodology for assessing renal sympathetic nerve function. PMID- 28070736 TI - Genome-wide analysis of miRNAs and Tasi-RNAs in Zea mays in response to phosphate deficiency. AB - Globally important cereal crop maize provides important nutritions and starch in dietary foods. Low phosphate (LPi) availability in the soil frequently limits the maize quality and yield across the world. Small non-coding RNAs (Snc-RNAs) play crucial roles in growth and adaptation of plants to the environment. Snc-RNAs like microRNAs (miRs) and trans-acting small interfering RNAs (Tasi-Rs) play important functions in posttranscriptional regulation of gene expression, which controls plant development, reproduction, and biotic/abiotic stress responses. In order to identify the miR and Tasi-R alterations in leaf and root of maize in response to sufficient phosphate and LPi at 3LS and 4LS, the snc-RNA population libraries for 0th, 1st, 2nd, 4th, and 8th day were constructed. These libraries were used for genome-wide alignment and RNA-fold analysis for possible prediction of potential miRs and Tasi-Rs. This study reported 174 known and conserved differentially expressed miRs of 27 miR families of maize plant. In addition, leaf and root specific potential novel miRs representing 155 new families were also discovered. Differentially expressed conserved as well as novel miR functions in root and leaf during early stage of Pi starvation were extensively discussed. Leaf and root specific miRs as well as common miRs with their target genes, participating in different biological, cellular, and metabolic processes were explored. Further, four miR390-directed Tasi-Rs which belong to TAS3 gene family along with other orthologs of Tasi-Rs were also identified. Finally, the study provides an insight into the composite regulatory mechanism of miRs in maize in response to Pi deficiency. PMID- 28070737 TI - In silico analysis of the anti-hypertensive drugs impact on myocardial oxygen balance. AB - Hypertension is a very common pathology, and its clinical treatment largely relies on different drugs. Some of these drugs exhibit specific protective functions in addition to those resulting from blood pressure reduction. In this work, we study the impact of commonly used anti-hypertensive drugs (RAAS, [Formula: see text] and calcium channel blockers) on myocardial oxygen supply consumption balance, which plays a crucial role in type 2 myocardial infarction. To this aim, 42 wash-out hypertensive patients were selected, a number of measured data were used to set a validated multi-scale cardiovascular model to subject-specific conditions, and the administration of different drugs was suitably simulated. Our results ascribe the well-known major cardioprotective efficiency of [Formula: see text] blockers compared to other drugs to a positive change of myocardial oxygen balance due to the concomitant: (1) reduction in aortic systolic, diastolic and pulse pressures, (2) decrease in left ventricular work, diastolic cavity pressure and oxygen consumption, (3) increase in coronary flow and (4) ejection efficiency improvement. RAAS blockers share several positive outcomes with [Formula: see text] blockers, although to a reduced extent. In contrast, calcium channel blockers seem to induce some potentially negative effects on the myocardial oxygen balance. PMID- 28070738 TI - Robotic assisted laparoscopic radical cystectomy with stentless intracorporeal modified Ves.Pa neobladder: early experience. AB - This study aimed at demonstrating the feasibility of robotic assisted laparoscopic radical cystectomy with pure intracorporeal modified Ves.Pa neobladder with stentless ureteroileal anastomosis. Pure intracorporeal robotic assisted laparoscopic technique has been recently developed with a select number of high-volume centers utilizing various operative and neobladder techniques. We reviewed the patient characteristics, operative details and perioperative courses in the two patients who have undergone robotic assisted laparoscopic radical cystectomy with pure intracorporeal modified Ves.Pa neobladder and one who has undergone the Hautmann W neobladder. These results were compared to other contemporary robotic neobladder series. We demonstrate technical success with similar operative and perioperative results with the modified Ves.Pa neobladder. The robotic pure intracorporeal modified Ves.Pa neobladder is a technically feasible operation and may be easier to perform compared to other neobladders. Initial experience suggests operative time and perioperative outcomes are similar to other robotic techniques. PMID- 28070739 TI - Delayed renal artery pseudoaneurysm after robotic partial nephrectomy. PMID- 28070740 TI - Generating Evidence of Clinical Outcomes of Drug-Drug Interactions. PMID- 28070741 TI - Comment on: "Social Media Mining for Toxicovigilance: Automatic Monitoring of Prescription Medication Abuse from Twitter". PMID- 28070742 TI - Authors' Reply to Jouanjus and Colleagues' Comment on "Social Media Mining for Toxicovigilance: Automatic Monitoring of Prescription Medication Abuse from Twitter". PMID- 28070743 TI - Cardiac CT Angiography (CCTA) predicts left atrial appendage occluder device size and procedure outcome. AB - AIM: To investigate the role of cardiac CT angiography (CCTA) in predicting optimal left atrial appendage (LAA) occluder size and procedure outcome. METHODS AND RESULTS: Thirty-six patients underwent pre-procedural CCTA. CCTA and TEE LAA orifice diameters and perimeters were compared with the implanted device size. CCTA 3D configuration was correlated with procedure outcome. WatchmanTM device (N = 18): diameters were 21 +/- 4, 26 +/- 5 and 25 +/- 3 mm for TEE, CCTA and inserted device, respectively. Average perimeters were 61 +/- 10, 74 +/- 8 and 78 +/- 11 mm for TEE, CCTA and inserted device, respectively. Better agreement with the device size was found for CCTA compared to TEE (Bland-Altman). ACPTM device (N = 15): diameters were 20 +/- 5, 25 +/- 4 and 23 +/- 4 for TEE, CCTA and inserted device, respectively. Average perimeters were 58 +/- 11, 72 +/- 15 and 72 +/- 13 mm for TEE, CCTA and inserted device, respectively. Excellent correlation and agreement with the device size was found for CCTA compared to TEE. CCTA perimeter >100 mm and "cactus" 3D configuration had a specificity of 96 and 81% respectively for procedure failure. CONCLUSIONS: CCTA LAA ostial perimeter predicted better the optimal occluder size as compared with the currently used LAA TEE diameter. Moreover, CCTA 3D data may help in predicting potential complications. PMID- 28070744 TI - Changes in patterns of uveitis at a tertiary referral center in Northern Italy: analysis of 990 consecutive cases. AB - PURPOSE: The role of uveitis, an uncommon ocular disease, is often neglected in research and treatment of autoimmune conditions. The study described the spectrum of uveitis at a referral center in North Italy, and compared that to a previously published series of patients. METHODS: We reviewed all patients with uveitis diagnosed from 2013 to 2015 at the Immunology Eye Unit, Arcispedale S. M. Nuova IRCCS, Reggio Emilia, Italy. We examined patient characteristics, disease spectrum, and etiologies. RESULTS: In total, 990 cases of uveitis were identified, who were mostly female (59%) with a median age at presentation of 44 years (interquartile range = 29-57). Anterior uveitis was most frequent (53.5%), followed by panuveitis (22.8%), posterior (16.2%), and intermediate uveitis (5.5%). Anterior herpetic uveitis (15.6%), Fuchs uveitis (9.7%), and HLA-B27 positive anterior uveitis (7.7%) were the most common specific diagnoses. Compared with the previous series, we observed an increased incidence of uveitis, and a different pattern of diagnoses. Rates of herpetic, HLA-B27 positive uveitis, and presumed ocular tuberculosis were higher, but Fuchs uveitis was less frequent. CONCLUSIONS: The pattern of uveitis appears to be changing, very likely due to population-level increases in infectious diseases, to the availability of new diagnostic tests and to the interdisciplinary approach used in patient diagnosis. PMID- 28070745 TI - Considering total intracranial volume and other nuisance variables in brain voxel based morphometry in idiopathic PD. AB - Voxel-based morphometry (VBM) studies of Parkinson's disease (PD), have yielded mixed results, possibly due to several studies not accounting for common nuisance variables (age, sex, and total intracranial volume [TICV]). TICV is particularly important because there is evidence for larger TICV in PD. We explored the influence of these covariates on VBM by 1) comparing PD patients and controls before adding covariates, after adding age and sex, and after adding age, sex and TICV, and 2) by comparing controls split into large and small TICV before and after controlling for TICV, with age and sex accounted for in both analyses. Experiment 1 consisted of 40 PD participants and 40 controls. Experiment 2 consisted of 88 controls median split by TICV. All participants completed an MRI on a 3 T scanner. TICV was calculated as gray + white + CSF from Freesurfer. VBM was performed on T1 images using an optimized VBM protocol. Volume differences were assessed using a voxel-wise GLM analysis. Clusters were considered significant at >10 voxels and p < .05 corrected for familywise error. Before controlling for covariates, PD showed reduced GM in temporal, occipital, and cerebellar regions. Controlling for age and sex did not affect the pattern of significance. Controlling for TICV reduced the size of the significant region although it still contained portions of bilateral temporal lobes, occipital lobes and cerebellum. The large TICV group showed reduced volume in temporal, parietal, and cerebellar areas. None of these differences survived controlling for TICV. This demonstrates that TICV influences VBM results independently from other factors. Controlling for TICV in VBM studies is recommended. PMID- 28070746 TI - Boundary Cap Neural Crest Stem Cells Promote Survival of Mutant SOD1 Motor Neurons. AB - ALS is a devastating disease resulting in degeneration of motor neurons (MNs) in the brain and spinal cord. The survival of MNs strongly depends on surrounding glial cells and neurotrophic support from muscles. We previously demonstrated that boundary cap neural crest stem cells (bNCSCs) can give rise to neurons and glial cells in vitro and in vivo and have multiple beneficial effects on co cultured and co-implanted cells, including neural cells. In this paper, we investigate if bNCSCs may improve survival of MNs harboring a mutant form of human SOD1 (SOD1G93A) in vitro under normal conditions and oxidative stress and in vivo after implantation to the spinal cord. We found that survival of SOD1G93A MNs in vitro was increased in the presence of bNCSCs under normal conditions as well as under oxidative stress. In addition, when SOD1G93A MN precursors were implanted to the spinal cord of adult mice, their survival was increased when they were co-implanted with bNCSCs. These findings show that bNCSCs support survival of SOD1G93A MNs in normal conditions and under oxidative stress in vitro and improve their survival in vivo, suggesting that bNCSCs have a potential for the development of novel stem cell-based therapeutic approaches in ALS models. PMID- 28070747 TI - Enhanced Bulbar Function in Amyotrophic Lateral Sclerosis: The Nuedexta Treatment Trial. AB - The goal of this randomized, blinded, crossover clinical trial was to determine whether Nuedexta (dextromethorphan and quinidine) enhanced speech, swallowing, and salivation in patients with ALS. Sixty patients with amyotrophic lateral sclerosis (ALS) received either Nuedexta or placebo for 28 to 30 days, followed by a 10 to 15-day washout period. Subsequently, patients were switched to the opposite treatment arm for the remaining days of the trial. The primary endpoint was a reduction in the self-report Center for Neurologic Study Bulbar Function Scale (CNS-BFS) score. The rater-administered ALS Functional Rating Scale Revised was the principal secondary endpoint. The CNS-BFS score improved with active treatment, decreasing from a mean of 59.3 in the placebo arm of the trial to 53.5 during the drug-treatment arm (p < 0.001). Each of the individual domains of bulbar function interrogated by the CNS-BFS responded to treatment with Nuedexta as follows: salivation: 15.8 versus 14.3 (p = 0.004); speech: 24.6 versus 22.2 (p = 0.003); swallowing: 18.9 versus 17.1 (p = 0.009). Similarly, the bulbar component of the ALS Functional Rating Scale Revised improved with active treatment (p = 0.003), although the drug did not affect the motor and respiratory components of this scale. This study is unique for several reasons. Firstly, it was driven by patient reports of improved speech and swallowing while taking Nuedexta for control of emotional lability. Secondly, the study was conducted over a short duration (70 days), and thirdly, a self-report scale was selected as the principle outcome measure. Considering the importance of bulbar functions, these results, if confirmed, point to an additional use of Nuedexta as an adjunct to the management of ALS. PMID- 28070749 TI - An automated microemboli detection and classification system using backscatter RF signals and differential evolution. AB - Embolic phenomena, whether air or particulate emboli, can induce immediate damages like heart attack or ischemic stroke. Embolus composition (gaseous or particulate matter) is vital in predicting clinically significant complications. Embolus detection using Doppler methods have shown their limits to differentiate solid and gaseous embolus. Radio-frequency (RF) ultrasound signals backscattered by the emboli contain additional information on the embolus in comparison to the traditionally used Doppler signals. Gaseous bubbles show a nonlinear behavior under specific conditions of the ultrasound excitation wave, this nonlinear behavior is exploited to differentiate solid from gaseous microemboli. In order to verify the usefulness of RF ultrasound signal processing in the detection and classification of microemboli, an in vitro set-up is developed. Sonovue micro bubbles are exploited to mimic the acoustic behavior of gaseous emboli. They are injected at two different concentrations (0.025 and 0.05 ul/ml) in a nonrecirculating flow phantom containing a tube of 0.8 mm in diameter. The tissue mimicking material surrounding the tube is chosen to imitate the acoustic behavior of solid emboli. Both gaseous and solid emboli are imaged using an Anthares ultrasound scanner with a probe emitting at a transmit frequency of 1.82 MHz and at two mechanical indices (MI) 0.2 and 0.6. We propose in this experimental study to exploit discrete wavelet transform and a dimensionality reduction algorithm based on differential evolution technique in the analysis and the characterization of the backscattered RF ultrasound signals from the emboli. Several features are evaluated from the detail coefficients. It should be noted that the features used in this study are the same used in the paper by Aydin et al. These all features are used as inputs to the classification models without using feature selection method. Then we perform feature selection using differential evolution algorithm with support vector machines classifier. The experimental results show clearly that our proposed method achieves better average classification rates compared to the results obtained in a previous study using also the same backscatter RF signals. PMID- 28070748 TI - Application of guidelines for aminoglycosides use in French hospitals in 2013 2014. AB - In 2011, the French Agency for Safety of Health Products issued guidelines underlining the principles of proper aminoglycosides' use. The aim of the survey was to evaluate adherence to these guidelines two years after their issue. Characteristics of patients receiving aminoglycosides were recorded by voluntary facilities during a 3-month survey in 2013-2014. The modalities of aminoglycosides treatment were analysed by comparison with the French guidelines. A total of 3,323 patients were included by 176 facilities. Patients were mainly hospitalized in medical wards (33.0%), and treated for urinary-tract infections (24.7%). Compliance regarding the clinical indication and the daily aminoglycosides dose was observed in 65.2% and 62.9% of the cases, respectively. A 30-min once-daily IV administration was recorded in 62.5% of the cases. Aminoglycosides treatment duration was appropriate (<=5 days) for 93.6% of the patients. When considering the four criteria together, 23.2% of the patients had a treatment regimen aligned with the guidelines. Requests for measurements of peak and trough AG serum concentrations matched the guidelines in 24.9% and 67.4% of the cases, respectively. Two years after guidelines issue, aminoglycosides use remains unsatisfactory in French health-care facilities. Efforts should be made for guidelines promotion, especially regarding the issue of underdosing. PMID- 28070750 TI - Examining trends in prediabetes and its relationship with the metabolic syndrome in US adolescents, 1999-2014. AB - AIMS: We sought to investigate temporal trends in prediabetes prevalence among US adolescents using two definitions and evaluate relationships with obesity and a MetS-severity score. METHODS: We evaluated data from 5418 non-Hispanic white, non Hispanic black, and Hispanic adolescents aged 12-19 participating in the National Health and Nutrition Examination Survey 1999-2014 with complete data regarding MetS and hemoglobin A1c (HbA1c). Prediabetes status was defined by American Diabetes Association (ADA) criteria: fasting glucose 100-125 mg/dL or HbA1c 5.7% 6.4%. MetS severity was assessed with a MetS-severity Z-score. RESULTS: Prevalence of prediabetes as defined by HbA1c abnormalities significantly increased from 1999-2014, while prevalence of prediabetes as defined by fasting glucose abnormalities showed no significant temporal trend. There were variations in these trends across different racial/ethnic groups. MetS Z-score was overall more strongly correlated with HbA1c, fasting insulin, and the homeostasis model of insulin resistance than was BMI Z-score. These correlations were true in each racial/ethnic group with the exception that in non-Hispanic white adolescents, in whom the MetS Z-score was not significantly correlated with HbA1c measurements. CONCLUSION: We found conflicting findings of temporal trends of US adolescent prediabetes prevalence based on the ADA's prediabetes criteria. The increasing prevalence of prediabetes by HbA1c assessment is concerning and raises the urgency for increased awareness and appropriate measures of prediabetes status among physicians and patients. PMID- 28070751 TI - Case-control studies in diabetes. Do they really use a case-control design? AB - AIMS: Studies defined as case-control do not always use this design. We aimed to estimate the frequency of mislabelled case-control studies in published articles in the area of diabetes and to identify the predictors of incorrect labelling. METHODS: We searched Medline and Web of Science for articles with "diabetes" and "case control" in title and filtered for language (English/Romance) and period (January 2010-December 2014). Inclusion criteria were: (1) statement to use a case-control design in title, (2) to be a final full-length publication and (3) to have original data in the area of diabetes. Three independent reviewers went through titles, looked for full texts and reviewed them. Discrepancies were settled with a fourth reviewer. Expert epidemiologist advice was requested in case of doubt. OUTCOME VARIABLE: case-control mislabelling; addressed predictors: publication year, journal impact factor and journal subject. STATISTICS: proportion of mislabelled CC articles and assessment of predictors by multivariate logistic regression analysis. RESULTS: We retrieved 362 articles, 251 of them fulfilling inclusion criteria. The proportion of mislabelled CC studies was 43.8% (confidence interval 95% 37.7-50.0%). Most mislabelled studies had a cross-sectional design (82.7%). Predictors of mislabelling were publication year, journal impact factor and journal area. CONCLUSIONS: A relevant subset of studies defined as case-control in the area of diabetes correspond to mislabelled cross-sectional studies. Incorrect labelling misleads readers regarding the interpretation of results and the cause-effect hypothesis. Researchers, reviewers and editors should be aware of and commit to settle this issue. PMID- 28070752 TI - Absence of macrophage migration inhibitory factor reduces proliferative retinopathy in a mouse model. AB - AIMS: Ischemia-induced neovascularization is the key feature of proliferative diabetic retinopathy. Macrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory and proangiogenic cytokine, and its levels are elevated in the vitreous of patients with proliferative diabetic retinopathy. In this study, we aimed at investigating the relative potential of MIF in the ischemia-induced retinal neovascularization. METHODS: Both WT and MIF-knockout mice were subjected to the retinopathy of prematurity (ROP) model. Intraretinal vessel regrowth was assessed by whole-mount immunofluorescence, and preretinal neovascularization was analyzed in retinal vertical sections after periodic acid Schiff staining in the hypoxic stage of the ROP model. Gene expression of selected proangiogenic and proinflammatory factors at postnatal day 13 (p13) was measured by real-time PCR. Vascular endothelial growth factor (VEGF) expression, recruitment of endothelial progenitor cells (EPCs) and microglial activation were analyzed with immunofluorescence. RESULTS: MIF deficiency increased areas of vascular obliteration by 49%, reduced sprouting tips by 27% and inhibited preretinal angiogenesis by 35%. VEGF expression was reduced in Muller cells of MIF-knockout mice. MIF absence reduced gene expression of erythropoietin, tumor necrosis factor alpha and intercellular adhesion molecule-1 by 30, 70 and 50%, respectively, decreased the number of retinal EPCs by 37.5% and inhibited microglial activation in the hypoxic condition. CONCLUSIONS: In conclusion, we found that MIF has proangiogenic and proinflammatory properties in retinal neovascularization. The proangiogenic role of MIF in ischemia-induced retinal neovascularization is associated with the expression of VEGF and erythropoietin, EPC recruitment and inflammation. Therefore, MIF has a potential role in the pathological angiogenesis of proliferative retinopathy. PMID- 28070753 TI - Dodecyl Amino Glucoside Enhances Transdermal and Topical Drug Delivery via Reversible Interaction with Skin Barrier Lipids. AB - PURPOSE: Skin permeation/penetration enhancers are substances that enable drug delivery through or into the skin. METHODS: To search for new enhancers with high but reversible activity and acceptable toxicity, we synthesized a series of D glucose derivatives, both hydrophilic and amphiphilic. RESULTS: Initial evaluation of the ability of these sugar derivatives to increase permeation and penetration of theophylline through/into human skin compared with a control (no enhancer) or sorbitan monolaurate (Span 20; positive control) revealed dodecyl 6 amino-6-deoxy-alpha-D-glucopyranoside 5 as a promising enhancer. Furthermore, this amino sugar 5 increased epidermal concentration of a highly hydrophilic antiviral cidofovir by a factor of 7. The effect of compound 5 on skin electrical impedance suggested its direct interaction with the skin barrier. Infrared spectroscopy of isolated stratum corneum revealed no effect of enhancer 5 on the stratum corneum proteins but an overall decrease in the lipid chain order. The enhancer showed acceptable toxicity on HaCaT keratinocyte and 3T3 fibroblast cell lines. Finally, transepidermal water loss returned to baseline values after enhancer 5 had been removed from the skin. CONCLUSIONS: Compound 5, a dodecyl amino glucoside, is a promising enhancer that acts through a reversible interaction with the stratum corneum lipids. PMID- 28070754 TI - Pow! Boom! Kablam! Effects of Viewing Superhero Programs on Aggressive, Prosocial, and Defending Behaviors in Preschool Children. AB - Many schools and parents try to motivate children to become defenders of victimized peers. Defending behavior is common in the media (particularly in superhero programs); however, no study has examined the effect of media on defending behavior. The aim of the study was to examine longitudinal associations between superhero engagement and a variety of aggressive, prosocial, and defending behaviors in preschool children. Participants consisted of 240 preschoolers (49% male) and their parents who reported on child media use and outcomes at 2 different time points. Preschooler's engagement with superheroes was related to increased physical and relational aggression 1 year later. Engagement with superheroes was not related to prosocial or defending behaviors. Implications of the results are discussed. PMID- 28070755 TI - Social Adversity and Antisocial Behavior: Mediating Effects of Autonomic Nervous System Activity. AB - The display of antisocial behaviors in children and adolescents has been of interest to criminologists and developmental psychologists for years. Exposure to social adversity is a well-documented predictor of antisocial behavior. Additionally, measures of autonomic nervous system (ANS) activity, including heart rate variability (HRV), pre-ejection period (PEP), and heart rate, have been associated with antisocial behaviors including rule-breaking and aggression. Social neuroscience research has begun to investigate how neurobiological underpinnings affect the relationship between social adversity and antisocial/psychopathic behavior in children and adolescents. This study investigated the potential mediating effects of ANS activity on the relationship between social adversity and antisocial behavior in a group of 7- to 10-year-old children from the community (N = 339; 48.2% male). Moderated multiple mediation analyses revealed that low resting heart rate, but not PEP or HRV, mediated the relationship between social adversity and antisocial behavior in males only. Social adversity but not ANS measures were associated with antisocial behavior in females. Findings have implications for understanding the neural influences that underlie antisocial behavior, illustrate the importance of the social environment regarding the expression of these behaviors, and highlight essential gender differences. PMID- 28070756 TI - Deviant Peer Affiliation as an Explanatory Mechanism in the Association between Corporal Punishment and Physical Aggression: a Longitudinal Study among Chinese Adolescents. AB - Previous research has focused primarily on corporal punishment as a cause and adolescents' physical aggression as an outcome. However, there is a large gap in knowledge of the potentially bidirectional association and explanatory mechanism underlying the association between corporal punishment and physical aggression. The current study, using a longitudinal design across three time points (the fall semester of 7th grade, the fall of 8th grade, and the fall of 9th grade), aimed to a) examine the reciprocal processes between corporal punishment and physical aggression, and b) explore whether deviant peer affiliation may explain such reciprocal connections. Only adolescents participating in all the three time points were included in this study, resulting in a final sample of 342 adolescents (175 boys, 167 girls) who completed questionnaires regarding corporal punishment, deviant peer affiliation, and aggression. Gender, age and socioeconomic status were controlled for in the analyses. Autoregressive cross lagged models showed that the results did not support the direct reciprocal effect between corporal punishment and physical aggression among Chinese adolescents. A direct longitudinal link from corporal punishment to physical aggression was found, however, the inverse association was not significant. Moreover, regarding the longitudinal underlying process, in one direction, corporal punishment at 7th grade predicted higher levels of deviant peer affiliation at 8th grade. In turn, higher deviant peer affiliation at 8th grade predicted increased physical aggression at 9th grade. At the same time, in the other direction, adolescent physical aggression at 7th grade significantly predicted deviant peer affiliation at 8th grade. In turn, higher deviant peer affiliation at 8th grade predicted decreased corporal punishment at 9th grade. Identifying the direct and underlying reciprocal processes between corporal punishment and adolescent physical aggression has important implications for an integrative framework of theory and prevention. PMID- 28070757 TI - RNAi-Induced Electrophysiological and Behavioral Changes Reveal two Pheromone Binding Proteins of Helicoverpa armigera Involved in the Perception of the Main Sex Pheromone Component Z11-16:Ald. AB - Pheromone binding proteins (PBPs) are thought to play key roles in insect sex pheromone recognition; however, there is little in vivo evidence to support this viewpoint in comparison to abundant biochemical data in vitro. In the present study, two noctuid PBP genes HarmPBP1 and HarmPBP2 of the serious agricultural pest, Helicoverpa armigera were selected to be knocked down by RNA interference, and then the changes in electrophysiological and behavioral responses of male mutants to their major sex pheromone component (Z)-11-hexadecenal (Z11-16:Ald) were recorded. There were no significant electrophysiological or behavioral changes of tested male moths in response to Z11-16:Ald when either single PBP gene was knocked down. However, decreased sensitivity of male moths in response to Z11-16:Ald was observed when both HarmPBP1 and HarmPBP2 genes were silenced. These results reveal that both HarmPBP1 and HarmPBP2 are required for the recognition of the main sex pheromone component Z11-16:Ald in H. armigera. Furthermore, these findings may help clarify physiological roles of moth PBPs in the sex pheromone recognition pathway, which in turn could facilitate pest control by exploring sex pheromone blocking agents. PMID- 28070758 TI - Phylogeography of the Asian rice gall midge Orseolia oryzae (Wood Mason) (Diptera: Cecidomyiidae) in Thailand. AB - The Asian rice gall midge (RGM) Orseolia oryzae (Wood Mason) (Diptera: Cecidomyiidae) is a major pest of rice, leading to yield losses in Thailand and many Asian countries. Despite an increasing number of reported midge outbreaks and the presence of many susceptible rice varieties, only a few studies have focused on the genetic variation of the midges. Therefore, we analyzed the phylogeography among Thai RGM populations covering north, northeast and central Thailand. Two mitochondrial DNA genes, cytochrome C oxidase I (COI) and 12S, and a non-coding repeat region (RR) situated just before COI were amplified. Overall, the haplotype diversity for COI and 12S genes of the Thai population was high, but the nucleotide diversity was quite low. Altogether, the phylogenetic tree and pairwise F st values indicated that Thai RGM populations recently expanded and were homogeneously distributed throughout the country, except for some populations in the north, which most likely became recently isolated from the main population. Two non-coding repeat motifs, that were recently observed in the mitogenome of RGM in India, were absent in Thai populations and replaced by an 89 bp non-coding sequence. Tandem nucleotide repeats of the sequence TA were also observed. The repeat copy number varied from 2 to 11 and was not correlated with geographical repartition of the midge. Finally, COI barcoding divergence between Indian and Thai populations was high (6.3% in average), giving insights into the potential existence of an RGM species complex in Asia. PMID- 28070759 TI - QTLs for heading date and plant height under multiple environments in rice. AB - Both heading date and plant height are important traits related to grain yield in rice. In this study, a recombinant inbred lines (RILs) population was used to map quantitative trait loci (QTLs) for both traits under 3 long-day (LD) environments and 1 short-day (SD) environment. A total of eight QTLs for heading date and three QTLs for plant height were detected by composite interval mapping under LD conditions. Additional one QTL for heading date and three QTLs for plant height were identified by Two-QTL model under LD conditions. Among them, major QTLs qHd7.1, qHd7.2 and qHd8 for heading date, and qPh1 and qPh7.1 for plant height were commonly detected. qHd7.1 and qHd7.2 were mapped to small regions of less than 1 cM. Genome position comparison of previously cloned genes with QTLs detected in this study revealed that qHd5 and qPh3.1 were two novel QTLs. The alleles of these QTLs increasing trait values were dispersed in both parents, which well explained the transgressive segregation observed in this population. In addition, the interaction between qHd7.1 and qHd8 was detected under all LD conditions. Multiple-QTL model analysis revealed that all QTLs and their interactions explained over 80% of heading date variation and 50% of plant height variation. Two heading date QTLs were detected under SD condition. Of them, qHd10 were commonly identified under LD condition. The difference in QTL detection between LD and SD conditions indicated most heading date QTLs are sensitive to photoperiod. These findings will benefit breeding design for heading date and plant height in rice. PMID- 28070761 TI - Effect of Long-Term Simulated Microgravity on Immune System and Lung Tissues in Rhesus Macaque. AB - We evaluated different lymphocyte populations and levels of plasma cytokines in peripheral blood as well as inflammatory infiltration and expressions of cytokines in lung tissues derived from macaque under long-term stimulated microgravity through being suspended in an antiorthostatic position so as to identify relevant immune parameters and to understand potential mechanisms of lung injury. Fifteen healthy male rhesus macaques were randomly divided into groups 1 (control, n = 5), groups 2 (head-down tilting for 6 weeks, n = 5), and groups 3 (head-down tilting for 6 weeks and recovery for 4 weeks, n = 5). Lymphocyte subsets in peripheral blood were analyzed using flow cytometry and the concentrations of 14 cytokines in plasma were measured with Luminex multiplexing technology. HE staining and transmission electron microscopy were employed to investigate the morphologies and subcellular structures of lung tissues. Immunohistochemistry and real-time PCR were employed to explore mRNA and protein expressions of cytokines in lung tissues. Immunohistochemical demonstrations were detected for CD3, CD4, CD8 T lymphocytes, CD20 B lymphocytes, and CD68 macrophages in lung tissues. Compared to group 1, groups 2 and 3 showed a decrease in the percentage of CD2+T cells, CD2+CD4+T helper cells, and CD2+CD8+cytotoxic T cells as well as an increase in the expression of CD95 on the surface of T lymphocytes in peripheral blood. The serum cytokine levels of IL-18 and TNF-alpha were increased in group 2 when compared to groups 1 and 3. HE and TEM observed changes in the structure and ultrastructure of lung tissues in groups 2 and 3. The number of CD3+T cell, CD4+T cell, CD8+T cells, and CD68+macrophage and the expression levels of IL-1beta, IL-6, and IL-18 in lung tissues were increased in groups 2 when compared with groups 1 and 3. Our data suggested that long-term microgravity might alter the functions of immune system and cause lung damage, changing lymphocyte distribution and functions as well as cytokine production. PMID- 28070762 TI - Being on Your Own or Feeling Lonely? Loneliness and Other Social Variables in Youths with Autism Spectrum Disorders. AB - A cross-sectional study was conducted to examine loneliness and its correlates in children (7 to 11 years) and adolescents (12 to 18 years) with autism spectrum disorders (ASD, n = 73) and control groups of clinically referred (ADHD, n = 76) and non-clinical (n = 106) youths. Youths completed questionnaires on loneliness and desire for social interaction, while parents and teachers filled out scales on other aspects of children's social functioning. Results indicated that only at an adolescent age, the ASD group reported higher levels of loneliness than the control groups. Further, the ASD group generally expressed relatively low levels of desire for social interaction, although these youths displayed a similar increase in the wish to belong during adolescence as participants in the control groups. Finally, the ASD group exhibited lower levels of social competence and social skills and higher levels of social problems and social anxiety than the control groups, and in all groups these social variables correlated in a theoretically meaningful with loneliness. PMID- 28070760 TI - The Generation R Study: design and cohort update 2017. AB - The Generation R Study is a population-based prospective cohort study from fetal life until adulthood. The study is designed to identify early environmental and genetic causes and causal pathways leading to normal and abnormal growth, development and health from fetal life, childhood and young adulthood. This multidisciplinary study focuses on several health outcomes including behaviour and cognition, body composition, eye development, growth, hearing, heart and vascular development, infectious disease and immunity, oral health and facial growth, respiratory health, allergy and skin disorders of children and their parents. Main exposures of interest include environmental, endocrine, genomic (genetic, epigenetic, microbiome), lifestyle related, nutritional and socio demographic determinants. In total, 9778 mothers with a delivery date from April 2002 until January 2006 were enrolled in the study. Response at baseline was 61%, and general follow-up rates until the age of 10 years were around 80%. Data collection in children and their parents includes questionnaires, interviews, detailed physical and ultrasound examinations, behavioural observations, lung function, Magnetic Resonance Imaging and biological sampling. Genome and epigenome wide association screens are available. Eventually, results from the Generation R Study contribute to the development of strategies for optimizing health and healthcare for pregnant women and children. PMID- 28070763 TI - Uveitis in childhood-onset systemic lupus erythematosus patients: a multicenter survey. AB - The aim of this study is to assess uveitis prevalence in a large cohort of childhood-onset systemic lupus erythematosus (cSLE) patients. A retrospective multicenter cohort study including 852 cSLE patients was performed in ten pediatric rheumatology centers (Brazilian cSLE group). An investigator meeting was held and all participants received database training. Uveitis was diagnosed through clinical assessment by the uveitis expert ophthalmologist of each center. Patients with and without uveitis were assessed for lupus clinical/laboratory features and treatments. Uveitis was observed in 7/852 cSLE patients (0.8%). Two of them had ocular complications: cataract and irreversible blindness in one patient and retinal ischemia with subsequent neovascularization and unilateral blindness in another. Uveitis was identified within the first 6 months of cSLE diagnosis in 6/7 patients (86%). Comparison of a subgroup of cSLE patients with (n = 7) and without uveitis (n = 73) and similar length of disease duration showed that patients with uveitis had increased SLEDAI-2K score (19 vs. 6; p < 0.01). In addition, fever (71 vs. 12%; p < 0.01), lymphadenopathy (29 vs. 1.4%; p = 0.02), arthritis (43 vs. 7%; p = 0.02), and use of intravenous methylprednisolone (71 vs. 22%; p = 0.01) were higher in cSLE patients with uveitis, as compared to those without this manifestation, respectively. Presence of fever was significantly associated with uveitis, independently of SLEDAI scores or use of intravenous methylprednisolone pulses, as shown by adjusted regression analysis (adjusted prevalence ratio 35.7, 95% CI 2.4-519.6; p < 0.01). Uveitis was a rare and initial manifestation of active cSLE patients. Early recognition is essential due to the possibility of irreversible blindness. PMID- 28070765 TI - Health Impacts of Religious Practices and Beliefs Associated with The Church of Jesus Christ of Latter-Day Saints. AB - The aim of the study is to discuss the relationship between lifestyle marked by The Church of Jesus Christ of Latter-day Saints and health. PubMed, CINAHL, PsycINFO, WOS y Scopus were the databases used for this literature review, with these descriptors: "Mormons", "mormons religion", "health". Inclusion criteria were articles with full text available, published between 2005 and 2016, in English or Spanish language. Results show that following the restrictive Mormon doctrine generates beneficial effects for the health. Habits related to toxics and food, as well as social support, from family and Mormon community are an important basis for good health. On the other hand, not following the prescriptions or leaving the group, opposed sexual identities or not fulfilling the roles associated with women are associated with worse mental and physical health. PMID- 28070764 TI - Serum 25-OH vitamin D levels in systemic sclerosis: analysis of 140 patients and review of the literature. AB - Hypovitaminosis D is increasingly reported in autoimmune diseases. We investigated the 25-OH-vitamin D (25-OH-vitD) levels in systemic sclerosis (SSc) patients, in correlation with disease's features. We measured the 25-OH-vitD serum levels in 140 consecutive patients (F/M 126/15; mean age 61 +/- 15.1 years), 91 without (group A) and 49 with (group B) 25-OH-cholecalciferol supplementation. Patients of group A invariably showed low 25-OH-vitD levels (9.8 +/- 4.1 ng/ml vs. 26 +/- 8.1 ng/ml of group B); in particular, 88/91 (97%) patients showed vitamin D deficiency (<20 ng/ml), with very low vitamin D levels (<10 ng/ml) in 40 (44%) subjects. Only 15/49 (30.6%) patients of group B reached normal levels of 25-OH-vitD (>=30 ng/ml), whereas vitamin D deficiency persisted in 12/49 (24.5%) individuals. Parathormone levels inversely correlated with 25-OH vitD (r = -0.3, p < 0.0001). Of interest, hypovitaminosis D was statistically associated with autoimmune thyroiditis (p = 0.008), while calcinosis was more frequently observed in patients of group A (p = 0.057). Moreover, we found significantly higher percentage of serum anticentromere antibodies in group B patients with 25-OH-vitD level >=30 ng/ml (8/15 vs. 6/34; p = 0.017). In literature, hypovitaminosis D is very frequent in SSc patients. An association with disease duration, calcinosis, or severity of pulmonary involvement was occasionally recognized. Hypovitaminosis D is very frequent in SSc and severe in a relevant percentage of patients; furthermore, less than one third of supplemented subjects reached normal levels of 25-OH-vitD. The evaluation of 25 OH-vitD levels should be included in the routine clinical work-up of SSc. The above findings expand previous observations and may stimulate further investigations. PMID- 28070766 TI - Radiofrequency ablation combined with transarterial chemoembolization versus hepatectomy for patients with hepatocellular carcinoma within Milan criteria: a retrospective case-control study. AB - PROPOSAL: To compare the effectiveness of TACE + RFA with hepatectomy in patients with HCC within Milan criteria. METHODS: It is a retrospective matched case control study from January 2006 to December 2010 in a tertiary cancer center. 74 patients with HCC within Milan criteria initially treated with TACE + RFA were identified and compared with 148 matched controls selected from a pool of 782 patients who received hepatectomy. Patients were matched with respect to age, gender, tumor size and number, AFP and liver function test. RESULTS: The 1, 3, and 5 years overall survival (OS) was 94.6, 75.1 and 55.3%, respectively, in the combination group, and 91.2, 64.4, and 47.7%, respectively, in the hepatectomy group (P = 0.488). The 1, 3, and 5 years disease-free survival (DFS) in the combination group was 87.8, 48.3, and 33.5%, respectively, and 68.9, 49.2, and 40.9%, respectively, in the hepatectomy group (P = 0.619). In subgroups analyses according to the tumor size and number, no significant difference was identified in either OS or DFS for patients with single tumor smaller than 3.0 cm, 3.0-5.0 cm, and multiple tumors. Multivariate analysis showed that tumor size, ALT, and CLIP score were significant prognostic factors for OS, and ALT and Child-Pugh class were significant prognostic factors for DFS. CONCLUSION: TACE + RFA is safe and as effective as hepatectomy for patients with HCC within Milan criteria. PMID- 28070767 TI - Strut-adjusted volume implant (SAVI) brachytherapy-based accelerated partial breast irradiation (APBI) in African American women. AB - PURPOSE: To examine the clinical outcomes of postmenopausal African American (AA) women treated with strut-adjusted volume implant brachytherapy-based accelerated partial breast irradiation for early-stage node-negative breast cancer. METHODS: From January 2011 through April 2015, a total of 50 AA patients, meeting criteria to receive APBI as defined by the National Surgical Adjuvant Breast and Bowel Project B-39 (NASBP B-39), completed treatment with the SAVI breast brachytherapy device at Howard University Hospital. RESULTS: 4% ipsilateral breast tumor recurrence and 2% breast cancer-specific mortality was observed. Median follow-up has been 3.8 years with a range of 0.29-4.69 years. Dosimetry parameters yielded a median V90 of 96.22% (range 77.86-105.00%), a median V150 of 31.27 cm3 (range 23.30-49.15 mL), and a median V200 of 14.53 cm3 (range 5.92-19.38 mL). Cosmesis was excellent. There were no infections, persistent seromas, fat necrosis, or telangiectasias observed to date. CONCLUSIONS: This study is the first study to describe the use of SAVI as APBI in an exclusively AA population. This study has demonstrated excellent local control in appropriately selected patients, similar clinical outcomes to the general population, and good to excellent cosmesis in AA women to date. PMID- 28070768 TI - Breast cancer is a systemic disease rather than an anatomical process. PMID- 28070769 TI - Emotional distress impacts quality of life evaluation: a report from the Childhood Cancer Survivor Study. AB - PURPOSE: We compared health-related quality of life (HRQOL) between adult survivors of childhood cancer and siblings by investigating the mediating role of emotional distress on HRQOL assessment, and examining the extent to which emotional distress affected the item responses of HRQOL measures given the same underlying HRQOL (i.e., measurement non-invariance). METHODS: Cancer survivors (7103) and siblings (390) enrolled in Childhood Cancer Survivor Study who completed the SF-36 measuring HRQOL and the Brief Symptom Inventory-18 measuring anxiety, depression, and somatization were analyzed. Multiple Indicators & Multiple Causes modeling was performed to identify measurement non-invariance related to emotional distress on the responses to HRQOL items. Mediation analysis was performed to test the effects of cancer experience on HRQOL accounting for the mediating role of emotional distress. RESULTS: Twenty-nine percent, 40%, and 34% of the SF-36 items were identified with measurement non-invariance related to anxiety, depression, and somatization, respectively. Survivors reported poorer HRQOL than siblings in all domains (ps < 0.05), except for pain. Other than physical functioning and general health perceptions, poorer HRQOL was explained by the mediating role of emotional distress (ps < 0.05). CONCLUSIONS: Differences in HRQOL between survivors and siblings appear due, in part, to the mediating effect of emotional distress through which cancer experience influences the responses to HRQOL measures. IMPLICATIONS OF CANCER SURVIVORS: Interventions to treat emotional distress may improve cancer survivors' HRQOL. PMID- 28070771 TI - The Importance of Framing. PMID- 28070770 TI - A dance intervention for cancer survivors and their partners (RHYTHM). AB - PURPOSE: The purpose of this study was to assess the feasibility, acceptability, and impact of a ballroom dance intervention on improving quality of life (QOL) and relationship outcomes in cancer survivors and their partners. METHODS: We conducted a pilot randomized controlled trial with two arms (Restoring Health in You (and Your Partner) through Movement, RHYTHM): (1) immediate dance intervention and (2) delayed intervention (wait-list control). The intervention consisted of 10 private weekly dance lessons and 2 practice parties over 12 weeks. Main outcomes were physical activity (Godin Leisure-Time Exercise Questionnaire), functional capacity (6 Minute Walk Test), QOL (SF-36), Couples' trust (Dyadic Trust Scale), and other dyadic outcomes. Exit interviews were completed by all participating couples. RESULTS: Thirty-one women survivors (68% breast cancer) and their partners participated. Survivors were 57.9 years old on average and 22.6% African American. Partners had similar characteristics. RHYTHM had significant positive effects on physical activity (p = 0.05), on the mental component of QOL (p = 0.04), on vitality (p = 0.03), and on the dyadic trust scale (p = 0.04). Couples expressed satisfaction with the intervention including appreciating the opportunity to spend time and exercise together. Survivors saw this light-intensity physical activity as easing them into becoming more physically active. CONCLUSIONS: Light intensity ballroom dancing has the potential to improve cancer survivors' QOL. Larger trials are needed to build strong support for this ubiquitous and acceptable activity. IMPLICATIONS FOR CANCER SURVIVORS: Ballroom dance may be an important tool for cancer survivors to return to a physically active life and improve QOL and other aspects of their intimate life. PMID- 28070772 TI - Primary Care Providers' Beliefs and Recommendations and Use of Screening Mammography by their Patients. AB - BACKGROUND: Revised breast cancer screening guidelines have fueled debate about the effectiveness and frequency of screening mammography, encouraging discussion between women and their providers. OBJECTIVE: To examine whether primary care providers' (PCPs') beliefs about the effectiveness and frequency of screening mammography are associated with utilization by their patients. DESIGN: Cross sectional survey data from PCPs (2014) from three primary care networks affiliated with the Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium, linked with data about their patients' mammography use (2011-2014). PARTICIPANTS: PCPs (n = 209) and their female patients age 40-89 years without breast cancer (n = 30,233). MAIN MEASURES: Outcomes included whether (1) women received a screening mammogram during a 2 year period; and (2) screened women had >1 mammogram during that period, reflecting annual screening. Principal independent variables were PCP beliefs about the effectiveness of mammography and their recommendations for screening frequency. KEY RESULTS: Overall 65.2% of women received >1 screening mammogram. For women 40-48 years, mammography use was modestly lower for those cared for by PCPs who believed that screening was ineffective compared with those who believed it was somewhat or very effective (59.1%, 62.3%, and 64.7%; p = 0.019 after controlling for patient characteristics). Of women with PCPs who reported they did not recommend screening before age 50, 48.1% were nonetheless screened. For women age 49-74 years, the vast majority were cared for by providers who believed that screening was effective. Provider recommendations were not associated with screening frequency. For women >=75 years, those cared for by providers who were uncertain about effectiveness had higher screening use (50.7%) than those cared for by providers who believed it was somewhat effective (42.8%). Patients of providers who did not recommend screening were less likely to be screened than were those whose providers recommended annual screening, yet 37.1% of patients whose providers recommended against screening still received screening. CONCLUSIONS: PCP beliefs about mammography effectiveness and screening recommendations are only modestly associated with use, suggesting other likely influences on patient participation in mammography. PMID- 28070773 TI - Challenges and Opportunities: Building a Relationship Between a Department of Biomedical Engineering and a Medical School. AB - A department of biomedical engineering can significantly enhance the impact of their research and training programs if a productive relationship with a medical school can be established. In order to develop such a relationship, significant hurdles must be overcome. This editorial summarizes some of the major challenges and opportunities for a department of biomedical engineering as they seek to build or enhance a relationship with a medical school. The ideas were formulated by engaging the collective wisdom from the Council of Chairs of the biomedical engineering departments. PMID- 28070774 TI - Restoring Fertility with Cryopreserved Prepubertal Testicular Tissue: Perspectives with Hydrogel Encapsulation, Nanotechnology, and Bioengineered Scaffolds. AB - New and improved oncological therapies are now able to cure more than 80% of cancer-affected children in Europe. However, such treatments are gonadotoxic and result in fertility issues, especially in boys who are not able to provide a sperm sample before starting chemo/radiotherapy because of their prepubertal state. For these boys, cryopreservation of immature testicular tissue (ITT) is the only available option, aiming to preserve spermatogonial stem cells (SSCs). Both slow-freezing and vitrification have been investigated to this end and are now applied in a clinical setting for SSC cryopreservation. Research now has to focus on methods that will allow fertility restoration. This review discusses different studies that have been conducted on ITT transplantation, including those using growth factor supplementation like free molecules, or tissue encapsulation with or without nanoparticles, as well as the possibility of developing a bioartificial testis that can be used for in vitro gamete production or in vivo transplantation. PMID- 28070775 TI - Reduction of Burnout in Mental Health Care Providers Using the Provider Resilience Mobile Application. AB - This pilot study examined the usability, acceptability, and effectiveness of a free Provider Resilience (PR) mobile application (app) designed by the National Center for Telehealth and Technology to reduce provider burnout. Outpatient mental health providers (N = 30) used the PR app for 1 month. Participants rated the PR app on the System Usability Scale with an overall score of 79.7, which is in the top quartile for usability. Results of paired sample t tests on the Professional Quality of Life Scale indicated significant decreases on the Burnout (t = 3.65, p < .001) and Compassion Fatigue (t = 4.54, p < .001) subscales. The Provider Resilience app shows promise in reducing burnout and compassion fatigue in mental health care providers. PMID- 28070776 TI - Computer-assisted delineation of cerebral infarct from diffusion-weighted MRI using Gaussian mixture model. AB - PURPOSE: Diffusion-weighted imaging (DWI) is a widely used medical imaging modality for diagnosis and monitoring of cerebral stroke. The identification of exact location of stroke lesion helps in perceiving its characteristics, an essential part of diagnosis and treatment planning. This task is challenging due to the typical shape of the stroke lesion. This paper proposes an efficient method for computer-aided delineation of stroke lesions from DWI images. METHOD: Proposed methodology comprises of three steps. At the initial step, image contrast has been improved by applying fuzzy intensifier leading to the better visual quality of the stroke lesion. In the following step, a two-class (stroke lesion area vs. non-stroke lesion area) segmentation technique based on Gaussian mixture model has been designed for the localization of stroke lesion. To eliminate the artifacts which would appear during segmentation process, a binary morphological post-processing through area operator has been defined for exact delineation of the lesion area. RESULT: The performance of the proposed methodology has been compared with the manually delineated images (ground truth) obtained from different experts, individually. Quantitative evaluation with respect to various performance measures (such as dice coefficient, Jaccard score, and correlation coefficient) shows the efficient performance of the proposed technique. PMID- 28070778 TI - The failure to increase social support: it just might be time to stop intervening (and start rigorously observing). AB - In 1986, Lichtenstein et al. (Behav Ther. 17(5):607-19, 1986) presented the results of five studies focused on enhancing social support for smoking cessation in community-based clinic and worksite interventions. The manuscript was titled Social Support in Smoking Cessation: In Search of Effective Interventions and its main conclusion was that "attempts to both increase social support and to enhance treatment effectiveness have not been successful." Thirty years later, the paper by Cutrona et al. (Transl Behav Med. 6(4):546-57, 2016) draws a similar conclusion from a study focused on providing social support through an online social network for smoking cessation. In reviewing these findings - and based on our knowledge of the extensive literature on social support interventions that has been published over the past 30+ years - we believe there is a need for a fundamental shift in research on social support. Our focus here is largely on smoking cessation, but our comments are applicable to other areas of behavior change. PMID- 28070777 TI - Breast ultrasound image segmentation: a survey. AB - PURPOSE: Breast cancer is the most common form of cancer among women worldwide. Ultrasound imaging is one of the most frequently used diagnostic tools to detect and classify abnormalities of the breast. Recently, computer-aided diagnosis (CAD) systems using ultrasound images have been developed to help radiologists to increase diagnosis accuracy. However, accurate ultrasound image segmentation remains a challenging problem due to various ultrasound artifacts. In this paper, we investigate approaches developed for breast ultrasound (BUS) image segmentation. METHODS: In this paper, we reviewed the literature on the segmentation of BUS images according to the techniques adopted, especially over the past 10 years. By dividing into seven classes (i.e., thresholding-based, clustering-based, watershed-based, graph-based, active contour model, Markov random field and neural network), we have introduced corresponding techniques and representative papers accordingly. RESULTS: We have summarized and compared many techniques on BUS image segmentation and found that all these techniques have their own pros and cons. However, BUS image segmentation is still an open and challenging problem due to various ultrasound artifacts introduced in the process of imaging, including high speckle noise, low contrast, blurry boundaries, low signal-to-noise ratio and intensity inhomogeneity CONCLUSIONS: To the best of our knowledge, this is the first comprehensive review of the approaches developed for segmentation of BUS images. With most techniques involved, this paper will be useful and helpful for researchers working on segmentation of ultrasound images, and for BUS CAD system developers. PMID- 28070779 TI - Hydrolytic Activity of Esterase-Antibody Complexes Retained Within Gel Capsules After Complex Isolation. AB - Delipidation in biological samples is important for some diagnostic tests and protein analyses. Lipids in the samples can be hydrolyzed by native esterases (ESs) within gel capsules after ES, and ES-antibody complexes are specifically trapped, extracted, and separated. Acrylamide and agarose gel capsules containing complexes of ES antibody were produced after the complexes were extracted using protein A-immobilized membranes, separated by non-denaturing electrophoresis, and stained by colloidal silver using glucose as a reductant. ES activity of ES antibody complexes within the gel capsule was significantly higher than that in the complexes with the control antibodies upon isolation, separation, and detection of the complex. In addition, lipids bound to human serum albumin decreased after human plasma was treated with gel capsules containing ES-antibody complexes. We demonstrate that the gel capsule containing ES-antibody complexes can be successfully isolated using techniques described in this study. Furthermore, delipidation of human plasma is obtained by incubation with the gel capsule. These results indicate that surplus materials such as lipids in biological samples can be removed or reduced by gel capsule containing enzymes. PMID- 28070780 TI - Laparoscopic sleeve gastrectomy in adolescents with or without syndromic obesity: two years follow-up. AB - INTRODUCTION: Childhood obesity is an emerging health problem. Surgical treatment of obese adolescents, particularly those affected by congenital syndrome, represents a controversial issue. The aim of this multicenter study was to retrospectively assess the results of laparoscopic sleeve gastrectomy (LSG) in a cohort of adolescents affected by morbid obesity, with or without congenital syndromes. MATERIALS AND METHODS: Forty-one obese (BMI 49 +/- 6 kg/m2) adolescents with mean age of 16 +/- 3 years (58.5% with previous intragastric balloon failure), and subjected to LSG, were retrospectively evaluated for complications rate, % excess weight loss (%EWL), and inhibition of co-morbidities after 2 years of follow-up. RESULTS: All the operations were completed laparoscopically and no intra-operative complications were recorded. No mortality was recorded while peri- or post-operative complications only occurred in two patients (4.9%). The EWL% at 6, 12, and 24 months were 42.3, 58.3, and 59.4, respectively. %EWL was comparable (p = 0.7) between non-syndromic and syndromic obese adolescents at 24 months. Conversely patients with previous intragastric balloon surgery had a significant lower EWL (%) at 24 month (p < 0.01). Moreover, at the same time point, co-morbidity resolution rate was 78.2% while improvement rate was 57.6%. Specifically, remission rate of type 2 diabetes (T2DM), hypertension and obstructive sleep apnea (OSA) were 71, 75 and 61%, respectively. CONCLUSION: LSG is advantageous in the treatment of morbidly obese juveniles concerning safety, weight loss and co-morbidity control and at same time presenting, a possible effective therapeutic option for patients affected by congenital syndrome. PMID- 28070781 TI - The Support Needs of Children with Intellectual Disability and Autism: Implications for Supports Planning and Subgroup Classification. AB - The Supports Intensity Scale-Children's version (SIS-C) was developed to provide a standardized measure of support needs of children with intellectual disability. Over half of the norming sample had a secondary diagnosis of autism. Using this subset of the sample, we engaged in exploratory analysis to examine the degree to which latent clusters were present in the data, and after identifying these clusters, the degree to which they mapped on the SIS-C standard scores. A four latent class solution provided the best fit to the data. When mapped on SIS-C standard scores, specific patterns of differences were found in life activity domain scores and overall support needs scores. Implications for future research and practice are discussed. PMID- 28070782 TI - Co-Parenting Quality, Parenting Stress, and Feeding Challenges in Families with a Child Diagnosed with Autism Spectrum Disorder. AB - 113 parents of children aged 5-13 with ASD completed online surveys assessing co parenting quality, parenting stress, and child feeding challenges. Results indicated that food selectivity was both the most frequently reported type of challenging feeding behavior and the most often reported as problematic but was also the only type of challenging feeding behavior that was not associated with parenting stress. Greater parenting stress was reported when co-parenting agreement and support were lower. Child disruptive behavior at mealtime was the only feeding challenge associated with quality of co-parenting. This paper points to the importance of addressing feeding challenges in addition to selectivity, such as disruptive mealtime behaviors, and doing so within the context of the family and home environment. PMID- 28070783 TI - Brief Report: Using a Point-of-View Camera to Measure Eye Gaze in Young Children with Autism Spectrum Disorder During Naturalistic Social Interactions: A Pilot Study. AB - Children with autism spectrum disorder (ASD) show reduced gaze to social partners. Eye contact during live interactions is often measured using stationary cameras that capture various views of the child, but determining a child's precise gaze target within another's face is nearly impossible. This study compared eye gaze coding derived from stationary cameras to coding derived from a "point-of-view" (PoV) camera on the social partner. Interobserver agreement for gaze targets was higher using PoV cameras relative to stationary cameras. PoV camera codes, but not stationary cameras codes, revealed a difference between gaze targets of children with ASD and typically developing children. PoV cameras may provide a more sensitive method for measuring eye contact in children with ASD during live interactions. PMID- 28070784 TI - Emotion Regulation and Parent Co-Regulation in Children with Autism Spectrum Disorder. AB - Children with autism spectrum disorder (ASD) often exhibit emotional problems, which can be associated with emotion regulation (ER) difficulties. Parent co regulation is often associated with child ER and emotional problems, though little work has been done with reference to youth with ASD. This study investigated the association among parent co-regulation, child ER, and internalizing and externalizing problems in 51 parents and school-aged children with ASD. Parent co-regulation strategies and scaffolding were not associated with parent-reported levels of child internalizing problems. Parent scaffolding and child ER predicted externalizing problems, after controlling for child age and IQ. Suggestions for future research on parent involvement in the emotional development of children with ASD are discussed, as well as implications for ER focused interventions. PMID- 28070785 TI - Understanding Behavioural Rigidity in Autism Spectrum Conditions: The Role of Intentional Control. AB - Although behavioural rigidity belongs to the core symptoms of autism spectrum conditions, little is known about its underlying cognitive mechanisms. The current study investigated the role of intentional control mechanisms in behavioural rigidity in autism. Autistic individuals and their matched controls were instructed to repeatedly choose between two simple cognitive tasks and to respond accordingly to the subsequently presented stimulus. Results showed that autistic participants chose to repeat tasks more often than their controls and when choosing to switch, they demonstrated larger performance costs. These findings illustrate that when required to make their own choices, autistic people demonstrate rigidity at different performance levels, suggesting that intentional control mechanisms might be important for a better understanding of behavioural rigidity in autism. PMID- 28070786 TI - Training Parents of Youth with Autism Spectrum Disorder to Advocate for Adult Disability Services: Results from a Pilot Randomized Controlled Trial. AB - This study presents findings from a pilot randomized controlled trial, testing a 12-week intervention to train parents of youth with autism spectrum disorder (ASD) to advocate for adult disability services-the Volunteer Advocacy Program Transition (VAP-T). Participants included 41 parents of youth with ASD within 2 years of high school exit, randomly assigned to a treatment (N = 20) or wait-list control (N = 21) group. Outcomes, collected before and after the intervention, included parental knowledge about adult services, advocacy skills-comfort, and empowerment. The VAP-T had acceptable feasibility, treatment fidelity, and acceptability. After participating in the VAP-T, intervention parents (compared to controls) knew more about the adult service system, were more skilled/comfortable advocating, and felt more empowered. PMID- 28070787 TI - Predictors of Self-Injurious Behavior and Self-Restraint in Autism Spectrum Disorder: Towards a Hypothesis of Impaired Behavioral Control. AB - Self-injury is common in autism spectrum disorder (ASD); however few studies have investigated correlates of self-injury or the putative associations with self restraint. Questionnaire data on self-injury, self-restraint, health conditions, overactivity/impulsivity and repetitive/restricted behavior were collected on 208 children and 216 adults with ASD (mean age = 24.10, range 6-61). Self-injury and self-restraint were frequent and significantly associated in both children (45.7% and 40.9%, p < 0.001) and adults (49.1, and 42.6%, p < 0.001). Severe self-injury was predicted by lower ability, health conditions and overactivity/impulsivity in children (p < 0.001) and repetitive/restricted behavior and overactivity/impulsivity in adults (p < 0.001). These data provide preliminary support for a developmental model of self-injury and self-restraint in which painful health conditions and compromised behavioral control influence the presence and trajectory of self-injury in ASD. PMID- 28070788 TI - Developmental Markers of Genetic Liability to Autism in Parents: A Longitudinal, Multigenerational Study. AB - Genetic liability to autism spectrum disorder (ASD) can be expressed in unaffected relatives through subclinical, genetically meaningful traits, or endophenotypes. This study aimed to identify developmental endophenotypes in parents of individuals with ASD by examining parents' childhood academic development over the school-age period. A cohort of 139 parents of individuals with ASD were studied, along with their children with ASD and 28 controls. Parents' childhood records in the domains of language, reading, and math were studied from grades K-12. Results indicated that relatively lower performance and slower development of skills (particularly language related skills), and an uneven rate of development across domains predicted ASD endophenotypes in adulthood for parents, and the severity of clinical symptoms in children with ASD. These findings may mark childhood indicators of genetic liability to ASD in parents, that could inform understanding of the subclinical expression of ASD genetic liability. PMID- 28070789 TI - Priming Facial Gender and Emotional Valence: The Influence of Spatial Frequency on Face Perception in ASD. AB - Adolescents with and without autism spectrum disorder (ASD) performed two priming experiments in which they implicitly processed a prime stimulus, containing high and/or low spatial frequency information, and then explicitly categorized a target face either as male/female (gender task) or as positive/negative (Valence task). Adolescents with ASD made more categorization errors than typically developing adolescents. They also showed an age-dependent improvement in categorization speed and had more difficulties with categorizing facial expressions than gender. However, in neither of the categorization tasks, we found group differences in the processing of coarse versus fine prime information. This contradicted our expectations, and indicated that the perceptual differences between adolescents with and without ASD critically depended on the processing time available for the primes. PMID- 28070790 TI - Brief Report: Mealtime Behaviors of Chinese American Children with Autism Spectrum Disorder. AB - This study investigated mealtime behaviors of Chinese-American children with autism spectrum disorder (ASD). Thirty-one parents of Chinese-American children with ASD participated in this study and the Brief Autism Mealtime Behavior Inventory (BAMBI) was used. The top problematic mealtime behaviors reported by parents were prefers "crunchy" food (54.2%); not willing to try new foods (48%); and does not remain seated at the table until the meal is finished (46%). This study found that the majority of the Chinese-American children with ASD seldom or never were aggressive (96%) or disruptive during mealtimes (92.3%). Compared to their white counterparts, Chinese-American children with ASD showed slightly lower scores on problematic mealtime behaviors. These findings may provide significant information to practitioners. PMID- 28070791 TI - Social and Non-social Hazard Response in Drivers with Autism Spectrum Disorder. AB - Driving is a complex task that relies on manual, cognitive, visual and social skill. The social demands of driving may be challenging for individuals with Autism Spectrum Disorder (ASD) due to known social impairments. This study investigated how drivers with ASD respond to social (e.g., pedestrians) and non social (e.g., vehicles) hazards in a driving simulator compared to typically developing drivers. Overall, participants responded faster to social hazards than non-social hazards. It was also found that drivers with typical development reacted faster to social hazards, while drivers with ASD showed no difference in reaction time to social versus non-social hazards. Future work should further investigate how social impairments in ASD may affect driving safety. PMID- 28070794 TI - Emerging neuroradiological topics in journals from related societies. PMID- 28070792 TI - Wearable Cameras Are Useful Tools to Investigate and Remediate Autobiographical Memory Impairment: A Systematic PRISMA Review. AB - Autobiographical memory, central in human cognition and every day functioning, enables past experienced events to be remembered. A variety of disorders affecting autobiographical memory are characterized by the difficulty of retrieving specific detailed memories of past personal events. Owing to the impact of autobiographical memory impairment on patients' daily life, it is necessary to better understand these deficits and develop relevant methods to improve autobiographical memory. The primary objective of the present systematic PRISMA review was to give an overview of the first empirical evidence of the potential of wearable cameras in autobiographical memory investigation in remediating autobiographical memory impairments. The peer-reviewed literature published since 2004 on the usefulness of wearable cameras in research protocols was explored in 3 databases (PUBMED, PsycINFO, and Google Scholar). Twenty-eight published studies that used a protocol involving wearable camera, either to explore wearable camera functioning and impact on daily life, or to investigate autobiographical memory processing or remediate autobiographical memory impairment, were included. This review analyzed the potential of wearable cameras for 1) investigating autobiographical memory processes in healthy volunteers without memory impairment and in clinical populations, and 2) remediating autobiographical memory in patients with various kinds of memory disorder. Mechanisms to account for the efficacy of wearable cameras are also discussed. The review concludes by discussing certain limitations inherent to using cameras, and new research perspectives. Finally, ethical issues raised by this new technology are considered. PMID- 28070793 TI - Object-location binding across a saccade: A retinotopic spatial congruency bias. AB - Despite frequent eye movements that rapidly shift the locations of objects on our retinas, our visual system creates a stable perception of the world. To do this, it must convert eye-centered (retinotopic) input to world-centered (spatiotopic) percepts. Moreover, for successful behavior we must also incorporate information about object features/identities during this updating - a fundamental challenge that remains to be understood. Here we adapted a recent behavioral paradigm, the "spatial congruency bias," to investigate object-location binding across an eye movement. In two initial baseline experiments, we showed that the spatial congruency bias was present for both gabor and face stimuli in addition to the object stimuli used in the original paradigm. Then, across three main experiments, we found the bias was preserved across an eye movement, but only in retinotopic coordinates: Subjects were more likely to perceive two stimuli as having the same features/identity when they were presented in the same retinotopic location. Strikingly, there was no evidence of location binding in the more ecologically relevant spatiotopic (world-centered) coordinates; the reference frame did not update to spatiotopic even at longer post-saccade delays, nor did it transition to spatiotopic with more complex stimuli (gabors, shapes, and faces all showed a retinotopic congruency bias). Our results suggest that object-location binding may be tied to retinotopic coordinates, and that it may need to be re-established following each eye movement rather than being automatically updated to spatiotopic coordinates. PMID- 28070795 TI - TD-DFT Study of Absorption and Emission Spectra of 2-(2' Aminophenyl)benzothiazole Derivatives in Water. AB - Reduction of aromatic azides to amines is an important property of hydrogen sulphide (H2S) which is useful in fluorescence microscopy and H2S probing in cells. The aim of this work is to study the substituent effect on the absorption and emission spectra of 2-(2'-aminophenyl)benzothiazole (APBT) in order to design APBT derivatives for the use of H2S detection. Absorption and emission spectra of APBT derivatives in aqueous environment were calculated using density functional theory (DFT) and time-dependent DFT (TD-DFT) at B3LYP/6-311+G(d,p) level. The computed results favoured the substitution of strong electron-donating group on the phenyl ring opposite to the amino group for their large Stokes' shifts and emission wavelengths of over 600 nm. Also, three designed compounds were suggested as potential candidates for the fluorescent probes. Such generalised guideline learnt from this work can also be useful in further designs of other fluorescent probes of H2S in water. PMID- 28070796 TI - Synthesis, Characterization and Photophysical Studies of Tricoumarin-Pyridines. AB - A series of novel tricoumarin-pyridines have been synthesized by the reaction of 4-formyl coumarins and substituted 3-acetylcoumarin with ammonium acetate for the application in organic electronics as well as fluorescent dyes. The structures of all new compounds were confirmed and characterized by IR, 1H NMR and ESI-Mass analysis. All the important photo physical prerequisites for organic electronic application such as strong and broad optical absorption, thermal stability were determined for the synthesized molecules. Optical properties were studied by UV Vis absorption and fluorescence spectroscopy. Optical band gaps of the tricoumarin-pyridines were found to be 2.72-3.10 eV as calculated from their onset absorption edge. The tricoumarin-pyridines were thermally stable up to 290 370 degrees C as determined by thermogravimetric analysis (TGA). Photophysical studies indicate the synthesized materials are promising candidates for organic electronic applications. PMID- 28070797 TI - Inhibition of MT1-MMP proteolytic function and ERK1/2 signalling influences cell migration and invasion through changes in MMP-2 and MMP-9 levels. AB - Membrane type-1 matrix metalloproteinase (MT1-MMP, MMP-14) is a unique protease that cleaves extracellular proteins, activates proMMPs, and initiates intracellular signalling. MCF-7 cells are non-invasive and deficient in MT1-MMP, MMP-2, and MMP-9 expression. We created an MCF-7 cell line (C2) that stably produces active MT1-MMP and demonstrated increased ERK1/2 phosphorylation. MAPK inhibition in this cell line showed an inverse relationship in MMP-2 and MMP-9 transcripts where levels of these genes increased and decreased, respectively. Using invasive MDA-MB 231 cells that endogenously produce MT1-MMP and have naturally high pERK levels, we demonstrated the identical inverse relationship between MMP-2 and -9 transcript and protein levels, suggesting that this novel relationship is conserved amongst MT1-MMP positive breast cancer cells. To further analyze the relationship between MMP-2 and -9 levels, we chemically inhibited activation and catalytic activity of MT1-MMP using a furin and MMP inhibitor, respectively, to show that interference with the functions of MT1-MMP induced changes in MMP-2 and 9 transcript levels that were always inverse of each other, and likely mediated by differential transcriptional activity of the NF kappaB transcription factor. Furthermore, we analyzed the functional consequences of these expression changes to show MMP, and in particular ERK, inhibition decreased migration and invasion using 2D culture, and inhibits the formation of an invasive phenotype in Matrigel 3D culture. This study demonstrated a novel inverse transcriptional relationship between MMP-2 and -9 levels and MT1-MMP activity that have functional consequences, and also showed that increases in the levels of MMPs does not necessarily correlate with an invasive phenotype. PMID- 28070800 TI - Enhancing Utility by More Realistic Criteria. PMID- 28070799 TI - Metabolic Alterations and the Protective Effect of Punicalagin Against Glutamate Induced Oxidative Toxicity in HT22 Cells. AB - Oxidative stress is involved in many neurological diseases, including Alzheimer's disease. Punicalagin (PC) is a hydrolysable polyphenol derived from Punica granatum and a potent antioxidant. In this study, the neuroprotective effect of PC on glutamate-induced oxidative stress was evaluated in the mouse hippocampal cell line, HT22. PC treatment protected HT22 cells from glutamate-induced cell death in a concentration-dependent manner, potentially attenuated glutamate induced intracellular reactive oxygen species (ROS) and restored the mitochondrial membrane depolarization. Metabolic alterations after glutamate induced oxidative stress and the protective effect of PC were evaluated with HPLC and GC-MS profiling methods with multivariate statistical analyses. Alterations in ten metabolites were identified, including amino acids, aspartic acid, asparagine, threonine, anserine, cysteine, tryptophan, lysine, as well as fatty acids palmitic acid, stearic acid, and palmitoleic acid. Metabolic pathway analysis revealed the involvement of multiple affected pathways, such as cysteine and methionine metabolism, tryptophan metabolism, alanine, aspartate, and glutamate and fatty acid oxidation. These results clearly demonstrate that PC is a promising therapeutic agent for oxidative stress-associated diseases. PMID- 28070798 TI - Does vitamin D play a role in autoimmune endocrine disorders? A proof of concept. AB - In the last few years, more attention has been given to the "non-calcemic" effect of vitamin D. Several observational studies and meta-analyses demonstrated an association between circulating levels of vitamin D and outcome of many common diseases, including endocrine diseases, chronic diseases, cancer progression, and autoimmune diseases. In particular, cells of the immune system (B cells, T cells, and antigen presenting cells), due to the expression of 1alpha-hydroxylase (CYP27B1), are able to synthesize the active metabolite of vitamin D, which shows immunomodulatory properties. Moreover, the expression of the vitamin D receptor (VDR) in these cells suggests a local action of vitamin D in the immune response. These findings are supported by the correlation between the polymorphisms of the VDR or the CYP27B1 gene and the pathogenesis of several autoimmune diseases. Currently, the optimal plasma 25-hydroxyvitamin D concentration that is necessary to prevent or treat autoimmune diseases is still under debate. However, experimental studies in humans have suggested beneficial effects of vitamin D supplementation in reducing the severity of disease activity. In this review, we summarize the evidence regarding the role of vitamin D in the pathogenesis of autoimmune endocrine diseases, including type 1 diabetes mellitus, Addison's disease, Hashimoto's thyroiditis, Graves' disease and autoimmune polyendocrine syndromes. Furthermore, we discuss the supplementation with vitamin D to prevent or treat autoimmune diseases. PMID- 28070801 TI - A Comparison of Sexual Function in Women with Polycystic Ovary Syndrome (PCOS) Whose Mothers Had PCOS During Their Pregnancy Period with Those Without PCOS. AB - Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women during reproductive ages. Clinical symptoms associated with PCOS, such as hirsutism, acne, alopecia, obesity, and infertility, may lead to emotional morbidity and then impaired sexual function in those affected. During intrauterine development, the fetus may program the development of diseases during adulthood. In this study, we aimed to examine sexual function in women with PCOS, exposed to maternal androgen excess during their prenatal life compared to non-exposed PCOS patients. In this cross-sectional study, 768 married women with PCOS, aged 18-49 years, were subdivided into two groups, based on their mothers' PCOS status: women whose mothers had PCOS (N = 94) and women whose mothers did not have PCOS (N = 674). Data were collected using a questionnaire including information on demographics, anthropometric and reproductive characteristics, and the Female Sexual Function Index. Blood serum samples were collected from patients for assessment of total testosterone and sex hormone binding globulin levels. Results revealed that sexual dysfunction was significantly higher in PCOS women whose mothers also had PCOS, compared to those whose mothers did not (38.6 vs. 25.3%, p = .01). After adjusting for confounding variables, logistic regression analysis showed that odds ratios for sexual dysfunction (total) and sexual dysfunction in the pain domain were significantly higher in the exposed PCOS women versus the non-exposed women (OR 1.81, 95% CI 1.06-3.07, p = .02 and 1.68, 95% CI 1.01-2.77, p = .04, respectively). Our study demonstrates increased sexual dysfunction in PCOS women whose mothers also had PCOS. PMID- 28070802 TI - Sexual Desire in Sexual Minority and Majority Women and Men: The Multifaceted Sexual Desire Questionnaire. AB - Sexual desire is increasingly understood to be multifaceted and not solely erotically oriented, but measures are still generally unitary and eroticism focused. Our goals in this article were to explore the multifaceted nature of sexual desire and develop a measure to do so, and to determine how multifaceted sexual desire might be related to gender/sex and sexual orientation/identity. In the development phase, we generated items to form the 65-item Sexual Desire Questionnaire (DESQ). Next, the DESQ was administered to 609 women, 705 men, and 39 non-binary identified participants. Results showed that the DESQ demonstrated high reliability and validity, and that sexual desire was neither unitary nor entirely erotic, but instead was remarkably multifaceted. We also found that multifaceted sexual desire was in part related to social location variables such as gender/sex and sexual orientation/identity. We propose the DESQ as a measure of multifaceted sexual desire that can be used to compare factor themes, total scores, and scores across individual items in diverse groups that take social context into account. Results are discussed in light of how social location variables should be considered when making generalizations about sexual desire, and how conceptualizations of desire as multifaceted may provide important insights. PMID- 28070803 TI - Life satisfaction of women of working age shortly after breast cancer surgery. AB - PURPOSE: To explore, among women of working age, satisfaction with life as a whole and with different life domains, and its associations with social and health variables, shortly after breast cancer surgery. METHODS: This cross sectional study included 605 women, aged 20-63 years, who had had breast cancer surgery with no distant metastasis, pre-surgical chemotherapy, or previous breast cancer. Associations between LiSat-11 and demographic and social factors as well as health- and treatment-related variables were analysed by multivariable logistic regression. RESULTS: Compared with Swedish reference levels, the women were, after breast cancer surgery, less satisfied with life, particularly sexual life. Women working shortly after breast cancer surgery were more often satisfied with life in provision domains compared with the reference population. Although most included variables showed associations with satisfaction, after adjustment for all significantly associated variables, only six variables-having children, being in work, having emotional and informational social support, and having good physical and emotional functioning-were positively associated with satisfaction with life as a whole. The odds ratios for satisfaction were higher in most life domains if the woman had social support and good emotional and cognitive functioning. CONCLUSIONS: One month after breast cancer surgery, satisfaction with different life domains was associated primarily with social support and health-related functioning. However, this soon after surgery, treatment-related variables showed no significant associations with life satisfaction. These results are useful for planning interventions to enhance e.g. social support and emotional as well as cognitive functioning. PMID- 28070805 TI - The Journal of the History of Biology at 50. PMID- 28070804 TI - Toward mindfulness in quality-of-life research: perspectives on how to avoid rigor becoming rigidity. AB - BACKGROUND: The field of quality-of-life (QOL) research has matured into a discipline with scientific rigor, sophisticated methods, and guidelines. While this maturation is laudable and needed, it can result in a limiting rigidity. We aim to highlight examples of practices that are based on shared research values and principles that, when dogmatically applied, may limit the potential impact of QOL research. METHODS: By juxtaposing rigorous standards with their rigid application for different stages of the research cycle, we suggest more balanced approaches. RESULTS: Rigidity in cultivating a research question relates to constraining our thinking, leading to 'safe' research focusing on small variations of similar studies. Rigidity in operationalizing key constructs focuses on problems with validation practices that hinder further innovations, the use of static questionnaires when a more flexible approach is needed, dismissing rarely endorsed items that are clinically relevant, use of insensitive generic measures when specific measures are required, and a rigid emphasis on short questionnaires. Rigidity in data analysis relates to an undue emphasis on delineating primary and secondary outcomes and an unquestioned insistence on reducing Type 1 errors regardless of the research context. Rigidity in research infrastructure focuses on the unquestioned validity of patient input on scientific matters, and increasingly rigid guidelines and checklists that end up driving grant applications. DISCUSSION: It is hoped that this overview will lead to a reconsideration of a more flexible application of research principles while retaining scientific rigor. PMID- 28070806 TI - A Health System-wide Moral Distress Consultation Service: Development and Evaluation. AB - Although moral distress is now a well-recognized phenomenon among all of the healthcare professions, few evidence-based strategies have been published to address it. In morally distressing situations, the "presenting problem" may be a particular patient situation, but most often signals a deeper unit- or system centered issue. This article describes one institution's ongoing effort to address moral distress in its providers. We discuss the development and evaluation of the Moral Distress Consultation Service, an interprofessional, unit/system-oriented approach to addressing and ameliorating moral distress. PMID- 28070807 TI - Successful synthesis of active human coagulation factor VII by co-expression of mammalian gamma-glutamyl carboxylase and modification of vit.K cycle in Drosophila Schneider S2 cells. AB - Mammalian gamma-glutamyl carboxylase and reduced vitamin K are indispensable for synthesis of mature mammalian vitamin K dependent proteins including some of blood coagulation factors (factors II, VII, IX, and X). It was well known that Drosophila melanogaster expressed gamma-glutamyl carboxylase and possessed a vit.K cycle although native substrates for them have not been identified yet. Despite the potential capability of gamma carboxylation in D. melanogaster derived cells such as S2 cells, Drosophila gamma-glutamyl carboxylase failed to gamma carboxylate a peptide fused to the human coagulation factor IX propeptide. Thus, it had been believed that the Drosophila system was not adequate to synthesize mammalian vit.K dependent proteins. Indeed, we previously attempted to synthesize biologically active factor VII in S2 cells although we were not able to obtain it. However, recently, a successful transient expression of biologically active human factor IX from S2 cells was reported. In the present study, several expression vectors which enable expressing mammalian GGCX, VKORC1, and/or PDIA2 along with F7 were developed. S2 cells transfected with pMKA85, pMAK86, and pMAK219 successfully synthesized active FVII. Thus, mammalian GGCX was indispensable to synthesize active FVII while mammalian VKORC1 and PDIA2 were not critical but supportive factors for S2 cells. PMID- 28070809 TI - Solution to water resource scarcity: water reclamation and reuse. PMID- 28070808 TI - Combined positive effect of oocyte extracts and brilliant cresyl blue stained recipient cytoplasts on epigenetic reprogramming and gene expression in buffalo nuclear transfer embryos. AB - This study examined the effects of buffalo oocyte extracts (BOE) on donor cells reprogramming and molecular characterisation of oocytes screened via brilliant cresyl blue (BCB) staining and comparison of gene expression profiles of developmentally important genes in blastocysts from IVF and cloned derived from BOE treated donor cells with BCB selected recipient cytoplasts. Relative abundance (RA) of OCT4 and NANOG was increased (P < 0.05) and HDAC-1, DNMT-1, and DNMT-3A decreased (P < 0.05) in extract treated cells (ETCs). This ETCs dedifferentiated into neuron-like lineage under appropriate induction condition. The RA of NASP, EEF1A1, DNMT1, ODC1 and RPS27A was increased (P < 0.05) in BCB+ oocytes, whereas ATP5A1 and S100A10 increased (P < 0.05) in BCB- oocytes. Total cell number and RA of OCT4, NANOG, SOX2, DNMT1, IGF2, IGF2R, MNSOD, GLUT1, BAX and BCL2 in cloned blastocysts derived from BCB+ oocytes with ETC more closely followed that of IVF counterparts compared to BCB+ oocytes with extract untreated cell and BCB- oocytes with ETC derived blastocysts. In conclusion, BOE influenced epigenetic reprogramming of buffalo fibroblasts making them suitable donors for nuclear transfer (NT). BCB staining can be effectively used for selection of developmentally competent oocytes for NT. The combined effects of epigenetic reprogramming of donor nuclei by BOE and higher nuclear reprogramming capacity of BCB+ oocytes improve developmentally important gene expression in cloned blastocysts. Whether these improvements have long-term effects on buffalo calves born following embryo transfer remains unknown. PMID- 28070810 TI - Trace element concentrations in muscle tissue of milk shark, (Rhizoprionodon acutus) from the Persian Gulf. AB - We analyze the heavy metals concentrations in muscle samples of milk shark (Rhizoprionodon acutus) from Persian Gulf. The metals distribution was Zn > Cu > Pb > Cd > Hg. No statistical differences were observed among size or weight by sex (p < 0.05). Metals concentrations in the population de R. acutus from Larak and Lavan islands are homogeneous along the coastal study area. Our study suggest that the results reflect the natural contents of trace metals in this species, and the health risk associated to milk shark consumption in Persian Gulf is relatively low. PMID- 28070811 TI - Encaged Chironomus riparius larvae in assessment of trace metal bioavailability and transfer in a landfill leachate collection pond. AB - Household wastes may constitute a vector of environmental contamination when buried, in particular through degradation and production of leachates containing significant trace metal (TM) concentrations that may constitute a serious risk to biota. The objectives of this study were to assess the bioavailability and transfer potential of various TMs present in water and sediments in a reservoir receiving landfill leachates. An active biomonitoring approach was adopted consisting of exposing naive laboratory organisms in cages deployed in the field. Aquatic insects such as Chironomus riparius larvae are good candidates since they represent key organisms in the trophic functioning of aquatic ecosystems. The results show that water, suspended particles, and sediments were significantly contaminated by various TMs (As, Cd, Cu, Ni, Pb, and Zn). Their contribution to the transfer of TMs depends, however, on the specific element considered, e.g., Cd in sediments or Pb in both suspended particles and sediments. The internal fate of TMs was investigated according to their fractionation between an insoluble and a cytosolic fraction. This approach revealed different detoxification strategies capable of preventing the induction of deleterious effects at the individual scale. However, the accumulation of several TMs in C. riparius larvae tissues may also represent a significant load potentially transferable to higher trophic levels. PMID- 28070812 TI - Plant species diversity reduces N2O but not CH4 emissions from constructed wetlands under high nitrogen levels. AB - Constructed wetlands (CWs) have been widely used for treating wastewater. CWs also are the sources of greenhouse gas (GHG) due to high pollutant load. It has been reported that plant species diversity can enhance nitrogen (N) removal efficiency in CWs for treating wastewater. However, the influence of plant species diversity on GHG emissions from CWs in habitats with high N levels still lack research. This study established four species richness levels (1, 2, 3, 4) and 15 species compositions by using 75 simulated vertical flow CWs microcosms to investigate the effects of plant species diversity on the GHG emissions and N removal efficiency of CWs with a high N level. Results showed plant species richness reduced nitrous oxide (N2O) emission and N (NO3--N, NH4+-N, and TIN) concentrations in wastewater, but had no effect on methane (CH4) emission. Especially, among the 15 compositions of plant species, the four-species mixture emitted the lowest N2O and had under-depletion of N (DminTIN < 0). The presence of Oenanthe javanica had a significantly negative effect on the N2O emission but had no effect on N removal efficiency. The presence of Rumex japonicus significantly reduced the N (NO3--N and TIN) concentrations in wastewater but had no effect on the N2O and CH4 emissions. The N concentrations and GHG emissions in the community of R. japonicus * Phalaris arundinacea were as low as those in the four-species mixture. Assembling plant communities with relatively high species richness (four-species mixture) or particular composition (R. japonicus * P. arundinacea) could enhance the N removal efficiency and reduce the GHG emissions from CWs for treating wastewater with a high N level. PMID- 28070813 TI - Cr(VI) reduction and Cr(III) immobilization by resting cells of Pseudomonas aeruginosa CCTCC AB93066: spectroscopic, microscopic, and mass balance analysis. AB - The aim of this study was to investigate the mechanism of Cr(VI) reduction and Cr(III) immobilization by resting cells of Pseudomonas aeruginosa using batch experiments and analysis techniques. Data showed that resting cells of this strain (3.2 g/L dry weight) reduced 10 mg/L of Cr(VI) by 86% in Tris-HCl buffer solution under optimized conditions of 5 g/L of sodium acetate as an electron donor, pH of 7.0 and temperature of 37 degrees C within 24 h. Cr(VI) was largely converted to nontoxic Cr(III), and both soluble crude cell-free extracts and membrane-associated fractions were responsible for Cr(VI) reduction. While remnant Cr(VI) existed only in the supernatant, the content of resultant Cr(III) in supernatant, on cell surface and inside cells was 2.62, 1.06, and 5.07 mg/L, respectively, which was an indicative of extracellular and intracellular reduction of chromate. Scanning electron microscopy analysis combined with energy dispersive X-ray spectroscopy revealed the adsorption of chromium on the bacterial surface. Interaction between Cr(III) and cell surface functional groups immobilized Cr(III) as indicated by Fourier transform infrared analyses and X-ray photoelectron spectroscopy. Transmission electron microscopy revealed Cr(III) precipitates in bacterial interior suggesting that Cr(II) could also be intracellularly accumulated. Thus, it can be concluded that interior and exterior surfaces of resting P. aeruginosa cells were sites for reduction and immobilization of Cr(VI) and Cr(III), respectively. This is further insight into the underlying mechanisms of microbial chromate reduction. PMID- 28070814 TI - Source identification and spatial distribution of heavy metals in tobacco-growing soils in Shandong province of China with multivariate and geostatistical analysis. AB - Samples of surface soil from tobacco (Nicotiana tabacum L.) fields were analysed for heavy metals and showed the following concentrations (mean of 246 samples, mg/kg): As, 5.10; Cd, 0.11; Cr, 49.49; Cu, 14.72; Hg, 0.08; Ni, 19.28; Pb. 20.20 and Zn, 30.76. The values of the index of geoaccumulation (I geo) and of the enrichment factor indicated modest enrichment with As, Cd, Cr, Hg, Ni or Pb. Principal component analysis and cluster analysis correctly allocated each investigated element to its source, whether anthropogenic or natural. The results were consistent with estimated inputs of heavy metals from fertilizers, irrigation water and atmospheric deposition. The variation in the concentrations of As, Cd, Cu, Pb and Zn in the soil was mainly due to long-term agricultural practises, and that of Cr and Ni was mainly due to the soil parent material, whereas the source of Hg was industrial activity, which ultimately led to atmospheric deposition. Atmospheric deposition was the main exogenous source of heavy metals, and fertilizers also played an important role in the accumulation of these elements in soil. Identifying the sources of heavy metals in agricultural soils can serve as a basis for appropriate action to control and reduce the addition of heavy metals to cultivated soils. PMID- 28070815 TI - Microbial transformation of intracellular dissolved organic matter from Microcystis aeruginosa and its effect on the binding of pyrene under oxic and anoxic conditions. AB - The environmental behaviour and the bioavailability of polycyclic aromatic hydrocarbons (PAHs) are strongly affected by dissolved organic matter (DOM) in aquatic environments. In this study, we investigated the dynamics of the bioavailability and character of the intracellular DOM (IDOM) from Microcystis aeruginosa (M. aeruginosa-IDOM) during 10 days oxic and anoxic incubations by spectroscopy. Subsequently, the binding affinity of pyrene with the initial/altered M. aeruginosa-IDOM was estimated by fluorescence quenching method. The incubation results indicated that changes in dissolved organic carbon (DOC) concentration and selected spectral descriptors of the M. aeruginosa-IDOM under oxic condition were different from those of anoxic condition. The microbial transformation of the M. aeruginosa-IDOM resulted in an enhancement of the organic carbon-normalized binding coefficient (K DOC) of pyrene in both oxic and anoxic treatments. Moreover, only for the oxic condition, Pearson correlation analysis demonstrated that aromaticity (specific UV absorbance at 254 nm, SUVA254), humification degree (humification index, HIX) and the percent distribution of humic-like component 2 (%C2) presented significantly positive correlations with the pyrene K DOC, while the percent distribution of protein like component 1 (%C1) exhibited a negative correlation with the K DOC. However, no significant correlation was observed between any spectral descriptor and the K DOC under anoxic condition. This result suggested that the binding affinity of pyrene may be primarily influenced by the altered M. aeruginosa-IDOM characteristics associated with the biological transformation. Hence, our results provided potential evidence for resolving the inconsistency in the relationships between DOM characteristics and the binding affinities of PAHs. PMID- 28070816 TI - Can oral isotretinoin be safely initiated and monitored in primary care? A case series. AB - BACKGROUND: Oral isotretinoin has traditionally been prescribed only in secondary care for severe or resistant acne. AIMS: To explore whether this drug can be safely initiated and monitored in primary care by a GP with extra training in dermatology. METHOD: One hundred consecutive patients who were started on oral isotretinoin therapy in a primary care centre were retrospectively reviewed. RESULTS: One hundred percent of the patients with acne who completed their course of isotretinoin were cleared at the end of treatment. Twenty-three of the eighty one patients (28%) who were followed-up after a mean of 5 years relapsed and eighteen (22%) had to have at least one more course of isotretinoin. Seventy-four of seventy-seven (96%) patients who had long-term follow-up were satisfied with the level of care they received in primary care. CONCLUSION: This study suggests that oral isotretinoin can be safely initiated and monitored by a GP with a special interest in dermatology and experience in prescribing systemic retinoids. PMID- 28070817 TI - Medicines containing codeine: perspectives of medical professionals in the Republic of Ireland. AB - AIMS: The aim of the study was to examine prescribing professional's perceptions on prescribed and OTC medicines, containing codeine in the Republic of Ireland. A secondary aim was to examine perceptions on codeine dependence, screening and treatment. METHODS: A cross-sectional study of a nationally representative group of prescribing professionals was conducted using a questionnaire containing a number of open and closed ended items. Data were analysed using SPSS version 21 and content analysis techniques. RESULTS: 398 medical professionals participated in the study giving a response rate of 18%. 77% of respondents agreed to routinely review patient prescribed codeine. 59% of respondents routinely asked patients about their use of OTC medicines and 50% documented use of OTC codeine in their patients' medical notes. 93% indicated concern about the potential to purchase codeine from multiple sources. 88% implied that patients did not fully understand the risks of taking OTC medicine containing codeine. Only 21% of respondents were confident in identifying codeine dependence without being informed by the patient and 11.4% agreed to have suitable screening methods in practice. 76% indicated that they would like more instruction on prescribing addictive medicines. CONCLUSION: Policy should examine the need for greater public health awareness on codeine use and should examine the role of OTC and internet sales in the development of dependence. Further consideration should be given to training and support for those who prescribe addictive medicines in practice. PMID- 28070818 TI - Entangling Relation of Micro RNA-let7, miRNA-200 and miRNA-125 with Various Cancers. AB - Involvement of micro RNAs (miRNA) is currently the focus for cancer studies as they effect the post transcriptional expression of different genes. Let-7 family is among the firstly discovered miRNAs that play important role in cell proliferation and dysregulation leading to cell based diseases including cancer. Another family, miRNA-200 prevents transformation of cell to malignant form and tumor formation by interacting with epidermal mesenchymal transition (EMT). Similarly miRNA-125 controls apoptosis and proliferation by affecting multiple genes involved in transcription, immunological defense, resistance against viral and bacterial infections that ultimately leads to cell proliferation, metastasis and finally cancer. All of these micro RNAs are known to be either upregulated or downregulated in various cancers. Current review is focused to elaborate the role of these three families of micro RNAs on different genes that ultimately cause cancer. In conclusion we can say that the miRNAs discussed here are mostly downregulated in various cancers with some exceptions when upregulation of miRNA 125 may be attributed to cancer formation. PMID- 28070819 TI - Inducing Polyclonal Eag1-Specific Antibodies by Vaccination with a Linear Epitope Immunogen and Its Relation to Breast Tumorigenesis. AB - Ether a-go-go 1 (KCNH1, Kv10.1) (Eag1) is a voltage-gated potassium channel, which is commonly overexpressed in tested breast cancer patients. This occurrence makes it a potential molecular marker and a promising tool for breast cancer diagnosis and therapy. In order to explore protective or specific polyclonal antibodies for further research, potential linear epitopes from Eag1 were collected by sequence alignment. The sequence was synthesized and then coupled to the carrier protein keyhole limpet hemocyanin (KLH) for animal immunization. Polyclonal antibodies against Eag1 were produced and purified from the rabbit antisera. Enzyme linked immunosorbent assay (ELISA) and western blot were performed to characterize their specificities. Immunohistochemical staining was carried out on normal and cancerous breast tissue sections using the purified polyclonal Eag1-specific antibodies. The results indicate that the overexpression of Eag1 might be associated with an increased risk of progression to breast cancer (Grade 1 tissue = 57.89%;Grade 2 tissue = 92.59%;Grade 3 tissue = 100%). These results also suggest that Eag1 gene is a putative growth-promoting gene that might be involved in breast tumorigenesis and development. Eag1 might further be represented as a potential target for some human diseases treatment. PMID- 28070820 TI - Development of a new catheter prototype for laser thrombolysis under guidance of optical coherence tomography (OCT): validation of feasibility and efficacy in a preclinical model. AB - In this feasibility study, a novel catheter prototype for laser thrombolysis under the guidance of optical coherence tomography (OCT) was designed and evaluated in a preclinical model. Human arteries and veins were integrated into a physiological flow model and occluded with thrombi made from the Chandler Loop. There were four experimental groups: placebo, 20 mg alteplase, laser, 20 mg alteplase + laser. The extent of thrombolysis was analyzed by weighing, OCT imaging and relative thrombus size. In the alteplase group, thrombus size decreased to 0.250 +/- 0.036 g (p < 0.0001) and 14.495 +/- 0.526 mm2 (p < 0.0001) at 60 min. The relative thrombus size decreased to 73.6 +/- 4.1% at 60 min (p < 0.0001). In the laser group, thrombus size decreased significantly to 0.145 +/- 0.028 g (p < 0.0001) and 11.559 +/- 1.034 mm2 (p < 0.0001). In the alteplase + laser group, thrombus size decreased significantly (0.051 +/- 0.026 g; p < 0.0001; 9.622 +/- 0.582 mm2; p < 0.0001; 47.4 +/- 6.1%; p < 0.0001) in contrast to sole alteplase and laser application. The reproducibility and accuracy of the OCT imaging was high (SD <10%). Histological examination showed no relevant destruction of the vascular layers after laser ablation (arteries: 745.8 +/- 5.5 MUm; p = 0.69; veins: 448.3 +/- 4.5 MUm; p = 0.27). Thus, laser ablation and OCT imaging are feasible with the novel catheter and thrombolysis combining alteplase with laser irradiation appears highly efficient. PMID- 28070821 TI - Evaluation of safety and effectiveness of standardized antifactor Xa-based unfractionated heparin protocols in obese versus non-obese patients. AB - Recent data have suggested that standard unfractionated heparin (UFH) protocols may over-anticoagulate obese patients. The goal of this retrospective study was to observe differences in anticoagulation parameters and safety outcomes for standardized antifactor Xa UFH protocols in obese and non-obese populations. Obese patients (N = 148) were identified over a 20-month period and matched to 148 non-obese patients based on age, gender, and admission date. Patients were included if they were on one of three approved UFH protocols [high (target antifactor Xa 0.3-0.7 IU/mL), moderate (0.3-0.5 IU/mL), or low (0.1-0.2 IU/mL) dose] for >=24 consecutive hours and had >=1 antifactor Xa level drawn during the infusion. Groups were compared for doses at first and second consecutive therapeutic antifactor Xa level, major bleeding, and in-hospital mortality. Obese patients required a significantly lower mean weight-based infusion rate to attain first therapeutic antifactor Xa level compared to non-obese patients in both the high dose (19.45 vs. 15.29 units/kg/h, p < 0.001) and the moderate dose populations (15.0 vs. 12.94 units/kg/h, p = 0.003). Similarly, patients in both the high and moderate dose populations had significant differences in mean infusion rates to attain second consecutive therapeutic antifactor Xa levels. There was no difference between infusion rates for the primary outcomes in the low dose population. There was no difference between groups in major bleeding or mortality outcomes. Similar to data using UFH protocols based on activated partial thromboplastin time, obese patients require lower weight-based UFH doses to attain therapeutic anticoagulation. Institutions using or changing to antifactor Xa based protocols may need to modify protocols for obese patients. PMID- 28070822 TI - "Our Doors Are Open to Everybody": Public Libraries as Common Ground for Public Health. PMID- 28070823 TI - Relationship between postoperative complications and fibular integrity in congenital pseudarthrosis of the tibia in children. AB - BACKGROUND: This study aimed to investigate the relationship between postoperative complications and fibular integrity in congenital pseudarthrosis of the tibia (CPT) in children. METHODS: A retrospective study was performed in 59 patients with Crawford type IV CPT who were treated with combined surgical technique from 2007 to 2011. The patients were divided into two groups, the CPT with fibular pseudarthrosis (group A) and CPT with intact fibula groups (group B), on the basis of fibula status after the union of CPT. The incidence rates of refracture, ankle valgus, tibial valgus, and limb length discrepancy in the two groups were investigated. RESULTS: In group A, 14 (36.8%) cases had refracture, 30 (78.9%) had ankle valgus; 27 (71%) exhibited tibial valgus with an average tibial valgus of 7 degrees (6 degrees -20 degrees ), and 24 (63.2%) had limb length discrepancy with an average limb length of 1.26 cm (0.6-4.4 cm). In group B, 2 (9.5%) cases had refracture, 11 (52.4%) had ankle valgus, 8 (42.9%) had tibial valgus with an average tibial valgus deformity of 2.9 degrees (6 degrees 13 degrees ), and 13 (61.9%) had limb length discrepancy with an average limb length of 1.48 cm (0.5-5 cm). Significant difference in refracture and ankle valgus was found between groups A and B (P<0.05). CONCLUSIONS: After the union of CPT, patients with fibular pseudarthrosis showed higher incidence of refracture and ankle valgus than those with intact fibula. Attention should be paid to the presence of fibular pseudarthrosis when managing CPT. PMID- 28070824 TI - Tolerability of an Immunologically Enhanced Subcutaneous Immunotherapy Preparation in Patients Treated with Concomitant Allergy Immunotherapy: A Non Interventional Observational Study. AB - BACKGROUND: For causal treatment by allergy immunotherapy (AIT) a single or few allergen products for the clinically most relevant allergens are applied to treat multiple allergies, but few data on the tolerability of multiple AIT applications are available. OBJECTIVE: The aim of our study was to investigate safety and tolerability in patients treated by subcutaneous immunotherapy (SCIT) and concomitant SCIT or sublingual immunotherapy (SLIT) products. METHODS: In a non interventional, observational study in Germany treatment of patients with a primary SCIT and concomitant AIT (SCIT or SLIT) was documented during the first 4 months of treatment. Adverse events (AEs) were recorded by the physicians and by patients in diaries, and coded using the Medical Dictionary for Regulatory Activities (MedDRA). RESULTS: Three hundred and seven patients were treated with the primary SCIT by 79 allergists, and 271 received a concomitant AIT. AEs were reported in 92 (33.9%) patients and adverse drug reactions (ADRs) in 63 (23.2%) patients related to the primary SCIT and in 69 (25.5%) to the concomitant AIT; six (2.2%) patients discontinued due to ADRs. ADRs were mild or moderate in 40 (14.8%) patients, severe in 23 (8.5%), and serious in one patient. The most frequent reactions were local swelling and pruritus. Overall tolerability was assessed as 'good' or 'very good' by 95.6% of patients and 96.7% of physicians. CONCLUSIONS: Compared with data from a large previous study no increase in the frequency of ADRs in real life or change in the tolerability profile was observed for SCIT with concomitant SCIT or SLIT. PMID- 28070825 TI - Prevalence and Predictors of Giardia in the United States. AB - BACKGROUND: Infection with Giardia lamblia is a common cause of diarrheal disease in the developing and industrialized world. AIMS: We aimed to assess the prevalence of giardiasis in the United States (US) among patients with duodenal biopsies, investigating demographic and clinical factors associated with this condition. METHODS: We conducted a cross-sectional study of patients with duodenal biopsies submitted to a national pathology laboratory between January 2, 2008, and December 31, 2015. The prevalence of giardiasis was calculated and categorized by the following patient sociodemographic and clinical data: age, sex, ethnicity, endoscopy indication, season, year, urban-rural setting, region, and presence of H. pylori and atrophic gastritis. RESULTS: Among all patients (n = 432,813), the mean age was 52.2 years. The prevalence of giardiasis was 0.11%. Patients with giardiasis were more likely to be male (57.8 vs. 34.1%, p < 0.0001). Among patients who had a gastric biopsy (n = 363,788), those with giardiasis were more likely to be colonized with H. pylori (25.7 vs. 9.4%, p < 0.0001). There was no statistically significant association with age, endoscopy indication, urban-rural setting, ethnicity, season, or the presence of atrophic gastritis. On multivariate analysis, male sex, Southern region, and the presence of H. pylori were independently associated with giardiasis. CONCLUSIONS: To our knowledge, this is the largest study to date to assess predictors of giardiasis in the US. We found that male sex, being colonized with H. pylori, and residing in the Southern US are independently associated with giardiasis infection. PMID- 28070826 TI - Interaction of Ethnicity and H. pylori Infection in the Occurrence of Microscopic Colitis. AB - BACKGROUND: Previous studies found that microscopic colitis is inversely associated with Helicobacter pylori infection and that microscopic colitis is characterized by a marked ethnic variation. AIM: The aim of the present study was to test whether an underlying ethnic variation of H. pylori infection is responsible for the ethnic variation of microscopic colitis. METHODS: The Miraca Life Sciences Database is a large national electronic repository of histopathologic records of patients distributed throughout the entire USA. A cross-sectional study evaluated the influence of age, gender, ethnicity, and histologic diagnosis of H. pylori on the occurrence of microscopic colitis among subjects who underwent esophago-gastro-duodenoscopies plus colonoscopy. RESULTS: The total study population comprised 228,506 subjects, of whom 28,890 carried a diagnosis of H. pylori gastritis and 3460 microscopic colitis. Female sex, old age, and H. pylori infection exerted the strongest influence on the occurrence of microscopic colitis. In comparison with the population comprising Caucasians and African-Americans, microscopic colitis was less common among subjects of Hispanic (0.34, 0.27-0.47), East Asian (0.13, 0.06-0.22), Indian (0.31, 0.10-0.73), or Middle Eastern descent (0.28, 0.07-0.74). All these ethnic subgroups were also characterized by a higher prevalence of H. pylori than the comparison group. A low prevalence of H. pylori was significantly associated with a high prevalence of microscopic colitis (R 2 = 0.91, p < 0.001). CONCLUSION: Ethnic variations in the gastric infection with H. pylori may be partly responsible for the observed ethnic distribution of microscopic colitis. PMID- 28070827 TI - Glutamic acid promotes monacolin K production and monacolin K biosynthetic gene cluster expression in Monascus. AB - This study investigated the effects of glutamic acid on production of monacolin K and expression of the monacolin K biosynthetic gene cluster. When Monascus M1 was grown in glutamic medium instead of in the original medium, monacolin K production increased from 48.4 to 215.4 mg l-1, monacolin K production increased by 3.5 times. Glutamic acid enhanced monacolin K production by upregulating the expression of mokB-mokI; on day 8, the expression level of mokA tended to decrease by Reverse Transcription-polymerase Chain Reaction. Our findings demonstrated that mokA was not a key gene responsible for the quantity of monacolin K production in the presence of glutamic acid. Observation of Monascus mycelium morphology using Scanning Electron Microscope showed glutamic acid significantly increased the content of Monascus mycelium, altered the permeability of Monascus mycelium, enhanced secretion of monacolin K from the cell, and reduced the monacolin K content in Monascus mycelium, thereby enhancing monacolin K production. PMID- 28070828 TI - Hypofractionated stereotactic radiosurgery for pituitary metastases. AB - Pituitary metastases (PMs) are uncommon, representing only 1% of pituitary lesions. The diagnosis of PMs can be challenging and an optimal management remains to be determined. Here, we present a pilot clinical study on the efficacy and safety of hypofractionated stereotactic radiosurgery (SRS) with an optimized dosimetric plan in treating PMs. Between June 2013 and December 2014, seven consecutive patients (4 men and 3 women; median age 62 years) had been diagnosed with PMs based on their characteristic clinical and radiological features and subsequently treated using hypofractionated SRS. Primary cancers originated from the lung (n = 5) or the breast (n = 2). All patients presented with diabetes insipidus (DI). Anterior pituitary and visual dysfunction were combined in 4 and 3 patients, respectively. On magnetic resonance imaging (MRI), PMs involved the pituitary stalk and/or the posterior lobe in all patients. SRS of a cumulative marginal dose 31 Gy with dose-volume constraints for the optic apparatus was delivered in 5 daily fractions. As results, tumor was locally controlled in all patients with substantial responses on MRI (including complete remission in 4 patients). The median survival time was 14 months (range, 6-24 months) after SRS. DI and visual dysfunction improved in all patients, although anterior pituitary dysfunction did not recover. No patients experienced any deterioration in visual, pituitary, or other cranial nerve functions. These results suggest a promising role of hypofractionated SRS in treating PMs in terms of both tumor control and functional outcomes. PMID- 28070829 TI - Functional analysis of KIF20A, a potential immunotherapeutic target for glioma. AB - Kinesin family member 20A (KIF20A), an ideal cancer-testis antigen, was reported to be a promising immunotherapeutic target for pancreatic cancers. Clinical trials of KIF20A peptide vaccine immunotherapy have been conducted against pancreatic cancers. To demonstrate the efficacy of KIF20A as a candidate molecular target for gliomas, we analyzed the expression and function of KIF20A in gliomas. Western blot and quantitative PCR analyses showed that KIF20A expression in glioma cell lines and glioma tissues was high compared with that found in a normal brain. KIF20A immunostaining of glioma cells and glioma tissues demonstrated that KIF20A was involved in spindle formation and cytokinesis, and that KIF20A was highly expressed, especially in glioma cells undergoing mitosis. In silico analysis of a cancer microarray database revealed that KIF20A was highly expressed in gliomas depending on the pathological grade, and glioma patients with higher expression of KIF20A showed poorer prognosis. Down regulating KIF20A reduced cell proliferation in glioma cells due to the failure of cytokinesis and generation of binucleated cells. Additionally, KIF20A inhibition induced significant apoptosis in SF126 glioma cells. Taken together, KIF20A is a tumor-associated antigen involved in the glioma cell growth and cell survival, suggesting that KIF20A is an oncoantigen of gliomas. Thus, KIF20A is a candidate novel immunotherapeutic target for gliomas. PMID- 28070830 TI - Mesenchymal subtype of glioblastomas with high DNA-PKcs expression is associated with better response to radiotherapy and temozolomide. AB - A better understanding of the relationship between glioblastomas molecular subtypes and radio-chemotherapy is needed for the development of individualized strategies. In this study, we aimed to assess whether non-homologous end-joining (NHEJ) protein expression is associated and could predict responses to treatment of mesenchymal (MES) and proneural (PN) subtypes. Tumors from 122 patients with a glioblastoma treated at the University Hospital of Poitiers between 2002-2013 by an association of radiotherapy and temozolomide were collected. Among these tumors, 80 were suitable for in situ analysis and were included in TissueMicroArray. The expression of DNA-PKcs, Ku70, Ku80 and CD44, Olig2 (respectively surrogate markers of MES and PN subtypes) were evaluated by immunohistochemistry. The median survival of patients with high and low CD44 expression was 11.9 months (95% CI 7.7-14) and 19.1 months (95% CI 15.2-22.4) respectively (p = 0.008). Median survival of patients with high and low DNA-PKcs levels was 20.0 months (95% CI 15.2-25.3) and 12.9 months (95% CI 9.9-19.5) respectively (p = 0.036). High levels of Olig2, Ku70 and Ku80 tended to be associated with better overall survival but no significant differences were found. Overall survival of class I patients (CD44+ and DNA-PKcs+) was longer than class II (CD44+ and DNA-PKcs- or CD44- and DNA-PKcs+) and class III (CD44- and DNA-PKcs-), (p = 0.005 and 0.003 respectively). High levels of CD44 and DNA-PK are associated with a better survival and better response to radiotherapy and temozolomide and could establish prognosis classes by predicting survival and response to therapy for GBMs patients. PMID- 28070831 TI - The prolyl oligopeptidase inhibitor SUAM-14746 attenuates the proliferation of human breast cancer cell lines in vitro. AB - BACKGROUND: Prolyl oligopeptidase (POP, EC 3.4.1.26) is a serine peptidase that hydrolyzes post-proline peptide bonds in peptides that are <30 amino acids in length. We previously reported that POP inhibition suppressed the growth of NB-1 human neuroblastomas cells and KATO III human gastric cancer cells. POP activity is commonly elevated in many cancers, which includes breast cancer. However, the effect of POP inhibition as a candidate breast cancer therapy is unknown. METHODS: The effects of POP inhibition and knockdown on the proliferation of cultured human estrogen receptor-positive (ER+) MCF7 and T47D, and ER-negative (ER-) MDA-MB-231 breast cancer cell lines and the MCF12A non-tumorigenic epithelial cell line were tested by analyzing their influence on cell proliferation (WST-1 assay), cell viability (trypan blue exclusion assay), and cell cycle arrest (cell cycle analysis, cell cycle regulator proteins expression). RESULTS: POP-specific inhibitors 3-({4-[2-(E) styrylphenoxy]butanoyl}-L-4-hydroxyprolyl)-thiazolidine (SUAM-14746) and benzyloxycarbonyl-thiopropyl-thioprolinal and RNAi-mediated POP knockdown inhibited the proliferation of MCF7 cells without inducing cell death. SUAM-14746 induced growth inhibition was also observed in T47D and MDA-MB-231 cells, but not in MCF12A cells. This growth inhibition was associated with G1 phase arrest; reduced cyclin D1 and D3, cyclin-dependent kinase 4 (CDK4), E2F1, and retinoblastoma protein (pRb) expression; and increased cyclin-dependent kinase inhibitor 1B (p27kip1) expression. Moreover, the SUAM-14746-mediated cell cycle arrest of MCF7 cells was associated with increased pRb2/p130 protein expression and an increase in the number of cells in the quiescent G0 state, as defined by low RNA levels. CONCLUSIONS: SUAM-14746 inhibited breast cancer cell growth in a cytostatic manner without inducing lethality, and POP-specific inhibitors may be an effective treatment against ER+ and ER- breast cancer. PMID- 28070832 TI - Objection to postoperative radiation therapy in breast cancer with one to three lymph nodes involvements. AB - My arguments regarding postmastectomy radiotherapy (PMRT) for this case are based on the following 4 reasons: (1) high rate of local recurrence in the no PMRT group in the Early Breast Cancer Trialists' Collaborative Group meta-analysis on which the present guideline is based, (2) stage migration by sentinel node biopsy, (3) possible adverse events of radiotherapy, and (4) problems on extrapolation of data from western countries. PMID- 28070833 TI - Assessing the accuracy of algorithm-derived cardiorespiratory fitness in surgical patients: a prospective cohort study. AB - PURPOSE: To determine if a non-exercise algorithm-derived assessment of cardiorespiratory fitness (CRFA) accurately predicted estimated values obtained using a six-minute walk test (CRF6MWD) and the Duke Activity Status Index (CRFDASI). METHODS: Following research ethics board approval, an observational cohort study was conducted in selected, consenting patients undergoing elective surgery. Participants completed questionnaires assessing their self-reported exercise capacity. Their height, weight, waist circumference, and vital signs were measured. A six-minute walk test was performed twice with a 45-min rest interval between tests. The correlation between CRFA and both CRF6MWD and CRFDASI was determined. RESULTS: Two hundred forty-two participants were included. Mean age was 62 (range 45-88 yr); 150 (62%) were male, 87 (36%) self-reported walking or jogging > 16 km per week, and 49 (20%) were current smokers. The CRFA and CRF6MWD were highly correlated (Pearson r = 0.878; P < 0.001). CRFA and CRFDASI were less strongly correlated (Pearson r = 0.252; P < 0.001). Among patients capable of walking > 427 m in the six-minute walk test, CRFA, CRF6MWD, and CRFDASI were equivalent. CONCLUSION: A non-exercise algorithm can estimate cardiorespiratory fitness in patients presenting for elective surgery. The variables required to compute CRFA can be obtained in a clinic setting without the need to engage in formal exercise testing. Further evaluation of CRFA as a predictor of long-term outcome in patients is warranted. PMID- 28070835 TI - Erratum to: Natural Minerals Coated by Biopolymer Chitosan: Synthesis, Physicochemical, and Adsorption Properties. PMID- 28070834 TI - Resveratrol modulates GSH system in C6 astroglial cells through heme oxygenase 1 pathway. AB - Resveratrol is a dietary polyphenol that displays neuroprotective properties in several in vivo and in vitro experimental models, by modulating oxidative and inflammatory responses. Glutathione (GSH) is a key antioxidant in the central nervous system (CNS) that modulates several cellular processes, and its depletion is associated with oxidative stress and inflammation. Therefore, this study sought to investigate the protective effects of resveratrol against GSH depletion pharmacologically induced by buthionine sulfoximine (BSO) in C6 astroglial cells, as well as its underlying cellular mechanisms. BSO exposure resulted in several detrimental effects, decreasing glutamate-cysteine ligase (GCL) activity, cystine uptake, GSH intracellular content and the activities of the antioxidant enzymes glutathione peroxidase (GPx) and glutathione reductase (GR). Moreover, BSO increased reactive oxygen/nitrogen species (ROS/RNS) levels and pro-inflammatory cytokine release. Resveratrol prevented these effects by protecting astroglial cells against BSO-induced cytotoxicity, by modulating oxidative and inflammatory responses. Additionally, we observed that pharmacological inhibition of heme oxygenase 1 (HO-1), an essential cellular defense against oxidative and inflammatory injuries, abolished all the protective effects of resveratrol. These observations suggest HO-1 pathway as a cellular effector in the mechanism by which resveratrol protects astroglial cells against GSH depletion, a condition that may be associated to neurodegenerative diseases. PMID- 28070836 TI - Solvent: A Key in Digestive Ripening for Monodisperse Au Nanoparticles. AB - This work has mainly investigated the influence of the solvent on the nanoparticles distribution in digestive ripening. The experiments suggested that the solvents played a key role in digestive ripening of Au nanoparticles (Au NPs). For the benzol solvents, the resulting size distribution of Au NPs was inversely related to the solvent polarity. It may be interpreted by the low Gibbs free energy of nanoparticles in the high polarity medium, which was supposedly in favor of reducing the nanoparticles distribution. Through digestive ripening in the highly polar benzol solvent of p-chlorotoluene, monodisperse Au NPs with relative standard deviation (RSD) of 4.8% were achieved. This indicated that digestive ripening was an effective and practical way to prepare high-quality nanoparticles, which holds great promise for the nanoscience and nanotechnology. Graphical Abstract The polarity of benzol solvent plays significant role in obtaining high-quality monodisperse Au nanoparticles. PMID- 28070837 TI - Optoelectronic Evaluation and Loss Analysis of PEDOT:PSS/Si Hybrid Heterojunction Solar Cells. AB - The organic/silicon (Si) hybrid heterojunction solar cells (HHSCs) have attracted considerable attention due to their potential advantages in high efficiency and low cost. However, as a newly arisen photovoltaic device, its current efficiency is still much worse than commercially available Si solar cells. Therefore, a comprehensive and systematical optoelectronic evaluation and loss analysis on this HHSC is therefore highly necessary to fully explore its efficiency potential. Here, a thoroughly optoelectronic simulation is provided on a typical planar polymer poly (3,4-ethylenedioxy thiophene):polystyrenesulfonate (PEDOT:PSS)/Si HHSC. The calculated spectra of reflection and external quantum efficiency (EQE) match well with the experimental results in a full-wavelength range. The losses in current density, which are contributed by both optical losses (i.e., reflection, electrode shield, and parasitic absorption) and electrical recombination (i.e., the bulk and surface recombination), are predicted via carefully addressing the electromagnetic and carrier-transport processes. In addition, the effects of Si doping concentrations and rear surface recombination velocities on the device performance are fully investigated. The results drawn in this study are beneficial to the guidance of designing high performance PEDOT:PSS/Si HHSCs. PMID- 28070838 TI - Late toxicity, evolving radiotherapy techniques, and quality of life in nasopharyngeal carcinoma. AB - PURPOSE: To analyze quality of life (QoL) and functional state (FS) by patient reported outcome (PRO) questionnaires (FACT-G, FACT-NP, PSS-HN, XeQOLS, and EQ-5D 3L) in long-term survivors nasopharyngeal carcinoma (NPC) treated with conventional radiotherapy (RT) and intensity modulated radiotherapy (IMRT). METHODS: 25 patients answered to five questionnaires about QoL and FS. All patients were assessed also for late toxicity. RESULTS: Functional Assessment of Cancer Therapy-General (FACT-G) and Performance Status Scale Head and Neck (PSS HN) scores were significantly elevated (better QoL) in age <50 years (p = 0.03). PSS-HN score was higher in IMRT group. The observed xerostomia was lower in the IMRT group and in patients who received conventional RT had worse QoL according to XeQOLS (University of Michigan Xerostomia-Related Quality of Life Scale) score questionnaire. Lower PSS-HN score and higher XeQOLS score were significantly related with the late xerostomia (p = 0.009 and 0.002, respectively). CONCLUSIONS: Our preliminary data suggest that age, older techniques, xerostomia, and hearing loss are negative predictors of QoL. PMID- 28070839 TI - 1H- and 31P-myocardial magnetic resonance spectroscopy in non-obstructive hypertrophic cardiomyopathy patients and competitive athletes. AB - PURPOSE: The clinical differentiation between athlete's heart and mild forms of non-obstructive hypertrophic cardiomyopathy (HCM) is crucial. We hypothesized that differences do exist between the myocardial metabolism of patients with non obstructive HCM and competitive athletes (CAs). Our aim was to evaluate myocardial metabolism with 31P-MRS and 1H-MRS in HCM patients and CAs. MATERIALS AND METHODS: After Ethics Committee approval, 15 CAs and 7 HCM patients were prospectively enrolled. They underwent a 1.5-T cardiac MR including electrocardiographically triggered cine images, single-voxel 1H-MRS and multivoxel 31P-MRS. 1H-MRS was performed after imaging using standard coil with the patient in the supine position; thereafter, 31P-MRS was performed using a dedicated coil, in the prone position. Data were reported as median and interquartile range. Mann-Whitney U test was used. RESULTS: In CAs, left ventricular mass index was 72 (66-83) g/m2, septal thickness 10 (10-11) mm, end diastolic volume index 95 (85-102) ml/m2, end systolic volume index 30 (28-32) ml/m2 and ejection fraction 68% (65-69%); in HCM patients, 81 (76-111) g/m2 (P = 0.052), 18 (15-21) mm (P = 0.003), 73 (58-76) ml/m2 (P = 0.029), 20 (16-34) ml/m2 (P = 0.274) and 68% (55-73%) (P = 1.000), respectively. At 1H-MRS, total lipids were 35 (0-183) arbitrary units (au) for CA and 763 (155-1994) au for HCM patients (P = 0.046). At 31P-MRS, PCr/gammaATP was 5 (4-6) au for CA and 4 (2-5) au for HCM patients (P = 0.230). Examination time was 20 min for imaging only, 5 min for 1H-MRS and 15 min for 31P-MRS. CONCLUSIONS: We observed a significant increase of myocardial lipids, but a preserved PCr/gammaATP ratio in the metabolism of HCM patients compared with competitive CAs. PMID- 28070840 TI - Clinical and magnetic resonance evolution of "infarct-like" myocarditis. AB - AIMS: To analyse the clinical and magnetic resonance evolution of myocarditis in patients with an "infarct-like" presentation pattern. METHODS: The study is a retrospective analysis of 52 patients with clinical diagnosis of "infarct-like" myocarditis confirmed by CMR as acute myocarditis according to Lake Louise criteria and 6 months follow-up. The CMR protocol included T2-weighted (oedema), early (hyperaemia) and late (fibrosis/necrosis) gadolinium enhancement sequences, according to Lake Louise criteria. Clinical and radiological follow-up by CMR was performed after a median time interval of 6 months (interquartile range 5-8). Quantitative outcomes were checked for normality and compared with the non parametric Wilcoxon's test for matched data. RESULTS: At the clinical follow-up all patients were free of symptoms and reported no cardiac complications. The CMR follow-up evidenced a significant increase of the ejection fraction (from 53 +/- 6 to 55 +/- 4%, p = 0.03), a decrease of the ventricular mass [from 67.0 (58.8 79.0) to 61.0 (54.0-67.0), p < 0.0001] without significant modification of the cardiac volume index (p = 0.26). No patient had residual oedema or capillary leakage: the T2 ratio decreased from 3.94 (3.00-4.86) to 0.98 (0.75-1.17) with p < 0.0001 and the Early gadolinium enhancement (EGE) ratio from 5.7 (4.8-6.5) to 2.9 (2.4-3.2) with p < 0.0001. Late gadolinium enhancement (LGE) persisted over the course of the follow-up in 48/52 patients, but with a significant reduction in every patient (LGE % from 34.3 +/- 9.1 to 19.4 +/- 6.6%; p < 0.0001). CONCLUSION: Patients diagnosed with "infarct-like" myocarditis, according to both clinical and CMR examinations may look forward to a positive evolution with a good prognosis. PMID- 28070842 TI - Diagnostic imaging and spending review: extreme problems call for extreme measures. AB - The number of diagnostic imaging tests has increased dramatically over the past decade and about 5 billion diagnostic examinations are performed worldwide each year. According to Health Ministry, Italy, is in second place for the number of CT and MR tests per thousand inhabitants in 2014 with a score of 83.3 (only Germany has a higher score, 95.2) that is a long way off from the European average of 46.5. It has also the highest ratio of magnetic resonances per person with 24,6 machines per million inhabitants, followed only by Greece and Finland. The development of the New Health Information System (NSIS) in 2010 made uniformly readable the non-homogeneous clinical data from all the different Italian regions and permitted a detailed analysis of all diagnostic imaging within the public outpatient care setting in Italy in 2012. Despite that MRI examinations represented only the 10% of the total number of imaging tests performed, their cost reached 30% of the health-care expenditure for outpatient diagnostic imaging with an overwhelming contribution coming from musculoskeletal MR which accounted for the 73% of the performed MR tests. It is reasonable to assume that these phenomena are likely due to a lack of appropriateness in MR requests that is difficult to analyze due to an absence or invalid query on the prescriptions which together accounted for the 98.7% of cases. Taking into account the above-mentioned situation, this is possibly why the Ministry of Health decided to perform "linear cuts" in expenditure for some diagnostic examinations. PMID- 28070841 TI - Reproducibility of dynamic contrast-enhanced MRI and dynamic susceptibility contrast MRI in the study of brain gliomas: a comparison of data obtained using different commercial software. AB - PURPOSE: Dynamic susceptibility contrast MRI (DSC) and dynamic contrast-enhanced MRI (DCE) are useful tools in the diagnosis and follow-up of brain gliomas; nevertheless, both techniques leave the open issue of data reproducibility. We evaluated the reproducibility of data obtained using two different commercial software for perfusion maps calculation and analysis, as one of the potential sources of variability can be the software itself. METHODS: DSC and DCE analyses from 20 patients with gliomas were tested for both the intrasoftware (as intraobserver and interobserver reproducibility) and the intersoftware reproducibility, as well as the impact of different postprocessing choices [vascular input function (VIF) selection and deconvolution algorithms] on the quantification of perfusion biomarkers plasma volume (Vp), volume transfer constant (K trans) and rCBV. Data reproducibility was evaluated with the intraclass correlation coefficient (ICC) and Bland-Altman analysis. RESULTS: For all the biomarkers, the intra- and interobserver reproducibility resulted in almost perfect agreement in each software, whereas for the intersoftware reproducibility the value ranged from 0.311 to 0.577, suggesting fair to moderate agreement; Bland-Altman analysis showed high dispersion of data, thus confirming these findings. Comparisons of different VIF estimation methods for DCE biomarkers resulted in ICC of 0.636 for K trans and 0.662 for Vp; comparison of two deconvolution algorithms in DSC resulted in an ICC of 0.999. CONCLUSIONS: The use of single software ensures very good intraobserver and interobservers reproducibility. Caution should be taken when comparing data obtained using different software or different postprocessing within the same software, as reproducibility is not guaranteed anymore. PMID- 28070843 TI - Noise-optimized monoenergetic post-processing improves visualization of incidental pulmonary embolism in cancer patients undergoing single-pass dual energy computed tomography. AB - PURPOSE: To evaluate noise-optimized monoenergetic postprocessing of dual-energy CT (DE-CT) on image quality in patients with incidental pulmonary embolism in single-pass portal-venous phase CT (CTpv). MATERIALS AND METHODS: 20 Consecutive patients with incidental pulmonary embolism in contrast-enhanced oncological follow-up DE-CTpv examination were included in this study. Images were acquired with a 3rd generation DE-CT system in DE mode (100/Sn150 kV) and activated tube current modulation 90 s after contrast agent administration. Subsequently, virtual monoenergetic images (MEI+) were reconstructed at five different keV levels (40, 55, 70, 85, 100) and compared to the standard linearly blended (M_0.8) CTpv images. Image quality was assessed qualitatively (vascular contrast and detectability of embolism, image noise, iodine influx artifact; two independent readers; 5-point Likert scale; 5 = excellent) and quantitatively by calculating signal-to-noise (SNR) and contrast-to-noise ratios (CNR). RESULTS: Highest vessel contrast and highest detectability of embolism were observed in MEI+ at 40 keV (4.7 +/- 0.4) and 55 keV (4.2 +/- 0.6) with significant differences as compared to CTpv (3.6 +/- 0.5) and high keV reconstructions (70, 85, 100; p <= 0.01). Image noise significantly increased at 40 keV MEI+ compared to all other MEI+ reconstructions and CTpv (p < 0.001). SNR and CNR calculations were highest at 40 keV MEI+ followed by 55 keV and CTpv with significant differences to high keV MEI+ (85-100). CONCLUSIONS: Computed MEI+ at low keV levels allow for improved vessel contrast and visualisation of incidental pulmonary embolism in patients with portal-venous phase CT scans by substantially increasing CNR and SNR. PMID- 28070844 TI - Gd-EOB-DTPA-enhanced MRI T1 mapping for assessment of liver function in rabbit fibrosis model: comparison of hepatobiliary phase images obtained at 10 and 20 min. AB - OBJECTIVES: To compare hepatobiliary phase (HBP) images obtained at 10 and 20 min after Gd-EOB-DTPA-enhanced MRI for assessment of liver function in rabbit fibrosis model on 3.0 T MR imaging. METHODS: 34 animals were separated into three groups: 5 for a control group, 14 for a mild fibrosis group, and 15 for a severe fibrosis group based on pathological proof. T1 relaxation times (T1rt) were measured on T1 mapping and reduction rates of T1rt (rrT1rt) were calculated. HBP images were obtained at 10 and 20 min after Gd-EOB-DTPA enhancement. Indocyanine green retention rates at 15 min (ICG R15) were performed for all animals. RESULTS: T1rt on pre-enhancement imaging showed no significant difference (p > 0.05) among all groups. T1rt on 10 min HBP and 20 min HBP showed significant difference (p < 0.05) among all groups. T1rt and rrT1rt in three groups showed no significant difference (p > 0.05) between 10 min HBP and 20 min HBP. T1rt on both 10 and 20 min HBP showed significant correlation with ICG R15 (p < 0.05); rrT1rt on both 10 min HBP and 20 min HBP showed significant inverse correlation with ICG R15 (p < 0.05). CONCLUSIONS: Comparing 10 min HBP and 20 min HBP T1 mapping after Gd-EOB-DTPA enhancement, our results suggest that 10 min HBP T1 mapping is feasible for quantitatively assessing liver function. PMID- 28070845 TI - Changes in the roles of transrectal ultrasonography for the diagnosis of prostate cancer. PMID- 28070846 TI - Development of a Convenient In Vitro Gel Diffusion Model for Predicting the In Vivo Performance of Subcutaneous Parenteral Formulations of Large and Small Molecules. AB - Parenteral delivery remains a compelling drug delivery route for both large- and small-molecule drugs and can bypass issues encountered with oral absorption. For injectable drug products, there is a strong patient preference for subcutaneous administration due to its convenience over intravenous infusion. However, in subcutaneous injection, in contrast to intravenous administration, the formulation is in contact with an extracellular matrix environment that behaves more like a gel than a fluid. This can impact the expected performance of a formulation. Since typical bulk fluid dissolution studies do not accurately simulate the subcutaneous environment, improved in vitro models to help better predict the behavior of the formulation are critical. Herein, we detail the development of a new model system consisting of a more physiologically relevant gel phase to simulate the rate of drug release and diffusion from a subcutaneous injection site using agarose hydrogels as a tissue mimic. This is coupled with continuous real-time data collection to accurately monitor drug diffusion. We show how this in vitro model can be used as an in vivo performance differentiator for different formulations of both large and small molecules. Thus, this model system can be used to improve optimization and understanding of new parenteral drug formulations in a rapid and convenient manner. PMID- 28070847 TI - Role of Water Sorption in Tablet Crushing Strength, Disintegration, and Dissolution. AB - Drugs formulated as tablets are subjected to accelerated stability conditions with the goal of identifying a stable formulation that will exhibit a sufficiently long shelf life. Water sorption at a condition such as 40 degrees C/75% RH can result in significant changes in tablet properties such as a decrease in dissolution rate, the cause of which may be difficult to interpret, given the complex nature of ingredients and their interactions in a tablet. In this research, three drugs, displaying a wide range of physicochemical properties, were formulated with commonly used diluents, disintegrants, and binders, using a design of experiments approach. The tablets were stored at accelerated conditions and assessed for content, dissolution, disintegration, and crushing strength, as well as other properties. The research demonstrated many water-induced effects in tablet properties. Due to the experimental design approach that revealed many interactions, it was possible to interpret all of the changes observed in tablet crushing strength, disintegration, and dissolution for the drugs using a common set of physical principles. Specifically, the relevant factors considered were (1) mechanical properties of materials, (2) water sorption surface effects in surface diffusion and capillary condensation, (3) water sorption bulk effects for amorphous materials such as viscous flow/spreading, and (4) water-induced stress on interparticle bonding arising from volume expansion. These physical principles enable a comprehensive interpretation of the complex changes observed in tablet properties, which should be valuable in the design of tablet formulations that will be stable to accelerated storage conditions. PMID- 28070849 TI - Investigation into the Manufacture and Properties of Inhalable High-Dose Dry Powders Produced by Comilling API and Lactose with Magnesium Stearate. AB - The aim of the study was to understand the impact of different concentrations of the additive material, magnesium stearate (MGST), and the active pharmaceutical ingredient (API), respectively, on the physicochemical properties and aerosol performance of comilled formulations for high-dose delivery. Initially, blends of API/lactose with different concentrations of MGST (1-7.5% w/w) were prepared and comilled by the jet-mill apparatus. The optimal concentration of MGST in comilled formulations was investigated, specifically for agglomerate structure and strength, particle size, uniformity of content, surface coverage, and aerosol performance. Secondly, comilled formulations with different API (1-40% w/w) concentrations were prepared and similarly analyzed. Comilled 5% MGST (w/w) formulation resulted in a significant improvement in in vitro aerosol performance due to the reduction in agglomerate size and strength compared to the formulation comilled without MGST. Higher concentrations of MGST (7.5% w/w) led to reduction in aerosol performance likely due to excessive surface coverage of the micronized particles by MGST, which led to failure in uniformity of content and an increase in agglomerate strength and size. Generally, comilled formulations with higher concentrations of API increased the agglomerate strength and size, which subsequently caused a reduction in aerosol performance. High-dose delivery was achieved at API concentration of >20% (w/w). The study provided a platform for the investigation of aerosol performance and physicochemical properties of other API and additive materials in comilled formulations for the emerging field of high-dose delivery by dry powder inhalation. PMID- 28070848 TI - Intravaginal Delivery of Polyphenon 60 and Curcumin Nanoemulsion Gel. AB - Polyphenon 60 (P60) and curcumin (CUR) were loaded in a single nanoemulsion system and their combined antibacterial action was studied against uropathogenic Escherichia coli. To enhance availability at target organs and to inhibit enzymatic degradation in gastro intestinal tract, vaginal route of administration was explored. P60 + CUR nanoemulsion (NE) was formulated by ultra-sonication and optimized using Box-Behnken design. Optimized NE showed Z-average of 211.2 nm, polydispersity index of 0.343, and zeta potential of -32.7 mV. Optimized P60+ CUR NE was characterized by stability testing and transmission electron microscopy, and it was observed that NE was stable at 4 degrees C for 30 days and monodisperse in nature with particle size of 195-205 nm. P60+ CUR NE was further formulated as gel and characterized by viscosity, growth curve analysis, and in vitro permeation studies. In vitro drug permeation studies in simulated vaginal media showed maximum permeation (84 +/- 0.21%) of curcumin within 5 h and (91 +/- 0.16%) of P60 within 8 h. Both the drugs maintained sustained permeation for 12 h. To investigate the transport via intravaginal route, gamma scintigraphy and biodistribution study of P60 + CUR NBG was performed on Sprague-Dawley rats using 99mtechnetium pertechnetate for radiolabeling to P60 molecule. Following intravaginal administration, P60 + CUR NBG dispersed in the kidney and urinary bladder with (3.07 +/- 0.15) and (3.35 +/- 0.45) percentage per gram after 3 h for P60 and CUR, respectively, and remained active for 12 h. Scintigraphy images suggested that the P60 + CUR NBG given by intravaginal route led to effective distribution of actives in urinary tract, and this observation was in agreement with the biodistribution results. PMID- 28070850 TI - Zolendronic Acid-Conjugated PLGA Ultrasmall Nanoparticle Loaded with Methotrexate as a Supercarrier for Bone-Targeted Drug Delivery. AB - Drug delivery to deep-seated tissues such as bone has been a major complication till date. This preferential drug delivery is further important in targeting anti tumour agents to bone metastasis owing to its complexity. The present study involves the formulation of PLGA nanoparticles and conjugation with zolendronic acid-a bisphosphonate which will anchor the nanosystem to bone due to its selective bone affinity. The conjugated nanosystem was characterized for particle size by TEM (average 36 nm) and morphology by AFM depicting surface irregularities due to ZOL conjugation on the surface of nanoparticles. NMR spectral data also showed the involvement of terminal -OH group of PLGA in bond formation with ZOL. Bone localization studies showed higher accumulation of the ZOL-conjugated nanosystem in bone than non-conjugated nanoparticles. This was confirmed with bone mineral affinity and specificity assay wherein the conjugated nanosystem was found to selectively bind to hydroxyapatite in comparison to other bone minerals. The biodistribution studies depicted that the conjugated nanosystem was selectively targeted to the bone area with concentrations of methotrexate reaching up to 127.4 +/- 1.41 MUg in 1 h. Hence, this multipronged approach using (1) ultrasmall size of nanoparticles, (2) bone selective polymer and (3) suitable bone-targeting agent resulted in mutual synergism for the specific delivery of the anti-tumour agent to the bone. PMID- 28070851 TI - Development of a Sustained Antiplaque and Antimicrobial Chewing Gum of a Decapeptide. AB - The objective of this paper was to design a chewing gum formulation delivery system in situations where typical dental hygiene practice is not practical. Thus, an analog of decapeptide KSL (KSL-W), known to possess antimicrobial and antiplaque activity, was incorporated into a chewing gum formulation containing cetylpyridinium chloride (CPC). The effect of the excipients, xylitol, and peppermint oil on active ingredients in vitro release was also assessed. Gum formulations were prepared with different excipient parameters, including heating xylitol and gum base at 65 or 85 degrees C, using ground and unground xylitol, and the addition of 1.5, 3, and 7% peppermint oil, to determine the effect of these changes on the in vitro release of KSL-W and CPC using a chewing machine. The antimicrobial and antiplaque activities of solutions released from chewed gum formulation as well as prepared standard solutions with different concentrations were tested against placebo. The optimal temperature to avoid crystallization of xylitol during preparation was 65 degrees C. Grinding xylitol to 104.5 MUm improved release of active ingredients as compared to commercially unground xylitol. Peppermint oil had opposite effects on release of KSL-W and CPC. Peppermint oil at 1.5% was determined to be suitable (91 and 88% of KSL-W and CPC released, respectively, after 40 min). The gum formulation illustrated good sustained release of KSL-W and CPC with antibacterial and antiplaque activities after chewing. An effective antimicrobial and antiplaque chewing gum formulation was developed. This formulation has the potential to overcome oral hygiene issues in those unable to follow normal dental protocols. PMID- 28070852 TI - Functional characterization of the powdery mildew susceptibility gene SmMLO1 in eggplant (Solanum melongena L.). AB - Eggplant (Solanum melongena L.) is one of the most important vegetables among the Solanaceae and can be a host to fungal species causing powdery mildew (PM) disease. Specific homologs of the plant Mildew Locus O (MLO) gene family are PM susceptibility factors, as their loss of function results in a recessive form of resistance known as mlo resistance. In a previous work, we isolated the eggplant MLO homolog SmMLO1. SmMLO1 is closely related to MLO susceptibility genes characterized in other plant species. However, it displays a peculiar non synonymous substitution that leads to a T -> M amino acid change at protein position 422, in correspondence of the MLO calmodulin-binding domain. In this study, we performed the functional characterization of SmMLO1. Transgenic overexpression of SmMLO1 in a tomato mlo mutant compromised resistance to the tomato PM pathogen Oidium neolycopersici, thus indicating that SmMLO1 is a PM susceptibility factor in eggplant. PM susceptibility was also restored by the transgenic expression of a synthetic gene, named s-SmMLO1, encoding a protein identical to SmMLO1, except for the presence of T at position 422. This indicates that the T -> M polymorphism does not affect the protein role as PM susceptibility factor. Overall, the results of this work are of interest for the functional characterization of MLO proteins and the introduction of PM resistance in eggplant using reverse genetics. PMID- 28070854 TI - Agency in Fertility Decisions in Western Europe During the Demographic Transition: A Comparative Perspective. AB - We use a set of linked reproductive histories taken from Sweden, the Netherlands, and Spain for the period 1871-1960 to address key issues regarding how reproductive change was linked specifically to mortality and survivorship and more generally to individual agency. Using event-history analysis, this study investigates how the propensity to have additional children was influenced by the number of surviving offspring when reproductive decisions were made. The results suggest that couples were continuously regulating their fertility to achieve reproductive goals. Families experiencing child fatalities show significant increases in the hazard of additional births. In addition, the sex composition of the surviving sibset also appears to have influenced reproductive decisions in a significant but changing way. The findings offer strong proof of active decision making during the demographic transition and provide an important contribution to the literature on the role of mortality for reproductive change. PMID- 28070853 TI - Is the Association Between Education and Fertility Postponement Causal? The Role of Family Background Factors. AB - A large body of literature has demonstrated a positive relationship between education and age at first birth. However, this relationship may be partly spurious because of family background factors that cannot be controlled for in most research designs. We investigate the extent to which education is causally related to later age at first birth in a large sample of female twins from the United Kingdom (N = 2,752). We present novel estimates using within-identical twin and biometric models. Our findings show that one year of additional schooling is associated with about one-half year later age at first birth in ordinary least squares (OLS) models. This estimate reduced to only a 1.5-month later age at first birth for the within-identical twin model controlling for all shared family background factors (genetic and family environmental). Biometric analyses reveal that it is mainly influences of the family environment-not genetic factors-that cause spurious associations between education and age at first birth. Last, using data from the Office for National Statistics, we demonstrate that only 1.9 months of the 2.74 years of fertility postponement for birth cohorts 1944-1967 could be attributed to educational expansion based on these estimates. We conclude that the rise in educational attainment alone cannot explain differences in fertility timing between cohorts. PMID- 28070855 TI - Place and Child Health: The Interaction of Population Density and Sanitation in Developing Countries. AB - A long literature in demography has debated the importance of place for health, especially children's health. In this study, we assess whether the importance of dense settlement for infant mortality and child height is moderated by exposure to local sanitation behavior. Is open defecation (i.e., without a toilet or latrine) worse for infant mortality and child height where population density is greater? Is poor sanitation is an important mechanism by which population density influences child health outcomes? We present two complementary analyses using newly assembled data sets, which represent two points in a trade-off between external and internal validity. First, we concentrate on external validity by studying infant mortality and child height in a large, international child-level data set of 172 Demographic and Health Surveys, matched to census population density data for 1,800 subnational regions. Second, we concentrate on internal validity by studying child height in Bangladeshi districts, using a new data set constructed with GIS techniques that allows us to control for fixed effects at a high level of geographic resolution. We find a statistically robust and quantitatively comparable interaction between sanitation and population density with both approaches: open defecation externalities are more important for child health outcomes where people live more closely together. PMID- 28070856 TI - MiR-29c/PRKCI Regulates Axonal Growth of Dorsal Root Ganglia Neurons Under Hyperglycemia. AB - Diabetes initially induces distal axonal damage of peripheral nerves, but molecular mechanisms that mediate axonal injury are not fully understood. MircoRNAs (miRNAs) regulate axonal growth. We found that diabetic db/db mice exhibited substantial upregulation of miR-29c in dorsal root ganglia (DRG) neurons, sciatic nerve, and foot pad tissues. Bioinformatic analysis revealed PRKCI, a gene that encodes a member of the protein kinase C (PKC) iota, as a putative target for miR-29c. Western blot analysis showed that diabetic mice exhibited a considerable reduction of PRKCI protein levels in sciatic nerve tissues and DRG neurons. Using dual-luciferase assay, we found that co transfection of a plasmid containing miR-29c binding site at 3' UTR of PRKCI gene and miR-29c mimics effectively reduced luminescence activity, which was abolished when miR-29c seed sequences at 3' UTR of PRKCI gene were mutated. In vitro, high glucose substantially upregulated and reduced miR-29c and PRKCI protein levels, respectively, in DRG neurons, which were associated with significant reduction of axonal growth. Knockdown of endogenous miR-29c in DRG neurons by siRNAs overcame reduced PRKCI protein and axonal growth under high glucose condition. Moreover, knockdown of PRKCI in DRG neurons by siRNAs under regular glucose condition considerably inhibited axonal growth. Together, these findings suggest that miR 29c is a negative regulator of axonal growth of DRG neurons by targeting PRKCI under hyperglycemia. PMID- 28070857 TI - A Small Organic Compound Mimicking the L1 Cell Adhesion Molecule Promotes Functional Recovery after Spinal Cord Injury in Zebrafish. AB - Tacrine is a small organic compound that was discovered to mimic the functions of the neural cell adhesion molecule L1 by promoting the cognate functions of L1 in vitro, such as neuronal survival, neuronal migration, neurite outgrowth, and myelination. Based on studies indicating that L1 enhances functional recovery in different central and peripheral nervous system disease paradigms of rodents, it deemed interesting to investigate the beneficial role of tacrine in the attractive zebrafish animal model, by evaluating functional recovery after spinal cord injury. To this aim, larval and adult zebrafish were exposed to tacrine treatment after spinal cord injury and monitored for locomotor recovery and axonal regrowth. Tacrine promoted the rapid recovery of locomotor activities in both larval and adult zebrafish, enhanced regrowth of severed axons and myelination, and reduced astrogliosis in the spinal cords. Tacrine treatment upregulated the expression of L1.1 (a homolog of the mammalian recognition molecule L1) and enhanced the L1.1-mediated intracellular signaling cascades in the injured spinal cords. These observations lead to the hope that, in combination with other therapeutic approaches, this old drug may become a useful reagent to ameliorate the deficits resulting from acute and chronic injuries of the mammalian nervous system. PMID- 28070858 TI - Exosome and Microvesicle-Enriched Fractions Isolated from Mesenchymal Stem Cells by Gradient Separation Showed Different Molecular Signatures and Functions on Renal Tubular Epithelial Cells. AB - Several studies have suggested that extracellular vesicles (EVs) released from mesenchymal stem cells (MSCs) may mediate MSC paracrine action on kidney regeneration. This activity has been, at least in part, ascribed to the transfer of proteins/transcription factors and different RNA species. Information on the RNA/protein content of different MSC EV subpopulations and the correlation with their biological activity is currently incomplete. The aim of this study was to evaluate the molecular composition and the functional properties on renal target cells of MSC EV sub-populations separated by gradient floatation. The results demonstrated heterogeneity in quantity and composition of MSC EVs. Two peaks of diameter were observed (90-110 and 170-190 nm). The distribution of exosomal markers and miRNAs evaluated in the twelve gradient fractions showed an enrichment in fractions with a flotation density of 1.08-1.14 g/mL. Based on this observation, we evaluated the biological activity on renal cell proliferation and apoptosis resistance of low (CF1), medium (CF2) and high (CF3) floatation density fractions. EVs derived from all fractions, were internalized by renal cells, CF1 and CF2 but not CF3 fraction stimulated significant cell proliferation. CF2 also inhibited apoptosis on renal tubular cells submitted to ischemia-reperfusion injury. Comparative miRNomic and proteomic profiles reveal a cluster of miRNAs and proteins common to all three fractions and an enrichment of selected molecules related to renal regeneration in CF2 fraction. In conclusion, the CF2 fraction enriched in exosomal markers was the most active on renal tubular cell proliferation and protection from apoptosis. PMID- 28070859 TI - Mouse Bone Marrow VSELs Exhibit Differentiation into Three Embryonic Germ Lineages and Germ & Hematopoietic Cells in Culture. AB - Very small embryonic-like stem cells (VSELs) have been reported in various adult tissues, express pluripotent and primordial germ cells (PGCs) specific markers, are mobilized under stress/disease conditions, give rise to tissue committed progenitors and thus help regenerate and maintain homeostasis. The aim of the present study was to evaluate in vitro differentiation potential of VSELs using a quantitative approach. VSELs were collected from mouse bone marrow after 4 days of 5-fluorouracil (5-FU, 150 mg/Kg) treatment, further enriched by size based filtration and cultured on a feeder support in the presence of specific differentiation media. Cultured VSELs were found to differentiate into all three embryonic germ cell lineages, germ and hematopoietic cells after 14 days in culture. This was confirmed by studying Nestin, PDX-1, NKX2.5, DAZL, CD45 and other markers expression by various approaches. Very small, CD45 negative cells collected and enriched from GFP positive 5-FU treated mice bone marrow transitioned into CD45 positive cells in vitro thus demonstrating that VSELs can give rise to hematopoietic stem cells (HSCs). We envision that VSELs may be responsible for plasticity and ability of bone marrow cells to give rise to non hematopoietic tissue progenitors of all 3 germ layers. Moreover the ability of VSELs to differentiate into germ cells as well as all the three lineages provides further evidence to support their pluripotent state and confirms developmental link between bone marrow VSELs and PGCs. The property of quiescence, no risk of teratoma formation and autologus source, make pluripotent VSELs a potential candidate to facilitate endogenous regeneration compared to cell replacement strategy envisioned using embryonic and induced pluripotent stem cells. PMID- 28070860 TI - Energetic, oxidative and ionic exchange in rat brain and liver mitochondria at experimental audiogenic epilepsy (Krushinsky-Molodkina model). AB - The role of brain and liver mitochondria at epileptic seizure was studied on Krushinsky-Molodkina (KM) rats which respond to sound with an intensive epileptic seizure (audiogenic epilepsy). We didn't find significant changes in respiration rats of brain and liver mitochondria of KM and control rats; however the efficiency of ATR synthesis in the KM rat mitochondria was 10% lower. In rats with audiogenic epilepsy the concentration of oxidative stress marker malondialdehyde in mitochondria of the brain (but not liver) was 2-fold higher than that in the control rats. The rate of H2O2 generation in brain mitochondria of KM rats was twofold higher than in the control animals when using NAD dependent substrates. This difference was less pronounced in liver mitochondria. In KM rats, the activity of mitochondrial ATP-dependent potassium channel was lower than in liver mitochondria of control rats. The comparative study of the mitochondria ability to retain calcium ions revealed that in the case of using the complex I and complex II substrates, permeability transition pore is easier to trigger in brain and liver mitochondria of KM and KMs rats than in the control ones. The role of the changes in the energetic, oxidative, and ionic exchange in the mechanism of audiogenic epilepsy generation in rats and the possible correction of the epilepsy seizures are discussed. PMID- 28070862 TI - Pharmacokinetic Evaluation of Once-Weekly and Once-Monthly Buprenorphine Subcutaneous Injection Depots (CAM2038) Versus Intravenous and Sublingual Buprenorphine in Healthy Volunteers Under Naltrexone Blockade: An Open-Label Phase 1 Study. AB - INTRODUCTION: CAM2038 q1w (once weekly) and q4w (once monthly) are investigational buprenorphine subcutaneous (SC) formulations based on FluidCrystal(r) injection depot technology. These two drug products are being developed for opioid dependence treatment, with a target for once-weekly and once monthly SC dosing. The rationale for developing two products with different dosing frequencies is that treatment strategies/routines, and hence different treatment preferences, can vary between patients, different stages of opioid maintenance treatment, and countries. This study evaluated the pharmacokinetics and safety of buprenorphine and norbuprenorphine following administration of CAM2038 q1w or q4w versus active controls. METHODS: Healthy volunteers were randomized to five treatment groups. All received a single intravenous dose of buprenorphine 600 ug, followed post-washout by a single dose of CAM2038 q4w 96 mg, a single dose of CAM2038 q4w 192 mg, or sublingual buprenorphine 8, 16, or 24 mg daily for 7 days, followed post-washout by a single dose of CAM2038 q4w 64 or 128 mg or four repeated weekly doses of CAM2038 q1w 16 mg. All subjects received daily naltrexone. RESULTS: Eighty-seven subjects were randomized. Median buprenorphine t max after CAM2038 q4w was 4-10 h (24 h for CAM2038 q1w); mean terminal half-life was 19-25 days (5 days for CAM2038 q1w). CAM2038 q4w showed dose-proportional buprenorphine release, with similar exposure to repeat-dose CAM2038 q1w at comparable monthly dose level. Both CAM2038 formulations showed complete absolute bioavailability of buprenorphine and 5.7- to 7.7-fold greater buprenorphine bioavailability versus sublingual buprenorphine. CAM2038 q1w and q4w were well tolerated; subjects' acceptance was higher for CAM2038 than for sublingual buprenorphine 1 h post-dose. CONCLUSIONS: The pharmacokinetic profiles of CAM2038 q1w and q4w versus sublingual buprenorphine support expected treatment efficacy with once-weekly and once-monthly dosing, respectively. CAM2038 formulations were safe and showed good local tolerability. TRIAL REGISTRATION: ISRCTN24987553. FUNDING: Camurus AB. PMID- 28070863 TI - Editorial. PMID- 28070861 TI - Efficacy and Safety of Vedolizumab in Ulcerative Colitis and Crohn's Disease Patients Stratified by Age. AB - INTRODUCTION: The efficacy and safety of vedolizumab, a gut-selective alpha4beta7 integrin antibody, were demonstrated in the GEMINI 1 and GEMINI 2 clinical trials of adults aged 18-80 years. We investigated the efficacy and safety of vedolizumab in patients stratified by age from the GEMINI trials. METHODS: Safety and efficacy, including clinical response, clinical remission, and corticosteroid free remission, at week 6 and/or 52 were determined post hoc in patients aged <35, 35 to <55, and >=55 years. RESULTS: At baseline, 353, 412, and 130 ulcerative colitis (UC) and 582, 443, and 90 Crohn's disease (CD) patients were aged <35, 35 to <55, and >=55. Of these patients, 56 were aged >=65 years (UC: 33, CD: 23). Trends favoring vedolizumab over placebo were observed for most efficacy endpoints irrespective of patient age; some variability between subgroups was observed. Safety profiles of vedolizumab and placebo were similar in all age groups. Vedolizumab-treated patients aged >=55 had the lowest incidence of serious infections (0.9 per 100 person-years) and adverse events leading to hospitalization (14.8 per 100 person-years). There were no age-related differences in the incidence of adverse hematological events, malignancy, or death. CONCLUSIONS: The safety and efficacy of vedolizumab in patients with UC or CD were similar for all age groups. The number of patients in the oldest age group in these analyses was small; thus further studies of vedolizumab in larger cohorts of elderly patients are warranted. FUNDING: Millennium Pharmaceuticals, Inc. (d/b/a Takeda Pharmaceuticals International Co.). PMID- 28070864 TI - Factors that Affect the Content of Cadmium, Nickel, Copper and Zinc in Tissues of the Knee Joint. AB - Osteoarthritis causes the degradation of the articular cartilage and periarticular bones. Trace elements influence the growth, development and condition of the bone tissue. Changes to the mineral composition of the bone tissue can cause degenerative changes and fractures. The aim of the research was to determine the content of cadmium (Cd), nickel (Ni), copper (Cu) and zinc (Zn) in the tibia, the femur and the meniscus in men and women who underwent a knee replacement surgery. Samples were collected from 50 patients, including 36 women and 14 men. The determination of trace elements content were performed by ICP-AES method, using Varian 710-ES. Average concentration in the tissues of the knee joint teeth amounted for cadmium 0.015, nickel 0.60, copper 0.89 and zinc 80.81 mg/kg wet weight. There were statistically significant differences in the content of cadmium, copper and zinc in different parts of the knee joint. There were no statistically significant differences in the content of cadmium, nickel, copper and zinc in women and men in the examined parts of the knee joint. Among the elements tested, copper and nickel showed a high content in the connective tissue (the meniscus) compared to the bone tissue (the tibia and the femur). PMID- 28070865 TI - Sphingosine-1-phosphate pretreatment amends hypoxia-induced metabolic dysfunction and impairment of myogenic potential in differentiating C2C12 myoblasts by stimulating viability, calcium homeostasis and energy generation. AB - Sphingosine-1-phosphate (S1P) has a role in transpiration in patho-physiological signaling in skeletal muscles. The present study evaluated the pre-conditioning efficacy of S1P in facilitating differentiation of C2C12 myoblasts under a normoxic/hypoxic cell culture environment. Under normoxia, exogenous S1P significantly promoted C2C12 differentiation as evident from morphometric descriptors and differentiation markers of the mature myotubes, but it could facilitate only partial recovery from hypoxia-induced compromised differentiation. Pretreatment of S1P optimized the myokine secretion, intracellular calcium release and energy generation by boosting the aerobic/anaerobic metabolism and mitochondrial mass. In the hypoxia-exposed cells, there was derangement of the S1PR1-3 expression patterns, while the same could be largely restored with S1P pretreatment. This is being proposed as a plausible underlying mechanism for the observed pro-myogenic efficacy of exogenous S1P preconditioning. The present findings are an invaluable addition to the existing knowledge on the pro-myogenic potential of S1P and may prove beneficial in the field of hypoxia-related myo-pathologies. PMID- 28070866 TI - Finite Element Analysis of Patient-Specific Mitral Valve with Mitral Regurgitation. AB - Functional mitral regurgitation (FMR) is a significant complication of left ventricular dysfunction and strongly associated with a poor prognosis. In this study, we developed a patient-specific finite element (FE) model of the mitral apparatus in a FMR patient which included: both leaflets with thickness, annulus, chordae tendineae, and chordae insertions on the leaflets and origins on the papillary muscles. The FE model incorporated human age- and gender-matched anisotropic hyperelastic material properties, and MV closure at systole was simulated. The model was validated by comparing the FE results from valve closure simulation with the in vivo geometry of the MV at systole. It was found that the FE model could not replicate the in vivo MV geometry without the application of tethering pre-tension force in the chordae at diastole. Upon applying the pre tension force and performing model optimization by adjusting the chordal length, position, and leaflet length, a good agreement between the FE model and the in vivo model was established. Not only were the chordal forces high at both diastole and systole, but the tethering force on the anterior papillary muscle was higher than that of the posterior papillary muscle, which resulted in an asymmetrical gap with a larger orifice area at the anterolateral commissure resulting in MR. The analyses further show that high peak stress and strain were found at the chordal insertions where large chordal tethering forces were found. This study shows that the pre-tension tethering force plays an important role in accurately simulating the MV dynamics in this FMR patient, particularly in quantifying the degree of leaflet coaptation and stress distribution. Due to the complexity of the disease, the patient-specific computational modeling procedure of FMR patients presented should be further evaluated using a large patient cohort. However, this study provides useful insights into the MV biomechanics of a FMR patient, and could serve as a tool to assist in pre-operative planning for MV repair or replacement surgical or interventional procedures. PMID- 28070867 TI - Analytical Modeling for Computing Lead Stress in a Novel Epicardial Micropacemaker. AB - Implantation and maintenance of a permanent cardiac pacing system in children remains challenging due to small patient size, congenital heart defects and somatic growth. We are developing a novel epicardial micropacemaker for children that can be implanted on the epicardium within the pericardial space via a minimally-invasive technique. The key design configurations include a novel open coiled lead in which living tissue replaces the usual polymeric support for the coiled conductor. To better understand and be able to predict the behavior of the implanted lead, we performed a radiographic image-based modeling study on a chronic animal test. We report a pilot study in which two mechanical dummy pacemakers with epicardial leads were implanted into an adult pig model via a minimally invasive approach. Fluoroscopy was obtained on the animal on Post Operative Days #9, #35 and #56 (necropsy). We then constructed an analytic model to estimate the in vivo stress conditions on the open-coil lead based on the analysis of orthogonal biplane radiographic images. We obtained geometric deformation data of the implanted lead including elongation magnitudes and bending radii from sequenced films of cardiac motion cycles. The lead stress distribution was investigated on each film frame and the point of maximum stress (Mean Stress = 531.4 MPa; Alternating Stress = +/- 216.4 MPa) was consistently where one of the leads exited the pericardial space, a deployment that we expected to be unfavorable. These results suggest the modeling approach can provide a basis for further design optimization. More animal tests and modeling will be needed to validate whether the novel lead design could meet the requirements to withstand ~200 million cardiac motion cycles over 5 years. PMID- 28070868 TI - Development of a Just-in-Time Adaptive Intervention for Smoking Cessation Among Korean American Emerging Adults. AB - PURPOSE: Cigarette smoking is a preventable risk factor that contributes to unnecessary lung cancer burden among Korean Americans and there is limited research on effective smoking cessation strategies for this population. Smartphone-based smoking cessation apps that leverage just-in-time adaptive interventions (JITAIs) hold promise for smokers attempting to quit. However, little is known about how to develop and tailor a smoking cessation JITAI for Korean American emerging adult (KAEA) smokers. METHOD: This paper documents the development process of MyQuit USC according to design guidelines for JITAI. Our development process builds on findings from a prior ecological momentary assessment study by using qualitative research methods. Semi-structured interviews and a focus group were conducted to inform which intervention options to offer and the decision rules that dictate their delivery. RESULTS: Qualitative findings highlighted that (1) smoking episodes are highly context-driven and that (2) KAEA smokers believe they need personalized cessation strategies tailored to different contexts. Thus, MyQuit USC operates via decision rules that guide the delivery of personalized implementation intentions, which are contingent on dynamic factors, to be delivered "just in time" at user-scheduled, high-risk smoking situations. CONCLUSION: Through an iterative design process, informed by quantitative and qualitative formative research, we developed a smoking cessation JITAI tailored specifically for KAEA smokers. Further testing is under way to optimize future versions of the app with the most effective intervention strategies and decision rules. MyQuit USC has the potential to provide cessation support in real-world settings, when KAEAs need them the most. PMID- 28070869 TI - Fast T1 and T2 mapping methods: the zoomed U-FLARE sequence compared with EPI and snapshot-FLASH for abdominal imaging at 11.7 Tesla. AB - OBJECTIVE: A newly adapted zoomed ultrafast low-angle RARE (U-FLARE) sequence is described for abdominal imaging applications at 11.7 Tesla and compared with the standard echo-plannar imaging (EPI) and snapshot fast low angle shot (FLASH) methods. MATERIALS AND METHODS: Ultrafast EPI and snapshot-FLASH protocols were evaluated to determine relaxation times in phantoms and in the mouse kidney in vivo. Owing to their apparent shortcomings, imaging artefacts, signal-to-noise ratio (SNR), and variability in the determination of relaxation times, these methods are compared with the newly implemented zoomed U-FLARE sequence. RESULTS: Snapshot-FLASH has a lower SNR when compared with the zoomed U-FLARE sequence and EPI. The variability in the measurement of relaxation times is higher in the Look Locker sequences than in inversion recovery experiments. Respectively, the average T1 and T2 values at 11.7 Tesla are as follows: kidney cortex, 1810 and 29 ms; kidney medulla, 2100 and 25 ms; subcutaneous tumour, 2365 and 28 ms. CONCLUSION: This study demonstrates that the zoomed U-FLARE sequence yields single-shot single-slice images with good anatomical resolution and high SNR at 11.7 Tesla. Thus, it offers a viable alternative to standard protocols for mapping very fast parameters, such as T1 and T2, or dynamic processes in vivo at high field. PMID- 28070870 TI - Defining the Risk and Associated Morbidity and Mortality of Severe Respiratory Syncytial Virus Infection Among Infants with Congenital Heart Disease. AB - INTRODUCTION: The REGAL (RSV Evidence-a Geographical Archive of the Literature) series provide a comprehensive review of the published evidence in the field of respiratory syncytial virus (RSV) in Western countries over the last 20 years. This fourth publication covers the risk and burden of RSV infection in infants with congenital heart disease (CHD). METHODS: A systematic review was undertaken for articles published between January 1, 1995 and December 31, 2015 across PubMed, Embase, The Cochrane Library, and Clinicaltrials.gov. Studies reporting data for hospital visits/admissions for RSV infection among children with CHD as well as studies reporting RSV-associated morbidity, mortality, and healthcare costs were included. The focus was on children not receiving RSV prophylaxis. Study quality and strength of evidence (SOE) were graded using recognized criteria. RESULTS: A total of 1325 studies were identified of which 38 were included. CHD, in particular hemodynamically significant CHD, is an independent predictor for RSV hospitalization (RSVH) (high SOE). RSVH rates were generally high in young children (<4 years) with CHD (various classifications), varying between 14 and 357/1000 (high SOE). Children (<6 years) with RSV infection spent 4.4-14 days in hospital, with up to 53% requiring intensive care (high SOE). Infants (<2 years) with CHD had a more severe course of RSVH than those without CHD (high SOE). Case fatality rates of up to 3% were associated with RSV infection in children with CHD (high SOE). RSV infection in the perioperative period of corrective surgery and nosocomial RSV infection in intensive care units also represent important causes of morbidity (moderate SOE). CONCLUSION: CHD poses a significant risk for RSVH and subsequent morbidity and mortality. RSV infection often complicates corrective heart surgery. To reduce the burden and improve outcomes, further research and specific studies are needed to determine the longer-term effects of severe RSV infection in young children with CHD. PMID- 28070871 TI - Treating HIV Infection in the Central Nervous System. AB - Combination antiretroviral treatment is associated with clear benefits in HIV positive subjects, and is also effective in the central nervous system (CNS), meaning HIV-associated dementia is now an uncommon event. Nevertheless, a significant number of patients show symptoms of neurocognitive impairment which may negatively affect their quality of life. Although several risk factors for HIV-associated neurocognitive disorders have been identified, there is no clear recommendation for their prevention and management. In this review, the penetration of drugs into the cerebrospinal fluid/CNS is discussed as well as the viral and clinical consequences associated with higher/lower compartmental exposure. We also review the potential interventions according to the currently identified underlying mechanisms, including persistent CNS immune activation, legacy effects, low-level viral replication and escape, co-morbidities, and antiretroviral-associated direct and indirect 'neurotoxicity'. Adjunctive therapies and interventions (including neuro-rehabilitation) are then briefly discussed. The treatment of HIV infection in the CNS is a complex area of therapeutics requiring multidisciplinary interventions and further study. PMID- 28070873 TI - Animal Models of PTSD: A Critical Review. AB - The goals of animal research in post-traumatic stress disorder (PTSD) include better understanding the neurophysiological etiology of PTSD, identifying potential targets for novel pharmacotherapies, and screening drugs for their potential use as PTSD treatment in humans. Diagnosis of PTSD relies on a patient interview and, as evidenced by changes to the diagnostic criteria in the DSM-5, an adequate description of this disorder in humans is a moving target. Therefore, it may seem insurmountable to model the construct of PTSD in animals such as rodents. Fortunately, the neural circuitry involved in fear and anxiety, thought to be essential to the etiology of PTSD in humans, is highly conserved throughout evolution. Furthermore, many symptoms can be modeled using behavioral tests that have face, construct, and predictive validity. Because PTSD is precipitated by a definite traumatic experience, animal models can simulate the induction of PTSD, and test causal factors with longitudinal designs. Accordingly, several animal models of physical and psychological trauma have been established. This review discusses the widely used animal models of PTSD in rodents, and overviews their strengths and weaknesses in terms of face, construct, and predictive validity. PMID- 28070872 TI - Sedative Effects of Levocetirizine: A Systematic Review and Meta-Analysis of Randomized Controlled Studies. AB - INTRODUCTION: As a substrate of P-glycoprotein, levocetirizine should not cause sedative effects. However, while cetirizine, a mixture of levocetirizine and dextrocetirizine, can slightly penetrate the blood brain barrier, the sedative effects of levocetirizine are still under study. OBJECTIVES: The aim of this study was to investigate the sedative effects of levocetirizine. METHODS: An electronic literature search was performed using Medline and EMBASE from January 01, 2001 through August 6, 2015. Randomized controlled trials (RCTs) comparing levocetirizine with other antihistamines or placebo for patients with allergy and healthy subjects were selected. Primary outcome was risk ratio between levocetirizine and comparators. Secondary outcome was change in psychomotor speed. Data were pooled for meta-analysis using a fixed-effect model. RESULTS: Forty-eight studies of 18,014 patients met the inclusion criteria. When compared to placebo, levocetirizine produced modest sedative effects (RR: 1.67; 95% CI 1.17, 2.38). However, when compared to other second-generation antihistamines, sedative effects of levocetirizine did not differ (RR: 1.23; 95% CI 0.96, 1.58). In subgroup analysis, there was no difference between the sedative effects of levocetirizine and fexofenadine (RR: 1.7; 95% CI 0.59, 4.88), desloratadine (RR: 1.58; 95% CI 0.9, 2.77), loratadine (RR: 1.56; 95% CI 0.28, 8.56), bilastine (RR: 1.17; 95% CI 0.48, 2.84), olopatadine (RR: 1.09; 95% CI 0.81, 1.47), azelastine (RR: 0.19; 95% CI 0.01, 3.68) and rupatadine (RR: 1.47; 95% CI 0.14, 15.72). When compared to first-generation antihistamines, levocetirizine had less sedative effects and less change of reaction time (mean difference: -250.76 s; 95% CI 338.53, -162.98). CONCLUSION: Levocetirizine has modest sedative effects with a risk ratio of 1.67 when compared with placebo. The sedative effects observed for levocetirizine are not different from other second-generation antihistamines. PMID- 28070874 TI - Infection of defective human T-lymphotropic virus type 1. AB - In a previous study, we reported that an identical defective provirus had integrated into multiple sites of the genome of a representative human T lymphotropic virus type 1 (HTLV-1) cell line, MT-2. A possible explanation for this may be the repeated infection of this defective provirus to a cell. Therefore, we attempted to determine whether a defective provirus could transmit during the co-culture of HTLV-1 uninfected human T-cell line, Jurkat, with MT-2 cells treated with mitomycin C. As a result, we established not only a cell line with the integration of one complete provirus, but also a cell line with the integration of one defective provirus. The rearrangement of the T-cell receptor gamma gene of these cell lines showed them to be derived from Jurkat cells. Both HTLV-1 Tax/Rex and HBZ RNA were detected in the cell line, which harbors a complete provirus. On the other hand, HBZ RNA and transcriptional product specific for the defective provirus were detected in the cell line, which harbors a defective HTLV-1 provirus only. These results suggested that a defective HTLV-1 provirus with large depletion of internal sequence could transmit to other cells. Moreover, the defective provirus can be transcriptionally active. This suggested the possibility that the defective HTLV-1 provirus found in the lymphocytes of HTLV-1 carriers and patients with adult T-cell leukemia may transmit to other T cells in vivo. The results also suggested that defective provirus in HTLV-1 carriers could be functional and may play a role in leukemogenesis. PMID- 28070875 TI - Atrial fibrillation inducibility during cavotricuspid isthmus-dependent atrial flutter ablation as a predictor of clinical atrial fibrillation. A meta-analysis. AB - BACKGROUND: Atrial fibrillation (AF) and cavotricuspid isthmus (CTI)-dependent atrial flutter (AFL) are two separate entities that coexist in a significant percentage of patients. We sought to investigate whether AF inducibility during CTI AFL ablation predicted the occurrence of AF at follow-up after successful AFL ablation. METHODS: A systemic review of Medline, Cochrane, and Embase was done for all the clinical studies in which assessment of AF inducibility in patients undergoing ablation for CTI AFL was performed. Given the low heterogeneity (i.e., I 2 <25), we used a fixed effect model for our analysis. RESULTS: A total of 10 studies (4 prospective and 6 retrospective) with a total of 1299 patients (male, 73%; mean age 59 +/- 11 years) fulfilled the inclusion criteria. During a mean follow-up period of 23 +/- 7.6 months, 407 patients (31%) developed AF during AFL ablation. The overall incidence for new-onset AF during follow-up was 29% (47% in the group with inducible AF vs. 21% in the non-inducible group). The odds ratio (OR) for developing AF after AFL ablation in patients with AF inducibility for all studies combined was 3.72, 95% CI 2.83-4.89 [prospective studies (OR 5.52, 95% CI 3.23-9.41) vs. retrospective studies (OR 3.23, 95% CI 2.35-4.45)]. CONCLUSIONS: Although ablation for CTI AFL is highly effective, AF continues to be a long-term risk for individuals undergoing this procedure. AF induced by pacing protocols in patients undergoing CTI AFL predicts for future AF. Inducible AF is a clinically relevant finding that may help guide decisions for long-term anticoagulation after successful typical AFL ablation especially in patients with elevated CHADS-VASc scores (>=2) and in considering prophylactic PVI during CTI AFL ablation. PMID- 28070876 TI - Pulmonary artery sarcoma resected via median sternotomy with thoracoscopic assistance. AB - Median sternotomy is frequently selected for the resection of pulmonary artery tumor, and pneumonectomy is performed for complete resection. However, it is difficult to see the inferior pulmonary vein and transect it safely via median sternotomy, so additional thoracotomy is often required and this is highly invasive. In the present case, we employed thoracoscopy (which we routinely use for VATS lobectomy) to transect the inferior pulmonary vein via median sternotomy without additional intercostal thoracotomy. This method has advantages for patients undergoing pneumonectomy via median sternotomy. PMID- 28070877 TI - Idiopathic retroperitoneal fibrosis and its overlap with IgG4-related disease. AB - Retroperitoneal fibrosis (RPF) is a rare disease characterised by fibrous tissue proliferation in the retroperitoneum, with encasement of the ureters and large vessels of the abdomen as the most destructive of potentially severe complications. It can either be idiopathic, or secondary to infections, malignancies, or the use of certain drugs. The idiopathic form accounts for approximately 75% of the cases, and is usually responsive to immunosuppressive therapy. In recent years, the emergence of a new clinical entity, IgG4-related disease (IgG4-RD), shed light on many fibro-inflammatory disorders once thought to be separate clinical entities, although frequently associated in the so-called multifocal fibrosclerosis. Among these, together with sclerosing pancreatitis and cholangitis, pseudotumour of the orbit, idiopathic mediastinal fibrosis and other conditions, is idiopathic retroperitoneal fibrosis (IRF). Both IRF and IgG4-RD can be associated with a wide variety of disorders, usually governed by immune mediated (and particularly auto-immune) mechanisms. In our review, we discuss the clinical and therapeutic challenges IRF presents to the internist, as well as the meaning of its recent inclusion in the IgG4-RD spectrum from a clinical practice standpoint. PMID- 28070878 TI - Effects of Caffeic Acid and Quercetin on In Vitro Permeability, Metabolism and In Vivo Pharmacokinetics of Melatonin in Rats: Potential for Herb-Drug Interaction. AB - BACKGROUND AND OBJECTIVES: Melatonin is a popular dietary supplement and also considered as pharmaceutical product for sleep disorders. Caffeic acid and quercetin are widely distributed in leafy vegetables, fruits, tea extract, and both are used as natural antioxidant. There is an immense concern for health researchers to study the herb/food-drug interactions of melatonin. It is mainly metabolized by CYP1A2 in human so that herbs/foods containing cytochrome P450 (CYP) inhibitors can affect pharmacokinetics of melatonin. By considering pharmacokinetic aspects, the present study was undertaken to evaluate the effects of caffeic acid and quercetin on Caco-2 cells permeability, metabolism, CYP1A inhibition in vitro assay systems and a single dose pharmacokinetics of melatonin in vivo rats. METHODS: The effects of caffeic acid and quercetin on melatonin permeability were tested in Caco-2 cells. Metabolic stability and CYP1A activity were investigated in rat liver microsomes (RLMs) using probe substrates (melatonin/phenacetin in vitro). Melatonin and phenacetin were incubated in RLMs with or without caffeic acid and quercetin, and the IC50 values were determined. The pharmacokinetics of melatonin conducted in rats after a single dose (15 mg/kg) pre-treatment with caffeic acid, quercetin and caffeic acid plus quercetin followed by oral dose of melatonin at 5 mg/kg. Analysis of all samples was with LC-MS/MS. RESULTS: Caffeic acid and quercetin did not alter Caco-2 permeability of melatonin in apical to basolateral direction and vice versa. Melatonin was metabolized in rat liver microsomes, which was inhibited by both caffeic acid and quercetin through CYP1A. The concomitant oral administration of melatonin along with 15 mg/kg of caffeic acid or quercetin or caffeic acid plus quercetin significantly (p < 0.05) increased the AUC0-t of melatonin by 30.0, 66.7 and 114.0%, respectively. The apparent oral rat plasma clearance (CL/F) of melatonin also decreased significantly (p < 0.05) by 28.78, 47.87 and 50% in presence of caffeic acid, quercetin and caffeic acid plus quercetin, respectively. CONCLUSION: These findings suggest that caffeic acid and quercetin improved oral exposure of melatonin via CYP1A inhibition pathway. PMID- 28070879 TI - A Review of Pharmacogenetics of Antimalarials and Associated Clinical Implications. AB - Genetic variability in drug-metabolizing enzymes and drug transporters is known to influence the pharmacokinetics of many drugs. Antimalarial drugs are a class of agents known to utilize metabolic and elimination pathways prone to genetic variation. This paper aims to review the genetic variants affecting antimalarial medications and discuss their clinical implications. Data were identified for the genes coding for the cytochrome P450 (CYP) enzymes: CYP2C8, CYP2C19, CYP2A6, CYP2D6, CYP2B6, and the P-glycoprotein drug transporter. Adverse effects of amodiaquine were more common in patients with decreased CYP2C8 metabolism. CYP2C19 variants influenced the metabolism of proguanil but no differences in efficacy outcomes were observed. Ultra-metabolizers of CYP2A6 showed increased incidence of adverse effects of artesunate (prodrug for active metabolite, dihydroartemisinin). In the presence of efavirenz, mutations in CYP2B6 influenced the number of patients achieving day-7 lumefantrine concentrations above accepted therapeutic cut-offs. Lumefantrine concentrations were also influenced by ABCB1 variants in the presence of nevirapine. The most critical pharmacogenetic consideration identified was the association of glucose-6-phosphate dehydrogenase deficiency with development of hemolytic anemia and decreased hemoglobin levels in patients treated with primaquine or a combination of chlorproguanil-dapsone artesunate. These findings demonstrate a need for close monitoring of patients originating from populations where genetic variation in metabolizing enzymes is prevalent, so as to ensure that optimal clinical outcomes are achieved. Future studies should determine which populations are at greatest risk of potential treatment failures and/or adverse effects, which drugs are most susceptible to genetic variation in metabolizing enzymes, and the impact of genetic influence on the efficacy and safety of first-line treatment regimens. PMID- 28070881 TI - Left ventricular function after takotsubo is not fully recovered in long-term follow-up: A speckle tracking echocardiography study. AB - BACKGROUND: Complete improvement of left ventricle (LV) systolic function is an essential feature of takotsubo cardiomyopathy (TTC). It is suggested that 2 dimensional speckle tracking echocardiography (2D STE) can evaluate LV dysfunction more accurately than conventional echocardiography. Thus, the purpose of this research was to assertain whether LV function recovery is complete after the acute phase of TTC using 2D STE commencing 6 to 9 months after discharge. METHODS: Thirty patients (29 females, 67 +/- 11 years) with an apical ballooning TTC pattern 225.5 +/- 27.4 days after their index event were enrolled. The control group consisted of 20 (19 females, 64 +/- 9 years) age- and sex-matched volunteers without structural heart disease. Classic echocardiographic parameters, longitudinal strain and LV twist parameters were assessed and compared between the groups. RESULTS: There were no differences in traditional LV systolic, diastolic parameters and in global peak longitudinal strain. In comparison to controls, patients with TTC had lower mean apical rotation (14.4 degrees +/- 6.5 degrees vs. 18.3 degrees +/- 6.7 degrees ; p = 0.048), slower mean peak early diastolic apical rotation rate (-85.1- degrees /s +/- 40.9- degrees /s vs -119.4- degrees /s +/- 41.9- degrees /s; p = 0.006) and higher pre stretch index in the apex (2.16, IQR 0.33-5.50 vs. 0.00, IQR 0.00-2.95, p = 0.008). CONCLUSIONS: The improvement of LV function in patients with TTC as assessed by 2D STE may not always be complete. Some residual abnormalities in LV apex function were observed in long-term recovery following TTC episodes. PMID- 28070880 TI - On the Molecular Basis Underlying the Metabolism of Tapentadol Through Sulfation. AB - BACKGROUND AND OBJECTIVES: Previous studies reported that tapentadol-sulfate represented one of the major metabolites of tapentadol excreted in urine. The current study aimed to identify the human cytosolic sulfotransferases (SULTs) that is(are) capable of sulfating tapentadol and to examine whether human cells and human organ specimens are capable of sulfating tapentadol. METHODS: Thirteen human SULTs, previously expressed and purified, as well as human organ cytosols, were analyzed for tapentadol-sulfating activity using an established sulfotransferase assay. Cultured HepG2 human hepatoma cells and Caco-2 human colon carcinoma cells were labeled with [35S]sulfate in the presence of different concentrations of tapentadol. RESULTS: Three of the thirteen human SULTs, SULT1A1, SULT1A3, and SULT1C4, were found to display sulfating activity toward tapentadol. Kinetic analysis revealed that SULT1A3 displayed the highest catalytic efficiency in mediating the sulfation of tapentadol, followed by SULT1A1 and SULT1C4. Using cultured HepG2 and Caco-2 cells, the generation and release of sulfated tapentadol under metabolic conditions was demonstrated. Moreover, of the four human organ specimens (kidney, liver, lung, and small intestine) tested, the cytosols prepared from small intestine and liver showed significant tapentadol-sulfating capacity (at 0.0203 and 0.0054 nmol/min/mg, respectively). CONCLUSION: Taken together, the results derived from the current study provided a molecular basis underlying the sulfation of tapentadol in humans. PMID- 28070882 TI - Effect of a 180 mg ticagrelor loading dose on myocardial necrosis in patients undergoing elective percutaneous coronary intervention: A preliminary study. AB - BACKGROUND: To examine whether a loading dose of ticagrelor on top of clopidogrel reduced postpercutaneous coronary intervention (PCI) myonecrosis. METHODS: Seventy seven coronary artery disease patients received a loading dose of 300 mg clopidogrel pre-PCI and were divided into three groups: group TT (n = 36): a loading dose of 180 mg ticagrelor pre-PCI, followed by ticagrelor 90 mg twice daily commencing one day post-PCI; group CT (n = 26): a maintenance dose of ticagrelor 90 mg twice daily; group CC (n = 15): clopidogrel 75 mg daily post- PCI. High sensitivity cardiac troponin T (hs-cTnT) and creatine kinase-MB (CK-MB) were measured pre-PCI and 0 h, 2 h or 24 h post-PCI. Platelet aggregation was measured in a separate cohort of 54 coronary artery disease patients (35 diabetic and 19 non-diabetic patients). RESULTS: There were no significant differences in hs-cTnT and CK-MB concentration among the three groups. In group TT, diabetic patients had significant higher Deltahs-cTnT2h-0h than non-diabetic patients. In the second cohort, although baseline platelet aggregation was higher in diabetic than non-diabetic patients, platelet aggregation was comparable between diabetic and non-diabetic patients at 0 and 2 h post-PCI. CONCLUSIONS: This study indicates that a loading dose of ticagrelor does not significantly reduce post- PCI myonecrosis. Diabetes is associated with more post-PCI myonecrosis. A loading dose of ticagrelor effectively reduces platelet aggregation in diabetic patients. PMID- 28070883 TI - Pilot of a Computerised Antithrombotic Risk Assessment Tool Version 2 (CARATV2.0) for stroke prevention in atrial fibrillation. AB - BACKGROUND: The decision-making process for stroke prevention in atrial fibrillation (AF) requires a comprehensive assessment of risk vs. benefit and an appropriate selection of antithrombotic agents (e.g., warfarin, non-vitamin K antagonist oral anticoagulants [NOACs]). The aim of this pilot-test was to examine the impact of a customised decision support tool - the Computerised Antithrombotic Risk Assessment Tool (CARATV2.0) using antithrombotic therapy on a cohort of patients with AF. METHODS: In this prospective interventional study, 251 patients with AF aged >= 65 years, admitted to a teaching hospital in Australia were recruited. CARATV2.0 generated treatment recommendations based on patient medical information. Recommendations were provided to prescribers for consideration. RESULTS: At baseline (admission), 30.3% of patients were prescribed warfarin, 26.7% an antiplatelet, 8.4% apixaban, 8.0% rivaroxaban, 3.6% dabigatran. CARATV2.0 recommended a change of therapy for 153 (61.0%) patients. Through recommendations of CARATV2.0, at discharge, 40.2% of patients were prescribed warfarin, 17.7% antiplatelet, 14.3% apixaban, 10.4% rivaroxaban, 5.6% dabigatran. Overall, the proportion of patients receiving an antithrombotic on discharge increased significantly from baseline (admission) (baseline 77.2% vs. 89.2%; p < 0.001). Prescribers moderately agreed with CARATV2.0's recommendations (kappa = 0.275, p < 0.001). Practical medication safety issues were cited as major reasons for not accepting a desire to continue therapy with CARATV2.0's recommendations. Factors predicting the prescription of antiplatelets rather than anticoagulants included higher bleeding risk and high risk of falls. An inter speciality difference in therapy selection was detected. CONCLUSIONS: This decision support tool can help optimise the use of antithrombotic therapy in patients with AF by considering risk versus benefit profiles and rationalising treatment selection. (Cardiol J 2017; 24, 2: 176-187). PMID- 28070884 TI - A national survey of neurological monitoring practice after obstetric regional anaesthesia in the UK. AB - Neuraxial anaesthesia is widely used in obstetrics and neurological complications are rare. However, when they occur, subsequent investigation and management are time-critical and correlate with the extent of neurological recovery. The Third National Audit Project recommended the implementation of guidelines in obstetric epidural management, including advice on monitoring for early signs of problems and acting upon concerns. However, no national guideline exists for postoperative management in the obstetric population. We conducted a national survey of monitoring after obstetric neuraxial blockade and the management of an abnormally prolonged block. We received responses from 112/189 (59.3%) obstetric anaesthetic leads invited to participate. We determined that post-neuraxial blockade monitoring in the UK is highly variable: only 63/112 (56.3%) respondents' units had a monitoring policy in place, although most of these did not undertake formal neurological monitoring, and a range of different monitoring methods and schedules were employed. In 12/63 (19%) local policies, the first review of neurology was performed at the standard postoperative visit the following day, and 66/112 (58.9%) units had no protocol in place to address emergency management of abnormally prolonged neuraxial blockade. Where a policy was in place, the initial recommended action and the type of imaging used were variable. PMID- 28070885 TI - Barriers toward organ donation in a Danish University Hospital. AB - BACKGROUND: In Denmark, organ donation-rates are below the average in the western countries. We investigated the donor potential and identified barriers toward organ donation in a Danish university hospital. METHODS: All patients who died in Aalborg University Hospital in 2012 were retrospectively identified. Patients with a CT- or MRI-proven deadly brain-lesion were eligible for inclusion. RESULTS: Eighty-five patients with deadly brain-lesions were included, and of these 47 patients died in the intensive care unit (ICU). Older age and diagnosis of brain-hemorrhage and infarction were associated with admission to general ward (GW). In 62.4% of the patients the potential of becoming a donor was not identified. No donations occurred from patients dying from intracerebral hemorrhage or brain-infarction although they represented 44.7% of the potential donors. DISCUSSION: This study reveals a huge, unrecognized donation potential at our hospital. About 30% was lost because they were never admitted to the ICU. After primary admission to the ICU, 15.3% of the potential donors were lost because they were transferred to the GW. In patients who died in the ICU 17.6% of the patients were not evaluated as potential donors. The relatives refused donation in 17.6% of cases. CONCLUSION: It would be possible to raise the donation rate considerably if patients with donation potential are intubated and admitted to the ICU. When active treatment is considered withdrawn, possibility of organ donation should be evaluated, and the next of kin be approached by experienced staff. PMID- 28070886 TI - Spinal cord atrophy in anterior-posterior direction reflects impairment in multiple sclerosis. AB - OBJECTIVE: To investigate how atrophy is distributed over the cross section of the upper cervical spinal cord and how this relates to functional impairment in multiple sclerosis (MS). METHODS: We analysed the structural brain MRI scans of 54 patients with relapsing-remitting MS (n=22), primary progressive MS (n=9), secondary progressive MS (n=23) and 23 age- and sex-matched healthy controls. We measured the cross-sectional area (CSA), left-right width (LRW) and anterior posterior width (APW) of the spinal cord at the segmental level C2. We tested for a nonparametric linear relationship between these atrophy measures and clinical impairments as reflected by the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Impairment Scale (MSIS). RESULTS: In patients with MS, CSA and APW but not LRW were reduced compared to healthy controls (P<.02) and showed significant correlations with EDSS, MSIS and specific MSIS subscores. CONCLUSION: In patients with MS, atrophy of the upper cervical cord is most evident in the antero-posterior direction. As APW of the cervical cord can be readily derived from standard structural MRI of the brain, APW constitutes a clinically useful neuroimaging marker of disease-related neurodegeneration in MS. PMID- 28070887 TI - Diversity in the organization of elastin bundles and intramembranous muscles in bat wings. AB - Unlike birds and insects, bats fly with wings composed of thin skin that envelops the bones of the forelimb and spans the area between the limbs, digits, and sometimes the tail. This skin is complex and unusual; it is thinner than typical mammalian skin and contains organized bundles of elastin and embedded skeletal muscles. These elements are likely responsible for controlling the shape of the wing during flight and contributing to the aerodynamic capabilities of bats. We examined the arrangement of two macroscopic architectural elements in bat wings, elastin bundles and wing membrane muscles, to assess the diversity in bat wing skin morphology. We characterized the plagiopatagium and dactylopatagium of 130 species from 17 families of bats using cross-polarized light imaging. This method revealed structures with distinctive relative birefringence, heterogeneity of birefringence, variation in size, and degree of branching. We used previously published anatomical studies and tissue histology to identify birefringent structures, and we analyzed their architecture across taxa. Elastin bundles, muscles, neurovasculature, and collagenous fibers are present in all species. Elastin bundles are oriented in a predominantly spanwise or proximodistal direction, and there are five characteristic muscle arrays that occur within the plagiopatagium, far more muscle than typically recognized. These results inform recent functional studies of wing membrane architecture, support the functional hypothesis that elastin bundles aid wing folding and unfolding, and further suggest that all bats may use these architectural elements for flight. All species also possess numerous muscles within the wing membrane, but the architecture of muscle arrays within the plagiopatagium varies among families. To facilitate present and future discussion of these muscle arrays, we refine wing membrane muscle nomenclature in a manner that reflects this morphological diversity. The architecture of the constituents of the skin of the wing likely plays a key role in shaping wings during flight. PMID- 28070888 TI - Addressing heterogeneous needs using cerebral palsy registers. PMID- 28070889 TI - Guided parent-delivered cognitive behaviour therapy for children with anxiety disorders: Outcomes at 3- to 5-year follow-up. AB - OBJECTIVES: Brief guided parent-delivered cognitive behaviour therapy (CBT) has been developed to meet the demand for non-intensive interventions for children with anxiety disorders, and initial trials have shown it to be effective for children with a range of anxiety disorders. This study examined outcomes 3-5 years post-treatment. DESIGN: A long-term follow-up (LTFU) cohort study. METHODS: Families who (1) completed at least 50% of allocated treatment sessions of guided parent-delivered CBT for childhood anxiety as part of a randomized control trial (RCT), (2) provided consent to be recontacted, (3) had not received further mental health interventions, and (4) were contactable were invited to take part. Fifty-seven families (29% of the original sample) completed structured diagnostic interviews on average 50 months after treatment (39-61 months). RESULTS: At LTFU, 79% of the assessed children who had received the treatment no longer met criteria for their primary diagnosis, 63% did not meet criteria for any anxiety disorder, and 61% did not meet criteria for any DSM-IV disorder. Treatment gains were mostly maintained (60%), and some children went on to recover during the follow-up period without additional input from mental health services (19%). Few young people had relapsed since their last assessment (12%). Mean scores on standardized symptom questionnaires were within the normal range. CONCLUSIONS: Children who recovered from anxiety disorders following brief guided parent delivered CBT typically maintained good outcomes and few relapsed. These findings suggest that this is a viable first-line, low-intensity treatment approach. This study only included a small subsample of those in the original RCT (29%), and more information is required about those who dropped out of treatment and those who required further intervention immediately after treatment. PRACTITIONER POINTS: Treatment gains from brief guided parent-delivered cognitive behaviour therapy for children with anxiety are maintained for most children 3-5 years later. The majority of children who completed at least 50% of the intervention required no further mental health intervention in that time. Some children make continued improvement after completing the intervention. Data are based on a sample of families from southern England where the primary caregiving parent was free of mental health difficulties. Further research is needed to explore the mental health needs of those who do not benefit from this intervention. PMID- 28070890 TI - The Role of Conventional and Right-Sided ECG Screening for Subcutaneous ICD in a Tetralogy of Fallot Population. AB - BACKGROUND: Information regarding suitability for subcutaneous implantable cardioverter-defibrillator (S-ICD) implant in tetralogy of Fallot (ToF) population is scarce and needs to be further explored. THE AIMS OF OUR STUDY WERE: (1) to determine the proportion of patients with ToF eligible for S-ICD, (2) to identify the optimal sensing vector in ToF patients, (3) to test specifically the eligibility for S-ICD with right-sided screening, and (4) to compare with the proportion of eligible patients in a nonselected ICD population. METHODS: We recruited 60 consecutive patients with ToF and 40 consecutive nonselected patients. Conventional electrocardiographic screening was performed as usual. Right-sided alternative screening was studied by positioning the left arm and right arm electrodes 1 cm right lateral to the xiphoid midline. The Boston Scientific electrocardiogram (ECG) screening tool was utilized. RESULTS: We found a higher proportion of patients with right-sided positive screening in comparison with standard screening (77 +/- 0.4% vs. 67 +/- 0.4%; P < 0.0001) and a trend to higher number of appropriate leads in right-sided screening (1.3 +/- 1 vs. 1.1 +/- 1 ms; P = 0.07). Patients who failed the screening had a longer QRS duration and longer QT interval. Standard and right-sided screening showed a higher percent of positive patients in the control group compared to ToF patients (P < 0.001). CONCLUSION: Right-sided screening was associated with a significant 10% increase in S-ICD eligibility in ToF patients. When comparing with an acquired cardiomyopathies group, ToF showed a lower eligibility for S-ICD. The most appropriate ECG vector was the alternate vector in contrast to what is observed in the general population. PMID- 28070891 TI - A ROP2-RIC1 pathway fine-tunes microtubule reorganization for salt tolerance in Arabidopsis. AB - The reorganization of microtubules induced by salt stress is required for Arabidopsis survival under high salinity conditions. RIC1 is an effector of Rho related GTPase from plants (ROPs) and a known microtubule-associated protein. In this study, we demonstrated that RIC1 expression decreased with long-term NaCl treatment, and ric1-1 seedlings exhibited a higher survival rate under salt stress. We found that RIC1 reduced the frequency of microtubule transition from shortening to growing status and knockout of RIC1 improved the reassembly of depolymerized microtubules caused by either oryzalin treatment or salt stress. Further investigation showed that constitutively active ROP2 promoted the reassembly of microtubules and the survival of seedlings under salt stress. A rop2-1 ric1-1 double mutant rescued the salt-sensitive phenotype of rop2-1, indicating that ROP2 functions in salt tolerance through RIC1. Although ROP2 did not regulate RIC1 expression upon salt stress, a quick but mild increase of ROP2 activity was induced, led to reduction of RIC1 on microtubules. Collectively, our study reveals an ROP2-RIC1 pathway that fine-tunes microtubule dynamics in response to salt stress in Arabidopsis. This finding not only reveals a new regulatory mechanism for microtubule reorganization under salt stress but also the importance of ROP signalling for salinity tolerance. PMID- 28070892 TI - Extraction, partial purification and characterization of amylase from parthenocarpic date (Phoenix dactylifera): effect on cake quality. AB - BACKGROUND: Phoenix dactylifera L. plays an important role in social, economic and ecological Tunisian sectors. Some date palms produce parthenocarpic fruit named Sish. The objective of the present study was to extract biomolecules from parthenocarpic fruit by producing value-added products from the fruits. RESULTS: The extraction of amylolytic activity from parthenocarpic fruit (AmyPF) was optimized using Box-Behnken design (BBD). Partial purification of about 250-fold with an activity yield of 47% was achieved. The amylase exhibited a specific activity of 80 U mg-1 protein. The optimum pH and temperature for enzyme activity were 5 and 55 degrees C respectively. The enzyme was highly active over a wide range of pH (5-10), and significant stabilization was observed at 60 degrees C. The purified enzyme belongs to the exo type of amylases. Given the economic and industrial relevance of amylases used in the food industry, three different concentrations of AmyPF (0.007, 0.014 and 0.018 U g-1 ) were incorporated into a cake formulation, resulting in a decrease in density, moisture retention and water activity and an increase in hardness. CONCLUSION: The beneficial effect of AmyPF on the technological characteristics of cakes was confirmed by sensory evaluation. (c) 2017 Society of Chemical Industry. PMID- 28070893 TI - Improving Nonmetric Sex Classification for Hispanic Individuals. AB - Current techniques used by forensic anthropologists for the identification of unknown human skeletal remains have largely been created using U.S. Black and White samples. When applied to Hispanics, these techniques perform poorly and can lead to misclassifications; consequently, there is an imperative need for population-specific standards for Hispanics. This research examines the classification accuracies obtained by the original Walker (Am J Phys Anthropol, 136, 2008) and Klales et al. (Am J Phys Anthropol, 149, 2012) methods for nonmetric sex estimation and provides recalibrated regression equations specifically for Hispanics. Ordinal data were collected for five skull and three pelvic traits from a sample of 54 modern Hispanic individuals. Recalibration of the Klales et al. equation improved accuracy (90.3% vs. 94.1%), while recalibration of the Walker method equation decreased accuracy (81.5% vs. 74.1%), but greatly improved sex bias (22.2% vs. -7.4%), thereby making the recalibrated equations more appropriate for use with Hispanics. PMID- 28070894 TI - A Phase 1, Open-Label, Randomized, Crossover Study Evaluating the Bioavailability of TAS-102 (Trifluridine/Tipiracil) Tablets Relative to an Oral Solution Containing Equivalent Amounts of Trifluridine and Tipiracil. AB - TAS-102 (trifluridine/tipiracil) is composed of an antineoplastic thymidine-based nucleoside analogue trifluridine (FTD), and a thymidine phosphorylase inhibitor, tipiracil (TPI), at a molar ratio of 1:0.5 (weight ratio, 1:0.471). A phase 1 study evaluated relative bioavailability of TAS-102 tablets compared with an oral solution containing equivalent amounts of FTD and TPI. In an open-label, 2 sequence, 3-period, crossover bioavailability study (part 1), patients 18 years or older with advanced solid tumors were randomized to receive TAS-102 tablets (60 mg; 3 * 20-mg tablets) on day 1 and TAS-102 oral solution (60 mg) on days 8 and 15, or the opposite sequence. In an extension (part 2), all patients received TAS-102 tablets. Of the 46 patients treated in the crossover study, 38 were evaluable in the crossover bioavailability pharmacokinetic population. For area under the concentration-time curve (AUC)0-infinity and AUC0-last for FTD and TPI, and maximum plasma concentration (Cmax ) for TPI, the 90% confidence intervals (CIs) of the geometric mean ratios were within the 0.80 to 1.25 boundary for demonstration of bioequivalence; for FTD Cmax , the lower limit of the 90%CI was 0.786. The most frequently reported treatment-related grade 3 or 4 adverse events were neutropenia (7 patients) and decreased neutrophil count (3 patients). Although the lower limit of the 90%CI for the geometric mean ratio of FTD Cmax was slightly lower than 0.80, the bioavailability of the TAS-102 tablet is considered clinically similar to that of a TAS-102 oral solution. TAS-102 was well tolerated in this population of patients with advanced solid tumors. PMID- 28070895 TI - Influence analysis for skew-normal semiparametric joint models of multivariate longitudinal and multivariate survival data. AB - The normality assumption of measurement error is a widely used distribution in joint models of longitudinal and survival data, but it may lead to unreasonable or even misleading results when longitudinal data reveal skewness feature. This paper proposes a new joint model for multivariate longitudinal and multivariate survival data by incorporating a nonparametric function into the trajectory function and hazard function and assuming that measurement errors in longitudinal measurement models follow a skew-normal distribution. A Monte Carlo Expectation Maximization (EM) algorithm together with the penalized-splines technique and the Metropolis-Hastings algorithm within the Gibbs sampler is developed to estimate parameters and nonparametric functions in the considered joint models. Case deletion diagnostic measures are proposed to identify the potential influential observations, and an extended local influence method is presented to assess local influence of minor perturbations. Simulation studies and a real example from a clinical trial are presented to illustrate the proposed methodologies. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28070896 TI - Tiny protein detection using pressure through solid-state nanopores. AB - Solid-state nanopore is a promising tool to detect proteins and its complexes. Small proteins (sub-35 kDa) translocate very fast which could not be detected by normal patch-clamp recording instrument due to low temporal resolution. We first introduce pressure into protein study and detection. The pressure-derived force, combined with the voltage bias, makes very tiny protein (MW < 6.5 kDa) detection possible. Capture rate for Aprotinin is enhanced five times more than that in traditional voltage-driven method by fine tuning of pressure and voltage. Temporal resolution of Aprotinin detection has improved by decreasing effective driving force. Moreover, we provide potential method to locate the equilibrium range for BSA movement in ionic solution by modulating driving pressure and retard voltage. Our study is of fundamental significance in nanopore research and provides unique platforms to study small proteins and other tiny biomolecules. PMID- 28070897 TI - Stable spline deconvolution for dynamic susceptibility contrast MRI. AB - PURPOSE: To present the stable spline (SS) deconvolution method for the quantification of the cerebral blood flow (CBF) from dynamic susceptibility contrast MRI. METHODS: The SS method was compared with both the block-circulant singular value decomposition (oSVD) and nonlinear stochastic regularization (NSR) methods. oSVD is one of the most popular deconvolution methods in dynamic susceptibility contrast MRI (DSC-MRI). NSR is an alternative approach that we proposed previously. The three methods were compared using simulated data and two clinical data sets. RESULTS: The SS method correctly reconstructed the dispersed residue function and its peak in presence of dispersion, regardless of the delay. In absence of dispersion, SS performs similarly to oSVD and does not correctly reconstruct the residue function and its peak. SS and NSR better differentiate healthy and pathologic CBF values compared with oSVD in all simulated conditions. Using acquired data, SS and NSR provide more clinically plausible and physiological estimates of the residue function and CBF maps compared with oSVD. CONCLUSION: The SS method overcomes some of the limitations of oSVD, such as unphysiological estimates of the residue function and NSR, the latter of which is too computationally expensive to be applied to large data sets. Thus, the SS method is a valuable alternative for CBF quantification using DSC-MRI data. Magn Reson Med 78:1801-1811, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28070898 TI - Clearance of recalcitrant warts in a patient with idiopathic immune deficiency following administration of the quadrivalent human papillomavirus vaccine. AB - Human papillomavirus (HPV)-induced cutaneous warts are potentially serious and debilitating. In immunosuppressed patients, these warts may be resistant to standard therapies. We report a case of a young patient with a primary immune deficiency whose recalcitrant cutaneous warts regressed completely following administration of a quadrivalent HPV vaccine. PMID- 28070899 TI - Sofosbuvir-based treatment regimens: real life results of 14 409 chronic HCV genotype 4 patients in Egypt. AB - BACKGROUND: Chronic hepatitis C virus infection is one of the most important health problems in Egypt. The Ministry of Health's National Treatment Programme introduced sofosbuvir-based therapy in October 2014. AIM: To assess the clinical effectiveness and predictors of response to SOF-based treatment regimens, either dual therapy, with SOF/ribavirin (RBV) for 6 months or triple therapy with SOF/peg-IFN-alfa-2a/RBV for 3 months, in a cohort of patients treated in National Treatment Programme affiliated centres in Egypt. METHODS: Between October 2014 and end of 2014, patients who were eligible for treatment were classified according to their eligibility for interferon therapy: Group 1 (interferon eligible) were treated with triple therapy for 12 weeks and Group 2 (interferon ineligible) were treated with dual therapy for 24 weeks. Difficult to treat patients included those with F3-F4 on Metavir score, Fib-4 >3.25, albumin <=3.5, total Bilirubin >1.2 mg/dL, INR >1.2 and platelet count <150 000 mm3 . RESULTS: Twelve weeks post-treatment data were available on 14 409 patients; 8742 in group 1 and 5667 in group 2. In group 1, the sustained virological response at week 12 (SVR12) was 94% and in group 2 the SVR12 was 78.7%. Multivariate logistic regression analysis in which treatment failure is the dependent variable was done. Male gender, being a difficult to treat patient and previous interferon therapy were significant predictors of nonresponse in both treatment groups. CONCLUSION: Results of sofosbuvir-based therapies in Egypt achieved similar rates of SVR12 as seen in phase III efficacy studies. PMID- 28070900 TI - Chemoselective Henry Condensations Catalyzed by Artificial Carboligases. AB - The promiscuity of de novo designed enzymes provides a privileged platform for diverse abiological reactions. In this work, we report the first example of a nitroolefin synthase that catalyzes the Henry condensation between aromatic aldehydes and nitromethane. Significant catalytic activity was discovered in the computationally designed and evolved carboligase RA95.5-8, and mutations around the active site were shown to improve the reaction rate, demonstrating the potential to optimize the enzyme by directed evolution. This novel nitroolefin synthase could participate in complex biological cascades, whereby the highly tunable chemoselectivity could afford useful synthetic building blocks. PMID- 28070901 TI - A case of blue naevus of the mucocutaneous junction of the lower eyelid margin associated with acquired bilateral naevus of Ota-like macule. PMID- 28070902 TI - A modified LVAD technique to augment caval and pulmonary arterial blood flow in the "failing Fontan" circulation. AB - BACKGROUND: There are minimal circulatory support options for patients with a failing Fontan. The Heartmate II (HMII) left ventricular assist device (Thoratec, Bedford, MA) in its packaged state cannot augment caval/pulmonary arterial blood flow. AIM: We hypothesized that a modified HMII pump could augment caval and pulmonary arterial blood flow. METHODS: A bifurcated ringed Gore-Tex graft (W. L. Gore & Associates, Flagstaff, AZ) was sewn to the HMII inflow, and the outflow graft transected and tapered from 16 mm to 8 mm in diameter. In three sheep, the inflow and outflow grafts were anastomosed end-to-side to both cava and the pulmonary artery. RESULTS: Following baseline measurements, the pump speed was increased to 8000 revolutions per minute (RPMs). Compared to baseline, at 8000 RPMs, there were no significant differences in mean arterial, central venous, or pulmonary arterial pressure. However, there was a significant decrease in right ventricular diastolic diameter (3.1 +/- 0.1 vs. 1.8 +/- 0.2 cm, R = 0.6, p = 0.02) and similarly a decrease in pulmonary arterial pulse pressure (8.5 +/- 2.1 vs. 2.1 +/- 2.9 mmHg, p = 0.01). As pump speed increased, there was a corresponding increase in pump flow and power, with a decrease in pulsatility index. CONCLUSIONS: These findings suggest that the HMII may be modified to provide caval/pulmonary circulatory support for the failing Fontan circulation. PMID- 28070904 TI - Re: Potassium-sodium citrate prevents the development of renal microcalculi into symptomatic stones in calcium stone-forming patients. PMID- 28070903 TI - Myocardial deformation in pediatric patients with mucopolysaccharidoses: A two dimensional speckle tracking echocardiography study. AB - BACKGROUND: Mucopolysaccharidoses (MPS) are inherited lysosomal storage disorders caused by deficiency of required glycosaminoglycans breakdown enzymes, inducing cardiac involvement. Little is known about myocardial deformation involvement in MPS. Our aim was to assess biventricular structure and function in asymptomatic children with MPS using standard echo Doppler and 2D speckle tracking (STE). METHODS: Fifteen MPS children (one type I, six type II, three type III A, one III B, three IV A, one VI), asymptomatic for cardiac symptoms, and 15 age and sex matched healthy controls underwent echo Doppler and STE. Left ventricular (LV) wall thicknesses, diameters, and mass were normalized by z-score. LV global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS) at papillary muscles, LV twisting, and right ventricular (RV) GLS were measured. RESULTS: The two groups were comparable for body mass index, heart rate, and blood pressure. LV mass index and relative wall thickness were higher in MPS. Ejection fraction (EF), and s' velocity did not differ between the two groups. E/A ratio was lower and E/e' higher in MPS. Tricuspid annular plane systolic excursion, RV s' and e' were lower in MPS. LV GLS did not differ between the two groups, but GCS (P=.014), GRS (P=.023), twisting (P=.012), and RV GLS (P<.001) were lower in the MPS group. CONCLUSIONS: LV strain abnormalities are detectable in MPS pediatric patients, independently of MPS type, when EF is still normal. RV GLS is also involved consensually with TAPSE reduction. STE can be useful for detection of subclinical myocardial damage in MPS. PMID- 28070905 TI - Dentists' perspective about dental amalgam: current use and future direction. AB - OBJECTIVES: In 2013, the United Nations Environment Programme (UNEP) reached a binding agreement - a.k.a. the Minamata treaty - to decrease dental amalgam use. This study aims to investigate US dentists' current practice and opinions about amalgam use, and to determine factors affecting their amalgam use and opinions. METHODS: A total of 45,557 general dentists and 5,101 pediatric dentists were invited to participate in a pre-tested electronic survey. The survey consisted of 12 close-ended questions using a 5-point Likert Scale. The QualtricsTM software was used to distribute the survey, followed by three reminders. RESULTS: Response rate was 5.2 percent for general dentists, and 17.6 percent for pediatric dentists. Sixty-two percent of general dentists and 56 percent of pediatric dentists reported using amalgam. Most dentists disagreed with banning amalgam, while agreeing with installing amalgam separators. Environmentally conscious dentists were more likely to agree with banning amalgam and installing amalgam separators. CONCLUSION: Responding dentists favor the continued use of dental amalgam. Their perspectives vary by several factors including dentists' environmental consciousness. Policies toward minimizing amalgam's environmental impact need to be implemented. PMID- 28070906 TI - Evolutionary aspects of the development of teeth and baleen in the bowhead whale. AB - In utero, baleen whales initiate the development of several dozens of teeth in upper and lower jaws. These tooth germs reach the bell stage and are sometimes mineralized, but toward the end of prenatal life they are resorbed and no trace remains after birth. Around the time that the germs disappear, the keratinous baleen plates start to form in the upper jaw, and these form the food-collecting mechanism. Baleen whale ancestors had two generations of teeth and never developed baleen, and the prenatal teeth of modern fetuses are usually interpreted as an evolutionary leftover. We investigated the development of teeth and baleen in bowhead whale fetuses using histological and immunohistochemical evidence. We found that upper and lower dentition initially follow similar developmental pathways. As development proceeds, upper and lower tooth germs diverge developmentally. Lower tooth germs differ along the length of the jaw, reminiscent of a heterodont dentition of cetacean ancestors, and lingual processes of the dental lamina represent initiation of tooth bud formation of replacement teeth. Upper tooth germs remain homodont and there is no evidence of a secondary dentition. After these germs disappear, the oral epithelium thickens to form the baleen plates, and the protein FGF-4 displays a signaling pattern reminiscent of baleen plates. In laboratory mammals, FGF-4 is not involved in the formation of hair or palatal rugae, but it is involved in tooth development. This leads us to propose that the signaling cascade that forms teeth in most mammals has been exapted to be involved in baleen plate ontogeny in mysticetes. PMID- 28070907 TI - Analysis of Explosives by GC-UV. AB - A mixture of explosives was analyzed by gas chromatography (GC) linked to ultraviolet (UV) spectrophotometry that enabled detection in the range of 178-330 nm. The gas-phase UV spectra of 2,4,6-trinitrotoluene (TNT), 2,4-dinitrotoluene (DNT), ethylene glycol dinitrate (EGDN), glycerine trinitrate (NG, nitroglycerine), triacetone triperoxide (TATP), and pentaerythritol tetranitrate (PETN) were successfully recorded. The most interesting aspect of the current application is that it enabled simultaneous detection of both the target analyte and its decomposition products. At suitable elevated temperatures of the transfer line between the GC instrument and the UV detector, a partial decomposition was accomplished. Detection was made in real time and resulted in overlaid spectra of the mother compound and its decomposition product. Hence, the presented approach added another level to the qualitative identification of the explosives in comparison with traditional methods that relies only on the detection of the target analyte. As expected, the decomposition product of EGDN, NG, and PETN was NO, while TATP degraded to acetone. DNT and TNT did not exhibit any decomposition at the temperatures used. PMID- 28070908 TI - Virilisation in siblings secondary to transdermal 'bioidentical' testosterone exposure. PMID- 28070909 TI - Peptide fibrils as monomer storage of the covalent HIV-1 integrase inhibitor. AB - We have recently reported the covalent inhibition of HIV-1 integrase by an N terminal succinimide-modified lens epithelium-derived growth factor (361-370) peptide. We also showed that this peptide is proteolytically stable. Here, we show that this inhibitor is stored as fibrils that serve as a stock for the inhibitory monomers. The fibrils increase the local concentration of the peptide at the target protein. When the monomers bind integrase, the equilibrium between the fibrils and their monomers shifts towards the formation of peptide monomers. The combination of fibril formation and subsequent proteolytic stability of the peptide may bring to new strategy for developing therapeutic agents. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd. PMID- 28070910 TI - Formation of Orthographic Representations in Spanish Dyslexic Children: The Role of Syllable Complexity and Frequency. AB - Recent studies have suggested that Spanish children with dyslexia have difficulty storing orthographic representations of new words. But given that the syllable plays an important role in word recognition in Spanish, it is possible that the formation of orthographic representations is influenced by the characteristics of the syllables that make up the words. The objective of this study was to determine whether syllabic frequency and syllabic complexity influence orthographic learning in children with dyslexia. We compared the performance of a group of dyslexic children with that of a group of typical readers on a task that involved reading short and long pseudowords six times; we manipulated the frequency and complexity of the syllables from which the pseudowords were constructed. The results showed that dyslexic children do not benefit from syllabic simplicity or frequency when it comes to storing orthographic representations as the length effect in the dyslexic group remained was unchanged after repeated readings, regardless of stimulus characteristics. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28070911 TI - Effects of exercise training on brain-derived neurotrophic factor in skeletal muscle and heart of rats post myocardial infarction. AB - NEW FINDINGS: What is the central question of this study? Exercise training increases brain-derived neurotrophic factor (BDNF) in the hippocampus, which depends on a myokine, fibronectin type III domain-containing protein 5 (FNDC5). Whether exercise training after myocardial infarction induces parallel increases in FNDC5 and BDNF expression in skeletal muscle and the heart has not yet been studied. What is the main finding and its importance? Exercise training after myocardial infarction increases BDNF protein in skeletal muscle and the non infarct area of the LV without changes in FNDC5 protein, suggesting that BDNF is not regulated by FNDC5 in skeletal muscle and heart. An increase in cardiac BDNF may contribute to the improvement of cardiac function by exercise training. Exercise training after myocardial infarction (MI) attenuates progressive left ventricular (LV) remodelling and dysfunction, but the peripheral stimuli induced by exercise that trigger these beneficial effects are still unclear. We investigated as possible mediators fibronectin type III domain-containing protein 5 (FNDC5) and brain-derived neurotrophic factor (BDNF) in the skeletal muscle and heart. Male Wistar rats underwent either sham surgery or ligation of the left descending coronary artery, and surviving MI rats were allocated to either a sedentary (Sed-MI) or an exercise group (ExT-MI). Exercise training was done for 4 weeks on a motor-driven treadmill. At the end, LV function was evaluated, and FNDC5 and BDNF mRNA and protein were assessed in soleus muscle, quadriceps and non-, peri- and infarct areas of the LV. At 5 weeks post MI, FNDC5 mRNA was decreased in soleus muscle and all areas of the LV, but FNDC5 protein was increased in the soleus muscle and the infarct area. Mature BDNF (mBDNF) protein was decreased in the infarct area without a change in mRNA. Exercise training attenuated the decrease in ejection fraction and the increase in LV end-diastolic pressure post MI. Exercise training had no effect on FNDC5 mRNA and protein, but increased mBDNF protein in soleus muscle, quadriceps and the non-infarct area of the LV. The mBDNF protein in the non-infarct area correlated positively with ejection fraction and inversely with LV end-diastolic pressure. In conclusion, mBDNF is induced by exercise training in skeletal muscle and the non-infarct area of the LV, which may contribute to improvement of muscle dysfunction and cardiac function post MI. PMID- 28070912 TI - Role of testosterone and Y chromosome genes for the masculinization of the human brain. AB - : Women with complete androgen insensitivity syndrome (CAIS) have a male (46,XY) karyotype but no functional androgen receptors. Their condition, therefore, offers a unique model for studying testosterone effects on cerebral sex dimorphism. We present MRI data from 16 women with CAIS and 32 male (46,XY) and 32 female (46,XX) controls. METHODS: FreeSurfer software was employed to measure cortical thickness and subcortical structural volumes. Axonal connections, indexed by fractional anisotropy, (FA) were measured with diffusion tensor imaging, and functional connectivity with resting state fMRI. RESULTS: Compared to men, CAIS women displayed a "female" pattern by having thicker parietal and occipital cortices, lower FA values in the right corticospinal, superior and inferior longitudinal tracts, and corpus callosum. Their functional connectivity from the amygdala to the medial prefrontal cortex, was stronger and amygdala connections to the motor cortex weaker than in control men. CAIS and control women also showed stronger posterior cingulate and precuneus connections in the default mode network. Thickness of the motor cortex, the caudate volume, and the FA in the callosal body followed, however, a "male" pattern. CONCLUSION: Altogether, these data suggest that testosterone modulates the microstructure of somatosensory and visual cortices and their axonal connections to the frontal cortex. Testosterone also influenced functional connections from the amygdala, whereas the motor cortex could, in agreement with our previous reports, be moderated by processes linked to X-chromosome gene dosage. These data raise the question about other genetic factors masculinizing the human brain than the SRY gene and testosterone. Hum Brain Mapp 38:1801-1814, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28070913 TI - Does Identification of Previously Undiagnosed Conditions Change Care-Seeking Behavior? AB - OBJECTIVE: To determine whether identification of previously undiagnosed high cholesterol, hypertension, and/or diabetes during an in-home assessment impacts care seeking among Medicare beneficiaries. DATA SOURCES/STUDY SETTING: Data from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study, which recruited African American and white participants across the continental United States from 2003-2007, were linked to Medicare claims. STUDY DESIGN: We used panel data models to analyze changes in doctor visits for evaluation and management of conditions after participants were assessed, utilizing the study's rolling recruitment to control for secular trends. DATA EXTRACTION METHODS: We extracted Medicare claims for the 24 months before through 24 months after assessment via REGARDS for 5,884 participants. PRINCIPAL FINDINGS: Semi-annual doctor visits for previously undiagnosed conditions increased by 22 percentage points (95 percent confidence interval: 16-28) 2 years following assessment. The effect was similar by gender, race, region, and Medicaid, but it may have been lower among participants who lacked a usual health care provider. CONCLUSIONS: In home assessment of cholesterol, blood pressure, and blood glucose can increase doctor visits for individuals with previously undiagnosed conditions. However, biomarker assessment may have more limited impact among individuals with low access to care. PMID- 28070915 TI - Mitral valve resistance determines hemodynamic consequences of severe rheumatic mitral stenosis and immediate outcomes of percutaneous valvuloplasty. AB - INTRODUCTION: The mitral valve area (MVA) poorly reflects the hemodynamic status of (MS). In this study, we compared the MVA with mitral valve resistance (MVR) with regard to the determination of hemodynamic consequences of MS and the immediate outcomes of percutaneous balloon mitral valvuloplasty (PBMV). METHODS: In a prospective study, 36 patients with severe rheumatic MS with left ventricular ejection fraction (LVEF) >50% were evaluated. They underwent transthoracic echocardiography (TTE) and catheterization. The MVA was measured by two-dimensional planimetry and pressure half-time (PHT), and the MVR was calculated using the equation: 1333 * transmitral pressure gradient mean transmitral diastolic flow rate. RESULTS: The patients' mean age was 47.8+/-10.5 years. MVR >=140.6 dynes.s/cm5 detected systolic pulmonary arterial pressure (sPAP) >55 mm Hg with a sensitivity of 100% and a specificity of 74%. The sensitivity and specificity of MVA<0.75 cm2 to discriminate elevated sPAP were 81% and 89%, respectively. PHT >=323.5 mseconds had a sensitivity of 78% and a specificity of 96% to detect an elevated sPAP. To predict a successful PBMV, preprocedural MVR >=106.1 dynes.s/cm5 had a sensitivity of 100% and a specificity of 67% (area under the curve [AUC]=0.763; 95% confidence interval [CI]=0.520 1.006; P=.034); preprocedural MVA <0.95 cm2 had a sensitivity of 78% and a specificity of 73% (AUC=0.730; 95% CI=0.503-0.956; P=.065); and preprocedural PHT >=210.5 mseconds had a sensitivity of 73% and a specificity of 78% (AUC=0.707; 95% CI=0.474-0.941; P=.095). CONCLUSIONS: MVR seems to be more accurate than MVA in determining the hemodynamic consequences of severe MS as determined by sPAP. In addition, preprocedural MVR detected successful PBMVs. PMID- 28070914 TI - Risk of Cesarean scar defect following single- vs double-layer uterine closure: systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: There is a growing body of evidence that suggests that the surgical technique for uterine closure following Cesarean delivery influences the healing of the Cesarean scar, but there is still no consensus on the optimal technique. The aim of this systematic review and meta-analysis was to compare the effect of single- vs double-layer uterine closure on the risk of uterine scar defect. METHODS: MEDLINE, Scopus, ClinicalTrials.gov, PROSPERO, EMBASE and the Cochrane Central Register of Controlled Trials were searched from inception of each database until May 2016. All randomized controlled trials (RCTs) evaluating the effect of single- vs double-layer uterine closure following low transverse Cesarean section on the risk of uterine scar defect were included. The primary outcome was the incidence of uterine scar defects detected on ultrasound. Secondary outcomes were residual myometrial thickness evaluated by ultrasound and the incidence of uterine dehiscence and/or rupture in subsequent pregnancy. Summary measures were reported as relative risk (RR) or mean difference (MD), with 95% CIs. Quality of the evidence was assessed using the GRADE approach. RESULTS: Nine RCTs (3969 participants) were included in the meta-analysis. The overall risk of bias of the included trials was low. Statistical heterogeneity within the studies was low, with no inconsistency in the primary and secondary outcomes. Women who received single-layer uterine closure had a similar incidence of uterine scar defects as did women who received double-layer closure (25% vs 43%; RR, 0.77 (95% CI, 0.36-1.64); five trials; 350 participants; low quality of evidence). Compared with double-layer uterine closure, women who received single layer closure had a significantly thinner residual myometrium on ultrasound (MD, 2.19 mm (95% CI, -2.80 to -1.57 mm); four trials; 374 participants; low quality of evidence). No difference was found in the incidence of uterine dehiscence (0.4% vs 0.2%; RR, 1.34 (95% CI, 0.24-4.82); three trials; 3421 participants; low quality of evidence) or uterine rupture (0.1% vs 0.1%; RR, 0.52 (95% CI, 0.05 5.53); one trial; 3234 participants; low quality of evidence) in a subsequent pregnancy. CONCLUSIONS: Single- and double-layer closure of the uterine incision following Cesarean delivery are associated with a similar incidence of Cesarean scar defects, as well as uterine dehiscence and rupture in a subsequent pregnancy. However, the quality level of summary estimates, as assessed by GRADE, was low, indicating that the true effect may be, or is even likely to be, substantially different from the estimate of the effect. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28070916 TI - Non-invasive assessment of muscle oxygenation may aid in optimising transfusion threshold decisions in ambulatory paediatric patients. AB - OBJECTIVE: To assess the potential utility of a novel non-invasive muscle oxygen measurement to determine the presence of muscle hypoxia in patients with anaemia. BACKGROUND: Recent assessment of the risk/benefit ratio of blood transfusion has led to clinical strategies optimising transfusion decisions. These decisions are primarily based on haematocrit (Hct) but not oxygen delivery, the primary function of red blood cells (RBCs). We hypothesised that muscle oxygenation (MOx) would correlate with Hct in patients with anaemia and may be a physiologically relevant determinant of the transfusion threshold. METHODS/MATERIALS: MOx was non invasively determined in children in the Cancer and Blood Disorders Center ambulatory clinic at Seattle Children's Hospital using a custom-designed optical probe and spectrometer. MOx was compared with contemporaneous Hct. In subjects receiving RBCs, MOx and Hct were also determined following transfusion. RESULTS: MOx ranged from 36.7 to 100%, and Hct ranged from 17.0 to 38.6% in 27 measurements from 16 patients. High MOx values were associated with high Hct. Mean MOx for patients with normal Hct for age (n = 5) was 95.9 +/- 2.9%. RBC transfusion increased mean Hct from 19.1 +/- 1.5% to 29.3 +/- 2.0 and mean MOx from 67.9 +/- 21.1% to 89.9 +/- 9.8%. Among six transfusion episodes (in five patients) with initial Hct < 22, only three had a pre-transfusion MOx of <70%. Patients with the lowest pre-transfusion MOx had the largest increase in MOx after transfusion. CONCLUSIONS: These preliminary data suggest that MOx may aid in making transfusion decisions when used in combination with Hct. PMID- 28070917 TI - Dual-energy CT quantitative imaging: a comparison study between twin-beam and dual-source CT scanners. AB - PURPOSE: To assess image quality and to quantify the accuracy of relative electron densities (rhoe ) and effective atomic numbers (Zeff ) for three dual energy computed tomography (DECT) scanners: a novel single-source split-filter (i.e., twin-beam) and two dual-source scanners. METHODS: Measurements were made with a second generation dual-source scanner at 80/140Sn kVp, a third-generation twin-beam single-source scanner at 120 kVp with gold (Au) and tin (Sn) filters, and a third-generation dual-source scanner at 90/150Sn kVp. Three phantoms with tissue inserts were scanned and used for calibration and validation of parameterized methods to extract rhoe and Zeff , whereas iodine and calcium inserts were used to quantify Contrast-to-Noise-Ratio (CNR). Spatial resolution in tomographic images was also tested. RESULTS: The third-generation scanners have an image resolution of 6.2, ~0.5 lp/cm higher than the second generation scanner. The twin-beam scanner has low imaging contrast for iodine materials due to its limited spectral separation. The parameterization methods resulted in calibrations with low fit residuals for the dual-source scanners, yielding values of rhoe and Zeff close to the reference values (errors within 1.2% for rhoe and 6.2% for Zeff for a dose of 20 mGy, excluding lung substitute tissues). The twin beam scanner presented overall higher errors (within 3.2% for rhoe and 28% for Zeff , also excluding lung inserts) and also larger variations for uniform inserts. CONCLUSIONS: Spatial resolution is similar for the three scanners. The twin-beam is able to derive rhoe and Zeff , but with inferior accuracy compared to both dual-source scanners. PMID- 28070918 TI - Stereotype threat and social function in opioid substitution therapy patients. AB - OBJECTIVES: People with a history of substance abuse are subject to widespread stigmatization. It seems likely that this societal disapproval will result in feelings of stereotype threat, or the belief that one is the target of demeaning stereotypes. If so, stereotype threat has the potential to contribute to functional difficulties including poor social outcomes. METHODS: Eighty drug users on opioid substitution therapy and 84 demographically matched controls completed measures of mental health and social function. The opioid substitution therapy group were additionally asked to complete a measure that focused on their feelings of stereotype threat in relation to their drug use history. Bivariate correlations and hierarchical regression analyses were conducted to establish the magnitude and specificity of the relationship between stereotype threat and social functioning. RESULTS: Relative to controls, the opioid substitution therapy group reported higher levels of negative affect and schizotypy, and poorer social functioning, with all three of these indices significantly correlated with their feelings of stereotype threat. The results also showed that stereotype threat contributed significant unique variance to social functioning in the opioid substitution therapy group, even after taking into account other background, clinical, and mental health variables. CONCLUSIONS: Social functioning is an important aspect of recovery, yet these data indicate that people with a history of drug abuse who believe they are the target of stereotypical attitudes have poorer social functioning. This relationship holds after controlling for the impact of other variables on social functioning, including mental health. The theoretical and practical implications of these findings are discussed. PRACTITIONER POINTS: Concerns about being stereotyped can shape the social experiences of opioid substitution therapy patients. Opioid substitution therapy patients who feel negatively stereotyped experience greater social function deficits, and this relationship emerges after controlling for important clinical and mental health variables. Understanding the relationship between feeling stereotyped and social function may assist practitioners in their treatment. The study is cross-sectional, and thus, experimental or longitudinal research is required to determine the causal direction between stereotype threat and social function. PMID- 28070919 TI - Clinical utility of the basophil activation test for analysis of allergic transfusion reactions: a pilot study. AB - BACKGROUND AND OBJECTIVES: In previous studies, we demonstrated that the basophil activating effects of supernatants found in residual-transfused platelet concentrates (PC-SNs) on whole blood basophils in cases of allergic transfusion reactions (ATRs) could be assessed by the basophil activation test (BAT) in terms of allergen/IgE dependency. However, in these studies, the basophils were derived from third-party healthy volunteers. In this study, we performed BAT using patients' own blood basophils to analyse ATRs. MATERIALS AND METHODS: The BAT was performed in two cases of severe ATRs using residual PC-SNs and the patients' own basophils in the presence and absence of dasatinib, an inhibitor of IgE-mediated basophil activation. RESULTS: In both cases, PC-SNs exhibited basophil-activating activity against the patients' basophils, but not against basophils from third party healthy volunteers. In addition, basophil activation was inhibited in the presence of dasatinib, indicating that the basophils were activated in an allergen/IgE-dependent manner. Of note, the basophils in Case 2, but not in Case 1, were activated by PC-SNs from some unrelated non-haemolytic transfusion reaction cases. CONCLUSION: This pilot study indicates that the BAT may be useful in clarifying the causal relationship between ATRs and transfused blood as well as in elucidating the mechanisms behind ATRs considering the allergen/IgE dependent pathway. PMID- 28070920 TI - Unusual skin changes on the neck. PMID- 28070921 TI - BRM/SMARCA2-negative clear cell renal cell carcinoma is associated with a high percentage of BRM somatic mutations, deletions and promoter methylation. AB - AIMS: The aim of this study was to investigate potential molecular mechanisms associated with loss of BRM expression in poorly differentiated clear cell renal cell carcinoma (ccRCC). METHODS AND RESULTS: Nineteen previously selected BRM negative RCC tissues were examined by DNA sequencing, fluorescence in-situ hybridization (FISH) and methylation-specific polymerase chain reaction (PCR) of the BRM gene. BRM mutation was identified in 78.9% (15 of 19) cases, chromosome 9 monosomy or BRM deletion in 43.8% (seven of 16) and BRM promoter region cytosine phosphate-guanine (CpG) methylation in 42.8% (six of 14). These results indicated that 89.5% (17 of 19) of the cases harboured at least one type of BRM genetic alteration, with two or more types of alteration in 47.4% (nine of 19). Such alterations were found rarely in adjacent non-neoplastic tissues and low-grade areas of composite tumours. CONCLUSIONS: BRM gene mutation, chromosome 9 monosomy or BRM deletion and CpG methylation contribute collectively to the loss of BRM expression in ccRCC. This work focusing on composite tumours indicated that BRM abnormality occurred during tumour progression. PMID- 28070922 TI - An open-label randomized control trial of hopping and jumping training versus sensorimotor rehabilitation programme on postural capacities in individuals with intellectual disabilities. AB - BACKGROUND: This study aimed to compare the effectiveness of a hopping and jumping training programme (HJP) versus a sensorimotor rehabilitation programme (SRP) on postural performances in children with intellectual disability. METHODS: Three groups of children with intellectual disability participated in the study: the HJP group, the SRP group and a control group. Postural capacities were tested with the Berg Balance Scale (BBS) and the Tinetti tests. The HJP and the SRP groups participated in the training programmes for eight weeks. Then, all participants were retested. RESULTS: Results showed that before the training period, there are no significant differences between the three groups. After the training period, the BBS and the Tinetti scores increased significantly in the HJP group and the SRP group with greater extent in the HJP group than in the STP group. CONCLUSION: We suggest that HJP training is more recommended to improve postural capacities in children with intellectual disability. PMID- 28070923 TI - The cascade of HIV care among refugees and nationals in Nakivale Refugee Settlement in Uganda. AB - OBJECTIVES: Refugees living in Uganda come from HIV-endemic countries, and many remain in refugee settlements for over a decade. Our objective was to evaluate the HIV care cascade in Nakivale Refugee Settlement and to assess correlates of linkage to care. METHODS: We prospectively enrolled individuals accessing clinic based HIV testing in Nakivale Refugee Settlement from March 2013 to July 2014. Newly HIV-diagnosed clients were followed for 3 months post-diagnosis. Clients underwent a baseline survey. The following outcomes were obtained from HIV clinic registers in Nakivale: clinic attendance ('linkage to HIV care'), CD4 testing, antiretroviral therapy (ART) eligibility, and ART initiation within 90 days of testing. Descriptive data were reported as frequency with 95% confidence interval (CI) or median with interquartile range (IQR). The impact of baseline variables on linkage to care was assessed with logistic regression models. RESULTS: Of 6850 adult clients tested for HIV, 276 (4%; CI: 3-5%) were diagnosed with HIV infection, 148 (54%; CI: 47-60%) of those were linked to HIV care, 54 (20%; CI: 15-25%) had a CD4 test, 22 (8%; CI: 5-12%) were eligible for ART, and 17 (6%; CI: 3-10%) initiated ART. The proportions of refugees and nationals at each step of the cascade were similar. We identified no significant predictors of linkage to care. CONCLUSIONS: Less than a quarter of newly HIV-diagnosed clients completed ART assessment, considerably lower than in other reports from sub-Saharan Africa. Understanding which factors hinder linkage to and engagement in care in the settlement will be important to inform interventions specific for this environment. PMID- 28070924 TI - Reproductive Rights and a New Administration. PMID- 28070926 TI - Identification and implication of an allergenic PR-10 protein from walnut in birch pollen associated walnut allergy. AB - SCOPE: English walnut (Juglans regia) belongs to the most important allergenic tree nuts. Co-sensitization with birch (Betula verrucosa) pollen has been reported. We aimed to identify a walnut allergen homologous to the major birch pollen allergen Bet v 1. METHODS AND RESULTS: A cDNA encoding a Bet v 1 homologous allergen (Jug r 5) in walnut kernels was cloned by RT-PCR. Jug r 5 was expressed in Escherichia coli, purified by column chromatography and characterized by circular dichroism spectroscopy. Specific IgE levels to walnut, Bet v 1, and Jug r 5 in birch pollen allergics (n = 16) with concomitant walnut allergy were measured by ImmunoCAP: 44% of the patients were tested positive to walnut while 94% were reactive to Jug r 5, and 100% to Bet v 1. Jug r 5 and Bet v 1 allergens showed bidirectional IgE cross-reactivity by competitive ELISA and were capable of inducing histamine release from effector cells. Immunoblot competition experiments demonstrated the presence of IgE-reactive Jug r 5 in walnut extract, but at low levels. CONCLUSION: A Bet v 1-like allergen was identified in walnut. Diagnostic use of Jug r 5 will compensate for the low sensitivity of walnut extract for patients with birch pollen associated walnut allergy. PMID- 28070927 TI - Lead-Sulfide-Selenide Quantum Dots and Gold-Copper Alloy Nanoparticles Augment the Light-Harvesting Ability of Solar Cells. AB - Lead-sulfide-selenide (PbSSe) quantum dots (QDs) and gold-copper (AuCu) alloy nanoparticles (NPs) were incorporated into a cadmium sulfide (CdS)/titanium oxide (TiO2 ) photoanode for the first time to achieve enhanced conversion of solar energy into electricity. PbSSe QDs with a band gap of 1.02 eV extend the light harvesting range of the photoanode from the visible region to the near-infrared region. The conduction band (CB) edge of the PbSSe QDs is wedged between the CBs of TiO2 and CdS; this additional level coupled with the good electrical conductivity of the dots facilitate charge transport and collection, and a high power conversion efficiency (PCE) of 4.44 % is achieved for the champion cell with the TiO2 /PbSSe/CdS electrode. Upon including AuCu alloy NPs in the QD sensitized electrodes, light absorption is enhance by plasmonic and light scattering effects and also by the injection of hot electrons to the CBs of the QDs. Comparison of the incident photon-to-current conversion efficiency enhancement factors in addition to fluorescence decay and impedance studies reveal that the PbSSe QDs and AuCu alloy NPs promote charge injection to the current collector and increase the photogenerated charges produced, which thus enables the TiO2 /PbSSe/CdS/AuCu cell to deliver the highest PCE of 5.26 % among all the various photoanode compositions used. PMID- 28070925 TI - Bio-orthogonal Fluorescent Labelling of Biopolymers through Inverse-Electron Demand Diels-Alder Reactions. AB - Bio-orthogonal labelling schemes based on inverse-electron-demand Diels-Alder (IEDDA) cycloaddition have attracted much attention in chemical biology recently. The appealing features of this reaction, such as the fast reaction kinetics, fully bio-orthogonal nature and high selectivity, have helped chemical biologists gain deeper understanding of biochemical processes at the molecular level. Listing the components and discussing the possibilities and limitations of these reagents, we provide a recent snapshot of the field of IEDDA-based biomolecular manipulation with special focus on fluorescent modulation approaches through the use of bio-orthogonalized building blocks. At the end, we discuss challenges that need to be addressed for further developments in order to overcome recent limitations and to enable researchers to answer biomolecular questions in more detail. PMID- 28070929 TI - Doping Effects on the Adsorption of a Nitric Oxide Molecule on an Anatase (101) Surface. AB - NO adsorption on n-type and p-type modified anatase (101) surfaces is studied by using first-principles calculations. Both types of modifications can facilitate the adsorption of a NO molecule on an anatase (101) surface. The adsorption mechanisms for these two types of adsorption are different. On n-type modified surfaces, the N atom of the NO molecule is bonded to a surface Ti5C ion, that is, the unpaired electron on the pi* orbital of the NO molecule forms a bond with an extra 3d electron of the surface Ti ion. On p-type modified surfaces, the N atom of the NO molecule is bonded to surface O2C . The unpaired electron of the NO molecule fills the empty 2p orbital of the modified surface, and the pi* orbital of the NO molecule hybridizes with the surface valence band. PMID- 28070928 TI - Convergent gustatory and viscerosensory processing in the human dorsal mid insula. AB - The homeostatic regulation of feeding behavior requires an organism to be able to integrate information from its internal environment, including peripheral visceral signals about the body's current energy needs, with information from its external environment, such as the palatability of energy-rich food stimuli. The insula, which serves as the brain's primary sensory cortex for representing both visceral signals from the body and taste signals from the mouth and tongue, is a likely candidate region in which this integration might occur. However, to date it has been unclear whether information from these two homeostatically critical faculties is merely co-represented in the human insula, or actually integrated there. Recent functional neuroimaging evidence of a common substrate for visceral interoception and taste perception within the human dorsal mid-insula suggests a model whereby a single population of neurons may integrate viscerosensory and gustatory signals. To test this model, we used fMRI-Adaptation to identify whether insula regions that exhibit repetition suppression following repeated interoception trials would then also exhibit adapted responses to subsequent gustatory stimuli. Multiple mid and anterior regions of the insula exhibited adaptation to interoceptive trials specifically, but only the dorsal mid-insula regions exhibited an adapted gustatory response following interoception. The discovery of this gustatory-interoceptive convergence within the neurons of the human insula supports the existence of a heretofore-undocumented neural pathway by which visceral signals from the periphery modulate the activity of brain regions involved in feeding behavior. Hum Brain Mapp 38:2150-2164, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28070930 TI - Pituitary adenoma with adipose tissue: A new metaplastic variant. AB - Pituitary adenomas are benign tumors representing approximately 15-20% of intracranial neoplasms. There have been few reports of metaplastic osseous transformation and about 60 cases of neuronal metaplasia in pituitary adenoma but adipose metaplasia has not been previously described in the English literature. Here we report a case of pituitary adenoma with metaplastic adipose tissue in a 58-year-old male patient. Histologically this case fulfilled the criteria of a non-functioning pituitary adenoma, and moreover a central area of adipose tissue, made by mature adipocytes, and many tumor cells, containing fat droplet were evident. Lipomatous transformation of tumor cells in the CNS has been previously observed but, to the best of our knowledge, our case is the first pituitary adenoma with such change. The histogenesis of the adipose element in pituitary adenoma is not well understood, and could be a result of a metaplastic change or divergent differentiation from a common progenitor cell. PMID- 28070931 TI - Anti-rheumatoid Arthritis Effect of Kaejadan via Analgesic and Antiinflammatory Activity in vivo and in vitro. AB - Although Kaejadan (KJD), an herbal cocktail of three medicinal plants (Lithospermum erythrorhizon, Cinnamomum loureirii, and Salvia miltiorrhiza), has been traditionally used for the treatment of rheumatoid arthritis, its scientific evidence is not fully understood. Hence, we investigated antiinflammatory and analgesic mechanism of KJD in vivo and in vitro. Kaejadan suppressed the number of writhing responses in mice treated by acetic acid and showed antinociceptive effect by tail-flick test. Kaejadan abrogated serotonin or carrageenan or Freund's complete adjuvant (FCA)-induced paw edema and also reduced the level of Evans Blue for vascular permeability. Furthermore, KJD effectively reduced the positive responses for C-reactive protein and rheumatoid arthritis test in FCA treated rats. Of note, KJD inhibited the level of lipid peroxide malondialdehyde and enhanced the level of superoxide dismutase in the hepatic tissues of FCA treated rats. Additionally, KJD abrogated the levels of IL-1beta and IL-6 in lipopolysaccharide and IFN-gamma-exposed RAW 264.7 cells. Also, KJD reduced the expression of cyclooxygenase 2 or inducible nitric oxide synthase at protein and mRNA levels in IFN-gamma and lipopolysaccharide-exposed RAW 264.7 cells. Overall, our findings demonstrate that KJD exerts antiinflammatory and analgesic effects via enhancement of antioxidant activity and inhibition of proinflammatory cytokines. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28070932 TI - The experience of adult children of mothers with intellectual disability: A qualitative retrospective study from Poland. AB - BACKGROUND: Little is known about the experience of growing up with a mother with intellectual disability. The aim of this study was to explore this experience from the perspective of adult children. METHOD: In-depth interviews with 23 adult children brought up by mothers with moderate-to-severe intellectual disability. The interview data were analysed using grounded theory methods. RESULTS: The childhood experiences of the interviewees and the role their mothers played in their upbringing varied, depending in part on the involvement of extended family. It was the stigma of maternal intellectual disability, rather than their mother's functional limitations, that posed the greatest challenge. CONCLUSION: Interviewees characterized their mothers and childhoods as different, yet ordinary. Understanding the social context, including but not limited to the availability of informal support, is critical to understanding the experience of children growing up with mothers with intellectual disability. PMID- 28070933 TI - Secretome analysis of diarrhea-inducing strains of Escherichia coli. AB - Secreted proteins constitute a major part of virulence factors that are responsible for pathogenesis caused by Gram-negative bacteria. Enterohemorrhagic Escherichia coli, O157:H7, is the major pathogen often causing outbreaks. However, studies have reported that the significant outbreaks caused by non O157:H7 E. coli strains, also known as "Big-Six" serogroup strains, are increasing. There is no systematic study describing differential secreted proteins from these non-O157:H7 E. coli strains. In this study, we carried out MS based differential secretome analysis using tandem mass tags labeling strategy of non-O157:H7 E. coli strains, O103, O111, O121, O145, O26, and O45. We identified 1241 proteins, of which 565 proteins were predicted to be secreted. We also found that 68 proteins were enriched in type III secretion system and several of them were differentially expressed across the strains. Additionally, we identified several strain-specific secreted proteins that could be used for developing potential markers for the identification and strain-level differentiation. To our knowledge, this study is the first comparative proteomic study on secretome of E. coli Big-Six serogroup and the several of these strain-specific secreted proteins can be further studied to develop potential markers for identification and strain level differentiation. Moreover, the results of this study can be utilized in several applications, including food safety, diagnostics of E. coli outbreaks, and detection and identification of bio threats in biodefense. PMID- 28070934 TI - Long-term outcomes after mechanical aortic valve replacement with aortic root enlargement in adolescents. AB - BACKGROUND: Deciding which prosthetic aortic valve to choose is difficult in adolescents who have not yet met their full growth potential. The aim of this study was to assess long-term outcomes following mechanical aortic valve replacement with aortic root enlargement in adolescents. METHODS: Between September 1997 and December 2006, 58 consecutive adolescents (49 male, 9 female, median age 15.5, range 13 to 17 years) underwent mechanical aortic valve replacement with aortic root enlargement. All patients received long-term anticoagulation treatment with warfarin, aiming to maintain an international normalized ratio between 2.0 and 2.5. Follow-up of all patients was closed in December 2015. RESULTS: The mean size of implanted valves was 20.1 +/- 1.3 mm. There were two operative deaths (3.4%) and one late death (1.7%). Mean follow-up was 11.6 +/- 3.3 years (range, 8.5 to 15.8 years). Actuarial survival at 15 years was 94.7 +/- 3.2%. No patient required a redo procedure. At the latest clinical evaluation, 47 patients (81.0%) were in New York Heart Association functional class I and 8 (13.8%) were in functional class II. Actuarial freedom from valve related complication was 88.1 +/- 2.8% at four years. The mean gradient across the aortic mechanical valve on echocardiography was 13.2 +/- 6.3 mmHg (range 6 to 38 mmHg). CONCLUSIONS: Mechanical aortic valve replacement with aortic root enlargement remains an excellent treatment option in adolescents with full growth potential. The mortality is very low and all surviving patients resumed normal lifestyles. It represents a good alternative to allografts and bioprostheses in adolescent patients with aortic valve disease. PMID- 28070936 TI - Alcohol industry marketing strategies in Latin America and the Caribbean: the way forward for policy research. PMID- 28070935 TI - Alendronate-anchored PEGylation of ceria nanoparticles promotes human hepatoma cell proliferation via AKT/ERK signaling pathways. AB - Previous work has suggested that ceria nanoparticles (CNPs) have regenerative antioxidant properties, which have motivated researchers to consider CNPs as therapeutic agents for treating a number of diseases, including cancer. Recent studies have shown CNPs to be toxic to cancer cells, to inhibit invasion and sensitize cancer cells to radiotherapy. In addition, several hydrophilic polymers have been used to coat the CNP surface in order to enhance its properties of extensive biocompatibility and systemic nontoxicity to normal cells and tissues. However, the results of previous studies were based on high CNP doses (10 MUg/mL or more), and these doses may cause serious side effects in clinical applications. The impact of low CNP doses on tumor cells remains unknown. In this study, we report experiments indicating that CNPs-AL- polyethylene glycol (PEG)600, a type of surface-modified CNP that is more stable and less toxic than traditional CNPs could promote proliferation of hepatoma cells in a dose dependent manner. In addition, further research showed that a low dose (0.01 MUg/mL) of CNPs-AL-PEG600 could reduce hepatoma cell apoptosis and activate AKT/ERK signaling pathways. These results may provide information that is important for using CNPs-AL-PEG600 as a therapeutic agent in clinical cancer treatments. PMID- 28070937 TI - Alcohol marketing regulation: from research to public policy. PMID- 28070938 TI - Toward a public health approach to the protection of vulnerable populations from the harmful effects of alcohol marketing. PMID- 28070940 TI - Microporous Crystalline gamma-Al2 O3 Replicated from Microporous Covalent Triazine Framework and Its Application as Support for Catalytic Hydrolysis of Ammonia Borane. AB - Significant progress has been made on the synthesis and application of mesoporous gamma-alumina. To date, little attention has been paid to the synthesis of microporous crystalline alumina. Here, fabrication of microporous crystalline gamma-alumina using a microporous covalent triazine framework (CTF-1) as a template is described. Microporous crystalline gamma-alumina with a micro-meso binary pore system was replicated by infiltration of aluminum nitrate into the micropores of the CTF-1 template through a NH3 /water-vapor-induced internal hydrolysis method, followed by thermal treatment, and subsequent removal of the CTF-1 template with a 30 % H2 O2 aqueous solution. The obtained crystalline gamma alumina material exhibits a large surface area (349 m2 g-1 ) with micropore distribution centered at about 1.27 nm. Ru supported on microporous gamma-Al2 O3 can be employed as catalyst for hydrolytic dehydrogenation of ammonia borane, and it exhibits high catalytic activity and good durability. This finding provides a new benchmark for preparing well-defined crystalline microporous alumina materials by a template method, which can be applied in a wide range of fields. PMID- 28070939 TI - Oncologists' perspectives on post-cancer treatment communication and care coordination with primary care physicians. AB - Post-treatment cancer care is often fragmented and of suboptimal quality. We explored factors that may affect cancer survivors' post-treatment care coordination, including oncologists' use of electronic technologies such as e mail and integrated electronic health records (EHRs) to communicate with primary care physicians (PCPs). We used data from a survey (357 respondents; participation rate 52.9%) conducted in 2012-2013 among medical oncologists caring for patients in a large US study of cancer care delivery and outcomes. Oncologists reported their frequency and mode of communication with PCPs, and role in providing post-treatment care. Seventy-five per cent said that they directly communicated with PCPs about post-treatment status and care recommendations for all/most patients. Among those directly communicating with PCPs, 70% always/usually used written correspondence, while 36% always/usually used integrated EHRs; telephone and e-mail were less used. Eighty per cent reported co-managing with PCPs at least one post-treatment general medical care need. In multivariate-adjusted analyses, neither communication mode nor intensity were associated with co-managing survivors' care. Oncologists' reliance on written correspondence to communicate with PCPs may be a barrier to care coordination. We discuss new research directions for enhancing communication and care coordination between oncologists and PCPs, and to better meet the needs of cancer survivors post-treatment. PMID- 28070941 TI - Effect of baseline characteristics on response to proton pump inhibitors in patients with peptic ulcer bleeding. AB - OBJECTIVE: The rate of rebleeding from peptic ulcers could differ between Asian and Western populations. This study aimed to determine whether the observed twofold difference in rebleeding rates in two similarly designed clinical trials (one in Hong Kong [n = 240], the other in a predominantly Western population [n = 764, ClinicalTrials.gov identifier: NCT00251979]) can be explained by differences in baseline patient characteristics. METHODS: Two-factor and multifactor analyses (adjusted by demographics, established risk factors for peptic ulcer and peptic ulcer bleeding, and disease severity variables) were performed using pooled data from the two studies. Cox regression analysis was used to predict the rebleeding risk at 3 days. RESULTS: In the two-factor analysis (placebo vs esomeprazole/omeprazole and Western study vs Hong Kong study), data trended towards a reduced risk of rebleeding in the Western study (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.44-1.07, P = 0.094). The risk of rebleeding was similar in both studies after adjusted for multiple factors (HR 1.10, 95% CI 0.60-1.99, P = 0.767). The strongest predictor of rebleeding (apart from study drug) was a classification of American Society of Anesthesiologists (ASA) grade IV (HR 4.15, 95% CI 1.49-11.56, P = 0.006). When such patients were excluded, the difference in rebleeding rates between the studies reduced. CONCLUSION: The difference in rebleeding rates between the two studies is explained by the factors in our analysis, most importantly a classification of ASA grade IV, suggesting that other differences, including ethnicity, did not influence the rebleeding rate. PMID- 28070943 TI - 'Dirty lesions' on the neck and abdomen. PMID- 28070942 TI - Should we recommend exercise to adolescents with depressive symptoms? A meta analysis. AB - There is growing interest in the potential role of exercise in the reduction of depressive symptoms. The aim of this meta-analysis was to examine whether exercise reduces depressive symptoms amongst depressed adolescents. The following databases were searched on 30 January 2015: MEDLINE, PsychINFO, SPORTDiscuss and PUBMED. Studies were included if they examined exercise interventions amongst adolescents with clinical levels of depressive symptoms, were published in peer reviewed journals in the English language and contained a control/comparison group. Of 6631 retrieved studies, eight studies were included in the meta analysis. Meta-analysis was conducted using a random effects model due to the high level of heterogeneity identified amongst studies ( I 2 = 65.1, P < .005). The analysis revealed a moderate reduction in depressive symptoms post intervention (Hedge's g = -0.61, P = .007). This analysis provides preliminary evidence that exercise is effective in reducing symptoms of depression among adolescents with clinical levels of depressive symptoms. The present meta analysis, however, is limited by the generally low quality of included studies, high level of between-study heterogeneity and restriction of inclusion criteria to published studies. Further high-quality trials with depressed adolescents are needed to determine the efficacy of exercise in the reduction of depressive symptoms and the exercise parameters associated with the antidepressant effects of exercise. PMID- 28070944 TI - Retinal vascular lesions. PMID- 28070945 TI - 'Dirty lesions' on the neck and abdomen. PMID- 28070946 TI - Retinal vascular lesions. PMID- 28070947 TI - Infant circumcision: Evidence, policy, and practice. PMID- 28070948 TI - Interactions with the mainstream media. PMID- 28070949 TI - Growth faltering, child rearing and social determinants of health in Aboriginal community children. PMID- 28070951 TI - Asthma, paracetamol and ibuprofen. PMID- 28070950 TI - Antibiotics and food allergy. PMID- 28070952 TI - Phototherapy and cancer. PMID- 28070953 TI - The ethics of parental refusal of newborn vitamin K prophylaxis. PMID- 28070954 TI - Asthma and innate immunity in Amish and Hutterite communities. PMID- 28070955 TI - Still locked: A reply to wodak, ziegler and morris. PMID- 28070956 TI - The view from the elevator. PMID- 28070957 TI - Controlled trial of Hartmann's solution versus 0.9% saline for diabetic ketoacidosis. AB - AIM: We aimed to determine whether using a balanced salt solution, Hartmann's solution (HS), in diabetic ketoacidosis (DKA) shortens the time to normalise acid base status through the avoidance of hyperchloremic metabolic acidosis compared with 0.9% normal saline (NS). METHODS: We conducted a double-blind, randomised controlled trial comparing HS to NS as the initial intravenous fluid in children with DKA. Patients were stratified by severity (pH < 7.1) and known or new diabetes. Electrolytes, venous blood gases and glucose were measured every 2 h until intravenous fluids were ceased. The primary outcome was the time for the plasma bicarbonate to reach 15 mmol/L. Secondary outcomes included time to normalise pH (7.3), time to receive subcutaneous (SC) insulin, change in sodium and insulin requirement. RESULTS: A total of 77 children were enrolled. The groups were similar at baseline. There was no difference in the time to reach a bicarbonate of 15 mmol/L: geometric mean (SD) 8.6 (2.3) h for NS versus 6.2 (4.7) h for HS, ratio 1.4 (95% confidence interval 0.8-2.5), and no difference in time to normalise pH: NS 8.5 (2.3) h versus HS group 7.5 (1.8) h, ratio 1.1 (0.8-1.6). Kaplan-Meier survival estimates showed shorter times for these end-points in the severe subgroup: log-rank test P = 0.0277 and 0.0024, respectively. There was no difference in time to SC insulin, NS: 15.2 (2.4) h versus HS 14.3 (1.6) h, ratio 1.1 (0.8-1.5). Patients treated with HS received significantly less total fluids/kg. CONCLUSIONS: HS is an acceptable alternative to NS in DKA and may benefit those with severe DKA. PMID- 28070958 TI - Rheumatic heart disease in paediatric critical care retrieval. PMID- 28070959 TI - Rapid infliximab infusions are generally well-tolerated in children with inflammatory bowel disease. PMID- 28070960 TI - American Diabetes Association Standards of Medical Care in Diabetes 2017. PMID- 28070961 TI - Does F-18 FDG-PET still play a role in metastatic renal cell carcinoma? PMID- 28070962 TI - Transjugular intrahepatic portosystemic shunt: Indications, complications, survival and its use as a bridging therapy to liver transplant in Western Australia. AB - INTRODUCTION: Insertion of transjugular intrahepatic portosystemic shunt (TIPS) is an established therapeutic option to treat the complications of portal hypertension. The purpose of this study is to review the experience of a single Australian institute with TIPS and evaluation of result to emphasize the indication, aetiology of portal hypertension, prognostic factors, complications and survival. Use of TIPS as a bridge to liver transplantation was also analysed. METHOD: A retrospective cohort study of patients treated with TIPS at The Western Australian Liver Transplant Unit, Sir Charles Gairdner Hospital, over a period of 12 years. Kaplan-Meier method was used for survival analysis and cox-regression analysis was used to analyse the predictors of survival. RESULTS: Fifty-three patients underwent TIPS between January 2000 and March 2012. The cumulative survival at 1 month, 1 year and 5 years was 90%, 70.9% and 43.9%, respectively. The predictors of survival were indication (variceal bleeding versus ascites, hazard ratio 3.19, CI 95%: 1.164-8.794, P = 0.024) and Model of End Stage Liver Disease score (Hazard ratio 2.513, CI 95%: 1.087-5.810, P = 0.031). Patients who underwent TIPS as a bridge to liver transplant had a 5-year survival of 71% that is comparable to the overall survival of Western Australian liver transplant unit. CONCLUSION: Transjugular intrahepatic portosystemic shunt is a safe and effective method of treatment of complications of portal hypertension. TIPS can be safely used as a bridging therapy to liver transplant. Despite small number of TIPS being performed at our institute, our technical results are comparable to the institutes with bigger number of patients. PMID- 28070964 TI - Redox-Flow Batteries: From Metals to Organic Redox-Active Materials. AB - Research on redox-flow batteries (RFBs) is currently experiencing a significant upturn, stimulated by the growing need to store increasing quantities of sustainably generated electrical energy. RFBs are promising candidates for the creation of smart grids, particularly when combined with photovoltaics and wind farms. To achieve the goal of "green", safe, and cost-efficient energy storage, research has shifted from metal-based materials to organic active materials in recent years. This Review presents an overview of various flow-battery systems. Relevant studies concerning their history are discussed as well as their development over the last few years from the classical inorganic, to organic/inorganic, to RFBs with organic redox-active cathode and anode materials. Available technologies are analyzed in terms of their technical, economic, and environmental aspects; the advantages and limitations of these systems are also discussed. Further technological challenges and prospective research possibilities are highlighted. PMID- 28070965 TI - The consequences of avian ocular trauma: histopathological evidence and implications of acute and chronic disease. AB - OBJECTIVE: To present a description and categorization of the histopathological lesions in avian ocular trauma. ANIMAL STUDIED: Seventy-five birds diagnosed with ocular trauma at to the Comparative Ocular Pathology Laboratory of Wisconsin. PROCEDURES: Histological slides were reviewed, and the type of trauma was classified by cause into either (i) blunt trauma or (ii) penetrating trauma and by duration into (i) acute or (ii) chronic. RESULTS: Blunt trauma was the most common source of trauma, and the most frequent lesions were observed in the retina (91%), with 71% of retinas having a tear or detachment and 46% of retinas showing chronic degenerative changes. Damage to the iris/ciliary body was present in 77% of cases. Corneal (17%) and lens (31%) lesions were relatively low. Acute traumatic events had a higher prevalence of readily identifiable discrete retinal tears/detachments (64%). Nearly all cases of chronic trauma exhibited chronic retinal lesions (93.7%), as well as a greater percentage of cartilage/bone lesions (71.4%), irido/cyclodialysis (51.9%), lenticular lesions (72.7%), and corneal damage (83.3%). However, the incidence of iridocyclodialysis was roughly equivalent for acute and chronic blunt trauma. CONCLUSIONS: Ocular trauma can lead to profound acute and chronic lesions within the eye. Here, we provide insight into understanding ocular damage caused by trauma, which may help future studies suggest new therapeutic options and provide insight regarding the releasability of avian wildlife. PMID- 28070966 TI - The 1-min Screening Test for Reading Problems in College Students: Psychometric Properties of the 1-min TIL. AB - Reading is a central cognitive domain, but little research has been devoted to standardized tests for adults. We, thus, examined the psychometric properties of the 1-min version of Teste de Idade de Leitura (Reading Age Test; 1-min TIL), the Portuguese version of Lobrot L3 test, in three experiments with college students: typical readers in Experiment 1A and B, dyslexic readers and chronological age controls in Experiment 2. In Experiment 1A, test-retest reliability and convergent validity were evaluated in 185 students. Reliability was >.70, and phonological decoding underpinned 1-min TIL. In Experiment 1B, internal consistency was assessed by presenting two 45-s versions of the test to 19 students, and performance in these versions was significantly associated (r = .78). In Experiment 2, construct validity, criterion validity and clinical utility of 1-min TIL were investigated. A multiple regression analysis corroborated construct validity; both phonological decoding and listening comprehension were reliable predictors of 1-min TIL scores. Logistic regression and receiver operating characteristics analyses revealed the high accuracy of this test in distinguishing dyslexic from typical readers. Therefore, the 1-min TIL, which assesses reading comprehension and potential reading difficulties in college students, has the necessary psychometric properties to become a useful screening instrument in neuropsychological assessment and research. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28070967 TI - Effective breeding programmes down under. PMID- 28070968 TI - Bacterial short-chain fatty acid metabolites modulate the inflammatory response against infectious bacteria. AB - Short-chain fatty acids (SCFAs), predominantly acetic, propionic, and butyric acids, are bacterial metabolites with an important role in the maintenance of homeostasis due to their metabolic and immunomodulatory actions. Some evidence suggests that they may also be relevant during infections. Therefore, we aimed to investigate the effects of SCFAs in the effector functions of neutrophils to an opportunistic pathogenic bacterium, Aggregatibacter actinomycetemcomitans. Using a subcutaneous model to generate a mono, isolated infection of A. actinomycetemcomitans, we demonstrated that the presence of the SCFAs in situ did not affect leukocyte accumulation but altered the effector mechanisms of migrating neutrophils by downregulating the production of cytokines, their phagocytic capacity, and killing the bacteria, thus impairing the containment of A. actinomycetemcomitans. Similar effects were observed with bacteria-stimulated neutrophils incubated with SCFAs in vitro. These effects were independent of free fatty acid receptor 2 (FFAR2) activation, the main SCFA receptor expressed on neutrophils, occurring possibly through inhibition of histone deacetylases because similar effects were obtained by using histone deacetylase inhibitors, such as SAHA, MS-275, and RGFP 966. Considering the findings of this study, we hypothesized that in an infectious condition, SCFAs may exert a detrimental effect on the host by inhibiting neutrophil's effector functions. PMID- 28070969 TI - Sensitizers for Aqueous-Based Solar Cells. AB - Aqueous dye-sensitized solar cells (DSSCs) are attractive due to their sustainability, the use of water as a safe solvent for the redox mediators, and their possible applications in photoelectrochemical water splitting. However, the higher tendency of dye leaching by water and the lower wettability of dye molecules are two major obstacles that need to be tackled for future applications of aqueous DSSCs. Sensitizers designed for aqueous DSSCs are discussed based on their functions, such as modification of the molecular skeleton and the anchoring group for better stability against dye leaching by water, and the incorporation of hydrophilic entities into the dye molecule or the addition of a surfactant to the system to increase the wettability of the dye for more facile dye regeneration. Surface treatment of the photoanode to deter dye leaching or improve the wettability of the dye molecule is also discussed. Redox mediators designed for aqueous DSSCs are also discussed. The review also includes quantum dot-sensitized solar cells, with a focus on improvements in QD loading and suppression of interfacial charge recombination at the photoanode. PMID- 28070971 TI - Abstracts of the AAGBI WSM London, London, UK, 11-13 January 2017. PMID- 28070970 TI - Influence of sunflower seed oil or baby lotion on the skin barrier function of newborns: A pilot study. AB - BACKGROUND: Skin care influences skin barrier function during the first postnatal weeks. Although the use of natural oils in preterms has been investigated, there are currently no data comparing the effect of sunflower oil to an emollient on barrier development in healthy term newborns. METHODS: In a prospective, randomized clinical study, 50 healthy full-term newborns aged <=72 h were randomly assigned to two groups: group baby lotion (L, n=22) and sunflower seed oil (SSO, n=24). The skin barrier function was evaluated in three anatomical areas (front, abdomen, and thigh) by noninvasive assessment of transepidermal water loss (TEWL), stratum corneum hydration (SCH), sebum, and skin pH at inclusion and after five weeks. RESULTS: In both groups, skin pH decreased and SCH increased statistically significantly in all measured areas at W5 compared to baseline. TEWL decreased statistically significantly on the forearm in both groups, on the upper leg in group L, and on the abdomen in group SSO. CONCLUSIONS: Both skin care regimes did not harm skin barrier function adaptation in healthy term neonates during the first five weeks of life. PMID- 28070973 TI - Dissociation between amygdala and bed nucleus of the stria terminalis during threat anticipation in female post-traumatic stress disorder patients. AB - Feelings of uncontrollability and anxiety regarding possibly harmful events are key features of post-traumatic stress disorder (PTSD) symptomatology. Due to a lack of studies, the neural correlates of anticipatory anxiety in PTSD are still poorly understood. During functional magnetic resonance imaging, female PTSD patients with interpersonal violence trauma and healthy controls (HC) anticipated the temporally unpredictable presentation of aversive (human scream) or neutral sounds. Based on separate analysis models, we investigated phasic and sustained brain activations. PTSD patients reported increased anxiety during anticipation of aversive versus neutral sounds. Furthermore, we found both increased initial, phasic amygdala activation and increased sustained activation of the bed nucleus of the stria terminalis (BNST) during anticipation of aversive versus neutral sounds in PTSD patients in comparison to HC. PTSD patients as compared with HC also showed increased phasic responses in mid-cingulate cortex (MCC), posterior cingulate cortex (PCC), mid-insula and lateral prefrontal cortex (PFC) as well as increased sustained responses in MCC, PCC, anterior insula and lateral and medial PFC. Our results demonstrate a relationship between anticipatory anxiety in PTSD patients and hyperresponsiveness of brain regions that have previously been associated with PTSD symptomatology. Additionally, the dissociation between amygdala and BNST indicates distinct temporal and functional characteristics and suggests that phasic fear and sustained anxiety responses are enhanced during unpredictable anticipation of aversive stimuli in PTSD. Hum Brain Mapp 38:2190 2205, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28070975 TI - Progressive dyspnea and signs of right heart dysfunction. AB - A 40-year-old woman was admitted due to dyspnea and fever. Transthoracic echocardiography revealed signs of right heart volume overload and vegetations on the tricuspid valve with insufficiency. Transesophageal echocardiography showed a sinus venosus defect (SVD) with significant left-to-right shunt. Computed tomography scanning was primarily performed to rule out pulmonary embolism; however, it showed interatrial communication. Due to the concomitant tricuspid insufficiency with additional volume overload, the diagnosis of SVD was more challenging. Usually, transthoracic echocardiography remains the initial diagnostic imaging modality; however, detection rates are very low. Therefore, further imaging is mandatory in unexplained substantial right heart dilatation. PMID- 28070974 TI - Stimulus-Responsive Short Peptide Nanogels for Controlled Intracellular Drug Release and for Overcoming Tumor Resistance. AB - Multidrug resistance (MDR) poses a major burden to cancer treatment. As one important factor contributing to MDR, overexpression of P-glycoprotein (P-gp) results in a reduced intracellular drug accumulation. Hence, the ability to effectively block the efflux protein and to accumulate the therapeutics in cancer cells is of great significance in clinical practice. In this work, we successfully developed a smart stimulus-responsive short peptide-assembled system, termed as PD/VER nanogels, which synergistically combined the acid activatable antitumor prodrug doxorubicin (Dox) with the P-gp inhibitor verapamil (VER) for reversing MDR. Systematic studies demonstrated that such an inhibitor encapsulated nanogel could effectively enhance the accumulation of Dox in resistant cancer cells, thereby revealing significantly higher antitumor activity compared to free Dox molecules. This work showed that the assembly of bioactive agents with a synergistic effect into nano-drugs could provide a useful strategy to overcome cancer drug resistance. PMID- 28070976 TI - Efficient Deep-Blue Electroluminescence Based on Phenanthroimidazole Dibenzothiophene Derivatives with Different Oxidation States of the Sulfur Atom. AB - Developing efficient deep-blue materials is a long-term research focus in the field of organic light-emitting diodes (OLEDs). In this paper, we report two deep blue molecules, PITO and PISF, which share similar chemical structures but exhibit different photophysical and device properties. These two molecules consist of phenanthroimidazole and dibenzothiophene analogs. The distinction of their chemical structures lies in the different oxidation states of the S atom. For PITO, the S atom is oxidized and the resulting structure dibenzothiophene S,S dioxide becomes electron deficient. Therefore, PITO displays remarkable solvatochromism, implying a charge-transfer (CT) excited state formed between the donor (D) phenanthroimidazole and acceptor (A) dibenzothiophene S,S-dioxide. For PISF, it is constituted of phenanthroimidazole and dibenzothiophene in which the S atom is not oxidized. PISF displays locally excited (LE) emission with little solvatochromism. Compared with PISF, the D-A molecule PITO with an electron deficient group shows a much lower LUMO energy level, which is in favor of electron injection in device. In addition, PITO exhibits more balanced carrier transport. However, PISF is capable of emitting in the shorter wavelength region, which is beneficial to obtain better color purity. The doped electroluminescence (EL) device of the D-A molecule PITO manifests deep-blue emission with CIE coordinates of (0.15, 0.08) and maximum external quantum efficiency (EQE) of 4.67 %. The doped EL device of the LE molecule PISF, however, reveals an even bluer emission with CIE coordinates of (0.15, 0.06) and a maximum EQE of 4.08 %. PMID- 28070977 TI - Five Rare MU4 -O-Centered Ln6 Clusters with Single-Molecule Magnet Behavior for Dy6. AB - Five hexanuclear lanthanide clusters of composition [Ln6 (MU4 -O)2 (HCOO)2 L4 (HL')2 (dmf)2 ] [Ln=Dy (1), Er (2), Ho (3), Tb (4), Gd (5); H2 L=2-{[2 (hydroxymethyl)phenylimino]methyl}-6-methoxyphenol; H3 L'=3-{[2 (hydroxymethyl)phenylimino]methyl}benzene-1,2-diol; H3 L' was derived in situ from the H2 L ligand] were prepared under solvothermal conditions. The [Ln6 ] cores of 1-5 possess an unprecedented motif, namely, two tetrahedron Ln4 units sharing an edge and two vertices. The six LnIII ions of 1-5 are connected through two MU4 -O anions. Magnetic susceptibility studies reveal that complex 1 exhibits frequency dependence of the alternating current susceptibility typical of single molecule magnets. Complex 1 possesses a relatively large energy barrier of 85 K among all of the reported Dy6 single-molecule magnets. PMID- 28070978 TI - Testing for local adaptation and evolutionary potential along altitudinal gradients in rainforest Drosophila: beyond laboratory estimates. AB - Predicting how species will respond to the rapid climatic changes predicted this century is an urgent task. Species distribution models (SDMs) use the current relationship between environmental variation and species' abundances to predict the effect of future environmental change on their distributions. However, two common assumptions of SDMs are likely to be violated in many cases: (i) that the relationship of environment with abundance or fitness is constant throughout a species' range and will remain so in future and (ii) that abiotic factors (e.g. temperature, humidity) determine species' distributions. We test these assumptions by relating field abundance of the rainforest fruit fly Drosophila birchii to ecological change across gradients that include its low and high altitudinal limits. We then test how such ecological variation affects the fitness of 35 D. birchii families transplanted in 591 cages to sites along two altitudinal gradients, to determine whether genetic variation in fitness responses could facilitate future adaptation to environmental change. Overall, field abundance was highest at cooler, high-altitude sites, and declined towards warmer, low-altitude sites. By contrast, cage fitness (productivity) increased towards warmer, lower-altitude sites, suggesting that biotic interactions (absent from cages) drive ecological limits at warmer margins. In addition, the relationship between environmental variation and abundance varied significantly among gradients, indicating divergence in ecological niche across the species' range. However, there was no evidence for local adaptation within gradients, despite greater productivity of high-altitude than low-altitude populations when families were reared under laboratory conditions. Families also responded similarly to transplantation along gradients, providing no evidence for fitness trade-offs that would favour local adaptation. These findings highlight the importance of (i) measuring genetic variation in key traits under ecologically relevant conditions, and (ii) considering the effect of biotic interactions when predicting species' responses to environmental change. PMID- 28070979 TI - Reading Comprehension: A Computerized Intervention with Primary-age Poor Readers. AB - The current study investigates the effectiveness of a computerized reading comprehension programme on the reading accuracy, reading comprehension and reading rate of primary-age poor readers. There is little published literature relating to computerized reading interventions in UK primary schools, and no previous studies have investigated the Comprehension Booster programme. Thirty eight children (26 boys and 12 girls; aged 6:7 to 11:0) from two schools in East Yorkshire, UK, took part. Half of the participants (the intervention group) undertook the Comprehension Booster programme for a 6-week period, whilst the other half (the control group) continued with their usual teaching. Significant effects of the intervention were found, with increases in reading accuracy and reading comprehension for the intervention group. It is concluded that computerized reading programmes can be effective in improving reading skills, and these are particularly useful for pupils with reading difficulties in disadvantaged areas, where resources are limited and family support in reading is lower. However, such programmes are not a replacement for good teaching, and regular monitoring of children with reading difficulties is required. Further research is necessary to compare the programme used here to other conventional and computerized intervention programmes, using a larger sample. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28070980 TI - Vibrational Spectrum of an Excited State and Huang-Rhys Factors by Coherent Wave Packets in Time-Resolved Fluorescence Spectroscopy. AB - Coherent nuclear wave packet motions in an electronic excited state of a molecule are measured directly by time-resolved spontaneous fluorescence spectroscopy with an unprecedented time resolution by using two-photon absorption excitation and fluorescence upconversion by noncollinear sum frequency generation. With an estimated time resolution of approximately 25 fs, wave packet motions of vibrational modes up to 1600 cm-1 are recorded for coumarin 153 in ethanol. Two color transient absorption at 13 fs time resolution are measured to confirm the result. Vibrational displacements between the ground and excited states and Huang Rhys factors (HRFs) are calculated by quantum mechanical methods and are compared with the experimental results. HRFs calculated by density functional theory (DFT) and time-dependent DFT reproduce the experiment adequately. This fluorescence based method provides a unique and direct way to obtain the vibrational spectrum of a molecule in an electronic excited state and the HRFs, as well as the dynamics of excited states, and it might provide information on the structure of an excited state through the HRFs. PMID- 28070981 TI - Synthesis of Asymmetrical Organic Carbonates using CO2 as a Feedstock in AgCl/Ionic Liquid System at Ambient Conditions. AB - Synthesis of asymmetrical organic carbonates from the renewable and inexpensive CO2 is of great importance but also challenging, especially at ambient conditions. Herein, we found that some metal salt/ionic liquid catalyst systems were highly active for the synthesis of asymmetrical organic carbonates from CO2 , propargylic alcohols, and primary alcohols. Especially, the AgCl/1-butyl-3 methylimidazolium acetate ([Bmim][OAc]) system was very efficient for the reactions of a wide range of substrates at room temperature and atmospheric pressure, and the yields of the asymmetrical organic carbonates could approach 100 %. The catalyst system could be reused at least five times without changing its catalytic performance, and could be easily recovered and reused. A detailed study indicated that AgCl and [Bmim][OAc] catalyzed the reactions cooperatively, resulting in unique catalytic performance. PMID- 28070982 TI - Response to Four-year entecavir therapy reduces hepatocellular carcinoma, cirrhotic events and mortality in chronic hepatitis B patients. PMID- 28070983 TI - Response to Is radiotherapy the best option for treating hepatocellular carcinoma with PVTT? PMID- 28070984 TI - An approach for sample size determination of average bioequivalence based on interval estimation. AB - In 1992, the US Food and Drug Administration declared that two drugs demonstrate average bioequivalence (ABE) if the log-transformed mean difference of pharmacokinetic responses lies in (-0.223, 0.223). The most widely used approach for assessing ABE is the two one-sided tests procedure. More specifically, ABE is concluded when a 100(1 - 2alpha) % confidence interval for mean difference falls within (-0.223, 0.223). As known, bioequivalent studies are usually conducted by crossover design. However, in the case that the half-life of a drug is long, a parallel design for the bioequivalent study may be preferred. In this study, a two-sided interval estimation - such as Satterthwaite's, Cochran-Cox's, or Howe's approximations - is used for assessing parallel ABE. We show that the asymptotic joint distribution of the lower and upper confidence limits is bivariate normal, and thus the sample size can be calculated based on the asymptotic power so that the confidence interval falls within (-0.223, 0.223). Simulation studies also show that the proposed method achieves sufficient empirical power. A real example is provided to illustrate the proposed method. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28070985 TI - Boosting the precision of mediation analyses of randomised experiments through covariate adjustment. AB - Analyses of randomised experiments frequently include attempts to decompose the intention-to-treat effect into a direct and indirect effect, mediated by given intermediaries, with the aim to shed light onto the treatment mechanism. Methods from causal mediation analysis have facilitated this by allowing for arbitrary models for the outcome and the mediator. They thereby generalise the traditional approach to direct and indirect effects, which is essentially limited to linear models. The default maximum likelihood methods make use of a model for the conditional distribution of the mediator, given treatment and baseline covariates, but are prone to bias when that model is misspecified. In randomised experiments, specification of such model can be easily avoided, but at the expense of a sometimes major efficiency loss when those baseline covariates are predictive of the mediator. In this article, we develop a compromise approach: it makes use of a model for the mediator to optimally extract information from the baseline covariate data but is insulated from the impact of misspecification of that model; it achieves this by exploiting the known randomisation probabilities. Simulation studies and the analysis of a randomised study show major efficiency gains and confirm our theoretical findings that the default methods from causal mediation analysis are sometimes, although not always, reasonably robust to model misspecification. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28070986 TI - Predicting Severity of Disease-Causing Variants. AB - Most diseases, including those of genetic origin, express a continuum of severity. Clinical interventions for numerous diseases are based on the severity of the phenotype. Predicting severity due to genetic variants could facilitate diagnosis and choice of therapy. Although computational predictions have been used as evidence for classifying the disease relevance of genetic variants, special tools for predicting disease severity in large scale are missing. Here, we manually curated a dataset containing variants leading to severe and less severe phenotypes and studied the abilities of variation impact predictors to distinguish between them. We found that these tools cannot separate the two groups of variants. Then, we developed a novel machine-learning-based method, PON PS (http://structure.bmc.lu.se/PON-PS), for the classification of amino acid substitutions associated with benign, severe, and less severe phenotypes. We tested the method using an independent test dataset and variants in four additional proteins. For distinguishing severe and nonsevere variants, PON-PS showed an accuracy of 61% in the test dataset, which is higher than for existing tolerance prediction methods. PON-PS is the first generic tool developed for this task. The tool can be used together with other evidence for improving diagnosis and prognosis and for prioritization of preventive interventions, clinical monitoring, and molecular tests. PMID- 28070987 TI - Reply: to Chronic venous ulcer treatment with topical sevoflurane by Imbernon et al. PMID- 28070988 TI - Renal clearable noble metal nanoparticles: photoluminescence, elimination, and biomedical applications. AB - Metal nanoparticles have demonstrated broad and promising biomedical applications in research laboratories, but how to fulfill their promises in the clinical practices demands extensive effort to minimize their non-specific accumulation in the body. In the past 6 years, we have developed a class of renal clearable noble metal nanoparticles with tunable visible and near-infrared emission, which can behave like small molecular contrast agents to be effectively eliminated through the kidneys. By taking advantage of the unique clearance pathway, we were able to gain some fundamental understanding of how engineering nanoparticles cleared out of the body through urinary system. Moreover, they also provided unique opportunities in early cancer detection and kidney functional imaging that were often challenging to be achieved with non-renal clearable nanoparticles and small molecular probes. In this review, we summarize key factors that govern in the renal clearance of luminescent noble metal nanoparticles and their strengths in cancer targeting and kidney functional imaging. At the end, we also outline several key challenges that need to be addressed before they can be considered in the clinical practices. WIREs Nanomed Nanobiotechnol 2017, 9:e1453. doi: 10.1002/wnan.1453 For further resources related to this article, please visit the WIREs website. PMID- 28070989 TI - Fullerenes in Space. AB - In 1985 the football structure of C60 , buckminsterfullerene was proposed and subsequently confirmed following its macroscopic synthesis in 1990. From the very beginning the role of C60 and C60+ in space was considered, particularly in the context of the enigmatic diffuse interstellar bands. These are absorption features found in the spectra of reddened star light. The first astronomical observations were made around one hundred years ago and despite significant efforts none of the interstellar molecules responsible have been identified. The absorption spectrum of C60+ was measured in a 5 K neon matrix in 1993 and two prominent bands near 9583 A and 9645 A were observed. On the basis of this data the likely wavelength range in which the gas phase C60+ absorptions should lie was predicted. In 1994 two diffuse interstellar bands were found in this spectral region and proposed to be due to C60+ . It took over 20 years to measure the absorption spectrum of C60+ under conditions similar to those prevailing in diffuse clouds. In 2015, sophisticated laboratory experiments led to the confirmation that these two interstellar bands are indeed caused by C60+ , providing the first answer to this century old puzzle. Here, we describe the experiments, concepts and astronomical observations that led to the detection of C60+ in interstellar space. PMID- 28070991 TI - A New ChemMedChem Era. AB - Moving in medchem: Editors David Peralta and Scott Williams look back at the ChemMedChem 10th anniversary celebration in 2016 and introduce exciting developments for the journal in 2017, including the expansion of its scope to nanomedicine, the introduction of Patent Reviews, the addition of new board members, and the publication of special issues related to the expanded scope. PMID- 28070990 TI - A targeted next-generation sequencing in the molecular risk stratification of adult acute myeloid leukemia: implications for clinical practice. AB - Conventional cytogenetics can categorize patients with acute myeloid leukemia (AML) into favorable, intermediate, and unfavorable-risk groups; however, patients with intermediate-risk cytogenetics represent the major population with variable outcomes. Because molecular profiling can assist with AML prognosis and next-generation sequencing allows simultaneous sequencing of many target genes, we analyzed 260 genes in 112 patients with de novo AML who received standard treatment. Multivariate analysis showed that karyotypes and mutation status of TET2, PHF6, KIT, and NPM1mutation /FLT3- internal tandem duplication (ITD)negative were independent prognostic factors for the entire cohort. Among patients with intermediate-risk cytogenetics, patients with mutations in CEBPAdouble mutation , IDH2, and NPM1 in the absence of FLT3-ITD were associated with improved Overall survival (OS), similar to those with favorable-risk cytogenetics; patients with mutations in TET2, RUNX1, ASXL1, and DNMT3A were associated with reduced OS, similar to those with unfavorable-risk cytogenetics. We concluded that integration of cytogenetic and molecular profiling improves prognostic stratification of patients into three groups with more distinct prognoses (P < 0.001) and significantly reduces the number of patients classified as intermediate risk. In addition, our study demonstrates that next-generation sequencing (NGS)-based multi-gene sequencing is clinically applicable in establishing an accurate risk stratification system for guiding therapeutic decisions. PMID- 28070994 TI - Involvement of microRNA-718, a new regulator of EGR3, in regulation of malignant phenotype of HCC cells. AB - OBJECTIVE: Hepatocellular carcinoma (HCC) is still one of the most common death related malignancies worldwide. Because the way onset and progression are hidden most, HCC diagnoses are made at an advanced stage, when they are unsuitable for surgical resection. MicroRNAs are a class of small non-coding RNAs, participating in many aspects of cancers. In this study, we tried to establish the role of microRNA-718 (miR-718) in the malignant phenotype of HCC cells and its possible role in HCC diagnosis. METHODS: Here we first used a methylthiazolyldiphenyl tetrazolium bromide (MTT) assay, Transwell migration and invasion assays, and colony formation assay to evaluate the impact of miR-718 on the malignant phenotypes of HCC cells. Then, we used bioinformatic methods to predict the target gene of miR-718 and used green fluorescence protein (GFP) reporter assay, Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR) to validate the regulation relationship. Finally, we determined the role of the target gene in the HCC phenotype. RESULTS: We found that the expression of miR 718 was significantly reduced in various HCC cell lines and HCC tissues. Re expression of miR-718 significantly reduced the cellular viability and colony formation ability as well as inhibited the migration and invasion abilities of HCC cell lines. Early growth response protein 3 (EGR3) is a direct target of miR 718 and is negatively regulated by miR-718. EGR3 could increase the viability and proliferation of HCC cells, and promot the migration and invasion of HCC cells. CONCLUSIONS: miR-718 acts as a tumor suppressive microRNA in HCC via regulating the expression of EGR3, which may provide a new diagnostic marker and treatment target for HCC. PMID- 28070992 TI - Molecular signal networks and regulating mechanisms of the unfolded protein response. AB - Within the cell, several mechanisms exist to maintain homeostasis of the endoplasmic reticulum (ER). One of the primary mechanisms is the unfolded protein response (UPR). In this review, we primarily focus on the latest signal webs and regulation mechanisms of the UPR. The relationships among ER stress, apoptosis, and cancer are also discussed. Under the normal state, binding immunoglobulin protein (BiP) interacts with the three sensors (protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1alpha (IRE1alpha)). Under ER stress, misfolded proteins interact with BiP, resulting in the release of BiP from the sensors. Subsequently, the three sensors dimerize and autophosphorylate to promote the signal cascades of ER stress. ER stress includes a series of positive and negative feedback signals, such as those regulating the stabilization of the sensors/BiP complex, activating and inactivating the sensors by autophosphorylation and dephosphorylation, activating specific transcription factors to enable selective transcription, and augmenting the ability to refold and export. Apart from the three basic pathways, vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR)-phospholipase C-gamma (PLCgamma)-mammalian target of rapamycin complex 1 (mTORC1) pathway, induced only in solid tumors, can also activate ATF6 and PERK signal cascades, and IRE1alpha also can be activated by activated RAC-alpha serine/threonine-protein kinase (AKT). A moderate UPR functions as a pro-survival signal to return the cell to its state of homeostasis. However, persistent ER stress will induce cells to undergo apoptosis in response to increasing reactive oxygen species (ROS), Ca2+ in the cytoplasmic matrix, and other apoptosis signal cascades, such as c-Jun N terminal kinase (JNK), signal transducer and activator of transcription 3 (STAT3), and P38, when cellular damage exceeds the capacity of this adaptive response. PMID- 28070993 TI - Use of liposomal doxorubicin for adjuvant chemotherapy of breast cancer in clinical practice. AB - Breast cancer is one of the malignant tumors with the highest morbidity and mortality. It is helpful to reduce the rate of tumor recurrence and metastasis by treating breast cancer with adjuvant chemotherapy, so as to increase the cure rate or survival of patients. In recent years, liposomes have been regarded as a kind of new carrier for targeted drugs. Being effective for enhancing drug efficacy and reducing side effects, they have been widely used for developing anticancer drugs. As a kind of anthracycline with high anticancer activity, doxorubicin can treat or alleviate a variety of malignant tumors effectively when it is used on its own or in combination with other anticancer drugs. Although liposomal doxorubicin has been extensively used in the adjuvant chemotherapy of breast cancer, its exact therapeutic efficacy and side effects have not been definitely proven. Various clinical studies have adopted different combined regimes, dosages, and staging, so their findings differ to certain extent. This paper reviews the clinical application of liposomal doxorubicin in the adjuvant chemotherapy of breast cancer and illustrates therapeutic effects and side effects of pegylated liposomal doxorubicin (PLD) and non-PLD (NPLD) in clinical research, in order to discuss the strategies for applying these drugs in such adjuvant chemotherapy, looking forward to providing references for related research and clinical treatment in terms of dosage, staging, combined regimes, and analysis methods and so on. PMID- 28070995 TI - Haplotype of platelet receptor P2RY12 gene is associated with residual clopidogrel on-treatment platelet reactivity. AB - OBJECTIVE: To investigate a possible association between common variations of the P2RY12 and the residual clopidogrel on-treatment platelet reactivity after adjusting for the influence of CYP2C19 tested by thromboelastography (TEG). METHODS: One hundred and eighty patients with acute coronary syndrome (ACS) treated with clopidogrel and aspirin were included and platelet function was assessed by TEG. Five selected P2RY12 single nucleotide polymorphisms (SNPs; rs6798347, rs6787801, rs6801273, rs6785930, and rs2046934), which cover the common variations in the P2RY12 gene and its regulatory regions, and three CYP2C19 SNPs (*2,*3,*17) were genotyped and possible haplotypes were analyzed. RESULTS: The high on-treatment platelet reactivity (HTPR) prevalence defined by a platelet inhibition rate <30% by TEG in adenosine diphosphate (ADP)-channel was 69 (38.33%). Six common haplotypes were inferred from four of the selected P2RY12 SNPs (denoted H0 to H5) according to the linkage disequilibrium R square (except for rs2046934). Haplotype H1 showed a significantly lower incidence of HTPR than the reference haplotype (H0) in the total study population while haplotypes H1 and H2 showed significantly lower incidences of HTPR than H0 in the nonsmoker subgroup after adjusting for CYP2C19 effects and demographic characteristics. rs2046934 (T744C) did not show any significant association with HTPR. CONCLUSIONS: The combination of common P2RY12 variations including regulatory regions rather than rs2046934 (T744C) that related to pharmacodynamics of clopidogrel in patients with ACS was independently associated with residual on clopidogrel platelet reactivity. This is apart from the established association of the CYP2C19. This association seemed more important in the subgroup defined by smoking. PMID- 28070996 TI - Distribution and differentiation of myeloid-derived suppressor cells after fluid resuscitation in mice with hemorrhagic shock. AB - OBJECTIVE: To investigate the distribution and differentiation of myeloid-derived suppressor cells (MDSCs) in hemorrhagic shock mice, which are resuscitated with normal saline (NS), hypertonic saline (HTS), and hydroxyethyl starch (HES). METHODS: BALB/c mice were randomly divided into control, NS, HTS, and HES resuscitation groups. Three subgroups (n=8) in each resuscitation group were marked as 2, 24, and 72 h. Flow cytometry was used to detect the MDSCs, monocytic MDSCs (M-MDSCs), and granulocytic/neutrophilic MDSCs (G-MDSCs) in peripheral blood nucleated cells (PBNCs), spleen single-cell suspension, and bone marrow nucleated cells (BMNCs). RESULTS: The MDSCs in BMNCs among three resuscitation groups were lower 2 h after shock, in PBNCs of the HTS group were higher, and in spleen of the NS group were lower (all P<0.05 vs. control). The M-MDSC/G-MDSC ratios in PBNCs of the HTS and HES groups were lower (both P<0.05 vs. control). At 24 h, the MDSCs in PBNCs of the NS and HTS groups were higher, while the spleen MDSCs in the HTS group were higher (all P<0.05 vs. control). The M-MDSC/G MDSC ratios were all less in PBNCs, spleen, and BMNCs of the NS and HTS groups, and were lower in BMNCs of the HES group (all P<0.05 vs. control). At 72 h, the elevated MDSCs in PBNCs were presented in the HTS and HES groups, and in spleen the augment turned up in three resuscitation groups (all P<0.05 vs. control). The inclined ratios to M-MDSC were exhibited in spleen of the NS and HTS groups, and in PBNCs of the NS group; the inclination to G-MDSC in BMNCs was shown in the HES group (all P<0.05 vs. control). CONCLUSIONS: HTS induces the earlier elevation of MDSCs in peripheral blood and spleen, and influences its distribution and differentiation, while HES has a less effect on the distribution but a stronger impact on the differentiation of MDSCs, especially in bone marrow. PMID- 28070997 TI - Involvement of endothelial progenitor cells in the formation of plexiform lesions in broiler chickens: possible role of local immune/inflammatory response. AB - Plexiform lesions (PLs), which are often accompanied by perivascular infiltrates of mononuclear cells, represent the hallmark lesions of pulmonary arteries in humans suffering from severe pulmonary arterial hypertension (PAH). Endothelial progenitor cells (EPCs) have been recently implicated in the formation of PLs in human patients. PLs rarely develop in rodent animal models of PAH but can develop spontaneously in broiler chickens. The aim of the present study was to confirm the presence of EPCs in the PLs in broilers. The immune mechanisms involved in EPC dysfunction were also evaluated. Lungs were collected from commercial broilers at 1 to 4 weeks of age. The right/total ventricle ratios indicated normal pulmonary arterial pressures for all sampled birds. Immunohistochemistry was performed to determine the expressions of EPC markers (CD133 and VEGFR-2) and proangiogenic molecule hepatocyte growth factor (HGF) in the lung samples. An EPC/lymphocyte co-culture system was used to investigate the functional changes of EPCs under the challenge of immune cells. PLs with different cellular composition were detected in the lungs of broilers regardless of age, and they were commonly surrounded by moderate to dense perivascular mononuclear cell infiltrates. Immunohistochemical analyses revealed the presence of CD133+ and VEGFR-2+ cells in PLs. These structures also exhibited a strong expression of HGF. Lymphocyte co-culture enhanced EPC apoptosis and completely blocked HGF stimulated EPC survival and in vitro tube formation. Taken together, this work provides evidence for the involvement of EPCs in the development of PLs in broilers. It is suggested that the local immune cell infiltrate might serve as a contributor to EPC dysfunction by inducing EPC death and limiting their response to angiogenic stimuli. Broiler chickens may be valuable for investigating reversibility of plexogenic arteriopathy using gene-modified inflammation resistant EPCs. PMID- 28070998 TI - Successful treatment of accessory breast cancer with endocrine therapy. AB - Accessory breast cancers in males are extremely rare, and only a few cases have been reported in the literature. In this paper, an 87-year-old male patient was diagnosed with an accessory breast cancer by means of computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET-CT), and immunohistochemistry based on needle biopsy, and has undergone successful resection and postoperative adjuvant endocrine therapy. He was the oldest male patient with an accessory breast cancer reported in the Chinese Hospital Knowledge Database and PubMed literature from 1975 to 2015. PMID- 28070999 TI - Inhibitory effect of Shenqi Fuzheng injection combined with docetaxel on lung cancer cells. AB - This study investigated the anticancer effect of Shenqi Fuzheng (SQFZ) injection combined with docetaxel on lung cancer cell lines of A549 and Lewis lung cancer (LLC). SQFZ injection alone cannot inhibit the vitality of lung cancer cells, but the antitumor activity of SQFZ combined with docetaxel was significantly higher than that using docetaxel alone. PMID- 28071001 TI - Purified isolation of vacuoles from Sedum alfredii leaf-derived protoplasts. AB - This study aims to develop a method for isolating and purifying protoplasts/vacuoles from fresh leaves of the Cd hyperaccumulator plant species, Sedum alfredii. The results revealed that preheating cellulase and macerozyme at 50 degrees C for 5 min significantly accelerated the cell wall degradation. For the most optimal conditions for mesophyll protoplast isolation, the mixture of fresh leaves and cell lysates was followed by a 2-h-long vibration. The protoplast lysate for vacuole isolation was diluted, and 0.675 mmol/L was identified as the most appropriate 3-[(3-cholamidopropyl) dimethylammonio]-1 propanesulfonic acid (CHAPS) level, in which S. alfredii large vacuoles are characterized by a high metal and malic acid content. For the best vacuole purification results, we established that 0.8 mol/L was the most optimal mannitol level in the vacuole buffer in terms of vacuole protection during centrifugation, whereas a Ficoll concentration of 0.10 g/ml was adopted in the density-gradient centrifugation. PMID- 28071000 TI - Chemical composition and antioxidant activities of essential oils from different parts of the oregano. AB - This research was undertaken in order to characterize the chemical compositions and evaluate the antioxidant activities of essential oils obtained from different parts of the Origanum vulgare L. It is a medicinal plant used in traditional Chinese medicine for the treatment of heat stroke, fever, vomiting, acute gastroenteritis, and respiratory disorders. The chemical compositions of the three essential oils from different parts of the oregano (leaves-flowers, stems, and roots) were identified by gas chromatography-mass spectrometry (GC-MS). The antioxidant activity of each essential oil was assessed using the 2,2-diphenyl-1 picrylhydrazyl (DPPH) free radical scavenging assay and reducing the power test. Among the essential oils from different parts of the oregano, the leaf-flower oils have the best antioxidant activities, whereas the stem oils are the worst. The results of the DPPH free radical scavenging assay showed that the half maximal inhibitory concentration (IC50) values of the essential oils were (0.332+/-0.040) mg/ml (leaves-flowers), (0.357+/-0.031) mg/ml (roots), and (0.501+/-0.029) mg/ml (stems), respectively. Interestingly, the results of reducing the power test also revealed that when the concentration exceeded 1.25 mg/ml, the leaf-flower oils had the highest reducing power; however, the stem oils were the lowest. PMID- 28071002 TI - Effect of antioxidants on polyunsaturated fatty acids - review. AB - This paper aims to review the available literature data and provide an overview regarding the efficiency of antioxidants to prevent peroxidation of polyunsaturated fatty acids. Lipid peroxidation is a serious problem that often leads to a loss of shelf-life, reduced consumer acceptability, poorer functionality, lower nutritional value, and poorer safety. It represents an oxidative degradation of polyunsaturated fatty acids incorporated in cell membrane lipids or in lipoproteins, but also in vegetables and food oils rich in PUFA n-3. It is a complex process that leads to the production of numerous highly reactive metabolites with consequences for food preservation and for the development of various diseases. The targets of lipid oxidation are polyunsaturated fatty acids. Lipid peroxidation can proceed by means of two different reactions that lead to the formation of hydroperoxides as primary products. Hydroperoxides decompose rapidly to give many secondary products, such as lipid free radicals, which contribute to increased oxidation of other molecules, such as proteins, nucleic acids and other lipids. Lipid peroxidation is a major problem for the food industry, as well as for human health, since it is associated with many diseases. The use of antioxidants reduces oxidative damage. PMID- 28071003 TI - New model for colour kinetics of plum under infrared vacuum condition and microwave drying. AB - BACKGROUND: Quality of dried foods is affected by the drying method and physiochemical changes in tissue. The drying method affects properties such as colour. The colour of processed food is one of the most important quality indices and plays a determinant role in consumer acceptability of food materials and the processing method. The colour of food materials can be used as an indirect factor to determine changes in quality, since it is simpler and faster than chemical methods. METHODS: The study focused on the kinetics of colour changes of plum slices, under infrared vacuum and microwave conditions. Drying the samples was implemented at the absolute pressures of 20 and 60 kPa, drying temperatures of 50 and 60 degrees C and microwave power of 90, 270, 450 and 630 W. Colour changes were quantified by the tri-stimulus L* (whiteness/darkness), a* (redness/greenness) and b* (yellowness/blueness) model, which is an international standard for color measurement developed by the Commission Internationale d'Eclairage (CIE). These values were also used to calculate total colour change (?E), chroma, hue angle, and browning index (BI). A new model was used for mathematical modelling of colour change kinetics. RESULTS: The drying process changed the colour parameters of L*, a*, and b*, causing a colour shift toward the darker region. The values of L* and hue angle decreased, whereas the values of a*, b*, ?E, chroma and browning index increased during exposure to infrared vacuum conditions and microwave drying. Comparing the results obtained using the new model with two conventional models of zero-order and first-order kinetics indicated that the new model presented more compatibility with the data of colour kinetics for all colour parameters and drying conditions. CONCLUSIONS: All kinetic changes in colour parameters can be explained by the new model presented in this study. The hybrid drying system included infrared vacuum conditions and microwave power for initial slow drying of plum slices and provided the desired results for colour change. PMID- 28071004 TI - Influence of freezing and storing cherry fruit on its nutritional value. AB - BACKGROUND: Cherries are a valuable dietary raw material and possess medicinal properties. Considering the nutritional, medical and vitamin value of cherry fruits, the purpose of this research was to produce a scientific justification for preserving the quality of cherry fruits using different freezing methods. METHODS: To do this, cherry fruits from the Lotovka (Cerasus vulgaris) variety were frozen in various ways: packed in polyethylene bags (control); previously suspended in a 20% sugar solution and packing frozen cherry in polyethylene bags; suspended in a 20% sugar solution with the addition of 4% ascorutin and frozen followed by pre-packaging in polyethylene bags; cherry fruits were frozen in a 20% sugar solution in plastic cups of 0.25 cm3; they were also frozen in a 20% sugar solution with the addition of 4% ascorutin in plastic cups. The frozen products were stored at a temperature not higher than -18 degrees C for up to 6 months. Result. Studies have shown the appropriateness of freezing cherry fruits, particularly in a 20% sugar solution with the addition of 4% ascorutin. The advantages of these fruits are in ascorbic acid preservation in 1. RESULTS: nd. Cherries are a valuable dietary raw material and possess medicinal properties. Considering the nutritional, medical and vitamin value of cherry fruits, the purpose of this research was to produce a scientific justification for preserving the quality of cherry fruits using different freezing methods. Material and methods. To do this, cherry fruits from the Lotovka (Cerasus vulgaris) variety were frozen in various ways: packed in polyethylene bags (control); previously suspended in a 20% sugar solution and packing frozen cherry in polyethylene bags; suspended in a 20% sugar solution with the addition of 4% ascorutin and frozen followed by pre-packaging in polyethylene bags; cherry fruits were frozen in a 20% sugar solution in plastic cups of 0.25 cm3; they were also frozen in a 20% sugar solution with the addition of 4% ascorutin in plastic cups. The frozen products were stored at a temperature not higher than -18 degrees C for up to 6 months. Result. Studies have shown the appropriateness of freezing cherry fruits, particularly in a 20% sugar solution with the addition of 4% ascorutin. The advantages of these fruits are in ascorbic acid preservation in 1.5 times and reduction of tanning and coloring substances only by 27%, soluble solids to 7%, sugars - 4%, acids - 12%, in tasting evaluation of 5 points. CONCLUSIONS: Frozen cherry fruits in a 20% sugar solution with the addition of 4% ascorutin can be used in dietary nutrition for patients with cardiovascular diseases. PMID- 28071005 TI - Fermentation optimization of goat milk with Lactobacillus acidophilus and Bifidobacterium bifidum by Box-Behnken design. AB - BACKGROUND: Goat milk is only limited to the processing of goat milk powder and liquid milk, the products are mainly about milk powder and a few of them are made as milk tablet. Therefore, the study of probiotic goat milk will have great significance in the full use of goats and the development of the goat milk industry in China. METHODS: The effect of fermentation temperature (35 degrees C, 37 degrees C, 39 degrees C), strain ratio (1:1:1, 2:1:1, 3:1:1) and inoculum size (4%, 5%, 6%) on viable counts of L. acidophilus and B. bifidum, total bacteria and sensory value during fermentation process of L. acidophilus and B. bifidum goat yogurt (AB-goat yogurt) was investigated. RESULTS: The optimum fermentation conditions for AB-goat yogurt were: fermentation temperature 38 degrees C, the strain ratio 2:1:1, inoculum size 6%. Under the optimum conditions, the viable counts of B. bifidum, L. acidophilus, total bacteria and sensory value reached (4.30 +/-0.11)*107 cfu/mL, (1.39 +/-0.09)*108 cfu/mL, (1.82+/-0.06)*109 cfu/mL and 7.90 +/-0.14, respectively. CONCLUSIONS: The fermentation temperature, the strain ratio and inoculum size had a significant effect on the fermentation of AB goat yogurt and these results are beneficial for developing AB-goat yogurt. PMID- 28071006 TI - Sensory qualities of pastry products enriched with dietary fiber and polyphenolic substances. AB - BACKGROUND: Growing consumer demand for products with pro-health properties is forcing food manufacturers to introduce new food items onto the market, which will not only possess such health-enhancing properties but will also compete on the grounds of sensory attributes - taste, flavour, texture etc. METHODS: The aim was to evaluate these sensory attributes of pastry products enhanced with biologically active compounds, such as inulin, buckwheat hull and buckwheat flour. For decreasing the energy value of the products tested (crispy cookies, muesli cookies, waffles and pancakes) some ingredients were replaced: vegetable butter or oil by inulin and wheat flour by roasted buckwheat flour and thermally processed buckwheat hull. The substances mentioned are rich sources of soluble and insoluble buckwheat fiber, and also polyphenolic substances. Dry chokeberry and mulberry leaf extract were added as a rich source of flavonoids and 1 deoxynorijimycin, respectively. These substances are recommended for people with obesity. The processing was carried out at 175 degrees C for 15 minutes using a convection oven (Rational Combi-Steamer CCC). RESULTS: Pastry products with buckwheat flour, buckwheat hulls, mulberry extract, chokeberry and inulin had a lower food energy, a higher dietary fiber content and scored high on customer desirability. CONCLUSIONS: Pastry products which contain ingredients carrying biologically active substances are not only attractive from the sensory point of view, but also low in calories, and are thus recommendable for obesity people. PMID- 28071007 TI - Evaluation the effect of gamma irradiation on microbial, chemical and sensorial properties of peanut (Arachis hypogaea l.) seeds. AB - BACKGROUND: The aim of the present study was to evaluate the possibility to apply gamma radiation treatment for decontaminating and assuring the quality of peanut seeds. METHODS: The radiation processing was carried out at dose levels of 3, 6 and 9 kGy. The irradiated and non-irradiated (control) samples were stored at room temperature for 12 months, and analyzed for microbial load, proximate composition, sensorial acceptance and chemical properties. RESULTS: The results indicated that gamma irradiation treatment significantly (p < 0.05) reduced microbial load and enhanced the safety of the irradiated samples. The irradiated samples were also acceptable sensorically. The total acidity and total volatile nitrogen (TVBN) contents increased with the increase of radiation dose. Furthermore, in general, no substantial change in proximate constituents was observed amongst the samples. No significant (p > 0.05) differences in the taste, flavor, color and texture score were observed among treatments (0, 3, 6 and 9 kGy). CONCLUSIONS: Irradiation protected again bacterial and fungal growth and retained the nutritional components of samples during long-term storage. PMID- 28071008 TI - MICROWAVE-ASSISTED EXTRACTION OF PHENOLIC COMPOUNDS FROM POLYGONUM MULTIFLORUM THUNB. ROOTS. AB - BACKGROUND: The aim of this study was to determine the best extraction conditions for total phenolic content (TPC) and antioxidant capacity (AC) of Polygonum multiflorum Thunb. root using microwave-assisted extraction (MAE). METHODS: The raw material used was Polygonum multiflorum Thunb. root powder. Five factors such as solvent type, solvent concentrations, solvent/material ratio, extraction time and microwave power were studied; TPC and AC values were determined by the Folin Ciocalteu method and DPPH free radical scavenging activity measurement, respectively. In addition, studies involved assaying the HPLC test of extracts and SEM of samples. RESULTS: Optimal results pointed to acetone as the solvent, acetone concentration of 60%, solvent/material ratio of 40/1 (v/w), extraction time of 5 mins and microwave power of 127 W. TPC and AC obtained were approximates 44.3 +/-0.13 mg GAE/g DW and 341.26 +/-1.54 MUmol TE/g DW, respectively. The effect of microwaving on the cell destruction of Polygonum multiflorum Thunb. root was observed by scanning electron microscopy (SEM). Some phenolic compounds were determined by the HPLC method, for instance, gallic acid, catechin and resveratrol. CONCLUSIONS: These factors significantly affected TPC and AC. We can use acetone as a solvent with microwave-assisted extraction to achieve the best result. PMID- 28071009 TI - Evolution of free amino acids, biogenic amines and n-nitrosoamines throughout ageing in organic fermented beef. AB - BACKGROUND: In recent years, interest in uncured meat products has grown and studies were carried out on the use of substances which could replace nitrites, such as acid whey. In spite of this problem in fermented meat products, there is no information regarding the effects of prolonged ageing on the formation of chemical (nitrosoamines, biogenic amines, secondary lipid oxidation products) and microbiological (L. monocytogenes, S. aureus, OLD) toxicants in fermented beef marinated with acid whey. The aim of this study was to determine the selected pathogenic bacteria, biogenic amines, N-nitrosamines contents in fermented beef subjected to extended ageing. METHODS: In this study, selected pathogenic bacteria, N-nitrosamines, biogenic amines, amino acids, TBARS values changes during the ageing of fermented beef marinated with acid whey were analyzed in 0-, 2- and 36-month-old samples. RESULTS: The pH values of fermented beef aged for 2 months (5.68, 5.49 and 5.68 respectively) were significantly lower (p < 0.05) than those obtained after the end of the manufacturing ripening period (5.96, 5.97 and 5.74 respectively), which confirmed the effectiveness of the fermentation process of acidification on beef. The high Lactic Acid Bacteria content (5.64-6.30 log cfu/g) confirmed this finding. Histamine was not detected in either of the products. The highest concentration of total biogenic amine (i.e. 1159.0 mg/kg) was found in fermented beef marinated with acid whey, whereas a total of only 209.8 mg/kg, was observed in control beef with nitrate and nitrite. N-nitrosamines were not detected in any of the ageing beef samples. CONCLUSIONS: In this study, marinating beef in acid whey did not inhibit the production of biogenic amines in the samples analyzed. The high concentration of FAAs, the potential precursor of BA, could lead to intense peptidase activity. The results obtained indicate that biogenic amines are not direct precursors for nitrosamines formation in fermented beef. The LAB strain from acid whey reduced the pH value during the first stages of ageing and ensured the microbiological safety of the product not only in the first stage of fermentation but also at the end of ageing (36 months). PMID- 28071010 TI - The role of intestinal microbiota in the pathogenesis of metabolic diseases. AB - The incidence of metabolic diseases is increasing rapidly all over the world. This situation has led researchers to attempt to explain the pathomechanisms of these disorders and to develop specific recommendations for the prevention and treatment of diseases such as obesity, type-2 diabetes, and atherosclerosis. Recent studies show clear evidence of the role of human intestinal microbiota in health and in predispositions to diseases. Gut microbiota affect a number of complex metabolic reactions, significantly altering the functioning of the human body. Numerous experiments have shown the key role played by the formation process of the intestinal ecosystem in the early stages of human life for programming its metabolic health. The following article is a compilation of the literature available on the formation of the complex intestinal ecosystem and its impact on the incidence of diseases such as obesity, type-2 diabetes, and atherosclerosis. PMID- 28071011 TI - The effects of a low-calorie diet or an isocaloric diet combined with metformin on sex hormones In obese women of child-bearing age. AB - BACKGROUND: The influence of weight loss treatment on sex hormones profile has been studied mainly in women with polycystic ovary syndrome (PCOS), but in obese premenopausal women without PCOS it still remains unclear. The aim of the study was to evaluate the effect of two approaches to obesity treatment on the serum level of sex hormones in obese women of child-bearing age without PCOS. METHODS: 77 obese Caucasian women (aged 31.2 +/-8.3 years) were randomized into two groups: 39 women received a low-calorie diet (LC) and 38 received an isocaloric diet plus metformin (IM), for 12 weeks. Anthropometric parameters, body composition and serum concentrations of estradiol (E2), testosterone (T), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and dehydroepiandrosterone (DHEA-S) sulfate were evaluated at baseline and after the study. RESULTS: Reductions in body weight, body mass index (BMI), waist and body fat content with an increase in lean body percent were significant and comparable between the LC and IM group after the trial. The concentrations of serum FSH, LH, E2, DHEA and T did not change in either group after treatment. A tendency towards an increase in the E2 concentration in both groups and a decrease in the T level in the LC group was observed. The correlations between a change in BMI, fat content, waist-hip ratio and a change in T were documented in the LC group. CONCLUSIONS: A 12-week low-calorie diet and an isocaloric diet combined with metformin produced comparable and significant weight loss with improvements in body composition. Both interventions did not significantly affect FSH, LH and DHEA sulfate serum concentrations, only a trend towards an E2 increase and a T decrease was observed, stronger in LC group. The significant correlations shown between the changes in anthropometric and body composition parameters and T serum levels in women treated with a low-calorie diet alone show the beneficial effect of a lifestyle intervention on the sex hormone in obese premenopausal women. PMID- 28071012 TI - Phenylketonuria is not a risk factor for changes of inflammation status as assessed by interleukin 6 and interleukin 8 concentrations. AB - BACKGROUND: High oxidative stress and a reduced potential for free radical scavenging in phenylketonuria (PKU) patients, a phenomenon confirmed in a few studies, may lead to systemic chronic inflammation. The aim of this study was to compare the inflammation status, as assessed by interleukin 6 and interleukin 8 concentrations, in patients with PKU and in healthy controls. METHODS: Twenty patients with classical PKU, aged 18-34 years and under dietary control, were enrolled in the study. The control group comprised of 20 healthy subjects matched for age and sex. Interleukin 6 and 8 levels were measured by enzyme-linked immunosorbent assay (ELISA) kits in all study participants. RESULTS: IL-6 concentrations in the study group ranged from 0.74 pg/ml to 1.34 pg/ml. No significant differences were found between IL-6 concentration between the study group and the control group (p = 0.989). IL-8 concentrations ranged from 17.56 pg/ml to 20.87 pg/ml. The obtained results of IL-8 levels did not differ significantly between the study group and control group (p = 0.192). No significant correlation was observed between Phe blood levels and IL-6 or IL-8 concentrations in the study group (rho respectively: -0.225, 0.177). In a multivariate analysis, neither IL-6 nor IL-8 concentrations were correlated with sex, age, BMI and Phe levels. CONCLUSIONS: Phenylketonuria is not a risk factor for changes of inflammation status as assessed by IL-6 and IL-8 concentrations. PMID- 28071013 TI - The industrial potential of herbs and spices - a mini review. AB - Herbs and spices have been used for food and medicinal purposes for centuries - the first recorded evidence of their use dates back to 1500BC and the Ebers Papyrus, which mentioned spices such as anise, mustard, saffron, cinnamon, and cassia. Now, in the 21st century, a variety of secondary compounds produced by plants are used in many fields of industry, such as food production (to improve taste, to provide vitamins and macro- and microelements, and also to inhibit food spoilage caused by foodborne bacteria), in medicine (in the treatment of various diseases; in chemoprevention and cancer therapy; as a source of natural antimicrobials for the treatment of infectious disease), and in pharmacology and cosmetology (in dietary supplements, and as a result of the demand for preservative-free cosmetics, to reduce the risk of methylparaben allergies). The aim of this review is to present the major active compounds in herbs and spices and explore their potential applications in industry. PMID- 28071014 TI - Properties of ice-cream fortified with zinc and Lactobacillus casei. AB - BACKGROUND: In this study, the possible effects of zinc on physicochemical properties of ice cream and the survival of Lactobacillus casei during a 90 days storage at -18 degrees C was investigated. METHODS: Samples were divided into four experimental groups as follows: control, zinc fortified ice cream, probiotic ice cream, zinc fortified and probiotic ice cream. The physicochemical, texture, organoleptic properties and the survival of probiotics, were investigated. RESULTS: Results showed that the addition of zinc did not affect the textural properties of ice creams. Viscosity and pH were independently decreased in all groups in the presence of zinc. A significant increase in the lipid oxidation rate especially in the zinc fortified group was also observed. The probiotic counts were maintained above the least advised quantities (106 cfu/g) which were subsequently reduced following the three months of storage. In the zinc fortified samples, the counts were higher compared to the other groups with no zinc addition. The addition of probiotics and zinc had no significant effect on the sensory properties of ice cream. CONCLUSIONS: As a final conclusion, the commercial production of zinc fortified ice cream is recommended. PMID- 28071015 TI - The changes of proteins fractions shares in milk and fermented milk drinks. AB - BACKGROUND: The aim of this research was to observe the changes which take place in the electrophoretic picture of milk proteins after pasteurisation and inoculation with different starter cultures (both traditional and probiotic). After incubation, the yoghurt, kefir, acidified milk, fermented Bifidobacterium bifidum drink and Lactobacillus acidophillus drink were chilled for 14 days to observe the changes which occurred. METHODS: The research materials were raw and pasteurised milk, as well as fermented milk- based drinks. The raw milk used for research came from Polish Holstein-Fresian black and white cows. The milk was sampled 3 times and divided into 5 parts, each of which was pasteurised at 95 degrees C for 10 min and then cooled for inoculation: yoghurt to 45 degrees C, kefir and acidified milk to 22 degrees C and drinks with Bifidobacterium bifidum and Lactobacillus acidophillus to 38 degrees C. Milk was inoculated with lyophilised, direct vat starter cultures, in an amount equal to 2% of the working starter. For the production of fermented drinks, the subsequent starters were applied: "YC-180" Christian Hansen for yoghurt, "D" Biolacta-Texel-Rhodia for kefir, CH-N--11 Christian Hansen for acidified milk, starter by Christian Hansen for the probiotic Bifidobacterium bifidum milk, starter by Biolacta-Texel-Rhodia for the probiotic Lactobacillus acidophillus milk. The analyses were conducted in raw, pasteurised and freshly fermented milk as well as in milk drinks stored for 14 days. The total solid content was estimated by the drying method; the fat content by the Gerber method; the lactose content by the Bertrand method; the protein content by the Kjeldahl method with Buchi apparatus; the density of milk was measured with lactodensimeter; acidity with a pH-meter; and potential acidity by Soxhlet-Henkl method (AOAC, 1990). The electrophoretic separation of proteins in raw and pasteurised milk, as well as in freshly produced milk drinks and those stored for 14 days, was performed with SDS-PAGE (on polyacrylamid gel) basing on procedure described by Laemmli (1970). RESULTS: It was shown that, in comparison with raw milk, the pasteurised milk had smaller amounts of alphas-, beta- and kappa-casein, whereas the shares of gamma-casein and peptides were greater, and there were no changes in immunoglobulin, alpha-lactalbumin or beta-lactoglobulin levels, which indicated that hydrolysis of caseins had occurred. In all freshly fermented milk drinks, a drop in alphas- and beta-casein was observed relative to raw milk. An increase in peptides and gamma-casein was also noticed (with the exception of acidified milk). There were differences in alpha-lactalbumin and beta-lactoglobulin levels between the different drinks: raw, pasteurised or freshly fermented milk. It was shown that kefir, compared to the other drinks, had the lowest levels of alphas- and beta-casein, alpha-lactalbumin and of peptides, as well as the highest level of gamma-casein, which is evidence of an increased rate of hydrolysis in that drink. It was stated that, during the storage of fermented milk drinks, the levels of lactoferrin, serum albumin and peptides significantly increased whereas the content of kappa-casein diminished. The proportions of serum albumin and lactoferrin in fermented milk drinks increased relative to raw milk and/or after storage, which is evidence of aggregation of proteins of low molecular mass into bigger conglomerates. CONCLUSIONS: The observed differences between fermented milks, including during chilled storage, in the amounts of individual proteins proves the different proteolytic abilities of starter cultures used in fermented milk production. alpha-lactoalbumin and beta-lactoglobulin are, besides caseins, the most allergenic milk proteins. So, kefir, because of its low alpha-lactoalbumin content, and Bifidobacterium bifidum milk, with the lowest content of beta lactoglobulin, were the most advantageous and least allergenic drinks examined. PMID- 28071017 TI - Evaluation of the potential use of probiotic strain Lactobacillus plantarum 299v in lactic fermentation of button mushroom fruiting bodies. AB - BACKGROUND: The available literature does not provide data on the application of probiotic strains in mushroom processing. The aim of the study was to evaluate the potential to use the L. plantarum 299v strain with documented probiotic properties in the process of lactic fermentation of button mushroom fruiting bodies (Agaricus bisporus). METHODS: Fresh button mushroom fruiting bodies and cultures of lactic acid bacteria L. plantarum Ib and a probiotic strain L. plantarum 299v were the material analysed. Sensory evaluation was performed with a 5-point scale, an instrumental method of colour measurement based on the CIA L*a*b* scale, total phenolic compounds were determined with the Folin method, antioxidant properties were assayed with the DPPH radical test, and reducing power was determined using the FRAP method. RESULTS: After a week-long lactic fermentation, the pH value in the samples declined to a level of 3.6 (L. plantarum Ib) and 3.75 (L. plantarum 299v); these values persisted or decreased slightly during the period of maturation of the fermented samples under refrigeration. Fermented mushrooms were assigned high grades in the organoleptic evaluation. The colour analysis revealed significant changes in the values of the L*a*b* parameters in the fermented product, in comparison with fresh mushrooms. Blanching contributed to a significant decrease in the content of total phenolic compounds in the mushroom fruiting bodies and to a decline in antioxidant activity. Mushrooms fermented with the probiotic strain were characterised by higher phenolic compound content and higher antioxidant activity. CONCLUSIONS: L. plantarum 299v strain with documented probiotic properties can be applied in fermentation of button mushroom fruiting bodies. Products obtained with the use of both strains were characterised by good sensory properties. The type of strain used in the lactic fermentation of mushroom fruiting bodies had an effect on the phenolic compound content and antioxidant properties of the final product. PMID- 28071016 TI - The antioxidant and phenolic profiles of five green vegetables grown in Southern Nigeria. AB - BACKGROUND: Regular consumption of vegetables has been associated with reduced risk of chronic diseases. The phenolic and free radical scavenging properties of five green vegetables grown in southern Nigeria were determined. METHODS: The phenolic and antioxidant profile of African spinach, bitter leaf, jute leaf, scent leaf and water leaf harvested in the month of August were assessed using standard protocols. RESULTS: The total phenolic content (GAE mg/100 g) of the fresh vegetables ranges from 738.70 +/-7.90 in African spinach to 1464.63 +/-7.60 in scent leaf. A higher flavonoid content (QE mg/100 g) was found in water leaf (512.07 +/-1.47) and jute leaf (510.13 +/-2.22) compared to the other vegetables examined; scent leaf (496.51 +/-1.31), African spinach (457.40 +/-1.50), bitter leaf (371.89 +/-0.44). Scent leaf possesses the highest DPPH radical scavenging activity with an EC50 [MUg/mL] of 74.64 +/-7.73. The other vegetables show a lower EC50 [MUg/mL]; jute leaf (125.86 +/-11.34) > water leaf (132.43 +/-9.43) > bitter leaf (156.02 +/-5.43) > African spinach (213.44 +/-9.29). The hydroxyl radical scavenging activity (EC50, MUg/mL) of the vegetables in order of decreasing activity, was bitter leaf (50.38 +/-7.17) > water leaf (103.41 +/ 6.27) > African spinach (110.54+/-8.15) > jute leaf (144.39 +/-9.37) > scent leaf (217.51 +/-6.90). The total antioxidant capacity (EC50, MUg/mL) of the vegetables increases in the following order; African spinach (227.39 +/-7.25) < bitter leaf (169.96+/-6.86) < water leaf (106.31 +/-7.66) < scent leaf (65.47 +/ 14.43) < jute leaf (27.52 +/-4.14). CONCLUSIONS: The green vegetables possess appreciable phenolic and antioxidant potentials, which underscore their regular consumption as part of healthy Nigerian diet. Principal component analysis (PCA) buttresses the correlations and variations of the aforementioned potential among vegetable species. PMID- 28071018 TI - Effect of roasting degree on the antioxidant activity of different Arabica coffee quality classes. AB - BACKGROUND: Coffee is one of the most widely consumed beverages in the world, because of its unique sensory properties and physiological properties. Coffee beverages represent a significant source of antioxidants in the consumers' diet and contribute significantly to their daily intake. The aim of this research was to investigate the effect of different roasting degrees on the content of biologically active compounds and antioxidant activity in different quality classes of Arabica coffee. METHODS: Samples of green Arabica coffee (Rio Minas) of two quality classes from two production batches were used for the research. Roasting was carried out at temperatures of 167, 175 and 171 degrees C. The total phenol content (TPC), total flavonoid content (TFC), flavonol content (FC) and antioxidant activity (DPPH, ABTS) in the coffee extracts was determined. RESULTS: This research shows that TPC was significantly higher (P < 0.05) in green coffee compared to TPC in roasted coffee, and TPC decreases as the roasting temperature increases. TFC and FC were significantly lower (P < 0.05) in green coffee than in roasted coffee. Differences in TPC between the 1st and 2nd classes of Arabica coffee were not significant (P > 0.05), while differences in TFC were significant (P < 0.05) only for green coffee from the second production batch and differences in FC were significant (P < 0.05) for green coffee and for coffee roasted at 175 degrees C. Roasting temperatures have different influences the antioxidant activity (DPPH, ABTS) of coffee and the highest antioxidant activity was determined in coffee roasted at 171 degrees C. An exception was 1st class Arabica coffee roasted at 167 degrees C (ABTS). All samples of 1st class Arabica coffee had higher antioxidant activity (DPPH, ABTS) compared to 2nd class Arabica. CONCLUSIONS: This research shows that the bioactive compounds content and antioxidant activity of different quality classes of Arabica coffee are dependent on the degree of roasting. TPC decreases when the roasting temperature increases, while TFC and FC also increase. These results indicate that the antioxidant activity of coffee depends on a variety of bioactive components in coffee beans. Antioxidant activity largely depends on the class of coffee. The coffee samples of 1stclass quality (maximum 8 black beans/300 g from the sample and large bean size) had higher antioxidant activity compared to samples of 2nd quality class (maximum 19 black beans/300 g in the sample and medium-sized beans). PMID- 28071019 TI - Influence of different extraction conditions on antioxidant properties of soursop peel. AB - BACKGROUND: Soursop is a healthy fruit. Peels form about 20% of the soursop fruit and are usually discarded as waste product. With a view to utilizing soursop peel as a source of valuable compounds, this study aimed to investigate the influence of different extraction conditions on total phenolic content (TPC) and antioxidant capacity (AC) of soursop (Annona muricata L.) peel. METHODS: Different ethanol concentrations (20-100%, v/v), extraction temperatures (25- 60 degrees C), and extraction time (1-5 h) were tested. Extracts were prepared on the basis of the best optimal extraction conditions (20% ethanol, 40 degrees C the extraction temperature, and 4 h of extraction time), an optimal TPC and AC was determined for the soursop peel using DPPH, ABTS, FRAP and beta-carotene bleaching (BCB) assays. The different extraction conditions tested at best optimum conditions have significantly affected the TPC and AC of the soursop peel. RESULTS: Soursop peel extract extracted in the best optimal extraction conditions had moderate levels of TPC (52.2 MUg GAE/ml), and FRAP value (58.9 MUg TE/ml extract). The extract demonstrated high BCB inhibitory activity (80.08%). The EC50 values of the extract were high, 1179.96 and 145.12 MUg/ml, as assessed using DPPH and ABTS assays, respectively. The TPC was positively and highly correlated with the AC of soursop peel assessed by ABTS, FRAP, and BCB assay, but it was moderately correlated with DPPH radical scavenging activity. A moderate correlation of TPC with DPPH suggested that polyphenols in the extracts were partially responsible for the AC. CONCLUSIONS: By-products of soursop such as its peel could be an inexpensive source of good natural antioxidants with nutraceutical potential in the functional food industry. PMID- 28071020 TI - The effect of microwave roasting on the antioxidant properties of the Bangladeshi groundnut cultivar. AB - BACKGROUND: Groundnut seeds are an important source of bioactive phenolic compounds with noteworthy antioxidant capacity, which may be enhanced by the microwave roasting process. The aim of this work is to study the changes in antioxidant activity in groundnut seeds during microwave roasting, as a function of roasting time and extract concentration, in order to maximise the phenolic content and antioxidant activity of roasted seeds. METHODS: The study was conducted to evaluate total phenolic content (TPC), total flavonoid content (TFC), and antioxidative activity of methanolic (GME), ethanolic (GEE), and chloroform (GCE) extracts and methanolic extract of oil (GMO) from groundnut seeds exposed to microwaves. The antioxidant activity was investigated using several assays, namely phosphomolybdenum assay, DPPH radical scavenging activity, H2O2 scavenging activity, hydroxyl radical scavenging activity and reducing power. RESULTS: The microwave roasting process significantly increased the TPC, whilst the TFC decreased with roasting time. Antioxidant activity increased with increased roasting time and extract concentration in all extracts. Antioxidant activity increased significantly at lower concentrations; however, the rate of increment decreased gradually as the concentration of the solvent extract increased. Thus, among all the extracts, methanol extracts at all roasting times and extract concentrations appeared to display the highest effectiveness. The various scavenging activities of the samples are ranked in the following order: GME > GEE > GCE > GMO, in both raw and roasted samples. CONCLUSIONS: Both roasting time and extract concentration were found to be critical factors in determining the overall quality of the product. This investigation is important to determine optimum roasting conditions, in order to maximise the anti-oxidative health benefits of the Bangladeshi groundnut cultivar. PMID- 28071022 TI - Research on the effect of culture time on the kombucha tea beverage's antiradical capacity and sensory value. AB - BACKGROUND: Recent consumption trends shows high consumer acceptability and growing medicinal interest in the biological value of kombucha tea. This tea is a sweetened tea leaf brew fermented with a layer containing mainly acetic acid bacteria, yeast and lactic acid bacteria. The main antioxidants in tea leaves are polyphenols, the consumption of which is proven to be beneficial for human health, e.g. protecting from reactive oxygen species (ROS). The aim of the present research was to evaluate antiradical activity, total polyphenol content (TPC) and sensory value of kombucha tea brews. METHODS: In the present study, Kombucha tea beverages were analyzed for TPC content, DPPH radical scavenging method and sensory value. RESULTS: The highest TPC content and DPPH radical scavenging capacity values were evaluated in yellow tea samples, both unfermented and kombucha, which did not differ within the storage time. The results of sensory evaluations of kombucha tea brews depend on the tea leaf variety used for preparing the drink. CONCLUSIONS: Research indicates that the fermentation process of tea brews with kombucha microbiota does not affect significantly its polyphenol content and antiradical capacity, and retains its components' biological activity. PMID- 28071021 TI - The effect of alcohol consumption on maternal and cord blood electrolyte and trace element levels. AB - BACKGROUND: Earlier studies demonstrated that alcoholism significantly alters electrolyte and trace element homeostasis. However, the existing data on the interplay between maternal alcohol consumption and fetal trace element status are contradictory. Therefore, the primary objective of the present study was to assess the influence of alcohol consumption on maternal and cord blood trace elements. METHODS: A total of 30 pregnant women (15 women consuming alcohol and 15 controls) were examined. Assessment of electrolyte and trace elements concentration in maternal (1 and 3 trimesters) and umbilical cord blood was performed using inductively-coupled plasma mass spectrometry. RESULTS: In the first trimester of pregnancy alcohol consumption is associated with increased whole blood Ca and Na levels. In the third trimester of pregnancy, women consuming alcohol are characterized by significantly increased Co levels. Conversely, the level of Co and Mn in the cord blood of offspring maternally exposed to ethanol is decreased. A significant correlation between first trimester blood and cord blood concentrations of K was revealed both in control women and those consuming alcohol. In the third trimester of pregnancy in the control women, a significant correlation with cord blood was detected for Fe, Mg, P, and Pb. Oppositely, in the third trimester in women consuming alcohol we detected a close association between maternal whole blood and cord blood levels for Ca, Cd, and Pb. CONCLUSIONS: The data obtained demonstrate that maternal alcohol consumption results in fetal Co and Mn deficiency. PMID- 28071023 TI - Effect of food processing on the physicochemical properties of dietary fibre. AB - Products derived from the manufacturing or processing of plant based foods: cereals, fruits, vegetables, as well as algae, are sources of abundant dietary fibre. Diets high in dietary fibre have been associated with the reduced risk of cardiovascular disease, diabetes, hypertension, obesity, and gastrointestinal disorders. These fibre-rich products and byproducts can also fortify foods, increase their dietary fibre content and result in healthy products, low in calories, cholesterol and fat. Traditionally, consumers have chosen foods such as whole grains, fruits and vegetables as sources of dietary fibre. Recently, food manufacturers have responded to consumer demand for foods with a higher fibre content by developing products in which highfibre ingredients are used. Different food processing methods also increase the dietary fiber content of food. Moreover, its chemical and physical properties may be affected by food processing. Some of them might even improve the functionality of fibre. Therefore, they may also be applied as functional ingredients to improve physical properties like the physical and structural properties of hydration, oil-holding capacity, viscosity. This study was conducted to examine the effect of different food processing methods on the physicochemical properties of dietary fibre. PMID- 28071024 TI - Effect of barley beta-glucan addition as a fat replacer on muffin quality. AB - BACKGROUND: The aim of this study was to perform the partial replacement of bakery fat with barley beta-glucan in muffins and to determine its effect on the physical properties of products. Most shortenings used in the industry are solid fats rich in saturated fatty acids and often trans fatty isomers, which are nutritionally unfavorable. METHODS: Dough and baked muffins were used as the research material. Five muffin recipes were prepared: control (K0%) with 16% fat content in the total dough weight, with fat content decreased by 10% (PG10%), 15% (PG15%), 20% (PG20%) and 25% (PG25%). beta-glucan was used as a fat replacer in the 1:4 ratio. The parameters determining the physical characteristics and sensory attributes were measured, compared and statistically analyzed using a principal component analysis (PCA) method. RESULTS: Although the partial replacement of shortening with barley beta-glucan is possible, it may negatively influence the physical properties of dough (aeration) and baked products (volume, density). It has been observed that increasing the content of this fat replacer enlarges the pores of the crumb. The textural properties of muffins with a fat content decreased by 20% are most similar to the control. Moreover, it has been shown that the overall sensory quality goes down when the amount of fat replacer in the muffin recipe is increased. However, adding beta-glucan to products in which fat content was decreased by 10% did not influence significantly the typical taste. CONCLUSIONS: Despite the adverse effect of beta-glucan on the physical and sensorial properties, it was found to be reasonable to use it even in small amounts (up to 10%) to increase the nutritional value of products. PMID- 28071025 TI - The effect of thermal treatment on antioxidant capacity and pigment contents in separated betalain fractions. AB - BACKGROUND: Increased consumption of fruits and vegetables significantly reduces the risk of cardio-vascular disease. This beneficial effect on the human organism is ascribed to the antioxidant compounds these foods contain. Unfortunately, many products, particularly vegetables, need to be subjected to thermal processing before consumption. The aim of this study was to determine the effect of such thermal treatment on the antioxidant capacity and pigment contents in separated fractions of violet pigments (betacyanins) and yellow pigments (betaxanthins and betacyanins). METHODS: Fractions of violet and yellow pigments were obtained by separation of betalain pigments from fresh roots of 3 red beet cultivars using column chromatography and solid phase extraction (SPE). The betalain pigment content was determined in all samples before and after thermal treatment (90 degrees C/30 min) by spectrophotometry, according to Nilsson's method [1970] and antioxidant capacity was assessed based on ABTS. Betalain pigments in the separated fractions were identified using HPLC-MS. RESULTS: After thermal treatment of betacyanin fractions a slight, but statistically significant degradation of pigments was observed, while the antioxidant capacity of these fractions did not change markedly. Losses of betacyanin content amounted to 13 15% depending on the cultivar, while losses of antioxidant capacity were approx. 7%. HPLC/MS analyses showed that before heating, betanin was the dominant pigment in the betacyanin fraction, while after heating it was additionally 15-decarboxy betanin. Isolated fractions of yellow pigments in red beets are three times less heat-resistant than betacyanin fractions. At losses of yellow pigment contents in the course of thermal treatment reaching 47%, antioxidant capacity did not change markedly (a decrease by approx. 5%). In the yellow pigment fractions neobetanin was the dominant peak in the HPLC chromatogram, while vulgaxanthin was found in a much smaller area, whereas after heating additionally 2-decarboxy-2,3-dehydro neobetanin was detected. CONCLUSIONS: Both groups of betalain pigments (betacyanins and betaxanthins) exhibit antioxidant capacity before and after heating. Violet beatacyjanins are 3 times more stable when heated than yellow betaxanthins. PMID- 28071026 TI - Antiradical capacity and polyphenol composition of asparagus spears varieties cultivated under different sunlight conditions. AB - BACKGROUND: Asparagus officinalis has a high nutritional value. Asparagus is rich in a number of bioactive compounds, mainly flavonoids (quercetin), glutathione, vitamin C, vitamin E, fructans (inulin and fructooligosaccharides) and phytosterols (b-sitosterol). These compounds may play an important role in human health. The purpose of this study was to examine the antioxidant potential and polyphenol composition of white, pale-colored and green asparagus spears of different cultivars. METHODS: Investigations were conducted on different asparagus spear extracts. The study included three colors of asparagus (white, pale-colored and green) from five different cultivars subjected to the ethanol extraction procedure. Total phenolic content was also determined by the Folin Ciocalteu method. Polyphenol (phenolic acids and flavonols) composition was estimated using the HPLC method. The antioxidant properties of extracts were examined using DPPH, ABTS and metal ion chelating assays. RESULTS: The highest contents of phenolic and flavonoids were observed in green asparagus from Grolim and the lowest in pale-colored asparagus from Gyjmlin. It was found that both the color of asparagus and the cultivar had a significant effect on the composition of phenolic acid and flavonols. Radical scavenging activity toward DPPH* and ABTS was highest for green asparagus cv. Grolim and Eposs. The greatest number of Fe ions was chelated by samples of green asparagus cv. Grolim and Huchel's Alpha and pale-colored asparagus cv. Huchel's Alpha. CONCLUSIONS: It was shown that the antioxidant activity of asparagus spears measured by antiradical and chelating activity test depends on variety and color. The highest activity was found in green asparagus and the lowest was identified in white asparagus extracts. It has also been clarified that changes in flavonol and phenolic acid composition and increases in their diversity depends on growing with sunlight and variety. Asparagus can provide a valuable source of phenolic compounds in the human diet. PMID- 28071027 TI - Antioxidant activity of the aqueous and methanolic extracts of coffee beans (Coffea arabica L.). AB - BACKGROUND: Coffee is important source of natural antioxidants in the diet, such as phenolic compounds, alkaloids, mainly caffeine, diterpenes (cafestol and kahweol) and Maillard reaction products formed during roasting. METHODS: In aqueous and methanolic extracts of coffee (Coffea arabica L.) roasted using traditional techniques from Brazil (B), Colombia (C), Ethiopia (E), Kenya (K) and coffee roasted using an industrial technique from Brazil (T), the phenolic and caffeine content as well as antioxidant properties were determined. RESULTS: Comparing the results from water and methanolic extracts it should be noted that the highest amount of phenolics was determined for a methanolic extract of coffee roasted using the industrial technique (650.96 mg GAE/g DW) and a water extract of Kenya coffee (461.63 mg GAE/g DW). Caffeine content was on average two times higher in all methanolic extracts than in water extracts. The radical scavenging activity of aqueous extracts was found to be higher than methanolic extracts. The highest antioxidant scavenging activity was determined for C (EC50 = 1.16 mg DW/ml) and E (EC50 = 1.3 mg DW/ml) water extracts. Compared to water extracts methanolic extracts showed significantly higher reducing power, ability to chelate Fe2+, inhibition of linoleic acid peroxidation and inhibition of lipoxygenase. CONCLUSIONS: This study demonstrated that the methanolic extracts obtained from different types of coffee exhibit potential anti-inflammatory and antioxidant properties. The highest antioxidant activity was shown by traditionally roasted coffees from Colombia and Ethiopia. PMID- 28071028 TI - Influence of impurities in raw material on sensory and physicochemical properties of cold-pressed rapeseedoil produced from conventionally and ecologically grown seeds. AB - BACKGROUND: The main problem of cold-pressed technology is its low yield and the varying quality of the end product, which is dependent on the quality of the raw material, technological process applied and also on conditions of packaging and storage. The effects of different contents of impurities in rapeseed on the sensory, physicochemical properties and oxidative stability of rapeseed oil produced by cold-pressing were investigated. METHODS: Cold-pressed oil produced from conventionally grown rapeseeds (individual cultivars and industrial seeds) and certified ecological rapeseeds. Quantified quality parameters included the following: the content of impurities, acid value, peroxide value, spectrophotometric indices (K232, K268), oxidative stability determined by the Rancimat test, pheophytin a content, and sensory assessment. RESULTS: The seeds which were homogenous in terms of cultivar contained the lowest level of impurities (up to 1.3%) and differed significantly in this regard from ecological and industrial seeds. It was found that the presence of impurities exerts an adverse effect on the sensory and physicochemical characteristics of the oil. Impurity content exceeding 5% resulted in the appearance of off -flavours, such as woody, strawy and fusty/musty. Furthermore, a positive correlation was found between impurity content and acid value (r = 0.781), peroxide value (r = 0.656), anisidine value (r = 0.645), K232 (r = 0.625), while in the case of oxidative stability, no such correlation was observed. CONCLUSIONS: The type and percentage of seed impurities in the rape crop determines the sensory and physicochemical properties of the cold-pressed oil. It seems advisable, therefore, to minimize the amount of impurities, in order to obtain high-quality cold-pressed rapeseed oil. PMID- 28071029 TI - Assessment of colour changes during storage of elderberry juice concentrate solutions using the optimization method. AB - BACKGROUND: Elderberries are a source of dietary supplements and bioactive compounds, such as anthocyanins. These dyes are used in food technology. The aim of the study was to assess the changes in colour parameters, anthocyanin contents and sensory attributes in solutions of elderberry juice concentrates during storage in a model system and to determine predictability of sensory attributes of colour in solutions based on regression equations using the response surface methodology. METHODS: The experiment was carried out according to the 3-level factorial design for three factors. Independent variables included pH, storage time and temperature. Dependent variables were assumed to be the components and colour parameters in the CIE L*a*b* system, pigment contents and sensory attributes. RESULTS: Changes in colour components X, Y, Z and colour parameters L*, a*, b*, C* and h* were most dependent on pH values. Colour lightness L* and tone h* increased with an increase in experimental factors, while the share of the red colour a* and colour saturation C* decreased. The greatest effect on the anthocyanin concentration was recorded for storage time. Sensory attributes deteriorated during storage. The highest correlation coefficients were found between the value of colour tone h* and anthocyanin contents in relation to the assessment of the naturalness and desirability of colour. A high goodness-of-fit of the model to data and high values of R2 for regression equations were obtained for all responses. CONCLUSIONS: The response surface method facilitates optimization of experimental factor values in order to obtain a specific attribute of the product, but not in all cases of the experiment. Within the tested range of factors, it is possible to predict changes in anthocyanin content and the sensory attributes of elderberry juice concentrate solutions as food dye, on the basis of the lack of a fit test. The highest stability of dyes and colour of elderberry solutions was found in the samples at pH 3.0, which confirms the advisability of using an anthocyanin preparation to shape the colour of high acidity food products, such as fruit fillings, beverages,desserts. PMID- 28071030 TI - The effect of replacing pork fat of inulin on the physicochemical and sensory quality of guinea fowl pate. AB - BACKGROUND: Potentially, pates could be a functional food and are an important source of proteins, vitamin A, B complex vitamins and iron. Unfortunately, one problem in pates is the high level of animal fat, about 30%. Pate with low-fat guinea fowl meat and animal fat replaced with inulin can result in this product being classified as a pro-health food. The objective of the present study was to determine the effect on pate with guinea fowl meat of reducing its pork back fat content (about 1/3, 2/3 and 100%) and the adding inulin as a partial fat substitute. The effects on the pate's chemical and physicochemical composition, as well as on its textural characteristics and sensory properties were analysed. METHODS: On the day after production, the following took place: chemical analysis: cooking loss, moisture, protein, total fat, total calories, the pH, lipid oxidation were analysed; physical analysis: colour parameters, texture profile analysis and sensory evaluation were analysed. RESULTS: The pate prepared with inulin gels as fat replacers had a fat content reduced (up to 82%), and decreased (up to 58%) energy value. The fat reduction and addition of inulin gels decreased hardness and chewiness, but the pate's appearance, taste and odour, as well as overall quality were similar to the control (full-fat samples). CONCLUSIONS: The study demonstrated that inulin can be used in guinea fowl pates as a total fat replacer and a potential source of prebiotic. PMID- 28071031 TI - Study of variation of tocochromanol and phytosterol contents in black and yellow seeds of Brassica napus L. doubled haploid populations. AB - BACKGROUND: In the study, an analysis of tocopherols, plastochomanol-8 and phytosterols was conducted using DH lines obtained from F1 hybrids of reciprocal crosses between yellow- and black-seeded lines. METHODS: The biological material for the study consisted of two DH populations of winter oilseed rape obtained from F1 hybrids of reciprocal crosses between two DH lines: yellow- and black seeded. Seed color was determined using a ColorFlex spectrophotometer. Fat content was determined via pulsed NMR. The levels of tocopherols, and plastochromanol-8 are analyzed using HPLC. Phytosterol contents and composition were determined by the GC method. RESULTS: The fat content of the black-seeded parental line was 49% and this was higher than that of the yellow-seeded parental line (44%). The fat content of DH line populations ranged from 44 to 51%. Total tocopherol content ranged from 460 to 602 mg/kg and the alpha-T/gamma-T ratio was from 0.66 to 1.09. In parental lines H2-26 and Z-114 the total tocopherol content was 534 and 525 mg/kg, but the alpha-T/gamma-T ratios were 0.81 and 1.21, respectively. The yellow-seeded parental line (Z-114) was characterized by a higher PC-8 content (81 mg/kg) than the H2-26 black-seeded parental line (58 mg/kg). The largest part of the total phytosterol content in seeds of both populations was beta-sitosterol from 976 to 2148 mg/kg, followed by campasterol, from 636 to 1364 mg/kg, and brassicasterol from 375 to 678 mg/kg. The total tocopherol content ranged from 462 to 595 mg/kg (population HxZ) and from 460 to 602 mg/kg (population ZxH). Significantly positive correlations were observed between the seed color with alpha-T (r = 0.38, p < 0.01), gamma-T (r = -0,34, p < 0.01) and PC-8 content (r = 0.29, p < 0.01). Correlations between the seed color with total tocopherol and total phytosterol content were not noted. CONCLUSIONS: Considering the range of genetic variation among doubled haploids of two populations, selected DH lines may be good parents for further breeding programs focused on increasing the amount and improving the quality of oilseed rapeseed oil. However, further studies will also be made to determine the influence of the environment on bioactive compounds in rapeseed oil. Cross direction of parental DH lines: yellow- and black-seeded has some influence, albeit not statistically significant, on the diversity of doubled haploid in their populations with regard to average fat, tocochromanol and phytosterol content. PMID- 28071032 TI - Legume seeds and cereal grains' capacity to accumulate iron while sprouting in order to obtain food fortificant. AB - BACKGROUND: Prepared sprouts, after culturing in a medium with an increased iron concentration, could become a beneficial food iron fortificant. However, the efficient iron accumulation depends on the plants genus, species and/or varieties. The aim of the study was to indicate the seeds or grains which accumulate iron most efficiently during the sprouting process. METHODS: Alfalfa, lentil, lupine and soybean seeds as well as wheat grains were sprouted in abiotic stress conditions induced by the excess of iron(II) in culture media. The tolerance of these plants to iron concentration and its accumulation in the material obtained (with FAAS method) were analyzed. RESULTS: The smallest tolerance was noted for lentil seeds and wheat grains. Other plants developed in 25 mM solution of FeSO4. The highest accumulation of iron was observed in alfalfa sprouts. However, lupine and soybean seeds are the most recommended raw material for the production of the sprouts on an industrial scale. PMID- 28071033 TI - An analysis of the meal pattern at the nutrient level in Polish women. AB - BACKGROUND: Before the 1990's, access to a variety of foods in Eastern Europe was limited, which could have influenced the currently analyzed dietary behaviors pertaining to overweight and obesity development. The aim of this study was to describe the daily profile of meal patterns in Polish women aged 50-70 at the nutrient level. METHODS: The anthropometrical parameters of four-hundred and fifty Polish women aged 50-70 were assessed. Three 24-hour dietary recalls and validated questionnaires regarding socio-demographic-economic status and meal frequency were applied. Timing in food intake was considered as follow: 6:00-8:59 CET - breakfast, 9:00-11:59 CET - morning snacks, 12:00-14:59 CET - lunch, 15:00 17:59 CET - afternoon snacks, 18:00-21:00 CET - dinner. Statistical analyses were conducted using Tukey's multiple comparison tests and discriminant analysis. RESULTS: No statistically significant differences were found in socio-demographic economic and anthropometrical characteristics between women categorized to differentiated meal frequency intakes. However, the subjects from the 5-meal-per day group were characterized by higher anthropometrical parameters, the statistically lowest percentage of regularity in meal consumption and skipping meals related to shortest breaks between meals. At the nutrient level, potassium, niacin, vitamin E and vitamin D were selected in the discriminant analysis as the nutrients most strongly related to different dietary behaviors. CONCLUSIONS: Our findings did not provide sufficient evidence that diverse nutrient intake could lead to the development of a specific nutritional profile in Polish women. PMID- 28071034 TI - Solid-Phase Extraction (SPE): Principles and Applications in Food Samples. AB - Solid-Phase Extraction (SPE) is a sample preparation method that is practised on numerous application fields due to its many advantages compared to other traditional methods. SPE was invented as an alternative to liquid/liquid extraction and eliminated multiple disadvantages, such as usage of large amount of solvent, extended operation time/procedure steps, potential sources of error, and high cost. Moreover, SPE can be plied to the samples combined with other analytical methods and sample preparation techniques optionally. SPE technique is a useful tool for many purposes through its versatility. Isolation, concentration, purification and clean-up are the main approaches in the practices of this method. Food structures represent a complicated matrix and can be formed into different physical stages, such as solid, viscous or liquid. Therefore, sample preparation step particularly has an important role for the determination of specific compounds in foods. SPE offers many opportunities not only for analysis of a large diversity of food samples but also for optimization and advances. This review aims to provide a comprehensive overview on basic principles of SPE and its applications for many analytes in food matrix. PMID- 28071035 TI - Elicitation and treatment with precursors of phenolics synthesis improve low molecular antioxidants and antioxidant capacity of buckwheat sprouts. AB - BACKGROUND: Recently, an increase of interest in the modification of food products on each step of production (breeding, production technology, storage condition) is observed. Nutritional properties as well as level and activity of bioactive compounds in plant-origin food may be modified using a range of technological and biotechnological practices and elicitation should be mentioned between them. METHODS: Elicitation with willow bark infusion supported by feeding with the phenylpropanoid pathway precursors were used for improving the quality of buckwheat sprouts. Special emphasis has been placed on the metabolomic and biochemical changes and the mechanism of overproduction of low-molecular antioxidants. RESULTS: The accumulation of phenolics is caused by stimulation of two main enzymes the phenylpropanoid pathway (tyrosine ammonia-lyase and phenylalanine ammonia-lyase). Tyrosine ammonia-lyase activities were effectively induced by feeding with tyrosine (about four times that of the control), whereas phenylalanine ammonia-lyase activity was the highest in the elicited control sprouts and those fed with shikimic acid (an increase by 60% compared to the control). Shikimic acid feeding (both elicited and non-elicited sprouts) effectively improved the total phenolics (by about 10% and 20%, respectively), condensed tannins (by about 30% and 28%, respectively), and flavonoids (by about 46% and 70%, respectively). Significant increase of vitexin, rutin, chlorogenic acid and isoorientin contents was also observed. The treatments increased the ascorbic acid content, too. Total antioxidant capacity of sprouts was most effectively increased by feeding with shikimic acid and further elicitation. CONCLUSIONS: The studies transfer biotechnology commonly used for the induction of overproduction of secondary metabolites in plant cell line systems to low processed food production. The obtained results could be used for better understanding of the effect of elicitation and precursor feeding on antioxidants production and contribute to improving the buckwheat sprouts quality. PMID- 28071036 TI - The effect of addition of selected milk protein preparations on the growth of Lactobacillus acidophilus and physicochemical properties of fermented milk. AB - BACKGROUND: The intake of fermented milk products, especially yoghurts, has been systematically increasing for a few decades. The purpose of this work was to obtain milk products fermented with a mix of bacterial cultures (yoghurt bacteria and Lactobacillus acidophillus LA-5) and enriched with selected milk protein preparations. Secondly, the aim of the work was to determine physiochemical and rheological properties of the obtained products. METHODS: The following additives were applied in the experiment: whey protein concentrate (WPC 65), whey protein isolate (WPI), demineralised whey powder (SPD), caseinoglycomacropeptide (CGMP), alpha-lactalbumin (alpha-la), sodium caseinate (KNa) and calcium caseinate (KCa). Milk was fermented using probiotic strain Lactobacillus acidophillus LA-5 and a typical yoghurt culture. The products were analysed in terms of the survivability of bacterial cells during refrigerated storage, rheological properties and syneresis. Fermented milk products were obtained using blends of bacterial strains: ST-B01:Lb-12 (1:1), ST-B01:Lb-12:LA-5 (1:1:2). RESULTS: Milk beverages fermented with typical yoghurt bacteria and LA-5 strain showed intensive syneresis. The addition of LA-5 strain caused formation of harder acid gels, comparing to typical yoghurts. Milk products which were prepared from skimmed milk possessed higher values of hardness and consistency coefficient. The increase of concentrations of milk preparations (except of WPI) did not cause significant differences in the hardness of acidic gels obtained by fermentation of mixed culture with a probiotic strain. CONCLUSIONS: The applied preparations improved physiochemical properties of the milk beverages which were prepared with a probiotic strain. The increase of protein milk preparations concentration resulted in a gradual decrease of the secreted whey. Among the products that were made of full milk powder and were subjected to three weeks of refrigerated storage the highest survivability of Lb. acidophilus LA-5 was noticed in the samples fortified with 1% WPC. PMID- 28071037 TI - The influence of the dose of calcium bisglycinate on physicochemical properties, sensory analysis and texture profile of kefirs during 21 days of cold storage. AB - BACKGROUND: In the process of enrichment of dairy products a priority element is the proper selection of compounds that are a mineral carrier. Calcium bisglycinate is better absorbed by the body than inorganic forms of calcium. Moreover, the lactic acid which is produced in kefir fermentation and the presence of lactose have also a positive effect on the improvement of absorption of calcium. The aim of the present study was to determine the influence of the applied dose of calcium in the form of calcium bisglycinate on the physicochemical and sensory properties and texture of kefirs during 21-day period of cold storage. METHODS: Processed cow milk was enriched with 0, 5, 10, 15, 20, 25 and 30 mg of calcium (for 100 g of milk), repasteurized (72 degrees C, 1 min), cooled down (26 degrees C), inoculated with Commercial VITAL kefir culture (Danisco, Poland) and fermented for 16 hours (26 degrees C). The assessment of the influence of addition of calcium bisglycinate on acidity, syneresis, texture and sensory characteristics (1-9 points) of kefirs was conducted at four fixed dates (after 1 day, 7 days, 14 days and 21 days of storage). RESULTS: During successive weeks of cold storage in all experimental groups there was observed a tendency to decrease general acidity. On the 1st and 7th days of cold storage reduced whey leakage was observed in kefirs enriched with 25 mg and 30 mg Ca/100 g of milk. With increasing doses of enrichment with calcium both the hardness, adhesiveness and gumminess of kefirs decreased. The applied doses of calcium did not cause changes in the sensory characteristics such as colour and consistency of the fermented beverages. CONCLUSIONS: Calcium bisglycinate may be used to enrich kefirs with calcium even with 30 mg of calcium in 100 g of milk without the modification of the product's parameters. PMID- 28071038 TI - Tapioca maltodextrin in the production of soft unripened cheese. AB - BACKGROUND: An excessive consumption of fat has been associated with an increased risk of health problems such as obesity, diabetes and cardiovascular diseases. Cheese is a highly concentrated product which is rich in protein and minerals such as calcium and phosphorus and essential amino acids, therefore it is an important food in the diet. But low fat cheeses are usually characterized as having poor body and flavour. Therefore, it is crucial to find ways of improving the acceptability of the product. The aim of this research was to investigate the possibility of using of tapioca maltodextrin in the production of soft cheese made from ultrafiltrated skimmed milk and to create organoleptic properties of a fat product in a non-fat product. METHODS: To estimate the possibility of using tapioca maltodextrin in the production of soft cheese, the influence of tapioca maltodextrin on rennet flocculation time (RFT) and rennet clotting time (RCT), pH values, moisture content were estimated. Improving the quality of cheese, rheological and sensory characteristics in the course of soft unripened cheese manufacturing has to be focused on. RESULTS: Using tapioca maltodextrin led to decrease in RFT and RCT. The concentration increase of the maltodextrin in milk for cheese production led to increase in moisture-binding capacity and moisture content of the cheeses, but led to decrease in RFT, RCT and pH-value. Based on the experiments data the optimal doses of tapioca maltodextrin were recommended. CONCLUSIONS: An addition of tapioca maltodextrin resulted in a tendency of decreasing RFT and RCT, pH-value for cheese made with different concentrations of tapioca maltodextrin when compared to cheese made without maltodextrin addition. At the same time an increased amount of tapioca maltodextrin led to moisture content increase of cheese samples. Inclusion of tapioca maltodextrin in natural, low fat cheese may improve texture and acceptability as compared to low fat control cheeses without maltodextrin. The recommended level of tapioca maltodextrin is 1.1% of the mixture weight. PMID- 28071039 TI - Effects of solvents and extraction methods on the content and antiradical activity of polyphenols from fruits Actinidia arguta, Crataegus monogyna, Gaultheria procumbens and Schisandra chinensis. AB - BACKGROUND: In line with the current tendency towards the production of the so called safe foods, the use of environmentally-friendly methods for the extraction of polyphenols from fruits has been sought. Citric acid is a good solvent in the preparation of phenolic compounds for the food and pharmaceutical industries because it is a natural antioxidant and is non-toxic for the environment. Furthermore, new sources of polyphenols from fruit of orchard plants that are less known in Poland have been looked for. The aim of this study was to assess the content and antiradical activity of polyphenolic compounds in fruit extracts, depending on the extraction method employed. In addition, the yield of extraction processes was assessed. METHODS: The experimental materials were fruits of the following plants: Actinidia arguta, Crataegus monogyna, Gaultheria procumbens, Schisandra chinensis. For the extraction, aqueous solutions of citric acid (CAE) and methanol (ME) were used. The following were determined in fruit extracts: the content of total phenols (TP) and anthocyanins (A), and antiradical activity (DPPH and ABTS). RESULTS: In general, the C. monogyna fruit extracts were distinguished by the highest TP and A content. The TP and A content was significantly higher in fruit extracts obtained with the CAE method than in the ones produced with the ME method. The highest mean A/TP ratio was determined for S. chinensis fruit extracts. The antiradical activity (DPPH and ABTS) in fruit extracts did not depend on an extraction method, but on fruit species. Overall, a higher yield of extraction processes was achieved for the CAE method than for the ME method. CONCLUSIONS: The present study indicates that the selected extraction methods are able to obtain polyphenolic extracts from fruits with a high antiradical activity and high yield. The use of citric acid in order to extract polyphenols from fruits may be an alternative to the conventional extraction method, while being eco-friendly and more effective than the latter. PMID- 28071041 TI - Effect of oil flushing with nitrogen on the quality and oxidative stability of coldpressed rapeseed and sunflower oils. AB - BACKGROUND: Oxidative stability means resistance to oxidation during purchase, processing and storage and is a key quality indicator of edible fats. Oils ought to be stored in dark-glass bottles, at low temperatures and with no access of light in order to effectively preserve their oxidative stability. Since all vegetable oils contain unsaturated fatty acids that can react with oxygen and deteriorate over time, displacement of oxygen with inert gases may result in a reduction of the rate of oxidation. In the study the effect of oil flushing with nitrogen on the quality and oxidative stability of cold-pressed rapeseed and sunflower oils was determinate. METHODS: Commercial samples of cold-pressed rapeseed and sunflower oils were stabilized by generating anaerobic atmosphere in the bottles by blowing through with nitrogen and generation of a "nitrogen cushion". Oils were tested in accelerated at 63 degrees C and long-term at 20 degrees C storage tests. RESULTS: After 20 days of Schaal oven test, the peroxide value in the flushing with nitrogen rapeseed and sunflower oils was, respectively, 4 and 7 times lower than in the control samples (without nitrogen). In turn, of the long-term storage test (with access of light 20 degrees C), the peroxide value of oil flushing with nitrogen after 6 months of storage was 2.3 to 2.8-fold lower, respectively, than in the control sample. In the oil samples flushed with nitrogen peroxide formation was inhibited, however, as a result of the breakdown of the peroxides already existed in the oil, gradual decrease of the oxidative stability (determined via Rancimat test) was observed along with prolonged storage of oils. CONCLUSIONS: Oil flushing with nitrogen was a very effective way to reduce the changes caused by oxidation in cold-pressed rapeseed and sunflower oil. PMID- 28071040 TI - Optimization of extraction parameters on the antioxidant properties of banana waste. AB - BACKGROUND: Banana is grown worldwide and consumed as ripe fruit or used for culinary purposes. Peels form about 18-33% of the whole fruit and are discarded as a waste product. With a view to exploiting banana peel as a source of valuable compounds, this study was undertaken to evaluate the effect of different extraction parameters on the antioxidant activities of the industrial by-product of banana waste (peel). METHODS: Influence of different extraction parameters such as types of solvent, percentages of solvent, and extraction times on total phenolic content (TPC) and antioxidant activity of mature and green peels of Pisang Abu (PA), Pisang Berangan (PB), and Pisang Mas (PM) were investigated. The best extraction parameters were initially selected based on different percentages of ethanol (0-100% v/v), extraction time (1-5 hr), and extraction temperature (25 60 degrees C) for extraction of antioxidants in the banana peels. Total phenolic content (TPC) was evaluated using Folin-Ciocalteu reagent assay while antioxidant activities (AA) of banana peel were accessed by DPPH, ABTS, and beta-carotene bleaching (BCB) assays at optimum extraction conditions. RESULTS: Based on different extraction solvents and percentages of solvents used, 70% and 90% of acetone had yielded the highest TPC for the mature and green PA peels, respectively; 90% of ethanol and methanol has yielded the highest TPC for the mature and green PB peels, respectively; while 90% ethanol for the mature and green PM peels. Similar extraction conditions were found for the antioxidant activities for the banana peel assessed using DPPH assay except for green PB peel, which 70% methanol had contributed to the highest AA. Highest TPC and AA were obtained by applying 4, 1, and 2 hrs extraction for the peels of PA, PB and PM, respectively. The best extraction conditions were also used for determination of AAs using ABTS and beta-carotene bleaching assays. Therefore, the best extraction conditions used have given the highest TPC and AAs. CONCLUSIONS: By products of banana (peel) can be considered as a potential source of antioxidants in food and pharmaceutical industry. PMID- 28071042 TI - Oat raw materials and bakery products - amino acid composition and celiac immunoreactivity. AB - BACKGROUND: The aim of this study was to compare the biochemical and immunochemical properties of avenins in some special oat raw materials and additionally the possibility of using them as a raw material for the gluten-free bakery products. METHODS: The compared oat raw materials were - oat flakes, commercial oat flours (including gluten-free oat flour) and residual oat flour, which is by-product of beta-glucan preparation. Biochemical characteristic included amino acid compositions and SDS-PAGE profiles of extracted avenins. The immunochemical reactivity with polyclonal anti-gluten and monoclonal anti-gliadin antibodies was evaluated qualitatively and quantitatively by immunoblotting and ELISA methods. Additionally, experimental bakery products made of examined raw materials were assessed according to their suitability for the celiac patients' diet. RESULTS: The highest protein content was measured in the beta-glucan preparation "Betaven" and gluten-free oat flour. Proteins of all materials are rich in glutamic and aspartic acid, leucine and arginine. Proportions of amino acids in avenins extracted from most of oat raw materials are similar, excluding gluten-free oat flour, which has a very low avenin content and proportions of individual amino acids are different. The SDS-PAGE protein pattern consisted of proteins with molecular weight of about 25-35 kDa. Polyclonal anti-gluten anti body recognized all protein fractions of molecular weight higher than 20 kDa. Quantitative ELISA analysis shows that the majority of samples has a gliadin-like protein content within the range of 80-260 mg/kg, excluding gluten-free flours and corresponding bakery products. Altogether, beta-glucan preparation has extremely high level of gliadin-like proteins. CONCLUSIONS: In the examined oat raw materials and foods the contents of immunoreactive amino acid sequences exceeded the limit of 20 mg/kg (considered as gluten-free) except for gluten-free flours (oat and the prepared mixture) and the bakery products based on gluten free flours. Unfortunately, the rest of oat raw materials and products cannot be considered gluten-free. PMID- 28071043 TI - Decreased adipose tissue zinc content is associated with metabolic parameters in high fat fed Wistar rats. AB - BACKGROUND: Limited data on adipose tissue zinc content in obesity exist. At the same time, the association between adipose tissue zinc content and metabolic parameters in dietary-induced obesity is poorly studied. Therefore, the primary objective of this study is to assess adipose tissue zinc content and its association with morphometric parameters, adipokine spectrum, proinflammatory cytokines, and apolipoprotein profile in high fat fed Wistar rats. METHODS: A total of 48 adult female Wistar rats were used in the present study. Rats were fed either control (10% of fat) or high fat diet (31.6% of fat). Adipose tissue zinc content was assessed using inductively coupled plasma mass spectrometry. Rats' serum was examined for adiponectin, leptin, insulin, interleukin-6, and tumor necrosis factor-alpha using enzyme-linked immunosorbent assay kits. Serum glucose and apolipoprotein spectrum were also evaluated. RESULTS: High fat feeding resulted in a significant 34% decrease in adipose tissue zinc content in comparison to the control values. Fat pad zinc levels were significantly inversely associated with morphometric parameters, circulating leptin, insulin, tumor necrosis factor-alpha levels and HOMA-IR values. At the same time, a significant correlation with apolipoprotein A1 concentration was observed. CONCLUSIONS: Generally, the obtained data indicate that (1) high fat feeding results in decreased adipose tissue zinc content; (2) adipose tissue zinc content is tightly associated with excessive adiposity, inflammation, insulin resistance and potentially atherogenic changes. PMID- 28071044 TI - Twelve weeks CLA supplementation decreases the hip circumference in overweight and obese women. A double-blind, randomized, placebo-controlled trial. AB - BACKGROUND: Conjugated linoleic acid (CLA) reduces body weight (BW), body fat mass (BFM), and increases or maintains lean body mass in animals. However, the results concerning the effect of CLA on weight reduction in humans are contradictory. The present study aimed to evaluate the effect of CLA supplementation on the BW and anthropometric parameters (waist and hip circumferences) in overweight and obese adult women. METHODS: A total of 74 subjects (BMI: 28-42 kg/m2) were included in a double blind, placebocontrolled trial. Subjects were randomized into two groups, those supplemented with either 3.0 g/d CLA or with placebo (sunflower oil) for 12 weeks. RESULTS: CLA significantly decreased the hip circumferences compared to placebo (p = 0.016209), but had no effect on body weight, BMI, or waist circumference. The number of subjects with a reduction in hip circumference in the CLA group was significantly larger compared to that in the placebo group (p = 0.0017; NNT= 2.65; CI [6.27-1.685]). CONCLUSIONS: In conclusion, our findings do not support the hypothesis that 12 weeks CLA supplementation, as dosed in the present study, is effective for body weight reduction in overweight and obese women. However, its local action in decreasing the hip circumference seems to be encouraging and suggests that CLA may represent an attractive dietary supplement. PMID- 28071045 TI - Graphene Quantum Dots Embedded in Bi2Te3 Nanosheets To Enhance Thermoelectric Performance. AB - Novel Bi2Te3/graphene quantum dots (Bi2Te3/GQDs) hybrid nanosheets with a unique structure that GQDs are homogeneously embedded in the Bi2Te3 nanosheet matrix have been synthesized by a simple solution-based synthesis strategy. A significantly reduced thermal conductivity and enhanced powder factor are observed in the Bi2Te3/GQDs hybrid nanosheets, which is ascribed to the optimized thermoelectric transport properties of the Bi2Te3/GQDs interface. Furthermore, by varying the size of the GQDs, the thermoelectric performance of Bi2Te3/GQDs hybrid nanostructures could be further enhanced, which could be attributed to the optimization of the density and dispersion manner of the GQDs in the Bi2Te3 matrix. A maximum ZT of 0.55 is obtained at 425 K for the Bi2Te3/GQDs-20 nm, which is higher than that of Bi2Te3 without hybrid nanostrucure. This work provides insights for the structural design and synthesis of Bi2Te3-based hybrid thermoelectric materials, which will be important for future development of broadly functional material systems. PMID- 28071046 TI - Quantifying Single-Carbon Nanotube-Electrode Contact via the Nanoimpact Method. AB - A new methodology is developed to enable the measurement of the resistance across individual carbon nanotube-electrode contacts. Carbon nanotubes (CNTs) are suspended in the solution phase and occasionally contact the electrified interface, some of which bridge a micron-sized gap between two microbands of an interdigitated gold electrode. A potential difference is applied between the contacts and the magnitude of the current increase after the arrival of the CNT gives a measure of the resistance associated with the single CNT-gold contact. These experiments reveal the presence of a high contact resistance (~50 MOmega), which significantly dominates the charge-transfer process. Further measurements on ensembles of CNTs made using a dilute layer of CNTs affixed to the interdigitated electrode surface and measured in the absence of solvent showed responses consistent with the same high value of contact resistance. PMID- 28071047 TI - Linking Load, Fuel, and Emission Controls to Photochemical Production of Secondary Organic Aerosol from a Diesel Engine. AB - Diesel engines are important sources of fine particle pollution in urban environments, but their contribution to the atmospheric formation of secondary organic aerosol (SOA) is not well constrained. We investigated direct emissions of primary organic aerosol (POA) and photochemical production of SOA from a diesel engine using an oxidation flow reactor (OFR). In less than a day of simulated atmospheric aging, SOA production exceeded POA emissions by an order of magnitude or more. Efficient combustion at higher engine loads coupled to the removal of SOA precursors and particle emissions by aftertreatment systems reduced POA emission factors by an order of magnitude and SOA production factors by factors of 2-10. The only exception was that the retrofitted aftertreatment did not reduce SOA production at idle loads where exhaust temperatures were low enough to limit removal of SOA precursors in the oxidation catalyst. Use of biodiesel resulted in nearly identical POA and SOA compared to diesel. The effective SOA yield of diesel exhaust was similar to that of unburned diesel fuel. While OFRs can help study the multiday evolution, at low particle concentrations OFRs may not allow for complete gas/particle partitioning and bias the potential of precursors to form SOA. PMID- 28071048 TI - Solvent-Free Strategy Yields Size and Shape-Uniform Capsules. AB - Capsules with a liquefied core were fabricated via the assembly of polymeric droplets induced by superamphiphobic surfaces. These highly repellent substrates exhibit distinct features such as (i) an easy and precise control over the particle size and shape, (ii) a high encapsulation efficiency, (iii) mild processing conditions, and (iv) the possibility to include any object in either a water or oil-based liquid core, which are not found on the current available strategies. As proof of concept, a photo-cross-linkable derivative of chitosan was used to produce the polymeric shell while a wealth variety of template cores were tested using a reversible cross-linking mechanism, interfacial gelation process or ice. Owing to the widespread application of polymeric capsules, the developed strategy is poised to usher the development of the next generation of materials not only for biomedical purposes but also for cosmetics, agriculture and electronics. PMID- 28071049 TI - Stereochemically Defined Various Multisubstituted Alkenes Bearing a Tetrafluoroethylene (-CF2CF2-) Fragment. AB - Highly regio- and stereoselective transformation of commercially available 4 bromo-3,3,4,4-tetrafluoro-1-butene into multisubstituted alkenes having a tetrafluoroethylene fragment through Heck reactions and/or Suzuki-Miyaura cross coupling reactions was established. Thus, the obtained alkenes underwent a smooth reductive coupling reaction with aldehydes under the influence of MeLi/LiBr-free, affording structurally unprecedented fluorinated materials. PMID- 28071050 TI - Hydroxytyrosol and the Colonic Metabolites Derived from Virgin Olive Oil Intake Induce Cell Cycle Arrest and Apoptosis in Colon Cancer Cells. AB - After the sustained consumption of virgin olive oil (VOO), the unabsorbed native phenols (mainly hydroxytyrosol (HT)) are transformed into its catabolites in the intestine by microbials. The role of these catabolites in preventing colon cancer has not been sufficiently investigated. This work aims to study the antiproliferative and apoptotic activities in colon (Caco-2; HT-29) cancer cell lines of the main catabolites detected in human feces (phenylacetic, phenylpropionic, hydroxyphenylpropionic, and dihydroxyphenylpropionic acids and catechol), after the sustained VOO intake. Additionally, an assessment of the ability of these colonic cells to metabolize the studied compounds was performed. The results showed that HT and phenylacetic and hydroxyphenylpropionic acids produce cell cycle arrest and promote apoptosis. HT-29 cells were more sensitive to phenol treatments than Caco-2. In synthesis, the results of the present study represent a good starting point for understanding the potential apoptotic and antiproliferative effects of VOO phenolic compounds and their colonic metabolites. PMID- 28071051 TI - Supramolecular Platform with Switchable Multivalent Affinity: Photo-Reversible Capture and Release of Bacteria. AB - Surfaces having dynamic control of interactions at the biological system-material interface are of great scientific and technological interest. In this work, a supramolecular platform with switchable multivalent affinity was developed to efficiently capture bacteria and on-demand release captured bacteria in response to irradiation with light of different wavelengths. The system consists of a photoresponsive self-assembled monolayer containing azobenzene (Azo) groups as guest and beta-cyclodextrin (beta-CD)-mannose (CD-M) conjugates as host with each CD-M containing seven mannose units to display localized multivalent carbohydrates. Taking the advantage of multivalent effect of CD-M, this system exhibited high capacity and specificity for the capture of mannose-specific type 1-fimbriated bacteria. Moreover, ultraviolet (UV) light irradiation caused isomerization of the Azo groups from trans-form to cis-form, resulting in the dissociation of the host-guest Azo/CD-M inclusion complexes and localized release of the captured bacteria. The capture and release process could be repeated for multiple cycles, suggesting good reproducibility. This platform provides the basis for development of reusable biosensors and diagnostic devices for the detection and measurement of bacteria and exhibits great potential for use as a standard protocol for the on-demand switching of surface functionalities. PMID- 28071052 TI - Switching Kinetics in Nanoscale Hafnium Oxide Based Ferroelectric Field-Effect Transistors. AB - The recent discovery of ferroelectricity in thin hafnium oxide films has led to a resurgence of interest in ferroelectric memory devices. Although both experimental and theoretical studies on this new ferroelectric system have been undertaken, much remains to be unveiled regarding its domain landscape and switching kinetics. Here we demonstrate that the switching of single domains can be directly observed in ultrascaled ferroelectric field effect transistors. Using models of ferroelectric domain nucleation we explain the time, field and temperature dependence of polarization reversal. A simple stochastic model is proposed as well, relating nucleation processes to the observed statistical switching behavior. Our results suggest novel opportunities for hafnium oxide based ferroelectrics in nonvolatile memory devices. PMID- 28071053 TI - Functional Characterization of the Unique Terminal Thioesterase Domain from Polymyxin Synthetase. AB - Polymyxins remain one of the few antibiotics available for treating antibiotic resistant bacteria. Here we describe polymyxin B thioesterase which performs the final step in polymyxin B biosynthesis. Isolated thioesterase catalyzed cyclization of an N-acetylcystamine polymyxin B analogue to form polymyxin B. The thioesterase contained a catalytic cysteine unlike most thioesterases which possess a serine. Supporting this, incubation of polymyxin B thioesterase with reducing agents abolished enzymatic activity, while mutation of the catalytic cysteine to serine significantly decreased activity. NMR spectroscopy demonstrated that uncyclized polymyxin B was disordered in solution, unlike other thioesterase substrates which adopt a transient structure similar to their product. Modeling showed the thioesterase substrate-binding cleft was highly negatively charged, suggesting a mechanism for the cyclization of the substrate. These studies provide new insights into the role of polymyxin thioesterase in polymyxin biosynthesis and highlight its potential use for the chemoenzymatic synthesis of polymyxin lipopeptides. PMID- 28071054 TI - High-Pressure Study of Perovskite-Like Organometal Halide: Band-Gap Narrowing and Structural Evolution of [NH3-(CH2)4-NH3]CuCl4. AB - Searching for nontoxic and stable perovskite-like alternatives to lead-based halide perovskites for photovoltaic application is one urgent issue in photoelectricity science. Such exploration inevitably requires an effective method to accurately control both the crystalline and electronic structures. This work applies high pressure to narrow the band gap of perovskite-like organometal halide, [NH3-(CH2)4-NH3]CuCl4 (DABCuCl4), through the crystalline-structure tuning. The band gap keeps decreasing below ~12 GPa, involving the shrinkage and distortion of CuCl42-. Inorganic distortion determines both band-gap narrowing and phase transition between 6.4 and 10.5 GPa, and organic chains function as the spring cushion, evidenced by the structural transition at ~0.8 GPa. The supporting function of organic chains protects DABCuCl4 from phase transition and amorphization, which also contributes to the sustaining band-gap narrowing. This work combines crystal structure and macroscopic property together and offers new strategies for the further design and synthesis of hybrid perovskite-like alternatives. PMID- 28071055 TI - Rapid and Efficient Conversion of All-E-astaxanthin to 9Z- and 13Z-Isomers and Assessment of Their Stability and Antioxidant Activities. AB - An optimized isomerization method was developed by heating all-E-astaxanthin in ethyl acetate (70 degrees C) with I-TiO2 catalyst, yielding 22.7% and 16.9% of 9Z- and 13Z-astaxanthin, respectively, in 2 h, with 92-95% purity after semipreparative HPLC purification. 13Z-Astaxanthin had higher antioxidant activity than all-E- and 9Z-astaxanthins in oxygen radical absorbing capacity assay for lipophilic compounds, photochemiluminescence, and cellular antioxidant activity (CAA) assays, and 9Z-astaxanthin was higher in DPPH radical-scavenging activity assay and lower in CAA assay. All isomers were relatively stable between pH 2.0 and 11.6, except 13Z- and 9Z-astaxanthins at pH 2.0, suggesting they may be converted after passing the gastric phase in vivo. Metal ions did not significantly (p < 0.05) affect the stability. Results of the current study provides a means for further study into the mechanisms related to in vivo transformation and bioavailability of Z-astaxanthins, and their application in the development of functional foods and nutraceutical products. PMID- 28071056 TI - Copper(I) Complexes Bearing 1,2-Phenyl-Bridged P?N, P?N?P, and N?P?N Chelate Ligands: Structures and Phosphorescence. AB - With the aim to obtain new phosphorescent Cu(I) compounds, several new 1,2-phenyl bridged P?N, P?N?P, and N?P?N chelate ligands were designed and synthesized. These ligands were found to form complexes with Cu(I) ion readily via either solution reactions or solid-state grinding process. The new Cu(I) compounds based on this class of ligands display phosphorescence with emission color ranging from blue to red. The structure of the ligand and the nature of the N-heterocycle in the chelate ligands were found to have a significant impact on the phosphorescent properties of the Cu(I) compounds. PMID- 28071057 TI - Programmed Transfer of Sequence Information into a Molecularly Imprinted Polymer for Hexakis(2,2'-bithien-5-yl) DNA Analogue Formation toward Single-Nucleotide Polymorphism Detection. AB - A new strategy of simple, inexpensive, rapid, and label-free single-nucleotide polymorphism (SNP) detection using robust chemosensors with piezomicrogravimetric, surface plasmon resonance, or capacitive impedimetry (CI) signal transduction is reported. Using these chemosensors, selective detection of a genetically relevant oligonucleotide under FIA conditions within 2 min is accomplished. An invulnerable-to-nonspecific interaction molecularly imprinted polymer (MIP) with electrochemically synthesized probes of hexameric 2,2'-bithien 5-yl DNA analogues discriminating single purine-nucleobase mismatch at room temperature was used. With density functional theory modeling, the synthetic procedures developed, and isothermal titration calorimetry quantification, adenine (A)- or thymine (T)-substituted 2,2'-bithien-5-yl functional monomers capable of Watson-Crick nucleobase pairing with the TATAAA oligodeoxyribonucleotide template or its peptide nucleic acid (PNA) analogue were designed. Characterized by spectroscopic techniques, molecular cavities exposed the ordered nucleobases on the 2,2'-bithien-5-yl polymeric backbone of the TTTATA hexamer probe designed to hybridize the complementary TATAAA template. In that way, an artificial TATAAA-promoter sequence was formed in the MIP. The purine nucleobases of this sequence are known to be recognized by RNA polymerase to initiate the transcription in eukaryotes. The hexamer strongly hybridized TATAAA with the complex stability constant KsTTTATA-TATAAA = ka/kd ~ 106 M-1, as high as that characteristic for longer-chain DNA-PNA hybrids. The CI chemosensor revealed a 5 nM limit of detection, quite appreciable as for the hexadeoxyribonucleotide. Molecular imprinting increased the chemosensor sensitivity to the TATAAA analyte by over 4 times compared to that of the nonimprinted polymer. The herein-devised detection platform enabled the generation of a library of hexamer probes for typing the majority of SNP probes as well as studying a molecular mechanism of the complex transcription machinery, physics of single polymer molecules, and stable genetic nanomaterials. PMID- 28071058 TI - H-Abstraction by OH from Large Branched Alkanes: Overall Rate Measurements and Site-Specific Tertiary Rate Calculations. AB - Reaction rate coefficients for the reaction of hydroxyl (OH) radicals with nine large branched alkanes (i.e., 2-methyl-3-ethyl-pentane, 2,3-dimethyl-pentane, 2,2,3-trimethylbutane, 2,2,3-trimethyl-pentane, 2,3,4-trimethyl-pentane, 3-ethyl pentane, 2,2,3,4-tetramethyl-pentane, 2,2-dimethyl-3-ethyl-pentane, and 2,4 dimethyl-3-ethyl-pentane) are measured at high temperatures (900-1300 K) using a shock tube and narrow-line-width OH absorption diagnostic in the UV region. In addition, room-temperature measurements of six out of these nine rate coefficients are performed in a photolysis cell using high repetition laser induced fluorescence of OH radicals. Our experimental results are combined with previous literature measurements to obtain three-parameter Arrhenius expressions valid over a wide temperature range (300-1300 K). The rate coefficients are analyzed using the next-nearest-neighbor (N-N-N) methodology to derive nine tertiary (T003, T012, T013, T022, T023, T111, T112, T113, and T122) site-specific rate coefficients for the abstraction of H atoms by OH radicals from branched alkanes. Derived Arrhenius expressions, valid over 950-1300 K, are given as (the subscripts denote the number of carbon atoms connected to the next-nearest neighbor carbon): T003 = 1.80 * 10-10 exp(-2971 K/T) cm3 molecule-1 s-1; T012 = 9.36 * 10-11 exp(-3024 K/T) cm3 molecule-1 s-1; T013 = 4.40 * 10-10 exp(-4162 K/T) cm3 molecule-1 s-1; T022 = 1.47 * 10-10 exp(-3587 K/T) cm3 molecule-1 s-1; T023 = 6.06 * 10-11 exp(-3010 K/T) cm3 molecule-1 s-1; T111 = 3.98 * 10-11 exp( 1617 K/T) cm3 molecule-1 s-1; T112 = 9.08 * 10-12 exp(-3661 K/T) cm3 molecule-1 s 1; T113 = 6.74 * 10-9 exp(-7547 K/T) cm3 molecule-1 s-1; T122 = 3.47 * 10-11 exp( 1802 K/T) cm3 molecule-1 s-1. PMID- 28071059 TI - Accuracy of ASGE criteria for the prediction of choledocholithiasis. AB - I read with interest the article "Accuracy of ASGE criteria for the prediction of choledocholithiasis" by Narvaez et al. Patients with suspicion of choledocholithiasis (CL) were categorized according to the American Society for Gastrointestinal Endoscopy (ASGE) recommendations. Those patients classified into high or intermediate-probability for CL underwent an endoscopic retrograde cholangiopancreatography (ERCP) without any further non-endoscopic biliary imaging modalities. In the ASGE recommendations for intermediate risk CL patients, they mention options for the evaluation of these patients including endoscopic ultrasound (EUS) and magnetic resonance cholangiography (MRC). PMID- 28071060 TI - Intramural gastric hematoma in the context of an acute pancreatitis. AB - Bleeding complications are well known in the context of acute pancreatitis however, intramural hematomas of the superior gastrointestinal tract are rare. The treatment of choice, in absence of active bleeding or other complications, must be conservative, resulting in spontaneous resolution of the hematoma in most of the cases. PMID- 28071061 TI - Validation of SPICE, a method to differentiate small bowel submucosal lesions from innocent bulges on capsule endoscopy. AB - BACKGROUND AND AIMS: Small bowel submucosal lesions (SBSL) and innocent bulges may have an identical appearance and be difficult to distinguish on small bowel capsule endoscopy (SBCE). Recently, Girelli et al. proposed a score, smooth, protruding lesion index on capsule endoscopy (SPICE), in order to differentiate between the two. We aimed to evaluate and validate SPICE as a differentiation method between innocent bulges and SBSLs. METHODS: We evaluated all SBCEs performed in our department between January 2005 and September 2015, and selected the ones with a smooth, round, protruding lesion in the small bowel. Lesions with suspicious characteristics were excluded. A video clip of the region of interest was created and SPICE was assigned blindly and independently by two endoscopists. We determined the discriminative ability of SPICE using the definitive diagnosis of each patient as the standard criteria. RESULTS: We included 30 SBCEs corresponding to 12 SBSLs (four gastrointestinal stromal tumors, two neuroendocrine tumors, four lipomas and two polypoid lymphangiectasias) and 18 innocent bulges. SPICE scores ranged from 0 to 4, allowing the distinction between SBSLs and innocent bulges (p < 0.001). SPICE > 2 had a 66.7% sensitivity, 100.0% specificity, 100.0% positive predictive value and 78.3% negative predictive value, and the area under the curve was 0.88 (95% CI, 0.73-1.00; p < 0.001) for the diagnosis of SBSL. CONCLUSIONS: Our data support SPICE, namely a score > 2, as a predictive method of SBSLs. Taking into account its simplicity, it may be very useful in the distinction between SBSLs and innocent bulges on SBCE. PMID- 28071062 TI - Accurate cut-offs for predicting endoscopic activity and mucosal healing in Crohn's disease with fecal calprotectin. AB - BACKGROUND: Fecal biomarkers, especially fecal calprotectin, are useful for predicting endoscopic activity in Crohn's disease; however, the cut-off point remains unclear. The aim of this paper was to analyze whether faecal calprotectin and M2 pyruvate kinase are good tools for generating highly accurate scores for the prediction of the state of endoscopic activity and mucosal healing. METHODS: The simple endoscopic score for Crohn's disease and the Crohn's disease activity index was calculated for 71 patients diagnosed with Crohn's. Fecal calprotectin and M2-PK were measured by the enzyme-linked immunosorbent assay test. RESULTS: A fecal calprotectin cut-off concentration of >= 170 ug/g (sensitivity 77.6%, specificity 95.5% and likelihood ratio +17.06) predicts a high probability of endoscopic activity, and a fecal calprotectin cut-off of <= 71 ug/g (sensitivity 95.9%, specificity 52.3% and likelihood ratio -0.08) predicts a high probability of mucosal healing. Three clinical groups were identified according to the data obtained: endoscopic activity (calprotectin >= 170), mucosal healing (calprotectin <= 71) and uncertainty (71 > calprotectin < 170), with significant differences in endoscopic values (F = 26.407, p < 0.01). Clinical activity or remission modified the probabilities of presenting endoscopic activity (100% vs 89%) or mucosal healing (75% vs 87%) in the diagnostic scores generated. M2-PK was insufficiently accurate to determine scores. CONCLUSIONS: The highly accurate scores for fecal calprotectin provide a useful tool for interpreting the probabilities of presenting endoscopic activity or mucosal healing, and are valuable in the specific clinical context. PMID- 28071063 TI - Acute psychotic episode secondary to Helicobacter pylori eradication treatment. AB - The side effects of Helicobacter pylori (H. pylori) eradication treatment are few, usually in the form of gastrointestinal or allergic complaints. However, occasionally, some antibiotics including clarithromycin, included in the classic eradication regimen, may result in reversible psychosis, a condition called "antibiomania" or "Hoigne syndrome". PMID- 28071064 TI - Chronic kidney disease may be differentially diagnosed from pre-eclampsia by serum biomarkers. PMID- 28071065 TI - Estimating baseline kidney function in hospitalized patients with impaired kidney function. PMID- 28071070 TI - Surgery for Cholesteatomatous Labyrinthine Fistula. AB - OBJECTIVE: There is uncertainty regarding the ideal surgical management of cholesteatomatous labyrinthine fistulae. The objective was to review the published evidence to determine whether a difference exists in hearing outcome for cholesteatoma matrix removal or matrix exteriorization. DATA SOURCES: Systematic MEDLINE and Web of Science searches identified publications describing hearing results after cholesteatoma matrix removal or matrix exteriorization. REVIEW METHODS: Three reviewers appraised the studies for quality, level of evidence, and extracted data. Fistula characteristics such as single-site, multisite, size, grade, and follow-up time were extracted for subanalyses, and when appropriate, data were pooled for statistical analysis. RESULTS: Twenty eight articles met inclusion criteria, and the level of evidence was judged no better than level 3b. There was no difference in hearing preservation detected between matrix removal and exteriorization (87% for matrix removal, 95% CI, 0.82 0.90; 95% for exteriorization, 95% CI, 0.85-0.98). An analysis of the individual cohort studies that compared these groups directly did not show a difference in calculated odds ratio (OR), 0.96 (95% CI, 0.66-1.40). CONCLUSION: The level of evidence on which to base surgical decision making related to cholesteatomatous labyrinthine fistula is poor, and the data do not demonstrate significant differences in hearing outcomes based on surgical technique. PMID- 28071075 TI - Anti-Mullerian hormone: correlation with testosterone and oligo- or amenorrhoea in female adolescence in a population-based cohort study. PMID- 28071076 TI - Reassessment of fracture risk in women after 3 years of treatment with zoledronic acid: when is it reasonable to discontinue treatment? PMID- 28071082 TI - Exploring necrotizing autoimmune myopathies with a novel immunoassay for anti-3 hydroxy-3-methyl-glutaryl-CoA reductase autoantibodies. PMID- 28071083 TI - Serum immunoglobulin G4 level is a poor predictor of immunoglobulin G4-related disease. PMID- 28071085 TI - The association between the use of proton pump inhibitors and the risk of hypomagnesemia: a systematic review and meta-analysis. PMID- 28071087 TI - Obesity: subclinical cardiac damage and heart failure. PMID- 28071092 TI - Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomized, placebo-controlled phase 2 study. PMID- 28071093 TI - Management of hypoparathyroidism: summary statement and guidelines. PMID- 28071094 TI - Relationship Between Subjectively Evaluated Health and Fear of Death Among Elderly in Three Cultural Contexts. AB - It is often argued that declining health in elderly people makes death more salient and threatening. However, we argue that health, optimism, and social support interact to predict fear of death in samples from Cameroon, the Czech Republic, and Germany. Low health was associated with enhanced fear of death for participants who received only little social support. As the measure of optimism did not comply with psychometric requirements in the Cameroonian sample, the three-way interaction was tested only in the Czech and German samples. It was found that the two-way interaction was further qualified by optimism in that low health was associated with enhanced fear of death for participants with little social support unless they reported pronounced optimism. Thus, internal and external resources, respectively, can serve to buffer the effect of declining health on the fear of death in the elderly. PMID- 28071097 TI - Insulin-like growth factor 1 bioactivity might reflect different aspects of quality of life than total insulin-like growth factor 1 in growth hormonedeficient patients during growth hormone treatment. PMID- 28071100 TI - Use of glycated (glycosylated) haemoglobin in the diagnosis of diabetes mellitus in the United Kingdom. The implementation of World Health Organization guidance 2011. PMID- 28071101 TI - High sensitivity cardiac troponin and the under-diagnosis of myocardial infarction in women: prospective cohort study. PMID- 28071107 TI - Thanks. PMID- 28071125 TI - Vacancy for the role of Editor-in-Chief for Journal of Hand Surgery (European Volume). PMID- 28071111 TI - New editor for Acta Radiologica. PMID- 28071127 TI - The Journal Manager's perspective. PMID- 28071133 TI - Effect of Transcutaneous Acupoint Electrical Stimulation on Post-Hemorrhoidectomy Associated Pain, Anxiety, and Heart Rate Variability: A Randomized-Controlled Study. AB - Hemorrhoidectomy is the current best treatment for severe hemorrhoids, but it causes significant postoperative pain and anxiety, which is associated with heart rate variability (HRV). Transcutaneous acupoint electrical stimulation (TAES) was assumed to alleviate pain and anxiety, and modify the autonomic nervous system. This study aimed to examine the effects of TAES intervention on postoperative pain, anxiety, and HRV in patients who received a hemorrhoidectomy. A randomized controlled trial with five repeated measures was conducted. The TAES group ( n = 39) received four 20-min sessions of electrical stimulation at chengshan (BL57) and erbai (EX-UE2) after hemorrhoidectomy, whereas the control group ( n = 41) did not. Data were collected using Visual Analogue Scale (VAS), State Anxiety Inventory (STAI), and HRV physiological signal monitor. TAES resulted in a significant group difference in pain scores, anxiety levels, and some HRV parameters. The findings indicate that TAES can help reduce pain and anxiety associated with hemorrhoidectomy. TAES is a noninvasive, simple, and convenient modality for post-hemorrhoidectomy-associated pain control and anxiety reduction. PMID- 28071136 TI - Erratum. PMID- 28071134 TI - Rapid prototyping using 3D printing in bioanalytical research. PMID- 28071137 TI - Seasonal variation in an acid mine drainage microbial community. AB - Environmental oxidation and microbial metabolism drive production of acid mine drainage (AMD). Understanding changes in the microbial community, due to geochemical and seasonal characteristics, is fundamental to AMD monitoring and remediation. Using direct sequencing of the 16S and 18S rRNA genes to identify bacterial, archaeal, and eukaryotic members of the microbial community at an AMD site in Northern Ontario, Canada, we found a dynamic community varying significantly across winter and summer sampling times. Community composition was correlated with physical and chemical properties, including water temperature, pH, conductivity, winter ice thickness, and metal concentrations. Within Bacteria, Acidithiobacillus was the dominant genus during winter (11%-57% of sequences) but Acidiphilium was dominant during summer (47%-87%). Within Eukarya, Chrysophyceae (1.5%-94%) and Microbotrymycetes (8%-92%) dominated the winter community, and LKM11 (4%-62%) and Chrysophyceae (25%-87%) the summer. There was less diversity and variability within the Archaea, with similar summer and winter communities mainly comprising Thermoplasmata (33%-64%) and Thermoprotei (5%-20%) classes but also including a large portion of unclassified reads (~40%). Overall, the active AMD community varied significantly between winter and summer, with changing community profiles closely correlated to specific differences in AMD geochemical and physical properties, including pH, water temperature, ice thickness, and sulfate and metal concentrations. PMID- 28071138 TI - Introductory paragraph. PMID- 28071140 TI - Development and characterization of polymer lipid hybrid nanoparticles for oral delivery of LMWH. AB - The present study aimed to develop an improved oral delivery system for low molecular-weight heparin (LMWH), novel polymer lipid hybrid nanoparticles were developed. LMWH loaded chitosan polymer lipid hybrid nanoparticles (LMWH-CS-PLNs) were developed using double emulsification and solvent evaporation method. The performance of developed formulations was evaluated by using in vitro and in vivo behavior, such as drug release studies, in vitro permeation study, in vivo venous thrombolytic study, in vitro uptake studies by using intestinal epithelium resembling Caco-2 cell lines. The new CS-PLNs might provide an effective strategy for oral delivery of LMWH with improved encapsulation efficiency as compared to CS-NPs and SA-LNPs. PMID- 28071142 TI - Erratum. AB - Lee J, Takeuchi H, Fervaha G, Sin GL, Foussias G, Agid O, Farooq S, Remington G. Subtyping schizophrenia by treatment response: antipsychotic development and the central role of positive symptoms. Can J Psychiatry. 2015;60(11):515-522. Original DOI: 10.1177/070674371506001107. In Table 2 of the above article, in "Proposed criteria for clozapine resistance" for "Current illness severity," the CGI-SCH positive was stated as "> 4" but it should be "CGI-SCH positive >= 4." The corrected table is below. [Table: see text]. PMID- 28071143 TI - Corrigendum. AB - Corrigendum to Warle'-Van Herwaarden MF, Roukens M, Pop GAM et al. (2014) Adherence to guidelines for the prescribing of double and triple combinations of antithrombotic agents. Eur J Prev Cardiol 21 (2) 231-243. DOI: 10.1177/2047487312451253 . PMID- 28071141 TI - Psychosocial Factors Mediating the Effect of the CHoBI7 Intervention on Handwashing With Soap: A Randomized Controlled Trial. AB - Inadequate hand hygiene is estimated to result in nearly 300,000 deaths annually, with the majority of deaths being among children younger than 5 years. In an effort to promote handwashing with soap and water treatment behaviors among highly susceptible household members of cholera patients, we recently developed the Cholera-Hospital-Based Intervention-for-7-Days (CHoBI7); chobi means picture in Bengali. This 1-week handwashing with soap and water treatment intervention is delivered by a promoter in the hospital and the home to cholera patients and their household members. In our randomized controlled trial of this intervention, we observed a significant reduction in symptomatic cholera infections during the 1-week intervention period compared to the control arm and sustained high uptake of observed handwashing with soap behaviors up to 12 months postintervention. The aim of the present study was to assess the underlying mechanism of change that led to the high handwashing with soap behavior observed among participants who received the CHoBI7 intervention. Handwashing with soap was measured using 5-hour structured observation, and psychosocial factors were assessed using a structured questionnaire among 170 intervention and 174 control household members enrolled in the CHoBI7 trial. To investigate potential mediators of the CHoBI7 intervention effect, mediation models were performed. Response efficacy was found to mediate the intervention's effect on habit formation for handwashing with soap at the 1-week follow-up, and disgust, convenience, and cholera awareness were mediators of habit maintenance at the 6- to 12-month follow-up. These results support the use of theory-driven approaches for the development and implementation of handwashing with soap interventions. PMID- 28071144 TI - Do Emotions Spark Interest in Alternative Tobacco Products? AB - BACKGROUND: Exposure to advertisements for tobacco products and tobacco warning labels evokes emotions. This study evaluated the association of discrete positive and negative emotions with interest in alternative tobacco products. METHOD: In 2013, 1,226 U.S. adult nonsmokers and current smokers viewed advertisements for moist snuff, snus, and electronic cigarettes (e-cigarettes) with various warning labels and then indicated their emotional responses in terms of anger, anxiety, sadness, guilt, disgust, discouragement, hope, and contentment. Outcomes were openness to using moist snuff, snus, and e-cigarettes in the future and interest in a free sample of each product. Data were analyzed in 2016. RESULTS: Hope was positively associated with openness and interest across all alternative tobacco products as was contentment for moist snuff and snus. Anger was negatively associated with openness to moist snuff and e-cigarettes, disgust negatively to moist snuff and snus, and anxiety negatively to e-cigarettes. Being a current smoker, ever trying a corresponding product, being male, and younger age were associated with greater openness to and interest in moist snuff and snus. For e cigarettes, being a current smoker, ever trying e-cigarettes, and being female were associated with greater openness, and being a current smoker was associated with greater odds of selecting a free sample. CONCLUSIONS: Positive emotions, particularly hope, were consistently positively associated with interest in alternative tobacco products. Hope is widely used by tobacco and e-cigarette companies to advertise their products. Antitobacco messages should aim to lower hope associated with tobacco products but increase hope for cessation or life without tobacco. PMID- 28071145 TI - Bacteriophages and their derivatives for the treatment and control of food producing animal infections. AB - Nowadays, the world is facing an increasing emergence of antibiotic resistant bacteria. Simultaneously, the banning of some existing antibiotics and the lack of development of new antimicrobials have created an urgent need to find new alternatives against animal infections. Bacteriophages (phages) are naturally occurring predators of bacteria, ubiquitous in the environment, with high host specificity and harmless to animals. For these reasons, phages and their derivatives are being considered valuable antimicrobial alternatives and an opportunity to reduce the current use of antibiotics in agri-food production, increasing animal productivity and providing environmental protection. Furthermore, the possibility of combining phage genetic material with foreign genes encoding peptides of interest has enabled their use as vaccine delivery tools. In this case, besides bacterial infections, they might be used to prevent viral infections. This review explores current data regarding advances on the use of phages and phage-encoded proteins, such as endolysins, exolysins and depolymerases, either for therapeutic or prophylactic applications, in animal husbandry. The use of recombinant phage-derived particles or genetically modified phages, including phage vaccines, will also be reviewed. PMID- 28071146 TI - Cardiac rehabilitation programme after transcatheter aortic valve implantation versus surgical aortic valve replacement: Systematic review and meta-analysis. AB - Background Aortic stenosis is a valvular heart disease characterised by fixed obstruction of the left ventricular outflow. It can be managed by surgical aortic valve replacement (sAVR) or transcatheter aortic valve implantation (TAVI). This review aimed to describe the evidence supporting a cardiac rehabilitation programme on functional capacity and quality of life in aortic stenosis patients after sAVR or TAVI. Methods The search was conducted on multiple databases from January to March 2016. All studies were eligible that evaluated the effects of a post-interventional cardiac rehabilitation programme in aortic stenosis patients. The methodological quality was assessed using the PEDro scale. Meta-analysis was performed separately by procedure and between procedures. The walked distance during the six-minute walk test (6MWD) and Barthel index were evaluated. The analysis was conducted in Review Manager. Results Five studies were included (292 TAVI and 570 sAVR patients). The meta-analysis showed that a cardiac rehabilitation programme was associated with a significant improvement in 6MWD (0.69 (0.47, 0.91); P < 0.001) and Barthel index (0.80 (0.29, 1.30); P = 0.002) after TAVI and 6MWD (0.79 (0.43, 1.15); P < 0.001) and Barthel index (0.93 (0.67, 1.18); P < 0.001) after sAVR. In addition, the meta-analysis showed that the cardiac rehabilitation programme promoted a similar gain in 6MWD (4.28% (-12.73, 21.29); P = 0.62) and Barthel index (-1.52 points (-4.81, 1.76); P = 0.36) after sAVR or TAVI. Conclusions The cardiac rehabilitation programme improved the functional capacity and quality of life in aortic stenosis patients. Patients who underwent TAVI benefitted with a cardiac rehabilitation programme similar to sAVR patients. PMID- 28071147 TI - Abstracts of Presentations at the Joint Meeting of the EEG & Clinical Neuroscience Society (ECNS), the International Society for Brain Electromagnetic Topography (ISBET), and the International Society for Neuroimaging in Psychiatry (ISNIP) in Halifax, Nova Scotia, Canada, September 3-7, 2014. PMID- 28071148 TI - Obituary. PMID- 28071149 TI - Abstracts from PACTRIMS, Bali, 26-28 August 2010. PMID- 28071150 TI - 36th Annual Meeting of the Society for Medical Decision Making. PMID- 28071152 TI - Fatal orbito-cerebral penetration by industrial grease viscous: Rare case report. AB - Assorted projectiles including shrapnel, sling shots, stones, metal and rock fragments and other missiles cause fatal penetrating skull injuries. In this case, a 34-year-old foreman suffered a fatal penetrating orbito-cerebral injury while lubricating a hydraulic rock-splitting machine with industrial grease viscous. PMID- 28071154 TI - Software, Database, and Information Services. PMID- 28071175 TI - Editorial: Editor-in-Chief. PMID- 28071165 TI - Erratum. AB - Hart, C. Product Focus: Microplates, Assay Reagents, Screening Consumables, and Kits. J. Biomol. Screen.2013, 18(9), 1138-1140. (Original DOI: 10.1177/1087057113500121). PMID- 28071176 TI - Using machine learning to predict laboratory test results. PMID- 28071177 TI - Liraglutide and cardiovascular outcomes in type 2 diabetes. PMID- 28071178 TI - Psychotropic drugs and ventricular repolarisation: The effects on QT interval, T peak to T-end interval and QT dispersion. AB - OBJECTIVE: We aimed to investigate in a clinical setting, the effects of different classes of psychotropic drugs on cardiac electrophysiological measures linked with an increased risk of sudden cardiac death. METHODS: We conducted a cross-sectional study in a population of 1059 psychiatric inpatients studying the effects of various psychotropic drugs on the T-peak to T-end (TpTe) interval, QT dispersion and QT interval. RESULTS: Methadone use showed a strong association with TpTe prolongation (odds ratio (OR)=12.66 (95% confidence interval (CI), 3.9 41.1), p<0.001), an effect independent from action on QT interval. Mood stabilisers showed significant effects on ventricular repolarisation: lithium was associated with a TpTe prolongation (OR=2.12 (95% CI, 1.12-4), p=0.02), while valproic acid with a TpTe reduction (OR=0.6 (95% CI, 0.37-0.98), p=0.04). Among antipsychotics, clozapine increased TpTe (OR=9.5 (95% CI, 2.24-40.39), p=0.002) and piperazine phenothiazines increased QT dispersion (OR=2.73 (95% CI, 1.06 7.02), p=0.037). CONCLUSIONS: Treatment with psychotropic drugs influences TpTe and QT dispersion. These parameters might be considered to better estimate the sudden cardiac death risk related to specific medications. Beyond antipsychotics and antidepressants, mood stabilisers determine significant effects on ventricular repolarisation. PMID- 28071181 TI - CD8+ T cells mediate the regenerative PTH effect in hPDL cells via Wnt10b signaling. AB - It was the aim of the present investigation to examine whether the stimulating effect of parathyroid hormone (PTH) on human periodontal ligament (hPDL) cell proliferation and differentiation would be enhanced by hPDL/T-cell interaction involving Wnt10b signaling as a mediating pathway. hPDL cells were cultured from healthy premolar tissues of three adolescent orthodontic patients and exposed to PTH(1-34) in monocultures or co-cultures with CD8+ T cells. At harvest, proliferation, alkaline phosphatase-specific activity (ALP), and osteocalcin production were determined by immunofluorescence cytochemistry, real-time PCR, biochemical assay, and ELISA. Wnt10b signaling was analyzed by the use of a specific WNT10b neutralizing antibody. PTH(1-34) stimulation of T cells significantly increased Wnt10b expression and production. Wnt10b exposure of hPDL cells enhanced proliferation and differentiation. PDL cells co-cultured with T cells showed a Wnt10b-dependent regulation of proliferation and differentiation parameters. The addition of a Wnt10b-neutralizing Ab to the co-culture medium resulted in a significant inhibition of the PTH(1-34) effect on proliferation, ALP-specific activity, and osteocalcin protein expression. Our findings provide novel insight into the mechanism of action of PTH on hPDL cells and establish the interplay of T cells and hPDL cells via the Wnt10b pathway as a modulating factor for the anabolic properties of the hormone in periodontal regeneration. PMID- 28071184 TI - Letter from the Editor. PMID- 28071183 TI - 5-Aminosalicylic acid inhibits inflammatory responses by suppressing JNK and p38 activity in murine macrophages. AB - CONTEXT: 5-Aminosalicylic acid (5-ASA), as an anti-inflammatory drug, has been extensively used for the treatment of mild to moderate active ulcerative colitis (UC), but the possible mechanisms of action remain unclear. OBJECTIVE: To investigate the effects of 5-ASA on the production of inflammatory mediators by murine macrophages stimulated with lipopolysaccharide (LPS), and determine the underlying pharmacological mechanism of action. MATERIALS AND METHODS: The levels of nitric oxide (NO) and interleukin-6 (IL-6) were measured by Varioskan Flash and IL-6 Enzyme-Linked Immunosorbent Assay sets. Real time quantitative polymerase chain reaction was used to determine the level of induced nitric oxide synthase (iNOS). The effects of 5-ASA on iNOS, the c-Jun N-terminal kinases (JNKs), p38 and nuclear factor (NF)-kappaB signaling pathways were examined using western blotting. RESULTS: 5-ASA suppressed the production of NO and IL-6, and also decreased the expression of iNOS in LPS-induced RAW264.7 cells. 5-ASA inhibited the phosphorylation of JNKs and p38, but did not block NF-kappaB activation at all doses tested. DISCUSSION AND CONCLUSION: The results indicated that the anti-inflammatory effect of 5-ASA was mainly regulated by the inhibition of the JNKs, p38 pathways rather than NF-kappaB pathway. Further research is required to clarify the detailed mechanism of the action. PMID- 28071185 TI - Outsourcing and Contract Services. PMID- 28071187 TI - The International Acta Radiologica Prize. PMID- 28071188 TI - "Classic papers" in this online issue of Acta Radiologica. PMID- 28071189 TI - Physical Facts of Roentgenological Importance. PMID- 28071190 TI - New editor of the musculoskeletal section of Acta Radiologica. PMID- 28071191 TI - A Radium Compensator for Ionization Measurements. PMID- 28071192 TI - Introductory paragraph. PMID- 28071193 TI - Screening of ESBL-producing Enterobacteriacae concomitant with low degree of transmission in intensive care and bone marrow transplant units. AB - BACKGROUND: Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL E) are spreading worldwide in both hospital and community settings. In this study, the molecular epidemiology and the transmission modalities of ESBL-E in intensive care- and bone marrow transplant were investigated. METHODS: All patients included in this study were screened for presence of ESBL-E on admission and weekly. Relevant beta-lactamase genes were identified by PCR and sequencing. RESULTS: A total of 669 patients were included in this study. On admission, ESBL producing Escherichia coli were detected in 49 (7.3%) patients and ESBL-producing Klebsiella pneumoniae in one patient. The most common ESBL types among E. coli isolates were CTX-M-15 (38.8%) and CTX-M-1 (38.8%). Furthermore, 12 of 49 (24.5%) ESBL-producing E. coli could be assigned to the epidemic clone ST131. A single patient acquired ESBL-producing E. coli during the hospital stay but cross transmission could not be demonstrated. Among 1095 environmental samples none revealed ESBL. CONCLUSIONS: Our results suggest that early detection of ESBL producing Enterobacteriaceae and consequent implementation of basic hygiene measures and contact isolation may reduce the transmission rate during the hospital stay. PMID- 28071196 TI - In Memoriam: Ayan Gulgonen. PMID- 28071198 TI - Fracture of the index metacarpal after TightRope suspension for carpometacarpal instability of the thumb. PMID- 28071199 TI - In gratitude. PMID- 28071203 TI - Automated Systems. PMID- 28071200 TI - Commentary on Unacceptable failure of the PI2(r) implant. J. van Aaken, N. Holzer, L. Wehrli, F. Delaquaize, I. A. Gonzalez and J. Y. Beaulieu. J Hand Surg Eur. 2016, 41: 917-22. PMID- 28071207 TI - From JRSM Short Reports. PMID- 28071205 TI - Long-Term Liver Diseases after Initiation of Antiretroviral Therapy in HIV Infected Patients with and without HBV or HCV Coinfection. AB - Coinfection of hepatitis B virus (HBV) or hepatitis C virus (HCV) with HIV is common and associated with increased mortality and increased risk of progression to chronic liver disease. We aimed to study long-term liver diseases after initiation of antiretroviral therapy (ART) in HIV-infected patients with and without HBV or HCV coinfection. A retrospective cohort of 92 patients (32 patients with HBV and/or HCV coinfection) was analyzed. Overall mean age was 38.3 years, and 54.3% were males. Immunological and virological responses were similar between the 2 groups ( P > .05). During a median follow-up period of 6.1 years, 12 (13.0%) patients had liver diseases. Kaplan-Meier analysis showed that the coinfection group had a significantly higher probability of developing liver diseases after ART (log-rank test, P < .001). Among the subgroup of 32 patients with coinfection, patients who were initiated ART at CD4 count <200 cells/mm3 had a higher rate of liver diseases compared to those who were initiated ART at CD4 count >=200 cells/mm3 (42.3% versus 16.7%; P = .004). PMID- 28071208 TI - Erratum. AB - Caris E Grimes and Robert HS Lane. Surgery and the global health agenda. J R Soc Med July 2013; 106: 256--258. DOI: 10.1177/0141076813476678 . PMID- 28071212 TI - Application Areas. PMID- 28071210 TI - Introducing the 2013 JALA Ten. PMID- 28071216 TI - Disinhibition of the rat prelimbic cortex promotes serotonergic activation of the dorsal raphe nucleus and panicolytic-like behavioral effects. AB - Several studies have shown that serotonin plays a dual role in the modulation of defensive behaviors related to anxiety and panic. A major source of serotonergic projections to limbic structures responsible for this modulation is the dorsal raphe nucleus (DR). Anatomical studies indicate that the prelimbic (PL) cortex sends dense glutamatergic projections to the DR, leading to stimulation or inhibition of serotonin release in structures innervated by the DR. The objective of the present study was to investigate if GABAergic disinhibition of the PL by means of local administration of picrotoxin (PIC), a chloride channel blocker, can affect serotonergic tone and the expression of defensive behaviors related to anxiety and panic. We used the elevated T-maze model and Vogel conflict test to evaluate defensive responses associated with anxiety or panic. The results showed that intra-PL PIC caused an increase in c-Fos activation in serotonergic cells in DR subregions. Furthermore, the intra-PL injection of PIC induced a panicolytic like effect without affecting behaviors associated with anxiety. Our findings suggest that the PL-DR pathway, through DR serotonergic stimulation, is involved in the control of panic-related behaviors by control of serotonin release in structures that modulate panic responses, such as the dorsal periaqueductal gray. PMID- 28071217 TI - Corrigendum. PMID- 28071220 TI - Life Sciences Discovery and Technology Highlights. PMID- 28071221 TI - Application Areas. PMID- 28071223 TI - 1st Asia-Pacific Meeting of the Society for Medical Decision Making. PMID- 28071224 TI - Medical Decision Making Reviewers, 2013. PMID- 28071233 TI - Poster Presentations. PMID- 28071226 TI - 31st Annual Meeting of the Society of Medical Decision Making Abstracts. PMID- 28071234 TI - TIA poems. PMID- 28071239 TI - Induction by arsenate of cell-type-specific cytotoxic effects in nerve and hepatoma cells. AB - The aim of the study was to compare the effect of sodium arsenate (AsV) on two different cell types: 158N murine oligodendrocytes and HepG2 human hepatoma cells. Exposure of 158N cells to AsV (0.1-400 uM; 48 h) induced a biphasic cytoxic effect defined as hormesis. Thus, low concentrations of AsV stimulate cell proliferation, as shown by phase-contrast microscopy, cell counting with trypan blue, and crystal violet assay, whereas high concentrations induce cell death associated with a loss of cell adhesion. These side effects were confirmed by staining with propidium iodide and cell cycle analysis, characterized by the presence of a subG1 peak, a criterion of apoptosis. The effects of AsV on mitochondrial function, as determined by the 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium (MTT) assay, the measurement of mitochondrial transmembrane potential with 3,3'-dihexyloxacarbocyanine iodide, and the rate of mitochondrial adenosine triphosphate confirm the impact of AsV on the mitochondria. In contrast to 158N cells, HepG2 cells were susceptible to all AsV concentrations as shown by microscopic observations, by counting with trypan blue. However, no alteration is noted in the cell membrane integrity, which indicated an apoptotic mode of cell death, and this side effect is confirmed by the cycle analysis, which revealed a subG1 peak. Of note, there was a loss of MTT, suggesting that AsV induces mitochondrial complex II dysfunction. Altogether, our data show that the cytotoxic characteristics of AsV depend on the cell type considered. PMID- 28071240 TI - Teucrium polium hexane extract downregulated androgen receptor in testis and decreased fertility index in rats. AB - Teucrium polium L. (Lamiaceae) is a commonly used medicinal plant in folk medicine. Among several uses, T. polium is used to treat male fertility problems. This research was conducted to study the effect of T. polium on spermatogenesis, testosterone level, androgen receptor expression, and fertility in male rats. Administration of hexane extract for 6 days to aging rats increased testosterone level. When administered for 60 days, T. polium hexane extract downregulated androgen receptors, decreased sperm count without producing histological changes in different stages of spermatogenesis. Also, fertility index decreased without making teratogenic effects when treated males were mated with untreated females on the 55th day of extract administration. Therefore, the downregulation of androgen receptor could be due to the continued elevation in testosterone level over time. In conclusion, this study suggests that the prolonged use of T. polium in folk medicine may negatively affect male fertility. PMID- 28071242 TI - Response to letter from Dr Hongliang Zhang entitled 'B-cell activating factor in the cerebrospinal fluid of neuromyelitis optica and multiple sclerosis'. PMID- 28071243 TI - Authors' reply to 'Report of extracranial venous stenosis in relapsing-remitting multiple sclerosis patients'. PMID- 28071246 TI - Family perspectives on organ and tissue donation for transplantation: a principlist analysis. AB - BACKGROUND: The family interview context is permeated by numerous ethical issues which may generate conflicts and impact on organ donation process. OBJECTIVE: This study aims to analyze the family interview process with a focus on principlist bioethics. METHOD: This exploratory, descriptive study uses a qualitative approach. The speeches were collected using the following prompt: "Talk about the family interview for the donation of organs and tissues for transplantation, from the preparation for the interview to the decision of the family to donate or not." For the treatment of qualitative data, we chose the method of content analysis and categorical thematic analysis. PARTICIPANTS: The study involved 18 nurses who worked in three municipal organ procurement organizations in Sao Paulo, Brazil, and who conducted family interviews for organ donation. Ethical considerations: The data were collected after approval of the study by the Research Ethics Committee of the School of Nursing of the University of Sao Paulo. RESULTS: The results were classified into four categories and three subcategories. The categories are the principles adopted by principlist bioethics. DISCUSSION: The principles of autonomy, beneficence, non-maleficence, and justice permeate the family interview and reveal their importance in the organs and tissues donation process for transplantation. CONCLUSION: The analysis of family interviews for the donation of organs and tissues for transplantation with a focus on principlist bioethics indicates that the process involves many ethical considerations. The elucidation of these aspects contributes to the discussion, training, and improvement of professionals, whether nurses or not, who work in organ procurement organizations and can improve the curriculum of existing training programs for transplant coordinators who pursue ethics in donation and transplantation as their foundation. PMID- 28071249 TI - Message from the editors. PMID- 28071250 TI - Prelims for ACTRIMS. PMID- 28071251 TI - Poster Presentations. PMID- 28071256 TI - Presentation to the best candidate in the European Board of Hand Surgery Diploma Examination 2013. PMID- 28071252 TI - Platform Presentations. PMID- 28071257 TI - Corrigendum. AB - The authors would like to bring attention to the error published in 'Corrective distal radius osteotomy following fracture malunion using a fixed-angle volar locking plate' 'S Opel, S Konan and E Sorene' Journal of Hand Surgery 39(4) pp. 431-435. DOI: 10.1177/1753193413497636. PMID- 28071259 TI - Reply to comment on: 'Multiple sclerosis: variation of incidence of onset over time in the Faroe Islands'. PMID- 28071260 TI - Message from the Editors. PMID- 28071261 TI - Response to Petch article on Benjamin Britten. PMID- 28071262 TI - Britten's death: Petch's response to Kildea. PMID- 28071267 TI - RIMS Poster Sessions. PMID- 28071266 TI - Biogen's portfolio and research efforts in multiple sclerosis: an interview with Dr Ralph Kern. AB - Ralph Kern speaks to Laura Dormer, Commissioning Editor: Dr Ralph Kern is Senior Vice President and Head of Worldwide Medical at Biogen in Cambridge, MA, USA. In this role, he oversees Biogen's global therapeutic, regional and country medical teams, global medical operations, as well as medical research and scientific communications functions. Prior to joining Biogen, he was head of the Neuroscience Medical Unit at Novartis Pharmaceuticals Corporation and held various medical and commercial leadership roles at Genzyme Corporation. Prior to joining industry, he was a consultant neurologist at Mount Sinai Hospital and the University Health Network in Toronto, Ontario and was head of the neurology postgraduate academic program at the University of Toronto. Ralph completed neurology postgraduate training at McGill University and completed a masters of health administration from the Institute for Health Policy, Management and Evaluation at the University of Toronto. He is a member of the College of Physicians and Surgeons of Ontario and the Royal College of Physicians and Surgeons of Canada. PMID- 28071269 TI - Progress in MS Research Conference, Melbourne, Australia, 2011: Conference Abstracts Oral Presentation Abstracts. PMID- 28071268 TI - RIMS Index. PMID- 28071271 TI - RIMS Oral Sessions. PMID- 28071270 TI - Progress in MS Research Conference, Melbourne, Australia, 2011 Conference Abstracts. PMID- 28071273 TI - RIMS Contents 2012. PMID- 28071272 TI - RIMS Keynotes. PMID- 28071274 TI - RIMS Oral sessions RCT 01. PMID- 28071288 TI - Vulnerable carotid plaque imaging and histopathology without a dedicated MRI receiver coil. AB - Stroke is associated with vulnerable carotid artery plaques showing specific histopathologic features, namely a lipid-rich necrotic core, intraplaque hemorrhage, ulceration, and thin fibrous cap. While ultrasound and computed tomography (CT) can identify carotid plaques and determine the extent of stenosis, magnetic resonance imaging (MRI) provides further information regarding plaque composition and morphology. In this feasibility study, three patients with symptomatic, moderately stenosed plaques were imaged with CT angiography (CTA) and MRI (3T and 1.5T) without a dedicated receiver coil. The patients subsequently underwent carotid endarterectomy with en-bloc excision of the plaque. The CT and MR images were analyzed independently by three neuroradiologists to identify vulnerable plaque features. The images were correlated with the histopathology to confirm the findings. All three patients had one or more vulnerable plaque features on histopathology. MRI allowed for better characterization of these features when compared to CTA. The pre- and post contrast T1-weighted (T1W) images were most helpful for identifying the lipid rich necrotic core and thin fibrous cap, while the time of flight-magnetic resonance angiography (TOF-MRA) and contrast-enhanced (CE)-MRA were excellent for detecting plaque hemorrhage and ulceration, respectively. The 3T images showed superior spatial and contrast resolution compared to the 1.5T images for all sequences. By providing direct correlation between imaging and histopathology, this study demonstrates that 3T MRI without a dedicated surface coil is an excellent tool for assessing plaque vulnerability. In smaller hospitals or those with limited resources, it is reasonable to consider conventional MRI for patient risk stratification. Further studies are needed to determine how MRI and plaque vulnerability can be incorporated into routine clinical practice. PMID- 28071289 TI - [Local barrier creams for skin care in newborns, infants and toddlers with incontinence-associated dermatitis (IAD) - Narrative Review] AB - Background: The incontinence-associated dermatitis (IAD) is a common condition in newborns, infants and toddlers. For the therapy nurses and parents have the choice between numerous barrier creams based on zinc oxide, Dexpanthenol or Vaseline in various combinations of active agents and with additional ingredients. Research question: Which combination of active ingredients in local barrier creams reduce pain, severity of or duration of healing in IAD in neonates, infants and young children? Method: MEDLINE and CINAHL was systematically search for randomized controlled trials on the effect of barrier creams in pediatric patients with IAD. These were evaluated on validity and applicability. Results: 15 RCTs were found, of which six were included in the systematic review. The methodological quality of these trials ranges from good to poor, partially high bias risk were recognizable. Barrier creams containing the active ingredients zinc oxide / lanolin, zinc oxide / cod liver oil, zinc oxide / Dexpanthenol, paraffin / beeswax / Dexpanthenol show effects. They reduce the IAD associated symptoms. Conclusions: The investigated barrier creams can be used in the pediatric nursing for the treatment of IAD. Because of limitations it cannot be ruled out that further studies will change the results. PMID- 28071295 TI - Corrigendum. AB - Rodeheffer, Christopher D., Hill, Sarah E., & Lord, Charles G. (2012). Does This Recession Make Me Look Black? The Effect of Resource Scarcity on the Categorization of Biracial Faces. Psychological Science, 23(12), 1476-1478. (Original DOI: 10.1177/0956797612450892 ). PMID- 28071296 TI - Corrigenda. PMID- 28071299 TI - From JRSM Short Reports. PMID- 28071306 TI - Nasty Data Can Still Be Real. PMID- 28071300 TI - "Going episodic": collaborative inhibition and facilitation when long-married couples remember together. AB - Two complementary approaches to the study of collaborative remembering have produced contrasting results. In the experimental "collaborative recall" approach within cognitive psychology, collaborative remembering typically results in "collaborative inhibition": laboratory groups recall fewer items than their estimated potential. In the cognitive ageing approach, collaborative remembering with a partner or spouse may provide cueing and support to benefit older adults' performance on everyday memory tasks. To combine the value of experimental and cognitive ageing approaches, we tested the effects of collaborative remembering in older, long-married couples who recalled a non-personal word list and a personal semantic list of shared trips. We scored amount recalled as well as the kinds of details remembered. We found evidence for collaborative inhibition across both tasks when scored strictly as number of list items recalled. However, we found collaborative facilitation of specific episodic details on the personal semantic list, details which were not strictly required for the completion of the task. In fact, there was a trade-off between recall of specific episodic details and number of trips recalled during collaboration. We discuss these results in terms of the functions of shared remembering and what constitutes memory success, particularly for intimate groups and for older adults. PMID- 28071307 TI - Erratum. AB - von Dawans, Bernadette, Fischbacher, Urs, Kirschbaum, Clemens, Fehr, Ernst, & Heinrichs, Markus. (2012). The Social Dimension of Stress Reactivity: Acute Stress Increases Prosocial Behavior in Humans. Psychological Science, 23(6), 651 660. (Original 10.1177/0956797611431576). PMID- 28071308 TI - Corrigendum. AB - Xu, Yangqing, Suzuki, Satoru, & Franconeri, Steven L. (2013). Shifting Selection May Control Apparent Motion. Psychological Science, 24(7), 1368-1370. (Original DOI: 10.1177/0956797612471685 ). PMID- 28071309 TI - 33rd Annual Meeting of the Society of Medical Decision Making. PMID- 28071315 TI - Sports Health Instructions for Authors. PMID- 28071330 TI - Subcutaneous peginterferon beta-1a injection-site reaction experience and mitigation: Delphi analysis of the ALLOW study. AB - AIM: The objective of this Delphi analysis was to obtain consensus on injection site reaction (ISR) experience and mitigation strategies for patients with relapsing-remitting multiple sclerosis switching from nonpegylated interferons (IFNs) to peginterferon beta-1a in the ALLOW Phase IIIb trial using a three-step approach. METHODS: Study investigators and coordinators from investigative sites enrolling four or more patients in ALLOW participated in three rounds of questionnaires and interviews. RESULTS: Respondents (n = 37) agreed that the most common ISR, erythema, was not disruptive to daily activities. Patient education, as a conversation with a clinician about ISR potential, was recommended. CONCLUSION: The consensus of Delphi respondents on ISR experience and ISR management after switching from nonpegylated IFNs to peginterferon beta-1a can help inform treatment decisions and manage patient expectations. PMID- 28071339 TI - Life Sciences R&D Technology Highlights. PMID- 28071331 TI - Clinical encounters of Australian general practice registrars with paediatric patients. AB - BACKGROUND: Whether general practitioner (GP) registrars have adequate exposure to, and feel confident in, managing children's health during training is unknown. OBJECTIVES: To determine the prevalence and associations of GP registrars' paediatric vs. non-paediatric consultations. METHODS: Cross-sectional analysis from a cohort study of Australian GP registrars' 2010-2014 consultations. RESULTS: 889 registrars contributed details for 26,427 (21.8% (95% CI: 21.4-22.2) paediatric consultations. Paediatric patients were more likely to be male and new to the practice. Although paediatric patients were less likely to have a chronic disease (OR 0.38, 95% CI 0.36, 0.40) and presented with fewer problems (OR 0.59, 95% CI 0.57, 0.61), registrars were more likely to seek in-consultation advice (OR 1.25, 95% CI 1.19, 1.31) and generate learning goals (OR 1.12, 95% CI 1.07, 1.18) for paediatric consultations. DISCUSSION: GP registrars appear to feel less confident in managing paediatric compared with adult consultations, suggesting an unmet training need. PMID- 28071340 TI - Respiration-Induced Intraorgan Deformation of the Liver. AB - Stereotactic body radiation therapy is a well-tolerated modality for the treatment of primary and metastatic liver lesions, and fiducials are often used as surrogates for tumor tracking during treatment. We evaluated respiratory induced liver deformation by measuring the rigidity of the fiducial configuration during the breathing cycle. Seventeen patients, with 18 distinct treatment courses, were treated with stereotactic body radiosurgery using multiple fiducials. Liver deformation was empirically quantified by measuring the intrafiducial distances at different phases of respiration. Data points were collected at the 0%, 50%, and 100% inspiration points, and the distance between each pair of fiducials was measured at the 3 phases. The rigid body error was calculated as the maximum difference in the intrafiducial distances. Liver disease was calculated with Child-Pugh score using laboratory values within 3 months of initiation of treatment. A peripheral fiducial was defined as within 1.5 cm of the liver edge, and all other fiducials were classified as central. For 5 patients with only peripheral fiducials, the fiducial configuration had more deformation (average maximum rigid body error 7.11 mm, range: 1.89-11.35 mm) when compared to patients with both central and peripheral and central fiducials only (average maximum rigid body error 3.36 mm, range: 0.5-9.09 mm, P = .037). The largest rigid body errors (11.3 and 10.6 mm) were in 2 patients with Child-Pugh class A liver disease and multiple peripheral fiducials. The liver experiences internal deformation, and the fiducial configuration should not be assumed to act as a static structure. We observed greater deformation at the periphery than at the center of the liver. In our small data set, we were not able to identify cirrhosis, which is associated with greater rigidity of the liver, as predictive for deformation. Treatment planning based only on fiducial localization must take potential intraorgan deformation into account. PMID- 28071341 TI - Identification of novel hits as highly prospective dual agonists for mu and kappa opioid receptors: an integrated in silico approach. AB - Opioid agonists are used clinically for the treatment of acute and chronic pain, however, their clinical use is limited due to the presence of undesired side effects. Dual agonists, simultaneously targeting mu and kappa opioid receptors, show fewer side effects than that of selective agonists. In the present work, 2D- and 3D- Quantitative Structure Activity Relationship studies were performed on a series of aminomorphinan derivatives as dual agonists, using a wide range of descriptors. The aim of the study was to identify the structural requirements for the activity of these compounds towards mu and kappa opioid receptors and using the models, with best external predictability, for predicting the activities of new hits obtained from shape based virtual screening of drug like compounds from ZINC database. Genetic algorithm-based GFA and G/PLS techniques were used to derive the 2D-QSAR models. Common feature-based pharmacophore was used for aligning the compounds for 3D-QSAR. All the models were validated both internally and externally using statistical metrics. The coverage estimation of the models was carried out with applicability domain calculation. Six enriched hits were identified as novel prospective dual agonist based on good Blood Brain Barrier permeability and their activities towards mu and kappa opioid receptors, predicted by the best QSAR models. The known potent dual agonist, cyclorphan, and two highly prospective dual agonists were docked to both the receptors and binding free energies were calculated using MMGBSA. Molecular dynamics studies were performed on the docked complexes with both the receptors to establish stability of the complexes. PMID- 28071342 TI - Pathology in Context. PMID- 28071352 TI - 2014 Psychological Science Badge Earners. PMID- 28071353 TI - Corrigendum: Cultural Relativity in Perceiving Emotion From Vocalizations. AB - Gendron, M., Roberson, D., van der Vyver, J. M., & Barrett, L. F. (2014). Cultural relativity in perceiving emotion from vocalizations. Psychological Science, 25, 911-920. (Original DOI: 10.1177/0956797613517239 ). PMID- 28071357 TI - Effects of the KIR7.1 Blocker VU590 on Spontaneous and Agonist-Induced Contractions of Human Pregnant Myometrium. AB - KIR7.1, an inwardly rectifying K+ channel, plays a critical role in regulating uterine excitability during pregnancy and has been suggested as a potential new target for the treatment of conditions arising from dysfunctional uterine contractility, for example, atonic postpartum hemorrhage. The aim of this study was to investigate the effects of the selective KIR7.1 blocker, VU590, on both spontaneous and agonist-stimulated contractions of human pregnant myometrium in vitro. At a concentration of 20 umol/L, VU590 significantly increased the mean contractile force and the frequency of spontaneous contractions ( P < 0.05) when compared to vehicle-treated tissues. However, there was a significant ( P < 0.0001) monoexponential decay in amplitude with time of exposure. When VU590 was coadministered with EC50 concentration of the uterotonics oxytocin, ergometrine, or carboprost, the only significant changes were an immediate decrease in the amplitude of oxytocin- and carboprost-induced contractions and a delayed reduction in amplitude and an increase in the frequency of ergometrine-induced contractions. Amplitude to all 3 agents in the presence of VU590 showed a monoexponential decay with time of exposure ( P < 0.0001). We conclude that VU590 modifies the contractility of pregnant human myometrium in support of a role for KIR7.1 in regulating that process. However, VU590 in vitro does not produce the types of contraction, either alone or in combination with other uterine stimulants that would suggest its usefulness as a first- or second-line clinical uterotonic agent. PMID- 28071376 TI - Union leaders rally protesters. AB - NHS staff will be left to deal with the mess caused by the government's health reforms, RCN general secretary Peter Carter told a protest rally in Westminster last week. PMID- 28071379 TI - Many private providers exemplify bill's pitfalls. AB - Much of the discussion about the Health and Social Care Bill has centred on concerns that private sector providers will take over responsibility for providing core healthcare services. Opponents of the bill argue that private firms, motivated by profit, will be able to make money from caring for the sick. PMID- 28071380 TI - Webwise. AB - Nursing Standard is campaigning to boost the number of nurses in the House of Lords through its Peer Pressure campaign. There are currently only four nurse members in the upper house. PMID- 28071381 TI - Caring for fail patients: best practice. AB - Frailty has become synonymous with vulnerability and is a state caused by many factors, including disability, recurrent infection and multiple co-morbidities. The Gwent frailty service recognises the importance of an interdisciplinary approach to care, including timely recognition of frailty in patients and referral to the most appropriate services to optimise management and treatment. PMID- 28071383 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28071384 TI - Food for thought. AB - While visiting my mother during a recent hospital stay, I overheard a nurse saying to a colleague: 'Oh for heaven's sake, how much longer do you intend to starve? Go for your break, and yes, fetch me a yoghurt.' PMID- 28071385 TI - The independent and voluntary sectors offer satisfying jobs. AB - RCN general secretary Peter Carter has spoken of hundreds of NHS nursing posts disappearing in recent months. Rachel Reeves, shadow chief secretary to the Treasury, claimed on BBC 1's Question Time on March 1 that at least 3,000 nurses had been lost from the health service last years. PMID- 28071386 TI - Give us the facts and figures on our pension contributions. AB - The Department of Health booked a four-page advert entitled 'NHS Pensions proposals: the facts' in the February 22 Nursing Standard. PMID- 28071387 TI - We could end up paying more for less if healthcare services start competing. AB - I share the concerns of Cath Moon (letters March 7) about the Health and Social Care Bill. I fear it will favour private competitors and profit is likely to become the main priority for the health service in England. PMID- 28071388 TI - Starting out patient's notes gave me a clearer insight into his difficult behaviour. AB - While on placement on a neurological rehabilitation ward, I helped nurse a patient with Guillain-Barre syndrome, a disease of the peripheral nerves that causes numbness and weakness in the limbs. PMID- 28071389 TI - Readers panel - Sending. AB - Our experts consider a hot topic of the day. PMID- 28071390 TI - Registrants invited to air views on equality strategy. AB - Nurses are being asked to give their opinions on how equality should be promoted in the profession. PMID- 28071391 TI - Not all glamour. AB - I once had to ask a bunch of police officers to name their favourite TV crime drama. The Sweeney had just begun, and viewers believed they were seeing the gritty reality of modern policing for the first time. PMID- 28071392 TI - World in brief. AB - What's happening in nursing across the globe. PMID- 28071393 TI - Political notebook. AB - A former Nursing Standard nurse of the year has appealed to Welsh assembly members for more public toilets in Wales after research revealed a 10 per cent fall since 2007. PMID- 28071395 TI - 'We were feeding a regulatory beast'. AB - As chair of Mid Staffordshire NHS Foundation Trust, Sir Stephen Moss battled to convince healthcare regulatory bodies that problems '20-plus years in the making' were not going to be put right overnight. PMID- 28071394 TI - CQC warns trust over patient dignity and quality of care. AB - An NHS trust already under the spotlight for poor staffing levels in its emergency department has been issued with two further formal warnings over the quality of its patient care. PMID- 28071396 TI - Midwife who concealed hepatitis C infects patient. AB - The Department of Health could review checks for healthcare staff after a midwife infected a woman with hepatitis C. PMID- 28071397 TI - Cuts were avoidable. AB - Each week a new story emerges about an NHS employer looking to cut staff pay and conditions. The harsh reality of a L20 billion gap in fi nances means such proposals are inevitable, but it did not have to be like this. PMID- 28071398 TI - Women undergoing planned caesarean section less likely to require a blood transfusion. AB - Planned caesarean section is associated with a reduced risk of excessive blood loss following delivery, which is a major cause of maternal morbidity. PMID- 28071400 TI - Increased risk of poor health in people who moved house regularly during childhood. AB - Frequent house moves during childhood increase the risk of psychological distress and unhealthy behaviours in later life, suggests a study in the west of Scotland. PMID- 28071399 TI - Shame on us. AB - 'No one has ever asked me how I feel about it before,' the patient said, and I experienced not only a personal shame but corporate disgrace on behalf of the NHS. I have been listening to the stories of patients who are blind or partially sighted for an assignment, and have been left emotionally wrung out. PMID- 28071401 TI - VOICES - In her final Voices column, Chris Beasley recommends nursing as a career. AB - My final Voices column as chief nursing officer for England is quite a milestone. It gives me the opportunity to acknowledge the people I have been privileged to work with, and those I have met throughout what has been a challenging and rewarding career. PMID- 28071402 TI - Focus on positive experiences proves up listing for hospital staff. AB - Five minutes is all it takes to make a difference to how nurses feel about their work - and to patient care. PMID- 28071403 TI - Exercise can benefit people who have been treated for cancer. AB - Exercise improves the health of people who have undergone treatment for cancer, suggest the results of a recent study. PMID- 28071404 TI - Access to kidney transplant is lower in black American patients than white patients. AB - Black Americans are less likely to have access to kidney transplantation, suggests a study of referrals to a transplant centre in the south eastern region of the United States. PMID- 28071405 TI - Positive effect of cognitive stimulation on cognitive performance is confirmed. AB - Activities that stimulate the mind are generally believed to help slow its decline, and there have been calls for cognitive stimulation to be routinely offered to people in the early stages of dementia. PMID- 28071406 TI - Careers student life time for a reality check. AB - Most nurses believe they are safe to practise, competent and generally good at their job. But are nurses the best judges of their own abilities? PMID- 28071407 TI - Union members to have final say on pension reforms. AB - Thousands of union members are to be consulted on the government's proposed final agreement for reforming NHS pensions. PMID- 28071408 TI - Young people say they want male School nurses. AB - Hundreds of young people have identified the need for more male school nurses and easier access to appointments and advice through text message. PMID- 28071409 TI - Trust rewrites 300 job descriptions to help develop academic clinical careers. AB - An NHS trust is reviewing the job descriptions of nearly 300 clinical nurse specialists and nurse consultants to encourage them to carry out more research. PMID- 28071410 TI - Another mid staffs crisis is brewing, warns former chair. AB - Pressures that led to appalling failures of care at Stafford Hospital six years ago are being replicated today in the NHS, according to the former chair of Mid Staffordshire NHS Foundation Trust. PMID- 28071412 TI - RCN and academics condemn cuts to nurse training places. AB - A position statement has been agreed by the RCN and the Council of Deans of Health outlining their concerns about a year-on-year reduction in the number of commissioned pre-registration nurse training places. PMID- 28071413 TI - Holby city nurses need to take note of 'bare below the elbows'. AB - Watching a recent episode of the medical drama series Holby City on BBC 1, I was shocked to see how the nurse practitioner was dressed. She was wearing a tunic, tight leggings, blue sneakers and a long-sleeved undershirt. PMID- 28071414 TI - Mental health students should be taught basic procedures. AB - As a mental health nursing student, I am concerned that some degree students are not being taught fundamental nursing skills. PMID- 28071415 TI - Japan's earthquake highlighted need for more medical personnel. AB - When the earthquake and tsunami struck Japan a year ago (features March 7), it soon became clear that the authorities were unprepared to deal with such a large scale disaster. PMID- 28071416 TI - Shirley Graham-Paul. AB - Cynthia 'Shirley' Graham-Paul, a community midwife in Reading, Berkshire and a founding member of the Friends of Mary Seacole, has died aged 73. PMID- 28071418 TI - Strictly exercising for the over-fifties. AB - Continence nurse Alison Wileman joined past and present judges of BBC's Strictly Come Dancing to promote exercise among people aged over 55 who have long-term health conditions. PMID- 28071417 TI - Being bipolar, my 'fix' is a legal drug that helps ease the stress. AB - I was interested to read that cannabis is the most widely used illicit substance globally and that its use is increasing (clinical digest March 7). PMID- 28071424 TI - Erratum. PMID- 28071426 TI - Guest Editorial: We Want You! PMID- 28071427 TI - Reply to Dr Vogel. PMID- 28071428 TI - ACVP/ASCVP 2012 Annual Meeting Focused Scientific Sessions. PMID- 28071439 TI - Article on cell biochemistry is an excellent revision aid. AB - It is important for nurses to understand basic chemical structures and the way cells function (art & science July 18), but this is probably not something most nurses think about every day. PMID- 28071440 TI - Multiple-mentor model should be widely adopted by universities. AB - As a third-year nursing student who is undertaking the final weeks of a14-week 'sign off' placement, I have been assessed throughout this by three mentors - one main mentor and two co-mentors. PMID- 28071442 TI - Doing away with doctors. PMID- 28071441 TI - Concern for our bodies as well as our minds boosts resilience. AB - I like the idea of using mindfulness and meditation to help avoid work stress and improve resilience (news July 18). It can surely do no harm for all nurses to allocate a few minutes every day for reflection and meditation. PMID- 28071443 TI - Nursing attitudes and practices have to be seen in the context of the times. AB - I congratulate Christine Hallett and colleagues on creating the UK Association for the History of Nursing (analysis July 18). It is another step towards ensuring the history of the profession is preserved. PMID- 28071444 TI - The self-care approach requires us to be skilled and confident. AB - Lynn Young's article on self-care (reflections July 18) was interesting and I agree that this is a subject nurses need to embrace. PMID- 28071445 TI - As nurses find their voice again they can express concerns better. AB - When reading the coroner's verdict on the death in 2009 of 22-year-old hospital patient Kane Gorny from dehydration (news July 18), inevitably one wonders whether standards of basic care are routinely falling to unacceptable levels. PMID- 28071446 TI - The past shows just what a long, hard journey it has been. AB - I welcome the launch of the UK Association for the History of Nursing (analysis July 18). It is important for all nurses to learn from the past. PMID- 28071448 TI - Edith cavell's name lives on in car park. AB - A decision to retain war heroine Edith Cavell's name on a car park in the city where she was educated has been welcomed by the nurses' trust set up in her memory. PMID- 28071449 TI - ? AB - Nurses on Twitter. PMID- 28071450 TI - 'We cannot get any answers'. AB - Nurses in south west England have told Nursing Standard they fear their pay is about to be cut. PMID- 28071453 TI - Patient handover delays being addressed by ambulance service. AB - Ambulance services across England and Wales are working with hospitals to help reduce the numbers of patients waiting in vehicles outside A&E. PMID- 28071451 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28071454 TI - Payout award for hospice worker. AB - A nurse has received L23,000 in compensation after an industrial tribunal ruled that she had been unfairly prevented from going back to work following a period of illness. PMID- 28071456 TI - World in brief. AB - What's happening in nursing across the globe. PMID- 28071455 TI - On the move. AB - Promotions / new appointments. PMID- 28071457 TI - Overqualified, male, recent immigrants more likely to suffer on-the-job injuries. AB - Men who are recent immigrants and overqualified for their jobs have a significantly greater risk of sustaining an injury at work than appropriately qualified peers who have been in the country for some time, suggests research in Canada. PMID- 28071458 TI - Medicines management. AB - I have recently taken a career break to start a family. Are there any requirements I need to fulfil before I can start prescribing medicines again? PMID- 28071459 TI - Female cyclists advised to sit up in the saddle to avoid genital nerve damage. AB - Female cyclists could avoid genital nerve damage by adjusting the position of the handlebars on their bikes to produce a more upright sitting position, easing saddle pressure on the genital area, according to a study by researchers in the United States. PMID- 28071460 TI - Benefits of metastatic breast cancer drug found to be 'modest'. AB - The cancer drug bevacizumab offers only a modest benefit to patients with advanced-stage breast cancer, according to a systematic review of the evidence by Cochrane researchers. PMID- 28071461 TI - Useful advice. AB - A friend of mine often exclaims: '24 hours in the day is never enough, I need 30.' PMID- 28071464 TI - Older men at high risk of aneurysm should be screened twice. AB - One-off aneurysm screening for men aged over 65 is known to be cost effective, but a new study suggests that high-risk men should be re-screened at least once. PMID- 28071465 TI - Webwise. AB - National Health Action is a political party campaigning against the coalition government's restructuring of the NHS in England. PMID- 28071466 TI - Low vitamin D could be the result rather than cause of depression, suggests study. AB - Treating vitamin D deficiency does not reduce symptoms of depression, according to a study in Norway that suggests low levels of vitamin D are the result, rather the cause, of the condition. PMID- 28071467 TI - Universities begin trials of personality tests aimed at improving student selection process. AB - Five universities are piloting personality tests in their admissions processes for prospective nursing students. PMID- 28071469 TI - Professionalism report stresses Role of support. AB - The Scottish Government wants nurses to develop ways of coping with stress by sharing their experiences of caring with their colleagues in structured groups. PMID- 28071468 TI - RCN is proved right over cuts in nurse numbers. AB - Official workforce statistics have confirmed RCN predictions that thousands of nursing posts would be cut from the NHS workforce. PMID- 28071470 TI - Readers panel-Time to settle new doctors. AB - Our experts consider a hot topic of the day. PMID- 28071471 TI - Olympic tribute to the NHS was a real honour. AB - Spending L9.3 billion on the Olympic games was always going to be contentious at a time of public spending cuts, and it is easy to dream up other ways of spending such a vast sum of money. But this large investment will bring many benefi ts, some of which will be felt directly by nurses. PMID- 28071472 TI - Rolling shock. AB - I was really chuffed when the new trains appeared on our line. Trains ... chuffed ... get it? Sorry, but I have not been sleeping well, on account of having to lie fl at on my back for the past two weeks. PMID- 28071474 TI - PM's care forum promises single national leadership programme. AB - Nurses stepping into ward sister roles should all have access to a national leadership development programme covering the core aspects of running a successful team. PMID- 28071473 TI - Starting out-training in Finland made me crave starting out greater responsibility in the UK. AB - On a recent three-month educational exchange programme in Finland, I was intrigued by the differences in the opportunities offered to nursing students between Finland and the UK. PMID- 28071475 TI - 'My daughter's experience proves the value of specialist nurses'. AB - As the recently re-elected deputy president of the RCN, Cecilia Anim hopes to raise the profile of learning disability nursing. PMID- 28071476 TI - Workforce. AB - 'Should I stay or should I go?' This is a question asked by millions of possible migrants and migrant returners every year. But some overseas nurses currently working in the UK will have no choice - new UK immigration requirements will mean that many will have to leave in 2016. PMID- 28071477 TI - Voices - lords reform is a great opportunity for nurses, says baroness emerton. AB - As an independent cross bench peer in the House of Lords, and a retired nurse, I endeavour to present a range of aspects affecting health care. I am not a representative of nursing - I am there for my personal qualities and experience - but I am particularly interested in areas that affect nursing, midwifery and health visiting. PMID- 28071479 TI - Being properly prepared is essential to fulfil this role. AB - Helen Winn, ward sister on a 27-bed orthopaedic ward at Royal Cornwall Hospitals NHS Trust: 'I became a ward sister 15 years ago and was totally unprepared. PMID- 28071478 TI - Leaders take time out to focus on the key areas where they require support. AB - Ward sisters at York Teaching Hospital NHS Foundation Trust have sometimes struggled to get access to professional development. PMID- 28071480 TI - Better health. AB - 'What is humankind's greatest invention?' we recently asked each other at my reading group. Predictably, for a collection of bookworms, we all leaned towards literary matters. PMID- 28071481 TI - Focus on the patient. AB - My partner and I have been nurses for 25 years. The majority of these have not involved the provision of acute adult care, so it was an eye-opener for both of us when she was recently admitted to hospital for elective surgery. PMID- 28071484 TI - Band 2 support staff are most likely to be off sick. AB - Sickness absence rates among NHS nurses, midwives and health visitors in England averaged 4.55 per cent in 2011/12, above the NHS average of 4.12 per cent, according to latest figures. PMID- 28071482 TI - Emergency care training initiative lauded. AB - An initiative involving nurse practitioners helping to cut A&E admissions has been highlighted in a best practice guide for clinical commissioning. PMID- 28071485 TI - Flu vaccine group will assess role of school nurses. AB - An expert group is to be set up by the Department of Health to look at whether school nurses or other professionals should administer an annual fl u vaccine to all children aged between two and 17 years. PMID- 28071487 TI - Monitoring proves that more staff are needed. AB - An NHS trust where ward sisters rate staffing levels using a traffic light system is recruiting more nurses after monitoring showed that its older people's wards were understaffed. PMID- 28071486 TI - The bag system that makes 'complete sense'. AB - Nurses in Surrey's community hospitals have developed a 'green bag' system for patients coming into their care and on discharge. PMID- 28071488 TI - Pathology in Context. PMID- 28071491 TI - Corrigendum. PMID- 28071492 TI - Veterinary Pathology Under the Microscope: Planning for the Future. PMID- 28071493 TI - A Green Journal Initiative. PMID- 28071495 TI - In Memoriam. PMID- 28071513 TI - Corrigendum: Women Can Keep the Vote: No Evidence That Hormonal Changes During the Menstrual Cycle Impact Political and Religious Beliefs. AB - Harris, C. R., & Mickes, L. (2014). Women can keep the vote: No evidence that hormonal changes during the menstrual cycle impact political and religious beliefs. Psychological Science, 25, 1147-1149. (Original DOI: 10.1177/0956797613520236 ). PMID- 28071514 TI - Can Emotion Regulation Change Political Attitudes in Intractable Conflicts? From the Laboratory to the Field. AB - Halperin, E., Porat, R., Tamir, M., & Gross, J. J. (2013). Can emotion regulation change political attitudes in intractable conflicts? From the laboratory to the field. Psychological Science, 24, 106-111. (Original DOI: 10.1177/0956797612452572 ) In Figure 1 of this article, the signs for the coefficients on the direct paths from reappraisal to policy support were reported incorrectly. The coefficients on the path from reappraisal to support for conciliatory policies (top panel) should be positive, and the coefficients on the path from reappraisal to support for aggressive policies (bottom panel) should be negative. The corrected figure is printed below. [Figure: see text]. PMID- 28071515 TI - Possible Sources for Some Trace Elements Found in Airborne Particles and Precipitation in Dorset, Ontario. AB - Two types of potential source contribution function analysis- Potential Source Contribution Function (PSCF) and Total Potential Source Contribution Function (TPSCF) analysiswere employed to study the source-receptor relationships for several trace elements (vanadium, selenium, arsenic, manganese, and indium) found in precipitation and airborne particles collected at Dorset, Ontario. This study identified areas in the United States and Canada as possible emission source areas that could contribute to the trace element concentrations observed at Dorset. The identified regions in the United States generally coincide well with the locations of known emission sources, whereas the possible source regions revealed in Canada could not be adequately explained because of the absence of emission source information. The likely emission sources for these trace elements include oiland coal-fired power plants, incinerators, motor vehicles, nonferrous metal smelters, iron and steel mills, ferrous-Mn alloy plants, and Mn chemicals production. PMID- 28071516 TI - Receptor Model Evaluation of the Southeast Michigan Ozone Study Ambient NMOC Measurements. AB - Large-scale studies like the Southeast Michigan Ozone Study (SEMOS) have focused attention on quantifying and spedating inventories for volatile organic compounds (VOCs). One approach for evaluating the accuracy of a VOC emission inventory is the development of a chemical mass balance (CMB) receptor model for ambient non methane organic compound (NMOC) measurements. CMB evaluations of ambient hydrocarbon data provide a sample-specific allocation of emissions to individual source categories. This study summarizes the results of an application of the CMB model to the NMOC data from the SEMOS study. Comparison of CMB results with emission inventory values for the Detroit area show that vehicle emissions are well represented by the inventory, as are architectural coatings and coke ovens. Estimated emissions from petroleum refineries and graphic arts industries are much lower in the inventory than determined from the receptor allocation. Under reporting of fugitive VOC emissions from petroleum refineries is an ongoing problem. Emissions from graphic arts industries are underestimated in the inventory partly because of the broad characterization of the emission factor (i.e., mass emitted/capita), which may be less useful when specific locations and days are under consideration. This study also demonstrates the effectiveness of the CMB approach when used prospectively to track the implementation of emission control strategies. While vehicle emission concentrations were unchanged from 1988 to 1993, measurement-based CMB results suggest a decrease in evaporative emissions during this time period resulting from Reid vapor pressure (RVP) reductions (from 11.0 psi in 1988 to 8.6 psi in 1993) and fleet turnover. Changes in emissions from coke plants and petroleum refineries were also seen in the CMB allocations for these sources. PMID- 28071517 TI - A Methodological Approach for Exposure Assessment Studies in Residences Using Volatile Organic-Compound-Contaminated Water. AB - This paper presents a methodological approach for assessing total exposures to volatile organic compounds (VOCs) in residences using contaminated water supplies. This approach is founded on assessment of ingestion, inhalation, and dermal exposures; both long-term (i.e., 12 to 24 hr) lowlevel exposures and short term (i.e., =10 min) high-level exposures are considered. The methodology is based on the collection of water samples to establish the identity of the contaminants, maximum source terms, and possible dermal and ingestion exposures; integrated whole-air samples are collected to assess long- and short-term inhalation exposures; whole-air grab samples are used to confirm peak and typical inhalation exposures; and alveolar breath samples are used to confirm exposures and to estimate contaminant concentrations in the blood of the test subjects. While we do not suggest that this methodology should supersede any current investigative approach, this material is primarily offered as a consolidated reference to the many people or organizations who might contemplate a study of this type. Application of this investigative protocol should provide detailed exposure assessment information, while it supplies critical real world data for risk assessment specialists, toxicologists, and modeling experts. Data from a recent field study assessing exposures to trichloroethylene are presented to illustrate the utility and some of the limitations of this strategy. PMID- 28071518 TI - A Central Composite Rotatable Analysis for the Catalyzed Hydrogen Peroxide Remediation of Diesel-Contaminated Soils. AB - A central composite rotatable design was used to investigate the interactions between hydrogen peroxide concentration, slurry volume, initial contaminant concentration, and soil organic carbon content in the catalyzed hydrogen peroxide remediation of diesel-contaminated soil. Two separate experimental matrices were investigated: (1) high slurry volumes and low peroxide concentrations, and (2) low slurry volumes with high peroxide concentrations. The time required for the high volume/low concentration system to proceed to completion was approximately three weeks; the low volume/high concentration reactions were complete within three days. The results showed that the soil organic carbon content was an insignificant variable in the catalyzed peroxide treatment of diesel-contaminated soils. However, significant interactions were found for the remaining three variables. The data were analyzed for total petroleum hydrocarbon (TPH) degradation and treatment stpichiometry. Although both systems could achieve equal levels of treatment, the stoichiometry of the high volume/low concentration system was significantly more efficient; therefore, the high volume/low concentration was determined to be the most economical system for the remediation of diesel-contaminated soils. PMID- 28071519 TI - Laboratory Scale Thermal Plasma Arc Vitrification Studies of Heavy Metal-Laden Waste. AB - Plasma processing has been identified as a useful tool for immobilizing heavy metal-contaminated wastes into safe, leach-resistant slag. Although much effort has gone into developing this technology on a pilot scale, not much information has been published on basic research topics. A laboratory-scale plasma arc furnace located at the University of Illinois was operated in cooperation with the U.S. Army Construction Engineering Research Laboratories in an effort to establish an understanding of the chemical and physical processes (such as metal volatilization and resultant gas evolution) that occur during thermal plasma treatment of metal-spiked samples. Experiments were conducted on nickel and chromium using a highly instrumented furnace equipped with a 75 kW transferred arc plasma torch. The volatility of nickel and chromium was examined as a function of varying oxygen partial pressures. Oxidizing conditions reduced the total dust gathered for both the nickel and chromium samples, although each dust sample was found to be metal-enriched. Plasma treating increased the leach resistance of the slags by at least one order of magnitude when compared to unprocessed specimens. The leach- resistance of the nickel-containing slags increased in the presence of oxygen, whereas chromium samples remained relatively constant. PMID- 28071520 TI - Evaluation of an In Situ, On-Line Purging System for the Cone Penetrometer. AB - Materials that will be used to construct an in situ, on-line purging system for the cone penetrometer were evaluated. Transfer efficiencies for volatile organic compounds (VOCs) through stainless steel, nickel, aluminum, and Teflon(r) tubings were determined using a gas-phase mixture of VOCs containing trichloromethane, tetrachloromethane, 1,1,1- trichloroethane, tetrachloroethene, hexane, benzene, toluene, and 1,2-dimethylbenzene. The water content of the gas stream had an insignificant effect on the quantitative transfer of VOCs through Teflon(r) tubing but was critical to efficiently transfer the compounds through metal tubing, particularly nickel. Transfer efficiencies for all eight analytes in moist gas streams through stainless steel were greater than 95%. Toluene, tetrachloroethene, and 1,2-dimethylbenzene were transferred with 93%, 81%, and 80% efficiency, respectively, when they were drawn through Teflon(r) PFA (perfluoroalkoxy) tubing. In general, the retention of the VOCs by Teflon(r) increases with decreasing aqueous solubility of the analyte. The efficiencies at which VOCs were purged from aqueous standards in Teflon(r) PFA, Type 304 stainless steel, and glass vessels were similar. Stainless steel was superior to nickel, aluminum, and the Teflon(r) polymers as a material for an in situ, on line purging system for the cone penetrometer. PMID- 28071521 TI - Thoughts on Predictive Emissions Monitoring from a Regulatory Perspective. AB - Predictive emissions monitoring systems (PEMS) are recognized as potentially acceptable monitoring methods and an alternative to hardware continuous emissions monitoring systems (CEMS) for demonstrating continuous compliance. Upcoming state and federal regulations are driving forces for regulatory agencies to develop standardized PEMS protocols for specific source categories and processes. PEMS is a promising technology whose use in the field remains to be demonstrated. For the first time, practical issues relating to accuracy, reliability, and quality assurance of these systems are surfacing. This paper provides an update of the current understanding and regulatory status of PEMS, and addresses practical issues and concerns relating to its quality assurance and field implementation. PMID- 28071522 TI - Determination of Exempt and Prohibited Compounds in Consumer Products by Headspace Gas Chromatography Mass Spectrometry. AB - Title 17, California Code of Regulations, Division 3, Chapter 1, Subchapter 8.5, Articles 1 and 2, Sections 94500-94517 specify limits for volatile organic compounds (VOCs) in a wide variety of consumer products. However, under these regulations, specific compounds that have been shown to contribute little to the formation of ozone in the lower atmosphere are exempt from the definition of VOC. A headspace sampling and analysis method has been developed for the analyses of these compounds in consumer products. This method has been used successfully for analyzing aerosol and non-aerosol products. PMID- 28071523 TI - Note on "Fewer Things, Lasting Longer: The Effects of Emotion on Quantity Judgments". AB - Young, L. N., & Cordes, S. (2013). Fewer things, lasting longer: The effects of emotion on quantity judgments. Psychological Science, 24, 1057-1059. (Original DOI: 10.1177/0956797612465294 ) A summary of the 2013 article by Laura N. Young and Sara Cordes ("Fewer Things, Lasting Longer: The Effects of Emotion on Quantity Judgments") was published as an Object Perception, Attention, and Memory conference abstract: Young, L. N., & Cordes, S. (2012). Time and number under the influence of emotion. Visual Cognition, 20, 1048-1051. PMID- 28071524 TI - Old practices, new windows: reflections on a communications skills innovation. AB - Most of the great innovations in communication skills education, from Balint's concept of the 'doctor as drug' to the Calgary Cambridge conceptualisation of the consultation, were founded in general practice. It can be argued however, that there has been a hiatus in the development of new approaches to analysing the consultation since the mid-1990s. It is most welcome therefore that in this issue of the journal two papers are presented that describe and evaluate a novel approach to consultation analysis entitled 'the windows method'. Building on the more structured approaches that preceded it, the windows method offers some genuine innovations in terms of its emphasis on emotional knowledge and the manner in which it addresses many of the potential deficiencies in feedback practice associated with older methods. The new approach is very much in step with current thinking about emotional development and the establishment of appropriate environments for feedback. The windows method has the potential to breathe fresh life into old and well-established communication skills education practices. PMID- 28071525 TI - Additive toxic effect of deltamethrin and cadmium on hepatic, hematological, and immunological parameters in mice. AB - Exposure to natural and man-made environmental toxins concurrently can pose a greater threat to multiple organs. In the present work, we investigated interactions between deltamethrin (DM) and cadmium (Cd), whose mechanisms of action in humans are poorly understood. Albino mice were randomly divided into four groups, each containing six mice: saline as control, DM-treated, cadmium chloride (CdCl2)-treated, and CdCl2 plus DM treated. After 2 weeks of treatment biochemical and hematological effects, total leukocyte count (TLC), differential leukocyte count, humoral-mediated immune responses, and histopathological studies were conducted. Mice exposed to DM and Cd showed a significant increase in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Also, DM and Cd administration resulted in suppression of humoral immunity, erythrocyte count, hemoglobin, hematocrit, and TLC. Histopathological evidence revealed hepatic damage, supporting the AST and ALT findings. Cd and DM exhibited an additive type of toxicity. It could be concluded that these toxins either target different cellular pathways, or the individual amounts used in this study were not enough to saturate the toxicological target, thus producing additive effects. PMID- 28071526 TI - Methylmercury in fish from the southern Baltic Sea and coastal lagoons as a function of species, size, and region. AB - BACKGROUND: Methylmercury (MeHg) is a highly toxic compound that traverses the blood-brain barrier with deleterious effects to the central nervous system. Exposure is generally through the ingestion of contaminated fish. Fish are a main source of MeHg. Goals and methods: The aim of this study was to determine the dependence of MeHg concentrations on fish species and age, the percentage of MeHg in total mercury (THg) and risk assessment depending on the size of fish. Assays of THg and MeHg were performed on the muscle tissues of 18 species of fish. RESULTS: The investigations indicated there were differences in the mercury concentrations depending on fish size. THg and MeHg concentrations in the muscles of fish species that have a wide length distribution were strongly, positively correlated with fish length. However, concentrations of MeHg were strongly, positively correlated with those of THg in all the fish species investigated. Variation in the percentage share of MeHg in THg in the muscles of fish of large sizes was also noted within species, but this correlation was not noted in small sized fish. The dose of MeHg in small-sized fish species was estimated and the risk posed to consumer health was assessed using mean MeHg concentrations determined for different fish species. CONCLUSIONS: For species of fish that occur within a wide length distribution, the dose of MeHg should be assessed separately in different length classes. Fish consumption of small-sized species poses no health risk. PMID- 28071527 TI - Protective role of silymarin and D-penicillamine against lead-induced liver toxicity and oxidative stress. AB - This study was performed to assess hepatotoxicity and alterations in liver antioxidant defence in acute lead (Pb) exposure and the protective effects of silymarin in comparison to D-penicillamine in rats. Forty eight Albino rats were divided in eight groups and received the following treatments in a 10-day experiment - group 1: normal saline as control; group 2: 25-mg/kg Pb acetate, intraperitoneally (IP) for the last 5 days; group 3: 100-mg/kg D-penicillamine, IP for the last 5 days; group 4: 200-mg/kg silymarin, orally for 10 days; and groups 5, 6, 7 and 8: in addition to Pb, they received D-penicillamine, for the last 5 days, silymarin for 10 days, a combination of silymarin for 10 days and D penicillamine for the last 5 days and silymarin for the last 5 days, respectively. Pb acetate exposure induced significant elevation in serum alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzyme activities in group 2 compared to control group. Significant reductions in serum total protein and albumin in all Pb-exposed groups and in serum glucose in groups 2, 6 and 8 were also observed. Liver tissue superoxide dismutase and glutathione peroxidase were significantly lower in groups 2 and 8 compared to control group. Silymarin pretreatment and D-penicillamine administration in groups 5, 7 and 8 could significantly lower ALP, ALT and AST and improve liver antioxidant enzymes. Thus, acute Pb exposure induced hepatotoxicity with suppression of liver antioxidant defence system and silymarin, as an antioxidant could alleviate this effect. PMID- 28071531 TI - Pathologic Lesions? PMID- 28071532 TI - Pathology in Context. PMID- 28071533 TI - Nightingale bear helps girl orphans. AB - A 'Florence Nightingale' teddy has gone on sale to raise funds for the orphaned daughters of nurses in developing countries. PMID- 28071534 TI - Leading children's nurse hails role for PCTs in secure settings. AB - Plans to make primary care trusts responsible for commissioning health care for children in secure settings have been broadly welcomed. PMID- 28071535 TI - Dual registration in Wales questioned. AB - The introduction of a legal duty requiring nurses who manage adult care homes to be regulated twice has been criticised as unnecessary by RCN Wales. PMID- 28071536 TI - Unions fight attempt to link pay and sickness. AB - An employment tribunal is set to hear at least 50 cases against one of England's largest teaching trusts as unions bid to stop incremental pay rises being linked to staff sickness, it has been revealed. PMID- 28071537 TI - How to be a starr performer. AB - As NHS efficiencies bite, essential jobs face the axe. How can you ensure that your employer knows that you and your job are too important to lose? PMID- 28071538 TI - Lack of support from a mentor while on a placement is something that, unfortunately, many of us will recognise (reflections May 25). AB - The Nursing and Midwifery Council code of conduct requires all nurses to support learners and expects all nurses to aspire to be a mentor. While this is great in theory, not everyone makes a good mentor and many nurses who attend mentorship programmes openly admit that they are doing it to aid their career progression. PMID- 28071541 TI - Nurse holding court. AB - England's only nurse coroner, Catherine Mason, says that other coroners pick her brains because of her nursing background and knowledge of hospital procedures. PMID- 28071540 TI - Trust boasts double employee awards scoop. AB - An NHS trust is celebrating after a nurse and doctor it employs were handed prestigious awards within days of each other. PMID- 28071542 TI - Computerised patient files have added to paperwork. AB - The Care Quality Commission has reported that a member of staff at Worcestershire Acute Hospitals NHS Trust had to prescribe water on medical charts to ensure patients got enough to drink (news June 1). PMID- 28071543 TI - Book helps to demystify the subject of leadership. AB - Leadership as a topic can feel like a murky quagmire. There are so many viewpoints and a plethora of buzzwords. It was good, therefore, to read the advice of Nursing and Midwifery Council chief executive and registrar Dickon Weir Hughes (analysis and reviews May 25) on the subject. In his new book on leadership, he says: 'Be a first rate version of yourself, not a second rate version of someone else.' PMID- 28071544 TI - Sickness leave linked to shrinking nurse numbers. AB - If England's chief nursing officer wants to cut nurses' sick leave percentage to 3 per cent, she should press the government to increase the number of clinical nurses working at the interface with patients. PMID- 28071546 TI - Debate on assisted suicide needs up-to-date information. AB - Stephen Wright's (reflections May 11) bases his 'slippery slope' argument about assisted suicide and euthanasia on Dutch figures from the early 1990s. He mistakenly says that the law to regulate euthanasia and assisted suicide preceded these figures. PMID- 28071545 TI - Parents' use of alternative therapies can be detrimental. AB - Your clinical article 'Traditional and complementary approaches to child health' (May 25) highlights some of the challenges faced by primary care nurses, particularly children's nurses in A&E and acute inpatient areas. PMID- 28071547 TI - Dialysis project wins innovation accolade. AB - A scheme allowing patients to receive dialysis at home, saving anNHS hospital hundreds of thousands of pounds a year, has won top prize in a national innovation award. PMID- 28071548 TI - Southern Cross staff quit as firm is hit by rent rises. AB - The RCN is continuing to hold talks with managers from the embattled care home provider Southern Cross Healthcare amid ongoing concerns about the company's future. PMID- 28071549 TI - Improved dementia outcomes stem from educated care. AB - Further to the news story, 'Emergency admissions ward gives dedicated dementia care' (May 25), it is heartening that a hospital is recognising the need to provide patients who have dementia with specialist attention. PMID- 28071551 TI - NMC to resume evaluations of nursing courses. AB - The quality of nursing courses across the UK will once again be assessed by the Nursing and Midwifery Council after the regulator opted to bring the task back in house. PMID- 28071550 TI - Student life-Support on schedule. AB - Nursing students experience a diverse range of care environments while contending with the intensity and unpredictability of clinical practice and learning about professional values. PMID- 28071552 TI - Placement facilitators needed to monitor mentors. AB - Mentors certainly need support, particularly in busy areas such as outpatients (reflections May 25). But it needs to be realised that some nurses are simply not suited to the responsibility of mentoring, and many staff are too busy to provide good support to students. PMID- 28071553 TI - Students can learn much by working in outpatients. AB - The nursing student's experience in an outpatients department placement made sad reading (reflections May 25). I am an outpatient nurse who mentors enthusiastic students. I do my best to provide learning opportunities that are not confined to making beds, bathing and toileting patients. PMID- 28071554 TI - Dying people should be allowed to choose how they die. AB - Stephen Wright conveniently omitted recent research on the workings of assisted dying laws in the Netherlands and Oregon (reflections, May 11), presumably because it did not fit his 'slippery slope' argument. PMID- 28071555 TI - Scarborough seafront initiative showed a proactive approach. AB - Last summer nurses patrolled Scarborough seafront's west pier in North Yorkshire with lifeguards to treat people with minor injuries such as sprains and sunburn. PMID- 28071557 TI - Readers panel-The cost of non-compliance. AB - Our experts consider a hot topic of the day. PMID- 28071556 TI - Starting out - Useful lesson in responding to needs of patient with dementia. AB - During one of my placements I looked after a patient with dementia who had been admitted to the ward for vascular investigation. PMID- 28071558 TI - Preloading with varenicline helps in smoking cessation. AB - Increasing the period when varenicline is given before an attempt to quit smoking can produce a substantial reduction in ad-lib smoking and enhance 12-week quit rates. PMID- 28071561 TI - GPs press on with consortia despite parliamentary 'pause'. AB - Less than a third of the new GP commissioning consortia have nurses on their governing bodies, according to an RCN survey. PMID- 28071559 TI - Moderate exercise has no effect on women's sex hormone levels. AB - In premenopausal women, 150 minutes a week of moderate aerobic exercise for 16 weeks does not significantly alter sex hormone levels, so is unlikely to reduce the risk of breast cancer. PMID- 28071562 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28071563 TI - In advance. AB - 'You have to go straight to Reading West,' said the train guard. 'You cannot go via Reading because you will technically get ahead of yourself. Your ticket does not cover that.' PMID- 28071568 TI - Pay protection change overruled by tribunal. AB - Health unions have welcomed an employment tribunal ruling that prevents a trust from reducing payment protection periods without consulting staff. PMID- 28071565 TI - Webwise. AB - Netmums is a bright, attractive and diverse parenting website that aims to link busy mothers. The site claims it is promoting 'real parenting', helping families to have fun and enjoy their children. PMID- 28071569 TI - Rehabilitation unit offers choice of art. AB - Patients are being invited to choose artwork for their bedsides while they are in hospital. PMID- 28071570 TI - Adherence to UK guidance on diet reduces chronic disease. AB - Substantial health benefits can be enjoyed by people who follow UK dietary guidance to consume five portions of fruit and vegetables per day, reduce salt intake to 3.5g per day, and lower saturated fat intake to 3 per cent of total energy. PMID- 28071571 TI - A caring society? AB - Regulation is in danger of becoming the most overused word in modern health care. The best way of regulating healthcare support workers and organisations providing care to vulnerable people was in the spotlight again last week, courtesy of the BBC's Panorama programme. PMID- 28071572 TI - All for nothing? AB - 'If a job is worth doing, it is worth doing well,' my mother was fond of saying. PMID- 28071573 TI - Voices - Sickle cell disease has some little-known complications, says Elizabeth Anionwu. AB - Recently I attended an event aimed at raising awareness about the increased risk of stroke among people with sickle cell disease. PMID- 28071574 TI - Outside in. AB - They must be used to people like me at the organ donor register. Either that or the woman I spoke to has learned not to let her feelings show. PMID- 28071575 TI - Brain tumour risk persists for many years after epilepsy. AB - Seizures may herald the development of cerebral tumours, both years after and soon after onset. This finding has implications for guidelines on continued surveillance of those with new-onset seizures. PMID- 28071577 TI - The Effect of Ethanol Fuel on the Emissions of Vehicles over a Wide Range of Temperatures. AB - The emissions from a fleet of 11 vehicles, including three from the State of Alaska, were tested at 75, 0, and -20 degrees F with base gasolines and E10 gasolines, that is, gasolines with 10% by volume ethanol added. The data for the changes in emissions for the test run at 75 degrees F are included, since most other studies on the effects of E10 gasoline on emissions were run at that temperature. The three Alaskan vehicles were also tested at 20 degrees F. The testing followed the Federal Test Procedure, and regulated emissions-CO, total hydrocarbons (THC), and nitrogen oxides (NOx)-CO2, speciated organics, and fuel economy were measured. A total of 490 FTP tests were run. The data obtained indicated that with most vehicles, at the temperatures tested, improvements in both CO and THC emissions were obtained with the use of E10 fuel. At the lowest temperature used, -20 degrees F, most vehicles had an increase in NO emissions with the use of E10 fuel. At the other temperatures, however, more vehicles showed a decrease in NOx emissions with the use of E10. With all vehicles at all temperatures tested, the emissions of acetaldehyde increased significantly when E10 fuel was used. The highest increase was about 8 to 1. Benzene, formaldehyde, and 1,3 butadiene showed both increases and decreases in the emissions when using E10 fuel. Unexpected results were obtained with the fuel economy, with about half of the tests showing an increase in fuel economy with the use of E10 fuel. PMID- 28071578 TI - Synthesis of Hybrid Gas Permeation Membrane/Condensation Systems for Pollution Prevention. AB - Pollution prevention is a major economic and environmental issue in the chemical processing industries. This paper addresses the design of cost-effective recovery systems for vaporous emissions, systems that allow environmentally sound recycling of the recovered components for re-use within the process as a means of pollution prevention. A methodology is proposed to design optimal hybrid systems that involve gas permeation membranes and vapor condensation systems. The design methodology is presented as a mixed-integer, nonlinear program. Based on a fixed structure of the system, a short-cut formulation is derived. Additionally, the incorporation of the system into the emerging mass integration methodology is presented. It is demonstrated, through an industrial case study, that hybrid membrane/condensation systems possess advantages over either separation technique alone. PMID- 28071579 TI - Daily Variability of Motor Vehicle Emissions Derived from Traffic Counter Data. AB - This work studied the daily variability of mobile sources in rural and urban areas, in and around the Atlanta Metropolitan Area. Traffic counter data collected during the 1992 Southern Oxidants Study Atlanta Intensive Study were used to analyze the spatial and temporal distribution of traffic volume. A simple method to study the daily variability of mobile emissions from the different types of urban and rural roads is presented. The method is based on hourly traffic volume data and emission factors and it has been generalized to describe the daily variability of mobile emissions for urban and rural areas and for the whole modeling domain. Implications of this study for improving mobile emission inventories are also discussed. PMID- 28071581 TI - Role of AQP4 Antibody Serostatus and its Prediction of Visual Outcome in Neuromyelitis Optica: A Systematic Review and Meta-Analysis. AB - : Backgroud: Neuromyelitis optica (NMO) is an autoimmune inflammatory disorder, which is characterized by severe attacks of optic neuritis and myelitis. Antibodies (Ab) to aquaporin-4 (AQP4) (or NMO-IgG) as a serological biomarker of NMO have been widespread used. Nevertheless, some NMO patients remain seronegative for AQP4-Ab and/or have no detected optic nerve involvement. In addition, no consensus exists on the association between AQP4-Ab serostatus and visual outcome in NMO. To drive a more precise estimate of this postulated relationship, a metaanalysis was performed based on existing relevant studies. METHODS: Studies were searched by PubMed and MEDLINE up to March 2016. Study quality was assessed, and meta-analysis was conducted using the RevMan 5.1. Odds ratios with 95% confidence interval were calculated and funnel plot was applied to assess the potential publication bias. RESULTS: In a total of 1288 relevant studies, 18 studies satisfied the eligibility criteria and were included in the systemic review. Only 9 studies appeared eligible for the meta-analysis, together including 624 AQP4-Ab-positive and 119 AQP4-Ab-negative NMO patients. The results revealed associations between AQP4-Ab seropositivity and visual impairment in NMO (OR, 3.16; 95% CI, 1.09, 9.19; P = 0.03). The results of subgroup analyses based on different methods of AQP-4 detection also showed significantly differences between AQP4-Ab seropositivity and visual impairment in NMO, especially in CBA subgroup. CONCLUSION: This meta-analysis indicates that AQP4-Ab serostatus has the positive with poor visual outcome in NMO. PMID- 28071582 TI - Reporter Mice Used for Dentinogenesis Study. AB - BACKGROUND: Dentinogenesis is a long and complex process not only in tooth development, but also throughout the lifespan. Reporter mice provided us a preferred model to study the dentin formation with characteristics of high sensitivity, visualization, and reliability, which makes the long-term and intricate period of dentinogenesis much clear. With the advent of different gene reporters, genetic engineering methods, and tissue specific promoters, various reporter mice can be created to solve different problems. OBJECTIVE: To understand the fundamental concepts and characteristics to use the reporter mice for dentinogenesis study. RESULTS: This review introduced the frequently used gene-based reporters, genetic engineering technologies, dentinogenesis-related promoters and the reporter mice commonly used in the dentin study, with the purpose of obtaining a better application of reporter mice and gaining more details about dentinogenesis. CONCLUSION: Reporter mice is a convenient and reliable model for studying dentinogenesis. PMID- 28071583 TI - Anticancer Activities of New N-hetaryl-2-cyanoacetamide Derivatives Incorporating 4,5,6,7-Tetrahydrobenzo[b]thiophene Moiety. AB - AIMS: Novel series of N-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl) cyanoacetamide derivatives are synthesized. METHOD: The structure of these compounds was elucidated using different spectral tools. Compounds were evaluated for their cytotoxic activities against different types of human cancer cell lines including, breast (MCF-7, T47D, MDA MB231); liver (HEPG-2); colon (HCT116); prostate (PC3); and cervix (HELA) cells. In this study, we used compounds 11 and 12 that showed the highest cytotoxicity on PC3 and HEPG2 cells, to explore their effects on apoptosis, metastasis and angiogenesis of cancer cells. RESULTS: Results revealed that the growth inhibition produced by the two selected compounds was due to cytocidal and not due to cytostatic effect in both cell lines. This cytocidal effect was due to up-regulation of caspases-3, and- 9. In addition, the two compounds inhibited the expression of metalloproteinases-2 and 9 (MMP 2&9). Moreover, HIF-1alpha and VEGF expressions were inhibited by both compounds. CONCLUSION: In conclusion, N-(4, 5, 6, 7-tetrahydrobenzo[b]thiophen-2 yl) cyanoacetamide derivatives showed different anticancer potential against different cancer cell lines. Compounds 11 and 12 showed the most active cytotoxicity against PC3 and HepG2 cells. Both compounds have apoptotic, anti- metastatic and anti-angiogenic effects. PMID- 28071584 TI - Major Highlights of the CAR-TCR Summit, Boston, 2016. AB - Cellular immunotherapies such as CAR-T cell therapy and TCR-T cell therapy are relatively new, highly promising approaches for the treatment of cancer. In CAR-T cell therapy, a patient's T cells are engineered to express chimeric antigen receptors targeting tumor-associated cell surface antigens. In TCR-T cell therapy, the patient's T cells are engineered to express receptors targeting intracellular antigens. This report will summarize presentations from the recent CAR-TCR summit in Boston on September 13-16, 2016. These presentations were given by leaders in the field and many were divided into three streams: Discovery and Genetic T Cell Engineering; Translation and Clinical Development; and Manufacturing, Supply Chain and Commercialization. The report summarizes major pharmaceutical companies developing these novel therapies and provides challenges and perspectives for future therapeutic developments. PMID- 28071585 TI - Newborn Bilirubin Screening for Preventing Severe Hyperbilirubinemia and Bilirubin Encephalopathy: A Rapid Review. AB - : According to the 2004 American Academy of Pediatrics guideline on the management of hyperbilirubinemia, every newborn should be assessed for the risk of developing severe hyperbilirubinemia with the help of predischarge total serum bilirubin or transcutaneous bilirubin measurements and/or assessments of clinical risk factors. The aim of this rapid review is 1) to review the evidence for 1) predicting and preventing severe hyperbilirubinemia and bilirubin encephalopathy, 2) determining the efficacy of home/community treatments (home phototherapy) in the prevention of severe hyperbilirubinemia, and 3) non-invasive/transcutaneous methods for estimating serum bilirubin level. METHODS: In this rapid review, studies were identified through the Medline database. The main outcomes of interest were severe hyperbilirubinemia and encephalopathy. A subset of articles was double screened and all articles were critically appraised using the SIGN and AMSTAR checklists. This review investigated if systems approach is likely to reduce the occurrence of severe hyperbilirubinemia. RESULTS: Fifty-two studies met the inclusion criteria. Included studies assessed the association between bilirubin measurement early in neonatal life and the subsequent development of severe hyperbilirubinemia and chronic bilirubin encephalopathy/kernicterus. It was observed that, highest priority should be given to (i) universal bilirubin screening programs; (ii) implementation of community and midwife practice; (iii) outreach to communities for education of prospective parents; and (iv) development of clinical pathways to monitor, evaluate and track infants with severe hyperbilirubinemia. CONCLUSIONS: We found substantial observational evidence that severe hyperbilirubinemia can be accurately predicted and prevented through universal bilirubin screening. So far, there is no evidence of any harm. PMID- 28071586 TI - Milestones in CRH Research. AB - The Corticotropin-releasing Hormone (CRH) mammalian family members include CRH, urocortin I, Stresscopin (SCP) and Stresscopin-related peptide (SRP), along with the CRH receptors type 1 (CRHR1) and type 2 (CRHR2), and CRH-binding protein (CRH BP). These family members differ in their tissue distribution and pharmacology. Several studies have provided evidence supporting an important role of this family in the regulation of the neuroendocrine and behavioral responses to stress. Regulation of the relative contribution of CRH and its homologs and the two CRH receptors in brain CRH pathways may be essential in coordinating physiologic responses to stress. The development of disorders related to heightened stress sensitivity and dysregulation of stress-coping mechanisms appears to involve regulatory mechanisms of the CRH family members. Therapeutic agents that target CRH family members may offer a new approach to the treatment of these disorders. The purpose of this review is to summarize the most significant discoveries related to CRH over time. PMID- 28071587 TI - New Imidazole-Based Compounds Active Against Trypanosoma cruzi. AB - BACKGROUND: Current drugs available for the treatment of Chagas disease are fraught with several challenges including severe toxicity and limited efficacy. These factors coupled with the absence of effective drugs for treating the chronic stage of the disease have rendered the development of new drugs against Chagas disease a priority. OBJECTIVE: This study screened several imidazole-based compounds for anti-Trypanosoma potential. METHOD: Using an in vitro experimental infection model, several imidazole-based compounds were screened for anti proliferative effect on Trypanosoma cruzi epimastigotes. Additionally, all test compounds were evaluated for unspecific cytotoxicity on L929 murine fibroblasts. Benznidazole (BZN) served as reference drug. RESULTS: All test compounds demonstrated interesting trypanocidal potential with IC50 values in the MUM range (1< 1C50 <8 MUM). The activities of the test compounds compared favorably with BZN, which had an IC50 value ca. 30 MUM. Conversely, most of the test compounds were highly cytotoxic, resulting in selectivity lower than that of BZN (SI > 9.42). CONCLUSION: We provide evidence which implicate the imidazole-based compounds as potential prototypes for the development of anti-parasitic agents. Findings have far-reaching relevance to drug discovery efforts for trypanosomiasis. PMID- 28071589 TI - Atopic Dermatitis in Adults: A Diagnostic Challenge. AB - Atopic dermatitis (AD) has a prevalence of 1%-3% in adults. Adult-onset AD has only been defined recently, and lack of familiarity with this condition and confusion regarding the appropriate terminology persist. AD may first appear in childhood or de novo in adults and is characterized by pronounced clinical heterogeneity. The disease often deviates from the classic pattern of flexural dermatitis, and there are forms of presentation that are specific to adults, such as head-and-neck dermatitis, chronic eczema of the hands, multiple areas of lichenification, or prurigo lesions. Although diagnosis is clinical, adult-onset AD frequently does not fit the traditional diagnostic criteria for the disease, which were developed for children. Thus, AD is often a diagnosis of exclusion, especially in de novo cases. Additional diagnostic tests, such as the patch test, prick test, skin biopsy, or blood test, are usually necessary to rule out other diseases or other types of eczema appearing concomitantly with AD. This article presents an update of the different forms of clinical presentation for AD in adults along with a proposed diagnostic approach, as new treatments will appear in the near future and many patients will not be able to benefit from them unless they are properly diagnosed. PMID- 28071588 TI - Genetic evidence that Nkx2.2 acts primarily downstream of Neurog3 in pancreatic endocrine lineage development. AB - Many pancreatic transcription factors that are essential for islet cell differentiation have been well characterized; however, because they are often expressed in several different cell populations, their functional hierarchy remains unclear. To parse out the spatiotemporal regulation of islet cell differentiation, we used a Neurog3-Cre allele to ablate Nkx2.2, one of the earliest and most broadly expressed islet transcription factors, specifically in the Neurog3+ endocrine progenitor lineage (Nkx2.2?endo). Remarkably, many essential components of the beta cell transcriptional network that were down regulated in the Nkx2.2KO mice, were maintained in the Nkx2.2?endo mice - yet the Nkx2.2?endo mice displayed defective beta cell differentiation and recapitulated the Nkx2.2KO phenotype. This suggests that Nkx2.2 is not only required in the early pancreatic progenitors, but has additional essential activities within the endocrine progenitor population. Consistently, we demonstrate Nkx2.2 functions as an integral component of a modular regulatory program to correctly specify pancreatic islet cell fates. PMID- 28071590 TI - Fabrication of nanopore and nanoparticle arrays with high aspect ratio AAO masks. AB - How to use high aspect ratio anodic aluminum oxide (AAO) membranes as an etching and evaporation mask is one of the unsolved problems in the application of nanostructured arrays. Here we describe the versatile utilizations of the highly ordered AAO membranes with a high aspect ratio of more than 20 used as universal masks for the formation of various nanostructure arrays on various substrates. The result shows that the fabricated nanopore and nanoparticle arrays of substrates inherit the regularity of the AAO membranes completely. The flat AAO substrates and uneven AAO frontages were attached to the Si substrates respectively as an etching mask, which demonstrates that the two kinds of replication, positive and negative, represent the replication of the mirroring of Si substrates relative to the flat AAO substrates and uneven AAO frontages. Our work is a breakthrough for the broad research field of surface nano-masking. PMID- 28071591 TI - High throughput micropatterning of interspersed cell arrays using capillary assembly. AB - A novel technology is reported to immobilize different types of particles or cells on a surface at predefined positions with a micrometric precision. The process uses capillary assembly on arrays of crescent-shaped structures with different orientations. Sequential assemblies in different substrate orientations with different types of particles allow for the creation of imbricated and multiplexed arrays. In this work up to four different types of particles were deterministically localized on a surface. Using this process, antibody coated microparticles were assembled on substrates and used as capture patterns for the creation of complex cell networks. This new technology may have numerous applications in biology, e.g. for fast cell imaging, cell-cell interactions studies, or construction of cell arrays. PMID- 28071592 TI - Development and evaluation of zinc phthalocyanine nanoemulsions for use in photodynamic therapy for Leishmania spp. AB - Photodynamic therapy (PDT) combines light with photosensitizers (PS) for production of reactive oxygen species (ROS) that can kill infectious microorganisms such as bacteria, fungi and protozoa. The application of nanotechnology has enabled the advancement of PDT because many PS are insoluble in water, necessitating a nanocarrier as a physiologically acceptable carrier. Nanoemulsions are efficient nanocarriers for solubilizing liposoluble drugs, like the PS, in water. Cutaneous (CL) and mucocutaneous leishmaniasis (ML) are caused by different species of the genus Leishmania, transmitted to humans by sandfly bites. Parasites are hosted in skin macrophages producing ulcerative lesions. Thus, a topical treatment, effective and inexpensive, for CL and ML is preferable to systemic interventions. There are topical treatments like paromomycin and amphotericin B, but they have many local side effects or a very high cost, limiting their use. This work aimed to develop a zinc phthalocyanine (photosensitizer) oil-in-water nanoemulsion, essential clove oil and polymeric surfactant (Pluronic(r) F127) for the formulation of a topical delivery system for use in PDT against Leishmania amazonensis and Leishmania infantum. The nanoemulsion was produced by a high-energy method and characterized by size, polydispersity, morphology, pH, content and stability studies. The toxicity in the dark and the photobiological activity of the formulations were evaluated in vitro for Leishmania and macrophages. The formulation presented was pH compatible with topical use, approximately 30 nm in size, with a polydispersity index <=0.1 and remained stable at room and refrigerator temperature during the stability study (60 days). The zinc phthalocyanine nanoemulsion is effective in PDT against Leishmania spp.; use against skin infections can be a future application of this topical formulation, avoiding the use of oral or injectable medications, decreasing systemic adverse effects. PMID- 28071593 TI - A lightweight feedback-controlled microdrive for chronic neural recordings. AB - OBJECTIVE: Chronic neural recordings have provided many insights into the relationship between neural activity and behavior. We set out to develop a miniaturized motorized microdrive that allows precise electrode positioning despite possibly unreliable motors. APPROACH: We designed a feedback-based motor control mechanism. It contains an integrated position readout from an array of magnets and a Hall sensor. MAIN RESULTS: Our extremely lightweight (<1 g) motorized microdrive allows remote positioning of both metal electrodes and glass pipettes along one motorized axis. Target locations can be defined with a range of 6 mm and they can be reached within 1 um precision. The incorporated headstage electronics are capable of both extracellular and intracellular recordings. We include a simple mechanism for repositioning electrodes in three dimensions and for replacing them during operation. We present neural data from different premotor areas of adult and juvenile zebra finches. SIGNIFICANCE: Our findings show that feedback-based microdrive control requires little extra size and weight, suggesting that such control can be incorporated into more complex multi electrode designs. PMID- 28071594 TI - First-principles study of the mechanism of wettability transition of defective graphene. AB - Hydrophobicity of graphene limits its application potential in polar media, therefore modifications of graphene wettability have been in an area of active research for many years. Recently, a reversible wettability transition of graphene has been reported (Xu et al 2014 Sci. Rep. 4 6450). The presence of undercoordinated carbon atoms in otherwise hydrophobic graphene is believed to trigger the hydrophobic to hydrophilic transition, but the underlying mechanism, especially of the reverse process, remained unclear. Using density functional theory with range-separated hybrid functional HSE06, we investigate the dissociative adsorption of up to two water molecules on the defective graphene layer containing odd number of missing lattice atoms. We show, that depending on the defect type either a full dissociation of the water molecule or a partial splitting of H2O to OH and H takes place leading to the saturation of graphene dangling bonds due to the formation of oxiranes or by hydroxyls, respectively. The dissociation barriers are significantly lower for the water dimer than for the single molecule. Our findings providing detailed insights into the remarkable differences between the reactivity of vacancy defects with water shed new light on the wettability-transition mechanism of defective graphene. PMID- 28071595 TI - Hybrid 3D-2D printing for bone scaffolds fabrication. AB - It is a well-known fact that bone scaffold topography on micro- and nanometer scale influences the cellular behavior. Nano-scale surface modification of scaffolds allows the modulation of biological activity for enhanced cell differentiation. To date, there has been only a limited success in printing scaffolds with micro- and nano-scale features exposed on the surface. To improve on the currently available imperfect technologies, in our paper we introduce new hybrid technologies based on a combination of 2D (nano imprint) and 3D printing methods. The first method is based on using light projection 3D printing and simultaneous 2D nanostructuring of each of the layers during the formation of the 3D structure. The second method is based on the sequential integration of preliminarily created 2D nanostructured films into a 3D printed structure. The capabilities of the developed hybrid technologies are demonstrated with the example of forming 3D bone scaffolds. The proposed technologies can be used to fabricate complex 3D micro- and nanostructured products for various fields. PMID- 28071596 TI - 3D bioprinting of GelMA scaffolds triggers mineral deposition by primary human osteoblasts. AB - Due to its relatively low level of antigenicity and high durability, titanium has successfully been used as the major material for biological implants. However, because the typical interface between titanium and tissue precludes adequate transmission of load into the surrounding bone, over time, load-bearing implants tend to loosen and revision surgeries are required. Osseointegration of titanium implants requires presentation of both biological and mechanical cues that promote attachment of and trigger mineral deposition by osteoblasts. While many factors contribute to differentiation, the relative importance of the various cues is unclear. To substantially improve osseointegration of titanium implants, we generated a gelatin methacryloyl (GelMA) scaffold, using an extrusion-based 3D bioprinter, which can be directly printed on and grafted to the titanium implant surface. We demonstrate that this scaffold is able to trigger mineral deposition of both MG63 osteoblasts and primary normal human osteoblasts in the absence of any exogenous osteogenic factors. Films of the same formulation failed to promote mineral deposition suggesting that the three dimensional scaffold was able to tip the balance in favor of differentiation despite other potentially unfavorable differentiation cues of the material. We further show that these GelMA lattices can be directly grafted to titanium alloy and are secure in vitro over a period of seven weeks. When grafted within a groove system, the GelMA hydrogel is protected from shearing forces in a marrow implantation model. This prepares the way for osteogenic coatings to be directly manufactured on the implant surface and packaged for surgery. PMID- 28071597 TI - Three-dimensional printing of a microneedle array on personalized curved surfaces for dual-pronged treatment of trigger finger. AB - The hand function of patients who suffer from trigger finger can be impaired by the use of traditional splints. There is also a risk of systemic side effects with oral non-steroidal anti-inflammatory drugs (NSAIDs) used for pain relief. Microneedle-assisted transdermal drug delivery offers an attractive alternative for local delivery of NSAIDs. However, traditional microneedle arrays fabricated on flat surfaces are unable to deliver drugs effectively across the undulating skin surface of affected finger(s). In this study, using 3D printing, a dual function microneedle array has been fabricated on personalized curved surfaces (microneedle splint) for drug delivery and splinting of the affected finger. The novel microneedle splint was assessed for its physical characteristics and the microneedles were shown to withstand up to twice the average thumb force without fracturing. An average skin penetration efficiency of 64% on dermatomed human cadaver skin was achieved and the final microneedle splint showed biocompatibility with human dermal cell lines. A significantly higher amount of diclofenac permeated through the skin by 0.5 h with the use of the microneedle splint as compared to intact skin. The fabricated microneedle splint can thus be a potential new approach to treat trigger finger via personalized splinting without affecting normal hand function. PMID- 28071598 TI - Extended Majorana zero modes in a topological superconducting-normal T-junction. AB - We investigate the sub gap properties of a three terminal Josephson T-junction composed of topologically superconducting wires connected by a normal metal region. This system naturally hosts zero energy Andreev bound states which are of self-conjugate Majorana nature and we show that they are, in contrast to ordinary Majorana zero modes, spatially extended in the normal metal region. If the T junction respects time-reversal symmetry, we show that a zero mode is distributed only in two out of three arms in the junction and tuning the superconducting phases allows for transfer of the mode between the junction arms. We further provide tunneling conductance calculations showing that these features can be detected in experiments. Our findings suggest an experimental platform for studying the nature of spatially extended Majorana zero modes. PMID- 28071599 TI - Unsupervised frequency-recognition method of SSVEPs using a filter bank implementation of binary subband CCA. AB - OBJECTIVE: Recently developed effective methods for detection commands of steady state visual evoked potential (SSVEP)-based brain-computer interface (BCI) that need calibration for visual stimuli, which cause more time and fatigue prior to the use, as the number of commands increases. This paper develops a novel unsupervised method based on canonical correlation analysis (CCA) for accurate detection of stimulus frequency. APPROACH: A novel unsupervised technique termed as binary subband CCA (BsCCA) is implemented in a multiband approach to enhance the frequency recognition performance of SSVEP. In BsCCA, two subbands are used and a CCA-based correlation coefficient is computed for the individual subbands. In addition, a reduced set of artificial reference signals is used to calculate CCA for the second subband. The analyzing SSVEP is decomposed into multiple subband and the BsCCA is implemented for each one. Then, the overall recognition score is determined by a weighted sum of the canonical correlation coefficients obtained from each band. MAIN RESULTS: A 12-class SSVEP dataset (frequency range: 9.25-14.75 Hz with an interval of 0.5 Hz) for ten healthy subjects are used to evaluate the performance of the proposed method. The results suggest that BsCCA significantly improves the performance of SSVEP-based BCI compared to the state of-the-art methods. The proposed method is an unsupervised approach with averaged information transfer rate (ITR) of 77.04 bits min-1 across 10 subjects. The maximum individual ITR is 107.55 bits min-1 for 12-class SSVEP dataset, whereas, the ITR of 69.29 and 69.44 bits min-1 are achieved with CCA and NCCA respectively. SIGNIFICANCE: The statistical test shows that the proposed unsupervised method significantly improves the performance of the SSVEP-based BCI. It can be usable in real world applications. PMID- 28071600 TI - A brief history of the multiverse. AB - The theory of the inflationary multiverse changes the way we think about our place in the world. According to its most popular version, our world may consist of infinitely many exponentially large parts, exhibiting different sets of low energy laws of physics. Since these parts are extremely large, the interior of each of them behaves as if it were a separate universe, practically unaffected by the rest of the world. This picture, combined with the theory of eternal inflation and anthropic considerations, may help to solve many difficult problems of modern physics, including the cosmological constant problem. In this article I will briefly describe this theory and provide links to the some hard to find papers written during the first few years of the development of the inflationary multiverse scenario. PMID- 28071601 TI - Applications of nuclear physics. AB - Today the applications of nuclear physics span a very broad range of topics and fields. This review discusses a number of aspects of these applications, including selected topics and concepts in nuclear reactor physics, nuclear fusion, nuclear non-proliferation, nuclear-geophysics, and nuclear medicine. The review begins with a historic summary of the early years in applied nuclear physics, with an emphasis on the huge developments that took place around the time of World War II, and that underlie the physics involved in designs of nuclear explosions, controlled nuclear energy, and nuclear fusion. The review then moves to focus on modern applications of these concepts, including the basic concepts and diagnostics developed for the forensics of nuclear explosions, the nuclear diagnostics at the National Ignition Facility, nuclear reactor safeguards, and the detection of nuclear material production and trafficking. The review also summarizes recent developments in nuclear geophysics and nuclear medicine. The nuclear geophysics areas discussed include geo-chronology, nuclear logging for industry, the Oklo reactor, and geo-neutrinos. The section on nuclear medicine summarizes the critical advances in nuclear imaging, including PET and SPECT imaging, targeted radionuclide therapy, and the nuclear physics of medical isotope production. Each subfield discussed requires a review article unto itself, which is not the intention of the current review; rather, the current review is intended for readers who wish to get a broad understanding of applied nuclear physics. PMID- 28071602 TI - Microgrooved topographical surface directs tenogenic lineage specific differentiation of mouse tendon derived stem cells. AB - Tendon derived stem cells (TDSCs) are the endogenous cell source for tenocyte turnover and tendon functional maintenance. They are also the important cell source for tendon engineering and regeneration. In addition, TDSCs also play an important role in tendinopathy via their non-tenogenic lineage differentiation. It has been well demonstrated that cell shape could determine mesenchymal stem cell (MSC) lineage differentiation. In this study, a parallel microgrooved polydimethylsiloxane (PDMS) membrane (10 um groove width and 3 um depth) was employed to investigate the role of cell elongation via this particular topographic surface in directing murine TDSC (mTDSC) lineage differentiation. The results showed that elongated mTDSCs exhibited significantly enhanced the gene expression of tenogenic markers when compared to the spread cells that grew on smooth PDMS membrane including tenomodulin, scleraxis, collagens I, III, and VI, decorin and tenascin (p < 0.05). Meanwhile, stemness related genes such as Nanog, Sox2 and Oct4 were significantly inhibited for their expression in elongated mTDSCs (p < 0.05). When under tri-lineage induced differentiation, cell elongation significantly inhibited mTDSC differentiation towards chondrogenic and adipogenic lineages (p < 0.05). Furthermore, cell elongation could significantly inhibit mTDSC osteogenic lineage differentiation (p < 0.05) induced by BMP-2, a tendinopathy mimicking stimulant. In conclusion, simulation of native tendon structure via using parallel microgrooved topography can promote mTDSC differentiation specifically towards tenogenic lineage and prevent non tenogenic lineage differentiation, providing an insight into the design of tendon regenerative materials. PMID- 28071603 TI - Heterogeneous nucleation of catalyst-free InAs nanowires on silicon. AB - We report on the heterogeneous nucleation of catalyst-free InAs nanowires on Si(111) substrates by chemical beam epitaxy. We show that nanowire nucleation is enhanced by sputtering the silicon substrate with energetic particles. We argue that particle bombardment introduces lattice defects on the silicon surface that serve as preferential nucleation sites. The formation of these nucleation sites can be controlled by the sputtering parameters, allowing the control of nanowire density in a wide range. Nanowire nucleation is accompanied by unwanted parasitic islands, but careful choice of annealing and growth temperature allows us to strongly reduce the relative density of these islands and to realize samples with high nanowire yield. PMID- 28071604 TI - Anion exchange strategy to synthesis of porous NiS hexagonal nanoplates for supercapacitors. AB - A facile anion exchange strategy was applied to the synthesis of porous NiS hexagonal nanoplates (NiS HNPs) as an electrode material for supercapacitors. It was found that Na2S concentration is a key factor to achieve porous NiS hexagonal nanoplates with well-defined architecture. Porous NiS hexagonal nanoplates exhibited a specific capacitance of 1897 F g-1 at a current density of 1 A g-1. NiS HNPs//activated carbon (AC) asymmetric supercapacitor (ASC) shows a long cycle lifespan (about 100% capacity retention after 4000 cycles at a current density of 3 A g-1) with a maximum energy density of 11.6 Wh kg-1 at a large loading mass of about 30 mg. Impressively, two NiS HNPs//AC ASCs in series could light up a red LED for about 30 min. The remarkable electrochemical performance of NiS HNPs is ascribed to their unique hierarchical porous architectures. The anion exchange method is a facile and versatile strategy for the synthesis of metal sulfides with high performance for energy storage. PMID- 28071605 TI - Eraser-based eco-friendly fabrication of a skin-like large-area matrix of flexible carbon nanotube strain and pressure sensors. AB - This paper reports a new type of electronic, recoverable skin-like pressure and strain sensor, produced on a flexible, biodegradable pencil-eraser substrate and fabricated using a solvent-free, low-cost and energy efficient process. Multi walled carbon nanotube (MWCNT) film, the strain sensing element, was patterned on pencil eraser with a rolling pin and a pre-compaction mechanical press. This induces high interfacial bonding between the MWCNTs and the eraser substrate, which enables the sensor to achieve recoverability under ambient conditions. The eraser serves as a substrate for strain sensing, as well as acting as a dielectric for capacitive pressure sensing, thereby eliminating the dielectric deposition step, which is crucial in capacitive-based pressure sensors. The strain sensing transduction mechanism is attributed to the tunneling effect, caused by the elastic behavior of the MWCNTs and the strong mechanical interlock between MWCNTs and the eraser substrate, which restricts slippage of MWCNTs on the eraser thereby minimizing hysteresis. The gauge factor of the strain sensor was calculated to be 2.4, which is comparable to and even better than most of the strain and pressure sensors fabricated with more complex designs and architectures. The sensitivity of the capacitive pressure sensor was found to be 0.135 MPa-1.To demonstrate the applicability of the sensor as artificial electronic skin, the sensor was assembled on various parts of the human body and corresponding movements and touch sensation were monitored. The entire fabrication process is scalable and can be integrated into large areas to map spatial pressure distributions. This low-cost, easily scalable MWCNT pin-rolled eraser-based pressure and strain sensor has huge potential in applications such as artificial e-skin in flexible electronics and medical diagnostics, in particular in surgery as it provides high spatial resolution without a complex nanostructure architecture. PMID- 28071606 TI - A non-healing oral ulcer as a manifestation of systemic tuberculosis in an immunocompetent man. PMID- 28071607 TI - Oral involvement in disseminated superficial porokeratosis. PMID- 28071608 TI - Necrobiosis lipoidica developing within a surgical scar in a non-diabetic patient: Type III Koebner phenomenon (isomorphic response), Wolf's isotopic response or Ruocco's immunocompromised cutaneous district? PMID- 28071609 TI - Verrucous eccrine angiomatous hamartoma. PMID- 28071610 TI - Importance of nutrition in pediatric oncology. PMID- 28071611 TI - Microsomal epoxide hydrolase gene polymorphisms and susceptibility to prostate cancer: A systematic review. AB - Microsomal epoxide hydrolase (mEH) is a crucial biotransformation enzyme that has capability to metabolize a large number of structurally divergent, highly reactive epoxides, and numerous environmentally exposed carcinogens. It catalyzes the conversion of xenobiotic epoxide compounds into more polar diol metabolites and may play important part of the enzymatic defense against adverse effects of foreign compounds. Most commonly, two functional polymorphisms affecting mEH enzyme activity have been identified: One in exon 3 and other in exon 4 of the mEH gene, which results in His113Tyr and Arg139His amino acid substitutions, respectively. Recent reports have shown that polymorphisms in mEH gene loci may an important risk factor for susceptibility of prostate cancers (PCs), worldwide, but inconsistent finding were also be illustrated. To the best of our knowledge, globally, there is no any systematic review has been published related to mEH gene polymorphisms and PC risk. Thus, in the current review, we have discussed the association between mEH gene polymorphisms, gene-environmental interaction, and PC risk. PMID- 28071612 TI - Expression of Raf kinase inhibitor protein in human hepatoma tissues by two dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight methods. AB - PURPOSE: Hepatocellular carcinoma (HCC) is the most common malignant liver tumor. To reduce the mortality and improve the effectiveness of therapy, it is important to search for changes in tumor-specific biomarkers whose function may involve in disease progression and which may be useful as potential therapeutic targets. Materials and Mehtods: In this study, we use two-dimensional polyacrylamide gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of flight mass spectrometry to observe proteome alterations of 12 tissue pairs isolated from HCC patients: Normal and tumorous tissue. Comparing the tissue types with each other, 40 protein spots corresponding to fifteen differentially expressed between normal and cancer part of HCC patients. RESULTS: Raf kinase inhibitor protein (RKIP), an inhibitor of Raf-mediated activation of mitogen activated protein kinase/extracellular signal-regulated kinase, may play an important role in cancer metastasis and cell proliferation and migration of human hepatoma cells. RKIP may be considered as a marker for HCC, because its expression level changes considerably in HCC compared with normal tissue. In addition, we used the methods of Western blotting and real time-polymerase chain reaction to analysis the protein expression and gene expression of RKIP. The result showed RKIP protein and gene expression in tumor part liver tissues of HCC patient is lower than peritumorous non-neoplastic liver tissue of the corresponding HCC samples. CONCLUSION: These results strongly suggest that RKIP may be considered to be a marker for HCC and RKIP are down-regulated in liver cancer cell. PMID- 28071613 TI - Clinical and pathologic response following taxane based neoadjuvant chemotherapy in locally advanced breast cancer patients in a tertiary care centre in India. AB - BACKGROUND: Neoadjuvant chemotherapy has become the standard recommendation in the management of patients with locally advanced breast cancer. At present anthracycline based regimen such as CAF (cyclophosphamide, adriamycin and 5-FU) is widely used in clinical practice. The introduction of taxanes has revolutionized this field because of superior results. AIMS AND OBJECTIVES: This study is designed to compare the efficacy of paclitaxel plus doxorubicin regimen and CAF (cyclophosphamide, doxorubicin and 5-fluorouracil) regimen as neoadjuvant treatment of locally advanced breast cancer and to compare their toxicity profiles and also to correlate the hormonal receptor status in predicting response to the NACT. MATERIALS AND METHODS: In this prospective study, 101 patients with newly diagnosed locally advanced breast cancer were randomized to receive either CAF or Paclitaxel/adriamycin as NACT for three cycles. The response was assessed objectively using CT scans and applying RECIST criteria. The patients were monitored for hematologic, cardiac and other minor toxicities. RESULTS: There was a significantly increased complete and objective response seen in the AP group when compared to CAF group (24% and 58% in the AP group versus 7.8% and 39.2% in the CAF group, P value 0.0313 for complete response). The pCR rate was also significantly higher in the AP group compared to CAF group. (20.93% versus 4.34%, P value 0.0237). There was no significant difference between the groups with respect to cardiotoxicity and hematotoxicity. Patients with ER negative tumors have responded well to neoadjuvant chemotherapy better than ER positive patients. (Objective response 62.8% vs. 40%, P - 0.0473). CONCLUSIONS: Based on these results, taxane based regimen such as Paclitaxel/adriamycin can be recommended as a first line neoadjuvant regimen in patients with locally advanced breast cancer. PMID- 28071614 TI - In silico analysis to predict lack of carcinogenicity of Zika virus. PMID- 28071615 TI - Knowledge, attitude and practice about breast cancer and breast self-examination among women seeking out-patient care in a teaching hospital in central India. AB - BACKGROUND: Breast cancer (BC) continues to be a major cause of morbidity and mortality throughout the world. Early detection of BC and early treatment increases the chance of survival. According to Breast Health Global Initiative guidelines for low and middle income countries, diagnosing BCs early by promoting breast self-awareness; clinical breast examination (CBE) and resource adapted mammographic screening will reduce BC mortality. There is a paucity of data on the knowledge and awareness of BC and self-breast examination in India. We designed this hospital based cross sectional descriptive study to evaluate the current status of knowledge, awareness and practices related to BC and breast self-examination in the female rural population attending a teaching hospital. MATERIALS AND METHODS: We did a random sampling to identify and enroll 360 women and their female relatives. We excluded a participant from the study if she had already undergone a screening mammography or had had a BC. The data was collected by a self-administered questionnaire in vernacular language. RESULTS: Our study population included 360 women with a mean age of 45.81 (+/-10.9) years. Only 5 (1.38%) females had a family history of BC. A whopping 81% of women did not have any knowledge about BC. All the women thought that CBE by doctors was the only way for screening BC. CONCLUSIONS: We concluded that with the results of this study, it is imperative to increase awareness about BC and its detection methods in the community through health education campaigns. We should have major policy changes to increase future screening programs and health education programs which would have an overall positive impact on reducing the disease burden. PMID- 28071616 TI - Presenting features, treatment patterns and outcomes of patients with breast cancer in Pakistan: Experience at a university hospital. AB - BACKGROUND: Breast cancer is the most common cancer in Pakistani women. We report the presenting features, treatment patterns and survival of breast cancer from a University Hospital in Southern Pakistan and compare the data with international population based studies. MATERIALS AND METHODS: Medical records of patients diagnosed to have breast cancer between January 1999 and November 2008 were reviewed retrospectively. RESULTS: A total of 845 patients were identified. Median age of diagnosis was 48 years (range 18-92). Clinical stage was as follows: Stage I 9.9%; Stage II 48.5%; Stage III 26.2%; Stage IV 13.8%; data not available 1.5%. Approximately, half (51.6%) were estrogen receptor (ER) positive and 17.5% over-expressed Her2/neu. Nearly 23% patients received neo-adjuvant chemotherapy while 68.9% received adjuvant chemotherapy. Anthracycline based treatment was the most common treatment until 2003 while later on, patients also received taxanes and trastuzumab based therapy. Age, stage, tumor size, lymph node status, tumor grade, ER status, treatment with hormonal therapy and radiation were the major predictive factors for overall survival (OS). We report an impressive 5 year OS of 75%, stage specific survival was 100%, 88% and 58% for Stages I, II and III respectively. CONCLUSION: The majority of patients present at a younger age and with locally advanced disease. However, short term follow-up reveals that the outcomes are comparable with the published literature from developed countries. Long-term follow-up and inclusion of data from population based registries are required for accurate comparison. PMID- 28071617 TI - Role of frozen section in the intra-operative margin assessment during breast conserving surgery. AB - BACKGROUND: Breast conserving surgery (BCS) is increasingly done for early breast cancers in many countries since it has been demonstrated by randomized trials that survival rates after BCS followed by adjuvant therapy are equivalent to those obtained after mastectomy. Frozen section analyses (FSA) is a technique used for intra-operative assessment of margin status in BCS. The aim of this study was to assess the concordance of margin status assessment by FSA and permanent sections and to assess correlation with local recurrence. MATERIALS AND METHODS: A total of 162 patients underwent BCS for in situ or invasive carcinoma with FSA of margins during the year 2008 at our center. The inclusion criteria in this study were patients with intact tumor at the time of surgery. After application of the inclusion criteria, 60 patients could be included in this study. RESULTS: After frozen section, 20 patients had an initial negative margin. 40 subjects underwent additional excisions at the time of initial surgery because of close or positive margins. Of these 40 patients, in 32 patients a negative margin could be achieved with re-excisions. Pathological analyses of frozen section showed concordance to permanent sections in all cases. At a median follow up of 40 months, there were no local recurrences. CONCLUSION: Intra-operative FSA allows resection of suspicious margins at the time of primary conservative surgery and results in low rates of local recurrence and second surgeries. There is good concordance between results of FSA and the final paraffin section in assessing margin status. PMID- 28071619 TI - Role of regional catheters for postoperative analgesia following reconstructive surgeries for breast cancer. PMID- 28071618 TI - Clinico-pathological factors affecting lymph node yield in Indian patients with locally advanced squamous cell carcinoma of mandibular Gingivo-Buccal sulcus. AB - AIM: Lymph node yield (LNY) is a valid marker of prognosis in oral cancer. Precise estimation of LNY in Indian patients with T3/T4 gingivobuccal sulcus squamous cell carcinoma (GBS-SCC) has not been well documented. Hence, the primary objective of the study was to determine the LNY in patients with T3/T4 SCC of mandibular GBS, and the secondary objective was to study the association of LNY with clinicopathological factors such as tumor thickness, histological differentiation, number of positive nodes, and extracapsular spread (ECS). MATERIALS AND METHODS: Study patients comprised biopsy proven T3/T4 SCC of mandibular GBS that underwent unilateral surgery (composite or bite composite resection with level I to level V-neck dissection and pectoralis major flap reconstruction) at our center between January 2012 and October 2014. Grossing of surgical specimens was done as per the guidelines established by the Royal College of Pathologists (December 2009). The data were analyzed using SPSS software (22nd version) and Chi-square test. RESULTS: The surgical specimens of 106 patients yielded 2329 lymph nodes with the mean LNY of 21.97 +/- 5.57. Higher mean LNY of over 21 was significantly associated with ECS, number of positive nodes, delay in surgery over 15 days, skin involvement by the tumor, and presence of oral potentially malignant disorders. CONCLUSION: With the single surgeon, pathologist and same surgical procedure, the mean LNY in Indian patients with T3/T4 SCC of mandibular GBS is 21.97 +/- 5.57. Although clinicopathological factors affect the estimation of LNY, further studies are needed to validate the findings of this study. PMID- 28071620 TI - Squamous cell carcinoma of the oral cavity and oropharynx in patients aged 18-45 years: A case-control study to evaluate the risk factors with emphasis on stress, diet, oral hygiene, and family history. AB - BACKGROUND: Increasing incidence of squamous cell carcinoma (SCC) of the oral cavity and oropharynx is reported in young adults. However, there is a paucity regarding etiology and risk factors. AIM: To evaluate the exposure potential carcinogenic factors among a sample aged 45 years and younger, diagnosed with SCC of the oral cavity and oropharynx. METHODOLOGY: Eighty-five case samples aged 18 45 years, diagnosed with SCC of the oral cavity and oropharynx were compared with 85 controls who had never had cancer, matched for age and sex. This study was conducted by questionnaire-based interviews. Questionnaire contained items about exposure to the following risk factors: Caries prevalence, oral hygiene status, dental trauma, dental visit, stress, family history of cancer, environmental exposure to potential carcinogens, diet, body mass index (BMI), habits such as smoking, tobacco chewing, betel quid/pan, or supari. STATISTICAL ANALYSIS: Odds ratios (ORs) of oral and pharyngeal cancer and the corresponding 95% confidence intervals were estimated using multiple logistic regression models. P< 0.05 was considered statistically significant. RESULTS: Elevated OR was seen in young adults who had poor oral hygiene, stress, dental trauma, low BMI, family history of cancer, exposure to environmental carcinogens, and habit of placement of quid for 11-20 years. CONCLUSIONS: An increased risk of oral and pharyngeal cancer was seen in cases who had poor oral hygiene, stress, dental trauma, low BMI, family history of cancer, exposure to environmental carcinogens, and habit of placement of quid. PMID- 28071621 TI - Assessment of the sociodemographic characteristics and efficacy of screening for oral, head and neck potential malignant lesions in apparently healthy adults in Jos Nigeria. AB - BACKGROUND: The efficacy of screening for oral, head and neck cancers (HNCs) in adequately identifying high-risk groups is controversial. OBJECTIVES: This study aims to review our experience with a free oral, HNC-screening program to determine the sociodemographic characteristics of the participants and the effectiveness of this program to improve future programs. MATERIALS AND METHODS: A prospective cross-sectional survey of participants in a free oral, HNC screening exercise was performed in the years 2009, 2012, and 2013. RESULTS: In the years of screening, 135 participants presented aged between 21 and 83 years (mean = 47.0; +/-15.6) with a male to female ratio of 1.2:1. 32.6% consumed alcohol, and 17.8% were smokers. Smoking (P = 0.04) and alcohol use (P = 0.05) were associated with higher rates of suspicious malignant symptoms. There was no statistical correlation between symptom prevalence and the number of participants requiring immediate consultation for oral, HNC (r = 0.47), and those referred for routine follow-up (r = 0.34). Premalignant and malignant lesions were diagnosed in 5 males aged 44-72 years. 83.7% found the screening program beneficial in increasing their awareness of the disease. CONCLUSIONS: This hospital-based screening demonstrates improved awareness among people about oral, HNCs, and survival outcomes on a small scale. A community-based screening with health education to target a larger high-risk population is recommended to encourage individuals to modify high-risk factors and improve outcomes. PMID- 28071622 TI - Oral health-related quality of life after prosthetic rehabilitation in patients with oral cancer: A longitudinal study with the Liverpool Oral Rehabilitation Questionnaire version 3 and Oral Health Impact Profile-14 questionnaire. AB - BACKGROUND: Prosthodontic rehabilitation helps to improve the oral health-related quality of life (OHRQOL). The Liverpool Oral Rehabilitation Questionnaire (LORQ) and Oral Health Impact Profile (OHIP) are specific tools that measure OHRQOL. OBJECTIVE: The primary objective of this study was to assess the impact of oral rehabilitation on patients' OHRQOL following treatment for cancer of oral cavity using LORQ version 3 (LORQv3) and OHIP-14 questionnaire. Secondary objectives were to identify issues specific to oral rehabilitation, patients compliance to prosthetic rehabilitation, the effect of radiation treatment on prosthetic rehabilitation, to achieve meaningful differences over a time before & after prosthetic intervention, to carryout and document specific patient-deprived problem. METHODOLOGY: Seventy-five oral cancer patients were studied. Patients were asked to rate their experience of dental problems before fabrication of prosthesis and after 1 year using LORQv3 and OHIP-14. The responses were compared on Likert scale. RESULTS: Patients reported with extreme problems before rehabilitation. After 1 year of prosthetic rehabilitation, there was improvement noticed in all the domain of LORQv3 and OHIP-14. Complete compliance to the use of prosthetic appliances for 1 year study period was noted. In response to the question no. 40 (LORQv3), only 15 patients who belonged to the obturator group, brought to notice the problems which were not addressed in the LORQv3 questionnaire. CONCLUSION: The study showed that the oral cancer patients coped well and adapted to near normal oral status after prosthetic rehabilitation. This contributed to the improved overall health-related quality of life. PMID- 28071623 TI - Differentiated thyroid cancer in Iran - initial observations, histological features, management of the disease, and tumor recurrence: A review of 1689 cases. AB - AIM: The main objective of this study was to define some histopathological aspects of differentiated thyroid cancer (DTC), describe the disease management, and evaluate potential predicting factors for tumor recurrence in Iran. MATERIALS AND METHODS: Medical records of 1689 patients of DTC treated over a 15-year period at a referral hospital located in the central region of Iran were reviewed retrospectively. RESULTS: The female/male ratio was 3.78. The mean size of tumors was 23.35 mm. Most patients had papillary thyroid cancer (PTC) followed by follicular thyroid cancer (FTC) (83% and 5.5%, respectively). Lymph node involvement was seen in 27.6% of patients, and 3.6% of them had distant metastasis. Tumor recurrence was reported in 36.4% of patients. Higher stages of cancer, presence of lymph node involvement, presence of distant metastasis, larger tumor size, history of goiter, and higher doses of 131-Iodine at the first admission were associated with more chance of recurrence (P < 0.05). Comparing features of PTC and FTC, we found a more invasive behavior in FTC patients, including more capsular and near tissue invasion, higher stages of cancer, more frequent distant metastasis, and larger tumor size. CONCLUSION: This study provides useful information on characteristics of DTC, its management, and some prognostic factors. Our findings suggest that higher stages of cancer at diagnosis, presence of lymph node involvement, presence of distant metastasis, larger tumor size, history of goiter, and higher doses of 131-iodine administered at the first admission are associated with more chance of tumor recurrence. Furthermore, we found that FTC follows a more aggressive behavior and recommends clinicians to handle FTC patients more cautiously. PMID- 28071624 TI - Comparison of two different radiation fractionation schedules with concurrent chemotherapy in head and neck malignancy. AB - INTRODUCTION: The worldwide incidence of head and neck malignancy exceeds half a million cases annually. In radiotherapy (RT), conventional fractionation comprises giving five fractions per week from Monday to Friday. Accelerated RT includes administration of six fractions per week is being advocated. It gives better locoregional control and the median overall treatment time is 39 days as compared to 46 days in conventional group. Our study involved comparison of conventional versus accelerated RT with concurrent chemotherapy, in evaluation of local control and toxicity in the two arms. MATERIALS AND METHODS: Sixty patients of locally advanced squamous cell carcinoma head and neck region were studied. All the patients received cisplatin (30 mg/m2) weekly during the therapy. The patients received RT dose of 70 Gray (Gy) in 35 fractions (#). The patients were randomly assorted into two groups: Group 1 - Study group (n = 30) - Six fractions RT per week (Monday-Saturday). Group 2 - Control group (n = 30) - Five fractions RT per week (Monday-Friday). During and after the treatment, locoregional control, acute and late radiation toxicity were assessed. Results and Observation: There was no significant difference between the two schedules regarding locoregional control rate. The Grade 3 or higher acute toxicities were significantly higher in the accelerated arm although there was no significant difference in late toxicities between the two arms. CONCLUSION: Accelerated fractionation regimen was not more efficacious than conventional fractionation in the treatment of previously untreated head and neck carcinoma. PMID- 28071625 TI - Thymic epithelial tumors: Can fluorodeoxyglucose positron emission tomography help in predicting histologic type and stage? AB - OBJECTIVES: To study the utility of fluorodeoxyglucose (FDG) positron emission tomography (PET) in predicting (1) the World Health Organization (WHO) histologic type and differentiating low-risk from high-risk types. (2) Tumor stage and differentiate early from advanced stage disease. MATERIALS AND METHODS: Patients with thymic epithelial neoplasia who underwent a pretreatment FDG-PET study were included. Tumor maximum standardized uptake value (SUVmax) was correlated with the WHO histologic type and also with the Masaoka-Koga (MK) staging system. Patients with WHO Type A, AB, and B1 were classified as low risk and those with B2 and B3 as high risk. Thymic carcinomas belonged to Type C. Patients with MK Stage I and II disease were grouped as early stage and those with Stage III and IV as an advanced stage. Differences in SUVmax between the various groups were calculated. RESULTS: The SUVmax of thymic carcinomas was significantly higher as compared to low-risk (P = 0.001) and high-risk groups (P = 0.007). The SUVmax of high-risk group was also significantly higher than the low-risk group (P = 0.002). SUVmax cutoff of 6.5 was able to differentiate thymic carcinomas from thymomas with 100% sensitivity and 87.2% specificity. The SUVmax in patients with advanced stage disease showed a higher trend compared to those with early stage, but the difference was not significant (P = 0.167). CONCLUSION: PET can differentiate thymic carcinomas from rest of the thymoma subtypes by the virtue of their higher FDG uptake. It can also provide valuable information in differentiating high-risk from low-risk thymomas and in predicting disease stage. PMID- 28071626 TI - Prognostic factors in postoperative radiotherapy in salivary gland carcinoma: A single institution experience from Turkey. AB - BACKGROUND: We reviewed clinical characteristics, treatment outcomes, local and distant failure and prognostic factors in patients with salivary gland carcinoma treated with surgery and postoperative radiotherapy. MATERIALS AND METHODS: We retrospectively reviewed 75 patients with salivary gland cancer. 69 (%92) patients had cancer of the parotid gland, 3 (%4) patients had cancer of the submandibular gland and 3 (%4) patients had cancer of the minor salivary gland. 4 patients underwent postoperative chemoradiotherapy and 71 patients underwent postoperative radiotherapy. Median radiotherapy dose was 60Gy (range, 30Gy to 69Gy). RESULTS: Median age was 59.6+/-17.9 (13-88) and the female/male ratio was 1/1.7. Median follow-up 52 months (2-228 months). The mean overall survival 69.2+/-8 (95%confidence interval[CI], 53.4-85.1) months. The 1-,3-,5- and 10- year overall survival rates were 79.8%, 53.2%, 37.4% and 22.8% respectively. The mean disease free survival 79.7+/-10 (95%CI, 60.1-99.3) months. The 1-,3-,5- and 10- year disaese free survival rates were 72.8%, 51.9%, 44.1% and 30.4% respectively. On multivariate analysis, the OS was significantly better for the female sex (hazard ratio[HR]:3,0;95%CI:1.5-5.6;P=0.001), absence of lymph node involvement ([HR]:3,0;95%CI:1.7-5.3;P=0.0001), lower tumor grade ([HR]:25,7;95%CI:3.3-199.3;P=0.002), negativity of the surgical margin ([HR]:2,3;95%CI:1.3-4.2;P=0.005), absence of lymphovasculer invasion ([HR]:2,6;95%CI:1.5-4.6;P=0.001), absence of extracapsuler extension ([HR]:6,5;95%CI:2.2-19.1;P=0.001), absence of perineural invasion ([HR]:4,8;95%CI:2.6-8.7;P=0.0001) and <=60Gy radiotherapy dose ([HR]:3,1;95%CI:1.7-5.5;P=0.0001). They observed local recurrens in17 (23%) patients and distant metastasis in 33 (44%) patients. CONCLUSIONS: Employing existing standards of postoperative radiotherapy is a possible treatment that was found to be effective mainly in patients with salivary gland carcinomas. PMID- 28071628 TI - An audit of cytoreductive surgeries in ovarian cancer from a rural based cancer center. AB - BACKGROUND AND OBJECTIVE: Ovarian cancers are frequently seen at an advanced stage in our center. This audit was planned to see the morbidity and efficacy of different types of cytoreductive surgeries (radical vs. ultra-radical) done in such patients. METHODS: This was a retrospective analysis of all ovarian cancer patients who underwent cytoreductive surgery at our center from January 2009 to August 2013. The case records of these patients were reviewed and the demographic, disease-related and treatment-related data were extracted. RESULTS: Fifty-fivepatients were identified. Ten (18.2%) patients underwent primary cytoreduction while 45 patients had (81.8%) interval cytoreduction. The resections achieved were optimal in 50 patients (90.9%) and suboptimal in five patients (9.1%). The postoperative median blood loss was 400 (350-600) mL. The median time interval for surgery was 4.0 h (3-5 h). The type of resection achieved (optimal vs. suboptimal) was the only factor affecting the progression free survival (PFS) (Hazard ratio = 0.08 95% confidence interval 0.02-0.3). There was no significant difference in postoperative morbidity in patients undergoing the ultra-radical surgery as compared to those who underwent radical surgery. CONCLUSION: Optimal cytoreduction may improve PFS in advanced ovarian cancer patients and needs to be done even if it mandates an ultra-radical surgery. PMID- 28071627 TI - Tolerance of weekly paclitaxel and carboplatin as neoadjuvant chemotherapy in advanced ovarian cancer patients who are unlikely to tolerate 3 weekly paclitaxel and carboplatin. AB - OBJECTIVE: There are little data regarding safety and effectiveness of neoadjuvant chemotherapy (NACT) in patients who are considered unfit for receiving 3 weekly paclitaxel and carboplatin. The aim of this study was to study the toxicity and response rates of weekly paclitaxel and carboplatin as NACT in such cohort of patients. METHODS: Study population included advanced ovarian cancer patients who were unlikely to tolerate 3 weekly paclitaxel and carboplatin and hence received weekly paclitaxel (80 mg/m2) and carboplatin AUC-2 as NACT. The data regarding the baseline characteristics, chemotherapy tolerance, completion rates, toxicity (CTCAE version 4.02), and radiological response rates are presented. SPSS version 16 was used for analysis. Descriptive statistics is presented. RESULT: Eleven patients received this schedule. Nine patients completed nine cycles of NACT. Except one, all patients completed NACT with an average relative dose intensity of >0.8. There was no chemotherapy-related mortality. Grade 3-4 life-threatening complications were seen in two patients. The post NACT response rate was 100%. CONCLUSION: Weekly paclitaxel and carboplatin chemotherapy is safe and efficacious in patients who are unsuitable for 3 weekly paclitaxel and carboplatin chemotherapy schedules. PMID- 28071629 TI - Clinical characteristics with patterns of relapse and survival analysis of ovarian clear cell carcinoma. AB - AIMS: To analyze clinical characteristics, patterns of relapse, and treatment outcomes of clearcell carcinoma of the ovary (CCO). MATERIALS AND METHODS: Case files of 51 patients diagnosed with CCO between 2003 and 2010 were reviewed. RESULTS: The median age at diagnosis was 48 years (27-64 years). Fifty percent presented with nonspecific gastrointestinal symptoms. The median serum Ca125 was 74 IU/ml (6-1567 U/ml). Optimal cytoreduction was achieved in 32 (62.7%) patients. Of the 51 patients in this series, 34 (66.6%) had Stage I disease; Stage Ia in 12 (23.6%), Stage Ib in 1(1.9%), and Stage Ic in 21 (41.1%). Thirteen (25.6%) presented with Stage III and 4 (7.8%) with Stage IV. No patient had Stage II disease. All patients received 4-6 cycles of platinum-based combination chemotherapy. There were 18 relapses (35.2%), with disease-free intervals <6 months in 9, 6-12 months in 4, and >12 months in 5, respectively. Of them 33.3% had a recurrent pelvic mass. The median survival after relapse was 14 months. There were 13 deaths, 11 due to disease progression, 1 due to chemo toxicity, and 1 unrelated to disease. At a median follow up of 28 months, disease-free survival (DFS) and overall survival (OS) of patients with Stage I-Stage II (early) disease was 64% and 80%, respectively. In patients with advanced disease, that is, Stages III and IV, DFS and OS were 35% and 38%, respectively. CONCLUSION: CCO generally presents at an early stage but has a high propensity for relapse. Patients with early-stage disease have a relatively good prognosis as compared with those with advanced-stage disease. PMID- 28071630 TI - Ovarian tumors in children: 10-year experience from a tertiary care center in South India. AB - BACKGROUND: Ovarian tumors are uncommon in childhood and constitute around 1% of childhood malignancies. Two thirds of pediatric ovarian tumors are germ cell tumors. Epithelial ovarian tumors and stromal tumors are less frequent. We share our experience in childhood ovarian cancers, analyzing a series of cases with respect to the clinical profile, treatment and survival. METHODS: All newly diagnosed ovarian tumors in children up to 14 years of age, registered in our Pediatric Oncology Division between January 2000 and December 2009 were retrospectively reviewed. OBSERVATIONS: There were 47 patients with newly diagnosed ovarian tumors. The mean age at presentation was 10.0 +/- 3.4 years. The most common symptoms at presentation were acute abdominal pain (48.9%) and abdominal mass (40.4%). Precocious puberty was uncommon (6.3%). Histology was germ cell tumors in 44 cases and nongerm cell tumors in three cases. The benign teratomas (mature and immature grade 1 and 2; n=9) underwent complete surgical resection alone; none had recurrence on follow up. Of the remaining 35 GCTs, 31 patients were given chemotherapy and 4 refused treatment.26 out of the 31 patients completed chemotherapy with BEP (bleomycin, etoposide, cisplatin) regimen with acceptable toxicities. 5 children i.e.; (19.2%) developed recurrence. At a median follow up of 80 months, 10 year disease free survival was 80.8 +/- 7.7% and 10 year overall survival was 92.7 +/- 4.9%. CONCLUSION: Germ cell tumors are the most common ovarian malignancy in children. With surgery and chemotherapy using BEP, good outcome can be expected in these patients. PMID- 28071631 TI - Profile of pancreatic tumors at a tertiary care center. AB - BACKGROUND: Pancreas, a relatively inaccessible organ, poses diagnostic difficulties with overlapping presentation among benign and malignant tumors. In the present study, pancreatic aspirates obtained by computed tomography (CT) guided procedures were used for cytodiagnosis. Our study aims at correlating clinical, cytological, biochemical, and histopathological results in obtaining a final diagnosis. METHODOLOGY: A retrospective study of 2 years was done which included 32 cases of pancreatic tumors at a tertiary care center. Patient data were retrieved and analyzed. RESULTS: Twenty-seven of the 32 (84.37%) cases were malignant tumors. Age distribution in malignant tumors was predominantly seen in the fourth to eighth decade, whereas in benign, it ranged in the second to third decade. Thirteen out of the 32 (40.62%) cases reported were females, with male:female ratio of 1.46:1. The most common presenting symptom was abdominal pain followed by jaundice and vomiting. Three of the 32 cases had visceral metastasis at the time of diagnosis. CT-guided aspirates in most cases yielded diagnostic material. Cytological and histopathological results concurred except for three cases. Cancer Antigen 19-9 was worked up for 14 of 27 malignant cases, 11 of which showed grossly elevated values (700-7000), and three cases showed mildly elevated values (100-300). Three of the four benign cases worked up for CA 19-9 showed normal values. CONCLUSIONS: Among the mass forming lesions in pancreas, malignancy was more common compared to benign tumors. A multidisciplinary approach in the assessment and diagnosis of pancreatic tumors yields accurate results in spite of the limitations faced in obtaining adequate samples by needle aspirates. PMID- 28071632 TI - Primary gastrointestinal lymphomas in children: An experience of 12 years from a tertiary care center of North India. AB - BACKGROUND AND AIM: Lymphomas are among the dominant solid tumors in children and primary gastrointestinal lymphomas (PGILs), although rare, are the most common extranodal lymphomas and the most common malignancies affecting the gastrointestinal tract in children. This study was undertaken to analyze childhood PGIL with reference to clinical presentation, anatomic distribution, histopathologic, and immunohistochemical (IHC) characteristics. MATERIALS AND METHODS: In this 12 year combined retrospective and prospective descriptive study, all the cases of PGIL in children were selected according to Dawson's criteria. RESULTS: A total of 11 cases were found which included 9 boys and 2 girls (male:female - 4.5:1) ranging in age from 1 to 14 years (mean 6.6 years). Abdominal pain (81.8%) and intestinal obstruction (63.6%) were the most common presenting features. Grossly, most of the lesions were ulcero-infiltrative (72.7%) and involved the terminal part of the ileum (36.4%) and ileocecal region (27.3%) most commonly. Histopathologically and IHC, all the cases were high-grade lymphomas of diffuse large B-cell type except for one case of mucosa-associated lymphoid tissue lymphoma. No case of Burkitt's lymphoma was found. CONCLUSION: PGILs are an important cause of morbidity and mortality in children worldwide with considerable variation in their clinicopathological features and treatment modalities. Only some studies are available in literature for comparison. Further studies are required to define the genetic and molecular basis of the different histopathological pattern found in our setting. PMID- 28071633 TI - Inadvertent intramuscular administration of vincristine in two pediatric patients with uneventful outcomes. PMID- 28071634 TI - Place of birth and risk of gallbladder cancer in India. AB - CONTEXT: Within India, the incidence of gallbladder cancer (GBC) is characterized by marked geographical variation; however, the reasons for these differences are unclear. AIMS: To evaluate the role of place of birth, length of residence, and effect of migration from high- to low-risk region on GBC development. SETTINGS AND DESIGN: Population-based cancer registries (PBCRs); case-control study. SUBJECTS AND METHODS: Data of PBCRs were used to demonstrate geographical variation in GBC incidence rates. A case-control study data examined the role of birth place, residence length, and effect of migration in etiology of GBC. STATISTICAL ANALYSIS: Rate ratios for different PBCRs were estimated using Chennai Cancer Registry as the reference population. Odds ratios (ORs) for developing GBC in a high-risk region compared to a low-risk region and associated 95% confidence interval (CI) were estimated through unconditional logistic regression models using case-control study. RESULTS: GBC shows marked variation in incidence with risk highest in Northeast regions and lowest in South India. OR of 4.82 (95% CI: 3.87-5.99) was observed for developing GBC for individuals born in a high-risk region compared to those born in a low-risk region after adjusting for confounders. A dose-response relationship with increased risk with increased length of residence in a high-risk region was observed (OR lifetime 5.58 [95% CI: 4.42-7.05]; Ptrend <= 0.001). The risk persisted even if study participant migrated from high- to low-risk region (OR = 1.36; 95% CI: 1.02-1.82). CONCLUSIONS: The present study signifies the importance of place of birth, length of stay, and effect of migration from high- to low-risk region in the development of GBC. The data indicate role of environmental and genetic factors in etiology of disease. PMID- 28071635 TI - Prognostic factors and 5-year survival of patients with carcinoma penis: Tertiary health center study. AB - CONTEXT: To identify prognostic factors in carcinoma penis with its impact on survival. AIMS: To find out the relation of various prognostic factors of carcinoma penis with the various outcomes. SETTINGS AND DESIGN: Retrospective cohort study. SUBJECTS AND METHODS: Each patient diagnosed as having carcinoma of penis by incision biopsy and operated from January 2004 to May 2009 at the institute was included in the study (n = 117). Data were collected and analyzed. STATISTICAL ANALYSIS USED: The Chi-square (chi2) test was used to test for the significance of association between the independent (predictor) and dependent (outcome) variables. Multivariate logistic regression analysis was used to determine predictor variables that predicted the outcome. Five year disease-free survival (DFS) and overall survival (OS) were calculated using the Kaplan-Meier method. RESULTS: Of the total 117 patients studied, 30 patients died within 5 years (median = 25 months). Recurrences (local or systemic) were seen in 23 patients (median = 14 months). Five-year DFS was 80.34% and OS was 72.22%. Kaplan Meier analysis showed that well to moderately differentiated grade, lymph node negative disease and low stage have higher survivals than poorly differentiated grade, lymph node positive disease and higher stage, respectively. Multiple logistic regression analysis revealed that inguinal lymph node positivity and grade were significantly associated with local or systemic recurrence. CONCLUSIONS: Penile cancer patients with advanced disease had poor survival. Tumor grade and inguinal lymph node metastasis are factors affecting DFS. Lymphadenectomy remains an integral part of the management of patients with penile cancer. PMID- 28071637 TI - Adrenocortical carcinoma in children and adults: Two decades experience in a single institution. AB - CONTEXT: Adrenocortical carcinoma (ACC) occurring in children and adults show distinct characteristics. However, due to rarity of the disease no large series addressing this issue has been published. AIMS: The aim of this study was to study clinico-pathologic profile and outcome of ACC in children and adults. SETTINGS AND DESIGN: Tertiary referral center. Retrospective study (January 1990 June 2011). SUBJECTS AND METHODS: Forty-five patients with ACC were included; 16children (aged < 18 years) and 29 adults. Clinical details, hormonal profile, operation records, pathology reports and follow-up findings were noted and compared. Survival analysis was performed using Kaplan-Meier method. Log rank test and Cox regressionan alysis were performed. RESULTS: Mean age was 8 +/- 5.7 (M: F = 1:2.1) in children and 44.4 +/- 15 years (M: F = 1:1.1) in adult groups. Prevalence of functioning tumors was significantly high in children (87.5 vs. 31% P = 0.001), while prevalence of incidentalomas was high in adults (6.3 vs. 51.7% P = 0.05). Tumor stage distribution at presentation, mean diameter (10.9 vs. 13.7 cm), and weight (392.9 vs. 892.9 g) didn't differ significantly in two groups. Adults had better albeit non-significant 5 year overall survival (OS) than children (0 vs. 13%). On univariate analysis stage of disease (P = 0.008), surgical intervention (P = 0.004), Weiss score (P = 0.04) and hormonal secretion (P = 0.04) were significantly associated with OS in adults but not in children. No factor was found significant on multivariate analysis. CONCLUSIONS: Except for high prevalence of functioning tumors in children, clinico-pathologic attributes and outcome of ACC in the two groups didn't differ significantly. PMID- 28071636 TI - Epidemiology of male seminomatous and nonseminomatous germ cell tumors and response to first-line chemotherapy from a tertiary cancer center in India. AB - INTRODUCTION: Unlike the developed countries, there is a lack of good epidemiologic data for testicular germ cell tumors (GCTs) in India with majority presenting in advanced stage. This study aims to elaborate on the epidemiology of testicular GCTs and response to standard first-line chemotherapy (CT). METHODS: GCTs treated at our center from January 2013 to June 2014 were retrospectively analyzed. Patients underwent orchidectomy either outside or at our hospital. Based on stage and risk group, standard CT (bleomycin, etoposide, and cisplatin/etoposide and cisplatin/carboplatin AUC7) and radiotherapy were given as appropriate. Response was calculated based on the Response Evaluation Criteria in Solid Tumors. Statistical analysis was performed using SPSS 18 software. RESULTS: Fifty nonseminomatous germ cell tumor (NSGCT) and 36 of SGCT cases were studied. 30%, 46%, and 64% of NSGCT and 11%, 28%, and 22% of SGCT had N2, N3, and M1 diseases, respectively. The mean nodal size was 7 cm (1.5-19) in NSGCT and 5.5 cm (1.3-11) in SGCT. As per the International Germ Cell Cancer Collaborative Group classification, in patients with metastatic disease, 9% of NSGCT were good, 53% were intermediate, and 38% were poor risk whereas 75% of SGCT were good and 25% were intermediate risk. Following CT among NSGCT, 5% and 71% had radiologic complete response (CR) and partial response (PR), respectively. Among SGCT, 46% and 38% had radiologic CR and PR, respectively. 22%, 53%, and 13% of NSGCT and 12%, 24%, and 20% of SGCT developed febrile neutropenia, Grade 3 or 4 hematological and nonhematological toxicities, respectively, after standard chemotherapy. CONCLUSIONS: GCTs in India present with high nodal and high-risk diseases wherein the standard first-line CT may not be adequate as curative therapy; however, significant chemotoxicity is also a hindrance. PMID- 28071638 TI - Smokeless tobacco use and perceptions of risk among students in Mumbai municipal schools. AB - INTRODUCTION: Nearly 15% of youth in India use tobacco. However, few studies have explored the use, knowledge, and attitudes of smokeless tobacco use among youth. AIM: To determine the patterns of use as well as knowledge and perceptions of smokeless tobacco among youth in Mumbai attending municipal schools. MATERIALS AND METHODS: A cross-sectional survey was performed among 1053 students in the 8th and 9th grades in 16 municipal schools in Mumbai to determine the knowledge and perceptions about smokeless tobacco products as well as the patterns of use. RESULTS AND CONCLUSIONS: Ever use of smokeless tobacco was reported by 47 (4.7%) students in the survey. Twenty-nine (2.9%) students reported ever using smoked tobacco. Students were more likely to identify cigarettes and bidis as tobacco products compared to smokeless tobacco products such as gutkha, mishri, and khaini. Betel nut products were used by 178 (17.9%) students. The high rate of smokeless tobacco and betel nut use coupled with low levels of knowledge about their contents and harms suggests that tobacco control programs targeting youth should ensure that these products are adequately explained and understood by students. PMID- 28071639 TI - The ban on smokeless tobacco products is systematically violated in Chennai, India. AB - BACKGROUND: India is the world's third largest consumer of tobacco. There are twice as many users of smokeless tobacco products (STPs) as cigarette smokers. The Government of Tamil Nadu has banned the sale of gutkha and pan masala in 2013. Our aim was to identify the varieties of illegal STP available in Chennai, India. METHODS: In systematically chosen zones and regions of Chennai city, we randomly identified three kinds of kiosks (n = 18) and asked for "gutkha" and "pan masala," one of each product available. Details of each product were reviewed based on the information printed on the sachets. RESULTS: Totally 65 STPs were collected; 26 distinct products and 23 brands. All products were claimed to be "tobacco" by the shop keepers. Sixty-five percent of the products informed to contain tobacco and 15.4% to contain pan masala. Five sachets did not inform about the content; 30.8% did not have a pictorial warning; a text warning was printed on 80.8%, but only two products had the messages in Tamil; 70% had promotional messages printed, and 57% had their registration numbers printed. CONCLUSION: The ban on STP is being systematically violated in Chennai. STP are cheap and easily available and due to promotional laudatory messages and lacking information about the content and warning of health damage, the consumers are left with the perception that they buy more or less harmless product. The Indian Government must introduce policies to control production, import, and sale of illicit STP but we also call for a coordinated international solution. PMID- 28071640 TI - Innovation in chemotherapy administration process. AB - INTRODUCTION: This project was started after patient's complaints of increased cost burden on patients with increase stay of patient in hospital for chemotherapy administration for 3-4 days, how to decrease this hospital stay and financial burden and how can we improve services to decrease hospital stay and expedite the process of chemotherapy administration. METHODS: A total of 100 patients' confidential files reviewed from February 12, 2013 to May 15, 2013, patients, who were admitted for chemotherapy administration only in inpatient area and all services timings, were reviewed and documented on sheet named as delays chemotherapy sheet, nine processes timings checked against their benchmarks. RESULTS: All services process timings analyzed and compared with their benchmarks, results of all services timings are nearly close to benchmark except lab test results of patients who were admitted without labs test for chemotherapy administration delays seen in collecting blood sample and sending this sample to the laboratory, significant delay is seen in chemotherapy order entry by physician if patient is admitted after 4 p.m. for chemotherapy administration. Delays also identified in administration of chemotherapy. CONCLUSION: After identifying the reasons of delays in chemotherapy administration, improvement and innovation in chemotherapy administration process done which not only decrease hospital stay, but also decrease the cost of chemotherapy administration. PMID- 28071641 TI - Epidemiological data and case load spectrum of patients presenting to bone and soft tissue disease management group at a tertiary cancer center. AB - INTRODUCTION AND BACKGROUND: This study was conducted to know the spectrum and number of bone and soft tissue (BST) tumors presenting to our institute. We needed to assess the gap between the number of patients seen and infrastructure available, and based on this information, help formulate guidelines for optimum utilization of resources and to provide best possible evidence-based cancer care. SETTINGS AND DESIGNS: This is a prospective observational study (epidemiological). MATERIALS AND METHODS: This study included all new patients seen in BST-disease management group (DMG) in the year 2010. An audit form was devised to capture all the relevant information. A comparison of our data with other national and international studies was also done. RESULTS: Out of total 31,951 new patients registered at our institute, 2007 patients availed BST-DMG services. Sixty percent were bone tumors and 36% were soft tissue tumors. In bone tumor, 66% were malignant, 15% were benign, and 19% were non-neoplastic. Osteosarcoma (43%) was the most common malignant tumor followed by primitive neuroectodermal tumor/Ewing's (27%) and chondrosarcoma (11%). Giant cell tumor was the most common benign bone tumor. Eighty-one percent of all soft tissue lesions were malignant, of which 75% were of mesenchymal origin and 25% were of cutaneous origin. CONCLUSION: This is an attempt to document the epidemiology of musculoskeletal tumors presenting to our institution while guiding the institute to frame and implement disease-specific protocols and generate further research questions. Continued data collection and follow-up can provide valuable information on long-term survival and treatment-related toxicities. This data (within limitations) may be extrapolated to national level to identify the need for infrastructure and human resources. PMID- 28071642 TI - A "Guided" technique for insertion of lumbar cerebrospinal fluid drains. PMID- 28071644 TI - Topologically protected modes in non-equilibrium stochastic systems. AB - Non-equilibrium driving of biophysical processes is believed to enable their robust functioning despite the presence of thermal fluctuations and other sources of disorder. Such robust functions include sensory adaptation, enhanced enzymatic specificity and maintenance of coherent oscillations. Elucidating the relation between energy consumption and organization remains an important and open question in non-equilibrium statistical mechanics. Here we report that steady states of systems with non-equilibrium fluxes can support topologically protected boundary modes that resemble similar modes in electronic and mechanical systems. Akin to their electronic and mechanical counterparts, topological-protected boundary steady states in non-equilibrium systems are robust and are largely insensitive to local perturbations. We argue that our work provides a framework for how biophysical systems can use non-equilibrium driving to achieve robust function. PMID- 28071643 TI - Development and validation of a questionnaire to measure preferences and expectations of patients undergoing palliative chemotherapy: EXPECT questionnaire. AB - OBJECTIVE: The objective was to design and validate the questionnaire for capturing palliative chemotherapy-related preferences and expectations. DESIGN: Single arm, unicentric, prospective observational study. METHODS: EXPECT questionnaire was designed to capture preferences and expectations of patients undergoing palliative chemotherapy. This questionnaire underwent a linguistic validation and then was tested in patients. Ten patients are undergoing chemotherapy for solid tumors who fulfilled the inclusion and exclusion criteria self-administered the EXPECT questionnaire in regional language. After filling this questionnaire, they self-administered quick questionnaire-10 (QQ-10). SPSS version 16 (IBM New York) was used for analysis. Completion rate of EXPECT questionnaire was calculated. The feasibility, face validity, utility and time taken for completion of EXPECT questionnaire was also assessed. RESULTS: The completion rate of this questionnaire was 100%. All patients completed questionnaire within 5 min. The QQ-10 tool confirmed the feasibility, face validity and utility of the questionnaire. CONCLUSION: EXPECT questionnaire was validated in the regional language, and it's an effective tool for capturing patient's preferences and expectation from chemotherapy. PMID- 28071645 TI - Integrating mass spectrometry with MD simulations reveals the role of lipids in Na+/H+ antiporters. AB - Na+/H+ antiporters are found in all kingdoms of life and exhibit catalysis rates that are among the fastest of all known secondary-active transporters. Here we combine ion mobility mass spectrometry and molecular dynamics simulations to study the conformational stability and lipid-binding properties of the Na+/H+ exchanger NapA from Thermus thermophilus and compare this to the prototypical antiporter NhaA from Escherichia coli and the human homologue NHA2. We find that NapA and NHA2, but not NhaA, form stable dimers and do not selectively retain membrane lipids. By comparing wild-type NapA with engineered variants, we show that the unfolding of the protein in the gas phase involves the disruption of inter-domain contacts. Lipids around the domain interface protect the native fold in the gas phase by mediating contacts between the mobile protein segments. We speculate that elevator-type antiporters such as NapA, and likely NHA2, use a subset of annular lipids as structural support to facilitate large-scale conformational changes within the membrane. PMID- 28071646 TI - Reinforcement learning accounts for moody conditional cooperation behavior: experimental results. AB - In social dilemma games, human participants often show conditional cooperation (CC) behavior or its variant called moody conditional cooperation (MCC), with which they basically tend to cooperate when many other peers have previously cooperated. Recent computational studies showed that CC and MCC behavioral patterns could be explained by reinforcement learning. In the present study, we use a repeated multiplayer prisoner's dilemma game and the repeated public goods game played by human participants to examine whether MCC is observed across different types of game and the possibility that reinforcement learning explains observed behavior. We observed MCC behavior in both games, but the MCC that we observed was different from that observed in the past experiments. In the present study, whether or not a focal participant cooperated previously affected the overall level of cooperation, instead of changing the tendency of cooperation in response to cooperation of other participants in the previous time step. We found that, across different conditions, reinforcement learning models were approximately as accurate as a MCC model in describing the experimental results. Consistent with the previous computational studies, the present results suggest that reinforcement learning may be a major proximate mechanism governing MCC behavior. PMID- 28071647 TI - Colossal negative thermal expansion in reduced layered ruthenate. AB - Large negative thermal expansion (NTE) has been discovered during the last decade in materials of various kinds, particularly materials associated with a magnetic, ferroelectric or charge-transfer phase transition. Such NTE materials have attracted considerable attention for use as thermal-expansion compensators. Here, we report the discovery of giant NTE for reduced layered ruthenate. The total volume change related to NTE reaches 6.7% in dilatometry, a value twice as large as the largest volume change reported to date. We observed a giant negative coefficient of linear thermal expansion alpha=-115 * 10-6 K-1 over 200 K interval below 345 K. This dilatometric NTE is too large to be attributable to the crystallographic unit-cell volume variation with temperature. The highly anisotropic thermal expansion of the crystal grains might underlie giant bulk NTE via microstructural effects consuming open spaces in the sintered body on heating. PMID- 28071648 TI - Foliar application of the leaf-colonizing yeast Pseudozyma churashimaensis elicits systemic defense of pepper against bacterial and viral pathogens. AB - Yeast associates with many plant parts including the phyllosphere, where it is subject to harsh environmental conditions. Few studies have reported on biological control of foliar pathogens by yeast. Here, we newly isolated leaf colonizing yeasts from leaves of field-grown pepper plants in a major pepper production area of South Korea. The yeast was isolated using semi-selective medium supplemented with rifampicin to inhibit bacterial growth and its disease control capacity against Xanthomonas axonopodis infection of pepper plants in the greenhouse was evaluated. Of 838 isolated yeasts, foliar spray of Pseudozyma churashimaensis strain RGJ1 at 108 cfu/mL conferred significant protection against X. axonopodis and unexpectedly against Cucumber mosaic virus, Pepper mottle virus, Pepper mild mottle virus, and Broad bean wilt virus under field conditions. Direct antagonism between strain RGJ1 and X. axonopodis was not detected from co-culture assays, suggesting that disease is suppressed via induced resistance. Additional molecular analysis of the induced resistance marker genes Capsicum annuum Pathogenesis-Related (CaPR) 4 and CaPR5 indicated that strain RGJ1 elicited plant defense priming. To our knowledge, this study is the first report of plant protection against bacterial and viral pathogens mediated by a leaf-colonizing yeast and has potential for effective disease management in the field. PMID- 28071649 TI - Effect of shortened sleep on energy expenditure, core body temperature, and appetite: a human randomised crossover trial. AB - The effects of sleep restriction on energy metabolism and appetite remain controversial. We examined the effects of shortened sleep duration on energy metabolism, core body temperature (CBT), and appetite profiles. Nine healthy men were evaluated in a randomised crossover study under two conditions: a 3.5-h sleep duration and a 7-h sleep duration for three consecutive nights followed by one 7-h recovery sleep night. The subjects' energy expenditure (EE), substrate utilisation, and CBT were continually measured for 48 h using a whole-room calorimeter. The subjects completed an appetite questionnaire every hour while in the calorimeter. Sleep restriction did not affect total EE or substrate utilisation. The 48-h mean CBT decreased significantly during the 3.5-h sleep condition compared with the 7-h sleep condition (7-h sleep, 36.75 +/- 0.11 degrees C; 3.5-h sleep, 36.68 +/- 0.14 degrees C; p = 0.016). After three consecutive nights of sleep restriction, fasting peptide YY levels and fullness were significantly decreased (p = 0.011), whereas hunger and prospective food consumption were significantly increased, compared to those under the 7-h sleep condition. Shortened sleep increased appetite by decreasing gastric hormone levels, but did not affect EE, suggesting that greater caloric intake during a shortened sleep cycle increases the risk of weight gain. PMID- 28071650 TI - Improved ethanol electrooxidation performance by shortening Pd-Ni active site distance in Pd-Ni-P nanocatalysts. AB - Incorporating oxophilic metals into noble metal-based catalysts represents an emerging strategy to improve the catalytic performance of electrocatalysts in fuel cells. However, effects of the distance between the noble metal and oxophilic metal active sites on the catalytic performance have rarely been investigated. Herein, we report on ultrasmall (~5 nm) Pd-Ni-P ternary nanoparticles for ethanol electrooxidation. The activity is improved up to 4.95 A per mgPd, which is 6.88 times higher than commercial Pd/C (0.72 A per mgPd), by shortening the distance between Pd and Ni active sites, achieved through shape transformation from Pd/Ni-P heterodimers into Pd-Ni-P nanoparticles and tuning the Ni/Pd atomic ratio to 1:1. Density functional theory calculations reveal that the improved activity and stability stems from the promoted production of free OH radicals (on Ni active sites) which facilitate the oxidative removal of carbonaceous poison and combination with CH3CO radicals on adjacent Pd active sites. PMID- 28071651 TI - Marine origin of retroviruses in the early Palaeozoic Era. AB - Very little is known about the ancient origin of retroviruses, but owing to the discovery of their ancient endogenous viral counterparts, their early history is beginning to unfold. Here we report 36 lineages of basal amphibian and fish foamy like endogenous retroviruses (FLERVs). Phylogenetic analyses reveal that ray finned fish FLERVs exhibit an overall co-speciation pattern with their hosts, while amphibian FLERVs might not. We also observe several possible ancient viral cross-class transmissions, involving lobe-finned fish, shark and frog FLERVs. Sequence examination and analyses reveal two major lineages of ray-finned fish FLERVs, one of which had gained two novel accessory genes within their extraordinarily large genomes. Our phylogenetic analyses suggest that this major retroviral lineage, and therefore retroviruses as a whole, have an ancient marine origin and originated together with, if not before, their jawed vertebrate hosts >450 million years ago in the Ordovician period, early Palaeozoic Era. PMID- 28071652 TI - The local nature of incompressibility of quantum Hall effect. AB - Since the experimental realization of the integer quantum Hall effect in a two dimensional electron system, the interrelation between the conductance quantization and the topological properties of the system has been investigated. Assuming that the two-dimensional electron system is described by a Bloch Hamiltonian, system is insulating in the bulk of sample throughout the quantum Hall plateau due to a magnetic field induced energy gap. Meanwhile, the system is conducting at the edges resembling a 2+1 dimensional topological insulator without time-reversal symmetry. Here, by our magneto-transport measurements performed on GaAs/AlGaAs high purity Hall bars with two inner contacts we show that incompressible strips formed at the edges result in Hall quantization, even if the bulk is compressible. Consequently, the relationship between the quantum Hall effect and topological bulk insulator breaks for specific field intervals within the plateaus. The measurement of conducting bulk, strongly challenges all existing single-particle theories. PMID- 28071653 TI - Prophylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys. AB - Ischaemic acute kidney injury (AKI), an inflammatory disease process, often progresses to chronic kidney disease (CKD), with no available effective prophylaxis. This is in part due to lack of clinically relevant CKD models in non human primates. Here we demonstrate that inhibition of the archetypal innate immune receptor CD11b/CD18 prevents progression of AKI to CKD in cynomolgus monkeys. Severe ischaemia-reperfusion injury of the right kidney, with subsequent periods of the left ureter ligation, causes irreversible right kidney failure 3, 6 or 9 months after AKI. Moreover, prophylactic inactivation of CD11b/CD18, using the orthosteric CD11b/CD18 inhibitor mAb107, improves microvascular perfusion and histopathology, reduces intrarenal pro-inflammatory mediators and salvages kidney function long term. These studies reveal an important early role of CD11b+ leukocytes in post-ischaemic kidney fibrosis and failure, and suggest a potential early therapeutic intervention to mitigate progression of ischaemic AKI to CKD in humans. PMID- 28071654 TI - Responsiveness of Endoscopic Indices of Disease Activity for Crohn's Disease. AB - OBJECTIVES: The Crohn's Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score for Crohn's Disease (SES-CD) are commonly used to assess Crohn's disease (CD) activity; however neither instrument is fully validated. We evaluated the responsiveness to change of the SES-CD and CDEIS using data from a trial of adalimumab, a drug therapy of known efficacy. METHODS: Paired video recordings (N=112) of colonoscopies (baseline and week 8-12) obtained from patients with CD who participated in a trial of adalimumab therapy were reviewed in random order, in duplicate, by four central readers (56 pairs of videos by 2 groups of readers). Responsiveness of the SES-CD and the CDEIS was evaluated by comparing correlations between the observed and pre-specified predictions of change scores for these endoscopic indices with a global endoscopic evaluation of severity (GELS), a patient reported outcome (PRO2), and the Crohn's disease activity index (CDAI), and by calculation of the standardized effect size, and Guyatt's Responsiveness statistic (GRS) using 2 definitions of change; (1) treatment assignment and (2) an absolute change in total PRO2 of 50. The potential application of effect size estimates was demonstrated by calculating hypothetical sample sizes for comparing two independent groups. The impact of removing stenosis as an index item and adjusting for the number of segments observed was also assessed. RESULTS: Changes in both endoscopic instruments and the GELS were highly correlated. The SES-CD displayed numerically higher effect sizes for both definitions of change. The standardized effect size and GRS estimates (95% confidence interval) for the SES-CD based on treatment assignment were 0.84 (0.53, 1.15) and 0.79 (0.48, 1.09). Corresponding values for the CDEIS were 0.72 (0.42, 1.02) and 0.75 (0.45, 1.06). The standardized effect size and GRS estimates for the SES-CD based on an absolute change in total PRO2 of 50 points or greater were 0.76 (0.49, 1.02) and 0.93 (0.64, 1.21). Corresponding values for CDEIS were 0.70 (0.44, 0.97), 0.83 (0.55, 1.10). Removal of stenosis as an index item and adjusting for observed segments did not improve responsiveness estimates. CONCLUSIONS: Although both the SES-CD and CDEIS are valid measures of endoscopic disease activity that are moderately responsive to changes in endoscopic disease activity, the SES-CD displayed numerically greater responsiveness in this data set. PMID- 28071655 TI - Effectiveness of Guideline-Recommended Cholecystectomy to Prevent Recurrent Pancreatitis. AB - OBJECTIVES: Cholecystectomy during or within 4 weeks of hospitalization for acute biliary pancreatitis is recommended by guidelines. We examined adherence to the guidelines for incident mild-to-moderate acute biliary pancreatitis and the effectiveness of cholecystectomy to prevent recurrent episodes of pancreatitis. METHODS: Individuals in the 2010-2013 MarketScan Commercial Claims & Encounters database with a hospitalization associated with International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes of 577.0 for acute pancreatitis and 574.x for gallstone disease were eligible. Guideline adherence was considered cholecystectomy within 30 days of the first/index hospitalization for biliary pancreatitis. Individuals with and without guideline adherent cholecystectomy were compared for subsequent hospitalization for acute or chronic pancreatitis using a Cox proportional hazards model adjusted for age, sex, comorbidities, and length of index hospital stay. RESULTS: Of the 17,010 patients who met the inclusion criteria, 78% were adherent with the guidelines, including 10,918 who underwent cholecystectomy during the index hospitalization and 2,387 who underwent cholecystectomy within 30 days. Among 3,705 patients non adherent with the guidelines, 1,213 had a cholecystectomy 1-6 months after the index hospitalization. Guideline-adherent cholecystectomy resulted in fewer subsequent hospitalizations for acute and chronic pancreatitis as compared with non-adherence to the guidelines (acute pancreatitis: 3% vs. 13%, P<0.001; chronic pancreatitis: 1% vs. 4%, P<0.001). CONCLUSIONS: Nearly four out of five patients underwent cholecystectomy for acute biliary pancreatitis in a timeframe, consistent with guidelines. Adherence resulted in a decrease in subsequent hospitalizations for both acute and chronic pancreatitis. However, the majority of non-adherent patients did not undergo a subsequent cholecystectomy. There may be factors that predict the need for immediate vs. delayed cholecystectomy. PMID- 28071657 TI - Corrigendum: 2016 ACG Abstracts-Inflammatory Bowel Disease. AB - This corrects the article DOI: 10.1038/ajg.2016.358. PMID- 28071658 TI - Corrigendum: 2016 ACG Abstracts- Outcomes Research. AB - This corrects the article DOI: 10.1038/ajg.2016.360. PMID- 28071656 TI - ACG Clinical Guideline: Preventive Care in Inflammatory Bowel Disease. AB - Recent data suggest that inflammatory bowel disease (IBD) patients do not receive preventive services at the same rate as general medical patients. Patients with IBD often consider their gastroenterologist to be the primary provider of care. To improve the care delivered to IBD patients, health maintenance issues need to be co-managed by both the gastroenterologist and primary care team. Gastroenterologists need to explicitly inform the primary care provider of the unique needs of the IBD patient, especially those on immunomodulators and biologics or being considered for such therapy. In particular, documentation of up to date vaccinations are crucial as IBD patients are often treated with long term immune-suppressive therapies and may be at increased risk for infections, many of which are preventable with vaccinations. Health maintenance issues addressed in this guideline include identification, safety and appropriate timing of vaccinations, screening for osteoporosis, cervical cancer, melanoma and non melanoma skin cancer as well as identification of depression and anxiety and smoking cessation. To accomplish these health maintenance goals, coordination between the primary care provider, gastroenterology team and other specialists is necessary. PMID- 28071660 TI - Corrigendum: 2016 ACG Abstracts- Clinical Vignettes/Case Reports - Esophagus. AB - This corrects the article DOI: 10.1038/ajg.2016.368. PMID- 28071662 TI - Experimental Array for Generating Dual Circularly-Polarized Dual-Mode OAM Radio Beams. AB - Recently, vortex beam carrying orbital angular momentum (OAM) for radio communications has attracted much attention for its potential of transmitting multiple signals simultaneously at the same frequency, which can be used to increase the channel capacity. However, most of the methods for getting multi mode OAM radio beams are of complicated structure and very high cost. This paper provides an effective solution of generating dual circularly-polarized (CP) dual mode OAM beams. The antenna consists of four dual-CP elements which are sequentially rotated 90 degrees in the clockwise direction. Different from all previous published research relating to OAM generation by phased arrays, the four elements are fed with the same phase for both left-hand circular polarization (LHCP) and right-hand circular polarization (RHCP). The dual-mode operation for OAM is achieved through the opposite phase differences generated for LHCP and RHCP, when the dual-CP elements are sequentially rotated in the clockwise direction. The measured results coincide well with the simulated ones, which verified the effectiveness of the proposed design. PMID- 28071661 TI - Neuronal sFlt1 and Vegfaa determine venous sprouting and spinal cord vascularization. AB - Formation of organ-specific vasculatures requires cross-talk between developing tissue and specialized endothelial cells. Here we show how developing zebrafish spinal cord neurons coordinate vessel growth through balancing of neuron-derived Vegfaa, with neuronal sFlt1 restricting Vegfaa-Kdrl mediated angiogenesis at the neurovascular interface. Neuron-specific loss of flt1 or increased neuronal vegfaa expression promotes angiogenesis and peri-neural tube vascular network formation. Combining loss of neuronal flt1 with gain of vegfaa promotes sprout invasion into the neural tube. On loss of neuronal flt1, ectopic sprouts emanate from veins involving special angiogenic cell behaviours including nuclear positioning and a molecular signature distinct from primary arterial or secondary venous sprouting. Manipulation of arteriovenous identity or Notch signalling established that ectopic sprouting in flt1 mutants requires venous endothelium. Conceptually, our data suggest that spinal cord vascularization proceeds from veins involving two-tiered regulation of neuronal sFlt1 and Vegfaa via a novel sprouting mode. PMID- 28071659 TI - ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. AB - Helicobacter pylori (H. pylori) infection is a common worldwide infection that is an important cause of peptic ulcer disease and gastric cancer. H. pylori may also have a role in uninvestigated and functional dyspepsia, ulcer risk in patients taking low-dose aspirin or starting therapy with a non-steroidal anti inflammatory medication, unexplained iron deficiency anemia, and idiopathic thrombocytopenic purpura. While choosing a treatment regimen for H. pylori, patients should be asked about previous antibiotic exposure and this information should be incorporated into the decision-making process. For first-line treatment, clarithromycin triple therapy should be confined to patients with no previous history of macrolide exposure who reside in areas where clarithromycin resistance amongst H. pylori isolates is known to be low. Most patients will be better served by first-line treatment with bismuth quadruple therapy or concomitant therapy consisting of a PPI, clarithromycin, amoxicillin, and metronidazole. When first-line therapy fails, a salvage regimen should avoid antibiotics that were previously used. If a patient received a first-line treatment containing clarithromycin, bismuth quadruple therapy or levofloxacin salvage regimens are the preferred treatment options. If a patient received first line bismuth quadruple therapy, clarithromycin or levofloxacin-containing salvage regimens are the preferred treatment options. Details regarding the drugs, doses and durations of the recommended and suggested first-line and salvage regimens can be found in the guideline. PMID- 28071663 TI - Covalent modification of pericardial patches for sustained rapamycin delivery inhibits venous neointimal hyperplasia. AB - Prosthetic grafts and patches are commonly used in cardiovascular surgery, however neointimal hyperplasia remains a significant concern, especially under low flow conditions. We hypothesized that delivery of rapamycin from nanoparticles (NP) covalently attached to patches allows sustained site-specific delivery of therapeutic agents targeted to inhibit localized neointimal hyperplasia. NP were covalently linked to pericardial patches using EDC/NHS chemistry and could deliver at least 360 ng rapamycin per patch without detectable rapamycin in serum; nanoparticles were detectable in the liver, kidney and spleen but no other sites within 24 hours. In a rat venous patch angioplasty model, control patches developed robust neointimal hyperplasia on the patch luminal surface characterized by Eph-B4-positive endothelium and underlying SMC and infiltrating cells such as macrophages and leukocytes. Patches delivering rapamycin developed less neointimal hyperplasia, less smooth muscle cell proliferation, and had fewer infiltrating cells but retained endothelialization. NP covalently linked to pericardial patches are a novel composite delivery system that allows sustained site-specific delivery of therapeutics; NP delivering rapamycin inhibit patch neointimal hyperplasia. NP linked to patches may represent a next generation of tissue engineered cardiovascular implants. PMID- 28071665 TI - Chemical complexity of odors increases reliability of olfactory threshold testing. AB - Assessment of odor thresholds is a widely recognized method of measuring olfactory abilities in humans. To date no attempts have been made to assess whether chemical complexity of odors used can produce more reliable results. To this end, we performed two studies of repeated measures design with 121 healthy volunteers (age 19-62 years). In Study 1, we compared thresholds obtained from tests based on one odor presented in a pen-like odor dispensing device with three odors and six odors mixtures presented in glass containers. In study 2 we compared stimuli of one and three odors, both presented in glass containers. In both studies measurements were performed twice, separated by at least three days. Results indicate that the multiple odor mixtures produced more reliable threshold scores, as compared to thresholds based on a single substance. PMID- 28071664 TI - Comparison of the glycopattern alterations of mitochondrial proteins in cerebral cortex between rat Alzheimer's disease and the cerebral ischemia model. AB - Alzheimer's disease (AD) and ischemic brain injury are two major neurodegenerative diseases. Mitochondrial dysfunction commonly occurs in AD and ischemic brain injury. Currently, little attention has been paid to the glycans on mitochondrial glycoproteins, which may play vital roles during the process of mitochondrial dysfunction. The aim of this study was to illustrate and compare the glycopattern alterations of mitochondrial glycoproteins extracted from the cerebral cortex of the rat models of these two diseases using High-throughput lectin microarrays. The results shown that the number of lectins with significant differences compared to normal brains was nine for the rat sporadic Alzheimer's disease (SAD) model and eighteen for the rat middle cerebral artery occlusion (MCAO) model. Interestingly, five lectins showed opposite expression patterns between the SAD and MCAO rat models. We conclude that glycopattern alterations of mitochondrial glycoproteins in the cerebral cortex may provide vital information to help understand mitochondrial dysfunction in AD and ischemic brain injury. In addition, glycans recognized by diverse lectins with opposite expression patterns between these two diseases hints at the different pathomechanisms of mitochondrial dysfunction in AD and ischemic brain injury. PMID- 28071666 TI - High power rechargeable magnesium/iodine battery chemistry. AB - Rechargeable magnesium batteries have attracted considerable attention because of their potential high energy density and low cost. However, their development has been severely hindered because of the lack of appropriate cathode materials. Here we report a rechargeable magnesium/iodine battery, in which the soluble iodine reacts with Mg2+ to form a soluble intermediate and then an insoluble final product magnesium iodide. The liquid-solid two-phase reaction pathway circumvents solid-state Mg2+ diffusion and ensures a large interfacial reaction area, leading to fast reaction kinetics and high reaction reversibility. As a result, the rechargeable magnesium/iodine battery shows a better rate capability (180 mAh g-1 at 0.5 C and 140 mAh g-1 at 1 C) and a higher energy density (~400 Wh kg-1) than all other reported rechargeable magnesium batteries using intercalation cathodes. This study demonstrates that the liquid-solid two-phase reaction mechanism is promising in addressing the kinetic limitation of rechargeable magnesium batteries. PMID- 28071667 TI - PhotoGate microscopy to track single molecules in crowded environments. AB - Tracking single molecules inside cells reveals the dynamics of biological processes, including receptor trafficking, signalling and cargo transport. However, individual molecules often cannot be resolved inside cells due to their high density. Here we develop the PhotoGate technique that controls the number of fluorescent particles in a region of interest by repeatedly photobleaching its boundary. PhotoGate bypasses the requirement of photoactivation to track single particles at surface densities two orders of magnitude greater than the single molecule detection limit. Using this method, we observe ligand-induced dimerization of a receptor tyrosine kinase at the cell surface and directly measure binding and dissociation of signalling molecules from early endosomes in a dense cytoplasm with single-molecule resolution. We additionally develop a numerical simulation suite for rapid quantitative optimization of Photogate experimental conditions. PhotoGate yields longer tracking times and more accurate measurements of complex stoichiometry than existing single-molecule imaging methods. PMID- 28071668 TI - Towards an emotional 'stress test': a reliable, non-subjective cognitive measure of anxious responding. AB - Response to stress or external threats is a key factor in mood and anxiety disorder aetiology. Current measures of anxious responding to threats are limited because they largely rely on retrospective self-report. Objectively quantifying individual differences in threat response would be a valuable step towards improving our understanding of anxiety disorder vulnerability. Our goal is to therefore develop a reliable, objective, within-subject 'stress-test' of anxious responding. To this end, we examined threat-potentiated performance on an inhibitory control task from baseline to 2-4 weeks (n = 50) and again after 5-9 months (n = 22). We also describe single session data for a larger sample (n = 157) to provide better population-level estimates of task performance variance. Replicating previous findings, threat of shock improved distractor accuracy and slowed target reaction time on our task. Critically, both within-subject self report measures of anxiety (ICC = 0.66) and threat-potentiated task performance (ICC = 0.58) showed clinically useful test-retest reliability. Threat-potentiated task performance may therefore hold promise as a non-subjective measure of individual anxious responding. PMID- 28071669 TI - Use of Fibonacci numbers in lipidomics - Enumerating various classes of fatty acids. AB - In lipid biochemistry, a fundamental question is how the potential number of fatty acids increases with their chain length. Here, we show that it grows according to the famous Fibonacci numbers when cis/trans isomerism is neglected. Since the ratio of two consecutive Fibonacci numbers tends to the Golden section, 1.618, organisms can increase fatty acid variability approximately by that factor per carbon atom invested. Moreover, we show that, under consideration of cis/trans isomerism and/or of modification by hydroxy and/or oxo groups, diversity can be described by generalized Fibonacci numbers (e.g. Pell numbers). For the sake of easy comprehension, we deliberately build the proof on the recursive definitions of these number series. Our results should be of interest for mass spectrometry, combinatorial chemistry, synthetic biology, patent applications, use of fatty acids as biomarkers and the theory of evolution. The recursive definition of Fibonacci numbers paves the way to construct all structural formulas of fatty acids in an automated way. PMID- 28071671 TI - Effect of seed morph and light level on growth and reproduction of the amphicarpic plant Amphicarpaea edgeworthii (Fabaceae). AB - Amphicarpic plants produce aerial and subterranean fruits on an individual plant, and these heteromorphic diaspores give rise to plants that differ in growth and ecology. Amphicarpaea edgeworthii is a summer annual amphicarpic species that grows over a range of light levels. We aimed to compare the response to shading intensity of plants of A. edgeworthii grown throughout their life cycle from aerial seeds (ASP) and from subterranean seeds (SSP). We hypothesized that vegetative and reproductive growth of plants from ASP and SSP respond differently to light. Plants were grown from ASP and SSP under 0, 46, 71 and 90% shading intensities. With plant height as a covariate, vegetative biomass of ASP and SSP did not differ. Leaf area and seed production of SSP were greater and internode length less than they were for ASP in all shading intensities. Aerial and subterranean seed yield, seed mass and number for both ASP and SSP were highest in full light. Aerial seed yield was affected more than subterranean seed yield by shading intensity. The growth and reproductive responses of ASP and SSP of A. edgeworthii may be adaptive to the range of low to high light environments in which this species grows. PMID- 28071672 TI - Metformin and the risk of prostate cancer across racial/ethnic groups: a population-based cohort study. AB - BACKGROUND: Men with diabetes may have a lower risk of prostate cancer than men without diabetes which may be altered by metformin use or race/ethnicity. METHODS: Using administrative databases, from 1994 to 2012, adult (age?50 years) men with diabetes were identified. Metformin exposure was defined as a time dependent variable, stratified first into any use, and into tertiles of cumulative dose. Surname algorithms identified individuals as Chinese or non Chinese. Multivariable Cox regression estimated the risk of prostate cancer. RESULTS: The cohort of 80 001 had a mean age of 64 years and median follow-up of 9 years. Chinese users of metformin aged 50-59, 60-69 and ?70 had similar risks of prostate cancer as non-users. Non-Chinese users aged 50-59 (adjusted hazards ratio (aHR): 0.86, 0.74 to 1.00) had a decreased risk whereas men aged 60-69 and ?70 did not. However, when metformin exposure was stratified into tertiles, there was no association in any strata except non-Chinese men aged 50-59 in the first (aHR: 0.68, 95% confidence interval (CI): 0.55, 0.84), second (aHR: 0.75, 95% CI: 0.61, 0.92) and third (aHR: 0.79, 95% CI: 0.64, 0.96) tertiles of metformin exposure and non-Chinese men aged 60-69 in the first (aHR: 0.81, 95% CI: 0.68, 0.95) tertiles of metformin exposure. CONCLUSIONS: There was no clear association between metformin and risk of prostate cancer in men with diabetes in either race/ethnicity. Our findings suggest a consistent relationship between metformin and prostate cancer across race/ethnicity. PMID- 28071670 TI - Benzyl Isothiocyanate potentiates p53 signaling and antitumor effects against breast cancer through activation of p53-LKB1 and p73-LKB1 axes. AB - Functional reactivation of p53 pathway, although arduous, can potentially provide a broad-based strategy for cancer therapy owing to frequent p53 inactivation in human cancer. Using a phosphoprotein-screening array, we found that Benzyl Isothiocynate, (BITC) increases p53 phosphorylation in breast cancer cells and reveal an important role of ERK and PRAS40/MDM2 in BITC-mediated p53 activation. We show that BITC rescues and activates p53-signaling network and inhibits growth of p53-mutant cells. Mechanistically, BITC induces p73 expression in p53-mutant cells, disrupts the interaction of p73 and mutant-p53, thereby releasing p73 from sequestration and allowing it to be transcriptionally active. Furthermore, BITC induced p53 and p73 axes converge on tumor-suppressor LKB1 which is transcriptionally upregulated by p53 and p73 in p53-wild-type and p53-mutant cells respectively; and in a feed-forward mechanism, LKB1 tethers with p53 and p73 to get recruited to p53-responsive promoters. Analyses of BITC-treated xenografts using LKB1-null cells corroborate in vitro mechanistic findings and establish LKB1 as the key node whereby BITC potentiates as well as rescues p53 pathway in p53-wild-type as well as p53-mutant cells. These data provide first in vitro and in vivo evidence of the integral role of previously unrecognized crosstalk between BITC, p53/LKB1 and p73/LKB1 axes in breast tumor growth inhibition. PMID- 28071673 TI - Prognostic value of the new Grade Groups in Prostate Cancer: a multi institutional European validation study. AB - BACKGROUND: We aimed to assess the prognostic relevance of the new Grade Groups in Prostate Cancer (PCa) within a large cohort of European men treated with radical prostatectomy (RP). METHODS: Data from 27 122 patients treated with RP at seven European centers were analyzed. We investigated the prognostic performance of the new Grade Groups (based on Gleason score 3+3, 3+4, 4+3, 8 and 9-10) on biopsy and RP specimen, adjusted for established clinical and pathological characteristics. Multivariable Cox proportional hazards regression models assessed the association of new Grade Groups with biochemical recurrence (BCR). Prognostic accuracies of the models were assessed using Harrell's C-index. RESULTS: Median follow-up was 29 months (interquartile range, 13-54). The 4-year estimated BCR-free survival (bRFS) for biopsy Grade Groups 1-5 were 91.3, 81.6, 69.8, 60.3 and 44.4%, respectively. The 4-year estimated bRFS for RP Grade Groups 1-5 were 96.1%, 86.7%, 67.0%, 63.1% and 41.0%, respectively. Compared with Grade Group 1, all other Grade Groups based both on biopsy and RP specimen were independently associated with a lower bRFS (all P<0.01). Adjusted pairwise comparisons revealed statistically differences between all Grade Groups, except for group 3 and 4 on RP specimen (P=0.10). The discriminations of the multivariable base prognostic models based on the current three-tier and the new five-tier systems were not clinically different (0.3 and 0.9% increase in discrimination for clinical and pathological model). CONCLUSIONS: We validated the independent prognostic value of the new Grade Groups on biopsy and RP specimen from European PCa men. However, it does not improve the accuracies of prognostic models by a clinically significant margin. Nevertheless, this new classification may help physicians and patients estimate disease aggressiveness with a user-friendly, clinically relevant and reproducible method. PMID- 28071675 TI - Lasing optical cavities based on macroscopic scattering elements. AB - Two major elements are required in a laser device: light confinement and light amplification. Light confinement is obtained in optical cavities by employing a pair of mirrors or by periodic spatial modulation of the refractive index as in photonic crystals and Bragg gratings. In random lasers, randomly placed nanoparticles embedded in the active material provide distributed optical feedback for lasing action. Recently, we demonstrated a novel architecture in which scattering nanoparticles and active element are spatially separated and random lasing is observed. Here we show that this approach can be extended to scattering media with macroscopic size, namely, a pair of sand grains, which act as feedback elements and output couplers, resulting in lasing emission. We demonstrate that the number of lasing modes depends on the surface roughness of the sand grains in use which affect the coherent feedback and thus the emission spectrum. Our findings offer a new perspective of material science and photonic structures, facilitating a novel and simple approach for the realization of new photonics devices based on natural scattering materials. PMID- 28071674 TI - Predictors of Exercise-Induced Pulmonary Hypertension in Patients with Asymptomatic Degenerative Mitral Regurgitation: Mechanistic Insights from 2D Speckle-Tracking Echocardiography. AB - Presence of exercise-induced pulmonary hypertension (EIPH) in asymptomatic degenerative mitral regurgitation (DMR) determines prognosis. This study aimed to elucidate the mechanism and predictors of EIPH in asymptomatic DMR. Ninety-one consecutive asymptomatic patients with DMR who underwent exercise stress echocardiography were prospectively included. We obtained various conventional echocardiographic parameters at rest and during peak exercise, as well as left atrial (LA) function at rest using 2-dimensional speckle-tracking analysis. The 25 patients (33.3%) with EIPH were significantly older and had a greater ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity during peak exercise than those without EIPH. LA strain (LAS)-s and LAS-e, indices of LA reservoir and conduit function, respectively, were significantly lower in those with EIPH than in those without EIPH. Multivariate analysis indicated that LAS-s was the only resting echocardiographic parameter that independently predicted EIPH, with a cut-off value of 26.9%. Furthermore, Kaplan Meier curve analysis showed that symptom-free survival was markedly lower among those with reduced LAS-s. In conclusion, decreased LA reservoir function contributes to EIPH, and LAS-s at rest is a useful indicator for predicting EIPH in asymptomatic patients with DMR. PMID- 28071676 TI - Transcriptome analysis of neo-tetraploid rice reveals specific differential gene expressions associated with fertility and heterosis. AB - Polyploid rice hybrids have a powerful biological and yield potential that may become a new way for rice breeding; however, low fertility is major hindrance in commercial utilization. Here, we developed a neo-tetraploid rice that could overcome the sterility of autotetraploid rice and produce high heterosis. Transcriptome analysis of F1 hybrid developed by crossing neo-tetraploid with autotetraploid rice displayed 807, 663 and 866 differentially expressed genes that uniquely associated with F1 and specific to (DEGFu-sp) anther, ovary and leaf, respectively. Of the DEGFu-sp, 1224 genes displayed nonadditive expression; 44 and 10 genes were annotated as TFs and methyltransferase or hydroxymethyltransferase, respectively. Gene ontology enrichment and co expression analysis revealed specific differential gene expressions in the DEGFu sp to leaf, anther and ovary, such as genes related to photosynthesis, metabolic process and transport, and co-expression network including fertility, resistance and epigenetic elements. Of the DEGFu-sp to anther, 42 meiosis stage-specific genes, eight meiosis-related genes, such as RAD51 and SMC2, were identified. We identified 38 miRNAs from DEGFu-sp to anther, and their targets were associated with pollen fertility and retrotransposon protein. Our study provides new germplasm for polyploid rice breeding, and revealed complex regulatory mechanisms that might be associated with heterosis and fertility. PMID- 28071677 TI - Renal-cell carcinoma in 2016: Advances in treatment - jostling for pole position. PMID- 28071678 TI - Multiple myeloma in 2016: Fresh perspectives on treatment and moments of clarity. PMID- 28071679 TI - Novel long-chain compounds with both immunomodulatory and MenA inhibitory activities against Staphylococcus aureus and its biofilm. AB - Menaquinone (MK) biosynthesis pathway is a potential target for evaluating antimicrobials in gram-positive bacteria. Here, 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA) was targeted to reduce methicillin-resistant Staphylococcus aureus (MRSA) growth. MenA inhibiting, long chain-based compounds were designed, synthesized and evaluated against MRSA and menaquinone utilizing bacteria in aerobic conditions. The results showed that these bacteria were susceptible to most of the compounds. Menaquinone (MK-4) supplementation rescued MRSA growth, suggesting these compounds inhibit MK biosynthesis. 3a and 7c exhibited promising inhibitory activities with MICs ranging 1-8 MUg/mL against MRSA strains. The compounds did not facilitate small colony variant formation. These compounds also inhibited the biofilm growth by MRSA at high concentration. Compounds 3a, 6b and 7c displayed a promising extracellular bactericidal activity against MRSA at concentrations equal to and four-fold less than their respective MICs. We also observed cytokines released from THP-1 macrophages treated with compounds 3a, 6b and 7c and found decreases in TNF-alpha and IL-6 release and increase in IL-1beta. These data provide evidence that MenA inhibitors act as TNF alpha and IL-6 inhibitors, raising the potential for development and application of these compounds as potential immunomodulatory agents. PMID- 28071680 TI - Loss of tricellular tight junction protein LSR promotes cell invasion and migration via upregulation of TEAD1/AREG in human endometrial cancer. AB - Lipolysis-stimulated lipoprotein receptor (LSR) is a unique molecule of tricellular contacts of normal and cancer cells. We investigated how the loss of LSR induced cell migration, invasion and proliferation in endometrial cancer cell line Sawano. mRNAs of amphiregulin (AREG) and TEA domain family member 1 (TEAD1) were markedly upregulated by siRNA-LSR. In endometrial cancer tissues, downregulation of LSR and upregulation of AREG were observed together with malignancy, and Yes-associated protein (YAP) was present in the nuclei. siRNA AREG prevented the cell migration and invasion induced by siRNA-LSR, whereas treatment with AREG induced cell migration and invasion. LSR was colocalized with TRIC, angiomotin (AMOT), Merlin and phosphorylated YAP (pYAP). siRNA-LSR increased expression of pYAP and decreased that of AMOT and Merlin. siRNA-YAP prevented expression of the mRNAs of AREG and TEAD1, and the cell migration and invasion induced by siRNA-LSR. Treatment with dobutamine and 2-deoxy-D-glucose and glucose starvation induced the pYAP expression and prevented the cell migration and invasion induced by siRNA-LSR. siRNA-AMOT decreased the Merlin expression and prevented the cell migration and invasion induced by siRNA-LSR. The loss of LSR promoted cell invasion and migration via upregulation of TEAD1/AREG dependent on YAP/pYAP and AMOT/Merlin in human endometrial cancer cells. PMID- 28071681 TI - Increased impedance near cut-off in plasma-like media leading to emission of high power, narrow-bandwidth radiation. AB - Ultra-intense, narrow-bandwidth, electromagnetic pulses have become important tools for exploring the characteristics of matter. Modern tuneable high-power light sources, such as free-electron lasers and vacuum tubes, rely on bunching of relativistic or near-relativistic electrons in vacuum. Here we present a fundamentally different method for producing narrow-bandwidth radiation from a broad spectral bandwidth current source, which takes advantage of the inflated radiation impedance close to cut-off in a medium with a plasma-like permittivity. We find that by embedding a current source in this cut-off region, more than an order of magnitude enhancement of the radiation intensity is obtained compared with emission directly into free space. The method suggests a simple and general way to flexibly use broadband current sources to produce broad or narrow bandwidth pulses. As an example, we demonstrate, using particle-in-cell simulations, enhanced monochromatic emission of terahertz radiation using a two colour pumped current source enclosed by a tapered waveguide. PMID- 28071682 TI - Ocular dominance plasticity: inhibitory interactions and contrast equivalence. AB - Brief monocular occlusion results in a transient change in ocular dominance, such that the previously patched eye makes a stronger contribution to the binocular percept after occlusion. The previously unpatched eye therefore makes a correspondingly weaker contribution to the binocular sum. To shed light on the mechanism underlying this change we investigate how the relationship between the perception of fusion, suppression, and diplopia changes after short-term monocular deprivation. Results show that fusible stimuli seen by the unpatched eye are actively suppressed as a result of patching and that this can be reversed by an interocular contrast imbalance. This suggests that dichoptic inhibition plays an important role in ocular dominance changes due to short-term occlusion, possibly by altering the contrast gain prior to binocular summation. This may help explain why this form of plasticity affects the perception of both fusible and rivalrous stimuli. PMID- 28071683 TI - A comparative analysis of three vector-borne diseases across Australia using seasonal and meteorological models. AB - Ross River virus (RRV), Barmah Forest virus (BFV), and dengue are three common mosquito-borne diseases in Australia that display notable seasonal patterns. Although all three diseases have been modeled on localized scales, no previous study has used harmonic models to compare seasonality of mosquito-borne diseases on a continent-wide scale. We fit Poisson harmonic regression models to surveillance data on RRV, BFV, and dengue (from 1993, 1995 and 1991, respectively, through 2015) incorporating seasonal, trend, and climate (temperature and rainfall) parameters. The models captured an average of 50-65% variability of the data. Disease incidence for all three diseases generally peaked in January or February, but peak timing was most variable for dengue. The most significant predictor parameters were trend and inter-annual periodicity for BFV, intra-annual periodicity for RRV, and trend for dengue. We found that a Temperature Suitability Index (TSI), designed to reclassify climate data relative to optimal conditions for vector establishment, could be applied to this context. Finally, we extrapolated our models to estimate the impact of a false-positive BFV epidemic in 2013. Creating these models and comparing variations in periodicities may provide insight into historical outbreaks as well as future patterns of mosquito-borne diseases. PMID- 28071684 TI - Genome-wide identification of novel ovarian-predominant miRNAs: new insights from the medaka (Oryzias latipes). AB - MicroRNAs (miRNAs) are small, highly conserved non-coding RNAs that play important roles in the regulation of many physiological processes. However, the role of miRNAs in vertebrate oocyte formation (i.e., oogenesis) remains poorly investigated. To gain new insights into the roles of miRNAs in oogenesis, we searched for ovarian-predominant miRNAs. Using a microarray displaying 3,800 distinct miRNAs originating from different vertebrate species, we identified 66 miRNAs that are expressed predominantly in the ovary. Of the miRNAs exhibiting the highest overabundance in the ovary, 20 were selected for further analysis. Using a combination of QPCR and in silico analyses, we identified 8 novel miRNAs that are predominantly expressed in the ovary, including 2 miRNAs (miR-4785 and miR-6352) that exhibit strict ovarian expression. Of these 8 miRNAs, 7 were previously uncharacterized in fish. The strict ovarian expression of miR-4785 and miR-6352 suggests an important role in oogenesis and/or early development, possibly involving a maternal effect. Together, these results indicate that, similar to protein-coding genes, a significant number of ovarian-predominant miRNA genes are found in fish. PMID- 28071685 TI - Mesoscopic superconductivity and high spin polarization coexisting at metallic point contacts on Weyl semimetal TaAs. AB - A Weyl semimetal is a topologically non-trivial phase of matter that hosts mass less Weyl fermions, the particles that remained elusive for more than 80 years since their theoretical discovery. The Weyl semimetals exhibit unique transport properties and remarkably high surface spin polarization. Here we show that a mesoscopic superconducting phase with critical temperature Tc=7 K can be realized by forming metallic point contacts with silver (Ag) on single crystals of TaAs, while neither Ag nor TaAs are superconductors. Andreev reflection spectroscopy of such point contacts reveals a superconducting gap of 1.2 meV that coexists with a high transport spin polarization of 60% indicating a highly spin-polarized supercurrent flowing through the point contacts on TaAs. Therefore, apart from the discovery of a novel mesoscopic superconducting phase, our results also show that the point contacts on Weyl semimetals are potentially important for applications in spintronics. PMID- 28071686 TI - Identification of temporal genes involved in the mechanisms of spinal cord injury. AB - OBJECTIVES: As a high-cost neurological disability, spinal cord injury (SCI) can result in permanent paralysis and loss of sensation. To identify the temporal genes involved in the pathogenesis of SCI, we analysed the expression profile of GSE45006. METHODS: GSE45006 was downloaded from Gene Expression Omnibus, including 20 SCI samples (samples at 1 day, 3 days, 1 week, 2 weeks and 8 weeks after injury, four repetitions for each time point) and 4 normal samples. The Bayesian Estimation of Temporal Regulation (BETR) and randomForest packages were used to screen the temporal genes and the top 100 temporal genes, respectively. Then, the gplots package and Pearson correlation analysis separately were used to perform hot map analysis and expression pattern clustering for the top 100 temporal genes. Using the clusterProfiler package and TargetMine tool, their potential functions were analysed by enrichment analyses. Moreover, interaction relationships between these temporal genes and pathways were investigated by pathway-gene crosslinking networks. RESULTS: In total, 1907 temporal genes were identified. The top 100 temporal genes were obtained and divided into six clusters. Most of the gene functions were enriched in biological process categories. ARG1 and NOS3 in cluster 4 were enriched in biological process of arginine catabolic process. TGFbeta2, TGFbeta3, ALDH2 and ALDH3A2 were correlated with numerous pathways in the pathway-gene crosslinking network. Pathways related to TGFbeta2 and TGFbeta3 were connected to pathways related to ARG1 and NOS3 via ARG1. CONCLUSION: Several temporal genes, including TGFbeta2, TGFbeta3, ALDH2, ALDH3A2, ARG1 and NOS3, might be involved in SCI. PMID- 28071687 TI - Bacterial load of conditioned pressure ulcers is not a predictor for early flap failure in spinal cord injury. AB - OBJECTIVES: Pressure ulcers impose a major lifetime medical problem to patients with high-grade spinal cord injury (SCI). For patients with stages 3-4 pressure ulcers, plastic surgery is often the only remaining treatment option. Despite considerable flap failure rates of around 30%, only sparse knowledge exists on predictors for flap failure. Hence, identification of predictors for flap failures is needed. METHODS: We prospectively enrolled 38 SCI patients with stages 3-4 pressure ulcers scheduled for plastic surgery. Preoperative wound swabs, intraoperative tissue samples and postoperative drainage liquids were microbiologically analyzed. In multivariable logistic regression analyses, bacterial loads of deep tissue cultures of intraoperative samples as well as other clinical variables were analyzed with respect to the prediction of flap failures. RESULTS: The flap failure rate was 27.5%. Bacterial loads of deep tissue cultures were not predictive for flap failure, neither was the colonization with a specific bacterial strain. We observed a considerable fluctuation of microbiological environment from initial swab cultures, intraoperative samples and postoperative drainage fluids. Antibioprophylaxis was sufficient in only 75% of deep tissue cultures and 69% of drainage fluids. Insufficient antibioprophylaxis was associated with a higher flap failure rates (odds ratio 6.3, confidence interval 1.2-41.0). CONCLUSION: After inpatient wound conditioning, bacterial load analysis of intraoperative wound tissue cultures is ineffective in order to predict flap failure rates in SCI patients with stages 3 4 pressure ulcers after flap surgery. Instead, insufficient antibioprophylaxis might be a factor contributing to flap failure. PMID- 28071688 TI - Epileptiform activity in the mouse visual cortex interferes with cortical processing in connected areas. AB - Epileptiform activity is associated with impairment of brain function even in absence of seizures, as demonstrated by failures in various testing paradigm in presence of hypersynchronous interictal spikes (ISs). Clinical evidence suggests that cognitive deficits might be directly caused by the anomalous activity rather than by its underlying etiology. Indeed, we seek to understand whether ISs interfere with neuronal processing in connected areas not directly participating in the hypersynchronous activity in an acute model of epilepsy. Here we cause focal ISs in the visual cortex of anesthetized mice and we determine that, even if ISs do not invade the opposite hemisphere, the local field potential is subtly disrupted with a modulation of firing probability imposed by the contralateral IS activity. Finally, we find that visual processing is altered depending on the temporal relationship between ISs and stimulus presentation. We conclude that focal ISs interact with normal cortical dynamics far from the epileptic focus, disrupting endogenous oscillatory rhythms and affecting information processing. PMID- 28071689 TI - Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation. AB - Heterozygous mutations or deletions of the human Euchromatin Histone Methyltransferase 1 (EHMT1) gene are the main causes of Kleefstra syndrome, a neurodevelopmental disorder that is characterized by impaired memory, autistic features and mostly severe intellectual disability. Previously, Ehmt1+/- heterozygous knockout mice were found to exhibit cranial abnormalities and decreased sociability, phenotypes similar to those observed in Kleefstra syndrome patients. In addition, Ehmt1+/- knockout mice were impaired at fear extinction and novel- and spatial object recognition. In this study, Ehmt1+/- and wild-type mice were tested on several cognitive tests in a touchscreen-equipped operant chamber to further investigate the nature of learning and memory changes. Performance of Ehmt1+/- mice in the Visual Discrimination &Reversal learning, object-location Paired-Associates learning- and Extinction learning tasks was found to be unimpaired. Remarkably, Ehmt1+/- mice showed enhanced performance on the Location Discrimination test of pattern separation. In line with improved Location Discrimination ability, an increase in BrdU-labelled cells in the subgranular zone of the dentate gyrus was observed. In conclusion, reduced levels of EHMT1 protein in Ehmt1+/- mice does not result in general learning deficits in a touchscreen-based battery, but leads to increased adult cell proliferation in the hippocampus and enhanced pattern separation ability. PMID- 28071690 TI - Generation of germline ablated male pigs by CRISPR/Cas9 editing of the NANOS2 gene. AB - Genome editing tools have revolutionized the generation of genetically modified animals including livestock. In particular, the domestic pig is a proven model of human physiology and an agriculturally important species. In this study, we utilized the CRISPR/Cas9 system to edit the NANOS2 gene in pig embryos to generate offspring with mono-allelic and bi-allelic mutations. We found that NANOS2 knockout pigs phenocopy knockout mice with male specific germline ablation but other aspects of testicular development are normal. Moreover, male pigs with one intact NANOS2 allele and female knockout pigs are fertile. From an agriculture perspective, NANOS2 knockout male pigs are expected to serve as an ideal surrogate for transplantation of donor spermatogonial stem cells to expand the availability of gametes from genetically desirable sires. PMID- 28071691 TI - Comparative mitochondrial genomics toward exploring molecular markers in the medicinal fungus Cordyceps militaris. AB - Cordyceps militaris is a fungus used for developing health food, but knowledge about its intraspecific differentiation is limited due to lack of efficient markers. Herein, we assembled the mitochondrial genomes of eight C. militaris strains and performed a comparative mitochondrial genomic analysis together with three previously reported mitochondrial genomes of the fungus. Sizes of the 11 mitochondrial genomes varied from 26.5 to 33.9 kb mainly due to variable intron contents (from two to eight introns per strain). Nucleotide variability varied according to different regions with non-coding regions showing higher variation frequency than coding regions. Recombination events were identified between some locus pairs but seemed not to contribute greatly to genetic variations of the fungus. Based on nucleotide diversity fluctuations across the alignment of all mitochondrial genomes, molecular markers with the potential to be used for future typing studies were determined. PMID- 28071692 TI - Diversity, distribution, and significance of transposable elements in the genome of the only selfing hermaphroditic vertebrate Kryptolebias marmoratus. AB - The Kryptolebias marmoratus is unique because it is the only self-fertilizing hermaphroditic vertebrate, known to date. It primarily reproduces by internal self-fertilization in a mixed ovary/testis gonad. Here, we report on a high quality genome assembly for the K. marmoratus South Korea (SK) strain highlighting the diversity and distribution of transposable elements (TEs). We find that K. marmoratus genome maintains number and composition of TEs. This can be an important genomic attribute promoting genome recombination in this selfing fish, while, in addition to a mixed mating strategy, it may also represent a mechanism contributing to the evolutionary adaptation to ecological pressure of the species. Future work should help clarify this point further once genomic information is gathered for other taxa of the family Rivulidae that do not self fertilize. We provide a valuable genome resource that highlights the potential impact of TEs on the genome evolution of a fish species with an uncommon life cycle. PMID- 28071693 TI - IK acts as an immunoregulator of inflammatory arthritis by suppressing TH17 cell differentiation and macrophage activation. AB - Pathogenic T helper cells (TH) and macrophages have been implicated in the development of rheumatoid arthritis (RA), which can lead to severe synovial inflammation and bone destruction. A range of therapies have been widely used for RA, including specific monoclonal antibodies and chemical inhibitors against inflammatory cytokines produced by these cells. However, these have not been sufficient to meet the medical need. Here, we show that in transgenic mice expressing truncated IK (tIK) cytokine, inflammatory arthritis symptoms were ameliorated as the result of suppression of the differentiation of TH1 and TH17 cells and of macrophage activation. During inflammatory responses, tIK cytokine systemically regulated macrophage functions and TH17 cell differentiation through inactivation of the MAPK and NF-kappaB pathways. Interestingly, the level of tIK cytokine was higher in synovial fluid of RA patients compared with that in osteoarthritis (OA) patients. Our observations suggest that tIK cytokine can counterbalance the induction of inflammatory cells related to RA and thus could be a new therapeutic agent for the treatment of RA. PMID- 28071694 TI - Structures, stabilities and spectral properties of borospherene B44- and metalloborospherenes MB440/- (M = Li, Na, and K). AB - Density functional theory (DFT) and time-dependent density functional theory (TD DFT) calculations are carried out to study the stabilities, photoelectron, infrared, Raman and electronic absorption spectra of borospherene B44- and metalloborospherenes MB440/- (M = Li, Na, and K). It is found that all atoms can form stable exohedral metalloborospherenes M&B440/-, whereas only Na and K atoms can be stably encapsulated inside B440/- cage. In addition, relative energies of these metalloborospherenes suggest that Na and K atoms favor exohedral configuration. Importantly, doping of metal atom can modify the stabilities of B44 with different structures, which provides a possible route to produce stable boron clusters or metalloborospherenes. The calculated results suggest that B44 tends to get electrons from the doped metal. Metalloborospherenes MB44- are characterized as charge-transfer complexes (M2+B442-), where B44 tends to get two electrons from the extra electron and the doped metal, resulting in similar features with anionic B442-. In addition, doping of metal atom can change the spectral features, such as blueshift or redshift and weakening or strengthening of characteristic peaks, since the extra metal atom can modify the electronic structure. The calculated spectra are readily compared with future spectroscopy measurements and can be used as fingerprints to identify B44- and metalloborospherenes. PMID- 28071696 TI - Ion irradiation induced structural modifications and increase in elastic modulus of silica based thin films. AB - Ion irradiation is an alternative to heat treatment for transforming organic inorganic thin films to a ceramic state. One major shortcoming in previous studies of ion-irradiated films is the assumption that constituent phases in ion irradiated and heat-treated films are identical and that the ion irradiation effect is limited to changes in composition. In this study, we investigate the effects of ion irradiation on both the composition and structure of constituent phases and use the results to explain the measured elastic modulus of the films. The results indicated that the microstructure of the irradiated films consisted of carbon clusters within a silica matrix. It was found that carbon was present in a non-graphitic sp2-bonded configuration. It was also observed that ion irradiation caused a decrease in the Si-O-Si bond angle of silica, similar to the effects of applied pressure. A phase transformation from tetrahedrally bonded to octahedrally bonded silica was also observed. The results indicated the incorporation of carbon within the silica network. A combination of the decrease in Si-O-Si bond angle and an increase in the carbon incorporation within the silica network was found to be responsible for the increase in the elastic modulus of the films. PMID- 28071695 TI - Development of a multiple-hybrid population for genome-wide association studies: theoretical consideration and genetic mapping of flowering traits in maize. AB - Various types of populations have been used in genetics, genomics and crop improvement, including bi- and multi-parental populations and natural ones. The latter has been widely used in genome-wide association study (GWAS). However, inbred-based GWAS cannot be used to reveal the mechanisms involved in hybrid performance. We developed a novel maize population, multiple-hybrid population (MHP), consisting of 724 hybrids produced using 28 temperate and 23 tropical inbreds. The hybrids can be divided into three subpopulations, two diallels and NC (North Carolina Design) II. Significant genetic differences were identified among parents, hybrids and heterotic groups. A cluster analysis revealed heterotic groups existing in the parental lines and the results showed that MHPs are well suitable for GWAS in hybrid crops. MHP-based GWAS was performed using 55 K SNP array for flowering time traits, days to tassel, days to silk, days to anthesis and anthesis-silking interval. Two independent methods, PEPIS developed for hybrids and TASSEL software designed for inbred line populations, revealed highly consistent results with five overlapping chromosomal regions identified and used for discovery of candidate genes and quantitative trait nucleotides. Our results indicate that MHPs are powerful in GWAS for hybrid-related traits with great potential applications in the molecular breeding era. PMID- 28071697 TI - Diel-scale temporal dynamics recorded for bacterial groups in Namib Desert soil. AB - Microbes in hot desert soil partake in core ecosystem processes e.g., biogeochemical cycling of carbon. Nevertheless, there is still a fundamental lack of insights regarding short-term (i.e., over a 24-hour [diel] cycle) microbial responses to highly fluctuating microenvironmental parameters like temperature and humidity. To address this, we employed T-RFLP fingerprinting and 454 pyrosequencing of 16S rRNA-derived cDNA to characterize potentially active bacteria in Namib Desert soil over multiple diel cycles. Strikingly, we found that significant shifts in active bacterial groups could occur over a single 24 hour period. For instance, members of the predominant Actinobacteria phyla exhibited a significant reduction in relative activity from morning to night, whereas many Proteobacterial groups displayed an opposite trend. Contrary to our leading hypothesis, environmental parameters could only account for 10.5% of the recorded total variation. Potential biotic associations shown through co occurrence networks indicated that non-random inter- and intra-phyla associations were 'time-of-day-dependent' which may constitute a key feature of this system. Notably, many cyanobacterial groups were positioned outside and/or between highly interconnected bacterial associations (modules); possibly acting as inter-module 'hubs' orchestrating interactions between important functional consortia. Overall, these results provide empirical evidence that bacterial communities in hot desert soils exhibit complex and diel-dependent inter-community associations. PMID- 28071698 TI - Increased levels of CSF total but not oligomeric or phosphorylated forms of alpha synuclein in patients diagnosed with probable Alzheimer's disease. AB - Several studies reported an association between CSF alpha-synuclein (alpha-syn) and tau in Alzheimer's disease (AD), and demonstrated the significance of alpha syn in improving the diagnostic sensitivity/specificity of classical AD CSF biomarkers. In the current study, we measured CSF levels of different alpha-syn species in a cohort of AD patients (n = 225) who showed a CSF profile typical of AD at baseline as well as in cognitively intact controls (n = 68). CSF total alpha-syn (t-alpha-syn) significantly increased in the AD group (p < 0.0001) compared to controls, while oligomeric- and phosphorylated-Ser129-alpha-syn did not change significantly. ROC analysis showed a sensitivity of 85% and a specificity of 84% (AUC = 0.88) in distinguishing AD from controls. T-alpha-syn levels correlated positively with tau species in AD group and negatively with baseline MMSE score. Our data support the added value of measurement of CSF alpha syn species for further characterization of the CSF AD profile. PMID- 28071699 TI - Rye polyphenols and the metabolism of n-3 fatty acids in rats: a dose dependent fatty fish-like effect. AB - As long-chain fatty acids (LCFA) of the n-3 series are critically important for human health, fish consumption has considerably increased in recent decades, resulting in overfishing to respond to the worldwide demand, to an extent that is not sustainable for consumers' health, fisheries economy, and marine ecology. In a recent study, it has been shown that whole rye (WR) consumption improves blood and liver n-3 LCFA levels and gut microbiota composition in rats compared to refined rye. The present work demonstrates that specific colonic polyphenol metabolites may dose dependently stimulate the synthesis of n-3 LCFA, possibly through their microbial and hepatic metabolites in rats. The intake of plant n-3 alpha-linolenic acid and WR results in a sort of fatty fish-like effect, demonstrating that the n-3 LCFA levels in blood and tissues could be increased without eating marine foods, and therefore without promoting unsustainable overfishing, and without damaging marine ecology. PMID- 28071700 TI - Temperature-dependent Schottky barrier in high-performance organic solar cells. AB - Organic solar cells (OSCs) have attracted great attention in the past 30 years, and the power conversion efficiency (PCE) now reaches around 10%, largely owning to the rapid material developments. Meanwhile with the progress in the device performance, more and more interests are turning to understanding the fundamental physics inside the OSCs. In the conventional bulk-heterojunction architecture, only recently it is realized that the blend/cathode Schottky junction serves as the fundamental diode for the photovoltaic function. However, few researches have focused on such junctions, and their physical properties are far from being well understood. In this paper based on PThBDTP:PC71BM blend, we fabricated OSCs with PCE exceeding 10%, and investigated temperature-dependent behaviors of the junction diodes by various characterization including current-voltage, capacitance-voltage and impedance measurements between 70 to 290 K. We found the Schottky barrier height exhibits large inhomogeneity, which can be described by two sets of Gaussian distributions. PMID- 28071701 TI - Simultaneous abrupt shifts in hydrology and fish assemblage structure in a floodplain lake in the central Amazon. AB - Combined effects of climate change and deforestation have altered precipitation patterns in the Amazon. This has led to changes in the frequency of extreme events of flood and drought in recent decades and in the magnitude of the annual flood pulse, a phenomenon that influences virtually all aspects of river floodplain ecosystem dynamics. Analysis of long-term data revealed abrupt and synchronous changes in hydrology and fish assemblage structure of a floodplain lake near the confluence of Amazon and Negro rivers. After an intense drought in 2005, the assemblage assumed a different and fairly persistent taxonomic composition and functional structure. Declines in abundance after 2005 were more pronounced for species of all sizes having equilibrium life history strategy, large species with periodic life history strategy, and for all trophic levels except primary consumers. Our results suggest that the extreme drought triggered changes in the fish assemblage and subsequent anomalous hydrological conditions have hampered assemblage recovery. These findings stress the need to account for climatic-driven hydrological changes in conservation efforts addressing aquatic biodiversity and fishery resources in the central Amazon. PMID- 28071702 TI - Nitrogen loss by anaerobic ammonium oxidation in unconfined aquifer soils. AB - Anaerobic ammonium oxidation (anammox) is recognized as an important process for nitrogen cycling, yet little is known about its role in the subsurface biosphere. In this study, we investigated the presence, abundance, and role of anammox bacteria in upland soil cores from Tianjin, China (20 m depth) and Basel, Switzerland (10 m depth), using isotope-tracing techniques, (q)PCR assays, and 16 S rRNA &hzsB gene clone libraries, along with nutrient profiles of soil core samples. Anammox in the phreatic (water-saturated) zone contributed to 37.5-67.6% of the N-loss (up to 0.675 gN m-2 d-1), with anammox activities of 0.005-0.74 nmolN g-1 soil h-1, which were even higher than the denitrification rates. By contrast, no significant anammox was measured in the vadose zone. Higher anammox bacterial cell densities were observed (0.75-1.4 * 107 copies g-1 soil) in the phreatic zone, where ammonia-oxidizing bacteria (AOB) maybe the major source of nitrite for anammox bacteria. The anammox bacterial cells in soils of the vadose zone were all <103 copies g-1 soil. We suggest that the subsurface provides a favorable niche for anammox bacteria whose contribution to N cycling and groundwater nitrate removal seems considerably larger than previously known. PMID- 28071703 TI - Mammary extracellular matrix directs differentiation of testicular and embryonic stem cells to form functional mammary glands in vivo. AB - Previously, we demonstrated the ability of the normal mammary microenvironment (niche) to direct non-mammary cells including testicular and embryonic stem cells (ESCs) to adopt a mammary epithelial cell (MEC) fate. These studies relied upon the interaction of transplanted normal MECs with non-mammary cells within the mammary fat-pads of recipient mice that had their endogenous epithelium removed. Here, we tested whether acellular mammary extracellular matrix (mECM) preparations are sufficient to direct differentiation of testicular-derived cells and ESCs to form functional mammary epithelial trees in vivo. We found that mECMs isolated from adult mice and rats were sufficient to redirect testicular derived cells to produce normal mammary epithelial trees within epithelial divested mouse mammary fat-pads. Conversely, ECMs isolated from omental fat and lung did not redirect testicular cells to a MEC fate, indicating the necessity of tissue specific components of the mECM. mECM preparations also completely inhibited teratoma formation from ESC inoculations. Further, a phenotypically normal ductal outgrowth resulted from a single inoculation of ESCs and mECM. To the best of our knowledge, this is the first demonstration of a tissue specific ECM driving differentiation of cells to form a functional tissue in vivo. PMID- 28071704 TI - High fat diet-induced changes of mouse hepatic transcription and enhancer activity can be reversed by subsequent weight loss. AB - Epigenetic factors have been suggested to play an important role in metabolic memory by trapping and maintaining initial metabolic changes within the transcriptional regulatory machinery. In this study we fed mice a high fat diet (HFD) for seven weeks followed by additional five weeks of chow, to identify HFD mediated changes to the hepatic transcriptional program that may persist after weight loss. Mice fed a HFD displayed increased fasting insulin levels, hepatosteatosis and major changes in hepatic gene transcription associated with modulation of H3K27Ac at enhancers, but no significant changes in chromatin accessibility, indicating that HFD-regulated gene transcription is primarily controlled by modulating the activity of pre-established enhancers. After return to the same body weight as chow fed control mice, the fasting insulin, glucose, and hepatic triglyceride levels were fully restored to normal levels. Moreover, HFD-regulated H3K27Ac and mRNA levels returned to similar levels as control mice. These data demonstrates that the transcription regulatory landscape in the liver induced by HFD is highly dynamic and can be reversed by weight loss. This provides hope for efficient treatment of early obesity-associated changes to hepatic complications by simple weight loss intervention without persistent reprograming of the liver transcriptome. PMID- 28071705 TI - Digestive and appendicular soft-parts, with behavioural implications, in a large Ordovician trilobite from the Fezouata Lagerstatte, Morocco. AB - Trilobites were one of the most successful groups of marine arthropods during the Palaeozoic era, yet their soft-part anatomy is only known from a few exceptionally-preserved specimens found in a handful of localities from the Cambrian to the Devonian. This is because, even if the sclerotized appendages were not destroyed during early taphonomic stages, they are often overprinted by the three-dimensional, mineralised exoskeleton. Inferences about the ventral anatomy and behavioural activities of trilobites can also be derived from the ichnological record, which suggests that most Cruziana and Rusophycus trace fossils were possibly produced by the actions of trilobites. Three specimens of the asaphid trilobite Megistaspis (Ekeraspis) hammondi, have been discovered in the Lower Ordovician Fezouata Konservat-Lagerstatte of southern Morocco, preserving appendages and digestive tract. The digestive structures include a crop with digestive caeca, while the appendages display exopodal setae and slight heteropody (cephalic endopods larger and more spinose than thoracic and pygidial ones). The combination of these digestive structures and the heteropody has never been described together among trilobites, and the latter could assist in the understanding of the production of certain comb-like traces of the Cruziana rugosa group, which are extraordinarily abundant on the shallow marine shelves around Gondwana. PMID- 28071706 TI - Fatty acid synthase 2 contributes to diapause preparation in a beetle by regulating lipid accumulation and stress tolerance genes expression. AB - Diapause, also known as dormancy, is a state of arrested development that allows insects to survive unfavorable environmental conditions. Diapause-destined insects store large amounts of fat when preparing for diapause. However, the extent to which these accumulated fat reserves influence diapause remains unclear. To address this question, we investigated the function of fatty acid synthase (FAS), which plays a central role in lipid synthesis, in stress tolerance, the duration of diapause preparation, and whether insects enter diapause or not. In diapause-destined adult female cabbage beetles, Colaphellus bowringi, FAS2 was more highly expressed than FAS1 at the peak stage of diapause preparation. FAS2 knockdown suppressed lipid accumulation and subsequently affected stress tolerance genes expression and water content. However, silencing FAS2 had no significant effects on the duration of diapause preparation or the incidence of diapause. FAS2 transcription was suppressed by juvenile hormone (JH) and the JH receptor methoprene-tolerant (Met). These results suggest that the absence of JH-Met induces FAS2 expression, thereby promoting lipid storage in diapause-destined female beetles. These results demonstrate that fat reserves regulate stress tolerance genes expression and water content, but have no significant effect on the duration of diapause preparation or the incidence of diapause. PMID- 28071707 TI - The Content of Imagined Sounds Changes Visual Motion Perception in the Cross Bounce Illusion. AB - Can what we imagine hearing change what we see? Whether imagined sensory stimuli are integrated with external sensory stimuli to shape our perception of the world has only recently begun to come under scrutiny. Here, we made use of the cross bounce illusion in which an auditory stimulus presented at the moment two passing objects meet promotes the perception that the objects bounce off rather than cross by one another to examine whether the content of imagined sound changes visual motion perception in a manner that is consistent with multisensory integration. The results from this study revealed that auditory imagery of a sound with acoustic properties typical of a collision (i.e., damped sound) promoted the bounce-percept, but auditory imagery of the same sound played backwards (i.e., ramped sound) did not. Moreover, the vividness of the participants' auditory imagery predicted the strength of this imagery-induced illusion. In a separate experiment, we ruled out the possibility that changes in attention (i.e., sensitivity index d') or response bias (response bias index c) were sufficient to explain this effect. Together, these findings suggest that this imagery-induced multisensory illusion reflects the successful integration of real and imagined cross-modal sensory stimuli, and more generally, that what we imagine hearing can change what we see. PMID- 28071708 TI - Photo-reduced Cu/CuO nanoclusters on TiO2 nanotube arrays as highly efficient and reusable catalyst. AB - Non-noble metal nanoparticles are becoming more and more important in catalysis recently. Cu/CuO nanoclusters on highly ordered TiO2 nanotube arrays are successfully developed by a surfactant-free photoreduction method. This non-noble metal Cu/CuO-TiO2 catalyst exhibits excellent catalytic activity and stability for the reduction of 4-nitrophenol (4-NP) to 4-aminophenol (4-AP) with the presence of sodium borohydride (NaBH4). The rate constant of this low-cost Cu/CuO based catalyst is even higher than that of the noble metal nanoparticles decorated on the same TiO2 substrate. The conversion efficiency remains almost unchanged after 7 cycles of recycling. The recycle process of this Cu/CuO-TiO2 catalyst supported by Ti foil is very simple and convenient compared with that of the common powder catalysts. This catalyst also exhibited great catalytic activity to other organic dyes, such as methylene blue (MB), rhodamine B (RhB) and methyl orange (MO). This highly efficient, low-cost and easily reusable Cu/CuO-TiO2 catalyst is expected to be of great potential in catalysis in the future. PMID- 28071709 TI - Early life peripheral lipopolysaccharide challenge reprograms catecholaminergic neurons. AB - Neonatal immune challenge with the bacterial mimetic lipopolysaccharide has the capacity to generate long-term changes in the brain. Neonatal rats were intraperitoneally injected with lipopolysaccharide (0.05 mg/kg) on postnatal day (PND) 3 and again on PND 5. The activation state of tyrosine hydroxylase (TH) was measured in the locus coeruleus, ventral tegmental area and substantia nigra on PND 85. In the locus coeruleus there was an approximately four-fold increase in TH activity. This was accompanied by a significant increase in TH protein together with increased phosphorylation of all three serine residues in the N terminal region of TH. In the ventral tegmental area, a significant increase in TH activity and increased phosphorylation of the serine 40 residue was seen. Neonatal lipopolysaccharide had no effect on TH activation in the substantia nigra. These results indicate the capacity of a neonatal immune challenge to generate long-term changes in the activation state of TH, in particular in the locus coeruleus. Overall, the current results demonstrate the enduring outcomes of a neonatal immune challenge on specific brain catecholaminergic regions associated with catecholamine synthesis. This highlights a novel mechanism for long-term physiological and behavioural alterations induced by this model. PMID- 28071710 TI - MicroPattern: a web-based tool for microbe set enrichment analysis and disease similarity calculation based on a list of microbes. AB - The microbiota colonized on human body is renowned as "a forgotten organ" due to its big impacts on human health and disease. Recently, microbiome studies have identified a large number of microbes differentially regulated in a variety of conditions, such as disease and diet. However, methods for discovering biological patterns in the differentially regulated microbes are still limited. For this purpose, here, we developed a web-based tool named MicroPattern to discover biological patterns for a list of microbes. In addition, MicroPattern implemented and integrated an algorithm we previously presented for the calculation of disease similarity based on disease-microbe association data. MicroPattern first grouped microbes into different sets based on the associated diseases and the colonized positions. Then, for a given list of microbes, MicroPattern performed enrichment analysis of the given microbes on all of the microbe sets. Moreover, using MicroPattern, we can also calculate disease similarity based on the shared microbe associations. Finally, we confirmed the accuracy and usefulness of MicroPattern by applying it to the changed microbes under the animal-based diet condition. MicroPattern is freely available at http://www.cuilab.cn/micropattern. PMID- 28071711 TI - Transient anhedonia phenotype and altered circadian timing of behaviour during night-time dim light exposure in Per3-/- mice, but not wildtype mice. AB - Industrialisation greatly increased human night-time exposure to artificial light, which in animal models is a known cause of depressive phenotypes. Whilst many of these phenotypes are 'direct' effects of light on affect, an 'indirect' pathway via altered sleep-wake timing has been suggested. We have previously shown that the Period3 gene, which forms part of the biological clock, is associated with altered sleep-wake patterns in response to light. Here, we show that both wild-type and Per3-/- mice showed elevated levels of circulating corticosterone and increased hippocampal Bdnf expression after 3 weeks of exposure to dim light at night, but only mice deficient for the PERIOD3 protein (Per3-/-) exhibited a transient anhedonia-like phenotype, observed as reduced sucrose preference, in weeks 2-3 of dim light at night, whereas WT mice did not. Per3-/- mice also exhibited a significantly smaller delay in behavioural timing than WT mice during weeks 1, 2 and 4 of dim light at night exposure. When treated with imipramine, neither Per3-/- nor WT mice exhibited an anhedonia-like phenotype, and neither genotypes exhibited a delay in behavioural timing in responses to dLAN. While the association between both Per3-/- phenotypes remains unclear, both are alleviated by imipramine treatment during dim night-time light. PMID- 28071712 TI - Independent Aftereffects of Fat and Muscle: Implications for neural encoding, body space representation, and body image disturbance. AB - Although research addressing body size misperception has focused on socio cognitive processes, such as internalization of the "ideal" images of bodies in the media, the perceptual basis of this phenomenon remains largely unknown. Further, most studies focus on body size per se even though this depends on both fat and muscle mass - variables that have very different relationships with health. We tested visual adaptation as a mechanism for inducing body fat and muscle mass misperception, and assessed whether these two dimensions of body space are processed independently. Observers manipulated the apparent fat and muscle mass of bodies to make them appear "normal" before and after inspecting images from one of four adaptation conditions (increased fat/decreased fat/increased muscle/decreased muscle). Exposure resulted in a shift in the point of subjective normality in the direction of the adapting images along the relevant (fat or muscle) axis, suggesting that the neural mechanisms involved in body fat and muscle perception are independent. This supports the viability of adaptation as a model of real-world body size misperception, and extends its applicability to clinical manifestations of body image disturbance that entail not only preoccupation with thinness (e.g., anorexia nervosa) but also with muscularity (e.g., muscle dysmorphia). PMID- 28071713 TI - Sinonasal Delivery of Resveratrol via Mucoadhesive Nanostructured Microparticles in a Nasal Polyp Mouse Model. AB - Resveratrol (RSV) has been shown to effectively suppress chronic rhinosinusitis with nasal polyps in a mouse model; however, when locally administered to the sinonasal cavity, bolus RSV is limited by low drug bioavailability owing to its low aqueous solubility and relatively rapid clearance from the administration site. To address this limitation, we propose mucoadhesive nanostructured microparticles (PLGA/PEG NM) as a potential carrier for the sinonasal delivery of RSV. In this study, PLGA/PEG NM released RSV in a sustained manner. Owing to the enlarged specific surface area of the nanostructures, PLGA/PEG NM had synergistically enhanced mucoadhesiveness and thus showed improved in vivo retention properties in the sinonasal cavity. Therefore, when tested in a mouse nasal polyp model, PLGA/PEG NM mitigated polyp formation and restored epithelial integrity better than the control treatments. The therapeutic effect was similar at half the dose of PLGA/PEG NM, suggesting improved local bioavailability of RSV in the sinonasal cavity. PMID- 28071714 TI - Three-dimensional surgical simulation improves the planning for correction of facial prognathism and asymmetry: A qualitative and quantitative study. AB - Traditional planning method for orthognathic surgery has limitations of cephalometric analysis, especially for patients with asymmetry. The aim of this study was to assess surgical plan modification after 3-demensional (3D) simulation. The procedures were to perform traditional surgical planning, construction of 3D model for the initial surgical plan (P1), 3D model of altered surgical plan after simulation (P2), comparison between P1 and P2 models, surgical execution, and postoperative validation using superimposition and root mean-square difference (RMSD) between postoperative 3D image and P2 simulation model. Surgical plan was modified after 3D simulation in 93% of the cases. Absolute linear changes of landmarks in mediolateral direction (x-axis) were significant and between 1.11 to 1.62 mm. The pitch, yaw, and roll rotation as well as ramus inclination correction also showed significant changes after the 3D planning. Yaw rotation of the maxillomandibular complex (1.88 +/- 0.32 degrees ) and change of ramus inclination (3.37 +/- 3.21 degrees ) were most frequently performed for correction of the facial asymmetry. Errors between the postsurgical image and 3D simulation were acceptable, with RMSD 0.63 +/- 0.25 mm for the maxilla and 0.85 +/- 0.41 mm for the mandible. The information from this study could be used to augment the clinical planning and surgical execution when a conventional approach is applied. PMID- 28071715 TI - In situ Characterization of Nanoparticles Using Rayleigh Scattering. AB - We report a theoretical analysis showing that Rayleigh scattering could be used to monitor the growth of nanoparticles under arc discharge conditions. We compute the Rayleigh scattering cross sections of the nanoparticles by combining light scattering theory for gas-particle mixtures with calculations of the dynamic electronic polarizability of the nanoparticles. We find that the resolution of the Rayleigh scattering probe is adequate to detect nanoparticles as small as C60 at the expected concentrations of synthesis conditions in the arc periphery. Larger asymmetric nanoparticles would yield brighter signals, making possible to follow the evolution of the growing nanoparticle population from the evolution of the scattered intensity. Observable spectral features include characteristic resonant behaviour, shape-dependent depolarization ratio, and mass-dependent line shape. Direct observation of nanoparticles in the early stages of growth with unobtrusive laser probes should give insight on the particle formation mechanisms and may lead to better-controlled synthesis protocols. PMID- 28071716 TI - Lytic polysaccharide monooxygenases disrupt the cellulose fibers structure. AB - Lytic polysaccharide monooxygenases (LPMOs) are a class of powerful oxidative enzymes that breakdown recalcitrant polysaccharides such as cellulose. Here we investigate the action of LPMOs on cellulose fibers. After enzymatic treatment and dispersion, LPMO-treated fibers show intense fibrillation. Cellulose structure modifications visualized at different scales indicate that LPMO creates nicking points that trigger the disintegration of the cellulose fibrillar structure with rupture of chains and release of elementary nanofibrils. Investigation of LPMO action using solid-state NMR provides direct evidence of modification of accessible and inaccessible surfaces surrounding the crystalline core of the fibrils. The chains breakage likely induces modifications of the cellulose network and weakens fibers cohesion promoting their disruption. Besides the formation of new initiation sites for conventional cellulases, this work provides the first evidence of the direct oxidative action of LPMOs with the mechanical weakening of the cellulose ultrastructure. LPMOs can be viewed as promising biocatalysts for enzymatic modification or degradation of cellulose fibers. PMID- 28071717 TI - Tryptophan and Non-Tryptophan Fluorescence of the Eye Lens Proteins Provides Diagnostics of Cataract at the Molecular Level. AB - The chemical nature of the non-tryptophan (non-Trp) fluorescence of porcine and human eye lens proteins was identified by Mass Spectrometry (MS) and Fluorescence Steady-State and Lifetime spectroscopy as post-translational modifications (PTM) of Trp and Arg amino acid residues. Fluorescence intensity profiles measured along the optical axis of human eye lenses with age-related nuclear cataract showed increasing concentration of fluorescent PTM towards the lens centre in accord with the increased optical density in the lens nucleolus. Significant differences between fluorescence lifetimes of "free" Trp derivatives hydroxytryptophan (OH-Trp), N-formylkynurenine (NFK), kynurenine (Kyn), hydroxykynurenine (OH-Kyn) and their residues were observed. Notably, the lifetime constants of these residues in a model peptide were considerably greater than those of their "free" counterparts. Fluorescence of Trp, its derivatives and argpyrimidine (ArgP) can be excited at the red edge of the Trp absorption band which allows normalisation of the emission spectra of these PTMs to the fluorescence intensity of Trp, to determine semi-quantitatively their concentration. We show that the cumulative fraction of OH-Trp, NFK and ArgP emission dominates the total fluorescence spectrum in both emulsified post surgical human cataract protein samples, as well as in whole lenses and that this correlates strongly with cataract grade and age. PMID- 28071718 TI - Reproducibility and Repeatability of Computer Tomography-based Measurement of Abdominal Subcutaneous and Visceral Adipose Tissues. AB - Excessive accumulation of abdominal adipose tissue is a widely recognized as a major feature of obesity, and it can be quantified by dual-energy x-ray absorptiometry (DXA). However, in a phantom study, the inter- and intra instrument reliability of DXA remains unpredictable. Thus, we attempted to determine the precision of estimates from computer tomography-based measurements and analysis with AZE Virtual Place software. To determine the inter-rater reproducibility and intra-rater repeatability of adipose tissue area estimates, we used the automatic boundary-tracing function of the AZE Virtual Place to generate cross-sectional areas of subcutaneous and visceral adipose tissues from the abdomen of reconstructed CT images. The variability of inter-rater and intra rater estimates expressed as the coefficient of variation ranged from 0.47% to 1.43% for subcutaneous adipose tissue and 1.08% to 2.20% for visceral adipose tissue; the optimal coefficient of variation of the fat rate calculation ranged from 0.55% to 1.13%, respectively. There was high and significant correlation between adipose tissue areas as estimated in 40 obese subjects by two raters or repeatedly on 20 obese subjects by either rater. This indicates excellent reproducibility and repeatability via a computer tomography-based measurement of abdominal subcutaneous and visceral adipose tissues. PMID- 28071719 TI - Quantitative proteomic profiling of the extracellular matrix of pancreatic islets during the angiogenic switch and insulinoma progression. AB - The angiogenic switch, the time at which a tumor becomes vascularized, is a critical step in tumor progression. Indeed, without blood supply, tumors will fail to grow beyond 1 mm3 and are unlikely to disseminate. The extracellular matrix (ECM), a major component of the tumor microenvironment, is known to undergo significant changes during angiogenesis and tumor progression. However the extent of these changes remains unknown. In this study, we used quantitative proteomics to profile the composition of the ECM of pancreatic islets in a mouse model of insulinoma characterized by a precisely timed angiogenic switch. Out of the 120 ECM proteins quantified, 35 were detected in significantly different abundance as pancreatic islets progressed from being hyperplastic to angiogenic to insulinomas. Among these, the core ECM proteins, EFEMP1, fibrillin 1, and periostin were found in higher abundance, and decorin, Dmbt1, hemicentin, and Vwa5 in lower abundance. The angiogenic switch being a common feature of solid tumors, we propose that some of the proteins identified represent potential novel anti-angiogenic targets. In addition, we report the characterization of the ECM composition of normal pancreatic islets and propose that this could be of interest for the design of tissue-engineering strategies for treatment of diabetes. PMID- 28071720 TI - Polychlorinated biphenyls target Notch/Dll and VEGF R2 in the mouse placenta and human trophoblast cell lines for their anti-angiogenic effects. AB - The intrauterine environment is particularly vulnerable to environmental exposures. We previously established a mouse model that provided evidence for pregnancy complications and placental anti-angiogenesis in response to Aroclor 1254 (A-1254), a mixture of polychlorinated biphenyls (PCBs). Importantly, these effects were observed in IL-10-/-, but not wild type, mice, suggesting that IL-10 deficiency predisposes to pregnancy disruptive effects of environmental toxicants. However, the mechanisms by which PCBs cause anti-angiogenic effects are unclear. Here, we evaluated PCB-mediated anti-angiogenic effects by diverse but complementary approaches, including HUVEC-mediated trophoblast invasion in nude mice, in vitro three-dimensional capillary tube formation involving HUVEC and/or HTR8 trophoblasts, and aortic ring endothelial cell outgrowth/sprouting. Taken together, our data suggest that PCBs act as potent anti-angiogenic agents. Importantly, we show that treatment of pregnant IL-10-/- mice with A-1254 resulted in placental activation of the Notch/Delta-like ligand (Dll) pathway, a master regulator of cell-cell interaction and vascular patterning. Similar results were obtained with HUVEC and HTR8 trophoblasts. Rescue of A-1254-induced disruption of HUVEC-based tube formation by gamma-secretase inhibitor L1790 confirmed the critical role of the Notch/Dll pathway. Our data suggest that PCBs impart pregnancy disruptive functions by activating the Notch/Dll pathway and by inducing anti-angiogenic effects at the maternal-fetal interface. PMID- 28071721 TI - Assessment of phospholipid synthesis related biomarkers for perinatal asphyxia: a piglet study. AB - The prompt and reliable identification of infants at risk of hypoxic-ischemic encephalopathy secondary to perinatal asphyxia in the first critical hours is important for clinical decision-making and yet still remains a challenge. This work strives for the evaluation of a panel of metabolic biomarkers that have been associated with the hypoxic-ischemic insult in the perinatal period. Plasma and urine samples from a consolidated newborn piglet model of hypoxia and withdrawn before and at different time points after a hypoxic insult were analyzed and compared to a control group. Time-dependent metabolic biomarker profiles were studied and observed patterns were similar to those of lactate levels, which are currently considered the gold standard for assessing hypoxia. Class prediction performance could be improved by the use of a combination of the whole panel of determined metabolites in plasma as compared to lactate values. Using a multivariate model including lactate together with the studied metabolic biomarkers allowed to improve the prediction performance of duration of hypoxia time, which correlates with the degree of brain damage. The present study evidences the usefulness of choline and related metabolites for improving the early assessment of the severity of the hypoxic insult. PMID- 28071722 TI - spict, a cyst cell-specific gene, regulates starvation-induced spermatogonial cell death in the Drosophila testis. AB - Tissues are maintained in a homeostatic state by balancing the constant loss of old cells with the continued production of new cells. Tissue homeostasis can shift between high and low turnover states to cope with environmental changes such as nutrient availability. Recently, we discovered that the elimination of transit-amplifying cells plays a critical role in maintaining the stem cell population during protein starvation in the Drosophila testis. Here, we identify spict, a gene expressed specifically in differentiating cyst cells, as a regulator of spermatogonial death. Spict is upregulated in cyst cells that phagocytose dying spermatogonia. We propose that phagocytosis and subsequent clearance of dead spermatogonia, which is partly promoted by Spict, contribute to stem cell maintenance during prolonged protein starvation. PMID- 28071723 TI - HCN1 channels reduce the rate of exocytosis from a subset of cortical synaptic terminals. AB - The hyperpolarization-activated cyclic nucleotide-gated (HCN1) channels are predominantly located in pyramidal cell dendrites within the cortex. Recent evidence suggests these channels also exist pre-synaptically in a subset of synaptic terminals within the mature entorhinal cortex (EC). Inhibition of pre synaptic HCN channels enhances miniature excitatory post-synaptic currents (mEPSCs) onto EC layer III pyramidal neurons, suggesting that these channels decrease the release of the neurotransmitter, glutamate. Thus, do pre-synaptic HCN channels alter the rate of synaptic vesicle exocytosis and thereby enhance neurotransmitter release? To address this, we imaged the release of FM1-43, a dye that is incorporated into synaptic vesicles, from EC synaptic terminals using two photon microscopy in slices obtained from forebrain specific HCN1 deficient mice, global HCN1 knockouts and their wildtype littermates. This coupled with electrophysiology and pharmacology showed that HCN1 channels restrict the rate of exocytosis from a subset of cortical synaptic terminals within the EC and in this way, constrain non-action potential-dependent and action potential-dependent spontaneous release as well as synchronous, evoked release. Since HCN1 channels also affect post-synaptic potential kinetics and integration, our results indicate that there are diverse ways by which HCN1 channels influence synaptic strength and plasticity. PMID- 28071724 TI - Osteoclastic miR-214 targets TRAF3 to contribute to osteolytic bone metastasis of breast cancer. AB - The role of osteoclastic miRNAs in regulating osteolytic bone metastasis (OBM) of breast cancer is still underexplored. Here, we examined the expression profiles of osteoclastogenic miRNAs in human bone specimens and identified that miR-214-3p was significantly upregulated in breast cancer patients with OBM. Consistently, we found increased miR-214-3p within osteoclasts, which was associated with the elevated bone resorption, during the development of OBM in human breast cancer xenografted nude mice (BCX). Furthermore, genetic ablation of osteoclastic miR 214-3p in nude mice prevent the development of OBM. Conditioned medium from MDA MB-231 cells dramatically stimulated miR-214-3p expression to promote osteoclast differentiation. Mechanistically, a series of in vitro study showed that miR-214 3p directly targeted Traf3 to promote osteoclast activity and bone-resorbing activity. In addition, osteoclast-specific miR-214-3p knock-in mice showed remarkably increased bone resorption when compared to the littermate controls, which was attenuated after osteoclast-targeted treatment with Traf3 3'UTR containing plasmid. In BCX nude mice, osteoclast-targeted antagomir-214-3p delivery could recover the TRAF3 protein expression and attenuate the development of OBM, respectively. Collectively, inhibition of osteoclastic miR-214-3p may be a potential therapeutic strategy for breast cancer patients with OBM. Meanwhile, the intraosseous TRAF3 could be a promising biomarker for evaluation of the treatment response of antagomir-214-3p. PMID- 28071725 TI - Astragalus polysaccharides attenuate PCV2 infection by inhibiting endoplasmic reticulum stress in vivo and in vitro. AB - This study explored the effects of Astragalus polysaccharide (APS) on porcine circovirus type 2 (PCV2) infections and its mechanism in vivo and vitro. First, fifty 2-week-old mice were randomly divided into five groups: a group without PCV2 infection and groups with PCV2 infections at 0, 100, 200 or 400 mg/kg APS treatments. The trial lasted for 28 days. The results showed that APS treatments at 200 and 400 mg/kg reduced the pathological injury of tissues, inhibited PCV2 infection and decreased glucose-regulated protein 78 (GRP78) and GADD153/CHOP gene mRNA and protein expression significantly (P < 0.05). Second, a study on endoplasmic reticulum stress mechanism was carried out in PK15 cells. APS treatments at 15 and 45 MUg/mL significantly reduced PCV2 infection and GRP78 mRNA and protein expression (P < 0.05). Tunicamycin supplementation increased GRP78 mRNA and protein expression and significantly attenuated the APS-induced inhibition of PCV2 infection (P < 0.05). Tauroursodeoxycholic acid supplementation decreased GRP78 mRNA and protein expression and significantly inhibited PCV2 infection (P < 0.05). In addition, fifty 2-week-old mice were randomly divided into five groups: Con, PCV2, APS + PCV2, TM + PCV2 and TM + APS + PCV2. The results were similar to those in PK15 cells. Taken together, it could be concluded that APS suppresses PCV2 infection by inhibiting endoplasmic reticulum stress. PMID- 28071726 TI - The PPE2 protein of Mycobacterium tuberculosis translocates to host nucleus and inhibits nitric oxide production. AB - Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is one of the most successful pathogens of humans. It has evolved several adaptive skills and evasion mechanisms to hijack the immunologically educated host to suit its intracellular lifestyle. Here, we show that one of the unique PPE family member proteins of M. tuberculosis, PPE2, can limit nitric oxide (NO) production by inhibiting inos gene transcription. PPE2 protein has a leucine zipper DNA-binding motif and a functional nuclear localization signal. PPE2 was translocated into the macrophage nucleus via the classical importin alpha/beta pathway where it interacted with a GATA-binding site overlapping with the TATA box of inos promoter and inhibited NO production. PPE2 prolonged intracellular survival of a surrogate bacterium M. smegmatis in vitro as well as in vivo. This information are likely to improve our knowledge of host-pathogen interactions during M. tuberculosis infection which is crucial for designing effective anti-TB therapeutics. PMID- 28071727 TI - Plasma Amino Acid Profile in Patients with Aortic Dissection. AB - Aortic dissection (AD), a severe cardiovascular disease with the characteristics of high mortality, is lack of specific clinical biomarkers. In order to facilitate the diagnosis of AD, we investigated plasma amino acid profile through metabolomics approach. Total 33 human subjects were enrolled in the study: 11 coronary heart disease (CHD) patients without aortic lesion and 11 acute AD and 11 chronic AD. Amino acids were identified in plasma using liquid chromatography and mass spectrometry (LC-MS/MS), and were further subjected to multiple logistic regression analysis. The score plots of principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA) showed clear discrimination of CHD patients with AD, acute AD or chronic AD patients, respectively. The contents of histidine, glycine, serine, citrate, ornithine, hydroxyproline, proline and sarcosine were significant different in acute AD patients comparing with CHD patients. The levels of citrate, GABA, glutamate and cysteine were significant different in chronic AD patients comparing with CHD patients. The contents of glutamate and phenylalanine were significant changed in acute AD patients comparing with chronic AD patients. Plasma aminograms were significantly altered in patients with AD comparing with CHD, especially in acute AD, suggesting amino acid profile is expected to exploit a novel, non-invasive, objective diagnosis for AD. PMID- 28071729 TI - Rules of tissue packing involving different cell types: human muscle organization. AB - Natural packed tissues are assembled as tessellations of polygonal cells. These include skeletal muscles and epithelial sheets. Skeletal muscles appear as a mosaic composed of two different types of cells: the "slow" and "fast" fibres. Their relative distribution is important for the muscle function but little is known about how the fibre arrangement is established and maintained. In this work we capture the organizational pattern in two different healthy muscles: biceps brachii and quadriceps. Here we show that the biceps brachii muscle presents a particular arrangement, based on the different sizes of slow and fast fibres. By contrast, in the quadriceps muscle an unbiased distribution exists. Our results indicate that the relative size of each cellular type imposes an intrinsic organization into natural tessellations. These findings establish a new framework for the analysis of any packed tissue where two or more cell types exist. PMID- 28071728 TI - Determining the relative contribution of retinal disparity and blur cues to ocular accommodation in Down syndrome. AB - Individuals with Down syndrome (DS) often exhibit hypoaccommodation alongside accurate vergence. This study investigates the sensitivity of the two systems to retinal disparity and blur cues, establishing the relationship between the two in terms of accommodative-convergence to accommodation (AC/A) and convergence accommodation to convergence (CA/C) ratios. An objective photorefraction system measured accommodation and vergence under binocular conditions and when retinal disparity and blur cues were removed. Participants were aged 6-16 years (DS n = 41, controls n = 76). Measures were obtained from 65.9% of participants with DS and 100% of controls. Accommodative and vergence responses were reduced with the removal of one or both cues in controls (p < 0.007). For participants with DS, removal of blur was less detrimental to accommodative responses than removal of disparity; accommodative responses being significantly better when all cues were available or when blur was removed in comparison to when proximity was the only available cue. AC/A ratios were larger and CA/C ratios smaller in participants with DS (p < 0.00001). This study demonstrates that retinal disparity is the main driver to both systems in DS and illustrates the diminished influence of retinal blur. High AC/A and low CA/C ratios in combination with disparity-driven responses suggest prioritisation of vergence over accurate accommodation. PMID- 28071730 TI - Structural basis of human PCNA sliding on DNA. AB - Sliding clamps encircle DNA and tether polymerases and other factors to the genomic template. However, the molecular mechanism of clamp sliding on DNA is unknown. Using crystallography, NMR and molecular dynamics simulations, here we show that the human clamp PCNA recognizes DNA through a double patch of basic residues within the ring channel, arranged in a right-hand spiral that matches the pitch of B-DNA. We propose that PCNA slides by tracking the DNA backbone via a 'cogwheel' mechanism based on short-lived polar interactions, which keep the orientation of the clamp invariant relative to DNA. Mutation of residues at the PCNA-DNA interface has been shown to impair the initiation of DNA synthesis by polymerase delta (pol delta). Therefore, our findings suggest that a clamp correctly oriented on DNA is necessary for the assembly of a replication competent PCNA-pol delta holoenzyme. PMID- 28071732 TI - Homoepitaxial Growth of Metal Halide Crystals Investigated by Reflection High Energy Electron Diffraction. AB - We report the homoepitaxial growth of a metal halide on single crystals investigated with in situ reflection high-energy electron diffraction (RHEED) and ex situ atomic force microscopy (AFM). Epitaxial growth of NaCl on NaCl (001) is explored as a function of temperature and growth rate which provides the first detailed report of RHEED oscillations for metal halide growth. Layer-by-layer growth is observed at room temperature accompanied by clear RHEED oscillations while the growth mode transitions to an island (3D) mode at low temperature. At higher temperatures (>100 degrees C), RHEED oscillations and AFM data indicate a transition to a step-flow growth mode. To show the importance of such metal halide growth, green organic light-emitting diodes (OLEDs) are demonstrated using a doped NaCl film with a phosphorescent emitter as the emissive layer. This study demonstrates the ability to perform in situ and non-destructive RHEED monitoring even on insulating substrates and could enable doped single crystals and crystalline substrates for a range of optoelectronic applications. PMID- 28071731 TI - In-silico experiments of zebrafish behaviour: modeling swimming in three dimensions. AB - Zebrafish is fast becoming a species of choice in biomedical research for the investigation of functional and dysfunctional processes coupled with their genetic and pharmacological modulation. As with mammals, experimentation with zebrafish constitutes a complicated ethical issue that calls for the exploration of alternative testing methods to reduce the number of subjects, refine experimental designs, and replace live animals. Inspired by the demonstrated advantages of computational studies in other life science domains, we establish an authentic data-driven modelling framework to simulate zebrafish swimming in three dimensions. The model encapsulates burst-and-coast swimming style, speed modulation, and wall interaction, laying the foundations for in-silico experiments of zebrafish behaviour. Through computational studies, we demonstrate the ability of the model to replicate common ethological observables such as speed and spatial preference, and anticipate experimental observations on the correlation between tank dimensions on zebrafish behaviour. Reaching to other experimental paradigms, our framework is expected to contribute to a reduction in animal use and suffering. PMID- 28071733 TI - An automated method for large-scale monitoring of seed dispersal by ants. AB - Myrmecochory is the process of seed dispersal by ants; however, it is highly challenging to study, mainly because of the small size of both partners and the comparatively large range of dispersal. The mutualistic interaction between ants and seeds involves the former retrieving diaspores, consuming their elaiosome (a nutrient-rich appendage), and the rejection of seeds from the nest. Here, we introduce a semi-automated method based on stitching high resolution images together, allowing the study of myrmecochory in a controlled environment over time. We validate the effectiveness of our method in detecting and discriminating seeds and ants. We show that the number of retrieved diaspores varies highly among colonies, and is independent of both their size and activity level, even though the dynamics of diaspore collection are correlated with the arrival of ants at the food source. We find that all retrieved seeds are rejected from the nest in a clustered pattern, and, surprisingly, they are also frequently redispersed within the arena afterwards, despite lacking elaiosome. This finding suggests that the dispersal pattern might be more complex and dynamic than expected. Our method unveils new insights on the mechanisms of myrmecochory, and could be usefully adapted to study other dispersal phenomena. PMID- 28071734 TI - A subwavelength resolution microwave/6.3 GHz camera based on a metamaterial absorber. AB - The design, fabrication and characterization of a novel metamaterial absorber based camera with subwavelength spatial resolution are investigated. The proposed camera is featured with simple and lightweight design, easy portability, low cost, high resolution and sensitivity, and minimal image interference or distortion to the original field distribution. The imaging capability of the proposed camera was characterized in both near field and far field ranges. The experimental and simulated near field images both reveal that the camera produces qualitatively accurate images with negligible distortion to the original field distribution. The far field demonstration was done by coupling the designed camera with a microwave convex lens. The far field results further demonstrate that the camera can capture quantitatively accurate electromagnetic wave distribution in the diffraction limit. The proposed camera can be used in application such as non-destructive image and beam direction tracer. PMID- 28071735 TI - Spatial mapping of metals in tissue-sections using combination of mass spectrometry and histology through image registration. AB - We describe a new procedure for the parallel mapping of selected metals in histologically characterized tissue samples. Mapping is achieved via image registration of digital data obtained from two neighbouring cryosections by scanning the first as a histological sample and subjecting the second to laser ablation inductively coupled plasma mass spectrometry. This computer supported procedure enables determination of the distribution and content of metals of interest directly in the chosen histological zones and represents a substantial improvement over the standard approach, which determines these values in tissue homogenates or whole tissue sections. The potential of the described procedure was demonstrated in a pilot study that analysed Zn and Cu levels in successive development stages of pig melanoma tissue using MeLiM (Melanoma-bearing-Libechov Minipig) model. We anticipate that the procedure could be useful for a complex understanding of the role that the spatial distribution of metals plays within tissues affected by pathological states including cancer. PMID- 28071736 TI - Orbital angular momentum mode division filtering for photon-phonon coupling. AB - Stimulated Brillouin scattering (SBS), a fundamental nonlinear interaction between light and acoustic waves occurring in any transparency material, has been broadly studied for several decades and gained rapid progress in integrated photonics recently. However, the SBS noise arising from the unwanted coupling between photons and spontaneous non-coherent phonons in media is inevitable. Here, we propose and experimentally demonstrate this obstacle can be overcome via a method called orbital angular momentum mode division filtering. Owing to the introduction of a new distinguishable degree-of-freedom, even extremely weak signals can be discriminated and separated from a strong noise produced in SBS processes. The mechanism demonstrated in this proof-of-principle work provides a practical way for quasi-noise-free photonic-phononic operation, which is still valid in waveguides supporting multi-orthogonal spatial modes, permits more flexibility and robustness for future SBS devices. PMID- 28071737 TI - Efficient biosynthesis of a Cecropin A-melittin mutant in Bacillus subtilis WB700. AB - The efficient production of antimicrobial peptides (AMPs) for clinical applications has attracted the attention of the scientific community. To develop a novel microbial cell factory for the efficient biosynthesis of a cecropin A melittin mutant (CAM-W), a recombinant Bacillus subtilis WB700 expression system was genetically modified with a novel vector, including a fusion gene encoding CAM-W, the autoprotease EDDIE and the signal peptide SacB under the control of the maltose-inducible promoter Pglv. A total of 159 mg of CAM-W was obtained from 1 L of fermentation supernatant. The purified CAM-W showed a consistent size with the expected molecular weight of 3.2 kDa. Our findings suggest that this novel expression system can be used as a powerful tool for the efficient production of CAM-W. PMID- 28071738 TI - Purification and differentiation of human adipose-derived stem cells by membrane filtration and membrane migration methods. AB - Human adipose-derived stem cells (hADSCs) are easily isolated from fat tissue without ethical concerns, but differ in purity, pluripotency, differentiation ability, and stem cell marker expression, depending on the isolation method. We isolated hADSCs from a primary fat tissue solution using: (1) conventional culture, (2) a membrane filtration method, (3) a membrane migration method where the primary cell solution was permeated through membranes, adhered hADSCs were cultured, and hADSCs migrated out from the membranes. Expression of mesenchymal stem cell markers and pluripotency genes, and osteogenic differentiation were compared for hADSCs isolated by different methods using nylon mesh filter membranes with pore sizes ranging from 11 to 80 MUm. hADSCs isolated by the membrane migration method had the highest MSC surface marker expression and efficient differentiation into osteoblasts. Osteogenic differentiation ability of hADSCs and MSC surface marker expression were correlated, but osteogenic differentiation ability and pluripotent gene expression were not. PMID- 28071739 TI - Sox10+ adult stem cells contribute to biomaterial encapsulation and microvascularization. AB - Implanted biomaterials and biomedical devices generally induce foreign body reaction and end up with encapsulation by a dense avascular fibrous layer enriched in extracellular matrix. Fibroblasts/myofibroblasts are thought to be the major cell type involved in encapsulation, but it is unclear whether and how stem cells contribute to this process. Here we show, for the first time, that Sox10+ adult stem cells contribute to both encapsulation and microvessel formation. Sox10+ adult stem cells were found sparsely in the stroma of subcutaneous loose connective tissues. Upon subcutaneous biomaterial implantation, Sox10+ stem cells were activated and recruited to the biomaterial scaffold, and differentiated into fibroblasts and then myofibroblasts. This differentiation process from Sox10+ stem cells to myofibroblasts could be recapitulated in vitro. On the other hand, Sox10+ stem cells could differentiate into perivascular cells to stabilize newly formed microvessels. Sox10+ stem cells and endothelial cells in three-dimensional co-culture self-assembled into microvessels, and platelet-derived growth factor had chemotactic effect on Sox10+ stem cells. Transplanted Sox10+ stem cells differentiated into smooth muscle cells to stabilize functional microvessels. These findings demonstrate the critical role of adult stem cells in tissue remodeling and unravel the complexity of stem cell fate determination. PMID- 28071740 TI - Elucidating the modes of action for bioactive compounds in a cell-specific manner by large-scale chemically-induced transcriptomics. AB - The identification of the modes of action of bioactive compounds is a major challenge in chemical systems biology of diseases. Genome-wide expression profiling of transcriptional responses to compound treatment for human cell lines is a promising unbiased approach for the mode-of-action analysis. Here we developed a novel approach to elucidate the modes of action of bioactive compounds in a cell-specific manner using large-scale chemically-induced transcriptome data acquired from the Library of Integrated Network-based Cellular Signatures (LINCS), and analyzed 16,268 compounds and 68 human cell lines. First, we performed pathway enrichment analyses of regulated genes to reveal active pathways among 163 biological pathways. Next, we explored potential target proteins (including primary targets and off-targets) with cell-specific transcriptional similarity using chemical-protein interactome. Finally, we predicted new therapeutic indications for 461 diseases based on the target proteins. We showed the usefulness of the proposed approach in terms of prediction coverage, interpretation, and large-scale applicability, and validated the new prediction results experimentally by an in vitro cellular assay. The approach has a high potential for advancing drug discovery and repositioning. PMID- 28071741 TI - Loss of Coupling Distinguishes GJB1 Mutations Associated with CNS Manifestations of CMT1X from Those Without CNS Manifestations. AB - CMT1X, an X-linked inherited neuropathy, is caused by mutations in GJB1, which codes for Cx32, a gap junction protein expressed by Schwann cells and oligodendrocytes. Many GJB1 mutations cause central nervous system (CNS) abnormality in males, including stable subclinical signs and, less often, short duration episodes characterized by motor difficulties and altered consciousness. However, some mutations have no apparent CNS effects. What distinguishes mutations with and without CNS manifestations has been unclear. Here we studied a total of 14 Cx32 mutations, 10 of which are associated with florid episodic CNS clinical syndromes in addition to peripheral neuropathy. The other 4 mutations exhibit neuropathy without clinical or subclinical CNS abnormalities. These "PNS only" mutations (Y151C, V181M, R183C and L239I) form gap junction plaques and produce levels of junctional coupling similar to those for wild-type Cx32. In contrast, mutants with CNS manifestations (F51L, E102del, V139M, R142Q, R142W, R164W T55I, R164Q and C168Y) either form no morphological gap junction plaques or, if they do, produce little or no detectable junctional coupling. Thus, PNS and CNS abnormalities may involve different aspects of connexin function. PMID- 28071742 TI - Core Transcription Factors, MicroRNAs, and Small Molecules Drive Transdifferentiation of Human Fibroblasts Towards The Cardiac Cell Lineage. AB - Transdifferentiation has been described as a novel method for converting human fibroblasts into induced cardiomyocyte-like cells. Such an approach can produce differentiated cells to study physiology or pathophysiology, examine drug interactions or toxicities, and engineer cardiac tissues. Here we describe the transdifferentiation of human dermal fibroblasts towards the cardiac cell lineage via the induced expression of transcription factors GATA4, TBX5, MEF2C, MYOCD, NKX2-5, and delivery of microRNAs miR-1 and miR-133a. Cells undergoing transdifferentiation expressed ACTN2 and TNNT2 and partially organized their cytoskeleton in a cross-striated manner. The conversion process was associated with significant upregulation of a cohort of cardiac-specific genes, activation of pathways associated with muscle contraction and physiology, and downregulation of fibroblastic markers. We used a genetically encoded calcium indicator and readily detected active calcium transients although no spontaneous contractions were observed in transdifferentiated cells. Finally, we determined that inhibition of Janus kinase 1, inhibition of Glycogen synthase kinase 3, or addition of NRG1 significantly enhanced the efficiency of transdifferentiation. Overall, we describe a method for achieving transdifferentiation of human dermal fibroblasts into induced cardiomyocyte-like cells via transcription factor overexpression, microRNA delivery, and molecular pathway manipulation. PMID- 28071743 TI - Self-Assembly Assisted Fabrication of Dextran-Based Nanohydrogels with Reduction Cleavable Junctions for Applications as Efficient Drug Delivery Systems. AB - In order to overcome the key challenge in improving both fabrication efficiency and their drug delivery capability of anti-cancer drug delivery systems (ACDDS), here polyacrylic acid (PAA) grafted dextran (Dex) nanohydrogels (NGs) with covalent crosslinked structure bearing redox sensitive disulfide crosslinking junctions (Dex-SS-PAA) were synthesized efficiently through a one-step self assembly assisted methodology (SAA). The Dex-SS-PAA were subsequently conjugated with doxorubicin through an acid-labile hydrazone bond (Dex-SS-PAA-DOX). The in vitro drug release behavior, anti-cancer effects in vivo, and biosafety of the as prepared acid- and redox-dual responsive biodegradable NGs were systematically investigated. The results revealed that the Dex-SS-PAA-DOX exhibited pH- and redox-controlled drug release, greatly reduced the toxicity of free DOX, while exhibiting a strong ability to inhibit the growth of MDA-MB-231 tumors. Our study demonstrated that the Dex-SS-PAA-DOX NGs are very promising candidates as ACDDS for anti-cancer therapeutics. PMID- 28071744 TI - Biodegradable Magnesium Screws Accelerate Fibrous Tissue Mineralization at the Tendon-Bone Insertion in Anterior Cruciate Ligament Reconstruction Model of Rabbit. AB - The incorporation of tendon graft into bone tunnel is one of the most challenging clinical issues in anterior cruciate ligament (ACL) reconstruction. As a biodegradable metal, Mg has appropriate mechanical strength and osteoinductive effects, thus may be a promising alternative to commercialized products used for graft fixation. Therefore, it was hypothesized that Mg based interference screws would promote tendon graft-bone junction healing when compared to Ti screws. Herein, we compared the effects of Mg and Ti screws on tendon graft healing in rabbits with ACL reconstruction via histological, HR-pQCT and mechanical analysis. The histological results indicated that Mg screws significantly improved the graft healing quality via promoting mineralization at the tendon graft enthesis. Besides, Mg screws significantly promoted bone formation in the peri-screw region at the early healing stage. Importantly, Mg screws exhibited excellent corrosion resistance and the degradation of Mg screws did not induce bone tunnel widening. In tensile testing, there were no significant differences in the load to failure, stress, stiffness and absorption energy between Mg and Ti groups due to the failure mode at the midsubstance. Our findings demonstrate that Mg screws can promote tendon graft healing after ACL reconstruction, implying a potential alternative to Ti screws for clinical applications. PMID- 28071745 TI - Molecularly Imprinted Biodegradable Nanoparticles. AB - Biodegradable polymer nanoparticles are promising carriers for targeted drug delivery in nanomedicine applications. Molecu- lar imprinting is a potential strategy to target polymer nanoparticles through binding of endogenous ligands that may promote recognition and active transport into specific cells and tissues. However, the lock-and-key mechanism of molecular imprinting requires relatively rigid cross-linked structures, unlike those of many biodegradable polymers. To date, no fully biodegradable molecularly imprinted particles have been reported in the literature. This paper reports the synthesis of a novel molecularly- imprinted nanocarrier, based on poly(lactide-co-glycolide) (PLGA) and acrylic acid, that combines biodegradability and molec- ular recognition properties. A novel three-arm biodegradable cross-linker was synthesized by ring opening polymerization of glycolide and lactide initiated by glycerol. The resulting macromer was functionalized by introduction of end-functions through reaction with acryloyl chloride. Macromer and acrylic acid were used for the synthesis of narrowly-dispersed nanoparticles by radical polymerization in diluted conditions in the presence of biotin as template molecule. The binding capacity of the imprinted nanoparticles towards biotin and biotinylated bovine serum albumin was twentyfold that of non-imprinted nanoparti- cles. Degradation rates and functional performances were assessed in in vitro tests and cell cultures, demonstrating effective biotin-mediated cell internalization. PMID- 28071746 TI - Allergy reduces the risk of meningioma: a meta-analysis. AB - Meningiomas are the most common brain tumours; however, little is known regarding their aetiology. The data are inconsistent concerning atopic disease and the risk of developing meningioma. Thus, we conducted a meta-analysis to investigate the association between allergic conditions and the risk of developing meningioma. A systematic literature search was conducted using PubMed and Web of SCI from Jan 1979 to Feb 2016. Two investigators independently selected the relevant articles according to the inclusion criteria. Eight case-control studies and 2 cohort studies were included in the final analysis, comprising 5,679 meningioma cases and 55,621 control subjects. Compared with no history of allergy, the pooled odds ratio (OR) for allergic conditions was 0.81 (0.70-0.94) for meningioma in a random-effects meta-analysis. Inverse correlations of meningioma occurrence were also identified for asthma and eczema, in which the pooled ORs were 0.78 (0.70 0.86) and 0.78 (0.69-0.87), respectively. A reduced risk of meningioma occurrence was identified in hay fever; however, the association was weak (0.88, 95% CI = 0.78-0.99). The source of this heterogeneity could be the various confounding variables in individual studies. Overall, the current meta-analysis indicated that allergy reduced the risk of developing meningiomas. Large cohort studies are required to investigate this relationship. PMID- 28071747 TI - Deficits in reinforcement learning but no link to apathy in patients with schizophrenia. AB - Negative symptoms in schizophrenia have been linked to selective reinforcement learning deficits in the context of gains combined with intact loss-avoidance learning. Fundamental mechanisms of reinforcement learning and choice are prediction error signaling and the precise representation of reward value for future decisions. It is unclear which of these mechanisms contribute to the impairments in learning from positive outcomes observed in schizophrenia. A recent study suggested that patients with severe apathy symptoms show deficits in the representation of expected value. Considering the fundamental relevance for the understanding of these symptoms, we aimed to assess the stability of these findings across studies. Sixty-four patients with schizophrenia and 19 healthy control participants performed a probabilistic reward learning task. They had to associate stimuli with gain or loss-avoidance. In a transfer phase participants indicated valuation of the previously learned stimuli by choosing among them. Patients demonstrated an overall impairment in learning compared to healthy controls. No effects of apathy symptoms on task indices were observed. However, patients with schizophrenia learned better in the context of loss-avoidance than in the context of gain. Earlier findings were thus partially replicated. Further studies are needed to clarify the mechanistic link between negative symptoms and reinforcement learning. PMID- 28071748 TI - Nrf2 regulates gene-environment interactions in an animal model of intrauterine inflammation: Implications for preterm birth and prematurity. AB - Preterm birth (PTB) is the leading cause of neonatal mortality, and surviving infants are at increased risk for lifelong disabilities. Intrauterine inflammation is an etiological factor that drives PTB, and oxidative stress is associated with PTB. Nuclear erythroid 2-related factor 2 (Nrf2) is a redox sensitive transcription factor that is the key regulator of the response to oxidative and inflammatory stress. Here, we used the established mouse model of intrauterine inflammation-induced PTB to determine whether Nrf2 is a modifier of susceptibility to PTB and prematurity-related morbidity and mortality in the offspring. We determined that Nr2-deficient (Nrf2-/-) mice exhibited a greater sensitivity to intrauterine inflammation, as indicated by decreased time to delivery, reduced birthweight, and 100% mortality. Placentas from preterm Nrf2-/- mice showed elevated levels of markers of inflammation, oxidative stress, and cell death, and transcriptomic analysis identified numerous key signaling pathways that were differentially expressed between wild-type (WT) and Nrf2-/- mice in both preterm and control samples. Thus, Nrf2 could be a critical factor for gene-environment interactions that may determine susceptibility to PTB. Further studies are needed to determine if Nrf2 is a viable therapeutic target in women who are at risk for PTB and associated complications in the affected offspring. PMID- 28071749 TI - Tomato progeny inherit resistance to the nematode Meloidogyne javanica linked to plant growth induced by the biocontrol fungus Trichoderma atroviride. AB - Root-knot nematodes (RKN) are major crop pathogens worldwide. Trichoderma genus fungi are recognized biocontrol agents and a direct activity of Trichoderma atroviride (Ta) against the RKN Meloidogyne javanica (Mj), in terms of 42% reduction of number of galls (NG), 60% of number of egg masses and 90% of number of adult nematodes inside the roots, has been observed in tomato grown under greenhouse conditions. An in vivo split-root designed experiment served to demonstrate that Ta induces systemic resistance towards Mj, without the need for the organisms to be in direct contact, and significantly reduces NG (20%) and adult nematodes inside tomato roots (87%). The first generation (F1) of Ta-primed tomato plants inherited resistance to RKN; although, the induction of defenses occurred through different mechanisms, and in varying degrees, depending on the Ta-Mj interaction. Plant growth promotion induced by Ta was inherited without compromising the level of resistance to Mj, as the progeny of Ta-primed plants displayed increased size and resistance to Mj without fitness costs. Gene expression results from the defense inductions in the offspring of Ta-primed plants, suggested that an auxin-induced reactive oxygen species production promoted by Ta may act as a major defense strategy during plant growth. PMID- 28071750 TI - In-gap corner states in core-shell polygonal quantum rings. AB - We study Coulomb interacting electrons confined in polygonal quantum rings. We focus on the interplay of localization at the polygon corners and Coulomb repulsion. Remarkably, the Coulomb repulsion allows the formation of in-gap states, i.e., corner-localized states of electron pairs or clusters shifted to energies that were forbidden for non-interacting electrons, but below the energies of corner-side-localized states. We specify conditions allowing optical excitation to those states. PMID- 28071751 TI - Transcriptional pausing at the translation start site operates as a critical checkpoint for riboswitch regulation. AB - On the basis of nascent transcript sequencing, it has been postulated but never demonstrated that transcriptional pausing at translation start sites is important for gene regulation. Here we show that the Escherichia coli thiamin pyrophosphate (TPP) thiC riboswitch contains a regulatory pause site in the translation initiation region that acts as a checkpoint for thiC expression. By biochemically probing nascent transcription complexes halted at defined positions, we find a narrow transcriptional window for metabolite binding, in which the downstream boundary is delimited by the checkpoint. We show that transcription complexes at the regulatory pause site favour the formation of a riboswitch intramolecular lock that strongly prevents TPP binding. In contrast, cotranscriptional metabolite binding increases RNA polymerase pausing and induces Rho-dependent transcription termination at the checkpoint. Early transcriptional pausing may provide a general mechanism, whereby transient transcriptional windows directly coordinate the sensing of environmental cues and bacterial mRNA regulation. PMID- 28071752 TI - Platelet to lymphocyte ratio in the prediction of adverse outcomes after acute coronary syndrome: a meta-analysis. AB - Recent studies have shown platelet to lymphocyte ratio (PLR) to be a potential inflammatory marker in cardiovascular diseases. We performed a meta-analysis to systematically evaluate the prognostic role of PLR in acute coronary syndrome (ACS). A comprehensive literature search up to May 18, 2016 was conducted from PUBMED, EMBASE and Web of science to identify related studies. The risk ratio (RR) with 95% confidence interval (CI) was extracted or calculated for effect estimates. Totally ten studies involving 8932 patients diagnosed with ACS were included in our research. We demonstrated that patients with higher PLR level had significantly higher risk of in-hospital adverse outcomes (RR = 2.24, 95%CI = 1.81-2.77) and long-term adverse outcomes (RR = 2.32, 95%CI = 1.64-3.28). Sensitivity analyses confirmed the stability of our results. We didn't detect significant publication bias by Begg's and Egger's test (p > 0.05). In conclusion, our meta-analysis revealed that PLR is promising biomarker in predicting worse prognosis in ACS patients. The results should be validated by future large-scale, standard investigations. PMID- 28071753 TI - De novo assembly, annotation, and characterization of the whole brain transcriptome of male and female Syrian hamsters. AB - Hamsters are an ideal animal model for a variety of biomedical research areas such as cancer, virology, circadian rhythms, and behavioural neuroscience. The use of hamsters has declined, however, most likely due to the dearth of genetic tools available for these animals. Our laboratory uses hamsters to study acute social stress, and we are beginning to investigate the genetic mechanisms subserving defeat-induced behavioural change. We have been limited, however, by the lack of genetic resources available for hamsters. In this study, we sequenced the brain transcriptome of male and female Syrian hamsters to generate the necessary resources to continue our research. We completed a de novo assembly and after assembly optimization, there were 113,329 transcripts representing 14,530 unique genes. This study is the first to characterize transcript expression in both female and male hamster brains and offers invaluable information to promote understanding of a host of important biomedical research questions for which hamsters are an excellent model. PMID- 28071754 TI - Far-infrared protects vascular endothelial cells from advanced glycation end products-induced injury via PLZF-mediated autophagy in diabetic mice. AB - The accumulation of advanced glycation end products (AGEs) in diabetic patients induces vascular endothelial injury. Promyelocytic leukemia zinc finger protein (PLZF) is a transcription factor that can be activated by low-temperature far infrared (FIR) irradiation to exert beneficial effects on the vascular endothelium. In the present study, we investigated the influence of FIR-induced PLZF activation on AGE-induced endothelial injury both in vitro and in vivo. FIR irradiation inhibited AGE-induced apoptosis in human umbilical vein endothelial cells (HUVECs). PLZF activation increased the expression of phosphatidylinositol 3 kinases (PI3K), which are important kinases in the autophagic signaling pathway. FIR-induced PLZF activation led to autophagy in HUVEC, which was mediated through the upregulation of PI3K. Immunofluorescence staining showed that AGEs were engulfed by HUVECs and localized to lysosomes. FIR-induced autophagy promoted AGEs degradation in HUVECs. In nicotinamide/streptozotocin induced diabetic mice, FIR therapy reduced serum AGEs and AGEs deposition at the vascular endothelium. FIR therapy also reduced diabetes-induced inflammatory markers in the vascular endothelium and improved vascular endothelial function. These protective effects of FIR therapy were not found in PLZF-knockout mice. Our data suggest that FIR-induced PLZF activation in vascular endothelial cells protects the vascular endothelium in diabetic mice from AGE-induced injury. PMID- 28071755 TI - Variation in short-term and long-term responses of photosynthesis and isoprenoid mediated photoprotection to soil water availability in four Douglas-fir provenances. AB - For long-lived forest tree species, the understanding of intraspecific variation among populations and their response to water availability can reveal their ability to cope with and adapt to climate change. Dissipation of excess excitation energy, mediated by photoprotective isoprenoids, is an important defense mechanism against drought and high light when photosynthesis is hampered. We used 50-year-old Douglas-fir trees of four provenances at two common garden experiments to characterize provenance-specific variation in photosynthesis and photoprotective mechanisms mediated by essential and non-essential isoprenoids in response to soil water availability and solar radiation. All provenances revealed uniform photoprotective responses to high solar radiation, including increased de epoxidation of photoprotective xanthophyll cycle pigments and enhanced emission of volatile monoterpenes. In contrast, we observed differences between provenances in response to drought, where provenances sustaining higher CO2 assimilation rates also revealed increased water-use efficiency, carotenoid chlorophyll ratios, pools of xanthophyll cycle pigments, beta-carotene and stored monoterpenes. Our results demonstrate that local adaptation to contrasting habitats affected chlorophyll-carotenoid ratios, pool sizes of photoprotective xanthophylls, beta-carotene, and stored volatile isoprenoids. We conclude that intraspecific variation in isoprenoid-mediated photoprotective mechanisms contributes to the adaptive potential of Douglas-fir provenances to climate change. PMID- 28071756 TI - Association between reductions in low-density lipoprotein cholesterol with statin therapy and the risk of new-onset diabetes: a meta-analysis. AB - A recent meta-analysis demonstrated that statin therapy was associated with a risk of diabetes. The present study investigated whether the relative reduction in low-density lipoprotein cholesterol (LDL-c) was a good indicator of the risk of new-onset diabetes. We searched the PubMed, Embase, Cochrane Central Register, Lilacs, Food and Drug Administration, and European Medicines Agency databases for randomized controlled trials of statins. Fourteen trials were included in the study. Eight trials with target LDL-c levels <=100 mg/dL (2.6 mmol/L) or LDL-c reductions of at least 30% were extracted separately. The results showed that the overall risk of incident diabetes increased by 11% (OR = 1.11; 95% CI 1.03-1.20). The group with intensive LDL-c-lowering statin had an 18% increase in the likelihood of developing diabetes (OR = 1.18; 95% CI, 1.10-1.28). Furthermore, the risks of incident diabetes were 13% (OR = 1.13; 95% CI 1.01-1.26) and 29% (OR = 1.29; 95% CI 1.13-1.47) in the subgroups with 30-40% and 40-50% reductions in LDL-c, respectively, suggesting that LDL-c reduction may provide a dynamic risk assessment parameter for new-onset diabetes. In conclusion, LDL-c reduction is positively related to the risk of new-onset diabetes. When LDL-c is reduced by more than 30% during lipid-lowering therapy, blood glucose monitoring is suggested to detect incident diabetes in high-risk populations. PMID- 28071758 TI - Prevalence of feral swine disturbance at important archaeological sites over a large landscape in Florida. AB - Feral swine are globally known as one of the most destructive invasive vertebrates, damaging native habitats, native plants and animals, agriculture, infrastructure, spreading diseases. There has been little quantification on their disturbance to archaeological sites across a broad landscape. Over 6 years we inspected 293 significant archaeological sites for swine disturbance across a vast area. We found a 42% prevalence of swine disturbance among all sites, with prevalence not distinguishable among prehistoric sites, historic sites, and sites with both components. The areas of disturbance mapped within three historic homestead sites showed 5-26% of total site surface area rooted. Disturbance was not evident upon re-inspection of one of these sites after 18 months, indicating how evidence of disturbance can be obscured in this environment. Thus, our observed 42% prevalence of disturbance should be considered a minimum for disturbance occurring through time. Artifacts depths were <10 cm of the surface at 85% of the sites and <20 cm of the surface for 90% of the sites. Feral swine rooting commonly exceeds 20 cm in depth, especially in soft sandy substrates typical of Florida, making the great majority of the studied sites highly vulnerable to artifact damage or displacement. PMID- 28071757 TI - New insights into the GINS complex explain the controversy between existing structural models. AB - GINS is a key component of eukaryotic replicative forks and is composed of four subunits (Sld5, Psf1, Psf2, Psf3). To explain the discrepancy between structural data from crystallography and electron microscopy (EM), we show that GINS is a compact tetramer in solution as observed in crystal structures, but also forms a double-tetrameric population, detectable by EM. This may represent an intermediate step towards the assembly of two replicative helicase complexes at origins, moving in opposite directions within the replication bubble. Reconstruction of the double-tetrameric form, combined with small-angle X-ray scattering data, allows the localisation of the B domain of the Psf1 subunit in the free GINS complex, which was not visible in previous studies and is essential for the formation of a functional replication fork. PMID- 28071759 TI - Characterization of Pairwise Correlations from Multiple Quantum Correlated Beams Generated from Cascaded Four-Wave Mixing Processes. AB - We theoretically characterize the performance of the pairwise correlations (PCs) from multiple quantum correlated beams based on the cascaded four-wave mixing (FWM) processes. The presence of the PCs with quantum corre- lation in these systems can be verified by calculating the degree of intensity difference squeezing for any pair of all the output fields. The quantum correlation characteristics of all the PCs under different cascaded schemes are also discussed in detail and the repulsion effect between PCs in these cascaded FWM processes is theoretically predicted. Our results open the way for the classification and application of quantum states generated from the cascaded FWM processes. PMID- 28071760 TI - Origin and evolution of MIR1444 genes in Salicaceae. AB - miR1444s are functionally significant miRNAs targeting polyphenol oxidase (PPO) genes for cleavage. MIR1444 genes were reported only in Populus trichocarpa. Through the computational analysis of 215 RNA-seq data, four whole genome sequences of Salicaceae species and deep sequencing of six P. trichocarpa small RNA libraries, we investigated the origin and evolution history of MIR1444s. A total of 23 MIR1444s were identified. Populus and Idesia species contain two MIR1444 genes, while Salix includes only one. Populus and Idesia MIR1444b genes and Salix MIR1444s were phylogenetically separated from Populus and Idesia MIR1444a genes. Ptr-miR1444a and ptr-miR1444b showed sequence divergence. Compared with ptr-miR1444b, ptr-miR1444a started 2 nt upstream of precursor, resulting in differential regulation of PPO targets. Sequence alignments showed that MIR1444 genes exhibited extensive similarity to their PPO targets, the characteristics of MIRs originated from targets through an inverted gene duplication event. Genome sequence comparison showed that MIR1444 genes in Populus and Idesia were expanded through the Salicoid genome duplication event. A copy of MIR1444 gene was lost in Salix through DNA segment deletion during chromosome rearrangements. The results provide significant information for the origin of plant miRNAs and the mechanism of Salicaceae gene evolution and divergence. PMID- 28071762 TI - Quantum dynamics study of energy requirement on reactivity for the HBr + OH reaction with a negative-energy barrier. AB - A time-dependent, quantum reaction dynamics approach in full dimensional, six degrees of freedom was carried out to study the energy requirement on reactivity for the HBr + OH reaction with an early, negative energy barrier. The calculation shows both the HBr and OH vibrational excitations enhance the reactivity. However, even this reaction has a negative energy barrier, the calculation shows not all forms of energy are equally effective in promoting the reactivity. On the basis of equal amount of total energy, the vibrational energies of both the HBr and OH are more effective in enhancing the reactivity than the translational energy, whereas the rotational excitations of both the HBr and OH hinder the reactivity. The rate constants were also calculated for the temperature range between 5 to 500 K. The quantal rate constants have a better slope agreement with the experimental data than quasi-classical trajectory results. PMID- 28071761 TI - Plasma heme-induced renal toxicity is related to a capillary rarefaction. AB - Severe hypertension can lead to malignant hypertension (MH) with renal thrombotic microangiopathy and hemolysis. The role of plasma heme release in this setting is unknown. We aimed at evaluating the effect of a mild plasma heme increase by hemin administration in angiotensin II (AngII)-mediated hypertensive rats. Prevalence of MH and blood pressure values were similar in AngII and AngII + hemin groups. MH rats displayed a decreased renal blood flow (RBF), increased renal vascular resistances (RVR), and increased aorta and interlobar arteries remodeling with a severe renal microcirculation assessed by peritubular capillaries (PTC) rarefaction. Hemin-treated rats with or without AngII displayed also a decreased RBF and increased RVR explained only by PCT rarefaction. In AngII rats, RBF was similar to controls (with increased RVR). PTC density appeared strongly correlated to tubular damage score (rho = -0.65, p < 0.0001) and also renal Heme Oygenase-1 (HO-1) mRNA (rho = -0.67, p < 0.0001). HO-1 was expressed in PTC and renal tubules in MH rats, but only in PTC in other groups. In conclusion, though increased plasma heme does not play a role in triggering or aggravating MH, heme release appears as a relevant toxic mediator leading to renal impairment, primarily through PTC endothelial dysfunction rather than direct tubular toxicity. PMID- 28071763 TI - Starved epithelial cells uptake extracellular matrix for survival. AB - Extracellular matrix adhesion is required for normal epithelial cell survival, nutrient uptake and metabolism. This requirement can be overcome by oncogene activation. Interestingly, inhibition of PI3K/mTOR leads to apoptosis of matrix detached, but not matrix-attached cancer cells, suggesting that matrix-attached cells use alternate mechanisms to maintain nutrient supplies. Here we demonstrate that under conditions of dietary restriction or growth factor starvation, where PI3K/mTOR signalling is decreased, matrix-attached human mammary epithelial cells upregulate and internalize beta4-integrin along with its matrix substrate, laminin. Endocytosed laminin localizes to lysosomes, results in increased intracellular levels of essential amino acids and enhanced mTORC1 signalling, preventing cell death. Moreover, we show that starved human fibroblasts secrete matrix proteins that maintain the growth of starved mammary epithelial cells contingent upon epithelial cell beta4-integrin expression. Our study identifies a crosstalk between stromal fibroblasts and epithelial cells under starvation that could be exploited therapeutically to target tumours resistant to PI3K/mTOR inhibition. PMID- 28071764 TI - Aligned copper nanorod arrays for highly efficient generation of intense ultra broadband THz pulses. AB - We demonstrate an intense broadband terahertz (THz) source based on the interaction of relativistic-intensity femtosecond lasers with aligned copper nanorod array targets. For copper nanorod targets with a length of 5 MUm, a maximum 13.8 times enhancement in the THz pulse energy (in <=20 THz spectral range) is measured as compared to that with a thick plane copper target under the same laser conditions. A further increase in the nanorod length leads to a decrease in the THz pulse energy at medium frequencies (<=20 THz) and increase of the electromagnetic pulse energy in the high-frequency range (from 20-200 THz). For the latter, we measure a maximum energy enhancement of 28 times for the nanorod targets with a length of 60 MUm. Particle-in-cell simulations reveal that THz pulses are mostly generated by coherent transition radiation of laser produced hot electrons, which are efficiently enhanced with the use of nanorod targets. Good agreement is found between the simulation and experimental results. PMID- 28071765 TI - Neural codes of seeing architectural styles. AB - Images of iconic buildings, such as the CN Tower, instantly transport us to specific places, such as Toronto. Despite the substantial impact of architectural design on people's visual experience of built environments, we know little about its neural representation in the human brain. In the present study, we have found patterns of neural activity associated with specific architectural styles in several high-level visual brain regions, but not in primary visual cortex (V1). This finding suggests that the neural correlates of the visual perception of architectural styles stem from style-specific complex visual structure beyond the simple features computed in V1. Surprisingly, the network of brain regions representing architectural styles included the fusiform face area (FFA) in addition to several scene-selective regions. Hierarchical clustering of error patterns further revealed that the FFA participated to a much larger extent in the neural encoding of architectural styles than entry-level scene categories. We conclude that the FFA is involved in fine-grained neural encoding of scenes at a subordinate-level, in our case, architectural styles of buildings. This study for the first time shows how the human visual system encodes visual aspects of architecture, one of the predominant and longest-lasting artefacts of human culture. PMID- 28071766 TI - An optimistic protein assembly from sequence reads salvaged an uncharacterized segment of mouse picobirnavirus. AB - Advances in Next Generation Sequencing technologies have enabled the generation of millions of sequences from microorganisms. However, distinguishing the sequence of a novel species from sequencing errors remains a technical challenge when the novel species is highly divergent from the closest known species. To solve such a problem, we developed a new method called Optimistic Protein Assembly from Reads (OPAR). This method is based on the assumption that protein sequences could be more conserved than the nucleotide sequences encoding them. By taking advantage of metagenomics, bioinformatics and conventional Sanger sequencing, our method successfully identified all coding regions of the mouse picobirnavirus for the first time. The salvaged sequences indicated that segment 1 of this virus was more divergent from its homologues in other Picobirnaviridae species than segment 2. For this reason, only segment 2 of mouse picobirnavirus has been detected in previous studies. OPAR web tool is available at http://bioinformatics.czc.hokudai.ac.jp/opar/. PMID- 28071767 TI - Reply #2 to: Glycemic Choreoballism. AB - In Response To: Lee D, Ahn, TB. Glycemic choreoballism. Tremor Other Hyperkinet Mov. 2016; 6. doi: 10.7916/D8QJ7HNF Original Article: Roy U, Das SK, Mukherjee A, et al. Irreversible hemichoreahemiballism in a case of nonketotic hyperglycemia presenting as the initial manifestation of diabetes mellitus. Tremor Other Hyperkinet Mov. 2016; 6. doi: 10.7916/D8QZ2B3F. PMID- 28071768 TI - Reply #1 to: Glycemic Choreoballism. AB - In Response To: Lee D, Ahn TB. Glycemic choreoballism. Tremor Other Hyperkinet Mov. 2016; 6. doi: 10.7916/D8QJ7HNF Original Article: Cosentino C, Torres L, Nunez Y, et al. Hemichorea/hemiballism associated with hyperglycemia: report of twenty cases. Tremor Other Hyperkinet Mov. 2016; 6. doi: 10.7916/D8DN454P. PMID- 28071774 TI - Intermolecular structure and hydrogen-bonding in liquid 1,2-propylene carbonate and 1,2-glycerol carbonate determined by neutron scattering. AB - Neutron diffraction with isotopic substitution has been used to investigate the liquid structures of propylene carbonate and glycerol carbonate. C-HO[double bond, length as m-dash]C hydrogen-bonding motifs dominate the local structure of propylene carbonate, giving rise to the formation of head-to-tail correlated chains of molecules. In contrast, glycerol carbonate exhibits a more disordered structure with no overall dominant interactions in which the pendant hydroxyl function disrupts structure-making correlations present in propylene carbonate. PMID- 28071775 TI - Copper-catalyzed C-O bond cleavage and cyclization: synthesis of indazolo[3,2 b]quinazolinones. AB - The first example of a copper-catalyzed halogen-free protocol to construct indazolo[3,2-b]quinazolinones was developed through sequential inert C-O bond cleavage followed by intramolecular C-N bond formation. This protocol represents an efficient synthetic tool for accessing a more diverse range of functionalized indazolo[3,2-b]quinazolinones. The structure of the newly synthesized indazolo[3,2-b]quinazolinones was unambiguously confirmed by X-ray crystal diffraction analysis. PMID- 28071776 TI - pi+-pi+ stacking of imidazolium cations enhances molecular layering of room temperature ionic liquids at their interfaces. AB - The interfacial structure of room temperature ionic liquids (RTILs) controls many of the unique properties of RTILs, such as the high capacitance of RTILs and the efficiency of charge transport between RTILs and electrodes. RTILs have been experimentally shown to exhibit interfacial molecular layering structures over a 10 A length scale. However, the driving force behind the formation of these layered structures has not been resolved. Here, we report ab initio molecular dynamics simulations of imidazolium RTIL/air and RTIL/graphene interfaces along with force field molecular dynamics simulations. We find that the pi+-pi+ interaction of imidazolium cations enhances the layering structure of RTILs, despite the electrostatic repulsion. The length scales of the molecular layering at the RTIL/air and RTIL/graphene interfaces are very similar, manifesting the limited effect of the substrate on the interfacial organization of RTILs. PMID- 28071777 TI - Radical recombination in interstellar ices, a not so simple mechanism. AB - Many complex organic molecules (hereafter COMs) have been detected in different regions of the interstellar medium (ISM). In each region, different energetic processes - UV irradiation, atom bombardments, etc. - that could be linked to the formation of detected COMs may occur depending on the environment. Several formation mechanisms were proposed but increasing attention is paid to radical recombination reactions. Previous studies showed that glycolaldehyde (HC(O)CH2OH) and ethylene glycol (HOCH2CH2OH) are formed by radical recombination between HCO and CH2OH, and by CH2OH dimerisation, respectively. Formyl (HCO), one of the most famous astrophysically-relevant radical species, has been detected as a gaseous component of the ISM. Its reactivity was already attributed to the formation of several COMs. This work aims to study the dimerisation of formyl radical HCO using a cryogenic matrix technique. The evolution of the chemical sample composition is monitored by infrared spectroscopy and by mass spectrometry during temperature programmed desorption (TPD) monitoring. Results indicate that the reaction of one HCO with another does not lead to the direct formation of glyoxal (HC(O)C(O)H) but yields H2CO and CO. Results are also compared with those for the reaction between two CH2OH radicals and the recombination between HCO and CH2OH. Also, glyceraldehyde was tentatively detected in our experiment using different spectroscopic techniques. A radical mechanism is proposed to explain its formation in our experiments. Complementary quantum chemical calculations provide an atomistic interpretation of the experimental findings. PMID- 28071778 TI - Ionic liquids and deep eutectic solvents for lignocellulosic biomass fractionation. AB - Lignocellulosic biomass has gained extensive research interest due to its potential as a renewable resource, which has the ability to overtake oil-based resources. However, this is only possible if the fractionation of lignocellulosic biomass into its constituents, cellulose, lignin and hemicellulose, can be conducted more efficiently than is possible with the current processes. This article summarizes the currently most commonly used processes and reviews the fractionation with innovative solvents, such as ionic liquids and deep eutectic solvents. In addition, future challenges for the use of these innovative solvents will be addressed. PMID- 28071779 TI - Diffusive escape through a narrow opening: new insights into a classic problem. AB - We study the mean first exit time (Tepsilon) of a particle diffusing in a circular or a spherical micro-domain with an impenetrable confining boundary containing a small escape window (EW) of an angular size epsilon. Focusing on the effects of an energy/entropy barrier at the EW, and of the long-range interactions (LRIs) with the boundary on the diffusive search for the EW, we develop a self-consistent approximation to derive for Tepsilon a general expression, akin to the celebrated Collins-Kimball relation in chemical kinetics and accounting for both rate-controlling factors in an explicit way. Our analysis reveals that the barrier-induced contribution to Tepsilon is the dominant one in the limit epsilon -> 0, implying that the narrow escape problem is not "diffusion limited" but rather "barrier-limited". We present the small-epsilon expansion for Tepsilon, in which the coefficients in front of the leading terms are expressed via some integrals and derivatives of the LRI potential. Considering a triangular well potential as an example, we show that Tepsilon is non-monotonic with respect to the extent of the attractive LRI, being minimal for the ones having an intermediate extent, neither too concentrated on the boundary nor penetrating too deeply into the bulk. Our analytical predictions are in good agreement with the numerical simulations. PMID- 28071780 TI - Correction: beta-Amyrin synthase from Euphorbia tirucalli L. functional analyses of the highly conserved aromatic residues Phe413, Tyr259 and Trp257 disclose the importance of the appropriate steric bulk, and cation-pi and CH-pi interactions for the efficient catalytic action of the polyolefin cyclization cascade. AB - Correction for 'beta-Amyrin synthase from Euphorbia tirucalli L. functional analyses of the highly conserved aromatic residues Phe413, Tyr259 and Trp257 disclose the importance of the appropriate steric bulk, and cation-pi and CH-pi interactions for the efficient catalytic action of the polyolefin cyclization cascade' by Ryousuke Ito et al., Org. Biomol. Chem., 2017, 15, 177-188. PMID- 28071781 TI - Rhodium-catalyzed enantioselective hydrogenation of alpha-amino acrylonitriles: an efficient approach to synthesizing chiral alpha-amino nitriles. AB - An efficient rhodium-catalyzed asymmetric hydrogenation of alpha-amino acrylonitriles has been developed, affording alpha-acylamino nitriles with high yields and excellent enantioselectivities (up to 99% yield and >99% ee). This novel methodology provides an efficient and concise synthetic route to chiral alpha-amino nitriles, which are versatile intermediates in organic synthesis. PMID- 28071782 TI - Synthesis of fully arylated (hetero)arenes. AB - Multiply arylated arenes are privileged structures with highly useful functions and fascinating optoelectronic and biological properties. This feature article reports the synthesis of fully arylated (hetero)arenes bearing more than two different aryl substituents and categorizes this emerging topic by the type of (hetero)arene core and the type of chemistry employed to install the (hetero)aryl substituents. PMID- 28071783 TI - Preparation and application of silver nanoparticle-functionalized magnetic graphene oxide nanocomposites. AB - Although selective enrichment of glycopeptides from complex biological samples is indispensable for mass spectrometry (MS)-based glycoproteomics, it still remains a great challenge due to the low abundance of glycoproteins and suppression of non-glycopeptides. In this study, silver nanoparticle-functionalized magnetic graphene oxide nanocomposites (GO/Fe3O4/PEI/Ag) were synthesized. Silver nanoparticles were generated in situ on the surface of magnetic graphene oxide using polyethylenimine as a reducing and stabilizing agent. The resulting material was used as an adsorbent for selective enrichment of glycopeptides. GO/Fe3O4/PEI/Ag nanocomposites offered excellent enrichment ability, which was attributed to the synergistic effect of polyethylenimine and silver nanoparticles. The nanocomposites showed superior specificity for glycopeptides even when non-glycopeptides were 100 times more concentrated than glycopeptides. The nanocomposites displayed advantages including rapid adsorption (1 min), low detection limit (25 fmol), repeatability (6 times), and high recovery (77.8%). Using these nanocomposites, 91 different glycoproteins and 136 N-linked glycopeptides were identified from among 20 MUg tryptic human serum proteins and this demonstrated the superior performance of the nanocomposites for glycopeptides enrichment. PMID- 28071784 TI - A continued role for signaling functions in the early evolution of feathers. AB - Persons and Currie (2015) argued against either flight, thermoregulation, or signaling as a functional benefit driving the earliest evolution of feathers; rather, they favored simple feathers having an initial tactile sensory function, which changed to a thermoregulatory function as density increased. Here, we explore the relative merits of early simple feathers that may have originated as tactile sensors progressing instead toward a signaling, rather than (or in addition to) a thermoregulatory function. We suggest that signaling could act in concert with a sensory function more naturally than could thermoregulation. As such, the dismissal of a possible signaling function and the presumption that an initial sensory function led directly to a thermoregulatory function (implicit in the title "bristles before down") are premature. PMID- 28071785 TI - Bioactive polyphenols and cardiovascular disease: chemical antagonists, pharmacological agents or xenobiotics that drive an adaptive response? AB - : Polyphenols are widely regarded to have a wide range of health-promoting qualities, including beneficial effects on cardiovascular disease. Historically, the benefits have been linked to their well-recognized powerful antioxidant activity. However, the concept that the beneficial effects are attributable to direct antioxidant activity in vivo does not pay sufficient heed to the fact that polyphenols degrade rapidly, are poorly absorbed and rapidly metabolized, resulting in very low bioavailability. This review explores alternative mechanisms by which polyphenols, or their metabolites, exert biological activity via mechanisms that can be activated by physiologically relevant concentrations. Evidence is presented to support the action of phenolic derivatives on receptors and signalling pathways to induce adaptive responses that drive changes in endogenous antioxidant, antiplatelet, vasodilatory and anti-inflammatory effects. The implications are that in vitro antioxidant measures as predictors of polyphenol protective activity in vivo hold little relevance and that closer attention needs to be paid to bioavailable metabolites to understand the mode of action of these diet-derived components. LINKED ARTICLES: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc. PMID- 28071786 TI - Functional and cardioprotective effects of simultaneous and individual activation of protein kinase A and Epac. AB - BACKGROUND AND PURPOSE: Myocardial cAMP elevation confers cardioprotection against ischaemia/reperfusion (I/R) injury. cAMP activates two independent signalling pathways, PKA and Epac. This study investigated the cardiac effects of activating PKA and/or Epac and their involvement in cardioprotection against I/R. EXPERIMENTAL APPROACH: Hearts from male rats were used either for determination of PKA and PKC activation or perfused in the Langendorff mode for either cardiomyocyte isolation or used to monitor functional activity at basal levels and after 30 min global ischaemia and 2 h reperfusion. Functional recovery and myocardial injury during reperfusion (LDH release and infarct size) were evaluated. Activation of PKA and/or Epac in perfused hearts was induced using cell permeable cAMP analogues in the presence or absence of inhibitors of PKA, Epac and PKC. H9C2 cells and cardiomyocytes were used to assess activation of Epac and effect on Ca2+ transients. KEY RESULTS: Selective activation of either PKA or Epac was found to trigger a positive inotropic effect, which was considerably enhanced when both pathways were simultaneously activated. Only combined activation of PKA and Epac induced marked cardioprotection against I/R injury. This was accompanied by PKCepsilon activation and repressed by inhibitors of PKA, Epac or PKC. CONCLUSION AND IMPLICATIONS: Simultaneous activation of both PKA and Epac induces an additive inotropic effect and confers optimal and marked cardioprotection against I/R injury. The latter effect is mediated by PKCepsilon activation. This work has introduced a new therapeutic approach and targets to protect the heart against cardiac insults. PMID- 28071787 TI - Interaction of Whey Proteins with Phenolic Derivatives Under Neutral and Acidic pH Conditions. AB - Integration of gallic acid (GA) and its derivative epigallocatechin gallate (EGCG; 20, 120, and 240 MUmol/g, protein basis) into whey protein isolate (WPI) at room temperature and pH 3.0 and pH 7.0 was investigated. At pH 7.0, both phenolics caused significant structural changes and EGCG induced greater digestibility of WPI. Total sulfhydryl in WPI decreased from 28.6 to 7.6 MUmol/g and surface hydrophobicity declined by nearly 50% with 240 MUmol/g EGCG at pH 7.0. Similar but less appreciable changes were produced by GA and at pH 3.0. Isothermal titration and fluorescence quenching tests showed moderately weak binding of WPI with GA but strong binding with EGCG at pH 7.0. Both phenolics at high concentrations lowered the thermal transition temperature of beta lactoglobulin by 0.5 degrees C to 1.4 degrees C and promoted its digestion. The phenolics also displayed a remarkable synergism with peptides in the WPI digest exerting radical scavenging activity. PMID- 28071789 TI - Aspirin-triggered lipoxin A4 inhibits atherosclerosis progression in apolipoprotein E-/- mice. AB - BACKGROUND AND PURPOSE: Atherosclerosis is characterized by a chronic non resolving inflammation in the arterial wall. Aspirin-triggered lipoxin A4 (ATL) is a potent anti-inflammatory mediator, involved in the resolution of inflammation. However, the therapeutic potential of immune targeting by means of ATL in atherosclerosis has not previously been explored. The aim of the present study was to determine the effects of ATL and its receptor Fpr2 on atherosclerosis development and progression in apolipoprotein E deficient (ApoE-/ ) mice. EXPERIMENTAL APPROACH: ApoE-/- * Fpr2+/+ and ApoE-/- * Fpr2-/- mice were generated. Four-week-old mice fed a high-fat diet for 4 weeks and 16-week old mice fed chow diet received osmotic pumps containing either vehicle or ATL for 4 weeks. Atherosclerotic lesion size and cellular composition were measured in the aortic root and thoracic aorta. Lipid levels and leukocyte counts were measured in blood and mRNA was isolated from abdominal aorta and spleen. KEY RESULTS: ATL blocked atherosclerosis progression in the aortic root and thoracic aorta of ApoE-/- mice. In addition, ATL reduced macrophage infiltration and apoptotic cells in atherosclerotic lesions. The mRNA levels of several cytokines and chemokines in the spleen and aorta were reduced by ATL, whereas circulating leukocyte levels were unchanged. The ATL-induced athero-protection was absent in ApoE-/- mice lacking the Fpr2 receptor. CONCLUSION AND IMPLICATIONS: ATL blocked atherosclerosis progression by means of an Fpr2-mediated reduced local and systemic inflammation. These results suggest this anti-inflammatory and pro resolving agent has therapeutic potential for the treatment of atherosclerosis. LINKED ARTICLES: This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc. PMID- 28071788 TI - Chromosome inversions and ecological plasticity in the main African malaria mosquitoes. AB - Chromosome inversions have fascinated the scientific community, mainly because of their role in the rapid adaption of different taxa to changing environments. However, the ecological traits linked to chromosome inversions have been poorly studied. Here, we investigated the roles played by 23 chromosome inversions in the adaptation of the four major African malaria mosquitoes to local environments in Africa. We studied their distribution patterns by using spatially explicit modeling and characterized the ecogeographical determinants of each inversion range. We then performed hierarchical clustering and constrained ordination analyses to assess the spatial and ecological similarities among inversions. Our results show that most inversions are environmentally structured, suggesting that they are actively involved in processes of local adaptation. Some inversions exhibited similar geographical patterns and ecological requirements among the four mosquito species, providing evidence for parallel evolution. Conversely, common inversion polymorphisms between sibling species displayed divergent ecological patterns, suggesting that they might have a different adaptive role in each species. These results are in agreement with the finding that chromosomal inversions play a role in Anopheles ecotypic adaptation. This study establishes a strong ecological basis for future genome-based analyses to elucidate the genetic mechanisms of local adaptation in these four mosquitoes. PMID- 28071790 TI - Synthesizing perspectives on the evolution of cooperation within and between species. AB - Cooperation is widespread both within and between species, but are intraspecific and interspecific cooperation fundamentally similar or qualitatively different phenomena? This review evaluates this question, necessary for a general understanding of the evolution of cooperation. First, we outline three advantages of cooperation relative to noncooperation (acquisition of otherwise inaccessible goods and services, more efficient acquisition of resources, and buffering against variability), and predict when individuals should cooperate with a conspecific versus a heterospecific partner to obtain these advantages. Second, we highlight five axes along which heterospecific and conspecific partners may differ: relatedness and fitness feedbacks, competition and resource use, resource generation abilities, relative evolutionary rates, and asymmetric strategy sets and outside options. Along all of these axes, certain asymmetries between partners are more common in, but not exclusive to, cooperation between species, especially complementary resource use and production. We conclude that cooperation within and between species share many fundamental qualities, and that differences between the two systems are explained by the various asymmetries between partners. Consideration of the parallels between intra- and interspecific cooperation facilitates application of well-studied topics in one system to the other, such as direct benefits within species and kin-selected cooperation between species, generating promising directions for future research. PMID- 28071791 TI - Niche evolution and diversification in a Neotropical radiation of birds (Aves: Furnariidae). AB - Rapid diversification may be caused by ecological adaptive radiation via niche divergence. In this model, speciation is coupled with niche divergence and lineage diversification is predicted to be correlated with rates of niche evolution. Studies of the role of niche evolution in diversification have generally focused on ecomorphological diversification but climatic-niche evolution may also be important. We tested these alternatives using a phylogeny of 298 species of ovenbirds (Aves: Furnariidae). We found that within Furnariidae, variation in species richness and diversification rates of subclades were best predicted by rate of climatic-niche evolution than ecomorphological evolution. Although both are clearly important, univariate regression and multivariate model averaging more consistently supported the climatic-niche as the best predictor of lineage diversification. Our study adds to the growing body of evidence, suggesting that climatic-niche divergence may be an important driver of rapid diversification in addition to ecomorphological evolution. However, this pattern may depend on the phylogenetic scale at which rate heterogeneity is examined. PMID- 28071792 TI - Thermal Stability Improvement of Rice Bran Albumin Protein Incorporated with Epigallocatechin Gallate. AB - Rice bran albumin protein (RAP) is sensitive to thermal changes and tends to degrade when exposed to high-temperature processing. In this work, RAP epigallocatechin-3-gallate (EGCG) complex (RAPE) was prepared and the thermal stability was evaluated. Fluorescence results showed that EGCG could interact with RAP with a binding number n of 0.0885:1 (EGCG:RAP, w/w) and a binding constant K of 1.02 (+/- 0.002) *104 /M, suggesting both hydrogen bonding and van der Waals forces played an important role. FTIR analysis demonstrated that EGCG could induce secondary structural changes in RAP above a ratio of 1.6:1 (EGCG:RAP, w/w). Interestingly, the secondary structure changes of RAPE at different temperatures (25, 50, 60, 70, and 80 degrees C) were inhibited compared with that for RAP, suggesting RAPE was more resistant and stable to the heat treatment. In addition, a dense porous structure of RAPE was achieved due to the EGCG binding after thermal treatment. Furthermore, the Tpeak temperature of RAPE increased significantly from 64.58 to 74.16 degrees C and the enthalpy also increased from 85.53 to 138.52 J/g with a mass ratio increasing from 0 to 3.2 (EGCG:RAP, w/w), demonstrating the thermal stability of RAPE. In addition, the valine, methionine, and lysine content in RAPE were significantly higher than RAP following 80 degrees C treatment for 20 min (P < 0.05), exhibiting enhanced amino acid profiles, which might be due to EGCG-RAP interactions and microenvironment changes around relevant amino acids. These findings demonstrate that EGCG has the potential to improve the thermal stability of sensitive proteins and is beneficial for usage in the food industry. PMID- 28071793 TI - Antioxidant Effect of Natural Table Olives Phenolic Extract Against Oxidative Stress and Membrane Damage in Enterocyte-Like Cells. AB - The phenolic fraction of a naturally fermented cultivar of table olives, "Tonda di Cagliari," was investigated for the ability to protect Caco-2 cells against oxidative stress and membrane damage induced by tert-butyl hydroperoxyde (TBH). TBH exposure resulted in an alteration of cellular redox status, with an increase in reactive oxygen species (ROS) and a decrease in reduced glutathione (GSH) level. A loss of the epithelial integrity, as indicated by the decrease of the transepithelial electrical resistance value, was also observed over time, together with an intense lipid peroxidation process. The olives phenolic extract significantly counteracted ROS generation and subsequent alteration of monolayer integrity and membrane oxidative damage. The protective action of the extract is likely due to the scavenging ability of its main components, as hydroxytyrosol, oleuropein, and verbascoside among the secoiridoids and derivatives. Since olives phenolic compounds concentrate in the intestinal lumen, they may be a useful tool in the prevention of intestinal disorders related to oxidative damage. PMID- 28071794 TI - Irrigation and fruit canopy position modify oil quality of olive trees (cv. Frantoio). AB - BACKGROUND: Fruit development and oil quality in Olea europaea L. are strongly influenced by both light and water availability. In the present study, the simultaneous effects of light environment and irrigation on fruit characteristics and oil quality were studied in a high-density orchard over two consecutive years. Olive fruits were harvested from three canopy positions (intercepting approximately 64%, 42% and 30% of above canopy radiation) of fully-productive trees subjected to full, deficit or complementary irrigation. RESULTS: Fruits receiving 61-67% of above canopy radiation showed the highest fruit weight, mesocarp oil content and maturation index, whereas those intercepting only 27-33% showed the lowest values. Palmitoleic and linoleic acids increased in oils obtained from fruits exposed to high light levels, whereas oleic acid and the oleic-linoleic acid ratio decreased. Neither canopy position, nor irrigation affected K232 , K270 , DeltaK and the concentration of lignan in virgin olive oils (VOOs). Total phenols, 3,4-DHPEA-EDA [2-(3,4-hydroxyphenyl)ethyl (3S,4E)-4 formyl-3-(2-oxoethyl)hex-4-enoate] and p-HPEA-EDA (decarboxymethyl ligstroside aglycone) increased in VOOs produced from fruits harvested from the top of the canopy, whereas full irrigation decreased total phenols and 3,4-DHPEA-EDA concentrations with respect to the complementary irrigation treatment. CONCLUSION: Light and water availability are crucial not only for tree productivity, but also they clearly affect olive oil quality. (c) 2017 Society of Chemical Industry. PMID- 28071795 TI - Consumers' expectations and acceptability for low saturated fat 'salami': healthiness or taste? AB - BACKGROUND: Nutritional properties of meat and meat products are becoming very important in purchasing behaviour, because consumers are even more concerned about healthiness. The present study aimed to examine the influence of health information on the expected and informed acceptability of salami. Traditional salami and two low saturated fat salami produced with partial or total substitution of pork backfat with extra virgin oil were evaluated. RESULTS: Perceived acceptability was the lowest in salami with total animal fat substitution. In both low saturated fat salami, expected acceptability was significantly higher than perceived acceptability, while in traditional salami it was lower. Consumers completely assimilated their liking in the direction of expectations for salami with partial animal fat substitution, whereas incomplete assimilation was observed for salami with total animal fat substitution. The results also revealed that some sociodemographic characteristics discriminate consumer clusters from each other. CONCLUSION: The present study highlights that nutritional information is not enough to satisfy consumers' expectations if the product is not sensorily acceptable. Findings about the relevance of information and consumers' segmentation could have important implications for policy makers and the meat product industry. (c) 2017 Society of Chemical Industry. PMID- 28071796 TI - Influence of Package Visual Cues of Sweeteners on the Sensory-Emotional Profiles of Their Products. AB - Substantial evidence suggests influence of color, physical state, and other extrinsic features on consumer perception and acceptability of food products. In this study, 560 subjects evaluated liking and emotional responses associated with 5 sweeteners (sucralose, stevia, saccharin, aspartame, and sucrose) under 2 eliciting conditions: control (brand name only) and informed (brand name/packet image), to assess impact of the packet color. For a given condition, 5 identical tea samples each labeled with a sweetener type were rated for sweetness and overall liking (9-point) and emotions (5-point). Nonsignificant interactions between eliciting condition and sweetener type were found for liking attributes and emotions (except peaceful), indicating their independent effects. However, overall differences existed among sweetener types and eliciting conditions based on both hedonic and emotional responses (MANOVA, P < 0.05), suggesting modulating effects of packet color on sweetener type in the sensory-emotion space. The sensory-emotion profile for sucrose was separate from that of nonnutritive sweeteners, with statistically significant Mahalanobis distances among sample centroids. Increases in positive emotion intensities contrasted with a decrease in negative emotion intensities were observed for some sweeteners moving from the control to informed condition. Sweetness liking was strongly correlated with the emotion satisfied (sucralose, saccharin) only in the control condition, whereas it was strongly correlated with the emotions pleased and satisfied (stevia), disgusted (aspartame), and satisfied (sucrose) only in the informed condition. Overall, results suggested that sensory liking and emotions during the consumption experience are related not entirely to the type of sweetener, but also the color of the packet. PMID- 28071797 TI - Classification and characterization of Japanese consumers' beef preferences by external preference mapping. AB - BACKGROUND: Over the past few decades, beef producers in Japan have improved marbling in their beef products. It was recently reported that marbling is not well correlated with palatability as rated by Japanese consumers. This study sought to identify the consumer segments in Japan that prefer sensory characteristics of beef other than high marbling. RESULTS: Three Wagyu beef, one Holstein beef and two lean imported beef longissimus samples were subjected to a descriptive sensory test, physicochemical analysis and a consumer (n = 307) preference test. According to consumer classification and external preference mapping, four consumer segments were identified as 'gradual high-fat likers', 'moderate-fat and distinctive taste likers', 'Wagyu likers' and 'distinctive texture likers'. Although the major trend of Japanese consumers' beef preference was 'marbling liking', 16.9% of the consumers preferred beef samples that had moderate marbling and distinctive taste. The consumers' attitudes expressed in a questionnaire survey were in good agreement with the preference for marbling among the 'moderate-fat and distinctive taste likers'. CONCLUSION: These results indicate that moderately marbled beef is a potent category in the Japanese beef market. (c) 2017 Society of Chemical Industry. PMID- 28071798 TI - Impact of rhizobial inoculation and reduced N supply on biomass production and biological N2 fixation in common bean grown hydroponically. AB - BACKGROUND: Testing rhizobial inoculation of common bean (Phaseolus vulgaris L.) in hydroponics enables accurate quantification of biological N2 fixation (BNF) and provides information about the potential of reducing inorganic N fertilizer use. In view of this background, common bean grown on pumice was inoculated with Rhizobium tropici CIAT899 (Rt) and supplied with either full-N (total nitrogen 11.2 mmol L-1 ), 1/3 of full-N or N-free nutrient solution (NS). BNF was quantified at the early pod-filling stage using the 15 N natural abundance method. RESULTS: Full-N supply to Rt-inoculated plants resulted in markedly smaller nodules than less- or zero-N supply, and no BNF. Rt inoculation of full-N treated plants did not increase biomass and pod yield compared with non inoculation. Restriction (1/3 of full-N) or omission of inorganic N resulted in successful nodulation and BNF (54.3 and 49.2 kg N ha-1 , corresponding to 58 and 100% of total plant N content respectively) but suppressed dry shoot biomass from 191.7 (full-N, +Rt) to 107.4 and 43.2 g per plant respectively. Nutrient cation uptake was reduced when inorganic N supply was less or omitted. CONCLUSION: Rt inoculation of hydroponic bean provides no advantage when full-N NS is supplied, while 1/3 of full-N or N-free NS suppresses plant biomass and yield, partly because the restricted NO3- supply impairs cation uptake. (c) 2017 Society of Chemical Industry. PMID- 28071799 TI - Seroepidemiological and phylogenetic characterization of neurotropic enteroviruses in Ireland, 2005-2014. AB - Enteroviruses (EVs) are associated with a broad spectrum of clinical presentation, including aseptic meningitis (AM), encephalitis, hand, foot and mouth disease, acute flaccid paralysis, and acute flaccid myelitis. Epidemics occur sporadically and are associated with increased cases of AM in children. The present study describes the seroepidemiological analysis of circulating EVs in Ireland from 2005 to 2014 and phylogenetic characterization of echovirus 30 (E 30), enterovirus A71 (EV-A71), and enterovirus D68 (EV-D68). EV VP1 genotyping was applied to viral isolates and clinical samples, including cerebrospinal fluid (CSF), and those isolates that remained untypeable by neutralising anti-sera. An increase in AM cases from 2010 to 2014 was associated with an E-30 genogroup variant VII and sequences clustered phylogenetically with those detected in AM outbreaks in France and Italy. EV-D68 viral RNA was not detected in CSF samples and no neurological involvement was reported. Three EV-A71 positive CSF samples were identified in patients presenting with AM. A phylogenetic analysis of respiratory-associated EV-D68 and EV-A71 cases in circulation was performed to determine baseline epidemiological data. EV-D68 segregated with clades B and B(1) and EV-A71 clustered as subgenogroup C2. The EV VP1 genotyping method was more sensitive than neutralising anti-sera methods by virus culture and importantly demonstrated concordance between EV genotypes in faecal and CSF samples which should facilitate EV screening by less invasive sampling approaches in AM presentations. PMID- 28071800 TI - Influence of Fermentation Process on the Anthocyanin Composition of Wine and Vinegar Elaborated from Strawberry. AB - Anthocyanins are the major polyphenolic compounds in strawberry fruit responsible for its color. Due to their sensitivity, they are affected by food processing techniques such as fermentation that alters both their chemical composition and organoleptic properties. This work aims to evaluate the impact of different fermentation processes on individual anthocyanins compounds in strawberry wine and vinegar by UHPLC-MS/MS Q Exactive analysis. Nineteen, 18, and 14 anthocyanin compounds were identified in the strawberry initial substrate, strawberry wine, and strawberry vinegar, respectively. Four and 8 anthocyanin compounds were tentatively identified with high accuracy for the 1st time to be present in the beverages obtained by alcoholic fermentation and acetic fermentation of strawberry, respectively. Both, the total and the individual anthocyanin concentrations were decreased by both fermentation processes, affecting the alcoholic fermentation to a lesser extent (19%) than the acetic fermentation (91%). Indeed, several changes in color parameters have been assessed. The color of the wine and the vinegar made from strawberry changed during the fermentation process, varying from red to orange color, this fact is directly correlated with the decrease of anthocyanins compounds. PMID- 28071801 TI - Formation and Characterization of Green Tea Extract Loaded Liposomes. AB - Green tea extract was encapsulated into liposomes to enhance bioavailability and stability of catechins by protecting their functional properties simultaneously. Encapsulation was achieved by dispersing 1% (w/v) soy lecithin through high pressure homogenization (microfluidization) and ultrasonication. Effects of homogenization type and pH of the dispersing medium on the physical properties and stability of the liposomes during 1-mo storage period were investigated. Mean particle size, total phenolic content by Folin-Ciocalteu method and antioxidant activity by 2-diphenyl-1-picrylhydrazyl radical scavenging and ferric reducing antioxidant power methods, and transmission electron microscopy (TEM) experiments were conducted for characterization. Green tea extract loaded liposomes prepared by microfluidization in distilled water were determined as the most stable system which demostrated no significant difference (P > 0.05) on mean particle size, total phenolic content, and antioxidant activity between the first and final day of 1-mo storage time. Additionally, uniform size and shape in TEM images supported the results. PMID- 28071802 TI - Essential Oils Against Pathogen and Spoilage Microorganisms of Fruit Juices: Use of Versatile Antimicrobial Delivery Systems. AB - Essential oils (EO) are increasingly used as natural antimicrobial compounds, however the effect of delivery system to enhance their antimicrobial activity has not been widely studied. Limonene (0 to 10 MUL/mL) was added to microbial suspensions (~105 CFU/mL) of selected foodborne pathogens (Listeria monocytogenes Scott A, Salmonella enterica Typhimurium, Escherichia coli and Staphylococcus aureus), and spoilage microorganisms (Lactobacillus plantarum, Saccharomyces cerevisiae, and Candida albicans). S. aureus was found to be the most sensitive foodborne pathogen while Salmonella enterica showed continued growth under all concentrations. Stable nanoemulsions and solid lipid nanoparticles (SLN) (d ~ 170 nm) were prepared using an alkane carrier oil (n-tetradecane and n-eicosane, respectively). Interfacial effects and homogenous distribution of limonene in nanoemulsions improved its (8 and 12 MUL/mL) antimicrobial effect against S. aureus. Higher aqueous concentrations as a result of expulsion from SLN further enhanced the antimicrobial activity pronounced at higher limonene concentrations. Therefore, our findings confirm that the emulsion-based delivery systems are able to effectively distribute limonene inside a microbial suspension to improve its antimicrobial activity. PMID- 28071803 TI - Effects of Catechol O-Methyl Transferase Inhibition on Anti-Inflammatory Activity of Luteolin Metabolites. AB - Although luteolin is known to have potent anti-inflammatory activities, much less information has been provided on such activities of its hepatic metabolites. Luteolin was subjected to hepatic metabolism in HepG2 cells either without or with catechol O-methyl transferase (COMT) inhibitor. To identify hepatic metabolites of luteolin without (luteolin metabolites, LMs) or with COMT inhibitor (LMs+CI), metabolites were treated by beta-glucuronidase and sulfatase, and found that they were composed of glucuronide and sulfate conjugates of diosmetin in LMs or these conjugates of luteolin in LMs+CI. LMs and LMs+CI were examined for their anti-inflammatory activities on LPS stimulated Raw 264.7 cells. Expression of iNOS and production of nitric oxide and pro-inflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6 were suppressed more effectively by the treatment with LMs+CI than LMs. Our data provide a new insight on possible improvement in functional properties of luteolin on target cells by modifying their metabolic pathway in hepatocytes. PMID- 28071804 TI - Differential Scanning Calorimetry Analysis of the Effects of Heat and Pressure on Protein Denaturation in Soy Flour Mixed with Various Types of Plasticizers. AB - The effects of heat and pressure on protein denaturation in soy flour were explored by an experimental design that used pressure (atmospheric to 600 MPa), temperature (room to 90 degrees C), time (1 to 60 min), and type of aqueous plasticizer (NaCl, sucrose, betaine, and lactobionic acid (LBA)) as factors. When 50% (w/w) soy flour-water paste was high hydrostatic pressure (HHP)-treated for 20 min at 25 degrees C, the treatment at 200 MPa showed a small effect on denaturation of only the 7S soy globulin, but the treatment at 600 MPa showed a significant effect on denaturation of both the 7S and 11S soy globulins. The treatment at 60 degrees C showed a less-pronounced effect on denaturation of the 11S globulin, even at 600 MPa, but that at 90 degrees C showed a similar extent of denaturation of the 11S globulin at 600 MPa to that at 25 degrees C. Chaotropic 2N NaCl, 50% sucrose-, 50% betaine-, or 50% LBA-water solutions showed protective effects on protein denaturation during HHP treatment at 25 degrees C. Although LBA enhanced the extent of thermostability of soy protein less than did 2N NaCl, LBA exhibited better stabilization against pressure. The results from DSC analysis demonstrated that thermostable soy proteins were not always barostable. PMID- 28071805 TI - Antioxidant and chelating capacity of Maillard reaction products in amino acid sugar model systems: applications for food processing. AB - BACKGROUND: Maillard reaction products (MRP) have gained increasing interest owing to their both positive and negative effects on human health. Aqueous amino acid-sugar model systems were studied in order to evaluate the antioxidant and chelating activity of MRP under conditions similar to those of food processing. Amino acids (cysteine, glycine, isoleucine and lysine) combined with different sugars (fructose or glucose) were heated to 100 and 130 degrees C for 30, 60 and 90 min. Antioxidant capacity was evaluated via ABTS and DPPH free radical scavenging assays, in addition to Fe2+ and Cu2+ ion chelating capacity. RESULTS: In the ABTS assay, the cysteine-fructose model system presented the highest antioxidant activity at 7.05 umol mL-1 (130 degrees C, 60 min), expressed in Trolox equivalents. In the DPPH assay, the cysteine-glucose system presented the highest antioxidant activity at 3.79 umol mL-1 (100 degrees C, 90 min). The maximum rate of chelation of Fe2+ and Cu2+ was 96.31 and 59.44% respectively in the lysine-fructose and cysteine-glucose systems (100 degrees C, 30 min). CONCLUSION: The model systems presented antioxidant and chelating activity under the analyzed temperatures and heating times, which are similar to the processing conditions of some foods. (c) 2017 Society of Chemical Industry. PMID- 28071806 TI - GPs' perspectives on prescribing for older people in primary care: a qualitative study. AB - AIMS: The aim of this study was firstly to reveal the determinants of GP prescribing behaviour for older adults in primary care and secondly to elicit GPs' views on the potential role for broad intervention strategies involving pharmacists and/or information technology systems in general practice. METHODS: Semi-structured qualitative interviews were carried out with a purposive sample of GPs. Three multidisciplinary researchers independently coded the interview data using a framework approach. Emerging themes were mapped to the Theoretical Domains Framework (TDF), a tool used to apply behaviour change theories. RESULTS: Sixteen GPs participated in the study. The following domains in the TDF were identified as being important determinants of GP prescribing behaviour: 'Knowledge', 'Skills', 'Reinforcement', 'Memory Attention and Decision Process', 'Environmental Context and Resources', 'Social Influences', 'Social/Professional Role and Identity'. Participants reported that the challenges associated with prescribing for an increasingly older population will require them to become more knowledgeable in pharmacology and drug interactions and they called for extra training in these topics. GPs viewed strategies such as academic detailing sessions delivered by pharmacists or information technology systems as having a positive role to play in optimizing prescribing. CONCLUSION: This study highlights the complexities of behavioural determinants of prescribing for older people in primary care and the need for additional supports to optimize prescribing for this growing cohort of patients. Interventions that incorporate, but are not limited to interprofessional collaboration with pharmacists and information technology systems, were identified by GPs as being potentially useful for improving prescribing behaviour, and therefore require further exploration. PMID- 28071807 TI - Increased protein content of chickpea (Cicer arietinum L.) inoculated with arbuscular mycorrhizal fungi and nitrogen-fixing bacteria under water deficit conditions. AB - BACKGROUND: Chickpea (Cicer arietinum L.) is a widely cropped pulse and an important source of proteins for humans. In Mediterranean regions it is predicted that drought will reduce soil moisture and become a major issue in agricultural practice. Nitrogen (N)-fixing bacteria and arbuscular mycorrhizal (AM) fungi have the potential to improve plant growth and drought tolerance. The aim of the study was to assess the effects of N-fixing bacteria and AM fungi on the growth, grain yield and protein content of chickpea under water deficit. RESULTS: Plants inoculated with Mesorhizobium mediterraneum or Rhizophagus irregularis without water deficit and inoculated with M. mediterraneum under moderate water deficit had significant increases in biomass. Inoculation with microbial symbionts brought no benefits to chickpea under severe water deficit. However, under moderate water deficit grain crude protein was increased by 13%, 17% and 22% in plants inoculated with M. mediterraneum, R. irregularis and M. mediterraneum + R. irregularis, respectively. CONCLUSION: Inoculation with N-fixing bacteria and AM fungi has the potential to benefit agricultural production of chickpea under water deficit conditions and to contribute to increased grain protein content. (c) 2017 Society of Chemical Industry. PMID- 28071808 TI - Structure and feasibility of extra practice during stroke rehabilitation: A systematic scoping review. AB - BACKGROUND/AIM: Improved motor performance is related to the amount of practice completed after a stroke. Australian guidelines recommend that at least one hour of active practice should be completed per day. Yet active practice levels remain low. The aims of this scoping review were to describe how extra practice at the activity level is structured for stroke survivors, and explore the feasibility of participants completing extra practice. METHODS: A systematic search was conducted of five electronic databases up to August 2015. Trials were included when the intended dose of the control intervention was less than the experimental intervention. The structure of extra practice was classified by the level of supervision, type of personnel, and whether equipment was used. Feasibility of practice was explored by comparing the intended and actual dose of practice completed. RESULTS: Thirty-five trials, comprising 40 comparisons were included. Multiple configurations of personnel, supervision and equipment were used to structure extra practice. The structure most often used was full supervision by staff without equipment (30 comparisons), typically involving a therapist (17 comparisons), with equipment being used occasionally (12 comparisons). Sixteen comparisons reported both the intended and the actual dose of extra practice completed. The mean percentage of actual extra practice completed was 80% (SD 18) of the intended dose. CONCLUSIONS: Extra practice during rehabilitation after stroke is most often structured using full supervision by a therapist, and appears feasible for stroke survivors to complete. Less often, extra practice is structured using equipment, non-therapists and/or group classes. PMID- 28071809 TI - Bioaccessibility of selenium from cooked rice as determined in a simulator of the human intestinal tract (SHIME). AB - BACKGROUND: As an essential but also potentially toxic element, both overexposure and underexposure to selenium (Se) can significantly affect public health. Rice is a common source of Se, especially in Asia. Not all Se may be released from the rice and become available for absorption into the bloodstream upon digestion in the gastrointestinal tract. Therefore, the bioaccessibility of Se in cooked white (polished) rice was assessed in vitro using the static gastrointestinal simulator SHIME (Simulator of the Human Intestinal Microbial Ecosystem). RESULTS: The common cooking procedure in China prior to consumption [i.e. boiling at low rice:water ratios (1:3) until all of the water is absorbed into the rice] did not change total Se levels in the rice. Gastrointestinal digestion of the cooked rice matrix revealed a Se bioaccessibility of 67-76% of total Se. Subsequent microbial activity in the colon reduced the accessibility of Se in the cooked rice to 51 62%. CONCLUSION: Not all Se present in cooked white rice should be considered as being bioavailable in the small intestine. A minor part is transferred with the remaining food matrix to the colon, where it is available for the microbial metabolism. (c) 2017 Society of Chemical Industry. PMID- 28071810 TI - Deer leather: analysis of the microstructure affecting pebble. AB - BACKGROUND: Deer leather has a characteristic pattern, referred to as 'pebble', which is accorded such importance that a lack of it renders a leather defective. Synchrotron-based small-angle X-ray scattering (SAXS), ultrasonic imaging, scanning electron microscopy, and tear tests were used to investigate the structural characteristics of well-pebbled and poorly pebbled cervine leathers. RESULTS: Poorly pebbled leather has a less open structure in the upper grain region than well-pebbled leather. The orientation index (OI) of leather with a poor pebble is less than that of the well-pebbled leather, particularly in the corium. The tear strength is also less for the poorly pebbled leather. CONCLUSIONS: The differences in structure between well- and poorly pebbled cervine leathers are not the same as the structural differences between tight and loose bovine leathers, to which they are sometimes compared. On the contrary, good pebble may reflect an internal structure similar to that of looseness. It is hoped that methods to prevent a reduction in pebbling during the processing of cervine leather may be developed by applying this knowledge of cervine leather's structural characteristics. (c) 2017 Society of Chemical Industry. PMID- 28071811 TI - Extraction of Epigallocatechin Gallate and Epicatechin Gallate from Tea Leaves Using beta-Cyclodextrin. AB - Use of organic solvents to extract phenolic compounds from plants may result in environmental pollution and cause health problems in persons. Replacing organic extraction solvents by green extracting agents without affecting the extraction yield is one of the most pressing problems to be solved. The aim of this study is to evaluate the capacity of beta-cyclodextrin (beta-CD) to recover phenolic compounds from tea leaves. The extract obtained using the ethanol/water mixture presented the highest total phenolic content, followed by those obtained using beta-CD solution and water. HPLC analysis of the extracts showed that the addition of beta-CD to the extracting agent had a selective effect on the extraction of epigallocatechin gallate (EGCG) and epicatechin gallate (ECG). The extraction yield of EGCG and ECG using 15 g/L beta-CD were higher than that obtained using water and 50% ethanol. Molecular docking results indicated that the molecules of EGCG and ECG were more inclined to interact with beta-CD than epigallocatechin, epicatechin, and gallocatechin. The impact of beta-CD concentration, temperature, and time on EGCG and ECG extraction from tea leaves was investigated and the maximum amount of EGCG (118.7 mg/g) and ECG (54.6 mg/g) were achieved when extracted with 25 g/L aqueous beta-CD solution at 60 degrees C for 60 min. The present study indicates that aqueous beta-CD can be used as an alternative to organic solvents to recover EGCG and ECG from tea leaves. PMID- 28071812 TI - Recovery of aquatic insect-mediated methylmercury flux from ponds following drying disturbance. AB - Small ponds exist across a permanence gradient, and pond permanence is hypothesized to be a primary determinant of insect community structure and insect mediated methylmercury (MeHg) flux from ponds to the surrounding terrestrial landscape. The present study describes the first experiment examining the recovery of insect-mediated MeHg flux following a drying disturbance that converted permanent ponds with insectivorous fish to semipermanent ponds without fish. Floating emergence traps were used to collect emergent insects for 10 wk in the spring and summer from 5 ponds with fish (permanent) and 5 ponds that were drained to remove fish, dried, and refilled with water (semipermanent). During the 73-d period after semipermanent ponds were refilled, total MeHg flux from semipermanent ponds was not significantly different than total MeHg flux from permanent ponds, indicating that insect-mediated MeHg flux had rapidly recovered in semipermanent ponds following the drying disturbance. Methylmercury fluxes from dragonflies (Odonata: Anisoptera) and phantom midges (Diptera: Chaoboridae) were significantly greater from newly refilled semipermanent ponds than permanent ponds, but the MeHg fluxes from the other 8 emergent insect taxa did not differ between treatments. The present study demonstrates the impact of drying disturbance and the effect of community structure on the cross-system transport of contaminants from aquatic to terrestrial ecosystems. Environ Toxicol Chem 2017;36:1986-1990. (c) 2017 SETAC. PMID- 28071813 TI - Sex differences in tendon structure and function. AB - Tendons play a critical role in the transmission of forces between muscles and bones, and chronic tendon injuries and diseases are among the leading causes of musculoskeletal disability. Little is known about sex-based differences in tendon structure and function. Our objective was to evaluate the mechanical properties, biochemical composition, transcriptome, and cellular activity of plantarflexor tendons from 4 month old male and female C57BL/6 mice using in vitro biomechanics, mass spectrometry-based proteomics, genome-wide expression profiling, and cell culture techniques. While the Achilles tendons of male mice were approximately 6% larger than female mice (p < 0.05), the cell density of female mice was around 19% greater than males (p < 0.05). No significant differences in mechanical properties (p > 0.05) of plantaris tendons were observed. Mass spectrometry proteomics analysis revealed no significant difference between sexes in the abundance of major extracellular matrix (ECM) proteins such as collagen types I (p = 0.30) and III (p = 0.68), but female mice had approximately twofold elevations (p < 0.05) in less abundant ECM proteins such as fibronectin, periostin, and tenascin C. The transcriptome of male and female tendons differed by only 1%. In vitro, neither the sex of the serum that fibroblasts were cultured in, nor the sex of the ECM in which they were embedded, had profound effects on the expression of collagen and cell proliferation genes. Our results indicate that while male mice expectedly had larger tendons, male and female tendons have very similar mechanical properties and biochemical composition, with small increases in some ECM proteins and proteoglycans evident in female tendons. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2117-2126, 2017. PMID- 28071814 TI - Genital porokeratosis with amyloid deposition mimicking extramammary Paget disease. PMID- 28071815 TI - Effect of glenohumeral elevation on subacromial supraspinatus compression risk during simulated reaching. AB - Mechanical subacromial rotator cuff compression is one theoretical mechanism in the pathogenesis of rotator cuff disease. However, the relationship between shoulder kinematics and mechanical subacromial rotator cuff compression across the range of humeral elevation motion is not well understood. The purpose of this study was to investigate the effect of humeral elevation on subacromial compression risk of the supraspinatus during a simulated functional reaching task. Three-dimensional anatomical models were reconstructed from shoulder magnetic resonance images acquired from 20 subjects (10 asymptomatic, 10 symptomatic). Standardized glenohumeral kinematics from a simulated reaching task were imposed on the anatomic models and analyzed at 0, 30, 60, and 90 degrees humerothoracic elevation. Five magnitudes of humeral retroversion were also imposed on the models at each angle of humerothoracic elevation to investigate the impact of retroversion on subacromial proximities. The minimum distance between the coracoacromial arch and supraspinatus tendon and footprint were quantified. When contact occurred, the magnitude of the intersecting volume between the supraspinatus tendon and coracoacromial arch was also quantified. The smallest minimum distance from the coracoacromial arch to the supraspinatus footprint occurred between 30 and 90 degrees , while the smallest minimum distance to the supraspinatus tendon occurred between 0 and 60 degrees . The magnitude of humeral retroversion did not significantly affect minimum distance to the supraspinatus tendon except at 60 or 90 degrees humerothoracic elevation. The results of this study provide support for mechanical rotator cuff compression as a potential mechanism for the development of rotator cuff disease. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2329-2337, 2017. PMID- 28071816 TI - Tritium-labelled alkaloids: Synthesis and applications. AB - This review discusses the synthetic methods used to tritiate nonmorphinan alkaloids as well as their applications. PMID- 28071817 TI - Solution and Gas-Phase Reactivity of Me12 Fe8- and Related Cluster Ions. AB - The cluster ion Me12 Fe8- is an unprecedented representative of organoiron species, which are of great interest because of their possible role as intermediates in iron-catalyzed cross-coupling reactions. To learn more about its behavior in solution, the possible formation of related cluster ions, and their reactivity, electrospray-ionization mass spectrometry and gas-phase experiments were performed. Me12 Fe8- adopts a highly dynamic behavior in solution and disappears in the presence of the chelating ligand N,N,N',N' tetramethylethylenediamine. Besides homoleptic Me12 Fe8- , its heteroleptic analogues Me12-n Fe8 Phn- , n=1-5, are also accessible. Me12 Fe8- undergoes iron halogen exchange reactions with aryl halides. These substrates, as well as their alkyl counterparts, mediate the formation of new homoleptic cluster ions up to Me18 Fe12- . In contrast, no evidence was found for oxidative additions or related reactions. Gas-phase fragmentation of the cluster ions results in numerous different reactions, ranging from the loss of single methyl radicals to the reductive elimination of MePh. PMID- 28071818 TI - Safety profile of the direct oral anticoagulants: an analysis of the WHO database of adverse drug reactions. AB - AIM: Direct oral anticoagulants (DOACs) have shown noninferiority to warfarin for stroke prevention in nonvalvular atrial fibrillation (AF) and a more promising safety profile. Unanswered safety aspects remain to be addressed and available evidence on the risk associated with these drugs are conflicting. In order to contribute to the debate on their safety profile, we conducted a comparative analysis of the reports of suspected adverse drug reactions (ADRs) associated with DOACs in VigiBase. METHODS: Study based on reports of suspected ADRs held in VigiBase as at December 2014, in which a DOAC or warfarin were administered in patients with nonvalvular AF and listed as suspected/interacting drugs. Medical Dictionary for Regulatory Activities was used to classify ADRs. Reporting odds ratio (ROR) with 95% confidence interval were calculated. Results with P <= 0.05 were statistically significant. RESULTS: We retrieved 32 972 reports. We identified 204 ADRs with a ROR >1 (P <= 0.05) and we focused on 105 reactions. Positive ROR emerged for DOACs and gastrointestinal haemorrhage compared with warfarin [(1.6 (1.47-1.75)], but no disproportionality with cerebral haemorrhage was found [0.31 (0.28-0.34)]. We identified other potential signals that have not been associated with DOACs previously. CONCLUSIONS: As well as premarketing authorization clinical trial studies, we found a reduced risk of intracranial haemorrhage, but an increased risk of gastrointestinal haemorrhage in patients treated with DOACs compared to warfarin. We provide new data and we highlight several differences between the three novel oral anticoagulants, in the rate and type of ADRs occurred. PMID- 28071819 TI - Evidence that interfibrillar load transfer in tendon is supported by small diameter fibrils and not extrafibrillar tissue components. AB - Collagen fibrils in tendon are believed to be discontinuous and transfer tensile loads through shear forces generated during interfibrillar sliding. However, the structures that transmit these interfibrillar forces are unknown. Various extrafibrillar tissue components (e.g., glycosaminoglycans, collagens XII and XIV) have been suggested to transmit interfibrillar loads by bridging collagen fibrils. Alternatively, collagen fibrils may interact directly through physical fusions and interfibrillar branching. The objective of this study was to test whether extrafibrillar proteins are necessary to transmit load between collagen fibrils or if interfibrillar load transfer is accomplished directly by the fibrils themselves. Trypsin digestions were used to remove a broad spectrum of extrafibrillar proteins and measure their contribution to the multiscale mechanics of rat tail tendon fascicles. Additionally, images obtained from serial block-face scanning electron microscopy were used to determine the three dimensional fibrillar organization in tendon fascicles and identify any potential interfibrillar interactions. While trypsin successfully removed several extrafibrillar tissue components, there was no change in the macroscale fascicle mechanics or fibril:tissue strain ratio. Furthermore, the imaging data suggested that a network of smaller diameter fibrils (<150 nm) wind around and fuse with their neighboring larger diameter fibrils. These findings demonstrate that interfibrillar load transfer is not supported by extrafibrillar tissue components and support the hypothesis that collagen fibrils are capable of transmitting loads themselves. Conclusively determining how fibrils bear load within tendon is critical for identifying the mechanisms that impair tissue function with degeneration and for restoring tissue properties via cell-mediated regeneration or engineered tissue replacements. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2127-2134, 2017. PMID- 28071820 TI - Response Profiling Using Shotgun Proteomics Enables Global Metallodrug Mechanisms of Action To Be Established. AB - Response profiling using shotgun proteomics for establishing global metallodrug mechanisms of action in two colon carcinoma cell lines, HCT116 and SW480, has been applied and evaluated with the clinically approved arsenic trioxide. Surprisingly, the complete established mechanism of action of arsenic trioxide was observed by protein regulations in SW480, but not HCT116 cells. Comparing the basal protein expression in the two cell lines revealed an 80 % convergence of protein identification, but with significant expression differences, which in turn seem to affect the extent of protein regulation. A clear-cut redox response was observed in SW480 cells upon treatment with arsenic, but hardly in HCT116 cells. Response profiling was then used to investigate four anti-cancer metallodrugs (KP46, KP772, KP1339 and KP1537). Proteome alterations were mapped to selected functional groups, including DNA repair, endocytosis, protection from oxidative stress, protection from endoplasmatic reticulum (ER) stress, cell adhesion and mitochondrial function. The present data suggest that knowledge of the mechanism of action of anti-cancer metallodrugs and improved patient stratification strategies are imperative for the design of clinical studies. PMID- 28071821 TI - Mouse models of kufor-rakeb disease link Parkinson's disease closer to neuronal ceroid lipofuscinosis, suggesting lysosomal dysfunction as shared mechanism. PMID- 28071822 TI - Responses to Treatment With Teriparatide in Patients With Atypical Femur Fractures Previously Treated With Bisphosphonates. AB - If oversuppression of bone turnover explained the association between bisphosphonate use and atypical subtrochanteric femur fractures (AFF), this could be reversed with anabolic treatment such as teriparatide. We conducted a prospective, open-label study in patients previously treated with bisphosphonates who sustained AFF, examining the response to 24-month treatment with teriparatide on bone mineral density (BMD), trabecular bone score (TBS), bone turnover markers (BTM), and fracture healing as well as quantitative histomorphometry. We studied 14 patients. Baseline BMD, BTM, and TBS varied widely. On initial bone biopsies, 12 of 14 patients showed tetracycline labels, but mineralizing surface/bone surface was below published normal values in all but 2. Lumbar spine BMD increased significantly at month 24 (6.1% +/- 4.3%, p < 0.05 versus baseline), whereas total hip BMD and TBS did not change significantly. Changes in BTM occurred as reported previously for patients without AFF treated with teriparatide after prior bisphosphonate treatment. At month 24, fractures were healed in 6 patients, showed partial healing in 3, were unchanged in 2, and showed nonunion in 1. In a patient with two fractures, the fracture that occurred before teriparatide treatment was reported as healed, but the fracture that occurred while on treatment showed only partial healing. Bisphosphonate-treated patients who sustain AFF show heterogeneity of bone turnover. Treatment with teriparatide resulted in increases in BTM and lumbar spine BMD, as has been reported for patients without AFF. There was no significant effect of teriparatide on hip BMD, mineralizing surface to bone surface (MS/BS), or TBS and no consistent effect on fracture healing. In the context of a patient who has experienced an AFF after receiving bisphosphonate treatment, therapy with teriparatide for 24 months would be expected to increase BMD and BTM (and probably reduce the risk of fractures resulting from osteoporosis) but should not be relied on to aid in healing of the AFF. (c) 2017 American Society for Bone and Mineral Research. PMID- 28071823 TI - Formal Total Synthesis of (+/-)-Strictamine by [2,3]-Sigmatropic Stevens Rearrangements. AB - To date, more than 100 congeners of the akuammiline alkaloid family have been isolated. Their signature structural element is a methanoquinolizidine moiety, a cage-like scaffold structurally related to adamantane. The structural variations of the family members originate from oxidative processes that mostly trigger rearrangements of the methanoquinolizidine motif. The family of the akuammiline alkaloids is best represented by strictamine. It bears the least functionalized carbon skeleton of all family members without lacking the signature structural motifs. Herein, we report the formal synthesis of strictamine through a Stevens [2,3]-sigmatropic rearrangement as a key step and the synthetic pitfalls related with its synthesis. PMID- 28071824 TI - Heart rate variability in leucine-rich repeat kinase 2-associated Parkinson's disease. AB - BACKGROUND: Heart rate variability is reduced in idiopathic PD, indicating cardiac autonomic dysfunction likely resulting from peripheral autonomic synucleinopathy. Little is known about heart rate variability in leucine-rich repeat kinase 2-associated PD. OBJECTIVES: This study investigated heart rate variability in LRRK2-associated PD. METHODS: Resting electrocardiograms were obtained from 20 individuals with LRRK2-associated PD, 37 nonmanifesting carriers, 48 related noncarriers, 26 idiopathic PD patients, and 32 controls. Linear regression modelling compared time and frequency domain values, adjusting for age, sex, heart rate, and disease duration. RESULTS: Low-frequency power and the ratio of low-high frequency power were reduced in idiopathic PD versus controls (P < .008, P < .029 respectively). In contrast, individuals with LRRK2 associated PD were not statistically different from controls in any parameter measured. Furthermore, all parameters trended toward being higher in LRRK2 associated PD when compared with idiopathic PD. CONCLUSIONS: Heart rate variability may remain intact in LRRK2-associated PD, adding to a growing literature supporting clinical-pathologic differences between LRRK2-associated and idiopathic PD. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28071825 TI - Systematic review of severity scales and screening instruments for tics: Critique and recommendations. AB - BACKGROUND: Several clinician, informant, and self-report instruments for tics and associated phenomena have been developed that differ in construct, comprehensiveness, and ease of administration. OBJECTIVE: A Movement Disorders Society subcommittee aimed to rate psychometric quality of severity and screening instruments for tics and related sensory phenomena. METHODS: Following the methodology adopted by previous Movement Disorders Society subcommittee papers, a review of severity and screening instruments for tics was completed, applying a classification as "recommended," "suggested," or "listed" to each instrument. RESULTS: A total of 5 severity scales (Yale Global Tic Severity Scale, Tourette Syndrome Clinical Global Impression, Tourette's Disorder Scale, Shapiro Tourette syndrome Severity Scale, Premonitory Urges for Tics Scale) were "recommended," and 6 (Rush Video-Based Tic Rating Scale, Motor tic, Obsessions and compulsions, Vocal tic Evaluation Survey, Tourette Syndrome Global Scale, Global Tic Rating Scale, Parent Tic Questionnaire, Tourette Syndrome Symptom List) were "suggested." A total of 2 screening instruments (Motor tic, Obsession and compulsions, Vocal tic Evaluation Survey and Autism-Tics, Attention Deficit/Hyperactivity Disorder and Other Comorbidities Inventory) were "recommended," whereas 2 others (Apter 4-questions screening and Proxy Report Questionnaire for Parents and Teachers) were "suggested." CONCLUSIONS: Our review does not support the need for developing new tic severity or screening instruments. Potential objectives of future research include developing a rating instrument targeting the full spectrum of tic-related abnormal behaviors, assessing/screening malignant forms of tic disorders, and developing patient reported outcome measures. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28071827 TI - Lithium Aryloxide Thin Films with Guest-Induced Structural Transformation by ALD/MLD. AB - Crystalline Li-organic thin films are grown with the atomic/molecular layer deposition (ALD/MLD) technique from lithium hexamethyldisilazide and hydroquinone. The as-deposited films are found to undergo a reversible structural transformation upon exposure to ambient humid air. According to density functional theory calculations, the guest-induced transformation may be related to an unsaturated Li site in the crystal structure. PMID- 28071826 TI - GAT-1 mediated GABA uptake in rat oligodendrocytes. AB - Stimulated by the results of a recent paper on the effects of tiagabine, a selective inhibitor of the main GABA transporter GAT-1, on oligodendrogenesis, we verified the possibility that GAT-1 may be expressed in oligodendrocytes using immunocytochemical methods and functional assays. Light microscopic analysis of the subcortical white matter of all animals revealed the presence of numerous GAT 1+ cells of different size (from 3 to 29 um) and morphology. An electron microscope analysis revealed that, besides fibrous astrocytes and interstitial neurons, GAT-1 immunoreactivity was present in immature and mature oligodendrocytes. Co-localization studies between GAT-1 and markers specific for oligodendrocytes (NG2 and RIP) showed that about 12% of GAT-1 positive cells in the white matter were immature oligodendrocytes, while about 15% were mature oligodendrocytes. In vitro functional assays showed that oligodendrocytes exhibit tiagabine-sensitive Na+ -dependent GABA uptake. Although relationships between GABA and oligodendrocytes have been known for many years, this is the first demonstration that GAT-1 is expressed in oligodendrocytes. The present results on the one hand definitely closes the era of "neuronal" and "glial" GABA transporters, on the other they suggest that oligodendrocytes may contribute to pathophysiology of the several diseases in which GAT-1 have been implicated to date. GLIA 2017;65:514-522. PMID- 28071828 TI - Electronic Structure and Excited-State Dynamics of an Arduengo-Type Carbene and its Imidazolone Oxidation Product. AB - We describe an investigation of the excited-state dynamics of isolated 1,3-di tert-butyl-imidazoline-2-ylidene (tBu2 Im, C11 H20 N2 , m/z=180), an Arduengo type carbene, by time- and frequency-resolved photoionization using a picosecond laser system. The energies of several singlet and triplet excited states were calculated by time-dependent density functional theory (TD-DFT). The S1 state of the carbene deactivates on a 100 ps time scale possibly by intersystem crossing. In the experiments we observed an additional signal at m/z=196, that was assigned to the oxidation product 1,3-di-tert-butyl-imidazolone, tBu2 ImO. It shows a well resolved resonance-enhanced multiphoton ionization (REMPI) spectrum with an origin located at 36951 cm-1 . Several low-lying vibrational bands could be assigned, with a lifetime that depends strongly on the excitation energy. At the origin the lifetime is longer than 3 ns, but drops to 49 ps at higher excess energies. To confirm formation of the imidazolone we also performed experiments on benzimidazolone (BzImO) for comparison. Apart from a redshift for BzImO the spectra of the two compounds are very similar. The TD-DFT values display a very good agreement with the experimental data. PMID- 28071829 TI - Gold-Catalyzed Intermolecular Formal Insertion of Aryldiazo Esters into Cp-H Bonds of Iron and Ruthenium Metallocenes. AB - The reaction of ferrocene and ruthenocene with aryldiazo acetates in the presence of gold catalysts produced new functionalized metallocenes resulting from a C-H bond functionalization process. This process is believed to proceed through initial decomposition of the diazo component and formation of an electrophilic gold-carbene intermediate, which is subsequently involved in an electrophilic aromatic substitution. The gold-catalyzed functionalization of ruthenocene exhibited a broad scope and a notable functional-group tolerance. Interestingly, the functionalized ferrocene derivatives were found to react with molecular oxygen to yield alpha-aryl-alpha-ferrocenyl-alpha-hydroxyacetates. Adsorption on silica gel was found to be essential for this dioxygen activation/C(sp3 )-H bond functionalization sequence. The methodologies reported herein provide a simple and efficient approach to functionalized metallocene derivatives that are difficult to access through conventional organic functional group transformations. PMID- 28071830 TI - Awareness of functional ability in people with early-stage dementia. AB - OBJECTIVES: Assessment of functional ability in people with early-stage dementia (PwD) is an important area of study because it forms part of the diagnostic process and may help in monitoring disease progression. Most researchers and clinicians rely on informant ratings rather than observing actual functional performance or employing self-ratings. There has however been little research to verify whether informant ratings of functioning are accurate, and there has been even less research investigating the accuracy of self-ratings of functional ability in PwD. No study has used the performance-monitoring metacognitive approach to investigate awareness of functional ability. METHODS: Thirty-seven people with early-stage dementia completed an objective functional assessment and provided self-ratings before and after completing each section of the objective test. Informants provided ratings of functioning and burden. Scores were converted to percentages to allow for direct comparison. RESULTS: Objectively assessed functional ability significantly correlated with self-ratings and informant ratings. Self-ratings did not correlate with informant ratings. For converted scores, self-ratings were more similar than informant ratings to the objectively assessed mean scores. Burden was unrelated to functional assessments after correcting for multiple comparisons. CONCLUSIONS: Self-rated functional ability was more accurate than informant ratings when compared with objectively assessed ability, with informants tending to significantly underestimate the functional ability of PwD. The findings call into question the likelihood that informants will provide accurate ratings of functional ability and suggests that self-ratings may offer a more accurate estimate of functional ability. Self ratings made by PwD should be more widely employed in clinical and research settings. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28071832 TI - The role of amyloidogenic proteins as a meeting point of type 2 diabetes and Parkinson's disease pathways. PMID- 28071831 TI - Protein Metalation by Anticancer Metallodrugs: A Joint ESI MS and XRD Investigative Strategy. AB - Interactions of metal-based drugs with proteins and consequent adduct formation (the so-called "protein metalation" process) play a key role in the mode of action of several anticancer agents and in determining their toxicological profile. Through a novel investigative strategy grounded on the combined use of electrospray ionization mass spectrometry (ESI MS) and biological macromolecule X ray crystallography we show that it is possible to clarify in depth the metalation process of small model proteins; a number of instructive examples are provided. Recently, this kind of investigative approach has been extended to bigger proteins such as human serum albumin and horse spleen ferritin, with rather encouraging results. Overall, by application of this strategy, metalation of proteins caused by anticancer metallodrugs can be disclosed in the molecular detail. PMID- 28071833 TI - Co-culture with macrophages enhances the clonogenic and invasion activity of endometriotic stromal cells. AB - OBJECTIVE: To study the effect on endometrial and endometriotic cells after co culture with macrophages, using clonogenic, invasion and self-renewal assays. MATERIALS AND METHODS: Peripheral blood samples, endometrium and endometriotic tissues were collected. Autologous macrophages were co-cultured with endometrial and endometriotic cells. The number of colony-forming units (CFU), invasiveness and self-renewal activity after co-culture with macrophages were determined. The cytokine level of colony-stimulating factor-1 (CSF-1) from macrophages with and without endometriosis was compared. RESULTS: Co-culture with macrophages significantly increased the clonogenic and invasion ability of endometriotic stromal cells in vitro. Colony-stimulating factor-1 (CSF-1) was up-regulated in endometriotic macrophages conditioned medium when compared to those without the disease. CONCLUSIONS: These data suggest that macrophages may increase the proliferation and invasion activity of stromal clonogenic cells in women with endometriosis. PMID- 28071835 TI - Macromolecular Design Strategies for Preventing Active-Material Crossover in Non Aqueous All-Organic Redox-Flow Batteries. AB - Intermittent energy sources, including solar and wind, require scalable, low cost, multi-hour energy storage solutions in order to be effectively incorporated into the grid. All-Organic non-aqueous redox-flow batteries offer a solution, but suffer from rapid capacity fade and low Coulombic efficiency due to the high permeability of redox-active species across the battery's membrane. Here we show that active-species crossover is arrested by scaling the membrane's pore size to molecular dimensions and in turn increasing the size of the active material above the membrane's pore-size exclusion limit. When oligomeric redox-active organics (RAOs) were paired with microporous polymer membranes, the rate of active material crossover was reduced more than 9000-fold compared to traditional separators at minimal cost to ionic conductivity. This corresponds to an absolute rate of RAO crossover of less than 3 MUmol cm-2 day-1 (for a 1.0 m concentration gradient), which exceeds performance targets recently set forth by the battery industry. This strategy was generalizable to both high and low-potential RAOs in a variety of non-aqueous electrolytes, highlighting the versatility of macromolecular design in implementing next-generation redox-flow batteries. PMID- 28071836 TI - Violated and vulnerable: women's experiences of contracting a sexually transmitted infection from a male partner. AB - AIMS AND OBJECTIVES: To explore women's stories of contracting a sexually transmitted infection from a male partner and elucidate the gendered constructs and violence experienced that made the women vulnerable to these infections. BACKGROUND: Violence against women can result in both physical and psychological consequences and expose women to multiple health risks including sexual health adversity. DESIGN: Feminist storytelling approach. METHODS: Qualitative interviews were conducted with 10 women. All data underwent thematic analysis. FINDINGS: Findings from this study revealed the women were vulnerable to contracting sexually transmitted infection/s from their male sexual partners as a result of unequal gender and abusive relationship dynamics. Subsequently, contracting a sexual infection within this context potentially increased their vulnerability in both current and future relationships, through their loss of self-confidence and perceived ability to have a trusting loving heterosexual relationship as women with sexually transmitted infection/s. CONCLUSION: Women in relationships in which they are subordinate to their male partner are at heightened risk of sexual health adversity, including contracting a sexually transmitted infection. Contracting a sexually transmitted infection within the context of an abusive relationship can further increase women's vulnerability to dominant male partners, thus further exposure to sexual risk and adversity. RELEVANCE TO CLINICAL PRACTICE: Nurses working in clinical settings are well placed to conduct opportunistic screening of women's sexual health, including assessment of sexually transmitted infections and the nature of the encounter in which they were contracted. Thorough assessment can potentially identify relationship and personal factors that can increase a woman's risk to both sexual adversity and forms of abuse. Also, if women do divulge that they have suffered abuse, nurses are positioned to provide support and guidance in implementing strategies to minimise risk as well as referring them to specialised services. PMID- 28071834 TI - Molecular Profiling of Human Induced Pluripotent Stem Cell-Derived Hypothalamic Neurones Provides Developmental Insights into Genetic Loci for Body Weight Regulation. AB - Recent data suggest that common genetic risks for metabolic disorders such as obesity may be human-specific and exert effects via the central nervous system. To overcome the limitation of human tissue access for study, we have generated induced human pluripotent stem cell (hiPSC)-derived neuronal cultures that recapture many features of hypothalamic neurones within the arcuate nucleus. In the present study, we have comprehensively characterised this model across development, benchmarked these neurones to in vivo events, and demonstrate a link between obesity risk variants and hypothalamic development. The dynamic transcriptome across neuronal maturation was examined using microarray and RNA sequencing methods at nine time points. K-means clustering of the longitudinal data was conducted to identify co-regulation and microRNA control of biological processes. The transcriptomes were compared with those of 103 samples from 13 brain regions reported in the Genotype-Tissue Expression database (GTEx) using principal components analysis. Genes with proximity to body mass index (BMI) associated genetic variants were mapped to the developmentally expressed genesets, and enrichment significance was assessed with Fisher's exact test. The human neuronal cultures have a transcriptional and physiological profile of neuropeptide Y/agouti-related peptide arcuate nucleus neurones. The neuronal transcriptomes were highly correlated with adult hypothalamus compared to any other brain region from the GTEx. Also, approximately 25% of the transcripts showed substantial changes in expression across neuronal development and potential co-regulation of biological processes that mirror neuronal development in vivo. These developmentally expressed genes were significantly enriched for genes in proximity to BMI-associated variants. We confirmed the utility of this in vitro human model for studying the development of key hypothalamic neurones involved in energy balance and show that genes at loci associated with body weight regulation may share a pattern of developmental regulation. These data support the need to investigate early development to elucidate the human-specific central nervous system pathophysiology underlying obesity susceptibility. PMID- 28071837 TI - Use of TNF-inhibitors and ustekinumab for psoriasis during pregnancy: A patient series. AB - From 2002 to 2016 a total of seven women with severe refractory psoriasis were exposed to the TNF-inhibitors infliximab and adalimumab or to the IL12/23 inhibitor ustekinumab during one or more pregnancies. Maternal, fetal or teratogenic toxicity were not detected during pregnancy and puerperium. All pregnancies were uneventful and resulted in delivery of 10 healthy children in total, one of the women is due February 2017. Postpartum, five of the women were lactating, but none of the women or newborns developed adverse reactions. Data on safety of treatment during breastfeeding are sparse, but so far appears to be safe due to the lack of absorption across the gastrointestinal lining. Currently biological therapy with either TNF-inhibitors or ustekinumab is not recommended during pregnancy, however in selected women with severe psoriasis these treatment modalities may be considered. PMID- 28071838 TI - Electron Solvation and the Unique Liquid Structure of a Mixed-Amine Expanded Metal: The Saturated Li-NH3 -MeNH2 System. AB - Metal-amine solutions provide a unique arena in which to study electrons in solution, and to tune the electron density from the extremes of electrolytic through to true metallic behavior. The existence and structure of a new class of concentrated metal-amine liquid, Li-NH3 -MeNH2 , is presented in which the mixed solvent produces a novel type of electron solvation and delocalization that is fundamentally different from either of the constituent systems. NMR, ESR, and neutron diffraction allow the environment of the solvated electron and liquid structure to be precisely interrogated. Unexpectedly it was found that the solution is truly homogeneous and metallic. Equally surprising was the observation of strong longer-range order in this mixed solvent system. This is despite the heterogeneity of the cation solvation, and it is concluded that the solvated electron itself acts as a structural template. This is a quite remarkable observation, given that the liquid is metallic. PMID- 28071839 TI - Life after a lung transplant: a balance of joy and challenges. AB - AIM AND OBJECTIVE: To describe patients' experiences throughout the first four months post-lung transplant. BACKGROUND: Health professionals are familiar with the fact that patients' average survival after a lung transplant is about seven years and that 74% of these patients reject new organs within the first two years. By contrast, knowledge of these patients' perspectives after lung transplantation is scant. DESIGN/METHOD: A qualitative study was conducted between May 2013-May 2014 in which 26 interviewees participated - four months post-transplant - based on a semistructured interview guide. The data were inductively analysed using a content thematic approach within a phenomenological and hermeneutic frame. RESULTS: The main findings in the study reveal that (1) having a lung transplant is an overwhelming experience, which for some patients includes (2) troubling physical and psychological challenges. The interviewees were happy to get another chance to live, although some of them suffered from medical side effects, postoperative complications and psychological problems. When asked about the future, interviewees stated that life could be described as (3) a balance of joy and challenges. They had received a new chance in life and were eager to fulfil their life hopes and dreams. At the same time, they were worried about the future. Having a lung transplant implies rules that have to be followed. What are the healthy choices they are supposed to make? And will there be a tomorrow? CONCLUSIONS: Having a lung transplant is described as an overwhelming experience because of the improvement in the physical function of the body. Patients were grateful to family, friends and healthcare professionals for supporting them. The first four months post-transplantation were described as both physically and psychologically challenging. Interviewees were aware of the prognosis for patients following lung transplantation. They expressed feelings of worry and insecurity but still had hopes and dreams. RELEVANCE TO CLINICAL PRACTICE: The patients are troubled by both physical and psychological challenges after lung transplantation. Several areas call for interventions from healthcare professionals during the early post-transplant period. PMID- 28071840 TI - beta-Adrenergic blockade does not impair the skin blood flow sensitivity to local heating in burned and nonburned skin under neutral and hot environments in children. AB - OBJECTIVE: We tested the hypothesis that propranolol, a drug given to burn patients to reduce hypermetabolism/cardiac stress, may inhibit heat dissipation by changing the sensitivity of skin blood flow (SkBF) to local heating under neutral and hot conditions. METHODS: In a randomized double-blind study, a placebo was given to eight burned children, while propranolol was given to 13 burned children with similar characteristics (mean+/-SD: 11.9+/-3 years, 147+/-20 cm, 45+/-23 kg, 56+/-12% Total body surface area burned). Nonburned children (n=13, 11.4+/-3 years, 152+/-15 cm, 52+/-13 kg) served as healthy controls. A progressive local heating protocol characterized SkBF responses in burned and unburned skin and nonburned control skin under the two environmental conditions (23 and 34 degrees C) via laser Doppler flowmetry. RESULTS: Resting SkBF was greater in burned and unburned skin compared to the nonburned control (main effect: skin, P<.0001; 57+/-32 burned; 38+/-36 unburned vs 9+/-8 control %SkBFmax ). No difference was found for maximal SkBF capacity to local heating between groups. Additionally, dose-response curves for the sensitivity of SkBF to local heating were not different among burned or unburned skin, and nonburned control skin (EC50 , P>.05) under either condition. CONCLUSION: Therapeutic propranolol does not negatively affect SkBF under neutral or hot environmental conditions and further compromise temperature regulation in burned children. PMID- 28071842 TI - Tip-Enhanced Raman Spectroscopy to Distinguish Toxic Oligomers from Abeta1-42 Fibrils at the Nanometer Scale. AB - For the first time, natural Abeta1-42 fibrils (WT) implicated in Alzheimer's disease, as well as two synthetic mutants forming less toxic amyloid fibrils (L34T) and highly toxic oligomers (oG37C), are chemically characterized at the scale of a single structure using tip-enhanced Raman spectroscopy (TERS). While the proportion of TERS features associated with amino acid residues is similar for the three peptides, a careful examination of amide I and amide III bands allows us to clearly distinguish WT and L34T fibers organized in parallel beta sheets from the small and more toxic oG37C oligomers organized in anti-parallel beta-sheets. PMID- 28071841 TI - Attending to power differentials: How NP-led group medical visits can influence the management of chronic conditions. AB - OBJECTIVE: In Canada, primary care reform has encouraged innovations, including nurse practitioners (NPs) and group medical visits (GMVs). NP-led GMVs provide an opportunity to examine barriers and enablers to implementing this innovation in primary care. DESIGN: An instrumental case study design (n=3): two cases where NPs were using GMVs and one case where NPs were not using GMVs, was completed. In depth interviews with patients and providers (N=24) and 10 hours of direct observation were completed. Interpretive descriptive methods were used to analyse data. RESULTS/FINDINGS: Two main themes were identified: (i) acquisition of knowledge and (ii) GMVs help shift relationships between patients and health-care providers. Participants discussed how patients and providers learn from one another to facilitate self-management of chronic conditions. They also discussed how the GMV shifts inherent power differentials between providers and between patients and providers. DISCUSSION: NP-led GMVs are a method of care delivery that harness NPs' professional agency through increased leadership and interprofessional collaboration. GMVs also facilitate an environment that is patient-centred and interprofessional, providing patients with increased confidence to manage their chronic conditions. The GMV provides the opportunity to meet both team-based and patient-centred health-care objectives and may disrupt inherent power differentials that exist in primary care. PMID- 28071843 TI - Automated measurement of pressure injury through image processing. AB - AIMS AND OBJECTIVES: To develop an image processing algorithm to automatically measure pressure injuries using electronic pressure injury images stored in nursing documentation. BACKGROUND: Photographing pressure injuries and storing the images in the electronic health record is standard practice in many hospitals. However, the manual measurement of pressure injury is time-consuming, challenging and subject to intra/inter-reader variability with complexities of the pressure injury and the clinical environment. DESIGN: A cross-sectional algorithm development study. METHODS: A set of 32 pressure injury images were obtained from a western Pennsylvania hospital. First, we transformed the images from an RGB (i.e. red, green and blue) colour space to a YCb Cr colour space to eliminate inferences from varying light conditions and skin colours. Second, a probability map, generated by a skin colour Gaussian model, guided the pressure injury segmentation process using the Support Vector Machine classifier. Third, after segmentation, the reference ruler - included in each of the images - enabled perspective transformation and determination of pressure injury size. Finally, two nurses independently measured those 32 pressure injury images, and intraclass correlation coefficient was calculated. RESULTS: An image processing algorithm was developed to automatically measure the size of pressure injuries. Both inter- and intra-rater analysis achieved good level reliability. CONCLUSIONS: Validation of the size measurement of the pressure injury (1) demonstrates that our image processing algorithm is a reliable approach to monitoring pressure injury progress through clinical pressure injury images and (2) offers new insight to pressure injury evaluation and documentation. RELEVANCE TO CLINICAL PRACTICE: Once our algorithm is further developed, clinicians can be provided with an objective, reliable and efficient computational tool for segmentation and measurement of pressure injuries. With this, clinicians will be able to more effectively monitor the healing process of pressure injuries. PMID- 28071844 TI - A Vesicle-to-Worm Transition Provides a New High-Temperature Oil Thickening Mechanism. AB - Diblock copolymer vesicles are prepared via RAFT dispersion polymerization directly in mineral oil. Such vesicles undergo a vesicle-to-worm transition on heating to 150 degrees C, as judged by TEM and SAXS. Variable-temperature 1 H NMR spectroscopy indicates that this transition is the result of surface plasticization of the membrane-forming block by hot solvent, effectively increasing the volume fraction of the stabilizer block and so reducing the packing parameter for the copolymer chains. The rheological behavior of a 10 % w/w copolymer dispersion in mineral oil is strongly temperature-dependent: the storage modulus increases by five orders of magnitude on heating above the critical gelation temperature of 135 degrees C, as the non-interacting vesicles are converted into weakly interacting worms. SAXS studies indicate that, on average, three worms are formed per vesicle. Such vesicle-to-worm transitions offer an interesting new mechanism for the high-temperature thickening of oils. PMID- 28071845 TI - Influence of age, sex and seriousness on reporting of adverse drug reactions in Sweden. AB - PURPOSE: To investigate how reporting of adverse drug reactions (ADRs) among adults in Sweden is associated to age and sex, in addition to seriousness of the reaction and drug utilisation. METHODS: Individual case safety reports (ICSRs) reported by healthcare professionals to the national pharmacovigilance database 2008-2011 were related to defined daily dose (DDD) in the Swedish Prescribed Drug Register (SPDR) for individual's >=20 years. Data were stratified into five age groups. Crude and adjusted (by age standardisation of prescribed drugs) reporting rate (RR) and reporting rate ratio was evaluated as well as impact of sex dependent drugs. RESULTS: Based on 9898 included ICSRs, the crude results show that overall RR was almost similar for both serious and non-serious reports and indicates highest RR in the youngest age group. Women had higher rates than men, with predominance for non-serious reports, contrary to men who had a higher RR of serious ones. Standardisation led partly to the same result, but age-related distribution was adjusted, with highest overall RR in the oldest age groups. Sex dependent drugs had marginal impact on the results. CONCLUSION: Age and sex have impact on spontaneous reporting of ADRs. After adjusting for dispensed drugs and by standardisation of age-related differences in prescribed drugs, results indicate that healthcare professionals more frequently reported ADRs for the oldest individuals and for women. Serious reports were more frequently reported for men. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28071846 TI - Trapping Rare and Elusive Phosphinidene Chalcogenides. AB - Four-membered rings with a P2 Ch2 core (Ch=S, Se) and phosphorus in the +3 oxidation state have been synthesized. The utility of these rings as a source of monomeric phosphinidene chalcogenides was probed by the addition of an N heterocyclic carbene, resulting in a base-stabilized phosphinidene sulfide. Similarly, persistence of the phosphinidene selenide in solution was shown through cycloaddition chemistry with 2,3-dimethylbutadiene at elevated temperatures. The observed reactivity was explained by detailed computational work that established the conditions upon which the P2 Ch2 rings can liberate phosphinidene chalcogenides. PMID- 28071847 TI - Hindfoot fusion in haemophilic arthropathy: 6-year mean follow-up of 41 procedures performed in 28 adult patients. AB - INTRODUCTION: Haemophilic arthropathy of the ankle is rare disorder caused by recurrent haemarthorses beginning in early adulthood. AIM: Our aim was to evaluate the fusion rate of various techniques of hindfoot fusion using internal fixation for the treatment of haemophilic arthropathy of the hindfoot. METHODS: We have evaluated the fusion rate of various techniques of hindfoot (tibiotalar and subtalar joints) fusion for the treatment of haemophilic arthropathy of the hindfoot. Twenty-eight patients underwent a total of 41 procedures. Thirty-four ankle (tibiotalar) fusions were performed, seven were done arthroscopically, six using a minimal access approach and 21 with an open approach. There were two isolated subtalar fusions, three combined tibiotalar and subtalar fusions, one of which included a talonavicular fusion at the second operation. There was one peritalar ankle fusion (tibiotalar, subtalar and talonavicular). The mean age at operation was 40.3 years (SD, 12.3; range, 18.7-65.7 years). The mean time to last follow-up was 77 months (SD, 50.4; range, 7-190). RESULTS: The overall non union rate was 9.7%. All non-unions occurred in tibiotalar fusions (there were no non-unions in cases of subtalar or talonavicular fusion). A single deep infection (2.4%) occurred in an arthroscopically fused ankle. The revision rate was 4.8% (2 cases) and was carried out for non-unions. Both revisions were successful. CONCLUSION: Hindfoot arthrodesis in patients with haemophilic ankle arthropathy provides a high fusion rate with few complications. Arthroscopic tibiotalar fusion did not result in shorter hospital stays. Revision surgery for the haemophilic hindfoot is successful, and fusion of the entire hindfoot can be achieved without complications. PMID- 28071849 TI - Activation of the B-F Bond by Diphenylcarbene: A Reversible 1,2-Fluorine Migration between Boron and Carbon. AB - Experiments in low-temperature matrices reveal that triplet diphenylcarbene inserts into the very strong B-F bond of BF3 in a two-step reaction. The first step is the formation of a strongly bound Lewis acid-base complex between the singlet state of diphenylcarbene and BF3 . This step involves an inversion of the spin state of the carbene from triplet to singlet. The second step requires visible-light photochemical activation to induce a 1,2-F migration from boron to the adjacent carbon atom under formation of the formal insertion product of the carbene center into BF3 . The 1,2-F migration is reversible under short wavelength UV irradiation, thus leading back to the Lewis acid-base adduct. PMID- 28071848 TI - GXXXG-Mediated Parallel and Antiparallel Dimerization of Transmembrane Helices and Its Inhibition by Cholesterol: Single-Pair FRET and 2D IR Studies. AB - Small-residue-mediated interhelical packings are ubiquitously found in helical membrane proteins, although their interaction dynamics and lipid dependence remain mostly uncharacterized. We used a single-pair FRET technique to examine the effect of a GXXXG motif on the association of de novo designed (AALALAA)3 helices in liposomes. Dimerization occurred with sub-second lifetimes, which was abolished by cholesterol. Utilizing the nearly instantaneous time-resolution of 2D IR spectroscopy, parallel and antiparallel helix associations were identified by vibrational couplings across helices at their interface. Taken together, the data illustrate that the GXXXG motif controls helix packing but still allows for a dynamic and lipid-regulated oligomeric state. PMID- 28071850 TI - A Two-Dimensional Lamellar Membrane: MXene Nanosheet Stacks. AB - Two-dimensional (2D) materials are promising candidates for advanced water purification membranes. A new kind of lamellar membrane is based on a stack of 2D MXene nanosheets. Starting from compact Ti3 AlC2 , delaminated nanosheets of the composition Ti3 C2 Tx with the functional groups T (O, OH, and/or F) can be produced by etching and ultrasonication and stapled on a porous support by vacuum filtration. The MXene membrane supported on anodic aluminum oxide (AAO) substrate shows excellent water permeance (more than 1000 L m-2 h-1 bar-1 ) and favorable rejection rate (over 90 %) for molecules with sizes larger than 2.5 nm. The water permeance through the MXene membrane is much higher than that of the most membranes with similar rejections. Long-time operation also reveals the outstanding stability of the MXene membrane for water purification. PMID- 28071851 TI - Preprogramming Complex Hydrogel Responses using Enzymatic Reaction Networks. AB - The creation of adaptive matter is heavily inspired by biological systems. However, it remains challenging to design complex material responses that are governed by reaction networks, which lie at the heart of cellular complexity. The main reason for this slow progress is the lack of a general strategy to integrate reaction networks with materials. Herein we use a systematic approach to preprogram the response of a hydrogel to a trigger, in this case the enzyme trypsin, which activates a reaction network embedded within the hydrogel. A full characterization of all the kinetic rate constants in the system enabled the construction of a computational model, which predicted different hydrogel responses depending on the input concentration of the trigger. The results of the simulation are in good agreement with experimental findings. Our methodology can be used to design new, adaptive materials of which the properties are governed by reaction networks of arbitrary complexity. PMID- 28071852 TI - Environmental and Excitation Power Effects on the Ratiometric Upconversion Luminescence Based Temperature Sensing Using Nanocrystalline NaYF4 :Yb3+ ,Er3. AB - The luminescence intensity ratio (LIR) of the green emissions of the near infrared excited NaYF4 :Yb3+ ,Er3+ nanocrystals is a promising method for temperature sensing. Here, the influence of excitation power density, excitation pulse length, excitation wavelength, silica shell, and solvent on the LIR and its temperature response is reported. The primary objective is to study the LIR mechanism and the impact of measurement and environmental parameters on the calibration and precision of the LIR. The LIR value is demonstrated to be unaffected by the excitation intensity in the studied range. This result is essential, considering the application feasibility of the LIR method as temperature sensor, where the effective excitation power density depends on the sample matrix and the distance excitation light travels in the sample. The pulsed excitation, however, results in an increase in the LIR value upon short pulse width. Silanization of bare nanocrystals has no effect on the LIR values, but the local warming of H2 O samples under laser exposure results in slightly increased LIR values compared to other solvents; D2 O, oleic acid, and dimethyl sulfoxide. The thermal quenching of luminescence lifetimes of Er3+ emission is proved to be too weak for sensing applications. PMID- 28071853 TI - Hydrodehalogenation of Haloarenes by a Sodium Hydride-Iodide Composite. AB - A simple protocol for hydrodebromination and -deiodination of halo(hetero)arenes was enabled by sodium hydride (NaH) in the presence of lithium iodide (LiI). Mechanistic studies showed that an unusual concerted nucleophilic aromatic substitution operates in the present process. PMID- 28071854 TI - Serum chemerin is associated with inflammatory and metabolic parameters-results of a population-based study. AB - OBJECTIVE: This study aimed to confirm existing assumptions about the associations of circulating chemerin with inflammatory and metabolic parameters in a large population-based study. METHODS: Data of 3,986 subjects from the Study of Health in Pomerania were analyzed. Residual method was used to investigate the different associations of visceral (VAT) and subcutaneous adipose tissue (SAT) with serum chemerin levels. Multivariable regression models were applied to examine the association of chemerin with high-sensitivity C-reactive protein, fibrinogen, glucose, glycated hemoglobin, lipid profile, blood pressure, diabetes, dyslipidemia, and hypertension. RESULTS: Positive associations with chemerin were observed for VAT and SAT with a stronger relation found for VAT. After adjustment for waist circumference, increased chemerin levels were related to higher inflammatory cytokines and glycated hemoglobin and an unfavorable lipid profile. Logistic regression revealed positive associations of chemerin with dyslipidemia [highest vs. lowest quartile: odds ratio (OR) 1.56 (95% confidence interval (CI) 1.25-1.94)] and hypertension [OR 1.31 (95% CI 1.03-1.68)]. CONCLUSIONS: Chemerin levels are significantly linked to inflammation and metabolic syndrome. The majority of the detected associations persisted even after adjustment for waist circumference, suggesting that the relation of chemerin with the analyzed traits cannot be solely explained by an accumulation of adipose tissue. PMID- 28071855 TI - Insights into the interaction of methotrexate and human serum albumin: A spectroscopic and molecular modeling approach. AB - In this study, fluorescence spectroscopy and molecular modeling approaches were employed to investigate the binding of methotrexate to human serum albumin (HSA) under physiological conditions. From the mechanism, it was demonstrated that fluorescence quenching of HSA by methotrexate results from the formation of a methotrexate/HSA complex. Binding parameters calculated using the Stern-Volmer method and the Scatchard method showed that methotrexate binds to HSA with binding affinities in the order 104 L.mol-1 . Thermodynamic parameter studies revealed that the binding reaction is spontaneous, and that hydrogen bonds and van der Waals interactions play a major role in the reaction. Site marker competitive displacement experiments and a molecular modeling approach demonstrated that methotrexate binds with appropriate affinity to site I (subdomain IIA) of HSA. Furthermore, we discuss some factors that influence methotrexate binding to HSA. PMID- 28071856 TI - Outcomes following conversion of a percutaneous to a transcutaneous bone conduction device in eight children. PMID- 28071857 TI - Risk of hypertensive disorders in pregnancy following assisted reproductive technology: overview and meta-analysis. AB - The extent of the increased risk of pregnancy hypertensive disorders following assisted reproductive technology (ART) was investigated. PubMed and the Cochrane Collaboration Library were used as data sources to identify and select longitudinal cohorts comparing pregnancies following ART with spontaneously conceived pregnancies, between 1978 and June 2016. Risk ratios and 95% confidence intervals (CIs) of three outcomes, ie, gestational hypertension (GH), preeclampsia (PE), and their sum (PHD), were calculated. Stratification of results by gestation order (singletons and nonsingletons) was pursued, but a separate "all orders" mixed stratification was considered. Sixty-six longitudinal studies (7 038 029 pregnancies; 203 375 following any ART) were eligible. All outcomes independent of gestation order ("all orders") were increased following any invasive ART: GH (+79% [95% CI, 24%-157%]) and PE (+75% [95% CI, 50%-103%]) to a greater extent, with smaller increases in PHD (+54% [95% CI, 39%-70%]). The risk of PHD following ART steadily increased independent of gestation order. PMID- 28071858 TI - Synthesis and Biological Evaluation of Novel 2-Aminonicotinamide Derivatives as Antifungal Agents. AB - Based on the structures of the reported compounds G884 [N-(3-(pentan-2 yloxy)phenyl)nicotinamide], E1210 [3-(3-(4-((pyridin-2 yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine], and 10 b [2-amino-N-((5-(3 fluorophenoxy)thiophen-2-yl)methyl)nicotinamide], which inhibit the biosynthesis of glycosylphosphatidylinositol (GPI)-anchored proteins in fungi, a series of novel 2-aminonicotinamide derivatives were designed, synthesized, and evaluated for in vitro antifungal activity. Most of these compounds were found to exhibit potent in vitro antifungal activity against Candida albicans, with MIC80 values ranging from 0.0313 to 4.0 MUg mL-1 . In particular, compounds 11 g [2-amino-N ((5-(((2-fluorophenyl)amino)methyl)thiophen-2-yl)methyl)nicotinamide] and 11 h [2 amino-N-((5-(((3-fluorophenyl)amino)methyl)thiophen-2-yl)methyl)nicotinamide] displayed excellent activity against C. albicans, with MIC80 values of 0.0313 MUg mL-1 , and exhibited broad-spectrum antifungal activity against fluconazole resistant C. albicans, C. parapsilosis, C. glabrata, and Cryptococcus neoformans, with a MIC80 range of 0.0313-2.0 MUg mL-1 . Further studies by electron microscopy and laser confocal microscopy indicated that compound 11 g targets the cell wall and decreases GPI anchor content on the cell surface of C. albicans. PMID- 28071860 TI - Using antenatal corticosteroids in pregnancies when there is a risk of very preterm delivery. PMID- 28071861 TI - Jan Winberg (1923-2003), a leader in urinary tract infection research. PMID- 28071862 TI - Unexpected, unexplained and life-threatening events in infants are age-dependent descriptive syndromes with different risk and management. PMID- 28071863 TI - Corrigendum. PMID- 28071864 TI - Simultaneous Determination of Four Triterpenoid Saponins in Aralia elata Leaves by HPLC-ELSD Combined with Hierarchical Clustering Analysis. AB - INTRODUCTION: Aralia elata leaves are known to have several biological activities, including anti-arrythmia, antitumor, anti-inflammatory, anti-fatigue, antimicrobial and antiviral effects. Our previous study found that triterpenoid saponins from the leaves of A. elata had antitumor effects. Quantification of the triterpenoids is important for the quality control of A. elata leaves. OBJECTIVE: To establish high-performance liquid chromatography coupled with evaporative light scattering detection (HPLC-ELSD) for the simultaneous determination of four major triterpenoid saponins, including Aralia-saponin IV, Aralia-saponin VI, 3-O beta-d- glucopyranosyl-(1 -> 3)-beta-d-glucopyranosyl-(1 -> 3)-beta-d glucopyranosyl oleanolic acid 28-O-beta-d-glucopyranoside (Aralia-saponin TTP)and Aralia-saponin V. METHODOLOGY: The separation was carried out on a Dikma Diamonsil C18 column (4.6 mm * 250 mm, 5 MUm) efficiently with gradient elution consisting of acetonitrile and water. RESULTS: All calibration curves showed good linear regression (R2 > 0.9996) within the ranges of tested concentrations. This validated method was applied to determine the contents of the four major triterpenoid saponins in 53 samples from different regions of northeast China. Hierarchical clustering analysis was first used to classify and differentiate Aralia elata leaves. CONCLUSION: The method developed was successfully applied to analyse four major triterpenoid saponins in Aralia elata leaves which is helpful for quality control of the herb. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28071865 TI - The impact of evidence-based sepsis guidelines on emergency department clinical practice: a pre-post medical record audit. AB - AIMS AND OBJECTIVES: To explore the number of patients presenting with sepsis before and after guideline implementation; the impact of sepsis guidelines on triage assessment, emergency department management and time to antibiotics. BACKGROUND: Sepsis remains one of the leading causes of mortality and morbidity within hospitals. Globally, strategies have been implemented to reduce morbidity and mortality rates, which rely on the early recognition and management of sepsis. To improve patient outcomes, the New South Wales government in Australia introduced sepsis guidelines into emergency departments. However, the impact of the guidelines on clinical practice remains unclear. DESIGN/METHODS: A 12-month pre-post retrospective randomised medical record audit of adult patients with a sepsis diagnosis. Data were extracted from the emergency department database and paper medical record. Data included patient demographic (age, gender), clinical information (time of arrival, triage code, seen by time, disposition, time to antibiotic, pathology, time to intravenous fluids) and patient assessment data (heart rate, respiratory rate, blood pressure, temperature, oxygen saturations, medication). RESULTS: This study demonstrated a statistically significant 230 minute reduction in time to antibiotics post implementation of the guidelines. The post group (n = 165) received more urgent triage categories (n = 81; 49.1%), a 758-minute reduction in mean time to second litre of intravenous fluids and an improvement in collection of lactate (n = 112, 67.9%), also statistically significant. CONCLUSIONS: The findings highlight the impact the guidelines can have on clinician decision-making and behaviour that support best practice and positive patient outcomes. The sepsis guidelines improved the early assessment, recognition and management of patients presenting with sepsis in one tertiary referral emergency department. RELEVANCE TO CLINICAL PRACTICE: The use of evidenced-based guidelines can impact clinical decision-making and behaviour, resulting in the translation and support of best practice and improving patient care. PMID- 28071866 TI - Exploration of the psychosocial issues associated with gastroparesis: a qualitative investigation. AB - AIMS AND OBJECTIVES: To build on the understanding of how individuals experience gastroparesis, how gastroparesis impacts on their lives and how they adapt to living with gastroparesis. BACKGROUND: Gastroparesis is a neurogastroenterological disorder associated with increased psychological distress and reduced quality of life. Research shows that gastroparesis poses a significant burden across many facets of life; however, less is known about how individuals cope and adapt to living with the condition. DESIGN: The study employed an interpretive phenomenological approach with semistructured interviews and thematic analysis. METHODS: Ten gastroparesis patients were interviewed over the telephone (n = 8), Skype (n = 1) or face-to-face (n = 1). All interviews were audio-recorded and transcribed. RESULTS: Key themes identified: (1) frustration, (2) identity and (3) coping and adaptation. Gastroparesis patients experience significant frustration around their diagnostic journey, being misunderstood and the burden of living with the illness. Patients differed in how they identified with the illness, and this appeared to be associated with adaptation and whether they remained socially engaged. CONCLUSIONS: Gastroparesis is associated with significant frustration and burden; however, some patients adapt to living with the condition more effectively than others. Identity appears to play an important role in this relationship. Support aimed at fostering a health-focused and resilient identity may assist gastroparesis patients in adaptation. RELEVANCE TO CLINICAL PRACTICE: The findings of this study can help nurses and other healthcare professionals better understand the experience of living with gastroparesis and the factors that help patients best adapt to living with the condition. Nurses can help promote resilience in patients by discussing the importance of being health-focused rather than illness-focused. Nurses can also support patients by helping them problem-solve issues that may arise around social eating and remaining socially engaged. PMID- 28071867 TI - Identifying Effective Nurse-Led Care Transition Interventions for Older Adults With Complex Needs Using a Structured Expert Panel. AB - BACKGROUND: Nursing plays a central role in facilitating care transitions for complex older adults, yet there is no consensus of the components of nurse-led care transitions interventions to facilitate high quality care transitions among complex older adults. A structured expert panel was established with the purpose of identifying effective nurse-led care transition interventions. METHODS: A modified Delphi consensus technique based on the RAND method was employed. Panelists (n = 23) were asked to individually rate a series of statements derived from a realist synthesis of the literature for relevance, feasibility and likely impact. Statements receiving an aggregate score of >=75% (7/9) were reviewed and revised at a face-to-face consensus meeting. A second round of rating following the same process as round one was used, followed by a final ranking of the statements. RESULTS: The five highest ranked intervention components and contextual factors were: (a) educating and coaching patients, their family members and caregivers about self-management skills; (b) ensuring patients, their family members and caregivers are aware of follow-up medical appointments and postdischarge care plan; (c) using standardized documentation tools and comprehensive communication strategies during care transitions; (d) optimizing nurses' roles and scopes of practice across the care transitions spectrum; and (e) having strong leadership, strategic alignment and accountability structures in organizations to enable quality care transitions for the complex older person population. LINKING EVIDENCE TO ACTION: Key insights on optimizing the nurses' roles and scope of practice during care transitions included having nurses provide "warm hand-offs" and serve as the "go-to person." The panel also identified current challenges to optimizing the nurses' roles and scope of practice across care transition points. Future research is required to determine effective nurse-led intervention components and in which context do they work or do not. PMID- 28071868 TI - Development and validation of two equations based on anthropometry, estimating body fat for the Greek adult population. AB - OBJECTIVE: To validate anthropometric equations in the current literature predicting body fat percentage (%BF) in the Greek population, to develop and validate two anthropometric equations estimating %BF, and to compare them with the retrieved equations. METHODS: Anthropometric data from 642 Greek adults were incorporated. Dual-energy X-ray absorptiometry was used as reference method. The comparison with other equations was made using Bland-Altman analysis, intraclass correlation coefficient, and Lin's concordance correlation coefficient. RESULTS: Nine of the thirty-one retrieved equations had no statistically significant bias. However, all of them had wide limits of agreement (+/-8.3 to +/-16%BF). The equations accrued were: BF% = -0.615-10.948 * sex + 0.321 * waist circumference + 0.502 * hips circumference-0.39 * forearm circumference - 19.768 * height (m) and BF% = -27.787-5.515 * sex-8.419 * height + 0.145 * waist circumference + 0.270 * hips circumference + 7.509 * log of thigh skinfold + 20.090 * log of sum of skinfolds (bicep + tricep + suprailiac + subscapular)-0.445 * forearm circumference. Bland-Altman's reliability analysis showed no significant bias of 0.058 and -0.148%BF and limits of agreement +/-8.100 and +/-6.056%BF; the intraclass correlation coefficient was 0.955 and 0.976; and Lin's concordance correlation coefficient was 0.914 and 0.951, respectively. CONCLUSIONS: Literature equations performed moderately on this study's population. Therefore, two equations were designed and validated. The first one was simple and easily applicable, with measures obtained from a measuring tape, and the second one more complicated yet more accurate and reliable. Both were found to be reliable for the assessment of body composition in the Greek population. PMID- 28071869 TI - Synthesis and luminescence properties of CaSnO3 :Bi3+ blue phosphor and the emission improvement by Li+ ion. AB - CaSnO3 :Bi3+ blue-emitting phosphor was synthesized using a high-temperature solid-state reaction method in air. The crystal structures and luminescence properties were investigated. A broad emission band peaking at ~448 nm upon excitation at 262 and 308 nm was observed in the range 330-680 nm at room temperature due to 3 P1 -> 1 S0 transition of the Bi3+ ion. The chromaticity coordinate was (0.1786, 0.1665). The optimal Bi3+ ion concentration was ~0.6 mol% in CaSnO3 :Bi3+ phosphor. The emission spectrum of CaSnO3 :Bi3+ phosphor showed a blue-shift with increasing temperature from 50 to 300 K due to the influence of temperature on the electron transition of the Bi3+ ion. The emission intensity of CaSnO3 :Bi3+ phosphor may be increased ~1.45 times by co-doping Li+ ions as a charge compensator and fluxing agent. The luminescence mechanism is explained by a configurational coordinate diagram of Bi3+ ion in CaSnO3 :Bi3+ phosphor. PMID- 28071870 TI - Accessing new understandings of trauma-informed care with queer birthing women in a rural context. AB - AIMS AND OBJECTIVES: Participant narratives from a feminist and queer phenomenological study aim to broaden current understandings of trauma. Examining structural marginalisation within perinatal care relationships provides insights into the impact of dominant models of care on queer birthing women. More specifically, validation of queer experience as a key finding from the study offers trauma-informed strategies that reconstruct formerly disempowering perinatal relationships. BACKGROUND: Heteronormativity governs birthing spaces and presents considerable challenges for queer birthing women who may also have an increased risk of trauma due to structurally marginalising processes that create and maintain socially constructed differences. DESIGN: Analysis of the qualitative data was guided by feminist and queer phenomenology. This was well suited to understanding queer women's storied narratives of trauma, including disempowering processes of structural marginalisation. METHODS: Semistructured and conversational interviews were conducted with a purposeful sample of thirteen queer-identified women who had experiences of birthing in rural Nova Scotia, Canada. RESULTS: Validation was identified as meaningful for queer women in the context of perinatal care in rural Nova Scotia. Offering new perspectives on traditional models of assessment provide strategies to create a context of care that reconstructs the birthing space insofar as women at risk do not have to come out as queer in opposition to the expectation of heterosexuality. CONCLUSIONS: Normative practices were found to further the effects of structural marginalisation suggesting that perinatal care providers, including nurses, can challenge dominant models of care and reconstruct the relationality between queer women and formerly disempowering expectations of heteronormativity that govern birthing spaces. RELEVANCE TO CLINICAL PRACTICE: New trauma-informed assessment strategies reconstruct the relationality within historically disempowering perinatal relationships through potentiating difference which avoids retraumatising women with re-experiencing the process of coming out as queer in opposition to the expectation of heterosexuality. PMID- 28071871 TI - Harmonization of Mangiferin on methylmercury engendered mitochondrial dysfunction. AB - Mangiferin (MGN), a C-glucosylxanthone abundantly found in mango plants, was studied for its potential to ameliorate methylmercury (MeHg) induced mitochondrial damage in HepG2 (human hepatocarcinoma) cell line. Cell viability experiments performed using 3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyltetrazolium bromide (MTT) showed protective property of MGN in annulling MeHg-induced cytotoxicity. Conditioning the cells with optimal dose of MGN (50 uM) lowered MeHg-induced oxidative stress, calcium influx/efflux, depletion of mitochondrial trans-membrane potential and prevented mitochondrial fission as observed by decrease in Mitotracker red fluorescence, expression of pDRP1 (serine 616), and DRP1 levels. MGN pre-treated cells demonstrated elevation in the activities of glutathione (GSH), Glutathione-S-transferase (GST), Glutathione peroxidase (GPx), Glutathione reductase (GR), reduced levels of Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) and mitochondrial electron transport chain (ETC) enzyme complexes. In addition, the anti-apoptotic effect of MGN was clearly indicated by the reduction in MeHg-induced apoptotic cells analyzed by flowcytometric analysis after Annexin V-FITC/propidium iodide staining. In conclusion, the present work demonstrates the ability of a dietary polyphenol, MGN to ameliorate MeHg-mediated mitochondrial dysfunction in human hepatic cells in vitro. This hepatoprotective potential may be attributed predominantly to the free radical scavenging/antioxidant property of MGN, by facilitating the balancing of cellular Ca2+ ions, maintenance of redox homeostasis and intracellular antioxidant activities, ultimately preserving the mitochondrial function and cell viability after MeHg intoxication. As MeHg intoxication occurs over a period of time, continuous consumption of such dietary compounds may prove to be very useful in promoting human health. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 630-644, 2017. PMID- 28071872 TI - Mutant botrocetin-2 inhibits von Willebrand factor-induced platelet agglutination. AB - : Essentials Botrocetin-2 (Bot2) binds to von Willebrand factor (VWF) and induces platelet agglutination. We identified Bot2 residues that are required for binding to VWF and glycoprotein (GP) Ib. We produced a mutant Bot2 that binds to VWF but inhibits platelet agglutination. Mutant Bot2 could be used as a potential anti thrombotic reagent to block VWF-GPIb interaction. SUMMARY: Background Botrocetin 2 (Bot2) is a botrocetin-like protein composed of alpha and beta subunits that have been cloned from the snake Bothrops jararaca. Bot2 binds specifically to von Willebrand factor (VWF), and the complex induces glycoprotein (GP) Ib-dependent platelet agglutination. Objectives To exploit Bot2's VWF-binding capacity in order to attempt to create a mutant Bot2 that binds to VWF but inhibits platelet agglutination. Methods and Results Several point mutations were introduced into Bot2 cDNA, and the recombinant protein (recombinant Bot2 [rBot2]) was purified on an anti-botrocetin column. The mutant rBot2 with either Ala at Asp70 in the beta subunit (Aspbeta70Ala), or Argbeta115Ala and Lysbeta117Ala, showed reduced platelet agglutination-inducing activity. rBot2 with Aspbeta70Ala showed little binding activity towards immobilized VWF on an ELISA plate, whereas rBot2 with Argbeta115Ala/Lysbeta117Ala showed reduced binding activity towards GPIb (glycocalicin) after forming a complex with VWF. rBot2 point-mutated to oppositely charged Glu at both Argbeta115 and Lysbeta117 showed normal binding activity towards VWF but no platelet-agglutinating activity. Furthermore, this doubly mutated protein inhibited ristocetin-induced or high shear stress-induced platelet aggregation, and restrained thrombus formation under flow conditions. Conclusions Asp70 in the beta subunit of botrocetin is important for VWF binding, and Arg115 and Lys117 in the beta subunit are essential for interaction with GPIb. Doubly mutated rBot2, with Argbeta115Glu and Lysbeta117Glu, repels GPIb and might have potential as an antithrombotic reagent that specifically blocks VWF function. This is the first report on an artificial botrocetin that can inhibit the VWF-GPIb interaction. PMID- 28071874 TI - Medicare Program; Advancing Care Coordination Through Episode Payment Models (EPMs); Cardiac Rehabilitation Incentive Payment Model; and Changes to the Comprehensive Care for Joint Replacement Model (CJR). Final rule. AB - This final rule implements three new Medicare Parts A and B episode payment models, a Cardiac Rehabilitation (CR) Incentive Payment model and modifications to the existing Comprehensive Care for Joint Replacement model under section 1115A of the Social Security Act. Acute care hospitals in certain selected geographic areas will participate in retrospective episode payment models targeting care for Medicare fee-forservice beneficiaries receiving services during acute myocardial infarction, coronary artery bypass graft, and surgical hip/femur fracture treatment episodes. All related care within 90 days of hospital discharge will be included in the episode of care. We believe these models will further our goals of improving the efficiency and quality of care for Medicare beneficiaries receiving care for these common clinical conditions and procedures. PMID- 28071873 TI - Cognitive Stress Reduces the Effect of Levodopa on Parkinson's Resting Tremor. AB - AIMS: Resting tremor in Parkinson's disease (PD) increases markedly during cognitive stress. Dopamine depletion in the basal ganglia is involved in the pathophysiology of resting tremor, but it is unclear whether this contribution is altered under cognitive stress. We test the hypothesis that cognitive stress modulates the levodopa effect on resting tremor. METHODS: Tremulous PD patients (n = 69) were measured in two treatment conditions (OFF vs. ON levodopa) and in two behavioral contexts (rest vs. cognitive co-activation). Using accelerometry, we tested the effect of both interventions on tremor intensity and tremor variability. RESULTS: Levodopa significantly reduced tremor intensity (across behavioral contexts), while cognitive co-activation increased it (across treatment conditions). Crucially, the levodopa effect was significantly smaller during cognitive co-activation than during rest. Resting tremor variability increased after levodopa and decreased during cognitive co-activation. CONCLUSION: Cognitive stress reduces the levodopa effect on Parkinson's tremor. This effect may be explained by a stress-related depletion of dopamine in the basal ganglia motor circuit, by stress-related involvement of nondopaminergic mechanisms in tremor (e.g., noradrenaline), or both. Targeting these mechanisms may open new windows for treatment. Clinical tremor assessments under evoked cognitive stress (e.g., counting tasks) may avoid overestimation of treatment effects in real life. PMID- 28071875 TI - 340B Drug Pricing Program Ceiling Price and Manufacturer Civil Monetary Penalties Regulation. Final rule. AB - The Health Resources and Services Administration (HRSA) administers section 340B of the Public Health Service Act (PHSA), referred to as the "340B Drug Pricing Program" or the "340B Program." This final rule will apply to all drug manufacturers that are required to make their drugs available to covered entities under the 340B Program. This final rule sets forth the calculation of the 340B ceiling price and application of civil monetary penalties (CMPs). PMID- 28071876 TI - Obstetrical and Gynecological Devices; Reclassification of Surgical Instrumentation for Use With Urogynecologic Surgical Mesh. Final order. AB - The Food and Drug Administration (FDA or the Agency) is reclassifying surgical instrumentation for use with urogynecologic surgical mesh from class I (general controls) exempt from premarket notification to class II (special controls) and subject to premarket notification, and identifying them as "specialized surgical instrumentation for use with urogynecologic surgical mesh." FDA is designating special controls that are necessary to provide a reasonable assurance of safety and effectiveness of the device. FDA is reclassifying this device on its own initiative based on new information. PMID- 28071877 TI - Clarification of When Products Made or Derived From Tobacco Are Regulated as Drugs, Devices, or Combination Products; Amendments to Regulations Regarding "Intended Uses." Final rule. AB - The Food and Drug Administration (FDA) is issuing this final rule to describe the circumstances in which a product made or derived from tobacco that is intended for human consumption will be subject to regulation as a drug, device, or a combination product under the Federal Food, Drug, and Cosmetic Act (the FD&C Act). This action is intended to provide direction to regulated industry and to help avoid consumer confusion. PMID- 28071878 TI - Occupational Exposure to Beryllium. Final rule. AB - The Occupational Safety and Health Administration (OSHA) is amending its existing standards for occupational exposure to beryllium and beryllium compounds. OSHA has determined that employees exposed to beryllium at the previous permissible exposure limits face a significant risk of material impairment to their health. The evidence in the record for this rulemaking indicates that workers exposed to beryllium are at increased risk of developing chronic beryllium disease and lung cancer. This final rule establishes new permissible exposure limits of 0.2 micrograms of beryllium per cubic meter of air (0.2 [mu]g/m?3?) as an 8-hour time weighted average and 2.0 [mu]g/m?3? as a short-term exposure limit determined over a sampling period of 15 minutes. It also includes other provisions to protect employees, such as requirements for exposure assessment, methods for controlling exposure, respiratory protection, personal protective clothing and equipment, housekeeping, medical surveillance, hazard communication, and recordkeeping. OSHA is issuing three separate standards--for general industry, for shipyards, and for construction--in order to tailor requirements to the circumstances found in these sectors. PMID- 28071879 TI - Standards for Accessible Medical Diagnostic Equipment. Final rule. AB - The Architectural and Transportation Barriers Compliance Board (Access Board or Board) is issuing accessibility standards for medical diagnostic equipment. The standards for medical diagnostic equipment (MDE Standards) contain minimum technical criteria to ensure that medical diagnostic equipment, including but not limited to, examination tables, examination chairs, weight scales, mammography equipment, and other imaging equipment used by health care providers for diagnostic purposes are accessible to, and usable by, individuals with disabilities. The MDE Standards will allow independent entry to, use of, and exit from the equipment by individuals with disabilities to the maximum extent possible. The MDE Standards do not impose any mandatory requirements on health care providers or medical device manufacturers. However, other agencies, referred to as enforcing authorities in the MDE Standards, may issue regulations or adopt policies that require health care providers subject to their jurisdiction to acquire accessible medical diagnostic equipment that complies with the MDE Standards. PMID- 28071880 TI - Oral Health Care and Coverage During Pregnancy. PMID- 28071881 TI - The Effect of Low Levels of Blood Lead on Children's Test Scores. PMID- 28071882 TI - Long-Term Care Hospitals Discharge Patients Strategically. PMID- 28071883 TI - Individually Stabilized, Superparamagnetic Nanoparticles with Controlled Shell and Size Leading to Exceptional Stealth Properties and High Relaxivities. AB - Superparamagnetic iron oxide nanoparticles (SPION) have received immense interest for biomedical applications, with the first clinical application as negative contrast agent in magnetic resonance imaging (MRI). However, the first generation MRI contrast agents with dextran-enwrapped, polydisperse iron oxide nanoparticle clusters are limited to imaging of the liver and spleen; this is related to their poor colloidal stability in biological media and inability to evade clearance by the reticuloendothelial system. We investigate the qualitatively different performance of a new generation of individually PEG-grafted core-shell SPION in terms of relaxivity and cell uptake and compare them to benchmark iron oxide contrast agents. These PEG-grafted SPION uniquely enable relaxivity measurements in aqueous suspension without aggregation even at 9.4 T magnetic fields due to their extraordinary colloidal stability. This allows for determination of the size-dependent scaling of relaxivity, which is shown to follow a d2 dependence for identical core-shell structures. The here introduced core-shell SPION with ~15 nm core diameter yield a higher R2 relaxivity than previous clinically used contrast agents as well as previous generations of individually stabilized SPION. The colloidal stability extends to control over evasion of macrophage clearance and stimulated uptake by SPION functionalized with protein ligands, which is a key requirement for targeted MRI. PMID- 28071884 TI - Carbon-Coated Fe3O4/VOx Hollow Microboxes Derived from Metal-Organic Frameworks as a High-Performance Anode Material for Lithium-Ion Batteries. AB - As the ever-growing demand for high-performance power sources, lithium-ion batteries with high storage capacities and outstanding rate performance have been widely considered as a promising storage device. In this work, starting with metal-organic frameworks, we have developed a facile approach to the synthesis of hybrid Fe3O4/VOx hollow microboxes via the process of hydrolysis and ion exchange and subsequent calcination. In the constructed architecture, the hollow structure provides an efficient lithium ion diffusion pathway and extra space to accommodate the volume expansion during the insertion and extraction of Li+. With the assistance of carbon coating, the obtained Fe3O4/VOx@C microboxes exhibit excellent cyclability and enhanced rate performance when employed as an anode material for lithium-ion batteries. As a result, the obtained Fe3O4/VOx@C delivers a high Coulombic efficiency (near 100%) and outstanding reversible specific capacity of 742 mAh g-1 after 400 cycles at a current density of 0.5 A g 1. Moreover, a remarkable reversible capacity of 556 mAh g-1 could be retained even at a current density of 2 A g-1. This study provides a fundamental understanding for the rational design of other composite oxides as high performance electrode materials for lithium-ion batteries. PMID- 28071885 TI - Transparent, Superhydrophobic Surface with Varied Surface Tension Responsiveness in Wettability Based on Tunable Porous Silica Structure for Gauging Liquid Surface Tension. AB - Any solid surface can spontaneously exhibit variational wettability toward liquids with varied surface tension (gamma). However, this correspondence has seldom been proposed or used on an artificial superhydrophobic surface, which should be more remarkable and peculiar. Herein, we fabricated robust, transparent superhydrophobic surfaces utilizing acid- and base-catalyzed silica (AC- and BC silica) particles combined with candle soot template for structural construction and the CVD process for chemical modification. Three types of porous silica structures were devised, which presented distinctive surface tension responsiveness in wettability. Interestingly, all types of surfaces (i.e., AC-, AC/BC-, and BC-silica) show high repellence to high surface tension liquid (gamma > 35 mN/m), and small differences are observed. With decreasing gamma of the ethanol-water mixtures (gamma < 35 mN/m), the static contact angles (SCAs) on all surfaces have an evident decline, but the features of the decreases are fairly different. As gamma decreases, the SCA on the AC-silica surface decreases gradually, but the extent of decline becomes larger when gamma < 27.42 mN/m. However, the SCA on the BC-silica surface decreases gradually except for gamma ~ 30.81 mN/m, and the SCA undergoes a sharp decline at gamma ~ 30.81 mN/m. The SCA on the AC/BC-silica surface has a similar variation as that of the SCA on the BC silica surface, but a lower rate of BC-silica particles, e.g., 1/16, 1/8, 1/1 (AC/BC), further diminishes the critical gamma values (where a sharp SCA drop occurs) to 30.16, 29.56, and 28.04 mN/m, respectively. The diversity is believed to be ascribed to the structure-induced selectivity of pore infiltration for the liquid. The tunable responsiveness can be generalized to various classes of organic aqueous solutions including methanol, acetic acid, acetone, and N,N dimethylformamide. Benefiting from this, we can estimate organics concentration of an organic aqueous solution as well as its liquid surface tension by detecting its wettability on all of the diverse superhydrophobic surfaces. PMID- 28071886 TI - Boronlectin/Polyelectrolyte Ensembles as Artificial Tongue: Design, Construction, and Application for Discriminative Sensing of Complex Glycoconjugates from Panax ginseng. AB - Ginsenoside is a large family of triterpenoid saponins from Panax ginseng, which possesses various important biological functions. Due to the very similar structures of these complex glycoconjugates, it is crucial to develop a powerful analytic method to identify ginsenosides qualitatively or quantitatively. We herein report an eight-channel fluorescent sensor array as artificial tongue to achieve the discriminative sensing of ginsenosides. The fluorescent cross responsive array was constructed by four boronlectins bearing flexible boronic acid moieties (FBAs) with multiple reactive sites and two linear poly(phenylene ethynylene) (PPEs). An "on-off-on" response pattern was afforded on the basis of superquenching of fluorescent indicator PPEs and an analyte-induced allosteric indicator displacement (AID) process. Most importantly, it was found that the canonical distribution of ginsenoside data points analyzed by linear discriminant analysis (LDA) was highly correlated with the inherent molecular structures of the analytes, and the absence of overlaps among the five point groups reflected the effectiveness of the sensor array in the discrimination process. Almost all of the unknown ginsenoside samples at different concentrations were correctly identified on the basis of the established mathematical model. Our current work provided a general and constructive method to improve the quality assessment and control of ginseng and its extracts, which are useful and helpful for further discriminating other complex glycoconjugate families. PMID- 28071887 TI - Polarization-Tailored Fano Interference in Plasmonic Crystals: A Mueller Matrix Model of Anisotropic Fano Resonance. AB - Fano resonance is observed in a wide range of micro- and nano-optical systems and has been a subject of intensive investigations due to its numerous potential applications. Methods that can control or modulate Fano resonance by tuning some experimentally accessible parameters are highly desirable for realistic applications. Here we present a simple yet elegant approach using the Mueller matrix formalism for controlling the Fano interference effect and engineering the resulting asymmetric spectral line shape in an anisotropic optical system. The approach is founded on a generalized model of anisotropic Fano resonance, which relates the spectral asymmetry to physically meaningful and experimentally accessible parameters of interference, namely, the Fano phase shift and the relative amplitudes of the interfering modes. The differences in these parameters between orthogonal linear polarizations in an anisotropic system are exploited to desirably tune the Fano spectral asymmetry using pre- and postselection of optimized polarization states. The concept is demonstrated on waveguided plasmonic crystals using Mueller matrix-based polarization analysis. The approach enabled tailoring of several exotic regimes of Fano resonance in a single device, including the complete reversal of the spectral asymmetry, and shows potential for applications involving control and manipulation of electromagnetic waves at the nanoscale. PMID- 28071888 TI - Synthesis and Supercapacitor Application of Alkynyl Carbon Materials Derived from CaC2 and Polyhalogenated Hydrocarbons by Interfacial Mechanochemical Reactions. AB - The discovery of new carbon materials and the reactive activation of CaC2 are challenging subjects. In this study, a series of alkynyl carbon materials (ACMs) were synthesized by the interfacial mechanochemical reaction of CaC2 with four typical polyhalogenated hydrocarbons. Their properties and structures were characterized, and their electrochemical performances were examined. The reaction was rapid and efficient arising from the intense mechanical activation of CaC2. The ACMs are micro-mesoporous materials with distinct layered structure, specific graphitization degree, and clear existence of sp-C. In addition, the ACMs exhibit high specific capacitance in the range of 57-133 F g-1 and thus can be ideal candidates for active materials used in supercapacitors. The results may imply an alternative synthesis of carbon allotropes, as well as an efficient approach for the activation of CaC2. PMID- 28071889 TI - Enzyme and Redox Dual-Triggered Intracellular Release from Actively Targeted Polymeric Micelles. AB - Highly effective delivery of therapeutic agents into target cells using nanocarriers and subsequently rapid intracellular release are of great importance in cancer treatment. Here, we developed an enzyme and redox dual-responsive polymeric micelle with active targeting abilities to achieve rapid intracellular drug release. To overcome both its poor solubility in water and instability in the blood circulation, camptothecin (CPT) was chemically conjugated to monomethyl poly(ethylene glycol) (mPEG) via a redox-responsive linker to form polymeric prodrugs. The enzyme-responsive function is achieved by connecting hydrophobic polycaprolactone segments and hydrophilic PEG segments with azo bonds. Additionally, the end of the PEG segment was decorated with phenylboronic acid (PBA), endowing the nanocarriers with active targeting abilities. The dual responsive targeting polymeric micelles can be generated by self-assembly of a mixture of the polymeric prodrug and enzyme-responsive copolymer. The in vitro drug release profile revealed that CPT was rapidly released from the micelles under a simulated condition similar to the tumor cell microenvironment. In vivo and ex vivo fluorescence imaging indicated that these micelles possess excellent specificity to target hepatoma carcinoma cells. The antitumor effect in mice liver cancer cells (H22) in tumor-bearing Kunming (KM) mice demonstrated that this nanocarrier exhibits high therapeutic efficiency in artificial solid tumors and low toxicity to normal tissues, with a survival rate of approximately 100% after 160 days of treatment. PMID- 28071890 TI - Peptide Conjugates of Benzene Carboxylic Acids as Agonists and Antagonists of Amylin Aggregation. AB - Human islet amyloid polypeptide (hIAPP), also known as amylin, is a 37 residue peptide hormone that is stored and co-secreted with insulin. hIAPP plays a pivotal role in type 2 diabetes and is the major component of amyloid deposits found in the pancreas of patients afflicted with the disease. The self-assembly of hIAPP and the formation of amyloid is linked to the death of insulin producing beta-cells. Recent findings suggest that soluble hIAPP oligomers are the cytotoxic species responsible for beta-cell loss whereas amyloid fibrils themselves may indeed be innocuous. Potential avenues of therapeutic intervention include the development of compounds that prevent hIAPP self-assembly as well as those that reduce or eliminate lag time and rapidly accelerate the formation of amyloid fibrils. Both of these approaches minimize temporal exposure to soluble cytotoxic hIAPP oligomers. Toward this end our laboratory has pursued an electrostatic repulsion approach to the development of potential inhibitors and modulators of hIAPP self-assembly. Peptide conjugates were constructed in which benzene carboxylic acids of varying charge were employed as electrostatic disrupting elements and appended to the N-terminal of the hIAPP22-29 (NFGAILSS) self-recognition sequence. The self-assembly kinetics of conjugates were characterized by turbidity measurements and the structure of aggregates probed by Raman and CD spectroscopy while the morphology was assessed using transmission electron microscopy. Several benzene carboxylic acid peptide conjugates failed to self-assemble and some were found to inhibit the aggregation of full-length amylin while others served to enhance the rate of amyloid formation and/or increase the yield of amyloid produced. Studies reveal that the geometric display of free carboxylates on the benzene ring of the conjugates plays an important role in the activity of conjugates. In addition, a number of free benzene carboxylic acids were found to modulate amylin self-assembly on their own. The results of these investigations confirm the viability of the electrostatic repulsion approach to the modulation of amyloid formation and may aid the design and development of potential therapeutic agents. PMID- 28071891 TI - Dual Enzymatic Reaction-Assisted Gemcitabine Delivery Systems for Programmed Pancreatic Cancer Therapy. AB - Dual enzymatic reactions were introduced to fabricate programmed gemcitabine (GEM) nanovectors for targeted pancreatic cancer therapy. Dual-enzyme-sensitive GEM nanovectors were prepared by conjugation of matrix metalloproteinase-9 (MMP 9) detachable poly(ethylene glycol) (PEG), cathepsin B-cleavable GEM, and targeting ligand CycloRGD to CdSe/ZnS quantum dots (QDs). The GEM nanovectors decorated with a PEG corona could avoid nonspecific interactions and exhibit prolonged blood circulation time. After GEM nanovectors were accumulated in tumor tissue by the enhanced permeability and retention (EPR) effect, the PEG corona can be removed by overexpressed MMP-9 in tumor tissue and RGD would be exposed, which was capable of facilitating cellular internalization. Once internalized into pancreatic cancer cells, the elevated lysosomal cathepsin B could further promote the release of GEM. By employing dual enzymatic reactions, the GEM nanovectors could achieve prolonged circulation time while maintaining enhanced cellular internalization and effective drug release. The proposed mechanism of the dual enzymatic reaction-assisted GEM delivery system was fully investigated both in vitro and in vivo. Meanwhile, compared to free GEM, the deamination of GEM nanovectors into inactive 2',2'-difluorodeoxyuridine (dFdU) could be greatly suppressed, while the concentration of the activated form of GEM (gemcitabine triphosphate, dFdCTP) was significantly increased in tumor tissue, thus exhibiting superior tumor inhibition activity with minimal side effects. PMID- 28071893 TI - Deterministic Reshaping of Breath Figure Arrays by Directional Photomanipulation. AB - The fabrication of desired structures is one of the most urgent topics in current research on porous polymer films. Herein, directional photomanipulation in conjunction with breath figure processing has been demonstrated for the preparation of porous polymeric films with finely tunable pore shape and size. Because of the photoinduced directional mass migration of azobenzene units upon vertical incident linearly polarized light (LPL) irradiation, round pores on honeycomb films can be reshaped into multifarious shapes including rectangle, rhombus, dumbbell, line, and so forth. In addition, slantwise LPL irradiation produces unique asymmetrical structure inside the pores oriented along the polarized direction. On the other hand, circularly polarized light (CPL) irradiation affords manipulation of the wall thickness without changing the pore shape. This versatile directional photomanipulation method can be implemented to large-area and high-throughput reshaping processes, which paves the way to a number of promising applications such as a flexible etching mask for patterning. PMID- 28071892 TI - Transient Adenosine Release Is Modulated by NMDA and GABAB Receptors. AB - Adenosine is a neuroprotective agent that modulates neurotransmission and is modulated by other neurotransmitters. Spontaneous, transient adenosine is a recently discovered mode of signaling where adenosine is released and cleared from the extracellular space quickly, in less than three seconds. Spontaneous adenosine release is regulated by adenosine A1 and A2a receptors, but regulation by other neurotransmitter receptors has not been studied. Here, we examined the effect of glutamate and GABA receptors on the concentration and frequency of spontaneous, transient adenosine release by measuring adenosine with fast-scan cyclic voltammetry in the rat caudate-putamen. The glutamate NMDA antagonist, 3 (R-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 6.25 mg/kg i.p.), increased the frequency of adenosine transients and the concentration of individual transients, but NMDA (agonist, 50 mg/kg, i.p.) did not change the frequency. In contrast, antagonists of other glutamate receptors had no effect on the frequency or concentration of transient adenosine release, including the AMPA antagonist NBQX (15 mg/kg i.p.) and the mGlu2/3 glutamate receptor antagonist LY 341495 (5 mg/kg i.p.). The GABAB antagonist CGP 52432 (30 mg/kg i.p.) significantly decreased the number of adenosine release events while the GABAB agonist baclofen (4 mg/kg i.p.) increased the frequency of adenosine release. The GABAA antagonist bicuculline (5 mg/kg i.p.) had no significant effects on adenosine. NMDA and GABAB likely act presynaptically, affecting the overall cell excitability for vesicular release. The ability to regulate adenosine with NMDA and GABAB receptors will help control the modulatory effects of transient adenosine release. PMID- 28071895 TI - Flexible, Cuttable, and Self-Waterproof Bending Strain Sensors Using Microcracked Gold Nanofilms@Paper Substrate. AB - Rapid advances in functional sensing electronics place tremendous demands on innovation toward creative uses of versatile advanced materials and effective designs of device structures. Here, we first report a feasible and effective fabrication strategy to integrate commercial abrasive papers with microcracked gold (Au) nanofilms to construct cuttable and self-waterproof crack-based resistive bending strain sensors. Via introducing surface microstructures, the sensitivities of the bending strain sensors are greatly enhanced by 27 times than that of the sensors without surface microstructures, putting forward an alternative suggestion for other flexible electronics to improve their performances. Besides, the bending strain sensors also endow rapid response and relaxation time of 20 ms and ultrahigh stability of >18 000 strain loading unloading cycles in conjunction with flexibility and robustness. In addition, the concepts of cuttability and self-waterproofness (attain and even surpass IPX-7) of the bending strain sensors have been demonstrated. Because of the distinctive sensing properties, flexibility, cuttability, and self-waterproofness, the bending strain sensors are attractive and promising for wearable electronic devices and smart health monitoring system. PMID- 28071894 TI - Noninvasive Monitoring of Blood Glucose with Raman Spectroscopy. AB - The successful development of a noninvasive blood glucose sensor that can operate reliably over sustained periods of time has been a much sought after but elusive goal in diabetes management. Since diabetes has no well-established cure, control of elevated glucose levels is critical for avoiding severe secondary health complications in multiple organs including the retina, kidney and vasculature. While fingerstick testing continues to be the mainstay of blood glucose detection, advances in electrochemical sensing-based minimally invasive approaches have opened the door for alternate methods that would considerably improve the quality of life for people with diabetes. In the quest for better sensing approaches, optical technologies have surfaced as attractive candidates as researchers have sought to exploit the endogenous contrast of glucose, notably its absorption, scattering, and polarization properties. Vibrational spectroscopy, especially spontaneous Raman scattering, has exhibited substantial promise due to its exquisite molecular specificity and minimal interference of water in the spectral profiles acquired from the blood-tissue matrix. Yet, it has hitherto been challenging to leverage the Raman scattering signatures of glucose for prediction in all but the most basic studies and under the least demanding conditions. In this Account, we discuss the newly developed array of methodologies that address the key challenges in measuring blood glucose accurately using Raman spectroscopy and unlock new prospects for translation to sustained noninvasive measurements in people with diabetes. Owing to the weak intensity of spontaneous Raman scattering, recent research has focused on enhancement of signals from the blood constituents by designing novel excitation collection geometries and tissue modulation methods while our attempts have led to the incorporation of nonimaging optical elements. Additionally, invoking mass transfer modeling into chemometric algorithms has not only addressed the physiological lag between the actual blood glucose and the measured interstitial fluid glucose values but also offered a powerful tool for predictive measurements of hypoglycemia. This framework has recently been extended to provide longitudinal tracking of glucose concentration without necessitating extensive a priori concentration information. These findings are advanced by the results of recent glucose tolerance studies in human subjects, which also hint at the need for designing nonlinear calibration models that can account for subject-to subject variations in skin heterogeneity and hematocrit levels. Together, the emerging evidence underscores the promise of a blood withdrawal-free optical platform-featuring a combination of high-throughput Raman spectroscopic instrumentation and data analysis of subtle variations in spectral expression-for diabetes screening in the clinic and, ultimately, for personalized monitoring. PMID- 28071896 TI - Fe on Sb(111): Potential Two-Dimensional Ferromagnetic Superstructures. AB - It is highly desirable to fabricate two-dimensional ferromagnetic membranes based on orthodox magnetic elements because of their inherent magnetic properties. In this work, we report on two superstructures including a honeycomb-like lattice and identical nanocluster arrays formed by depositing Fe on Sb(111). Combined with first-principles calculations, both detailed atomic structures have been clarified. The honeycomb structure consists of a single layered Fe-Sb phase, and the cluster phase is assigned as a (3 * 3) Fe3Sb7 superlattice. Both structural phases exhibit high magnetic moments localized on d bands of Fe. Our results provide a method to fabricate 2D magnetic superstructures possessing great potential in the realization of the Haldane model, spintronics applications, and single atom catalysis. PMID- 28071898 TI - Abnormal Multiple Charge Memory States in Exfoliated Few-Layer WSe2 Transistors. AB - To construct reliable nanoelectronic devices based on emerging 2D layered semiconductors, we need to understand the charge-trapping processes in such devices. Additionally, the identified charge-trapping schemes in such layered materials could be further exploited to make multibit (or highly desirable analog tunable) memory devices. Here, we present a study on the abnormal charge-trapping or memory characteristics of few-layer WSe2 transistors. This work shows that multiple charge-trapping states with large extrema spacing, long retention time, and analog tunability can be excited in the transistors made from mechanically exfoliated few-layer WSe2 flakes, whereas they cannot be generated in widely studied few-layer MoS2 transistors. Such charge-trapping characteristics of WSe2 transistors are attributed to the exfoliation-induced interlayer deformation on the cleaved surfaces of few-layer WSe2 flakes, which can spontaneously form ambipolar charge-trapping sites. Our additional results from surface characterization, charge-retention characterization at different temperatures, and density functional theory computation strongly support this explanation. Furthermore, our research also demonstrates that the charge-trapping states excited in multiple transistors can be calibrated into consistent multibit data storage levels. This work advances the understanding of the charge memory mechanisms in layered semiconductors, and the observed charge-trapping states could be further studied for enabling ultralow-cost multibit analog memory devices. PMID- 28071897 TI - Wear Protection without Surface Modification Using a Synergistic Mixture of Molecular Brushes and Linear Polymers. AB - We describe the design of lubricating and wear protecting fluids based on mixtures of bottle-brushes (BB) and linear polymer solutions. To illustrate this concept, we used hyaluronic acid (HA), a naturally occurring linear polyelectrolyte, and a water-soluble synthetic BB polymer. Individually, these two polymers exhibit poor wear protecting capabilities compared to that of saline solutions. Mixture of the two polymers in pure water or in saline allows the wear protection of surfaces over a wide range of shearing conditions to drastically increase. We demonstrate that this synergy between the BB and HA polymers emerges from a strong cohesion between the two components forming the boundary film due to entanglements between both polymers. We show that this concept can be applied to other types of linear polymers and surfaces and is independent of the chemical and mechanical properties of the surfaces. PMID- 28071899 TI - Near-IR-Absorbing Gold Nanoframes with Enhanced Physiological Stability and Improved Biocompatibility for In Vivo Biomedical Applications. AB - This paper describes the synthesis of near-infrared (NIR)-absorbing gold nanoframes (GNFs) and a systematic study comparing their physiological stability and biocompatibility with those of hollow Au-Ag nanoshells (GNSs), which have been used widely as photothermal agents in biomedical applications because of their localized surface plasmon resonance (LSPR) in the NIR region. The GNFs were synthesized in three steps: galvanic replacement, Au deposition, and Ag dealloying, using silver nanospheres (SNP) as the starting material. The morphology and optical properties of the GNFs were dependent on the thickness of the Au coating layer and the degree of Ag dealloying. The optimal GNF exhibited a robust spherical skeleton composed of a few thick rims, but preserved the distinctive LSPR absorbance in the NIR region-even when the Ag content within the skeleton was only 10 wt %, 4-fold lower than that of the GNSs. These GNFs displayed an attractive photothermal conversion ability and great photothermal stability, and could efficiently kill 4T1 cancer cells through light-induced heating. Moreover, the GNFs preserved their morphology and optical properties after incubation in biological media (e.g., saline, serum), whereas the GNSs were unstable under the same conditions because of rapid dissolution of the considerable silver content with the shell. Furthermore, the GNFs had good biocompatibility with normal cells (e.g., NIH-3T3 and hepatocytes; cell viability for both cells: >90%), whereas the GNSs exhibited significant dose-dependent cytotoxicity (e.g., cell viability for hepatocytes at 1.14 nM: ca. 11%), accompanied by the induction of reactive oxygen species. Finally, the GNFs displayed good biocompatibility and biosafety in an in vivo mouse model; in contrast, the accumulation of GNSs caused liver injury and inflammation. Our results suggest that GNFs have great potential to serve as stable, biocompatible NIR-light absorbers for in vivo applications, including cancer detection and combination therapy. PMID- 28071900 TI - Enantioselective Organocatalyzed Vinylogous Michael Reactions of 3-Alkylidene Oxindoles with Enals. AB - An efficient asymmetric vinylogous Michael addition of 3-alkylidene oxindoles and enals has been achieved using a chiral TBS-protected diphenylprolinol catalyst. The gamma-substituted alkylidene oxindoles obtained bear a chiral tertiary center and are afforded in moderate to good yields and good to excellent enantioselectivities. PMID- 28071901 TI - Accurate Theoretical Thermochemistry for Fluoroethyl Radicals. AB - An accurate coupled-cluster (CC) based model chemistry was applied to calculate reliable thermochemical quantities for hydrofluorocarbon derivatives including radicals 1-fluoroethyl (CH3-CHF), 1,1-difluoroethyl (CH3-CF2), 2-fluoroethyl (CH2F-CH2), 1,2-difluoroethyl (CH2F-CHF), 2,2-difluoroethyl (CHF2-CH2), 2,2,2 trifluoroethyl (CF3-CH2), 1,2,2,2-tetrafluoroethyl (CF3-CHF), and pentafluoroethyl (CF3-CF2). The model chemistry used contains iterative triple and perturbative quadruple excitations in CC theory, as well as scalar relativistic and diagonal Born-Oppenheimer corrections. To obtain heat of formation values with better than chemical accuracy perturbative quadruple excitations and scalar relativistic corrections were inevitable. Their contributions to the heats of formation steadily increase with the number of fluorine atoms in the radical reaching 10 kJ/mol for CF3-CF2. When discrepancies were found between the experimental and our values it was always possible to resolve the issue by recalculating the experimental result with currently recommended auxiliary data. For each radical studied here this study delivers the best heat of formation as well as entropy data. PMID- 28071902 TI - Reversible Single-Crystal-to-Single-Crystal Transformation and Magnetic Change of Nonporous Copper(II) Complexes by the Chemisorption/Desorption of HCl and H2O. AB - Vapor-responsive magnetic materials are highly promising for applications as chemical switches or sensors. Compared with porous materials, nonporous species benefit in overcoming the intrinsic conflict between magnetic exchange and porosity but usually suffer from the powdering of single crystals, which hinders the understanding of the structural nature of vapor response and magnetic switch. Single-crystal-to-single-crystal (SCSC) transformation of nonporous compounds through the desorption/absorption of gaseous HCl is unprecedented. Reported here is a discrete nonporous copper(II) complex, (H3O)[K(15-crown-5)2][CuCl4], that exhibits reversible SCSC transformation and magnetic change by the chemisorption/desorption of HCl and H2O. Significant changes in the coordination number (4 <-> 3), space group (P1 <-> P21/c), color (green <-> red), and magnetic behavior (antiferromagnetic <-> paramagnetic) were found during the SCSC transformation. PMID- 28071903 TI - Revisiting the Mossbauer Isomer Shifts of the FeMoco Cluster of Nitrogenase and the Cofactor Charge. AB - Despite decades of research, the structure-activity relationship of nitrogenase is still not understood. Only recently was the full molecular structure of the FeMo cofactor (FeMoco) revealed, but the charge and metal oxidation states of FeMoco have been controversial. With the recent identification of the interstitial atom as a carbide and the more recent revised oxidation-state assignment of the molybdenum atom as Mo(III), here we revisit the Mossbauer properties of FeMoco. By a detailed error analysis of density functional theory computed isomer shifts and computing isomer shifts relative to the P-cluster, we find that only the charge of [MoFe7S9C]1- fits the experimental data. In view of the recent Mo(III) identification, the charge of [MoFe7S9C]1- corresponds to a formal oxidation-state assignment of Mo(III)3Fe(II)4Fe(III), although due to spin delocalization, the physical oxidation state distribution might also be interpreted as Mo(III)1Fe(II)4Fe(2.5)2Fe(III), according to a localized orbital analysis of the MS = 3/2 broken symmetry solution. These results can be reconciled with the recent spatially resolved anomalous dispersion study by Einsle et al. that suggests the Mo(III)3Fe(II)4Fe(III) distribution, if some spin localization (either through interactions with the protein environment or through vibronic coupling) were to take place. PMID- 28071904 TI - New Insight into the Formation Mechanism of Imidazolium-Based Ionic Liquids from N-Alkyl Imidazoles and Halogenated Hydrocarbons: A Polar Microenvironment Induced and Autopromoted Process. AB - To illustrate the formation mechanism of imidazolium-based ionic liquids (ILs) from N-alkyl imidazoles and halogenated hydrocarbons, density functional theory calculations have been carried out on a representative system, the reaction of N methyl imidazole with chloroethane to form 1-ethyl-3-methyl imidazolium chloride ([Emim]Cl) IL. The reaction is shown to proceed via an SN2 transition state with a free energy barrier of 34.4 kcal/mol in the gas phase and 27.6 kcal/mol in toluene solvent. The reaction can be remarkably promoted by the presence of ionic products and water molecules. The calculated barriers in toluene are 22.0, 21.7, and 19.9 kcal/mol in the presence of 1-3 ionic pairs of [Emim]Cl and 23.5, 21.3, and 19.4 kcal/mol in the presence of 1-3 water molecules, respectively. These ionic pairs and water molecules do not participate directly in the reaction but provide a polar environment that favors stabilizing the transition state with large charge separation. Hence, we propose that the synthesis of imidazolium based ILs from N-alkyl imidazoles and halogenated hydrocarbons is an autopromoted process and a polar microenvironment induced reaction, and the existence of water molecules (a highly polar solvent) in the reaction may be mainly responsible for the initiation of reaction. PMID- 28071905 TI - Heterogeneous Nucleation of an n-Alkane on Tetrahedrally Coordinated Crystals. AB - Heterogeneous nucleation refers to the propensity for phase transformations to initiate preferentially on foreign surfaces, such as vessel walls, dust particles, or formulation additives. In crystallization, the form of the initial nucleus has ramifications for the crystallographic form, morphology, and properties of the resulting solid. Nevertheless, the discovery and design of nucleating agents remains a matter of trial and error because of the very small spatiotemporal scales over which the critical nucleus is formed and the extreme difficulty of examining such events empirically. Using molecular dynamics simulations, we demonstrate a method for the rapid screening of entire families of materials for activity as nucleating agents and for characterizing their mechanism of action. The method is applied to the crystallization of n pentacontane, a model surrogate for polyethylene, on the family of tetrahedrally coordinated crystals, including diamond and silicon. A systematic variation of parameters in the interaction potential permits a comprehensive, physically based screening of nucleating agents in this class of materials, including both real and hypothetical candidates. The induction time for heterogeneous nucleation is shown to depend strongly on crystallographic registry between the nucleating agent and the critical nucleus, indicative of an epitaxial mechanism in this class of materials. Importantly, the severity of this registry requirement weakens with decreasing rigidity of the substrate and increasing strength of attraction to the surface of the nucleating agent. Employing this method, a high throughput computational screening of nucleating agents becomes possible, facilitating the discovery of novel nucleating agents within a broad "materials genome" of possible additives. PMID- 28071906 TI - Single Conformation Spectroscopy of Suberoylanilide Hydroxamic Acid: A Molecule Bites Its Tail. AB - Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor that causes growth arrest and differentiation of many tumor types and is an approved drug for the treatment of cancer. The chemical structure of SAHA consists of formanilide "head" and a hydroxamic acid "tail" separated by an n-hexyl chain, C6H5NH(C?O)-(CH2)6-(C?O)NHOH. The alkyl chain's preference for extended structures is in competition with tail-to-head (T-H) or head-to-tail (H-T) hydrogen bonds between the amide and hydroxamic acid groups. Laser desorption was used to bring SAHA into the gas phase and cool it in a supersonic expansion before interrogation with mass-resolved resonant two-photon ionization spectroscopy. Single conformation UV spectra in the S0-S1 region and infrared spectra in the hydride stretch and mid-IR regions were recorded using IR-UV hole burning and resonant ion-dip infrared spectroscopy, respectively. Three conformers of SAHA were distinguished and spectroscopically characterized. Comparison of the experimental IR spectra with the predictions of density functional theory calculations (DFT, B3LYP D3BJ/6-31+G(d)) leads to assignments for the three conformers, all of which possess tightly folded alkyl chains that enable formation of a T-H (conformer A) or H-T (conformers B and C) hydrogen bonds. A modified version of the generalized Amber force field was developed to more accurately describe the hydroxamic acid OH internal rotor potential, leading to predictions for the relative energies in reasonable agreement with experiment. This force field was used to generate a disconnectivity graph for the low-energy portion of the potential energy landscape of SAHA. This disconnectivity graph contains more than one hundred minima and maps out the lowest-energy pathways between them, which could then be characterized via DFT calculations. This combination of force field and DFT calculations provides insight into the potential energy landscape and how population was funneled into the three observed conformers. PMID- 28071907 TI - The Influence of para Substituents in Bis(N-Heterocyclic Carbene) Palladium Pincer Complexes for Electrocatalytic CO2 Reduction. AB - The effect of modifying the pyridyl para position of lutidine-linked bis(N heterocyclic carbene) Pd pincer complexes is studied both experimentally (R = OMe, H, Br, and COOR) and computationally, showing a strong effect on the first reduction potential of the complex and allowing the reduction potential to be tuned over a wide range in relation to the Hammett sigmap constant of the para substituent. The effect of the pyridyl para substituent on electron density of the metal center, frontier orbital energies, and dissociation energy of the trans ligand are also investigated in the context of reactivity with CO2 through electrochemical characterization of the complexes under N2 and CO2 and controlled potential electrolysis experiments where CO2 is reduced to CO. PMID- 28071908 TI - Mechanically Induced Homochirality in Nucleated Enantioselective Polymerization. AB - Understanding how biological homochirality may have emerged during chemical evolution remains a challenge for origin of life research. In keeping with this goal, we introduce and solve numerically a kinetic rate equation model of nucleated cooperative enantioselective polymerization in closed systems. The microreversible scheme includes (i) solution-phase racemization of the monomers, (ii) linear chain growth by stepwise monomer attachment, in both nucleation and elongation phases, and (iii) annealing or fusion of homochiral chains. Mechanically induced breakage of the longest chains maintains the system out of equilibrium and drives a breakage-fusion recycling mechanism. Spontaneous mirror symmetry breaking can be achieved starting from small initial enantiomeric excesses due to the intrinsic statistical fluctuations about the idealized racemic composition. The subsequent chiral amplification confirms the model's capacity for absolute asymmetric synthesis, without chiral cross-inhibition and without explicit autocatalysis. PMID- 28071909 TI - Current Status and Bioinspired Perspective of Electrochemical Conversion of CO2 to a Long-Chain Hydrocarbon. AB - Electrocatalytic conversion of CO2 into a long-chain hydrocarbon represents an important research direction in adding value to CO2-based chemicals and realizing its practical application. Long-chain hydrocarbons may change the current fossil fuel-based industry in that those chemicals have a similar energy density as gasoline, high compatibility with the current infrastructure, and low hydroscopicity for pipeline distribution. However, most of the electrocatalysts produce C1, C2, and C3 chemicals, and methods for producing long-chain hydrocarbons are not available thus far. Interestingly, nature utilizes many enzymes to generate long-chain hydrocarbons using C2 building blocks and suggests key mechanisms, inspiring new perspective in the design of electrocatalysts. In this Perspective, we present case studies to demonstrate how CO2 and its reductive derivatives interact with the electrode surface during C-C bond formation and introduce how these issues are addressed in biological systems. We end this Perspective by outlining possible strategies to translate the natural mechanism into a heterogeneous electrode. PMID- 28071911 TI - High Defect Tolerance in Lead Halide Perovskite CsPbBr3. AB - The formation energies and charge-transition levels of intrinsic point defects in lead halide perovskite CsPbBr3 are studied from first-principles calculations. It is shown that the formation energy of dominant defect under Br-rich growth condition is much lower than that under moderate or Br-poor conditions. Thus avoiding the Br-rich condition can help to reduce the defect concentration. Interestingly, CsPbBr3 is found to be highly defect-tolerant in terms of its electronic structure. Most of the intrinsic defects induce shallow transition levels. Only a few defects with high formation energies can create deep transition levels. Therefore, CsPbBr3 can maintain its good electronic quality despite the presence of defects. Such defect tolerance feature can be attributed to the lacking of bonding-antibonding interaction between the conduction bands and valence bands. PMID- 28071910 TI - Direct Measurement of the Effect of Cholesterol and 6-Ketocholestanol on the Membrane Dipole Electric Field Using Vibrational Stark Effect Spectroscopy Coupled with Molecular Dynamics Simulations. AB - Biological membranes are heterogeneous structures with complex electrostatic profiles arising from lipids, sterols, membrane proteins, and water molecules. We investigated the effect of cholesterol and its derivative 6-ketocholestanol (6 kc) on membrane electrostatics by directly measuring the dipole electric field (F?d) within lipid bilayers containing cholesterol or 6-kc at concentrations of 0 40 mol% through the vibrational Stark effect (VSE). We found that adding low concentrations of cholesterol, up to ~10 mol %, increases F?d, while adding more cholesterol up to 40 mol% lowers F?d. In contrast, we measured a monotonic increase in F?d as 6-kc concentration increased. We propose that this membrane electric field is affected by multiple factors: the polarity of the sterol molecules, the reorientation of the phospholipid dipole due to sterol, and the impact of the sterol on hydrogen bonding with surface water. We used molecular dynamics simulations to examine the distribution of phospholipids, sterol, and helix in bilayers containing these sterols. At low concentrations, we observed clustering of sterols near the vibrational probe whereas at high concentrations, we observed spatial correlation between the positions of the sterol molecules. This work demonstrates how a one-atom difference in a sterol changes the physicochemical and electric field properties of the bilayer. PMID- 28071912 TI - Insights into the Catalytic Mechanism of Unsaturated Glucuronyl Hydrolase of Bacillus sp. GL1. AB - Together with polysaccharide lyases (PLs), the unsaturated glucuronyl hydrolase of Bacillus sp., GL1, is responsible for the metabolism of glycosaminoglycans (GAGs), which plays an important role in various crucial physiological events. More importantly, the degradation mechanism of GAGs often causes extracellular bacterial infection and is thought to be one of the virulence factors. We have previously studied the first degradation step catalyzed by PLs. In this work, we focused on the degradation of the unsaturated chondroitin disaccharide, which is produced from chondroitin by chondroitin lyase. A combined quantum mechanical and molecular mechanical method was employed in all simulations. First of all, molecular dynamics simulations were performed to obtain a stable initial enzyme substrate complex structure. Almost all interactions between the substrate and enzyme were found to be related to the d-glucuronic acid unit, whereas no recognition specificity was observed for the N-acetyl-d-galactosamine unit. Experimentally, two different pathways have been proposed on the basis of X-ray structures and kinetic isotopic effects. In our simulation, the pathway involving the formation of an epoxide intermediate has been found to be favorable rather than that involving direct hydration of the vinyl ether group around carbons 4 and 5. A metastable oxocarbenium-ion-like intermediate can be found in our simulation. PMID- 28071913 TI - Oxygenate-Induced Tuning of Aldehyde-Amine Reactivity and Its Atmospheric Implications. AB - Atmospheric aerosols often contain a significant fraction of carbon-nitrogen functionality, which makes gas-phase aldehyde-amine chemistries an important source of nitrogen containing compounds in aerosols. Here we use high-level ab initio calculations to examine the key determinants of amine (ammonia, methylamine, and dimethylamine) addition onto three different aldehydes (acetaldehyde, glycolaldehyde, and 2-hydroperoxy acetaldehyde), with each reaction being catalyzed by a single water molecule. The model aldehydes reflect different degrees of oxygenation at a site adjacent to the carbonyl moiety, the alpha-site, and represent typical oxygenates that can arise from atmospheric oxidation especially under conditions where the concentration of NO is low. Our results show that the reaction barrier is influenced not only by the nature of the amine but also by the nature of the aldehyde. We find that, for a given amine, the reaction barrier decreases with increasing oxygenation of the aldehyde. This observed trend in barrier height can be explained through a distortion/interaction analysis, which reveals a gradual increase in internal hydrogen bonding interactions upon increased oxygenation, which, in turn, impacts the reaction barrier. Further, the calculations reveal that the reactions of methylamine and dimethylamine with the oxygenated aldehydes are barrierless under catalysis by a single water molecule. As a result, we expect these addition reactions to be energetically feasible under atmospheric conditions. The present findings have important implications for atmospheric chemistry as amine-aldehyde addition reactions can facilitate aerosol growth by providing low-energy neutral pathways for the formation of larger, less volatile compounds, from readily available smaller components. PMID- 28071914 TI - Synthesis and NMR Analysis of a Conformationally Controlled beta-Turn Mimetic Torsion Balance. AB - The molecular torsion balance concept was applied to a new conformationally controlled scaffold and synthesized to accurately evaluate pairwise amino acid interactions in an antiparallel beta-sheet motif. The scaffold's core design combines (ortho-tolyl)amide and o,o,o'-trisubstituted biphenyl structural units to provide a geometry better-suited for intramolecular hydrogen bonding. Like the dibenzodiazocine hinge of the traditional torsion balance, the (ortho-tolyl)amide unit offers restricted rotation around an N-aryl bond. The resulting two-state folding model is a powerful template for measuring hydrogen bond stability between two competing sequences. The aim of this study was to improve the alignment between the amino acid sequences attached to the upper and lower aromatic rings in order to promote hydrogen bond formation at the correct distance and antiparallel orientation. Bromine substituents were introduced ortho to the upper side chains and compared to a control to test our hypothesis. Hydrogen bond formation has been identified between the NH amide proton of the upper side chain (proton donor) and glycine acetamide of the lower side chain (proton acceptor). PMID- 28071915 TI - Variational Flooding Study of a SN2 Reaction. AB - We have studied the reaction dynamics of a prototypical organic reaction using a variationally optimized truncated bias to accelerate transitions between educt and product reactant states. The asymmetric SN2 nucleophilic substitution reaction of fluoromethane and chloromethane CH3F + Cl- ? CH3Cl + F- is considered, and many independent biased molecular dynamics simulations have been performed at 600, 900, and 1200 K, collecting several hundred transitions at each temperature. The transition times and relative rate constants have been obtained for both reaction directions. The activation energies extracted from an Arrhenius plot compare well with standard static calculations. PMID- 28071916 TI - Gold-Catalyzed Unexpected Ring Transformation of Pyrimidodiazepine Derivatives. AB - Pyrimidodiazepine derivatives underwent an unexpected gold-catalyzed retro Mannich-type carbon-carbon bond cleavage and intramolecular nucleophilic cyclization. The pyrimidodiazepines bearing an alkyne moiety showed novel orthogonal reactivity in the presence of a gold catalyst, as opposed to the alkynophilicity that is commonly observed with gold catalysts. The ring transformation reaction of pyrimidodiazepines probably proceeds through an acyclic iminium intermediate. The potential of this synthetic method for the skeletal diversification of pyrimidine-containing macrocycles was also demonstrated. PMID- 28071917 TI - Tunable Adsorption and Film Formation of Mussel Adhesive Protein by Potential Control. AB - Mussel adhesive proteins are of great interest in many applications because of their outstanding adhesive property and film-forming ability. Understanding and controlling the film formation and its performance is crucial for the effective use of such proteins. In this study, we focus on the potential controlled film formation and compaction of one mussel adhesive protein, Mefp-1. The adsorption and film-forming behavior of Mefp-1 on a platinum (Pt) substrate under applied potentials were investigated by cyclic voltammetry, potential-controlled electrochemical impedance spectroscopy (EIS), and quartz crystal microbalance with dissipation monitoring (QCM-D). Moreover, microfriction measurements were performed to evaluate the mechanical properties of the Mefp-1 films formed at selected potentials. The results led to the conclusion that Mefp-1 adsorbs on the Pt substrate through both electrostatic and nonelectrostatic interactions and shows an effective blocking effect for the electroactive sites on the substrate. The properties of the adsorbed Mefp-1 film vary with the applied potential, and the compactness of the adsorbed Mefp-1 film can be reversibly tuned by the applied potential. PMID- 28071918 TI - Stereoelectronic Effect-Induced Conductance Switching in Aromatic Chain Single Molecule Junctions. AB - Biphenyl, as the elementary unit of organic functional materials, has been widely used in electronic and optoelectronic devices. However, over decades little has been fundamentally understood regarding how the intramolecular conformation of biphenyl dynamically affects its transport properties at the single-molecule level. Here, we establish the stereoelectronic effect of biphenyl on its electrical conductance based on the platform of graphene-molecule single-molecule junctions, where a specifically designed hexaphenyl aromatic chain molecule is covalently sandwiched between nanogapped graphene point contacts to create stable single-molecule junctions. Both theoretical and temperature-dependent experimental results consistently demonstrate that phenyl twisting in the aromatic chain molecule produces different microstates with different degrees of conjugation, thus leading to stochastic switching between high- and low conductance states. These investigations offer new molecular design insights into building functional single-molecule electrical devices. PMID- 28071919 TI - Characterization of the Intrinsic Water Wettability of Graphite Using Contact Angle Measurements: Effect of Defects on Static and Dynamic Contact Angles. AB - Elucidating the intrinsic water wettability of the graphitic surface has increasingly attracted research interests, triggered by the recent finding that the well-established hydrophobicity of graphitic surfaces actually results from airborne hydrocarbon contamination. Currently, static water contact angle (WCA) is often used to characterize the intrinsic water wettability of graphitic surfaces. In the current paper, we show that because of the existence of defects, static WCA does not necessarily characterize the intrinsic water wettability. Freshly exfoliated graphite of varying qualities, characterized using atomic force microscopy and Raman spectroscopy, was studied using static, advancing, and receding WCA measurements. The results showed that graphite of different qualities (i.e., defect density) always has a similar advancing WCA, but it could have very different static and receding WCAs. This finding indicates that defects play an important role in contact angle measurements, and the static contact angle does not always represent the intrinsic water wettability of pristine graphite. On the basis of the experimental results, a qualitative model is proposed to explain the effect of defects on static, advancing, and receding contact angles. The model suggests that the advancing WCA reflects the intrinsic water wettability of pristine (defect-free) graphite. Our results showed that the advancing WCA for pristine graphite is 68.6 degrees , which indicates that graphitic carbon is intrinsically mildly hydrophilic. PMID- 28071920 TI - Side Gate Tunable Josephson Junctions at the LaAlO3/SrTiO3 Interface. AB - Novel physical phenomena arising at the interface of complex oxide heterostructures offer exciting opportunities for the development of future electronic devices. Using the prototypical LaAlO3/SrTiO3 interface as a model system, we employ a single-step lithographic process to realize gate-tunable Josephson junctions through a combination of lateral confinement and local side gating. The action of the side gates is found to be comparable to that of a local back gate, constituting a robust and efficient way to control the properties of the interface at the nanoscale. We demonstrate that the side gates enable reliable tuning of both the normal-state resistance and the critical (Josephson) current of the constrictions. The conductance and Josephson current show mesoscopic fluctuations as a function of the applied side gate voltage, and the analysis of their amplitude enables the extraction of the phase coherence and thermal lengths. Finally, we realize a superconducting quantum interference device in which the critical currents of each of the constriction-type Josephson junctions can be controlled independently via the side gates. PMID- 28071924 TI - Corrigendum. PMID- 28071922 TI - Anxiety symptoms and risk of dementia and mild cognitive impairment in the oldest old women. AB - OBJECTIVES: Research is limited and findings conflict regarding anxiety as a predictor of future cognitive decline in the oldest old persons. We examined the relationship between levels of and changes in anxiety symptoms, and subsequent dementia and mild cognitive impairment (MCI) in the oldest old women. METHOD: We conducted secondary analyses of data collected from 1425 community-dwelling women (mean age = 82.8, SD +/-3.1 years) followed on average for five years. The Goldberg Anxiety Scale was used to assess anxiety symptoms at baseline, and an expert clinical panel adjudicated dementia and MCI at follow-up. Participants with probable cognitive impairment at baseline were excluded. RESULTS: At baseline, 190 (13%) women had moderate/severe anxiety symptoms and 403 (28%) had mild anxiety symptoms. Compared with those with no anxiety symptoms at baseline, women with mild anxiety symptoms were more likely to develop dementia at follow up (multivariable-adjusted odds ratio = 1.66, 95% confidence interval 1.12-2.45). No significant association was observed between anxiety symptoms and MCI. CONCLUSION: In the oldest old women, our findings suggest that mild anxiety symptoms may predict future risk of dementia, but not MCI. Future studies should explore potential biological mechanisms underlying associations of anxiety with cognitive impairment. PMID- 28071925 TI - Gene editing and genetic engineering approaches for advanced probiotics: A review. AB - The applications of probiotics are significant and thus resulted in need of genome analysis of probiotic strains. Various omics methods and systems biology approaches enables us to understand and optimize the metabolic processes. These techniques have increased the researcher's attention towards gut microbiome and provided a new source for the revelation of uncharacterized biosynthetic pathways which enables novel metabolic engineering approaches. In recent years, the broad and quantitative analysis of modified strains relies on systems biology tools such as in silico design which are commonly used methods for improving strain performance. The genetic manipulation of probiotic microorganisms is crucial for defining their role in intestinal microbiota and exploring their beneficial properties. This review describes an overview of gene editing and systems biology approaches, highlighting the advent of omics methods which allows the study of new routes for studying probiotic bacteria. We have also summarized gene editing tools like TALEN, ZFNs and CRISPR-Cas that edits or cleave the specific target DNA. Furthermore, in this review an overview of proposed design of advanced customized probiotic is also hypothesized to improvise the probiotics. PMID- 28071926 TI - Response to Panayiotopoulos: Visual aura of migraine versus visual occipital lobe seizures. PMID- 28071928 TI - Recent advancements in lateral flow immunoassays: A journey for toxin detection in food. AB - Biotechnology embraces various physical and chemical phenomena toward advancement of health diagnostics. Toward such advancement, detection of toxins plays an important role. Toxins produce severe health impacts on consumption with high mortality associated in acute cases. The most prominent route of infection and intoxication is through food matrices. Therefore, rapid detection of toxins at low concentrations is the need of modern diagnostics. Lateral flow immunoassays are one of the emergent and popularly used rapid detection technology developed for detecting various kinds of analytes. This review thus focuses on recent advancements in lateral flow immunoassays for detecting different toxins in agricultural food. Appropriate emphasis was given on how the labels, recognition elements, or detection strategy has laid an impact on improvement in immunochromatographic assays for toxins. The paper also discusses the gradual change in sensitivities and specificities of assays in accordance with the method of food processing used. The review concludes with the major challenges faced by this technology and provides an outlook and insight of ideas to improve it in the future. PMID- 28071929 TI - Effects of smartphone-based memory training for older adults with subjective memory complaints: a randomized controlled trial. AB - OBJECTIVES: We explored whether newly developed application (Smartphone-based brain Anti-aging and memory Reinforcement Training, SMART) improved memory performance in older adults with subjective memory complaints (SMC). METHOD: A total of 53 adults (range: 50-68 years; 52.8% female) were randomized into either one of two intervention groups [SMART (n = 18) vs. Fit Brains(r) (n = 19)] or a wait-list group (n = 16). Participants in the intervention groups underwent 15-20 minutes of training per day, five days per week for 8 weeks. We used objective cognitive measures to evaluate changes with respect to four domains: attention, memory, working memory (WM), and response inhibition. In addition, we included self-report questionnaires to assess levels of SMC, depression, and anxiety. RESULTS: Total WM quotient [t(17) = 6.27, p < .001] as well as auditory-verbal WM score [t(17) = 4.45, p < .001] increased significantly in the SMART group but not in the control groups. Self-reports of memory contentment, however, increased in the Fit Brains(r) group only [t(18) = 2.12, p < .05). CONCLUSION: Use of an 8 week smartphone-based memory training program may improve WM function in older adults. However, objective improvement in performance does not necessarily lead to decreased SMC. PMID- 28071932 TI - The International Journal of Research and Practice celebrates 20 years. PMID- 28071935 TI - Response to "OnabotulinumtoxinA for the treatment of chronic migraine not quite there. . ." PMID- 28071936 TI - Concussion Baseline Testing: Preexisting Factors, Symptoms, and Neurocognitive Performance. AB - CONTEXT: Neurocognitive test scores are often considered an important aspect of concussion management. To best use these data, clinicians must understand potential factors that may influence baseline performance on these tests. OBJECTIVE: To determine preexisting factors that may influence performance on the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT). DESIGN: Cross sectional study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 486 National Collegiate Athletic Association Division I collegiate student-athletes. MAIN OUTCOME MEASURE(S): To determine neurocognitive functioning and total symptom score at baseline, ImPACT was administered. Outcomes were verbal memory, visual memory, visual motor speed, reaction time, and total symptom score. A self-report demographic section at the beginning of ImPACT was used to gather information concerning previous treatment for headaches, migraines, and psychiatric conditions; diagnosis of attention deficit/hyperactivity disorder; and exposure to previous strenuous exercise. We conducted multivariate analyses of variance to determine if the ImPACT composite and total symptom scores differed according to preexisting factors (P < .0083). RESULTS: Sex showed an effect on verbal memory (P = .001), visual motor speed (P < .001), and reaction time (P = .006), with women performing better than men. A previous diagnosis of attention-deficit/hyperactivity disorder affected visual motor speed (P = .008). Previous treatment for headaches (P < .001), migraines (P = .001), a psychiatric condition (P < .001), or a diagnosis of attention deficit/hyperactivity disorder (P < .001) all showed effects on the total symptom score. Strenuous exercise did not affect neurocogntive performance or total symptom score. CONCLUSIONS: Based on our findings and the previous literature, we suggest that many preexisting factors influence baseline neurocognitive data. Baseline testing is an important aspect of concussion management. Sports medicine professionals should be cognizant of these factors when developing concussion management protocols. PMID- 28071939 TI - Corrigendum. PMID- 28071938 TI - Tailoring structure and technological properties of plant proteins using high hydrostatic pressure. AB - The demand for proteins is rising and alternatives to meat proteins are necessary since animal husbandry is expensive and intensive to the environment. Plant proteins appear as an alternative; however, their techno-functional properties need improvement. High-pressure processing (HPP) is a non-thermal technology that has several applications including the modification of proteins. The application of pressure allows modifying proteins' structure hence allowing to change several of their properties, such as hydration, hydrophobicity, and hydrophilicity. These properties may influence the solubility of proteins and their ability to stabilize emulsions or foams, create aggregates or gels, and their general role in stability and texture of food commodities. Commonly HPP decreases the proteins' solubility yet increasing their surface hydrophobicity exposing sulfhydryl groups, which promotes aggregation or gelation or enhance their ability to stabilize emulsions/foams. However, these effects are not verifiable for all the proteins and are immensely dependent on the type and concentration of the protein, environmental conditions (pH, ionic strength, and co-solutes), and HPP conditions. This review collects and critically discusses the available information on how HPP affects the structure of plant proteins and how their techno-functional properties can be tailored using this approach. PMID- 28071940 TI - Resilience and personal growth: A potential resource for therapeutic programmes in people with congenital heart disease. PMID- 28071942 TI - Erratum. PMID- 28071941 TI - Board Walk - April 2014. PMID- 28071945 TI - Author contact information. PMID- 28071944 TI - Response to the letter 'Minimization: not all it's cracked up to be' by Berger. PMID- 28071946 TI - Author Response. PMID- 28071947 TI - Presacral abscess as a rare complication of sacral nerve stimulator implantation. AB - A 50-year-old man with intractable anal pain attributed to proctalgia fugax underwent insertion of a sacral nerve stimulator via the right S3 vertebral foramen for pain control with good symptomatic relief. Thirteen months later, he presented with signs of sepsis. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a large presacral abscess. MRI demonstrated increased enhancement along the pathway of the stimulator electrode, indicating that the abscess was caused by infection introduced at the time of sacral nerve stimulator placement. The patient was treated with broad spectrum antibiotics, and the sacral nerve stimulator and electrode were removed. Attempts were made to drain the abscess transrectally using minimally invasive techniques but these were unsuccessful and CT guided transperineal drainage was then performed. Despite this, the presacral abscess progressed, developing enlarging gas locules and extending to the pelvic brim to involve the aortic bifurcation, causing hydronephrosis and radiological signs of impending sacral osteomyelitis. MRI showed communication between the rectum and abscess resulting from transrectal drainage. In view of the progressive presacral sepsis, a laparotomy was performed with drainage of the abscess, closure of the upper rectum and formation of a defunctioning end sigmoid colostomy. Following this, the presacral infection resolved. Presacral abscess formation secondary to an infected sacral nerve stimulator electrode has not been reported previously. Our experience suggests that in a similar situation, the optimal management is to perform laparotomy with drainage of the presacral abscess together with simultaneous removal of the sacral nerve stimulator and electrode. PMID- 28071949 TI - Lateral thyroid cartilage thyrotomy approach to an embedded paraglottic fishbone. AB - Fishbones are of particular interest to otolaryngologists. Most fishbones can be removed transorally or via endoscopic guidance. Transcervical neck exploration is occasionally necessary, especially in cases of an embedded foreign body. Computed tomography is the most sensitive and specific imaging modality for identifying embedded fishbones. To our knowledge, this is the first reported case of a laryngeal foreign body embedded in the paraglottic space that was removed using an open approach via a lateral thyroid cartilage window. PMID- 28071948 TI - Current practice of antibiotic prophylaxis during elective laparoscopic cholecystectomy. AB - INTRODUCTION Current guidelines do not recommend antibiotic prophylaxis in elective laparoscopic cholecystectomy. Despite this, there is wide variation in antibiotic prophylaxis during cholecystectomy in population-based studies. The aim of this survey was to establish the current rationale for antibiotic prophylaxis in elective laparoscopic cholecystectomy. METHODS A short questionnaire was designed and disseminated across collaborators for a population based study investigating outcomes following cholecystectomy and via the Association of Upper Gastrointestinal Surgeons, Researchgate and Surginet membership. RESULTS Responses were received from 234 people; 50.9% had no written policy for the use of prophylactic antibiotics in elective cholecystectomy; 5.6% never used antibiotics, while 30.8% always did and 63.7% selectively used antibiotics. Contamination with bile, stones and pus were scenarios in which antibiotics were most commonly used in selective practices to reduce infective complications. Interestingly, 87% of respondents would be happy to participate in a trial investigating the effectiveness of antibiotics in elective laparoscopic cholecystectomy where contamination has occurred. CONCLUSIONS The disparity between current practice and guidelines appears to arise because of a lack of evidence to show that antibiotics reduce surgical site infection following elective laparoscopic cholecystectomy where contamination has occurred. This question needs to addressed before practice will change. PMID- 28071950 TI - Reporting individual surgeon outcomes does not lead to risk aversion in abdominal aortic aneurysm surgery. AB - INTRODUCTION Reporting surgeons' outcomes has recently been introduced in the UK. This has the potential to result in surgeons becoming risk averse. The aim of this study was to investigate whether reporting outcomes for abdominal aortic aneurysm (AAA) surgery impacts on the number and risk profile (level of fitness) of patients offered elective treatment. METHODS Publically available National Vascular Registry data were used to compare the number of AAAs treated in those centres across the UK that reported outcomes for the periods 2008-2012, 2009-2013 and 2010-2014. Furthermore, the number and characteristics of patients referred for consideration of elective AAA repair at a single tertiary unit were analysed yearly between 2010 and 2014. Clinic, casualty and theatre event codes were searched to obtain all AAAs treated. The results of cardiopulmonary exercise testing (CPET) were assessed. RESULTS For the 85 centres that reported outcomes in all three five-year periods, the median number of AAAs treated per unit increased between the periods 2008-2012 and 2010-2014 from 192 to 214 per year (p=0.006). In the single centre cohort study, the proportion of patients offered elective AAA repair increased from 74% in 2009-2010 to 81% in 2013-2014, with a maximum of 84% in 2012-2013. The age, aneurysm size and CPET results (anaerobic threshold levels) for those eventually offered elective treatment did not differ significantly between 2010 and 2014. CONCLUSIONS The results do not support the assumption that reporting individual surgeon outcomes is associated with a risk averse strategy regarding patient selection in aneurysm surgery at present. PMID- 28071951 TI - Spontaneous extrusion of gallstones after percutaneous drainage. AB - There have been reports of late discharge of gallstones through operative wounds after spillage into the peritoneal cavity during laparoscopic cholecystectomy and after the development of spontaneous cholecystocutaneous fistulae. However, spontaneous discharge of gallstones from the tract of a percutaneous cholecystostomy or percutaneous drainage of a perforated gall bladder has not, to the best of our knowledge, been reported previously. We report a case in which a patient who had a percutaneous drain inserted for a perforated gall bladder discharged 34 gallstones from the tract after removal of the 7-F pigtail catheter. PMID- 28071952 TI - The decline of elective operating at major trauma centres. AB - INTRODUCTION Major trauma is a leading cause of death in those aged under 40 years. In order to improve the care for multiply injured patients, the major trauma network was activated in April 2012 in England. Its goal was to link all district hospitals to major trauma centres (MTCs) and allow for rapid transfer of patients. Anecdotally, this has affected elective orthopaedic operating at MTCs. The aim of this study was to compare the number of lower limb arthroplasty procedures performed before and after the establishment of the trauma network. METHODS Data on hip and knee arthroplasties in England during the two years prior to and the two years following the introduction of the trauma network were obtained from the National Joint Registry. These were broken down by type of unit (MTCs vs non-MTCs). Differences between the number of hip and knee arthroplasties undertaken in the two time periods were analysed. The chi-squared test was used to assess statistical significance. RESULTS The total number of lower limb arthroplasties increased after the activation of the trauma network by 5.5% (from 211,453 to 223,119). When stratifying the data by type of unit, this increasing trend was present for non-MTCs; however, in MTCs, a reduction occurred: the number reduced by 13.6% (from 13,492 to 11,657). This reversal of trend was seen in both hip and knee procedures independently (both p<0.01). CONCLUSIONS The introduction of the trauma network has led to a reduction in the total number of lower limb arthroplasty procedures performed in MTCs. Various reasons have been postulated for this but its impact on surgical training and hospital finances must be scrutinised in future research. PMID- 28071955 TI - Leprosy. PMID- 28071958 TI - Is type D personality an independent risk factor for recurrent myocardial infarction or all-cause mortality in post-acute myocardial infarction patients? AB - Background Type D personality refers to a combination of simultaneously high levels of negative affectivity and social inhibition. The present study aimed to examine whether type D personality was independently associated with recurrent myocardial infarction or all-cause mortality in post-acute myocardial infarction patients, using any of the previously proposed methods for measuring type D personality. Design This was a prospective cohort study. Methods Utilising data from the Vastmanland Myocardial Infarction Study, 946 post-acute myocardial infarction patients having data on the DS14 instrument used to measure type D personality were followed-up for recurrent myocardial infarction and all-cause mortality until 9 December 2015. Data were analysed using Cox regression, adjusted for established risk factors. Results In total, 133 (14.1%) patients suffered from type D personality. During a mean follow-up time for recurrent myocardial infarction of 5.7 (3.2) years, 166 (17.5%) patients were affected by recurrent myocardial infarction, of which 26 (15.7%) had type D personality, while during a mean follow-up time for all-cause mortality of 6.3 (2.9) years, 321 (33.9%) patients died, of which 42 (13.1%) had type D personality. After adjusting for established risk factors, type D personality was not significantly associated with recurrent myocardial infarction or all-cause mortality using any of the previously proposed methods for measuring type D personality. A weak association was found between the social inhibition part of type D personality and a decreased risk of all-cause mortality, but this association was not significant after taking missing data into account in a multiple imputation analysis. Conclusions No support was found for type D personality being independently associated with recurrent myocardial infarction or all-cause mortality in post-acute myocardial infarction patients, using any of the previously proposed methods for measuring type D personality. PMID- 28071959 TI - Tenfold risk increase of major cardiovascular events after high limb amputation with non-compliance for secondary prevention measures. AB - Background The aim of the study was to evaluate the impact of compliance with lifestyle recommendations and medication on 1-year prevention of major adverse cardiovascular events (MACE) in patients with type 2 diabetes (T2D) after trans femoral amputation (TFA). Methods In this prospective single-center interventional cohort study, 179 consecutive T2D patients with symptomatic coronary artery disease (CAD) underwent 1-year follow-up examination after TFA in 2013. Lower limb and coronary artery CT angiography were provided before surgery; physical examination and laboratory tests were performed at baseline and every month after TFA for 1 year. A total of 77 patients (43%) were defined as compliant. They followed all recommendations, including >80% drug intake (anti diabetic, antihypertensive drugs, dual antiplatelet and statin treatment), healthy diet, smoking cessation, physical exercise >=30 min/day. A total of 102 patients (57%) were non-compliant (drug intake <=80%, and did not fully follow lifestyle change recommendations). Results There were no significant differences at baseline between the two groups. Fuster-BEWAT score in 1 year was 9.83 +/- 3.1 in compliant and 7.74 +/- 2.9 in non-compliant patients ( p = 0.0001). At 1-year follow-up, there were 43 myocardial infarctions (40 patients (93%) were non compliant) and 28 deaths (26 cases (92.8%) were non-compliant). Patients from the non-compliant group with three- and two-vessel obstructive CAD had higher 1-year MACE rate than those with one-vessel obstructive and non-obstructive CAD (95.24% and 70.5% versus 17.2% and 8.6%; p < 0.0001); more proximal coronary lesions were related to a worse prognosis. Conclusions Non-compliant diabetic patients had a tenfold increased risk for MACE within 1 year after TFA. PMID- 28071960 TI - Community-based prevalence study of rheumatic heart disease in rural Ethiopia. AB - Background Chronic Rheumatic Heart disease (RHD) continues to be a health problem in many low and middle income countries and especially in sub-Saharan Africa. Echocardiography has shown that the disease is far more widespread than may be detected by clinical assessment, but data are lacking on the prevalence and epidemiological features in rural Africa. Design Community-based prevalence survey Methods We used transthoracic echocardiography to carry out a population based study of RHD in a rural area of Ethiopia. A total of 987 participants aged 6 to 25 were selected by cluster sampling. The prevalence of RHD was assessed by the current consensus World Heart Federation criteria. Results There were 37 definite cases of RHD and a further 19 borderline cases giving an overall prevalence of 37.5 cases per 1000 population (95% CI 26.9-51.8) rising to 56.7 (95% CI 43.9-73.5) if the borderline cases are included. The prevalence of definite disease rose to a peak of 60 cases per 1000 in those aged 16-20 years before falling to 11 cases per 1000 in subjects aged 21-25 years. Of the 37 with definite disease, 36 had evidence of mitral valve and seven evidence of aortic valve disease. Conclusions RHD has a high prevalence in rural Ethiopia. Although follow-up is needed to determine how the disease develops with advancing age, the data provide evidence that the disease is an important health problem in rural sub-Saharan Africa requiring urgent concerted action. PMID- 28071962 TI - The Feasibility of Functional Electrical Stimulation to Improve Upper Extremity Function in a Two-year-old Child with Perinatal Stroke: A Case Report. AB - AIMS: To evaluate the effectiveness and feasibility (i.e. tolerability, adherence) of functional electrical stimulation (FES) for the upper extremity (UE) in a two-year-old child with perinatal stroke. METHODS: Forty hours of FES over eight weeks was prescribed. FES to the hemiplegic triceps, extensor carpi radialis longus and brevis, extensor carpi ulnaris and extensor digitorum was timed with reaching during play. Assessments were performed before, during, and two months post-intervention. UE function (Melbourne Assessment 2 (MA2), Assisting Hand Assessment (AHA)) and spasticity (Modified Tardieu with electrogoniometry and electromyography) were measured. The mother completed a semi-structured interview post-intervention. Descriptive statistics were used for adherence and UE measures. A repeated-measures ANOVA compared Modified Tardieu parameters (e.g. catch angle) over time. Conventional content analysis was used for the interview data. RESULTS: The child completed 39.2/40 hours. Immediately post-intervention, improvements were observed on MA2's Range of Motion subscale and catch angle (Modified Tardieu, p < 0.001). Two months post-intervention, improvements were observed on MA2's Accuracy and Fluency subscales. No change in AHA score occurred. Three themes emerged from the interview: (1) Ingredients for program success; (2) Information about the FES device; and (3) The child's response. CONCLUSIONS: UE FES was feasible in a two-year-old child with hemiplegia. PMID- 28071961 TI - Cellular analysis of the action of epigenetic drugs and probes. AB - Small molecule drugs and probes are important tools in drug discovery, pharmacology, and cell biology. This is of course also true for epigenetic inhibitors. Important examples for the use of established epigenetic inhibitors are the study of the mechanistic role of a certain target in a cellular setting or the modulation of a certain phenotype in an approach that aims toward therapeutic application. Alternatively, cellular testing may aim at the validation of a new epigenetic inhibitor in drug discovery approaches. Cellular and eventually animal models provide powerful tools for these different approaches but certain caveats have to be recognized and taken into account. This involves both the selectivity of the pharmacological tool as well as the specificity and the robustness of the cellular system. In this article, we present an overview of different methods that are used to profile and screen for epigenetic agents and comment on their limitations. We describe not only diverse successful case studies of screening approaches using different assay formats, but also some problematic cases, critically discussing selected applications of these systems. PMID- 28071963 TI - Impaired verbal learning in forensic inpatients with Schizophrenia Spectrum Disorder. AB - The present study aimed to: (a) examine verbal learning performances among forensic inpatients diagnosed with Schizophrenia Spectrum Disorder (SSD); and (b) compare verbal learning performances among forensic SSD inpatients, SSD outpatients, and a small control sample. Participants included forensic SSD inpatients (n = 71), SSD outpatients (n = 305; see Stone et al.), and a control sample from the California Verbal Learning Test-II (CVLT-II) manual (n = 78; see Delis, Kramer, Kaplan, & Ober). Five verbal learning outcomes were measured using the CVLT-II. The average forensic SSD inpatients performed 1 to 1.5 standard deviations below the mean across the five verbal learning outcomes, many of whom (26.8% to 36.6%) performed in the impaired range across the five outcomes. Forensic SSD inpatients performed significantly lower than the SSD outpatients on three verbal learning outcomes and significantly lower than healthy controls on all five verbal learning outcomes. Results indicated forensically committed SSD inpatients have diminished verbal learning performances. Study findings could help define normative verbal learning performances in different types of SSD patients, may guide the development of compensatory strategies for verbal learning deficits, and could subsequently lead to more successful clinical outcomes in this population. PMID- 28071965 TI - Standing activity intervention and motor function in a young child with cerebral palsy: A case report. AB - PURPOSE: There is limited evidence to fully justify the use of standing interventions for children with cerebral palsy (CP). This case report describes the impact of an 8-week standing program on motor function in a child with severe CP living in western Africa. METHODS: The subject was diagnosed with ischemic - hypoxic encephalopathy shortly after birth and with CP at 12 months of age. Gross Motor Function Classification of CP was level IV. Early attempts at physical therapy were interrupted by limited access to medical services. At 18 months, a standing program using a locally constructed standing frame was initiated. The standing intervention was completed at home 5 times a week for 8 weeks. Motor skills were assessed at baseline and post-intervention using the Gross Motor Function Measure (GMFM-66). RESULTS: Scores on the GMFM-66 increased from 28 at baseline to 37.4 in 8 weeks. Improvements in motor function included improved head control, improved upper extremity function, and increased sitting ability. CONCLUSIONS: Implementation of a home-based standing program may have contributed to improved motor skills for this child. Further research is needed to determine the effect of standing interventions on functional motor development for children with severe CP. PMID- 28071964 TI - Hypercapnia is essential to reduce the cerebral oxidative metabolism during extreme apnea in humans. AB - The cerebral metabolic rate of oxygen (CMRO2) is reduced during apnea that yields profound hypoxia and hypercapnia. In this study, to dissociate the impact of hypoxia and hypercapnia on the reduction in CMRO2, 11 breath-hold competitors completed three apneas under: (a) normal conditions (NM), yielding severe hypercapnia and hypoxemia, (b) with prior hyperventilation (HV), yielding severe hypoxemia only, and (c) with prior 100% oxygen breathing (HX), yielding the greatest level of hypercapnia, but in the absence of hypoxemia. The CMRO2 was calculated from the product of cerebral blood flow (ultrasound) and the radial artery-jugular venous oxygen content difference (cannulation). Secondary measures included net-cerebral glucose/lactate exchange and nonoxidative metabolism. Reductions in CMRO2 were largest in the HX condition (-44 +/- 15%, p < 0.05), with the most severe hypercapnia (PaCO2 = 58 +/- 5 mmHg) but maintained oxygen saturation. The CMRO2 was reduced by 24 +/- 27% in NM ( p = 0.05), but unchanged in the HV apnea where hypercapnia was absent. A net-cerebral lactate release was observed at the end of apnea in the HV and NM condition, but not in the HX apnea (main effect p < 0.05). These novel data support hypercapnia/pH as a key mechanism mediating reductions in CMRO2 during apnea, and show that severe hypoxemia stimulates lactate release from the brain. PMID- 28071966 TI - The duty of candour: Openness, transparency and candour. PMID- 28071967 TI - Tobacco cessation counseling within physical therapist practice: Results of a statewide survey of Florida physical therapists. AB - INTRODUCTION: Tobacco use is the leading preventable risk factor for chronic disease, disability, and premature mortality. People with disabilities experience higher tobacco use and reduced access to services when compared with the general population. The negative impact on treatment outcomes across all practice settings provides a strong incentive for physical therapists (PTs) to engage in tobacco cessation counseling (TCC). METHODS: Prevalence of TCC and barriers toward implementation was explored using an anonymous cross-sectional survey of Florida-licensed PTs. Data were analyzed using frequency counts and percentages. Logistic regression was used to quantify relationships between individual knowledge and opinions, and rates of counseling. RESULTS: Of the 212 respondents, 31% regularly provide cessation advice, 7% assist in identifying specific cessation strategies, 13% recommend additional resources, and 3% arrange for follow-up. More than 90% were unfamiliar with evidence-based TCC guidelines; approximately 80% had no prior training in screening for tobacco use or TCC. CONCLUSIONS: Most respondents agreed that patients should be screened for tobacco use and counseled accordingly, but few were familiar with evidence-based TCC guidelines. Further training is required to promote knowledge and skill in TCC, along with systems changes to reduce barriers toward the implementation of TCC within the clinical environment. PMID- 28071968 TI - Rapid and robust authentication of deer antler velvet product by fast PCR-RFLP analysis. AB - Deer antler velvet is widely used as a vitalizing, tonifying, haemopoietic and strengthening agent for debilitated persons in East Asia. To develop a rapid and sensitive method for the identification of the biological source or origin in antler velvet products, a molecular approach was applied using PCR-restriction fragment length polymorphism analysis. The cytochrome b gene sequences of nine cervidae species were analyzed, and a Dde I restriction endonuclease recognition site was found only in sika deer and red deer, the official origin of deer velvet in Chinese pharmacopoeia. A specific primer was designed, and rapid PCR amplified products were subjected to restriction digestion using a fast RFLP procedure. Sika deer and red deer showed two bands of 161 and 102 bp, in contrast to the undigested state of 263 from other antlers. The established PCR-RFLP method was applied in commercial velvet products, and a high frequency of substitution (50%) was revealed in collected commercial samples. The method was successful in detecting contaminated and adulterated antler products in Chinese patent drugs, and the whole detection process was accomplished within 1-1.5 h. PMID- 28071969 TI - Curcumin induces apoptosis in human leukemic cell lines through an IFIT2 dependent pathway. AB - Curcumin, the primary bioactive component isolated from turmeric, has been shown to possess variety of biologic functions including anti-cancer activity. However, molecular mechanisms in different cancer cells are various. In the present study, we demonstrated that curcumin induced G2/M cell cycle arrest and apoptosis by increasing the expression levels of cleaved caspase-3, cleaved PARP and decreasing the expression of BCL-2 in U937 human leukemic cells but not in K562 cells. We found some interferon induced genes, especially interferon-induced protein with tetratricopeptide repeats 2 (IFIT2), were significantly upregulated when treated with curcumin in U937 cells by gene expression chip array, and further confirmed that the expression of IFIT2 was obviously higher in U937 than that in K562 cells by Western blot assay. In addition, inhibiting the expression of IFIT2 by shRNA in U937 rescued curcumin-induced apoptosis and exogenous overexpression of IFIT2 by lentiviral transduction or treating with IFNgamma in K562 cells enhanced anti-cancer activity of curcumin. These results indicated for the first time that curcumin induced leukemic cell apoptosis via an IFIT2 dependent signaling pathways. The present study identified a novel mechanism underlying the antitumor effects of curcumin, and may provide a theoretical basis for curcumin combined with interferon in the cancer therapeutics. PMID- 28071971 TI - Neuropsychological implications of Cobalamin C (CblC) disease in Hispanic children detected through newborn screening. AB - Cobalamin C (CblC) disease is the most common inborn error of cobalamin metabolism and recent data has indicated a higher prevalence among children of Hispanic heritage in particular. The purpose of this study was to (a) describe the neuropsychological characteristics of a pilot sample of Hispanic children with CblC disease and (b) explore potential differences in outcome based on underlying genetic mutation(s) and biochemical levels. Six Hispanic children (ages 2-10) diagnosed with CblC disease through newborn screening (NBS) underwent neuropsychological evaluation with a bilingual examiner. Biochemical levels and underlying mutation(s) were obtained through medical records. The overall sample performed below normative expectations across neuropsychological domains, including general cognition, adaptive functioning, language ability, and visual motor integration. Underlying mutations and associative clinical phenotypes were found to significantly predict general cognitive abilities, while plasma methionine and Hcy at the time of diagnosis were significantly correlated with language outcomes. Despite limited sample size, results indicate that Hispanic children with CblC disease detected through NBS and treated early experience neuropsychological deficits even when treated with current standard treatments. However, consistent with prior research in non-Hispanic children with CblC disease, underlying mutations and early biochemical levels may predict better outcomes in this population as well. PMID- 28071972 TI - Genetic identification for prey birds of the Endangered peregrine falcon (Falco peregrinus). AB - To reveal the dietary ecology of the peregrine falcon (Falco peregrinus), we conducted a molecular analysis for mitochondrial genes (COI and CYTB) to identify the prey species collected from a feeding place found on Sasu Island, South Korea. The results from noninvasive genetic analysis showed that the sequences obtained came from nine species of birds (Cuculus canorus, Eurystomus orientalis, Limosa limosa, Microscelis amaurotis, Oriolus chinensis, Phasianus colchicus, Sterna hirundo, Streptopelia orientalis, and Turdus pallidus). Five of the species (C. canorus, M. amaurotis, S. hirundo, S. orientalis, and T. pallidus) had previously been observed on this island, but the other four species (E. orientalis, L. limosa, O. chinensis, and P. colchicus) were newly identified as present. No mtDNA sequences of land animals such as amphibians, reptiles, and mammals were found in the dietary remains, suggesting that the peregrine falcon preys mostly on other birds rather than on other animals inhabiting Sasu Island. This island has rich avian diversity and abundant animal populations and therefore supplies sufficient dietary resources for the peregrine falcon. Our findings suggested that a DNA-based molecular method may be useful to identify the prey species of these birds and may be valuable in future studies of the Endangered peregrine falcon. PMID- 28071973 TI - * Collagen Cross-Linking: Biophysical, Biochemical, and Biological Response Analysis. AB - Extracted forms of collagen are subjected to chemical cross-linking to enhance their stability. However, traditional cross-linking approaches are associated with toxicity and inflammation. This work investigates the stabilization capacity, cytotoxicity and inflammatory response of collagen scaffolds cross linked with glutaraldehyde (GTA), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 4-arm polyethylene glycol (PEG) succinimidyl glutarate (4SP), genipin (GEN), and oleuropein. Although all cross-linking methods reduced free amine groups, variable data were obtained with respect to denaturation temperature, resistance to collagenase digestion, and mechanical properties. With respect to biological analysis, fibroblast cultures showed no significant difference between the treatments. Although direct cultures with human-derived leukemic monocyte cells (THP-1) clearly demonstrated the cytotoxic effect of GTA, THP-1 cultures supplemented with conditioned medium from the various groups showed no significant difference between the treatments. With respect to cytokine profile, no significant difference in secretion of proinflammatory (e.g., interleukin [IL] 1beta, IL-8, tumor necrosis factor-alpha) and anti-inflammatory (e.g., vascular endothelial growth factor) cytokines was observed between the noncross-linked and the 4SP and GEN cross-linked groups, suggesting the suitability of these agents as collagen cross-linkers. PMID- 28071974 TI - From ancient Greece to the cognitive revolution: A comprehensive view of physical rehabilitation sciences. AB - The development of rehabilitation has traditionally focused on measurements of motor disorders and measurements of the improvements produced during the therapeutic process; however, physical rehabilitation sciences have not focused on understanding the philosophical and scientific principles in clinical intervention and how they are interrelated. The main aim of this paper is to explain the foundation stones of the disciplines of physical therapy, occupational therapy, and speech/language therapy in recovery from motor disorder. To reach our goals, the mechanistic view and how it is integrated into physical rehabilitation will first be explained. Next, a classification into mechanistic therapy based on an old version (automaton model) and a technological version (cyborg model) will be shown. Then, it will be shown how physical rehabilitation sciences found a new perspective in motor recovery, which is based on functionalism, during the cognitive revolution in the 1960s. Through this cognitive theory, physical rehabilitation incorporated into motor recovery of those therapeutic strategies that solicit the activation of the brain and/or symbolic processing; aspects that were not taken into account in mechanistic therapy. In addition, a classification into functionalist rehabilitation based on a computational therapy and a brain therapy will be shown. At the end of the article, the methodological principles in physical rehabilitation sciences will be explained. It will allow us to go deeper into the differences and similarities between therapeutic mechanism and therapeutic functionalism. PMID- 28071975 TI - Dynamics of fluoroquinolones induced resistance in DNA gyrase of Mycobacterium tuberculosis. AB - DNA gyrase is a validated target of fluoroquinolones which are key components of multidrug resistance tuberculosis (TB) treatment. Most frequent occurring mutations associated with high level of resistance to fluoroquinolone in clinical isolates of TB patients are A90V, D94G, and A90V-D94G (double mutant [DM]), present in the larger subunit of DNA Gyrase. In order to explicate the molecular mechanism of drug resistance corresponding to these mutations, molecular dynamics (MD) and mechanics approach was applied. Structure-based molecular docking of complex comprised of DNA bound with Gyrase A (large subunit) and Gyrase C (small subunit) with moxifloxacin (MFX) revealed high binding affinity to wild type with considerably high Glide XP docking score of -7.88 kcal/mol. MFX affinity decreases toward single mutants and was minimum toward the DM with a docking score of -3.82 kcal/mol. Docking studies were also performed against 8-Methyl moxifloxacin which exhibited higher binding affinity against wild and mutants DNA gyrase when compared to MFX. Molecular Mechanics/Generalized Born Surface Area method predicted the binding free energy of the wild, A90V, D94G, and DM complexes to be -55.81, -25.87, -20.45, and -12.29 kcal/mol, respectively. These complexes were further subjected to 30 ns long MD simulations to examine significant interactions and conformational flexibilities in terms of root mean square deviation, root mean square fluctuation, and strength of hydrogen bond formed. This comparative drug interaction analysis provides systematic insights into the mechanism behind drug resistance and also paves way toward identifying potent lead compounds that could combat drug resistance of DNA gyrase due to mutations. PMID- 28071976 TI - Precise, flexible and affordable gene stacking for crop improvement. AB - The genetic engineering of plants offers a revolutionary advance for crop improvement, and the incorporation of transgenes into crop species can impart new traits that would otherwise be difficult to obtain through conventional breeding. Transgenes introduced into plants, however, can only be useful when bred out to field cultivars. As new traits are continually added to further improve transgenic cultivars, clustering new DNA near previously introduced transgenes keep from inflating the number of segregating units that breeders must assemble back into a breeding line. Here we discuss various options to introduce DNA site specifically into an existing transgenic locus. As food security is becoming a pressing global issue, the old proverb resonates true to this day: "give a man a fish and you feed him for a day; teach a man to fish and you feed him for a lifetime." Hence, we describe a recombinase-mediate gene stacking system designed with freedom to operate, providing an affordable option for crop improvement by less developed countries where food security is most at risk. PMID- 28071977 TI - Effect of Touch Screen Tablet Use on Fine Motor Development of Young Children. AB - AIM: To investigate the effects of touch-screen tablet use on the fine motor development of preschool children without developmental delay. METHODS: 40 children who used a touch-screen tablet more 60 minutes per week for at least 1 month received a 24-week home fine motor activity program using a touch-screen tablet. 40 children matched for age (mean = 61.0 months) and sex who did not meet the criteria for previous tablet use received a 24-week program consisting of manual play activities. Motor performance was measured using the Bruininks Oseretsky Test of Motor Proficiency. The two-factor mixed design ANOVA was used to compare performance of the touch-screen tablet and non-touch-screen tablet groups. RESULTS: Pretest analysis showed no group differences in motor performance and pinch strength. At posttest, children in the nontouch-screen tablet group made significantly greater changes in fine motor precision (p < 0.001), fine motor integration (p = 0.008), and manual dexterity (p = 0.003). CONCLUSION: Using a touch screen tablet extensively might be disadvantageous for the fine motor development of preschool children. PMID- 28071970 TI - The making of bispecific antibodies. AB - During the past two decades we have seen a phenomenal evolution of bispecific antibodies for therapeutic applications. The 'zoo' of bispecific antibodies is populated by many different species, comprising around 100 different formats, including small molecules composed solely of the antigen-binding sites of two antibodies, molecules with an IgG structure, and large complex molecules composed of different antigen-binding moieties often combined with dimerization modules. The application of sophisticated molecular design and genetic engineering has solved many of the technical problems associated with the formation of bispecific antibodies such as stability, solubility and other parameters that confer drug properties. These parameters may be summarized under the term 'developability'. In addition, different 'target product profiles', i.e., desired features of the bispecific antibody to be generated, mandates the need for access to a diverse panel of formats. These may vary in size, arrangement, valencies, flexibility and geometry of their binding modules, as well as in their distribution and pharmacokinetic properties. There is not 'one best format' for generating bispecific antibodies, and no single format is suitable for all, or even most of, the desired applications. Instead, the bispecific formats collectively serve as a valuable source of diversity that can be applied to the development of therapeutics for various indications. Here, a comprehensive overview of the different bispecific antibody formats is provided. PMID- 28071979 TI - Vytautas Kontrimavicius (1930-2016). AB - [Figure: see text]. PMID- 28071978 TI - Nup82 functions redundantly with Nup136 in a salicylic acid-dependent defense response of Arabidopsis thaliana. AB - The nuclear pore complex (NPC) comprises more than 30 nucleoporins (Nups). NPC mediates macromolecular trafficking between the nucleoplasm and the cytoplasm, but specific roles of individual Nups are poorly understood in higher plants. Here, we show that the novel nucleoporin unique to angiosperm plants (designated as Nup82) functions in a salicylic acid-dependent defense in a redundant manner with Nup136, which is a component of the nuclear basket in the NPC. Arabidopsis thaliana Nup82 had a similar amino acid sequence to the N-terminal half of Nup136 and a Nup82-GFP fusion was localized on the nuclear envelope. Immunoprecipitation and bimolecular fluorescence complementation analyses revealed that Nup82 interacts with the NPC components Nup136 and RAE1. The double knockout mutant nup82 nup136 showed severe growth defects, while the single knockout mutant nup82 did not, suggesting that Nup82 functions redundantly with Nup136. nup82 nup136 impaired benzothiadiazole (an analog of salicylic acid)-induced resistance to the virulent bacteria Pseudomonas syringae pv. tomato DC3000. Furthermore, transcriptome analysis of nup82 nup136 indicates that deficiency of Nup82 and Nup136 causes noticeable downregulation of immune-related genes. These results suggest that Nup82 and Nup136 are redundantly involved in transcriptional regulation of salicylic acid-responsive genes through nuclear transport of signaling molecules. PMID- 28071980 TI - Metabolic syndrome, hypertension, and nervous system injury: Epidemiological correlates. AB - : Metabolic syndrome (MetS) is a common and complex disorder combining hypertension, obesity, dyslipidemia, and insulin resistance. MetS represents a risk factor for changes in cognitive functions in older age, and several studies have suggested that MetS may be linked to dementia. This article reviews the main evidences about the relationship between MetS and neurodegenerative disease. Starting from an epidemiological point of view, the article analyzes medico social aspects related to MetS, considering the reduction of work capacity and the condition of disability that it involves. Some authors affirm that on the basis of current Italian legislation, it is possible to consider the syndrome as a disability. This is because all the diseases that make up MetS are high-risk clinical pathological conditions. For these reasons, a joint action is required to contain the incidence of MetS, the high social costs, and the loss of productivity related to the syndrome. In conclusion, healthcare initiatives could be adopted in order to increase the understanding of the pathogenic contributions of each element on MetS and how they can be modified. These actions will be useful to reduce healthcare costs and can lead to more effective prevention of metabolic disease, thus promoting good health. ABBREVIATIONS: MetS: Metabolic syndrome; WHO: World Health Organization; CVD: cerebrovascular diseases; AD: Alzheimer's Disease; VaD: Vascular Dementia; IDF: International Diabetes Federation; T2DM: type 2 diabetes mellitus; CAD: coronary artery disease; MCI: mild cognitive impairment; NCDs: Non Communicable Diseases; BMI: Body Mass Index; ICIDH: International classification of impairments, disabilities and handicaps. PMID- 28071981 TI - Genetic variation in wild and hatchery population of Catla catla (Hamilton, 1822) analyzed through mtDNA cytochrome b region. AB - Catla (Catla catla) is a one of the most harvested Indian major carps and is widely cultured fish species in Indian subcontinent. In the present study, genetic variability between hatchery and wild stocks of Catla was surveyed using sequence data of mitochondrial DNA of partial 307 bp of cytochrome b region. A total of 174 Catla individuals were examined from three different river basins and hatcheries. Significant genetic heterogeneity was observed for the sequence data (FST = 0.308, p <= 0.001). However, analysis of molecular variance (AMOVA) resulted in insignificant genetic differentiation among the samples of three rivers and culture zones (FCT = -0.10, p = 0.44). The result suggested a significant genetic variation within different riverine system, low genetic differentiation among samples from river basins and a lack of genetic variation in hatchery populations. PMID- 28071982 TI - Longitudinal Prediction of Suicide Attempts for a Diverse Adolescent Sample of Native Hawaiians, Pacific Peoples, and Asian Americans. AB - The objective of this study was to determine the longitudinal predictors of past 6-month suicide attempts for a diverse adolescent sample of Native Hawaiians, Pacific peoples, and Asian Americans. The study used longitudinal data from the Hawaiian High Schools Health Survey (N = 2,083, 9th to 11th graders, 1992-1993 and 1993-1994 school years). A stepwise multiple logistic regression was conducted. The final model consisted of three statistically significant predictors: (1) Time 1 suicide attempt, odds ratio = 30.6; (2) state anxiety, odds ratio = 4.9; and (3) parent expectations, odds ratio = 1.9. Past suicide attempt was by far the strongest predictor of future suicide attempts. Implications are discussed, including the need for screening of prior suicide attempts and focused interventions after suicide attempts. PMID- 28071983 TI - What Does Leaders' Character Add to Transformational Leadership? AB - The influence of leaders' character (e.g., integrity, humility/forgiveness) has rarely been examined in leadership research. The current investigation focused on the impact of integrity and humility/forgiveness on both followers' perceptions of leaders' worthiness of being followed (WBF) and stress. Results from a scenario experiment (n = 347) and a field study (n = 110) indicated that these aspects incrementally predict WBF above and beyond the impact of transformational leadership. Similar results were found concerning followers' stress with the exception of leader integrity in the field study. According to relative importance analyses, integrity and transformational leadership predict WBF equally well. The results have conceivable implications for human resources (personnel selection and development). Future research should examine additional outcome variables that are affected by certain leader characteristics as well as potential negative effects of the examined character aspects. PMID- 28071984 TI - Particulate matter-mediated release of long pentraxin 3 (PTX3) and vascular endothelial growth factor (VEGF) in vitro: Limited importance of endotoxin and organic content. AB - Exposure to particulate matter (PM) is associated with adverse health effects, but it is still relatively unknown which role PM sources and physicochemical properties play in the observed effects. It was postulated that PM in vitro induces release of long pentraxin 3 (PTX3) and vascular endothelial growth factor (VEGF) and that endotoxin and organic compounds present in the PM regulate this release. A contact coculture of THP-1 human leukemia monocytes and A549 human adenocarcinoma alveolar pneumocytes was exposed to PM from Traffic, Wood, Diesel, and Quartz (10-40 ug/cm2) for 12-64 h to determine release of PTX3 and VEGF. The role of endotoxin and the organic fraction in the mediator release was assessed using polymyxin B sulfate and organic extracts, respectively. Finally, antagonists were used to investigate whether the early proinflammatory cytokines interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha affected the PTX3 and VEGF release. All PM samples induced a time-dependent release of both PTX3 and VEGF. Traffic mediated the greatest release of PTX3, whereas Wood and Diesel were more potent inducers of VEGF. The endotoxin content did not markedly affect release of either mediator, while the organic fraction exerted no significant effect on VEGF release and limited influence on PTX3 release. In addition, the IL 1 and TNF-alpha agonists affected PTX3 release more strongly than VEGF release. In conclusion, the current data show a limited impact of endotoxin and organic compounds on PTX3 and VEGF release. Further, the observed differences in response patterns may point toward differential regulation of PM-mediated release of PTX3 and VEGF. PMID- 28071985 TI - The contribution of prenatal maternal factors to maternal gestational weight gain. AB - Data from 807 mothers in Iran delivering a singleton live infant and their offspring-during the last 2 years up to August 2014-were collected from eight public health care centers and analyzed. Of the women, 46.2% gained weight within the recommended range, 29.4% had inadequate gestational weight gain (GWG), and 24.4% had excessive GWG. Excessive GWG was more common among overweight and obese women, whereas inadequate GWG was prevalent among 50% of under and normal weight women. A significant correlation was found between maternal anthropometric characteristics, folic acid intake during pregnancy, and birth order with GWG. Maternal GWG was positively correlated with neonates' weight and height. PMID- 28071986 TI - Evaluation of a Two-Year Routine Application of Molecular Testing of Thyroid Fine Needle Aspirations Using a Seven-Gene Panel in a Primary Referral Setting in Germany. AB - BACKGROUND: Major differences with respect to the diagnostic performance of a "ruling in" approach in the presurgical diagnosis of indeterminate thyroid fine needle aspirations (FNAs) have been reported. Therefore, the aim of this prospective multicenter study was to investigate the specific diagnostic impact of mutation testing using a seven-gene panel in a routine primary referral setting analyzing FNAs from endocrinology and nuclear medicine practices in Germany. METHODS: RNA and DNA was extracted from 564 routine air-dried FNA smears obtained from 64 physicians and cytologically graded by one experienced cytopathologist. PAX8/PPARG and RET/PTC rearrangements were detected by quantitative polymerase chain reaction, while BRAF and RAS mutations were detected by pyrosequencing. Molecular data were compared to histology and follow up >1 year, which were available for 322/348 patients undergoing surgery and 33/74 patients having follow-up. Histology results were obtained from the local routine pathologists who were blinded to the molecular test results. RESULTS: BRAF and RET/PTC mutations were associated with carcinoma in 98% and 100% of samples, respectively. RAS and PAX8/PPARG mutations were associated with carcinoma in 31% and 0% of samples, respectively. Thirty-six percent of the carcinomas were identified by molecular testing in the atypia of undetermined significance/follicular lesion of undetermined significance and follicular neoplasm/suspicious for a follicular neoplasm categories, with malignancy rates of 15% and 17%, respectively. Due to a low percentage of RAS mutation-positive carcinomas in combination with a rather high percentage of RAS mutation-positive benign nodules, the positive predictive values of 41% and 36% in the atypia of undetermined significance/follicular lesion of undetermined significance and follicular neoplasm/suspicious for a follicular neoplasm categories offer only limited diagnostic potential. CONCLUSION: In conclusion, the data suggest that the application of the current seven-gene panel in a routine primary referral setting does not improve the presurgical diagnosis of thyroid FNAs. While the diagnostic relevance of RAS mutations in thyroid tumors needs further investigation, more comprehensive mutation panels with more cancer-specific mutations may improve the presurgical diagnosis of thyroid FNAs. PMID- 28071987 TI - A Computer-Aided Diagnosis System Using Artificial Intelligence for the Diagnosis and Characterization of Thyroid Nodules on Ultrasound: Initial Clinical Assessment. AB - BACKGROUND: An initial clinical assessment is described of a new, commercially available, computer-aided diagnosis (CAD) system using artificial intelligence (AI) for thyroid ultrasound, and its performance is evaluated in the diagnosis of malignant thyroid nodules and categorization of nodule characteristics. METHODS: Patients with thyroid nodules with decisive diagnosis, whether benign or malignant, were consecutively enrolled from November 2015 to February 2016. An experienced radiologist reviewed the ultrasound image characteristics of the thyroid nodules, while another radiologist assessed the same thyroid nodules using the CAD system, providing ultrasound characteristics and a diagnosis of whether nodules were benign or malignant. The diagnostic performance and agreement of US characteristics between the experienced radiologist and the CAD system were compared. RESULTS: In total, 102 thyroid nodules from 89 patients were included; 59 (57.8%) were benign and 43 (42.2%) were malignant. The CAD system showed a similar sensitivity as the experienced radiologist (90.7% vs. 88.4%, p > 0.99), but a lower specificity and a lower area under the receiver operating characteristic (AUROC) curve (specificity: 74.6% vs. 94.9%, p = 0.002; AUROC: 0.83 vs. 0.92, p = 0.021). Classifications of the ultrasound characteristics (composition, orientation, echogenicity, and spongiform) between radiologist and CAD system were in substantial agreement (kappa = 0.659, 0.740, 0.733, and 0.658, respectively), while the margin showed a fair agreement (kappa = 0.239). CONCLUSION: The sensitivity of the CAD system using AI for malignant thyroid nodules was as good as that of the experienced radiologist, while specificity and accuracy were lower than those of the experienced radiologist. The CAD system showed an acceptable agreement with the experienced radiologist for characterization of thyroid nodules. PMID- 28071989 TI - Parental bereavement: Looking beyond grief. AB - Bereaved parents have higher morbidity and mortality rates when compared to nonbereaved parents. Although parental grief is well studied, the complexities of challenges bereaved parents face are not understood. This study describes parental bereavement challenges during the first 6 months following the death of their child. The complex parental bereavement challenges are characterized by the absence of the child, their emotional response, and the changed relationships with family and friends. The adaptive leadership framework is a useful framework to identify and classify challenges. Future research can use this framework to provide a structure that test interventions to address the challenges. PMID- 28071988 TI - Braided and Stacked Electrospun Nanofibrous Scaffolds for Tendon and Ligament Tissue Engineering. AB - Tendon and ligament injuries are a persistent orthopedic challenge given their poor innate healing capacity. Nonwoven electrospun nanofibrous scaffolds composed of polyesters have been used to mimic the mechanics and topographical cues of native tendons and ligaments. However, nonwoven nanofibers have several limitations that prevent broader clinical application, including poor cell infiltration, as well as tensile and suture-retention strengths that are inferior to native tissues. In this study, multilayered scaffolds of aligned electrospun nanofibers of two designs-stacked or braided-were fabricated. Mechanical properties, including structural and mechanical properties and suture-retention strength, were determined using acellular scaffolds. Human bone marrow-derived mesenchymal stem cells (MSCs) were seeded on scaffolds for up to 28 days, and assays for tenogenic differentiation, histology, and biochemical composition were performed. Braided scaffolds exhibited improved tensile and suture-retention strengths, but reduced moduli. Both scaffold designs supported expression of tenogenic markers, although the effect was greater on braided scaffolds. Conversely, cell infiltration was superior in stacked constructs, resulting in enhanced cell number, total collagen content, and total sulfated glycosaminoglycan content. However, when normalized against cell number, both designs modulated extracellular matrix protein deposition to a similar degree. Taken together, this study demonstrates that multilayered scaffolds of aligned electrospun nanofibers supported tenogenic differentiation of seeded MSCs, but the macroarchitecture is an important consideration for applications of tendon and ligament tissue engineering. PMID- 28071991 TI - Nurses should test patients for HIV at every opportunity. AB - As an HIV clinical nurse specialist, I share the concerns of your readers panellists about over-the-counter HIV tests (reflections June 20). PMID- 28071990 TI - Natural Course of Euthyroidism and Clues for Early Diagnosis of Thyroid Dysfunction: Tehran Thyroid Study. AB - OBJECTIVE: Considering the limited data available on the natural course of euthyroidism, this study was designed to evaluate the progression in time from euthyroidism to subclinical or overt hypo- or hyperthyroidism. METHODS: This study was conducted within the framework of the Tehran Thyroid Cohort Study, in which 5783 individuals aged 40.4 +/- 0.2 years were followed for six years. The overall loss to follow-up rate was 8.3%. After applying exclusion criteria, data of 4204 euthyroid subjects remained for analysis of a six-year natural course analysis. Thyroid function tests, clinical characteristics, and metabolic characteristics were assessed at baseline and every three years. RESULTS: The annual incidence rates [confidence intervals (CI)] of subclinical and overt hypothyroidism were 7.62 [CI 7.39-7.85) and 2.0 [CI 1.94-2.06] per 1000 persons, respectively. For thyroid hyperfunction, the annual incidence rates of subclinical and overt hyperthyroidism were 0.92 [0.90-0.95) and 0.68 [0.66-0.70) per 1000 persons, respectively. Euthyroid persistency was 93.24% during 6 years. Predictive factors for conversion to thyroid dysfunction were thyrotropin, free thyroxine and thyroid peroxidase antibody levels, sex, and smoking. Criteria for early diagnosis of hypothyroidism (i.e., sensitivity of 94% and specificity of 82%, p < 0.0001) were obtained based on baseline and three-year follow-ups of thyroid function tests and thyroid peroxidase antibody. Early diagnosis of hypothyroidism was significantly associated with impaired glucose tolerance (relative risk with 3.03 [CI 1.36-6.75]; p = 0.007), high cholesterol (relative risk 2.46 [CI 1.45-4.18]; p = 0.001), obesity (relative risk 2.92 [CI 1.64-5.2]; p < 0.001), and hypertension (relative risk 1.68 [CI 1.53-1.84]; p < 0.04). CONCLUSION: This study shows that after a six-year follow-up in an iodine sufficient area, 6.7% of euthyroid subjects were found to progress to thyroid dysfunction, in particular subclinical hypothyroidism. PMID- 28071992 TI - Spirituality is personal and cannot be forced on others. AB - In 'Why spirituality is essential for nurses' (features June 6), Stephen Wright and Julia Neuberger appear to assume that we all understand and adhere to a form of supernatural belief, and that everyone understands what spirituality means. PMID- 28071996 TI - Webwise. AB - From 1753 until it closed in 2009, the Royal Haslar Hospital in Gosport, Hampshire, treated 'sick and hurt seamen' of the Royal Navy, service men and women, and the people of Gosport and the surrounding area. PMID- 28071993 TI - Cultural change has to continue for the sake of patient care and safety. AB - I read with interest the interview with Colin Ovington, director of nursing and midwifery at Mid Staffordshire NHS Foundation Trust (features June 20). PMID- 28071997 TI - Trauma lead hopes to inspire others. AB - A nurse who is believed to be the only member of her profession to head one of England's major trauma centres hopes her appointment will encourage others to take up executive duties. PMID- 28071998 TI - World in brief. AB - What's happening in nursing across the globe. PMID- 28071999 TI - Political notebook. AB - Scottish health boards have been criticised by MSPs for failing to provide clear information on how they spend their budgets. PMID- 28072000 TI - Snapshot of fortunes. AB - Bulgaria The financial crisis has affected the healthcare system in Bulgaria 'very severely', according to the European Federation of Nurses Association report. Following government elections in 2009, salaries for nurses and midwives fell to a monthly average of 220 (L175). In 2010 at least 836 nurses migrated to other countries and about 1,000 left the profession. Smaller hospitals have closed and many Bulgarians are without health insurance. 'Nurses in Bulgaria cannot establish a high quality of care because of the reduced staff, low motivation and low salary,' says the report. PMID- 28072001 TI - Nurse research on continence care wins top GP accolade. AB - A nurse-led research paper on improving continence care for people with dementia living at home has been awarded the Royal College of General Practitioners' research paper of the year. PMID- 28072002 TI - Medicines management. AB - This is an accident waiting to happen. The Nursing and Midwifery Council (NMC) standards for medicines management stipulate that registrants must not prepare substances for injection in advance of their immediate use, or administer medication drawn into a syringe or container by another practitioner when not in their presence. PMID- 28072003 TI - Workforce. AB - 'On your bike.' During the last big recession in the UK, that was the advice of one government minister: if you are unemployed, move to where the jobs are. We are all familiar with the north-south divide, and a sense that south east England is where the money and prospects are. PMID- 28072006 TI - Commissioning groups need nursing input, says RCN. AB - The RCN is calling for more substantial nurse posts to be created on clinical commissioning groups following concern that some are planning to take on nurses for just two days a month. PMID- 28072007 TI - Great outdoors. AB - It is quintessentially British to talk about the weather. It took me a while to get used to this when I first arrived here 40 years ago, but I soon got the hang of it and learned to take advantage of it. PMID- 28072008 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28072009 TI - Three more trusts join pay cartel. AB - At least three further NHS trusts in the south west of England have joined a regional 'pay club' that is considering ways to drive down nurses' pay and conditions. PMID- 28072010 TI - A place To. AB - The final article in our leadership series reveals how a learning disability forensic trust made spirituality a core element of a leadership programme for ward managers. PMID- 28072011 TI - Private patient. AB - The taxi driver was cheery, chirpy and chatty. He sounded like the chimney sweep in Mary Poppins, full of banter and bonhomie. I half expected him to treat me to the chim-chiminee chorus. PMID- 28072012 TI - Voices - seize the opportunity to develop your leadership skills, says yvonne coghill. AB - This month, the leadership directorate of the NHS Institute for Innovation and Improvement will become part of the new NHS Leadership Academy. PMID- 28072013 TI - Get set for McGames to go. AB - Our experts consider a hot topic of the day. PMID- 28072014 TI - Unwelcome surprise. AB - Times are tough for nurses working in the UK today. The past few years have seen a torrent of unwelcome news regarding their pay, pensions and reputation. PMID- 28072015 TI - Liver transplant recipients have less risk of miscarriage than general population. AB - Research has shown that female liver transplant recipients have a lower miscarriage risk and a higher live birth rate than the United States general population. PMID- 28072016 TI - Late menopause and HRT therapy may protect against cerebral aneurysms. AB - Early menopause significantly increases the risk of cerebral aneurysm, according to a study in the United States which suggests that hormone replacement therapy may have a protective role. PMID- 28072017 TI - Boiling point. AB - How much tea is too much? How many cuppas are a couple too many? Researchers at Glasgow University, who tracked the health of 6,000 men for 37 years, found that those who drank more than seven cups a day were 50 per cent more likely to develop prostate cancer than those who did not. PMID- 28072018 TI - Starting out - Effective teamwork resulted in the best outcome for everyone. AB - I was on a placement in a rheumatology clinic and was helping to look after a patient who had been given a local anaesthetic and a steroid injection as part of a procedure. PMID- 28072019 TI - Assessment of older people affected by comparisons and negative stereotypes. AB - Negative stereotypes about ageing may adversely affect how older people perform in assessments of their physical capability, suggests a study. Previous research has shown. PMID- 28072020 TI - Failed IVF treatment increases chance of relapse for women with multiple sclerosis. AB - Women with multiple sclerosis who are considering undergoing in vitro fertilisation should be warned that the fertility treatment significantly increases the risk of relapse. PMID- 28072021 TI - A feel for smart thinking. AB - Caring for patients involves many personal interactions with people whose emotions are high and whose circumstances emphasise their vulnerability. PMID- 28072022 TI - Refuse to do tasks above your banding, says college. AB - Nurses who have been downbanded should refuse to carry out tasks that fall outside the remit of their new, lower grade, according to the RCN's director of legal services Chris Cox. PMID- 28072023 TI - Regulator urged to cut number of fitness to practise referrals. AB - With the number of registrants referred to the Nursing and Midwifery Council up 48 per cent since 2010, the regulator says it has 'no choice' but to increase fees to deal with the soaring cost of referrals. PMID- 28072024 TI - 'These people left their handprints on my heart'. AB - Natalie Yates-Bolton has had cancer four times. Now aged 45, she was fi rst diagnosed with Hodgkin's lymphoma as a nursing student more than 20 years ago. PMID- 28072027 TI - Top honour for midwifery champion. AB - A midwife who has been made a dame for her work raising the profi le of midwifery and women's health in the UK and Africa has said she is 'thrilled' with the honour. PMID- 28072026 TI - Hero's legacy lives on. AB - Six nursing and midwifery students (pictured right) at various stages of their studies have become the first beneficiaries of new scholarship awards offered by the Cavell Nurses' Trust. PMID- 28072028 TI - Clarification on issue of barring NHS staff from agency work. AB - With reference to the letter 'Barring NHS staff from agency work is anti competitive' (June 27), the legal situation is simple. Each trust determines its own approach to engaging temporary staffing agencies. PMID- 28072029 TI - Eat properly, keep fit, work on your posture and lead by example. AB - YOUR POSTURE AND LEAD BY EXAMPLE I agree heartily with nurse and life coach Lynne Healy that we have a duty of care to ourselves (reflections June 27). PMID- 28072030 TI - Blinkered assumptions imply that i do not belong in nursing. AB - Starjeena D'Costa writes that barring nurses employed on NHS contracts from agency work is anti-competitive and potentially in breach of sex discrimination legislation (June 27). She writes: 'Would hospital trusts want to prevent tradesmen from doing paid work at the weekends or doctors working for an agency?' As a male third-year nursing. PMID- 28072031 TI - Young cancer survivors need support to make healthy lifestyle choices. AB - People who survive a cancer diagnosis in adolescence or early adulthood are known to have increased risks of long-term illness and premature death owing to the late side-effects of treatments for the disease. A new study suggests that unhealthy lifestyle behaviours are also contributory factors. PMID- 28072033 TI - Care Quality Commission links staff levels with care standards. AB - Staff shortages are one of the main reasons health and social care organisations fail to provide adequate services, according to the Care Quality Commission. PMID- 28072032 TI - Breaking up the NHS is devastating for its staff. AB - The extent to which the NHS in England will become even more fragmented as a result of the Health and Social Care Act was laid bare by the Department of Health last week. It published a circular graphic that is designed to explain how the various components of the NHS will fi t together once the act takes full effect next April. Check it out at tinyurl.com/825q2sn. PMID- 28072034 TI - Laurence Dopson 1942-2012. AB - Laurence Dopson, who has died aged 88, enjoyed a career in journalism spanning more than 65 years. He witnessed the end of the Poor Law era in 1948, and was writing about the contemporary NHS until shortly before his last illness. PMID- 28072035 TI - Laurence Dopson was a great chronicler of nursing lives. AB - CHRONICLER OF NURSING LIVES I was very sorry to read about the death of freelance journalist Laurence Dopson, who was a regular and much-valued contributor to Nursing Standard (analysis June 27). PMID- 28072036 TI - Differential effects of the MEK inhibitor SL327 on the acquisition and expression of ethanol-elicited conditioned place preference and aversion in mice. AB - The involvement of mitogen-activating extracellular kinase (MEK) in place conditioning may vary depending on the motivational sign (positive or negative) and nature (pharmacological or nociceptive) of the unconditioned stimulus (US) and on the phase (acquisition or expression) of the learning process. This study investigated the role of MEK on the acquisition and expression of ethanol elicited (given 2 g/kg) backward (preference, CPP) and forward (aversion, CPA) place conditioning. The MEK inhibitor SL327 (50 mg/kg for CPP, and 50 and 100 mg/kg for CPA) was administered to CD-1 mice 60 minutes before an ethanol dose (acquisition) or 60 minutes before the post-conditioning tests (expression). Ethanol significantly elicited CPP and CPA; SL327 (50 mg/kg) significantly blocked the acquisition of ethanol-elicited CPP, but not that of CPA. Moreover, SL327 (50 and 100 mg/kg) significantly reduced the expression of ethanol-elicited CPP, but not that of CPA. Finally, SL327 also prevented ethanol-elicited (given 2 g/kg) increases of phosphorylated extracellular signal regulated kinase (pERK) positive neurons in the nucleus accumbens and other nuclei of the extended amygdala. Overall, these results confirmed the differential involvement of MEK in the acquisition and expression of drug-elicited place conditioning and suggested its differential involvement in distinct behavioral outcomes, depending on the motivational sign of the (same) US and on the significance of the experimental phase of the learning process. PMID- 28072037 TI - Benzodiazepine maintenance in opiate substitution treatment: Good or bad? A retrospective primary care case-note review. AB - BACKGROUND: Co-prescribing benzodiazepines to patients in opiate substitution treatment is controversial and often alleged to increase mortality. In an inner London general practice, patients with problematic benzodiazepine co-dependence were allowed benzodiazepine maintenance treatment (BMT) since 1994, providing an opportunity for analysis. METHOD: 1) Case-note review of all 278 opiate substitution treatment patients, accruing 1289 patient treatment years; 46% had concurrent BMT. 2) National Health Service database search for patients who died after leaving accrued a further 883 years of information; only patients who left the UK were unaccounted for (4%). Three groups were studied: 1) never obtained benzodiazepine prescription (NOB): n=80); 2) briefly/occasionally prescribed benzodiazepines (BOP): n=71; 3) BMT: n=127. OUTCOMES MEASURED: Treatment retention (months); deaths/100 patient treatment years; deaths after leaving the service/100 years of information. RESULTS: Treatment retention: NOB: 34 months; BOP: 51 months; BMT: 72 months. In-treatment mortality: NOB: 1.79/100 patient treatment years; BOP: 0.33/100 patient treatment years; BMT: 1.31/100 patient treatment years. Deaths after leaving service: NOB: 2.24/100 years of information, BOP: 0.63/100 years of information. However, mortality for previously BMT-patients increased by 450% to 5.90/100 years of information. DISCUSSION: BMT patients had longer treatment retention than NOB or BOP and lower mortality than NOB patients. It is unlikely that patients had access to prescribed benzodiazepines on leaving the service because of restrictions in the national guidelines but co-dependent patients are a high-risk group who may stand to gain most benefit from opiate substitution treatment if combined with benzodiazepine-maintenance. PMID- 28072038 TI - Reliability, Factor Structure, and Associations With Measures of Problem Relationship and Behavior of the Personality Inventory for DSM-5 in a Sample of Italian Community-Dwelling Adolescents. AB - In order to assess the reliability, factorial validity, and criterion validity of the Personality Inventory for DSM-5 (PID-5) among adolescents, 1,264 Italian high school students were administered the PID-5. Participants were also administered the Questionnaire on Relationships and Substance Use as a criterion measure. In the full sample, McDonald's omega values were adequate for the PID-5 scales (median omega = .85, SD = .06), except for Suspiciousness. However, all PID-5 scales showed average inter-item correlation values in the .20-.55 range. Exploratory structural equation modeling analyses provided moderate support for the a priori model of PID-5 trait scales. Ordinal logistic regression analyses showed that selected PID-5 trait scales predicted a significant, albeit moderate (Cox & Snell R2 values ranged from .08 to .15, all ps < .001) amount of variance in Questionnaire on Relationships and Substance Use variables. PMID- 28072039 TI - A Mother's Borderline Personality Disorder and Her Sensitivity, Autonomy Support, Hostility, Fearful/Disoriented Behavior, and Role Reversal With Her Young Child. AB - There is some evidence that maternal borderline personality disorder (BPD) adversely affects parenting in infancy, resulting in disorganized attachment, which longitudinally predicts BPD symptoms in adulthood. We examined parenting related to disorganized attachment beyond infancy in offspring of mothers with BPD, when parenting becomes a goal-corrected partnership. We observed puzzle solving in a low socioeconomic status (SES) sample of mothers with BPD and their children ages 4-7, n = 36, and normative comparisons, n = 34. Compared with normative mothers and controlling for maternal mood disorders, mothers with BPD were less likely to be sensitive and provide autonomy support, and were more likely to be hostile and display fearful/disoriented behavior and higher levels of parent-child role reversal. We additionally found correlations between parenting and self-reported maternal borderline features. We discuss implications for child development, including possible transmission of BPD from mothers to children via representational models, and developmentally appropriate preventive interventions. PMID- 28072040 TI - Altered Empathy for Psychological and Physical Pain in Borderline Personality Disorder. AB - Many patients with borderline personality disorder (BPD) experience difficulties in empathizing with others and are sensitive to social exclusion. Accordingly, the authors developed a novel Social Interaction Empathy Task to examine empathy for physical and psychological pain from first- and third-person perspectives. Fifty female patients with BPD and forty-eight controls matched for age and gender were included. Alexithymia was also measured. Patients with BPD rated neutral and psychologically painful situations as more painful than healthy controls, and patients with BPD rated psychological pain as more intense in the first-person perspective than in the third-person perspective. In contrast, controls did not differentiate between the perspectives and rated physical pain as most intense. The impact of early adversity on empathy for psychological pain was mediated by alexithymia. Increased sensitivity for psychological pain in BPD correlated with symptom severity. BPD is associated with altered empathy for pain, which is related to difficulties in reflecting emotional states. PMID- 28072041 TI - Interpersonal Threat Sensitivity in Borderline Personality Disorder: An Eye Tracking Study. AB - Threat sensitivity is a prominent predictor of interpersonal dysfunctions in borderline personality disorder (BPD), leading to intense, aversive feelings of threat and eventually dysfunctional behaviors, such as aggression. In the present study, BPD patients and healthy volunteers classified angry, fearful, neutral, and happy faces presented for 150 ms or 5,000 ms to investigate initial saccades and facial scanning. Patients more often wrongly identified anger, responded slower to all faces, and made faster saccades towards the eyes of briefly presented neutral faces and slower saccades away from fearful eyes compared with healthy volunteers. Latency of initial saccades and fixation duration correlated negatively with the patients' aggressiveness. Supporting previous results, BPD patients did not experience general deficits in facial emotion processing, but a specific hypersensitivity for and deficits in detailed evaluation of threat cues, which was particularly enhanced in aggressive patients. Interventions might benefit from relocating attention towards positive information and detailed evaluation of social cues. PMID- 28072042 TI - Construct Validity of the DSM-5 Section III Maladaptive Trait Domains in Older Adults. AB - The DSM-5 Section III model of personality disorders remains largely unexplored in older adults. More specifically, there is a need for further research on the generalizability of the five trait domains in old age. The development of a short operationalization to screen for maladaptive trait domains, the Personality Inventory for DSM-5 Brief Form (PID-5-BF), can stimulate the use of the alternative DSM-5 model in older adults by addressing the need for short instruments. The primary goal of this study was to examine the construct validity of the PID-5-BF by comparing its structural model and nomological network with the original PID-5 in terms of relations with domains of personality functioning and a gero-specific personality disorder indicator. A five-factor model was supported, but the domain Disinhibition was not replicated in the original PID-5, and some PID-5-BF items showed weak loadings. Nevertheless, the nomological network was similar and showed meaningful relations, supporting the use of the Brief PID-5 in older clinical samples. PMID- 28072043 TI - Compelled to Risk: Does Sexual Compulsivity Explain the Connection Between Borderline Personality Disorder Features and Number of Sexual Partners? AB - Having more sexual partners increases the likelihood of new HIV infections among women. Women with more borderline personality disorder (BPD) features have been known to have greater numbers of sexual partners. However, the mechanisms linking BPD features with more sexual partners remain to be clarified. Sexual compulsivity (lack of control, increased distress over sexual behavior) may be one such explanatory factor, as it overlaps with BPD features (e.g., impulsivity, negative affectivity). The present study examined whether sexual compulsivity explained the relation of BPD features with number of sexual partners among a diverse sample of college females (N = 1,326). Results demonstrated a significant indirect effect of BPD features via sexual compulsivity on number of sexual partners. These findings support the relation between BPD features and sexual compulsivity and suggest sexual compulsivity as a target in the promotion of the sexual health of women with BPD who demonstrate risky sexual practices. PMID- 28072044 TI - Predicting Nonsuicidal Self-Injury in Borderline Personality Disorder Using Ecological Momentary Assessment. AB - Borderline personality disorder (BPD) is a highly comorbid disorder, and these comorbidities increase the impairment associated with BPD. For example, depression, which occurs in the majority of individuals with BPD, increases the likelihood of an individual with BPD to engage in nonsuicidal self-injury (NSSI). Little research, however, has investigated potential mechanisms of NSSI engagement in this population. The current study aimed to fill this gap by examining momentary experiences, levels of distress tolerance, and NSSI among 51 individuals meeting current diagnostic criteria for BPD and a comorbid depressive disorder. Using data from an ecological momentary assessment across 7 days, it was found that daily urges to hurt oneself and impulsive urges, but not daily negative affect or aggressive urges, predicted NSSI occurrence. Furthermore, low levels of distress tolerance was a stronger predictor of NSSI behavior than daily experiences. These findings have important implications with regard to state versus trait dispositions in NSSI engagement among those with BPD and depression. PMID- 28072045 TI - Politicians: hands off the NHS and let us have some stability. AB - I read the Andy Burnham interview with interest (analysis September 26), but many people are disappointed by the Labour Party's lacklustre response to the unpopular Health and Social Care Act and the chaos this legislation has brought to managers and front line staff. PMID- 28072046 TI - Nurses' agenda is patient care - but what drives politicians? AB - It is good to see Andy Burnham is considering reviewing the NHS reforms, but it may be all too late (analysis September 26). He also fails to admit that much of the marketisation of the NHS was started on the Labour party's watch. PMID- 28072047 TI - Hopefully Andy Burnham can rectify the impractical reforms. AB - The main revelation from the interview with shadow health secretary Andy Burnham (analysis September 26) was that he just might have some firm ideas about what to do with the NHS other than make it cheaper to provide. PMID- 28072049 TI - National drive aims to boost uptake of flu jab by NHS staff. AB - Nurses vaccinated almost 500 staff from Colchester Hospital University NHS Foundation Trust against seasonal flu on the first day of the hospital's flu campaign. PMID- 28072048 TI - We may not like politics but we can't ignore it. AB - We have a letter from a reader this week that ends by saying 'most nurses have stopped listening to politicians. I know I have.' Now this set me thinking. As we reach the end of the party conference season, what have the politicians had to say for themselves and has it been worth listening to? Have they managed to engage people and communicate their vision, or have they just been making annoying white noise in the background as we have got on with our lives? PMID- 28072050 TI - 10,000 set to receive leadership training. AB - Leadership training for around 1,000 nurses will be made available by April next year, with a further 9,000 ward leaders and community nurses expected to receive training by 2015. PMID- 28072051 TI - Early in the shift is best time to do safety-critical tasks. AB - Drug rounds and other safety-critical tasks should not be carried out late in a nurse's shift, new RCN guidance states. PMID- 28072052 TI - Obituary. AB - Carolyn Carter has died in Newton, Massachusetts, after a long illness. She was 79. PMID- 28072053 TI - Connecting with nature is vital to many older people's wellbeing. AB - Your article on outdoor spaces for people with dementia (features September 26) struck a chord. From where I sit, I hear the birds calling and have a view down a valley to the village and the sea. It is about a 4km walk from here to the beach and I like to do that every day. PMID- 28072054 TI - Seeking counsellors who have undergone nurse training. AB - I am a palliative care nurse undertaking training as a counsellor and studying for a degree in integrative-relational counselling at Kingston College, Surrey. As part of my dissertation I am carrying out a small qualitative research study looking at the experience of counsellors who have also undergone nurse training. PMID- 28072055 TI - The benefits of smaller care homes is not a new discovery. AB - It is dispiriting to note the finding that people with dementia thrive in smaller care homes (clinical digest September 26). This is a classic lost opportunity. In 1988, the Griffiths report recommended that care homes have no more than 21 residents. PMID- 28072057 TI - 'Recommendations may be impractical and unnecessary'. AB - Cavette Castillo, children's surgical ward manager, King's College Hospital NHS Foundation Trust, London 'It is not practical to give family members a summary sheet of information discussed in every ward round. Some patients may be in hospital for some time and their conditions are not changing every day. You do not always need to have a senior nurse on a ward round. A lower band nurse may be appropriate if she or he knows the patient well.' PMID- 28072058 TI - Readers panel - Read the treatment directory. AB - Our experts consider a hot topic of the day. PMID- 28072060 TI - Evidence supports wider use of tranexamic acid in traumatic bleeding. AB - The clot stabiliser drug tranexamic acid can be administered safely to a wide range of patients with traumatic bleeding and should not be restricted to the most severe cases, suggests a study. PMID- 28072059 TI - Starting out - I saved a person's life by following my instincts and acting quickly. AB - While studying mental health nursing, I took on extra work as a mental health support worker to gain experience and improve my finances. PMID- 28072061 TI - Marijuana use linked to the worst prognoses of testicular cancer. AB - Researchers in the United States have found a link between the use of marijuana and an increased risk of developing subtypes of testicular cancer that tend to have a worse prognosis than other forms of the disease. PMID- 28072063 TI - Trial proves apremilast is effective long-term treatment for psoriasis. AB - Psoriasis treatment apremilast is safe, effective and well tolerated by patients, according to a randomised controlled trial in the United States and Canada. PMID- 28072064 TI - X-rays increase breast cancer risk in women with gene mutation. AB - Women carrying a mutation in the BRCA1 and BRCA2 genes are more likely to develop breast cancer if they have undergone diagnostic radiation to the chest before the age of 30, according to a large European study. PMID- 28072065 TI - High consumption of fructose can lead to liver disease for people with type 2 diabetes. AB - Obese patients with type 2 diabetes who consume large amounts of fructose may be at increased risk of liver damage. PMID- 28072066 TI - One or the other. AB - Help! I need a doctor. Not as in: 'Someone fetch a doctor quickly. My leg has turned green/wife has stopped breathing/symptoms are worsening', but as in: 'I really ought to register with a GP soon because I have recently moved house.' PMID- 28072067 TI - Your future in his hands - meet the minister for nursing and NHS pay. AB - Hospital doctor Dan Poulter attended his first Conservative Party conference as a health minister this week. His ministerial brief includes nursing, maternity, children's services and public health, NHS pay, pensions, education and training and NHS procurement. Here he answers questions on being a medic and a minister. PMID- 28072068 TI - 'we would freeze public sector pay too'. AB - Labour Party leader Ed Miliband has conceded that if a Labour government was currently in power, public sector pay would be frozen. PMID- 28072069 TI - Burnham highlights extent of privatisation in primary care. AB - Contracts for nearly 400 primary care services worth L250 million are out to tender as part of the 'biggest single act of privatisation the NHS has ever seen', Labour's health spokesperson Andy Burnham has revealed. PMID- 28072070 TI - A boost in awareness. AB - Every year on October 12, specialists in musculoskeletal health mark World Arthritis Day. This is an important date for raising awareness of this group of diseases, with charities invariably bumping elbows as we rush to publish research and share insights. PMID- 28072071 TI - Lucky way out. AB - I am attempting to get to grips with an instrument we use for measuring intra ocular pressure, but for some reason it eludes me. The machine clicks when it should beep, and beeps when it should click. I want to throw it out of the window. PMID- 28072072 TI - 'Nurses are welcome in the force'. AB - A chance conversation with a police officer in the long night hours of the emergency department where she then worked led to custody nurse practitioner Samantha Hill applying for her present post with the Metropolitan Police. Ms Hill explains: 'The. PMID- 28072073 TI - Voices the nurse regulator is on the right path, says new chair mark addison. AB - I was pleased to be asked to chair the Nursing and Midwifery Council (NMC), and two weeks into the role I am still glad I accepted it. PMID- 28072074 TI - Older workers could still draw on NHS pension. AB - A government-commissioned group examining how to encourage NHS staff to work beyond the age of 60 will consider the option of paying pensions to those who delay retirement, Nursing Standard understands. PMID- 28072075 TI - Conference notes. AB - During a debate on the future of health and social care, Royal College of Midwives general secretary Cathy Warwick criticised the government's view that increased patient choice will bolster care. PMID- 28072076 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28072077 TI - Live and learn. AB - Life-long learning has undoubtedly improved my practice over the years. Patients have, mostly inadvertently, added to this process, and a stray remark would become the basis of a thoughtful discussion. PMID- 28072078 TI - Checklist reduces catheter use. AB - Three hospitals in Lincolnshire have reduced the use of urinary catheters by almost a third following the introduction of a standardised form that prompts nurses to carry out daily checks. PMID- 28072080 TI - Staff handed redundancy notices after months of being paid late. AB - Nurses employed at a private hospital whose pay is overdue for the third time in five months have been handed redundancy notices, Nursing Standard has learned. PMID- 28072081 TI - Higher private admissions driven by NHS patients. AB - Independent sector hospitals in the UK admitted 1.64 million patients for surgical treatments in the first six months of the year, a record number and equivalent to 14.5 per cent of total surgical admissions in the UK, latest data shows. PMID- 28072082 TI - Webwise. AB - The UK Centre for the History of Nursing website provides a platform for a large number of resources relating to the rich fi eld of nursing history. PMID- 28072084 TI - Trade unions have long since dropped divisive attitudes. AB - The letter by Brid Hehir from the Do Good Charity (September 26) will no doubt stir up a lot of reaction by her provocative views on trade union values. Well Ms Hehir, if you think there is too much 'chaff' in the NHS that needs chucking out then please bring your 'do good' skills to the table. PMID- 28072085 TI - World in brief. AB - What's happening in nursing across the globe. PMID- 28072086 TI - Dingy buildings point to decay in the NHS rather than in nursing. AB - I was saddened by 'Waiting room blues' (reflections September 19) and the way nursing student Jennifer Rawles interpreted the attitude of the triage nurse in A&E. Considering the pressures there, it is not surprising that the nurse appeared resigned. PMID- 28072088 TI - High-quality mentoring should be restored as a top priority. AB - According to your news story, one in six nursing students do not spend the. PMID- 28072087 TI - It is vital to highlight attacks on hospitals in conflict zones. AB - Well done for highlighting the bombing of two hospitals in Syria (news September 19). The Free Syrian Army claimed it carried out the attacks because the hospitals were being used by government troops. PMID- 28072090 TI - Good mentors now will make the next generation of nurses great. AB - The people a nursing student works with can make or break the student's potential to be a good qualified nurse. The story 'Mentors can inspire or discourage' (news September 26) testifies to this. PMID- 28072092 TI - Snack attack. AB - 'There is someone on board this plane with a nut allergy,' said the flight attendant. 'Therefore nuts will not be on sale for the duration of the flight.' PMID- 28072093 TI - Royal visits. PMID- 28072095 TI - From here to maternity. AB - This time last year, midwives from across the globe came together to attend the International Confederation of Midwives triennial meeting in Durban, South Africa. PMID- 28072094 TI - VOICES - Increased registration fees are necessary to continue our work, says Judith Ellis. AB - The Nursing and Midwifery Council exists as a regulator to protect the public. It sets standards for practice, approves education and takes timely action if a nurse or midwife fails to uphold the standards required of a registered professional. PMID- 28072096 TI - On the move. AB - Promotions / new appointments. PMID- 28072097 TI - Series of NHS events aims to promote equality and diversity. AB - NHS trusts across England held events last week to celebrate and promote equality and diversity in the NHS. PMID- 28072098 TI - As nurse regulation costs soar, is it time for the public to contribute? AB - As soon as the Nursing and Midwifery Council (NMC) announced plans to increase its registration fee by 58 per cent, the regulator was inundated with calls to stop the hike. PMID- 28072099 TI - Department of health calls for nurses' it skills to be assessed. AB - The ten-year strategy, drawn up by the Department of Health (DH), includes an expectation that healthcare professionals will keep their IT skills up to date. The skills could be factored into assessments of work performance, the strategy's authors explain. PMID- 28072100 TI - New in brief. AB - A roundup of the latest nursing news. PMID- 28072101 TI - Labelled with dementia Readers panel. AB - Our experts consider a hot topic of the day. PMID- 28072102 TI - Political notebook. AB - Members of the Scottish Parliament plan to quiz patients in Glasgow about the work of heart failure nurses as part of a parliamentary inquiry into cardiology services. PMID- 28072103 TI - Heart rhythm disorders are becoming an epidemic. AB - Cardiac arrhythmias are the number one killer in the UK, with sudden cardiac arrest claiming more lives than breast cancer, lung cancer and AIDS combined. PMID- 28072104 TI - World in brief. AB - What's happening in nursing across the globe. PMID- 28072105 TI - National Audit Office report slams standard of diabetes care in England. AB - Diabetes nurse specialist posts are being cut without consideration for the long term cost savings the clinicians deliver, according to a damning report on diabetes care services. PMID- 28072106 TI - Regular joggers do live longer - as long as runners stick to a moderate pace. AB - Regular jogging at a moderate pace increases the life expectancy of people by more than five years, reveals a study that appears to provide a definitive answer to the question of whether jogging is beneficial or hazardous to health. PMID- 28072107 TI - Press coverage of celebrity suicides shown to lead to rise in copycat deaths. AB - Media reports about celebrity suicides can trigger an increase in suicides, suggests an analysis of the evidence. PMID- 28072108 TI - More dementia patients can stay in their own homes than commonly thought. AB - The first major study tracking the living arrangements of dementia patients contradicts the commonly held view that most make a permanent move to a nursing home. PMID- 28072109 TI - HPV vaccine cuts future disease risk for women diagnosed with pre-cancers. AB - Women diagnosed with pre-cancerous cervical conditions after receiving the human papilloma virus vaccine can still benefit from a considerably reduced risk of further virus-related disease, suggests a global study. PMID- 28072110 TI - Fertility clinic clients respond well to nurses' lifestyle guidance. AB - One of the first studies to examine the outcomes of preconception care by nurses has found that it has a beneficial effect on the weight and smoking behaviour of patients attending a fertility clinic for in vitro fertilisation. PMID- 28072112 TI - Cancer trust garden wins top chelsea award. AB - Teenagers with cancer received a horticultural lesson from Chelsea Flower Show gold medal winner Joe Swift last week. PMID- 28072113 TI - On hold. AB - I recently worked in an offi ce where everyone seemed awfully quiet. They kept their heads down and sipped their coffee without making a sound. PMID- 28072115 TI - 'Tackling waste can help increase quality and care'. AB - Scotland's chief nursing officer has called on all nurses to tackle inappropriate waste, harm and variation to help remove the 'bumps and holes' in the patient journey. PMID- 28072116 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28072117 TI - Address the reasons for the fitness to practise workload. AB - I am grateful to Judith Ellis, interim chair of the NMC (letters May 23), for taking the time to reply to my letter in the previous issue asking for the expenditure on fitness to practise NMC hearings to be scrutinised. PMID- 28072118 TI - Medicalising normal human conditions is unscientific. AB - Writing in response to a learning zone article (May 2) on the assessment and treatment of patients experiencing anxiety, David Lee (letters May 16) asks if we are medicalising a range of normal human conditions. PMID- 28072119 TI - Obituary. AB - Delegates at RCN congress in Harrogate gave a rousing minute's applause in tribute to Khalil Dale, the English nurse and college member kidnapped and murdered in the Pakistan city of Quetta, near the border with Afghanistan. PMID- 28072120 TI - Webwise. AB - According to the NHS Blood and Transplant organ donation website, 10,000 people in the UK need a transplant. Three of them die each day because there are not enough organs available. PMID- 28072122 TI - Proposal to raise registration fee by 58 per cent is unjustifiable. AB - The Nursing and Midwifery Council (NMC) is proposing to raise its registration fees on January 1 from L76 a year to L120 - a staggering 58 per cent increase (news and editorial May 23). PMID- 28072124 TI - High court rules NMC u-turn was 'unlawful'. AB - The nurse, who is employed by Cardiff and Vale NHS Trust, was referred to the Nursing and Midwifery Council (NMC) by Gwent Police in June 2009 over allegations of mistreatment and neglect of residents at three care homes. PMID- 28072123 TI - Sign the e-petition opposing the increase in registration fees. AB - The NMC proposes to increase our annual registration fee to L120. It is not an organisation, like a union or professional association, that we would choose to join or contribute to. PMID- 28072125 TI - Patients in wales compliment nurses on fundamental care. AB - More than 95 per cent of patients in Wales report that they feel respected by nursing staff, according to a national audit of Welsh hospitals. PMID- 28072126 TI - Starting out - Student experiences in the real world of nursing. AB - During a second-year placement at a local hospital for people with learning disabilities, I was assigned a night shift on a new ward so I could gain extra experience. PMID- 28072127 TI - Trusts accused of colluding to drive down NHS staff pay. AB - Unions are poised to do battle with 16 trusts in south west England that have joined forces to drive down nurses' pay and conditions. PMID- 28072128 TI - 'people queued for hours to see him'. AB - I met Khalil Dale (pictured) in 1995 when writing about the International Committee of the Red Cross (ICRC) campaign to end the use of landmines. I spent a week alongside him, reporting on his work for the ICRC in northern Afghanistan. Khalil was a gentle, quiet man who left a big impression on everyone who met him. PMID- 28072129 TI - RCN seeks 'Diamond Nurses' to celebrate Queen's 60-year reign. AB - As patron of the RCN, the Queen has delighted nurses throughout her 60-year reign by visiting hospitals across the UK to celebrate their contribution to the NHS. PMID- 28072130 TI - The ritualistic circumcision of male babies and boys is abuse. AB - In his article on conditions affecting the foreskin (art&science May 16), David Hunter writes: 'Many nurses may not be aware that the majority of men in the UK remain uncircumcised.' PMID- 28072131 TI - Rugby captain tries her best. AB - The captain of the Welsh women's rugby union team Rhian Bowden (pictured), has been successful in tackling full-time study and the intensive regime of a sporting career. PMID- 28072132 TI - College listened to our concerns about governance planning. AB - As RCN steward for Gwynedd, I was one of the small group of members who met RCN council chair Kath McCourt and senior staff to discuss concerns that a review of legal and governance structures at the college could weaken the influence of its regional boards and branches (news May 23). PMID- 28072133 TI - Paying tribute to florence nightingale and Mary Seacole. AB - Lynn McDonald (letters May 16) says the grounds of St Thomas' Hospital in London are the wrong place for the proposed memorial statue to Mary Seacole, pointing out that the hospital is more associated with Florence Nightingale and her work. PMID- 28072135 TI - Leadership reforms are too important to ignore. AB - The Power to Care campaign run by Nursing Standard in recent years was set up with the aim of freeing up time for ward sisters and charge nurses to provide leadership on hospital wards and in community settings. Our priority was for these nursing managers to be given a supervisory role to oversee care while teaching and supporting staff. PMID- 28072136 TI - Explore china's possibilities. AB - According to China's ministry of health, the country needs a staggering 1.9 million nurses. So far, opportunities for overseas nurses have been limited because of the requirement to pass a nurse practitioner test in Mandarin. PMID- 28072137 TI - Paternalistic, didactic health care is unsustainable in the UK. AB - Further to Lynn Young's article on quantifying self-care (reflections July 18), I agree that we need to encourage patients with long-term conditions to be empowered through self-care, starting from when they receive their diagnosis. PMID- 28072138 TI - ? PMID- 28072140 TI - Fundamental failings show up the organisational culture of the NHS. AB - The inquest into the death from dehydration of hospital patient Kane Gorny in 2009 (news July 18) has again highlighted fundamental failings by nurses. PMID- 28072141 TI - Mindfulness as a key resource for development and resilience. AB - I welcome the initiative to teach nurses to include mindfulness and stress management in their personal development (news July 18) and for this to count towards four hours of their continuing professional development. PMID- 28072142 TI - Angela Booth Dobbie. AB - Angela Booth Dobbie (nee Wilkie) was born in Edinburgh, the daughter of an Australian mother and Scottish father. She spent most of the second world war in Australia with her brother and mother, while her father served in the Royal Navy. PMID- 28072143 TI - The quality of food served in hospitals varies enormously. AB - Some hospitals encourage visitors to bring in food for their relatives, but others discourage the practice (features July 18). PMID- 28072145 TI - Inventive help to prevent falls. AB - Caroline Brown (pictured) has won praise from the RCN for inventing a device to prevent falls among people who use walking sticks. PMID- 28072144 TI - Childhood obesity is a problem that parents need help with. AB - In terms of childhood obesity, there is a link between fast food joints and schoolchildren's easy access to them (clinical digest July 18). But action to limit children's access to such outlets will not solve the problem. PMID- 28072147 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28072148 TI - College hopes to see more BME nurses at board level. AB - A meeting between former and aspiring black nurse directors and the RCN is being organised in a drive to boost their dwindling numbers. PMID- 28072149 TI - Spirituality is integral to the wellbeing of everyone. AB - Further to 'Why spirituality is essential for nurses' (features June 6) and subsequent letters, I firmly believe that spirituality is part of holistic health care and relevant to staff and patients. PMID- 28072153 TI - Carter: rethink over NHS pension reform is inevitable. AB - RCN general secretary Peter Carter has warned that the government's plans for the NHS pension scheme are 'untenable' and will need to be reviewed again. PMID- 28072152 TI - 'This should be all about implementation'. PMID- 28072154 TI - Number crunch care. AB - The health service is encouraged increasingly to learn lessons from the private sector and adopt good business principles, such as being more accountable and cost-effective while still meeting patient demands. PMID- 28072155 TI - Voices. AB - The end of July is the last chance to nominate a candidate for this year's SADS UK annual awards, celebrating individuals who have taken action to save a life. PMID- 28072156 TI - England's chief nurse rejects minimum staffing levels. AB - Hospital nurses may have to accept new ways of working that could result in more patients being cared for in the community, according to England's chief nursing officer. PMID- 28072157 TI - Reassurance over commissioning roles. AB - England's chief nursing officer is adamant that a nurse will be a part of every clinical commissioning group, despite fears that it is not happening in practice. PMID- 28072158 TI - Who me, obese? AB - Getting older is not all that bad when wisdom and experience help you make better choices. Victoria sponge or broccoli? A horizontal, on-the-sofa phone call to a friend or the ironing? PMID- 28072159 TI - Student life - The science of wellbeing. AB - Undergraduate nursing and midwifery students commonly have a limited background in the sciences, and there has been a long-standing debate about how subjects such as anatomy, physiology and pathophysiology should be taught. PMID- 28072160 TI - A write mess. AB - It was like a bad memory from primary school. What was it to be, David? A ruler across the hand or 100 lines on why I should not be indolent? PMID- 28072161 TI - What's in a name? Quite a lot, actually. AB - How do we define someone who is not ill, but is an NHS user? Are they a patient, a service user, a customer or a client? PMID- 28072163 TI - Readers panel-What is stopping mentors from failing poorly performing students? AB - Our experts consider a hot topic of the day. PMID- 28072162 TI - 'We will build a consensus on the future direction of nursing care'. AB - As chair of the nursing and care quality forum, Sally Brearley leads an initiative that she believes can give nurses the clout they need to stop 'soldiering on' and start delivering the high-quality care their patients need. PMID- 28072164 TI - World in brief. AB - What's happening in nursing across the globe. PMID- 28072165 TI - 'Twitter is an amazing communication tool'. AB - Sarah Gilligan (pictured), a service manager at Oakwood Hall, a Community Links care home, says that for her, learning about Twitter was one of the main outcomes of the Leadership for Informed Practice programme. PMID- 28072166 TI - A&E staff trained to spot signs of assault from loan sharks. AB - Emergency nurses are receiving specialist training to spot patients who have been physically assaulted by illegal money lenders. PMID- 28072167 TI - Political notebook. AB - Welsh assembly members have called on health minister Lesley Griffiths to prove that all the country's health boards' financial plans can be sustained. PMID- 28072168 TI - Midwives pedal workforce message. AB - Midwifery students cycled through London to publicise their call for a bigger workforce. PMID- 28072169 TI - Webwise. AB - The Macfarlane Trust gives assistance to people with haemophilia who have been infected with HIV through contaminated blood products. It also supports their families, including widows and dependents. PMID- 28072172 TI - Education can help reduce use of restraints in nursing homes. AB - Education and support for nurses can help bring about a 'culture change', reducing the use of physical restraints in nursing homes, suggests a study in Germany. PMID- 28072173 TI - Patients with chronic illness survive longer when they use telehealth technology. AB - One of the largest telehealth studies ever conducted has found it can reduce deaths and avoid the need for emergency care but the cost savings are modest. PMID- 28072174 TI - Supervised exercise reaps significant benefits for people who have had a lung transplant. AB - Lung transplant patients benefit from improved physical functioning and cardiovascular health if they exercise after discharge from hospital, a study has found. PMID- 28072175 TI - Let's hope roles dovetail and avoid duplication. AB - A year later and, after much campaigning from professional leaders, three nurses have been appointed to national leadership positions. Jane Cummings has become chief nursing offi cer (CNO) at the National Commissioning Board; Viv Bennett has taken up her post as director of nursing at the Department of Health; and Sally Brearley is chair of the prime minister's nursing and care quality forum. PMID- 28072176 TI - Patient safety has improved, but trusts still have work to do. AB - I read with sadness about an inquest and research study that exposed failures in care delivery (news July 18). PMID- 28072177 TI - Self-care lifestyle changes for the menopause and beyond. AB - Lynn Young's thought-provoking piece about self-care for older people prompted me to think about changes in earlier life that can have a positive impact on health in later years, and how nurses might encourage this. PMID- 28072178 TI - Starting out -Handover experience taugh me the risks that lie in listeing to gossip. AB - At the start of a morning shift, I was present as a night nurse handed over details of a patient, Mr Smith, to the ward's day staff. PMID- 28072179 TI - London staff to sleep over near work during Olympics. AB - Nurses in London are preparing for long journeys to work, with some planning to stay in hospital accommodation overnight when the Olympic games begin on Friday. PMID- 28072181 TI - Study reveals evidence of disordered eating in up to a third of women aged over 50. AB - Eating disorders are commonly seen as an issue that affects teenage girls and young women, but a new study in the United States has found evidence of disordered eating in women aged 50 and older. PMID- 28072180 TI - Socioeconomic inequalities remain a factor in rates of stillbirth in England. AB - Rates of stillbirth are twice as high in the most deprived areas of England compared with the least deprived, and the deprivation gap has not narrowed in eight years, according to a population-based study. PMID- 28072183 TI - Student life-When the going gets tough. AB - The traditional image of a student entering higher education - young, single and fresh from sitting A levels - does not always fit the profile of today's students. The 21st century student can be of almost any age or background - and may have complex needs. PMID- 28072184 TI - None of your business. AB - Sir Stephen Moss recently commented that problems at Mid Staffordshire NHS Foundation Trust had been '20-plus years in the making' (features March 14). PMID- 28072185 TI - Porky pies. AB - Would I lie to you? Patients would, and they do. A woman arrived in our eye clinic with the kind of problem usually dealt with by the family doctor. PMID- 28072186 TI - What to do when an employer acts unfairly. AB - Employers may discriminate against their employees directly and indirectly. PMID- 28072187 TI - News update. AB - The RCN, Royal College of Midwives, Unite and Unison are joining together to survey their members about changes in pay and conditions. PMID- 28072188 TI - Care without prejudice. AB - A nurse-led initiative in South Africa is bringing palliative care to the country's prisoners. Supported by the Diana, Princess of Wales Fund, the initiative means prisoners who would previously have died without any support will now receive pain control, help with daily tasks and companionship. PMID- 28072189 TI - We would negotiate over pension reform. AB - In a year when nurses have faced cuts to jobs and services, plus uncertainty about pay and pensions, it would perhaps have been no surprise if health secretary Andrew Lansley had chosen to dodge difficult questions at last week's RCN congress. PMID- 28072190 TI - Congress celebrates distinguished nurse leader and cross-bench peer. AB - Hundreds of nurses at RCN congress joined in a one-minute standing ovation last week to honour the life of eminent nurse Baroness McFarlane, who had died the previous weekend aged 86. PMID- 28072191 TI - Why cough up L120 for the privilege of working? AB - Nurses and midwives will be shocked to read in this week's Nursing Standard that their Nursing and Midwifery Council (NMC) re-registration fees are set to soar, from L76 a year to L120. The 58 per cent increase is being justified on various grounds, principally the cost of clearing a backlog of fitness to practise cases that the NMC has allowed to build up. PMID- 28072192 TI - Another hurdle to overcome? PMID- 28072193 TI - Voices. AB - I recently attended the Florence Nightingale commemoration service at London's Westminster Abbey. It was the first time I had been, and it proved to be an uplifting occasion. PMID- 28072194 TI - Legal advice. AB - Healthcare assistants (HCAs) are increasingly being asked to provide care and treatment that would previously have been undertaken by registered nurses. The correct delegation of nursing tasks to HCAs results in effective and safe care for patients. PMID- 28072195 TI - Regulator blames IT and human error for mistakes on register. AB - Human error and incompatible IT systems have been blamed for sanctions given to around 100 nurses and midwives not being recorded on the Nursing and Midwifery Council register. PMID- 28072196 TI - Get a good. AB - Research has established a clear correlation between high patient satisfaction and better clinical outcomes, so understanding what can improve patients' perception of healthcare services may help improve care. PMID- 28072197 TI - Fury at NMC's plan to increase registration fees to L120 a year. AB - Nurses have reacted furiously to a 'deeply unfair' proposal that could see Nursing and Midwifery Council fees soar to L120 per year. PMID- 28072198 TI - Profession celebrated at downing street. AB - Nursing leaders joined prime minister David Cameron and health secretary Andrew Lansley at a Downing Street reception to recognise their work. PMID- 28072199 TI - Lost for words on hearing of opposition to seacole statue. AB - When I read Lynn McDonald's letter informing us of the opposition to the siting of Mary Seacole's memorial statue on the sacred soil of St Thomas' Hospital in south east London (letters May 16), I was so astonished that, for the first time in my life, I was absolutely speechless. PMID- 28072200 TI - Poor understanding of learning disability careers. AB - I was sorry to read that learning disability care services 'are heading towards a timebomb' (news May 2). RCN learning disabilities adviser Ann Norman says there are not enough learning disabilities nurses working in the NHS, social care or the independent sector - with the number of new registrants declining in recent years. PMID- 28072201 TI - After a few days in harrogate my batteries have been recharged. AB - I would like to thank everyone involved in organising RCN congress for a wonderful few days in Harrogate. Everything ran smoothly and efficiently. PMID- 28072202 TI - Fitness to practise hearings are there to protect the public. AB - In response to Malcolm Harrison's letter (May 16), the Nursing and Midwifery Council's fitness to practise activity last year cost L43 million. PMID- 28072203 TI - Lansley's one-to-one midwife promise is simply 'hot air'. AB - As part of the government's plans to support the family, health secretary Andrew Lansley has promised that new mothers will receive one-to-one care from a named midwife (see news in brief page 8 ). PMID- 28072204 TI - On the inside. AB - After working in a care home and then in retail, healthcare assistant Fiona Humphreys applied for a position at HMP Rye Hill, an all-male prison near Rugby, Warwickshire. Some 11 years later, Ms Humphreys still finds great job satisfaction caring for more than 600 offenders. PMID- 28072206 TI - International council fee still under negotiation. AB - The RCN is withholding part of its L700,000 fee towards an international nursing body while it negotiates a reduced annual levy, RCN general secretary Peter Carter revealed at congress. PMID- 28072207 TI - Dignity commission chair pushes for HCA regulation. AB - The co-chair of the commission on improving dignity in care has vowed to champion the work of healthcare assistants and join calls for them to be regulated alongside nurses. PMID- 28072208 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28072209 TI - Time is on your side. AB - Do you ever feel that there are not enough hours - or minutes - in a day to accomplish everything that needs to be done? PMID- 28072210 TI - Article on bariatric surgery has helped me to stop snacking. AB - Nicky Green's overview of bariatric surgery (learning zone May 9) made for fascinating, if grisly, reading. The statistics are frightening. It is estimated that 60 per cent of adult males, 50 per cent of adult females and 25 per cent of schoolchildren under the age of 16 could be obese by 2050. PMID- 28072212 TI - A process to ensure public protection Private employer leads. AB - Regulation of healthcare assistants is back in the spotlight. The English government has rejected mandatory regulation, although unions continue to press for it, and is instead working on a code of practice for support staff. PMID- 28072213 TI - We need to restore the pride in those who care for older people. AB - I support your Care campaign to improve fundamental care ( www.thecarecampaign.co.uk ). PMID- 28072215 TI - Webwise. AB - Autism affects adults and children all over the world. There are more than half a million people with autism in the UK alone, and it is more common than many people realise. PMID- 28072216 TI - Guess who i met on the train? AB - When mental health nurse Iain Gibson boarded a train from York to Harrogate with friends last week, he had not expected to bump into Labour leader Ed Miliband. PMID- 28072217 TI - I was surprised by the number of obese delegates at RCN congress. AB - Bariatric nurse specialist Nicky Green's excellent and informative overview of bariatric surgery (learning zone May 9) highlights the growing obesity problem in the UK and the importance of long-term weight management. PMID- 28072218 TI - We need to be proficient in a wide range of procedures. AB - I agree with Nichola McCarthy (letters May 2) that all nursing students should be taught ECG, phlebotomy, cannulation and IV administration skills. PMID- 28072219 TI - Students learn from clinicians who explain what they are doing and why. AB - I have some points to make following the discussion at RCN congress on the fitness for purpose of nurse education (see news page 11 ). PMID- 28072221 TI - Step change Ian McMillan Step change is a Freelance journalist. AB - Staff at a south east London NHS trust are discovering how dance can improve their communication with patients with learning disabilities. Weekly dance sessions, run by Magpie Dance, are now also being made available to people with dementia, autism and other conditions. Through dance people can express emotion, build confidence and change their lives. PMID- 28072220 TI - Self-injury and harm minimisation on acute wards. AB - Practitioners' attitudes to self-injury vary widely. While some healthcare professionals are comfortable providing advice about safe self-injury in the inpatient setting, others believe they have a duty of care to protect patients from harming themselves, including removing all potentially sharp implements and increasing observation levels. This article describes work undertaken at South Staffordshire and Shropshire Healthcare NHS Foundation Trust to explore self injurious behaviour in inpatient settings, including staff knowledge and perceptions and service users' experiences. Development of clinical guidelines for safe self-injury is also discussed. PMID- 28072222 TI - Starting out - I reached out to a withdrawn patient by speaking her language. AB - During my second year, I was placed on a busy medical ward. There were some long stay patients on the ward, one of whom remained in a side room with the curtains shut and without television, radio or visitors. Her notes indicated a recent diagnosis of Alzheimer's disease. PMID- 28072223 TI - Readers panel Check-ups for doctors. AB - Our experts consider a hot topic of the day. PMID- 28072225 TI - Majority votes against paying organ donors amid fears of exploitation. AB - Nurses have voted to lobby against moves to introduce payments for organ donors after hearing that vulnerable people, including those on low incomes, could be coerced into selling organs. PMID- 28072224 TI - Long shifts with insufficient breaks are increasing risk of clinical errors. AB - RCN council has been asked to demand greater action by NHS employers 'to reduce the recognised harmful effects of shift working on staff and patients'. PMID- 28072226 TI - Link with trades union congress. AB - A fierce debate about whether the RCN should be affi liated to the Trades Union Congress was held last week. PMID- 28072227 TI - Delegates reject cash for healthy choices proposal. AB - The idea that people who smoke or are overweight should be paid to adopt healthy lifestyles was rejected by nurses at RCN congress last week. PMID- 28072228 TI - Raise parents' awareness about content of video games. AB - Nurses want parents and children to be better educated about the adverse effects of adult-themed video games. PMID- 28072229 TI - Board and branch review will ensure fitness for purpose. AB - The RCN has allayed members' fears that a review of legal and governance structures at the college could weaken the influence of its regional boards and branches. PMID- 28072230 TI - Speed and ecstasy linked to depression in teenagers, especially if both are used. AB - Secondary school children who use methamphetamine (speed) and MDMA (ecstasy) are prone to subsequent depression, suggests a study of almost 4,000 young people in Canada. PMID- 28072231 TI - Carter urges ministers to acknowledge job cuts. AB - A letter outlining the exact number of nursing posts that have been cut from the NHS will be sent to prime minister David Cameron and health secretary Andrew Lansley. PMID- 28072232 TI - Women tend to be more anxious than men before they have day surgery. AB - Women experience greater levels of anxiety than men before day surgery according to a study that suggests nursing should adapt to meet the psychological needs of short-stay patients. The study by Mark Mitchell, senior lecturer at the College of Health and Social Care, University of Salford, Greater Manchester, also looked at the impact of general and local anaesthesia. PMID- 28072233 TI - Lessons learnt from an earlier age of austerity. AB - At the end of another week at the coalface of primary care, browsing through my well-thumbed vintage cookery books is a great way to relax. PMID- 28072234 TI - Eating lots of berries may halt cognitive decline by more than two years. AB - High consumption of blueberries and strawberries can slow cognitive decline by up to 2.5 years, a study examining berry intake and cognition found. PMID- 28072235 TI - Benefits of self-management programme for diabetes patients are not long term. AB - The benefits of a one-off education and self-management programme for people diagnosed with type 2 diabetes do not last, suggests a study of participants in one of the first programmes to meet the Department of Health's quality criteria. PMID- 28072236 TI - Cigarette pack health warnings help to stop ex-smokers lighting up. AB - Health warnings on cigarette packs can help ex-smokers resist the urge to smoke, according to the first major study to assess how effective the warnings are with people who have given up. PMID- 28072237 TI - Courses & resources. AB - Induction The RCN has released a web-based learning resource to help healthcare assistants (HCAs) and their employers to design induction programmes. The college has also issued a guidance document with accompanying fi lm, leafl ets and checklist for delegation. The material is intended to be used by all members of the nursing team to clarify the meaning of delegation-related terminology and how it should be used in practice. www.rcn.org.uk/development/health_care_support_workers. PMID- 28072238 TI - Hot topic. AB - They say that families should sit down together for at least one meal a day. Really? I reckon if 'they' came to dinner with my family, they would not last fi ve minutes. PMID- 28072240 TI - Boiler Briquette Coal versus Raw Coal: Part II-Energy, Greenhouse Gas, and Air Quality Implications. AB - The objective of this paper is to conduct an integrated analysis of the energy, greenhouse gas, and air quality impacts of a new type of boiler briquette coal (BB-coal) in contrast to those of the raw coal from which the BB-coal was formulated (R-coal). The analysis is based on the source emissions data and other relevant data collected in the present study and employs approaches including the construction of carbon, energy, and sulfur balances. The results show that replacing R-coal with BB-coal as the fuel for boilers such as the one tested would have multiple benefits, including a 37% increase in boiler thermal efficiency, a 25% reduction in fuel demand, a 26% reduction in CO2 emission, a 17% reduction in CO emission, a 63% reduction in SO2 emission, a 97% reduction in fly ash and fly ash carbon emission, a 22% reduction in PM2.5 mass emission, and a 30% reduction in total emission of five toxic hazardous air pollutant (HAP) metals contained in PM10. These benefits can be achieved with no changes in boiler hardware and with a relatively small amount of tradeoffs: a 30% increase in PM10 mass emission and a 9-16% increase in fuel cost. PMID- 28072241 TI - Boiler Briquette Coal versus Raw Coal: Part I-Stack Gas Emissions. AB - Stack gas emissions were characterized for a steam-generating boiler commonly used in China. The boiler was tested when fired with a newly formulated boiler briquette coal (BB-coal) and when fired with conventional raw coal (R-coal). The stack gas emissions were analyzed to determine emission rates and emission factors and to develop chemical source profiles. A dilution source sampling system was used to collect PM on both Teflon membrane filters and quartz fiber filters. The Teflon filters were analyzed gravimetrically for PM10 and PM2.5 mass concentrations and by X-ray fluorescence (XRF) for trace elements. The quartz fiber filters were analyzed for organic carbon (OC) and elemental carbon (EC) using a thermal/optical reflectance technique. Sulfur dioxide was measured using the standard wet chemistry method. Carbon monoxide was measured using an Orsat combustion analyzer. The emission rates of the R-coal combustion (in kg/hr), determined using the measured stack gas concentrations and the stack gas emission rates, were 0.74 for PM10, 0.38 for PM25, 20.7 for SO2, and 6.8 for CO, while those of the BB-coal combustion were 0.95 for PM10, 0.30 for PM2 5, 7.5 for SO2, and 5.3 for CO. The fuel-mass-based emission factors (in g/kg) of the R-coal, determined using the emission rates and the fuel burn rates, were 1.68 for PM10, 0.87 for PM25, 46.7 for SO2, and 15 for CO, while those of the BB-coal were 2.51 for PM10, 0.79 for PM2.5, 19.9 for SO2, and 14 for CO. The task-based emission factors (in g/ton steam generated) of the R-coal, determined using the fuel-mass based emission factors and the coal/ steam conversion factors, were 0.23 for PM10, 0.12 for PM2.5, 6.4 for SO2, and 2.0 for CO, while those of the BB-coal were 0.30 for PM10, 0.094 for PM2.5, 2.4 for SO2, and 1.7 for CO. PM10 and PM2.5 elemental compositions are also presented for both types of coal tested in the study. PMID- 28072242 TI - A Special Issue from the NARSTO Symposium on Tropospheric Aerosols. AB - This dedicated issue of the Journal of the Air & Waste Management Association contains nine peer-reviewed scientific papers that were presented at the NARSTO Symposium on Tropospheric Aerosols: Science and Decisions in an International Community, held October 24-26, 2000, in Queretaro, Mexico.1 Other peer-reviewed papers2-9 appear in a companion issue of Science of the Total Environment to be published in February 2002. More than 130 papers were presented in platform and poster sessions at the meeting. Approximately 28% of the technical presentations dealt with topics from Mexico, and 15% related to Canada, with the remainder discussing U.S. and global topics. PMID- 28072248 TI - Fly flaps ensure catheter comfort. AB - A nurse has helped redesign hospital pyjamas to increase comfort and reduce the risk of bladder infections for post-surgical and urology patients. PMID- 28072249 TI - MID staffs chief nurse says trust needs leadership. AB - The nurse director of Mid Staffordshire NHS Foundation Trust has revealed his plans to embed cultural change at the troubled organisation. PMID- 28072250 TI - MPs are targeted in protest against pay cartels. AB - Thousands of nurses have written to their MPs amid fears that the establishment of pay cartels could signal a 'large-scale' move away from nationally agreed terms and conditions. PMID- 28072251 TI - Responsible leadership on the ward would avert more scandals. AB - Your editorial (July 18) on the timely action needed to prevent poor care in hospitals raises an important issue for the nursing profession. PMID- 28072252 TI - 'Dose of reality' needed when comparing chaplains and nurses. AB - Blair Robertson, the head of chaplaincy and spiritual care at NHS Greater Glasgow and Clyde, wants to embed spiritual care in the NHS (letters July 18). PMID- 28072254 TI - It astounds me that the care of older people is so overlooked. AB - It is absolutely right that the contribution of professional colleagues in the care of older people is being applauded (letters July 11 and 18). It astounds me that there has been so little recognition of their work. PMID- 28072253 TI - A collaborative partnership between patient and caregiver. AB - Lynn Young highlights not just the financial benefits of self-care, but touches on the important elements that make self-management strategies a success (reflections July 18). PMID- 28072255 TI - If a private company can listen to staff then why can't the NHS? AB - As a nurse researcher and author of The Unpopular Patient, I contributed to Nursing Standard's first webcast to share my understandings about one of the factors leading to poor standards of nursing care in hospitals. PMID- 28072256 TI - Healthcare organisations have an obligation to minimise stress. AB - I applaud the RCN for recognising a course to help nurses cope in stressful situations and perform better under pressure (news July 18). Course founder Caroline Hopkins. PMID- 28072257 TI - Internal controls and external frameworks to boost standards. AB - There need to be robust internal controls to ensure good standards in any organisation that provides care to vulnerable people (analysis July 18). PMID- 28072258 TI - Obituary. AB - Beryl Hutchinson MBE, former director of nursing and assistant manager of patient services in Grantham, Lincolnshire, died on July 30 aged 78. PMID- 28072259 TI - Webwise. AB - Nurses and other healthcare professionals are generally conscious of the wider state of the planet and will welcome the Happy Planet Index website - providing global data on human wellbeing and our environmental impact. PMID- 28072260 TI - Olympic opening ceremony was a vibrant feast of fun and energy. AB - If director Danny Boyle's intention at the Olympic opening ceremony was to provide a snapshot of Britain today, he succeeded. It was an inspired feast of energy, colour and vibrancy - as well as being great fun. PMID- 28072265 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28072267 TI - 'Equality is what nursing is about'. AB - Nurse Joanne Stevenson helped celebrate diversity at Belfast's Pride celebrations on Saturday. PMID- 28072268 TI - An ideal subject. AB - Richard Windle wanted to sign up to clinical trials soon after he was diagnosed with Parkinson's three years ago. PMID- 28072269 TI - 'The problem does not lie with nursing culture...' AB - Dame June Clark professor emeritus, Swansea University: 'The problem does not lie with nursing culture but with acute sector culture and its money-is-everything ethos. For an example of how to get it right, look no further than hospices, our best care homes or the community nursing service.' PMID- 28072270 TI - Finally something to thank Lansley for. AB - Well done Andrew Lansley. Now there's a sentence you don't get to say very often. But the health secretary's intervention in the sorry saga of the Nursing and Midwifery Council's (NMC) bungling attempts to balance its books by picking nurses' pockets is welcome. Particularly welcome is his statement that 'a fee increase for registrants is difficult to justify at a time of pay restraint'. It certainly is, especially an increase of nearly 60 per cent. PMID- 28072272 TI - NHS head praises senior nurse's dignity initiative. AB - A nurse-led initiative to improve the experiences of hospital patients has been highlighted as good practice in an NHS Wales report. PMID- 28072271 TI - Agent of change. AB - Michael J Fox is now arguably as well known for his role in promoting research into Parkinson's as he is for his acting career. He was already a star when he was diagnosed with the progressive neurological condition at the age of 29. He announced publicly that he had the condition eight years later in 1998. PMID- 28072273 TI - Huge cultural change is needed to embed self-care strategies. AB - Lynn Young identifies the challenges that an ageing population presents to primary care in terms of staffing and financial resources (reflections July 18). We ignore the benefits of self-management approaches to long-term conditions at our peril. PMID- 28072274 TI - Starting out the trust i developed with a patient was vital to the success of his care. AB - During a recent placement with the community nursing team, I made daily visits to a young male patient with Crohn's disease who had recently undergone a hemicolectomy and formation of an ileostomy. PMID- 28072275 TI - ICN emphasises the benefits of flexible working practices. AB - The organisation that represents nurses across the globe says if employers adopted fl exible working practices it would be a 'win-win' for them and their staff. PMID- 28072277 TI - Our health service is a priceless form of artistry. AB - The Olympic opening ceremony was amazing. What made it special was its refusal to be populated solely by celebrities and the establishment, focusing instead on our history and the role of ordinary people in it. PMID- 28072276 TI - Prescribing system could identify criminal activity. AB - A specialised drug prescribing system could improve surveillance in hospitals and highlight patients at risk of harm resulting from clinical error or criminal activity, researchers claim. PMID- 28072278 TI - Be proud of your hard-earned professional status. AB - What is your first thought when you think about your registration? Are you proud of what you have achieved, or defensive and fearful of losing it? Have you noticed how often you or. PMID- 28072279 TI - Get the culture of the organisation right, and good care will follow. AB - When a clinical matron who had breast cancer stood before a celebration of nursing event to share her story about the great care and compassion she had experienced at the hospital where she worked, there was hardly a dry eye in the house. PMID- 28072280 TI - Where have all the flowers gone? AB - When I took some fl owers to a friend in hospital recently, I was asked by her nurse to take them home because of 'cross infection' and was given a short lecture on bacteria in fl ower water. PMID- 28072283 TI - More staff, better outcomes. AB - Our experts consider a hot topic of the day. PMID- 28072281 TI - Call circumcision what it is - male genital mutilation. AB - A court in Germany ruled in July that boys could no longer be circumcised other than for medical reasons. PMID- 28072284 TI - Patient contact time rises at Hinchingbrooke. AB - Nurses at the first part-privately run NHS hospital are spending nearly 40 per cent more time with patients than they did six months ago when it was managed by the NHS, new bosses claim. PMID- 28072285 TI - Finding those who empower people. AB - When it comes to culture and values, nursing could learn much from social care, says Bill Mumford, a member of the nursing and care quality forum and chief executive of learning disability charity MacIntyre. PMID- 28072286 TI - World in brief. AB - What's happening in nursing across the globe. PMID- 28072287 TI - Suffolk Community Healthcare staff set to transfer to private provider. AB - More than 1,000 healthcare workers, including 440 nursing staff, will move to private provider Serco in the biggest transfer of nurses carried out by the group. PMID- 28072289 TI - Adolescents are at risk of high blood pressure from drinking alcohol and use of the pill. AB - Alcohol consumption among adolescent boys and use of the contraceptive pill among girls has a significant adverse effect on their blood pressure and cardiovascular risk, suggests a study in Australia. PMID- 28072288 TI - Memorial to crimean nurse icon unveiled. AB - The life and work of iconic Welsh nurse Betsi Cadwaladr was celebrated at an official ceremony last week. PMID- 28072290 TI - Giving up smoking is likely to lead to more weight gain than people tend to expect. AB - People who give up smoking are likely to gain more weight than is commonly supposed, according to a new analysis of the evidence by researchers based in France and the UK. PMID- 28072291 TI - College labels bursary cuts plan 'discriminatory'. AB - The RCN has condemned a Northern Ireland executive plan to cut financial support for nursing students by more than L1,000 each per year. PMID- 28072292 TI - Maternal rather than fetal factors have the greatest effect on growth restriction. AB - A study by researchers in Japan has found that maternal rather than fetal factors are associated with fetal growth restriction. PMID- 28072293 TI - Eating a lot of vegetables could reduce the risk of some types of acute pancreatitis. AB - High consumption of vegetables may reduce the risk of non-gallstone-related acute pancreatitis, according to a Swedish study. PMID- 28072294 TI - Store kudos. AB - My reputation at the supermarket has been improving steadily thanks to self scanning. Trustworthy, reliable, a man of means - you should see me swipe my card with pride, knowing that I am an exemplary customer. PMID- 28072295 TI - Children's weight can be reduced by teaching good habits early on. AB - A home-based early intervention by community nurses has proved effective in reducing children's body mass index at two years of age, reducing their risk of going on to become obese. PMID- 28072296 TI - A standardised early warning system will save lives, says Janet Davies. AB - Around 5 per cent of deaths in hospital are preventable, according to a recent study by the British Medical Journal. PMID- 28072297 TI - How to stay afloat. AB - Nursing must find new ways of navigation in a perfect storm. This may sound like hyperbole, but it is no exaggeration to suggest that nursing in England finds itself in the midst of an unprecedented situation that could have far-reaching consequences. PMID- 28072298 TI - Mutual terror. AB - For a self-styled hardman, he was a bit of a wuss. But perhaps the sight of a young nurse advancing towards you with a pair of scissors and trembling hands would test anyone's mettle. PMID- 28072299 TI - A Flow-Through Leaching Model for Monolithic Chemically Stabilized/Solidified Hazardous Waste. AB - Cement-based stabilization/solidification is a technology that is being used for the treatment of hazardous wastes before they are land disposed. It involves adding one or more solidification reagents to a waste stream and turning it into a monolithic solid. The resulting solidified waste products usually have improved handling characteristics, lower permeability and, hence, the leaching of contaminants from the waste can be reduced. Leaching occurs when a leachant contacts a waste and carries away contaminants from the waste. In this paper, the common leaching test methods for the evaluation of solidified/stabilized wastes and the leaching models that have been applied are reviewed. This paper also introduces a new model for the prediction of the long-term leaching behavior of cement-based stabilized/solidified hazardous wastes in a flow-through leaching test environment. The flow-through leaching environment, which is based on flexible wall permeameter test equipment, is different from other leaching test methods since the leaching occurs under a combination of diffusion and dispersion actions. The assumptions and limitations in applying the new model are highlighted. PMID- 28072300 TI - Bioaerosol Concentration at an Outdoor Composting Center. AB - Compost centers are one of many environments that produce airborne microorganisms. The objective of this study was to compare the bacterial, fungal, and acti-nomycete concentrations at the Norman, OK, compost center to background concentration of these same microorganisms. For this comparison, a modified Andersen Microbial Sampler was used. Sampling was performed at three sites at the outdoor compost center and at two background sites. The concentration of each microorganism was measured as total colony forming units per cubic meter (CFU/m3). The predominantly downwind compost center site had a 10-fold increase in all the microorganisms in comparison with the other sites (p < 0.05). The median concentrations (95% confidence interval) of total viable bacteria, Gram negative bacteria, fungi, and actinomycetes at this site were 5059 (CI95= 4952 9600) CFU/m3, 2023 (CI95= 2586-6806) CFU/m3, 972 (CI95= 964-1943) CFU/m3, and 2159 (CI95= 1755-4190) CFU/m3, respectively. PMID- 28072301 TI - Fuel Type as a Factor Influencing Compliance by Utilities under The Acid Rain Program. AB - Passage of the 1990 Clean Air Act Amendments launched the Acid Rain Program in the United States. This initiative, based on the market mechanism of a sulfur dioxide tradable "allowance" system, was a dramatic departure from traditional command and control strategies designed to reduce air pollution emissions. Power plant managers have flexibility under the program to select and implement a variety of options to reduce emissions below mandated levels. Federal agencies have collected annual performance data for affected facilities covered by the program for a number of years. Coal-burning plants are typically greater generators of sulfur dioxide (SO2) than oil burners of equivalent size. This study examined the effect of fuel type as a significant factor influencing a plant's achievement in reducing pollution emissions. Achievement was measured by using a derived variable, delta (A), defined as the difference between pounds of SO2 produced divided by the energy (in million Btu) generated, for the years 1990 and 1995. Rigorous nonparametric statistical analyses were used to compare the two populations of coal-fired and oil-fired plants. Results indicated that coal burning facilities achieved greater program success, measured by the expected value of delta, than the oil combustors for the five-year period reviewed. Since utility managers must take steps to ensure all applicable requirements of the program are met, findings of the inquiry should prove to be useful in assessing achievable emissions reductions and aid in long-range facility planning. PMID- 28072302 TI - Tracking Regional Background in a Haze Attribution Experiment. AB - Emissions from distant source areas are often imagined to provide a steady background to the emissions of whatever local sources are being studied. As part of Project MOHAVE in summer 1992, several air mass markers and an injected stack tracer were measured hourly near the Grand Canyon. Observed haze events generally coincided with transients in methylchloroform and water vapor, which we interpret as endemic tags for air from southern California and the subtropics. The results depict a dynamic regional background. PMID- 28072303 TI - Beyond Detectability. AB - Part of the input to a dispersion model consists of a source odor concentration that typically is determined by a panel of six to eight observers using a forced choice dynamic triangle olfactometer. A series of dilutions of the sampled odor are presented and the dilution at which one-half of the panel can detect odor is considered to be the source odor concentration (often described as ED50 or as Dilutions-to-Threshold [D/T]). The output from the dispersion model generates a predicted ambient odor concentration (expressed as D/T or as odor units). An ambient odor concentration (D/T) of 1 means that 50% of the panel will detect odor. It is not clear what D/T values other than 1 mean. Thus, only limited information is given on the detectability (threshold) dimension of odor. In this paper, a procedure is outlined that can be used to obtain information on all four dimensions of odor and still keep the simplicity and usefulness of the source odor concentration/ambient odor concentration concept that the dispersion modeler needs. The panel members are asked to report for each dilution presented the four dimensions of odor-detectability (as a "yes" or "no" odor response), intensity (butanol or category scale), quality (odor descriptors), and the he-donic tone. The paper illustrates how the procedure can be used with either inexperienced or experienced panels who provided information on three (detectabil-ity, intensity, and quality) of the four dimensions of odor. The procedure is applied to odors from two wastewater treatment plants. Essentially a dilution profile of the sample is prepared. For a given D/T, the procedure can provide an estimate of the percent of the panel that will detect odor, the average odor intensity, and the odor quality. PMID- 28072304 TI - Hazardous Air Pollution from Mobile Sources: A Comparison of Alternative Fuel and Reformulated Gasoline Vehicles. AB - Although there have been several studies examining emissions of criteria pollutants from in-use alternative fuel vehicles (AFVs), little is known about emissions of hazardous air pollutants (HAPs) from these vehicles. This paper explores HAP tailpipe emissions from a variety of AFVs operating in the federal government fleet and compares these emissions to emissions from identical vehicles operating on reformulated gasoline. Emissions estimates are presented for a variety of fuel/model combinations and on four HAPs (acetaldehyde, 1,3 butadi-ene, benzene, and formaldehyde). The results indicate that all AFVs tested offer reduced emissions of HAPs, with the following exceptions: ethanol fueled vehicles emit more acetaldehyde than RFG vehicles, and ethanol- and methanol fueled vehicles emit more formaldehyde than RFG vehicles. The results from this paper can lead to more accurate emissions factors for HAPs, thus improving HAP inventory and associated risk estimates for both AFVs and conventional vehicles. PMID- 28072305 TI - Assessment of Nontailpipe Hydrocarbon Emissions from Motor Vehicles. AB - This report evaluates tailpipe and nontailpipe hydrocarbon (HC) emissions from light-duty spark-ignition (SI) vehicles. The sources of information were unpublished data sets, generated mainly from 1990 through 1994, on emissions from volunteer fleets of in-use vehicles in chassis dynamometer and sealed housing for evaporative determination tests, and published chemical mass balance (CMB) source apportionments of HC in roadway tunnels and in urban air. The nontailpipe emissions evaluated comprise running-loss, hot soak, diurnal emissions, and resting-loss emissions. Relations between pressure and purge test failures and actual nontailpipe emissions were also examined. PMID- 28072306 TI - Environmental Beneficiation of Machining Wastes-Part III: Effects of Metal Working Fluids on the Spontaneous Heating of Machining Swarf. AB - Machining swarf is a finely divided metal powder that is prone to spontaneous heating and, in some cases, spontaneous combustion. The fine particle size, large amount of particle surface area, and the presence of moisture all promote rapid oxidation. This hazard dramatically increases disposal costs for swarf and interferes with recycling efforts. A potential method for minimizing spontaneous heating and facilitating recycling of the swarf is to spray a fluid on the material that coats the particles and creates a barrier between the metal and oxygen. Surface coatings could be tested for their effects on the spontaneous heating potential of swarf by treating a sample of swarf with a fluid that would coat the particles, then monitoring its heating behavior. This paper describes the results of applying corrosion inhibitors and machining fluids to the swarf, and monitoring the spontaneous heating behavior using a testing method developed specifically for this purpose. The effects of different types of surfactants and the effects of surfactant concentration on the spontaneous heating of swarf are discussed. PMID- 28072307 TI - Airborne Emissions of Mercury from Municipal Landfill Operations: A Short-Term Measurement Study in Florida. AB - Large quantities of mercury (Hg) have been placed in municipal landfills from a wide array of sources, including fluorescent lights, batteries, electrical switches, thermometers, and general waste. Despite its known volatility, persistence, and toxicity in the environment, the fate of this Hg has not been widely studied. Using automated flux chambers and atmospheric sampling, we quantified the primary pathways of Hg vapor releases to the atmosphere at two municipal landfill operations in south Florida for eight days in April 1997. These pathways included landfill gas (LFG) releases from passive and active vent systems, passive emissions from landfill surface covers of different ages (including CH4 "hot spots"), and emissions from daily activities at a working face (WF). Hg vapor was released to the atmosphere at readily detectable rates from all sources measured. Emission rates ranged from ~1 to 20 ng m-2 hr-1 over aged surface covers (generally comparable to background soils), from ~6 to 2400 ng/hr from LFG vents and flares, and from ~5 to 60 mg/hr at the WF. In general the fluxes increased from older to newer landfills, from fresh to aged cover, and from passive to active venting systems. Limited data suggest that methyl- and other organo-mercury compounds may also be emitted from these sites, suggesting an important area for future research. We estimate that atmospheric Hg releases from municipal landfill operations in the state of Florida are on the order of 10 kg/yr, or <1% of the estimated total anthropogenic Hg releases to air in this region. PMID- 28072308 TI - Starting out - Family's concerns led me to clarify my thinking on end of life practice. AB - During a recent community placement, I accompanied one of the nursing sisters to see an older, female patient with metastatic pancreatic cancer. PMID- 28072309 TI - Carter demands investment in more dementia training. AB - The RCN has welcomed government plans to spend L50 million on improving care environments for people with dementia, but general secretary Peter Carter called for further investment in staff training. PMID- 28072310 TI - Management of self-harm wounds. AB - Self-harm may be used by individuals as a means to relieve distress and may be a coping and suicide prevention strategy. This article focuses on risk assessment of patients who may self-harm as well as the treatment of those presenting with self-harm wounds. PMID- 28072311 TI - Readers panel-Fitness to assess sickness. AB - Our experts consider a hot topic of the day. PMID- 28072312 TI - Bail out sparks fears for independent regulation. AB - The Nursing and Midwifery Council's decision to accept L20 million from the government, enabling it to limit the size of the fee rise, has sparked a debate about the regulator's independence. PMID- 28072313 TI - Nursing interventions are needed to help staff promote hopefulness in stroke patients. AB - Patients in stroke units would benefit from interventions to encourage 'realistic hopefulness', suggest British researchers. PMID- 28072314 TI - Women's genetic make-up plays a significant role in their desire to be thin. AB - Genetics may make some women more vulnerable to the cultural pressure to be thin, suggests a study of identical twins in the United States. PMID- 28072316 TI - A healthy and social lifestyle helps older people live longer. AB - Healthy lifestyle factors such as taking physical exercise and not smoking add years to life, even among people in their late eighties and those with chronic health conditions, according to a long-term study in Sweden. PMID- 28072315 TI - 'I was groped by sir jimmy as a student'. AB - A nursing student claims she was sexually assaulted by the late presenter Sir Jimmy Savile in 1973. PMID- 28072318 TI - Pick and click. AB - So, a transfusion of young blood can rejuvenate an old brain. If it works with mice, might it work with humans? If so, make mine a pint. I clearly need something of that nature after what happened last week. PMID- 28072319 TI - Patients hospitalised with advanced cancer need fatigue screening. AB - Cancer patients in hospital should be monitored and treated for fatigue, suggests a British study that emphasises the need for nursing interventions. PMID- 28072320 TI - Young patients with strong immune systems may benefit from treatment for hepatitis B. AB - Children and young adults with chronic hepatitis B virus may be suitable candidates for treatment, suggests a study that challenges current practice. PMID- 28072321 TI - Gagging clauses are being used to hide failings and bad practice. AB - Patient safety ombudsman Delilah Hesling is fortunate that her trust is introducing a range of reforms, removing fear from the care culture and focusing on accountability in clinical practice (reflections October 17). PMID- 28072322 TI - Racism may be abhorrent, but it is not a psychiatric condition. AB - I was horrified to read mental health nurse Tony Leiba's assertion that racism might be a psychiatric condition (features October 3). However abhorrent and misinformed, racism remains opinion, thoughts and assumptions. To suggest that these attitudes are in some way psychiatric is a step towards totalitarianism. PMID- 28072323 TI - L40m of leadership training would be better spent on the font line. AB - Funded by a L40 million grant from the Department of Health, the NHS Leadership Academy will organise training for up to 10,000 nurses and ward leaders by 2015 (news October 10). PMID- 28072324 TI - Effective leadership is essential if we are to drive up standards. AB - Leadership is crucial to the successful running of any team and department. Effective leaders and leadership will be essential for all staff in the NHS if we are to deliver on the quality agenda and drive up standards, especially at a time of cutbacks. PMID- 28072325 TI - Deadline extended for awards entries. AB - Nurses and healthcare assistants have been given an extra week to enter the Nurse Awards 2013, organised by Nursing Standard. PMID- 28072327 TI - 'The boy who nominated me still keeps in touch'. AB - Launched in 2008, the first patient's choice award was given jointly to two nurses, Rachel Andrews and Gill Donovan. PMID- 28072329 TI - Feed the family or fill the car: the stark choice facing nurses. AB - Living within a tight budget is second nature to most nurses. But the government imposed pay freeze, which the RCN claims has cut the value of nurses' incomes by 9 per cent, is leaving many struggling to pay their bills. PMID- 28072330 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28072331 TI - SSKIN - the care bundle that puts the emphasis on prevention. AB - Many organisations base their pressure ulcer prevention strategies on SSKIN, a bundle of care that includes five simple steps. Nurse lecturer Jacqueline Fletcher explains. PMID- 28072333 TI - Political notebook. AB - Jeremy Hunt last week appeared at the Commons despatch box for the first time since becoming England's health secretary to set out his four priorities. PMID- 28072332 TI - Use patient complaints to build a case for improved resources. AB - Nurses should use negative patient feedback to push for more resources on the front line, according to health minister Dan Poulter. PMID- 28072334 TI - 'The awards ceremony was the best night of my life'. AB - The winner of the 2009 patient's choice award was already a well-known figure. Margaret Haywood had been found guilty of misconduct and removed from the register by the Nursing and Midwifery Council in April that year. PMID- 28072336 TI - World in brief. AB - What's happening in nursing across the globe. PMID- 28072335 TI - The ultimate honour. AB - The Claire Rayner patient's choice award acknowledges an individual who improves a patient's quality of life, is there for someone in distress or blows the whistle on poor care. PMID- 28072337 TI - 'We don't use end of life pathway to clean NHS of the old and infirm'. AB - Palliative care nurses have reacted furiously to criticism that some patients are 'shunted' on to an end of life care pathway because they are a burden to the NHS. PMID- 28072338 TI - Another debacle in a long-running farce. AB - Nurses are entitled to be angered by the Nursing and Midwifery Council's decision to increase their re-registration fees from L76 to L100 a year. Not only does it come in the midst of a protracted pay freeze, but there is scant evidence that pumping more money into the regulator's coffers will do anything to enhance public protection. PMID- 28072339 TI - Student life - Watch, listen and learn. AB - Reaping the maximum benefit from the mentoring process requires commitment from nursing students, honesty and openness about learning needs and a willingness to learn. PMID- 28072340 TI - 'I may have to move in with mum'. AB - Band 5 community nurse Isobel Blake works a 42.5 hour week, but struggles to pay the bills because her pay has not risen since April 2009. PMID- 28072341 TI - I will have to sell my home as i cannot afford the mortgage. AB - In almost 30 years of nursing, I have seen many changes and most have been for the better. PMID- 28072343 TI - The RCN needs a headquarters that reflects its size and prestige. AB - Sue Green (letters October 17) says the RCN needs to economise and get its house in order - the big one in London. PMID- 28072345 TI - A chance to start a new life. AB - While career opportunities in the UK may be in short supply, with nurses struggling to find work that suits their talents, opportunities in other parts of the world are plentiful. PMID- 28072344 TI - NHS needs to retain valuable experience of older workers. AB - Nurses in their sixties could be moved into training and mentoring roles to allow them to continue working longer, says health minister Dan Poulter. PMID- 28072346 TI - We are no longer recruiting the right sort of people into nursing. AB - Sally-Anne Driver (letters October 17) is spot on. Much substantive research has been undertaken on dignity in care. It is time to see some action. PMID- 28072347 TI - 'It was a humbling experience'. AB - It has been a good year, says Diane Singleton, who won the 2012 award. As lead nurse for older people at Liverpool Community Health NHS Trust, she set up the Liveability service more than ten years ago. PMID- 28072349 TI - 'There is a feeling that our views were disregarded'. PMID- 28072348 TI - Regulator says extra money will clear backlog of fitness to practise cases. AB - The nursing regulator has justified its decision to increase re-registration fees to L100 a year, claiming the money will help clear its fitness to practise backlog. PMID- 28072350 TI - Voices - 'Winners of Mary Seacole awards make me so proud,' says Elizabeth Anionwu. AB - There was a wonderful buzz among those attending the recent Mary Seacole Leadership and Development Awards. PMID- 28072351 TI - Older and wiser. AB - The Bigger Picture was an exhibition at the Royal Academy of Arts in London, celebrating the work of David Hockney. It was his portrayals of the Yorkshire countryside that took centre stage; the light and shade, the starkness and abundance. It was a body of work by a confi dent, mature master-artist. PMID- 28072354 TI - Planning for change. AB - Despite a number of public health initiatives in recent years, there are still worryingly high rates of unplanned pregnancies in the UK. PMID- 28072352 TI - Webwise. AB - The Valuing Complaints website approaches the topic of complaints positively. It sees complaints as a mechanism for organisations to obtain low-cost feedback, and one that should be embraced by the NHS, local authorities and government bodies. PMID- 28072355 TI - Subservient hospital culture may explain silence about savile. AB - I have been shocked by the allegations of abuse by Sir Jimmy Savile and how he got away with it for so long (letters October 24).SAVILE I have been shocked by the allegations of abuse by Sir Jimmy Savile and how he got away with it for so long (letters October 24). PMID- 28072357 TI - Warfarin-induced tissue necrosis: a case study. AB - Warfarin-induced tissue necrosis is a rare and serious side effect associated with warfarin treatment. A case study of a patient with warfarin-induced tissue necrosis taken from clinical practice illustrates the importance of timely diagnosis and treatment to avoid the devastating consequences of this adverse drug reaction. Nurse prescribers must be alert to and aware of potential adverse drug reactions that may be caused by any prescribing decision, and should be able to take appropriate action when such an event occurs. PMID- 28072366 TI - Polyfunctional Plants for Industrial Waste Disposal-Part II: Economics and Model Evaluation. AB - This is the second part of a two-part paper dealing with the preliminary design and costing of polyfunctional waste treatment plants. In this article, we present some criteria for estimating capital investment and annual operating costs of polyfunctional plants for industrial waste treatment. The process and equipment design methods presented in Part I of this article, together with the economic approach proposed here, allow for complete technical/economic analyses. The overall mathematical model appears to be a useful tool in economic feasibility studies. The accuracy of the developed computer mathematical model has been demonstrated, referring to actual cost data from the literature. PMID- 28072367 TI - Polyfunctional Plants for Industrial Waste Disposal-Part I: Process and Equipment Design. AB - This article is the first of two papers dealing with development of a design and costing procedure for polyfunctional waste treatment plants. Part I reviews equipment sizing aspects. Part II defines and validates the cost estimation procedure. In this article, the structure of a general purpose polyfunctional plant for liquid and solid industrial waste treatment is discussed, highlighting the high level of process integration obtainable and the consequent benefits. The plant comprises an incineration section, a section for chemical/physical/biological treatments, and a stabilization/solidification section. Each section is briefly described, and an overview of the sizing procedure for main equipment is presented. Such a procedure forms the basis of a computer model for process and equipment preliminary design to be used in economic feasibility evaluation studies. PMID- 28072368 TI - The Plume Volume Molar Ratio Method for Determining NO2/NOx Ratios in Modeling Part II: Evaluation Studies. AB - A previous paper1 discusses the methodology for a new method for deriving the nitrogen dioxide/nitrogen oxide (NO2/NOx) ratio in plumes that originally are composed mainly of (NOx). It is called the Plume Volume Molar Ratio Method (PVMRM). This paper documents its performance against six different data sets. These performance evaluations show that the PVMRM can realistically predict the NO2 fraction at close-in receptors yet still provide conservative estimates so that the air quality standards can be protected. PMID- 28072369 TI - The Plume Volume Molar Ratio Method for Determining NO2/NOx Ratios in Modeling Part I: Methodology. AB - During New Source Review modeling of proposed major sources of oxides of nitrogen (NOx), maximum impacts are often predicted to occur very close to the source. At the same time, current modeling guidance recommends techniques that may be overly conservative in estimating the fraction of nitrogen dioxide (NO2) in these plumes. A new technique called the Plume Volume Molar Ratio Method (PVMRM) is being proposed that simulates both chemistry and dispersion to better estimate the fraction of NO2. This paper documents the methodology behind the technique. A follow-up pa-per1 will evaluate its performance against a number of databases. This method is designed to realistically predict NO2 fraction at close-in receptors yet still provide conservative estimates so that the air quality standards can be protected. PMID- 28072370 TI - Continuous Sorbent Reactions in a High-Temperature Fabric Filter Following Convective Pass Ca(OH)2 Injection for SO2 Removal. AB - A specially designed two-stage reactor was used to study solid sorbent reactions in the filtration stage of a high-temperature fabric which follow convective pass Ca(OH)2 injection. Solid conversions during the progress of the sorbent reactions were thoroughly analyzed. It was found that, unlike the sorbent reactions in the injection stage, which proceed extremely fast with strong carbonation under high temperatures, the subsequent sorbent reactions in the filtration stage are much slower and residual sorbent is mainly utilized in removing sulfur dioxide (SO2). Two major reaction pathways are discovered in the filtration stage. The first route is through the decomposition of residual calcium hydroxide (Ca(OH)2), which is critical in inducing further sorbent reactions when there is sufficient residual sorbent. The second route is the sulfation of the carbonation product, calcium carbonate (CaCO3), which may become the principal reaction to remove SO2 after the residual sorbent is consumed. The con-vective pass and the fabric filter are found to be equally important reaction sites in the combined process of convec-tive pass sorbent injection with high-temperature filtration. The overall SO2 removal efficiency of the system is affected by both the sorbent injection and filtration conditions. PMID- 28072371 TI - Measurements of Rural Sulfur Dioxide and Particle Sulfate: Analysis of CASTNet Data, 1987 through 1996. AB - The Clean Air Status and Trends Network (CASTNet) was implemented by the U.S. Environmental Protection Agency (EPA) in 1991 in response to Title IX of the Clean Air Amendments of 1990, which mandated the deployment of a national ambient air monitoring network to track progress of the implementation of emission reduction programs in terms of deposition, air quality, and changes to affected ecosystems. CASTNet evolved from the National Dry Deposition Network (NDDN). CASTNet currently consists of 45 sites in the eastern United States and 28 sites in the West. Each site measures sulfur dioxide (SO2), nitric acid (HNO3), particle sulfate (SO4=), particle nitrate (NO3- ), and ozone. Nineteen sites collect precipitation samples. NDDN/CASTNet uses a uniform set of site-selection criteria which provides the data user with consistent measures to compare each site. These criteria also ensure that, to the extent possible, CASTNet sites are located away from local emission sources. This paper presents an analysis of SO2 and SO4= concentration data collected from 1987 through 1996 at rural NDDN/CASTNet sites. Annual and seasonal variability is examined. Gradients of SO2 and SO4= are discussed. The variability of the atmospheric mix of SO2 and SO4= is explored spatially and seasonally. Data from CASTNet are also compared to SO2 and SO4= data from concurrent monitoring studies in rural areas. PMID- 28072372 TI - The Impact of California Phase 2 Reformulated Gasoline on Real-World Vehicle Emissions. AB - In mid-1996, California implemented Phase 2 Reformulated Gasoline (RFG). The new fuel was designed to further decrease emissions of hydrocarbons (HCs), oxides of nitrogen (NOx), carbon monoxide (CO), sulfur dioxide (SO2), and other toxic species. In addition, it was formulated to reduce the ozone-forming potential of the HCs emitted by vehicles. Previous studies have observed that emissions from on-road vehicles can differ significantly from those predicted by mobile source emissions models, and so it is important to quantify the change in emissions in a real-world setting. In October 1995, prior to the introduction of California Phase 2 RFG, the Desert Research Institute (DRI) performed a study of vehicle emissions in Los Angeles' Sepulveda Tunnel. This study provided a baseline against which the results of a second experiment, conducted in July 1996, could be compared to evaluate the impact of California Phase 2 RFG on emissions from real-world vehicles. Compared with the 1995 experiment, CO and NOx emissions exhibited statistically significant decreases, while the decrease in non-methane hydrocarbon emissions was not statistically significant. Changes in the speciated HC emissions were evaluated. The benzene emission rate decreased by 27% and the overall emission rate of aromatic compounds decreased by 22% comparing the runs with similar speeds. Emissions of alkenes were virtually unchanged; however, emissions of combustion related unsaturates (e.g., acetylene, ethene) increased, while heavier alkenes decreased. The emission rate of methyl tertiary butyl ether (MTBE) exhibited a larger increase. Overall changes in the ozone-forming potential of the emissions were not significantly different, with the increased contributions to reactivity from paraffins, ole-fins, and MTBE being offset by a large decrease in reactivity due to aromatics. PMID- 28072373 TI - Enhanced VOC Absorption Using the Ozone/Hydrogen Peroxide Advanced Oxidation Process. AB - Promoting fast chemical reactions in the liquid phase can significantly increase the absorption rate of low-solubility volatile organic compounds (VOCs) in a packed column. In this research, an innovative scrubbing process was examined in which ozone was injected into the VOC stream while the aqueous stream was augmented with hydrogen peroxide. The liquid phase reaction of ozone and hydrogen peroxide results in the formation of highly reactive hydroxyl radicals in an advanced oxidation process. In this research, the effect of primary process parameters on the efficiency of the advanced oxidative scrubber (AOS) was examined. Test compounds included toluene, benzene, xylene, tetrachloroethylene (PCE), trichloroethylene (TCE), and 1,1,1-trichloroethane. A mathematical absorption model was developed for AOS system. Ozone, hydrogen peroxide, contaminant, and scavenger concentrations, as well as pH, all had a significant effect on the AOS efficiency. PMID- 28072374 TI - The Influence of Gasoline Formulation on Specific Pollutant Emissions. AB - Many recent works have dealt with the influence of fuel composition on regulated and specific pollutant emissions from spark ignition engines. While many qualitative correlations have been already proposed, only a few quantitative ones are known (benzene remains an exception). This paper describes qualitative and quantitative correlations between fuel composition and specific pollutant emissions (individual hydrocarbons, aldehydes, ketones, alcohols, and organic acids) of a spark ignition engine. The aim of this work was to find the precursors of the main specific pollutants. Then, for each of them, a multilinear equation has been calculated, illustrating the correlation between its concentration in exhaust gases and its content in the fuel. The results of these calculations point out which initial compound favors the formation of a determined pollutant. As lean conditions are probably going to be used in future commercial engines, the fuel effect has been studied for a broad range of equivalence ratios (from 0.8 to 1.2). PMID- 28072375 TI - Kinetics and Mechanism of the Reaction of Azide with Ozone in Aqueous Solution. AB - The stoichiometry of the reaction of aqueous ozone with sodium azide was studied at pH 12 (mainly) where a yellow metastable intermediate is observed. We propose that this is hypoazidite (N3O- ), analogous to hypobromite, and that it plays a central role in the azide catalyzed decompostion of ozone. The yellow intermediate is unstable in acid, in which it rapidly decomposes, generating N2 and NO2-. The rate of reaction was studied at pH 2.0-3.5, with the ionic strength at 0.6 M and temperature at 3-15 degrees C. The intrinsic second-order rate constants were found to be k HN3 <= ~ 400 M-1sec-1 and k N3- = (8.7 +/- 0.5) * 105 M-1sec-1 (3 degrees C, 0.6 M), both in agreement with the only other previous study. The rate constant at 25 degrees C was estimated using the following experimentally determined parameters: ln kN3- (M-1sec-1) = (5.73 +/- 0.36) * 103/T (K) + (28.34 +/- 1.27). The value of kN3- estimated in this way is (2.5 +/- 0.1) * 106 M-1sec-1 at 25 degrees C and 0.6 M. The enthalpy of reaction (A H) is -48 +/- 3 kJ mol-1. PMID- 28072376 TI - Pilot-Scale Demonstration of an Innovative Treatment for Vapor Emissions. AB - Researchers from the National Renewable Energy Laboratory recently conducted a pilot-scale study at McClellan Air Force Base (AFB) in Sacramento, CA. The objective of the test was to determine the effectiveness of an ambient temperature, solar-powered photocatalytic oxidation treatment unit for destroying emissions of chlorinated organic compounds from an air stripper. This paper reports test results and discusses applications and limitations of the technology. A 10-standard-cubic-foot-per-minute (SCFM) (28.3 L/min) slip stream of air from an air stripper at Operative Unit 29-31 at McClellan AFB was passed through a reactor that contained a lightweight, perforated, inert support coated with photoactive titanium dioxide. The reactor faced south and was tilted at a 45 degrees angle from vertical so that the light-activated catalyst received most of the available sunlight. An online portable gas chro-matograph with two identical columns simultaneously analyzed the volatile organic compounds contained in the reactor inlet and outlet air streams. Summa canister grab samples of the inlet and outlet were also collected and sent to a certified laboratory for U.S. Environmental Protection Agency Method TO-14 analysis and verification of our field analyses. Three weeks of testing demonstrated that the treatment system's destruction and removal efficiencies (DREs) are greater than 95% at 10 SCFM with UV intensities at or greater than 1.5 milliwatts/square centimeter (mW/cm2). DREs greater than 95% at 20 SCFM were obtained under conditions where UV irradiation measured at or greater than 2 mW/cm2. In Sacramento, this provided 6 hours of operation per clear or nearly clear day in April. A solar tracking system could extend operating time. The air stream also contained trace amounts of benzene. We observed no loss of system performance during testing. PMID- 28072377 TI - Core Self-Evaluations and Job and Life Satisfaction: The Mediating and Moderated Mediating Role of Job Insecurity. AB - This study examined the mediating role of job insecurity in the relationship between core self-evaluations (CSE) and job satisfaction, while also investigating the moderating role of job insecurity in the mediated relationship between CSE and life satisfaction via job satisfaction. Survey data were collected from a sample of 346 full-time employees in Taiwan. We found that job insecurity partially mediated the CSE-job satisfaction relationship. Moreover, we found that job insecurity moderated not only the relationship between CSE and job satisfaction but also the mediated relationship between CSE and life satisfaction via job satisfaction. Specifically, both the CSE-job satisfaction relationship and the CSE-job satisfaction-life satisfaction relationship became stronger when job insecurity was low. Our results emphasize the importance of raising employees' CSE, which is beneficial not only for diminishing their perceptions of job insecurity, but also for boosting their job and life satisfaction. Practical implications and directions for future research are discussed. PMID- 28072379 TI - The challenge of in vivo tissue characterization, connectivity and big data. PMID- 28072380 TI - Network functional connectivity and whole-brain functional connectomics to investigate cognitive decline in neurodegenerative conditions. AB - Non-invasive mapping of brain functional connectivity (FC) has played a fundamental role in neuroscience, and numerous scientists have been fascinated by its ability to reveal the brain's intricate morphology and functional properties. In recent years, two different techniques have been developed that are able to explore FC in pathophysiological conditions and to provide simple and non invasive biomarkers for the detection of disease onset, severity and progression. These techniques are independent component analysis, which allows a network-based functional exploration of the brain, and graph theory, which provides a quantitative characterization of the whole-brain FC. In this paper we provide an overview of these two techniques and some examples of their clinical applications in the most common neurodegenerative disorders associated with cognitive decline, including mild cognitive impairment, Alzheimer's disease, Parkinson's disease, dementia with Lewy Bodies and behavioral variant frontotemporal dementia. PMID- 28072381 TI - Magnetic resonance imaging and positron emission tomography in the diagnosis of neurodegenerative dementias. AB - Neuroimaging, both with magnetic resonance imaging (MRI) and positron emission tomography (PET), has gained a pivotal role in the diagnosis of primary neurodegenerative diseases. These two techniques are used as biomarkers of both pathology and progression of Alzheimer's disease (AD) and to differentiate AD from other neurodegenerative diseases. MRI is able to identify structural changes including patterns of atrophy characterizing neurodegenerative diseases, and to distinguish these from other causes of cognitive impairment, e.g. infarcts, space occupying lesions and hydrocephalus. PET is widely used to identify regional patterns of glucose utilization, since distinct patterns of distribution of cerebral glucose metabolism are related to different subtypes of neurodegenerative dementia. The use of PET in mild cognitive impairment, though controversial, is deemed helpful for predicting conversion to dementia and the dementia clinical subtype. Recently, new radiopharmaceuticals for the in vivo imaging of amyloid burden have been licensed and more tracers are being developed for the assessment of tauopathies and inflammatory processes, which may underlie the onset of the amyloid cascade. At present, the cerebral amyloid burden, imaged with PET, may help to exclude the presence of AD as well as forecast its possible onset. Finally PET imaging may be particularly useful in ongoing clinical trials for the development of dementia treatments. In the near future, the use of the above methods, in accordance with specific guidelines, along with the use of effective treatments will likely lead to more timely and successful treatment of neurodegenerative dementias. PMID- 28072383 TI - Reconstructing contralateral fiber tracts: methodological aspects of cerebello thalamocortical pathway reconstruction. AB - The identification of pathways connecting the cerebral cortex with subcortical structures is critical to understanding how large-scale brain networks operate. The cerebellum, for example, is known to project numerous axonal bundles to thecerebral cortex passing through the thalamus. This paper focuses on the technical details of cerebello-thalamo-cortical pathway reconstruction using advanced diffusion MRI techniques in humans in vivo. Pathways reconstructed using seed/target placement on super-resolution maps, created with track density imaging (TDI), were compared with those reconstructed by defining regions of interest (ROIs) on non-diffusion weighted images (b0). We observed that the reconstruction of the pathways was more anatomically accurate when using ROIs placed on TDI rather than on b0 maps, while inter-subject variability and reproducibility were similar between the two methods. Diffusion indices along pathways showed a position-dependent specificity that will need to be taken into consideration in future clinical investigations. PMID- 28072382 TI - Modeling white matter microstructure. AB - Quantitative magnetic resonance imaging can be combined with advanced biophysical models to measure microstructural features of white matter. Non-invasive microstructural imaging has the potential to revolutionize neuroscience, and acquiring these measures in clinically feasible times would greatly improve patient monitoring and clinical studies of drug efficacy. However, a good understanding of microstructural imaging techniques is essential to set realistic expectations and to prevent over-interpretation of results. This review explains the methodology behind microstructural modeling and imaging, and gives an overview of the breakthroughs and challenges associated with it. PMID- 28072385 TI - Connectivity measures in the Poffenberger paradigm indicate hemispheric asymmetries. AB - The Poffenberger paradigm is a well-known measure of interhemispheric transfer delays, calculated on the basis of the crossed vs uncrossed reaction time difference (CUD). However, the proper interpretation of CUD is extensively debated in the literature. In this study we used connectivity measures in an attempt to interpret CUD from the perspective of functional connectivity. Accordingly, we tried to define functional couplings in the Poffenberger paradigm; we used a simple choice version of the paradigm, and included a stimulation only (SO) condition for comparison. As an index of functional coupling we employed partial directed coherence, exploiting bilateral grouping of the electrodes to compute intra-and interhemispheric connection weight ratios (CWRs). Our findings indicated modulations in functional weights in relation to the SO condition, rather than the crossed and uncrossed conditions, such that the response executed by the right hemisphere yielded a decrease in intra-, yet an increase in interhemispheric CWRs, whereas the left hemisphere interactions showed connectivity patterns similar to the SO condition irrespective of the side of movement. Overall, our results suggest modulation of connectivity in the same/similar system, which was found to be optimized, in terms of hemispheric asymmetries, to different tasks. PMID- 28072384 TI - Impact of cerebellar atrophy on cortical gray matter and cerebellar peduncles as assessed by voxel-based morphometry and high angular resolution diffusion imaging. AB - In recent years the cerebellum has been attributed amore important role in higher level functions than previously believed. We examined a cohort of patients suffering from cerebellar atrophy resulting in ataxia, with two main objectives: first to investigate which regions of the cerebrum were affected by the cerebellar degeneration, and second to assess whether diffusion magnetic resonance imaging (dMRI) metrics within the medial (MCP) and superior cerebellar peduncle (SCP) - namely fractional anisotropy (FA) and radial diffusivity (RD) - could be used as a biomarker in patients with this condition. Structural and dMRI data of seven patients with cerebellar atrophy (2 with spinocerebellar atrophy type 2, 1 with Friedreich's ataxia, 4 with idiopathic cerebellar ataxia) and no visible cortical lesions or cortical atrophy were investigated with Freesurfer and voxel-based morphometry (VBM) of gray matter (GM) as well as MCP and SCP FA maps. Correlations of MCP and SCP mean FA with ataxia scores and subscores were also evaluated. Freesurfer showed that patients had significantly reduced volume of the thalamus, ventral diencephalon and pallidum. VBM also demonstrated significantly lower local GM volumes in patients, notably in the head of the caudate nucleus, posterior cingulate gyrus and orbitofrontal cortex bilaterally, as well as in Broca's area in the left hemisphere, and a significant increase in RD in the MCP and SCP of both hemispheres. A significant correlation was found between MCP mean FA and total ataxia score (R=-0.7, p=0.03), and subscores for kinetic functions (R=-0.74, p=0.03) and oculomotor disorders (R=-0.70, p=0.04). The regions of the cerebrum found to have significantly lower local GM volumes have been described to be involved in higher-level cerebellar functions such as initiation of voluntary movements, emotional control, memory retrieval and general cognition. Our findings corroborate recent research pointing to a more extensive corticocerebellar system than previously thought. The significant difference in the MCP and SCP dMRI metrics between patients and controls as well as the significant correlation with ataxia total score and subscores support the use of dMRI metrics as an imaging biomarker for cerebellar degeneration and ataxia. PMID- 28072386 TI - Main effects and interactions of cerebral hemispheres, gender, and age in the calculation of volumes and asymmetries of selected structures of episodic memory. AB - The aim of this study was to clarify the influence of anatomical (cerebral hemisphere) and demographic (age and gender) variables on the gray matter (GM) volumes and volumetric asymmetry indices (VAIs) of selected structures involved in episodic memory. A cross-sectional study was performed in 47 healthy volunteers. Neuropsychological evaluation revealed similar IQs across the sample. Using SPM-based software, brain segmentation, labeling and volume measurements of the hippocampus, amygdala, middle temporal gyrus and parahippocampal gyrus were performed in each cerebral hemisphere. A two-way between-groups multivariate analysis of covariance (MANCOVA) was applied to GM volumes and VAIs. The main effects of gender and cerebral hemisphere on GM volumes were significant (p < .001), while there was no significant interaction effect between gender and cerebral hemisphere. VAI measurements showed a nonsignificant effect of gender, but a significant influence of age (p = .015). The linear model of interactions and main effects explained 33% of the variance influencing the GM volume quantification. While cerebral hemisphere and gender were found to affect the volumes of brain structures involved in episodic memory, the calculation of VAIs was affected only by age. A comprehensive understanding of the main effects and interaction effects of cerebral hemisphere, gender and age on the volumes and asymmetries of structures related to episodic memory might help neurologists, psychiatrists, geriatricians and other neuroscientists in the study of degenerative brain diseases. PMID- 28072387 TI - Embryonic origin of adult stem cells required for tissue homeostasis and regeneration. AB - Planarian neoblasts are pluripotent, adult somatic stem cells and lineage-primed progenitors that are required for the production and maintenance of all differentiated cell types, including the germline. Neoblasts, originally defined as undifferentiated cells residing in the adult parenchyma, are frequently compared to embryonic stem cells yet their developmental origin remains obscure. We investigated the provenance of neoblasts during Schmidtea mediterranea embryogenesis, and report that neoblasts arise from an anarchic, cycling piwi-1+ population wholly responsible for production of all temporary and definitive organs during embryogenesis. Early embryonic piwi-1+ cells are molecularly and functionally distinct from neoblasts: they express unique cohorts of early embryo enriched transcripts and behave differently than neoblasts in cell transplantation assays. Neoblast lineages arise as organogenesis begins and are required for construction of all major organ systems during embryogenesis. These subpopulations are continuously generated during adulthood, where they act as agents of tissue homeostasis and regeneration. PMID- 28072388 TI - A sequential multi-target Mps1 phosphorylation cascade promotes spindle checkpoint signaling. AB - The master spindle checkpoint kinase Mps1 senses kinetochore-microtubule attachment and promotes checkpoint signaling to ensure accurate chromosome segregation. The kinetochore scaffold Knl1, when phosphorylated by Mps1, recruits checkpoint complexes Bub1-Bub3 and BubR1-Bub3 to unattached kinetochores. Active checkpoint signaling ultimately enhances the assembly of the mitotic checkpoint complex (MCC) consisting of BubR1-Bub3, Mad2, and Cdc20, which inhibits the anaphase-promoting complex or cyclosome bound to Cdc20 (APC/CCdc20) to delay anaphase onset. Using in vitro reconstitution, we show that Mps1 promotes APC/C inhibition by MCC components through phosphorylating Bub1 and Mad1. Phosphorylated Bub1 binds to Mad1-Mad2. Phosphorylated Mad1 directly interacts with Cdc20. Mutations of Mps1 phosphorylation sites in Bub1 or Mad1 abrogate the spindle checkpoint in human cells. Therefore, Mps1 promotes checkpoint activation through sequentially phosphorylating Knl1, Bub1, and Mad1. This sequential multi target phosphorylation cascade makes the checkpoint highly responsive to Mps1 and to kinetochore-microtubule attachment. PMID- 28072389 TI - Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA binding protein Zfp106. AB - Expanded GGGGCC repeats in the first intron of the C9orf72 gene represent the most common cause of familial amyotrophic lateral sclerosis (ALS), but the mechanisms underlying repeat-induced disease remain incompletely resolved. One proposed gain-of-function mechanism is that repeat-containing RNA forms aggregates that sequester RNA binding proteins, leading to altered RNA metabolism in motor neurons. Here, we identify the zinc finger protein Zfp106 as a specific GGGGCC RNA repeat-binding protein, and using affinity purification-mass spectrometry, we show that Zfp106 interacts with multiple other RNA binding proteins, including the ALS-associated factors TDP-43 and FUS. We also show that Zfp106 knockout mice develop severe motor neuron degeneration, which can be suppressed by transgenic restoration of Zfp106 specifically in motor neurons. Finally, we show that Zfp106 potently suppresses neurotoxicity in a Drosophila model of C9orf72 ALS. Thus, these studies identify Zfp106 as an RNA binding protein with important implications for ALS. PMID- 28072392 TI - Impact of scaling base thickness on the performance of heterojunction phototransistors. AB - In this letter we report the effect of vertical scaling on the optical and electrical performance of mid-wavelength infrared heterojunction phototransistors based on type-II InAs/GaSb/AlSb superlattices. The performance of devices with different base thickness was compared as the base was scaled from 60 down to 40 nm. The overall optical performance shows enhancement in responsively, optical gain, and specific detectivity upon scaling the base width. The saturated responsivity for devices with 40 nm bases reaches 8845 and 9528 A W-1 at 77 and 150 K, respectively, which is almost five times greater than devices with 60 nm bases. The saturated optical gain for devices with 40 nm bases is measured as 2760 at 77 K and 3081 at 150 K. The devices with 40 nm bases also exhibit remarkable enhancement in saturated current gain, with 17690 at 77 K, and 19050 at 150 K. PMID- 28072393 TI - Stability of icosahedral quasicrystals in a simple model with two-length scales. AB - The phase behaviour of a free energy functional with two length scales is examined by comparing the free energy of different candidate phases including three-dimensional icosahedral quasicrystals. Accurate free energy of the quasicrystals has been obtained using the recently developed projection method. The results reveal that the icosahedral quasicrystal and body-centred-cubic spherical phase are the stable ordered phases of the model. Furthermore, the difference between the results obtained from the projection method and the one mode approximation has been analyzed in detail. The present study extends previous results on two-dimensional systems, demonstrating that the interactions between density waves at two length scales can stabilize two- and three dimensional quasicrystals. PMID- 28072391 TI - BRAFV600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis. AB - While 20-30% of colorectal cancers (CRCs) may arise from precursors with serrated glands, only 8-10% of CRCs manifest serrated morphology at diagnosis. Markers for distinguishing CRCs arising from 'serrated' versus 'conventional adenoma' precursors are lacking. We studied 36 human serrated CRCs and found CDX2 loss or BRAF mutations in ~60% of cases and often together (p=0.04). CDX2Null/BRAFV600E expression in adult mouse intestinal epithelium led to serrated morphology tumors (including carcinomas) and BRAFV600E potently interacted with CDX2 silencing to alter gene expression. Like human serrated lesions, CDX2Null/BRAFV600E-mutant epithelium expressed gastric markers. Organoids from CDX2Null/BRAFV600E-mutant colon epithelium showed serrated features, and partially recapitulated the gene expression pattern in mouse colon tissues. We present a novel mouse tumor model based on signature defects seen in many human serrated CRCs - CDX2 loss and BRAFV600E. The mouse intestinal tumors show significant phenotypic similarities to human serrated CRCs and inform about serrated CRC pathogenesis. PMID- 28072390 TI - A molecular portrait of maternal sepsis from Byzantine Troy. AB - Pregnancy complications are poorly represented in the archeological record, despite their importance in contemporary and ancient societies. While excavating a Byzantine cemetery in Troy, we discovered calcified abscesses among a woman's remains. Scanning electron microscopy of the tissue revealed 'ghost cells', resulting from dystrophic calcification, which preserved ancient maternal, fetal and bacterial DNA of a severe infection, likely chorioamnionitis. Gardnerella vaginalis and Staphylococcus saprophyticus dominated the abscesses. Phylogenomic analyses of ancient, historical, and contemporary data showed that G. vaginalis Troy fell within contemporary genetic diversity, whereas S. saprophyticus Troy belongs to a lineage that does not appear to be commonly associated with human disease today. We speculate that the ecology of S. saprophyticus infection may have differed in the ancient world as a result of close contacts between humans and domesticated animals. These results highlight the complex and dynamic interactions with our microbial milieu that underlie severe maternal infections. PMID- 28072394 TI - Three-dimensional cascaded system analysis of a 50 um pixel pitch wafer-scale CMOS active pixel sensor x-ray detector for digital breast tomosynthesis. AB - High-resolution, low-noise x-ray detectors based on the complementary metal-oxide semiconductor (CMOS) active pixel sensor (APS) technology have been developed and proposed for digital breast tomosynthesis (DBT). In this study, we evaluated the three-dimensional (3D) imaging performance of a 50 um pixel pitch CMOS APS x-ray detector named DynAMITe (Dynamic Range Adjustable for Medical Imaging Technology). The two-dimensional (2D) angle-dependent modulation transfer function (MTF), normalized noise power spectrum (NNPS), and detective quantum efficiency (DQE) were experimentally characterized and modeled using the cascaded system analysis at oblique incident angles up to 30 degrees . The cascaded system model was extended to the 3D spatial frequency space in combination with the filtered back-projection (FBP) reconstruction method to calculate the 3D and in plane MTF, NNPS and DQE parameters. The results demonstrate that the beam obliquity blurs the 2D MTF and DQE in the high spatial frequency range. However, this effect can be eliminated after FBP image reconstruction. In addition, impacts of the image acquisition geometry and detector parameters were evaluated using the 3D cascaded system analysis for DBT. The result shows that a wider projection angle range (e.g. +/-30 degrees ) improves the low spatial frequency (below 5 mm-1) performance of the CMOS APS detector. In addition, to maintain a high spatial resolution for DBT, a focal spot size of smaller than 0.3 mm should be used. Theoretical analysis suggests that a pixelated scintillator in combination with the 50 um pixel pitch CMOS APS detector could further improve the 3D image resolution. Finally, the 3D imaging performance of the CMOS APS and an indirect amorphous silicon (a-Si:H) thin-film transistor (TFT) passive pixel sensor (PPS) detector was simulated and compared. PMID- 28072396 TI - Quantification of static magnetic field effects on radiotherapy ionization chambers. AB - Integrated magnetic resonance (MR) imaging and radiotherapy (RT) delivery machines are currently being developed, with some already in clinical use. It is anticipated that the strong magnetic field used in some MR-RT designs will have a significant impact on routine measurements of dose in the MR-linac performed using ionization chambers, which provide traceability back to a primary standard definition of dose. In particular, the presence of small air gaps around ionization chambers may introduce unacceptably high uncertainty into these measurements. In this study, we investigate and quantify the variation attributable to air gaps for several routinely-used cylindrical ionization chambers in a magnetic field, as well as the effect of the magnetic field alone on the response of the chambers. The measurements were performed in a Co-60 beam, while the ionization chambers were positioned in custom-made Perspex phantoms between the poles of an electromagnet, which was capable of generating magnetic fields of up to 2 T field strength, although measurements were focused around 1.5 T. When an asymmetric air gap was rotated at cardinal angles around the ionization chambers investigated here, variation of up to 8.5 +/- 0.2 percentage points (PTW 31006 chamber) was observed in an applied magnetic field of 1.5 T. The minimum peak-to-peak variation was 1.1 +/- 0.1% (Exradin A1SL). When the same experiment was performed with a well-defined air gap of known position using the PTW 30013 chamber, a variation of 3.8 +/- 0.2% was observed. When water was added to the phantom cavity to eliminate all air gaps, the variation for the PTW 30013 was reduced to 0.2 +/- 0.01%. PMID- 28072395 TI - Evaluation of adaptive treatment planning for patients with non-small cell lung cancer. AB - The purpose of this study was to develop metrics to evaluate uncertainties in deformable dose accumulation for patients with non-small cell lung cancer (NSCLC). Initial treatment plans (primary) and cone-beam CT (CBCT) images were retrospectively processed for seven NSCLC patients, who showed significant tumor regression during the course of treatment. Each plan was developed with IMRT for 2 Gy * 33 fractions. A B-spline-based DIR algorithm was used to register weekly CBCT images to a reference image acquired at fraction 21 and the resultant displacement vector fields (DVFs) were then modified using a finite element method (FEM). The doses were calculated on each of these CBCT images and mapped to the reference image using a tri-linear dose interpolation method, based on the B-spline and FEM-generated DVFs. Contours propagated from the planning image were adjusted to the residual tumor and OARs on the reference image to develop a secondary plan. For iso-prescription adaptive plans (relative to initial plans), mean lung dose (MLD) was reduced, on average from 17.3 Gy (initial plan) to 15.2, 14.5 and 14.8 Gy for the plans adapted using the rigid, B-Spline and FEM-based registrations. Similarly, for iso-toxic adaptive plans (considering MLD relative to initial plans) using the rigid, B-Spline and FEM-based registrations, the average doses were 69.9 +/- 6.8, 65.7 +/- 5.1 and 67.2 +/- 5.6 Gy in the initial volume (PTV1), and 81.5 +/- 25.8, 77.7 +/- 21.6, and 78.9 +/- 22.5 Gy in the residual volume (PTV21), respectively. Tumor volume reduction was correlated with dose escalation (for isotoxic plans, correlation coefficient = 0.92), and with MLD reduction (for iso-fractional plans, correlation coefficient = 0.85). For the case of the iso-toxic dose escalation, plans adapted with the B Spline and FEM DVFs differed from the primary plan adapted with rigid registration by 2.8 +/- 1.0 Gy and 1.8 +/- 0.9 Gy in PTV1, and the mean difference between doses accumulated using the B-spline and FEM DVF's was 1.1 +/ 0.6 Gy. As a dose mapping-induced energy change, energy defect in the tumor volume was 20.8 +/- 13.4% and 4.5 +/- 2.4% for the B-spline and FEM-based dose accumulations, respectively. The energy defect of the B-Spline-based dose accumulation is significant in the tumor volume and highly correlated to the difference between the B-Spline and FEM-accumulated doses with their correlation coefficient equal to 0.79. Adaptive planning helps escalate target dose and spare normal tissue for patients with NSCLC, but deformable dose accumulation may have a significant loss of energy in regressed tumor volumes when using image intensity-based DIR algorithms. The metric of energy defect is a useful tool for evaluation of adaptive planning accuracy for lung cancer patients. PMID- 28072397 TI - Agrp neuron activity is required for alcohol-induced overeating. AB - Alcohol intake associates with overeating in humans. This overeating is a clinical concern, but its causes are puzzling, because alcohol (ethanol) is a calorie-dense nutrient, and calorie intake usually suppresses brain appetite signals. The biological factors necessary for ethanol-induced overeating remain unclear, and societal causes have been proposed. Here we show that core elements of the brain's feeding circuits-the hypothalamic Agrp neurons that are normally activated by starvation and evoke intense hunger-display electrical and biochemical hyperactivity on exposure to dietary doses of ethanol in brain slices. Furthermore, by circuit-specific chemogenetic interference in vivo, we find that the Agrp cell activity is essential for ethanol-induced overeating in the absence of societal factors, in single-housed mice. These data reveal how a widely consumed nutrient can paradoxically sustain brain starvation signals, and identify a biological factor required for appetite evoked by alcohol. PMID- 28072398 TI - Transportable hyperpolarized metabolites. AB - Nuclear spin hyperpolarization of 13C-labelled metabolites by dissolution dynamic nuclear polarization can enhance the NMR signals of metabolites by several orders of magnitude, which has enabled in vivo metabolic imaging by MRI. However, because of the short lifetime of the hyperpolarized magnetization (typically <1 min), the polarization process must be carried out close to the point of use. Here we introduce a concept that markedly extends hyperpolarization lifetimes and enables the transportation of hyperpolarized metabolites. The hyperpolarized sample can thus be removed from the polarizer and stored or transported for use at remote MRI or NMR sites. We show that hyperpolarization in alanine and glycine survives 16 h storage and transport, maintaining overall polarization enhancements of up to three orders of magnitude. PMID- 28072400 TI - Prostate cancer: Light, camera, action - photodynamic therapy for low-risk disease. PMID- 28072401 TI - Infection: A new threat on the horizon - Zika virus and male fertility. PMID- 28072402 TI - Prostate cancer: On the down-low - low luminal cell CD38 expression is prognostic. PMID- 28072399 TI - Organization of high-level visual cortex in human infants. AB - How much of the structure of the human mind and brain is already specified at birth, and how much arises from experience? In this article, we consider the test case of extrastriate visual cortex, where a highly systematic functional organization is present in virtually every normal adult, including regions preferring behaviourally significant stimulus categories, such as faces, bodies, and scenes. Novel methods were developed to scan awake infants with fMRI, while they viewed multiple categories of visual stimuli. Here we report that the visual cortex of 4-6-month-old infants contains regions that respond preferentially to abstract categories (faces and scenes), with a spatial organization similar to adults. However, precise response profiles and patterns of activity across multiple visual categories differ between infants and adults. These results demonstrate that the large-scale organization of category preferences in visual cortex is adult-like within a few months after birth, but is subsequently refined through development. PMID- 28072403 TI - Antimicrobial-resistant sexually transmitted infections: gonorrhoea and Mycoplasma genitalium. AB - The emergence of antimicrobial resistance (AMR) is a major concern worldwide and already compromises treatment effectiveness and control of several bacterial sexually transmitted infections (STIs). Neisseria gonorrhoeae and Mycoplasma genitalium are evolving into so-called superbugs that can become resistant, both in vitro and clinically, to essentially all antimicrobials available for treatment, causing exceedingly difficult-to-treat or untreatable STIs and threatening global public health. Widespread AMR in these bacteria is likely to persist and even worsen in the future, owing to the high number of infections, widespread and uncontrolled use of antimicrobials, limited surveillance of AMR and clinical failures, as well as the extraordinary capacity of these bacteria to develop AMR. This development would not only result in an increased prevalence of N. gonorrhoeae and M. genitalium infections but also in a considerably increasing number of severe complications affecting reproductive health. To combat this threat, clinicians need to be aware of the current guidelines on diagnostic procedures, recommended treatment regimens, as well as therapeutic options for multidrug-resistant bacteria. AMR testing needs to be more frequently performed, inform treatment decisions and elucidate how AMRs compromise treatment effectiveness, guiding research for effective future therapies. PMID- 28072407 TI - CORRIGENDUM: Low-pass whole-genome sequencing in clinical cytogenetics: a validated approach. PMID- 28072404 TI - Autophagic membrane delivery through ATG9. AB - One of the key questions regarding macroautophagy/autophagy is the mechanism through which the transmembrane protein ATG9 functions in delivering membrane to the expanding phagophore, the sequestering compartment that matures into an autophagosome. In a recent study, Zhou et al. identified a novel mechanism that regulates ATG9 trafficking from the plasma membrane and trans-Golgi network, which involves two conserved sorting signals required for ATG9 interaction with the AP1/2 adaptor complex and phosphorylation of ATG9 at Tyr8 by SRC kinase and at Ser14 by ULK1 for proper function during basal and starvation-induced autophagy. PMID- 28072409 TI - Alcohol-dose-dependent DNA methylation and expression in the nucleus accumbens identifies coordinated regulation of synaptic genes. AB - Alterations in DNA methylation have been associated with alcohol exposure and proposed to contribute to continued alcohol use; however, the molecular mechanisms involved remain obscure. We investigated the escalating effects of alcohol use on DNA methylation, gene expression and predicted neural effects in the nucleus accumbens of rhesus macaques that self-administered 4% alcohol for over 12 months. Using an exploratory approach to identify CpG-rich regions, followed by bisulfite sequencing, the methylation levels of 2.7 million CpGs were compared between seven low-binge drinkers and nine heavy-very heavy drinking subjects. We identified 17 significant differential methylation regions (DMRs), including 14 with methylation levels that were correlated with average daily alcohol consumption. The size of the DMRs ranged from 29 to 158 bp (mean=63.7), included 4-19 CpGs per DMR (mean=8.06) and spanned a range of average methylation values from 5 to 34%. Eight of the DMRs mapped to genes implicated in modulating synaptic plasticity. Six of the synaptic genes have not previously been linked to alcohol use. Validation studies of these eight DMRs using bisulfite amplicon sequencing and an expanded set of 30 subjects confirmed the significant alcohol dose-associated methylation of the DMRs. Expression analysis of three of the DMR associated genes, LRP5, GPR39 and JAKMIP1, revealed significant correlations between DMR methylation and whole-gene or alternative transcript expression, supporting a functional role in regulating gene expression. Together, these studies suggest that alcohol-associated synaptic remodeling may be regulated and coordinated at the level of DNA methylation. PMID- 28072410 TI - Pre-trauma Methylphenidate in rats reduces PTSD-like reactions one month later. AB - In basic research, the etiology of fear-related pathologies, such as post traumatic stress disorder (PTSD), is conceptualized using fear-conditioning protocols that pair environmental stimuli (that is, a conditioned stimulus-CS) with an aversive, unconditioned stimulus (US) to elicit an assessable conditioned fear response. Although pathophysiological models agree that regulatory dysfunctions in this associative process may instigate fear-related pathology, current opinions differ in regard to the nature of these dysfunctions. Primarily derived from studies in rodents, the prevailing perspective proposes that pathological fear-reactions develop from intensified and overly consolidated CS US associations. Alternatively, models derived from studies in humans suggest that tempospatial inaccuracies in representations of associative fear might precipitate pathology by engendering failure to differentiate present experiences and past memories of threat. To test this concept in rodents, we administered rats with cognition enhancing doses of Methylphenidate before or after fear conditioning and measured long-term alterations in their conditioned fear behaviors and PTSD-like reactions. The administration of Methylphenidate before fear-memory formation indeed reduced anxious-like responses during fear-memory retrieval one month later. An individual profiling analysis revealed that Methylphenidate onset had opposing effects on the risk for PTSD-like classification. The modulation of initial learning and formation of associative fear normalized the risk for developing PTSD-like reaction. In contrast, when the effects of Methylphenidate were exerted only over later consolidation this risk increased markedly. When examined under current psychiatric and neuropharmacologic literature, these results reveal a possible strategy of using low-dose Methylphenidate for the prevention of PTSD in high risk populations. PMID- 28072411 TI - The early growth response protein 1-miR-30a-5p-neurogenic differentiation factor 1 axis as a novel biomarker for schizophrenia diagnosis and treatment monitoring. AB - To date, diagnosis of schizophrenia is still based on clinical interviews and careful observations, which is subjective and variable, and can lead to misdiagnosis and/or delay in diagnosis. As early intervention in schizophrenia is important in improving outcomes, objective tests that can be used for schizophrenia diagnosis or treatment monitoring are thus in great need. MicroRNAs (miRNAs) negatively regulate target gene expression and their biogenesis is tightly controlled by various factors including transcription factors (TFs). Dysregulation of miRNAs in brain tissue and peripheral blood mononuclear cells (PBMNCs) from patients with schizophrenia has been well documented, but analysis of the sensitivity and specificity for potential diagnostic utility of these alternations is limited. In this study, we explored the TF-miRNA-30-target gene axis as a novel biomarker for schizophrenia diagnosis and treatment monitoring. Using bioinformatics analysis, we retrieved all TFs that control the biogenesis of miRNA 30 members as well as all target genes that are regulated by miRNA-30 members. Further, reverse transcription-quantitative PCR analysis revealed that the early growth response protein 1 (EGR1) and miR-30a-5p were remarkably downregulated, whereas neurogenic differentiation factor 1 (NEUROD1) was significantly upregulated in PBMNCs from patients in acute psychotic state. Antipsychotics treatment resulted in the elevation of EGR1 and miR-30a-5p but the reduction of NEUROD1. Receiver operating characteristic analysis showed that the EGR1-miR-30a-5p-NEUROD1 axis possessed significantly greater diagnostic value than miR-30a-5p alone. Our data suggest the EGR1-miR-30a-5p-NEUROD1 axis might serve as a promising biomarker for diagnosis and treatment monitoring for those patients in acute psychotic state. PMID- 28072412 TI - Glutamatergic and GABAergic gene sets in attention-deficit/hyperactivity disorder: association to overlapping traits in ADHD and autism. AB - Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) often co-occur. Both are highly heritable; however, it has been difficult to discover genetic risk variants. Glutamate and GABA are main excitatory and inhibitory neurotransmitters in the brain; their balance is essential for proper brain development and functioning. In this study we investigated the role of glutamate and GABA genetics in ADHD severity, autism symptom severity and inhibitory performance, based on gene set analysis, an approach to investigate multiple genetic variants simultaneously. Common variants within glutamatergic and GABAergic genes were investigated using the MAGMA software in an ADHD case only sample (n=931), in which we assessed ASD symptoms and response inhibition on a Stop task. Gene set analysis for ADHD symptom severity, divided into inattention and hyperactivity/impulsivity symptoms, autism symptom severity and inhibition were performed using principal component regression analyses. Subsequently, gene-wide association analyses were performed. The glutamate gene set showed an association with severity of hyperactivity/impulsivity (P=0.009), which was robust to correcting for genome-wide association levels. The GABA gene set showed nominally significant association with inhibition (P=0.04), but this did not survive correction for multiple comparisons. None of single gene or single variant associations was significant on their own. By analyzing multiple genetic variants within candidate gene sets together, we were able to find genetic associations supporting the involvement of excitatory and inhibitory neurotransmitter systems in ADHD and ASD symptom severity in ADHD. PMID- 28072413 TI - Decreased hippocampal translocator protein (18 kDa) expression in alcohol dependence: a [11C]PBR28 PET study. AB - Repeated withdrawal from alcohol is clinically associated with progressive cognitive impairment. Microglial activation occurring during pre-clinical models of alcohol withdrawal is associated with learning deficits. We investigated whether there was microglial activation in recently detoxified alcohol-dependent patients (ADP), using [11C]PBR28 positron emission tomography (PET), selective for the 18kDa translocator protein (TSPO) highly expressed in activated microglia and astrocytes. We investigated the relationship between microglial activation and cognitive performance. Twenty healthy control (HC) subjects (45+/-13; M:F 14:6) and nine ADP (45+/-6, M:F 9:0) were evaluated. Dynamic PET data were acquired for 90 min following an injection of 331+/-15 MBq [11C]PBR28. Regional volumes of distribution (VT) for regions of interest (ROIs) identified a priori were estimated using a two-tissue compartmental model with metabolite-corrected arterial plasma input function. ADP had an ~20% lower [11C]PBR28 VT, in the hippocampus (F(1,24) 5.694; P=0.025), but no difference in VT in other ROIs. Hippocampal [11C]PBR28 VT was positively correlated with verbal memory performance in a combined group of HC and ADP (r=0.720, P<0.001), an effect seen in HC alone (r=0.738; P=0.001) but not in ADP. We did not find evidence for increased microglial activation in ADP, as seen pre-clinically. Instead, our findings suggest lower glial density or an altered activation state with lower TSPO expression. The correlation between verbal memory and [11C]PBR28 VT, raises the possibility that abnormalities of glial function may contribute to cognitive impairment in ADP. PMID- 28072414 TI - Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder. AB - We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 * 10-8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2=0.35; BD II SNP h2=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined. PMID- 28072415 TI - Functional neuroimaging effects of recently discovered genetic risk loci for schizophrenia and polygenic risk profile in five RDoC subdomains. AB - Recently, 125 loci with genome-wide support for association with schizophrenia were identified. We investigated the impact of these variants and their accumulated genetic risk on brain activation in five neurocognitive domains of the Research Domain Criteria (working memory, reward processing, episodic memory, social cognition and emotion processing). In 578 healthy subjects we tested for association (i) of a polygenic risk profile score (RPS) including all single nucleotide polymorphisms (SNPs) reaching genome-wide significance in the recent genome-wide association studies (GWAS) meta-analysis and (ii) of all independent genome-wide significant loci separately that showed sufficient distribution of all allelic groups in our sample (105 SNPs). The RPS was nominally associated with perigenual anterior cingulate and posterior cingulate/precuneus activation during episodic memory (PFWE(ROI)=0.047) and social cognition (PFWE(ROI)=0.025), respectively. Single SNP analyses revealed that rs9607782, located near EP300, was significantly associated with amygdala recruitment during emotion processing (PFWE(ROI)=1.63 * 10-4, surpassing Bonferroni correction for the number of SNPs). Importantly, this association was replicable in an independent sample (N=150; PFWE(ROI)<0.025). Other SNP effects previously associated with imaging phenotypes were nominally significant, but did not withstand correction for the number of SNPs tested. To assess whether there was true signal within our data, we repeated single SNP analyses with 105 randomly chosen non-schizophrenia-associated variants, observing fewer significant results and lower association probabilities. Applying stringent methodological procedures, we found preliminary evidence for the notion that genetic risk for schizophrenia conferred by rs9607782 may be mediated by amygdala function. We critically evaluate the potential caveats of the methodological approaches employed and offer suggestions for future studies. PMID- 28072416 TI - Preclinical amyloid pathology biomarker positivity: effects on tau pathology and neurodegeneration. AB - Brain autopsy and biomarker studies indicate that the pathology of Alzheimer's disease (AD) is initiated at least 10-20 years before clinical symptoms. This provides a window of opportunity to initiate preventive treatment. However, this emphasizes the necessity for biomarkers that identify individuals at risk for developing AD later in life. In this cross-sectional study, originating from three epidemiologic studies in Sweden (n=1428), the objective was to examine whether amyloid pathology, as determined by low cerebrospinal fluid (CSF) concentration of the 42 amino acid form of beta-amyloid (Abeta42), is associated with biomarker evidence of other pathological changes in cognitively healthy elderly. A total of 129 patients were included and CSF levels of Abeta42, total tau, tau phosphorylated at threonine 181 (p-tau), neurogranin, VILIP-1, VEGF, FABP3, Abeta40, neurofilament light, MBP, orexin A, BDNF and YKL-40 were measured. Among these healthy elderly, 35.6% (N=46) had CSF Abeta42 levels below 530 pg ml-1. These individuals displayed significantly higher CSF concentrations of t-tau (P<0.001), p-tau (181) (P<0.001), neurogranin (P=0.009) and FABP3 (P=0.044) compared with amyloid-negative individuals. Our study indicates that there is a subpopulation among healthy older individuals who have amyloid pathology along with signs of ongoing neuronal and synaptic degeneration, as well as tangle pathology. Previous studies have demonstrated that increase in CSF tau and p-tau is a specific sign of AD progression that occurs downstream of the deposition of Abeta. On the basis of this, our data suggest that these subjects are at risk for developing AD. We also confirm the association between APOE E4 and amyloid pathology in healthy older individuals. PMID- 28072417 TI - Dopaminergic dynamics underlying sex-specific cocaine reward. AB - Although both males and females become addicted to cocaine, females transition to addiction faster and experience greater difficulties remaining abstinent. We demonstrate an oestrous cycle-dependent mechanism controlling increased cocaine reward in females. During oestrus, ventral tegmental area (VTA) dopamine neuron activity is enhanced and drives post translational modifications at the dopamine transporter (DAT) to increase the ability of cocaine to inhibit its function, an effect mediated by estradiol. Female mice conditioned to associate cocaine with contextual cues during oestrus have enhanced mesolimbic responses to these cues in the absence of drug. Using chemogenetic approaches, we increase VTA activity to mechanistically link oestrous cycle-dependent enhancement of VTA firing to enhanced cocaine affinity at DAT and subsequent reward processing. These data have implications for sexual dimorphism in addiction vulnerability and define a mechanism by which cellular activity results in protein alterations that contribute to dysfunctional learning and reward processing. PMID- 28072418 TI - Microbial community dynamics in Inferno Crater Lake, a thermally fluctuating geothermal spring. AB - Understanding how microbial communities respond and adjust to ecosystem perturbation is often difficult to interpret due to multiple and often simultaneous variations in observed conditions. In this research, we investigated the microbial community dynamics of Inferno Crater Lake, an acidic geothermal spring in New Zealand with a unique thermal cycle that varies between 30 and 80 degrees C over a period of 40-60 days. Using a combination of next-generation sequencing, geochemical analysis and quantitative PCR we found that the microbial community composition was predominantly chemolithotrophic and strongly associated with the thermal cycle. At temperatures >65 degrees C, the microbial community was dominated almost exclusively by sulphur-oxidising archaea (Sulfolobus-like spp.). By contrast, at mesophilic temperatures the community structure was more mixed, comprising both archaea and bacteria but dominated primarily by chemolithotrophic sulphur and hydrogen oxidisers. Multivariate analysis of physicochemical data confirmed that temperature was the only significant variable associated with community turnover. This research contributes to our understanding of microbial community dynamics in variable environments, using a naturally alternating system as a model and extends our limited knowledge of acidophile ecology in geothermal habitats. PMID- 28072419 TI - An acid-tolerant ammonia-oxidizing gamma-proteobacterium from soil. AB - Nitrification, the microbial oxidation of ammonia to nitrate via nitrite, occurs in a wide range of acidic soils. However, the ammonia-oxidizing bacteria (AOB) that have been isolated from soil to date are acid-sensitive. Here we report the isolation and characterization of an acid-adapted AOB from an acidic agricultural soil. The isolated AOB, strain TAO100, is classified within the Gammaproteobacteria based on phylogenetic characteristics. TAO100 can grow in the pH range of 5-7.5 and survive in highly acidic conditions until pH 2 by forming cell aggregates. Whereas all known gammaproteobacterial AOB (gamma-AOB) species, which have been isolated from marine and saline aquatic environments, are halophiles, TAO100 is not phenotypically halophilic. Thus, TAO100 represents the first soil-originated and non-halophilic gamma-AOB. The TAO100 genome is considerably smaller than those of other gamma-AOB and lacks several genes associated with salt tolerance which are unnecessary for survival in soil. The ammonia monooxygenase subunit A gene of TAO100 and its transcript are higher in abundance than those of ammonia-oxidizing archaea and betaproteobacterial AOB in the strongly acidic soil. These results indicate that TAO100 plays an important role in the nitrification of acidic soils. Based on these results, we propose TAO100 as a novel species of a new genus, Candidatus Nitrosoglobus terrae. PMID- 28072420 TI - Where less may be more: how the rare biosphere pulls ecosystems strings. AB - Rare species are increasingly recognized as crucial, yet vulnerable components of Earth's ecosystems. This is also true for microbial communities, which are typically composed of a high number of relatively rare species. Recent studies have demonstrated that rare species can have an over-proportional role in biogeochemical cycles and may be a hidden driver of microbiome function. In this review, we provide an ecological overview of the rare microbial biosphere, including causes of rarity and the impacts of rare species on ecosystem functioning. We discuss how rare species can have a preponderant role for local biodiversity and species turnover with rarity potentially bound to phylogenetically conserved features. Rare microbes may therefore be overlooked keystone species regulating the functioning of host-associated, terrestrial and aquatic environments. We conclude this review with recommendations to guide scientists interested in investigating this rapidly emerging research area. PMID- 28072421 TI - On the ecosystemic network of saliva in healthy young adults. AB - A dysbiotic state is believed to be a key factor in the onset of oral disease. Although oral diseases have been studied for decades, our understanding of oral health, the boundaries of a healthy oral ecosystem and ecological shift toward dysbiosis is still limited. Here, we present the ecobiological heterogeneity of the salivary ecosystem and relations between the salivary microbiome, salivary metabolome and host-related biochemical salivary parameters in 268 healthy adults after overnight fasting. Gender-specific differences in the microbiome and metabolome were observed and were associated with salivary pH and dietary protein intake. Our analysis grouped the individuals into five microbiome and four metabolome-based clusters that significantly related to biochemical parameters of saliva. Low salivary pH and high lysozyme activity were associated with high proportions of streptococcal phylotypes and increased membrane-lipid degradation products. Samples with high salivary pH displayed increased chitinase activity, higher abundance of Veillonella and Prevotella species and higher levels of amino acid fermentation products, suggesting proteolytic adaptation. An over specialization toward either a proteolytic or a saccharolytic ecotype may indicate a shift toward a dysbiotic state. Their prognostic value and the degree to which these ecotypes are related to increased disease risk remains to be determined. PMID- 28072422 TI - The fitness costs and trade-off shapes associated with the exclusion of nine antibiotics by OmpF porin channels. AB - The trade-off relationship between antibiotic exclusion and nutrient access across the Gram-negative outer membrane is determined by structural constraints in porin channels. The precise nutritional cost of exclusion is unknown for different antibiotics, as are the shapes of the nutrition-susceptibility trade off. Using a library of 10 engineered isogenic Escherichia coli strains with structural modifications of OmpF porin expressed at a constant level, susceptibilities were measured for nine antibiotics and the nutritional fitness costs estimated by competitions in chemostats. Different antibiotics exhibited a remarkably varied range of geometries in the nutrition-susceptibility trade-off, including convex, concave and sigmoidal trade-off shapes. The trade-off patterns predict the possibility of adaptations in contributing to antibiotic resistance; exclusion of amoxicillin or trimethoprim in ompF mutants can occur with little loss of fitness whereas kanamycin and streptomycin exclusion has a high cost. Some individual OmpF changes even allow positive correlations (trade-ups), resulting in increased fitness and decreased susceptibility specifically to cephalexin or ciprofloxacin. The surprising plasticity of the nutrition-exclusion relationship means that there are no generalisable rules that apply to decreasing susceptibility for all antibiotics. The protein changes are exquisitely specific in determining nutritional fitness and adaptive outcomes in a structural constraint trade-off. PMID- 28072423 TI - Nanotechnology-based Cryopreservation of Cell-Scaffold Constructs: A New Breakthrough to Clinical Application. AB - The developments of "off-the-shelf" cell-scaffold constructs received an increasing interest in tissue engineering and regenerative medicine. Although the direct cryopreservation of a single-cell suspension in the tube is a relative mature technology, the cryopreservation of cell-scaffold constructs remains a challenge. Nanotechnology shows tremendous potential for cryopreservation in regulating of freezing and thawing processes. For example, nanoparticles have been reported to modify the cryoprotective agent (CPA), adjust the process of cooling and warming cycles. In this review, we provide an overview of cryopreservation of cell-scaffold constructs firstly. The review further focuses on the effects of nanotechnology on cryopreservation of cell-scaffold constructs, including the nanostructure of scaffold, nanoparticles in cooling and warming process in cryopreservation. The perspectives on future challenges in this filed are also pointed out. PMID- 28072424 TI - A Theoretical and Experimental Investigation of Mechanical Damage to Rodent Sperm Generated by Microscale Ice Formation. AB - : BACKGROUND: Rodent sperm cryopreservation is of critical importance for the maintenance of lines or strains of genetically engineered mice and rats. However, rodent sperm are extremely mechanically sensitive due to their unusual morphology, and are severely damaged using current methods of cryopreservation. Those methods result in poor post thaw motility (PTM) for mouse. OBJECTIVE: To investigate the mechanism of mechanical damage introduced to rodent sperm during freezing, a micro-mechanical model was established to analyze the sperm radial and axial thermal stresses generated by microscale extracellular ice formation. MATERIALS AND METHODS: PTM of mouse sperm cryopreserved in capillaries of different radii (100, 200, 344, 526, 775um) was measured using a standard computer-assisted sperm analysis system. RESULTS: The model predicts that when one of the inner dimensions of the containers (the inner diameter of plastic straws or straw capillaries) is on the same order of magnitude of sperm length, axial stress is significantly increased. The experimental results showed that the value of PTM was decreased from 38 +/- 8 % in the larger (775um) capillaries to 0 +/- 0 % in the smaller (100 um) ones. CONCLUSION: Theoretical analysis based on the established model were experimentally validated and can be used to guide the design of novel devices to improve the efficiency of rodent sperm cryopreservation. PMID- 28072425 TI - Direct Microscale Measurement of Mouse Oocyte Membrane Permeability to Water and Ethylene Glycol at Subzero Temperatures Using Cryomicroscopy. AB - : BACKGROUND: Investigation of cell osmotic behavior at subzero temperatures is of critical importance to the optimization of cooling procedures for cryopreservation. Based on established thermodynamic models, plasma membrane permeability coefficients for water and cryoprotectant agent (CPA) (Lcpa, Pp) and their activation energies (EaLp, EaPcpa) are essential to predict the change of cell volume and composition of intracellular solutions corresponding to different cooling procedures. However, currently available methods to measure Lp at subzero temperatures suffer from technical difficulties due to ice formation and there are no generalized methods to measure Pcpa at subzero temperatures. OBJECTIVE: The present study aims to investigate cell osmotic behavior at subzero temperatures without ice formation. MATERIALS AND METHODS: In the study cells were directly injected into super-cooled CPA solutions mounted on a cryomicroscope, and the corresponding osmotic properties were measured. RESULTS: Using ethylene glycol (EG), the value of PEG for mouse (CD-1) metaphase II oocytes at 0, -5, -10 degree C was determined to be 8.451.20, 7.430.91, 6.401.10, x10-6 cm/min, respectively, and EaPEG was calculated to be 3.9 kCal/mol. Lp in the presence of EG (LpEG) at 0, -5, -10 , -15 degree C was determined to be 7.0 1.15, 4.90 1.20, 2.44 0.31, 1.200.24, x 10-2 um/min/atm, respectively, and EaLp was calculated to be 15.5 kCal/mol. CONCLUSION: Comparing these values with those previously measured at superzero temperatures, we concluded that for mouse oocytes, the Arrhenius relationship for LpEG is consistent at superzero and subzero temperatures, but the values of PEG at subzero temperatures are much lower than the extrapolated values from the Arrhenius relationship at superzero temperatures, possibly caused by membrane phase transition at low temperatures. PMID- 28072426 TI - Effect of Nanoparticles on the Survival and Development of Vitrified Porcine GV Oocytes. AB - : BACKGROUND: Some mammalian oocytes have been successfully cryopreserved by vitrification. However, the survival and developmental rate of vitrified oocytes is still low. The incorporation of nanoparticles into cryoprotectant (CPA) may improve the efficiency of vitrification by changing the properties of solutions. MATERIALS AND METHODS: The toxicity of different concentrations of hydroxy apatite (HA), silica dioxide (SO2), aluminum oxide (Al2O3) and titanium dioxide (TiO2) nanoparticles (20 nm in diameter) to oocytes was tested and the toxicity threshold value of each nanoparticle was determined. Porcine GV oocytes were vitrified in optimized nano-CPA, and effects of diameter and concentration of nanoparticles on the survival rate and developmental rate of porcine GV oocytes were compared. RESULTS: HA nanoparticles have demonstrated the least toxicity among four nanoparticles and the developmental rate of GV-stage porcine oocytes was 100% when its concentration was lower than 0.5%. By adding 0.1% HA into VS, the developmental rate of GV-stage porcine oocytes (22%) was significantly higher than other groups. The effect of vitrification in nano-CPA on oocytes was related to the concentration of HA nanoparticles rather than their size. By adding 0.05% HA nanoparticles (60nm in diameter), the developmental rate increased dramatically from 14.7% to 30.4%. CONCLUSION: Nano-cryopreservation offers a new way to improve the effect of survival and development of oocytes, but the limitation of this technology shall not be ignored. PMID- 28072427 TI - Calorimetric Studies on Thermal Properties of Nano-Cryoprotectant Solutions during Vitrification. AB - : BACKGROUND: Vitrification, the ice-free cryopreservation, develops rapidly and can become an ideal method for long-term preservation of cells and tissues. But up to now it is not practical for samples with large size because of the ultra rapid cooling rate required. It has been reported that nanoparticles improve heat conductivity of solutions. MATERIALS AND METHODS: In this study, Hydroxyapatite (HA) nanoparticles(20, 40 or 60nm)at 0.1 %, 0.5 % or 1 % (w/w) were added into glycerol solutions. Glass transition temperature and devitrification temperature of aqueous glycerol solutions with/without HA nanoparticles were measured by a differential scanning calorimeter(DSC) at a cooling rate of 150 degree C/min and a warming rate of 10 degree C/ min. RESULTS AND CONCLUSION: Glass-transition temperatures and devitrification temperatures of glycerol aqueous solutions increased after the incorporation of HA nanoparticles. In the study using slow cooling rate of 10 degree C/min and warming rate of 5 degree C/min, the fraction of unfrozen water in the 50 % (w/w) glycerol solution increases steadily with the addition of HA nanoparticles. The findings have significant implications for biomaterial cryopreservation. PMID- 28072428 TI - 3D Modelling on Biodegradable Nanoparticle-Enhanced Cryoablation of Liver Tumor Based on Real Anatomical Model. AB - BACKGROUND: Nanoparticle-enhanced freezing is of great importance for developing a conformal targeted cryoablation for liver tumor with complex shape. However, the safety and biocompatibility of nanoparticles should also be of major concerns. OBJECTIVE: This study is to investigate the enhanced cryoablation mediated by the MgO nanoparticles which are nontoxic, biodegradable, and have few side-effects on the human body. MATERIALS AND METHODS: A three-dimensional numerical model has been developed based on a real geometrical anatomical structure to characterize such nanocryosurgical freezing of liver tumor. The evolutions of temperature field and ablation volume were investigated subject to different concentrations and scopes of the loaded nanoparticles, respectively. Additionally, the results of different probe numbers were also taken into consideration. RESULTS: It was found that the lesion growth was evidently affected by the configurations of both the nanoparticles and cryoprobes. Both ablation and frozen regions were enlarged with the increase of the loading ratio and scope of MgO nanoparticles. It was worth mentioning that thermal physiological behavior of the adjacent large blood vessels also played an important role in affecting the target temperature field distribution. CONCLUSION: The present study established a feasible way for verisimilarly simulating the physiological manifestation of human liver in the process of nano freezing modality, which would provide a valuable guidance for future clinical practice of conformal nano-cryoablation on liver tumor. PMID- 28072429 TI - Integrating Micro- or Nanoscale Encapsulation Technology with Vitreous Cryopreservation: A New Strategy to Improve Biopreservation. AB - : BACKGROUND: None-uniform distributions of temperatures, limited freezing and thawing rates, and thermal stresses are three main hindering factors for successful vitreous cryopreservation of mass volume of biosamples. Micro- and nanoscale encapsulation, owning the intrinsic features to avoid those limitations introduced by the traditional approaches, has been opened up a new way for effective and high-efficiency biopreservation. NEW APPROACH: This short review article summarizes recent advances in cell encapsulation technology for biopreservation by manipulating cells and biological agents in micro- or nanoscale volume droplets and microgels, and discusses its promising applications for future vitreous cryopreservation. PMID- 28072430 TI - Measurement of Thermal Conductivity of Porcine Liver in the Temperature Range of Cryotherapy and Hyperthermia (250~315k) by A Thermal Sensor Made of A Micron Scale Enameled Copper Wire. AB - : BACKGROUND: Cryotherapy and hyperthermia are effective treatments for several diseases, especially for liver cancers. Thermal conductivity is a significant thermal property for the prediction and guidance of surgical procedure. However, the thermal conductivities of organs and tissues, especially over the temperature range of both cryotherapy and hyperthermia are scarce. OBJECTIVE: To provide comprehensive thermal conductivity of liver for both cryotherapy and hyperthermia. MATERIALS AND METHODS: A hot probe made of stain steel needle and micron-sized copper wire is used for measurement. To verify data processing, both the least square method and the Monte Carlo inversion method are used to determine the hot probe constants, respectively, with reference materials of water and 29.9 % Ca2Cl aqueous solution. Then the thermal conductivities of Hanks solution and pork liver bathed in Hanks solution are measured. RESULTS: The effective length for two methods is nearly the same, but the heat capacity of probe calibrated by the Monte Carlo inversion is temperature dependent. Fairly comprehensive thermal conductivity of porcine liver measured with these two methods in the target temperature range is verified to be similar. CONCLUSION: We provide an integrated thermal conductivity of liver for cryotherapy and hyperthermia in two methods, and make more accurate predictions possible for surgery. The least square method and the Monte Carlo inversion method have their advantages and disadvantages. The least square method is available for measurement of liquids that not prone to convection or solids in a wide temperature range, while the Monte Carlo inversion method is available for accurate and rapid measurement. PMID- 28072432 TI - Closed Vitrification System as A Platform for Cryopreservation of Tissue Engineered Constructs. AB - BACKGROUND: Cryopreservation of mesenchymal stromal cells (MSCs) and MSCs-based tissue engineered constructs (TECs) is a promising strategy for regenerative medicine. OBJECTIVE: To examine vitrification system consisting of multicomponent vitreous solution, closed type container, human adult MSCs and two-step exposure procedure as a platform for cryopreservation of MSCs-based TECs. MATERIALS AND METHODS: Vitrification properties of solutions were studied by visual analysis and calorimetry. Viability (trypan blue, MTT-test), metabolic activity (Alamar Blue assay) and adhesion of cells were assessed both after exposure with vitreous solutions and following rapid cooling-thawing in standard cryovials. RESULTS: The feasibility of the vitrification system was tested on MSCs suspensions (S-MSCs) and alginate encapsulated MSCs (AE-MSCs). The minimal concentrations of cryoprotectants, which allowed avoiding ice formation during rapid cooling and rewarming comprised 10 % for dimethylsulfoxide, 20 % for ethylene glycol, 20 % for 1.2-propanediol and 0.5 M sucrose. To achieve viability and metabolic activity rates of AE-MSCs comparable to S-MSCs after vitrification the extension of the exposure time within the same vitreous solution was sufficient. After vitrification both S-MSCs and AE-MSCs retained the capacity to osteogenic and adipogenic differentiation. CONCLUSION: Data demonstrate that this vitrification system can be used as a platform for development of effective protocols for cryopreservation of MSCs-based TECs. PMID- 28072431 TI - Expression Patterns of Three Genes Under Short and Long Term Cold Exposure in Thitarodes pui (Lepidoptera: Hepialidae), A Host of Ophiocordyceps sinensis. AB - : BACKGROUND: Thitarodes larvae are the host of the caterpillar fungus Ophiocordyceps sinensis. Low temperature is the main environmental limitation for larvae growth. OBJECTIVE: To better understand the cold adaption process in T. pui larvae, the expression patterns of trehalose-6-phosphate synthase (TpTPS), heat shock protein 70 (TpHSP70), and heat shock protein 90 (TpHSP90) were investigated upon short and long-term exposure to 0 degrees C. MATERIALS AND METHODS: The 6th instar T. pui larvae were collected in July 2013. TpTPS was firstly sequenced and expression patterns of TpTPS, TpHSP70 and TpHSP90 were investigated using quantitative PCR. RESULTS: Full-length cDNA of TpTPS was 3,012 bp, with an open reading frame of 2,472 bp and an encoding protein of 823 amino acids. TpTPS up-regulation was induced by cold exposure. TpHSP70 expression is altered by cold exposure, but remained low. TpHSP90 expression was obviously up regulated in long-term cold stimulation. CONCLUSION: All three genes (TpTPS, TpHSP70 and TpHSP90) have likely contributed to cold tolerance in T. pui larvae, TpTPS and TpHSP90 potentially being more important. PMID- 28072433 TI - Effects of Superparamagnetic Nanoparticles on Nucleation and Crystal Growth in the Vitrified VS55 During Warming. AB - : BACKGROUND:Magnetic nanoparticles (mNPs), once excited by radiofrequency (RF) energy, could heat uniformly and rapidly the vitrified biospecimens. However, there are few studies about the impact of mNPs on crystallization kinetics of vitrified samples. OBJECTIVES: The present work aims to investigate the nucleation and crystal growth in the vitrification solution VS55 with mNPs. MATERIALS AND METHODS: Ferrotec EMG308 superparamagnetic nanoparticles (10 +/- 2.5 nm in diameter) coated with an anionic surfactant was used in this study with Fe2+ concentration around 10 mg/ml. The thermal range and the kinetics of nucleation and crystal growth are conducted by DSC and cryomicroscope through different thermal treatments. RESULTS: The fusion heat of VS55+ mNPs is lower than that of VS55 around the rubbery region (-110 to -82 degree C), which suggests the suppression of ice nuclei formation at this temperature range by mNPs. Upon slow cooling especially, much more nuclei in vitrified VS55 forms than that in vitrified VS55+mNPs. The activation energy Ea of VS55 is lower than that of VS55+mNPs (41.6 kJ/mol vs 46.2 kJ/mol) during devitrification. The presence of mNPs helps to form more stable glass. And these results are consistent with the observations by cryomicroscope. CONCLUSION: The presence of mNPs suppresses ice nuclei formation, especially at slow cooling conditions, and stabilize the cryoprotective solution. The findings can assist the design of magnetic nanoparticles with functional surface coating. PMID- 28072434 TI - [Referral with images--equitable and cost-effective care]. AB - This study evaluates the use of teledermatology at Norrland University Hospital in Northern Sweden between 2009 and 2014. In total, there were 27 198 incoming referrals. Of these, 1504 had photo attachments, and could be answered directly without a face-to-face appointment. Most of these referrals (73%) came from health care providers more than 100 kilometres away and 71% were answered within a week. Patients received care sooner and saved both time and money by less travelling. Teledermatology lead to less delay to a face-to-face appointment for patients where teledermatology was not an option. PMID- 28072435 TI - ? PMID- 28072436 TI - [Metabolic surgery is an effective treatment for type 2 diabetes--but several questions remains to be answered]. PMID- 28072437 TI - ? PMID- 28072438 TI - ["Nobody misses the coccyx". Coccygectomy is recommended]. PMID- 28072440 TI - ? PMID- 28072439 TI - ? PMID- 28072441 TI - ? PMID- 28072442 TI - ? PMID- 28072443 TI - [Value-based care is well worth an evaluation]. PMID- 28072444 TI - Predator effects on reef fish settlement depend on predator origin and recruit density. AB - During major life-history transitions, animals often experience high mortality rates due to predation, making predator avoidance particularly advantageous during these times. There is mixed evidence from a limited number of studies, however, regarding how predator presence influences settlement of coral-reef fishes and it is unknown how other potentially mediating factors, including predator origin (native vs. nonnative) or interactions among conspecific recruits, mediate the non-consumptive effects of predators on reef fish settlement. During a field experiment in the Caribbean, approximately 52% fewer mahogany snapper (Lutjanus mahogoni) recruited to reefs with a native predator (graysby grouper, Cephalopholis cruentata) than to predator-free control reefs and reefs with an invasive predator (red lionfish, Pterois volitans) regardless of predator diet. These results suggest that snapper recruits do not recognize nonnative lionfish as a threat. However, these effects depended on the density of conspecific recruits, with evidence that competition may limit the response of snapper to even native predators at the highest recruit densities. In contrast, there was no effect of predator presence or conspecific density on the recruitment of bicolor damselfish (Stegastes partitus). These context-dependent responses of coral-reef fishes to predators during settlement may influence individual survival and shape subsequent population and community dynamics. PMID- 28072445 TI - A Joint Analytic Method for Estimating Aquitard Hydraulic Parameters. AB - The vertical hydraulic conductivity (Kv ), elastic (Sske ), and inelastic (Sskv ) skeletal specific storage of aquitards are three of the most critical parameters in land subsidence investigations. Two new analytic methods are proposed to estimate the three parameters. The first analytic method is based on a new concept of delay time ratio for estimating Kv and Sske of an aquitard subject to long-term stable, cyclic hydraulic head changes at boundaries. The second analytic method estimates the Sskv of the aquitard subject to linearly declining hydraulic heads at boundaries. Both methods are based on analytical solutions for flow within the aquitard, and they are jointly employed to obtain the three parameter estimates. This joint analytic method is applied to estimate the Kv , Sske , and Sskv of a 34.54-m thick aquitard for which the deformation progress has been recorded by an extensometer located in Shanghai, China. The estimated results are then calibrated by PEST (Doherty 2005), a parameter estimation code coupled with a one-dimensional aquitard-drainage model. The Kv and Sske estimated by the joint analytic method are quite close to those estimated via inverse modeling and performed much better in simulating elastic deformation than the estimates obtained from the stress-strain diagram method of Ye and Xue (2005). The newly proposed joint analytic method is an effective tool that provides reasonable initial values for calibrating land subsidence models. PMID- 28072446 TI - Randomized clinical trial of preoperative dexamethasone on postoperative nausea and vomiting after laparoscopy for suspected appendicitis. AB - BACKGROUND: Few studies have investigated the effects of preoperative dexamethasone in acute surgical patients. This study examined the effects of 8 mg dexamethasone administered intravenously 30 min before surgery for suspected acute appendicitis. METHODS: A multicentre, parallel-group, double-blind, placebo controlled study was conducted at two university hospitals in Denmark. Adults undergoing laparoscopic surgery for suspected appendicitis were eligible for inclusion. Participants, healthcare staff and investigators were blinded until all data analysis had been done. The primary outcome was the incidence of postoperative nausea and vomiting (PONV) during the first postoperative day. Secondary outcomes were pain, fatigue, sleep, opioid consumption, use of antiemetics, quality of recovery and duration of convalescence. Analysis was done according to the intention-to-treat principle. RESULTS: A total of 120 patients were enrolled; 57 patients in the dexamethasone group and 59 in the placebo group were eligible for primary analysis. In the dexamethasone group, 47 (95 per cent c.i. 35 to 60) per cent of patients experienced PONV compared with 63 (50 to 74) per cent) in the placebo group. The absolute risk reduction in PONV was 15 (-3 to 33) per cent in favour of the dexamethasone group (P = 0.098). Patients in the dexamethasone group had less pain at rest (difference in score on visual analogue scale (VAS) 9 (95 per cent c.i. 1 to 17) mm; P = 0.024), were less fatigued (difference in VAS score 7 (0 to 14) mm; P = 0.038), used fewer opioids (absolute risk reduction 17 (2 to 33) per cent; P = 0.033) and had better quality of recovery (difference in QoR-15 score 13 (4 to 22); P = 0.006) during the first postoperative day. There was no difference in postoperative complications (P = 0.595). CONCLUSION: Preoperative dexamethasone did not reduce PONV by the target level of 50 per cent. Registration number: NCT02415335 ( http://www.clinicaltrials.gov). PMID- 28072447 TI - Randomized clinical trial comparing standard diet with perioperative oral immunonutrition in total gastrectomy for gastric cancer. AB - BACKGROUND: Total gastrectomy for gastric cancer is associated with excessive weight loss and decreased calorie intake. Nutritional support using eicosapentaenoic acid modulates immune function and limits catabolism in patients with advanced cancer, but its impact in the perioperative period is unclear. METHODS: This was a randomized phase III clinical trial of addition of eicosapentaenoic acid-rich nutrition to a standard diet in patients having total gastrectomy for gastric cancer. Patients were randomized to either a standard diet or standard diet with oral supplementation of an eicosapentaenoic acid (ProSure(r)), comprising 600 kcal with 2.2 g eicosapentaenoic acid, for 7 days before and 21 days after surgery. The primary endpoint was percentage bodyweight loss at 1 and 3 months after surgery. RESULTS: Of 127 eligible patients, 126 were randomized; 124 patients (61 standard diet, 63 supplemented diet) were analysed for safety and 123 (60 standard diet, 63 supplemented diet) for efficacy. Across both groups, all but three patients underwent total gastrectomy with Roux-en-Y reconstruction. Background factors were well balanced between the groups. Median compliance with the supplement in the immunonutrition group was 100 per cent before and 54 per cent after surgery. The surgical morbidity rate was 13 per cent in patients who received a standard diet and 14 per cent among those with a supplemented diet. Median bodyweight loss at 1 month after gastrectomy was 8.7 per cent without dietary supplementation and 8.5 per cent with eicosapentaenoic acid enrichment (P = 0.818, adjusted P = 1.000). Similarly, there was no difference between groups in percentage bodyweight loss at 3 months (P = 0.529, adjusted P = 1.000). CONCLUSION: Immunonutrition based on an eicosapentaenoic acid-enriched oral diet did not reduce bodyweight loss after total gastrectomy for gastric cancer compared with a standard diet. Registration number: UMIN000006380 ( http://www.umin.ac.jp/). PMID- 28072449 TI - A survival guide to Landsat preprocessing. AB - Landsat data are increasingly used for ecological monitoring and research. These data often require preprocessing prior to analysis to account for sensor, solar, atmospheric, and topographic effects. However, ecologists using these data are faced with a literature containing inconsistent terminology, outdated methods, and a vast number of approaches with contradictory recommendations. These issues can, at best, make determining the correct preprocessing workflow a difficult and time-consuming task and, at worst, lead to erroneous results. We address these problems by providing a concise overview of the Landsat missions and sensors and by clarifying frequently conflated terms and methods. Preprocessing steps commonly applied to Landsat data are differentiated and explained, including georeferencing and co-registration, conversion to radiance, solar correction, atmospheric correction, topographic correction, and relative correction. We then synthesize this information by presenting workflows and a decision tree for determining the appropriate level of imagery preprocessing given an ecological research question, while emphasizing the need to tailor each workflow to the study site and question at hand. We recommend a parsimonious approach to Landsat preprocessing that avoids unnecessary steps and recommend approaches and data products that are well tested, easily available, and sufficiently documented. Our focus is specific to ecological applications of Landsat data, yet many of the concepts and recommendations discussed are also appropriate for other disciplines and remote sensing platforms. PMID- 28072450 TI - Spatial heterogeneity can resolve the nitrogen paradox of tropical forests. AB - Many tropical forests are characterized by large losses of plant-available forms of nitrogen (N), indicating that they are N rich, and by an abundance of plants capable of symbiotic N fixation. These N-fixing plants can fix enough N to drive N richness. However, biological N fixation (BNF) is more expensive than using plant-available N, so sustained BNF in N-rich soils appears to be a paradox. Here, we use spatially explicit ecosystem models to analyze the conditions under which spatial heterogeneity can induce simultaneous BNF and loss of plant available N (hereafter, we call this combination "N-rich BNF"). Spatial movement of litter to neighboring plants' rooting zones can maintain N-rich BNF under a variety of conditions. For example, when N-fixers have higher N demand than non fixers, N-fixers export N-rich litter to non-fixers, inducing large losses of plant-available N from the ecosystem, and receive N-poor litter from non-fixers, inducing BNF. BNF and N loss fluxes increase in proportion to the ratio of N fixer litter N:P to non-fixer litter N:P, and also in proportion to the fraction of litter transferred out of a tree's rooting zone. Stoichiometric variability augments N-rich BNF, as does increasing the fraction of the landscape occupied by N-fixers, at least when they are rare. On the contrary, greater root overlap between neighbors and clumping of N-fixers diminish N-rich BNF. Finally, we examined how spatial litter transfer interacts with another mechanism that can sustain N-rich BNF, incomplete down-regulation of BNF. Spatial transfer and incomplete down-regulation can both sustain N-rich BNF, but they are compensatory rather than additive. These mechanisms can be distinguished by examining where N losses occur. Incomplete down-regulation of BNF leads to greater N loss under N fixing trees, whereas spatial litter transfer leads to greater N loss under non fixing trees. Along with time lags in regulating BNF, these results comprise a series of hypotheses that could help understand the N paradox of tropical forests. PMID- 28072451 TI - The impact of salience and visual working memory on the monitoring and control of saccadic behavior: An eye-tracking and EEG study. AB - In a concurrent eye-tracking and EEG study, we investigated the impact of salience on the monitoring and control of eye movement behavior and the role of visual working memory (VWM) capacity in mediating this effect. Participants made eye movements to a unique line-segment target embedded in a search display also containing a unique distractor. Target and distractor salience was manipulated by varying degree of orientation offset from a homogenous background. VWM capacity was measured using a change-detection task. Results showed greater likelihood of incorrect saccades when the distractor was relatively more salient than when the target was salient. Misdirected saccades to salient distractors were strongly represented in the error-monitoring system by rapid and robust error-related negativity (ERN), which predicted a significant adjustment of oculomotor behavior. Misdirected saccades to less-salient distractors, while arguably representing larger errors, were not as well detected or utilized by the error/performance-monitoring system. This system was instead better engaged in tasks requiring greater cognitive control and by individuals with higher VWM capacity. Our findings show that relative salience of task-relevant and task irrelevant stimuli can define situations where an increase in cognitive control is necessary, with individual differences in VWM capacity explaining significant variance in the degree of monitoring and control of goal-directed eye movement behavior. The present study supports a conflict-monitoring interpretation of the ERN, whereby the level of competition between different responses, and the stimuli that define these responses, was more important in the generation of an enhanced ERN than the error commission itself. PMID- 28072448 TI - Identification of altered brain metabolites associated with TNAP activity in a mouse model of hypophosphatasia using untargeted NMR-based metabolomics analysis. AB - Tissue non-specific alkaline phosphatase (TNAP) is a key player of bone mineralization and TNAP gene (ALPL) mutations in human are responsible for hypophosphatasia (HPP), a rare heritable disease affecting the mineralization of bones and teeth. Moreover, TNAP is also expressed by brain cells and the severe forms of HPP are associated with neurological disorders, including epilepsy and brain morphological anomalies. However, TNAP's role in the nervous system remains poorly understood. To investigate its neuronal functions, we aimed to identify without any a priori the metabolites regulated by TNAP in the nervous tissue. For this purpose we used 1 H- and 31 P NMR to analyze the brain metabolome of Alpl (Akp2) mice null for TNAP function, a well-described model of infantile HPP. Among 39 metabolites identified in brain extracts of 1-week-old animals, eight displayed significantly different concentration in Akp2-/- compared to Akp2+/+ and Akp2+/- mice: cystathionine, adenosine, GABA, methionine, histidine, 3 methylhistidine, N-acetylaspartate (NAA), and N-acetyl-aspartyl-glutamate, with cystathionine and adenosine levels displaying the strongest alteration. These metabolites identify several biochemical processes that directly or indirectly involve TNAP function, in particular through the regulation of ecto-nucleotide levels and of pyridoxal phosphate-dependent enzymes. Some of these metabolites are involved in neurotransmission (GABA, adenosine), in myelin synthesis (NAA, NAAG), and in the methionine cycle and transsulfuration pathway (cystathionine, methionine). Their disturbances may contribute to the neurodevelopmental and neurological phenotype of HPP. PMID- 28072452 TI - What our eyes tell us about feelings: Tracking pupillary responses during emotion regulation processes. AB - Emotion regulation is essential for adaptive behavior and mental health. Strategies applied to alter emotions are known to differ in their impact on psychological and physiological aspects of the emotional response. However, emotion regulation outcome has primarily been assessed via self-report, and studies comparing regulation strategies with regard to their peripheral physiological mechanisms are limited in number. In the present study, we therefore aimed to investigate the effects of different emotion regulation strategies on pupil dilation, skin conductance responses, and subjective emotional responses. Thirty healthy females were presented with negative and neutral pictures and asked to maintain or up- and downregulate their upcoming emotional responses through reappraisal or distraction. Pupil dilation and skin conductance responses were significantly enhanced when viewing negative relative to neutral pictures. For the pupil, this emotional arousal effect manifested specifically late during the pupillary response. In accordance with subjective ratings, increasing negative emotions through reappraisal led to the most prominent pupil size enlargements, whereas no consistent effect for downregulation was found. In contrast, early peak dilations were enhanced in all emotion regulation conditions independent of strategy. Skin conductance responses were not further modulated by emotion regulation. These results indicate that pupil diameter is modulated by emotional arousal, but is initially related to the extent of mental effort required to regulate automatic emotional responses. Our data thus provide first evidence that the pupillary response might comprise two distinct temporal components reflecting cognitive emotion regulation effort on the one hand and emotion regulation success on the other hand. PMID- 28072453 TI - Posttreatment Low-Risk Drinking as a Predictor of Future Drinking and Problem Outcomes Among Individuals with Alcohol Use Disorders: A 9-Year Follow-Up. AB - BACKGROUND: Treatment for alcohol use disorders (AUDs) has traditionally been abstinence oriented, but new research and regulatory guidelines suggest that low risk drinking may also be an acceptable treatment outcome. However, little is known about long-term outcomes for patients who become low-risk drinkers posttreatment. This study explores a posttreatment low-risk drinking outcome as a predictor of future drinking and psychosocial outcomes over 9 years. METHODS: Study participants were adults with AUDs at treatment entry who received follow up interviews 6 months posttreatment intake (N = 1,061) in 2 large randomized studies conducted at Kaiser Permanente Northern California, a large private, nonprofit, integrated health system. Six-month drinking status was defined as abstinent, low-risk (nonabstinent, no 5+ drinking days), or heavy drinking (1 or more days of 5+ drinks). Using logistic regression models, we explored the relationship between past 30-day drinking status at 6 months and odds of being abstinent or a low-risk drinker (compared to heavy drinking), and positive Addiction Severity Index psychosocial outcomes over 9 years (9-year follow-up rate of 73%). RESULTS: Abstainers and low-risk drinkers at 6 months had higher odds of recent abstinence/low-risk drinking over 9 years than heavy drinkers; abstainers had better drinking outcomes than low-risk drinkers. Additionally, among those with interview data, 95% of abstainers and 94% of low-risk drinkers at 6 months were abstinent/low-risk drinkers at 9 years; surprisingly, 89% of heavy drinkers at 6 months were also abstinent/low-risk drinkers although still significantly fewer than the other groups. Abstainers and low-risk drinkers at 6 months had better psychiatric outcomes, and abstainers had better family/social outcomes than heavy drinkers; medical outcomes did not differ. Low-risk drinkers and abstainers showed no reliable differences across psychosocial measures. CONCLUSIONS: The findings suggest that a low-risk drinking outcome may be reasonable over the long-term for some alcohol-dependent individuals receiving addiction treatment. PMID- 28072454 TI - Non-neuronal acetylcholine involved in reproduction in mammals and honeybees. AB - Bacteria and archaea synthesize acetylcholine (ACh). Thus, it can be postulated that ACh was created by nature roughly three billion years ago. Therefore, the wide expression of ACh in nature (i.e., in bacteria, archaea, unicellular organisms, plants, fungi, non-vertebrates and vertebrates and in the abundance of non-neuronal cells of mammals) is not surprising. The term non-neuronal ACh and non-neuronal cholinergic system have been introduced to describe the auto- and paracrine, that is, local regulatory actions of ACh in cells not innervated by neuronal cholinergic fibers and to communicate among themselves. In this way non neuronal ACh binds to the nicotinic or muscarinic receptors expressed on these local and migrating cells and modulates basic cells functions such as proliferation, differentiation, migration and the transport of ions and water. The present article is focused to the effects of non-neuronal ACh linked to reproduction; data on the expression and function of the non-neuronal cholinergic system in the following topics are summarized: (i) Sperm, granulosa cells, oocytes; (ii) Auxiliary systems (ovary, oviduct, placenta); (iii) Embryonic stem cells as first step for reproduction of a new individual after fertilization; (iv) Larval food as an example of reproduction in insects (honeybees) and adverse effects of the neonicotinoids, a class of world-wide applied insecticides. The review article will show that non-neuronal ACh is substantially involved in the regulation of reproduction in mammals and also non-mammals like insects (honeybees). There is a need to learn more about this biological role of ACh. In particular, we have to consider that insecticides like the neonicotinoids, but also carbamates and organophosphorus pesticides, interfere with the non-neuronal cholinergic system thus compromising for example the breeding of honeybees. But it is possible that other species may also be adversely affected as well, a mechanism which may contribute to the observed decline in biodiversity. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms. PMID- 28072455 TI - Src and phospho-FAK kinases are activated by allopregnanolone promoting Schwann cell motility, morphology and myelination. AB - Schwann cells' (SCs) development and maturation require coordinate and complementary activation of several signals and intracellular pathways. Among factors controlling these processes, the signalling intermediates Src tyrosine kinase and focal adhesion kinase (FAK) are relevant for SCs', participating in regulation of their adhesion, motility and migration. Recently, the progesterone metabolite allopregnanolone (ALLO) was proved to be synthesized by SCs, whereas it acts autocrinally on SCs motility and proliferation, which are crucial processes for nerve development, maturation and regeneration. Herein, we investigate the hypothesis that the molecular mechanisms behind the ALLO's action on SCs involve the signalling intermediates Src and FAK. We first demonstrated that ALLO 10-6 M regulates SCs morphology, motility and myelination, also increasing the internode distance in the in vitro myelination model of neuron/SCs co-culture. ALLO's actions were mediated by the modulation of Src/FAK pathway, since they were counteracted by PP2 10-5 M, a selective inhibitor of Src kinase. Then, we proved that Src/FAK activation in SCs involves GABA-A dependent mechanisms and actin re-arrangements. In conclusion, our findings are the first to corroborate the importance of the neuroactive steroid ALLO in regulating SCs development and maturation via the Src and phospho-FAK signalling activation. Cover Image for this issue: doi: 10.1111/jnc.13795. PMID- 28072456 TI - Systemic inflammatory markers and outcome in patients with locally advanced adenocarcinoma of the oesophagus and gastro-oesophageal junction. AB - BACKGROUND: Raised levels of systemic inflammatory markers are associated with poor survival in patients with cancer. The aim of this study was to assess the prognostic value of markers of systemic inflammation in patients with adenocarcinoma of the oesophagus or gastro-oesophageal junction. METHODS: Data from a consecutive series of patients undergoing transthoracic oesophagectomy following neoadjuvant therapy at a single centre were analysed. Fibrinogen, albumin, C-reactive protein, leucocyte differential and platelet counts were measured before surgery. The upper quartile (75th percentile) was used as a cut off for dichotomization. Multivariable regression analysis was performed to identify independent prognostic factors. RESULTS: A series of 199 patients underwent transthoracic oesophagectomy following neoadjuvant therapy. Univariable analysis indicated that reduced median survival was associated with a raised platelet : lymphocyte ratio (158 or above; 25.6 versus 44.4 months for patients with a normal ratio, P = 0.038) and increased fibrinogen levels (4.9 g/l or above; 22.8 versus 59.9 months for those with a normal level, P = 0.005). On multivariable analysis a combination of one or more markers of systemic inflammation was associated with poorer overall survival (hazard ratio 2.12, 95 per cent c.i. 1.20 to 3.74; P = 0.010). CONCLUSION: Preoperative markers of systemic inflammation predict poor outcome in patients undergoing curative treatment for locally advanced oesophageal and gastro-oesophageal adenocarcinoma. PMID- 28072457 TI - Effects of Binge-Like Ethanol Exposure During Adolescence on the Febrile Response in Rats. AB - BACKGROUND: Ethanol (EtOH) exposure during different phases of life may increase the risk of infections and cause alterations in the central nervous system. The present study investigated the effects of binge-like EtOH exposure in adolescent rats on the febrile response that was induced by lipopolysaccharide (LPS) and interleukin-1beta (IL-1beta). METHODS: Male rats were exposed to EtOH from postnatal days 25 to 38 in a binge-like pattern. Fever was induced by LPS (5 and 50 MUg/kg, intraperitoneally) and evaluated on postnatal days 51 and 63, or by IL beta (3 ng) and evaluated on postnatal day 51. Hematological parameters, the status of peritoneal macrophages, and plasma and cerebrospinal IL-1beta levels were also evaluated on postnatal day 51. RESULTS: EtOH exposure during adolescence did not alter normal body temperature. However, a significant reduction in the febrile response that was induced by LPS at both doses was observed on postnatal day 51. However, no changes in the febrile response were observed on postnatal day 63 in EtOH-exposed animals. The febrile response that was induced by intracerebroventricular IL-1beta also significantly decreased in animals that received binge-like EtOH exposure during adolescence. Acute oral treatment with EtOH 24 h prior to LPS administration did not alter the febrile response that was induced by LPS. Binge-like EtOH exposure during adolescence did not alter hematological parameters or the number or viability of peritoneal macrophages. Binge-like EtOH exposure did not alter plasma IL-1beta levels but reduced the cerebrospinal fluid levels of this cytokine. CONCLUSIONS: These results suggest that binge-like EtOH exposure during adolescence causes changes in the central nervous system that can impair the febrile response that can be observed after the cessation of EtOH exposure. These changes were reversible and appeared to involve the LPS/IL-1beta system. PMID- 28072458 TI - Liana effects on biomass dynamics strengthen during secondary forest succession. AB - Secondary forests are important carbon sinks, but their biomass dynamics vary markedly within and across landscapes. The biotic and abiotic drivers of this variation are still not well understood. We tested the effects of soil resource availability and competition by lianas on the biomass dynamics of young secondary tropical forests in Panama and assessed the extent to which liana effects were mediated by soil resource availability. Over a five-year period, growth, mortality, and recruitment of woody plants of >=1 cm diameter were monitored in 84 plots in 3-30-year-old secondary forests across the Agua Salud site in central Panama. Biomass dynamics and the effects of lianas and soil resources were examined using (generalized) linear mixed-effect models and a model averaging approach. There was strong spatial and temporal variation in liana biomass within and across the plots. The relative biomass of lianas had a strong negative effect on overall tree growth, growth of understory trees decreased with soil fertility and dry season soil water content, and the effect of lianas on tree mortality varied with soil fertility. Tree recruitment was not associated with any of the predictor variables. Our model indicates that tree biomass growth across our landscape was reduced with 22% due to competition with lianas, and that the effect of lianas increased during succession, from 19% after five years to 32% after 30 years. The projected liana-induced growth reduction after 60 years was 47%, which was consistent with data from a nearby site. Our study shows that the observed liana proliferation across tropical forests may reduce the sequestration and storage of carbon in young secondary forests, with important implications for the carbon balance of tropical forest landscapes and consequently for global climate change. Our study highlights the need to incorporate lianas and soil variables in research on the biomass dynamics of secondary forest across tropical landscapes, and the need for well-replicated longitudinal studies to cover landscape-level variability in the relevant abiotic and biotic components. PMID- 28072459 TI - Client Retrospective Accounts of Corrective Experiences in Motivational Interviewing Integrated With Cognitive Behavioral Therapy for Generalized Anxiety Disorder. AB - A corrective experience (CE) is one "in which a person comes to understand or experience affectively an event or relationship in a different and unexpected way" (Castonguay & Hill, 2012, p. 5). CEs disconfirm clients' expectations based on past problematic experiences, and can be emotional, relational, behavioral, and/or cognitive. This qualitative study explored corrective shifts among recovered participants (N = 8) who had received motivational interviewing (MI) integrated with cognitive behavioral therapy (CBT) in a randomized controlled trial comparing CBT alone to MI-CBT for generalized anxiety disorder (Westra, Constantino, & Antony, 2016). We administered a posttherapy interview querying their experience of, and explanations for, any shifts in therapy. Grounded theory analysis yielded three core themes: in command of the worry train, experiencing myself in new ways in therapy, and oriented toward change. Findings are discussed in terms of MI theory, and clinical implications for therapists are provided. PMID- 28072460 TI - Psychosocial interventions for recurrent abdominal pain in childhood. AB - BACKGROUND: This review supersedes the original Cochrane review first published in 2008 (Huertas-Ceballos 2008).Between 4% and 25% of school-aged children complain of recurrent abdominal pain (RAP) severe enough to interfere with their daily activities. No organic cause for this pain can be found on physical examination or investigation for the majority of such children. Although many children are managed by reassurance and simple measures, a large range of psychosocial interventions involving cognitive and behavioural components have been recommended. OBJECTIVES: To determine the effectiveness of psychosocial interventions for reducing pain in school-aged children with RAP. SEARCH METHODS: In June 2016 we searched CENTRAL, MEDLINE, Embase, eight other databases, and two trials registers. We also searched the references of identified studies and relevant reviews. SELECTION CRITERIA: Randomised controlled trials comparing psychosocial therapies with usual care, active control, or wait-list control for children and adolescents (aged 5 to 18 years) with RAP or an abdominal pain related functional gastrointestinal disorder defined by the Rome III criteria were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Five review authors independently selected studies, assessed them for risk of bias, and extracted relevant data. We also assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: This review includes 18 randomised controlled trials (14 new to this version), reported in 26 papers, involving 928 children and adolescents with RAP between the ages of 6 and 18 years. The interventions were classified into four types of psychosocial therapy: cognitive behavioural therapy (CBT), hypnotherapy (including guided imagery), yoga, and written self-disclosure. The studies were carried out in the USA, Australia, Canada, the Netherlands, Germany, and Brazil. The majority of the studies were small and short term; only two studies included more than 100 participants, and only five studies had follow-up assessments beyond six months. Small sample sizes and the degree of assessed risk of performance and detection bias in many studies led to the overall quality of the evidence being rated as low to very low for all outcomes.For CBT compared to control, we found evidence of treatment success postintervention (odds ratio (OR) 5.67, 95% confidence interval (CI) 1.18 to 27.32; Z = 2.16; P = 0.03; 4 studies; 175 children; very low-quality evidence), but no evidence of treatment success at medium-term follow-up (OR 3.08, 95% CI 0.93 to 10.16; Z = 1.85; P = 0.06; 3 studies; 139 children; low-quality evidence) or long-term follow-up (OR 1.29, 95% CI 0.50 to 3.33; Z = 0.53; P = 0.60; 2 studies; 120 children; low-quality evidence). We found no evidence of effects of intervention on pain intensity scores measured postintervention (standardised mean difference (SMD) -0.33, 95% CI -0.74 to 0.08; 7 studies; 405 children; low-quality evidence), or at medium term follow-up (SMD -0.32, 95% CI -0.85 to 0.20; 4 studies; 301 children; low quality evidence).For hypnotherapy (including studies of guided imagery) compared to control, we found evidence of greater treatment success postintervention (OR 6.78, 95% CI 2.41 to 19.07; Z = 3.63; P = 0.0003; 4 studies; 146 children; low quality evidence) as well as reductions in pain intensity (SMD -1.01, 95% CI 1.41 to -0.61; Z = 4.97; P < 0.00001; 4 studies; 146 children; low-quality evidence) and pain frequency (SMD -1.28, 95% CI -1.84 to -0.72; Z = 4.48; P < 0.00001; 4 studies; 146 children; low-quality evidence). The only study of long term effect reported continued benefit of hypnotherapy compared to usual care after five years, with 68% reporting treatment success compared to 20% of controls (P = 0.005).For yoga therapy compared to control, we found no evidence of effectiveness on pain intensity reduction postintervention (SMD -0.31, 95% CI 0.67 to 0.05; Z = 1.69; P = 0.09; 3 studies; 122 children; low-quality evidence).The single study of written self-disclosure therapy reported no benefit for pain.There was no evidence of effect from the pooled analyses for any type of intervention on the secondary outcomes of school performance, social or psychological functioning, and quality of daily life.There were no adverse effects for any of the interventions reported. AUTHORS' CONCLUSIONS: The data from trials to date provide some evidence for beneficial effects of CBT and hypnotherapy in reducing pain in the short term in children and adolescents presenting with RAP. There was no evidence for the effectiveness of yoga therapy or written self-disclosure therapy. There were insufficient data to explore effects of treatment by RAP subtype.Higher-quality, longer-duration trials are needed to fully investigate the effectiveness of psychosocial interventions. Identifying the active components of the interventions and establishing whether benefits are sustained in the long term are areas of priority. Future research studies would benefit from employing active control groups to help minimise potential bias from wait-list control designs and to help account for therapist and intervention time. PMID- 28072461 TI - Adverse and beneficial effects in Chinese hamster lung fibroblast cells following radiofrequency exposure. AB - In this study, the effect of radiofrequency (RF) exposure to 1950 MHz, Universal Mobile Telecommunication System signal, was investigated in Chinese hamster lung fibroblast cell line (V79). Genotoxic and cytotoxic effects of 20-h exposure at specific absorption rate (SAR) values from 0.15 W/kg to 1.25 W/kg were measured by means of cytokinesis-block micronucleus (MN) assay. Exposure was carried out blinded under strictly controlled conditions of dosimetry and temperature. The effect of RF exposure alone at four SAR values was tested, that is, 0.15, 0.3, 0.6, and 1.25 W/kg. A statistically significant increase in MN frequency was found in cultures exposed to 0.15 and 0.3 W/kg (P < 0.05) compared to sham exposed ones, in the absence of cytotoxicity. SAR values of 0.6 and 1.25 W/kg did not exert any effect. Moreover, to evaluate the ability of RF to exert protective effects with respect to a chemical mutagen, cell cultures were also pre-exposed for 20 h at 0.3 or 1.25 W/kg, and then treated with 500 ng/ml of mitomycin-C (MMC). A significant reduction in the frequency of MN was detected in cultures pre-exposed to 1.25 W/kg compared to cultures treated with MMC alone (P < 0.05), indicating induction of adaptive response. Such a decrease was not induced by pre exposure at 0.3 W/kg SAR. Taken together, our results indicated that V79 is a sensitive cell model to evidence either adverse or beneficial effects of RF exposure, depending on experimental conditions applied. Bioelectromagnetics. 38:245-254, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28072462 TI - Reliability of the electrocortical response to gains and losses in the doors task. AB - The ability to differentiate between rewards and losses is critical for motivated action, and aberrant reward and loss processing has been associated with psychopathology. The reward positivity (RewP) and feedback negativity (FN) are ERPs elicited by monetary gains and losses, respectively, and are promising individual difference measures. However, few studies have reported on the psychometric properties of the RewP and FN-crucial characteristics necessary for valid individual difference measures. The current study examined the internal consistency and 1-week test-retest reliability of the RewP and FN as elicited by the doors task among 59 young adults. The RewP, FN, and their difference score (DeltaRewP) all showed significant correlations between Time 1 and Time 2. The RewP and FN also achieved acceptable internal consistency at both time points within 20 trials using both Cronbach's alpha and a generalizability theory derived dependability measure. Internal consistency for DeltaRewP was notably weaker at both time points, which is expected from two highly intercorrelated constituent scores. In conclusion, the RewP and FN have strong psychometric properties in a healthy adult sample. Future research is needed to assess the psychometric properties of these ERPs in different age cohorts and in clinical populations. PMID- 28072463 TI - Pilot study of mobile phone technology in allergic rhinitis in European countries: the MASK-rhinitis study. AB - BACKGROUND: The use of Apps running on smartphones and tablets profoundly affects medicine. The MASK-rhinitis (MACVIA-ARIA Sentinel NetworK for allergic rhinitis) App (Allergy Diary) assesses allergic rhinitis symptoms, disease control and impact on patients' lives. It is freely available in 20 countries (iOS and Android platforms). AIMS: To assess in a pilot study whether (i) Allergy Diary users were able to properly provide baseline characteristics (ii) simple phenotypic characteristics based upon data captured by the Allergy Diary could be identified and (iii) information gathered by this study could suggest novel research questions. METHODS: The Allergy Diary users were classified into six groups according to the baseline data that they entered into the App: (i) asymptomatic; (ii) nasal symptoms excluding rhinorrhea; (iii) rhinorrhea; (iv) rhinorrhea plus 1-2 nasal/ocular symptoms; (v) rhinorrhea plus >=3 nasal/ocular symptoms; and (vi) rhinorrhea plus all nasal/ocular symptoms. RESULTS: By 1 June 2016, 3260 users had registered with the Allergy Diary and 2710 had completed the baseline questionnaire. Troublesome symptoms were found mainly in the users with the most symptoms. Around 50% of users with troublesome rhinitis and/or ocular symptoms suffered work impairment. Sleep was impaired by troublesome symptoms and nasal obstruction. CONCLUSIONS: This is the first App (iOS and Android) to have tested for allergic rhinitis and conjunctivitis. A simple questionnaire administered by cell phones enables the identification of phenotypic differences between a priori defined rhinitis groups. The results suggest novel concepts and research questions in allergic rhinitis that may not be identified using classical methods. PMID- 28072464 TI - Genistein and tyrphostin AG556 decrease ultra-rapidly activating delayed rectifier K+ current of human atria by inhibiting EGF receptor tyrosine kinase. AB - BACKGROUND AND PURPOSE: The ultra-rapidly activating delayed rectifier K+ current IKur (encoded by Kv 1.5 or KCNA5) plays an important role in human atrial repolarization. The present study investigates the regulation of this current by protein tyrosine kinases (PTKs). EXPERIMENTAL APPROACH: Whole-cell patch voltage clamp technique and immunoprecipitation and Western blotting analysis were used to investigate whether the PTK inhibitors genistein, tyrphostin AG556 (AG556) and PP2 regulate human atrial IKur and hKv1.5 channels stably expressed in HEK 293 cells. KEY RESULTS: Human atrial IKur was decreased by genistein (a broad spectrum PTK inhibitor) and AG556 (a highly selective EGFR TK inhibitor) in a concentration-dependent manner. Inhibition of IKur induced by 30 MUM genistein or 10 MUM AG556 was significantly reversed by 1 mM orthovanadate (a protein tyrosine phosphatase inhibitor). Similar results were observed in HEK 293 cells stably expressing hKv 1.5 channels. On the other hand, the Src family kinase inhibitor PP2 (1 MUM) slightly enhanced IKur and hKv 1.5 current, and the current increase was also reversed by orthovanadate. Immunoprecipitation and Western blotting analysis showed that genistein, AG556, and PP2 decreased tyrosine phosphorylation of hKv 1.5 channels and that the decrease was countered by orthovanadate. CONCLUSION AND IMPLICATIONS: The PTK inhibitors genistein and AG556 decrease human atrial IKur and cloned hKv 1.5 channels by inhibiting EGFR TK, whereas the Src kinase inhibitor PP2 increases IKur and hKv 1.5 current. These results imply that EGFR TK and the soluble Src kinases may have opposite effects on human atrial IKur . PMID- 28072465 TI - Splicing regulation and dysregulation of cholinergic genes expressed at the neuromuscular junction. AB - We humans have evolved by acquiring diversity of alternative RNA metabolisms including alternative means of splicing and transcribing non-coding genes, and not by acquiring new coding genes. Tissue-specific and developmental stage specific alternative RNA splicing is achieved by tightly regulated spatiotemporal regulation of expressions and activations of RNA-binding proteins that recognize their cognate splicing cis-elements on nascent RNA transcripts. Genes expressed at the neuromuscular junction are also alternatively spliced. In addition, germline mutations provoke aberrant splicing by compromising binding of RNA binding proteins, and cause congenital myasthenic syndromes (CMS). We present physiological splicing mechanisms of genes for agrin (AGRN), acetylcholinesterase (ACHE), MuSK (MUSK), acetylcholine receptor (AChR) alpha1 subunit (CHRNA1), and collagen Q (COLQ) in human, and their aberration in diseases. Splicing isoforms of AChET , AChEH , and AChER are generated by hnRNP H/F. Skipping of MUSK exon 10 makes a Wnt-insensitive MuSK isoform, which is unique to human. Skipping of exon 10 is achieved by coordinated binding of hnRNP C, YB-1, and hnRNP L to exon 10. Exon P3A of CHRNA1 is alternatively included to generate a non-functional AChR alpha1 subunit in human. Molecular dissection of splicing mutations in patients with CMS reveals that exon P3A is alternatively skipped by hnRNP H, polypyrimidine tract-binding protein 1, and hnRNP L. Similarly, analysis of an exonic mutation in COLQ exon 16 in a CMS patient discloses that constitutive splicing of exon 16 requires binding of serine arginine-rich splicing factor 1. Intronic and exonic splicing mutations in CMS enable us to dissect molecular mechanisms underlying alternative and constitutive splicing of genes expressed at the neuromuscular junction. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms. PMID- 28072467 TI - A Cross-Lagged Panel Study of Dissociation and Posttraumatic Stress in a Treatment-Seeking Sample of Survivors of Childhood Sexual Abuse. AB - OBJECTIVE: The current prospective study assessed the temporal relations between dissociation and posttraumatic stress (PTS) in a sample of treatment-seeking female survivors of childhood sexual abuse. PTS refers to symptoms associated with posttraumatic stress disorder (PTSD) in the absence of a clinical diagnosis of PTSD. METHOD: Initial assessment was on average 23 years after the onset of abuse (N = 405), and participants were followed-up after 6 months (N = 245) and 12 months (N = 119). RESULTS: Findings indicated that dissociative experiences and PTS were highly correlated within each wave of data collection. Cross-lagged panel analysis revealed that at each assessment period dissociative symptoms and PTS levels, respectively, were primarily explained by scores on the same variable at the previous assessment period. Although further reciprocal relations between dissociation and PTS were evident, these associations were relatively weak in magnitude. CONCLUSION: Current results provide important insights into the temporal relations between dissociative symptoms and PTS. The high correlations between dissociative experiences and PTS several years after trauma exposure have important clinical implications that may affect their treatment and trauma recovery. PMID- 28072466 TI - Chronic pain and impaired glial glutamate transporter function in lupus-prone mice are ameliorated by blocking macrophage colony-stimulating factor-1 receptors. AB - Systemic lupus erythematosus (SLE) is a multi-organ disease of unknown etiology in which the normal immune responses are directed against the body's own healthy tissues. Patients with SLE often suffer from chronic pain. Currently, no animal studies have been reported about the mechanisms underlying pain in SLE. In this study, the development of chronic pain in MRL lupus-prone (MRL/lpr) mice, a well established lupus mouse model, was characterized for the first time. We found that female MRL/lpr mice developed thermal hyperalgesia at the age of 13 weeks, and mechanical allodynia at the age of 16 weeks. MRL/lpr mice with chronic pain had activation of microglia and astrocytes, over-expression of macrophage colony stimulating factor-1 (CSF-1) and interleukin-1 beta (IL-1beta), as well as suppression of glial glutamate transport function in the spinal cord. Intrathecal injection of either the CSF-1 blocker or IL-1 inhibitor attenuated thermal hyperalgesia in MRL/lpr mice. We provide evidence that the suppressed activity of glial glutamate transporters in the spinal dorsal horn in MRL/lpr mice is caused by activation of the CSF-1 and IL-1beta signaling pathways. Our findings suggest that targeting the CSF-1 and IL-1beta signaling pathways or the glial glutamate transporter in the spinal cord is an effective approach for the management of chronic pain caused by SLE. PMID- 28072469 TI - Burnout mediates the association between depression and patient safety perceptions: a cross-sectional study in hospital nurses. AB - AIMS: The aim of this study was to investigate the relationships between depressive symptoms, burnout and perceptions of patient safety. A mediation model was proposed whereby the association between symptoms of depression and patient safety perceptions was mediated by burnout. BACKGROUND: There is growing interest in the relationships between depressive symptoms and burnout in healthcare staff and the safety of patient care. Depressive symptoms are higher in healthcare staff than the general population and overlap conceptually with burnout. However, minimal research has investigated these variables in nurses. Given the conceptual overlap between depressive symptoms and burnout, there is also a need for an explanatory model outlining the relative contributions of these factors to patient safety. DESIGN: A cross-sectional questionnaire was distributed at three acute NHS Trusts. METHOD: Three-hundred and twenty-three hospital nursing staff completed measures of depressive symptoms, burnout and patient safety perceptions (including measures at the level of the individual and the work area/unit) between December 2015 - February 2016. RESULTS: When tested in separate analyses, depressive symptoms and burnout facets were each associated with both patient safety measures. Furthermore, the proposed mediation model was supported, with associations between depressive symptoms and patient safety perceptions fully mediated by burnout. CONCLUSION: These results suggest that symptoms of depression and burnout in hospital nurses may have implications for patient safety. However, interventions to improve patient safety may be best targeted at improving burnout in particular, with burnout interventions known to be most effective when focused at both the individual and the organisational level. PMID- 28072468 TI - A multi-dimensional functional principal components analysis of EEG data. AB - The electroencephalography (EEG) data created in event-related potential (ERP) experiments have a complex high-dimensional structure. Each stimulus presentation, or trial, generates an ERP waveform which is an instance of functional data. The experiments are made up of sequences of multiple trials, resulting in longitudinal functional data and moreover, responses are recorded at multiple electrodes on the scalp, adding an electrode dimension. Traditional EEG analyses involve multiple simplifications of this structure to increase the signal-to-noise ratio, effectively collapsing the functional and longitudinal components by identifying key features of the ERPs and averaging them across trials. Motivated by an implicit learning paradigm used in autism research in which the functional, longitudinal, and electrode components all have critical interpretations, we propose a multidimensional functional principal components analysis (MD-FPCA) technique which does not collapse any of the dimensions of the ERP data. The proposed decomposition is based on separation of the total variation into subject and subunit level variation which are further decomposed in a two-stage functional principal components analysis. The proposed methodology is shown to be useful for modeling longitudinal trends in the ERP functions, leading to novel insights into the learning patterns of children with Autism Spectrum Disorder (ASD) and their typically developing peers as well as comparisons between the two groups. Finite sample properties of MD-FPCA are further studied via extensive simulations. PMID- 28072470 TI - Sonographic Dynamic Description of the Laryngeal Tract: Definition of Quantitative Measures to Characterize Vocal Fold Motion and Estimation of Their Normal Values. AB - Vocal fold motion was analyzed during free breathing using two-dimensional dynamic ultrasound imaging. Two cadavers were first analyzed to define easily identifiable landmarks. Motion of the laryngeal tract was then analyzed in an axial plane. Left and right arytenoids and thyroid cartilage were defined on images corresponding to abduction and adduction of the laryngeal tract. Associated area measurements were established for 50 healthy subjects. All area indices were significantly larger during abduction than adduction. Symmetry of motion was established by comparing each hemi-larynx, and mobility fractions were defined. Normal values of laryngeal motion during free breathing were thus established. PMID- 28072471 TI - The Negative Chronotropic Effect in Rat Heart Stimulated by Ultrasonic Pulses: Role of Sex and Age. AB - OBJECTIVES: The goal of this study is to investigate the role of sex and age of the negative chronotropic effect after exposure of 3.5-MHz pulsed ultrasound (US) to the rat heart. METHODS: Forty F344 rats were exposed transthoracically to ultrasonic pulses at a duty factor of approximately 1.0% at 2.0-MPa peak rarefactional pressure amplitude. The transthoracic ultrasonic bursts were delivered consecutively in five 10-s intervals, that is, 10 s of 6-Hz pulse repetition frequency (PRF), 10 s of 5-Hz PRF, 10 s of 4-Hz PRF, 10 s of 5-Hz PRF, and 10 s of 6-Hz, for a 50-s total exposure duration. The rats were divided into 8 groups (n = 5 each): US young male, control young male, US young female, control young female, US old male, control old male, US old female, and control old female. RESULTS: Two-way ANOVA for repeated measures was used to compare heart rate, cardiac output, arterial pressure, and other hemodynamic values (baseline) before and after US stimulation. Sex versus age versus US interaction was detected for heart rate. Cardiac output showed an age effect, and ejection fraction showed age and US effects. The arterial pressure showed a sex effect. A negative chronotropic effect (~30% decrease in heart rate) was observed for young female rats. An hypothesis is that the US effect is weight (menopause) dependent, because the young (premenopausal) female rats weighed approximately 40 to 60% less than other groups of rats. CONCLUSIONS: It is likely that the ovarian hormones are responsible for different US-induced cardiac bioeffects in different ages and sexes. PMID- 28072472 TI - Sonographic Findings of Chondral Avulsion Fractures of the Lateral Ankle Ligaments in Children. AB - In this series, we aimed to describe the sonographic findings of chondral avulsion fractures that develop concomitant with lateral ankle ligament injury in children. We performed stress sonography during a manual anterior drawer stress procedure of the ankle in 9 skeletally immature patients who had recently had a lateral ankle sprain. Echo videos were obtained through the course of treatment, and all videos were reviewed. We elucidated the common features of chondral avulsion fractures of the lateral ankle ligaments in the children. The features of avulsion fractures on conventional sonography included absence of a fracture with hyperechoic spots (sonographic occult fracture type), cortical discontinuity with hyperechoic spots (cortical disruption fracture type), fracture line in the cortical bone (double-line fracture type), and a step-off deformity of the cortical bone with cartilage (displaced fracture type). In contrast, the features of chondral fractures on stress sonography included abnormal motion of the chondral lesions and mobility/fluidity of hyperechoic spots along the chondral fracture site. The presence of hyperechoic spots around the chondral lesion is an important sonographic sign for diagnosing chondral fractures concomitant with ankle lateral ligament injury. Hence, we believe that stress sonography should be considered for the detection of chondral fractures concomitant with radiographically negative ankle lateral ligament injuries in skeletally immature patients with lateral ankle pain and ankle sprains, if hyperechoic spots are present in the cartilage of the distal fibula. PMID- 28072473 TI - Pharmacokinetics of obinutuzumab in Chinese patients with B-cell lymphomas. AB - AIM: The Phase Ib GERSHWIN study (NCT01680991) assessed the pharmacokinetic (PK) profile of obinutuzumab following multiple intravenous (i.v.) doses to Chinese patients with B-cell lymphomas, and compared findings with previous obinutuzumab PK studies in mainly Caucasian (non-Chinese) patients. METHODS: GERSHWIN was an open-label, single-arm intervention study. Patients aged >18 years with CD20+ relapsed/refractory chronic lymphocytic leukaemia (CLL), diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) were enrolled from four centres in China. The treatment period was 24 weeks; patients received obinutuzumab 1000 mg i.v. on Days (D)1, 8 and 15 of Cycle (C)1 (CLL patients: first infusion split over 2 days) and on D1 of C2-8 (all cycles: 21 days). PK parameters were estimated using non-compartmental analysis (NCA), and a population PK analysis was used to determine whether observed GERSHWIN PK data were in accordance with previous obinutuzumab PK studies in non-Chinese patients. RESULTS: The PK analysis population included 48 patients: 28 patients completed all treatment cycles. NCA showed a similar PK profile in Chinese patients with FL, DLBCL and CLL. Steady-state concentrations of obinutuzumab appeared to be reached at the start of C2 irrespective of histology. There was no apparent relationship between body weight and systemic exposure. Most PK profiles observed in GERSHWIN lay within the 90% prediction interval of simulated profiles. CONCLUSIONS: Obinutuzumab exposure was comparable in CLL, DLBCL and FL patients. NCA and population PK analysis indicate that PK characteristics of Chinese patients with B-cell lymphomas are similar to those in non-Chinese patients. PMID- 28072474 TI - Abused women's experiences of a primary care identification and referral intervention: a case study analysis. AB - AIMS: The aim of this study was to report the findings of a qualitative case study that investigated abused women's experiences of an identification and referral intervention and to discuss the implications for nurses, specifically those working in primary and community care. BACKGROUND: Domestic violence and abuse is a significant public health issue globally but it is a hidden problem that is under-reported. In the UK, Identification and Referral to Improve Safety is a primary care-based intervention that has been found to increase referral rates of abused women to support and safety services. This paper reports on the findings of an evaluation study of two sites in England. DESIGN: Qualitative study with a case study design. METHODS: In line with case study design, the entire evaluation study employed multiple data collection methods. We report on the qualitative interviews with women referred through the programme. The aim was to elicit their experiences of the three aspects of the intervention: identification; referral; safety. Data collection took place March 2016. FINDINGS: Ten women took part. Eight had exited the abusive relationship but two remained with the partner who had perpetrated the abuse. Women were overwhelmingly positive about the programme and irrespective of whether they had remained or exited the relationship all reported perceptions of increased safety and improved health. CONCLUSION: Nurses have an important role to play in identifying domestic violence and abuse and in referral and safety planning. As part of a portfolio of domestic violence and abuse interventions, those that empower women to take control of their safety (such as Identification and Referral to Improve Safety) are important. PMID- 28072476 TI - Aberrant Right Subclavian Artery: Correlation Between Fetal and Neonatal Abnormalities and Abnormal Genetic Screening or Testing. AB - OBJECTIVES: To determine whether fetuses with an isolated aberrant course of the right subclavian artery (ARSA) have increased risk for chromosomal abnormalities, including trisomy 21 or 22q11 deletion. METHODS: We performed a retrospective chart review of all fetuses with antenatally diagnosed ARSA. Data were collected from fetal anatomic surveys, fetal echocardiograms, noninvasive trisomy 21 screening programs, invasive genetic studies, and neonatal records. RESULTS: Seventy-nine fetuses with ARSA were identified at 20.3 +/- 3.8 weeks' gestation. Forty-eight fetuses underwent chromosomal evaluation. Of those, seven had trisomy 21. Four other fetuses had unusual karyotype abnormalities. All fetuses with genetic anomalies had additional aberrant ultrasound findings. There were three spontaneous fetal deaths (trisomy 21-2 and Wolf-Hirshhorn-1). Nine pregnancies were terminated because of abnormalities and one died as a result of hypoplastic left heart syndrome. No neonate was found or suspected to have 22q11.2 deletion. The ARSA was isolated in 43 fetuses; all had unremarkable neonatal outcomes, and none were readmitted within 6 months after discharge. CONCLUSIONS: As an apparently isolated finding, ARSA is benign and not associated with trisomy 21 or 22q11.2 deletion. The finding of ARSA, however, warrants a detailed fetal ultrasound. All fetuses with ARSA and genetic anomalies had additional ultrasound findings. PMID- 28072475 TI - Safety of Sulfur Hexafluoride Microbubbles in Sonography of Abdominal and Superficial Organs: Retrospective Analysis of 30,222 Cases. AB - OBJECTIVES: The purpose of this study was to investigate the safety of the sulfur hexafluoride microbubble contrast agent SonoVue (Bracco SpA, Milan, Italy) and to implement precautions with the intent of further improving the safety of this contrast agent. METHODS: A total of 30,222 patients undergoing contrast-enhanced sonography of abdominal and superficial organs in our hospital from January 2005 to December 2014 were retrospectively investigated. SonoVue was used as the ultrasound contrast agent. The symptoms and treatments of adverse reactions occurring during the contrast-enhanced sonographic examinations were reviewed and analyzed. RESULTS: No patient died as a result of any adverse reaction. Six patients (0.020%) had adverse reactions of varying degrees, including 2 patients (0.007%) who had signs of early anaphylactic shock (chest tightness, palpitations, sweating, and rapid and weak pulse, followed by cyanosis, a disappearing pulse, and a drop in blood pressure) that improved after active rescue. The remaining 4 patients developed the following: redness and a rash on the arm above the injection site, nasal bleeding and nausea, nausea and vomiting, and back pain with numbness of the lips and limbs. Symptoms in these 4 patients self-resolved after a period of rest. CONCLUSIONS: Contrast-enhanced sonography with sulfur hexafluoride microbubbles had good clinical safety, but rare adverse reactions were observed. A comprehensive emergency plan and rescue measures for adverse reactions should be prepared and made available to minimize the occurrence of negative clinical outcomes. PMID- 28072477 TI - Recurrent NAB2-STAT6 gene fusions and oestrogen receptor-alpha expression in pulmonary adenofibromas. AB - AIMS: Pulmonary adenofibromas are rare benign fibroepithelial tumours of the lung with unknown histogenesis and an indolent clinical behaviour. Their stroma resembles that of solitary fibrous tumours, whereas the glands are composed of respiratory epithelium organized in a phyllodes-like architecture. Differentiation of pulmonary adenofibromas from other more aggressive intrathoracic tumours is clinically relevant. However, their biology is unknown. Here, we sought to characterize pulmonary adenofibromas at a clinicopathological level and to define whether they could be underpinned by a highly recurrent somatic genetic alteration akin to tumours with similar morphology. METHODS AND RESULTS: Seven pulmonary adenofibromas were subjected to immunohistochemical analysis for thyroid transcription factor 1 (TTF1), napsin A, cytokeratin 7, E cadherin, CD99, CD34, CD31, STAT6, oestrogen receptor (ER), progesterone receptor, androgen receptor, bcl-2, and vimentin, as well as electron microscopy and capillary sequencing on microdissected samples to evaluate the presence of NAB2-STAT6 fusion genes and MED12 exon 2 mutations in their discrete components. A control group comprising pulmonary solitary fibrous tumours, pulmonary hamartomas and breast fibroadenomas was also analysed. We confirmed that the stromal elements of pulmonary adenofibromas pertain to the fibroblastic lineage, and show ER overexpression in 71% of cases, whereas the epithelium consists of TTF1-positive, E-cadherin positive bronchiolar elements. A highly recurrent NAB2 STAT6 fusion variant (exon 4-exon 2) was detected in the stroma but not in the epithelium. No MED12 mutations were identified. CONCLUSIONS: Here, we demonstrate that pulmonary adenofibromas are neoplastic lesions harbouring the molecular hallmark of solitary fibrous tumours. PMID- 28072478 TI - The difficulties experienced by nurses and healthcare staff involved in the process of breaking bad news. AB - AIMS: The aim of this study was to explore the difficulties experienced by nurses and healthcare professionals when engaging in the process of breaking bad news. BACKGROUND: The challenges faced by staff when breaking bad news have previously been researched in relation to particular settings or participants. This study involved staff from diverse settings and roles to develop broader insights into the range of difficulties experienced in clinical practice. DESIGN: The study used a descriptive survey design involving self-reported written accounts and framework analysis. METHODS: Data were collected using a structured questionnaire containing a free text section that asked participants to describe a difficult experience they had encountered when involved in the process of breaking bad news. Data were collected from healthcare staff from hospital, community, hospice and care home settings attending training days on breaking bad news between April 2011 and April 2014. FINDINGS: Multiple inter-related factors presented challenges to staff engaging in activities associated with breaking bad news. Traditional subjects such as diagnostic and treatment information were described but additional topics were identified such as the impact of illness and care at the end of life. A descriptive framework was developed that summarizes the factors that contribute to creating difficult experiences for staff when breaking bad news. CONCLUSION: The framework provides insights into the scope of the challenges faced by staff when they engage in the process of breaking bad news. This provides the foundation for developing interventions to support staff that more closely matches their experiences in clinical practice. PMID- 28072479 TI - Reference Values for Sonographically Estimated Fetal Weight in Twin Gestations Stratified by Chorionicity: A Single Center Study. AB - OBJECTIVES: To determine reference values for sonography-based estimated fetal weight (EFW) in twin gestations in one single tertiary medical center in the United States. METHODS: A retrospective longitudinal analysis of EFW evaluations of fetuses of twin gestations between November 2006 and June 2016. Fetuses with major congenital anomalies or chromosomal abnormalities were excluded. Estimated fetal weight was calculated using the Hadlock 1985 formula. Linear mixed models were used to allow for multiple but inconsistent observations among individuals, and to account for intertwin differences as well as for gender. Reference values were constructed using a best-fit regression model for estimation of mean and standard deviation at each gestational age after normalization of variables. Chorionicity-specific curves were constructed. RESULTS: A total of 5515 ultrasound examinations were performed in 2115 twin pregnancies between 24 and 38 weeks of gestation (2.6 +/- 4.0 scans/pregnancy). Values corresponding to the 5th, 10th, 50th, 90th, and 95th percentiles for EFW are presented for every gestational age. At 28, 32, and 36 weeks, values were as follows: 855, 1109, and 1363 g; 1351, 1732, and 2294 g; and 1363, 2112, and 2881 g for the 10th, 50th, and 90th percentiles, respectively. Chorionicity-specific curves are presented for comparison with previously published references. CONCLUSIONS: Reference values for sonographic-based fetal growth are presented for clinical and research use. PMID- 28072480 TI - Free Fatty Acids Induce Autophagy and LOX-1 Upregulation in Cultured Aortic Vascular Smooth Muscle Cells. AB - Elevation of free fatty acids (FFAs) is known to affect microvascular function and contribute to obesity-associated insulin resistance, hypertension, and microangiopathy. Proliferative and synthetic vascular smooth muscle cells (VSMCs) increase intimal thickness and destabilize atheromatous plaques. This study aimed to investigate whether saturated palmitic acid (PA) and monounsaturated oleic acid (OA) modulate autophagy activity, cell proliferation, and vascular tissue remodeling in an aortic VSMC cell line. Exposure to PA and OA suppressed growth of VSMCs without apoptotic induction, but enhanced autophagy flux with elevation of Beclin-1, Atg5, and LC3I/II. Cotreatment with autophagy inhibitors potentiated the FFA-suppressed VSMC growth and showed differential actions of PA and OA in autophagy flux retardation. Both FFAs upregulated lectin-like oxidized low density lipoprotein receptor 1 (LOX-1) but only OA increased LDL uptake by VSMCs. Mechanistically, FFAs induced hyperphosphorylation of Akt, ERK1/2, JNK1/2, and p38 MAPK. All pathways, except OA-activated PI3K/Akt cascade, were involved in the LOX-1 upregulation, whereas blockade of PI3K/Akt and MEK/ERK cascades ameliorated the FFA-induced growth suppression on VSMCs. Moreover, both FFAs exhibited tissue remodeling effect through increasing MMP-2 and MMP-9 expression and their gelatinolytic activities, whereas high-dose OA significantly suppressed collagen type I expression. Conversely, siRNA-mediated LOX-1 knockdown significantly attenuated the OA-induced tissue remodeling effects in VSMCs. In conclusion, OA and PA enhance autophagy flux, suppress aortic VSMC proliferation, and exhibit vascular remodeling effect, thereby leading to the loss of VSMCs and interstitial ECM in vascular walls and eventually the instability of atheromatous plaques. J. Cell. Biochem. 118: 1249-1261, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28072481 TI - Can Contrast-Enhanced Sonography Detect Bowel Wall Fibrosis in Mixed Inflammatory and Fibrotic Crohn Disease Lesions in an Animal Model? AB - OBJECTIVES: To determine whether contrast-enhanced sonographic quantitative perfusion parameters can detect bowel wall fibrosis in the setting of mixed inflammatory and fibrotic lesions in a Crohn disease animal model. METHODS: This study was approved by the institutional Committee on the Use and Care of Animals. Multiple (range, 1-5) 2,4,6-trinitrobenzenesulfonic acid-ethanol enemas were used to create intestinal inflammatory lesions with variable fibrosis in female Lewis rats. Low-mechanical index contrast-enhanced sonography was performed 3 days after the final enema using a 0.2-mL bolus of sulfur hexafluoride microbubbles injected through a tail vein. Contrast-enhanced sonographic data were analyzed with software that converts video data into echo-power (linearized) data. Colorectal lesions were scored for histopathologic inflammation and fibrosis; bowel wall collagen was quantified by Western blotting. The Spearman correlation was used to assess associations between contrast-enhanced sonographic quantitative parameters and bowel wall collagen; the Kruskal-Wallis test was used to compare continuous results between histopathologic groups. RESULTS: Thirty-one animals were included in our analysis. Animals were placed into 3 histopathologic cohorts: (1) severe bowel wall inflammation/minimal or no fibrosis (n = 11); (2) severe bowel wall inflammation/moderate fibrosis (n = 9); and (3) severe bowel wall inflammation/severe fibrosis (n = 11). Western blotting showed a significant difference in bowel wall collagen between histopathologic cohorts (P = .0001). There was no correlation between any contrast-enhanced sonographic quantitative parameter and bowel wall collagen (P > .05). There was no difference between histopathologic cohorts for any contrast-enhanced sonographic quantitative parameter (P > .05). CONCLUSIONS: Contrast-enhanced sonographic quantitative perfusion parameters failed to effectively detect bowel wall fibrosis in the setting of superimposed inflammation in a Crohn disease animal model. PMID- 28072482 TI - A systematic review of evidence relating to clinical supervision for nurses, midwives and allied health professionals. AB - AIM: The aim of this study was to systematically review evidence relating to clinical supervision for nurses, midwives and allied health professionals. BACKGROUND: Since 1902 statutory supervision has been a requirement for UK midwives, but this is due to change. Evidence relating to clinical supervision for nurses and allied health professions could inform a new model of clinical supervision for midwives. DESIGN: A systematic review with a contingent design, comprising a broad map of research relating to clinical supervision and two focussed syntheses answering specific review questions. DATA SOURCES: Electronic databases were searched from 2005 - September 2015, limited to English-language peer-reviewed publications. REVIEW METHODS: Systematic reviews evaluating the effectiveness of clinical supervision were included in Synthesis 1. Primary research studies including a description of a clinical supervision intervention were included in Synthesis 2. Quality of reviews were judged using a risk of bias tool and review results summarized in tables. Data describing the key components of clinical supervision interventions were extracted from studies included in Synthesis 2, categorized using a reporting framework and a narrative account provided. RESULTS: Ten reviews were included in Synthesis 1; these demonstrated an absence of convincing empirical evidence and lack of agreement over the nature of clinical supervision. Nineteen primary studies were included in Synthesis 2; these highlighted a lack of consistency and large variations between delivered interventions. CONCLUSION: Despite insufficient evidence to directly inform the selection and implementation of a framework, the limited available evidence can inform the design of a new model of clinical supervision for UK-based midwives. PMID- 28072483 TI - Optimization of Ultrasound Transducer Positioning for Endotracheal Tube Placement Confirmation in Cadaveric Model. AB - OBJECTIVES: Sonography has been suggested as a possible means of endotracheal tube (ETT) placement confirmation. However, optimum ultrasound transducer placement has not been established. Using a cadaveric model, ETT placement by the sonographic appearance at the thyroid cartilage, cricoid cartilage, and suprasternal notch in the upper airway was assessed to determine which ultrasound transducer placement offered the most optimal images for ETT confirmation in the airway. METHODS: One provider intubated 5 cadavers, with the ultrasound transducer at each of the 3 levels, for a total of 30 intubations per specimen, while 2 providers assigned a visual score of 1 (subtle), 2 (clear), or 3 (pronounced) to each sonogram of the ETT in the airway. RESULTS: At the level of the thyroid cartilage, tracheal intubation was detected at a rate of 40%, with a median visualization scale of 1 (subtle movement). At the level of the cricoid cartilage, the visualization scale improved to a median of 2 (clear movement), with a 70% intubation detection rate. At the level of the suprasternal notch, 100% of the tracheal intubations were visualized on sonography, with a median score of 3 (pronounced movement). CONCLUSIONS: In comparing sonographic detection of ETT placement at 3 levels of the upper airway in a cadaveric model, our results clearly indicate that visualization was superior at the level of the suprasternal notch, with 100% of intubations detected with the best visualization scores. PMID- 28072484 TI - Letter to the editor regarding neutrophil-to-lymphocyte ratio in laryngeal squamous cell carcinoma. PMID- 28072486 TI - Radiopacity of Composite Luting Cements Using a Digital Technique. AB - PURPOSE: The aim of this in vitro study was to evaluate the radiopacity of 20 common dental composite luting materials using a digital technique. MATERIALS AND METHODS: A 1-mm-thick specimen of each material with a human tooth slice and aluminium step wedge were tested using digital radiographs under four combinations of exposure and voltage. The radiopacity in pixels was determined using computer software. The equivalent thickness of aluminium for each material was then calculated based on the calibration curve. RESULTS: All tested materials except one had higher radiopacity than dentin (p > alpha; alpha = 0.01), and 80% of the materials had radiopacity above enamel value (p > alpha; alpha = 0.01). Moreover, 40% of tested materials had radiopacity of three times above the minimal International Organization for Standardization (ISO) values for composite luting cements. At all exposure values, the highest radiopacity was for Solocem and Multilink groups of materials, at three to six times above dentin radiopacity. Only Variolink Veneer showed radiopacity below dentin and enamel. CONCLUSIONS: Composite luting materials should have radiopacity above ISO values or greater than the dentin or enamel equivalent. The highest radiopacity values were for the Solocem and Multilink family composite luting cements. Clinicians should choose materials with high radiopacity values, and manufacturers should be aware of the radiopacity values when introducing materials on the market. PMID- 28072485 TI - Water-Soluble Polymer Nanoparticles Constructed by Three-Component Self-Assembly: An Efficient Theranostic Agent for Phosphorescent Imaging and Photodynamic Therapy. AB - Water-soluble polymer nanoparticles NP-1 and NP-2 were prepared by using a three component self-assembly of an iridium complex, poly(4-vinyl pyridine-b-ethylene oxide) (P4VP-b-PEO), and methane sulfonic acid (MSA). Due to the unique metal ligand charge-transfer transition property and the heavy-atom effect of the iridium atom, NP-1 and NP-2 showed bright phosphorescence and generated the singlet oxygen (1 O2 ) species effectively under visible-light irradiation (lambda>400 nm) with a power density of 300 mW cm-2 . NP-2, an example of the polymer nanoparticles, showed minimal cytotoxic activity in the dark. Laser confocal fluorescence and flow-cytometry microscopy experiments demonstrated that NP-2 could be taken up by a model cancer-cell line of 4T1 cells, which could be used as a phosphorescent probe for cell imaging by preferentially staining the cytoplasm. After 6 hours of incubation with NP-2 (100 MUg mL-1 ), the cell viability of 4T1 cells decreased to approximately 10 % upon visible-light irradiation (lambda>400 nm, 300 mW cm-2 ) only for 10 minutes as a result of the generation of the 1 O2 species, thus indicating a proof of concept for effective photodynamic therapy for cancer cells. PMID- 28072487 TI - The Structure of Linkers Affects the DNA Binding Properties of Tethered Dinuclear Ruthenium(II) Metallo-Intercalators. AB - With the long-term aim of enhancing the binding properties of dinuclear RuII based DNA light-switch complexes, a series of eight structurally related mono- and dinuclear systems are reported in which the linker of the bridging ligand has been modulated. These tethered systems have been designed to explore issues of steric demand at the binding site and the thermodynamic cost of entropy loss upon binding. Detailed spectroscopic and isothermal titration calorimetry (ITC) studies on the new complexes reveal that one of the linkers produces a dinuclear system that binds to duplex DNA with an affinity (Kb >107 m-1 ) that is higher than its corresponding monometallic complex and is the highest affinity for a non threading bis-intercalating metal complex. These studies confirm that the tether has a major effect on the binding properties of dinuclear complexes containing intercalating units and establishes key design rules for the construction of dinuclear complexes with enhanced DNA binding characteristics. PMID- 28072488 TI - The influence of memory, sample size effects, and filter paper material on online laser-based plant and soil water isotope measurements. AB - RATIONALE: The recent development of isotope ratio infrared spectroscopy (IRIS) was quickly followed by the addition of online extraction and analysis systems, making it faster and easier to measure soil and plant water isotopes. However, memory and sample size effects limit the efficiency and accuracy of these new setups. In response, this study presents a scheme dedicated to estimating and eliminating these two effects. METHODS: Memory effect was determined by injecting two standard waters alternately. Each standard was injected nine times in a row and analyzed using induction module cavity ring-down spectroscopy (IM-CRDS). Memory coefficients were calculated using a new "multistage jump" algorithm. Sample size effects were evaluated by injecting water volumes ranging from 1 MUL to 6 MUL. Finally, the influence of cellulose filter paper on the isotopic measurements, the memory, and the sample size effect was evaluated by comparing it with glass filter paper. RESULTS: Memory effects were detected for both delta18 O and delta2 H values, with the latter being stronger. Isotopic differences between replicates of the same plant or soil sample showed a clear decrease after memory correction. A small water volume effect was found only when the injected water volume was larger than 3 MUL. However, while the correction method performed well for laboratory-made samples, it did not for field samples, due to the heterogeneity of the isotopic composition of the samples. Stronger memory and water volume effects were found for cellulose filter paper. CONCLUSIONS: The memory coefficients and the water volume-isotope relationship improved the consistency and accuracy of both laboratory and field data. Our results indicate that cellulose filter paper may not be a suitable medium to measure standard waters and evaluate memory and water volume effects. Finally, a detailed correction and calibration protocol is suggested, along with notes on best practices to obtain good-quality IM-CRDS data. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28072489 TI - Development and application of sub-2-MUm particle CO2 -based chromatography coupled to mass spectrometry for comprehensive analysis of lipids in cottonseed extracts. AB - RATIONALE: Refined cottonseed oil has widespread applications in the food and chemical industries. Although the major lipids comprising cottonseed oil (triacylglycerols) are well known, there are many diverse lipid species in cotton seeds that occur at much lower levels and have important nutritional or anti nutritional properties. METHODS: The lipid technical samples were prepared in chloroform. The biological samples were extracted using a mixture of isopropanol/chloroform/H2 O (2:1:0.45). The data were collected using high and low collision energy with simultaneous data collection on a time-of-flight (TOF) mass spectrometer which allowed the characterization of lipids by precursor and product ion alignment. The supercritical fluid chromatography methodology is flexible and can be altered to provide greater retention and separation. The comprehensive method was used to screen seed lipid extracts from several cotton genotypes using multivariate statistical analysis. RESULTS: Method variables influencing the peak integrity and chromatographic separation for a mixture of lipids with different degrees of polarity were explored. The experiments were designed to understand the chromatographic behavior of lipids in a controlled setting using a variety of lipid extracts. Influences of acyl chain length and numbers of double bonds were investigated using single moiety standards. CONCLUSIONS: The methodology parameters were examined using single moiety lipid standards and standard mixtures. The method conditions were applied to biological lipid extracts, and adjustments were investigated to manipulate the chromatography. Insights from these method variable manipulations will help to frame the development of targeted lipid profiling and screening protocols. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28072490 TI - Reply regarding prognostic value of neutrophil-to-lymphocyte ratio in laryngeal squamous cell carcinoma. PMID- 28072491 TI - Paradoxical bradycardia during surgical caudal vena cava occlusion in an anesthetized dog. AB - OBJECTIVE: To describe the anesthetic management of a dog undergoing caudal vena cava (CVC) occlusion during adrenalectomy, and to discuss a reflex bradycardia that was observed during the procedure. CASE SUMMARY: General anesthesia of a 10 year-old Rhodesian ridgeback for excision of an adrenal mass and associated CVC tumor thrombus was performed. The dog was premedicated with IV methadone and anesthesia was induced with IV alfaxalone and maintained with isoflurane in 100% oxygen. An IV remifentanil infusion was administered for intraoperative analgesia. Surgical removal of the thrombus necessitated temporary complete occlusion of the CVC. During CVC occlusion an acute paradoxical bradycardia occurred, which was successfully treated with IV atropine. The cardiovascular change resembled a Bezold-Jarisch or reverse Bainbridge reflex, and was believed to be mediated by cardiac mechanoreceptors following the sudden decrease in preload. Increased myocardial contractility subsequent to increased sympathetic nervous system activity may also have contributed. A decrease in urine output was observed following CVC occlusion but had returned to normal 2 hours following the end of anesthesia. Recovery from anesthesia was otherwise uneventful. NEW OR UNIQUE INFORMATION PROVIDED: Although the mechanism is unclear, a paradoxical bradycardia may occur during complete CVC occlusion in the dog. Factors that increase sympathetic nervous system outflow, such as administration of dopamine, may have contributed to the occurrence of the reflex. PMID- 28072492 TI - Identification and characterization of novel host defense peptides from the skin secretion of the fungoid frog, Hydrophylax bahuvistara (Anura: Ranidae). AB - Two novel peptides (brevinin1 HYba1 and brevinin1 HYba2) were identified from the skin secretion of the frog Hydrophylax bahuvistara, endemic to Western Ghats, India, and their amino acid sequences were confirmed using cDNA cloning and LC/MS/MS. Antibacterial, hemolytic, and cytotoxic activities of brevinin1 peptides and their synthetic analogs (amidated C-terminus) were investigated and compared. All the peptides except the acidic forms showed antibacterial activity against all tested Gram-positive and Gram-negative bacteria. They exhibited low hemolysis on human erythrocytes and showed potent cytotoxic activity against Hep 3B cancer cell line. Upon amidation, the peptides showed increased activity against the tested microbes without altering their hemolytic and cytotoxic properties. The study also emphasizes the need for screening endemic amphibian fauna of Western Ghats, as a potential source of host defense peptides with possible therapeutic applications in the future. PMID- 28072493 TI - Patterns of infections, aetiological agents and antimicrobial resistance at a tertiary care hospital in northern Tanzania. AB - OBJECTIVE: To determine the causative agents of infections and their antimicrobial susceptibility at a tertiary care hospital in Moshi, Tanzania, to guide optimal treatment. METHODS: A total of 590 specimens (stool (56), sputum (122), blood (126) and wound swabs (286)) were collected from 575 patients admitted in the medical and surgical departments. The bacterial species were determined by conventional methods, and disc diffusion was used to determine the antimicrobial susceptibility pattern of the bacterial isolates. RESULTS: A total of 249 (42.2%) specimens were culture-positive yielding a total of 377 isolates. A wide range of bacteria was isolated, the most predominant being Gram-negative bacteria: Proteus spp. (n = 48, 12.7%), Escherichia coli (n = 44, 11.7%), Pseudomonas spp. (n = 40, 10.6%) and Klebsiella spp (n = 38, 10.1%). Wound infections were characterised by multiple isolates (n = 293, 77.7%), with the most frequent being Proteus spp. (n = 44, 15%), Pseudomonas (n = 37, 12.6%), Staphylococcus (n = 29, 9.9%) and Klebsiella spp. (n = 28, 9.6%). All Staphylococcus aureus tested were resistant to penicillin (n = 22, 100%) and susceptible to vancomycin. Significant resistance to cephalosporins such as cefazolin (n = 62, 72.9%), ceftriaxone (n = 44, 51.8%) and ceftazidime (n = 40, 37.4%) was observed in Gram-negative bacteria, as well as resistance to cefoxitin (n = 6, 27.3%) in S. aureus. CONCLUSION: The study has revealed a wide range of causative agents, with an alarming rate of resistance to the commonly used antimicrobial agents. Furthermore, the bacterial spectrum differs from those often observed in high-income countries. This highlights the imperative of regular generation of data on aetiological agents and their antimicrobial susceptibility patterns especially in infectious disease endemic settings. The key steps would be to ensure the diagnostic capacity at a sufficient number of sites and implement structures to routinely exchange, compare, analyse and report data. Sentinel sites (hospitals) across the country (and region) should report on a representative subset of bacterial species and their susceptibility to drugs at least annually. A central organising body should collate the data and report to relevant national and international stakeholders. PMID- 28072494 TI - Hepatitis B virus reactivation in breast cancer patients undergoing chemotherapy: A review and meta-analysis of prophylaxis management. AB - Hepatitis B virus (HBV) reactivation during or after chemotherapy in patients with breast cancer has become a remarkable clinical problem. Prophylactic nucleos(t)ide analogues (NAs) are recommended for patients with breast cancer who are hepatitis B surface antigen (HBsAg) positive before chemotherapy. We performed an up-to-date meta-analysis to compare the efficacy of prophylactic lamivudine use with nonprophylaxis in HBsAg-positive breast cancer patients undergoing chemotherapy. PubMed, the Cochrane Library and China National Knowledge Infrastructure (CNKI) databases were searched for relevant articles until June 2016. Eligible articles comparing the efficacy of prophylactic lamivudine use with nonprophylaxis in HBsAg-positive breast cancer patients undergoing chemotherapy were identified. Eight studies which had enrolled 709 HBsAg-positive breast cancer patients undergoing chemotherapy were analysed. Lamivudine prophylaxis significantly reduced the rates of chemotherapy-associated hepatitis B flares in chronic hepatitis B in breast cancer compared with patients with nonprophylaxis (odds ratio [OR]=0.15, 95% confidence interval [CI]: 0.07 0.35, P<.00001). Chemotherapy disruption rates attributed to HBV reactivation in the prophylaxis groups were significantly lower than the nonprophylaxis groups (OR=0.17, 95% CI: 0.07-0.43, P=.0002). Patients with lamivudine prophylaxis had a higher risk for tyrosine-methionine-aspartate-aspartate (YMDD) motif mutations than patients with nonprophylaxis (OR=6.33, 95% CI: 1.01-39.60, P=.05). Prophylactic antiviral therapy management is necessary for HBsAg-positive breast cancer patients undergoing chemotherapy, in spite of high correlation with lamivudine-resistant HBV variants with YMDD motif mutations. PMID- 28072495 TI - Pelagostrobilidium liui n. sp. (Ciliophora, Choreotrichida) from the Coastal Waters of Northeastern Taiwan and an Improved Description of Pelagostrobilidium minutum Liu et al., 2012. AB - The number of somatic kineties in Pelagostrobilidium ranges from 4 to 6 according to the present state of knowledge. This study investigates Pelagostrobilidium liui n. sp. using live observation, protargol stain, and small subunit rDNA data sequencing. Pelagostrobilidium liui n. sp. is characterized by having a spherical shaped body, four somatic kineties, with kinety 2 spiraled around the left side of body, about six elongated external membranelles, and invariably no buccal membranelle. It differs from its most similar congener, Pelagostrobilidium minutum Liu et al., , in (i) cell shape; (ii) macronucleus width; (iii) oral apparatus; (iv) anterior orientation of kinety 2; (v) location where kinety 2 commences; (vi) arrangement of kinety 1; (vii) distance between the anterior cell end and the locations where kineties commence; and (viii) the presence of 12 different bases (including two deletions) in the small subunit rDNA sequences. The diagnosis of P. minutum Liu et al., is also improved to include the following new characteristics: invariably four somatic kineties; kineties 2 and 4 alone commence at the same level; kinety 2 originates from right anterior cell half on ventral side, extends sinistrally posteriorly, over kinety 1, around left posterior region, terminates near posterior cell end on dorsal side; kinety 1 commences below anterior third of kinety 2. PMID- 28072496 TI - Structural Reconstruction of the Perivascular Space in the Adult Mouse Neurohypophysis During an Osmotic Stimulation. AB - Oxytocin (OXT) and arginine vasopressin (AVP) neuropeptides in the neurohypophysis (NH) control lactation and body fluid homeostasis, respectively. Hypothalamic neurosecretory neurones project their axons from the supraoptic and paraventricular nuclei to the NH to make contact with the vascular surface and release OXT and AVP. The neurohypophysial vascular structure is unique because it has a wide perivascular space between the inner and outer basement membranes. However, the significance of this unique vascular structure remains unclear; therefore, we aimed to determine the functional significance of the perivascular space and its activity-dependent changes during salt loading in adult mice. The results obtained revealed that pericytes were the main resident cells and defined the profile of the perivascular space. Moreover, pericytes sometimes extended their cellular processes or 'perivascular protrusions' into neurohypophysial parenchyma between axonal terminals. The vascular permeability of low-molecular weight (LMW) molecules was higher at perivascular protrusions than at the smooth vascular surface. Axonal terminals containing OXT and AVP were more likely to localise at perivascular protrusions than at the smooth vascular surface. Chronic salt loading with 2% NaCl significantly induced prominent changes in the shape of pericytes and also increased the number of perivascular protrusions and the surface area of the perivascular space together with elevations in the vascular permeability of LMW molecules. Collectively, these results indicate that the perivascular space of the NH acts as the main diffusion route for OXT and AVP and, in addition, changes in the shape of pericytes and perivascular reconstruction occur in response to an increased demand for neuropeptide release. PMID- 28072497 TI - Covalently Connected Polymer-Protein Nanostructures Fabricated by a Reactive Self Assembly Approach. AB - The synthesis of polymer-protein nanostructures opens up a new avenue for the development of new biomaterials. In this research, covalently connected polymer protein nanostructures were fabricated through a reactive self-assembly approach. Poly(tert-butyl methacrylate-co-pyridyl disulfide methacrylamide) (PtBMA-co PPDSMA) was synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization. Covalently connected nanostructures (CCNs) with hydrophobic polymer cores and hydrophilic protein coronae were prepared by adding solutions of PtBMA-co-PPDSMA/DMF to aqueous solutions of bovine serum albumin (BSA). The thiol-disulfide exchange reaction between pyridyl disulfide groups on the polymer chains and thiol groups on the protein molecules plays a key role in the fabrication of CCNs. The self-assembly process was investigated by dynamic light scattering (DLS) and stopped-flow techniques. DLS results indicated that the sizes of the CCNs were determined by the initial polymer concentration, the BSA concentration, and the average number of thiol groups on BSA molecules. TEM and sodium dodecyl sulfate polyacrylamide gel electrophoresis were used to analyze the nanostructures. Far-UV circular dichroism results demonstrated that the original folded conformations of BSA molecules were basically maintained in the reactive self-assembly process. Compared with native BSA, the secondary structure and conformation change of coronal BSA induced by urea or thermal treatment were remarkably suppressed. The cytotoxicity assays demonstrated that the CCNs were essentially nontoxic to Hela and COS-7 cells. PMID- 28072498 TI - Scaling-up HCV treatment to achieve WHO targets by 2030. PMID- 28072499 TI - In silico analysis of the deleterious nsSNPs (missense) in the homeobox domain of human HOXB13 gene responsible for hereditary prostate cancer. AB - The human HOXB13 gene encodes a transcription factor containing a DNA-binding homeobox domain and a HoxA13 N-terminal domain. SNP is considered to be the primary genetic cause for hereditary prostate cancer (PCa). The study of functional nsSNPs would give an insight into the exact cause underlying the onset of hereditary PCa and possible methodologies for the cure or early management of the disease. Several in silico tools were used to screen and map the deleterious nsSNPs to the protein structure for predicting the structure-function effects. Among the 23 homeobox nsSNPs, sift predicted 20, whereas PolyPhen, panther, and provean predicted 21 nsSNP's as deleterious. W63R, D244N, K239Q, P222R, K218R, and G216C were found to have higher energy values than the native 2CRA. The RMSD value showed increased deviation for T253P(2.53 A), P222R(2.27 A), G216C(2.15 A), K218R(1.66 A), and K239Q(1.62 A). The I-Mutant showed increase in the stability of R258C, S254T, S250L, K239Q, and Q227E. Ramachandran plot showed mutants P222R, G216C, W263R, and K218R having drastically unfavorable pattern of amino acid residues. The presence of these mutations may result in the altered structure and function of the transcription factor; however, the exact mechanism and pathology of those predicted nsSNPs should further be validated by in vivo experiments and population-based studies. PMID- 28072500 TI - Ultrasound-guided intracardiac xenotransfusion of canine packed red blood cells and epinephrine to the left ventricle of a severely anemic cat during cardiopulmonary resuscitation. AB - OBJECTIVE: To describe the use of an ultrasound-guided intracardiac xenotransfusion of canine packed red blood cells (pRBC) to the left ventricle of a severely anemic cat during cardiopulmonary resuscitation (CPR). CASE SUMMARY: An 8-year-old previously healthy neutered female cat was presented with severe weakness after she had disappeared for 1 month. On presentation, the cat was in hypovolemic shock, laterally recumbent, and severely anemic with massive flea infestation. Within minutes of admission, the cat became agonal and suffered cardiopulmonary arrest. CPR was immediately initiated; however, attempts to gain IV access during CPR were unsuccessful. As the cat's blood type was yet unknown, 10 mL of canine pRBC was transfused directly into the left ventricular chamber using ultrasound guidance, as well as 0.02 mg/kg of epinephrine using a similar technique. The cat regained cardiac activity and once the jugular vein was cannulated it received 20 additional mL of canine pRBC intravenously. The packed cell volume and total plasma protein following the intracardiac transfusion were 0.09 L/L [9%] and 30 g/L [3.0 g/dL], respectively. Subsequent blood typing revealed the cat had type B blood. The cat was discharged 3 days post-CPR and was alive and doing well 3 months following discharge. NEW OR UNIQUE INFORMATION PROVIDED: This is the first reported case of ultrasound-guided intracardiac canine-to-feline xenotransfusion during CPR. PMID- 28072502 TI - Wallerian Degeneration Beyond the Corticospinal Tracts: Conventional and Advanced MRI Findings. AB - Wallerian degeneration (WD) is defined as progressive anterograde disintegration of axons and accompanying demyelination after an injury to the proximal axon or cell body. Since the 1980s and 1990s, conventional magnetic resonance imaging (MRI) sequences have been shown to be sensitive to changes of WD in the subacute to chronic phases. More recently, advanced MRI techniques, such as diffusion weighted imaging (DWI) and diffusion tensor imaging (DTI), have demonstrated some of earliest changes attributed to acute WD, typically on the order of days. In addition, there is increasing evidence on the value of advanced MRI techniques in providing important prognostic information related to WD. This article reviews the utility of conventional and advanced MRI techniques for assessing WD, by focusing not only on the corticospinal tract but also other neural tracts less commonly thought of, including corticopontocerebellar tract, dentate-rubro olivary pathway, posterior column of the spinal cord, corpus callosum, limbic circuit, and optic pathway. The basic anatomy of these neural pathways will be discussed, followed by a comprehensive review of existing literature supported by instructive clinical examples. The goal of this review is for readers to become more familiar with both conventional and advanced MRI findings of WD involving important neural pathways, as well as to illustrate increasing utility of advanced MRI techniques in providing important prognostic information for various pathologies. PMID- 28072501 TI - Nasopharyngeal carriage of respiratory pathogens in Warao Amerindians: significant relationship with stunting. AB - OBJECTIVE: To assess risk factors for nasopharyngeal carriage of potential pathogens in geographically isolated Warao Amerindians in Venezuela. METHODS: In this point prevalence survey, nasopharyngeal swabs were obtained from 1064 Warao Amerindians: 504 children aged 0-4 years, 227 children aged 5-10 years and 333 caregivers. Written questionnaires were completed to obtain information on demographics and environmental risk factors. Anthropometric measurements were performed in children aged 0-4 years. RESULTS: Carriage rates of Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae and Moraxella catarrhalis were 51%, 7%, 1% and 13%, respectively. Crowding index, method of cooking and tobacco exposure were not associated with increased carriage. In multivariable analysis, an increase in height-for-age Z score (i.e. improved chronic nutritional status) was associated with decreased odds of S. pneumoniae colonisation (OR 0.76, 95% CI 0.70-0.83) in children aged 0-4 years. CONCLUSIONS: Better knowledge of demographic and environmental risk factors facilitates better understanding of the dynamics of colonisation with respiratory bacteria in an Amerindian population. Poor chronic nutritional status was associated with increased pathogen carriage in children <5 years of age. The high rates of stunting generally observed in indigenous children may fuel the acquisition of respiratory bacteria that can lead to respiratory and invasive disease. PMID- 28072504 TI - Vexatious Litigants and the ADA: Strategies to Fairly Address the Need to Improve Access for Individuals with Disabilities. AB - This Article addresses the need to reform the ADA to prevent vexatious litigation and to promote the underlying goals of the Act. Part I of this Article introduces the topic of vexatious litigation and the importance of remedying the effects of exploitation of the ADA. Part II provides an overview of the ADA and its efforts to increase accessibility to individuals with disabilities, emphasizing the provisions of the Act that create incentives to engage in vexatious litigation. Part III examines and analyzes the judiciary's response to vexatious litigation under the ADA, and sanctions that have been issued to limit exploitation. Finally, Part IV provides recommendations to reform the ADA and state disability law counterparts, suggests corrective actions to address vexatious litigation, and identifies methods to promote equality for individuals with disabilities. PMID- 28072503 TI - Posttraumatic stress disorder symptoms and cognitive function in a large cohort of middle-aged women. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) has been linked to cognitive decline, but research in women is generally lacking. We examined whether trauma and elevated PTSD symptoms were associated with worse cognitive function in middle-aged civilian women. A secondary objective was to investigate the possible role of depression in the relation of PTSD symptoms to cognitive function. METHODS: The sample comprised 14,029 middle-aged women in the Nurses' Health Study II. Lifetime trauma exposure, lifetime PTSD symptoms, and past-week depressive symptoms were measured in 2008. Cognitive function was measured in 2014-2016 using the Cogstate Brief Battery, a self-administered online cognitive battery that assesses psychomotor speed, attention, learning, and working memory. We used linear regression models to estimate mean differences in cognition across PTSD symptom levels. RESULTS: Compared to no trauma, elevated PTSD symptoms consistent with probable PTSD (i.e., 4+ symptoms on a screening questionnaire) were associated with worse performance on psychomotor speed/attention (b = -0.08 standard units, p = .001) and learning/working memory (b = -0.09, p < .001) composites, after adjusting for sociodemographics. Although attenuated, associations remained significant when adjusted for depressive symptoms and other cognitive risk factors. We found the strongest associations among women with comorbid probable PTSD and depression. CONCLUSIONS: PTSD symptoms were negatively related to measures of psychomotor speed/attention and learning/working memory in middle-aged women. Our study adds to a growing literature that suggests that mental disorders are associated with worse cognitive function over the life course. PMID- 28072505 TI - Radial artery harvesting. PMID- 28072506 TI - How Much of a Factor Is the Affordable Care Act in the Declining Uninsured Rate? AB - Issue: While the number of uninsured has decreased substantially since the Affordable Care Act (ACA) expanded coverage in 2014, questions remain about howmuch the economic recovery and other changes might have influenced this decline. Goal: Assess the direct impact of the ACA marketplaces and the Medicaid expansion on the uninsured rate among nonelderly adults. Methods: Analysis of insurance coverage rates before and after the ACA's first open enrollment period (fall 2013 to spring 2014) using the National Health Interview Survey (NHIS) and the Behavioral Risk Factor Surveillance Survey (BRFSS). Key findings: Based on NHIS data, enrollment in ACA-related coverage options explains about 76 percent of the 4-percentage-point decline in the uninsured rate during the first open enrollment period. Marketplace enrollments reduced the adult uninsured rate by an estimated 1.7 percentage points to 2.3 percentage points. The effects were substantially more pronounced among adults eligible for income-related subsidies. Medicaid expansions in participating states further reduced the uninsured rate by an estimated 0.76 points to 1.0 points. Conclusion: The great majority of nonelderly adults who enrolled during the first open enrollment period would likely not have held health coverage without the ACA expansions. PMID- 28072507 TI - A Long Way in a Short Time: States' Progress on Health Care Coverage and Access, 2013-2015. AB - Issue: The Affordable Care Act's policy reforms sought to expand health insurance coverage and make health care more affordable. As the nation prepares for policy changes under a new administration, we assess recent gains and challenges. Goal: To compare access to affordable health care across the U.S. between 2013 and 2015. Methods: Analysis of most recent publicly available data from the U.S. Census Bureau and the Behavioral Risk Factor Surveillance System.Key findings and conclusions: Between 2013 and 2015, uninsured rates for adults ages 19 to 64 declined in all states and by at least 3 percentage points in 48 states and the District of Columbia. For children, uninsured rates declined by at least 2 percentage points in 28 states. The share of adults age 18 and older who reported forgoing a visit to the doctor when needed because of costs dropped by at least 2 percentage points in 38 states and D.C. In contrast, there was littleprogress in expanding access to dental care for adults, which is not a required benefit under the ACA. These findings illustrate the impact that policy can have on access to care and offer a focal point for assessing future policy changes. PMID- 28072508 TI - Repealing Federal Health Reform: Economic and Employment Consequences for States. AB - Issue: The incoming Trump administration and Republicans in Congress are seeking to repeal the Affordable Care Act (ACA), likely beginning with the law's insurance premium tax credits and expansion of Medicaid eligibility. Research shows that the loss of these two provisions would lead to a doubling of the number of uninsured, higher uncompensated care costs for providers, and higher taxes for low-income Americans. Goal: To determine the state-by-state effect of repeal on employment and economic activity. Methods: A multistate economic forecasting model (PI+ from Regional Economic Models, Inc.) was used to quantify for each state the effects of the federal spending cuts. Findings and Conclusions: Repeal results in a $140 billion loss in federal funding for health care in 2019, leading to the loss of 2.6 million jobs (mostly in the private sector) that year across all states. A third of lost jobs are in health care, with the majority in other industries. If replacement policies are not in place, there will be a cumulative $1.5 trillion loss in gross state products and a $2.6 trillion reduction in business output from 2019 to 2023. States and health care providers will be particularly hard hit by the funding cuts. PMID- 28072509 TI - Achieving High Current Density of Perovskite Solar Cells by Modulating the Dominated Facets of Room-Temperature DC Magnetron Sputtered TiO2 Electron Extraction Layer. AB - The short circuit current density of perovskite solar cell (PSC) was boosted by modulating the dominated plane facets of TiO2 electron transport layer (ETL). Under optimized condition, TiO2 with dominant {001} facets showed (i) low incident light loss, (ii) highly smooth surface and excellent wettability for precursor solution, (iii) efficient electron extraction, and (iv) high conductivity in perovskite photovoltaic application. A current density of 24.19 mA cm-2 was achieved as a value near the maximum limit. The power conversion efficiency was improved to 17.25%, which was the record value of PSCs with DC magnetron sputtered carrier transport layer. What is more, the room-temperature process had a great significance for the cost reduction and flexible application of PSCs. PMID- 28072510 TI - CO2 Photoreduction by Formate Dehydrogenase and a Ru-Complex in a Nanoporous Glass Reactor. AB - In this study, we demonstrated the conversion of CO2 to formic acid under ambient conditions in a photoreduction nanoporous reactor using a photosensitizer, methyl viologen (MV2+), and formate dehydrogenase (FDH). The overall efficiency of this reactor was 14 times higher than that of the equivalent solution. The accumulation rate of formic acid in the nanopores of 50 nm is 83 times faster than that in the equivalent solution. Thus, this CO2 photoreduction nanoporous glass reactor will be useful as an artificial photosynthesis system that converts CO2 to fuel. PMID- 28072511 TI - Resistance Switching Characteristics Induced by O2 Plasma Treatment of an Indium Tin Oxide Film for Use as an Insulator in Resistive Random Access Memory. AB - In this study, an O2 inductively coupled plasma (ICP) treatment was developed in order to modify the characteristics of indium tin oxide (ITO) film for use as an insulator in resistive random access memory (RRAM). After the O2 plasma treatment, the previously conductive ITO film is oxidized and becomes less conductive. In addition, after capping the same ITO material for use as a top electrode, we found that the ITO/ITO(O2 plasma)/TiN device exhibits very stable and robust resistive switching characteristics. On the contrary, the nontreated ITO film for use as an insulator in the ITO/ITO/TiN device cannot perform resistance switching behaviors. The material analysis initially investigated the ITO film characteristics with and without O2 plasma treatment. The surface was less rough after O2 plasma treatment. However, the molar concentration of each element and measured sheet resistance results for the O2-plasma-treated ITO film were dramatically modified. Next, electrical measurements were carried out to examine the resistance switching stability under continuous DC and AC operation in this ITO/ITO(O2 plasma)/TiN device. Reliability tests, including endurance and retention, also proved its capability for use in data storage applications. In addition to these electrical measurements, current fitting method experiments at different temperatures were performed to examine and confirm the resistance switching mechanisms. This easily fabricated device, using a simple material combination, achieves excellent performance by using ITO with an O2 plasma treatment and can further the abilities of RRAM for use in remarkable potential applications. PMID- 28072513 TI - Synthesis of Graphene Oxide-Based Sulfonated Oligoanilines Coatings for Synergistically Enhanced Corrosion Protection in 3.5% NaCl Solution. AB - As a vital derivative of graphene, graphene oxide (GO) is widely applied in various fields, such as transparent electrodes, solar cells, energy storage, and corrosion protection due to the large specific surface area and abundant active sites. However, compared with graphene, the application of GO has been less reported in metal corrosion protection field. Therefore, in our study, 3 aminobenzenesulfonic acid was selected to combine with oligoanilines to fabricate the GO-based sulfonated oligoanilines coatings for marine corrosion protection application. The obtained composite coatings were covered on the surface of Q235 steel, which is one of the most important structural marine materials. Fourier transform infrared spectra were utilized to prove the existence of different bonds and functional groups of aniline trimer and sulfonated aniline trimer (SAT). Scanning electron microscopy was applied to verify the combination of GO and SAT. What's more, transmission electron microscopy was applied to observe the surface appearance of the obtained GO-SAT composite material. Besides, the results of electrochemical measurements performed in 3.5 wt % NaCl solution showed excellent corrosion-protective properties of GO/SAT-coated epoxy resin with a dosage of 10 mg of GO compared with the pure epoxy resin. Moreover, the enhancement of surface hydrophobic property, to some extent, is in favor of preventing the absorption of corrosive medium and water molecules revealed by contact angle test. The addition of GO can make the diffusion pathway of the corrosive medium longer and more circuitous, while SAT has displayed excellent solvent solubility while maintaining corrosion-protective properties similar to those of polyanilines so that the corrosion-protective properties of the modified coatings improve significantly due to the synergistically enhanced corrosion protection of GO and SAT. PMID- 28072512 TI - High-Performance Hybrid Bismuth-Carbon Nanotube Based Contrast Agent for X-ray CT Imaging. AB - Carbon nanotubes (CNTs) have been used for a plethora of biomedical applications, including their use as delivery vehicles for drugs, imaging agents, proteins, DNA, and other materials. Here, we describe the synthesis and characterization of a new CNT-based contrast agent (CA) for X-ray computed tomography (CT) imaging. The CA is a hybrid material derived from ultrashort single-walled carbon nanotubes (20-80 nm long, US-tubes) and Bi(III) oxo-salicylate clusters with four Bi(III) ions per cluster (Bi4C). The element bismuth was chosen over iodine, which is the conventional element used for CT CAs in the clinic today due to its high X-ray attenuation capability and its low toxicity, which makes bismuth a more-promising element for new CT CA design. The new CA contains 20% by weight bismuth with no detectable release of bismuth after a 48 h challenge by various biological media at 37 degrees C, demonstrating the presence of a strong interaction between the two components of the hybrid material. The performance of the new Bi4C@US-tubes solid material as a CT CA has been assessed using a clinical scanner and found to possess an X-ray attenuation ability of >2000 Hounsfield units (HU). PMID- 28072514 TI - Predicting Salt Permeability Coefficients in Highly Swollen, Highly Charged Ion Exchange Membranes. AB - This study presents a framework for predicting salt permeability coefficients in ion exchange membranes in contact with an aqueous salt solution. The model, based on the solution-diffusion mechanism, was tested using experimental salt permeability data for a series of commercial ion exchange membranes. Equilibrium salt partition coefficients were calculated using a thermodynamic framework (i.e., Donnan theory), incorporating Manning's counterion condensation theory to calculate ion activity coefficients in the membrane phase and the Pitzer model to calculate ion activity coefficients in the solution phase. The model predicted NaCl partition coefficients in a cation exchange membrane and two anion exchange membranes, as well as MgCl2 partition coefficients in a cation exchange membrane, remarkably well at higher external salt concentrations (>0.1 M) and reasonably well at lower external salt concentrations (<0.1 M) with no adjustable parameters. Membrane ion diffusion coefficients were calculated using a combination of the Mackie and Meares model, which assumes ion diffusion in water swollen polymers is affected by a tortuosity factor, and a model developed by Manning to account for electrostatic effects. Agreement between experimental and predicted salt diffusion coefficients was good with no adjustable parameters. Calculated salt partition and diffusion coefficients were combined within the framework of the solution-diffusion model to predict salt permeability coefficients. Agreement between model and experimental data was remarkably good. Additionally, a simplified version of the model was used to elucidate connections between membrane structure (e.g., fixed charge group concentration) and salt transport properties. PMID- 28072515 TI - Ultralight, Flexible, and Semi-Transparent Metal Oxide Papers for Photoelectrochemical Water Splitting. AB - Thanks to their versatile functionality, metal oxides (MOs) constitute one of the key family materials in a variety of current demands for sensor, catalysis, energy storage and conversion, optical electronics, and piezoelectric mechanics. Much effort has focused on engineering specific nanostructure and macroscopic morphology of MOs that aims to enhance their performances, but the design and controlled synthesis of ultrafine nanostructured MOs in a cost-effective and facile way remains a challenge. In this work, we have exploited the advantages of intrinsic structures of graphene oxide (GO) papers, serving as a sacrificial template, to design and synthesize two-dimensional (2D) layered and free-standing MO papers with ultrafine nanostructures. Physicochemical characterizations showed that these MO materials are nanostructured, porous, flexible, and ultralight. The as-synthesized materials were tested for their potential application in photoelectrochemical (PEC) energy conversion. In terms of PEC water splitting, copper oxide papers were used as an example and exhibited excellent performances with an extremely high photocurrent-to-weight ratio of 3 A cm-2 g-1. We have also shown that the synthesis method is generally valid for many earth-abundant transition metals including copper, nickel, iron, cobalt, and manganese. PMID- 28072516 TI - Cobalt-Based Single-Ion Magnets on an Apatite Lattice: Toward Patterned Arrays for Magnetic Memories. AB - Single-ion magnets (SIMs) that can maintain magnetization direction on an individual transition metal atom represent the smallest atomic-scale units for future magnetic data storage devices and molecular electronics. Here we present a robust extended inorganic solid hosting efficient SIM centers, as an alternative to molecular SIM crystals. We show that unique dioxocobaltate(II) ions, confined in the channels of strontium hydroxyapatite, exhibit classical SIM features with a large energy barrier for magnetization reversal (Ueff) of 51-59 cm-1. The samples have been tuned such that a magnetization hysteresis opens below 8 K and Ueff increases by a factor of 4 and can be further enhanced to the highest values among 3d metal complexes of 275 cm-1 when Ba is substituted for Sr. The SIM properties are preserved without any tendency toward spin ordering up to a high Co concentration. At a maximal Co content, a hypothetical regular hexagonal grid of SIMs with a 1 nm interspacing on the (001) crystal facet would allow a maximal magnetic recording density of 105 Gb/cm2. PMID- 28072518 TI - Chirality-Controlled Synthesis and Applications of Single-Wall Carbon Nanotubes. AB - Preparation of chirality-defined single-wall carbon nanotubes (SWCNTs) is the top challenge in the nanotube field. In recent years, great progress has been made toward preparing single-chirality SWCNTs through both direct controlled synthesis and postsynthesis separation approaches. Accordingly, the uses of single chirality-dominated SWCNTs for various applications have emerged as a new front in nanotube research. In this Review, we review recent progress made in the chirality-controlled synthesis of SWCNTs, including metal-catalyst-free SWCNT cloning by vapor-phase epitaxy elongation of purified single-chirality nanotube seeds, chirality-specific growth of SWCNTs on bimetallic solid alloy catalysts, chirality-controlled synthesis of SWCNTs using bottom-up synthetic strategy from carbonaceous molecular end-cap precursors, etc. Recent major progresses in postsynthesis separation of single-chirality SWCNT species, as well as methods for chirality characterization of SWCNTs, are also highlighted. Moreover, we discuss some examples where single-chirality SWCNTs have shown clear advantages over SWCNTs with broad chirality distributions. We hope this review could inspire more research on the chirality-controlled preparation of SWCNTs and equally important inspire the use of single-chirality SWCNT samples for more fundamental studies and practical applications. PMID- 28072519 TI - Single-Molecule Fluorescence Spectroscopy of Photosynthetic Systems. AB - Photosynthesis begins when a network of pigment-protein complexes captures solar energy and transports it to the reaction center, where charge separation occurs. When necessary (under low light conditions), photosynthetic organisms perform this energy transport and charge separation with near unity quantum efficiency. Remarkably, this high efficiency is maintained under physiological conditions, which include thermal fluctuations of the pigment-protein complexes and changing local environments. These conditions introduce multiple types of heterogeneity in the pigment-protein complexes, including structural heterogeneity, energetic heterogeneity, and functional heterogeneity. Understanding how photosynthetic light-harvesting functions in the face of these fluctuations requires understanding this heterogeneity, which, in turn, requires characterization of individual pigment-protein complexes. Single-molecule spectroscopy has the power to probe individual complexes. In this review, we present an overview of the common techniques for single-molecule fluorescence spectroscopy applied to photosynthetic systems and describe selected experiments on these systems. We discuss how these experiments provide a new understanding of the impact of heterogeneity on light harvesting and thus how these systems are optimized to capture sunlight under physiological conditions. PMID- 28072520 TI - Bioenergy Potential from Food Waste in California. AB - Food waste makes up approximately 15% of municipal solid waste generated in the United States, and 95% of food waste is ultimately landfilled. Its bioavailable carbon and nutrient content makes it a major contributor to landfill methane emissions, but also presents an important opportunity for energy recovery. This paper presents the first detailed analysis of monthly food waste generation in California at a county level, and its potential contribution to the state's energy production. Scenarios that rely on excess capacity at existing anaerobic digester (AD) and solid biomass combustion facilities, and alternatives that allow for new facility construction, are developed and modeled. Potential monthly electricity generation from the conversion of gross food waste using a combination of AD and combustion varies from 420 to 700 MW, averaging 530 MW. At least 66% of gross high moisture solids and 23% of gross low moisture solids can be treated using existing county infrastructure, and this fraction increases to 99% of high moisture solids and 55% of low moisture solids if waste can be shipped anywhere within the state. Biogas flaring practices at AD facilities can reduce potential energy production by 10 to 40%. PMID- 28072521 TI - Quantifying Biodiversity Losses Due to Human Consumption: A Global-Scale Footprint Analysis. AB - It is increasingly recognized that human consumption leads to considerable losses of biodiversity. This study is the first to systematically quantify these losses in relation to land use and greenhouse gas (GHG) emissions associated with the production and consumption of (inter)nationally traded goods and services by presenting consumption-based biodiversity losses, in short biodiversity footprint, for 45 countries and world regions globally. Our results showed that (i) the biodiversity loss per citizen shows large variations among countries, with higher values when per-capita income increases; (ii) the share of biodiversity losses due to GHG emissions in the biodiversity footprint increases with income; (iii) food consumption is the most important driver of biodiversity loss in most of the countries and regions, with a global average of 40%; (iv) more than 50% of the biodiversity loss associated with consumption in developed economies occurs outside their territorial boundaries; and (v) the biodiversity footprint per dollar consumed is lower for wealthier countries. The insights provided by our analysis might support policymakers in developing adequate responses to avert further losses of biodiversity when population and incomes increase. Both the mitigation of GHG emissions and land use related reduction options in production and consumption should be considered in strategies to protect global biodiversity. PMID- 28072517 TI - Arthropod Innate Immune Systems and Vector-Borne Diseases. AB - Arthropods, especially ticks and mosquitoes, are the vectors for a number of parasitic and viral human diseases, including malaria, sleeping sickness, Dengue, and Zika, yet arthropods show tremendous individual variation in their capacity to transmit disease. A key factor in this capacity is the group of genetically encoded immune factors that counteract infection by the pathogen. Arthropod specific pattern recognition receptors and protease cascades detect and respond to infection. Proteins such as antimicrobial peptides, thioester-containing proteins, and transglutaminases effect responses such as lysis, phagocytosis, melanization, and agglutination. Effector responses are initiated by damage signals such as reactive oxygen species signaling from epithelial cells and recognized by cell surface receptors on hemocytes. Antiviral immunity is primarily mediated by siRNA pathways but coupled with interferon-like signaling, antimicrobial peptides, and thioester-containing proteins. Molecular mechanisms of immunity are closely linked to related traits of longevity and fertility, and arthropods have the capacity for innate immunological memory. Advances in understanding vector immunity can be leveraged to develop novel control strategies for reducing the rate of transmission of both ancient and emerging threats to global health. PMID- 28072522 TI - Evaluating Electronic Couplings for Excited State Charge Transfer Based on Maximum Occupation Method DeltaSCF Quasi-Adiabatic States. AB - Electronic couplings of charge-transfer states with the ground state and localized excited states at the donor/acceptor interface are crucial parameters for controlling the dynamics of exciton dissociation and charge recombination processes in organic solar cells. Here we propose a quasi-adiabatic state approach to evaluate electronic couplings through combining maximum occupation method (mom)-DeltaSCF and state diabatization schemes. Compared with time dependent density functional theory (TDDFT) using global hybrid functional, mom DeltaSCF is superior to estimate the excitation energies of charge-transfer states; moreover it can also provide good excited electronic state for property calculation. Our approach is hence reliable to evaluate electronic couplings for excited state electron transfer processes, which is demonstrated by calculations on a typical organic photovoltaic system, oligothiophene/perylenediimide complex. PMID- 28072523 TI - Snapshotting the Excited-State Planarization of Chemically Locked N,N' Disubstituted Dihydrodibenzo[a,c]phenazines. AB - For deeper understanding of the coupling of electronic processes with conformational motions, we exploit a tailored strategy to harness the excited state planarization of N,N'-disubstituted dihydrodibenzo[a,c]phenazines by halting the structural evolution via a macrocyclization process. In this new approach, 9,14-diphenyl-9,14-dihydrodibenzo[a,c]phenazine (DPAC) is used as a prototype, in which the para sites of 9,14-diphenyl are systematically enclosed by a dialkoxybenzene-alkyl-ester or -ether linkage with different chain lengths, imposing various degrees of constraint to impede the structural deformation. Accordingly, a series of DPAC-n (n = 1-8) derivatives were synthesized, in which n correlates with the alkyl length, such that the strength of the spatial constraint decreases as n increases. The structures of DPAC-1, DPAC-3, DPAC-4, and DPAC-8 were identified by the X-ray crystal analysis. As a result, despite nearly identical absorption spectra (onset ~400 nm) for DPAC-1-8, drastic chain length dependent emission is observed, spanning from blue (n = 1, 2, ~400 nm) and blue-green (n = 3-5, 500-550 nm) to green-orange (n = 6) and red (n = 7, 8, ~610 nm) in various regular solvents. Comprehensive spectroscopic and dynamic studies, together with a computational approach, rationalized the associated excited-state structure responding to emission origin. Severing the linkage for DPAC-5 via lipase treatment releases the structural freedom and hence results in drastic changes of emission from blue-green (490 nm) to red (625 nm), showing the brightening prospect of these chemically locked DPAC-n in both fundamental studies and applications. PMID- 28072524 TI - Common Hits Approach: Combining Pharmacophore Modeling and Molecular Dynamics Simulations. AB - We present a new approach that incorporates flexibility based on extensive MD simulations of protein-ligand complexes into structure-based pharmacophore modeling and virtual screening. The approach uses the multiple coordinate sets saved during the MD simulations and generates for each frame a pharmacophore model. Pharmacophore models with the same pharmacophore features are pooled. In this way the high number of pharmacophore models that results from the MD simulation is reduced to only a few hundred representative pharmacophore models. Virtual screening runs are performed with every representative pharmacophore model; the screening results are combined and rescored to generate a single hit list. The score for a particular molecule is calculated based on the number of representative pharmacophore models which classified it as active. Hence, the method is called common hits approach (CHA). The steps between the MD simulation and the final hit-list are performed automatically and without user interaction. We test the performance of CHA for virtual screening using screening databases with active and inactive compounds for 40 protein-ligand systems. The results of the CHA are compared to the (i) median screening performance of all representative pharmacophore models of protein-ligand systems, as well as to the virtual screening performance of (ii) a random classifier, (iii) the pharmacophore model derived from the experimental structure in the PDB, and (iv) the representative pharmacophore model appearing most frequently during the MD simulation. For the 34 (out of 40) protein-ligand complexes, for which at least one of the approaches was able to perform better than a random classifier, the highest enrichment was achieved using CHA in 68% of the cases, compared to 12% for the PDB pharmacophore model and 20% for the representative pharmacophore model appearing most frequently. The availabilithy of diverse sets of different pharmacophore models is utilized to analyze some additional questions of interest in 3D pharmacophore-based virtual screening. PMID- 28072525 TI - Anionic Lanthanide MOFs as a Platform for Iron-Selective Sensing, Systematic Color Tuning, and Efficient Nanoparticle Catalysis. AB - New porous anionic Ln-MOFs, namely, [Me2NH2][Ln(CPA)2(H2O)2] (Ln = Eu, Gd), have been prepared through the self-assembly of 5-(4-carboxy phenyl)picolinic acid (H2CPA) and lanthanide ions. They feature open anionic frameworks with 1-D hydrophilic channels and exchangeable dimethylamine ions. The Eu phase could detect Fe3+ ions with high selectivity and sensitivity in either aqueous solution or biological condition. The ratios of lanthanide ions on this structure platform could be rationally tuned to not only achieve dichromatic emission colors with linear correlation but also attain three primary colors (RGB) and even white light with favorable correlated color temperature. Furthermore, the Ag(I) exchanged phases can be readily reduced to afford Ag nanoparticles. The as prepared Ag@Ln-MOFs composite shows highly efficient catalytic performance for the reduction of 4-nitrophenol. PMID- 28072526 TI - Type I DNA Topoisomerases. AB - DNA topoisomerases constitute a large family of enzymes that are essential for all domains of life. Although they share general reaction chemistry and the capacity to govern DNA topology and resolve strand entanglements during fundamental molecular processes, they are characterized by differences in their structural organization, modes of enzymatic catalysis, and biological functions. Moreover, hundreds of compounds interfere with bacterial and/or eukaryotic enzymes, some of which are effective drugs for the treatment of infectious diseases and cancers. Research over the past decade has focused on the biological functions of DNA topoisomerases, and several findings have revealed unexpected roles of type I DNA topoisomerases, a subclass of these enzymes, in regulating gene expression and DNA and chromatin conformations. These new findings highlight that type I topoisomerases are still interesting targets for drug discovery for the treatment of several human diseases, including multidrug-resistant infections and genetic disorders. PMID- 28072527 TI - Rational Synthesis and Investigation of Porous Metal-Organic Framework Materials from a Preorganized Heterometallic Carboxylate Building Block. AB - The tetranuclear heterometallic complex [Li2Zn2(piv)6(py)2] (1, where piv- = pivalate and py = pyridine) has been successfully employed as a presynthesized node for the construction of four porous metal-organic frameworks (MOFs) [Li2Zn2(R-bdc)3(bpy)].solv (2-R, R-bdc2-; R = H, Br, NH2, NO2) by reaction with 4,4'-bipyridine (bpy) and terephthalate anionic linkers. The [Li2Zn2] node is retained in the products, representing a rare example of the rational step-by step design of isoreticular MOFs based on complex heterometallic building units. The permanent porosity of the activated frameworks was confirmed by gas adsorption isotherm measurements (N2, CO2, CH4). Three compounds, 2-H, 2-Br, and 2-NH2 (but not 2-NO2), feature extensive hysteresis between the adsorption and desorption curves in the N2 isotherms at low pressures. The substituents R decorate the inner surface and also control the aperture of the channels, the volume of the micropores, and the overall surface area, thus affecting both the gas uptake and adsorption selectivity. The highest CO2 absorption at ambient conditions (105 cm3.g-1 or 21 wt % at 273 K and 1 bar for 2-NO2) is above the average values for microporous MOFs. The photoluminescent properties of the prototypic 2-H as well as the corresponding host-guest compounds with various aromatic molecules (benzene, toluene, anisole, and nitrobenzene) were systematically investigated. We discovered a rather complex pattern in the emission response of this material depending on the wavelength of excitation as well as the nature of the guest molecules. On the basis of the crystal structure of 2-H, a mechanism for these luminescent properties is proposed and discussed. PMID- 28072528 TI - Triosephosphate Isomerase and Filamin C Share Common Epitopes as Novel Allergens of Procambarus clarkii. AB - Triosephosphate isomerase (TIM) is a key enzyme in glycolysis and has been identified as an allergen in saltwater products. In this study, TIM with a molecular mass of 28 kDa was purified from the freshwater crayfish (Procambarus clarkii) muscle. A 90-kDa protein that showed IgG/IgE cross-reactivity with TIM was purified and identified as filamin C (FLN c), which is an actin-binding protein. TIM showed similar thermal and pH stability with better digestion resistance compared with FLN c. The result of the surface plasmon resonance (SPR) experiment demonstrated the infinity of anti-TIM polyclonal antibody (pAb) to both TIM and FLN c. Five linear and 3 conformational epitopes of TIM, as well as 9 linear and 10 conformational epitopes of FLN c, were mapped by phage display. Epitopes of TIM and FLN c demonstrated the sharing of certain residues; the occurrence of common epitopes in the two allergens accounts for their cross reactivity. PMID- 28072529 TI - Correlation between the Structure and Catalytic Activity of [Cp*Rh(Substituted Bipyridine)] Complexes for NADH Regeneration. AB - A series of water-soluble half-sandwich [Cp*RhIII(N^N)Cl]+ (Cp* = pentamethylcyclopentadiene, N^N-substituted 2,2'-bipyridine) complexes containing electron-donating substituents around the 2,2'-bipyridyl ligand were synthesized and fully characterized for the regioselective reduction of nicotinamide coenzyme (NAD+). The influence of the positional effect of the substituents on the structural, electrochemical, and catalytic properties of the catalyst was systematically studied in detail. The catalytic efficiency of the substituted bipyridine Cp*RhIII complexes are inversely correlated with their redox potentials. The 5,5'-substituted bipyridine Cp*RhIII complex, which had the lowest reduction potential, most effectively regenerated NADH with a turnover frequency of 1100 h-1. Detailed kinetic studies on the generation of intermediate(s) provide valuable mechanistic insight into this catalytic cycle and help to direct the future design strategy of corresponding catalysts. PMID- 28072530 TI - Effect of beta-Cyclodextrin on the Multistate Species Distribution of 3-Methoxy 4',7-dihydroxyflavylium. Discrimination of the Two Hemiketal Enantiomers. AB - The effect of beta-cyclodextrin on the mole fraction distribution of the multistate species of the anthocyanin model compound, 3-methoxy-4',7 dihydroxyflavylium, was studied by NMR, stopped flow, circular dichroism, and UV visible absorption spectroscopy. The formation of inclusion complexes with hemiketal and trans-chalcone, possessing transition dipole moments in a parallel orientation to the cyclodextrin n-fold axis, was unequivocally proved by means of the positive-induced circular dichroism signal. The discrimination of the two hemiketal enantiomers was achieved by the splitting of 1H NMR peaks in the presence beta-cyclodextrin. The spectroscopic data shows that the beta cyclodextrin has only moderate enantioselectivity, slightly favoring one of the optical isomers. The observed binding affinity of beta-cyclodextrin for the 3 methoxy-4',7-dihydroxyflavylium multistate species increases in the order flavylium cation < quinoidal base < hemiketal < trans-chalcone < cis-chalcone. As a result of this selectivity and the dynamic nature of the network, the equilibrium is displaced toward the formation of the chalcone species. PMID- 28072532 TI - Controlling the Isomerization Rate of an Azo-BF2 Switch Using Aggregation. AB - A novel visible-light activated azo-BF2 switch possessing a phenanthridinyl pi system has been synthesized, and its switching properties have been characterized as a function of concentration. The switch self-aggregates through pi-pi interactions, and the degree of aggregation modulates the Z -> E thermal isomerization rate. This property allows for the active tuning of the thermal relaxation half-life of the same switch from seconds to days. PMID- 28072531 TI - Discovery of 2-(((1r,4r)-4-(((4 Chlorophenyl)(phenyl)carbamoyl)oxy)methyl)cyclohexyl)methoxy)acetate (Ralinepag): An Orally Active Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension. AB - The design and synthesis of a new series of potent non-prostanoid IP receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) are described. Detailed profiling of a number of analogues resulted in the identification of 5c (ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the prostanoid receptor family and a more modest 30- to 50-fold selectivity over the EP3 receptor. In our hands, its potency and efficacy are comparable or superior to MRE269 (the active metabolite of the clinical compound NS-304) with respect to in vitro IP receptor dependent cAMP accumulation assays. 5c had an excellent PK profile across species. Enterohepatic recirculation most probably contributes to a concentration-time profile after oral administration in the cynomolgus monkey that showed a very low peak-to-trough ratio. Following the identification of an acceptable solid form, 5c was selected for further development for the treatment of PAH. PMID- 28072533 TI - Coupled-Cluster Valence-Bond Singles and Doubles for Strongly Correlated Systems: Block-Tensor Based Implementation and Application to Oligoacenes. AB - We demonstrate a block-tensor based implementation of coupled-cluster valence bond singles and doubles (CCVB-SD) [Small, D. W.; Head-Gordon M. J. Chem. Phys. 2012, 137, 114103] which is a simple modification to restricted CCSD (RCCSD) that provides a qualitatively correct description of valence correlations even in strongly correlated systems. We derive the Lambda-equation of CCVB-SD and the corresponding unrelaxed density matrices. The resulting production-level implementation is applied to oligoacenes, correlating up to 318 electrons in 318 orbitals. CCVB-SD shows a qualitative agreement with exact methods for short acenes and reaches the bulk limit of oligoacenes in terms of natural orbital occupation numbers, whereas RCCSD shows nonvariational behavior even for relatively short acenes. A significant reduction in polyradicaloid character is found when correlating all valence electrons instead of only the pi-electrons. PMID- 28072534 TI - Structure, Magnetism, and Thermoelectric Properties of Magnesium-Containing Antimonide Zintl Phases Sr14MgSb11 and Eu14MgSb11. AB - New Mg-containing antimonide Zintl phases, Sr14MgSb11 and Eu14MgSb11, were synthesized from high-temperature solid-state reactions in Ta tubes at 1323 K. Their structures can be viewed as derived from the Ca14AlSb11 structure type, which adopt the tetragonal space group I41/acd (No. 142, Z = 8) with the cell parameters of a = 17.5691(14)/17.3442(11) A and c = 23.399(4)/22.981(3) A for the Sr- and Eu-containing compounds, respectively. The corresponding thermoelectric properties were probed, which demonstrated high potential of these compounds as new thermoelectrics for their very low thermal conductivity and moderate Seebeck coefficient. Magnetism studies and theoretical calculations were conducted as well to better understand the structure-and-property correlation of these materials. PMID- 28072535 TI - Mechanistic Study of the Validity of Using Hydroxyl Radical Probes To Characterize Electrochemical Advanced Oxidation Processes. AB - The detection of hydroxyl radicals (OH*) is typically accomplished by using reactive probe molecules, but prior studies have not thoroughly investigated the suitability of these probes for use in electrochemical advanced oxidation processes (EAOPs), due to the neglect of alternative reaction mechanisms. In this study, we investigated the suitability of four OH* probes (coumarin, p chlorobenzoic acid, terephthalic acid, and p-benzoquinone) for use in EAOPs. Experimental results indicated that both coumarin and p-chlorobenzoic acid are oxidized via direct electron transfer reactions, while p-benzoquinone and terephthalic acid are not. Coumarin oxidation to form the OH* adduct product 7 hydroxycoumarin was found at anodic potentials lower than that necessary for OH* formation. Density functional theory (DFT) simulations found a thermodynamically favorable and non-OH* mediated pathway for 7-hydroxycoumarin formation, which is activationless at anodic potentials > 2.10 V/SHE. DFT simulations also provided estimates of E degrees values for a series of OH* probe compounds, which agreed with voltammetry results. Results from this study indicated that terephthalic acid is the most appropriate OH* probe compound for the characterization of electrochemical and catalytic systems. PMID- 28072536 TI - Role of Ionic Strength and pH in Modulating Thermodynamic Profiles Associated with CO Escape from Rice Nonsymbiotic Hemoglobin 1. AB - Type 1 nonsymbiotic hemoglobins are found in a wide variety of land plants and exhibit very high affinities for exogenous gaseous ligands. These proteins are presumed to have a role in protecting plant cells from oxidative stress under etiolated/hypoxic conditions through NO dioxygenase activity. In this study we have employed photoacoustic calorimetry, time-resolved absorption spectroscopy, and classical molecular dynamics simulations in order to elucidate thermodynamics, kinetics, and ligand migration pathways upon CO photodissociation from WT and a H73L mutant of type 1 nonsymbiotic hemoglobin from Oryza sativa (rice). We observe a temperature dependence of the resolved thermodynamic parameters for CO photodissociation from CO-rHb1 which we attribute to temperature dependent formation of a network of electrostatic interactions in the vicinity of the heme propionate groups. We also observe slower ligand escape from the protein matrix under mildly acidic conditions in both the WT and H73L mutant (tau = 134 +/- 19 and 90 +/- 15 ns). Visualization of transient hydrophobic channels within our classical molecular dynamics trajectories allows us to attribute this phenomenon to a change in the ligand migration pathway which occurs upon protonation of the distal His73, His117, and His152. Protonation of these residues may be relevant to the functioning of the protein in vivo given that etiolation/hypoxia can cause a decrease in intracellular pH in plant cells. PMID- 28072537 TI - QM/MM Study of Substituent and Solvent Effects on the Excited State Dynamics of the Photoactive Yellow Protein Chromophore. AB - Substituent and solvent effects on the excited state dynamics of the Photoactive Yellow Protein chromophore are studied using the average solvent electrostatic potential from molecular dynamics (ASEP/MD) method. Four molecular models were considered: the ester and thioester derivatives of the p-coumaric acid anion and their methylated derivatives. We found that the solvent produces dramatic modifications on the free energy profile of the S1 state: 1) Two twisted structures that are minima in the gas phase could not be located in aqueous solution. 2) Conical intersections (CIs) associated with the rotation of the single bond adjacent to the phenyl group are found for the four derivatives in water solution but only for thio derivatives in the gas phase. 3) The relative stability of minima and CIs is reverted with respect to the gas phase values, affecting the prevalent de-excitation paths. As a consequence of these changes, three competitive de-excitation channels are open in aqueous solution: the fluorescence emission from a planar minimum on S1, the trans-cis photoisomerization through a CI that involves the rotation of the vinyl double bond, and the nonradiative, nonreactive, de-excitation through the CI associated with the rotation of the single bond adjacent to the phenyl group. In the gas phase, the minima are the structures with the lower energy, while in solution these are the conical intersections. In solution, the de-excitation prevalent path seems to be the photoisomerization for oxo compounds, while thio compounds return to the initial trans ground state without emission. PMID- 28072538 TI - Formation Mechanisms of Naphthalene and Indene: From the Interstellar Medium to Combustion Flames. AB - The article addresses the formation mechanisms of naphthalene and indene, which represent prototype polycyclic aromatic hydrocarbons (PAH) carrying two six membered and one five- plus a six-membered ring. Theoretical studies of the relevant chemical reactions are overviewed in terms of their potential energy surfaces, rate constants, and product branching ratios; these data are compared with experimental measurements in crossed molecular beams and the pyrolytic chemical reactor emulating the extreme conditions in the interstellar medium (ISM) and the combustion-like environment, respectively. The outcome of the reactions potentially producing naphthalene and indene is shown to critically depend on temperature and pressure or collision energy and hence the reaction mechanisms and their contributions to the PAH growth can be rather different in the ISM, planetary atmospheres, and in combustion flames at different temperatures and pressures. Specifically, this paradigm is illustrated with new theoretical results for rate constants and product branching ratios for the reaction of phenyl radical with vinylacetylene. The analysis of the formation mechanisms of naphthalene and its derivatives shows that in combustion they can be produced via hydrogen-abstraction-acetylene-addition (HACA) routes, recombination of cyclopentadienyl radical with itself and with cyclopentadiene, the reaction of benzyl radical with propargyl, methylation of indenyl radical, and the reactions of phenyl radical with vinylacetylene and 1,3-butadiene. In extreme astrochemical conditions, naphthalene and dihydronaphthalene can be formed in the C6H5 + vinylacetylene and C6H5 + 1,3-butadiene reactions, respectively. Ethynyl-substituted naphthalenes can be produced via the ethynyl addition mechanism beginning with benzene (in dehydrogenated forms) or with styrene. The formation mechanisms of indene in combustion include the reactions of the phenyl radical with C3H4 isomers allene and propyne, reaction of the benzyl radical with acetylene, and unimolecular decomposition of the 1 phenylallyl radical originating from 3-phenylpropene, a product of the C6H5 + propene reaction, or from C6H5 + C3H5. PMID- 28072539 TI - Extension of the ReaxFF Combustion Force Field toward Syngas Combustion and Initial Oxidation Kinetics. AB - A detailed insight of key reactive events related to oxidation and pyrolysis of hydrocarbon fuels further enhances our understanding of combustion chemistry. Though comprehensive kinetic models are available for smaller hydrocarbons (typically C3 or lower), developing and validating reaction mechanisms for larger hydrocarbons is a daunting task, due to the complexity of their reaction networks. The ReaxFF method provides an attractive computational method to obtain reaction kinetics for complex fuel and fuel mixtures, providing an accuracy approaching ab-initio-based methods but with a significantly lower computational expense. The development of the first ReaxFF combustion force field by Chenoweth et al. (CHO-2008 parameter set) in 2008 has opened new avenues for researchers to investigate combustion chemistry from the atomistic level. In this article, we seek to address two issues with the CHO-2008 ReaxFF description. While the CHO 2008 description has achieved significant popularity for studying large hydrocarbon combustion, it fails to accurately describe the chemistry of small hydrocarbon oxidation, especially conversion of CO2 from CO, which is highly relevant to syngas combustion. Additionally, the CHO-2008 description was obtained faster than expected H abstraction by O2 from hydrocarbons, thus underestimating the oxidation initiation temperature. In this study, we seek to systemically improve the CHO-2008 description and validate it for these cases. Additionally, our aim was to retain the accuracy of the 2008 description for larger hydrocarbons and provide similar quality results. Thus, we expanded the ReaxFF CHO-2008 DFT-based training set by including reactions and transition state structures relevant to the syngas and oxidation initiation pathways and retrained the parameters. To validate the quality of our force field, we performed high-temperature NVT-MD simulations to study oxidation and pyrolysis of four different hydrocarbon fuels, namely, syngas, methane, JP-10, and n butylbenzene. Results obtained from syngas and methane oxidation simulation indicated that our redeveloped parameters (named as the CHO-2016 parameter set) has significantly improved the C1 chemistry predicted by ReaxFF and has solved the low-temperature oxidation initiation problem. Moreover, Arrhenius parameters of JP-10 decomposition and initiation mechanism pathways of n-butylbenzene pyrolysis obtained using the CHO-2016 parameter set are also in good agreement with both experimental and CHO-2008 simulation results. This demonstrated the transferability of the CHO-2016 description for a wide range of hydrocarbon chemistry. PMID- 28072540 TI - Impact of Water-Dilution on the Solvation Properties of the Ionic Liquid 1 Methyltriethoxy-3-ethylimidazolium Acetate for Model Biomass Molecules. AB - Many studies have suggested that the processing of lignocellulosic biomass could provide a renewable feedstock to supplant much of the current demand on petroleum sources. Currently, alkyl imidazolium-based ionic liquids (ILs) have shown considerable promise in the pretreatment, solvation, and hydrolysis of lignocellulosic materials although their high cost and unfavorable viscosity has limited their widespread use. Functionalizing these ILs with an oligo(ethoxy) tail has previously been shown through experiment to decrease the IL's viscosity resulting in enhanced mass transport characteristics, in addition to other favorable traits including decreased inhibition of some enzymes. Additionally, the use of cosolvents to mitigate the cost and unfavorable traits of ILs is an area of growing interest with particular attention on water as the presence of water in biomass processes is inevitable. Through the use of biased and unbiased molecular dynamics (MD) simulations, this study provides a molecular-level perspective of the various solvent-solvent and solvent-solute interactions in binary mixtures of water and 1-methyltriethoxy-3-ethylimidazolium acetate ([Me (OEt)3-Et-IM+] [OAc-]) in the presence of model cellulose compounds (i.e., glucose and cellobiose). It is observed that at ~75% w/w IL and water a transition in the nanostructure of the solvent occurs between water-like and IL like solvation characteristics. It is shown that H-bonding interactions between the anion and water are a major driving force that significantly impacts the solvent properties of the IL as well as conformational preferences of the cellulosic model compound. In addition, it is found that the oligo(ethoxy) cation tail is responsible for the reduction in the propensity for tail aggregation as compared to alkyl tails of similar length, which, combined with increased ionic shielding, results in increased diffusion and enhanced water-like solvation characteristics. PMID- 28072541 TI - Proximity Effect Transfer from NbTi into a Semiconductor Heterostructure via Epitaxial Aluminum. AB - We demonstrate the transfer of the superconducting properties of NbTi, a large gap high-critical-field superconductor, into an InAs heterostructure via a thin intermediate layer of epitaxial Al. Two device geometries, a Josephson junction and a gate-defined quantum point contact, are used to characterize interface transparency and the two-step proximity effect. In the Josephson junction, multiple Andreev reflections reveal near-unity transparency with an induced gap Delta* = 0.50 meV and a critical temperature of 7.8 K. Tunneling spectroscopy yields a hard induced gap in the InAs adjacent to the superconductor of Delta* = 0.43 meV with substructure characteristic of both Al and NbTi. PMID- 28072543 TI - Nanoscale Nucleation and Growth of Electrodeposited Lithium Metal. AB - Lithium metal has re-emerged as an exciting anode for high energy lithium-ion batteries due to its high specific capacity of 3860 mAh g-1 and lowest electrochemical potential of all known materials. However, lithium has been plagued by the issues of dendrite formation, high chemical reactivity with electrolyte, and infinite relative volume expansion during plating and stripping, which present safety hazards and low cycling efficiency in batteries with lithium metal electrodes. There have been a lot of recent studies on Li metal although little work has focused on the initial nucleation and growth behavior of Li metal, neglecting a critical fundamental scientific foundation of Li plating. Here, we study experimentally the morphology of lithium in the early stages of nucleation and growth on planar copper electrodes in liquid organic electrolyte. We elucidate the dependence of lithium nuclei size, shape, and areal density on current rate, consistent with classical nucleation and growth theory. We found that the nuclei size is proportional to the inverse of overpotential and the number density of nuclei is proportional to the cubic power of overpotential. Based on this understanding, we propose a strategy to increase the uniformity of electrodeposited lithium on the electrode surface. PMID- 28072542 TI - Insights into the Distinct Lithiation/Sodiation of Porous Cobalt Oxide by in Operando Synchrotron X-ray Techniques and Ab Initio Molecular Dynamics Simulations. AB - Sodium-ion batteries (SIBs) have been considered as one of the promising power source candidates for the stationary storage industries owing to the much lower cost of sodium than lithium. It is well-known that the electrode materials largely determine the energy density of the battery systems. However, recent discoveries on the electrode materials showed that most of them present distinct lithium and sodium storage performance, which is not yet well understood. In this work, we performed a comparative understanding on the structural changes of porous cobalt oxide during its electrochemical lithiation and sodiation process by in operando synchrotron small angel X-ray scattering, X-ray diffraction, and X ray absorption spectroscopy. It was found that compared to the lithiation process, the porous cobalt oxide undergoes less pore structure changes, oxidation state, and local structure changes as well as crystal structure evolution during its sodiation process, which is attributed to the intrinsic low sodiation activity of cobalt oxide as evidenced by ab initio molecular dynamics simulations. Moreover, it was indicated that the sodiation activity of metal sulfides is higher than that of metal oxides, indicating a better candidate for SIBs. Such understanding is crucial for future design and improvement of high performance electrode materials for SIBs. PMID- 28072544 TI - Why Can Unnatural Electron Acceptors Protect Photosynthesizing Organisms but Kill the Others? AB - The polychlorinated compounds captafol (CPL) and 2,6-dichloroisonicotinic acid (INA) are able to protect plants acting as a fungicide or an inductor of plant resistance, respectively. At the same time, CPL and INA are dangerous for the respiratory organisms, i.e. mammalians, bacteria, and fungi. The high electron withdrawing ability of these compounds enables them to serve as unnatural electron acceptors in the cellular ambient near to electron transport pathways located in the thylakoid membrane of chloroplasts or in the mitochondrial respiratory chain. Low-energy electron attachment to CPL and INA in vacuo leads to formation of many fragment species mainly at thermal electron energy as it is shown using dissociative electron attachment spectroscopy. On the basis of the experimental findings, assigned with the support of density functional theory calculations it is suggested that the different bioactivity of CPL and INA in respiratory and photosynthetic organisms is due to the interplay between the dissociative electron attachment process and the energies of electrons leaked from the electron transport pathways. PMID- 28072545 TI - Ultrafast Photoinduced Deactivation Dynamics of Proteorhodopsin. AB - We report femtosecond time-resolved absorption change measurements of the photoinduced deactivation dynamics of a microbial rhodopsin in the ultraviolet visible and mid-infrared range. The blue light quenching process is recorded in green proteorhodopsin's (GPR) primary proton donor mutant E108Q from the deprotonated 13-cis photointermediate. The return of GPR to the dark state occurs in two steps, starting with the photoinduced 13-cis to all-trans reisomerization of the retinal. The subsequent Schiff base reprotonation via the primary proton acceptor (D97) occurs on a nanosecond time scale. This step is two orders of magnitude faster than that in bacteriorhodopsin, potentially because of the very high pKA of the GPR primary proton acceptor. PMID- 28072546 TI - Three-Dimensional Integration of Black Phosphorus Photodetector with Silicon Photonics and Nanoplasmonics. AB - We demonstrate the integration of a black phosphorus photodetector in a hybrid, three-dimensional architecture of silicon photonics and metallic nanoplasmonics structures. This integration approach combines the advantages of the low propagation loss of silicon waveguides, high-field confinement of a plasmonic nanogap, and the narrow bandgap of black phosphorus to achieve high responsivity for detection of telecom-band, near-infrared light. Benefiting from an ultrashort channel (~60 nm) and near-field enhancement enabled by the nanogap structure, the photodetector shows an intrinsic responsivity as high as 10 A/W afforded by internal gain mechanisms, and a 3 dB roll-off frequency of 150 MHz. This device demonstrates a promising approach for on-chip integration of three distinctive photonic systems, which, as a generic platform, may lead to future nanophotonic applications for biosensing, nonlinear optics, and optical signal processing. PMID- 28072547 TI - Mild Photochemical Biofunctionalization of Glass Microchannels. AB - The ability to locally modify the inside of microfluidic channels with bioactive molecules is of ever-rising relevance. In this article, we show the direct photochemical coupling of a N-hydroxysuccinimide-terminated omega-alkene onto hydrogen-terminated silicon oxide, and its subsequent functionalization with a catalytically active DNAzyme. To achieve this local attachment of a DNAzyme, we prepared hydrogen-phenyl-terminated glass (H-Phi-glass) by the reaction of glass with H-SiPhCl2. The presence of a radical-stabilizing substituent on the Si atom (i.e., phenyl) enabled the covalent modification of bare glass substrates and of the inside of glass microchannels with a functional organic monolayer that allowed direct reaction with an amine-functionalized biomolecule. In this study, we directly attached an NHS-functionalized alkene to the modified glass surface using light with a wavelength of 328 nm, as evidenced by SCA, G-ATR, XPS, SEM, AFM and fluorescence microscopy. Using these NHS-based active esters on the surface, we performed a direct localized attachment of a horseradish peroxidase (HRP)-mimicking hemin/G-quadruplex (hGQ) DNAzyme complex inside a microfluidic channel. This wall-coated hGQ DNAzyme effectively catalyzed the in-flow oxidation of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) [ABTS] in the presence of hydrogen peroxide. This proof-of-concept of mild biofunctionalization will allow the facile preparation of modified microchannels for myriad biorelevant applications. PMID- 28072548 TI - Conference Report: Biosignature Preservation and Detection in Mars Analog Environments. AB - The Conference on Biosignature Preservation and Detection in Mars Analog Environments held in May 2016 brought together scientists to discuss microbial biosignatures in Mars analog habitable environments. Five analog environments were discussed: (1) hydrothermal spring systems, (2) subaqueous environments, (3) subaerial environments, (4) subsurface environments, and (5) iron-rich systems. This paper details the major messages that resulted from the discussions and will be followed by a review paper that adds significant detail from the published literature and interpretations from the writing committee of the workshop for future research and application to astrobiological exploration missions. Key Words: Biosignature preservation-Biosignature detection-Mars analog environments Conference report-Astrobiological exploration. Astrobiology 17, 1-2. PMID- 28072549 TI - Free Flight Physiology: Paragliding and the Study of Extreme Altitude. PMID- 28072550 TI - Rotational Advancement in Cleft Nose Rhinoplasty - Buccal Mucosal Grafts Serve as a Powerful Tool. AB - OBJECTIVE: Our aim was to analyze our technique of a modified rotational advancement in conjunction with buccal mucosal grafts (BMGs) in a subgroup of severe cleft cases. DESIGN: A retrospective clinical and photographic evaluation was conducted. Columella angle (CA) and tip projection (TPR) served as instruments in a photometric analysis. SETTING: Academic university hospital and specialized craniofacial cleft center. PATIENTS: At the time of the secondary rhinoplasty, 61 cleft patients were included, all 17 years or older. INTERVENTIONS: Rotational advancement with usage of BMGs was performed in selected cases by a single surgeon. MAIN OUTCOME MEASURES: Nasal symmetry and aesthetic appearance. RESULTS: From 2003 to 2011, 29 unilateral severe cleft cases (group I) underwent a modified alar rotational advancement with BMGs. Group II, with 32 cases, represented patients without BMGs. Technique and management of BMGs were described in detail. The complication rate of donor and recipient site presented as very low. The CA was improved significantly in both groups. Also, TPR improved (not significantly) in group I. Using our technique, we considerably enhanced the aesthetic results and symmetry in secondary cleft rhinoplast. CONCLUSIONS: Rotating the vestibular skin makes it possible to eliminate the traction of this skin on the repositioned alar cartilage, therefore achieving a more pleasing and stable nasal symmetry in secondary cleft rhinoplasty. Versatile BMGs close this gap, thus making them a powerful tool in the arsenal of the reconstructive cleft surgeon. PMID- 28072551 TI - Assessment of subclinical left ventricular changes in essential hypertensive patients with hyperuricemia: A three-dimensional speckle-tracking echocardiography study. AB - OBJECTIVE: To evaluate the effect of hyperuricemia (HU) on subclinical changes of left ventricle (LV) function and structure in patients with hypertension (HT) using three-dimensional speckle-tracking echocardiography (3DSTE) and to explore the relationships between serum uric acid (SUA) levels and three-dimensional speckle tracking echocardiography (3DSTE) parameters in hypertensive and nonhypertensive patients with HU. METHODS: Four age- and sex-matched groups were studied: I: healthy controls, HT- HU- (n = 40); II: HT- HU+ (n = 40); III: HT+ HU (n = 40); IV: HT+ HU+ (n = 44). Conventional echocardiography and 3DSTE were recorded. Relative wall thickness (RWT) and left ventricular mass index assessed by M-mode echocardiography (LVMi-M) were calculated. 3DSTE parameters including LV volumes and ejection fraction (EF), LVMi-3D, global longitudinal strain (GLS), and global circumferential strain (GCS) were compared. The relationships between SUA levels and 3DSTE parameters were investigated. RESULTS: Despite LV diameters, LV volumes and EF were similar among groups (all p > 0.05), GLS decreased and LVMi-3D increased from controls (group I) to patients with HU or HT alone (group II or III), and patients with both HU and HT (group IV) (all p < 0.05). SUA levels were significantly correlated with the absolute value of GLS (r = -0.461, p < 0.05) and LVMi-3D (r = 0.504, p < 0.05) in hypertensive and nonhypertensive patients with HU. CONCLUSIONS: HU may exacerbate LV systolic dysfunction and remodeling in hypertensive patients, which can be detected by 3DSTE. Early uric acid lowing treatment may be beneficial for hypertensive patients with HU. PMID- 28072552 TI - Vehicle-Controlled, Phase 2 Clinical Trial of a Sustained-Release Dexamethasone Intracanalicular Insert in a Chronic Allergen Challenge Model. AB - PURPOSE: To evaluate the efficacy and safety of a sustained-release dexamethasone intracanalicular insert (DextenzaTM) in a model of allergic conjunctivitis. METHODS: This was a randomized, double-masked, vehicle-controlled, Phase 2 study. Subjects had to have a positive conjunctival allergen challenge (CAC) reaction to allergen (bilateral +2 itching and redness on 5-point, 0-4 scales) at Visit 1, and for 2 of 3 time points on subsequent visits. Subjects who met entry criteria were randomized to receive Dextenza or PV (vehicle insert). Challenges occurred over 42 days, with efficacy assessed at 14 (primary endpoint visit), 28, and 40 days postinsertion. Outcome measures included the evaluation of ocular itching, redness, tearing, chemosis, eyelid swelling, rhinorrhea, and congestion. RESULTS: Twenty-eight subjects completed the study in the Dextenza group and 31 in the vehicle group. At 14 days postinsertion, Dextenza was statistically superior to PV, with least square mean differences for ocular itching of -0.76, -0.97, and 0.87 at 3, 5, and 7 min post-CAC, and for conjunctival redness of -0.46, -0.66, and -0.68 at 7, 15, and 20 min post-CAC. Clinical significance, defined as a 1-U decrease from PV, was not met for primary efficacy. Secondary endpoints, including number of subjects reporting itching and conjunctival redness, indicated superior performance of Dextenza compared with vehicle. Eleven Dextenza treated (35.5%) and 10 vehicle-treated (30.3%) subjects each experienced a single adverse event. CONCLUSION: This Phase 2 study demonstrated preliminary efficacy and safety data of Dextenza for treatment of allergic conjunctivitis. PMID- 28072553 TI - Decreased Killing Activity of Micafungin Against Candida guilliermondii, Candida lusitaniae, and Candida kefyr in the Presence of Human Serum. AB - Currently, echinocandins are first-line drugs for treatment of invasive candidiasis. However, data on how serum influences killing activity of echinocandins against uncommon Candida species are limited. Therefore, the killing activity of micafungin in RPMI-1640 and in 50% serum was compared against Candida guilliermondii, Candida lusitaniae, and Candida kefyr. Minimum inhibitory concentration (MIC) ranges in RPMI-1640 were 0.5-1, 0.12-0.25, and 0.06-0.12 mg/L, respectively. In 50% serum, MICs increased 32- to 256-fold. In RPMI-1640 >= 0.25, >=4, and 32 mg/L micafungin was fungicidal against all four C. kefyr (<=4.04 hours), two of three C. lusitaniae (<=16.10 hours), and two of three C. guilliermondii (<=12.30 hours), respectively. In 50% serum, all three species grew at <=4 mg/L. Micafungin at 16-32 mg/L was fungicidal against all C. kefyr isolates (<=3.03 hours) and at 32 mg/L was fungistatic against one of three C. lusitaniae isolates. Two C. lusitaniae isolates and all three C. guilliermondii grew at all tested concentrations. Adding human serum to susceptibility test media drew attention to loss of fungicidal or fungistatic activity of micafungin in the presence of serum proteins, which is not predicted by MICs in case of C. kefyr and C. lusitaniae in RPMI-1640. Our results strongly suggest that micafungin and probably other echinocandins should be used with caution against rare Candida species. PMID- 28072554 TI - Personality Traits and Health-Related Quality of Life Among Adolescent and Young Adult Cancer Patients: The Role of Psychological Distress. AB - Personality may affect the way adolescents and young adults (AYAs) with cancer report health-related quality of life (HRQoL). Patients aged 15-39 years (n = 165) completed a survey at 12-16 months postdiagnosis. The survey included questions on HRQoL (SF-36), distress Brief Symptom Inventory-18, and personality (NEO-Five-Factor Inventory). Personality traits were not associated with physical HRQoL. The personality trait neuroticism was negatively associated with mental HRQoL (beta = -0.37; p < 0.001) and positively with psychological distress (beta = 0.47; p < 0.001). Hierarchical regression and mediation analyses indicated that psychological distress fully mediated the association between neuroticism and mental HRQoL. Findings emphasize the importance of psychosocial intervention for distress in AYAs with cancer. PMID- 28072555 TI - On Constructing Ensembles for Combinatorial Optimisation. AB - Although the use of ensemble methods in machine-learning is ubiquitous due to their proven ability to outperform their constituent algorithms, ensembles of optimisation algorithms have received relatively little attention. Existing approaches lag behind machine-learning in both theory and practice, with no principled design guidelines available. In this article, we address fundamental questions regarding ensemble composition in optimisation using the domain of bin packing as an example. In particular, we investigate the trade-off between accuracy and diversity, and whether diversity metrics can be used as a proxy for constructing an ensemble, proposing a number of novel metrics for comparing algorithm diversity. We find that randomly composed ensembles can outperform ensembles of high-performing algorithms under certain conditions and that judicious choice of diversity metric is required to construct good ensembles. The method and findings can be generalised to any metaheuristic ensemble, and lead to better understanding of how to undertake principled ensemble design. PMID- 28072556 TI - Therapeutic Management of Pyriform Sinus Cancer. AB - Objective To analyze the survival rate of a nonselected pyriform sinus cancer population. Study Design Case series with chart review. Setting University hospital. Subjects and Methods A total of 122 patients were included in this study covering the 2002-2008 period. All patients had squamous cell carcinoma originating from the pyriform sinus. Survival and prognostic factors were analyzed. Results The 3- and 5-year overall survival rates were 39.7% and 2.4%, respectively. The 3- and 5-year survival rates without recurrence were 34% and 27%, respectively. The median survival rates by UICC stage were as follows: stage 1 and 2 patients, 60 months; stage 3, 40 months; stage 4, 19 months. Stage 4 patients had a lower median survival rate than other stages ( P = .039). The 5 year survival rate was 46% for patients having T3-T4 operable cancers treated by surgery vs 45% for patients treated by laryngeal conservation protocol (not significant). The 5-year survival rate for patients having nonoperable T4 cancers was 17.2%. The 3- and 5-year overall survival rates of N0 patients was significantly higher than N1 patients ( P = .042). N2 and N3 patients had 100% 5 year mortality. Conclusion This study showed that overall survival and therapeutic management depend on the initial stage of pyriform sinus cancer, notably on the N status. In particular, nonoperable T4 pyriform sinus cancer and N2 and N3 patients had a very poor prognosis. A laryngeal conservation protocol seemed as effective as surgical management in terms of survival. PMID- 28072557 TI - Expression and localization of the AT1 and AT2 angiotensin II receptors and alpha1A and alpha1D adrenergic receptors in aorta of hypertensive and diabetic rats. AB - Hypertension and diabetes are multifactorial diseases that frequently coexist and exacerbate each another. During the development of diabetes, the impairment of noradrenergic and renin-angiotensin systems has been reported in the response mediated by alpha1-AR and AT1 receptors. Although their participation in the development of cardiovascular complications is still controversial, some studies have found increased or diminished response to the vasoconstrictive effect of noradrenaline or angiotensin II in a time-dependent manner of diabetes. Thus, the aim of this work was to investigate the possible changes in the expression or localization of alpha1-AR (alpha1A and alpha1D) and angiotensin II receptors (AT1 and AT2) in aorta of rats after 4 weeks of the onset of diabetes. In order to be able to examine the expression of these receptors, immunofluorescence procedure was performed in tunica intima and tunica media of histological sections of aorta. Fluorescence was detected by a confocal microscopy. Our results showed that the receptors are expressed in both tunics, where adrenergic receptors have a higher density in tunica intima and tunica media of SHR compared with WKY; meanwhile, the expression of angiotensin II receptors is not modified in both groups of rats. On the other hand, the results showed that diabetes produced an increase or a decrease in the expression of receptors that is not associated to a specific type of receptor, vascular region, or strain of rat. In conclusion, diabetes and hypertension modify the expression of the receptors in tunica intima and tunica media of aorta in a different way. PMID- 28072558 TI - A link between transcription fidelity and pausing in vivo. AB - Pausing by RNA polymerase is a major mechanism that regulates transcription elongation but can cause conflicts with fellow RNA polymerases and other cellular machineries. Here, we summarize our recent finding that misincorporation could be a major source of transcription pausing in vivo, and discuss the role of misincorporation-induced pausing. PMID- 28072559 TI - Control of Endophytic Frankia Sporulation by Alnus Nodule Metabolites. AB - A unique case of microbial symbiont capable of dormancy within its living host cells has been reported in actinorhizal symbioses. Some Frankia strains, named Sp+, are able to sporulate inside plant cells, contrarily to Sp- strains. The presence of metabolically slowed-down bacterial structures in host cells alters our understanding of symbiosis based on reciprocal benefits between both partners, and its impact on the symbiotic processes remains unknown. The present work reports a metabolomic study of Sp+ and Sp- nodules (from Alnus glutinosa), in order to highlight variabilities associated with in-planta sporulation. A total of 21 amino acids, 44 sugars and organic acids, and 213 secondary metabolites were detected using UV and mass spectrometric-based profiling. Little change was observed in primary metabolites, suggesting that in-planta sporulation would not strongly affect the primary functionalities of the symbiosis. One secondary metabolite (M27) was detected only in Sp+ nodules. It was identified as gentisic acid 5-O-beta-d-xylopyranoside, previously reported as involved in plant defenses against microbial pathogens. This metabolite significantly increased Frankia in-vitro sporulation, unlike another metabolite significantly more abundant in Sp- nodules [M168 = (5R)-1,7-bis-(3,4-dihydroxyphenyl)-heptane-5-O beta-d-glucopyranoside]. All these results suggest that the plant could play an important role in the Frankia ability to sporulate in planta and allow us to discuss a possible sanction emitted by the host against less cooperative Sp+ symbionts. PMID- 28072560 TI - A Prostacyclin Analog, Cicaprost, Exhibits Potent Anti-Inflammatory Activity in Human Primary Immune Cells and a Uveitis Model. AB - PURPOSE: To investigate the therapeutic potential of a prostacyclin (IP) receptor agonist for ocular inflammation and the effect on immune cells. METHODS: The anti inflammatory activities of cicaprost were determined in primary human monocyte derived macrophages and human monocyte-derived dendritic cells (MoDC), as well as a lipopolysaccharides (LPS)-induced rat uveitis model. Multiple cytokine release was measured by utilizing Luminex Technology. Prostacyclin (IP) Receptor expression was detected by reverse transcription-polymerase chain receptor. Leukocyte infiltration and protein exudation in the rat uveitis model were measured using a hemocytometer and protein concentration by a NanoDrop instrument. RESULTS: Cicapost, an IP receptor agonist, potently inhibits proinflammatory chemokines/cytokine production not only from LPS- or TNFalpha (tumor necrosis factor-alpha)-induced primary human monocyte-derived macrophages, but also from LPS-stimulated MoDC. While constitutively expressed in macrophages, the IP receptor was inducible by LPS stimulation in MoDCs. In a LPS-induced rat uveitis model, cicaprost efficaciously prevents ocular inflammatory cell and protein leakage, as well as inflammatory cytokine release. CONCLUSION: The IP receptor agonist cicaprost is a potent anti-inflammatory agent, implicating that the tightly controlled PGI2/IP signaling pathway is important in regulating inflammation. This response could be harnessed in ocular inflammatory disease where steroids are currently the standard of care. PMID- 28072561 TI - Primary Leptomeningeal Melanoma in a Patient With Multiple Congenital Melanocytic Nevi Treated With Ipilimumab. PMID- 28072562 TI - A Systematic Review. AB - Objectives (1) To systematically identify studies evaluating the use of intralesional cidofovir or bevacizumab as an adjunct in adult recurrent respiratory papillomatosis, determine disease severity and functional outcomes, and assess study quality. (2) To compare outcomes between the 2 adjuncts. Data Sources Ovid Medline, EMBASE, Scopus, and Clinical-Trials.gov . Review Methods Data sources were systematically searched. A priori inclusion and exclusion criteria were instituted. Quality was evaluated with the Newcastle-Ottawa Quality Assessment Scale. A priori criteria were instituted to select studies suitable for comparison. Results A total of 254 identified studies led to 16 for full-text review, including 14 for cidofovir and 2 for bevacizumab. Disease severity outcomes were reported in all studies, including remission rate, Derkay scores, time interval between operations, and/or lesion volume reduction. Remission rate was the most commonly reported (14 studies). Functional outcomes were reported in 5 studies (36%), including quality-of-life questionnaires, acoustic/aerodynamic analysis, and perceptual voice analysis. Voice-related quality of life was the most commonly reported (2 studies). Of 16 studies, 12 (75%) were rated poor quality. Reports almost invariably showed improved disease severity and functional outcomes following treatment; however, variable outcome measures and inadequate follow-up disallowed direct comparison of adjuncts. Conclusion Remission rate was the most commonly reported disease severity outcome, and voice related quality of life was the most commonly reported functional outcome. Most studies were of poor quality. No studies met criteria for comparative analysis between adjuncts. Future research would be improved by reporting consistent and comparable disease severity and functional outcomes, treatment protocols, and follow-up. PMID- 28072564 TI - Clinical Factors Associated with the Diagnosis of Granulomatosis with Polyangiitis. AB - Objective To determine the predictive value of nasal endoscopic findings and symptoms in the diagnosis of granulomatosis with polyangiitis (GPA). Study Design A cross-sectional study. Setting A tertiary university hospital. Subjects and Methods A total of 116 adults were enrolled in the study: 19 patients with GPA, 29 patients with other rheumatic diseases, and 68 healthy volunteers. All patients were examined with a flexible endoscope, and nasal endoscopic images were recorded and evaluated blindly. The medical history of each patient was taken by a physician blinded to the patient's diagnosis. Results Univariate analysis indicated a statistically significant difference in rhinorrhea ( P = .002), postnasal drip ( P = .015), epistaxis ( P < .001), and saddle nose ( P = .017). However, binary logistic regression analysis demonstrated that only history of epistaxis ( P = .012; odds ratio, 5.6) was statistically significant in predicting GPA. Univariate analysis showed a statistically significant difference in nasal secretion ( P = .028), nasal septal perforation ( P < .017), nasal crusting ( P < .001), nasal adhesion ( P < .001), nasal granuloma ( P = .017), and hemorrhagic fragile nasal mucosa ( P < .001). A binary logistic regression analysis demonstrated that only hemorrhagic fragile nasal mucosa ( P < .001; odds ratio, 52.9) was a statistically significant predictor of GPA. Conclusions Given the results of this study, we believe that hemorrhagic fragile nasal mucosa and history of recurrent epistaxis may put patients at risk for GPA and should be investigated accordingly. PMID- 28072563 TI - Inefficiencies in Computed Tomography Sinus Imaging for Management of Sinonasal Disease. AB - Objective A subset of patients with sinonasal disease who obtain a diagnostic computed tomography (CT) sinus scan may require repeat preoperative CT due to the inadequacy of diagnostic CT for image-guided sinus surgery (IGSS). This leads to increased CT utilization, health care costs, and patient exposure to ionizing radiation. The objective of this study is to determine the frequencies of diagnostic CT sinus studies that were inadequate for IGSS and repeat CT studies for purposes of IGSS. Study Design A retrospective chart study was performed between May 2012 and August 2013. Setting Tertiary care rhinology practice. Subjects and Methods New patients with any sinonasal diagnosis who presented with CT sinus scans acquired from outside institutions were included. CT scans were considered inadequate for IGSS for any of the following reasons: >1.5-mm slice thickness, oblique axial planes due to gantry tilt, and incompletely defined or missing IGSS anatomic landmarks. Results Of 183 patients, 85 (46%) presented with diagnostic CT sinus scans that were inadequate for IGSS. Seventy-one patients met indications for IGSS, of which 37 (52%) required repeat CT due to an IGSS inadequate diagnostic scan. Conclusion The frequency of repeat preoperative CT sinus imaging may be high at tertiary care centers where IGSS is performed. A standardized IGSS-adequate CT sinus protocol may avoid the need for repeat preoperative scans. Potential advantages include improved efficiency, decreased health care costs, and reduced ionizing radiation exposure to the patient. PMID- 28072565 TI - Corrigendum. AB - Corrigendum to Ghezzi A, Annovazzi P, Amato MP et al. (2013). Adverse events after endovascular treatment of chronic cerebro-spinal venous insufficiency (CCSVI) in patients with multiple sclerosis. Mult Scler 19(7) 961-963. [DOI: 10.1177_1352458513475491 ]. PMID- 28072566 TI - Guard the guardian: A CRL4 ligase stands watch over histone production. AB - Histones are evolutionarily conserved proteins that together with DNA constitute eukaryotic chromatin in a defined stoichiometry. Core histones are dynamic scaffolding proteins that undergo a myriad of post-translational modifications, which selectively engage chromosome condensation, replication, transcription and DNA damage repair. Cullin4-RING ubiquitin E3 ligases are known to hold pivotal roles in a wide spectrum of chromatin biology ranging from chromatin remodeling and transcriptional repression, to sensing of cytotoxic DNA lesions. Our recent work uncovers an unexpected function of a CRL4 ligase upstream of these processes in promoting histone biogenesis. The CRL4WDR23 ligase directly controls the activity of the stem-loop binding protein (SLBP), which orchestrates elemental steps of canonical histone transcript metabolism. We demonstrate that non proteolytic ubiquitination of SLBP ensures sufficient histone reservoirs during DNA replication and is vital for genome integrity and cellular fitness. PMID- 28072567 TI - Commentary on the integration of model sharing and reproducibility analysis to scholarly publishing workflow in computational biomechanics. AB - OBJECTIVE: The overall goal of this paper is to demonstrate that dissemination of models and analyses for assessing the reproducibility of simulation results can be incorporated in the scientific review process in biomechanics. METHODS: As part of a special issue on model sharing and reproducibility in the IEEE Transactions on Biomedical Engineering, two manuscripts on computational biomechanics were submitted: Rajagopal et al., IEEE Trans. Biomed. Eng., 2016 and Schmitz and Piovesan, IEEE Trans. Biomed. Eng., 2016. Models used in these studies were shared with the scientific reviewers and the public. In addition to the standard review of the manuscripts, the reviewers downloaded the models and performed simulations that reproduced results reported in the studies. RESULTS: There was general agreement between simulation results of the authors and those of the reviewers. Discrepancies were resolved during the necessary revisions. The manuscripts and instructions for download and simulation were updated in response to the reviewers' feedback; changes that may otherwise have been missed if explicit model sharing and simulation reproducibility analysis was not conducted in the review process. Increased burden on the authors and the reviewers, to facilitate model sharing and to repeat simulations, were noted. CONCLUSION: When the authors of computational biomechanics studies provide access to models and data, the scientific reviewers can download and thoroughly explore the model, perform simulations, and evaluate simulation reproducibility beyond the traditional manuscript-only review process. SIGNIFICANCE: Model sharing and reproducibility analysis in scholarly publishing will result in a more rigorous review process, which will enhance the quality of modeling and simulation studies and inform future users of computational models. PMID- 28072568 TI - Disorders of sex development. PMID- 28072569 TI - Perinatal critical care and ethics in perinatal medicine: the role of the perinatologist. PMID- 28072570 TI - What's new in preterm birth prediction and prevention? PMID- 28072571 TI - A geometric atlas to predict lung tumor shrinkage for radiotherapy treatment planning. AB - To develop a geometric atlas that can predict tumor shrinkage and guide treatment planning for non-small-cell lung cancer. To evaluate the impact of the shrinkage atlas on the ability of tumor dose escalation. The creation of a geometric atlas included twelve patients with lung cancer who underwent both planning CT and weekly CBCT for radiotherapy planning and delivery. The shrinkage pattern from the original pretreatment to the residual posttreatment tumor was modeled using a principal component analysis, and used for predicting the spatial distribution of the residual tumor. A predictive map was generated by unifying predictions from each individual patient in the atlas, followed by correction for the tumor's surrounding tissue distribution. Sensitivity, specificity, and accuracy of the predictive model for classifying voxels inside the original gross tumor volume were evaluated. In addition, a retrospective study of predictive treatment planning (PTP) escalated dose to the predicted residual tumor while maintaining the same level of predicted complication rates for a clinical plan delivering uniform dose to the entire tumor. The effect of uncertainty on the predictive model's ability to escalate dose was also evaluated. The sensitivity, specificity and accuracy of the predictive model were 0.73, 0.76, and 0.74, respectively. The area under the receiver operating characteristic curve for voxel classification was 0.87. The Dice coefficient and mean surface distance between the predicted and actual residual tumor averaged 0.75, and 1.6 mm, respectively. The PTP approach allowed elevation of PTV D95 and mean dose to the actual residual tumor by 6.5 Gy and 10.4 Gy, respectively, relative to the clinical uniform dose approach. A geometric atlas can provide useful information on the distribution of resistant tumors and effectively guide dose escalation to the tumor without compromising the organs at risk complications. The atlas can be further refined by using more patient data sets. PMID- 28072572 TI - A 3D time reversal cavity for the focusing of high-intensity ultrasound pulses over a large volume. AB - Shock wave ultrasound therapy techniques, increasingly used for non-invasive surgery, require extremely high pressure amplitudes in precise focal spots, and large high-power transducers arranged on a spherical shell are usually used to achieve that. This solution allows limited steering of the beam around the geometrical focus of the device at the cost of a large number of transducer elements, and the treatment of large and moving organs like the heart is challenging or impossible. This paper validates numerically and experimentally the possibility of using a time reversal cavity (TRC) for the same purpose. A 128 element, 1 MHz power transducer combined with different multiple scattering media in a TRC was used. We were able to focus high-power ultrasound pulses over a large volume in a controlled manner, with a limited number of transducer elements. We reached sufficiently high pressure amplitudes to erode an Ultracal(r) target over a 10 cm2 area. PMID- 28072573 TI - Design and application of a structured phantom for detection performance comparison between breast tomosynthesis and digital mammography. AB - This paper introduces and applies a structured phantom with inserted target objects for the comparison of detection performance of digital breast tomosynthesis (DBT) against 2D full field digital mammography (FFDM). The phantom consists of a 48 mm thick breast-shaped polymethyl methacrylate (PMMA) container filled with water and PMMA spheres of different diameters. Three-dimensionally (3D) printed spiculated masses (diameter range: 3.8-9.7 mm) and non-spiculated masses (1.6-6.2 mm) along with microcalcifications (90-250 um) were inserted as targets. Reproducibility of the phantom application was studied on a single system using 30 acquisitions. Next, the phantom was evaluated on five different combined FFDM & DBT systems and target detection was compared for FFDM and DBT modes. Ten phantom images in both FFDM and DBT modes were acquired on these 5 systems using automatic exposure control. Five readers evaluated target detectability. Images were read with the four-alternative forced-choice (4-AFC) paradigm, with always one segment including a target and 3 normal background segments. The percentage of correct responses (PC) was assessed based on 10 trials of each reader for each object type, size and imaging modality. Additionally, detection threshold diameters at 62.5 PC were assessed via non linear regression fitting of the psychometric curve. The reproducibility study showed no significant differences in PC values. Evaluation of target detection in FFDM showed that microcalcification detection thresholds ranged between 110 and 118 um and were similar compared to the detection in DBT (range of 106-158 um). In DBT, detection of both mass types increased significantly (p = 0.0001 and p = 0.0002 for non-spiculated and spiculated masses respectively) compared to FFDM, achieving almost 100% detection for all spiculated mass diameters. In conclusion, a structured phantom with inserted targets was able to show evidence for detectability differences between FFDM and DBT modes for five commercial systems. This phantom has potential for application in task-based assessment at acceptance and commissioning testing of DBT systems. PMID- 28072574 TI - Motion compensation using origin ensembles in awake small animal positron emission tomography. AB - In emission tomographic imaging, the stochastic origin ensembles algorithm provides unique information regarding the detected counts given the measured data. Precision in both voxel and region-wise parameters may be determined for a single data set based on the posterior distribution of the count density allowing uncertainty estimates to be allocated to quantitative measures. Uncertainty estimates are of particular importance in awake animal neurological and behavioral studies for which head motion, unique for each acquired data set, perturbs the measured data. Motion compensation can be conducted when rigid head pose is measured during the scan. However, errors in pose measurements used for compensation can degrade the data and hence quantitative outcomes. In this investigation motion compensation and detector resolution models were incorporated into the basic origin ensembles algorithm and an efficient approach to computation was developed. The approach was validated against maximum liklihood-expectation maximisation and tested using simulated data. The resultant algorithm was then used to analyse quantitative uncertainty in regional activity estimates arising from changes in pose measurement precision. Finally, the posterior covariance acquired from a single data set was used to describe correlations between regions of interest providing information about pose measurement precision that may be useful in system analysis and design. The investigation demonstrates the use of origin ensembles as a powerful framework for evaluating statistical uncertainty of voxel and regional estimates. While in this investigation rigid motion was considered in the context of awake animal PET, the extension to arbitrary motion may provide clinical utility where respiratory or cardiac motion perturb the measured data. PMID- 28072575 TI - Systematics of relative biological effectiveness measurements for proton radiation along the spread out Bragg peak: experimental validation of the local effect model. AB - The purpose of this study is to compare the predictions of the local effect model (LEM) in an extensive analysis to proton relative biological effectiveness (RBE) experiments found in the literature, and demonstrate the capabilities of the model as well as to discuss potential limitations. 19 publications with in vitro experiments and 10 publications with in vivo experiments focusing on proton RBE along the spread out Bragg peak (SOBP) were considered. In total the RBE values of over 100 depth positions were compared to LEM predictions. The treatment planning software TRiP98 was used to reconstruct the proton depth dose profile, and, together with the physical dose distribution, the RBE prediction was conducted based on the LEM. Only parameters from photon dose response curves are used as input for the LEM, and no free parameters are introduced, thus allowing us to demonstrate the predictive power of the LEM for protons. The LEM describes the RBE adequately well within the SOBP region with a relative deviation of typically less than 10% up to 10 keV um-1. In accordance with previous publications a clear dependence of RBE on the dose-averaged linear energy transfer (LETD) was observed. The RBE in the experiments tends to increase above 1.1 for LETD values above 2 keV um-1 and above 1.5 for LETD values higher than 10 keV um-1 (distal part of the SOBP). The dose dependence is most pronounced for doses lower than 3 Gy (RBE). However, both the LEM predictions and experimental data show only a weak dependence of RBE on the tissue type, as characterized by the alpha/beta ratio, which is considered insignificant with regard to the general uncertainties of RBE. The RBE predicted by the LEM shows overall very good agreement with the experimental data within the SOBP region and is in better agreement with the experimental data than the constant RBE of 1.1 that is currently applied in the clinics. All RBE trends deduced from the experiments were also reflected by the LEM predictions, which are purely based on input parameters derived from low-LET photon radiation. PMID- 28072576 TI - Ultrasonic computed tomography imaging of iron oxide nanoparticles. AB - Iron oxide nanoparticles (IONPs) are becoming increasingly used and intensively investigated in the field of medical imaging. They are currently FDA approved for magnetic resonance imaging (MRI), and it would be highly desirable to visualize them by ultrasound as well. Previous reports using the conventional ultrasound B scan (pulse-echo) imaging technique have shown very limited detectability of these particles. The aim of this study is to explore the feasibility of imaging IONPs using the through-transmission ultrasound methodology and demonstrate their detectability using ultrasonic computed tomography (UCT). Commercially available IONPs were acoustically analysed to quantify their effect on the speed of sound (SOS) and acoustic attenuation as a function of concentration. Next, through transmission projection and UCT imaging were performed on a breast mimicking phantom and on an ex vivo tissue model, to which IONPs were injected. Finally, an MRI scan was performed to verify that the same particles examined in the ultrasound experiment can be imaged by magnetic resonance, using the same clinically relevant concentrations. The results have shown a consistent concentration dependent speed of sound increase (1.86 [Formula: see text] rise per 100 ug . ml-1 IONPs). Imaging based on this property has shown a substantial contrast-to-noise ratio improvement (up to 5 fold, p < 0.01). The SOS-related effect generated a well discernible image contrast and allowed the detection of the particles existence and location, in both raster-scan projection and UCT imaging. Conversely, no significant change in the acoustic attenuation coefficient was noted. Based on these findings, it is concluded that IONPs can be used as an effective SOS-based contrast agent, potentially useful for ultrasonic breast imaging. Furthermore, the particle offers the capacity of significantly enhancing diagnosis accuracy using multimodal MRI-ultrasound imaging capabilities. PMID- 28072577 TI - Feasibility of tungsten functional paper in electron grid therapy: a Monte Carlo study. AB - Electron grid therapy is expected to be a valid treatment for bulky superficial tumors. It is difficult, however, to fit irradiation fields to bulky superficial tumor shapes for conventional electron grid therapy with a cerrobend grid collimator. In this study, we investigated whether a grid collimator using tungsten functional paper (TFP), with its radiation shielding ability, could be used for electron grid therapy. Dose distributions were measured using 9 MeV electron grid beams from a cerrobend grid collimator. For the simulation study, the same grid irradiation fields were shaped using a TFP grid collimator (thicknesses of 0.15, 0.3, 0.6, 0.9, and 1.2 cm) by laying them on a phantom. We then determined the dose distributions using Monte Carlo calculations and compared the cerrobend and TFP electron grid beams regarding dose distributions, including the depths of the maximum dose (d max), 90% dose (d 90), and 80% dose (d 80), and the ratios of the doses in the areas with and without shielding (valley to peak ratios). The equivalent dosimetric thickness was obtained with the TFP grid collimator that was equivalent to the dose distribution of the cerrobend grid collimator. For the cerrobend electron grid beams, the d max, d 90, and d 80 were 1.0, 2.1, and 2.5 cm, respectively, and the valley to peak ratios at those depths were 0.48, 0.66, and 0.73, respectively. The equivalent dosimetric thickness of TFP was 0.52 cm. The d max, d 90, and d 80 for the 0.52 cm thick TFP electron grid beams were 1.1, 1.9, and 2.3 cm, respectively, and the valley to peak ratios at those depths were 0.49, 0.63, and 0.71, respectively. The TFP grid collimator flexibly delivered excellent dose distributions by simply attaching it to the patient's skin. It could thus be used for electron grid therapy instead of the cerrobend grid collimator. PMID- 28072578 TI - Mathematical modelling of scanner-specific bowtie filters for Monte Carlo CT dosimetry. AB - The purpose of bowtie filters in CT scanners is to homogenize the x-ray intensity measured by the detectors in order to improve the image quality and at the same time to reduce the dose to the patient because of the preferential filtering near the periphery of the fan beam. For CT dosimetry, especially for Monte Carlo calculations of organ and tissue absorbed doses to patients, it is important to take the effect of bowtie filters into account. However, material composition and dimensions of these filters are proprietary. Consequently, a method for bowtie filter simulation independent of access to proprietary data and/or to a specific scanner would be of interest to many researchers involved in CT dosimetry. This study presents such a method based on the weighted computer tomography dose index, CTDIw, defined in two cylindrical PMMA phantoms of 16 cm and 32 cm diameter. With an EGSnrc-based Monte Carlo (MC) code, ratios CTDIw/CTDI100,a were calculated for a specific CT scanner using PMMA bowtie filter models based on sigmoid Boltzmann functions combined with a scanner filter factor (SFF) which is modified during calculations until the calculated MC CTDIw/CTDI100,a matches ratios CTDIw/CTDI100,a, determined by measurements or found in publications for that specific scanner. Once the scanner-specific value for an SFF has been found, the bowtie filter algorithm can be used in any MC code to perform CT dosimetry for that specific scanner. The bowtie filter model proposed here was validated for CTDIw/CTDI100,a considering 11 different CT scanners and for CTDI100,c, CTDI100,p and their ratio considering 4 different CT scanners. Additionally, comparisons were made for lateral dose profiles free in air and using computational anthropomorphic phantoms. CTDIw/CTDI100,a determined with this new method agreed on average within 0.89% (max. 3.4%) and 1.64% (max. 4.5%) with corresponding data published by CTDosimetry (www.impactscan.org) for the CTDI HEAD and BODY phantoms, respectively. Comparison with results calculated using proprietary data for the PHILIPS Brilliance 64 scanner showed agreement on average within 2.5% (max. 5.8%) and with data measured for that scanner within 2.1% (max. 3.7%). Ratios of CTDI100,c/CTDI100, p for this study and corresponding data published by CTDosimetry (www.impactscan.org) agree on average within about 11% (max. 28.6%). Lateral dose profiles calculated with the proposed bowtie filter and with proprietary data agreed within 2% (max. 5.9%), and both calculated data agreed within 5.4% (max. 11.2%) with measured results. Application of the proposed bowtie filter and of the exactly modelled filter to human phantom Monte Carlo calculations show agreement on the average within less than 5% (max. 7.9%) for organ and tissue absorbed doses. PMID- 28072579 TI - Development of advanced signal processing and source imaging methods for superparamagnetic relaxometry. AB - Superparamagnetic relaxometry (SPMR) is a highly sensitive technique for the in vivo detection of tumor cells and may improve early stage detection of cancers. SPMR employs superparamagnetic iron oxide nanoparticles (SPION). After a brief magnetizing pulse is used to align the SPION, SPMR measures the time decay of SPION using super-conducting quantum interference device (SQUID) sensors. Substantial research has been carried out in developing the SQUID hardware and in improving the properties of the SPION. However, little research has been done in the pre-processing of sensor signals and post-processing source modeling in SPMR. In the present study, we illustrate new pre-processing tools that were developed to: (1) remove trials contaminated with artifacts, (2) evaluate and ensure that a single decay process associated with bounded SPION exists in the data, (3) automatically detect and correct flux jumps, and (4) accurately fit the sensor signals with different decay models. Furthermore, we developed an automated approach based on multi-start dipole imaging technique to obtain the locations and magnitudes of multiple magnetic sources, without initial guesses from the users. A regularization process was implemented to solve the ambiguity issue related to the SPMR source variables. A procedure based on reduced chi-square cost-function was introduced to objectively obtain the adequate number of dipoles that describe the data. The new pre-processing tools and multi-start source imaging approach have been successfully evaluated using phantom data. In conclusion, these tools and multi-start source modeling approach substantially enhance the accuracy and sensitivity in detecting and localizing sources from the SPMR signals. Furthermore, multi-start approach with regularization provided robust and accurate solutions for a poor SNR condition similar to the SPMR detection sensitivity in the order of 1000 cells. We believe such algorithms will help establishing the industrial standards for SPMR when applying the technique in pre-clinical and clinical settings. PMID- 28072580 TI - In vivo real-time cavitation imaging in moving organs. AB - The stochastic nature of cavitation implies visualization of the cavitation cloud in real-time and in a discriminative manner for the safe use of focused ultrasound therapy. This visualization is sometimes possible with standard echography, but it strongly depends on the quality of the scanner, and is hindered by difficulty in discriminating from highly reflecting tissue signals in different organs. A specific approach would then permit clear validation of the cavitation position and activity. Detecting signals from a specific source with high sensitivity is a major problem in ultrasound imaging. Based on plane or diverging wave sonications, ultrafast ultrasonic imaging dramatically increases temporal resolution, and the larger amount of acquired data permits increased sensitivity in Doppler imaging. Here, we investigate a spatiotemporal singular value decomposition of ultrafast radiofrequency data to discriminate bubble clouds from tissue based on their different spatiotemporal motion and echogenicity during histotripsy. We introduce an automation to determine the parameters of this filtering. This method clearly outperforms standard temporal filtering techniques with a bubble to tissue contrast of at least 20 dB in vitro in a moving phantom and in vivo in porcine liver. PMID- 28072581 TI - 131I activity quantification of gamma camera planar images. AB - A procedure to estimate the activity in target tissues in patients during the therapeutic administration of 131I radiopharmaceutical treatment for thyroid conditions (hyperthyroidism and differentiated thyroid cancer) using a gamma camera (GC) with a high energy (HE) collimator, is proposed. Planar images are acquired for lesions of different sizes r, and at different distances d, in two HE GC systems. Defining a region of interest (ROI) on the image of size r, total counts n g are measured. Sensitivity S (cps MBq-1) in each acquisition is estimated as the product of the geometric G and the intrinsic efficiency eta 0. The mean fluence of 364 keV photons arriving at the ROI per disintegration G, is calculated with the MCNPX code, simulating the entire GC and the HE collimator. Intrinsic efficiency eta 0 is estimated from a calibration measurement of a plane reference source of 131I in air. Values of G and S for two GC systems-Philips Skylight and Siemens e-cam-are calculated. The total range of possible sensitivity values in thyroidal imaging in the e-cam and skylight GC measure from 7 cps MBq-1 to 35 cps MBq-1, and from 6 cps MBq-1 to 29 cps MBq-1, respectively. These sensitivity values have been verified with the SIMIND code, with good agreement between them. The results have been validated with experimental measurements in air, and in a medium with scatter and attenuation. The counts in the ROI can be produced by direct, scatter and penetration photons. The fluence value for direct photons is constant for any r and d values, but scatter and penetration photons show different values related to specific r and d values, resulting in the large sensitivity differences found. The sensitivity in thyroidal GC planar imaging is strongly dependent on uptake size, and distance from the GC. An individual value for the acquisition sensitivity of each lesion can significantly alleviate the level of uncertainty in the measurement of thyroid uptake activity for each patient. PMID- 28072582 TI - The effect of system geometry and dose on the threshold detectable calcification diameter in 2D-mammography and digital breast tomosynthesis. AB - Digital breast tomosynthesis (DBT) is under consideration to replace or to be used in combination with 2D-mammography in breast screening. The aim of this study was the comparison of the detection of microcalcification clusters by human observers in simulated breast images using 2D-mammography, narrow angle (15 degrees /15 projections) and wide angle (50 degrees /25 projections) DBT. The effects of the cluster height in the breast and the dose to the breast on calcification detection were also tested. Simulated images of 6 cm thick compressed breasts were produced with and without microcalcification clusters inserted, using a set of image modelling tools for 2D-mammography and DBT. Image processing and reconstruction were performed using commercial software. A series of 4-alternative forced choice (4AFC) experiments was conducted for signal detection with the microcalcification clusters as targets. Threshold detectable calcification diameter was found for each imaging modality with standard dose: 2D mammography: 2D-mammography (165 +/- 9 um), narrow angle DBT (211 +/- 11 um) and wide angle DBT (257 +/- 14 um). Statistically significant differences were found when using different doses, but different geometries had a greater effect. No differences were found between the threshold detectable calcification diameters at different heights in the breast. Calcification clusters may have a lower detectability using DBT than 2D imaging. PMID- 28072583 TI - Superconductivity and spin-orbit coupling in non-centrosymmetric materials: a review. AB - In non-centrosymmetric superconductors, where the crystal structure lacks a centre of inversion, parity is no longer a good quantum number and an electronic antisymmetric spin-orbit coupling (ASOC) is allowed to exist by symmetry. If this ASOC is sufficiently large, it has profound consequences on the superconducting state. For example, it generally leads to a superconducting pairing state which is a mixture of spin-singlet and spin-triplet components. The possibility of such novel pairing states, as well as the potential for observing a variety of unusual behaviors, led to intensive theoretical and experimental investigations. Here we review the experimental and theoretical results for superconducting systems lacking inversion symmetry. Firstly we give a conceptual overview of the key theoretical results. We then review the experimental properties of both strongly and weakly correlated bulk materials, as well as two dimensional systems. Here the focus is on evaluating the effects of ASOC on the superconducting properties and the extent to which there is evidence for singlet-triplet mixing. This is followed by a more detailed overview of theoretical aspects of non centrosymmetric superconductivity. This includes the effects of the ASOC on the pairing symmetry and the superconducting magnetic response, magneto-electric effects, superconducting finite momentum pairing states, and the potential for non-centrosymmetric superconductors to display topological superconductivity. PMID- 28072584 TI - Verification of respiratory-gated radiotherapy with new real-time tumour-tracking radiotherapy system using cine EPID images and a log file. AB - A combined system comprising the TrueBeam linear accelerator and a new real-time tumour-tracking radiotherapy system, SyncTraX, was installed at our institution. The objectives of this study are to develop a method for the verification of respiratory-gated radiotherapy with SyncTraX using cine electronic portal image device (EPID) images and a log file and to verify this treatment in clinical cases. Respiratory-gated radiotherapy was performed using TrueBeam and the SyncTraX system. Cine EPID images and a log file were acquired for a phantom and three patients during the course of the treatment. Digitally reconstructed radiographs (DRRs) were created for each treatment beam using a planning CT set. The cine EPID images, log file, and DRRs were analysed using a developed software. For the phantom case, the accuracy of the proposed method was evaluated to verify the respiratory-gated radiotherapy. For the clinical cases, the intra- and inter-fractional variations of the fiducial marker used as an internal surrogate were calculated to evaluate the gating accuracy and set-up uncertainty in the superior-inferior (SI), anterior-posterior (AP), and left-right (LR) directions. The proposed method achieved high accuracy for the phantom verification. For the clinical cases, the intra- and inter-fractional variations of the fiducial marker were ?3 mm and +/-3 mm in the SI, AP, and LR directions. We proposed a method for the verification of respiratory-gated radiotherapy with SyncTraX using cine EPID images and a log file and showed that this treatment is performed with high accuracy in clinical cases. PMID- 28072585 TI - Arterial Ventricular Uncoupling With Age and Disease and Recoupling With Exercise. PMID- 28072586 TI - Assessing the Quality of Services Provided in the Teaching Hospitals: A Case Study of Iran. AB - Service quality is the most important factor in the success of health care organizations; because of their vital and important services, even very small errors can be followed by great and irreparable harm and damage. This study aimed to assess the quality of services provided in the teaching hospitals affiliated to Shiraz University of Medical Sciences in 2015. This is an applied, cross sectional, and descriptive-analytical study conducted in 2015 in the teaching hospitals affiliated to Shiraz University of Medical Sciences. A sample of 290 inpatients with at least 2 days of admission to hospital was selected using stratified sampling proportional to size and simple random sampling methods. The results showed that there were significant negative gaps in all dimensions (P > .001), and the highest and lowest means and SD of negative gaps were related to empathy (-1.35 +/- 1.4) and assurance (-0.52 +/- 0.95). Moreover, the results showed that there was a significant negative correlation between the patients' age and the total mean of the patients' expectations. According to the results, the studied hospitals had not been able to meet the expectations of their patients in any of the service quality dimensions. Therefore, to improve the service quality dimensions, the authors recommend holding training courses on how to interact with patients and meet their needs, providing adequate and proper information about the diseases and their treatment for the patients, having adequate medical staff, and so on. PMID- 28072587 TI - Re: Estimating the Causal Effect of an Exposure on Change From Baseline Using Directed Acyclic Graphs and Path Analysis. PMID- 28072588 TI - Fertility Treatment and Childhood Epilepsy: A Nationwide Cohort Study. AB - BACKGROUND: Fertility treatment includes hormonal stimulation of the woman and in vitro manipulation of gametes and embryos that may influence prenatal brain development. We aimed to investigate the association between fertility treatment and childhood epilepsy, including specific types of treatment and indications, as well as subtypes of epilepsy. METHODS: In this nationwide birth cohort study, we included all pregnancies in Denmark resulting in live-born singletons, 1995-2003. Children conceived by fertility treatment and children developing epilepsy (until 2013) were identified from Danish national registers. RESULTS: A total of 565,116 pregnancies were included; 8,071 children (1.4%) developed epilepsy. Children conceived after ovulation induction or intrauterine insemination had a slightly higher risk of childhood epilepsy (hazard ratio [HR]: 1.15; 95% confidence interval [CI]: 1.00, 1.31). The association was more pronounced for the subtypes idiopathic generalized and focal epilepsy. Regarding the specific hormonal treatments, only clomiphene citrate was associated with an increased risk of childhood epilepsy, also in a sibling analysis (HR: 2.07; 95% CI: 1.05, 4.08). In vitro fertilization or intracytoplasmic sperm injection was not associated with an overall increased risk of childhood epilepsy but with idiopathic generalized epilepsy (HR: 1.43; 95% CI: 0.99, 2.05). No clear associations were seen regarding other treatment types or indications. CONCLUSIONS: Children conceived by ovulation induction or intrauterine insemination with clomiphene citrate may be at slightly increased risk of childhood epilepsy. Furthermore, children conceived by in vitro fertilization or intracytoplasmic sperm injection may be at slightly increased risk of idiopathic generalized epilepsy. PMID- 28072589 TI - The Authors Respond. PMID- 28072590 TI - Incorporating the patient's perspective in outcomes research. AB - PURPOSE OF REVIEW: Incorporation of the patients' perspective in clinical research is critical to ensure that outcomes measured reflect those, which matter most to patients. This review summarizes recent efforts to include the patients' perspective in the development of outcome measures and the importance of encouraging patient participation in decision-making and self-management. RECENT FINDINGS: Since the inclusion of fatigue as a patient-endorsed core outcome measure in rheumatoid arthritis (RA) trials, OMERACT has been instrumental in advocating for patient involvement in the development of core domains and instruments; current endeavors include cultivating an understanding of remission through the eyes of patients and gaining a sense of how to measure features of pain and 'stiffness' deemed as important to patients. The concept of remission was further explored in RA patients, highlighting a common goal of returning to normality; additionally, various tools have been developed to assess for unmet needs in rheumatology patients. Advances have also been made in the development and revision of patient-centered core measures in rheumatologic diagnoses outside of RA. SUMMARY: Incorporating the patients' perspective is now considered an essential feature in outcomes research. Future research should focus on how best to involve patients in specific research activities. PMID- 28072591 TI - Osteoporosis: fracture epidemiology update 2016. AB - PURPOSE OF REVIEW: The purpose of this review is to provide an update on osteoporosis epidemiology. The focus is on fractures because fractures are the most important clinical consequence of osteoporosis. Studies published over the past 18 months are identified and reviewed. Finally, the clinical impact of these new findings is discussed. RECENT FINDINGS: Important research in 2015-2016 include analyses of screening and rescreening in younger women and older men, risk factors for hip fractures in older men, obesity and weight loss/gain, and risk of fracture. Several dietary factors, including adherence to a Mediterranean diet and a diet rich in protein, fruits, and vegetables and maintenance of physical function with increasing age represent modifiable nonpharmacologic risk factors that improve bone health. Sarcopenia may have a more important role in fracture in men than women. Important biomarkers for fracture include low 25 hydroxyvitamin D and hemoglobin A1c. SUMMARY: Updated literature on fracture epidemiology have identified important risk factors for fracture. PMID- 28072592 TI - Metabolic syndrome-associated osteoarthritis. AB - PURPOSE OF REVIEW: Interest in the metabolic syndrome-associated osteoarthritis phenotype is increasing. Here, we summarize recently published significant findings. RECENT FINDINGS: Meta-analyses confirmed an association between type 2 diabetes and osteoarthritis and between cardiovascular diseases and osteoarthritis. Recent advances in the study of metabolic syndrome-associated osteoarthritis have focused on a better understanding of the role of metabolic diseases in inducing or aggravating joint damage. In-vivo models of obesity, diabetes, or dyslipidemia have helped to better decipher this association. They give emerging evidence that, beyond the role of common pathogenic mechanisms for metabolic diseases and osteoarthritis (i.e., low-grade inflammation and oxidative stress), metabolic diseases have a direct systemic effect on joints. In addition to the impact of weight, obesity-associated inflammation is associated with osteoarthritis severity and may modulate osteoarthritis progression in mouse models. As well, osteoarthritis synovium from type 2 diabetic patients shows insulin-resistant features, which may participate in joint catabolism. Finally, exciting data are emerging on the association of gut microbiota and circadian rhythm and metabolic syndrome-associated osteoarthritis. SUMMARY: The systemic role of metabolic syndrome in osteoarthritis pathophysiology is now better understood, but new avenues of research are being pursued to better decipher the metabolic syndrome-associated osteoarthritis phenotype. PMID- 28072593 TI - Use of benzodiazepines and related drugs is associated with a risk of stroke among persons with Alzheimer's disease. AB - The aim of our study was to investigate the risk of any, ischemic, and hemorrhagic stroke associated with incident benzodiazepine and related drug (BZDR) use among community-dwelling individuals with Alzheimer's disease (AD). Data from the MEDALZ cohort including all community-dwelling persons newly diagnosed with AD between 2005 and 2011 in Finland were utilized. Incident BZDR users were identified with a 1-year washout period for previous use. Persons with a previous stroke were excluded, resulting in a final study sample of 45 050 individuals. Incident any, ischemic, and hemorrhagic strokes were identified from the Hospital Discharge and Causes of Death registers. The risk of stroke between time on BZDRs was compared with nonuse time with Cox proportional hazard models. During the follow-up, 21.9% (N=9879) of persons started BZDR use. Compared with nonuse, BZDR use was associated with an increased risk of any stroke [adjusted hazard ratio (aHR): 1.21; 95% confidence interval (CI): 1.04-1.40] and ischemic stroke (aHR: 1.21; 95% CI: 1.02-1.44), but the association between BZDR use and hemorrhagic stroke did not reach significance (aHR: 1.26; 95% CI: 0.91-1.74). Z drug use was associated with a similar risk as benzodiazepine use. In conclusion, BZDR use was associated with an increased risk of stroke among older individuals with AD. PMID- 28072595 TI - Fluoroquinolone-Associated Muscle Tear and Hematoma: A Case Report. PMID- 28072594 TI - Genetics Consultation Rates Following a Diagnosis of High-Grade Serous Ovarian Carcinoma in the Canadian Province of Ontario. AB - OBJECTIVE: In 2001, the province of Ontario expanded cancer genetic testing eligibility to include all women with high-grade serous ovarian carcinoma (HGSC) of the ovary, fallopian tube, and peritoneum. The aim of this study was to determine the proportion of women who attended genetics counseling for consideration of BRCA1/2 gene analysis. We also sought to examine if regional differences in consultation rate exist across administrative health regions in the province of Ontario. METHODS: We identified all women with a pathological diagnosis of HGSC in the province of Ontario between 1997 until 2011. Our primary outcome was the 2-year rate of genetics consultation following a diagnosis of HGSC. We compared consultation rates over time and geographical regions and applied multiple logistic regression to identify predictors of genetics consultation. RESULTS: Of the 5412 women with a diagnosis of HGSC over the study period, 6.6% were seen for genetics consultation within 2 years of diagnosis. Factors predictive of genetics consultation included history of breast cancer (odds ratio [OR], 3.56; 95% confidence interval [CI], 1.87-6.78), era of diagnosis (2009-2011 vs 1997-2000; OR, 10.59; 95% CI, 5.02-22.33), and younger age at diagnosis (OR, 0.95; 95% CI, 0.94-0.97 for each additional year). No regional differences in consultation rate were seen. CONCLUSIONS: Despite an increasing rate across eras, a small proportion of women with HGSC undergo genetics consultation. Efforts are required to increase cancer genetics consultation in patients with HGSC in the province of Ontario. PMID- 28072596 TI - Expression of Glucose-Regulated Protein 78 and miR-199a in Rat Brain After Fatal Ligature Strangulation. AB - The roles of endoplasmic reticulum (ER) stress and microRNA in the brain tissue after fatal mechanical asphyxia have not been clearly elucidated. We examined the expression of glucose-regulated protein 78 (GRP78), the key regulator of unfolded protein response, and miR-199a in the brain tissues of rats subjected to fatal ligature strangulation to understand the roles of ER stress and microRNA in ligature strangulation. The expressions of GRP78 and miR-199a in rat cortex, hippocampi, and midbrain were measured by immunohistochemistry and Western blot analysis in a rat model of ligature strangulation. Furthermore, the levels of miR 199a-3p and miR-199a-5p were detected by real-time fluorescent quantitative polymerase chain reaction. Glucose-regulated protein 78 was highly expressed in the cortex and midbrain in the ligature strangulation group (P < 0.01) when compared with the control group. The expression of GRP78 in the hippocampi showed no significant difference between the 2 groups. miR-199a-3p in the cortex and midbrain was significantly down-regulated in the ligature strangulation group (P < 0.01). However, miR-199a-5p in each brain region showed no significant difference between the 2 groups. In conclusion, ER stress was involved in the physiological and pathological processes of ligature strangulation. Furthermore, upstream miR-199a may play an important regulatory role in mechanical asphyxia. PMID- 28072597 TI - Reperfusion injury in ST-segment elevation myocardial infarction: the final frontier. AB - ST-segment elevation myocardial infarction is a major cause of morbidity and mortality worldwide. Reperfusion injury (RI) following the opening of an occluded coronary artery mitigates the effect of reperfusion by further accentuating ischemic damage and increasing infarct size. Experimental studies have shown that nearly 50% of final infarct size is attributable to RI, an elusive phenomenon that remains resistant to treatment. This review proposes a hypothesis to explain the failure of strategies that have been used in an attempt to prevent RI. This hypothesis suggests that, after a certain duration of myocardial ischemia in the affected myocardium, three phases of myocardial damage occur: reversible ischemia, irreversible ischemia, and necrosis. In the reversible ischemia phase, cellular adaptive responses remain functional, and cellular repair and thus recovery of cellular functions is possible, whereas in the irreversible ischemia phase protective maneuvers fail to confer cytoprotection. Preventive therapies for RI fail because they cannot prevent cell death once cells have entered the irreversible ischemia phase, although they may succeed in postponing cell death. Failure to salvage myocardium with irreversible ischemia in addition to postponement and change in the mode of cell death (mainly from necrosis to apoptosis) by various RI preventive strategies may be the key to understanding the failure of these strategies in the clinical setting, despite their success in the reduction of infarct size in the experimental setting. Early reperfusion before large amounts of myocardium at risk reach the stage of irreversible ischemia is the best strategy for reduction of RI-related myocardial damage. PMID- 28072598 TI - Should patients with higher blood pressure variability be excluded from validation studies? An assessment of the '12/8' rule. AB - To limit the inclusion of participants with increased blood pressure (BP) variability and presumably to avoid potential bias, the International Standards Organization BP device validation standard recommends exclusion of patients with a BP variability of more than 12/8 mmHg across reference readings. This '12/8 rule' is based on expert consensus and lacks empirical justification. In a post hoc analysis of a study comparing two types of cuff designs carried out according to the International Standards Organization standard, we divided the study sample into patients who did not have (n=79) and patients who had (n=55) more than 12/8 mmHg variability. Patients with more than 12/8 mmHg variability were older and had a higher prevalence of diabetes (41.8 vs. 22.8%; P=0.02) and hypertension (43.6 vs. 29.1%; P=0.08). The mean systolic BP differences between the two cuff designs were not significantly different in participants who did not show more than 12/8 mmHg variability versus those who did (2.2+/-3.5 vs. 3.1+/-3.4; mean difference of differences -0.9+/-3.4; P=0.14). Similarly, the mean diastolic BP differences were not significantly different in participants who did not have more than 12/8 mmHg variability versus those who did (1.5+/-2.2 vs. 1.4+/-2.6; mean difference of differences 0.1+/-2.4; P=0.82). A limitation of our analysis is that the original study data focused on a comparison of different cuff designs and not formal validation of a specific device. Therefore, replication of these findings is warranted. Nevertheless, our findings do not support the use of the 12/8 rule and indicate that this rule may be promoting unnecessarily homogenous study samples, limiting external generalizability, and needlessly increasing workload and expense. PMID- 28072599 TI - Validation of the BPUMP BF1112 upper-arm blood pressure monitor for home blood pressure monitoring according to the European Society of Hypertension International Protocol revision 2010. AB - OBJECTIVE: The present study aimed to evaluate the accuracy of the automated oscillometric upper-arm blood pressure (BP) monitor BPUMP BF1112 for home BP monitoring according to the International Protocol of the European Society of Hypertension revision 2010 (ESH-IP2010). PARTICIPANTS AND METHODS: Systolic and diastolic BPs were sequentially measured in 33 adult Chinese (13 women, mean age 46.7 years) using a mercury sphygmomanometer (two observers) and the BF1112 device (one supervisor). A total of 99 pairs of comparisons were obtained from 33 participants for judgments in two parts with three grading phases. RESULTS: The BPUMP BF1112 device achieved the targets in part 1 of the validation study. The number of absolute differences between device and observers within 5, 10, and 15 mmHg was 85/99, 96/99, and 97/99, respectively, for systolic BP, and 83/99, 97/99, and 99/99, respectively, for diastolic BP. The device also fulfilled the criteria in part 2 of the validation study. A total of 31 and 30 participants for systolic and diastolic BP, respectively, had at least two of the three device observer differences within 5 mmHg (required>=24mmHg). No participant for systolic or diastolic BP had all the three device-observer comparisons greater than 5 mmHg. CONCLUSION: The BPUMP BP monitor BF1112 has passed the requirements of the ESH-IP2010, and hence can be recommended for home use in adults. PMID- 28072600 TI - Adjusting the Focus on Transfusion-associated Circulatory Overload. PMID- 28072601 TI - Risk Factors and Clinical Outcomes Associated with Perioperative Transfusion associated Circulatory Overload. AB - BACKGROUND: Transfusion-associated circulatory overload remains underappreciated in the perioperative environment. The authors aimed to characterize risk factors for perioperative transfusion-associated circulatory overload and better understand its impact on patient-important outcomes. METHODS: In this case control study, 163 adults undergoing noncardiac surgery who developed perioperative transfusion-associated circulatory overload were matched with 726 transfused controls who did not develop respiratory complications. Univariate and multivariable logistic regression analyses were used to evaluate potential risk factors for transfusion-associated circulatory overload. The need for postoperative mechanical ventilation, lengths of intensive care unit and hospital stay, and mortality were compared. RESULTS: For this cohort, the mean age was 71 yr and 56% were men. Multivariable analysis revealed the following independent predictors of transfusion-associated circulatory overload: emergency surgery, chronic kidney disease, left ventricular dysfunction, previous beta-adrenergic receptor antagonist use, isolated fresh frozen plasma transfusion (vs. isolated erythrocyte transfusion), mixed product transfusion (vs. isolated erythrocyte transfusion), and increasing intraoperative fluid administration. Patients who developed transfusion-associated circulatory overload were more likely to require postoperative mechanical ventilation (73 vs. 33%; P < 0.001) and experienced prolonged intensive care unit (11.1 vs. 6.5 days; P < 0.001) and hospital lengths of stay (19.9 vs. 9.6 days; P < 0.001). Survival was significantly reduced (P < 0.001) in transfusion recipients who developed transfusion-associated circulatory overload (1-yr survival 72 vs. 84%). CONCLUSIONS: Perioperative transfusion associated circulatory overload was associated with a protracted hospital course and increased mortality. Efforts to minimize the incidence of transfusion associated circulatory overload should focus on the judicious use of intraoperative blood transfusions and nonsanguineous fluid therapies, particularly in patients with chronic kidney disease, left ventricular dysfunction, chronic beta-blocker therapy, and those requiring emergency surgery. PMID- 28072602 TI - 'JAK-ing' up the treatment of primary myelofibrosis: building better combination strategies. AB - PURPOSE OF REVIEW: The article discusses the promising agents that are approved or currently under investigation for the treatment of myelofibrosis and reviews the ongoing Janus kinase (JAK) inhibitors-based combinatorial strategies in this setting. RECENT FINDINGS: Myelofibrosis is a Philadelphia-negative myeloproliferative neoplasm with constitutive JAK/STAT activation. The JAK inhibitor ruxolitinib is the only approved drug for this disease in the United States and Europe based on two randomized phase III studies that demonstrated clinically meaningful reduction in spleen size, improvement in symptoms, quality of life, and an overall survival advantage with prolonged follow-up. Emerging data have revealed the complex molecular architecture of myelofibrosis with clonal evolution playing a central role in disease progression or transformation. These molecular pathways may explain the heterogeneous benefits obtained by JAK inhibitors in patients with myelofibrosis. In addition, the genetic and epigenetic mutations appear to work in concert with overactive JAK/STAT signaling and contribute to myelofibrosis pathogenesis and prognosis, suggesting a potential to exploit them as potential therapeutic targets. SUMMARY: Combining JAK-inhibitors with agents that target parallel prosurvival pathways or agents that enhance hematopoiesis may enhance efficacy and/or mitigate on-target myelosuppression, thereby extending the therapeutic benefits observed with JAK inhibitors alone. PMID- 28072603 TI - Dyserythropoiesis of myelodysplastic syndromes. AB - PURPOSE OF REVIEW: Myelodysplastic syndromes (MDS) are heterogeneous diseases of the hematopoietic stem cell in the elderly. Anemia is the main symptom that mostly correlates with dysplastic erythropoiesis in the bone marrow. We will review the recent advances in understanding the diverse mechanisms of dyserythropoiesis. RECENT FINDINGS: Dyserythropoiesis defined as 10% dysplastic erythroid cells in the bone marrow is found in more than 80% of early MDS. Immature erythroblasts accumulate at the expense of mature erythroblasts due to differentiation arrest and apoptosis. In early MDS with dyserythropoiesis, caspase-dependent cleavage of the erythroid transcription factor GATA-1 occurring in basophilic erythroblasts accounts for impairment of final maturation. Depending on initiating genetic alteration, specific mechanisms contribute to erythroid defect. In MDS with 5q deletion, the haploinsufficiency of ribosomal protein gene, RPS14, opposes the transition of immature to mature erythroblasts by inducing a p53-dependent ribosome stress, cell cycle arrest and apoptosis. Recent work identifies the activation of a p53-S100A8/9 innate immune pathway that both intrinsically and extrinsically contributes to defective erythropoiesis. In MDS with ring sideroblasts, a paradigm of dyserythropoiesis, a unique mutation in SF3B1 splicing factor gene induces a multiplicity of alterations at RNA level that deeply modifies the patterns of gene expression. SUMMARY: Insights in the pathophysiology of MDS with dyserythropoiesis may guide the choice of the appropriate therapy, for instance lenalidomide in MDS with del(5q). A better understanding of the mechanisms of dyserthropoiesis is required to treat anemia in non-del(5q) MDS, especially in case of resistance to first line therapy by erythropoiesis-stimulating agents. PMID- 28072604 TI - Epigenetic upregulation of CXCL12 expression mediates antitubulin chemotherapeutics-induced neuropathic pain. AB - Clinically, Microtubule-targeted agents-induced neuropathic pain hampers chemotherapeutics for patients with cancer. Here, we found that application of paclitaxel or vincristine increased the protein and mRNA expression of CXCL12 and frequency and amplitude of miniature excitatory post synaptic currents (mEPSCs) in spinal dorsal horn neurons. Spinal local application of CXCL12 induced the long-term potentiation of nociceptive synaptic transmission and increased the amplitude of mEPSCs. Inhibition of CXCL12 using the transgenic mice (CXCL12) or neutralizing antibody or siRNA ameliorated the mEPSC's enhancement and mechanical allodynia. In addition, paclitaxel and vincristine both could increase the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the acetylation of histone H4 in the CXCL12-expressing neurons. Immunoprecipitation and chromatin immunoprecipitation assays demonstrated that antitubulin chemotherapeutics increased the binding of STAT3 to the CXCL12 gene promoter and the interaction between STAT3 and p300, and contributed to the enhanced transcription of CXCL12 by increasing the acetylation of histone H4 in CXCL12 gene promoter. Inhibition of STAT3 by intrathecal injection of adeno associated virus encoding Cre and green fluorescent protein into STAT3 mice or inhibitor S3I-201 into rats suppressed the CXCL12 upsurge by decreasing the acetylation of histone H4. Finally, blockade of CXCR4 but not CXCR7 ameliorated the paclitaxel- or vincristine-induced mechanical allodynia. Together, these results suggested that enhanced interaction between STAT3 and p300 mediated the epigenetic upregulation of CXCL12 in dorsal horn neurons, which contributed to the antitubulin chemotherapeutics-induced persistent pain. PMID- 28072605 TI - Oxytocin alleviates orofacial mechanical hypersensitivity associated with infraorbital nerve injury through vasopressin-1A receptors of the rat trigeminal ganglia. AB - Oxytocin (OXT) is a neuropeptide hormone synthesized and secreted by hypothalamic neurons and has been reported to play a significant role in pain modulation. However, the mechanisms underlying OXT's antinociceptive effect on neuropathic pain are not fully understood. In this study, we examined the peripheral effect of OXT on mechanical hypersensitivity induced by partial ligation of the infraorbital nerve (PNL) in rats. Mechanical hypersensitivity in the whisker pad skin after PNL was attenuated by the direct administration of OXT into the trigeminal ganglion (TG). The proportion of vasopressin-1A receptor (V1A-R) immunoreactive, but not OXT-receptor-immunoreactive, neurons significantly increased among TG neurons innervating the whisker pad skin after PNL. In a patch clamp recording from TG neurons isolated from PNL rats, the resting membrane potential of OXT-treated neurons was significantly decreased, and the current thresholds of OXT-treated neurons for spike generation (rheobases) were significantly greater than those of vehicle-treated neurons. In addition, OXT increased voltage-gated K channel currents in PNL animals. Furthermore, intra-TG administration of a selective V1A-R antagonist reversed the OXT-induced alleviation of mechanical hypersensitivity, and coapplication of the antagonist opposed OXT's effects on the resting membrane potential, rheobase, and K current. These findings suggest that OXT is effective at suppressing TG neuronal hyperexcitability after nerve injury, likely by modulation of voltage-gated K channels through V1A-R. This signaling mechanism represents a potential therapeutic target for the treatment of orofacial neuropathic pain. PMID- 28072606 TI - An Innovative Approach: Using Simulation to Teach Primary Care Gynecologic Procedures. AB - INTRODUCTION: In response to the growing body of evidence that simulation is a satisfactory way to instruct procedural skills, we developed an innovative model to teach common gynecologic procedures such as cervical cancer screening, cervical polyp removal, intrauterine device removal, and endometrial biopsy. The objectives of this study were to describe the construction of the model and to assess participants' satisfaction and confidence in applying the learning objectives to their clinical practice. METHODS: The researchers created the model with reusable and readily available materials. During a hands-on skills workshop, practicing clinicians performed simulated cervical cancer screening, endocervical polyp removal, intrauterine device removal, and an endometrial biopsy on a low fidelity gynecologic model. Using convenience sampling, each participant completed a survey designed to measure satisfaction with the workshop and self confidence in their newly acquired skills. RESULTS: All (N = 30,100%) of the participants agreed at the "agree" or "strongly agree" level that the gynecologic skills workshop using lecture and a hands-on model was a satisfying and self confidence-building experience. CONCLUSIONS: An easily reproducible and reusable gynecologic procedure simulator was highly rated as a means of teaching common primary care gynecologic procedures. The simulated model provided an opportunity for hands-on skills learning for clinicians who wish to expand their gynecologic procedure skill set. PMID- 28072608 TI - Is it WISE to link vasomotor symptoms with cardiovascular disease? PMID- 28072609 TI - The impact of estrogen alone hormone therapy on breast cancer risk and health outcomes: reassurance for the treatment of climacteric symptoms in black women? PMID- 28072610 TI - Sexual activity and function assessment in middle-aged Chinese women using the female sexual function index. AB - OBJECTIVE: To assess sexual activity, sexual function, and their correlation with vaginal maturation status among middle-aged Chinese women. METHODS: A cross sectional study with comparisons across age groups was carried out. In all, 120 women aged 45 to 60 years were recruited into three groups: 45 to 50 (youngest group), 51 to 55 (intermediate group), and 56 to 60 years old (eldest group). Sexual function was assessed through the Female Sexual Function Index (FSFI); vaginal maturation status was determined through the Vaginal Maturation Index (VMI) and pH value. Sexual activity was recorded with self-administered questionnaires. RESULTS: Low sexual frequency was present in a higher proportion of women, but sexual distress was identified within a lower proportion of women in the eldest group. The total FSFI score was significantly lower in the eldest group than in the youngest and intermediate groups (P < 0.01 and 0.05, respectively); however, the domain score of sexual desire, arousal, and satisfaction was lower in the eldest group than in the youngest group (P < 0.01, 0.05, and 0.05) only. The domain score for lubrication was lower in the eldest group than in both the youngest and intermediate groups (P < 0.01 and 0.05), and the pain score was lower in both the intermediate and eldest groups than in the youngest group (P < 0.01 and 0.05). A lower VMI (P < 0.001) and a higher pH value (P < 0.01) were observed in the eldest group, compared with the youngest group. Moreover, VMI was positively correlated with the total FSFI score, the domain score for sexual desire, and lubrication (r = 0.26, 0.25, 0.34; P < 0.05, 0.05, 0.01), but the opposite associations were demonstrated for pH value (r = -0.47, 0.37, -0.38; P < 0.01, respectively), especially with vaginal pain (r = -0.44, P < 0.01). CONCLUSIONS: Among middle-aged Chinese women, sexual desire is lower in 56 to 60-year-old women, compared with those aged 45 to 55 years, whereas vaginal dryness and dyspareunia become more prevalent with age. Importantly, sexual function is associated with vaginal maturation status in women at midlife. PMID- 28072611 TI - Baby Shampoo Versus Povidone-Iodine or Isopropyl Alcohol in Reducing Eyelid Skin Bacterial Load. AB - PURPOSE: Baby shampoo is used as an alternative surgical skin preparation, but the evidence supporting its use is scarce with no descriptions of efficacy in the periocular region. The authors compare the efficacy of baby shampoo, povidone iodine (PI, Betadine) and isopropyl alcohol (IA) in reducing eyelid skin bacterial load. METHODS: Prospective, randomized, comparative, and interventional trial. Bacterial load on adult, human eyelid skin was quantitated before and after cleansing with 1) dilute baby shampoo, 2) 10% PI, or 3) 70% IA. Paired skin swabs were collected from a 1 cm area of the upper eyelid of subjects before and after a standardized surgical scrub technique. Samples were cultured on 5% sheep blood agar for 24 hours. The number of colony forming units (CFU) was assessed and bacterial load per square centimeter of eyelid skin was quantified. RESULTS: Baseline and postcleansing samples were assessed from 42 eyelids of 42 subjects (n = 14 for each of baby shampoo, PI, and IA). Before cleansing, similar amounts of bacterial flora were grown from all specimens (median log CFU/cm = 2.04 before baby shampoo, 2.01 before PI, 2.11 before IA; p > 0.05). All 3 cleansing agents significantly reduced the bacterial load (p < 0.01 for each). There was no statistically significant difference in postcleansing bacterial load between the 3 cleansing agents (median log CFU/cm = 0.48 after baby shampoo, 0.39 after PI, 0.59 after IA; p > 0.05). Change from baseline in bacterial load was statistically similar for all 3 agents (median reduction in log CFU/cm = 1.28 with baby shampoo, 1.57 with PI, 1.40 with IA; p > 0.05). These corresponded to bacterial load reductions of 96.3%, 96.6%, and 98.4% for baby shampoo, PI, and IA, respectively. CONCLUSIONS: Baby shampoo achieved comparable diminution in eyelid skin bacterial load to PI or IA. These data suggest baby shampoo may be an effective preoperative cleansing agent. PMID- 28072612 TI - Prophylactic Antibiotics for Enucleation and Evisceration: A Retrospective Study and Systematic Literature Review. AB - PURPOSE: To report surgical site infection (SSI) rates of eviscerations and enucleations with implants performed without perioperative intravenous (IV) antibiotics or postoperative oral antibiotics, and to give SSI prevention recommendations. METHODS: A single-center retrospective chart review was performed after obtaining institutional review board approval. Charts were found by Current Procedural Terminology codes. Demographics, surgical indication, procedure, implant, antibiotic use, and postoperative course were recorded. SSIs occurring within 30 days after surgery were reviewed and postoperative infection rates were determined. RESULTS: Four hundred eighty-one cases from January 1999 to December 2015 were analyzed. There were 102 eviscerations with implants, 314 enucleations with implants, 23 enucleations without implants, 23 implant exchanges, 15 implants placed secondarily after enucleation, and 4 implant removals. Seventy cases (14.6%) were given perioperative IV antibiotics, and in this group one periorbital infection occurred unrelated to orbital surgery (1.4%). Of the 411 cases (85.4%) not given perioperative IV antibiotics, 1 of 87 eviscerations with implants developed an SSI (1.1%), 2 of 273 enucleations with implants developed SSIs (0.7%), and none of the 13 enucleations without implants developed SSIs. CONCLUSIONS: To our knowledge, this is the first published case series reporting SSI rates of enucleations and eviscerations with implants performed without perioperative IV antibiotics or postoperative oral antibiotics. With infection rates comparing favorably to other case series where antibiotics were given, the routine use of perioperative IV antibiotics and postoperative oral antibiotics for enucleations and eviscerations may not be indicated. PMID- 28072613 TI - Pediatric lead exposure and the water crisis in Flint, Michigan. AB - Changing the source of the water supply to save money had the unintended consequence of exposing residents of Flint, Mich., to elevated lead levels in their drinking water. A study done at Flint's Hurley Children's Hospital demonstrated that the incidence of elevated blood lead levels of children living in the affected area nearly doubled after the change in the water source. This article reviews the recommendations for lead screening and for reporting, following, and treating children with blood lead levels greater than 5 mcg/dL. PMID- 28072614 TI - Cell Phone Calls in the Operating Theater and Staff Distractions: An Observational Study. AB - OBJECTIVES: Cell phones are the primary communication tool in our institution. There are no restrictions on their use in the operating rooms. The goal of this study was to evaluate the extent of cell phone use in the operating rooms during elective surgery and to evaluate whether they cause staff distractions. METHODS: The following data on cell phone use were recorded anonymously: number of incoming and outgoing cell phone calls, duration of cell phone calls and their content (patient related, work related, private), who was distracted by the cell phone calls, and duration of distractions. RESULTS: We made observations during 52 surgeries. There were 205 cell phone calls, 197 (96.1%; median, 3 per surgery; interquartile range, 2-5) incoming and 8 (3.9%) outgoing. Incoming calls were answered on 110 (55.8%) of 197 (median, 2; interquartile range, 1-3) occasions. The mean duration of incoming calls (64 +/- 40 seconds) was shorter than those of the outgoing calls (137 +/- 242 seconds, P < 0.001). During 29 (14.7%) of 197 incoming calls, 30 staff distractions occurred. Distractions were caused mainly for surgeons talking on their cell phones (24/30, 80.0%). The mean duration of the distractions was 43.6 +/- 22.3 seconds. During all 8 outgoing calls, no other staff members were distracted. CONCLUSION: The number of cell phone calls in the operating rooms during elective surgery was lower than expected and caused short lived distractions mainly to the operating surgeons. We recommend that operating surgeons turn off their cell phones before surgery. PMID- 28072615 TI - RETINAL DETACHMENT ASSOCIATED WITH PERIPAPILLARY STAPHYLOMA IMAGED WITH SWEPT SOURCE OPTICAL COHERENCE TOMOGRAPHY. AB - PURPOSE: To examine a rhegmatogenous retinal detachment (RRD) associated with a peripapillary staphyloma with swept source optical coherence tomography (SS-OCT) before and after vitrectomy and circumferential photocoagulation. METHODS: The SS OCT images including the montage images of two patients with a RRD associated with peripapillary staphylomas were analyzed. A 34-year-old woman (Case 1) and a 70-year-old woman (Case 2) both noticed temporal visual field defects in their left eyes. Ophthalmoscopy showed a retinal detachment in the nasal quadrant without any peripheral breaks in both patients. The best-corrected visual acuity was 20/20 with -8.5 diopters in Case 1 and 20/25 with -7.0 diopters and moderate cataract in Case 2. SS-OT was used to follow the clinical course of the RRD. RESULTS: Preoperatively, retinal tears were detected nasal to the optic disk within the excavated staphyloma in the SS-OCT images. A posterior vitreous detachment was not present in Case 1 but was present in Case 2. The glial tissue at the edge of the excavated staphyloma was removed from both eyes, and the subretinal fluid was drained internally through the retinal breaks. Hemicircumferential photocoagulation was performed at the nasal edge of the staphyloma, and the retina was reattached in both eyes. Postoperative SS-OCT montage images showed retinal reattachment but a detachment was still present within the staphyloma. CONCLUSION: Vitreous surgery was effective for an RRD associated with a peripapillary staphyloma. Examinations by SS-OCT can follow the changes in the RRD and the excavated lesion of a peripapillary staphyloma. PMID- 28072616 TI - Gastrointestinal Stromal Tumor Showing Intense Tracer Uptake on PSMA PET/CT. AB - A 70-year-old man with suspected prostate cancer was referred for Ga-PSMA-HBED-CC PET/CT (short PSMA PET/CT) for staging of tumor extent. Apart from vivid tracer uptake in the prostate gland and osseous metastasis, PSMA PET/CT revealed a large soft tissue mass with calcifications in the left upper abdomen showing intense tracer uptake. Histologic examination revealed the mass to be a gastrointestinal stromal tumor. PMID- 28072617 TI - Evaluation of the Response to Breast Cancer Neoadjuvant Chemotherapy Using 18F FDG Positron Emission Mammography Compared With Whole-Body 18F-FDG PET: A Prospective Observational Study. AB - PURPOSE: The aim of this study was to assess therapeutic response to breast cancer neoadjuvant chemotherapy (NAC) by F-FDG positron emission mammography (PEM) compared with that to whole-body F-FDG PET (WBPET). METHODS: Twenty patients underwent WBPET and PEM 3 times: the first time was before NAC, the second time was after 2 courses of NAC, and the third time was after all courses of NAC. A pathological complete response (pCR) was defined as no evidence of residual invasive cancer with or without ductal carcinoma in situ. The relationships between each modality's SUVmax and pathological response were evaluated. RESULTS: Nine patients achieved a pCR, whereas the other 11 patients had a non-pCR. The SUVmax of WBPET after 2 courses of NAC was significantly lower in the pCR group than in the non-pCR group (1.4 +/- 0.4 vs 2.7 +/- 2.1, P = 0.0334). There were no significant differences in the SUVmax of PEM (ie, PEM uptake value [PUV]) between the groups. The SUVmax of WBPET (area under the ROC curve [AUC] = 0.761) was superior to the PUVmax (AUC, 0.648) for predicting non pCR at the interim time point. After all courses of chemotherapy, there were no significant differences between the groups in the SUVmax of WBPET; however, PUVmax was significantly lower in the pCR group than in the non-pCR group (1.0 +/ 0.2 vs 2.5 +/- 2.7, P = 0.0351). After NAC, the PUVmax (AUC, 0.796) was superior to the SUVmax of WBPET (AUC, 0.671). CONCLUSIONS: There proved to be no apparent superiority of PEM in predicting pCR at the interim time point. Positron emission mammography had greater diagnostic capability for detecting residual cancer after all courses of NAC. PMID- 28072618 TI - 18F-FDG PET/CT Versus Contrast-Enhanced CT for Staging and Prognostic Prediction in Patients With Salivary Gland Carcinomas. AB - PURPOSE: Salivary gland carcinoma (SGC) is rare tumor with various histological type and metastatic potential. Pretreatment detection of metastases can contribute to planning the appropriate treatment of SGC. Therefore, the present study evaluated the utility of F-FDG PET/CT versus contrast-enhanced CT for detection of metastases and prediction of outcomes in SGC patients. METHODS: Sixty-seven consecutive SGC patients who were prospectively evaluated by F-FDG PET/CT and contrast-enhanced CT and subsequently underwent surgery with or without postoperative radiotherapy/chemoradiotherapy were included. The diagnostic values of both imaging modalities for detection of metastatic diseases were compared with McNemar test and logistic regression using generalized estimating equations. Cox proportional hazard modeling was used to assess the prognostic values of the quantitative metabolic measurements detected by F-FDG PET/CT and of other clinical factors. RESULTS: Among 67 SGC patients, 17 (25.4%) had cervical metastasis, and 4 (6%) had distant metastasis at initial staging. The sensitivity of F-FDG PET/CT for detection of cervical metastasis was significantly higher than those of CT (P < 0.05), and those of F-FDG PET/CT and CT for detection of distant metastasis did not differ (P > 0.5). Regional and distant site metastases were most reliably predicted by high-grade pathological analysis (P < 0.05). Extranodal extension and metabolic tumor volume measured by F-FDG PET/CT were independent predictors of progression-free survival and overall survival (all P < 0.05). CONCLUSIONS: In SGC patients, F-FDG PET/CT detected metastatic diseases with high sensitivity and specificity, and metabolic tumor volumes helped to predict survival outcomes. PMID- 28072619 TI - Radio-Guided Lymph Node Mapping in Bladder Cancer Using SPECT/CT and Intraoperative gamma-Probe Methods: Reply. PMID- 28072620 TI - Fibrous Dysplasia Mimicking Malignancy on 68Ga-DOTATATE PET/CT. AB - Fibrous dysplasia of the bone is a developmental benign skeletal disorder characterized by replacement of normal bone and normal bone marrow with abnormal fibro-osseous tissue. We report on a case of a biopsy-proven fibrous dysplasia lesion in the left temporal bone, with intensely increased activity (SUVmax, 56.7) on Ga-DOTATATE PET/CT. The presented data indicate cell surface overexpression of somatostatin receptors by fibrous dysplastic cells and highlight the need of cautious management of Ga-DOTATATE-avid bone lesions, which could mimic malignancy especially in patients with history of neuroendocrine tumors. PMID- 28072621 TI - Risk Stratification of Pediatric Patients With Neuroblastoma Using Volumetric Parameters of 18F-FDG and 18F-DOPA PET/CT. AB - PURPOSE: This study determined the prognostic value of volumetric parameters derived from pretreatment F-FDG and F-DOPA PET/CT of neuroblastoma and their correlation with clinical and histopathologic features. PATIENTS AND METHODS: A total of 25 children with neuroblastoma underwent pretreatment F-FDG and F-DOPA PET/CT within 4 weeks. The SUVmax of primary tumors on F-FDG and F-DOPA PET were recorded as SUVFDG and SUVDOPA, respectively. For volumetric parameters of primary tumors, 40% of SUVmax was used to generate volume of interest. If the 40% of SUVmax was below 2.5, an SUV threshold of 2.5 was used instead. Metabolic tumor volume (MTV), total lesion glycolysis (TLG), dopaminergic tumor volume (DTV), and total lesion F-DOPA activity (TLDA) were recorded as F-FDG and F-DOPA volumetric parameters. All indices were compared between groups distinguished by survival status and clinical features, including bone marrow involvement, lymph node metastasis, amplification of the MYCN oncogene, invasive features on anatomic images, and risk categories. The Kaplan-Meier method and log-rank test were used to compare the survival curves between groups. RESULTS: The median follow-up period was 28.2 months. Nonsurvivors (20%) tended to have lower SUVDOPA, DTV, and TLDA (P <= 0.05), and higher SUVFDG, MTV, and TLG (all P < 0.05). Lower F-DOPA uptake is associated with bone marrow and lymph node metastases (all P < 0.05). Higher F-FDG uptake is associated with MYCN amplification (all P < 0.05) and anatomic invasive features of tumors such as vascular encasement or adjacent organ invasion (TLG, P = 0.05). Only volumetric indices (DTV, TLDA, MTV, and TLG) significantly differed among risk groups (all P < 0.05). CONCLUSIONS: Pretherapeutic F-DOPA and F-FDG PET provided complementary information, and both can be served for risk stratification. Volumetric indices of F-DOPA and F-FDG PET correlate more highly with risk grouping. PMID- 28072622 TI - 170Tm-EDTMP: A Prospective Alternative of 89SrCl2 for Theranostic Treatment of Metastatic Bone Pain. AB - We have earlier reported the potential of Tm-EDTMP as an alternative cost effective radiopharmaceutical of SrCl2 for bone pain palliation application. Encouraging results obtained in the radiochemical studies and biological evaluations in animal model have prompted us to initiate the clinical study to evaluate the potential of Tm-EDTMP in human cancer patients. The serial scintigraphic images represent the whole-body scans of a patient (68 years old woman) with skeletal metastases of carcinoma of the breast origin recorded after administering 370 MBq (10 mCi) of Tm-EDTMP at different post-administration time points along with the pre-therapy images recorded with Tc-MDP in the same patient. PMID- 28072623 TI - Effect of Substituting 50% Isovue for Sterile Water as the Delivery Medium for SIR-Spheres: Improved Dose Delivery and Decreased Incidence of Stasis. AB - PURPOSE: The objective of this study was to evaluate the effect of substituting 50% Isovue (Bracco Diagnostics Inc, Monroe Township, NJ) for sterile water on the delivery of Y resin microspheres (SIR-Spheres [Sirtex Medical Limited, Sydney, Australia]). MATERIALS AND METHODS: The authors retrospectively reviewed all SIR Spheres radioembolizations at the authors' institution from January 1, 2011, to February 10, 2014. From January 1, 2011, to April 30, 2013, all users performed SIR-Spheres radioembolization per the manufacturer's original instructions using sterile water in the B and D lines and intermittently checking the progress of the embolization by injecting contrast via the B line. Beginning May 1, 2013, a modified technique using Isovue diluted 50% with saline in place of sterile water in both the B and D lines of the infusion set. The authors compared the prepared versus administered activity of Y SIR-Spheres, fluoroscopy time, administration time, and frequency of radioembolizations terminated for stasis when using water versus dilute contrast in the B and D lines. RESULTS: One hundred seventy-five radioembolizations were performed, 132 (75%) with water as the delivery medium and 43 (25%) with 50% contrast as delivery medium. The mean percentage of the Y activity administered was 98% with contrast versus 87% with water (P < 0.01). More than 95% of cases using contrast resulted in 90% or more delivery of the prepared Y activity versus 59% of cases with water (P < 0.01). For cases using water, 17% were terminated for stasis, whereas 2% (1 case) using contrast was terminated for stasis. The mean Y administration time was 7 minutes with contrast versus 22 minutes with water (P = 0.015). Excluding the 37 cases involving coil embolization, the mean fluoroscopy time was 8.3 minutes with contrast versus 11.5 minutes with water (P < 0.05). No complications occurred with the contrast method; however, there were 4 complications with water, including 1 nontarget gastric ulceration. CONCLUSIONS: Using dilute contrast as the delivery medium for SIR-Spheres resulted in a significantly greater percentage of the prepared activity administered to the patient with substantially shorter administration time. Termination for stasis occurred less often with dilute contrast. No complications were observed when using dilute contrast, which allowed continuous real-time monitoring of the Y microsphere administration. PMID- 28072624 TI - The Effect of Antiseptic on 99mTc-DMSA Scans. AB - Approximately 30 years ago, it has been suggested that chlorhexidine, which is used as antiseptic, can produce Tc colloid complex during Tc-dimercaptosuccinic acid (DMSA) preparation. However, in all cases of liver and spleen uptake in Tc DMSA scan, it should still be kept in mind because of the introduction of new antiseptic brands with different formulation under various names. Our case is just a sample of this effect, which resulted from application of a new brand of antiseptic by technologists in our center that unintentionally led to low-quality Tc-DMSA scans for a period, and after restrict control of all other confounding factors in the preparation of kit, it was just resolved by changing antiseptic to ethanol. PMID- 28072625 TI - Evaluation of a Large Renal Mass Using 99mTc-MIBI SPECT/CT in a Patient With Chronic Kidney Disease. AB - The differentiation of benign and indolent renal masses from aggressive tumor histologies cannot be reliably performed by CT or MRI. Additionally, renal mass biopsy risks complications and has a nondiagnostic rate of 10% to 20%. Tc-MIBI SPECT/CT has been shown to allow for the accurate differentiation of benign renal oncocytomas and hybrid oncocytic/chormophobe tumors from other more aggressive renal tumor types. We present the case of an 84-year-old man with chronic kidney disease and an 11.2-cm renal mass. Results of his Tc-MIBI SPECT/CT allowed avoidance of a radical nephrectomy. PMID- 28072626 TI - Acquired coronary artery disease in adult patients with congenital heart disease: a true or a false problem? AB - BACKGROUND: The population of adults with congenital heart disease (ACHD) is increasing and aging, and a large percentage of this population is now over 65 years of age. For this reason, it is probable that acquired coronary artery disease (CAD) will become an important issue that needs to be addressed also in these patients. We retrospectively analyzed all ACHD patients who underwent surgery in our Institution with the aim to investigate the incidence of associated CAD and the results of surgical treatment. METHODS: From January 2000 to December 2015, a total of 1154 ACHD underwent surgery in our center. Fifty patients (4.3%) were diagnosed with acquired CAD and required coronary artery bypass grafting. The mean age at surgery was 66 years (range 41-78 years). The primary diagnosis were atrial septal defect (n = 40 patients), Tetralogy of Fallot (n = 4 patients), ventricular septal defect (n = 2 patients), partial AV canal (n = 1), partial anomalous pulmonary venous drainage (n = 1), Ebstein's anomaly (n = 1), and subaortic stenosis (n = 1). RESULTS: Hospital mortality was 2% (one patient). During a mean follow-up of 9 years (maximum follow-up: 15 years), seven patients died (14%). The actuarial survival was 83% at 5 years and 77% at 10 years. Freedom from reoperation for coronary artery bypass grafting or percutaneous coronary intervention was 88% at 5 years and 82% at 10 years. CONCLUSION: Acquired CAD may coexist with congenital heart defects but the association is quite rare. It typically occurs later during adulthood and it is usually associated with atrial septal defect. Acquired CAD and congenital heart defects can be treated contemporarily with good early and late results. PMID- 28072627 TI - An unsolved conundrum: right ventricular dysfunction. PMID- 28072628 TI - Clinical recommendations of cardiac magnetic resonance, Part I: ischemic and valvular heart disease: a position paper of the working group 'Applicazioni della Risonanza Magnetica' of the Italian Society of Cardiology. AB - Cardiac magnetic resonance (CMR) has emerged as a reliable and accurate diagnostic tool for the evaluation of patients with cardiac disease in several clinical settings and with proven additional diagnostic and prognostic value compared with other imaging modalities. This document has been developed by the working group on the 'application of CMR' of the Italian Society of Cardiology to provide a perspective on the current state of technical advances and clinical applications of CMR and to inform cardiologists on how to implement their clinical and diagnostic pathways with the inclusion of this technique in clinical practice. The writing committee consisted of members of the working group of the Italian Society of Cardiology and two external peer reviewers with acknowledged experience in the field of CMR. PMID- 28072629 TI - The key clues to reach the diagnosis of Loeffler endomyocardial fibrosis associated with eosinophilic granulomatosis with polyangiitis. PMID- 28072630 TI - Bracing of the Reconstructed and Osteoarthritic Knee during High Dynamic Load Tasks. AB - PURPOSE: Lateral compartment osteoarthritis accompanied by abnormal knee biomechanics is frequently reported in individuals with knee osteoarthritis after anterior cruciate ligament reconstruction (ACLR). The aim of this study was to evaluate changes in knee biomechanics produced by an adjusted and unadjusted varus knee brace during high dynamic loading activities in individuals with lateral knee osteoarthritis after ACLR and valgus malalignment. METHODS: Nineteen participants who had undergone ACLR 5 to 20 yr previously and had symptomatic and radiographic lateral knee osteoarthritis with valgus malalignment were assessed. Quantitative motion analysis experiments were conducted during hopping, stair ascent, and descent under three test conditions: (i) no brace, (ii) unadjusted brace with sagittal plane support and neutral frontal plane alignment, and (iii) adjusted brace with sagittal plane support and varus realignment (valgus to neutral). Sagittal, frontal, and transverse plane knee kinematics, external joint moment, and angular impulse data were calculated. RESULTS: Relative to an unbraced knee, braced conditions significantly increased knee flexion and adduction angles during hopping (P = 0.003 and P = 0.005; respectively), stair ascent (P = 0.003 and P < 0.001, respectively), and descent (P = 0.009 and P < 0.001, respectively). In addition, the brace conditions increased knee flexion (P < 0.001) and adduction (P = 0.001) angular impulses and knee stiffness (P < 0.001) during hopping, as well as increased knee adduction moments during stair ascent (P = 0.008) and flexion moments during stair descent (P = 0.006). There were no significant differences between the adjusted and the unadjusted brace conditions (P > 0.05). CONCLUSION: A knee brace, with or without varus alignment, can modulate knee kinematics and external joint moments during hopping, stairs ascent, and descent in individuals with predominant lateral knee osteoarthritis after ACLR. Longer-term use of a brace may have implications in slowing osteoarthritis progression. PMID- 28072631 TI - Terbutaline Accumulates in Blood and Urine after Daily Therapeutic Inhalation. AB - PURPOSE: This study investigated pharmacokinetics of terbutaline after single and seven consecutive days of inhalation in exercising trained men. METHODS: Twelve healthy trained men underwent two pharmacokinetic trials comparing single dose (2 mg) and seven consecutive days (2 mg.d) of inhaled terbutaline. After inhalation of terbutaline at each trial, subjects performed 90 min of bike ergometer exercise at 55%-65% of maximal oxygen consumption after which they stayed inactive. Blood and urine samples were collected before and after inhalation of terbutaline. Samples were analyzed by high-performance liquid chromatography tandem mass spectrometry. RESULTS: Maximum serum concentration of terbutaline (Cmax) (6.4 +/- 1.2 vs 4.9 +/- 1.2 ng.mL, P = 0.01) (mean +/- 95% confidence interval) and area under serum concentration-time curve from 0 to 4 h after inhalation (AUC0-4) (16 +/- 3 vs 13 +/- 2 ng.mL.h, P <= 0.005) were higher after 7 d of inhalation compared with the first day. Seven days of terbutaline inhalation resulted in accumulation of terbutaline in urine, in which total urine excretion of terbutaline was higher after 7 d of inhalation compared with the first day (274 +/- 43 vs 194 +/- 33 MUg, P <= 0.001). These differences were partly attributed to systemic accumulation of terbutaline after consecutive days of inhalation, in that baseline serum and urine samples revealed incomplete elimination of terbutaline. CONCLUSION: Terbutaline accumulates in serum and urine after consecutive days of inhalation. For doping control purposes, these observations are of relevance if a urine threshold and decision limit is to be introduced for terbutaline on the World Anti-Doping Agency's list of prohibited substances because asthmatic athletes may use their bronchorelievers for consecutive days. PMID- 28072633 TI - Visual Motion Processing Subserves Faster Visuomotor Reaction in Badminton Players. AB - INTRODUCTION: Athletes participating in ball or racquet sports have to respond to visual stimuli under critical time pressure. Previous studies used visual contrast stimuli to determine visual perception and visuomotor reaction in athletes and nonathletes; however, ball and racquet sports are characterized by motion rather than contrast visual cues. Because visual contrast and motion signals are processed in different cortical regions, this study aimed to determine differences in perception and processing of visual motion between athletes and nonathletes. METHODS: Twenty-five skilled badminton players and 28 age-matched nonathletic controls participated in this study. Using a 64-channel EEG system, we investigated visual motion perception/processing in the motion sensitive middle temporal (MT) cortical area in response to radial motion of different velocities. In a simple visuomotor reaction task, visuomotor transformation in Brodmann area 6 (BA6) and BA4 as well as muscular activation (EMG onset) and visuomotor reaction time (VMRT) were investigated. Stimulus- and response-locked potentials were determined to differentiate between perceptual and motor-related processes. RESULTS: As compared with nonathletes, athletes showed earlier EMG onset times (217 vs 178 ms, P < 0.001), accompanied by a faster VMRT (274 vs 243 ms, P < 0.001). Furthermore, athletes showed an earlier stimulus-locked peak activation of MT (200 vs 182 ms, P = 0.002) and BA6 (161 vs 137 ms, P = 0.009). Response-locked peak activation in MT was later in athletes ( 7 vs 26 ms, P < 0.001), whereas no group differences were observed in BA6 and BA4. Multiple regression analyses with stimulus- and response-locked cortical potentials predicted EMG onset (r = 0.83) and VMRT (r = 0.77). CONCLUSION: The athletes' superior visuomotor performance in response to visual motion is primarily related to visual perception and, to a minor degree, to motor-related processes. PMID- 28072632 TI - ASC Methylation and Interleukin-1beta Are Associated with Aerobic Capacity in Heart Failure. AB - BACKGROUND: Aerobic capacity, as measured by peak oxygen uptake (VO2), is one of the most powerful predictors of prognosis in heart failure (HF). Inflammation is a key factor contributing to alterations in aerobic capacity, and interleukin (IL)-1 cytokines are implicated in this process. The adaptor protein ASC is necessary for inflammasome activation of IL-1beta and IL-18. ASC expression is controlled through epigenetic modification; lower ASC methylation is associated with worse outcomes in HF. The purpose of this study is to examine the relationships between ASC methylation, IL-1beta, and IL-18 with VO2peak in persons with HF. METHODS: This study examined the relationship between ASC methylation, IL-1beta, and IL-18 with VO2peak in 54 stable outpatients with HF. All participants were NYHA class II or III, not engaged in an exercise program, and physically able to complete an exercise treadmill test. RESULTS: Mean VO2peak was 16.68 +/- 4.7 mL.kg.min. VO2peak was positively associated with mean percent ASC methylation (r = 0.47, P = 0.001) and negatively associated with IL-1beta (r = -0.38, P = 0.007). Multiple linear regression models demonstrated that VO2peak increased by 2.30 mL.kg.min for every 1% increase in ASC methylation and decreased by 1.91 mL.kg.min for every 1 pg.mL increase in plasma IL-1beta. CONCLUSIONS: Mean percent ASC methylation and plasma IL-1beta levels are associated with clinically meaningful differences in VO2peak in persons with HF. Inflammasome activation may play a mechanistic role in determining aerobic capacity. ASC methylation is a potentially modifiable mechanism for reducing the inflammatory response, thereby improving aerobic capacity in HF. PMID- 28072635 TI - Does the Timing of Preoperative Epidural Steroid Injection Affect Infection Risk After ACDF or Posterior Cervical Fusion? AB - STUDY DESIGN: A retrospective database analysis. OBJECTIVE: The aim of this study was to determine whether any association exists between preoperative cervical epidural steroid injections (CESIs) at various time intervals before anterior cervical discectomy and fusion (ACDF) or posterior cervical fusion (PCF) and the incidence of postoperative infection. SUMMARY OF BACKGROUND DATA: Although infectious complications following CESI are uncommon, the association between preoperative CESI and postoperative infection following ACDF or PCF has yet to be evaluated in the current literature. METHODS: A national insurance database was utilized to compare postoperative infection rates within 90 days in patients who received a CESI before ACDF or PCF. Three cohorts were created for each procedure: PCF (n = 402) or ACDF (n = 4354) within 3 months, PCF (n = 586) or ACDF (n = 5183) between 3 and 6 months, and PCF (n = 629) or ACDF (3648) between 6 and 12 months following a CESI. These cohorts were compared with control cohorts who underwent PCF (n = 61,253) or ACDF (n = 241,678) without prior CESI. Postoperative infection rates within 90 days were assessed using International Classification of Disease, 9th Revision (ICD-9) and Current Procedural Terminology (CPT) codes. Odds ratios (ORs), 95% confidence intervals (95% CIs), and P values were then calculated using SPSS. A multivariate binomial logistic regression analysis was performed to determine the independent effect of preoperative injection on postoperative infection following ACDF or PCF controlling for known risk factors for infection, including age, gender, obesity, diabetes, and smoking. RESULTS: Patients who underwent CESI within 3 months (OR 2.21, P < 0.0001) and within 3 to 6 months (OR 1.95, P = 0.0002) before PCF had significantly increased odds of developing a postoperative infection. Patients who underwent CESI within 3 months (OR 1.83, P < 0.0001) before ACDF had significantly increased odds of developing a postoperative infection. CONCLUSION: The present study demonstrates that cervical ESI within 6 months of PCF, and within 3 months of ACDF, is independently associated with significantly increased rates of postoperative infection. LEVEL OF EVIDENCE: 3. PMID- 28072636 TI - Accelerated Discharge Protocol for Posterior Spinal Fusion Patients With Adolescent Idiopathic Scoliosis Decreases Hospital Postoperative Charges 22. AB - STUDY DESIGN: A retrospective study of consecutive patients. OBJECTIVE: The purpose of this study was to determine implementing an accelerated protocol could decrease our average hospital stay and what impact this had on postoperative pain management. SUMMARY OF BACKGROUND DATA: To our knowledge, no prior studies have reviewed the effect of an accelerated discharge protocol on postoperative pain control for adolescent idiopathic scoliosis (AIS) following posterior spinal fusion. METHODS: This is a retrospective review of all consecutive patients undergoing posterior spinal fusion (PSF) for AIS before (June 1, 2008-May 31, 2013 = traditional protocol) and after (June 1, 2013-October 22, 2014 = accelerated protocol) protocol implementation. Subjective response to the FACES Pain Intensity scale was collected for each postoperative day while in the hospital by the nursing staff. RESULTS: There were 194 patients in the traditional pathway and 90 patients in the accelerated pathway. No significant differences in age at surgery, sex, or number of levels fused were present between the groups. Patients managed under the accelerated discharge had an average hospital stay of 3.7 days compared with 5.0 days for the traditional discharge (P < 0.001). There was no increased incidence of wound complications between the two groups [3.6% (7/194) vs. 3.3% (3/90), P = 0.91] or readmission [1.5% (3/194) vs. 4.4% (4/90), P = 0.213]. Hospital charges for postoperative care were significantly less in the accelerated discharge group than in the traditional group ($18,360 vs. $23,640, P < 0.0001). This corresponded to a 22% ($5280/$23,640) decrease in postoperative hospital charges. Patients had a small (<1 point change on FACES pain scale) but statistically significant increase in pain on postoperative days 2, 3, and 4 (P = 0.0001, P = 0.0079, P = 0.0076). CONCLUSION: Accelerated discharge following PSF for AIS was associated with a 22% decrease in hospital charges in the postoperative period. LEVEL OF EVIDENCE: 4. PMID- 28072637 TI - Response to Letter. PMID- 28072638 TI - Response to the Letter. PMID- 28072639 TI - Psychotherapy in the Age of Trump. PMID- 28072640 TI - Impact of a Type D Personality on Clinical and Psychometric Properties in a Sample of Turkish Patients With a First Myocardial Infarction. AB - BACKGROUND: Recent studies have shown that a Type D personality is associated with an increased risk of cardiac mortality. OBJECTIVE: This study aimed to examine the impact of a Type D personality on clinical and psychometric properties in a sample of Turkish patients with a first myocardial infarction (MI). METHOD: The study included 131 patients who were admitted to the coronary care unit of a hospital. All of the patients underwent a psychiatric assessment within 2 to 6 months after their MI. Psychiatric interviews were conducted using the Structured Clinical Interview for DSM-IV (SCID-I). Patients also completed the Beck Depression Inventory, the Spielberger State-Trait Anxiety Inventory, the Health Anxiety Inventory, and the Type D personality scale. RESULTS: The patients were divided into 2 groups on the basis of the presence or absence of Type D personality. There was a 38.2% prevalence of Type D personality in the patients with a first MI. Those with this type of personality had a significantly higher frequency of hypertension and stressful life events. The Type D patients also had more psychiatric disorders, including depressive and anxiety disorders, than the non-Type D patients. CONCLUSIONS: Our findings suggest that Type D personality traits may increase the risk of hypertension and the risk of psychiatric morbidity in patients with a first MI. We suggest that this type of personality is a contributor to depression and anxiety disorders. These findings emphasize the importance of screening for Type D personality as both a cardiovascular and psychiatric risk marker in patients who have had an MI. PMID- 28072641 TI - Sensory Hypersensitivity Predicts Reduced Sleeping Quality in Patients With Major Affective Disorders. AB - The goal of this study was to examine the sensory profile (expressed as hypersensitivity or hyposensitivity) of patients with major affective disorders and its relative contribution to the prediction of sleep quality while considering affective temperaments and depression, which may impact sleep quality. We recruited 176 participants (mean age, 47.3 y), of whom 56.8% had a diagnosis of unipolar major depressive disorder and 43.2% a diagnosis of bipolar disorder. Reduced sleep quality was evaluated using the Pittsburgh Sleep Quality Index. Affective temperaments were assessed using the Temperament Evaluation of Memphis, Pisa, Paris and San Diego. Sensory hypersensitivity, assessed using the Adolescent/Adult Sensory Profile, significantly distinguished between poor and good sleepers. Sleep quality was mainly predicted by the Beck Depression Inventory-II total score and anxious temperament. Sensory hypersensitivity contributed to this prediction mainly with regard to sleep efficiency and related daytime dysfunction. PMID- 28072642 TI - Acute Neuropsychiatric Symptoms Associated With Antibiotic Treatment of Helicobacter Pylori Infections: A Review. AB - Helicobacter pylori infects half the global population. Because serious complications can result from this infection, a so-called "triple therapy" is recommended: treatment with a proton-pump inhibitor and clarithromycin, along with amoxicillin or metronidazole. Although these antibiotics have been associated with neuropsychiatric symptoms, it is difficult to disentangle the effects of antibiotics from the effects of acute infections that may precipitate acute neuropsychiatric symptoms. Study of patients with chronic H. pylori infections who undergo antibiotic treatment may provide a clearer view of the associations between acute neuropsychiatric symptoms and antibiotics. The literature concerning this association in patients with H. pylori has not been reviewed. We therefore undertook a review of MEDLINE and postmarket surveillance data concerning this issue and identified 25 cases. Postmarket data indicated that gastrointestinal symptoms were the most commonly reported adverse reactions, followed by neurological adverse reactions; neuropsychiatric symptoms were less commonly reported, with variable and nonspecific terminology used to describe them. More specific, yet still variable terminology was found in the literature. Anxiety, delirium, dissociation, mania, and psychosis were reported, with approximately half of these neuropsychiatric symptoms occurring without symptoms of delirium. The use of standardized neuropsychiatric symptom rating scales and the Confusion Assessment Method for monitoring adverse reactions may improve our knowledge of neuropsychiatric symptoms and their association with antibiotics and thus mitigate underreporting. Physicians should remain alert to the possibility that neuropsychiatric symptoms may occur during antibiotic treatment of H. pylori and recognize that rapid resolution typically occurs with discontinuation of the antibiotics. PMID- 28072643 TI - Early-Life Trauma in Hospitalized Patients With Mood Disorders and Its Association With Clinical Outcomes. AB - BACKGROUND: The prevalence of childhood trauma and its impact on clinical outcomes in hospitalized patients with mood disorders is unknown. We studied the frequency of childhood trauma among inpatient adults with mood disorders and its association with clinical outcomes. METHODS: Patients admitted to our hospital with a primary diagnosis of mood disorders completed the short form of the Early Trauma Inventory-Self-Report (ETISR-SF), the Sheehan Disability Scale, and the Clinician-Rated Dimensions of Psychosis Symptom Severity scale. A regression model adjusted for multiple comparisons was used to examine the association between scores on the ETISR-SF and clinical outcomes. RESULTS: Subjects were 167 patients, all of whom reported >=1 types of childhood trauma: 90% general trauma, 75% physical abuse, 71% emotional abuse, 50% sexual abuse, and 35% all 4 types of abuse. The subtypes of abuse did not differ by sex or race. Diagnoses in the sample were bipolar disorder 56%, major depressive disorder 24%, schizoaffective disorder 14%, and substance-induced mood disorder 5%. The mean age in the sample was 35+/-11.5 years, 53% were male, and 64% also had substance abuse disorders. Higher scores on the ETISR-SF were associated with longer hospital stays [odds ratio (OR)=1.13; 95% confidence interval (CI), 1.05-1.22], and greater disruption of work/school life (OR=1.12; 95% CI, 1.04-1.21). There was also a trend for higher ETISR-SF scores to be associated with more severe psychotic symptoms (OR=1.13; 95% CI, 1.01-1.27) and more disruption in social (OR=1.14; 95% CI, 1.06 1.22) and family life (OR=1.09; 95% CI, 1.02-1.17). CONCLUSION: Childhood trauma was reported by all of the 167 patients, with general trauma the most common and approximately half reporting sexual abuse. Childhood trauma was associated with poor clinical outcomes. Early recognition of trauma and trauma-related therapeutic interventions may improve outcomes. PMID- 28072644 TI - Use of an Analog Scale in the Treatment of Patients With Bipolar Disorder to Optimize Assessment and Clinical Outcome. AB - This column explains how a clinician can use an analog scale for patients with bipolar disorder: (1) to elucidate the course of the illness in a specific patient and (2) to assess response to treatment. This scale complements other standardized rating scales, such as the Young Mania Rating Scale, because its anchors are tailored to each specific patient in terms of the worst depressive or hypomanic/manic episode (ie, a -10 or +10, respectively) the person has ever experienced. The scale also allows clinicians to track how the individual patient's episodes have responded to treatment in the past, including whether the patient ever has achieved a full remission (ie, score of 0) following the initial onset of the disorder. The scale can then be used to assess how the patient in an acute or chronic active episode responds to new treatment, whether somatic and/or psychotherapeutic, and how that compares with historical responses to previous treatments. Going forward, the scale can be used to assess the course of the patient's illness (eg, episodic with full recovery or chronic with more severe episodes and increasing residual symptoms). Through use of this analog scale, the patient also develops a better understanding of his or her illness, including how episodes develop and resolve and whether there are factors (eg, interpersonal relationships, inflammatory processes, substance use) that either aggravate and/or are aggravated by the disorder. This simple scale thus fulfills many purposes including history gathering, monitoring the usefulness of different treatment interventions, and patient education. PMID- 28072645 TI - Psychotherapy, Parity, and Ethical Utilization Management. AB - Managed care has long functioned with the assumption of a split in clinical and ethical responsibility for treatment. The insurance company clinician has been seen as owing a primary obligation to the insurance company and its utilization management standards, while the treating clinician is seen as holding primary clinical and ethical responsibility for the patient and the treatment. This article explores the potential impact of mental health parity mandates and recent clarifications of the American Psychiatric Association's ethical code on this split for psychiatrists and other clinicians who develop utilization management standards or serve as utilization reviewers. PMID- 28072646 TI - Clozapine Treatment of Olanzapine-induced Tardive Dyskinesia: A Case Report. AB - Tardive dyskinesias (TD) are serious, often irreversible side effects of dopamine blocking agents, most commonly first-generation antipsychotics. No definitive treatment exists, with different interventions showing inconsistent results. We report a case of TD presenting after 12 years of olanzapine therapy in a 66-year old Hispanic male with paranoid schizophrenia. The TD symptoms were successfully treated within a few weeks by switching to clozapine. Two cases of olanzapine induced TD treated with clozapine have previously been reported, but in those cases, the symptom onset was quicker, ranging from a few months to a few years after initiation of olanzapine therapy, and the treatment response was relatively slower. Clinicians should carefully monitor for symptoms of TD after prolonged treatment with olanzapine and other antipsychotics. If otherwise indicated for psychiatric treatment, clozapine can be considered a good choice for patients with TD in preventing or reversing the debilitating consequences of this condition. PMID- 28072647 TI - Tools for Practical Psychotherapy: A Transtheoretical Collection (or Interventions Which Have, At Least, Worked for Us). AB - BACKGROUND AND OBJECTIVES: Regardless of their historical and theoretical roots, strategies, tactics, and techniques used in everyday psychotherapy across diverse theoretical schools contain common factors and methods from other specific psychotherapeutic modalities that contribute substantially to psychotherapy outcomes. Common factors include alliance, empathy, goal consensus/collaboration, positive regard/affirmation, and congruence/genuineness, among others. All therapies also recognize that factors specific to therapists impact treatment. Starting with these common factors, we add psychotherapeutic methods from many theoretical orientations to create a collection of clinical tools. We then provide concrete suggestions for enacting psychotherapy interventions, which constitute a transtheoretical collection. METHODS: We begin with observations made by earlier scholars, our combined clinical and teaching experiences, and oral traditions and clinical pearls passed down from our own supervisors and mentors. We have compiled a list of tools for students with foundational knowledge in the basic forms of psychotherapy, which may expand their use of additional interventions for practicing effective psychotherapy. RESULTS: Our toolbox is organized into 4 categories: Relating; Exploring; Explaining; and Intervening. We note how these tools correspond to items previously published in a list of core psychotherapy competencies. CONCLUSIONS: In our view, the toolbox can be used most judiciously by students and practitioners schooled and grounded in frameworks for conducting established psychotherapies. Although they are still a work in progress, these tools can authorize and guide trainees and practitioners to enact specific approaches to psychotherapy utilizing other frameworks. We believe that psychotherapy education and training might benefit from explicitly focusing on the application of such interventions. PMID- 28072648 TI - Locking Cap Designs Improve Fatigue Properties of Polyaxial Screws in Upper Extremity Applications. AB - OBJECTIVES: This study sought to examine fatigue characteristics of 2 polyaxial locking screw designs: locking cap (LC) and cross-threaded (CT). The goal was to compare LC and CT implants at 0, 10, and 15 degrees of angulation to determine the effect of locking mechanism on screw-plate interface failure. The hypothesis was that LC implants would have superior fatigue properties in comparison to CT designs and that increased angulation of the screw would have a negative impact on the fatigue life of CT implants, but would not have any effect on LC implants. METHODS: A total of 72 screws were tested in 4 upper extremity implants. Implants were subjected to cyclic shear loads and subsequent ramp to failure. Performance characteristics were statistically compared using nonparametric statistical methods. RESULTS: Fatigue testing demonstrated that LC designs were consistently able to sustain a significantly higher number of cyclic loads than CT designs. There were no significant differences in the number of cycles sustained by LC designs because of changes in screw angle, but CT implants exhibited decreases in screw stability with increasing angulation. CONCLUSIONS: Likely because of the spherical screw head geometry, LC fatigue characteristics are not influenced by the orientation of the screw relative to the plate. Application of an LC in the operating room requires additional time, but provides significantly more robust fixation of the screw, especially at oblique angles to the plate and provides a more predictable and consistent biomechanical result. PMID- 28072649 TI - Is Early Definitive Fixation of Bicondylar Tibial Plateau Fractures Safe? An Observational Cohort Study. AB - OBJECTIVES: The optimal treatment protocol for bicondylar plateau fractures remains controversial. Contrary to popular practice which favors a staged protocol in many high-energy fracture patterns, we have used early single-stage open reduction and internal fixation (ORIF) to treat these injuries whenever possible. The purpose of this study was to determine the complication rate and the functional and radiographic outcomes of this strategy. DESIGN: Retrospective cohort study and prospective data collection. SETTING: Level I trauma center. PATIENTS/PARTICIPANTS: One hundred one patients with 102 OTA/AO type 41-C bicondylar tibial plateau fractures were treated with early definitive ORIF, defined as nonstaged surgery performed within 72 hours from injury. A subset of patients was part of a longitudinal study and reported functional outcomes at 1 year. INTERVENTION: Early definitive ORIF. MAIN OUTCOME MEASUREMENT: Primary outcome: reoperation rate, defined as any surgery within 12 months after the index operation; secondary outcomes: quality and stability of radiographic fracture reduction; and functional outcome [Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) and short musculoskeletal functional assessment (SMFA)]. RESULTS: Nonstaged operative treatment of bicondylar plateau fractures was performed in 91.3% of the fractures during the study period. For those, early definitive ORIF (surgery within 72 hours from injury) was performed in 82.3% fractures. Mean time from injury to ORIF, for closed fractures, was 29.8 hours. Sixteen (15.7%) fractures, which were treated with early definitive ORIF, required an additional surgical procedure within 12 months. Complications included wound infection requiring surgical management, compartment syndrome requiring fasciotomies, nonunion, early fixation failure, and implant removal for discomfort. The reoperation rate was 12.7% if implant removal was excluded. At least 3 of the 4 radiographic criteria used to assess the adequacy of reduction were achieved in 95.1% of cases, and all 4 criteria were met in 59.8% of fractures. The Physical Component of the SF-36 at 12 months was 42.6, which is comparable to values reported in previous studies for operative treatment of bicondylar plateau fractures. CONCLUSIONS: In a model where surgery is performed without delay by experienced orthopaedic trauma surgeons, a large proportion of bicondylar tibial plateau fractures can be safely treated with early definitive ORIF. Early surgery was associated with satisfactory postoperative radiographic reductions. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28072650 TI - Posterior Wall Osteotomy of the Acetabulum to Access Incarcerated Marginal Impaction. AB - Marginal impaction of the acetabulum is typically accessible through fracture planes specific to the nature of the injury. Infrequently, however, incarcerated marginal impaction or free osteochondral fragments are not accessible through these existing fracture planes. As such, alternative methods to access these articular pieces must be considered to ensure adequate reduction. We describe an osteotomy of the posterior wall to access incarcerated fragments and marginal impaction of the acetabulum, enabling concentric articular reduction. PMID- 28072651 TI - Relationship of Sacral Fractures to Nerve Injury: Is the Denis Classification Still Accurate? AB - OBJECTIVE: Use modern computed tomographic imaging to reassess neurological injury risks associated with zone I-III sacral fractures as originally described by Denis et al. DESIGN: Retrospective case-control study. SETTING: University Level I Trauma Center. PATIENTS/PARTICIPANTS: One thousand five hundred seven consecutive patients who presented with sacral fractures between January 2000 and August 2012. MAIN OUTCOME MEASUREMENTS: Patients were stratified based on the diagnosis of acute neurological injury. The risk of severe and complex sacral fractures based on the presence of nerve injury was assessed. RESULTS: The rate of nerve injury was significantly lower compared with historic data (3.5% vs. 21.6%, P < 0.001). Acute nerve injury was a significant risk factor for displaced (odds ratio [OR]: 8.4, 95% confidence interval [CI], 1.4-51.9) and comminuted (OR: 5.2, 95% CI, 1.7-16.3) sacral fractures as well as zone II (OR: 3.4, 95% CI, 1.1-10.1) and III (OR: 3.9, 95% CI, 1.0-16.4) fractures. CONCLUSIONS: The incidence of nerve injuries associated with sacral fractures is significantly lower than originally published by Denis et al. Patients with a nerve injury were highly correlated with having a displaced, comminuted, or zone III fracture, or spinopelvic dissociation; the authors recommend a fine cut computerized tomography for further investigation if these findings are not apparent on initial radiographic imaging. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28072653 TI - Invited Commentary Related to: "Does a Staged Posterior Approach Have a Negative Effect on OTA 43C Fracture Outcomes?" PMID- 28072652 TI - In Vivo Correlation of Radiographic Scoring (Radiographic Union Scale for Tibia Fractures) and Biomechanical Data in a Sheep Osteotomy Model: Can We Define Union Radiographically? AB - OBJECTIVE: To determine (1) the reliability of the standard and modified Radiographic Union Scale for Tibia fractures (RUST) score in a sheep osteotomy model, and (2) the standard and modified RUST scores that represent biomechanical union. DESIGN: The tibia cortices in a sheep osteotomy model treated by intramedullary nails were radiographically evaluated using standard and modified RUST scores. Scores that correlated with biomechanical union, based on the torsional stiffness of the contralateral tibia, were determined. INTERVENTION: Two groups of sheep had transverse midshaft osteotomies treated with 10-mm nails after reaming to 11.5 mm. Weight-bearing was allowed as tolerated. Anteroposterior and lateral radiographs were taken at standard intervals from 4 to 12 weeks. The tibial cortices at each time interval were evaluated in a random order by 5 senior orthopaedic trauma surgeons. Each tibia was scored using the standard and modified RUST methods and was assessed for union. MAIN OUTCOME MEASURES: The intraclass correlation coefficient (ICC) was determined for standard and modified RUST scores at each time interval and for the assessment of union. The percentages of fractures that were defined as united by the surgeons were tabulated by RUST and modified RUST scores. The torsional stiffness of each tibia was tested at 12 weeks and expressed as a percentage of the contralateral side. We considered biomechanical union to be >=90% of the torsional stiffness of the normal side. RESULTS: The modified RUST score demonstrated consistently higher ICCs than the standard RUST. All reviewers considered a standard RUST of 10 and a modified RUST of 14 to represent radiographic union. The standard RUST was 10.4 (range: 8.6-12) and modified RUST was 14.2 (range: 12.2-16) for tibiae that were biomechanically united. CONCLUSIONS: The modified RUST score has a slightly higher ICC than the standard RUST. A standard RUST of 10 and a modified RUST of 14 provide an excellent definition of union based on surgeons' opinion and biomechanical testing for a transverse fracture. PMID- 28072654 TI - Adverse Events Following Vestibular Schwannoma Surgery: A Comparison of Surgical Approach. AB - OBJECTIVE: Compare complications of vestibular schwannoma (VS) resection by surgical approach. STUDY DESIGN: Retrospective cohort. SETTING: The 2008 to 2013 American College of Surgeons-National Surgical Quality Improvement Program. PATIENTS: Adult patients with VS resection by an otolaryngologist. INTERVENTIONS: VS resection via transtemporal (TT), retrosigmoid (RS), or middle cranial fossa (MCF) approaches. MAIN OUTCOME MEASURES: Hearing preservation approaches were compared with hearing sacrificing approaches. Demographics and intraoperative factors were analyzed to identify predictors of medical and surgical complications, return to the operating room, and death. The effect of trainee presence was evaluated with respect to complications, operative length, and hospital length of stay. RESULTS: One hundred eleven VS resections were identified. Patients were predominantly women (57%) and older than 50 years (69%). The TT approach accounted for 50% of the cases, while RS (36%) and MCF (14%) were less common. The risk of any postoperative complication was 17%. There were no patient deaths. There was no difference in the overall complication rate among surgical approaches, nor in the overall, surgical, or medical complication rates between hearing preservation and hearing sacrificing approaches. Trainee presence did not change operation length, hospital length of stay, or complication rates. CONCLUSIONS: Complication rates of VS resection are no different when comparing TT, RS, or MCF approaches. Trainee involvement did not significantly affect complications. This study is limited by the inability to evaluate procedure-specific variables (e.g., facial nerve weakness and hearing preservation rates), but offers a unique survey of global 30-day complication rates reported to a large, multi-institutional, publically available database. PMID- 28072655 TI - Skin Necrosis After Implantation With the BAHA Attract: A Case Report and Review of the Literature. AB - OBJECTIVE: The bone-anchored hearing aid (BAHA) Attract is a transcutaneous bone conduction hearing aid that uses magnetic coupling to enable sound conduction. We report the first case of skin necrosis associated with the BAHA Attract and perform a literature review of soft tissue complications related to the device. PATIENT: A single patient who was found to develop skin necrosis 2 weeks after being fitted for the BAHA Attract speech processor. INTERVENTION: After the patient developed skin necrosis from the device, she was advised to immediately discontinue use of the Attract to allow complete wound healing, upon which the Attract was successfully converted to a percutaneous BAHA. MAIN OUTCOME AND RESULTS: We monitored for the development of skin complications from the BAHA Attract. The patient's immediate postoperative course was unremarkable and she was fitted with a speech processor of M5 magnet strength at 1 month postoperatively. After 1 week of use, she reported discomfort and was advised to downgrade to an M4 magnet; however, she continued to use the M5 and the following week was found to have developed skin necrosis around the device. CONCLUSION: Despite the infrequency of skin necrosis related to the BAHA Attract, it must be considered in counseling and managing candidates for the device. PMID- 28072656 TI - Isosorbide-Induced Decompression Effect on the Scala Media: Participation of Plasma Osmolality and Plasma Arginine Vasopressin. AB - OBJECTIVE: The correlation between the isosorbide-induced decompression effect on the endolymphatic space and plasma osmolality (p-OSM) or plasma arginine vasopressin (p-AVP) was investigated on comparing two different dosages of isosorbide (2.8 and 1.4 g/kg) to elucidate why the decompression effect is delayed with a large dose of isosorbide. MATERIALS AND METHODS: Two experiments were performed using 80 guinea pigs. Experiment 1 was designed to morphologically investigate the sequential influence of the oral intake of 1.4- and 2.8-g/kg doses of isosorbide on the endolymphatic volume. The animals used were 50 guinea pigs (control: 10, experimental: 40). All animals underwent surgical obliteration of the endolymphatic sac of the left ear. One month after the surgery, control animals were sacrificed 3 hours after the intake of distilled water, and experimental animals were sacrificed 3 and 6 hours after the isosorbide intake. All of the left temporal bone served for the quantitative assessment of changes in the endolymphatic space, and the cross-sectional area of the scala media was measured from the mid-modiolar sections of the cochlea.Experiment 2 was designed to investigate changes in p-OSM and p-AVP levels 3 hours after the oral intake of isosorbide. Animals used were 15 guinea pigs (control: 5, experimental: 10). The control group received the oral administration of distilled water (4 ml/kg), and the experimental animals were subdivided into two groups consisting of 10 animals each by the dosage of isosorbide (1.4 or 2.8 g/kg). All animals were sacrificed for the measurement of p-OSM and p-AVP concentrations 3 hours after the intake of water or 70% isosorbide solution. RESULTS: Morphologically, an isosorbide-induced decompression effect was noted in animals with both 1.4- and 2.8-g/kg doses of isosorbide. According to the regression analysis, however, the volumetric decrease of the endolymphatic space was more evident in cases with the small dose (1.4 g/kg) 3 hours after the intake (analysis of covariance [ANCOVA], p < 0.001). Six hours after, the decompression effect was significantly greater in cases with the large dose (2.8 g/kg) (ANCOVA, p < 0.001).Isosorbide intake caused a rise in p-OSM levels dose-dependently. The Cochran-Cox test revealed that the differences in the mean values among control and isosorbide groups were significant (p < 0.01). Regarding the p-AVP level, a significant increase was evident in cases with the large dose (2.8 g/kg) (p < 0.01, Cochran-Cox test), and not in cases with the small dose (1.4 g/kg). CONCLUSION: An isosorbide-induced decompression effect of the endolymphatic space was evident in spite of two different dosages of isosorbide (2.8 and 1.4 g/kg). Three hours after the isosorbide intake, however, the decompression effect was more marked in the group with the small dose (1.4 g/kg). Since significant rises in p-OSM and p-AVP were evident in the group with the large dose, this early rise of p-AVP due to dehydration seems to be the major reason for the delayed decompression effect in cases with a large isosorbide intake. PMID- 28072657 TI - Assessment of Cochlea Endolymphatic Hydrops Using 3-D FLAIR and 3-D Real IR Sequence in Guinea Pigs via 3T MRI After Intratympanic Gadolinium: A Histopathological Comparison. AB - OBJECTIVE: We assessed whether the three-dimensional fluid-attenuated inversion recovery (3-D FLAIR) and three-dimensional inversion-recovery with real reconstruction (3-D real IR) sequences can be used to detect cochlea endolymphatic hydrops (EHs) in guinea pigs using 3 Tesla magnetic resonance imaging (3T MRI). The results of 3-D real IR imaging were compared with histopathological outcomes. MATERIALS AND METHODS: Fourteen healthy men and women albino guinea pigs were used in this study. Their right ears received procedures that promoted EHs, and their left ears were used as untreated controls. High resolution 3T MRI, combined with the intratympanic injection of gadolinium (Gd) in both ears, was performed 8 to 12 weeks after surgery. Both sides of the cochlea midmodiolar sections were observed under a light microscope and saved as the histopathological images. The signal-to-noise ratios (SNRs) and contrast-to noise ratios (CNRs) between the T2-weighted 3-D FLAIR and T2-weighted 3-D real IR sequences were compared. The appearance of EHs in the basal, second, third, and apical turns of the cochlea was further evaluated using 3-D FLAIR, 3-D real IR, and the histopathological images. Moreover, the maximum scala media area ratios (SMRs) on the histopathological sections were compared with the grading of the EHs on the 3-D real IR sequence with regard to each turn of the cochlea. RESULTS: Significant differences were found between the 3-D FLAIR and 3-D-real IR sequences with regard to the SNRs and CNRs (p < 0.05): the 3-D FLAIR sequence exhibited higher SNRs (SNRROI: 347.95 +/- 105.01; SNRB: 103.28 +/- 17.61) compared with the 3-D real IR sequence (SNRROI: 86.71 +/- 30.11; SNRB: 11.11 +/- 3.45), whereas the 3-D real IR sequence showed higher CNRs (2.78 +/- 0.58) compared with the 3-D FLAIR sequence (2.18 +/- 0.55). Various degrees of EHs were observed in each turn of the cochlea in the experimental ears on the basis of the histopathological images. Thirteen, 10, 4, and 0 EHs were observed in the basal, second, third, and apical turns of the cochlear using 3-D FLAIR images, respectively, whereas 14, 14, 14, and 13 EHs were found using 3-D real IR images, respectively. Significant differences were found between the two sequences when evaluating the second, third, and apical turns of the cochlear but not with regard to the basal turn (p < 0.05). The SMRs were proportional to the extent of the EHs on 3-D real IR imaging in each turn of the cochlea. CONCLUSIONS: 3-D real IR images are clearer than 3-D FLAIR images, and they can display cochlea EHs more precisely using 3T MRI in guinea pigs. The extent of the EHs on 3-D real IR imaging was more consistent with the histopathological observations in each turn of the cochlea. PMID- 28072658 TI - Clinical Applicability of Monitoring the Time Interval Between Anesthesia and Electroconvulsive Therapy. AB - The anesthetic-electroconvulsive therapy (ECT) time interval (time interval elapsed from the beginning of anesthesia injection to the beginning of ECT stimulus) has been reported to have an important impact on seizure quality outcomes, because it is an indirect measure of the anesthetic plasma concentration when the ECT electrical stimulus is administered. We report the importance of the routine monitoring of this time interval in clinical settings, as an additional measure to interpret seizure quality outcomes at each ECT session, to further assist on ECT dosing decisions during the treatment course. PMID- 28072659 TI - Effects of Transcranial Magnetic Stimulation on the Cognitive Control of Emotion: Potential Antidepressant Mechanisms. AB - Depression negatively impacts quality of life and is associated with high mortality rates. Recent research has demonstrated that improvement in depression symptoms with transcranial magnetic stimulation (TMS) to the dorsolateral prefrontal cortex (DLPFC) may involve changes in the cognitive control network, a regulatory system modulating the function of cognitive and emotional systems, composed of the DLPFC, dorsal anterior cingulate, and posterior parietal cortices. Transcranial magnetic stimulation to the DLPFC node of the cognitive control network may have antidepressant efficacy via direct effects on cognitive control processes involved in emotion regulation. This review provides a review of the impact of TMS on cognitive control processes, especially those related to emotion regulation, and posits that these effects are critical to the mechanism of action of TMS for depression. Treatment implications and future directions for study are discussed. PMID- 28072660 TI - Two Versus One High-Frequency Repetitive Transcranial Magnetic Stimulation Session per Day for Treatment-Resistant Depression: A Randomized Sham-Controlled Trial. AB - OBJECTIVES: High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has proven antidepressant effects, but the optimal frequency of sessions remains unclear. METHODS: We conducted a 3-week, sham-controlled trial to assess the antidepressant efficacy of 1 active HF-rTMS session per day (A1 group) compared with 2 per day (A2 group) and equivalent sham sessions (once a day, S1 group; twice a day, S2 group) in patients with treatment-resistant major depression with a subsequent 2-week follow-up period. One hundred seventy-seven patients were screened, of whom 105 met eligibility criteria and 98 consented and were randomized. The HF-rTMS (20 Hz) was targeted to the left prefrontal cortex in sessions of approximately 40 trains (2 seconds each) at 100% resting motor threshold with an intertrain interval of 1 minute. Treatment response was defined as a 50% or greater decrease in the Hamilton Depression Rating Scale (HDRS) score and/or Clinician Global Impressions-Severity of Illness (CGI-S) score of 3 or less. Remission was defined as HDRS score less than 8 and/or CGI-S score of 2 or less. RESULTS: Practically none of the subjects in either sham groups achieved remission. Increased odds of remission were present for CGI-S by stimulating twice rather than once per day (odds ratio [OR] = 1.5, P = 0.018), whereas there was a marginal result for HDRS (OR = 3.9, P = 0.066). Patients who had lower baseline HDRS (OR = 0.75, P = 0.014) and CGI-S scores (OR = 0.18, P = 0.001) were more likely to achieve remission. CONCLUSIONS: Twice per day active HF-rTMS might be more effective than once per day active HF-rTMS or sham stimulation. PMID- 28072661 TI - Serum Oxytocin Concentration in Patients Receiving Electroconvulsive Therapy: An Exploratory Study and Review of Literature. AB - BACKGROUND: Neuroendocrine biomarkers have long been studied in the context of electroconvulsive therapy (ECT). We prospectively assessed serum oxytocin change and moderators thereof in an exploratory study of patients receiving ECT. METHODS: Serum oxytocin concentrations were assessed immediately before and 1 to 3 minutes after the first ECT in 33 patients with schizophrenia (n = 14), other nonaffective psychosis (n = 6), mania (n = 10), and depression (n = 3) who received 6 to 7 bitemporal, brief-pulse ECTs. Change in serum oxytocin was assessed in the sample as a whole, and as a function of age, sex, diagnosis, and treatment response. The primary outcome was change in serum oxytocin in the overall sample. RESULTS: There was much variation across patients; oxytocin concentrations increased marginally by a mean (standard deviation) (M [SD]) of 6.4 (82.7) pg/mL (P = 0.43). The M (SD) change was -8.2 (85.0) pg/mL in patients with schizophrenia and other nonaffective psychoses (P = 0.84). There was no significant correlation between change in Brief Psychiatric Rating Scale scores and change in oxytocin concentrations in patients with schizophrenia, other nonaffective psychoses, and mania (rho = 0.10, P = 0.61). Serum oxytocin rose in men, after ECT, and fell in women (P = 0.01). CONCLUSIONS: Change in serum oxytocin immediately after the first ECT in a course may not be a useful biomarker of ECT action. This is the first report on the subject in a sample comprising mostly patients with nonaffective psychosis and mania rather than depression. We discuss our findings in the light of previous research and offer general conclusions about the field. PMID- 28072662 TI - Successful Treatment With Electroconvulsive Therapy of a Patient With Bipolar Disorder and a 7-mm Cerebral Aneurysm. PMID- 28072663 TI - Commentary on Bennett and Colleagues: Differences in Cognitive Outcomes After Electroconvulsive Therapy Depending on BDNF and COMT Polymorphisms. PMID- 28072664 TI - Clinical Pathway Effectiveness: Febrile Young Infant Clinical Pathway in a Pediatric Emergency Department. AB - OBJECTIVE: Young infants are often treated in emergency departments (EDs) for febrile illnesses. Any delay in care or ineffective management could lead to increased patient morbidity and mortality. A standardized ED clinical pathway may improve care for these patients. The objective of this study is to evaluate the impact of a febrile young infant clinical pathway implemented in a large, urban children's hospital ED on the timeliness and consistency of care. METHODS: This study used a before-and-after retrospective observational study design comparing 2 separate periods: prepathway from September 2007 through August 2008 and postpathway from September 2009 through August 2010. Subjects were infants aged 56 days or younger presenting with a rectal temperature of 38.0 degrees C or higher. Patients were excluded if they were transferred from another hospital or if they developed a fever after initial presentation. RESULTS: Five hundred twenty infants were enrolled. The mean time to urine collection and time to the first antibiotic administration were reduced after pathway implementation (23 minute reduction to urine collection vs 36-minute reduction to the first antibiotic administration). There was improvement in the proportion of infants who received the pathway-specific antibiotics based on age (odds ratio, 7.2; 95% confidence interval, 4.4, 11.9) and the proportion of infants who were administered acyclovir based on pathway guidelines (odds ratio, 8.8; 95% confidence interval, 2.9-30.0). CONCLUSIONS: An ED-based febrile young infant clinical pathway improved the timeliness of initiation of work-up as measured by urine collection and of therapy by an earlier administration of the first antibiotic, as well as decreased variability of care. PMID- 28072665 TI - Idiopathic Unilateral Paralysis of the Palate in a Youth. AB - Unilateral isolated paralysis of the soft palate is a rare clinical entity that is associated with rhinolalia and the flow of nasal fluids from the nostril on the affected side. We report a case of a 17-year-old boy admitted complaining of nasal speech and drinks flowing into his right nostril. Most cases of soft palate palsy are idiopathic, whereas a few cases are caused by viral infections or tumors. We describe an isolated case of soft palate palsy with spontaneous recovery within 1 month. PMID- 28072666 TI - Outcomes From Referrals and Unscheduled Visits From Community Emergency Departments to a Regional Pediatric Emergency Department in Canada. AB - OBJECTIVES: Existing pediatric literature describing repeat visits to the emergency department (ED) for the same medical complaint has yet to report on patient flow patterns from general EDs (GEDs) to a pediatric ED (PED). We sought to characterize the population of patients who are treated in a GED and subsequently present to a PED for further care. METHODS: We conducted a retrospective cohort study reviewing all pediatric visits (age < 17 y) at 5 GEDs in Vancouver. Our primary outcome measure was the proportion of visits with a subsequent visit to a PED (<7 days) during the 2012 to 2013 fiscal year. Secondary outcomes included reasons for PED consultation, the clinical services accessed, and disposition at the PED. RESULTS: During the study period, 581 (3.3%) of the 17,824 children seen at GEDs subsequently presented to the PED within 7 days. The top 3 diagnoses among these were fracture, viral infection, and musculoskeletal complaints. Of the 581 children with a visit to the PED, 180 (31.0%) were referred to the PED for a consultation, whereas the rest were family initiated. Referred visits were more frequently associated with pediatric subspecialist consultation than family-initiated visits (45.0% vs 19.5%, P < 0.01). The referred group more frequently resulted in a surgical procedure (13.9% vs 2.5%, P < 0.01) or hospital admission (51.7% vs 8.7%, P < 0.01). CONCLUSIONS: Knowing the proportion, management, and outcomes of children who are treated in a GED and subsequently at a PED may provide an important quality measure and opportunities to improve the management of common pediatric emergencies in the community. PMID- 28072667 TI - Does the Use of a Vein Visualization Device for Peripheral Venous Catheter Placement Increase Success Rate in Pediatric Patients? AB - BACKGROUND: Peripheral intravenous catheterization is one of the most frequently encountered medical procedures for hospitalized children and is one that can often be painful. Pediatric nurses should therefore use techniques that increase the success rate or shorten the duration of peripheral intravenous catheterization. OBJECTIVES: This study was performed with the objective of determining the effect of using a vein visualization device on the success of the procedure. Success was determined based on the number of attempts per patient, the duration of the procedure, and the first stick success rate. METHODS: This was a randomized, controlled experimental study on 129 children aged 3 to 18 years. RESULTS: The duration of peripheral intravenous catheterization was shorter in the study group (S) than in the control (C) patients (37.24 +/- 20.07 vs 172.65 +/- 153.21 seconds; P = 0.001), with fewer attempts (S, 1.08 +/- 0.28; C, 2.23 +/- 1.57; P < 0.01). The first stick success rate was higher in the control group (S, 91.7%; C, 47.4%; P = 0.001). CONCLUSIONS: Peripheral intravenous catheterization using vein visualization device support reduces the number of attempts per patient and the operation duration but increases the rate of first stick success. We may therefore state that vein visualization device support improves the success of peripheral intravenous catheterization. PMID- 28072668 TI - Genital and Extragenital Gonorrhea and Chlamydia in Children and Adolescents Evaluated for Sexual Abuse. AB - OBJECTIVE: The aim of this study was to describe the use of a nucleic acid amplification test in detecting genital and extragenital Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) in children and adolescents assessed for sexual abuse/assault. METHODS: The charts of children aged 0 to 17 years, consecutively evaluated for sexual victimization, in emergency department and outpatient settings were reviewed. Data extracted included age, sex, type of sexual contact, anogenital findings, previous sexual contact, toxicology results, and sites tested for NG and CT. RESULTS: Of the 1319 patients who were tested, 579 were tested at more than 1 site, and 120 had at least 1 infected site. Chlamydia trachomatis was identified in 104 patients, and NG was found in 33. In bivariate analysis, a positive test was associated with female sex, age older than 11 years, previous sexual contact, acute or healed genital injury, drug/alcohol intoxication, and examination within 72 hours of sexual contact. Fifty-one patients had positive anal tests, and 24 had positive oral tests. More than 75% of patients with positive extragenital tests had additional positive tests or anogenital injury. Most with a positive anal (59%) or oral (77%) test did not report that the assailant's genitals came into contact with that site. CONCLUSIONS: Positive tests for NG and CT in patients evaluated for sexual victimization may represent infection from sexual contact, contiguous spread of infection, or the presence of infected assailant secretions. Relying on patient reports of symptoms, or types of sexual contact, to determine need for testing may miss NG and CT infections in patients evaluated for sexual victimization. PMID- 28072669 TI - Swimming Pool Electrical Injuries: Steps Toward Prevention. AB - OBJECTIVE: Electrical injuries in swimming pools are an important pediatric public health concern. We sought to (1) improve our understanding of the clinical presentation and outcomes following and (2) describe the epidemiology of swimming pool electrical injuries in the United States. METHODS: We reviewed 4 cases of pediatric (<18 y old) electrical injury from a single, urban level 1 pediatric trauma center. We also queried the National Electronic Injury Surveillance System (NEISS) for emergency department visits due to electrical injury associated with swimming pools, occurring between 1991 and 2013. RESULTS: Overall, 566 cases were reported, with a mean (SD) age of 9.2 (4.1) years. Patients were mostly treated and released from the emergency department (91.8%), whereas 8.2% were hospitalized. When stated, injuries occurred most frequently at home (57.0%), followed by public (23.9%) and sports facilities (19.1%). Electrical outlets or receptacles (39.8%) were most commonly implicated, followed by electrical system doors (18.2%), electric wiring systems (17.0%), thermostats (16.3%), hair dryers (4.6%), and radios (4.1%). Pediatric cases represented 48.4% of swimming pool related electrical injuries reported to NEISS. CONCLUSIONS: Electrical injuries occurring in and around swimming pools remain an important source of morbidity and mortality. Although NEISS monitors sentinel events, current efforts at preventing such cases are less than adequate. All electrical outlets near swimming pools should be properly wired with ground fault circuit interrupter devices. Possible approaches to increasing safe electrical device installation are through strengthening public awareness and education of the potential for injury, as well as changes to current inspection regulations. PMID- 28072670 TI - Instruments to Identify Commercially Sexually Exploited Children: Feasibility of Use in an Emergency Department Setting. AB - OBJECTIVE: This review examines the screening instruments that are in existence today to identify commercially sexually exploited children. The instruments are compared and evaluated for their feasibility of use in an emergency department setting. METHODS: Four electronic databases were searched to identify screening instruments that assessed solely for commercial sexual exploitation. Search terms included "commercially sexually exploited children," "CSEC," "domestic minor sex trafficking," "DMST," "juvenile sex trafficking," and "JST." Those terms were then searched in combination with each of the following: "tools," "instruments," "screening," "policies," "procedures," "data collection," "evidence," and "validity." RESULTS: Six screening instruments were found to meet the inclusion criteria. Variation among instruments included number of questions, ease of administration, information sources, scoring methods, and training information provided. Two instruments were determined to be highly feasible for use in the emergency department setting, those being the Asian Health Services and Banteay Srei's CSEC Screening Protocol and Greenbaum et al's CSEC/child sex trafficking 6 item screening tool. CONCLUSIONS: A current dearth of screening instruments was confirmed. It is recommended that additional screening instruments be created to include developmentally appropriate instruments for preadolescent children. Numerous positive features were identified within the instruments in this review and are suggested for use in future screening instruments, including succinctness, a simple format, easy administration, training materials, sample questions, multiple information sources, designation of questions requiring mandatory reporting, a straightforward scoring system, and an algorithm format. PMID- 28072671 TI - Evaluation of the Association of Early Elevated Lactate With Outcomes in Children With Severe Sepsis or Septic Shock. AB - OBJECTIVE: The aim of the study was to assess the association of initial lactate (L0) with mortality in children with severe sepsis. METHODS: This prospective cohort study included 74 patients younger than 18 years with severe sepsis admitted to the pediatric intensive care unit (PICU) of a tertiary, academic children's hospital with lactate measured within 3 hours of meeting severe sepsis or septic shock. The primary outcome was in-hospital mortality. The secondary outcomes included PICU and hospital length of stay. RESULTS: Although overall mortality was 10.5% (n = 18), patients with L0 measured (n = 72) had a higher mortality (16% vs 6%, P = 0.03) and higher median PRISM-III risk of mortality scores (P = 0.02) than those who did not. Median L0 was no different between nonsurvivors and survivors (3.6 mmol/L [interquartile range, 2.0-9.0] in nonsurvivors vs 2.3 mmol/L [interquartile range, 1.4-3.5] in survivors, P = 0.11). However, L0 was independently associated with PRISM-III score (coefficient, 1.12; 95% confidence interval, 0.4-1.8; P = 0.003) with an increase in mean PRISM-III score of 1.12 U for every 1 mmol/L increase in L0, with L0 accounting for 12% of the variability in PRISM-III scores between patients. There was no association between L0 and PICU or hospital length of stay. CONCLUSIONS: Although our single center study did not demonstrate that an elevated early lactate is associated with mortality in pediatric severe sepsis, L0 did correlate strongly with PRISM-III, the most robust measure of mortality risk in pediatrics. Therefore, early lactate measurement may be important as an early biomarker of disease severity. These data should be validated in a larger, multicenter, prospective study. PMID- 28072672 TI - A Simplified Electroencephalogram Monitoring System in the Emergency Room. AB - OBJECTIVES: The study aims to assess the clinical usefulness and related limitations of our simplified emergency electroencephalography (eEEG) as an assessment tool of lethal abnormal brain waves in the emergency room (ER). METHODS: Electrodes were placed on 4 places: bilateral frontal poles and parietal regions. The derivations to judge consisted of only 2 bipolar leads on the left and right. Abnormal wave was defined as either persistent rhythmic waves or persistent high-amplitude slow waves (<2 Hz). The indications of eEEG were as follows: prolonged impairment of consciousness, suspected subclinical or subtle seizure, and requirement of evaluation of consciousness or seizure during administration of muscle relaxants for endotracheal intubation. RESULTS: We performed eEEG for 86 patients between July 2013 and February 2014. The persistent rhythmic waves were observed in 7 (8.1%), whereas high-amplitude slow waves were observed in 10 (11.6%). Among 69 patients with normal eEEG, 2 were diagnosed with encephalopathy after hospitalization. The mean time taken to attach electrodes was 5.4 minutes. CONCLUSIONS: For the ER physician, the simple EEG, such as eEEG, is useful as a biological monitor because it enables quick assessment of lethal abnormal brain waves in the ER. The clinical usefulness and limitations of our eEEG method should be investigated further in a large population. PMID- 28072673 TI - The Use of Ultrasound-Measured Optic Nerve Sheath Diameter to Predict Ventriculoperitoneal Shunt Failure in Children. AB - OBJECTIVE: The goal of this study was to assess the accuracy of ultrasound measured optic nerve sheath diameter (ONSD) as a screen for ventriculoperitoneal shunt failure. METHODS: We prospectively enrolled a convenience sample of children presenting to the ED with suspected shunt failure. The ONSD was measured by ultrasound and compared with computed tomography/magnetic resonance imaging (CT/MRI) and neurosurgical impression. We defined shunt failure on ultrasound as an ONSD greater than 4.0 mm in infants 12 months and younger or greater than 4.5 mm in children older than 12 months. A single emergency radiologist at our institution read all CTs and MRIs for categorical determination of shunt failure. We defined shunt failure based on neurosurgical impression as a decision to admit and perform shunt revision. We report test characteristics and 95% confidence intervals of ONSD as a predictor for shunt failure. RESULTS: We enrolled 32 subjects. The sensitivities of ONSD compared with CT/MRI and neurosurgical impression, 60.0% and 75.0%, respectively, were low. However, the negative predictive values of ONSD compared with CT/MRI and neurosurgical impression were 90.0% and 95.0%, respectively. CONCLUSIONS: Optic nerve sonography may be a useful tool to identify children presenting with suspected ventriculoperitoneal shunt failure who do not require further imaging. This would reduce the use of CT scan and exposure to ionizing radiation in children with suspected shunt malfunction who do not require neurosurgical intervention. Consideration of additional risk factors and a larger sample size may yield stronger results. PMID- 28072675 TI - Message from Editor. PMID- 28072674 TI - Editor in Chief's Address. PMID- 28072676 TI - Zika Virus Molecular Biology and Perspectives for Vaccine Development: A Review. PMID- 28072677 TI - The Current Status of Nursing Professionalism Among Nursing Faculty in Japan. AB - BACKGROUND: The faculty of nursing schools plays an important role in the successful execution of nursing education. Therefore, faculty behavior strongly affects the professional development of nurses. However, few studies have examined professional nursing behaviors from the perspective of nursing faculty. PURPOSE: Members of nursing faculty in Japan were surveyed regarding their perspectives on behaviors related to professionalism. METHODS: The model, Miller's Wheel of Professionalism in Nursing, was used as the theoretical framework. The Behavioral Inventory for Professionalism in Nursing (BIPN) was completed by 74 full-time nursing faculty who were currently working at 10 institutes of nursing education in Japan. RESULTS: The mean BIPN score for the participants was 11.56 (SD = 6.08) of a possible total of 27. The highest and lowest BIPN category scores were for "research development, use, and evaluation" and "community service," respectively. Professionalism was found to relate significantly to higher educational preparation (F = 32.17, p < .0001). The Tukey Kramer multiple comparison test found a significant association between having a graduate degree and higher scores for professionalism (p < .0001). The Spearman correlation coefficient was significant and positive for the relationship between professionalism and both educational preparation (r = .85, p < .0001) and number of years as a nursing educator (r = .31, p = .0077). CONCLUSIONS: The results support the idea that a higher level of educational preparation and more years of experience as a member of a nursing faculty are associated with higher levels of nursing professionalism. The professional behavior scores suggest that "community service" is an issue that requires further improvement among Japanese nursing faculty. Awareness of extrinsic factors such as education is important to maximize nursing professionalism. The findings of this study may help nursing faculty continue their self-development. PMID- 28072678 TI - Pain, Anxiety, and Fatigue During Labor: A Prospective, Repeated Measures Study. AB - BACKGROUND: Pain, anxiety, and fatigue are known to significantly influence labor; however, the interacting relationships among the three symptoms have not been empirically shown. PURPOSE: The aim of this study was to investigate the interrelationships among intrapartum pain, anxiety, and fatigue relative to the mode of delivery, with or without epidural analgesia (EDA). METHODS: A prospective, repeated measures design was adopted, and women with uncomplicated pregnancies at term (N = 186) were enrolled. Self-reported visual analog scales were used to assess pain, anxiety, and fatigue during the four phases of labor, as determined by cervical dilation (e.g., Phase 1 = 2-4 cm, Phase 2 = 4-6 cm, Phase 3 =10 cm, and Phase 4 = immediately after delivery of the placenta). Of the 186 participants, 48 received EDA when their cervical dilation was 3-4 cm. RESULTS: Throughout the process of labor, pain, anxiety, and fatigue were significantly correlated, no matter whether participants had received EDA, especially during Phases 1 and 3. For the participants undergoing EDA, the level of fatigue decreased more slowly than the levels of pain and anxiety. The participants who received EDA had significantly greater pain and fatigue in Phase 1 of labor than those who did not receive EDA. Mode of delivery was correlated with age, parity, and pain level in Phase 2 of labor and anxiety level in Phase 2 of labor. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Intrapartum pain, anxiety, and fatigue were strongly interrelated. Intrapartum pain management (EDA) led to a significant decline in anxiety and fatigue. Furthermore, fatigue accumulated during the course of labor and was not easily diminished. These findings provide a reference for maternity nurses to develop strategies for managing multiple symptoms. PMID- 28072679 TI - Correlation Between Critical Thinking Disposition and Mental Self-Supporting Ability in Nursing Undergraduates: A Cross-Sectional Descriptive Study. AB - BACKGROUND: There is universal agreement on the essential role of critical thinking in nursing practice. Most studies into this topic have provided descriptive statistical information and insights on related external factors such as educational environment and teaching strategies. However, there has been limited research into the psychological factors that may predict the disposition of students toward critical thinking. PURPOSE: This study explored the relationship between the disposition of nursing students toward critical thinking and their mental self-supporting ability to obtain a profile and determine the psychological predictors of critical thinking. METHODS: A cross-sectional descriptive study was conducted in 2013 using a convenience sample from four nursing schools. Four hundred six Chinese nursing undergraduates completed two questionnaires including (a) the California Critical Thinking Disposition Inventory (Chinese version) and (b) the Mental Self-Supporting Questionnaire for University Students. Pearson's correlation and linear regression analysis were used to investigate the relationship between these two variables and the predicted positive psychological qualities for the critical thinking disposition of participants. RESULTS: Average participant scores for critical thinking disposition and mental self-supporting were 280.91 +/- 28.43 and 76.40 +/- 8.47, respectively. Positive correlations were observed between these two variables (r = .583, p < .01) and participants' self-decision, self-cognition, self confidence, and self-responsibility, which suggest that these factors play a significant role in critical thinking disposition (R = .435, p < .01). CONCLUSIONS: The participants earned midlevel scores for both disposition toward critical thinking and mental self-supporting abilities.The four factors that had a major influence on critical thinking disposition included self-decision, self cognition, self-confidence, and self-responsibility. Nursing educators should focus on improving the critical thinking ability of their students in these four aspects. PMID- 28072680 TI - Translation and Psychometric Testing of the Chinese Version of the Multidimensional Assessment of Interoceptive Awareness. AB - BACKGROUND: Mind-body interventions are used to alleviate physical and psychological symptoms. The multidimensional assessment of interoceptive awareness (MAIA), which is used to self-report the effects of mind-body interventions, is not currently available in Chinese. PURPOSE: This study aimed to translate the MAIA from English into Chinese (MAIA-C) and to examine the psychometric properties of the MAIA-C. METHODS: This was a methodological study. The MAIA was translated forward and backward systematically, and content validity was assessed by a panel of experts. A convenience sample of adult participants with mind-body practice was recruited from social clubs in Taiwan. The MAIA-C was administered to study participants. Internal consistency and test-retest reliability were tested using Cronbach's alpha and intraclass correlation coefficient. Construct validity was assessed in two ways: using confirmatory factor analysis and using the differences between the known groups to divide the sample into two groups of highly experienced and less experienced participants. RESULTS: The complete data for the 294 participants were analyzed. The eight factor structure of the MAIA-C was confirmed. Cronbach's alpha was .91 overall and .46-.88 for the individual scales of the instrument. Intraclass correlation coefficient and composite reliability for the scales ranged from .60 to .85 and .55 to .87, respectively. The result of confirmatory factor analysis revealed a fair fit of the model to the data with a root mean square error of approximation of .076 and a comparative fit index of .95. Significant differences were found for the seven scales between the two groups. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The MAIA-C showed acceptable reliability and validity in psychometric testing. Therefore, this scale may be used in studies that assess interoceptive awareness in Chinese-speaking populations who are undergoing mind-body interventions. PMID- 28072681 TI - Effects of a group-focused cognitive behavioral health education program on cigarette smoking in a sample of Nigerian prisoners. AB - BACKGROUND: Smoking is a learned habit that has an impact on the psychological and biochemical health of individuals. It is the leading preventable cause of chronic illness worldwide. The purpose of this study was to examine the effects of a group-focused cognitive behavioral health education program (GCBHEP) on cigarette smoking in a sample of Nigerian prisoners. METHODS: The study used a pretest-posttest randomized control group design. Twenty inmates were identified through self-reporting, 1-to-1 counseling, and observation. The treatment group took part in a GCBHEP for 10 weeks, while the control group received 10 weeks' conventional counseling. After the intervention program, both the treatment and control groups were evaluated. The repeated measures analysis of variance was used for data analysis and partial eta was also used as a measure of effect size. RESULTS: The findings showed that the GCBHEP had a strong effect on cigarette smoking habits among the inmates in the treatment group compared with those in the control group. The effect of the GCBHEP by age was moderate, and modest by educational qualification. CONCLUSION: Group-focused cognitive behavioral health education is effective in breaking the habit of cigarette smoking among Nigerian prisoners. Therefore, future researchers are encouraged to adopt this approach in helping individuals with a smoking problem and other drug-abuse behaviors in Nigerian prisons. PMID- 28072682 TI - Increasing LAG-3 expression suppresses T-cell function in chronic hepatitis B: A balance between immunity strength and liver injury extent. AB - Weak or absent virus-specific CD8 T-cell responses to hepatitis B virus (HBV) infection are thought to be responsible for persistent HBV infection. Previous studies have indicated that multiple inhibitory receptors, including lymphocyte activation gene-3 (LAG-3), can suppress the CD8 T-cell response in chronic viral infection. This study aimed to detect LAG-3 expression and to investigate the manner in which the immune response is regulated to balance the strength of the response with the extent of liver injury in chronic HBV infection. The results showed that LAG-3 expression levels were significantly higher in CD8 T cells from chronic hepatitis B patients in the immune-active phase compared with chronic asymptomatic HBV carriers and healthy controls. CD8 T-cell function was suppressed in cells with high LAG-3 expression, and these cells exhibited reduced interferon-gamma (IFN-gamma) secretion. Furthermore, IFN-gamma secretion was restored in CD8 T cells that were treated with a specific antibody to LAG-3. Taken together, liver injury was prominent in the immune-active phase, but suppressing T-cell function could mitigate this damage. Importantly, the inhibitory function of LAG-3 can be blocked using a LAG-3-specific antibody, and this can restore the activity of non-functional T cells. PMID- 28072683 TI - Knowledge of Greek adolescents on human papilloma virus (HPV) and vaccination: A national epidemiologic study. AB - The aim of the present study was to identify the sexual behavior, attitudes, beliefs, and knowledge on sexually transmitted infections (STIs) focused on human papilloma virus (HPV) in the Greek adolescent population. The participants were 4547 adolescents, a representative sample for Greek territory with a mean age of 17 years. After written permission from Greek ministry of education each student completed a questionnaire with 36 questions. The fields covered were demographic characteristics, sexual life data, and basic knowledge on HPV. In the present study, 43% and 75% of the participants knew about HPV or cervical cancer, while more than 6 out of 10 did not know the association between the 2. More than 60% of the participants could not answer correctly neither about HPV infection and cervical cancer frequency in sexually active women, nor about protection methods against HPV and cervical cancer. This study shows that the low vaccination coverage of the Greek population may be due to lack of information and awareness of the adolescents and their parents. It is our duty to increase our efforts in order to better educate the population and vaccinate the population as early as possible in their reproductive years. PMID- 28072684 TI - Assessment of hepatocellular carcinoma risk based on peg-interferon plus ribavirin treatment experience in this new era of highly effective oral antiviral drugs. AB - In this new era of highly effective oral antiviral drugs for chronic hepatitis C virus (HCV), indications for antiviral treatment may be extendable. This study undertaken to identify suitable candidates for peg-interferon plus ribavirin (PEG IFN/RBV) treatment by evaluating hepatocellular carcinoma (HCC) risk in patients with chronic HCV treated or not with PEG-IFN/RBV.This large-scale retrospective study was conducted on 1176 patients with chronic HCV without a history of HCC (treatment group [n = 489] and no-treatment group [n = 687]). In the treatment group, patients treated with PEG-IFN/RBV were dichotomized based on the achievement of sustained virologic response (SVR) into SVR (+) and SVR (-) groups.Median follow-up for all study subjects was 31 months (range 6-144 months). Three-year cumulative HCC development rates in the SVR (+) (1.1%) and SVR (-) (8.6%) subgroups were significantly lower than in the no-treatment group (13.5%) (P < 0.01 and P < 0.01, respectively). In all study subjects, presence of cirrhosis (hazard ratio [HR], 9.92, P < 0.01), age (HR 1.03, P < 0.01), SVR (-) (HR 7.02, P < 0.01), and no-treatment (HR 6.76, P < 0.01) were found to be independent risk factors of HCC development. In the treatment group, age, the presence of cirrhosis, and SVR (-) were predictors of HCC development. In the no treatment group, age, male, and the presence of cirrhosis were independent predictors for HCC development.HCC risk increased in patients with chronic HCV with older age, cirrhosis, SVR (-) after PEG-IFN/RBV treatment, and no PEG IFN/RBV treatment. Active antiviral therapy based on highly effective oral drugs needs to be considered in these patients. PMID- 28072685 TI - Nephrotic syndrome associated with metastatic thymoma treated with chemotherapy. AB - RATIONALE: Nephropathy with concurrent invasive thymoma is a type of paraneoplastic syndrome. PATIENT CONCERNS AND DIAGNOSES: We report a 32-year-old female with nephrotic syndrome that was first diagnosed along with invasive thymoma and treated by means of cisplatin-based chemotherapy for the thymoma. The patient initially presented with dyspnea and generalized edema. Chest radiography and computed tomography scans revealed right pleural effusion and a mass in the right middle lung field, which were confirmed by a percutaneous lung biopsy as metastatic invasive thymoma. Severe hypoalbuminemia, heavy proteinuria, hyponatremia, and hypercholesterolemia were features of the nephrotic syndrome. A kidney needle biopsy suggested focal segmental glomerulosclerosis. INTERVENTIONS AND OUTCOMES: All of the symptoms of nephrotic syndrome were resolved simultaneously during the first 2 cycles of chemotherapy. The patient was on regular follow-up with no specific treatment for nephrotic syndrome and underwent successful resection of the left pleura and anterior thymoma. The patient has shown no evidence of recurrence for 2 years. LESSONS: We conclude that chemotherapy for invasive thymoma is an effective treatment for nephrotic syndrome accompanying the thymoma. PMID- 28072686 TI - Design and fabrication of complete dentures using CAD/CAM technology. AB - The aim of the study was to test the feasibility of using commercially available computer-aided design and computer-aided manufacturing (CAD/CAM) technology including 3Shape Dental System 2013 trial version, WIELAND V2.0.049 and WIELAND ZENOTEC T1 milling machine to design and fabricate complete dentures.The modeling process of full denture available in the trial version of 3Shape Dental System 2013 was used to design virtual complete dentures on the basis of 3-dimensional (3D) digital edentulous models generated from the physical models. The virtual complete dentures designed were exported to CAM software of WIELAND V2.0.049. A WIELAND ZENOTEC T1 milling machine controlled by the CAM software was used to fabricate physical dentitions and baseplates by milling acrylic resin composite plates. The physical dentitions were bonded to the corresponding baseplates to form the maxillary and mandibular complete dentures.Virtual complete dentures were successfully designed using the software through several steps including generation of 3D digital edentulous models, model analysis, arrangement of artificial teeth, trimming relief area, and occlusal adjustment. Physical dentitions and baseplates were successfully fabricated according to the designed virtual complete dentures using milling machine controlled by a CAM software. Bonding physical dentitions to the corresponding baseplates generated the final physical complete dentures.Our study demonstrated that complete dentures could be successfully designed and fabricated by using CAD/CAM. PMID- 28072687 TI - The negative chronotropic effect during lumbar spine surgery: A systemic review and aggregation of an emerging model of spinal cardiac reflex. AB - BACKGROUND: Hemodynamic perturbations in spine surgeries are predominantly reported in cervical and thoracic level procedures. The literature related to negative cardiovascular changes (decrease of heart rate and blood pressure) in lumbar spine procedures is still scarce and only highlighted in few case reports/letters until now. METHODS: With the help of a systematic literature review with predefined criteria, we, therefore, examined and synthesized here the probable underlying common cause of these hemodynamic disturbances in lumbar spine surgeries. Data aggregation to a model was done by a case survey method and established by a cause-effect relationship. RESULTS: There are only 5 cases that met our strict predefined criteria and that were aggregated to an emergent model of an autonomous reflex arc. CONCLUSION: This review and consecutive data aggregation provides, for the first time, a concept of spinal cardiac reflex in lumbar spine surgeries. PMID- 28072688 TI - Factors associated with unattained LDL-cholesterol goals in Chinese patients with acute coronary syndrome one year after percutaneous coronary intervention. AB - Reducing low-density lipoprotein cholesterol (LDL-C) to target <=1.81 mmol/L is a common therapeutic goal after acute coronary syndrome (ACS). This study aimed to examine the factors associated with reaching or not this LDL-C target after 1 year of optimal statin therapy postpercutaneous coronary intervention (PCI). This was a retrospective study of 633 consecutive prospectively enrolled patients with ACS treated between January 2011 and December 2012 at the Beijing Hospital (China). All patients were treated with PCI and statins for 1 year. A multivariate analysis was carried out to identify the factors associated with reaching the LDL-C target of <=1.81 mmol/L. The rate of unreached LDL-C goal after 1 year was 48%. Compared with those who achieved their LDL-C goal, patients not achieving their LDL-C goal showed a higher proportion of females (37.9% vs 28.7%, P < 0.001), higher LDL-C levels at admission (2.82 +/- 0.75 vs 2.08 +/- 0.70 mmol/L, P < 0.001), lower proportion of patients with a history of PCI (17.6% vs 24.8%, P = 0.03), and younger age (66.7 +/- 10.6 vs 68.9 +/- 10.1 years, P = 0.009). A multivariate analysis showed that lower LDL-C levels on admission were predictive of LDL-C goal achievement (odds ratio [OR] = 4.81; 95% confidence interval [CI]: 3.46-6.70; P < 0.001), together with older age (OR: 0.98; 95% CI: 0.96-0.997; P = 0.026), and male gender (OR: 0.64; 95% CI: 0.42 0.98; P = 0.040). Higher LDL-C levels at admission, younger age, and female gender were independently associated with not reaching the LDL-C target after 1 year of optimal statin therapy after PCI. PMID- 28072689 TI - An observational study on the effect of premature ventricular complex burden on long-term outcome. AB - The long-term clinical impact of premature ventricular complexes (PVCs) on mortality and morbidity has not been fully studied. This study aimed to investigate the association between the burden of PVCs and adverse clinical outcome.A total of 5778 subjects, who were pacemaker-free and ventricular tachycardia-free at baseline, received 24-hour electrocardiography monitoring between January 1, 2002 and December 31, 2004. Clinical event data were retrieved from the Bureau of National Health Insurance of Taiwan. Multivariate Cox hazards regression models and propensity-score matching were applied to assess the association between PVCs and adverse clinical outcome.Average follow-up time was 10[REPLACEMENT CHARACTER]+/- 1 year. In all, 1403 subjects expired, 1301 subjects were hospitalized in the cardiovascular (CV) ward, 3384 were hospitalized for any reason, and 631 subjects developed new-onset heart failure (HF). The optimal cut off PVC frequency (12 beats per day) was obtained through receiver operator characteristic curves, with a sensitivity of 58.4% and specificity of 59.8%. Upon multivariate analysis, a PVC frequency >12 beats per day was an independent predictor for all mortality (hazard ratio [HR]: 1.429, 95% confidence interval [CI]: 1.284-1.590), CV hospitalization (HR: 1.127, 95% CI: 1.008-1.260), all cause hospitalization (HR 1.094, 95% CI: 1.021-1.173), and new-onset HF (HR: 1.411, 95% CI: 1.203-1.655). Subjects with a PVC frequency >12 beats per day had an increased risk of cardiac death attributable to HF and sudden cardiac death. The incidence rates for mortality and HF were significantly increased in cases of raised PVC frequency. Propensity-score matching analysis also echoed the main findings.Increased PVC burden was associated with a higher incidence of all-cause mortality, CV hospitalization, all-cause hospitalization, and new-onset HF which was independent of other clinical risk factors. PMID- 28072690 TI - Comparison of jet injector and insulin pen in controlling plasma glucose and insulin concentrations in type 2 diabetic patients. AB - This study is conducted to investigate efficacy of an insulin jet injector and an insulin pen in treatment of type 2 diabetic patients. Sixty patients with type 2 diabetes were treated with rapid-acting insulin (regular insulin) and insulin analog (insulin aspart) using the jet injector and the pen in 4 successive test cycles. Postprandial glucose and insulin concentrations in blood were measured over time. Areas under curves of glucose and the insulin were calculated, and efficacy of 2 injection methods in treatment of the diabetes was compared. Regular insulin and insulin aspart administration by the jet injector showed significant decreases in plasma glucose levels as compared to the pen injection (P < 0.05). Postprandial plasma glucose excursions at the time points of 0.5 to 3 hours were obviously lower in the jet-treated patients than the pen-treated ones (P < 0.05). Postprandial plasma insulin levels were markedly higher in the jet treated patients than the pen-treated ones (P < 0.05). Area under the glucose curve in the pen-treated patients was significantly increased as compared to the jet-treated ones (P < 0.01). Efficacy of the insulin jet injector in treatment of type 2 diabetic patients is obviously superior to the insulin pen in regulating plasma glucose and insulin levels. PMID- 28072691 TI - The effectiveness and safety of dual antiplatelet therapy in ischemic cerebrovascular disease with intracranial and extracranial arteriostenosis in Chinese patients: A randomized and controlled trail. AB - BACKGROUND: There are limited data on the effect of dual antiplatelet treatment with clopidogrel plus aspirin in patients with ischemic cerebrovascular disease and intracranial and extracranial arteriostenosis. The aim of our study was to evaluate the efficacy and safety of aspirin plus clopidogrel in the treatment of ischemic cerebrovascular disease with intracranial and extracranial arteriostenosis. METHODS: Patients with clinically evident acute cerebral infarction or transient ischemic attack combined with intracranial and extracranial arteriostenosis (greater than 50%) who were unsuitable or reluctance to perform stent implantation were enrolled in this study. We randomly assigned these patients to receive clopidogrel (75 or 50 mg) plus aspirin (100 mg) or aspirin (100 mg) once daily through 90 days, and followed them for 90 days. We examined the main endpoints including the recurrence of stroke, death from cardiovascular causes, and bleeding events. RESULTS: In all, 200 patients were recruited and followed for 90 days. Ischemic stroke occurred in 6 patients (9.1%) treated with 50 mg clopidogrel and aspirin, 6 patients (9.1%) receiving 75 mg clopidogrel and aspirin, whereas 19 patients (27.9%) in the aspirin group (aspirin alone vs copidogrel 50 mg plus aspirin; 95% confidence intervals 1.704 23.779, P < 0.05; aspirin alone vs copidogrel 75 mg plus aspirin; 95% confidence intervals 1.190-13.240, P < 0.05). There were more hemorrhagic events among recipients (3 patients [2.3%]) in the copidogrel plus aspirin group than aspirin recipients (0 patient [0%]), including 1 subcutaneous hemorrhage in the group of 50 mg clopidogrel and aspirin, doubling the number of nasal and gum bleeding in the group of 75 mg clopidogrel and aspirin (P > 0.05). No intracranial hemorrhage and gastro-intestinal hemorrhage occurred in these 3 groups. CONCLUSION: Accordingly, 50 mg clopidogrel plus aspirin, and 75 mg clopidogrel plus aspirin were all superior to aspirin alone as stroke prevention in patients with cerebral infarction or transient ischemic attack combined with intracranial and extracranial arteriostenosis. The effect of secondary stroke prevention was similar between 50 mg clopidogrel plus aspirin and 75 mg clopidogrel plus aspirin. The therapy of 75 mg clopidogrel plus aspirin resulted in a worrisome tread in bleeding events. PMID- 28072692 TI - Role of biochemistry and cytological analysis of cyst fluid for the differential diagnosis of pancreatic cysts: A retrospective cohort study. AB - BACKGROUND: Management of pancreatic cysts is based on neoplastic-nonneoplastic discrimination. Endoscopic ultrasound (EUS) enables to differentiate neoplastic nonneoplastic lesions and also allows fine-needle aspiration (FNA). In this study, we aim to assess feasibility and clinical relevance of cytological and biochemical analysis in differential diagnosis of cystic pancreatic lesions in patients who had undergone endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) due to pancreatic cysts. METHODS: Participants were 96 patients who had undergone EUS-FNA for differential diagnosis of pancreatic cysts. Pancreatic cysts were classified as benign-mucinous, nonmucinous, and malignant according to patient history, physical examination, EUS appearance, and cystic fluid assessment. Tumor markers (CEA, CA(cancer antigens) 72.4, CA 19-9) , amylase, lipase and cytological assesment were compared between 3 different groups. Receiver-operating characteristics (ROC) curves were constructed to identify appropriate cut-off values. RESULTS: Fluid CEA and CA 72.4 levels for benign mucinous and malignant cysts were significantly higher than for nonmucinous cysts (P <= 0.04). A cut-off CEA level of 207 ng/mL differentiated mucinous etiology with a sensitivity of 72.7%, specificity of 97.7%, and accuracy of 89.5%. The sensitivity, specificity, and accuracy of the CA 72.4 cut-off level of 3.32 ng/mL were 80%, 69.5%, and 73.6%, respectively. CONCLUSION: Cyst fluid CEA and CA 72.4 levels have a high accuracy in discriminating mucinous from nonmucinous cysts. When combined with cytology their accuracy rate increases. PMID- 28072693 TI - Comparative evaluation of target volumes defined by deformable and rigid registration of diagnostic PET/CT to planning CT in primary esophageal cancer. AB - BACKGROUND: To evaluate the geometrical differences of target volumes propagated by deformable image registration (DIR) and rigid image registration (RIR) to assist target volume delineation between diagnostic Positron emission tomography/computed tomography (PET/CT) and planning CT for primary esophageal cancer (EC). METHODS: Twenty-five patients with EC sequentially underwent a diagnostic F-fluorodeoxyglucose (F-FDG) PET/CT scan and planning CT simulation. Only 19 patients with maximum standardized uptake value (SUVmax) >= 2.0 of the primary volume were available. Gross tumor volumes (GTVs) were delineated using CT and PET display settings. The PET/CT images were then registered with planning CT using MIM software. Subsequently, the PET and CT contours were propagated by RIR and DIR to planning CT. The properties of these volumes were compared. RESULTS: When GTVCT delineated on CT of PET/CT after both RIR and DIR was compared with GTV contoured on planning CT, significant improvements using DIR were observed in the volume, displacements of the center of mass (COM) in the 3 dimensional (3D) direction, and Dice similarity coefficient (DSC) (P = 0.003; 0.006; 0.014). Although similar improvements were not observed for the same comparison using DIR for propagated PET contours from diagnostic PET/CT to planning CT (P > 0.05), for DSC and displacements of COM in the 3D direction of PET contours, the DIR resulted in the improved volume of a large percentage of patients (73.7%; 68.45%; 63.2%) compared with RIR. For diagnostic CT-based contours or PET contours at SUV2.5 propagated by DIR with planning CT, the DSC and displacements of COM in 3D directions in the distal segment were significantly improved compared to the upper and middle segments (P > 0.05). CONCLUSION: We observed a trend that deformable registration might improve the overlap for gross target volumes from diagnostic PET/CT to planning CT. The distal EC might benefit more from DIR. PMID- 28072694 TI - Effect of hyperthermic intrathoracic chemotherapy (HITHOC) on the malignant pleural effusion: A systematic review and meta-analysis. AB - BACKGROUND: Although hyperthermic intraperitoneal chemotherapy (HIPEC) has been widely used to treat malignant ascites or as a preventive strategy for microscopic carcinomatosis following surgical resection of abdominal tumors, application of hyperthermic intrathoracic chemotherapy (HITHOC) in the treatment of malignant pleural effusion is limited. The objective of the current study was to conduct a systematic review and meta-analysis on the application of HITHOC in the palliative treatment of malignant pleural effusion. METHODS: After thorough searching of online databases, total 27 articles were included into qualitative systematic review and 5 of them were used to conduct qualitative meta-analysis. RESULTS: It was found that most of HITHOC was used in combination of cytoreductive surgery (CRS) including pleurectomy/decortication or after surgical resection of primary tumors, which mainly were lung cancer, thymoma or thymic carcinoma, breast cancer, and ovarian cancer. Patients who received HITHOC had significantly longer median survival length compared to the patients without HITHOC (Hedges g = 0.763, P < 0.001). In addition, HITHOC therapy was favored (Hedges g = 0.848, P < 0.001) in terms of median survival length, tumor-free survival rate, with tumor survival rate or Karnofsky performance status (KPS) scale. CONCLUSION: HITHOC is a safe and effective therapy in controlling pleural effusion and increasing patient's survival rate. PMID- 28072695 TI - Acute pulmonary edema caused by takotsubo cardiomyopathy in a pregnant woman undergoing transvaginal cervical cerclage: A case report. AB - BACKGROUND: The physiological changes associated with pregnancy may predispose pregnant women to pulmonary edema. Other known causes of pulmonary edema during pregnancy include tocolytic drugs, preeclampsia, eclampsia, and peripartum cardiomyopathy. METHODS: We describe a rare case of pulmonary edema caused by takotsubo cardiomyopathy in a pregnant woman at 14 weeks of gestation who was undergoing emergency transvaginal cervical cerclage. RESULTS: Intraoperative chest radiography revealed severe pulmonary edema and echocardiography indicated moderate left ventricular dysfunction with akinesia of the mid to apical left ventricular wall segment, which is reflective of takotsubo cardiomyopathy. CONCLUSION: With early detection and appropriate management, the patient was stabilized in a relatively short period of time. Based on her clinical signs and symptoms, we suspect that the pulmonary edema was caused by takotsubo cardiomyopathy. PMID- 28072696 TI - Cerebroretinal microangiopathy with calcifications and cysts: A case report. AB - RATIONAL: Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is believed to be an autosomal recessive genetic disease, with disorders in multisystem organs. Its characteristic neurological disorders manifested on neuroimaging are a triad of leukoencephalopathy, intracranial calcifications, and parenchymal cysts. In this paper, we report a CRMCC patient with multisystem involvement, focusing on the neuroimaging features, to get a better understanding of the rare disease and improve our diagnostic ability. PATIENT CONCERNS: The 23 year-old female patient firstly presented with an adolescence onset of ophthalmological manifestations. Four years later, hematological and neurological disorders occurred, the latter of which demonstrated a relatively slow progression in the following 7 years preceding her presentation to our hospital. INTERVENTIONS: During hospitalization, disorders involving digestive, cardiovascular and respiratory systems were also detected. In addition, a more comprehensive depiction of neurological disorders on neuroimaging was also obtained. DIAGNOSES: On the basis of multiple system disorders and the detection of mutations in conserved telomere maintenance component 1(CTC1) gene, a diagnosis of CRMCC was made. OUTCOMES: After supportive therapy during her 4-week hospitalization, the patient's general condition improved and was released from the hospital. LESSONS: CRMCC could be primarily diagnosed with the aid of its multiple system disorders and remarkable neuroimaging features. Cerebral micro hemorrhages determined by the combination of CT and T2-weighted magnetic resonance images in our case could provide some additional information for diagnosis. Furthermore, several other associated disorders were depicted for the first time in our case, expanding the clinical spectrum of CRMCC. PMID- 28072697 TI - Usefulness of HATCH score in the prediction of new-onset atrial fibrillation for Asians. AB - The HATCH score (hypertension <1 point>, age >75 years <1 point>, stroke or transient ischemic attack <2 points>, chronic obstructive pulmonary disease <1 point>, and heart failure <2 points>) was reported to be useful for predicting the progression of atrial fibrillation (AF) from paroxysmal to persistent or permanent AF for patients who participated in the Euro Heart Survey. The goal of the current study was to investigate whether the HATCH score was a useful scheme in predicting new-onset AF. Furthermore, we aimed to use the HATCH scoring system to estimate the individual risk in developing AF for patients with different comorbidities. We used the "Taiwan National Health Insurance Research Database." From January 1, 2000, to December 31, 2001, a total of 670,804 patients older than 20 years old and who had no history of cardiac arrhythmias were enrolled. According to the calculation rule of the HATCH score, 599,780 (score 0), 46,661 (score 1), 12,892 (score 2), 7456 (score 3), 2944 (score 4), 802 (score 5), 202 (score 6), and 67 (score 7) patients were studied and followed for the new onset of AF. During a follow-up of 9.0 +/- 2.2 years, there were 9174 (1.4%) patients experiencing new-onset AF. The incidence of AF was 1.5 per 1000 patient-years. The incidence increased from 0.8 per 1000 patient-years for patients with a HATCH score of 0 to 57.3 per 1000 patient-years for those with a HATCH score of 7. After an adjustment for the gender and comorbidities, the hazard ratio (95% confidence interval) of each increment of the HATCH score in predicting AF was 2.059 (2.027-2.093; P < 0.001). The HATCH score was useful in risk estimation and stratification of new-onset AF. PMID- 28072698 TI - Efficacy of Kirschner-wires and tension band in hip arthroplasty for aged patients with unstable intertrochanteric osteoporotic fracture: A 2-to-11-year follow-up. AB - The aim of this study was to evaluate the efficacy of supplementary fixation in hip arthroplasty with the use of Kirschner-wires and tension band for geriatric patients suffering unstable intertrochanteric osteoporotic fractures. A total of 103 patients aged more than 75 years were recruited. A bipolar or total hip replacement was performed with additional application of Kirschner-wires and tension band, and the participants were followed up for 2 to 11 years. Physical component summary (PCS), mental component summary (MCS), visual analog scale (VAS), and Harris hip score were utilized to evaluate patients' hip pain and function, as well as the mental condition postoperatively after 1.5 months, 3 months, 6 months, 1 year, and annually thereafter until the latest follow-up in 2015. Patients showed a significant improvement in all scores between 1.5 months and 1 year (P < 0.001), with the good efficacy lasting at least until the 2-year follow-up. None of the patients showed dislocation, implant loosening, or nonunion of the fracture throughout the follow-up period. In conclusion, it was beneficial to treat unstable intertrochanteric osteoporotic fractures in aged patients with hip arthroplasty coupled with Kirschner-wires and tension band. PMID- 28072699 TI - Prevention preferable to treatment: 3 case reports of patients experiencing right sided heart failure after Ebstein anomaly correction. AB - RATIONALE: Ebstein anomaly is a common congenital heart disease that may induce severe tricuspid regurgitation and dilation of the "atrialized" portion of the right ventricle. Patients who undergo surgery to correct Ebstein anomaly are at high risk of postoperative right-sided heart failure, yet little is known about what pre-, peri-, or postoperative procedures may help reduce this risk. PATIENT CONCERNS: Here, we describe 3 cases of adults with Ebstein anomaly who underwent corrective surgery and in whom right-sided heart failure occurred with severe tricuspid regurgitation detected by transesophageal echocardiography. DIAGNOSES: Ebstein anomaly. INTERVENTION: Various approaches were applied to prevent right heart failure: perioperative control of atrial and ventricle arrhythmia, protection of myocardium, reduction of right-side cardiac workload after cardiopulmonary bypass, and mechanical support for right heart. OUTCOMES: One of the 3 patients died, another experienced kidney failure despite postoperative support on extracorporeal membrane oxygenation, and the third patient survived without complications. LESSONS: Our case series suggests that surgical prognosis can be improved through aggressive preoperative treatment, vasoactive and anti arrhythmia medications, and comprehensive measures designed to reduce myocardial injury, prevent myocardial edema, and reduce pre- and afterload on the right ventricle. PMID- 28072700 TI - Is prophylactic tranexamic acid administration effective and safe for postpartum hemorrhage prevention?: A systematic review and meta-analysis. AB - BACKGROUND: To assess the efficacy and safety of tranexamic acid (TA) in reducing blood loss and lowering transfusion needs for patients undergoing caesarean section (CS) or vaginal delivery (VD). METHODS: An electronic literature search of PubMed, EMBASE, OVID, Cochrane library, Scopus, Central, and Clinical trials.gov was performed to identify studies that evaluating the usage of TA in CS or VD. The methodological quality of included trials was assessed and data extraction was performed. RESULTS: Finally, 25 articles with 4747 participants were included. Our findings indicated TA resulted in a reduced intra-, postoperative, and total blood loss by a mean volume of 141.25 mL (95% confidence interval [CI] -186.72 to -95.79, P < 0.00001), 36.42 mL (95% CI -46.50 to -26.34, P < 0.00001), and 154.25 mL (95% CI -182.04 to -126.47, P < 0.00001) in CS. TA administration in VD was associated with a reduced intra-, postoperative, and total blood loss by a mean volume of 22.88 mL (95% CI -50.54 to 4.77, P = 0.10), 41.24 mL (95% CI -55.50 to -26.98, P < 0.00001), and 84.79 mL (95% CI -109.93 to 59.65, P < 0.00001). In addition, TA could lower the occurrence rate of postpartum hemorrhage (PPH) and severe PPH, and reduce the risk of blood transfusions. No increased risk of deep vein thrombosis (DVT) after CS or VD was associated with TA usage, while the minor side effects were more common. CONCLUSIONS: Our findings indicated that intravenous TA for patients undergoing CS was effective and safe. Although prophylactic TA administration is associated with reduced PPH, current existing data are insufficient to draw definitive recommendations about its clinical significance due to the poor to moderate quality of the included literatures. Thus, high-quality randomized controlled trials with larger samples are needed to validate our findings. PMID- 28072701 TI - Pathophysiology of refractory obsessive-compulsive disorder: A study of visual search combined with overactive performance monitoring. AB - Based on both functional and structural studies of excessive activity, fronto striatal-thalamic-cortical and cortico-striatal circuits have been hypothesized to underlie the pathophysiology of obsessive-compulsive disorder (OCD). However, the neurobiological underpinnings of OCD refractory to medication and therapy remain controversial. This study aimed to evaluate neuroanatomical abnormalities of the whole brain and to evaluate visual processing in patients with refractory OCD.This study was comprised of 2 experiments. The neuroanatomical abnormalities of the whole brain were evaluated using a visual search in combination with overactive performance monitoring (Experiment I), and visual processing was evaluated using event-related potentials recorded from subjects during performance of a visual search task. We also examined the amplitudes and latency of the error-related negativity (ERN) using a modified flanker task (Experiment II). Standard low-resolution electromagnetic tomography analysis was applied to determine the special areas.Patients with refractory OCD had a significantly greater number of saccades and prolonged latencies relative to the healthy controls. Scalp map topography confirmed that visual cognitive and executive dysfunction was localized to the fusiform gyrus. Furthermore, we found that during a modified flanker task, ERNs had a greater amplitude and a prolonged latency relative to those of the healthy controls. Further data analysis suggested that cognitive dysfunction and compulsive behavior in OCD patients were linked to abnormalities within the dorsolateral prefrontal cortex (DLPFC).We identified abnormal activities within the fusiform gyrus and DLPFC that likely play important roles in the pathophysiology of OCD. PMID- 28072702 TI - Hypersomnia due to injury of the ventral ascending reticular activating system following cerebellar herniation: A case report. AB - RATIONALE: We report on a patient with hypersomnia who showed injury of the lower ascending reticular activating system (ARAS) following cerebellar herniation due to a cerebellar infarct, detected on diffusion tensor tractography (DTT). PATIENT CONCERNS: A 53-year-old male patient was diagnosed as a left cerebellar infarct, and underwent decompressive suboccipital craniectomy due to brain edema at 2 days after the onset of a cerebellar infarct. Three weeks after onset when the patient started rehabilitation, he showed hypersomnia without impairment of consciousness; he fell asleep most of daytime without external stimulation and showed an abnormal score on the Epworth Sleepiness Scale: 15 (full score: 24, cut off for hypersomnia: 10). DIAGNOSES AND OUTCOMES: On 3-week DTT, narrowing of the upper portion of the lower ventral ARAS between the pontine reticular formation and the hypothalamus was observed on both sides. In addition, partial tearing was observed in the middle portion of the right lower ventral ARAS. LESSONS: In conclusion, we found injury of the lower ventral ARAS in a patient with hypersomnia following cerebellar herniation due to a cerebellar infarct. PMID- 28072703 TI - Screening the key microRNAs and transcription factors in prostate cancer based on microRNA functional synergistic relationships. AB - Prostate cancer (PC) is a common neoplasm, and metastatic PC remains incurable. The study aims to screen key microRNAs (miRNAs) and transcription factors (TFs) involved in PC.The miRNA expression profile dataset (GSE45604) was downloaded from Gene Expression Omnibus database, including 50 PC and 10 normal specimens. Differentially expressed miRNAs (DEmiRNAs) were identified through limma package in R, and DEmiRNA-DEmiRNA co-regulation network was constructed based on the number of co-regulated target genes. Functional enrichment analysis of co regulated target genes was performed using clusterProfiler package in R, and miRNA interactions sharing at least 1 functional term were used to construct a DEmiRNA-DEmiRNA functional synergistic network (MFSN). Based on Transcriptional Regulatory Element Database, cancer-related TFs which were co-regulated by DEmiRNAs were utilized to construct a DEmiRNA-TF regulation network.A total of 66 DEmiRNAs were identified, including 7 up-regulated miRNAs with 18,642 target genes and 59 down-regulated miRNAs with 130,694 target genes. Then, the DEmiRNA DEmiRNA co-regulation network was constructed, including 66 DEmiRNAs and 2024 co regulation relationships. In MFSN, hsa-miR-1184, hsa-miR-1207-5p, and hsa-miR-24 had significant functional synergistic relationships. The DEmiRNA-TF network contained 6 up-regulated DEmiRNAs and 4 of them were highlighted, as hsa-miR 1184, hsa-miR-1207-5p, hsa-miR-182, and hsa-miR-183. In subnetwork of the 4 miRNAs, peroxisome proliferative activated receptor, alpha (PPARA) and cyclic AMP responsive element modulator (CREM) were the critical regulated TFs.Four up regulated miRNAs (hsa-miR-1207-5p, hsa-miR-1184, hsa-miR-182, and hsa-miR-183) and 2 TFs (PPARA and CREM) were identified as key regulators in PC progression. The above 4 miRNAs might participate in PC progression by targeting PPARA and CREM. PMID- 28072704 TI - Sudden death due to the atrioventricular node contusion: Three cases report. AB - INTRODUCTION: Atrioventricular node (AVN) contusion usually results in cardiogenic shock and arrhythmia and is a rare but fatal condition. The condition is difficult to diagnose and easily overlooked because it develops rapidly and is asymptomatic. We here report 3 cases that demonstrate blunt chest impact and hemorrhages of the posterior atrioventricular junction, eventually result in death. CLINICAL FINDINGS: Autopsy and histological examination were performed on all cases. External inspection revealed bruises in the hearts and fractures in the sternum and ribs. However, histological examinations were conclusive and showed cardiac contusion on the surface of the posterior atrioventricular junction of the individuals, and the death was due to the AVN contusion. The position of the AVN on the heart surface is determined by detailed examinations via an autopsy and microscopic, both of which are critical in the certification of cause of death. CONCLUSION: The report is intended to raise our understanding and make forensic pathologists aware of the surface of the posterior atrioventricular junction. PMID- 28072705 TI - Posterior-only vertebral column resection for revision surgery in post laminectomy rotokyphoscoliosis associated with late-onset paraplegia: A case report and literature review. AB - RATIONALE: Severe post-laminectomy spinal deformity associated with late-onset paraplegia is a complex and rare disorder. Little is known about revision surgery in post-laminectomy rotokyphoscoliosis associated with late-onset paraplegia treated by the single stage posterior-only vertebral column resection (VCR) procedure. PATIENT CONCERNS AND DIAGNOSES: The patient was a 14-year-old male diagnosed as post-laminectomy rotokyphoscoliosis associated with late-onset paraplegia. He underwent posterior total laminectomy through the thoracic spine for intramedullary spinal cord tumors at the age of 3 years in another hospital. He then developed kyphosis deformity 1 year after laminectomy, and underwent posterior spinal fusion without instrumentation at 9 years of age. However, the deformity gradually progressed over the years. Seven months before admission to our hospital, he developed a significant progression of neurological deficits, including weakness of strength and sensation in lower extremities bilaterally, with no bladder or bowel dysfunction. There was no improvement of spinal cord function with conservative measures, and he required a wheelchair for movement. INTERVENTIONS: The patient underwent posterior-only VCR by single stage with the purposes of spinal cord decompression and spinal deformity correction. OUTCOMES: Postoperatively, he was transferred to the intensive care unit (ICU) and required positive pressure ventilation support to improve his respiratory condition. The child experienced cerebrospinal fluid leak (CSF) which resulted in an unplanned return to the operating room. The neurological function improved from preoperative Frankel C to Frankel D within 12 months of surgery, and recovered completely to Frankel E by 18 months. At the 24 month follow-up, the good neurological function was maintained; pulmonary function tests (PFTs) revealed improved forced vital capacity (FVC) and forced expiratory volume for 1 second (FEV1). The patient's coronal major curve and sagittal kyphosis were corrected from 70 degrees to 21 degrees , and 170 degrees to 75 degrees , respectively. LESSONS: These findings demonstrated that single-stage posterior-only VCR is efficacious but challenging for revision surgery in post-laminectomy rotokyphoscoliosis associated with late-onset paraplegia. PMID- 28072706 TI - A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. AB - BACKGROUND: This phase III trial compared the efficacy and safety of gemcitabine plus capecitabine (GemCap) versus single-agent gemcitabine (Gem) in advanced pancreatic cancer as first-line chemotherapy. METHODS: A total of 214 advanced pancreatic cancer patients were enrolled from 16 hospitals in South Korea between 2007 and 2011. Patients were randomly assigned to receive GemCap (oral capecitabine 1660 mg/m plus Gem 1000 mg/m by 30-minute intravenous infusion weekly for 3 weeks followed by a 1-week break every 4 weeks) or Gem (by 30-minute intravenous infusion weekly for 3 weeks every 4 weeks). RESULTS: Median overall survival (OS) time, the primary end point, was 10.3 and 7.5 months in the GemCap and Gem arms, respectively (P = 0.06). Progression-free survival was 6.2 and 5.3 months in the GemCap and Gem arms, respectively (P = 0.08). GemCap significantly improved overall response rate compared with Gem alone (43.7% vs 17.6%; P = 0.001). Overall frequency of grade 3 or 4 toxicities was similar in each group. Neutropenia was the most frequent grade 3 or 4 toxicity in both groups. CONCLUSION: GemCap failed to improve OS at a statistically significant level compared to Gem treatment. This study showed a trend toward improved OS compared to Gem alone. GemCap and Gem both exhibited similar safety profiles. PMID- 28072707 TI - Psychosocial effects of workplace physical exercise among workers with chronic pain: Randomized controlled trial. AB - While workplace physical exercise can help manage musculoskeletal disorders, less is known about psychosocial effects of such interventions. This aim of this study was to investigate the effect of workplace physical exercise on psychosocial factors among workers with chronic musculoskeletal pain.The trial design was a 2 armed parallel-group randomized controlled trial with allocation concealment. A total of 66 slaughterhouse workers (51 men and 15 women, mean age 45 years [standard deviation (SD) 10]) with upper limb chronic musculoskeletal pain were randomly allocated to group-based strength training (physical exercise group) or individual ergonomic training and education (reference group) for 10 weeks. Social climate was assessed with the General Nordic Questionnaire for Psychological and Social Factors at Work, and vitality and mental health were assessed with the 36-item Short Form Health Survey. All scales were converted to 0 to 100 (higher scores are better). Between-group differences from baseline to follow-up were determined using linear mixed models adjusted for workplace, age, gender, and baseline values of the outcome.Mean baseline scores of social climate, mental health, and vitality were 52.2 (SD 14.9), 79.5 (SD 13.7), and 53.9 (SD 19.7), respectively. Complete baseline and follow-up data were obtained from 30 and 31 from the physical exercise and reference groups, respectively. The between-group differences from baseline to follow-up between physical exercise and reference were 7.6 (95% CI 0.3 to 14.9), -2.3 (95% CI -10.3 to 5.8), and 10.1 (95% CI 0.6 to 19.5) for social climate, mental health, and vitality, respectively. For social climate and vitality, this corresponded to moderate effect sizes (Cohen d = 0.51 for both) in favor of physical exercise. There were no reported adverse events.In conclusion, workplace physical exercise performed together with colleagues improves social climate and vitality among workers with chronic musculoskeletal pain. Mental health remained unchanged. PMID- 28072708 TI - Life-threatening motor vehicle crashes in bright sunlight. AB - : Bright sunlight may create visual illusions that lead to driver error, including fallible distance judgment from aerial perspective. We tested whether the risk of a life-threatening motor vehicle crash was increased when driving in bright sunlight.This longitudinal, case-only, paired-comparison analysis evaluated patients hospitalized because of a motor vehicle crash between January 1, 1995 and December 31, 2014. The relative risk of a crash associated with bright sunlight was estimated by evaluating the prevailing weather at the time and place of the crash compared with the weather at the same hour and location on control days a week earlier and a week later.The majority of patients (n = 6962) were injured during daylight hours and bright sunlight was the most common weather condition at the time and place of the crash. The risk of a life threatening crash was 16% higher during bright sunlight than normal weather (95% confidence interval: 9-24, P < 0.001). The increased risk was accentuated in the early afternoon, disappeared at night, extended to patients with different characteristics, involved crashes with diverse features, not apparent with cloudy weather, and contributed to about 5000 additional patient-days in hospital. The increased risk extended to patients with high crash severity as indicated by ambulance involvement, surgical procedures, length of hospital stay, intensive care unit admission, and patient mortality. The increased risk was not easily attributed to differences in alcohol consumption, driving distances, or anomalies of adverse weather.Bright sunlight is associated with an increased risk of a life threatening motor vehicle crash. An awareness of this risk might inform driver education, trauma staffing, and safety warnings to prevent a life-threatening motor vehicle crash. LEVEL OF EVIDENCE: Epidemiologic Study, level III. PMID- 28072709 TI - Tranexamic acid reduces perioperative blood loss of posterior lumbar surgery for stenosis or spondylolisthesis: A randomized trial. AB - BACKGROUND: A prospective, randomized, double-blind, placebo-controlled study was performed. The routine usage of TA in spinal surgery is controversial. Only a few studies have focused on patients undergoing posterior lumbar surgery for stenosis or spondylolisthesis, although a large clinical cohort exists in the population. This study aimed to evaluate the effect and safety of TA in reducing perioperative blood loss in posterior lumbar surgery for stenosis or spondylolisthesis. METHODS: 100 eligible patients out of 126 were randomized to receive either a bolus dose of 30 mg/kg TA i.v, a maintenance dosage of 2 mg/kg/h TA, or an equivalent volume of normal saline. The pedicle screw system was used for fixing in all the patients, followed by decompression and posterior lumbar interbody fusion. The primary outcomes were intraoperative estimated blood loss and total blood loss. The secondary outcomes were receiving packed red blood cells and postoperative hemoglobin and hematocrit levels. RESULTS: In total, 4 patients were excluded from the analyses, 50 patients were in the TA group, and 46 in the placebo group. The demographic and baseline data between the groups were not statistically different. The intraoperative estimated blood loss and the total blood loss were 33% and 41% lower in the TA group than the placebo group, respectively. The blood transfusion rate did not vary significantly (P = 0.191). Except a patient with a dural tear in the placebo group, no other complications were observed. CONCLUSION: TA significantly reduced the perioperative blood loss in patients undergoing posterior lumbar surgery for stenosis or spondylolisthesis. PMID- 28072710 TI - Metastatic renal clear cell carcinoma to the rectum, lungs, ilium, and lymph nodes: A case report. AB - BACKGROUND: Renal cell carcinoma metastasizing to rectum is very rare, and the unusual metastatic sites should be paid attention to during the follow-up of renal cell carcinoma. CASE SUMMARY: We describe a case of a 65-year-old male who was diagnosed with metastatic renal cell carcinoma to rectum 10 years after the right radical nephrectomy. Histopathology and immunohistochemical examinations contribute to making differential diagnosis between rectal metastasis of renal cell carcinoma and primary rectal clear cell carcinoma. Positron emission tomography-computed tomography with fluorodeoxyglucose shows hypermetabolic activity in upper rectum and other sites of metastasis at the same time. CONCLUSION: Possibility of unusual metastatic sites of renal cell carcinoma such as rectum indeed exists, which should not be ignored in the surveillance after resection of the primary tumor. PMID- 28072711 TI - The coexistence of SAPHO syndrome and rheumatoid arthritis: A case report. AB - RATIONAL: SAPHO (Synovitis-Acne-Pustulosis-Hyperstosis-Osteitis) syndrome is a rare disease featured by its dermatological and osteoarthritic disorders, the latter of which mainly affecting the anterior chest wall, spine, and sacroiliac joint. However, rheumatoid arthritis (RA) is a chronic autoimmune disease, mainly affecting the synovial tissue of small joints in hands and feet. Here, we present an extremely rare case diagnosed with both SAPHO syndrome and RA, with an onset interval of 10 years. So far, only 1 similar case has been reported in the English literature. PATIENT CONCERNS: In Sep 2015, a 59-year-old female patient presented to our hospital, complaining of refractory low back pain, left sternoclavicular joint pain, and palmoplanar pustulosis (PPP). In addition, RA had been diagnosed 10 years earlier in the patient, manifested as pain and swelling in bilateral hands and wrists, accompanied by morning stiffness, as well as positive serologic tests. INTERVENTIONS: In our hospital, laboratory tests revealed elevated inflammatory markers, and imaging examinations of relevant sites showed specific osteoarthritic lesions for SAPHO syndrome. DIAGNOSES: These findings lead us to make an easy diagnosis of the coexistence of SAPHO syndrome and RA in this petient. OUTCOMES: Treatment with tripterygium wilfordii polyglycosidium and prednisone was introduced. Both dermatological and osteoarthritic symptoms improved during a 3-month follow-up. Symptoms of RA were successfully controlled with prednisone and leflunomide since 2005. LESSONS: We present an extremely rare case diagnosed with both SAPHO syndrome and RA, with an onset interval of 10 years. With this case report, we want to draw attention to the diverse features of SAPHO syndrome. PMID- 28072712 TI - SENIORLAB: a prospective observational study investigating laboratory parameters and their reference intervals in the elderly. AB - BACKGROUND: In clinical practice, laboratory results are often important for making diagnostic, therapeutic, and prognostic decisions. Interpreting individual results relies on accurate reference intervals and decision limits. Despite the considerable amount of resources in clinical medicine spent on elderly patients, accurate reference intervals for the elderly are rarely available. The SENIORLAB study set out to determine reference intervals in the elderly by investigating a large variety of laboratory parameters in clinical chemistry, hematology, and immunology. METHODS/DESIGN: The SENIORLAB study is an observational, prospective cohort study. Subjectively healthy residents of Switzerland aged 60 years and older were included for baseline examination (n = 1467), where anthropometric measurements were taken, medical history was reviewed, and a fasting blood sample was drawn under optimal preanalytical conditions. More than 110 laboratory parameters were measured, and a biobank was set up. The study participants are followed up every 3 to 5 years for quality of life, morbidity, and mortality. The primary aim is to evaluate different laboratory parameters at age-related reference intervals. The secondary aims of this study include the following: identify associations between different parameters, identify diagnostic characteristics to diagnose different circumstances, identify the prevalence of occult disease in subjectively healthy individuals, and identify the prognostic factors for the investigated outcomes, including mortality. DISCUSSION: To obtain better grounds to justify clinical decisions, specific reference intervals for laboratory parameters of the elderly are needed. Reference intervals are obtained from healthy individuals. A major obstacle when obtaining reference intervals in the elderly is the definition of health in seniors because individuals without any medical condition and any medication are rare in older adulthood. Reference intervals obtained from such individuals cannot be considered representative for seniors in a status of age-specific normal health. In addition to the established methods for determining reference intervals, this longitudinal study utilizes a unique approach, in that survival and long-term well-being are taken as indicators of health in seniors. This approach is expected to provide robust and representative reference intervals that are obtained from an adequate reference population and not a collective of highly selected individuals. TRIAL REGISTRATION: The present study was registered under International Standard Randomized Controlled Trial Number registry: ISRCTN53778569. PMID- 28072713 TI - [11C]-(R)-PK11195 positron emission tomography in patients with complex regional pain syndrome: A pilot study. AB - Complex regional pain syndrome (CRPS) is characterized by severe and chronic pain, but the pathophysiology of this disease are not clearly understood. The primary aim of our case-control study was to explore neuroinflammation in patients with CRPS using positron emission tomography (PET), with an 18-kDa translocator protein specific radioligand [C]-(R)-PK11195. [C]-(R)-PK11195 PET scans were acquired for 11 patients with CRPS (30-55 years) and 12 control subjects (30-52 years). Parametric image of distribution volume ratio (DVR) for each participant was generated by applying a relative equilibrium-based graphical analysis. The DVR of [C]-(R)-PK11195 in the caudate nucleus (t(21) = -3.209, P = 0.004), putamen (t(21) = -2.492, P = 0.022), nucleus accumbens (t(21) = -2.218, P = 0.040), and thalamus (t(21) = -2.395, P = 0.026) were significantly higher in CRPS patients than in healthy controls. Those of globus pallidus (t(21) = -2.045, P = 0.054) tended to be higher in CRPS patients than in healthy controls. In patients with CRPS, there was a positive correlation between the DVR of [C]-(R) PK11195 in the caudate nucleus and the pain score, the visual analog scale (r = 0.661, P = 0.026, R = 0.408) and affective subscales of McGill Pain Questionnaire (r = 0.604, P = 0.049, R = 0.364). We demonstrated that neuroinflammation of CRPS patients in basal ganglia. Our results suggest that microglial pathology can be an important pathophysiology of CRPS. Association between the level of caudate nucleus and pain severity indicated that neuroinflammation in this region might play a key role. These results may be essential for developing effective medical treatments. PMID- 28072714 TI - Optical coherence tomography assessment of a complex bifurcation lesion treated with double kissing Crush technique: A case report. AB - The DEFINITION (Impact of the complexity of bifurcation lesions treated with drug eluting stents) study has provided a novel classification to evaluate the complexity of coronary bifurcation lesion according to coronary angiography, but angiographic imaging due to its low resolution and inherited limitation may result in an inaccurate adjudication.We used optical coherence tomography (OCT) to further evaluate the coronary characteristics in a patient with "simple" bifurcation lesion which was classified by the DEFINITION criteria. However, a "complex" bifurcation lesion was defined and confirmed according to the OCT results.A double kissing Crush stenting approach was adopted to treat this "complex" case finally. The immediate and long-term angiographic and OCT results were excellent.OCT may be useful imaging modality to classify complexity of coronary bifurcation lesion and subsequently guide its treatment strategy. PMID- 28072715 TI - Conditional disease-free survival among patients with breast cancer. AB - Conditional disease-free survival (CDFS) reflects changes over time. Because traditional disease-free survival (DFS) is estimated from the date of diagnosis, it is limited in the ability to predict risk of recurrence in patients who have been disease free. In this study, we determined CDFS of breast cancer patients and estimated the prognostic factors for DFS.We retrospectively reviewed clinical data of 7587 consecutive patients who underwent curative surgery for breast cancer between January 2004 and December 2013 at Samsung Medical Center. Univariate and multivariate analyses were performed to identify risk factors for DFS, which was computed using the Kaplan-Meier method. CDFS rates were based on cumulative DFS estimates.Median follow-up duration was 20.59 months. Three-year DFS was 93.46% at baseline. Three-year CDFS survival estimates for patients who had been disease free for 1, 2, 3, 4, and 5 years after treatment were calculated as 92.84%, 92.37%, 93.03%, 89.41%, and 79.64%, respectively. Three-year CDFS increased continuously each year after 1 year of DFS in hormone receptor (HR) negative patients but decreased each year in HR-positive patients.In HR-positive patients who are disease free after 3 years, continuous care including surveillance and metastases workup should be considered, although this is not recommended in the current guidelines. On the other hand, the social costs may be reduced in HR-negative patients by extending the surveillance interval. Further studies are needed to identify indicators of DFS prognosis in breast cancer patients. PMID- 28072716 TI - Pneumonitis in cancer patients receiving anti-PD-1 and radiotherapies: Three case reports. AB - INTRODUCTION: In development of novel therapies for the treatment of patient with cancer, the use of radiotherapy (RT) can produce significant local control and, in recent studies, has also been shown to mediate anti-tumor responses at distant sites by triggering and enhancing the endogenous cellular immune responses. Although RT induces an abscopal effect in some patients due to enhanced immune response to the tumor, immune-escape mechanisms, including up-regulation of programmed death-ligand 1 (PD-L1) on tumor cells, limit this benefit in other patients. Hence, many studies have promoted the synergy of RT and anti-programmed cell death protein 1 (PD-1) treatment for antitumor immunity. However, outcome may be improved when more therapies are combined, but risk of side effects can be increased. CASE PRESENTATION: We herein present 3 advanced cancer patients with pulmonary metastasis and who received RT. Later, they underwent anti-PD-1 treatment and unfortunately suffered from anti-PD-1-related pneumonitis over the nonirradiated areas after 4 cycles of treatment. The upregulation of cellular PD 1 expression in these areas was considered and the immune overreaction by anti-PD 1 treatment may cause these severe pulmonary adverse effects. CONCLUSION: Our review of 3 cases warrants careful workup to reduce the risk of side effects by combinative therapy with RT and anti-PD-1 treatment. PMID- 28072717 TI - Clinics, prognosis and new therapeutic options in patients with mucosal melanoma: A retrospective analysis of 75 patients. AB - Mucosal melanomas represent a rare entity with different risk factors and molecular features compared to cutaneous melanomas. They arise most commonly from mucosal surfaces in the head/neck region, the female genital tract (FGT) and the anorectal region. The aim of this study was to evaluate clinics, prognosis, and treatment options of patients with mucosal melanoma, in particular with regard to different primary sites.We retrospectively analyzed 75 patients with mucosal melanomas diagnosed in the years 1993 to 2015 in our department. The primary melanomas were located in the head/neck region (n = 32), the FGT (n = 24), and the anorectal region (n = 19).The median age of the patients was 66 years. At initial diagnosis the primary melanoma was not completely resectable in 11 (15%) patients, 18 (24%) patients had regional lymph node metastases, and 7 (9%) patients distant metastases. During follow-up, 22 (29%) patients suffered from a local recurrence, in particular patients with primary melanoma in the head/neck region without postoperative radiotherapy. By multivariate analysis location of the primary melanoma in the head/neck area or anorectal region and presence of metastases at time of diagnosis represented poor prognostic factors for recurrence-free survival. In 62 tested individuals 7 KIT mutations were found, 2 BRAF mutations in 57 tested patients. Four patients received targeted therapies, 14 checkpoint inhibitors, 4 (1/1 on vemurafenib, 1/7 on ipilimumab, and 2/7 on PD 1 inhibitors) patients showed responses of more than 100 days duration.Mucosal melanomas are often locally advanced or metastatic at initial diagnosis, thus they require extensive staging procedures. The high rate of local recurrences in the head/neck region can be significantly reduced by postoperative radiotherapy. For the potential use of medical treatment a mutation analysis for KIT and BRAF genes should be performed. The use of new immunologic and targeted therapies has to be further evaluated. PMID- 28072718 TI - Private ownership of primary care providers associated with patient perceived quality of care: A comparative cross-sectional survey in three big Chinese cities. AB - Ownership of primary care providers varies in different cities in China. Shanghai represented the full public ownership model of primary providers; Shenzhen had public-owned but private-operated providers; and Hong Kong represented the full private ownership. The study aims to assess the association of primary care ownership and patient perceived quality of care in 3 Chinese megacities.We conducted multistage stratified random surveys in 2013 in the 3 cities. Quality scores of primary care were measured using the validated primary care assessment tools. Multivariate linear regression models were used to compare quality scores after controlling potential confounders of patient demographic, socioeconomic, and healthcare utilization factors.Overall, 797 primary care users in Shanghai, 802 in Shenzhen, and 1325 in Hong Kong participated in the study. The mean total quality scores were reported the highest in Shanghai (28.39), followed by Shenzhen (25.82) and then Hong Kong (25.21) (P < 0.001). Shanghai participants reported the highest scores for 1st contact accessibility, coordination of information, comprehensiveness of service availability, and culture competence, while Hong Kong participants reported the lowest for these domains (P < 0.001). Hong Kong participants from rich households reported higher total scores than those from poor households (P < 0.05); however, this was not found in Shanghai and Shenzhen.The study suggests that private primary care ownership may be associated with lower quality and less equitable care distribution. In China, it suggests that it may be beneficial to promote public-owned and nonprofit providers. Promoting privatization in primary care may be at the cost of quality and equity of primary care. PMID- 28072719 TI - Association between dietary fat intake and colorectal adenoma in korean adults: A cross-sectional study. AB - The incidence of colorectal cancer is rapidly increasing in South Korea. It is important to clarify the association between colorectal cancer and diet, being one of the main modifiable risk factors, as such studies in the Korean population are lacking.A cross-sectional study was performed using data from participants who had undergone a screening colonoscopy and a nutritional assessment during a routine health check-up from January 2008 to December 2011. Dietary intake data were derived from 1-day food records; colorectal adenoma was histopathologically confirmed by biopsy during colonoscopy. Eventually, 2604 participants were included in the analysis. The risk of colorectal adenoma by quintile of dietary fat intake was analyzed using logistic regression. Subgroup analyses by degree of risk and by location of colorectal adenoma were additionally performed.In men, total fat intake was not associated with risk of colorectal adenoma. However, risk of colorectal adenoma increased with higher saturated fatty acid (SFA) intake. The adjusted odds ratio in the highest quintile was 1.71 (95% confidence interval, 1.01-2.91) compared with that in the lowest quintile. There was no significant association between fat intake and risk of colorectal adenoma characterized by subsite. In female participants, total fat and specific fatty acid intake were not associated with risk of colorectal adenoma.These data support that high SFA intake is associated with risk of colorectal adenoma in Korean men. PMID- 28072720 TI - Smoking and incidence of glaucoma: The SUN Cohort. AB - Smoking is a serious global public health concern that has been related to many chronic diseases. However, the effect of smoking on eye disorders has been less studied. The aim of this cohort study was to assess the association between current tobacco smokers and the risk of developing glaucoma and furthermore to evaluate the relationship between passive or former smokers and glaucoma.In this prospective and dynamic cohort, 16,797 participants initially who were found not to have glaucoma were followed up for a median of 8.5 years. Validated data on lifestyle, including tobacco consumption, were assessed at baseline. Information about new diagnosis of glaucoma was collected by follow-up questionnaires every 2 years. The outcome was the incidence of self-reported glaucoma during the follow up. A subsample was used to validate the glaucoma diagnosis.During the 8.5 years of follow-up, 184 new glaucoma cases were identified. Current smokers had a significantly higher risk of glaucoma compared to participants who had never smoked after controlling for potential confounders (Hazard ratio [HR] 1.88 [95% coefficient interval (CI): 1.26-2.81]; P = 0.002). A nonsignificant increased risk was found among former smokers (HR 1.27 [95% CI: 0.88-1.82]; P = 0.198). When we assessed the exposure as per the number of cigarette pack-years, a dose response relationship between pack-years and the risk of glaucoma was found (HR for the 5th quintile versus the 1st quintile: 1.70 [95% IC: 1.10-2.64], P for trend, 0.009). However, no relationship was found between passive smokers and glaucoma. (HR 0.67 [95% CI: 0.37-1.21]; P = 0.189).Our results suggest a direct association between current smokers and the incidence of glaucoma. In particular, this association was related to the number of pack-years, which was not found in the case of former smokers nor in the case of passive smokers. PMID- 28072721 TI - Total bilirubin level may be a biomarker of nephropathy in type 2 diabetes mellitus: A meta-analysis of observational studies based on MOOSE compliant. AB - Recently, the number of the studies on the relationship between the total bilirubin level (TBL) and diabetic nephropathy (DN) is increasing, but their results were not consistent. Therefore, we performed a meta-analysis to analyze the relationship between TBL and the risk of DN.We searched 5 databases before October 31, 2016, and reviewed the reference list of relevant articles. The fixed or random-effects model was used to pool risk estimates. We conducted the dose response meta-analysis to evaluate the relationship between TBL and the risk of DN.Our meta-analysis showed that TBL in the DN group was lower than that in diabetes without the kidney disease (NDN) group (standard mean difference [SMD]: 0.63, 95% CI: -0.80, -0.46). The result of each subgroup also showed that TBL in the DN group was lower than that in the NDN group. The result of meta-regression indicated that duration of diabetes mellitus might be the source of heterogeneity. Our meta-analysis also showed that there was a significant negative relationship between TBL and the risk of DN (OR: 0.86, 95%CI: 0.82, 0.90). The results of subgroup analysis were similar to those of SMD; no sources of heterogeneity were detected by meta-regression. Sensitivity analysis indicated that the results were robust. We observed a linear association between TBL and the risk of DN, and there was a negative dose-response association between TBL and the risk of DN.In conclusion, bilirubin may be used as a biomarker of DN. It helps early diagnosis and effective therapeutic strategies on DN. PMID- 28072722 TI - Dexmedetomidine prevent postoperative nausea and vomiting on patients during general anesthesia: A PRISMA-compliant meta analysis of randomized controlled trials. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is a frequent complication in postoperative period. The aim of this article was to evaluate the effect of dexmedetomidine on PONV. METHOD: RevMan 5.3 software was applied for performing statistic analysis. Twenty-four trials with 2046 patients were included. RESULTS: The PONV of the dexmedetomidine group was significantly lower compared with the placebo group (0.56, 95% CI: 0.46, 0.69). Subgroup analysis further confirmed the effect of dexmedetomidine (irrespective of administration mode) (P < 0.00001). Perioperative fentanyl consumption in dexmedetomidine group were also reduced significantly (P < 0.00001). Whereas, side effects such as bradycardia, hypotension increased in dexmedetomidine group (especially in loading dose mode and loading dose plus continuous infusion mode). CONCLUSIONS: Dexmedetomidine administrated in continuous infusion mode has the advantage to prevent PONV as well as reduce side effects such as bradycardia and hypotension. PMID- 28072723 TI - High VEGFR1/2 expression levels are predictors of poor survival in patients with cervical cancer. AB - The aim of the study to evaluate the prognostic significance of vascular endothelial growth factor receptor 1 and 2 (VEGFR1/2) expression levels and to correlate these levels with clinicopathological parameters in patients with cervical cancer.Forty-two patients with International Federation of Gynecology and Obstetrics Stage IIB-IVB cervical cancer were analyzed between January 2011 and December 2012. RNA expression levels of VEGFR1/2 were assessed by branched DNA-liquidchip technology and immunohistochemistry. Associations between RNA expression levels, important clinicopathological parameters, and patient survival were statistically evaluated.Higher VEGFR1/2 expression levels were predictive of poor overall survival (P = 0.009 and P = 0.024, respectively). Patients with higher VEGFR1 expression levels were associated with poorer progression-free survival than those with lower VEGFR1 expression levels (P = 0.043). In addition, patients with higher VEGFR1 expression levels were more likely to develop distant metastases than those with lower VEGFR1 expression levels (P = 0.049). Higher VEGFR2 expression levels were associated with larger tumor size (P = 0.037).VEGFR1/2 expression levels were prognostic factors for patients with cervical cancer. Higher VEGFR1/2 expression levels were also predictive of poor overall survival. PMID- 28072724 TI - Fatal antiphospholipid syndrome following endoscopic transnasal-transsphenoidal surgery for a pituitary tumor: A case report. AB - INTRODUCTION: The fatal type of antiphospholipid syndrome is a rare but life threating condition. It may be triggered by surgery or infection. Endoscopic transnasal-transsphenoidal surgery is a common procedure for pituitary tumor. We report a catastrophic case of a young woman died of fatal antiphospholipid syndrome following endoscopic transnasal-transsphenoidal surgery. METHODS AND RESULT: A 31-year-old woman of a history of stroke received endoscopic transnasal transsphenoidal surgery for a pituitary tumor. The whole procedure was smooth. However, the patient suffered from acute delirium on postoperative day 4. Then, her consciousness became comatose state rapidly with dilatation of pupils. Urgent magnetic resonance imaging of brain demonstrated multiple acute lacunar infarcts. The positive antiphosphoipid antibody and severe thrombocytopenia were also noted. Fatal antiphospholipid syndrome was diagnosed. Plasma exchange, corticosteroids, anticoagulant agent were prescribed. The hemodynamic condition was gradually stable. However, the consciousness was still in deep coma. The patient died of organ donation 2 months later. CONCLUSION: If patients have a history of cerebral stroke in their early life, such as a young stroke, the APS and higher risk of developing fatal APS after major surgery should be considered. The optimal management of APS remains controversial. The best treatment strategies are only early diagnosis and aggressive therapies combing of anticoagulant, corticosteroid, and plasma exchange. The intravenous immunoglobulin is prescribed for patients with refractory APS. PMID- 28072726 TI - No further gain can be achieved by calculating Disease Activity Score in 28 joints with high-sensitivity assay of C-reactive protein because of high intraindividual variability of C-reactive protein: A cross-sectional study and theoretical consideration. AB - Disease Activity Score in 28 joints (DAS28) is commonly used to evaluate disease activity of rheumatoid arthritis (RA) and is a guide to treatment decision.The aim of this study was to evaluate the impact of lower reporting limit for C reactive protein (CRP), with respect to intraindividual biological variability, on the calculation of DAS28 and subsequent patient classification.This study consists of 2 sections: a theoretical consideration discussing the performance of CRP in calculating DAS28 taking intraindividual biological variation and lower reporting limit for CRP into account and a cross-sectional study of RA patients applying our theoretical results. Therefore, we calculated DAS28 twice, with the actual CRP values and CRP = 9 mg/L, the latter to elucidate the positive effects of reducing the lower reporting limit of CRP from <10 to <3 mg/L.Lower-reporting limit of <10 mg/L leads to overestimate DAS28. However, reducing lower reporting limit for CRP to <3 mg/L results in optimizing DAS28 calculation. Further lowering of reporting limit for CRP to <3 mg/L does not increase the precision of DAS28 owing to the relatively large intraindividual biological variation.Five hundred twelve patients were included. There was a significant difference between recalculated and patients DAS28 (P < 0.001). One hundred nine patients had DAS28 deviation (compatible to remission to low: 66, low to moderate: 39. and moderate to high: 4).Owing to significant impact of intraindividual biologic variation on DAS28 and patient classification, special attention should be paid to calculate DAS28 when CRP values are within normal range. Furthermore, we conclude that results of different studies evaluating DAS28 and treatment response are not comparable if the reporting limits of CRP are unknown. PMID- 28072725 TI - Laparoscopic revision surgery for gastroesophageal reflux disease. AB - Laparoscopic antireflux surgery is a frequently performed procedure for the treatment of gastroesophageal reflux in surgical clinics. Reflux can recur in between 3% and 30% of patients on whom antireflux surgery has been performed, and so revision surgery can be required due to recurrent symptoms or dysphagia in approximately 3% to 6% of the patients. The objective of this study is to evaluate the mechanism of recurrences after antireflux surgery and to share our results after revision surgery in recurrent cases.From 2001 to 2014, revision surgery was performed on 43 patients (31 men, 12 women) between the ages of 24 and 70 years. The technical details of the first operation, recurrence symptoms, endoscopy, and manometry findings were evaluated. The findings of revision surgery, surgical techniques, morbidity rates, length of hospitalization, and follow-up period were also recorded and evaluated.The first operation was Nissen fundoplication in 34 patients and Toupet fundoplication in 9 patients. Mesh hiatoplasty was performed for enforcement in 18 (41.9%) of these patients. The period between the first operation and the revision surgery ranged from 4 days to 60 months. The most common finding was slipped fundoplication and presence of hiatal hernia during revision surgery. Revision fundoplication and hernia repair with mesh reinforcement were used in 33 patients. The other techniques were Collis gastroplasty, revision fundoplication, and hernia repair without mesh. The range of follow-up period was from 2 to 134 months. Recurrence occurred in 3 patients after revision surgery (6.9%). Although revision surgery is difficult and it has higher morbidity, it can be performed effectively and safely in experienced centers. PMID- 28072727 TI - Association between arterial stiffness and left ventricular diastolic function in relation to gender and age. AB - Left ventricular (LV) diastolic dysfunction and subsequent overt heart failure are more prevalent in elderly women. Close interaction between arterial stiffness and LV morphology/function has been reported. The aim of this study was to investigate whether there is an age- and gender-dependent relationship between arterial stiffness and LV diastolic function. A total of 819 subjects (58.6 +/- 13.3 years, 50.2% men) without structural heart disease (LV ejection fraction >=50%) were retrospectively analyzed. All participants underwent transthoracic echocardiography and brachial-ankle pulse wave velocity (baPWV) measurement on the same day. The association of baPWV with septal e' velocity and average E/e' was assessed. In the total study subjects, baPWV was negatively correlated with septal e' velocity (r = 0.383, P < 0.001), and positively correlated with E/e' (r = -0.266, P < 0.001). These linear correlations remained significant even after stratificaion of the study subjects by age (<65 years vs >=65 years) and genders (P < 0.05 for each). There were obvious differences in baPWV according to groups with normal LV diastolic function, intermediate profile and LV diastolic dysfunction in young (P = 0.010) and elderly (>=65 years) women (P < 0.001) and eldery men (P = 0.012) but not in elderly men (P = 0.270). There was a significant association of baPWV with septal e' velocity (beta = -0.258, P = 0.020) and E/e' (beta = 0.122, P = 0.030) in elderly women even after controlling for multiple clinical covariates. This independent association was not seen in younger women and men (P > 0.05 for each). In conclusion, baPWV was independently associated with septal e' velocity and E/e' in elderly women but not in younger women or men. The results of this study provide additional evidence that increased arterial stiffness plays an important role in the development of heart failure with preserved ejection fraction as well as LV diastolic dysfunction in elderly women. PMID- 28072728 TI - Upper gastrointestinal symptoms in autoimmune gastritis: A cross-sectional study. AB - Autoimmune gastritis is often suspected for its hematologic findings, and rarely the diagnosis is made for the presence of gastrointestinal symptoms. Aims of this cross-sectional study were to assess in a large cohort of patients affected by autoimmune gastritis the occurrence and the pattern of gastrointestinal symptoms and to evaluate whether symptomatic patients are characterized by specific clinical features.Gastrointestinal symptoms of 379 consecutive autoimmune gastritis patients were systematically assessed and classified following Rome III Criteria. Association between symptoms and anemia pattern, positivity to gastric autoantibodies, Helicobacter pylori infection, and concomitant autoimmune disease were evaluated.In total, 70.2% of patients were female, median age 55 years (range 17-83). Pernicious anemia (53.6%), iron deficiency anemia (34.8%), gastric autoantibodies (68.8%), and autoimmune disorders (41.7%) were present. However, 56.7% of patients complained of gastrointestinal symptoms, 69.8% of them had exclusively upper symptoms, 15.8% only lower and 14.4% concomitant upper and lower symptoms. Dyspepsia, subtype postprandial distress syndrome was the most represented, being present in 60.2% of symptomatic patients. Univariate and multivariate analyses showed that age <55 years (OR 1.6 [CI:1-2.5]), absence of smoking habit (OR 2.2 [CI:1.2-4]), and absence of anemia (OR 3.1 [CI:1.5-6.4]) were independent factors associated to dyspepsia.Autoimmune gastritis is associated in almost 60% of cases with gastrointestinal symptoms, in particular dyspepsia. Dyspepsia is strictly related to younger age, no smoking, and absence of anemia. PMID- 28072729 TI - Hypertonic saline protects brain endothelial cells against hypoxia correlated to the levels of epidermal growth factor receptor and interleukin-1beta. AB - OBJECTIVE: The aim of this study was to verify the protective effect of hypertonic saline (HS) on brain endothelial cells under hypoxic conditions and the relevant underlying mechanism. METHODS: bEnd.3 cells were treated with oxygen glucose deprivation (OGD)-induced injury. To measure HS performance, cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt assay, and cell apoptosis was assessed by flow cytometry and Terminal deoxynucleotidyl transferase UTP nick-end labeling staining. RNA-seq was performed to assess the expression profiles and screen the candidate genes that participated in OGD induced injury and the HS protective effect. Quantitative real-time polymerase chain reaction (qPCR) and western blot analysis were used to confirm the expression of candidate genes, and enzyme-linked immunosorbent assay was used to measure the level of interleukin (IL)-1beta. Overexpression analyses were performed to confirm the functions of the differentially expressed genes. RESULTS: HS with a concentration of 40 mmol/L NaCl had an obvious protective effect on bEnd.3 cells after OGD-induced injury, resulting in increased cell viability and a smaller percentage of apoptotic cells. According to the RNA-seq results, epidermal growth factor receptor (EGFR) was chosen as the differentially expressed gene target in this study. The qPCR and western blot analyses further confirmed that the levels of EGFR/phosphorylated epidermal growth factor receptor and IL-1beta were enhanced after OGD-induced injury, but attenuated after treatment with 40 mmol/L of NaCl HS. Overexpressed EGFR reversed the protective effect of HS that caused low viability and high rates of apoptosis in cells. CONCLUSION: HS can protect endothelial cells against OGD-induced injury, but is affected by the expression of EGFR/p-EGFR and IL-1beta. PMID- 28072730 TI - Bortezomib combined with lenalidomide as the first-line treatment for the rare synchronous occurrence of multiple myeloma and pulmonary adenocarcinoma: A case report. AB - BACKGROUND: Simultaneous multiple myeloma (MM) and pulmonary adenocarcinoma is a rare occurrence, and thus, treatment is a challenge. This study reports on 1 such case of MM with concurrent lung cancer, where an accurate diagnosis was made and the patient underwent treatment for both cancers. CASE SUMMARY: A 68-year-old man presented with 2 months of progressive lower back pain. Visualization with magnetic resonance imaging (MRI) revealed multiple collapsed vertebrae from T12 to S3, as well as an altered signal intensity at the T3 vertebra. The patient was diagnosed with MM upon examination. A chest computed tomography (CT) scan revealed a round mass in the left lower lobe of the lungs, and a CT-guided needle biopsy uncovered a moderately differentiated adenocarcinoma. There were no additional notable findings in the left lung using positron emission tomography computed tomography (PET-CT). Therefore, a diagnosis of MM with pulmonary adenocarcinoma was made. Surgery was performed to excise the lung cancer. Bortezomib was used as first-line induction therapy against both tumors and lenalidomide was used for maintenance. The patient went into complete remission. Using this combined chemotherapy, the patient has survived for over 3 years since a diagnosis was made despite relapsing twice after the first year. CONCLUSION: This report clearly delineates the diagnosis and treatment of a rare case of synchronous MM and pulmonary adenocarcinoma, as well as depicts a potentially positive outcome for the patient. It also overviews some diagnostic and therapeutic implications for clinicians. PMID- 28072731 TI - Focal segmental glomerulosclerosis lagged behind the onset of rheumatoid arthritis by 7 years: A case report and literature review. AB - INTRODUCTION: The co-existence of focal segmental glomerulosclerosis (FSGS) and rheumatoid arthritis (RA), presenting either together or in succession, is very rare. A variety of histopathological features in the clinical renal disease may occur in RA. Only 8 studies have previously reported this poorly understood connection. CLINICAL FINDINGS/DIAGNOSES: A case of a 54-year-old male with RA lasting for more than 7 years developed cheirarthritis as the first signs. Symmetric polyarthralgia and multiple swollen joints throughout the body were followed, accompanied with morning stiffness. Gradually, he suffered from albuminuria, hypoalbuminemia, edema, and hyperlipidemia in 2014. The patient had the history of administering loxoprofen, celecoxib, leflunomide, and methotrexate. He was diagnosed as RA, nephrotic syndrome. Renal biopsy confirmed FSGS. CONCLUSION: Our case and the review of the literature indicate that FSGS is one of the causes of nephrotic syndrome in RA. It strongly suggested that RA patients with the abnormal kidney functions should be routinely screened for FSGS to guide the therapy, achieve both RA and FSGS remission, determine a prognosis, and avoid end-stage renal lesion. PMID- 28072732 TI - Comparison of the i-gel and other supraglottic airways in adult manikin studies: Systematic review and meta-analysis. AB - BACKGROUND: The i-gel has a gel-like cuff composed of thermoplastic elastomer that does not require cuff inflation. As the elimination of cuff inflation may shorten insertion time, the i-gel might be a useful tool in emergency situations requiring prompt airway care. This systematic review and meta-analysis of previous adult manikin studies for inexperienced personnel was performed to compare the i-gel with other supraglottic airways. METHODS: We searched PubMed, the Cochrane Library, and EMBASE for eligible randomized controlled trials (RCTs) published before June 2015, including with a crossover design, using the following search terms: "i-gel," "igel," "simulation," "manikin," "manikins," "mannequin," and "mannequins." The primary outcomes of this review were device insertion time and the first-attempt success rate of insertion. RESULTS: A total of 14 RCTs were included. At the initial assessment without difficult circumstances, the i-gel had a significantly shorter insertion time than the LMA Classic, LMA Fastrach, LMA Proseal, LMA Unique, laryngeal tube, Combitube, and EasyTube. However, a faster insertion time of the i-gel was not observed in comparisons with the LMA Supreme, aura-i, and air-Q. In addition, the i-gel did not show the better results for the insertion success rate when compared to other devices. CONCLUSION: The findings of this meta-analysis indicated that inexperienced volunteers placed the i-gel more rapidly than other supraglottic airways with the exception of the LMA Supreme, aura-i, and air-Q in manikin studies. However, the quicker insertion time is clinically not relevant. The unapparent advantage regarding the insertion success rate and the inherent limitations of the simulation setting indicated that additional evidence is necessary to confirm these advantages of the i-gel in an emergency setting. PMID- 28072733 TI - Efficacy and safety of puerarin injection in curing acute ischemic stroke: A meta analysis of randomized controlled trials. AB - BACKGROUND: Previous studies indicated that the puerarin injection has been widely employed in China for the treatment of acute ischemic stroke. We aim to evaluate the efficacy and safety of the puerarin injection for the treatment of acute ischemic stroke. METHODS: A systematic literature search was performed in PUBMED, EMBASE, SPRINGER LINK, Scopus, Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP Journals Database, Wanfang database and the China Biological Medicine database before November 2016, randomized controlled clinical trials (RCTs) of puerarin injection treating acute ischemic stroke were included. In addition, we searched reference lists of relevant retrieved articles. Two authors extracted data independently. The effective rate, the neurologic deficit score, the blood rheology indexes, and fibrinogen were assessed and analyzed by the Review Manager 5.3 software. The continuous variables were expressed as MD with 95% CI and dichotomous data used RR or ORs. Adverse reactions related to the puerarin injection were also examined. RESULTS: Thirty-five RCTs with a total of 3224 participants were identified in the meta-analysis. The combined results of 32 trials indicated that the puerarin injection was better than control drugs at the clinical effective rate (RR 1.22, 95% CI 1.17 to 1.28, P < 0.001) and 16 studies showed the neurological deficit was significantly improved (MD -3.69, 95% CI -4.67 to -2.71, P < 0.001); the hemorheology index and fibrinogen were much lower with the puerarin injection when compared with western conventional medicines (WCM) or other control drugs (the whole blood viscosity: MD -0.89, 95% CI -1.37 to -0.41, P < 0.001; the HCT: MD -0.04, 95% CI -0.06 to -0.02, P < 0.001; the fibrinogen: MD -0.64, 95% CI -0.96 to -0.31, P < 0.001). Eleven trials reported that the adverse reactions related to the puerarin injection included facial flushing, dizziness, vomiting, nausea, and other mild gastrointestinal discomfort and allergic reaction. No serious adverse drug reactions were reported. CONCLUSIONS: Puerarin injection may be more effective and relatively safe in clinic for treating acute ischemic stroke. However, the current evidence is insufficient due to the poor methodological quality and lack of adequate safety data. Further RCTs are required to examine its efficacy. PMID- 28072734 TI - Closed reduction using the percutaneous leverage technique and internal fixation with K-wires to treat angulated radial neck fractures in children-case report. AB - : Pediatric radial neck fractures are uncommon. Severely displaced and angulated fractures usually require treatment. Our goals for treatment are to avoid incision, reduce the fracture adequately with no reduction loss, and achieve good postoperative function. We aimed to observe the clinical outcomes of closed reduction with the percutaneous leverage technique and internal fixation with Kirschner-wires (K-wires) to treat angulated radial neck fractures in children.From January 2011 to April 2013, we treated 16 cases of angulated radial neck fracture in 12 boys and 4 girls. Five fractures were type II and 11 fractures were type III using the O'Brien classification. One K-wire was percutaneously introduced into the fracture site using the leverage technique to attain good reduction. Two K-wires were introduced from the proximal to the distal areas of the fracture site. The elbow was immobilized by cast in 90 degrees of flexion and the forearm in supination for 3 to 4 weeks. The K-wires were removed at 3 to 4 weeks postoperatively. All cases were followed up for a mean duration of 3 years 6 months.According to the Metaizeau reduction classification, 12 cases were excellent, and 4 cases were good. According to the Metaizeau clinical classification, 14 cases were excellent, and 2 cases were good. There was no necrosis of the radial head. There was no infection, radioulnar synostosis, and damage of the radial nerve deep branch. There was no limitation in the pronation and supination functions of the forearm.Closed reduction using the percutaneous leverage technique and internal fixation using K wires is easy to perform. It is encouraged to use this approach as the clinical outcome is good. LEVEL OF EVIDENCE: level IV-retrospective case, treatment study. PMID- 28072735 TI - Localized type Volkmann's contracture treated with tendon transfer and tension reduced early mobilization: A case report. AB - RATIONALE: For localized type Volkmann's contracture, in which degeneration of the flexor digitorum profundus (FDP) muscle to one or two fingers and restriction of finger extension occur, dissection or excision of the affected muscle is usually recommended. However, these surgical procedures need relatively wide exposure of the muscle, because the FDP muscle is in the deep portion of the forearm. PATIENT CONCERNS: In this report, the case of a 35-year-old woman with localized type Volkmann's contracture is presented. Her left forearm had been compressed with an industrial roller 4 months earlier, and severe flexion contracture of the long finger and mild flexion contracture of the ring finger developed gradually. DIAGNOSES:: localized type Volkmann's contracture. INTERVENTION: Five months after the injury, transection of the FDP tendon to the long finger and transfer of the transected tendon to the FDP tendon to the index finger was performed after adjusting the tonus of these two tendons using a small skin incision. This procedure was followed by a tension-reduced early mobilization technique in which a tension-reduced position of the tendon suture site was maintained by taping the long finger to the volar side of the index finger, and then immediate active range of motion (ROM) exercise was started. OUTCOMES: Within 9 weeks after surgery, full ROM had been regained. LESSONS: Using the treatment procedure presented in this case report, a good clinical result was obtained in a minimally invasive manner. PMID- 28072736 TI - Von Hippel-Lindau disease involving pancreas and biliary system: A rare case report. AB - RATIONALE: Von Hippel-Lindau (VHL) disease is a rare inherited, autosomal dominant syndrome caused by heterozygous germline mutations in the VHL gene. VHL patients are prone to develop benign and malignant tumors and cysts in multiple organ systems involving kidneys, pancreas and central nervous system (CNS). The varied and complex clinical manifestations and radiological findings of VHL are of interest. PATIENT CONCERNS: We report a 38-year-old woman with a ten-year history of VHL disease involving both pancreas and biliary system. To the best of our knowledge, direct involvement of the biliary system in VHL disease has never been reported. DIAGNOSES: The diagnosis was established via computed tomography scan and was confirmed by genetic testing. INTERVENTIONS: The patient chose to receive conservative treatment and was followed up by magnetic resonance cholangiopancreatography and magnetic resonance imaging examination. OUTCOMES: Renal angiomas and cysts were found during follow-up and there were no evidence of malignant change of the pancreas and biliary system. LESSONS: We described the first case of VHL-associated choledochal cysts and may present new visceral manifestations of VHL disease. Gastroenterologists should be aware of the clinical presentations of this rare disease for early detection of its life threatening manifestations. PMID- 28072737 TI - The efficacy of dexmedetomidine-remifentanil versus dexmedetomidine-propofol in children undergoing flexible bronchoscopy: A retrospective trial. AB - Flexible bronchoscopy has been more and more used for diagnosis and management diseases of respiratory system in pediatrics. Previous studies have reported that remifentanil (RF) and propofol are safe and effective for flexible bronchoscopy in adults, however, there have no trials evaluate the efficacy of DEX-RF versus dexmedetomidine-propofol in children undergoing flexible bronchoscopy.We divided 123 children undergoing flexible bronchoscopy with DEX-RF or dexmedetomidine propofol into 2 groups: Group DR (n = 63, DEX infusion at 1.0 MUg kg for 10 minutes, then adjusted to 0.5-0.7 MUg kg h; RF infusion at 1.0 MUg kg for 5 minutes, then adjusted to 0.05-0.2 MUg kg min), Group DP (n = 60, DEX infusion at 1.0 MUg kg for 10 minutes, then adjusted to 0.5-0.7 MUg kg h; propofol infusion at 10 MUg kg for 5 minutes, then adjusted to 0.05-0.1 MUg kg min). Ramsay sedation scale of the 2 groups was maintained at 3. Anesthesia onset time; total number of intraoperative patient movements; hemodynamics; total cumulative dose of DEX; amount of and time to first-dose rescue midazolam and lidocaine; postoperative recovery time; adverse events; and bronchoscopist satisfaction score were recorded.Anesthesia onset time was significantly shorter in DP (8.22 +/- 2.48 vs 12.25 +/- 6.43 minutes, respectively, for DP, DR, P = 0.015). The perioperative hemodynamic profile was more stable in DR than DP group. More children moved during flexible bronchoscopy in DP group (P = 0.009). Total dose of rescue midazolam and lidocaine was significantly higher in DR than in DP (P < 0.001). Similarly, the time to first dose of rescue midazolam and lidocaine was significantly longer in DP than in DR (P < 0.001). Total cumulative dose of DEX was more in DR than DP group (P < 0.001). The time to recovery for discharge from the postanesthesia care unit (PACU) was significantly shorter in DP than in DR group (P < 0.001). The bronchoscopist-satisfaction scores were higher for DR than DP (P = 0.036). There were significant differences between the 2 groups in terms of the overall incidence of hypertension, tachycardia, and hypoxemia (P < 0.05).Although underwent longer recovery time and more incidence of rescue scheme, DEX-RF resulted in more stable hemodynamic profiles and bronchoscopist satisfaction scores, lesser patient movements, and can hence be more effectively used in children undergoing flexible bronchoscopy than dexmedetomidine-propofol. PMID- 28072738 TI - Expression quantitative trait loci for PI3K/AKT pathway. AB - A genome-wide association study (GWAS) was conducted to identify expression quantitative trait loci (eQTLs) for the genes involved in phosphatidylinositol-3 kinase/v-akt murine thymoma viral oncogene homolog (PI3K/AKT) pathway.Data on mRNA expression of 341 genes in lymphoblastoid cell lines of 373 Europeans recruited by the 1000 Genomes Project using Illumina HiSeq2000 were utilized. We used their genotypes at 5,941,815 nucleotide variants obtained by Genome Analyzer II and SOLiD.The association analysis revealed 4166 nucleotide variants associated with expression of 85 genes (P < 5 * 10). A total of 73 eQTLs were identified as association signals for the expression of multiple genes. They included 9 eQTLs for both of the genes encoding collagen type I alpha 1 (COL1A1) and integrin alpha 11 (ITGA11), which synthesize a major complex of plasma membrane. They also included eQTLs for type IV collagen molecules; 13 eQTLs for both collagen type IV alpha 1 (COL4A1) and collagen type IV alpha 2 (COL4A2) and 18 eQTLs for both collagen type IV alpha 5 (COL4A5) and collagen type IV alpha 6 (COL4A6). Some genes expressed by the eQTLs might induce expression of the genes encoding type IV collagen. One eQTL (rs16871986) was located in the promoter of palladin (PALLD) gene which might synthesize collagen by activating fibroblasts through the PI3K/AKT pathway. Another eQTL (rs34845474) was located in an enhancer of cadherin related family member 3 (CDHR3) gene which can mediate cell adhesion.This study showed a profile of eQTLs for the genes involved in the PI3K/AKT pathway using a healthy population, revealing 73 eQTLs associated with expression of multiple genes. They might be candidates of common variants in predicting genetic susceptibility to cancer and in targeting cancer therapy. Further studies are required to examine their underlying mechanisms for regulating expression of the genes. PMID- 28072739 TI - Risk factors and outcomes associated with a higher use of inotropes in kidney transplant recipients. AB - Preservation of adequate perfusion pressures to the graft is a main focus of intraoperative management during kidney transplantation. We undertook this study to investigate the incidence of the higher use of inotropes in kidney transplant recipients and identify the patient outcomes and preoperative and intraoperative variables related to this.We retrospectively analyzed 1053 patients who underwent kidney transplantation at Asan Medical Center between January 2006 and February 2012, stratified by their inotropic score ([dopamine] + [dobutamine] + [epinephrine * 100] + [norepinephrine * 100]) <7 versus >=7, wherein all doses are expressed as MUg/kg/min. We evaluated preoperative characteristics, hemodynamic parameters, and intraoperative variables as well as postoperative outcomes, such as length of hospital stay and 1-year rejection and mortality rate.Receiver-operating characteristic analysis was performed to determine inotropic score to predict 1-year mortality. An inotropic score of 7 had the best combined sensitivity and specificity. An inotropic score >=7 (137 patients, 13.0%) was significantly more prevalent in older patients, those with polycystic kidney disease, and at a 2nd transplant. Anesthesia time, the amounts of crystalloid and 5% albumin infused, and the need for red blood cell transfusion were significantly higher in the inotropic score >=7 group. The patients with a higher use of inotropes required longer postoperative hospital stay and experienced a >2-fold higher rejection within the 1st year and a 4-fold higher 1 year mortality rate.A higher use of inotropes in kidney transplant recipients is more prevalent in older patients, those with a 2nd transplant and in patients with polycystic kidney disease as their primary renal disease. The postoperative hospital stay, rejection within the 1st year, and 1-year mortality rate are increased in patients with an inotropic score >=7. PMID- 28072740 TI - Keyhole approach in the neuroendoscopic treatment for hydrocephalus. AB - The aim of the study was to explore keyhole approach and dura suture in the neuroendoscopic treatment for hydrocephalus.Twelve cases of hydrocephalus patients who were treated with neuroendoscope by this approach were analyzed retrospectively from April 2015 to April 2016 in our department. The basic steps of this procedure was using drill and milling cutter to form a small bone flap instead of burr hole, and then making a cruciate incision on the dura. After endoscopic third ventriculostomy or endoscopic third ventriculostomy + ventriculocystostomy finished, dura was sutured and the bone flap was reset.All 12 patients could suture dura effectively, and no cerebrospinal fluid leak and subcutaneous cerebrospinal fluid collection happened; symptoms of hydrocephalus were also improved. Moreover, during the operation, we found this approach could suspend dura, and avoid the cerebral sulcus and cortical coarse vein effectively, which could reduce the risk of intracranial hemorrhage. In addition, we found this approach could increase the reachable range of the neuroendoscope significantly.Keyhole approach can suture dura and avoid the cerebral sulcus and cortical coarse vein effectively, increase the indications, and reduce complications of neuroendoscope. So, this approach has clinical values and can be used in hydrocephalus. PMID- 28072741 TI - Daughter and mother diagnosed with hereditary multiple exostoses: A case report and a review of the literature. AB - INTRODUCTION: Hereditary multiple exostoses (HME) or osteochondromatosis is a rare autosomal dominant disease characterized by multiple osteochondromas and skeletal deformities. PATIENT CONCERNS & DIAGNOSES: We present the case of a 5 years and 9 month-old patient who presented with inferior limb pain for approximately 6 months, associating also deformity of the right index finger for a month. Hand X-ray revealed a radiologic abnormality of the right radius, therefore the child was referred to our clinic for further investigations. The X rays revealed multiple osteochondromas of the radius, metacarpal bones, hand phalangeal bones, femur, tibia, fibula, metatarsal bones, and foot phalangeal bones. We mention that the same radiological aspect was identified in the case of the patient's mother, undiagnosed until that moment. OUTCOMES: The particularity of this case consists in identification of a rare genetic pathology, HME in a 5 year-old patient, without any known familial history, after the occurrence of a nontraumatic joint dislocation of the right index finger. CONCLUSION: HME is a rare genetic condition, without a curative treatment, burdened by multiple complications, and whose diagnosis is usually established during childhood. PMID- 28072742 TI - The nonlinear association between apolipoprotein B to apolipoprotein A1 ratio and type 2 diabetes. AB - The ratio of ApoB/apolipoprotein A1 (ApoA1) has been found to be associated with type 2 diabetes, and it was proposed as a new biomarker for type 2 diabetes predictions. Previous studies have assumed that the association between apoB/apoA1 and type 2 diabetes was linear. However, the linearity assumption has rarely been examined. In the present study, we aimed to examine whether this association showed a linear trend in a nationally representative population.Participants aged 18 years and over (n = 8220) were selected from the China Health Nutrition Survey (CHNS). We used restricted cubic spline to model the association between ApoB/ApoA1 ratio and type 2 diabetes using logistic regression models. Additionally, we categorized the ApoB/ApoA1 ratio according to quartiles to compare with previous results. Age, gender, education, smoking status, high sensitivity C-reactive protein (hsCRP), lipid, body mass index (BMI), and hypertension were controlled as potential confounders.We found that the association between apoB/apoA1 ratio and type 2 diabetes may be nonlinear after adjusting for multiple potential confounders. Compared with the lowest quartile of apoB/apoA1 ratio, participants in the fourth quartile had a higher odds of type 2 diabetes [odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.01-1.81].Our results suggest that, higher apoB/apoA1 ratio was associated with higher prevalence of type 2 diabetes. However, the association may be nonlinear. PMID- 28072743 TI - Bilateral anterior capsulotomy and amygdalotomy for mental retardation with psychiatric symptoms and aggression: A case report. AB - RATIONALE: Mental retardation (MR) is a chronic condition that often has no readily identifiable cause or treatment. Aggression and psychiatric symptoms are prevalent in children with MR. Surgical treatment of aggression and psychiatric symptoms of MR is seldom investigated and studies are limited. PATIENT CONCERNS: We encountered a 19-year-old female who had MR with aggression and psychiatric symptoms. DIAGNOSES: She was diagnosed with mild MR with aggressiveness and psychiatric symptoms. INTERVENTIONS: Because the patient was refractory to conservative treatment, bilateral anterior capsulotomy and amygdaloid neurosurgery were performed for her psychiatric symptoms and aggression. The benefits and side effects of the surgery were analyzed. OUTCOMES: After surgery, the patient showed significant alleviation of her psychiatric symptoms and aggression with no observed side effects. LESSONS: Bilateral anterior capsulotomy in combination with amygdaloid neurosurgery may resolve both psychiatric and aggressive symptoms. Future investigations of control studies with large patient cohorts are needed. PMID- 28072744 TI - Posterior arthrodesis of C1-C3 for the stabilization of multiple unstable upper cervical fractures with spinal cord compromise: A case report and literature review. AB - BACKGROUND: Multiple fractures of the atlas and axis are rare. The management of multiple fragment axis fractures and unstable atlas fractures is still challenging for the spinal surgeon. There are no published reports of similar fractures with 3-part fracture of axis associated with an unstable atlas fracture. CASE SUMMARY: We present a patient with concurrent axis and atlas fractures, which have not been reported. The patient suffered hyperextension injury with neck pain and numbness of the bilateral upper extremity associated with weakness after a 2-m fall. The axis fractures included an odontoid type IIA fracture and traumatic spondylolisthesis of C2-C3. The atlas fracture was unstable. The neurological examination manifested as central canal syndrome, which was due to the hyperextension injury of cervical spine and spondylolisthesis of C2-C3. The patient was diagnosed as multiple unstable upper cervical fractures with spinal cord compromise. We performed posterior arthrodesis of C1-C3. Postoperatively, the patient showed neurological improvement, and C1-C3 had fused at the 3-month follow-up. CONCLUSION: Posterior arthrodesis of C1-C3 could provide a stable fixation for the 3 parts of axis (an odontoid type IIA fracture and traumatic spondylolisthesis of C2-C3) combined an unstable atlas fracture. Both the patient and the doctor were satisfied with the results of the treatment. So posterior arthrodesis of C1-C3 is a suitable treatment option for the treatment of a concurrent unstable atlas fracture and multiple fractures of the axis. PMID- 28072745 TI - Safety and efficacy of chloral hydrate for conscious sedation of infants in the pediatric cardiovascular intensive care unit. AB - This study evaluates the safety and efficacy of chloral hydrate administration for the conscious sedation of infants in the pediatric cardiovascular intensive care unit (PCICU).We conducted a retrospective review of the charts of 165 infants with congenital heart disease who received chloral hydrate in our PCICU between January 2014 and December 2014. Chloral hydrate was administered orally or rectally to infants using doses of 50 mg/kg. We collected and analyzed relevant clinical parameters.The overall length of time to achieve sedation was ranged from 5 to 35 min (10.8 +/- 6.2 min); the overall mean duration of sedation was ranged from 15 to 60 min (33.5 +/- 11.3 min); and the overall mean length of time to return to normal activity was 10 min to 6 h (34.3 +/- 16.2 min). The length of the PCICU stay was ranged from 3 to 30 days (8.2 +/- 7.1 days). Physiologically, there were no clinically significant changes in heart rate, mean arterial pressure, respiratory rate, or peripheral oxygen saturation before, during, or after use of the chloral hydrate. There were no significant differences regarding sedative effects in the subgroups (cyanotic vs acyanotic group, with pulmonary infection vs without pulmonary infection group, and with pulmonary hypertension vs without pulmonary hypertension group).Our experience suggests that chloral hydrate is a safe and efficacious agent for conscious sedation of infants in the PCICU. PMID- 28072746 TI - ZNF148 modulates TOP2A expression and cell proliferation via ceRNA regulatory mechanism in colorectal cancer. AB - BACKGROUND: Competing endogenous RNA (ceRNA) regulation is a novel hypothesized mechanism that states RNA molecules share common target microRNAs (miRNAs) and may competitively combine into the same miRNA pool. METHODS: Zinc finger protein 148 (ZNF148) and TOP2A expression were analyzed in 742 colorectal cancer (CRC) tissues using immunohistochemistry (IHC). ZNF148 mRNA, TOP2A mRNA, miR101, miR144, miR335, and miR365 expression were estimated in 53 fresh frozen CRC tissues by reverse transcription polymerase chain reaction. Mechanisms underpinning ceRNA were examined using bioinformatics, correlation analysis, RNA interference, gene over-expression, and luciferase assays. RESULTS: Protein levels of ZNF148 and TOP2A detected by IHC positively correlated (Spearman correlation coefficient [rs] = 0.431, P < 0.001); mRNA levels of ZNF148 and TOP2A also positively correlated (r = 0.591, P < 0.001). Bioinformatics analysis demonstrated that ZNF148 and TOP2A mRNA had 13 common target miRNAs, including miR101, miR144, miR335, and miR365. Correlation analysis demonstrated that levels of ZNF148 mRNA were negatively associated with levels of miR144, miR335, and miR365. Knockdown and overexpression tests showed that ZNF148 mRNA and TOP2A mRNA regulated each other in HCT116 cells, respectively, but not in Dicer-deficient HCT116 cells. Luciferase assays demonstrated that ZNF148 and TOP2A regulated each other through 3'UTR. Overexpression of ZNF148 mRNA and TOP2A mRNA caused significant downregulation of miR101, miR144, miR335, and miR365 in the HCT116 cells. We also found that knockdown of ZNF148 and TOP2A significantly promoted cell growth, and overexpression of ZNF148 and TOP2A inhibited cell proliferation, which was abrogated in Dicer-deficient HCT116 cells. CONCLUSION: ZNF148 and TOP2A regulate each other through ceRNA regulatory mechanism in CRC, which has biological effects on cell proliferation. PMID- 28072747 TI - The clinical characteristics and short-term prognosis in elderly patients with Guillain-Barre syndrome. AB - To investigate the clinical characteristics and short-term prognosis of elderly patients with Guillain-Barre syndrome (GBS).We retrospectively analyzed the clinical data of adult GBS. According to the age, the enrolled subjects were divided into 2 groups, that is, patients >=60 years (elderly group) and those aged 18 to 59 years (nonelderly group). The clinical characteristics and short term prognosis of the patients in the 2 groups were compared.In total, 535 patients were enrolled. There were 67 patients fell into the elderly group with a mean age of 69 years old; while 468 patients fell into the nonelderly group with a mean age of 39 years old. We found that the elderly patients had significantly lower incidence of antecedent infections (49.3% vs 66.2%, P < 0.01). The time from onset to admission (5 vs 4 days, P < 0.05) and time from onset to nadir (7 vs 6 days, P < 0.05) were significantly longer in the elderly patients. It was noteworthy that more elderly patients were found with lymphocytopenia (55.4% vs 37.3%, P < 0.01), hyponatremia (25.0% vs 10.2%, P < 0.01), hypoalbuminemia (9.0% vs 2.6%, P < 0.05), and hyperglycemia (34.3% vs 15.2%, P < 0.01). Importantly, the elderly patients had longer duration of hospitalization (17 vs 14 days, P < 0.05), higher incidence of pneumonia (29.9% vs 18.8%, P < 0.05), and poorer short term prognosis (58.2% vs 42.7%, P < 0.05). In patients with severe GBS, no significant differences were observed in disease severity, treatment modality, incidence of pneumonia, and duration of hospitalization between the 2 groups. However, more patients in the elderly group showed poor short-term prognosis (84.1% vs 63.8%, P < 0.01). Further, old age (>=60 years) (OR = 2.906, 95% CI: 1.174-7.194, P < 0.05) and lower Medical Research Council (MRC) score at nadir (OR = 0.948, 95% CI: 0.927-0.969, P < 0.01) were risk factors for poor short-term prognosis in severe GBS patients.The clinical characteristics and short-term prognosis of elderly patients with GBS are distinct from nonelderly adults. Old age (>=60 years) and lower nadir MRC score serve as predictor for poor short-term prognosis in severe GBS patients. PMID- 28072748 TI - Giant polypoid gastric heterotopia in the small intestine in a boy: A case report and literature review. AB - RATIONALE: Heterotopic gastric mucosa has been described at various locations of the body; however, the polyp composed of heterotopic gastric mucosa in the small intestine is rare. PATIENT CONCERNS: A 15-year-old boy visited us for investigation of recurrent episodes of melena. Capsule endoscopy (CE) revealed a polypoid tumor in the ileum, with an active nearby hemorrhage. Contrast-enhanced computed tomography (CECT) showed a tumor in the right quadrant of the abdomen, with a diameter of about 18 * 14 mm. DIAGNOSES: The patient was diagnosed with polypoid gastric heterotopia. INTERVENTIONS: We performed an operation to resect the lesion. OUTCOMES: The patient recovered smoothly after surgery and was discharged on postoperative day 7 and followed up for 3 months. He has not experienced gastrointestinal intestinal (GI) symptoms up to now. LESSONS: Giant polypoid gastric heterotopia in the small intestine is extremely rare, which can express as an occasional finding with or without symptoms. Surgical resection is the preferred therapy when symptoms appear. PMID- 28072749 TI - Ultrasound-guided pulsed radiofrequency treatment of the cervical sympathetic chain for complex regional pain syndrome: A retrospective observational study. AB - The stellate ganglion is a common target to manage neuropathic pain in the upper extremities. However, the effect duration of a single stellate ganglion block is often temporary. To overcome the short-term effects of a single sympathetic block, pulsed radiofrequency (PRF) can be applied. The aim of the present study was to investigate the efficacy of PRF on the cervical sympathetic chain under ultrasound guidance for complex regional pain syndrome (CRPS).Twelve CRPS patients who underwent PRF on the cervical sympathetic chain were enrolled in this retrospective analysis. Under ultrasound guidance, PRF was performed for 420 seconds at 42 degrees C on the C6- and C7-level sympathetic chain.The pain intensity decreased significantly at 1 week after the procedure. Overall, 91.7% of patients experienced at least moderate improvement. A positive correlation was observed between the extent of pain reduction at 1 week after PRF and the degree of overall benefit (r = 0.605, P = 0.037). This reduction in symptoms was maintained for a mean of 31.41 +/- 26.07 days after PRF. There were no complications associated with this procedure.PRF on the cervical sympathetic chain, which can be performed easily and safely under ultrasound guidance, should be considered an option for managing CRPS of the upper extremities. PMID- 28072750 TI - Upper gastrointestinal ectopic variceal bleeding treated with various endoscopic modalities: Case reports and literature review. AB - RATIONALE: Ectopic variceal bleeding is a rare (2-5%) but fatal gastrointestinal bleed in patients with portal hypertension. Patients with ectopic variceal bleeding manifest melena, hematochezia, or hematemesis, which require urgent managements. Definitive therapeutic modalities of ectopic varices are not yet standardized because of low incidence. Various therapeutic modalities have been applied on the basis of the experiences of experts or availability of facilities, with varying results. PATIENT CONCERNS: We have encountered eight cases of gastrointestinal ectopic variceal bleeding in five patients in the last five years. DIAGNOSES: All patients were diagnosed with liver cirrhosis presenting melena or hematemesis. INTERVENTIONS: All patients were treated with various endoscopic modalities (endoscopic variceal obturation [EVO] with cyanoacrylate in five cases, endoscopic variceal band ligation (EVL) in two cases, hemoclipping in one case). OUTCOMES: Satisfactory hemostasis was achieved without radiologic interventions in all cases. EVO and EVL each caused one case of portal biliopathy, and EVL induced ulcer bleeding in one case. LESSONS: EVO generally accomplished better results of variceal obturations than EVL or hemoclipping, without serious adverse events. EVO may be an effective modality for control of ectopic variceal bleeding without radiologic intervention or surgery. PMID- 28072751 TI - Duodenal plexiform fibromyxoma as a cause of obscure upper gastrointestinal bleeding: A case report. AB - RATIONALE: We are reporting the first-to our knowledge-case of duodenal Plexiform Fibromyxoma causing obscure upper gastrointestinal bleeding. PATIENT CONCERNS: Plexiform fibromyxoma triggered recurrent upper gastrointestinal bleeding episodes in a 63-year-old man who remained undiagnosed, despite multiple hospitalizations, extensive diagnostic workups and surgical interventions (including gastrectomies), for almost 17 years. DIAGNOSES-INTERVENTIONS: During hospitalization for the last bleeding episode, an upper gastrointestinal endoscopy revealed an intestinal hemorrhagic nodule. The lesion was deemed unresectable by endoscopic means. An abdominal computerized tomography disclosed no further lesions and surgery was decided. The lesion at operation was found near the edge of the duodenal stump and treated with pancreas-preserving duodenectomy (1st and 2nd portion). OUTCOMES: Postoperative recovery was mainly uneventful and a 20-month follow-up finds the patient in good health with no need for blood transfusions.Plexiform fibromyxomas stand for a rare and widely unknown mesenchymal entity. Despite the fact that they closely resemble other gastrointestinal tumors, they distinctly vary in clinical management as well as the histopathology. Clinical awareness and further research are compulsory to elucidate its clinical course and prognosis. PMID- 28072752 TI - A Simpler Blood Test for Monitoring Kidney Transplant Recipients: "A Disrupting Innovation". PMID- 28072753 TI - Engraftment Site and Effectiveness of the Pan-Caspase Inhibitor F573 to Improve Engraftment in Mouse and Human Islet Transplantation in Mice. AB - BACKGROUND: Islet transplantation is an effective therapy in type 1 diabetes and recalcitrant hypoglycemia. However, there is an ongoing need to circumvent islet loss posttransplant. We explore herein the potential of the pan-caspase inhibitor F573 to mitigate early apoptosis-mediated islet death within portal and extrahepatic portal sites in mice. METHODS: Mouse or human islets were cultured in standard media +/-100 MUM F573 and subsequently assessed for viability and apoptosis via terminal deoxynucleotidyl transferase dUTP nick end labeling staining and caspase-3 activation. Diabetic mice were transplanted with syngeneic islets placed under the kidney capsule (KC) or into the subcutaneous deviceless (DL) site at a marginal islet dose (150 islets), or into the portal vein (PV) at a full dose (500 islets). Human islets were transplanted under the KC of diabetic immunodeficient mice at a marginal dose (500 islet equivalents). Islets were cultured in the presence of F573, and F573 was administered subcutaneously on days 0 to 5 posttransplant. Control mice were transplanted with nontreated islets and were injected with saline. Graft function was measured by nonfasting blood glucose and glucose tolerance testing. RESULTS: F573 markedly reduced human and mouse islet apoptosis after in vitro culture (P < 0.05 and P < 0.05, respectively). Furthermore, F573 improved human islet function when transplanted under the KC (P < 0.05); whereas F573 did not enhance murine islet marginal KC transplants. Conversely, F573 significantly improved mouse islet engraftment in the PV and DL site (P < 0.05 and P < 0.05, respectively). CONCLUSIONS: The pan caspase inhibitor F573 markedly reduces human and mouse islet apoptosis and improves engraftment most effectively in the portal and DL subcutaneous sites. PMID- 28072754 TI - Initial Outcomes of Pure Laparoscopic Living Donor Right Hepatectomy in an Experienced Adult Living Donor Liver Transplant Center. AB - BACKGROUND: Only a limited number of centers have performed laparoscopic living donor hepatectomy to date. In particular, laparoscopic right hepatectomy is rarely performed because the procedure can only be performed by surgeons with significant experience in both laparoscopic liver surgery and liver transplantation with living donor liver grafts. METHODS: Between November 2014 and February 2015, in a pure laparoscopic approach program for living right lobe donors at Asan Medical Center, 92 living donors underwent right hepatectomy for adult living donor liver transplantation. Among these, 3 pure laparoscopic living donor right hepatectomies were performed in 3 young female donors. RESULTS: The intraoperative and postoperative courses for all 3 donors and recipients were uneventful without any complications. Laparoscopic living donor hepatectomy has definite advantages over conventional open surgery, including decreased wound morbidity and faster recovery. CONCLUSIONS: According to the data of the present report, pure laparoscopic living donor right hepatectomy in properly selected living donors (only 4% of potential donors in this cohort) appears to be a safe and feasible procedure in adult living donor liver transplantation. PMID- 28072755 TI - Strategies for an Expanded Use of Kidneys From Elderly Donors. AB - The old-for-old allocation policy used for kidney transplantation (KT) has confirmed the survival benefit compared to remaining listed on dialysis. Shortage of standard donors has stimulated the development of strategies aimed to expand acceptance criteria, particularly of kidneys from elderly donors. We have systematically reviewed the literature on those different strategies. In addition to the review of outcomes of expanded criteria donor or advanced age kidneys, we assessed the value of the Kidney Donor Profile Index policy, preimplantation biopsy, dual KT, machine perfusion and special immunosuppressive protocols. Survival and functional outcomes achieved with expanded criteria donor, high Kidney Donor Profile Index or advanced age kidneys are poorer than those with standard ones. Outcomes using advanced age brain-dead or cardiac-dead donor kidneys are similar. Preimplantation biopsies and related scores have been useful to predict function, but their applicability to transplant or refuse a kidney graft has probably been overestimated. Machine perfusion techniques have decreased delayed graft function and could improve graft survival. Investing 2 kidneys in 1 recipient does not make sense when a single KT would be enough, particularly in elderly recipients. Tailored immunosuppression when transplanting an old kidney may be useful, but no formal trials are available.Old donors constitute an enormous source of useful kidneys, but their retrieval in many countries is infrequent. The assumption of limited but precious functional expectancy for an old kidney and substantial reduction of discard rates should be generalized to mitigate these limitations. PMID- 28072756 TI - Rapid Testing for Creutzfeldt-Jakob Disease in Donors of Cornea. AB - BACKGROUND: Creutzfeldt-Jakob disease (CJD) has been accidentally transmitted by contaminated corneal transplants. Eye donors are not ordinarily tested for CJD, in part because an easy test is not available. We propose a relatively simple postmortem procedure to collect brain samples without performing full autopsy and show that a test currently marketed for veterinary diagnosis would offer an effective screening test. METHODS: We selected 6 brains from confirmed cases of human sporadic CJD and sampled each in triplicate (18 specimens), 28 control brains of individuals with non-CJD neurodegenerative diseases and 10 normal brains. We also applied a procedure involving retro-orbital puncture after enucleation and biopsied the frontal lobes and optic nerves of a macaque experimentally infected with variant CJD. All samples were tested with the IDEXX HerdChek BSE-Scrapie Ag Kit to detect the abnormal prion protein, PrP. RESULTS: The test discriminated between control and CJD-infected brains. All 18 infected brain samples diluted to 0.1%, except one, showed signals above cutoff, and a number of samples were reactive at even higher dilutions. These results suggest the test could detect the low concentrations of PrP probably present in brains of donors at early stages of CJD. Our collection procedure obtained sufficient macaque brain and optic nerve tissues to detect PrP. CONCLUSIONS: We showed that a commercial test combined with rapid sample collection might offer a practical solution to screen brains of cornea donors for evidence of CJD. Such a test might enhance safety of corneal transplants and some other tissue-derived products. PMID- 28072757 TI - Organ Procurement Organization Survey of Practices and Beliefs Regarding Prerecovery Percutaneous Liver Biopsy in Donation After Neurologic Determination of Death. AB - BACKGROUND: Prerecovery liver biopsy (PLB) allows histological evaluation of the organ before procurement. The opinions and what factors might influence PLB use within Organ Procurement Organizations (OPOs) are unknown. METHODS: A survey instrument was distributed by the Association of OPOs to the clinical directors of all 58 OPOs. Descriptive statistics were calculated. Results were also stratified based on OPO characteristics. RESULTS: Forty-nine (84.5%) of 58 OPOs responded to the survey; 40 (81.6%) of 49 currently perform PLB. This did not vary based on land mass, population, livers discarded, transplanted, donor age, or recipient MELD scores. Donor age, obesity, alcohol abuse, hepatitis serology, liver only donor, imaging results, and transplant center request were the most common indications for PLB in over 80% of OPOs. The median rate of performance is 5% to 10% of donors. Most use interventional radiologists to perform and the donor hospital pathologist/s to interpret PLB. Most OPOs believe PLBs are safe, reliable, useful, and performed often enough. Most say they did not believe they are easy to obtain. Beliefs were mixed regarding accuracy. The topics likely to influence PLB use were utility and accuracy of PLB, and availability of staff to perform PLB. OPOs that perform PLB more often were more likely to have favorable opinions of safety and pathologist availability, and more influenced by safety, reliability, availability, and a national consensus on the use of PLB. CONCLUSIONS: Considerable variability exists in the use of PLB. Additional information on the utility, accuracy, and safety of PLB are needed to optimize its use. PMID- 28072758 TI - How to Escape the Immune Response: What Tumors Teach to Transplant Physicians/Immunologists. AB - Recent progress in deciphering the mechanisms underlying the concepts of tumor immunosurveillance and immunoevasion has opened new opportunities for the development of effective antitumor therapies. Transplant physicians and immunologists have much to learn from those direct clinical translations of basic science. The 2016 Beaune Seminar in Transplant research brought together researchers from both fields to explore and discuss significant advances in cancer biology, immunotherapies and their potential impacts for the management of cancer in transplant recipients. PMID- 28072759 TI - Induction of K562 Cell Apoptosis by As4S4 via Down-Regulating miR181. AB - BACKGROUND Chronic myelogenous leukemia (CML) has unsatisfactory treatment efficacy at present. As the major component of red orpiment, tetra-arsenic tetra sulfide (As4S4) has been recently used in treating leukemia, but with unclear mechanism targeting CML. MicroRNA (miR) is a group of endogenous non-coding RNAs regulating pathogenesis. MiR181 has been shown to exert important roles in tumor progression. The relationship between miR181 and As4S4 in inducing K562 cell apoptosis, however, is still unclear. MATERIAL AND METHODS CML cell line K562 was cultured in vitro in a control group and in groups receiving various dosages (20 MUM and 40 MUM) of As4S4. MTT assay was employed to detect the effect on K562 cell survival. MiR181 expression was quantified by real-time PCR. MTT assay and assay kit were used to determine K562 cell survival and caspase 3 expression. Cell apoptosis was assessed by flow cytometry. Bcl-2 expression was determined by real-time PCR and Western blotting. RESULTS As4S4 significantly suppressed proliferation of K562 cells (p<0.05) and decreased miR181 expression, and increased caspase3 activity compared to the control group. It can induce K562 cell apoptosis via remarkably down-regulating mRNA and protein expressions of Bcl 2 (p<0.05). CONCLUSIONS As4S4 can facilitate K562 cell apoptosis via down regulating miR181, inhibiting Bcl02 expression, and enhancing apoptotic protein caspase3 activity. PMID- 28072760 TI - Pentoxifylline inhibits TLR- and inflammasome-mediated in vitro inflammatory cytokine production in human blood with greater efficacy and potency in newborns. AB - BACKGROUND: Toll-like receptor (TLR)-mediated inflammation may contribute to neonatal sepsis, for which pentoxifylline (PTX), a phosphodiesterase inhibitor that raises intracellular cAMP, is a candidate adjunctive therapy. We characterized the anti-inflammatory effects of PTX toward TLR-mediated production of inflammatory (tumor necrosis factor (TNF) and interleukin (IL)-1beta) and proresolution (IL-6 and IL-10) cytokines in human newborn and adult blood. METHODS: Newborn cord and adult blood were treated with PTX (50-400 umol/l) before, during or after stimulation with LPS (TLR4 agonist), R848 (TLR7/8 agonist) or LPS/ATP (inflammasome activation). Cytokines were measured by multiplex assay (supernatants), intracellular cytokines and signaling molecules by flow cytometry, and mRNA by quantitative real-time PCR. RESULTS: Whether added 2 h pre-, simultaneously to, or 2 h post-TLR stimulation, PTX inhibited TLR mediated cytokine production in a concentration-dependent manner, with greater efficacy and potency in newborn blood, decreasing intracellular TNF and IL-1beta with relative preservation of IL-10 and IL-6. PTX decreased TLR-mediated TNF mRNA while increasing IL-10 mRNA. Neonatal plasma factors contributed to the anti inflammatory effects of PTX in newborn blood that were independent of soluble TNF receptor concentrations, p38 MAPK phosphorylation and IKB degradation. CONCLUSION: PTX is a potent and efficacious inhibitor of TLR-mediated inflammatory cytokines in newborn cord blood and a promising neonatal anti inflammatory agent. PMID- 28072761 TI - Immediate chest X-ray for patients at risk of lung cancer presenting in primary care: randomised controlled feasibility trial. AB - BACKGROUND: Achieving earlier stage diagnosis is one option for improving lung cancer outcomes in the United Kingdom. Patients with lung cancer typically present with symptoms to general practitioners several times before referral or investigation. METHODS: We undertook a mixed methods feasibility individually randomised controlled trial (the ELCID trial) to assess the feasibility and inform the design of a definitive, fully powered, UK-wide, Phase III trial of lowering the threshold for urgent investigation of suspected lung cancer. Patients over 60, with a smoking history, presenting with new chest symptoms to primary care, were eligible to be randomised to intervention (urgent chest X-ray) or usual care. RESULTS: The trial design and materials were acceptable to GPs and patients. We randomised 255 patients from 22 practices, although the proportion of eligible patients who participated was lower than expected. Survey responses (89%), and the fidelity of the intervention (82% patients X-rayed within 3 weeks) were good. There was slightly higher anxiety and depression in the control arm in participants aged >75. Three patients (1.2%) were diagnosed with lung cancer. CONCLUSIONS: We have demonstrated the feasibility of individually randomising patients at higher risk of lung cancer, to a trial offering urgent investigation or usual care. PMID- 28072762 TI - Giving AXL the axe: targeting AXL in human malignancy. AB - The receptor tyrosine kinase AXL, activated by a complex interaction between its ligand growth arrest-specific protein 6 and phosphatidylserine, regulates various vital cellular processes, including proliferation, survival, motility, and immunologic response. Although not implicated as an oncogenic driver itself, AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is overexpressed in several haematologic and solid malignancies, including acute myeloid leukaemia, non-small cell lung cancer, gastric and colorectal adenocarcinomas, and breast and prostate cancers. In the context of malignancy, evidence suggests that AXL overexpression drives wide-ranging processes, including epithelial to mesenchymal transition, tumour angiogenesis, resistance to chemotherapeutic and targeted agents, and decreased antitumor immune response. As a result, AXL is an attractive candidate not only as a prognostic biomarker in malignancy but also as a target for anticancer therapies. Several AXL inhibitors are currently in preclinical and clinical development. This article reviews the structure, regulation, and function of AXL; the role of AXL in the tumour microenvironment; the development of AXL as a therapeutic target; and areas of ongoing and future investigation. PMID- 28072763 TI - Epithelial to mesenchymal transition and HPV infection in squamous cell oropharyngeal carcinomas: the papillophar study. AB - BACKGROUND: Human Papillomavirus (HPV) infection is recognised as aetiological factor of carcinogenesis in oropharyngeal squamous cell carcinomas (OPC). HPV related OPC respond better to treatments and have a significantly favourable outcome. Epithelial to mesenchymal transition (EMT) implicated in tumour invasion, is a hallmark of a poor prognosis in carcinomas. METHODS: We have studied the relationship of EMT markers (E-cadherin, beta-catenin and vimentin) with HPV infection (DNA and E6/E7 mRNA detection), p16INK4a expression and survival outcomes in a cohort of 296 patients with OPC. RESULTS: Among the 296 OPSSC, 26% were HPV positive, 20.3% had overt EMT (>25% of vimentin positive tumour cells). Lower E-cadherin expression was associated with a higher risk of distant metastasis in univariate (P=0.0110) and multivariate analyses (hazard ratios (HR)=6.86 (1.98; 23.84)). Vimentin expression tends towards worse metastasis-free survival (MFS; HR=2.53 (1.00; 6.41)) and was an independent prognostic factor of progression-free survival (HR=1.55 (1.03; 2.34)). CONCLUSIONS: There was a non significant association of EMT with HPV status. This may be explained by a mixed subpopulation of patients HPV positive with associated risk factors (HPV, tobacco and alcohol). Thus, the detection of EMT in OPC represents another reliable approach in the prognosis and the management of OPC whatever their HPV status. PMID- 28072764 TI - Antitumour activity of trabectedin in myelodysplastic/myeloproliferative neoplasms. AB - BACKGROUND: Juvenile myelomonocytic leukaemia (JMML) and chronic myelomonocytic leukaemia (CMML) are myelodysplastic myeloproliferative (MDS/MPN) neoplasms with unfavourable prognosis and without effective chemotherapy treatment. Trabectedin is a DNA minor groove binder acting as a modulator of transcription and interfering with DNA repair mechanisms; it causes selective depletion of cells of the myelomonocytic lineage. We hypothesised that trabectedin might have an antitumour effect on MDS/MPN. METHODS: Malignant CD14+ monocytes and CD34+ haematopoietic progenitor cells were isolated from peripheral blood/bone marrow mononuclear cells. The inhibition of CFU-GM colonies and the apoptotic effect on CD14+ and CD34+ induced by trabectedin were evaluated. Trabectedin's effects were also investigated in vitro on THP-1, and in vitro and in vivo on MV-4-11 cell lines. RESULTS: On CMML/JMML cells, obtained from 20 patients with CMML and 13 patients with JMML, trabectedin - at concentration pharmacologically reasonable, 1-5 nM - strongly induced apoptosis and inhibition of growth of haematopoietic progenitors (CFU-GM). In these leukaemic cells, trabectedin downregulated the expression of genes belonging to the Rho GTPases pathway (RAS superfamily) having a critical role in cell growth and cytoskeletal dynamics. Its selective activity on myelomonocytic malignant cells was confirmed also on in vitro THP-1 cell line and on in vitro and in vivo MV-4-11 cell line models. CONCLUSIONS: Trabectedin could be good candidate for clinical studies in JMML/CMML patients. PMID- 28072765 TI - Phase II study of the PI3K inhibitor BKM120 in patients with advanced or recurrent endometrial carcinoma: a stratified type I-type II study from the GINECO group. AB - : Backround:Patients with metastatic endometrial carcinoma have a poor prognosis and PIK3CA mutations and amplifications are common in these cancers. This study evaluated the efficacy and safety of the pure PI3K inhibitor BKM120 in advanced or recurrent endometrial carcinoma. METHODS: This phase II, multicentre, single arm, double strata (histological low grade (LG) or high grade (HG)) open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinoma who had received not more than one prior chemotherapy regimen. Patients received initially BKM120 100 mg tablets once daily. Primary end points were proportion of patients free of progression at 2 months (HG strata) or at 3 months (LG strata), objective response rate (ORR), and safety. RESULTS: A total of 40 patients were enrolled, of whom 16 patients had received BKM120 at 100 mg. Because of high toxicities (cutaneous rash (54%), depressive events (47%), and anxiety (40%), the IDMC has proposed to stop recruitment at 100 mg and to continue the clinical trial with a lower dose of 60 mg per day. In addition, 24 patients (median age 67 years old) were newly enrolled (14 in the LG strata and 10 in the HG strata). Rate of nonprogression at 2 months in the HG strata was 70% and at 3 months was 60% in the LG strata. Median progression-free survival (PFS) for all patients is 4.5 months (CI 95% 2.8-6.1), and the median PFS for LG strata is 8.3 months compared with 3.8 months for the HG strata. No response was reported. At 60 mg per day, the most commonly reported treatment related adverse events (AEs) were hyperglycaemia (58%), cognitive (31%), digestive (28%), hepatic liver functions (26%), and rash (23%). The most commonly reported treatment-related grade ?3 AEs were HTA (17%), hyperglycaemia (17%), and increased alanine aminotransferase (24%). Five patients (21%) stopped BKM120 for toxicity. CONCLUSIONS: The BKM120 was associated with an unfavourable safety profile and minimal antitumour activity in monotherapy in advanced or recurrent endometrial carcinoma. The clinical trial was stopped before end of recruitment for toxicity. PMID- 28072766 TI - The impact of body composition parameters on ipilimumab toxicity and survival in patients with metastatic melanoma. AB - BACKGROUND: Body composition is an important predictor of drug toxicity and outcome. Ipilimumab (Ipi), a monoclonal antibody used to treat metastatic melanoma, has specific toxicities. No validated biomarkers that predict Ipi toxicity and efficacy exist. Also, the impact of Ipi on body composition has not been established. METHODS: Patients with metastatic melanoma treated with Ipi between 2009 and 2015 were included. Body composition was assessed by computed tomography at baseline and after four cycles of Ipi. Sarcopenia and low muscle attenuation (MA) were defined using published cut-points. All adverse events (AEs) and immune-related AEs (irAEs) were recorded (Common Terminology Criteria For Adverse Event V.4.0). RESULTS: Eighty-four patients were included in this study (62% male, median age 54 years). At baseline, 24% were sarcopenic and 33% had low MA. On multivariate analysis, sarcopenia and low MA were significantly associated with high-grade AEs (OR=5.34, 95% CI: 1.15-24.88, P=0.033; OR=5.23, 95% CI: 1.41-19.30, P=0.013, respectively), and low MA was associated with high grade irAEs (OR=3.57, 95% CI: 1.09-11.77, P=0.036). Longitudinal analysis (n=59) revealed significant reductions in skeletal muscle area (SMA), total body fat free mass, fat mass (all P<0.001) and MA (P=0.030). Mean reduction in SMA was 3.3%/100 days (95% CI: -4.48 to -1.79%, P<0.001). A loss of SMA ?7.5%/100 days (highest quartile) was a significant predictor of overall survival in multivariable Cox regression analysis (HR: 2.1, 95% CI: 1.02-4.56, P=0.046). CONCLUSIONS: Patients with sarcopenia and low MA are more likely to experience severe treatment-related toxicity to Ipi. Loss of muscle during treatment was predictive of worse survival. Treatments to increase muscle mass and influence outcome warrant further investigation. PMID- 28072767 TI - CYP3A7*1C allele is associated with reduced levels of 2-hydroxylation pathway oestrogen metabolites. AB - BACKGROUND: Endogenous sex hormones are well-established risk factors for breast cancer; the contribution of specific oestrogen metabolites (EMs) and/or ratios of specific EMs is less clear. We have previously identified a CYP3A7*1C allele that is associated with lower urinary oestrone (E1) levels in premenopausal women. The purpose of this analysis was to determine whether this allele was associated with specific pathway EMs. METHODS: We measured successfully 12 EMs in mid-follicular phase urine samples from 30 CYP3A7*1C carriers and 30 non-carriers using HPLC MS/MS. RESULTS: In addition to having lower urinary E1 levels, CYP3A7*1C carriers had significantly lower levels of four of the 2-hydroxylation pathway EMs that we measured (2-hydroxyestrone, P=1.1 * 10-12; 2-hydroxyestradiol, P=2.7 * 10-7; 2 methoxyestrone, P=1.9 * 10-12; and 2-methoxyestradiol, P=0.0009). By contrast, 16alpha-hydroxylation pathway EMs were slightly higher in carriers and significantly so for 17-epiestriol (P=0.002). CONCLUSIONS: The CYP3A7*1C allele is associated with a lower urinary E1 levels, a more pronounced reduction in 2 hydroxylation pathway EMs and a lower ratio of 2-hydroxylation:16alpha hydroxylation EMs in premenopausal women. To further characterise the association between parent oestrogens, EMs and subsequent risk of breast cancer, characterisation of additional genetic variants that influence oestrogen metabolism and large prospective studies of a broad spectrum of EMs will be required. PMID- 28072768 TI - Effect of low-dose aspirin use on survival of patients with gastrointestinal malignancies; an observational study. AB - BACKGROUND: Previous studies suggested a relationship between aspirin use and mortality reduction. The mechanism for the effect of aspirin on cancer outcomes remains unclear. The aim of this study was to evaluate aspirin use and survival in patients with gastrointestinal tract cancer. METHODS: Patients with gastrointestinal tract cancer diagnosed between 1998 and 2011 were included. The population-based Eindhoven Cancer Registry was linked to drug-dispensing data from the PHARMO Database Network. The association between aspirin use after diagnosis and overall survival was analysed using Cox regression models. RESULTS: In total, 13 715 patients were diagnosed with gastrointestinal cancer. A total of 1008 patients were identified as aspirin users, and 8278 patients were identified as nonusers. The adjusted hazard ratio for aspirin users vs nonusers was 0.52 (95% CI 0.44-0.63). A significant association between aspirin use and survival was observed for patients with oesophageal, hepatobiliary and colorectal cancer. CONCLUSIONS: Post-diagnosis use of aspirin in patients with gastrointestinal tract malignancies is associated with increased survival in cancers with different sites of origin and biology. This adds weight to the hypothesis that the anti-cancer effects of aspirin are not tumour-site specific and may be modulated through the tumour micro-environment. PMID- 28072769 TI - The impact of postdoctoral training on early careers in biomedicine. PMID- 28072770 TI - An optical probe of synaptic plasticity. PMID- 28072771 TI - Should you profit from your genome? PMID- 28072773 TI - Photosynthesis gets a boost. PMID- 28072774 TI - CAR-T's forge ahead, despite Juno deaths. PMID- 28072775 TI - BMS in microbiome immuno-oncology deal. PMID- 28072776 TI - Gut microbiome profiling tests propelled by customer demand. PMID- 28072777 TI - Pancreatic islets find a new transplant home in the omentum. PMID- 28072780 TI - Recent patents in metagenomics. PMID- 28072779 TI - Will a Trump administration let sleeping cells lie? PMID- 28072781 TI - Where are the data? PMID- 28072783 TI - After Theranos. PMID- 28072784 TI - Concerns over Cures. PMID- 28072785 TI - Mining ancient proteins for next-generation drugs. PMID- 28072786 TI - First Rounders Podcast: Jeremy Levin. PMID- 28072787 TI - Obama signs 21st Century Cures Act. PMID- 28072788 TI - CRISPR therapeutics push into human testing. PMID- 28072789 TI - Ganymed's Claudin win. PMID- 28072790 TI - Innovative academic startups 2016. PMID- 28072791 TI - First mitochondrial DNA transfer go-ahead. PMID- 28072792 TI - The rise of the ethical license. PMID- 28072793 TI - Merit-Based Incentive Payment System: Meaningful Changes in the Final Rule Brings Cautious Optimism. AB - The Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) eliminated the flawed Sustainable Growth Rate (SGR) act formula - a longstanding crucial issue of concern for health care providers and Medicare beneficiaries. MACRA also included a quality improvement program entitled, "The Merit-Based Incentive Payment System, or MIPS." The proposed rule of MIPS sought to streamline existing federal quality efforts and therefore linked 4 distinct programs into one. Three existing programs, meaningful use (MU), Physician Quality Reporting System (PQRS), value-based payment (VBP) system were merged with the addition of Clinical Improvement Activity category. The proposed rule also changed the name of MU to Advancing Care Information, or ACI. ACI contributes to 25% of composite score of the four programs, PQRS contributes 50% of the composite score, while VBP system, which deals with resource use or cost, contributes to 10% of the composite score. The newest category, Improvement Activities or IA, contributes 15% to the composite score. The proposed rule also created what it called a design incentive that drives movement to delivery system reform principles with the inclusion of Advanced Alternative Payment Models (APMs).Following the release of the proposed rule, the medical community, as well as Congress, provided substantial input to Centers for Medicare and Medicaid Services (CMS),expressing their concern. American Society of Interventional Pain Physicians (ASIPP) focused on 3 important aspects: delay the implementation, provide a 3-month performance period, and provide ability to submit meaningful quality measures in a timely and economic manner. The final rule accepted many of the comments from various organizations, including several of those specifically emphasized by ASIPP, with acceptance of 3-month reporting period, as well as the ability to submit non-MIPS measures to improve real quality and make the system meaningful. CMS also provided a mechanism for physicians to avoid penalties for non-reporting with reporting of just a single patient. In summary, CMS has provided substantial flexibility with mechanisms to avoid penalties, reporting for 90 continuous days, increasing the low volume threshold, changing the reporting burden and data thresholds and, finally, coordination between performance categories. The final rule has made MIPS more meaningful with bonuses for exceptional performance, the ability to report for 90 days, and to report on 50% of the patients in 2017 and 60% of the patients in 2018. The final rule also reduced the quality measures to 6, including only one outcome or high priority measure with elimination of cross cutting measure requirement. In addition, the final rule reduced the burden of ACI, improved the coordination of performance, reduced improvement activities burden from 60 points to 40 points, and finally improved coordination between performance categories. Multiple concerns remain regarding the reduction in scoring for quality improvement in future years, increase in proportion of MIPS scoring for resource use utilizing flawed, claims based methodology and the continuation of the disproportionate importance of ACI, an expensive program that can be onerous for providers which in many ways has not lived up to its promise. Key words: Medicare Access and CHIP Reauthorization Act of 2015, merit-based incentive payment system, quality performance measures, resource use, improvement activities, advancing care information performance category. PMID- 28072794 TI - Does Percutaneous Vertebroplasty or Balloon Kyphoplasty for Osteoporotic Vertebral Compression Fractures Increase the Incidence of New Vertebral Fractures? A Meta-Analysis. AB - BACKGROUND: Because of an aging population,osteoporotic vertebral fractures are becoming more frequent.Conservative therapy was considered the gold standard for treating osteoporotic vertebral compression fractures (OVCFs) in the past. Percutaneous vertebroplasty (PVP) or balloon kyphoplasty (BKP) as minimally invasive techniques are new treatments that are widely used for painful OVCFs. However, an increase in new vertebral compression fractures at non-treated levels following augmentation is of concern. There is no convincing evidence that new fractures are inevitable after augmentation compared to after conservative treatment, and it is still unclear whether further fractures are the consequence of augmentation or a result of the natural progression of osteoporosis. OBJECTIVE: The objective of this study was to evaluate the new-level fracture risk after PVP or BKP compared with conservative (non-operative) treatment and to determine the dominant risk factor associated with new OVCFs. STUDY DESIGN: A meta-analysis of comparative studies was performed to evaluate the incidence of new vertebral fractures between vertebral augmentation, such as vertebroplasty and kyphoplasty, and no operation. SETTING: The PubMed, ISI Web of Science, ELSEVIER ScienceDirect, and Cochrane Library databases and abstracts published in annual proceedings were systematically searched.In addition, we also retrieved data from references when titles met our inclusion criteria. METHODS: Detailed searches of a number of online databases comparing operative and non-operative groups were performed. We included randomized controlled trials,clinical controlled trials,and prospective clinical studies to provide available data. All studies were reviewed by two reviewers independently, and all the references that met our inclusion criteria were searched for additional trials, using the guidelines set by the QUOROM (Quality of Reporting of Meta-analysis) statement. RESULTS: We evaluated 12 studies encompassing 1,328 patients in total, including 768 who underwent operation with polymethylmethacrylateand 560 who received non operative treatments. For new-level vertebral fractures, our meta-analysis found no significant difference between the 2 methods, including total new fractures (P = 0.55) and adjacent fractures (P = 0.5). For pre-existing vertebral fractures, there was no significant difference between the 2 groups (operative and non operative groups) (P = 0.24). Additionally,there was no significant difference in bone mineral density, both in the lumbar (P = 0 .13) and femoral neck regions (P = 0.37), between the 2 interventions. LIMITATION: All studies we screened were published online except for unpublished articles. Moreover, only a few data sources could be extracted from the published studies.There were only 5 randomized clinical trials and 7 prospective studies that met our inclusion criteria. CONCLUSION: Vertebral augmentation techniques, such as vertebroplasty and kyphoplasty, have been widely used to treat osteoporotic vertebral fractures in order to alleviate back pain and correct the deformity, and it has been frequently reported that many new vertebral fractures occurred after this operation. Our analysis did not reveal evidence of an increased risk of fracture of vertebral bodies, especially those adjacent to the treated vertebrae, following augmentation with either method compared with conservative treatment.Key words: Vertebroplasty, kyphoplasty, new osteoporotic compression vertebral fracture, meta-analysis. PMID- 28072795 TI - Treatment Outcomes for Patients with Failed Back Surgery. AB - BACKGROUND: Failed back surgery syndrome (FBSS) is a frequently encountered disease entity following lumbar spinal surgery. Although many plausible reasons have been investigated, the exact pathophysiology remains unknown. Various medications, reoperations, interventions such as spinal cord stimulation, epidural adhesiolysis or epidural injection, exercise therapy, and psychotherapy have been suggested treatment options. However, the evidence of the clinical outcome for each treatment has not been clearly determined. OBJECTIVES: To evaluate the outcomes of each treatment modality and to present treatment guidelines for patients with FBSS. STUDY DESIGN: A systematic review of each treatment regimen in patients with FBSS. METHODS: The available literature regarding each modality for the treatment of refractory back pain or radiating pain for FBSS was reviewed. The quality assessment and the level of evidence were analyzed using the "Methodology Checklist" of SIGN (Scottish Intercollegiate Guidelines Network). Data sources included relevant English language literature identified through searches of Pubmed, EMBASE, and Cochrane library from 1980 to Feb 2016. The primary outcome measure was pain relief of back pain or radiating pain for at least 3 months. Secondary outcome measures were improvement of the patient's functional status, health-related quality of life, return to work, and reduction of opioid use. RESULTS: Twenty-three articles were finally identified and reviewed. Based on our analysis, epidural adhesiolysis showed a short-term (6 to 24 months) effect (grade A) and spinal cord stimulation showed a mid-term (2 or 3 years) effect (grade B). Epidural injections showed a short-term (up to 2 years) effect (grade C). However, other treatments were recommended as grade D or inconclusive. LIMITATIONS: The limitations of this systematic review included the rarity of relevant literature. CONCLUSIONS: Epidural adhesiolysis or spinal cord stimulation can be effective in order to control chronic back pain or leg pain due to FBSS, and its recommendation grades are A and B, respectively. Other treatments showed poor or inconclusive evidence.Key words: Failed back surgery syndrome, post spinal surgery syndrome, chronic low back pain, post lumbar surgery syndrome, epidural adhesiolysis, spinal cord stimulation, epidural injection, revision. PMID- 28072796 TI - Incidence of Spontaneous Resorption of Lumbar Disc Herniation: A Meta-Analysis. AB - BACKGROUND: Lumbar disc herniation (LDH), a common disease, is often treated conservatively, frequently resulting in spontaneous resorption of the herniated disc. The incidence of this phenomenon, however, remains unknown. OBJECTIVE: To analyze the incidence of spontaneous resorption after conservative treatment of LDH using computed tomography and magnetic resonance imaging. STUDY DESIGN: Meta analysis and systematic review of cohort studies. SETTING: The work was performed at The Suzhou Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine. METHODS: We initiated a search for the period from January 1990 to December 2015 using PubMed, Embase, and the Cochrane Library. Two independent reviewers examined the relevant reports. The references from these reports were also searched for additional trials using the criteria established in the PRISMA statement. RESULTS: Our results represent the pooled results from 11 cohort studies. The overall incidence of spontaneous resorption after LDH was 66.66% (95% CI 51% - 69%). The incidence in the United Kingdom was 82.94% (95% CI 63.77% - 102.11%). The incidence in Japan was 62.58% (95% CI 55.71% - 69.46%). LIMITATIONS: Our study was limited because there were few sources from which to extract data, either in abstracts or published studies. There were no randomized, controlled trials that met our criteria. CONCLUSIONS: The phenomenon of LDH reabsorption is well recognized. Because its overall incidence is now 66.66% according to our results, conservative treatment may become the first choice of treatment for LDH. More large-scale, double-blinded, randomized, controlled trials are necessary to study the phenomenon of spontaneous resorption of LDH.Key words: Lumbar, disc herniation, spontaneous resorption, conservative treatment, incidence, country, meta-analysis, systematic review, observational studies, study designs. PMID- 28072797 TI - Effect of Concomitant Pain Medications on Response to Pregabalin in Patients with Postherpetic Neuralgia or Spinal Cord Injury-Related Neuropathic Pain. AB - BACKGROUND: Patients with neuropathic pain (NeP) often receive combination therapy with multiple agents in the hopes of improving both pain and any comorbidities that may be present. While pregabalin is often recommended as a first-line treatment of NeP, few studies have examined the effects of concomitant medications on the efficacy of pregabalin. OBJECTIVE: To examine the effects of concomitant medications on the efficacy and safety of pregabalin for the treatment of NeP. STUDY DESIGN: Data were derived from 7 randomized placebo controlled trials of pregabalin (150, 300, 600, and flexible 150 - 600 mg/d) for the treatment of postherpetic neuralgia (PHN) and 2 randomized placebo-controlled trials for the treatment of NeP due to spinal cord injury (SCI-NeP). On each day, patients rated the severity of their pain and pain-related sleep interference (PRSI) over the previous 24 hours on a scale from 0 to 10, with higher scores indicating greater severity. Patients were also continually monitored for the occurrence of adverse events. SETTING: A pooled retrospective analyses of data from randomized clinical trials. METHODS: Changes from baseline in mean weekly pain and PRSI scores were compared between patients who received concomitant NeP medications and patients who did not receive concomitant NeP medications. Results of these comparisons are presented separately for the PHN (through 4, 8, and 12 weeks) and SCI-NeP (through 12 weeks) cohorts. Common adverse events are also presented for each treatment group. RESULTS: Pregabalin significantly improved both pain and PRSI scores relative to placebo at most dose levels and time points examined. Notably, little difference was observed in the extent of therapeutic response to pregabalin between patients who received concomitant NeP medications and patients who did not receive concomitant NeP medications. Additionally, the profile of treatment-emergent adverse events appeared to be largely unaffected by the use of concomitant NeP medications in the pooled patient population. LIMITATIONS: Our analysis is limited in that the original trials of pregabalin were not powered to examine the effects of concomitant NeP medications. CONCLUSIONS: The data presented here demonstrate that therapeutic response to pregabalin and the occurrence of adverse events in patients with NeP are generally unaffected by the concurrent use of other NeP medications.Trial Registration numbers: NCT00159666; NCT00301223; NCT00407745Key words: Pregabalin, neuropathic pain, pain-related sleep interference, concomitant medications, postherpetic neuralgia, spinal cord injury, efficacy, safety. PMID- 28072798 TI - Reliability and Safety of Contra-Lateral Oblique View for Interlaminar Epidural Needle Placement. AB - Cord trauma is a risk with a cervical and thoracic interlaminar epidural approach to the epidural space. Intermittent lateral fluoroscopic imaging to detect needle depth is often cumbersome and may be difficult to interpret. In comparison, the contra-lateral oblique (CLO) fluoroscopic view is efficient and easy to interpret. However, the in vivo reliability and safety of this technique has not been formally investigated.The senior author collected fluoroscopic images on 278 consecutive patients undergoing an interlaminar epidural block at the T1-T2 level performed using a 17 gauge Tuohy needle. Before catheter placement, anterior posterior (AP) and CLO fluoroscopic images were saved with the needle at the ligamentum flavum and the needle just through the ligamentum flavum.We randomly selected the images of 40 cases that included the paired CLO images (total 80 images) documenting the views at and through the ligamentum flavum. Three interventionalists were asked to review, in a blinded fashion, the randomly selected, paired CLO images and to score each image, recording whether the 17 gauge needle was in or out of the epidural space to determine the accuracy and reliability of this technique.There was a 97.5%, 95%, and 93.8% agreement between each reviewing physician and the senior author resulting in a correlation using the Kappa statistic value of 0.950, 0.875, and 0.874, respectively (P < 0.001). The 3 reviewing physicians disagreed with the senior author's correct answer in 2.5%, 5%, and 6.2%, respectively, however, the disagreement occurred primarily because of poor image quality. Agreement between the 3 reviewing physicians was 93.8%, 96.3%, and 90%, with a Kappa value of 0.875, 0.924, and 0.799, respectively (P < 0.001). There was 100% technical success in the 278 case series without "wet taps," provocation of pain during entry, or any other immediate post procedural complication.We conclude the CLO view provides an efficient and reliable method to visualize needle tip depth in relation to the epidural space. The close inter-observer agreement was possible with minimal physician instruction.Key words: Cervical interlaminar, cervical epidural, contra-lateral oblique, fluoroscopic imaging. PMID- 28072799 TI - Percutaneous Endoscopic Lumbar Discectomy for Highly Migrated Lumbar Disc Herniation. AB - BACKGROUND: Percutaneous endoscopic lumbar discectomy (PELD) has been growing in popularity for the treatment of lumbar disc herniation (LDH) due to its irreplaceable advantages over conventional open surgery. Compared with common lumbar disc herniations, discectomy of highly migrated LDH by PELD is known to be very difficult. Highly migrated lumbar disc herniation has long been a challenge for its specific characteristics. Three approaches for PELD have been applied to access a highly migrated LDH, including an interlaminar approach (IL), transforaminal approach (TF), and contralateral transforaminal approach (CTF). However, none of the existing research has systematically described the selection of the most appropriate procedure from the 3 approaches or the individualization of an operative procedure in different cases. OBJECTIVES: The purpose of this study was to present a detailed surgical approach selection and individualization of procedure in the treatment of highly migrated LDH with PELD. We also mean to compare the outcomes of patients with highly migrated LDH treated with PELD by the 3 approaches. STUDY DESIGN: Single-center retrospective observational study. SETTING: An interventional pain management practice, a medical center, major metropolitan city, China. METHODS: In our retrospective analysis between March 2011 and March 2013, 73 patients with single level highly migrated LDH received PELD. Clinical outcomes were assessed with the visual analogue scale (VAS) score, the modified MacNab criteria, and the Oswestry disability index (ODI). Relevant data such as operation duration and fluoroscopy frequency of the 3 operative approaches were recorded. RESULTS: The mean operating time of IL was 56 minutes, compared with 64 minutes for TF and 112 minutes for CTF. The mean intraoperative fluoroscopy times were 5.5 for IL, 9.7 for TF, and 14.6 for CTF. In each group, the mean VAS and ODI after surgery and 3 months after surgery improved dramatically compared with preoperative counterparts. However, the difference between postoperative results and the results 3 months after surgery was not significant (P > 0.05). The overall excellent rate was 90.4% according to the modified MacNab criteria; there was no significant statistical difference between the 3 operative routes. Operative complications occurred in 3 patients (2 after IL and one after CTF, 3 of 73, 4.1%). LIMITATIONS: This study is limited by its sample size. CONCLUSION: In our research, PELD with all 3 approaches was similarly effective to highly migrated disc herniation. The CTF approach required the longest operation duration and the most intraoperative times. On the contrary, the least operation time and radiographfrequency was required with the IL approach. In addition, we came to a conclusion of surgery approach selection when it comes to varied HM-LDH. Key words: Highly migrated, lumbar disc herniation, percutaneous endoscopic lumbar discectomy, minimally invasive treatment. PMID- 28072800 TI - Modified Percutaneous Lumbar Foraminoplasty and Percutaneous Endoscopic Lumbar Discectomy: Instrument Design, Technique Notes, and 5 Years Follow-up. AB - BACKGROUND: Conventional percutaneous endoscopic lumbar discectomy (PELD) with an "inside-outside" technique has 4.3% - 10.3% surgical failure rate, especially in central herniated discs (HDs), migrated HDs, and axillary type HDs. PELD with foraminoplasty has been used for complex HDs. Percutaneous lumbar foraminoplasty (PLF), which is performed with a trephine or bone reamer introduced over a guidewire without a protective working cannula in the original Tessys technique, can quickly cut the hypertrophied bony structure under fluoroscopic guidance, and risk injury to the exiting and traversing nerve roots. STUDY DESIGN: A prospective cohort study. SETTING: Hospital and outpatient surgical center. OBJECTIVE: To evaluate the outcome and safety of modified PLF-PELD with a specially designed instrument for complex uncontained lumbar HDs. METHOD: From April of 2007 to April of 2009, 148 patients with uncontained lumbar HDs were treated with modified PLF-PELD. Magnetic resonance imaging (MRI) checkup was performed the next morning after the operation. Outcomes of symptoms were evaluated by follow-up interviews at 3 months, 6 months, one year, and 5 years after surgery. Low back pain and leg pain were measured by visual analog scale (VAS) score (1 - 100). Functional outcomes were assessed by using the Oswestry Disability Index (ODI) and modified MacNab criteria. RESULTS: Follow-up data were obtained from 134 cases, including 14 cases on L3-4, 78 cases on L4-5, and 42 cases on L5-S1. One hundred-eight cases were prolapse type, while 26 cases were sequestration type. Pre-operative symptoms and deficits included nerve root dermatome hypoesthesia in 98 patients (73%), nerve root myotome muscle weakness in 32 patients (23%), and weakening or disappearance of tendon reflex in 43 patients (32%). No case required conversion to an open procedure during the surgery. Low back pain and leg pain were significantly relieved immediately after surgery in all patients. MRI examination showed adequate removal of HD in all patients. VAS scores and ODI values were significantly lower at all time points after surgery than before surgery. The percentage of pain relief in leg pain was significantly higher than that in low back pain (P < 0.01). But there was no significant correlation between duration of the preoperative symptoms and the percentage of pain relief. MacNab scores at 5 years after surgery were obtained from 134 patients. Seventy-five cases were rated "excellent"; 49 were rated "good," Five patients experienced heavier low back pain, thus being classified as "fair." Five cases with recurrence were rated "poor." Preoperative and postoperative (5 years follow-up) related nerve root function status was compared. Sensation and muscle strength recovered significantly (P < 0.01), while tendon reflex was not changed (P = 0.782). No patients had infections. Five patients were complicated with dysesthesia in distribution of the exiting nerve that was all operated at L5-S1. Complaints were reduced one week after treatment with medium frequency pulse electrotherapy. Five cases required a revision surgery after recurrence. LIMITATIONS: This is an observational clinical case series study without comparison. CONCLUSION: Modified PLF-PELD with a specially designed instrument is a less invasive, effective and safe surgery for complex uncontained lumbar DH.Key words: Lumbar disc herniation, minimally invasive treatment, foraminoplasty, percutaneous endoscopic lumbar discectomy. PMID- 28072801 TI - Vitamin D Supplementation in Patients with Chronic Low Back Pain: An Open Label, Single Arm Clinical Trial. AB - BACKGROUND: Vitamin-D deficiency may possibly be related to chronic low back pain (CLBP). OBJECTIVE: The study is aimed to assess the impact of vitamin-D supplementation on pain intensity, functional disability, and vitamin-D levels in patients with CLBP. STUDY DESIGN: Single arm open-label study. SETTING: Outpatient pain clinic of a tertiary care hospital. METHODS: Sixty-eight eligible patients (CLBP for = 3 months, pain score = 50 on visual analogue scale (VAS) and plasma 25-Hydroxyvitamin D3 levels < 30 ng/mL) were enrolled. Patients were supplemented with 60,000 IU of oral vitamin-D3 given every week for 8 weeks. Efficacy parameters included pain intensity and functional disability measured by VAS and modified Oswestry disability questionnaire (MODQ) scores at baseline, 2, 3, and 6 months post-supplementation. Plasma 25(OH) D3 levels were measured at baseline and 8 weeks. RESULTS: Baseline mean (SD) vitamin-D levels were 12.8 (5.73) ng/mL and increased to 36.07 (12.51) post supplementation (P < 0.01). Forty-five (66%) patients attained normal levels (> 29 ng/mL) post supplementation. Significant reduction in VAS was observed at 2, 3, and 6 months [61 (19), 45 (19), 36 (18)] as compared to 81 (19) at baseline (P = 0.001 at all time intervals). A significant improvement in the functional ability was also observed at 2, 3, and 6 months [36 (12), 31 (13), and 26 (10)] as compared to baseline 45 (16) (P = 0.001 at all-time intervals). CONCLUSION: Vitamin-D supplementation in deficient CLBP patients may lead to improvement in pain intensity and functional ability apart from normalization of the levels. Future controlled clinical trials are required to confirm the hypothesis.Key words: Vitamin D, deficiency, screening, low back pain, chronic, supplementation. PMID- 28072802 TI - Efficacy of Adjuvant 10% Hypertonic Saline in Transforaminal Epidural Steroid Injection: A Retrospective Analysis. AB - BACKGROUND: Chronic lower back pain with or without radiculopathy represents an important medical, social, and economic problem. Many treatment modalities and techniques, including surgery and epidural administration of steroids, have been used to manage this pain. Hypertonic saline, which has been used as an adjunct to percutaneous epidural adhesiolysis, can also be injected via a transforaminal approach in expectation of longer-lasting effects. OBJECTIVES: This study aimed to determine the effect of adding hypertonic saline to conventional transforaminal epidural steroid injections (TFEI) to provide pain relief for chronic radiculopathy patients. STUDY DESIGN: A retrospective study. SETTING: Pain clinic of a university hospital. METHODS: Between January 2010 and December 2013, the medical records of 246 patients (94 in the hypertonic group, 153 in the control group) who received transforaminal epidural block were reviewed and analyzed. The hypertonic group received 10% sodium chloride solution added to lidocaine, triamcinolone, and hyaluronidase. Outcomes on pain reduction were measured using a numerical rating scale (NRS) and the responder rate at baseline, one, 3, and 6 months after procedure. RESULTS: The estimated difference in NRS scores from baseline throughout a 6-month follow-up period in the hypertonic group were significantly higher (P = 0.0003). The proportion of substantial responders (41.9% vs. 34.6% at one month, 40.9% vs. 26.8% at 3 months, and 33.3% vs. 14.4% at 6 months, respectively, P = 0.0058) and substantial/moderate responders (71.0% vs. 58.8% at one month, 65.6% vs. 40.4% at 3 months, and 48.4% vs. 20.3% at 6 months, respectively, P < 0.0001) were significantly higher in the hypertonic group. The Oswestry disability index (ODI) was not different between the groups (P = 0.2697). LIMITATIONS: Retrospective design without a control group. CONCLUSIONS: Hypertonic saline provides more superior and longer lasting pain relieving effects when added to TFEIs.Key words: Back pain, epidural injections, epidural steroids, hypertonic saline, lumbar, radiculopathy, transforaminal. PMID- 28072803 TI - Neural Correlates of Maladaptive Pain Behavior in Chronic Neck Pain - A Single Case Control fMRI Study. AB - Chronic neck pain patients display functional impairments like decreased range of motion, decreased strength, and reduced sensorimotor function. In patients without structural damage, the reason for the persistence of pain is not well understood. Therefore, it is assumed that in chronic pain states, memory processes play an important role. We have now detected and tested a patient that might help us to better understand the neural correlates of maladaptive pain expectation/memory. This patient displays chronic neck pain and restricted unilateral motion of the cervical spine to the left. However, when the patient is distracted, she can perform head rotations without experiencing pain and without restricting her range of movement. Based on this observation, we asked her to imagine movements shown in a video: conscious, non-distracted head rotations (pain-provoking) versus distracted head rotations (pain-free) and compared these results with an age and gender matched control volunteer. Functional magnetic resonance imaging (fMRI) showed distinct brain activation patterns that depended on the side of rotation (pain-free versus painful side) and the kind of movement (distracted versus non-distracted head rotation). Interestingly, brain areas related to the processing of pain such as primary somatosensory cortex, thalamus, insula, anterior cingulate cortex, primary motor cortex, supplementary motor area, prefrontal cortex, and posterior cingulate cortex were always more strongly activated in the non-distracted condition and when turning to the left. The age and gender matched control volunteer displayed no comparable activation of pain centers. In the patient, maladaptive pain behavior and the activity of pain related brain areas during imagined head rotations were task-specific, indicating that the activation and/or recall of pain memories were context-dependent. These findings are important not only to improve the understanding of the neural organization of maladaptive pain behavior but also to reconsider clinical evaluation and treatment strategies. The current results therefore suggest that treatment strategies have to take into account and exploit the context in which the movement is performed.Key words: Maladaptive pain behavior, pain memory, brain plasticity, motor control, neck pain, fMRI, action observation, motor imagery. PMID- 28072804 TI - Multidisciplinary Care of Unruptured Brain Arteriovenous Malformations to Improve Symptomatic Headache and the Onset, Progression, and Outcomes of Unruptured Brain Arteriovenous Malformations. AB - BACKGROUND: Symptomatic headaches attributed to unruptured brain arteriovenous malformations (ubAVMs) are very common and affect patients' quality life, but multidisciplinary care of ubAVMs to improve symptomatic headache remains unclear. OBJECTIVE: The objective is to identify the features of symptomatic headaches, and to obtain headache outcomes following multidisciplinary care of ubAVMs, as well as provide background on the natural history of ubAVMs. STUDY DESIGN: The features of symptomatic headaches and headache outcomes were analyzed in a large cohort of cases after multidisciplinary care of ubAVMs. We have also provided information on the natural history of ubAVMs. SETTING: This study was conducted at the Department of Neurosurgery of Zhujiang Hospital where 336 patients from 1998 to 2014 were reviewed by a multidiscipline team. Only 124 patients were eligible. METHODS: The demographics, clinical features, imaging features, and headache details of eligible patients were reviewed. An 11-point pain scale score was used to assess symptomatic headaches before, during, and after treatment. The headache outcomes, death or stroke, and adverse functional outcomes (modified Rankin Scale score = 2, mRS = 2) were assessed following multidisciplinary care of ubAVMs. RESULTS: Twenty-three (56.1%) of 41 patients had migraine-like headaches located in occipital lobe (P < 0.001), while forty (63.5%) of 63 patients had tension-type-like headaches located in frontotemporal lobe (P < 0.001). For patients with tension-type-like or all types of headache, headache improvement differed between the multidisciplinary group and medical group (87.8% vs. 31.8%, P < 0.001; 85.7% vs. 40.7%, P < 0.001). The risk of death or stroke did not differ between multidisciplinary group and medical group (P = 0.393), whereas the risk of adverse functional outcome (mRS = 2) differed significantly by long-time follow-up (23.0% vs.10.0%, P = 0.022). LIMITATIONS: This study provides the initial experience to support multidisciplinary care for ubAVMs to improve symptomatic headaches and patients' quality life, but based on the retrospective study with inherent limitations, larger samples and multi-center trials are needed on this interesting issue. CONCLUSIONS: Occipital ubAVM is more likely to present with migraine-like headache, while frontotemporal ubAVM tends to present with tension-type-like headache. The effectiveness of multidisciplinary care for ubAVM to improve headache has been shown, but the natural history of ubAVM patients with headache remains unclear.Key Words: Unruptured brain arteriovenous malformations, headache, headache improvement, natural history. PMID- 28072805 TI - Anatomical Variants of the Pudendal Nerve Observed during a Transgluteal Surgical Approach in a Population of Patients with Pudendal Neuralgia. AB - BACKGROUND: Several studies have described the course and anatomical relations of the pudendal nerve. Several surgical nerve decompression techniques have been described, but only the transgluteal approach has been validated by a prospective randomized clinical trial. The purpose of this study was to describe the course of the nerve and its variants in a population of patients with pudendal neuralgia in order to guide the surgeon in the choice of surgical approach for pudendal nerve decompression. OBJECTIVES: In order to support the choice of the transgluteal approach, used in our institution, we studied the exact topography, anatomical relations, and zones of entrapment of the pudendal nerve in a cohort of operated patients. STUDY DESIGN: Observational study. SETTING: University hospital. METHODS: One hundred patients underwent unilateral or bilateral nerve decompression performed by a single operator via a transgluteal approach. All patients satisfied the Nantes criteria for pudendal neuralgia. The operator meticulously recorded zones of entrapment, anatomical variants of the course of the nerve, and the appearance of the nerve in the operative report. RESULTS: One hundred patients and 145 nerves were operated consecutively. Compression of at least one segment of the pudendal nerve (infrapiriform foramen, ischial spine, and Alcock's canal) was observed in 95 patients. The zone of entrapment was situated at the ischial spine between the sacrospinous ligament (or ischial spine) and the sacrotuberous ligament in 74% of patients.Anatomical variants were observed in 13 patients and 15 nerves. Seven patients presented an abnormal transligamentous course of the nerve (sacrotuberous or sacrospinous). A perineal branch of the fourth sacral nerve to the external anal sphincter was identified in 7 patients. In this population of patients with pudendal neuralgia, the pudendal nerve was stenotic in 27% of cases, associated with an extensive venous plexus that could make surgery more difficult in 25% of cases, and the nerve had an inflammatory appearance in 24% of cases. LIMITATIONS: We obviously cannot be sure that the anatomical variants identified in this study can be extrapolated to the general population, as our study population was composed of patients experiencing perineal pain due to pudendal nerve entrapment and their pain could possibly be related to these anatomical variants, especially a transligamentous course of the pudendal nerve. The absence of other prospective randomized clinical trials evaluating other surgical approaches also prevents comparison of these results with those of other surgical approaches. CONCLUSIONS: This is the first study to describe the surgical anatomy of the pudendal nerve in a population of patients with pudendal neuralgia. In more than 70% of cases, pudendal nerve entrapment was situated in the space between the sacrospinous ligament and the sacrotuberous ligament. Anatomical variants of the pudendal nerve were also observed in 13% of patients, sometimes with a transligamentous course of the nerve. In the light of these results, we believe that a transgluteal approach is the most suitable surgical approach for safe pudendal nerve decompression by allowing constant visual control of the nerve.Key words: Surgical, operative technique, pudendal, neuralgia, transgluteal approach. PMID- 28072806 TI - Endoscopic Spine Surgery: Distance Patients Will Travel for Minimally Invasive Spine Surgery. AB - BACKGROUND: Transforaminal lumbar endoscopic discectomy is a minimally invasive spine surgery procedure performed principally for the treatment of lumbar herniated discs. Endoscopic spine surgeons around the world have noted how far patients will travel to undergo this minimally invasive spine surgery, but the actual distance patients travel has never been investigated. OBJECTIVE: We present here our analysis of how far patients will travel for endoscopic spine surgery by studying the referral patterns of patients to 3 centers in 3 different countries. STUDY DESIGN: Retrospective chart review of de-identified patient data was performed to analyze the distance patients travel for spine surgery. METHODS: Patient demographic data was analyzed for patients undergoing transforaminal lumbar endoscopic discectomy procedures over the same 8 month period in 2015 at centers in the United States (U.S.), Netherlands, and Germany. RESULTS: Travel distances for patients were determined for 327 patients. The average distance traveled for the U.S. center was 91 miles, the Dutch center was 287 miles, and the German center was 103 miles. For the U.S. center 16% of patients traveled out of state for surgery and for the European centers combined, 4% of patients traveled out of the country for surgery. LIMITATIONS: The period of data analyzed was less than one year and the data collected was analyzed retrospectively. CONCLUSIONS: Quality metrics in health care tend to be focused on how health care is delivered. Another health care metric that focuses more on what patients desire is presented here: how far patients will travel for innovative spine care.Key words: Endoscopic spine surgery, transforaminal, minimally invasive, travel, lumbar disc herniation. PMID- 28072807 TI - Occipital Nerve Stimulation for Refractory Chronic Migraine: Results of a Long Term Prospective Study. AB - BACKGROUND: Refractory chronic migraine affects approximately 4% of the population worldwide and results in severe pain, lifestyle limitations, and decreased quality of life. Occipital nerve stimulation (ONS) refers to the electric stimulation of the distal branches of greater and lesser occipital nerves; the surgical technique has previously been described and has demonstrated efficacy in the treatment of a wide variety of headache disorders. OBJECTIVES: The aim of this study is to evaluate the long-term efficacy and tolerability of ONS for medically intractable chronic migraine. STUDY DESIGN: Prospective, long term, open-label, uncontrolled observational study. SETTING: Single public university hospital. METHODS: Patients who met the International Headache Society criteria for chronic migraine, all of them having been previously treated with other therapeutic alternatives, and who met all inclusion and exclusion criteria for neurostimulation, received the implantation of an ONS system after a positive psychological evaluation and a positive response to a preliminary occipital nerve blockage. The implantation was performed in 2 phases: a 10 day trial with implanted occipital leads connected to an external stimulator and, if more than 50% pain relief was obtained, permanent pulse generator implantation and connection to the previously implanted leads. After the surgery, the patients were thoroughly evaluated annually using different scales: pain Visual Analogue Scale (VAS), number of migraine attacks per month, sleep quality, functionality in social and labor activities, reduction in pain medication, patient satisfaction, tolerability, and reasons for termination. The average follow-up time was 9.4 +/- 6.1 years, and 31 patients completed a 7-year follow-up period. RESULTS: Thirty-seven patients were enrolled and classified according to the location and quality of their pain, accompanying symptoms, work status, and psychological effects. Substantial pain reduction was obtained in most patients, and the VAS decreased by 4.9 +/- 2.0 points. These results remained stable over the follow-up period. Five of the 35 permanently implanted patients with migraine attacks at baseline were free from these attacks at their last visits, whereas the pain severity decreased 3.8 +/- 2.5 (according to the VAS) in the remaining patients. Seven of the 35 permanent implanted devices were definitively removed: 2 devices because of treatment inefficacy, and 5 devices because the patients were asymptomatic and considered to be cured from their pain, even with the stimulation off. Systemic side effects were not observed. LIMITATIONS: Limitations of the current study include its uncontrolled and open-label design. Additionally, not all patients completed the 7-year follow-up period. CONCLUSIONS: We consider that the trigemino-cervical autonomous and cervical connection may explain why ONS might relieve chronic migraine pain, but this is just a theoretical explanation which should be demonstrated in future studies. The results achieved in this study suggest that ONS may provide long-term benefits for patients with medically intractable chronic migraine. These outcomes are slightly better than previous reports and were maintained over the 7-year follow-up. We believe that an accurate selection of patients, realization of diagnostic occipital nerve blocks, psychological evaluations, rigorous surgical technique, and appropriate parameter programming helped us achieve these outcomes. Key words: Refractory chronic migraine, headache, occipital nerve stimulatino, peripheral nerve stimulation, occipital nerve block. PMID- 28072808 TI - Use of High-Concentration Capsaicin Patch for the Treatment of Pelvic Pain: Observational Study of 60 Inpatients. AB - BACKGROUND: Chronic pelvic, perineal and gluteal neuralgia is often experienced in a similar way to neuropathic pain, in the territories of four nerves: ilio inguinal, pudendal, inferior cluneal and posterior gluteal nerves. These pains are often refractory to medical treatment based on the use of systemic molecules with disabling adverse effects and surgical procedure may be necessary. OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of treatment with a high-concentration capsaicin patch in these indications. STUDY DESIGN: This study was prospective, nonrandomized, and observational. SETTING: Federative Center of Pelvi-Perineology in the University Hospital of Nantes, France. METHODS: Sixty patients with pelvic neuralgia were treated with high concentration capsaicin patch. The primary endpoint was Patient Global Impression of Change (PGIC) and secondary endpoints included pain intensity on a Numerical Rating Scale (NRS), maximum sitting duration at the end of the day, Medication Consumption Score (MQS), and patient global improvement (from -100% to + 100%). RESULTS: Twenty four percent of the 60 patients included in the study declared that they felt "very much improved" or "much improved" (PGIC = 1 or 2) and these patients reported an average 58% improvement and a 3.4-point reduction on the NRS. Among the "good responder" patients, patients with coccygodynia appear to obtain the bestresults, as 37% of these patients declared that they were much improved with an average 63% improvement No serious adverse effects were observed and treatment was well tolerated. LIMITATION: This study is limited by its relatively small sample size and non-randomized study. CONCLUSION: These results suggest the value of high-concentration capsaicin 8% patch in the treatment strategy for patients with chronic pelvic, perineal and gluteal neuralgia. This treatment would be particularly indicated in the management of coccygodynia.Key words: Pelvic pain, neuropathic pain, pudendal nerve, ilio-inguinal nerve, inferior cluneal nerve, posterior gluteal nerve, capsaicin, capsaicin patch, coccygodynia. PMID- 28072809 TI - Optimal Angle of Contralateral Oblique View in Cervical Interlaminar Epidural Injection Depending on the Needle Tip Position. AB - BACKGROUND: Chronic neck and upper extremity pain associated with cervical origin is common, and cervical interlaminar epidural steroid injections (CILESIs) are frequently used to manage the symptoms of cervical spinal disorders. However, CILESIs are associated with risks such as dural puncture and cord injury. OBJECTIVES: We aimed to determine the optimal needle tip visualization, in order to minimize CILESIs-induced complications. STUDY DESIGN: Retrospective observational study. SETTING: The single center study in Seoul, Republic of Korea. METHODS: Participants were 312 adults with neck or upper extremity pain caused by cervical lesion such as cervical herniated nucleus pulposus (HNPs). They underwent magnetic resonance imaging (MRI). Patients with severe cervical spinal stenosis, prior posterior cervical spine surgery, or other anatomical abnormalities of the vertebral laminae were excluded from the study. By using axial T2-weighted spin-echo MRI, we defined the area between the spinous processes as the anterior posterior zone 1 (APZ1), and the area lateral to the spinous processes as the anterior posterior zone 2 (APZ2). Line 1 was drawn along the ventral margin of lamina that confined APZ1, and line 2 was similarly drawn in order to define APZ2. The angles between the midsagittal line and lines 1 and 2 were defined as angle 1 and angle 2, respectively. Angles were measured at the C5-6, C6-7, and C7-T1 levels, on both right and left sides at each level. RESULTS: Angle 1 values (in degrees) at right C5-6, left C5-6, right C6-7, left C6-7, right C7-T1, and left C7-T1 were 62.54 +/- 10.52, 64.34 +/- 9.86, 62.03 +/- 10.27, 62.87 +/- 10.64, 61.64 +/- 11.0, and 62.58 +/- 10.83, respectively. Angle 2 values at right C5-6, left C5-6, right C6-7, left C6-7, right C7-T1, and left C7-T1 were 50.44 +/- 6.84, 50.77 +/- 7.00, 49.15 +/- 6.07, 49.89 +/- 6.45, 50.84 +/- 6.68, and 50.24 +/- 6.60, respectively. There were significant differences between angles 1 and 2 at each level. LIMITATIONS: This study is a retrospective review and did not employ controls, blinding, or randomization. Additionally, the optimal CLO angles for CILESIs and cervicothoracic interlaminar epidural steroid injections (CTILESIs) have not been assessed in clinical studies. Another limitation is that we divided lamina into only APZ1 and APZ2. CONCLUSIONS: During CILESIs, a contralateral oblique (CLO) view at 60 degrees is superior to other angles for visualizing the epidural space when the needle tip is placed in the interlaminar space and within the spinous processes margin. When the needle tip is placed in the interlaminar space and lateral to the spinous processes, a CLO view at 50 degrees is most appropriate.Institutional Review Board (IRB) approval number: S2016-0390-0001Key words: Chronic neck pain, chronic upper extremity pain, cervical epidural injections, cervical interlaminar steroid injections, steroid, needle tip position, needle tip visualization, fluoroscopy, complication, contralateral oblique view. PMID- 28072810 TI - High Frequency Spinal Cord Stimulation for Complex Regional Pain Syndrome: A Case Report. AB - Complex regional pain syndrome (CRPS) is a chronic, debilitating, neuropathic pain condition which is often misdiagnosed, difficult to manage, and lacks proven methods for remission. Most available methods provide some relief to a small percentage of patients. Recent FDA approval and superiority of the Nevro Senza 10 kHz high frequency (HF10) spinal cord stimulation (SCS) therapy over traditional low-frequency spinal cord stimulation for treatment of chronic back and leg pain may provide a new interventional therapeutic option for patients suffering from CRPS. We provide a case report of a 53-year-old Caucasian woman who suffered with CRPS in the right knee and thigh for over 7 years. Implantation of the HF10 device provided over 75% relief of pain, erythema, heat, swelling, and tissue necrosis to the entire region within 1 month of treatment. Because the HP10 therapy provides pain relief without paresthesia typical of traditional low frequency, this system may provide relief for patients suffering from chronic pain.Key words: Complex regional pain syndrome, spinal cord stimulation, Nevro Senza HF10, erythema, knee, thigh. PMID- 28072811 TI - Evaluation of the Ototoxicity Potential of Once-Daily, Single-Entity Hydrocodone in Patients with Chronic Pain: Results of Two Phase-3 Clinical Studies. AB - BACKGROUND: Use/misuse of the opioid combination hydrocodone-acetaminophen has been associated with permanent hearing loss. Although reports have been rare, this potential effect can have significant detrimental effect on patients' overall quality of life. To date, the ototoxic effect of hydrocodone alone has not been systematically investigated. OBJECTIVE: In this report, we aimed to evaluate the potential ototoxicity of a novel, single-entity, once-daily, extended-release hydrocodone tablet (Hysingla(r) ER; HYD). STUDY DESIGN: Clinical study. SETTING: Audiology clinics in US. METHODS: Results from 1207 patients in two phase 3 clinical studies were evaluated: A placebo-controlled study with an enriched enrollment, randomized withdrawal design in patients with chronic low back pain, and an open-label, long-term, safety study in patients with chronic nonmalignant and non-neuropathic pain. Comprehensive audiologic assessments (comprising pure-tone air-conduction audiometry in the conventional [0.25-8 kHz] and ultra-high [10-16 kHz] frequencies, pure-tone bone-conduction audiometry, tympanometry, speech reception thresholds, and word recognition) were conducted at baseline and end-of-studies; air-conduction audiometry was conducted periodically during the studies. All audiologic assessments were performed in audiology clinics in the United States by licensed audiologists. The primary endpoint was changes from baseline in pure-tone air-conduction thresholds in the conventional frequencies during the studies. These trials are registered with ClinicalTrials.gov, identifiers NCT01400139 and NCT01452529. RESULTS: During the studies, mean changes from baseline in air-conduction thresholds were clinically unremarkable. Bidirectional variability across all test frequencies was observed; 82% of patients did not experience significant threshold changes during the studies, 7% had potential hearing decrement, and 10% experienced hearing sensitivity improvement. No notable differences were observed between patients receiving HYD and placebo or between different HYD doses. CONCLUSION: No ototoxic signal was observed for single-entity hydrocodone tablets at the dosages and treatment durations investigated. Key words: Audiologic monitoring, clinical trials, hydrocodone, opioids, ototoxicity monitoring, sensorineural hearing loss. PMID- 28072812 TI - Is Kratom the New 'Legal High' on the Block?: The Case of an Emerging Opioid Receptor Agonist with Substance Abuse Potential. AB - Kratom is an unscheduled opioid receptor agonist that comes in the form of dietary supplements currently being abused by chronic pain patients on prescription opioids. Active alkaloids isolated from kratom such as mitragynine and 7-hydroxymitragynine are thought to act on mu- and delta-opioid receptors as well as alpha-2 adrenergic and 5-HT2A receptors. Animal studies suggest that kratom may be more potent than morphine. Consequently, kratom consumption produces analgesic and euphoric feelings among users. In particular, some chronic pain patients on opioids take kratom to counteract the effects of opioid withdrawal. Although the Food and Drug Administration has banned its use as a dietary supplement, kratom continues to be widely available and easily accessible on the Internet at much less expensive rates than some opioid replacement therapies like buprenorphine. There are no federal regulations monitoring the sale and distribution of this drug, yet kratom has been associated with severe signs and symptoms such as hallucinations, delusions, depressions, myalgias, chills, nausea/vomiting, respiratory hepatoxicity, seizures, coma, and death. A search of the pain literature shows past research has not described the use and potential deleterious effects of this drug. Many pain physicians are not familiar with kratom and as providers who take care of high-risk chronic pain patients using prescribed opioids, knowledge of current unregulated opioid receptor agonists with abuse potential is of paramount importance. The goal of this article is to introduce kratom to pain specialists and to spur a conversation on how pain physicians may take the lead to help curb the opioid abuse and overdose epidemic. Further studies may be required to help better understand the clinical and long-term effects of kratom use among chronic pain patients.Key words: Opioid receptor agonist, Kratom, Mitragynine, opioid overdose, chronic pain, substance abuse. PMID- 28072813 TI - A Case Report on Red Ear Syndrome with Tinnitus Successfully Treated with Transcranial Random Noise Stimulation. AB - BACKGROUND: The red ear syndrome represents a rare symptom complex consisting of auricular erythema associated with painful and burning sensations. It has been described in combination with tinnitus rarely. It has been hypothesized to be etiologically related to altered trigeminal afferent input, temporomandibular disorders, and thalamic dysfunction. OBJECTIVES: The initial objective of applying transcranial random noise stimulation (tRNS) in a case of red ear syndrome in combination with tinnitus was the alleviation of the phantom sounds. STUDY DESIGN: This is a case report on the successful treatment of red ear syndrome with tinnitus by means of transcranial random noise stimulation (tRNS) and a short review on the published cases of this condition. SETTING: We present the case of a 50-year-old woman reporting a simultaneous onset of constant left sided tinnitus and feelings of warmth accompanied by an intermittent stabbing and/or oppressive pain stretching from the ipsilateral ear to the head/neck/shoulder region, occasionally accompanied by nausea/vomiting and dizziness. After failure of pharmacological treatment attempts, either because of lacking clinical effects (gabapentin, zolmitriptan, and indomethacin) or because of adverse reactions (pregabaline), the patient was offered an experimental neuromodulatory treatment with bitemporal tRNS primarily targeting the tinnitus complaints of the patient. METHODS: tRNS was conducted in 2 - 3 day sessions (stimulation site: bilateral temporal cortex/2.0 mA/10 s on-and-off-ramp/offset 0 mA/20 min/random frequencies 101 - 640 Hz / NeuroConn Eldith DC-Stimulator plus). RESULTS: In 3 consecutive pain attacks repeated sessions of tRNS resulted in substantial alleviation of pain intensity and a prolongation of the interval between attacks. This was an expected finding as the proposed tRNS treatment was initially offered to the patient aiming at an alleviation of the tinnitus complaints (which remained unaffected by tRNS). LIMITATIONS: The reported data derive from compassionate use treatment in one single patient. Application of a sham condition would have been desirable, but is not possible in the context of compassionate use treatment. Nevertheless, we would consider it rather unlikely that the reported effects are purely unspecific as the patient did exclusively report symptom alleviation of pain-related parameters without affecting the tinnitus. CONCLUSIONS: This case report demonstrates the feasibility and therapeutic potential of applying neuromodulatory treatment approaches in red ear syndrome, a rare form of trigemino-autonomal headache. Therefore, it deserves detailed observation in clinical routine applications as well as controlled trials further investigating its neurobiological effects. Key words: Red ear syndrome, pain, trigemino-autonomal headache, chronic tinnitus, transcranial electrical stimulation, random noise stimulation. PMID- 28072814 TI - Transarterial Embolization Followed by Percutaneous Vertebroplasty in Treating Vertebral Metastases with Paravetebral Extension. PMID- 28072815 TI - Author's Reply to the Letter to Editor, "Transarterial Embolization Followed by Percutaneous Vertebroplasty in Treating Vertebral Metastases with Paravetebral Extension". PMID- 28072816 TI - Systematic Analysis of Transcriptional and Post-transcriptional Regulation of Metabolism in Yeast. AB - Cells react to extracellular perturbations with complex and intertwined responses. Systematic identification of the regulatory mechanisms that control these responses is still a challenge and requires tailored analyses integrating different types of molecular data. Here we acquired time-resolved metabolomics measurements in yeast under salt and pheromone stimulation and developed a machine learning approach to explore regulatory associations between metabolism and signal transduction. Existing phosphoproteomics measurements under the same conditions and kinase-substrate regulatory interactions were used to in silico estimate the enzymatic activity of signalling kinases. Our approach identified informative associations between kinases and metabolic enzymes capable of predicting metabolic changes. We extended our analysis to two studies containing transcriptomics, phosphoproteomics and metabolomics measurements across a comprehensive panel of kinases/phosphatases knockouts and time-resolved perturbations to the nitrogen metabolism. Changes in activity of transcription factors, kinases and phosphatases were estimated in silico and these were capable of building predictive models to infer the metabolic adaptations of previously unseen conditions across different dynamic experiments. Time-resolved experiments were significantly more informative than genetic perturbations to infer metabolic adaptation. This difference may be due to the indirect nature of the associations and of general cellular states that can hinder the identification of causal relationships. This work provides a novel genome-scale integrative analysis to propose putative transcriptional and post-translational regulatory mechanisms of metabolic processes. PMID- 28072817 TI - Drosophila Clock Is Required in Brain Pacemaker Neurons to Prevent Premature Locomotor Aging Independently of Its Circadian Function. AB - Circadian clocks control many self-sustained rhythms in physiology and behavior with approximately 24-hour periodicity. In many organisms, oxidative stress and aging negatively impact the circadian system and sleep. Conversely, loss of the clock decreases resistance to oxidative stress, and may reduce lifespan and speed up brain aging and neurodegeneration. Here we examined the effects of clock disruptions on locomotor aging and longevity in Drosophila. We found that lifespan was similarly reduced in three arrhythmic mutants (ClkAR, cyc0 and tim0) and in wild-type flies under constant light, which stops the clock. In contrast, ClkAR mutants showed significantly faster age-related locomotor deficits (as monitored by startle-induced climbing) than cyc0 and tim0, or than control flies under constant light. Reactive oxygen species accumulated more with age in ClkAR mutant brains, but this did not appear to contribute to the accelerated locomotor decline of the mutant. Clk, but not Cyc, inactivation by RNA interference in the pigment-dispersing factor (PDF)-expressing central pacemaker neurons led to similar loss of climbing performance as ClkAR. Conversely, restoring Clk function in these cells was sufficient to rescue the ClkAR locomotor phenotype, independently of behavioral rhythmicity. Accelerated locomotor decline of the ClkAR mutant required expression of the PDF receptor and correlated to an apparent loss of dopaminergic neurons in the posterior protocerebral lateral 1 (PPL1) clusters. This neuronal loss was rescued when the ClkAR mutation was placed in an apoptosis-deficient background. Impairing dopamine synthesis in a single pair of PPL1 neurons that innervate the mushroom bodies accelerated locomotor decline in otherwise wild-type flies. Our results therefore reveal a novel circadian-independent requirement for Clk in brain circadian neurons to maintain a subset of dopaminergic cells and avoid premature locomotor aging in Drosophila. PMID- 28072818 TI - Glucose-ABL1-TOR Signaling Modulates Cell Cycle Tuning to Control Terminal Appressorial Cell Differentiation. AB - The conserved target of rapamycin (TOR) pathway integrates growth and development with available nutrients, but how cellular glucose controls TOR function and signaling is poorly understood. Here, we provide functional evidence from the devastating rice blast fungus Magnaporthe oryzae that glucose can mediate TOR activity via the product of a novel carbon-responsive gene, ABL1, in order to tune cell cycle progression during infection-related development. Under nutrient free conditions, wild type (WT) M. oryzae strains form terminal plant-infecting cells (appressoria) at the tips of germ tubes emerging from three-celled spores (conidia). WT appressorial development is accompanied by one round of mitosis followed by autophagic cell death of the conidium. In contrast, Deltaabl1 mutant strains undergo multiple rounds of accelerated mitosis in elongated germ tubes, produce few appressoria, and are abolished for autophagy. Treating WT spores with glucose or 2-deoxyglucose phenocopied Deltaabl1. Inactivating TOR in Deltaabl1 mutants or glucose-treated WT strains restored appressorium formation by promoting mitotic arrest at G1/G0 via an appressorium- and autophagy-inducing cell cycle delay at G2/M. Collectively, this work uncovers a novel glucose-ABL1 TOR signaling axis and shows it engages two metabolic checkpoints in order to modulate cell cycle tuning and mediate terminal appressorial cell differentiation. We thus provide new molecular insights into TOR regulation and cell development in response to glucose. PMID- 28072819 TI - Testing the Efficacy of DNA Barcodes for Identifying the Vascular Plants of Canada. AB - Their relatively slow rates of molecular evolution, as well as frequent exposure to hybridization and introgression, often make it difficult to discriminate species of vascular plants with the standard barcode markers (rbcL, matK, ITS2). Previous studies have examined these constraints in narrow geographic or taxonomic contexts, but the present investigation expands analysis to consider the performance of these gene regions in discriminating the species in local floras at sites across Canada. To test identification success, we employed a DNA barcode reference library with sequence records for 96% of the 5108 vascular plant species known from Canada, but coverage varied from 94% for rbcL to 60% for ITS2 and 39% for matK. Using plant lists from 27 national parks and one scientific reserve, we tested the efficacy of DNA barcodes in identifying the plants in simulated species assemblages from six biogeographic regions of Canada using BLAST and mothur. Mean pairwise distance (MPD) and mean nearest taxon distance (MNTD) were strong predictors of barcode performance for different plant families and genera, and both metrics supported ITS2 as possessing the highest genetic diversity. All three genes performed strongly in assigning the taxa present in local floras to the correct genus with values ranging from 91% for rbcL to 97% for ITS2 and 98% for matK. However, matK delivered the highest species discrimination (~81%) followed by ITS2 (~72%) and rbcL (~44%). Despite the low number of plant taxa in the Canadian Arctic, DNA barcodes had the least success in discriminating species from this biogeographic region with resolution ranging from 36% with rbcL to 69% with matK. Species resolution was higher in the other settings, peaking in the Woodland region at 52% for rbcL and 87% for matK. Our results indicate that DNA barcoding is very effective in identifying Canadian plants to a genus, and that it performs well in discriminating species in regions where floristic diversity is highest. PMID- 28072820 TI - p-Cymene Promotes Its Catabolism through the p-Cymene and the p-Cumate Pathways, Activates a Stress Response and Reduces the Biofilm Formation in Burkholderia xenovorans LB400. AB - p-Cymene is an aromatic terpene that is present in diverse plant species. The aims of this study were to study the p-cymene metabolism in the model aromatic degrading bacterium Burkholderia xenovorans LB400, and its response to p-cymene. The catabolic p-cymene (cym) and p-cumate (cmt) genes are clustered on the LB400 major chromosome. B. xenovorans LB400 was able to grow on p-cymene as well as on p-cumate as a sole carbon and energy sources. LB400 growth attained higher cell concentration at stationary phase on p-cumate than on p-cymene. The transcription of the key cymAb and cmtAb genes, and p-cumate dioxygenase activity were observed in LB400 cells grown on p-cymene and on p-cumate, but not in glucose-grown cells. Diverse changes on LB400 proteome were observed in p-cymene-grown cells compared to glucose-grown cells. An increase of the molecular chaperones DnaK, GroEL and ClpB, the organic hydroperoxide resistance protein Ohr, the alkyl hydroperoxide reductase AhpC and the copper oxidase CopA during growth on p-cymene strongly suggests that the exposure to p-cymene constitutes a stress condition for strain LB400. Diverse proteins of the energy metabolism such as enolase, pyruvate kinase, aconitase AcnA, succinyl-CoA synthetase beta subunit and ATP synthase beta subunit were induced by p-cymene. Electron microscopy showed that p-cymene grown cells exhibited fuzzy outer and inner membranes and an increased periplasm. p-Cymene induced diverse membrane and transport proteins including the p-cymene transporter CymD. Biofilm formation was reduced during growth in p-cymene in strain LB400 compared to glucose-grown cells that may be associated with a decrease of diguanylate cyclase protein levels. Overall, these results indicate active p-cymene and p-cumate catabolic pathways in B. xenovorans LB400. In addition, this study showed that p-cymene activated a stress response in strain LB400 and reduced its biofilm formation. PMID- 28072821 TI - Maysin and Its Flavonoid Derivative from Centipedegrass Attenuates Amyloid Plaques by Inducting Humoral Immune Response with Th2 Skewed Cytokine Response in the Tg (APPswe, PS1dE9) Alzheimer's Mouse Model. AB - Alzheimer's disease (AD) is a slow, progressive neurodegenerative disease and the most common type of dementia in the elderly. The etiology of AD and its underlying mechanism are still not clear. In a previous study, we found that an ethyl acetate extract of Centipedegrass (CG) (i.e., EA-CG) contained 4 types of Maysin derivatives, including Luteolin, Isoorientin, Rhamnosylisoorientin, and Derhamnosylmaysin, and showed protective effects against Amyloid beta (Abeta) by inhibiting oligomeric Abeta in cellular and in vitro models. Here, we examined the preventative effects of EA-CG treatment on the Abeta burden in the Tg (Mo/Hu APPswe PS1dE9) AD mouse model. We have investigated the EA-CG efficacy as novel anti-AD likely preventing amyloid plaques using immunofluorescence staining to visually analyze Abeta40/42 and fibril formation with Thioflavin-S or 6E10 which are the profile of immunoreactivity against epitope Abeta1-16 or neuritic plaque, the quantitation of humoral immune response against Abeta, and the inflammatory cytokine responses (Th1 and Th2) using ELISA and QRT-PCR. To minimize the toxicity of the extracted CG, we addressed the liver toxicity in response to the CG extract treatment in Tg mice using relevant markers, such as aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) measurements in serum. The EA-CG extract significantly reduced the Abeta burden, the concentration of soluble Abeta40/42 protein, and fibril formation in the hippocampus and cortex of the Tg mice treated with EA-CG (50 mg/kg BW/day) for 6 months compared with the Tg mice treated with a normal diet. Additionally, the profile of anti inflammatory cytokines revealed that the levels of Th2 (interleukin-4 (IL-4) and interleukin-10 (IL-10)) cytokines are more significantly increased than Th1 (interferon-gamma (IFN-gamma), interleukin-2(IL-2)) in the sera. These results suggest that the EA-CG fraction induces IL-4/IL-10-dependent anti-inflammatory cytokines (Th2) rather than pro-inflammatory cytokines (Th1), which are driven by IL-2/IFN-gamma. With regard to the immune response, EA-CG induced an immunoglobulin IgG and IgM response against the EA-CG treatment in the Tg mice. Furthermore, EA-CG significantly ameliorated the level of soluble Abeta42 and Abeta40. Similarly, we observed that the fibril formation was also decreased by EA-CG treatment in the hippocampus and cortex after quantitative analysis with Thioflavin-S staining in the Tg brain tissues. Taken together, our findings suggested that Maysin and its derivative flavonoid compounds in the EA-CG fraction might be beneficial therapeutic treatments or alternative preventative measures to adjuvant for boosting humoral and cellular include immune response and anti-inflammation which may lead to amyloid plaque accumulation in Alzheimer's patients' brains. PMID- 28072822 TI - Point-of-Care Versus Central Laboratory Measurements of Hemoglobin, Hematocrit, Glucose, Bicarbonate and Electrolytes: A Prospective Observational Study in Critically Ill Patients. AB - INTRODUCTION: Rapid detection of abnormal biological values using point-of-care (POC) testing allows clinicians to promptly initiate therapy; however, there are concerns regarding the reliability of POC measurements. We investigated the agreement between the latest generation blood gas analyzer and central laboratory measurements of electrolytes, bicarbonate, hemoglobin, hematocrit, and glucose. METHODS: 314 paired samples were collected prospectively from 51 critically ill patients. All samples were drawn simultaneously in the morning from an arterial line. BD Vacutainer tubes were analyzed in the central laboratory using Beckman Coulter analyzers (AU 5800 and DxH 800). BD Preset 3 ml heparinized-syringes were analyzed immediately in the ICU using the POC Siemens RAPIDPoint 500 blood gas system. We used CLIA proficiency testing criteria to define acceptable analytical performance and interchangeability. RESULTS: Biases, limits of agreement (+/-1.96 SD) and coefficients of correlation were respectively: 1.3 (-2.2 to 4.8 mmol/L, r = 0.936) for sodium; 0.2 (-0.2 to 0.6 mmol/L, r = 0.944) for potassium; -0.9 ( 3.7 to 2 mmol/L, r = 0.967) for chloride; 0.8 (-1.9 to 3.4 mmol/L, r = 0.968) for bicarbonate; -11 (-30 to 9 mg/dL, r = 0.972) for glucose; -0.8 (-1.4 to -0.2 g/dL, r = 0.985) for hemoglobin; and -1.1 (-2.9 to 0.7%, r = 0.981) for hematocrit. All differences were below CLIA cut-off values, except for hemoglobin. CONCLUSIONS: Compared to central Laboratory analyzers, the POC Siemens RAPIDPoint 500 blood gas system satisfied the CLIA criteria of interchangeability for all tested parameters, except for hemoglobin. These results are warranted for our own procedures and devices. Bearing these restrictions, we recommend clinicians to initiate an appropriate therapy based on POC testing without awaiting a control measurement. PMID- 28072823 TI - Syntactic Recursion Facilitates and Working Memory Predicts Recursive Theory of Mind. AB - In this study, we focus on the possible roles of second-order syntactic recursion and working memory in terms of simple and complex span tasks in the development of second-order false belief reasoning. We tested 89 Turkish children in two age groups, one younger (4;6-6;5 years) and one older (6;7-8;10 years). Although second-order syntactic recursion is significantly correlated with the second order false belief task, results of ordinal logistic regressions revealed that the main predictor of second-order false belief reasoning is complex working memory span. Unlike simple working memory and second-order syntactic recursion tasks, the complex working memory task required processing information serially with additional reasoning demands that require complex working memory strategies. Based on our results, we propose that children's second-order theory of mind develops when they have efficient reasoning rules to process embedded beliefs serially, thus overcoming a possible serial processing bottleneck. PMID- 28072824 TI - D19S Mutation of the Cationic, Cysteine-Rich Protein PAF: Novel Insights into Its Structural Dynamics, Thermal Unfolding and Antifungal Function. AB - The cysteine-rich, cationic, antifungal protein PAF is abundantly secreted into the culture supernatant of the filamentous Ascomycete Penicillium chrysogenum. The five beta-strands of PAF form a compact beta-barrel that is stabilized by three disulphide bonds. The folding of PAF allows the formation of four surface exposed loops and distinct charged motifs on the protein surface that might regulate the interaction of PAF with the sensitive target fungus. The growth inhibitory activity of this highly stable protein against opportunistic fungal pathogens provides great potential in antifungal drug research. To understand its mode of action, we started to investigate the surface-exposed loops of PAF and replaced one aspartic acid at position 19 in loop 2 that is potentially involved in PAF active or binding site, with a serine (Asp19 to Ser19). We analysed the overall effects, such as unfolding, electrostatic changes, sporadic conformers and antifungal activity when substituting this specific amino acid to the fairly indifferent amino acid serine. Structural analyses revealed that the overall 3D solution structure is virtually identical with that of PAF. However, PAFD19S showed slightly increased dynamics and significant differences in the surface charge distribution. Thermal unfolding identified PAFD19S to be rather a two state folder in contrast to the three-state folder PAF. Functional comparison of PAFD19S and PAF revealed that the exchange at residue 19 caused a dramatic loss of antifungal activity: the binding and internalization of PAFD19S by target cells was reduced and the protein failed to trigger an intracellular Ca2+ response, all of which are closely linked to the antifungal toxicity of PAF. We conclude that the negatively charged residue Asp19 in loop 2 is essential for full function of the cationic protein PAF. PMID- 28072825 TI - Dietary Chromium Restriction of Pregnant Mice Changes the Methylation Status of Hepatic Genes Involved with Insulin Signaling in Adult Male Offspring. AB - Maternal undernutrition is linked with an elevated risk of diabetes mellitus in offspring regardless of the postnatal dietary status. This is also found in maternal micro-nutrition deficiency, especial chromium which is a key glucose regulator. We investigated whether maternal chromium restriction contributes to the development of diabetes in offspring by affecting DNA methylation status in liver tissue. After being mated with control males, female weanling 8-week-old C57BL mice were fed a control diet (CON, 1.19 mg chromium/kg diet) or a low chromium diet (LC, 0.14 mg chromium/kg diet) during pregnancy and lactation. After weaning, some offspring were shifted to the other diet (CON-LC, or LC-CON), while others remained on the same diet (CON-CON, or LC-LC) for 29 weeks. Fasting blood glucose, serum insulin, and oral glucose tolerance test was performed to evaluate the glucose metabolism condition. Methylation differences in liver from the LC-CON group and CON-CON groups were studied by using a DNA methylation array. Bisulfite sequencing was carried out to validate the results of the methylation array. Maternal chromium limitation diet increased the body weight, blood glucose, and serum insulin levels. Even when switched to the control diet after weaning, the offspring also showed impaired glucose tolerance and insulin resistance. DNA methylation profiling of the offspring livers revealed 935 differentially methylated genes in livers of the maternal chromium restriction diet group. Pathway analysis identified the insulin signaling pathway was the main process affected by hypermethylated genes. Bisulfite sequencing confirmed that some genes in insulin signaling pathway were hypermethylated in livers of the LC-CON and LC-LC group. Accordingly, the expression of genes in insulin signaling pathway was downregulated. There findings suggest that maternal chromium restriction diet results in glucose intolerance in male offspring through alterations in DNA methylation which is associated with the insulin signaling pathway in the mice livers. PMID- 28072826 TI - RNA-Dependent RNA Polymerases of Both Virulent and Benign Rabbit Caliciviruses Induce Striking Rearrangement of Golgi Membranes. AB - The extremely pathogenic Rabbit haemorrhagic disease virus (RHDV) and the completely benign Rabbit calicivirus (RCV) are closely related members of the genus Lagovirus (family Caliciviridae). The molecular mechanisms that determine the dramatic difference in virulence are unknown, but indirect evidence suggests that different properties of their RNA-dependent RNA polymerases (RdRps) may at least partially be responsible for the contrasting phenotypes. Here we report that the unusual ability of the RHDV RdRp to induce a striking rearrangement of the Golgi network is not specific to RHDV, but a common feature of virulent and benign rabbit caliciviruses alike. Expression of rabbit calicivirus RdRps induced a redistribution of both cis/medial and medial/trans Golgi membrane markers, but not that of an endoplasmic reticulum membrane marker. Inactivating mutations in the conserved GDD motif did not abolish the ability of RHDV RdRp to rearrange the Golgi network, suggesting that polymerase activity and metal co-factors are not required for this function. Finally, we discuss possible implications of RdRp induced membrane rearrangements on virus replication and host immune responses. PMID- 28072827 TI - Comprehensive N-Glycan Profiling of Cetuximab Biosimilar Candidate by NP-HPLC and MALDI-MS. AB - Monitoring glycosylation of the mAbs have been emphasized and routinely characterized in biopharmaceutical industries because the carbohydrate components are closely related to the safety, efficacy, and consistency of the antibodies. In this study, the comprehensive glycan profiling of a biosimilar candidate of cetuximab was successfully characterized using Normal phase high-performance liquid chromatography (NP-HPLC) in combination with Matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS). The presence of minor N linked glycans containing sialic acid lactone residues (NeuAcLac) was observed in the biosimilar for the first time, which could influence the quantitative analysis of sialylated glycans and interfere with quantification of neutral glycans when it was analyzed by high performance liquid chromatography fluorescence (HPLC-FL). To overcome this issue, mild alkali treatment was used to hydrolyze lactone of the sialic acid to their neutral formation, which had no impact on the analysis of other glycans before and after the treatment. As a result, the mild alkali treatment might be helpful to obtain quantitative glycan profiling of the mAbs drugs with enhanced accuracy and robustness. PMID- 28072829 TI - Predicting the Metabolic Sites by Flavin-Containing Monooxygenase on Drug Molecules Using SVM Classification on Computed Quantum Mechanics and Circular Fingerprints Molecular Descriptors. AB - As an important enzyme in Phase I drug metabolism, the flavin-containing monooxygenase (FMO) also metabolizes some xenobiotics with soft nucleophiles. The site of metabolism (SOM) on a molecule is the site where the metabolic reaction is exerted by an enzyme. Accurate prediction of SOMs on drug molecules will assist the search for drug leads during the optimization process. Here, some quantum mechanics features such as the condensed Fukui function and attributes from circular fingerprints (called Molprint2D) are computed and classified using the support vector machine (SVM) for predicting some potential SOMs on a series of drugs that can be metabolized by FMO enzymes. The condensed Fukui function fA- representing the nucleophilicity of central atom A and the attributes from circular fingerprints accounting the influence of neighbors on the central atom. The total number of FMO substrates and non-substrates collected in the study is 85 and they are equally divided into the training and test sets with each carrying roughly the same number of potential SOMs. However, only N-oxidation and S-oxidation features were considered in the prediction since the available C oxidation data was scarce. In the training process, the LibSVM package of WEKA package and the option of 10-fold cross validation are employed. The prediction performance on the test set evaluated by accuracy, Matthews correlation coefficient and area under ROC curve computed are 0.829, 0.659, and 0.877 respectively. This work reveals that the SVM model built can accurately predict the potential SOMs for drug molecules that are metabolizable by the FMO enzymes. PMID- 28072828 TI - GGPP-Mediated Protein Geranylgeranylation in Oocyte Is Essential for the Establishment of Oocyte-Granulosa Cell Communication and Primary-Secondary Follicle Transition in Mouse Ovary. AB - Folliculogenesis is a progressive and highly regulated process, which is essential to provide ova for later reproductive life, requires the bidirectional communication between the oocyte and granulosa cells. This physical connection mediated communication conveys not only the signals from the oocyte to granulosa cells that regulate their proliferation but also metabolites from the granulosa cells to the oocyte for biosynthesis. However, the underlying mechanism of establishing this communication is largely unknown. Here, we report that oocyte geranylgeranyl diphosphate (GGPP), a metabolic intermediate involved in protein geranylgeranylation, is required to establish the oocyte-granulosa cell communication. GGPP and geranylgeranyl diphosphate synthase (Ggpps) levels in oocytes increased during early follicular development. The selective depletion of GGPP in mouse oocytes impaired the proliferation of granulosa cells, primary secondary follicle transition and female fertility. Mechanistically, GGPP depletion inhibited Rho GTPase geranylgeranylation and its GTPase activity, which was responsible for the accumulation of cell junction proteins in the oocyte cytoplasm and the failure to maintain physical connection between oocyte and granulosa cells. GGPP ablation also blocked Rab27a geranylgeranylation, which might account for the impaired secretion of oocyte materials such as Gdf9. Moreover, GGPP administration restored the defects in oocyte-granulosa cell contact, granulosa cell proliferation and primary-secondary follicle transition in Ggpps depletion mice. Our study provides the evidence that GGPP-mediated protein geranylgeranylation contributes to the establishment of oocyte-granulosa cell communication and then regulates the primary-secondary follicle transition, a key phase of folliculogenesis essential for female reproductive function. PMID- 28072830 TI - Protective Effects of Dexrazoxane against Doxorubicin-Induced Cardiotoxicity: A Metabolomic Study. AB - Cardioprotection of dexrazoxane (DZR) against doxorubicin (DOX)-induced cardiotoxicity is contentious and the indicator is controversial. A pairwise comparative metabolomics approach was used to delineate the potential metabolic processes in the present study. Ninety-six BALB/c mice were randomly divided into two supergroups: tumor and control groups. Each supergroup was divided into control, DOX, DZR, and DOX plus DZR treatment groups. DOX treatment resulted in a steady increase in 5-hydroxylysine, 2-hydroxybutyrate, 2-oxoglutarate, 3 hydroxybutyrate, and decrease in glucose, glutamate, cysteine, acetone, methionine, asparate, isoleucine, and glycylproline.DZR treatment led to increase in lactate, 3-hydroxybutyrate, glutamate, alanine, and decrease in glucose, trimethylamine N-oxide and carnosine levels. These metabolites represent potential biomarkers for early prediction of cardiotoxicity of DOX and the cardioprotective evaluation of DZR. PMID- 28072831 TI - A Probabilistic Method for Estimation of Bowel Wall Thickness in MR Colonography. AB - MRI has recently been applied as a tool to quantitatively evaluate the response to therapy in patients with Crohn's disease, and is the preferred choice for repeated imaging. Bowel wall thickness on MRI is an important biomarker of underlying inflammatory activity, being abnormally increased in the acute phase and reducing in response to successful therapy; however, a poor level of interobserver agreement of measured thickness is reported and therefore a system for accurate, robust and reproducible measurements is desirable. We propose a novel method for estimating bowel wall-thickness to improve the poor interobserver agreement of the manual procedure. We show that the variability of wall thickness measurement between the algorithm and observer measurements (0.25mm +/- 0.81mm) has differences which are similar to observer variability (0.16mm +/- 0.64mm). PMID- 28072832 TI - Objectively Assessed Exercise Behavior in Chinese Patients with Early-Stage Cancer: A Predictor of Perceived Benefits, Communication with Doctors, Medical Coping Modes, Depression and Quality of Life. AB - This study sought to identify factors associated with objectively assessed exercise behavior in Chinese patients with early-stage cancer. Three hundred and fifty one cancer patients were recruited from the Affiliated Jiangyin Hospital of Southeast University Medical College and the Nantong Tumor Hospital. One-way ANOVA, Pearson Chi-square tests and regression analysis were employed to identify the correlations between physical exercise and the measured factors. The results showed that occupation type (chi2 = 14.065; p = 0.029), monthly individual monthly income level (chi2 = 24.795; p = 0.003), BMI (chi2 = 15.709; p = 0.015) and diagnosis (chi2 = 42.442; p < 0.000) were significantly correlated with the subjects self-reported exercise with different frequency per week. Differences in the frequency of exercise were associated with different degrees of reported Benefit Finding (BF) (F = 24.651; p < 0.000), communication with doctors (F = 15.285; p < 0.000), medical coping modes (F = 45.912; p < 0.000), social support (F = 2.938; p = 0.030), depression (F = 6.017; p < 0.000), and quality of life (F = 12.288; p < 0.000). Multiple regression analysis showed that 1.6%-6.4% of the variance in five variables, excluding social support and optimism could be explained by exercise. Our results indicated that benefit finding, medical coping modes, communication with doctors, social support, depression and quality of life were significantly correlated with exercise. The variance in several psychosocial factors (benefit finding, medical coping modes, the communication with doctors, depression and quality of life) could be explained by exercise. Psychosocial factors should be addressed and examined over time when evaluating the effect of physical exercise that is prescribed as a clinically relevant treatment. PMID- 28072835 TI - Storage of Maize in Purdue Improved Crop Storage (PICS) Bags. AB - Interest in using hermetic technologies as a pest management solution for stored grain has risen in recent years. One hermetic approach, Purdue Improved Crop Storage (PICS) bags, has proven successful in controlling the postharvest pests of cowpea. This success encouraged farmers to use of PICS bags for storing other crops including maize. To assess whether maize can be safely stored in PICS bags without loss of quality, we carried out laboratory studies of maize grain infested with Sitophilus zeamais (Motshulsky) and stored in PICS triple bags or in woven polypropylene bags. Over an eight month observation period, temperatures in the bags correlated with ambient temperature for all treatments. Relative humidity inside PICS bags remained constant over this period despite the large changes that occurred in the surrounding environment. Relative humidity in the woven bags followed ambient humidity closely. PICS bags containing S. zeamais infested grain saw a significant decline in oxygen compared to the other treatments. Grain moisture content declined in woven bags, but remained high in PICS bags. Seed germination was not significantly affected over the first six months in all treatments, but declined after eight months of storage when infested grain was held in woven bags. Relative damage was low across treatments and not significantly different between treatments. Overall, maize showed no signs of deterioration in PICS bags versus the woven bags and PICS bags were superior to woven bags in terms of specific metrics of grain quality. PMID- 28072834 TI - A Computational Model Based on Multi-Regional Calcium Imaging Represents the Spatio-Temporal Dynamics in a Caenorhabditis elegans Sensory Neuron. AB - Due to the huge number of neuronal cells in the brain and their complex circuit formation, computer simulation of neuronal activity is indispensable to understanding whole brain dynamics. Recently, various computational models have been developed based on whole-brain calcium imaging data. However, these analyses monitor only the activity of neuronal cell bodies and treat the cells as point unit. This point-neuron model is inexpensive in computational costs, but the model is unrealistically simplistic at representing intact neural activities in the brain. Here, we describe a novel three-unit Ordinary Differential Equation (ODE) model based on the neuronal responses derived from a Caenorhabditis elegans salt-sensing neuron. We recorded calcium responses in three regions of the ASER neuron using a simple downstep of NaCl concentration. Our simple ODE model generated from a single recording can adequately reproduce and predict the temporal responses of each part of the neuron to various types of NaCl concentration changes. Our strategy which combines a simple recording data and an ODE mathematical model may be extended to realistically understand whole brain dynamics by computational simulation. PMID- 28072833 TI - Accurate Breakpoint Mapping in Apparently Balanced Translocation Families with Discordant Phenotypes Using Whole Genome Mate-Pair Sequencing. AB - Familial apparently balanced translocations (ABTs) segregating with discordant phenotypes are extremely challenging for interpretation and counseling due to the scarcity of publications and lack of routine techniques for quick investigation. Recently, next generation sequencing has emerged as an efficacious methodology for precise detection of translocation breakpoints. However, studies so far have mainly focused on de novo translocations. The present study focuses specifically on familial cases in order to shed some light to this diagnostic dilemma. Whole genome mate-pair sequencing (WG-MPS) was applied to map the breakpoints in nine two-way ABT carriers from four families. Translocation breakpoints and patient specific structural variants were validated by Sanger sequencing and quantitative Real Time PCR, respectively. Identical sequencing patterns and breakpoints were identified in affected and non-affected members carrying the same translocations. PTCD1, ATP5J2-PTCD1, CADPS2, and STPG1 were disrupted by the translocations in three families, rendering them initially as possible disease candidate genes. However, subsequent mutation screening and structural variant analysis did not reveal any pathogenic mutations or unique variants in the affected individuals that could explain the phenotypic differences between carriers of the same translocations. In conclusion, we suggest that NGS-based methods, such as WG-MPS, can be successfully used for detailed mapping of translocation breakpoints, which can also be used in routine clinical investigation of ABT cases. Unlike de novo translocations, no associations were determined here between familial two-way ABTs and the phenotype of the affected members, in which the presence of cryptic imbalances and complex chromosomal rearrangements has been excluded. Future whole exome or whole-genome sequencing will potentially reveal unidentified mutations in the patients underlying the discordant phenotypes within each family. In addition, larger studies are needed to determine the exact percentage for phenotypic risk in families with ABTs. PMID- 28072836 TI - Pre-Migration Trauma Exposure and Mental Health Functioning among Central American Migrants Arriving at the US Border. AB - In recent years, increasing numbers of families and individuals have arrived at the U.S. border from Central America, in particular, from Honduras, El Salvador, and Guatemala. This study sought to examine pre-migration trauma exposure and current mental health functioning of migrant families arriving at the U.S. border from the Northern Triangle region, with specific attention to the reasons offered for leaving their home country and the frequency with which migrant families appear to satisfy legal criteria for asylum We interviewed 234 adults in McAllen, Texas, using a structured interview and standardized questionnaires to assess exposure to trauma prior to migration, reasons for leaving their home country and symptoms of posttraumatic stress and depression. We found that 191 participants (83%) cited violence as a reason for fleeing their country, 119 individuals (69%) did not report the events to the police out of fear of gang-related retaliation or police corruption, and 90% (n = 204) reported being afraid to return to their native country. Based on self-report symptom checklists, 32% of the sample met diagnostic criteria for PTSD (n = 51), 24% for depression (n = 36), and 17% for both disorders (n = 25). Examining these data against the criteria for asylum in the U.S., we found that 70% of the overall sample (n = 159) met criteria for asylum, including 80% of those from El Salvador, 74% from Honduras, and 41% from Guatemala. These findings suggest that the majority of Central American migrants arriving at the U.S. border have significant mental health symptoms in response to violence and persecution, and warrant careful consideration for asylum status. PMID- 28072837 TI - Locally Produced BDNF Promotes Sclerotic Change in Alveolar Bone after Nerve Injury. AB - Brain-derived neurotrophic factor (BDNF), which is released due to nerve injury, is known to promote the natural healing of injured nerves. It is often observed that damage of mandibular canal induces local sclerotic changes in alveolar bone. We reported that peripheral nerve injury promotes the local production of BDNF; therefore, it was possible to hypothesize that peripheral nerve injury affects sclerotic changes in the alveolar bone. This study aimed to evaluate the effect of BDNF on osteogenesis using in vitro osteoblast-lineage cell culture and an in vivo rat osteotomy model. MC3T3-E1 cells were cultured with BDNF and were examined for cell proliferative activity, chemotaxis and mRNA expression levels of osteoblast differentiation markers. For in vivo study, inferior alveolar nerve (IAN) injury experiments and mandibular cortical osteotomy were performed using a rat model. In the osteotomy model, exogenous BDNF was applied to bone surfaces after corticotomy of the mandible, and we morphologically analyzed the new bone formation. As a result, mRNA expression of osteoblast differentiation marker, osteocalcin, was significantly increased by BDNF, although cell proliferation and migration were not affected. In the in vivo study, osteopontin-positive new bone formation was significantly accelerated in the BDNF-grafted groups, and active bone remodeling, involving trkB-positive osteoblasts and osteocytes, continued after 28 days. In conclusion, BDNF stimulated the differentiation of MC3T3-E1 cells and it promoted new bone formation and maturation. These results suggested that local BDNF produced by peripheral nerve injury contributes to accelerating sclerotic changes in the alveolar bone. PMID- 28072838 TI - Reporting Items for Updated Clinical Guidelines: Checklist for the Reporting of Updated Guidelines (CheckUp). AB - BACKGROUND: Scientific knowledge is in constant development. Consequently, regular review to assure the trustworthiness of clinical guidelines is required. However, there is still a lack of preferred reporting items of the updating process in updated clinical guidelines. The present article describes the development process of the Checklist for the Reporting of Updated Guidelines (CheckUp). METHODS AND FINDINGS: We developed an initial list of items based on an overview of research evidence on clinical guideline updating, the Appraisal of Guidelines for Research and Evaluation (AGREE) II Instrument, and the advice of the CheckUp panel (n = 33 professionals). A multistep process was used to refine this list, including an assessment of ten existing updated clinical guidelines, interviews with key informants (response rate: 54.2%; 13/24), a three-round Delphi consensus survey with the CheckUp panel (33 participants), and an external review with clinical guideline methodologists (response rate: 90%; 53/59) and users (response rate: 55.6%; 10/18). CheckUp includes 16 items that address (1) the presentation of an updated guideline, (2) editorial independence, and (3) the methodology of the updating process. In this article, we present the methodology to develop CheckUp and include as a supplementary file an explanation and elaboration document. CONCLUSIONS: CheckUp can be used to evaluate the completeness of reporting in updated guidelines and as a tool to inform guideline developers about reporting requirements. Editors may request its completion from guideline authors when submitting updated guidelines for publication. Adherence to CheckUp will likely enhance the comprehensiveness and transparency of clinical guideline updating for the benefit of patients and the public, health care professionals, and other relevant stakeholders. PMID- 28072839 TI - Assessment of Attention Deficits in Adolescent Offspring Exposed to Maternal Type 1 Diabetes. AB - OBJECTIVE: The aim of this study was to examine the potential association between intrauterine exposure to maternal diabetes and attention deficits in the offspring. RESEARCH DESIGN AND METHODS: Adolescent offspring of a prospectively followed cohort of women with type 1 diabetes (n = 269) and a control group from the background population (n = 293) participated in a follow-up assessment in 2012-2013. We used scores from Conners Continuous Performance Test II to assess attention and based on a principal component analysis we evaluated scores on five different attention factors: focused attention, vigilance, hyperactivity/impulsivity, sustained attention and response style. RESULTS: A higher frequency of the exposed offspring had a parent/self-reported use of Attention Deficit Hyperactivity Disorder (ADHD) medication compared to the control group (2.2% vs. 0.0%, p = 0.01). Clinical significant differences between adolescents exposed to maternal diabetes and unexposed controls were not found in either single scores on Conners Continuous Performance Test or on any of the five attention factors identified. CONCLUSIONS: Exposure to maternal type 1 diabetes did not seem to increase the risk of attention deficits in the adolescent offspring. However, a higher self-reported use of ADHD medication in the exposed group could suggest a difference in attention not revealed by the applied test. PMID- 28072840 TI - Locomotor Activity and Body Temperature Patterns over a Temperature Gradient in the Highveld Mole-Rat (Cryptomys hottentotus pretoriae). AB - African mole-rats are strictly subterranean mammals that live in extensive burrow systems. High humidity levels in the burrows prevent mole-rats from thermoregulating using evaporative cooling. However, the relatively stable environment of the burrows promotes moderate temperatures and small daily temperature fluctuations. Mole-rats therefore display a relatively wide range of thermoregulation abilities. Some species cannot maintain their body temperatures at a constant level, whereas others employ behavioural thermoregulation. Here we test the effect of ambient temperature on locomotor activity and body temperature, and the relationship between the two parameters, in the highveld mole-rat. We exposed mole-rats to a 12L:12D and a DD light cycle at ambient temperatures of 30 degrees C, 25 degrees C and 20 degrees C while locomotor activity and body temperature were measured simultaneously. In addition, we investigated the endogenous rhythms of locomotor activity and body temperature at different ambient temperatures. Mole-rats displayed nocturnal activity at all three ambient temperatures and were most active at 20 degrees C, but least active at 30 degrees C. Body temperature was highest at 30 degrees C and lowest at 20 degrees C, and the daily cycle was highly correlated with locomotor activity. We show that the mole-rats have endogenous rhythms for both locomotor activity and body temperature. However, the endogenous body temperature rhythm appears to be less robust compared to the locomotor activity rhythm. Female mole-rats appear to be more sensitive to temperature changes than males, increased heterothermy is evident at lower ambient temperatures, whilst males show smaller variation in their body temperatures with changing ambient temperatures. Mole-rats may rely more heavily on behavioural thermoregulation as it is more energy efficient in an already challenging environment. PMID- 28072841 TI - A Small Insulinomimetic Molecule Also Improves Insulin Sensitivity in Diabetic Mice. AB - Dramatic increase of diabetes over the globe is in tandem with the increase in insulin requirement. This is because destruction and dysfunction of pancreatic beta-cells are of common occurrence in both Type1 diabetes and Type2 diabetes, and insulin injection becomes a compulsion. Because of several problems associated with insulin injection, orally active insulin mimetic compounds would be ideal substitute. Here we report a small molecule, a peroxyvanadate compound i.e. DmpzH[VO(O2)2(dmpz)], henceforth referred as dmp, which specifically binds to insulin receptor with considerable affinity (KD-1.17MUM) thus activating insulin receptor tyrosine kinase and its downstream signaling molecules resulting increased uptake of [14C] 2 Deoxy-glucose. Oral administration of dmp to streptozotocin treated BALB/c mice lowers blood glucose level and markedly stimulates glucose and fatty acid uptake by skeletal muscle and adipose tissue respectively. In db/db mice, it greatly improves insulin sensitivity through excess expression of PPARgamma and its target genes i.e. adiponectin, CD36 and aP2. Study on the underlying mechanism demonstrated that excess expression of Wnt3a decreased PPARgamma whereas dmp suppression of Wnt3a gene increased PPARgamma expression which subsequently augmented adiponectin. Increased production of adiponectin in db/db mice due to dmp effected lowering of circulatory TG and FFA levels, activates AMPK in skeletal muscle and this stimulates mitochondrial biogenesis and bioenergetics. Decrease of lipid load along with increased mitochondrial activity greatly improves energy homeostasis which has been found to be correlated with the increased insulin sensitivity. The results obtained with dmp, therefore, strongly indicate that dmp could be a potential candidate for insulin replacement therapy. PMID- 28072842 TI - Fractal Analysis of Brain Blood Oxygenation Level Dependent (BOLD) Signals from Children with Mild Traumatic Brain Injury (mTBI). AB - BACKGROUND: Conventional imaging techniques are unable to detect abnormalities in the brain following mild traumatic brain injury (mTBI). Yet patients with mTBI typically show delayed response on neuropsychological evaluation. Because fractal geometry represents complexity, we explored its utility in measuring temporal fluctuations of brain resting state blood oxygen level dependent (rs-BOLD) signal. We hypothesized that there could be a detectable difference in rs-BOLD signal complexity between healthy subjects and mTBI patients based on previous studies that associated reduction in signal complexity with disease. METHODS: Fifteen subjects (13.4 +/- 2.3 y/o) and 56 age-matched (13.5 +/- 2.34 y/o) healthy controls were scanned using a GE Discovery MR750 3T MRI and 32-channel RF coil. Axial FSPGR-3D images were used to prescribe rs-BOLD (TE/TR = 35/2000ms), acquired over 6 minutes. Motion correction was performed and anatomical and functional images were aligned and spatially warped to the N27 standard atlas. Fractal analysis, performed on grey matter, was done by estimating the Hurst exponent using de-trended fluctuation analysis and signal summation conversion methods. RESULTS AND CONCLUSIONS: Voxel-wise fractal dimension (FD) was calculated for every subject in the control group to generate mean and standard deviation maps for regional Z-score analysis. Voxel-wise validation of FD normality across controls was confirmed, and non-Gaussian voxels (3.05% over the brain) were eliminated from subsequent analysis. For each mTBI patient, regions where Z-score values were at least 2 standard deviations away from the mean (i.e. where |Z| > 2.0) were identified. In individual patients the frequently affected regions were amygdala (p = 0.02), vermis(p = 0.03), caudate head (p = 0.04), hippocampus(p = 0.03), and hypothalamus(p = 0.04), all previously reported as dysfunctional after mTBI, but based on group analysis. It is well known that the brain is best modeled as a complex system. Therefore a measure of complexity using rs-BOLD signal FD could provide an additional method to grade and monitor mTBI. Furthermore, this approach can be personalized thus providing unique patient specific assessment. PMID- 28072843 TI - Chemokine Ligand 5 (CCL5) Derived from Endothelial Colony-Forming Cells (ECFCs) Mediates Recruitment of Smooth Muscle Progenitor Cells (SPCs) toward Critical Vascular Locations in Moyamoya Disease. AB - The etiology and pathogenesis of moyamoya disease (MMD) are still obscure. Previous studies indicated that angiogenic chemokines may play an important role in the pathogenesis of the disease. Recently, it was discovered that peripheral blood-derived endothelial colony-forming cells (ECFCs) and smooth muscle progenitor cells (SPCs) have defective functions in MMD patients. Therefore, the interaction of ECFCs and SPCs, the precursors of two crucial cellular components of vascular walls, with some paracrine molecules is an intriguing subject. In this study, co-culture of ECFCs and SPCs from MMD patients and healthy normal subjects revealed that MMD ECFCs, not SPCs, are responsible for the defective functions of both ECFCs and SPCs. Enhanced migration of SPCs toward MMD ECFCs supported the role for some chemokines secreted by MMD ECFCs. Expression arrays of MMD and normal ECFCs suggested that several candidate cytokines differentially produced by MMD ECFCs. We selected chemokine (C-X-C motif) ligand 6 (CXCR6), interleukin-8 (IL8), chemokine (C-C motif) ligand 2 (CCL2), and CCL5 for study, based on the relatively higher expression of these ligands in MMD ECFCs and their cognate receptors in MMD SPCs. Migration assays showed that only CCL5 significantly augmented the migration activities of SPCs toward ECFCs. Treatment with siRNA for the CCL5 receptor (CCR5) abrogated the effect, confirming that CCL5 is responsible for the interaction of MMD ECFCs and SPCs. These data indicate that ECFCs, not SPCs, are the major players in MMD pathogenesis and that the chemokine CCL5 mediates the interactions. It can be hypothesized that in MMD patients, defective ECFCs direct aberrant SPC recruitment to critical vascular locations through the action of CCL5. PMID- 28072844 TI - Exploring the Possibility of Cryopreservation of Feline and Canine Erythrocytes by Rapid Freezing with Penetrating and Non-Penetrating Cryoprotectants. AB - Efficient application of veterinary blood transfusion approaches for small companion animals requires readily available supply of the donor material. This can be achieved by developing of effective biobanking technologies allowing long term storage of donor blood components via cryopreservation. Transfusion of an erythrocyte concentrate allows the successful correction of various hematological pathologies, severe bleeding, and etc. While in the past there were several approaches to cryopreserve red blood cells of dogs, to our knowledge there is virtually no data on cryopreservation of feline erythrocytes. In this paper, we performed a comprehensive parameter optimization for low temperature storage of RBCs of both species. Here, the efficiency of single-component and multicomponent cryoprotective media as well as necessary time of pre-incubation with penetrating and non-penetrating cryoprotectants prior to rapid freezing is analyzed. This study showed that glycerol was not sufficient for cryopreservation of red blood cells of the studied species under the investigated conditions. Application of 10% (v/v) ME2SO allowed for a significant reduction of canine and feline erythrocytes hemolysis after thawing. 17.5% hydroxyethyl starch demonstrated the highest cryoprotective activity for both species. It was found that dog RBCs should be incubated in cryoprotective media for 30 min at 22 degrees C prior to freezing, while for cat RBCs 20 min is sufficient. Combination of CPAs was less effective. Presented data may be considered in further studies in veterinary transfusion and blood banking optimization. PMID- 28072845 TI - Tuberculosis Detection in Paratuberculosis Vaccinated Calves: New Alternatives against Interference. AB - Paratuberculosis vaccination in cattle has been restricted due to its possible interference with the official diagnostic methods used in tuberculosis eradication programs. To overcome this drawback, new possibilities to detect Mycobacterium bovis infected cattle in paratuberculosis vaccinated animals were studied under experimental conditions. Three groups of 5 calves each were included in the experiment: one paratuberculosis vaccinated group, one paratuberculosis vaccinated and M. bovis infected group and one M. bovis infected group. The performance of the IFN-gamma release assay (IGRA) and the skin test using conventional avian and bovine tuberculins (A- and B-PPD) but also other more specific antigens (ESAT-6/CFP10 and Rv3615c) was studied under official and new diagnostic criteria. Regarding the IGRA of vaccinated groups, when A- and B PPD were used the sensitivity reached 100% at the first post-challenge sampling, dropping down to 40-80% in subsequent samplings. The sensitivity for the specific antigens was 80-100% and the specificity was also improved. After adapting the diagnostic criteria for the conventional antigens in the skin test, the ability to differentiate between M. bovis infected and non-infected animals included in paratuberculosis vaccinated groups was enhanced. Taking for positive a relative skin thickness increase of at least 100%, the single intradermal test specificity and sensitivity yielded 100%. The comparative intradermal test was equally accurate considering a B-PPD relative skin increase of at least 100% and greater than or equal to that produced by A-PPD. Using the specific antigens as a proteic cocktail, the specificity and sensitivity reached 100% considering the new relative and absolute cut-offs in all experimental groups (Delta>=30% and Deltamm >= 2, respectively). Results suggest that the interference caused by paratuberculosis vaccination in cattle could be completely overcome by applying new approaches to the official tuberculosis diagnostic tests. PMID- 28072846 TI - A Hypothesis Testing Based Method for Normalization and Differential Expression Analysis of RNA-Seq Data. AB - Next-generation sequencing technologies have made RNA sequencing (RNA-seq) a popular choice for measuring gene expression level. To reduce the noise of gene expression measures and compare them between several conditions or samples, normalization is an essential step to adjust for varying sample sequencing depths and other unwanted technical effects. In this paper, we develop a novel global scaling normalization method by employing the available knowledge of housekeeping genes. We formulate the problem from the hypothesis testing perspective and find an optimal scaling factor that minimizes the deviation between the empirical and the nominal type I error. Applying our approach to various simulation studies and real examples, we demonstrate that it is more accurate and robust than the state of-the-art alternatives in detecting differentially expression genes. PMID- 28072847 TI - Heuristic Strategies for Persuader Selection in Contagions on Complex Networks. AB - Individual decision to accept a new idea or product is often driven by both self adoption and others' persuasion, which has been simulated using a double threshold model [Huang et al., Scientific Reports 6, 23766 (2016)]. We extend the study to consider the case with limited persuasion. That is, a set of individuals is chosen from the population to be equipped with persuasion capabilities, who may succeed in persuading their friends to take the new entity when certain conditions are satisfied. Network node centrality is adopted to characterize each node's influence, based on which three heuristic strategies are applied to pick out persuaders. We compare these strategies for persuader selection on both homogeneous and heterogeneous networks. Two regimes of the underline networks are identified in which the system exhibits distinct behaviors: when networks are sufficiently sparse, selecting persuader nodes in descending order of node centrality achieves the best performance; when networks are sufficiently dense, however, selecting nodes with medium centralities to serve as the persuaders performs the best. Under respective optimal strategies for different types of networks, we further probe which centrality measure is most suitable for persuader selection. It turns out that for the first regime, degree centrality offers the best measure for picking out persuaders from homogeneous networks; while in heterogeneous networks, betweenness centrality takes its place. In the second regime, there is no significant difference caused by centrality measures in persuader selection for homogeneous network; while for heterogeneous networks, closeness centrality offers the best measure. PMID- 28072848 TI - Physiologic Determinants of Exercise Capacity in Pulmonary Langerhans Cell Histiocytosis: A Multidimensional Analysis. AB - BACKGROUND: Reduced exercise capacity severely impacts quality of life in pulmonary Langerhans cell histiocytosis. Ascertaining mechanisms that impair exercise capacity is necessary to identify targets for symptomatic treatments. METHODS: Dyspnea, pulmonary function tests and cardiopulmonary exercise test were analysed in 62 study participants. Data were compared between subjects with impaired and normal aerobic capacity (V'O2 peak less than 84% versus 84% predicted or more). Data were reduced using a principal component analysis. Multivariate analysis included V'O2 peak as the dependent variable and principal components as covariates. RESULTS: V'O2 peak was reduced in 44 subjects (71%). Subjects with impaired aerobic capacity presented: (i) decreased FEV1, FVC, FEV1/FVC, DLCO and DLCO/VA and increased AaDO2, (ii) increased ventilatory equivalents at ventilatory threshold, VD/VT peak, AaDO2 peak and PaCO2 peak and decreased ventilatory reserve and PaO2 peak. There was no difference between groups in dyspnea scores. Principal component analysis extracted 4 principal components interpreted as follows: PC1: gas exchange; PC2: "pseudorestriction"; PC3: exercise-induced hyperpnea; PC4: air trapping. Multivariate analysis explained 65% of V'O2 peak. The 4 principal components were independently associated with V'O2 peak (betacoefficients: PC1: 9.3 [4.6; 14], PC2: 7.5 [3; 11.9], PC3: -5.3 [-9.6;-1.], PC4: -9.8 [-14,9;-4.7]). CONCLUSION: Impaired exercise capacity is frequent in pulmonary Langerhans cell histiocytosis. It is mainly caused by pulmonary changes but is not associated with increased dyspnea intensity. Therefore, treating the lung represents a relevant approach for improving exercise capacity, even in patients experiencing mild dyspnea. PMID- 28072849 TI - Analysis of the Importance of Oxides and Clays in Cd, Cr, Cu, Ni, Pb and Zn Adsorption and Retention with Regression Trees. AB - This study determines the influence of the different soil components and of the cation-exchange capacity on the adsorption and retention of different heavy metals: cadmium, chromium, copper, nickel, lead and zinc. In order to do so, regression models were created through decision trees and the importance of soil components was assessed. Used variables were: humified organic matter, specific cation-exchange capacity, percentages of sand and silt, proportions of Mn, Fe and Al oxides and hematite, and the proportion of quartz, plagioclase and mica, and the proportions of the different clays: kaolinite, vermiculite, gibbsite and chlorite. The most important components in the obtained models were vermiculite and gibbsite, especially for the adsorption of cadmium and zinc, while clays were less relevant. Oxides are less important than clays, especially for the adsorption of chromium and lead and the retention of chromium, copper and lead. PMID- 28072850 TI - Chaos-Based Simultaneous Compression and Encryption for Hadoop. AB - Data compression and encryption are key components of commonly deployed platforms such as Hadoop. Numerous data compression and encryption tools are presently available on such platforms and the tools are characteristically applied in sequence, i.e., compression followed by encryption or encryption followed by compression. This paper focuses on the open-source Hadoop framework and proposes a data storage method that efficiently couples data compression with encryption. A simultaneous compression and encryption scheme is introduced that addresses an important implementation issue of source coding based on Tent Map and Piece-wise Linear Chaotic Map (PWLM), which is the infinite precision of real numbers that result from their long products. The approach proposed here solves the implementation issue by removing fractional components that are generated by the long products of real numbers. Moreover, it incorporates a stealth key that performs a cyclic shift in PWLM without compromising compression capabilities. In addition, the proposed approach implements a masking pseudorandom keystream that enhances encryption quality. The proposed algorithm demonstrated a congruent fit within the Hadoop framework, providing robust encryption security and compression. PMID- 28072851 TI - A Secure and Efficient Scalable Secret Image Sharing Scheme with Flexible Shadow Sizes. AB - In a general (k, n) scalable secret image sharing (SSIS) scheme, the secret image is shared by n participants and any k or more than k participants have the ability to reconstruct it. The scalability means that the amount of information in the reconstructed image scales in proportion to the number of the participants. In most existing SSIS schemes, the size of each image shadow is relatively large and the dealer does not has a flexible control strategy to adjust it to meet the demand of differen applications. Besides, almost all existing SSIS schemes are not applicable under noise circumstances. To address these deficiencies, in this paper we present a novel SSIS scheme based on a brand new technique, called compressed sensing, which has been widely used in many fields such as image processing, wireless communication and medical imaging. Our scheme has the property of flexibility, which means that the dealer can achieve a compromise between the size of each shadow and the quality of the reconstructed image. In addition, our scheme has many other advantages, including smooth scalability, noise-resilient capability, and high security. The experimental results and the comparison with similar works demonstrate the feasibility and superiority of our scheme. PMID- 28072852 TI - Efficacy of Peer Education for Adopting Preventive Behaviors against Head Lice Infestation in Female Elementary School Students: A Randomised Controlled Trial. AB - BACKGROUND: Pediculosis is a common parasitic infestation in students worldwide, including Iran. This condition is more prevalent in populous and deprived communities with poor personal hygiene. This study sought to assess the efficacy of peer education for adopting preventive behaviors against pediculosis in female elementary school students based on the Health Belief Model (HBM). METHODS: A total of 179 female fifth grade students were selected using multistage random sampling and were randomly allocated to control and intervention groups. A standard questionnaire was designed and administered to collect baseline information. An educational intervention was then designed based on the conducted needs assessment. The educational program consisted of three sessions, held by peers for the intervention group. The questionnaire was re-administered one month after the intervention. Independent and paired t-test, Pearson's correlation coefficient, and regression analysis were applied as appropriate. RESULTS: The two groups had no significant differences in the scores of knowledge, HBM constructs, or behavior before the intervention. After the intervention, however, the mean scores of all parameters significantly improved in the intervention group. CONCLUSION: Peer education based on HBM is an effective strategy to promote preventive behaviors against pediculosis in among fifth grade female elementary school students in Iran. PMID- 28072853 TI - Terrestrial Macrofungal Diversity from the Tropical Dry Evergreen Biome of Southern India and Its Potential Role in Aerobiology. AB - Macrofungi have long been investigated for various scientific purposes including their food and medicinal characteristics. Their role in aerobiology as a fraction of the primary biological aerosol particles (PBAPs), however, has been poorly studied. In this study, we present a source of macrofungi with two different but interdependent objectives: (i) to characterize the macrofungi from a tropical dry evergreen biome in southern India using advanced molecular techniques to enrich the database from this region, and (ii) to assess whether identified species of macrofungi are a potential source of atmospheric PBAPs. From the DNA analysis, we report the diversity of the terrestrial macrofungi from a tropical dry evergreen biome robustly supported by the statistical analyses for diversity conclusions. A total of 113 macrofungal species belonging to 54 genera and 23 families were recorded, with Basidiomycota and Ascomycota constituting 96% and 4% of the species, respectively. The highest species richness was found in the family Agaricaceae (25.3%) followed by Polyporaceae (15.3%) and Marasmiaceae (10.8%). The difference in the distribution of commonly observed macrofungal families over this location was compared with other locations in India (Karnataka, Kerala, Maharashtra, and West Bengal) using two statistical tests. The distributions of the terrestrial macrofungi were distinctly different in each ecosystem. We further attempted to demonstrate the potential role of terrestrial macrofungi as a source of PBAPs in ambient air. In our opinion, the findings from this ecosystem of India will enhance our understanding of the distribution, diversity, ecology, and biological prospects of terrestrial macrofungi as well as their potential to contribute to airborne fungal aerosols. PMID- 28072854 TI - Functional Richness and Identity Do Not Strongly Affect Invasibility of Constructed Dune Communities. AB - Biotic effects are often used to explain community structure and invasion resistance. We evaluated the contribution of functional richness and identity to invasion resistance and abiotic resource availability using a mesocosm experiment. We predicted that higher functional richness would confer greater invasion resistance through greater resource sequestration. We also predicted that niche pre-emption and invasion resistance would be higher in communities which included functional groups similar to the invader than communities where all functional groups were distinct from the invader. We constructed communities of different functional richness and identity but maintained constant species richness and numbers of individuals in the resident community. The constructed communities represented potential fore dune conditions following invader control activities along the Australian east coast. We then simulated an invasion event by bitou (Chrysanthemoides monilifera ssp. rotundata DC. Norl.), a South African shrub invader. We used the same bitou propagule pressure across all treatments and monitored invasion success and resource availability for 13 months. Contrary to our predictions, we found that functional richness did not mediate the number of bitou individuals or bitou cover and functional identity had little effect on invasion success: there was a trend for the grass single functional group treatment to supress bitou individuals, but this trend was obscured when grasses were in multi functional group treatments. We found that all constructed communities facilitated bitou establishment and suppressed bitou cover relative to unplanted mesocosms. Abiotic resource use was either similar among planted communities, or differences did not relate to invasion success (with the exception of light availability). We attribute invasion resistance to bulk plant biomass across planted treatments rather than their functional group arrangement. PMID- 28072855 TI - SDF-1alpha/CXCR4 Signaling in Lipid Rafts Induces Platelet Aggregation via PI3 Kinase-Dependent Akt Phosphorylation. AB - Stromal cell-derived factor-1alpha (SDF-1alpha)-induced platelet aggregation is mediated through its G protein-coupled receptor CXCR4 and phosphatidylinositol 3 kinase (PI3K). Here, we demonstrate that SDF-1alpha induces phosphorylation of Akt at Thr308 and Ser473 in human platelets. SDF-1alpha-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the CXCR4 antagonist AMD3100 or the PI3K inhibitor LY294002. SDF-1alpha also induces the phosphorylation of PDK1 at Ser241 (an upstream activator of Akt), GSK3beta at Ser9 (a downstream substrate of Akt), and myosin light chain at Ser19 (a downstream element of the Akt signaling pathway). SDF-1alpha-induced platelet aggregation is inhibited by pretreatment with the Akt inhibitor MK-2206 in a dose dependent manner. Furthermore, SDF-1alpha-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the raft-disrupting agent methyl-beta-cyclodextrin. Sucrose density gradient analysis shows that 35% of CXCR4, 93% of the heterotrimeric G proteins Galphai-1, 91% of Galphai-2, 50% of Gbeta and 4.0% of PI3Kbeta, and 4.5% of Akt2 are localized in the detergent resistant membrane raft fraction. These findings suggest that SDF-1alpha/CXCR4 signaling in lipid rafts induces platelet aggregation via PI3K-dependent Akt phosphorylation. PMID- 28072857 TI - Quantification of Local Warming Trend: A Remote Sensing-Based Approach. AB - Understanding the warming trends at local level is critical; and, the development of relevant adaptation and mitigation policies at those levels are quite challenging. Here, our overall goal was to generate local warming trend map at 1 km spatial resolution by using: (i) Moderate Resolution Imaging Spectroradiometer (MODIS)-based 8-day composite surface temperature data; (ii) weather station based yearly average air temperature data; and (iii) air temperature normal (i.e., 30 year average) data over the Canadian province of Alberta during the period 1961-2010. Thus, we analysed the station-based air temperature data in generating relationships between air temperature normal and yearly average air temperature in order to facilitate the selection of year-specific MODIS-based surface temperature data. These MODIS data in conjunction with weather station based air temperature normal data were then used to model local warming trends. We observed that almost 88% areas of the province experienced warming trends (i.e., up to 1.5 degrees C). The study concluded that remote sensing technology could be useful for delineating generic trends associated with local warming. PMID- 28072856 TI - Socioeconomic Inequalities in Body Mass Index across Adulthood: Coordinated Analyses of Individual Participant Data from Three British Birth Cohort Studies Initiated in 1946, 1958 and 1970. AB - BACKGROUND: High body mass index (BMI) is an important contributor to the global burden of ill-health and health inequality. Lower socioeconomic position (SEP) in both childhood and adulthood is associated with higher adult BMI, but how these associations have changed across time is poorly understood. We used longitudinal data to examine how childhood and adult SEP relates to BMI across adulthood in three national British birth cohorts. METHODS AND FINDINGS: The sample comprised up to 22,810 participants with 77,115 BMI observations in the 1946 MRC National Survey of Health and Development (ages 20 to 60-64), the 1958 National Child Development Study (ages 23 to 50), and the 1970 British Cohort Study (ages 26 to 42). Harmonized social class-based SEP data (Registrar General's Social Class) was ascertained in childhood (father's class at 10/11 y) and adulthood (42/43 years), and BMI repeatedly across adulthood, spanning 1966 to 2012. Associations between SEP and BMI were examined using linear regression and multilevel models. Lower childhood SEP was associated with higher adult BMI in both genders, and differences were typically larger at older ages and similar in magnitude in each cohort. The strength of association between adult SEP and BMI did not vary with age in any consistent pattern in these cohorts, but were more evident in women than men, and inequalities were larger among women in the 1970 cohort compared with earlier-born cohorts. For example, mean differences in BMI at 42/43 y amongst women in the lowest compared with highest social class were 2.0 kg/m2 (95% CI: -0.1, 4.0) in the 1946 NSHD, 2.3 kg/m2 (1.1, 3.4) in the 1958 NCDS, and 3.9 kg/m2 (2.3, 5.4) the in the 1970 BCS; mean (SD) BMI in the highest and lowest social classes were as follows: 24.9 (0.8) versus 26.8 (0.7) in the 1946 NSHD, 24.2 (0.4) versus 26.5 (0.4) in the 1958 NCDS, and 24.2 (0.3) versus 28.1 (0.8) in the 1970 BCS. Findings did not differ whether using overweight or obesity as an outcome. Limitations of this work include the use of social class as the sole indicator of SEP-while it was available in each cohort in both childhood and adulthood, trends in BMI inequalities may differ according to other dimensions of SEP such as education or income. Although harmonized data were used to aid inferences about birth cohort differences in BMI inequality, differences in other factors may have also contributed to findings-for example, differences in missing data. CONCLUSIONS: Given these persisting inequalities and their public health implications, new and effective policies to reduce inequalities in adult BMI that tackle inequality with respect to both childhood and adult SEP are urgently required. PMID- 28072858 TI - Proton Pump Inhibitors Do Not Reduce the Risk of Esophageal Adenocarcinoma in Patients with Barrett's Esophagus: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: Proton pump inhibitors (PPIs) have been used for treatment of Barrett's esophagus (BE) for many years. However, the connection between PPIs and esophageal adenocarcinoma (EAC) in patients with BE has still been controversial. The current systematic review and meta-analysis was designed to evaluate the association between PPIs and the risk of EAC or high-grade dysplasia (HGD) in patients with BE. METHODS: A systematic literature search of studies reporting the association between PPIs and the risk of EAC and/or HGD in patients with BE was conducted in PubMed, Embase, Web of Science and the Cochrane Library. Next, literature was screened using previously established criteria and relevant data were extracted from included studies. Finally, the software program Review Manage 5.2 was applied to aggregate data and analyze the results. RESULTS: Nine observational studies, comprising five cohort and four case-control studies (including a total of 5712 patients with BE), were identified. Upon meta analysis, PPIs were found to have no association with the risk of EAC and/or HGD in patients with BE (unadjusted OR 0.43, 95% CI 0.17-1.08). Analysis for duration response relationship revealed no significant trend toward protection against EAC or HGD with PPIs usage for >2~3 years (one study using 7-year cutoff) when compared to usage for shorter time periods (PPIs usage >2~3 years vs. <2~3 years: OR 0.91 (95% CI 0.25-3.31) vs. 0.91 (0.40-2.07)).There also was considerable heterogeneity between studies. CONCLUSION: No dysplasia- or cancer-protective effects of PPIs usage in patients with BE were identified by our analysis. Therefore, we conclude that clinicians who discuss the potential chemopreventive effects of PPIs with their patients, should be aware that such an effect, if exists, has not been proven with statistical significance. PMID- 28072859 TI - Increased PD-1 Expression and Altered T Cell Repertoire Diversity Predict Mortality in Patients with Septic Shock: A Preliminary Study. AB - Sepsis causes impairment of innate and adaptive immunity by multiple mechanisms, including depletion of immune effector cells and T cell exhaustion. Although lymphocyte dysfunction is associated with increased mortality and potential reactivation of latent viral infection in patients with septic shock, the relation between viral reactivation and lymphocyte dysfunction is obscure. The objectives of this study were 1) to determine the relation of lymphocyte dysfunction to viral reactivation and mortality, and 2) to evaluate recovery of lymphocyte function during septic shock, including T cell receptor (TCR) diversity and the expression of programmed death 1 (PD-1). In 18 patients with septic shock and latent cytomegalovirus (CMV) infection, serial blood samples were obtained on days 1, 3, and 7 after the onset of shock, and immune cell subsets and receptor expression were characterized by flow cytometry. TCR diversity of peripheral blood mononuclear cells was analyzed by Multi-N-plex PCR, and CMV DNA was quantified using a real-time PCR kit. A decrease of TCR diversity and monocyte HLA-DR expression were observed in the early stage of septic shock, while CD4+ T cells displayed an increase of PD-1 expression. Significant lymphopenia persisted for at least 7 days following the onset of septic shock. Normalization of TCR diversity and PD-1 expression was observed by day 7, except in patients who died. CMV reactivation was detected in 3 of the 18 patients during the first week of their ICU stay and all 3 patients died. These changes are consistent with the early stage of immune cell exhaustion and indicate the importance of normal lymphocyte function for recovery from septic shock. Ongoing lymphocyte dysfunction is associated with CMV reactivation and dissemination, as well as with unfavorable outcomes. PMID- 28072860 TI - Hyperbilirubinemia Influences Sleep-Wake Cycles of Term Newborns in a Non-Linear Manner. AB - Hyperbilirubinemia is a common cause for irreversible neuronal influence in the brain of term newborns, while the feature of neurological symptoms associated with hyperbilirubinemia has not been well characterized yet. In the present study, we examined a total of 203 neonates suffering from hyperbilirubinemia with a bedside amplitude-integrated Electroencephalography (aEEG) device, in order to determine whether there is any special change in sleep-wake cycles (SWCs). Among these patients, 14 cases showed no recognizable SWCs with the total serum bilirubin (TSB) level at 483.9-996.2 MUmol/L; 75 cases exhibited reduced SWCs with the TSB level at 311.2-688.5 MUmol/L; and the rest cases had the normal SWCs. The number of the normal SWCs occurrence had a significant negative correlation with the increased TSB level in a non-linear manner (r = -0.689, p <0.001). In addition, the increased TSB reshaped the structure of SWC by narrowing down the broadband and broadening the narrowband. Spearman's correlation analysis indicated a significant negative correlation between the TSB level and the ratio of broadband (r = -0.618, p < 0.001), a significant positive correlation between the TSB level and the narrowband ratio (r = 0.618, p < 0.001), respectively. Furthermore, the change of SWC seemed like a continuous phenomenon, and the hyperbilirubinemia caused SWC changes was fit into a loess model in this paper. In summary, the hyperbilirubinemia influenced SWC of term newborns significantly at a non-linear manner, and these results revealed the feature of the neurological sequela that is associated with TSB. PMID- 28072861 TI - Identification of the Molecular Clockwork of the Oyster Crassostrea gigas. AB - Molecular clock system constitutes the origin of biological rhythms that allow organisms to anticipate cyclic environmental changes and adapt their behavior and physiology. Components of the molecular clock are largely conserved across a broad range of species but appreciable diversity in clock structure and function is also present especially in invertebrates. The present work aimed at identify and characterize molecular clockwork components in relationship with the monitoring of valve activity behavior in the oyster Crassostrea gigas. Results provided the characterization of most of canonical clock gene including clock, bmal/cycle, period, timeless, vertebrate-type cry, rev-erb, ror as well as other members of the cryptochrome/photolyase family (plant-like cry, 6-4 photolyase). Analyses of transcriptional variations of clock candidates in oysters exposed to light / dark regime and to constant darkness led to the generation of a putative and original clockwork model in C. gigas, intermediate of described systems in vertebrates and insects. This study is the first characterization of a mollusk clockwork. It constitutes essential bases to understand interactions of the different components of the molecular clock in C. gigas as well as the global mechanisms associated to the generation and the synchronization of biological rhythms in oysters. PMID- 28072862 TI - Efficacy and Safety of Initial Combination Treatment of an Alpha Blocker with an Anticholinergic Medication in Benign Prostatic Hyperplasia Patients with Lower Urinary Tract Symptoms: Updated Meta-Analysis. AB - BACKGROUND: There is still controversy as to whether initial combination treatment is superior to serial addition of anticholinergics after maintenance or induction of alpha blockers in benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS). OBJECTIVE: The objective of this study was to determine the benefits and safety of initial combination treatment of an alpha blocker with anticholinergic medication in BPH/LUTS through a systematic review and meta analysis. METHODS: We conducted a meta-analysis of improvement in LUTS using International Prostate Symptom Score (IPSS), maximal urinary flow rate (Qmax), post-voided residual volume (PVR), and quality of life (QoL). RESULTS: In total, 16 studies were included in our analysis, with a total sample size of 3,548 subjects (2,195 experimental subjects and 1,353 controls). The mean change in total IPSS improvement from baseline in the combination group versus the alpha blocker monotherapy group was -0.03 (95% CI: -0.14-0.08). The pooled overall SMD change of storage IPSS improvement from baseline was -0.28 (95% CI: -0.40 - 0.17). The pooled overall SMD changes of QoL, Qmax, and PVR were -0.29 (95% CI: 0.50 - -0.07), 0.00 (95% CI: -0.08-0.08), and 0.56 (95% CI: 0.23-0.89), respectively. There was no significant difference in the number of acute urinary retention (AUR) events or PVR. CONCLUSIONS: Initial combination treatment of an alpha blocker with anticholinergic medication is efficacious for in BPH/ LUTS with improved measures such as storage symptoms and QoL without causing significant deterioration of voiding function. PMID- 28072863 TI - A Single Dose Oral Azithromycin versus Intramuscular Benzathine Penicillin for the Treatment of Yaws-A Randomized Non Inferiority Trial in Ghana. AB - BACKGROUND: Yaws is a treponemal infection that was almost eradicated fifty years ago; however, the disease has re-emerged in a number of countries including Ghana. A single-dose of intramuscular benzathine penicillin has been the mainstay of treatment for yaws. However, intramuscular injections are painful and pose safety and logistical constraints in the poor areas where yaws occurs. A single center randomized control trial (RCT) carried out in Papua New Guinea in 2012 demonstrated the efficacy of a single-dose of oral azithromycin for the treatment of yaws. In this study, we also compared the efficacy of a single oral dose of azithromycin as an alternative to intramuscular benzathine penicillin for the treatment of the disease in another geographic setting. METHODOLOGY: We conducted an open-label, randomized non-inferiority trial in three neighboring yaws-endemic districts in Southern Ghana. Children aged 1-15 years with yaws lesions were assigned to receive either 30mg/kg of oral azithromycin or 50,000 units/kg of intramuscular benzathine penicillin. The primary end point was clinical cure rate, defined as a complete or partial resolution of lesions 3 weeks after treatment. The secondary endpoint was serological cure, defined as at least a 4 fold decline in baseline RPR titre 6 months after treatment. Non- inferiority of azithromycin treatment was determined if the upper bound limit of a 2 sided 95% CI was less than 10%. FINDINGS: The mean age of participants was 9.5 years (S.D.3.1, range: 1-15 years), 247(70%) were males. The clinical cure rates were 98.2% (95% CI: 96.2-100) in the azithromycin group and 96.9% (95% CI: 94.1-99.6) in the benzathine penicillin group. The serological cure rates at 6 months were 57.4% (95% CI: 49.9-64.9) in the azithromycin group and 49.1% (95% CI: 41.2-56.9) in the benzathine penicillin group, thus achieving the specified criteria for non inferiority. CONCLUSIONS: A single oral dose of azithromycin, at a dosage of 30mg/kg, was non-inferior to a single dose of intramuscular benzathine penicillin for the treatment of early yaws among Ghanaian patients, and provides additional support for the WHO policy for use of oral azithromycin for the eradication of yaws in resource-poor settings. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR2013030005181 http://www.pactr.org/. PMID- 28072864 TI - 1H NMR Metabolomics Reveals Association of High Expression of Inositol 1, 4, 5 Trisphosphate Receptor and Metabolites in Breast Cancer Patients. AB - 1H NMR is used to detect alterations in metabolites and their linkage to metabolic processes in a number of pathological conditions including breast cancer. Inositol 1, 4, 5 trisphosphate (IP3R) receptor is an intracellular calcium channel known to regulate metabolism and cellular bioenergetics. Its expression is up regulated in a number of cancers. However, its linkage to metabolism in disease conditions has not been evaluated. This study was designed to determine the association if any, of these metabolites with altered expression of IP3R in breast cancer. We used 1H NMR to identify metabolites in the serum of breast cancer patients (n = 27) and performed Real-time Polymerase Chain Reaction analysis for quantifying the expression of IP3R type 3 and type 2 in tissues from breast cancer patients (n = 40). Principal Component Analysis (PCA) and Partial Least Square-Discriminant Analysis (PLS-DA) clearly distinguished patients with high/low IP3R expression from healthy subjects. The present study revealed high expression of IP3R type 2 and type 3 in human breast tumor tissue compared to adjacent non-tumorous tissue. Moreover, patients with >= 2-fold increase in IP3R (high IP3R group) had significantly higher concentration of metabolic intermediates compared to those with < 2-fold increase in IP3R (low IP3R group). We observed an increase in lipoprotein content and the levels of metabolites like lactate, lysine and alanine and a decrease in the levels of pyruvate and glucose in serum of high IP3R group patients when compared to those in healthy subjects. Receiver operating characteristic (ROC) curve analysis was performed to show the clinical utility of metabolites. In addition to the human studies, functional relevance of IP3Rs in causing metabolic disruption was observed in MCF-7 and MDA MB-231 cells. Results from our studies bring forth the importance of metabolic (or metabolomics) profiling of serum by 1H NMR in conjunction with tissue expression studies for characterizing breast cancer patients. The results from this study provide new insights into relationship of breast cancer metabolites with IP3R. PMID- 28072865 TI - Reading the Evolution of Compartmentalization in the Ribosome Assembly Toolbox: The YRG Protein Family. AB - Reconstructing the transition from a single compartment bacterium to a highly compartmentalized eukaryotic cell is one of the most studied problems of evolutionary cell biology. However, timing and details of the establishment of compartmentalization are unclear and difficult to assess. Here, we propose the use of molecular markers specific to cellular compartments to set up a framework to advance the understanding of this complex intracellular process. Specifically, we use a protein family related to ribosome biogenesis, YRG (YlqF related GTPases), whose evolution is linked to the establishment of cellular compartments, leveraging the current genomic data. We analyzed orthologous proteins of the YRG family in a set of 171 proteomes for a total of 370 proteins. We identified ten YRG protein subfamilies that can be associated to six subcellular compartments (nuclear bodies, nucleolus, nucleus, cytosol, mitochondria, and chloroplast), and which were found in archaeal, bacterial and eukaryotic proteomes. Our analysis reveals organism streamlining related events in specific taxonomic groups such as Fungi. We conclude that the YRG family could be used as a compartmentalization marker, which could help to trace the evolutionary path relating cellular compartments with ribosome biogenesis. PMID- 28072866 TI - The Regulatory Roles of MicroRNA in Effects of 2,2'4,4'-Tetrabromodiphenyl Ether (BDE47) on the Transcriptome of Zebrafish Larvae. AB - The developmental neurotoxicity caused by environmental pollutants has received great concern; however, there were still barely known about the underlying toxic mechanisms, especially the influence of varieties of regulatory factors such as microRNA (miRNA). A representative flame retardant, 2,2',4,4'-tetrabromodiphenyl ether (BDE47), was found to disrupt zebrafish development in visual perception and bone formation in previous study, thus here we investigated its effects on miRNA expression profiling of 6 days post fertilization (dpf) zebrafish larvae by deep sequencing. To overcome the shortage of zebrafish miRNA annotation, multiple data processing approaches, especially constructed network based on the interactions between miRNAs and enrichment terms, were adopted and helped us acquire several validated zebrafish miRNAs and two novel miRNAs in BDE47-induced effects, and identify corresponding biological processes of the miRNAs. Among them, miR-735 was supposed to play essential roles in larval sensory development according to analysis results. Our study also provided an effective strategy for analyzing biological effects on non-mammalian miRNAs with limited basic information. PMID- 28072867 TI - Complex Economies Have a Lateral Escape from the Poverty Trap. AB - We analyze the decisive role played by the complexity of economic systems at the onset of the industrialization process of countries over the past 50 years. Our analysis of the input growth dynamics, considering a further dimension through a recently introduced measure of economic complexity, reveals that more differentiated and more complex economies face a lower barrier (in terms of GDP per capita) when starting the transition towards industrialization. As a consequence, we can extend the classical concept of a one-dimensional poverty trap, by introducing a two-dimensional poverty trap: a country will start the industrialization process if it is rich enough (as in neo-classical economic theories), complex enough (using this new dimension and laterally escaping from the poverty trap), or a linear combination of the two. This naturally leads to the proposal of a Complex Index of Relative Development (CIRD) which shows, when analyzed as a function of the growth due to input, a shape of an upside down parabola similar to that expected from the standard economic theories when considering only the GDP per capita dimension. PMID- 28072868 TI - Phosphatidylserine Outer Layer Translocation Is Implicated in IL-10 Secretion by Human Regulatory B Cells. AB - B cells can have a regulatory role, mainly mediated by interleukin 10 (IL-10). IL 10 producing B cells (B10 cells) cells remain to be better characterized. Annexin V binds phosphatidylserine (PS), which is externalized during apoptosis. Previous works suggested that B10 cells are apoptotic cells since they bind Annexin V. Others showed that Annexin V binding could also be expressed on viable B cells. We aimed to explore if PS exposure can be a marker of B10 cells and if PS exposure has a functional role on B cell IL-10 production in healthy subjects. We found that B10 cells were significantly more often Annexin V+ than IL-10 non producing B cells. After CpG activation, Annexin V+ B cells differentiated more often into B10 cells than Annexin Vneg B cells. Cell death and early apoptosis were similar between Annexin V+ and Annexin Vneg B cells. PS blockage, using biotinylated AnV and glyburide, decreased B10 cell differentiation. This study showed that B10 cells have an increased PS exposure independently of any apoptotic state. B cells exposing PS differentiate more into B10 cells whereas PS blockage inhibits B10 cells generation. These results strongly suggest a link between PS exposure and B10 cells. PMID- 28072870 TI - Mathematical Modeling of Intestinal Iron Absorption Using Genetic Programming. AB - Iron is a trace metal, key for the development of living organisms. Its absorption process is complex and highly regulated at the transcriptional, translational and systemic levels. Recently, the internalization of the DMT1 transporter has been proposed as an additional regulatory mechanism at the intestinal level, associated to the mucosal block phenomenon. The short-term effect of iron exposure in apical uptake and initial absorption rates was studied in Caco-2 cells at different apical iron concentrations, using both an experimental approach and a mathematical modeling framework. This is the first report of short-term studies for this system. A non-linear behavior in the apical uptake dynamics was observed, which does not follow the classic saturation dynamics of traditional biochemical models. We propose a method for developing mathematical models for complex systems, based on a genetic programming algorithm. The algorithm is aimed at obtaining models with a high predictive capacity, and considers an additional parameter fitting stage and an additional Jackknife stage for estimating the generalization error. We developed a model for the iron uptake system with a higher predictive capacity than classic biochemical models. This was observed both with the apical uptake dataset used for generating the model and with an independent initial rates dataset used to test the predictive capacity of the model. The model obtained is a function of time and the initial apical iron concentration, with a linear component that captures the global tendency of the system, and a non-linear component that can be associated to the movement of DMT1 transporters. The model presented in this paper allows the detailed analysis, interpretation of experimental data, and identification of key relevant components for this complex biological process. This general method holds great potential for application to the elucidation of biological mechanisms and their key components in other complex systems. PMID- 28072869 TI - Discovery and Molecular Basis of a Diverse Set of Polycomb Repressive Complex 2 Inhibitors Recognition by EED. AB - Polycomb repressive complex 2 (PRC2), a histone H3 lysine 27 methyltransferase, plays a key role in gene regulation and is a known epigenetics drug target for cancer therapy. The WD40 domain-containing protein EED is the regulatory subunit of PRC2. It binds to the tri-methylated lysine 27 of the histone H3 (H3K27me3), and through which stimulates the activity of PRC2 allosterically. Recently, we disclosed a novel PRC2 inhibitor EED226 which binds to the K27me3-pocket on EED and showed strong antitumor activity in xenograft mice model. Here, we further report the identification and validation of four other EED binders along with EED162, the parental compound of EED226. The crystal structures for all these five compounds in complex with EED revealed a common deep pocket induced by the binding of this diverse set of compounds. This pocket was created after significant conformational rearrangement of the aromatic cage residues (Y365, Y148 and F97) in the H3K27me3 binding pocket of EED, the width of which was delineated by the side chains of these rearranged residues. In addition, all five compounds interact with the Arg367 at the bottom of the pocket. Each compound also displays unique features in its interaction with EED, suggesting the dynamics of the H3K27me3 pocket in accommodating the binding of different compounds. Our results provide structural insights for rational design of novel EED binder for the inhibition of PRC2 complex activity. PMID- 28072871 TI - Atrophic and Metaplastic Progression in the Background Mucosa of Patients with Gastric Adenoma. AB - BACKGROUND: In patients with adenoma, assessing premalignant changes in the surrounding mucosa is important for surveillance. This study evaluated atrophic and metaplastic progression in the background mucosa of adenoma or early gastric cancer (EGC) cases. METHODS: Among 146 consecutive patients who underwent endoscopic resection for intestinal-type gastric neoplasia, the adenoma group included 56 patients with low-grade dysplasia and the ECG group included 90 patients with high-grade dysplasia or invasive carcinoma. For histology, 3 paired biopsies were obtained from the antrum, corpus lesser curvature (CLC), and corpus greater curvature (CGC). Serological atrophy was determined based on pepsinogen A (PGA), progastricsin (PGC), gastrin-17, and total ghrelin levels. Topographic progression of atrophy and/or metaplasia was staged using the operative link on gastritis assessment (OLGA) and operative link on gastric intestinal metaplasia assessment (OLGIM) systems. RESULTS: Rates of moderate-to-marked histological atrophy/metaplasia in patients with adenoma were 52.7%/78.2% at the antrum (vs. 58.8%/76.4% in EGC group), 63.5%/75.0% at the CLC (vs. 60.2%/69.7% in EGC group), and 10.9%/17.9% at the CGC (vs. 5.6%/7.8% in EGC group). Serological atrophy indicated by PGA and PGC occurred in 23.2% and 15.6% of cases in the adenoma and ECG groups, respectively (p = 0.25). Mean serum gastrin-17 concentrations of the adenoma group and EGC group were 10.4 and 9.0 pmol/L, respectively (p = 0.54). Mean serum total ghrelin levels were 216.6 and 209.5 pg/mL, respectively (p = 0.71). Additionally, between group rates of stage III-IV OLGA and OLGIM were similar (25.9% vs. 25.0%, p = 0.90; 41.8% vs. 44.9%, p = 0.71, respectively). CONCLUSIONS: Atrophic and metaplastic progression is extensive and severe in gastric adenoma patients. A surveillance strategy for metachronous tumors should be applied similarly for patients with adenoma or EGC. PMID- 28072872 TI - Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis. AB - BACKGROUND: Artemisinin-based combination therapies (ACTs) are the mainstay of the current treatment of uncomplicated Plasmodium falciparum malaria, but ACT resistance is spreading across Southeast Asia. Dihydroartemisinin-piperaquine is one of the five ACTs currently recommended by the World Health Organization. Previous studies suggest that young children (<5 y) with malaria are under-dosed. This study utilised a population-based pharmacokinetic approach to optimise the antimalarial treatment regimen for piperaquine. METHODS AND FINDINGS: Published pharmacokinetic studies on piperaquine were identified through a systematic literature review of articles published between 1 January 1960 and 15 February 2013. Individual plasma piperaquine concentration-time data from 11 clinical studies (8,776 samples from 728 individuals) in adults and children with uncomplicated malaria and healthy volunteers were collated and standardised by the WorldWide Antimalarial Resistance Network. Data were pooled and analysed using nonlinear mixed-effects modelling. Piperaquine pharmacokinetics were described successfully by a three-compartment disposition model with flexible absorption. Body weight influenced clearance and volume parameters significantly, resulting in lower piperaquine exposures in small children (<25 kg) compared to larger children and adults (>=25 kg) after administration of the manufacturers' currently recommended dose regimens. Simulated median (interquartile range) day 7 plasma concentration was 29.4 (19.3-44.3) ng/ml in small children compared to 38.1 (25.8-56.3) ng/ml in larger children and adults, with the recommended dose regimen. The final model identified a mean (95% confidence interval) increase of 23.7% (15.8%-32.5%) in piperaquine bioavailability between each piperaquine dose occasion. The model also described an enzyme maturation function in very young children, resulting in 50% maturation at 0.575 (0.413-0.711) y of age. An evidence-based optimised dose regimen was constructed that would provide piperaquine exposures across all ages comparable to the exposure currently seen in a typical adult with standard treatment, without exceeding the concentration range observed with the manufacturers' recommended regimen. Limited data were available in infants and pregnant women with malaria as well as in healthy individuals. CONCLUSIONS: The derived population pharmacokinetic model was used to develop a revised dose regimen of dihydroartemisinin-piperaquine that is expected to provide equivalent piperaquine exposures safely in all patients, including in small children with malaria. Use of this dose regimen is expected to prolong the useful therapeutic life of dihydroartemisinin-piperaquine by increasing cure rates and thereby slowing resistance development. This work was part of the evidence that informed the World Health Organization technical guidelines development group in the development of the recently published treatment guidelines (2015). PMID- 28072873 TI - Association Study with 77 SNPs Confirms the Robust Role for the rs10830963/G of MTNR1B Variant and Identifies Two Novel Associations in Gestational Diabetes Mellitus Development. AB - CONTEXT: Genetic variation in human maternal DNA contributes to the susceptibility for development of gestational diabetes mellitus (GDM). OBJECTIVE: We assessed 77 maternal single nucleotide gene polymorphisms (SNPs) for associations with GDM or plasma glucose levels at OGTT in pregnancy. METHODS: 960 pregnant women (after dropouts 820: case/control: m99'WHO: 303/517, IADPSG: 287/533) were enrolled in two countries into this case-control study. After genomic DNA isolation the 820 samples were collected in a GDM biobank and assessed using KASP (LGC Genomics) genotyping assay. Logistic regression risk models were used to calculate ORs according to IADPSG/m'99WHO criteria based on standard OGTT values. RESULTS: The most important risk alleles associated with GDM were rs10830963/G of MTNR1B (OR = 1.84/1.64 [IADPSG/m'99WHO], p = 0.0007/0.006), rs7754840/C (OR = 1.51/NS, p = 0.016) of CDKAL1 and rs1799884/T (OR = 1.4/1.56, p = 0.04/0.006) of GCK. The rs13266634/T (SLC30A8, OR = 0.74/0.71, p = 0.05/0.02) and rs7578326/G (LOC646736/IRS1, OR = 0.62/0.60, p = 0.001/0.006) variants were associated with lower risk to develop GDM. Carrying a minor allele of rs10830963 (MTNR1B); rs7903146 (TCF7L2); rs1799884 (GCK) SNPs were associated with increased plasma glucose levels at routine OGTT. CONCLUSIONS: We confirmed the robust association of MTNR1B rs10830963/G variant with GDM binary and glycemic traits in this Caucasian case-control study. As novel associations we report the minor, G allele of the rs7578326 SNP in the LOC646736/IRS1 region as a significant and the rs13266634/T SNP (SLC30A8) as a suggestive protective variant against GDM development. Genetic susceptibility appears to be more preponderant in individuals who meet both the modified 99'WHO and the IADPSG GDM diagnostic criteria. PMID- 28072874 TI - Similarity of Center of Pressure Progression during Walking and Jogging of Anterior Cruciate Ligament Deficient Patients. AB - OBJECTIVE: To evaluate the center of pressure (COP) progression similarity and its change during walking and jogging in Anterior Cruciate Ligament deficient (ACLD) patients. METHODS: A study was performed in 64 unilateral ACLD subjects and 32 healthy volunteers who walked and jogged on footscan(r) system at a self selected speed. COP trajectory during walking and jogging was calculated. The robustness and similarity scores of COP (SSCOP, similarity scores with respect to corresponding COP trajectories) were computed, and then the Analysis of Variance test was employed to compare among different conditions (left or right side, within a subject or between subjects, walking or jogging). RESULTS: (1) During the same motion status (walking or jogging), SSCOP were higher than 0.885. However, SSCOP between walking and jogging were lower than 0.25 in both the healthy and ACLD group. SSCOP between the intrasubjects were statistically higher than those between the intersubjects (p<0.01). (2) SSCOP in the ACLD group were statistically significantly reduced to 0.885+/-0.074 compared to 0.912+/-0.057 in healthy volunteers during walking, and 0.903+/-0.066 in the ACLD group compared to 0.919+/-0.050 in the healthy group during jogging (p<0.01). CONCLUSIONS: SSCOP can distinguish walking from jogging, and SSCOP of ACLD patients would be different from that of healthy controls. The study protocol was approved by the Institutional Research Board of Peking University Third Hospital (IRB00006761 2012010). PMID- 28072875 TI - Characterization of the Activity Spectrum of MON 88702 and the Plant-Incorporated Protectant Cry51Aa2.834_16. AB - The spectrum of insecticidal activity of Cry51Aa2.834_16 protein targeting hemipteran and thysanopteran insect pests in cotton was characterized by selecting and screening multiple pest and non-pest species, based on representation of ecological functional groups, taxonomic relatedness (e.g. relationship to species where activity was observed), and availability for effective testing. Seven invertebrate orders, comprising 12 families and 17 representative species were screened for susceptibility to Cry51Aa2.834_16 protein and/or the ability of the protein to protect against feeding damage in laboratory, controlled environments (e.g. greenhouse/growth chamber), and/or field studies when present in cotton plants. The screening results presented for Cry51Aa2.834_16 demonstrate selective and limited activity within three insect orders. Other than Orius insidiosus, no activity was observed for Cry51Aa2.834_16 against several groups of arthropods that perform key ecological roles in some agricultural ecosystems (e.g. pollinators, decomposers, and natural enemies). PMID- 28072876 TI - Genetic Nature of Elemental Contents in Wheat Grains and Its Genomic Prediction: Toward the Effective Use of Wheat Landraces from Afghanistan. AB - Profiling elemental contents in wheat grains and clarifying the underlying genetic systems are important for the breeding of biofortified crops. Our objective was to evaluate the genetic potential of 269 Afghan wheat landraces for increasing elemental contents in wheat cultivars. The contents of three major (Mg, K, and P) and three minor (Mn, Fe, and Zn) elements in wheat grains were measured by energy dispersive X-ray fluorescence spectrometry. Large variations in elemental contents were observed among landraces. Marker-based heritability estimates were low to moderate, suggesting that the elemental contents are complex quantitative traits. Genetic correlations between two locations (Japan and Afghanistan) and among the six elements were estimated using a multi-response Bayesian linear mixed model. Low-to-moderate genetic correlations were observed among major elements and among minor elements respectively, but not between major and minor elements. A single-response genome-wide association study detected only one significant marker, which was associated with Zn, suggesting it will be difficult to increase the elemental contents of wheat by conventional marker assisted selection. Genomic predictions for major elemental contents were moderately or highly accurate, whereas those for minor elements were mostly low or moderate. Our results indicate genomic selection may be useful for the genetic improvement of elemental contents in wheat. PMID- 28072877 TI - Motor Cortex Theta and Gamma Architecture in Young Adult APPswePS1dE9 Alzheimer Mice. AB - Alzheimer's disease (AD) is a multifactorial disorder leading to progressive memory loss and eventually death. In this study, an APPswePS1dE9 AD mouse model has been analyzed for motor cortex theta, beta and gamma frequency alterations using computerized 3D stereotaxic electrode positioning and implantable video-EEG radiotelemetry to perform long-term M1 recordings from both genders considering age, circadian rhythm and activity status of experimental animals. We previously demonstrated that APPswePS1dE9 mice exibit complex alterations in hippocampal frequency power and another recent investigation reported a global increase of alpha, beta and gamma power in APPswePS1dE9 in females of 16-17 weeks of age. In this cortical study in APPswePS1dE9 mice we did not observe any changes in theta, beta and particularly gamma power in both genders at the age of 14, 15, 18 and 19 weeks. Importantly, no activity dependence of theta, beta and gamma activity could be detected. These findings clearly point to the fact that EEG activity, particularly gamma power exhibits developmental changes and spatial distinctiveness in the APPswePS1dE9 mouse model of Alzheimer's disease. PMID- 28072878 TI - Signal-Amplified Lateral Flow Test Strip for Visual Detection of Cu2. AB - A signal-amplified lateral flow test strip (SA-LFTS) for the detection of Cu2+ in aqueous solution was constructed based on Cu+-catalyzed click chemistry and hybridization of single-stranded DNA (ssDNA). Alkyne and azide modified ssDNA acted as specific elements for Cu2+ recognition, and a chemical ligation product formed through Cu+-catalyzed alkyne-azide cycloaddition. Hybridization of ssDNA labeled gold nanoparticles resulted in high sensitivity, and the output signal could be observed directly by the naked eye. Using the developed SA-LFTS under optimal conditions, Cu2+ could be detected rapidly with limit of detections of 5 nM and 4.2 nM by visual observation and quantitative analysis, respectively. The sensitivity (i.e. the visual limit of detection) of the SA-LFTS was 80-times higher than that of traditional LFTS. The SA-LFTS was applied to the determination of Cu2+ in municipal water and river water samples with the results showing good recovery and accuracy. The developed test strip is promising for point-of-care applications and detection of Cu2+ in the field. PMID- 28072879 TI - Transcriptomic Analysis of Calonectria pseudoreteaudii during Various Stages of Eucalyptus Infection. AB - Eucalyptus leaf blight caused by Calonectria spp. is a serious disease in Eucalyptus seedling and plantations. However, the molecular mechanisms of the infection process and pathogenesis of Calonectria to Eucalyptus is not well studied. In this study, we analyzed the transcriptomes of C. pseudoreteaudii at three stages of Eucalyptus leaf infection, and in mycelium grown in potato dextrose broth using Illumina RNA-Seq technology. We identified 161 differentially expressed genes between C. pseudoreteaudii from leaf and mycelium grown in potato dextrose broth. GO and KEGG enrichment analyses of these genes suggested that they were mainly involved in oxidoreductase activity, hydrolase activity, and transmembrane transporter activity. Most of the differentially expressed genes at the early infection stage were upregulated. These upregulated genes were mainly involved in cell wall hydrolysis and toxin synthesis, suggesting a role for toxin and cell wall hydrolases in the establishment of Calonectria leaf blight. Genes related to detoxification of phytoalexins were continually upregulated during infection. The candidate effectors and putative pathogenicity determinants identified in this study will help in the functional analysis of C. pseudoreteaudii virulence and pathogenicity. PMID- 28072881 TI - Reciprocal Symbiont Sharing in the Lodging Mutualism between Walking Corals and Sipunculans. AB - Solitary scleractinian corals of the genera Heterocyathus and Heteropsammia inhabit soft marine bottoms without attaching to hard substrata. The corallums of these genera contain a coiled cavity inhabited by a sipunculan that roams the seafloor, carrying the host coral with it. The coral serves as a sturdy shelter that protects the sipunculan from possible predators. At the same time, the sipunculan maintains the coral in an upright position on the soft bottom. This coral-sipunculan association is unique because two phylogenetically distant coral genera have developed convergent associations with sipunculans. We investigate the process of convergent evolution of two coral species, Hc. aequicostatus and Hp. cochlea, in Okinawa, Japan, with their symbiotic sipunculans, using phylogenetic and morphological analyses. Phylogenetic analyses clarified that the symbiotic sipunculans comprise two distinct clades, surprisingly both of which are associated with both coral species. The bodily habitus of the sipunculan differed between coral species and fit the morphologies of the coiled cavities of their respective host corals. Our results suggest that the two coral species share two sipunculan clades and that sipunculan morphology is plastic and determined by the internal structure of their host corals. PMID- 28072880 TI - Characterisation of Early-Life Fecal Microbiota in Susceptible and Healthy Pigs to Post-Weaning Diarrhoea. AB - Early-life microbial exposure is of particular importance to growth, immune system development and long-lasting health. Hence, early microbiota composition is a promising predictive biomarker for health and disease but still remains poorly characterized in regards to susceptibility to diarrhoea. In the present study, we aimed to assess if gut bacterial community diversity and composition during the suckling period were associated with differences in susceptibility of pigs to post-weaning diarrhoea. Twenty piglets from 5 sows (4 piglets / litter) were weaned in poor housing conditions to challenge their susceptibility to post weaning diarrhoea. Two weeks after weaning, 13 pigs exhibited liquid faeces during 2 or 3 days and were defined as diarrhoeic (D) pigs. The other 7 pigs did not have diarrhea during the whole post-weaning experimental periodand were defined as healthy (H) pigs. Using a molecular characterisation of fecal microbiota with CE-SSCP fingerprint, Next Generation Sequencing and qPCR, we show that D and H pigs were mainly discriminated as early as postnatal day (PND) 7, i.e. 4 weeks before post-weaning diarrhoea occurence. At PND 7 H pigs displayed a lower evenness and a higher abundance of Prevotellaceae, Lachnospiraceae, Ruminocacaceae and Lactobacillaceae compared to D pigs. The sPLS regression method indicates that these bacterial families were strongly correlated to a higher Bacteroidetes abundance observed in PND 30 H pigs one week before diarrhoea. These results emphasize the potential of early microbiota diversity and composition as being an indicator of susceptibility to post-weaning diarrhoea. Furthermore, they support the health promoting strategies of pig herds through gut microbiota engineering. PMID- 28072882 TI - Impact of Dietary Protein Concentration and Quality on Immune Function of Cats. AB - Protein levels and quality in cat food can vary significantly and might affect immune function in various ways. In the present study, 3 diets with a low protein quality (LQ) and 3 diets with a high protein quality (HQ) were offered to 10 healthy adult cats for 6 weeks each, using a randomized cross-over design. The LQ and HQ diets differed in the collagen content and had low (36.7% and 36.2%), medium (45.0% and 43.3%) and high (56.1% and 54.9%) protein levels. At the end of each feeding period, blood was collected for phenotyping of leukocyte subsets, lymphocyte proliferation assay and cytokine measurements, phagocytosis assay and differential blood count. The results demonstrated no group differences for numbers of CD4+CD8-, CD4+CD8+, CD4-CD8+, MHCII+, CD21+, SWC3+ and CD14+ cells in the blood of the cats. Proliferative activity of lymphocytes when stimulated with pokeweed mitogen, Concanavalin A and Phytohemagglutinin, M form did not differ depending on the dietary protein concentration and quality. Concentrations of tumor necrosis factor alpha and interferon gamma in the supernatant of the proliferation assay were also not affected by the dietary treatment. Blood monocyte phagocytic activity was higher (P = 0.048) and cell numbers of eosinophilic granulocytes in the blood were lower (P = 0.047) when cats were fed the low protein diets. In conclusion, only a few differences in feline immune cell populations and activity depending on dietary protein supply could be detected. However, the observed increase of eosinophilic granulocytes by a higher protein intake indicates an activation of immunological mechanisms and requires further investigation. PMID- 28072883 TI - Variability in the Effectiveness of Two Ornithological Survey Methods between Tropical Forest Ecosystems. AB - Birds are a frequently chosen group for biodiversity monitoring as they are comparatively straightforward and inexpensive to sample and often perform well as ecological indicators. Two commonly used techniques for monitoring tropical forest bird communities are point counts and mist nets. General strengths and weaknesses of these techniques have been well-defined; however little research has examined how their effectiveness is mediated by the ecology of bird communities and their habitats. We examine how the overall performance of these methodologies differs between two widely separated tropical forests-Cusuco National Park (CNP), a Honduran cloud forest, and the lowland forests of Buton Forest Reserves (BFR) located on Buton Island, Indonesia. Consistent survey protocols were employed at both sites, with 77 point count stations and 22 mist netting stations being surveyed in each location. We found the effectiveness of both methods varied considerably between ecosystems. Point counts performed better in BFR than in CNP, detecting a greater percentage of known community richness (60% versus 41%) and generating more accurate species richness estimates. Conversely, mist netting performed better in CNP than in BFR, detecting a much higher percentage of known community richness (31% versus 7%). Indeed, mist netting proved overall to be highly ineffective within BFR. Best Akaike's Information Criterion models indicate differences in the effectiveness of methodologies between study sites relate to bird community composition, which in turn relates to ecological and biogeographical influences unique to each forest ecosystem. Results therefore suggest that, while generalized strengths and weaknesses of both methodologies can be defined, their overall effectiveness is also influenced by local characteristics specific to individual study sites. While this study focusses on ornithological surveys, the concept of local factors influencing effectiveness of field methodologies may also hold true for techniques targeting a wide range of taxonomic groups; this requires further research. PMID- 28072884 TI - Structural and Ultrastructural Alterations in Human Olfactory Pathways and Possible Associations with Herpesvirus 6 Infection. AB - Structural and ultrastructural alterations in human olfactory pathways and putative associations with human herpesvirus 6 (HHV-6) infection were studied. The olfactory bulb/tract samples from 20 subjects with an unspecified encephalopathy determined by pathomorphological examination of the brain autopsy, 17 healthy age-matched and 16 younger controls were used. HHV-6 DNA was detected in 60, 29, and 19% of cases in these groups, respectively. In the whole encephalopathy group, significantly more HHV-6 positive neurons and oligodendrocytes were found in the gray matter, whereas, significantly more HHV-6 positive astrocytes, oligodendrocytes, microglia/macrophages and endothelial cells were found in the white matter. Additionally, significantly more HHV-6 positive astrocytes and, in particular, oligodendrocytes were found in the white matter when compared to the gray matter. Furthermore, when only HHV-6 PCR+ encephalopathy cases were studied, we observed similar but stronger associations between HHV-6 positive oligodendrocytes and CD68 positive cells in the white matter. Cellular alterations were additionally evidenced by anti-S100 immunostaining, demonstrating a significantly higher number of S100 positive cells in the gray matter of the whole encephalopathy group when compared to the young controls, and in the white matter when compared to both control groups. In spite the decreased S100 expression in the PCR+ encephalopathy group when compared to PCR- cases and controls, groups demonstrated significantly higher number of S100 positive cells in the white compared to the gray matter. Ultrastructural changes confirming the damage of myelin included irregularity of membranes and ballooning of paranodal loops. This study shows that among the cellular targets of the nervous system, HHV-6 most severely affects oligodendrocytes and the myelin made by them. PMID- 28072885 TI - Functional Role of Intracellular Calcium Receptor Inositol 1,4,5-Trisphosphate Type 1 in Rat Hippocampus after Neonatal Anoxia. AB - Anoxia is one of the most prevalent causes of neonatal morbidity and mortality, especially in preterm neonates, constituting an important public health problem due to permanent neurological sequelae observed in patients. Oxygen deprivation triggers a series of simultaneous cascades, culminating in cell death mainly located in more vulnerable metabolic brain regions, such as the hippocampus. In the process of cell death by oxygen deprivation, cytosolic calcium plays crucial roles. Intracellular inositol 1,4,5-trisphosphate receptors (IP3Rs) are important regulators of cytosolic calcium levels, although the role of these receptors in neonatal anoxia is completely unknown. This study focused on the functional role of inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) in rat hippocampus after neonatal anoxia. Quantitative real-time PCR revealed a decrease of IP3R1 gene expression 24 hours after neonatal anoxia. We detected that IP3R1 accumulates specially in CA1, and this spatial pattern did not change after neonatal anoxia. Interestingly, we observed that anoxia triggers translocation of IP3R1 to nucleus in hippocampal cells. We were able to observe that anoxia changes distribution of IP3R1 immunofluorescence signals, as revealed by cluster size analysis. We next examined the role of IP3R1 in the neuronal cell loss triggered by neonatal anoxia. Intrahippocampal injection of non-specific IP3R1 blocker 2-APB clearly reduced the number of Fluoro-Jade C and Tunel positive cells, revealing that activation of IP3R1 increases cell death after neonatal anoxia. Finally, we aimed to disclose mechanistics of IP3R1 in cell death. We were able to determine that blockade of IP3R1 did not reduced the distribution and pixel density of activated caspase 3-positive cells, indicating that the participation of IP3R1 in neuronal cell loss is not related to classical caspase-mediated apoptosis. In summary, this study may contribute to new perspectives in the investigation of neurodegenerative mechanisms triggered by oxygen deprivation. PMID- 28072886 TI - Dynamic change in the NS3 protease domain in HIV/HCV-coinfected patients naive to anti-HCV protease inhibitors. AB - The genetic analysis of THE natural protease inhibitors (PI) resistance of HCV genotype (GT)1 involves subtypes 1a and 1b. NS3 protease domain was sequentially analysed in 10 HIV/HCV GT1-coinfected individuals naive to HCV treatment. Analysis at different time points showed that 2/3 GT1b patients were infected by a GT1a clade1 during follow-up. In one patient a switch from clade1 to clade2 and in one other patient a switch from clade2 to clade1 was revealed. Four out of ten patients had resistance-associated substitutions (RASs) at baseline. The dynamics of the dominant infecting subtype suggests the presence of mixed infection in some patients. PMID- 28072887 TI - Dengue fever in travellers and risk of local spreading: case reports from Southern Italy and literature update. AB - Dengue fever (DF), an arbovirosis caused by Dengue viruses (DV, serotypes 1-4), is responsible for an increasing number of travel-related acute febrile illnesses due to population growth, climate changes, spreading by viremic travellers, and improved laboratory diagnosis. The presence of efficient vectors (mosquito Aedes albopictus) has also been described in temperate regions including Italy which is considered the most heavily infected European country. Normally characterized by non-specific signs and symptoms, DF incidence is probably underestimated, especially in non-endemic countries, but the risk of severe forms is substantial. Between August and November 2013, five DF patients (4 males, age 23-38) were observed in the Infectious Disease Clinic (University of Bari, Southern Italy). All had just returned from DF endemic areas (2 French Polynesia, 3 Dominican Republic); 4/5 were hospitalized. Common clinical features included acute febrile syndrome, headache (2 with retro-orbital pain), rash (all patients), two with bleeding manifestations and one with gum bleeding. Laboratory tests demonstrated leukopenia (4 patients), elevated liver enzymes (3 patients), and thrombocytopenia (1 patient). Serum samples for DV antibodies and RNA detection were analyzed by the Regional Arbovirosis Reference Laboratory. Viral RNA was identified in 2/5 patients (DV-4) and seroconversion in the remaining cases. All patients made a complete recovery. Recent literature was reviewed, focusing on epidemiology and vector distribution (especially European and Italian territories), pathogenesis, clinical features, diagnosis, and treatment including vaccine strategies. The occurrence of 5 DF cases during the period of highest vector activity (June-November) in Italy emphasizes the risk of local outbreaks in temperate regions. This paper highlights the importance of clinical alert for dengue also in non-endemic countries. PMID- 28072888 TI - Clinical and virological predictors of sustained response with an interferon based simeprevir regimen for patients with chronic genotype 1 hepatitis C virus infection. AB - Simeprevir plus peg-interferon/ribavirin (PR) is approved to treat chronic hepatitis C (HCV) genotype 1 (GT1) and GT4 infection. This study aimed to assess baseline and on-treatment the factors predictive of sustained virologic response 12-weeks post-treatment (SVR12) in patients receiving 12 weeks of simeprevir plus PR followed by 12 or 36 weeks of PR. Data from participants in four studies (QUEST-1, QUEST-2, ATTAIN and PROMISE) were pooled to examine the efficacy and safety of simeprevir+PR in HCV GT1 patients. The predictive power of baseline variables for SVR12 was assessed using univariate and multivariate logistic regression models while the relationship between early (Week 4) on-treatment response and SVR12 was analyzed by GT1 subtype and treatment experience. Data for 1160 patients were analyzed (overall SVR12: 71%). Baseline factors predictive of SVR12 were: IL28B CC genotype, GT1a/Q80K-negative, treatment-naive/prior relapser, no cirrhosis, HCV-RNA <=2,000,000IU/mL, albumin >42g/L, platelets >200x109 /L. Patients with HCV GT1b (86%), IL28B CC genotype (87%), and treatment naive patients (83%) were predicted to achieve the highest SVR12 rates and rates of rapid virologic response. Week 4 early on-treatment response identified treatment-naive and prior relapse patients likely to achieve SVR12. Patients likely to respond to simeprevir+PR can be identified using baseline factors. Early on-treatment response predicts treatment success. PMID- 28072889 TI - In-depth analysis of compartmentalization of HIV-1 matrix protein p17 in PBMC and plasma. AB - HIV-1 p17 plays an important role in the virus life-cycle and disease pathogenesis. Recent studies indicated a high heterogeneity of p17. A high number of insertions in the p17 carboxy-terminal region have been more frequently detected in patients with non-Hodgkin lymphoma (NHL), suggesting a role of altered p17 in lymphomagenesis. Based on p17 heterogeneity, possible PBMC/plasma compartmentalization of p17 variants was explored by ultra-deep pyrosequencing in five NHL patients. The high variability of p17 with insertions at the carboxy terminal region was confirmed in plasma and observed for the first time in proviral genomes. Quasispecies compartmentalization was evident in 4/5 patients. Further studies are needed to define the possible role of p17 quasispecies compartmentalization in lymphomagenesis. PMID- 28072892 TI - Use of statins and aspirin to prevent cardiovascular disease among HIV-positive patients. A survey among Italian HIV physicians. AB - We conducted a survey among Italian HIV specialists to study the utilization of statins and aspirin, administering a questionnaire aimed at investigating their use, the use of guidelines and scores, and the management of interactions. The answers were uniform in the different geographic areas. The majority directly prescribe statins and 43% of them prescribe aspirin. The majority follows guidelines and utilize scores to calculate the CV risk. Our survey demonstrates the commitment and autonomy in prescribing statins and aspirin of Italian physicians. There is a rationale to generate guidelines to overcome the differences and limitations among current recommendations. PMID- 28072893 TI - A Pediatric Application of the STRAC Regional Hospital Trauma Registry Database: Pediatric Trauma Deaths in South Central Texas During 2004-2013. AB - The purpose of this study was to define the demographics of pediatric traumatic injuries and to understand the predictive value of injury type, prehospital, and emergency department (ED) data regarding the mortality of pediatric trauma patients (<14 years of age) in South Central Texas. We report a retrospective review of pediatric trauma patients presenting to Trauma Service Area P in South Central Texas during 2004-2013. The primary outcome was mortality; secondary outcomes were ventilator days, hospital days, and intensive care unit stay. Demographics, Abbreviated Injury Score (AIS) codes, ICD-9 codes, transport times, Emergency Medical Services (EMS) vital signs en route and on arrival to the emergency department (ED), and outcomes were evaluated. A total of 8004 traumatically injured children presented to EDs in South Central Texas during the study period; 4109 of these presented via EMS. Most patients were Hispanic and male. Distribution was even across age groups. Overall mortality was 2%, and the mortality of those arriving by EMS was 3.7%. Abnormal vital signs and Glasgow Coma Score upon presentation to both EMS and the ED were strongly associated with mortality. Increased Injury Severity Score, the need for transfusion in the ED, and increased maximal AIS were also strongly associated with mortality. African American race was associated with increased mortality, although transport time and age were not. Most injuries overall were caused by motor vehicle collisions; however, burns and falls were most common in infants. The most lethal injuries were caused by firearms (mostly seen in preteens) and assaults (mostly seen in infants). This analysis of injured children in Southwest Texas offers insight into areas of needed quality improvement in the trauma system and potential areas to focus prevention efforts. PMID- 28072891 TI - Molecular epidemiology and resistome analysis of multidrug-resistant ST11 Klebsiella pneumoniae strain containing multiple copies of extended-spectrum beta lactamase genes using whole-genome sequencing. AB - The aim of this work was to investigate the mechanism responsible for multidrug resistance in ST11 Klebsiella pneumoniae YMC 2013/7/B3993 containing multiple copies of ESBL genes using multiple parallel sequencing technology. In-depth analysis of the strain revealed multiple copies of ESBL genes, 2 copies of blaSHV 12 and 1 copy of blaCTX-M-15. Furthermore, 1 copy of blaOXA-9 and 3 copies of blaTEM-1 were found. The insertion of Tn1331 was detected, which consisted of blaOXA-9, blaTEM-1, aac(6')-lb-cr, and aadA1 genes. The acquisition of multiple copies of resistance genes was due to the insertion of transposons in the bacterial genome and plasmid. The genotypic analysis revealed that the isolates belonging to ST11 showed severe resistance phenotypes and greater dissemination potential. To the best of our knowledge, this is the first report demonstrating multiple copies of same ESBL genes in K. pneumoniae ST11 isolate. Furthermore, massive parallel sequencing studies of genetic factors to enhance the fitness of this type strain would be warranted to determine whether ST11 K. pneumoniae can spread the KPC-type gene. PMID- 28072894 TI - MACRA: Easing the Pain? AB - Medicare's final MACRA regulations acquiesce to medicine's call for more flexibility for small practices in the first year but moves full speed ahead with the transition to value-based payment. PMID- 28072895 TI - Standing Up for Scope. AB - The Texas Medical Association triumphed when a Travis County district court sided with medicine in a lawsuit against the Texas Board of Chiropractic Examiners over its granting chiropractors the authority to perform certain diagnostic tests. PMID- 28072896 TI - The Medical Home Machine. AB - Practices that achieve patient-centered medical home (PCMH) status could realize reduced costs and incentive payments from insurance payers if they see the value in contracting with a PCMH. PMID- 28072897 TI - Building on Success. AB - Undaunted by what could be a challenging 2017 Texas legislative session, TMA is poised to build on significant successes medicine achieved over the past two legislative sessions, including reforming the state's Medicaid program and expanding graduate medical education opportunities. TMA will defend the patient physician relationship against a backdrop of some potentially big shifts for Texas, such as a major review of the state's health professions licensing boards. PMID- 28072898 TI - Three-Year Results with a Ringless Third-Generation Porous Plasma Sprayed Acetabular Component in Primary Total Hip Arthroplasty. AB - INTRODUCTION: We previously reported promising early results in patients undergoing primary total hip arthroplasty (THA) with a third-generation cementless acetabular system that has a porous plasma-sprayed coating on a titanium alloy substrate shell, a ringless barb and groove locking mechanism, and a vitamin E-infused highly crosslinked polyethylene insert. The purpose of this study was to examine the outcomes and need for revision in a subset of patients previously reviewed who now have potential for three-year follow-up. PATIENTS AND METHODS: A query of our practice registry revealed 235 consented patients (241 hips) who underwent cementless primary THA performed by three surgeons with the G7(r) Acetabular System (Zimmer Biomet, Warsaw, Indiana) between April 2013 and September 2013. All liners were vitamin E-infused highly crosslinked polyethylene with a neutral face. Mean patient age was 65.8 years and mean BMI was 31.3 kg/m2. Heads used were 179 Biolox(r) delta (74%; CeramTec AG, Plochingen, Germany) and 62 cobalt-chromium (26%), with diameters of 32mm in 105 (41%) and 36mm in 136 (56%). RESULTS: A minimum three-year follow-up was available for 152 hips in 146 patients. Harris Hip Scores improved from 47.8 to 88.2, and UCLA activity scale from 3.9 to 5.4. One patient from this study period required cup revision secondary to failure of biological fixation at 15.1 months postoperative. There have been no dislocations or other revisions of the acetabular component. Kaplan Meier survival with endpoint of acetabular revision was 99.5% (95% CI: 99.0% to 100%) at 3.4 years. Radiographic findings in all cases were satisfactory position and alignment with no radiolucencies observed. CONCLUSION: In this study, with minimum three-year follow-up, good results with 99.5% survival were achieved using a third-generation cementless acetabular system with a ringless barb and groove locking mechanism. PMID- 28072899 TI - Endoluminal Vacuum Therapy as Treatment for Anastomotic Colorectal Leakage. AB - BACKGROUND: The clinical leakage rate after anterior resection varies from 2.8 20%, with a 6-22% mortality rate and a 10-80% risk of permanent stoma. Endo SPONGE(r) (B. Braun Melsungen AG, Melsungen, Germany) may treat extraperitoneal anastomotic leakage in the lesser pelvis. It consists of an open-pored sponge inserted into the cavity. A drainage tube fixed to a low vacuum drainage system is then connected to the sponge through the anus. MATERIAL AND METHODS: Between January 2007 and December 2014, 14 patients with anastomotic leakage following low anterior resection were treated with Endo-SPONGE(r) and were prospectively evaluated. In all patients, a CT-scan was performed and they received an intravenous antibiotic therapy with piperacillin+tazobactam (4.5g,3 times/daily). Complete healing was defined as endoscopically proven closure of the insufficiency cavity with a normal mucosa. RESULTS: Stapled straight end to end, colorectal anastomoses were performed in all patients between 3-7 cm above the anal verge, a protective loop ileostomy was performed in every patient. The diagnosis of anastomotic leakage was performed after a median interval of 14 days, the median size of the cavity was 81x46 mm. Fluid collection was drained, percutaneosly in 12 cases, surgically in two patients. The median duration of therapy was 35 days, with 3-14 sponge exchanges for each patient. Median healing time was 37 days. No intraoperative complications were recorded, however, we found five cases of mild anal pain treated medically. CONCLUSION: Considering the literature and our results, the Endo-SPONGE(r) seems an effective, minimally invasive procedure to treat extraperitoneal anastomotic leakage, reducing morbidity, mortality, and hospital stay. PMID- 28072900 TI - Efficacy of Adductor Canal Blockade Compared to Multimodal Peri-Articular Analgesia Following Total Knee Arthroplasty. AB - INTRODUCTION: Postoperative pain after total knee arthroplasty (TKA) can be an impediment to patient recovery. Many commonly used pain control modalities are effective, but are also associated with adverse effects. Other modalities, such as adductor canal blocks (ACB) and multimodal periarticular analgesia (MPA), have gained popularity due to their efficacy and high safety profile. However, to the best of our knowledge, there are no published studies indicating if a therapeutic advantage exists between the two pain control modalities. Therefore, the purpose of this study was to assess the: 1) length of stay; 2) level of pain; 3) discharge status; and 4) opioid consumption, in TKA patients who received either ACB or MPA. MATERIALS AND METHODS: A single hospital, single surgeon database was reviewed for patients who had a TKA between January 2015 and April 2016, and received either ACB or MPA. This search yielded 98 patients who had a mean age of 63 years (range, 38 to 90 years), comprised of 29 men and 69 women. Patients were divided into those who received ACB alone (n= 54) and those who received MPA alone (n= 44). With the use of electronic medical records, demographic and endpoint data were obtained. Pain was quantified using the Visual Analog Scale (VAS). Continuous variables were compared using the student's t-test, while categorical variables were compared utilizing a chi-square test. RESULTS: The mean length of hospital stay (LOS) was significantly shorter for patients who had ACB when compared to patients who had MPA (2.12 days vs. 2.88 days; p = 0.005). There was no significant difference in VAS scores (p= 0.448), proportion of patients discharged home (p= 0.432), or total opioid consumption (p= 0.247) between the two groups. CONCLUSION: Total knee arthroplasty patients who received an adductor canal block had shorter lengths of stay when compared to those who received multimodal peri-articular analgesia. Shortened hospital stays may be cost-effective for institutions and providers, however, larger studies are needed to further assess the effect on quality of care provided. PMID- 28072901 TI - Achilles Tendon Repair Using the InternalBrace? Principle. AB - Despite extensive research, the management of acute ruptures of the Achilles tendon remains an area of controversy, and there is no consensus regarding the optimal treatment. An InternalBrace? (Arthrex, Inc., Naples, Florida) is a ligament augmentation repair using high strength sutures/tape and knotless bone anchors which encourages healing and allows early mobilization. This article describes, with video illustration, a knotless Achilles tendon repair technique using the InternalBrace? principle. PMID- 28072902 TI - Development of an Encompassing Questionnaire for Evaluating the Outcomes Following Total Knee Arthroplasty. AB - INTRODUCTION: There are many standardized scales and questionnaires used to evaluate TKA patients; however, individually they do not always assess patients adequately. Consequently, many are used in combinations to provide a thorough evaluation. However, this leads to redundancy, confusion, and an excessive patient time-burden. Therefore, the purpose of this study was to develop a usable combined knee questionnaire that combines questions in a non-redundant manner. Specifically, we aimed to: 1) create a combined knee questionnaire that encompasses questions from multiple systems, while eliminating redundancy; 2) correlate the new system with the existing validated questionnaires; and 3) determine the length of time it takes to administer this new questionnaire. MATERIALS AND METHODS: In a previous study, it was determined that the six most commonly cited validated systems to assess the knee were the: Knee Society Score (KSS), The Western Ontario and McMaster Universities Arthritis Index (WOMAC), Knee injury and Osteoarthritis Outcome Score (KOOS), Lower Extremity Functional Scale (LEFS), Activity Rating Scale (ARS), and Short-Form-36 (SF-36). Therefore, we ensured that the new questionnaire encompassed all elements of these systems. After development of the combined questionnaire, we co-administered it to 20 subjects alongside the above validated questionnaires. We then transposed the corresponding answers from the combined questionnaire to each selected validated system to perform an intra-class correlation analysis. In addition, we recorded the length of time it took to administer the new questionnaire and compared it to the time it took to administer the individual validated questionnaires. RESULTS: Intra-class correlation analysis demonstrated statistically significant positive correlations between the KSS, WOMAC, KOOS, LEFS, ARS, SF-36, and the corresponding questions in the combined questionnaire. The mean length of time it took to administer the combined questionnaire (mean, 10.1 minutes, range, 6.6 to 12.6 minutes) was significantly shorter than the time it took to administer the selected validated questionnaires (mean, 21.3 minutes, range, 17.3 to 24.1 minutes). CONCLUSION: We have proposed an all-encompassing combined knee questionnaire that eliminates redundancy and inefficiency during the evaluation of TKA patients. It is a reliable, time-efficient system that can be utilized to fill out the most commonly used questionnaires for assessing TKA. Standardization and uniform use of this questionnaire may simplify future patient assessment following TKA. PMID- 28072903 TI - Laparoscopic Treatment of Giant Ventral Hernia: Experience of 35 Patients. AB - BACKGROUND: Minimal access surgery for incisional hernia repair is still debated, especially for giant wall defects. Laparoscopic repair may reduce pain and hospital stay. This study was designed to evaluate the feasibility of the laparoscopic technique in giant hernia. MATERIALS AND METHODS: From 2007 to 2013, 35 consecutive patients with giant ventral hernia, according to the Chevrel classification, underwent laparoscopic repair. Fourteen patients were obese, with a body mass index (BMI) > 30 and in 21 patients the mean BMI was 24 (range 22 28). In all patients, the wall defect was larger than 20 cm. RESULTS: Mean operative time was 159+/-30 minutes, and, for defects larger than 25 cm, it was 210+/-20 minutes. Patient conversion did not occur. In 29 patients, the mean wall defect was 20x25 cm, and in six patients the mean wall defect was 26x31 cm, and, as measured from within the peritoneal cavity, the mean overlap was 5 cm (range 3 6). Short-term antibiotic prophylaxis consisted of Cefazolin 2 g IV (intravenous) the day of surgery. All patients were discharged within 72-96 hrs. The mean follow-up was 24 months. No infection occurred and no chronic pain was recorded. However, three seroma were observed (outpatient treatment) and two xiphoid recurrences were observed. CONCLUSIONS: Laparoscopic hernia repair is technically feasible and is safe in patients with giant fascial defects as well as obese patients. This operation decreases postoperative pain, hastens the recovery period, and reduces postoperative morbidity and recurrence. This approach should be reserved for patients with no history of previous hernia repair. Further studies are expected to confirm these promising results. PMID- 28072904 TI - Resistance diagnosis and the changing economics of antibiotic discovery. AB - Point-of-care diagnostics that can determine an infection's antibiotic sensitivity increase the profitability of new antibiotics that enjoy patent protection, even when such diagnostics reduce the quantity of antibiotics sold. Advances in the science and technology underpinning rapid resistance diagnostics can therefore be expected to spur efforts to discover and develop new antibiotics, especially those with a narrow spectrum of activity that would otherwise fail to find a market. PMID- 28072905 TI - Saccharomyces cerevisiae Shuttle vectors. AB - Yeast shuttle vectors are indispensable tools in yeast research. They enable cloning of defined DNA sequences in Escherichia coli and their direct transfer into Saccharomyces cerevisiae cells. There are three types of commonly used yeast shuttle vectors: centromeric plasmids, episomal plasmids and integrating plasmids. In this review, we discuss the different plasmid systems and their characteristic features. We focus on their segregational stability and copy number and indicate how to modify these properties. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28072906 TI - "No Posttraumatic Stress Disorder in Lithuania": National Health Care Fails to Identify PTSD. AB - Lithuanian National Health Insurance (NHI) registry data from 2014 and 2015 were used to estimate the annual rates of posttraumatic stress disorder (PTSD) and other stress-related disorders in Lithuania. A large gap was found between 12 month PTSD prevalence based on epidemiological data and annual PTSD rates based on health care service utilization in Lithuania. Estimations from the health care service's utilization data revealed that only about 0.01% to 0.02% of the population in Lithuania is diagnosed with PTSD annually, indicating that the national health care system identifies only about 1% of potential PTSD cases in Lithuania. The low rates of PTSD diagnoses in the health care system seem to indicate a lack of recognition of psychological trauma among general practitioners and mental health professionals in Lithuania. The lack of visibility of PTSD in the national health care system could be a major barrier to the treatment of PTSD in the country. The study indicates the importance of social factors, especially the recognition of trauma and PTSD, among health care professionals. PMID- 28072909 TI - Use of Charge-Charge Repulsion to Enhance pi-Electron Delocalization into Anti Aromatic and Aromatic Systems. AB - A series of 9-fluorenyl cations has been studied and it is shown that increasing charge on a heterocyclic substituent group enhances the anti-aromatic character of the carbocation system. Similarly, a series of dibenzosuberenyl cations has been studied and increasing charge on a substituent group is shown to enhance aromatic character in the carbocation system. These studies include the direct observations of dicationic and tricationic species using stable-ion conditions and low temperature NMR. The structures of these ions were further characterized using DFT calculations, confirming that highly charged organic ions may exhibit unusual distributions of pi-electrons and delocalization of electrons in 4n or 4n+2 pi-systems. PMID- 28072907 TI - Symptomatic treatments for amyotrophic lateral sclerosis/motor neuron disease. AB - BACKGROUND: Motor neuron disease (MND), which is also known as amyotrophic lateral sclerosis (ALS), causes a wide range of symptoms but the evidence base for the effectiveness of the symptomatic treatment therapies is limited. OBJECTIVES: To summarise the evidence from Cochrane Systematic Reviews of all symptomatic treatments for MND. METHODS: We searched the Cochrane Database of Systematic Reviews (CDSR) on 15 November 2016 for systematic reviews of symptomatic treatments for MND. We assessed the methodological quality of the included reviews using the Assessment of Multiple Systematic Reviews (AMSTAR) tool and the GRADE approach. We followed standard Cochrane study (review) selection and data extraction procedures. We reported findings narratively and in tables. MAIN RESULTS: We included nine Cochrane Systematic Reviews of interventions to treat symptoms in people with MND. Three were empty reviews with no included randomised controlled trials (RCTs); however, all three reported on non-RCT evidence and the remaining six included mostly one or two studies. We deemed all of the included reviews of high methodological quality. Drug therapy for painThere is no RCT evidence in a Cochrane Systematic Review exploring the efficacy of drug therapy for pain in MND. Treatment for crampsThere is evidence (13 RCTs, N = 4012) that for the treatment of cramps in MND, compared to placebo: memantine and tetrahydrocannabinol (THC) are probably ineffective (moderate quality evidence);- vitamin E may have little or no effect (low-quality evidence); and- the effects of L-threonine, gabapentin, xaliproden, riluzole, and baclofen are uncertain as the evidence is either very low quality or the trial specified the outcome but did not report numerical data.The review reported adverse effects of riluzole, but it is not clear whether other interventions had adverse effects. Treatment for spasticityIt is uncertain whether an endurance based exercise programme improved spasticity or quality of life, measured at three months after the programme, as the quality of evidence is very low (1 RCT, comparison "usual activities", N = 25). The review did not evaluate other approaches, such as use of baclofen as no RCTs were available. Mechanical ventilation for supporting respiratory functionNon-invasive ventilation (NIV) probably improves median survival and quality of life in people with respiratory insufficiency and normal to moderately impaired bulbar function compared to standard care, and improves quality of life but not survival for people with poor bulbar function (1 RCT, N = 41, moderate-quality evidence; a second RCT did not provide data). The review did not evaluate other approaches such as tracheostomy assisted ('invasive') ventilation, or assess timing of NIV initiation. Treatment for sialorrhoeaA single session of botulinum toxin type B injections to parotid and submandibular glands probably improves sialorrhoea and quality of life at up to 4 weeks compared to placebo injections, but not at 8 or 12 weeks after the injections (moderate-quality evidence from 1 placebo-controlled RCT, N = 20). The review authors found no trials of other approaches. Enteral tube feeding for supporting nutritionThere is no RCT evidence in a Cochrane Systematic Review to support benefit or harms of enteral tube feeding in supporting nutrition in MND. Repetitive transcranial magnetic stimulationIt is uncertain whether repetitive transcranial magnetic stimulation (rTMS) improves disability or limitation in activity in MND in comparison with sham rTMS (3 RCTs, very low quality evidence, N = 50). Therapeutic exerciseThere is evidence that exercise may improve disability in MND at three months after the exercise programme, but not quality of life, in comparison with "usual activities" or "usual care" including stretching (2 RCTs, low-quality evidence, N = 43). Multidisciplinary careThere is no RCT evidence in a Cochrane Systematic Review to demonstrate any benefit or harm for multidisciplinary care in MND.None of the reviews, other than the review of treatment for cramps, reported that adverse events occurred. However, the trials were too small for reliable adverse event reporting. AUTHORS' CONCLUSIONS: This overview has highlighted the lack of robust evidence in Cochrane Systematic Reviews on interventions to manage symptoms resulting from MND. It is important to recognise that clinical trials may fail to demonstrate efficacy of an intervention for reasons other than a true lack of efficacy, for example because of insufficient statistical power, the wrong choice of dose, insensitive outcome measures or inappropriate participant eligibility. The trials were mostly too small to reliably assess adverse effects of the treatments. The nature of MND makes it difficult to research clinically accepted or recommended practice, regardless of the level of evidence supporting the practice. It would not be ethical, for example, to design a placebo-controlled trial for treatment of pain in MND or to withhold multidisciplinary care where such care is available. It is therefore highly unlikely that there will ever be classically designed placebo controlled RCTs in these areas.We need more research with appropriate study designs, robust methodology, and of sufficient duration to address the changing needs-of people with MND and their caregivers-associated with MND disease progression and mortality. There is a significant gap in studies assessing the effectiveness of interventions for symptoms relating to MND, such as pseudobulbar emotional lability and cognitive and behavioural difficulties. Future studies should use appropriate outcome measures that are reliable, have internal and external validity, and are sensitive to change in what is being measured (such as quality of life). PMID- 28072910 TI - Crosstalk between intestinal epithelial cell and adaptive immune cell in intestinal mucosal immunity. AB - Constantly challenged by luminal bacteria, intestinal epithelium forms both a physical and biochemical defense against pathogens. Besides, intestinal epithelium senses dynamic and continuous changes in luminal environment and transmits signals to subjacent immune cells accordingly. It has been long accepted that adaptive immune cells fulfill their roles partly by modulating function of intestinal epithelial cells. Recent studies have brought up the proposal that intestinal epithelial cells also actively participate in the regulation of adaptive immunity, especially CD4+ adaptive T cells, which indicates that there is reciprocal crosstalk between intestinal epithelial cells and adaptive immune cells, and the crosstalk may play important role in intestinal mucosal immunity. This Review makes a comprehensive summary about crosstalk between intestinal epithelial cells and CD4+ adaptive T cells in intestinal immunity. Special attention would be given to their implications in inflammatory bowel disease pathogenesis and potential therapeutic targets. PMID- 28072912 TI - Temperature Mapping in Hydrogel Matrices Using Unmodified Digital Camera. AB - We report a simple, generally applicable, and noninvasive fluorescent method for mapping thermal fluctuations in hydrogel matrices using an unmodified commercially available digital single-lens reflex camera (DSLR). The nanothermometer is based on the complexation of short conjugated polyelectrolytes, poly(phenylene ethynylene) carboxylate, with an amphiphilic polymer, polyvinylpyrrolidone, which is in turn trapped within the porous network of a gel matrix. Changes in the temperature lead to a fluorescent ratiometric response with a maximum relative sensitivity of 2.0% and 1.9% at 45.0 degrees C for 0.5% agarose and agar, respectively. The response was reversible with no observed hysteresis when samples were cycled between 20 and 40 degrees C. As a proof of concept, the change in fluorescent signal/color was captured using a digital camera. The images were then dissected into their red-green-blue (RGB) components using a Matlab routine. A linear correlation was observed between the hydrogel temperature and the green and blue intensity channels. The reported sensor has the potential to provide a wealth of information when thermal fluctuations mapped in soft gels matrices are correlated with chemical or physical processes. PMID- 28072911 TI - Potential protective effect of lactation against incidence of type 2 diabetes mellitus in women with previous gestational diabetes mellitus: A systematic review and meta-analysis. AB - Lactation may protect women with previous gestational diabetes mellitus (GDM) from developing type 2 diabetes mellitus, but the results of existing studies are inconsistent, ranging from null to beneficial. We aimed to conduct a systematic review to gather available evidence. Databases MEDLINE, CINAHL, PubMed, and EMBASE were searched on December 15, 2015, without restriction of language or publication year. A manual search was also conducted. We included observational studies (cross-sectional, case-control, and cohort study) with information on lactation and type 2 diabetes mellitus incidence among women with previous GDM. We excluded case studies without control data. Data synthesis was conducted by random-effect meta-analysis. Fourteen reports of 9 studies were included. Overall risk of bias using RoBANS ranged from low to unclear. Longer lactation for more than 4 to 12 weeks postpartum had risk reduction of type 2 diabetes mellitus compared with shorter lactation (OR 0.77, 95% CI 0.01-55.86; OR 0.56, 95% CI 0.35 0.89; OR 0.22, 95% CI 0.13-0.36; type 2 diabetes mellitus evaluation time < 2 y, 2-5 y, and >5 y, respectively). Exclusive lactation for more than 6 to 9 weeks postpartum also had lower risk of type 2 diabetes mellitus compared with exclusive formula (OR 0.42, 95% CI 0.22-0.81). The findings support the evidence that longer and exclusive lactation may be beneficial for type 2 diabetes mellitus prevention in women with previous GDM. However, the evidence relies only on observational studies. Therefore, further studies are required to address the true causal effect. PMID- 28072913 TI - Chemical Analysis of the Interface in Bulk-Heterojunction Solar Cells by X-ray Photoelectron Spectroscopy Depth Profiling. AB - Despite the wide use of blends combining an organic p-type polymer and molecular fullerene-based electron acceptor, the proper characterization of such bulk heterojunction materials is still challenging. To highlight structure-to-function relations and improve the device performance, advanced tools and strategies need to be developed to characterize composition and interfaces with sufficient accuracy. In this work, high-resolution X-ray photoelectron spectroscopy (XPS) is combined with very low energy argon ion beam sputtering to perform a nondestructive depth profile chemical analysis on full Al/P3HT:PCBM/PEDOT:PSS/ITO (P3HT, poly(3-hexylthiophene); PCBM, [6,6]-phenyl-C61-butyric acid methyl ester; PEDOT, poly(3,4-ethylenedioxythiophene; PSS, polystyrenesulfonate; ITO, indium tin oxide) bulk-heterojunction solar cell device stacks. Key information, such as P3HT and PCBM composition profiles and Al-PCBM chemical bonding, are deduced in this basic device structure. The interface chemical analysis allows us to evidence, with unprecedented accuracy, the inhomogeneous distribution of PCBM, characterized by a strong segregation toward the top metal electrode. The chemical analysis high-resolution spectra allows us to reconstruct P3HT/PCBM ratio through the active layer depth and correlate with the device deposition protocol and performance. Results evidence an inhomogeneous P3HT/PCBM ratio and poorly controllable PCBM migration, which possibly explains the limited light-to power conversion efficiency in this basic device structure. The work illustrates the high potential of XPS depth profile analysis for studying such organic/inorganic device stacks. PMID- 28072914 TI - Presence of Pathogenic Rickettsiae and Protozoan in Samples of Raw Milk from Cows, Goats, and Sheep. AB - OBJECTIVE: The aim of the present work was to determine the presence of various rickettsiae and protozoan in raw milk and the assessment the potential, milk borne route in the spread of selected zoonotic pathogens. MATERIALS: A total of 119 raw milk samples collected randomly from 63 cows, 29 goats, and 27 sheep bred on 34 farms situated on eight communities in eastern Poland were examined by polymerase chain reaction (PCR) method for the presence of pathogenic rickettsiae (Coxiella burnetii, Anaplasma phagocytophilum, and Rickettsia spp.) and protozoan (Toxoplasma gondii). RESULTS: The only prevalent pathogen was T. gondii, which was found in 10 samples of cow milk (15.9%), in one sample of goat milk (3.4%), and in one sample of sheep milk (3.7%). One sample of cow milk was positive for C. burnetii; however, the sequence analysis did not confirm any species of Coxiella or Coxiella-like organisms, but showed 100% homology to Psychrobacter alimentarius. None of the examined samples showed the presence of A. phagocytophilum or Rickettsia spp. CONCLUSIONS: The results of this study suggest a potential hazard of milk-borne Toxoplasma infection, mostly by consumption of raw cow milk. The milk-borne spread seems to be limited or nonsignificant in the case of C. burnetii, A. phagocytophilum, and Rickettsia spp. The false-positive sample for Coxiella spp. suggests that some care should be taken in the interpretation of the results obtained by using the PCR method. PMID- 28072915 TI - Association Between Duration of Breast Feeding and Metabolic Syndrome: The Korean National Health and Nutrition Examination Surveys. AB - BACKGROUND: This study aimed to evaluate the association of the lifelong duration of breast feeding with metabolic syndrome (MetS) and its components in Korean parous women aged 19-50 years. MATERIALS AND METHODS: A total of 4724 participants from the Korean National Health and Nutritional Survey were included. Subjects were divided into four groups according to the duration of breast feeding: <=5, 6-11, 12-23, or >=24 months groups. The adjusted odds ratios (ORs) of MetS and its components were assessed according to the duration of breast feeding. RESULTS: Women who breastfed for 6-11 months had an OR of 0.67 (95% confidence interval [CI], 0.54-0.86) for elevated blood pressure (BP) compared with those who breastfed for <=5 months after adjustment for possible confounders in a multivariable logistic regression analyses. Women who breastfed for 12-23 months were associated with an OR of 0.68 (95% CI, 0.54-0.86) for elevated BP, an OR of 0.78 (95% CI, 0.62-0.97) for elevated glucose, and an OR of 0.73 (95% CI, 0.56-0.95) for MetS compared with those who breastfed for <=5 months in a multivariable logistic regression analyses. Women who breastfed for >=24 months had an OR of 0.62 (95% CI, 0.52-0.84) for elevated glucose, an OR of 0.76 (95% CI, 0.60-0.96) for elevated triglycerides, and an OR of 0.70 (95% CI, 0.53-0.92) for MetS compared with those who breastfed for <=5 months in a multivariable logistic regression analyses. CONCLUSIONS: Our results suggest that lifelong breast feeding for >=12 months may be associated with lower risk for MetS. PMID- 28072916 TI - A Preliminary Study Examining Women's Physical Health and Nonmedical Prescription Opioid Use in a Recovering Framework. AB - BACKGROUND: There is a growing need for research on women recovering from nonmedical prescription opioid use. A paradigm shift is to focus on wellness and factors that support, rather than hinder, recovering women. For example, although physical health is impacted by nonmedical prescription opioid use, improved health may be a strength-based factor among recovering women. The aim of this preliminary study was to examine physical health in a recovering framework as women begin recovering from nonmedical prescription opiate use. MATERIALS AND METHODS: This study conducted secondary data analysis using self-report data from Kentucky's Targeted Assessment Program (TAP). TAP assesses and provides pretreatment for problems impeding work or interfering with parental responsibilities. Data included 1247 adult women reporting a history of nonmedical prescription opioid use and receiving pretreatment. Bivariate and logistic regression analyses examined whether physical health and access to health services at baseline were associated with substance-related behavior change upon completion of pretreatment. RESULTS: Women reporting better physical health and fewer days with no activities due to health barriers were more likely to engage in pretreatment substance-related behavior change [chi2(8) = 34.6, p < 0.05]. However, ~40% of women reported barriers in accessing healthcare. CONCLUSION: Using a recovering framework, women's physical health, as expected, is associated with engagement in pretreatment substance-related behavior change. Ongoing service coordination with practitioners and medical providers should be incorporated into care to meet the need. Future research should continue to examine factors that support recovering women, using a recovering framework. PMID- 28072917 TI - A Provider-Based Survey To Assess Bereavement Care Knowledge, Attitudes, and Practices in Pediatric Oncologists. AB - BACKGROUND: Bereavement support is a core tenet of palliative care that may prove difficult for clinicians as it is time-consuming, emotionally charged, and not emphasized in pediatrics training. This project is intended to describe the opinions, knowledge, and practice of bereavement care among pediatric oncologists to identify gaps in clinical care. PROCEDURES: An internet-based survey instrument was pilot tested, refined, and distributed to pediatric oncologists in the United States. Statistical analysis was performed using SAS 9.2. RESULTS: Electronic surveys were distributed to 2,061 pediatric oncologists and 522 surveys (25%) were fully completed. Participants were asked how likely they are to engage in particular bereavement activities (phone calls, condolence cards, memorial services, family meetings, or referrals for counseling) following the death of a pediatric cancer patient. Eighty-two percent of participants, at least, sometimes engage in at least one of these activities. Being female, an attending physician, and increased time in clinical practice were predictive of active participation in bereavement care. Nearly all participants (96%) believe that bereavement care is part of good clinical care, while 8% indicate that bereavement support is not their responsibility. Lack of time and resources were the biggest barriers to providing bereavement support. CONCLUSIONS: The majority of pediatric oncologists engage in clinical practices to support bereaved families. Lack of time and physical resources pose significant barriers to clinician's efforts. Additional supports should be explored to increase pediatric oncology physician uptake of bereavement care practices. PMID- 28072918 TI - Production of Staphylococcal Enterotoxins D and R in Milk and Meat Juice by Staphylococcus aureus Strains. AB - Seventeen Staphylococcus aureus strains were tested for production of staphylococcal enterotoxin D (SED) and staphylococcal enterotoxin R (SER) in milk and meat juice. SED was secreted in milk by 12 S. aureus strains at 6-54 ng/mL at 24 h and 9-98 ng/mL at 48 h. Another five strains secreted SED at 0.9-1.9 MUg/mL at 24 h and at 1.2-2.4 MUg/mL at 48 h. Strains producing high levels of SED in milk secreted 77-666 MUg/mL of SED in meat juice at 24 h and 132-1225 MUg/mL at 48 h. Strains producing lower amounts of SED in milk secreted 228-1109 ng/mL of SED at 24 h and 377-1782 ng/mL at 48 h in meat juice. Tested S. aureus strains produced SER in milk at 33-183 ng/mL at 24 h and 41-832 ng/mL at 48 h. Fourteen strains produced more SER in meat juice than in milk (17- to 232-fold and 15- to 269-fold more at 24 and 48 h, respectively). Three S. aureus strains secreted less than 74 ng/mL of SER in meat juice. Expression pattern of known enterotoxin regulators, that is, agrA, sarA, hld, rot, and sigB, was similar in selected strong and weak SED producers grown in both food matrices and could not explain differences in enterotoxin protein level. This suggests that enterotoxin regulation is more complex than previously thought. We demonstrated that in a number of tested S. aureus strains, production of SED and SER was significantly decreased in milk when compared with meat juice, supporting previous reports. However, certain strains secreted high amounts of SED and SER, irrespective of environment, likely contributing to higher food safety risk. PMID- 28072919 TI - Perspectives on Temperature Management. PMID- 28072920 TI - Outcome Measurement for Children and Young People. PMID- 28072921 TI - Sidewalk Chalk Art: A Creative Way To Engage Millennials in Palliative Care. PMID- 28072923 TI - Language, the "Diabetes Restricted Code/Dialect," and What It Means for People With Diabetes and Clinicians. AB - Purpose The purpose of the paper is to explore the notion of a diabetes language restricted code or "dialect" and its effect on people with diabetes. Language is a complex phenomenon comprising verbal and nonverbal components used to communicate in human interactions. Methods Information was collected from a literature review, during clinical consultations, and from an email survey. Results Language and the way clinicians use language affect motivation, behaviors, and outcomes of people with diabetes. Language is influenced by culture, experience, and familiarity with words and their use and is idiosyncratic. "Diabetes" is a particular restricted code or dialect that people with diabetes gradually learn to speak, usually after they are diagnosed with diabetes. The diabetes dialect contains many metric and target words and very few positive, encouraging words, and it is often discriminatory, negative, judgmental, labelling, distressing, and stigmatizing: for example, victim, sufferer, and lifestyle disease. Conclusion Language codes/dialects can compound the already high levels of emotional distress and self-care burden associated with living with diabetes and can affect outcomes. The information presented in this article will be useful for clinicians caring for people with diabetes and will be helpful for professionals who develop information for people with diabetes and those who create policies and guidelines. PMID- 28072924 TI - Cryopreservation of Carp (Cyprinus carpio L.) Sperm: Impact of Seeding and Freezing Rates on Post-Thaw Outputs. AB - In the present study, we examined various freezing protocols, effects of controlled seeding, and changes in cooling rate and determined the endpoint (temperature at which sample could be plugged into liquid nitrogen (LN) without visible effect on survival rate after thawing) to reveal the relative importance of each different stage of cooling on freezing success during cryobanking of carp sperm. Sperm samples from different individual carp males were frozen in 0.5 mL straws by conventional freezing. Cooling rates were determined by monitoring the sample's internal temperature. We compared four freezing protocols, which involved placing sperm samples at various levels (1, 3, 6, and 9 cm) above the LN surface (corresponding to -190 degrees C, -150 degrees C, -110 degrees C, and -70 degrees C, respectively) for 20 minutes followed by transferring the samples into LN. Freezing at 3 cm above the LN surface resulted in the highest motility (33% +/- 8%) and velocity (118 +/- 9 MUm/s) of spermatozoa after thawing and diluting in swimming medium. We determined that -90 degrees C is an optimal temperature at which immersing the samples in LN does not affect sperm motility after thawing and shorten the process of freezing for around three times. Motility of spermatozoa cryopreserved with or without a seeding procedure was not significantly different after thawing. Therefore, we hypothesize that supercooling the sample during the conventional freezing procedure is not the main damaging factor during carp spermatozoa cryopreservation. However, the cooling rate itself is important, because it determines the ability of the sperm to dehydrate and survive cryopreservation. PMID- 28072925 TI - Impact of Low and High Doses of Marbofloxacin on the Selection of Resistant Enterobacteriaceae in the Commensal Gut Flora of Young Cattle: Discussion of Data from 2 Study Populations. AB - In the context of requested decrease of antimicrobial use in veterinary medicine, our objective was to assess the impact of two doses of marbofloxacin administered on young bulls (YBs) and veal calves (VCs) treated for bovine respiratory disease, on the total population of Enterobacteriaceae in gut flora and on the emergence of resistant Enterobacteriaceae. In two independent experiments, 48 YBs from 6 commercial farms and 33 VCs previously colostrum deprived and exposed to cefquinome were randomly assigned to one of the three groups LOW, HIGH, and Control. In LOW and HIGH groups, animals received a single injection of, respectively, 2 and 10 mg/kg marbofloxacin. Feces were sampled before treatment, and at several times after treatment. Total and resistant Enterobacteriaceae enumerating were performed by plating dilutions of fecal samples on MacConkey agar plates that were supplemented or not with quinolone. In YBs, marbofloxacin treatment was associated with a transient decrease in total Enterobacteriaceae count between day (D)1 and D3 after treatment. Total Enterobacteriaceae count returned to baseline between D5 and D7 in all groups. None of the 48 YBs harbored marbofloxacin-resistant Enterobacteriaceae before treatment. After treatment, 1 out of 20 YBs from the Control group and 1 out of 14 YBs from the HIGH group exhibited marbofloxacin-resistant Enterobacteriaceae. In VCs, the rate of fluoroquinolone-resistant Enterobacteriaceae significantly increased after low and high doses of marbofloxacin treatment. However, the effect was similar for the two doses, which was probably related to the high level of resistant Enterobacteriaceae exhibited before treatment. Our results suggest that a single treatment with 2 or 10 mg/kg marbofloxacin exerts a moderate selective pressure on commensal Enterobacteriaceae in YBs and in VCs. A fivefold decrease of marbofloxacin regimen did not affect the selection of resistances among commensal bacteria. PMID- 28072926 TI - Relationship Between Marital Transitions, Health Behaviors, and Health Indicators of Postmenopausal Women: Results from the Women's Health Initiative. AB - BACKGROUND: Historically, marital status has been associated with lower mortality and transitions into marriage were generally accompanied by improved health status. Conversely, divorce has been associated with increased mortality, possibly mediated by changes in health behaviors. METHODS: This study uses data from a prospective cohort of 79,094 postmenopausal women participating in the Women's Health Initiative Observational Study (WHI-OS) to examine the relationship between marital transition and health indicators (blood pressure, waist circumference, body mass index [BMI]) as well as health behaviors (diet pattern, alcohol use, physical activity, and smoking) in a sample of relatively healthy and employed women. Linear and logistic regression modeling were used to test associations, controlling for confounding factors. RESULTS: Women's transitions into marriage/marriage-like relationship after menopause were associated with greater increase in BMI (beta = 0.22; confidence interval (95% CI), 0.11-0.33) and alcohol intake (beta = 0.08; 95% CI, 0.04-0.11) relative to remaining unmarried. Divorce/separation was associated with a reduction in BMI and waist circumference, changes that were accompanied by improvements in diet quality (beta = 0.78, 95% CI, 0.10-1.47) and physical activity (beta = 0.98, 95% CI, 0.12-1.85), relative to women who remained married. CONCLUSION: Contrary to earlier literature, these findings among well-educated, predominantly non Hispanic white women suggest that marital transitions after menopause are accompanied by modifiable health outcomes/behaviors that are more favorable for women experiencing divorce/separation than those entering a new marriage. PMID- 28072928 TI - Pharmacological treatment of shock-strychnine. PMID- 28072927 TI - Artificial Induction of Native Aquaporin-1 Expression in Human Salivary Cells. AB - Gene therapy for dry mouth disorders has transitioned in recent years from theoretical to clinical proof of principle with the publication of a first-in-man phase I/II dose escalation clinical trial in patients with radiation-induced xerostomia. This trial used a prototype adenoviral vector to express aquaporin-1 (AQP1), presumably in the ductal cell layer and/or in surviving acinar cells, to drive transcellular flux of interstitial fluid into the labyrinth of the salivary duct. As the development of this promising gene therapy continues, safety considerations are a high priority, particularly those that remove nonhuman agents (i.e., viral vectors and genetic sequences of bacterial origin). In this study, we applied 2 emerging technologies, artificial transcriptional complexes and epigenetic editing, to explore whether AQP1 expression could be achieved by activating the native gene locus in a human salivary ductal cell line and primary salivary human stem/progenitor cells (hS/PCs), as opposed to the conventional approach of cytomegalovirus promoter-driven expression from an episomal vector. In our first study, we used a cotransfection strategy to express the components of the dCas9-SAM system to create an artificial transcriptional complex at the AQP1 locus in A253 and hS/PCs. We found that AQP1 expression was induced at a magnitude comparable to adenoviral infection, suggesting that AQP1 is primarily silenced through pretranscriptional mechanisms. Because earlier literature suggested that pretranscriptional silencing of AQP1 in salivary glands is mediated by methylation of the promoter, in our second study, we performed global, chemical demethylation of A253 cells and found that demethylation alone induced robust AQP1 expression. These results suggest the potential for success by inducing AQP1 expression in human salivary ductal cells through epigenetic editing of the native promoter. PMID- 28072929 TI - Correctly name your poison. PMID- 28072930 TI - Left ventricular outflow tract obstruction-be prepared! AB - The current trend to treat hypotension in critically ill patients is to place a greater emphasis on inotropic support and less on fluid resuscitation in order to limit the potential harm from fluid overload. This combination may trigger left ventricular outflow tract obstruction (LVOTO) in susceptible patients. Although LVOTO is classically described in patients with hypertrophic cardiomyopathy it has been reported in other conditions including septic shock, apical ballooning syndrome, myocardial infarction, respiratory failure, and post valvular surgery. It is more common in the elderly, females, and in patients with hypertension, diabetes, and chronic vascular disease because of predisposing anatomical conditions such as left ventricular hypertrophy, small left ventricle size, sigmoid septum and alterations in the positions of the aortic and mitral valve annular planes. The onset of LVOTO is largely unpredictable due to a complex interplay between preload, afterload, heart rhythm and rate in susceptible patients. The consequences of missing this treatable condition may lead to life threatening hypotension refractory to, or exacerbated by, a further increase in inotropic support. Dynamic LVOTO should be considered in any hypotensive intensive care patient. Echocardiography is perhaps the best tool to assess LVOTO and its underlying pathophysiology in the critically ill. Detection of LVOTO is a relatively simple task using a combination of two-dimensional, M-mode and spectral Doppler imaging by an operator alert to the possible diagnosis. PMID- 28072931 TI - Apnoeic oxygenation during intubation: a systematic review and meta-analysis. AB - Apnoeic oxygenation during intubation is used to prevent desaturation during intubation. The aim of this review was to assess whether apnoeic oxygenation during endotracheal intubation reduced the incidence of hypoxaemia. Five major databases were systematically searched for all relevant studies published up to May 2016. All study designs with a control group and a group receiving apnoeic oxygenation were included in this review. These studies were then assessed for level of evidence and risk of bias. The data were then analysed using a meta analysis. Eleven studies (six high quality randomised controlled trials, four low quality level two studies and one low quality level three study) were found. In the meta-analysis there was strong evidence for benefit of apnoeic oxygenation in terms of improved SpO2 in elective surgical patients, obese patients and those undergoing emergency intubation without respiratory failure. However, no significant benefit was found in patients with respiratory failure. This is the first meta-analysis to be performed on apnoeic oxygenation during intubation. Apnoeic oxygenation provides significant benefit in terms of improving SpO2 for the majority of intubations, although there appears to be no benefit in patients whose indication for intubation is respiratory failure. Apnoeic oxygenation ought to be considered for integration into intubation protocols. PMID- 28072932 TI - A cross-sectional overview of the first 4,000 incidents reported to webAIRS, a de identified web-based anaesthesia incident reporting system in Australia and New Zealand. AB - webAIRS is a web-based de-identified anaesthesia incident reporting system, which was introduced in Australia and New Zealand in September 2009. By July 2016, 4,000 incident reports had been received. The incidents covered a wide range of patient age (<28 days to >90 years), American Society of Anesthesiologists physical status, and body mass index (<18.5 to >50 kg/m2). They occurred across a wide range of anaesthesia techniques and grade of anaesthesia provider, and over a wide range of anaesthetising locations and times of day. In a high proportion the outcome was not benign; about 26% of incidents were associated with patient harm and a further 4% with death. Incidents appeared to be an ever-present risk in anaesthetic practice, with extrapolated estimates exceeding 200 per week across Australia and New Zealand. Independent of outcomes, many anaesthesia incidents were associated with increased use of health resources. The four most common main categories of incident were Respiratory/Airway, Medication, Cardiovascular, and Medical Device/Equipment. Over 50% of incidents were considered preventable. The narratives accompanying each incident provide a rich source of information, which will be analysed in subsequent reports on particular incident types. The summary data in this initial overview are a sober reminder of the prevalence and unpredictability of anaesthesia incidents, and their potential morbidity and mortality. The data justify current efforts to better prevent and manage anaesthesia incidents in Australia and New Zealand, and identify areas in which increased resources or additional initiatives may be required. PMID- 28072933 TI - Altered blood levels of vitamin D, cathelicidin and parathyroid hormone in patients with sepsis-a pilot study. AB - It has been recognised that vitamin D (VitD) has a potential role in the regulation of inflammation and protection from infection. In a prospective clinical observational pilot study, we investigated the serum levels of 25 hydroxyvitamin-D3 (25(OH)D3), 1,25-hydroxyvitamin-D3 (1,25(OH)2D3), parathyroid hormone (PTH), and cathelicidin in intensive care unit (ICU) patients with or without systemic inflammatory response syndrome (SIRS). We included 32 patients with SIRS (septic patients), 16 ICU patients without SIRS, and 16 healthy controls. To substantiate the findings of the clinical study, we stimulated monocyte-derived macrophages with microbial patterns and analysed the impact of VitD on release of cytokines and antimicrobial activity. We found that patients with or without SIRS had relatively low levels of 25(OH)D3 and 1,25(OH)2D3. Patients with sepsis had significantly lower levels of 25(OH)D3 as compared to ICU control patients and healthy controls (10.53 +/- 11.3 ug/l versus 16.46 +/- 12.58 ug/l versus 24.04 +/- 12.07 ug/l); the same was true for 1,25(OH)2D3. Serum levels of PTH and cathelicidin were significantly increased in sepsis patients, as compared to the other groups. In vitro, VitD significantly decreased the release of pro-inflammatory cytokines from macrophages and increased the antimicrobial activity of the cells. We concluded that patients with sepsis have significantly lower VitD levels. In vitro, VitD modulates inflammation and increases the antibacterial activity of innate immune cells. These findings suggest that VitD insufficiency is mechanistically related to increased susceptibility to SIRS and sepsis. PMID- 28072934 TI - Aetiology of preoperative anaemia in patients undergoing elective cardiac surgery the challenge of pillar one of Patient Blood Management. AB - Preoperative anaemia is common in patients undergoing cardiac surgery. Whilst there is a strong association with increased morbidity and mortality, it is currently unclear whether treatment of anaemia leads to patient benefit. This retrospective study aimed to determine the aetiology of preoperative anaemia in a cohort of patients undergoing elective cardiac surgery over two years at a tertiary hospital. Laboratory data obtained at the preoperative assessment clinic visit were assessed to stratify patients into four groups-iron deficiency anaemia (IDA), possible IDA, anaemia of chronic disease (ACD) and non-anaemic patients with low ferritin according to the 'Preoperative haemoglobin assessment and optimisation template' of the Australian Patient Blood Management (PBM) Guidelines. Of patients with preoperative anaemia, 23.1% had IDA, 6.6% had possible IDA and 70.3% had possible ACD. Of the patients with possible ACD, 30% had a ferritin <100 ug/l, representing limited iron stores or coexisting absolute iron deficiency in the setting of chronic disease. In addition, 46.2% of those with possible ACD had iron studies indicative of functional iron deficiency. Time between assessment and surgery was as little as one day in a third of patients and in only 7% was it more than seven days. Our findings indicate that about one third of our patients with preoperative anaemia had evidence of iron deficiency, a potentially reversible cause of anaemia. In addition, a significant number had either limited iron stores that may render them iron deficient by surgery, or a functional iron deficiency. PMID- 28072935 TI - The addition of tick-boxes related to tobacco cessation improves smoking-related documentation in the anaesthesia chart. AB - The Australian and New Zealand College of Anaesthetists (ANZCA) 'Guidelines on Smoking as Related to the Perioperative Period (PS12)' recommends that anaesthetists should always ask about smoking, advise quitting and refer patients to their general practitioner (GP) or a telephone quit-line for quit support. In this study we evaluated the effect of adding tick-boxes for 'quit advice given' and 'referral to GP/Quitline' to anaesthesia charts of elective surgical patients to assess whether this intervention changed documentation of compliance with the ANZCA guideline. The anaesthesia charts of all smokers were reviewed for evidence of asking, advising and referring, over two three-month periods (n=999) separated by the intervention of placing a sticker to modify the preoperative charts of all elective patients which added tick-box prompts of advice and referral. No educational campaigns occurred to encourage tick-box use. No changes were made to non-elective charts. Evidence of advice to quit was 1.8% prior to, rising to 18.7% after, the intervention (P <0.001), while evidence of referral rose from 0.9% to 5.8%. There was negligible change in non-elective patients, who did not receive the intervention. The addition of tick-boxes improved the documentation of smoking cessation support, but as documented rates of quit support remained relatively low even after the intervention, tick-boxes alone cannot be relied upon to improve alignment of care with the ANZCA guidelines. PMID- 28072936 TI - Haptoglobin and free haemoglobin during cardiac surgery-is there a link to acute kidney injury? AB - Acute kidney injury (AKI) is frequently observed after cardiac surgery (CS) with cardiopulmonary bypass (CPB). Multiple mechanisms underlie this phenomenon, including CPB-dependent haemolysis. Haemoglobin is released during haemolysis, and free haemoglobin (frHb) causes tubular cell injury after exceeding the binding capacity of haptoglobin (Hp). The objective of this study was to investigate the influence of perioperative changes in frHb and Hp levels on the incidence of CS-associated (CSA) AKI. After receiving local ethics committee approval and obtaining informed consent from our patients, we analysed the data pertaining to 154 patients undergoing CPB surgery. We recorded frHb and Hp concentrations pre-, intra- and postoperatively and defined AKI using the Kidney Disease Improving Global Outcomes (KDIGO) classification. We observed that frHb levels increased significantly during surgery and then decreased at ten hours thereafter and that Hp levels decreased during surgery and remained at low levels until the first postoperative day. We noted a moderate negative correlation between frHb and Hp levels. AKI was identified in 45.5% of patients; however, there was no significant difference in frHb or Hp levels between patients with and without AKI. We did not observe a relationship between frHb or Hp levels and CSA AKI and thus could not confirm the hypothesis that patients with higher baseline Hp concentrations experience a lower incidence of AKI than patients with lower baseline Hp concentrations. PMID- 28072937 TI - Prognosis of patients with rheumatic diseases admitted to intensive care. AB - Variable mortality rates have been reported for patients with rheumatic diseases admitted to an intensive care unit (ICU). Due to the absence of appropriate control groups in previous studies, it is not known whether the presence of a rheumatic disease constitutes a risk factor. Moreover, the accuracy of the Acute Physiology and Chronic Health Evaluation II (APACHE II) score for predicting outcome in this group of patients has been questioned. The primary goal of this study was to compare outcome of patients with rheumatic diseases admitted to a medical ICU to those of controls. The records of all patients admitted between 1 April 2003 and 30 June 2014 (n=4020) were screened for the presence of a rheumatic disease during admission (n=138). The diagnosis of a rheumatic disease was by standard criteria for these conditions. An age- and gender-matched control group of patients without a rheumatic disease was extracted from the patient population in the database during the same period (n=831). Mortality in ICU, in hospital and after 180 days did not differ significantly between patients with and without rheumatic diseases. There was no difference in the performance of the APACHE II score for predicting outcome in patients with rheumatic diseases and controls. This score, as well as a requirement for the use of inotropes or vasopressors, accurately predicted hospital mortality in the group of patients with rheumatic diseases. In conclusion, patients with a rheumatic condition admitted to intensive care do not do significantly worse than patients without such a disease. PMID- 28072938 TI - Welfare of anaesthesia trainees survey. AB - This study was designed to investigate levels of stress, anxiety or depression and to identify factors compounding or relieving stress in anaesthesia trainees within the Australian and New Zealand College of Anaesthetists (ANZCA) training scheme. An electronic survey was sent to 999 randomly selected trainees and 428 responses were received. In addition to demographics, psychological wellbeing was assessed using the Kessler Psychological Distress Scale (K10) and questions were asked about depression and anxiety, exacerbating factors, personal healthcare and strategies used to manage stress. The majority of respondents (73%) reported being satisfied or very satisfied with their job and training. However, 28% of respondents had K10 scores indicating high or very high distress levels. Eleven percent reported being currently on treatment for anxiety and/or depression. Twenty-two percent reported having experienced bullying and 14% sexism. Twenty eight percent reported that they did not have a regular general practitioner (GP), and 41% reported having not visited their GP in the previous year. Forty seven percent of trainees reported that they self-prescribe medications. Major stressors reported were exams, critical clinical events and fear of making errors. Two stressors previously not identified in similar studies were concern about job prospects in 71% of respondents and workplace-based assessments in 51%. This survey demonstrates significant psychological impairment and poor personal healthcare amongst many trainees. Education, careful continuing assessment of trainees' welfare and a review of current support and remedial measures may be required. PMID- 28072939 TI - Evaluating team-based inter-professional advanced life support training in intensive care-a prospective observational study. AB - Recent focus on national standards within Australian hospitals has prompted a focus on the training of our staff in advanced life support (ALS). Research in critical care nursing has questioned the traditional annual certification of ALS competence as the best method of delivering this training. Simulation and team based training may provide better ALS education to intensive care unit (ICU) staff. Our new inter-professional team-based advanced life support program involved ICU staff in a large private metropolitan ICU. A prospective observational study using three standardised questionnaires and two multiple choice questionnaire assessments was conducted. Ninety-nine staff demonstrated a 17.8% (95% confidence interval 4.2-31, P=0.01) increase in overall ICU nursing attendance at training sessions. Questionnaire response rates were 93 (94%), 99 (100%) and 60 (61%) respectively; 51 (52%) staff returned all three. Criteria were assessed by scores from 0 to 10. Nurses reported improved satisfaction with the education program (9.4 to 7.1, P <0.001), as well as improvement in role understanding (8.7 and 9.1 versus 7.9 and 8.2, P <0.001) and confidence (8.4 and 8.8 versus 7.4 and 7.8, P <0.001) during ALS provision (outside ICU and inside ICU) following the course when compared to before the program. Doctors' only statistically significant improvement was in their confidence in ALS provision outside ICU (8.7 versus 8.1, P=0.04). The new program cost approximately an extra $16,500 in nursing salaries. We concluded that team-based, inter-professional ALS training produced statistically significant improvements in nursing attendance, satisfaction with ALS education, confidence and role understanding compared to traditional ALS training. PMID- 28072940 TI - Elective use of veno-venous extracorporeal membrane oxygenation and high-flow nasal oxygen for resection of subtotal malignant distal airway obstruction. AB - We describe the use of peripheral veno-venous extracorporeal membrane oxygenation (VV ECMO) and high-flow nasal oxygen as procedural support in a patient undergoing debulking of a malignant tumour of the lower airway. Due to the significant risk of complete airway obstruction upon induction of anaesthesia, ECMO was established while the patient was awake, and was maintained without systemic anticoagulation to minimise the risk of intraoperative bleeding. This case illustrates that ECMO support with high-flow nasal oxygen can be considered as part of the algorithm for airway management during surgery for subtotal lower airway obstruction, as it may be the only viable option for maintaining adequate gas exchange. PMID- 28072941 TI - The expanding role of extracorporeal membrane oxygenation retrieval services in Australia. AB - Herein we detail the cases of three patients transferred on veno-arterial extracorporeal membrane oxygenation (VA ECMO) from a tertiary referral hospital to an ECMO centre. We highlight the benefits of such a transfer and offer this as a model of care for unwell patients likely to require a prolonged period of ECMO support. PMID- 28072942 TI - Introduction of a simple algorithm improves thromboelastography-guided blood product use during cardiac surgery. PMID- 28072943 TI - SWAPNET: Ethically bankrupt or ethically blinded? PMID- 28072944 TI - The three-dimensional (3D) printing of a flexible trachea. PMID- 28072945 TI - Uneventful prolonged propofol infusion in a patient with Brugada syndrome. PMID- 28072946 TI - Eve Rocker journal cover. PMID- 28072947 TI - What's beneath the surface? Stevens-Johnson syndrome/toxic epidermal necrolysis combined with haemophagocytic lymphohistiocytosis: a case report. PMID- 28072948 TI - What is the evidence that twenty-five millilitres of gastric fluid puts patients at risk of aspiration? PMID- 28072949 TI - Response to letter to editor. PMID- 28072951 TI - [Futher strengthen the immunoglobulin G replacement therapy of primary immunodeficiency diseases]. PMID- 28072950 TI - [Epidemiology and etiology of bacillary dysentery in Xinjiang Uigur Autonomous Region, 2004-2014]. AB - Objective: To understand the epidemiological and etiological characteristics of bacillary dysentery in Xinjiang Uigur Autonomous Region (Xinjiang) during 2004 2014, and provide evidence for the prevention and control of bacillary dysentery. Methods: Descriptive epidemiological analysis was conducted by using the incidence data of bacillary dysentery in Xinjiang during 2004-2014 and the serotyping and the antibiotic susceptibility test of the pathogens isolated were performed. Results: A total of 123 238 cases of bacillary dysentery were reported in Xinjiang from 2004 to 2014. The average annual incidence of bacillary dysentery ranged from 25.91 per 100 000 to 76.04 per 100 000 and the average annual mortality ranged from 0.00 to 46.90 per 100 000. The incidence of bacillary dysentery was higher in eastern Xinjiang than other areas. The incidence peak was during July-September. The incidence of bacillary dysentery in males was higher than that in females. The incidence was highest in infants and young children under five years old. Most cases were children outside child care settings, farmers and students. Shigella flexneri was the predominant pathogen and F2a was the most frequently detected subtype. The isolated strains were highly resistant to streptomycin, penicillin, doxycycline and tetracycline. The resistant rates to penicillin, tetracycline, doxycycline and streptomycin increased with year. Up to 71.43% of the strains were resistant to more than five antibiotics. Conclusion: The incidence of bacillary dysentery was in decrease in Xinjiang from 2004 to 2014, but in some area, the incidence of bacterial dysentery was higher than national average level. It is necessary to strengthen the surveillance and conduct targeted prevention and control in areas and population at high risk and in season with high incidence. The serious drug resistance and multi drug resistance of the pathogens have posed challenge to the prevention and treatment of bacillary dysentery in Xinjiang. PMID- 28072952 TI - [Rome IV diagnostic criteria of childhood functional gastrointestinal disorders]. PMID- 28072953 TI - [Interpretation of the 2016 revision to the World Health Organization classification of acute leukemia]. PMID- 28072954 TI - [Clinical and immunological analysis of patients with activated phosphoinositide 3-kinase delta syndrome resulting from PIK3CD mutation]. AB - Objective: To explore the clinical and immunological features, gene mutations, treatment and prognosis in patients with activated phosphoinositide 3-kinase delta syndrome (APDS) caused by PIK3CD gene heterozygous germline mutation. Method: The data of clinical, immunological phenotype, treatment, and prognosis of 15 patients with APDS, who visited Children's Hospital of Chongqing Medical University, Peking Union Medical College Hospital, and Shenzhen Children's Hospital from June 2014 to November 2016, were collected and analyzed. Result: Of the 15 patients, 11 were males, remaining 4 patients were females. The median age of disease onset was 1 year, and median age at diagnosis was 4 years and 4 months. All patients had the de novo heterozygous germline mutation in PIK3CD (c. 3061G>A, p. E1021K). The common initial symptoms were respiratory infections, including pneumonia (12 cases) , bronchiectasis (5 cases). Other common clinical manifestations were recurrent and chronic diarrhea (11 cases), Epstein-Barr virus (EBV) and/or cytomegalovirus (CMV) viremia (10 cases), hepatosplenomegaly (13 cases), and lymphadenopathy (10 cases). The main immunological features were increased IgM (11 cases), decreased IgG (6 cases), decreased numbers of CD4+ T cell (7 cases) especially naive CD4+ T cell (9 cases), reduced numbers of B cells (11 cases) particularly naive B cells (9 cases), increased numbers of transitional B cells (5 cases) and CD8+ terminally differentiated effector memory T cells (5 cases). After 1-29 months follow up, 13 of the 15 cases remain survived, of whom 5 cases received regular intravenous immunoglobulin (IVIG) therapy, with reduced frequency of infections and improved severity of infections; of whom 3 cases received oral rapamycin therapy at the dosage of 1 mg/ (m2.d) and with a decrease in nonneoplastic lymphoproliferation. Conclusion: E1021K is a hotspot for mutation in the PIK3CD gene in patients with APDS. Regular IVIG can improve their quality of life. Targetel treatment with rapamycin could mitigate hepatosplenomegaly. PMID- 28072955 TI - [Clinical analysis of 12 patients with pediatric antiphospholipid syndrome with pulmonary embolism]. AB - Objective: To identify the clinical and immunological characteristics of pediatric antiphospholipid syndrome (APS) patients with pulmonary embolism. Method: Among 47 pediatric APS patients from Peking Union Medical College Hospital during the year of 2000 to 2015, 12 patients were diagnosed of pulmonary embolism, who were investigated and compared with APS patients without pulmonary embolism. Result: Twelve patients (among whom 6 cases were primary and the other 6 were secondary APS)had pulmonary embolism and all of them were non-shock type, which was the first presenting manifestation in 6 of them.Eight cases were misdiagnosed as infection, while 3 cases were missed.Among patients with pulmonary embolism, 10 patients suffered from deep vein thrombosis at the same time, mainly in lower extremities.2 cases had thrombotic recurrence, which happened only in primary APS patients, because of irregular monitoring of International Normalized Ratio, or not taking aspirin after quitting warfarin.Positive anticardiolipin (ACL) and lupus anticoagulant (LA) were found in 10 and 9 patients respectively.Four primary APS patients had positive anti nuclear antibodies (ANA). During follow-up of 3-100 months (median 23 months) of primary APS, no one had evolved manifestations of systemic lupus erythematosus.Primary APS was more often seen in males (M?F 5?1 vs. 0?6) and the patients were much younger ((15+/-1) vs. (17+/-0) years old) than those with secondary APS.Besides that, no statistically significant difference was seen between primary and secondary APS (P all>0.05). Compared with APS patients without pulmonary embolism, pulmonary hypertension was more common in patients suffered from pulmonary embolism (3/12 vs. 0, P<0.05). Conclusion: Pulmonary embolism can be the first symptom in pediatric APS patients and all of them are non-shock type, which tends to be misdiagnosed or missed. A majority of them suffer from deep vein thrombosis in the lower extremities.Rethrombosis takes place when the anticoagulant therapy is irregular.Positive anti-nuclear antibodies can be seen in primary APS patients, but no manifestations of lupus come out during follow-up.There is no significant difference between primary APS and secondary APS.Pulmonary hypertension is more common in APS patients suffered from pulmonary embolism. PMID- 28072956 TI - [Clinical and immunological analysis of the patient with autoimmunity due to germline STAT3 gain-of-function mutation]. AB - Objective: To investigate the clinical and immunological laboratory features and gene mutation in a female patient who carried a germline gain-of-function mutation in STAT3. Method: A patient with lymphadenopathy and pancytopenia, visited the Department of Rheumatology and Immunology of Children's Hospital of Chongqing Medical University in May 2016. The clinical and laboratory characteristics, results of immunophenotyping and exome sequencing were analyzed retrospectively and related literature was reviewed. Result: The patient was a four years old girl. The clinical manifestation consisted of autoimmune pancytopenia, lymphadenopathy and recurrent infections. Multiple exams showed that peripheral blood leukocyte count was (2.2-4.9)*109/L, red blood cell count was (2.09-5.75)*109/L, hemoglobin level was 64-165 g/L, platelet count was (52 138) *109/L. Percentages of lymphocyte subsets showed that CD3+ T lymphocyte was 0.716 0 (CD4+ T lymphocyte was 0.326 0, CD8+ T lymphocyte was 0.323 0 and CD4- CD8-T TCRalphabeta+ lymphocyte was 0.029 0), CD19+ B lymphocyte was 0.235 0 (transitional B was 0.004 3), NK was 0.032 0. Percentages of CD4+ T lymphocyte release IL-4, IFN-gamma, IL-17 and IL-21 were 0.014 9, 0.213, 0.024 0 and 0.021 0, respectively. Lymphocyte proliferation function and TCRVbeta diversity were normal. The serum immunoglobulin levels were 16.4 g/L (IgG), 1.53 g/L (IgA), 3.99 g/L (IgM) and 3.20 kU/L (IgE). The patient carried a missense variant in the 21st exon of STAT3, c. 1974G>C, p.K658N, which was previously described as a gain-of function mutation. The patient was treated with methylprednisolone and prednisone intermittently. There were significant improvements of hepatosplenomegaly, lymphadenopathy and pancytopenia. We searched internal database and literature for cases with gain-of-function mutations in STAT3. A total of 19 cases were identified, all were non-Chinese. Among 16 cases who had clinical data, age of onset of 11 patients was less than 5 years. 14 cases had autoimmune hemolytic anemia, autoimmune thrombocytopenia or autoimmune neutropenia. Twelve patients had lymphadenopathy while 11 had infections and 5 had endocrine abnormalities. Conclusion: The patient with Primary immunodeficiency disease (PID) due to gain of-function mutation in STAT3 gene often has early-onset autoimmune disorders, lymphadenopathy and recurrent infections. Since the routine immunological examination may be normal or slightly abnormal, comprehensive evaluation of immune function should be done. Genetic testing ultimately helps to confirm the diagnosis. PMID- 28072957 TI - [A cross-sectional survey on the patterns of primary teeth eruption in 2 581 children]. AB - Objective: To investigate the patterns of primary teeth eruption by a cross sectional survey in 0-40 months old children in Chongqing and to provide normal timetables of tooth eruption that are practical in general physical growth assessment. Method: Data of 2 581 0-40 months old healthy children were collected from January 2014 to January 2016 at Children's Hospital of Chongqing Medical University. General information was recorded by primary child health care doctors, including age, gender, gestation age, birth weight, time and sequence of first primary tooth eruption, number of teeth and age of totally primary teeth emergence. Median and constituent ratio were used in describing the age of tooth eruption and eruption characteristics at different age. Moreover, independent sample t test, variance analysis, Pearson product-moment correlation and Logistic regression were also involved in data analysis. Result: Totally 2 581 children were involved in this survey, including 506 infants of 0-6 months old, 600 infants of 7-12 months old, 730 toddlers of 13-24 months old and 745 children of 25-40 months old. There were 1 473 boys and 1 108 girls, 89 preterm babies and 2 492 full term babies, 1 829 children with tooth erupted and 626 children with all primary teeth erupted.The age of the first primary tooth eruption was between 2 15 months old ( median age: 8 months old, 95%CI: 2.7-12.7)and for the last primary tooth emergence was between 23-35 months of age (median age: 31 months, 95%CI: 24.7-36.7). The time of first tooth eruption was positively correlated with that of total teeth emergence (r=0.879, P<0.05). Dental charts (number of tooth for age) of different gender were drawn according to teeth eruption information. The first primary tooth eruption was the incisor of mandible in 95.3% (1 743/1 829)infants and was the incisor of maxilla in 4.6% (84/1 829)infants. During the period of tooth emerging actively (number of teeth <=16), the number of primary teeth might be calculated by formula: number of teeth=chronological age in months-age of first eruption in months+ 1. There was no statistically significant difference between the number of actual teeth and calculated by the present formula(t=-2.957, P=0.05). Conclusion: The median age of first primary tooth eruption and total teeth emergence was 8 and 31 months of age respectively. The first primary tooth eruption is incisor of mandible in most infants.The formula (number of teeth=chronological age in months-age of first eruption in months+ 1 )can be used to estimate the number of primary teeth. Dental charts might provide normal and supplement datasets for evaluating child physical growth. PMID- 28072958 TI - [Investigation on immunization program coverage rate and its safety in children with tuberous sclerosis]. AB - Objective: To investigate the status of immunization of National Immunization Program (NIP) and its adverse reaction rate in children with tuberous sclerosis. Method: Questionnaire survey was adopted to identify the vaccination coverage and its adverse events; 72 cases of children with tuberous sclerosis and 78 normal controls (healthy children completing age-appropriate NIP) admitted to Chinese People's Liberation Army General Hospital from December 2014 to November 2015 were involved into this study. Result: The age-appropriate NIP coverage rate of tuberous sclerosis was 36%(26/72). The coverage rate of bacillus calmette-guerin (BCG), hepatitis B vaccine 1st to 3rd doses (HepB1-3), oral poliovaccine 1st dose (OPV1), diphtheria, pertussis and tetanus 1st dose (DPT1), DPT1-3, meningococcal polysaccharide vaccine group A (MPVA), measles amd rubella vaccine/measles vaccine 1st dose (MRV/MCV1), and Japanese encephalitis vaccine 1st dose (JEV1) were 100%(72 cases), 75%(51 cases), 97%(66 cases), 91%(62 cases), 82%(56 cases), 66%(45 cases), 69%(42 cases), and 61%(37 cases) respectively. The reasons why the children did not complete the vaccination plan were that parents were concerned about vaccination-induced seizures or seizures had not been controlled. Among 72 children with TSC, the rate of adverse events or suspected adverse events after vaccination was 17% (12 cases), which was higher than the normal control children (2 cases, 3%) (chi2=8.799, P<0.05). The main adverse events were seizure events, which accounted for 92%(11 cases). Conclusion: The age-appropriate NIP coverage rate among children with tuberous sclerosis is low. The high incidence of adverse events may be associated with a fact that there are some nervous system abnormalities in cases with tuberous sclerosis. TSC children vaccination is relatively safe, with no serious adverse events. PMID- 28072959 TI - [Diagnosis of pulmonary hemorrhage of the newborn infants using lung ultrasonography]. AB - Objective: To investigate the accuracy and reliability of lung ultrasound in diagnosis of pulmonary hemorrhage of the newborn infants. Method: From January 2014 to May 2016, 142 neonates from the Army General Hospital of the Chinese PLA were enrolled in the study. They were divided into two groups: a study group of 42 neonates, who were diagnosed with pulmonary hemorrhage according to their medical history, clinical manifestations and chest X-ray findings, and a control group of 100 neonates with no lung disease. All subjects underwent bedside lung ultrasound in a quiet state in a supine, lateral or prone posture, performed by a single experienced physician. The ultrasound findings were compared between the two groups.Fisher's exact test was uesd for comparison between two groups. Result: The lung ultrasound main findings associated with pulmonary hemorrhage included: (1) Shred sign: which was seen in 40 patients(95%). (2) Lung consolidation with air bronchograms: which were seen in 35 patients(83%). (3) Pleural effusion: which was seen in 34 infants(81%), pleurocentesis confirmed that the fluid was really bleeding.(4)Atelectasis: which was seen in 14 cases(33%). (5) Pleural line abnormalities and disappearing A-lines with an incidence of 100%. (6) Alveolar-interstitial syndrome: 5 patients(12%)had the main manifestations of alveolar-interstitial syndrome. The above signs were not seen in normal controls (all P<0.01) and the normal lung mainly manifested with clear pleural line and A-lines under ultrasound. Conclusion: Lung ultrasonography is accurate and reliable for diagnosing pulmonary hemorrhage, which is suitable for routine application for the diagnosis of pulmonary hemorrhage in the neonatal intensive care unit. PMID- 28072960 TI - [Novel compound heterozygous TBC1D24 mutations in a boy with infantile focal myoclonic epilepsy and literature review]. AB - Objective: To investigate the clinical features and genetic characteristics of patients with TBC1D24 gene mutations. Method: The clinical data of a patient with novel TBC1D24 compound heterozygous mutations from Children's Hospital of Fudan University were collected, the related literature was searched from China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, National Center from Biotechnology Information and Pubmed (up to April 2016) by using search terms "TBC1D24" "epilepsy" . The clinical features, electroencephalogram (EEG) and prognosis of the patients with TBC1D24 gene mutations were studied. Result: The patient was a boy with non-consanguineous healthy parents.He had an acute episode of focal continuous myoclonus lasting a few hours with consciousness preserved at the age of 3 months.Myoclonic jerks alternatively affected the eyelids, either the right or left limbs, sometimes triggered by fever or fatigue.The frequency was once 3-7 days.At the age of 6 months he was found to have myoclonus seizures with onset from a unilateral eyes lid and limb lasting 10 more minutes and subsequently affected four extremities or the trunk.They occurred once 3-4 months with perserved consciousness and lasted from several hours to up to ten more hours.They mostly disappeared during sleep.He had ataxia and mild mental retarding.Paroxysmal anomalies were not found on ictal traces.A novel compound heterozygous mutation of TBC1D24 gene, c. 730G>A, p.A244T and c. 1571G>C, p.R524P were found in the patient.Further study showed that c. 730G>A mutation was inherited from his father and c. 1571G>C from his mother. These two were not reported in public databases and predicted deleterious by Mutation Taster and polyphen-2.Literature relevant to TBC1D24 published all around the world was reviewed, no Chinese cases with TBC1D24 gene mutations had been reported. The total of 24 cases including the present case with TBC1D24 gene mutation were reported.Among them, 11 cases had compound heterozygous mutations and 13 cases had homozygous mutations.Ten mutations were identified, including 1 termination mutation, 1 frameshift mutation and 8 missense mutations. Conclusion: TBC1D24 gene mutational analysis should be performed on patients with early-onset focal continuous myoclonus, if the etiology was unclear. PMID- 28072961 TI - [A case report of childhood Farber's disease and literature review]. AB - Objective: To explore the clinical features, diagnosis, treatment and the prognosis of Farber disease by case report and literature review. Method: The clinical information of a case with farber's disease diagnosed in October 2015 at Peking University First Hospital was collected and analyzed, including clinical manifestation, electrophysiology, magnetic resonance imaging, pathology, treatments and prognosis.ASAH1 gene mutational analysis was conducted in the patient and her parents.By using "Farber's disease, ASAH1" as keywords, literature was searched from Pubmed, CHKD and HGMD database from January 1951 to January 2016. Result: The girl, 2 years 2 months old, was sent to our hospital in October 2015, with complains of "joint swelling for 17 months, development regress of intelligence and movement for 11 months, intermittent seizures for 2 months" .The clinical manifestation of the patient was characterized by painful and deformed joints, subcutaneous nodules, progressive hoarseness, and the progressive neurological system deterioration.Joints swelling and deformity behave as the first symptoms.A series of electroencephalogram showed slow background and spike wave.Visual evoked potential was significantly abnormal.Brain magnetic resonance imaging (MRI) showed hypomyelination and progressive diffuse brain atrophy.Histology of subcutaneous nodule showed proliferation of the connective tissue with hyalinization, cholesterol crystal like changes, and a large number of foamy cell infiltration.Compound heterozygous mutations of ASAH1 gene, c. 304_305 ins A (p.T102Nfs14) and c. 314T>C (p.L105p), were found in the patient, and the former is inherited from her mother, the latter from her father.Antiepileptic treatment and other symptomatic treatments were delivered to the patient, but the effectiveness was poor.One reference from China hownet and 35 references from Pubmed have reported a total of 26 cases.Twenty out of 26 patients (77%) had the onset under 1 year of age.By region, there were 12 patients (12/26, 46%) from India, and the others around world.Among these 12 indian patients, 10 lack of complete clinical data.Among the rest 16 patients, 4 patients' parents were consanguineous; 8 patients with the main clinical manifestation of painful and deformed joints, subcutaneous nodules, and hoarse cry; 4 patients with hepatic failure and impaired spleen; 5 patients with rapid neurological deterioration; 1 patient with bone destruction; 7 patients under liver and skin biopsies, pathologically showing a large number of foam cells and "Farber bodies" . There are 33 genetic mutations, and 45% (15/33) mutations are concentrated in ASAH1 exon 6-10. Conclusion: Farber disease is a rare autosomal recessive disease caused by deficiency of lysosomal acid ceramidase.Histopathology of granulomatous tissue plays an important role in the early diagnosis. PMID- 28072962 TI - [Relationship between blood routine test parameters and syncopal recurrence of vasovagal syncope in children]. AB - Objective: To explore the relationship between venous blood routine test parameters and syncopal recurrence of children with vasovagal syncope (VVS). Method: Sixty-three children (male 32, female 31) diagnosed as VVS in Department of Pediatrics, Peking University First Hospital from November 2010 to October 2015 were included in a case observational study.Their mean age was (11.2+/-2.7) years and basic treatment such as predisposing causes avoiding, standing training, autonomic nervous function exercise and oral rehydration salts were advised to them.The clinical data were obtained by out-patient visit and over telephone from December 2015 to January 2016, with a median follow-up period of 10 (4, 26) months. The effects of baseline venous blood routine test parameters, gender, age, and body mass index (BMI) on syncopal recurrence were studied via univariate and multivariate Cox regression analysis.Kaplan-Meier curve was used to evaluate the long-term prognosis. Result: Among the 63 VVS children in this study, 31 cases were diagnosed as VVS vasodepressor type, 4 cases as VVS cardioinhibitory type and 28 cases as VVS mixed type, 16 cases (25%) had experienced recurrence of syncope while 47 cases (75%) had not.The result of univariate analysis of Cox regression showed that baseline platelet count (PLT) (HR=1.012, 95%CI: 1.003-1.022) had a marked impact on the survival rate.And the result of multivariate analysis of Cox regression showed that baseline hemoglobin concentration (HGB) (HR=1.055, 95%CI: 1.007-1.105), mean corpuscular hemoglobin (MCH) (HR=0.612, 95%CI: 0.423-0.884) and PLT(HR=1.015, 95%CI: 1.006-1.024) had significant effects on survival rate of VVS children.In this study, the one-year, two-year, and three-year survival rate were 83% (52/63), 79% (50/63) and 75% (47/63), respectively. Conclusion: The baseline venous blood routine test parameters HGB, MCH and PLT might be the influencing factors of the syncopal recurrence of VVS children. PMID- 28072963 TI - [No. 143: fever, cardiac insufficiency, abdominalgia, jaundice]. PMID- 28072964 TI - [Avian influenza virus H9N2 found in a child with influenza like illness in Beijing]. PMID- 28072965 TI - [Development of newborn screening for severe combined immunodeficiency]. PMID- 28072966 TI - [Transcutaneous bilirubin measurement in neonatal jaundice]. PMID- 28072967 TI - [Pay more attention to molecular detection in pathologic diagnosis]. PMID- 28072969 TI - [Pathologic consensus of pulmonary neuroendocrine tumors]. PMID- 28072968 TI - [Novel markers in triple-negative breast cancers]. PMID- 28072970 TI - [Histologic classification and prognosis factors in phyllodes tumors of breast]. AB - Objective: To study the relationship between morphological characteristics, grading, diagnosis and prognosis in phyllodes tumors (PT) of the breast. Methods: A retrospective study was carried out on 83 PTs diagnosed between 1999 and 2003 that were classified semi-quantitatively according to the WHO recommendation. Follow-up data was available for some cases, and Cox regression analysis was used to evaluate factors affecting metastasis and recurrence. Results: All cases were classified into the benign (57.8%), borderline (28.9%) and malignant (13.3%). The overall recurrence rate for the 72 cases with follow-up data was 20.8% (15/72), and was 17.5% (7/40) in benign, 22.7% (5/22) in borderline and 3/10 in malignant PT, respectively, with no significant difference (P>0.05). The median interval between the initial diagnosis and the first recurrence was 24 months. Lung or bone metastases occurred in 1/22 borderline and 3/10 malignant PT patients 5 years post-surgery. The mitotic count and the degree of stromal cell atypia were significantly correlated with recurrence (P=0.001 and P=0.006). Multivariate analysis showed that severe stromal cell atypia was an independent predictor of recurrence-free survival in PT [HR=6.40 (95% CI=1.378 to 29.732), P=0.018]. Conclusions: Each parameter in the histological grading of PT may have different prognostic value, and markedly increased mitotic count and were predictive of relapse. PMID- 28072971 TI - [Expression of PD-1/PD-L1 in triple-negative breast carcinoma and its significance]. AB - Objective: To investigate the correlation between the expression of PD-1, PD-L1 and clinicopathologic parameters in triple negative breast carcinoma (TNBC). Methods: Samples from 151 patients with TNBC and 65 cases of other breast carcinomas (non-TNBC) were examined for PD-L1 and PD-1 expression by immunohistochemical staining on tissue microarray. Results: The expression of PD L1 and PD-1 in the tumor cells and interstitial lymphocytes in TNBC was significantly (P<0.05)higher than that in non-TNBC.In TNBC, the expression rates of PD-L1 in the cancer nests and stroma were 16.6%(25/151) and 25.2%(38/151)respectively.The former was positively correlated with tumor histological grade and lymph node metastasis (P<0.05), and the latter only with tumor histological grade (P<0.05). The expression rate of PD-1 was 27.2% (41/151), and correlated with PD-L1 expression in stromal tumor-infiltrating lymphocytes (P<0.05). Conclusion: The expression of PD-L1 in TNBC is significantly correlated with high-grade histology, lymph node metastasis and PD L1 expression in stromal tumor-infiltrating lymphocytes. PMID- 28072972 TI - [Clinicopathologic features of adenoid cystic carcinoma of breast]. AB - Objective: To investigate the clinicopathologic features and grading of adenoid cystic carcinoma (ACC) of the breast. Methods: Sixteen cases of ACC of the breast were analyzed and graded according to the previous report. Immunohistochemical (IHC) staining was used to detect the immunophenotype, Ki-67 proliferative index and expression of EZH2, and the association with tumor grade and outcome was analyzed. Results: Of the 16 cases, 11 were grade I, with the epithelial and myoepithelial cells being arranged into tubular and cribriform structure with no solid component; three were grade II, which were composed of mixed tubular, cribriform and solid component (<30%); and two were grade III, which showed mainly solid component (>90%) and the tumor cells showed basaloid features with scanty cytoplasm and hyperchromatic nuclei, and mitotic count was>5/10 HPF. Immunophenotypically, the epithelial cells expressed CK7, CK8/18 and CD117; the myoepithelial cells expressed p63 and CK5/6; while the basaloid cells were positive for CK5/6 and CD117.Tubular and cibriform ACC showed low Ki-67 and EZH2 expression, while the two cases of solid variant with basaloid features showed high level of Ki-67 and EZH2 expression. Follow-up data were available in 13 cases with a median follow-up period of 42 months. Lung metastasis occurred after 12 months in one grade II case and the patient died of disease after 34 months. Vertebral metastasis occurred after 12 months in one grade III case and axillary lymph node metastasis occurred in another grade III case. All other patients were free of disease at the end of the follow-up periods. Conclusions: ACC shows morphologic spectrum varying from low to high grade, the latter can may give rise to local and distant metastasis. ACC should not be regarded simply as low malignant potential, and should be graded for optimal treatment. PMID- 28072973 TI - [Expression of FoxM1 and BCRP in invasive breast carcinoma of no special type and its prognosis significance]. AB - Objective: To investigate the relationship between expression of FoxM1 and BCRP in invasive breast carcinoma of no special type (IBC-NST) tissues and the clinical pathological characteristics and prognosis of the patients. Methods: Seventy-eight cases of IBC-NST with excision were included. The expression of FoxM1 and BCRP was assessed by immunohistochemistry and its relationship with the clinical pathological characteristics and prognosis was evaluated. Results: FoxM1 was expressed in 71.8%(56/78) of IBC-NST, and the expression was related to tumor diameter, TNM staging, ER, PR and HER2. BCRP was expressed in 53.8% (42/78) of IBC-NST, and the expression was related to age, tumor diameter, lymph node metastasis, ER and HER2. Kaplan-Meier survival analysis showed the survival time was related to tumor diameter, TNM staging, lymph node metastasis and the expression of FoxM1, BCRP, ER, PR and HER2. Cox multivariate analysis showed that TNM staging, FoxM1, BCRP, HER2 were determinants of patient survival time. Conclusions: The expression of FoxM1 is associated with tumor diameter, TNM staging, ER, PR and HER2 while BCRP is associated with age, tumor diameter, lymph node metastasis, ER and HER2. Both FoxM1 and BCRP have prognostic significance in IBC-NST patients. PMID- 28072974 TI - [Clinicopathologic features of mammary analogue secretory carcinoma of salivary glands]. AB - Objective: To investigate the clinicopathological features of mammary analogue secretory carcinoma (MASC) of salivary glands, and its diagnosis, differential diagnosis, immunohistochemistry and molecular pathology. Methods: Seventeen cases of MASC were enrolled, with 9 cases of salivary acinar cell carcinoma and 18 cases of adenoid cystic carcinoma as control groups from Nanjing General Hospital from 1997 to 2014 were included in this retrospective study, combined with immunohistochemistry and molecular detection of ETV6-NTRK3 gene fusion. All cases were histologically reviewed with immunohistochemical staining (EnVision) for S 100 protein, SOX10, GATA3, CD117 expression in each group. Fluorescence in situ hybridization (FISH) was used to detect the ETV6-NTRK3 gene fusion. Results: The age of MASC patients ranged from 27 to 74 years with mean age of 47 and ratio of male and female was 4?3. All cases showed infiltrative growth and diverse cytology and histology, including lobular (8 cases), cystic papillary (3 cases), cribriform mixed with papillary and glandular structures (6 cases) at various proportions. Some tumors of MASC also exhibited solid growth areas with occasional microcystic honeycombed pattern composed of small cysts merged into larger cysts resembling thyroid follicles. S-100 protein and SOX10 were strongly positive in all MASC cases (17/17). In addition, there was insignificant positivity for GATA3 (3/17) and CD117 (4/17). ETV6 gene fusion detection was informative in 12 MASC cases by FISH with 10 positive cases and 2 negative cases. Conclusions: Combined immunohistochemical positivity of S-100 protein, CD117 and SOX10 are useful in the diagnosis and differential diagnosis of MASC. FISH detection of ETV6-NTRK3 fusion offers an additional molecular diagnostic marker for the diagnosis. PMID- 28072975 TI - [Molecular features of metanephric adenoma and their values in differential diagnosis]. AB - Objective: To study the molecular features of metanephric adenoma (MA) and discuss their values in differential diagnosis. Methods: BRAF V600E immunohistochemistry (IHC) using the mutation-specific VE1 monoclonal antibody and Sanger sequencing of BRAF mutations were performed on 21 MAs, 16 epithelial predominant Wilms tumors (e-WT) and 20 the solid variant of papillary renal cell carcinomas (s-PRCC) respectively. p16 protein was detected by IHC also. Fluorescence in situ hybridization (FISH) analyses using centromeric probes for chromosome 7 and 17 were performed on the three renal tumors in parallel. Results: Fourteen (14/21, 66.7%) of 21 MA cases demonstrated diffuse, moderate to strong cytoplasmic BRAF V600E IHC staining and the BRAF V600E protein expression was detected in 2 (2/16) of 16 e-WT cases for the first time, whereas all s-PRCCs were negative (P<0.05). All cases (including 14 MAs and 2 e-WTs) with diffuse, moderate to strong cytoplasmic BRAF V600E IHC staining were confirmed to harbor BRAF V600E missense mutations using Sanger sequencing, and no BRAF mutations were detected in cases with negative BRAF V600E protein expression. One case (1/21, 4.8%) showed trisomy of chromosome 7 alone, and another one (1/21, 4.8%) showed trisomy of chromosome 17 alone in 21 MAs. Two cases (2/16) of 16 e-WTs showed trisomy of chromosome 17 alone. In 20 s-PRCCs, trisomy of chromosomes 7 alone was reported in 2 cases (2/20), trisomy of chromosome 17 alone in 3 cases (3/20) and trisomy of chromosome 7 and 17 in 14 cases (14/20). The total positive rates of trisomy of chromosome 7 and/or 17 in MAs, e-WTs and s-PRCCs were 9.6% (2/21), 2/16 and 95.0% (19/20). p16 protein was positive in 81.0% (17/21) MAs, whereas the positive rates in e-WTs and s-PRCCs were 2/16 and 5.0% (1/20). Conclusions: Most MAs harbor BRAF V600E mutations, and MAs lack the gains of chromosome 7 and 17 that are characteristic of papillary renal cell carcinoma. These molecular features can be used to distinguish MA from its mimics. BRAF V600E IHC using the mutation-specific VE1 monoclonal antibody provides an effective method in BRAF V600E mutations detection of renal tumors. p16 is overexpressed in MA, and the finding suggests that the low proliferative rate of the tumor might be attributed to BRAF V600E-induced senescence mediated by p16. PMID- 28072977 TI - [Breast Rosen triad: a clinicopathologic analysis of 5 cases]. PMID- 28072978 TI - [Infantile hepatic hemangioendothelioma: a clinicopathologic features of 6 cases]. PMID- 28072976 TI - [Establishment and validation of human cancer cell lines with stable Cas9 expression]. AB - Objective: To establish human cancer cell strains with stable Cas9 expression, and to validate the gene editing activity of Cas9 for simple gene editing in future study. Methods: Fifteen cancer cell lines of different tissue origins were infected with pLv-EF1alpha-Cas9-Flag-Neo or pLv-EF1alpha-Cas9-Flag-Puro by lentivirus and clone selection was employed to screen Cas9 stably expressed cancer cell lines. Afterward designed guide RNA vectors targeting TSC22 gene were transiently transfected into 3 of cell lines, and subsequently the gene editing activity of Cas9 was evaluated by genomic PCR, sequencing and Western blot. Results: Sixty-nine human cancer cell strains with stable Cas9 expression from different cancers were established, and by transient transfection with designed guide RNA, long fragment deletion was detected in TSC22 gene. Conclusions: Sixty nine human cancer cell strains are successfully established with stable expression of Cas9 protein and gene editing activity. These cell strains may be employed in large-scale drug screening, screening of new drug targets and gene function investigation. PMID- 28072979 TI - [Paraffin-embedded tissue fragment suspension: a novel method for quality control preparation in in-situ hybridization for Epstein-Barr virus encoded RNA]. PMID- 28072980 TI - [Primary ALK-negative anaplastic large cell lymphoma of breast: report of a case]. PMID- 28072981 TI - [Gastric myoglandular hematoma: report of a case]. PMID- 28072982 TI - [Metastatic pleomorphic adenoma of lung: report of a case]. PMID- 28072983 TI - [Progress in clinicopathologic studies of mammary pleomorphic adenoma]. PMID- 28072984 TI - [Mediation of high-mobility group box-1 protein to vascular endothelial barrier dysfunction and adjustment role of leukocyte-endothelial adhesion]. PMID- 28072985 TI - [Recent advance of IgG4 related thyroid disease]. PMID- 28072986 TI - [Stride forward to continue publishing magnificent achievements]. PMID- 28072987 TI - [A pilot clinical study of immediate provisionalization with a chairside computer aided design and computer aided manufacture monolithic crown for single tooth immediate implant placement]. AB - Objective: To evaluate the primary clinical outcomes of immediate provisionalization with a monolithic crown utilizing a novel chairside computer aided design and computer aided manufacture (CAD/CAM) workflow for single tooth immediate implant placement. Methods: This pilot study was a prospective within subjects design. Thirteen consecutive patients were included and diagnosed with untreatable single incisor or premolar with fine general and local anatomical conditions. The trial was conducted at Department of Implantology, Peking University School and Hospital of Stomatology, Beijing, between January 2016 and June 2016. The teeth were extracted atraumatically and implants were immediately placed in the fresh sockets. Two screw-retained interim crowns were fabricated for the same site utilizing different workflows, a monolithic lithium disilicate (LS2) crown produced by CEREC (Sirona, Germany) chairside CAD/CAM system (CER group) and a manually fabricated resin crown utilizing conventional workflow (CONV group) respectively. The patients were blinded to the group allocation of the two interim crowns. After the clinical try-in for both crowns in a randomized sequence, the patients' level of satisfaction was assessed with a virtual analogue scale (VAS) questionnaire. The restorations chosen by patients themselves were seated in the implants by one experienced prosthodontist. The accuracy, aesthetic effect and clinical time consumption of both groups were compared. Statistical analyses were performed with the Wilcoxon signed rank test. Results: All patients were treated with atraumatic tooth extraction, immediate implant placement using flapless surgery and immediate provisionalization in a single visit. The interim crowns of both groups could be fitted with or without slight adjustments. For each patient, the interim crown of CER group was chosen to be seated with a relatively higher VAS result. The white esthetic score (WES) results demonstrated no statistically significant difference between CER group (7.5+/-1.1) and CONV group (7.9+/-0.9) (P>0.05). The mean total work time was significantly different resulting in (131.9+/-5.0) min for CER group and (205.2+/ 6.3) min(P<0.05). The major difference lied in the laboratory work time, resulting in (113.5+/-6.3) min for CER group which was significantly shorter than (185.6+/-6.6) min for CONV group. As for impression taking time, the CER group (7.5+/-0.8) min was significantly shorter than CONV group (11.7+/- 1.1) min (P<0.05). However, analysis for clinical adjustment time showed a significantly longer time for CER group [(11.0+/-2.1) min vs (8.0+/-2.8) min, P<0.05]. After 3 6 months of observation, the overall survival rate was 100%. Screw loosening occurred in 4 patients and was tightened again. No other major complication soccurred. Conclusions: The full digital workflow utilizing CEREC chairside CAD/CAM system to fabricate interim crowns after immediate implant placement in one single visit was feasible. It was more time-efficient and could effectively shorten the laboratory work time compared to the conventional workflow. Patients demonstrated high satisfaction and there was no statistical difference in WES results compared to the conventional workflow. Favorable clinical outcomes were gained in this short-term follow-up study. PMID- 28072988 TI - [Retrospective analysis of pulp revascularization in immature permanent teeth with diffuse pulpitis]. AB - Objective: To evaluate the treatment effectiveness of revascularization in immature permanent teeth with diffuse pulpitis and to provide an alternative approach for the treatment of these teeth. Methods: Clinical and radiographic data were collected from 17 immature permanent teeth which were diagnosed as diffuse pulpitis and with their pulp extirpated at Emergency Department of Peking University School and Hospital of Stomatology. All these teeth were treated using pulp revascularization at Department of Pediatric Dentistry. Clinical success rate was then evaluated based on the clinical and radiographic findings. The increase of root length and dentin wall thickness of the revascularized teeth and the contralateral control teeth were measured and compared according to the preoperative and recall periapical radiographs. Results: The average follow uptime is (25.8+/-9.9) months (12-46 months). Totally 13 out of the 17 teeth showed normal clinical and radiographic manifestation and achieved the increasein root length and dentin wall thickness. They met criteria for success treatment. The rest 4 out of the 17 teeth also showed root length and dentin wall thickness increaseand apical foramen closure. However, periapical inflammations were observed during 12 to 36 monthfollow-ups. These cases were recognized as failed. In all the17 teeth, the increase of root length and dentin wall thickness was not significantly different between the revascularized teeth and the contralateral control teeth (P>0.05). Conclusions: Pulp revascularization in young permanent teeth with diffuse pulpitis resulted in similar clinical outcomes in root development and root canal wall formation compared with the contralateral control teeth. However, reinfection might occur during long-term follow-up. PMID- 28072989 TI - [Clinical effectiveness of salvianolic acid B and triamcinolone acetonide in treatment of oral submucous fibrosis]. AB - Objective: To evaluate the clinical effectiveness of salvianolic acid B (SA-B) and triamcinolone acetonide (TA) by means of combined intralesional injection in the treatment of oral submucous fibrosis (OSF). Methods: According to clinical findings and symptoms, TA combined with SA-B were consecutively applied intralesionally 1 time weekly for 30 times. Mouth opening degree, color change of the buccal mucosae and numeral increase of the capillary vessels were determined by degree I-IV visual analog scale were evaluated at 12, 24, and 36 months, respectively. Results: One hundred and fourteen subjects fulfilled the study without obvious adverse reactions. After treatment for 1 year, the net gain in mouth opening of the early stage group was (5.5 +/- 1.5) mm at 12 months, (8.8 +/ 1.6) mm at 24 months and (12.0+/-1.2) mm at 36 months. The net gain in mouth opening of the middle stage group were (5.3+/-1.7) mm at 12 months, (10.5+/-1.5) mm at 24 months and (14.5+/-2.4) mm at 36 months. The net gain in mouth opening of the advanced stage group were (5.7+/-1.3) mm at 12 months, (13.7+/-1.3) mm at 24 months and (15.5+/-1.5) mm at 36 months. The effective rates of color change of the buccal mucosae and numeral increase of the capillary vessels after treatment for 36 months were 100% in early stage group, 93% (51/55) in middle stage group and 90% (36/40) in advanced stage group. Conclusions: TA and SA-B combined intralesional injection in the treatment of oral submucous fibrosis is effective. PMID- 28072990 TI - [The images of osteoarthrosis associated with anterior disc displacement without reduction detected by cone-beam CT]. AB - Objective: To analyze the radiological characteristics of the condylar bone in patients with anterior disc displacement without reduction of temporomandibular joint using cone-beam CT (CBCT), and to further investigate the clinical factors possibly associated with the early-stage osteoarthritic changes. Methods: Two hundred and four individuals (<=30 years old) diagnosed as unilateral anterior disc displacement without reduction (disease duration<=1 year) were recruited. CBCT images of bilateral condyles were independently evaluated by two assessors and documented. Correlation between the early-stage osteoarthritic (OA) changes and gender, age, disease duration and mouth opening were analyzed using SPSS 21.0 software. Results: About sixty percent were presented with OA changes in the symptomatic joints, and most of them (47.1%) (96/204) were early-stage OA changes characterized by loss of continuity of articular cortex (I) and/or surface erosion (II). Logistics regression analyses indicated that disease duration (P =0.000) and mouth opening (P =0.002) were correlated significantly with early stage OA changes. Conclusions: Disc displacement without reduction was closely related to OA occurrence. OA changes occurred in more than half of the patients after one month of the joint locked and more possibly in patients with increased mouth opening. PMID- 28072991 TI - [Expression of Oct4 and Sox2 and their clinical significance in tongue squamous cell carcinoma]. AB - Objective: To investigate Oct4 and Sox2 protein expression in tongue squamous cell carcinoma (TSCC) and the relationships between the expressions of Oct4 and Sox2 and clinical pathological characteristics and survival of patients. Methods: The paraffin imbedded tissue specimens of 51 patients with histologically confirmed TSCC were included. Immunohistochemistry was employed to detect the protein expression of Oct4 and Sox2 in 51 TSCC tissue samples. The protein expression levels of Oct4 and Sox2 and their relationships with both clinicopathological features and survival of patients with TSCC were evaluated. Results: In 51 TSCC cases,positive expressions of Oct4 and Sox2 were mainly located in the nucleus of tumor cells. The expression of Oct4 was strongly positive in 27 cases (53%), weakly positive in 16 (31%) and negative in 8 (16%), whereas that of Sox2 was strongly positive in 25 cases (49%), weakly positive in 22 (43%) and negative in 4 (8%). Oct4 and Sox2 expression levels were significantly correlated with the histological grade of TSCC (P=0.004, P=0.006, respectively), not correlated with age, gender, T stage, tobacco smoking and alcohol consumption status (P>0.05), but Oct4 expression level was significantly associated with lymph node metastasis (P=0.001). Sox2 expression level was not associated with lymph node metastasis (P>0.05). The expression of Sox2 was significantly correlated with Oct4 (P<0.001). Oct4 and Sox2 expression was associated with poor overall survival of patients with TSCC (P=0.001, P=0.002, respectively), cases with higher Oct4 and Sox2 expression had the poorest overall survival (P<0.001). Sox2 expression and lymph node metastasis were independent prognostic factors of overall survival in patients with TSCC (P=0.02, P=0.001, respectively). Conclusions: Sox2 had independent prognostic effects on overall survival, suggesting that Sox2 expression may be an usefull indicator for predicting the prognosis of patients with TSCC. PMID- 28072992 TI - [Comparison of free anterolateral thigh perforator flaps versus free forearm flap for reconstruction in elderly patients undergoing glossectomy]. AB - Objective: To evaluate the quality of life (QOL) in elderly patients with tongue cancer who underwent immediate free flap reconstruction surgery. In addition, the efficacy of the anterolateral thigh perforator free flap (ALTFF) and the radial free forearm flap (RFFF) for reconstruction was compared in patients with glossectomy. Methods: Ninty-eight patients undergoing complete or partial glossectomy and reconstruction with free flaps were grouped according to flap type. Oral functions were assessed using The University of Washington Quality of Life (UW-QOL), and the 14-item Oral Health Impact Profile questionnaires (OHIP 14) at 6 and 12 months after reconstructive surgery. Results: Eighty-six of 98 questionnaires (88%) were returned. There was significant difference between the 2 groups in the style of resection (P<0.05). For all oral function domains, the score improved progressively after the operation (6 and 12 months after the procedure). The UW-QOL questionnaire showed a significant difference between the 6 months postoperatively (ALTFF: 290.0 +/- 7.8, RFFF: 236.6 +/- 24.2) and 12 months postoperatively (ALTFF: 302.0+/-21.1, RFFF: 331.1+/-20.4) (P<0.05). The OHIP-14 questionnaire showed a total score of ALTFF (422.0+/- 15.2) which was significantly less than RFFF (434.0+/-38.7) at 6 months postoperatively (P<0.05). There were no meaningful differences between the 2 flap types for all oral function domains at 12 months. Conclusions: Using the RFFF or ALTFF for reconstruction of tongue defects after cancer resection influences oral function. There was no significant difference in quality of life between the two flaps at 12 months postoperatively. PMID- 28072993 TI - [Effect of inserted angle on the stability of loaded microscrews]. AB - Objective: To evaluate the effect of different insertion angles on the osseointegration of loaded microscrews in beagle jaws. Methods: Forty-eight microscrews were inserted at four different angles (30 degrees , 50 degrees , 70 degrees and 90 degrees ) into the interradicular zones between the mandibular first molar and third premolar in twelve beagles and the microscrews had been loaded with a force of 2 N immediately for 8 weeks. After microscrew-bone specimens fixed, the maximum output value (Fmax) of pull-out test was recorded and the histomorphological changes of hard tissue were observed. The bone-implant contact (BIC%) was quantitatively analyzed and the osseointegration of microscrew bone interface was comprehensively evaluated. Results: Both Fmax and BIC% values of microscrews were influenced by the insertion angles. The maximum value of Fmax was (385+/-23) N in the group with 50 degrees angle, and the minimum value was (198+/-16) N in the group with 30 degrees angle(P <0.05). The maximum value of BIC% was (59.1+/-6.0)% in the group with 70 degrees angle, and the minimum value was (30.2+/-3.2)% in the group with 30 degrees angle (P <0.05). Histomorphology observation revealed that in peri-screws region, the various degree of bone remodeling was found in different angle samples. Conclusions: The insertion angles (50 degrees and 70 degrees ) were favorable to the stability of the microscrew. PMID- 28072994 TI - [Effect of triptolide on human oral cancer cell proliferation and PTEN gene mRNA expression in oral cancer]. AB - Objective: To investigate the effect of triptolide on human oral cancer cell (HB) proliferation and phosphates and tensin homologue deleted on chromosome ten gene (PTEN) mRNA expression in oral cancer. Methods: The cancer cells were cultured in the medium containing triptolide of different concentrations for 24, 48 and 72 h. Methyl thiazolyl tetrazolium (MTT) method was used to test the rate of growth inhibition of cancer cells, flow cytometer to detect the change of cell cycle and reveres transcription-PCR (RT-PCR) to examine the expression of PTEN mRNA. The expression of PTEN protein was examined by Western blotting. Results: The rate of growth inhibition was (26.92 +/- 0.14)%, (38.67 +/- 0.11)%, (72.62 +/- 0.89)% and (90.42 +/- 0.28)%, respectively. The corresponding expression of PTEN mRNA was (3.59+/-0.21)%, (5.27+/-0.40)%, (7.18+/-0.44)% and (9.16+/-0.50)%, respectively and the corresponding A value of PTEN protein was 0.135+/-0.007, 0.410+/-0.020, 0.447+/-0.017 and 0.884+/-0.066, respectively. The proportion of G1 phase cells increased from (58.78+/-0.98)% to (84.13+/-0.47)%, but the proportion of S phase cells decreased from (25.40+/-0.43)% to (9.41+/-0.73)%. Conclusions: The triptolide not only had inhibitory effect on the HB proliferation, but also affected the cell cycle. PMID- 28072995 TI - [The effects of platelet-rich fibrin extract on MC3T3-E1 cells cultured on the titanium discs]. AB - Objective: To evaluate the effect of platelet-rich fibrin extract (PRFe) on the adhesion, proliferation and differentiation of MC3T3-E1 cells cultured on the titanium discs. Methods: Samples were divided into experimental group (P) and control group (D). Group P used the alpha-minimal essential medium (alpha-MEM) containing PRFe (0.5%), while group D used only the alpha-MEM. Cell adhesion and cytoskeleton were observed using scanning electron microscopy (SEM) and laser scanning confocal microscopy (LSCM). Methyl thiazolyl tetrazolium (MTT) assay to detect the number of the osteoblasts at 1, 3, 5, 7 d; the activity of alkaline phosphatase (ALP) to detect the differentiation of osteoblast at 1, 3, 5, 7 d; the level of osteogenetic biomarkers core-binding factoralpha1 (cbfalpha1) and osteocalcin (OCN) were quantified by quantitative real-time PCR (qRT-PCR) at 3 and 7 d. Results: SEM and LSCM showed that the adhesion and filaments of group P were higher than those of group D at each time point. MTT assay showed that the absorbance were significantly increased in group P (1 d: 0.299+/-0.002, 3 d: 0.517+/-0.004, 5 d: 0.810+/-0.002, 7 d: 1.203+/-0.011) compared with group D (1 d: 0.198+/-0.003, 3 d: 0.399+/-0.002, 5 d: 0.588+/-0.002, 7 d: 0.897+/-0.005) at each time points (P<0.05). Furthermore, the ALP activity of group P (1 d: 0.162+/ 0.004, 3 d: 0.289+/-0.001, 5 d: 0.491+/-0.006, 7 d: 0.647+/-0.005) was significantly higher than that of group D (1 d: 0.121+/-0.003, 3 d: 0.191+/- 0.006, 5 d: 0.252+/-0.004, 7 d: 0.365+/-0.012), (P<0.05). Moreover, the qRT-PCR showed that the Cbfalpha1 and OCN gene expression in group P (Cfbalpha1, 3 d: 1.50+/-0.04, 7 d: 1.94+/-0.06; OCN, 3 d: 3.37+/-0.17, 7 d: 3.92+/- 0.04) were significantly higher than that in group D(Cfbalpha1, 3 d: 1, 7 d: 1.18+/-0.13; OCN, 3 d: 1, 7 d: 2.34+/- 0.09) (P<0.05). Conclusions: PRFe promoted the adhension, proliferation and differentiation of MC3T3-E1 cells on the titanium discs. PMID- 28072996 TI - [Meeting Minutes of 2016 International Congress of Oral Implantology: Pujiang Forum]. PMID- 28072997 TI - [Summary of The 2016 Symposium on Oral and Maxillofacial Surgery at Peking University]. PMID- 28072998 TI - [Immediate restoration of dental implant using computer-assisted navigation in the esthetic zone: a case report]. PMID- 28072999 TI - [Features and advances of Morse taper connection in oral implant]. AB - Dental implants have been widely accepted as a predictable and reliable tool for dental reconstruction with the development of the economy. The design of implant abutment connections has influence on mechanical properties and biological characteristics of implants. There are two types of implant-abutment connections, the external and the internal connections. Morse taper connection is one of the internal connections and its conical shape creates significant friction via the high propensity of parallelism between the two structures within the joint space. Several studies showed that Morse taper connection performed well in terms of survival rate, stability, bacterial seal and marginal bone loss. Recently, clinical studies indicate implants combining Morse taper connection with platform switching are helpful in reducing marginal bone absorption. This review aims at analyzing the features and advantages of Morse taper connection. PMID- 28073000 TI - Settling a Nervous Stomach: The Neural Regulation of Enteric Cancer. AB - The nervous system is emerging as a regulator of malignancy. In this issue of Cancer Cell, Hayakawa et al. demonstrate a feedforward signaling loop in which tumor-derived nerve growth factor promotes enteric tumor innervation, and recruited nerves drive cancer growth through acetylcholine-regulated Wnt signaling and stimulation of further NGF release. PMID- 28073001 TI - Normalization of Tumor Vessels by Tie2 Activation and Ang2 Inhibition Enhances Drug Delivery and Produces a Favorable Tumor Microenvironment. PMID- 28073002 TI - Cancer and Apoptosis: Who Is Built to Last? AB - Effective cancer therapy requires that a cancer be more susceptible to a treatment than are the essential tissues in the body. A paper by Sarosiek et al. in this issue now shows that, unlike those of cancer cells, mitochondria in many tissues in adults are in an apoptosis-resistant state. PMID- 28073003 TI - Employing Metabolism to Improve the Diagnosis and Treatment of Pancreatic Cancer. AB - Pancreatic ductal adenocarcinoma is on pace to become the second leading cause of cancer-related death. The high mortality rate results from a lack of methods for early detection and the inability to successfully treat patients once diagnosed. Pancreatic cancer cells have extensively reprogrammed metabolism, which is driven by oncogene-mediated cell-autonomous pathways, the unique physiology of the tumor microenvironment, and interactions with non-cancer cells. In this review, we discuss how recent efforts delineating rewired metabolic networks in pancreatic cancer have revealed new in-roads to develop detection and treatment strategies for this dreadful disease. PMID- 28073004 TI - Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma. AB - Given the paucity of druggable mutations in high-risk neuroblastoma (NB), we undertook chromatin-focused small interfering RNA and chemical screens to uncover epigenetic regulators critical for the differentiation block in high-risk NB. High-content Opera imaging identified 53 genes whose loss of expression led to a decrease in NB cell proliferation and 16 also induced differentiation. From these, the secondary chemical screen identified SETD8, the H4K20me1 methyltransferase, as a druggable NB target. Functional studies revealed that SETD8 ablation rescued the pro-apoptotic and cell-cycle arrest functions of p53 by decreasing p53K382me1, leading to activation of the p53 canonical pathway. In pre-clinical xenograft NB models, genetic or pharmacological (UNC0379) SETD8 inhibition conferred a significant survival advantage, providing evidence for SETD8 as a therapeutic target in NB. PMID- 28073005 TI - Simultaneous Inhibition of PI3Kdelta and PI3Kalpha Induces ABC-DLBCL Regression by Blocking BCR-Dependent and -Independent Activation of NF-kappaB and AKT. AB - Compared with follicular lymphoma, high PI3Kalpha expression was more prevalent in diffuse large B cell lymphoma (DLBCL), although both tumor types expressed substantial PI3Kdelta. Simultaneous inhibition of PI3Kalpha and PI3Kdelta dramatically enhanced the anti-tumor profile in ABC-DLBCL models compared with selective inhibition of PI3Kdelta, PI3Kalpha, or BTK. The anti-tumor activity was associated with suppression of p-AKT and a mechanism of blocking nuclear factor kappaB activation driven by CD79mut, CARD11mut, TNFAIP3mut, or MYD88mut. Inhibition of PI3Kalpha/delta resulted in tumor regression in an ibrutinib resistant CD79BWT/MYD88mut patient-derived ABC-DLBCL model. Furthermore, rebound activation of BTK and AKT was identified as a mechanism limiting CD79Bmut-ABC DLBCL to show a robust response to PI3K and BTK inhibitor monotherapies. A combination of ibrutinib with the PI3Kalpha/delta inhibitor copanlisib produced a sustained complete response in vivo in CD79Bmut/MYD88mut ABC-DLBCL models. PMID- 28073007 TI - Mesenchymal MicroRNA Function Branches Out. AB - Significant amounts of microRNAs (miRs) are detected in exosomes, but their function during fetal development is poorly understood. In this issue of Developmental Cell, Hayashi et al. (2017) show that exosomal miRs secreted by mesenchymal cells can regulate epithelial KIT+ progenitor cell expansion during murine salivary gland organogenesis. PMID- 28073006 TI - BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer. AB - Chromosomal instability (CIN) contributes to cancer evolution, intratumor heterogeneity, and drug resistance. CIN is driven by chromosome segregation errors and a tolerance phenotype that permits the propagation of aneuploid genomes. Through genomic analysis of colorectal cancers and cell lines, we find frequent loss of heterozygosity and mutations in BCL9L in aneuploid tumors. BCL9L deficiency promoted tolerance of chromosome missegregation events, propagation of aneuploidy, and genetic heterogeneity in xenograft models likely through modulation of Wnt signaling. We find that BCL9L dysfunction contributes to aneuploidy tolerance in both TP53-WT and mutant cells by reducing basal caspase-2 levels and preventing cleavage of MDM2 and BID. Efforts to exploit aneuploidy tolerance mechanisms and the BCL9L/caspase-2/BID axis may limit cancer diversity and evolution. PMID- 28073008 TI - CENP-A Modifications on Ser68 and Lys124 Are Dispensable for Establishment, Maintenance, and Long-Term Function of Human Centromeres. AB - CENP-A is a histone H3 variant key to epigenetic specification of mammalian centromeres. Using transient overexpression of CENP-A mutants, two recent reports in Developmental Cell proposed essential centromere functions for post translational modifications of human CENP-A. Phosphorylation at Ser68 was proposed to have an essential role in CENP-A deposition at centromeres. Blockage of ubiquitination at Lys124 was proposed to abrogate localization of CENP-A to the centromere. Following gene inactivation and replacement in human cells, we demonstrate that CENP-A mutants that cannot be phosphorylated at Ser68 or ubiquitinated at Lys124 assemble efficiently at centromeres during G1, mediate early events in centromere establishment at an ectopic chromosomal locus, and maintain centromere function indefinitely. Thus, neither Ser68 nor Lys124 post translational modification is essential for long-term centromere identity, propagation, cell-cycle-dependent deposition, maintenance, function, or mediation of early steps in centromere establishment. PMID- 28073009 TI - How Meiosis Creates the Single-Copy Genome. AB - Genome haploidization involves two meiotic divisions following a single round of DNA replication. In this issue of Developmental Cell, Arguello-Miranda et al. (2017) show that production and packaging of the single-copy genome into gametes during the second meiotic division is coordinated by a conserved casein kinase 1. PMID- 28073010 TI - Ser68 Phosphorylation Ensures Accurate Cell-Cycle-Dependent CENP-A Deposition at Centromeres. PMID- 28073011 TI - CENP-A Ubiquitylation Is Required for CENP-A Deposition at the Centromere. PMID- 28073012 TI - Can biological invasions save Caribbean coral reefs? AB - It is widely accepted that coral reefs are in decline globally, due to climate change as well as more direct human impacts such as poor water quality and overharvesting [1-3]. Biological invasions are also seen as a major threat [4-6]; however, they may not all be negative. An invasion of Red Sea rabbitfishes is disrupting Mediterranean ecosystems by removing macro-algae - meanwhile, in contrast, the Caribbean is suffering from excess macro-algal growth. We suggest that an invasion of the Caribbean by rabbitfishes may prove beneficial, and that the future of Caribbean coral reefs may depend upon a rabbitfish invasion. PMID- 28073013 TI - Newly discovered deep-branching marine plastid lineages are numerically rare but globally distributed. AB - Ocean surface warming is resulting in an expansion of stratified, low-nutrient environments, a process referred to as ocean desertification [1]. A challenge for assessing the impact of these changes is the lack of robust baseline information on the biological communities that carry out marine photosynthesis. Phytoplankton perform half of global biological CO2 uptake, fuel marine food chains, and include diverse eukaryotic algae that have photosynthetic organelles (plastids) acquired through multiple evolutionary events [1-3]. While amassing data from ocean ecosystems for the Baselines Initiative (6,177 near full-length 16S rRNA gene sequences and 9.4 million high-quality 16S V1-V2 amplicons) we identified two deep-branching plastid lineages based on 16S rRNA gene data. The two lineages have global distributions, but do not correspond to known phytoplankton. How the newly discovered phytoplankton lineages contribute to food chains and vertical carbon export to the deep sea remains unknown, but their prevalence in expanding, low nutrient surface waters suggests they will have a role in future oceans. PMID- 28073015 TI - Plant Development: Differential Growth Rates in Distinct Zones Shape an Ancient Plant Form. AB - A long-standing question in biology is how a group of primordial cells can give rise to complex organs. A new study finds that, in an ancient land plant, growth rate variation patterned by meristematic cells primarily determines shape. PMID- 28073014 TI - Evolution of condensin and cohesin complexes driven by replacement of Kite by Hawk proteins. AB - Mitotic chromosome condensation, sister chromatid cohesion, and higher order folding of interphase chromatin are mediated by condensin and cohesin, eukaryotic members of the SMC (structural maintenance of chromosomes)-kleisin protein family. Other members facilitate chromosome segregation in bacteria [1]. A hallmark of these complexes is the binding of the two ends of a kleisin subunit to the apices of V-shaped Smc dimers, creating a tripartite ring capable of entrapping DNA (Figure 1A). In addition to creating rings, kleisins recruit regulatory subunits. One family of regulators, namely Kite dimers (Kleisin interacting winged-helix tandem elements), interact with Smc-kleisin rings from bacteria, archaea and the eukaryotic Smc5-6 complex, but not with either condensin or cohesin [2]. These instead possess proteins containing HEAT (Huntingtin/EF3/PP2A/Tor1) repeat domains whose origin and distribution have not yet been characterized. Using a combination of profile Hidden Markov Model (HMM) based homology searches, network analysis and structural alignments, we identify a common origin for these regulators, for which we propose the name Hawks, i.e. HEAT proteins associated with kleisins. PMID- 28073016 TI - Larval Evolution: I'll Tail You Later.... AB - Larval stages can be astonishingly different from their adult forms. A new study in acorn worms shows that the whole larval body is patterned only with a subset of anterior genes, revealing the intricate developmental bases that underlie the evolution of larval forms. PMID- 28073017 TI - Cell Migration: Making the Waves. AB - Coordinated changes of cell shape are often the result of the excitable, wave like dynamics of the actin cytoskeleton. New work shows that, in migrating cells, protrusion waves arise from mechanochemical crosstalk between adhesion sites, membrane tension and the actin protrusive machinery. PMID- 28073018 TI - Meiotic Recombination: Taking the Path Less Traveled. AB - The proper distribution of crossovers during meiosis I ensures accurate chromosome segregation at the first meiotic division. A new study reveals both the consequences of improper crossover patterning in Drosophila and the role of Blm helicase in controlling this patterning. PMID- 28073019 TI - Plant Physiology: Out in the Midday Sun, Plants Keep Their Cool. AB - Plants use context-dependent information to calibrate growth responses to temperature signals. A new study shows that plants modulate their sensitivity to temperature depending on whether or not they are in direct sunlight. This enables them to make adaptive decisions in a complex natural environment. PMID- 28073020 TI - Regeneration: Recorded Live! AB - Salamanders and fish can regenerate amputated limbs/fins. Which cells drive this intriguing process? Two recent papers have used live imaging of labelled clones of cells to reveal the contribution of connective tissue. PMID- 28073021 TI - DNA Replication Checkpoint: New ATR Activator Identified. AB - The ATR kinase is a master regulator of replication stress responses. Four new studies show that the protein ETAA1 is an important activator of ATR in human cells, providing insights into how the ATR pathway reacts to replication stress. PMID- 28073022 TI - Ocean Depths: The Mesopelagic and Implications for Global Warming. AB - The mesopelagic or 'twilight zone' of the oceans occurs too deep for photosynthesis, but is a major part of the world's carbon cycle. Depth boundaries for the mesopelagic have now been shown on a global scale using the distribution of pelagic animals detected by compiling echo-soundings from ships around the world, and been used to predict the effect of global warming on regional fish production. PMID- 28073023 TI - Functional Connectomics: How Maggots Make Up Their Minds. AB - How Drosophila larvae select one behavior or a sequence of behaviors, and then persist in the final one, has been addressed by a powerful combination of electron-microscopy reconstruction of neuronal connections, genetic manipulations, electrophysiology, and neuronal modeling. Surprisingly, reciprocal inhibitory synaptic connections are major players in choosing, sequencing and maintaining behaviors. PMID- 28073024 TI - Anemonefishes. AB - Feeney and Brooker introduce sea-anemone associated fish. PMID- 28073025 TI - Tropomyosins. AB - The actin cytoskeleton provides not only the underpinning for cell architecture but also mechanical force and the ability to drive movement of cells and their organelles. It is tempting to think of it simply as a set of stable structural elements, but nothing could be further from the truth. The cells of our bodies are continually remodelling their architecture by responding to a range of imposed biomechanical forces and intracellular functional demands. Studies of the dynamic and functional properties of the actin cytoskeleton have been dominated by a focus on actin and the view that actin filaments are essentially 'generic'. However, the 'other' component of most actin filaments in animals - tropomyosin - is coming into prominence. With this discovery is the realisation that far from being generic, actin filaments have their own functional individuality provided to them by their associated tropomyosin. This is changing the way we understand and study the actin cytoskeleton and has delivered a new therapeutic opportunity in what had come to be considered a 'no-go zone'. PMID- 28073026 TI - The role of Visfatin in atherosclerotic peripheral arterial obstructive disease. AB - Visfatin is an adipokine molecule acting as an essential coenzyme in multiple cellular redox reactions. The increased serum levels of Visfatin have been correlated with metabolic syndrome and endothelial homeostasis. In this study we investigate the possible relationship of Visfatin serum levels with the severity and location of atherosclerotic peripheral arterial occlusive disease (PAOD). Study protocol included 45 consecutive PAOD and 20 Control patients with age >55years old. Definition of PAOD was based in Rutherord's classification (RC). End-stage PAOD patients (RC-V & -VI) were excluded from study. Data were collected prospectively and included age, gender, atherosclerotic risk factors and the body mass index (BMI). In PAOD patients recorded the PAOD's clinical stage and the presence of carotid stenosis >50%. PAOD patients divided in two subgroups, those with mild (RC-I & -II) and moderate disease (RC-III & -IV). In all serum samples Visfatin was measured, blindly, twice by anosoenzymatic technique. Statistical analysis was performed by non-parametric Mann-Whitney U test, Pearson's chi-square, One Way Anova and Kruskall-Wallis tests, as appropriate. The mean Visfatin value in PAOD and Control groups were 38.5+/-16.0 and 13.9+/-3.8ng/ml respectively (p<0.0005). In-PAOD subgroup of patients the visfatin values were not affected by demographics, BMI and atherosclerotic risk factors (p>0.05). Univariate analysis showed that severity of PAOD (mild vs severe), presence of carotid stenosis >50% and multilevel disease significantly affected outcomes (p=0.018, p=0.010 and p=0.006 respectively). In multivariate regression analysis severity of PAOD was the solely factor with strong correlation with high visfatin values (p=0.001). High Visfatin levels seem to be strongly correlated with the presence and severity of PAOD. Further and in depth investigation is needed to define the possible role of Visfatin in atherosclerosis and it's value as a potential prognostic biomarker of PAOD. PMID- 28073027 TI - Epileptic features and survival in glioblastomas presenting with seizures. AB - INTRODUCTION: The prognostic value of seizures in patients with glioblastoma is currently under discussion. The objective of this research was to study the risk factors associated with seizures occurring at the diagnosis of glioblastoma and the role of seizures as a predictive factor for survival. MATERIAL AND METHODS: We prospectively analyzed the clinical data over the course of the disease, baseline MR imaging, and histological characteristics (p53 overexpression, the Ki67 proliferation index, and presence of the IDH1 R132H mutation), in glioblastomas treated in a single hospital from November 2012 to July 2014. The study follow-up cutoff point was October 2015. RESULTS: In total, 56 patients were recruited (57% men, mean age 57 years). Median baseline score on the Karnofsky performance scale was 80. Complete tumor debulking followed by radiochemotherapy was achieved in 58.9%. Mean survival was 13.6 months. Epileptic seizures were the presenting symptom in 26.6% of patients, and 44.6% experienced seizures at some point during the course of the disease. On multivariate analysis, the single factor predicting shorter survival was age older than 60 years (hazard ratio 3.565 (95%CI, 1.491-8.522), p=0.004). Seizures were associated with longer survival only in patients younger than 60 years (p=0.035). Younger age, the IDH1 R132H mutation, and p53 overexpression (>40%) were related to seizures at presentation. Baseline MRI findings, including tumor size, and the Ki67 proliferation index were not associated with the risk of epileptic seizures or with survival. Prophylactic antiepileptic drugs did not increase survival time. CONCLUSIONS: Seizures as the presenting symptom of glioblastoma predicted longer survival in adults younger than 60 years. The IDH1 R132H mutation and p53 overexpression (>40%) were associated with seizures at presentation. Seizures showed no relationship with the tumor size or proliferation parameters. PMID- 28073028 TI - Multiplexed detection of lung cancer biomarkers in patients serum with CMOS compatible silicon nanowire arrays. AB - In this work, a real-time assay for highly sensitive, label-free, multiplexed electrical detection of lung cancer biomarkers was developed by using silicon nanowire field-effect (SiNW-FET) devices. Highly responsive SiNW arrays were fabricated using a CMOS-compatible anisotropic self-stop etching technique with mass reproducibility and low cost character. The SiNW nanosensor was integrated with PDMS microfluidic device, which allows rapid analyte delivery, makes the analysis to be conducted using exceedingly small samples and enables potential multiplexed detection. The nanowire arrays allowed highly selective and sensitive multiplexed detection of microRNA (miRNA)-126 and CEA. Due to high surface-to volume ratio that the nanowire dimensions confer, the detection floor of single molecule was achieved. The potential utility in identifying clinical samples for early diagnosis of cancer was demonstrated by analyzing biomarkers in clinical related samples. The developed nanosensor with capability for multiplexed real time monitoring of biomarkers with high sensitivity and selectivity in clinically relevant samples is highly attractive for diagnosis and treatment of cancer and other diseases. PMID- 28073029 TI - Multiplexed efficient on-chip sample preparation and sensitive amplification-free detection of Ebola virus. AB - An automated microfluidic sample preparation multiplexer (SPM) has been developed and evaluated for Ebola virus detection. Metered air bubbles controlled by microvalves are used to improve bead-solution mixing thereby enhancing the hybridization of the target Ebola virus RNA with capture probes bound to the beads. The method uses thermally stable 4-formyl benzamide functionalized (4FB) magnetic beads rather than streptavidin coated beads with a high density of capture probes to improve the target capture efficiency. Exploiting an on-chip concentration protocol in the SPM and the single molecule detection capability of the antiresonant reflecting optical waveguide (ARROW) biosensor chip, a detection limit of 0.021pfu/mL for clinical samples is achieved without target amplification. This RNA target capture efficiency is two orders of magnitude higher than previous results using streptavidin beads and the limit of detection (LOD) improves 10*. The wide dynamic range of this technique covers the whole clinically applicable concentration range. In addition, the current sample preparation time is ~1h which is eight times faster than previous work. This multiplexed, miniaturized sample preparation microdevice establishes a key technology that intended to develop next generation point-of-care (POC) detection system. PMID- 28073030 TI - To screen or not to screen for chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is the most severe long term complication of acute pulmonary embolism (PE). Untreated, CTEPH is associated with a very poor prognosis and high risk of mortality, although curation can be achieved by surgical removal of the obstructive endothelialised thromboemboli from the pulmonary arteries. Early CTEPH diagnosis may improve surgical possibilities and patients outcome. Currently, early diagnosis of CTEPH is a major challenge as demonstrated by an unacceptable median diagnostic delay of over a year and as a result, surgery is impossible in 40% of patients. Most important reasons for this delay are the non-specific clinical presentation of CTEPH and lack of guideline recommendations with regard to the optimal follow-up of patients with acute PE. Despite compelling reasons to diagnose CTEPH earlier, acute PE is not classified among the conditions that warrant screening for pulmonary hypertension. Meaningful screening programs improve the patients' prognosis, and screening tools should be simple, widely available, non-invasive and acceptable to patients. In this review, we discuss current knowledge of available screening instruments for CTEPH, provide recommendations for clinical practice and expand on future developments of this particular subject. PMID- 28073031 TI - Plasma concentrations of free amyloid beta cannot predict the development of Alzheimer's disease. AB - INTRODUCTION: Biomarkers that identify individuals at risk of Alzheimer's disease (AD) development would be highly valuable. Plasma concentration of amyloid beta (Abeta)-central in the pathogenesis of AD-is a logical candidate, but studies to date have produced conflicting results on its utility. METHODS: Plasma samples from 339 preclinical AD cases (76.4% women, mean age 61.3 years) and 339 age- and sex-matched dementia-free controls, taken an average of 9.4 years before AD diagnosis, were analyzed using Luminex xMAP technology and INNO-BIA plasma Abeta form assays to determine concentrations of free plasma Abeta40 and Abeta42. RESULTS: Plasma concentrations of free Abeta40 and Abeta42 did not differ between preclinical AD cases and dementia-free controls, in the full sample or in subgroups defined according to sex and age group (<60 and >= 60 years). The interval between sampling and AD diagnosis did not affect the results. Abeta concentrations did not change in the years preceding AD diagnosis among individuals for whom longitudinal samples were available. DISCUSSION: Plasma concentrations of free Abeta could not predict the development of clinical AD, and Abeta concentrations did not change in the years preceding AD diagnosis in this sample. These results indicate that free plasma Abeta is not a useful biomarker for the identification of individuals at risk of developing clinical AD. PMID- 28073032 TI - Diabetes mellitus and first episode mania associated with cardiovascular diseases in patients with older-age bipolar disorder. AB - Patients with bipolar disorder (BD) are at high risk for developing cardiovascular diseases (CVDs) during aging process. However, investigations are lacking regarding the risk factors for CVDs specific to BD patients. The aim of this study was to examine the relationship between CVDs and traditional risk factors in association with the characteristics of BD in older age. Totally, we recruited 124 patients with BD-I (DSM-IV) who had at least one psychiatric admission and cardiologist-confirmed CVD diagnosis (ICD-9 code 401-414) at mean age of 61.7+4.9 years. Each case subject was matched with one BD-I patient without CVDs based on age, sex, and date of the most recent psychiatric admission (+2 years). Clinical data were obtained by retrospectively reviewing the medical record. A multiple logistic regression model showed that not only traditional risk factor (e.g., diabetes mellitus) but also non-traditional one associated with BD (e.g., first episode mania) significantly increased the risk of CVDs. Given the limitation of this cross-sectional study, longitudinal investigations are needed to elucidate the contributions of both traditional risk factors and the BD characteristics for CVD risk in patients with BD. PMID- 28073033 TI - Situating violent ideations within the landscape of mental health: Associations between violent ideations and dimensions of mental health. AB - Violent ideations occur more frequently in individuals with mental health problems. They may be of interest in clinical contexts as possible indicators of dangerousness, as corollaries of mental health problems, as candidate treatment targets and as potentially playing a role in perpetuation or onset of symptoms. In spite of their relevance to mental health, some fundamental questions about their place within the broader landscape of mental health problems remain unanswered. To provide a basic characterisation of the relations between violent ideations and dimensions of mental health and provide a foundation for future research in this area we factor analysed a measure of violent ideations and an omnibus measure of mental health dimensions in a normative sample of 1306 youth (at age 17). Results supported a separate dimension of violent ideations with a small to moderate correlation with five other dimensions of mental health: internalising, prosociality, ADHD, indirect/proactive aggression, and physical/reactive aggression. Controlling for comorbidity among mental health dimensions, all but ADHD had unique relations with violent ideations. This suggests that violent ideations are potentially of broad relevance to mental health and related behaviours and there should be a greater research effort aimed at understanding their possible role in mental health. PMID- 28073034 TI - Unraveling the different toxic effect of flufenoxuron on the thyroid endocrine system of the Mongolia racerunner (Eremias Argus) at different stages. AB - Flufenoxuron is a widely used pesticide to inhibit the synthesis of chitin during insect development and its effect on the growth of lizards has been little addressed. The hypothalamus-pituitary-thyroid (HPT) axis plays an important role on the development of lizards. In this study, the lizards at different development stages (proliferation and resting stages) were exposed to flufenoxuron for 21 days. The plasma thyroid hormone levels, thyroid gland histopathology and expression profiles of thyroid hormone receptors (tralpha, trbeta), deiodinases (dio1, dio2), and transthyretin (ttr) genes were measured to evaluated the toxic effect of flufenoxuron on the HPT axis at different stages. The flufenoxuron exposure showed more seriously effect on the triiodothyronine (T3) level at resting phase than that at proliferation stage. The follicle epithelium cell height in the thyroid was only significantly increased when the exposed male lizards were at proliferation stage. The alteration of HPT axis related genes expression was gender and tissue dependent after flufenoxuron treatment. The lizards exposed to flufenoxuron showed that the tralpha, trbeta, dio1, dio2, and ttr genes in the female liver were more sensitive at the proliferation stage than that at the resting stage. In the male brain, the expressions of tralpha, trbeta, dio1, and dio2 gene were significant decreased at proliferation stage while significant increased at resting stage after flufenoxuron exposure. Therefore, the thyroid endocrine system of lizards could be affected by the flufenoxuron exposure and the different development stage should also be considered when study the toxic effect of contaminants on the lizards. PMID- 28073036 TI - Does preoperative oral carbohydrate treatment reduce the postoperative surgical stress response in lumbar disc surgery? AB - OBJECTIVES: Surgical trauma produces metabolic and hormonal responses, which are characterized by insulin resistance. Due to extension of the preoperative fasting period, which increases the magnitude of postoperative insulin resistance, preoperative oral carbohydrates (POC) have been developed. PATIENTS AND METHODS: This prospective, randomized, controlled study was performed on 43 ASA I-II patients undergoing elective microsurgical lumbar discectomy. The intervention group received oral carbohydrate solution 800mL the night before and 400mL 2h prior to operation. The other group fasted for 8h prior to operation. Blood samples were obtained the day before the operation, before induction of anesthesia, after skin incision, 1h, 2h, 6h and 24h following skin incision. Blood glucose, plasma insulin, cortisol and interleukin-6 (IL-6) levels were determined. The primary endpoint was to assess the effect of POC treatment on insulin resistance and surgical stress response following lumbar disc surgery. The secondary endpoint was to assess POC's effects on postoperative nausea and vomiting. RESULTS: The serum insulin levels were higher before induction of anesthesia in the study group and returned to fasted group levels by 2h after skin incision. The plasma IL-6 levels were higher in the intervention group at 6h after the skin incision. There were no differences between the two groups with respect to blood glucose, plasma cortisol levels and the incidence of nausea and vomiting. CONCLUSION: This study suggests that use of POC treatment does not attenuate development of insulin resistance in patients undergoing lumbar disc surgery. PMID- 28073035 TI - Criterion validity of measures of perceived relative harm of e-cigarettes and smokeless tobacco compared to cigarettes. AB - Beliefs about the relative harmfulness of one product compared to another (perceived relative harm) are central to research and regulation concerning tobacco and nicotine-containing products, but techniques for measuring such beliefs vary widely. We compared the validity of direct and indirect measures of perceived harm of e-cigarettes and smokeless tobacco (SLT) compared to cigarettes. On direct measures, participants explicitly compare the harmfulness of each product. On indirect measures, participants rate the harmfulness of each product separately, and ratings are compared. The U.S. Health Information National Trends Survey (HINTS-FDA-2015; N=3738) included direct measures of perceived harm of e-cigarettes and SLT compared to cigarettes. Indirect measures were created by comparing ratings of harm from e-cigarettes, SLT, and cigarettes on 3-point scales. Logistic regressions tested validity by assessing whether direct and indirect measures were associated with criterion variables including: ever-trying e-cigarettes, ever-trying snus, and SLT use status. Compared to the indirect measures, the direct measures of harm were more consistently associated with criterion variables. On direct measures, 26% of adults rated e-cigarettes as less harmful than cigarettes, and 11% rated SLT as less harmful than cigarettes. Direct measures appear to provide valid information about individuals' harm beliefs, which may be used to inform research and tobacco control policy. Further validation research is encouraged. PMID- 28073037 TI - Amino acid chelated iron versus an iron salt in the treatment of iron deficiency anemia with pregnancy: A randomized controlled study. AB - OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of iron amino acid chelate (IAAC) and ferrous fumarate (FF) in treatment of iron deficiency anemia (IDA) with pregnancy. STUDY DESIGN: A total of 150 pregnant women having iron deficiency anemia (IDA) were randomized to receive either IAAC or FF for 12 weeks. Hemoglobin, red cell indices, serum iron, and serum ferritin were measured at baseline and then 4, 8, and 12 weeks after treatment. Adverse effects were questioned in both groups. RESULTS: The mean values of hemoglobin, red cell indices, serum iron, and serum ferritin were not significantly different between both groups after 12 weeks of treatment. However, the rise in hemoglobin level after 4, 8, and 12 weeks of treatment was significantly faster in the IAAC group (p=<0.001). Constipation and abdominal colicky pain were significantly more common in the FF group (p=0.022 and 0.031 respectively). CONCLUSION: IAAC and FF are comparable in curing IDA with pregnancy; however, IAAC has the advantage of providing a faster rate of improvement of hemoglobin level and is better tolerated by the patients. PMID- 28073038 TI - Persistence in the treatment of overactive bladder syndrome (OAB) with mirabegron in a multicenter clinical study. AB - OBJECTIVE: The objective of this project was to evaluate treatment persistence in patients being treated for overactive bladder syndrome (OAB) with mirabegron, employing clinical follow-up in a prospective, multicenter study. STUDY DESIGN: This is an analysis of patients who started treatment with mirabegron between May and September 2014 and were evaluated 1year after treatment commenced. During this evaluation we determined how many patients stopped treatment and established their reasons for discontinuation. RESULTS: 206 patients being treated for OAB with mirabegron were evaluated a year after starting treatment. It emerged that 60 patients (29.1%) had discontinued the treatment, citing the following reasons: 24/60 insufficient treatment efficacy, 26/60 other reasons, while 10 members of the group discontinued treatment because of side effects. 75 out of 206 patients were <=60 years old and 28% terminated the study prematurely: 131 out of 206 were >60years old and 29.2% terminated the study prematurely. In the group of patients without previous OAB treatment 35.7% discontinued treatment with mirabegron, while 28.1% of patients with previous anticholinergic treatment discontinued treatment. CONCLUSION: In our clinical prospective multicenter study, persistence in treatment with mirabegron reached a figure of 71%. PMID- 28073039 TI - Effect of sleep problems on depressive disorders 1 year after developing acute coronary syndrome: The K-DEPACS study. AB - INTRODUCTION: This study investigated the effects of sleep disturbance evaluated within 2 weeks after patients developed acute coronary syndrome (ACS) on depressive disorders at the 1-year follow-up. METHODS: A total of 1152 patients were recruited consecutively within 2 weeks after a confirmed ACS episode, and 828 were followed 1 year later. Sleep disturbances were evaluated at baseline using the Leeds Sleep Evaluation Questionnaire (LSEQ), which subjectively assesses four sleep factors. At both examinations, depressive disorders were diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Baseline covariates included sociodemographic data, characteristics of depression, cardiovascular risk factors, and current cardiac status. RESULTS: Almost all aspects of the sleep disturbance and the increase in their worst state evaluated by the LSEQ within 2 weeks of ACS predicted both incident and persistent depressive disorders at the 1-year follow-up independent of covariates related to sleep problems. LIMITATION: Data on sleep disturbance were obtained only by subjective reports. CONCLUSIONS: A simple evaluation of sleep disturbance in patients who recently developed ACS in a hospital setting could help predict depression at the chronic phase. PMID- 28073040 TI - The application of the interpersonal-psychological theory of suicide to a sample of Swiss patients attending a psychiatric emergency department for a non-lethal suicidal event. AB - BACKGROUND: Visits to emergency departments (EDs) for suicidal ideation or a suicide attempt have increased in the past decades. Yet comprehensive models of suicide are scarce, potentially enhancing misunderstandings from health professionals. This study aimed to investigate the applicability of the interpersonal-psychological theory of suicide (IPTS) in a population visiting EDs for suicide-related issues. METHODS: Three major hypotheses formulated by the IPTS were tested in a sample of 167 individuals visiting EDs for suicidal ideation or a suicide attempt. RESULTS: As predicted by the IPTS, greater levels of perceived burdensomeness (PB) were associated with presence of current suicidal ideation. However, contrary to the theory assumptions, thwarted belongingness (TB) was not predictive of current suicidal ideation (Hypothesis 1). Similarly, the interaction between PB, TB and hopelessness did not account for the transition from passive to active suicidal ideation (Hypothesis 2). The interaction between active suicidal ideation and fearlessness of death did not either predict the transition from active suicidal ideation to suicidal intent (Hypothesis 3). LIMITATIONS: The cross-sectional design limited the interpretation of causal hypotheses. Patients visiting EDs during nights and weekends were underrepresented. A general measure of hopelessness was considered, not a measure of hopelessness specifically related to PB and TB. CONCLUSIONS: Although the three hypotheses were only partially verified, health professionals might consider the IPTS as useful for the management of patient with suicide related issues. Clinical intervention based on perceived burdensomeness could notably be proposed shortly after ED admission. PMID- 28073041 TI - Major depressive disorder with subthreshold hypomanic (mixed) features: A real world assessment of treatment patterns and economic burden. AB - BACKGROUND: To compare outcomes for individuals with major depressive disorder (MDD) with or without subthreshold hypomania (mixed features) in naturalistic settings. METHODS: Using the Optum Research Database (1/1/2009?10/31/2014), a retrospective analysis of individuals newly diagnosed with MDD was conducted. Continuous enrollment for 12-months before and after the initial MDD diagnosis was required. MDD with subthreshold hypomania (mixed features) (MDD-MF) was defined based on >=1 hypomania diagnosis within 30 days after an MDD diagnosis during the one-year follow-up period, in the absence of bipolar I diagnoses. Psychiatric medication use, healthcare utilization, and costs during the one-year follow-up period were compared using multivariate logistic and gamma regressions, controlling for baseline differences. RESULTS: Of 130,626 MDD individuals, 652 (0.5%) met the operational definition of MDD-MF. Compared to the MDD-only group, the MDD-MF group had more suicidality (2.0% vs. 0.5%), anxiety disorders (46.8% vs. 34.0%), and substance use disorders (15.5% vs. 6.1%, all P<0.001). More individuals with MDD-MF were treated with antidepressants (83.6% vs. 71.6%), mood stabilizers (50.5% vs. 2.7%), atypical antipsychotics (39.0% vs. 5.5%), and polypharmacy with multiple drug classes (72.1% vs. 22.7%, all P<0.001). Individuals with MDD-MF had higher hospitalizations rates (24.2% vs. 10.5%) and total healthcare costs (mean: $15,660 vs. $10,744, all P<0.001). LIMITATIONS: The commercial claims data used were not collected for research purposes and may over or under-represent certain populations. No specific claims-based diagnostic code for MDD with mixed features exists. CONCLUSIONS: Greater use of mood stabilizers, atypical antipsychotics, polypharmacy, and healthcare resources provides evidence of the complexity and severity of MDD-MF. Identifying optimal treatment regimens for this population represents a major unmet medical need. PMID- 28073042 TI - Rapid infusions of human normal immunoglobulin 50g/l are safe and well tolerated in immunodeficiencies and immune thrombocytopenia. AB - Intravenous immunoglobulin (IVIg) is accepted as an effective and well-tolerated treatment for primary and secondary immunodeficiencies (ID) and immune thrombocytopenia (ITP). Adverse reactions of IVIg are usually mild, comprising transient flu-like symptoms, change in blood pressure and tachycardia. However IVIg therapy can be burdensome for both patients and healthcare facilities, since the infusion may take up to 4h to administer. The objective of our multicentre, prospective, open-label phase III trial was to evaluate the tolerability and safety of human normal immunoglobulin 50g/l (Ig VENA) at high intravenous infusion rates in adult patients with ID and ITP who had previously tolerated IVIg treatment, by progressively increasing infusion rate up to 8ml/kg/hr. 39 ID patients received three infusions, 5 ITP patients received up to a maximum of 5 infusions for a maximum of 5days. Overall 55 adverse events were reported in 18 patients, and all were mild and self-limiting. Two serious adverse events occurred in ID patients and 1 in an ITP patient; none was fatal or treatment related. No clinically significant changes or abnormalities were observed in vital signs, laboratory results and HRQoL. In summary, in this study, more rapid IVIg infusions were well tolerated by ID and ITP patients, while maintaining their quality of life, helping to minimise the time spent in outpatient hospital visiting to potentially optimise adherence to treatment. PMID- 28073043 TI - Periplocoside A ameliorated type II collagen-induced arthritis in mice via regulation of the balance of Th17/Treg cells. AB - Periplocoside A (PSA) has been extracted from the Chinese herbal medicine Periploca sepium Bge to treat rheumatoid arthritis (RA) via immune regulation. We previously found that PSA exhibits immunosuppressive activity both in vitro and in vivo. Balanced regulation of helper T 17 (Th17)/regulatory T (Treg) cells is the current therapeutic direction for the treatment of RA. The present study investigated the mechanism of PSA in treating collagen-induced arthritis (CIA). The therapeutic effects and potential pharmacological mechanisms of PSA were specifically clarified by examining its effects on CIA in DBA/1 mice. PSA administration significantly relieved the severity of the arthritis, and preventive administration of PSA reduced the incidence of arthritis in the mice with CIA and relieved joint damage in terms of morphology. PSA was also able to reduce the levels of anti-collagen II (CII) antibodies and pro-inflammatory cytokines in the serum. As a result, the proportion of Th17 cells decreased, and the proportion of Treg cells increased. A follow-up study of the ex vivo immunological reactions induced by a specific antigen found that PSA suppressed lymphocyte proliferation, inhibited the differentiation and reactivity of Th17 cells, and promoted the proportion of Treg cells among helper T cells. PSA also exhibited pharmacological effect in regulating the balance between Th17 and Treg cells in CIA through relevant signalling pathways. Thus, PSA played a specific role in CIA treatment. In particular, our results suggest that the therapeutic effects of PSA on RA are partially realized via the regulation of the balance of Th17/Treg cells. PMID- 28073044 TI - Influence of the body schema on mirror-touch synesthesia. AB - Individuals with mirror-touch synesthesia (MTS) report feeling touch on their own body when seeing someone else being touched. We examined how the body schema - an on-line representation of body position in space - is involved in mapping touch from a viewed body to one's own body. We showed 45 mirror-touch synesthetes videos of a hand being touched, varying the location of the viewed touch by hand (left, right), skin surface (palmar, dorsal) and finger (index, ring). Participant hand posture was either congruent or incongruent with the posture of the viewed hand. After seeing the video, participants were asked to report whether they felt touch on their own body and, if so, the intensity and location of their percepts. We found that participants reported more frequent and more veridical (i.e., felt at the same somatotopic location as the viewed touch) mirror-touch percepts on posturally congruent versus posturally incongruent trials. Furthermore, participant response patterns varied as a function of postural congruence. Some participants consistently felt sensations on the hand surface that was stimulated in the video - even if their hands were in the opposite posture. Other participants' responses were modulated based on their own hand position, such that percepts were more likely to be felt on the upright, plausible hand surface in the posturally incongruent condition. These results provide evidence that mapping viewed touch to one's own body involves an on-line representation of body position in space. PMID- 28073045 TI - Adhesive barnacle peptides exhibit a steric-driven design rule to enhance adhesion between asymmetric surfaces. AB - Barnacles exhibit superior underwater adhesion simply through sequencing of the 21 proteinogenic amino acids, without post processing or using special amino acids. Here, we measure and discuss the molecular interaction of two distinct and recurring short peptide sequences (Bp1 and Bp2) inspired from the surface binding 19kDa protein from the barnacle attachment interface. Using self-assembled monolayer (SAMs) of known physical and chemical properties on molecularly smooth gold substrates in 5mM NaCl at pH 7.3, (1) the adsorption mechanisms of the barnacle inspired peptides are explored using quartz crystal microbalance, and (2) adhesion mediating properties are measured using the surface force apparatus. The hydrophobic Bp1 peptide with a cysteine residue adsorbs irreversibly onto Au surfaces due to thiol bond formation, while on hydrophobic CH3 SAM surface, the interactions are hydrophobic in nature. Interestingly, Bp2 that contains both hydrophobic and protonated amine units exhibits asymmetric bridging with an exceptionally high adhesion energy up to 100mJ/m2 between mica and both gold and CH3 SAM. Surprisingly on hydrophilic surfaces such as COOH- or OH-SAMs both peptides fail to show any interactions, implying the necessity of surface charge to promote bridging. Our results provide insights into the molecular aspects of manipulating and utilizing barnacle-mediated peptides to promote or inhibit underwater adhesion. PMID- 28073046 TI - Olanzapine and aripiprazole differentially affect glucose uptake and energy metabolism in human mononuclear blood cells. AB - The use of antipsychotics carries the risk of metabolic side effects, such as weight gain and new onset type-2 diabetes mellitus. The mechanisms of the observed metabolic alterations are not fully understood. We compared the effects of two atypical antipsychotics, one known to favor weight gain (olanzapine), the other not (aripiprazole), on glucose metabolism. Primary human peripheral blood mononuclear cells (PBMC) were isolated and stimulated with olanzapine or aripiprazole for 72 h. Cellular glucose uptake was analyzed in vitro by 18F-FDG uptake. Further measurements comprised mRNA expression of glucose transporter (GLUT) 1 and 3, GLUT1 protein expression, DNA methylation of GLUT1 promoter region, and proteins involved in downstream glucometabolic processes. We observed a 2-fold increase in glucose uptake after stimulation with aripiprazole. In contrast, olanzapine stimulation decreased glucose uptake by 40%, accompanied by downregulation of the cellular energy sensor AMP activated protein kinase (AMPK). GLUT1 protein expression increased, GLUT1 mRNA expression decreased, and GLUT1 promoter was hypermethylated with both antipsychotics. Pyruvat-dehydrogenase (PDH) complex activity decreased with olanzapine only. Our findings suggest that the atypical antipsychotics olanzapine and aripiprazole differentially affect energy metabolism in PBMC. The observed decrease in glucose uptake in olanzapine stimulated PBMC, accompanied by decreased PDH point to a worsening in cellular energy metabolism not compensated by AMKP upregulation. In contrast, aripiprazole stimulation lead to increased glucose uptake, while not affecting PDH complex expression. The observed differences may be involved in the different metabolic profiles observed in aripiprazole and olanzapine treated patients. PMID- 28073048 TI - Perfluoroalkyl substances and fish consumption. AB - BACKGROUND: Perfluoroalkyl substances (PFAS) are an emerging class of contaminants. Certain PFAS are regulated or voluntarily limited due to concern about environmental persistence and adverse health effects, including thyroid disease and dyslipidemia. The major source of PFAS exposure in the general population is thought to be consumption of seafood. OBJECTIVES: In this analysis we examine PFAS levels and their determinants, as well as associations between PFAS levels and self-reported fish and shellfish consumption, using a representative sample of the U.S. POPULATION: METHODS: Data on PFAS levels and self-reported fish consumption over the past 30 days were collected from the 2007 2008, 2009-2010, 2011-2012, and 2013-2014 cycles of the National Health and Nutrition Examination Survey. Twelve different PFAS were measured in serum samples from participants. Ordinary least squares regression models were used to identify factors (demographic characteristics and fish consumption habits) associated with serum PFAS concentrations. Additional models were further adjusted for other potential exposures including military service and consumption of ready-to-eat and fast foods. RESULTS: Seven PFAS were detected in at least 30% of participants and were examined in subsequent analyses (PFDA, PFOA, PFOS, PFHxS, MPAH, PFNA, PFUA). The PFAS with the highest concentrations were PFOS, followed by PFOA, PFHxS and PFNA (medians of 8.3, 2.7, 1.5 and 1.0ng/mL). Fish consumption was generally low, with a median of 1.2 fish meals and 0.14 shellfish meals, reported over the past 30 days. After adjusting for demographic characteristics, total fish consumption was associated with reduced MPAH, and with elevated PFDE, PFNA and PFuDA. Shellfish consumption was associated with elevations of all PFAS examined except MPAH. Certain specific fish and shellfish types were also associated with specific PFAS. Adjustment for additional exposure variables resulted in little to no change in effect estimates for seafood variables. CONCLUSIONS: PFAS are emerging contaminants with widespread exposure, persistence, and potential for adverse health effects. In the general population, fish and shellfish consumption are associated with PFAS levels, which may indicate an avenue for education and outreach. PMID- 28073047 TI - Examining Cognitive Processes and Drinking Urge in PTSD. AB - Despite their centrality to learning theories, strikingly little attention has been paid to the role of cognitions in efforts to understand associations between posttraumatic stress disorder (PTSD) and alcohol drinking. In the present study, we sought to examine information processing pathways for trauma and alcohol information, and the effects of posttraumatic stress and trauma cue exposure on these pathways. Participants were college students (N = 232; 49% female; Mage = 19.56,SD = 1.44) categorized into three diagnostic groups based on current PTSD status determined by structured clinical interview. These students then were exposed to a personalized trauma or neutral cue script, followed by a Stroop task modified to include trauma, alcohol, and contrast words. Indices of mood and urge to drink alcohol were administered throughout the task. Findings revealed that those with PTSD who were exposed to the personalized trauma cue showed a general response slowing across all stimuli types on the Stroop task. Intriguingly, this slowing effect was significantly associated with urge to drink alcohol for only those PTSD participants who were exposed to the trauma cues. In contrast, we did not find support for the hypothesis that trauma cues would lead to attention bias to trauma and alcohol specific Stroop stimuli among participants with PTSD, nor did slower RT for specific word types predict unique variance in urge to drink alcohol. Findings suggest that individual (PTSD) and environmental (cue) circumstances may work conjointly to precipitate changes in cognitive processing changes that may have implications for drinking motivation. Given the importance of cognition in the etiology of both PTSD and drinking, this is a mechanism that warrants further investigation. PMID- 28073049 TI - Iodine nutritional status and thyroid effects of exposure to ethylenebisdithiocarbamates. AB - INTRODUCTION: Italy is still characterized by a mild iodine deficiency and is among the most intensive users of chemical products for agriculture in Europe. The aim of this study was i) to evaluate thyroid effects of exposure to mancozeb, a fungicide widely used in agriculture, in a sample of Italian grapevine workers, and ii) to verify whether the iodine intake may modulate the risk of thyroid disruption due to the mancozeb metabolite ethylenthiourea (ETU). METHODS: One hundred seventy-seven occupationally exposed male workers (29 from Chianti, a mild iodine deficient area, and 148 from Bolzano an iodine sufficient province) and 74 non-occupationally exposed male controls (34 from Chianti and 40 from Bolzano) were enrolled in the study. Serum biomarkers of thyroid function, as well as urinary iodine and ETU concentrations were assessed. Moreover all the recruited subjects underwent clinical examination and thyroid ultrasound. RESULTS: Multivariate comparisons showed lower mean serum levels of FT4 in Chianti-workers as compared to Bolzano-workers. Moreover, an increased urinary iodine excretion (>250ug/L) was more frequently found among more exposed workers (ETU>20ug/L) than among less exposed ones and this effect was more pronounced in Chianti- than in Bolzano-workers. Chianti-workers also showed a significantly higher frequency of very low thyroid volume (<=6.0ml) as compared to controls. CONCLUSIONS: These findings showed a mild thyroid disrupting effect due to occupational exposure to mancozeb, more pronounced in workers residing in an area characterized by a mild to moderate iodine deficiency as compared to workers residing in an area covered by a long-lasting iodine prophylaxis program. PMID- 28073050 TI - Genome-wide identification of ATP-binding cassette (ABC) transporters and their roles in response to polycyclic aromatic hydrocarbons (PAHs) in the copepod Paracyclopina nana. AB - The ATP-binding cassette (ABC) protein superfamily is one of the largest gene families and is highly conserved in all domains. The ABC proteins play roles in several biological processes, including multi-xenobiotic resistance (MXR), by functioning as transporters in the cellular membrane. They also mediate the cellular efflux of a wide range of substrates against concentration gradients. In this study, 37 ABC genes belonging to eight distinct subfamilies were identified in the marine copepod Paracyclopina nana and annotated based on a phylogenetic analysis. Also, the functions of P-glycoproteins (P-gp) and multidrug resistance associated proteins (MRPs), conferring MXR, were verified using fluorescent substrates and specific inhibitors. The activities of MXR-mediated ABC proteins and their transcriptional level were examined in response to polyaromatic hydrocarbons (PAHs), main components of the water-accommodated fraction. This study increases the understanding of the protective role of MXR in response to PAHs over the comparative evolution of ABC gene families. PMID- 28073051 TI - Older peoples' strategies for coping with chronic non-malignant pain: A qualitative meta-synthesis. AB - BACKGROUND: There is evidence that chronic pain is not recognised or managed effectively in older people. It is important to examine how older people cope with this because of the impact it can have on their quality of life and mortality. It will also enable nurses to work with older people to support effective coping skills and provide information on other useful coping strategies. OBJECTIVES: To examine how older people cope with non-malignant chronic pain. DESIGN: This is a qualitative meta-synthesis using Confidence in the Evidence from Reviews of Qualitative Research developed by Grading of Recommendations Assessment Development and Evaluation working group to evaluate the strength of the evidence. DATA SOURCES: PubMed and Ovid Medline from 1995 to 2015. REVIEW METHODS: Following a systematic search strategy all papers were assessed in relation to inclusion criteria and quality. Only qualitative studies were included. Themes were extracted from each study and a meta-synthesis conducted before completing an evaluation of confidence in the findings. RESULTS: Seventeen primary studies were included in the meta-synthesis. Three meta-themes were identified: 'adjusting to the inevitable', 'doing it my way without medication' and 'the importance of support in managing the struggle'. There was high confidence in the evidence for 'doing it my way without medication' and moderate confidence in the evidence for the other two meta-themes. CONCLUSION: Given that the participants in the primary studies were generally wary of health professionals and stoic in their response to pain, it is important for nurses to communicate in ways that engage older people and ensure their independence and sense of control remains intact. Identification of current coping strategies will enable the nurse and the older person to work together to assess their effectiveness and to adapt these if more effective coping is required. PMID- 28073052 TI - Deciduous neonatal line: Width is associated with duration of delivery. AB - The delivery-related neonatal line (NNL) appears into the enamel of primary teeth and first permanent molars at birth and is a marker of live birth process. It varies in width and its location, is different in each deciduous tooth type, and is indicative of gestation time. It is unclear which triggers determine NNL at birth. Our objective was to investigate the effect of the duration and mode of delivery on NNL width. NNL of 129 teeth, a collection derived from a long-term, prospectively followed population cohort, was measured under light microscope. Altogether, 54 sections with most optimal plane of sectioning were analysed for the duration and mode of delivery. NNL was detected in 98% of the deciduous teeth with the median width of 9.63MUm (min 3.16MUm, max 27.58MUm). A prolonged duration of vaginal delivery was highly significantly associated with a narrower NNL (r=-0.41, p=0.0097). No significant association was found between the width of NNL and mode of delivery (p=0.36). NNL is demonstrable in virtually all deciduous teeth. The width seems to be inversely proportional to the duration of delivery. Causes of the inverse proportion are speculated to result from altered amelogenesis induced by prolonged and intensified delivery-associated stress. Further research is needed to clarify the underlying mechanisms. PMID- 28073053 TI - Applying 3D measurements and computer matching algorithms to two firearm examination proficiency tests. AB - In order for a crime laboratory to assess a firearms examiner's training, skills, experience, and aptitude, it is necessary for the examiner to participate in proficiency testing. As computer algorithms for comparisons of pattern evidence become more prevalent, it is of interest to test algorithm performance as well, using these same proficiency examinations. This article demonstrates the use of the Congruent Matching Cell (CMC) algorithm to compare 3D topography measurements of breech face impressions and firing pin impressions from a previously distributed firearms proficiency test. In addition, the algorithm is used to analyze the distribution of many comparisons from a collection of cartridge cases used to construct another recent set of proficiency tests. These results are provided along with visualizations that help to relate the features used in optical comparisons by examiners to the features used by computer comparison algorithms. PMID- 28073054 TI - Adrenal failure due to bilateral adrenal metastasis of rectal cancer: A case report. AB - INTRODUCTION: It is rare for a patient to present with adrenal insufficiency secondary to bilateral adrenal metastases from a malignant colorectal tumor. CASE PRESENTATION: An 82-year-old Japanese man presented to our hospital with high fever and malaise. He was receiving oral chemotherapy for the treatment of rectal cancer with multiple metastases. Computed tomography showed new bilateral adrenal gland metastases. A rapid adrenocorticotropic hormone (ACTH) test showed adrenal insufficiency. Treatment with hydrocortisone provided immediate symptom improvement. DISCUSSION: Adrenal insufficiency secondary to bilateral adrenal metastases from rectal cancer is rare. A rapid ACTH test is useful to diagnose adrenal insufficiency. CONCLUSION: The incidence of adrenal insufficiency may be underestimated in patients with multiple metastasis. Appropriate therapy with adrenal corticosteroid hormone supplementation may lead to a significant improvement in the patient's symptoms and quality of life. PMID- 28073055 TI - CO2 emissions from German drinking water reservoirs. AB - Globally, reservoirs are a significant source of atmospheric CO2. However, precise quantification of greenhouse gas emissions from drinking water reservoirs on the regional or national scale is still challenging. We calculated CO2 fluxes for 39 German drinking water reservoirs during a period of 22years (1991-2013) using routine monitoring data in order to quantify total emission of CO2 from drinking water reservoirs in Germany and to identify major drivers. All reservoirs were a net CO2 source with a median flux of 167gCm-2y-1, which makes gaseous emissions a relevant process for the carbon budget of each reservoir. Fluxes varied seasonally with median fluxes of 13, 48, and 201gCm-2y-1 in spring, summer, and autumn respectively. Differences between reservoirs appeared to be primarily caused by the concentration of CO2 in the surface water rather than by the physical gas transfer coefficient. Consideration of short term fluctuations of the gas transfer coefficient due to varying wind speed had only a minor effect on the annual budgets. High CO2 emissions only occurred in reservoirs with pH<7 and total alkalinity <0.2mEql-1. Annual CO2 emissions correlated exponentially with pH but not with dissolved organic carbon (DOC). There was significant correlation between land use in the catchment and CO2 emissions. In total, German drinking water reservoirs emit 44000t of CO2 annually, which makes them a negligible CO2 source (<0.005% of national CO2 emissions) in Germany. PMID- 28073056 TI - Effects of meteorological factors on incidence of scarlet fever during different periods in different districts of China. AB - OBJECTIVE: To reveal the difference of meteorological effect on scarlet fever in Beijing and Hong Kong, China, during different periods among 2004-2014. METHODS: The data of monthly incidence of scarlet fever and meteorological variables from 2004 to 2014 in Beijing and Hong Kong were collected from Chinese science data center of public health, meteorological data website and Hong Kong observatory website. The whole study period was separated into two periods by the outbreak year 2011 (Jan 2004-Dec 2010 and Jan 2011-Dec 2014). A generalized additive Poisson model was conducted to estimate the effect of meteorological variables on monthly incidence of scarlet fever during two periods in Beijing and Hong Kong, China. RESULTS: Incidence of scarlet fever in two districts were compared and found the average incidence during period of 2004-2010 were significantly different (Z=203.973, P<0.001) while average incidence became generally equal during 2011-2014 (Z=2.125, P>0.05). There was also significant difference in meteorological variables between Beijing and Hong Kong during whole study period, except air pressure (Z=0.165, P=0.869). After fitting GAM model, it could be found monthly mean temperature showed a negative effect (RR=0.962, 95%CI: 0.933, 0.992) on scarlet fever in Hong Kong during the period of 2004-2010. By comparison, for data in Beijing during the period of 2011-2014, the RRs of monthly mean temperature range growing 1 degrees C and monthly sunshine duration growing 1h was equal to 1.196(1.022, 1.399) and 1.006(1.001, 1.012), respectively. The changes of meteorological effect on scarlet fever over time were not significant both in Beijing and Hong Kong. CONCLUSION: This study suggests that meteorological variables were important factors for incidence of scarlet fever during different period in Beijing and Hong Kong. It also support that some meteorological effects were opposite in different period although these differences might not completely statistically significant. PMID- 28073057 TI - Neonicotinoids transference from the field to the hive by honey bees: Towards a pesticide residues biomonitor. AB - The beehive as a quantitative monitor of pesticide residues applied over a soybean crop was studied through a semi field experiment of controlled exposure of honey bees to pesticides in macro tunnels. The distribution within exposed beehives of pesticides commonly used in soybean plantation, was assessed. Residue levels of insecticides in soybean leaves, honey bees, wax, honey and pollen were analyzed. The transference from pesticides present in the environment into the beehive was evidenced. The obtained results allow relating pesticide concentrations present in the environment with traces found in foraging bees. Therefore, pesticide transference ratios could be calculated for each detected compound (acetamiprid, imidacloprid and thiamethoxam) which showed a linear inverse trend with their 1-octanol/water partition coefficient (Kow). The least transferred pesticide to the hive (acetamiprid) has the highest vapor pressure (Vp). This study gives new insights on the usefulness of monitoring the environment through beehives aiming to evaluate if agroecosystems remain sustainable. It also contributes to generate valuable information for model building aiming to predict environmental quality through beehive's analysis. PMID- 28073058 TI - Surface Engineering of PAMAM-SDB Chelating Resin with Diglycolamic Acid (DGA) Functional Group for Efficient Sorption of U(VI) and Th(IV) from Aqueous Medium. AB - A novel chelating resin obtained via growth of PAMAM dendron on surface of styrene divinyl benzene resin beads, followed by diglycolamic acid functionalization of the dendrimer terminal. Batch experiments were conducted to study the effects of pH, nitric acid concentration, amount of adsorbent, shaking time, initial metal ion concentration and temperature on U(VI) and Th(IV) adsorption efficiency. Diglycolamic acid terminated PAMAM dendrimer functionalized styrene divinylbenzene chelating resin (DGA-PAMAM-SDB) is found to be an efficient candidate for the removal of U(VI) and Th(IV) ions from aqueous (pH >4) and nitric acid media (>3M). The sorption equilibrium could be reached within 60min, and the experimental data fits with pseudo-second-order model. Langmuir sorption isotherm model correlates well with sorption equilibrium data. The maximum U(VI) and Th(IV) sorption capacity onto DGA-PAMAMG5-SDB was estimated to be about 682 and 544.2mgg-1 respectively at 25 degrees C. The interaction of actinides and chelating resin is reversible and hence, the resin can be regenerated and reused. DFT calculation on the interaction of U(VI) and Th(IV) ions with chelating resin validates the experimental findings. PMID- 28073059 TI - Role of microgel formation in scavenging of chromophoric dissolved organic matter and heavy metals in a river-sea system. AB - We use riverine and marine dissolved organic carbon (DOC) polymers to examine their aggregation behavior, and to evaluate the roles of microgel formation in scavenging of chromophoric dissolved organic matter (CDOM) and heavy metals in a river-sea system. Our results indicate that riverine and marine microgels did not exhibit very much difference in size and self-assembly curve; however, the assembly effectiveness ([microgel]/DOC) of marine samples was much higher than riverine. Instead of concentration of DOC, other factors such as types and sources of DOC polymers may control the microgel abundance in aquatic environments. After filtering water samples (microgels removed), the CDOM and selected metals (Cu, Ni, Mn) in the filtrate were quantified. CDOM and metals were concurrently removed to an extent via DOC polymer re-aggregation, which also suggested that the microgels had sequestering capability in CDOM and metals. This finding provides an alternative route for CDOM and heavy metals removal from the water column. As such the process of re-aggregation into microgels should then be considered besides traditional phase partitioning in the assessment of the ecological risk and fate of hazardous materials. PMID- 28073060 TI - Acute behavioral effects of co-administration of mephedrone and MDMA in mice. AB - BACKGROUND: Abuse of more than one psychoactive drug is becoming a global problem. Our experiments were designed to examine the effects of a concomitant administration of 3,4-methylenedioxy-methamphetamine (MDMA) and mephedrone on depression- and anxiety-like behaviors and cognitive processes in Swiss mice. METHODS: In order to investigate the drug interactions the forced swimming test (FST) - an animal model of depression, the passive avoidance (PA) test - a memory and learning paradigm, as well as the elevated plus maze (EPM) test - test for anxiety level were used. RESULTS: The results revealed that a concomitant administration of non-effective doses of mephedrone (1mg/kg) and MDMA (1mg/kg) exerted marked antidepressive effects in the FST. Also a co-administration of mephedrone (2.5mg/kg) and MDMA (1mg/kg) displayed a pro-cognitive action in the PA paradigm. Furthermore, even though mephedrone and MDMA can, in general, exert some anxiogenic effects in mice, the concomitant administration of nonactive doses of both drugs (0.05 and 0.1mg/kg, respectively) in the EPM test, did not show any synergistic effect in our study. CONCLUSIONS: The effects of mephedrone and MDMA combination on mammalian organisms were attempted to be evaluated in our study and the results are described in the present report. These results may help explain the reasons for and consequences of a concomitant administration of psychoactive substances with regards to the central nervous system, while being possibly useful in the treatment of polydrug intoxication. PMID- 28073061 TI - The significance of microRNAs in the course of rDD. AB - BACKGROUND: In recent years, special attention in genetic studies dedicated to the development of various diseases, including mental disorders, has been paid to micro ribonucleic acids (miRNA, microRNA). As an object of our analysis we have selected the miRNAs which - due to the profile of their activity - may be significant in the aetiology and course of recurrent depressive disorders, i.e. miRNA-370, miRNA-411, miRNA-433, miRNA-487b and miRNA-539. METHODS: The examined population included 138 patients suffering from depression and 95 individuals from the control group (CG). The subjects suffering from depression were divided into two sub-groups: ED-I group (46 patients), rDD group (92 patients). RESULTS: No significant statistical differences were observed between the ED-I and rDD group for all the variables included in the analysis. No significant interrelation was noticed between the number of depression episodes, the severity of depressive disorders and the expression of miRNA selected. Results of the analysis indicate statistically significant differences between the control subjects and the patients with symptoms of depression in terms of all the variables analysed. CONCLUSIONS: 1. There is no significant difference in miRNAs expression between patients with recurrent depressive disorders and those in the first episode of depression. 2. The differences in terms of expression of the analysed variables between the subjects with symptoms of depression and healthy individuals were confirmed. PMID- 28073062 TI - Effects of payment reform in more versus less competitive markets. AB - Policymakers are increasingly interested in reducing healthcare costs and inefficiencies through innovative payment strategies. These strategies may have heterogeneous impacts across geographic areas, potentially reducing or exacerbating geographic variation in healthcare spending. In this paper, we exploit a major payment reform for home health care to examine whether reductions in reimbursement lead to differential changes in treatment intensity and provider costs depending on the level of competition in a market. Using Medicare claims, we find that while providers in more competitive markets had higher average costs in the pre-reform period, these markets experienced larger proportional reductions in treatment intensity and costs after the reform relative to less competitive markets. This led to a convergence in spending across geographic areas. We find that much of the reduction in provider costs is driven by greater exit of "high-cost" providers in more competitive markets. PMID- 28073063 TI - Self-assembled micelles based on Chondroitin sulfate/poly (d,l-lactideco glycolide) block copolymers for doxorubicin delivery. AB - Doxorubicin (DOX) is one of the most common chemotherapeutic agents for the treatment of various cancers, but its clinical usage is limited by dose-dependent cardiotoxicity. We have recently synthesized a series of Chondroitin sulfate/poly (d,l-lactideco-glycolide) block copolymers (Chs-b-PLGA) with different length of hydrophobic block by an end-to-end coupling strategy. The structure of the amphiphilic block copolymers with low critical micelle concentration (~28mg/L) were confirmed by 1H NMR. The copolymers could self-assemble into stable micelles in aqueous environment with homogeneous size distribution and negative zeta potential. The hemolytic study indicated their excellent blood compatibility and potential application for intravenous administration. DOX can be efficiently encapsulated by the Chs-b-PLGA micelles. The DOX-loaded micelles showed a sustained and pH dependent drug release behavior. The cytotoxicity assay showed no associated toxicity with blank micelles while concentration-related cell inhibition with DOX-loaded micelles. Moreover, fast cellular uptake of DOX-loaded micelles was observed by fluorescent microscope. In vivo pharmacokinetics study showed that the Chs-b-PLGA micelles could significantly prolong the blood circulation time of DOX. The maximum tolerated dose (MTD) of DOX-loaded micelles in Kunming mice was about 2-fold higher of the MTD of free DOX, indicating a high tolerance of the DOX-loaded micelles. In conclusion, the Chs-b-PLGA micelles would be a potentially useful drug delivery system for cancer therapy. PMID- 28073064 TI - A comparative study on electromagnetic interference shielding behaviors of chemically reduced and thermally reduced graphene aerogels. AB - Electromagnetic interference (EMI) shielding performance of chemically and thermally reduced graphene aerogels (GAs) was systematically studied. The EMI shielding mechanisms were extensively analyzed in terms of the distinct surface characteristics resulted from the different reduction methods for the first time. EMI shielding effectiveness (SE) of chemically and thermally reduced GAs reached 27.6 (GAC) and 40.2dB (GAT) at the thickness of 2.5mm, respectively. It was found that the introduction of nitrogen atoms through chemical reduction induced localized charges on the carbon backbone leading to strong polarization effects of GAC. The relatively incomplete reduction caused a large number of side polar groups which prevented the graphene sheets from pi-pi stacking. In contrast, the higher extent of reduction of graphene sheets in GAT left a smaller amount of side polar groups and formed more sp2 graphitic lattice, both factors favored pi pi stacking between the adjacent graphene sheets, resulting in higher electrical conductivity and enhanced EMI SE. The EMI shielding performance of the GAs prepared outperformed the recent reported porous carbon materials with respect to the absolute SE value at the similar thickness and/or density. PMID- 28073065 TI - In silico approach to identify non-synonymous SNPs in human obesity related gene, MC3R (melanocortin-3-receptor). AB - The melanocortin-3-receptor (MC3R) is a novel gene candidate for human obesity, which involved in controlling the energy homeostasis and food intake behavior. The main aim behind this work is to investigate the potentially deleterious non synonymous single nucleotide polymorphisms (nsSNPs) in obesity related gene MC3R by using six computational tools viz., PolyPhen, I-Mutant, PROVEAN, SIFT, PANTHER and PhD-SNP. In our study, we predicted eight nsSNPs i.e., rs74315393 (Ile146Asn), rs368205448 (Asp121Tyr), rs143321797 (Phe45Ser), rs17847261 (Cys274Ser), rs144166442 (Pro257His), rs370533946 (Leu224Pro), rs371354428 (Pro72Leu) and rs373708098 (Gly249Ser) found to be potentially deleterious. The functional impact of three nsSNPs i.e., rs74315393, rs368205448 and rs143321797 have already been validated experimentally in the context of human obesity. Moreover, Homology modeling and structural analysis were carried out for already experimentally validated nsSNPs i.e., rs74315393, rs368205448 and rs143321797 to check the stability of predicted models. The mutant models showed higher energy and RMSD (Root mean square deviation) values. In addition, FTSite server predicted one nsSNP i.e., rs368205448 (Asp121Tyr) out of eight identified nsSNPs found in the MC3R protein binding site. Thus, the present computational study may suggest that predicted nsSNPs possibly be a better drug target and contribute to the treatment and better understanding of human obesity. PMID- 28073066 TI - Unique optical properties of Eu3+ doped l-histidine hydrochloride mono hydrate single crystals from low temperature growth technique. AB - A low-temperature solution method was utilized to grow single crystals of Eu3+doped l-histidine hydrochloride monohydrate. The quality of the crystals was confirmed by high-resolution X-ray diffraction measurements with full width at half maximum (FWHM) of rocking curve at 8arc per sec. The incorporation of Eu3+ ions into the lattice was confirmed by functional group analysis using Fourier Transform Infrared (FTIR) spectroscopy. The amount of Eu3+ ions was found to be 0.08 weight (%) using energy dispersive X-ray analysis. The crystal's thermal and mechanical properties were tested as well. The unique spectral properties such as UV-Vis transmittance, nonlinear optical efficiency (NLO), photoluminescence (PL) and its lifetime were measured. The PL study revealed that the intensity of 5D0 >7F2 emission of Eu3+ is stronger than that of 5D0->7F1 emission and the decay measurement showed a life time of 7.2410MUs. The photoluminescence results prove that l-histidine hydrochloride monohydrate is a new, highly efficient host material for europium ion red emissions. PMID- 28073067 TI - DFT study of the molecular and crystal structure and vibrational analysis of cisplatin. AB - DFT and periodic-DFT (PAW-PBE method, code VASP) calculations have been performed to study the structural and vibrational characteristics of cis diamminedichloroplatinum(II) (cisplatin) at molecular and outside molecular level. To estimate the effect of the intermolecular interactions in crystal on the structural and vibrational properties of cisplatin, three theoretical models are considered in the present study: monomer (isolated molecule), hydrogen bonded dimer and periodic solid state structures. The work focused on the role of the theoretical models for correct modeling and prediction of geometrical and vibrational parameters of cisplatin. It has been found that the elaborate three dimensional intermolecular hydrogen bonding network in the crystalline cisplatin significantly influences the structural and vibrational pattern of cisplatin and therefore the isolated cisplatin molecule is not the correct computational model regardless of the theoretical level used. To account for the whole intermolecular hydrogen bonding network in direction of both a and c axis and for more reliable calculations of structural and vibrational parameters periodic DFT calculations were carried out in the full crystalline periodic environment with the known lattice parameters for each cisplatin polymorph phase. The model calculations performed both at molecular level and for the periodic structures of alpha and beta cisplatin polymorph forms revealed the decisive role of the extended theoretical model for reliable prediction of the structural and vibrational characteristics of cisplatin. The powder diffraction pattern and the calculated IR and Raman spectra predicted beta polymorph form of our cisplatin sample freshly synthesized for the purposes of the present study using the Dhara's method. The various rotamers realized in the polymorph forms of cisplatin were explained by the low population of the large number of rotamers in solution as well as with the high rotamer interconversion rate due to the low energy barrier. PMID- 28073068 TI - Comparative analysis of isotropic diffusion weighted imaging sequences. AB - Visualisation of living tissue structure and function is a challenging problem of modern imaging techniques. Diffusion MRI allows one to probe in vivo structures on a micrometer scale. However, conventional diffusion measurements are time consuming procedures, because they require several measurements with different gradient directions. Considerable time savings are therefore possible by measurement schemes that generate an isotropic diffusion weighting in a single shot. Multiple approaches for generating isotropic diffusion weighting are known and have become very popular as useful tools in clinical research. Thus, there is a strong need for a comprehensive comparison of different isotropic weighting approaches. In the present work we introduce two new sequences based on simple (co)sine modulations and compare their performance to established q-space magic angle spinning sequences and conventional DTI, using a diffusion phantom assembled from microcapillaries and in vivo experiments at 7T. The advantages and disadvantages of all compared schemes are demonstrated and discussed. PMID- 28073069 TI - Horizontal pollen transmission of Gentian ovary ring-spot virus is initiated during penetration of the stigma and style by infected pollen tubes. AB - Gentian ovary ring-spot virus (GORV) infected gentian plants by pollination with GORV-infected gentian pollen grains, but the virus was not horizontally transmitted to gentian plants by transfer of pollen from GORV-infected Nicotiana benthamiana plants. However, N. benthamiana plants were infected with the virus by pollination with infected gentian pollen as well as by pollination with infected N. benthamiana pollen. When infected gentian pollen grains were placed on N. benthamiana stigmas, germinating pollen tubes penetrated into the stigmas and the styles (stigma-style). Virus infection occurred during penetration of the stigma-style, and the virus subsequently spread systemically to the mother plant. On the other hand, most infected N. benthamiana pollen grains failed to germinate on gentian stigmas, and virus infections were not detected in the stigma-style. PMID- 28073070 TI - Negotiating intersex: A case for revising the theory of social diagnosis. AB - The theory of social diagnosis recognizes two principles: 1) extra-medical social structures frame diagnosis; and 2) myriad social actors, in addition to clinicians, contribute to diagnostic labels and processes. The relationship between social diagnosis and (de)medicalization remains undertheorized, however, because social diagnosis does not account for how social actors can also resist the pathologization of symptoms and conditions-sometimes at the same time as they clamor for medical recognition-thereby shaping societal definitions of disease in different, but no less important, ways. In this article, we expand the social diagnosis framework by adding a third principle, specifically that 3) social actors engage with social structures to both contribute to, and resist, the framing of a condition as pathological (i.e. medicalization and demedicalization). This revised social diagnosis framework allows for the systematic investigation of multi-directional, dynamic processes, formalizing the link between diagnosis and (de)medicalization. It also responds to long-standing calls for more contextualized research in (de)medicalization studies by offering a framework that explicitly accounts for the social contexts in which (de)medicalizing processes operate. To showcase the utility of this revised framework, we use it to guide our analyses of a highly negotiated diagnosis: intersex. PMID- 28073071 TI - Morphology of four new solitary sessile peritrich ciliates from the Yellow Sea, China, with description of an unidentified species of Paravorticella (Ciliophora, Peritrichia). AB - Sessile peritrichs are a large assemblage of ciliates that have a wide distribution in soil, freshwater and marine waters. Here, we document four new and one unidentified species of solitary sessile peritrichs from aquaculture ponds and coastal waters of the northern Yellow Sea, China. Based on their living morphology, infraciliature and silverline system, four of the five forms were identified as new members belonging to one of three genera, Vorticella, Pseudovorticella and Scyphidia, representing two families, Vorticellidae and Scyphidiidae. The other isolate was found to be an unidentified species of the poorly known genus Paravorticella. Vorticella chiangi sp. nov. is characterized by its inverted bell-shaped zooid, short row 3 in infundibular polykinety 3 and marine habitat. Pseudovorticella liangae sp. nov. posseses a thin, broad peristomial lip and a granular pellicle. Pseudovorticella haiboensis sp. nov. is differentiated from its congeners by having an elongated zooid that is covered by a layer of thin pellicular vesicles, and two rows of kineties in infundibular polykinety 3. Scyphidia perezuzae sp. nov. and Paravorticella sp. are stalkless ectoparasites or ectocommensals of aquatic animals. The former has a short, plump body, a narrow peristomial lip and a conspicuous, flattened, disc-shaped scopula for adhesion. Paravorticella sp. has an extremely elongated clavate body, a broad peristomial lip, and a narrow scopula. PMID- 28073072 TI - Life cycle of Blastocrithidia papi sp. n. (Kinetoplastea, Trypanosomatidae) in Pyrrhocoris apterus (Hemiptera, Pyrrhocoridae). AB - Blastocrithidia papi sp. n. is a cyst-forming trypanosomatid parasitizing firebugs (Pyrrhocoris apterus). It is a member of the Blastocrithidia clade and a very close relative of B. largi, to which it is almost identical through its SSU rRNA gene sequence. However, considering the SL RNA gene these two species represent quite distinct, not even related typing units. Morphological analysis of the new species revealed peculiar or even unique features, which may be useful for future taxonomic revision of the genus Blastocrithidia. These include a breach in the microtubular corset of rostrum at the site of contact with the flagellum, absence of desmosomes between flagellum and rostrum, large transparent vacuole near the flagellar pocket, and multiple vacuoles with fibrous content in the posterior portion of the cell. The study of the flagellates' behavior in the host intestine revealed that they may attach both to microvilli of enterocytes using swollen flagellar tip and to extracellular membranes layers using hemidesmosomes of flagellum. Laboratory experiments on B. papi transmission in P. apterus demonstrated that the parasite may be transmitted vertically (via contaminated surface of eggs) and horizontally (via contaminated substrate and/or necrophagy). We argue that the parasite exploits transmission mechanisms intended for obligate bacterial symbionts of P. apterus. PMID- 28073073 TI - Development and validation of a liquid chromatography-MS/MS method for simultaneous quantification of tenofovir and efavirenz in biological tissues and fluids. AB - Millions of people worldwide live with human immunodeficiency virus (HIV) infection thus justifying the continuous search for new prevention and treatment strategies, including topical microbicide products combining antiretroviral drugs (ARVs) such as tenofovir (TFV) and efavirenz (EFV). Therefore, the aim of this work was to develop and validate a high performance liquid chromatography method coupled to triple quadrupole-tandem mass spectrometry (HPLC-MS/MS) for the quantification of TFV and EFV in biological matrices (mouse vaginal tissue, vaginal lavage and blood plasma). Chromatographic separation was achieved using a reversed phase C18 column (3MUm, 100*2.1mm) at 45 degrees C and elution in gradient mode using a combination of 0.1% (v/v) formic acid in water and 0.1% (v/v) formic acid in acetonitrile at 0.35mLmin-1. Total run time was 9min, with retention time of 2.8 and 4.1min for TFV and EFV, respectively. The MS was operated in positive ionization mode (ESI+) for TFV and in negative ionization mode (ESI-) for EFV detection. Data were acquired in selected reaction monitoring (SRM) mode and deuterated ARVs were employed as internal standards. Calibration curves were linear for ARV concentrations ranging from 4 to 500ngmL-1 with LOD and LOQ for both analytes <=0.4 and <=0.7ngmL-1 in sample extracts, respectively. The method was found to be specific, accurate (96.0-106.0% of nominal values) and precise (RSD<2.4%) in all matrices. Both TFV and EFV were found to be stable in all matrices after standing 24h at room temperature (20 degrees C) or in the autosampler, and after three freeze-thawing cycles. Mean recovery values of ARVs spiked in mice tissues or fluids were >=88.4%. Matrix effects were observed for EFV determination in tissue and plasma extracts but compensated by the use of deuterated internal standards. The proposed methodology was successfully applied to a pharmacokinetic study following intravaginal administration of both ARVs. PMID- 28073074 TI - Tribocorrosion behavior of bio-functionalized highly porous titanium. AB - Titanium and its alloys are widely used in orthopedic and dental implants, however, some major clinical concerns such as poor wear resistance, lack of bioactivity, and bone resorption due to stress shielding are yet to be overcome. In order to improve these drawbacks, highly porous Ti samples having functionalized surfaces were developed by powder metallurgy with space holder technique followed by anodic treatment. Tribocorrosion tests were performed in 9g/L NaCl solution using a unidirectional pin-on-disc tribometer under 3N normal load, 1Hz frequency and 4mm track diameter. Open circuit potential (OCP) was measured before, during and after sliding. Worn surfaces investigated by field emission gun scanning electron microscope (FEG-SEM) equipped with energy dispersive X-ray spectroscopy (EDS). Results suggested bio-functionalized highly porous samples presented lower tendency to corrosion under sliding against zirconia pin, mainly due to the load carrying effect given by the hard protruded oxide surfaces formed by the anodic treatment. PMID- 28073075 TI - Freeform extrusion fabrication of titanium fiber reinforced 13-93 bioactive glass scaffolds. AB - Although implants made with bioactive glass have shown promising results for bone repair, their application in repairing load-bearing long bone is limited due to their poor mechanical properties in comparison to human bone. This work investigates the freeform extrusion fabrication of bioactive silicate 13-93 glass scaffolds reinforced with titanium (Ti) fibers. A composite paste prepared with 13-93 glass and Ti fibers (~16um in diameter and lengths varying from ~200um to ~2 mm) was extruded through a nozzle to fabricate scaffolds (0-90 degrees filament orientation pattern) on a heated plate. The sintered scaffolds measured pore sizes ranging from 400 to 800um and a porosity of ~50%. Scaffolds with 0.4vol% Ti fibers measured fracture toughness of ~0.8MPam1/2 and a flexural strength of ~15MPa. 13-93 glass scaffolds without Ti fibers had a toughness of ~0.5MPam1/2 and a strength of ~10MPa. The addition of Ti fibers increased the fracture toughness of the scaffolds by ~70% and flexural strength by ~40%. The scaffolds' biocompatibility and their degradation in mechanical properties in vitro were assessed by immersing the scaffolds in a simulated body fluid over a period of one to four weeks. PMID- 28073076 TI - Spastic diplegia in preterm-born children: Executive function impairment and neuroanatomical correlates. AB - BACKGROUND: The neuropsychological literature on preterm-born children with spastic diplegia due to periventricular leukomalacia is convergent in reporting deficits in non-verbal intelligence and in visuo-spatial abilities. Nevertheless, other cognitive functions have found to be impaired, but data are scant and not correlated with neuroimaging findings. AIMS: This study analyzes the neuropsychological strengths and weaknesses in preterm-born children with spastic diplegia (pSD) and their relationships with neuroanatomical findings, investigated by a novel scale for MRI classification. METHODS AND PROCEDURES: Nineteen children with pSD, mild to moderate upper limb impairment and Verbal IQ>80, and 38 normal controls were evaluated with a comprehensive neuropsychological battery (NEPSY-II), assessing Attention/Executive Functioning, Language, Memory, Sensorimotor, Social Perception and Visuospatial Processing domains. The MRIs were quantitatively scored for lesion severity. OUTCOMES AND RESULTS: The results showed that, beyond core visuo-spatial and sensory-motor deficits, impairments in attention and executive functions were present in more than half of the sample, particularly in children with damage to the anterior corpus callosum. CONCLUSIONS AND IMPLICATIONS: The findings are discussed in terms of clinical and rehabilitative implications tailored for pSD subgroups diversified for neuropsychological and neuroanatomical characteristics. PMID- 28073077 TI - Hypertext comprehension of deaf and hard-of-hearing students and students with specific language impairment. AB - This paper provides insight into the reading comprehension of hierarchically structured hypertexts within D/HH students and students with SLI. To our knowledge, it is the first study on hypertext comprehension in D/HH students and students with SLI, and it also considers the role of working memory. We compared hypertext versus linear text comprehension in D/HH students and students with SLI versus younger students without language problems who had a similar level of decoding and vocabulary. The results demonstrated no difference in text comprehension between the hierarchically structured hypertext and the linear text. Text comprehension of D/HH students and students with SLI was comparable to that of the students without language problems. In addition, there was a similar positive predictive value of visuospatial and not verbal working memory on hypertext comprehension for all three groups. The findings implicate that educational settings can make use of hierarchically structured hypertexts as well as linear texts and that children can navigate in the digital world from young age on, even if language or working memory problems are present. PMID- 28073078 TI - TRIM52: A nuclear TRIM protein that positively regulates the nuclear factor-kappa B signaling pathway. AB - Emerging evidence suggests that TRIM family proteins play a crucial role in regulating the NF-kappaB signaling pathway. TRIM52 is a novel noncanonical antiviral TRIM gene with a unique expanded RING domain. Information on the biological function of TRIM52 is limited. Herein, we demonstrated TRIM52 involvement in NF-kappaB activation. We found that TRIM52 overexpression specifically activated the NF-kappaB signal. TRIM52 overexpression can significantly induce TNFalpha and IL-6 expression. We also found that the RING domain of TRIM52 was essential for its activation of the NF-kappaB signal. Further study showed that TRIM52 overexpression did not affect the protein level of IkappaBalpha and phosphorylated p65 protein. We found that the pro inflammatory cytokines TNFalpha and IL-6 could induce TRIM52 expression. Overall, these data suggested that TRIM52 was a positive regulator of the NF-kappaB pathway. PMID- 28073079 TI - TRAIL facilitates cytokine expression and macrophage migration during hypoxia/reoxygenation via ER stress-dependent NF-kappaB pathway. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is known as a key molecule to induce cancer cell apoptosis, has also been found to participate in the process of ischemia/reperfusion (I/R) injury. Infiltrated macrophages play dual roles in inflammatory injury and healing following I/R. Whether TRAIL has any effect on macrophages during this process remains elusive. Here we showed that I/R triggered the expressions of TRAIL, DR5 and cytokines (IL 1beta, TNFalpha, CCL-2 and ICAM-1), in addition to macrophage infiltration, which could be abolished by TRAIL neutralizing antibody. In vitro, TRAIL enhanced DR5 expression and facilitated the macrophages migration following hypoxia/reoxygenation (H/R) treatment in a dose-dependent manner via ER stress and NF-kappaB signaling pathways, which is accompanied by inflammatory factors expression. The increased cytokines production (such as TNFalpha and IL-1beta) stimulated by TRAIL can be blocked by the NF-kappaB and ER stress inhibitor. The results also suggested that NF-kappaB activation of macrophages during H/R was regulated by ER stress. Thus, our research present that TRAIL affects functional activities of macrophages during I/R injury, which may be a potential therapeutic target for ischemic heart disease. PMID- 28073080 TI - Impact of environmental factors on the culturability and viability of Listeria monocytogenes under conditions encountered in food processing plants. AB - The ability of Listeria monocytogenes to adhere to and persist on surfaces for months or even years may be responsible for its transmission from contaminated surfaces to food products. Hence the necessity to find effective means to prevent the establishment of L. monocytogenes in food processing environments. The aim of this study was to assess, through a fractional experimental design, the environmental factors that could affect the survival of L. monocytogenes cells on surfaces to thereby prevent the persistence of this pathogen in conditions mimicking those encountered in food processing plants: culture with smoked salmon juice or meat exudate, use of two materials with different hygiene status, biofilm of L. monocytogenes in pure-culture or dual-culture with a Pseudomonas fluorescens strain, application of a drying step after cleaning and disinfection (C&D) and comparison of two strains of L. monocytogenes. Bacterial survival was assessed by culture, qPCR to quantify total cells, and propidium monoazide coupled with qPCR to quantify viable cells and highlight viable but non culturable (VBNC) cells. Our results showed that failure to apply C&D causes cell persistence on surfaces. Moreover, the sanitation procedure leads only to a loss of culturability and appearance of VBNC populations. However, an additional daily drying step after C&D optimises the effectiveness of these procedures to reduce culturable populations. Our results reinforce the importance to use molecular tools to monitor viable pathogens in food processing plants to avoid underestimating the amounts of cells using only methods based on cell culture. PMID- 28073081 TI - Antibacterial effect of 405+/-5nm light emitting diode illumination against Escherichia coli O157:H7, Listeria monocytogenes, and Salmonella on the surface of fresh-cut mango and its influence on fruit quality. AB - To investigate a potential of 405+/-5nm light emitting diode (LED) as a novel technology for food preservation, the antibacterial effect of 405+/-5nm LED on Escherichia coli O157:H7, Listeria monocytogenes, and Salmonella spp. on the surface of fresh-cut mango and its influence on fruit quality were evaluated at different storage temperatures. LED-illumination inactivated 1.0-1.6 logCFU/cm2 of populations at 4 and 10 degrees C for 36-48h (total dose, 2.6-3.5kJ/cm2) regardless of bacterial species, while those on non-illuminated mange remained unchanged or slightly increased during storage. At 20 degrees C for 24h (total dose, 1.7kJ/cm2), non-illuminated E. coli O157:H7 and Salmonella gradually grew, whereas LED-illumination reduced 1.2 log of Salmonella and inhibited the growth of E. coli O157:H7. Unlike these, non-illuminated L. monocytogenes cells rapidly increased to 7.3 log, while illuminated cells reached 4.6 log, revealing that LED illumination delayed their growth. There were no significant (P>0.05) differences in color, antioxidant capacity, ascorbic acid, beta-carotene, and flavonoid between non-illuminated and illuminated cut mangoes, regardless of storage temperature. These results suggest that 405+/-5nm LEDs in combination with chilling temperatures could be applied to preserve fresh-cut fruits without deterioration of physicochemical quality of fruits at food establishments, minimizing the risk of foodborne disease. PMID- 28073082 TI - Vibrio parahaemolyticus O4:K8 forms a potential predominant clone in southern China as detected by whole-genome sequence analysis. AB - Vibrio parahaemolyticus has been the most common food-borne pathogen in southern China, especially the O3:K6 pandemic clone and its serovariants. Recently, the serotype O4:K8 became more and more prevalent in southern China, which was different from the O3:K6 pandemic clone. Thus, the aim of the present work was to elucidate the molecular characteristics of the O4:K8. Some O3:K6 pandemic clone and its serovariants isolated in the same period were selected for comparative analysis, which were still dominant clone locally. The whole genome sequencing (WGS) was applied to characterize 20 strains of V. parahaemolyticus isolated from food-borne diarrheal cases and belonging to the serotype O4:K8, O3:K6 and O1:KUT (untypable), prevalent serotypes in recent southern China. The results showed that all these isolates were positive for the thermostable direct hemolysin gene (tdh), while negative for the TDH-related hemolysin gene (trh). We compared the V. parahaemolyticus strains to those of 31 strains isolated overseas and were available from NCBI genome database. A WGS-SNPs phylogenetic analysis of all the genomes revealed that the strains formed an important genetic lineage, which was genetically distinct from the O3:K6, O1:KUT and other internationals strains. Comparative genome analysis also revealed that all the O4:K8 strains carried the entire T3SS-1 and VpaI-7 (T3SS-2) regions, the most important virulent elements of the O3:K6 pandemic clone. However, all the O4:K8 strains lacked the entire VpaI-1 and VpaI-4 regions and carried only few ORFs of the VpaI-5 and VpaI-6, which were considered to be unique among post-1995 strains belonging to the O3:K6 pandemic clone. Our data showed that the O4:K8 strains possessed the virulence factors similar to the O3:K6 pandemic clone, which may have enabled them to become prevalent in southern China. Our study also revealed that WGS-bases analysis may help improve understanding epidemiology of this bacterium in food borne disease surveillance. PMID- 28073083 TI - The Edinburgh visual gait score - The minimal clinically important difference. AB - OBJECTIVE: The primary aim was to define the minimal clinically important difference (MCID) of the Edinburgh Visual Gait Score (EVGS) using correlations with the Gross Motor Function Classification System (GMFCS) and the Functional Assessment Questionnaire (FAQ). The secondary aim was to confirm the numerical value of the MCID in the Gait Profile Score (GPS). METHOD: The EVGS and GPS scores for 151 patients with diplegic cerebral palsy (GMFCS Levels I-III) were retrospectively identified from a database held at the study centre. One-hundred and forty-one patients had FAQ data available. RESULTS: The EVGS and GPS correlated with increasing GMFCS level (p<0.001) and FAQ score (p<0.001). A gradient of 3.8 (2.9-4.7) for the EVGS and 2.9 (2.1-3.7) for the GPS corresponded to a one-level change in GMFCS level. A gradient of 1.9 (1.3-2.4) for EVGS and 1.5 (1.1-2.0) for GPS corresponded to a one-point change in FAQ. CONCLUSIONS: The authors propose an MCID value of 2.4 for the EVGS; representing the improvement in gait score after surgery that is likely to reflect a clinical improvement in function. This MCID is closely related to other studies defining post-operative improvements in kinematic data (GPS) and may offer guidance to post-surgical changes that might reasonably be expected to either improve or prevent deteriorating function. PMID- 28073084 TI - Reliability and Minimum Detectable Change of the Gait Deviation Index (GDI) in post-stroke patients. AB - The Gait Deviation Index (GDI) is a summary measure that provides a global picture of gait kinematic data. Since the ability to walk is critical for post stroke patients, the aim of this study was to determine the reliability and Minimum Detectable Change (MDC) of the GDI in this patient population. Twenty post-stroke patients (11 males, 9 females; mean age, 55.2+/-9.9years) participated in this study. Patients presented with either right- (n=14) or left sided (n=6) hemiparesis. Kinematic gait data were collected in two sessions (test and retest) that were 2 to 7days apart. GDI values in the first and second sessions were, respectively, 59.0+/-8.1 and 60.2+/-9.4 for the paretic limb and 53.3+/-8.3 and 53.4+/-8.3 for the non-paretic limb. The reliability in each session was determined by the intra-class correlation coefficient (ICC) of three strides and, in the test session, their values were 0.91 and 0.97 for the paretic and non-paretic limbs, respectively. Between-session reliability and MDC were determined using the average GDI of three strides from each session. For the paretic limb, between-session ICC, standard error of measurement (SEM), and MDC were 0.84, 3.4 and 9.4, respectively. Non paretic lower limb exhibited between session ICC, standard error of measurement (SEM), and MDC of 0.89, 2.7 and 7.5, respectively. These MDC values indicate that very large changes in GDI are required to identify gait improvement. Therefore, the clinical usefulness of GDI with stroke patients is questionable. PMID- 28073085 TI - Effect of investigator observation on gait parameters in individuals with and without chronic low back pain. AB - Despite the ubiquity of gait assessment in clinic and research, it is unclear how observation impacts gait, particularly in persons with chronic pain and psychological stress. We compared temporal spatial gait patterns in people with and without chronic low back pain (CLBP) when they were aware and unaware of being observed. This was a repeated-measures, deception study in 55 healthy persons (32.0+/-12.4 yr, 24.2+/-2.7kg/m2) and persons with CLBP (51.9+/-17.9 yr, 27.8+/-4.4kg/m2). Participants performed one condition in which they were unaware of observation (UNW), and three conditions under investigator observation: (1) aware of observation (AWA), (2) investigators watching cadence, (3) investigators watching step length. Participants walked across an 8.4m gait mat, while temporal spatial parameters of gait were collected. The Medical Outcomes Short Form (SF 12), Beck Depression Inventory (BDI), State Trait Anxiety Inventory (STAI), and Oswestry Disability Index (ODI) were completed. Significant condition by group interactions were found for velocity and step length (p<0.05). Main effects of study condition existed for all gait variables except for step width. Main effects of group (healthy, LBP) were significant for all variables except for step width (p<0.05). Regression analyses revealed that after accounting for age, sex, and SF-12 mental component score, BDI scores predict velocity changes during walking from the UNW to AWA conditions. These findings show that people change their gait patterns when being observed. Gait analyses may require additional trials before data can reliably be interpreted and used for clinical decision making. PMID- 28073087 TI - A nearest neighbour approach by genetic distance to the assignment of individual trees to geographic origin. AB - During the past decade, the use of DNA for forensic applications has been extensively implemented for plant and animal species, as well as in humans. Tracing back the geographical origin of an individual usually requires genetic assignment analysis. These approaches are based on reference samples that are grouped into populations or other aggregates and intend to identify the most likely group of origin. Often this grouping does not have a biological but rather a historical or political justification, such as "country of origin". In this paper, we present a new nearest neighbour approach to individual assignment or classification within a given but potentially imperfect grouping of reference samples. This method, which is based on the genetic distance between individuals, functions better in many cases than commonly used methods. We demonstrate the operation of our assignment method using two data sets. One set is simulated for a large number of trees distributed in a 120km by 120km landscape with individual genotypes at 150 SNPs, and the other set comprises experimental data of 1221 individuals of the African tropical tree species Entandrophragma cylindricum (Sapelli) genotyped at 61 SNPs. Judging by the level of correct self-assignment, our approach outperformed the commonly used frequency and Bayesian approaches by 15% for the simulated data set and by 5-7% for the Sapelli data set. Our new approach is less sensitive to overlapping sources of genetic differentiation, such as genetic differences among closely-related species, phylogeographic lineages and isolation by distance, and thus operates better even for suboptimal grouping of individuals. PMID- 28073088 TI - Characterization of the Iberian Y chromosome haplogroup R-DF27 in Northern Spain. AB - The European paternal lineage R-DF27 has been proposed as a haplogroup of Iberian origin due to its maximum frequencies in the Iberian Peninsula. In this study, the distribution and structure of DF27 were characterized in 591 unrelated male individuals from four key populations of the north area of the Iberian Peninsula through the analysis of 12 Y-SNPs that define DF27 main sublineages. Additionally, Y-SNP allele frequencies were also gathered from the reference populations in the 1000 Genomes Project to compare and obtain a better landscape of the distribution of DF27. Our results reveal frequencies over 35% of DF27 haplogroup in the four North Iberian populations analyzed and high frequencies for its subhaplogroups. Considering the low frequency of DF27 and its sublineages in most populations outside of the Iberian Peninsula, this haplogroup seems to have geographical significance; thus, indicating a possible Iberian patrilineal origin of vestiges bearing this haplogroup. The dataset presented here contributes with new data to better understand the complex genetic variability of the Y chromosome in the Iberian Peninsula, that can be applied in Forensic Genetics. PMID- 28073089 TI - Application of a mitochondrial DNA control region frequency database for UK domestic cats. AB - DNA variation in 402bp of the mitochondrial control region flanked by repeat sequences RS2 and RS3 was evaluated by Sanger sequencing in 152 English domestic cats, in order to determine the significance of matching DNA sequences between hairs found with a victim's body and the suspect's pet cat. Whilst 95% of English cats possessed one of the twelve globally widespread mitotypes, four new variants were observed, the most common of which (2% frequency) was shared with the evidential samples. No significant difference in mitotype frequency was seen between 32 individuals from the locality of the crime and 120 additional cats from the rest of England, suggesting a lack of local population structure. However, significant differences were observed in comparison with frequencies in other countries, including the closely neighbouring Netherlands, highlighting the importance of appropriate genetic databases when determining the evidential significance of mitochondrial DNA evidence. PMID- 28073086 TI - Human neural progenitors derived from integration-free iPSCs for SCI therapy. AB - As a potentially unlimited autologous cell source, patient induced pluripotent stem cells (iPSCs) provide great capability for tissue regeneration, particularly in spinal cord injury (SCI). However, despite significant progress made in translation of iPSC-derived neural progenitor cells (NPCs) to clinical settings, a few hurdles remain. Among them, non-invasive approach to obtain source cells in a timely manner, safer integration-free delivery of reprogramming factors, and purification of NPCs before transplantation are top priorities to overcome. In this study, we developed a safe and cost-effective pipeline to generate clinically relevant NPCs. We first isolated cells from patients' urine and reprogrammed them into iPSCs by non-integrating Sendai viral vectors, and carried out experiments on neural differentiation. NPCs were purified by A2B5, an antibody specifically recognizing a glycoganglioside on the cell surface of neural lineage cells, via fluorescence activated cell sorting. Upon further in vitro induction, NPCs were able to give rise to neurons, oligodendrocytes and astrocytes. To test the functionality of the A2B5+ NPCs, we grafted them into the contused mouse thoracic spinal cord. Eight weeks after transplantation, the grafted cells survived, integrated into the injured spinal cord, and differentiated into neurons and glia. Our specific focus on cell source, reprogramming, differentiation and purification method purposely addresses timing and safety issues of transplantation to SCI models. It is our belief that this work takes one step closer on using human iPSC derivatives to SCI clinical settings. PMID- 28073090 TI - Hair dyeing, hair washing and hair cortisol concentrations among women from the healthy start study. AB - BACKGROUND: Hair cortisol concentration (HCC) has been suggested as a promising marker for chronic stress. However, studies investigating the influence of hair dyeing and hair washing frequency on HCC have shown inconsistent results. OBJECTIVE: To examine associations between HCC and hair dyeing status or weekly hair washing frequency among women. METHODS: This cross-sectional study was based on data from 266 mothers participating in the Healthy Start intervention study. HCC was measured in the proximal end of the hair (1-2cm closest to the scalp) while hair dyeing status, frequency of hair washing and covariates were reported by the women. Linear regression analyses were applied to assess the associations between HCC and hair dyeing or weekly frequency of hair washing. RESULTS: No statistically significant difference (p=0.91) in HCC was found between women who dyed hair (adjusted mean: 137pg/mg [95% CI: 122,153]) and women with natural hair color (adjusted mean: 139pg/mg [95% CI: 123,155]). Frequency of hair washing was not associated with HCC (beta: -3.7 [95% CI: -9.0, 1.5; P=0.20]). CONCLUSIONS: This study of 266 Danish women provides no evidence in support of an association between HCC and hair dyeing status or hair washing frequency. PMID- 28073091 TI - The effect of Platycodin D on the expression of cytoadherence proteins P1 and P30 in Mycoplasma pneumoniae models. AB - Platycodin D is one of the most important monomers of the Qinbaiqingfei pellet (Qinbai), which has already been approved as the first effective new Traditional Chinese Medicine used to fight against Mycoplasma pneumoniae (M. pneumoniae) in clinic in China. In previous studies, pharmacodynamics experiment has proved that Platycodin D has anti-M. pneumoniae effect and the minimum inhibitory concentration (MIC) is 16mMUg/ml. This paper further clarified that the mechanism underlying the anti-M. pneumoniae effect of Platycodin D might be due to M. pneumoniae adhesion proteins P1 and P30. P1 and P30 expression levels in M. pneumoniae strain, M. pneumoniae-infected BALB/c mice, and M. pneumoniae-infected A549 cells were determined by reverse transcription PCR. Platycodin D strongly inhibited P1 and P30 expression in M. pneumonia and high dosage of Platycodin D exhibited a greater effect on reducing P1 and P30 expression than low dose Platycodin D. Platycodin D prevented M. pneumoniae infection through inhibiting the expression of adhesion proteins, which might be one of the mechanisms for the anti-M. pneumoniae properties of Qinbai. These results provide a foundation to further explore the mechanisms of action of Qinbai in future studies. PMID- 28073092 TI - Acute suicidal affective disturbance: Factorial structure and initial validation across psychiatric outpatient and inpatient samples. AB - BACKGROUND: A new clinical entity, Acute Suicidal Affective Disturbance (ASAD), was recently proposed to characterize rapid-onset, acute suicidality including the cardinal symptom of behavioral intent. This study examines the proposed ASAD criteria factor-analytically and in relation to correlates of suicidal behavior and existing psychiatric disorders in samples of psychiatric outpatients and inpatients. METHODS: Two samples of psychiatric outpatients (N=343, aged 18-71 years, 60.6% female, 74.9% White) and inpatients (N=7,698, aged 15-99 years, 57.2% female, 87.8% White) completed measures of their ASAD symptoms and psychological functioning. RESULTS: Across both samples, results of a confirmatory factor analysis supported the unidimensional nature of the ASAD construct. Additionally, results provided evidence for the convergent and discriminant validity of ASAD, demonstrating its relation to, yet distinction from, other psychiatric disorders and correlates of suicide in expected ways. Importantly, ASAD symptoms differentiated multiple attempters, single attempters, and non-attempters, as well as attempters, ideators, and non-suicidal patients, and was an indicator of past suicide attempts above and beyond symptoms of depression and other psychiatric disorders. LIMITATIONS: This study utilized cross-sectional data and did not use a standardized measure of ASAD. CONCLUSIONS: ASAD criteria formed a unidimensional construct that was associated with suicide related variables and other psychiatric disorders in expected ways. If supported by future research, ASAD may fill a gap in the current diagnostic classification system (DSM-5) by characterizing and predicting acute suicide risk. PMID- 28073093 TI - Subject-specific finite element analysis of the carpal tunnel cross-sectional to examine tunnel area changes in response to carpal arch loading. AB - BACKGROUND: Manipulating the carpal arch width (i.e. distance between hamate and trapezium bones) has been suggested as a means to increase carpal tunnel cross sectional area and alleviate median nerve compression. The purpose of this study was to develop a finite element model of the carpal tunnel and to determine an optimal force direction to maximize area. METHODS: A planar geometric model of carpal bones at hamate level was reconstructed from MRI with inter-carpal joint spaces filled with a linear elastic surrogate tissue. Experimental data with discrete carpal tunnel pressures (50, 100, 150, and 200mmHg) and corresponding carpal bone movements were used to obtain material property of surrogate tissue by inverse finite element analysis. The resulting model was used to simulate changes of carpal arch widths and areas with directional variations of a unit force applied at the hook of hamate. FINDINGS: Inverse finite element model predicted the experimental area data within 1.5% error. Simulation of force applications showed that carpal arch width and area were dependent on the direction of force application, and minimal arch width and maximal area occurred at 138 degrees (i.e. volar-radial direction) with respect to the hamate-to trapezium axis. At this force direction, the width changed to 24.4mm from its initial 25.1mm (3% decrease), and the area changed to 301.6mm2 from 290.3mm2 (4% increase). INTERPRETATION: The findings of the current study guide biomechanical manipulation to gain tunnel area increase, potentially helping reduce carpal tunnel pressure and relieve symptoms of compression median neuropathy. PMID- 28073094 TI - The role of lesser trochanter fragment in unstable pertrochanteric A2 proximal femur fractures - is refixation of the lesser trochanter worth the effort? AB - BACKGROUND: Instability of osteoporotic pertrochanteric fractures is defined by loss of medial/lateral cortical integrity with the posteromedial fragment including the lesser trochanter being pivotal for load distribution. Literature addressing the importance of lesser trochanter refixation is scarce. To clarify the effect of lesser trochanter refixation on primary stability in these fractures, following study was performed. METHODS: 21 femora were match-paired in 3 groups and osteotomized, creating pertrochanteric fractures (AO-31A2). Group 1 was stabilized with a proximal femoral nail, group 2 with a dynamic hip screw and group 3 with an augmented proximal femoral nail. Each femur was tested non destructively at 200 and 400N with and without refixation of the lesser trochanter (configuration A/B). The overall stiffness and movement of the femoral neck was recorded. FINDINGS: At 200N, refixation reduced movement of the femoral neck and increased overall stiffness significantly in group 1 and 3. At 400N, refixation decreased movement of the femoral neck not significantly in all groups (1=38%, 2=36%, 3=43%). The augmented proximal femoral nail after refixation showed the highest stability of all constructs. INTERPRETATION: Refixation of the lesser trochanter may increase the primary stability of pertrochanteric fracture osteosynthesis as all groups showed a higher primary stability. Therefore, refixation should be considered in unstable, osteoporotic fractures. If additional trauma through refixation appears inappropriate, cement augmentation should be performed as it showed only 9% less stability than a non-augmented proximal femoral nail with refixation of the lesser trochanter. PMID- 28073095 TI - Enhanced WWTP effluent organic matter removal in hybrid ozonation-coagulation (HOC) process catalyzed by Al-based coagulant. AB - A novel hybrid ozonation-coagulation (HOC) process was developed for application in wastewater reclamation. In this process, ozonation and coagulation occurred simultaneously within a single unit. Compared with the conventional pre-ozonation coagulation process, the HOC process exhibited much better performance in removing dissolved organic matters. In particular, the maximal organic matters removal efficiency was obtained at the ozone dosage of 1mgO3/mg DOC at each pH value (pH 5, 7 and 9). In order to interpret the mechanism of the HOC process, ozone decomposition was monitored. The results indicated that ozone decomposed much faster in the HOC process. Moreover, by using the reagent of O3-resistant hydroxyl radical (OH) probe compound, para-chlorobenzoic acid (pCBA), and electron paramagnetic resonance (EPR) analysis, it was observed that the HOC process generated higher content of OH compared with pre-ozonation process. This indicates that the OH oxidation reaction as the key step can be catalyzed and enhanced by Al-based coagulants and their hydrolyzed products in this developed process. Thus, based on the catalytic effects of Al-based coagulants on ozonation, the HOC process provides a promising alternative to the conventional technology for wastewater reclamation in terms of higher efficiency. PMID- 28073096 TI - High density scalp EEG in frontal lobe epilepsy. AB - PURPOSE: Localization of seizures in frontal lobe epilepsy using the 10-20 system scalp EEG is often challenging because neocortical seizure can spread rapidly, significant muscle artifact, and the suboptimal spatial resolution for seizure generators involving mesial frontal lobe cortex. Our aim in this study was to determine the value of visual interpretation of 76 channel high density EEG (hdEEG) monitoring (10-10 system) in patients with suspected frontal lobe epilepsy, and to evaluate concordance with MRI, subtraction ictal SPECT co registered to MRI (SISCOM), conventional EEG, and intracranial EEG (iEEG). METHODS: We performed a retrospective cohort study of 14 consecutive patients who underwent hdEEG monitoring for suspected frontal lobe seizures. The gold standard for localization was considered to be iEEG. Concordance of hdEEG findings with MRI, subtraction ictal SPECT co-registered to MRI (SISCOM), conventional 10-20 EEG, and iEEG as well as correlation of hdEEG localization with surgical outcome were examined. RESULTS: hdEEG localization was concordant with iEEG in 12/14 and was superior to conventional EEG 3/14 (p<0.01) and SISCOM 3/12 (p<0.01). hdEEG correctly lateralized seizure onset in 14/14 cases, compared to 9/14 (p=0.04) cases with conventional EEG. Seven patients underwent surgical resection, of whom five were seizure free. CONCLUSIONS: hdEEG monitoring should be considered in patients with suspected frontal epilepsy requiring localization of epileptogenic brain. hdEEG may assist in developing a hypothesis for iEEG monitoring and could potentially augment EEG source localization. PMID- 28073097 TI - Moringa oleifera, a species with potential analgesic and anti-inflammatory activities. AB - Moringa oleifera has long been used in large demand in folk medicine to treat pain. The present study was undertaken to examine the antinociceptive and anti inflammatory spectrum of M. oleifera leaf extracts discriminating the constituents' nature by using different kind of experimental models in rats. Pharmacological evaluation of a non-polar and/or polar extracts at several doses (30-300mg/kg, p.o.) was explored through experimental nociception using formalin test, carrageenan-induced paw edema and arthritis with subcutaneous injection of collagen in rats. Basic morphology characterization was done by scanning electronic microscopy and laser scanning confocal microscopy. Not only polar (from 30 or 100mg/kg, p.o.) but also non-polar extract produced significant inhibition of the nociceptive behavior with major efficacy in the inflammatory response in different assessed experimental models. This antinociceptive activity involved constituents of different nature and depended on the intensity of the induced painful stimulus. Phytochemical analysis showed the presence of kaempferol-3-glucoside in the polar extract and fatty acids like chlorogenic acid, among others, in the non-polar extract. Data obtained with M. oleifera leaf extracts give evidence of its potential for pain treatment. PMID- 28073098 TI - The effect of Elettaria cardamomum extract on anxiety-like behavior in a rat model of post-traumatic stress disorder. AB - Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition which develops in 6-8% of the general population. Current standard pharmacological treatments for PTSD cannot be widely used due to having various side effects. Nowadays, various pharmacological properties have been related to Elettaria cardamomum L. (family of Zingiberaceae). The present study aims to evaluate the efficacy of E. cardamomum methanolic extract on anxiety-like behavior in a rat model of PTSD. Adult male Wistar rats (200-250gr) were used in this study. The rats underwent single prolonged stress (SPS) or control and intraperitoneally received either saline or different dosages (200, 400, and 800mg/kg) of E. cardamomum methanolic extract before and after stress sessions. Moreover, open field, elevated plus-maze, and rotarod tests were used to evaluate locomotion and anxiety-like behavior in the rats. Findings demonstrated that E. Cardamomum methanolic extract, particularly at the dose of 400mg/kg, significantly (P<0.05) improved anxiety-like behavior in a rat model of PTSD, as examined by the open field, elevated plus-maze, and rotarod tests. Administration of E. cardamomum methanolic extract after stress might help to prevent the formation of anxiety-like behavior in the animals. However, further studies are requiredto clarify the exact mechanisms involved. PMID- 28073099 TI - Golden root: A wholesome treat of immunity. AB - Rhodiola is native to the high altitude regions of Asia, Europe and Northern Hemisphere. It has a long history of use as a medicinal plant in various ailments, boosting immunity, increasing energy and mental capacity. It is also known as "Adaptogen" to help the body to adapt and resist stress. The part of the plant, which is used for medicinal values, is rhizome, which is an underground stem. The rhizome contains mainly salidroside, rosin, rosavin and p-tyrosol. There are many studies, which have reported the effects of Rhodiola spp. on different organs and health conditions. In this review, we have selected the articles from Pubmed and Google Scholar from year 1992-2016 to report the effects of Rhodiola spp. and their role in curtailing various diseases and stress. The present review emphasizes the medicinal and therapeutic applications of Rhodiola spp. on different experimental models. Overall conclusion is that Rhodiola spp. has immense therapeutic potential and hence, this review would give impetus to new research for the development of Rhodiola based herbal nutraceuticals as well as pharmaceuticals. PMID- 28073100 TI - Investigating the use of appropriation in the writing of a child with autism: A case study. AB - This case study investigated how a 10year old child with ASD (Autism Spectrum Disorder), Kameron (pseudonym), utilized appropriation as a writing strategy in the context of group therapy. Using the same questions as Lensmire and Beals (1994) in their study of a typically developing third-grader, written products were collected over the course of one semester and analyzed, along with video, audio, and participant observation data, to consider the following questions: 1) Where did the material come from? 2) What was taken? and 3) How was it used? Analysis of the process of Kameron's writing revealed utilization of appropriation as a strategy for 2 of the 4 written products. Material was appropriated from both adult authored texts performed via read alouds and from topics and values located in the local peer culture. Kameron's appropriation of shared experiences provided substance to initiate and engage in a shared peer culture. Increased engagement in the writing process and fewer off task behaviors were noted when appropriations were evidenced compared to the writing pieces where no appropriation occurred. The results demonstrate the powerful implications of both a process oriented and strength-based approach to writing and greater social awareness than expected in children with ASD. PMID- 28073101 TI - Impact of targeted therapies in metastatic renal cell carcinoma on patient reported outcomes: Methodology of clinical trials and clinical benefit. AB - BACKGROUND: Molecular targeted therapies have improved progression-free survival (PFS) without translating systematically into overall survival (OS) for patients with metastatic renal cell carcinoma (mRCC). In this population, patient-reported outcomes (PROs) have become a significant outcome. We evaluated the methodological quality of the assessment of PROs in randomized controlled trials (RCTs) and the clinical benefit of the different treatments including survival and quality of life (QoL). METHODS: A systematic review identified RCTs published between January 2005 and July 2014. They were evaluated according to 11 items derived from the 2013 CONSORT PROs reporting guidelines. Survival outcomes and PROs main results were analyzed and the magnitude of clinical benefit was assessed with the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). RESULTS: 12 RCTs were included with a total of 22 publications. The mean CONSORT score for all items was 4.5 on an 11-point scale. No publication reported the power of the PROs analysis and only one reported a PRO hypothesis. 50% of studies did not interpret PROs in relation to clinical outcomes and only 18% discussed specific limitations of PROs and their implications for generalizability. By adding the QoL criterion to PFS, 4 trials (36.4%) obtained a high level of proven clinical benefit according to the ESMO MCBS. CONCLUSION: The methodology for assessing PROs in mRCC is not optimal. Efforts should focus on defining PROs endpoint and increasing the quality of reporting of QoL. New-generation therapies in mRCC should demonstrate a gain not only in survival but also in QoL to be included in the therapeutic arsenal. PMID- 28073103 TI - Associate Editor Remy F. Meier. PMID- 28073102 TI - Cancer resistance to therapies against the EGFR-RAS-RAF pathway: The role of MEK. AB - The mitogen-activated protein kinases (MAPKs) mediate intracellular signals activated by a wide variety of extracellular stimuli. The activation of the RAS RAF-MEK-MAPK cascade culminates in the regulation of gene transcription promoting cancer cell proliferation, survival, migration and angiogenesis. MEK (mitogen activated protein kinase kinase-MAPKK) 1/2 is a transducer of the growth factor receptor-RAS-RAF-MAPK signalling cascade and plays a relevant role in development and progression of human cancers, such as colorectal cancer (CRC), non small cell lung cancer (NSCLC). Direct inhibition of MEK is a promising strategy and several inhibitors are currently under evaluation in clinical trials showing initial clinical activity in different tumours. MEK activation, by different genetic mechanisms, has been described for both intrinsic and acquired resistance to drugs targeting the EGFR (Epidermal Growth Factor Receptor)-RAS-RAF pathway in CRC, NSCLC. Combination therapies with chemotherapy and/or with molecular targeted agents are warranted and biomarkers studies are needed to identify those tumours dependent on MEK signalling. PMID- 28073105 TI - Associate Editor J. Alfredo Martinez. PMID- 28073104 TI - Use of Transcutaneous Bilirubin to Determine the Need for Phototherapy in Resource-Limited Settings. AB - BACKGROUND: Routine and timely determination of total serum bilirubin (TSB) remains a challenge in many resource-limited countries with substantial burden of severe neonatal hyperbilirubinemia. Limited evidence exists on the potential usefulness of transcutaneous bilirubin (TcB) to identify infants who may require phototherapy based on possible treatment criteria in such settings. OBJECTIVE: To compare the number of infants requiring phototherapy across different TSB criteria and determine the predictive performance of TcB under each criterion. METHODS: Infants with paired TcB and TSB measurements in a maternity hospital in Lagos, Nigeria, were assessed for phototherapy based on TSB criteria by the American Academy of Pediatrics (AAP), National Institute for Health and Clinical Excellence (NICE) UK, and World Health Organization (WHO), and an absolute threshold of >=12 mg/dL. The predictive performance of TcB across treatment criteria was evaluated with receiver operating curve analysis. RESULTS: A total of 1,011 infants with a mean TcB of 10.54 +/- 3.19 (range: 2.7-19.9) mg/dL and TSB of 9.63 +/- 2.61 (range: 0.3-19.5) mg/dL were assessed. Some 60 (5.9%) infants required phototherapy by 1 or more TSB criteria, with TSB >=12 mg/dL identifying 55 (91.7%) and AAP 27 (45%) of these infants. All infants identified by the NICE and WHO criteria were equally detected by the AAP criterion. TcB showed negative predictive values of 99.0-99.9%, and positive predictive values of 7.7-15.5% across all criteria. CONCLUSIONS: The number of infants requiring phototherapy varies significantly across treatment criteria. TcB may be useful in identifying infants who do not require phototherapy, but may also identify a high proportion of false positives that is burdensome in resource-limited settings. PMID- 28073107 TI - Associate Editor Anja Kroke. PMID- 28073106 TI - Surfactant Need by Gestation for Very Preterm Babies Initiated on Early Nasal CPAP: A Danish Observational Multicentre Study of 6,628 Infants Born 2000-2013. AB - BACKGROUND: In recent years, early nasal continuous positive airway pressure (nCPAP) as respiratory support for preterm infants is being advocated as an alternative to prophylactic surfactant and treatment with mechanical ventilation. A number of infants treated with early nCPAP do not need treatment with surfactant, but few studies provide data on this. Since the 1990s, the first approach to respiratory support to preterm infants in Denmark has been early nCPAP combined with surfactant administration by the INSURE method by which the infant is intubated and surfactant administration is followed by rapid extubation to nCPAP if possible. OBJECTIVES: To investigate how often surfactant was administered in preterm infants with a gestational age below 34 weeks treated with early nCPAP as a first approach to respiratory support. METHODS: An observational multicentre study including all inborn infants with a gestational age below 34 weeks admitted to 1 of the 4 level 3 neonatal intensive care units in Denmark in the period from 2000 to 2013. RESULTS: A total of 6,628 infants were included in this study. We found that surfactant was administered in 1,056 of 1,799 (59%; 95% CI: 57-61%), in 821 of 2,864 (29%; 95% CI: 27-31%), and in 132 of 1,796 (7%; 95% CI: 6-8%) of the infants with a gestational age from 24 to 27, 28 to 31, and 32 to 33 weeks and 6 days, respectively. CONCLUSIONS: A large proportion of preterm infants treated with early nCPAP as the first approach to respiratory support was never treated with surfactant. PMID- 28073108 TI - Salivary Testosterone during the Minipuberty of Infancy?. AB - BACKGROUND: The hypothalamic-pituitary-gonadal axis is transiently activated during the postnatal months in boys, a phenomenon termed "minipuberty" of infancy, when serum testosterone (T) increases to pubertal levels. Despite high circulating T there are no signs of virilization. We hypothesize that free T as measured in saliva is low, which would explain the absence of virilization. METHODS: We measured serum total T and free T in saliva using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 30 infant boys, aged 1-6 months, and in 12 adolescents, aged 11-17 years. RESULTS: Total serum T in all infants was, as expected, high (172 +/- 78 ng/dL) while salivary T was low (7.7 +/- 4 pg/mL or 0.45 +/- 0.20%). In contrast, salivary T in the adolescents was much higher (41 +/- 18 pg/mL or 1.3 +/- 0.36%) in relation to their total serum T (323 +/- 117 ng/dL). We provide for the first time reference data for salivary T in infants. CONCLUSION: Measurement of salivary T by LC-MS/MS is a promising noninvasive technique to reflect free T in infants. The low free T explains the absence of virilization. The minipuberty of infancy is more likely of intragonadal than peripheral significance.?. PMID- 28073109 TI - Associate Editor Bev Muhlhausler. PMID- 28073110 TI - Relationship between the Pathogenesis of Glaucoma and miRNA. AB - Small RNA (microRNA or miRNA) is a kind of small noncoding single-stranded RNA that regulates complementary mRNA at the posttranscriptional level in eukaryotic organisms. As important regulatory factors, miRNAs play an important role in the occurrence and development of glaucoma and widely participate in regulating biological processes of glaucoma-related genes. This article reviews the connection between the aqueous humor, trabecular meshwork, the apoptosis of retinal ganglion cells, and miRNA. PMID- 28073112 TI - Space and Objects: On the Phenomenology and Cognitive Neuroscience of Anomalous Perception in Schizophrenia (Ancillary Article to EAWE Domain 1). AB - BACKGROUND/AIMS: Perception of space and objects is a traditional focus within phenomenology, and disturbances in these aspects of perception among people with schizophrenia have long been discussed within phenomenological psychiatry. Despite this, there has been little empirical work on the causes and effects of most of these perceptual alterations in people with schizophrenia. Progress towards this goal can be accelerated by the use of EAWE (Examination of Anomalous World Experience), an interview-based tool to elicit, categorize, and quantify abnormal perceptual and other experiential phenomena. METHODS: In this brief paper, we review the main types of disturbances in space and object perception in schizophrenia - as described by phenomenologists, clinicians from other theoretical orientations, and experimental psychopathologists - as a first step in a research agenda to achieve a better integration of the clinical and experimental literatures. RESULTS/CONCLUSION: This review indicates that in some cases the cognitive and neurobiological mechanisms of altered space and object perception in schizophrenia are relatively well understood, while in other cases there exist only plausible hypotheses. In still other cases, however, almost nothing is known. Moreover, a fundamental hypothesis of phenomenological psychiatry - that perceptual changes are related to disturbances in the sense of self - has yet to be investigated actively. From this context, we offer suggestions for future research and suggest general research designs that may be useful for advancing progress in this area. PMID- 28073113 TI - In vitro to in vivo extrapolation for drug-induced liver injury using a pair ranking method. AB - Preclinical animal toxicity studies may not accurately predict human toxicity. In light of this, in vitro systems have been developed that have the potential to supplement or even replace animal use. We examined in vitro to in vivo extrapolation (IVIVE) of gene expression data obtained from The Open Japanese Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (Open TG GATEs) for 131 compounds given to rats for 28 days, and to human or rat hepatocytes for 24 hours. Notably, a pair ranking (PRank) method was developed to assess IVIVE potential with a PRank score based on the preservation of the order of similarity rankings of compound pairs between the platforms using a receiver operating characteristic (ROC) curve analysis to measure area under the curve (AUC). A high IVIVE potential was noted for rat primary hepatocytes when compared to rat 28-day studies (PRank score = 0.71) whereas the IVIVE potential for human primary hepatocytes compared to rat 28-day studies was lower (PRank score = 0.58), indicating that species difference plays a critical role in IVIVE. When limiting the analysis to only those drugs causing drug-induced liver injury, the IVIVE potential was slightly improved both for rats (from 0.71 to 0.76) and for humans (from 0.58 to 0.62). Similarly, PRank scores were improved when the analysis focused on specific hepatotoxic endpoints such as hepatocellular injury, or cholestatic injury. In conclusion, toxicogenomic data generated in vitro yields a ranking of drugs regarding their potential to cause toxicity which is comparable to that generated by in vivo analyses. PMID- 28073114 TI - A Study of Acute Poisoning Cases Admitted to the University Hospital Emergency Department in Tabriz, Iran. AB - Chemical substances have an important threat due to extensive use in medicine, agriculture, industry and environment. In this retrospective study, etiological and demographic characteristics of acute poisoning cases admitted to a hospital in Iran were investigated. We compared these data with those reported from other parts of the country and the international experiences to evaluate any difference if exists. 7 052 poisoned cases admitted to the hospital from April 2006 to March 2013, by data collected from the medical record in poison center section. According to our results there is a predominance of male patients and the majority of the poisoned patients were between 20-30 years old. Drug poisoning was the most common cause of poisonings. The most frequently involved drugs were benzodiazepines and antidepressants. The seasonal distribution of our study showed a peak in summer. To prevent acute poisonings, the social education about the risk assessment of central nervous system-acting drugs and reduction of the exposure period of people to pesticides are recommended. This study suggested a proper educational program for the public and primary care units. Our results provide useful information for preventive strategies. PMID- 28073115 TI - Pyridazine Based Scaffolds as Privileged Structures in anti-Cancer Therapy. AB - Pyridazines, their oxo derivatives; pyridazinone as well as fused bi- or tricyclic pyridazine containing scaffolds are key structural features of many biologically active compounds with diverse pharmacological applications, including cancer therapy. Since protein kinases play prominent role in tumor biology, the inhibition of its signaling pathway is considered an effective therapeutic option for the treatment of cancer.Based on the various advantages of pyridazines in drug design including modulation of the physico-chemical properties, improving ADME and toxicity profile as well as easy and diverse synthetic methods of access, makes them an invaluable tool for designing compounds as future drugs for targeted cancer treatment.In this review, we have compiled and discussed the anticancer potential of pyridazine based scaffold, with special focus on those targeting protein kinase inhibition. PMID- 28073116 TI - A 12-Year-Old Returning Traveler with Fever, Retro-orbital Headache and Rash. PMID- 28073117 TI - Antibiotic Stewardship in Paediatric Inpatients and C. Difficile Associated Disease? PMID- 28073118 TI - In Vitro Metabolism of Artepillin C by Rat and Human Liver Microsomes. AB - Artepillin C, a natural product present in the Brazilian green propolis, has several biological properties. Among these properties, the antitumor action of this product is noteworthy and makes it a promising drug candidate for the treatment of several types of cancer. This paper describes the in vitro metabolism of Artepillin C in rat and human liver microsomes. The rat model suggested a sigmoidal profile for the metabolism, adapted to the Hill's kinetic model. The enzymatic kinetic parameters were as follows: maximal velocity = 0.757 +/- 0.021 umol/mg protein/min, Hill coefficient = 10.90 +/- 2.80, and substrate concentration at which half-maximal velocity of a Hill enzyme is achieved = 33.35 +/- 0.55 uM. Based on these results, the calculated in vitro intrinsic clearance for Artepillin C was 16.63 +/- 1.52 uL/min/mg protein. The in vitro metabolism assay conducted on the human model did not fit any enzymatic kinetic model. Two novel metabolites were formed in both mammal microsomal models and their chemical structures were elucidated for the first time. The main human cytochrome P450 isoforms involved in Artepillin C metabolism had been identified, and the results suggest a majority contribution of CYP2E1 and CYP2C9 in the formation of the two metabolites. PMID- 28073120 TI - Nano-Pelargonidin Protects Hyperglycemic-Induced L6 Cells against Mitochondrial Dysfunction. AB - Nano-encapsulation of several natural products has become an important tool in enhancing the bioavailability of some modern drugs against many diseases. Pelargonidin is an anthocyanidin found in many fruits and vegetables. Pelargonidin is loaded with poly-lactide-co-glycolic-acid, a non-toxic biodegradable polymer, to produce nano-pelargonidin. Size, morphology, zeta potential, and planar uniformity of formulated nano-pelargonidin were determined by atomic force microscopy and dynamic light scattering. The time required for cellular entry, folds of nano-pelargonidin, and drug encapsulation efficiency of poly-lactide-co-glycolic-acid were also ascertained. Relative functional efficacy of nano-pelargonidin and pelargonidin was evaluated by examining markers such as pyruvate kinase, glucokinase, calcium ion level, ATP/ADP ratio, mitochondrial membrane potential, cytosolic release of mitochondrial cytochrome-c, and structural analysis of mitochondrial DNA in controlled and experimental sets of alloxan-induced hyperglycemic L6 cells. Expressions of mitochondrial apoptotic proteins, such as bcl2 and caspase3, and glucose signalling cascades, such as GLUT4, IRS1, IRS2, and PI3, were analyzed. Nano-pelargonidin at a nearly 10-fold reduced dose significantly enhanced protection, presumably due to its smaller size, ability of faster entry, and drug delivery at target-specific sites. Thus, nano-pelargonidin can be used in formulating protective drugs for therapeutic management of mitochondrial dysfunction often encountered in diabetic conditions. PMID- 28073119 TI - In Vitro Inhibition of Human CYP450s 1A2, 2C9, 3A4/5, 2D6 and 2E1 by Grandisin. AB - Grandisin, a lignan isolated from many species of plants, such as Virola surinamensis, is a potential drug candidate due to its biological properties, highlighted by its antitumor and trypanocidal activities. In this study, the inhibitory effects of grandisin on the activities of human cytochrome P450 enzymes were investigated by using human liver microsomes. Results showed that grandisin is a competitive inhibitor of CYP2C9 and a competitive and mechanism based inhibitor of CYP3A4/5. The apparent Ki value for CYP2C9 was 50.60 uM and those for CYP3A4/5 were 48.71 uM and 31.25 uM using two different probe substrates, nifedipine and midazolam, respectively. The apparent KI, kinact, and kinact/KI ratio for the mechanism-based inhibition of CYP3A4/5 were 6.40 uM, 0.037 min-1, and 5.78 mL . min-1 umol-1, respectively, by examining nifedipine oxidation, and 31.53 uM, 0.049 min-1, and 1.55 mL . min-1 umol-1, respectively, by examining midazolam 1'-hydroxylation. These apparent kinact/KI values were comparable to or even higher than those for several therapeutic drugs that act as mechanism-based inhibitors of CYP3A4/5. CYP1A2 and CYP2D6 activities, in turn, were not substantially inhibited by grandisin (IC50 > 200 uM and 100 uM, respectively). In contrast, from a concentration of 4 uM, grandisin significantly stimulated CYP2E1 activity. These results improve the prediction of grandisin drug interactions, suggesting that the risk of interactions with drugs metabolized by CYP3A4/5 and CYP2E1 cannot be overlooked. PMID- 28073121 TI - Small bowel obstruction caused by a migrated Obalon gastric bariatric balloon: nonsurgical management by antegrade double-balloon panenteroscopy. PMID- 28073122 TI - Central MU-Opioidergic System Activation Evoked by Heavy and Severe-Intensity Cycling Exercise in Humans: a Pilot Study Using Positron Emission Tomography with 11C-Carfentanil. AB - The central opioid receptor system likely contributes to the mechanism underlying the changes in affect elicited by exercise. Our aim was to use positron emission tomography (PET) to test whether exercise intensity influences activation of the MU-opioid receptor system in the brain, and whether changes in opioid receptor activation correlate with exercise-induced changes in affect. 7 healthy young male subjects (23+/-2 years) performed 20-min constant-load cycling exercises at heavy (ExH) and severe-intensity (ExS), and PET was performed using [11C]carfentanil as a tracer before and after each exercise. Exercise elicited the MU-opioidergic system activation in the large areas of the limbic system, particularly in the insular cortex, and cerebellum. Of note, deactivation of the MU-opioidergic system in the pituitary gland was identified as a specific finding in ExS, which evoked a distinctive sensation of fatigue. Within these brain areas, MU-opioid receptor activation correlated positively with increased positive affect (R2=0.67-0.95) in ExH and negative affect (R2=0.63-0.77) in ExS. These findings suggest that central MU-opioidergic neurotransmission evoked by continuous exercise is discriminated by work intensity. Notably, we also observed a possible contribution of the central MU-opioidergic system to the development of the sensation of fatigue during exhaustive exercise. PMID- 28073123 TI - Effects of Precooling on 30-km Cycling Performance and Pacing in Hot and Temperate Environments. AB - This study examined the effects of precooling on performance and pacing during 30 km cycling exercise in hot and temperate environments. 8 trained male cyclists performed 4 trials involving either cooling (PRECTEMP and PRECHOT) or no-cooling interventions (TEMP and HOT) prior to a 30-km self-paced cycling exercise in either a hot (35 degrees C, 68% relative humidity) or temperate environment (24 degrees C, 68% relative humidity). Exercise time was longer in HOT (60.62+/-3.47 min) than in TEMP (58.28+/-3.30 min; P<0.001), and precooling attenuated this thermal strain performance impairment (PRECHOT 58.28+/-3.30 min; P=0.048), but it was still impaired compared with TEMP (P=0.02). Exercise performance in PRECTEMP (54.58+/-4.35 min) was no different from TEMP. Initial power output was sustained until the end of the exercise in both TEMP and PRECTEMP, but was reduced from the 12th km until the end of the trial in HOT (P<0.05). This reduction was delayed by precooling because power output was reduced only after the 20th km during PRECHOT (P<0.05). Heart rate was similar in all conditions throughout almost the entire exercise, suggesting the maintenance of similar relative intensities. In conclusion, precooling was effective in attenuating, but not completely reversing thermal strain performance impairment and offered no ergogenic effect in the temperate environment. PMID- 28073124 TI - The Effects of Blood Glucose Regulation in Omentin-1 Levels among Diabetic Patients. AB - Objectives: Omentin-1, an adipocytokine that increases the insulin sensitivity, has been determined to be reduced in patients with insulin resistance, impaired glucose tolerance, and Type-2 diabetes mellitus. In this study, we have investigated the alterations in Omentin-1 levels with the blood glucose regulation in diabetic patients having poor glycemic control. By this way, we aimed to determine the role of Omentin-1 as a marker in follow-up and monitoring progression of diabetes. Methods: Totally 58 patients with type 2 diabetes mellitus, older than 18 years of age who were having poor glycemic control (HbA1c>=9) were included in this study. In the first visit, all clinical and biochemical parameters of patients were recorded. After baseline evaluation, the patients were advised life style changes, and their medical treatment was determined individually according to the recommendations of the American Diabetes Association guidelines. At the end of the third month patients were re-evaluated. Serum Omentin-1 levels were measured with ELISA. Results: In patients using only oral antidiabetic agents, after exchanging the treatment with insulin, on 3rd month of treatment, there was a significant decrease in serum C-peptide and Omentin-1 levels compared with the initial results (p=0.034, p=0.048, respectively). On the other hand, in patients using insulin treatment from the beginning of the study, there was not any significant alterations in serum C peptide or Omentin-1 levels compared with the initial results (p>0.05). Conclusions: Serum Omentin-1 levels may change with insulin and metformin treatments in Type-2 diabetic patients. In patients with poor glycemic control, Omentin-1 levels do not change with the regulation of blood glucose levels. A decrease in Omentin-1 and C-peptide levels has been determined after the initiation of insulin therapy. This suggests that, Omentin-1 levels are closely associated with the endogenous insulin reserve and may be used in follow-up of patients. PMID- 28073125 TI - Osteocalcin Improves Metabolic Profiles, Body Composition and Arterial Stiffening in an Induced Diabetic Rat Model. AB - Recent studies have demonstrated the benefits of osteocalcin (OCN) on glucose homeostasis and metabolic dysregulation. However, its role in body composition and vascular function remains unknown. This study was designed to examine changes in metabolic parameters and body composition as well as arterial stiffness after OCN treatment in type 2 diabetic rats. Adult male Sprague Dawley (SD) rats were fed chow or high fat diet (HFD) for 8 weeks, and then diabetes was induced with an injection of low-dose streptozotocin (STZ) and treated daily with intraperitoneal injections of OCN for 12 weeks. Our data showed that OCN treatment improved glucose homeostasis and lipid metabolism. Further analysis revealed that OCN treatment resulted in increased insulin sensitivity. In addition, untreated diabetic rats experienced significant weight loss, whereas OCN-treated rats better maintained body weight (300.75+/-38.14 g vs. 335.50+/ 23.70, p=0.005). OCN also changed body composition, as evidenced by reduced body fat mass, specifically abdominal fat mass. OCN-treated diabetic rats also demonstrated decreased pulse-wave velocity, indicating of improved arterial stiffness. Taken together, our findings in the current study revealed that OCN therapy prevents arteriosclerosis in an induced diabetic rat model by exerting beneficial effects on glucose levels, insulin sensitivity, lipid metabolites, and body composition changes. PMID- 28073126 TI - Brown and White Adipose Tissue Expression of IL6, UCP1 and SIRT1 are Associated with Alterations in Clinical, Metabolic and Anthropometric Parameters in Obese Humans. AB - Aim: The present study aimed to analyze the expression of IL6, UCP1 and SIRT1 in adipose tissue (WAT and BAT) in association to clinical, metabolic and anthropometric parameters in obese humans. Methods: WAT and BAT samples from obese patients (n=27) were collected. IL6, UCP1 and SIRT1 markers were measured by qRT-PCR. The association between IL6, UCP1 and SIRT1 mRNA expression and anthropometric and clinical parameters were evaluated, using appropriate statistical tests. Results: Our results demonstrated that high levels of IL6 are associated with altered glucose levels in the WAT (p=0.01). In contrast, high levels of IL6 in the BAT were associated with decreased % fat (p=0.01) and fat weight (p=0.02) and increased mVO2 (p=0.02) and VO2 (p=0.02). For UCP1, a higher expression in the BAT was observed when compared to the WAT (p=0.0001). This gene expression was associated with lower values of BMI (p=0.03), % fat (P=0.02) and fat weight (P=0.02) and increased mVO2 (p=0.041) and VO2 (p=0.001). In the WAT, decreased levels of SIRT1 were associated with increased fat weight (p=0.02); in the BAT, associations were found for % fat (p=0.018) and mVO2 (p=0.03). Conclusion: These results reveal different characteristics in the biological actions between WAT and BAT in obese humans. Increased levels of IL6, UCP1 and SIRT1 in the BAT were associated with metabolic parameters improvements. PMID- 28073127 TI - Long-term Consequences of Congenital Adrenal Hyperplasia due to Classic 21 hydroxylase Deficiency in Adolescents and Adults. AB - Background The management of congenital adrenal hyperplasia (CAH) from pediatric to adulthood is challenging to achieve optimal growth and puberty. This study characterizes the clinical outcomes of 21-hydroxylase deficiency. Methods 53 CAH patients were included (33 females, 15 and 18 patients with the salt-wasting [SW] and simple-virilizing [SV] forms; and 20 males, 16 and 4 patients with the SW and SV forms). We reviewed growth parameters, pubertal status, and long-term morbidities. Results In females, the age at pubertal onset and pubarche was 9.6+/ 0.9 and 10.5+/-1.9 years, respectively, which was significantly earlier in the SV form (p=0.005). In males, the ages at pubertal onset and pubarche were 10.1+/-2.0 and 10.7+/-2.5 years, respectively, which were not significantly different between the groups. Forty patients reached adult height: -2.1+/-1.6 SDS in males and -1.5+/-1.1 SDS in females. Obesity and overweight was significantly common in adult patients. Testicular adrenal rest tumors were found in 4 SW males. 5 patients had adrenal tumor including adenoma, adenocarcinoma, or myelolipoma. Conclusions Reduced adult height and obesity/overweight are prevalent in adulthood. Adolescents and adults with 21-hydroxylase deficiency should be monitored for long-term consequences. PMID- 28073129 TI - Alternative Treatment Strategies in Women Poorly Tolerating Moderate Doses of Bromocriptine. AB - Background: Metformin as well as dopaminergic agents exert a beneficial effect on glucose and lipid metabolism, often impaired in patients with hyperprolactinemia. Objective: The aim of this study was to compare metabolic- and prolactin-lowering effects of low-dose bromocriptine/metformin combination therapy and cabergoline in patients with elevated prolactin levels. Methods: The study included 27 women with hyperprolactinemia and impaired glucose tolerance who were treated with moderate doses of bromocriptine but experienced adverse effects of this treatment. In 12 of these patients bromocriptine was replaced with cabergoline (group A), while the remaining ones continued treatment with bromocriptine, the dose of which was halved, and administered together with metformin (group B). Plasma lipids, glucose homeostasis markers, as well as serum levels of prolactin, thyrotropin and insulin-like growth factor-1 (IGF-1) were assessed before and after 4 months of metformin treatment. Results: Both groups did not differ in baseline levels of plasma glucose and lipids, in insulin sensitivity, as well as in circulating levels of all measured hormones. All patients from group A and 12 patients from group B completed the study. Cabergoline reduced prolactin levels, while no effect on plasma prolactin was found in group B. Neither cabergoline nor bromocriptine plus metformin affected circulating levels of thyrotropin and IGF 1. Both treatment options, particularly low-dose bromocriptine plus metformin, improved glucose and lipid homeostasis. Conclusions: Low-dose bromocriptine combined with metformin may be an interesting alternative to cabergoline in patients with mild hyperprolactinemia and early glucose metabolism abnormalities, in whom moderate doses of bromocriptine are poorly tolerated. PMID- 28073128 TI - The Effect of Vitamin D on Thyroid Autoimmunity in Levothyroxine-Treated Women with Hashimoto's Thyroiditis and Normal Vitamin D Status. AB - Background: Low vitamin D status is associated with autoimmune thyroid disease. Oral vitamin D supplementation was found to reduce titers of thyroid antibodies in levothyroxine-treated women with postpartum thyroiditis and low vitamin D status. Methods: The study included 34 women with Hashimoto's thyroiditis and normal vitamin D status (serum 25-hydroxyvitamin D levels above 30 ng/mL) who had been treated for at least 6 months with levothyroxine. On the basis of patient preference, women were divided into 2 groups, receiving (n=18) or not receiving (n=16) oral vitamin D preparations (2000 IU daily). Serum levels of thyrotropin, free thyroxine, free triiodothyronine and 25-hydroxyvitamin D, as well as titers of thyroid peroxidase and thyroglobulin antibodies were measured at the beginning of the study and 6 months later. Results: There were no significant differences in baseline values between both study groups. 25-hydroxyvitamin D levels inversely correlated with titers of thyroid antibodies. No changes in hypothalamic-pituitary-thyroid axis activity and thyroid antibody titers were observed in vitamin-naive patients. Vitamin D increased serum levels of 25 hydroxyvitamin D, as well as reduced titers of thyroid antibodies. This effect was more pronounced for thyroid peroxidase than for thyroglobulin antibodies and correlated with their baseline titers. Conclusions: Vitamin D preparations may reduce thyroid autoimmunity in levothyroxine-treated women with Hashimoto's thyroiditis and normal vitamin D status. PMID- 28073130 TI - Testosterone Plasma Concentration is Associated with Insulin Resistance in Male Hypertensive Patients. AB - Background: Low testosterone levels are a common finding among men with Type 2 Diabetes Mellitus (T2DM) and are inversely related to insulin resistance. Whether this relationship holds true in patients with hypertension, but normal glucose tolerance or prediabetes, is unclear. Methods: We recruited 87 male outpatients with essential arterial hypertension, aged 35-70 years. Anthropometric data were collected, an Oral Glucose Tolerance Test (OGTT) performed, and the homeostasis model assessment of insulin resistance (HOMA-IR) score calculated. Follicle Stimulating Hormone, Luteinizing Hormone, testosterone, Sex Hormone-Binding Globulin and free-testosterone were measured. The concentrations of sex hormones were compared between normoglucotolerant, prediabetic and diabetic patients. Non parametric tests were applied as appropriate to verify differences among groups, while multiple linear regression was used to predict the variability of testosterone and free-testosterone. Results: Total serum testosterone concentration was significantly lower in T2DM in comparison to normoglucotolerant subjects (p<0.01) and was inversely related to body mass index (r=- 0.25, p<0.01), waist circumference (r=- 0.27, p<0.01), pre and post-OGTT plasma glucose (r=- 0.4, p<0.0001 and r=- 0.29, p<0.01, respectively), pre and post-OGTT plasma insulin (r=- 0.42, p<0.0001 and r=- 0.42, p<0.0001) and HOMA-IR (r=- 0.46, p<0.0001). Similar associations were observed for free testosterone; HOMA-IR was related to testosterone and free-testosterone even in patients with normal glucose tolerance (r=- 0.47, p<0.01 and r=- 0.34, p<0.05, respectively). At multivariate analysis HOMA-IR was the only variable associated to testosterone (p<0.001) and free-testosterone (p<0.05) plasma concentration. Conclusions: In males with hypertension, the link between insulin sensitivity and hypothalamic pituitary-gonadal axis is maintained along the entire spectrum of glucose tolerance. PMID- 28073131 TI - Evaluation of Glutathione Peroxidase and KCNJ11 Gene Polymorphisms in Patients with New Onset Diabetes Mellitus After Renal Transplantation. AB - Introduction Genetic mutations such as C599T polymorphism in glutathione peroxidase [GPX1] gene and polymorphisms in potassium channel (KCNJ11) genes have recently been proposed in the etiopathogenesis of new onset diabetes mellitus after renal transplantation (NODAT). We aimed to examine the association of GPX1 and KCNJ11 polymorphisms in NODAT. Materials and Methods This is a monocenter case-control study with a total of 118 renal transplant recipients who were divided into 2 groups; NODAT and normal glucose tolerance. Relation of GPX1 and KCNJ11 polymorphisms were investigated between these groups. PCR-RFLP method was used for genotyping of polymorphisms in the GPX1 (rs1050450) and KCNJ11 (rs1805127) genes. Two alleles were visualized for each gene (C/T for GPX1 and A/G for KCNJ11). Results NODAT was correlated with age at transplantation (p<0.001, r=0.380), post-transplant systolic blood pressure (BP) (p=0.02, r=0.211), post-transplant non-HDL cholesterol levels (p=0.01, r=0.803), degree of weight change at the end of the first year (p=0.01, r=0.471), presence of pre transplant hypertension (HT) (p=0.02, r=0.201), family history of diabetes (p=0.01, r=0.29) and dyslipidemia (p=0.012, r=0.362). GPX1 polymorphism of TT (mutant) allele was significantly more frequent in patients with NODAT (p<0.001, r=0.396) independent from other diabetogenic risk factors. KCNJ11 polymorphisms were similar in both groups and did not show any significant association with NODAT (p=0.10). Conclusions In addition to several diabetogenic risk factors, C599T polymorphisms in GPX1 gene might also contribute to the development of NODAT. Further studies on larger patient series are necessary in order to reach definitive suggestions. PMID- 28073132 TI - Hypothyroidism in Cancer Patients on Immune Checkpoint Inhibitors with anti-PD1 Agents: Insights on Underlying Mechanisms. AB - Background: Immune therapy using monoclonal antibodies against cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death 1 receptor (PD 1) for various cancers have been reported to cause thyroid dysfunction. Little is known, however, about the underlying pathogenic mechanisms and the course of hypothyroidism that subsequently develops. In this report, we use the change in thyroglobulin and thyroid antibody levels in patients on immune therapy who develop hypothyroidism to better understand its pathogenesis as well as examine the status of hypothyroidism in the long term. Methods: We report a case series of 10 patients who developed hypothyroidism after initiation of immune therapy (either anti-PD-1 alone or in combination with anti-CTLA-4). Available thyroid antibodies including anti-thyroglobulin (anti-Tg), anti-thyroid peroxidase (anti TPO), and thyroid stimulating immunoglobulin (TSI) were noted during the initial thyroiditis phase as well as the hypothyroid phase. Persistence or remission of hypothyroidism was noted at 6 months. Summary: During the thyroiditis phase, 50% of the patients had elevated Tg titers, 40% had elevated anti-Tg, and 40% had elevated TSI. All of these titers decreased during the hypothyroid phase. Permanent hypothyroidism was noted in 80% of the cases. Conclusion: Hypothyroidism following initiation of immune therapy has immunologic and non immunologic mediated mechanisms and is likely to be persistent. PMID- 28073134 TI - ? PMID- 28073133 TI - Diabetes Mellitus and Bone Metabolism. AB - Diabetes mellitus and bone metabolism affect mesenchymal tissues and have numerous epidemiological and pathophysiological associations in common. Diabetes mellitus affects bone metabolism and increases fracture risk. The pathophysiological mechanims how type 1 and type 2 diabetes impair bone metabolism and bone strength may differ which is outlined in this review. Direct metabolic effects in additon to centrally controlled endocrine loops exert suppressive effects on bone formation and may also stimulate bone Resorption. Decreased bone formation in combination with increased bone resorption strongly increases fracture risk. PMID- 28073135 TI - ? AB - The DGVS aims to develop high quality clinical guidelines. Version 2 of the guideline program takes up new methodical demands to optimise the development process. PMID- 28073137 TI - [Relapse after withdrawal from anti-TNF therapy for inflammatory bowel disease]. PMID- 28073136 TI - [Proton pump inhibitor - side effects and complications of long-term proton pump inhibitor administration]. AB - Proton Pump Inhibitors are among the most common drugs taken. The indication is for treatment of heartburn, reflux disease, prophylaxis and treatment of peptic ulcers, in combination with NSAIDs and steroids as well as H. pylori-eradication. PPI's are widely used, even with non-specific symptoms. This certainly has to do with good tolerability and a previously considered low side effect profile. At the moment, there is growing evidence that the long-term intake of PPI's may not be as safe as assumed. In addition to interactions with some drugs, including platelet aggregation inhibitors, recent studies have shown an increased risk of myocardial infarction, interstitial nephritis, chronic renal injury, infections, vitamin deficiencies and electrolyte shifts as well developing dementia. PMID- 28073138 TI - [Long Term Complications Due to Polyethylene Wear in Total Knee Arthroplasty: a Case Report]. AB - This is the case of an 84-year-old patient 18 years after total knee replacement. Regular follow-up examinations did not take place beyond 10 years of implantation, so that subsequent wear of the polyethylene insert was not detected. The patient presented because of knee pain, swelling of the calf, and a drop foot. Examination showed a large ganglion with pressure on the peroneal nerve, and a loose knee replacement with severe inlay wear and extensive osteolysis around the tibial and femoral implants. This rare case demonstrates the importance of regular clinical and radiological follow-up examinations after total joint replacements, particularly in the long term. PMID- 28073140 TI - [Clinical and Radiological Results after Anterior Cervical Corpectomy with Cage Fusion - a Retrospective Comparison of PEEK vs. Titanium Cages]. AB - Background Anterior cervical corpectomy and fusion (ACCF) has become a standard procedure for patients with spondylotic myelopathy due to multisegmental stenosis of the cervical canal. Beside the fusion technique using autogenous bone grafts, synthetic cages have been increasingly used in recent years. Published information on the clinical and radiological results of different cage materials for ACCF is still limited. The study presented here is the largest series to date reporting clinical and radiological outcomes and complication rates after one- to three-level ACCF using structural polyetheretherketone (PEEK) or titanium cages augmented by anterior plate-screw osteosynthesis. Materials and Methods Retrospective comparative study on 126 patients after cage ACCF using modular PEEK (n = 101) or distractable titanium (n = 25) cages with a minimum follow-up of 6 months. The numbers of hardware failures and implant-related surgical revisions were determined. The rate of subsidence and fusion and the course of lordotic alignment (segmental and regional Cobb's angles) were analysed. Neck Disability Index (NDI) and European Myelopathy Score (EMS) were assessed. Results Significantly greater number of screw and cage complications were detected in the titanium cage group (36 vs. 7.9 % and 64 vs. 36.6 %, respectively). Non significant trend to a higher rate of implant related revision rate in the titanium cage group (16 vs. 2.97 %). Significantly greater rate of grade I or II fusion in the PEEK cage group after 6 months (82 vs. 52 %). NDI, EMS and lordotic alignment improved significantly in both groups. There were neither significant differences between the two groups nor significant correlations between these clinico-radiological parameters and the cage material. Partial correlations performed with control of parameters showing inhomogenous distribution (patient age, fusion distance, rate of multilevel corpectomy and the rate of intraoperative segmental overdistraction) showed no significant correlations for any of the clinical or radiological outcome parameters and the complications or revisions to the cage material. Conclusion Cages are a safe and effective alternative to autogenous bone graft for ACCF. A significant improvement in clinical and radiological parameters can be achieved with both titanium and PEEK implants. Significant differences between the two cage material groups or significant correlations of clinico-radiological outcome and cage material were not proven. Moreover there is no evidence in the literature for clinical advantages of one special cage material, to date. Therefore further prospective randomised evaluation of different fusion techniques in ACCF is still necessary. PMID- 28073139 TI - [Influence of Comorbidities on Revision Rate within the First Year after Primary Total Hip Arthroplasty]. AB - : Background Total hip arthroplasty (THA) is very frequently performed. Despite low complication rates, revisions play an important clinical and economical role. The aim of this study was to identify comorbid diseases of patients undergoing primary THA and their potential influence on the survival of hip replacements. Patients/Material and Methods A total of 867 patients were included in this retrospective study. All revisions were reviewed that took place at our hospital within one year of primary implantation of THA. Comorbid diseases were detected by administrative data, using the Elixhauser definition, which includes thirty diseases. The Cox regression model and Fisher's exact test were used to examine correlations between comorbidities and risk of revision. Results 41 Patients required re-operation within the first year of surgery. The presence of one or more of the analysed comorbidities was associated with a greater risk of revision. Deficiency anemia, obesity, drug abuse, alcohol abuse, fluid and electrolyte disorders and peripheral vascular disorders were associated with increased risk of revision (p < 0.05 for all comparisons). CONCLUSION: The total number of comorbidities and specific comorbid diseases was independently associated with an increased risk of re-operation within the first year of total hip arthroplasty. This information could be helpful in pre- and post-operative risk adjustment and patient selection. PMID- 28073141 TI - [Current Recommendations for the Therapy of Dislocated Talus Fractures Weber and Marti Type IV - Literature Research]. AB - Introduction Talar dislocation fractures of type IV (Marti and Weber) are extremely rare injuries with special challenges to the surgeon and poor results. Due to their low incidence and the sparse literature, it is unclear what is the optimal treatment and how complications can be minimised. Material and Methods A literature research was carried out using the online medical database "PubMed". The findings of the literature were then applied to a clinical case of type IV talar dislocation fracture (Marti and Weber). Results Modern osteosynthesis with generous and multiple access paths is to be preferred to the previously prioritised methods of talectomy and arthrodesis. Priority is put on the fastest possible reposition of the fracture, while sparing the soft tissue and the conditions of vascularisation. It can be assumed that with increasing degree of dislocation the risk of necrosis of the talus rises too, but this does not necessarily correlate with the clinical outcome. Conclusions In totally dislocated fractures of the talus, the focus is on prompt reposition and sufficient osteosynthetic supply. Nevertheless, frequent complications have to be expected. Medial explantation, which is described in the clinical example and lateral re-implantation of the talar body have never been described before in the literature and were an encouraging development. PMID- 28073142 TI - Cardio-Oncology: Progress in Diagnosis and Treatment of Cardiac Dysfunction. PMID- 28073143 TI - Demyelinating polyneuropathy in a case of anti-LGI1 encephalitis. PMID- 28073144 TI - Food Effect Studies for Oncology Drug Products. AB - Oral antineoplastic agents provide convenience to the patient, but are accompanied by challenges distinct from parenteral cancer treatment. Challenges include a more complex pharmacokinetic profile, with food influencing the absorption of many agents. Standards for evaluating and labeling prandial implications on oral chemotherapy are inconsistent; studies to determine food effects should be conducted early, and potentially often, during drug development with standardization on how rational fasting or fed recommendations are presented in the package insert (PI). PMID- 28073145 TI - Does partial muscle reinnervation preserve future re-innervation potential? AB - INTRODUCTION: Late revision nerve surgery for incomplete motor recovery due to partial reinnervation would improve muscle function if all muscle fibers were protected from developing denervation atrophy. METHODS: Sixty immature Sprague Dawley rats underwent the following tibial nerve manipulations (n = 15/group): group A, partial denervation (two thirds of nerve resected and the remaining one third crushed), revision repair at 8 months; group B, partial denervation; group C, complete denervation, immediate reconstruction; group D, complete denervation, reconstruction at 8 months; and group E, control. Final testing at 11 months included muscle force, weight, and histology. RESULTS: Muscle weight was significantly (P < 0.05) different among all groups (highest to lowest: E > B > C > A > D), and force was significantly lower in groups A and D compared with E. Muscle fiber cross-sectional area was statistically smaller in group A than in groups B, C, or E. DISCUSSION: Partial reinnervation still allowed substantial muscle recovery, but it did not preserve the non-innervated muscle fibers. Muscle Nerve 56: 1143-1148, 2017. PMID- 28073146 TI - Value-based care in hepatology. AB - The migration from legacy fee-for-service reimbursement to payments linked to high-value health care is accelerating in the United States because of new legislation and redesign of payments from the Centers for Medicare and Medicaid Services. Because patients with chronic diseases account for substantial use of health care resources, payers and health systems are focusing on maximizing the value of care for these patients. Because chronic liver diseases impose a major health burden worldwide affecting the health and lives of many individuals and families as well as substantial costs for individuals and payers, hepatologists must understand how they can improve their practices. Hepatologists practice a high-intensity cognitive subspecialty, using complex and costly procedures and medications. High-value patient care requires multidisciplinary coordination, labor-intensive support for critically ill patients, and effective chronic disease management. Under current fee-for-service reimbursement, patient values, medical success, and financial success can all be misaligned. Many current attempts to link health outcomes to reimbursement are based on compliance with process measures, with less emphasis on outcomes that matter most to patients, thus slowing transformation to higher-value team-based care. Outcome measures that reflect the entire cycle of care are needed to assist both clinicians and administrators in improving the quality and value of care. A comprehensive set of outcome measures for liver diseases is not currently available. Numerous researchers now are attempting to fill this gap by devising and testing outcome indicators and patient-reported outcomes for the major liver conditions. These indicators will provide tools to implement a value-based approach for patients with chronic liver diseases to compare results and value of care between referral centers, to perform health technology assessment, and to guide decision-making processes for health authorities. This review sets the groundwork for implementing a value-based, patient-centered approach to chronic liver diseases within a health system. (Hepatology 2017;65:1749-1755). PMID- 28073147 TI - Treating nonalcoholic steatohepatitis in children: Not a cinch task. PMID- 28073148 TI - European Medicines Agency Perspective on Oncology Study Design for Marketing Authorization and Beyond. AB - In the development of highly active anticancer drugs, the European situation may be viewed as paradoxical. Limited data may support marketing authorization, but may be insufficient for the health economic appraisal needed for reimbursement and market uptake. To achieve this, conventional confirmatory studies may be needed. For products of special interest, studies aimed at optimizing cost effectiveness may be warranted. Efficient designs of studies to meet these objectives constitute challenges to all stakeholders. PMID- 28073149 TI - Smoking at the time of diagnosis and mortality in cancer patients: What benefit does the quitter gain? AB - Few studies have examined the association between smoking behavior (especially quitters) at the time of diagnosis and mortality among cancer patients. Our objective was to examine the benefits of quitting on all-cause mortality among cancer patients. 30,658 eligible cancer patients diagnosed between 1985 and 2009, identified by a hospital-based cancer registry in Japan, were followed up for up to 10 years. We evaluated smoking behavior at cancer diagnosis (especially recent quitters vs. current smokers) in association with all-cause mortality using Cox proportional hazards models and covariates-adjusted survival curves. Risk of death was estimated to be reduced by 11% in recent quitters compared with current smokers. According to adjusted survival curves, median survival time was 8.25 years for recent quitters versus 7.18 years for current smokers, indicating an absolute difference of 1.07 year for a median survivor. Similarly, never and former smokers had 18% and 16% lower risk of death with 1.90 years and 1.77 years gained, respectively, compared with current smokers. In addition to former and never smokers, recent quitters showed consistently higher survival rates than current smokers during the 10-year calendar period after diagnosis among cancer patients. Because recent quitters may be similar to patients who stop smoking shortly after cancer diagnosis in terms of smoking duration, the latter may be able to decrease their risk of death, suggesting that smoking cessation could be part of cancer care. PMID- 28073150 TI - The impact of overdiagnosis on the selection of efficient lung cancer screening strategies. AB - The U.S. Preventive Services Task Force (USPSTF) recently updated their national lung screening guidelines and recommended low-dose computed tomography (LDCT) for lung cancer (LC) screening through age 80. However, the risk of overdiagnosis among older populations is a concern. Using four comparative models from the Cancer Intervention and Surveillance Modeling Network, we evaluate the overdiagnosis of the screening program recommended by USPSTF in the U.S. 1950 birth cohort. We estimate the number of LC deaths averted by screening (D) per overdiagnosed case (O), yielding the ratio D/O, to quantify the trade-off between the harms and benefits of LDCT. We analyze 576 hypothetical screening strategies that vary by age, smoking, and screening frequency and evaluate efficient screening strategies that maximize the D/O ratio and other metrics including D and life-years gained (LYG) per overdiagnosed case. The estimated D/O ratio for the USPSTF screening program is 2.85 (model range: 1.5-4.5) in the 1950 birth cohort, implying LDCT can prevent ~3 LC deaths per overdiagnosed case. This D/O ratio increases by 22% when the program stops screening at an earlier age 75 instead of 80. Efficiency frontier analysis shows that while the most efficient screening strategies that maximize the mortality reduction (D) irrespective of overdiagnosis screen through age 80, screening strategies that stop at age 75 versus 80 produce greater efficiency in increasing life-years gained per overdiagnosed case. Given the risk of overdiagnosis with LC screening, the stopping age of screening merits further consideration when balancing benefits and harms. PMID- 28073153 TI - Reminder: RMSSD and SD1 are identical heart rate variability metrics. AB - Assessment of heart rate variability (HRV) is a common approach to examine cardiac autonomic nervous system modulation that has been employed in a variety of settings. Frequently, both the root mean square of successive differences (RMSSD) and SD1, which is a Poincare plot component, have been used to quantify short-term heart rate variability. It is not typically appreciated, however, that RMSSD and SD1 are identical metrics of HRV. As a reminder to clinicians and researchers who use and study HRV, we show both empirically and mathematically that RMSSD and SD1 are identical metrics. Because the homology between RMSSD and SD1 is not commonly known, the inclusion of both measures has been reported in many recent publications. The inappropriate use of such redundant data may affect the interpretation of HRV studies. Muscle Nerve 56: 674-678, 2017. PMID- 28073151 TI - CCBE1 mutation causing sclerosing cholangitis: Expanding the spectrum of lymphedema-cholestasis syndrome. AB - A 52-year old patient presented with lymphedema, protein loosing enteropathy, and sclerosing cholangitis and was diagnosed with lymphedema cholestasis syndrome (LCS). Cholangioscopy revealed dilated lymphatic vessels obstructing the bile duct and compound heterozygosity for collagen and calcium-binding epidermal growth factor domain-containing protein 1 (CCBE1) mutations was identified defining a novel type of LCS. (Hepatology 2017;66:286-288). PMID- 28073154 TI - Volume 100 but how old is Clinical and Experimental Optometry? PMID- 28073152 TI - Characterizing Pharmacogenomic-Guided Medication Use With a Clinical Data Repository. AB - The extent to which pharmacogenomic-guided medication use has been adopted in various health systems is unclear. To assess the uptake of pharmacogenomic-guided medication use, we determined its frequency across our health system, which does not have a structured testing program. Using a multisite clinical data repository, we identified adult patients' first prescribed medications between January 2011 and December 2013 and investigated the frequency of germline and somatic pharmacogenomic testing, by the Pharmacogenomics Knowledgebase level of the US Food and Drug Administration label information. There were 268,262 medication orders for drugs with germline pharmacogenomic testing information in their drug labels. Pharmacogenomic testing was detected for 1.5% (129/8,718) of medication orders with recommended or required testing. Of the 3,817 medication orders associated with somatic pharmacogenomic testing information in their drug labels, 20% (372/1,819) of required tests were detected. The low rates of detectable pharmacogenomic testing suggest that structured testing programs are required to achieve the success of precision medicine. PMID- 28073155 TI - Differential effects of myostatin deficiency on motor and sensory axons. AB - INTRODUCTION: Deletion of myostatin in mice (MSTN-/- ) alters structural properties of peripheral axons. However, properties like axon diameter and myelin thickness were analyzed in mixed nerves, so it is unclear whether loss of myostatin affects motor, sensory, or both types of axons. METHODS: Using the MSTN /- mouse model, we analyzed the effects of increasing the number of muscle fibers on axon diameter, myelin thickness, and internode length in motor and sensory axons. RESULTS: Axon diameter and myelin thickness were increased in motor axons of MSTN-/- mice without affecting internode length or axon number. The number of sensory axons was increased without affecting their structural properties. DISCUSSION: These results suggest that motor and sensory axons establish structural properties by independent mechanisms. Moreover, in motor axons, instructive cues from the neuromuscular junction may play a role in co-regulating axon diameter and myelin thickness, whereas internode length is established independently. Muscle Nerve 56: E100-E107, 2017. PMID- 28073156 TI - Paraparetic Guillain-Barre syndrome: Non-demyelinating reversible conduction failure restricted to the lower limbs. PMID- 28073158 TI - Antimicrobial activity and mechanism of action of a thionin-like peptide from Capsicum annuum fruits and combinatorial treatment with fluconazole against Fusarium solani. AB - Many Fusarium species are able to cause severe infections in plants as well as in animals and humans. Therefore, the discovery of new antifungal agents is of paramount importance. CaThi belongs to the thionins, which are cationic peptides with low molecular weights (~5 kDa) that have toxic effects against various microorganisms. Herein, we study the mechanism of action of CaThi and its combinatory effect with fluconazole (FLC) against Fusarium solani. The mechanism of action of CaThi was studied by growth inhibition, viability, plasma membrane permeabilization, ROS induction, caspase activation, localization, and DNA binding capability, as assessed with Sytox green, DAB, FITC-VAD-FMK, CaThi-FITC, and gel shift assays. The combinatory effect of CaThi and FLC was assessed using a growth inhibition assay. Our results demonstrated that CaThi present a dose dependent activity and at the higher used concentration (50 ug mL-1 ) inhibits 83% of F. solani growth, prevents the formation of hyphae, permeabilizes membranes, induces endogenous H2 O2 , activates caspases, and localizes intracellularly. CaThi combined with FLC, at concentrations that alone do not inhibit F. solani, result in 100% death of F. solani when combined. The data presented in this study demonstrate that CaThi causes death of F. solani via apoptosis; an intracellular target may also be involved. Combined treatment using CaThi and FLC is a strong candidate for studies aimed at improved targeting of F. solani. This strategy is of particular interest because it minimizes selection of resistant microorganisms. PMID- 28073157 TI - Comparison of Parent, Peer, Psychiatric, and Cannabis Use Influences Across Stages of Offspring Alcohol Involvement: Evidence from the COGA Prospective Study. AB - BACKGROUND: All stages of development of alcohol use disorder (AUD) have not been equally studied. While initiation of drinking has been given considerable attention, other stages have not been as thoroughly investigated. It is not clear whether the same factors are associated consistently across early and late transitions in AUD involvement. High-risk family samples that are enriched for AUD vulnerability and transitions in AUD development offer an opportunity to examine influences across multiple stages of AUD development. METHODS: Data from adolescents and young adults from high-risk families were used to study 4 transitions in AUD development-time to first drink, first drink to first problem, first drink to first diagnosis, and first problem to first diagnosis. Cox modeling was used to compare associations of parental AUD, parental separation, peer substance use, offspring ever-use of cannabis, trauma exposures, and internalizing and externalizing psychopathology across transitions. RESULTS: Hazards of most transitions were elevated for those who had ever used cannabis, those who attributed substance use to their peers, those with externalizing disorders, and those with parents with AUD. Many risk factors were linked to early initiation of alcohol, particularly cannabis use. Internalizing disorders were associated with later stages. Nonassaultive trauma was associated only with early initiation; assaultive trauma was not associated with any transition. CONCLUSIONS: In this large, ethnically diverse sample of high-risk youth, significant influences across transitions were fairly consistent, with externalizing disorders and cannabis ever-use elevating the likelihood of each stage, and peer and parental (and especially maternal AUD) influences linked to initiation and some later stages. Finally, in light of the increasingly permissive legal and social stances toward cannabis in the United States, the marked elevations of all alcohol outcomes observed for cannabis use underscore the importance of studying the underpinnings of this relationship. PMID- 28073159 TI - Polymeric immunoglobulin receptor promotes tumor growth in hepatocellular carcinoma. AB - : Deregulation of the immune system is believed to contribute to cancer malignancy, which has led to recent therapeutic breakthroughs facilitating antitumor immunity. In a malignant setting, immunoglobulin receptors, which are fundamental components of the human immune system, fulfill paradoxical roles in cancer pathogenesis. This study describes a previously unrecognized pro-oncogenic function of polymeric immunoglobulin receptor (pIgR) in the promotion of cell transformation and proliferation. Mechanistically, pIgR overexpression is associated with YES proto-oncogene 1, Src family tyrosine kinase (Yes) activation, which is required for pIgR-induced oncogenic growth. Specifically, pIgR activates the Yes-DNAX-activating protein of 12 kDa-spleen tyrosine kinase Rac1/CDC42-MEK (extracellular signal-regulated kinase kinase)/ERK (extracellular signal-regulated kinase) cascade in an immunoreceptor tyrosine-based activating motif (ITAM)-dependent manner to promote cell transformation and tumor growth, although pIgR itself does not contain an ITAM sequence. Additionally, the combination of pIgR and phosphorylated Yes (p-Yes) levels serves as a prognostic biomarker for hepatitis B surface antigen-positive and early-stage hepatocellular carcinoma (HCC) patients. Moreover, pharmacological targeting of MEK/ERK or Yes represents a therapeutic option for the subgroup of patients with pIgR/p-Yes positive HCC based on our results with both cancer cell-line-based xenografts and primary patient-derived xenografts. CONCLUSION: Our findings reveal the molecular mechanism by which pIgR promotes cancer malignancy, suggest the clinical potential of targeting this pathway in HCC, and provide new insight into the oncogenic role of immunoglobulin receptors. (Hepatology 2017;65:1948-1962). PMID- 28073161 TI - The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells. AB - : The genetic polymorphism I148M of patatin-like phospholipase domain-containing 3 (PNPLA3) is robustly associated with hepatic steatosis and its progression to steatohepatitis, fibrosis, and cancer. Hepatic stellate cells (HSCs) are key players in the development of liver fibrosis, but the role of PNPLA3 and its variant I148M in this process is poorly understood. Here we analyzed the expression of PNPLA3 during human HSC activation and thereby explored how a PNPLA3 variant impacts hepatic fibrogenesis. We show that expression of PNPLA3 gene and protein increases during the early phases of activation and remains elevated in fully activated HSCs (P < 0.01). Knockdown of PNPLA3 significantly decreases the profibrogenic protein alpha-smooth muscle actin (P < 0.05). Primary human I148M HSCs displayed significantly higher expression and release of proinflammatory cytokines, such as chemokine (C-C motif) ligand 5 (P < 0.01) and granulocyte-macrophage colony-stimulating factor (P < 0.001), thus contributing to migration of immune cells (P < 0.05). Primary I148M HSCs showed reduced retinol (P < 0.001) but higher lipid droplet content (P < 0.001). In line with this, LX-2 cells stably overexpressing I148M showed augmented proliferation and migration, lower retinol, and abolished retinoid X receptor/retinoid A receptor transcriptional activities but more lipid droplets. Knockdown of I148M PNPLA3 (P < 0.001) also reduces chemokine (C-C motif) ligand 5 and collagen1alpha1 expression (P < 0.05). Notably, I148M cells display reduced peroxisome proliferator-activated receptor gamma transcriptional activity, and this effect was attributed to increased c-Jun N-terminal kinase, thereby inhibiting peroxisome proliferator-activated receptor gamma through serine 84 phosphorylation and promoting activator protein 1 transcription. Conversely, the c-Jun N-terminal kinase inhibitor SP600125 and the peroxisome proliferator activated receptor gamma agonist rosiglitazone decreased activator protein 1 promoter activity. CONCLUSIONS: These data indicate that PNPLA3 is required for HSC activation and that its genetic variant I148M potentiates the profibrogenic features of HSCs, providing a molecular mechanism for the higher risk of progression and severity of liver diseases conferred to patients carrying the I148M variant. (Hepatology 2017;65:1875-1890). PMID- 28073160 TI - Activation of the c-Jun N-terminal kinase pathway aggravates proteotoxicity of hepatic mutant Z alpha1-antitrypsin. AB - : Alpha1-antitrypsin deficiency is a genetic disease that can affect both the lung and the liver. The vast majority of patients harbor a mutation in the serine protease inhibitor 1A (SERPINA1) gene leading to a single amino acid substitution that results in an unfolded protein that is prone to polymerization. Alpha1 antitrypsin defciency-related liver disease is therefore caused by a gain-of function mechanism due to accumulation of the mutant Z alpha1-antitrypsin (ATZ) and is a key example of an disease mechanism induced by protein toxicity. Intracellular retention of ATZ triggers a complex injury cascade including apoptosis and other mechanisms, although several aspects of the disease pathogenesis are still unclear. We show that ATZ induces activation of c-Jun N terminal kinase (JNK) and c-Jun and that genetic ablation of JNK1 or JNK2 decreased ATZ levels in vivo by reducing c-Jun-mediated SERPINA1 gene expression. JNK activation was confirmed in livers of patients homozygous for the Z allele, with severe liver disease requiring hepatic transplantation. Treatment of patient derived induced pluripotent stem cell-hepatic cells with a JNK inhibitor reduced accumulation of ATZ. CONCLUSION: These data reveal that JNK is a key pathway in the disease pathogenesis and add new therapeutic entry points for liver disease caused by ATZ. (Hepatology 2017;65:1865-1874). PMID- 28073162 TI - Refractory subacute steatohepatitis after biliopancreatic diversion. PMID- 28073163 TI - Hydrocarbon-stapled lipopeptides exhibit selective antimicrobial activity. AB - Antimicrobial peptides (AMPs) occur widely in nature and have been studied for their therapeutic potential. AMPs are of interest due to the large number of possible chemical structural combinations using natural and unnatural amino acids, with varying effects on their biological activities. Using physicochemical properties from known naturally occurring amphipathic cationic AMPs, several hydrocarbon-stapled lipopeptides (HSLPs) were designed, synthesized, and tested for antimicrobial properties. Peptides were chemically modified by N-terminal acylation, C-terminal amidation, and some were hydrocarbon stapled by intramolecular olefin metathesis. The effects of peptide length, amphipathic character, and stapling on antimicrobial activity were tested against Escherichia coli, three species of Gram-positive bacteria (Staphylococcus aureus, Bacillus megaterium, and Enterococcus faecalis), and two strains of Candida albicans. Peptides were shown to disrupt liposomes of different phospholipid composition, as measured by leakage of a fluorescent compound from vesicles. Peptides with (S) 2-(4'-pentenyl)-alanine substituted for l-alanine in a reference peptide showed a marked increase in antimicrobial activity, hemolysis, and membrane disruption. Stapled peptides exhibited slightly higher antimicrobial potency; those with greatest hydrophobic character showed the greatest hemolysis and liposome leakage, but lower antimicrobial activity. The results support a model of HSLPs as membrane-disruptive AMPs with potent antimicrobial activity and relatively low hemolytic potential at biologically active peptide concentrations. PMID- 28073165 TI - Description of a new species of Hoolock gibbon (Primates: Hylobatidae) based on integrative taxonomy. AB - We describe a species of Hoolock gibbon (Primates: Hylobatidae) that is new to science from eastern Myanmar and southwestern China. The genus of hoolock gibbons comprises two previously described living species, the western (Hoolock hoolock) and eastern hoolock (H. leuconedys) gibbons, geographically isolated by the Chindwin River. We assessed the morphological and genetic characteristics of wild animals and museum specimens, and conducted multi-disciplinary analyses using mitochondrial genomic sequences, external morphology, and craniodental characters to evaluate the taxonomic status of the hoolock population in China. The results suggest that hoolocks distributed to the east of the Irrawaddy-Nmai Hka Rivers, which were previously assigned to H. leuconedys, are morphologically and genetically distinct from those to the west of the river, and should be recognized as a new species, the Gaoligong hoolock gibbon or skywalker hoolock gibbon (H. tianxing sp. nov.). We consider that the new species should be categorized as Endangered under IUCN criteria. The discovery of the new species focuses attention on the need for improved conservation of small apes, many of which are in danger of extinction in southern China and Southeast Asia. PMID- 28073164 TI - Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis in mice. AB - : Free cholesterol (FC) accumulation in the liver is an important pathogenic mechanism of nonalcoholic steatohepatitis (NASH). Plasmalogens, key structural components of the cell membrane, act as endogenous antioxidants and are primarily synthesized in the liver. However, the role of hepatic plasmalogens in metabolic liver disease is unclear. In this study, we found that hepatic levels of docosahexaenoic acid (DHA)-containing plasmalogens, expression of glyceronephosphate O-acyltransferase (Gnpat; the rate-limiting enzyme in plasmalogen biosynthesis), and expression of Pparalpha were lower in mice with NASH caused by accumulation of FC in the liver. Cyclodextrin-induced depletion of FC transactivated Delta-6 desaturase by increasing sterol regulatory element binding protein 2 expression in cultured hepatocytes. DHA, the major product of Delta-6 desaturase activation, activated GNPAT, thereby explaining the association between high hepatic FC and decreased Gnpat expression. Gnpat small interfering RNA treatment significantly decreased peroxisome proliferator activated receptor alpha (Pparalpha) expression in cultured hepatocytes. In addition to GNPAT, DHA activated PPARalpha and increased expression of Pparalpha and its target genes, suggesting that DHA in the DHA-containing plasmalogens contributed to activation of PPARalpha. Accordingly, administration of the plasmalogen precursor, alkyl glycerol (AG), prevented hepatic steatosis and NASH through a PPARalpha-dependent increase in fatty acid oxidation. Gnpat+/- mice were more susceptible to hepatic lipid accumulation and less responsive to the preventive effect of fluvastatin on NASH development, suggesting that endogenous plasmalogens prevent hepatic steatosis and NASH. CONCLUSION: Increased hepatic FC in animals with NASH decreased plasmalogens, thereby sensitizing animals to hepatocyte injury and NASH. Our findings uncover a novel link between hepatic FC and plasmalogen homeostasis through GNPAT regulation. Further study of AG or other agents that increase hepatic plasmalogen levels may identify novel therapeutic strategies against NASH. (Hepatology 2017;66:416-431). PMID- 28073166 TI - Low sugar nutrition policies and dental caries: A study of primary schools in South Auckland. AB - AIM: The study assessed whether a healthy food policy implemented in one school, Yendarra Primary, situated in a socio-economically deprived area of South Auckland, had improved student oral health by comparing dental caries levels with students of similar schools in the same region with no such policy. METHODS: Records of caries of the primary and adult teeth were obtained between 2007 and 2014 for children attending Yendarra, and were compared to those of eight other public schools in the area, with a similar demographic profile. Children were selected between the ages of 8 and 11 years. Linear regression models were used to estimate the strength of association between attending Yendarra school and dental caries. RESULTS: During the study period, 3813 records were obtained of children who attended dental examinations and the schools of interest. In a linear model, mean number of carious primary and adult teeth were 0.37 lower (95% confidence interval: 0.09-0.65) in Yendarra school children, compared to those in other schools, after adjustment for confounders. Pacific students had higher numbers of carious teeth (adjusted beta coefficient: 0.25; 95% confidence interval: 0.03-0.46) than Maori. CONCLUSION: This nutrition policy, implemented in a school in the poorest region of South Auckland, which restricted sugary food and drink availability, was associated with a marked positive effect on the oral health of students, compared to students in surrounding schools. We recommend that such policies are a useful means of improving child oral health. PMID- 28073167 TI - Large extents of intensive land use limit community reorganization during climate warming. AB - Climate change is increasingly altering the composition of ecological communities, in combination with other environmental pressures such as high intensity land use. Pressures are expected to interact in their effects, but the extent to which intensive human land use constrains community responses to climate change is currently unclear. A generic indicator of climate change impact, the community temperature index (CTI), has previously been used to suggest that both bird and butterflies are successfully 'tracking' climate change. Here, we assessed community changes at over 600 English bird or butterfly monitoring sites over three decades and tested how the surrounding land has influenced these changes. We partitioned community changes into warm- and cold associated assemblages and found that English bird communities have not reorganized successfully in response to climate change. CTI increases for birds are primarily attributable to the loss of cold-associated species, whilst for butterflies, warm-associated species have tended to increase. Importantly, the area of intensively managed land use around monitoring sites appears to influence these community changes, with large extents of intensively managed land limiting 'adaptive' community reorganization in response to climate change. Specifically, high-intensity land use appears to exacerbate declines in cold-adapted bird and butterfly species, and prevent increases in warm-associated birds. This has broad implications for managing landscapes to promote climate change adaptation. PMID- 28073168 TI - How clean is your stethoscope? PMID- 28073169 TI - Vascular complication rates in living donor liver transplantation: How low can we go? PMID- 28073170 TI - Loss of hSef promotes metastasis through upregulation of EMT in prostate cancer. AB - We have previously reported that the negative signaling regulator Similar Expression to FGF (hSef) is downregulated in prostate cancer and its loss is associated with clinical metastasis. Here, we explored the mechanistic basis of this finding. We first confirmed our clinical observation by testing hSef manipulation in an in vivo metastasis model. hSef stable expressing cells (PC3M hSef) or empty vector controls (PC3M-EV) were injected subcutaneously into the lateral thoracic walls of NOD-SCID gamma mice and lungs were harvested at autopsy. In this model, 6/7 PC3M-EV xenografts had definitive lung micro metastasis whilst only 1/6 PC3M-hSef xenografts exhibited metastasis recapitulating the clinical scenario (p = 0.03). Gene expression studies revealed key perturbations in genes involved in cell motility and epithelial to mesenchymal transition (EMT) along with alterations in cognate signaling pathways. These results were validated in an EMT specific PCR array whereby hSef over-expression and silencing reciprocally altered E-Cadherin expression (p = <0.001) amongst other EMT markers. Immunohistochemistry of excised tumors from the xenografts also confirmed the effect of hSef in suppressing E-Cadherin expression at the protein level. Phosphokinase arrays further demonstrated a role for hSef in attenuating signaling of not only ERK-MAPK but also the JNK and p38 pathways as well. Taken together, these data suggest evidence that loss of hSef may be a critical event facilitating tumor dissemination of prostate cancer through alteration of EMT. Detection of downregulated hSef, along with other negative regulators, may therefore be a useful biomarker heralding a transition to a metastatic phenotype and warrants further exploration in this context. PMID- 28073172 TI - Living donation to the extreme: Saving a life not once, but twice. PMID- 28073173 TI - Expression of CD43 in chronic lymphoproliferative leukemias. AB - BACKGROUND: CD43 has been used on histological samples for the differential diagnosis of lymphoproliferative disorders but there is scarce data on its use by flow cytometry (FC). We set out to characterize the expression of CD43 by FC in B cell lymphoproliferative disorders and to determine its possible role in the differential diagnosis of these malignancies. METHODS: We analyzed the expression of CD43 in clonal B-cell lymphoproliferative disorders with exclusive peripheral blood and/or bone marrow involvement based on their Moreau chronic lymphocytic leukemia (CLL) score with particular emphasis on Moreau CLL score 3 (MS3) cases, which often present a diagnostic challenge. The cohort included 433 CLL (score 4 5), 34 MS3 and 166 lymphoproliferative disorders with lower scores. RESULTS: Generally, the higher the Moreau CLL score, the higher CD43-positivity (425/443 [96%] for CLL, 23/34 [67%] for MS3 and 18/166 [11%] for cases with lower scores). MS3 cases constituted 5.4% of all cases and were more frequently CD5, CD200, CD43 positive and had del(q13) than score 0-2 cases. Among MS3 cases, del(13q) cases were predominantly CD43-positive (12/13). CONCLUSIONS: The frequency of CD43 positivity increases sharply with the Moreau score. MS3 cases seem to include both CLL and non-CLL lymphoproliferative disorders and CD43 could aid in the differential diagnosis between the two. However, studies analyzing the correlation between CD43 expression and the underlying biologic changes of these cases are warranted. (c) 2017 International Clinical Cytometry Society. PMID- 28073171 TI - Pan-cancer survey of epithelial-mesenchymal transition markers across the Cancer Genome Atlas. AB - BACKGROUND: While epithelial-mesenchymal transition (EMT) can be readily induced experimentally in cancer cells, the EMT process as manifested in human tumors needs to be better understood. Pan-cancer genomic datasets from The Cancer Genome Atlas (TCGA), representing over 10,000 patients and 32 distinct cancer types, provide a rich resource for examining correlative patterns involving EMT mediators in the setting of human cancers. RESULTS: Here, we surveyed a 16-gene signature of canonical EMT markers in TCGA pan-cancer cohort. The histology or cell-of-origin of a tumor sample may align more with mesenchymal or epithelial phenotype, and noncancer as well as cancer cells can contribute to the overall molecular patterns observed within a tumor sample; correlation models involving EMT markers can factor in both of the above variables. EMT-associated genes appear coordinately expressed across all cancers and within each cancer type surveyed. Gene signatures of immune cells correlate highly with EMT marker expression in tumors. In pan-cancer analysis, several EMT-related genes can be significantly associated with worse patient outcome. CONCLUSIONS: Gene correlates of EMT phenotype in human tumors could include novel mediators of EMT that might be confirmed experimentally, by which TCGA datasets may serve as a platform for discovery in ongoing studies. Developmental Dynamics 247:555-564, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28073174 TI - Successful application of supraceliac aortohepatic conduit using saphenous venous graft in right Lobe living donor liver transplantation. PMID- 28073175 TI - Postreperfusion microcirculatory derangements after liver transplantation: Relationship to hemodynamics, serum mediators, and outcome. AB - Despite the growing data supporting the role of microcirculation in regulating liver function, little of this knowledge has been translated into clinical practice. The aim of this study is to quantify hepatic microcirculation in vivo using sidestream dark field (SDF) imaging and correlate these findings with hepatic blood flow, hemodynamic parameters, and soluble mediators. Postreperfusion hepatic microcirculation was assessed using SDF imaging. Hepatic microcirculation measurements included functional sinusoidal density (cm/cm2 ), sinusoidal diameter (MUm), red blood cell velocity (MUm/second), volumetric blood flow (pl/second), and flow heterogeneity (FH) index. The serum concentrations of endothelin 1 (ET-1) and other inflammatory markers were analyzed with Luminex technology. Portal venous and hepatic artery flows were measured using a flowmeter. Twenty-eight patients undergoing cadaveric liver transplantations have been included in this study. Early allograft dysfunction (EAD) occurred in 7 (25%) patients and was associated with microcirculatory dysfunction. Low arterial and portal flow, high dose of inotropes, cold ischemia time, steatosis, and high ET-1 levels were all associated with impaired microcirculation. The time interval between portal venous and hepatic arterial reperfusion significantly correlated with the changes of the liver grafts' microcirculation. EAD patients tended to have higher serum levels of ET-1 on postoperative days 1, 2, 5, and 7 (all P < 0.01). Serum levels of ET-1 correlated significantly with microcirculation parameters. In conclusion, postreperfusion hepatic microcirculation is a determinant of organ dysfunction after liver reperfusion and could be used to identify very early patients at risk of EAD. Liver Transplantation 23 527-536 2017 AASLD. PMID- 28073176 TI - Parental perceptions of clown care in paediatric intensive care units. AB - AIM: The objective of this study was to report family satisfaction with regards to the presence of clowns in the paediatric intensive care unit (PICU). METHODS: This is a single-centre survey-based study, conducted over 4 months in a 12-bed third level PICU in a university hospital. All parents present at the bedside of their child during clowning were considered as potential participants. Eligible parents were approached by one of the two intensivists as investigators and asked to complete a survey within the 48 h following the clowns' intervention. RESULTS: Thirty-three parents consented to complete the survey. Median age of children was 14 months (15 days to 16 years) and median Pediatric Logistic Organ Dysfunction (PELOD) score was 1 (0-22). Twenty-four (72.7%) were considered as clinically stable while the clowns intervened. Twenty-eight parents (84.8%) and 27 (81.8%) considered that clowns had a positive effect on themselves and on their child, respectively. Clown care was considered as necessary in 19 cases (57.6%), optional in 13 (39.4%) and unnecessary in 1 (3.0%). The degree of parental satisfaction was not significantly associated with the child's clinical stability. CONCLUSION: We suggested that medical clowning in the PICU is well accepted by parents, regardless of severity of their child's condition. This study supports the adoption of medical clowning in PICUs as a patient- and family centred care practice. PMID- 28073177 TI - Idiosyncratic drug-induced liver injury associated with bile duct loss and vanishing bile duct syndrome: Rare but has severe consequences. PMID- 28073178 TI - Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients. AB - BACKGROUND: Prolonging kidney transplant survival is an important clinical priority. Induction immunosuppression with antibody therapy is recommended at transplantation and non-depleting interleukin-2 receptor monoclonal antibodies (IL2Ra) are considered first line. It is suggested that recipients at high risk of rejection should receive lymphocyte-depleting antibodies but the relative benefits and harms of the available agents are uncertain. OBJECTIVES: We aimed to: evaluate the relative and absolute effects of different antibody preparations (except IL2Ra) when used as induction therapy in kidney transplant recipients; determine how the benefits and adverse events vary for each antibody preparation; determine how the benefits and harms vary for different formulations of antibody preparation; and determine whether the benefits and harms vary in specific subgroups of recipients (e.g. children and sensitised recipients). SEARCH METHODS: Randomised controlled trials (RCTs) comparing monoclonal or polyclonal antibodies with placebo, no treatment, or other antibody therapy in adults and children who had received a kidney transplant. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing monoclonal or polyclonal antibodies with placebo, no treatment, or other antibody therapy in adults and children who had received a kidney transplant. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed risk of bias. Dichotomous outcomes are reported as relative risk (RR) and continuous outcomes as mean difference (MD) together with their 95% confidence intervals (CI). MAIN RESULTS: We included 99 studies (269 records; 8956 participants; 33 with contemporary agents). Methodology was incompletely reported in most studies leading to lower confidence in the treatment estimates.Antithymocyte globulin (ATG) prevented acute graft rejection (17 studies: RR 0.63, 95% CI 0.51 to 0.78). The benefits of ATG on graft rejection were similar when used with (12 studies: RR 0.61, 0.49 to 0.76) or without (5 studies: RR 0.65, 0.43 to 0.98) calcineurin inhibitor (CNI) treatment. ATG (with CNI therapy) had uncertain effects on death (3 to 6 months, 3 studies: RR 0.41, 0.13 to 1.22; 1 to 2 years, 5 studies: RR 0.75, 0.27 to 2.06; 5 years, 2 studies: RR 0.94, 0.11 to 7.81) and graft loss (3 to 6 months, 4 studies: RR 0.60, 0.34 to 1.05; 1 to 2 years, 3 studies: RR 0.65, 0.36 to 1.19). The effect of ATG on death-censored graft loss was uncertain at 1 to 2 years and 5 years. In non-CNI studies, ATG had uncertain effects on death but reduced death censored graft loss (6 studies: RR 0.55, 0.38 to 0.78). When CNI and older non CNI studies were combined, a benefit was seen with ATG at 1 to 2 years for both all-cause graft loss (7 studies: RR 0.71, 0.53 to 0.95) and death-censored graft loss (8 studies: RR 0.55, 0.39 to 0.77) but not sustained longer term. ATG increased cytomegalovirus (CMV) infection (6 studies: RR 1.55, 1.24 to 1.95), leucopenia (4 studies: RR 3.86, 2.79 to 5.34) and thrombocytopenia (4 studies: RR 2.41, 1.61 to 3.61) but had uncertain effects on delayed graft function, malignancy, post-transplant lymphoproliferative disorder (PTLD), and new onset diabetes after transplantation (NODAT).Alemtuzumab was compared to ATG in six studies (446 patients) with early steroid withdrawal (ESW) or steroid minimisation. Alemtuzumab plus steroid minimisation reduced acute rejection compared to ATG at one year (4 studies: RR 0.57, 0.35 to 0.93). In the two studies with ESW only in the alemtuzumab arm, the effect of alemtuzumab on acute rejection at 1 year was uncertain compared to ATG (RR 1.27, 0.50 to 3.19). Alemtuzumab had uncertain effects on death (1 year, 2 studies: RR 0.39, 0.06 to 2.42; 2 to 3 years, 3 studies: RR 0.67, 95% CI 0.15 to 2.95), graft loss (1 year, 2 studies: RR 0.39, 0.13 to 1.30; 2 to 3 years, 3 studies: RR 0.98, 95% CI 0.47 to 2.06), and death-censored graft loss (1 year, 2 studies: RR 0.38, 0.08 to 1.81; 2 to 3 years, 3 studies: RR 2.45, 95% CI 0.67 to 8.97) compared to ATG. Creatinine clearance was lower with alemtuzumab plus ESW at 6 months (2 studies: MD -13.35 mL/min, -23.91 to -2.80) and 2 years (2 studies: MD -12.86 mL/min, 23.73 to -2.00) compared to ATG plus triple maintenance. Across all 6 studies, the effect of alemtuzumab versus ATG was uncertain on all-cause infection, CMV infection, BK virus infection, malignancy, and PTLD. The effect of alemtuzumab with steroid minimisation on NODAT was uncertain, compared to ATG with steroid maintenance.Alemtuzumab plus ESW compared with triple maintenance without induction therapy had uncertain effects on death and all-cause graft loss at 1 year, acute rejection at 6 months and 1 year. CMV infection was increased (2 studies: RR 2.28, 1.18 to 4.40). Treatment effects were uncertain for NODAT, thrombocytopenia, and malignancy or PTLD.Rituximab had uncertain effects on death, graft loss, acute rejection and all other adverse outcomes compared to placebo. AUTHORS' CONCLUSIONS: ATG reduces acute rejection but has uncertain effects on death, graft survival, malignancy and NODAT, and increases CMV infection, thrombocytopenia and leucopenia. Given a 45% acute rejection risk without ATG induction, seven patients would need treatment to prevent one having rejection, while incurring an additional patient experiencing CMV disease for every 12 treated. Excluding non-CNI studies, the risk of rejection was 37% without induction with six patients needing treatment to prevent one having rejection.In the context of steroid minimisation, alemtuzumab prevents acute rejection at 1 year compared to ATG. Eleven patients would require treatment with alemtuzumab to prevent 1 having rejection, assuming a 21% rejection risk with ATG.Triple maintenance without induction therapy compared to alemtuzumab combined with ESW had similar rates of acute rejection but adverse effects including NODAT were poorly documented. Alemtuzumab plus steroid withdrawal would cause one additional patient experiencing CMV disease for every six patients treated compared to no induction and triple maintenance, in the absence of any clinical benefit. Overall, ATG and alemtuzumab decrease acute rejection at a cost of increased CMV disease while patient-centred outcomes (reduced death or lower toxicity) do not appear to be improved. PMID- 28073179 TI - Sleep duration and obesity in children: A systematic review and meta-analysis of prospective cohort studies. AB - AIM: Childhood obesity is a major public problem worldwide, and sleep duration may be associated with childhood obesity. We conducted a systematic review and meta-analysis of prospective cohort studies to estimate the associations between sleep duration and obesity/body mass index (BMI) in children. METHODS: PubMed, Embase and the Cochrane Library were searched. For the meta-analysis, the pooled relative risk (RR) and 95% confidence intervals (CI) were estimated to reveal the association between short sleep duration and obesity. For the review, the outcomes focused on BMI change or subsequent BMI status. RESULTS: A total of 12 studies (15 populations) met the criteria for inclusion in the meta-analysis. Short sleep duration was significantly associated with obesity (RR: 1.45; 95% CI: 1.14-1.85). After excluding two cohorts that substantially affected the heterogeneity, the pooled results remained significant (RR: 1.30; 95% CI: 1.20 1.42), and the association was not substantially altered in the subgroup analysis. In addition, we summarised 24 studies that met the criteria for our review of the relationship between sleeping and BMI. CONCLUSION: The present meta analysis indicated that short sleep duration increased the risk of childhood obesity. Public health efforts that encourage children to have sufficient sleep time may be important in combating obesity. PMID- 28073180 TI - Portosystemic collaterals in living donor liver transplantation: What is all the fuss about? AB - Portosystemic collaterals are a common finding in patients with cirrhosis undergoing liver transplantation. Recently, there has been a renewed interest regarding their significance in the setting of living donor liver transplantation (LDLT) due to concerns of graft hypoperfusion or hyperperfusion and its impact on early posttransplant outcomes. Presence of these collaterals has greater significance in the LDLT setting when compared with the deceased donor liver transplantation setting as dictated by the difference in the physiology of partial liver grafts. We discuss current thinking of portal flow dynamics and the techniques for dealing with this clinical problem. Liver Transplantation 23 537 544 2017 AASLD. PMID- 28073181 TI - Participation restrictions in ambulatory amyotrophic lateral sclerosis patients: Physical and psychological factors. AB - INTRODUCTION: The aim of this study was to assess the prevalence of participation restrictions in ambulatory patients with amyotrophic lateral sclerosis (ALS) and to identify physical and psychological contributory factors. METHODS: In this cross-sectional study, self-reported participation restrictions of 72 ambulatory ALS patients were assessed using the social health status dimension (SIPSOC) of the Sickness Impact Profile (SIP-68). Associations between SIPSOC and physical functioning, psychological factors, and demographic factors were analyzed using hierarchical regression analyses. RESULTS: Ninety-two percent of the patients reported participation restrictions; 54.9% could be explained by physical functioning; psychological factors accounted for 8.1% of the variance. Lung capacity, functional mobility, fatigue, and helplessness were independently associated with participation restrictions. CONCLUSIONS: Ambulatory ALS patients have participation restrictions, which may be influenced if early ALS care is directed toward lung capacity, functional mobility, fatigue, and feelings of helplessness. Muscle Nerve 56: 912-918, 2017. PMID- 28073182 TI - Over-expression of the molecular chaperone Hsp104 in Saccharomyces cerevisiae results in the malpartition of [PSI+ ] propagons. AB - The ability of a yeast cell to propagate [PSI+ ], the prion form of the Sup35 protein, is dependent on the molecular chaperone Hsp104. Inhibition of Hsp104 function in yeast cells leads to a failure to generate new propagons, the molecular entities necessary for [PSI+ ] propagation in dividing cells and they get diluted out as cells multiply. Over-expression of Hsp104 also leads to [PSI+ ] prion loss and this has been assumed to arise from the complete disaggregation of the Sup35 prion polymers. However, in conditions of Hsp104 over-expression in [PSI+ ] cells we find no release of monomers from Sup35 polymers, no monomerization of aggregated Sup35 which is not accounted for by the proportion of prion-free [psi- ] cells present, no change in the molecular weight of Sup35 containing SDS-resistant polymers and no significant decrease in average propagon numbers in the population as a whole. Furthermore, they show that over-expression of Hsp104 does not interfere with the incorporation of newly synthesised Sup35 into polymers, nor with the multiplication of propagons following their depletion in numbers while growing in the presence of guanidine hydrochloride. Rather, they present evidence that over-expression of Hsp104 causes malpartition of [PSI+ ] propagons between mother and daughter cells in a sub-population of cells during cell division thereby generating prion-free [psi- ] cells. PMID- 28073183 TI - A liver-specific long noncoding RNA with a role in cell viability is elevated in human nonalcoholic steatohepatitis. AB - : Hepatocyte apoptosis in nonalcoholic steatohepatitis (NASH) can lead to fibrosis and cirrhosis, which permanently damage the liver. Understanding the regulation of hepatocyte apoptosis is therefore important to identify therapeutic targets that may prevent the progression of NASH to fibrosis. Recently, increasing evidence has shown that long noncoding (lnc) RNAs are involved in various biological processes and that their dysregulation underlies a number of complex human diseases. By performing gene expression profiling of 4,383 lncRNAs in 82 liver samples from individuals with NASH (n = 48), simple steatosis but no NASH (n = 11), and healthy controls (n = 23), we discovered a liver-specific lncRNA (RP11-484N16.1) on chromosome 18 that showed significantly elevated expression in the liver tissue of NASH patients. This lncRNA, which we named lnc18q22.2 based on its chromosomal location, correlated with NASH grade (r = 0.51, P = 8.11 * 10-7 ), lobular inflammation (r = 0.49, P = 2.35 * 10-6 ), and nonalcoholic fatty liver disease activity score (r = 0.48, P = 4.69 * 10-6 ). The association of lnc18q22.2 to liver steatosis and steatohepatitis was replicated in 44 independent liver biopsies (r = 0.47, P = 0.0013). We provided a genetic structure of lnc18q22.2 showing an extended exon 2 in liver. Knockdown of lnc18q22.2 in four different hepatocyte cell lines resulted in severe phenotypes ranging from reduced cell growth to lethality. This observation was consistent with pathway analyses of genes coexpressed with lnc18q22.2 in human liver or affected by lnc18q22.2 knockdown. CONCLUSION: We identified an lncRNA that can play an important regulatory role in liver function and provide new insights into the regulation of hepatocyte viability in NASH. (Hepatology 2017;66:794-808). PMID- 28073185 TI - Congenital Disorders of Glycosylation: A Pipeline to Treatment? PMID- 28073184 TI - Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. AB - : Lipids are essential cellular components and energy sources of living organisms, and altered lipid composition is increasingly recognized as a signature of cancer. We performed lipidomic analysis in a series of hepatocellular carcinoma (HCC) cells and identified over 1,700 intact lipids originating from three major lipid categories. Comparative lipidomic screening revealed that 93 significantly changed lipids and decreased palmitic acyl (C16:0) containing glycerophospholipids were positively associated with metastatic abilities of HCC cells. Furthermore, both in vitro and in vivo experiments demonstrated that C16:0 incubation specifically reduced malignant cell proliferation, impaired cell invasiveness, and suppressed tumor growth in mouse xenograft models. Biochemical experiments demonstrated that C16:0 treatment decreased cell membrane fluidity and limited glucose metabolism. A phosphoproteomics approach further revealed such C16:0 incubation attenuated phosphorylation levels of mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3) pathway proteins. Multiple reaction monitoring analysis of 443 lipid molecules showed 8 reduced C16:0 containing lipids out of total 10 altered lipids when cancer tissues were compared with adjacent nontumor tissues in a cohort of clinical HCC specimens (P < 0.05). CONCLUSION: These data collectively demonstrate the biomedical potential of using altered lipid metabolism as a diagnostic marker for cancerous cells and open an opportunity for treating aggressive HCCs by targeting altered C16:0 metabolism. (Hepatology 2017;66:432-448). PMID- 28073186 TI - Factors affecting the course of body and kidney growth in infants with urolithiasis: A critical long-term evaluation. AB - OBJECTIVE: To investigate the possible effects of dietary, patient and stone related factors on the clinical course of the stone disease as well as the body and renal growth status of the infants. PATIENTS AND METHODS: A total of 50 children with an history of stone disease during infancy period were studied. Patient (anatomical abnormalities, urinary tract infection - UTI, associated morbidities), stone (obstruction, UTI and required interventions) and lastly dietary (duration of sole breast feeding, formula feeding) related factors which may affect the clinical course of the disease were all evaluated for their effects on the body and renal growth during long-term follow-up. RESULTS: Mean age of the children was 2.40 +/- 2.65 years. Our findings demonstrated that infants receiving longer period of breast feeding without formula addition seemed to have a higher rate of normal growth percentile values when compared with the other children. Again, higher frequency of UTI and stone attacks affected the growth status of the infants in a remarkable manner than the other cases. Our findings also demonstrated that thorough a close follow-up and appropriately taken measures; the possible growth retardation as well as renal growth problems could be avoided in children beginning to suffer from stone disease during infancy period. CONCLUSIONS: Duration of breast feeding, frequency of UTI, number of stone attacks and stone removal procedures are crucial factors for the clinical course of stone disease in infants that may affect the body as well as kidney growth during long-term follow-up. PMID- 28073187 TI - Laparoscopic heminephrectomy for benign and malignant diseases of the horseshoe kidney. AB - OBJECTIVES: In the current study, we present our pure laparoscopic heminephrectomy experience in 13 patients with horseshoe kidney (HK). MATERIAL AND METHODS: A total of 13 patients with HK underwent pure laparoscopic heminephrectomy (Transperitoneal= 7, Retroperitoneal = 6) due to benign and malign renal conditions (non-functional hydronephrotic and/or infected kidney = 12, kidney mass = 1). RESULTS: The mean age of the patients was 45.8 years. The mean operating time was 140 minutes, and estimated blood loss was 131 ml. The mean hospital stay was 2.3 days. Division of istmus was performed with stapler in 5 patients, ultrasonic scalpel in 3, 15 mm Hem-o-lok clip in 3, 10 mm LigaSure vessel seal system in one and endoscopic suture by 0 polyglactin in one patient without bleeding. Twelve patients underwent pure laparoscopic heminephrectomy due to nonfunctional hydronephrotic and or infected kidney. One patient underwent transperitoneal laparoscopic right heminephrectomy due to kidney mass. According to modifies Clavien classification, Grade I complication (wound infection) occurred in one patient (7.7%) who underwent heminephrectomy due to non functional kidney. CONCLUSIONS: Laparoscopic heminephrectomy seems to be technically feasible and safe for benign and malignant diseases in patients with HK. PMID- 28073188 TI - Effects of obesity surgery (laparoscopic sleeve gastrectomy technique) on lower urinary tract symptoms, depression and quality of life of males: Prospective study. AB - PURPOSE: Technically, obesity weakens the pelvic base muscles by causing an increase in the intraabdominal pressure and intravesical pressure due to increasing fat and it triggers the occurrence of lower urinary tract symptoms. However it is believed that weight loss will cause recovery of these symptoms. Our purpose in this study is to research about the effects of the weight loss achieved by using especially the Laparoscopic Sleeve Gastrectomy (LSG) technique of bariatric surgery which is being more and more widely used today. MATERIALS AND METHODS: Out of all patients who had LSG surgery due to obesity earlier in our center during the period between April 2014 and March 2015, 22 applicable male patients were considered after a brief exclusion criteria application. Age, height, weight, and body mass index (BMI) data of these patients were recorded before the operation. International Prostate Symptom Score (IPSS), International Consultation on Incontinence Questionnaire - short from) (ICIQ-SF), Beck depression inventory (BECK) and Short form - 36 (SF-36) were filled for the patients and the data were recorded. Also, the weight loss amounts and BMI decreases of the patients after the operation were recorded. RESULTS: After the procedure, the decrease in the averages of BECK depression inventory, IPSS, ICIQ SF and the increase in the Mental and Physical subgroup scores of SF-36 were found statistically coherent. CONCLUSION: The adverse effect of obesity, which is observed more and more often in today's world, on lower urinary tract symptoms and on the quality of life is undeniable. In our study, we think that the bariatric surgery made by using the LSG technique, not only causes serious amount of weight loss, but also reduces urinary dysfunction and enhances the quality of life among males. PMID- 28073189 TI - Relationship between lower urinary tract symptoms and inguinal hernia. AB - AIM: To determine the relationship between inguinal hernia (and inguinal hernia subtypes) and low urinary tract symptoms (LUTS) due to benign prostate hyperplasia (BPH), that could be more common than we think. METHOD: The study was designed retrospectively and was done in accordance with the principles of the Declaration of Helsinki, including 100 patients aged > 50 years that were divided into 2 groups: patients with BPH (BPH group) and patients with BPH and inguinal hernia (BPH-IH group 2). In addition, the BPH-IH group was subdivided according to 2 inguinal hernia subtypes; patients of BPH-IH subgroup A had direct inguinal hernia (n = 25) and those of BPH-IH subgroup B had indirect inguinal hernia (n = 25). RESULTS: There was no statistical relationship and difference in rates between IPSS scores in both groups (p = 0.659) and there wasn't a significant correlation between IPSS symptom severity and type of hernia, based on chi square analysis (p = 0.104) Conclusion: We were not able to prove our hypothesis that patients with inguinal hernia and BPH would have higher IPSS scores because of voiding dysfunction. PMID- 28073190 TI - Different patterns of pelvic ureteral endometriosis. What is the best treatment? Results of a retrospective analysis. AB - OBJECTIVE: Endometriosis is an estrogendependent disease. The incidence of urinary tract endometriosis (UE) increased during the last few years and, nowadays, it ranges from 0.3 to 12% of all women affected by the disease. The ureter is the second most common site affected. The ureteral endometriosis is classified in extrinsic and intrinsic. The aim of this study is to individuate the best treatments for each subset of ureteral endometriosis. MATERIALS AND METHODS: 32 patients diagnosed with surgically treated UE were retrospectively reviewed. The patients were divided into 3 subsets (intrinsic UE, extrinsic UE with and without obstruction). The patients with intrinsic UE (n = 10) were treated with laser endoureterotomy. The patients with extrinsic UE (n = 22) were divided in two subsets with (n = 16) and without (n = 6) hydronephrosis. All the patients underwent ureteral stenting, and resection and reimplantation was performed in the first group, and when the mass was > 2.5 cm (n = 3) Boari flap was performed. Laparoscopic ureterolysis (shaving) was performed in the second group. RESULTS: In the extrinsic subset of UE, we obtained an high therapeutic success (84%). Conversely, in the intrinsic subset there was a recurrence rate of the disease in 6/10 of the patients (60%). CONCLUSIONS: Ureterolysis seems to be a good treatment in extrinsic UE without obstruction. Resection and reimplantation allows excellent results in the extrinsic UE with obstruction. In the intrinsic subset, the endoureterotomy approach is inadequate. PMID- 28073191 TI - Are erectile functions affected by AB0 blood group? AB - AIM: The aim of this study was to investigate whether there is a relationship between erectile dysfunction (ED), thought to be a vascular disease, and AB0 blood group. MATERIAL AND METHOD: The study included 350 people abiding by the study criteria who applied to our clinic from April 2012-April 2015. The patients were divided into two groups including those with ED (Group 1) and those without (Group 2). Age, blood group, IIEF-5 score and presence of additional diseases were recorded. Erectile functions were analyzed according to blood group. RESULTS: There was no difference between the mean age of 111 patients with ED and that of 239 patients without ED included in the study (p = 0.284). There was no difference between patients in the two groups in terms of smoking, alcohol use, hypertension and diabetes (p > 0.05). Among patients in the ED group, the mean IIEF-5 score according to blood group was 19.8 +/- 5.04 in the 0 blood group, 16.5 +/- 5.2 in the A blood group, 17.2 +/- 5.3 in the B blood group and 13.3 +/- 3.02 in the AB blood group. The IIEF-5 scores of individuals in the 0 blood group were significantly high compared to individuals in other blood groups (p = 0.004). Logistic regression analysis found that compared to the 0 blood group, the erectile dysfunction risk was 3.9 times greater for the A blood group, 3.5 times greater for the B blood group and 4.7 times greater for the AB blood group (p = 0.001) (Table 3). CONCLUSION: The risk of erectile dysfunction was significantly increased for individuals in the A, B and AB blood groups compared to individuals in the 0 blood group. PMID- 28073192 TI - The use of autologous platelet rich plasma gel in bulbar and penile buccal mucosa urethroplasty: Preliminary report of our first series. AB - OBJECTIVE: The Buccal Mucosa (BM) UrethroPlasty (UP) is one of the preferred treatments for long or compli-cated urethral strictures. We propose the use of autologous Platelet Rich Plasma gel (aPRPg) in order to enhance to vascularization of BM graft and reduce the fibrous spongy. We report the outcome of our ten cases of bulbar and penile UP and the safety of this technique. Materials and metods: Ten patients underwent to BM UP with use of aPRP gel. Median age was 46. Stricture etiology was idiopathic, failed hypospadias and flogistic. Average stricture length was 3.7 cm. All patient were preoperatively evaluated with uroflowmetry , retrograde urethrography, cystoscopy and questionnaire. The harvesting of the aPRP was performed in blood bank from peripheral venous sample. Catheter was usually removed after 3 weeks and urethrography was performed after 6 weeks. RESULTS: All patients reported no problem on the donor site. At time of follow-up (median 20 month, 12-34) all patients refer no problem and a good uroflowmetry. No re-strictures at the anastomotic sites were demonstrated in any of the patients. CONCLUSION: However in our experience the follow-up is limited and no definitive conclusion or comparison can be made with the original BM UP. The use of aPRP gel seems feasible and safe. In our opinion it is important to continue investigating this procedure for its advantages in case of complex urethral strictures complicated by fibrous spongy, above all in penile urethral strictures post hypospadia repair. PMID- 28073193 TI - Analysis of MYO-Inositol effect on spermatozoa motility, in hyper viscous ejaculates and in patients with grades II and III varicocele. AB - The goal of this study is to evaluate MYOInositol effects on spermatozoa motility, in patients' ejaculates with severe varicocele or hyper viscosity. The study included normal viscosity ejaculate from 30 patients affected by varicocele and hyper viscosity ejaculate from 33 patients without any testicular pathologies. All selected samples showed sperm concentration > 2 million/ml and progressive motility < 32%. In both groups, the pellet obtained after centrifugation in buffered medium, was divided in two aliquots, both incubated for 15 minutes at 37 degrees C: one with MYO-Inositol and the other one, as control, only in phosphate buffered saline (PBS). Afterwards, the sperm progressive motility was assessed using Computer Assisted Sperm Analysis (CASA system). Incubation with MYO-Inositol improved sperm progressive motility in high viscosity samples compared to control group (38.9% +/- 3.0 vs 24.35% +/- 2.41, respectively; p <= 0.0001). Conversely, no statistically significant difference was observed in total sperm progressive motility in varicocele samples compared with control group (22.7% +/- 2.07 vs 26.7% +/- 3.31, respectively; p = 0.085). The MYO-Inositol positive effect on spermatozoa motility may depend on the type of sperm damage: heavy structural and biochemical defects which typically affects patients with varicocele are not restored by Inositol. On the contrary, MYOInositol is able to improve sperm motility in semen samples with high viscosity, since those samples show no substantial structural sperm defects. PMID- 28073194 TI - Verruciform xanthoma of the penis: A rare benign lesion that simulates carcinoma. AB - Verruciform xanthoma is a rare and benign condition predominantly affecting the oral cavity, but also skin and female anogenital mucosa. It can be flat, papular warty or crateriform-cystic. Furthermore it can simulate HPV viral lesion such as condyloma and malignant neoplasia such as verrucous squamous cell carcinoma. An accurate diagnosis is important to avoid overtreatment, considering it is a benign lesion that does not require any radical treatment. We present an extremely rare case of a 64 year-old man with a small, slighty raised, gray reddish-dotted lesion on the left portion of the ventral side of his glans. PMID- 28073195 TI - Cognitive zonal fusion biopsy of the prostate: Original technique between target and saturation. AB - : We describe our experience in prostate biopsy using a new standardized cognitive fusion techniques, that we call "cognitive zonal fusion biopsy". This new technique is based on two operative options: the first based on target biopsies, the Cognitive Target Biopsy (CTB) if the same target was detected with transrectal ultrasound (TRUS) and multiparametric magnetic resonance (mpMRI); the second based on saturation biopsies, the Zonal Saturation Biopsy (ZSB) on anatomical zone/s containing the region of interest if the same target was not evident with TRUS and MRI. We evaluated results of our technique compared to standard biopsy in order to identify clinically relevant prostate cancer. METHODS: This is a single-center prospective study conducted in 58 pts: 25 biopsy naive, 25 with previous negative biopsy and in 8 with cancer in active surveillance. Based on mpMRI and transrectal ultrasonography (TRUS), all patients were scheduled for standard 12-core TRUS-guided biopsy. If mpMRI was suggestive or positive (PI-RADS 3, 4 or 5): patients underwent additional targeted 2 to 6 cores using cognitive zonal fusion technique. RESULTS: 31/58 (53.4%) patients had a cancer. Our technique detected 80.6% (25 of 31) with clinically significant prostate cancer, leading to detection of insignificant cancer in 20%. Using standard mapping in MR negative areas we found 5 clinically significant cancer and 4 not significant cancers. MRI cancer detection rate was 18/31 (58.1%), and 9/18 (50%) in high grade tumors. Therefore MRI missed 50% of high grade cancers. The mean number of cores taken with cognitive zonal fusion biopsy was 6.1 (2-17), in addition biopsy sampling was done outside the ROI areas. Overall 15.4 cores (12-22) were taken. Cancer amount in Zonal Biopsy was larger than 7.3 mm (1-54.5) in comparison with 5.2 mm (1-23.5) in standard mapping. Largest percentage of cancer involvement with cognitive zonal fusion technique was detected in 19.4% vs 15.9%. CONCLUSIONS: Cognitive Zonal Saturation Biopsies should be used to reduce operator variability of cognitive fusion biopsy in addition to standard biopsy. Cognitive zonal biopsy based on mpMRI findings identifies clinically relevant prostate in 80%, has larger cancer extension in fusion biopsies than in random biopsies, and reduce the number of cores if compared to saturation biopsy. PMID- 28073196 TI - MRI/US fusion prostate biopsy: Our initial experience. AB - AIM: The objective of this study is to present our initial experience with magnetic resonance imaging/ultrasound (MRI/US) fusion biopsy using the Koelis Trinity device after the first consecutive 59 patients. MATERIALS AND METHODS: 59 consecutive patients with suspected prostate cancer (PCA) underwent prostate biopsy using Trinity Koelis(r) (Koelis, Grenoble, France). We divided the patients into 2 groups: patients with a previous negative mapping underwent to a MRI/US fusion re-biopsy (Group A); and biopsy-naive patients who underwent to a first stereotactic 3-D mapping of the prostate (Group B). Group A (22 patients):mean age 64 years (CI 48-73), mean PSA = 7.7 ng/ml (CI 4.2- 9.9); mean prostate volume 55 ml(CI 45-82), Digital Rectal Examination (DRE) positive in 2/22, number of lesions detected by MRI 1.4, mean cores from each MRI target lesion 3 (CI 2-5), mean total cores 15 ( CI 12-19). Group B (37 patients): mean age 66 years (CI 49-77), mean PSA= 4.7 (3.2- 7.9); mean prostate volume 45 ml (33 67), DRE positive in 5/37, mean total cores 14 ( CI 10-16) Results: In Group A 10/22 patients were positive for PCA (overall detection rate of 45.5%): 6 PCA were detected by target biopsy and 4 cancer by random biopsy. Significant prostate cancer (defined as the presence of Gleason pattern 4) was detected in 4/10 patients (Significant PCA detection rate of 40%) and all significant PCA were detected by MRI target biopsy. All PCA detected by random biopsy had Gleason score 3 + 3 = 6. In Group B (biopsy naive patients) 14/37 patients were positive for PCA (overall detection rate of 37.8%), Significant prostate cancer was detected in 5/14 patients (Significant PCA detection rate of 35,7%). No significant side effects were recorded. CONCLUSIONS: Our overall detection rate was 45.5% and 37.8% in Group A (patients with previous negative biopsy and persistent suspicion of PCA) and in Group B (biopsy naive patients) respectively; clinical significant PCA detection rate was respectively 40% and 35.7%. These results are similar to current literature and promising for the future. We believe that using platforms of co-registered MRI/US fusion biopsy can potentially improve risk stratification and reduces understaging, undergrading and the need for repeat biopsies in biopsy naive patients (using a stereotactic first mapping) and in patients with previous negative biopsy and persistent suspicion of PCA ( using a second MRI/US fusion biopsy). PMID- 28073197 TI - Detection rate for significant cancer at confirmatory biopsy in men enrolled in Active Surveillance protocol: 20 cores vs 30 cores vs MRI/TRUS fusion prostate biopsy. AB - INTRODUCTION: The detection rate for significant prostate cancer of extended vs saturation vs mMRI/TRUS fusion biopsy was prospectively evaluated in men enrolled in active surveillance (AS) protocol. Mterials and methods: From May 2013 to September 2016 75 men aged 66 years (median) with very low risk PCa were enrolled in an AS protocol and elegible criteria were: life expectancy greater than 10 years, cT1C, PSA below 10 ng/ml, PSA density < 0.20, 2 < unilateral positive biopsy cores, Gleason score (GS) equal to 6, greatest percentage of cancer (GPC) in a core < 50%. All patients underwent 3.0 Tesla pelvic mpMRI before confirmatory transperineal extended (20 cores) or saturation biopsy (SPBx; 30 cores) combined with mpMRI/TRUS fusion targeted biopsy (4 cores) of suspicious lesions (PI-RADS 3-5). RESULTS: 21/75 (28%) patients were reclassified by SPBx based on upgraded GS >= 7; mpMRI lesions PI-RADS 4-5 vs PI-RADS 3-5 diagnosed 9/21 (42.8%) vs 16/21 (76.2%) significant PCa with 2 false positives (6.5%). The detection rate for significant PCa was equal to 76.2% (mpMRI/TRUS fusion biopsy) vs 81% (extended) vs 100% (SPBx) (p = 0.001); mpMRI/TRUS targeted biopsy and extended biopsy missed 5/21 (23.8%) and 4/21 (19%) significant PCa which were found by SPBx (p = 0.001) being characterised by the presence of a single positive core of GS >= 7 with GPC < 10%. CONCLUSIONS: Although mpMRI improve the diagnosis of clinically significant PCa, SPBx is provided of the best detection rate for PCa in men enrolled in AS protocols who underwent confirmatory biopsy. PMID- 28073198 TI - Prostatic calculi detected in peripheral zone of the gland during a transrectal ultrasound biopsy can be significant predictors of prostate cancer. AB - PURPOSE: Prostatic calculi (PC) are usually associated with benign prostatic hyperplasia or chronic inflammation. However, in several studies prostatic inflammation and calcification have been implicated in the pathogenesis of prostate cancer (CaP). We evaluated the prevalence of PC during transrectal ultrasound (TRUS) and correlate the ultrasonographic patterns with histological findings. METHODS: A prospective study of 664 patients undergoing TRUS and prostate biopsy was planned. A standardized reproducible technique was used with using a GE Logiq 7 machine equipped with a 5-9MHz multi-frequency convex probe "end-fire". We defined marked presence of PC as multiple hyperechoic foci with significant area (>= 3 mm in the largest diameter). PC were classified according to zone distribution into the gland: transitional zone (TZ), central zone (CZ), and peripheral zone (PZ). RESULTS: No significant difference was noted between the patients with PC and without PC, when comparing age, preoperative PSA level, prostate volume, and biopsy number, except for DRE findings. 168 patients (25.3%) had marked presence of PC on TRUS: 50.6% in TZ, 20.2% in CZ, and 29.2% in PZ. 31 patients (63.3%) with presence of PC in PZ had CaP on biopsy. The correlation observed between CaP and the presence of PC in PZ was statistically significant (p < 0.001). However, among patients in the CaP group there was no statistical association between PC and moderate or high Gleason grade. CONCLUSIONS: This study suggests that chronic prostatic inflammation and PC have a role in the biogenesis of cancer. CaP was more frequent in patients with PC in PZ of the gland, but was not associated with higher Gleason grade among these patients (p < 0.001). PMID- 28073199 TI - Transrectal ultrasound (TRUS) guided prostate biopsy: Three different types of local anesthesia. AB - : Transrectal Ultrasound (TRUS) guided prostate biopsy is regarded as the gold standard for prostate cancer diagnosis. The majority of patients perceive TRUS guided prostate biopsy as a physically and psychologically traumatic experience. We aimed to compare in this paper the efficacy of three different anesthesia techniques to control the pain during the procedure. MATERIALS AND METHODS: 150 patients who underwent transrectal ultrasound (TRUS) guided prostate biopsy were randomly divided into three groups. Group A included 50 patients who received one hour before the procedure a mixture of 2.5% lidocaine and 2.5% prilocaine, Group B: 50 patients who received intrarectal local anesthetic administration (lidocaine 5 ml 10%) and lidocaine local spray 15 % and Group C included 50 patients who received periprostatic block anesthesia (lidocaine 10 ml 10%). Visual analogue scale (VAS) of patients in different groups was evaluated at the end of the biopsy and 30 minutes after the procedure. RESULTS: The VAS of patients in Group A was 1.32 +/- 0.65 (VAS I) and 2.47 +/- 0.80 (VAS II). In group B the VAS of patients was 1.09 +/- 0.47 (VAS I) and 1.65 +/- 0.61 (VAS II). In group C the VAS of patients was 2.63 +/- 0.78 (VAS I) and 1.70 +/- 0.85 (VAS II). There was no statistically significant difference in term of VAS I between group A and B. A statistically significant difference was determined in terms of VAS II between group A and B. There was no statistically significant difference in term of VAS between group B and C. CONCLUSIONS: The most effective of the three methods for pain control we used was intrarectal local anesthetic administration and lidocaine local spray 15% that enables an ideal patient comfort. PMID- 28073200 TI - The role of intraoperative ultrasound in small renal mass robotic enucleation. AB - INTRODUCTION: As a result of the growing evidence on tumor radical resection in literature, simple enucleation has become one of the best techniques associated to robotic surgery in the treatment of renal neoplasia, as it guarantees minimal invasiveness and the maximum sparing of renal tissue, facilitating the use of reduced or zero ischemia techniques during resection. The use of a robotic ultrasound probe represents a useful tool to detect and define tumor location, especially in poorly exophytic small renal mass. MATERIALS AND METHODS: A total of 22 robotic enucleations were performed on < 3 cm renal neoplasias (PADUA score 18 Pz 6/7 e 4 Pz 8) using a 12-5 MHz robotic ultrasound probe (BK Drop-In 8826). RESULTS: Once kidney had been isolated from the adipose capsule at the site of the neoplasia (2), the exact position of the lesion could be easily identified in all cases (22/22), even for mostly endophytic lesions, thanks to the insertion of the ultrasound probe through the assistant port. Images were produced and visualized by the surgeon using the TilePro feature of the DaVinci surgical system for producing a picture-in-picture image on the console screen. The margins of resection were then marked with cautery, thus allowing for speedy anatomical dissection. This reduced the time of ischemia to 8 min (6-13) and facilitated the enucleation technique when performed without clamping the renal peduncle (6/22). No complications due to the use of the ultrasound probe were observed. CONCLUSIONS: The use of an intraoperative robotic ultrasound probe has allowed for easier identification of small, mostly endophytic neoplasias, better anatomical approach, shorter ischemic time, reduced risk of pseudocapsule rupture during dissection, and easier enucleation in cases performed without clamping. It is noteworthy that the use of intraoperative ultrasound probe allows mental reconstruction of the tumor through an accurate 3D vision of the hidden field during surgical dissection. PMID- 28073201 TI - Azoospermic patient's treatment: An experience of a PMA hospital unit and role of ultrasonography. AB - INTRODUCTION: Azoospermia causes about 10% of male infertility and the best therapeutic option is the retrieval of sperm from testis or epididymis. MATERIAL AND METHODS: From Juanary 2008 to June 2016, 92 men (median 36 years; range: 25 54 years) were submitted in 47 cases to TESE (testicular sperm extraction) and in 45 cases to PESA (percutaneous epididymal sperm aspiration) for secretory and obstructive azoospermia, respectively; moreover, all the patients previously underwent color Doppler ultrasound of the testis and transrectal ultrasound of the prostate. RESULTS: Serum FSH values were 9.4 ml/UI and 36.4 ml/UI (median 18.2 ml/UI) with an estimated volume of the testis equal to 5 ml; 40 men had the mutation for cystic fibrosis with bilateral agenesis of the deferentia vasa, 4 men had a cyst of the prostatic utricle, 1 man had retrograde ejaculation, 7 had an epididymis cyst and 2 had anejaculation secondary to traumatic neurologic spinal cord injury. The retrieval of sperm was performed in 39 (83%) and 36 (80%) of the patients submitted to TESE and PESA, respectively. The pregnancy rate was equal to 28% and 33% in men with secretory and obstructive azoospermia, respectively. DISCUSSION: Assisted reproduction technology with a multidisciplinary team is provided of a pregnancy rate equal about 30% in men with azoospermia; ultrasound allows to evaluate abnormalities of the testis and prostate improving the percentage of pregnancy. PMID- 28073202 TI - Pseudoaneurysm with arteriovenous fistula of the prostate after pelvic trauma: Ultrasound imaging. AB - Pseudoaneurysm (PA) associated with an arteriovenous fistula (AVF) of the internal pudendal artery branches are very uncommon. We report a case of post traumatic PA with AVF connected to Santorini plexus. Diagnosis was made with trans-rectal ultrasound (TRUS) after recurrent hematuria. TRUS reported a 1.7 * 1.4 * 1.5 cm anechoic area, on anterior prostate apex close to Santorini plexus. The use of color Doppler in this area revealed high flow velocity that was indicative for AVF. The feeding artery was a distal branch of the left pudenda artery. After selective embolization was observed complete occlusion of the feeding branches and disappearance of PA with AVF. Prostate PA with concomitant symptomatic AVF detected with TRUS has not yet described in literature after pelvic trauma and represents complex diagnostic challenges. This case report suggests that the use of TURS and color Doppler can provide an important diagnostic and follow-up to address the clinical suspicion of occult vascular injuries using a noninvasive approach. PMID- 28073203 TI - Testicular sparing surgery in small testis masses: A multinstitutional experience. AB - INTRODUCTION: The incidence of benign testicular tumors is increasing in particular in small lesion incidentally found at scrotal ultrasonography. Primary aim of this study was to perform radical surgery in malignant tumor. Secondary aim was to verify the efficacy of the diagnostic-therapeutic pathway recently adopted in management of small masses with testis sparing surgery in benign lesions. MATERIALS AND METHODS: In this multicenter study, we reviewed all patients with single testis lesion less than 15 mm at ultrasound as main diameter. We applied the diagnostic-therapeutic pathway described by Sbrollini et al. (Arch Ital Urol Androl 2014; 86:397) which comprises: 1) testicular tumor markers, 2) repeated scrotal ultrasound at the tertiary center, 3) surgical exploration with inguinal approach, intraoperative ultrasound, and intraoperative pathological examination. Definitive histology was reviewed by a dedicated uro pathologist. RESULTS: Twenty-eight patients completed this clinical flowchart. The mean lesion size was 9.3 mm (range 2.5-15). Testicular tumor markers were normal except in a case. Intraoperative ultrasound was necessary in 8/28 cases. We treated 11/28 (39.3%) with immediate radical orchiectomy and 17/28 (60.7%) with testis-sparing surgery. Definitive pathological results were: malignant tumor in 6 cases (seminoma), benign tumor in 10 cases (5 Leydig tumors, 2 Sertoli tumors, 1 epidermoid cyst, 1 adenomatoid tumor, 1 angiofibroma), benign disease in 11 (8 inflammation with haemorragic infiltration, 2 tubular atrophy, 1 fibrosis), and normal parenchyma in 1 case. We observed a good concordance between frozen section examination and definitive histology. Any malignant tumor was treated conservatively. Any delayed orchiectomy was necessary based on definitive histology. CONCLUSIONS: The incidence of benign lesions in 60% of small testis lesions with normal tumor markers makes orchiectomy an overtreatment. Testicular sparing surgery of single testicular nodules below 15 mm is a safe option, but requires a standardized pathway in diagnosis. Our pathway has shown good reliability and security profile to be applied in a multicenter management for small scrotal masses. Our study has shown the reliability of the diagnostic-therapeutic pathway in the management of single testicular masses. The higher incidence of benign lesions in 60% of patients makes often orchiectomy an overtreatment. PMID- 28073204 TI - Who "apparently" more spends, "in reality" spends less. Spending "a little" more for the rental of the extracorporeal lithotripter can save "a lot" about the days of hospitalization for urinary stones. AB - OBJECTIVE: The right to health (according to the Article 32 of the Italian Republic Constitution) is financially conditioned; for this reason the National Health System (NHS) has the objective of rationalize health expenditure according to the criteria of efficiency, effectiveness and economy. This paper is an example of rationalization concerning the extracorporeal shock wave lithotripsy (ESWL). MATERIALS AND METHODS: Hospital admissions for urinary stones were taken into account. "Edotto", the database of the Puglia region has identified 23 inpatient admissions during which was performed ESWL. A single operator performed ESWLs with a Storz lithotripter, Modulith SLK. RESULTS: The average hospital stay is conditioned by days "to wait" lithotripsy. In 2014 the hospitalization days "waiting for" lithotripsy were 100. The results were subjected to SWOT analysis and discussed with the Boston Consulting Group Matrix. DISCUSSION: Constant availability of the lithotripter would spare 100 days of hospitalization, amounting to ? 88,200.00. This waste of resources corresponds to an additional cost equal to 98.3% on the cost for the rental of the lithotripter. Instead, reducing "unnecessary" hospitalization days would get a saving of 79.3% on the rental cost. It is as if for 46 days of the lithotripter rent were paid 46 days, while for 365 days of the lithotripter rent were paid only 11.8 sessions per year. CONCLUSIONS: Rationalization of resources is not necessarily a synonym of "reduction" of resources, but of reduction of waste in the NHS. A good plan is the most important rational basis to get more resources. About the process taken into account it is seen as an investment of ? 21,450.00 would keep unchanged the effectiveness of lithotripsy service but would add efficiency and economy (increase of sessions/year, increase in the active mobility, increase in orthopedic treatments) and would drastically reduce the number hospital days (a waste). PMID- 28073205 TI - Rare presentation of a testicular angiofibroma treated with testis sparing surgery. AB - INTRODUCTION: Testicular benign tumors are very rare (< 5%). Testicular Angiofibroma (AF) is one of those, however the gold standard of treatment and follow-up is still unclear. CASE REPORT: A 47 years-old man with only one functioning testis was referred to our clinic for a palpable right testicular mass and atrophic contralateral testis. Patient underwent testis-sparing surgery with inguinal approach and intraoperative frozen sections examination with diagnosis of AF. Final histology confirmed AF. Post-operative follow-up was uneventful. Clinical and ultrasonographic follow-up was negative after 8 months. CONCLUSION: We report a conservative surgery in a patient with AF of the solitary testis. AF is a benign para-testicular fibrous neoplasm that could be misinterpreted as malignant tumor and treated with orchiectomy. Testis-sparing surgery is recommended in this case with intraoperative pathological examination. The excision of the mass is enough but in front of a possible recurrence a long follow-up is advisable. PMID- 28073206 TI - A singular case of polyorchidism. AB - We report a case of polyorchidism, a rare congenital anomaly, frequently discovered by chance. At current knowledge is still not defined which is the best clinical and therapeutic approach as well the best follow- up scheme due to the unclear malignant potential and rate of complications if a conservative approach is used. MRI (Magnetic Resonance Imaging) seems to be a good method to discriminate this mass from others pathological findings but there is still not enough evidence to standardize the procedure. PMID- 28073207 TI - Intraoperative ultrasound-guided enucleation of testicular nodule. AB - OBJECTIVE: We report a case of enucleation of a non-palpable right testicular lesion found incidentally at testicular ultrasonography during investigations in a patient with azoospermia. MATERIALS AND METHODS: In 2011 bilateral hypoechoic nonpalpable testicular lesions (5 mm and 3 mm to the right, 3 mm to the left) were found in a 28 years old patient, during diagnostic investigations for azoospermia. In March 2016, ultrasonography showed that the diameter of the right major nodule had grown to 12 mm, characterized by increased vascularization and increased texture. Blood exams showed serum FSH above normal levels with negative oncologic markers. The patients underwent surgical enucleation of the right nodule under ultrasonography guidance. RESULTS: In post operative day 1 a control ultrasonography documented the disappearance of the lesion. Hystopathologic examination diagnosed a Leydig cell tumor, with negative surgical margins. The patient is in good clinical conditions and is under periodic ultrasonographic follow up. CONCLUSION: Organ sparing surgery represent a good therapeutic option for little intraparenchymal lesions, mostly in young patients in which is preferable to preserve fertility. Intraoperatory ultrasonography represent an important tool for the localization of the lesion. PMID- 28073208 TI - Experience of percutaneous access under ultrasound guidance in renal transplant patients with allograft lithiasis. AB - OBJECTIVE: Urolithiasis of the transplanted kidney has an incidence of 0.2 to 1.7%, it increases the risk of infection in immunosuppressed patients and it can lead to ureteral obstruction that is often associated with deterioration of renal function. Urolithiasis of the transplanted kidney has different characteristics compared to the native kidney, due to the absence of innervation, which does not lead to colic pain. Percutaneous approach is an optimal choice in transplant patients. MATERIAL AND METHODS: Here we report our experience in two cadaveric transplant patients with urolithiasis. The first case was a patient of 68 years with a 20 mm stone located in the transplanted kidney pelvis and another smaller in a lower calyx. The second case was a patient of 65 years with a 15 mm stone in the distal part of the transplanted ureter. In both cases the patients were asymptomatic, but they had a reduction in urine output associated with worsening of the transplanted kidney function. The diagnosis was performed in both cases with ultrasound study, showing a severe hydronephrosis and it was confirmed by computed tomography scan. In both cases, we performed a Percutaneous Nephrolithotomy (PCNL). Access was made after targeting the stone, through a lower pole puncture under ultrasound guidance. The first case was treated with pneumatic and laser energy, breaking stones through a nephroscope. In the second case we performed a laser lithotripsy of the ureteral stone, using a flexible videoureteroscope. At the end of both procedures a Double-J stent and a 14 Fr Malecot nephrostomy were positioned, that were removed at 6 weeks and 10 days, respectively. RESULTS: Both patients achieved a resolution of the worsening of renal function, recovering the spontaneous diuresis. The surgical procedure using ultrasound guidance was safe and allowed quick access to the renal pelvis. Both patients experienced no bleeding or infection during hospitalization. CONCLUSIONS: Percutaneous Nephrolithotomy (PCNL) is an established safe and effective surgical treatment option for larger renal calculi in renal allografts. The ultrasound guided access to the transplanted kidney in percutaneous treatment of urolithiasis is useful and fast, minimizing patient exposure to ionizing radiation. PMID- 28073209 TI - The importance of potassium citrate and potassium bicarbonate in the treatment of uric acid renal stones. AB - Uric acid calculi can also be treated without surgery, with simple medical lytic therapy. After appropriate dietary adjustments and add of mineral water, the needed amount of alkali supplementation can increase pH values of the urine in order to dissolve the stones. Treatment should be prolonged to prevent stone recurrence. A case of bilateral renal uric acid stones that were successfully treated by alakalizing treatment was presented. PMID- 28073210 TI - The importance of citrates in treatment and prophylaxis of calcium oxalate urinary stones. AB - About 10% of the people is the subject of an episode of kidney stones during their lifetime, about 70% of these people undergoes relapses. About 80% of the urinary stones contains calcium, of wich 80% is formed of calcium oxalate, in pure form or associated with calcium phosphate. Therefore we can saythat in most cases (about 65%) the urinary stones are composedof calcium oxalate. Use of supplements of potassium citrate and magnesium citrate can help in the prevention of kidney stones of calcium oxalate, but mostly they can be used in the days before a shockwaves lithotripsy treatment to make the stones more fragile to the effect of the shock waves. A case of successful treatment with magnesium potassium citrate of a SWL resistant ureteral stone is presented. PMID- 28073211 TI - An unusual case of primary intrascrotal lipoma. AB - In daily clinical practice, intrascrotal lesion are commonly detected, both by clinical examination either by ultrasound scan. While 95% of testicular lesions are malignant, most paratesticular lesions are benign. Among these, intrascrotal lipomas must be take into account in differential diagnosis. When they originate from scrotal wall, they named "primary scrotal lipoma". We describe a case of a primary intrascrotal lipoma diagnosed after surgical excision in a young man presented at our Urological Department complaining a painful left scrotal mass. PMID- 28073212 TI - Ultrasound features of a metastatic seminal vesicle melanoma: A case report. AB - In this report we describe what we consider to be the second case of seminal vescicle (SV) metastasis from an unknown primary melanoma. only presenting symptom was a palpable firm nodule of the right prostate base on digital rectal examination (DRE). The diagnosis, after prostatic transrectal ultrasound examination (TRUS), was performed by ultrasound guided biopsy. We underline that prostatic TRUS evaluation is mandatory in case of abnormal digital rectal examination. Seminal vesicle must be always evaluated. PMID- 28073213 TI - The numbers speak for themselves. PMID- 28073214 TI - [The body as the Achilles heel in sports]. PMID- 28073215 TI - [Sports at a slippery slope?]. PMID- 28073216 TI - Don't tamper with nature. PMID- 28073217 TI - [Re: Family planning, pregnancy and breastfeeding in multiple sclerosis]. PMID- 28073218 TI - [Re: Children in vulnerable situations need child protective services]. PMID- 28073219 TI - [Drug therapy for older people with functional impairments]. PMID- 28073220 TI - What do we know about the safety of the HPV vaccines? PMID- 28073221 TI - HPV vaccines are safe to use. PMID- 28073222 TI - [Guidelines for rehabilitation after acquired upper limb amputation]. PMID- 28073223 TI - [New evidence based guideline on epilepsy]. PMID- 28073224 TI - Model for research on risks in the home and living environments PMID- 28073226 TI - ? PMID- 28073225 TI - [Who should investigate chronic fatigue?]. PMID- 28073227 TI - Labial adhesion - diagnostics and treatment. AB - BACKGROUND: Labial adhesion is relatively common, but the condition is little known among doctors and parents. The article assesses treatment in the specialist health service. MATERIAL AND METHOD: The treatment and course are assessed in 105 girls in the age group 0 - 15 years who were referred to St. Olavs Hospital in the period 2004 - 14. RESULTS: The majority of the girls (n = 63) were treated topically with oestrogen cream. In 26 of 51 girls (51 %) for whom the final result is known, the adhesion opened after one treatment. When 1 - 4 oestrogen treatments were administered, the introitus had opened completely in two out of three (65 %). Fewer than half of those who received supplementary surgical treatment achieved permanent opening. INTERPRETATION: Treatment for labial adhesion had a limited effect in this study. As the literature suggests that the condition results in few symptoms and resolves spontaneously in virtually all girls in puberty, no compelling medical reason exists for opening the adhesion in asymptomatic girls. It is important that doctors are aware of the condition in order to prevent misdiagnosis and to provide parents with adequate information. For parents it is important to know that spontaneous resolution may result in soreness and dysuria. Knowledge of the condition can most likely prevent unnecessary worry. PMID- 28073228 TI - [Statin intolerance]. AB - In 2015, more than 530 000 people were prescribed statins in Norway. Adverse effects from the musculoskeletal system as well as less specific side effects are frequently reported. The extent of these contrasts with observations made in randomised controlled studies which report the prevalence of such adverse effects as being in line with placebo. Breaks from drug treatment, low doses, switching medication and use of other lipid-lowering drugs are the most relevant approaches to dealing with adverse effects. PMID- 28073229 TI - Sialoceles of the parotid gland. PMID- 28073230 TI - [A woman in her 40s with anisocoria and unilateral facial flushing]. PMID- 28073232 TI - [The two worlds of helper professions]. PMID- 28073231 TI - [Internet-based treatment of depression]. PMID- 28073233 TI - Asthma in elite sport - from the 1960s to today PMID- 28073234 TI - [Echo and ecco]. PMID- 28073235 TI - ? PMID- 28073236 TI - ? PMID- 28073237 TI - ? PMID- 28073238 TI - ? PMID- 28073239 TI - ? PMID- 28073240 TI - ? PMID- 28073241 TI - Prognostic value of total triiodothyronine and free thyroxine levels for the heart failure in patients with acute myocardial infarction. AB - BACKGROUND/AIMS: Although a low triiodothyronine (T3) state is closely associated with heart failure (HF), it is uncertain whether total T3 levels on admission is correlated with the clinical outcomes of acute myocardial infarction (AMI). The aim of this study is to investigate the prognostic value of total T3 levels for major adverse cardiovascular and cerebrovascular events (MACCEs) in patients with AMI undergone percutaneous coronary intervention (PCI). METHODS: A total of 765 PCI-treated AMI patients (65.4 +/- 12.6 years old, 215 women) between January 2012 and July 2014 were included and 1-year MACCEs were analyzed. We assessed the correlation of total T3 and free thyroxine (fT4) with prevalence of 1-year MACCEs and the predictive values of total T3, fT4, and the ratio of total T3 to fT4 (T3/fT4), especially for HF requiring re-hospitalization. RESULTS: Thirty patients (3.9%) were re-hospitalized within 12 months to control HF symptoms. Total T3 levels were lower in the HF group than in the non-HF group (84.32 +/- 21.04 ng/dL vs. 101.20 +/- 20.30 ng/dL, p < 0.001). Receiver operating characteristic curve analysis showed the cut-offs of total T3 levels (<= 85 ng/dL) and T3/fT4 (<= 60) for HF (area under curve [AUC] = 0.734, p < 0.001; AUC = 0.774, p < 0.001, respectively). In multivariate analysis, lower T3/fT4 was an independent predictor for 1-year HF in PCI-treated AMI patients (odds ratio, 1.035; 95% confidential interval, 1.007 to 1.064; p = 0.015). CONCLUSIONS: Lower levels of total T3 were well correlated with 1-year HF in PCI-treated AMI patients. The T3/fT4 levels can be an additional marker to predict HF. PMID- 28073242 TI - Clinical phenotypes of Korean patients with Behcet disease according to gender, age at onset, and HLA-B51. AB - BACKGROUND/AIMS: The clinical manifestations of Behcet disease (BD) have been reported to differ according to country, region, and race. Gender, onset age, and human leukocyte antigen (HLA)-B51 have also been known as the factors that influence the clinical features of BD. The aim of this study is to investigate the clinical phenotypes of Korean patients who visited the rheumatology clinic with BD with respect to gender, onset age, and HLA-B51. METHODS: Total 193 Korean patients (129 females and 64 males) fulfilling the international criteria for BD were retrospectively assessed. RESULTS: The mean age at disease onset and disease duration of the BD patients were 32.2 +/- 11.1 and 14.2 +/- 9.3 years, retrospectively. Females suffered more frequently from genital ulcers (90.7% vs. 75.0%, p < 0.01), peripheral arthritis (67.4% vs. 43.8%, p < 0.01), and inf lammatory low back pain (38.8% vs. 23.4%, p = 0.03) than males, while skin involvement was more frequent in males than in females (90.6% vs. 75.2%, p = 0.01). The patients with late onset of BD (> 40 years) suffered from neurologic involvement (15.9% vs. 4.2%, p = 0.007) more frequently than those with early onset of BD. The patients with HLA-B51 showed earlier onset of disease than without HLA-B51 (28.3 +/- 11.4 years vs. 33.8+/-11.6 years, p = 0.02) and the neurologic and gastrointestinal involvements were more frequent in the patients without HLA-B51 than with HLA-B51 (17.2% vs. 2.5%, p = 0.02 and 20.7% vs. 2.5%, p = 0.01, respectively). CONCLUSION: The clinical phenotypes in Korean patients with BD may be influenced by gender, onset age and HLA-B51. PMID- 28073243 TI - Cytokeratin 13, Cytokeratin 17, and Ki-67 Expression in Human Acquired Cholesteatoma and Their Correlation With Its Destructive Capacity. AB - OBJECTIVES: Cholesteatoma is a nonneoplastic destructive lesion of the temporal bone with debated pathogenesis and bone resorptive mechanism. Both molecular and cellular events chiefly master its activity. Continued research is necessary to clarify factors related to its aggressiveness. We aimed to investigate the expression of Ki-67, cytokeratin 13 (CK13) and cytokeratin 17 (CK17) in acquired nonrecurrent human cholesteatoma and correlate them with its bone destructive capacity. METHODS: A prospective quantitative immunohistochemical study was carried out using fresh acquired cholesteatoma tissues (n=19), collected during cholesteatoma surgery. Deep meatal skin tissues from the same patients were used as control (n=8). Cholesteatoma patients were divided into 2 groups and compared (invasive and noninvasive) according to a grading score for bone resorption based upon clinical, radiologic and intraoperative findings. To our knowledge, the role of CK17 in cholesteatoma aggressiveness was first investigated in this paper. RESULTS: Both Ki-67 and CK17 were significantly overexpressed in cholesteatoma than control tissues (P<0.001 for both Ki-67 and CK17). In addition, Ki-67 and CK17 were significantly higher in the invasive group than noninvasive group of cholesteatoma (P=0.029, P=0.033, respectively). Furthermore, Ki-67 and CK17 showed a moderate positive correlation with bone erosion scores (r=0.547, P=0.015 and r=0.588, P=0.008, respectively). In terms of CK13, no significant difference was found between cholesteatoma and skin (P=0.766). CONCLUSION: Both Ki-67 and CK17 were overexpressed in cholesteatoma tissue and positively correlated with bone resorption activity. The concept that Ki-67 can be a predictor for aggressiveness of cholesteatoma was supported. In addition, this is the first study demonstrating CK17 as a favoring marker in the aggressiveness of acquired cholesteatoma. PMID- 28073244 TI - Enthalpic Effects of Chain Length and Unsaturation on Water Permeability across Droplet Bilayers of Homologous Monoglycerides. AB - A deeper understanding of unassisted passive transport processes can better delineate basic lipid dynamics in biological membranes. A droplet interface bilayer (DIB) is made by contacting two aqueous droplets covered with a lipid monolayer, and has increasingly been employed as a model artificial biological membrane. In this study, we have investigated the effect of acyl chain structure of amphiphilic monoglycerides on the osmotic permeability of water across DIB membranes composed of these monoglycerides, where the acyl chain length (C14 C24), number of double bonds (1-4), and the position of double bond are varied systematically along the acyl chains. Both permeability values and activation energies have been extracted for water transport across a lipid bilayer formed of a homologous series of lipids, allowing us to make ready comparisons between the different lipids and potentially better elucidate the contributions that molecular motifs make to the permeation process. PMID- 28073245 TI - Cyclodextrin-Assisted Two-Component Sonogel for Visual Humidity Sensing. AB - In this work, two naphthalimide-based compounds, 1a and 1b, have been designed and synthesized. Both compounds can form stable two-component gels in n-propanol or n-butanol upon addition of alpha-cyclodextrin (alpha-CD) followed by sonication at room temperature. Interestingly, the 1a/alpha-CD gel is thixotropic and very sensitive to water. Addition of a small amount of water induces rapid gel collapse, allowing further development of the gel as a visual relative humidity sensor. Specificity of the sensor has been confirmed using several approaches, such as scanning electron microscopy and fluorescence, Fourier transform infrared, and 1H NMR spectroscopy experiments. The results show that alpha-CD acts as a junction for the assembly of 1a or 1b through hydrogen bonding between hydroxyl and amide groups. Upon addition of water, alpha-CD interacts with the adamantane group of 1a via an incomplete host-guest encapsulation, resulting in the dissociation of the hydrogen-bonding-assisted two-component assembly, accompanied by gel collapse. PMID- 28073246 TI - A New Era of Genome Integration-Simply Cut and Paste! AB - Genome integration is a powerful tool in both basic and applied biological research. However, traditional genome integration, which is typically mediated by homologous recombination, has been constrained by low efficiencies and limited host range. In recent years, the emergence of homing endonucleases and programmable nucleases has greatly enhanced integration efficiencies and allowed alternative integration mechanisms such as nonhomologous end joining and microhomology-mediated end joining, enabling integration in hosts deficient in homologous recombination. In this review, we will highlight recent advances and breakthroughs in genome integration methods made possible by programmable nucleases, and their new applications in synthetic biology and metabolic engineering. PMID- 28073247 TI - Tuning for Visible Fluorescence and Near-Infrared Phosphorescence on a Unimolecular Mechanically Sensitive Platform via Adjustable CH-pi Interaction. AB - CH-pi interaction-assisted alignment of organic conjugated systems has played an important role to regulate molecular electronic and photophysical properties, whereas harnessing such a smart noncovalent interaction into the tuning of unimolecular complex emissive bands covering a wide spectral region remains a challenging research topic. Since the tuning for visible and near-infrared emissive properties in a single pi-functional platform relates to its multicolor luminescent behaviors and potential superior application in analysis, bioimaging, and sensing, herein, we report a proportional control of the singlet and triplet emissions that cover visible and near-infrared spectral regions, respectively, can be straightforwardly achieved by CH-pi interaction-assisted self-assembly at the unimolecular level. Employing an octathionaphthalene-based single luminophore as a prototype, we find that a strength-adjustable CH-pi interaction-assisted self-assembly can be established in mixed DMF/H2O and in the film state. The hybridization of planar local excited and intramolecular charge transfer transitions occurs on the basis, allowing a competitive inhibition to the intersystem crossing process to generate a complex emission composed of visible fluorescence and near-infrared phosphorescence. Furthermore, reversible mechanochromic and mechanoluminescent conversions of the corresponding solid sample can both be observed to rely on a corresponding self-assembly alternation. These results can probably provide new visions for the development of future intelligent and multifunctional luminescent materials. PMID- 28073248 TI - Interplay of G Protein-Coupled Receptors with the Membrane: Insights from Supra Atomic Coarse Grain Molecular Dynamics Simulations. AB - G protein-coupled receptors (GPCRs) are central to many fundamental cellular signaling pathways. They transduce signals from the outside to the inside of cells in physiological processes ranging from vision to immune response. It is extremely challenging to look at them individually using conventional experimental techniques. Recently, a pseudo atomistic molecular model has emerged as a valuable tool to access information on GPCRs, more specifically on their interactions with their environment in their native cell membrane and the consequences on their supramolecular organization. This approach uses the Martini coarse grain (CG) model to describe the receptors, lipids, and solvent in molecular dynamics (MD) simulations and in enough detail to allow conserving the chemical specificity of the different molecules. The elimination of unnecessary degrees of freedom has opened up large-scale simulations of the lipid-mediated supramolecular organization of GPCRs. Here, after introducing the Martini CGMD method, we review these studies carried out on various members of the GPCR family, including rhodopsin (visual receptor), opioid receptors, adrenergic receptors, adenosine receptors, dopamine receptor, and sphingosine 1-phosphate receptor. These studies have brought to light an interesting set of novel biophysical principles. The insights range from revealing localized and heterogeneous deformations of the membrane bilayer at the surface of the protein, specific interactions of lipid molecules with individual GPCRs, to the effect of the membrane matrix on global GPCR self-assembly. The review ends with an overview of the lessons learned from the use of the CGMD method, the biophysical chemical findings on lipid-protein interplay. PMID- 28073249 TI - Introduction: G-Protein Coupled Receptors. PMID- 28073251 TI - Interfaces Select Specific Stereochemical Conformations: The Isomerization of Glyoxal at the Liquid Water Interface. AB - Interfacial chemistry involving glyoxal at aerosol surfaces is postulated to catalyze aerosol growth. This chemistry remains speculative due to a lack of detailed information concerning the physicochemical behavior of glyoxal at the interface of atmospheric aerosols. Here, we report results from high-level electronic structure calculations as well as both classical and Born-Oppenheimer ab initio molecular dynamics simulations of glyoxal solvation at the air/liquid water interface. When compared to the gas phase, the trans to cis isomerization of glyoxal at the liquid water interface is found to be catalyzed; additionally, the trans conformation is selectively solvated within the bulk to a greater degree than is the cis conformation. These two processes, i.e., the catalytic effect at the water interface and the differentially selective solvation, act to enhance the concentration of the cis isomer of glyoxal at the water interface. This has important consequences for the interpretation of experiments and for the modeling of glyoxal chemistry both at the interface of water clouds and at aerosols. Broader implications of this work relate to describing the role of interfaces in selecting specific stereo molecular structures at interfacial environments. PMID- 28073252 TI - JAFC-Most Trusted Partner in a Global Transition of Agriculture-Food-Nutrition Research! PMID- 28073253 TI - Harnessing Insect-Microbe Chemical Communications To Control Insect Pests of Agricultural Systems. AB - Insect pests cause serious economic, yield, and food safety problems to managed crops worldwide. Compounding these problems, insect pests often vector pathogenic or toxigenic microbes to plants. Previous work has considered plant-insect and plant-microbe interactions separately. Although insects are well-understood to use plant volatiles to locate hosts, microorganisms can produce distinct and abundant volatile compounds that in some cases strongly attract insects. In this paper, we focus on the microbial contribution to plant volatile blends, highlighting the compounds emitted and the potential for variation in microbial emission. We suggest that these aspects of microbial volatile emission may make these compounds ideal for use in agricultural applications, as they may be more specific or enhance methods currently used in insect control or monitoring. Our survey of microbial volatiles in insect-plant interactions suggests that these emissions not only signal host suitability but may indicate a distinctive time frame for optimal conditions for both insect and microbe. Exploitation of these host-specific microbe semiochemicals may provide important microbe- and host based attractants and a basis for future plant-insect-microbe chemical ecology investigations. PMID- 28073254 TI - Bottom-up Design of Three-Dimensional Carbon-Honeycomb with Superb Specific Strength and High Thermal Conductivity. AB - Low-dimensional carbon allotropes, from fullerenes, carbon nanotubes, to graphene, have been broadly explored due to their outstanding and special properties. However, there exist significant challenges in retaining such properties of basic building blocks when scaling them up to three-dimensional materials and structures for many technological applications. Here we show theoretically the atomistic structure of a stable three-dimensional carbon honeycomb (C-honeycomb) structure with superb mechanical and thermal properties. A combination of sp2 bonding in the wall and sp3 bonding in the triple junction of C-honeycomb is the key to retain the stability of C-honeycomb. The specific strength could be the best in structural carbon materials, and this strength remains at a high level but tunable with different cell sizes. C-honeycomb is also found to have a very high thermal conductivity, for example, >100 W/mK along the axis of the hexagonal cell with a density only ~0.4 g/cm3. Because of the low density and high thermal conductivity, the specific thermal conductivity of C honeycombs is larger than most engineering materials, including metals and high thermal conductivity semiconductors, as well as lightweight CNT arrays and graphene-based nanocomposites. Such high specific strength, high thermal conductivity, and anomalous Poisson's effect in C-honeycomb render it appealing for the use in various engineering practices. PMID- 28073255 TI - Biaxial Strain Transfer in Supported Graphene. AB - Understanding the mechanism and limits of strain transfer between supported 2D systems and their substrate is a most needed step toward the development of strain engineering at the nanoscale. This includes applications in straintronics, nanoelectromechanical devices, or new nanocomposites. Here, we have studied the limits of biaxial compressive strain transfer among SiO2, diamond, and sapphire substrates and graphene. Using high pressure-which allows maximizing the adhesion between graphene and the substrate on which it is deposited-we show that the relevant parameter governing the graphene mechanical response is not the applied pressure but rather the strain that is transmitted from the substrate. Under these experimental conditions, we also show the existence of a critical biaxial stress beyond which strain transfer become partial and introduce a parameter, alpha, to characterize strain transfer efficiency. The critical stress and alpha appear to be dependent on the nature of the substrate. Under ideal biaxial strain transfer conditions, the phonon Raman G-band dependence with strain appears to be linear with a slope of -60 +/- 3 cm-1/% down to biaxial strains of -0.9%. This evolution appears to be general for both biaxial compression and tension for different experimental setups, at least in the biaxial strain range -0.9% < epsilon < 1.8%, thus providing a criterion to validate total biaxial strain transfer hypotheses. These results invite us to cast a new look at mechanical strain experiments on deposited graphene as well as to other 2D layered materials. PMID- 28073256 TI - Quantum Transport in Gated Dangling-Bond Atomic Wires. AB - A single line of dangling bonds (DBs) on Si(100)-2 * 1:H surface forms a perfect metallic atomic-wire. In this work, we investigate quantum transport properties of such dangling bond wires (DBWs) by a state-of-the-art first-principles technique. It is found that the conductance of the DBW can be gated by electrostatic potential and orbital overlap due to only a single DB center (DBC) within a distance of ~16 A from the DBW. The gating effect is more pronounced for two DBCs and especially, when these two DB "gates" are within ~3.9 A from each other. These effective length scales are in excellent agreement with those measured in scanning tunnelling microscope experiments. By analyzing transmission spectrum and density of states of DBC-DBW systems, with or without subsurface doping, for different length of the DBW, distance between DBCs and the DBW, and distance between DB gates, we conclude that charge transport in a DBW can be regulated to have both an on-state and an off-state using only one or two DBs. PMID- 28073257 TI - Protein-Containing Lipid Bilayers Intercalated with Size-Matched Mesoporous Silica Thin Films. AB - Proteins are key components in a multitude of biological processes, of which the functions carried out by transmembrane (membrane-spanning) proteins are especially demanding for investigations. This is because this class of protein needs to be incorporated into a lipid bilayer representing its native environment, and in addition, many experimental conditions also require a solid support for stabilization and analytical purposes. The solid support substrate may, however, limit the protein functionality due to protein-material interactions and a lack of physical space. We have in this work tailored the pore size and pore ordering of a mesoporous silica thin film to match the native cell membrane arrangement of the transmembrane protein human aquaporin 4 (hAQP4). Using neutron reflectivity (NR), we provide evidence of how substrate pores host the bulky water-soluble domain of hAQP4, which is shown to extend 7.2 nm into the pores of the substrate. Complementary surface analytical tools, including quartz crystal microbalance with dissipation monitoring (QCM-D) and fluorescence microscopy, revealed successful protein-containing supported lipid bilayer (pSLB) formation on mesoporous silica substrates, whereas pSLB formation was hampered on nonporous silica. Additionally, electron microscopy (TEM and SEM), light scattering (DLS and stopped-flow), and small-angle X-ray scattering (SAXS) were employed to provide a comprehensive characterization of this novel hybrid organic inorganic interface, the tailoring of which is likely to be generally applicable to improve the function and stability of a broad range of membrane proteins containing water-soluble domains. PMID- 28073258 TI - Controlled Growth of Ceria Nanoarrays on Anatase Titania Powder: A Bottom-up Physical Picture. AB - The leading edge of catalysis research motivates physical understanding of the growth of nanoscale oxide structures on different supporting oxide materials that are themselves also nanostructured. This research opens up for consideration a diverse range of facets on the support material, versus the single facet typically involved in wide-area growth of thin films. Here, we study the growth of ceria nanoarchitectures on practical anatase titania powders as a showcase inspired by recent experiments. Density functional theory (DFT)-based methods are employed to characterize and rationalize the broad array of low energy nanostructures that emerge. Using a bottom-up approach, we are able to identify and characterize the underlying mechanisms for the facet-dependent growth of various ceria motifs on anatase titania based on formation energy. These motifs include 0D clusters, 1D chains, 2D plates, and 3D nanoparticles. The ceria growth mode and morphology are determined by the interplay of several factors including the role of the common cation valence, the interface template effect for different facets of the anatase support, enhanced ionic binding for more compact ceria motifs, and the local structural flexibility of oxygen ions in bridging the interface between anatase and ceria structures. PMID- 28073259 TI - Polarity-Induced Selective Area Epitaxy of GaN Nanowires. AB - We present a conceptually novel approach to achieve selective area epitaxy of GaN nanowires. The approach is based on the fact that these nanostructures do not form in plasma-assisted molecular beam epitaxy on structurally and chemically uniform cation-polar substrates. By in situ depositing and nitridating Si on a Ga polar GaN film, we locally reverse the polarity to induce the selective area epitaxy of N-polar GaN nanowires. We show that the nanowire number density can be controlled over several orders of magnitude by varying the amount of predeposited Si. Using this growth approach, we demonstrate the synthesis of single crystalline and uncoalesced nanowires with diameters as small as 20 nm. The achievement of nanowire number densities low enough to prevent the shadowing of the nanowire sidewalls from the impinging fluxes paves the way for the realization of homogeneous core-shell heterostructures without the need of using ex situ prepatterned substrates. PMID- 28073260 TI - Promoting Active Species Generation by Electrochemical Activation in Alkaline Media for Efficient Electrocatalytic Oxygen Evolution in Neutral Media. AB - In this study, by using dicobalt phosphide nanoparticles as precatalysts, we demonstrated that electrochemical activation of metallic precatalysts in alkaline media (comparing with directly electrochemical activation in neutral media) could significantly promote the OER catalysis in neutral media, specifically realizing a 2-fold enhanced activity and meanwhile showing a greatly decreased overpotential of about 100 mV at 10 mA cm-2. Compared directly with electrochemical activation in neutral media, the electrochemical activation in harsh alkaline media could easily break the strong Co-Co bond and promote active species generation on the surface of metallic Co2P, thus accounting for the enhancement of neutral OER activity, which is also evidenced by HRTEM and the electrochemical double-layer capacitance measurement. The activation of electrochemical oxidation of metallic precatalysts in alkaline media enhanced neutral OER catalysis could also be observed on CoP nanoparticles and Ni2P nanoparticles, suggesting this is a generic strategy. Our work highlights that the activation of electrochemical oxidation of metallic precatalysts in alkaline media would pave new avenues for the design of advanced neutral OER electrocatalysts. PMID- 28073261 TI - Insulating Nanomagnets Driven by Spin Torque. AB - Magnetic insulators, such as yttrium iron garnet (Y3Fe5O12), are ideal materials for ultralow power spintronics applications due to their low energy dissipation and efficient spin current generation and transmission. Recently, it has been realized that spin dynamics can be driven very effectively in micrometer-sized Y3Fe5O12/Pt heterostructures by spin-Hall effects. We demonstrate here the excitation and detection of spin dynamics in Y3Fe5O12/Pt nanowires by spin-torque ferromagnetic resonance. The nanowires defined via electron-beam lithography are fabricated by conventional room temperature sputtering deposition on Gd3Ga5O12 substrates and lift-off. We observe field-like and antidamping-like torques acting on the magnetization precession, which are due to simultaneous excitation by Oersted fields and spin-Hall torques. The Y3Fe5O12/Pt nanowires are thoroughly examined over a wide frequency and power range. We observe a large change in the resonance field at high microwave powers, which is attributed to a decreasing effective magnetization due to microwave absorption. These heating effects are much more pronounced in the investigated nanostructures than in comparable micron sized samples. By comparing different nanowire widths, the importance of geometrical confinements for magnetization dynamics becomes evident: quantized spin-wave modes across the width of the wires are observed in the spectra. Our results are the first stepping stones toward the realization of integrated magnonic logic devices based on insulators, where nanomagnets play an essential role. PMID- 28073263 TI - Low-Frequency Electronic Noise in Quasi-1D TaSe3 van der Waals Nanowires. AB - We report results of investigation of the low-frequency electronic excess noise in quasi-1D nanowires of TaSe3 capped with quasi-2D h-BN layers. Semimetallic TaSe3 is a quasi-1D van der Waals material with exceptionally high breakdown current density. It was found that TaSe3 nanowires have lower levels of the normalized noise spectral density, SI/I2, compared to carbon nanotubes and graphene (I is the current). The temperature-dependent measurements revealed that the low-frequency electronic 1/f noise becomes the 1/f2 type as temperature increases to ~400 K, suggesting the onset of electromigration (f is the frequency). Using the Dutta-Horn random fluctuation model of the electronic noise in metals, we determined that the noise activation energy for quasi-1D TaSe3 nanowires is approximately EP ~ 1.0 eV. In the framework of the empirical noise model for metallic interconnects, the extracted activation energy, related to electromigration is EA = 0.88 eV, consistent with that for Cu and Al interconnects. Our results shed light on the physical mechanism of low-frequency 1/f noise in quasi-1D van der Waals semimetals and suggest that such material systems have potential for ultimately downscaled local interconnect applications. PMID- 28073262 TI - Fluorescence Self-Quenching from Reporter Dyes Informs on the Structural Properties of Amyloid Clusters Formed in Vitro and in Cells. AB - The characterization of the aggregation kinetics of protein amyloids and the structural properties of the ensuing aggregates are vital in the study of the pathogenesis of many neurodegenerative diseases and the discovery of therapeutic targets. In this article, we show that the fluorescence lifetime of synthetic dyes covalently attached to amyloid proteins informs on the structural properties of amyloid clusters formed both in vitro and in cells. We demonstrate that the mechanism behind such a "lifetime sensor" of protein aggregation is based on fluorescence self-quenching and that it offers a good dynamic range to report on various stages of aggregation without significantly perturbing the process under investigation. We show that the sensor informs on the structural density of amyloid clusters in a high-throughput and quantitative manner and in these aspects the sensor outperforms super-resolution imaging techniques. We demonstrate the power and speed of the method, offering capabilities, for example, in therapeutic screenings that monitor biological self-assembly. We investigate the mechanism and advantages of the lifetime sensor in studies of the K18 protein fragment of the Alzheimer's disease related protein tau and its amyloid aggregates formed in vitro. Finally, we demonstrate the sensor in the study of aggregates of polyglutamine protein, a model used in studies related to Huntington's disease, by performing correlative fluorescence lifetime imaging microscopy and structured-illumination microscopy experiments in cells. PMID- 28073264 TI - Metal-Organic Polyhedra-Coated Si Nanowires for the Sensitive Detection of Trace Explosives. AB - Surface-modified silicon nanowire-based field-effect transistors (SiNW-FETs) have proven to be a promising platform for molecular recognition in miniature sensors. In this work, we present a novel nanoFET device for the sensitive and selective detection of explosives based on affinity layers of metal-organic polyhedra (MOPs). The judicious selection of the geometric and electronic characteristics of the assembly units (organic ligands and unsaturated metal site) embedded within the MOP cage allowed for the formation of multiple charge-transfer (CT) interactions to facilitate the selective explosive inclusion. Meanwhile, the host stabilized CT complex inside the cage acted as an effective molecular gating element to strongly modulate the electrical conductance of the silicon nanowires. By grafting the MOP cages onto a SiNW-FET device, the resulting sensor showed a good electrical sensing capability to various explosives, especially 2,4,6 trinitrotoluene (TNT), with a detection limit below the nanomolar level. Importantly, coupling MOPs-which have tunable structures and properties-to SiNW based devices may open up new avenues for a wide range of sensing applications, addressing various target analytes. PMID- 28073265 TI - Correction to Enhancing the Brightness of Cesium Lead Halide Perovskite Nanocrystal Based Green Light-Emitting Devices through the Interface Engineering with Perfluorinated Ionomer. PMID- 28073266 TI - Surface Magnetism of Cobalt Nanoislands Controlled by Atomic Hydrogen. AB - Controlling the spin states of the surface and interface is key to spintronic applications of magnetic materials. Here, we report the evolution of surface magnetism of Co nanoislands on Cu(111) upon hydrogen adsorption and desorption with the hope of realizing reversible control of spin-dependent tunneling. Spin polarized scanning tunneling microscopy reveals three types of hydrogen-induced surface superstructures, 1H-(2 * 2), 2H-(2 * 2), and 6H-(3 * 3), with increasing H coverage. The prominent magnetic surface states of Co, while being preserved at low H coverage, become suppressed as the H coverage level increases, which can then be recovered by H desorption. First-principles calculations reveal the origin of the observed magnetic surface states by capturing the asymmetry between the spin-polarized surface states and identify the role of hydrogen in controlling the magnetic states. Our study offers new insights into the chemical control of magnetism in low-dimensional systems. PMID- 28073267 TI - Folding Sheets with Ion Beams. AB - Focused ion beams (FIBs) are versatile tools with cross-disciplinary applications from the physical and life sciences to archeology. Nevertheless, the nanoscale patterning precision of FIBs is often accompanied by defect formation and sample deformation. In this study, the fundamental mechanisms governing the large-scale plastic deformation of nanostructures undergoing FIB processes are revealed by a series of molecular dynamic simulations. A surprisingly simple linear correlation between atomic volume removed from the film bulk and film deflection angle, regardless of incident ion energy and current, is revealed, demonstrating that the mass transport to the surface of material caused by energetic ion bombardment is the primary cause leading to nanostructure deformation. Hence, by controlling mass transport by manipulation of the incident ion energy and flux, it is possible to control the plastic deformation of nanostructures, thereby fabricating nanostructures with complex three-dimensional geometries. PMID- 28073268 TI - Dual-Wavelength Switchable Vibronic Lasing in Single-Crystal Organic Microdisks. AB - Wavelength switchable micro/nanoscale laser is essential to construct various ultracompact photonic devices. However, traditional semiconductors as the gain media generally provide only monochromatic laser output due to their continuous energy band structures. For luminescent conjugated molecules, the broad emission band usually contains a series of vibronic peaks, which is very helpful for extending the lasing spectrum to several different wavelengths. Here we propose a novel strategy to realize wavelength switchable lasers based on the controlled competition of dual-wavelength vibronic lasing in single-component organic microcrystals. The vibrationally structured fluorescence property of the single crystal organic microdisks brings dual-wavelength lasing at different vibronic bands. Their relative optical gain intensity was modulated by controlling the population on the certain vibronic level of the ground state with varied temperature, which consequently enabled the reversible switching of the dual wavelength vibronic lasing. The results point out a promising route to the rational design of miniaturized lasers and other photonic elements with desired performances. PMID- 28073269 TI - Efficient Photothermoelectric Conversion in Lateral Topological Insulator Heterojunctions. AB - Tuning the electron and phonon transport properties of thermoelectric materials by nanostructuring has enabled improving their thermopower figure of merit. Three dimensional topological insulators, including many bismuth chalcogenides, attract increasing attention for this purpose, as their topologically protected surface states are promising to further enhance the thermoelectric performance. While individual bismuth chalcogenide nanostructures have been studied with respect to their photothermoelectric properties, nanostructured p-n junctions of these compounds have not yet been explored. Here, we experimentally investigate the room temperature thermoelectric conversion capability of lateral heterostructures consisting of two different three-dimensional topological insulators, namely, the n-type doped Bi2Te2Se and the p-type doped Sb2Te3. Scanning photocurrent microscopy of the nanoplatelets reveals efficient thermoelectric conversion at the p-n heterojunction, exploiting hot carriers of opposite sign in the two materials. From the photocurrent data, a Seebeck coefficient difference of DeltaS = 200 MUV/K was extracted, in accordance with the best values reported for the corresponding bulk materials. Furthermore, it is in very good agreement with the value of DeltaS = 185 MUV/K obtained by DFT calculation taking into account the specific doping levels of the two nanostructured components. PMID- 28073270 TI - Cooperative Molecular Behavior Enhances the Thermal Conductance of Binary Self Assembled Monolayer Junctions. AB - The effect of the local molecular environment on thermal transport through organic-inorganic heterojunctions is investigated using binary self-assembled monolayer (SAM) junctions built from a mixture of alkanethiol and alkanedithiol species sandwiched between gold leads. Thermoreflectance measurements and molecular dynamics simulations demonstrate that the thermal conductances of the binary SAM junctions vary with molecular composition and are greater than predictions of a parallel resistance model. The enhancement results from increased thermal transport through the alkanethiols, whose terminal methyl groups are confined by the anchored alkanedithiols. This confinement effect extends over length scales that are more than twice the range of the van der Waals interactions between molecules and are commensurate to the sizes of experimentally observed molecular domains. Conversely, for a partially packed (i.e., submonolayer) alkanedithiol unary SAM, increasing the molecular packing density decreases the per molecule thermal conductance. This finding indicates that thermal transport measurements of SAMs cannot be used to predict the thermal transport properties of single molecules. PMID- 28073271 TI - Molecular Rectification Tuned by Through-Space Gating Effect. AB - Inspired by transistors and electron transfer in proteins, we designed a group of pyridinoparacyclophane based diodes to study the through-space electronic gating effect on molecular rectification. It was shown that an edge-on gate effectively tunes the rectification ratio of a diode via through-space interaction. Higher rectification ratio was obtained for more electron-rich gating groups. The transition voltage spectroscopy showed that the forward transition voltage is correlated to the Hammett parameter of the gating group. Combining theoretical calculation and experimental data, we proposed that the change in rectification was induced by a shift in HOMO level both spatially and energetically. This design principle based on through-space edge-on gate is demonstrated on molecular wires, switches, and now diodes, showing the potential of molecular design in increasing the complexity of single-molecule electronic devices. PMID- 28073272 TI - Phase Transitions in Spin-Crossover Thin Films Probed by Graphene Transport Measurements. AB - Future multifunctional hybrid devices might combine switchable molecules and 2D material-based devices. Spin-crossover compounds are of particular interest in this context since they exhibit bistability and memory effects at room temperature while responding to numerous external stimuli. Atomically thin 2D materials such as graphene attract a lot of attention for their fascinating electrical, optical, and mechanical properties, but also for their reliability for room-temperature operations. Here, we demonstrate that thermally induced spin state switching of spin-crossover nanoparticle thin films can be monitored through the electrical transport properties of graphene lying underneath the films. Model calculations indicate that the charge carrier scattering mechanism in graphene is sensitive to the spin-state dependence of the relative dielectric constants of the spin-crossover nanoparticles. This graphene sensor approach can be applied to a wide class of (molecular) systems with tunable electronic polarizabilities. PMID- 28073273 TI - Ultrafast Exciton Dissociation and Long-Lived Charge Separation in a Photovoltaic Pentacene-MoS2 van der Waals Heterojunction. AB - van der Waals heterojunctions between two-dimensional (2D) layered materials and nanomaterials of different dimensions present unique opportunities for gate tunable optoelectronic devices. Mixed-dimensional p-n heterojunction diodes, such as p-type pentacene (0D) and n-type monolayer MoS2 (2D), are especially interesting for photovoltaic applications where the absorption cross-section and charge transfer processes can be tailored by rational selection from the vast library of organic molecules and 2D materials. Here, we study the kinetics of excited carriers in pentacene-MoS2 p-n type-II heterojunctions by transient absorption spectroscopy. These measurements show that the dissociation of MoS2 excitons occurs by hole transfer to pentacene on the time scale of 6.7 ps. In addition, the charge-separated state lives for 5.1 ns, up to an order of magnitude longer than the recombination lifetimes from previously reported 2D material heterojunctions. By studying the fractional amplitudes of the MoS2 decay processes, the hole transfer yield from MoS2 to pentacene is found to be ~50%, with the remaining holes undergoing trapping due to surface defects. Overall, the ultrafast charge transfer and long-lived charge-separated state in pentacene-MoS2 p-n heterojunctions suggest significant promise for mixed-dimensional van der Waals heterostructures in photovoltaics, photodetectors, and related optoelectronic technologies. PMID- 28073274 TI - Quantum Dots Embedded in Graphene Nanoribbons by Chemical Substitution. AB - Bottom-up chemical reactions of selected molecular precursors on a gold surface can produce high quality graphene nanoribbons (GNRs). Here, we report on the formation of quantum dots embedded in an armchair GNR by substitutional inclusion of pairs of boron atoms into the GNR backbone. The boron inclusion is achieved through the addition of a small amount of boron substituted precursors during the formation of pristine GNRs. In the pristine region between two boron pairs, the nanoribbons show a discretization of their valence band into confined modes compatible with a Fabry-Perot resonator. Transport simulations of the scattering properties of the boron pairs reveal that they selectively confine the first valence band of the pristine ribbon while allowing an efficient electron transmission of the second one. Such band-dependent electron scattering stems from the symmetry matching between the electronic wave functions of the states from the pristine nanoribbons and those localized at the boron pairs. PMID- 28073275 TI - Highly Efficient Retention of Polysulfides in "Sea Urchin"-Like Carbon Nanotube/Nanopolyhedra Superstructures as Cathode Material for Ultralong-Life Lithium-Sulfur Batteries. AB - Despite high theoretical energy density, the practical deployment of lithium sulfur (Li-S) batteries is still not implemented because of the severe capacity decay caused by polysulfide shuttling and the poor rate capability induced by low electrical conductivity of sulfur. Herein, we report a novel sulfur host material based on "sea urchin"-like cobalt nanoparticle embedded and nitrogen-doped carbon nanotube/nanopolyhedra (Co-NCNT/NP) superstructures for Li-S batteries. The hierarchical micromesopores in Co-NCNT/NP can allow efficient impregnation of sulfur and block diffusion of soluble polysulfides by physical confinement, and the incorporation of embedded Co nanoparticles and nitrogen doping (~4.6 at. %) can synergistically improve the adsorption of polysulfides, as evidenced by beaker cell tests. Moreover, the conductive networks of Co-NCNT/NP interconnected by nitrogen-doped carbon nanotubes (NCNTs) can facilitate electron transport and electrolyte infiltration. Therefore, the specific capacity, rate capability, and cycle stability of Li-S batteries are significantly enhanced. As a result, the Co NCNT/NP based cathode (loaded with 80 wt % sulfur) delivers a high discharge capacity of 1240 mAh g-1 after 100 cycles at 0.1 C (based on the weight of sulfur), high rate capacity (755 mAh g-1 at 2.0 C), and ultralong cycling life (a very low capacity decay of 0.026% per cycle over 1500 cycles at 1.0 C). Remarkably, the composite cathode with high areal sulfur loading of 3.2 mg cm-2 shows high rate capacities and stable cycling performance over 200 cycles. PMID- 28073277 TI - An Editor's Musings for the New Year. PMID- 28073276 TI - Interlaced, Nanostructured Interface with Graphene Buffer Layer Reduces Thermal Boundary Resistance in Nano/Microelectronic Systems. AB - Improving heat transfer in hybrid nano/microelectronic systems is a challenge, mainly due to the high thermal boundary resistance (TBR) across the interface. Herein, we focus on gallium nitride (GaN)/diamond interface-as a model system with various high power, high temperature, and optoelectronic applications-and perform extensive reverse nonequilibrium molecular dynamics simulations, decoding the interplay between the pillar length, size, shape, hierarchy, density, arrangement, system size, and the interfacial heat transfer mechanisms to substantially reduce TBR in GaN-on-diamond devices. We found that changing the conventional planar interface to nanoengineered, interlaced architecture with optimal geometry results in >80% reduction in TBR. Moreover, introduction of conformal graphene buffer layer further reduces the TBR by ~33%. Our findings demonstrate that the enhanced generation of intermediate frequency phonons activates the dominant group velocities, resulting in reduced TBR. This work has important implications on experimental studies, opening up a new space for engineering hybrid nano/microelectronics. PMID- 28073278 TI - Wear Resistance Limited by Step Edge Failure: The Rise and Fall of Graphene as an Atomically Thin Lubricating Material. AB - Owing to its intrinsically lubricious property, graphene has a high potential to be an atomically thin solid lubricant for sliding interfaces. Despite its ultrahigh breaking strength at the nanoscale, graphene often fails to maintain its integrity when subjected to macroscale tribological tests. To reveal the true wear characteristics of graphene, a nanoscale diamond tip was used to scratch monolayer graphene mechanically exfoliated to SiO2 substrates. Our experimental results show that while graphene exhibited extraordinary wear resistance in the interior region, it could be easily damaged at the step edge under a much lower normal load (~2 orders of magnitude smaller). Similar behavior with substantially reduced wear resistance at the edge was also observed for monatomic graphene layer on graphite surface. Using molecular dynamics simulations, we attributed this markedly weak wear resistance at the step edge to two primary mechanisms, i.e., atom-by-atom adhesive wear and peel induced rupture. Our findings shed light on the paradox that graphene is nanoscopically strong yet macroscopically weak. As step edge is ubiquitous for two-dimensional materials at the macroscale, our study also provides a guiding direction for maximizing the mechanical and tribological performance of these atomically thin materials. PMID- 28073279 TI - The optical method of measurement of sizes and the refractive index of nanoparticles Ag@Fe3O4. AB - The spectrophotometric method and the electron microscope have been used to determine the distribution function of Ag@Fe3O4 nanoparticles by sizes and to measure their complex refractive index. These particles have been synthesized as acomponent of magnetically controlled drugs with antibacterial properties. The algorithm of processing the results of the experiment has been designed to measure the sizes of nanoparticles (1-100 nm).Key words: nanoparticle sizes measuring spectrum attenuation. PMID- 28073280 TI - [The conscientious objection among pharmacists in the Slovak Republic]. AB - There were two primary objectives of this study: 1. bibliographic analysis of literature on pharmacists and conscientious objection, 2. analysis of present condition and attitudes of pharmacists (n = 100) and pharmacy students (n = 100) towards conscientious objection in the Slovak Republic. Data were obtained from the survey using by questionnaire.Almost all, 191 (95.5%) respondents knew the phrase "conscientious objection". The respondents claimed this right to refuse filling prescriptions written for emergency post-coital contraception in 43.5%, and dispensing of hormonal contraception in 26.5%. Most participants, 178 (89.0%) think that pharmacists have the right to conscientious objection. 65 respondents (32.5%) implement this right in their practice.Key words: conscientious objection pharmacists pharmacy students Pro-life pharmacies. PMID- 28073283 TI - Corrigendum. AB - Rhee YG, Cho NS, Parke CS. Arthroscopic rotator cuff repair using modified Mason Allen medial row stitch: knotless versus knot-tying suture bridge technique. Am J Sports Med. 2012;40(11):2440-2447. (Original DOI: 10.1177/0363546512459170 ). PMID- 28073281 TI - [Jews in European pharmacy from the seventh to the early twentieth centuries]. AB - This article deals with less familiar theme - the status of Jewish doctors and pharmacists in the history of pharmacy from the 7th century AD to the early 20th century. They played an important role in the history of the Iberian Peninsula - initially under Muslim and after the Reconquista in 1492 under Christian rule. Most of them chose assimilation into the surrounding milieu, some of them escaped before the Christian Inquisition. Despite persecution, it was the golden age of Jewish medicine and pharmacy. During the existence of the Frankish empire we find only rare mentions of them - Jews isolated in the area of urban Jewish ghettos. Jewish doctors and pharmacists found better employment first in some Protestant countries (England, Holland). In Germany and Central Europe they gained ground at the end of the 19th century. A number of prominent scientists, especially from Eastern Europe, at the turn of the 19th and 20th centuries found a solution in immigration to the US to escape were anti-Semitism.Key words: Jews pharmacy Arab empire pharmacology. PMID- 28073284 TI - Posterior Glottic Insufficiency in Children. AB - BACKGROUND: Dysphonia secondary to posterior glottic insufficiency (PGI) can be difficult to identify and correct. Inadequate arytenoid approximation from medial arytenoid erosion results in a breathy, soft voice. The anatomical location of the gap is difficult to correct by vocal fold injection laryngoplasty. This study reviews the presentation, evaluation, and treatment for pediatric patients who were identified with PGI. METHODS: An Institutional Review Board-approved chart review was performed on all patients who were diagnosed with PGI at our institution from 2013 to 2015. We studied the presentation, workup, and treatment for these patients, including laryngoscopy, parent or patient-based voice impairment ratings, and response to treatment. RESULTS: Seven patients were identified. Erosion of the medial arytenoid was identified on microlaryngoscopy for all of these patients. The patients had suboptimal improvement from injection laryngoplasty. Three patients underwent surgical correction with an endoscopic posterior cricoid reduction laryngoplasty (EPCRL) with significant improvement in voice, assessed by perceptual, laryngoscopic, and patient-based measures. CONCLUSION: The key diagnostic procedures to identify posterior glottic insufficiency include laryngoscopic findings of a posterior glottal gap, microlaryngoscopy with close inspection of the posterior glottis and medial arytenoids, and suboptimal response to injection laryngoplasty. The EPCRL is an effective procedure to treat dysphonia from PGI. PMID- 28073285 TI - Muscle-Nerve-Muscle Grafting for Facial Reanimation in Rats. AB - OBJECTIVE: Facial paralysis is a devastating condition leaving patients with a myriad of aesthetic and functional consequences. Muscle-nerve-muscle (MNM) neurotization is a reinnervation technique that involves implanting an autogenous nerve graft as a conduit between an innervated "donor" muscle and a denervated "recipient" muscle. We investigated the use of MNM reinnervation, alone or in combination with electrical stimulation (ES) and testosterone propionate (TP) in comparison to nerve reanastomosis (RE), on functional recovery following rat facial nerve injury. METHODS: Thirty-one male, Sprague-Dawley rats were assigned to groups: no graft (control), MNM grafting alone (MNM), MNM grafting with ES and TP (MNM+ES+TP), or RE. Harvested right facial nerve branches were used as the MNM graft. Functional recovery was assessed by behavioral observations and electromyographic recordings. RESULTS: The MNM grafting improved muscle tone and vibrissae movement. The ES+TP treatment further enhanced muscle tone as well as reduced recovery time for coordinated movement in a manner that is comparable to those of RE. Electromyographic recordings demonstrated electrical conductance across all MNM grafts. CONCLUSION: These data have important implications for patients with unilateral paralysis from facial or laryngeal nerve injury, particularly those who are not candidates for nerve reanastomosis. PMID- 28073286 TI - Bipolar Plasmakinetic Enucleoresection of the Prostate: Our Experience with 245 Patients for 3 Years of Follow-Up. AB - OBJECTIVE: The aim of this study was to evaluate the safety, feasibility, and effectiveness of bipolar transurethral plasmakinetic enucleation of the prostate (PKEP). PATIENTS AND METHODS: Between January 2010 and October 2013, 245 patients with lower urinary tract symptoms due to benign prostatic hyperplasia underwent transurethral enucleation of prostate using bipolar plasma vaporization energy. Patients were evaluated preoperatively by full detailed history, routine preoperative investigation digital rectal examination, serum prostate-specific antigen, abdominal and transrectal ultrasonography, and maximum flow rates (Qmax). RESULTS: Patients' ages ranged from 50 to 81 (65.5 +/- 6) years with transrectal ultrasound-measured prostate volume of 97.1 +/- 36.7 mL resulting in an operating time of 76.9 +/- 27.9 minutes, and postoperative irrigation and catheterization times were 3.5 +/- 3.2 and 12.7 +/- 6.1 hours, respectively. No significant complication occurred intra- or postoperatively. Qmax increased from 7.1 +/- 3.2 mL/second preoperative to 18.4 +/- 4.2 mL/second (p < 0.001). The International Prostate Symptom Score decreased from 25 +/- 6 to 7.9 +/- 2.4 (p < 0.01). CONCLUSION: This study confirmed that PKEP is a safe, easy to learn, and durable technique suitable for any prostate sizes. PMID- 28073287 TI - Psychological growth and well-being in individuals born with cleft: An application of self-determination theory. AB - OBJECTIVE: Many studies of individuals born with cleft lip and/or palate (CLP) address the psychological impact of CLP in terms of stigma and/or 'resilience'. The present study challenges the usefulness of resilience in CLP research with the application of self-determination theory (SDT). It is proposed that SDT can serve to better understand how individuals born with CLP can achieve psychological growth and well-being. DESIGN: Interviews were conducted with 15 individuals born with CLP in the UK. RESULTS: A thematic analysis was conducted and four main themes emerged: (1) personal challenges, (2) support and strategies for social interaction, (3) experience of treatment and outcomes, and (4) personal development. The thematic analysis and the interpretation in the context of SDT leads to a greater understanding of the development of psychological growth and well-being in individuals born with CLP. CONCLUSION: Interpreting the life experiences of individuals with CLP through the theoretical lens of SDT allows the conceptualisation of individuals with CLP as a positive psychological resource when faced with the exclusionary practice of stigma. This resourcefulness is primarily nurtured by a supportive family and social environment that leads to the development of positive psychological growth and well-being. A new direction in CLP research is proposed that seeks to inform and implement change in professional practice to support individuals with CLP and their families. PMID- 28073288 TI - Pattern Versus Change: Community-Based Dyadic Heart Failure Self-Care. AB - It is imperative that dyadic heart failure (HF) self-care be carefully examined so we can develop interventions which improve patient outcomes. The purpose of this study was to qualitatively examine how patient/informal caregiver dyads mutually engage in managing the patient's HF at home. Twenty-seven dyads were interviewed using a theoretically derived interview guide. All interviews were digitally recorded and professionally transcribed, and iterative thematic analysis was conducted. Three descriptive themes emerged-Mutual engagement in self-care involves maintaining established patterns of engagement across the life course of the relationship, changing patterns according to whether it is day-to day care or symptom management, and mobilizing the help of a third party as consultant. These themes reveal the dyadic conundrum-whether to change or remain the same in the face of a dynamic and progressive condition like HF. The themes suggest potential targets for intervention-interventions focused on the relationship or caregiver activation. PMID- 28073289 TI - Generation and Characterization of HIV-1 Transmitted and Founder Virus Consensus Sequence from Intravenous Drug Users in Xinjiang, China. AB - HIV-1 transmission in intravenous drug users (IDUs) has been characterized by high genetic multiplicity and suggests a greater challenge for HIV-1 infection blocking. We investigated a total of 749 sequences of full-length gp160 gene obtained by single genome sequencing (SGS) from 22 HIV-1 early infected IDUs in Xinjiang province, northwest China, and generated a transmitted and founder virus (T/F virus) consensus sequence (IDU.CON). The T/F virus was classified as subtype CRF07_BC and predicted to be CCR5-tropic virus. The variable region (V1, V2, and V4 loop) of IDU.CON showed length variation compared with the heterosexual T/F virus consensus sequence (HSX.CON) and homosexual T/F virus consensus sequence (MSM.CON). A total of 26 N-linked glycosylation sites were discovered in the IDU.CON sequence, which is less than that of MSM.CON and HSX.CON. Characterization of T/F virus from IDUs highlights the genetic make-up and complexity of virus near the moment of transmission or in early infection preceding systemic dissemination and is important toward the development of an effective HIV-1 preventive methods, including vaccines. PMID- 28073290 TI - Intra- and Interorgan Communication in the Cardiovascular System: A Special View on Redox Regulation. AB - Intraorgan communication in the cardiovascular system is exerted not only by direct cell-cell contacts but also by locally released factors, which modulate neighboring cells by paracrine signals (e.g., NO, vascular endothelial growth factor, adenosine, reactive oxygen species). Moreover, cells in close proximity to the typical cardiovascular cells such as fibroblasts, red blood cells, as well as resident and invading immune cells must be considered in attempts to understand cardiovascular function in physiology and pathology. The second level of communication is the interorgan communication, which may be distinguished from intraorgan communication, since it involves signaling from remote organs to the heart and circulation. Therefore, mediators released by, for example, the kidney or skeletal muscle reach the heart and modulate its function. This is not only the case under physiological conditions, because there is increasing evidence that the organ-specific response to a primary insult may affect also the function of remote organs by the release of factors. This Forum will summarize novel mechanisms involved in intraorgan and interorgan communication of the cardiovascular system, with a special view on the remote organs, skeletal muscle and kidney. Antioxid. Redox Signal. 26, 613-615. PMID- 28073292 TI - Health-Care Utilization After Hospice Enrollment in Patients With Heart Failure and Cancer. AB - This study aimed to examine the role of diagnosis in health-care utilization patterns after hospice enrollment. Using 2007 National Home and Hospice Care Survey data from hospice patients with heart failure (n = 311) and cancer (n = 946), we analyzed emergency service use and discharge to hospital via logistic regression pre- and postpropensity score matching. Prematching, patients with heart failure had twice the odds of emergency services use than patients with cancer ( P < .001) and twice the odds of discharge to hospital ( P = .02). Differences were reduced postmatching for emergency service use (odds ratio [OR]: 1.6, P = .05) and eliminated for discharge to hospital (OR: 1.32, P = .45). Health-care utilization correlates included diagnosis, place of care, and advance directives. Attention to the unique needs of patients with heart failure is needed, along with improved advanced care planning. PMID- 28073293 TI - Restricted Interests and Autism: Further Assessment of Preferences for a Variety of Leisure Items. AB - Researchers have yet to identify the conditions under which people diagnosed with autism spectrum disorder demonstrate restricted interests; it is possible that the impression of restricted interests is strengthened when a limited variety of items are included in a client's preference assessments. This study will extend past research on preferences of children with autism by (a) examining participants' preferences for unreplenished (familiar) play or leisure items versus items that are replenished frequently, (b) assessing if participants who prefer replenished items select items with properties that are matched or unmatched to their most preferred unreplenished item, and (c) assessing if participants who show an exclusive preference for unreplenished items will select replenished items during response-restriction and enhanced-replenished pool manipulations. Participants were four adolescents with autism and a caregiver reported history of restricted interests. One participant selected both unreplenished (familiar) items and replenished (novel) items without further manipulations. The remaining three participants only selected replenished-matched leisure items after additional manipulations. Results are discussed in terms of the ethical and practical importance of assessing a range of potential reinforcers, particularly with clients who demonstrate restricted interests. PMID- 28073291 TI - Future of rAAV Gene Therapy: Platform for RNAi, Gene Editing, and Beyond. AB - The use of recombinant adeno-associated viruses (rAAVs) ushered in a new millennium of gene transfer for therapeutic treatment of a number of conditions, including congenital blindness, hemophilia, and spinal muscular atrophy. rAAV vectors have remarkable staying power from a therapeutic standpoint, withstanding several ebbs and flows. As new technologies such as clustered regularly interspaced short palindromic repeat genome editing emerge, it is now the delivery tool-the AAV vector-that is the stalwart. The long-standing safety of this vector in a multitude of clinical settings makes rAAV a selling point in the advancement of approaches for gene replacement, gene knockdown, gene editing, and genome modification/engineering. The research community is building on these advances to develop more tailored delivery approaches and to tweak the genome in new and unique ways. Intertwining these approaches with newly engineered rAAV vectors is greatly expanding the available tools to manipulate gene expression with a therapeutic intent. PMID- 28073294 TI - Circulating tumor cells and DNA for real-time EGFR detection and monitoring of non-small-cell lung cancer. AB - AIM: We investigate the suitability of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in non-small-cell lung cancer management, which is challenging in conventional biopsies. MATERIALS & METHODS: We performed serial blood extraction from 120 patients of varying EGFR status. Molecular profiling was performed using droplet digital PCR and correlated to survival outcome. RESULTS: Overall, we observed 95% agreement using CTCs and ctDNA with conventional tissue biopsies, which indicated the disease's close correlation. The mutant signature was stable and captured the dynamic changes during treatment. It aided to stratify patients with worse survival outcome. CONCLUSION: CTCs and ctDNA can complement current disease management. We demonstrated its effectiveness in continuous disease profiling, which is critical for clinical decision-making. PMID- 28073295 TI - The frequency and predictors of poly-victimisation of South African children and the role of schools in its prevention. AB - Violence has become a characteristic feature of South African society, with women and children often bearing the brunt of this. Contemporary research suggests that the key to stemming the tide of child victimisation is understanding the complete inventory of victimisations that may co-occur during childhood. There is growing recognition that children in South Africa typically experience abuse in the context of other forms of maltreatment and victimisation. This article draws on the empirical data collected for a national prevalence and incidence study on child sexual abuse and maltreatment in South Africa and draws attention to the frequency of poly-victimisation amongst South African children and highlights why some children experience multiple co-occurring forms of victimisations while others do not. Understanding the complete victim profile of young children, and how the different forms of victimisation they experience intersect, is critical to ensuring that the most vulnerable South Africans are provided with the extensive and targeted interventions required to break free from their heightened vulnerability to victimisation. PMID- 28073297 TI - Effective public involvement in the HoST-D Programme for dementia home care support: From proposal and design to methods of data collection (innovative practice). AB - Public involvement is an important element in health and social care research. However, it is little evaluated in research. This paper discusses the utility and impact of public involvement of carers and people with dementia in a five-year programme on effective home support in dementia, from proposal and design to methods of data collection, and provides a useful guide for future research on how to effectively involve the public. The Home SupporT in Dementia (HoST-D) Programme comprises two elements of public involvement, a small reference group and a virtual lay advisory group. Involving carers and people with dementia is based on the six key values of involvement - respect, support, transparency, responsiveness, fairness of opportunity, and accountability. Carers and people with dementia gave opinions on study information, methods of data collection, an economic model, case vignettes, and a memory aid booklet, which were all taken into account. Public involvement has provided benefits to the programme whilst being considerate of the time constraints and geographical locations of members. PMID- 28073298 TI - Extraperitoneal vs Transperitoneal Robot-Assisted Radical Prostatectomy in the Setting of Prior Abdominal or Pelvic Surgery. AB - INTRODUCTION: During robot-assisted radical prostatectomy (RARP), the prostate may be approached extraperiteoneally (extraperitoneal robot-assisted radical prostatectomy [eRARP]) or transperitoneally (transperitoneal robot-assisted radical prostatectomy [tRARP]). The former avoids the abdominal cavity, which might be of benefit in patients who have had prior abdominal or pelvic surgery (PAPS). Our objective was to compare the outcomes of patients with PAPS undergoing either technique. METHODS: A retrospective review of patients treated with RARP from July 1, 2003 to December 31, 2014 with a minimum follow-up of 3 months was undertaken. Of 2927 patients, 620 were identified as having undergone RARP (without concomitant unrelated procedures) and PAPS (excluding patients with prior inguinal hernia repair with mesh or unclear surgical histories) for prostate adenocarcinoma without prior pelvic radiotherapy. Of these, 340 patients underwent eRARP and 280 patients underwent tRARP. RESULTS: Patients in the eRARP group were younger (61.04 years vs 62.32, p = 0.02), had a higher body mass index (29.65 vs 28.98, p = 0.09), lower American Society of Anesthesiologists scores (p = 0.03), and lower D'Amico risk classification disease (p < 0.0001). The two groups had similar rates of 1, 2, and >2 PAPS. On univariate analysis, the eRARP group had lower operative time (188.96 minutes vs 197.92 minutes, p = 0.003), extensive lysis of adhesions (0.9% vs 14.3%, p < 0.0001), length of hospital stay (LOS) (1.13 days +/-0.45 vs 1.33 day +/-1.08, p = 0.003), and higher estimated blood loss (210.74 mL vs 190.79 mL, p = 0.06). The eRARP group had a lower rate of gastrointestinal complications (0% vs 3.21%, p = 0.0007), a trend toward lower early post-operative complications (8.53% vs 12.86%, p = 0.08), and lower overall complications (9.41% vs 15%, p = 0.03). In regression analysis with model selection, only LOS was lower in the eRARP group (p = 0.02). CONCLUSIONS: Both methods are safe in patients with prior abdominal surgeries. A lower incidence of gastrointestinal complications and a shorter length of stay were noted in the extraperitoneal cohort. PMID- 28073296 TI - The Microbiome and Complement Activation: A Mechanistic Model for Preterm Birth. AB - Preterm birth (PTB, <37 completed weeks' gestation) is one of the leading obstetrical problems in the United States, affecting approximately one of every nine births. Even more concerning are the persistent racial disparities in PTB, with particularly high rates among African Americans. There are several recognized pathophysiologic pathways to PTB, including infection and/or exaggerated systemic or local inflammation. Intrauterine infection is a causal factor linked to PTB thought to result most commonly from inflammatory processes triggered by microbial invasion of bacteria ascending from the vaginal microbiome. Trials to treat various infections have shown limited efficacy in reducing PTB risk, suggesting that other complex mechanisms, including those associated with inflammation, may be involved in the relationship between microbes, infection, and PTB. The complement system, a key mediator of the inflammatory response, is an innate defense mechanism involved in both normal physiologic processes that occur during pregnancy implantation and processes that promote the elimination of pathogenic microbes. Recent research has demonstrated an association between this system and PTB. The purpose of this article is to present a mechanistic model of inflammation-associated PTB, which hypothesizes a relationship between the microbiome and dysregulation of the complement system. Exploring the relationships between the microbial environment and complement biomarkers may elucidate a potentially modifiable biological pathway to PTB. PMID- 28073299 TI - The Changing Impact of Gastroesophageal Reflux Disease in Clinical Practice. AB - OBJECTIVES: The National Ambulatory Medical Care Survey (NAMCS) database was utilized to understand evolving national trends in diagnosis and management of reflux. METHODS: The NAMCS database was queried for visits related to gastroesophageal reflux diagnosis and management. Analysis performed for time periods 1998-2001, 2002-2005, and 2006-2009 was weighted to provide national estimates of care. Results were compared to previously reported time periods from 1990 to 2001 to evaluate patterns in overall visits, age and ethnicity of patients, provider type, and prescriptions provided. RESULTS: The number of ambulatory visits for reflux increased from 8 684 000 in 1998-2001 to 15 750 000 in 2006-2009. Visits increased across each time period for internal medicine, family, and gastroenterology physicians. Among otolaryngologists, absolute visits increased from 1998-2001 to 2002-2005 but decreased in 2006-2009; difference between these time periods did not reach statistical significance. From 1998-2001 to 2006-2009, reflux medication use increased 233%, with continuing trends toward increased proton pump inhibitor use. CONCLUSIONS: Reflux visits have increased across all demographic subgroups studied. Knowledge of these trends may inform further paradigm shifts in diagnosis and management of reflux. PMID- 28073300 TI - From Dynamics to Function. AB - A vast majority of psychological science focuses on snapshots of individuals. Clinical outcome studies may integrate multiple snapshots, typically with yearly intervals. However, there is much to learn about psychological processes as they unfold over real time, including minutes, days, weeks, and months. This special issue contains several articles that make significant advances in real-time assessment of psychological processes using state-of-the-art measurement. This is a brief summary of the specific innovations of this special issue. The summary includes suggestions for applying these measurement innovations to the study of functional dynamics that lead to clinically and socially significant events. Several examples provide ways in which a dynamical analysis of function may be revealing. Most important, the assessment of dynamic mechanisms underlying the amplification of psychopathology seems especially useful for tailoring clinical interventions to meet clients' specific needs. PMID- 28073302 TI - Is the average shortest path length of gene set a reflection of their biological relatedness? AB - When a set of genes are identified to be related to a disease, say through gene expression analysis, it is common to examine the average distance among their protein products in the human interactome as a measure of biological relatedness of these genes. The reasoning for this is that, genes associated with a disease would tend to be functionally related, and that functionally related genes would be closely connected to each other in the interactome. Typically, average shortest path length (ASPL) of disease genes (although referred to as genes in the context of disease-associations, the interactions are among protein-products of these genes) is compared to ASPL of randomly selected genes or to ASPL in a randomly permuted network. We examined whether the ASPL of a set of genes is indeed a good measure of biological relatedness or whether it is simply a characteristic of the degree distribution of those genes. We examined the ASPL of genes sets of some disease and pathway associations and compared them to ASPL of three types of randomly selected control sets: uniform selection, from entire proteome, degree-matched selection, and random permutation of the network. We found that disease associated genes and their degree-matched random genes have comparable ASPL. In other words, ASPL is a characteristic of the degree of the genes and the network topology, and not that of functional coherence. PMID- 28073303 TI - Stereoscopic Depth Contrast in a 3D Muller-Lyer Configuration: Evidence for Local Normalization. AB - Depth contrast is a stereoscopic visual phenomenon in which the slant of an element is affected by that of adjacent elements. Normalization has been proposed to be a possible cause of depth contrast, but it is still unclear how depth contrast involves normalization. To address this issue, we devised stereograms consisting of a vertical test line accompanied by several inducer lines, like a three-dimensional variation of the well-known Muller-Lyer configuration. The inducer lines had horizontal binocular disparities that defined a stereoscopic slant about a horizontal axis with respect to the endpoints of the test line. The observer's task was to adjust the slant of the test line about a horizontal axis until it appeared subjectively vertical. The results of two psychophysical experiments found that slant settings were affected by the slant of local inducers, but not by the overall slant of the whole stimulus. These results suggest that, at least for line patterns, the stereo system normalizes depth locally. PMID- 28073304 TI - The Impact of Stress on Odor Perception. AB - The olfactory system and emotional systems are highly intervened and share common neuronal structures. The current study investigates whether emotional (e.g., anger and fear) and physiological (saliva cortisol) stress responses are associated with odor identification ability and hedonic odor judgments (intensity, pleasantness, and unpleasantness). Nineteen men participated in the modified Trier Social Stress Test (TSST) and a control session (cycling on a stationary bike). The physiological arousal was similar in both sessions. In each session, participants' odor identification score was assessed using the University of Pennsylvania Smell Identification Test, and their transient mood was recorded on the dimensions of valence, arousal, anger, and anxiety. Multivariate regression analyses show that an increase of cortisol in the TSST session (as compared with the control session) is associated with better odor identification performance (beta = .491) and higher odor intensity ratings (beta = .562). However, increased anger in the TSST session (as compared with the control session) is associated with lower odor identification performance (beta = -.482). The study shows divergent effects of the emotional and the physiological stress responses, indicating that an increase of cortisol is associated with better odor identification performance, whereas increased anger is associated with poorer odor identification performance. PMID- 28073305 TI - * Human Amniotic Mesenchymal Stromal Cells as Favorable Source for Cartilage Repair. AB - INTRODUCTION: Localized trauma-derived breakdown of the hyaline articular cartilage may progress toward osteoarthritis, a degenerative condition characterized by total loss of articular cartilage and joint function. Tissue engineering technologies encompass several promising approaches with high therapeutic potential for the treatment of these focal defects. However, most of the research in tissue engineering is focused on potential materials and structural cues, while little attention is directed to the most appropriate source of cells endowing these materials. In this study, using human amniotic membrane (HAM) as scaffold, we defined a novel static in vitro model for cartilage repair. In combination with HAM, four different cell types, human chondrocytes, human bone marrow-derived mesenchymal stromal cells (hBMSCs), human amniotic epithelial cells, and human amniotic mesenchymal stromal cells (hAMSCs) were assessed determining their therapeutic potential. MATERIAL AND METHODS: A chondral lesion was drilled in human cartilage biopsies simulating a focal defect. A pellet of different cell types was implanted inside the lesion and covered with HAM. The biopsies were maintained for 8 weeks in culture. Chondrogenic differentiation in the defect was analyzed by histology and immunohistochemistry. RESULTS: HAM scaffold showed good integration and adhesion to the native cartilage in all groups. Although all cell types showed the capacity of filling the focal defect, hBMSCs and hAMSCs demonstrated higher levels of new matrix synthesis. However, only the hAMSCs-containing group presented a significant cytoplasmic content of type II collagen when compared with chondrocytes. More collagen type I was identified in the new synthesized tissue of hBMSCs. In accordance, hBMSCs and hAMSCs showed better International Cartilage Research Society scoring although without statistical significance. CONCLUSION: HAM is a useful material for articular cartilage repair in vitro when used as scaffold. In combination with hAMSCs, HAM showed better potential for cartilage repair with similar reparation capacity than chondrocytes. PMID- 28073306 TI - The gap in scientific knowledge and role of science communication in South Korea. AB - Using data from a national survey of South Koreans, this study explores the role of science communication in enhancing three different forms of scientific knowledge ( factual, procedural, and subjective). We first assess learning effects, looking at the extent to which citizens learn science from different channels of communication (interpersonal discussions, traditional newspapers, television, online newspapers, and social media). We then look into the knowledge gap hypothesis, investigating how different communication channels can either widen or narrow the gap in knowledge between social classes. Television was found to function as a "knowledge leveler," narrowing the gap between highly and less educated South Koreans. The role of online newspapers in science learning is pronounced in our research. Reading newspapers online indicated a positive relationship to all three measures of knowledge. Contrary to the knowledge leveling effect of television viewing, reading online newspapers was found to increase, rather than decrease, the gap in knowledge. Implications of our findings are discussed in detail. PMID- 28073307 TI - Effect of sample storage temperature and buffer formulation on faecal immunochemical test haemoglobin measurements. AB - Objectives Faecal immunochemical test accuracy may be adversely affected when samples are exposed to high temperatures. This study evaluated the effect of two sample collection buffer formulations (OC-Sensor, Eiken) and storage temperatures on faecal haemoglobin readings. Methods Faecal immunochemical test samples returned in a screening programme and with >=10 ug Hb/g faeces in either the original or new formulation haemoglobin stabilizing buffer were stored in the freezer, refrigerator, or at room temperature (22C-24C), and reanalysed after 1 14 days. Samples in the new buffer were also reanalysed after storage at 35C and 50C. Results were expressed as percentage of the initial concentration, and the number of days that levels were maintained to at least 80% was calculated. Results Haemoglobin concentrations were maintained above 80% of their initial concentration with both freezer and refrigerator storage, regardless of buffer formulation or storage duration. Stability at room temperature was significantly better in the new buffer, with haemoglobin remaining above 80% for 20 days compared with six days in the original buffer. Storage at 35C or 50C in the new buffer maintained haemoglobin above 80% for eight and two days, respectively. Conclusion The new formulation buffer has enhanced haemoglobin stabilizing properties when samples are exposed to temperatures greater than 22C. PMID- 28073309 TI - Psychometric Evaluation of a New Instrument to Evaluate School Nurses' Perceptions on Concussion Care Management. AB - The rate of concussions in adolescents has risen over the last decade, resulting in cognitive and emotional problems. Neurologists recommend cognitive and physical rest during the recovery period, followed by a transitional return-to classroom protocol. The purpose of the study was to develop and test an instrument that explores the beliefs and roles of school nurses in concussion care management. The instrument was a cross-sectional descriptive survey based on the theory of planned behavior, using Qualtrics(r). The psychometric properties of the instrument were assessed through exploratory factor analysis with orthogonal rotation. The reliability of the instrument was assessed for internal consistency reliability using Cronbach's alpha. Kaiser-Meyer-Olkin for sample adequacy was .8; Cronbach's alpha strong (.851). PMID- 28073308 TI - High lifetime probability of screen-detected cervical abnormalities. AB - Objective Regular screening and follow-up is an important key to cervical cancer prevention; however, screening inevitably detects mild or borderline abnormalities that would never progress to a more severe stage. We analysed the cumulative probability and recurrence of cervical abnormalities in the Finnish organized screening programme during a 22-year follow-up. Methods Screening histories were collected for 364,487 women born between 1950 and 1965. Data consisted of 1 207,017 routine screens and 88,143 follow-up screens between 1991 and 2012. Probabilities of cervical abnormalities by age were estimated using logistic regression and generalized estimating equations methodology. Results The probability of experiencing any abnormality at least once at ages 30-64 was 34.0% (95% confidence interval [CI]: 33.3-34.6%) . Probability was 5.4% (95% CI: 5.0 5.8%) for results warranting referral and 2.2% (95% CI: 2.0-2.4%) for results with histologically confirmed findings. Previous occurrences were associated with an increased risk of detecting new ones, specifically in older women. Conclusion A considerable proportion of women experience at least one abnormal screening result during their lifetime, and yet very few eventually develop an actual precancerous lesion. Re-evaluation of diagnostic criteria concerning mild abnormalities might improve the balance of harms and benefits of screening. Special monitoring of women with recurrent abnormalities especially at older ages may also be needed. PMID- 28073310 TI - Linda Marie Wayland Pote (11 June 1953-26 September 2016). AB - [Figure: see text]. PMID- 28073311 TI - Cervical artery tortuosity is associated with intracranial aneurysm. AB - Background Intracranial aneurysms may be associated with an underlying arteriopathy, leading to arterial wall fragility. Arterial tortuosity is a major characteristic of some connective tissue disease. Aim To determine whether intracranial aneurysm is associated with an underlying arteriopathy. Methods Using a case-control design, from May 2012 to May 2013, we selected intracranial aneurysm cases and controls from consecutive patients who had conventional cerebral angiography in our center. Cases were patients with newly diagnosed intracranial aneurysm. Controls were patients who had diagnostic cerebral angiography and free of aneurysm. The prevalence of tortuosity, retrospectively assessed according to standard definitions, was compared between cases and controls and, association between tortuosity and some aneurysm characteristics was examined, in cases only. Results About 659 arteries from 233 patients (112 cases and 121 controls) were examined. Tortuosity was found in 57 (51%) cases and 31 (26%) controls (adjusted OR = 2.71; 95%CI, 1.53-4.80). The same trend was found when looking at each tortuosity subtype (simple tortuosity, coil, kink) or at carotid or vertebral territory separately. In contrast, no association between tortuosity and rupture status, aneurysm number or neck size was found. Conclusions Cervical artery tortuosity is significantly associated with intracranial aneurysm, although not related to main aneurysm characteristics. Our results support the presence of an underlying diffuse arteriopathy in intracranial aneurysm patients. PMID- 28073312 TI - Female chronic pelvic pain: the journey to diagnosis and beyond. PMID- 28073313 TI - Conjugal leprosy: is there a need for active surveillance in endemic areas? PMID- 28073314 TI - Safety of the Peripheral Administration of Vasopressor Agents. AB - Vasopressors are an integral component of the management of septic shock and are traditionally given via a central venous catheter (CVC) due to the risk of tissue injury and necrosis if extravasated. However, the need for a CVC for the management of septic shock has been questioned, and the risk of extravasation and incidence of severe injury when vasopressors are given via a peripheral venous line (PVL) remains poorly defined. We performed a retrospective chart review of 202 patients who received vasopressors through a PVL. The objective was to describe the vasopressors administered peripherally, PVL size and location, the incidence of extravasation events, and the management of extravasation events. The primary vasopressors used were norepinephrine and phenylephrine. The most common PVL sites used were the forearm and antecubital fossa. The incidence of extravasation was 4%. All of the events were managed conservatively; none required an antidote or surgical management. Vasopressors were restarted at another peripheral site in 88% of the events. The incidence of extravasation was similar to prior studies. The use of a PVL for administration of vasopressors can be considered in patients with a contraindication to a CVC. PMID- 28073315 TI - Metabolically Active Three-Dimensional Brown Adipose Tissue Engineered from White Adipose-Derived Stem Cells. AB - Brown adipose tissue (BAT) has a unique capacity to expend calories by decoupling energy expenditure from ATP production, therefore BAT could realize therapeutic potential to treat metabolic diseases such as obesity and type 2 diabetes. Recent studies have investigated markers and function of native BAT, however, successful therapies will rely on methods that supplement the small existing pool of brown adipocytes in adult humans. In this study, we engineered BAT from both human and rat adipose precursors and determined whether these ex vivo constructs could mimic in vivo tissue form and metabolic function. Adipose-derived stem cells (ASCs) were isolated from several sources, human white adipose tissue (WAT), rat WAT, and rat BAT, then differentiated toward both white and brown adipogenic lineages in two-dimensional and three-dimensional (3D) culture conditions. ASCs derived from WAT were successfully differentiated in 3D poly(ethylene glycol) hydrogels into mature adipocytes with BAT phenotype and function, including high uncoupling protein 1 (UCP1) mRNA and protein expression and increased metabolic activity (basal oxygen consumption, proton leak, and maximum respiration). By utilizing this "browning" process, the abundant and accessible WAT stem cell population can be engineered into 3D tissue constructs with the metabolic capacity of native BAT, ultimately for therapeutic intervention in vivo and as a tool for studying BAT and its metabolic properties. PMID- 28073316 TI - Clinical implications of the anatomical variation of deep venous thrombosis. AB - Introduction Little is known about the anatomic variation and its implication in patients with lower limb deep venous thrombosis (DVT). We studied the clinical presentation, site of thrombosis and risk factors based on the anatomic distribution of lower limb DVT. Methods A retrospective analysis of clinically suspected DVT cases was conducted between 2008 and 2012. DVT was categorized by the location of the thrombosed segment and limb involved. The DVT anatomic segments were assessed according to left-to-right ratio, predisposing factors and clinical presentations. Results A total of 637 patients with DVT were included with a mean age of 50 +/- 17 years (51%; females). The most frequently thrombosed segments were popliteal, posterior tibial and profunda femoris veins. DVT was more common at the left side, with a left-to-right ratio of 1.5:1. Bilateral DVT cases (38.5%) had more prior history of DVT as compared to left- (20.3%) and right-sided DVTs (22.6%); p = 0.01. Bilateral DVT was complicated more with post thrombotic syndrome (leg ulcer) ( p = 0.02). The rates of pulmonary embolism (25%) and mortality (23.1%) were significantly higher for bilateral DVT in comparison to left- and right-sided DVT. Abnormal coagulation profile was significantly associated with posterior tibial DVT (81% vs. 71.4%; p = 0.01) as compared to patients with normal coagulation profile. Conclusion Lower limb DVTs are more common at the left side; however, patients with bilateral DVT have higher frequency of recurrence, post-thrombotic syndrome, pulmonary embolism and mortality. The anatomic segments of DVT show specific distribution depending on the predisposing factors. These findings could improve our understanding of the pathophysiology and management of DVT patients. PMID- 28073318 TI - Effects of hydroxyl-functionalized multiwalled carbon nanotubes on sperm health and testes of Wistar rats. AB - Carbon nanotubes (CNTs) are promising candidates for various applications including biomedical purposes. Owing to their remarkable physical, mechanical, electrical and chemical properties, CNTs have become an area of intense research and industrial activity in recent years. Therefore, toxicity and risk assessment studies are becoming increasingly important. The present study was designed to assess the effects of hydroxyl-functionalized multiwalled CNTs (OH-f MWCNTs) on sperm health and testes of adult Wistar rats. Animals were treated with different doses of OH-f MWCNTs (0.4, 2.0 and 10.0 mg/kg) along with a control group receiving only vehicle. Assessments after 15 alternate intraperitoneal doses revealed dose-related adverse effects on many endpoints tested. Results of the study showed significant impairment of sperm health at 2.0 and 10.0 mg/kg. Histology of testes demonstrated degeneration of germinal epithelium and loss of germ cells in the treatment groups. The exposure resulted in increased oxidative stress in testes in a dose-dependent manner. The findings of the study demonstrate that CNTs are potentially harmful for male reproductive health. PMID- 28073317 TI - Activation of KCNQ Channels Suppresses Spontaneous Activity in Dorsal Root Ganglion Neurons and Reduces Chronic Pain after Spinal Cord Injury. AB - A majority of people who have sustained spinal cord injury (SCI) experience chronic pain after injury, and this pain is highly resistant to available treatments. Contusive SCI in rats at T10 results in hyperexcitability of primary sensory neurons, which contributes to chronic pain. KCNQ channels are widely expressed in nociceptive dorsal root ganglion (DRG) neurons, are important for controlling their excitability, and their activation has proven effective in reducing pain in peripheral nerve injury and inflammation models. The possibility that activators of KCNQ channels could be useful for treating SCI-induced chronic pain is strongly supported by the following findings. First, SCI, unlike peripheral nerve injury, failed to decrease the functional or biochemical expression of KCNQ channels in DRG as revealed by electrophysiology, real-time quantitative polymerase chain reaction, and Western blot; therefore, these channels remain available for pharmacological targeting of SCI pain. Second, treatment with retigabine, a specific KCNQ channel opener, profoundly decreased spontaneous activity in primary sensory neurons of SCI animals both in vitro and in vivo without changing the peripheral mechanical threshold. Third, retigabine reversed SCI-induced reflex hypersensitivity, adding to our previous demonstration that retigabine supports the conditioning of place preference after SCI (an operant measure of spontaneous pain). In contrast to SCI animals, naive animals showed no effects of retigabine on reflex sensitivity or conditioned place preference by pairing with retigabine, indicating that a dose that blocks chronic pain-related behavior has no effect on normal pain sensitivity or motivational state. These results encourage the further exploration of U.S. Food and Drug Administration-approved KCNQ activators for treating SCI pain, as well as efforts to develop a new generation of KCNQ activators that lack central side effects. PMID- 28073319 TI - No clinically relevant effects in children after accidental ingestion of Panaeolina foenisecii (lawn mower's mushroom). AB - INTRODUCTION: Panaeolina foenisecii is one of the most common and widely distributed lawn mushrooms in Europe and North America, and frequently involved in accidental mushroom ingestion, mainly in children. Nevertheless, there is contradictory information regarding the toxicity profile of P. foenisecii in the literature. Objective of the study was to assess clinical effects with particular attention on psychoactive properties of P. foenisecii in case of accidental oral exposure. METHODS: This observational case series is based on prospectively collected data on mushroom poisoning using a structured data collection form, and it was performed in seven poisons centres in Germany and Switzerland. Inclusion criteria were accidental ingestion of at least one cap of P. foenisecii identified by a mycologist, and a follow up of at least 4 hours. RESULTS: Nineteen cases met all inclusion criteria, and only children were involved with a mean age of 3 years. They ingested 1-2 mushrooms in 14 cases and 3-5 mushrooms in five cases. Three patients received a single dose of activated charcoal. Sixteen out of 19 cases did not develop any symptoms, 2/19 complained of minor abdominal discomfort. One child was temporarily mildly hyperactive, and this was the only patient observed in a hospital for 12 hours. None of the children showed signs of hallucinations. CONCLUSIONS: This multicentre study demonstrates that the typically small amounts of P. foenisecii ingested by children probably do not lead to clinically significant symptoms. PMID- 28073321 TI - In response to: "A systematic analysis of methylene blue for drug-induced shock". PMID- 28073320 TI - Early recovery of T-cell function predicts improved survival after T-cell depleted allogeneic transplant. AB - Infection, relapse, and GVHD can complicate allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although the effect of poor immune recovery on infection risk is well-established, there are limited data on the effect of immune reconstitution on relapse and survival, especially following T-cell depletion (TCD). To characterize the pattern of immune reconstitution in the first year after transplant and its effects on survival and relapse, we performed a retrospective study in 375 recipients of a myeloablative TCD allo-HSCT for hematologic malignancies. We noted that different subsets recover sequentially, CD8 + T cells first, followed by total CD4 + and naive CD4 + T cells, indicating thymic recovery during the first year after HSCT. In the multivariate model, a fully HLA-matched donor and recovery of T-cell function, assessed by PHA response at 6 months, were the only factors independently associated with OS and EFS. In conclusion, T-cell recovery is an important predictor of outcome after TCD allo HSCT. PMID- 28073322 TI - Effects of Group-Focused Cognitive-Behavioral Coaching Program on Depressive Symptoms in a Sample of Inmates in a Nigerian Prison. AB - This study investigated the effects that a group-focused cognitive-behavioral coaching program had on depressive symptoms of a sample of inmates from Nsukka Prisons, Enugu State, Nigeria. The design of the study was pretest-posttest control group . The participants were 30 male inmates, experiencing high levels of depressive symptoms, and randomly assigned to treatment and control groups. The primary outcome measure was depression symptoms as measured using Beck's Depression Inventory. Repeated-measures ANOVA and the Mann-Whitney U Test were used for data analysis. Results show that exposing inmates to the group-focused cognitive-behavioral coaching program significantly reduced the depressive symptoms of inmates in the treatment group compared with those in the control group. Our results support the use of cognitive-behavioral coaching interventions designed to assist the severely depressed inmates in Nigeria. Further studies should be conducted both in other states of Nigeria and in other countries. PMID- 28073323 TI - Protective effect exerted by soil phosphorus on soybean subjected to arsenic and fluoride. AB - : Objetive: Arsenic (As) and fluoride (F) are found in groundwater and soils around the world, causing different problems to crops. Because these elements compete against phosphorus (P) in soils and plants, their relationship is complex. The aim of this work was to study the oxidative stress of soybean plants subjected to different concentrations of As and F, and the effect of P. METHODS: The following 10 treatments were carried out in each of two soils with different P content: three As levels (low 10 mg As kg-1, medium 50 mg As kg-1 and high 100 mg As kg-1), three F levels (low 160 mg F kg-1, medium 250 mg F kg-1 and high 500 mg F kg-1) and three As + F levels (same concentrations), and the control treatment (soil with the background As and F concentrations) Lipid peroxidation, chlorophyll, gluthatione contents and antioxidant enzymes activities were determination. RESULTS: Increased lipid peroxidation and alterations in glutathione content, catalase, superoxide dismutase and peroxidase activities as well as in chlorophyll content revealed that As causes higher oxidative stress in plants grown in soils with low P content. CONCLUSION: Stress parameters in F treatments were less affected. Plants grown in soils enriched with P revealed a decrease in the toxic effects caused by As and F. PMID- 28073324 TI - 3-methoxy aroylhydrazones - free radicals scavenging, anticancer and cytoprotective potency. AB - OBJECTIVE: This study aimed to determine the capability of newly designed 3 methoxy derivatives of salicylaldehyde benzoylhydrazone to influence the oxidative stress processes and to test their in vitro cytotoxicity. METHODS: We have used chemiluminescent and spectrophotometric model systems containing different types of reactive oxygen species (OH?, OCl? and O2??). The hydrazones effect on the viability of Hep-G2, HEK-293 and SH-SY5Y cell lines was determined via MTT assay. RESULTS: The comparative analysis of the C50 values of the chemiluminescent investigation demonstrated moderate activity against the hydroxyl radicals (C50 > 50 MUmol/L) and remarkable reactivity in the systems containing a superoxide radical and a hypochlorous anion (C50 < 3.7 MUmol/L). Further experiments in the spectrophotometric system of UV-induced OH? generation and consequent 2'-deoxyribose oxidative damage excluded the possibility of quenching effect and proved the direct interaction of the studied compounds with that generated in the system reactive oxygen species (ROS). The encapsulation of the studied derivatives into chitosan-alginate particles led to the protection and stabilization of their antioxidant activity as revealed by a one-month study using the ABTS ?+ method. The cytotoxic study revealed less pronounced effects against the non-malignant cell line (HEK-293) compared to Hep-G2 and SH-SY-5Y cells. DISCUSSION: The incorporation of a hydroxyl group in the hydrazide part of a parent molecule which relates to better antioxidant effect in most of the studied systems is associated with higher IC50 values in all cytotoxicity experiments and relates to the cytoprotective effect against N-methyl-D-aspartate induced excitotoxicity in SH-SY5Y human neuronal cells. PMID- 28073325 TI - The Moderating Role of Insulin-Like Growth Factor 1 in the Relationship Between Cognitive and Aerobic Endurance Change. AB - BACKGROUND: Improvements in cognition often accompany fitness improvements in older adults, and research suggests insulin-like growth factor 1 (IGF-1) may influence this association. No prior work has examined this in mild cognitive impairment (MCI). We predicted that IGF-1 would moderate the relationship between cognition and aerobic endurance improvement, such that greater baseline IGF-1 would accompany a stronger relationship between cognition and aerobic endurance change. METHOD: Twenty-seven individuals with MCI completed assessments of aerobic endurance (2-minute step test [2MST]) and global cognition (Modified Mini Mental State [3MS]) before and after a 6-month period of twice-weekly exercise. Serum IGF-1 levels were assessed at baseline via fasted blood draw. The Johnson Neyman technique determined whether baseline IGF-1 levels moderated the relationship between changes in aerobic endurance (Delta2MST) and cognition (Delta3MS). RESULTS: A significant interaction was found; however, Delta2MST was inversely associated with Delta3MS in individuals with above-average serum IGF-1 levels; this relationship was strengthened as IGF-1 increased and was not seen when IGF-1 was below average. CONCLUSION: The relationship between cognitive and aerobic endurance change varies as a function of IGF-1 in persons with MCI. Additional work is needed to clarify the mechanisms of these findings. PMID- 28073326 TI - Hierarchical Decline of the Initiative and Performance of Complex Activities of Daily Living in Dementia. AB - OBJECTIVES: While basic activities of daily living hierarchically decline in dementia, little is known about the decline of individual instrumental activities of daily living (IADLs). The objective of this study was to assess initiative and performance deficits in IADLs in dementia. METHODS: A total of 581 carers completed the revised Interview for Deterioration in Daily Living Activities in Dementia 2 to rate their relative's everyday functioning. RESULTS: Initiating and performing IADLs deteriorated hierarchically, while people with dementia were consistently most impaired in initiating using the computer and managing finances. Initiating preparing a cold or hot meal and managing finances were more impaired than their performance, whereas performing maintaining an active social life for example were more impaired than their initiative. CONCLUSION: Findings can help identify the severity of dementia by understanding deficits in initiative and performance. This study has implications for the development of targeted interventions depending on the stage of dementia. PMID- 28073327 TI - Nonmotor Symptoms in Parkinson Disease: A Descriptive Review on Social Cognition Ability. AB - Parkinson disease (PD) is a neurodegenerative disorder characterized by motor and nonmotor symptoms. Nonmotor symptoms include cognitive deficits and impairment in emotions recognition ability associated with loss of dopaminergic neurons in the substantia nigra and with alteration in frontostriatal circuits. In this review, we analyzed the studies on social cognition ability in patients with PD. We searched on PubMed and Web of Science databases and screening references of included studied and review articles for additional citations. From initial 260 articles, only 18 met search criteria. A total of 496 patients were compared with 514 health controls, through 16 different tests that assessed some subcomponents of social cognition, such as theory of mind, decision-making, and emotional face recognition. Studies on cognitive function in patients with PD have focused on executive function. Patients with PD showed impairment in social cognition from the earliest stages of disease. This ability seems to not be significantly associated with other cognitive functions. PMID- 28073328 TI - What Constitutes Strong Psychological Science? The (Neglected) Role of Diagnosticity and A Priori Theorizing. AB - A Bayesian perspective on Ioannidis's (2005) memorable statement that "Most Published Research Findings Are False" suggests a seemingly inescapable trade off: It appears as if research hypotheses are based either on safe ground (high prior odds), yielding valid but unsurprising results, or on unexpected and novel ideas (low prior odds), inspiring risky and surprising findings that are inevitably often wrong. Indeed, research of two prominent types, sexy hypothesis testing and model testing, is often characterized by low priors (due to astounding hypotheses and conjunctive models) as well as low-likelihood ratios (due to nondiagnostic predictions of the yin-or-yang type). However, the trade off is not inescapable: An alternative research approach, theory-driven cumulative science, aims at maximizing both prior odds and diagnostic hypothesis testing. The final discussion emphasizes the value of pluralistic science, within which exploratory phenomenon-driven research can play a similarly strong part as strict theory-testing science. PMID- 28073329 TI - The Other Side of Magic. AB - When magicians perform spectacles that seem to defy the laws of nature, they do so by manipulating psychological reality. Hence, the principles underlying the art of conjuring are potentially of interest to psychological science. Here, we argue that perceptual and cognitive principles governing how humans experience hidden things and reason about them play a central role in many magic tricks. Different from tricks based on many other forms of misdirection, which require considerable skill on the part of the magician, many elements of these tricks are essentially self-working because they rely on automatic perceptual and cognitive processes. Since these processes are not directly observable, even experienced magicians may be oblivious to their central role in creating strong magical experiences and tricks that are almost impossible to debunk, even after repeated presentations. We delineate how insights from perceptual psychology provide a framework for understanding why these tricks work so well. Conversely, we argue that studying magic tricks that work much better than one intuitively would believe provides a promising heuristic for charting unexplored aspects of perception and cognition. PMID- 28073330 TI - The Eyes as Windows Into Other Minds. AB - Eyes have been shown to play a key role during human social interactions. However, to date, no comprehensive cross-discipline model has provided a framework that can account for uniquely human responses to eye cues. In this review, I present a framework that brings together work on the phylogenetic, ontogenetic, and neural bases of perceiving and responding to eyes. Specifically, I argue for a two-process model: a first process that ensures privileged attention to information encoded in the eyes and is important for the detection of other minds and a second process that permits the decoding of information contained in the eyes concerning another person's emotional and mental states. To some degree, these processes are unique to humans, emerge during different times in infant development, can be mapped onto distinct but interconnected brain regions, and likely serve critical functions in facilitating cooperative interactions in humans. I also present evidence to show that oxytocin is a key modulator of sensitive responding to eye cues. Viewing eyes as windows into other minds can therefore be considered a hallmark feature of human social functioning deeply rooted in our biology. PMID- 28073331 TI - The Specificity Principle in Acculturation Science. AB - The specificity principle in acculturation science asserts that specific setting conditions of specific people at specific times moderate specific domains in acculturation by specific processes. Our understanding of acculturation depends critically on what is studied where, in whom, how, and when. This article defines, explains, and illustrates the specificity principle in acculturation science. Research hypotheses about acculturation can be more adequately tested, inconsistencies and discrepancies in the acculturation literature can be satisfactorily resolved, acculturation interventions can be tailored to be more successful, and acculturation policies can be brought to new levels of effectiveness if the specificity principle that governs acculturation science is more widely recognized. PMID- 28073333 TI - How Orthogonal Are the Big Two of Social Perception? On the Curvilinear Relation Between Agency and Communion. AB - Humans make sense of their social environment by forming impressions of others that allow predicting others' actions. In this process of social perception, two types of information carry pivotal importance: other entities' communion (i.e., warmth and trustworthiness) and agency (i.e., status and power). Although commonly thought of as orthogonal dimensions, we propose that these Big Two of social perception are curvilinearly related. Specifically, as we delineate from four different theoretical explanations, impressions of communion should peak at average agency, while entities too high or too low on agency should be perceived as low on communion. We show this pattern for social groups across one novel and five previously published data sets, including a meta-analysis of the most comprehensive data collection in the group perception literature, consisting of 36 samples from more than 20 countries. Addressing the generalizability of this curvilinear relation, we then report recent and unpublished experiments establishing the effect for the perception of individuals and animals. On the basis of the proposed curvilinear relation, we revisit the primacy of processing communion (rather than agency) information. Finally, we discuss the possibility of a more general curvilinear relation between communion and dimensions other than agency. PMID- 28073334 TI - Through a Glass, Darkly. AB - In this rejoinder, I respond to the comments from three sets of eminent scholars regarding my critique of the microaggression research program (MRP). I concur with Haidt (2017, this issue) that a significant shortcoming of the MRP is its insufficient emphasis on the subjective appraisal of microaggressions. I concur with Ong and Burrow (2017, this issue) that intensive longitudinal studies of microaggressions should enhance our knowledge of their short-term and long-term impact, although I urge researchers to assess microaggressions in conjunction with personality traits using a multi-informant framework. In contrast to Sue (2017, this issue), I argue that psychological science is our best hope for understanding microaggressions and that well-intentioned but untested interventions designed to reduce microaggressions may do more harm than good. I conclude that the MRP would benefit from greater modesty in its assertions and more open acknowledgment of its marked scientific limitations. PMID- 28073332 TI - An Examination of Age-Based Stereotype Threat About Cognitive Decline. AB - "Stereotype threat" is often thought of as a singular construct, with moderators and mechanisms that are stable across groups and domains. However, this is not always true. To illustrate this, the current review focuses on the stereotype threat that older adults face about their cognitive abilities. Drawing upon the multithreat framework, I first provide evidence that this is a self-concept threat and not a group-reputation threat. Because this differs from the forms of stereotype threat experienced by other groups (e.g., the threat that minority students face about their intellectual abilities), the moderators of stereotype threat observed in other groups (i.e., group identification) do not always generalize to age-based stereotype threat about cognitive decline. Looking beyond the forms of stereotype threat elicited, this review also provides evidence that the mechanisms underlying stereotype-threat effects may vary across the adult life span. Because of age-related improvements in emotion-regulation abilities, stereotype threat does not seem to reduce older adults' executive-control resources. Overall, this review highlights the need to approach the concept of stereotype threat with more granularity, allowing researchers to design more effective stereotype-threat interventions. It will also shed light on why certain stereotype threat effects "fail to replicate" across domains or groups. PMID- 28073335 TI - Microaggressions and "Evidence". PMID- 28073336 TI - The Unwisest Idea on Campus. PMID- 28073338 TI - Microaggressions and Daily Experience. AB - Psychologists use the term microaggressions to describe subtle forms of bias and discrimination experienced by members of marginalized groups. Lilienfeld (2017, this issue) makes an important contribution to the literature by presenting a critical review of the meaning and measurement of microaggression experiences. In this commentary, we argue that advancing the construct of microaggressions rests on research approaches that move beyond static representations of individuals to dynamic frameworks that observe people's lives as they unfold day to day. We discuss the conceptual potential of microaggressions as a bridging concept across multiple levels of analysis. We conclude that the intensive study of individuals over time can contribute to theory evaluation and offer new insights into the nature of unfolding processes that are theorized to be central to the manifestation of microaggressions in everyday life. PMID- 28073337 TI - Microaggressions. AB - The microaggression concept has recently galvanized public discussion and spread to numerous college campuses and businesses. I argue that the microaggression research program (MRP) rests on five core premises, namely, that microaggressions (1) are operationalized with sufficient clarity and consensus to afford rigorous scientific investigation; (2) are interpreted negatively by most or all minority group members; (3) reflect implicitly prejudicial and implicitly aggressive motives; (4) can be validly assessed using only respondents' subjective reports; and (5) exert an adverse impact on recipients' mental health. A review of the literature reveals negligible support for all five suppositions. More broadly, the MRP has been marked by an absence of connectivity to key domains of psychological science, including psychometrics, social cognition, cognitive behavioral therapy, behavior genetics, and personality, health, and industrial organizational psychology. Although the MRP has been fruitful in drawing the field's attention to subtle forms of prejudice, it is far too underdeveloped on the conceptual and methodological fronts to warrant real-world application. I conclude with 18 suggestions for advancing the scientific status of the MRP, recommend abandonment of the term "microaggression," and call for a moratorium on microaggression training programs and publicly distributed microaggression lists pending research to address the MRP's scientific limitations. PMID- 28073339 TI - Dermal safety assessment of Arm & Hammer laundry products formulated for sensitive skin. AB - CONTEXT: The prevalence of sensitive skin among the general population in industrialized countries is reported to be over 50%. Sensitive skin subjects often report significant reactions to contact with cosmetics, soaps and other consumer products. OBJECTIVE: This paper describes the overall skin compatibility and mildness program for a newly developed, lightly fragranced, colorant free laundry product (i.e. Arm & HammerTM Sensitive Skin plus Skin-Friendly Fresh Scent), specially formulated for individuals with sensitive skin. The skin mildness of the product was compared to Arm & HammerTM Free & Clear liquid laundry detergent with no fragrance or colorant, and an established history of safe use by sensitive skin consumers. MATERIALS AND METHODS: The test material was a liquid laundry product with a light scent formulated for sensitive skin consumers (Arm & HammerTM Sensitive Skin plus Skin-Friendly Fresh Scent). The product was compared to commercially marketed products for sensitive skin with a history of skin safety in the marketplace, including: a very similar product formulation (Arm & HammerTM Free & Clear with no fragrance), and several selected competitors' products. Studies were conducted among individuals with self assessed sensitive skin (based on a questionnaire) using standard protocols for the Human Repeat Insult Patch Test (HRIPT), 10-Day Cumulative Irritation, the Wrist Band Wear test, and the Safety In-Use testing. Responses in all protocols were evaluated by visual scoring of potential dermatologic reactions, and recording any sensory effects at the time of the examination. In addition, sensory effects collected from panelists' daily diaries were also evaluated. RESULTS: The HRIPT confirmed that neither the fragrance alone, nor the product formulation with fragrance, induced contact sensitization in sensitive skin subjects. The 10-Day cumulative irritation study conducted using sensitive skin subjects showed highly favorable skin compatibility, and the test product was comparable to the control product (Arm & Hammer Free & Clear) and other nonirritant controls. In the Wrist Band Wear test, exposure to laundered fabrics under exaggerated conditions gave similar results for the test and control products, with no objective signs of skin irritation, and no self-reported persistent adverse sensory effects. Very mild, transient and isolated sensory effects were noted in daily diaries by a small proportion of subjects, and were similar for the test and control products. The Safety In-Use tests evaluated 4 week exposure to product and laundered fabrics under realistic use conditions. There were no clinically objective signs of skin irritation, and reports of transitory, mild sensory effects were minimal and similar for the test and controls. DISCUSSION AND CONCLUSION: A comprehensive skin safety program on a lightly scented sensitive skin laundry formulation (i.e. Arm & HammerTM Sensitive Skin plus Skin-Friendly Fresh Scent) conducted among panels of self-assessed sensitive skin subjects demonstrated that the presence of a light fragrance did not adversely impact skin compatibility in any of the testing protocols when the product was compared to a similar product with no fragrance. The lightly fragranced product demonstrated overall skin compatibility and mildness when tested in a self-assessed sensitive skin population, and compared favorably to currently marketed sensitive skin products. PMID- 28073340 TI - A comparative genomic analysis of putative pathogenicity genes in the host specific sibling species Colletotrichum graminicola and Colletotrichum sublineola. AB - BACKGROUND: Colletotrichum graminicola and C. sublineola cause anthracnose leaf and stalk diseases of maize and sorghum, respectively. In spite of their close evolutionary relationship, the two species are completely host-specific. Host specificity is often attributed to pathogen virulence factors, including specialized secondary metabolites (SSM), and small-secreted protein (SSP) effectors. Genes relevant to these categories were manually annotated in two co occurring, contemporaneous strains of C. graminicola and C. sublineola. A comparative genomic and phylogenetic analysis was performed to address the evolutionary relationships among these and other divergent gene families in the two strains. RESULTS: Inoculation of maize with C. sublineola, or of sorghum with C. graminicola, resulted in rapid plant cell death at, or just after, the point of penetration. The two fungal genomes were very similar. More than 50% of the assemblies could be directly aligned, and more than 80% of the gene models were syntenous. More than 90% of the predicted proteins had orthologs in both species. Genes lacking orthologs in the other species (non-conserved genes) included many predicted to encode SSM-associated proteins and SSPs. Other common groups of non conserved proteins included transporters, transcription factors, and CAZymes. Only 32 SSP genes appeared to be specific to C. graminicola, and 21 to C. sublineola. None of the SSM-associated genes were lineage-specific. Two different strains of C. graminicola, and three strains of C. sublineola, differed in no more than 1% percent of gene sequences from one another. CONCLUSIONS: Efficient non-host recognition of C. sublineola by maize, and of C. graminicola by sorghum, was observed in epidermal cells as a rapid deployment of visible resistance responses and plant cell death. Numerous non-conserved SSP and SSM-associated predicted proteins that could play a role in this non-host recognition were identified. Additional categories of genes that were also highly divergent suggested an important role for co-evolutionary adaptation to specific host environmental factors, in addition to aspects of initial recognition, in host specificity. This work provides a foundation for future functional studies aimed at clarifying the roles of these proteins, and the possibility of manipulating them to improve management of these two economically important diseases. PMID- 28073342 TI - Implementing flexible bronchoscopy in least developed countries according to international guidelines is feasible and sustainable: example from Phnom-Penh, Cambodia. AB - BACKGROUND: Flexible bronchoscopy is pivotal for the diagnosis of most respiratory diseases. A flexible bronchoscopy unit (FBU) was created in 2008 in the Preah Kossamak university hospital (Phnom Penh, Cambodia) through a cooperation program between a French and a Cambodian team. In 2009 we conducted an assessment of the compliance of the FBU to international standards and found that most of French and British guidelines were fully applied or adapted to local practice. The aim of the current work was to assess FBU again 6 years later, in order to determine if compliance to international guidelines was sustainable. METHODS: The 2015 evaluation was conducted identically to 2009. All recommendation items from the French and the British Thoracic Societies guidelines were assessed individually. Each recommendation was assigned a status expressing the level at which it was respected in Cambodia: applied, adapted, not applied and not evaluable. An endoscope microbial sampling was performed as recommended by the French Ministry of Health. RESULTS: Between 2009 and 2015, the pattern of international recommendations in the Cambodian FBU did not change. Notably the rates of applied French evaluable recommendations remained stable: respectively 58% vs 57%. Main changes in French guidelines occurred in adapted items that became applied (n = 5/15) while 4 previously adapted/applied items became not applied. Furthermore, all microbial analyses showed sterile results. CONCLUSIONS: Our results show that implementation of a high quality FBU in a least-developed country is feasible. In addition, the performance is maintained in the long-term. PMID- 28073341 TI - Sijunzi Decoction attenuates 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats and ameliorates TNBS-induced claudin-2 damage via NF-kappaB pathway in Caco2 cells. AB - BACKGROUND: SijunziDecoction (SJZD) is a traditional Chinese medicine prescription used to treat the diseases of gastrointestinal tract since ancient times. The objective of this study was to investigate the protective effects of SJZD on TNBS-induced colitis in rats and TNBS-damaged Caco2 cells. METHODS: The rat colitis model was induced by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). SJZD (2.8 5.6, 11.2 g/kg) or salazosulfapyridine (SASP) (0.4 g/kg) was administrated orally in rats for 7 days. DAI, pathological scores and the expression of claudin-2 were evaluated. Then we explored the effect and mechanism of SijunziDecoction Serum (SJZDS) onTNBS-damaged Caco2 cells to figure out intestinal barrier protective effect and mechanism of SJZD. RESULTS: SJZD significantly ameliorated the severity of TNBS-induced colitis and downregulated the level of claudin-2 in colonic tissues. SJZDS promoted proliferation and inhibited apoptosis ofTNBS-damaged Caco2 cells. In Caco2 cell monolayers, we provided mechanistic evidence that SJZDS-induced increased TEER and decreased permeability after TNBS damage, which were mediated through claudin-2 and NF kappaB pathway, including the upregulation of claudin-2, decreased activity of NF kappaB p65, reduced level of NF-kappaB p65 and MLCK. CONCLUSIONS: Our results indicated that SJZD possesses protective effect of intestinal barrier towards TNBS-induced colitis in rats and TNBS-damaged Caco2 cells in vitro. SJZDis a potential protective agent of intestinal barrier that deserves further investigation. PMID- 28073344 TI - Multidrug-resistant tuberculosis (MDR-TB) disease burden in China: a systematic review and spatio-temporal analysis. AB - BACKGROUND: Surveillance data on the proportion of incident TB cases with MDR was limited and there is no systematic study of MDR-TB in China to date. Our aim was to estimate MDR-TB disease burden in 2012 and change trends during 2003-2012 using spatio-temporal systematic analysis. METHODS: We systematically searched Chinese and English databases for primary articles and reviews that contain MDR TB survey data about China during the period of 2003-2012. We estimated the proportion of incident TB cases with MDR in cities which had no data to report in 2012 by Kriging spatial interpolation analysis. The primary outcomes were the proportion of incident TB cases with MDR at 2012 and the change trend during 2003 2012. RESULTS: Total 487 articles met the screening criteria, including 450 in Chinese and 37 in English, and have been used in analysis. The proportion of incident TB cases with MDR among all cases in 2012 showed clear geographic differences. From 2003 to 2012, the proportion of incident TB cases with MDR in all, new and previously treated TB cases were higher during 2006-2009 and significantly lower during 2010-2012 in comparison with the period during 2003 2005 (P < 0.0167). The estimated median proportion of incident TB cases with MDR among all cases, as well as in new and previously treated cases in 2012 was 12.8% (IQR 9.8-17.3%), 5.4% (4.5-7.3%) and 28.5% (20.5-30.9%) respectively, which led to an estimate of 121,600 (IQR93,000-164,350) MDR-TB cases in China. CONCLUSIONS: This estimate of MDR-TB burden is considerably higher than data reported by the Chinese fifth national tuberculosis epidemiological sampling survey in 2010 but close to the WHO report, which implies that detailed investigations of MDR-TB burden in China is needed. This research provides data to guide public health decisions at various scales; methods described here can be extended to estimate of the other chronic diseases as well. PMID- 28073343 TI - Risk factors and clinical course of hungry bone syndrome after total parathyroidectomy in dialysis patients with secondary hyperparathyroidism. AB - BACKGROUND: Hungry bone syndrome (HBS) is an important postoperative complication after parathyroidectomy for severe secondary hyperparathyroidism (SHPT). There is, however, little data in the literature on its detailed clinical course, and the associated risk factors remain controversial. METHODS: We did a single-center retrospective study on 62 consecutive dialysis patients who underwent total parathyroidectomy for SHPT to examine the risk factors, clinical course and outcome. Data on demographic characteristics, perioperative laboratory parameters including serum calcium, phosphate, alkaline phosphatase (ALP) and parathyroid hormone (PTH), drug treatment for SHPT and operative details of parathyroidectomy were collected. RESULTS: Seventeen (27.4%) patients developed severe postoperative hypocalcemia with HBS. The serum calcium dropped progressively while serum ALP rose after operation until 2 weeks later when serum calcium reached the trough and serum ALP peaked. Serum phosphate also fell but stabilized between 4 and 14 days. The total postoperative calcium and vitamin D supplementation was significantly larger, and hospital stay was significantly longer in the group with HBS as compared with those without HBS. Young age, high body weight, high preoperative ALP level, and low preoperative calcium level independently predicted the development of HBS while preoperative PTH and use of cinacalcet or paricalcitol did not. CONCLUSION: HBS was common after total parathyroidectomy in patients with SHPT, and it is important to closely monitor the postoperative serum calcium, phosphate and ALP levels in the following 2 weeks, especially for those at risk. The implications of our findings on perioperative management are discussed. PMID- 28073346 TI - Experiencing integration: a qualitative pilot study of consumer and provider experiences of integrated primary health care in Australia. AB - BACKGROUND: The terms integration and integrated care describe the complex, patient-centred strategies to improve coordination of healthcare services. Frameworks exist to conceptualise these terms, but these have been developed from a professional viewpoint. The objective of this study was to explore consumers' and providers' concepts, expectations and experience of integrated care. A key focus was whether frameworks developed from a professional perspective are effective models to explore people's experiences. METHODS: A qualitative pilot study was undertaken at one Australian multidisciplinary primary health care centre. Semi-structured interviews were conducted with consumers (N = 19) and staff (N = 10). Data were analysed using a framework analysis approach. RESULTS: Consumers' experience of integrated care tended to be implicit in their descriptions of primary healthcare experiences more broadly. Experiences related to the typologies involved clinical and functional integration, such as continuity of providers and the usefulness of shared information. Staff focused on clinical level integration, but also talked about a cultural shift that demonstrated normative, professional and functional integration. CONCLUSIONS: Existing frameworks for integration have been heavily influenced by the provider and organisational perspectives. They are useful for conceptualising integration from a professional perspective, but are less relevant for consumers' experiences. Consumers of integrated primary health care may be more focussed on relational aspects of care and outcomes of care. PMID- 28073345 TI - Reasons for faculty departures from an academic medical center: a survey and comparison across faculty lines. AB - BACKGROUND: Faculty departure can present significant intellectual costs to an institution. The authors sought to identify the reasons for clinical and non clinical faculty departures at one academic medical center (AMC). METHOD: In May and June 2010, the authors surveyed 137 faculty members who left a west coast School of Medicine (SOM) between 1999 and 2009. In May and June 2015, the same survey was sent to 40 faculty members who left the SOM between 2010-2014, for a total sample size of 177 former faculty members. The survey probed work history and experience, reasons for departure, and satisfaction at the SOM versus their current workplace. Statistical analyses included Pearson's chi-square test of independence and independent sample t-tests to understand quantitative differences between clinical and non-clinical respondents, as well as coding of qualitative open-ended responses. RESULTS: Eighty-eight faculty members responded (50%), including three who had since returned to the SOM. Overall, professional and advancement opportunities, salary concerns, and personal/family reasons were the three most cited factors for leaving. The average length of time at this SOM was shorter for faculty in clinical roles, who expressed lower workplace satisfaction and were more likely to perceive incongruence and inaccuracy in institutional expectations for their success than those in non-clinical roles. Clinical faculty respondents noted difficulty in balancing competing demands and navigating institutional expectations for advancement as reasons for leaving. CONCLUSIONS: AMCs may not be meeting faculty needs, especially those in clinical roles who balance multiple missions as clinicians, researchers, and educators. Institutions should address the challenges these faculty face in order to best recruit, retain, and advance faculty. PMID- 28073347 TI - Assessing the performance of centralized waiting lists for patients without a regular family physician using clinical-administrative data. AB - BACKGROUND: With 4.6 million patients who do not have a regular family physician, Canada performs poorly compared to other OECD countries in terms of attachment to a family physician. To address this issue, several provinces have implemented centralized waiting lists to coordinate supply and demand for attachment to a family physician. Although significant resources are invested in these centralized waiting lists, no studies have measured their performance. In this article, we present a performance assessment of centralized waiting lists for unattached patients implemented in Quebec, Canada. METHODS: We based our approach on the Balanced Scorecard method. A committee of decision-makers, managers, healthcare professionals, and researchers selected five indicators for the performance assessment of centralized waiting lists, including both process and outcome indicators. We analyzed and compared clinical-administrative data from 86 centralized waiting lists (GACOs) located in 14 regions in Quebec, from April 1, 2013, to March 31, 2014. RESULTS: During the study period, although over 150,000 patients were attached to a family physician, new requests resulted in a 30% median increase in patients on waiting lists. An inverse correlation of average strength was found between the rates of patients attached to a family physician and the proportion of vulnerable patients attached to a family physician meaning that as more patients became attached to an FP through GACOs, the proportion of vulnerable patients became smaller (r = -0.31, p < 0.005). The results showed very large performance variations both among GACOs of different regions and among those of a same region for all performance indicators. CONCLUSIONS: Centralized waiting lists for unattached patients in Quebec seem to be achieving their twofold objective of attaching patients to a family physician and giving priority to vulnerable patients. However, the demand for attachment seems to exceed the supply and there appears to be a tension between giving priority to vulnerable patients and attaching of a large number of patients. Results also showed heterogeneity in the performance of centralized waiting lists across Quebec. Finally, our findings suggest it is critical that similar mechanisms should use available data to identify the best strategies for reducing variations and improving performance. PMID- 28073348 TI - Wild carrot pentane-based fractions suppress proliferation of human HaCaT keratinocytes and protect against chemically-induced skin cancer. AB - BACKGROUND: Previous studies in our laboratory showed that the Lebanese Daucus carota ssp. carota (wild carrot) oil extract possesses in vitro and in vivo anticancer activities. The present study aims to examine the cytotoxic effect of Daucus carota oil fractions on human epidermal keratinocytes and evaluate the chemopreventive activity of the pentane diethyl ether fraction on DMBA/TPA induced skin carcinogenesis in mice. METHODS: Wild carrot oil extract was chromatographed to yield four fractions (F1, 100% pentane; F2, 50:50 pentane:diethyl ether; F3, 100% diethyl ether; F4 93:7 chloroform:methanol). The cytotoxic effect of fractions (10, 25, 50 and 100 MUg/mL) was tested on human epidermal keratinocytes (non-tumorigenic HaCaT cells and tumorigenic HaCaT-ras variants) using WST a ssay. Cell cycle phase distribution of tumorigenic HaCaT ras variants was determined by flow cytometry post-treatment with F2 fraction. Apoptosis related proteins were also assessed using western blot. The antitumor activity of F2 fraction was also evaluated using a DMBA/TPA induced skin carcinoma in Balb/c mice. RESULTS: All fractions exhibited significant cytotoxicity, with HaCaT cells being 2.4-3 times less sensitive than HaCaT-ras A5 (benign tumorigenic), and HaCaT-ras II4 (malignant) cells. GC-MS analysis revealed the presence of a major compound (around 60%) in the pentane/diethylether fraction (F2), identified as 2-himachalen-6-ol. Treatment of HaCaT-ras A5 and HaCaT-ras II4 cells with F2 fraction resulted in the accumulation of cells in the sub-G1 apoptotic phase and decreased the population of cells in the S and G2/M phases. Additionally, F2 fraction treatment caused an up-regulation of the expression of pro-apoptotic (Bax) and down-regulation of the expression of anti-apoptotic (Bcl2) proteins. A decrease in the phosphorylation of AKT and ERK was also observed. Intraperitoneal treatment with F2 fraction (50 or 200 mg/kg) in the DMBA/TPA skin carcinogenesis mouse model showed a significant inhibition of papilloma incidence (mice with papilloma), yield (number of papilloma/mouse) and volume (tumor relative size) at weeks 15, 18 and 21. CONCLUSION: The present data reveal that F2 fraction has a remarkable antitumor activity against DMBA/TPA-induced skin carcinogenesis, an effect that may be mediated through inhibition of the MAPK/ERK and PI3K/AKT pathways. PMID- 28073349 TI - The miR-34a-5p promotes the multi-chemoresistance of osteosarcoma via repression of the AGTR1 gene. AB - BACKGROUND: Chemoresistance hinders the curative cancer chemotherapy. MicroRNAs (miRNAs) are key players in diverse biological processes including the chemoresistance of cancers. METHODS: A RNA-seq-based miR-omic analysis of osteosarcoma (OS) cells was performed to detect the levels of miR-34a-5p. Bioinformatics analysis revealed that AGTR1 is one of the target genes of miR-34a 5p. The mRNA and protein levels of AGTR1 were detected in both the miR-34a-5p mimic transfected G-292 and miR-34a-5p-antagomiR transfected SJSA-1 cells. The involvement of AGTR1 with OS chemoresistance was validated by the experiments with siRNA-mediated repression or overexpression of the AGTR1 gene. RESULTS: We showed that miR-34a-5p promotes the multi- chemoresistance of OS. The angiotensin II type 1 receptor (AGTR1) gene, is one of the targets of miR-34a-5p in OS and thus negatively correlates with OS chemoresistance by systematic investigations of a multi-drug sensitive (G-292) and resistant (SJSA-1) OS cell lines. Down regulation of the AGTR1 expression by siRNA passivates G-292 cells and suppresses cell apoptosis, while over-expression of AGTR1 sensitizes SJSA-1 cells and thus promotes the drug-triggered cell death. CONCLUSIONS: The miR-34a-5p and its target gene AGTR1 are the potential targets for an effective chemotherapy of OS. Our results also provide novel insights into the effective chemotherapy for OS patients. PMID- 28073350 TI - B-type natriuretic peptides in chronic obstructive pulmonary disease: a systematic review. AB - BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have increased cardiovascular risk. Natriuretic peptides (NP) in other populations are useful in identifying cardiovascular disease, stratifying risk, and guiding therapy. METHODS: We performed a systematic literature review to examine NP in COPD, utilising Medline, EMBASE, and the Cochrane Library. RESULTS: Fifty one studies were identified. NP levels were lower in stable compared to exacerbation of COPD, and significantly increased with concomitant left ventricular systolic dysfunction or cor pulmonale. Elevation occurred in 16 to 60% of exacerbations and persisted in approximately one half of patients at discharge. Cardiovascular comorbidities were associated with increased levels. Levels consistently correlated with pulmonary artery pressure and left ventricular ejection fraction, but not pulmonary function or oxygen saturation. NP demonstrated high negative predictive values (0.80 to 0.98) to exclude left ventricular dysfunction in both stable and exacerbation of COPD, but relatively low positive predictive values. NP elevation predicted early adverse outcomes, but the association with long term mortality was inconsistent. CONCLUSION: NP reflect diverse aspects of the cardiopulmonary continuum which limits utility when applied in isolation. Strategies integrating NP with additional variables, biomarkers and imaging require further investigation. PMID- 28073351 TI - Exploring neurodevelopmental outcome measures used in children with cerebral malaria: the perspectives of caregivers and health workers in Malawi. AB - BACKGROUND: Progress has been made in tackling malaria however there are still over 207 million cases worldwide, the majority in children. As survival rates improve, numbers of children with long-term neurodisabling sequelae are likely to increase. Most outcome studies in cerebral malaria (CM) have focused only on body function and structure and less on outcomes within the broader framework of the International Classification of Functioning and Disability (ICF). The aim of this study was to utilise qualitative methods to identify relevant clinical outcomes in CM to support formulation of a core outcome set relevant to CM and other acquired brain injuries for use in future clinical trials. METHODS: In depth interviews with parent/caregivers (CGs) of children with/without previous CM (N = 19), and in depth interviews with health professionals (N = 18) involved in their care were conducted in community and clinical settings in and around Blantyre, Malawi. Interviews were audio taped, transcribed, translated and a thematic content analysis was conducted. Themes were categorised and placed firstly in an iterative framework derived from the data but then within the ICF framework. RESULTS: Outcomes perceived as important to carers and professionals fulfilled each level of the ICF. These included impairment in body function and structure (contractures, impaired mobility, visual problems, seizures, cognitive function and feeding); activity and participation outcomes (learning, self-care, relationships in school, play and activities of daily living). Other issues emerging included the social and emotional implications of CM on the family, and balancing care of children with neurodisability with demands of daily life, financial pressures, and child protection. Themes of stigma and discrimination were described; these were perceived to negatively influence care, participation and integration of carer and child into the community. CONCLUSIONS: Outcomes considered important for parents/caregivers and professionals working with children post CM cross all aspects of the ICF framework (impairment, functioning and participation). Outcomes emphasised by families and carers in cross-cultural settings must be given adequate attention when conducting clinical studies in these settings. PMID- 28073352 TI - You are what you eat: diet shapes body composition, personality and behavioural stability. AB - BACKGROUND: Behavioural phenotypes vary within and among individuals. While early life experiences have repeatedly been proposed to underpin interactions between these two hierarchical levels, the environmental factors causing such effects remain under-studied. We tested whether an individual's diet affected both its body composition, average behaviour (thereby causing among-individual variation or 'personality') and within-individual variability in behaviour and body weight (thereby causing among-individual differences in residual within-individual variance or 'stability'), using the Southern field cricket Gryllus bimaculatus as a model. We further asked whether effects of diet on the expression of these variance components were sex-specific. METHODS: Manipulating both juvenile and adult diet in a full factorial design, individuals were put, in each life-stage, on a diet that was either relatively high in carbohydrates or relatively high in protein. We subsequently measured the expression of multiple behavioural (exploration, aggression and mating activity) and morphological traits (body weight and lipid mass) during adulthood. RESULTS: Dietary history affected both average phenotype and level of within-individual variability: males raised as juveniles on high-protein diets were heavier, more aggressive, more active during mating, and behaviourally less stable, than conspecifics raised on high carbohydrate diets. Females preferred more protein in their diet compared to males, and dietary history affected average phenotype and within-individual variability in a sex-specific manner: individuals raised on high-protein diets were behaviourally less stable in their aggressiveness but this effect was only present in males. Diet also influenced individual differences in male body weight, but within-individual variance in female body weight. DISCUSSION: This study thereby provides experimental evidence that dietary history explains both heterogeneous residual within-individual variance (i.e., individual variation in 'behavioural stability') and individual differences in average behaviour (i.e., 'personality'), though dietary effects were notably trait-specific. These findings call for future studies integrating proximate and ultimate perspectives on the role of diet in the evolution of repeatedly expressed traits, such as behaviour and body weight. PMID- 28073353 TI - Discovery of large genomic inversions using long range information. AB - BACKGROUND: Although many algorithms are now available that aim to characterize different classes of structural variation, discovery of balanced rearrangements such as inversions remains an open problem. This is mainly due to the fact that breakpoints of such events typically lie within segmental duplications or common repeats, which reduces the mappability of short reads. The algorithms developed within the 1000 Genomes Project to identify inversions are limited to relatively short inversions, and there are currently no available algorithms to discover large inversions using high throughput sequencing technologies. RESULTS: Here we propose a novel algorithm, VALOR, to discover large inversions using new sequencing methods that provide long range information such as 10X Genomics linked-read sequencing, pooled clone sequencing, or other similar technologies that we commonly refer to as long range sequencing. We demonstrate the utility of VALOR using both pooled clone sequencing and 10X Genomics linked-read sequencing generated from the genome of an individual from the HapMap project (NA12878). We also provide a comprehensive comparison of VALOR against several state-of-the-art structural variation discovery algorithms that use whole genome shotgun sequencing data. CONCLUSIONS: In this paper, we show that VALOR is able to accurately discover all previously identified and experimentally validated large inversions in the same genome with a low false discovery rate. Using VALOR, we also predicted a novel inversion, which we validated using fluorescent in situ hybridization. VALOR is available at https://github.com/BilkentCompGen/VALOR. PMID- 28073354 TI - Intermittent catheterisation with hydrophilic and non-hydrophilic urinary catheters: systematic literature review and meta-analyses. AB - BACKGROUND: Intermittent catheterisation is the method of choice for the management of bladder dysfunctions. Different urinary catheters are available, but there is conflicting evidence on which type of catheter is best. The present study provides an objective evaluation of the clinical effectiveness of different subsets of urinary catheters. METHODS: A systematic literature review was performed for published RCTs regarding hydrophilic coated and PVC (standard) catheters for intermittent catheterisation. Separate meta-analyses were conducted to combine data on frequencies of urinary tract infections (UTIs) and haematuria. Two separate analyses were performed, including or excluding reused standard catheters. RESULTS: Seven studies were eligible for inclusion in the review. The meta-analyses exploring UTI frequencies showed a lower risk ratio associated with hydrophilic catheters in comparison to standard ones (RR = 0.84; 95% CI, 0.75 0.94; p = 0.003). Results for the "reuse" scenario were consistent with the ones related to "single-use" scenario in terms of frequency of UTIs. The meta-analyses exploring haematuria were not able to demonstrate any statistically significant difference between hydrophilic catheters in comparison to standard ones. CONCLUSIONS: The findings confirm previously reported benefits of hydrophilic catheters but a broader evaluation that takes into account also patient preferences, compliance of therapy, quality of life and costs would be needed to assess the economic sustainability of these advanced devices. PMID- 28073355 TI - Factors associated with improvement or decline in cognitive function after an ischemic stroke in Korea: the Korean stroke cohort for functioning and rehabilitation (KOSCO) study. AB - BACKGROUND: We conducted a prospective cohort study to investigate prevalence of poststroke cognitive impairment at 3 and 12 months after stroke onset and identify clinical and demographic factors associated with improvement or decline in cognitive function between 3 months and 12 months. METHODS: We analyzed the cognitive assessments of total patients and patients older than 65 years separately. All patients with an ischemic stroke were divided into normal cognitive group (NCG) and impaired cognition group (ICG) by using a cutoff score on the Korean Mini-Mental State Examination (K-MMSE). Patients were additionally classified into 3 subgroups according to the changes in their K-MMSE scores between 3 and 12 months: Stable group with K-MMSE scores changes ranging from -2 to +2 points (-2 <= ?MMSE <= +2); converter group with increase more than 3 points (3 <= ?MMSE); and reverter group with decrease more than 3 points (-3 <= ?MMSE). We also analyzed factors affecting cognitive change from 3 months to 12 months among the 3 groups including baseline medical record, stroke and treatment characteristics, and various functional assessments after 3 months. RESULTS: This study included 2,625 patients with the first time ischemic stroke. Among these patients, 1,735 (66.1%) were classified as NCG, while 890 patients (33.9%) were belonged to the ICG at 3 month. Within the NCG, 1,460 patients (82.4%) were stable group, 93 patients (5.4%) were converter group, and 212 patients (12.2%) were reverter group at 12 months onset. Within the ICG group, 472 patients (53.0%) were stable group, 321 patients (36.1%) were converter group, and 97 patients (10.9%) were reverter group. When different factors were investigated, the three subgroups in NCG and ICG showed significant different factors affecting cognitive function from 3 to 12 month. CONCLUSIONS: The prevalence of cognitive impairment showed difference between 3,12 months. To analyze the cognitive change from 3 month to 12 month, the proportion stable group was dominant in NCG and converter group was higher in ICG. By investigating the influencing factors from each group, we were able to identify the predictors including the age factor. PMID- 28073356 TI - Gut microbiota disturbance during helminth infection: can it affect cognition and behaviour of children? AB - BACKGROUND: Bidirectional signalling between the brain and the gastrointestinal tract is regulated at neural, hormonal, and immunological levels. Recent studies have shown that helminth infections can alter the normal gut microbiota. Studies have also shown that the gut microbiota is instrumental in the normal development, maturation and function of the brain. The pathophysiological pathways by which helminth infections contribute to altered cognitive function remain poorly understood. DISCUSSION: We put forward the hypothesis that gastrointestinal infections with parasitic worms, such as helminths, induce an imbalance of the gut-brain axis, which, in turn, can detrimentally manifest in brain development. Factors supporting this hypothesis are: 1) research focusing on intelligence and school performance in school-aged children has shown helminth infections to be associated with cognitive impairment, 2) disturbances in gut microbiota have been shown to be associated with important cognitive developmental effects, and 3) helminth infections have been shown to alter the gut microbiota structure. Evidence on the complex interactions between extrinsic (parasite) and intrinsic (host-derived) factors has been synthesised and discussed. While evidence in favour of the helminth-gut microbiota-central nervous system hypothesis is circumstantial, it would be unwise to rule it out as a possible mechanism by which gastrointestinal helminth infections induce childhood cognitive morbidity. Further empirical studies are necessary to test an indirect effect of helminth infections on the modulation of mood and behaviour through its effects on the gut microbiota. PMID- 28073357 TI - Long noncoding RNA repertoire in chicken liver and adipose tissue. AB - BACKGROUND: Improving functional annotation of the chicken genome is a key challenge in bridging the gap between genotype and phenotype. Among all transcribed regions, long noncoding RNAs (lncRNAs) are a major component of the transcriptome and its regulation, and whole-transcriptome sequencing (RNA-Seq) has greatly improved their identification and characterization. We performed an extensive profiling of the lncRNA transcriptome in the chicken liver and adipose tissue by RNA-Seq. We focused on these two tissues because of their importance in various economical traits for which energy storage and mobilization play key roles and also because of their high cell homogeneity. To predict lncRNAs, we used a recently developed tool called FEELnc, which also classifies them with respect to their distance and strand orientation to the closest protein-coding genes. Moreover, to confidently identify the genes/transcripts expressed in each tissue (a complex task for weakly expressed molecules such as lncRNAs), we probed a particularly large number of biological replicates (16 per tissue) compared to common multi-tissue studies with a larger set of tissues but less sampling. RESULTS: We predicted 2193 lncRNA genes, among which 1670 were robustly expressed across replicates in the liver and/or adipose tissue and which were classified into 1493 intergenic and 177 intragenic lncRNAs located between and within protein-coding genes, respectively. We observed similar structural features between chickens and mammals, with strong synteny conservation but without sequence conservation. As previously reported, we confirm that lncRNAs have a lower and more tissue-specific expression than mRNAs. Finally, we showed that adjacent lncRNA-mRNA genes in divergent orientation have a higher co-expression level when separated by less than 1 kb compared to more distant divergent pairs. Among these, we highlighted for the first time a novel lncRNA candidate involved in lipid metabolism, lnc_DHCR24, which is highly correlated with the DHCR24 gene that encodes a key enzyme of cholesterol biosynthesis. CONCLUSIONS: We provide a comprehensive lncRNA repertoire in the chicken liver and adipose tissue, which shows interesting patterns of co-expression between mRNAs and lncRNAs. It contributes to improving the structural and functional annotation of the chicken genome and provides a basis for further studies on energy storage and mobilization traits in the chicken. PMID- 28073358 TI - Applying openEHR's Guideline Definition Language to the SITS international stroke treatment registry: a European retrospective observational study. AB - BACKGROUND: Interoperability standards intend to standardise health information, clinical practice guidelines intend to standardise care procedures, and patient data registries are vital for monitoring quality of care and for clinical research. This study combines all three: it uses interoperability specifications to model guideline knowledge and applies the result to registry data. METHODS: We applied the openEHR Guideline Definition Language (GDL) to data from 18,400 European patients in the Safe Implementation of Treatments in Stroke (SITS) registry to retrospectively check their compliance with European recommendations for acute stroke treatment. RESULTS: Comparing compliance rates obtained with GDL to those obtained by conventional statistical data analysis yielded a complete match, suggesting that GDL technology is reliable for guideline compliance checking. CONCLUSIONS: The successful application of a standard guideline formalism to a large patient registry dataset is an important step toward widespread implementation of computer-interpretable guidelines in clinical practice and registry-based research. Application of the methodology gave important results on the evolution of stroke care in Europe, important both for quality of care monitoring and clinical research. PMID- 28073359 TI - Whole Transcriptome Analysis of Pre-invasive and Invasive Early Squamous Lung Carcinoma in Archival Laser Microdissected Samples. AB - BACKGROUND: Preinvasive squamous cell cancer (PSCC) are local transformations of bronchial epithelia that are frequently observed in current or former smokers. Their different grades and sizes suggest a continuum of dysplastic change with increasing severity, which may culminate in invasive squamous cell carcinoma (ISCC). As a consequence of the difficulty in isolating cancerous cells from biopsies, the molecular pathology that underlies their histological variability remains largely unknown. METHOD: To address this issue, we have employed microdissection to isolate normal bronchial epithelia and cancerous cells from low- and high-grade PSCC and ISCC, from paraffin embedded (FFPE) biopsies and determined gene expression using Affymetric Human Exon 1.0 ST arrays. Tests for differential gene expression were performed using the Bioconductor package limma followed by functional analyses of differentially expressed genes in IPA. RESULTS: Examination of differential gene expression showed small differences between low- and high-grade PSCC but substantial changes between PSCC and ISCC samples (184 vs 1200 p-value <0.05, fc +/-1.75). However, the majority of the differentially expressed PSCC genes (142 genes: 77%) were shared with those in ISCC samples. Pathway analysis showed that these shared genes are associated with DNA damage response, DNA/RNA metabolism and inflammation as major biological themes. Cluster analysis identified 12 distinct patterns of gene expression including progressive up or down-regulation across PSCC and ISCC. Pathway analysis of incrementally up-regulated genes revealed again significant enrichment of terms related to DNA damage response, DNA/RNA metabolism, inflammation, survival and proliferation. Altered expression of selected genes was confirmed using RT-PCR, as well as immunohistochemistry in an independent set of 45 ISCCs. CONCLUSIONS: Gene expression profiles in PSCC and ISCC differ greatly in terms of numbers of genes with altered transcriptional activity. However, altered gene expression in PSCC affects canonical pathways and cellular and biological processes, such as inflammation and DNA damage response, which are highly consistent with hallmarks of cancer. PMID- 28073360 TI - Centralising and optimising decentralised stroke care systems: a simulation study on short-term costs and effects. AB - BACKGROUND: Centralisation of thrombolysis may offer substantial benefits. The aim of this study was to assess short term costs and effects of centralisation of thrombolysis and optimised care in a decentralised system. METHODS: Using simulation modelling, three scenarios to improve decentralised settings in the North of Netherlands were compared from the perspective of the policy maker and compared to current decentralised care: (1) improving stroke care at nine separate hospitals, (2) centralising and improving thrombolysis treatment to four, and (3) two hospitals. Outcomes were annual mean and incremental costs per patient up to the treatment with thrombolysis, incremental cost-effectiveness ratio (iCER) per 1% increase in thrombolysis rate, and the proportion treated with thrombolysis. RESULTS: Compared to current decentralised care, improving stroke care at individual community hospitals led to mean annual costs per patient of $US 1,834 (95% CI, 1,823-1,843) whereas centralising to four and two hospitals led to $US 1,462 (95% CI, 1,451-1,473) and $US 1,317 (95% CI, 1,306 1,328), respectively (P < 0.001). The iCER of improving community hospitals was $US 113 (95% CI, 91-150) and $US 71 (95% CI, 59-94), $US 56 (95% CI, 44-74) when centralising to four and two hospitals, respectively. Thrombolysis rates decreased from 22.4 to 21.8% and 21.2% (P = 0.120 and P = 0.001) in case of increasing centralisation. CONCLUSIONS: Centralising thrombolysis substantially lowers mean annual costs per patient compared to raising stroke care at community hospitals simultaneously. Small, but negative effects on thrombolysis rates may be expected. PMID- 28073361 TI - Sustainability of health information systems: a three-country qualitative study in southern Africa. AB - BACKGROUND: Health information systems are central to strong health systems. They assist with patient and program management, quality improvement, disease surveillance, and strategic use of information. Many donors have worked to improve health information systems, particularly by supporting the introduction of electronic health information systems (EHIS), which are considered more responsive and more efficient than older, paper-based systems. As many donor driven programs are increasing their focus on country ownership, sustainability of these investments is a key concern. This analysis explores the potential sustainability of EHIS investments in Malawi, Zambia and Zimbabwe, originally supported by the United States President's Emergency Plan for AIDS Relief (PEPFAR). METHODS: Using a framework based on sustainability theories from the health systems literature, this analysis employs a qualitative case study methodology to highlight factors that may increase the likelihood that donor supported initiatives will continue after the original support is modified or ends. RESULTS: Findings highlight commonalities around possible determinants of sustainability. The study found that there is great optimism about the potential for EHIS, but the perceived risks may result in hesitancy to transition completely and parallel use of paper-based systems. Full stakeholder engagement is likely to be crucial for sustainability, as well as integration with other activities within the health system and those funded by development partners. The literature suggests that a sustainable system has clearly-defined goals around which stakeholders can rally, but this has not been achieved in the systems studied. The study also found that technical resource constraints - affecting system usage, maintenance, upgrades and repairs - may limit EHIS sustainability even if these other pillars were addressed. CONCLUSIONS: The sustainability of EHIS faces many challenges, which could be addressed through systems' technical design, stakeholder coordination, and the building of organizational capacity to maintain and enhance such systems. All of this requires time and attention, but is likely to enhance long-term outcomes. PMID- 28073362 TI - Elevated levels of prebeta1-high-density lipoprotein are associated with cholesterol ester transfer protein, the presence and severity of coronary artery disease. AB - BACKGROUND: Prebeta1-high-density lipoprotein (prebeta1-HDL), plays an important role in reverse cholesterol transport and exhibits potent risk for coronary artery disease (CAD). However, the association of plasma prebeta1-HDL and cholesterol ester transfer protein (CETP) levels in CAD patients and the relationship of prebeta1-HDL with extent of CAD are debatable. METHODS: Prebeta1 HDL and CETP levels were measured by enzymed-linked immunosorbent assay (ELISAs) in 88 acute coronary syndromes (ACS), 79 stable coronary artery disease (SCAD) patients and 85 control subjects. The correlation analyses, multiple linear regression analyses and logistic regression analyses were performed, respectively. RESULTS: The prebeta1-HDL and CETP levels in ACS patients were significantly higher than those in SCAD patients and both of them were higher than controls'. Prebeta1-HDL levels were positively associated with CETP (R = 0.348, P = 0.000), the diameter of stenosis (R = 0.253, P = 0.005), the number of vessel disease (R = 0.274, P = 0.002) and Gensini score (R = 0.227, P = 0.009) in CAD patients. Stepwise multiple linear regression analyses showed that CETP was one of the determinants of prebeta1-HDL levels. Logistic regression analysis revealed that elevated prebeta1-HDL and CETP were potential risk factors for both ACS and SCAD. CONCLUSION: The elevated prebeta1-HDL levels may change with CETP concentrations in CAD patients and were related to the presence and severity of CAD. PMID- 28073363 TI - Swept away: ocean currents and seascape features influence genetic structure across the 18,000 Km Indo-Pacific distribution of a marine invertebrate, the black-lip pearl oyster Pinctada margaritifera. AB - BACKGROUND: Genetic structure in many widely-distributed broadcast spawning marine invertebrates remains poorly understood, posing substantial challenges for their fishery management, conservation and aquaculture. Under the Core-Periphery Hypothesis (CPH), genetic diversity is expected to be highest at the centre of a species' distribution, progressively decreasing with increased differentiation towards outer range limits, as populations become increasingly isolated, fragmented and locally adapted. The unique life history characteristics of many marine invertebrates such as high dispersal rates, stochastic survival and variable recruitment are also likely to influence how populations are organised. To examine the microevolutionary forces influencing population structure, connectivity and adaptive variation in a highly-dispersive bivalve, populations of the black-lip pearl oyster Pinctada margaritifera were examined across its ~18,000 km Indo-Pacific distribution. RESULTS: Analyses utilising 9,624 genome wide SNPs and 580 oysters, discovered differing patterns of significant and substantial broad-scale genetic structure between the Indian and Pacific Ocean basins. Indian Ocean populations were markedly divergent (F st = 0.2534-0.4177, p < 0.001), compared to Pacific Ocean oysters, where basin-wide gene flow was much higher (F st = 0.0007-0.1090, p < 0.001). Partitioning of genetic diversity (hierarchical AMOVA) attributed 18.1% of variance between ocean basins, whereas greater proportions were resolved within samples and populations (45.8% and 35.7% respectively). Visualisation of population structure at selectively neutral loci resolved three and five discrete genetic clusters for the Indian and Pacific Oceans respectively. Evaluation of genetic structure at adaptive loci for Pacific populations (89 SNPs under directional selection; F st = 0.1012-0.4371, FDR = 0.05), revealed five clusters identical to those detected at neutral SNPs, suggesting environmental heterogeneity within the Pacific. Patterns of structure and connectivity were supported by Mantel tests of isolation by distance (IBD) and independent hydrodynamic particle dispersal simulations. CONCLUSIONS: It is evident that genetic structure and connectivity across the natural range of P. margaritifera is highly complex, and produced by the interaction of ocean currents, IBD and seascape features at a broad scale, together with habitat geomorphology and local adaptation at regional levels. Overall population organisation is far more elaborate than generalised CPH predictions, however valuable insights for regional fishery management, and a greater understanding of range-wide genetic structure in a highly-dispersive marine invertebrate have been gained. PMID- 28073364 TI - Lack of MRE11-RAD50-NBS1 (MRN) complex detection occurs frequently in low-grade epithelial ovarian cancer. AB - BACKGROUND: BRCA1/2-deficient ovarian carcinomas are recognized as target for Poly (ADP-ribose) polymerase (PARP) inhibitors. BRCA1 and BRCA2 proteins are involved in homologous recombination repair of double-strand DNA breaks. The relevance of other homologous recombination repair proteins, e.g. MRE11, RAD50, NBS1 (MRN complex) in ovarian carcinomas is unclear. The objective of this study was to investigate the prevalence of lack of MRE11, RAD50, NBS1 protein detection in epithelial ovarian cancer (EOC). METHODS: A tissue microarray (TMA) with 134 EOC was immunohistochemically evaluated for MRE11, RAD50 and NBS1. Data was analysed for associations with clinicopathological parameters, histological subtype, patient overall survival and mismatch repair (MMR) protein status. Sensitivity towards the PARP inhibitor BMN673 was tested in two ovarian cancer cell lines (TOV-21 and OVTOKO) using colony formation assays. RESULTS: Lack of MRN complex protein detection was seen in 41% (55/134) of EOC and was more frequent in low-grade (57.6%; 19/33) than in high-grade EOC (18.8%; 36/101; n = 134; p = 0.04). There was an association with the ovarian carcinoma subtype (60.3%; 35/58 lack of detection in type I versus 26.3%; 20/76 in type II; n = 134; p < 0.001) as well as undetectable DNA mismatch repair proteins MLH1 and MSH2 (89.3%; 25/28; n = 131; p < 0.001). MRE11 knockdown led to moderately increased sensitivity towards the PARP inhibitor BMN673 in one ovarian carcinoma cell line in vitro. CONCLUSIONS: Frequent lack of MRE11, RAD50, NBS1 protein detection in type I human ovarian carcinomas is observed in EOC and our data suggests further investigation regarding sensitivity to PARP-inhibition in tumours lacking MRE11 expression. PMID- 28073365 TI - Neurophthalmological conditions mimicking glaucomatous optic neuropathy: analysis of the most common causes of misdiagnosis. AB - BACKGROUND: To analyze the most common neurophthalmological conditions that may mimic glaucomatous optic neuropathy and to determine which most often lead to misdiagnosis when evaluated by a glaucoma specialist. METHODS: We reviewed the charts of consecutive patients with optic neuropathies caused by neurophthalmological conditions screened in a single Eye Clinic within a period of 24 months. Within these enrolled patients, we selected the eyes whose fundoscopic appearance could resemble glaucoma based in pre-defined criteria (vertical cup-to-disc ratio >=0.6, asymmetry of the cup-to-disc ratio >=0.2 between eyes, presence of localized retinal nerve fiber layer and/or neuroretinal rim defects, and disc haemorrhages). Then, color fundus photographs and Humphrey Visual Field tests (HVF) of these eyes were mixed with tests from 21 consecutive glaucomatous patients (42 eyes with normal tension glaucoma). These images were mixed randomly and a masked glaucoma specialist was asked to distinguish if each set of exams was from a patient with glaucoma or with a neurophthalmologic condition. RESULTS: Among the 101 eyes (68 patients) enrolled with neurophthalmological diseases, 16 (15.8%) were classified as conditions that could mimic glaucoma. The most common diagnoses were ischemic optic neuropathy (25%), compressive optic neuropathy (18.7%) and hereditary optic neuropathy (18.7%). Based on the analysis of fundus photographs and HVF tests, 25% of these were misdiagnosed as glaucoma (two ischemic optic neuropathies and two congenital optic disc anomalies). Conversely, 11.9% of the glaucomatous neuropathies were misdiagnosed as neurophthalmological disorders. Overall, the glaucoma specialist correctly diagnosed 84.5% of the eyes. CONCLUSIONS: Some neurophthalmological disorders can mimic glaucoma. In our study, isquemic and compressive optic neuropathies were the ones that most often did so. Almost one quarter of the eyes were misdiagnosed when evaluated by a glaucoma specialist, which can lead to inadequate management and influence the prognosis of these patients. PMID- 28073366 TI - Oral treatment with Lactobacillus rhamnosus attenuates behavioural deficits and immune changes in chronic social stress. AB - BACKGROUND: Stress-related disorders involve systemic alterations, including disruption of the intestinal microbial community. Given the putative connections between the microbiota, immunity, neural function, and behaviour, we investigated the potential for microbe-induced gut-to-brain signalling to modulate the impact of stress on host behaviour and immunoregulation. METHODS: Male C57BL/6 mice treated orally over 28 days with either Lactobacillus rhamnosus (JB-1) TM or vehicle were subjected to chronic social defeat and assessed for alterations in behaviour and immune cell phenotype. 16S rRNA sequencing and mass spectrometry were employed to analyse the faecal microbial community and metabolite profile. RESULTS: Treatment with JB-1 decreased stress-induced anxiety-like behaviour and prevented deficits in social interaction with conspecifics. However, JB-1 did not alter development of aggressor avoidance following social defeat. Microbial treatment attenuated stress-related activation of dendritic cells while increasing IL-10+ regulatory T cells. Furthermore, JB-1 modulated the effect of stress on faecal metabolites with neuroactive and immunomodulatory properties. Exposure to social defeat altered faecal microbial community composition and reduced species richness and diversity, none of which was prevented by JB-1. Stress-related microbiota disruptions persisted in vehicle-treated mice for 3 weeks following stressor cessation. CONCLUSIONS: These data demonstrate that despite the complexity of the gut microbiota, exposure to a single microbial strain can protect against certain stress-induced behaviours and systemic immune alterations without preventing dysbiosis. This work supports microbe-based interventions for stress-related disorders. PMID- 28073367 TI - No convincing association between genetic markers and respiratory symptoms: results of a GWA study. AB - BACKGROUND: Respiratory symptoms are associated with accelerated lung function decline, and increased hospitalization and mortality rates in the general population. Although several environmental risk factors for respiratory symptoms are known, knowledge on genetic risk factors is lacking. We aim to identify genetic variants associated with respiratory symptoms by genome-wide association (GWA) analyses. METHODS: We conducted the first GWA study on cough, dyspnea and phlegm among 7,976 participants in the LifeLines I cohort and used the LifeLines II cohort (n = 5,260) and the Vlagtwedde-Vlaardingen cohort (n = 1,529) for replication. RESULTS: We identified 50 SNPs that were assessed for replication. Rs16918212, located in the alpha-2-macroglobulin pseudogene 1 (A2MP1), was associated with cough in both the identification (odds ratio (OR) = 0.72, p = 5.41 * 10-5) and the meta-analyzed replication cohorts (OR = 0.83, p = 0.033). No other significant replicated associations were found. CONCLUSIONS: Given that only 1 out of 50 SNPs showed significant replication (i.e. 2%) we conclude that we did not find a convincing association between genetic markers and respiratory symptoms. Since, environmental exposures are important risk factors for respiratory symptoms, the next step is to perform a genome-wide interaction (GWI) study to identify genetic susceptibility loci for respiratory symptoms in interaction with known harmful environmental exposures. PMID- 28073369 TI - High body mass index in rheumatoid arthritis: why we should promote physical activity. PMID- 28073368 TI - Advanced Knee Structure Analysis (AKSA): a comparison of bone mineral density and trabecular texture measurements using computed tomography and high-resolution peripheral quantitative computed tomography of human knee cadavers. AB - BACKGROUND: A change of loading conditions in the knee causes changes in the subchondral bone and may be a cause of osteoarthritis (OA). However, quantification of trabecular architecture in vivo is difficult due to the limiting spatial resolution of the imaging equipment; one approach is the use of texture parameters. In previous studies, we have used digital models to simulate changes of subchondral bone architecture under OA progression. One major result was that, using computed tomography (CT) images, subchondral bone mineral density (BMD) in combination with anisotropy and global homogeneity could characterize this progression. The primary goal of this study was a comparison of BMD, entropy, anisotropy, variogram slope, and local and global inhomogeneity measurements between high-resolution peripheral quantitative CT (HR-pQCT) and CT using human cadaveric knees. The secondary goal was the verification of the spatial resolution dependence of texture parameters observed in the earlier simulations, two important prerequisites for the interpretation of in vivo measurements in OA patients. METHOD: The applicability of texture analysis to characterize bone architecture in clinical CT examinations was investigated and compared to results obtained from HR-pQCT. Fifty-seven human knee cadavers (OA status unknown) were examined with both imaging modalities. Three-dimensional (3D) segmentation and registration processes, together with automatic positioning of 3D analysis volumes of interest (VOIs), ensured the measurement of BMD and texture parameters at the same anatomical locations in CT and HR-pQCT datasets. RESULTS: According to the calculation of dice ratios (>0.978), the accuracy of VOI locations between methods was excellent. Entropy, anisotropy, and global inhomogeneity showed significant and high linear correlation between both methods (0.68 < R 2 < 1.00). The resolution dependence of these parameters simulated earlier was confirmed by the in vitro measurements. CONCLUSION: The high correlation of HR-pQCT- and CT-based measurements of entropy, global inhomogeneity, and anisotropy suggests interchangeability between devices regarding the quantification of texture. The agreement of the experimentally determined resolution dependence of global inhomogeneity and anisotropy with earlier simulations is an important milestone towards their use to quantify subchondral bone structure. However, an in vivo study is still required to establish their clinical relevance. PMID- 28073370 TI - Expression site of P2RY12 in residential microglial cells in astrocytomas correlates with M1 and M2 marker expression and tumor grade. AB - The role of resident microglial cells in the pathogenesis and progression of glial tumors is still obscure mainly due to a lack of specific markers. Recently P2RY12, a P2 purinergic receptor, was introduced as a specific marker for microglial cells under normal and pathologic conditions. Here we analyzed the expression of P2RY12 in astrocytomas of various malignancy grades in relation to markers for M1 and M2 macrophage activation profiles by using two web-based glioma datasets and confocal immunohistochemistry to 28 astrocytoma samples grades II-IV. In the gliomas, P2RY12 immunoreactivity delineated CD68 negative cells with otherwise microglial features from CD68 positive tumor associated macrophages (TAMs). The presence of P2RY12 positive cells correlated positively with overall survival. P2RY12 mRNA levels and membrane-bound localization of P2RY12 were inversely correlated with increasing malignancy grade, and the expression site of P2RY12 shifted from cytoplasmic in low-grade gliomas, to nuclear in high-grade tumors. The cytoplasmic expression of P2RY12 was associated with the expression of M1 markers, characteristic of the pro-inflammatory macrophage response. In contrast, the nuclear localization of P2RY12 was predominant in the higher graded tumors and associated with the expression of the M2 marker CD163.We conclude that P2RY12 is a specific marker for resident microglia in glioma and its expression and localization correspond to tumor grade and predominant stage of M1/M2 immune response. PMID- 28073371 TI - Should we assume that hypothermia is a dysfunction in sepsis? PMID- 28073372 TI - A novel method for the quantification of fatty infiltration in skeletal muscle. AB - BACKGROUND: Fatty infiltration of the skeletal muscle is a common but poorly understood feature of many myopathies. It is best described in human muscle, where non-invasive imaging techniques and representative histology have been optimized to view and quantify infiltrating fat. However, human studies are limited in their ability to identify cellular and molecular mechanisms regulating fatty infiltration, a likely prerequisite to developing targeted interventions. As mechanistic investigations move to small animals, studies may benefit from new or adapted imaging tools optimized for high resolution and whole muscle quantification. RESULTS: Here, we describe a novel method to evaluate fatty infiltration, developed for use with mouse muscle. In this methodology, muscle cellular membranes and proteins are removed via decellularization, but fatty infiltrate lipid is spared, trapped in its native distribution in a transparent extracellular matrix construct. This lipid can then be stained with visible or fluorescent dyes and imaged. We present three methods to stain and evaluate lipid in decellularized muscles which can be used individually or combined: (1) qualitative visualization of the amount and 3D spatial distribution of fatty infiltration using visible lipid soluble dye Oil Red O (ORO), (2) quantitative analysis of individual lipid droplet metrics (e.g., volume) via confocal imaging of fluorescent lipid soluble dye boron-dipyrromethene (BODIPY), and (3) quantitative analysis of total lipid content by optical density reading of extracted stained lipid. This methodology was validated by comparing glycerol induced fatty infiltration between two commonly used mouse strains: 129S1/SvlmJ (129S1) and C57BL/6J (BL/6J). All three methods were able to detect a significant increase in fatty infiltrate volume in the 129S1 muscle compared with that in BL/6J, and methods 1 and 2 additionally described a difference in the distribution of fatty infiltrate, indicating susceptibility to glycerol-induced fatty infiltration is strain-specific. CONCLUSIONS: With more mechanistic studies of fatty infiltration moving to small animal models, having an alternative to expensive non-invasive imaging techniques and selective representative histology will be beneficial. In this work, we present a method that can quantify both individual adipocyte lipids and whole muscle total fatty infiltrate lipid. PMID- 28073374 TI - Successful multimodal treatment of intraoral salivary duct carcinoma in a patient with multiple lymph node metastases: a case report. AB - BACKGROUND: Salivary duct carcinoma (SDC) is a high-grade salivary gland malignancy that is associated with an aggressive clinical behavior and poor prognosis. Herein, we report on a long surviving case of SDC of the minor salivary gland with multiple lymph node metastases (LNMs). CASE PRESENTATION: An 83-year-old woman presented with a history of lymphadenopathy in the right side of the neck and recent onset and rapid growth of a mass in the right buccal region. Clinical examinations and biopsy findings were suggestive of a salivary gland malignant tumor with regional LNMs. The patient was treated with neoadjuvant chemotherapy. Tumor excision and ipsilateral radical neck dissection were performed, followed by adjuvant chemoradiotherapy. Postoperative histological examination revealed a tumor with irregular nests of atypical ductal epithelial cells, a cribriform growth pattern, and comedo-like central necrosis that lead to a final diagnosis of SDC. LNMs were observed in six lymph nodes of the right side of the neck. The patient underwent postoperative chemotherapy using single-agent cisplatin that was administered concurrently with radiotherapy (total, 65 Gy). There was no evidence of local recurrence or distant metastasis for >6 years. CONCLUSIONS: Although available data on treatment modalities for SDC remain limited, multimodal therapy may contribute to improved clinical outcomes in patients with advanced intraoral SDC. PMID- 28073375 TI - Promoting early identification of sepsis in hospitalized patients with nurse-led protocols. PMID- 28073376 TI - Treatment and outcome prognosis of patients with high-energy transsyndesmotic ankle fracture dislocation-the "Logsplitter" injury. AB - BACKGROUND: This study aimed to retrospectively review the clinical efficacy of open reduction and internal fixation (ORIF) for treatment of high-energy transsyndesmotic ankle fracture dislocation-the "Logsplitter" injury. METHODS: Between December 2006 and December 2014, 41 patients (29 males and 12 females; mean age, 41.46 +/- 13.42 years) with Logsplitter injury were treated by ORIF procedure. Patients were grouped as typical injury (mainly vertical axial stress) and untypical injury (mainly rotational stress) according to the injury mechanism and the degree of the talus wedged into the distal tibiofibular joint. RESULTS: After the follow-up of 32.48 +/- 24.18 weeks, average American Orthopedic Foot and Ankle Society (AOFAS) score at final follow-up was 78.54 +/- 10.66 and the excellent and good rate of 82.9%. Three patients in typical group developed nonunion, and other three cases had infection vs. none in untypical group (both P = 0.053). Burwell-Charnely scoring system revealed anatomic reduction of fracture was achieved in 22 cases, fair reduction in 16 cases, and poor in only 3 cases. Patients in untypical group had better fracture reduction (P = 0.015) and lower incidence rate of posttraumatic ankle arthritis (P = 0.042) than typical cases as well as the range of motion (P < 0.01). CONCLUSIONS: The ORIF may be an optimal approach to treat Logsplitter injuries. Patients with untypical injury had better fracture reduction, range of motion, and low incidence rate of posttraumatic ankle arthritis than those typical ones, and the postoperative outcome was affected by the injury and treatment characteristics. PMID- 28073373 TI - T cell exhaustion: from pathophysiological basics to tumor immunotherapy. AB - The immune system is capable of distinguishing between danger- and non-danger signals, thus inducing either an appropriate immune response against pathogens and cancer or inducing self-tolerance to avoid autoimmunity and immunopathology. One of the mechanisms that have evolved to prevent destruction by the immune system, is to functionally silence effector T cells, termed T cell exhaustion, which is also exploited by viruses and cancers for immune escape In this review, we discuss some of the phenotypic markers associated with T cell exhaustion and we summarize current strategies to reinvigorate exhausted T cells by blocking these surface marker using monoclonal antibodies. PMID- 28073377 TI - Magnitude and influencing factors of respiration-induced liver motion during abdominal compression in patients with intrahepatic tumors. AB - PURPOSE: The purpose of this study was to use 4-dimensional-computed tomography (4D-CT) to evaluate respiration-induced liver motion magnitude and influencing factors in patients with intrahepatic tumors undergoing abdominal compression. METHODS: From January 2012 to April 2016, 99 patients with intrahepatic tumors were included in this study. They all underwent 4D-CT to assess respiratory liver motion. This was performed during abdominal compression in 53 patients and during free-breathing (no abdominal compression) in 46 patients. We defined abdominal compression as being effective in managing the breath amplitude if respiration induced liver motion in the cranial-caudal (CC) direction during compression was <=5 mm and as being ineffective if >5 mm of motion was observed. Gender, age, body mass index (BMI), transarterial chemoembolization history, liver resection history, tumor area, tumor number, and tumor size (diameter) were determined. Multivariate logistic regression analysis was used to analyze influencing factors associated with a breath amplitude <=5 mm in the CC direction. RESULTS: The mean respiration-induced liver motion during abdominal compression in the left-right (LR), CC, anterior-posterior (AP), and 3-dimensional vector directions was 2.9 +/ 1.2 mm, 5.3 +/- 2.2 mm, 2.3 +/- 1.1 mm and 6.7 +/- 2.1 mm, respectively. Univariate analysis indicated that gender and BMI significantly affected abdominal compression effectiveness (both p < 0.05). Multivariate analysis confirmed these two factors as significant predictors of effective abdominal compression: gender (p = 0.030) and BMI (p = 0.006). There was a strong correlation between gender and compression effectiveness (odds ratio [OR] = 7.450) and an even stronger correlation between BMI and compression effectiveness (OR = 10.842). CONCLUSIONS: The magnitude of respiration-induced liver motion of patients with intrahepatic carcinoma undergoing abdominal compression is affected by gender and BMI, with abdominal compression being less effective in men and overweight patients. PMID- 28073378 TI - HECTD1 controls the protein level of IQGAP1 to regulate the dynamics of adhesive structures. AB - BACKGROUND: Cell migration including collective cell movement and individual cell migration are crucial factors in embryogenesis. During the spreading/migration of cells, several types of adhesive structures physically interacting with the extracellular matrix (ECM) or with another cell have been described and the formation and maturation of adhesion structures are coordinated, however the molecular pathways involved are still not fully understood. RESULTS: We generated a mouse embryonic fibroblast line (MEF) from homozygous mutant (Hectd1 R/R , Hectd1 Gt(RRC200) ) mouse of the E3 ubiquitin ligase for inhibin B receptor (Hectd1). Detailed examination of cell motion on MEF cells demonstrated that loss of Hectd1 resulted in accelerated cell spreading and migration but impaired directionality of migration. In Hectd1 R/R cells paxillin and zyxin were largely mis-localized, whereas their expression levels were unchanged. In addition the formation of focal adhesions (FAs) was impaired and the focal complexes (FXs) were increased. We further identified HECTD1 as a key regulator of IQGAP1. IQGAP1 co-localized together with HECTD1 in the leading edge of cells. HECTD1 interacted with IQGAP1 and regulated its degradation through ubiquitination. Over-expression of IQGAP1 in control MEF phenocopied the spreading and migration defects of Hectd1 R/R cells. In contrast, siRNA-mediated knockdown of IQGAP1 rescued the defects in cellular movement of Hectd1 R/R cells. CONCLUSIONS: The E3 ligase activity of Hectd1 regulates the protein level of IQGAP1 through ubiquitination and therefore mediates the dynamics of FXs including the recruitment of paxillin and actinin. IQGAP1 is one of the effectors of HECTD1. PMID- 28073379 TI - Tau passive immunization inhibits not only tau but also Abeta pathology. AB - BACKGROUND: Accumulation of hyperphosphorylated tau protein is a histopathological hallmark of Alzheimer's disease (AD) and related tauopathies. Currently, there is no effective treatment available for these progressive neurodegenerative diseases. In recent years, tau immunotherapy has shown great potential in animal models. We report the effect of immunization with tau antibodies 43D against tau 6-18 and 77E9 against tau 184-195 on tau and amyloid beta (Abeta) pathologies and cognition in triple-transgenic (3*Tg)-AD mice at mild to moderate stages of the disease. METHODS: We immunized 12-month-old female 3*Tg-AD mice with two to six or seven intravenous weekly doses of 15 MUg of mouse monoclonal antibody 43D, 77E9, a combination of one-half dose each of 43D and 77E9, or as control of mouse immunoglobulin G (IgG). Age-matched wild-type mice treated with mouse IgG or a mixture of 43D and 77E9 were also used as controls. The effect of immunization with tau antibodies on tau and Abeta pathologies was assessed by Western blot and immunofluorescence analysis, and the effect on cognition was analyzed by using Morris water maze, one-trial novel object recognition, and novel object location tasks. RESULTS: We found that two doses of 43D and 77E9 reduced total tau but had no significant impact on hyperphosphorylation of tau. However, six doses of 43D reduced levels of both total tau and tau hyperphosphorylated at Ser262/356 and Ser396/404 sites in the hippocampus. Importantly, both 43D and 77E9 antibodies rescued spatial memory and short-term memory impairments in 3*Tg-AD mice. The beneficial effect of 43D and 77E9 antibodies on cognitive performance was sustained up to 3 months after the last dose. Six doses of immunization with 43D also decreased amyloid precursor protein (APP) level in CA1 and amyloid plaques in subiculum, and showed a trend toward reducing Abeta40 and Abeta42 in the forebrain. Immunization with 43D increased levels of complement components C1 and C9 and resulted in activation of microglia, especially surrounding Abeta plaques. CONCLUSIONS: These findings suggest the potential of passive immunization targeting proximal N-terminal domain tau 6-18 as a disease-modifying approach to AD and related tauopathies. PMID- 28073380 TI - Long non-coding RNA small nucleolar RNA host gene 12 (SNHG12) promotes tumorigenesis and metastasis by targeting miR-199a/b-5p in hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is third leading cause of cancer related death globally. Evidence suggest that long non-coding RNAs (lncRNAs) have emerged as key regulators of tumorigenesis and metastasis in HCC. In this study, we investigated the functional significance of SNHG12 and explored whether SNHG12 can directly interact with miR-199a/b-5p in the progression of HCC. METHODS: We determined the expression level of SNHG12 in HCC tissues with quantitative real time PCR and then studied its clinical significance. The binding site between SNHG12 and miR-199a/b-5p was confirmed using dual luciferase assay and RNA immunoprecipitation (RIP) assay. SNHG12 was silenced through the siRNA transfection to determine whether SNHG12-siRNA is able to affect cell proliferation, invasion and metastasis. RESULTS: SNHG12 was significantly higher in the HCC tissues than that in the adjacent normal tissues. There were direct interactions between miR-199a/b-5p and the binding site of SNHG12. SNHG12 functioned as an endogenous sponge for miR-199a/b-5p to regulate the expression of MLK3 and affect the NF-kappaB pathway. CONCLUSION: SNHG12 may serve as a valuable biomarker and a potential therapeutic target for HCC. PMID- 28073381 TI - Immediate and lag effects of pesticide exposure on parasite resistance in larval amphibians. AB - Across host-parasite systems, there is evidence that pesticide exposure increases parasite loads and mortality following infection. However, whether these effects are driven by reductions in host resistance to infection or slower rates of parasite clearance is often unclear. Using controlled laboratory experiments, we examined the ability of larval northern leopard frogs (Lithobates pipiens) and American toads (Anaxyrus americanus) to resist and clear trematode (Echinoparyphium sp.) infections following exposure to the insecticide carbaryl. Northern leopard frogs exposed to 1 mg L-1 of carbaryl had 61% higher parasite loads compared with unexposed individuals, while there was no immediate effect of carbaryl on parasite encystment in American toads. However, when tadpoles were exposed to carbaryl and moved to freshwater for 14 days before the parasite challenge, we recovered 37 and 63% more parasites from carbaryl-exposed northern leopard frogs and American toads, respectively, compared with the control. No effects on clearance were found for either species. Collectively, our results suggest that pesticide exposure can reduce the ability of amphibians to resist parasite infections and that these effects can persist weeks following exposure. It is critical for researchers to incorporate species interactions into toxicity studies to improve our understanding of how contaminants affect ecological communities. PMID- 28073382 TI - A retrospective study comparing agar plate culture, indirect immunofluorescence and real-time PCR for the diagnosis of Strongyloides stercoralis infection. AB - Strongyloides stercoralis is a parasite that can cause death in immunocompromised people. A proper diagnosis is hence essential. The real-time polymerase-chain reaction (RT-PCR) is a novel, promising diagnostic method, that detects the DNA of the parasite in stool samples. In this retrospective study, we compared the sensitivity of agar plate coproculture (APC), an in-house immunofluorescence test (IFAT) and an in-house RT-PCR for the diagnosis of S. stercoralis infection. The study sample was composed by 223 samples. Samples resulting positive to APC, IFAT and RT-PCR were 20, 140 and 25, respectively. When sensitivity was calculated against a composite reference standard, serology confirmed the best performance (sensitivity 95%), followed by RT-PCR (57%) and APC (45%). In conclusion, in a non-endemic setting, serology is the best screening method, while the combination of APC and RT-PCR does not seem a reasonable approach to increase sensitivity. Both methods can have a role as confirmatory tests for selected cases. PMID- 28073383 TI - Evaluation of methylene blue, pyrimethamine and its combination on an in vitro Neospora caninum model. AB - Neospora caninum is an apicomplexan parasite strongly related to reproductive problems in cattle. The neosporosis control is not well established and several fronts are under development, predominantly based on immune protection, immunomodulation and chemotherapy. The use of anti-malarial drugs as therapeutic sources has, in theory, considerable potential for any apicomplexan. Drugs such as methylene blue (MB) and pyrimethamine (Pyr) represent therapeutic options for malaria; thus, their use for neosporosis should be assessed. In this work, we tested the effects of MB and Pyr on N. caninum proliferation and clearance, using LacZ-tagged tachyzoites. The drugs inhibited at nanomolar dosages and its combination demonstrated an antagonistic interaction in proliferation assays, according to the Chou and Talalay method for drug combination index. However, the drug combination significantly improved the parasite in vitro clearance. The repositioning of well-established drugs opens a short-term strategy to obtain low cost therapeutics approaches against neosporosis. PMID- 28073384 TI - Do blood parasites infect Magellanic penguins (Spheniscus magellanicus) in the wild? Prospective investigation and climatogeographic considerations. AB - Magellanic penguins (Spheniscus magellanicus) are native to Argentina, Chile and the Falkland Islands. Magellanic penguins are highly susceptible to blood parasites such as the mosquito-borne Plasmodium spp., which have been documented causing high morbidity and mortality in zoos and rehabilitation centres. However, to date no blood parasites have been detected in wild Magellanic penguins, and it is not clear whether this is reflective of their true absence or is instead related to an insufficiency in sampling effort or a failure of the diagnostic methods. We examined blood smears of 284 Magellanic penguins from the Argentinean coast and tested their blood samples with nested polymerase chain reaction tests targeting Haemoproteus, Plasmodium, Leucocytozoon and Babesia. No blood parasites were detected. Analysing the sampling effort of previous studies and the climatogeography of the region, we found there is strong basis to conclude that haemosporidians do not infect wild Magellanic penguins on the Argentinean coast. However, at present it is not possible to determine whether such parasites occur on the Chilean coast and at the Falkland Islands. Furthermore, it is troubling that the northward distribution expansion of Magellanic penguins and the poleward distribution shift of vectors may lead to novel opportunities for the transmission of blood parasites. PMID- 28073385 TI - The cestode parasite Schistocephalus pungitii: castrator or nutrient thief of ninespine stickleback fish? AB - In this investigation, the host-parasite relationship of ninespine stickleback fish Pungitius pungitius and the cestode parasite Schistocephalus pungitii was studied using samples from Dog Bone Lake, Kenai Peninsula, Alaska, to test the hypothesis that S. pungitii is a castrator of ninespine stickleback. Infected, adult females of all sizes (ages) were capable of producing clutches of eggs. S. pungitii had a negative effect on the ability of host females to produce a clutch, which was related to increasing parasite:host mass ratio (parasite index, PI). Among infected females with egg clutches, both clutch size and egg size were reduced; and the reduction increased with greater PI. The results of this study are consistent with the hypothesis that S. pungitii causes host sterility as a result of simple nutrient theft and is not a true castrator as hypothesized in earlier reports. The degree of parasite-induced sterility appears to vary among populations of the ninespine stickleback, perhaps reflecting differences in resource availability. Populations of ninespine stickleback appear to show a greater reduction in host reproductive capacity with PI than populations of the threespine stickleback infected by Schistocephalus solidus, possibly owing, in part, to the length-adjusted somatic mass of the threespine stickleback being greater. PMID- 28073386 TI - Disclosure of mental health problems: findings from an Australian national survey. AB - AIMS: The aim of the current study was to carry out a national population-based survey to assess the proportion of people disclosing mental health problems in a variety of settings. A further aim was to explore respondent characteristics associated with disclosure. METHODS: In 2014, telephone interviews were carried out with 5220 Australians aged 18+, 1381 of whom reported a mental health problem or scored highly on a symptom screening questionnaire. Questions covered disclosure of mental health problems to friends, intimate partners, other family members, supervisors or other colleagues in the workplace, teachers, lecturers or other students in the educational institution, health professionals and others in the community. Other than for intimate partners or supervisors, participants were asked whether or not they told everybody, some people or no one. Multinomial logistic regression was used to model the correlates of disclosure in each setting. RESULTS: For friends and family, respondents were more likely to disclose to some people than to everyone or to no one. In most other domains, non disclosure was most common, including in the workplace, where non-disclosure to supervisors was more likely than disclosure. Disclosure was associated with having received treatment or with support in all settings except healthcare, while it was only associated with discrimination in two settings (healthcare and education). CONCLUSIONS: Disclosure of mental health problems does not appear to be linked to discrimination in most settings, and is typically associated with receiving support. Selective or non-disclosure may be particularly critical in workplaces, education and healthcare settings. PMID- 28073387 TI - Recurrent acute otitis media detracts from health-related quality of life. AB - OBJECTIVE: Acute otitis media causes discomfort to children and inconvenience to their parents. This study evaluated the quality of life in children with recurrent acute otitis media aged less than 24 months. METHODS: Quality of life was evaluated in 149 children aged 10 to 24 months who were referred to the Oulu University Hospital on account of recurrent acute otitis media. The children were treated with or without surgery. Age-matched controls were selected randomly from the general child population. Parents completed the Child Health Questionnaire. RESULTS: The children with recurrent acute otitis media had a significantly poorer quality of life than control children. The control children with a history of a few acute otitis media episodes had a significantly poorer quality of life than those without any such history. The quality of life of the children with recurrent acute otitis media improved during the one-year follow up, regardless of the treatment, but did not reach the same level as healthy children. CONCLUSION: Acute otitis media detracted from quality of life when a generic measure was used. The mode of treatment used to prevent further recurrences of acute otitis media did not influence quality of life improvement. PMID- 28073389 TI - The distribution of echinostome parasites in ponds and implications for larval anuran survival. AB - Parasites can influence host population dynamics, community composition and evolution. Prediction of these effects, however, requires an understanding of the influence of ecological context on parasite distributions and the consequences of infection for host fitness. We address these issues with an amphibian - trematode (Digenea: Echinostomatidae) host-parasite system. We initially performed a field survey of trematode infection in first (snail) and second (larval green frog, Rana clamitans) intermediate hosts over 5 years across a landscape of 23 ponds in southeastern Michigan. We then combined this study with a tadpole enclosure experiment in eight ponds. We found echinostomes in all ponds during the survey, although infection levels in both snails and amphibians differed across ponds and years. Echinostome prevalence (proportion of hosts infected) in snails also changed seasonally depending on host species, and abundance (parasites per host) in tadpoles depended on host size and prevalence in snails. The enclosure experiment demonstrated that infection varied at sites within ponds, and tadpole survival was lower in enclosures with higher echinostome abundance. The observed effects enhance our ability to predict when and where host-parasite interactions will occur and the potential fitness consequences of infection, with implications for population and community dynamics, evolution and conservation. PMID- 28073388 TI - Isolation and biological and molecular characterization of Neospora caninum (NC SP1) from a naturally infected adult asymptomatic cattle (Bos taurus) in the state of Sao Paulo, Brazil. AB - The biological and genetic diversity of Neospora caninum is very limited because of availability of only a few viable isolates worldwide. This study describes the isolation and biological and molecular characterization of a new viable isolate of N. caninum (NC-SP1), from a cattle in Brazil. Approximately 400 g of brain from a naturally infected adult male cattle from an abattoir was fed to a 2-month old dog. Neospora-like oocysts were observed on day 7 post-inoculation (PI) and the duration of oocyst shedding was 14 days. The DNA obtained from oocysts was characterized molecularly and the final sequence was 99% identical to homologous sequences of N. caninum available in GenBank(r). For bioassay, gerbils (Meriones unguiculatus) were orally inoculated with 10 100 and 1000 oocysts; all gerbils remained clinically normal but developed N. caninum antibodies 14 days PI. Cell culture isolation was successful using the brain homogenate from one of the gerbils and tachyzoites were observed 24 days PI. Microsatellite genotyping revealed a unique genetic profile for this new reference isolate. PMID- 28073390 TI - The behavioural constellation of deprivation: Causes and consequences. AB - Socioeconomic differences in behaviour are pervasive and well documented, but their causes are not yet well understood. Here, we make the case that a cluster of behaviours is associated with lower socioeconomic status (SES), which we call "the behavioural constellation of deprivation." We propose that the relatively limited control associated with lower SES curtails the extent to which people can expect to realise deferred rewards, leading to more present-oriented behaviour in a range of domains. We illustrate this idea using the specific factor of extrinsic mortality risk, an important factor in evolutionary theoretical models. We emphasise the idea that the present-oriented behaviours of the constellation are a contextually appropriate response to structural and ecological factors rather than a pathology or a failure of willpower. We highlight some principles from evolutionary theoretical models that can deepen our understanding of how socioeconomic inequalities can become amplified and embedded. These principles are that (1) small initial disparities can lead to larger eventual inequalities, (2) feedback loops can embed early-life circumstances, (3) constraints can breed further constraints, and (4) feedback loops can operate over generations. We discuss some of the mechanisms by which SES may influence behaviour. We then review how the contextually appropriate response perspective that we have outlined fits with other findings about control and temporal discounting. Finally, we discuss the implications of this interpretation for research and policy. PMID- 28073391 TI - Magnetic Resonance Myelography in Congenital Absence of the Cervical Pedicle. AB - Absence of the cervical pedicle is a very rare congenital anomaly, easily misrecognized as a unilateral facet dislocation in a setting of acute trauma or a neoplastic process like a nerve sheath tumor. Although correct diagnosis can be achieved on the cervical radiograph and confirmed by the CT, MRI Myelography is clearly of additional value because shows the specific relationship and orientation of the nerve roots. To the best to our knowledge, this is the first description of MR Myelography findings. PMID- 28073392 TI - Does the dilution effect generally occur in animal diseases? AB - The dilution effect (DE) has been reported in many diseases, but its generality is still highly disputed. Most current criticisms of DE are related to animal diseases. Particularly, some critical studies argued that DE is less likely to occur in complex environments. Here our meta-analyses demonstrated that the magnitude of DE did not differ between animal vs plant diseases. Moreover, DE generally occurs in all three subgroups of animal diseases, namely direct transmitted diseases, vector-borne diseases and diseases caused by parasites with free-living stages. Our findings serve as an important contribution to understanding the generality of DE. PMID- 28073393 TI - Study on the mitochondrial apoptosis pathways of small cell lung cancer H446 cells induced by Trichinella spiralis muscle larvae ESPs. AB - Trichinella spiralis (T.spiralis) muscle-larva (ML) excretory-secretory proteins (ESPs) contain antitumour-active substances. ESPs have been shown to inhibit tumour growth. To explore the effects of these proteins on small cell lung cancer cells and the possible mechanisms of their antineoplastic action, H446 SCLC cells were co-cultured with different concentrations of T. spiralis ML ESPs for 12, 24 and 48 h. Our results showed that T. spiralis ML ESPs significantly inhibited H446 cell proliferation, which was dose-and time-dependent. The results of flow cytometry testing indicate a clear apoptosis trend in H446 cells co-cultured with ESPs for 24 h. Reverse transcription polymerase chain reaction and Western blotting results showed increased expression of pro-apoptosis genes Bax, Cyt-C, Apaf-1, caspase-9 and caspase-3, compared with the negative control group, and decreased the expression of anti-apoptosis genes Bcl-2 and Livin. Our results suggest that T. spiralis ML ESPs can induce apoptosis in H446 cells through a mitochondrial pathway, which may be a mechanism of antineoplastic action in T. spiralis ML ESPs. PMID- 28073394 TI - Gregarine infection accelerates larval development of the cat flea Ctenocephalides felis (Bouche). AB - A high degree of specialization between host and parasite is a well-known outcome of a long history of coevolution, and it is strikingly illustrated in a coordination of their life cycles. In some cases, the arms race ensued at the establishment of a symbiotic relationship results in the adoption of manipulative strategies by the parasite. We have already learned that Steinina ctenocephali, a gregarine living in the alimentary canal of cat flea, Ctenocephalides felis follows its phenology and metamorphosis. Despite these findings the outcome of their symbiotic partnership (mutualist, parasitic or commensal) remains unclear. To address this important question, we measured life history parameters of the flea in the presence of varying infection intensities of gregarine oocysts in laboratory conditions. We found that neither the emergence nor survival rate of fleas was affected by harbouring the gregarines. More surprisingly, our results show that flea larvae infected with gregarines developed faster and emerged earlier than the control group. This gregarine therefore joins the selected group of protists that can modify physiological host traits and provides not only new model taxa to be explored in an evolutionary scenario, but also potential development of control strategies of cat flea. PMID- 28073395 TI - Actinophytocola xanthii sp. nov., an actinomycete isolated from rhizosphere soil of the plant Xanthium sibiricum. AB - A novel actinomycete strain, 11-183T, was isolated from the rhizosphere soil of Xanthium sibiricum, which was collected in Tangshan, Hebei, China. A phylogenetic analysis based on 16S rRNA gene sequences showed that strain 11-183T formed a clade within the genus Actinophytocola, with a maximum similarity of 98.44 % to Actinophytocola xinjiangensis QAIII60T, followed by 97.76 % similarity to Actinophytocola sediminis YIM M13705T. The average nucleotide identity and digital DNA-DNA hybridization values differed by 79.24 and 23.4 %, respectively, between strain 11-183T and Actinophytocolaxinjiangensis QAIII60T. Strain 11-183T grew well on N-Z-amine agar, and it produced a scant, white aerial mycelium. The isolate formed pale yellow to brown-black colonies and a dense, non-fragmented, branched substrate mycelium, and produced aerial hyphae on which nodular spore chains formed. Growth was observed at salinities ranging from 0 to 2 %, at pH values ranging from pH 6.5 to 8.0 and at temperatures ranging from 15 to 37 degrees C. The cell-wall amino acids included meso-diaminopimelic acid. Whole cell hydrolysates contained galactose and glucose. The principal fatty acids were iso-C16 : 0, iso-C16 : 1 H and C17 : 1omega6c. Diphosphatidylglycerol, phosphatidylmonomethylethanolamine and phosphatidylethanolamine were the diagnostic phospholipids. The isoprenoid quinones included MK-9(H4) and MK 10(H4). The G+C content of the genomic DNA was 71.7 mol%. Based on the genotypic and phenotypic data, we conclude that strain 11-183T belongs to a novel species of the genus Actinophytocola. The name proposed for the novel species is Actinophytocola xanthii sp. nov., with the type strain 11-183T (=KCTC 39690T= MCCC 1K02062T). PMID- 28073396 TI - Nonomuraea ceibae sp. nov., an actinobacterium isolated from Ceiba speciosa rhizosphere. AB - Strain XMU 110T, isolated from the rhizosphere soil of a flowering tree, Ceiba speciosa, was characterized by polyphasic taxonomy. Phylogenetic analysis based on 16S rRNA gene comparisons revealed that strain XMU 110T showed the highest similarity of 97.9 % to Nonomuraea jabiensis DSM 45507T, and indicated the closest relatives were Nonomuraearoseoviolaceasubsp.roseoviolacea ATCC 27297T (97.8 % 16S rRNA gene sequence similarity) and Nonomuraea salmonea DSM 43678T (97.4 %) after a neighbour-joining analysis. The phenotypic characteristics, as well as the DNA-DNA relatedness values between strain XMU 110T and N. roseoviolaceasubsp. roseoviolacea ATCC 27297T (48.07+/-1.99 %) and N. salmonea DSM 43678T (40.55+/-8.30 %), distinguished the novel strain from its closest phylogenetic neighbours. The morphological, physiological and chemotaxonomic characteristics such as phospholipid type, diagnostic diamino acid of the peptidoglycan, whole-cell sugars, major menaquinones and major fatty acids further supported the assignment of strain XMU 110T to the genus Nonomuraea. The G+C content of the genomic DNA was 66.2 mol%. Based on the taxonomic data, strain XMU 110Trepresents a novel species of the genus Nonomuraea, for which the name Nonomuraea ceibae sp. nov. is proposed. The type strain is XMU 110T (=MCCC 1K03213T= KCTC 39826T). PMID- 28073397 TI - Identification of new members of the Escherichia coli K-12 MG1655 SlyA regulon. AB - SlyA is a member of the MarR family of bacterial transcriptional regulators. Previously, SlyA has been shown to directly regulate only two operons in Escherichia coli K-12 MG1655, fimB and hlyE (clyA). In both cases, SlyA activates gene expression by antagonizing repression by the nucleoid-associated protein H NS. Here, the transcript profiles of aerobic glucose-limited steady-state chemostat cultures of E. coli K-12 MG1655, slyA mutant and slyA over-expression strains are reported. The transcript profile of the slyA mutant was not significantly different from that of the parent; however, that of the slyA expression strain was significantly different from that of the vector control. Transcripts representing 27 operons were increased in abundance, whereas 3 were decreased. Of the 30 differentially regulated operons, 24 have previously been associated with sites of H-NS binding, suggesting that antagonism of H-NS repression is a common feature of SlyA-mediated transcription regulation. Direct binding of SlyA to DNA located upstream of a selection of these targets permitted the identification of new operons likely to be directly regulated by SlyA. Transcripts of four operons coding for cryptic adhesins exhibited enhanced expression, and this was consistent with enhanced biofilm formation associated with the SlyA over-producing strain. PMID- 28073398 TI - 'Candidatus Moeniiplasma glomeromycotorum', an endobacterium of arbuscular mycorrhizal fungi. AB - Arbuscular mycorrhizal fungi (AMF, subphylum Glomeromycotina) are symbionts of most terrestrial plants. They commonly harbour endobacteria of a largely unknown biology, referred to as MRE (Mollicutes/mycoplasma-related endobacteria). Here, we propose to accommodate MRE in the novel genus 'Candidatus Moeniiplasma.' Phylogeny reconstructions based on the 16S rRNA gene sequences cluster 'Ca.Moeniiplasma' with representatives of the class Mollicutes, whereas phylogenies derived from amino acid sequences of 19 genes indicate that it is a discrete lineage sharing ancestry with the members of the family Mycoplasmataceae. Cells of 'Ca.Moeniiplasma' reside directly in the host cytoplasm and have not yet been cultivated. They are coccoid, ~500 nm in diameter, with an electron-dense layer outside the plasma membrane. However, the draft genomes of 'Ca.Moeniiplasma' suggest that this structure is not a Gram positive cell wall. The evolution of 'Ca.Moeniiplasma' appears to be driven by an ultrarapid rate of mutation accumulation related to the loss of DNA repair mechanisms. Moreover, molecular evolution patterns suggest that, in addition to vertical transmission, 'Ca.Moeniiplasma' is able to transmit horizontally among distinct Glomeromycotina host lineages and exchange genes. On the basis of these unique lifestyle features, the new species 'Candidatus Moeniiplasma glomeromycotorum' is proposed. PMID- 28073399 TI - Enterovirus 71 induces apoptosis by directly modulating the conformational activation of pro-apoptotic protein Bax. AB - Enterovirus 71 (EVA71), a virus of the genus Enterovirus in the family Picornaviridae, is one of the main causative agents of hand, foot and mouth disease in infected infants and young children. In this study, we report that cells with EVA71 infection exhibit increased levels of cytochrome c release and caspase-3 activation. EVA71 infection induces the conformational activation of pro-apoptotic protein Bax and the subsequent formation of oligomers of Bax in mitochondria. Inhibitors that block caspase-8 activation cannot inhibit apoptosis induced by EVA71 infection. Importantly, cells with Bax but not Bak or caspase-8 knockdown show resistance to apoptosis induced by EVA71 infection. Mitochondria isolated from EVA71-infected cells display clear Bax-binding ability and the subsequent release of cytochrome c. Therefore, these results indicate that EVA71 infection directly impacts the mitochondrial apoptotic pathway by modulating the recruitment and activation of Bax. PMID- 28073400 TI - Haloactinomyces albus gen. nov., sp. nov., isolated from the Dead Sea. AB - A novel halophilic, filamentous actinomycete strain, designated AFM 10258T, was isolated from a sediment sample collected from the Dead Sea of Israel. The isolate grew with 10-35 % NaCl and did not grow without NaCl. The isolate formed white aerial mycelium and long spore chains, and two spores were separated by sterile mycelium. The spores were non-motile, spherical and rugose-surfaced. The isolate contained meso-diaminopimelic acid as the diagnostic diamino acid and galactose and arabinose as the major whole-cell sugars. The polar lipids were diphosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and three unknown phospholipids. Major fatty acids were anteiso-C17 : 0, iso-C16 : 0 and iso-C15 : 0. MK-9(H4) was the predominant menaquinone and the DNA G+C content was 62.8 mol%. 16S rRNA gene sequence analysis indicated that strain AFM 10258T shared low sequence similarity with the closely related representatives of the families Pseudonocardiaceae (below 94.47 %) and Actinopolysporaceae (below 93.76 %). Phylogenetic analysis based on 16S rRNA gene sequences showed that strain AFM 10258T formed a robust clade with members of the family Actinopolysporaceae. On the basis of analysis of phenotypic, chemical and molecular characteristics, strain AFM 10258T is considered to represent a novel species of a new genus, for which the name Haloactinomyces albus gen. nov., sp. nov., is proposed. The type strain is AFM 10258T (=DSM 45977T=CGMCC 4.7115T). PMID- 28073401 TI - Proteome analysis reveals differential expression of proteins involved in triacylglycerol accumulation by Rhodococcus jostii RHA1 after addition of methyl viologen. AB - Rhodococcus jostii RHA1 is able to degrade toxic compounds and accumulate high amounts of triacylglycerols (TAG) upon nitrogen starvation. These NADPH-dependent processes are essential for the adaptation of rhodococci to fluctuating environmental conditions. In this study, we used an MS-based, label-free and quantitative proteomic approach to better understand the integral response of R. jostii RHA1 to the presence of methyl viologen (MV) in relation to the synthesis and accumulation of TAG. The addition of MV promoted a decrease of TAG accumulation in comparison to cells cultivated under nitrogen-limiting conditions in the absence of this pro-oxidant. Proteomic analyses revealed that the abundance of key proteins of fatty acid biosynthesis, the Kennedy pathway, glyceroneogenesis and methylmalonyl-CoA pathway, among others, decreased in the presence of MV. In contrast, some proteins involved in lipolysis and beta oxidation of fatty acids were upregulated. Some metabolic pathways linked to the synthesis of NADPH remained activated during oxidative stress as well as under nitrogen starvation conditions. Additionally, exposure to MV resulted in the activation of complete antioxidant machinery comprising superoxide dismutases, catalases, mycothiol biosynthesis, mycothione reductase and alkyl hydroperoxide reductases, among others. Our study suggests that oxidative stress response affects TAG accumulation under nitrogen-limiting conditions through programmed molecular mechanisms when both stresses occur simultaneously. PMID- 28073402 TI - Deep sequencing analysis of tick-borne encephalitis virus from questing ticks at natural foci reveals similarities between quasispecies pools of the virus. AB - Every year, tick-borne encephalitis virus (TBEV) causes severe central nervous system infection in 10 000 to 15 000 people in Europe and Asia. TBEV is maintained in the environment by an enzootic cycle that requires a tick vector and a vertebrate host, and the adaptation of TBEV to vertebrate and invertebrate environments is essential for TBEV persistence in nature. This adaptation is facilitated by the error-prone nature of the virus's RNA-dependent RNA polymerase, which generates genetically distinct virus variants called quasispecies. TBEV shows a focal geographical distribution pattern where each focus represents a TBEV hotspot. Here, we sequenced and characterized two TBEV genomes, JP-296 and JP-554, from questing Ixodes ricinus ticks at a TBEV focus in central Sweden. Phylogenetic analysis showed geographical clustering among the newly sequenced strains and three previously sequenced Scandinavian strains, Toro 2003, Saringe-2009 and Mandal-2009, which originated from the same ancestor. Among these five Scandinavian TBEV strains, only Mandal-2009 showed a large deletion within the 3' non-coding region (NCR), similar to the highly virulent TBEV strain Hypr. Deep sequencing of JP-296, JP-554 and Mandal-2009 revealed significantly high quasispecies diversity for JP-296 and JP-554, with intact 3'NCRs, compared to the low diversity in Mandal-2009, with a truncated 3'NCR. Single-nucleotide polymorphism analysis showed that 40 % of the single-nucleotide polymorphisms were common between quasispecies populations of JP-296 and JP-554, indicating a putative mechanism for how TBEV persists and is maintained within its natural foci. PMID- 28073403 TI - Arcanobacterium wilhelmae sp. nov., isolated from the genital tract of a rhinoceros (Rhinoceros unicornis). AB - A taxonomic study using a polyphasic approach was performed on an unidentified Arcanobacterium-like Gram-stain-positive bacterium isolated from the genital tract of a rhinoceros. Comparative 16S rRNA gene sequencing showed that the bacterium belonged to the genus Arcanobacterium and was most closely related to the type strains of Arcanobacterium canis (98.8 % 16S rRNA gene sequence similarity), Arcanobacterium phocisimile (97.8 %), Arcanobacterium phocae (97.7 %), Arcanobacterium haemolyticum (97.4 %), Arcanobacterium hippocoleae (96.6 %), Arcanobacterium pinnipediorum (96.4 %) and Arcarnobacterium pluranimalium (95.4 %). DNA-DNA hybridization values between strain 647T and Arcanobacterium canisDSM 25104T were very low, 13.4 % (reciprocal 15.9 %). The genomic DNA G+C content of strain 647T was 58.7 mol%. The presence of the major menaquinone MK-9(H4) supported the affiliation of this strain to the genus Arcanobacterium. The polar lipid profile consisted of the major components diphosphatidylglycerol, phosphatidylcholine and an unidentified phosphoglycolipid. The results of physiological and biochemical testing clearly distinguished the unknown bacterium from other species of the genus Arcanobacterium. Based on these tests, it is proposed that the unknown bacterium should be classified as a representative of a novel species of the genus Arcanobacterium named Arcanobacterium wilhelmaesp. nov. The type strain is 647T (=DSM 102162T=LMG 29418T). PMID- 28073404 TI - Isolation and characterization of an HIV-1 envelope glycoprotein-specific B-cell from an immortalized human naive B-cell library. AB - With the recent development of single B-cell cloning techniques, an increasing number of human immunodeficiency virus type 1 (HIV-1)-specific broadly neutralizing antibodies have been isolated since 2009. However, knowledge regarding HIV-1-specific B cells in vivo is limited. In this study, an HIV-1 specific B-cell line was established using healthy PBMC donors by the highly efficient Epstein-Barr virus transformation method to generate immortalized human naive B-cell libraries. The enrichment of HIV-1 envelope-specific B cells was observed after four rounds of cell panning with the HIV-1 envelope glycoprotein. An HIV-1 envelope-specific stable B-cell line (LCL-P4) was generated. Although this cell line acquired a lymphoblastic phenotype, no expression was observed for activation-induced cytidine deaminase, an enzyme responsible for initiating somatic hypermutation and class switch recombination in B cells. This study describes a method that enables fast isolation of HIV-1-specific B cells, and this approach may extend to isolating other B-cell-specific antigens for further experiments. PMID- 28073405 TI - Rhodanobacter humi sp. nov., an acid-tolerant and alkalitolerant gammaproteobacterium isolated from forest soil. AB - A novel acid-tolerant and alkalitolerant gammaproteobacterium designated strain RS22T was isolated from Kyonggi University forest soil. Cells were aerobic, Gram stain-negative, catalase- and oxidase-positive, non-motile, non-spore-forming, rod-shaped and yellow-pigmented. Flexirubin-type pigments were absent. Strain RS22T was able to assimilate lactic acid, l-proline and 3-hydroxybenzoic acid; it tolerated 4 % (w/v) NaCl, fermented glucose and was able to grow at pH 11.0. Phylogenetic analysis based on its 16S rRNA gene sequence revealed that strain RS22T formed a lineage within the class Gammaproteobacteria of the phylum Proteobacteria that was distinct from various species of the genus Rhodanobacter, including Rhodanobacter denitrificans 2APBS1T (97.7 % sequence similarity), Rhodanobacter thiooxydans LCS2T (97.5 %), Rhodanobacter terrae GP18-1T (97.5 %) and Rhodanobacter soli DCY45T (97.2 %). The predominant respiratory quinone was Q 8. The major polar lipids of strain RS22T were phosphatidylethanolamine, phosphatidyl-N-methylethanolamine, diphosphatidylglycerol and phosphatidylglycerol. The major cellular fatty acids were summed feature 9 (iso C17 : 1omega9c and/or C16 : 0 10-methyl), iso-C15 : 0, iso-C17 : 0, iso-C16 : 0, anteiso-C15 : 0 and C16 : 0. The DNA G+C content of strain RS22T was 63.2 mol%. DNA-DNA hybridization between strain RS22T and other closest members of the genus Rhodanobacterrevealed relatedness values from 28 to 51 %. On the basis of phenotypic, genotypic, chemotaxonomic and phylogenetic analysis, strain RS22T represents a novel species of the genus Rhodanobacter, for which the name Rhodanobacter humi sp. nov. is proposed. The type strain is RS22T (=KEMB 9005 480T=KACC 19048T=NBRC 112473T). PMID- 28073406 TI - [Prevention of mother-to-child transmission of hepatitis B virus]. AB - Mother-to-child transmission (MTCT) is a major mode of hepatitis B virus (HBV) transmission, especially in high endemic areas. Administration of hepatitis B immunoglobulin (HBIG) and hepatitis B vaccine to infants at birth, followed by completion of the vaccine series, prevented approximately 95% of HBV transmission from HBsAg-positive mothers to their infants. However, immunoprophylaxis failure was still observed in 5~10% infants born to mothers with high levels of viremia. It was demonstrated that antiviral nucleot(s)ide analogues (NUCs) provided to pregnant women with high viral loads in late pregnancy further reduced MTCT. This paper discussed criteria of antiviral treatment for prevention of MTCT including threshold of HBV DNA level in pregnant women, time of starting treatment, time of stopping treatment, and kind of NUCs. The route of hepatitis B vaccine administration was also discussed. PMID- 28073407 TI - [The practice guideline on prophylaxis and treatment of hepatitis B for liver transplantation in China (2016 edition)]. PMID- 28073408 TI - [Establishment of a cell co-culture system in accordance with the immunological characteristics of chronic HBV infection]. AB - Objective: To investigate whether the co-culture of Huh7.93 cells and peripheral blood mononucleated cells from chronic hepatitis B patients (cPBMCs) can simulate the replication features of hepatitis B virus (HBV) and immune function in chronic hepatitis B (CHB) patients, and to provide an in vitro cell co-culture system for the research on immune clearance in chronic HBV infection. Methods: Huh7.93 cells were cultured alone or co-cultured with peripheral blood mononucleated cells from healthy people who underwent physical examination (nPBMCs) or cPBMCs for 7 days. The CCK8 assay was performed to measure the proliferative activity of Huh7.93 cells, and quantitative real-time PCR and Southern blot were used to measure HBV replication in cPBMCs and co-cultured cells. The independent samples t-test was used for comparison between two groups. Results: When Huh7.93 cells were co-cultured with peripheral blood mononucleated cells (PBMCs) at a certain ratio, Huh7.93 cells had a high proliferative activity and good cell growth. HBV could not infect or replicate in cPBMCs. HBV DNA in the supernatant of Huh7.93 cells co-cultured with cPBMCs showed significant increases and significantly higher than that in the supernatant of Huh7.93 cells cultured alone on day 4 (6.01 +/- 0.20 log10copies/ml vs 4.99 +/- 0.08 log10copies/ml, P = 0.000) and day 7 (7.82 +/- 0.24 log10copies/ml vs 6.96+/-0.09 log10copies/ml, P = 0.000). On day 7 of culture, the cell lysis buffer of Huh7.93 cells co-cultured with cPBMCs had a significant increase in the level of HBV replicative intermediate compared with that of Huh7.93 cells cultured alone. After HepG2.2.15 cells were co-cultured with cPBMCs, there was no significant increase in HBV replication. Conclusion: The co-culture of Huh7.93 cells and cPBMCs produces similar viral replication as human body infected with HBV and can well simulate the liver microenvironment and immune function in CHB patients, which provides a new method for the research on immune clearance in chronic HBV infection. PMID- 28073409 TI - [A study of immune response to HBsAg mediated by CD4+ memory T lymphocytes in immunized HBV transgenic mice]. AB - Objective: To investigate the mechanism of immune response to HBsAg mediated by CD4+ memory T lymphocytes in immunized HBV transgenic (Tg) mice. Methods: Peripheral CD4+ memory T lymphocytes were isolated and collected by magnetic bead sorting from C57BL/6 mice successfully immunized by hepatitis B vaccine. Adoptive immunization was performed for Tg mice by caudal vein injection, and the peripheral blood was collected at 4 and 8 weeks after adoptive immunization. Enzyme-linked immunosorbent assay was used to measure the levels of HBsAg, anti HBs, interferon-gamma (IFNgamma), and interleukin-2 (IL-2), and immunohistochemistry was used to measure the level of HBsAg in the liver. The t test was used for comparison of continuous data, and the chi-square test was used for comparison of categorical data. Results: Compared with the control group, the experimental group had a significant reduction in HBsAg titer[(243.5+/-12.4) ng/ml vs 0 ng/ml, t = 3.939, P = 0.011] and significant increases in the levels of anti-HBs [0 ng/ml vs (530.7+/-17.5) ng/ml, t = 4.414, P = 0.006 9], IFNgamma [(12.25+/-2.9) pg/ml vs (38.8+/-6.8) pg/ml, t = 2.785, P = 0.049 6], and IL-2 [(11.3+/-3.5) pg/ml vs (82.3+/-9.2) pg/ml, t = 2.993, P = 0.040 2]. Conclusion: As for immune response to HBsAg mediated by CD4+ memory T lymphocytes in immunized HBV Tg mice, increases in the levels of IFNgamma and IL-2 help to enhance humoral and cellular immunity and mediate the clearance of HBsAg in Tg mice. PMID- 28073410 TI - [Correlation of FibroTouch and FibroScan with the stage of primary biliary cirrhosis]. AB - Objective: To investigate the diagnostic value of FibroTouch and FibroScan for the stage of primary biliary cirrhosis (PBC). Methods: A total of 66 PBC patients who visited our hospital from January 2014 to March 2016 were enrolled, and all the patients underwent liver biopsy and FibroTouch and FibroScan tests. Liver stiffness measurement (LSM) was used to assess fibrosis degree, and the receiver operating characteristic (ROC) curve was used to compare the cut-off values, sensitivities, and specificities of these two methods in determining fibrosis stage. The Spearman rank correlation test was used to investigate the correlation between FibroTouch and FibroScan values. Results: The correlation coefficients between FibroTouch or FibroScan values and fibrosis stage determined by liver biopsy were 0.904 and 0.880, respectively (both P < 0.01). The cut-off values of FibroTouch in the diagnosis of PBC with fibrosis stages of >=S1, >=S2, >=S3, and >=S4 were 6.25 kPa, 9.05 kPa, 11.75 kPa, and 18.95 kPa, respectively, with sensitivities of 89.7%, 94.7%, 80.0%, and 80.0% and specificities of 100%, 100%, 87.0%, and 100%, respectively; the cut-off values of FibroScan were 6.05 kPa, 8.85 kPa, 12.40 kPa, and 16.20 kPa, respectively, with sensitivities of 96.4%, 88.6%, 76.2%, and 100% and specificities of 77.8%, 100%, 86.4%, and 93.0%, respectively. There were no significant differences in the diagnostic performance between FibroTouch and FibroScan in determining fibrosis stage [>=S1 (P = 0.109), >=S2 (P = 0.853), >=S3 (P = 0.387), >=S4 (P = 0.224)]. Conclusion: FibroTouch and FibroScan can be used as noninvasive diagnostic tools for the determination of fibrosis stage and the monitoring of disease progression in PBC patients and have good sensitivity and specificity. PMID- 28073411 TI - [Effect of umbilical cord mesenchymal stem cell transplantation on immune function and prognosis of patients with decompensated hepatitis B cirrhosis]. AB - Objective: To investigate the effect of human umbilical cord mesenchymal stem cells (hUCMSCs) on the immune function and prognosis of patients with decompensated hepatitis B cirrhosis. Methods: A total of 65 patients with decompensated hepatitis B cirrhosis were divided into observation group and control group. The patients in the observation group were given intervention (via the proper hepatic artery or the portal vein) and intravenous infusion of 4*108 hUCMSCs in two doses, as well as the same basic treatment as in the control group. The patients in the control group were given conventional medical treatment. ELISA as used to measure the serum levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFalpha), interleukin-10 (IL-10), and transforming growth factor-beta (TGFbeta) in the observation group before surgery and at 1 week after surgery, as well as the serum levels of IL-6, TNFalpha, IL-10, and TGFbeta in the control group on admission and at 1 week after admission. Flow cytometry was used to measure the percentage of lymphocyte subsets in the observation group before surgery and at 1 week after surgery, as well as that in the control group on admission and at 1 week after admission. In addition, the patients' prognosis and major complications during hospitalization were observed in both groups, and the patients were followed up for 24 weeks to record the number of deaths. The t-test was used for comparison of continuous data, and the chi-square test was used for comparison of categorical data which were expressed as percentages. Results: At 1 week after the transplantation of hUCMSCs, compared with the control group, the observation group had significant reductions in the serum levels of IL-6 and TNFalpha and significant increases in the serum levels of IL-10 and TGFbeta (all P < 0.001), as well as significant increases in the percentages of T4 cells and Treg cells and significant reductions in the percentages of T8 cells and B cells (all P < 0.05). There were no significant differences in the changes in T3 cells and natural killer cells between the two groups (P > 0.05). Compared with the control group, the observation group had a significantly lower probability of progression to liver failure (6.45% vs 14.71%, P = 0.017). Conclusion: In the treatment of patients with decompensated hepatitis B cirrhosis, transplantation of UCMSCs can inhibit the proliferation of T cells and B cells and the differentiation of T8 cells, upregulate Treg cells, promote the secretion of immunosuppressive cytokines, and reduce the production of inflammatory cytokines. Therefore, it can alleviate liver inflammatory response and liver cell damage and reduce the probability of hepatic failure. PMID- 28073412 TI - [Clinical effect of ultrasound-guided injection of biodegradable poly(lactic-co glycolic acid)-Fe3O4 in situ implant for magnetic thermal ablation in treatment of nude mice with human liver cancer SMMC-7721 cells]. AB - Objective: To prepare the Fe3O4-loaded biodegradable liquid-solid phase inversion poly(lactic-co-glycolic acid) (PLGA) in situ implant for ultrasound-guided injection into nude mouse tumor model, and to investigate its clinical effect in thermomagnetic treatment of nude mice with human liver cancer SMMC-7721 cells in an alternating magnetic field. Methods: An in situ implant containing 10% Fe3O4 was prepared, and 50 MUl Fe3O4-PLGA-NMP gel was injected into the subcutaneous tissue of Kunming mice. The degradation of this material was observed for 2 consecutive months, and the changes in body weight were recorded. HE staining and Prussian blue staining were performed for the heart, liver, spleen, lung, and kidney of Kunming mice. Fresh ex vivo bovine liver was taken and cut into cubes with a dimension of 2 cm*2 cm*2 cm and then 50 MUl Fe3O4-PLGA-NMP gel was injected; after phase inversion, the cubes of ex vivo bovine liver were heated for 1, 2, 3, 4, and 5 minutes, respectively, and then cut open for observing the range of ablation; HE staining was also performed. Micro-CT scan was performed after ultrasound-guided injection of 50 MUl Fe3O4-PLGA gel into the tumors of the nude mice, and then the nude mice were divided into treatment group and control group. The mice in the treatment group were given thermomagnetic treatment for 3 minutes, and tumor growth was observed daily. Results: The biodegradation of Fe3O4-PLGA-NMP implant showed that the subcutaneously injected material was gradually metabolized at 2 weeks after injection and that the nude mice were in good condition. The bovine liver ablation experiment showed that the range of ablation of 50 MUl Fe3O4-PLGA implant reached 1.46 +/- 0.11 cm. HE staining showed that part of bovine liver had coagulative necrosis. The phase inversion experiment of Fe3O4-PLGA gel showed quick liquid-solid phase inversion of the material after injection into the tumor, and the process of liquid-solid phase inversion could be monitored by ultrasound and CT. The detachment and incrustation of the tumor started at 2 days after treatment, the wound started to heal 15 days later, and the tumor tissue disappeared completely. Conclusion: Ultrasound-guided injection of biodegradable Fe3O4-PLGA in situ implant combined with magnetic thermal ablation can effectively treat human liver cancer SMMC-7721 cells in nude mice. PMID- 28073413 TI - [Cellular and molecular mechanisms of anti-inflammatory effect of peroxisome proliferator-activated receptor alpha]. AB - Objective: To investigate the cellular and molecular mechanisms of the anti inflammatory effect of peroxisome proliferator-activated receptor alpha (PPARalpha). Methods: Firstly, bone marrow-derived macrophages (BMDMs) were randomly divided into control group, LPS group, WY14643 10 MUmol/L group, WY14643 25 MUmol/L group, and WY14643 50 MUmol/L group using a random number table. Secondly, BMDMs were randomly divided into LPS group, WY14643+LPS group, and 3 MA+WY14643+LPS group. Primary BMDMs were stimulated by LPS (20 ng/ml) to establish the cellular model of inflammation. The selective agonist of PPARalpha WY14643 was administered at doses of 10, 25, and 50 MUmol/L (50 MUmol/L for the second part of the experiment) at 2 hours before model establishment. The autophagy inhibitor 3-MA was administered at a dose of 10 mmol/L at 2 hours before model establishment. The cells in the control group were treated with dimethylsulfoxide (DMSO) at the same dose. The cells were transfected with GFP LC3 plasmids at 24 hours before model establishment. The cells were harvested at 6 hours after LPS stimulation and related tests were performed. Green fluorescent protein was measured under a fluorescence microscope to evaluate autophagy activity. Quantitative real-time PCR was used to measure tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and mRNA expression of chemokine-1 (CXCL-1) and chemokine-10 (CXCL-10). Western blot was used to measure PPARalpha and autophagy-related proteins LC3, ATG-5, ATG-7, and LAMP-1. A one-way analysis of variance was used for comparison between groups, and the LSD-t test was used for comparison between any two groups. Results: In vitro, PPARalpha activation inhibited LPS-induced inflammatory response in primary macrophages in a dose-dependent manner. The results of gene expression showed that the relative expression of TNF-alpha, IL-1beta, IL-6, CXCL-1, and CXCL-10 was as follows in the control group, LPS group, WY14643 10 MUmol group, WY14643 25 MUmol group, and WY14643 50 MUmol group: TNF-alpha (0.085+/-0.009, 4.065+/-0.544, 3.281+/-0.368, 1.780+/-0.293, and 0.781+/-0.303, P < 0.01), IL 1beta (0.081+/-0.017, 0.776+/-0.303, 0.225+/-0.154, 0.161+/-0.068, and 0.101+/ 0.025, P < 0.05), IL-6 (0.041+/-0.011, 0.189+/-0.014, 0.144+/-0.033, 0.126+/ 0.013, and 0.048+/-0.015, P < 0.01), CXCL-1 (0.051+/-0.011, 0.515+/-0.145, 0.356+/-0.078, 0.257+/-0.068, and 0.069+/-0.030, P < 0.01), and CXCL-10 (0.126+/ 0.068, 0.831+/-0.093, 0.508+/-0245, 0.474+/-0.047, and 0.204+/-0.021, P < 0.05). In vitro, PPARalpha activation promoted autophagy in vitro in a dose-dependent manner. The results of Western blot and fluorescence microscopy in the control group, LPS group, WY14643 10 MUmol group, WY14643 25 MUmol group, and WY14643 50 MUmol group showed that the expression of autophagy-related proteins and autophagosome formation gradually increased with the increasing concentration of WY14643. In vitro, WY14643 inhibited autophagy, promoted inflammatory response in primary macrophages, and reversed the anti-inflammatory effect of PPARalpha. The results of gene expression showed that the relative expression of TNF-alpha, IL 1beta, IL-6, CXCL-1, and CXCL-10 was as follows in the LPS group, WY14643+LPS group, and 3-MA+WY14643+LPS group: TNFalpha (4.327+/-0.478, 1.218+/-0.424, and 3.901+/-0.447, P < 0.05), IL-1beta (4.277+/-0.407, 1.418+/-0.424, and 3.029+/ 0.192, P < 0.01), IL-6 (4.175+/-0.549, 1.373+/-0.499, and 4.031+/-0.475, P < 0.05), CXCL-1 (8.199+/-1.149, 2.024+/-0.547, and 5.973+/-0.843, P < 0.05), and CXCL-10 (1.208+/-0.148, 0.206+/-0.069, and 0.798+/-0.170, P < 0.05). Conclusion: PPARalpha can promote cell autophagy and inhibit inflammatory response and may become a new therapeutic target for clinical prevention and treatment of inflammatory disease. PMID- 28073415 TI - [Pathological features of the liver in patients with chronic HBV infection and normal alanine aminotransferase]. PMID- 28073416 TI - [Pathogenic features and prognosis of ventilator-associated pneumonia in patients with liver failure]. PMID- 28073414 TI - [Protective effect of Saccharomyces boulardii against intestinal mucosal barrier injury in rats with nonalcoholic fatty liver disease]. AB - Objective: To investigate the protective effect of Saccharomyces boulardii against intestinal mucosal barrier injury in rats with nonalcoholic fatty liver disease (NAFLD). Methods: A total of 36 healthy male Sprague-Dawley rats with a mean body weight of 180+/-20 g were randomly divided into control group, model group, and treatment group, with 12 rats in each group, after adaptive feeding for 1 week. The rats in the control group were given basic feed, and those in the model group and treatment group were given high-fat feed. After 12 weeks of feeding, the treatment group was given Saccharomyces boulardii (75*108 CFU/kg/d) by gavage, and those in the control group and model group were given isotonic saline by gavage. At the 20th week, blood samples were taken from the abdominal aorta to measure the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), intestinal fatty acid binding protein (IFABP), tumor necrosis factor-alpha (TNF-alpha), and endotoxins. The liver pathological changes, intestinal histopathological changes, and expression of occludin in the intestinal mucosa were observed. Fecal samples were collected to measure the changes in Escherichia coli and Bacteroides. A one-way analysis of variance and the SNK test were used for comparison between multiple groups, and the rank sum test was used as the non-parametric test. Results: Compared with the control group, the model group had significantly higher body weight, liver mass, and liver index (P < 0.05), and compared with the model group, the treatment group had significant reductions in body weight, liver mass, and liver index (P < 0.05). The model group had significant increases in TG, ALT, and AST compared with the control group (P < 0.05), the treatment group had a significant reduction in AST compared with the model group (P < 0.05), and the treatment group had slight reductions in TG and ALT compared with the model group (P > 0.05). Compared with the control group, the model group had significant increases in the levels of endotoxin, TNF-alpha, and IFABP (P < 0.05), and the treatment group had significant reductions in the levels of endotoxin, TNF-alpha, and IFABP (P < 0.05). Liver tissue staining showed that the model group had significantly increased hepatocyte steatosis compared with the control group (P < 0.05), and that the treatment group had significantly reduced hepatocyte steatosis compared with the model group (P < 0.05). The intestinal villi in the control group had ordered arrangement and a complete structure; in the model group, the intestinal villi were shortened with local shedding and a lack of ordered arrangement; compared with the model group, the treatment group had mild edema and ordered arrangements of the intestinal villi. The model group had a significantly reduced level of occludin protein compared with the control group (P < 0.05), and the treatment group had a slight increase compared with the model group. The model group had a significantly increased number of Escherichia coli and a significantly reduced number of Bacteroides compared with the control group (P < 0.05), and the treatment group had a significantly reduced number of Escherichia coli and a significantly increased number of Bacteroides compared with the model group (P < 0.05). Conclusion: High-fat diet can successfully induce NAFLD in rats, and intervention with Saccharomyces boulardii can reduce body weight and improve hepatocyte steatosis. Saccharomyces boulardii can reduce endotoxemia in NAFLD rats and thus alleviate inflammatory response. Saccharomyces boulardii can also adjust the proportion of Escherichia coli and Bacteroides in the intestine of NAFLD rats. PMID- 28073417 TI - [A case of Budd-Chiari syndrome misdiagnosed as liver cancer]. PMID- 28073418 TI - [Current status and perspectives of artificial liver for treatment of acute-on chronic liver failure]. AB - This article briefly introduces the mechanisms and characteristics of several new artificial liver therapies, the advantages and disadvantages of different sites for placement of the drainage tube, and commonly used anticoagulation methods, as well as the prevention and treatment of common complications of the artificial liver support system. The future direction of development of artificial liver includes new regimens for "individualized treatment" based on patients' conditions, combination of non-biological artificial liver and biological active ingredients, and development of efficient and perfected hybrid bioartificial liver, which can further improve the therapeutic outcome of liver failure. PMID- 28073419 TI - [The 2016 Annual Meeting of Chinese Society of Hepatology & The 3rd Forum of Youngth Committee of CSH & The 6th Conference of the China-Indonesia Joint International Symposium on Hepatobiliary Medicine and Surgery (6th CISHMS)]. PMID- 28073420 TI - [Report of the Eighth Symposium on the Hotspots and Challenges in Research of Antiviral Therapy for Chronic Hepatitis B and Chronic Hepatitis C]. PMID- 28073421 TI - [Research advances in the role of sphingolipids in HCV and HBV life cycles]. AB - Sphingolipids and their metabolites are not only important structural molecules of the cell membrane, but also involved in all phases of viral life cycle, including cell adhesion, membrane fusion, viral replication, viral assembly, intracellular transport, protein sorting, and exocytosis. In recent years, sphingolipids have become one of the focuses of lipid research. This article reviews the role of sphingolipids in the life cycles of hepatitis C virus and hepatitis B virus with reference to recent research achievements in China and foreign countries. PMID- 28073422 TI - [Research advances in the association between deacetylase Sirtuin3 and liver diseases]. AB - The deacetylase Sirtuin 3 (SIRT3) is a member of the Sirtuins mainly located in the mitochondrial matrix, and as a nicotinamide adenine dinucleotide (NAD+) dependent deacetylase, it can regulate cellular energy metabolism and oxidative stress-related pathways. The liver is the largest solid organ in the human body and plays a very important role in substance metabolism. Based on the features of SIRT3, it is closely associated with the development and progression of certain liver diseases. This article reviews the research advances in the role of SIRT3 in non-alcoholic fatty liver disease, liver cancer, and hepatic ischemia reperfusion injury. PMID- 28073423 TI - [Research advances in application of isobaric tags for relative and absolute quantitation in proteomics of hepatocellular carcinoma]. AB - Due to the features of strong heterogeneity, difficult early diagnosis, poor prognosis, and high fatality rate, hepatocellular carcinoma (HCC) has become an important disease which threatens the health of the Chinese population. Accurate early diagnosis is crucial to improving the success rate of liver cancer resection and reducing postoperative recurrence and metastasis, and its core is the screening and validation of biomarkers for early diagnosis. Isobaric tags for relative and absolute quantitation (iTRAQ) and stable isotope labeling with amino acids in cell culture are important parts of proteomics technology, and iTRAQ has become the most important technique in quantitative proteomics technology due to its advantages of high throughput, high quantitative accuracy, and no limitation by sample source. This article reviews the research advances in molecular mechanism of the development and progression of HCC and screening of markers, in order to establish a theoretical foundation for in-depth understanding of the molecular mechanisms of the development and progression of HCC and the development of new biomarkers. PMID- 28073424 TI - [NACHT-LRR-PYD-containing proteins 3 inflammasome and nonalcoholic fatty liver disease]. AB - NACHT-LRR-PYD-containing proteins 3 (NLRP3) inflammasome regulates the maturation and secretion of proinflammatory cytokines including interleukin-1beta and interleukin-18, as well as immune and inflammatory response, through the activation of cysteine aspartate specific protease-1. Inflammatory response caused by the activation of NLRP3 inflammasome may participate in the development and progression of nonalcoholic fatty liver disease (NAFLD). Therefore, exploration of the role of NLRP3 inflammasome in NAFLD is important for the understanding of the pathogenesis of NAFLD and discovery of new therapeutic targets. PMID- 28073425 TI - Hypertension in Germany. AB - BACKGROUND: Hypertension is a key risk factor. However, population data based on blood pressure measurements in Germany are scarce. METHODS: Standardized blood pressure (BP) measurements and medication data from seven population-based studies conducted in Germany between 1994 and 2012 (66 845 participants, 25-74 years) were analyzed: the EPICPotsdam study (1994-1998, EPIC), the KORA-S4 Study (1999-2001) in Augsburg, and the Gutenberg Health Study (2007-2012, GHS) in Mainz/Mainz-Bingen provided data for descriptive comparisons. Time trends were analyzed based on identical study regions for the German National Health Interview and Examination Survey 1998 (BGS98) and the German Health Examination Survey for Adults (2008-11, DEGS1) as well as the Study of Health in Pomerania (SHIP) in Northeast Germany (1997-2001) and the SHIP-TREND study (2008-2012). BP data were adjusted for study-specific measurement devices based on calibration studies. RESULTS: After adjustment for study-specific measurement devices, mean systolic and diastolic BP values were lower and treatment proportions higher in recent (2007-2012) compared to older (1994-2001) studies. Mean BP decrease was most pronounced (systolic >= 10 mmHg) in the elderly (55-74 years). The regional SHIP-TREND data for Northeast Germany showed a decrease in mean systolic BP in young men aged 25 to 34 years; on a national level according to the DEGS1 data, however, no such decrease was observed for this group. CONCLUSION: New data add evidence for lower BP in Germany. However, the prevention potential remains high. Future research based on population-based data should place a special focus on blood pressure data in young men. PMID- 28073427 TI - A 76-Year-Old Man with COPD and Acute Dyspnea. PMID- 28073426 TI - The Prevention and Treatment of Retinal Complications in Diabetes. AB - BACKGROUND: Microvascular complications of diabetes mellitus can cause retino pathy and maculopathy, which can irreversibly damage vision and lead to blindness. The prevalence of retinopathy is 9-16% in patients with type 2 diabetes and 24-27% in patients with type 1 diabetes. 0.2-0.5% of diabetics are blind. METHODS: The National Disease Management Guideline on the prevention and treatment of retinal complications in diabetes was updated according to recommendations developed by seven scientific medical societies and organizations and by patient representatives and then approved in a formal consensus process. These recommendations are based on international guidelines and systematic reviews of the literature. RESULTS: Regular ophthalmological examinations enable the detection of retinopathy in early, better treatable stages. The control intervals should be based on the individual risk profile: 2 years for low-risk patients and 1 year for others, or even shorter depending on the severity of retinopathy. General risk factors for retinopathy include the duration of diabetes, the degree of hyperglycemia, hypertension, and diabetic nephropathy. The general, individually adapted treatment strategies are aimed at improving the risk profile. The most important specifically ophthalmological treatment recommendations are for panretinal laser coagulation in proliferative diabetic retinopathy and, in case of clinically significant diabetic macular edema with foveal involvement, for the intravitreal application of medications (mainly, vascular endothelial growth factor [VEGF] inhibitors), if an improvement of vision with this treatment is thought to be possible. CONCLUSION: Regular, risk adapted ophthalmological examinations, with standardized documentation of the findings for communication between ophthalmologists and the patients' treating primary care physicians/diabetologists, is essential for the prevention of diabetic retinal complications, and for their optimal treatment if they are already present. PMID- 28073428 TI - Formation of Charge Carriers in Liquids. AB - After presenting a brief historical overview of the classic contributions of Faraday, Arrhenius, Kohlrausch, Bjerrum, Debye, Huckel and Onsager to understanding the conductivity of true electrolytes in aqueous solutions, we present an in-depth review of the 1933 work of Fuoss & Kraus who explored the effect of the solvent on electrolyte dissociation equilibria in either polar or nonpolar media. Their theory predicts that the equilibrium constant for dissociation decays exponentially with the ratio of the Bjerrum length lambdaB to the ion-pair size a. Fuoss & Kraus experimentally confirmed the dependence on lambdaB of the solvent, while more recent experiments explored the dependence on a. We also present an in-depth review of the charge-fluctuation theory used to explain the sharp increase in conductivity with added water for water-in-oil microemulsions stabilized by ionic surfactants. Water swells the droplets making a greater fraction of them charged. At least for low-water content, the same exponential dependence on lambdaB/a is predicted, provided a is chosen as the size of the polar core of the droplet or inverted micelle. Potential electrolytes like alcohols acquire charge by exchanging a proton. The dissociation equilibrium of the resulting ion-pair in mixtures of toluene and alcohol appears to be well modelled by the Fuoss theory. Solutions of inverted micelles are also thought to acquire charge by exchanging a small ion between two net-neutral micelles. Except for the dissociation of true electrolytes, all of the charging scenarios described above can be represented by a two-reaction sequence: 1) the disproportionation of charge between two neutral molecules, inverted micelles or droplets; followed by 2) the dissociation of the "ion"-pair intermediates. (The dissociation of true electrolytes involves only the second.) For each of the above charging theories, the extent of the second reaction decays exponentially with lambdaB/a. PMID- 28073429 TI - Relation of the Myocardial Contraction Fraction, as Calculated from M-Mode Echocardiography, With Incident Heart Failure, Atherosclerotic Cardiovascular Disease and Mortality (Results from the Cardiovascular Health Study). AB - We evaluated the association between 2-dimensional (2D) echocardiography (echo) determined myocardial contraction fraction (MCF) and adverse cardiovascular outcomes including incident heart failure (HF), atherosclerotic cardiovascular disease (ASCVD), and mortality. The MCF, the ratio of left ventricular (LV) stroke volume (SV) to myocardial volume (MV), is a volumetric measure of myocardial shortening that can distinguish pathologic from physiological hypertrophy. Using 2D echo-guided M-mode data from the Cardiovascular Health Study, we calculated MCF in subjects with LV ejection fraction (EF) >=55% and used Cox models to evaluate its association with incident HF, ASCVD, and all cause mortality after adjusting for clinical and echo parameters. We assessed whether log2(SV) and log2(MV) were consistent with the expected 1:-1 ratio used in the definition of MCF. Among 2,147 participants (age 72 +/- 5 years), average MCF was 59 +/- 13%. After controlling for clinical and echo variables, each 10% absolute increment in MCF was associated with lower risk of HF (hazard ratio [HR] 0.88; 95% confidence interval [CI] 0.82, 0.94), ASCVD (HR 0.90; 95% CI 0.85, 0.95), and death (HR 0.93; 95% CI 0.89, 0.97). Moreover, the MCF was still significantly associated with ASCVD and mortality, but not HF, after adjustment for percent-predicted LV mass. Significant departure from the 1:-1 ratio was not observed for ASCVD or death, but did occur for HF, driven by a stronger association for MV than SV. In conclusion, among older adults without CVD or low LV ejection fraction, 2D echo-guided M-mode-derived MCF was independently associated with lower risk of adverse cardiovascular outcomes, but this ratiometric index may not capture the full relation that is apparent when its components are modeled separately in the case of HF. PMID- 28073430 TI - Outcomes of First- Versus Second-Generation Drug-Eluting Stent Implanted for Right Coronary Artery Ostial Narrowing. AB - Clinical outcome is generally poor when stents are implanted at right coronary artery ostial lesion (RCAos). We compared the clinical outcome between the first generation drug-eluting stent (first DES) and second-generation drug-eluting stent (second DES) used for RCAos. Consecutive 88 patients who underwent percutaneous coronary interventions of de novo RCAos using the first DES (33 patients) or second DES (55 patients) were analyzed. The incidence of major adverse cardiac events (MACE) defined as the composite of cardiac death, myocardial infarction attributed to right coronary artery, and target lesion revascularization within 2.5 years was compared. The incidence of MACE was significantly lower in second DES (11% vs 36%, p = 0.010) than that in the first DES. Multivariate analysis revealed use of second DES (odds ratio 0.24, 95% CI 0.11 to 0.93, p = 0.008) alone was significantly associated with MACE. In conclusion, second DES revealed better clinical outcome than the first DES when used in de novo RCAos. PMID- 28073431 TI - Cholesterol granuloma of ethmoid sinuses: Report of two cases. PMID- 28073432 TI - Common urologic diseases in older men and their treatment: how they impact fertility. AB - As men age, medical and surgical diseases involving the genitourinary tract become more common. The conditions themselves, if not their treatments, can negatively impact the fertility potential of an affected man. Many older men maintain the desire to father children, so it is critical to understand the disturbed anatomy and physiology involved to properly counsel that individual. Should this or that treatment regimen be employed? Should sperm banking be undertaken before institution of a permanently ablative/suppressive therapy? What are the long-term consequences of one therapy over another vis-a-vis sperm production, sperm quality, and/or sperm transport? In this context, some of the more common genitourinary afflictions of the older male and the treatment options that are available will be discussed. PMID- 28073433 TI - Misperceptions and Parkinson's disease. AB - Most of the neurobehavioral aspects of Parkinson's disease have been well established and studied, but many are not well known, and hardly studied. This article focuses on several behavioral abnormalities that are common, and frequently cause difficulty for the patient and family due to lack of recognition as part of the disease. While it is well known that L-Dopa dyskinesias are frequently not recognized or under appreciated by patients, a similar lack of recognition may affect the patient's own speech volume, where their center of gravity is located, whether they are tilted to one side, and their under recognition of others' emotional displays. In addition, PD patients are often misperceived by others incorrect impression of their emotional and cognitive state based purely on facial expression. These changes and others are briefly reviewed. PMID- 28073434 TI - Two to one CRTD pacing: When the T wave and the P wave interact. AB - We presented a unique phenomenon of 2:1 cardiac resynchronization therapy pacing due to T wave oversensing. Ultimately, by utilizing a unique feature of integrated bipolar sensing, we succeeded to eliminate the T wave oversensing signals, and restore 1:1 CRTD pacing. Importantly, this feature enabled us to overcome the T wave oversensing issue, without the need to decrease the ventricular sensitivity, which could potentially interfere with ventricular arrhythmia detection and appropriate shock delivery when required. PMID- 28073435 TI - Evaluation of the efficacy of a therapeutic HIV vaccine by in vitro stimulation assay. AB - A novel method for HIV vaccine efficacy evaluation was established and the experimental conditions optimized. This novel method was then applied to determine whether a recombinant adenovirus type 5 HIV therapeutic vaccine expressing Gag antigen (Ad5-HIVgag) could stimulate HIV-specific cellular responses in vitro. The results indicated that HIV-specific IFN-gama production lymphocytes were induced by the Ad5-HIVgag vaccine. Compared with other methods, this in vitro stimulation method is safe and time-efficient, and the result is more intuitive. It has the potential to be regarded as a supplement to other methods for evaluating the IFN-gamma production by PBMCs to HIV vaccination. PMID- 28073436 TI - Forecasting the risk of harmful algal blooms. AB - The "Applied Simulations and Integrated Modelling for the Understanding of Harmful Algal Blooms" (Asimuth) project sought to develop a harmful algal bloom (HAB) alert system for Atlantic Europe. This was approached by combining, at a national or regional level, regulatory monitoring phytoplankton and biotoxin data with satellite remote sensing and other information on current marine conditions, coupled with regional scale models that included a representation of HAB transport. Synthesis of these products was achieved by expert interpretation within HAB risk alert bulletins that were prepared on a regular basis (typically weekly) for use by the aquaculture industry. In this preface to the Asimuth Special Issue we outline the main HAB species of concern in the region and the strengths and limitations of different methodologies to provide early warning of their blooms. PMID- 28073437 TI - A high resolution hydrodynamic model system suitable for novel harmful algal bloom modelling in areas of complex coastline and topography. AB - Fjordic coastlines provide sheltered locations for finfish and shellfish aquaculture, and are often subject to harmful algal blooms (HABs) some of which develop offshore and are then advected to impact nearshore aquaculture. Numerical models are a potentially important tool for providing early warning of such HAB events. However, the complex topography of fjordic shelf regions is a significant challenge to modelling. This is frequently compounded by complex bathymetry and local weather patterns. Existing structured grid models do not provide the resolution needed to represent these coastlines in their wider shelf context. In a number of locations advectively transported blooms of the ichthyotoxic dinoflagellate Karenia mikimotoi are of particular concern for the finfish industry. Here were present a novel hydrodynamic model of the coastal waters to the west of Scotland that is based on unstructured finite volume methodology, providing a sufficiently high resolution hydrodynamical structure to realistically simulate the transport of particles (such as K. mikimotoi cells) within nearshore waters where aquaculture sites are sited. Model-observation comparisons reveal close correspondence of tidal elevations for major semidiurnal and diurnal tidal constituents. The thermohaline structure of the model and its current fields are also in good agreement with a number of existing observational datasets. Simulations of the transport of Lagrangian drifting buoys, along with the incorporation of an individual-based biological model, based on a bloom of K. mikimotoi, demonstrate that unstructured grid models have considerable potential for HAB prediction in Scotland and in complex topographical regions elsewhere. PMID- 28073438 TI - Individual-based modelling of the development and transport of a Karenia mikimotoi bloom on the North-west European continental shelf. AB - In 2006, a large and prolonged bloom of the dinoflagellate Karenia mikimotoi occurred in Scottish coastal waters, causing extensive mortalities of benthic organisms including annelids and molluscs and some species of fish (Davidson et al., 2009). A coupled hydrodynamic-algal transport model was developed to track the progression of the bloom around the Scottish coast during June-September 2006 and hence investigate the processes controlling the bloom dynamics. Within this individual-based model, cells were capable of growth, mortality and phototaxis and were transported by physical processes of advection and turbulent diffusion, using current velocities extracted from operational simulations of the MRCS ocean circulation model of the North-west European continental shelf. Vertical and horizontal turbulent diffusion of cells are treated using a random walk approach. Comparison of model output with remotely sensed chlorophyll concentrations and cell counts from coastal monitoring stations indicated that it was necessary to include multiple spatially distinct seed populations of K. mikimotoi at separate locations on the shelf edge to capture the qualitative pattern of bloom transport and development. We interpret this as indicating that the source population was being transported northwards by the Hebridean slope current from where colonies of K. mikimotoi were injected onto the continental shelf by eddies or other transient exchange processes. The model was used to investigate the effects on simulated K. mikimotoi transport and dispersal of: (1) the distribution of the initial seed population; (2) algal growth and mortality; (3) water temperature; (4) the vertical movement of particles by diurnal migration and eddy diffusion; (5) the relative role of the shelf edge and coastal currents; (6) the role of wind forcing. The numerical experiments emphasized the requirement for a physiologically based biological model and indicated that improved modelling of future blooms will potentially benefit from better parameterisation of temperature dependence of both growth and mortality and finer spatial and temporal hydrodynamic resolution. PMID- 28073439 TI - The competitive dynamics of toxic Alexandrium fundyense and non-toxic Alexandrium tamarense: The role of temperature. AB - The dinoflagellate Alexandrium produces paralytic shellfish poisoning toxins. The genus is globally distributed, with Scottish waters being of particular interest due to the co-occurrence of different species and strains. In Scottish waters, Alexandrium was historically thought to be dominated by the highly toxic (Group I) Alexandrium fundyense. However, the morphologically indistinguishable (Group III) Alexandrium tamarense has recently also been found to co-occur, raising important questions in relation to Alexandrium biogeography. To begin to address these, we investigated Alexandrium growth, yield and toxin production in a range of temperature conditions characteristics of present and potential future conditions, using a recently developed flow cytometry method that allowed, for the first time, simultaneous enumeration of the cryptic species in co-culture. Experiments were undertaken in a range of temperatures (12, 15, 18 and 21 degrees C) in the phosphate (P) limiting conditions that promotes A. fundyense toxicity. Cell/biomass yield was greater for A. tamarense at all temperatures, with observed growth rates varying with temperature. Growth rather and yield were different in mono- and co-culture with the outcome of these interactions also being temperature dependent. For toxic A. fundyense, GTX-3, STX and NEO were the dominant analogues, but total toxicity, toxicity per cell and the number of, and relative proportion of, toxin analogues changed in relation to the onset of P limitation and also as a function of temperature, with the highest toxin concentrations per cell being observed at 12 degrees C. Toxin concentrations were approximately double in P limited stationary phase compared to exponential growth. Toxin concentrations were lower in the co-cultures, indicating inhibition of production in the presence of non-toxic A. tamarense. The strong performance of A. tamarense is in co-culture at odds with the historical understanding that Scottish waters were dominated by A. fundyense and indicates that changes in water temperatures, and also potentially alleopathic interactions, will influence Alexandrium populations and hence the PSP toxicity threat to humans from shellfish. PMID- 28073440 TI - Climate variability and Dinophysis acuta blooms in an upwelling system. AB - Dinophysis acuta is a frequent seasonal lipophilic toxin producer in European Atlantic coastal waters associated with thermal stratification. In the Galician Rias, populations of D. acuta with their epicentre located off Aveiro (northern Portugal), typically co-occur with and follow those of Dinophysis acuminata during the upwelling transition (early autumn) as a result of longshore transport. During hotter than average summers, D. acuta blooms also occur in August in the Rias, when they replace D. acuminata. Here we examined a 30-year (1985-2014) time series of D. acuta from samples collected by the same method in the Galician Rias. Our main objective was to identify patterns of distribution and their relation with climate variability, and to explain the exceptional summer blooms of D. acuta in 1989-1990. A dome-shaped relationship was found between summer upwelling intensity and D. acuta blooms; cell maxima were associated with conditions where the balance between upwelling intensity and heating, leading to deepened thermoclines, combined with tidal phase (3 days after neap tides) created windows of opportunity for this species. The application of a generalized additive model based on biological (D. acuta inoculum) and environmental predictors (Cumulative June-August upwelling CUIJJA, average June-August SSTJJA and tidal range) explained more than 70% of the deviance for the exceptional summer blooms of D. acuta, through a combination of moderate (35,000-50,000m3s-1km-1) summer upwelling (CUIJJA), thermal stratification (SSTJJA>17 degrees C) and moderate tidal range (~2.5m), provided D. acuta cells (inoculum) were present in July. There was no evidence of increasing trends in D. acuta bloom frequency/intensity nor a clear relationship with NAO or other long-term climatic cycles. Instead, the exceptional summer blooms of 1989-1990 appeared linked to extreme hydroclimatic anomalies (high positive anomalies in SST and NAO index), which affected most of the European Atlantic coast. PMID- 28073441 TI - Applied simulations and integrated modelling for the understanding of toxic and harmful algal blooms (ASIMUTH): Integrated HAB forecast systems for Europe's Atlantic Arc. AB - Reasons for the emergent interest in HABs are abundant, including concerns associated with human health, adverse effects on biological resources, economic losses attributed to recreation, tourism and seafood related industries, and the cost of maintaining public advisory services and monitoring programs for shellfish toxins and water quality. The impact of HABs can potentially be mitigated by early warning of their development. In this regard the project ASIMUTH (Applied Simulations and Integrated Modelling for the Understanding of Toxic and Harmful algal blooms) was borne in order to develop short term HAB alert systems for Atlantic Europe. This was achieved using information on the most current marine conditions (weather, water characteristics, toxicity, harmful algal presence etc.) combined with high resolution local numerical predictions. This integrated, multidisciplinary, trans-boundary approach to the study of HABs developed during ASIMUTH led to a better understanding of the physical, chemical and ecological factors controlling these blooms, as well as their impact on human activities. The outcome was an appropriate alert system for an effective management of areas that are usually associated with HAB events and where these episodes may have a more significant negative impact on human activities. Specifically for the aquaculture industry, the information provided enabled farmers to adapt their working practices in time to prevent mortalities in finfish farms and/or manage their shellfish harvest more effectively. This paper summarises the modelling and alert developments generated by the ASIMUTH project. PMID- 28073442 TI - Toward predicting Dinophysis blooms off NW Iberia: A decade of events. AB - Dinophysis acuminata and Dinophysis acuta are recurrent species off NW Iberia but their outbreaks occur under different conditions. A decade (2004-2013) of weekly data for each species at two sentinel stations located at the entrance of Rias de Aveiro-AV (NW Portugal, 40 degrees 38.6'N) and Pontevedra-PO (Galicia, Spain, 42 degrees 21.5'N), were used to investigate the regional synchronism and mesoscale differences related to species detection, bloom (>200cellsL-1) initiation and development. Results highlight the high interannual variability of bloom events and summarize the associated meteorological/oceanographic conditions. D. acuta blooms were observed in 2004-2008 and 2013, and the species highest maxima at AV occurred after the highest maxima of its prey Mesodinium, with a time-lag of 2-3 weeks. D. acuminata blooms were observed every year at both stations. The cell concentration time series shows that the blooms generally present a sequence starting in March with D. acuminata in PO and three weeks later in AV, followed by D. acuta that starts at AV and three months later in PO. Exceptionally, D. acuminata blooms occurred earlier at AV than PO, namely in high spring upwelling (2007) or river runoff (2010) years. A four-year gap (2009-2012) of D. acuta blooms occurred after an anomalous 2008 autumn with intense upwelling which is interpreted as the result of an equatorward displacement of the population core. Numerical model solutions are used to analyze monthly alongshore current anomalies and test transport hypotheses for selected events. The results show a strong interannual variability in the poleward/equatorward currents associated with changes in upwelling forcing winds, the advection of D. acuta blooms from AV to PO and the possibility that D. acuminata blooms at AV might result from inocula advected southward from PO. However, the sensitivity of the results to vertical position of the lagrangian tracers call for more studies on species distribution at the various bloom stages. PMID- 28073443 TI - A HAB warning system for shellfish harvesting in Portugal. AB - The development of sustainable shellfish aquaculture is highly dependent on the provision of reliable monitoring and predictive information on the occurrence of harmful algal blooms (HABs). The Portuguese HAB early warning system and shellfish closures presented here is a prototype, developed in the ASIMUTH project. It relies on weekly monitoring data composed of observations of HAB species and toxin concentrations within shellfish, and ocean circulation forecasts generated by an operational oceanographic model. The shellfish harvesting areas comprise coastal areas, estuaries+rias and coastal lagoons. The weekly bulletin characterizes the current shellfish closure situation and next week's forecasts for potentially impacted areas. The period analyzed ranged from 27 July 2013 to 17 March 2014, and describes the first skill assessment of the warning system. The forecast accuracy was evaluated, considering the number of forecasts that were verified to be correct the following week (85%) as well as the number of events not forecasted (false negatives, 12%) and those expected but did not occur (false positives, 3%). Variations were most visible in the first weeks of bulletin implementation and during autumn-winter months. The complementary use of field data, remote sensing and operational models led to more accurate predictions of blooms and range of the event. PMID- 28073444 TI - Modelling the hydrodynamic conditions associated with Dinophysis blooms in Galicia (NW Spain). AB - The northwestern Iberian coast (Galician Rias and shelf) is frequently affected by toxic harmful algal blooms (HABs) (mainly Dinophysis spp.), leading to lengthy harvesting closures in a region where aquaculture has a strong socioeconomic impact. The project ASIMUTH (http://www.asimuth.eu) aimed to develop forecasting capabilities to warn of impending HABs along the European Atlantic coast. Simulations with the ROMS model (hydrodynamical and ecological simulations complemented with Lagrangian particle tracking simulations) of the Galician coastal circulation have been performed in the framework of the ASIMUTH project to characterize and forecast oceanographic conditions before and during HAB periods. In this work, we present the Galician ASIMUTH forecast system and demonstrate its skill in predicting HAB transport and its usefulness to provide assessment for the management of the areas affected by toxic outbreaks. Experience gained during DSP events in 2005 and 2013 is shown. We also describe the Galician pilot HAB bulletins, aimed at distributing forecasts of HAB events that might induce closures of harvesting areas or, when the areas are already closed, at giving information on forthcoming oceanographic conditions that could favour or hamper the opening of an area. Our results show that the model forecasts and the bulletins can provide early warning of the risk of Dinophysis spp. events and the risk of closures linked to the presence of DSP toxins above regulatory levels in harvesting areas. PMID- 28073445 TI - Distribution and dynamics of two species of Dinophyceae producing high biomass blooms over the French Atlantic Shelf. AB - The frequency and distribution of high biomass blooms produced by two dinoflagellate species were analysed along the French continental shelf from 1998 to 2012. Two species were specifically studied: Karenia mikimotoi and Lepidodinium chlorophorum. Based on remote-sensing reflectances at six channels (410, 430, 480, 530, 550 and 670nm), satellite indices were created to discriminate the species forming the blooms. A comparison with observations showed that the identification was good for both species in spite of a lower specificity for L. chlorophorum. The overall analysis of the satellite indices, in association with some monitoring data and cruise observations, highlights the regularity of these events and their extent on the continental shelf. L. chlorophorum blooms may occur all along the South Coast of Brittany. All the coastal areas under the influence of river plumes and the stratified northern shelf area of the Western English Channel appear to be areas of bloom events for both species. These two species are likely to be in competitive exclusion as they share the same spatial distribution and the timing of their bloom is very close. Finally, due to the scarcity of off-shore observations, these satellite indices provide useful information regarding HABs management and the development of a warning system along the French coast. PMID- 28073446 TI - Harmful algal bloom forecast system for SW Ireland. Part I: Description and validation of an operational forecasting model. AB - A 3D primitive equation coastal ocean model for southwest Ireland, called the Bantry Bay model, was developed and implemented operationally. Validated model outputs have multiple uses. One of the incentives to develop the model was to explore the possible transport pathways that carry harmful algae blooms (HAB) into Bantry Bay. The model is nested offline in a regional North East Atlantic operational model. Surface forcing is taken from the half-degree Global Forecasting System, available at three-hourly intervals. Heat fluxes are calculated from the bulk formulae. Surface freshwater fluxes are obtained from the prescribed rainfall rates and the evaporation rates calculated by the model. Freshwater discharges from five rivers are included in the model. Model validation and the model skill in representing the water level, currents, temperature and salinity in the bay are reported. A scoring system based on the average adjusted relative mean absolute error for the predicted currents was used. An upgrade to a higher score was achieved through the incorporation of local winds into the surface forcing and by varying the bottom roughness coefficient. The model, designed to work in forecast mode, can replicate the main oceanographic features in the region. The model forecast is used in a decision support system for HAB alerts. An operational HAB alert system did not exist in Ireland prior to the use of this model. PMID- 28073447 TI - Potential impact of an exceptional bloom of Karenia mikimotoi on dissolved oxygen levels in waters off western Ireland. AB - In the summer of 2005 an exceptional bloom of the dinoflagellate Karenia mikimotoi occurred along Ireland's Atlantic seaboard and was associated with the mass mortality of both benthic and pelagic marine life. Oxygen depletion, cellular toxicity and physical smothering, are considered to be the main factors involved in mortality. In this paper we use a theoretical approach based on stoichiometry (the Anderson ratio) and an average K. mikimotoi cellular carbon content of 329pgCcell-1 (n=20) to calculate the carbonaceous and nitrogenous oxygen demand following bloom collapse. The method was validated against measurements of biochemical oxygen demand and K. mikimotoi cell concentration. The estimated potential oxygen utilisation (POU) was in good agreement with field observations across a range of cell concentrations. The magnitude of POU following bloom collapse, with the exception of three coastal areas, was considered insufficient to cause harm to most marine organisms. This indicates that the widespread occurrence of mortality was primarily due to other factors such as cellular toxicity and/or mucilage production, and not oxygen depletion or related phenomena. In Donegal Bay, Kilkieran Bay and inner Dingle Bay, where cell densities were in the order of 106cellsL-1, estimated POU was sufficient to cause hypoxia. Of the three areas, Donegal Bay is considered to be the most vulnerable due to its hydrographic characteristics (seasonally stratified, weak residual flow) and hypoxic conditions (2.2mgL-1 O2) were directly observed in the Bay post bloom collapse. Here, depending on the time of bloom collapse, depressed DO levels could persist for weeks and continue to have a potentially chronic impact on the Bay. PMID- 28073448 TI - Modeling the transport pathways of harmful algal blooms in the Iberian coast. AB - The prediction of the path of harmful algal blooms (HABs) along the coast can be achieved using numerical models of ocean circulation in order to reproduce the hydrodynamics of the study area. With this setting, our work aimed at the (1) study of key past events to evaluate the model ability to reproduce the transport pathways of blooms along the Iberian coast, and (2) to assess the relevance of such strictly physical approach. The simulations described here rely on the advection of lagrangian elements after a point release in a hypothetical location for bloom initiation, and the subsequent assessment of the influence of the surface currents transport on the extent of the bloom. Five events were simulated, accounting for blooms of Gymnodinium catenatum, Dinophysis acuminata and Pseudo-nitzschia spp. Model results were compared with field data from the National HAB monitoring program, and were used to evaluate some hypothesis in their interpretation. The effort compiled in this paper, though focused on the transport and dispersion of HAB (after bloom detection), was a critical step toward an integrative forecasting system to determine potential HAB impacted areas, also addressed in this Special Issue. PMID- 28073449 TI - Harmful algal bloom forecast system for SW Ireland. Part II: Are operational oceanographic models useful in a HAB warning system. AB - This study investigated the application of a three-dimensional physical hydrodynamic model in a harmful algal bloom forecast system for Bantry Bay, southwest Ireland. Modelled oceanographic conditions were studied and used to help understand observed changes in the chemical and biological patterns from the national biotoxins and phytoplankton monitoring program. The study focused on two toxic events in 2013. An upwelling event was predicted by the model prior to the appearance and population increase of potentially toxic diatoms, Pseudo nitzschia, and associated domoic acid in shellfish. A downwelling episode was provided as a forecast in the model prior to the arrival of a Dinophysis bloom and detection of its associated biotoxins in Bay shellfish. The modelled forecast products developed included expected surface, mid-depth and bottom current pathways at the mouth of the Bay and on the adjacent shelf. The rate and direction of water volume flow at the mouth and mid-bay sections were produced by the model to examine predicted upwelling and downwelling pulses. The model also calculated the evolution of water properties (temperature, salinity and density) with depth along the Bay axis and on the adjacent continental shelf. Direct measurements of water properties at a fixed point, mid-bay, were comparable to model calculations. The operational model for southwest Ireland produces a reliable 3-day physical hydrodynamic forecast of the dominant regional physical processes that result in water exchange events between Bantry Bay and its adjacent shelf. While simulated physical hydrodynamics were provided as a 3-day forecast, the upwelling and downwelling signals from the model, closely linked to toxic HAB episodes, were evident up to 10 days prior to the contamination of shellfish in the Bay. PMID- 28073450 TI - Editor's perspectives - January 2017. PMID- 28073451 TI - Implications of turbulent flow in connecting capillaries used in high performance liquid chromatography. AB - The ongoing movement in HPLC toward the use of small columns packed with small particles for high speed separations results in eluted peaks with very small volumetric variances. Avoiding degradation of separation performance under these conditions requires careful consideration of all sources of extra-column peak dispersion. Recent trends towards decreased diameters of connecting capillaries and increased flow rates for analytical-scale separations can result in Reynolds numbers that exceed 2000. This raises the possibility of a transition from laminar to turbulent flow, thereby resulting in a higher than expected pressure drop across the capillary at a given flow rate. In this study we collected pressure drop data as a function of flow rate under many conditions relevant to modern HPLC. The variables studied included capillary diameter (50-120MUm) and length (100-550mm), acetonitrile/water composition (0-100%), and temperature (20 80 degrees C). Most of the work involved stainless steel capillaries, but a subset of experiments involved fused silica. We then used the experimental data to train a model that enables prediction of pressure drops for all of the conditions studied. We find that a single global friction factor profile is sufficient to predict pressure drops as a function of flow rate that are in qualitative agreement with the experimental results. The quantitative accuracy of these predictions is generally quite good, with a mean prediction error of about 2% over the entire range of conditions studied. Predictions for some outlying capillaries are not as good, with errors as high as -40%. This variability is probably due mainly to capillary-to-capillary variability, especially in the wall roughness, which is difficult to characterize definitively. We believe the model described here will be very useful to practicing chromatographers for predicting the conditions under which turbulent flow might develop in their connecting capillaries, and the magnitude of the pressure drop increase over that expected if flow were exclusively laminar. PMID- 28073452 TI - Characterization of cyclitol glycosides by gas chromatography coupled to mass spectrometry. AB - Several cyclitol glycosides have been characterised as trimethylsilyl derivatives by their gas chromatographic (GC) retention data (linear retention indices) and electron impact mass spectrometric (MS) profiles. Both GC-MS results have been related to cyclitol glycosides structural features. Abundance ratios of characteristic m/z ions 133/129 and 260/265 have been proposed to distinguish glycosyl-inositols from glycosyl-methyl-inositols. These ratios in combination with the presence or absence of m/z 375 ion allowed the unequivocal characterization of cyclitol glycosides. These criteria have been applied to the characterization of new cyclitol glycosides in chickpea (Cicer arietinum) and adzuki bean (Vigna angularis) and in leaves of Coriaria myrtifolia and Coriaria ruscifolia. PMID- 28073453 TI - The use of a mucus trap by Dinophysis acuta for the capture of Mesodinium rubrum prey under culture conditions. AB - A capture mechanism observed in a culture of the dinoflagellate Dinophysis acuta when preying on the ciliate Mesodinium rubrum (also sometimes referred to as Myrionecta rubra) is described. The dinoflagellate released cohesive clumps of mucilage into the culture media. When M. rubrum cells came into contact with this mucilage, they were immediately immobilized, but remained alive for a short period of time. Observations of D. acuta cells 'visiting and probing' trapped M. rubrum cells were made and at a critical point D. acuta cells removed individual M. rubrum cells from the mucus to swim away with them. The removal of M. rubrum from the mucus coincided with the cells losing all their cilia and becoming swollen, presumably signifying the death of the cell. These changes may enable the D. acuta peduncle to penetrate the ciliate cell cortex. It is hypothesized that toxins produced by D. acuta play a role in the immobilization process within the mucilage trap. PMID- 28073454 TI - Molecular tools to detect anatoxin-a genes in aquatic ecosystems: Toward a new nested PCR-based method. AB - Over the last few decades, cyanobacterial mass occurrence has become a recurrent feature of aquatic ecosystems. This has led to ecosystem exposure and health hazards associated with cyanotoxin production. The neurotoxin anatoxin-a and its homologs can be synthesized by benthic cyanobacterial species in lotic systems, but also by planktonic lacustrine species such as Dolichospermum (also known as Anabaena). However, only a few studies have focused on anatoxin-a occurrence and its biosynthesis genes in freshwater lakes. The initial aim of this study was to evaluate the molecular tools available in the literature to detect anatoxin-a biosynthesis genes in lacustrine environments. Having tested different sets of PCR primers, we found that that some sets of primers, such as anxC, were too specific and did not amplify anatoxin-a biosynthesis genes in all producing strains. On the other hand, some sets of primers, such as atxoa, seemed not to be specific enough, amplifying numerous non-specific bands in environmental samples, especially those from sediments. Furthermore, anaC and anaF amplification exhibited different band intensities during electrophoresis, suggesting a high variation in number of gene copies between samples. As a result, we proposed a new nested PCR-based method which considerably improved the amplification of the anaC gene in our environmental samples, eliminating non-specific bands and weak detections. Using this tool, our study also highlighted that anatoxin-a genes are widely distributed throughout freshwater lakes. This suggests the need for further ecological investigations into anatoxin-a in these ecosystems. PMID- 28073455 TI - Estimating microcystin levels at recreational sites in western Lake Erie and Ohio. AB - Cyanobacterial harmful algal blooms (cyanoHABs) and associated toxins, such as microcystin, are a major global water-quality issue. Water-resource managers need tools to quickly predict when and where toxin-producing cyanoHABs will occur. This could be done by using site-specific models that estimate the potential for elevated toxin concentrations that cause public health concerns. With this study, samples were collected at three Ohio lakes to identify environmental and water quality factors to develop linear-regression models to estimate microcystin levels. Measures of the algal community (phycocyanin, cyanobacterial biovolume, and cyanobacterial gene concentrations) and pH were most strongly correlated with microcystin concentrations. Cyanobacterial genes were quantified for general cyanobacteria, general Microcystis and Dolichospermum, and for microcystin synthetase (mcyE) for Microcystis, Dolichospermum, and Planktothrix. For phycocyanin, the relations were different between sites and were different between hand-held measurements on-site and nearby continuous monitor measurements for the same site. Continuous measurements of parameters such as phycocyanin, pH, and temperature over multiple days showed the highest correlations to microcystin concentrations. The development of models with high R2 values (0.81-0.90), sensitivities (92%), and specificities (100%) for estimating microcystin concentrations above or below the Ohio Recreational Public Health Advisory level of 6MUgL-1 was demonstrated for one site; these statistics may change as more data are collected in subsequent years. This study showed that models could be developed for estimates of exceeding a microcystin threshold concentration at a recreational freshwater lake site, with potential to expand their use to provide relevant public health information to water resource managers and the public for both recreational and drinking waters. PMID- 28073456 TI - Long-term trend of Ulva prolifera blooms in the western Yellow Sea. AB - Blooms of the green macroalga Ulva prolifera in the western Yellow Sea occurred every year since 2008, and they have been reported and studied extensively using a variety of means including remote sensing. However, to date, long-term bloom patterns have not been reported except for a few case studies showing examples in different years. Here, using MODIS observations and an objective method to perform statistical analysis, mean Ulva coverage in the western Yellow Sea has been derived and analyzed between 2007 and 2015 at both monthly and annual scales. On annual scale, mean Ulva coverage decreased after 2008, but increased rapidly after 2012 from 8km2 in 2012 to 116km2 in 2015 (the largest ever reported in history for this region). In the month of June the mean coverage increased from 18km2 in 2012 to 363km2 in 2015. Other than 2009 and 2010, the month of June showed maximum Ulva coverage in every year. These coverage estimates are significantly lower than previously reported values as they represent "pure" algae coverage after taking into account of partial pixel coverage. Several environmental factors were examined in an attempt to determine the reasons behind such long-term changes, yet the results are inconclusive, suggesting a strong necessity of further coordinated and multi-disciplinary researches. PMID- 28073457 TI - Production of BMAA and DAB by diatoms (Phaeodactylum tricornutum, Chaetoceros sp., Chaetoceros calcitrans and, Thalassiosira pseudonana) and bacteria isolated from a diatom culture. AB - Microalgae have previously been reported to contain beta-N-methylamino-l-alanine (BMAA), and the global presence of these primary producers has been associated with the widespread occurrence of BMAA in marine organisms. It has been repeatedly shown that filter-feeding bivalves accumulate phytoplankton species and their toxins. In this study, the concentrations of total soluble BMAA and DAB as a function of growth phase were observed for four non-axenic diatom species (i.e. Phaeodactylum tricornutum, Chaetoceros sp., Chaetoceros calcitrans and Thalassiosira pseudonana). These strains had previously been shown to contain BMAA using a highly selective HILIC-MS/MS method. BMAA cell quota appeared to be species-specific, however, highest BMAA concentrations were always obtained during the stationary growth phase, for all four species, suggesting that BMAA is a secondary metabolite. While DAB was detected in a bacterial culture isolated from a culture of P. tricornutum, the presence or absence of a bacterial population did not influence production of BMAA and DAB by P. tricornutum, i.e. no significant difference was noted for BMAA and DAB production between axenic and non-axenic cultures. The presence of DAB in bacteria had previously been shown, and raised the question as to whether DAB observed in many species of microalgae may arise from the non-axenic culture conditions or from the microalgae themselves. PMID- 28073458 TI - The ichthyotoxic genus Pseudochattonella (Dictyochophyceae): Distribution, toxicity, enumeration, ecological impact, succession and life history - A review. AB - The marine genus Pseudochattonella is a recent addition to the list of fish killing microalgae. Currently two species are recognised (viz. P. verruculosa and P. farcimen) which both form recurrent coastal blooms sometimes overlapping in space and time. These events and their ecological and economic consequences have resulted in great interest and concern from marine biologists and the aquaculture industry. Since the first recorded blooms in Japanese (late 1980s), Scandinavian (1993) and Chilean (2004) waters numerous studies have focused on understanding the causative means of the fish killing. Mortality is probably due to Pseudochattonella discharging mucocysts that cause gill irritation and damage to the fish fills. Here, a review is provided of the literature on Pseudochattonella that covers the last ca. 25 years and focus on a number of topics relevant to understanding the general biology of the genus including ways to distinguish the two species. The literature addressing biogeography and known harmful events is evaluated and based on these findings an updated distribution map is proposed. P. farcimen is presently restricted to North European waters. Despite being very difficult to delineate based on morphology alone the two Pseudochattonella species seem to have separate growth optima. In laboratory experiments P. verruculosa consistently has higher temperature growth optima compared to P. farcimen though periods of overlap have been noted in the field. The review ends by proposing five areas with knowledge gaps and each of these could form the basis of future studies. PMID- 28073459 TI - Vertical migration of Karenia brevis in the northeastern Gulf of Mexico observed from glider measurements. AB - The toxic marine dinoflagellate, Karenia brevis (the species responsible for most of red tides or harmful algal blooms in the Gulf of Mexico), is known to be able to swim vertically to adapt to the light and nutrient environments, nearly all such observations have been made through controlled experiments using cultures. Here, using continuous 3-dimensional measurements by an ocean glider across a K. brevis bloom in the northeastern Gulf of Mexico between 1 and 8 August 2014, we show the vertical migration behavior of K. brevis. Within the bloom where K. brevis concentration is between 100,000 and 1,000,000cellsL-1, the stratified water shows a two-layer system with the depth of pycnocline ranging between 14 20m and salinity and temperature in the surface layer being <34.8 and >28 degrees C, respectively. The bottom layer shows the salinity of >36 and temperature of <26 degrees C. The low salinity is apparently due to coastal runoff, as the top layer also shows high amount of colored dissolved organic matter (CDOM). Within the top layer, chlorophyll-a fluorescence shows clear diel changes in the vertical structure, an indication of K. brevis vertical migration at a mean speed of 0.5-1mh-1. The upward migration appears to start at sunrise at a depth of 8 10m, while the downward migration appears to start at sunset (or when surface light approaches 0) at a depth of ~2m. These vertical migrations are believed to be a result of the need of K. brevis cells for light and nutrients in a stable, stratified, and CDOM-rich environment. PMID- 28073460 TI - Two new karlotoxins found in Karlodinium veneficum (strain GM2) from the East China Sea. AB - The dinoflagellate Karlodinium veneficum is a harmful algal bloom species with a worldwide distribution. This small athecate dinoflagellate makes a family of polyketide toxins that are hemolytic, cytotoxic and ichthyotoxic. The first chemical structure for karlotoxins from East China Sea (ECS) is reported here. The two new karlotoxins, namely 4,5-dihydro-KmTx 2 (compound 1) and 4,5-dihydro dechloro-KmTx 2 (compound 2), were isolated and purified from monoalgal cultures of K. veneficum strain GM2. Their structures were determined by spectroscopic analysis, including tandem mass spectrometry as well as 1D and 2D NMR experiments. These new karlotoxin congeners feature a saturated polyol arm different from previously reported for KmTx 2 that appears to increase hemolytic activity. PMID- 28073461 TI - Assessing in situ dominance pattern of phytoplankton classes by dominance analysis as a proxy for realized niches. AB - This study looks at two facets of dominant phytoplankton classes during phytoplankton succession. A detailed assessment of this issue is of special interest with regard to realized niches from a theoretical point of view but also for lake management as practical application. A realized niche mirrors the functional adaptability of an organism in a lake-specific constellation of environmental parameters. Therefore, the characterization of realized niches could be a key factor for management of problematic waters. Different strategies exist to control eutrophication and the risk of blooms by harmful algae. During the last decades, many restoration measures were initiated to manage eutrophicated inland lakes. In the past, it has become evident several times that restoration strategies do not necessarily lead to a reduction of biomass of undesirable cyanobacteria but can even promote their development. Due to this uncertainty of success and the high costs for remediation strategies, new prediction tools are required - ideally, based on routine monitoring data. Therefore, we developed a new method to extract potential optimal growth conditions (POGC) as indicators of realized niches for different phytoplankton taxa from existing data to improve existing strategies used in lake remediation and restoration. The analysis presented in this work is based on dominance pattern of different phytoplankton groups relative to environmental variables. Interpretation of these dominance patterns as indicators of POGC showed distinct pattern for several phytoplankton classes for all investigated objects. We identified low nitrogen and phosphate concentrations as favorable condition for cyanobacteria in Lake Auensee and Lake Feldberger Haussee. The reservoir Bleilochtalsperre showed a high N/P-concentration and cyanobacteria dominance was generally very low. PMID- 28073462 TI - Gonyaulax taylorii, a new yessotoxins-producer dinoflagellate species from Chilean waters. AB - In summer 2009, during a survey in Bahia Mejillones, a dense bloom of a dinoflagellate from the genus Gonyaulax was detected, as well as the presence of yessotoxin. Phytoplankton samples were analyzed in detail by light and scanning electron microscopy (SEM), revealing the presence of Gonyaulax taylorii. Morphological examination showed that the cells in the bloom fit in Gonyaulax jollifei Murray et Whitting sensu Dodge, subsequently classified as Gonyaulax taylorii by Carbonell-Moore. In this context, some inconsistencies have been found in regard to the holotype; the plate 1"' appears as two plates, 1''' and 2''', showing a suture that does not exist in Dodge's figure of G. jollifei, from where the holotype was drawn, nor within the samples collected. Therefore, this plate has been originally described erroneously as two plates named 1"' and 2"' instead of only one named 1'''. After this correction, this species has five instead of six postcingular plates. For this reason, the description of this species must be emended. Phytoplankton net samples were found to contain yessotoxin and homoyessotoxin, with concentrations below 1pgcell-1. The present study identifies, therefore, the dinoflagellate G. taylorii as a new source of yessotoxins. PMID- 28073463 TI - The effect of exogenous beta-N-methylamino-l-alanine (BMAA) on the diatoms Phaeodactylum tricornutum and Thalassiosira weissflogii. AB - beta-N-methylamino-l-alanine (BMAA), a non-protein amino acid with neurodegenerative features, is known to be produced by cyanobacteria, diatoms and a dinoflagellate. BMAA research has intensified over the last decade, and knowledge has been gained about its bioaccumulation in aquatic and terrestrial ecosystems, toxic effects in model organisms and neurotoxicity in vivo and in vitro. Nevertheless, knowledge of the actual physiological role of BMAA in the producing species or of the ecological factors that regulate BMAA production is still lacking. A few studies propose that BMAA functions to signal nitrogen depletion in cyanobacteria. To investigate whether BMAA might have a similar role in diatoms, two diatom species - Phaeodactylum tricornutum and Thalassiosira weissflogii - were exposed to exogenous BMAA at environmental relevant concentrations, i.e. 0.005, 0.05 and 0.5MUM. BMAA was taken up in a concentration dependent manner in both species in the BMAA free fraction and in the protein fraction of T. weissflogii. As a result of the treatments, the diatom cells at some of the time points and at some of the BMAA concentrations exhibited lower concentrations of chlorophyll a and protein, in comparison to controls. At the highest (0.5MUM) concentration of BMAA, extracellular ammonia was found in the media of both species at all time points. These results suggest that BMAA interferes with nitrogen metabolism in diatoms, possibly by inhibiting ammonium assimilation via the GS/GOGAT pathway. PMID- 28073464 TI - Gambierdiscus balechii sp. nov (Dinophyceae), a new benthic toxic dinoflagellate from the Celebes Sea (SW Pacific Ocean). AB - A new benthic toxic dinoflagellate is described from the Celebes Sea. Gambierdiscus balechii sp. nov. was isolated from seaweeds growing in tidal ponds. Its morphology was studied by means of LM and SEM; G. balechii has a very ornamented theca, a hatchet shaped second apical plate, a narrow second antapical plate and an asymmetrical third precigular plate, a unique combination of characters among Gambierdiscus species. It has a very wide size range with widths from 36 to 88MUm. Phylogenetic analyses of two G. balechii strains, based on LSU rRNA (D8-D10) and partial SSUrRNA sequences confirmed that these clustererd in its' own group, separated from the rest of Gambierdiscus species and with G. pacificus, G. belizeanus and G. scabrosus as its closest relatives. Thecate cysts are described from culture as non motile vegetative-like cells which germinated after being isolated and transferred to fresh medium. Mouse tests showed that this species is toxic and hence it is a potential cause of ciguatera in the Celebes Sea. PMID- 28073465 TI - [Depression in relatives of patients with schizophrenia: 8-month longitudinal outcome of ProFamille Program]. AB - INTRODUCTION: Mental illness such as schizophrenia is a major public health concern. In France, the economic cost of schizophrenia represents 2% of total medical expenditures. Schizophrenia has an impact on health and quality of life not only for patients but also for relatives. Family psychoeducation is a complementary therapeutic intervention to ordinary clinical care deigned to alleviate the burden of care among relatives of patients with schizophrenia. Literature suggests such programs including the patients' family members reduce the risk of relapse. Current studies also suggest that negative emotions expressed by family members have negative consequences on patients' mental health and need to be addressed. However, family psychoeducation is still underdeveloped in France. The objective of this study was to assess the longitudinal outcome on depression level of a psychoeducation program for relatives of schizophrenic patients. The program was held in Paris and Region Ile-de-France "Cluster ProFramille Ile-de-France" between 2012 and 2014. METHODS: Level of participant's depression was assessed by the Center for Epidemiologic Studies - Depression Scale (CES-D). Measures of depression were made for four time points: 2 months before joining the program (T1), at the beginning of the program (T2), at midpoint of the first program module (3 months, T3) and at the end of the first program module (6 months, T4). Repeated-measures ANOVA were performed to assess longitudinal change in a participant's level of depression. Type of coping strategies, knowledge about the disease, dominant thoughts and emotional progress are assessed by the program. Univariate correlation with CES-D differences between T1 and T4 were assessed. Variables with a significant association were included in a multivariate linear model to explain CES-D difference. RESULTS: Sixty-five relatives participated to the "Cluster ProFramille Ile-de-France" between 2012 and 2014 and terminated with the first module of the program. Repeated-measures ANOVA on CES-D scores between T1 and T4 (8 months) showed a significant decrease in average scores for all participants. The mean of decrease was 7 points, equivalent to a 26.6% pre-post decrease level of depression. Significant univariate correlations with depression decrease over 8 months were with "psychomotor tiredness", "frequent worries" and "dealing with worries". Multivariate linear regression only confirmed the significant role of diminishing fatigue in relation to the decrease of depression. CONCLUSION: Our study's results showed that the ProFamille program was efficient in reducing the level of depression for its participants over an 8 month period. As the participants progressed on managing their fatigue, their depressed moods improved. PMID- 28073466 TI - Quantity of the dinoflagellate sxtA4 gene and cell density correlates with paralytic shellfish toxin production in Alexandrium ostenfeldii blooms. AB - Many marine dinoflagellates, including several species of the genus Alexandrium, Gymnodinium catenatum, and Pyrodinium bahamense are known for their capability to produce paralytic shellfish toxins (PST), which can cause severe, most often food related poisoning. The recent discovery of the first PST biosynthesis genes has laid the foundation for the development of molecular detection methods for monitoring and study of PST-producing dinoflagellates. In this study, a probe based qPCR method for the detection and quantification of the sxtA4 gene present in Alexandrium spp. and Gymnodinium catenatum was designed. The focus was on Alexandrium ostenfeldii, a species which recurrently forms dense toxic blooms in areas within the Baltic Sea. A consistent, positive correlation between the presence of sxtA4 and PST biosynthesis was observed, and the species was found to maintain PST production with an average of 6 genomic copies of sxtA4. In August 2014, A. ostenfeldii populations were studied for cell densities, PST production, as well as sxtA4 and species-specific LSU copy numbers in Foglo, Aland, Finland, where an exceptionally dense bloom, consisting of 6.3*106cellsL-1, was observed. Cell concentrations, and copy numbers of both of the target genes were positively correlated with total STX, GTX2, and GTX3 concentrations in the environment, the cell density predicting toxin concentrations with the best accuracy (Spearman's rho=0.93, p<0.01). The results indicated that all A. ostenfeldii cells in the blooms harbored the genetic capability of PST production, making the detection of sxtA4 a good indicator of toxicity. PMID- 28073467 TI - Quantitative PCR assay for detection and enumeration of ciguatera-causing dinoflagellate Gambierdiscus spp. (Gonyaulacales) in coastal areas of Japan. AB - In Japan, ciguatera fish poisoning (CFP) has been increasingly reported not only in subtropical areas but also in temperate areas in recent years, causing a serious threat to human health. Ciguatera fish poisoning is caused by the consumption of fish that have accumulated toxins produced by an epiphytic/benthic dinoflagellate, genus Gambierdiscus. Previous studies revealed the existence of five Gambierdiscus species/phylotypes in Japan: Gambierdiscus australes, Gambierdiscus scabrosus, Gambierdiscus sp. type 2, Gambierdiscus sp. type 3, and Gambierdiscus (Fukuyoa) cf. yasumotoi. Among these, G. australes, G. scabrosus, and Gambierdiscus sp. type 3 strains exhibited toxicities in mice, whereas Gambierdiscus sp. type 2 strains did not show any toxicity. Therefore, it is important to monitor the cell abundance and dynamics of these species/phylotypes to identify and characterize CFP outbreaks in Japan. Because it is difficult to differentiate these species/phylotypes by observation under a light microscope, development of a rapid and reliable detection and enumeration method is needed. In this study, a quantitative PCR assay was developed using a TaqMan probe that targets unique SSU rDNA sequences of four Japanese Gambierdiscus species/phylotypes and incorporates normalization with DNA recovery efficiency. First, we constructed standard curves with high linearity (R2=1.00) and high amplification efficiency (>=1.98) using linearized plasmids that contained SSU rDNA of the target species/phylotypes. The detection limits for all primer and probe sets were approximately 10 gene copies. Further, the mean number of SSU rDNA copies per cell of each species/phylotype was determined from single cells in culture and from those in environmental samples using the qPCR assay. Next, the number of cells of each species/phylotype in the mixed samples, which were spiked with cultured cells of the four species/phylotypes, was calculated by division of the total number of rDNA copies of each species/phylotype in each sample by the number of rDNA copies per cell. The numbers of cells of each species/phylotype quantified by qPCR assay were similar to the number of cells of each species/phylotype that were spiked. Finally, the cell densities of the target species/phylotypes were quantified using the qPCR assay in 30 environmental samples collected from Japanese coastal areas. Total cell densities of the four Gambierdiscus species/phylotypes quantified by qPCR assay were similar to those of Gambierdiscus spp. quantified by direct counting under a light microscope. The qPCR assay developed in this study is expected to be a powerful new tool for determining detailed distribution patterns and for monitoring the cell abundance and dynamics of each Japanese Gambierdiscus species/phylotype in the coastal areas of Japan. PMID- 28073468 TI - Cryptophyte gene regulation in the kleptoplastidic, karyokleptic ciliate Mesodinium rubrum. AB - Photosynthesis in the ciliate Mesodinium rubrum is achieved using a consortium of cryptophyte algal organelles enclosed in its specialized vacuole. A time-series microarray analysis was conducted on the photosynthetic ciliate using an oligochip containing 15,654 primers designed from EST data of the cryptophyte prey, Teleaulax amphioxeia. The cryptophycean nuclei were transcriptionally active over 13 weeks and approximately 13.5% of transcripts in the ciliate came from the sequestered nuclei. The cryptophyte nuclei and chloroplasts could divide in the ciliate, which were loosely synchronized with host cell division. A large epigenetic modification occurred after the cryptophyte nuclei were sequestered into the ciliate. Most cryptophyte genes involved in the light and dark reactions of photosynthesis, chlorophyll assimilation, as well as in DNA methylation, were consistently up-regulated in the ciliate. The imbalance of division rate between the sequestered cryptophyte nuclei and host nuclei may be the reason for the eventual cessation of the kleptoplastidy. PMID- 28073469 TI - Effect of the toxin (microcystin) content of Microcystis on copepod grazing. AB - Although phytoplankton chemical defense may regulate plankton dynamics, demonstrating an ecologically relevant anti-grazer cue is challenging. Presented here is a novel approach to evaluate the quantitative effect of microcystin (MC), the most studied group of cyanobacterial metabolites, on grazing by the common copepod Eudiaptomus gracilis. A temperature-induced gradient in the intracellular MC concentration of three different Microcystis strains enabled the comparison of grazing pressure on cells of the same cyanobacterial strain producing different amounts of MC, in a diet with alternative food (Chlamydomonas). In all treatments, grazing pressure on Microcystis was inversely related to its MC-LR content, while selection for alternative prey was positively related to the MC-LR content of Microcystis. Moreover, grazing on Chlamydomonas also declined with increasing Microcystis MC-LR content, suggesting toxicity related inhibition of E. gracilis. The negative relation between cellular MC-LR concentration and feeding responses supported the anti-grazer hypothesis. Not all MC variants responded to temperature, and some were therefore not associated to grazing responses. Using an induced gradient in the concentration of a suspected phytoplankton defense metabolite to evaluate its quantitative relationship with grazing pressure offers an improved inference on the ecological roles of toxins. Results suggest that either MC-LR or a correlating trait may be inversely linked to the grazer pressure on Microcystis. PMID- 28073470 TI - Preface for Special Issue on "Global expansion of harmful cyanobacterial blooms: Diversity, ecology, causes, and controls". PMID- 28073471 TI - Biochemistry and genetics of taste- and odor-producing cyanobacteria. AB - Cyanobacteria are one of the principal sources of volatile organic compounds (VOCs) which cause offensive taste and odor (T&O) in drinking and recreational water, fish, shellfish and other seafood. Although non-toxic to humans, these T&O compounds severely undermine public trust in these commodities, resulting in substantial costs in treatment, and lost revenue to drinking water, aquaculture, food and beverage and tourist/hospitality industries. Mitigation and control have been hindered by the complexity of the communities and processes which produce and modify T&O events, making it difficult to source-track the major producer(s) and the factors governing VOC production and fate. Over the past decade, however, advances in bioinformatics, enzymology, and applied detection technologies have greatly enhanced our understanding of the pathways, the enzymes and the genetic coding for some of the most problematic VOCs produced by cyanobacteria. This has led to the development of tools for rapid and sensitive detection and monitoring for the VOC production at source, and provided the basis for further diagnostics of endogenous and exogenous controls. This review provides an overview of current knowledge of the major cyanobacterial VOCs, the producers, the biochemistry and the genetics and highlight the current applications and further research needs in this area. PMID- 28073472 TI - The interaction between cyanobacteria and zooplankton in a more eutrophic world. AB - As blooms of cyanobacteria expand and intensify in freshwater systems globally, there is increasing interest in their ecological effects. In addition to being public health hazards, cyanobacteria have long been considered a poor quality food for key zooplankton grazers that link phytoplankton to higher trophic levels. While past laboratory studies have found negative effects of nutritional constraints and defensive traits (i.e., toxicity and colonial or filamentous morphology) on the fitness of large generalist grazers (i.e., Daphnia), cyanobacterial blooms often co-exist with high biomass of small-bodied zooplankton in nature. Indeed, recent studies highlight the remarkable diversity and flexibility in zooplankton responses to cyanobacterial prey. Reviewed here are results from a wide range of laboratory and field experiments examining the interaction of cyanobacteria and a diverse zooplankton taxa including cladocerans, copepods, and heterotrophic protists from temperate to tropical freshwater systems. This synthesis shows that longer exposure to cyanobacteria can shift zooplankton communities toward better-adapted species, select for more tolerant genotypes within a species, and induce traits within the lifetime of individual zooplankton. In turn, the function of bloom-dominated plankton ecosystems, the coupling between primary producers and grazers, the stability of blooms, and the potential to use top down biomanipulation for controlling cyanobacteria depend largely on the species, abundance, and traits of interacting cyanobacteria and zooplankton. Understanding the drivers and consequences of zooplankton traits, such as physiological detoxification and selective vs. generalist grazing behavior, are therefore of major importance for future studies. Ultimately, co-evolutionary dynamics between cyanobacteria and their grazers may emerge as a critical regulator of blooms. PMID- 28073473 TI - How rising CO2 and global warming may stimulate harmful cyanobacterial blooms. AB - Climate change is likely to stimulate the development of harmful cyanobacterial blooms in eutrophic waters, with negative consequences for water quality of many lakes, reservoirs and brackish ecosystems across the globe. In addition to effects of temperature and eutrophication, recent research has shed new light on the possible implications of rising atmospheric CO2 concentrations. Depletion of dissolved CO2 by dense cyanobacterial blooms creates a concentration gradient across the air-water interface. A steeper gradient at elevated atmospheric CO2 concentrations will lead to a greater influx of CO2, which can be intercepted by surface-dwelling blooms, thus intensifying cyanobacterial blooms in eutrophic waters. Bloom-forming cyanobacteria display an unexpected diversity in CO2 responses, because different strains combine their uptake systems for CO2 and bicarbonate in different ways. The genetic composition of cyanobacterial blooms may therefore shift. In particular, strains with high-flux carbon uptake systems may benefit from the anticipated rise in inorganic carbon availability. Increasing temperatures also stimulate cyanobacterial growth. Many bloom-forming cyanobacteria and also green algae have temperature optima above 25 degrees C, often exceeding the temperature optima of diatoms and dinoflagellates. Analysis of published data suggests that the temperature dependence of the growth rate of cyanobacteria exceeds that of green algae. Indirect effects of elevated temperature, like an earlier onset and longer duration of thermal stratification, may also shift the competitive balance in favor of buoyant cyanobacteria while eukaryotic algae are impaired by higher sedimentation losses. Furthermore, cyanobacteria differ from eukaryotic algae in that they can fix dinitrogen, and new insights show that the nitrogen-fixation activity of heterocystous cyanobacteria can be strongly stimulated at elevated temperatures. Models and lake studies indicate that the response of cyanobacterial growth to rising CO2 concentrations and elevated temperatures can be suppressed by nutrient limitation. The greatest response of cyanobacterial blooms to climate change is therefore expected to occur in eutrophic and hypertrophic lakes. PMID- 28073474 TI - Challenges for mapping cyanotoxin patterns from remote sensing of cyanobacteria. AB - Using satellite imagery to quantify the spatial patterns of cyanobacterial toxins has several challenges. These challenges include the need for surrogate pigments since cyanotoxins cannot be directly detected by remote sensing, the variability in the relationship between the pigments and cyanotoxins - especially microcystins (MC), and the lack of standardization of the various measurement methods. A dual-model strategy can provide an approach to address these challenges. One model uses either chlorophyll-a (Chl-a) or phycocyanin (PC) collected in situ as a surrogate to estimate the MC concentration. The other uses a remote sensing algorithm to estimate the concentration of the surrogate pigment. Where blooms are mixtures of cyanobacteria and eukaryotic algae, PC should be the preferred surrogate to Chl-a. Where cyanobacteria dominate, Chl-a is a better surrogate than PC for remote sensing. Phycocyanin is less sensitive to detection by optical remote sensing, it is less frequently measured, PC laboratory methods are still not standardized, and PC has greater intracellular variability. Either pigment should not be presumed to have a fixed relationship with MC for any water body. The MC-pigment relationship can be valid over weeks, but have considerable intra- and inter-annual variability due to changes in the amount of MC produced relative to cyanobacterial biomass. To detect pigments by satellite, three classes of algorithms (analytic, semi-analytic, and derivative) have been used. Analytical and semi-analytical algorithms are more sensitive but less robust than derivatives because they depend on accurate atmospheric correction; as a result derivatives are more commonly used. Derivatives can estimate Chl-a concentration, and research suggests they can detect and possibly quantify PC. Derivative algorithms, however, need to be standardized in order to evaluate the reproducibility of parameterizations between lakes. A strategy for producing useful estimates of microcystins from cyanobacterial biomass is described, provided cyanotoxin variability is addressed. PMID- 28073475 TI - Toxic cyanobacteria and drinking water: Impacts, detection, and treatment. AB - Blooms of toxic cyanobacteria in water supply systems are a global issue affecting water supplies on every major continent except Antarctica. The occurrence of toxic cyanobacteria in freshwater is increasing in both frequency and distribution. The protection of water supplies has therefore become increasingly more challenging. To reduce the risk from toxic cyanobacterial blooms in drinking water, a multi-barrier approach is needed, consisting of prevention, source control, treatment optimization, and monitoring. In this paper, current research on some of the critical elements of this multi-barrier approach are reviewed and synthesized, with an emphasis on the effectiveness of water treatment technologies for removing cyanobacteria and related toxic compounds. This paper synthesizes and updates a number of previous review articles on various aspects of this multi-barrier approach in order to provide a holistic resource for researchers, water managers and engineers, as well as water treatment plant operators. PMID- 28073476 TI - Health impacts from cyanobacteria harmful algae blooms: Implications for the North American Great Lakes. AB - Harmful cyanobacterial blooms (cHABs) have significant socioeconomic and ecological costs, which impact drinking water, fisheries, agriculture, tourism, real estate, water quality, food web resilience and habitats, and contribute to anoxia and fish kills. Many of these costs are well described, but in fact are largely unmeasured. Worldwide cHABs can produce toxins (cyanotoxins), which cause acute or chronic health effects in mammals (including humans) and other organisms. There are few attempts to characterize the full health-related effects other than acute incidences, which may go unrecorded. At present these are difficult to access and evaluate and may be ascribed to other causes. Such information is fundamental to measure the full costs of cHABs and inform the need for often-costly management and remediation. This paper synthesizes information on cHABs occurrence, toxicology and health effects, and relates this to past and current conditions in the Great Lakes, a major global resource which supplies 84% of the surface water in North America. This geographic region has seen a significant resurgence of cHABs since the 1980s. In particular we focus on Lake Erie, where increased reporting of cHABs has occurred from the early 1990's. We evaluate available information and case reports of cHAB-related illness and death and show that cHABs occur throughout the basin, with reports of animal illness and death, especially dogs and livestock. Lake Erie has consistently experienced cHABs and cyanotoxins in the last decade with probable cases of human illness, while the other Great Lakes show intermittent cHABs and toxins, but no confirmed reports on illness or toxicity. The dominant toxigenic cyanobacterium is the genus Microcystis known to produce microcystins. The presence of other cyanotoxins (anatoxin-a, paralytic shellfish toxins) implicates other toxigenic cyanobacteria such as Anabaena (Dolichospermum) and Lyngbya. PMID- 28073477 TI - A review of the phylogeny, ecology and toxin production of bloom-forming Aphanizomenon spp. and related species within the Nostocales (cyanobacteria). AB - The traditional genus Aphanizomenon comprises a group of filamentous nitrogen fixing cyanobacteria of which several memebers are able to develop blooms and to produce toxic metabolites (cyanotoxins), including hepatotoxins (microcystins), neurotoxins (anatoxins and saxitoxins) and cytotoxins (cylindrospermopsin). This genus, representing geographically widespread and extensively studied cyanobacteria, is in fact heterogeneous and composed of at least five phylogenetically distant groups (Aphanizomenon, Anabaena/Aphanizomenon like cluster A, Cuspidothrix, Sphaerospermopsis and Chrysosporum) whose taxonomy is still under revision. This review provides a thorough insight into the phylogeny, ecology, biogeography and toxicogenomics (cyr, sxt, and ana genes) of the five best documented "Aphanizomenon" species with special relevance for water risk assessment: Aphanizomenon flos-aquae, Aphanizomenon gracile, Cuspidothrix issatschenkoi, Sphaerospermopsis aphanizomenoides and Chrysosporum ovalisporum. Aph. flos-aquae, Aph. gracile and C. issatschenkoi have been reported from temperate areas only whereas S. aphanizomenoides shows the widest distribution from the tropics to temperate areas. Ch. ovalisporum is found in tropical, subtropical and Mediterranean areas. While all five species show moderate growth rates (0.1-0.4day-1) within a wide range of temperatures (15-30 degrees C), Aph. gracile and A. flos-aquae can grow from around (or below) 10 degrees C, whereas Ch. ovalisporum and S. aphanizomenoides are much better competitors at high temperatures over 30 degrees C or even close to 35 degrees C. A. gracile has been confirmed as the producer of saxitoxins and cylindrospermopsin, C. issatschenkoi of anatoxins and saxitoxins and Ch. ovalisporum of cylindrospermopsin. The suspected cylindrospermopsin or anatoxin-a production of A. flos-aquae or microcystin production of S. aphanizomenoides is still uncertain. This review includes a critical discussion on the the reliability of toxicity reports and on the invasive potential of "Aphanizomenon" species in a climate change scenario, together with derived knowledge gaps and research needs. As a whole, this work is intended to represent a key reference for scientists and water managers involved in the major challenges of identifying, preventing and mitigating toxic Aphanizomenon blooms. PMID- 28073478 TI - Mitigating cyanobacterial harmful algal blooms in aquatic ecosystems impacted by climate change and anthropogenic nutrients. AB - Mitigating the global expansion of cyanobacterial harmful blooms (CyanoHABs) is a major challenge facing researchers and resource managers. A variety of traditional (e.g., nutrient load reduction) and experimental (e.g., artificial mixing and flushing, omnivorous fish removal) approaches have been used to reduce bloom occurrences. Managers now face the additional effects of climate change on watershed hydrologic and nutrient loading dynamics, lake and estuary temperature, mixing regime, internal nutrient dynamics, and other factors. Those changes favor CyanoHABs over other phytoplankton and could influence the efficacy of control measures. Virtually all mitigation strategies are influenced by climate changes, which may require setting new nutrient input reduction targets and establishing nutrient-bloom thresholds for impacted waters. Physical-forcing mitigation techniques, such as flushing and artificial mixing, will need adjustments to deal with the ramifications of climate change. Here, we examine the suite of current mitigation strategies and the potential options for adapting and optimizing them in a world facing increasing human population pressure and climate change. PMID- 28073481 TI - Understanding the winning strategies used by the bloom-forming cyanobacterium Cylindrospermopsis raciborskii. AB - The cyanobacterium Cylindrospermopsis raciborskii is a widespread species increasingly being recorded in freshwater systems around the world. It is of particular concern because strains in some geographic areas are capable of producing toxins with implications for human and animal health. Studies of this species have increased rapidly in the last two decades, especially in the southern hemisphere where toxic strains are prevalent. A clearer picture is emerging of the strategies adopted by this species to bloom and out-compete other species. This species has a high level of flexibility with respect to light and nutrients, with higher temperatures and carbon dioxide also promoting growth. There are two types of toxins produced by C. raciborskii: cylindrospermopsins (CYNs) and saxitoxins (STXs). The toxins CYNs are constitutively produced irrespective of environmental conditions and the ecological or physiological role is unclear, while STXs appear to serve as protection against high salinity and/or water hardness. It is also apparent that strains of this species can vary substantially in their physiological responses to environmental conditions, including CYNs production, and this may explain discrepancies in findings from studies in different geographical areas. The combination of a flexible strategy with respect to environmental conditions, and variability in strain response makes it a challenging species to manage. Our ability to improve bloom prediction will rely on a more detailed understanding of the complex physiology of this species. PMID- 28073480 TI - A review of the global ecology, genomics, and biogeography of the toxic cyanobacterium, Microcystis spp. AB - This review summarizes the present state of knowledge regarding the toxic, bloom forming cyanobacterium, Microcystis, with a specific focus on its geographic distribution, toxins, genomics, phylogeny, and ecology. A global analysis found documentation suggesting geographic expansion of Microcystis, with recorded blooms in at least 108 countries, 79 of which have also reported the hepatatoxin microcystin. The production of microcystins (originally "Fast-Death Factor") by Microcystis and factors that control synthesis of this toxin are reviewed, as well as the putative ecophysiological roles of this metabolite. Molecular biological analyses have provided significant insight into the ecology and physiology of Microcystis, as well as revealed the highly dynamic, and potentially unstable, nature of its genome. A genetic sequence analysis of 27 Microcystis species, including 15 complete/draft genomes are presented. Using the strictest biological definition of what constitutes a bacterial species, these analyses indicate that all Microcystis species warrant placement into the same species complex since the average nucleotide identity values were above 95%, 16S rRNA nucleotide identity scores exceeded 99%, and DNA-DNA hybridization was consistently greater than 70%. The review further provides evidence from around the globe for the key role that both nitrogen and phosphorus play in controlling Microcystis bloom dynamics, and the effect of elevated temperature on bloom intensification. Finally, highlighted is the ability of Microcystis assemblages to minimize their mortality losses by resisting grazing by zooplankton and bivalves, as well as viral lysis, and discuss factors facilitating assemblage resilience. PMID- 28073479 TI - Global solutions to regional problems: Collecting global expertise to address the problem of harmful cyanobacterial blooms. A Lake Erie case study. AB - In early August 2014, the municipality of Toledo, OH (USA) issued a 'do not drink' advisory on their water supply directly affecting over 400,000 residential customers and hundreds of businesses (Wilson, 2014). This order was attributable to levels of microcystin, a potent liver toxin, which rose to 2.5MUgL-1 in finished drinking water. The Toledo crisis afforded an opportunity to bring together scientists from around the world to share ideas regarding factors that contribute to bloom formation and toxigenicity, bloom and toxin detection as well as prevention and remediation of bloom events. These discussions took place at an NSF- and NOAA-sponsored workshop at Bowling Green State University on April 13 and 14, 2015. In all, more than 100 attendees from six countries and 15 US states gathered together to share their perspectives. The purpose of this review is to present the consensus summary of these issues that emerged from discussions at the Workshop. As additional reports in this special issue provide detailed reviews on many major CHAB species, this paper focuses on the general themes common to all blooms, such as bloom detection, modeling, nutrient loading, and strategies to reduce nutrients. PMID- 28073482 TI - An overview of diversity, occurrence, genetics and toxin production of bloom forming Dolichospermum (Anabaena) species. AB - The new genus name Dolichospermum, for most of the planktonic former members of the genus Anabaena, is one of the most ubiquitous bloom-forming cyanobacterial genera. Its dominance and persistence have increased in recent years, due to eutrophication from anthropogenic activities and global climate change. Blooms of Dolichospermum species, with their production of secondary metabolites that commonly include toxins, present a worldwide threat to environmental and public health. In this review, recent advances of the genus Dolichospermum are summarized, including taxonomy, genetics, bloom occurrence, and production of toxin and taste-and-odor compounds. The recent and continuing acquisition of genome sequences is ushering in new methods for monitoring and understanding the factors regulating bloom dynamics. PMID- 28073483 TI - The dual role of nitrogen supply in controlling the growth and toxicity of cyanobacterial blooms. AB - Historically, phosphorus (P) has been considered the primary limiting nutrient for phytoplankton assemblages in freshwater ecosystems. This review, supported by new findings from Lake Erie, highlights recent molecular, laboratory, and field evidence that the growth and toxicity of some non-diazotrophic blooms of cyanobacteria can be controlled by nitrogen (N). Cyanobacteria such as Microcystis possess physiological adaptations that allow them to dominate low-P surface waters, and in temperate lakes, cyanobacterial densities can be controlled by N availability. Beyond total cyanobacterial biomass, N loading has been shown to selectively promote the abundance of Microcystis and Planktothrix strains capable of synthesizing microcystins over strains that do not possess this ability. Among strains of cyanobacteria capable of synthesizing the N-rich microcystins, cellular toxin quotas have been found to depend upon exogenous N supplies. Herein, multi-year observations from western Lake Erie are presented demonstrating that microcystin concentrations peak in parallel with inorganic N, but not orthophosphate, concentrations and are significantly lower (p<0.01) during years of reduced inorganic nitrogen loading and concentrations. Collectively, this information underscores the importance of N as well as P in controlling toxic cyanobacteria blooms. Furthermore, it supports the premise that management actions to reduce P in the absence of concurrent restrictions on N loading may not effectively control the growth and/or toxicity of non diazotrophic toxic cyanobacteria such as the cosmopolitan, toxin-producing genus, Microcystis. PMID- 28073484 TI - The genetics, biosynthesis and regulation of toxic specialized metabolites of cyanobacteria. AB - The production of toxic metabolites by cyanobacterial blooms represents a significant threat to the health of humans and ecosystems worldwide. Here we summarize the current state of the knowledge regarding the genetics, biosynthesis and regulation of well-characterized cyanotoxins, including the microcystins, nodularin, cylindrospermopsin, saxitoxins and anatoxins, as well as the lesser known marine toxins (e.g. lyngbyatoxin, aplysiatoxin, jamaicamides, barbamide, curacin, hectochlorin and apratoxins). PMID- 28073485 TI - Spatial distribution and sources of organic matter and pollutants in the SE Mediterranean (Levantine basin) deep water sediments. AB - A study of deep sea sediment quality was conducted at 52 stations off the Mediterranean coast of Israel (50-1900m depth). Total Organic Carbon (TOC), Polycyclic Aromatic Hydrocarbons (?PAHs), Poly Chlorinated Biphenyls (?PCBs) ranged between 0.58 and 1.44%, 12-190 and <0.3-7.7MUgkg-1, respectively. The TOC distribution indicated the Nile delta as an important source of organic matter and the important effect of topography on deposition patterns in this region. PCBs and PAHs quantitative levels were associated with nearby gas well drilling (well below environmental criteria) and dredge-material dumping sites. A significant correlation between these pollutants and TOC was found in the southernmost stations suggesting a common source. PAHs isomer ratios in most of the stations indicated a petrogenic source, while the contribution of pyrogenic sources appears to be very small. These findings form a sound baseline for assessing the potential impact of future deep sea drilling activities that are expected to increase significantly in the Eastern Mediterranean basin. PMID- 28073486 TI - Indication of spatial variations in annual cycles of functional groups of planktonic ciliates to environmental change in marine ecosystems. AB - The indication of spatial variations in annual cycles of functional groups of planktonic ciliates to environmental changes was studied in a bay, northern Yellow Sea. Samples were biweekly collected at five stations with different hydrographic conditions during a 1-year cycle. The second-stage-matrix-based multivariate approach was used to summarize the internal interactions of the ciliate functional groups among five stations during a 1-year period. The functional groups of the ciliates represented a clear spatial variation in annual cycle among five stations. Mantel analysis demonstrated that the spatial variation in annual cycles of the ciliate functional groups were significantly correlated with the changes nutrients (mainly soluble reactive phosphates and nitrates), alone or in combination with salinity among five stations. Based the results, it is suggested that the spatial variation in annual cycles of functional groups of planktonic ciliates may indicated the changes of hydrographic conditions. PMID- 28073487 TI - Distribution and ecological risk assessment of heavy metals in surface sediments of a typical restored mangrove-aquaculture wetland in Shenzhen, China. AB - The restoration of wetlands has attracted the attention in different countries. Restored coastal wetlands, especially urban wetlands, are sensitive to external pressures. Thus, it is necessary to evaluate the efficiency of the restoration of coastal wetlands, which benefits their management and functional maintenance. In this study, a restored mangrove-aquaculture system in Waterlands Resort at Shenzhen was selected for analysis. The distribution and ecological risk assessment of heavy metals in surface sediments were investigated. The results showed that restoration could effectively decrease the heavy metal concentrations in the sediment, while the restored mangrove posed a moderate ecological risk. Most of the heavy metal concentrations were higher during the dry season compared with the wet season. In addition, during the whole investigation, the sediment quality remained failed to achieve the marine sediment criteria required for aquaculture in China. PMID- 28073488 TI - Plasma mitochondrial DNA levels were independently associated with lung injury in elderly hip fracture patients. AB - INTRODUCTION: Hip fracture in the elderly can induce systemic inflammatory response (SIRS) and lung injury which increases the risk of lung infection and death. Mitochondrial DNA (mtDNA) plays a role in SIRS and lung injury in patients with multi-trauma, and also in patients with hip fractures. This study evaluated the potential value of plasma mtDNA in the early prognosis of lung injury in elderly fracture patients. METHODS: This study enrolled 156 elderly patients with intertrochanteric fracture. Plasma mtDNA, IL-6, IL-10, prostaglandin E2 (PGE2) levels were measured at admission. Sixty-one and 31 patients were diagnosed with systemic inflammatory response syndrome (SIRS) and lung injury, respectively. RESULTS: Plasma mtDNA levels were higher in hip fracture patients compared to healthy controls (P<0.001) and significantly higher in the lung injury subgroup compared to the lung injury absent subgroup (P<0.001). MtDNA levels were correlated with the SIRS score (r=0.446, P<0.001), IL-6 (r=0.506, P<0.001), IL-10 (r=0.523, P<0.001), and PGE2 (r=0.360, P<0.001). Logistic regression analysis revealed that plasma mtDNA, IL-6, PGE2 and SIRS score were independent predictors of the risk of lung injury. CONCLUSION: Plasma mtDNA release induced by hip fracture in elderly patients, might be an early predictor of lung injury in these patients. PMID- 28073489 TI - Cost comparison of initial lobectomy versus fine-needle aspiration for diagnostic workup of thyroid nodules in children. AB - BACKGROUND: Though uncommon in children, pediatric thyroid nodules carry a higher risk of malignancy than adult nodules. While fine-needle aspiration (FNA) has been well established as the initial diagnostic test in adults, it has been more slowly adopted in children. The purpose of this study was to examine the comparative cost of FNA versus initial diagnostic lobectomy (DL) in the pediatric patient with an ultrasound-confirmed thyroid nodule. METHODS: A decision tree model was created using an adolescent with an asymptomatic thyroid nodule as the reference case. Probabilities were defined based on review of the pediatric and adult literature. Costs were determined from previous literature and the publicly available Medicare physician fee schedule. Tornado plot and sensitivity analyses were performed to assess sources of cost variation. RESULTS: Using decision analysis, FNA was less costly than DL with an estimated cost of $2529 vs. $5680. Tornado analysis demonstrated that the probability of an initial indeterminate FNA result contributed most to cost variation. On sensitivity analysis, when probability of an indeterminate FNA result was increased to 35%, the maximum value found in the literature, FNA remained less costly. In Monte Carlo simulation set to 10,000 iterations, FNA was superior to DL in 74% of cases. CONCLUSIONS: In this theoretical model based on available literature and costs, FNA is less costly than DL for initial diagnostic workup of thyroid nodules in children. Securing resources to offer FNA in the work-up of thyroid nodules may be financially beneficial to hospitals and patients. LEVEL OF EVIDENCE: Level 1 cost effectiveness study - using reasonable costs and alternatives used in study with values obtained from many studies, study used multi-way sensitivity analysis. PMID- 28073490 TI - Mapping pediatric injuries to target prevention, education, and outreach. AB - BACKGROUND: Initiatives exist to prevent pediatric injuries, but targeting these interventions to specific populations is challenging. We hypothesized that mapping pediatric injuries by zip code could be used to identify regions requiring more interventions and resources. METHODS: We queried the trauma registries of two level I trauma centers for children 0-17years of age injured between 2009 and 2013 with home zip codes in our state. Maps were created to identify outlier zip codes. Multivariate linear regression analysis identified predictors within these zip codes. RESULTS: There were 5380 children who resided in the state and were admitted for traumatic injuries during the study period, with hospital costs totaling more than 200 million dollars. Choropleth mapping of patient addresses identified outlier zip codes in our metro area with higher incidences of specific mechanisms of injury and greater hospital charges. Multivariate analysis identified demographic features associated with higher rates of pediatric injuries and hospital charges, to further target interventions. CONCLUSIONS: We identified outlier zip codes in our metro area with higher frequencies of pediatric injuries and higher costs for treatment. These data have helped obtain funding for prevention and education efforts. Techniques such as those presented here are becoming more important as evidence based public health initiatives expand. LEVEL OF EVIDENCE: Type of Study: Cost Effectiveness, II. PMID- 28073491 TI - Gray Matter Neuritic Microstructure Deficits in Schizophrenia and Bipolar Disorder. AB - BACKGROUND: Postmortem studies have demonstrated considerable dendritic pathologies among persons with schizophrenia and to some extent among those with bipolar I disorder. Modeling gray matter (GM) microstructural properties is now possible with a recently proposed diffusion-weighted magnetic resonance imaging modeling technique: neurite orientation dispersion and density imaging. This technique may bridge the gap between neuroimaging and histopathological findings. METHODS: We performed an extended series of multishell diffusion-weighted imaging and other structural imaging series using 3T magnetic resonance imaging. Participants scanned included individuals with schizophrenia (n = 36), bipolar I disorder (n = 29), and healthy controls (n = 35). GM-based spatial statistics was used to compare neurite orientation dispersion and density imaging-driven microstructural measures (orientation dispersion index and neurite density index [NDI]) among groups and to assess their relationship with neurocognitive performance. We also investigated the accuracy of these measures in the prediction of group membership, and whether combining them with cortical thickness and white matter fractional anisotropy further improved accuracy. RESULTS: The GM-NDI was significantly lower in temporal pole, anterior parahippocampal gyrus, and hippocampus of the schizophrenia patients than the healthy controls. The GM-NDI of patients with bipolar I disorder did not differ significantly from either schizophrenia patients or healthy controls, and it was intermediate between the two groups in the post hoc analysis. Regardless of diagnosis, higher performance in spatial working memory was significantly associated with higher GM-NDI mainly in the frontotemporal areas. The addition of GM-NDI to cortical thickness resulted in higher accuracy to predict group membership. CONCLUSIONS: GM-NDI captures brain differences in the major psychoses that are not accessible with other structural magnetic resonance imaging methods. Given the strong association of GM-NDI with disease state and neurocognitive performance, its potential utility for biological subtyping should be further explored. PMID- 28073492 TI - Stress-responsive expression of a glutathione S-transferase (delta) gene in waterflea Daphnia magna challenged by microcystin-producing and microcystin-free Microcystis aeruginosa. AB - Harmful cyanobacterial blooms resulting from eutrophication and global warming have emerged as a worldwide environmental concern. Some zooplankton populations, including Daphnia, have been shown to adapt locally to microcystin-producing Microcystis. Previous in vitro experiments indicate that glutathione-S transferase (GST) may act as the first step of detoxification in Daphnia by conjugating microcystins (MCs) with glutathione. The GST family is categorized into many classes, and different classes present distinct responses to MC detoxification. To date, however, the molecular mechanism of single class GST participation in buffering the toxic effects of MCs in Daphnia remains poorly known. In this study, a full-length delta-GST cDNA of Daphnia magna (Dm-dGST) was isolated and characterized through bioinformatics. Differential gene expression studies revealed that short-term exposure to microcystin-producing (MP) Microcystis aeruginosa increased Dm-dGST transcript levels. By contrast, long term exposure to MP or microcystin-free (MF) M. aeruginosa decreased Dm-dGST transcript levels. Together with changes in three other antioxidation biomarkers (catalase, CuZn- and Mn-superoxide dismutase), it is concluded that Dm-dGST can potentially biotransform MCs to reduce their toxicity. The present study highlights the importance of Dm-dGST in response to MC toxicity and may thus facilitate future research on the molecular mechanisms of MC tolerance in zooplankton under an increasing eutrophic world. PMID- 28073493 TI - Abiotic variables affect STX concentration in a meso-oligotrophic subtropical coastal lake dominated by Cylindrospermopsis raciborskii (Cyanophyceae). AB - The cyanobacterium Cylindrospermopsis raciborskii is capable of producing toxins including saxitoxin (STX). Few studies have verified the influence of environmental variables on the production of STX and most have only been studied in the laboratory. The goal of this work was to identify the abiotic variables related to STX concentration in situ. The relationship among STX concentration and the physical variables, nutrients and chlorophyll-a (chl-a) concentration was examined in a meso-oligotrophic subtropical coastal lake dominated by C. raciborskii. A generalized linear model was developed, incorporating all variables measured monthly over a 45-month monitoring period. Conductivity and dissolved inorganic nitrogen (DIN) concentration provided the greatest explanatory power for STX concentration in situ. Previous studies suggested that C. raciborskii cells exposed to stress associated with higher ionic concentrations appear to activate the biosynthesis of STX suggesting that STX can elicit changes cell permeability and may contribute to the homeostasis of this organism. An increase of DIN concentration results in a higher concentration of STX which may be related to a reduced metabolic demand, since the uptake of inorganic nitrogen requires less energy than N2-fixation. Thus, increased DIN can favor the growth of C. raciborskii population or improve cellular homeostasis, both potentially increasing STX concentration in the aquatic system, which was observed through a delayed response pattern. The developed model, while providing only a moderate predictive power, can assist in the understanding of the environmental variables associated with increases in STX concentration, and in monitoring and minimizing the risks of toxic blooms. PMID- 28073494 TI - A mutualistic interaction between the bacterium Pseudomonas asplenii and the harmful algal species Chattonella marina (Raphidophyceae). AB - Several studies on various Chattonella species have reported that bacteria may play an important role in Chattonella bloom initiation, however, no studies have described how these bacteria promote the growth of C. marina. The interaction between C. marina and bacteria was investigated for identification and characterization of potential growth-promoting bacteria. In preliminary tests, the growth promoting effect of Pseudomonas species (25 strains) was investigated and P. asplenii (>=2.27) was determined as a growth-promoting bacteria for both C. marina strains (CCMP 2049 and 2050). This bacterium exerted optimal growth promoting effects on C. marina, causing an increase in the initial density of P. asplenii to approximately 1*107cellsmL-1, which was used as the initial density in this study. To determine whether the growth-promoting activity was direct or indirect, P. asplenii was incubated in the algal media and then a filtrate of this culture was added to both C. marina strains. The P. asplenii filtrate stimulated the growth of C. marina and maintained the growth-promoting effects after high temperature (121 degrees C for 20min) and pressure (15psi) treatment. Thus, P. asplenii is able to promote C. marina growth through the release of a heat-resistant substance, such as inorganic nutrients. A nutrient analysis indicated that this bacterium elevated the phosphate concentration. Interestingly, P. asplenii was unable to survive in phosphate-limited media but could grow in phosphate-limited media incubating C. marina. Moreover, this bacterium could secrete significantly more phosphate in the presence of C. marina (p<0.0001). These results suggested that P. asplenii and C. marina may have a mutualistic interaction. PMID- 28073495 TI - Influence of nitrogen availability on the expression of genes involved in the biosynthesis of saxitoxin and analogs in Cylindrospermopsis raciborskii. AB - The development of cyanobacterial blooms in inland aquatic ecosystems is greatly promoted by nutrient availability, especially nitrogen and phosphorous. When blooms are dominated by toxigenic species the harmful effects of nutrient loading becomes particularly relevant. Among toxic species, Cylindrospermopsis raciborskii found in South American ecosystems is characterized by the production of saxitoxin and analogs (Paralytic Shellfish Poisoning, PSP), for which the factors that trigger their production have not been elucidated. In this study, the effect of nitrate availability on the relative transcript abundance of two genes (sxtU and sxtI), both involved in different steps of PSP biosynthetic pathway, was addressed in C. raciborskii MVCC19 by qPCR. The relative transcript abundance of both genes significantly increased from the beginning to the end of growth, independent of nitrate availability in the culture medium. Differences between the genes in terms of the levels of relative expression were also found, implying that during growth in nitrate-rich or nitrate-deprived conditions C. raciborskii MVCC19 has the ability to produce different kind of PSP molecules. The presence of nifH transcripts in the nitrogen-depleted treatment confirmed that in the absence of nitrate C. raciborskii fixed atmospheric N2. Moreover, after transferring filaments to nitrate-rich conditions the synthesis of nifH mRNA continued for few hours, suggesting that cell adjustments enabling the utilization of soluble nitrogen sources are not immediate. Our results show that biosynthesis of saxitoxin and analogs in C. raciborskii is not related to nitrate availability, but rather is linked to cyanobacteria growth rate. PMID- 28073497 TI - Development of a quantitative PCR method to explore the historical occurrence of a nuisance microalga under expansion. AB - A number of marine and freshwater harmful algal bloom (HAB) species have colonized new areas and expanded their habitat range in recent years. Nevertheless it is notoriously difficult to establish when colonization first occurred, what the dispersal routes are, and to separate recent invasion from increases in existent but small populations. The freshwater raphidophyte Gonyostomum semen is a nuisance species that has expanded its habitat range and increased in abundance in northern Europe during the past decades. To evaluate to what extent sediments can be used for determining historic occurrence of G. semen, a quantitative real-time PCR method for detecting cysts of this algae was developed. This paper presents a qPCR protocol with a set of primers that are specific to Gonyostomum and with PCR conditions optimized for sediment samples from humic lakes, which are the common habitat of G. semen. With this sensitive method as few as 1.6 cysts per PCR reaction could be reliably quantified, corresponding to 320 cysts per g wet weight sediment. Cysts were present in sediments with ages ranging from years to decades and their persistence allows detection of historic populations up to at least 50 years old. With this qPCR assay it will be possible to trace the presence of G. semen in environments prior to the onset of algae-specific monitoring programs as well as for quantification in water column samples. PMID- 28073496 TI - The re-eutrophication of Lake Erie: Harmful algal blooms and hypoxia. AB - Lake Erie supplies drinking water to more than 11 million consumers, processes millions of gallons of wastewater, provides important species habitat and supports a substantial industrial sector, with >$50 billion annual income to tourism, recreational boating, shipping, fisheries, and other industries. These and other key ecosystem services are currently threatened by an excess supply of nutrients, manifested in particular by increases in the magnitude and extent of harmful planktonic and benthic algal blooms (HABs) and hypoxia. Widespread concern for this important international waterbody has been manifested in a strong focus of scientific and public material on the subject, and commitments for Canada-US remedial actions in recent agreements among Federal, Provincial and State agencies. This review provides a retrospective synthesis of past and current nutrient inputs, impairments by planktonic and benthic HABs and hypoxia, modelling and Best Management Practices in the Lake Erie basin. The results demonstrate that phosphorus reduction is of primary importance, but the effects of climate, nitrogen and other factors should also be considered in the context of adaptive management. Actions to reduce nutrient levels by targeted Best Management Practices will likely need to be tailored for soil types, topography, and farming practices. PMID- 28073498 TI - Cyanotoxins in inland lakes of the United States: Occurrence and potential recreational health risks in the EPA National Lakes Assessment 2007. AB - A large nation-wide survey of cyanotoxins (1161 lakes) in the United States (U.S.) was conducted during the EPA National Lakes Assessment 2007. Cyanotoxin data were compared with cyanobacteria abundance- and chlorophyll-based World Health Organization (WHO) thresholds and mouse toxicity data to evaluate potential recreational risks. Cylindrospermopsins, microcystins, and saxitoxins were detected (ELISA) in 4.0, 32, and 7.7% of samples with mean concentrations of 0.56, 3.0, and 0.061MUg/L, respectively (detections only). Co-occurrence of the three cyanotoxin classes was rare (0.32%) when at least one toxin was detected. Cyanobacteria were present and dominant in 98 and 76% of samples, respectively. Potential anatoxin-, cylindrospermopsin-, microcystin-, and saxitoxin-producing cyanobacteria occurred in 81, 67, 95, and 79% of samples, respectively. Anatoxin a and nodularin-R were detected (LC/MS/MS) in 15 and 3.7% samples (n=27). The WHO moderate and high risk thresholds for microcystins, cyanobacteria abundance, and total chlorophyll were exceeded in 1.1, 27, and 44% of samples, respectively. Complete agreement by all three WHO microcystin metrics occurred in 27% of samples. This suggests that WHO microcystin metrics based on total chlorophyll and cyanobacterial abundance can overestimate microcystin risk when compared to WHO microcystin thresholds. The lack of parity among the WHO thresholds was expected since chlorophyll is common amongst all phytoplankton and not all cyanobacteria produce microcystins. PMID- 28073499 TI - Physiological and transcriptional responses to inorganic nutrition in a tropical Pacific strain of Alexandrium minutum: Implications for the saxitoxin genes and toxin production. AB - Saxitoxins (STXs) constitute a family of potent sodium channel blocking toxins, causative agents of paralytic shellfish poisoning (PSP), and are produced by several species of marine dinoflagellates and cyanobacteria. Two STX-core genes, sxtA and sxtG, have been well elucidated in Alexandrium but the expression of these genes under various nutritional modes in tropical species remains unclear. This study investigates the physiological responses of a tropical Pacific strain of Alexandrium minutum growing with nitrate or ammonium, and with various nitrogen to phosphorus (N:P) supply ratios. The transcriptional responses of the sxt genes were observed. Likewise, a putative sxtI encoding O carbamoyltransferase (herein designated as AmsxtI) was recovered from the transcriptomic data, and its expression was investigated. The results revealed that the cellular toxin quota (Qt) was higher in P-depleted, nitrate-grown cultures. With cultures at similar N:P (<16), cells grown with excess ammonium showed a higher Qt than those grown with nitrate. sxtA1 was not expressed under any culture conditions, suggesting that this gene might not be involved in STX biosynthesis by this strain. Conversely, sxtA4 and sxtG showed positive correlations with Qt, and were up-regulated in P-depleted, nitrate-grown cultures and with excess ambient ammonium. On the other hand, AmsxtI was expressed only when induced by P-depletion, suggesting that this gene may play an important role in P-recycling metabolism, while simultaneously enhancing toxin production. PMID- 28073500 TI - Initial skill assessment of the California Harmful Algae Risk Mapping (C-HARM) system. AB - Toxic algal events are an annual burden on aquaculture and coastal ecosystems of California. The threat of domoic acid (DA) toxicity to human and wildlife health is the dominant harmful algal bloom (HAB) concern for the region, leading to a strong focus on prediction and mitigation of these blooms and their toxic effects. This paper describes the initial development of the California Harmful Algae Risk Mapping (C-HARM) system that predicts the spatial likelihood of blooms and dangerous levels of DA using a unique blend of numerical models, ecological forecast models of the target group, Pseudo-nitzschia, and satellite ocean color imagery. Data interpolating empirical orthogonal functions (DINEOF) are applied to ocean color imagery to fill in missing data and then used in a multivariate mode with other modeled variables to forecast biogeochemical parameters. Daily predictions (nowcast and forecast maps) are run routinely at the Central and Northern California Ocean Observing System (CeNCOOS) and posted on its public website. Skill assessment of model output for the nowcast data is restricted to nearshore pixels that overlap with routine pier monitoring of HABs in California from 2014 to 2015. Model lead times are best correlated with DA measured with solid phase adsorption toxin tracking (SPATT) and marine mammal strandings from DA toxicosis, suggesting long-term benefits of the HAB predictions to decision making. Over the next three years, the C-HARM application system will be incorporated into the NOAA operational HAB forecasting system and HAB Bulletin. PMID- 28073501 TI - Ecological niche partitioning of the invasive dinoflagellate Prorocentrum minimum and its native congeners in the Baltic Sea. AB - This study analyses three decades of the peculiar bloom-formation history of the potentially toxic invasive planktonic dinoflagellates Prorocentrum minimum (Pavillard) Schiller in the SW Baltic Sea. We tested a research hypothesis that the unexpectedly long delay (nearly two decades) in population development of P. minimum prior to its first bloom was caused by competition with one or several closely related native dinoflagellate species due to ecological niche partitioning which hampered the spread and bloom-forming potential of the invader. We applied the ecological niche concept to a large, long-term phytoplankton database and analysed the invasion history and population dynamics of P. minimum in the SW Baltic Sea coastal waters using the data on phytoplankton composition, abundance and biomass. The ecological niche dimensions of P. minimum and its congener P. balticum were identified as the optimum environmental conditions for the species during the bloom events based on water temperature, salinity, pH, concentration of nutrients (PO43-; total phosphorus, TP; total nitrogen, TN; SiO44-), TN/TP-ratio and habitat type. The data on spatial distribution and ecological niche dimensions of P. minimum have contributed to the development of the "protistan species maximum concept". High microplankton diversity at critical salinities in the Baltic Sea may be considered as a possible reason for the significant niche overlap and strong competitive interactions among congeners leading to prolonged delay in population growth of P. minimum preceding its first bloom in the highly variable brackishwater environment. PMID- 28073502 TI - Lethal effects of ichthyotoxic raphidophytes, Chattonella marina, C. antiqua, and Heterosigma akashiwo, on post-embryonic stages of the Japanese pearl oyster, Pinctada fucata martensii. AB - The inimical effects of the ichthyotoxic harmful algal bloom (HAB)-forming raphidophytes Heterosigma akashiwo, Chattonella marina, and Chattonella antiqua on the early-life stages of the Japanese pearl oyster Pinctada fucata martensii were studied. Fertilized eggs and developing embryos were not affected following exposure to the harmful raphidophytes; however, all three algal species severely affected trochophores and D-larvae, early-stage D-larvae, and late-stage pre settling larvae. Exposure to C. marina (5*102cellsml-1), C. antiqua (103cellsml 1), and H. akashiwo (5*103cellsml-1) resulted in decreased success of metamorphosis to the trochophore stage. A complete inhibition of trochophore metamorphosis was observed following exposure to C. antiqua at 5*103cellsml-1 and C. marina at 8*103cellsml-1. In all experiments, more than 80% of newly formed trochophores were anomalous, and in the case of exposure to H. akashiwo at 105cellsml-1 more than 70% of D-larvae were anomalous. The activity rates of D larvae (1-day-old) were significantly reduced following exposure to C. antiqua (8*103cellsml-1, 24h), C. marina (8*103cellsml-1, 24h), and H. akashiwo (104cellsml-1, 24h). The activity rates of pre-settling larvae (21-day-old) were also significantly reduced following exposure to C. antiqua (103cellsml-1, 24h),C. marina (8*103cellsml-1, 24h), and H. akashiwo (5*104cellsml-1, 24h). Significant mortalities of both larval stages were induced by all three raphidophytes, with higher mortality rates registered for pre-settling larvae than D-larvae, especially following exposure to C. marina (5*102-8*103cellsml-1, 48-86h) and C. antiqua (103-8*103cellsml-1, 72-86h). Contact between raphidophyte cells and newly metamorphosed trochophores and D-larvae, 1-day-old D-larvae, and 21-day-old larvae resulted in microscopic changes in the raphidophytes, and then, in the motile early-life stages of pearl oysters. Upon contact and physical disturbance of their cells by larval cilia, H. akashiwo, C. marina and C. antiqua became immotile and shed their glycocalyx. The trochophores and larvae were observed trapped in a conglomerate of glycocalyx and mucus, most probably a mixture of larval mucous and raphidophyte tricosyts and mucocytes. All motile stages of pearl oyster larvae showed a typical escape behavior translating into increased swimming in an effort to release themselves from the sticky mucous traps. The larvae subsequently became exhausted, entrapped in more heavy mucous, lost their larval cilia, sank, become immotile, and died. Although other toxic mediators could have been involved, the results of the present study indicate that all three raphidophytes were harmful only for motile stages of pearl oysters, and that the physical disturbance of their cells upon contact with the ciliary structures of pearl oyster larvae initiated the harmful mechanism. The present study is the first report of lethal effects of harmful Chattonella spp. towards larvae of a bivalve mollusc. Blooms of H. akashiwo, C. antiqua and C. marina occur in all major cultivation areas of P. fucata martensii during the developmental period of their larvae. Therefore, exposure of the motile early life stages of Japanese pearl oysters could adversely affect their population recruitment. In addition, the present study shows that further research with early-life development of pearl oysters and other bivalves could contribute to improving the understanding of the controversial harmful mechanisms of raphidophytes in marine organisms. PMID- 28073503 TI - The fate of cryptophyte cell organelles in the ciliate Mesodinium cf. rubrum subjected to starvation. AB - Mesodinium rubrum Lohmann is a mixotrophic ciliate and one of the best studied species exhibiting acquired phototrophy. To investigate the fate of cryptophyte organelles in the ciliate subjected to starvation, we conducted ultrastructural studies of a Korean strain of M. cf. rubrum during a 10 week starvation experiments. Ingested cells of the cryptophyte Teleaulax amphioxeia were first enveloped by ciliate membrane, and then prey organelles, including ejectisomes, flagella, basal bodies and flagellar roots, were digested. Over time, prey nuclei protruded into the cytoplasm of the ciliate, their size and volume increased, and their number decreased, suggesting that the cryptophyte nuclei likely fused with each other in the ciliate cytoplasm. At 4 weeks of starvation, M. cf. rubrum cells without cryptophyte nuclei started to appear. At 10 weeks of starvation, only two M. cf. rubrum cells still possessing a cryptophyte nucleus had relatively intact chloroplast-mitochondria complexes (CMCs), while M. cf. rubrum cells without cryptophyte nuclei had a few damaged CMCs. This is the first ultrastructural study demonstrating that cryptophyte nuclei undergo a dramatic change inside M. cf. rubrum in terms of size, shape, and number following their acquisition. PMID- 28073504 TI - Distribution of Dinophysis species and their association with lipophilic phycotoxins in plankton from the Argentine Sea. AB - Dinophysis is a cosmopolitan genus of marine dinoflagellates, considered as the major proximal source of diarrheic shellfish toxins and the only producer of pectenotoxins (PTX). From three oceanographic expeditions carried out during autumn, spring and late summer along the Argentine Sea (~38-56 degrees S), lipophilic phycotoxins were determined by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in size-fractionated plankton samples. Lipophilic toxin profiles were associated with species composition by microscopic analyses of toxigenic phytoplankton. Pectenotoxin-2 and PTX-11 were frequently found together with the presence of Dinophysis acuminata and Dinophysis tripos. By contrast, okadaic acid was rarely detected and only in trace concentrations, and dinophysistoxins were not found. The clear predominance of PTX over other lipophilic toxins in Dinophysis species from the Argentine Sea is in accordance with previous results obtained from north Patagonian Gulfs of the Argentine Sea, and from coastal waters of New Zealand, Chile, Denmark and United States. Dinophysis caudata was rarely found and it was confined to the north of the sampling area. Because of low cell densities, neither D. caudata nor Dinophysis norvegica could be biogeographically related to lipophilic toxins in this study. Nevertheless, the current identification of D. norvegica in the southern Argentine Sea is the first record for the southwestern Atlantic Ocean. Given the typical toxigenicity of this species on a global scale, this represents an important finding for future surveillance of plankton-toxin associations. PMID- 28073505 TI - Characterization of akinetes from cyanobacterial strains and lake sediment: A study of their resistance and toxic potential. AB - Nostocalean cyanobacteria are known to proliferate abundantly in eutrophic aquatic ecosystems, and to produce several cyanotoxins, including anatoxin-a. In this study, we investigated both the resistance and toxic potential of the akinetes (resistant cells), using cyanobacterial cultures and akinetes extracted from the sediment of Lake Aydat (France) sampled in the winter and spring. Intact and lysed akinetes were differentiated using a double control based on the autofluorescence of akinetes and SYTOX-green staining. The percentage of resistant akinetes found in several different abiotic stress conditions was highly variable, depending on the species and also on the sampling season. Thus, the resistance of akinetes and their ability to germinate seems to follow a species-specific process, and akinetes can undergo physiologic changes during the sedimentary phase of the Nostocale life cycle. This study also revealed the first evidence of anatoxin-a genes in akinetes, with anaC and anaF genes detected in akinetes from all cyanobacterial producer cultures. The low number of anaC genes, almost exclusively detected using nested PCR, in the sediment at Lake Aydat suggests a limited but existent past population of toxic Nostocales in this lake. Given the key role of akinetes in the annual cycle and subsequent summer proliferation, it can be interesting to integrate the surveillance of akinetes in the management of lakes exposed to recurrent cyanobacterial blooms. PMID- 28073506 TI - Changes in morphological plasticity of Ulva prolifera under different environmental conditions: A laboratory experiment. AB - The large-scale green tides, consisting mainly of Ulva prolifera, have invaded the coastal zones of western Yellow Sea each year since 2008, resulting in tremendous impacts on the local environment and economy. A large number of studies have been conducted to investigate the physiological traits of U. prolifera to explain its dominance in the green tides. However, little has been reported regarding the response of U. prolifera to changing environmental factors via morphological variation. In our experiments, we found remarkable morphological acclimation of U. prolifera to various temperature (20 and 25 degrees C) and salinity (10, 20, and 30) conditions. U. prolifera had more, but shorter branches when they were cultured at lower temperature and salinity conditions. To investigate the significance of these morphological variations in its acclimation to changes of environmental factors, physiological and biochemical traits of U. prolifera grown under different conditions were measured. Higher temperature increased the relative growth rate while salinity did not affect it. On the other hand, higher temperature did not enhance the net photosynthetic rate whilst lower salinity did. The increased net photosynthetic rate at lower salinity conditions could be attributed to more photosynthetic pigments-chlorophyll a, chlorophyll b, and carotenoids-in thalli due to there being more branches at lower salinity conditions. Increased numbers of branches and thus an increased intensity of thalli may be helpful to protect thalli from increased osmotic pressure caused by lower salinity, but it led to more shading. In order to capture enough light when being shaded, thalli of U. prolifera synthesized more photosynthetic pigments at lower salinity levels. In addition, higher temperature increased nitrate reductase activity and soluble protein content but variations in salinity did not impose any effect on them. Our results demonstrate conclusively that U. prolifera can acclimatize in the laboratory to the changes of environmental factors (salinity and temperature) by morphology driven physiological and biochemical variation. We suggest that the morphological plasticity of U. prolifera may be an important factor for it to outcompete other algal species in a changing ocean. PMID- 28073507 TI - Evidence of freshwater algal toxins in marine shellfish: Implications for human and aquatic health. AB - The occurrence of freshwater harmful algal bloom toxins impacting the coastal ocean is an emerging threat, and the potential for invertebrate prey items to concentrate toxin and cause harm to human and wildlife consumers is not yet fully recognized. We examined toxin uptake and release in marine mussels for both particulate and dissolved phases of the hepatotoxin microcystin, produced by the freshwater cyanobacterial genus Microcystis. We also extended our experimental investigation of particulate toxin to include oysters (Crassostrea sp.) grown commercially for aquaculture. California mussels (Mytilus californianus) and oysters were exposed to Microcystis and microcystin toxin for 24h at varying concentrations, and then were placed in constantly flowing seawater and sampled through time simulating riverine flushing events to the coastal ocean. Mussels exposed to particulate microcystin purged the toxin slowly, with toxin detectable for at least 8 weeks post-exposure and maximum toxin of 39.11ng/g after exposure to 26.65MUg/L microcystins. Dissolved toxin was also taken up by California mussels, with maximum concentrations of 20.74ng/g after exposure to 7.74MUg/L microcystin, but was purged more rapidly. Oysters also took up particulate toxin but purged it more quickly than mussels. Additionally, naturally occurring marine mussels collected from San Francisco Bay tested positive for high levels of microcystin toxin. These results suggest that ephemeral discharge of Microcystis or microcystin to estuaries and the coastal ocean accumulate in higher trophic levels for weeks to months following exposure. PMID- 28073508 TI - Mixotrophic ability of the phototrophic dinoflagellates Alexandrium andersonii, A. affine, and A. fraterculus. AB - The dinoflagellate Alexandrium spp. have received much attention due to their harmful effects on diverse marine organisms, including commercially important species. For minimizing loss due to red tides or blooms of Alexandrium spp., it is very important to understand the eco-physiology of each Alexandrium species and to predict its population dynamics. Its trophic mode (i.e., exclusively autotrophic or mixotrophic) is one of the most critical parameters in establishing prediction models. However, among the 35 Alexandrium species so far described, only six Alexandrium species have been revealed to be mixotrophic. Thus, mixotrophic ability of the other Alexandrium species should be explored. In the present study, whether each of three Alexandrium species (A. andersonii, A. affine, and A. fraterculus) isolated from Korean waters has or lacks mixotrophic ability, was investigated. When diets of diverse algal prey, cyanobacteria, and bacteria sized micro-beads were provided, A. andersonii was able to feed on the prasinophyte Pyramimonas sp., the cryptophyte Teleaulax sp., and the dinoflagellate Heterocapsa rotundata, whereas neither A. affine nor A. fraterculus fed on any prey item. Moreover, mixotrophy elevated the growth rate of A. andersonii. The maximum mixotrophic growth rates of A. andersonii on Pyramimonas sp. under a 14:10h light/dark cycle of 20MUEm-2s-1 was 0.432d-1, while the autotrophic growth rate was 0.243d-1. With increasing mean prey concentration, the ingestion rate of A. andersonii increased rapidly at prey concentrations <650ngCml-1 (ca. 16,240 cellsml-1), but became saturated at the higher prey concentrations. The maximum ingestion rate by A. andersonii of Pyramimonas sp. was 1.03ngC predator-1d-1 (25.6 cells predator-1d-1). This evidence suggests that the mixotrophic ability of A. andersonii should be taken into consideration in predicting the outbreak, persistence, and decline of its harmful algal blooms. PMID- 28073509 TI - Harmful effects of Dinophysis to the ciliate Mesodinium rubrum: Implications for prey capture. AB - Toxigenic Dinophysis spp. are obligate mixotrophic dinoflagellates that require a constant supply of prey-Mesodinium rubrum-to achieve long-term growth by means of kleptoplasty. Mesodinium rubrum is, however, a fast moving, jumping ciliate exhibiting an effective escape response from suspensivorous predators. In the present study, a series of laboratory experiments evaluating the motility and survival of M. rubrum in the presence of Dinophysis cells and/or substances contained in their culture medium was designed, in order to assess the mechanisms involved in prey capture by Dinophysis spp. Cell abundance of M. rubrum decreased in the presence of Dinophysis cf. ovum cells producing okadaic acid (OA; up to 7.94+/-2.67pgcell-1) and smaller amounts of dinophysistoxin-1 (DTX-1) and pectenotoxin-2 (PTX-2). Prey capture was often observed after the ciliate had been attached to adhesive "mucus traps", which only appeared in the presence of Dinophysis cells. Before being attached to the mucus traps, M. rubrum cells reduced significantly their swimming frequency (from ~41 to 19+/-3 jumps min-1) after only 4h of initial contact with D. cf. ovum cells. M. rubrum survival was not affected in contact with purified OA, DTX-1 and PTX-2 solutions, but decreased significantly when the ciliate was exposed to cell-free or filtered culture medium from both D. cf. ovum and D. caudata, the latter containing moderate concentrations of free eicosapentaenoic acid and docosahexaenoic acid. The results thus indicate that Dinophysis combines the release of toxic compounds other than shellfish toxins, possibly free PUFAs, and a "mucus trap" to enhance its prey capture success by immobilizing and subsequently arresting M. rubrum cells. PMID- 28073510 TI - Tracing the origin of green macroalgal blooms based on the large scale spatio temporal distribution of Ulva microscopic propagules and settled mature Ulva vegetative thalli in coastal regions of the Yellow Sea, China. AB - From 2008 to 2016, massive floating green macroalgal blooms occurred annually during the summer months in the Yellow Sea. The original source of these blooms was traced based on the spatio-temporal distribution and species composition of Ulva microscopic propagules and settled Ulva vegetative thalli monthly from December 2012 to May 2013 in the Yellow Sea. High quantities of Ulva microscopic propagules in both the water column and sediments were found in the Pyropia aquaculture area along the Jiangsu coast before a green macroalgal bloom appeared in the Yellow Sea. The abundance of Ulva microscopic propagules was significantly lower in outer areas compared to in Pyropia aquaculture areas. A molecular phylogenetic analysis suggested that Ulva prolifera microscopic propagules were the dominant microscopic propagules present during the study period. The extremely low biomass of settled Ulva vegetative thalli along the coast indicated that somatic cells of settled Ulva vegetative thalli did not provide a propagule bank for the green macroalgal blooms in the Yellow Sea. The results of this study provide further supporting evidence that the floating green macroalgal blooms originate from green macroalgae attached to Pyropia aquaculture rafts along the Jiangsu coastline of the southern Yellow Sea. PMID- 28073511 TI - The importance of patient safety. PMID- 28073512 TI - Importance of GAP anion in the absence of clinical information: Description of one clinical case of severe oral methanol poisoning. PMID- 28073513 TI - A fatal drug interaction. PMID- 28073514 TI - Erratum to "Clinical consequences of using the new cardiovascular risk tables SCORE OP in patients aged over 65 years". PMID- 28073515 TI - Sentinel node in lung cancer. PMID- 28073516 TI - Early diagnosis of systemic amyloidosis by means of a transverse carpal ligament biopsy carried out during carpal tunnel syndrome surgery. AB - INTRODUCTION AND OBJECTIVE: The systematic analysis of a carpal transverse ligament (CTL) sample obtained during routine carpal tunnel syndrome (CTS) surgery may constitute a method of early diagnosis for systemic amyloidosis. MATERIAL AND METHODS: Prospective study carried out on 147 consecutive CTL samples collected from patients intervened for CTS at the University Hospital of Leon from April 2006 to May 2007. In those cases in which amyloid deposition was observed in the CTL sample, the study was completed with a fine needle aspiration biopsy (FNAB) of the subcutaneous fascia, using the Red Congo stain in both cases. Positive cases were referred to the Internal Medicine and/or Hematology departments, and their evolution was monitored for up to 8 years. RESULTS: CTL amyloid deposition was observed in 29 patients (19.7%), with a FNAB only being performed in 19 of them (65.5%). The test was positive in 11 cases (57.9%), and 4 patients in this subgroup (3% of the total) developed events attributable to amyloidosis over the following 3 years. CONCLUSIONS: A CTL routine biopsy carried out during CTS surgery may anticipate the systemic amyloidosis diagnosis. PMID- 28073517 TI - Predictive factors of long-term colorectal cancer survival after ultrasound controlled ablation of hepatic metastases. AB - BACKGROUND AND OBJECTIVE: The risk factors associated to long-term survival were assessed in patients with liver metastases of colorectal carcinoma undergoing ablative therapies. PATIENTS AND METHODS: Single-centre cohort study, retrospectively analysed and prospectively collected consecutive patients with unresectable metastatic liver disease of colorectal carcinoma treated with ablative therapies between 1996 and 2013. Factors associated with survival time were identified using Cox's proportional hazard model with time-dependent covariates. A forward variable selection based on Akaike information criterion was performed. Relative risk and 95% confidence intervals for each factor were calculated. Statistical significance was set as P<.05. RESULTS: Seventy-five patients with liver metastases of colorectal cancer, with a mean age of 65.6 (10.3) underwent 106 treatments. Variables selected were good quality of life (RR 0.308, 95% CI 0.150-0.632) and tumour extension (RR 3.070, 95% CI 1.776-5.308). The median overall survival was 18.5 months (95% CI 17.4-24.4). The survival prognosis in median was 13.5 vs. 23.4 months for patients with and without tumour extension, and 23.0 vs. 12.8 months for patients with good and fair or poor quality of life, respectively. CONCLUSIONS: Good quality of life and tumour extension were the only statistically significant predictors of long-term survival in patients of colorectal carcinoma with liver metastatic disease undergoing ablative treatment with ultrasound. PMID- 28073518 TI - Antisynthetase syndrome. Multidisciplinary evaluation and comittment. PMID- 28073519 TI - Erratum to "Pseudopseudohypoparathyroidism vs. progressive osseous heteroplasia in absence of family history". PMID- 28073520 TI - Livedo reticularis in the legs. PMID- 28073521 TI - Current status of iron metabolism: Clinical and therapeutic implications. AB - Hepcidin is the main regulator of iron metabolism and a pathogenic factor in iron disorders. Hepcidin deficiency causes iron overload, whereas hepcidin excess causes or contributes to the development of iron-restricted anaemia in chronic inflammatory diseases. We know the mechanisms involved in the synthesis of hepcidin and, under physiological conditions, there is a balance between activating signals and inhibitory signals that regulate its synthesis. The former include those related to plasmatic iron level and also those related to chronic inflammatory diseases. The most important inhibitory signals are related to active erythropoiesis and to matriptase-2. Knowing how hepcidin is synthesised has helped design new pharmacological treatments whose main target is the hepcidin. In the near future, there will be effective treatments aimed at correcting the defect of many of these iron metabolism disorders. PMID- 28073522 TI - Antisynthetase syndrome: Analysis of 11 cases. AB - INTRODUCTION: Antisynthetase syndrome (ASS) is characterised by a series of clinical manifestations such as myositis, fever, mechanic's hands and diffuse interstitial lung disease (ILD), all associated with positivity to antisynthetase antibodies. The presence of ILD will be that, to a great extent it will mark the response to treatment and prognosis. PATIENTS AND METHODS: Eleven cases of patients with ASS and pulmonary involvement in monitoring at a Pulmonary monographic consult in a third level hospital consult are described. RESULTS: Nine patients presented positivity to anti-Jo antibody and 2 to anti-PL12. Four patients' HRCT pattern showed NSIP, four UIP, one COP and 2 ground-glass opacity. A percentage of 73 were accompanied by bronchiectasis and bronchiolectasis and 27% honeycombing. Functional exploration was mainly affected by DLCO with up to 45% of the positive walking test. Corticodependence is highlighted, often requiring immunosuppressive treatment both chronically and in exacerbations. All patients maintain good prognosis so far. CONCLUSIONS: Patients with interstitial lung disease should have at least a determination of antisynthetase antibodies in order to identify this disease, better prognosis than other interstitial diseases such as idiopathic pulmonary fibrosis. PMID- 28073523 TI - Metabolic and physiological changes in Prymnesium parvum when grown under, and grazing on prey of, variable nitrogen:phosphorus stoichiometry. AB - Mixotrophy is found in almost all classes of phytoplankton in a wide range of aquatic habitats ranging from oligotrophic to eutrophic marine and freshwater systems. Few studies have addressed how the nutritional status of the predator and/or the prey affects mixotrophic metabolism despite the realization that mixotrophy is important ecologically. Laboratory experiments were conducted to examine changes in growth rates and physiological states of the toxic haptophyte Prymnesium parvum when fed Rhodomonas salina of varying nutritional status. Haemolytic activity of P. parvum and prey mortality of R. salina were also measured. P. parvum cultures grown to be comparatively low in nitrogen (low-N), phosphorus (low-P) or low in both nutrients (low-NP) were mixed with low-NP, low N, and low-P R. salina in all possible combinations, i.e., a 3*3 factorial design. N deficiency was obtained in the low-N cultures, while true P deficiency may not have been obtained in the low-P cultures. Mortality rates of R. salina (both due to ingestion and/or cell rupture as a function of grazing or toxic effects) were higher when R. salina cells were low-P, N-rich, regardless of the nutritional state of P. parvum. Mortality rates were, however, directly related to the initial prey:predator cell ratios. On the other hand, growth of the predator was a function of nutritional status and a significant positive correlation was observed between growth rates of P. parvum and cell-specific depletion rates of N, whereas no such relationship was found between P. parvum growth rates and depletion rates of P. In addition, the greatest changes in chlorophyll content and stoichiometric ratios of P. parvum were observed in high N:P conditions. Therefore, P. parvum may show enhanced success under conditions of higher inorganic N:P, which are likely favored in the future due to increases in eutrophication and altered nutrient stoichiometry driven by anthropogenic nutrient loads that are increasingly enriched in N relative to P. PMID- 28073524 TI - Distribution, occurrence and biotoxin composition of the main shellfish toxin producing microalgae within European waters: A comparison of methods of analysis. AB - Harmful algal blooms (HABs) are a natural global phenomena emerging in severity and extent. Incidents have many economic, ecological and human health impacts. Monitoring and providing early warning of toxic HABs are critical for protecting public health. Current monitoring programmes include measuring the number of toxic phytoplankton cells in the water and biotoxin levels in shellfish tissue. As these efforts are demanding and labour intensive, methods which improve the efficiency are essential. This study compares the utilisation of a multitoxin surface plasmon resonance (multitoxin SPR) biosensor with enzyme-linked immunosorbent assay (ELISA) and analytical methods such as high performance liquid chromatography with fluorescence detection (HPLC-FLD) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) for toxic HAB monitoring efforts in Europe. Seawater samples (n=256) from European waters, collected 2009 2011, were analysed for biotoxins: saxitoxin and analogues, okadaic acid and dinophysistoxins 1/2 (DTX1/DTX2) and domoic acid responsible for paralytic shellfish poisoning (PSP), diarrheic shellfish poisoning (DSP) and amnesic shellfish poisoning (ASP), respectively. Biotoxins were detected mainly in samples from Spain and Ireland. France and Norway appeared to have the lowest number of toxic samples. Both the multitoxin SPR biosensor and the RNA microarray were more sensitive at detecting toxic HABs than standard light microscopy phytoplankton monitoring. Correlations between each of the detection methods were performed with the overall agreement, based on statistical 2*2 comparison tables, between each testing platform ranging between 32% and 74% for all three toxin families illustrating that one individual testing method may not be an ideal solution. An efficient early warning monitoring system for the detection of toxic HABs could therefore be achieved by combining both the multitoxin SPR biosensor and RNA microarray. PMID- 28073525 TI - Delineation of the role of nutrient variability and dreissenids (Mollusca, Bivalvia) on phytoplankton dynamics in the Bay of Quinte, Ontario, Canada. AB - The Bay of Quinte, a Z-shaped embayment at the northeastern end of Lake Ontario, has a long history of eutrophication problems primarily manifested as spatially extensive algal blooms and predominance of toxic cyanobacteria. The purpose of this study was to identify the structural changes of the phytoplankton community induced by two environmental alterations: point-source phosphorus (P) loading reduction in the late 1970s and establishment of dreissenid mussels in the mid 1990s. A combination of statistical techniques was used to draw inference about compositional shifts of the phytoplankton assemblage, the consistency of the seasonal succession patterns along with the mechanisms underlying the algal biovolume variability in the Bay of Quinte over the past three decades. Based on a number of diversity and similarity indices, the algal assemblages in the upper and middle segments of the Bay are distinctly different from those typically residing in the outer segments. Our analysis also identified significant differences among the phytoplankton communities, representing the pre- and post-P control as well as the pre- and post-dreissenid invasion periods. Recent shifts in phytoplankton community composition were mainly associated with increased frequency of occurrence of toxin-producing Microcystis outbreaks and reduced biovolume of N2 fixers, such as Aphanizomenon and Anabaena. Bayesian hierarchical models were developed to elucidate the importance of different abiotic factors (light attenuation, water temperature, phosphorus, and ammonium) on total cyanobacteria, Microcystis, Aphanizomenon, and Anabaena relative biovolume. Our modelling exercise suggests that there is significant spatial heterogeneity with respect to the role of the factors examined, and thus total phosphorus alone cannot always explain the year-to-year variability of cyanobacteria succession patterns in the system. The lessons learned from the present analysis will be helpful to the water quality criteria setting process and could influence the management decisions in order to delist the system as an Area of Concern. PMID- 28073526 TI - Prevalence of algal toxins in Alaskan marine mammals foraging in a changing arctic and subarctic environment. AB - Current climate trends resulting in rapid declines in sea ice and increasing water temperatures are likely to expand the northern geographic range and duration of favorable conditions for harmful algal blooms (HABs), making algal toxins a growing concern in Alaskan marine food webs. Two of the most common HAB toxins along the west coast of North America are the neurotoxins domoic acid (DA) and saxitoxin (STX). Over the last 20 years, DA toxicosis has caused significant illness and mortality in marine mammals along the west coast of the USA, but has not been reported to impact marine mammals foraging in Alaskan waters. Saxitoxin, the most potent of the paralytic shellfish poisoning toxins, has been well documented in shellfish in the Aleutians and Gulf of Alaska for decades and associated with human illnesses and deaths due to consumption of toxic clams. There is little information regarding exposure of Alaskan marine mammals. Here, the spatial patterns and prevalence of DA and STX exposure in Alaskan marine mammals are documented in order to assess health risks to northern populations including those species that are important to the nutritional, cultural, and economic well-being of Alaskan coastal communities. In this study, 905 marine mammals from 13 species were sampled including; humpback whales, bowhead whales, beluga whales, harbor porpoises, northern fur seals, Steller sea lions, harbor seals, ringed seals, bearded seals, spotted seals, ribbon seals, Pacific walruses, and northern sea otters. Domoic acid was detected in all 13 species examined and had the greatest prevalence in bowhead whales (68%) and harbor seals (67%). Saxitoxin was detected in 10 of the 13 species, with the highest prevalence in humpback whales (50%) and bowhead whales (32%). Pacific walruses contained the highest concentrations of both STX and DA, with DA concentrations similar to those detected in California sea lions exhibiting clinical signs of DA toxicosis (seizures) off the coast of Central California, USA. Forty-six individual marine mammals contained detectable concentrations of both toxins emphasizing the potential for combined exposure risks. Additionally, fetuses from a beluga whale, a harbor porpoise and a Steller sea lion contained detectable concentrations of DA documenting maternal toxin transfer in these species. These results provide evidence that HAB toxins are present throughout Alaska waters at levels high enough to be detected in marine mammals and have the potential to impact marine mammal health in the Arctic marine environment. PMID- 28073527 TI - New scenario for speciation in the benthic dinoflagellate genus Coolia (Dinophyceae). AB - In this study, inter- and intraspecific genetic diversity within the marine harmful dinoflagellate genus Coolia Meunier was evaluated using isolates obtained from the tropics to subtropics in both Pacific and Atlantic Ocean basins. The aim was to assess the phylogeographic history of the genus and to clarify the validity of established species including Coolia malayensis. Phylogenetic analysis of the D1-D2 LSU rDNA sequences identified six major lineages (L1-L6) corresponding to the morphospecies Coolia malayensis (L1), C. monotis (L2), C. santacroce (L3), C. palmyrensis (L4), C. tropicalis (L5), and C. canariensis (L6). A median joining network (MJN) of C. malayensis ITS2 rDNA sequences revealed a total of 16 haplotypes; however, no spatial genetic differentiation among populations was observed. These MJN results in conjunction with CBC analysis, rDNA phylogenies and geographical distribution analyses confirm C. malayensis as a distinct species which is globally distributed in the tropical to warm-temperate regions. A molecular clock analysis using ITS2 rDNA revealed the evolutionary history of Coolia dated back to the Mesozoic, and supports the hypothesis that historical vicariant events in the early Cenozoic drove the allopatric differentiation of C. malayensis and C. monotis. PMID- 28073528 TI - Use of cholinesterase activity as an ecotoxicological marker to assess anatoxin a(s) exposure: Responses of two cladoceran species belonging to contrasting geographical regions. AB - The specificity of cholinesterase (ChE) activity to detect the presence of anatoxin-a(s) and sublethal effects of a 7-day exposure to Anabaena spiroides extract containing anatoxin-a(s) were assessed in two freshwater cladoceran species. Activities of ChE of both Pseudosida ramosa and Daphnia magna can be used to indicate the presence of the neurotoxin anatoxin-a(s), but not for the hepatotoxic microcystin. Activity of ChE of P. ramosa, however, performed better as a biomarker of exposure to A. spiroides than that of D. magna. Furthermore, sublethal exposure to A. spiroides extract significantly inhibited the ChE activity in P. ramosa and negatively affected both individual and population endpoints. For D. magna, the inhibition of ChE activity was not related to effects at higher levels of biological organization, since no direct effect was recorded on the individual and population endpoints. The activity of ChE in P. ramosa also proved to be a good predictor of chronic effects of the A. spiroides extract at higher levels of biological organization, since 48-h ChE inhibition was linked to the sublethal effects on the individual and population. These relationships could not be established for D. magna. Since relationships between the effects of A. spiroides extract at different levels of biological organization were species-specific, it can be concluded that the choice of test organism interferes with the accuracy of the environment risk assessment of this neurotoxin and, hence, the use of native species is recommended for its assessment. PMID- 28073529 TI - Seasonality and toxin production of Pyrodinium bahamense in a Red Sea lagoon. AB - Harmful algal blooms of the dinoflagellate Pyrodinium bahamense have caused human and economic losses in the last decades. This study, for the first time, documents a bloom of P. bahamense in the Red Sea. The alga was recurrently present in a semi-enclosed lagoon throughout nearly 2 years of observations. The highest cell densities (104-105cellsL-1) were recorded from September to beginning of December at temperatures and salinities of ~26-32 degrees C and ~41, respectively. The peak of the bloom was recorded mid-November, before a sharp decrease in cell numbers at the end of December. Minimum concentrations in summer were at ~103cellsL-1. A saxitoxin ELISA immunoassay of cultures and water samples confirmed the toxicity of the strain found in the Red Sea. Moreover, a gene expression analysis of the saxitoxin gene domain SxtA4 showed that transcript production peaked at the culmination of the bloom, suggesting a relation between transcript production, sudden cells increment-decline, and environmental factors. PMID- 28073530 TI - Variation in the abundance of Pseudo-nitzschia and domoic acid with surf zone type. AB - Most harmful algal blooms (HAB) originate away from the shore and, for them to endanger human health, they must be first transported to shore after which they must enter the surf zone where they can be feed upon by filter feeders. The last step in this sequence, entrance into the surf zone, depends on surf zone hydrodynamics. During two 30-day periods, we sampled Pseudo-nitzschia and particulate domoic acid (pDA) in and offshore of a more dissipative surf zone at Sand City, California (2010) and sampled Pseudo-nitzschia in and out of reflective surf zones at a beach and rocky shores at Carmel River State Beach, California (2011). At Sand City, we measured domoic acid in sand crabs, Emerita analoga. In the more dissipative surf zone, concentrations of Pseudo-nitzschia and pDA were an order of magnitude higher in samples from a rip current than in samples collected just seaward of the surf zone and were 1000 times more abundant than in samples from the shoals separating rip currents. Domoic acid was present in all the Emerita samples and varied directly with the concentration of pDA and Pseudo-nitzschia in the rip current. In the more reflective surf zones, Pseudo nitzschia concentrations were 1-2 orders of magnitude lower than in samples from 125 and 20m from shore. Surf zone hydrodynamics affects the ingress of Pseudo nitzschia into surf zones and the exposure of intertidal organisms to HABs on the inner shelf. PMID- 28073531 TI - Effects of the bloom of harmful benthic dinoflagellate Ostreopsis cf. ovata on the microphytobenthos community in the northern Adriatic Sea. AB - Composition and temporal variation of the microphytobenthos communities of the Conero Riviera (northern Adriatic Sea) were investigated in the course of an annual cycle, focusing on their relationships with blooms of the benthic dinoflagellate Ostreopsis cf. ovata. Sampling was carried out from March 2009 to March 2010 on undisturbed benthic substrata (macroalgae and pebbles). Samples for the study of microphytobenthos were collected with a monthly frequency, while those for the study of Ostreopsis bloom weekly. Benthic diatoms dominated the microphytobenthos communities for most of the annual cycle (except the summer), both in terms of abundance and biomass. In summer, cyanobacteria were dominant (54.04+/-9.18 and 24.29+/-11.11% of total abundance and biomass, respectively), while benthic dinoflagellates were an important component of the community in terms of biomass only at the peak of the Ostreopsis bloom in late summer (up to 91% of the total biomass). Among diatoms, the most abundant forms throughout the year were motile species (77.5+/-3.71% of the population), while erect diatoms formed the majority of the biomass in winter and spring (48.66+/-16.66 and 48.05+/-5.56% of total population, respectively). Diatoms were mainly affected by DIN availability, while the patterns of biomass of O. cf. ovata and cyanobacteria were related to salinity and temperature. The biomass of Ostreopsis was also affected by the availability of phosphorus. The results of this study suggest that the proliferation of Ostreopsis affected the structure of the benthic diatom community: motile diatoms were significantly more abundant during the Ostreopsis bloom peak than during the rest of summer, probably because they benefited from the abundant mucilaginous mat covering the benthic substrata. In the course of the O. cf. ovata bloom the diversity of the microphytobenthos was significantly lower than during the rest of the year, suggesting an influence of both the shading produced by the mucous mat and allelopathic compounds possibly produced by O. cf. ovata. PMID- 28073532 TI - Toxigenic algae and associated phycotoxins in two coastal embayments in the Ebro Delta (NW Mediterranean). AB - Harmful Algal Bloom (HAB) surveillance is complicated by high diversity of species and associated phycotoxins. Such species-level information on taxonomic affiliations and on cell abundance and toxin content is, however, crucial for effective monitoring, especially of aquaculture and fisheries areas. The aim addressed in this study was to determine putative HAB taxa and related phycotoxins in plankton from aquaculture sites in the Ebro Delta, NW Mediterranean. The comparative geographical distribution of potentially harmful plankton taxa was established by weekly field sampling throughout the water column during late spring-early summer over two years at key stations in Alfacs and Fangar embayments within the Ebro Delta. Core results included not only confirmed identification of HAB taxa that are common for the time period and geographical area, but also provided evidence of potentially new taxa. At least 25 HAB taxa were identified to species level, and an additional six genera were confirmed, by morphological criteria under light microscopy and/or by molecular genetics approaches involving qPCR and next generation DNA pyrosequencing. In particular, new insights were gained by the inclusion of molecular techniques, which focused attention on the HAB genera Alexandrium, Karlodinium, and Pseudo nitzschia. Noteworthy is the discovery of Azadinium sp., a potentially new HAB species for this area, and Gymnodinium catenatum or Gymnodinium impudicum by means of light microscopy. In addition, significant amounts of the neurotoxin domoic acid (DA) were found for the first time in phytoplankton samples in the Ebro Delta. While the presence of the known DA-producing diatom genus Pseudo nitzschia was confirmed in corresponding samples, the maximal toxin concentration did not coincide with highest cell abundances of the genus and the responsible species could not be identified. Combined findings of microscopic and molecular detection approaches underline the need for a synoptic strategy for HAB monitoring, which integrates the respective advantages and compensates for limitations of individual methods. PMID- 28073533 TI - Effects of N and P availability on carbon allocation in the toxic dinoflagellate Ostreopsis cf. ovata. AB - Blooms of the toxic dinoflagellate Ostreopsis cf. ovata are usually associated with shallow and calm coastal waters, characterized by low nutrient concentrations. The algal cells typically cover the benthic substrates, such as the macroalgal and invertebrate communities and rocks, forming a mucilaginous film. Data reported on O. cf. ovata toxin production observed under both field and culture conditions show high variability in terms of toxic profile and cellular content; little is known about the environmental and physiological aspects which regulate the toxin dynamics. In this study, O. cf. ovata physiology was investigated using batch cultures supplied with nutrient concentrations similar to those found in the Adriatic Sea during the recurrent blooms and the observed cellular dynamics were compared with those found in a culture grown under optimal conditions, used as a reference. Data on the cellular C, N and P content during the growth highlighted a possible important role of the cellular nutritional status in regulating the toxin production that resulted to be promoted under specific intervals of the C:N and C:P ratios. The variable toxicity found for O. cf. ovata in various geographic areas could be related to the different in situ prevalent environmental conditions (e.g., nutrient concentrations) which affect the cellular elemental composition and carbon allocation. The obtained results strongly suggest that in the environment toxin production is steadily sustained by a low and constant nutrient supply, able to maintain appropriate cellular C:N (>12) or C:P (>170) ratios for a long period. These results explain to some extent the variability in toxicity and growth dynamics observed in blooms occurring in the different coastal areas. PMID- 28073534 TI - Turbulence increases the risk of microcystin exposure in a eutrophic lake (Lake Taihu) during cyanobacterial bloom periods. AB - Toxic cyanobacterial harmful algal blooms (CyanoHABs) have posed serious water use and public health threats because of the toxins they produce, such as the microcystins (MCs). The direct physical effects of turbulence on MCs, however, have not yet been addressed and is still poorly elucidated. In this study, a 6 day mesocosm experiment was carried out to evaluate the effects of wind wave turbulence on the competition of toxic Microcystis and MCs production in highly eutrophicated and turbulent Lake Taihu, China. Under turbulent conditions, MCs concentrations (both total and extracellular) significantly increased and reached a maximum level 3.4 times higher than in calm water. Specifically, short term (~3 days) turbulence favored the growth of toxic Microcystis species, allowing for the accumulation of biomass which also triggered the increase in MCs toxicity. Moreover, intense turbulence raises the shear stress and could cause cell mechanical damage or cellular lysis resulting in cell breakage and leakage of intracellular materials including the toxins. The results indicate that short term (~3 days) turbulence is beneficial for MCs production and release, which increase the potential exposure of aquatic organisms and humans. This study suggests that the importance of water turbulence in the competition of toxic Microcystis and MCs production, and provides new perspectives for control of toxin in CyanoHABs-infested lakes. PMID- 28073535 TI - New oxylipins produced at the end of a diatom bloom and their effects on copepod reproductive success and gene expression levels. AB - Diatoms are dominant photosynthetic organisms in the world's oceans and are considered essential in the transfer of energy to higher trophic levels. However, these unicellular organisms produce secondary metabolites deriving from the oxidation of fatty acids, collectively termed oxylipins, with negative effects on predators, such as copepods, that feed on them (e.g. reduction in survival, egg production and hatching success) and, indirectly, on higher trophic levels. Here, a multidisciplinary study (oxylipin measurements, copepod fitness, gene expression analyses, chlorophyll distribution, phytoplankton composition, physico chemical characteristics) was carried out at the end of the spring diatom bloom in April 2011 in the Northern Adriatic Sea (Mediterranean Sea) in order to deeply investigate copepod-diatom interactions, chemical communication and response pathways. The results show that the transect with the lowest phytoplankton abundance had the lowest copepod egg production and hatching success, but the highest oxylipin concentrations. In addition, copepods in both the analyzed transects showed increased expression levels of key stress-related genes (e.g. heat-shock proteins, catalase, glutathione S-transferase, aldehyde dehydrogenase) compared to control laboratory conditions where copepods were fed with the dinoflagellate Prorocentrum minimum which does not produce any oxylipins. New oxylipins that have never been reported before for microalgae are described for the first time, giving new insights into the complex nature of plant-animal signaling and communication pathways at sea. This is also the first study providing insights on the copepod response during a diatom bloom at the molecular level. PMID- 28073536 TI - Microelectrode array (MEA) platform as a sensitive tool to detect and evaluate Ostreopsis cf. ovata toxicity. AB - In the last decade, the occurrence of harmful dinoflagellate blooms of the genus Ostreopsis has increased both in frequency and in geographic distribution with adverse impacts on public health and the economy. Ostreopsis species are producers of palytoxin-like toxins (putative palytoxin and ovatoxins) which are among the most potent natural non-protein compounds known to date, exhibiting extreme toxicity in mammals, including humans. Most existing toxicological data are derived from in vivo mouse assay and are related to acute effects of pure palytoxin, without considering that the toxicity mechanism of dinoflagellates can be dependent on the varying composition of complex biotoxins mixture and on the presence of cellular components. In this study, in vitro neuronal networks coupled to microelectrode array (MEA)-based system are proposed, for the first time, as sensitive biosensors for the evaluation of marine alga toxicity on mammalian cells. Toxic effect was investigated by testing three different treatments of laboratory cultured Ostreopsis cf. ovata cells: filtered and re suspended algal cells; filtered, re-suspended and sonicated algal cells; conditioned growth medium devoid of algal cells. The great sensitivity of this system revealed the mixture of PTLX-complex analogues naturally released in the growth medium and the different potency of the three treatments to inhibit the neuronal network spontaneous electrical activity. Moreover, by means of the multiparametric analysis of neuronal network activity, the approach revealed a different toxicity mechanism of the cellular component compared to the algal conditioned growth medium, highlighting the potential active role of the first treatment. PMID- 28073537 TI - Role of resting cysts in Chilean Alexandrium catenella dinoflagellate blooms revisited. AB - The detection of sparse Alexandrium catenella-resting cysts in sediments of southern Chilean fjords has cast doubts on their importance in the recurrence of massive toxic dinoflagellate blooms in the region. The role of resting cysts and the existence of different regional Chilean populations was studied by culturing and genetic approaches to define: (1) cyst production; (2) dormancy period; (3) excystment success; (4) offspring viability and (5) strain mating compatibility. This study newly revealed a short cyst dormancy (minimum 69 days), the role of key abiotic factors (in decreasing order salinity, irradiance, temperature and nutrients) controlling cyst germination (max. 60%) and germling growth rates (up to 0.36-0.52div.day-1). Amplified fragment length polymorphism (AFLP) characterization showed significant differences in genetic distances (GD) among A. catenella populations that were primarily determined by the geographical origin of isolates and most likely driven by oceanographic dispersal barriers. A complex heterothallic mating system pointed to variable reproductive compatibility (RCs) among Chilean strains that was high among northern (Los Lagos/North Aysen) and southern populations (Magallanes), but limited among the genetically differentiated central (South Aysen) populations. Field cyst surveys after a massive 2009 bloom event revealed the existence of exceptional high cyst densities in particular areas of the fjords (max. 14.627cystscm-3), which contrast with low cyst concentrations (<221.3cystscm-3) detected by previous oceanographic campaigns. In conclusion, the present study suggests that A. catenella resting cysts play a more important role in the success of this species in Chilean fjords than previously thought. Results from in vitro experiments suggest that pelagic-benthic processes can maintain year-round low vegetative cell concentrations in the water column, but also can explain the detection of high cysts aggregations after the 2009-bloom event. Regional drivers that lead to massive outbreaks, however, are still unknown but potential scenarios are discussed. PMID- 28073538 TI - Margalef revisited: A new phytoplankton mandala incorporating twelve dimensions, including nutritional physiology. AB - Building on the classic depiction of the progression from a diatom to a dinoflagellate bloom as a function of nutrients and turbulence, known as the "Margalef mandala", a new conceptual model or mandala is presented here. The new mandala maps twelve response or effects traits, or environmental characteristics, related to different phytoplankton functional types: (1) relative preference for chemically reduced vs chemically oxidized forms of nitrogen; (2) relative availability of inorganic nitrogen and phosphorus; (3) adaptation to high vs low light and the tendency to be autotrophic vs mixotrophic; (4) cell motility; (5) environmental turbulence; (6) pigmentation quality; (7) temperature; (8) cell size; (9) relative growth rate; (10) relative production of bioactive compounds such as toxins or reactive oxygen species (ROS); (11) r vs K strategy; and (12) fate of the production in terms of grazing. The new mandala serves to highlight the differences and trade-offs between traits and/or environmental conditions, and illustrates some traits tend to track each other, a concept that may be helpful in trait-based modeling approaches and in understanding environmental factors associated with harmful algal blooms. It is hoped that this new mandala captures some of our recent insight into phytoplankton physiology and functional traits, and has contemporary relevance in light of anthropogenic changes in nutrient form and ratio. PMID- 28073539 TI - Physical processes leading to the development of an anomalously large Cochlodinium polykrikoides bloom in the East sea/Japan sea. AB - An anomalously large Harmful Algal Bloom (HAB) was observed in the southwest coast of the East/Japan Sea (hereafter the East Sea) during the summer of 2013. During this time period, the presence of Cochlodinium polykrikoides (C. polykrikoides) was detected by the Geostationary Ocean Color Imager (GOCI) and validated by in-situ observations. GOCI observations have been available since 2011, thus allowingto examine various stages of the physical condition of the developing C. polykrikoides bloom, thereby other multi-satellite and buoy measurements obtained between 2011 and 2013. Research results indicate that this HAB is related to four processes: the transport of C. polykrikoides from the south coast of Korea to the HAB area; a relatively high insolation; continuous coastal upwelling; and a favorable Sea Surface Temperature (SST) for C.polykrikoide growth. In examination of the main transport mechanisms, geostrophic current measurements were used to estimate the flow trajectories, showing water from the south coast to the HAB area off the southeast coast of Korea. Result shows that ninety percent of the water from the south coast reached the HAB area in 2013. Furthermore, to examine the insolation mechanism, the Photosynthetically available radiation (PAR) value was derived from the Moderate Resolution Imaging Spectoradiometer (MODIS), showing that PAR values were relatively high in the HAB area during HAB period (47Einm-1day-1). Moreover, Upwelling age (UA) was calculated in order to investigate the strength of coastal upwelling events, which were found to support relatively high UA values during the HAB period. The mean UA value during the HAB period was 1.01, higher than those in 2011 and 2012 which were 0.61 and 0.76, respectively. Finally, SST in the HAB area was also analyzed to examine which conditions were most favorable for HAB growth. Therefore, the results of this study suggest that the four mechanisms can explain the relative contributions of the anomalously HAB development observed off the southeast coast of Korea. PMID- 28073540 TI - Phylogenetic structure of bacterial assemblages co-occurring with Ostreopsis cf. ovata bloom. AB - Extensive blooms of the toxic epiphytic/benthic dinoflagellate Ostreopsis cf. ovata are being reported with increasing frequency and spatial distribution in temperate coastal regions including the Mediterranean. These blooms are of human and environmental health concern due to the production of isobaric palytoxin and a wide range of ovatoxins by Ostreopsis cf. ovata. Bacterial-microalgal interactions are important regulators in algal bloom dynamics and potentially toxin dynamics. This study investigated the bacterial assemblages co-occurring with O. cf. ovata (OA) and from ambient seawaters (SW) during the early and peak phases of bloom development in NW Adriatic Sea. Fractions of the bacterial assemblages co-occurring with O. cf. ovata (OA) and more closely associated to the mucilage layer (LA) embedding O. cf. ovata cells were also reported. In total, 14 bacterial phyla were detected by targeted 454 pyrosequencing of the 16S rRNA gene. The dominant bacterial phyla in the OA assemblages were Proteobacteria and Bacteroidetes; while at the class level, Alphaproteobacteria were the most abundant (83 and 66%, relative abundance, early and peak bloom phases), followed by Flavobacteria (7 and 19%, early and peak phases). Actinobacteria and Cyanobacteria were of minor importance (<5% of the relative bacterial abundance each). Gammaproteobacteria showed a notably presence in OA assemblage only at the early phase of the bloom (genus Haliea, 13%). The Alphaproteobacteria were predominately composed by the genera Ruegeria, Jannaschia and Erythrobacter which represented about half of the total phylotypes' contribution of OA at both early and peak phases of the O. cf. ovata bloom, suggesting interactions between this consortium and the microalga. Moreover, the highest contribution of Ruegeria (30% of the total phylotypes) was observed at the early phase of the bloom in LA assemblage. Microbial assemblages associated with the ambient seawaters while being also dominated by Alphaproteobacteria and Flavobacteria were partially distinct from those associated with O. cf. ovata due to the presence of genera almost not retrieved in the latter assemblages. PMID- 28073541 TI - The main nitrate transporter of the dinoflagellate Lingulodinium polyedrum is constitutively expressed and not responsible for daily variations in nitrate uptake rates. AB - Dinoflagellates are unicellular eukaryotes capable of forming spectacular harmful algal blooms (HABs). Eutrophication of coastal waters by fertilizer runoff, nitrate in particular, has contributed to recent increases in the frequency, magnitude and geographic extent of HABs. Although physiological nitrate uptake and assimilation in dinoflagellates have often been measured in the field and in the laboratory, no molecular components involved in nitrate transport have yet been reported. This study reports the first identification and characterization of dinoflagellate nitrate transporters, found in the transcriptome of the bloom forming Lingulodinium polyedrum. Of the 23 putative transporters found by BLAST searches, only members of the nitrate transporter 2 (NRT2) family contained all key amino acids known to be essential for nitrate transport. The dinoflagellate NRT2 sequences have 12 predicted transmembrane domains, as do the NRT2 sequences of bacteria, plants and fungi. The NRT2 sequences in Lingulodinium appear to have two different evolutionary origins, as determined by phylogenetic analyses. The most expressed transcript of all putative nitrate transporters was determined by RNA-Seq to be LpNRT2.1. An antibody raised against this transporter showed that the same amount of protein was found at different times over the light dark cycle and with different sources of N. Finally, global nitrate uptake was assessed using a 15N tracer, which showed that the process was not under circadian-control as previously suggested, but simply light-regulated. PMID- 28073542 TI - The rise of toxic benthic Phormidium proliferations: A review of their taxonomy, distribution, toxin content and factors regulating prevalence and increased severity. AB - There has been a marked increase in the distribution, intensity and frequency of proliferations of some species of the benthic mat-forming, toxin-producing genus Phormidium in rivers globally over the last decade. This review summarises current knowledge on their taxonomy, distribution, toxin content, environmental drivers of proliferations, and monitoring and management strategies in New Zealand. Although toxic Phormidium proliferation occurs in rivers worldwide little is known about these factors in most countries. Proliferations, defined as >20% cover of a riverbed, have been identified in 103 rivers across New Zealand. Morphological and molecular data indicate the main species responsible is Phormidium autumnale. In New Zealand Phormidium produces anatoxins (anatoxin-a, homoanatoxin-a, dihydroanatoxin-a, and dihydrohomoanatoxin-a) and these were detected in 67% of 771 samples from 40 rivers. The highest concentration measured was 712mgkg-1 dried weight (Oreti River, Southland), with considerable spatial and temporal variability in anatoxin concentrations between and within rivers. A synthesis of field based studies suggests that Phormidium proliferations are most likely when there is some enrichment of dissolved inorganic nitrogen but when water-column dissolved reactive phosphorus is less than 0.01mgL-1. Once established Phormidium-dominated mats trap sediment and internal mat biogeochemistry can mobilise sediment-bound phosphorus, which is then available for growth. Removal of Phormidium-dominated mats is primarily due to shear stress and substrate disturbance, although there is also evidence for autogenic detachment. A combination of factors including; changes to riparian margins, increased nitrate and fine sediment loads, and alterations in flow regimes are likely to have contributed to the rise in Phormidium proliferations. PMID- 28073543 TI - Corrigendum to 'Production of ciguatoxin and maitotoxin by strains of Gambierdiscus australes, G. pacificus and G. polynesiensis (Dinophyceae) isolated from Rarotonga, Cook Islands' [Harmful Algae 39 (2014) 185-190]. PMID- 28073544 TI - Corrigendum to "Cyanobacteria and cyanotoxins in fishponds and their effects on fish tissue" [Harmful Algae 55 (2016) 66-76]. PMID- 28073546 TI - Killing potential protist predators as a survival strategy of the newly described dinoflagellate Alexandrium pohangense. AB - Blooms caused by some species belonging to the dinoflagellate genus Alexandrium are known to cause large-scale mortality of fish. Thus, the dynamics of these species is important and of concern to scientists, officials, and people in the aquaculture industry. To understand the dynamics of such species, their growth and mortality due to predation need to be assessed. The newly described dinoflagellate Alexandrium pohangense is known to grow slowly, with a maximum autotrophic growth rate of 0.1d-1. Thus, it may not form bloom patches if its mortality due to predation is high. Therefore, to explore the mortality of A. pohangense due to predation, feeding on this species by the common heterotrophic dinoflagellates Gyrodinium dominans, Gyrodinium moestrupii, Luciella masanensis, Noctiluca scintillans, Oxyrrhis marina, Oblea rotunda, Polykrikos kofoidii, and Pfiesteria piscicida, as well as by the ciliate Tiarina fusus, was examined. None of these potential predators was able to feed on A. pohangense. In contrast, these potential predators were killed and their bodies were dissolved when incubated with A. pohangense cells or cell-free culture filtrates. The survival of G. moestrupii, O. marina, P. kofoidii, and T. fusus on incubation with 10cellsml-1 of A. pohangense was 20-60%, while that at the equivalent culture filtrates was 20-70%. With increasing A. pohangense cell-concentration (up to 1000cellsml-1 or equivalent culture filtrates), the survival rate of G. moestrupii, O. marina, P. kofoidii, and T. fusus rapidly decreased. The lethal concentration (LC50) for G. moestrupii, O. marina, P. kofoidii, and T. fusus at the elapsed time of 24h with A. pohangense cells (cultures of 11.4, 13.3, 1.6, and 3.3cellsml-1, respectively) was lower than that with A. pohangense filtrates (culture filtrates of 35.5, 30.6, 5.5, and 5.0cellsml-1, respectively). Furthermore, most of the ciliates and heterotrophic dinoflagellates in the water collected from the coast of Tongyoung, Korea, were killed when incubated with cultures of 1000 A. pohangense cells ml-1 and equivalent culture filtrates. The relatively slow growing A. pohangense may form blooms by reducing mortality due to predation through killing potential protist predators. PMID- 28073545 TI - A validated UPLC-MS/MS method for the surveillance of ten aquatic biotoxins in European brackish and freshwater systems. AB - Over the past few decades, there has been an increased frequency and duration of cyanobacterial Harmful Algal Blooms (HABs) in freshwater systems globally. These can produce secondary metabolites called cyanotoxins, many of which are hepatotoxins, raising concerns about repeated exposure through ingestion of contaminated drinking water or food or through recreational activities such as bathing/swimming. An ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) multi-toxin method has been developed and validated for freshwater cyanotoxins; microcystins-LR, -YR, -RR, -LA, -LY and -LF, nodularin, cylindrospermopsin, anatoxin-a and the marine diatom toxin domoic acid. Separation was achieved in around 9min and dual SPE was incorporated providing detection limits of between 0.3 and 5.6ng/L of original sample. Intra- and inter day precision analysis showed relative standard deviations (RSD) of 1.2-9.6% and 1.3-12.0% respectively. The method was applied to the analysis of aquatic samples (n=206) from six European countries. The main class detected were the hepatotoxins; microcystin-YR (n=22), cylindrospermopsin (n=25), microcystin-RR (n=17), microcystin-LR (n=12), microcystin-LY (n=1), microcystin-LF (n=1) and nodularin (n=5). For microcystins, the levels detected ranged from 0.001 to 1.51MUg/L, with two samples showing combined levels above the guideline set by the WHO of 1MUg/L for microcystin-LR. Several samples presented with multiple toxins indicating the potential for synergistic effects and possibly enhanced toxicity. This is the first published pan European survey of freshwater bodies for multiple biotoxins, including two identified for the first time; cylindrospermopsin in Ireland and nodularin in Germany, presenting further incentives for improved monitoring and development of strategies to mitigate human exposure. PMID- 28073547 TI - Morphology, molecular phylogeny and azaspiracid profile of Azadinium poporum (Dinophyceae) from the Gulf of Mexico. AB - Azadinium poporum produces a variety of azaspiracids and consists of several ribotypes, but information on its biogeography is limited. A strain of A. poporum (GM29) was incubated from a Gulf of Mexico sediment sample. Strain GM29 was characterized by a plate pattern of po, cp, x, 4', 3a, 6", 6C, 5S, 6''', 2'''', a distinct ventral pore at the junction of po and the first two apical plates, and a lack of an antapical spine, thus fitting the original description of A. poporum. The genus Azadinium has not been reported in waters of the United States of America before this study. Molecular phylogeny, based on large subunit ribosomal DNA (LSU rDNA) and internal transcribed spacer (ITS) sequences, reveals that strain GM29 is nested within the well-resolved A. poporum complex, but forms a sister clade either to ribotype B (ITS) or ribotype C (LSU). It is, therefore, designated as a new ribotype, termed as ribotype D. LSU and ITS sequences similarity among different ribotypes of A. poporum ranges from 95.4% to 98.2%, and from 97.1% to 99.2% respectively, suggesting that the LSU fragment is a better candidate for molecular discrimination. Azaspiracid profiles were analyzed using LC-MS/MS and demonstrate that strain GM29 produces predominantly AZA-2 with an amount of 45fg/cell. The results suggest that A. poporum has a wide distribution and highlights the risk potential of azaspiracid intoxication in the United States. PMID- 28073548 TI - Cyanobacteria and cyanotoxins in fishponds and their effects on fish tissue. AB - Cyanobacteria can produce toxic metabolites known as cyanotoxins. Common and frequently investigated cyanotoxins include microcystins (MCs), nodularin (NOD) and saxitoxins (STXs). During the summer of 2011 extensive cyanobacterial growth was found in several fishponds in Serbia. Sampling of the water and fish (common carp, Cyprinus carpio) was performed. Water samples from 13 fishponds were found to contain saxitoxin, microcystin, and/or nodularin. LC-MS/MS showed that MC-RR was present in samples of fish muscle tissue. Histopathological analyses of fish grown in fishponds with cyanotoxin production showed histopathological damage to liver, kidney, gills, intestines and muscle tissues. This study is among the first so far to report severe hyperplasia of intestinal epithelium and severe degeneration of muscle tissue of fish after cyanobacterial exposure. These findings emphasize the importance of cyanobacterial and cyanotoxin monitoring in fishponds in order to recognize cyanotoxins and their potential effects on fish used for human consumption and, further, on human health. PMID- 28073549 TI - Mass entrapment and lysis of Mesodinium rubrum cells in mucus threads observed in cultures with Dinophysis. AB - The entrapment and death of the ciliate Mesodinium rubrum in the mucus threads in cultures with Dinophysis is described and quantified. Feeding experiments with different concentrations and predator-prey ratios of Dinophysis acuta, Dinophysis acuminata and M. rubrum to study the motility loss and aggregate formation of the ciliates and the feeding behaviour of Dinophysis were carried out. In cultures of either Dinophysis species, the ciliates became entrapped in the mucus, which led to the formation of immobile aggregates of M. rubrum and subsequent cell lysis. The proportion of entrapped ciliates was influenced by the concentration of Dinophysis and the ratio of predator and prey in the cultures. At high cell concentrations of prey (136 cells mL-1) and predator (100 cells mL-1), a maximum of 17% of M. rubrum cells became immobile and went through cell lysis. Ciliates were observed trapped in the mucus even when a single D. acuminata cell was present in a 3.4mL growth medium. Both Dinophysis species were able to detect immobile or partly immobile ciliates at a distance and circled around the prey prior to the capture with a stretched out peduncle. Relatively high entrapment and lysis of M. rubrum cells in the mucus threads indicates that under certain conditions Dinophysis might have a considerable impact on the population of M. rubrum. PMID- 28073550 TI - Growth and bioactive secondary metabolites of arctic Protoceratium reticulatum (Dinophyceae). AB - Harmful algal blooms are mainly caused by marine dinoflagellates and are known to produce potent toxins that may affect the ecosystem, human activities and health. Such events have increased in frequency and intensity worldwide in the past decades. Numerous processes involved in Global Change are amplified in the Arctic, but little is known about species specific responses of arctic dinoflagellates. The aim of this work was to perform an exhaustive morphological, phylogenetical and toxinological characterization of Greenland Protoceratium reticulatum and, in addition, to test the effect of temperature on growth and production of bioactive secondary metabolites. Seven clonal isolates, the first isolates of P. reticulatum available from arctic waters, were phylogenetically characterized by analysis of the LSU rDNA. Six isolates were further characterized morphologically and were shown to produce both yessotoxins (YTX) and lytic compounds, representing the first report of allelochemical activity in P. reticulatum. As shown for one of the isolates, growth was strongly affected by temperature with a maximum growth rate at 15 degrees C, a significant but slow growth at 1 degrees C, and cell death at 25 degrees C, suggesting an adaptation of P. reticulatum to temperate waters. Temperature had no major effect on total YTX cell quota or lytic activity but both were affected by the growth phase with a significant increase at stationary phase. A comparison of six isolates at a fixed temperature of 10 degrees C showed high intraspecific variability for all three physiological parameters tested. Growth rate varied from 0.06 to 0.19d-1, and total YTX concentration ranged from 0.3 to 15.0pg YTXcell-1 and from 0.5 to 31.0pgYTXcell-1 at exponential and stationary phase, respectively. All six isolates performed lytic activity; however, for two isolates lytic activity was only detectable at higher cell densities in stationary phase. PMID- 28073551 TI - The common bloom-forming cyanobacterium Microcystis is prone to a wide array of microbial antagonists. AB - Many degraded waterbodies around the world are subject to strong proliferations of cyanobacteria - notorious for their toxicity, high biomass build-up and negative impacts on aquatic food webs - the presence of which puts serious limits on the human use of affected water bodies. Cyanobacterial blooms are largely regarded as trophic dead ends since they are a relatively poor food source for zooplankton. As a consequence, their population dynamics are generally attributed to changes in abiotic conditions (bottom-up control). Blooms however generally contain a vast and diverse community of micro-organisms of which some have shown devastating effects on cyanobacterial biomass. For Microcystis, one of the most common bloom-forming cyanobacteria worldwide, a high number of micro-organisms (about 120 taxa) including viruses, bacteria, microfungi, different groups of heterotrophic protists, other cyanobacteria and several eukaryotic microalgal groups are currently known to negatively affect its growth by infection and predation or by the production of allelopathic compounds. Although many of these specifically target Microcystis, sharp declines of Microcystis biomass in nature are only rarely assigned to these antagonistic microbiota. The commonly found strain specificity of their interactions may largely preclude strong antagonistic effects on Microcystis population levels but may however induce compositional shifts that can change ecological properties such as bloom toxicity. These highly specific interactions may form the basis of a continuous arms race (co-evolution) between Microcystis and its antagonists which potentially limits the possibilities for (micro)biological bloom control. PMID- 28073552 TI - Ciguatera fish poisoning: Incidence, health costs and risk perception on Moorea Island (Society archipelago, French Polynesia). AB - Ciguatera Fish Poisoning (CFP) is a non-bacterial seafood poisoning well characterized in the remote archipelagos of French Polynesia, yet poorly documented in the Society archipelago, most notably on Moorea, the second most populated island in French Polynesia, which counts a high proportion of fishermen fishing on a regular basis. To address this knowledge gap, a holistic study of the ciguatera issue was conducted on Moorea. First, ciguatera risk was analysed in terms of incidence rate, fish species most commonly involved and risk stratification in Moorea lagoon based on 2007-2013 epidemiological data. A mean incidence rate of 8 cases per 10,000 inhabitants for the study period and an average under-reporting rate of 54% were found. Taking into account hospitalization and medication fees, and loss of productive days, the health related costs due to CFP were estimated to be USD $1613 and $749 for each reported and unreported case, respectively, with an overall cost of USD $241,847 for the study period. Comparison of the present status of CFP on Moorea with a risk map established in the late 1970's showed that the spatial distribution of the risk has stayed relatively stable in time, with the north shore of the island remaining the most prone to ciguatera. Evaluation of the current knowledge on CFP among different populations groups, i.e. fishermen, residents and visitors, was also conducted through direct and indirect interviews. About half of the fishermen interviewed were actually able to identify risky fishing areas. While, overall, the CFP risk perception in the fishing community of Moorea seemed accurate, although not scientifically complete, it was sufficient for the safe practice of their fishing activities. This may be due in part to adaptive responses adopted by 36% of the fishermen interviewed, such as the avoidance of either high-risk fishing sites or toxic species. At the residents and visitors' level, the study points out a striking lack of awareness of the CFP issue among visitors, as compared to local residents. Indeed, less than 25% of Moorea visitors vs. an average of 98% in residents were aware of CFP or of its presence on the island. Interestingly, evaluation of the fish consumption preferences showed that 70% of visitors do not consume lagoon fish during their stay, not for fear of CFP, but mainly due to the lack of availability of these species in recreational facilities or because they have nutritional preference for pelagic fish. This lack of awareness, along with the report by several CFP patients of the consumption of fish species yet banned for sale, stress the need for improved communication efforts on this critical issue among both residents and visitors on Moorea. The implementation of a public outreach strategy is proposed, based on both existing information networks and low-cost communication actions through information displays at various strategic locations, e.g. Tahiti-Faa'a international airport, the ferry boat station, recreational facilities, as well as the major trading points on Moorea Island. PMID- 28073553 TI - The effects of light intensity on the growth of Japanese Gambierdiscus spp. (Dinophyceae). AB - Marine toxic dinoflagellates of the genus Gambierdiscus are the causative agents of ciguatera fish poisoning (CFP), a form of seafood poisoning that is widespread in tropical, subtropical and temperate regions worldwide. The distributions of Gambierdiscus australes, Gambierdiscus scabrosus and two phylotypes of Gambierdiscus spp. type 2 and type 3 have been reported for the waters surrounding the main island of Japan. To explore the bloom dynamics and the vertical distribution of these Japanese species and phylotypes of Gambierdiscus, the effects of light intensity on their growth were tested, using a photoirradiation-culture system. The relationship between the observed growth rates and light intensity conditions for the four species/phylotypes were formulated at R>0.92 (p<0.01) using regression analysis and photosynthesis-light intensity (P-L) model. Based on this equation, the optimum light intensity (Lmax) and the semi-optimum light intensity range (Ls-opt) that resulted in the maximum growth rate (MUmax) and >=80% MUmax values of the four species/phylotypes, respectively, were as follows: (1) the Lmax and Ls-opt of G. australes were 208MUmol photons m-2s-1 and 91-422MUmol photons m-2s-1, respectively; (2) those of G. scabrosus were 252 and 120-421MUmol photons m-2s-1, respectively; (3) those of Gambierdiscus sp. type 2 were 192 and 75-430MUmol photons m-2s-1, respectively; and (4) those of Gambierdiscus sp. type 3 were >=427 and 73 427MUmol photons m-2s-1, respectively. All four Gambierdiscus species/phylotypes required approximately 10MUmol photons m-2s-1 to maintain growth. The light intensities in coastal waters at a site in Tosa Bay were measured vertically at 1m intervals once per season. The relationships between the observed light intensity and depth were formulated using Beer's Law. Based on these equations, the range of the attenuation coefficients at Tosa Bay site was determined to be 0.058-0.119m-1. The values 1700MUmol photons m-2s-1, 500MUmol photons m-2s-1, and 200MUmol photons m-2s-1 were substituted into the equations to estimate the vertical profiles of light intensity at sunny midday, cloudy midday and rainy midday, respectively. Based on the regression equations coupled with the empirically determined attenuation coefficients for each of the four seasons, the ranges of the projected depths of Lmax and Ls-opt for the four Gambierdiscus species/phylotypes under sunny midday conditions, cloudy midday conditions, and rainy midday conditions were 12-38m and 12-54m, 1-16m and 1-33m, and 0m and 0 16m, respectively. These results suggest that light intensity plays an important role in the bloom dynamics and vertical distribution of Gambierdiscus species/phylotypes in Japanese coastal waters. PMID- 28073554 TI - An overview of cyanobacterial bloom occurrences and research in Africa over the last decade. AB - Cyanobacterial blooms are a current cause for concern globally, with vital water sources experiencing frequent and increasingly toxic blooms in the past decade. These increases are resultant of both anthropogenic and natural factors, with climate change being the central concern. Of the more affected parts of the world, Africa has been considered particularly vulnerable due to its historical predisposition and lag in social economic development. This review collectively assesses the available information on cyanobacterial blooms in Africa as well as any visible trends associated with reported occurrences over the last decade. Of the 54 countries in Africa, only 21 have notable research information in the area of cyanobacterial blooms within the last decade, although there is substantial reason to attribute these blooms as some of the major water quality threats in Africa collectively. The collected information suggests that civil wars, disease outbreaks and inadequate infrastructure are at the core of Africa's delayed advancement. This is even more so in the area of cyanobacteria related research, with 11 out of 21 countries having recorded toxicity and physicochemical parameters related to cyanobacterial blooms. Compared to the rest of the continent, peripheral countries are at the forefront of research related to cyanobacteria, with countries such as Angola having sufficient rainfall, but poor water quality with limited information on bloom occurrences. An assessment of the reported blooms found nitrogen concentrations to be higher in the water column of more toxic blooms, validating recent global studies and indicating that phosphorous is not the only factor to be monitored in bloom mitigation. Blooms occurred at low TN: TP ratios and at temperatures above 12 degrees C. Nitrogen was linked to toxicity and temperature also had a positive effect on bloom occurrence and toxicity. Microcystis was the most ubiquitous of the cyanobacterial strains reported in Africa and the one most frequently toxic. Cylindrospermopsis was reported more in the dry, north and western parts of the continent countries as opposed to the rest of the continent, whilst Anabaena was more frequent on the south eastern regions. In light of the entire continent, the inadequacy in reported blooms and advances in this area of research require critical intervention and action. PMID- 28073555 TI - Molecular and phylogenetic characterization of Ostreopsis (Dinophyceae) and the description of a new species, Ostreopsis rhodesae sp. nov., from a subtropical Australian lagoon. AB - Cryptic and pseudo-cryptic species are common amongst marine phytoplankton, and may cause misleading inferences of ecological and physiological data of plankton community studies. Deciphering the diversity and distribution of species of the benthic dinoflagellate Ostreopsis is one example, as there are many morphologically indistinct clades that differ greatly genetically and toxicologically from one another. In this study, a new species, Ostreopsis rhodesae from the southern Great Barrier Reef was described. While it initially appeared to be highly similar to several other Ostreopsis species, we found O. rhodesae can be distinguished based on the relative size of the second apical plate (2'), which is twice as long as the APC plate, and separates the third apical (3') from the third precingular (3'') plate. Phylogenetic trees based on the SSU, ITS/5.8S and D1-D2 and D8-D10 regions of the LSU rRNA were well supported, and showed a clear difference to other Ostreopsis clades. Compensatory base changes (CBCs) were identified in helices of the ITS2 between O. rhodesae and O. cf. ovata and O. cf. siamensis, which were also present in the same habitat. Fish gill cell lines were toxic to O. rhodesae, cell extracts but no palytoxin-like analogues were found in them. The findings highlight a case of pseudo-cryptic speciation, found in sympatry with closely related and morphologically similar species, but biologically and functionally distinct. PMID- 28073556 TI - The role of heterocytes in the physiology and ecology of bloom-forming harmful cyanobacteria. AB - Dolichospermum flos-aquae and Cylindrospermopsis raciborskii are two cyanobacteria species which cause harmful blooms around the world. Both these species share the capacity to fix atmospheric nitrogen in heterocytes (cell where fixation occurs). While Dolichospermum can express heterocytes at rather regular intervals across the filament, Cylindrospermopsis can only express heterocytes at the end of the filament. The aim of this study was to experimentally assess the role of heterocyte position in the eco-physiological responses of these bloom forming cyanobacteria. Replicated monocultures of each species were grown at different eutrophication scenarios (limiting and sufficient nitrogen and phosphorus concentrations, in factorial design). Dolichospermum reached high biomass regardless of the nitrogen (and phosphorus) provided, suggesting that this species could bloom in situations with and without nitrogen limitation. In contrast, Cylindrospermopsis reached high biomass only when nitrogen supply was high; its biomass was 15-20 times lower when relying on nitrogen fixation. Hence, despite its ability to fix nitrogen, blooms of Cylindrospermopsis would be expected only under high total nitrogen availability. In Dolichospermum heterocytes occurred only in the scenarios without supplied nitrogen while in Cylindrospermopsis heterocytes occurred regardless of nitrogen availability. Yet, in both species nitrogen fixation occurred (heterocytes were functional) only when nitrogen was limiting, and nitrogen fixation increased significantly at higher phosphorus concentration. Finally, in the absence of supplied nitrogen, filament length in Dolichospermum was the longest, while filaments in Cylindrospermopsis were the shortest (up to 13 times shorter than at nitrogen sufficiency). Therefore, heterocyte expression in Dolichospermum, and filament length in Cylindrospermopsis seem good proxies of nitrogen fixation. The eco physiological responses recorded here help understand the distribution of these species along nutrient gradients in nature. PMID- 28073557 TI - Diatom Nitzschia navis-varingica (Bacillariophyceae) and its domoic acid production from the mangrove environments of Malaysia. AB - The distribution of the toxic pennate diatom Nitzschia was investigated at four mangrove areas along the coastal brackish waters of Peninsular Malaysia. Eighty two strains of N. navis-varingica were isolated and established, and their identity confirmed morphologically and molecularly. Frustule morphological characteristics of the strains examined are identical to previously identified N. navis-varingica, but with a sightly higher density of the number of areolae per 1MUm (4-7 areolae). Both LSU and ITS rDNAs phylogenetic trees clustered all strains in the N. navis-varingica clade, with high sequence homogeneity in the LSU rDNA (0-0.3%), while the intraspecific divergences in the ITS2 data set reached up to 7.4%. Domoic acid (DA) and its geometrical isomers, isodomoic A (IA) and isodomoic B (IB), were detected in cultures of N. navis-varingica by FMOC-LC-FLD, and subsequently confirmed by LC-MS/MS, with selected ion monitoring (SIM) and multiple reaction monitoring (MRM) runs. DA contents ranged between 0.37 and 11.06pgcell-1. This study demonstrated that the toxigenic euryhaline diatom N. navis-varingica is widely distributed in Malaysian mangrove swamps, suggesting the risk of amnesic shellfish poisoning and the possibility of DA contamination in the mangrove-related fisheries products. PMID- 28073558 TI - Selective growth promotion of bloom-forming raphidophyte Heterosigma akashiwo by a marine bacterial strain. AB - Algal bloom is typically caused by aberrant propagation of a single species, resulting in its predomination in the local population. While environmental factors including temperature and eutrophication are linked to bloom, the precise mechanism of its formation process is still obscure. Here, we isolated a bacterial strain that promotes growth of Heterosigma akashiwo, a Raphidophyceae that causes harmful algal blooms. Based on 16S rRNA gene sequence, the strain was identified as Altererythrobacter ishigakiensis, a member of the class Alphaproteobacteria. When added to culture, this strain facilitated growth of H. akashiwo and increased its cell culture yield significantly. Importantly, this strain did not affect the growth of other raphidophytes, Chattonella ovate and C. antiqua, indicating that it promotes growth of H. akashiwo in a species-specific manner. We also found that, in co-culture, H. akashiwo suppressed the growth of C. ovate. When A. ishigakiensis was added to the mixed culture, H. akashiwo growth was facilitated while C. ovate propagation was markedly suppressed, indicating that the presence of the bacterium enhances the dominance of H. akashiwo over C. ovate. This is the first example of selective growth promotion of H. akashiwo by a marine bacterium, and may exemplify importance of symbiotic bacterium on algal bloom forming process in general. PMID- 28073559 TI - Characterization of total retinoid-like activity of compounds produced by three common phytoplankton species. AB - Phytoplankton can produce various bioactive metabolites, which may affect other organisms in the aquatic environment. This study provides the first information on the total retinoid-like activity associated with both intracellular and extracellular metabolites produced by selected phytoplankton species that could play a role in teratogenic effects and developmental disruption in exposed organisms. The studied species included a coccoid cyanobacteria (Microcystis aeruginosa), a filamentous cyanobacteria (Aphanizomenon gracile) and a green alga (Desmodesmus quadricauda), all of which commonly occur in freshwater bodies in Europe. Methanolic extracts from cellular material and extracellular exudates were prepared from cultures cultivated in two light-intensity variants with five replicates for each species. The retinoid-like activity was evaluated by in vitro assays along with chemical analyses of two potent retinoic acids (all-trans retinoic acid (ATRA) and 9cis-RA). The mean total retinoid-like activity of metabolites produced by the three studied species representing different phytoplankton taxonomic groups ranged from 705 to 5572ng ATRA equivalent/g dry matter corresponding to 0.064-0.234ng ATRA/106 cells. Retinoid-like activity was found in the cellular extracts of all species, while only the extracellular exudates of cyanobacteria exhibited detectable activity (41-1081ng ATRA/L). The greatest extracellular as well as total (extra- and intra- cellular together) retinoid-like activity was detected for Microcystis aeruginosa. The two potent retinoic acids studied were more frequently detected in cellular extracts than in extracellular exudates of all species. Their contribution to observed in vitro effects was relatively low for all tested samples (<10%), indicating a substantial contribution of other retinoid-like compounds to the overall activity. The results indicate possible influence of light intensity and cell density on the production of metabolites with retinoid-like activity and the cyanotoxin microcystin by the studied species. The recalculation of the results per dry weight, water volume, per 106 cells and biovolume enables a direct comparison of the retinoid-like activity distribution between extracts and exudates and the use of the data for risk assessment in water bodies. PMID- 28073560 TI - An alternative explanation for cyanobacterial scum formation and persistence by oxygenic photosynthesis. AB - The cause of persistent cyanobacteria scum formation in lakes is an unresolved subject. Scum refers to the event in which cyanobacteria are at the water surface of a lake. Factors like low turbulence levels, long day-light, high water temperatures and the buoyant capacity of cyanobacterial cells play a role in the occurrence of scums. However, they do not explain why scums are observed at periods during the day when according to theory they should have disappeared into the deeper water layers. In this study, we present an alternative explanation. The hypothesis we present here is that irreversible buoyancy of cyanobacteria colonies is created by the growth of gas bubbles on or within the mucilage of the colonies. These bubbles grow under oxygen super-saturated conditions. At low wind speed and high chlorophyll levels, the dissolved oxygen (DO) produced during photosynthesis by cyanobacteria, cannot escape sufficiently fast to the atmosphere hence a DO supersaturated condition arises in the water. At this stage, growth of oxygen bubbles may occur inside or attached to the mucilage. We present results of compression experiments to support our hypothesis. In a chamber, the pressure on lake water containing a natural cyanobacteria population is increased. At 3*105 and 4*105Pa the cyanobacteria colonies were not able to float anymore and sank. This pressure is lower than the 106Pa needed to collapse all gas vacuoles inside the cyanobacteria cells (Walsby, 1994). The observed change from floating to sinking colonies due to increased water pressure suggests that gas bubbles were present inside the colonies. In lakes, these gas bubbles may lead to permanent buoyancy, i.e. a persistent scum. PMID- 28073561 TI - Development of real-time RT-PCR for detecting viable Cochlodinium polykrikoides (Dinophyceae) cysts in sediment. AB - Morphological observations have confirmed that cysts are produced by dinoflagellates. However, finding a seed bed or unknown cysts in field samples by microscopy is extremely time consuming. Real-time PCR has been used to facilitate the detection of dinoflagellate cysts in sediment. However, DNA from dead vegetative cells remaining on the surface sediment may persist for a long period of time, which can cause false positive DNA detection. In this study, a non quantitative RNA targeted probe using real-time RT-PCR was developed for detection of viable cysts in sediment. Large-subunit rRNA was used to develop a species-specific RNA targeted probe for the ichthyotoxic dinoflagellate Cochlodinium polykrikoides. The sediment samples were sieved and incubated at 30 degrees C for 3h prior to RNA extraction to remove RNA from dead cells remaining in the sediment. Nested-PCR was conducted to maximize assay sensitivity. A field survey to determine the distribution of cysts at 155 sampling stations in the western and southern part of the Korean peninsula showed that C. polykrikoides cysts were detected at five sampling stations. PMID- 28073562 TI - A new Gambierdiscus species (Dinophyceae) from Rarotonga, Cook Islands: Gambierdiscus cheloniae sp. nov. AB - Ciguatera fish poisoning (CFP) has been reported for many years in Rarotonga, Cook Islands, and has had the world's highest reported incidence of this illness for the last 20 years. Following intensive sampling to understand the distribution of the causative organisms of CFP, an undescribed Gambierdiscus species was isolated from the Rarotongan lagoon. Gambierdiscus cheloniae sp. nov. has the common Gambierdiscus Kofoidian plate formula (except for a variability in the number of precingular plates in aberrant cells): Po, 3', 6" (7"), 6C?, 6 or 7S, 5'", 1p and 2"". The 2' plate is hatchet shaped and the dorsal end of 1p is pointed and the relatively narrow 1p plate. Morphologically G. cheloniae is similar to the genetically closely related species G. pacificus, G. toxicus and G. belizeanus, although smaller (depth and length) than G. toxicus. The apical pore plate varies from those of G. belizeanus and G. pacificus, which are shorter and narrower, and from G. toxicus, which is larger. G. cheloniae also differs from G. pacificus in the shape of the 2' plate. The description of this new species is supported by phylogenetic analyses using three different gene regions. G. cheloniae produced the putative maitotoxin-3 analogue, MTX-3, but neither maitotoxin or monitored ciguatoxin. Extracts of G. cheloniae were shown to be highly toxic to mice by intraperitoneal (i.p.) injection, although they were less toxic by gavage. It is possible that this species produces toxins other than putative MTX-3. PMID- 28073563 TI - Genetic and toxinological characterization of North Atlantic strains of the dinoflagellate Ostreopsis and allelopathic interactions with toxic and non-toxic species from the genera Prorocentrum, Coolia and Gambierdiscus. AB - The genus Ostreopsis includes several toxic species that can develop blooms in benthic ecosystems, with potential harmful consequences for human health and marine invertebrates. Despite of this, little is known about the allelopathic interactions between these organisms and other co-occurring microalgae that exploit similar spatial and nutrient resources in benthic ecosystems. The aim of this study was to follow these interactions in cultures of two Ostreopsis ribotypes with different toxin profiles (O. cf. ovata contained ovatoxins-a, b, c and e, while only ovatoxin-d was found in O .sp. "Lanzarote-type"), mixed with species of three benthic dinoflagellate genera (Coolia, Prorocentrum and Gambierdiscus), isolated from the same area (North East Atlantic, Canary Islands). In a first experiment, the potential allelopathic effects on growth rates were followed, in mixed cultures of Coolia monotis (a non toxic species) exposed to the clarified medium and to cells of O. sp."Lanzarote-type" and O. cf. ovata. Growth delayed in C. monotis was observed specially in clarified medium, while the O. sp. "Lanzarote-type" strain attained much lower densities in mixed cultures. In a second experiment, we examined the potential effects of clarified media from O. sp."Lanzarote-type" and O. cf. ovata on the adherence capacity in two toxic species (Prorocentrum hoffmannianum and Gambierdiscus excentricus). Contrasting effects were found: a significant increase of adherence capacity in P. hoffmannianum vs attachment decline in G. excentricus, that experienced also severe deleterious effects (cell lysis). Our results suggest the existence of weak to moderate allelopathic interactions between the studied organisms, although the outcome is dependent on the species involved. PMID- 28073564 TI - Education and notification approaches for harmful algal blooms (HABs), Washington State, USA. AB - While numerous strategies have been used to educate and notify the public about potential hazards from exposure to Harmful Algal Blooms (HABs), at present there are no national guidelines or suggested outreach approaches. To raise public awareness and determine effective HAB outreach methods, two Washington State agencies and three counties in the Puget Sound region implemented several education and notification strategies. These approaches were rated for effectiveness by state and county public health and water quality professionals. At the state level, the most effective action was a three-tiered advisory posting protocol for notifying external users that was introduced to local health jurisdictions at workshops around the state. Supplemental permanent signage is recommended for lakes with blooms to overcome the time lag between HAB onset and testing/posting. The state also implements effective notification of toxicity test results through a web-based HAB database and listserv. Lake residents were best notified through electronic alerts including email and social media while mailers to lake residents were useful during initial HAB events and to gain subscribers to electronic alerts. Press releases were most valuable when used sparingly for severe blooms or for blooms in large lakes. Initial analyses of lake recreational use indicates these strategies encourage behavior change in lake users. Based on these findings, a general framework for HAB outreach and a specific notification strategy is proposed to assist other regions or agencies that are developing HAB education and notification programs. PMID- 28073565 TI - Heterogeneous distribution in sediments and dispersal in waters of Alexandrium minutum in a semi-enclosed coastal ecosystem. AB - Within the framework of research aimed at using genetic methods to evaluate harmful species distribution and their impact on coastal ecosystems, a portion of the ITS1rDNA of Alexandrium minutum was amplified by real-time PCR from DNA extracts of superficial (1-3cm) sediments of 30 subtidal and intertidal stations of the Bay of Brest (Brittany, France), during the winters of 2013 and 2015. Cell germinations and rDNA amplifications of A. minutum were obtained for sediments of all sampled stations, demonstrating that the whole bay is currently contaminated by this toxic species. Coherent estimations of ITS1rDNA copy numbers were obtained for the two sampling cruises, supporting the hypothesis of regular accumulation of A. minutum resting stages in the south-eastern, more confined embayments of the study area, where fine-muddy sediments are also more abundant. Higher ITS1rDNA copy numbers were detected in sediments of areas where blooms have been seasonally detected since 2012. This result suggests that specific genetic material estimations in superficial sediments of the bay may be a proxy of the cyst banks of A. minutum. The simulation of particle trajectory analyses by a Lagrangian physical model showed that blooms occurring in the south-eastern part of the bay are disconnected from those of the north-eastern zone. The heterogeneous distribution of A. minutum inferred from both water and sediment suggests the existence of potential barriers for the dispersal of this species in the Bay of Brest and encourages finer analyses at the population level for this species within semi-enclosed coastal ecosystems. PMID- 28073566 TI - Mixotrophy in the phototrophic dinoflagellate Takayama helix (family Kareniaceae): Predator of diverse toxic and harmful dinoflagellates. AB - Takayama spp. are phototrophic dinoflagellates belonging to the family Kareniaceae and have caused fish kills in several countries. Understanding their trophic mode and interactions with co-occurring phytoplankton species are critical steps in comprehending their ecological roles in marine ecosystems, bloom dynamics, and dinoflagellate evolution. To investigate the trophic mode and interactions of Takayama spp., the ability of Takayama helix to feed on diverse algal species was examined, and the mechanisms of prey ingestion were determined. Furthermore, growth and ingestion rates of T. helix feeding on the dinoflagellates Alexandrium lusitanicum and Alexandrium tamarense, which are two optimal prey items, were determined as a function of prey concentration. T. helix ingested large dinoflagellates >=15MUm in size, except for the dinoflagellates Karenia mikimotoi, Akashiwo sanguinea, and Prorocentrum micans (i.e., it fed on Alexandrium minutum, A. lusitanicum, A. tamarense, A. pacificum, A. insuetum, Cochlodinium polykrikoides, Coolia canariensis, Coolia malayensis, Gambierdiscus caribaeus, Gymnodinium aureolum, Gymnodinium catenatum, Gymnodinium instriatum, Heterocapsa triquetra, Lingulodinium polyedrum, and Scrippsiella trochoidea). All these edible prey items are dinoflagellates that have diverse eco-physiology such as toxic and non-toxic, single and chain forming, and planktonic and benthic forms. However, T. helix did not feed on small flagellates and dinoflagellates <13MUm in size (i.e., the prymnesiophyte Isochrysis galbana; the cryptophytes Teleaulax sp., Storeatula major, and Rhodomonas salina; the raphidophyte Heterosigma akashiwo; the dinoflagellates Heterocapsa rotundata, Amphidinium carterae, Prorocentrum minimum; or the small diatom Skeletonema costatum). T. helix ingested Heterocapsa triquetra by direct engulfment, but sucked materials from the rest of the edible prey species through the intercingular region of the sulcus. With increasing mean prey concentration, the specific growth rates of T. helix on A. lusitanicum and A. tamarense increased continuously before saturating at prey concentrations of 336-620ngC mL-1. The maximum specific growth rates (mixotrophic growth) of T. helix on A. lusitanicum and A. tamarense were 0.272 and 0.268d-1, respectively, at 20 degrees C under a 14:10 h light/dark cycle of 20MUE m-2 s-1 illumination, while its growth rates (phototrophic growth) under the same light conditions without added prey were 0.152 and 0.094d-1, respectively. The maximum ingestion rates of T. helix on A. lusitanicum and A. tamarense were 1.23 and 0.48ng C predator-1d-1, respectively. The results of the present study suggest that T. helix is a mixotrophic dinoflagellate that is able to feed on a diverse range of toxic species and, thus, its mixotrophic ability should be considered when studying red tide dynamics, food webs, and dinoflagellate evolution. PMID- 28073567 TI - The influence of native aortic valve calcium and transcatheter valve oversize on the need for pacemaker implantation after transcatheter aortic valve insertion. AB - OBJECTIVE: Native aortic valve calcium and transcatheter aortic valve oversize have been reported to predict pacemaker implantation after transcatheter aortic valve insertion. We reviewed our experience to better understand the association. METHODS: We retrospectively reviewed the records of 300 patients with no prior permanent pacemaker implantation who underwent transcatheter aortic valve insertion from November 2008 to February 2015. Valve oversize was calculated using area. The end point of the study was 30-day postoperative pacemaker implantation. RESULTS: Patient data included age of 81.1 +/- 8.4 years, female sex in 135 patients (45%), atrial fibrillation in 74 patients (24.7%), Society of Thoracic Surgeons predicted risk of mortality of 7.6% (interquartile range [IQR], 5.3-10.6), aortic valve calcium score of 2568 (IQR, 1775-3526) Agatston units, and annulus area of 471 +/- 82 mm2. Balloon-expandable valves were inserted in 244 patients (81.3%). Transcatheter aortic valve oversize was 12.8% (IQR, 3.9 23.3). Pacemaker implantation was performed in 59 patients (19.7%). Aortic valve calcium score (adjusted P = .275) and transcatheter valve oversize (adjusted P = .833) were not independent risk factors for pacemaker implantation when controlling for preoperative right bundle branch block (adjusted odds ratio, 3.49; 95% confidence interval, 1.61-8.55; P = .002), implantation of self expanding valve (adjusted odds ratio, 4.09; 95% confidence interval, 1.53-10.96; P = .005), left bundle branch block (adjusted P = .331), previous percutaneous coronary intervention (adjusted P = .053), or valve surgery (adjusted P = .111), and PR interval (adjusted P = .350). CONCLUSIONS: Right bundle branch block and implantation of a self-expanding prosthesis were predictive of pacemaker implantation, but not native aortic valve score or transcatheter valve oversize. PMID- 28073569 TI - Discussion. PMID- 28073568 TI - Three mechanisms of early failure of transcatheter aortic valves: Valve thrombosis, cusp rupture, and accelerated calcification. PMID- 28073570 TI - Are men from Mars and women from Venus? PMID- 28073571 TI - Early clinical outcomes of a novel self-expanding transapical transcatheter aortic valve bioprosthesis. AB - OBJECTIVE: Coronary obstruction remains a challenging complication of transcatheter aortic valve replacement; however, a new self-expanding transapical prosthesis may reduce this risk. The purpose of this study was to evaluate the early 1-year outcomes of patients with low coronary heights who received the Acurate TA bioprosthesis (Symetis, Ecublens, Switzerland). METHODS: Between May 2014 and April 2015, 30 consecutive patients (aged 85 +/- 6 years, 63% were female, Society of Thoracic Surgeons score 8.4 +/- 6.0) with severe, symptomatic aortic stenosis underwent transcatheter aortic valve replacement with the Acurate TA bioprosthesis. Relevant patient characteristics included reoperation in 47% (n = 14), peripheral vascular disease in 43% (n = 13), and porcelain aorta in 30% (n = 9). The mean left and right coronary heights were 10.8 +/- 1.5 mm and 16.4 +/- 4.1 mm, respectively, with a sinus of Valsalva : annular ratio of 1.3 +/- 0.8. RESULTS: All 30 device implants were successful. The 30-day in-hospital mortality was 3.3% (n = 1), and no patients had coronary obstruction or stroke. One patient (3.3%) had apical rupture requiring cardiopulmonary bypass for repair, 1 patient (3.3%) had a localized femoral artery dissection, and 1 patient (3.7%) required a new pacemaker. There were no other complications. Mean and peak transaortic valve gradients decreased from 59 +/- 17 and 84 +/- 31 mm Hg to 14 +/- 7 and 28 +/- 12 mm Hg, respectively (P < .0005). No patients had more than mild paravalvular aortic insufficiency. At 30 days, there were no further complications and 96.7% (n = 29) were in New York Heart Association class I/II. Survival at 30 days and 1 year was 97% and 89%, respectively. CONCLUSIONS: The Symetis Acurate TA device demonstrates high procedural success and excellent acute and 1-year patient outcomes. The device allows safe implantation in patients at higher risk for coronary artery obstruction. PMID- 28073572 TI - Routine preoperative laboratory testing in elective pediatric cardiothoracic surgery is largely unnecessary. AB - OBJECTIVE: Routine preoperative laboratory testing (RLT) is common practice in pediatric cardiothoracic surgery and is associated with significant cost burden to patients and families. We sought to examine the value of RLT in patients undergoing elective pediatric cardiothoracic surgery. METHODS: We conducted a retrospective study of all scheduled elective pediatric cardiothoracic surgery at our institution from 2012 to 2014. Inpatients were excluded. Patient charts were reviewed to obtain preoperative laboratory values and determine relationship to case cancellation. RLT includes complete blood count, prothrombin time, partial thromboplastin time, urinalysis, 7 chemistry metabolic panel, electrocardiogram, and 2-view chest radiograph. RESULTS: RLT was completed for 1106 scheduled elective cases. Six (0.5%) cancellations were related to abnormal preoperative laboratory test results: 5 complete blood counts and 1 urinalysis. Hospital charge for RLT averaged $2064 per patient. Based on this incidence, we estimated that 184 routine preoperative laboratory tests, which generated a total hospital charge of $379,776, were required to capture 1 abnormal test significant enough to cancel surgery. An estimated charge of $2,169,552 was generated on prothrombin time, partial thromboplastin time, 7 chemistry metabolic panel, electrocardiogram, and 2-view chest radiograph, and none of these tests resulted in a cancellation. CONCLUSIONS: RLT does not significantly impact decision-making in elective pediatric cardiothoracic surgery. The decision to order a specific screening test should be clinically driven. Selective preoperative laboratory testing may have a positive impact on healthcare costs without affecting outcomes. PMID- 28073573 TI - Surgery for predominant lesion in nonlocalized bronchiectasis. AB - OBJECTIVE: Patients with nonlocalized bronchiectasis are encountered commonly; however, there is little information regarding surgical intervention in this patient population. The aim of this study was to evaluate symptomatic response and safety of anatomic resection of the predominant lesion via the use of lobectomy for the management of nonlocalized bronchiectasis. METHODS: We reviewed the medical records of 37 consecutive patients who underwent lobectomy via thoracotomy for nonlocalized bronchiectasis between 2010 and 2013. The main surgical indications were nonlocalized bronchiectasis with one predominant lesion, failure of medical treatment, and adequate cardiopulmonary reserve. The predominant lesion was determined by preoperative computed tomography and/or bronchoscopy. Preoperative symptoms were compared with postoperative symptoms and analyzed by the use of paired techniques. RESULTS: The mean patient age was 54.5 +/- 6.4 years. There was no operative mortality. Postoperative complications occurred in 8 (21.6%) patients, including 1 with empyema, 1 with persistent air leak, and 6 with minor transient complications, all of which were manageable without any reoperation. After lobectomy, the median extent of residual bronchiectatic areas in the remaining lungs was 25% (range, 12.5%-42.9%). The frequency of acute infection (5.3 +/- 2.1/year vs 1.8 +/- 2.3/year) and hemoptysis (4.9 +/- 2.8/year vs 1.1 +/- 0.7/year) decreased significantly and the amount of sputum also decreased (37.1 +/- 3.4 mL/day vs 10.7 +/- 4.6 mL/day). Twenty-three (62.2%) patients were asymptomatic after surgery, 10 (27.0%) were symptomatic with clinical improvement, and 4 (10.8%) had no change or worsened. CONCLUSIONS: Lobectomy for the predominant lesion is a safe procedure in the surgical treatment of nonlocalized bronchiectasis and leads to significant relief of symptoms with good rates of satisfaction. PMID- 28073575 TI - Discussion. PMID- 28073576 TI - Preoperative right ventricular dysfunction should not preclude surgical ventricular restoration. PMID- 28073574 TI - Massive donor transfusion potentially increases recipient mortality after lung transplantation. AB - OBJECTIVE: Donor blood transfusion has been identified as a potential risk factor for primary graft dysfunction and by extension early mortality. We sought to define the contributing risk of donor transfusion on early mortality for lung transplant. METHODS: Donor and recipient data were abstracted from the Organ Procurement and Transplantation Network database updated through June 30, 2014, which included 86,398 potential donors and 16,255 transplants. Using the United Network for Organ Sharing 4-level designation of transfusion (no blood, 1-5 units, 6-10 units, and >10 units, massive), we analyzed all-cause mortality at 30 days with the use of logistic regression adjusted for confounders (ischemic time, donor age, recipient diagnosis, lung allocation score and recipient age, and recipient body mass index). Secondary analyses assessed 90-day and 1-year mortality and hospital length of stay. RESULTS: Of the 16,255 recipients transplanted, 8835 (54.35%) donors received at least one transfusion. Among those transfused, 1016 (6.25%) received a massive transfusion, defined as >10 units. Those donors with massive transfusion were most commonly young trauma patients. After adjustment for confounding variables, donor massive transfusion was associated significantly with an increased risk in 30-day (P = .03) and 90-day recipient mortality (P = .01) but not 1-year mortality (P = .09). There was no significant difference in recipient length of stay or hospital-free days with respect to donor transfusion. CONCLUSIONS: Massive donor blood transfusion (>10 units) was associated with early recipient mortality after lung transplantation. Conversely, submassive donor transfusion was not associated with increased recipient mortality. The mechanism of increased early mortality in recipients of lungs from massively transfused donors is unclear and needs further study but is consistent with excess mortality seen with primary graft dysfunction in the first 90 days posttransplant. PMID- 28073577 TI - Zika virus. A teratogenic agent for the eyes. PMID- 28073579 TI - Robustness of 4D-optimized scanned carbon ion beam therapy against interfractional changes in lung cancer. AB - BACKGROUND AND PURPOSE: Moving targets could be conformally treated with actively scanned carbon ion beams using 4D-optimization. As this heavily exploits 4D-CTs, an important question is whether the conformity also upholds in the context of interfractional changes, i.e. variable positioning, anatomy and breathing patterns. MATERIALS AND METHODS: In 4 lung cancer patients, 6 weekly 4D-CTs were available. 4D-CTs and their phases were non-rigidly registered to propagate contours and 4D-doses. On the first 4D-CT, a 4D-optimized plan delivering a uniform dose to each motion phase (total dose 9.4Gy(RBE)) was simulated, as well as an ITV plan for comparison. On the five following 4D-CTs, 4D-dose was forward calculated and evaluated for target coverage and conformity. Variable uniform (3 7mm) and range margins (2mm/%) were investigated. RESULTS: For all patients, target coverage (V95>95% accumulated over 5 fractions) could be achieved, but with variable margin size weakly depending on motion amplitude and range changes. The same margins were also necessary for ITV plans, which lead to lower conformity and higher integral doses. CONCLUSION: 4D-optimization appears feasible also under interfractional changes and maintains a dosimetric advantage over less conformal ITV irradiations. Further studies are needed to identify patients benefiting most from the technically more complex 4D-optimization. PMID- 28073578 TI - Prophylactic cranial irradiation after definitive chemoradiotherapy for limited stage small cell lung cancer: Do all patients benefit? AB - PURPOSE: Prophylactic cranial irradiation (PCI) can improve overall survival (OS) and suppress brain metastases (BM) in patients with limited-stage small cell lung cancer (LS-SCLC) after complete response to primary therapy. However, PCI can be toxic. We sought to identify characteristics of patients who may not benefit from PCI. METHODS: We identified 658 patients who received chemoradiotherapy at MD Anderson in 1986-2012; 364 received PCI and 294 did not. Median follow-up time was 21.2months (range 1.2-240.8months). Cox proportional hazards regression, competing-risk regression, and Kaplan-Meier analyses were used to identify factors influencing OS and BM. RESULTS: PCI reduced risks of death [HR 0.73, 95% CI 0.61-0.88, P=0.001] and BM [HR 0.54, 95% CI 0.39-0.76, P<0.001]. Having tumors ?5cm increased the risk of BM [HR 1.77, 95% CI 1.22-2.55, P=0.002] but not death [HR 1.16, 95% CI 0.96-1.40, P=0.114]. Among patients ?70years with ?5-cm tumors, PCI did not improve OS [2-year rates 39.4% vs 40.9%, P=0.739]. CONCLUSIONS: PCI remains standard therapy after complete response to chemoradiotherapy for LS SCLC. However, older patients may be at risk from comorbidity or extracranial disease. Further work is warranted to identify patients who may not benefit from PCI. PMID- 28073580 TI - Drug information by public health and regulatory institutions: Results of an 8 country survey in Europe. AB - PURPOSE: To evaluate the framework of drug information produced by public health and regulatory institutions in Europe. MATERIALS AND METHODS: We carried out a short survey asking editors of ISDB bulletins of the European region to indicate the main sources of drug information provided by public health and regulatory authorities in their countries, the specific kind of information produced and their opinions about strengths and weaknesses of such information. The availability of evaluations about the added therapeutic value of drugs and of tools facilitating the implementation of such information were particularly addressed and checked on the websites of those institutions. RESULTS: Answers pertaining to eight countries were available. Regulatory information and safety alerts are generally available, but just UK and Germany stand out by showing quite an advanced framework of evidence-based, comparative drug information for health professionals, decision-makers and for the general public. National plans to implement evidence-based drug information seem lacking. CONCLUSION: More efforts are warranted to develop sharp formats to make evidence-based drug information easier to access, understand and put in context, showing the place in therapy of medicines and their added therapeutic value. Harmonization of different sources, also at European level, would be important to favor their access and limit dispersion. Appropriate tools and specific plans are then necessary to favor implementation of information materials. PMID- 28073581 TI - Acute cholecystitis, chronic cholecystitis or gallbladder cancer? PMID- 28073582 TI - Risk of inflammatory bowel disease in patients with rosacea: Results from a nationwide cohort study in Taiwan. AB - BACKGROUND: A link between rosacea and inflammatory bowel disease (IBD) has been proposed with unknown mechanisms. Epidemiologic evidence of this association needs to be examined. METHODS: In this nationwide cohort study, a total of 89,356 patients with rosacea and 178,712 matched patients without rosacea between 1997 and 2013 were identified in the Taiwanese National Health Insurance Research Database. Cumulative incidences of IBD were compared between these 2 cohorts. Frailty Cox proportional hazard model was used and subgroup analyses were conducted to examine the risk factors for IBD. RESULTS: The 15-year cumulative incidences of IBD were 0.036% (95% confidence interval [CI] 0.00%-1.57%) and 0.019% (95% CI 0.00%-0.83%) in rosacea and nonrosacea cohorts, respectively (P = .05). Rosacea (adjusted hazard ratio 1.94, 95% CI 1.04-3.63, P = .04) and male gender (adjusted hazard ratio 3.52, 95% CI 2.03-6.11, P < .01) were independently associated with IBD, after adjustment for major comorbidities. Multivariate subgroup analyses revealed consistent results. The incidence rates of IBD decreased with increasing antibiotic use in patients with rosacea, but without statistical significance. LIMITATION: Information related to lifestyle, diet, alcohol, and smoking was not included in the database. CONCLUSION: Patients with rosacea may have an increased risk of IBD. PMID- 28073583 TI - Clinical factors associated with subclinical spread of in situ melanoma. AB - BACKGROUND: Subclinical spread of in situ melanoma occurs at a wide frequency, ranging from 12% to 71%. OBJECTIVE: To identify clinical factors associated with subclinical spread of in situ melanoma. METHODS: We used a retrospective, cross sectional study of 674 consecutive in situ melanomas to examine 627 patients treated with Mohs surgery and melanoma antigen recognized by T cells 1 immunostaining. The presence of subclinical spread was correlated with clinical characteristics. Univariate and multivariate logistic regression analyses were performed to generate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Both univariate and multivariate analyses demonstrated significantly increased odds for subclinical spread of in situ melanomas when they were located on the head or neck, at acral sites, or on the pretibial leg (OR 1.97, 95% CI 1.41-3.40); in persons with a history of prior treatment (OR 2.77, 95% CI 1.74 4.420); melanomas of preoperative size >1 cm (OR 1.74, 95% CI 1.23-2.46, P = .002); or in persons >=60 years old (OR 1.47, 95% CI 1.01-2.13, P = .042). A count prediction model demonstrated that the risk for subclinical spread increased with the number of clinical risk factors. LIMITATION: We used a single site, retrospective study design. CONCLUSION: Clarifying the risk factors for subclinical spread might help to refine triage of in situ melanomas to the appropriate surgical techniques for margin assessment prior to reconstruction. PMID- 28073584 TI - Coincident Tuberculosis and Tracheobronchopathia Osteochondroplastica in a Patient. PMID- 28073585 TI - Influence of climate change on the multi-generation toxicity to Enchytraeus crypticus of soils polluted by metal/metalloid mining wastes. AB - This study aimed at assessing the effects of increased air temperature and reduced soil moisture content on the multi-generation toxicity of a soil polluted by metal/metalloid mining wastes. Enchytraeus crypticus was exposed to dilution series of the polluted soil in Lufa 2.2 soil under different combinations of air temperature (20 degrees C and 25 degrees C) and soil moisture content (50% and 30% of the soil water holding capacity, WHC) over three generations standardized on physiological time. Generation time was shorter with increasing air temperature and/or soil moisture content. Adult survival was only affected at 30% WHC (~30% reduction at the highest percentages of polluted soil). Reproduction decreased with increasing percentage of polluted soil in a dose-related manner and over generations. Toxicity increased at 30% WHC (>50% reduction in EC50 in F0 and F1 generations) and over generations in the treatments at 20 degrees C (40 60% reduction in EC50 in F2 generation). At 25 degrees C, toxicity did not change when combined with 30% WHC and only slightly increased with 50% WHC. So, higher air temperature and/or reduced soil moisture content does affect the toxicity of soils polluted by metal/metalloid mining wastes to E. crypticus and this effect may exacerbate over generations. PMID- 28073586 TI - Experimental comparison of point-of-use filters for drinking water ultrafiltration. AB - BACKGROUND: Waterborne pathogens such as Pseudomonas spp. and Legionella spp. may persist in hospital water networks despite chemical disinfection. Point-of-use filtration represents a physical control measure that can be applied in high-risk areas to contain the exposure to such pathogens. New technologies have enabled an extension of filters' lifetimes and have made available faucet hollow-fibre filters for water ultrafiltration. AIM: To compare point-of-use filters applied to cold water within their period of validity. METHODS: Faucet hollow-fibre filters (filter A), shower hollow-fibre filters (filter B) and faucet membrane filters (filter C) were contaminated in two different sets of tests with standard bacterial strains (Pseudomonas aeruginosa DSM 939 and Brevundimonas diminuta ATCC 19146) and installed at points-of-use. Every day, from each faucet, 100 L of water was flushed. Before and after flushing, 250 mL of water was collected and analysed for microbiology. FINDINGS: There was a high capacity of microbial retention from filter C; filter B released only low Brevundimonas spp. counts; filter A showed poor retention of both micro-organisms. CONCLUSION: Hollow-fibre filters did not show good micro-organism retention. All point-of-use filters require an appropriate maintenance of structural parameters to ensure their efficiency. PMID- 28073587 TI - Translational approach to the pathophysiology of panic disorder: Focus on serotonin and endogenous opioids. AB - Panic patients experience recurrent panic attacks. Two main neurochemical hypotheses have been proposed to explain this vulnerability. The first suggests that panic patients have deficient serotonergic inhibition of neurons localized in the dorsal periaqueductal gray matter of the midbrain that organizes defensive reactions to cope with proximal threats as well as of sympathomotor control areas of the rostral ventrolateral medulla that generate neurovegetative symptoms of the panic attack. The second proposes that endogenous opioids buffer panic attacks in normal subjects, and their deficit results in heightened sensitivity to suffocation and separation anxiety in panic patients. Experimental results obtained in rat models of panic indicate that serotonin interacts synergistically with endogenous opioids in the dorsal periaqueductal gray through 5-HT1A and MU opioid receptors to inhibit proximal defense and, supposedly, panic attacks. These findings allow reconciliation of the serotonergic and opioidergic hypotheses of panic pathophysiology. They also indicate that endogenous opioids are likely to participate in the panicolytic action of antidepressants and suggest that exogenous opioids may be useful for treating panic patients resistant to conventional pharmacotherapy. PMID- 28073588 TI - Overexpression of cytochrome P450 2A6 in adrenocortical carcinoma. AB - BACKGROUND: Cytochrome P450-mediated metabolism of chemotherapeutic agents contributes to chemotherapy resistance in multiple malignancies. Adrenocortical carcinoma is known to have a poor response to adjuvant therapies; however, the mechanism remains unknown. Recent comprehensive genetic analyses of adrenocortical carcinomas demonstrated recurrent copy number gains in multiple cytochrome P450 genes prompting investigation into whether cytochrome P450 overexpression potentiates adrenocortical carcinoma chemoresistance. METHODS: We determined the expression patterns of 6 cytochrome P450 genes (CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2S1, and CYP4F2) predicted to be amplified in adrenocortical carcinoma (n = 29) relative to normal adrenal cortex (n = 10). Gene copy numbers were determined with the TaqMan copy number assay. Gene silencing was performed via small interfering RNA (siRNA) in the adrenocortical carcinoma cell line NCI H295R and treated with mitotane and cisplatin. RESULTS: Of the 6 cytochrome P450 genes tested, CYP2A6 was overexpressed with a 55-fold mean increase compared to normal adrenal samples (P < .05). Immunohistochemical analysis confirmed protein overexpression. Copy gains of CYP2A6 were found in 26% (7/27) of adrenocortical carcinoma specimens. Silencing of CYP2A6 in NCI-H295R cells resulted in decreased cell viability and increased chemosensitivity (P < .05). CONCLUSION: Frequent upregulation in adrenocortical carcinomas and the reversal of chemoresistance in adrenocortical carcinoma cells via enforced silencing suggest a role for CYP2A6 in adrenocortical malignancy. PMID- 28073590 TI - Objective detection of apoptosis in rat renal tissue sections using light microscopy and free image analysis software with subsequent machine learning: Detection of apoptosis in renal tissue. AB - OBJECTIVE: The current study proposes an automated machine learning approach for the quantification of cells in cell death pathways according to DNA fragmentation. METHODS: A total of 17 images of kidney histological slide samples from male Wistar rats were used. The slides were photographed using an Axio Zeiss Vert.A1 microscope with a 40x objective lens coupled with an Axio Cam MRC Zeiss camera and Zen 2012 software. The images were analyzed using CellProfiler (version 2.1.1) and CellProfiler Analyst open-source software. RESULTS: Out of the 10,378 objects, 4970 (47,9%) were identified as TUNEL positive, and 5408 (52,1%) were identified as TUNEL negative. On average, the sensitivity and specificity values of the machine learning approach were 0.80 and 0.77, respectively. CONCLUSION: Image cytometry provides a quantitative analytical alternative to the more traditional qualitative methods more commonly used in studies. PMID- 28073589 TI - Mechanisms of oncogene-induced genomic instability. AB - Activating mutations in oncogenes promote uncontrolled proliferation and malignant transformation. Approximately 30% of human cancers carry mutations in the RAS oncogene. Paradoxically, expression of mutant constitutively active Ras protein in primary human cells results in a premature proliferation arrest known as oncogene-induced senescence (OIS). This is more commonly observed in human pre neoplasia than in neoplastic lesions, and is considered a tumor suppressor mechanism. Senescent cells are still metabolically active but in a status of cell cycle arrest characterized by specific morphological and physiological features that distinguish them from both proliferating cells, and cells growth-arrested by other means. Although the molecular mechanisms by which OIS is established are not totally understood, the current view is that OIS in human cells is tightly linked to persistent activation of the DNA damage response (DDR) pathway, as a consequence of replication stress. Here we will highlight recent advances in our understanding of molecular mechanisms leading to hyper-replication stress in response to oncogene activation, and of the crosstalk between replication stress and persistent activation of the DDR. We will also discuss new evidence for DNA repair deficiencies during OIS, which might increase the genomic instability that drives senescence bypass and malignant transformation. PMID- 28073591 TI - Neuropeptide Y neuronal network dysfunction in the frontal lobe of a genetic mouse model of schizophrenia. AB - Neuropeptide Y (NPY) has been found to play a critical role in various mental functions as a neurotransmitter and is involved in the development of schizophrenia, a particularly intractable psychiatric disease whose precise etiology remains unknown. Recent molecular biological investigations have identified several candidate genes which may be associated with this disease, including disrupted-in-schizophrenia 1 (DISC1). The role of DISC1 would involve neurogenesis and neuronal migration. However, the functional consequences of this gene defect have not yet been fully clarified in neuronal systems. In the present study, to clarify the neuropathological changes associated with the function of DISC1, we explored how DISC1 dysfunction can induce abnormalities in the NPY neuronal network in the central nervous system. We performed immunohistochemical analyses (including the observation of the distribution and density) of prefrontal cortex specimens from DISC1-knockout (KO) mice, which are considered to be a novel animal model of schizophrenia. We then evaluated the number and size of NPY-immunoreactive (NPY-IR) neurons and the length of NPY-IR fibers. The number of NPY-IR neurons and the length of the fibers were decreased in the prefrontal cortex of DISC1-KO mice. The decrease was particularly prominent in the superficial regions, and the distribution of NPY-IR neurons differed between wild-type and DISC1-KO mice. However, the size of the neurons in the cortices of the DISC1-KO and wild-type mice did not differ markedly. Our findings suggest that dysfunction of DISC1 may lead to the alteration of NPY neurons and neurotransmission issues in NPY-containing neuron systems, which seem to play important roles in both the mental function and neuronal development. DISC1 dysfunction may be involved in the pathogenesis of schizophrenia through the impairment of the NPY neuronal network. PMID- 28073592 TI - Corrigendum to "Toxic polyacetylenes in the genus Bupleurum (Apiaceae) - Distribution, toxicity, molecular mechanism and analysis" [J. Ethnopharmacol. 193 (2016) 566-573]. PMID- 28073593 TI - Integrative Cardiopulmonary Ultrasound for Interstitial Lung Disease Assessment: Correlation between Lung Ultrasound Performance and Cardiac Involvement. AB - The aims of this study were to apply integrative cardiopulmonary ultrasound (thoracic ultrasound) to the evaluation of patients with interstitial lung disease (ILD) and to determine the relationship between lung ultrasound signs and echocardiographic parameters such as systolic pulmonary artery pressure (SPAP) and various right ventricular parameters. ILD patients and healthy controls underwent lung ultrasound (LUS) and echocardiographic tests. In addition to traditional echocardiographic parameters, right ventricular free wall longitudinal strain (RVLS_FW) was measured using 2-D speckle-tracking echocardiography. The degree of pulmonary fibrosis or the disease severity of each ILD patient was scored with a semiquantitative scoring method, taking into account multiple LUS signs. Statistical analyses were performed to compare various parameters between ILD patients with and those without pulmonary hypertension. Correlations between the different parameters were then evaluated, and the LUS scores were used to predict pulmonary hypertension using a receiver operating characteristic curve analysis. Among the 90 patients who qualified for entry into this study, 30% (n = 27) had pulmonary hypertension. The patients with pulmonary hypertension had larger right ventricular dimensions, lower RVLS_FW and higher LUS scores. An effective correlation was found between ILD LUS scores and echocardiographic parameters, especially SPAP (r = 0.735, p < 0.001). The groups were comparable with respect to most echocardiographic parameters, with mild, moderate and severe pulmonary fibrosis, whereas SPAP was significantly higher in the moderate and severe groups. RVLS_FW was obviously reduced in the group with severe pulmonary fibrosis. Although RVLS_FW in the mild pulmonary fibrosis group was in the normal range, it was slightly reduced compared with that of the controls. A cutoff of more than 16 LUS points had 85.2% sensitivity and 80.3% specificity in predicting elevated SPAP (>36 mm Hg). Thoracic ultrasound is useful in the assessment of ILD. As ILD progresses, the structure or function of the right ventricle gradually deteriorates. LUS not only detects lung conditions in ILD, but also indirectly reflects SPAP and right ventricular function. Integrated use of LUS and echocardiography will provide an invaluable point-of care imaging modality to facilitate the diagnosis, management and treatment of patients with ILD. PMID- 28073594 TI - Analysis of readmission rates to the intensive care unit after implementation of a rapid response team in a University Hospital. AB - OBJECTIVES: To compare readmission rates to the intensive care unit (ICU) before and after the implementation of a rapid response team (RRT), and to identify risk factors for readmission. DESIGN: A quasi-experimental before-after study was carried out. SETTING: A University Hospital. PATIENTS: All patients discharged from the ICU from January to December 2008 (control group) and from January 2010 to December 2012 (intervention group). INTERVENTION: Implementation of an RRT. MAIN VARIABLES OF INTEREST: The data included demographic parameters, diagnoses upon admission, ICU readmission, APACHE II, SOFA, and TISS 28 scores, and routine daily assessment by an RRT of patients discharged from the ICU. RESULTS: During the study interval, 380 patients were analyzed in the period prior to the implementation of the RRT and 1361 after implementation. There was a tendency toward decreased readmission rates one year after RRT implementation. The APACHE II score and SOFA score at ICU discharge were independent factors associated to readmission, as well as clinical referral to the ICU. CONCLUSIONS: The RRT intervention resulted in a sustained decrease in readmission rates one year after implementation of this service. The use of a specialized team in health institutions can be recommended for ICU survivors. PMID- 28073596 TI - Quantitative EEG during normal aging: association with the Alzheimer's disease genetic risk variant in PICALM gene. AB - Genome-wide association studies have identified novel risk variants for Alzheimer's disease (AD). Among these, a gene carrying one of the highest risks for AD is PICALM. The PICALM rs3851179 A allele is thought to have a protective effect, whereas the G allele appears to confer risk for AD. The influence of the PICALM genotype on brain function in nondemented subjects remains largely unknown. We examined the possible effect of the PICALM rs3851179 genotype on quantitative electroencephalography recording at rest in 137 nondemented volunteers (age range: 20-79 years) subdivided into cohorts of those younger than and those older than 50 years of age. The homozygous presence of the AD risk variant PICALM GG was associated with an increase in beta relative power, with the effect being more pronounced in the older cohort. Beta power elevation in resting-state electroencephalography has previously been linked to cortical disinhibition and hyperexcitability. The increase in beta relative power in the carriers of the AD risk PICALM GG genotype suggests changes in the cortical excitatory-inhibitory balance, which are heightened during normal aging. PMID- 28073595 TI - Genetically encoded calcium indicators for studying long-term calcium dynamics during apoptosis. AB - Intracellular calcium release is essential for regulating almost all cellular functions. Specific spatio-temporal patterns of cytosolic calcium elevations are critical determinants of cell fate in response to pro-apoptotic cellular stressors. As the apoptotic program can take hours or days, measurement of long term calcium dynamics are essential for understanding the mechanistic role of calcium in apoptotic cell death. Due to the technical limitations of using calcium-sensitive dyes to measure cytosolic calcium little is known about long term calcium dynamics in living cells after treatment with apoptosis-inducing drugs. Genetically encoded calcium indicators could potentially overcome some of the limitations of calcium-sensitive dyes. Here, we compared the performance of the genetically encoded calcium indicators GCaMP6s and GCaMP6f with the ratiometric dye Fura-2. GCaMP6s performed as well or better than Fura-2 in detecting agonist-induced calcium transients. We then examined the utility of GCaMP6s for continuously measuring apoptotic calcium release over the course of ten hours after treatment with staurosporine. We found that GCaMP6s was suitable for measuring apoptotic calcium release over long time courses and revealed significant heterogeneity in calcium release dynamics in individual cells challenged with staurosporine. Our results suggest GCaMP6s is an excellent indicator for monitoring long-term changes cytosolic calcium during apoptosis. PMID- 28073597 TI - En-bloc resection of the pelvis (EnBRP) in patients with stage IIIC-IV ovarian cancer: A 10 steps standardised technique. Surgical and survival outcomes of primary vs. interval surgery. AB - OBJECTIVE: In this study we describe the technique of the En-bloc resection of the pelvis (EnBRP) in 10 standardised and reproducible steps, whereby all pelvic organs, except the bladder, are removed together with the peritoneum. In addition, we compare the surgical and survival outcomes of patients who underwent upfront vs. interval surgery. METHODS: Retrospective analysis of patients with FIGO Stage IIIC-IV ovarian cancer treated with Visceral Peritoneal Debulking (VPD) who had EnBRP. The study population was divided into Group 1 (up-front VPD) and group 2 (VPD after neo-adjuvant chemotherapy). The aim was to assess the incidence of EnBRP. We also assessed rate of complete resection (CR), procedure specific and overall morbidity, disease free and overall survival. Results were compared between group 1 and 2. RESULTS: Overall 92 out of 200 patients (46%) needed an EnBRP during the VPD. Forty-eight patients were in Group 1 and 44 patients in Group 2. CR was achieved in all patients. No intra-operative procedure specific morbidity was recorded. Dehiscence of bowel anastomosis was the only procedure specific morbidity. Rate was 2%, with 1 episode recorded in each group. Both patients were managed and settled with formation of a bowel diversion. The overall morbidity rate was 33%, 35% in group 1 and 31% in group 2. The mortality rate was 1%. Median disease free survival was 20months, 25 in group 1 vs. 15 in group 2 (P=0.009). CONCLUSIONS: EnBRP is a safe and effective technique to tackle the pelvic disease of patients with advanced ovarian cancer. The reduced blood loss, the high rate of clear margins and CR of the disease are accompanied by a low rate of surgical morbidity. These features are particularly suitable for patients who are due to start or re-start chemotherapy. The standardization of the technique will make it more reproducible and easier to be taught. In addition, it will facilitate comparison of results and the inclusion of this technique in the portfolio of procedures as part of debulking surgery. PMID- 28073599 TI - Psychotic mania induced by diffuse meditation. PMID- 28073598 TI - HDAC10 as a potential therapeutic target in ovarian cancer. AB - OBJECTIVE: We analyzed histone deacetylase 10 (HDAC10) for function in the context of the DNA damage response in BRCA1-null ovarian cancer cells as well as evaluated the potential of general HDAC inhibitors in primary ovarian carcinoma cells. HDAC10 had previously been shown to be highly stimulatory to the process of homology directed repair in HeLa cells, and in this study we investigated whether HDAC10 could impact in vitro the response to anticancer therapies. We hypothesized that the loss of HDAC10 would sensitize cells to platinum therapy. METHODS: We combined informatics analysis of large DNA sequencing datasets from ovarian cancer tumors with tissue culture based assays of primary and established cell lines to test for sensitivity to platinum therapy if HDAC10 activity was inhibited or depleted. RESULTS: Using The Cancer Genome Atlas (TCGA) dataset, we found that deep deletions in HDAC10 occurred in 5-10% of ovarian cancer tumors. From the TCGA data we found that low HDAC10 mRNA levels correlated with platinum sensitivity of the tumors. Cell proliferation and DNA damage assays in a BRCA1 null ovarian carcinoma cell line demonstrated reduced DNA repair capacity and sensitization of platinum therapy. Similarly, primary ovarian carcinoma cells demonstrated a sensitization to platinum therapies when treated with HDAC inhibitors. CONCLUSIONS: From the results of this study, we suggest that the inhibition of HDAC10 may potentiate the effects of platinum therapies in ovarian tumors. PMID- 28073600 TI - E-cigarettes and Urologic Health: A Collaborative Review of Toxicology, Epidemiology, and Potential Risks. AB - CONTEXT: Use of electronic cigarettes (ECs) is on the rise in most high-income countries. Smoking conventional cigarettes is a known risk factor for urologic malignancy incidence, progression, and mortality, as well as for other urologic health indicators. The potential impact of EC use on urologic health is therefore of clinical interest to the urology community. OBJECTIVE: To review the available data on current EC use, including potential benefits in urologic patients, potential issues linked to toxicology of EC constituents, and how this might translate into urologic health risks. EVIDENCE ACQUISITION: A Medline search was carried out in August 2016 for studies reporting urologic health outcomes and EC use. Snowballing techniques were also used to identify relevant studies from recent systematic reviews. A narrative synthesis of data around EC health outcomes, toxicology, and potential use in smoking cessation and health policy was carried out. EVIDENCE SYNTHESIS: We found no studies to date that have been specifically designed to prospectively assess urologic health risks, even in an observational setting. Generating such data would be an important contribution to the debate on the role of ECs in public health and clinical practice. There is evidence from a recent Cochrane review of RCTs that ECs can support smoking cessation. There are emerging data indicating that potentially harmful components of ECs such as tobacco-specific nitrosamines, polyaromatic hydrocarbons, and heavy metals could be linked to possible urologic health risks. CONCLUSIONS: ECs might be a useful tool to encourage cessation of conventional cigarette smoking. However, data collection around the specific impact of ECs on urologic health is needed to clarify the possible patient benefits, outcomes, and adverse events. PATIENT SUMMARY: While electronic cigarettes might help some people to stop smoking, their overall impact on urologic health is not clear. PMID- 28073601 TI - Re: Management of Nonmuscle Invasive Bladder Cancer: A Comprehensive Analysis of Guidelines from the Unites States, Europe, and Asia. PMID- 28073602 TI - Report on the 6th international FESTEM symposium on "New horizons on trace elements and minerals role in human and animal health" (Catania, Sicily, Italy, May 26-28th, 2016). PMID- 28073603 TI - Relationship between serum selenium, sociodemographic variables, other trace elements and lipid profile in an adult Spanish population. AB - INTRODUCTION: Several studies have shown an inverse relationship between selenium status and cardiovascular health, although epidemiologic evidence yielded by the randomized trials did not find a beneficial effect of selenium administration. The aim of this study was to analyze the association between serum selenium levels and lipid profile adjusted by age, sex and other associated factors among a general adult population in Spain. MATERIALS AND METHODS: We recruited 372 hospital employee volunteers (60 men and 312 women) with a mean age of 47 (SD: 10.9), whom were given a standardized questionnaire. Serum selenium concentration was measured by electrothermal atomization atomic absorption spectrometry. Serum copper and zinc concentrations were measured using flame atomic absorption spectrometry. RESULTS: The mean of serum selenium was 79.5MUg/L (SD: 11.7) with no sex-dependent differences. In the multivariate linear regression analysis, the associated factors with the mean levels of selenium were: age (beta=0.223; CI 95%: 0.101-0.345), p<0.001; widowhood (beta=-9.668; CI 95%: -17.234 to -2.102), p=0.012; calcium supplements (beta=3.949; CI 95%: 0.059-7.838), p=0.047; zinc (beta=0.126; CI 95%: 0.013-0.238), p=0.028 and glucose (beta=0.172; CI 95%: 0.062 0.281), p=0.002; Participants with serum selenium>=79.5MUg/L were 1.98 (OR=1.98; CI 95% 1.17-3.35; p=0.011) and 2.04 times (OR=2.04; CI 95% 1.06-3.97; p=0.034) more likely to have cholesterol >=200mg/dL and LDL-c >=100mg/dL respectively than those with serum selenium <79.5MUg/L. CONCLUSIONS: Higher selenium was positively associated with increased total and LDL cholesterol but not with HDL-c and triglycerides. More studies are needed in order to confirm the lower serum selenium findings in widows. PMID- 28073604 TI - Morphometric and genetic analysis of Arcella intermedia and Arcella intermedia laevis (Amoebozoa, Arcellinida) illuminate phenotypic plasticity in microbial eukaryotes. AB - Testate amoebae are eukaryotic microorganisms characterized by the presence of an external shell (test). The shell morphology is used as a diagnostic character, but discordance between morphological and molecular data has been demonstrated in groups of arcellinids (Amoebozoa), one of the principal groups of testate amoebae. Morphology of the test is supposed to differentiate genera and species and it is applied in ecological, monitoring and paleontological studies. However, if phenotype does not reflect genotype, conclusions in these types of studies become severely impaired. The objective of this work is to evaluate the morphometrical and morphological variation of the closely related and morphologically similar taxa Arcella intermedia laevis Tsyganov and Mazei, 2006 and Arcella intermedia (Deflandre 1928) Tsyganov and Mazei, 2006 in nature and in cultured individuals and see how these are correlated with molecular data. Our results demonstrate that phenotypic plasticity in Arcella intermedia make morphological distinctions impossible in both taxa. Arcella intermedia and Arcella intermedia laevis are molecularly identical for SSU rDNA and a mitochondrial molecular marker (NAD9/7). We conclude that morphological techniques alone cannot identify phenotypic plasticity from natural populations. More work is clearly needed to better understand the morphological, morphometric and molecular variability in these organisms. PMID- 28073605 TI - Comprehensive association analysis of 27 genes from the GABAergic system in Japanese individuals affected with schizophrenia. AB - Involvement of the gamma-aminobutyric acid (GABA)-ergic system in schizophrenia pathogenesis through disrupted neurodevelopment has been highlighted in numerous studies. However, the function of common genetic variants of this system in determining schizophrenia risk is unknown. We therefore tested the association of 375 tagged SNPs in genes derived from the GABAergic system, such as GABAA receptor subunit genes, and GABA related genes (glutamate decarboxylase genes, GABAergic-marker gene, genes involved in GABA receptor trafficking and scaffolding) in Japanese schizophrenia case-control samples (n=2926; 1415 cases and 1511 controls). We observed nominal association of SNPs in nine GABAA receptor subunit genes and the GPHN gene with schizophrenia, although none survived correction for study-wide multiple testing. Two SNPs located in the GABRA1 gene, rs4263535 (Pallele=0.002; uncorrected) and rs1157122 (Pallele=0.006; uncorrected) showed top hits, followed by rs723432 (Pallele=0.007; uncorrected) in the GPHN gene. All three were significantly associated with schizophrenia and survived gene-wide multiple testing. Haplotypes containing associated variants in GABRA1 but not GPHN were significantly associated with schizophrenia. To conclude, we provided substantiating genetic evidence for the involvement of the GABAergic system in schizophrenia susceptibility. These results warrant further investigations to replicate the association of GABRA1 and GPHN with schizophrenia and to discern the precise mechanisms of disease pathophysiology. PMID- 28073606 TI - Load-dependent hyperdeactivation of the default mode network in people with schizophrenia. AB - Schizophrenia is associated with impairment in a range of cognitive functions. Neuroimaging studies have reported lower, but also higher, task-induced activation accompanying impaired performance. Differences in task-load and the ability of people with schizophrenia (PSZ) to stay engaged in the cognitive operations probed appear to underlie such discrepancies. Similarly, task-induced deactivation of the default mode network (DMN) was weaker in PSZ relative to healthy control subjects (HCS) in most studies, but some reported greater deactivation. An inability to stay engaged in the cognitive operations could account for these discrepancies, too, as it would lead to more time off-task and consequently less deactivation of DMN functions. The present study employed a change detection paradigm with small to moderate set sizes (SSs) of 1, 2, and 4 items. Task training prior to fMRI scanning abolished the group difference in no response trials. Task-positive regions of interest (ROIs) displayed greater activation with increasing SS in both groups. PSZ showed greater activation relative to HCS at SSs 1 and 2. DMN ROIs displayed greater deactivation with increasing SS in PSZ, but not in HCS, and PSZ tended to hyperdeactivate DMN regions at SS 4. No hypodeactivation was observed in PSZ. In conclusion, when minimizing differences in task-engagement, PSZ tend to over-recruit task-positive regions during low-load operations, and hyperdeactivate DMN functions at higher load, perhaps reflecting heightened non-specific vigilance or effort when dealing with cognitive challenges. This speaks against an inability to down-regulate task independent thought processes as a primary mechanism underlying cognitive impairment in schizophrenia. PMID- 28073607 TI - Thermal Ablation versus Surgical Resection for the Treatment of Stage T1 Hepatocellular Carcinoma in the Surveillance, Epidemiology, and End Results Database Population. AB - PURPOSE: To compare survival outcomes of small solitary hepatocellular carcinomas (HCCs) treated with thermal ablation vs resection in the Surveillance, Epidemiology, and End Results (SEER) cohort. MATERIALS AND METHODS: SEER data (November 2014 submission) were searched for histologic diagnoses of HCC and stage T1 disease (<= 5-cm solitary tumor without vascular invasion). Comparison was made between thermal ablation and resection as the primary treatment. Overall and disease-specific survival were compared by log-rank tests (stratified for presence of fibrosis) and Cox regression (with tumor size and presence of fibrosis covariates). RESULTS: Of 264 patients with <= 2-cm HCCs, 185 underwent thermal ablation and 79 underwent resection. Patients undergoing ablation had higher Ishak scores (P = .0002). There was no difference in survival (observed P = .698, disease-specific P = .446). Of 544 patients with 2.1-4-cm HCCs, 335 underwent thermal ablation and 209 underwent resection. Patients undergoing ablation were more likely to have higher Ishak scores (P < .001), but had slightly smaller tumors (2.9 vs 3.1 cm; P < .001). There was no difference in survival (observed P = .174, disease-specific P = .609). Of 112 patients with 4.1 5-cm HCCs, 46 underwent thermal ablation and 66 underwent resection. Patients undergoing ablation had higher Ishak scores (P = .0002). Surgical resection was associated with improved survival (observed P = .009, disease-specific P = .046). CONCLUSIONS: There was no difference in overall or disease-specific survival between surgical resection and thermal ablation for T1 HCCs <= 4 cm after adjusting for the presence of histologic fibrosis and tumor size in the SEER cohort. Significant benefit was observed with surgery for tumors measuring 4.1-5 cm. PMID- 28073608 TI - Design, synthesis and biological evaluation of 7-(aryl)-2,3-dihydro [1,4]dioxino[2,3-g]quinoline derivatives as potential Hsp90 inhibitors and anticancer agents. AB - A new series of quinoline analogues was designed and synthesized as Hsp90 inhibitors. The cytotoxic activity of the synthesized compounds was evaluated against three human cancer cell lines including MCF-7 (human breast cancer cells), DU145 (human prostate cancer cell lines), and A549 (adenocarcinomic human alveolar basal epithelial cells). Some of our compounds (13a-13f) showed significant cytotoxic activity on MCF-7 cells. The most potent anti-proliferative compounds were also tested against Her2, a client protein of Hsp90. Compound 13d that demonstrated the highest antiproliferative activity in the series, was found the most potent one for both Her2 protein degradation and Hsp70 protein induction as well. Molecular modeling studies displayed possible mode of interaction between this compound and N-terminal ATP-binding site of Hsp90. PMID- 28073609 TI - Interaction of older donor age and survival after weight-matched pediatric heart transplantation. AB - BACKGROUND: Donors are matched for weight in pediatric heart transplantation (PHT), yet age differences are not considered in this decision. In this study we attempt to identify the effect of age differences in weight-matched patients and the effect these differences have on post-transplant survival. METHODS: The United Network of Organ Sharing (UNOS) database was queried for the period from October 1987 to March 2014 for all pediatric heart transplant patients. Transplants with donor-to-recipient (D-R) weight ratios of 0.8 to 1.5 were identified (weight-matched). D-R age differences were categorized as: donors 5 years younger than recipients (DR+5). RESULTS: A total of 4,408 patients were identified as weight-matched transplants. Of these transplants, 681 were D>R+5, 3,596 were D=R+/-5 and 131 were DR+5 transplants were found to be associated with decreased post-transplant survival compared with D=R+/-5 (p = 0.002). Rates of acute rejection were similar among all groups but post transplant coronary allograft vasculopathy (CAV) was more prevalent in D>R+5 than D=R+/-5 patients (28% and 18%, respectively; p < 0.001). Increasing age difference by each year was associated with decreasing median post-transplant survival time (p < 0.001; hazard ratio 1.018, range 1.011 to 1.025). The overall negative association with mortality was due to the adolescent cohort (11 to 17 years), specifically D>R+5 transplants, utilizing organs from donors >25 of age. CONCLUSION: In PHT, increasing D-R age difference decreases survival; however, this effect is driven by recipients 11 to 17 years old and donors >25 years old. Allocation of younger donor organs to adolescent recipients should be a priority. PMID- 28073610 TI - Anonymous biomedical publications for security reason? An open letter to the ICJME. PMID- 28073611 TI - Propofol versus midazolam for procedural sedation in the emergency department: A study on efficacy and safety. AB - BACKGROUND: Procedural sedation for painful procedures in the emergency department (ED) can be accomplished with various pharmacological agents. The choice of the sedative used is highly dependent on procedure- and patient characteristics and on personal- or local preferences. METHODS: We conducted a multicenter retrospective cohort study of procedural sedations performed in the EDs of 5 hospitals in the Netherlands over a 4year period to evaluate the efficacy- (success rate of the intended procedure) and safety (incidence of sedation (adverse) events) of propofol sedations compared to midazolam sedations. RESULTS: A total of 592 ED sedations were included in our study. Patients sedated with propofol (n=284, median dose 75mg) achieved a deeper level of sedation (45% vs. 25% deep sedation, p<0.001), had a higher procedure success rate (92% vs. 81%, p<0.001) and shorter median sedation duration (10 vs. 17min, p<0.001) compared to patients receiving midazolam (n=308, median dose 4mg). A total of 112 sedation events were registered for 99 patients. Transient apnea was the most prevalent event (n=73), followed by oxygen desaturation (n=18) airway obstruction responsive to simple maneuvers (n=13) and hypotension (n=6). Propofol sedations were more often associated with the occurrence of apnea's (20% vs. 10%, p=0.004), whereas clinically relevant oxygen desaturations (<90%) were found more often in patients sedated with midazolam (8% vs. 1%, p=0.001). No sedation adverse events were registered CONCLUSION: Propofol is more effective and at least as safe as midazolam for procedural sedation in the ED. PMID- 28073612 TI - Gonorrhea and chlamydia in the emergency department: Continued need for more focused treatment for men, women and pregnant women. AB - INTRODUCTION: Delay in current nucleic acid amplification testing for Neisseria gonorrhoeae and Chlamydia trachomatis has led to recommendations for presumptive treatment in patients with concern for infection and unreliable follow-up. In the urban setting, it is assumed that many patients have unreliable follow-up, therefore presumptive therapy is thought to be used frequently. We sought to measure the frequency of disease and accuracy of presumptive treatment for these infections. METHODS: This was an observational cohort study performed at an urban academic Level 1 trauma center ED with an annual census of 95,000 visits per year. Testing was performed using the APTIMA Unisex swab assay (Gen-Probe Incorporated, San Diego, CA). Presumptive therapy was defined as receiving treatment for both infections during the initial encounter without confirmation of diagnosis. RESULTS: A total of 1162 patients enrolled. Infection was present in 26% of men, 14% of all women and 11% of pregnant women. Despite high frequency of presumptive treatment, >4% of infected patients in each category went untreated. CONCLUSION: Inaccuracy of presumptive treatment was common for these sexually transmitted infections. There is an opportunity to improve diagnostic accuracy for treatment. PMID- 28073613 TI - Effect of nasal allergen challenge in allergic rhinitis on mitochondrial function of peripheral blood mononuclear cells. PMID- 28073614 TI - Underuse of allergy services for patients having systemic reactions to Hymenoptera venom stings. PMID- 28073616 TI - Challenges and Research in Managing Blood Supply in China. AB - Although considerable progress has been made in improving the blood service system in China over the last 2 decades, many challenges remain. A number of issues have received public attentions; however, others continue to be underacknowledged and controversial. This article describes 3 of these important and less emphasized issues: first, the ambiguity of the definition of voluntary nonremunerated blood donation and its relationship to an adequate blood supply; second, the current inadequacies of cost recovery from the blood service system; and third, the lack of a universally implemented program of hemovigilance. Currently, there is controversy regarding these challenges. Open recognition and discussion offers the prospect of bringing solutions closer to reality. PMID- 28073615 TI - Randomized trial of a question prompt list to increase patient active participation during interactions with black patients and their oncologists. AB - OBJECTIVE: Communication during racially-discordant interactions is often of poor quality and may contribute to racial treatment disparities. We evaluated an intervention designed to increase patient active participation and other communication-related outcomes during interactions between Black patients and non Black oncologists. METHODS: Participants were 18 non-Black medical oncologists and 114 Black patients at two cancer hospitals in Detroit, Michigan, USA. Before a clinic visit to discuss treatment, patients were randomly assigned to usual care or to one of two question prompt list (QPL) formats: booklet (QPL-Only), or booklet and communication coach (QPL-plus-Coach). Patient-oncologist interactions were video recorded. Patients reported perceptions of the intervention, oncologist communication, role in treatment decisions, and trust in the oncologist. Observers assessed interaction length, patient active participation, and oncologist communication. RESULTS: The intervention was viewed positively and did not increase interaction length. The QPL-only format increased patient active participation; the QPL-plus-Coach format decreased patient perceptions of oncologist communication. No other significant effects were found. CONCLUSION: This QPL booklet is acceptable and increases patient active participation in racially-discordant oncology interactions. Future research should investigate whether adding physician-focused interventions might improve other outcomes. PRACTICE IMPLICATIONS: This QPL booklet is acceptable and can improve patient active participation in racially-discordant oncology interactions. PMID- 28073617 TI - District Policies and Practices Vary in Their Association With Adolescents' Consumption of Milk and 100% Fruit Juice. AB - PURPOSE: Researchers previously examined the relationship between school beverage policies and sugar-sweetened beverage (SSB) consumption. This study addressed a research gap by examining cross-sectional associations between district-level policies and practices and U.S. high school students' consumption of milk and 100% fruit juice. METHODS: Data from the 2012 School Health Policies and Practices Study and 2013 Youth Risk Behavior Surveillance System were linked for 12 large urban school districts. Outcome variables were daily milk consumption (>=1 glass/day) and 100% fruit juice consumption (>=1 time/day). Exposure variables were five district policies (i.e., restrict SSB sales, maintain closed campuses, offer/sell healthful alternatives, restrict promotional products, and require nutrition education). Logistic regression models estimated the odds of consuming milk or 100% fruit juice daily, conditional on the policies and adjusting for sex, race/ethnicity, grade level, weight status, and district free/reduced-price lunch eligibility (n = 23,173). RESULTS: Students in districts that required/recommended restricting the times of SSB sales had 55% higher (adjusted odds ratio [AOR], 1.55; 95% confidence interval [CI], 1.28-1.87) odds of consuming >=1 glass/day of milk than students in districts without this policy. Closed campus policies were associated with lower odds of consuming milk (AOR, .72; 95% CI, .63-.82) and higher odds of consuming juice (AOR, 1.27; 95% CI, 1.07-1.50). Policies requiring/recommending that districts offer/sell healthful alternatives were associated with lower odds of consuming 100% fruit juice daily. CONCLUSIONS: Results suggest that restricting SSB sales may support adolescents' milk consumption. Future studies should assess whether the implementation of federal standards that further restrict SSB sales in school leads to increased milk consumption. PMID- 28073618 TI - Characteristics of Adolescents Lacking Provider-Recommended Human Papillomavirus Vaccination. AB - PURPOSE: To characterize subgroups of teens in the United States for whom provider recommendation is less likely to impact human papillomavirus (HPV) vaccine initiation. METHODS: We analyzed provider-verified vaccination data from the Centers for Disease Control and Prevention's 2014 National Immunization Survey-Teen. Poisson regression models identified characteristics associated with the lack of HPV vaccine initiation among teens who received a provider recommendation (n = 12,742). Top qualitative reasons for nonvaccination among teens who received a provider recommendation were summarized (n = 1,688). RESULTS: Among teens with provider recommendations, males, younger teens, and white teens were less likely to initiate vaccination, compared to peers. Believing the vaccine was unnecessary, concerns about safety and lack of vaccine knowledge were common reasons parents did not initiate the vaccine, despite receiving provider recommendations. CONCLUSIONS: These key subgroups and barriers to HPV vaccination should be targeted with interventions that complement provider recommendation to achieve broad vaccine uptake in the United States. PMID- 28073620 TI - Electrochemical monitoring of native catalase activity in skin using skin covered oxygen electrode. AB - A skin covered oxygen electrode, SCOE, was constructed with the aim to study the enzyme catalase, which is part of the biological antioxidative system present in skin. The electrode was exposed to different concentrations of H2O2 and the amperometric current response was recorded. The observed current is due to H2O2 penetration through the outermost skin barrier (referred to as the stratum corneum, SC) and subsequent catalytic generation of O2 by catalase present in the underlying viable epidermis and dermis. By tape-stripping the outermost skin layers we demonstrate that SC is a considerable diffusion barrier for H2O2 penetration. Our experiments also indicate that skin contains a substantial amount of catalase, which is sufficient to detoxify H2O2 that reaches the viable epidermis after exposure of skin to high concentrations of peroxide (0.5-1mM H2O2). Further, we demonstrate that the catalase activity is reduced at acidic pH, as compared with the activity at pH 7.4. Finally, experiments with often used penetration enhancer thymol shows that this compound interferes with the catalase reaction. Health aspect of this is briefly discussed. Summarizing, the results of this work show that the SCOE can be utilized to study a broad spectrum of issues involving the function of skin catalase in particular, and the native biological antioxidative system in skin in general. PMID- 28073619 TI - Cytomegalovirus Serostatus as Predictor for Adverse Events After Cardiac Surgery: A Prospective Observational Study. AB - OBJECTIVE: To clarify whether reactivated cytomegalovirus (CMV) infections in critically ill patients lead to worse outcome or just identify more severely ill patients. If CMV has a pathogenic role, latently infected (CMV-seropositive) patients should have worse outcome than seronegative patients because only seropositive patients can experience a CMV reactivation. DESIGN: Post-hoc analysis of a prospective observational study. SETTING: Single university hospital. PARTICIPANTS: The study comprised 983 consecutive patients scheduled for on-pump surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: CMV antibodies were analyzed in preoperative plasma samples. Postoperative adverse events (reintubation, low cardiac output or reinfarction, dialysis, stroke) and 30-day and 1-year mortality were evaluated prospectively. The plasma of reintubated patients and matched control patients was tested for CMV deoxyribonucleic acid, and 618 patients were found to be seropositive for CMV (63%). Among these, the risk for reintubation was increased (10% v 4%, p = 0.001). This increase remained significant after correction for confounding factors (odds ratio 2.70, p = 0.003) and was detectable from the third postoperative day throughout the whole postoperative period. Other outcome parameters were not different. Reintubated seropositive patients were more frequently CMV deoxyribonucleic acid-positive than were matched control patients (40% v 8%, p<0.001). CONCLUSIONS: CMV-seropositive patients had an increased risk of reintubation after cardiac surgery, which was associated with reactivations of their CMV infections. Additional studies should determine whether this complication may be prevented by monitoring of latently infected patients and administering antiviral treatment for reactivated CMV infections. PMID- 28073621 TI - Community Engagement for Pediatric Nurses: No Longer a Choice. PMID- 28073622 TI - Cost of Children's Healthy vs Unhealthy Snacks Does Not Differ at Convenience Stores. AB - OBJECTIVE: This study compared the prices of unhealthy (chips) and healthy (ready to-eat fruit) snacks that students are likely to purchase from corner stores. METHODS: Snacks were purchased from 325 New Jersey corner stores; chip prices were compared with fruit prices overall and by store sales volume and block group characteristics. RESULTS: Prices did not differ significantly between chips and fruit in the overall sample in which both items were available (n = 104) (chips: $0.46 +/- $0.15; fruit: $0.49 +/- $0.19; P = .48) or by store or block group characteristics. Neither mean fruit prices nor mean chip prices differed by store sales volume or by neighborhood characteristics. CONCLUSIONS AND IMPLICATIONS: Promoting ready-to-eat fruits in corner stores to children as a price-neutral alternative to calorically dense snacks can be a viable strategy to improve the nutritional quality of snacks commonly purchased at corner stores. PMID- 28073624 TI - European College of Orthodontics: Commission of affiliation and titularisation. AB - : Date of birth: 2/8/1982; sex: male. A. PRETREATMENT RECORDS: 25 years; 7/3/2008. DIAGNOSIS: Very severe Class III malocclusion in adult dentition in hyperdivergent facial pattern; Sagittal dimension: skeletal and dental Class II, severe alveolar retrusion of the mandibular incisors, negative overjet (-11mm); transverse dimension: Class III-related bilateral crossbite with no transverse maxillary deficiency; vertical dimension: incisor overbite, increased height of the lower facial third; Teeth missing prior to treatment: 16-26. TREATMENT PLAN: Appliances or procedures: multi-bracket bi-maxillary appliance and maxillofacial surgery; arch decompensation; maxillofacial surgery; fixed retainers; beginning of treatment: 26 years; 10/01/2009. B. POSTTREATMENT RECORDS: 17/2/2011; 28 years. DURATION OF ACTIVE TREATMENT: 25 months. RETENTION: Maxillary: 17/2/2011; mandibular: 17/2/2011. C. POST-RETENTION RECORDS: (1 year minimum): 25/04/2016; 33 years; duration of retention: lifelong. Post-retention duration: 5years and 2months. PMID- 28073623 TI - Stretching Food and Being Creative: Caregiver Responses to Child Food Insecurity. AB - OBJECTIVE: To examine the strategies and behaviors caregivers use to manage the household food supply when their children experience food insecurity as measured by the US Department of Agriculture's Household Food Security Survey Module. DESIGN: Cross-sectional survey with open-ended questions collected in person. SETTING: Urban and nonurban areas, South Carolina, US. PARTICIPANTS: Caregivers who reported food insecurity among their children (n = 746). PHENOMENON OF INTEREST: Strategies and behaviors used to manage the household food supply. ANALYSIS: Emergent and thematic qualitative coding of open-ended responses. RESULTS: The top 3 strategies and behaviors to change meals were (1) changes in foods purchased or obtained for the household, (2) monetary and shopping strategies, and (3) adaptations in home preparation. The most frequently mentioned foods that were decreased were protein foods (eg, meat, eggs, beans), fruits, and vegetables. The most frequently mentioned foods that were increased were grains and starches (eg, noodles), protein foods (eg, beans, hot dogs), and mixed foods (eg, sandwiches). CONCLUSIONS AND IMPLICATIONS: Caregivers use a wide variety of strategies and behaviors to manage the household food supply when their children are food insecure. Future work should examine how these strategies might affect dietary quality and well-being of food-insecure children. PMID- 28073625 TI - ? PMID- 28073626 TI - ? PMID- 28073627 TI - Angular photogrammetric analysis and evaluation of facial esthetics of young Ivorians with normal dental occlusion. AB - AIM: The aim of this study was to evaluate the angular photogrammetric characteristics of subjects according to the facial esthetics criteria applicable in Cote d'Ivoire. MATERIAL AND METHODS: This was a horizontal study, concerning of group of young people from Cote d'Ivoire whose attractiveness and photogrammetric characteristics were assessed. The data obtained were analyzed using SPSS 20.0 statistical software. The limit of statistical significance was P<0.05. Subjects were characterized by PCA. RESULTS: Attractive subjects had a large mid-face section with an upturned nose (P<0.01). Attractive women had facial profiles that were more convex than men who were judged handsome. CONCLUSION: Despite the subjectivity of the notion of beauty, certain angles of the facial profile contribute to the esthetic balance of black Ivorian faces. PMID- 28073628 TI - Response to correspondence regarding Cutshall, Bergstrom, Kalish's "Evaluation of a functional medicine approach to treating fatigue, stress, and digestive issues in women". PMID- 28073629 TI - Needs of fathers during labour and childbirth: A cross-sectional study. AB - Fathers play an important role in the childbearing process, but are sometimes sidelined by midwives. The objectives were: identify fathers' needs during the labor and childbirth process; determine if their needs were met by midwives; and identify variables influencing these needs. The questionnaire was designed based on a systematic literature search and validated by a multistage consensus method. Data were collected during a cross-sectional study in two maternity wards in Belgium, where a medical-led model is used. Fathers present during natural childbirth were recruited via consecutive sampling. Based on multivariate analyses, fathers with a higher education level and multiparous fathers needed less information about the process of birth compared to less educated fathers (p<0.05; OR=4.08; 95% CI=1.02-16.31) or first-time fathers (p<0.001; OR=0.04; 95% CI=0.01-0.18). For multiparous fathers, a tour of the delivery room was less important than for primiparous fathers (p=0.005; OR=0.14; 95% CI=0.03-0.54). Married fathers needed less information on how to support their partners physically (p<0.005; OR=0.18; 95% CI=0.06-0.59) and emotionally (p=0.01; OR=0.24; 95% CI=0.08-0.72) compared to cohabiting fathers. Information needs are more important to fathers compared to needs focusing on the birth experience or their involvement. Socio-demographic variables like educational level, parity, and marital status were associated with fathers' needs. Midwives need to be aware of fathers' needs during the birth process and to fulfill these needs appropriately. PMID- 28073630 TI - ADONA and perfluoroalkylated substances in plasma samples of German blood donors living in South Germany. AB - Perfluorinated compounds are fully fluorinated anthropogenic substances that have been used in various products, applications, and industrial processes. Due to their persistence and toxic effects, some of them are restricted, and therefore replacement products have been developed. The aim of the study was to quantify the body burden of different perfluorinated substances in two adult populations living close to or about 80km apart from a former perfluorooctanoate (PFOA) production plant who are exposed via drinking water, and in a control population. In this plant, the replacement emulsifier 3H-perfluoro-3-[(3-methoxy propoxy)propanoic acid] (ADONA) has been used in the production of fluoropolymers since 2008. We quantified 7 perfluorinated compounds and ADONA in a total of 396 plasma samples collected at different time points. With regard to samples collected in 2015 or 2016, the highest 95th percentile levels were 13.5MUg/l for perfluorooctane sulfonate (PFOS), 3.0MUg/l for perfluorononanoate (PFNA), and 1.5MUg/l for perfluorohexane sulfonate (PFHxS). For PFOA, the highest 95th percentile was found at the site close to the facility (85.5MUg/l), while in the control region the value was 2.4MUg/l. Overall, the concentration of PFOA and PFOS declined over time in all study regions. ADONA was detected only in few samples slightly above the limit of quantification (0.2MUg/l). While health risks related to ADONA are unlikely under the present exposure situation, the exposure to PFOA via tap water should be reduced markedly, especially for the population living close to the plant. PMID- 28073632 TI - Chronic wounds? PMID- 28073631 TI - Assessing motivation to smoking cessation in hospitalized patients. AB - AIM: To assess motivation to quit smoking in patients admitted to an acute care hospital, determine predictors of readiness to change, and identify a risk group that requires targeted motivational interviewing. METHODS: A cross-sectional descriptive study. A retrospective study was performed on the medical records of 248 patients aged >18 years with smoking habits admitted to the medical and surgery units of a district hospital between May 2014 and April 2015. The data collected included sociodemographic data, data on respiratory function, number of cigarettes smoked per day, motivation to quit smoking, patient-reported readiness to quit, history of respiratory diseases and previous admissions. RESULTS: The Richmond test revealed that 54% of patients (n=134) were poorly motivated to quit smoking vs. 11.74% (n=29) who reported to be highly motivated. The group of patients who reported to be willing to receive support (n=77) was prevailingly composed of men (p=.009) admitted to a medical care unit (p=.026) -mainly the Unit of Cardiology (51%)- who smoked 11/29 cigarettes/day (p=.015). Dyspnoea at admission, a history of respiratory disease and previous admissions for respiratory problems were not predictors of readiness to quit. CONCLUSIONS: This study identifies a risk group of patients with respiratory disease, low motivation to quit smoking and poor readiness to receive smoke cessation support, that should be the target of motivational approaches to behavior change. PMID- 28073633 TI - University teaching in how to manage emotions and establish a therapeutic bond with the patient. PMID- 28073634 TI - Cystic adenomatoid pulmonary malformation in adults: A retrospective study in a tertiary university hospital. PMID- 28073636 TI - Prognosis of double crown-retained removable dental prostheses compared with clasp-retained removable dental prostheses: A retrospective study. AB - PURPOSE: The present study compared the clinical prognosis of double crown retained removable dental prostheses (D-DRPs) with that of clasp-retained removable dental prostheses (C-RDPs). METHODS: Clinical records of 201 patients who had received 52 D-RDPs with 144 abutment teeth (D-teeth) and 199 C-RDPs with 399 abutment teeth (C-teeth) at the Prosthetic Dentistry Clinic in Hokkaido University Hospital between April 2005 and June 2015 were analyzed. Survival and complication probabilities of the two types of prostheses and abutment teeth were evaluated using the Kaplan-Meier method and compared using the log-rank test. Cox regression analysis was used to determine the impact of covariates on abutment teeth survival and complications such as gender, age, type of retainer, Eichner classification, jaw, type of tooth, endodontic therapy performed, type of edentulous space, and presence of opposing teeth. RESULTS: Statistical analysis showed no significant differences between the two types of prostheses in terms of prostheses survival, prostheses complication, and abutment teeth survival. However, a significant difference was observed for complications of abutment teeth. Decementation was the most frequent cause of failure, which occurred in 76.9% of D-teeth and 28.3% of C-teeth. Patient's age, jaw, endodontic therapy performed, and type of edentulous space affected the survival of abutment teeth, whereas the type of retainer and edentulous space affected complications of abutment teeth. CONCLUSION: The prognosis of both types of prostheses was considered to be acceptable. Although D-RDP had lower complication-free rates for abutment teeth, most of the observed complications were decementation, which was considered to be reparable. PMID- 28073637 TI - Variable angle stereo imaging for rapid patient position correction in an in house real-time position monitoring system. AB - PURPOSE: To develop and validate a variable angle stereo image based position correction methodology in an X-ray based in-house online position monitoring system. MATERIALS AND METHODS: A stereo imaging module that enables 3D position determination and couch correction of the patient based on images acquired at any arbitrary angle and arbitrary angular separation was developed and incorporated to the in-house SeedTracker real-time position monitoring system. The accuracy of the developed system was studied by imaging an anthropomorphic phantom implanted with radiopaque markers set to known offset positions from its reference position in an Elekta linear accelerator (LA) and associated XVI imaging system. The accuracy of the system was further validated using CBCT data set from 10 prostate SBRT patients. The time gains achieved with the stereo image based position correction was compared with the manual matching of seed positions in Digitally Reconstructed Radiographs (DRRs) and kV images in the Mosaiq record and verify system. RESULTS: Based on phantom and patient CBCT dataset study stereo imaging module implemented in the SeedTracker shown to have an accuracy of 0.1(sigma=0.5)mm in detecting the 3D position offset. The time comparison study showed that stereo image based methodology implemented in SeedTracker was a minimum of 80(4)s faster than the manual method implemented in Mosaiq R&V system with a maximum time saving of 146(6)s. CONCLUSION: The variable angle stereo image based position correction method was shown to be accurate and faster than the standard manual DRR-kV image based correction approach, leading to more efficient treatment. PMID- 28073635 TI - PCNA dependent cellular activities tolerate dramatic perturbations in PCNA client interactions. AB - Proliferating cell nuclear antigen (PCNA) is an essential cofactor for DNA replication and repair, recruiting multiple proteins to their sites of action. We examined the effects of the PCNAS228I mutation that causes PCNA-associated DNA repair disorder (PARD). Cells from individuals affected by PARD are sensitive to the PCNA inhibitors T3 and T2AA, showing that the S228I mutation has consequences for undamaged cells. Analysis of the binding between PCNA and PCNA-interacting proteins (PIPs) shows that the S228I change dramatically impairs the majority of these interactions, including that of Cdt1, DNMT1, PolD3p66 and PolD4p12. In contrast p21 largely retains the ability to bind PCNAS228I. This property is conferred by the p21 PIP box sequence itself, which is both necessary and sufficient for PCNAS228I binding. Ubiquitination of PCNA is unaffected by the S228I change, which indirectly alters the structure of the inter-domain connecting loop. Despite the dramatic in vitro effects of the PARD mutation on PIP-degron binding, there are only minor alterations to the stability of p21 and Cdt1 in cells from affected individuals. Overall our data suggests that reduced affinity of PCNAS228I for specific clients causes subtle cellular defects in undamaged cells which likely contribute to the etiology of PARD. PMID- 28073638 TI - Stimulation of the human medial temporal lobe between learning and recall selectively enhances forgetting. AB - BACKGROUND: Direct electrical stimulation applied to the human medial temporal lobe (MTL) typically disrupts performance on memory tasks, however, the mechanism underlying this effect is not known. OBJECTIVE: To study the effects of MTL stimulation on memory performance. METHODS: We studied the effects of MTL stimulation on memory in five patients undergoing invasive electrocorticographic monitoring during various phases of a memory task (encoding, distractor, recall). RESULTS: We found that MTL stimulation disrupted memory performance in a timing dependent manner; we observed greater forgetting when applying stimulation during the delay between encoding and recall, compared to when it was applied during encoding or recall. CONCLUSIONS: The results suggest that recall is most dependent on the MTL between learning and retrieval. PMID- 28073639 TI - Association between volume and glucose metabolism of abdominal adipose tissue in healthy population. AB - OBJECTIVE: We investigated the association of adipose tissue volume and metabolic activity with cardiometabolic risk factors. METHODS: 232 healthy subjects (43.23+/-4.09y) having 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) results were included. Clinical information, anthropometry and laboratory results were obtained. Volume and metabolic activity of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) was obtained from FDG PET/CT. Metabolic activity was presented as mean standardised uptake value (SUV). Adipose tissue parameters were compared with clinical and biochemical factors. Independent factors affecting adipose tissue volume were assessed. RESULTS: Both SAT and VAT volume showed strong positive correlation with most of cardiometabolic risk factors. Among them, lipid profiles, insulin and C-reactive protein (CRP) had more significant relationship with SUV of SAT than that of VAT. On the contrary, glucose, glycated hemoglobin, and degree of fatty liver showed more significant correlation with SUV of VAT. BMI, age, sex and CRP were independent predictors of SAT volume. BMI, age, triglyceride, CRP and fatty liver were independent variables predicting VAT volume. Adding SUV of adipose tissue improved the model performance. CONCLUSION: This study demonstrated that metabolic activities of SAT and VAT were differently correlated with risk factors, suggesting different biologic mechanism for obesity. PMID- 28073640 TI - Pharmaceuticals in a temperate forest-water reuse system. AB - Forest-water reuse systems infiltrate municipal, industrial, and agricultural wastewaters through forest soils to shallow aquifers that ultimately discharge to surface waters. Their ability to mitigate regulated nutrients, metals, and organic chemicals is well known, but the fate of non-regulated chemicals in these systems is largely unstudied. This study quantified 33 pharmaceuticals and personal care products (PPCPs) in soils, groundwaters, and surface waters in a 2000-hectare forest that receives ~1200mm/year of secondary-treated, municipal wastewater in addition to natural rainfall (~1300mm/year). This forest-water reuse system does contribute PPCPs to soils, groundwater, and surface waters. PPCPs were more abundant in soils versus underlying groundwater by an order of magnitude (5-10ng/g summed PPCPs in soil and 50-100ng/L in groundwater) and the more hydrophobic chemicals were predominant in soil over water. PPCP concentrations in surface waters were greater at the onset of significant storm events and during low-rainfall periods when total summed PPCPs were >80ng/L, higher than the annual average. With few exceptions, the margins of exposure for PPCPs in groundwater and surface waters were several orders of magnitude above values indicative of human health risk. PMID- 28073641 TI - Effect of surfactants on the aggregation and sedimentation of zinc oxide nanomaterial in natural water matrices. AB - The wide application of surfactants and engineered nanomaterials (ENMs) in industrial and consumer products lead to the high possibility of their co presence in natural water environment, making it important to study the effect of surfactants on the environmental behavior and fate of ENMs. In this work, we selected an anionic sodium dodecyl sulfate (SDS) and a nonionic nonylphenol ethoxylate (NPEO, Tergitol NP-9) to study their effects on the aggregation and sedimentation of a 20nm ZnO ENM in different water matrices. The adsorption of SDS and NP-9 by ZnO ENM were fitted with Langmuir model, and the maximum adsorption capacities were 43.73+/-4.62mg/g and 13.79+/-1.09 respectively. As the surfactant concentration increased from 0 to 0.030% (m:v), SDS reduced the zeta potential of ZnO ENM from 17.56+/-2.13 to -27.96+/-2.59mV, whereas NP-9 did not affect the zeta potential. After a 24-h batch reactor experiment, SDS and NP-9 reduced 93.02% and 80.26% of the aggregate size of ZnO ENM (50mgL-1) in maximum at surfactant concentrations>=0.015%. The ZnO ENM was not stable in natural aqueous matrices, mainly because of the relatively high ionic strength. However, surfactants were found to reduce the aggregation and sedimentation of ZnO ENM in six natural water matrices in different degrees. With the presence of 0.030% SDS in tap water, maximum reduction rates of aggregate size and sedimentation were recorded as 69.54% and 26.69%, respectively. The results of this study indicate that the presence of surfactants may alter the behaviors and fate of ENMs in natural water environment. PMID- 28073642 TI - Long-term impact of primary domestic sewage on metal/loid accumulation in drainage ditch sediments, plants and water: Implications for phytoremediation and restoration. AB - We evaluate the long-term performance of a vegetated drainage ditch (VDD) treating domestic sewage with respect to heavy metal/metalloid (HM/M) accumulation in sediments, plants and water. VDD sediment contained significantly higher macro and trace elements compared to an agricultural ditch (AD) sediment. However, concentrations of HM/Ms in VDD sediment were below the ranges considered toxic to plants. Most HM/Ms were efficiently removed in the VDD, whereby removal efficiencies varied between 11% for Al and 89% for K. Accumulation of HM/Ms varied among species and plant parts, although sequestration by plants represents only a small proportion (<1%) of the inflow load. Accumulation of Al, As, Cd, Pb, Cr, Fe and Ni in VDD plants were mostly distributed in the roots, indicating an exclusive strategy for metal tolerance. The opposite was found for Zn, Cu, K, Ca, P, K, Na, N and Mg, which were accumulated either in the stems or leaves. Overall, concentrations of metals in sediment showed significant positive correlations with those in ditch plants. None of the studied species were identified as metal hyper-accumulators (i.e. >10,000mgkg-1 of Zn or Mn). Nevertheless, the high translocation factor (TF) values for Mn, Ni, Cu, Zn, Na, Mg, P, K and Ca in the ditch plants make them suitable for phytoextraction from water/soil, while the low TF values for Pb, Cd, As, Fe, Cr and Al make them suitable for their phytostabilization. PMID- 28073643 TI - Corrigendum to "Intracortical inhibition abnormality during the remission phase of multiple sclerosis is related to upper limb dexterity and lesions" [Clin. Neurophysiol. 127 (2016) 1503-1511]. PMID- 28073644 TI - Left Ventricular Ejection Fraction in Patients With Acute Heart Failure: A Limited Tool? PMID- 28073645 TI - Percutaneous Closure of a "Whale Tail" Left Atrial Appendage. PMID- 28073646 TI - Hypertrophic Cardiomyopathy Without Ventricular Hypertrophy: Usefulness of Genetic and Pathological Study in Preventing Sudden Death. PMID- 28073647 TI - [Prevalence of diabetes mellitus in the province of Cadiz, Spain]. PMID- 28073649 TI - Accurate respiratory rates count: So should you! AB - It is well documented that the respiratory rate is the least accurately recorded vital sign. Despite nurses consistently confirming that they understand the physiological importance of the respiratory rate, more often than not, they estimate a value rather than count for an entire minute. Until recently, little has been known about why this phenomenon perpetuates. However, it has now been established that many emergency department registered nurses believe they are enhancing patients' outcomes by performing tasks other than counting a patient's respiratory rate. This discussion highlights the significance of recording accurate respiratory rates, as opposed to estimating a rate; emphasizing that just four breaths either side of the normal range could be indicative of impending clinical deterioration. PMID- 28073648 TI - Elevated Neutrophil Elastase in Tears of Ocular Graft-Versus-Host Disease Patients. AB - PURPOSE: To investigate the levels of neutrophil elastase (NE), matrix metalloproteinases (MMPs), and myeloperoxidase (MPO) in tear washes of patients with ocular graft-vs-host disease (oGVHD). DESIGN: Case-control study. METHODS: Based on established criteria, oGVHD patients (n = 14; 28 eyes) and age-/sex matched healthy controls (n = 14; 28 eyes) were enrolled. Tear washes were collected and analyzed for NE using a single-analyte enzyme-linked immunosorbent assay (ELISA). MMPs (1, 2, 3, 7, 8, 9, 12), MPO, and tissue inhibitor of matrix metalloproteinase (TIMP)-1 were analyzed using multianalyte bead-based ELISA assays. Total MMP activity was measured using a fluorimetric assay. Correlation studies were performed between NE, MMP-8, MMP-9, and MPO within study groups. RESULTS: NE, MMP-8, MMP-9, and MPO levels were elevated in oGVHD tears when compared with controls (P < .0001). NE was the most elevated analyte. MMP activity was higher and TIMP-1 levels were lower in oGVHD than in control (P < .0001). In oGVHD, NE significantly correlated with MMP-8 (r = 0.92), MMP-9 (r = 0.90), and MPO (r = 0.79) (P < .0001). MMP-8 correlated with MMP-9 (r = 0.96, P < .0001), and MPO (r = 0.60, P = .001). MMP-9 correlated with MPO (r = 0.55, P = .002). In controls, NE, MMP-9, and MPO significantly correlated with each other (P < .0001). CONCLUSIONS: The marked increase in NE in oGVHD tears that correlated strongly with elevated MMP-8, MMP-9, and MPO suggests a common neutrophilic source and provides evidence of neutrophil activity on the ocular surface of oGVHD patients. PMID- 28073650 TI - The utilisation of one district hospital emergency department by people with Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder in Australia and the economic burden is more than $8.3 billion a year and predicted to escalate. However, little is known of the trends and characteristics of people with Parkinson's disease presenting to emergency departments (ED). METHOD: The study design was a 12 month retrospective medical record audit. The study was conducted in one metropolitan 300 bed district hospital in an outer suburb of Sydney. RESULTS: One hundred and twenty nine adult patients (0.4%) with PD presented with a mean age of 79.5 years (SD 7.7); all were over 60 years of age. Of the 129 PD patient cases, there were 260 separate ED episodes of care with the majority (n=151; 58.1%) of patients living in the community and presenting with falls (n=108; 41.5%). There was no statistical difference in triage code allocation when comparing PD patients and ED adult patients (over 60years). There was no difference in representation rate when comparing those over 80years (n=128) with those under 80 years (n=132). The average length of stay for PD patient episodes was 323min (SD 225) compared with 193min (SD 136) for ED patients. Younger adult patient episodes (n=132; 51.0%) were admitted to hospital more frequently than those aged over 80 years (Pearson's X2 test 162.2; df 1; p<0.001. CONCLUSION: We identified in this study that people with PD have a high rate of falls, longer length of stay, high admission rate and represent frequently to the ED. Improved detection, management and a multidisciplinary approach for people with PD along with strict medication regime adherence is likely to improve safety, quality of life, reduce symptom aggravation and ongoing risk of falls. PMID- 28073651 TI - I know I've seen you before: Distinguishing recent-single-exposure-based familiarity from pre-existing familiarity. AB - This study examines how individuals differentiate recent-single-exposure-based familiarity from pre-existing familiarity. If these are two distinct cognitive processes, are they supported by the same neural bases? This study examines how recent-single-exposure-based familiarity and multiple-previous-exposure-based familiarity are supported and represented in the brain using functional MRI. In a novel approach, we first behaviorally show that subjects can divide retrieval of items in pre-existing memory into judgments of recollection and familiarity. Then, using functional magnetic resonance imaging, we examine the differences in blood oxygen level dependent activity and regional connectivity during judgments of recent-single-exposure-based and pre-existing familiarity. Judgments of these two types of familiarity showed distinct regions of activation in a whole-brain analysis, in medial temporal lobe (MTL) substructures, and in MTL substructure functional-correlations with other brain regions. Specifically, within the MTL, perirhinal cortex showed increased activation during recent-single-exposure-based familiarity while parahippocampal cortex showed increased activation during judgments of pre-existing familiarity. We find that recent-single-exposure-based and pre-existing familiarity are represented as distinct neural processes in the brain; this is supported by differing patterns of brain activation and regional correlations. This spatially distinct regional brain involvement suggests that the two separate experiences of familiarity, recent-exposure-based familiarity and pre-existing familiarity, may be cognitively distinct. PMID- 28073652 TI - Tarsal Tunnel Syndrome Due To Three Different Types of Ganglion During a 12-Year Period: A Case Report. AB - A 52-year-old male complained of numbness and radiating pain affecting the plantar region of his left foot. He was found to have recurrent tarsal tunnel syndrome due to posterior tibial nerve compression by 3 different types of ganglion during a 12-year period. To the best of our knowledge, a similar case has not been documented. At the first operation, flexor retinaculum release and simple excision of an epineural ganglion were performed without injuring the nerve fascicles; however, an intrafascicular ganglion developed approximately 2 years later. At the second operation, the ganglion cyst was resected completely to prevent recurrence, despite the risk of nerve fiber injury. The cyst originated from the subtalar joint; thus, the joint was closed, and a free fat graft was placed to prevent adhesion formation. However, an extraneural ganglion occurred about 3 years later. At the third operation, the cyst was resected completely, and a free periosteal graft was used to close the joint more effectively. No recurrence had developed at 6 years after the third operation. The findings of the present case show the need for long-term monitoring of patients with tarsal tunnel syndrome caused by a ganglion owing to the possibility of recurrence related to different ganglion types. PMID- 28073653 TI - Rare Lateral Dislocation of the First Metatarsophalangeal Joint: A Case Report and Review of the Literature. AB - Traumatic lateral dislocations of the first metatarsophalangeal (MTP) joint are very rare. A 44-year-old male was referred after a motorcycle to car accident because of an exposed head of the left first metatarsal through a laceration on the medial aspect of the first MTP joint. Radiographs showed a lateral dislocation of the first MTP joint, with concomitant fractures of the neck of the second metatarsal and the base of the third and fourth metatarsal bones. The dislocation was reduced in the emergency department with the patient under conscious sedation after thorough irrigation. At the 1-year postoperative visit, the patient had full painless range of motion of the first and second MTP joints without any complaints. Lateral dislocation of the first MTP joint is an injury usually associated with fracture of the adjacent metatarsals and/or ligamentous injuries. It is easily reducible, with acceptable midterm outcomes. PMID- 28073654 TI - Staphylococcus lugdunensis: An Underreported Pathogen in Osteomyelitis. PMID- 28073655 TI - Fusion of the First Metatarsophalangeal Joint and Second to Fifth Metatarsal Head Resection for Rheumatoid Forefoot Deformity. AB - The goals of the present study were to evaluate the mid-term results of first metatarsophalangeal joint fusion combined with second to fifth metatarsal head resection in rheumatoid forefoot deformity and identify the prognostic factors. The inclusion criteria were 2010 American College of Rheumatology and/or European League Against Rheumatism criteria for rheumatoid arthritis; symptomatic forefoot deformity; first metatarsophalangeal joint fusion and second to fifth metatarsal head resection; and a minimum of 4 years of follow-up data available. The patients were evaluated using the Disease Activity Score 28 for rheumatoid arthritis, Health Assessment Questionnaire for Rheumatoid Arthritis, Foot Function Index, forefoot American Orthopaedic Foot and Ankle Society scale, and weightbearing radiographs. Different pre-, intra-, and postoperative variables were investigated to identify the prognostic factors. Sixty-two patients (89 feet) with a mean age of 60.8 degrees +/- 9.4 years and 85.5 degrees +/- 22.4 months of follow-up data were included. The preoperative American Orthopaedic Foot and Ankle Society scale score was 33.4 +/- 16 points and improved significantly (p < .001) after surgery (mean 82.9 +/- 11.7 points). The mean Foot Function Index improved significantly (p < .001) from 131.6 +/- 37.4 to 77.4 +/- 46.3 points at the last follow-up visit. Only the revision surgery variable was significantly (p = .02) related to poor outcomes. Revision was necessary in 8 feet (9%). This procedure produced satisfactory results. Poor outcomes were significantly related to the necessity for revision surgery for nonunion, malunion, inadequate metatarsal resection, and painful hardware. PMID- 28073656 TI - Preventive Health Behavior Change Text Message Interventions: A Meta-analysis. AB - CONTEXT: Existing evidence shows that text message interventions can produce short-term health behavior change. However, understanding is limited regarding intervention characteristics moderating this effect or the long-term effectiveness of text message interventions on behavior change after contact stops. EVIDENCE ACQUISITION: MEDLINE, PubMed Central, ERIC, PsycINFO, and Web of Science were searched for articles published between April 2008 and December 2014 that evaluated an intervention targeting preventive health behaviors, delivered primarily by text message. EVIDENCE SYNTHESIS: Intervention development and design characteristics and research outcomes were evaluated for 51 studies. Thirty-five studies were included in a meta-analysis (conducted in 2015) examining overall effect size and moderators of effect size. The overall pooled effect of interventions was d=0.24 (95% CI=0.16, 0.32, p<0.001) using outcome data collected most proximal to intervention cessation. Seven studies collected data following a no-intervention maintenance period and showed a small but significant pooled maintenance effect (d=0.17, 95% CI=0.03, 0.31, p=0.017, k=7). Few variables significantly moderated intervention efficacy. Interventions that did not use a theoretic basis, used supplementary intervention components, and had a duration of 6-12 months were most effective. The specific behavior being targeted was not associated with differences in efficacy nor was tailoring, targeting, or personalization of text message content. CONCLUSIONS: Text message interventions are capable of producing positive change in preventive health behaviors. Preliminary evidence indicates that these effects can be maintained after the intervention stops. The moderator analysis findings are at odds with previous research, suggesting a need to examine moderators at the behavior specific level. PMID- 28073657 TI - Response to: Joveini (Al-Akhawayni) and the early knowledge on Circle of Willis. PMID- 28073658 TI - Copeptin levels in patients with vasovagal syncope. AB - BACKGROUND AND PURPOSE: Vasovagal syncope (VVS) is linked to more than one pathophysiologic mechanisms. Copeptin, an emerging cardiovascular marker, is a surrogate for arginine-vasopressin, which increases following VVS. We aimed to assess the dynamic pattern of copeptin levels in typical VVS, categorized by the degree of vasoconstriction during orthostasis, and healthy controls. METHODS: The following groups were studied: Group A (n=21), with adequate limb vasoconstriction during the first min. of tilt, assessed by limb plethysmography (at least 30% flow reduction); Group B (n=15), showing impaired vasoconstriction during orthostasis (<10% reduction); Group C (n=18), history of VVS and negative tilt test result; Group D (n=18), healthy controls. Copeptin plasma levels were assessed before and 5min following tilt test positivity or termination. RESULTS: Baseline copeptin values were similar in all groups (8.3+/-6.4 in Group A, 5.7+/ 2.3pmol/l in B, 6.0+/-1.9 in C, and 6.9+/-2.6 in D, p: 0.41). Significant increases in copeptin during tilt were observed in all Groups of VVS patients (A, B, C), including those with negative tilt (Group C: from 6.0+/-1.9 to 27.7+/ 12.6pmol/l, p: 0.001), but not in controls. Following tilt termination, a greater increase was observed in copeptin values in Group B vs all other Groups A, C, and D (111.6+/-63.5 vs 29.5+/-51.3, 27.7+/-12.6, and 8.3+/-2.9, respectively). CONCLUSIONS: Copeptin increases following tilt not only in VVS with a positive response, but also in typical history patients with a negative test. Increased copeptin levels following orthostasis may be useful for diagnosing VVS. PMID- 28073659 TI - Serotonin norepinephrine re-uptake inhibitor (SNRI)-, selective norepinephrine reuptake inhibitor (S-NRI)-, and exogenously administered norepinephrine-induced takotsubo syndrome: Analysis of published cases. AB - BACKGROUND: Takotsubo syndrome (TS) may be triggered by numerous physical stress factors including exogenous Norepinephrine administration. The aim of this study is to report on the clinical features and outcome of serotonin-norepinephrine reuptake inhibitor (SNRI)-, selective NRI (S-NRI)-, and exogenously administered norepinephrine-induced TS in a largest possible cohort of published cases. METHODS: A computer assisted search of the electronic data base Pubmed was performed from 1990 to August 2016. All cases deemed to have SNRI-, S-NRI-, and norepinephrine-induced TS were retrieved. RESULTS: Twenty two cases of SNRI-, S NRI-, and norepinephrine-induced TS were retrieved from the literature. At presentation, the 22 patients with TS were 11 to 82years of age (mean age 49.9+/ 20years). Seventeen of 21 (81%) of the patients were women. The most common presenting symptom was chest pain, which occurred in 59% of cases. The TS localization pattern was apical in 68%, mid-ventricular in 13.6%, basal in 13.6% and global in 4.5% of cases. Complications occurred in 7 of 22 (32%) with more complications in exogenously administered norepinephrine-induced TS (4 of 6, 66.7%) than SNRI-, and S-NRI-induced TS (3 of 16, 18, 8%) (p=0.054). All 4 male patients in the study developed complications. One patient (exogenous norepinephrine-induced TS) died during hospitalization. CONCLUSION: The SNRI-, and S-NRI-induced TS have clinical features, complications and course comparable to that of all-TS population cohorts, whereas the exogenously administered norepinephrine-induced TS has a more dramatic clinical presentation and complication rates, which resembles that of exogenously administered epinephrine induced TS. PMID- 28073660 TI - Effectiveness of subcutaneous implantable cardioverter-defibrillator testing in patients with hypertrophic cardiomyopathy. AB - BACKGROUND: Subcutaneous ICD (S-ICD) is a promising option for Hypertrophic Cardiomyopathy (HCM) patients at risk of Sudden Cardiac Death (SCD). However, its effectiveness in terminating ventricular arrhythmias in HCM is yet unresolved. METHODS: Consecutive HCM patients referred for S-ICD implantation were prospectively enrolled. Patients underwent one or two attempts of VF induction by the programmer. Successful conversion was defined as any 65J shock that terminated VF (not requiring rescue shocks). Clinical and instrumental parameters were analyzed to study predictors of conversion failure. RESULTS: Fifty HCM patients (34 males, 40+/-16years) with a mean BMI of 25.2+/-4.4kg/m2 were evaluated. Mean ESC SCD risk of was 6.5+/-3.9% and maximal LV wall thickness (LVMWT) was 26+/-6mm. In 2/50 patients no arrhythmias were inducible, while in 7 (14%) only sustained ventricular tachycardia was induced and cardioverted. In the remaining 41 (82%) patients, 73 VF episodes were induced (1 episode in 14 and >1 in 27 patients). Of these, 4 (6%) spontaneously converted. In 68/69 (98%) the S ICD successfully cardioverted, but failed in 1 (2%) patient, who needed rescue defibrillation. This patient was severely obese (BMI 36) and LVMWT of 25mm. VF was re-induced and successfully converted by the 80J reversed polarity S-ICD. CONCLUSIONS: Acute DT at 65J at the implant showed the effectiveness of S-ICD in the recognition and termination of VT/VF in all HCM patients except one. Extreme LVH did not affect the performance of the device, whereas severe obesity was likely responsible for the single 65J failure. PMID- 28073661 TI - Reply to letter: "5-Methoxytryptophan: A promising early marker for predicting post-myocardial infarction heart failure". PMID- 28073662 TI - Outpatient follow-up during the first year after heart transplantation is safe. PMID- 28073663 TI - ApoM/HDL-C and apoM/apoA-I ratios are indicators of diabetic nephropathy in healthy controls and type 2 diabetes mellitus. AB - BACKGROUND: Apolipoprotein M (apoM) concentrations were decreased in type 2 diabetes mellitus (T2DM). ApoM was selectively expressed in renal tubular epithelial cells. We investigated the changes in plasma apoM concentrations in diabetic nephropathy (DN) patients and the potential of apoM as a biomarker of DN. METHODS: A total of 96 DN patients and 100 age- and sex-matched diabetic non nephropathy (non-DN) patients and 110 healthy controls were included. All T2DM patients were divided into 3 groups according to urinary albumin excretion: normoalbuminuria (n=100), microalbuminuria (n=50) and macroalbuminuria (n=46). Plasma apoM concentrations were measured by enzyme-linked immunosorbent assay. RESULTS: DN Patients had higher plasma apoM concentrations than those in non-DN patients (22.23+/-11.69 vs. 18.96+/-7.85ng/MUl, P<0.05). In addition, microalbuminuria group showed higher plasma apoM concentrations than those in normoalbuminuria group (22.67+/-11.40 vs. 18.96+/-7.85ng/MUl, P<0.05). The areas under curve (AUC) of apoM using a receiver-operating characteristic (ROC) curve analysis showed that plasma apoM concentrations were not indicators for identification of DN from healthy people (AUC=0.478, P=0.585) and from T2DM (AUC=0.563, P=0.125). DN patients had higher ratios of apoM/HDL-C and apoM/apoA1 than those in healthy controls and in non-DN patients. ApoM/HDL-C and apoM/apoA1 ratios could be used as indicators for identification of DN from healthy people (AUC=0.597, P=0.016; AUC=0.665, P=0.000, respectively) and from T2DM (AUC=0.580, P=0.050; AUC=0.601, P=0.015, respectively). CONCLUSIONS: ApoM/HDL-C and apoM/apoA1 ratios could be used as indicators for identification of DN from healthy people and from T2DM patients. PMID- 28073664 TI - Extract of bulbus Fritillaria cirrhosa perturbs spindle assembly checkpoint, induces mitotic aberrations and genomic instability in human colon epithelial cell line. AB - BACKGROUND: Bulbus Fritillaria cirrhosa D. Don (BFC) has been used in China as a folk medicine for the treatment of cough and asthma for more than 2000 years. The antitussive and antiasthmatic effects of BFC have been reported before, nevertheless its toxicity and safety have not been documented. This study investigated the possible effects of BFC on spindle assembly checkpoint (SAC), mitotic fidelity and genomic stability in human NCM460 colon epithelial cells. METHODS: Cells were treated with BFC (0, 20, 40, 80 and 160MUg/ml) for 24, 48 and 72h and harvested differently according to the biomarkers observed. Mitotic aberrations were assessed by the biomarkers of chromosome misalignment (CMA), chromosome lagging (CL) and chromatin bridge (CB). Frequencies of micronuclei (MN), nucleoplasmic bridge and nuclear bud (NB) in cytokinesis-block micronucleus assay were used as indicators of genomic instability (GIN). SAC activity was determined by anaphase to metaphase ratio (AMR) and the expression of several SAC genes, including CENP-E, Mps1, Bub1, Mad-1, BubR1 and Mad-2. RESULTS: Compared with the control, cells in BFC treated groups (80 and 160MUg/ml) showed: 1) increased AMR (p<0.05), up-regulated expression of Mps1, Bub1 and Mad-1 (p<0.05) and down-regulated expression of CENP-E, BubR1 and Mad-2 (p<0.05); 2) increased frequencies of CMA, CL and CB (p<0.01); 3) increased incidences of MN and NB (p<0.01). CONCLUSIONS: This study revealed for the first time that BFC causes mitotic aberrations and GIN in human colon epithelial cells and these effects maybe the result of SAC dysfunction. PMID- 28073665 TI - Predictive ability of the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system after first-time lower extremity revascularizations. AB - OBJECTIVE: The Society for Vascular Surgery (SVS) Wound, Ischemia and foot Infection (WIfI) classification system was proposed to predict 1-year amputation risk and potential benefit from revascularization. Our goal was to evaluate the predictive ability of this scale in a real-world selection of patients undergoing a first-time lower extremity revascularization for chronic limb-threatening ischemia (CLTI). METHODS: From 2005 to 2014, 1336 limbs underwent a first-time lower extremity revascularization for CLTI, of which 992 had sufficient data to classify all three WIfI components (wound, ischemia, and foot infection). Limbs were stratified into the SVS WIfI clinical stages (from 1 to 4) for 1-year amputation risk estimation, a novel WIfI composite score from 0 to 9 (that weighs all WIfI variables equally), and a novel WIfI mean score from 0 to 3 (that can incorporate limbs missing any of the three WIfI components). Outcomes included major amputation; revascularization, major amputation, or stenosis (>3.5* step-up by duplex; RAS) events; and death. Predictors were identified using Cox regression models and Kaplan-Meier survival estimates. RESULTS: Of the 1336 first time procedures performed, 992 limbs were classified in all three WIfI components (524 endovascular and 468 bypass; 26% rest pain and 74% tissue loss). Cox regression demonstrated that a one-unit increase in the WIfI clinical stage increases the risk of major amputation (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.7-3.2) and RAS events in all limbs (HR, 1.2; 95% CI, 1.1-1.3). Separate models of the entire cohort, a bypass-only cohort, and an endovascular only cohort showed that a one-unit increase in the WIfI mean score is associated with an increase in the risk of major amputation (all three cohorts: HR, 5.3 [95% CI, 3.6-6.8], 4.1 [2.4-6.9], and 6.6 [3.8-11.6], respectively) and RAS events (all three cohorts: HR, 1.7 [95% CI, 1.4-2.0], 1.9 [1.4-2.6], and 1.4 [1.1-1.9], respectively). The novel WIfI composite and WIfI mean scores were the only consistent predictors of death among the three cohorts, with the WIfI mean score proving most strongly predictive in the entire cohort (HR, 1.4; 95% CI, 1.1-1.7), the bypass-only cohort (HR, 1.5; 95% CI, 1.1-1.9), and the endovascular-only cohort (HR, 1.4; 95% CI, 1.0-1.8). Although the individual WIfI wound component was able to predict mortality among all patients (HR, 1.1; 95% CI, 1.0-1.2) and bypass-only patients (HR, 1.2; 95% CI, 1.1-1.3), neither the additional individual WIfI components nor the WIfI clinical stage were able to significantly predict mortality among any cohort. CONCLUSIONS: This study supports the ability of the SVS WIfI classification system to predict major amputation; however, the novel WIfI mean and WIfI composite scores predict amputation, RAS events, and mortality more consistently than any other current WIfI scoring system. The WIfI mean score allows inclusion of all limbs, and both novel scoring systems are easier to conceptualize, give equal weight to each WIfI component, and may provide clinicians more effective comparisons in outcomes between patients. PMID- 28073666 TI - Standard endovascular aneurysm repair in patients with wide infrarenal aneurysm necks is associated with increased risk of adverse events. AB - OBJECTIVE: Endovascular aneurysm repair (EVAR) has progressively expanded to treat more challenging anatomies. Although EVAR in patients with wide infrarenal necks has been reported with acceptable results, there is still controversy regarding the longer-term outcomes. Our aim is to determine the impact of infrarenal neck diameter on midterm outcome following EVAR with a single endograft with suprarenal fixation. METHODS: A retrospective case-control study was designed using data from a prospective multicenter database. Patients who electively underwent standard EVAR with an Endurant stent graft (Medtronic Ave, Santa Rosa, Calif) for a degenerative abdominal aortic aneurysm from January 2008 to December 2012 in three high-volume centers in The Netherlands were included. All measurements were obtained using dedicated reconstruction software and center lumen line reconstruction. Patients with an infrarenal neck diameter of >=30 mm were compared with patients with a neck diameter of <30 mm. The primary end point was freedom from neck-related adverse events (a composite of type Ia endoleak, neck-related secondary intervention, and endograft migration). Secondary end points were primary clinical success, type Ia endoleak, neck-related reinterventions, endoleaks, and aneurysm-related secondary interventions. RESULTS: Four-hundred twenty-seven patients were included. Seventy-four patients (17.3%) with a neck diameter of >=30 mm were compared with a control group of 353 patients. There were no significant differences at baseline between groups including demographics, comorbidities, baseline aneurysm diameter, infrarenal neck length, suprarenal angulation, or infrarenal neck angulation. Median stent graft oversizing was 12.5% (7.9-16.1) and 16.6% (12.0-23.1) in the >=30-mm neck diameter and control groups, respectively (P < .001). Median follow-up was 3.1 years (1.2-4.7) and 4.1 years (2.7-5.6) for the large neck and control groups, respectively (P < .001). Type Ia endoleaks occurred in 17 patients (4.0%) and were significantly more frequent in patients with >=30-mm neck diameter (9.5% vs 2.8%; P = .005). Neck-related secondary interventions were performed in 20 patients (4.7%) and were also more common among patients with neck diameters of >=30 mm (9.5% vs 3.7%; P = .04). The 4-year freedom from neck-related adverse events were 75% and 95% for the large neck and control groups, respectively (P < .001). On multivariable regression analysis, infrarenal neck diameter of >=30 mm was an independent risk factor for neck-related adverse events (odds ratio [OR], 3.8; 95% confidence interval [CI], 1.6-9.1), type Ia endoleak (OR, 2.7; 95% CI, 1.0-8.3), and neck-related secondary interventions (OR, 3.2, 95% CI, 1.1-9.2). CONCLUSIONS: EVAR in patients with large diameter necks is associated with an increased risk of neck-related adverse events in midterm follow-up. This may influence the clinical decision regarding choice of repair and toward a more intensive surveillance following EVAR in these patients in the long term. PMID- 28073667 TI - Enlargement of aortic arch vessels after surgical repair of type A aortic dissection. AB - BACKGROUND: Information on the growth rate of the diameter of the residual dissected supra-aortic trunk after surgical repair of type A aortic dissection is limited. METHODS: We retrospectively reviewed 95 consecutive postsurgical patients with type A aortic dissection (acute, 91; chronic, 4) between 2005 and 2016 who were followed up with computed tomography. The diameter of the residual dissected supra-aortic trunk was measured by axial images and multiplanar reformatting, and the growth rate was calculated. RESULTS: The mean age was 67.2 +/- 12.8 years (range, 34-89 years). Forty-one brachiocephalic arteries (43%), 14 left common carotid arteries (15%), and 7 left subclavian arteries (10%) exhibited residual dissection. The diameter of the residual dissected branch with a patent false lumen (FL) gradually increased over time, whereas that with a thrombosed FL decreased and reached a plateau. The growth rate of brachiocephalic, left common carotid, and left subclavian arteries with a patent FL was 1.3 +/- 1.2, 0.8 +/- 0.3, and 0.6 +/- 0.4 mm/y, respectively. One patient required surgical intervention for dilation of the brachiocephalic artery 8 years postoperatively. Multivariate analysis showed that male sex was an independent risk factor for a patent FL in the brachiocephalic artery (P = .0431; odds ratio, 2.04). CONCLUSIONS: A residual dissected supra-aortic trunk with a thrombosed FL seems to be a benign condition. However, long-term follow-up is necessary for patients with a patent FL of residual dissected supra-aortic trunk, which might occasionally require surgical intervention. PMID- 28073669 TI - Reoperation rates after open and endovascular abdominal aortic aneurysm repairs. AB - OBJECTIVE: This study compared reoperation rates associated with open abdominal aortic aneurysm (AAA) repair (OR) outcomes vs endovascular AAA repair (EVAR). METHODS: A retrospective review of the Veterans Affairs Surgical Quality Improvement Project data was performed with inclusion criteria defined as all patients who underwent AAA repair from October 1, 2007, to October 1, 2013. The primary outcome was the incidence of reoperations. Reoperations included subsequent OR or EVAR procedures performed on the abdominal aorta or iliac arteries, surgical treatment of temporally related bowel obstruction, as well as treatment of abdominal or groin wound complications <=6 months and treatment of bowel or lower limb ischemia <=10 days. RESULTS: Of 6677 patients who underwent AAA repair, 476 (7.1%) required reoperations. OR was associated with a higher rate of reoperations overall (10.0% vs 6.3%; P < .01), with most being intra abdominal and wound complications. OR also had higher rates of bowel ischemia requiring operation (0.7% vs 0.3%; P = .01) and lower extremity ischemia (0.5% and 0.06%; P < .01). Significantly more endovascular stents were placed during EVAR (2.8% vs 0.5%; P < .01). Logistic regression showed EVAR is a negative predictor for reoperation after controlling for comorbidities (P < .001). CONCLUSIONS: The long-term burden of reoperations after OR may actually be more significant than current understanding when including all possible abdominal complications in an extended analysis. Future prospective trials should include all potential reoperations extended >30 days with associated cost analysis. As surgical innovation in EVAR technology advances, complication comparisons with OR should undergo frequent re-evaluation given that endovascular indications and outcomes continue to expand and improve. PMID- 28073668 TI - Drug-eluting stenting for femoropopliteal lesions, followed by cilostazol treatment, reduces stent restenosis in patients with symptomatic peripheral artery disease. AB - BACKGROUND: Cilostazol improves clinical endovascular therapy outcomes for femoropopliteal (FP) lesions in patients with symptomatic peripheral arterial disease, but whether it also has clinical benefits for patients after drug eluting stent implantation remains unclear. METHODS: This study is a subanalysis of the ZilvEr PTX for tHe Femoral ArterY and Proximal Popliteal ArteRy (ZEPHYR) study, a prospective multicenter study investigating FP lesions treated with the Zilver (Cook Medical, Bloomington, Ind) paclitaxel-eluting stent. The present study analyzed 475 lesions in 459 limbs of 399 patients who maintained therapy with aspirin and thienopyridine, with or without cilostazol, during the 1-year follow-up period. RESULTS: Restenosis rates at 1 year were assessed with duplex ultrasound imaging (peak systolic velocity ratio >2.4) or angiography (>=50% diameter stenosis) and compared in the groups with and without cilostazol. Propensity score matching was performed to minimize intergroup differences in baseline characteristics. The present study included 93 cilostazol-treated and 382 cilostazol-free cases. Among the patients, 71% had diabetes mellitus and 31% were on dialysis. Critical limb ischemia accounted for 29% of cases. The prevalence of de novo lesions was 76%, and in-stent restenosis was present in 15%. Propensity score matching was performed in 91 pairs. The 1-year restenosis rate was 33% (95% confidence interval [CI], 23%-43%) in the cilostazol-treated group and 51% (95% CI, 41%-62%) in the cilostazol-free group (P = .008). The odds ratio was 0.5 (95% CI, 0.3-0.8). CONCLUSIONS: The propensity score-matching analysis demonstrated that additional cilostazol administration was associated with a significantly lower restenosis incidence 1 year after drug-eluting stent implantation for FP lesions. PMID- 28073670 TI - Simulation-Based Training Platforms for Arthroscopy: A Randomized Comparison of Virtual Reality Learning to Benchtop Learning. AB - PURPOSE: To determine whether a virtual reality (VR) arthroscopy simulator or benchtop (BT) arthroscopy simulator showed superiority as a training tool. METHODS: Arthroscopic novices were randomized to a training program on a BT or a VR knee arthroscopy simulator. The VR simulator provided user performance feedback. Individuals performed a diagnostic arthroscopy on both simulators before and after the training program. Performance was assessed using wireless objective motion analysis and a global rating scale. RESULTS: The groups (8 in the VR group, 9 in the BT group) were well matched at baseline across all parameters (P > .05). Training on each simulator resulted in significant performance improvements across all parameters (P < .05). BT training conferred a significant improvement in all parameters when trainees were reassessed on the VR simulator (P < .05). In contrast, VR training did not confer improvement in performance when trainees were reassessed on the BT simulator (P > .05). BT trained subjects outperformed VR-trained subjects in all parameters during final assessments on the BT simulator (P < .05). There was no difference in objective performance between VR-trained and BT-trained subjects on final VR simulator wireless objective motion analysis assessment (P > .05). CONCLUSIONS: Both simulators delivered improvements in arthroscopic skills. BT training led to skills that readily transferred to the VR simulator. Skills acquired after VR training did not transfer as readily to the BT simulator. Despite trainees receiving automated metric feedback from the VR simulator, the results suggest a greater gain in psychomotor skills for BT training. Further work is required to determine if this finding persists in the operating room. CLINICAL RELEVANCE: This study suggests that there are differences in skills acquired on different simulators and skills learnt on some simulators may be more transferable. Further work in identifying user feedback metrics that enhance learning is also required. PMID- 28073671 TI - Fast-track recovery technique applied to primary total hip and knee replacement surgery. Analysis of costs and complications. AB - PURPOSE: To determine the cost reduction and complication rates of using an enhanced recovery pathway (Fast-track) when compared to traditional recovery in primary total hip replacement (THR) and total knee replacement (TKR), as well as to determine if there were significant differences in complication rates. MATERIAL AND METHODS: Retrospective review of 100 primary total arthroplasties using the Fast-track recovery system and another 100 using conventional recovery. Gender, Charlston comorbidity index, ASA score, length of stay and early complications were measured, as well in-hospital complications and those in the first six months, re-admissions and transfusion rates. The total and daily cost of stay was determined and the cost reduction was calculated based on the reduction in the length of stay found between the groups. RESULTS: Both groups where comparable as regards age, gender, ASA score, and Charlston index. The mean reduction in length of stay was 4.5 days for TKR and 2.1 days for THR. The calculated cost reduction was 1266 euros for TKR and 583 euros for THR. There were no statistically significant differences between groups regarding in hospital complications, transfusion requirements, re-admissions and complication rates in the first six months. DISCUSSION: There are few publications in the literature reviewed that analyse the cost implications of using fast-track recovery protocols in arthroplasty. Several published series comparing recovery protocols found no significant differences in complication rates either. The use of a fast-track recovery protocol resulted in a significant cost reduction of 1266 euros for the TKR group and 583 for the THR group, without affecting complication rates. PMID- 28073672 TI - The long story of camptothecin: From traditional medicine to drugs. AB - 20-(S)-Camptothecin (CPT) is a natural alkaloid extracted from the bark of Camptotheca acuminata (Chinese happy tree). It acts as a DNA topoisomerase 1 poison with an interesting antitumor activity and its use is limited by low stability and solubility and unpredictable drug-drug interactions. Since the late 20th century, it has been widely used in cancer therapy and, since extraction yields from plant tissues are very low, various synthetic routes have been developed to satisfy the increase in demand for CPT. Moreover, SAR studies have allowed for the development of more potent CPT analogues topotecan and irinotecan. Unfortunately, resistance has already occurred in several tumour lines. Additional studies are needed to better understand the relationship between substituents and resistance, its clinical relevance and the impact of related gene polymorphism. One of the latest research approaches focuses on modifying the delivery mode to improve tumour cell uptake and reduce toxicity. PMID- 28073673 TI - Discovery of FZU-03,010 as a self-assembling anticancer amphiphile for acute myeloid leukemia. AB - Recently various drug candidates with excellent anticancer potency have been demonstrated, whereas their clinical application largely suffers from several limitations especially poor solubility. Ursolic acid (UA) as one of ubiquitous pentacyclic triterpenes in plantkingdom exhibited versatile antiproliferative effects in various cancer cell lines. However, the unfavorable pharmaceutical properties became the main obstacle for its clinical development. With the aim of development of novel derivatives with enhanced potency, a series of diversified UA amphiphiles have been designed, synthesized, and pharmacologically evaluated. Amphiphile 10 (FZU-03,010) with significant improved antiproliferative effect can self-assemble into stable nanoparticles in water, which may serve as a promising candidate for further development. PMID- 28073674 TI - Inhibition of invasion by N-trans-feruloyloctopamine via AKT, p38MAPK and EMT related signals in hepatocellular carcinoma cells. AB - N-trans-feruloyloctopamine (FO) isolated from Garlic skin was identified as the primary antioxidant constituents, however, the effect of which on HCC invasion is still unclear. Herein, the FO was synthesized and its antitumor activities were evaluated in HCC cell lines. Cellular functional analyses have revealed that the reformed FO owns strong abilities of inhibiting cell proliferation and invasion in HCC cells. Molecular data have further showed that FO could significantly decrease the phosphorylation levels of Akt and p38 MAPK. In addition, the expression of Slug was inhibited and the level of E-cadherin increased. Molecular docking analysis indicates that the H-bond and hydrophobic interactions were critical for FO and E-cadherin binding, but FO did not seem to act directly on phosphorylated Akt and p38 MAPK. We have thus concluded that reformed FO inhibits cell invasion might be directly through EMT related signals (E-cadherin) and indirectly through PI3K/Akt, p38 MAPK signaling pathways. FO might be a promising drug in HCC treatment and prognosis. PMID- 28073675 TI - Design, synthesis and biological evaluation of regioisomers of 666-15 as inhibitors of CREB-mediated gene transcription. AB - cAMP-response element binding protein (CREB) is a nuclear transcription factor that has been implicated in the pathogenesis and maintenance of various types of human cancers. Identification of small molecule inhibitors of CREB-mediated gene transcription has been pursued as a novel strategy for developing cancer therapeutics. We recently discovered a potent and cell-permeable CREB inhibitor called 666-15. 666-15 is a bisnaphthamide and has been shown to possess efficacious anti-breast cancer activity without toxicity in vivo. In this study, we designed and synthesized a series of analogs of 666-15 to probe the importance of regiochemistry in naphthalene ring B. Biological evaluations of these analogs demonstrated that the substitution pattern of the alkoxy and carboxamide in naphthalene ring B is very critical for maintaining potent CREB inhibition activity, suggesting that the unique bioactive conformation accessible in 666-15 is critically important. PMID- 28073676 TI - Sulfamic and succinic acid derivatives of 25-OH-PPD and their activities to MCF 7, A-549, HCT-116, and BGC-823 cell lines. AB - In the search for new anti-tumor agents with higher potency than our previously identified compound 1 (25-OH-PPD, 25-hydroxyprotopanaxadiol), 12 novel sulfamic and succinic acid derivatives that could improve water solubility and contribute to good drug potency and pharmacokinetic profiles were designed and synthesized. Their in vitro anti-tumor activities in MCF-7, A-549, HCT-116, and BGC-823 cell lines and one normal cell line were tested by standard MTT assay. Results showed that compared with compound 1, compounds 2, 3, and 7 exhibited higher cytotoxic activity on A-549 and BGC-823 cell lines, together with lower toxicity in the normal cell. In particular, compound 2 exhibited the best anti-tumor activity in the in vitro assays, which may provide valuable data for the research and development of new anti-tumor agents. PMID- 28073677 TI - Synthesis and cell imaging applications of fluorescent mono/di/tri-heterocyclyl 2,6-dicyanoanilines. AB - Synthesis of 3,4,5-triheterocyclyl-2,6-dicyanoanilines, starting from heterocyclic aldehydes and 1,2-diheterocycle-substituted ethanones, is described. 2,6-Dicyanoanilines with one or two heterocyclic substituents have also been synthesized. It was found that some of these molecules have selective cell staining properties useful for cell imaging applications. The compounds 1g, 10f and 11 were found to stain cytoplasm of the cells in contact but not the nucleus while the compound 12 showed affinity to apoptotic cells resulting in blue fluorescence. The cell imaging results with compound 12 were similar to Annexin V FITC, a known reagent containing recombinant Annexin V conjugated to green fluorescent FITC dye, used for detection of apoptotic cells. These compounds were found to be non-cytotoxic and have potential application as cell imaging agents. PMID- 28073678 TI - Natural potential neuroinflammatory inhibitors from Alhagi sparsifolia Shap. AB - Neuroinflammation is a key contributor to neuronal damage in neurodegenerative diseases. In our previous work on natural effective neuroinflammatory inhibitors, Alhagi sparsifolia Shap. (Leguminosae), a folk medicine widely distributed in Xinjiang, attracted our attention because of its significant anti neuroinflammatory effect. Therefore, further investigation of the bioactive material basis was carried out. As a result, 33 major components were characterized and identified by chromatographic and spectral methods, respectively. Furthermore, the anti-neuroinflammatory effects of the extract and purified constituents were evaluated in LPS-induced N9 cells in vitro. The results displayed that compounds 1, 2, 3, 5, 6, 8, 11, 15, 16, 17, 22, 23, 25, 26, 28, 30, 33 could exhibit significant inhibitory activities without obvious cytotoxicities at their effective concentrations. Especially, isorhamnetin (1) (IC50 17.87MUM), quercetin (2) (10.22MUM), 3',7-dihydroxyl-4'-methoxylisoflavone (5) (17.43MUM), 3',7-dihydroxyl-4',6-dimethoxylisoflavone (6) (11.21MUM), syringgaresinol (16) (2.68MUM), bombasinol A (17) (7.61MUM), aurantiamide (23) (14.91MUM) and 1,3,3,4-tetramethyl cyclopentene (33) (2.63MUM) showed much stronger inhibiting effect than that of the positive control minocycline (19.89MUM). Therefore, the effective compositions might be responsible for the significant neuroinflammation inhibitory activities exhibited by the herb. Moreover, compounds 16 and 33 could be good leading compounds for the development of potential therapeutic agents against neurodegenerative diseases. PMID- 28073679 TI - Identification of early neurodegenerative change in presymptomatic spinocerebellar ataxia type 1: A diffusion tensor imaging study. AB - We report a 41-year-old man of presymptomatic spinocerebellar ataxia type 1. Diffusion tensor imaging (DTI) verified decreased fractional anisotropy of cerebellar afferent and efferent pathways compared to 5 age-matched healthy controls while conventional MRI revealed normal brain. DTI was valuable in detection of early microstructural damage of cerebellar pathways. PMID- 28073680 TI - Rationale and Design of PEMVITASTART-An Open-label Randomized Trial Comparing Simultaneous Versus Standard Initiation of Vitamin B12 and Folate Supplementation in Nonsquamous, Non-Small-cell Lung Cancer Patients Undergoing First-line Pemetrexed-based Chemotherapy. AB - Pemetrexed is the preferred chemotherapeutic drug for nonsquamous, non-small-cell lung cancer patients whenever the predictive molecular biomarkers for targeted therapy have either not been assessed or are absent. As per manufacturers' instructions, supplementation with folic acid (FA; folate) at a dose of 350 to 1000 MUg daily should be started seven days before the first dose of pemetrexed based chemotherapy and continued during therapy and for 21 days after therapy cessation. Vitamin B12 injections (1000 MUg intramuscularly) should also be started one week before the first dose of chemotherapy. However, the evidence for delaying chemotherapy by one week for the purpose of providing vitamin B12 and FA supplementation is not robust. Observational and prospective single-arm studies have not shown any increased toxicity if pemetrexed was started earlier than the recommended duration of supplementation. In a resource-constrained setting, the standard (conventional) approach would lead to one additional visit and a 1-week chemotherapy delay, both of which could be inconvenient for patients. Hence, an open-label, randomized trial (PEMVITASTART [Vitamin Supplementation in NSCLC Patients on Pemetrexed Based Chemotherapy]; ClinicalTrials.gov identifier, NCT02679443) is being undertaken to evaluate whether any differences exist in pemetrexed-related hematologic toxicity among patients who receive delayed initiation of chemotherapy (after 5-7 days of vitamin B12 and FA supplementation [delayed arm]) compared with those for whom vitamin B12 and FA supplementation is started simultaneously (within 24 hours) of chemotherapy initiation (immediate arm). The present report describes the rationale and detailed design of the PEMVITASART trial. PMID- 28073681 TI - Association of Cytoplasmic CXCR4 With Loss of Epithelial Marker and Activation of ERK1/2 and AKT Signaling Pathways in Non-Small-Cell Lung Cancer. AB - OBJECTIVES: Compelling evidence demonstrates that CXC-chemokine receptor 4 (CXCR4) is involved in tumor invasion, angiogenesis, metastasis, and resistance to chemotherapy in addition to being one of the coreceptors for T-tropic human immunodeficiency virus entry into T cells. However, it remains controversial as to how to identify functionally activated CXCR4 in tumor biopsies, which would assist in determining which patients may benefit from potential CXCR4-targeted therapy. MATERIALS AND METHODS: Immunohistochemistry (IHC) staining on archival tissues of patients with non-small-cell lung cancer (NSCLC) was used to detect a panel of biomarkers, including phospho-ERK1/2, phospho-AKT, and E-cadherin, which are relevant to downstream signaling of CXCR4 and epithelial to mesenchymal transition (EMT). We also examined whether subcellular localization of CXCR4 could help define possible activation of CXCR4. RESULTS: A total of 94 primary tumor tissue samples from patients with NSCLC were included. Sixty-six patients had both cytomembranous and nuclear staining of CXCR4, 22 had solely nuclear staining, 5 had solely cytomembranous staining, and 1 had negative staining. Cytoplasmic location of CXCR4 with or without nuclear location was associated with loss of the epithelial marker E-cadherin (P = .0015) and activation of ERK1/2 (P = .0121) and AKT (P = .0024), suggesting EMT in these tumors; whereas tumors with only nuclear location of CXCR4 were more indolent and preserved an epithelial phenotype. CONCLUSIONS: Our study suggests that different subcellular localization of CXCR4 may be associated with different activation states; cytoplasmic CXCR4 seems to correlate with biomarker changes associated with EMT in NSCLC. PMID- 28073682 TI - Study design for control of HEART rate in inFant and child tachyarrhythmia with heart failure Using Landiolol (HEARTFUL): A prospective, multicenter, uncontrolled clinical trial. AB - BACKGROUND: Persistent tachycardia in pediatric patients after congenital heart surgery further deteriorates their hemodynamic condition, and may become fatal. Therefore, immediate control of the tachycardia is mandatory in these patients. For this purpose, quick-acting, short-acting, titratable intravenous agents are required. However, there are no agents with such characteristics among the drugs approved for control of pediatric arrhythmias in Japan, and thus novel and effective medications for these patients are awaited. Landiolol, an ultrashort acting beta-blocker, was approved in 2013 for tachyarrhythmias in adult patients with heart failure. However, its efficacy and safety in pediatric patients remain unclear. The aim of this prospective, multicenter, open-label phase IIb/III study is to investigate the efficacy and safety of landiolol in pediatric patients with tachyarrhythmias as well as heart failure. METHODS: Eligible patients are aged >= 3 months and <15 years, and have tachyarrhythmia (atrial fibrillation, atrial flutter, supraventricular tachycardia) as well as heart failure. The primary endpoint of the study is >=20% reduction from baseline heart rate or return to normal sinus rhythm within 2h after starting intravenous administration of landiolol. Patients will receive intravenous infusion of landiolol, starting at 1MUg/kg/min. The dose will be increased by 1MUg/kg/min every 15-20min until the tachycardia rate has decreased by >20% or tachycardia has terminated, and the dose will then be maintained or further increased depending on the patient's condition. The study was started in April 2015 and will end within a few years. CONCLUSIONS: The study was designed and designated the "HEARTFUL study" in the hope of establishing a basis for control of HEART rate in inFant and child tachyarrhythmia Using Landiolol in children with heart failure. PMID- 28073683 TI - Mutant-Allele Tumor Heterogeneity Scores Correlate With Risk of Metastases in Colon Cancer. AB - BACKGROUND: Colorectal cancer is a leading cause of cancer-related mortality, has a very broad mutational spectrum, and there is no clinically available biomarker that can predict which patients with stage II or stage III colorectal cancer will develop metastatic disease. PATIENTS AND METHODS: We used a targeted next generation sequencing approach to analyze the mutational spectra in stage II and III colon cancer patient samples. RESULTS: Amidst a broad range of acquired mutations and variants, we found evidence of tumor heterogeneity that distinguished the tumors in different groups. When heterogeneity was quantified using the Mutant-Allele Tumor Heterogeneity (MATH) score, there was a strong correlation between higher MATH score and risk of metastases. CONCLUSIONS: Measures of tumor heterogeneity might be useful biomarkers for identifying patients with colon cancer who are at risk of developing metastases. This might allow for more specific, tailored follow-up and adjuvant therapies after standard surgery. PMID- 28073686 TI - Interventions to improve dissemination and implementation of Hepatitis B vaccination in patients with diabetes. AB - OBJECTIVE: The purpose of this study was to assess provider awareness of routine vaccinations recommended for patients with diabetes and to determine whether pharmacist-led interventions are associated with increased provider implementation of recommendations for hepatitis B vaccination. METHODS: This study was conducted in 3 phases at 2 outpatient clinics affiliated with an academic institution. In phase 1, adults with diabetes who visited the clinics between January and November 2012 and who were eligible for the hepatitis B vaccine were identified. In phase 2, medical residents were surveyed twice for vaccine recommendations and reasons for (not) recommending the hepatitis B vaccine, specifically. Residents were then provided a pharmacist-led in-service about hepatitis B vaccine recommendations. The third phase was initiated in April 2013, following postintervention observation from December 2012 through March 2013. RESULTS: Forty-eight of 100 (48%) medical residents attended the in-service and completed both surveys, with 77% indicating they did not recommend the hepatitis B vaccine. During phase 1, 1441 patients were identified, 0.6% (n = 8) of whom had received at least the first dose of the series. In phase 3, 946 patients were identified with 1.7% (n = 16) having received at least the first dose (P = 0.007). CONCLUSION: An attempt to disseminate updated recommendations to providers via educational in-service was successful in increasing the percentage of eligible patients vaccinated with the hepatitis B vaccine. PMID- 28073687 TI - Adverse event detection using the FDA post-marketing drug safety surveillance system: Cardiotoxicity associated with loperamide abuse and misuse. AB - OBJECTIVE: The purpose of this investigation was to identify and characterize post-marketing reports of cardiotoxicity, including torsades de pointes (TdP), associated with loperamide use. METHODS: We searched the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database for post-marketing reports of serious cardiac adverse events associated with loperamide use from December 28, 1976 (U.S. drug approval date), through December 14, 2015. We also conducted a Pubmed and Google Scholar search to identify additional published reports of cardiotoxicity associated with loperamide in the medical literature through February 11, 2016. RESULTS: Forty-eight cases of serious cardiac adverse events associated with loperamide use composed the case series. The most frequently reported cardiac adverse events were syncope (n = 24), cardiac arrest (n = 13), QT-interval prolongation (n = 13), ventricular tachycardia (n = 10), and TdP (n = 7). There were 10 cases that resulted in death. Of the 48 cases, the most commonly reported reasons for use can be characterized as drug abuse (n = 22) and diarrhea treatment (n = 17). More than one-half of the 48 cases were reported after 2010. Of the 22 drug abuse cases, the median daily dose was 250 mg (range 70 mg to 1600 mg) and events occurred as early as 6 hours after a dose and as long as 18 months after initiation of loperamide. Thirteen of the 22 cases reported using loperamide for euphoric or analgesic effects, and 9 reported use to prevent opioid withdrawal symptoms. CONCLUSION: The FAERS case reports provide evidence to suggest that high doses of loperamide are associated with TdP and other serious cardiac adverse events. The majority of cases in this series occurred in the setting of drug abuse for the purpose of preventing opioid withdrawal or to produce euphoric effects. It is important for both clinicians and patients to be aware of this potential risk, because prompt therapy and discontinuation of the offending agent are often essential to management and prevention of loperamide-induced cardiac arrhythmias. PMID- 28073688 TI - State legal innovations to encourage naloxone dispensing. AB - OBJECTIVES: The opioid overdose epidemic continues to claim the lives of tens of thousands of Americans every year. Increased access to the opioid antagonist naloxone can reduce opioid-related morbidity and mortality. In this commentary, we describe several recent legal innovations designed to encourage pharmacists to ensure that naloxone is available when and where it is needed, and dispel some common misconceptions regarding potential legal risks associated with pharmacy naloxone dispensing. DATA SOURCES: Data are drawn from state laws and regulations, as catalogued by the Westlaw database. SUMMARY: States have rapidly modified law and policy to increase layperson access to naloxone. As of August 2016, 44 states permit naloxone to be prescribed for administration to a person with whom the prescriber does not have a prescriber-patient relationship. Forty two states permit naloxone to be dispensed via a non-patient-specific mechanism such as a standing or protocol order, and 5 states permit some pharmacists to prescribe naloxone on their own authority. The liability risk associated with naloxone dispensing is no higher than any other medication, and may be lower than some. However, to encourage the prescription and dispensing of naloxone, 36 states provide additional protection from civil liability for pharmacy naloxone dispensing, and 32 states provide protection from potential criminal action. Naloxone access laws in 31 states explicitly provide that dispensing naloxone as permitted by law cannot be grounds for disciplinary action by the state board of pharmacy or similar entity. CONCLUSION: Pharmacists are key members of the health care team and are uniquely situated to reduce potential opioid overdose risk. Pharmacists should be aware of and utilize innovative state laws designed to increase access to naloxone. PMID- 28073689 TI - Corneo-scleral contact lens in a piggyback system for keratoconus: A case report. AB - PURPOSE: We describe a case of fitting a corneo-scleral contact lens with a multi aspheric geometry design (MAGD CScL) on top of a daily silicone hydrogel lens (piggyback system) for keratoconus management. METHODS: A 48-year-old man using soft toric contact lenses required an improvement in the unsatisfactory quality of his vision. He presented with bilateral asymmetric keratoconus with high myopia in the right eye (RE) and severe myopia in the left eye (LE). In addition, he had low vision in his LE because of a maculopathy. He was fitted with MAGD CScL to correct his irregular astigmatism. A diagnostic trial set was used in the fitting process and the patient was assessed according to a standardised fitting methodology. Visual acuity, corneal topography and contrast sensitivity were evaluated. The follow-up period was 1year. RESULTS: The best spectacle-corrected visual acuity was 0.5 logMAR for the RE with -10 D/-5 D*60 degrees and 2 logMAR for the LE with -20 D/-3 D*105 degrees . After fitting MAGD CScL, visual acuity improved significantly to 0.1 logMAR for the RE and 1.3 logMAR for the LE, as well as contrast sensitivity. The fitting parameters of the base curve, diameter, and power were 7.05mm, 12.60mm, -18.50 D and 7.15mm, 12.60mm, -19 D for the RE and LE, respectively. Optimal fitting characteristics were found in terms of lens position and lens movement. To increase the time of MAGD CScL wear, they piggybacked on daily silicone hydrogel lenses of low power (-0.5 D). The patient reported being comfortable with this piggyback system for approximately 15h a day. After 1year of using the piggyback system, visual quality and wearing time were maintained. In addition, no adverse ocular effects were found during this period. CONCLUSION: This case report shows that in this patient a MAGD CScL could be fitted successfully on a daily silicone hydrogel lens in a piggyback system for keratoconus management, providing good visual quality along with prolonged use times and without adverse effects on the cornea. PMID- 28073690 TI - Citrate pathophysiology and metabolism. AB - By chelating ionized calcium, citrate allows extracorporeal circuit anticoagulation without a bleeding risk for the patient. Citrate anticoagulation is also associated with a reduced activation of leucocytes and platelets. Citrate clearance by citric acid cycle (Krebs cycle) is not modified by renal failure, but is reduced by about 50% in patients with cirrhosis. Toxic effects of citrate result from a decrease in plasma ionized calcium of the patient. The first side effect is a prolongation of the QT interval. Clinical signs of hypocalcemia and hypotension in humans appear below 0.9mmol/L of plasma ionized calcium. PMID- 28073691 TI - Rapid dactylitis resolution in a patient with psoriatic arthritis after treatment with ustekinumab. PMID- 28073692 TI - Population data of 15 autosomal STR loci in Chinese Han population from Jilin Province, Northeast China. PMID- 28073694 TI - HIV Latency: Should We Shock or Lock? AB - Combinatory antiretroviral therapy (cART) increases the survival and quality of life of HIV-1-infected patients. However, interruption of therapy almost invariably leads to the re-emergence of detectable viral replication because HIV 1 persists in viral latent reservoirs. Improved understanding of the molecular mechanisms involved in HIV-1 latency has paved the way for innovative strategies that attempt to purge latent virus. In this article we discuss the results of the broadly explored 'shock and kill' strategy, and also highlight the major hurdles facing this approach. Finally, we present recent innovative works suggesting that locking out latent proviruses could be a potential alternative therapeutic strategy. PMID- 28073693 TI - Crosstalk between Cytoplasmic RIG-I and STING Sensing Pathways. AB - Detection of evolutionarily conserved molecules on microbial pathogens by host immune sensors represents the initial trigger of the immune response against infection. Cytosolic receptors sense viral and intracellular bacterial genomes, as well as nucleic acids produced during replication. Once activated, these sensors trigger multiple signaling cascades, converging on the production of type I interferons and proinflammatory cytokines. Although distinct classes of receptors are responsible for the RNA and DNA sensing, the downstream signaling components are physically and functionally interconnected. This review highlights the importance of the crosstalk between retinoic acid inducible gene-I (RIG-I) mitochondrial antiviral-signaling protein (MAVS) RNA sensing and the cyclic GMP AMP synthase (cGAS)- stimulator of interferon genes (STING) DNA sensing pathways in potentiating efficient antiviral responses. The potential of cGAS-STING manipulation as a component of cancer immunotherapy is also reviewed. PMID- 28073695 TI - Paradoxical bradycardia and blood pressure elevation during dobutamine stress echocardiography reveal ischemia in a patient with syncope. PMID- 28073696 TI - SPOP promotes SIRT2 degradation and suppresses non-small cell lung cancer cell growth. AB - SIRT2 is a NAD-dependent deacetylase and inhibition of SIRT2 has a broad anticancer activity. Here we report that SPOP binds to SIRT2 and mediates its degradation by the 26S proteasome, which can be blocked by MG132 treatment. We also found that the levels of SPOP significantly decreased, while the levels of SIRT2 significantly increased in non-small cell lung cancer (NSCLC) cell lines, compared to normal bronchial epithelial cell line and NSCLC specimens, compared to the paired non-tumor lung tissue. Furthermore, SPOP can suppress NSCLC cell growth. Notably, mutations in NSCLC inhibit the abilities of SPOP to degrade SIRT2 and suppress NSCLC cell growth. These results reveal a novel regulation of SIRT2 by SPOP mediated degradation, which is important for the growth of lung tumor cells. PMID- 28073697 TI - Proliferation of mouse endometrial stromal cells in culture is highly sensitive to lysophosphatidic acid signaling. AB - Endometrial stromal cells (ESCs) proliferate rapidly both in vivo and in vitro. Here we show that proliferation of ESCs in vitro is strongly dependent on lysophosphatidic acid (LPA) signaling. LPA is produced by autotaxin (ATX) and induces various kinds of cellular processes including migration, proliferation and inhibition of cell death possibly through six G protein-coupled receptors (LPA1-6). We found that ESCs proliferated rapidly in vitro in an autocrine manner and that the proliferation was prominently suppressed by either an ATX inhibitor (ONO-8430506) or an LPA1/3 antagonist (Ki16425). Among the cells lines tested, mouse ESCs were the most sensitive to these inhibitors. Proliferation of ESCs isolated from either LPA1- or LPA3-deficient mice was comparable to proliferation of ESCs isolated from control mice. An LPA receptor antagonist (AM095), which was revealed to be a dual LPA1/LPA3 antagonist, also suppressed the proliferation of ESCs. The present results show that LPA signaling has a critical role in the proliferation of ESCs, and that this role is possibly mediated redundantly by LPA1 and LPA3. PMID- 28073698 TI - Ectopic expression of an apple cytochrome P450 gene MdCYPM1 negatively regulates plant photomorphogenesis and stress response in Arabidopsis. AB - Cytochrome P450s play an important role in plant growth and are involved in multiple stresses response. However, little is known about the functions of cytochrome P450s in apple. Here, a Malus * domestica cytochrome P450 monooxygenase 1 gene, MdCYPM1, was identified and subsequently cloned from apple 'Gala' (Malus * domestica). To verify the functions of MdCYPM1, we generated transgenic Arabidopsis plants expressing the apple MdCYPM1 gene under the control of the Cauliflower mosaic virus 35S promoter. Four transgenic lines (#3, #5, #7 and #8) were selected for further study. The transgenic plants exhibited a series of skotomorphogenesis phenotypes relative to wild-type controls, such as reduction of the chlorophyll, anthocyanins content and hypocotyls elongation. In addition, overexpression of MdCYPM1 influenced auxin transport and flowering time in transgenic Arabidopsis. Furthermore, MdCYPM1 expression was induced by salt and mannitol treatments, and the transgenic plants were negatively regulated by salinity and osmotic stresses during germination. These results suggest that MdCYPM1 plays a vital role in plant growth and development. PMID- 28073699 TI - Activation of Nrf2 attenuates carbonyl stress induced by methylglyoxal in human neuroblastoma cells: Increase in GSH levels is a critical event for the detoxification mechanism. AB - The present study focused on the methylglyoxal (MG) detoxification mechanism in neuroblastoma cells. The involvement of nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) pathway as a defense response against the formation of MG-modified proteins, which is well-known evidence of carbonyl stress, was also examined. We found that MG treatment resulted in accumulation of modified proteins bearing the structure of advanced glycation end products (AGEs) derived from MG in SH-SY5Y cells. This accumulation was suppressed by activation of the Nrf2 pathway prior to MG exposure via pre treatment with an Nrf2 activator, carnosic acid and CDDO-Im, confirming the involvement of the Nrf2 pathway in MG detoxification. Although pre-treatment with the Nrf2 activator did not affect mRNA levels of GLO1, AKR1B1, and AKR7A2, the expressions of GCL and xCT mRNA, involved in GSH synthesis, were induced prior to increase in GSH levels. Furthermore, we demonstrated that a GSH synthesis inhibitor eliminated the MG detoxification effect derived from pretreatment with the Nrf2 activator. These results indicated that increase in GSH levels, induced by pre-treatment with carnosic acid, promoted the formation of the GLO1 substrate, hemithioacetal, thereby accelerating MG metabolism via the glyoxalase system and suppressing its toxicity. It was, therefore, determined that promotion of GSH synthesis via the Nrf2/Keap1pathway is important in the MG detoxification mechanism against neuronal MG-induced carbonyl stress, and Nrf2 activators contribute to reduction in the accumulation and toxic expression of carbonyl proteins. PMID- 28073700 TI - The yeast Ste2p G protein-coupled receptor dimerizes on the cell plasma membrane. AB - Dimerization of G protein-coupled receptors (GPCR) may play an important role in maturation, internalization, signaling and/or pharmacology of these receptors. However, the location where dimerization occurs is still under debate. In our study, variants of Ste2p, a yeast mating pheromone GPCR, were tagged with split EGFP (enhanced green fluorescent protein) fragments inserted between transmembrane domain seven and the C-terminus or appended to the C-terminus. Bimolecular Fluorescence Complementation (BiFC) assay was used to determine where receptor dimerization occurred during protein trafficking by monitoring generation of EGFP fluorescence, which occurred upon GPCR dimerization. Our results suggest that these tagged receptors traffic to the membrane as monomers, undergo dimerization or higher ordered oligomerization predominantly on the plasma membrane, and are internalized as dimers/oligomers. This study is the first to provide direct in vivo visualization of GPCR dimerization/oligomerization, during trafficking to and from the plasma membrane. PMID- 28073701 TI - Effect of asthma therapies on the natural course of asthma. AB - OBJECTIVE: To provide an evidence-based review on the role of pharmacologic (inhaled corticosteroids, leukotriene receptor antagonists, biologic therapies, aeroallergen immunotherapy) and nonpharmacologic therapies (environmental modifications, microbiome) in secondary and tertiary asthma prevention. DATA SOURCES: A PubMed search for English-language publications regarding asthma and secondary or tertiary prevention was performed. Some articles cited in selected studies were also considered for inclusion in this review. STUDY SELECTIONS: Studies were included that were original research and specifically addressed the question of asthma prevention and use of pharmacologic or nonpharmacologic therapies. When possible, we selected the articles with the most robust level of evidence. RESULTS: More than 100 articles were initially identified, 79 were reviewed in depth, and 60 were included in this review. Several studies suggest no disease-modifying effect for inhaled corticosteroids. Small studies suggest a tertiary preventive effect for leukotriene receptor antagonists. Biological therapies have somewhat conflicting evidence with a paucity of pediatric data, although some have tremendous promise. A role of allergen immunotherapy (specifically pollen) in secondary asthma prevention has been suggested, with no firm conclusions possible for tertiary prevention. One large trial suggests a role for environmental modifications in secondary asthma prevention, whereas the preponderance of evidence does not suggest a role in tertiary prevention. The microbiome is an active area of research that has promise for a disease-modifying effect. CONCLUSION: Further work needs to be performed to allow physicians to intervene early and alter the natural course of asthma in children. PMID- 28073702 TI - Serum progranulin as an indicator of neutrophilic airway inflammation and asthma severity. AB - BACKGROUND: Progranulin, a protein secreted from the airway epithelium, is known to attenuate the downstream cascade of neutrophilic inflammation in particular. We hypothesized that progranulin may have a role in inflammatory regulation in asthma. OBJECTIVE: To investigate the association between serum progranulin levels and various clinical features in patients with asthma. METHODS: Serum samples and clinical data of 475 patients with asthma and 35 healthy controls at a tertiary referral hospital and its affiliated health promotion center were collected. Serum progranulin levels were compared between patients with asthma and healthy controls and then were compared within the patients with asthma in terms of pulmonary function and measures of inflammatory status. Univariate and multivariate analyses were performed to identify factors associated with severity of asthma. RESULTS: Serum progranulin levels were significantly lower in the asthma group than in healthy group and were positively correlated with prebronchodilator forced expiratory volume in 1 second predicted within patients with asthma. We found a negative correlation between serum progranulin levels and blood neutrophil counts. Multivariate analysis revealed that higher serum progranulin levels were associated with a lower risk of severe asthma (odds ratio, 0.888; 95% confidence interval, 0.846-0.932; P < .001) after adjustment for other variables, such as age, sex, smoking status, blood neutrophil count, and current use of systemic corticosteroids. CONCLUSION: Although the exact mechanism of the anti-inflammatory action of progranulin remains unknown, we suggest that serum progranulin may be an indicator of severe asthma with airflow limitation. Future studies with comprehensive airway sampling strategies are warranted to clarify its role, particularly in neutrophilic asthma. PMID- 28073703 TI - Development of sesame tolerance and cosensitization of sesame allergy with peanut and tree nut allergy in children. PMID- 28073704 TI - Raltegravir-induced drug reaction with eosinophilia and systemic symptoms syndrome in a child. PMID- 28073705 TI - Contact urticaria caused by alcohol: Clinical characteristics and cross reactions. PMID- 28073706 TI - Cutaneous Rosai-Dorfman disease associated with uveitis. PMID- 28073707 TI - Analytical performances of Optilite(r) turbidimeter (The Binding Site): a new dedicated analyser for specific proteins determination. AB - We checked analytical performances of Optilite(r) analyser for immunoglobulins G, A, M, subclasses of IgG, free light chains of Ig (Freelite(r)) and complement's fractions using Binding Site reagents. CVs for repeteability and reproducibility showed very good results, respectively <3% and <10% for all tested parameters, in agreement with Ricos and SFBC recommendations. Comparisons with results obtained on BNTMII (Siemens) or SPAPLUS (r) (Binding site) analysers showed a good agreement (>83%) according to Bland and Altman analysis. Sample throughput with either a batch of Freelite(r) only or Freelite(r) and immunoglobulins showed a gain of total realisation time on Optilite(r) versus BNTMII. Optilite(r) analyser performed automatic dilutions until result and antigen excess determination for parameters as Freelite(r) or IgG4. In terms of practicability, traceability and maintenance, Optilite(r) turbidimeter alone or connected to LIS via DataSite software is well adapted to specialized laboratory for proteins determinations. PMID- 28073708 TI - Juvenile dermatomyositis positive for anti-DNA mismatch repair enzyme antibodies. PMID- 28073709 TI - The French Muskoka Fund for the health of mothers and children. PMID- 28073710 TI - Salamatou, Nana and the others. PMID- 28073711 TI - Grants by the French Muskoka Fund, by agency and by country (2012-2016). PMID- 28073712 TI - Zero infant mortality in Baoule. PMID- 28073713 TI - The French Muskoka Fund: origin, objectives, and implementation. AB - Through its Priority Solidarity Fund, France set up a partnership with four United Nations agencies, WHO, UNICEF, UNFPA, and UN WOMEN for the years 2011-2015 with an annual budget of 19 M ?. An additional sixth year supplementary is underway. The program was developed through a common framework of actions coordinated and harmonized at the level of the target countries: integrated management of childhood diseases, mother-child nutrition, prenatal, perinatal, and postpartum follow-up, sexual and reproductive health, and adolescent health. The contribution of WHO was based on its normative role; UNICEF offered its operational capacity in the field, and UNFPA its focus on reproductive health, while UN WOMEN dealt with gender questions. The countries targeted specifically were: Benin, Burkina Faso, Cote d'Ivoire, Guinea, Haiti, Mali, Nigeria, Central Africa Republic, Democratic Republic of the Congo, Senegal, Chad, and Togo. PMID- 28073714 TI - Prudence, 33 years old. Champion of family planning. PMID- 28073715 TI - Improving the availability of maternal and child healthcare staff Organizing equitable access to competent healthcare professionals. AB - From now until 2030, low-income countries are expected to have a deficit of around 18 million healthcare workers, unless significant action is taken to reduce these shortages. The French Muskoka Fund has made it possible to improve the strategies of management of maternal and child healthcare personnel in 9 French-speaking countries in sub-Saharan Africa. The objective was to improve policies for the training, recruitment, and retention of healthcare personnel in these countries to ensure effective staff coverage in healthcare facilities for mothers and children. PMID- 28073716 TI - "The machine that pulls babies out". PMID- 28073717 TI - Quality of care in women's, children's, and adolescent health. Methods for assessing evaluation and implementation in West Africa. Experience in the Cote d'Ivoire. AB - A tool developed by WHO was used to assess the quality of care for mothers, newborns, and children in some healthcare facilities in French-speaking Africa; this study led to the development of recommendations for the implementation of actions intended to resolve the problems observed and to optimize patient management. We report here the experience of the maternity units of the university hospital center of Treichville, in Abidjan, discuss the presentation of the results of the assessment, and make some recommendations as part of an action program. The experience of the monthly review of referred cases is also reported. PMID- 28073718 TI - The ordeal of Haoua, married from the age to 16 to an abuser. PMID- 28073719 TI - Practice communities: innovative mechanisms for sharing and producing knowledge about health-care systems. PMID- 28073720 TI - Children, Healh Care, and Pediatrics in West Africa (ENSPEDIA): Research-Action Project to Help Improve the Quality of Care in Pediatrics Departments in West Africa (Benin, Burkina-Faso, Guinea, Mali, Mauritania, Niger, Senegal, and Togo). PMID- 28073721 TI - The contribution of the French Muskoka Fund to improving access to essential medicines and priority health products for mothers and children. AB - One objective of the French Muskoka Fund since 2011 has been to improve the availability of quality healthcare services for mothers and children and thus to contribute to the continued presence of essential drugs and affordable quality health products and to their rational use by healthcare personnel. This project thus contributed to reinforcing the work of the national regulatory authorities, guarantor of the quality of the products supplied to the populations, but also to strengthening the coordination of supplies at the country level. It also enabled the provision of support for the implementation of drug price controls and helped to strengthen the ability of healthcare staff to optimize their use of the products available to them. This work should be continued in these countries as they meet the agenda of the Sustainable Development Goals, which require the establishment of universal healthcare coverage. PMID- 28073722 TI - Haoua and Halime: a victory against malnutrition. PMID- 28073723 TI - "That's Life!" An Innovative Project. PMID- 28073724 TI - Follow the reporter from the African World who travelled 4000 km from the coast of Senagal to Lake Chad to meet the women of the Sahel. PMID- 28073725 TI - After Muskoka. AB - Substantial progress has been accomplished in reducing maternal, neonatal, and infant mortality, but the work to meet the Millennium Development Goals, boosted by numerous initiatives, including Muskoka, is far from finished. Since 2016, the Sustainable Development Goals, as well as the International Strategy for Women's, Children's, and Adolescent Health 2016 - 2030, have provided to the countries and development partners a consistent framework for action enlarged to all of the dimensions of human development, while keeping women, children, and adolescents at its heart. In this context, the Muskoka program, after an initial 5-year cycle, will continue in 2017. PMID- 28073726 TI - Breast cancer in women younger than 35 years : features and outcomes in the breast unit at Aristide le Dantec Teaching Hospital, Dakar. AB - The aim of this study was to determine the clinical features and outcomes of women younger than 35 years with breast cancer. This study was performed at Gynecologic and Obstetric Clinic of Dakar Teaching Hospital and retrospectively reviewed the records of all women younger than 35 years seen in our department for histologically proven breast cancer. Data were analyzed with SPSS software (Statistical Package for Social Science) Version 23. Between 2007 and 2015, 62 women with breast cancer met the inclusion criteria and were included. The incidence of women in this age group treated in our department was 22.6%. The median age at diagnosis was 29.7 years. The mean time to consultation was 12.5 months, and the disease was locally advanced at diagnosis in 79% of cases. Histological study found 85.5% of cancers were invasive ductal carcinoma. The immunohistochemical study found positive hormone receptors in 12 women (19.4%) and overexpression of HER-2 in 8 (12.9%). Chemotherapy was performed in 54 patients (87.1%), and surgery in 47 (62.9%). Recurrence occurred in 12. In all, 22 women died (35.5%) by the end of the study period. Mean survival was 36.7 months (CI 29.5 to 43.9) and median survival 39.7 months (CI 22.1 to 57.5). This high incidence rate in our study is consistent with that found in young African American women and is worrisome. These results seem to point towards a genetic origin and call for a thorough search of the profile. They also call also for the involvement of pathologists and collaboration with other research teams. PMID- 28073727 TI - Psychosocial vulnerability and HIV/AIDS epidemiological situation among people with hearing disabilities in four towns in Cameroon. AB - The scientific literature about disabled people has stressed their high exposure to social exclusion and marginalization, linked to ways of thinking and representations about them. In the area of HIV/AIDS, this marginalization, which results in higher levels of self-stigmatization and especially in inequalities in prevention, continues to put disabled people at high risk of HIV infection. The current study, conducted with a socioepidemiological and behavioral approach, included 317 people with hearing disabilities, recruited through purposive sampling combined with a snowball approach. Participants, after providing informed consent in accordance with the declaration of Helsinki, completed a questionnaire and underwent HIV screening. The results showed a high rate of early sexual intercourse and a high prevalence of HIV, associated with their many risk factors and vulnerability. The analysis also revealed that social marginalization, erroneous beliefs, lack of communication and more generally of appropriate prevention adapted to them, a high rate of multiple partners, a low rate of condom use, psychosexual violence, and difficulties in negotiating social relations, particularly those of sexual relations, are the principal factors of vulnerability and risk. PMID- 28073728 TI - Biermer anemia: Hematologic characteristics of 66 patients in a Clinical Hematology Unit at Senegal. AB - Hematological manifestations can lead to diagnosis of pernicious anemia, also known as Biermer disease and Biermer anemia. This disease has been little studied among black Africans. Our aim is to describe its diagnostic and therapeutic aspects and outcome in our practice. This descriptive study retrospectively examined the records of 66 patients with pernicious anemia seen at the Clinical Hematology Unit of Le Dantec Hospital in Senegal from January 1, 2000, to June 30, 2014. Symptoms were anemic syndrome (40 cases), hemolytic anemia (13), anemic heart failure (7), isolated pallor of the mucous membranes (5), and venous thrombosis (2). Their mean hemoglobin on diagnosis was 6.52 g/dL [1.3-15.2 g/dL], macrocytosis (52), normocytosis (14), hypochromia (4), thrombocytopenia (39), and leukopenia (28 cases). Cytopenia was associated with pancytopenia (25) and bicytopenia (18). Cytologic abnormalities were documented in 42 cases: megaloblastic erythrosis (37 cases) and hypersegmented neutrophils (24 cases). After vitamin B12 therapy - intramuscular (52) or oral (14) -, a reticulocyte crisis was noted on the 8th day and followed by correction of the blood count. Macrocytic anemia, frequently associated with thrombocytopenia and/or leukopenia, is the main hematologic sign evoking pernicious anemia. Venous thrombosis is a rare circumstance of diagnosis that must not be ignored. Intramuscular or oral vitamin B12 is recognized to be effective in these cases and reverses hematological manifestations. PMID- 28073729 TI - Phytotherapy against buruli ulcer in the Health District of Yamoussoukro (Cote d'Ivoire) : Identification, description, and symbolic functions of the plants and recipes used. AB - This study aims to describe the plants and recipes proposed by traditional healers against Buruli ulcer in Cote d'Ivoire and to analyze their symbolic aspects. Buruli ulcer is an increasingly serious health problem in Cote d'Ivoire. The ivorian state through the National Buruli Ulcer Control Programme and its partners, has developed various actions to fight that disease. Medical and surgical treatments are offered free of charge to patients. Hundreds of health centers in different health districts have been converted into Buruli ulcer management centers. Despite these actions, traditional treatment continues to dominate the treatment journey. In rural areas, traditional healers provide management for Buruli ulcer. This qualitative and descriptive study studied 4 traditional healers and 37 patients at the Kongouanou care center. The traditional healers offer patients products that are disinfectants and ointments prepared from leaves, bark, roots, and fruits of different plants. The modes of treatment are supported by both dietary restrictions and a set of symbolic elements. Several reasons explain the predominance of traditional medicine in patients' treatment routes, although none of the patients interviewed was cured. It is, however, appropriate to establish collaboration with traditional healers to promote early detection and immediate recourse to specialized treatment centers. PMID- 28073730 TI - 2014 Anthrax epidemic in Koubia prefecture, Guinea-Conakry. AB - Anthrax disease is an anthropozoonosis caused by a Gram-positive bacterium, Bacillus anthracis. Our objective was to describe the epidemiological, clinical and therapeutic features of the 2014 epidemic in Koubia prefecture. This retrospective study examined all of the anthrax cases reported in Fafaya, Koubia Prefecture. In March and April 2014, there were 39 cases of human anthrax reported, for an incidence of 1.135%. The mean age was 20.9 (+/- 18.3) with a sex ratio of 2.54 (28/11) in favor of men. Seventy-six percent (23/39) were single. More than one half were students (53.8%). The main clinical signs were fever in 71, 8% (n = 28 /), papules 59% (n = 23), vesicles of 59% (n = 23) Digestive and cutaneous signs represented 35.9 % and 64.1% respectively; 35% had ingested contaminated meat and 17.95% were in direct contact with a sick animal. We didn't find any correlation between the mode of infection and onset of signs. The fatality rate was 28.21%. The 2014 epidemic of anthrax disease in the Koubia prefecture was marked by a high incidence and lethality. Clinical manifestations were cutaneaous and digestive. These results may serve further interventions to fight against anthrax disease. They should mainly focus on an awareness of peasants, surveillance and vaccination of cattle. Other studies seem to be necessary. PMID- 28073731 TI - Discoveries about tubercolosis from autopsies: topographical and morphological profiles of lesions in dakar (Senegal). AB - Tuberculosis is endemic in Senegal. It is rate of increase and high mortality rate make it a major public health problem. The aim of this study was to describe the topographic, macroscopic, and microscopic aspects of tuberculosis lesions responsible for deaths in Dakar. This is a retrospective study of 158 autopsy reports, collected over 10 years, of deaths due to tuberculosis. The diagnosis of tuberculosis was essentially macroscopic; only equivocal cases had histological analysis. The average age at death was 47 years, and nearly all patients were men (all but 5). The largest percentage of deaths were in the 56-60 year old age group (21.6%, n = 34). Cachexia (70.3%), pallor (44.3%), and hemoptysis (20.9%) were found in the external examination of these corpses. Autopsy of the viscera showed pulmonary disease in 98.7% of cases (n = 156), both bilateral and extensive. Renal and pericardial disease were rare, found in respectively 3.8% and 2.5% of cases. Macroscopic aspects of tuberculosis were various and often related. Miliary tuberculosis (81%), small nodule tuberculosis (76.6%), and tuberculomas (62%) were the lesions most commonly encountered. Histologic analysis showed these lesions were of different ages. Tubercles (Koster follicles) were found consistently. Caseous necrosis was pathognomonic. Tuberculosis remains a deadly disease in Dakar, it mainly affects men and older individuals. PMID- 28073732 TI - Insecticide resistance in Anopheles mosquitoes : additional obstacles in the battle against malaria. AB - Mosquitoes of the genus Anopheles are malaria vectors in tropical areas and were of course designated as primary targets by programs for malaria control. Repellent sprays, indoor use of insecticides, and massive delivery of mosquito nets are standard examples of the means widely used to combat malaria. This synthetic review supplies an overview of all of the modes of resistance developed by Anopheles mosquitoes against these human actions. The misuse of each available tool has gradually led to a decrease in its global effectiveness. Newly-emerging forms of resistance, due to modification or overexpression of molecular targets, as well as behavioral adaptations by mosquitoes, are some examples of the consequences. To enable a categorical reduction in malaria incidence, a thorough adjustment of the use of the various means of control should be envisioned. PMID- 28073733 TI - Antibiotic therapy and staphylococcal skin infections in a tropical malarial zone (Guyana). Practices in conventional and exceptional situations. AB - A problem of community-acquired Staphylococcus aureus skin infections emerged in the French armed forces in 2004, in a malaria-endemic areas. The high incidence rate led us to evaluate military staff practices. This was a cross-sectional survey of doctors and nurses deployed as officers in French Guyana since 2006. The definition of skin and soft-tissue infection came from the criteria for epidemiological surveillance of the armed forces. We studied the management of antibiotic therapy and its related difficulties. In all, 47 officers responded. At the Military Medical Center (MMC), 23.4% of respondents routinely prescribed antibiotics, compared with 36.2% when stationed in the jungle (p<0.05%). Complication led 68.1 of staff to prescribe antibiotic prescriptions at the MMC, compared with 46.8% in the jungle (p<0.05%). Finally, 22.5% of those at MMC prescribed antibiotic coverage of surgical drainage, compared with 14.8% in the jungle (p<0.05%). Pristinamycin and fusidic acid were the preferred antibiotics. Two-thirds of the staff reported difficulties in jungle management. This first study indicates the need for an update of military medical recommendations. Personnel training must continue to enable them to provide appropriate aggressive management in the current endemic context. PMID- 28073734 TI - Acute parasitic and other infectious myelopathies in the tropics: 26 cases at the University Hospital in Conakry. AB - In tropical countries, laboratory-confirmed diagnostic certainty of parasitic and other infectious causes of acute myelopathy is difficult because of a shortage of medical professionals and consulting delays. We performed a retrospective study of 168 patients hospitalized for spinal disorders between 2007 and 2013 and identified 26 diagnosed with acute non-compressive myelopathy of presumed sudden onset. An parasitic or other infectious cause was established for all. A preliminary clinical infection preceding the development of neurologic signs was reported for 22 patients (84.6 %). Neurological signs were limited to the existence of a progressive sensorimotor symptomatology with sphincter disorders. PMID- 28073735 TI - Patient Information Websites About Medically Induced Second-Trimester Abortions: A Descriptive Study of Quality, Suitability, and Issues. AB - BACKGROUND: Patients undergoing medically induced second-trimester abortions feel insufficiently informed and use the Web for supplemental information. However, it is still unclear how people who have experience with pregnancy termination appraise the quality of patient information websites about medically induced second-trimester abortions, whether they consider the websites suitable for patients, and what issues they experience with the websites. OBJECTIVE: Our objective was to investigate the quality of, suitability of, and issues with patient information websites about medically induced second-trimester abortions and potential differences between websites affiliated with the health care system and private organizations. METHODS: We set out to answer the objective by using 4 laypeople who had experience with pregnancy termination as quality assessors. The first 50 hits of 26 systematic searches were screened (N=1300 hits) using search terms reported by the assessors. Of these hits, 48% (628/1300) were irrelevant and 51% (667/1300) led to websites about medically induced second-trimester abortions. After correcting for duplicate hits, 42 patient information websites were included, 18 of which were affiliated with the health care system and 24 with private organizations. The 4 assessors systematically assessed the websites with the DISCERN instrument (total score range 16-80), the Ensuring Quality Information for Patients (EQIP) tool (total score range 0-100), as well as questions concerning website suitability and perceived issues. RESULTS: The interrater reliability was 0.8 for DISCERN and EQIP, indicating substantial agreement between the assessors. The total mean score was 36 for DISCERN and 40 for EQIP, indicating poor overall quality. Websites from the health care system had greater total EQIP (45 vs 37, P>.05) and reliability scores (22 vs 20, P>.05). Only 1 website was recommended by all assessors and 57% (24/42) were rated as very unsuitable by at least one assessor. The most reported issues with the websites involved lack of information (76%, 32/42), and poor design (36%, 15/42). CONCLUSIONS: The high number of irrelevant hits and poor quality of patient information websites are considerable issues that must be addressed and considered when consulting patients awaiting medically induced second-trimester abortions. In clinical encounters, health professionals should initiate discussions concerning websites about medically induced second-trimester abortions and inform patients about the issues and quality deficits associated with these websites. PMID- 28073736 TI - Development of an Educational Game to Set Up Surgical Instruments on the Mayo Stand or Back Table: Applied Research in Production Technology. AB - BACKGROUND: Existing research suggests that digital games can be used effectively for educational purposes at any level of training. Perioperative nursing educators can use games to complement curricula, in guidance and staff development programs, to foster team collaboration, and to give support to critical thinking in nursing practice because it is a complex environment. OBJECTIVE: To describe the process of developing an educational game to set up surgical instruments on the Mayo stand or back table as a resource to assist the instructor in surgical instrumentation training for students and nursing health professionals in continued education. METHODS: The study was characterized by applied research in production technology. It included the phases of analysis and design, development, and evaluation. The objectives of the educational game were developed through Bloom's taxonomy. Parallel to the physical development of the educational game, a proposed model for the use of digital elements in educational game activities was applied to develop the game content. RESULTS: The development of the game called "Playing with Tweezers" was carried out in 3 phases and was evaluated by 15 participants, comprising students and professional experts in various areas of knowledge such as nursing, information technology, and education. An environment was created with an initial screen, menu buttons containing the rules of the game, and virtual tour modes for learning and assessment. CONCLUSIONS: The "digital" nursing student needs engagement, stimulation, reality, and entertainment, not just readings. "Playing with Tweezers" is an example of educational gaming as an innovative teaching strategy in nursing that encourages the strategy of involving the use of educational games to support theoretical or practical classroom teaching. Thus, the teacher does not work with only 1 type of teaching methodology, but with a combination of different methodologies. In addition, we cannot forget that skill training in an educational game does not replace curricular practice, but helps. PMID- 28073737 TI - Using Real-Time Social Media Technologies to Monitor Levels of Perceived Stress and Emotional State in College Students: A Web-Based Questionnaire Study. AB - BACKGROUND: College can be stressful for many freshmen as they cope with a variety of stressors. Excess stress can negatively affect both psychological and physical health. Thus, there is a need to find innovative and cost-effective strategies to help identify students experiencing high levels of stress to receive appropriate treatment. Social media use has been rapidly growing, and recent studies have reported that data from these technologies can be used for public health surveillance. Currently, no studies have examined whether Twitter data can be used to monitor stress level and emotional state among college students. OBJECTIVE: The primary objective of our study was to investigate whether students' perceived levels of stress were associated with the sentiment and emotions of their tweets. The secondary objective was to explore whether students' emotional state was associated with the sentiment and emotions of their tweets. METHODS: We recruited 181 first-year freshman students aged 18-20 years at University of California, Los Angeles. All participants were asked to complete a questionnaire that assessed their demographic characteristics, levels of stress, and emotional state for the last 7 days. All questionnaires were completed within a 48-hour period. All tweets posted by the participants from that week (November 2 to 8, 2015) were mined and manually categorized based on their sentiment (positive, negative, neutral) and emotion (anger, fear, love, happiness) expressed. Ordinal regressions were used to assess whether weekly levels of stress and emotional states were associated with the percentage of positive, neutral, negative, anger, fear, love, or happiness tweets. RESULTS: A total of 121 participants completed the survey and were included in our analysis. A total of 1879 tweets were analyzed. A higher level of weekly stress was significantly associated with a greater percentage of negative sentiment tweets (beta=1.7, SE 0.7; P=.02) and tweets containing emotions of fear (beta=2.4, SE 0.9; P=.01) and love (beta=3.6, SE 1.4; P=.01). A greater level of anger was negatively associated with the percentage of positive sentiment (beta=-1.6, SE 0.8; P=.05) and tweets related to the emotions of happiness (beta=-2.2, SE 0.9; P=.02). A greater level of fear was positively associated with the percentage of negative sentiment (beta=1.67, SE 0.7; P=.01), particularly a greater proportion of tweets related to the emotion of fear (beta=2.4, SE 0.8; P=.01). Participants who reported a greater level of love showed a smaller percentage of negative sentiment tweets (beta=-1.3, SE 0.7; P=0.05). Emotions of happiness were positively associated with the percentage of tweets related to the emotion of happiness (beta=-1.8, SE 0.8; P=.02) and negatively associated with percentage of negative sentiment tweets (beta=-1.7, SE 0.7; P=.02) and tweets related to the emotion of fear (beta=-2.8, SE 0.8; P=.01). CONCLUSIONS: Sentiment and emotions expressed in the tweets have the potential to provide real-time monitoring of stress level and emotional well-being in college students. PMID- 28073738 TI - Evaluating YouTube as a Source of Patient Education on the Role of the Hospitalist: A Cross-Sectional Study. AB - BACKGROUND: Hospital medicine is a relatively new specialty field, dedicated to the delivery of comprehensive medical care to hospitalized patients. YouTube is one of the most frequently used websites, offering access to a gamut of videos from self-produced to professionally made. OBJECTIVE: The aim of our study was to determine the adequacy of YouTube as an effective means to define and depict the role of hospitalists. METHODS: YouTube was searched on November 17, 2014, using the following search words: "hospitalist," "hospitalist definition," "what is the role of a hospitalist," "define hospitalist," and "who is a hospitalist." Videos found only in the first 10 pages of each search were included. Non-English, noneducational, and nonrelevant videos were excluded. A novel 7-point scoring tool was created by the authors based on the definition of a hospitalist adopted by the Society of Hospital Medicine. Three independent reviewers evaluated, scored, and classified the videos into high, intermediate, and low quality based on the average score. RESULTS: A total of 102 videos out of 855 were identified as relevant and included in the analysis. Videos uploaded by academic institutions had the highest mean score. Only 6 videos were classified as high quality, 53 as intermediate quality, and 42 as low quality, with 82.4% (84/102) of the videos scoring an average of 4 or less. CONCLUSIONS: Most videos found in the search of a hospitalist definition are inadequate. Leading medical organizations and academic institutions should consider producing and uploading quality videos to YouTube to help patients and their families better understand the roles and definition of the hospitalist. PMID- 28073740 TI - What can eye-tracking tell us? PMID- 28073739 TI - The Associations Among Individual Factors, eHealth Literacy, and Health-Promoting Lifestyles Among College Students. AB - BACKGROUND: eHealth literacy is gaining importance for maintaining and promoting health. Studies have found that individuals with high eHealth literacy are more likely to adopt healthy eating, exercise, and sleep behaviors. In addition, previous studies have shown that various individual factors (eg, frequency of seeking information on health issues, degree of health concern, frequency of eating organic food, and students' college major) are associated with eHealth literacy and health-promoting lifestyles. Nevertheless, few studies have explored the associations among individual factors, eHealth literacy, and health-promoting lifestyles among college students. Moreover, there is a lack of studies that focus on eHealth literacy as a predictor of psychological health behaviors. OBJECTIVE: To examine the associations among various individual factors, eHealth literacy, and health-promoting lifestyles. METHODS: The eHealth Literacy Scale is a 12-item instrument designed to measure college students' functional, interactive, and critical eHealth literacy. The Health-promoting Lifestyle Scale is a 23-item instrument developed to measure college students' self actualization, health responsibility, interpersonal support, exercise, nutrition, and stress management. A nationally representative sample of 556 valid college students in Taiwan was surveyed. A questionnaire was administered to gather the respondents' background information, including the frequency of seeking information on health issues, the frequency of eating organic food, the degree of health concern, and the students' major. We then conducted a multiple regression analysis to examine the associations among individual factors, eHealth literacy, and health-promoting lifestyles. RESULTS: The study found that factors such as medical majors (t550=2.47-7.55, P<.05) and greater concern with health (t550=2.15 9.01, P<.05) predicted college students' 4-6 health-promoting lifestyle dimensions and the 3 dimensions of eHealth literacy. Moreover, critical eHealth literacy positively predicted all 6 health-promoting lifestyle dimensions (t547=2.66-7.28, P<.01), functional literacy positively predicted 2 dimensions (t547=2.32-2.98, P<.05), and interactive literacy predicted only the self actualization dimension (t547=2.81, P<.01). CONCLUSIONS: This study found that participants who majored in medical fields had greater concern with their health and frequently sought health information, exhibited better eHealth literacy, and had a positive health-promoting lifestyle. Moreover, this study showed that college students with a higher critical eHealth literacy engaged better in health promoting activities than those with functional and interactive literacy. PMID- 28073741 TI - Learning from excellence and patient safety incidents. PMID- 28073742 TI - Genomics, proteomics and evolution of dengue virus. AB - The genome of a pathogenic organism possesses a specific order of nucleotides that contains not only information about the synthesis and expression of proteomes, which are required for its growth and survival, but also about its evolution. Inhibition of any particular protein, which is required for the survival of that pathogenic organism, can be used as a potential therapeutic target for the development of effective drugs to treat its infections. In this review, the genomics, proteomics and evolution of dengue virus have been discussed, which will be helpful in better understanding of its origin, growth, survival and evolution, and may contribute toward development of new efficient anti-dengue drugs. PMID- 28073743 TI - Referrals to dentists by GPs could delay diagnosis of oral cancer. PMID- 28073744 TI - Better referrals and funding are needed for preserving fertility. PMID- 28073745 TI - Norovirus infections in England hit highest rate for five years. PMID- 28073747 TI - Exercising as "weekend warrior" still yields mortality benefit, study finds. PMID- 28073746 TI - miRDis: a Web tool for endogenous and exogenous microRNA discovery based on deep sequencing data analysis. AB - Small RNA sequencing is the most widely used tool for microRNA (miRNA) discovery, and shows great potential for the efficient study of miRNA cross-species transport, i.e., by detecting the presence of exogenous miRNA sequences in the host species. Because of the increased appreciation of dietary miRNAs and their far-reaching implication in human health, research interests are currently growing with regard to exogenous miRNAs bioavailability, mechanisms of cross species transport and miRNA function in cellular biological processes. In this article, we present microRNA Discovery (miRDis), a new small RNA sequencing data analysis pipeline for both endogenous and exogenous miRNA detection. Specifically, we developed and deployed a Web service that supports the annotation and expression profiling data of known host miRNAs and the detection of novel miRNAs, other noncoding RNAs, and the exogenous miRNAs from dietary species. As a proof-of-concept, we analyzed a set of human plasma sequencing data from a milk-feeding study where 225 human miRNAs were detected in the plasma samples and 44 show elevated expression after milk intake. By examining the bovine-specific sequences, data indicate that three bovine miRNAs (bta-miR-378, 181* and -150) are present in human plasma possibly because of the dietary uptake. Further evaluation based on different sets of public data demonstrates that miRDis outperforms other state-of-the-art tools in both detection and quantification of miRNA from either animal or plant sources. The miRDis Web server is available at: http://sbbi.unl.edu/miRDis/index.php. PMID- 28073748 TI - David Oliver: Is NHS "candour" on a break for winter? PMID- 28073749 TI - Cost effectiveness of a government supported policy strategy to decrease sodium intake: global analysis across 183 nations. AB - OBJECTIVE: To quantify the cost effectiveness of a government policy combining targeted industry agreements and public education to reduce sodium intake in 183 countries worldwide. DESIGN: Global modeling study. SETTING: 183 countries. POPULATION: Full adult population in each country. INTERVENTION: A "soft regulation" national policy that combines targeted industry agreements, government monitoring, and public education to reduce population sodium intake, modeled on the recent successful UK program. To account for heterogeneity in efficacy across countries, a range of scenarios were evaluated, including 10%, 30%, 0.5 g/day, and 1.5 g/day sodium reductions achieved over 10 years. We characterized global sodium intakes, blood pressure levels, effects of sodium on blood pressure and of blood pressure on cardiovascular disease, and cardiovascular disease rates in 2010, each by age and sex, in 183 countries. Country specific costs of a sodium reduction policy were estimated using the World Health Organization Noncommunicable Disease Costing Tool. Country specific impacts on mortality and disability adjusted life years (DALYs) were modeled using comparative risk assessment. We only evaluated program costs, without incorporating potential healthcare savings from prevented events, to provide conservative estimates of cost effectiveness MAIN OUTCOME MEASURE: Cost effectiveness ratio, evaluated as purchasing power parity adjusted international dollars (equivalent to the country specific purchasing power of US$) per DALY saved over 10 years. RESULTS: Worldwide, a 10% reduction in sodium consumption over 10 years within each country was projected to avert approximately 5.8 million DALYs/year related to cardiovascular diseases, at a population weighted mean cost of I$1.13 per capita over the 10 year intervention. The population weighted mean cost effectiveness ratio was approximately I$204/DALY. Across nine world regions, estimated cost effectiveness of sodium reduction was best in South Asia (I$116/DALY); across the world's 30 most populous countries, best in Uzbekistan (I$26.08/DALY) and Myanmar (I$33.30/DALY). Cost effectiveness was lowest in Australia/New Zealand (I$880/DALY, or 0.02*gross domestic product (GDP) per capita), although still substantially better than standard thresholds for cost effective (<3.0*GDP per capita) or highly cost effective (<1.0*GDP per capita) interventions. Most (96.0%) of the world's adult population lived in countries in which this intervention had a cost effectiveness ratio <0.1*GDP per capita, and 99.6% in countries with a cost effectiveness ratio <1.0*GDP per capita. CONCLUSION: A government "soft regulation" strategy combining targeted industry agreements and public education to reduce dietary sodium is projected to be highly cost effective worldwide, even without accounting for potential healthcare savings. PMID- 28073750 TI - First Mid Staffordshire, now the whole country. PMID- 28073751 TI - Happy corporate holidays from Coca-Cola. PMID- 28073752 TI - Doctors speak out from the front line. PMID- 28073753 TI - Migraine and risk of perioperative ischemic stroke and hospital readmission: hospital based registry study. AB - OBJECTIVE: To evaluate whether patients with migraine are at increased risk of perioperative ischemic stroke and whether this may lead to an increased hospital readmission rate. DESIGN: Prospective hospital registry study. SETTING: Massachusetts General Hospital and two satellite campuses between January 2007 and August 2014. PARTICIPANTS: 124 558 surgical patients (mean age 52.6 years; 54.5% women). MAIN OUTCOME MEASURES: The primary outcome was perioperative ischemic stroke occurring within 30 days after surgery in patients with and without migraine and migraine aura. The secondary outcome was hospital readmission within 30 days of surgery. Exploratory outcomes included post discharge stroke and strata of neuroanatomical stroke location. RESULTS: 10 179 (8.2%) patients had any migraine diagnosis, of whom 1278 (12.6%) had migraine with aura and 8901 (87.4%) had migraine without aura. 771 (0.6%) perioperative ischemic strokes occurred within 30 days of surgery. Patients with migraine were at increased risk of perioperative ischemic stroke (adjusted odds ratio 1.75, 95% confidence interval 1.39 to 2.21) compared with patients without migraine. The risk was higher in patients with migraine with aura (adjusted odds ratio 2.61, 1.59 to 4.29) than in those with migraine without aura (1.62, 1.26 to 2.09). The predicted absolute risk is 2.4 (2.1 to 2.8) perioperative ischemic strokes for every 1000 surgical patients. This increases to 4.3 (3.2 to 5.3) for every 1000 patients with any migraine diagnosis, 3.9 (2.9 to 5.0) for migraine without aura, and 6.3 (3.2 to 9.5) for migraine with aura. : Patients with migraine had a higher rate of readmission to hospital within 30 days of discharge (adjusted odds ratio 1.31, 1.22 to 1.41). CONCLUSIONS: Surgical patients with a history of migraine are at increased risk of perioperative ischemic stroke and have an increased 30 day hospital readmission rate. Migraine should be considered in the risk assessment for perioperative ischemic stroke. PMID- 28073755 TI - Advanced Boolean modeling of biological networks applied to systems pharmacology. AB - Motivation: Literature on complex diseases is abundant but not always quantitative. Many molecular pathways are qualitatively well described but this information cannot be used in traditional quantitative mathematical models employed in drug development. Tools for analysis of discrete networks are useful to capture the available information in the literature but have not been efficiently integrated by the pharmaceutical industry. We propose an expansion of the usual analysis of discrete networks that facilitates the identification/validation of therapeutic targets. Results: In this article, we propose a methodology to perform Boolean modeling of Systems Biology/Pharmacology networks by using SPIDDOR (Systems Pharmacology for effIcient Drug Development On R) R package. The resulting models can be used to analyze the dynamics of signaling networks associated to diseases to predict the pathogenesis mechanisms and identify potential therapeutic targets. Availability and Implementation: The source code is available at https://github.com/SPIDDOR/SPIDDOR . Contact: itzirurzun@alumni.unav.es , itroconiz@unav.es. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28073754 TI - Fast and accurate phylogeny reconstruction using filtered spaced-word matches. AB - Motivation: Word-based or 'alignment-free' algorithms are increasingly used for phylogeny reconstruction and genome comparison, since they are much faster than traditional approaches that are based on full sequence alignments. Existing alignment-free programs, however, are less accurate than alignment-based methods. Results: We propose Filtered Spaced Word Matches (FSWM) , a fast alignment-free approach to estimate phylogenetic distances between large genomic sequences. For a pre-defined binary pattern of match and don't-care positions, FSWM rapidly identifies spaced word-matches between input sequences, i.e. gap-free local alignments with matching nucleotides at the match positions and with mismatches allowed at the don't-care positions. We then estimate the number of nucleotide substitutions per site by considering the nucleotides aligned at the don't-care positions of the identified spaced-word matches. To reduce the noise from spurious random matches, we use a filtering procedure where we discard all spaced word matches for which the overall similarity between the aligned segments is below a threshold. We show that our approach can accurately estimate substitution frequencies even for distantly related sequences that cannot be analyzed with existing alignment-free methods; phylogenetic trees constructed with FSWM distances are of high quality. A program run on a pair of eukaryotic genomes of a few hundred Mb each takes a few minutes. Availability and Implementation: The program source code for FSWM including a documentation, as well as the software that we used to generate artificial genome sequences are freely available at http://fswm.gobics.de/. Contact: chris.leimeister@stud.uni-goettingen.de. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28073757 TI - Rebuttal to the Letter to the Editor in response to the paper: proper evaluation of alignment-free network comparison methods. PMID- 28073756 TI - Feature selection using a one dimensional naive Bayes' classifier increases the accuracy of support vector machine classification of CDR3 repertoires. AB - Motivation: Somatic DNA recombination, the hallmark of vertebrate adaptive immunity, has the potential to generate a vast diversity of antigen receptor sequences. How this diversity captures antigen specificity remains incompletely understood. In this study we use high throughput sequencing to compare the global changes in T cell receptor beta chain complementarity determining region 3 (CDR3beta) sequences following immunization with ovalbumin administered with complete Freund's adjuvant (CFA) or CFA alone. Results: The CDR3beta sequences were deconstructed into short stretches of overlapping contiguous amino acids. The motifs were ranked according to a one-dimensional Bayesian classifier score comparing their frequency in the repertoires of the two immunization classes. The top ranking motifs were selected and used to create feature vectors which were used to train a support vector machine. The support vector machine achieved high classification scores in a leave-one-out validation test reaching >90% in some cases. Summary: The study describes a novel two-stage classification strategy combining a one-dimensional Bayesian classifier with a support vector machine. Using this approach we demonstrate that the frequency of a small number of linear motifs three amino acids in length can accurately identify a CD4 T cell response to ovalbumin against a background response to the complex mixture of antigens which characterize Complete Freund's Adjuvant. Availability and implementation: The sequence data is available at www.ncbi.nlm.nih.gov/sra/?term1/4SRP075893 . The Decombinator package is available at github.com/innate2adaptive/Decombinator . The R package e1071 is available at the CRAN repository https://cran.r project.org/web/packages/e1071/index.html . Contact: b.chain@ucl.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28073758 TI - Resolution and reconciliation of non-binary gene trees with transfers, duplications and losses. AB - Summary: Gene trees reconstructed from sequence alignments contain poorly supported branches when the phylogenetic signal in the sequences is insufficient to determine them all. When a species tree is available, the signal of gains and losses of genes can be used to correctly resolve the unsupported parts of the gene history. However finding a most parsimonious binary resolution of a non binary tree obtained by contracting the unsupported branches is NP-hard if transfer events are considered as possible gene scale events, in addition to gene origination, duplication and loss. We propose an exact, parameterized algorithm to solve this problem in single-exponential time, where the parameter is the number of connected branches of the gene tree that show low support from the sequence alignment or, equivalently, the maximum number of children of any node of the gene tree once the low-support branches have been collapsed. This improves on the best known algorithm by an exponential factor. We propose a way to choose among optimal solutions based on the available information. We show the usability of this principle on several simulated and biological datasets. The results are comparable in quality to several other tested methods having similar goals, but our approach provides a lower running time and a guarantee that the produced solution is optimal. Availability and Implementation: Our algorithm has been integrated into the ecceTERA phylogeny package, available at http://mbb.univ montp2.fr/MBB/download_sources/16__ecceTERA and which can be run online at http://mbb.univ-montp2.fr/MBB/subsection/softExec.php?soft=eccetera . Contact: celine.scornavacca@umontpellier.fr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28073760 TI - Better diagnostic signatures from RNAseq data through use of auxiliary co-data. AB - Summary: Our aim is to improve omics based prediction and feature selection using multiple sources of auxiliary information: co-data. Adaptive group regularized ridge regression (GRridge) was proposed to achieve this by estimating additional group-based penalty parameters through an empirical Bayes method at a low computational cost. We illustrate the GRridge method and software on RNA sequencing datasets. The method boosts the performance of an ordinary ridge regression and outperforms other classifiers. Post-hoc feature selection maintains the predictive ability of the classifier with far fewer markers. Availability and Implementation: GRridge is an R package that includes a vignette. It is freely available at ( https://bioconductor.org/packages/GRridge/ ). All information and R scripts used in this study, including those on retrieval and processing of the co-data, are available from http://github.com/markvdwiel/GRridgeCodata . Contact: mark.vdwiel@vumc.nl. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28073761 TI - Seeing the trees through the forest: sequence-based homo- and heteromeric protein protein interaction sites prediction using random forest. AB - Motivation: Genome sequencing is producing an ever-increasing amount of associated protein sequences. Few of these sequences have experimentally validated annotations, however, and computational predictions are becoming increasingly successful in producing such annotations. One key challenge remains the prediction of the amino acids in a given protein sequence that are involved in protein-protein interactions. Such predictions are typically based on machine learning methods that take advantage of the properties and sequence positions of amino acids that are known to be involved in interaction. In this paper, we evaluate the importance of various features using Random Forest (RF), and include as a novel feature backbone flexibility predicted from sequences to further optimise protein interface prediction. Results: We observe that there is no single sequence feature that enables pinpointing interacting sites in our Random Forest models. However, combining different properties does increase the performance of interface prediction. Our homomeric-trained RF interface predictor is able to distinguish interface from non-interface residues with an area under the ROC curve of 0.72 in a homomeric test-set. The heteromeric-trained RF interface predictor performs better than existing predictors on a independent heteromeric test-set. We trained a more general predictor on the combined homomeric and heteromeric dataset, and show that in addition to predicting homomeric interfaces, it is also able to pinpoint interface residues in heterodimers. This suggests that our random forest model and the features included capture common properties of both homodimer and heterodimer interfaces. Availability and Implementation: The predictors and test datasets used in our analyses are freely available ( http://www.ibi.vu.nl/downloads/RF_PPI/ ). Contact: k.a.feenstra@vu.nl. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28073762 TI - A DNA intercalation methodology for an efficient prediction of ligand binding pose and energetics. AB - Motivation: Drug intercalation is an important strategy for DNA inhibition which is often employed in cancer chemotherapy. Despite its high significance, the field is characterized by limited success in identification of novel intercalator molecules and lack of automated and dedicated drug-DNA intercalation methodology. Results: We report here a novel intercalation methodology (christened ' Intercalate' ) for predicting both the structures and energetics of DNA intercalator complexes, covering the processes of DNA unwinding and (non covalent) binding. Given a DNA sequence and intercalation site information, Intercalate generates the 3D structure of DNA, creates the intercalation site, performs docking at the intercalation site and evaluates DNA-intercalator binding energy in an automated way. The structures and energetics of the DNA-intercalator complexes produced by Intercalate methodology are seen to be in good agreement with experiment. The dedicated attempt made in developing a drug-DNA intercalation methodology (compatible with its mechanism) with high accuracy should prove useful in the discovery of potential intercalators for their use as anticancers, antibacterials or antivirals. Availability and Implementation: http://www.scfbio-iitd.res.in/intercalate/. Contact: anjali@scfbio-iitd.res.in or bjayaram@chemistry.iitd.ac.in. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28073765 TI - Tracing a Path to the Past: Exploring the Use of Commercial Credit Reporting Data to Construct Residential Histories for Epidemiologic Studies of Environmental Exposures. AB - Large-scale environmental epidemiologic studies often rely on exposure estimates based on linkage to residential addresses. This approach, however, is limited by the lack of residential histories typically available for study participants. Our objective was to evaluate the feasibility of using address data from LexisNexis (a division of RELX, Inc., Dayton, Ohio), a commercially available credit reporting company, to construct residential histories for participants in the California Teachers Study (CTS), a prospective cohort study initiated in 1995 1996 to study breast cancer (n = 133,479). We evaluated the degree to which LexisNexis could provide retrospective addresses prior to study enrollment, as well as the concordance with existing prospective CTS addresses ascertained at the time of the completion of 4 self-administered questionnaires. For approximately 80% of CTS participants, LexisNexis provided at least 1 retrospective address, including nearly 25,000 addresses completely encompassed by time periods prior to enrollment. This approach more than doubled the proportion of the study population for whom we had an address of residence during the childbearing years-an important window of susceptibility for breast cancer risk. While overall concordance between the prospective addresses contained in these 2 data sources was good (85%), it was diminished among black women and women under the age of 40 years. PMID- 28073764 TI - Causal Effect of Genetic Variants Associated With Body Mass Index on Multiple Sclerosis Susceptibility. AB - Multiple sclerosis (MS) is an autoimmune disease with both genetic and environmental risk factors. Recent studies indicate that childhood and adolescent obesity double the risk of MS, but this association may reflect unmeasured confounders rather than causal effects of obesity. We used separate-sample Mendelian randomization to estimate the causal effect of body mass index (BMI) on susceptibility to MS. Using data from non-Hispanic white members of the Kaiser Permanente Medical Care Plan of Northern California (KPNC) (2006-2014; 1,104 cases of MS and 10,536 controls) and a replication data set from Sweden (the Epidemiological Investigation of MS (EIMS) and the Genes and Environment in MS (GEMS) studies, 2005-2013; 5,133 MS cases and 4,718 controls), we constructed a weighted genetic risk score using 97 variants previously established to predict BMI. Results were adjusted for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS. Estimates in KPNC and Swedish data sets suggested that higher genetically induced BMI predicted greater susceptibility to MS (odds ratio = 1.13, 95% confidence interval: 1.04, 1.22 for the KPNC sample; odds ratio = 1.09, 95% confidence interval: 1.03, 1.15 for the Swedish sample). Although the mechanism remains unclear, to our knowledge, these findings support a causal effect of increased BMI on susceptibility to MS for the first time, and they suggest a role for inflammatory pathways that characterize both obesity and the MS disease process. PMID- 28073766 TI - A Comprehensive Model of Colorectal Cancer by Risk Factor Status and Subsite Using Data From the Nurses' Health Study. AB - We expanded and updated our colon cancer risk model to evaluate colorectal cancer (CRC) and whether subsite-specific risk models are warranted. Using data from 1980-2010 for 90,286 women enrolled in the Nurses' Health Study, we performed competing-risks regression and tests for subsite heterogeneity (proximal colon: n = 821; distal colon: n = 521; rectum: n = 376). Risk factors for CRC were consistent with those in our colon cancer model. Processed meat consumption was associated with a higher risk of distal (hazard ratio (HR) = 1.45; P = 0.02) but not proximal (HR = 0.95; P = 0.72) colon cancer. Smoking was associated with both colon (HR = 1.21) and rectal (HR = 1.27) cancer and was more strongly associated with proximal (HR = 1.31) than with distal (HR = 1.04) colon cancer (P = 0.029). We observed a significant trend of cancer risk for smoking in subsites from the cecum (HR = 1.41) to the proximal colon (excluding the cecum; HR = 1.27) to the distal colon (HR = 1.04; P for trend = 0.040). The C statistics for colorectal (C = 0.607), colon (C = 0.603), and rectal (C = 0.639) cancer were similar, although C was slightly higher for rectal cancer. Despite evidence for site-specific differences for several risk factors, overall our findings support the application of risk prediction models for colon cancer to CRC. PMID- 28073767 TI - Analyses of Sensitivity to the Missing-at-Random Assumption Using Multiple Imputation With Delta Adjustment: Application to a Tuberculosis/HIV Prevalence Survey With Incomplete HIV-Status Data. AB - Multiple imputation with delta adjustment provides a flexible and transparent means to impute univariate missing data under general missing-not-at-random mechanisms. This facilitates the conduct of analyses assessing sensitivity to the missing-at-random (MAR) assumption. We review the delta-adjustment procedure and demonstrate how it can be used to assess sensitivity to departures from MAR, both when estimating the prevalence of a partially observed outcome and when performing parametric causal mediation analyses with a partially observed mediator. We illustrate the approach using data from 34,446 respondents to a tuberculosis and human immunodeficiency virus (HIV) prevalence survey that was conducted as part of the Zambia-South Africa TB and AIDS Reduction Study (2006 2010). In this study, information on partially observed HIV serological values was supplemented by additional information on self-reported HIV status. We present results from 2 types of sensitivity analysis: The first assumed that the degree of departure from MAR was the same for all individuals with missing HIV serological values; the second assumed that the degree of departure from MAR varied according to an individual's self-reported HIV status. Our analyses demonstrate that multiple imputation offers a principled approach by which to incorporate auxiliary information on self-reported HIV status into analyses based on partially observed HIV serological values. PMID- 28073768 TI - Government fails to assuage doctors' concerns over NHS crisis. PMID- 28073770 TI - Impact of Beta-Blocker Initiation Timing on Mortality Risk in Patients With Diabetes Mellitus Undergoing Noncardiac Surgery: A Nationwide Population-Based Cohort Study. AB - BACKGROUND: Relevant clinical studies have been small and have not convincingly demonstrated whether the perioperative initiation of beta-blockers should be considered in patients with diabetes mellitus undergoing noncardiac surgery. METHODS AND RESULTS: In this nationwide propensity score-matched study, we included patients with diabetes mellitus undergoing noncardiac surgery between 2000 and 2011 from Taiwan's National Health Insurance Research Database. Patients were classified as beta-blocker and non-beta-blocker cohorts. We further stratified beta-blocker users into cardioprotective beta-blocker (atenolol, bisoprolol, metoprolol, or carvedilol) and other beta-blocker users. To investigate time of initiation of beta-blocker use, initiation time was stratified into 2 periods (>30 and <=30 days preoperatively). The outcomes of interest were in-hospital and 30-day mortality. After propensity score matching, we identified 50 952 beta-blocker users and 50 952 matched controls. Compared with non-beta-blocker users, cardioprotective beta-blocker users were associated with lower risks of in-hospital (odds ratio 0.75, 95% CI 0.68-0.82) and 30-day (odds ratio 0.75, 95% CI 0.70-0.81) mortality. Among initiation times, only the use of cardioprotective beta-blockers for >30 days was associated with decreased risk of in-hospital (odds ratio 0.72, 95% CI 0.65-0.78) and 30-day (odds ratio 0.72, 95% CI 0.66-0.78) mortality. Of note, use of other beta-blockers for <=30 days before surgery was associated with increased risk of both in-hospital and 30 day mortality. CONCLUSIONS: The use of cardioprotective beta-blockers for >30 days before surgery was associated with reduced mortality risk, whereas short term use of beta-blockers was not associated with differences in mortality in patients with diabetes mellitus. PMID- 28073769 TI - Aldosterone Does Not Predict Cardiovascular Events Following Acute Coronary Syndrome in Patients Initially Without Heart Failure. AB - BACKGROUND: Aldosterone may have adverse effects in the myocardium and vasculature. Treatment with an aldosterone antagonist reduces cardiovascular risk in patients with acute myocardial infarction complicated by heart failure (HF) and left ventricular systolic dysfunction. However, most patients with acute coronary syndrome do not have advanced HF. Among such patients, it is unknown whether aldosterone predicts cardiovascular risk. METHODS AND RESULTS: To address this question, we examined data from the dal-OUTCOMES trial that compared the cholesteryl ester transfer protein inhibitor dalcetrapib with placebo, beginning 4 to 12 weeks after an index acute coronary syndrome. Patients with New York Heart Association class II (with LVEF <40%), III, or IV HF were excluded. Aldosterone was measured at randomization in 4073 patients. The primary outcome was a composite of coronary heart disease death, nonfatal myocardial infarction, stroke, hospitalization for unstable angina, or resuscitated cardiac arrest. Hospitalization for HF was a secondary endpoint. Over a median follow-up of 37 months, the primary outcome occurred in 366 patients (9.0%), and hospitalization for HF occurred in 72 patients (1.8%). There was no association between aldosterone and either the time to first occurrence of a primary outcome (hazard ratio for doubling of aldosterone 0.92, 95% confidence interval 0.78-1.09, P=0.34) or hospitalization for HF (hazard ratio 1.38, 95% CI 0.96-1.99, P=0.08) in Cox regression models adjusted for covariates. CONCLUSIONS: In patients with recent acute coronary syndrome but without advanced HF, aldosterone does not predict major cardiovascular events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00658515. PMID- 28073771 TI - Out of Borneo: biogeography, phylogeny and divergence date estimates of Artocarpus (Moraceae). AB - Background and Aims: The breadfruit genus ( Artocarpus , Moraceae) includes valuable underutilized fruit tree crops with a centre of diversity in Southeast Asia. It belongs to the monophyletic tribe Artocarpeae, whose only other members include two small neotropical genera. This study aimed to reconstruct the phylogeny, estimate divergence dates and infer ancestral ranges of Artocarpeae, especially Artocarpus , to better understand spatial and temporal evolutionary relationships and dispersal patterns in a geologically complex region. Methods: To investigate the phylogeny and biogeography of Artocarpeae, this study used Bayesian and maximum likelihood approaches to analyze DNA sequences from six plastid and two nuclear regions from 75% of Artocarpus species, both neotropical Artocarpeae genera, and members of all other Moraceae tribes. Six fossil-based calibrations within the Moraceae family were used to infer divergence times. Ancestral areas and estimated dispersal events were also inferred. Key Results: Artocarpeae, Artocarpus and four monophyletic Artocarpus subgenera were well supported. A late Cretaceous origin of the Artocarpeae tribe in the Americas is inferred, followed by Eocene radiation of Artocarpus in Asia, with the greatest diversification occurring during the Miocene. Borneo is reconstructed as the ancestral range of Artocarpus , with dozens of independent in situ diversification events inferred there, as well as dispersal events to other regions of Southeast Asia. Dispersal pathways of Artocarpus and its ancestors are proposed. Conclusions: Borneo was central in the diversification of the genus Artocarpus and probably served as the centre from which species dispersed and diversified in several directions. The greatest amount of diversification is inferred to have occurred during the Miocene, when sea levels fluctuated and land connections frequently existed between Borneo, mainland Asia, Sumatra and Java. Many species found in these areas have extant overlapping ranges, suggesting that sympatric speciation may have occurred. By contrast, Artocarpus diversity east of Borneo (where many of the islands have no historical connections to the landmasses of the Sunda and Sahul shelves) is unique and probably the product of over water long-distance dispersal events and subsequent diversification in allopatry. This work represents the most comprehensive Artocarpus phylogeny and biogeography study to date and supports Borneo as an evolutionary biodiversity hotspot. PMID- 28073772 TI - A water availability gradient reveals the deficit level required to affect traits in potted juvenile Eucalyptus globulus. AB - Background and aims: Drought leading to soil water deficit can have severe impacts on plants. Water deficit may lead to plant water stress and affect growth and chemical traits. Plant secondary metabolite (PSM) responses to water deficit vary between compounds and studies, with inconsistent reports of changes to PSM concentrations even within a single species. This disparity may result from experimental water deficit variation among studies, and so multiple water deficit treatments are used to fully assess PSM responses in a single species. Methods: Juvenile Eucalyptus globulus were grown for 8 weeks at one of ten water deficit levels based on evapotranspiration from control plants (100 %). Treatments ranged from 90 % of control evapotranspiration (mild water deficit) to 0 % of control evapotranspiration (severe water deficit) in 10 % steps. Plant biomass, foliar abscisic acid (ABA) levels, Psi leaf , leaf C/N, selected terpenes and phenolics were quantified to assess responses to each level of water deficit relative to a control. Key Results: Withholding >=30 % water resulted in higher foliar ABA levels and withholding >=40 % water reduced leaf water content. Psi leaf became more negative when >=60 % water was withheld. Plant biomass was lower when >=80 % water was withheld, and no water for 8 weeks (0 % water) resulted in plant death. The total oil concentration was lower and C/N was higher in dead and desiccated juvenile E. globulus leaves (0 % water). Concentrations of individual phenolic and terpene compounds, along with condensed tannin and total phenolic concentrations, remained stable regardless of water deficit or plant stress level. Conclusions: These juvenile E. globulus became stressed with a moderate reduction in available water, and yet the persistent concentrations of most PSMs in highly stressed or dead plants suggests no PSM re-metabolization and continued ecological roles of foliar PSMs during drought. PMID- 28073773 TI - Long-term Survival and Clinical Benefit from Adoptive T-cell Transfer in Stage IV Melanoma Patients Is Determined by a Four-Parameter Tumor Immune Signature. AB - The presence of tumor-infiltrating immune cells is associated with longer survival and a better response to immunotherapy in early-stage melanoma, but a comprehensive study of the in situ immune microenvironment in stage IV melanoma has not been performed. We investigated the combined influence of a series of immune factors on survival and response to adoptive cell transfer (ACT) in stage IV melanoma patients. Metastases of 73 stage IV melanoma patients, 17 of which were treated with ACT, were studied with respect to the number and functional phenotype of lymphocytes and myeloid cells as well as for expression of galectins 1, -3, and -9. Single factors associated with better survival were identified using Kaplan-Meier curves and multivariate Cox regression analyses, and those factors were used for interaction analyses. The results were validated using The Cancer Genome Atlas database. We identified four parameters that were associated with a better survival: CD8+ T cells, galectin-9+ dendritic cells (DC)/DC-like macrophages, a high M1/M2 macrophage ratio, and the expression of galectin-3 by tumor cells. The presence of at least three of these parameters formed an independent positive prognostic factor for long-term survival. Patients displaying this four-parameter signature were found exclusively among patients responding to ACT and were the ones with sustained clinical benefit. Cancer Immunol Res; 5(2); 170-9. (c)2017 AACR. PMID- 28073774 TI - Temporally Distinct PD-L1 Expression by Tumor and Host Cells Contributes to Immune Escape. AB - Antibody blockade of programmed death-1 (PD-1) or its ligand, PD-L1, has led to unprecedented therapeutic responses in certain tumor-bearing individuals, but PD L1 expression's prognostic value in stratifying cancer patients for such treatment remains unclear. Reports conflict on the significance of correlations between PD-L1 on tumor cells and positive clinical outcomes to PD-1/PD-L1 blockade. We investigated this issue using genomically related, clonal subsets from the same methylcholanthrene-induced sarcoma: a highly immunogenic subset that is spontaneously eliminated in vivo by adaptive immunity and a less immunogenic subset that forms tumors in immunocompetent mice, but is sensitive to PD-1/PD-L1 blockade therapy. Using CRISPR/Cas9-induced loss-of-function approaches and overexpression gain-of-function techniques, we confirmed that PD L1 on tumor cells is key to promoting tumor escape. In addition, the capacity of PD-L1 to suppress antitumor responses was inversely proportional to tumor cell antigenicity. PD-L1 expression on host cells, particularly tumor-associated macrophages (TAM), was also important for tumor immune escape. We demonstrated that induction of PD-L1 on tumor cells was IFNgamma-dependent and transient, but PD-L1 induction on TAMs was of greater magnitude, only partially IFNgamma dependent, and was stable over time. Thus, PD-L1 expression on either tumor cells or host immune cells could lead to tumor escape from immune control, indicating that total PD-L1 expression in the immediate tumor microenvironment may represent a more accurate biomarker for predicting response to PD-1/PD-L1 blockade therapy, compared with monitoring PD-L1 expression on tumor cells alone. Cancer Immunol Res; 5(2); 106-17. (c)2017 AACR. PMID- 28073776 TI - Managers must respond to doctors' patient safety concerns, GMC says. PMID- 28073775 TI - Dasatinib Changes Immune Cell Profiles Concomitant with Reduced Tumor Growth in Several Murine Solid Tumor Models. AB - Dasatinib, a broad-range tyrosine kinase inhibitor, induces rapid mobilization of lymphocytes and clonal expansion of cytotoxic cells in leukemia patients. Here, we investigated whether dasatinib could induce beneficial immunomodulatory effects in solid tumor models. The effects on tumor growth and on the immune system were studied in four different syngeneic mouse models (B16.OVA melanoma, 1956 sarcoma, MC38 colon, and 4T1 breast carcinoma). Both peripheral blood (PB) and tumor samples were immunophenotyped during treatment. Although in vitro dasatinib displayed no direct cytotoxicity to B16 melanoma cells, a significant decrease in tumor growth was observed in dasatinib-treated mice compared with vehicle-treated group. Further, dasatinib-treated melanoma-bearing mice had an increased proportion of CD8+ T cells in PB, together with a higher amount of tumor-infiltrating CD8+ T cells. Dasatinib-mediated antitumor efficacy was abolished when CD4+ and CD8+ T cells were depleted with antibodies. Results were confirmed in sarcoma, colon, and breast cancer models, and in all cases mice treated daily with dasatinib had a significant decrease in tumor growth. Detailed immunophenotyping of tumor tissues with CyTOF indicated that dasatinib had reduced the number of intratumoral regulatory T cells in all tumor types. To conclude, dasatinib is able to slow down the tumor growth of various solid tumor models, which is associated with the favorable blood/tumor T-cell immunomodulation. The assessment of synergistic combinatorial therapies with other immunomodulatory drugs or targeted small-molecule oncokinase inhibitors is warranted in future clinical trials. Cancer Immunol Res; 5(2); 157-69. (c)2017 AACR. PMID- 28073777 TI - Son speaks out on behalf of Indian doctors charged over death of patient. PMID- 28073779 TI - Glucose-dependent insulinotropic polypeptide promotes lipid deposition in subcutaneous adipocytes in obese type 2 diabetes patients: a maladaptive response. AB - Glucose-dependent insulinotropic polypeptide (GIP) beyond its insulinotropic effects may regulate postprandial lipid metabolism. Whereas the insulinotropic action of GIP is known to be impaired in type 2 diabetes mellitus (T2DM), its adipogenic effect is unknown. We hypothesized that GIP is anabolic in human subcutaneous adipose tissue (SAT) promoting triacylglycerol (TAG) deposition through reesterification of nonesterified fatty acids (NEFA), and this effect may differ according to obesity status or glucose tolerance. Twenty-three subjects categorized into four groups, normoglycemic lean (n = 6), normoglycemic obese (n = 6), obese with impaired glucose regulation (IGR; n = 6), and obese T2DM (n = 5), participated in a double-blind, randomized, crossover study involving a hyperglycemic clamp with a 240-min GIP infusion (2 pmol.kg-1.min-1) or normal saline. Insulin, NEFA, SAT-TAG content, and gene expression of key lipogenic enzymes were determined before and immediately after GIP/saline infusions. GIP lowered NEFA concentrations in the obese T2DM group despite diminished insulinotropic activity (mean NEFA AUC0-4 h +/- SE, 41,992 +/- 9,843 umol.l-1.min 1 vs. 71,468 +/- 13,605 with placebo, P = 0.039, 95% CI: 0.31-0.95). Additionally, GIP increased SAT-TAG in obese T2DM (1.78 +/- 0.4 vs 0.86 +/- 0.1 fold with placebo, P = 0.043, 95% CI: 0.1-1.8). Such effect with GIP was not observed in other three groups despite greater insulinotropic activity. Reduction in NEFA concentration with GIP correlated with adipose tissue insulin resistance for all subjects (Pearson, r = 0.56, P = 0.005). There were no significant gene expression changes in key SAT lipid metabolism enzymes. In conclusion, GIP appears to promote fat accretion and thus may exacerbate obesity and insulin resistance in T2DM. PMID- 28073781 TI - Sixty seconds on . . . diet drinks. PMID- 28073778 TI - Overexpression of PGC-1alpha increases peroxisomal activity and mitochondrial fatty acid oxidation in human primary myotubes. AB - Peroxisomes are indispensable organelles for lipid metabolism in humans, and their biogenesis has been assumed to be under regulation by peroxisome proliferator-activated receptors (PPARs). However, recent studies in hepatocytes suggest that the mitochondrial proliferator PGC-1alpha (peroxisome proliferator activated receptor gamma coactivator-1alpha) also acts as an upstream transcriptional regulator for enhancing peroxisomal abundance and associated activity. It is unknown whether the regulatory mechanism(s) for enhancing peroxisomal function is through the same node as mitochondrial biogenesis in human skeletal muscle (HSkM) and whether fatty acid oxidation (FAO) is affected. Primary myotubes from vastus lateralis biopsies from lean donors (BMI = 24.0 +/- 0.6 kg/m2; n = 6) were exposed to adenovirus encoding human PGC-1alpha or GFP control. Peroxisomal biogenesis proteins (peroxins) and genes (PEXs) responsible for proliferation and functions were assessed by Western blotting and real-time qRT-PCR, respectively. [1-14C]palmitic acid and [1-14C]lignoceric acid (exclusive peroxisomal-specific substrate) were used to assess mitochondrial oxidation of peroxisomal-derived metabolites. After overexpression of PGC-1alpha, 1) peroxisomal membrane protein 70 kDa (PMP70), PEX19, and mitochondrial citrate synthetase protein content were significantly elevated (P < 0.05), 2) PGC-1alpha, PMP70, key PEXs, and peroxisomal beta-oxidation mRNA expression levels were significantly upregulated (P < 0.05), and 3) a concomitant increase in lignoceric acid oxidation by both peroxisomal and mitochondrial activity was observed (P < 0.05). These novel findings demonstrate that, in addition to the proliferative effect on mitochondria, PGC-1alpha can induce peroxisomal activity and accompanying elevations in long-chain and very-long-chain fatty acid oxidation by a peroxisomal-mitochondrial functional cooperation, as observed in HSkM cells. PMID- 28073780 TI - Chronic kidney disease and obesity bias surrogate estimates of insulin sensitivity compared with the hyperinsulinemic euglycemic clamp. AB - Insulin sensitivity can be measured by procedures such as the hyperinsulinemic euglycemic clamp or by using surrogate indices. Chronic kidney disease (CKD) and obesity may differentially affect these measurements because of changes in insulin kinetics and organ-specific effects on insulin sensitivity. In a cross sectional study of 59 subjects with nondiabetic CKD [estimated glomerular filtration rate: (GFR) <60 ml.min-1.1.73 m2] and 39 matched healthy controls, we quantified insulin sensitivity by clamp (SIclamp), oral glucose tolerance test, and fasting glucose and insulin. We compared surrogate insulin sensitivity indices to SIclamp using descriptive statistics, graphical analyses, correlation coefficients, and linear regression. Mean age was 62.6 yr; 48% of the participants were female, and 77% were Caucasian. Insulin sensitivity indices were 8-38% lower in participants with vs. without CKD and 13-59% lower in obese compared with nonobese participants. Correlations of surrogate indices with SIclamp did not differ significantly by CKD or obesity status. Adjusting for SIclamp in addition to demographic factors, Matsuda index was 15% lower in participants with vs. without CKD (P = 0.09) and 36% lower in participants with vs. without obesity (P = 0.0001), whereas 1/HOMA-IR was 23% lower in participants with vs. without CKD (P = 0.02) and 46% lower in participants with vs. without obesity (P < 0.0001). We conclude that CKD and obesity do not significantly alter correlations of surrogate insulin sensitivity indices with SIclamp, but they do bias surrogate measurements of insulin sensitivity toward lower values. This bias may be due to differences in insulin kinetics or organ-specific responses to insulin. PMID- 28073782 TI - Young people with cancer lack clear information about preserving fertility. PMID- 28073783 TI - Podoplanin expression in primary brain tumors induces platelet aggregation and increases risk of venous thromboembolism. AB - Venous thromboembolism (VTE) is common in patients with brain tumors, and underlying mechanisms are unclear. We hypothesized that podoplanin, a sialomucin like glycoprotein, increases the risk of VTE in primary brain tumors via its ability to induce platelet aggregation. Immunohistochemical staining against podoplanin and intratumoral platelet aggregates was performed in brain tumor specimens of 213 patients (mostly high-grade gliomas [89%]) included in the Vienna Cancer and Thrombosis Study, a prospective observational cohort study of patients with newly diagnosed cancer or progressive disease aimed at identifying patients at risk of VTE. Platelet aggregation in response to primary human glioblastoma cells was investigated in vitro. During 2-year follow-up, 29 (13.6%) patients developed VTE. One-hundred fifty-one tumor specimens stained positive for podoplanin (33 high expression, 47 medium expression, 71 low expression). Patients with podoplanin-positive tumors had lower peripheral blood platelet counts (P < .001) and higher D-dimer levels (P < .001). Podoplanin staining intensity was associated with increasing levels of intravascular platelet aggregates in tumor specimens (P < .001). High podoplanin expression was associated with an increased risk of VTE (hazard ratio for high vs no podoplanin expression: 5.71; 95% confidence interval, 1.52-21.26; P =010), independent of age, sex, and tumor type. Podoplanin-positive primary glioblastoma cells induced aggregation of human platelets in vitro, which could be abrogated by an antipodoplanin antibody. In conclusion, high podoplanin expression in primary brain tumors induces platelet aggregation, correlates with hypercoagulability, and is associated with increased risk of VTE. Our data indicate novel insights into the pathogenesis of VTE in primary brain tumors. PMID- 28073784 TI - Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice. AB - Neutrophil extracellular traps (NETs; webs of DNA coated in antimicrobial proteins) are released into the vasculature during sepsis where they contribute to host defense, but also cause tissue damage and organ dysfunction. Various components of NETs have also been implicated as activators of coagulation. Using multicolor confocal intravital microscopy in mouse models of sepsis, we observed profound platelet aggregation, thrombin activation, and fibrin clot formation within (and downstream of) NETs in vivo. NETs were critical for the development of sepsis-induced intravascular coagulation regardless of the inciting bacterial stimulus (gram-negative, gram-positive, or bacterial products). Removal of NETs via DNase infusion, or in peptidylarginine deiminase-4-deficient mice (which have impaired NET production), resulted in significantly lower quantities of intravascular thrombin activity, reduced platelet aggregation, and improved microvascular perfusion. NET-induced intravascular coagulation was dependent on a collaborative interaction between histone H4 in NETs, platelets, and the release of inorganic polyphosphate. Real-time perfusion imaging revealed markedly improved microvascular perfusion in response to the blockade of NET-induced coagulation, which correlated with reduced markers of systemic intravascular coagulation and end-organ damage in septic mice. Together, these data demonstrate, for the first time in an in vivo model of infection, a dynamic NET platelet-thrombin axis that promotes intravascular coagulation and microvascular dysfunction in sepsis. PMID- 28073785 TI - Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma. AB - Anti-programmed cell death protein 1 (PD-1) monoclonal antibodies are being increasingly tested in patients with advanced lymphoma. Following treatment, many of those patients are likely to be candidates for allogeneic hematopoietic stem cell transplant (HSCT). However, the safety and efficacy of HSCT may be affected by prior PD-1 blockade. We conducted an international retrospective analysis of 39 patients with lymphoma who received prior treatment with a PD-1 inhibitor, at a median time of 62 days (7-260) before HSCT. After a median follow-up of 12 months, the 1-year cumulative incidences of grade 2-4 and grade 3-4 acute graft versus-host disease (GVHD) were 44% and 23%, respectively, whereas the 1-year incidence of chronic GVHD was 41%. There were 4 treatment-related deaths (1 from hepatic sinusoidal obstruction syndrome, 3 from early acute GVHD). In addition, 7 patients developed a noninfectious febrile syndrome shortly after transplant requiring prolonged courses of steroids. One-year overall and progression-free survival rates were 89% (95% confidence interval [CI], 74-96) and 76% (95% CI, 56 87), respectively. One-year cumulative incidences of relapse and nonrelapse mortality were 14% (95% CI, 4-29) and 11% (95% CI, 3-23), respectively. Circulating lymphocyte subsets were analyzed in 17 patients. Compared with controls, patients previously treated with PD-1 blockade had significantly decreased PD-1+ T cells and decreased ratios of T-regulatory cells to conventional CD4 and CD8 T cells. In conclusion, HSCT after PD-1 blockade appears feasible with a low rate of relapse. However, there may be an increased risk of early immune toxicity, which could reflect long-lasting immune alterations triggered by prior PD-1 blockade. PMID- 28073786 TI - Phase 1 study of twice weekly pulse dose and daily low-dose erlotinib as initial treatment for patients with EGFR-mutant lung cancers. AB - Background: Patients with EGFR-mutant lung cancers treated with EGFR tyrosine kinase inhibitors (TKIs) develop clinical resistance, most commonly with acquisition of EGFR T790M. Evolutionary modeling suggests that a schedule of twice weekly pulse and daily low-dose erlotinib may delay emergence of EGFR T790M. Pulse dose erlotinib has superior central nervous system (CNS) penetration and may result in superior CNS disease control. Methods: We evaluated toxicity, pharmacokinetics, and efficacy of twice weekly pulse and daily low-dose erlotinib. We assessed six escalating pulse doses of erlotinib. Results: We enrolled 34 patients; 11 patients (32%) had brain metastases at study entry. We observed 3 dose-limiting toxicities in dose escalation: transaminitis, mucositis, and rash. The MTD was erlotinib 1200 mg days 1-2 and 50 mg days 3-7 weekly. The most frequent toxicities (any grade) were rash, diarrhea, nausea, fatigue, and mucositis. 1 complete and 24 partial responses were observed (74%, 95% CI 60 84%). Median progression-free survival was 9.9 months (95% CI 5.8-15.4 months). No patient had progression of an untreated CNS metastasis or developed a new CNS lesion while on study (0%, 95% CI 0-13%). Of the 18 patients with biopsies at progression, EGFR T790M was identified in 78% (95% CI 54-91%). Conclusion: This is the first clinical implementation of an anti-cancer TKI regimen combining pulse and daily low-dose administration. This evolutionary modeling-based dosing schedule was well-tolerated but did not improve progression-free survival or prevent emergence of EGFR T790M, likely due to insufficient peak serum concentrations of erlotinib. This dosing schedule prevented progression of untreated or any new central nervous system metastases in all patients. PMID- 28073787 TI - COL6A5 variants in familial neuropathic chronic itch. AB - Itch is thought to represent the peculiar response to stimuli conveyed by somatosensory pathways shared with pain through the activation of specific neurons and receptors. It can occur in association with dermatological, systemic and neurological diseases, or be the side effect of certain drugs. However, some patients suffer from chronic idiopathic itch that is frequently ascribed to psychological distress and for which no biomarker is available to date. We investigated three multigenerational families, one of which diagnosed with joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT), characterized by idiopathic chronic itch with predominantly proximal distribution. Skin biopsy was performed in all eight affected members and revealed in six of them reduced intraepidermal nerve fibre density consistent with small fibre neuropathy. Whole exome sequencing identified two COL6A5 rare variants co-segregating with chronic itch in eight affected members and absent in non-affected members, and in one unrelated sporadic patient with type 1 painless diabetic neuropathy and chronic itch. Two families and the diabetic patient carried the nonsense c.6814G>T (p.Glu2272*) variant and another family carried the missense c.6486G>C (p.Arg2162Ser) variant. Both variants were predicted as likely pathogenic by in silico analyses. The two variants were rare (minor allele frequency < 0.1%) in 6271 healthy controls and absent in 77 small fibre neuropathy and 167 JHS/EDS-HT patients without itch. Null-allele test on cDNA from patients' fibroblasts of both families carrying the nonsense variant demonstrated functional haploinsufficiency due to activation of nonsense mediated RNA decay. Immunofluorescence microscopy and western blotting revealed marked disorganization and reduced COL6A5 synthesis, respectively. Indirect immunofluorescence showed reduced COL6A5 expression in the skin of patients carrying the nonsense variant. Treatment with gabapentinoids provided satisfactory itch relief in the patients carrying the mutations. Our findings first revealed an association between COL6A5 gene and familiar chronic itch, suggesting a new contributor to the pathogenesis of neuropathic itch and identifying a new candidate therapeutic target. PMID- 28073788 TI - Dopamine controls Parkinson's tremor by inhibiting the cerebellar thalamus. AB - Parkinson's resting tremor is related to altered cerebral activity in the basal ganglia and the cerebello-thalamo-cortical circuit. Although Parkinson's disease is characterized by dopamine depletion in the basal ganglia, the dopaminergic basis of resting tremor remains unclear: dopaminergic medication reduces tremor in some patients, but many patients have a dopamine-resistant tremor. Using pharmacological functional magnetic resonance imaging, we test how a dopaminergic intervention influences the cerebral circuit involved in Parkinson's tremor. From a sample of 40 patients with Parkinson's disease, we selected 15 patients with a clearly tremor-dominant phenotype. We compared tremor-related activity and effective connectivity (using combined electromyography-functional magnetic resonance imaging) on two occasions: ON and OFF dopaminergic medication. Building on a recently developed cerebral model of Parkinson's tremor, we tested the effect of dopamine on cerebral activity associated with the onset of tremor episodes (in the basal ganglia) and with tremor amplitude (in the cerebello thalamo-cortical circuit). Dopaminergic medication reduced clinical resting tremor scores (mean 28%, range -12 to 68%). Furthermore, dopaminergic medication reduced tremor onset-related activity in the globus pallidus and tremor amplitude related activity in the thalamic ventral intermediate nucleus. Network analyses using dynamic causal modelling showed that dopamine directly increased self inhibition of the ventral intermediate nucleus, rather than indirectly influencing the cerebello-thalamo-cortical circuit through the basal ganglia. Crucially, the magnitude of thalamic self-inhibition predicted the clinical dopamine response of tremor. Dopamine reduces resting tremor by potentiating inhibitory mechanisms in a cerebellar nucleus of the thalamus (ventral intermediate nucleus). This suggests that altered dopaminergic projections to the cerebello-thalamo-cortical circuit have a role in Parkinson's tremor.aww331media15307619934001. PMID- 28073789 TI - Dynamics of convulsive seizure termination and postictal generalized EEG suppression. AB - It is not fully understood how seizures terminate and why some seizures are followed by a period of complete brain activity suppression, postictal generalized EEG suppression. This is clinically relevant as there is a potential association between postictal generalized EEG suppression, cardiorespiratory arrest and sudden death following a seizure. We combined human encephalographic seizure data with data of a computational model of seizures to elucidate the neuronal network dynamics underlying seizure termination and the postictal generalized EEG suppression state. A multi-unit computational neural mass model of epileptic seizure termination and postictal recovery was developed. The model provided three predictions that were validated in EEG recordings of 48 convulsive seizures from 48 subjects with refractory focal epilepsy (20 females, age range 15-61 years). The duration of ictal and postictal generalized EEG suppression periods in human EEG followed a gamma probability distribution indicative of a deterministic process (shape parameter 2.6 and 1.5, respectively) as predicted by the model. In the model and in humans, the time between two clonic bursts increased exponentially from the start of the clonic phase of the seizure. The terminal interclonic interval, calculated using the projected terminal value of the log-linear fit of the clonic frequency decrease was correlated with the presence and duration of postictal suppression. The projected terminal interclonic interval explained 41% of the variation in postictal generalized EEG suppression duration (P < 0.02). Conversely, postictal generalized EEG suppression duration explained 34% of the variation in the last interclonic interval duration. Our findings suggest that postictal generalized EEG suppression is a separate brain state and that seizure termination is a plastic and autonomous process, reflected in increased duration of interclonic intervals that determine the duration of postictal generalized EEG suppression. PMID- 28073790 TI - Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome. AB - Dravet syndrome is a catastrophic childhood epilepsy with early-onset seizures, delayed language and motor development, sleep disturbances, anxiety-like behaviour, severe cognitive deficit and an increased risk of fatality. It is primarily caused by de novo mutations of the SCN1A gene encoding a neuronal voltage-activated sodium channel. Zebrafish with a mutation in the SCN1A homologue recapitulate spontaneous seizure activity and mimic the convulsive behavioural movements observed in Dravet syndrome. Here, we show that phenotypic screening of drug libraries in zebrafish scn1 mutants rapidly and successfully identifies new therapeutics. We demonstrate that clemizole binds to serotonin receptors and its antiepileptic activity can be mimicked by drugs acting on serotonin signalling pathways e.g. trazodone and lorcaserin. Coincident with these zebrafish findings, we treated five medically intractable Dravet syndrome patients with a clinically-approved serotonin receptor agonist (lorcaserin, Belviq(r)) and observed some promising results in terms of reductions in seizure frequency and/or severity. Our findings demonstrate a rapid path from preclinical discovery in zebrafish, through target identification, to potential clinical treatments for Dravet syndrome. PMID- 28073791 TI - Rapid Deployment Aortic Replacement (RADAR) Registry in Spain: a protocol. AB - INTRODUCTION: Rapid deployment valves (RDV) represent a newly introduced approach to aortic valve replacement which facilitates surgical implantation and minimally invasive techniques, shortens surgical times and shows excellent haemodynamic performance. However, evidence on their safety, efficacy and potential complications is mostly fitted with small-volume and retrospective studies. Moreover, no current guidelines exist. To improve our knowledge on this technology, The Rapid Deployment Aortic Replacement (RADAR) Registry will be established across Spain with the aim of assessing RDV outcomes in the real-world setting. METHODS AND ANALYSIS: The RADAR Registry is designed as a product registry that would provide information on its use and outcomes in clinical practice. This multicentre, prospective, national effort will initially involve 4 centres in Spain. Any patient undergoing cardiac surgery for aortic valve replacement and receiving an RDV as an isolated operation or in combination with other cardiac procedures may be included. Participation is voluntary. Data collection is equal to information obtained during standard care and is prospectively entered by the participating physicians perioperatively and during subsequent follow-up visits. The primary outcome assessed is in-hospital and up to 5 years of follow-up, prosthetic valve functioning and clinical status. Secondary outcomes are to perform subgroup analysis, to compare outcomes with other existing approaches and to develop future clinical guidelines. The follow up assessments are timed with routine clinical appointments. Dissociated data will be extracted and collectively analysed. Initial target sample size for the registry is 500 participants entered with complete follow-up information. Different substudies will be implemented within the registry to investigate specific populations undergoing aortic valve replacement. ETHICS AND DISSEMINATION: The protocol is approved by all local institutional ethics committees. Findings will be shared by the participant hospitals, policymakers and the academic community to promote quality monitoring and efficient use of this technology. PMID- 28073792 TI - Adult parenteral nutrition in the North of England: a region-wide audit. AB - OBJECTIVES: Parenteral nutrition (PN) is widely used to provide nutritional support to patients with inaccessible or inadequate length of gut or non functioning gut. The objective was to compare practice in PN administration to results of the National Confidential Enquiry into Patient Outcome and Death (NCEPOD) report, 'A Mixed Bag', and to establish whether good practice was being followed within this part of the UK. SETTING: Using the Northern Nutrition Network (NNN), we examined the care of adult patients receiving PN in all 10 secondary care hospitals in our region. PARTICIPANTS: All patients receiving PN were included with no exclusions. Data were collected on 192 patients (51% females, median age 65 years (range 18-96)). OUTCOME MEASURES: A data collection tool was designed based on the recommendations of the NCEPOD report. RESULTS: PN was used for a median of 7 days with a 30-day mortality rate of 8%. Metabolic complications occurred in 34%, of which only 13% were avoidable. The catheter sepsis rate was 1.5 per 1000 PN days. The audit suggests that nutrition team input improves patient assessment prior to starting PN and review once PN is established. Risk of refeeding syndrome was identified in 75%. Areas for improvement are documentation of treatment goal (39%), review of PN constitution (38%), ensuring patients are weighed regularly (56%) and documentation of line tip position (52%). CONCLUSIONS: This region-wide prospective audit suggests improved practice within the UK compared to the NCEPOD audit with lower mortality and line sepsis rates. However, documentation remains suboptimal. This work strengthens the case for introducing nutrition teams in hospitals without this service. These findings are likely to be reproduced across the UK and in other healthcare settings. We provide a template for similar audits of clinical practice. PMID- 28073794 TI - Socioeconomic, remoteness and sex differences in life expectancy in New South Wales, Australia, 2001-2012: a population-based study. AB - OBJECTIVES: Despite being one of the healthiest countries in the world, Australia displays substantial mortality differentials by socioeconomic disadvantage, remoteness and sex. In this study, we examined how these mortality differentials translated to differences in life expectancy between 2001 and 2012. DESIGN AND SETTING: Population-based study using mortality and estimated residential population data from Australia's largest state, New South Wales (NSW), between 2001 and 2012. Age-group-specific death rates by socioeconomic disadvantage quintile, remoteness (major cities vs regional and remote areas), sex and year were estimated via Poisson regression, and inputted into life table calculations to estimate life expectancy. RESULTS: Life expectancy decreased with increasing socioeconomic disadvantage in males and females. The disparity between the most and least socioeconomically deprived quintiles was 3.77 years in males and 2.39 years in females in 2012. Differences in life expectancy by socioeconomic disadvantage were mostly stable over time. Gender gaps in life expectancy ranged from 3.50 to 4.93 years (in 2012), increased with increasing socioeconomic disadvantage and decreased by ~1 year for all quintiles between 2001 and 2012. Overall, life expectancy varied little by remoteness, but was 1.8 years higher in major cities compared to regional/remote areas in the most socioeconomically deprived regions in 2012. CONCLUSIONS: Socioeconomic disadvantage and sex were strongly associated with life expectancy. The disparity in life expectancy across the socioeconomic spectrum was larger in males and was stable over time. In contrast, gender gaps reduced for all quintiles between 2001 and 2012, and a remoteness effect was evident in 2012, but only for those living in the most deprived areas. PMID- 28073793 TI - Adverse drug reactions to anticoagulants in Spain: analysis of the Spanish National Hospital Discharge Data (2010-2013). AB - OBJECTIVE: To describe and analyse hospitalisations for adverse drug reactions (ADRs) involving anticoagulants. We also analysed the progress of the reactions over time, the factors related with ADRs. DESIGN: A retrospective, descriptive, epidemiological study. SETTING: This study used the Spanish National Hospital Discharge Database (Conjunto Minimo Basico de Datos, CMBD), over a 4-year period. PARTICIPANTS: We selected CMBD data corresponding to hospital discharges with a diagnosis of ADRs to anticoagulants (International Classification of Diseases Ninth Revision, Clinical Modification (ICD-9-CM) code E934.2) in any diagnostic field during the study period. MAIN OUTCOME MEASURES: We calculated the annual incidence of ADRs to anticoagulants according to sex and age groups. The median lengths of hospital stay and in-hospital mortality (IHM) were also estimated for each year studied. Bivariate analyses of the changes in variables according to year were based on Poisson regression. IHM was analysed using logistic regression models. The estimates were expressed as ORs and their 95% CI. RESULTS: During the study period, 50 042 patients were hospitalised because of ADRs to anticoagulants (6.38% of all ADR-related admissions). The number of cases increased from 10 415 in 2010 to 13 891 in 2013. Cumulative incidence of ADRs to anticoagulants was significantly higher for men than women and in all age groups. An adjusted multivariate analysis revealed that IHM did not change significantly over time. We observed a statistically significant association between IHM and age, with the highest risk for the >=85 age group (OR 2.67; 95% CI 2.44 to 2.93). CONCLUSIONS: The incidence of ADRs to anticoagulants in Spain increased from 2010 to 2013, and was significantly higher for men than women and in all age groups. Older patients were particularly susceptible to being hospitalised with an adverse reaction to an anticoagulant. PMID- 28073795 TI - In patients presenting to the emergency department with skin and soft tissue infections what is the diagnostic accuracy of point-of-care ultrasonography for the diagnosis of abscess compared to the current standard of care? A systematic review and meta-analysis. AB - OBJECTIVES: The primary objective of this systematic review was to determine the accuracy of point-of-care ultrasonography (POCUS) in diagnosing abscess in emergency department (ED) patients with skin and soft tissue infections (SSTI). The secondary objective was the accuracy of POCUS in the paediatric population subgroup. SETTING: Prospective studies set in emergency departments. PARTICIPANTS: Emergency department patients (adult and paediatric) presenting with SSTI and suspected abscess. PRIMARY AND SECONDARY OUTCOME MEASURES: This systematic review was conducted according to Cochrane Handbook guidelines, and the following databases were searched: PubMed, MEDLINE, EMBASE and the Cochrane database of systematic reviews (1946-2015). We included prospective cohort and case-control studies investigating ED patients with SSTI and abscess or cellulitis, a defined POCUS protocol, a clearly defined gold standard for abscess and a contingency table describing sensitivity and specificity. Two reviewers independently ascertained all potentially relevant citations for methodologic quality according to QUADAS-2 criteria. The primary outcome measure was the sensitivity and specificity of POCUS for abscess. A preplanned subgroup (secondary) analysis examined the effects in paediatric populations, and changes in management were explored post hoc. RESULTS: Of 3028 articles, 8 were identified meeting inclusion criteria; all were rated as good to excellent according to QUADAS-2 criteria. Combined test characteristics of POCUS on the ED diagnosis of abscess for patients with SSTI were as follows: sensitivity 96.2% (95% CI 91.1% to 98.4%), specificity 82.9% (95% CI 60.4% to 93.9%), positive likelihood ratio 5.63 (95% CI 2.2 to 14.6) and negative likelihood ratio 0.05 (95% CI 0.01 to 0.11). CONCLUSIONS: A total of 8 studies of good-to-excellent quality were included in this review. The use of POCUS helps differentiate abscess from cellulitis in ED patients with SSTI. TRIAL REGISTRATION NUMBER: CRD42015017115. PMID- 28073796 TI - Comparative efficacy and tolerability of pharmacological interventions for attention-deficit/hyperactivity disorder in children, adolescents and adults: protocol for a systematic review and network meta-analysis. AB - INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a major public health issue. Pharmacological treatments play an important role in the multimodal treatment of ADHD. Currently, there is a lack of up-to-date and comprehensive evidence on how available ADHD drugs compare and rank in terms of efficacy and tolerability, in children or adolescents as well as in adults. We will conduct a network meta-analysis (NMA), integrating direct and indirect comparisons from randomised controlled trials (RCTs), to rank pharmacological treatments for ADHD according to their efficacy and tolerability profiles. METHODS AND ANALYSIS: We will search a broad range of electronic databases, including PubMed, MEDLINE, EMBASE, PsycINFO, ERIC and Web of Science, with no date or language restrictions. We will also search for unpublished studies using international clinical trial registries and contacting relevant drug companies. We will identify and include available parallel-group, cross-over and cluster randomised trials that compare methylphenidate, dexmethylphenidate, amphetamine derivatives (including lisdexamfetamine), atomoxetine, clonidine, guanfacine, bupropion or modafinil (as oral therapy) either with each other or to placebo, in children, adolescents or adults with ADHD. Primary outcomes will be efficacy (indicated by reduction in severity of ADHD core symptoms measured on a standardised scale) and tolerability (the proportion of patients who left a study early due to side effects). Secondary outcomes will be global functioning, acceptability (proportion of patients who left the study early by any cause) and changes in blood pressure and body weight. NMA will be conducted in STATA within a frequentist framework. The quality of RCTs will be evaluated using the Cochrane risk of bias tool, and the quality of the evidence will be assessed using the GRADE approach. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. ETHICS AND DISSEMINATION: No ethical issues are foreseen. Results from this study will be published in a peer-reviewed journal and possibly presented at relevant national and international conferences. TRIAL REGISTRATION NUMBER: CRD42014008976. PMID- 28073798 TI - Effectiveness of a lumbopelvic monitor and feedback device to change postural behaviour: a protocol for the ELF cluster randomised controlled trial. AB - INTRODUCTION: Low back pain (LBP) is the most common, costly and disabling musculoskeletal disorder worldwide, and is prevalent in healthcare workers. Posture is a modifiable risk factor for LBP shown to reduce the prevalence of LBP. Our feasibility research suggests that postural feedback might help healthcare workers avoid hazardous postures. The Effectiveness of Lumbopelvic Feedback (ELF) trial will investigate the extent to which postural monitor and feedback (PMF) can reduce exposure to hazardous posture associated with LBP. METHODS: This is a participant-blinded, randomised controlled trial with blocked cluster random allocation. Participants will include volunteer healthcare workers recruited from aged care institutions and hospitals. A postural monitoring and feedback device will monitor and record lumbopelvic forward bending posture, and provide audio feedback whenever the user sustains a lumbopelvic forward bending posture that exceeds predefined thresholds. The primary outcome measure will be postural behaviour (exceeding thresholds). Secondary outcome measures will be incidence of LBP, participant-reported disability and adherence. Following baseline assessment, we will randomly assign participants to 1 of 2 intervention arms: a feedback group and a no-feedback control group. We will compare between group differences of changes in postural behaviour by using a repeated measures mixed-effect model analysis of covariance (ANCOVA) at 6 weeks. Postural behaviour baseline scores, work-related psychosocial factors and disability scores will be input as covariates into the statistical models. We will use logistic mixed model analysis and Cox's proportional hazards for assessing the effect of a PMF on LBP incidence between groups. DISCUSSION: Posture is a modifiable risk factor for low back disorders. Findings from the ELF trial will inform the design of future clinical trials assessing the effectiveness of wearable technology on minimising hazardous posture during daily living activities in patients with low back disorders. TRIAL REGISTRATION NUMBER: ACTRN12616000449437. PMID- 28073799 TI - Should gluten-free foods be available on prescription? PMID- 28073797 TI - Physical and cultural determinants of postpartum pelvic floor support and symptoms following vaginal delivery: a protocol for a mixed-methods prospective cohort study. AB - INTRODUCTION: Pelvic floor disorders (PFDs), including pelvic organ prolapse (POP), stress and urgency urinary incontinence, and faecal incontinence, are common and arise from loss of pelvic support. Although severe disease often does not occur until women become older, pregnancy and childbirth are major risk factors for PFDs, especially POP. We understand little about modifiable factors that impact pelvic floor function recovery after vaginal birth. This National Institutes of Health (NIH)-funded Program Project, 'Bridging physical and cultural determinants of postpartum pelvic floor support and symptoms following vaginal delivery', uses mixed-methods research to study the influences of intra abdominal pressure, physical activity, body habitus and muscle fitness on pelvic floor support and symptoms as well as the cultural context in which women experience those changes. METHODS AND ANALYSIS: Using quantitative methods, we will evaluate whether pelvic floor support and symptoms 1 year after the first vaginal delivery are affected by biologically plausible factors that may impact muscle, nerve and connective tissue healing during recovery (first 8 weeks postpartum) and strengthening (remainder of the first postpartum year). Using qualitative methods, we will examine cultural aspects of perceptions, explanations of changes in pelvic floor support, and actions taken by Mexican American and Euro-American primipara, emphasising early changes after childbirth. We will summarise project results in a resource toolkit that will enhance opportunities for dialogue between women, their families and providers, and across lay and medical discourses. We anticipate enrolling up to 1530 nulliparous women into the prospective cohort study during the third trimester, following those who deliver vaginally 1 year postpartum. Participants will be drawn from this cohort to meet the project's aims. ETHICS AND DISSEMINATION: The University of Utah and Intermountain Healthcare Institutional Review Boards approved this study. Data are stored in a secure password-protected database. Papers summarising the primary results and ancillary analyses will be published in peer reviewed journals. PMID- 28073800 TI - Relationship between exposure to tumour necrosis factor inhibitor therapy and incidence and severity of myocardial infarction in patients with rheumatoid arthritis. AB - OBJECTIVES: Patients with rheumatoid arthritis (RA) are at increased risk of myocardial infarction (MI) compared with subjects without RA, with the increased risk driven potentially by inflammation. Tumour necrosis factor inhibitors (TNFi) may modulate the risk and severity of MI. We compared the risk and severity of MI in patients treated with TNFi with that in those receiving synthetic disease modifying antirheumatic drugs (sDMARDs). METHODS: This analysis included patients with RA recruited from 2001 to 2009 to the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis starting TNFi (etanercept/infliximab/adalimumab) and a biologic-naive comparator cohort receiving sDMARD. All patients were followed via physician and patient questionnaires and national death register linkage. Additionally, all patients were linked to the Myocardial Ischaemia National Audit Project, a national registry of hospitalisations for MI. Patients were censored at first verified MI, death, 90 days following TNFi discontinuation, last physician follow-up or 20 April 2010, whichever came first. The risk of first MI was compared between cohorts using COX regression, adjusted with propensity score deciles (PD). MI phenotype and severity were compared using descriptive statistics. 6-month mortality post MI was compared using logistic regression. RESULTS: 252 verified first MIs were analysed: 58 in 3058 patients receiving sDMARD and 194 in 11 200 patients receiving TNFi (median follow-up per person 3.5 years and 5.3 years, respectively). The PD-adjusted HR of MI in TNFi referent to sDMARD was 0.61 (95% CI 0.41 to 0.89). No statistically significant differences in MI severity or mortality were observed between treatment groups. CONCLUSIONS: Patients with RA receiving TNFi had a decreased risk of MI compared with patients with RA receiving sDMARD therapy over the medium term. This might be attributed to a direct action of TNFi on the atherosclerotic process or better overall disease control. PMID- 28073801 TI - Predictors of work disability after start of anti-TNF therapy in a national cohort of Swedish patients with rheumatoid arthritis: does early anti-TNF therapy bring patients back to work? AB - OBJECTIVES: To examine predictors of work ability gain and loss after anti-tumour necrosis factor (TNF) start, respectively, in working-age patients with rheumatoid arthritis (RA) with a special focus on disease duration. METHODS: Patients with RA, aged 19-62 years, starting their first TNF inhibitor 2006-2009 with full work ability (0 sick leave/disability pension days during 3 months before bio-start; n=1048) or no work ability (90 days; n=753) were identified in the Swedish biologics register (Anti-Rheumatic Treatment In Sweden, ARTIS) and sick leave/disability pension days retrieved from the Social Insurance Agency. Outcome was defined as work ability gain >=50% for patients without work ability at bio-start and work ability loss >=50% for patients with full work ability, and survival analyses conducted. Baseline predictors including disease duration, age, sex, education level, employment, Health Assessment Questionnaire, Disease Activity Score 28 and relevant comorbidities were estimated using Cox regression. RESULTS: During 3 years after anti-TNF start, the probability of regaining work ability for totally work-disabled patients was 35% for those with disease duration <5 years and 14% for disease duration >=5 years (adjusted HR 2.1 (95% CI 1.4 to 3.2)). For patients with full work ability at bio-start, disease duration did not predict work ability loss. Baseline disability pension was also a strong predictor of work ability gain after treatment start. CONCLUSIONS: A substantial proportion of work-disabled patients with RA who start anti-TNF therapy regain work ability. Those initiating treatment within 5 years of symptom onset have a more than doubled 3-year probability of regaining work ability compared with later treatment starts. This effect seems largely due to the impact of disease duration on disability pension status. PMID- 28073802 TI - Assemblage composition of fungal wood-decay species has a major influence on how climate and wood quality modify decomposition. AB - The interactions among saprotrophic fungal species, as well as their interactions with environmental factors, may have a major influence on wood decay and carbon release in ecosystems. We studied the effect that decomposer diversity (species richness and assemblage composition) has on wood decomposition when the climatic variables and substrate quality vary simultaneously. We used two temperatures (16 and 21 degrees C) and two humidity levels (70% and 90%) with two wood qualities (wood from managed and old-growth forests) of Pinus sylvestris. In a 9-month experiment, the effects of fungal diversity were tested using four wood-decaying fungi (Antrodia xantha, Dichomitus squalens, Fomitopsis pinicola and Gloeophyllum protractum) at assemblage levels of one, two and four species. Wood quality and assemblage composition affected the influence of climatic factors on decomposition rates. Fungal assemblage composition was found to be more important than fungal species richness, indicating that species-specific fungal traits are of paramount importance in driving decomposition. We conclude that models containing fungal wood-decay species (and wood-based carbon) need to take into account species-specific and assemblage composition-specific properties to improve predictive capacity in regard to decomposition-related carbon dynamics. PMID- 28073803 TI - Abdominal aortic occlusion caused by a cardiac myxoma: a multi-modality imaging approach. PMID- 28073804 TI - Hemodynamic Support With a Microaxial Percutaneous Left Ventricular Assist Device (Impella) Protects Against Acute Kidney Injury in Patients Undergoing High-Risk Percutaneous Coronary Intervention. AB - RATIONALE: Acute kidney injury (AKI) is common during high-risk percutaneous coronary intervention (PCI), particularly in those with severely reduced left ventricular ejection fraction. The impact of partial hemodynamic support with a microaxial percutaneous left ventricular assist device (pLVAD) on renal function after high-risk PCI remains unknown. OBJECTIVE: We tested the hypothesis that partial hemodynamic support with the Impella 2.5 microaxial pLVAD during high risk PCI protected against AKI. METHODS AND RESULTS: In this retrospective, single-center study, we analyzed data from 230 patients (115 consecutive pLVAD supported and 115 unsupported matched-controls) undergoing high-risk PCI with ejection fraction <=35%. The primary outcome was incidence of in-hospital AKI according to AKI network criteria. Logistic regression analysis determined the predictors of AKI. Overall, 5.2% (6) of pLVAD-supported patients versus 27.8% (32) of unsupported control patients developed AKI (P<0.001). Similarly, 0.9% (1) versus 6.1% (7) required postprocedural hemodialysis (P<0.05). Microaxial pLVAD support during high-risk PCI was independently associated with a significant reduction in AKI (adjusted odds ratio, 0.13; 95% confidence intervals, 0.09-0.31; P<0.001). Despite preexisting CKD or a lower ejection fraction, pLVAD support protection against AKI persisted (adjusted odds ratio, 0.63; 95% confidence intervals, 0.25-0.83; P=0.04 and adjusted odds ratio, 0.16; 95% confidence intervals, 0.12-0.28; P<0.001, respectively). CONCLUSIONS: Impella 2.5 (pLVAD) support protected against AKI during high-risk PCI. This renal protective effect persisted despite the presence of underlying CKD and decreasing ejection fraction. PMID- 28073807 TI - Next Steps in Modeling the Tricuspid Valve. PMID- 28073805 TI - Sheet-Like Remodeling of the Transverse Tubular System in Human Heart Failure Impairs Excitation-Contraction Coupling and Functional Recovery by Mechanical Unloading. AB - BACKGROUND: Cardiac recovery in response to mechanical unloading by left ventricular assist devices (LVADs) has been demonstrated in subgroups of patients with chronic heart failure (HF). Hallmarks of HF are depletion and disorganization of the transverse tubular system (t-system) in cardiomyocytes. Here, we investigated remodeling of the t-system in human end-stage HF and its role in cardiac recovery. METHODS: Left ventricular biopsies were obtained from 5 donors and 26 patients with chronic HF undergoing implantation of LVADs. Three dimensional confocal microscopy and computational image analysis were applied to assess t-system structure, density, and distance of ryanodine receptor clusters to the sarcolemma, including the t-system. Recovery of cardiac function in response to mechanical unloading was assessed by echocardiography during turndown of the LVAD. RESULTS: The majority of HF myocytes showed remarkable t-system remodeling, particularly sheet-like invaginations of the sarcolemma. Circularity of t-system components was decreased in HF versus controls (0.37+/-0.01 versus 0.46+/-0.02; P<0.01), and the volume/length ratio was increased in HF (0.36+/ 0.01 versus 0.25+/-0.02 um2; P<0.0001). T-system density was reduced in HF, leading to increased ryanodine receptor-sarcolemma distances (0.96+/-0.05 versus 0.64+/-0.1 um; P<0.01). Low ryanodine receptor-sarcolemma distances at the time of LVAD implantation predicted high post-LVAD left ventricular ejection fractions (P<0.01) and ejection fraction increases during unloading (P<0.01). Ejection fraction in patients with pre-LVAD ryanodine receptor-sarcolemma distances >1 um did not improve after mechanical unloading. In addition, calcium transients were recorded in field-stimulated isolated human cardiomyocytes and analyzed with respect to local t-system density. Calcium release in HF myocytes was restricted to regions proximal to the sarcolemma. Local calcium upstroke was delayed (23.9+/ 4.9 versus 10.3+/-1.7 milliseconds; P<0.05) and more asynchronous (18.1+/-1.5 versus 8.9+/-2.2 milliseconds; P<0.01) in HF cells with low t-system density versus cells with high t-system density. CONCLUSIONS: The t-system in end-stage human HF presents a characteristic novel phenotype consisting of sheet-like invaginations of the sarcolemma. Our results suggest that the remodeled t-system impairs excitation-contraction coupling and functional recovery during chronic LVAD unloading. An intact t-system at the time of LVAD implantation may constitute a precondition and predictor for functional cardiac recovery after mechanical unloading. PMID- 28073806 TI - Functional Tricuspid Regurgitation Caused by Chronic Atrial Fibrillation: A Real Time 3-Dimensional Transesophageal Echocardiography Study. AB - BACKGROUND: Functional tricuspid regurgitation (TR) with a structurally normal tricuspid valve (TV) may occur secondary to chronic atrial fibrillation (AF). However, the clinical and echocardiographic differences according to functional TR subtypes are unclear. Therefore, characterization of functional TR because of chronic AF (AF-TR) remains undetermined. METHODS AND RESULTS: To investigate the prevalence of AF-TR, 437 patients with moderate to severe TR underwent 3 dimensional (3D) transesophageal echocardiography. TR severity was determined by the averaged vena contracta width on apical and parasternal inflow views. The prevalence of AF-TR was 9.2%, whereas that of functional TR because of left-sided heart disease was 45.3%. Clinical features of AF-TR included advanced age, female sex, greater right atrial than left atrial enlargement and lower systolic pulmonary artery pressure compared with left-sided heart disease-TR with sinus rhythm (all P<0.05). In 3D TV assessment, patients with AF-TR had a larger TV annular area with weaker annular contraction (both P<0.001) but a smaller tethering angle (P<0.001) despite a similar leaflet coaptation status compared with patients with left-sided heart disease-TR with sinus rhythm. On multivariable analysis, only the TV annular area in midsystole (coefficient, 0.059; 95% confidence interval, 0.041-0.078 per 100 mm2; P<0.001) was associated with TR severity in AF-TR. The annular area was more closely correlated with the right atrial volume than right ventricular end-systolic volume in AF-TR (P<0.001). CONCLUSIONS: AF-TR is not rare and is associated with advanced age and right atrial enlargement. TV deformations and their association with right heart remodeling differ between AF-TR and left-sided heart disease-TR. Our results suggest that in patients with TR secondary to AF, TV annuloplasty should be effective because this entity has annular dilatation without leaflet deformation. PMID- 28073808 TI - Fifteen-minute consultation: assessment of a child with suspected shunt problems. AB - Cerebrospinal fluid diversion procedures have saved more lives than any other neurosurgical procedure. However, they do have a unique set of complications which a paediatrician in a district general hospital may encounter. Timely recognition and appropriate referral to the neurosurgeon is vital in order to avoid serious consequences and to have a favourable outcome. PMID- 28073809 TI - Diabetes insipidus and the use of desmopressin in hospitalised children. PMID- 28073811 TI - Exploratory trials in mental health: anything to learn from other disciplines? AB - OBJECTIVE: Confirmatory randomised controlled trials require solid justifications, especially with regard to whether the experimental intervention is promising. Such evidence is generated in exploratory trials. However, empirical evidence shows that the quality of such trials is still suboptimal. More generally, the development process of healthcare interventions and especially of drugs, remains inefficient. Over the past 10-20 years, a vast amount of methodological work has been published about exploratory trials. This overview introduces some of the concepts and recent developments in the field. METHODS: A narrative approach was taken for this overview. This article focuses on study designs developed outside the mental health field to introduce concepts that might not be familiar to clinical researchers in psychiatry and psychology. Non-randomised and randomised exploratory trial designs are covered. The article ends with a brief discussion on pilot studies and their difference to exploratory studies. RESULTS: Classical designs for exploratory trials such as Simon's two stage design still have a role. However, randomised exploratory trials are probably more suitable for mental health interventions. Newer, more flexible designs such as multistage, multiarm trials or platform trials have the potential to improve the efficiency of exploratory and subsequently confirmatory experiments. CONCLUSIONS: Although often not directly applicable, borrowing (study) design ideas from other medical disciplines has the potential to improve exploratory trials in the mental health field. At the same time, more explicit use of study designs specifically designed for exploratory trials will help to improve the transparency of such trials. PMID- 28073810 TI - Cognitive-behavioural therapy for non-motor symptoms of Parkinson's disease: a clinical review. AB - Neuropsychiatric symptoms are common in Parkinson's disease (PD) and have a disproportionate impact on quality of life and carer burden. Pharmacological treatment is the main approach in dealing with these symptoms, but it is limited by variable efficacy and risk of drug interactions. Non-pharmacological approaches using the cognitive-behavioural therapy (CBT) model are viable alternatives and in this review paper we summarise the evidence of CBT for three of the most common psychiatric manifestations of PD: depression and anxiety, impulse-control disorders and insomnia. Most studies modified the usual CBT format to include modules accounting for problems specific to PD: activity scheduling around motoric function, motor symptoms as triggers of anxiety, fear of falling and preparation for disease progression as well as accommodation of materials for suspected executive dysfunction. We found a growing evidence base that CBT (modified to account for PD-specific problems) is effective in the treatment of PD psychiatric symptoms. Where controlled study design was used, moderate effect sizes are reported for the efficacy of CBT for depression, including with distance administration of CBT. The effects were sustained during follow-up which was between 1 and 6 months. In addition, there are some initial data on the effects of CBT on impulse-control disorders and insomnia. The studies were limited by their small and potentially unrepresentative samples and the quality of sample reporting (eg, concomitant antidepressant and dopaminergic therapy use). Additional well-designed and adequately powered studies are required to determine the utility of CBT in PD. PMID- 28073812 TI - The conserved hypothetical protein PSPTO_3957 is essential for virulence in the plant pathogen Pseudomonas syringae pv. tomato DC3000. AB - The plant pathogen Pseudomonas syringae accounts for substantial crop losses and is considered an important agricultural issue. To better manage disease in the field, it is important to have an understanding of the underlying genetic mechanisms that mediate virulence. There are a substantial number of genes in sequenced bacterial genomes, including P. syringae, that encode for conserved hypothetical proteins; some of these have been functionally characterized in other Pseudomonads and have been demonstrated to play important roles in disease. PSPTO_3957 encodes a conserved hypothetical protein of unknown function. To evaluate the role of PSPTO_3957 in P. syringae pv. tomato DC3000, a PSPTO_3957 deletion mutant was constructed. Here, we show that PSPTO_3957 does not influence growth on rich media, motility or biofilm formation but is necessary for nitrate assimilation and full virulence in P. syringae. Our results have revealed an important role for PSPTO_3957 in the biology of P. syringae. Given the conservation of this protein among many bacteria, this protein might serve as an attractive target for disease management of this and other bacterial plant pathogens. PMID- 28073813 TI - Association between the Healthy Eating Index-2010 and nutrient and energy densities of German households' food purchases. AB - Background: The USDA Healthy Eating Index (HEI) is used widely to measure diet quality because it allows a number of different applications. Although several evaluations of the HEI-2010 have already been carried out, there is lack of those which focus on associations between the HEI and nutrient intakes. This study updates and expands upon previous findings on these associations. Using German consumption data, where ~12 million purchases from 13 131 households are recorded, HEI-2010 total and individual scores, as well as several energy and nutrient densities were calculated. Correlations between the HEI and individual energy and nutrient densities were carried out to identify which nutrients are more or less well represented by the HEI. The HEI had the highest correlations with energy density and the densities of water-soluble vitamins (e.g. folic acid) and minerals (e.g. calcium). Weaker associations were identified for the densities of fat-soluble vitamins (e.g. vitamin D) as well as of the vitamins B1 and B12. Negligible correlations were detected for the densities of trace elements (e.g. fluoride and iodine), salt and fat composition. Given that energy intake and the intake of plant-based foods are relevant dietary issues, the HEI 2010 can be defined as a meaningful index to describe diet quality. However, because the intakes of salt, trace elements (e.g. fluoride and iodine) and fat soluble vitamins, as well as the fat composition may be less reflected, they should be analyzed separately when using the HEI for measuring diet quality. PMID- 28073814 TI - Donor-derived mycosis fungoides following reduced intensity haematopoietic stem cell transplantation from a matched unrelated donor. AB - A 46-year-old woman with a history of dasatinib-resistant chronic myeloid leukaemia, clonal evolution and monosomy 7 underwent reduced intensity conditioned in vivo T-cell-depleted allogeneic haematopoietic stem cell transplantation (HSCT) from a matched unrelated donor. Following the transplantation, she developed recurrent cutaneous graft versus host disease (GvHD), which required treatment with systemic immunosuppression and electrocorporeal photophoresis. Concurrently, she developed a lichenoid rash with granulomatous features suggestive of cutaneous sarcoidosis. Additional treatment with hydroxychloroquine was initially successful, but 2 months later, she developed erythroderma with palpable lymphadenopathy. Repeated histological analysis established a diagnosis of folliculotropic mycosis fungoides stage IVA2, and the malignant clone was confirmed to be of donor origin. A positive response to brentuximab has been shown. This is the first reported case of primary mycosis fungoides after matched unrelated donor HSCT, and in a patient still undergoing treatment for GvHD. PMID- 28073815 TI - Costs of Care for Hospitalized Children Associated With Preferred Language and Insurance Type. AB - OBJECTIVE: The study goal was to determine whether preferred language for care and insurance type are associated with cost among hospitalized children. METHODS: A retrospective cohort study was conducted of inpatients at a freestanding children's hospital from January 2011 to December 2012. Patient information and hospital costs were obtained from administrative data. Cost differences according to language and insurance were calculated using multivariate generalized linear model estimates, allowing for language/insurance interaction effects. Models were also stratified according to medical complexity and length of stay (LOS) >=3 days. RESULTS: Of 19 249 admissions, 8% of caregivers preferred Spanish and 6% preferred another language; 47% of admissions were covered by public insurance. Models controlled for LOS, medical complexity, home-to-hospital distance, age, asthma diagnosis, and race/ethnicity. Total hospital costs were significantly higher for publicly insured Spanish speakers ($20 211 [95% confidence interval (CI), 7781 to 32 641]) and lower for privately insured Spanish speakers (-$16 730 [95% CI, -28 265 to -5195]) and publicly insured English speakers (-$4841 [95% CI, -6781 to -2902]) compared with privately insured English speakers. Differences were most pronounced among children with medical complexity and LOS >=3 days. CONCLUSIONS: Hospital costs varied significantly according to preferred language and insurance type, even adjusting for LOS and medical complexity. These differences in the amount of billable care provided to medically similar patients may represent either underprovision or overprovision of care on the basis of sociodemographic factors and communication, suggesting problems with care efficiency and equity. Further investigation may inform development of effective interventions. PMID- 28073816 TI - Technology Access and Use, and Their Associations With Social Engagement Among Older Adults: Do Women and Men Differ? AB - Objectives: To examine how information and communication technology (ICT) access and use are conceptually incorporated in the Successful Aging 2.0 framework. Method: Using data from the 2011 National Health and Aging Trends Study (N = 6,476), we examined how ICT access and use for different purposes are associated with social engagement (i.e., informal and formal social participation) by gender. Weighted logistic regression analyses were performed. Results: Findings revealed that men were more likely to access and use ICT than women. ICT access was positively associated with all types of women's social engagement, but only with men's informal social participation. Information technology (IT) use for health matters was positively associated with formal social participation for women and with informal social participation for men. IT use for personal tasks was negatively associated with formal social participation for older adults. Communication technology use was positively associated with formal and informal social participation for women and men. Discussion: This study supports the expansion of the successful aging model by incorporating ICT access and use. Further, it assists in the identification of specific technologies that promote active engagement in later life for women and men. PMID- 28073817 TI - Paranodal dissection in chronic inflammatory demyelinating polyneuropathy with anti-neurofascin-155 and anti-contactin-1 antibodies. AB - OBJECTIVE: To investigate the morphological features of chronic inflammatory demyelinating polyneuropathy (CIDP) with autoantibodies directed against paranodal junctional molecules, particularly focusing on the fine structures of the paranodes. METHODS: We assessed sural nerve biopsy specimens obtained from 9 patients with CIDP with anti-neurofascin-155 antibodies and 1 patient with anti contactin-1 antibodies. 13 patients with CIDP without these antibodies were also examined to compare pathological findings. RESULTS: Characteristic light and electron microscopy findings in transverse sections from patients with anti neurofascin-155 and anti-contactin-1 antibodies indicated a slight reduction in myelinated fibre density, with scattered myelin ovoids, and the absence of macrophage-mediated demyelination or onion bulbs. Teased-fibre preparations revealed that segmental demyelination tended to be found in patients with relatively higher frequencies of axonal degeneration and was tandemly found at consecutive nodes of Ranvier in a single fibre. Assessment of longitudinal sections by electron microscopy revealed that detachment of terminal myelin loops from the axolemma was frequently found at the paranode in patients with anti neurofascin-155 and anti-contactin-1 antibody-positive CIDP compared with patients with antibody-negative CIDP. Patients with anti-neurofascin-155 antibodies showed a positive correlation between the frequencies of axo-glial detachment at the paranode and axonal degeneration, as assessed by teased-fibre preparations (p<0.05). CONCLUSIONS: Paranodal dissection without classical macrophage-mediated demyelination is the characteristic feature of patients with CIDP with autoantibodies to paranodal axo-glial junctional molecules. PMID- 28073818 TI - Transcriptional coregulator RIP140: an essential regulator of physiology. AB - Transcriptional coregulators drive gene regulatory decisions in the transcriptional space. Although transcription factors including all nuclear receptors provide a docking platform for coregulators to bind, these proteins bring enzymatic capabilities to the gene regulatory sites. RIP140 is a transcriptional coregulator essential for several physiological processes, and aberrations in its function may lead to diseased states. Unlike several other coregulators that are known either for their coactivating or corepressing roles, in gene regulation, RIP140 is capable of acting both as a coactivator and a corepressor. The role of RIP140 in female reproductive axis and recent findings of its role in carcinogenesis and adipose biology have been summarised. PMID- 28073820 TI - Predicting 6-month mortality risk of patients commencing dialysis treatment for end-stage kidney disease. AB - Background: There is evidence that end-stage kidney disease patients who are older or with more comorbidity may have a poor trade-off between benefits of dialysis and potential harms. We aimed to develop a tool for predicting patient mortality in the early stages of receiving dialysis. Methods: In 23 658 patients aged 15+ years commencing dialysis between 2000 and 2009 in Australia and New Zealand a point score tool was developed to predict 6-month mortality based on a logistic regression analysis of factors available at dialysis initiation. Temporal validation used 2009-11 data from Australia and New Zealand. External validation used the UK Renal Registry. Results: Within 6 months of commencing dialysis 6.1% of patients had died. A small group (4.7%) of patients had a high predicted mortality risk (>20%), as predicted by the point score tool. Predictive variables were: older age, underweight, chronic lung disease, coronary artery disease, peripheral vascular disease, cerebrovascular disease (particularly for patients <60 years of age), late referral to nephrologist care and underlying cause of renal disease. The new point score tool outperformed existing models, and had an area under the receiver operating characteristic curve of 0.755 on temporal validation with acceptable calibration and 0.713 on external validation with poor calibration. Conclusion: Our point score tool for predicting 6-month mortality in patients at dialysis commencement has sufficient prognostic accuracy to use in Australia and New Zealand for prognosis and identification of high risk patients who may be given appropriate supportive care. Use in other countries requires further study. PMID- 28073821 TI - Learning from Cross-Border Reproduction. AB - Drawing upon the preliminary findings of an Australian empirical project on cross border reproduction (CBR), this article argues that regulators and policymakers could learn from the experiences of those who travel overseas in order to access fertility treatment and surrogacy. It makes four principal observations. First, the distinction between so-called 'altruistic' and 'commercial' gamete donation and surrogacy is increasingly unsustainable and is not experienced as meaningful by many participants in CBR. Secondly, the status of the law in CBR is profoundly equivocal; for participants it is often there and not there at the same time. Thirdly, self-sourced information, from the internet and more specifically social media such as Facebook, is now the principal source of information and peer support for reproductive travellers. Fourthly, and relatedly, domestic reproductive services providers are often sidestepped. If one of the goals of regulation is to minimise the risk of harm to participants, it is not clear that it is currently achieving this aim, and this article argues that any reforms will only work if they are more responsive to the reality of CBR. PMID- 28073819 TI - The opioid epidemic and neonatal abstinence syndrome in the USA: a review of the continuum of care. AB - As the prescription opioid epidemic grew in the USA, its impact extended to pregnant women and their infants. This review summarises how increasing rates of neonatal abstinence syndrome resulted in a need to improve care to pregnant women and opioid-exposed infants. We discuss the variations in care delivery with particular emphasis on screening at-risk mothers, scoring systems for neonatal drug withdrawal, type and duration of pharmacotherapy, and discharge safety. PMID- 28073822 TI - Obstructive sleep apnoea and quality of life in Ehlers-Danlos syndrome: a parallel cohort study. AB - BACKGROUND: Patients with the connective tissue disorder Ehlers-Danlos syndrome (EDS) often suffer from fatigue, excessive daytime sleepiness and impaired quality of life. Obstructive sleep apnoea (OSA) may be an underlying cause for these symptoms but its prevalence in this population is unclear. METHODS: In this prospective parallel-cohort study, we included 100 adult patients with EDS (46% hypermobile-type, 35% classical-type and 19% other), which were one-to-one matched to 100 healthy adult controls according to sex, age, weight and height. Participants underwent structured interviews (including short-form 36) and level 3 respiratory polygraphy. OSA was defined as apnoea-hypopnea index >=5/hour. Photographic craniofacial phenotyping was conducted in a subgroup. Conditional logistic regression was used to compare the prevalence of OSA. RESULTS: In patients with EDS, OSA prevalence was 32% versus 6% in the matched control group (OR 5.3 (95% CI 2.5 to 11.2); p<0.001). The EDS group reported impaired quality of life in all dimensions (p<0.05) and significantly higher excessive daytime sleepiness measured by the Epworth Sleepiness Scale (median (quartiles) 11 (7-14) vs 7 (5-10); p<0.001). OSA severity was positively associated with daytime sleepiness and lower quality of life in the EDS group. There was no evidence of a difference between the two study groups in terms of craniofacial phenotypes. CONCLUSIONS: The prevalence of OSA is higher in patients with EDS than in a matched control group. This is of clinical relevance as it is associated with fatigue, excessive daytime sleepiness and impaired quality of life. Further studies are needed to assess the clinical benefit of OSA treatment in patients with EDS. TRIAL REGISTRATION NUMBER: NCT02435745. PMID- 28073823 TI - A bloody bronchoscopy. PMID- 28073824 TI - A Drosophila toolkit for defining gene function in spermatogenesis. AB - Expression profiling and genomic sequencing methods enable the accumulation of vast quantities of data that relate to the expression of genes during the maturation of male germ cells from primordial germ cells to spermatozoa and potential mutations that underlie male infertility. However, the determination of gene function in specific aspects of spermatogenesis or linking abnormal gene function with infertility remain rate limiting, as even in an era of CRISPR analysis of gene function in mammalian models, this still requires considerable resources and time. Comparative developmental biology studies have shown the remarkable conservation of spermatogenic developmental processes from insects to vertebrates and provide an avenue of rapid assessment of gene function to inform the potential roles of specific genes in rodent and human spermatogenesis. The vinegar fly, Drosophila melanogaster, has been used as a model organism for developmental genetic studies for over one hundred years, and research with this organism produced seminal findings such as the association of genes with chromosomes, the chromosomal basis for sexual identity, the mutagenic properties of X-irradiation and the isolation of the first tumour suppressor mutations. Drosophila researchers have developed an impressive array of sophisticated genetic techniques for analysis of gene function and genetic interactions. This review focuses on how these techniques can be utilised to study spermatogenesis in an organism with a generation time of 9 days and the capacity to introduce multiple mutant alleles into an individual organism in a relatively short time frame. PMID- 28073825 TI - Comparison of characteristics and outcomes of percutaneous coronary intervention in military and non-military men. AB - OBJECTIVES: Living in a military environment, as a unique job and lifestyle, may affect the physical and mental status of military personnel. Coronary artery disease (CAD) status and outcomes of percutaneous coronary intervention (PCI) in military personnel as a unique part of each society are less investigated. METHOD: In a registry-based study, data of 338 military men and 1954 non-military men who underwent successful PCI from March 2012 to March 2013 were analysed. The primary endpoint was major adverse cardiac events (MACE) after hospital discharge during 1-year follow-up. RESULTS: Military men were significantly younger and had a higher frequency of hypertension, familial history of CAD and cigarette smoking. Other risk factors were more prevalent in non-military men. PCI for ST segment elevation myocardial infarction and lower left ventricular ejection fraction were also more prevalent in soldiers. After mean follow-up duration of 12.3 months, MACE that was defined as the composite endpoint of all-cause mortality, non-fatal myocardial infarction or target vessel revascularisation was similar in both groups (HR=1.01 (95% CI 0.88 to 1.16); p=0.872). By adjustment for confounding factors, results were unchanged. CONCLUSIONS: Although there are a number of differences in basic and procedural characteristics between military and non-military men who underwent PCI, 1-year clinical outcomes of this procedure are not different in these patient groups. PMID- 28073826 TI - Testing the psychological pain hypothesis for postnatal depression: Reproductive success versus evidence of design. PMID- 28073827 TI - Reply to Hagen and Thornhill. PMID- 28073828 TI - An Activating Mutation in STAT3 Results in Neonatal Diabetes Through Reduced Insulin Synthesis. AB - Neonatal diabetes mellitus (NDM) is a rare form of diabetes diagnosed within the first 6 months of life. Genetic studies have allowed the identification of several genes linked to the development of NDM; however, genetic causes for ~20% of the cases remain to be clarified. Most cases of NDM involve isolated diabetes, but sometimes NDM appears in association with other pathological conditions, including autoimmune diseases. Recent reports have linked activating mutations in STAT3 with early-onset autoimmune disorders that include diabetes of autoimmune origin, but the functional impact of STAT3-activating mutations have not been characterized at the pancreatic beta-cell level. By using whole-exome sequencing, we identified a novel missense mutation in the binding domain of the STAT3 protein in a patient with NDM. The functional analyses showed that the mutation results in an aberrant activation of STAT3, leading to deleterious downstream effects in pancreatic beta-cells. The identified mutation leads to hyperinhibition of the transcription factor Isl-1 and, consequently, to a decrease in insulin expression. These findings represent the first functional indication of a direct link between an NDM-linked activating mutation in STAT3 and pancreatic beta-cell dysfunction. PMID- 28073829 TI - dUTPase (DUT) Is Mutated in a Novel Monogenic Syndrome With Diabetes and Bone Marrow Failure. AB - We describe a new syndrome characterized by early-onset diabetes associated with bone marrow failure, affecting mostly the erythrocytic lineage. Using whole-exome sequencing in a remotely consanguineous patient from a family with two affected siblings, we identified a single homozygous missense mutation (chr15.hg19:g.48,626,619A>G) located in the dUTPase (DUT) gene (National Center for Biotechnology Information Gene ID 1854), affecting both the mitochondrial (DUT-M p.Y142C) and the nuclear (DUT-N p.Y54C) isoforms. We found the same homozygous mutation in an unrelated consanguineous patient with diabetes and bone marrow aplasia from a family with two affected siblings, whereas none of the >60,000 subjects from the Exome Aggregation Consortium (ExAC) was homozygous for this mutation. This replicated observation probability was highly significant, thus confirming the role of this DUT mutation in this syndrome. DUT is a key enzyme for maintaining DNA integrity by preventing misincorporation of uracil into DNA, which results in DNA toxicity and cell death. We showed that DUT silencing in human and rat pancreatic beta-cells results in apoptosis via the intrinsic cell death pathway. Our findings support the importance of tight control of DNA metabolism for beta-cell integrity and warrant close metabolic monitoring of patients treated by drugs affecting dUTP balance. PMID- 28073830 TI - Adiponectin Deficiency Impairs Maternal Metabolic Adaptation to Pregnancy in Mice. AB - Hypoadiponectinemia has been widely observed in patients with gestational diabetes mellitus (GDM). To investigate the causal role of hypoadiponectinemia in GDM, adiponectin gene knockout (Adipoq-/- ) and wild-type (WT) mice were crossed to produce pregnant mouse models with or without adiponectin deficiency. Adenoviral vector-mediated in vivo transduction was used to reconstitute adiponectin during late pregnancy. Results showed that Adipoq-/- dams developed glucose intolerance and hyperlipidemia in late pregnancy. Increased fetal body weight was detected in Adipoq-/- dams. Adiponectin reconstitution abolished these metabolic defects in Adipoq-/- dams. Hepatic glucose and triglyceride production rates of Adipoq-/- dams were significantly higher than those of WT dams. Robustly enhanced lipolysis was found in gonadal fat of Adipoq-/- dams. Interestingly, similar levels of insulin-induced glucose disposal and insulin signaling in metabolically active tissues in Adipoq-/- and WT dams indicated that maternal adiponectin deficiency does not reduce insulin sensitivity. However, remarkably decreased serum insulin concentrations were observed in Adipoq-/- dams. Furthermore, beta-cell mass, but not glucose-stimulated insulin release, in Adipoq-/- dams was significantly reduced compared with WT dams. Together, these results demonstrate that adiponectin plays an important role in controlling maternal metabolic adaptation to pregnancy. PMID- 28073832 TI - Reperfusion therapy with recombinant human relaxin-2 (Serelaxin) attenuates myocardial infarct size and NLRP3 inflammasome following ischemia/reperfusion injury via eNOS-dependent mechanism. AB - Aims: The preconditioning-like infarct-sparing and anti-inflammatory effects of the peptide hormone relaxin following ischemic injury have been studied in the heart. Whether reperfusion therapy with recombinant human relaxin-2, serelaxin, reduces myocardial infarct size and attenuates the subsequent NLRP3 inflammasome activation leading to further loss of functional myocardium following ischemia/reperfusion (I/R) injury is unknown. Methods and results: After baseline echocardiography, adult male wild-type C57BL or eNOS knockout mice underwent myocardial infarction (MI) by coronary artery ligation for 30 min followed by 24 h reperfusion. Mice were treated with either serelaxin (10 ug/kg; sc) or saline 1 h prior to ischemia or 5 min before reperfusion. In both pre-treatment and reperfusion therapy arms, serelaxin improved survival at 24 h post MI in wild type mice (79% and 82%) as compared with controls (46% and 50%, P = 0.01), whereas there was no difference in survival between serelaxin- and saline-treated eNOS knockout mice. Moreover, serelaxin significantly reduced infarct size (64% and 67% reduction, P < 0.05), measured with TTC staining, and preserved LV fractional shortening (FS) and end-systolic diameter (LVESD) in wild-type mice as compared with controls (P < 0.05). Interestingly, caspase-1 activity in the heart tissue, a measure of inflammasome formation, was markedly reduced in serelaxin treated wild-type mice compared with controls at 24 h post-MI in both treatment modalities (P < 0.05). Genetic deletion of eNOS abolished the infarct-sparing and anti-inflammatory effects of serelaxin as well as functional preservation. Serelaxin plasma levels assessed at 5 min and 1 h after treatment, using ELISA, approximated physiologic relaxin levels during pregnancy in mice and parallels that in humans. Conclusion: Serelaxin attenuates myocardial I/R injury and the subsequent caspase-1 activation via eNOS-dependent mechanism. PMID- 28073833 TI - Exosomal miR-142-3p is increased during cardiac allograft rejection and augments vascular permeability through down-regulation of endothelial RAB11FIP2 expression. AB - Aims: Exosome-mediated microRNA transfer is a recently discovered mode of cell-to cell communication, in which microRNAs act as paracrine molecules, exerting their regulatory effects in recipient cells. T cells and endothelial cells are two main players in the mechanism of acute cellular cardiac rejection. The aim of this study was to investigate the role of exosomal microRNAs in the crosstalk between T cells and endothelial cells and its implications for the molecular mechanisms that drive acute cellular rejection in heart transplantation. Methods and results: Exosomes isolated from serum samples of heart transplant patients with and without acute cardiac allograft rejection were profiled and showed enrichment of miR-142-3p, miR-92a-3p, miR-339-3p and miR-21-5p. Treatment of endothelial cells with the respected serum exosomes resulted the increased of miR-142-3p level in endothelial cells. Using T cells isolated from healthy donors and activated with either anti-CD3/CD28 antibody or IL-2/PHA, we could show that miR 142-3p is released from activated cells, is contained in exosomes and can be transferred to human vascular endothelial cells in vitro. Transcriptome analysis of endothelial cells treated with activated T cell supernatant with or without exosomes was used to identify mRNA targets of transferred miR-142-3-p. Overexpression of miR-142-3p in endothelial cells resulted in a significant down regulation of RAB11FIP2, and interaction of miR-142-3p with its predicted target site was confirmed with a reporter assay. Moreover, treatment of endothelial cells with serum exosomes from heart transplant patients with acute cellular rejection resulted in down-regulation of RAB11FIP2 expression and increase in vascular endothelial permeability. Conclusion: We have identified a novel mechanism whereby miR-142-3p, a microRNA enriched in exosomes during acute cellular rejection, is transferred to endothelial cells and compromises endothelial barrier function via down-regulation of RAB11FIP2. This study sheds new light on the interaction between host immune system and cardiac allograft endothelium during acute cellular rejection. PMID- 28073834 TI - Dynamic and coordinated single-molecular interactions at TM4SF5-enriched microdomains guide invasive behaviors in 2- and 3-dimensional environments. AB - Membrane proteins sense extracellular cues and transduce intracellular signaling to coordinate directionality and speed during cellular migration. They are often localized to specific regions, as with lipid rafts or tetraspanin-enriched microdomains; however, the dynamic interactions of tetraspanins with diverse receptors within tetraspanin-enriched microdomains on cellular surfaces remain largely unexplored. Here, we investigated effects of tetraspan(in) TM4SF5 (transmembrane 4 L6 family member 5)-enriched microdomains (T5ERMs) on the directionality of cell migration. Physical association of TM4SF5 with epidermal growth factor receptor (EGFR) and integrin alpha5 was visualized by live fluorescence cross-correlation spectroscopy and higher-resolution microscopy at the leading edge of migratory cells, presumably forming TM4SF5-enriched microdomains. Whereas TM4SF5 and EGFR colocalized at the migrating leading region more than at the rear, TM4SF5 and integrin alpha5 colocalized evenly throughout cells. Cholesterol depletion and disruption in TM4SF5 post-translational modifications, including N-glycosylation and palmitoylation, altered TM4SF5 interactions and cellular localization, which led to less cellular migration speed and directionality in 2- or 3-dimensional conditions. TM4SF5 controlled directional cell migration and invasion, and importantly, these TM4SF5 functions were dependent on cholesterol, TM4SF5 post-translational modifications, and EGFR and integrin alpha5 activity. Altogether, we showed that TM4SF5 dynamically interacted with EGFR and integrin alpha5 in migratory cells to control directionality and invasion.-Kim, H.-J., Kwon, S., Nam, S. H., Jung, J. W., Kang, M., Ryu, J., Kim, J. E., Cheong, J.-G., Cho, C. Y., Kim, S., Song, D.-G., Kim, Y. N., Kim, T. Y., Jung, M.-K., Lee, K.-M., Pack, C.-G., Lee, J. W. Dynamic and coordinated single-molecular interactions at TM4SF5-enriched microdomains guide invasive behaviors in 2- and 3-dimensional environments. PMID- 28073831 TI - Deletion of Protein Kinase C lambda in POMC Neurons Predisposes to Diet-Induced Obesity. AB - Effectors of the phosphoinositide 3-kinase (PI3K) signal transduction pathway contribute to the hypothalamic regulation of energy and glucose homeostasis in divergent ways. Here we show that central nervous system (CNS) action of the PI3K signaling intermediate atypical protein kinase C (aPKC) constrains food intake, weight gain, and glucose intolerance in both rats and mice. Pharmacological inhibition of CNS aPKC activity acutely increases food intake and worsens glucose tolerance in chow-fed rodents and causes excess weight gain during high-fat diet (HFD) feeding. Similarly, selective deletion of the aPKC isoform Pkc-lambda in proopiomelanocortin (POMC) neurons disrupts leptin action, reduces melanocortin content in the paraventricular nucleus, and markedly increases susceptibility to obesity, glucose intolerance, and insulin resistance specifically in HFD-fed male mice. These data implicate aPKC as a novel regulator of energy and glucose homeostasis downstream of the leptin-PI3K pathway in POMC neurons. PMID- 28073835 TI - Mechanosensitive transient receptor potential vanilloid 4 regulates Dermatophagoides farinae-induced airway remodeling via 2 distinct pathways modulating matrix synthesis and degradation. AB - Contributions of mechanical signals to airway remodeling during asthma are poorly understood. Transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel, has been implicated in cardiac and pulmonary fibrosis; however, its role in asthma remains elusive. Employing a Dermatophagoides farinae-induced asthma model, we report here that TRPV4-knockout mice were protected from D. farinae-induced airway remodeling. Furthermore, lung fibroblasts that were isolated from TRPV4-knockout mice showed diminished differentiation potential compared with wild-type mice. Fibroblasts from asthmatic lung exhibited increased TRPV4 activity and enhanced differentiation potential compared with normal human lung fibroblasts. Of interest, TGF-beta1 treatment enhanced TRPV4 activation in a PI3K-dependent manner in normal human lung fibroblasts in vitro Mechanistically, TRPV4 modulated matrix remodeling in the lung via 2 distinct but dependent pathways: one enhances matrix deposition by fibrotic gene activation, whereas the other slows down matrix degradation by increased plasminogen activator inhibitor 1. Of importance, both pathways are regulated by Rho/myocardin-related transcription factor-A and contribute to fibroblast differentiation and matrix remodeling in the lung. Thus, our results support a unique role for TRPV4 in D. farinae-induced airway remodeling and warrant further studies in humans for it to be used as a novel therapeutic target in the treatment of asthma.-Gombedza, F., Kondeti, V., Al-Azzam, N., Koppes, S., Duah, E., Patil, P., Hexter, M., Phillips, D., Thodeti, C. K., Paruchuri, S. Mechanosensitive transient receptor potential vanilloid 4 regulates Dermatophagoides farinae-induced airway remodeling via 2 distinct pathways modulating matrix synthesis and degradation. PMID- 28073837 TI - Chronic Co-species Housing Mice and Rats Increased the Competitiveness of Male Mice. AB - Rats are predators of mice in nature. Nevertheless, it is a common practice to house mice and rats in a same room in some laboratories. In this study, we investigated the behavioral and physiological responsively of mice in long-term co-species housing conditions. Twenty-four male mice were randomly assigned to their original raising room (control) or a rat room (co-species-housed) for more than 6 weeks. In the open-field and light-dark box tests, the behaviors of the co species-housed mice and controls were not different. In a 2-choice test of paired urine odors [rabbit urine (as a novel odor) vs. rat urine, cat urine (as a natural predator-scent) vs. rabbit urine, and cat urine vs. rat urine], the co species-housed mice were more ready to investigate the rat urine odor compared with the controls and may have adapted to it. In an encounter test, the rat-room exposed mice exhibited increased aggression levels, and their urines were more attractive to females. Correspondingly, the levels of major urinary proteins were increased in the co-species-housed mouse urine, along with some volatile pheromones. The serum testosterone levels were also enhanced in the co-species housed mice, whereas the corticosterone levels were not different. The norepinephrine, dopamine, and 5-HT levels in the right hippocampus and striatum were not different between the 2. Our findings indicate that chronic co-species housing results in adaptation in male mice; furthermore, it appears that long term rat-odor stimuli enhance the competitiveness of mice, which suggests that appropriate predator-odor stimuli may be important to the fitness of prey animals. PMID- 28073836 TI - Ionotropic glutamate receptors activate cell signaling in response to glutamate in Schwann cells. AB - In the peripheral nervous system, Schwann cells (SCs) demonstrate surveillance activity, detecting injury and undergoing trans-differentiation to support repair. SC receptors that detect peripheral nervous system injury remain incompletely understood. We used RT-PCR to profile ionotropic glutamate receptor expression in cultured SCs. We identified subunits required for assembly of N methyl-d-aspartic acid (NMDA) receptors (NMDA-Rs), alpha-amino-3-hydroxy-5-methyl 4-isoxazolepropionic acid receptors, and kainate receptors. Treatment of SCs with 40-100 uM glutamate or with 0.5-1.0 uM NMDA robustly activated Akt and ERK1/2. The response was transient and bimodal; glutamate concentrations that exceeded 250 uM failed to activate cell signaling. Phosphoprotein profiling identified diverse phosphorylated proteins in glutamate-treated SCs in addition to ERK1/2 and Akt, including p70 S6-kinase, glycogen synthase kinase-3, ribosomal S6 kinase, c-Jun, and cAMP response element binding protein. Activation of SC signaling by glutamate was blocked by EGTA and dizocilpine and by silencing expression of the NMDA-R NR1 subunit. Phosphoinositide 3-kinase/PI3K functioned as an essential upstream activator of Akt and ERK1/2 in glutamate-treated SCs. When glutamate or NMDA was injected directly into crush-injured rat sciatic nerves, ERK1/2 phosphorylation was observed in myelinated and nonmyelinating SCs. Glutamate promoted SC migration by a pathway that required PI3K and ERK1/2. These results identified ionotropic glutamate receptors and NMDA-Rs, specifically, as potentially important cell signaling receptors in SCs.-Campana, W. M., Mantuano, E., Azmoon, P., Henry, K., Banki, M. A., Kim, J. H., Pizzo, D. P., Gonias, S. L. Ionotropic glutamate receptors activate cell signaling in response to glutamate in Schwann cells. PMID- 28073838 TI - Gender-Specific Relation Between Olfactory Sensitivity and Disgust Perception. AB - The perception of disgust is a powerful but yet puzzling emotion, aiming at the prevention of potential microbial pathogens and being directly linked to olfactory processing in its neurophysiological pathways via the anterior insular cortex. In sample of healthy participants with a natural variation in olfactory function, we investigated the relation between olfactory sensitivity and disgust perception. A total of 123 healthy individuals were surveyed with a disgust sensitivity questionnaire. Olfactory threshold was assessed in all participants using the Sniffin' Sticks. Additionally, tactile 2-point discrimination threshold was tested in a subgroup of the participants as a controlling factor for the specificity of the relationship between olfactory sensitivity and disgust. Only in men, a significant relation between disgust ratings and olfactory threshold was observed. Men with high olfactory sensitivity reported as high levels of disgust as female participants, while men with low olfactory sensitivity reported significantly lower disgust than women. There was no such relation for tactile sensitivity. Investigating sensory subscales of the disgust questionnaire, olfactory sensitivity was related to olfactory and tactile, but not to visual disgust ratings. In conclusion, there is a specific relation between the level of disgust and olfactory sensitivity in men, who generally present lower values of disgust than women. When disgust ratings are low, there seems to be an additional merit in the ability to perceive subtle olfactory stimuli. Thus high olfactory sensitivity may facilitate the perception of potential pathogenic threats and contribute to the evolutionary function of disgust as disease avoidance mechanism. PMID- 28073839 TI - Unsupervised Clustering of Quantitative Image Phenotypes Reveals Breast Cancer Subtypes with Distinct Prognoses and Molecular Pathways. AB - Purpose: To identify novel breast cancer subtypes by extracting quantitative imaging phenotypes of the tumor and surrounding parenchyma and to elucidate the underlying biologic underpinnings and evaluate the prognostic capacity for predicting recurrence-free survival (RFS).Experimental Design: We retrospectively analyzed dynamic contrast-enhanced MRI data of patients from a single-center discovery cohort (n = 60) and an independent multicenter validation cohort (n = 96). Quantitative image features were extracted to characterize tumor morphology, intratumor heterogeneity of contrast agent wash-in/wash-out patterns, and tumor surrounding parenchyma enhancement. On the basis of these image features, we used unsupervised consensus clustering to identify robust imaging subtypes and evaluated their clinical and biologic relevance. We built a gene expression-based classifier of imaging subtypes and tested their prognostic significance in five additional cohorts with publically available gene expression data but without imaging data (n = 1,160).Results: Three distinct imaging subtypes, that is, homogeneous intratumoral enhancing, minimal parenchymal enhancing, and prominent parenchymal enhancing, were identified and validated. In the discovery cohort, imaging subtypes stratified patients with significantly different 5-year RFS rates of 79.6%, 65.2%, 52.5% (log-rank P = 0.025) and remained as an independent predictor after adjusting for clinicopathologic factors (HR, 2.79; P = 0.016). The prognostic value of imaging subtypes was further validated in five independent gene expression cohorts, with average 5-year RFS rates of 88.1%, 74.0%, 59.5% (log-rank P from <0.0001 to 0.008). Each imaging subtype was associated with specific dysregulated molecular pathways that can be therapeutically targeted.Conclusions: Imaging subtypes provide complimentary value to established histopathologic or molecular subtypes and may help stratify patients with breast cancer. Clin Cancer Res; 23(13); 3334-42. (c)2017 AACR. PMID- 28073840 TI - FDA Approval Summary: Sonidegib for Locally Advanced Basal Cell Carcinoma. AB - On July 24, 2015, the FDA approved sonidegib (ODOMZO; Novartis) for the treatment of patients with locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy. The approval was based on data from one randomized, double-blind, noncomparative trial of two doses of sonidegib administered to 230 hedgehog inhibitor-naive patients with metastatic basal cell carcinoma (mBCC, n = 36) or laBCC (n = 194). Patients were randomized 2:1 to receive sonidegib 800 mg (n = 151) or 200 mg (n = 79) daily. The objective response rate (ORR) for patients with laBCC was 58% [95% confidence interval (CI), 45-70] in the 200 mg group and 44% (95% CI, 35-53) in the 800 mg group. The median duration of response for patients with laBCC was nonestimable (NE) in the 200 mg arm and 15.7 months (95% CI, NE) in the 800 mg arm. The ORR for patients with mBCC was 8% (95% CI, 0.2-36) and 17% (95% CI, 5-39) in patients treated with 200 and 800 mg, respectively. The most common adverse events occurring in >=10% of patients were muscle spasms, alopecia, dysgeusia, nausea, fatigue, increased serum creatine kinase, decreased weight, and diarrhea. Clin Cancer Res; 23(10); 2377-81. (c)2017 AACR. PMID- 28073841 TI - Activation of EIF4E by Aurora Kinase A Depicts a Novel Druggable Axis in Everolimus-Resistant Cancer Cells. AB - Purpose: Aurora kinase A (AURKA) is overexpressed in several cancer types, making it an attractive druggable target in clinical trials. In this study, we investigated the role of AURKA in regulating EIF4E, cap-dependent translation, and resistance to mTOR inhibitor, RAD001 (everolimus).Experimental Design: Tumor xenografts and in vitro cell models of upper gastrointestinal adenocarcinomas (UGC) were used to determine the role of AURKA in the activation of EIF4E and cap dependent translation. Overexpression, knockdown, and pharmacologic inhibition of AURKA were used in vitro and in vivoResults: Using in vitro cell models, we found that high protein levels of AURKA mediate phosphorylation of EIF4E and upregulation of c-MYC. Notably, we detected overexpression of endogenous AURKA in everolimus-resistant UGC cell models. AURKA mediated phosphorylation of EIF4E, activation of cap-dependent translation, and an increase in c-MYC protein levels. Targeting AURKA using genetic knockdown or a small-molecule inhibitor, alisertib, reversed these molecular events, leading to a decrease in cancer cell survival in acquired and intrinsic resistant cell models. Mechanistic studies demonstrated that AURKA binds to and inactivates protein phosphatase 2A, a negative regulator of EIF4E, leading to phosphorylation and activation of EIF4E in an AKT-, ERK1/2-, and mTOR-independent manner. Data from tumor xenograft mouse models confirmed that everolimus-resistant cancer cells are sensitive to alisertib.Conclusions: Our results indicate that AURKA plays an important role in the activation of EIF4E and cap-dependent translation. Targeting the AURKA-EIF4E-c-MYC axis using alisertib is a novel therapeutic strategy that can be applicable for everolimus resistant tumors and/or subgroups of cancers that show overexpression of AURKA and activation of EIF4E and c-MYC. Clin Cancer Res; 23(14); 3756-68. (c)2017 AACR. PMID- 28073843 TI - Active Estrogen Receptor-alpha Signaling in Ovarian Cancer Models and Clinical Specimens. AB - Purpose: High-grade serous ovarian cancer (HGSOC) is an aggressive disease with few available targeted therapies. Despite high expression of estrogen receptor alpha (ERalpha) in approximately 80% of HGSOC and some small but promising clinical trials of endocrine therapy, ERalpha has been understudied as a target in this disease. We sought to identify hormone-responsive, ERalpha-dependent HGSOC.Experimental Design: We characterized endocrine response in HGSOC cells across culture conditions [ two-dimensional (2D), three-dimensional (3D), forced suspension] and in patient-derived xenograft (PDX) explants, assessing proliferation and gene expression. Estrogen-regulated transcriptome data were overlapped with public datasets to develop a comprehensive panel of ERalpha target genes. Expression of this panel and ERalpha H-score were assessed in HGSOC samples from patients who received endocrine therapy. Time on endocrine therapy was used as a surrogate for clinical response.Results: Proliferation is ERalpha regulated in HGSOC cells in vitro and in vivo, and is partly dependent on 3D context. Transcriptomic studies identified genes shared by cell lines and PDX explants as ERalpha targets. The selective ERalpha downregulator (SERD) fulvestrant is more effective than tamoxifen in blocking ERalpha action. ERalpha H-score is predictive of efficacy of endocrine therapy, and this prediction is further improved by inclusion of target gene expression, particularly IGFBP3Conclusions: Laboratory models corroborate intertumor heterogeneity of endocrine response in HGSOC but identify features associated with functional ERalpha and endocrine responsiveness. Assessing ERalpha function (e.g., IGFBP3 expression) in conjunction with H-score may help select patients who would benefit from endocrine therapy. Preclinical data suggest that SERDs might be more effective than tamoxifen. Clin Cancer Res; 23(14); 3802-12. (c)2017 AACR. PMID- 28073842 TI - Expression of CD14, IL10, and Tolerogenic Signature in Dendritic Cells Inversely Correlate with Clinical and Immunologic Response to TARP Vaccination in Prostate Cancer Patients. AB - Purpose: Despite the vast number of clinical trials conducted so far, dendritic cell (DC)-based cancer vaccines have mostly shown unsatisfactory results. Factors and manufacturing procedures essential for these therapeutics to induce effective antitumor immune responses have yet to be fully characterized. We here aimed to identify DC markers correlating with clinical and immunologic response in a prostate carcinoma vaccination regimen.Experimental Design: We performed an extensive characterization of DCs used to vaccinate 18 patients with prostate carcinoma enrolled in a pilot trial of T-cell receptor gamma alternate reading frame protein (TARP) peptide vaccination (NCT00908258). Peptide-pulsed DC preparations (114) manufactured were analyzed by gene expression profiling, cell surface marker expression and cytokine release secretion, and correlated with clinical and immunologic responses.Results: DCs showing lower expression of tolerogenic gene signature induced strong antigen-specific immune response and slowing in PSA velocity, a surrogate for clinical response. These DCs were also characterized by lower surface expression of CD14, secretion of IL10 and MCP-1, and greater secretion of MDC. When combined, these four factors were able to remarkably discriminate DCs that were sufficiently potent to induce strong immunologic response.Conclusions: DC factors essential for the activation of immune responses associated with TARP vaccination in prostate cancer patients were identified. This study highlights the importance of in-depth characterization of DC vaccines and other cellular therapies, to understand the critical factors that hinder potency and potential efficacy in patients. Clin Cancer Res; 23(13); 3352-64. (c)2017 AACR. PMID- 28073844 TI - FDA Approval of Nivolumab for the First-Line Treatment of Patients with BRAFV600 Wild-Type Unresectable or Metastatic Melanoma. AB - On November 23, 2015, the FDA approved nivolumab (OPDIVO; Bristol-Myers Squibb) as a single agent for the first-line treatment of patients with BRAFV600 wild type, unresectable or metastatic melanoma. An international, double-blind, randomized (1:1) trial conducted outside of the United States allocated 418 patients to receive nivolumab 3 mg/kg intravenously every 2 weeks (n = 210) or dacarbazine 1,000 mg/m2 intravenously every 3 weeks (n = 208). Patients with disease progression who met protocol-specified criteria (~25% of each trial arm) were permitted to continue with the assigned treatment in a blinded fashion until further disease progression is documented. Overall survival was statistically significantly improved in the nivolumab arm compared with the dacarbazine arm [hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.30-0.60; P < 0.0001]. Progression-free survival was also statistically significantly improved in the nivolumab arm (HR, 0.43; 95% CI, 0.34-0.56; P < 0.0001). The most common adverse reactions (>=20%) of nivolumab were fatigue, diarrhea, constipation, nausea, musculoskeletal pain, rash, and pruritus. Nivolumab demonstrated a favorable benefit-risk profile compared with dacarbazine, supporting regular approval; however, it remains unclear whether treatment beyond disease progression contributes to the overall clinical benefit of nivolumab. Clin Cancer Res; 23(14); 3479-83. (c)2017 AACR. PMID- 28073845 TI - Agreement between Programmed Cell Death Ligand-1 Diagnostic Assays across Multiple Protein Expression Cutoffs in Non-Small Cell Lung Cancer. AB - Purpose: Immunotherapies targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) demonstrate encouraging antitumor activity and manageable tolerability in non-small cell lung cancer (NSCLC), especially in patients with high tumor PD-L1 expression, as detected by companion or complementary diagnostic assays developed for individual agents. A laboratory is unlikely to use multiple assay platforms. Furthermore, commercially available diagnostic assays are not standardized, and different assay methods could lead to inappropriate treatment selection. This study establishes the extent of concordance between three validated, commercially available PD-L1 IHC diagnostic assays for NSCLC patients [Ventana SP263 (durvalumab), Dako 22C3 (pembrolizumab), and Dako 28-8 (nivolumab)].Experimental Design: Five hundred formalin-fixed, paraffin-embedded archival NSCLC samples were obtained from commercial sources. Stained slides were read in batches on an assay-by-assay basis by a single pathologist trained in all methods, in a Clinical Laboratory Improvements Amendments program-certified laboratory. An additional pathologist performed an independent review of 200 stained samples for each assay.Results: PD-L1 expression was evaluable with all assays in 493 samples. The three assays showed similar patterns of tumor membrane staining, with high correlation between percent PD-L1 staining. An overall percentage agreement of >90% was achieved between assays at multiple expression cutoffs, including 1%, 10%, 25%, and 50% tumor membrane staining.Conclusions: This study builds optimism that harmonization between assays may be possible, and that the three assays studied could potentially be used interchangeably to identify patients most likely to respond to anti-PD-1/PD-L1 immunotherapies, provided the appropriate clinically defined algorithm and agent are always linked. Clin Cancer Res; 23(14); 3585-91. (c)2017 AACR. PMID- 28073846 TI - Extended Treatment with Single-Agent Ibrutinib at the 420 mg Dose Leads to Durable Responses in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. AB - Purpose: Ibrutinib, a first-in-class, once-daily, oral inhibitor of Bruton tyrosine kinase, promotes apoptosis, and inhibits B-cell proliferation, adhesion, and migration. Ibrutinib has demonstrated single-agent efficacy and acceptable tolerability at doses of 420 and 840 mg in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who were treatment-naive (TN) or had relapsed/refractory (R/R) CLL after >=1 prior therapy in a phase Ib/II study (PCYC-1102). Subsequently, the ibrutinib 420 mg dose was approved in CLL.Experimental Design: We report data with 44 months of follow-up on 94 patients with TN and R/R CLL/SLL receiving ibrutinib 420 mg once-daily in PCYC 1102 and the long-term extension study PCYC-1103.Results: Ninety-four CLL/SLL patients (27 TN, 67 R/R) were treated with ibrutinib (420 mg/day). Patients with R/R disease had received a median of four prior therapies (range, 1-12). Responses were rapid and durable and median duration of response was not reached. Best overall response was 91% [85% TN (complete response, CR 26%) and 94% R/R (9% CR)]. Median progression-free survival (PFS) was not reached in either group. The 30-month PFS rate was 96% and 76% for TN and R/R patients, respectively. Ibrutinib was well tolerated with extended follow-up; rates of grade >=3 cytopenias and fatigue, as well as discontinuations due to toxicities decreased over time.Conclusions: Single-agent ibrutinib at 420 mg once-daily resulted in durable responses and was well tolerated with up to 44 months follow-up in patients with TN and R/R CLL/SLL. Currently, 66% of patients continue on ibrutinib. Clin Cancer Res; 23(5); 1149-55. (c)2017 AACR. PMID- 28073847 TI - Identification of CCR2 and CD180 as Robust Pharmacodynamic Tumor and Blood Biomarkers for Clinical Use with BRD4/BET Inhibitors. AB - Purpose: AZD5153 is a novel BRD4/BET inhibitor with a distinctive bivalent bromodomain binding mode. To support its clinical development, we identified pharmacodynamic (PD) biomarkers for use in clinical trials to establish target engagement.Experimental Design: CCR2 and CD180 mRNAs, initially identified from whole transcriptome profiling, were further evaluated by quantitative PCR in hematologic cell lines, xenografts, and whole blood from rat, healthy volunteers, and patients with cancer. MYC and HEXIM1 mRNAs were also evaluated.Results: RNA sequencing data showed consistent decreases in CCR2/CD180 expression across multiple hematologic cell lines upon AZD5153 treatment. Evaluation of dose dependence in MV4,11 cells confirmed activity at clinically relevant concentrations. In vivo downregulation of CCR2/CD180 mRNAs (>80%) was demonstrated in MV4,11 and KMS-11 xenograft tumors at efficacious AZD5153 doses. Consistent with in vitro rat blood data, an in vivo rat study confirmed greater inhibition of CCR2/CD180 mRNA in whole blood versus MYC at an efficacious dose. Finally, in vitro treatment of whole blood from healthy volunteers and patients with cancer demonstrated, in contrast to MYC, almost complete downregulation of CCR2/CD180 at predicted clinically achievable concentrations.Conclusions: Our data strongly support the use of CCR2 and CD180 mRNAs as whole blood PD biomarkers for BRD4 inhibitors, especially in situations where paired tumor biopsies are unavailable. In addition, they can be used as tumor-based PD biomarkers for hematologic tumors. MYC mRNA is useful as a hematologic tumor based biomarker but suboptimal as a whole blood biomarker. Utility of HEXIM1 mRNA may be limited to higher concentrations. Clin Cancer Res; 23(4); 1025-35. (c)2017 AACR. PMID- 28073848 TI - Cardiac and Noncardiac Causes of Long-Term Mortality in ST-Segment-Elevation Acute Myocardial Infarction Patients Who Underwent Primary Percutaneous Coronary Intervention. AB - BACKGROUND: In patients with ST-segment-elevation acute myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention, long-term risks for cardiac and noncardiac death beyond acute phase of STEMI have not been thoroughly evaluated yet. METHODS AND RESULTS: We identified 3942 STEMI patients who had primary percutaneous coronary intervention within 24 hours after onset between January 2005 and December 2007 in the CREDO-Kyoto AMI registry (Coronary Revascularization Demonstrating Outcome study in Kyoto Acute Myocardial Infarction) and evaluated their short-term (within 6-month) and long-term (beyond 6-month) incidences and causes of deaths. The cumulative 5-year incidence of all cause death in the current study population was 20.4% (cardiac death, 12.2% and noncardiac death, 9.4%, respectively). The vast majority of deaths were cardiac in origin within 6-month (cardiac death, 8.0% and noncardiac death, 0.9%), whereas noncardiac death accounted for nearly two thirds of all-cause death beyond 6-month (cardiac death, 4.6% and noncardiac death, 8.5%). In the stratified analysis according to age, the proportion of noncardiac death was similar regardless of age although the absolute mortality rate was higher with increasing age. By the multivariable Cox regression models, the independent risk factors of all-cause death were advanced age, cardiogenic shock, renal dysfunction, large infarct size, and anterior wall infarction within 6 months after STEMI, and advanced age, previous heart failure, renal dysfunction, and liver cirrhosis beyond 6 months after STEMI, respectively. CONCLUSIONS: In STEMI patients who underwent primary percutaneous coronary intervention, the long-term risk for cardiac death was relatively low compared with that for noncardiac death, which accounted for nearly two thirds of all-cause death beyond 6 months. PMID- 28073849 TI - Caregivers of Patients With Left Ventricular Assist Devices: Possible Impacts on Patients' Mortality and Interagency Registry for Mechanically Assisted Circulatory Support-Defined Morbidity Events. AB - BACKGROUND: How caregivers contribute to positive or negative outcomes for left ventricular assist device (LVAD) patients remains unclear. Our primary study objectives were to (1) identify caregiver support attributes through a retrospective chart review of social workers' psychosocial assessments for LVAD patients and (2) determine how these attributes associated with patients' post LVAD placement mortality and Interagency Registry for Mechanically Assisted Circulatory Support-defined morbidity events. METHODS AND RESULTS: We retrospectively reviewed and recorded social workers' clinical assessments of adult patients implanted with durable continuous-flow LVADs as bridge to transplant, destination therapy, or bridge to decision from January 2010 to December 2014. Associations between caregiver characteristics and patient mortality and morbidity events were analyzed using Kaplan-Meier curves and Cox proportional hazards regression. Patient follow-up time was calculated as the time from hospital discharge until the earliest among death with LVAD, transplant, or the last day of the study (December 31, 2015). Patients were censored for death with LVAD at the time of transplant or the last day of the study. A total of 96 LVAD recipients were included in this study. Having a caregiver who understands the severity of the illness and options available to the patient (as determined and documented by the social worker; P=0.01), a caregiver who has identified a backup plan (P=0.02), and a caregiver who is able to provide logistical support (P=0.04) significantly mitigated risk of death. The risk of death for an LVAD patient was also significantly lower among those who have at least 1 adult child who lives within 50 miles (P=0.03) and those who have an extended family who can care for the patient (P=0.03). The risk of death was 3.1* more likely among patients who live alone compared with those who do not live alone (P=0.04). No caregiver characteristics were significantly associated with morbidity. CONCLUSIONS: This exploratory, hypothesis-generating study suggests that mortality after LVAD placement is impacted by caregiver understanding of patient severity of illness and caregiver presence. This study provides initial evidence to support further work in understanding the associations between caregivers and LVAD patients, as well as interventions that may improve patient outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02248974. PMID- 28073850 TI - Characterization of Mineralocorticoid Receptor Antagonist Therapy Initiation in High-Risk Patients With Heart Failure. AB - BACKGROUND: Heart failure guidelines recommend routine monitoring of serum potassium, and renal function in patients treated with a mineralocorticoid receptor antagonist (MRA). How these recommendations are implemented in high-risk patients or according to setting of drug initiation is poorly characterized. METHODS AND RESULTS: We conducted a retrospective cohort study of Medicare beneficiaries linked to laboratory data in 10 states with prevalent heart failure as of July 1, 2011, and incident MRA use between May 1 and September 30, 2011. Outcomes included laboratory testing before MRA initiation and in the early (days 1-10) and extended (days 11-90) post-initiation periods, based on setting of drug initiation and the presence of renal insufficiency. Additional outcomes included abnormal laboratory results and adverse events proximate to MRA initiation. Of 10 443 Medicare beneficiaries with heart failure started on an MRA, 19.7% were initiated during a hospitalization. Appropriate follow-up laboratory testing across all time periods occurred in 25.2% of patients with inpatient initiation compared with 2.8% of patients begun as an outpatient. Patients with chronic kidney disease had higher rates of both hyperkalemia and acute kidney failure in the early (1.3% and 2.7%, respectively) and extended (5.6% and 9.8%, respectively) post-initiation periods compared with those without chronic kidney disease. CONCLUSIONS: Patients initiated on MRA therapy as an outpatient had extremely poor rates of guideline indicated follow-up laboratory monitoring after drug initiation. In particular, patients with chronic kidney disease are at high risk for adverse events after MRA initiation. Quality improvement initiatives focused on systems to improve appropriate laboratory monitoring are needed. PMID- 28073851 TI - Increased Risk of Adverse Neurocognitive Outcomes With Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors. AB - BACKGROUND: There is encouraging evidence of the efficacy of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors; however, their long-term safety remains unclear. We performed a meta-analysis of studies to evaluate the long-term safety of PCSK9 inhibitors. METHODS AND RESULTS: Our search strategy yielded 11 studies (9 smaller early-phase and 2 larger outcome trials). The outcomes assessed were cumulative serious adverse events, musculoskeletal adverse events, neurocognitive adverse events, and stroke. Odds ratio (OR) was calculated using the Mantel-Haenszel method. Subgroup analysis was done to assess the difference in safety between the smaller early-phase studies and the larger outcome studies. Our meta-analysis suggested no difference in the incidence of serious adverse events (OR, 1.00; 95% confidence interval [CI], 0.88-1.15), musculoskeletal adverse events (OR, 1.01; 95% CI, 0.87-1.13), neurocognitive adverse events (OR, 1.29; 95% CI, 0.64-2.59), or stroke (OR, 1.44; 95% CI, 0.57 3.65) with the use of PCSK9 inhibitors. Subgroup analysis of the 2 large outcome studies did suggest an increased incidence of neurocognitive adverse events (OR, 2.85; 95% CI, 1.34-6.06) with the use of PCSK9 inhibitors. However, the overall incidence of neurocognitive adverse events and stroke was <1%, whereas the cumulative incidence of serious adverse events and musculoskeletal events was >10% in both the groups. CONCLUSIONS: Our analysis suggests that PCSK9 inhibitors are not associated with an increased risk of cumulative severe adverse effects, musculoskeletal effects, or stroke. There is a signal toward adverse neurocognitive effects, seen in the outcome studies with a larger sample size and longer follow-up. There should be close monitoring, for the increased risk of neurocognitive events in the ongoing outcome studies and post-marketing surveillance. PMID- 28073852 TI - Heat Maps of Hypertension, Diabetes Mellitus, and Smoking in the Continental United States. AB - BACKGROUND: Geographic variations in cardiovascular mortality are substantial, but descriptions of geographic variations in major cardiovascular risk factors have relied on data aggregated to counties. Herein, we provide the first description of geographic variation in the prevalence of hypertension, diabetes mellitus, and smoking within and across US counties. METHODS AND RESULTS: We conducted a cross-sectional analysis of baseline risk factor measurements and latitude/longitude of participant residence collected from 2003 to 2007 in the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Of the 30 239 participants, all risk factor measurements and location data were available for 28 887 (96%). The mean (+/-SD) age of these participants was 64.8(+/-9.4) years; 41% were black; 55% were female; 59% were hypertensive; 22% were diabetic; and 15% were current smokers. In logistic regression models stratified by race, the median(range) predicted prevalence of the risk factors were as follows: for hypertension, 49% (45%-58%) among whites and 72% (68%-78%) among blacks; for diabetes mellitus, 14% (10%-20%) among whites and 31% (28%-41%) among blacks; and for current smoking, 12% (7%-16%) among whites and 18% (11% 22%) among blacks. Hypertension was most prevalent in the central Southeast among whites, but in the west Southeast among blacks. Diabetes mellitus was most prevalent in the west and central Southeast among whites but in south Florida among blacks. Current smoking was most prevalent in the west Southeast and Midwest among whites and in the north among blacks. CONCLUSIONS: Geographic disparities in prevalent hypertension, diabetes mellitus, and smoking exist within states and within counties in the continental United States, and the patterns differ by race. PMID- 28073853 TI - Resuscitation of prolonged cardiac arrest from massive pulmonary embolism by extracorporeal membrane oxygenation. AB - Extracorporeal cardiopulmonary resuscitation can be used as a rescue strategy in cases of prolonged cardiac arrest caused by massive pulmonary embolism. We present a case of a male patient who was in prolonged cardiac arrest following massive pulmonary embolism. Veno-arterial extracorporeal membrane oxygenation was initiated approximately 93 min after prolonged cardiopulmonary resuscitation. After resuscitation, bedside echocardiography and a chest computed tomography angiogram revealed a massive pulmonary embolism during extracorporeal membrane oxygenation support. The patient received transcatheter mechanical thrombectomy without haemodynamic instability in extracorporeal membrane oxygenation support. He was also treated with therapeutic hypothermia to improve neurological outcome. Renal replacement therapy for acute kidney injury was continued for 36 days. The patient was discharged at 60 days after admission with no serious complications. This case demonstrates that veno-arterial extracorporeal membrane oxygenation and therapeutic hypothermia are an effective treatment strategy for prolonged cardiac arrest caused by massive pulmonary embolism. PMID- 28073854 TI - Reply to De Santo et al. PMID- 28073855 TI - The Politics of Framing Policy Solutions and Whether Policies Address Problems. PMID- 28073857 TI - First Newborn Baby to Receive Experimental Therapies Survives Ebola Virus Disease. AB - A neonate born to an Ebola virus-positive woman was diagnosed with Ebola virus infection on her first day of life. The patient was treated with monoclonal antibodies (ZMapp), a buffy coat transfusion from an Ebola survivor, and the broad-spectrum antiviral GS-5734. On day 20, a venous blood specimen tested negative for Ebola virus by quantitative reverse-transcription polymerase chain reaction. The patient was discharged in good health on day 33 of life. Further follow-up consultations showed age-appropriate weight gain and neurodevelopment at the age of 12 months. This patient is the first neonate documented to have survived congenital infection with Ebola virus. PMID- 28073860 TI - Cardiac dysfunction and cognitive decline. PMID- 28073859 TI - Experimental Therapies for Ebola Virus Disease: What Have We Learned? PMID- 28073858 TI - Boosting Immune Responses Following Fractional-Dose Inactivated Poliovirus Vaccine: A Randomized, Controlled Trial. AB - Background: Fractional-dose administration of inactivated poliovirus vaccine (fIPV) could increase IPV affordability and stretch limited supplies. We assessed immune responses following fIPV administered intradermally, compared with full dose IPV administered intramuscularly, among adults with a history of oral poliovirus vaccine (OPV) receipt. Methods: We conducted a randomized, controlled noninferiority trial in Cuba. fIPV or IPV were administered on days 0 and 28; serum was collected on days 0, 7, 28, and 56 for analysis by a neutralization assay. The primary end point was seroconversion or a >=4-fold rise in antibody titer. The noninferiority limit was 10%. The secondary end point was safety, assessed by the number and intensity of adverse reactions. Results: A total of 503 of 534 enrolled participants (94.2%) completed all study requirements. Twenty eight days after the first dose, 94.8%, 98.0%, and 98.0% of fIPV recipients had an immune response to poliovirus types 1, 2, and 3, respectively, compared with 98.1% (P = .06), 98.0% (P = 1.00), and 99.2% (P = .45) in the IPV arm. Noninferiority was achieved on days 7, 28, and 56 for all serotypes. No serious adverse events were reported. Conclusion: fIPV induced similar boosting immune responses, compared with full-dose IPV. This suggests that fIPV would be an effective strategy to boost population immunity in an outbreak situation. Clinical Trials Registration: ACTRN12615000305527. PMID- 28073861 TI - The quest for a successful cell-based therapeutic approach for heart failure. PMID- 28073862 TI - Transcatheter tricuspid valve repair toward a surgical standard: first-in-man report of direct annuloplasty with a cardioband device to treat severe functional tricuspid regurgitation. PMID- 28073863 TI - Revisiting sex differences in outcomes in non-valvular atrial fibrillation: a population-based cohort study. AB - Aims: In patients with non-valvular atrial fibrillation (NVAF), it is uncertain whether the higher risk of ischaemic stroke in women reported in some studies is due to residual confounding. We assessed this association using standard time fixed and more accurate time-dependent adjustment for confounders. Methods and results: Using the computerized databases of the Regie de l'assurance maladie du Quebec (RAMQ), we identified a cohort of patients with NVAF during 2000-2009 and RAMQ medication coverage. Cox proportional hazards models were used to estimate the hazard ratio (HR) of ischaemic stroke, death, and bleeding, associated with sex, adjusting for time-fixed covariates at cohort entry. This was compared with adjustment for time-dependent covariates using an age and time-matched nested case-control analysis. The cohort included 147 622 patients. During a mean follow up of 2.9 years 11 326 patients had a stroke (incidence rate 2.6 per 100 per year). Using time-fixed adjustment for confounders, women had a moderately higher risk of ischaemic stroke than men (HR 1.16 (Confidence interval (CI) 95% 1.11 1.21). Matching on age and using time-dependent adjustment for confounders, women were not at higher risk of stroke than men (Rate Ratio 1.01; 95% CI 0.97-1.05). Mortality and bleeding rates were lower in women compared with men in both analyses. Conclusion: In NVAF, women were not at higher risk of thromboembolic events than men in our study. The small increased risk reported in previous studies may be related to residual confounding, in particular from insufficient control for age. PMID- 28073864 TI - MitraClip improves mitral valve geometry in complex organic mitral regurgitation: insights from three-dimensional-echocardiography. PMID- 28073865 TI - Angiogenic gene therapy in cardiovascular diseases: dream or vision? AB - Chronic cardiovascular diseases are significant health problems. Although current treatment strategies have tremendously improved disease management, up to 30% of these patients cannot be successfully treated with current treatment approaches and new treatment strategies are clearly needed. Gene therapy and therapeutic vascular growth may provide a new treatment option for these patients. Several growth factors, like vascular endothelial growth factors, fibroblast growth factors and hepatocyte growth factor have been tested in clinical trials. However, apart from demonstration of increased vascularity, very few results with clinical significance have been obtained. Problems with gene transfer efficiency, short duration of transgene expression, selection of endpoints, and suboptimal patients for gene therapy have been recognized. Ongoing gene therapy trials have included improvements in study protocols, vector delivery and endpoints, addressing the identified problems. Better, targeted delivery systems and new, more optimal growth factors have been taken to clinical testing. Recent advances in these areas will be discussed and the concept of angiogenic therapy as a sole treatment is re-evaluated. A combination with regenerative therapies or standard revascularization operations might be needed to improve tissue function and clinical benefits. PMID- 28073866 TI - In simulation modelling, there are multiple ways to effectively screen for colorectal cancer. PMID- 28073867 TI - The Maimed Martian, credible intervals and bias against benefit. AB - A sad little story about a maimed Martian astronaut is used to illustrate a method of improving confidence interval (CI) calculations. CIs in medical statistics are currently calculated from the data available in a clinical trial or meta-analysis considered in isolation from all other information available on earth. Likewise, the Martian in the story uses only information available to it, in isolation from further information from earth. However, there is further objective knowledge available to people on earth to improve the Martian's estimate. In the same way, we have objective prior knowledge available to us outside of the current clinical trial results which we can use to improve CI calculations. This prior knowledge is incorporated into the CI calculations using Bayesian methods. The objective prior knowledge that is available is the fact that there were researchers who felt it worthwhile to conduct the trial and journal editors who felt it worthwhile publishing the results. It is shown here that the use of this information contracts the width of the log CI by a factor of about three quarters on average. Unlike standard CIs, these new intervals also have the advantage of being directly interpretable in terms of probabilities. These probabilities also enable calculation of improved point estimates. These calculations are applied to 100 randomly selected Cochrane systematic reviews and show serious problems in assessing medical treatments. For treatments not involving new drugs or devices, it is shown that there is evidence of a bias towards a negative assessment. The calculations here make a quantitative adjustment for publication bias. They show that the proportion of negative assessments do not reflect an appropriate adjustment for publication bias. PMID- 28073868 TI - Delayed diagnosis of fractured anterior arch of the atlas in a young child. AB - A 2-year-old girl fell off a bunk bed onto a parquet floor. She immediately reported neck pain and presented with muscle spasm and limited motion of the cervical spine (C-spine). Plain X-rays of the C-spine showed no osseous lesion. Owing to persisting pain and limited motion in the neck, MRI of the C-spine was obtained which revealed intact ligaments and cervical spinal cord, as well as soft tissue swelling in front of the anterior arch of the atlas. Subsequent CT of the C-spine confirmed a complete, undisplaced fracture of the anterior arch of the atlas (Gehweiler type I fracture). A Minerva cast was applied for 2 months, followed by a soft cervical collar. Persistent neck pain and limited range of motion of the neck after a fall may be indicative of atlas fracture that should be ruled out by CT. PMID- 28073869 TI - Pancreatic lymphoma complicating early stage chronic hepatitis C. AB - Hepatitis C virus (HCV) infection has also been associated with many extrahepatic manifestations including the development of B-cell non-Hodgkin's lymphoma (NHL). Primary pancreatic lymphoma is very rare and comprises 2.2% of NHL and 4.9% of all pancreatic malignancies. Our patient was a woman with a history of infection with HCV found to have a mass in the head of the pancreas. Biopsy of the mass revealed a high-grade B-cell lymphoma consistent with Burkitt's lymphoma. Our case reflects a need to initiate antiviral therapy for all patients infected with HCV even in early stages of fibrosis to prevent cirrhosis and other extrahepatic manifestations of infection with HCV. PMID- 28073870 TI - Successful treatment of Takayasu arteritis with rituximab as a first-line immunosuppressant. AB - Takayasu arteritis is a rare large vessel vasculitis which has traditionally been treated with high-dose steroids. There have been a small number of publications where biological agents have been used to manage refractory cases. To the authors knowledge, there are no publications using biological agents in combination with steroids as a first-line treatment in Takayasu arteritis. In this publication, we document the case of Takayasu arteritis, in a 39-year-old woman, where rituximab was used in combination with steroids as a first-line agent in the setting of poorly controlled bipolar affective disorder. PMID- 28073871 TI - Benign cystic mediastinal teratoma presenting as a massive pleural effusion in a 17-year-old boy. AB - Mediastinal teratomas are a rare, albeit an important differential diagnosis of anterior/middle mediastinal masses in young adults and various atypical presentations have been reported. The authors report a case of a 17-year-old boy who presented with a 2-month history of worsening shortness of breath and pleuritic chest pain. A massive left-sided pleural fluid collection was seen on a chest radiograph (CXR). The pleural fluid was drained and a CT Thorax confirmed the presence of a cystic mass. Following re-accumulation of the fluid, thoracotomy was performed and a benign mediastinal teratoma excised. The patient remained well with no evidence of recurrence on follow-up CXRs a year post operatively. PMID- 28073872 TI - Gambling disorder: a side effect of an off-label prescription of baclofen literature review. AB - The use of high-dose baclofen emerged in 2008 in the treatment of alcohol-use disorders. Its prescription is still off-label in France, but recent trials have suggested the interest of using high doses for alcohol dependence, so we have to deal with an increase in its use. However, we still have few data about the adverse effects of a high-dose baclofen prescription, especially in complex addictive disorders. We present a case of a 32-year-old man who sought treatment for gambling disorders (GDs). He had complex addictive disorders, including alcohol-use disorders and GDs. He developed a severe GD, after treatment with a high dose of baclofen. The maximum dose was 160 mg/day, prescribed for his alcohol-use disorders. According to the Naranjo algorithm, the score was +7, it enabled to conclude that problem of gambling was probably imputable to baclofen. We discuss this case with reference to literature. PMID- 28073873 TI - Recurrent angioedema associated with pharmacological inhibition of dipeptidyl peptidase IV. AB - Angioedema (AE) of the upper airways is a severe and potentially life-threatening condition. The incidence has been increasing in the past two decades, primarily due to increased use of medications inhibiting the degradation of vasoactive peptides. Acquired angioedema related to angiotensin-converting enzyme inhibitors (ACEI-AAE) is well known, but other pharmaceutical agents also affect the degradation of bradykinin and substance P. We present a middle-aged man with recurrent episodes of severe AE of the oral cavity, hypopharynx and larynx due to pharmacological inhibition of dipeptidyl peptidase IV. PMID- 28073874 TI - Successful pregnancy following treatment of recurrent chronic histiocytic intervillositis. AB - Chronic histiocytic intervillositis (CHI) is a rare placental lesion associated with adverse obstetric outcomes and high recurrence rate. We report a case of six consecutive pregnancies in one woman, where CHI was detected following an intrauterine death in the fifth pregnancy, after being missed in four earlier losses. The successful sixth pregnancy was treated with a combination of immunosuppressive and antithrombotic agents. While low-molecular-weight heparin (LMWH) and aspirin had been shown to improve pregnancy outcome in recurrent pregnancy loss, there was limited evidence of improved outcome in CHI. It has been suggested that CHI may result from a maternal immunological process and there have been a few reports of the use of corticosteroids because of this possibility, though without convincing evidence of efficacy. We too tried a corticosteroid, in combination with LMWH and aspirin. Comparative histopathological analysis of the placentae supported post-treatment effectiveness of our intervention strategy. PMID- 28073875 TI - Unexpected complication after radical (inguinal) orchidectomy: trans-sphincteric anoscrotal fistula. AB - Anoscrotal fistula is an extremely rare condition involving an epithelialised tract between the anal canal and scrotal wall. It is more commonly seen as a congenital phenomenon in the paediatric population, and has not previously been described in the literature in adults. We present the case of a man aged 52 years who developed a complex anoscrotal fistula after a radical inguinal orchidectomy for an intratesticular seminoma. A postsurgical wound-site infection developed into a chronically discharging wound refractory to antibiotic treatment prompting further investigation. By way of MRI, a 10 cm long trans-sphincteric anoscrotal fistula was found. The patient was successfully treated by fistuloscopic curettage, internal closure using an Ovesco clip, and negative pressure dressing. We present for the first time a rare anoscrotal fistula in an adult. PMID- 28073876 TI - Radial artery pseudoaneurysm: rare complication of a frequent procedure. PMID- 28073877 TI - Pacemaker pocket infection due to Mycobacterium goodii, a rapidly growing mycobacteria. AB - A woman aged 74 years with an implanted dual-chamber pacemaker presented with pacemaker site infection after failing empiric antimicrobial therapy. The pathogen was later identified as Mycobacterium goodii, a rapidly growing mycobacteria species. The pacemaker was subsequently removed and the patient was treated with oral ciprofloxacin and doxycycline with clinical improvement. In this article, we describe a rare case of pacemaker site infection by M. goodii. PMID- 28073878 TI - Foamy gland variant of adenocarcinoma of prostate: a rare pathological variant. PMID- 28073879 TI - Superficial temporal artery haemorrhage caused by neurophysiological monitoring: a unique MRI finding. PMID- 28073880 TI - Healing of pathological fracture in a case of multiple myeloma. PMID- 28073881 TI - Combined central retinal artery and vein occlusion in lupus. PMID- 28073882 TI - The role of superior vena cava in catheter ablation of long-standing persistent atrial fibrillation. AB - Aims: The superior vena cava (SVC) has been established as an important source of atrial fibrillation (AF). The role of SVC in long-standing persistent AF and the efficacy of empiric electrical isolation of the SVC are still unclear. The purpose of this study was to judge the role of SVC in catheter ablation of long standing persistent AF. Methods and results: A total of 102 consecutive patients with long-standing persistent AF were enrolled. All patients underwent circumferential pulmonary vein isolation, complex fractionated atrial electrograms ablation, and linear ablation during the index procedure. Superior vena cava-triggered AF and an SVC associated with the maintenance of AF were evaluated by mapping catheters during the procedure. The arrhythmogenicity of the SVC was confirmed in only 1 of the patients (0.98%). At the end of 12 months follow-up, the arrhythmia-free survival rate after a single procedure was 43.1%. After the last procedure (mean 1.47 +/- 0.58 procedures), sinus rhythm was maintained in 71 (69.6%) patients, 63 of whom without antiarrhythmic drugs. The patients in AF recurrence group had higher rates of right atrium enlargement (71 vs. 34%, P = 0.03), >=2 procedures (65 vs. 34%, P < 0.05), longer AF duration (84 +/- 46 vs. 45 +/- 34 months, P < 0.05), and larger left atrium diameter (50 +/- 5 vs. 45 +/- 6 mm, P < 0.05). In the multivariate analysis, left atrium diameter and AF duration were independent predictors of AF recurrence. Conclusion: The arrhythmogenic SVC is rarely detected in patients with long-standing persistent AF. Empiric SVC electrical isolation in the stepwise approach of long-standing persistent AF seems unnecessary. PMID- 28073883 TI - Infective endocarditis and risk of death after cardiac implantable electronic device implantation: a nationwide cohort study. AB - Aims: To determine the incidence, risk factors, and mortality of infective endocarditis (IE) following implantation of a first-time, permanent, cardiac implantable electronic device (CIED). Methods and results : From Danish nationwide administrative registers (beginning in 1996), we identified all de novo permanent pacemakers (PMs) and implantable cardioverter defibrillators (ICDs) together with the occurrence of post-implantation IE-events in the period from 2000-2012. Included were 43 048 first-time PM/ICD recipients. Total follow up time was 168 343 person-years (PYs). The incidence rate (per 1000 PYs) of IE in PM was 2.1 (95% confidence interval [CI]: 1.7-2.6) for single chamber devices and 6.2 (95% CI: 4.5-8.7) for cardiac resynchronization therapy (CRT); similarly, the rate of IE in ICD was 3.7 (95% CI: 2.9-4.7) in single chamber devices and 6.3 (95% CI: 4.4-9.0) in CRT. In multivariable analysis, increased PM complexity served as independent risk factor for IE {dual chamber PM [hazard ratio (HR) 1.39; 95% CI: 1.07-1.80] and CRT [HR: 1.84; 95% CI: 1.20-2.84]}. During follow up, generator replacement (HR: 2.79; 95% CI: 1.87-4.17) and lead revision (HR: 4.33; 95% CI: 3.25-5.78) in PMs were associated with increased risk. Corresponding estimates in ICDs were 2.49 (95% CI: 1.28-4.86) and 6.58 (95% CI: 4.49-9.63). Risk of death after IE was significantly increased in PM and ICD with HRs of 1.56 (95% CI: 1.33-1.82) and 2.63 (95% CI: 2.00-3.48), respectively. Conclusion: The risk of IE increased with increasing PM complexity. Other important risk factors were subsequent generator replacement and lead revision. IE was associated with an increased risk of mortality in the area of CIED. PMID- 28073884 TI - Pacemaker-detected severe sleep apnea predicts new-onset atrial fibrillation. AB - Aims: Sleep apnea (SA) diagnosed on overnight polysomnography is a risk factor for atrial fibrillation (AF). Advanced pacemakers are now able to monitor intrathoracic impedance for automatic detection of SA events. Methods and results: We enrolled 160 consecutive recipients of a dual-chamber pacemaker endowed with the ApneaScan algorithm (Boston Scientific). If the pacemaker measured Respiratory Disturbance Index was >=30 episodes per hour for at least one night during the first week after implantation, SA was defined as severe. Patients were considered to have experienced AF episodes if the device detected a cumulative AF burden >=6 h in a day. Sixteen patients in AF at the time of implantation were excluded from our analysis. During follow-up, AF burden >=6 h/day was documented in 35 (24%) of the patients included in the analysis and in 12 (13%) of the 96 patients with no history of AF. Severe SA was detected in 89 patients during the first week after implantation; 58 of these had no history of AF. Severe SA at the baseline was associated with a higher risk of AF both in the whole population (log-rank test, hazard ratio: 2.38; 95% CI: 1.21-4.66; P = 0.025) and among patients with no previous history of AF (log-rank test, hazard ratio: 2.80; 95% CI: 1.10-7.10; P = 0.047). Moreover, severe SA at the time of follow-up device interrogation predicted AF occurrence within the next 3 months (log-rank test, hazard ration: 2.13; 95% CI: 1.11-4.08; P = 0.036). Conclusions: In pacemaker patients, device-diagnosed severe SA was independently associated with a higher risk of AF (>=6 h/day) and new-onset AF. In particular, severe SA on follow-up data review identified patients who were ~2-fold more likely to experience an AF episode in the next 3 months. PMID- 28073885 TI - Reduction of atrial fibrillation burden by pulmonary vein isolation leads to a decrease of CD11b expression on inflammatory cells. AB - Aims: It is hypothesized that inflammation could promote structural and electrical remodelling processes in atrial fibrillation (AF). Atrial infiltration of monocytes and granulocytes has been shown to be dependent on CD11b expression. The aim of this study was to investigate whether treatment of AF by pulmonary vein isolation (PVI) may lead to reduced inflammation, as indicated by a decrease of CD11b expression on monocytes and granulocytes. Methods and results: Flow cytometric quantification analysis and determination of systemic inflammatory markers of peripheral blood were performed in 75 patients undergoing PVI 1 day before and 6 months after PVI. The extent of activation of monocytes and granulocytes was measured by quantifying the cell adhesion molecule CD11b. The mean expression of CD11b on monocytes (20.9 +/- 2.5 vs. 10.2 +/- 1.4; P < 0.001) and granulocytes (13.9 +/- 1.6 vs. 6.8 +/- 0.5; P < 0.001), as well as the relative count of CD11b-positive monocytes (P < 0.05) and CD11b-positive granulocytes (P < 0.01) were significantly reduced when comparing the identical patients before and 6 months after PVI. Systemic inflammatory parameters showed only a declining tendency after 6 months. Patients with unsuccessful PVI and ongoing AF on the day of follow-up showed no decrease in CD11b expression. Conclusions: A significant reduction of CD11b expression on monocytes and granulocytes, as a sign of reduced cellular inflammation, was achieved by treatment of AF using PVI. These data strongly support that AF is not only a consequence of but also a cause for inflammatory processes, which, in turn, may contribute to atrial remodelling. PMID- 28073886 TI - Endocardial left ventricular pacing for cardiac resynchronization: systematic review and meta-analysis. AB - Aims: Endocardial left ventricular (LV) pacing for Cardiac Resynchronization Therapy has been proposed as an alternative to conventional LV lead placement via the coronary sinus. In order to assess the relative benefits and risks of this technique, we have performed a meta-analysis of published reports. Methods and results: A systemic search was performed using online databases to identify studies of lead-based endocardial pacing. A random-effects meta-analysis was performed, to assess the rate of complications and clinical response (defined as >=1 decrease in NYHA class). We selected 23 studies, including 384 patients. The trans-atrial septal technique was used in 20 studies, 1 used the trans ventricular apical technique, and 2 used the trans-ventricular septal technique. Mean age was 66 years, male 66%, EF 26%, NYHA class 3.0. Procedural success rates were over 95% in all studies. Clinical response was reported by 16 studies for 262 patients, giving a response estimate of 82% (95% CI 71-89%). There was significant heterogeneity, and response in the only large study was 59%. Thromboembolic (TE) complications were reported by all studies, over 22 +/-32 months follow up. The rate of stroke was 2.5 events per 100 patient years (95% CI 1.5-4.3), and TIA 2.6 (1.1-6.1). The mortality rate was 4.5 (1.5-13.6) per 100 patient years. Conclusion: LV endocardial pacing appears to be a viable technique when conventional lead placement is not possible. Response rates were heterogeneous but comparable with conventional CRT. There is likely to be a small increase over expected rates of stroke, although included patients were high risk. PMID- 28073887 TI - Perioperative predictors of permanent pacing and long-term dependence following tricuspid valve surgery: a multicentre analysis. AB - Aims: Permanent pacemaker placement (PPM) is often required after valvular surgery and is especially common following tricuspid valve surgery [tricuspid valve repair or replacement (TVR)]. Literature suggests that surgical intervention for isolated tricuspid valve disease is becoming more prevalent. Predictors of PPM dependency following TVR are currently unknown and would be clinically useful from a prognostication standpoint. Methods and results: We conducted a multicentre, retrospective study to assess perioperative factors of TVR that predispose to PPM placement and long-term PPM dependency from 2008 to 2014. Regression analysis was used to determine independent predictors of PPM implantation. A total of 237 patients (age 66 +/- 15 years, 29% male) were studied, and the incidence of PPM placement following TVR was 27% (65/237). No significant differences were observed between those who received PPM and those who did not in age (P = 0.092), gender (P = 0.359), and co-morbidities. Regression analysis identified cross-clamp time >60 min (OR 4.1, 95% CI 1.3-12.9, P = 0.015) and concomitant mitral valve surgery (OR 3.8, 95% CI 1.2-12.2, P = 0.026) as independent risk factors for PPM following TVR. Long-term PPM dependency data were only available in 28 patients who received PPM with 14 of these patients developing long-term dependence. The only statistically significant difference noted was an increased frequency of coronary artery disease in the long-term dependent group vs. the non-dependent group (64% vs. 14%, P = 0.018). Conclusion: Cross-clamp time >60 min and concomitant mitral valve surgery were independent predictors of PPM implantation following TVR. Long term PPM dependency is more prevalent after TVR than other types of valvular surgery. PMID- 28073888 TI - Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal. AB - BACKGROUND/AIMS: We studied the role of lysyl oxidase-like 2 (LOXL2) in collagen crosslinking and hepatic progenitor cell (HPC) differentiation, and the therapeutic efficacy of a LOXL2-blocking monoclonal antibody on liver fibrosis progression/reversal in mice. METHODS: Anti-LOXL2 antibody, control antilysyl oxidase antibody or placebo was administered during thioacetamide (TAA)-induced fibrosis progression or during recovery. Therapeutic efficacy in biliary fibrosis was tested in BALB/c.Mdr2-/- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) fed mice. Collagen crosslinking, fibrosis progression and reversal were assessed histologically and biochemically. HPC differentiation was studied in primary EpCAM(+) liver cells in vitro. RESULTS: LOXL2 was virtually absent from healthy but strongly induced in fibrotic liver, with predominant localisation within fibrotic septa. Delayed anti-LOXL2 treatment of active TAA fibrosis significantly reduced collagen crosslinking and histological signs of bridging fibrosis, with a 53% reduction in morphometric collagen deposition. In established TAA fibrosis, LOXL2 inhibition promoted fibrosis reversal, with enhanced splitting and thinning of fibrotic septa, and a 45% decrease in collagen area at 4 weeks of recovery. In the Mdr2-/- and DDC-induced models of biliary fibrosis, anti-LOXL2 antibody similarly achieved significant antifibrotic efficacy and suppressed the ductular reaction, while hepatocyte replication increased. Blocking LOXL2 had a profound direct effect on primary EpCAM(+) HPC behaviour in vitro, promoting their differentiation towards hepatocytes, while inhibiting ductal cell lineage commitment. CONCLUSIONS: LOXL2 mediates collagen crosslinking and fibrotic matrix stabilisation during liver fibrosis, and independently promotes fibrogenic HPC differentiation. By blocking these two convergent profibrotic pathways, therapeutic LOXL2 inhibition attenuates both parenchymal and biliary fibrosis and promotes fibrosis reversal. PMID- 28073889 TI - Toward chronic hepatitis C eradication in HIV-positive patients, including those cirrhotic and infected with genotype 3 viruses. PMID- 28073891 TI - Vedolizumab safety in pregnancy and newborn outcomes. PMID- 28073890 TI - Pancreatic cancer cell lines as patient-derived avatars: genetic characterisation and functional utility. AB - OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a therapy recalcitrant disease with the worst survival rate of common solid tumours. Preclinical models that accurately reflect the genetic and biological diversity of PDAC will be important for delineating features of tumour biology and therapeutic vulnerabilities. DESIGN: 27 primary PDAC tumours were employed for genetic analysis and development of tumour models. Tumour tissue was used for derivation of xenografts and cell lines. Exome sequencing was performed on the originating tumour and developed models. RNA sequencing, histological and functional analyses were employed to determine the relationship of the patient-derived models to clinical presentation of PDAC. RESULTS: The cohort employed captured the genetic diversity of PDAC. From most cases, both cell lines and xenograft models were developed. Exome sequencing confirmed preservation of the primary tumour mutations in developed cell lines, which remained stable with extended passaging. The level of genetic conservation in the cell lines was comparable to that observed with patient-derived xenograft (PDX) models. Unlike historically established PDAC cancer cell lines, patient-derived models recapitulated the histological architecture of the primary tumour and exhibited metastatic spread similar to that observed clinically. Detailed genetic analyses of tumours and derived models revealed features of ex vivo evolution and the clonal architecture of PDAC. Functional analysis was used to elucidate therapeutic vulnerabilities of relevance to treatment of PDAC. CONCLUSIONS: These data illustrate that with the appropriate methods it is possible to develop cell lines that maintain genetic features of PDAC. Such models serve as important substrates for analysing the significance of genetic variants and create a unique biorepository of annotated cell lines and xenografts that were established simultaneously from same primary tumour. These models can be used to infer genetic and empirically determined therapeutic sensitivities that would be germane to the patient. PMID- 28073892 TI - Socioeconomic and ethnic inequities within organised colorectal cancer screening programmes worldwide. AB - OBJECTIVE: Colorectal cancer (CRC) screening programmes can reduce CRC mortality. However, the implementation of a screening programme may create or exacerbate socioeconomic and ethnic health inequities if participation varies by subgroup. We determined which organised programmes characterise participation inequities by socioeconomic and ethnic subgroups, and assessed the variation in subgroup participation among programmes collecting group-specific data. DESIGN: Employing a literature review and survey among leaders of national or regional screening programmes, this study identified published and unpublished data on participation by socioeconomic status and ethnicity. We assessed programmes offering faecal occult blood tests (FOBT) for screening. Primary outcome was screening participation rate. RESULTS: Across 24 organised FOBT-screening programmes meeting the inclusion criteria, participation rates ranged from 21% to 73%. Most programmes (13/24, 54%) did not collect data on participation by socioeconomic status and ethnicity. Among the 11 programmes with data on participation by socioeconomic status, 90% (28/31 publications) reported lower participation among lower socioeconomic groups. Differences across socioeconomic gradients were moderate (66% vs 71%) to severe (35% vs 61%). Only six programmes reported participation results by ethnicity. Ethnic differences were moderate, though only limited data were available for evaluation. CONCLUSIONS: Across organised CRC screening programmes worldwide, variation in participation by socioeconomic status and ethnicity is often not assessed. However, when measured, marked disparities in participation by socioeconomic status have been observed. Limited data were available to assess inequities by ethnicity. To avoid exacerbating health inequities, screening programmes should systematically monitor participation by socioeconomic status and ethnicity, and investigate and address determinants of low participation. PMID- 28073893 TI - The caecal mucus sign. PMID- 28073894 TI - Patient Consent and the Commercialization of Lab Data. PMID- 28073895 TI - Evaluation of Genotypic and Phenotypic Methods to Detect Carbapenemase Production in Gram-Negative Bacilli. AB - BACKGROUND: Carbapenemase-producing gram-negative bacteria (CP-GNB) are an urgent and expanding public health threat. Rapid and accurate identification of these organisms facilitates infection prevention efforts in healthcare facilities. The objective of our study was to evaluate methods to detect and identify CP-GNB. METHODS: We examined 189 carbapenem-resistant GNB(CR-GNB), including Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii complex, using 3 different methods: 2 methods to screen isolates of GNB for carbapenemase production [the carbapenem inactivation method (CIM) and 2 chromogenic agars] and a molecular method (Cepheid GeneXpert Carba-R) to identify the mechanism of carbapenem resistance and the associated resistance genes (blaKPC, blaNDM, blaIMP, blaOXA-48-like, and blaVIM). RESULTS: The CIM was a simple and inexpensive phenotypic screen to differentiate between CR-GNB and CP-GNB, with improved analytical performance characteristics and inter-reader correlation compared to the modified Hodge test. Both chromogenic agars evaluated (HardyCHROM CRE and chromID CARBA) were able to support growth of most of the organisms tested, including isolates possessing the blaOXA-48-like gene. However, these media had a low analytical specificity for carbapenemase production, with breakthrough of CR-GNB that did not produce a carbapenemase. The Xpert Carba-R assay was rapid and easy to perform, and demonstrated 100% positive and negative agreement for characterization of genetic determinants of carbapenem resistance. CONCLUSIONS: Screening by CIM followed by the Xpert Carba-R PCR is an accurate method for detecting and characterizing CP-GNB, including Enterobacteriaceae, P. aeruginosa, and A. baumannii complex. PMID- 28073896 TI - Patient-Specific Circulating Tumor DNA Detection during Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer. AB - BACKGROUND: In nonmetastatic triple-negative breast cancer (TNBC) patients, we investigated whether circulating tumor DNA (ctDNA) detection can reflect the tumor response to neoadjuvant chemotherapy (NCT) and detect minimal residual disease after surgery. METHODS: Ten milliliters of plasma were collected at 4 time points: before NCT; after 1 cycle; before surgery; after surgery. Customized droplet digital PCR (ddPCR) assays were used to track tumor protein p53 (TP53) mutations previously characterized in tumor tissue by massively parallel sequencing (MPS). RESULTS: Forty-six patients with nonmetastatic TNBC were enrolled. TP53 mutations were identified in 40 of them. Customized ddPCR probes were validated for 38 patients, with excellent correlation with MPS (r = 0.99), specificity (>=2 droplets/assay), and sensitivity (at least 0.1%). At baseline, ctDNA was detected in 27/36 patients (75%). Its detection was associated with mitotic index (P = 0.003), tumor grade (P = 0.003), and stage (P = 0.03). During treatment, we observed a drop of ctDNA levels in all patients but 1. No patient had detectable ctDNA after surgery. The patient with rising ctDNA levels experienced tumor progression during NCT. Pathological complete response (16/38 patients) was not correlated with ctDNA detection at any time point. ctDNA positivity after 1 cycle of NCT was correlated with shorter disease-free (P < 0.001) and overall (P = 0.006) survival. CONCLUSIONS: Customized ctDNA detection by ddPCR achieved a 75% detection rate at baseline. During NCT, ctDNA levels decreased quickly and minimal residual disease was not detected after surgery. However, a slow decrease of ctDNA level during NCT was strongly associated with shorter survival. PMID- 28073897 TI - Identification of ALK, ROS1, and RET Fusions by a Multiplexed mRNA-Based Assay in Formalin-Fixed, Paraffin-Embedded Samples from Advanced Non-Small-Cell Lung Cancer Patients. AB - BACKGROUND: Anaplastic lymphoma receptor tyrosine kinase (ALK), ROS proto oncogene 1, receptor tyrosine kinase (ROS1), and ret proto-oncogene (RET) fusions are present in 5%-7% of patients with advanced non-small-cell lung cancer (NSCLC); their accurate identification is critical to guide targeted therapies. FISH and immunohistochemistry (IHC) are considered the gold standards to determine gene fusions, but they have limitations. The nCounter platform is a potentially useful genomic tool for multiplexed detection of gene fusions, but has not been validated in the clinical setting. METHODS: Formalin-fixed, paraffin embedded (FFPE) samples from 108 patients with advanced NSCLC were analyzed with an nCounter-based assay and the results compared with FISH, IHC, and reverse transcription PCR (RT-PCR). Data on response to fusion kinase inhibitors was retrospectively collected in a subset of 29 patients. RESULTS: Of 108 FFPE samples, 98 were successfully analyzed by nCounter (91%), which identified 55 fusion-positive cases (32 ALK, 21 ROS1, and 2 RET). nCounter results were highly concordant with IHC for ALK (98.5%, CI = 91.8-99.7), while 11 discrepancies were found compared with FISH (87.5% concordance, CI = 79.0-92.9). For ROS1, nCounter showed similar agreement with IHC and FISH (87.2% and 85.9%), but a substantial number of samples were positive only by 1 or 2 techniques. Of the 25 patients deriving clinical benefit from fusion kinase inhibitors, 24 were positive by nCounter and 22 by FISH. CONCLUSIONS: nCounter compares favorably with IHC and FISH and can be used for identifying patients with advanced NSCLC positive for ALK/ROS1/RET fusion genes. PMID- 28073899 TI - Paper-Based MicroRNA Expression Profiling from Plasma and Circulating Tumor Cells. AB - BACKGROUND: Molecular characterization of circulating tumor cells (CTCs) holds great promise for monitoring metastatic progression and characterizing metastatic disease. However, leukocyte and red blood cell contamination of routinely isolated CTCs makes CTC-specific molecular characterization extremely challenging. METHODS: Here we report the use of a paper-based medium for efficient extraction of microRNAs (miRNAs) from limited amounts of biological samples such as rare CTCs harvested from cancer patient blood. Specifically, we devised a workflow involving the use of Flinders Technology Associates (FTA)(r) Elute Card with a digital PCR-inspired "partitioning" method to extract and purify miRNAs from plasma and CTCs. RESULTS: We demonstrated the sensitivity of this method to detect miRNA expression from as few as 3 cancer cells spiked into human blood. Using this method, background miRNA expression was excluded from contaminating blood cells, and CTC-specific miRNA expression profiles were derived from breast and colorectal cancer patients. Plasma separated out during purification of CTCs could likewise be processed using the same paper-based method for miRNA detection, thereby maximizing the amount of patient-specific information that can be derived from a single blood draw. CONCLUSIONS: Overall, this paper-based extraction method enables an efficient, cost-effective workflow for maximized recovery of small RNAs from limited biological samples for downstream molecular analyses. PMID- 28073898 TI - Two-Stage Isothermal Enzymatic Amplification for Concurrent Multiplex Molecular Detection. AB - BACKGROUND: The wide array of pathogens responsible for infectious diseases makes it difficult to identify causative pathogens with single-plex tests. Although multiplex PCR detects multiple targets, it is restricted to centralized laboratories, which delays test results or makes multiplexing unavailable, depriving healthcare providers of critical, real-time information. METHODS: To address the need for point-of-care (POC) highly multiplexed tests, we propose the 2-stage, nested-like, rapid (<40 min) isothermal amplification assay, dubbed rapid amplification (RAMP). RAMP's first-stage uses outer loop-mediated isothermal amplification (LAMP) primers to amplify all targets with recombinase polymerase amplification (RPA). First-stage amplicons are aliquoted to second stage reactors, each specialized for a specific target, to undergo LAMP. The assay is implemented in a microfluidic chip. LAMP amplicons are detected in situ with colorimetric dye or with a fluorescent dye and a smartphone. RESULTS: In experiments on a benchtop and in a microfluidic format, RAMP demonstrated high level of multiplexing (>=16); high sensitivity (i.e., 1 plaque-forming unit of Zika virus) and specificity (no false positives or negatives); speed (<40 min); ease of use; and ability to cope with minimally processed samples. CONCLUSIONS: RAMP is a hybrid, 2-stage, rapid, and highly sensitive and specific assay with extensive multiplexing capabilities, combining the advantages of RPA and LAMP, while circumventing their respective shortcomings. RAMP can be used in the lab, but one of its distinct advantages is amenability to simple implementation in a microfluidic format for use at the POC, providing healthcare personnel with an inexpensive, highly sensitive tool to detect multiple pathogens in a single sample, on site. PMID- 28073900 TI - The Longer, the Better? An Empirical Study of the Extent and Mechanisms of Attenuating Biomarker Associations in Cardiovascular Patient Cohorts. AB - BACKGROUND: Identifying novel risk markers in cardiovascular patients remains a research priority. Longer follow-up generally is considered favorable in such studies, but associations of interest may become attenuated with increasing follow-up. This issue has not been adequately addressed in the context of patient cohorts. The current study analyzed the extent and mechanisms of attenuating associations in a cardiovascular patient cohort. METHODS: The associations of numerous biomarkers with all-cause mortality were estimated by multiple Cox regression in the Langzeiterfolge der KARdiOLogischen Anschlussheilbehandlung (KAROLA) prospective cohort study of 1204 patients who had participated in an inpatient rehabilitation program after an acute coronary syndrome (ACS) or coronary bypass operation. Hazard ratios were estimated based on the entire follow-up period (13 years), and after truncation at previous follow-up times (3, 4.5, 6, 8, 10 years). RESULTS: For the majority of markers, a clear and sometimes very pronounced attenuation of the hazard ratios could be observed with increasing follow-up duration. Differential attrition generally was not a sufficient explanation for this phenomenon, whereas further analyses suggested a role for reverse causality for some of the markers. Power analyses showed that the relationship of follow-up duration and statistical power can be counterintuitive in the presence of realistic amounts of attenuation. CONCLUSIONS: The attenuation of estimates of association in patient cohorts is a much more substantial and complex issue than currently appreciated. This has important implications for the design and interpretation of prognostic, as well as etiologic, studies which may be particularly relevant in the case of patient cohorts defined by an initial acute event. PMID- 28073901 TI - Cardiac Troponin T: Smaller Molecules in Patients with End-Stage Renal Disease than after Onset of Acute Myocardial Infarction. AB - BACKGROUND: We have found previously that in acute myocardial infarction (AMI), cardiac troponin T (cTnT) is degraded in a time-dependent pattern. We investigated whether cTnT forms differed in patients with chronic cTnT increases, as seen with renal dysfunction, from those in the acute phase of myocardial infarction. METHODS: We separated cTnT forms by gel filtration chromatography (GFC) in end-stage renal disease (ESRD) patients: prehemodialysis (pre-HD) and post-HD (n = 10) and 2 months follow-up (n = 6). Purified (cTnT) standards, quality control materials of the clinical cTnT immunoassay (Roche), and AMI patients' sera also were analyzed. Immunoprecipitation and Western blotting were performed with the original cTnT antibodies from the clinical assay and antibodies against the N- and C-terminal end of cTnT. RESULTS: GFC analysis revealed the retention of purified cTnT at 27.5 mL, identical to that for cTnT in quality controls. For all ESRD patients, one cTnT peak was found at 45 mL, pre- and post-HD, and stable over time. Western blotting illustrated that this peak corresponded to cTnT fragments <18 kDa missing the N- and C-terminal ends. AMI patients' sera revealed cTnT peaks at 27.5 and 45 mL, respectively, corresponding to N-terminal truncated cTnT of 29 kDa and N- and C-terminal truncated fragments of <18 kDa, respectively. CONCLUSIONS: We found that cTnT forms in ESRD patients are small (<18 kDa) and different from forms seen in AMI patients. These insights may prove useful for development of a more specific cTnT immunoassay, especially for the acute and diagnostic phase of myocardial infarction. PMID- 28073902 TI - State of Harmonization of 24 Serum Albumin Measurement Procedures and Implications for Medical Decisions. AB - BACKGROUND: Measurements of serum and plasma albumin are widely used in medicine, including as indicators of quality of patient care in renal dialysis centers. METHODS: Pools were prepared from residual patient serum (n = 50) and heparin plasma (n = 48) from patients without renal disease, and serum from patients with kidney failure before hemodialysis (n = 53). Albumin was measured in all samples and in ERM-DA470k/IFCC reference material (RM) by 3 immunochemical, 9 bromcresol green (BCG), and 12 bromcresol purple (BCP) methods. RESULTS: Two of 3 immunochemical procedures, 5 of 9 BCG, and 10 of 12 BCP methods recovered the RM value within its uncertainty. One immunochemical and 3 BCG methods were biased vs the RM value. Random error components were small for all measurement procedures. The Tina-quant immunochemical method was chosen as the reference measurement procedure based on recovery and results of error analyses. Mean biases for BCG vs Tina-quant were 1.5% to 13.9% and were larger at lower albumin concentrations. BCP methods' mean biases were -5.4% to 1.2% irrespective of albumin concentration. Biases for plasma samples were generally higher than for serum samples for all method types. For most measurement procedures, biases were lower for serum from patients on hemodialysis vs patients without kidney disease. CONCLUSIONS: Significant differences among immunochemical, BCG, and BCP methods compromise interpretation of serum albumin results. Guidelines and calculations for clinical management of kidney and other diseases must consider the method used for albumin measurement until harmonization can be achieved. PMID- 28073903 TI - Assessing patient safety culture in Tunisian operating rooms: A multicenter study. AB - Objective: To assess the patient safety culture (PSC) in operating rooms (ORs) and to determine influencing factors. Design: A cross-sectional descriptive multicenter study which was conducted over a period of 7 months (October 2014 April 2015) using the French validated version of the Hospital Survey On Patient Safety Culture questionnaire. Setting: Of the note, 15 ORs of public and private healthcare institutions. Participants: In total, there were 368 participants including surgeons, anesthesiologists, surgical and anesthesia technicians, nurses and caregivers, divided into 316 professionals exercising in public sector and 52 working in private one. Main Outcome Measure(s): A self-administrated questionnaire investigating 10 dimensions of PSC (including 45 items), two items examining the staff perception of patient safety quality and reporting events, and five items regarding demographic characteristics of respondents. Results: The participation rate in the study was 70.8%. All 10 dimensions were to be improved. The overall perception of patient safety had a score of 34.9%. The dimension that had the lowest score (20.5%) was the non-punitive response to error, and the one that had the highest score (41.67%) was teamwork in the ORs. Three dimensions were developed in private sector, and none in public hospitals. Conclusion: This study showed that the level of the PSC needs to be improved not only in public hospitals but also in private ones. The obtained results highlight the importance of implementing quality management systems and developing PSC. PMID- 28073904 TI - Comparability of health service use by veterans with multisymptom illness and those with chronic diseases. AB - Objective: To compare health service utilization and disability claims among military personnel with multisymptom illness (MSI) (but no chronic diseases), those with chronic disease(s) and those without MSI or chronic diseases. MSI is also known as Gulf War illness. Design: Cohort study. Setting: Australia. Participants: In total, 1288 participants of a Gulf War veterans' study conducted in 2000-2003 (Wave-1) were followed up in 2011-2012 (Wave-2), aged on average 40 years. About 160 had MSI, 217 had chronic disease(s) and 911 had neither chronic disease(s) nor MSI. Methods: At Wave-2, the cohort was linked to the national Medicare and Department of Veterans' Affairs (DVA) databases to obtain health service utilization and disability claims data recorded between 2001 and 2012. Results: The likelihood of visiting a general practitioner (GP) (risk ratio [RR] = 1.04, 95% confidence interval [CI] = 0.92, 1.19) or visiting a specialist medical doctor (RR = 0.83; 95% CI = 0.54, 1.28) or hospitalizations (RR = 0.89; 95% CI = 0.61, 1.29) or) in the 12 months preceding Wave-2 or successfully claiming for DVA disability compensation (RR = 1.13; 95% CI = 0.86, 1.47) was similar for personnel with MSI and those with chronic disease(s). However, GP consultations, hospitalizations, specialist doctor consultations and disability claims were significantly higher among those with MSI than those without MSI/chronic diseases. Conclusions: Health service use and disability claims by personnel with MSI were comparable to those with chronic disease(s), but were in excess of those without MSI/chronic diseases. Hence recognition of the high health service use by personnel with MSI is important to ensure adequate provision of health services. PMID- 28073905 TI - Feeding by Melanaphis sacchari (Hemiptera: Aphididae) Facilitates Use of Sorghum by Rhopalosiphum padi (Hemiptera: Aphididae), but Reciprocal Effects Are Negative. AB - In the process of feeding, aphids modify the physiology of their host plants in species-specific ways, and plant responses to these aggressions are often genotype- or cultivar-specific. Thus, different aphid species sharing a host can influence each other's fitness via plant-mediated interactions, usually with negative and asymmetric impacts. Here, we show that feeding by the sugarcane aphid, Melanaphis sacchari Zehntner, can improve the suitability of sorghum as a host plant for the bird cherry-oat aphid, Rhopalosiphum padi L. Whereas the reciprocal effects were generally negative for sugarcane aphid, the specific life history impacts varied with sorghum cultivar. Line 'PI 550610' was a more suitable host plant for both aphid species than the hybrid 'P8500', contrary to expectations based on the former representing a source of resistance to Schizaphis graminum (Rondani). Whereas coinfestation with sugarcane aphid had positive effects on bird cherry-oat aphid survival, development, and reproduction on both cultivars, the presence of bird cherry-oat aphid reduced the sugarcane aphid fecundity on both cultivars, although other negative effects (lower survival and delayed development) were evident only on the less suitable P8500. A second experiment using previously infested plants yielded similar results, although a gradual decay of aphid-induced effects postinfestation was apparent. Bird cherry-oat aphid is the second aphid species, after S. graminum, shown to benefit from sugarcane aphid facilitation on sorghum. We conclude that facilitation by sugarcane aphid at least partly accounts for the various aphid species forming mixed infestations with this invasive species in fields of susceptible sorghum cultivars. PMID- 28073906 TI - MRI follow-up is unnecessary in patients with macroprolactinomas and long-term normal prolactin levels on dopamine agonist treatment. AB - OBJECTIVE: Both antitumor and antisecretory efficacies of dopamine agonists (DA) make them the first-line treatment of macroprolactinomas. However, there is no guideline for MRI follow-up once prolactin is controlled. The aim of our study was to determine whether a regular MRI follow-up was necessary in patients with long-term normal prolactin levels under DA. PATIENTS AND METHODS: We conducted a retrospective multicenter study (Marseille, Paris La Pitie Salpetriere and Nancy, France; Liege, Belgium) including patients with macroprolactinomas (largest diameter: >10 mm and baseline prolactin level: >100 ng/mL) treated by dopamine agonists, and regularly followed (pituitary MRI and prolactin levels) during at least 48 months once normal prolactin level was obtained. RESULTS: In total, 115 patients were included (63 men and 52 women; mean age at diagnosis: 36.3 years). Mean baseline prolactin level was 2224 +/- 6839 ng/mL. No significant increase of tumor volume was observed during the follow-up. Of the 21 patients (18%) who presented asymptomatic hemorrhagic changes of the macroprolactinoma on MRI, 2 had a tumor increase (2 and 7 mm in the largest size). Both were treated by cabergoline (1 mg/week) with normal prolactin levels obtained for 6 and 24 months. For both patients, no further growth was observed on MRI during follow-up at the same dose of cabergoline. CONCLUSION: No significant increase of tumor size was observed in our patients with controlled prolactin levels on DA. MRI follow-up thus appears unnecessary in patients with biologically controlled macroprolactinomas. PMID- 28073907 TI - Metformin prevents metabolic side effects during systemic glucocorticoid treatment. AB - OBJECTIVES: Patients receiving glucocorticoid treatment are prone to develop metabolic complications. In preclinical studies, metformin prevented the development of the metabolic syndrome during glucocorticoid excess. We herein investigated the metabolic effect of metformin during glucocorticoid treatment in non-diabetic patients. METHODS: In a double-blind, placebo-controlled trial, patients starting glucocorticoid treatment (prednisone, prednisolone or methylprednisolone) for four weeks were randomised to concomitantly receive metformin (850 mg once daily for one week followed by 850 mg twice daily for three weeks) or placebo. All patients underwent a standardised oral glucose tolerance test at baseline and after four weeks. The primary endpoint was change in the 2-h area under the curve (AUC) of glucose during the oral glucose tolerance test between baseline and four weeks. RESULTS: 29 of 34 randomised non diabetic patients completed the trial (17 metformin and 12 placebo). In patients allocated to placebo, median glucose 2-h AUC increased from baseline to four weeks (836 (IQR 770-966) to 1202 (1009-1271) mmol/L per min; P = 0.01). In contrast, glucose levels remained similar to baseline in the metformin group (936 (869-1003) to 912 (825-1011) mmol/L per min; P = 0.83). This change within four weeks was different between both groups (P = 0.005). Glucocorticoid equivalent doses were similar in both groups (placebo: 980.0 (560.0-3259.8) mg/28 days; metformin: 683.0 (437.5-1970.5) mg/28 days; P = 0.26). CONCLUSIONS: In this first randomised controlled trial of metformin targeting metabolic complications in patients needing glucocorticoid therapy, we observed a beneficial effect of metformin on glycaemic control. Metformin thus seems to be a promising drug for preventing metabolic side effects during systemic glucocorticoid treatment. PMID- 28073908 TI - The neuroendocrine sequelae of paediatric craniopharyngioma: a 40-year meta-data analysis of 185 cases from three UK centres. AB - OBJECTIVES: The management of paediatric craniopharyngiomas was traditionally complete resection (CR), with better reported tumour control compared to that by partial resection (PR) or limited surgery (LS). The subsequent shift towards hypothalamic sparing, conservative surgery with adjuvant radiotherapy (RT) to any residual tumour aimed at reducing neuroendocrine morbidity, has not been systematically studied. Hence, we reviewed the sequelae of differing management strategies in paediatric craniopharyngioma across three UK tertiary centres over four decades. METHODS: Meta-data was retrospectively reviewed over two periods before (1973-2000 (Group A: n = 100)) and after (1998-2011 (Group B: n = 85)) the introduction of the conservative strategy at each centre. RESULTS: Patients had CR (A: 34% and B: 19%), PR (A: 48% and B: 46%) or LS (A: 16% and B: 34%), with trends reflecting the change in surgical approach over time. Overall recurrence rates between the two periods did not change (A: 38% vs B: 32%). More patients received RT in B than A, but recurrence rates were similar: for A, 28% patients received RT with 9 recurrences (32%); for B, 62% received RT with 14 recurrences (26%). However, rates of diabetes insipidus (P = 0.04), gonadotrophin deficiency (P < 0.001) and panhypopituitarism (P = 0.001) were lower in B than those in A. In contrast, post-operative obesity (BMI SDS >+2.0) (P = 0.4) and hypothalamic (P = 0.1) and visual (P = 0.3) morbidity rates were unchanged. CONCLUSION: The shift towards more conservative surgery has reduced the prevalence of hormone deficiencies, including diabetes insipidus, which can be life threatening. However, it has not been associated with reduced hypothalamic and visual morbidities, which remain a significant challenge. More effective targeted therapies are necessary to improve outcomes. PMID- 28073909 TI - The Detection of Spotted Fever Group Rickettsia DNA in Tick Samples From Pastoral Communities in Kenya. AB - In this study, ticks from pastoral communities in Kenya were tested for Rickettsia spp. infections in geographical regions where the presence of tick borne arboviruses had previously been reported. Rickettsial and arbovirus infections have similar clinical features which makes differential diagnosis challenging when both diseases occur. The tick samples were tested for Rickettsia spp. by conventional PCR using three primer sets targeting the gltA, ompA, and ompB genes followed by amplicon sequencing. Of the tick pools screened, 25% (95/380) were positive for Rickettsia spp. DNA using the gltA primer set. Of the tick-positive pools, 60% were ticks collected from camels. Rickettsia aeschlimannii and R. africae were the main Rickettsia spp. detected in the tick pools sequenced. The findings of this study indicate that multiple Rickettsia species are circulating in ticks from pastoral communities in Kenya and could contribute to the etiology of febrile illness in these areas. Diagnosis and treatment of rickettsial infections should be a public health priority in these regions. PMID- 28073910 TI - Implantation of the Subcutaneous Implantable Cardioverter-Defibrillator: An Evaluation of 4 Implantation Techniques. AB - BACKGROUND: Alternative techniques to the traditional 3-incision subcutaneous implantation of the subcutaneous implantable cardioverter-defibrillator may offer procedural and cosmetic advantages. We evaluate 4 different implant techniques of the subcutaneous implantable cardioverter-defibrillator. METHODS AND RESULTS: Patients implanted with subcutaneous implantable cardioverter-defibrillators from 2 hospitals between 2009 and 2016 were included. Four implantation techniques were used depending on physician preference and patient characteristics. The 2- and 3-incision techniques both place the pulse generator subcutaneously, but the 2-incision technique omits the superior parasternal incision for lead positioning. Submuscular implantation places the pulse generator underneath the serratus anterior muscle and subfascial implantation underneath the fascial layer on the anterior side of the serratus anterior muscle. Reported outcomes include perioperative parameters, defibrillation testing, and clinical follow-up. A total of 246 patients were included with a median age of 47 years and 37% female. Fifty four patients were implanted with the 3-incision technique, 118 with the 2 incision technique, 38 with submuscular, and 37 with subfascial. Defibrillation test efficacy and shock lead impedance during testing did not differ among the groups; respectively, P=0.46 and P=0.18. The 2-incision technique resulted in the shortest procedure duration and time-to-hospital discharge compared with the other techniques (P<0.001). A total of 18 complications occurred, but there were no significant differences between the groups (P=0.21). All infections occurred in subcutaneous implants (3-incision, n=3; 2-incision, n=4). In the 2-incision group, there were no lead displacements. CONCLUSIONS: The presented implantation techniques are feasible alternatives to the standard 3-incision subcutaneous implantation, and the 2-incision technique resulted in shortest procedure duration. PMID- 28073911 TI - A Truncated Granulocyte Colony-stimulating Factor Receptor (G-CSFR) Inhibits Apoptosis Induced by Neutrophil Elastase G185R Mutant: IMPLICATION FOR UNDERSTANDING CSF3R GENE MUTATIONS IN SEVERE CONGENITAL NEUTROPENIA. AB - Mutations in ELANE encoding neutrophil elastase (NE) have been identified in the majority of patients with severe congenital neutropenia (SCN). The NE mutants have been shown to activate unfolded protein response and induce premature apoptosis in myeloid cells. Patients with SCN are predisposed to acute myeloid leukemia (AML), and progression from SCN to AML is accompanied by mutations in CSF3R encoding the granulocyte colony-stimulating factor receptor (G-CSFR) in ~80% of patients. The mutations result in the expression of C-terminally truncated G-CSFRs that promote strong cell proliferation and survival. It is unknown why the CSF3R mutations, which are rare in de novo AML, are so prevalent in SCN/AML. We show here that a G-CSFR mutant, d715, derived from an SCN patient inhibited G-CSF-induced expression of NE in a dominant negative manner. Furthermore, G-CSFR d715 suppressed unfolded protein response and apoptosis induced by an SCN-derived NE mutant, which was associated with sustained activation of AKT and STAT5, and augmented expression of BCL-XL. Thus, the truncated G-CSFRs associated with SCN/AML may protect myeloid precursor cells from apoptosis induced by the NE mutants. We propose that acquisition of CSF3R mutations may represent a mechanism by which myeloid precursor cells carrying the ELANE mutations evade the proapoptotic activity of the NE mutants in SCN patients. PMID- 28073912 TI - Distinct Features of Cyanophage-encoded T-type Phycobiliprotein Lyase PhiCpeT: THE ROLE OF AUXILIARY METABOLIC GENES. AB - Auxiliary metabolic genes (AMG) are commonly found in the genomes of phages that infect cyanobacteria and increase the fitness of the cyanophage. AMGs are often homologs of host genes, and also typically related to photosynthesis. For example, the PhicpeT gene in the cyanophage P-HM1 encodes a putative phycobiliprotein lyase related to cyanobacterial T-type lyases, which facilitate attachment of linear tetrapyrrole chromophores to Cys-155 of phycobiliprotein beta-subunits, suggesting that PhiCpeT may also help assemble light-harvesting phycobiliproteins during infection. To investigate this possibility, we structurally and biochemically characterized recombinant PhiCpeT. The solved crystal structure of PhiCpeT at 1.8-A resolution revealed that the protein adopts a similar fold as the cyanobacterial T-type lyase CpcT from Nostoc sp. PCC7120 but overall is more compact and smaller. PhiCpeT specifically binds phycoerythrobilin (PEB) in vitro leading to a tight complex that can also be formed in Escherichia coli when it is co-expressed with genes encoding PEB biosynthesis (i.e. ho1 and pebS). The formed PhiCpeT.PEB complex was very stable as the chromophore was not lost during chromatography and displayed a strong red fluorescence with a fluorescence quantum yield of PhiF = 0.3. This complex was not directly able to transfer PEB to the host phycobiliprotein beta-subunit. However, it could assist the host lyase CpeS in its function by providing a pool of readily available PEB, a feature that might be important for fast phycobiliprotein assembly during phage infection. PMID- 28073913 TI - Raf Kinases Are Essential for Phosphate Induction of ERK1/2 Phosphorylation in Hypertrophic Chondrocytes and Normal Endochondral Bone Development. AB - Hypophosphatemia causes rickets by impairing hypertrophic chondrocyte apoptosis. Phosphate induction of MEK1/2-ERK1/2 phosphorylation in hypertrophic chondrocytes is required for phosphate-mediated apoptosis and growth plate maturation. MEK1/2 can be activated by numerous molecules including Raf isoforms. A- and B-Raf ablation in chondrocytes does not alter skeletal development, whereas ablation of C-Raf decreases hypertrophic chondrocyte apoptosis and impairs vascularization of the growth plate. However, ablation of C-Raf does not impair phosphate-induced ERK1/2 phosphorylation in vitro, but leads to rickets by decreasing VEGF protein stability. To determine whether Raf isoforms are required for phosphate-induced hypertrophic chondrocyte apoptosis, mice lacking all three Raf isoforms in chondrocytes were generated. Raf deletion caused neonatal death and a significant expansion of the hypertrophic chondrocyte layer of the growth plate, accompanied by decreased cleaved caspase-9. This was associated with decreased phospho-ERK1/2 immunoreactivity in the hypertrophic chondrocyte layer and impaired vascular invasion. These data further demonstrated that Raf kinases are required for phosphate-induced ERK1/2 phosphorylation in cultured hypertrophic chondrocytes and perform essential, but partially redundant roles in growth plate maturation. PMID- 28073914 TI - Serine/Threonine Kinase Unc-51-like Kinase-1 (Ulk1) Phosphorylates the Co chaperone Cell Division Cycle Protein 37 (Cdc37) and Thereby Disrupts the Stability of Cdc37 Client Proteins. AB - The serine/threonine kinase Unc-51-like kinase-1 (Ulk1) is thought to be essential for induction of autophagy, an intracellular bulk degradation process that is activated by various stresses. Although several proteins have been suggested as Ulk1 substrates during autophagic process, it still remains largely unknown about Ulk1's physiological substrates. Here, by performing in vitro and in vivo phosphorylation assay, we report that the co-chaperone cell division cycle protein 37 (Cdc37) is a Ulk1 substrate. Ulk1-mediated phosphorylation of Ser-339 in Cdc37 compromised the recruitment of client kinases to a complex comprising Cdc37 and heat shock protein 90 (Hsp90) but only modestly affected Cdc37 binding to Hsp90. Because the recruitment of protein kinase clients to the Hsp90 complex is essential for their stability and functions, Ser-339 phosphorylation of Cdc37 disrupts its ability as a co-chaperone to coordinate Hsp90. Hsp90 inhibitors are cancer chemotherapeutic agents by inducing depletion of clients, many of which are oncogenes. Upon treatment with an Hsp90 inhibitor in cancer cells, Ulk1 promoted the degradation of Hsp90-Cdc37 client kinases, resulting in increased cellular sensitivity to Hsp90 inhibitors. Thus, our study provides evidence for an anti-proliferative role of Ulk1 in response to Hsp90 inhibition in cancer cells. PMID- 28073915 TI - UbE2E1/UBCH6 Is a Critical in Vivo E2 for the PRC1-catalyzed Ubiquitination of H2A at Lys-119. AB - UbE2E1/UbcH6 is an E2 ubiquitin-conjugating enzyme that is regulated by USP7. We identified UbE2E1 as a novel component of Polycomb repressive complex 1 (PRC1), the E3 ligase complex responsible for histone H2A ubiquitination and gene silencing. We demonstrate that UbE2E1 is critical for the monoubiquitination of H2A at residue Lys-119 (uH2AK119) through its association with the PRC1 complex. UbE2E1 interacts with PRC1 subunits including Ring1A and Ring1B. Overexpression of UbE2E1 results in increased levels of uH2AK119, whereas overexpression of catalytically inactive UbE2E1_C131A or UbE2E1 knockdown results in decreased levels of uH2AK119. The down-regulation of H2A ubiquitination by loss of function of UbE2E1 is correlated with alleviated p16INK4a promoter repression and induced growth inhibition in HCT116 cells. These results are specific to UbE2E1 as knockdown of UbE2D E2s does not show any effect on uH2AK119. We extended the UbE2E1 regulation of uH2AK119 to USP7 and showed that USP7 is also a key regulator for monoubiquitination at H2A Lys-119 as both knockdown and deletion of USP7 results in decreased levels of uH2AK119. This study reveals that UbE2E1 is an in vivo E2 for the PRC1 ligase complex and thus plays an important role in the regulation of H2A Lys-119 monoubiquitination. PMID- 28073916 TI - Ceramide-CD300f Binding Inhibits Lipopolysaccharide-induced Skin Inflammation. AB - LPS triggers inflammatory responses; however, the negative regulation of LPS responses in vivo remains poorly understood. CD300f is an inhibitory receptor among the CD300 family of paired activating and inhibitory receptors. We have previously identified ceramide as a ligand for CD300f and shown that the binding of ceramide to CD300f inhibits IgE-mediated mast cell activation and allergic responses in mouse models. Here we identify the critical role of CD300f in inhibiting LPS-induced skin inflammation. CD300f deficiency remarkably enhanced LPS-induced skin edema and neutrophil recruitment in mice. Higher levels of factors that increase vascular permeability and of factors that induce neutrophil recruitment were detected in LPS-injected skin pouch exudates of CD300f-/- mice as compared with wild-type mice. CD300f was highly expressed in mast cells and recruited neutrophils, but not in macrophages, among skin myeloid cells. CD300f deficiency failed to influence the intrinsic migratory ability of neutrophils. Ceramide-CD300f binding suppressed the release of chemical mediators from mast cells and from neutrophils in response to LPS. Adoptive transfer experiments indicated that mast cells mediated enhanced edema in LPS-stimulated skin of CD300f-/- mice, whereas mast cells together with recruited neutrophils mediated robust neutrophil accumulation. Importantly, administering a ceramide antibody or ceramide-containing vesicles enhanced or suppressed LPS-induced skin inflammation of wild-type mice, respectively. Thus, ceramide-CD300f binding inhibits LPS induced skin inflammation, implicating CD300f as a negative regulator of Toll like receptor 4 (TLR4) signaling in vivo. PMID- 28073917 TI - The E3 ubiquitin ligase RNF114 and TAB1 degradation are required for maternal-to zygotic transition. AB - The functional role of the ubiquitin-proteasome pathway during maternal-to zygotic transition (MZT) remains to be elucidated. Here we show that the E3 ubiquitin ligase, Rnf114, is highly expressed in mouse oocytes and that knockdown of Rnf114 inhibits development beyond the two-cell stage. To study the underlying mechanism, we identify its candidate substrates using a 9,000-protein microarray and validate them using an in vitro ubiquitination system. We show that five substrates could be degraded by RNF114-mediated ubiquitination, including TAB1. Furthermore, the degradation of TAB1 in mouse early embryos is required for MZT, most likely because it activates the NF-kappaB pathway. Taken together, our study uncovers that RNF114-mediated ubiquitination and degradation of TAB1 activate the NF-kappaB pathway during MZT, and thus directly link maternal clearance to early embryo development. PMID- 28073919 TI - TRUB1 is the predominant pseudouridine synthase acting on mammalian mRNA via a predictable and conserved code. AB - Following synthesis, RNA can be modified with over 100 chemically distinct modifications, which can potentially regulate RNA expression post transcriptionally. Pseudouridine (Psi) was recently established to be widespread and dynamically regulated on yeast mRNA, but less is known about Psi presence, regulation, and biogenesis in mammalian mRNA. Here, we sought to characterize the Psi landscape on mammalian mRNA, to identify the main Psi-synthases (PUSs) catalyzing Psi formation, and to understand the factors governing their specificity toward selected targets. We first developed a framework allowing analysis, evaluation, and integration of Psi mappings, which we applied to >2.5 billion reads from 30 human samples. These maps, complemented with genetic perturbations, allowed us to uncover TRUB1 and PUS7 as the two key PUSs acting on mammalian mRNA and to computationally model the sequence and structural elements governing the specificity of TRUB1, achieving near-perfect prediction of its substrates (AUC = 0.974). We then validated and extended these maps and the inferred specificity of TRUB1 using massively parallel reporter assays in which we monitored Psi levels at thousands of synthetically designed sequence variants comprising either the sequences surrounding pseudouridylation targets or systematically designed mutants perturbing RNA sequence and structure. Our findings provide an extensive and high-quality characterization of the transcriptome-wide distribution of pseudouridine in human and the factors governing it and provide an important resource for the community, paving the path toward functional and mechanistic dissection of this emerging layer of post transcriptional regulation. PMID- 28073920 TI - Sweet food preference in amyotrophic lateral sclerosis. PMID- 28073918 TI - Identical bacterial populations colonize premature infant gut, skin, and oral microbiomes and exhibit different in situ growth rates. AB - The initial microbiome impacts the health and future development of premature infants. Methodological limitations have led to gaps in our understanding of the habitat range and subpopulation complexity of founding strains, as well as how different body sites support microbial growth. Here, we used metagenomics to reconstruct genomes of strains that colonized the skin, mouth, and gut of two hospitalized premature infants during the first month of life. Seven bacterial populations, considered to be identical given whole-genome average nucleotide identity of >99.9%, colonized multiple body sites, yet none were shared between infants. Gut-associated Citrobacter koseri genomes harbored 47 polymorphic sites that we used to define 10 subpopulations, one of which appeared in the gut after 1 wk but did not spread to other body sites. Differential genome coverage was used to measure bacterial population replication rates in situ. In all cases where the same bacterial population was detected in multiple body sites, replication rates were faster in mouth and skin compared to the gut. The ability of identical strains to colonize multiple body sites underscores the habit flexibility of initial colonists, whereas differences in microbial replication rates between body sites suggest differences in host control and/or resource availability. Population genomic analyses revealed microdiversity within bacterial populations, implying initial inoculation by multiple individual cells with distinct genotypes. Overall, however, the overlap of strains across body sites implies that the premature infant microbiome can exhibit very low microbial diversity. PMID- 28073921 TI - Parascapular muscle atrophy as a delayed effect of radiation treatment. PMID- 28073922 TI - Practical Neurology linked to the curriculum: an online resource. PMID- 28073923 TI - What to do when patients with epilepsy cannot take their usual oral medications. AB - When people with epilepsy are hospitalised for medical or surgical conditions, they may be unable to take their home antiepileptic drugs (AEDs). Such 'nil by mouth' people with epilepsy require alternative AED regimens to prevent breakthrough seizures. Here, we describe several strategies for maintaining seizure control in patients with epilepsy who have medical or surgical contraindications to their home oral regimens. These strategies include using non pill oral formulations, using an intravenous formulation of the patient's home AED(s), using a benzodiazepine bridge and/or using alternative intravenous AED(s) when there are no intravenous formulations. PMID- 28073924 TI - Temporary replacements for oral epilepsy treatments. PMID- 28073925 TI - Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes. AB - Progranulin (PGRN) haploinsufficiency resulting from loss-of-function mutations in the PGRN gene causes frontotemporal lobar degeneration accompanied by TDP-43 accumulation, and patients with homozygous mutations in the PGRN gene present with neuronal ceroid lipofuscinosis. Although it remains unknown why PGRN deficiency causes neurodegenerative diseases, there is increasing evidence that PGRN is implicated in lysosomal functions. Here, we show PGRN is a secretory lysosomal protein that regulates lysosomal function and biogenesis by controlling the acidification of lysosomes. PGRN gene expression and protein levels increased concomitantly with the increase of lysosomal biogenesis induced by lysosome alkalizers or serum starvation. Down-regulation or insufficiency of PGRN led to the increased lysosomal gene expression and protein levels, while PGRN overexpression led to the decreased lysosomal gene expression and protein levels. In particular, the level of mature cathepsin D (CTSDmat) dramatically changed depending upon PGRN levels. The acidification of lysosomes was facilitated in cells transfected with PGRN. Then, this caused degradation of CTSDmat by cathepsin B. Secreted PGRN is incorporated into cells via sortilin or cation independent mannose 6-phosphate receptor, and facilitated the acidification of lysosomes and degradation of CTSDmat. Moreover, the change of PGRN levels led to a cell-type-specific increase of insoluble TDP-43. In the brain tissue of FTLD TDP patients with PGRN deficiency, CTSD and phosphorylated TDP-43 accumulated in neurons. Our study provides new insights into the physiological function of PGRN and the role of PGRN insufficiency in the pathogenesis of neurodegenerative diseases. PMID- 28073926 TI - Mutations of PQBP1 in Renpenning syndrome promote ubiquitin-mediated degradation of FMRP and cause synaptic dysfunction. AB - Renpenning syndrome is a group of X-linked intellectual disability syndromes caused by mutations in human polyglutamine-binding protein 1 (PQBP1) gene. Little is known about the molecular pathogenesis of the various mutations that cause the notable variability in patients. In this study, we examine the cellular and synaptic functions of the most common mutations found in the patients: c.461_462delAG, c.459_462delAGAG and c.463_464dupAG in an AG hexamer in PQBP1 exon 4. We discovered that PQBP1 c.459_462delAGAG and c.463_464dupAG mutations encode a new C-terminal epitope that preferentially binds non-phosphorylated fragile X mental retardation protein (FMRP) and promotes its ubiquitin-mediated degradation. Impairment of FMRP function up-regulates its targets such as MAP1B, and disrupts FMRP-dependent synaptic scaling in primary cultured neurons. In Drosophila neuromuscular junction model, PQBP1 c.463_464dupAG transgenic flies showed remarkable defects of synaptic over-growth, which can be rescued by exogenously expressing dFMRP. Our data strongly support a gain-of-function pathogenic mechanism of PQBP1 c.459_462delAGAG and c.463_464dupAG mutations, and suggest that therapeutic strategies to restore FMRP function may be beneficial for those patients. PMID- 28073928 TI - Evidence of epigenetic admixture in the Colombian population. AB - DNA methylation (DNAm) measured in lymphoblastoid cell lines has been repeatedly demonstrated to differ between various human populations. Due to the role that DNAm plays in controlling gene expression, these differences could significantly contribute to ethnic phenotypic differences. However, because previous studies have compared distinct ethnic groups where genetic and environmental context are confounded, their relative contribution to phenotypic differences between ethnicities remains unclear. Using DNAm assayed in whole blood and colorectal tissue of 132 admixed individuals from Colombia, we identified sites where differential DNAm levels were associated with the local ancestral genetic context. Our results are consistent with population specific DNAm being primarily driven by between population genetic differences in cis, with little environmental contribution, and with consistent effects across tissues. The findings offer new insights into a possible mechanism driving phenotypic differences among different ethnic groups, and could help explain ethnic differences in colorectal cancer incidence. PMID- 28073930 TI - Editorial: 3Rs tightly intertwined to maintain genome stability. PMID- 28073932 TI - Thoracic splenosis mimicking pleural mass: the importance of clinical history. PMID- 28073929 TI - Improving heterologous production of phenylpropanoids in Saccharomyces cerevisiae by tackling an unwanted side reaction of Tsc13, an endogenous double-bond reductase. AB - Phenylpropanoids, such as flavonoids and stilbenoids, are of great commercial interest, and their production in Saccharomyces cerevisiae is a very promising strategy. However, to achieve commercially viable production, each step of the process must be optimised. We looked at carbon loss, known to occur in the heterologous flavonoid pathway in yeast, and identified an endogenous enzyme, the enoyl reductase Tsc13, which turned out to be responsible for the accumulation of phloretic acid via reduction of p-coumaroyl-CoA. Tsc13 is an essential enzyme involved in fatty acid synthesis and cannot be deleted. Hence, two approaches were adopted in an attempt to reduce the side activity without disrupting the natural function: site saturation mutagenesis identified a number of amino acid changes which slightly increased flavonoid production but without reducing the formation of the side product. Conversely, the complementation of TSC13 by a plant gene homologue essentially eliminated the unwanted side reaction, while retaining the productivity of phenylpropanoids in a simulated fed batch fermentation. PMID- 28073931 TI - Histones and Neutrophil Extracellular Traps Enhance Tubular Necrosis and Remote Organ Injury in Ischemic AKI. AB - Severe AKI is often associated with multiorgan dysfunction, but the mechanisms of this remote tissue injury are unknown. We hypothesized that renal necroinflammation releases cytotoxic molecules that may cause remote organ damage. In hypoxia-induced tubular epithelial cell necrosis in vitro, histone secretion from ischemic tubular cells primed neutrophils to form neutrophil extracellular traps. These traps induced tubular epithelial cell death and stimulated neutrophil extracellular trap formation in fresh neutrophils. In vivo, ischemia-reperfusion injury in the mouse kidney induced tubular necrosis, which preceded the expansion of localized and circulating neutrophil extracellular traps and the increased expression of inflammatory and injury-related genes. Pretreatment with inhibitors of neutrophil extracellular trap formation reduced kidney injury. Dual inhibition of neutrophil trap formation and tubular cell necrosis had an additive protective effect. Moreover, pretreatment with antihistone IgG suppressed ischemia-induced neutrophil extracellular trap formation and renal injury. Renal ischemic injury also increased the levels of circulating histones, and we detected neutrophil infiltration and TUNEL-positive cells in the lungs, liver, brain, and heart along with neutrophil extracellular trap accumulation in the lungs. Inhibition of neutrophil extracellular trap formation or of circulating histones reduced these effects as well. These data suggest that tubular necrosis and neutrophil extracellular trap formation accelerate kidney damage and remote organ dysfunction through cytokine and histone release and identify novel molecular targets to limit renal necroinflammation and multiorgan failure. PMID- 28073933 TI - Anterior interosseous nerve syndrome. PMID- 28073927 TI - New insights into the genetics of primary open-angle glaucoma based on meta analyses of intraocular pressure and optic disc characteristics. AB - Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk. PMID- 28073934 TI - The influence of customer-medicine seller transactional dynamics on childhood diarrhoea management: a qualitative study in Ghana. AB - In 2004, the World Health Organization (WHO) and United Nations Children's Fund (UNICEF) jointly revised the recommended treatment for acute paediatric diarrhoea to specify supplementing reduced osmolarity oral rehydration salts (ORS) with zinc. In many countries, however, a significant knowledge-practice gap persists in appropriate diarrhoea management among private healthcare providers. For example, the United States Agency for International Development (USAID)-funded Strengthening Health Outcomes through the Private Sector (SHOPS) project recently demonstrated that over-the-counter medicine sellers (MS) in Ghana recommended inappropriate diarrhoea treatments, despite their demonstrated knowledge of appropriate treatment protocols. To explore and explain these results, we conducted 26 focus groups with MS and their customers using an indirect elicitation approach, presenting simulated drug shop transaction scenarios for each group to analyze and discuss. Through inductive and deductive data analysis, we found that the pattern of customer-MS interactions within the transactional context plays a critical role in shaping dispensing outcomes, not only in diarrhoea management but in other contexts as well. MS who engaged and negotiated with their customers were better able to introduce and promote the appropriate diarrhoea treatment protocol. Several factors hinder optimal interactions. Although MS in fact serve as frontline medical providers, they lack the perceived status of a clinician. Moreover, the need to maintain their customer base creates a power imbalance that favours accommodating customer requests and discourages educational interaction. Finally, many MS lack a complete understanding of the recommended treatment, limiting their ability to educate and negotiate. These findings have important implications for efforts to position community-level private providers to improve outcomes across a number of health areas; the study recommends three broad approaches related to training design, marketing, and professional linkages. More generally, behaviour change initiatives should recognize the potential impact of provider interaction dynamics in facilitating or impeding desired health outcomes. PMID- 28073936 TI - Human Exploration of Enclosed Spaces through Echolocation. AB - Some blind humans have developed echolocation, as a method of navigation in space. Echolocation is a truly active sense because subjects analyze echoes of dedicated, self-generated sounds to assess space around them. Using a special virtual space technique, we assess how humans perceive enclosed spaces through echolocation, thereby revealing the interplay between sensory and vocal-motor neural activity while humans perform this task. Sighted subjects were trained to detect small changes in virtual-room size analyzing real-time generated echoes of their vocalizations. Individual differences in performance were related to the type and number of vocalizations produced. We then asked subjects to estimate virtual-room size with either active or passive sounds while measuring their brain activity with fMRI. Subjects were better at estimating room size when actively vocalizing. This was reflected in the hemodynamic activity of vocal motor cortices, even after individual motor and sensory components were removed. Activity in these areas also varied with perceived room size, although the vocal motor output was unchanged. In addition, thalamic and auditory-midbrain activity was correlated with perceived room size; a likely result of top-down auditory pathways for human echolocation, comparable with those described in echolocating bats. Our data provide evidence that human echolocation is supported by active sensing, both behaviorally and in terms of brain activity. The neural sensory motor coupling complements the fundamental acoustic motor-sensory coupling via the environment in echolocation.SIGNIFICANCE STATEMENT Passive listening is the predominant method for examining brain activity during echolocation, the auditory analysis of self-generated sounds. We show that sighted humans perform better when they actively vocalize than during passive listening. Correspondingly, vocal motor and cerebellar activity is greater during active echolocation than vocalization alone. Motor and subcortical auditory brain activity covaries with the auditory percept, although motor output is unchanged. Our results reveal behaviorally relevant neural sensory-motor coupling during echolocation. PMID- 28073935 TI - Brain Structure and Function Associated with Younger Adults in Growth Hormone Receptor-Deficient Humans. AB - Growth hormone receptor deficiency (GHRD) results in short stature, enhanced insulin sensitivity, and low circulating levels of insulin and insulin-like growth factor 1 (IGF-1). Previous studies in mice and humans suggested that GHRD has protective effects against age-related diseases, including cancer and diabetes. Whereas GHRD mice show improved age-dependent cognitive performance, the effect of GHRD on human cognition remains unknown. Using MRI, we compared brain structure, function, and connectivity between 13 people with GHRD and 12 unaffected relatives. We assessed differences in white matter microstructural integrity, hippocampal volume, subregional volumes, and cortical thickness and surface area of selected regions. We also evaluated brain activity at rest and during a hippocampal-dependent pattern separation task. The GHRD group had larger surface areas in several frontal and cingulate regions and showed trends toward larger dentate gyrus and CA1 regions of the hippocampus. They had lower mean diffusivity in the genu of the corpus callosum and the anterior thalamic tracts. The GHRD group showed enhanced cognitive performance and greater task-related activation in frontal, parietal, and hippocampal regions compared with controls. Furthermore, they had greater functional synchronicity of activity between the precuneus and the rest of the default mode network at rest. The results suggest that, compared with controls, GHRD subjects have brain structure and function that are more consistent with those observed in younger adults reported in previous studies. Further investigation may lead to improved understanding of underlying mechanisms and could contribute to the identification of treatments for age-related cognitive deficits.SIGNIFICANCE STATEMENT People and mice with growth hormone receptor deficiency (GHRD or Laron syndrome) are protected against age-related diseases including cancer and diabetes. However, in humans, it is unknown whether cognitive function and brain structure are affected by GHRD. Using MRI, we examined cognition in an Ecuadorian population with GHRD and their unaffected relatives. The GHRD group showed better memory performance than their relatives. The differences in brain structure and function that we saw between the two groups were not consistent with variations typically associated with brain deficits. This study contributes to our understanding of the connection between growth genes and brain aging in humans and provides data indicating that GHR inhibition has the potential to protect against age-dependent cognitive decline. PMID- 28073937 TI - Activity of Tachykinin1-Expressing Pet1 Raphe Neurons Modulates the Respiratory Chemoreflex. AB - Homeostatic control of breathing, heart rate, and body temperature relies on circuits within the brainstem modulated by the neurotransmitter serotonin (5-HT). Mounting evidence points to specialized neuronal subtypes within the serotonergic neuronal system, borne out in functional studies, for the modulation of distinct facets of homeostasis. Such functional differences, read out at the organismal level, are likely subserved by differences among 5-HT neuron subtypes at the cellular and molecular levels, including differences in the capacity to coexpress other neurotransmitters such as glutamate, GABA, thyrotropin releasing hormone, and substance P encoded by the Tachykinin-1 (Tac1) gene. Here, we characterize in mice a 5-HT neuron subtype identified by expression of Tac1 and the serotonergic transcription factor gene Pet1, referred to as the Tac1-Pet1 neuron subtype. Transgenic cell labeling showed Tac1-Pet1 soma resident largely in the caudal medulla. Chemogenetic [clozapine-N-oxide (CNO)-hM4Di] perturbation of Tac1-Pet1 neuron activity blunted the ventilatory response of the respiratory CO2 chemoreflex, which normally augments ventilation in response to hypercapnic acidosis to restore normal pH and PCO2Tac1-Pet1 axonal boutons were found localized to brainstem areas implicated in respiratory modulation, with highest density in motor regions. These findings demonstrate that the activity of a Pet1 neuron subtype with the potential to release both 5-HT and substance P is necessary for normal respiratory dynamics, perhaps via motor outputs that engage muscles of respiration and maintain airway patency. These Tac1-Pet1 neurons may act downstream of Egr2-Pet1 serotonergic neurons, which were previously established in respiratory chemoreception, but do not innervate respiratory motor nuclei.SIGNIFICANCE STATEMENT Serotonin (5-HT) neurons modulate physiological processes and behaviors as diverse as body temperature, respiration, aggression, and mood. Using genetic tools, we characterize a 5-HT neuron subtype defined by expression of Tachykinin1 and Pet1 (Tac1-Pet1 neurons), mapping soma localization to the caudal medulla primarily and axonal projections to brainstem motor nuclei most prominently, and, when silenced, observed blunting of the ventilatory response to inhaled CO2Tac1-Pet1 neurons thus appear distinct from and contrast previously described Egr2-Pet1 neurons, which project primarily to chemosensory integration centers and are themselves chemosensitive. PMID- 28073938 TI - Sonic Hedgehog Guides Axons via Zipcode Binding Protein 1-Mediated Local Translation. AB - Sonic hedgehog (Shh) attracts spinal cord commissural axons toward the floorplate. How Shh elicits changes in the growth cone cytoskeleton that drive growth cone turning is unknown. We find that the turning of rat commissural axons up a Shh gradient requires protein synthesis. In particular, Shh stimulation increases beta-actin protein at the growth cone even when the cell bodies have been removed. Therefore, Shh induces the local translation of beta-actin at the growth cone. We hypothesized that this requires zipcode binding protein 1 (ZBP1), an mRNA-binding protein that transports beta-actin mRNA and releases it for local translation upon phosphorylation. We found that Shh stimulation increases phospho ZBP1 levels in the growth cone. Disruption of ZBP1 phosphorylation in vitro abolished the turning of commissural axons toward a Shh gradient. Disruption of ZBP1 function in vivo in mouse and chick resulted in commissural axon guidance errors. Therefore, ZBP1 is required for Shh to guide commissural axons. This identifies ZBP1 as a new mediator of noncanonical Shh signaling in axon guidance.SIGNIFICANCE STATEMENT Sonic hedgehog (Shh) guides axons via a noncanonical signaling pathway that is distinct from the canonical Hedgehog signaling pathway that specifies cell fate and morphogenesis. Axon guidance is driven by changes in the growth cone in response to gradients of guidance molecules. Little is known about the molecular mechanism of how Shh orchestrates changes in the growth cone cytoskeleton that are required for growth cone turning. Here, we show that the guidance of axons by Shh requires protein synthesis. Zipcode binding protein 1 (ZBP1) is an mRNA-binding protein that regulates the local translation of proteins, including actin, in the growth cone. We demonstrate that ZBP1 is required for Shh-mediated axon guidance, identifying a new member of the noncanonical Shh signaling pathway. PMID- 28073939 TI - Nanoscale Molecular Reorganization of the Inhibitory Postsynaptic Density Is a Determinant of GABAergic Synaptic Potentiation. AB - Gephyrin is a key scaffold protein mediating the anchoring of GABAA receptors at inhibitory synapses. Here, we exploited superresolution techniques combined with proximity-based clustering analysis and model simulations to investigate the single-molecule gephyrin reorganization during plasticity of inhibitory synapses in mouse hippocampal cultured neurons. This approach revealed that, during the expression of inhibitory LTP, the increase of gephyrin density at postsynaptic sites is associated with the promoted formation of gephyrin nanodomains. We demonstrate that the gephyrin rearrangement in nanodomains stabilizes the amplitude of postsynaptic currents, indicating that, in addition to the number of synaptic GABAA receptors, the nanoscale distribution of GABAA receptors in the postsynaptic area is a crucial determinant for the expression of inhibitory synaptic plasticity. In addition, the methodology implemented here clears the way to the application of the graph-based theory to single-molecule data for the description and quantification of the spatial organization of the synapse at the single-molecule level.SIGNIFICANCE STATEMENT The mechanisms of inhibitory synaptic plasticity are poorly understood, mainly because the size of the synapse is below the diffraction limit, thus reducing the effectiveness of conventional optical and imaging techniques. Here, we exploited superresolution approaches combined with clustering analysis to study at unprecedented resolution the distribution of the inhibitory scaffold protein gephyrin in response to protocols inducing LTP of inhibitory synaptic responses (iLTP). We found that, during the expression of iLTP, the increase of synaptic gephyrin is associated with the fragmentation of gephyrin in subsynaptic nanodomains. We demonstrate that such synaptic gephyrin nanodomains stabilize the amplitude of inhibitory postsynaptic responses, thus identifying the nanoscale gephyrin rearrangement as a key determinant for inhibitory synaptic plasticity. PMID- 28073940 TI - Vividness of Visual Imagery Depends on the Neural Overlap with Perception in Visual Areas. AB - : Research into the neural correlates of individual differences in imagery vividness point to an important role of the early visual cortex. However, there is also great fluctuation of vividness within individuals, such that only looking at differences between people necessarily obscures the picture. In this study, we show that variation in moment-to-moment experienced vividness of visual imagery, within human subjects, depends on the activity of a large network of brain areas, including frontal, parietal, and visual areas. Furthermore, using a novel multivariate analysis technique, we show that the neural overlap between imagery and perception in the entire visual system correlates with experienced imagery vividness. This shows that the neural basis of imagery vividness is much more complicated than studies of individual differences seemed to suggest. SIGNIFICANCE STATEMENT: Visual imagery is the ability to visualize objects that are not in our direct line of sight: something that is important for memory, spatial reasoning, and many other tasks. It is known that the better people are at visual imagery, the better they can perform these tasks. However, the neural correlates of moment-to-moment variation in visual imagery remain unclear. In this study, we show that the more the neural response during imagery is similar to the neural response during perception, the more vivid or perception-like the imagery experience is. PMID- 28073941 TI - Prognostic roles of tetrahydroxy bile acids in infantile intrahepatic cholestasis. AB - Tetrahydroxy bile acids (THBAs) are hydrophilic and are present at minimal or undetectable levels in healthy human adults, but are present at high levels in bile salt export pump (abcb11)-knockout mice. The roles of THBAs in human cholestatic diseases are unclear. We aimed to investigate the presence of THBAs in patients with infantile intrahepatic cholestasis and its correlation with outcome. Urinary bile acids (BAs) were analyzed by GC-MS. Data were compared between good (n = 21) (disease-free before 1 year old) and poor prognosis groups (n = 19). Good prognosis patients had a higher urinary THBA proportion than poor prognosis patients [25.89% (3.45-76.73%) vs. 1.93% (0.05-48.90%)]. A urinary THBA proportion >7.23% predicted good prognosis with high sensitivity (95.24%), specificity (84.21%), and area under the curve (0.91) (P < 0.0001). A THBA proportion ?7.23% was an independent factor for decreased transplant-free survival (hazard ratio = 7.16, confidence interval: 1.24-41.31, P = 0.028). Patients with a confirmed ABCB11 or tight junction protein 2 gene mutation (n = 7) had a minimally detectable THBA proportion (0.23-2.99% of total BAs). Three patients with an ATP8B1 mutation had an elevated THBA proportion (7.51-37.26%). In conclusion, in addition to disease entity as a major determinant of outcome, a high THBA level was associated with good outcome in the infantile intrahepatic cholestasis patients. PMID- 28073942 TI - Emergency department visits related to functional abdominal pain in the pediatric age group. AB - To analyze visits to and admissions from the emergency department (ED) in children with a primary diagnosis of functional abdominal pain (FAP). This was a cross-sectional study using data from the Nationwide Emergency Department Sample (HCUP-NEDS 2008-2012). FAP-related ED visits were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes. The most frequent secondary diagnoses associated with FAP-related ED visits were also extracted. In 2012, a total of 796,665 children presented to the ED with a primary diagnosis of FAP. This correlated to a rate of 11.5 ED visits/1000 population. The highest incidence of ED visits was observed for children in the 10-14-year age group; median (IQR) age of 11 (8) years. In analyzing the temporal trends associated with FAP-related ED visits, we observed an increase in both the overall number of visits (14.0%) as well as the population-adjusted incidence (16.0%) during the period 2008-2012. This coincided with a decreasing trend in hospital admissions from the ED; from 1.4% in 2008 to 1.0% in 2012 (-28.5%). The overwhelming majority (96.7%) of patients with FAP who presented to the ED were treated and released. On multivariate analysis, the leading factor associated with an increased likelihood of admission from the ED was teaching hospital status (aOR 2.07; 95% CI 1.97 to 2.18). The secondary diagnosis most commonly associated with FAP-related ED visits was nausea and/or emesis (19.8%). Pediatric FAP-related ED visits increased significantly from the period 2008 to 2012. However, the incidence of hospital admissions from the ED declined during the same period. PMID- 28073943 TI - KDM4B/JMJD2B is a p53 target gene that modulates the amplitude of p53 response after DNA damage. AB - The p53 tumor suppressor protein plays a critical role in orchestrating the genomic response to various stress signals by acting as a master transcriptional regulator. Differential gene activity is controlled by transcription factors but also dependent on the underlying chromatin structure, especially on covalent histone modifications. After screening different histone lysine methyltransferases and demethylases, we identified JMJD2B/KDM4B as a p53 inducible gene in response to DNA damage. p53 directly regulates JMJD2B gene expression by binding to a canonical p53-consensus motif in the JMJD2B promoter. JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B. Conversely, JMJD2B silencing led to an enhancement of the DNA damage driven induction of p21 and PIG3. These findings indicate that JMJD2B acts in an auto-regulatory loop by which p53, through JMJD2B activation, is able to influence its own transcriptional program. Functionally, exogenous expression of JMJD2B enhanced subcutaneous tumor growth of colon cancer cells in a p53 dependent manner, and genetic inhibition of JMJD2B impaired tumor growth in vivo. These studies provide new insights into the regulatory effect exerted by JMJD2B on tumor growth through the modulation of p53 target genes. PMID- 28073944 TI - A novel bifunctional transcriptional regulator of riboflavin metabolism in Archaea. AB - Riboflavin (vitamin B2) is the precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide, which are essential coenzymes in all free-living organisms. Riboflavin biosynthesis in many Bacteria but not in Archaea is controlled by FMN-responsive riboswitches. We identified a novel bifunctional riboflavin kinase/regulator (RbkR), which controls riboflavin biosynthesis and transport genes in major lineages of Crenarchaeota, Euryarchaeota and Thaumarchaeota. RbkR proteins are composed of the riboflavin kinase domain and a DNA-binding winged helix-turn-helix-like domain. Using comparative genomics, we predicted RbkR operator sites and reconstructed RbkR regulons in 94 archaeal genomes. While the identified RbkR operators showed significant variability between archaeal lineages, the conserved core of RbkR regulons includes riboflavin biosynthesis genes, known/predicted vitamin uptake transporters and the rbkR gene. The DNA motifs and CTP-dependent riboflavin kinase activity of two RbkR proteins were experimentally validated in vitro. The DNA binding activity of RbkR was stimulated by CTP and suppressed by FMN, a product of riboflavin kinase. The crystallographic structure of RbkR from Thermoplasma acidophilum was determined in complex with CTP and its DNA operator revealing key residues for operator and ligand recognition. Overall, this study contributes to our understanding of metabolic and regulatory networks for vitamin homeostasis in Archaea. PMID- 28073946 TI - A randomized Phase III trial of comparing two dose-fractionations stereotactic body radiotherapy (SBRT) for medically inoperable Stage IA non-small cell lung cancer or small lung lesions clinically diagnosed as primary lung cancer: Japan Clinical Oncology Group Study JCOG1408 (J-SBRT trial). AB - A randomized Phase III trial commenced in Japan in February 2016. Currently, 42 Gy in four fractions of stereotactic body radiotherapy prescribed at the D95% of the planning target volume, which is considered equal to the commonly used 48 Gy in four fractions at the isocenter using an old dose calculation algorithm, is the standard treatment in Japan for medically inoperable Stage IA non-small cell lung cancer and small lung lesions clinically diagnosed as primary lung cancer. This study aims to examine the superiority of 55 Gy in four fractions over 42 Gy in four fractions. A total of 750 patients are expected to be accrued in 5 years. The primary endpoint is overall survival and the secondary endpoints are progression-free survival, local progression-free survival, patterns of failure, local control period, adverse events and serious adverse events. This trial is registered at the UMIN Clinical Trials Registry as UMIN000021029 (http://www.umin.ac.jp/ctr/index.htm) the dose covering 95% of the volume (D95%) of the planning target volume. PMID- 28073945 TI - Surgery and imatinib therapy for liver oligometastasis of GIST: a study of Japanese Study Group on GIST. AB - We conducted a multicenter prospective study to clarify the efficacy and safety of surgery and imatinib for liver oligometastasis of gastrointestinal stromal tumors. Eligible gastrointestinal stromal tumor patients were enrolled in the surgery trial or the imatinib trial. Primary endpoints were recurrence-free survival and progression-free survival, respectively. The trials were prematurely terminated due to amendment of guidelines for adjuvant imatinib therapy and low patient accrual. In the surgery trial, all the six patients showed hepatic recurrence: median recurrence-free survival was 145 days (range: 62-1366 days). Of the five patients receiving salvage imatinib therapy, two showed progressive disease although no death was observed. Of the five patients enrolled in the imatinib trial, one died of pneumonia after progressive disease, and four had not shown progressive disease as of last visit. The results suggest that liver oligometastasis of gastrointestinal stromal tumor may not be controllable by surgery alone and require concomitant imatinib therapy. PMID- 28073947 TI - Redefining the child pedestrian safety paradigm: identifying high fatality concentrations in urban areas. AB - OBJECTIVES: Child pedestrians are some of the most vulnerable users of our transportation systems, and they deserve particular attention when we consider traffic safety. The objective of this work is to identify urban locations in which child pedestrians are at particular risk for fatal collisions with vehicles. METHODS: This paper examines 30 years of crash data for six American cities to locate areas with high child pedestrian fatality concentrations. Phase I of the study, which examines Denver, Colorado, USA, reveals higher concentrations of child pedestrian fatalities around parks as compared with other areas that children have been shown to frequent. In phase II of the study, we specifically examine fatality concentrations near parks as compared with schools. RESULTS: Statistical analyses suggest that, once exposure is controlled for, child pedestrian fatalities concentrate around parks in densities 1.04-2.23 times higher than around schools. Also, the concentration of child pedestrian fatalities around parks is 1.16-1.81 times higher than the respective citywide concentration. CONCLUSION: Traffic risks for children around parks deserve further examination as we pursue the goals of Vision Zero and child safety on our streets. PMID- 28073948 TI - Functioning and health-related quality of life following injury in older people: a systematic review. AB - AIM AND BACKGROUND: There is growing evidence around the impact of injury and recovery trajectories but little focuses on older people, despite rising burden. The aim of this review was to describe the evidence for postinjury functioning and health-related quality of life (HRQoL) in older people. METHOD: A systematic search of three databases and an extensive search of the grey literature was carried out on prospective injury outcome studies in older people (age >=65 years) that used a generic health status outcome measure. The search results were reported using PRISMA reporting guidelines, and risk of bias was assessed using a modification of the Quality in Prognosis Studies tool. RESULTS: There was limited evidence on functioning and HRQoL postinjury in older people. There were 367 studies identified, with 13 eligible for inclusion. Most focused on hip fracture or traumatic brain injury. Older people appeared to have poorer postinjury functioning and HRQoL compared with younger adults or preinjury levels. Poor preinjury function, pre-existing conditions and increasing age were associated with poorer outcomes, whereas preinjury-independent living was associated with better outcomes. DISCUSSION: The studies were heterogeneous, limiting synthesis. There was a lack of evidence around the impact of injury on older people in terms of paid work and unpaid work. It was unclear if existing injury outcome guidelines are appropriate for older people. CONCLUSIONS: Further research is required on older people's postinjury course, outcomes and determinants. This will require standardised methodologies and qualitative studies. The findings will inform clinical care, policy development, health and compensation systems. PMID- 28073949 TI - The effects of feedback and incentive-based insurance on driving behaviours: study approach and protocols. AB - BACKGROUND: Road injury is the leading cause of death for young people, with human error a contributing factor in many crash events. This research is the first experimental study to examine the extent to which direct feedback and incentive-based insurance modifies a driver's behaviour. The study applies in vehicle telematics and will link the information obtained from the technology directly to personalised safety messaging and personal injury and property damage insurance premiums. METHODS: The study has two stages. The first stage involves laboratory experiments using a state-of-the-art driving simulator. These experiments will test the effects of various monetary incentives on unsafe driving behaviours. The second stage builds on these experiments and involves a randomised control trial to test the effects of both direct feedback (safety messaging) and monetary incentives on driving behaviour. DISCUSSION: Assuming a positive finding associated with the monetary incentive-based approach, the study will dramatically influence the personal injury and property damage insurance industry. In addition, the findings will also illustrate the role that in-vehicle telematics can play in providing direct feedback to young/novice drivers in relation to their driving behaviours which has the potential to transform road safety. PMID- 28073950 TI - Differential coupling of gibberellin responses by Rht-B1c suppressor alleles and Rht-B1b in wheat highlights a unique role for the DELLA N-terminus in dormancy. AB - During the Green Revolution, substantial increases in wheat (Triticum aestivum) yields were realized, at least in part, through the introduction of the Reduced height (Rht)-B1b and Rht-D1b semi-dwarfing alleles. In contrast to Rht-B1b and Rht-D1b, the Rht-B1c allele is characterized by extreme dwarfism and exceptionally strong dormancy. Recently, 35 intragenic Rht-B1c suppressor alleles were created in the spring wheat cultivar Maringa, and termed overgrowth (ovg) alleles. Here, 14 ovg alleles with agronomically relevant plant heights were reproducibly classified into nine tall and five semi-dwarf alleles. These alleles differentially affected grain dormancy, internode elongation rate, and coleoptile and leaf lengths. The stability of these ovg effects was demonstrated for three ovg alleles in different genetic backgrounds and environments. Importantly, two semi-dwarf ovg alleles increased dormancy, which correlated with improved pre harvest sprouting (PHS) resistance. Since no negative effects on grain yield or quality were observed, these semi-dwarf ovg alleles are valuable for breeding to achieve adequate height reduction and protection of grain quality in regions prone to PHS. Furthermore, this research highlights a unique role for the first 70 amino acids of the DELLA protein, encoded by the Rht-1 genes, in grain dormancy. PMID- 28073951 TI - Nod factors potentiate auxin signaling for transcriptional regulation and lateral root formation in Medicago truncatula. AB - Nodulation (Nod) factors (NFs) are symbiotic molecules produced by rhizobia that are essential for establishment of the rhizobium-legume endosymbiosis. Purified NFs can stimulate lateral root formation (LRF) in Medicago truncatula, but little is known about the molecular mechanisms involved. Using a combination of reporter constructs, pharmacological and genetic approaches, we show that NFs act on early steps of LRF in M. truncatula, independently of the ethylene signaling pathway and of the cytokinin receptor MtCRE1, but in interaction with auxin. We conducted a whole-genome transcriptomic study upon NF and/or auxin treatments, using a lateral root inducible system adapted for M. truncatula. This revealed a large overlap between NF and auxin signaling and, more interestingly, synergistic interactions between these molecules. Three groups showing interaction effects were defined: group 1 contained more than 1500 genes responding specifically to the combinatorial treatment of NFs and auxin; group 2 comprised auxin-regulated genes whose expression was enhanced or antagonized by NFs; and in group 3 the expression of NF regulated genes was antagonized by auxin. Groups 1 and 2 were enriched in signaling and metabolic functions, which highlights important crosstalk between NF and auxin signaling for both developmental and symbiotic processes. PMID- 28073952 TI - Alcohol and coronary artery calcification: an investigation using alcohol flushing as an instrumental variable. AB - Background: We examined whether alcohol flushing could be used as an instrumental variable (IV) and investigated the effect of alcohol consumption on coronary calcification using alcohol flushing status as an IV. Methods: We analysed cross sectional data from 24 681 Korean adults (20 696 men and 3985 women) who had been administered a questionnaire assessing alcohol consumption and alcohol flushing, as well as a coronary artery calcium (CAC) measurement. The associations of alcohol flushing status with potential confounders and alcohol consumption were examined. We employed two-stage predictor substitution methodology for the IV analysis. Results: The prevalence of alcohol flushing did not differ depending on gender, education, household income, cigarette smoking or physical activity. Balanced levels of confounders were observed between alcohol flushers and non flushers. Alcohol flushing was closely related to alcohol consumption and levels of liver enzymes. In men, a doubling in alcohol consumption was associated with increased odds of coronary calcification in both the IV analysis [odds ratio (OR) of CAC scores of 1 or over = 1.11; 95% confidence interval (CI) = 1.03-1.20) and the multivariable regression analysis (OR = 1.04; 95% CI = 1.01-1.07). For cardiovascular risk factors, the IV analysis showed a positive association between alcohol consumption and blood pressure and high-density lipoprotein cholesterol. Conclusions: Alcohol flushing can be used as an IV in studies evaluating the health impact of alcohol consumption, especially in East Asian countries. Through such an analysis, we found that increased alcohol consumption was associated with an increased risk of subclinical coronary atherosclerosis. PMID- 28073953 TI - Commentary: Mining gene-lifestyle interactions in UK Biobank: all that glitters isn't gold. PMID- 28073954 TI - Gene-obesogenic environment interactions in the UK Biobank study. AB - Background: Previous studies have suggested that modern obesogenic environments accentuate the genetic risk of obesity. However, these studies have proven controversial as to which, if any, measures of the environment accentuate genetic susceptibility to high body mass index (BMI). Methods: We used up to 120 000 adults from the UK Biobank study to test the hypothesis that high-risk obesogenic environments and behaviours accentuate genetic susceptibility to obesity. We used BMI as the outcome and a 69-variant genetic risk score (GRS) for obesity and 12 measures of the obesogenic environment as exposures. These measures included Townsend deprivation index (TDI) as a measure of socio-economic position, TV watching, a 'Westernized' diet and physical activity. We performed several negative control tests, including randomly selecting groups of different average BMIs, using a simulated environment and including sun-protection use as an environment. Results: We found gene-environment interactions with TDI (Pinteraction = 3 * 10 -10 ), self-reported TV watching (Pinteraction = 7 * 10 -5 ) and self-reported physical activity (Pinteraction = 5 * 10 -6 ). Within the group of 50% living in the most relatively deprived situations, carrying 10 additional BMI-raising alleles was associated with approximately 3.8 kg extra weight in someone 1.73 m tall. In contrast, within the group of 50% living in the least deprivation, carrying 10 additional BMI-raising alleles was associated with approximately 2.9 kg extra weight. The interactions were weaker, but present, with the negative controls, including sun-protection use, indicating that residual confounding is likely. Conclusions: Our findings suggest that the obesogenic environment accentuates the risk of obesity in genetically susceptible adults. Of the factors we tested, relative social deprivation best captures the aspects of the obesogenic environment responsible. PMID- 28073955 TI - Establishment of a rat model of thrombosis induced by intravenous injection of anti-phosphatidylserine-prothrombin complex antibody. AB - Objective: Recent studies have suggested that aPS-PT antibody is one of the most relevant autoantibodies to APS. This study aimed to demonstrate the pathogenicity of aPS-PT antibody in vivo . Methods: At first, cultured rat vascular endothelial cells (RECs) were exposed to calf thymus-derived histones. Two hours later, lactate dehydrogenase release from the RECs and expression of PS on the cell surface were assessed. Next, we administered an i.v. injection of calf thymus derived histones into Wistar rats (12.5 ug/g weight of 8-week-old female rats), and 2 h later they were given an i.v. injection of aPS-PT mAb (1.25 mg/g weight, n = 6) or an equal dose of rat IgM as controls (n = 5). Three days later, histological examination was conducted. Results: Calf thymus-derived histones (>12.5 ug/ml) could injure RECs in vitro . Simultaneously, annexin V could bind to the RECs; thereby, this result indicated that cell-free histone exposure of vascular endothelial cells induced cell surface expression of PS, which is naturally present inside the plasma membrane. Thrombosis developed with higher frequency in the rats given an i.v. injection of aPS-PT mAb than in controls. Conclusion: We established a rat model of thrombosis induced by i.v. injection of aPS-PT mAb. PMID- 28073956 TI - The effect of rheumatoid arthritis-associated autoantibodies on the incidence of cardiovascular events in a large inception cohort of early inflammatory arthritis. AB - Objective: . RA is associated with an increased risk of cardiovascular events (CVEs). The objective was to estimate independent effects of RA autoantibodies on the incident CVEs in patients with early RA. Methods: Patients were enrolled in the Canadian Early Inflammatory Arthritis Cohort, a prospective multicentre inception cohort. Incident CVEs, including acute coronary syndromes and cerebrovascular events, were self-reported by the patient and partially validated by medical chart review. Seropositive status was defined as either RF or ACPA positive. Multivariable Cox proportional hazards survival analysis was used to estimate the effects of seropositive status on incident CVEs, controlling for RA clinical variables and traditional cardiovascular risk factors. Results: . A total of 2626 patients were included: the mean symptom duration at diagnosis was 6.3 months ( s . d . 4.6), the mean age was 53 years ( s . d . 15), 72% were female and 86% met classification criteria for RA. Forty-six incident CVEs occurred over 6483 person-years [incidence rate 7.1/1000 person-years (95% confidence interval 5.3, 9.4)]. The CVE rate did not differ in seropositive vs seronegative subjects and seropositivity was not associated with incident CVEs in multivariable Cox regression models. Baseline covariates independently associated with incident CVEs were older age, a history of hypertension and a longer duration of RA symptoms prior to diagnosis. Conclusion: The rate of CVEs early in the course of inflammatory arthritis was low; however, delays in the diagnosis of arthritis increased the rate of CVEs. Hypertension was the strongest independent risk factor for CVEs. Results support early aggressive management of RA disease activity and co-morbidities to prevent severe complications. PMID- 28073957 TI - Primary inefficacy of TNF inhibitors in patients with axial spondyloarthritis: a long-term follow-up of 25 patients. AB - Objectives: Primary inefficacy of TNF inhibitors (TNFi) for axial spondyloarthritis (axSpA) is infrequent. The objective of this study was to assess the long-term evolution and final diagnosis of patients with primary inefficacy of TNFi for axSpA. Methods: This was a systematic retrospective study of all patients receiving a TNFi for axSpA in one tertiary referral centre. Patients had axSpA confirmed by a rheumatologist and were started on a first course of TNFi according to usual practice. If the rheumatologist interrupted treatment at 3 months for inefficacy, this was defined as primary inefficacy. Five to 10 years later, these patients were re-evaluated. Results: Of 222 patients receiving a first TNFi for axSpA, 27 (12%) were considered as having primary inefficacy. These patients were more often females (48 vs 27%, P = 0.04), had higher functional impairment [BASDAI (0-100) 68 vs 42, P = 0.001] and less increased CRP (50 vs 78%, P = 0.008.) At the follow-up, 25 (92%) patients were re evaluated: the diagnosis of axSpA was confirmed for 21/25 (84%) patients according to the Assessment of SpondyloArthritis criteria and 20/25 (80%) patients according to the rheumatologist; but 18/25 (72%) had at least one other cause of their symptoms from among OA, widespread pain syndrome or depression. A second TNFi was prescribed for 16 patients and was efficacious for 9 (56%). Conclusion: Most patients with primary inefficacy had a confirmed diagnosis of axSpA, but they often had other causes of pain. We suggest that patients with primary inefficacy to TNFi should be screened for comorbidities that may interfere with axSpA activity assessment. PMID- 28073958 TI - Rudeness and Medical Team Performance. AB - OBJECTIVES: Rudeness is routinely experienced by medical teams. We sought to explore the impact of rudeness on medical teams' performance and test interventions that might mitigate its negative consequences. METHODS: Thirty-nine NICU teams participated in a training workshop including simulations of acute care of term and preterm newborns. In each workshop, 2 teams were randomly assigned to either an exposure to rudeness (in which the comments of the patient's mother included rude statements completely unrelated to the teams' performance) or control (neutral comments) condition, and 2 additional teams were assigned to rudeness with either a preventative (cognitive bias modification [CBM]) or therapeutic (narrative) intervention. Simulation sessions were evaluated by 2 independent judges, blind to team exposure, who used structured questionnaires to assess team performance. RESULTS: Rudeness had adverse consequences not only on diagnostic and intervention parameters (mean therapeutic score 3.81 +/- 0.36 vs 4.31 +/- 0.35 in controls, P < .01), but also on team processes (such as information and workload sharing, helping and communication) central to patient care (mean teamwork score 4.04 +/- 0.34 vs 4.43 +/- 0.37, P < .05). CBM mitigated most of these adverse effects of rudeness, but the postexposure narrative intervention had no significant effect. CONCLUSIONS: Rudeness has robust, deleterious effects on the performance of medical teams. Moreover, exposure to rudeness debilitated the very collaborative mechanisms recognized as essential for patient care and safety. Interventions focusing on teaching medical professionals to implicitly avoid cognitive distraction such as CBM may offer a means to mitigate the adverse consequences of behaviors that, unfortunately, cannot be prevented. PMID- 28073959 TI - Surrogate Pregnancy After Prenatal Diagnosis of Spina Bifida. AB - Some pregnancies today involve infertile individuals or couples who contract with a fertile woman to carry a pregnancy for them. The woman who carries the pregnancy is referred to as a "gestational carrier." The use of such arrangements is increasing. Most of the time, these arrangements play out as planned; sometimes, however, problems arise. This article discusses a case in which a fetal diagnosis of spina bifida led the infertile couple to request that the gestational carrier terminate the pregnancy, and the gestational carrier did not wish to do so. Experts in the medical and legal issues surrounding surrogacy discuss the considerations that should go into resolving such a conflict. PMID- 28073960 TI - Ligand characterization of CYP4B1 isoforms modified for high-level expression in Escherichia coli and HepG2 cells. AB - Human CYP4B1, a cytochrome P450 monooxygenase predominantly expressed in the lung, inefficiently metabolizes classical CYP4B1 substrates, such as the naturally occurring furan pro-toxin 4-ipomeanol (4-IPO). Highly active animal forms of the enzyme convert 4-IPO to reactive alkylating metabolite(s) that bind(s) to cellular macromolecules. By substitution of 13 amino acids, we restored the enzymatic activity of human CYP4B1 toward 4-IPO and this modified cDNA is potentially valuable as a suicide gene for adoptive T-cell therapies. In order to find novel pro-toxins, we tested numerous furan analogs in in vitro cell culture cytotoxicity assays by expressing the wild-type rabbit and variants of human CYP4B1 in human liver-derived HepG2 cells. To evaluate the CYP4B1 substrate specificities and furan analog catalysis, we optimized the N-terminal sequence of the CYP4B1 variants by modification/truncation and established their heterologous expression in Escherichia coli (yielding 70 and 800 nmol.l-1 of recombinant human and rabbit enzyme, respectively). Finally, spectral binding affinities and oxidative metabolism of the furan analogs by the purified recombinant CYP4B1 variants were analyzed: the naturally occurring perilla ketone was found to be the tightest binder to CYP4B1, but also the analog that was most extensively metabolized by oxidative processes to numerous non-reactive reaction products. PMID- 28073961 TI - Genetic characterization of mcr-1-bearing plasmids to depict molecular mechanisms underlying dissemination of the colistin resistance determinant. AB - OBJECTIVES: To analyse and compare mcr-1-bearing plasmids from animal Escherichia coli isolates, and to investigate potential mechanisms underlying dissemination of mcr-1. METHODS: Ninety-seven ESBL-producing E. coli strains isolated from pig farms in China were screened for the mcr-1 gene. Fifteen mcr-1-positive strains were subjected to molecular characterization and bioinformatic analysis of the mcr-1-bearing plasmids that they harboured. RESULTS: Three major types of mcr-1 bearing plasmids were recovered: IncX4 (~33 kb), IncI2 (~60 kb) and IncHI2 (~216 280 kb), among which the IncX4 and IncI2 plasmids were found to harbour the mcr-1 gene only, whereas multiple resistance elements including blaCTX-M, blaCMY, blaTEM, fosA, qnrS, floR and oqxAB were detected, in various combinations, alongside mcr-1 in the IncHI2 plasmids. The profiles of mcr-1-bearing plasmids in the test strains were highly variable, with coexistence of two mcr-1-bearing plasmids being common. However, the MIC of colistin was not affected by the number of mcr-1-carrying plasmids harboured. Comparative analysis of the plasmids showed that they contained an mcr-1 gene cassette with varied structures (mcr-1 orf, ISApl1-mcr-1-orf and Tn6330), with the IncHI2 type being the most active in acquiring foreign resistance genes. A novel transposon, Tn6330, with the structure ISApl1-mcr-1-orf-ISApl1 was found to be the key element mediating translocation of mcr-1 into various plasmid backbones through formation of a circular intermediate. CONCLUSIONS: The mcr-1 gene can be disseminated via multiple mobile elements including Tn6330, its circular intermediate and plasmids harbouring such elements. It is often co-transmitted with other resistance determinants through IncHI2 plasmids. The functional mechanism of Tn6330, a typical composite transposon harbouring mcr-1, should be further investigated. PMID- 28073963 TI - In vitro activity of daptomycin combined with dalbavancin and linezolid, and dalbavancin with linezolid against MRSA strains. AB - OBJECTIVES: Combination therapies have a distinct advantage over monotherapies in terms of their broad spectrum, synergistic effect and prevention of the emergence of drug resistance. In the present study, the in vitro antibacterial activity of daptomycin combinations with linezolid and dalbavancin, and dalbavancin with linezolid were evaluated against 30 clinical MRSA strains. METHODS: The MICs of all antibiotics were determined using microbroth dilution as described by the CLSI. The in vitro activities of antibiotics in combination were assessed by using a microbroth 'chequerboard' assay. The MIC values of all antibiotics determined were evaluated in accordance with the recommendations of the CLSI for daptomycin and linezolid, and the FDA for dalbavancin. RESULTS: All strains (100%) were found to be susceptible to daptomycin, dalbavancin and linezolid. The MIC50, MIC90 and MICrange values of these antibiotics were determined to be 1, 1 and 0.5-1 mg/L, 0.12, 0.12 and 0.03-0.12 mg/L, and 1, 2 and 1-2 mg/L, respectively. The rates of synergistic effects were 67% for daptomycin combined with dalbavancin and with linezolid, and 60% for dalbavancin combined with linezolid. CONCLUSIONS: The results of this study show that in vitro combinations of these new antimicrobials will be effective in the therapy of MRSA infections. PMID- 28073962 TI - A case of multiple contamination with methylase ArmA-producing pathogens. PMID- 28073964 TI - Single-dose pharmacokinetics and pharmacodynamics of oral tenofovir and emtricitabine in blood, saliva and rectal tissue: a sub-study of the ANRS IPERGAY trial. AB - OBJECTIVES: In the ANRS IPERGAY pre-exposure prophylaxis (PrEP) trial, a single dose of tenofovir disoproxil fumarate and emtricitabine was taken orally 2-24 h before sexual intercourse. A sub-study was conducted to assess the pharmacokinetics of tenofovir and emtricitabine in blood, saliva and rectal tissue following this initial oral intake. METHODS: Plasma, PBMC, saliva and rectal tissue sampling was performed over 24 h in 12 seronegative men before enrolment in the ANRS IPERGAY trial, following a single dose of 600 mg tenofovir disoproxil fumarate/400 mg emtricitabine. Ex vivo HIV infectibility of rectal biopsies was also assessed. RESULTS: The median plasma Tmax of tenofovir (median Cmax: 401 MUg/L) and emtricitabine (median Cmax: 2868 MUg/L) was obtained 1 h (range: 0.5-4) and 2 h (range: 1-4) after dosing, respectively. The median C24 of tenofovir and emtricitabine was 40 and 63 MUg/L, respectively. The median PBMC tenofovir diphosphate and emtricitabine triphosphate levels were 12.2 and 16.7 fmol/106 cells and 2800 and 2000 fmol/106 cells at 2 and 24 h after dosing, respectively. Saliva/plasma AUC0-24 ratios were 2% and 17% for tenofovir and emtricitabine, respectively. Emtricitabine was detected in rectal tissue 30 min after dosing, whereas tenofovir was only detectable at 24 h. Ex vivo HIV infectibility assays of rectal biopsies showed partial protection after dosing (P < 0.07). DISCUSSION: A single high dose of oral tenofovir disoproxil fumarate/emtricitabine provides rapid and high blood levels of tenofovir and emtricitabine, with rapid diffusion of emtricitabine in saliva and rectal tissue. PMID- 28073965 TI - Spread of mcr-1-carrying Enterobacteriaceae in sewage water from Spain. AB - Objectives: The mobile colistin resistance gene mcr-1 has been identified worldwide in human and animal sources, while its occurrence in the environment is still largely unknown. The aim of this study was to investigate the presence of mcr-1 -harbouring Enterobacteriaceae in water samples obtained from rivers and waste water treatment plants in the area of Barcelona, Spain. Methods: The presence of mcr-1 was detected by PCR. Bacterial identification was performed via MALDI-TOF MS. Resistance to colistin was determined by a broth dilution method. The epidemiological relationship between the positive isolates was assessed with PFGE and ST was determined by MLST. Plasmid characterization was performed by transformation experiments, antimicrobial susceptibility testing and incompatibility group PCR. Results: Thirty MDR isolates bearing mcr-1 , 29 Escherichia coli (ST632 and ST479) and 1 Klebsiella pneumoniae (ST526), were identified in sewage from two different waste water treatment plants, whereas the gene was not found in river water. All isolates, including the K. pneumoniae , harboured bla CTX-M-55 and bla TEM-1 . mcr-1 was in all cases associated with an IncI2 plasmid, which only conferred resistance to colistin. mcr-1 was harboured by two predominant E. coli clones that were found in both waste water treatment plants. Conclusions: This study showed a high occurrence of mcr-1 in the sewage of Barcelona, mainly due to the dissemination of two E. coli pulsotypes that are circulating in the population. The presence of mcr-1 in the environment is a cause for concern, and suggests high prevalence of mcr-1 in the community. PMID- 28073966 TI - Extended stability of antimicrobial agents in administration devices. AB - Background: Outpatient parenteral antimicrobial therapy (OPAT) is an established approach to patient care. A lack of data on antimicrobial stability within administration devices is a barrier to service expansion, and poses an antimicrobial stewardship dilemma. Often broad-spectrum, long half-life agents are used instead of narrow-spectrum agents, which need more frequent administration, but could possibly be used if stability data were available. Objectives: To complete a comprehensive literature review of published antimicrobial stability data, and assess these against a nationally recognized minimum dataset for medicines compounded into administration devices. Methods: Medline, EMBASE, Global Health, International Pharmaceutical Abstracts and Biomedical Research Database were interrogated in April 2014 and updated in November 2015. Results: A total of 420 citations were reviewed with 121 selected for full text review. None of these papers met the inclusion criteria stipulated in the national standards. The most frequent reason for study exclusion was the tolerance limit for the level of the active pharmaceutical ingredient being wider than 95%-105% and absence of 'in-use' testing at 37 degrees C. Conclusions: This review found no published studies that comply with UK national standards for stability testing. We recommend further research and publication of antimicrobial stability data to support OPAT within the antimicrobial stewardship agenda. PMID- 28073967 TI - DNA replication proteins as potential targets for antimicrobials in drug resistant bacterial pathogens. AB - With the impending crisis of antimicrobial resistance, there is an urgent need to develop novel antimicrobials to combat difficult infections and MDR pathogenic microorganisms. DNA replication is essential for cell viability and is therefore an attractive target for antimicrobials. Although several antimicrobials targeting DNA replication proteins have been developed to date, gyrase/topoisomerase inhibitors are the only class widely used in the clinic. Given the numerous essential proteins in the bacterial replisome that may serve as a potential target for inhibitors and the relative paucity of suitable compounds, it is evident that antimicrobials targeting the replisome are underdeveloped so far. In this review, we report on the diversity of antimicrobial compounds targeting DNA replication and highlight some of the challenges in developing new drugs that target this process. PMID- 28073968 TI - Variants of AbGRI3 carrying the armA gene in extensively antibiotic-resistant Acinetobacter baumannii from Singapore. AB - Objectives: To investigate the context of the ribosomal RNA methyltransferase gene armA in carbapenem-resistant global clone 2 (GC2) Acinetobacter baumannii isolates from Singapore. Methods: Antibiotic resistance was determined using disc diffusion; PCR was used to identify resistance genes. Whole genome sequences were determined and contigs were assembled and ordered using PCR. Resistance regions in unsequenced isolates were mapped. Results: Fifteen GC2 A. baumannii isolated at Singapore General Hospital over the period 2004-11 and found to carry the armA gene were resistant to carbapenems, third-generation cephalosporins, fluoroquinolones and most aminoglycosides. In these isolates, the armA gene was located in a third chromosomal resistance island, previously designated AbGRI3. In four isolates, armA was in a 19 kb IS 26 -bounded transposon, designated Tn 6180 . In three of them, a 2.7 kb transposon carrying the aphA1b gene, designated Tn 6179 , was found adjacent to and sharing an IS 26 with Tn 6180. However, in these four isolates a 3.1 kb segment of the adjacent chromosomal DNA has been inverted by an IS 26 -mediated event. The remaining 11 isolates all contained a derivative of Tn 6180 that had lost part of the central segment and only one retained Tn 6179 . The chromosomal inversion was present in four of these and in seven the deletion extended beyond the inversion into adjacent chromosomal DNA. AbGRI3 forms were found in available GC2 sequences carrying armA. Conclusions: In GC2 A. baumannii , the armA gene is located in various forms of a third genomic resistance island named AbGRI3. An aphA1b transposon is variably present in AbGRI3. PMID- 28073969 TI - Characterization of carbapenemase-producing Enterobacteriaceae in the West Midlands region of England: 2007-14. AB - Objectives: Carbapenemase-producing Enterobacteriaceae (CPE) have been increasingly reported in the UK since 2003. We analysed patient and isolate data for CPE confirmed by the national reference laboratory from laboratories in the West Midlands region from November 2007 to December 2014. Methods: MICs were determined by BSAC agar dilution methodology and isolates exhibiting resistance to one or more carbapenems were screened for carbapenemase genes by PCR. Plasmid analyses were performed after electro-transformation of carbapenemase-encoding plasmids. WGS was performed on both transformants and clinical isolates. Patient data provided by the sending laboratories were reviewed. Results: During the study period, CPE ( n = 139) were submitted from 13 laboratories in the West Midlands region, originating from 108 patients and including one environmental isolate. CPE submissions increased significantly from 2009 onwards. Isolates were predominantly Klebsiella pneumoniae (89/139) obtained from inpatients. WGS was performed on all clinical isolates and transformants. After deduplication 119 isolates and 96 transformants remained for analysis. Within these, four families of carbapenemase genes were identified: bla NDM (69/119), bla KPC (26/119), bla OXA-48-like (16/119) and bla VIM (7/119); one isolate carried both bla NDM and bla OXA-48-like . Isolates represented diverse STs and plasmid replicon types. Plasmid analyses identified plasmids of different replicon types encoding bla KPC , bla NDM and bla OXA-48-like genes, found across several species and STs. Conclusions: CPE have been reported increasingly in the West Midlands region over a 7 year period. bla NDM , bla KPC and bla OXA-48-like were the dominant carbapenemase genes and were found in a range of diverse genomic/plasmid environments, highlighting their ability to mobilize across different plasmids, often impeding the detection of outbreaks. PMID- 28073970 TI - Estimated generic prices for novel treatments for drug-resistant tuberculosis. AB - Background: The estimated worldwide annual incidence of MDR-TB is 480 000, representing 5% of TB incidence, but 20% of mortality. Multiple drugs have recently been developed or repurposed for the treatment of MDR-TB. Currently, treatment for MDR-TB costs thousands of dollars per course. Objectives: To estimate generic prices for novel TB drugs that would be achievable given large scale competitive manufacture. Methods: Prices for linezolid, moxifloxacin and clofazimine were estimated based on per-kilogram prices of the active pharmaceutical ingredient (API). Other costs were added, including formulation, packaging and a profit margin. The projected costs for sutezolid were estimated to be equivalent to those for linezolid, based on chemical similarity. Generic prices for bedaquiline, delamanid and pretomanid were estimated by assessing routes of synthesis, costs/kg of chemical reagents, routes of synthesis and per step yields. Costing algorithms reflected variable regulatory requirements and efficiency of scale based on demand, and were validated by testing predictive ability against widely available TB medicines. Results: Estimated generic prices were US$8-$17/month for bedaquiline, $5-$16/month for delamanid, $11-$34/month for pretomanid, $4-$9/month for linezolid, $4-$9/month for sutezolid, $4 $11/month for clofazimine and $4-$8/month for moxifloxacin. The estimated generic prices were 87%-94% lower than the current lowest available prices for bedaquiline, 95%-98% for delamanid and 94%-97% for linezolid. Estimated generic prices were $168-$395 per course for the STREAM trial modified Bangladesh regimens (current costs $734-$1799), $53-$276 for pretomanid-based three-drug regimens and $238-$507 for a delamanid-based four-drug regimen. Conclusions: Competitive large-scale generic manufacture could allow supplies of treatment for 5-10 times more MDR-TB cases within current procurement budgets. PMID- 28073971 TI - Sexual dimorphisms in genetic loci linked to body fat distribution. AB - Obesity is a chronic condition associated with increased morbidity and mortality and is a risk factor for a number of other diseases including type 2 diabetes and cardiovascular disease. Obesity confers an enormous, costly burden on both individuals and public health more broadly. Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes. Body fat distribution is distinct from overall obesity in measurement, but studies of body fat distribution can yield insights into the risk factors for and causes of overall obesity. Sexual dimorphism in body fat distribution is present throughout life. Though sexual dimorphism is subtle in early stages of life, it is attenuated in puberty and during menopause. This phenomenon could be, at least in part, due to the influence of sex hormones on the trait. Findings from recent large genome-wide association studies (GWAS) for various measures of body fat distribution (including waist-to-hip ratio, hip or waist circumference, trunk fat percentage and the ratio of android and gynoid fat percentage) emphasize the strong sexual dimorphism in the genetic regulation of fat distribution traits. Importantly, sexual dimorphism is not observed for overall obesity (as assessed by body mass index or total fat percentage). Notably, the genetic loci associated with body fat distribution, which show sexual dimorphism, are located near genes that are expressed in adipose tissues and/or adipose cells. Considering the epidemiological and genetic evidence, sexual dimorphism is a prominent feature of body fat distribution. Research that specifically focuses on sexual dimorphism in fat distribution can provide novel insights into human physiology and into the development of obesity and its comorbidities, as well as yield biological clues that will aid in the improvement of disease prevention and treatment. PMID- 28073972 TI - Awareness and attitude regarding reproductive options of persons carrying a BRCA mutation and their partners. AB - STUDY QUESTION: To what extent are BRCA mutation carriers and their partners in the Netherlands aware about preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND) as reproductive options and what is their attitude towards these options? SUMMARY ANSWER: Awareness of PGD (66%) and PND (61%) among BRCA mutation carriers and their partners is relatively high and 80% and 26%, respectively, of BRCA carriers and their partners find offering PGD and PND for hereditary breast and ovarian cancer (HBOC) acceptable. WHAT IS KNOWN ALREADY: Internationally, awareness of PGD among persons with a genetic cancer predisposition appears to be relatively low (35%) and although acceptability is generally high (71%), only a small proportion of mutation carriers would consider using PGD (36%). However, for HBOC, there are no studies available that investigated the perspective of individuals with a confirmed BRCA1/2 mutation and their partners about PGD and PND including demographic and medical correlates of awareness and acceptability. STUDY DESIGN, SIZE, DURATION: A cross-sectional survey was completed by 191 participants between July 2012 and June 2013. Participants were recruited through patient organizations (88%) and the databases of two Clinical Genetics departments in the Netherlands (12%). PARTICIPANTS/MATERIALS, SETTING, METHODS: Male and female BRCA carriers and their partners completed an online survey, which assessed demographic and medical characteristics, and awareness, knowledge, acceptability and consideration of PGD and PND as main outcomes. Correlations between demographic and medical characteristics and the main outcomes were investigated. MAIN RESULTS AND ROLE OF CHANCE: The majority of respondents were female (87%), of reproductive age (86%) and about half reported a desire for a child in the future. About two-thirds (66%) were aware of PGD and 61% of PND for HBOC. PGD knowledge was moderate (5.5 on a 9-point scale) and acceptability of PGD and PND for HBOC was 80% and 26%, respectively. A minority would personally consider using PGD (39%) or PND (20%). Individuals with a higher educational level were more likely to be aware of PGD (P < 0.001) and PND (P < 0.001) and persons with a more immediate child wish were more often aware of PGD (P = 0.044) and had more knowledge about PGD (P = 0.001). PGD acceptability was positively associated with knowledge about PGD (P = 0.047), and PND acceptability was higher among partners in comparison to carriers (P = 0.001). Participants with a history of cancer and with a higher perceived seriousness of breast and ovarian cancer were more likely to consider using PGD (P = 0.003 and P < 0.001 respectively) or PND (P = 0.021 and P = 0.017 respectively). LIMITATIONS, REASONS FOR CAUTION: The response rate (23%) of participants invited by the clinical genetics departments was low, probably related to a simultaneous study that used a similar recruitment strategy within the same target group, which may have resulted in selection bias. Moreover, PGD knowledge was measured with an instrument that is not yet validated since to date such an instrument is not available in the literature. Finally, the cross-sectional design of this study limits us from drawing any causal conclusions. WIDER IMPLICATIONS OF THE FINDINGS: Improvement of information provision remains needed, in order to timely inform all couples with HBOC about the available reproductive options and enable them to make a balanced reproductive decision. This may limit the risk of negative psychological impact due to decisional conflict and possible regret. STUDY FUNDING/COMPETING INTEREST(S): The Dutch breast cancer foundation Stichting Pink Ribbon (grant number 2010.PS11.C74). None of the authors have competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 28073973 TI - Human foetal ovary shares meiotic preventing factors with the developing testis. AB - STUDY QUESTION: How can pre-meiotic germ cells persist in the human foetal ovary? SUMMARY ANSWER: Numerous oogonia escaping meiotic entry were retrieved throughout human ovarian development simultaneously with the expression of signalling pathways preventing meiosis, typically described in the rodent embryonic testis. WHAT IS KNOWN ALREADY: The transition from mitosis to meiosis is a key event in female germ cells that remains poorly documented in research on the human ovary. Previous reports described a strikingly asynchronous differentiation in the human female germ line during development, with the persistence of oogonia among oocytes and follicles during the second and third trimesters. The possible mechanisms allowing some cells to escape meiosis remain elusive. STUDY DESIGN SIZE, DURATION: In order to document the extent of this phenomenon, we detailed the expression profile of germ cell differentiation markers using 73 ovaries ranging from 6.4 to 35 weeks post-fertilization. PARTICIPANTS/MATERIALS SETTING, METHODS: Pre-meiotic markers were detected by immunohistochemistry or qRT-PCR. The expression of the main meiosis-preventing factors identified in mice was analysed, and their functionality assessed using organ cultures. MAIN RESULTS AND THE ROLE OF CHANCE: Oogonia stained for AP2gamma could be traced from the first trimester until the end of the third trimester. Female germ cell differentiation is organized both in time and space in a centripetal manner in the foetal human ovary. Unexpectedly, some features usually ascribed to rodent pre-spermatogonia could be observed in human foetal ovaries, such as NANOS2 expression and quiescence in some germ cells. The two main somatic signals known to inhibit meiosis in the mouse embryonic testis, CYP26B1 and FGF9, were detected in the human ovary and act simultaneously to repress STRA8 and meiosis in human foetal female germ cells. LARGE SCALE DATA: N/A. LIMITATIONS REASON FOR CAUTION: Our conclusions relied partly on in vitro experiments. Germ cells were not systematically identified with immunostaining and some may have thus escaped analysis. WIDER IMPLICATIONS OF THE FINDINGS: We found evidence that a robust repression of meiotic entry is taking place in the human foetal ovary, possibly explaining the exceptional long-lasting presence of pre-meiotic germ cells until late gestational age. This result calls for a redefinition of the markers known as classical male markers, which may in fact characterize mammalian developing gonads irrespectively of their sex. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Universite Paris Diderot-Paris 7 and Universite Paris-Sud, CEA, INSERM, and Agence de la Biomedecine. The authors declare no conflict of interest. PMID- 28073975 TI - Modeling Environmental Influences in the Psyllaephagus bliteus (Hymenoptera: Encyrtidae)-Glycaspis brimblecombei (Hemiptera: Aphalaridae) Parasitoid-Host System. AB - Glycaspis brimblecombei Moore (Hemiptera: Aphalaridae) is an invasive psyllid introduced into the Mediterranean area, where it affects several species of Eucalyptus. Psyllaephagus bliteus Riek (Hymenoptera: Encyrtidae) is a specialized parasitoid of this psyllid that was accidentally introduced into Italy in 2011. We developed a model of this host-parasitoid system that accounts for the influence of environmental conditions on the G. brimblecombei population dynamics and P. bliteus parasitism rates in the natural ecosystem. The Lotka-Volterra based model predicts non-constant host growth and parasitoid mortality rates in association with variation in environmental conditions. The model was tested by analyzing sampling data collected in Naples in 2011 (before the parasitoid was present) and defining several environmental patterns, termed Temperature-Rain or T-R patterns, which correspond to the host growth rate. A mean value of the host growth rate was assigned to each T-R pattern, as well as a variation of the parasitoid mortality rate based on temperature thresholds. The proposed model was applied in simulation tests related to T-R patterns carried out with a data series sampled between June 2014 and July 2015 in five Italian sites located in Campania, Lazio, Sicily, and Sardinia regions. The simulation results showed that the proposed model provides an accurate approximation of population trends, although oscillation details may not be apparent. Results predict a 64% reduction in G. brimblecombei population density owing to P. bliteus parasitoid activity. Our results are discussed with respect to features of the host-parasitoid interaction that could be exploited in future biological control programs. PMID- 28073974 TI - Infertile women who screen positive for depression are less likely to initiate fertility treatments. AB - STUDY QUESTION: Are infertile women who screen positive for depression less likely to initiate infertility treatments? SUMMARY ANSWER: Infertile women who screen positive for depression are less likely to initiate treatment for infertility. WHAT IS ALREADY KNOWN: Infertility imposes a psychological burden on many couples. Depression and anxiety have been demonstrated in ~40% of infertile women, which is twice that of fertile women. Further, the psychological burden associated with infertility treatment has been cited as a major factor for discontinuation of infertility care. STUDY DESIGN, SIZE, DURATION: Prospective, observational study in a clinical-based cohort of 416 women who completed a questionnaire after the new patient visit, from January 2013 until December 2014 inclusive. PARTICIPANTS/MATERIALS, SETTING, METHODS: All new female infertility patients (n = 959) seen between January 2013 and December 2014 at University of North Carolina Fertility received an electronic questionnaire to screen for mental health disorders and to evaluate their perception of mental health disorders on infertility. MAIN RESULTS AND THE ROLE OF CHANCE: Of 959 surveys sent, 416 women completed the questionnaire (43%). The prevalence screening positive for depression, using the NIH PROMIS screening tool, was 41%. Sixty-two percent of all women initiated infertility treatment, and of these, 81% did so within 4 months. In multivariate analysis, women who screened positive for depression had 0.55 times the odds of initiating treatment for infertility (95% CI: 0.31-0.95). Similarly, women who screened positive for depression had 0.58 times the odds of initiating infertility treatment within 4 months (95% CI: 0.35 0.97), which was the time of censoring from the most recent patient evaluated. Women who screened positive for depression were less likely to pursue treatment with oral medications or IVF (P = 0.01 and P = 0.03, respectively), as compared to women who did not screen positive for depression. LIMITATIONS, REASONS FOR CAUTION: Questionnaire-based evaluations may result in a lower prevalence of psychological disorder as some participants feign emotional well-being. Although we did not identify differences in women who responded to our survey and those who did not, responder bias may still be present. In addition, infertility is a couple's disease. However, this study only included psychological evaluation of the female partner. We have no information about the women's previous treatment. WIDER IMPLICATIONS OF THE FINDINGS: Screening for depression is important in the infertility patient population, as further evaluation and psychological interventions may improve compliance with fertility treatments, quality of life, and potentially, the overall chance of pregnancy. STUDY FUNDING/COMPETING INTERESTS: None. PMID- 28073976 TI - Effects of Carriers, Emulsifiers, and Biopesticides for Direct Silk Treatments on Caterpillar Feeding Damage and Ear Development in Sweet Corn. AB - In the northeastern United States, control of Lepidopteran pests of sweet corn, particularly corn earworm [Helicoverpa zea (Boddie)], is difficult using organic methods. The direct application of corn oil and Bacillus thuringiensis (Bt) to corn silk has been shown to reduce ear damage from corn earworm in past studies; these studies sought to optimize this method by evaluating additional carrier and biopesticide mixtures that comply with the United States Federal Insecticide, Fungicide, and Rodenticide Act and National Organic Standards. Carriers, which are liquids used to dissolve the biopesticide and deliver it into the tip of the ear, may have phytotoxic or insecticidal properties. Experiments conducted from 2001 to 2005 evaluated caterpillar damage and ear development effects from carriers (vegetable and paraffinic oils and carrageenan), biopesticides (Bt, spinsosad, and neem), and three emulsifiers in various combinations when applied directly to the tips of the ears 5-7 d after silk initiation. There were no effects of emulsifiers on ear quality, except for slight reduction in caterpillar damage in one of the two years. There were no differences among corn, soy, canola, and safflower oils in corn earworm control or tip development. The carrageenan carrier had the least effect upon ear development as measured by the length of nonpollinated kernels at the tip, compared to corn oil or paraffinic oil (JMS Stylet Oil), which caused the greatest tip damage as well as an oily discoloration. The carrier-pesticide combinations with the best ear quality overall were spinosad in carrageenan or corn oil, and Bt in carrageenan. PMID- 28073977 TI - The Effects of a Modified Hot Water Treatment on Anastrepha ludens (Diptera: Tephritidae)-Infested Mango. AB - The Mexican fruit fly, Anastrepha ludens (Loew), is a quarantine pest in mango (Mangifera indica L.) that can be controlled by using a hot water treatment (HWT). This treatment is normally followed by a 30-min hydrocooling (HYC) process that reduces the negative effects that the treatment has on fruit quality. However, if hot water-treated fruits are immediately immersed in water at 21 degrees C, the survival rate of third-instar A. ludens may be increased. The current approved treatment protocol states that if HYC is used, then treated fruit should undergo an additional 10-min HWT or on platform for 30 min before HYC. We aimed to determine the efficacy of HWT without an additional 10-min treatment before being subjected to HYC, while taking into consideration that the most important conditions are the temperature of the fruit core throughout treatment and the type of infestation, either oviposition or inoculation. Two experimental tests were conducted. Our first aim was to determine the effectiveness of HWT followed by HYC using three varieties and different size classes of mangoes ('Ataulfo' 200-375 and 401-570 g; 'Tommy Atkins' 401-500 and 501-700 g; 'Kent' 401-500 g). The four treatment combinations used to test HWT and immediate HYC at 21 degrees C were 1) HWT, 2) HWT/HYC, 3) HWT + 10 min/HYC, and 4) HWT/30 min on platform/HYC; an independent experiment was used for each variety. The second aim was to validate the HWT/HYC combination by performing confirmatory tests in commercial packing houses. The results showed that as long as the mango core temperature reached 45 degrees C during the HWT, it was not necessary to add the 10-min treatment to the HWT before HYC at 21 degrees C was applied. To ensure that the larvae are subjected to the HWT treatment for sufficient time to be lethal, the temperature of the fruit core throughout the treatment must be recorded. PMID- 28073978 TI - Effects of Bt Corn and Egg Density on Western Corn Rootworm (Coleoptera: Chrysomelidae) Adult Emergence and Estimation of Effective Bt Dose. AB - Since 2003, rootworm-protected transgenic corn has been commercially deployed in the United States as a principal method of control of western corn rootworm, Diabrotica virgifera virgifera LeConte. Durability of this technology depends partly on larval mortality ("dose") exerted by the traits, but density-dependent mortality can confound calculations of dose. Research reported here examined the effects of density-dependent mortality on adult emergence and estimates of trait dose. At sites in Illinois and Indiana, western corn rootworm eggs were infested at four densities on non-Bt corn and at a single density on corn hybrids with transgenic events MON 88017 (VT Triple PRO), DAS-59122-7 (Herculex Insect Protection), and MON 88017 * DAS-59122-7 (SmartStax corn). Beetles were collected weekly in large emergence cages. Density-dependent mortality and the effect of Bt traits were examined using percent survival from egg to adult, sex ratio, and beetle mass. Beetle emergence from Bt treatments was very low, and percent survival from non-Bt treatments was greatest at the lowest egg density (410 eggs per row-meter). Therefore, emergence from the lowest infestation density on non Bt corn was used to estimate the effective dose of the Bt treatments. Sex ratio and beetle mass were unaffected by density-dependent effects and were not consistently affected by Bt traits. Dose was estimated at 97.4-99.3% for MON 88017, 98.8-99.9% for DAS-59122-7, and 99.7-100.0% for MON 88017 * DAS-59122-7. This study confirms the need to account for density-dependent mortality when estimating dose of corn rootworm protection events even at relatively low egg infestation densities. PMID- 28073979 TI - Effect of the Presence of Live or Dead Insects on Subsequent Captures of Six Stored-Product Beetle Species: The Relative Species Matters. AB - In trapping programs prior capture of individuals of the same or different species may influence subsequent attractiveness of the trap. To evaluate this process with stored-product insects, the effect of the presence of dead or alive adults in traps on the behavioral responses of six stored-product insect species, Tribolium confusum Jacquelin du Val, T. castaneum (Herbst) (Coleoptera: Tenebrionidae), Sitophilus oryzae (L.), S. granarius (L.) (Coleoptera: Curculionidae), Oryzaephilus surinamensis (L.) and O. mercator (Fauvel) (Coleoptera: Silvanidae), was studied in choice tests under laboratory conditions. Two series of tests were carried out. In the first series, the choice was between either alive or dead adults of same species and blank (no adults). Overall, dead adults had the strongest influence, increasing the response of S. oryzae, S. granarius, O. surinamensis, and O. mercator and decreasing the response of the two Tribolium species. Presence of alive adults generally did not result in a response different from blank, except for T. castaneum and O. surinamensis that had a reduced response. In the second series of tests, the choice was between alive or dead individuals of the species vs. alive or dead individuals of its relative cogeneric species. For choices between alive individuals, S. oryzae, S. granarius, and O. surinamensis showed a preference for alive individuals of the same species vs. the cogeneric species, and for all the other species there was no preference. For choices between dead individuals, T. castaneum exhibited a preference for individuals of the same species, while S. oryzae, S. granarius, and O. mercator showed a preference for individuals of the cogeneric species, and all other combinations did exhibit a preference. Our results suggest that traps containing alive and dead individuals of the same and other species can seriously affect the response and capture of additional insects. PMID- 28073980 TI - Presence and Prevalence of Raffaelea lauricola, Cause of Laurel Wilt, in Different Species of Ambrosia Beetle in Florida, USA. AB - We summarize the information available on ambrosia beetle species that have been associated in Florida with Raffaelea lauricola T.C. Harr., Fraedrich & Aghayeva, the primary symbiont of Xyleborus glabratus Eichhoff and cause of laurel wilt. In total, 14 species in Ambrosiodmus, Euwallacea, Premnobius, Xyleborus, Xyleborinus, and Xylosandrus were either reared from laurel wilt-affected host trees or trapped in laurel wilt-affected stands of the same, and assayed for R. lauricola. In six collections from native species in the southeastern United States [Persea borbonia (L.), Persea palustris (Raf.) Sarg., and Persea humilis Nash] and four from avocado (Persea americana Mill.), extracted mycangia or heads (taxa with mandibular mycangia) or intact bodies (taxa with mycangia in other locations) were surface-disinfested before assays on a semi-selective medium for the isolation of Raffaelea (CSMA+). Raffaelea lauricola was identified based on its characteristic phenotype on CSMA+, and the identity of a random subset of isolates was confirmed with taxon-specific microsatellite markers. The pathogen was recovered from 34% (246 of 726) of the individuals that were associated with the native Persea spp., but only 6% (58 of 931) of those that were associated with avocado. Over all studies, R. lauricola was recovered from 10 of the ambrosia beetle species, but it was most prevalent in Xyleborus congeners. This is the first record of R. lauricola in Ambrosiodmus lecontei Hopkins, Xyleborinus andrewesi (Blandford), and Xyleborus bispinatus Eichhoff. The potential effects of R. lauricola's promiscuity are discussed. PMID- 28073981 TI - Effect of Resin Ducts and Sap Content on Infestation and Development of Immature Stages of Anastrepha obliqua and Anastrepha ludens (Diptera: Tephritidae) in Four Mango (Sapindales: Anacardiaceae) Cultivars. AB - We determined the influence of resin ducts, sap content, and fruit physicochemical features of four mango cultivars (Criollo, Manila, Ataulfo, and Tommy Atkins) on their susceptibility to the attack of the two most pestiferous fruit fly species infesting mangoes in Mexico: Anastrepha ludens (Loew) and Anastrepha obliqua (Macquart). We performed three studies: 1) analysis of resin ducts in mango fruit exocarp to determine the density and area occupied by resin ducts in each mango cultivar, 2) assessment of mango physicochemical features including fruit sap content, and 3) a forced infestation trial under field conditions using enclosed fruit-bearing branches to expose mangoes to gravid A. ludens or A. obliqua females. Infestation rates, development time from egg to prepupae and pupae, pupal weight, and percent of adult emergence, were assessed. 'Ataulfo' and 'Tommy Atkins' cultivars exhibited the highest resin duct density and sap content, the lowest infestation rate, and had a negative effect on immature development and pupal weight. In sharp contrast, 'Manila' and 'Criollo' cultivars, with the lowest resin duct density and sap content, were highly susceptible to A. ludens and A. obliqua attack. We conclude that sap content and the number, size, and distribution of resin ducts as well as firmness in mango fruit exocarp are all involved in the resistance of mango to A. ludens and A. obliqua attack. PMID- 28073982 TI - Urinary triclosan concentrations and early outcomes of in vitro fertilization embryo transfer. AB - Triclosan (TCS) exists ubiquitously in the environment. Several in vitro and in vivo studies have demonstrated that TCS exerts endocrine disruptive effects on reproduction, but data from human populations are limited and conflicting. The objective of our study was to investigate whether high urinary TCS concentration is adversely associated with early reproductive outcomes in women undergoing in vitro fertilization-embryo transfer (IVF-ET). This prospective cohort study was conducted from September 2015 to June 2016, including 156 infertile women undergoing their first IVF-ET cycle. Two spot urine samples were collected prior to oocyte retrieval for TCS detection using solid-phase extraction (SPE) and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Linear regression model and binary logistic regression model were used to evaluate the association between urinary TCS concentrations and IVF outcomes. The intake of aquaculture food may have positive influences on urinary TCS concentrations. After adjustment for age, body mass index (BMI), baseline follicle-stimulating hormone (FSH), antral follicle count (AFC) and smoking status, a significant decrease of top quality embryo formation and implantation rate was observed in patients with urinary TCS concentration greater than or equal to the median level (0.045 MUmol/mol Cr). We concluded that TCS exposure may exert negative effects during early stages of human reproduction. PMID- 28073983 TI - A novel embryo culture media supplement that improves pregnancy rates in mice. AB - The preimplantation embryo in vivo is exposed to numerous growth factors in the female reproductive tract, which are not recapitulated in embryo culture media in vitro The IGF2 and plasminogen activator systems facilitate blastocyst development. We hypothesized that the addition of IGF2 in combination with urokinase plasminogen activator (uPA) and plasminogen could improve rates of blastocyst hatching and implantation in mice. B6BcF1 and CBAB6F2 mouse embryos were divided into one of four supplemented culture media treatment groups: (1) control (media only); (2) 12.5 nM IGF2; (3) 10 ug/mL uPA and 5 ug/mL plasminogen; or (4) a combination of IGF2, uPA and plasminogen treatments. Embryo development to blastocyst stage and hatching were assessed before transfer to pseudopregnant recipient females and implantation, pregnancy rates and postnatal growth were assessed. After 90.5 h of culture, IGF2 + U + P treatment increased the percentage of B6BcF1 embryos that were hatching/hatched and percentage developing to blastocyst stage compared with controls (P < 0.02). Following B6BcF1 embryo transfer, IGF2 + U + P treatment increased implantation sites at day 8 of pregnancy compared with controls (P < 0.05). Replication in the CBAB6F2 mouse strain showed significant improvements in pregnancy rates at days 8 and 18 but not in blastocyst development. No adverse effects were seen on gestational age, litter size or birthweight, or the reproductive capacity of offspring of IGF2 + U + P treated embryos. For embryos susceptible to detrimental effects of in vitro culture, IGF2, uPA and plasminogen supplementation of culture media can improve pregnancy success, but the effect of treatment is dependent on the mouse strain. PMID- 28073984 TI - Transcription Factors PvERF15 and PvMTF-1 Form a Cadmium Stress Transcriptional Pathway. AB - In plants, cadmium (Cd)-responsive transcription factors are key downstream effectors of Cd stress transcriptional pathways, which are capable of converging Cd stress signals through triggering the expression of Cd detoxification genes. However, the upstream transcriptional regulatory pathways that modulate their responses to Cd are less clear. Previously, we identified the bean (Phaseolus vulgaris) METAL RESPONSE ELEMENT-BINDING TRANSCRIPTION FACTOR1 (PvMTF-1) that responds to Cd and confers Cd tolerance in planta. Here, we demonstrate an upstream transcriptional regulation of the PvMTF-1 response to Cd Using a yeast one-hybrid system, we cloned the bean ETHYLENE RESPONSE FACTOR15 (PvERF15) that binds to the PvMTF-1 promoter. PvERF15 was strongly induced by Cd stress, and its overexpression resulted in the up-regulation of PvMTF-1 DNA-protein interaction assays further revealed that PvERF15 binds directly to a 19-bp AC-rich element in the PvMTF-1 promoter. The AC-rich element serves as a positive element bound by PvERF15 to activate gene expression. More importantly, knockdown of PvERF15 by RNA interference resulted in reduced Cd-induced expression of PvMTF-1PvERF15 seems to be involved in Cd tolerance, since knockdown of PvERF15 by RNA interference in bean leaf discs decreased Cd tolerance in a transient assay. Since PvERF15 is a component of the Cd stress transcriptional pathway in beans and PvMTF-1 is one of its downstream targets, our findings provide a PvERF15/PvMTF-1 transcriptional pathway and thereby contribute to the understanding of Cd stress transcriptional regulatory pathways in plants. PMID- 28073985 TI - Population-Based Pertussis Incidence and Risk Factors in Infants Less Than 6 Months in Nepal. AB - Background.: Pertussis is estimated to cause 2 percent of childhood deaths globally and is a growing public health problem in developed countries despite high vaccination coverage. Infants are at greatest risk of morbidity and mortality. Maternal vaccination during pregnancy may be effective to prevent pertussis in young infants, but population-based estimates of disease burden in infants are lacking, particularly in low-income countries. The objective of this study was to estimate the incidence of pertussis in infants less than 6 months of age in Sarlahi District, Nepal. Methods.: Nested within a population-based randomized controlled trial of influenza vaccination during pregnancy, infants were visited weekly from birth through 6 months to assess respiratory illness in the prior week. If any respiratory symptoms had occurred, a nasal swab was collected and tested with a multitarget pertussis polymerase chain reaction (PCR) assay. The prospective cohort study includes infants observed between May 2011 and August 2014. Results.: The incidence of PCR-confirmed Bordetella pertussis was 13.3 cases per 1000 infant-years (95% confidence interval, 7.7-21.3) in a cohort of 3483 infants with at least 1 day of follow-up. Conclusions.: In a population-based active home surveillance for respiratory illness, a low risk for pertussis was estimated among infants in rural Nepal. Nepal's immunization program, which includes a childhood whole cell pertussis vaccine, may be effective in controlling pertussis in infants. PMID- 28073986 TI - Does the addition of postoperative radiotherapy to adjuvant chemotherapy offer any benefit in patients with non-small cell lung cancer and mediastinal lymphadenopathy? AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether the addition of postoperative radiotherapy (PORT) to adjuvant chemotherapy offers any benefit in patients undergoing curative resection for non-small cell lung cancer found to harbour mediastinal lymphadenopathy. A total of 77 papers were identified using the reported search, of which 11 represented the best evidence to answer the clinical question. Only studies reporting on survival data of patients receiving adjuvant chemotherapy with and without PORT were included in this analysis. The authors, date, journal, country, study type, population, outcomes and key results are tabulated. Six studies reported a statistically significant positive impact of PORT on long-term or disease-free survival (DFS) (P = 0.048-0.0001). Five more studies found no difference in terms of survival between patients receiving and not receiving PORT. Among the 11 studies, only two were randomized controlled, with one of them reporting improved disease-free (P = 0.041) but not overall survival (P = 0.073), while the other finding no difference in survival. Furthermore, three more studies reported on DFS and/or locoregional recurrence of the disease. One of these studies reported a significantly improved DFS among patients receiving PORT (P = 0.003), while two of them reported a reduced rate of locoregional recurrence in this group (P = 0.032-0.009). Many studies report a positive effect of PORT when combined in parallel or sequentially with adjuvant chemotherapy in terms of long-term, disease free survival or locoregional control of the disease in patients who have undergone surgical resection of NSCLC and are found to harbour N2 disease. However, these reports are counterbalanced by an almost equal number of studies which show no difference between PORT and no PORT. Only one study reported significantly increased radiation related adverse effects in patients undergoing chemotherapy and PORT. PMID- 28073987 TI - Neutrophil-lymphocyte ratio and risk of atrial fibrillation after thoracic surgery. AB - Objectives: Postoperative atrial fibrillation (POAF) occurs frequently in patients after noncardiac thoracic surgery and has been associated with increased morbidity and risk of stroke. Recent studies have shown conflicting results on the role of neutrophil-lymphocyte ratio (NLR) and its association with the development of POAF after cardiac surgery. Our goal was to determine whether an association exists between NLR and the incidence of POAF after non-cardiac thoracic surgery. Methods: Using a database of 259 consecutive patients age 60 or older who had anatomic lung resection or oesophagectomy for oncologic resection, we compared preoperative, postanaesthesia care unit and postoperative day 1 NLR between patients who did and did not develop POAF during their hospitalization using Fisher's exact test or logistic regression. We also compared NLR in patients who underwent minimally invasive resection versus open surgery. Results: POAF occurred in 50/259 (19%) of patients during their hospitalization. There were no significant differences in NLR between patients who did and did not develop POAF. In a secondary analysis of 180 patients who underwent open anatomic lung resection or oesophagectomy and 79 who underwent minimally invasive anatomic lung resection there was no difference in preoperative or immediate postoperative NLR, or an interaction in terms of odds of developing POAF. Conclusions: In contrast to cardiac surgery, in patients undergoing major non-cardiac thoracic surgery, we had no evidence to show that either preoperative or early postoperative NLR was associated with the development of POAF. PMID- 28073988 TI - Posteromedial papillary muscle rupture due to squeezing of the left anterior descending coronary artery. AB - An unusual case of posteromedial papillary muscle (PPM) rupture due to isolated left anterior descending (LAD) artery ischaemia, associated with severe myocardial bridge contraction, is presented. The unusual blood supply to the PPM was associated with its apical origin and apex-forming LAD. PMID- 28073989 TI - Patency of the vein of Labbe after venous stenting of the transverse and sigmoid sinuses. AB - BACKGROUND: Venous sinus stenting is an emerging treatment for patients with idiopathic intracranial hypertension and evidence of venous stenosis. Stents placed across the transverse and sigmoid sinuses often cover the vein of Labbe (VOL), a major anastomotic vein draining the cerebral hemisphere. The patency of the VOL after stenting and its clinical implications are poorly understood. METHODS: A retrospective analysis was performed of a prospectively collected database of patients undergoing venous sinus stenting. Pre- and post-stent angiography were compared to assess changes in VOL patency, clinical and radiographic outcomes. RESULTS: The study cohort comprised 56 patients. The stent covered the VOL in 92.9% of cases. Thirty-two cases with VOL coverage had evaluable angiograms immediately after stent placement. Among these, VOL filled normally in 75.0%, exhibited diminished caliber with normal transit time in 3.1%, filled sluggishly in 18.8%, and was occluded in 3.1%. Follow-up was assessed in patients with at least 3 months' angiographic follow-up (46 patients, mean 7.2 months). Of these, normal filling was seen in 71.7%, diminished caliber in 26.1%, and sluggish filling in 2.2% of cases. Neither stent coverage of the VOL nor its patency immediately after stenting or at follow-up correlated with stent-adjacent stenosis. There were no neurological sequelae from coverage of the VOL or alteration of its drainage pattern. CONCLUSIONS: In the majority of venous stenting cases involving the transverse and sigmoid sinuses, the VOL remains widely patent. Complete VOL occlusion rarely occurs after stenting and may not result in clinical sequelae. Stent coverage of the VOL should not deter the therapeutic use of venous sinus stenting. PMID- 28073990 TI - Amyloidotic pseudo-spectacles. PMID- 28073991 TI - Man of stone. PMID- 28073992 TI - Low productivity of stress cardiac magnetic resonance imaging for screening of coronary artery disease. PMID- 28073993 TI - Daily Goals Formulation and Enhanced Visualization of Mechanical Ventilation Variance Improves Mechanical Ventilation Score. AB - BACKGROUND: The systematic implementation of evidence-based practice through the use of guidelines, checklists, and protocols mitigates the risks associated with mechanical ventilation, yet variation in practice remains prevalent. Recent advances in software and hardware have allowed for the development and deployment of an enhanced visualization tool that identifies mechanical ventilation goal variance. Our aim was to assess the utility of daily goal establishment and a computer-aided visualization of variance. METHODS: This study was composed of 3 phases: a retrospective observational phase (baseline) followed by 2 prospective sequential interventions. Phase I intervention comprised daily goal establishment of mechanical ventilation. Phase II intervention was the setting and monitoring of daily goals of mechanical ventilation with a web-based data visualization system (T3). A single score of mechanical ventilation was developed to evaluate the outcome. RESULTS: The baseline phase evaluated 130 subjects, phase I enrolled 31 subjects, and phase II enrolled 36 subjects. There were no differences in demographic characteristics between cohorts. A total of 171 verbalizations of goals of mechanical ventilation were completed in phase I. The use of T3 increased by 87% from phase I. Mechanical ventilation score improved by 8.4% in phase I and 11.3% in phase II from baseline (P = .032). The largest effect was in the low risk VT category, with a 40.3% improvement from baseline in phase I, which was maintained at 39% improvement from baseline in phase II (P = .01). mechanical ventilation score was 9% higher on average in those who survived. CONCLUSIONS: Daily goal formation and computer-enhanced visualization of mechanical ventilation variance were associated with an improvement in goal attainment by evidence of an improved mechanical ventilation score. Further research is needed to determine whether improvements in mechanical ventilation score through a targeted, process-oriented intervention will lead to improved patient outcomes. (ClinicalTrials.gov registration NCT02184208.). PMID- 28073994 TI - Vibrating Mesh Nebulizer Compared With Metered-Dose Inhaler in Mechanically Ventilated Subjects. AB - BACKGROUND: The impact of various aerosol delivery devices on patient outcomes during mechanical ventilation is unknown. If one method of delivery results in a higher ventilator-associated pneumonia (VAP) rate than another, multiple patient outcomes may be affected. This study aimed to determine whether there was a difference in VAP occurrence and patient outcomes (days receiving ventilation and in-hospital mortality) between the vibrating mesh nebulizer (AeroNeb Solo) and the metered-dose inhaler (MDI). METHODS: This retrospective study reviewed medical records for all mechanically ventilated, adult patients with an order for aerosol treatment from August 2011 to August 2013. The hospital converted from MDI to vibrating mesh nebulizers in August 2012, and data were gathered 1 y before/after conversion. Excluded were patients with a tracheostomy, patients who were mechanically ventilated for <24 h, patients who received a combination of nebulizer and MDI treatments, or patients who were re-intubated. RESULTS: Two hundred twenty-eight subjects were included. Forty-eight (21%) received treatment with an MDI, and 180 (79%) were treated with the vibrating mesh nebulizer. Descriptive data did not significantly differ for age or APACHE II (Acute Physiology and Chronic Health Evaluation II) scores between the groups but did for sex (P = .03). Difference in median days receiving ventilation for the MDI (5 d, interquartile range 3.0-8.5 d) and the vibrating mesh nebulizer (6 d, interquartile range 4.0-10.0 d) was not statistically significant. No correlation was found between the use of either device and the primary outcomes of VAP and in hospital mortality. In multivariable logistic regression analysis, the number of days receiving ventilation increased the odds of VAP (odds ratio [OR] 1.3, 95% CI 1.14-1.49, P < .001) and mortality (OR 1.12, 95% CI 1.04-1.21, P = .002). Higher APACHE II scores increased the odds of mortality (OR 1.05, 95% CI 1.001-1.092, P = .044). CONCLUSION: We found no association between an MDI or vibrating mesh nebulizer and our primary outcomes, days receiving ventilation, in-hospital mortality, or VAP, in mechanically ventilated subjects. PMID- 28073995 TI - A pericentric inversion of chromosome X disrupting F8 and resulting in haemophilia A. AB - AIMS: The frequency of X chromosome pericentric inversion is much less than that of autosome chromosome. We hereby characterise a pericentric inversion of X chromosome associated with severe factor VIII (FVIII) deficiency in a sporadic haemophilia A (HA) pedigree. METHODS: PCR primer walking and genome walking strategies were adopted to identify the exact breakpoints of the inversion. Copy number variations (CNVs) of the F8 and the whole chromosomes were detected by AccuCopy and Affymetrix CytoScan High Definition (HD) assays, respectively. A karyotype analysis was performed by cytogenetic G banding technique. RESULTS: We identified a previously undescribed type of pericentric inversion of the X chromosome [inv(X)(p11.21q28)] in the proband with FVIII:C <1%. One breakpoint was located in the intron 7 of the F8, which disrupted the transcription of the F8, and the other located in the upstream of the PFKFB1 of the X chromosome. The inversion segment was approximately 64.4% of the total chromosomal length. The karyotype analysis of the X chromosome confirmed the pericentric inversion of the X chromosome in the proband and his mother. A haplotype analysis traced the inversion to his maternal grandfather, who was not a somatic mosaic of the inversion. This finding indicated that the causative mutation may originate from his germ cells or a rare possibility of germ-cell mosaicism. CONCLUSIONS: The characterisation of pericentric inversion involving F8 extended the molecular mechanisms causing HA. The pericentric inversion rearrangement involves F8 by non homologous end joining is responsible for pathogensis of severe HA. PMID- 28073997 TI - Beyond Ageist Attitudes: Researchers Call for NIH Action to Limit Funding for Older Academics. AB - Purpose: This article explores manifestations of ageism in response to a proposed National Institutes of Health (NIH) Emeritus Grant initiative aimed at funding older investigators. Design and Methods: Comments were requested by NIH in 2015, through a Request for Information (RFI) as well as a public blog regarding the merits of a proposed grant mechanism that would help older researchers transfer their labs to junior scientists and transition into retirement. This article reports content analysis of comments from 134 respondents to the blog. Results: We found consistent patterns of disapproval of the proposed NIH initiative, which was viewed by most respondents as an undeserved benefit for older scientists. Negative attitudes were also expressed toward senior investigators by a large majority of commenters. In addition to broad opposition to new grant funding for senior investigators, many commenters also advocated for other punitive actions toward older investigators, including forced retirement. These opinions were generally justified by negative appraisals of senior investigators' competence, productivity, and even their character. Ageist comments were not limited to younger researchers, suggesting potential internalized ageism by older investigators. Implications: We discuss manifestations of ageism and advocacy for age discrimination in the broader social context of modernization theory, intergenerational conflict and social closure. Our findings raise important questions about the limited value of higher education in counteracting prejudice toward older people. We propose potential remedies to reduce ageism in academia. PMID- 28073996 TI - Estimate of false-positive breast cancer diagnoses from accuracy studies: a systematic review. AB - BACKGROUND: False-positive histological diagnoses have the same consequences of overdiagnosis in terms of unnecessary treatment. The aim of this systematic review is to assess their frequency at needle core biopsy (CB) and/or surgical excision of the breast. METHODS: PubMed, Embase, Cochrane Library were systematically searched up to 30 October 2015. Eligibility criteria: cross sectional studies assessing diagnostic accuracy of CB compared with surgical excision; studies assessing reproducibility of pathologists reading the same slides. OUTCOMES: false-positive rates; Misclassification of Benign as Malignant (MBM) histological diagnosis; K statistic. Independent reviewers extracted data and assessed quality using an adapted QUADAS-2 tool. RESULTS: Sixteen studies assessed CB false-positive rates. In 10 studies (41 989 screen-detected lesions), the range of false-positive rates was 0%-7.1%. Twenty-seven studies assessed pathologists' reproducibility. Studies with consecutive, random or stratified samples of all the specimens: at CB the MBM range was 0.25%-2.4% (K values 0.83 0.98); at surgical excision, it was 0.67%-1.2% (K values 0.86-0.94). Studies with enriched samples: the MBM range was 1.4%-6.2% (K values 0.57-0.86). Studies of cases selected for second opinion: the MBM range was 0.29%-12.2% (K values 0.48 and 0.50). CONCLUSIONS: High heterogeneity of the included studies precluded formal pooling estimates. When considering studies of higher sample size or methodological quality, false-positive rates and MBM are around 1%. The impact of false-positive histological diagnoses of breast cancer on unnecessary treatment, as well as that of overdiagnosis, is not negligible and is of importance in clinical practice. PMID- 28073998 TI - Recent Health Care Use and Medicaid Entry of Medicare Beneficiaries. AB - Purpose of the Study: To examine the relationship between Medicaid entry and recent health care use among Medicare beneficiaries. Design and Methods: We identified Medicare beneficiaries without full Medicaid or use of hospital or nursing home services in 2008 (N = 2,163,387). A discrete survival analysis estimated beneficiaries' monthly likelihood of entry into the full Medicaid program between January 2009 and June 2010. Results: During the 18-month study period, Medicaid entry occurred for 1.1% and 3.7% of beneficiaries who aged into Medicare or originally qualified for Medicare due to disability, respectively. Among beneficiaries who aged into Medicare, 49% of new Medicaid participants had no use of inpatient, skilled nursing facility, or nursing home services during the study period. Individuals who recently used inpatient, skilled nursing facility or nursing home services had monthly rates of 1.9, 14.0, and 38.1 new Medicaid participants per 1,000 beneficiaries, respectively, compared with 0.4 new Medicaid participants per 1,000 beneficiaries with no recent use of these services. Implications: Although recent health care use predicted greater likelihood of Medicaid entry, half of new Medicaid participants used no hospital or nursing home care during the study period. These patterns should be considered when designing and evaluating interventions to reform health care delivery for dual-eligible beneficiaries. PMID- 28073999 TI - Everyday Support to Aging Parents: Links to Middle-Aged Children's Diurnal Cortisol and Daily Mood. AB - Purpose of the Study: Middle-aged adults are often called upon to support aging parents. However, providing support to an aging parent with health problems and disability may be a stressful experience. This study asked whether giving everyday support to parents in the context of health problems and disability has implications for middle-aged children's diurnal cortisol and daily mood. Design and Methods: During four consecutive days, 148 middle-aged adults (mean age = 55) reported the support they gave to their parents and provided saliva 4 times a day (wake, 30 min post-wake, lunchtime, and bedtime). Multilevel models estimated within-person differences in positive affect (PA) and negative affect (NA), cortisol awakening response and area under the curve with respect to ground (AUC G) as a function of giving same-day and previous-day support. We examined whether these associations are exacerbated when a parent has health problems or activities of daily living (ADL) needs. Results: Middle-aged children had significantly higher next-day AUC-G on days after they gave support to parents with ADL needs. When participants gave support to parents with ADL needs, they had significantly greater same-day PA and lower next-day NA. Giving support to parents with health problems was associated with significantly higher next-day NA. Implications: Giving support to parents is an ambiguous experience with implications for biological stress and daily mood. A biopsychosocial approach reveals under what conditions giving support to parents may become detrimental to health and well-being; this knowledge is essential for the development and implementation of interventions. PMID- 28074000 TI - How Does Rurality Influence the Staffing of Social Service Departments in Nursing Homes? AB - Purpose of the Study: Social service departments in nursing homes (NHs) are staffed by qualified social workers (QSWs) and paraprofessionals. Due to greater workforce challenges in rural areas, this article aims to describe the staffing levels and composition of these departments by rurality. Design and Methods: Certification and Survey Provider Enhanced Reports data from 2009 to 2015 are used to examine the effect of rurality on social service staffing using random effects linear panel regressions. Results: The average NH employed 1.8 full-time equivalents (FTEs), with approximately two thirds of social services staffed by QSWs. Large NHs had more staff, but employed fewer staff hours per resident day. Staffing levels were lower and QSWs made up a smaller percentage of staff in rural areas. Implications: National trends indicate variability in staffing by NH size and degree of rurality. Very low staffing within rural NHs is a concern, as staff may have less time to respond to residents' needs and these NHs may utilize fewer QSWs. PMID- 28074001 TI - The Family Time Squeeze: Perceived Family Time Adequacy Buffers Work Strain in Certified Nursing Assistants With Multiple Caregiving Roles. AB - Purpose of the Study: This study examined how certified nursing assistants (CNAs) with unpaid family caregiving roles for children ("double-duty-child caregivers"), older adults ("double-duty-elder caregivers"), and both children and older adults ("triple-duty caregivers") differed from their nonfamily caregiving counterparts ("workplace-only caregivers") on four work strain indicators (emotional exhaustion, job satisfaction, turnover intentions, and work climate for family sacrifices). The moderating effects of perceived family time adequacy were also evaluated. Design and Methods: Regression analyses were conducted on survey data from 972 CNAs working in U.S.-based nursing homes. Results: Compared with workplace-only caregivers, double-and-triple-duty caregivers reported more emotional exhaustion and pressure to make family sacrifices for the sake of work. Triple-duty caregivers also reported less job satisfaction. Perceived family time adequacy buffered double-duty-child and triple-duty caregivers' emotional exhaustion and turnover intentions, as well as reversed triple-duty caregivers' negative perceptions of the work climate. Implications: Perceived family time adequacy constitutes a salient psychological resource for double-duty-child and triple-duty caregivers' family time squeezes. Amid an unprecedented demand for long-term care and severe direct-care workforce shortages, future research on workplace factors that increase double-and-triple duty caregiving CNAs' perceived family time adequacy is warranted to inform long term care organizations' development of targeted recruitment, retention, and engagement strategies. PMID- 28074002 TI - Metabolic Profiling in Formalin-Fixed and Paraffin-Embedded Prostate Cancer Tissues. AB - Metabolite profiling has significantly contributed to a deeper understanding of the biochemical metabolic networks and pathways in cancer cells. Metabolomics based biomarker discovery would greatly benefit from the ability to interrogate retrospective annotated clinical specimens archived as formalin-fixed, paraffin embedded (FFPE) material. Mass spectrometry-based metabolomic analysis was performed in matched frozen and FFPE human prostate cancers as well as isogenic prostate cancer cell lines. A total of 352 and 460 metabolites were profiled in human tissues and cell lines, respectively. Classes and physical-chemical characteristics of the metabolites preserved in FFPE material were characterized and related to their preservation or loss following fixation and embedding. Metabolite classes were differentially preserved in archival FFPE tissues, regardless of the age of the block, compared with matched frozen specimen, ranging from maximal preservation of fatty acids (78%) to loss of the majority of peptides and steroids. Generally, FFPE samples showed a decrease of metabolites with functional groups, such as carboxamide. As an adjunct technique, metabolic profiles were also obtained in situ from FFPE tissue sections where metabolites were extracted in a manner that preserves tissue architecture. Despite the fact that selected metabolites were not retained after processing, global metabolic profiles obtained from FFPE can be used to predict biologic states and study biologic pathways. These results pave the way for metabolomics-based biomarker discovery/validation utilizing retrospective and clinically annotated FFPE collections.Implications: Metabolic profiles can be performed in archival tissue and may be used to complement other profiling methods such as gene expression for biomarker discovery or pathway analysis in the assessment of biologic states. Mol Cancer Res; 15(4); 439-47. (c)2017 AACR. PMID- 28074003 TI - DNA Polymerase Beta Germline Variant Confers Cellular Response to Cisplatin Therapy. AB - Resistance to cancer chemotherapies leads to deadly consequences, yet current research focuses only on the roles of somatically acquired mutations in this resistance. The mutational status of the germline is also likely to play a role in the way cells respond to chemotherapy. The carrier status for the POLB rs3136797 germline mutation encoding P242R DNA polymerase beta (Pol beta) is associated with poor prognosis for lung cancer, specifically in response to treatment with cisplatin. Here, it is revealed that the P242R mutation is sufficient to promote resistance to cisplatin in human cells and in mouse xenografts. Mechanistically, P242R Pol beta acts as a translesion polymerase and prefers to insert the correct nucleotide opposite cisplatin intrastrand cross links, leading to the activation of the nucleotide excision repair (NER) pathway, removal of crosslinks, and resistance to cisplatin. In contrast, wild-type (WT) Pol beta preferentially inserts the incorrect nucleotide initiating mismatch repair and cell death. Importantly, in a mouse xenograft model, tumors derived from lung cancer cells expressing WT Pol beta displayed a slower rate of growth when treated with cisplatin, whereas tumors expressing P242R Pol beta had no response to cisplatin. Pol beta is critical for mediating crosstalk in response to cisplatin. The current data strongly suggest that the status of Pol beta influences cellular responses to crosslinking agents and that Pol beta is a promising biomarker to predict responses to specific chemotherapies. Finally, these results highlight that the genetic status of the germline is a critical factor in the response to cancer treatment.Implications: Pol beta has prognostic biomarker potential in the treatment of cancer with cisplatin and perhaps other intrastrand crosslinking agents. Mol Cancer Res; 15(3); 269-80. (c)2017 AACR. PMID- 28074005 TI - Synergistic regulation of serotonin and opioid signaling contributes to pain insensitivity in Nav1.7 knockout mice. AB - Genetic loss of the voltage-gated sodium channel Nav1.7 (Nav1.7-/-) results in lifelong insensitivity to pain in mice and humans. One underlying cause is an increase in the production of endogenous opioids in sensory neurons. We analyzed whether Nav1.7 deficiency altered nociceptive heterotrimeric guanine nucleotide binding protein-coupled receptor (GPCR) signaling, such as initiated by GPCRs that respond to serotonin (pronociceptive) or opioids (antinociceptive), in sensory neurons. We found that the nociceptive neurons of Nav1.7 knockout (Nav1.7 /-) mice, but not those of Nav1.8 knockout (Nav1.8-/-) mice, exhibited decreased pronociceptive serotonergic signaling through the 5-HT4 receptors, which are Galphas-coupled GPCRs that stimulate the production of cyclic adenosine monophosphate resulting in protein kinase A (PKA) activity, as well as reduced abundance of the RIIbeta regulatory subunit of PKA. Simultaneously, the efficacy of antinociceptive opioid signaling mediated by the Galphai-coupled mu opioid receptors was increased. Consequently, opioids inhibited more efficiently tetrodotoxin-resistant sodium currents, which are important for pain-initiating neuronal activity in nociceptive neurons. Thus, Nav1.7 controls the efficacy and balance of GPCR-mediated pro- and antinociceptive intracellular signaling, such that without Nav1.7, the balance is shifted toward antinociception, resulting in lifelong endogenous analgesia. PMID- 28074004 TI - Signaling by two-component system noncognate partners promotes intrinsic tolerance to polymyxin B in uropathogenic Escherichia coli. AB - Bacteria use two-component systems (TCSs) to react appropriately to environmental stimuli. Typical TCSs comprise a sensor histidine kinase that acts as a receptor coupled to a partner response regulator that coordinates changes in bacterial behavior, often through its activity as a transcriptional regulator. TCS interactions are typically confined to cognate pairs of histidine kinases and response regulators. We describe two distinct TCSs in uropathogenic Escherichia coli (UPEC) that interact to mediate a response to ferric iron. The PmrAB and QseBC TCSs were both required for proper transcriptional response to ferric iron. Ferric iron induced the histidine kinase PmrB to phosphotransfer to both its cognate response regulator PmrA and the noncognate response regulator QseB, leading to transcriptional responses coordinated by both regulators. Pretreatment of the UPEC strain UTI89 with ferric iron led to increased resistance to polymyxin B that required both PmrA and QseB. Similarly, pretreatment of several UPEC isolates with ferric iron increased tolerance to polymyxin B. This study defines physiologically relevant cross talk between TCSs in a bacterial pathogen and provides a potential mechanism for antibiotic resistance of some strains of UPEC. PMID- 28074006 TI - Autocrine Wnt regulates the survival and genomic stability of embryonic stem cells. AB - Wnt signaling plays an important role in the self-renewal and differentiation of stem cells. The secretion of Wnt ligands requires Evi (also known as Wls). Genetically ablating Evi provides an experimental approach to studying the consequence of depleting all redundant Wnt proteins, and overexpressing Evi enables a nonspecific means of increasing Wnt signaling. We generated Evi deficient and Evi-overexpressing mouse embryonic stem cells (ESCs) to analyze the role of autocrine Wnt production in self-renewal and differentiation. Self renewal was reduced in Evi-deficient ESCs and increased in Evi-overexpressing ESCs in the absence of leukemia inhibitory factor, which supports the self renewal of ESCs. The differentiation of ESCs into cardiomyocytes was enhanced when Evi was overexpressed and teratoma formation and growth of Evi-deficient ESCs in vivo were impaired, indicating that autocrine Wnt ligands were necessary for ESC differentiation and survival. ESCs lacking autocrine Wnt signaling had mitotic defects and showed genomic instability. Together, our study demonstrates that autocrine Wnt secretion is important for the survival, chromosomal stability, differentiation, and tumorigenic potential of ESCs. PMID- 28074010 TI - Tumors block pain with CXCL12. AB - The chemokine CXCL12 released from early stage pancreatic cancer recruits Schwann cells and suppresses pain signaling. PMID- 28074011 TI - New connections: NHERF gates activity. AB - The NHERF molecular adaptors serve as gates for TRPC4 and TRPC5 regulation by diacylglycerol and recognition of CFTR by the quality control checkpoint. PMID- 28074012 TI - Reduced abundance of the E3 ubiquitin ligase E6AP contributes to decreased expression of the INK4/ARF locus in non-small cell lung cancer. AB - The tumor suppressor p16INK4a, one protein encoded by the INK4/ARF locus, is frequently absent in multiple cancers, including non-small cell lung cancer (NSCLC). Whereas increased methylation of the encoding gene (CDKN2A) accounts for its loss in a third of patients, no molecular explanation exists for the remainder. We unraveled an alternative mechanism for the silencing of the INK4/ARF locus involving the E3 ubiquitin ligase and transcriptional cofactor E6AP (also known as UBE3A). We found that the expression of three tumor suppressor genes encoded in the INK4/ARF locus (p15INK4b, p16INK4a, and p19ARF) was decreased in E6AP-/- mouse embryo fibroblasts. E6AP induced the expression of the INK4/ARF locus at the transcriptional level by inhibiting CDC6 transcription, a gene encoding a key repressor of the locus. Luciferase assays revealed that E6AP inhibited CDC6 expression by reducing its E2F1-dependent transcription. Chromatin immunoprecipitation analysis indicated that E6AP reduced the amount of E2F1 at the CDC6 promoter. In a subset of NSCLC samples, an E6AP-low/CDC6 high/p16INK4a-low protein abundance profile correlated with low methylation of the gene encoding p16INK4a (CDKN2A) and poor patient prognosis. These findings define a previously unrecognized tumor-suppressive role for E6AP in NSCLC, reveal an alternative silencing mechanism of the INK4/ARF locus, and reveal E6AP as a potential prognostic marker in NSCLC. PMID- 28074013 TI - Exposure to Radiofrequency Electromagnetic Fields From Wi-Fi in Australian Schools. AB - The increasing use of Wi-Fi in schools and other places has given rise to public concern that the radiofrequency (RF) electromagnetic fields from Wi-Fi have the potential to adversely affect children. The current study measured typical and peak RF levels from Wi-Fi and other sources in 23 schools in Australia. All of the RF measurements were much lower than the reference levels recommended by international guidelines for protection against established health effects. The typical and peak RF levels from Wi-Fi in locations occupied by children in the classroom were of the order of 10-4 and 10-2% of the exposure guidelines, respectively. Typical RF levels in the classroom were similar between Wi-Fi and radio but higher than other sources. In the schoolyard typical RF levels were higher for radio, TV and mobile phone base stations compared to Wi-Fi. The results of this study showed that the typical RF exposure of children from Wi-Fi at school is very low and comparable or lower to other sources in the environment. PMID- 28074014 TI - RISKS AND RADIATION DOSES DUE TO RESIDENTIAL RADON IN GERMANY. AB - The population-averaged risk rate and the annual average effective dose due to residential radon in Germany were calculated. The calculations were based on an epidemiological approach taking into account the age- and gender-specific lung cancer incidence rates for the German population and the excess relative risk of 0.16 per 100 Bq.m-3 for residential radon. In addition, the risk estimates adjusted for the smoking habits were determined. The population-averaged risk rate for the whole population was estimated with 4.1.10-5 y-1 (95% confidence interval (CI) 1.4.10-5-7.6.10-5 y-1). Residential radon causes a detriment per year of 3.3.10-5 y-1 (95% CI 1.1.10-5-6.0.10-5 y-1), which corresponds to an annual average effective dose of 0.6 mSv (95% CI 0.2-1.1 mSv). Annually, ~3400 lung cancer incidences are attributed to residential radon. The results from the epidemiological approach exercised in this study are considerably lower than the effective dose, which would be obtained from the dose conversion coefficient calculated using biokinetic and dosimetric models. PMID- 28074015 TI - ELECTRON ABSORBED FRACTIONS IN AN IMAGE-BASED MICROSCOPIC SKELETAL DOSIMETRY MODEL OF CHINESE ADULT MALE. AB - Based on the Chinese reference adult male voxel model, a set of microscopic skeletal models of Chinese adult male is constructed through the processes of computed tomography (CT) imaging, bone coring, micro-CT imaging, image segmentation, merging into macroscopic bone model and implementation in Geant4. At the step of image segmentation, a new bone endosteum (BE) segmentation method is realized by sampling. The set of model contains 32 spongiosa samples with voxel size of 19 MUm cubes. The microscopic spongiosa bone data for Chinese adult male are provided. Electron absorbed fractions in red bone marrow (RBM) and BE are calculated. Source tissues include the bone marrow (red and yellow), trabecular bone (surfaces and volumes) and cortical bone (surfaces and volumes). Target tissues include RBM and BE. Electron energies range from 10 keV to 10 MeV. Additionally, comparison of the result with other investigations is provided. PMID- 28074016 TI - CARI-7A: DEVELOPMENT AND VALIDATION. AB - Aircrew members can be exposed to higher annual doses of natural ionizing radiation than members of the general population in most parts of the world. The principal ionizing radiation to which they are exposed is galactic cosmic radiation (GCR). Among the particles present in the primary spectrum are heavy ions: relativistic nuclei of lithium and heavier elements. These ions have very high radiation weighting factors and can contribute significantly to the effective dose at altitudes above the Pfotzer maximum. This report describes the latest version of the US Federal Aviation Administration's GCR flight dose calculation software, CARI-7A. Unlike its predecessor, CARI-6, CARI-7A directly includes heavy ion transport, using a database of atmospheric particle spectra generated by incident GCR ions pre-calculated with MCNPX 2.7.0. to enable calculations to the edge of space. Results are compared with measurements aboard commercial passenger aircraft, high altitude research aircraft and similar calculations by others. PMID- 28074017 TI - The Mayak Worker Dosimetry System-2013: Treatment of Organ Masses in the Calculation of Organ Doses. AB - Previous Mayak worker epidemiological studies designed to quantify the risk of cancer following exposure to airborne plutonium have calculated organ doses by dividing the organ-absorbed energy by the individual's estimated organ mass. For living workers, this was done by using a relationship between organ mass and total mass and height. For autopsy cases, this was measured directly. In the Mayak Worker Dosimetry System-2013 study, organ doses are calculated by dividing this energy by a population average organ mass. The reasons for departing from previous methodologies are described in this note. The average organ masses that were used in the final analysis are tabulated for males and females. PMID- 28074018 TI - Evaluation of Dose Homogeneity in Cone-Beam Breast Computed Tomography. AB - The aim of this study is to determine, via measurements on phantoms and Monte Carlo (MC) simulations, the dose distribution of absorbed dose in a cone-beam breast computed tomography scan. The absorbed dose volume distribution was measured inside a polyethylene cylindrical phantom, simulating adipose breast tissue, using LiF:Mg,Ti thermoluminescence dosimeters. A reasonable agreement (between 2 and 8%) between the simulated and measured data was observed. The 3D distribution of absorbed dose was evaluated at 40, 60 and 80 kV in a phantom simulating a pendant breast. MC simulations indicate a significantly lower spread of volume dose than in mammography. The dose variation along the radial distance in the simulated phantoms was in the range of 4-14%. These findings might be useful when devising models for breast imaging dose assessment that take into account the uneven distribution of the glandular mass in the breast volume. PMID- 28074019 TI - Point Organ Radiation Dose in Abdominal CT: Effect of Patient Off-Centering in an Experimental Human Cadaver Study. AB - To determine the effect of patient off-centering on point organ radiation dose measurements in a human cadaver scanned with routine abdominal CT protocol. A human cadaver (88 years, body-mass-index 20 kg/m2) was scanned with routine abdominal CT protocol on 128-slice dual source MDCT (Definition Flash, Siemens). A total of 18 scans were performed using two scan protocols (a) 120 kV-200 mAs fixed-mA (CTDIvol 14 mGy) (b) 120 kV-125 ref mAs (7 mGy) with automatic exposure control (AEC, CareDose 4D) at three different positions (a) gantry isocenter, (b) upward off-centering and (c) downward off-centering. Scanning was repeated three times at each position. Six thimble (in liver, stomach, kidney, pancreas, colon and urinary bladder) and four MOSFET dosimeters (on cornea, thyroid, testicle and breast) were placed for calculation of measured point organ doses. Organ dose estimations were retrieved from dose-tracking software (eXposure, Radimetrics). Statistical analysis was performed using analysis of variance. There was a significant difference between the trends of point organ doses with AEC and fixed mA at all three positions (p < 0.01). Variation in point doses between fixed-mA and AEC protocols were statistically significant across all organs at all Table positions (p < 0.001). There was up to 5-6% decrease in point doses with upward off-centering and in downward off-centering. There were statistical significant differences in point doses from dosimeters and dose-tracking software (mean difference for internal organs, 5-36% for fixed-mA & 7-48% for AEC protocols; p < 0.001; mean difference for surface organs, >92% for both protocols; p < 0.0001). For both protocols, the highest mean difference in point doses was found for stomach and lowest for colon. Measured absorbed point doses in abdominal CT vary with patient-centering in the gantry isocenter. Due to lack of consideration of patient positioning in the dose estimation on automatic software-over estimation of the doses up to 92% was reported. PMID- 28074020 TI - LEAD COMPOSITE VS. NONLEAD PROTECTIVE GARMENTS: WHICH ARE BETTER? A MULTIVENDOR COMPARISON. AB - This study aims to provide more insight in attenuation characteristics and corresponding lead (Pb) equivalences of a broad range of commercially available lead composite and nonlead protective garments. Thirty garments of five manufacturers (listed as 0.25-0.35-0.50 mm Pb equivalent) were tested. Transmission values were determined at 70, 90 and 110 kVp using an inverse broad beam geometry. Pb equivalence was determined using lead sheets as reference material. A substantial variability in photon transmission across garments was found. Differences between lead composite and nonlead garments were not statistically significant. Depending on tube voltage, between 9 and 12 out of 30 garments had a lower Pb equivalence than the indicated value. This work shows that lead equivalence as indicated on a garment's label may overestimate its protective performance. Depending on the application a more thorough verification of the effectiveness of protective garments at the desired kVp is warranted. PMID- 28074021 TI - The Assimilation of Diazotroph-Derived Nitrogen by Scleractinian Corals Depends on Their Metabolic Status. AB - : Tropical corals are associated with a diverse community of dinitrogen (N2) fixing prokaryotes (diazotrophs) providing the coral an additional source of bioavailable nitrogen (N) in oligotrophic waters. The overall activity of these diazotrophs changes depending on the current environmental conditions, but to what extent it affects the assimilation of diazotroph-derived N (DDN) by corals is still unknown. Here, in a series of 15N2 tracer experiments, we directly quantified DDN assimilation by scleractinian corals from the Red Sea exposed to different environmental conditions. We show that DDN assimilation strongly varied with the corals' metabolic status or with phosphate availability in the water. The very autotrophic shallow-water (~5 m) corals showed low or no DDN assimilation, which significantly increased under elevated phosphate availability (3 uM). Corals that depended more on heterotrophy (i.e., bleached and deep-water [~45 m] corals) assimilated significantly more DDN, which contributed up to 15% of the corals' N demand (compared to 1% in shallow corals). Furthermore, we demonstrate that a substantial part of the DDN assimilated by deep corals was likely obtained from heterotrophic feeding on fixed N compounds and/or diazotrophic cells in the mucus. Conversely, in shallow corals, the net release of mucus, rich in organic carbon compounds, likely enhanced diazotroph abundance and activity and thereby the release of fixed N to the pelagic and benthic reef community. Overall, our results suggest that DDN assimilation by corals varies according to the environmental conditions and is likely linked to the capacity of the coral to acquire nutrients from seawater. IMPORTANCE: Tropical corals are associated with specialized bacteria (i.e., diazotrophs) able to transform dinitrogen (N2) gas into a bioavailable form of nitrogen, but how much of this diazotroph-derived nitrogen (DDN) is assimilated by corals under different environmental conditions is still unknown. Here, we used 15N2 labeling to trace the fate of DDN within the coral symbiosis. We show that DDN is assimilated by both the animal host and the endosymbiotic algae. In addition, the amount of assimilated DDN was significantly greater in mesophotic, bleached, or phosphorus enriched corals than in surface corals, which almost did not take up this nitrogen form. DDN can thus be of particular importance for the nutrient budget of corals whenever they are limited by the availability of other forms of dissolved nutrients. PMID- 28074023 TI - Emergence of Epidemic Zika Virus Transmission and Congenital Zika Syndrome: Are Recently Evolved Traits to Blame? AB - The mechanisms responsible for the dramatic emergence of Zika virus (ZIKV), accompanied by congenital Zika syndrome and Guillain-Barre syndrome (GBS), remain unclear. However, two hypotheses are prominent: (i) evolution for enhanced urban transmission via adaptation to mosquito vectors, or for enhanced human infection to increase amplification, or (ii) the stochastic introduction of ZIKV into large, naive human populations in regions with abundant Aedes aegypti populations, leading to enough rare, severe infection outcomes for their first recognition. Advances in animal models for human infection combined with improvements in serodiagnostics, better surveillance, and reverse genetic approaches should provide more conclusive evidence of whether mosquito transmission or human pathogenesis changed coincidentally with emergence in the South Pacific and the Americas. Ultimately, understanding the mechanisms of epidemic ZIKV emergence, and its associated syndromes, is critical to predict future risks as well as to target surveillance and control measures in key locations. PMID- 28074022 TI - Making Home Sweet and Sturdy: Toxoplasma gondii ppGalNAc-Ts Glycosylate in Hierarchical Order and Confer Cyst Wall Rigidity. AB - : The protozoan intracellular parasite Toxoplasma gondii forms latent cysts in the central nervous system (CNS) and persists for the lifetime of the host. This cyst is cloaked with a glycosylated structure called the cyst wall. Previously, we demonstrated that a mucin-like glycoprotein, CST1, localizes to the cyst wall and confers structural rigidity on brain cysts in a mucin-like domain-dependent manner. The mucin-like domain of CST1 is composed of 20 units of threonine-rich tandem repeats that are O-GalNAc glycosylated. A family of enzymes termed polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-Ts) initiates O-GalNAc glycosylation. To identify which isoforms of ppGalNAc-Ts are responsible for the glycosylation of the CST1 mucin-like domain and to evaluate the function of each ppGalNAc-T in the overall glycosylation of the cyst wall, all five ppGalNAc-T isoforms were deleted individually from the T. gondii genome. The ppGalNAc-T2 and -T3 deletion mutants produced various glycosylation defects on the cyst wall, implying that many cyst wall glycoproteins are glycosylated by T2 and T3. Both T2 and T3 glycosylate the CST1 mucin-like domain, and this glycosylation is necessary for CST1 to confer structural rigidity on the cyst wall. We established that T2 is required for the initial glycosylation of the mucin-like domain and that T3 is responsible for the sequential glycosylation on neighboring acceptor sites, demonstrating hierarchical glycosylation by two distinct initiating and filling-in ppGalNAc-Ts in an intact organism. IMPORTANCE: Toxoplasma gondii is an obligate intracellular parasite that infects a third of the world's population. It can cause severe congenital disease and devastating encephalitis in immunocompromised individuals. We identified two glycosyltransferases, ppGalNAc T2 and -T3, which are responsible for glycosylating cyst wall proteins in a hierarchical fashion. This glycosylation confers structural rigidity on the brain cyst. Our studies provide new insights into the mechanisms of O-GalNAc glycosylation in T. gondii. PMID- 28074024 TI - Whole-Genome Sequencing of Invasion-Resistant Cells Identifies Laminin alpha2 as a Host Factor for Bacterial Invasion. AB - : To understand the role of glycosaminoglycans in bacterial cellular invasion, xylosyltransferase-deficient mutants of Chinese hamster ovary (CHO) cells were created using clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated gene 9 (CRISPR-cas9) gene targeting. When these mutants were compared to the pgsA745 cell line, a CHO xylosyltransferase mutant generated previously using chemical mutagenesis, an unexpected result was obtained. Bacterial invasion of pgsA745 cells by group B Streptococcus (GBS), group A Streptococcus, and Staphylococcus aureus was markedly reduced compared to the invasion of wild-type cells, but newly generated CRISPR-cas9 mutants were only resistant to GBS. Invasion of pgsA745 cells was not restored by transfection with xylosyltransferase, suggesting that an additional mutation conferring panresistance to multiple bacteria was present in pgsA745 cells. Whole-genome sequencing and transcriptome sequencing (RNA-Seq) uncovered a deletion in the gene encoding the laminin subunit alpha2 (Lama2) that eliminated much of domain L4a. Silencing of the long Lama2 isoform in wild-type cells strongly reduced bacterial invasion, whereas transfection with human LAMA2 cDNA significantly enhanced invasion in pgsA745 cells. The addition of exogenous laminin alpha2beta1gamma1/laminin-alpha2beta2gamma1 strongly increased bacterial invasion in CHO cells, as well as in human alveolar basal epithelial and human brain microvascular endothelial cells. Thus, the L4a domain in laminin alpha2 is important for cellular invasion by a number of bacterial pathogens. IMPORTANCE: Pathogenic bacteria penetrate host cellular barriers by attachment to extracellular matrix molecules, such as proteoglycans, laminins, and collagens, leading to invasion of epithelial and endothelial cells. Here, we show that cellular invasion by the human pathogens group B Streptococcus, group A Streptococcus, and Staphylococcus aureus depends on a specific domain of the laminin alpha2 subunit. This finding may provide new leads for the molecular pathogenesis of these bacteria and the development of novel antimicrobial drugs. PMID- 28074027 TI - A Unique cis-Encoded Small Noncoding RNA Is Regulating Legionella pneumophila Hfq Expression in a Life Cycle-Dependent Manner. AB - : Legionella pneumophila is an environmental bacterium that parasitizes protozoa, but it may also infect humans, thereby causing a severe pneumonia called Legionnaires' disease. To cycle between the environment and a eukaryotic host, L. pneumophila is regulating the expression of virulence factors in a life cycle dependent manner: replicating bacteria do not express virulence factors, whereas transmissive bacteria are highly motile and infective. Here we show that Hfq is an important regulator in this network. Hfq is highly expressed in transmissive bacteria but is expressed at very low levels in replicating bacteria. A L. pneumophila hfq deletion mutant exhibits reduced abilities to infect and multiply in Acanthamoeba castellanii at environmental temperatures. The life cycle dependent regulation of Hfq expression depends on a unique cis-encoded small RNA named Anti-hfq that is transcribed antisense of the hfq transcript and overlaps its 5' untranslated region. The Anti-hfq sRNA is highly expressed only in replicating L. pneumophila where it regulates hfq expression through binding to the complementary regions of the hfq transcripts. This results in reduced Hfq protein levels in exponentially growing cells. Both the small noncoding RNA (sRNA) and hfq mRNA are bound and stabilized by the Hfq protein, likely leading to the cleavage of the RNA duplex by the endoribonuclease RNase III. In contrast, after the switch to transmissive bacteria, the sRNA is not expressed, allowing now an efficient expression of the hfq gene and consequently Hfq. Our results place Hfq and its newly identified sRNA anti-hfq in the center of the regulatory network governing L. pneumophila differentiation from nonvirulent to virulent bacteria. IMPORTANCE: The abilities of L. pneumophila to replicate intracellularly and to cause disease depend on its capacity to adapt to different extra- and intracellular environmental conditions. Therefore, a timely and fine tuned expression of virulence factors and adaptation traits is crucial. Yet, the regulatory circuits governing the life cycle of L. pneumophila from replicating to virulent bacteria are only partly uncovered. Here we show that the life cycle dependent regulation of the RNA chaperone Hfq relies on a small regulatory RNA encoded antisense to the hfq-encoding gene through a base pairing mechanism. Furthermore, Hfq regulates its own expression in an autoregulatory loop. The discovery of this RNA regulatory mechanism in L. pneumophila is an important step forward in the understanding of how the switch from inoffensive, replicating to highly virulent, transmissive L. pneumophila is regulated. PMID- 28074028 TI - Assessment of Postoperative Pain Control with an Elastomeric Pain Pump Following Cardiothoracic Surgery. AB - Objective: To assess the effectiveness of local anesthesia, delivered via elastomeric pump to manage pain in patients undergoing cardiothoracic surgery. Methods: A retrospective, comparative analysis evaluating adult cardiothoracic surgery patients (by median sternotomy) who received continuous infusion bupivacaine + traditional methods of pain control (N = 100) or traditional pain control alone (N = 100) from July 2011-October 2013. The primary efficacy end point was total postoperative opioid requirements for 96 hours following surgery. Secondary end points included postoperative pain scores, nonopioid analgesic requirements for 96 hours after surgery, and frequency of postoperative adverse events. Results: Demographic characteristics were similar between both groups. No difference was noted in overall opioid utilization for the first 96 hours postoperatively between the two groups ( P = 0.36). Similar pain scores were reported by patients in both groups for 96 hours following surgery, with the highest pain scores reported during the first 24 hours following surgery ( P = 0.37). No difference between groups was noted in utilization of ketorolac or acetaminophen. Frequency of postoperative adverse events, including the use of antiemetic agents for nausea and vomiting, was similar in between both groups. Conclusion: The use of elastomeric pumps in patients undergoing cardiothoracic surgery for reducing postoperative opioid consumption and pain may not be as beneficial as previously reported. PMID- 28074026 TI - Promyelocytic Leukemia Protein (PML) Controls Listeria monocytogenes Infection. AB - : The promyelocytic leukemia protein (PML) is the main organizer of stress responsive subnuclear structures called PML nuclear bodies. These structures recruit multiple interactors and modulate their abundance or their posttranslational modifications, notably by the SUMO ubiquitin-like modifiers. The involvement of PML in antiviral responses is well established. In contrast, the role of PML in bacterial infection remains poorly characterized. Here, we show that PML restricts infection by the pathogenic bacterium Listeria monocytogenes but not by Salmonella enterica serovar Typhimurium. During infection, PML undergoes oxidation-mediated multimerization, associates with the nuclear matrix, and becomes de-SUMOylated due to the pore-forming activity of the Listeria toxin listeriolysin O (LLO). These events trigger an antibacterial response that is not observed during in vitro infection by an LLO-defective Listeria mutant, but which can be phenocopied by specific induction of PML de SUMOylation. Using transcriptomic and proteomic microarrays, we also characterized a network of immunity genes and cytokines, which are regulated by PML in response to Listeria infection but independently from the listeriolysin O toxin. Our study thus highlights two mechanistically distinct complementary roles of PML in host responses against bacterial infection. IMPORTANCE: The promyelocytic leukemia protein (PML) is a eukaryotic protein that can polymerize in discrete nuclear assemblies known as PML nuclear bodies (NBs) and plays essential roles in many different cellular processes. Key to its function, PML can be posttranslationally modified by SUMO, a ubiquitin-like modifier. Identification of the role of PML in antiviral defenses has been deeply documented. In contrast, the role of PML in antibacterial defenses remains elusive. Here, we identify two mechanistically distinct complementary roles of PML in antibacterial responses against pathogens such as Listeria: (i) we show that PML regulates the expression of immunity genes in response to bacterial infection, and (ii) we unveil the fact that modification of PML SUMOylation by bacterial pore-forming toxins is sensed as a danger signal, leading to a restriction of bacterial intracellular multiplication. Taken together, our data reinforce the concept that intranuclear bodies can dynamically regulate important processes, such as defense against invaders. PMID- 28074025 TI - Flavivirus Infection Uncouples Translation Suppression from Cellular Stress Responses. AB - : As obligate parasites, viruses strictly depend on host cell translation for the production of new progeny, yet infected cells also synthesize antiviral proteins to limit virus infection. Modulation of host cell translation therefore represents a frequent strategy by which viruses optimize their replication and spread. Here we sought to define how host cell translation is regulated during infection of human cells with dengue virus (DENV) and Zika virus (ZIKV), two positive-strand RNA flaviviruses. Polysome profiling and analysis of de novo protein synthesis revealed that flavivirus infection causes potent repression of host cell translation, while synthesis of viral proteins remains efficient. Selective repression of host cell translation was mediated by the DENV polyprotein at the level of translation initiation. In addition, DENV and ZIKV infection suppressed host cell stress responses such as the formation of stress granules and phosphorylation of the translation initiation factor eIF2alpha (alpha subunit of eukaryotic initiation factor 2). Mechanistic analyses revealed that translation repression was uncoupled from the disruption of stress granule formation and eIF2alpha signaling. Rather, DENV infection induced p38-Mnk1 signaling that resulted in the phosphorylation of the eukaryotic translation initiation factor eIF4E and was essential for the efficient production of virus particles. Together, these results identify the uncoupling of translation suppression from the cellular stress responses as a conserved strategy by which flaviviruses ensure efficient replication in human cells. IMPORTANCE: For efficient production of new progeny, viruses need to balance their dependency on the host cell translation machinery with potentially adverse effects of antiviral proteins produced by the infected cell. To achieve this, many viruses evolved mechanisms to manipulate host cell translation. Here we find that infection of human cells with two major human pathogens, dengue virus (DENV) and Zika virus (ZIKV), leads to the potent repression of host cell translation initiation, while the synthesis of viral protein remains unaffected. Unlike other RNA viruses, these flaviviruses concomitantly suppress host cell stress responses, thereby uncoupling translation suppression from stress granule formation. We identified that the p38-Mnk1 cascade regulating phosphorylation of eIF4E is a target of DENV infection and plays an important role in virus production. Our results define several molecular interfaces by which flaviviruses hijack host cell translation and interfere with stress responses to optimize the production of new virus particles. PMID- 28074029 TI - Response to Crudele et al. Commentary on Gudin et al. "Comparing the Effect of Tampering on the Oral Pharmacokinetic Profiles of Two Extended-Release Oxycodone Formulations with Abuse-Deterrent Properties". PMID- 28074032 TI - Opinion: Urban resilience efforts must consider social and political forces. PMID- 28074030 TI - A Working Model of the Deep Relationships of Diverse Modern Human Genetic Lineages Outside of Africa. AB - A major topic of interest in human prehistory is how the large-scale genetic structure of modern populations outside of Africa was established. Demographic models have been developed that capture the relationships among small numbers of populations or within particular geographical regions, but constructing a phylogenetic tree with gene flow events for a wide diversity of non-Africans remains a difficult problem. Here, we report a model that provides a good statistical fit to allele-frequency correlation patterns among East Asians, Australasians, Native Americans, and ancient western and northern Eurasians, together with archaic human groups. The model features a primary eastern/western bifurcation dating to at least 45,000 years ago, with Australasians nested inside the eastern clade, and a parsimonious set of admixture events. While our results still represent a simplified picture, they provide a useful summary of deep Eurasian population history that can serve as a null model for future studies and a baseline for further discoveries. PMID- 28074034 TI - Reply to Janoschek et al.: The excited delta-phase of plutonium. PMID- 28074035 TI - Relevance of Kondo physics for the temperature dependence of the bulk modulus in plutonium. PMID- 28074036 TI - Redox crisis underlies conditional light-dark lethality in cyanobacterial mutants that lack the circadian regulator, RpaA. AB - Cyanobacteria evolved a robust circadian clock, which has a profound influence on fitness and metabolism under daily light-dark (LD) cycles. In the model cyanobacterium Synechococcus elongatus PCC 7942, a functional clock is not required for diurnal growth, but mutants defective for the response regulator that mediates transcriptional rhythms in the wild-type, regulator of phycobilisome association A (RpaA), cannot be cultured under LD conditions. We found that rpaA-null mutants are inviable after several hours in the dark and compared the metabolomes of wild-type and rpaA-null strains to identify the source of lethality. Here, we show that the wild-type metabolome is very stable throughout the night, and this stability is lost in the absence of RpaA. Additionally, an rpaA mutant accumulates excessive reactive oxygen species (ROS) during the day and is unable to clear it during the night. The rpaA-null metabolome indicates that these cells are reductant-starved in the dark, likely because enzymes of the primary nighttime NADPH-producing pathway are direct targets of RpaA. Because NADPH is required for processes that detoxify ROS, conditional LD lethality likely results from inability of the mutant to activate reductant-requiring pathways that detoxify ROS when photosynthesis is not active. We identified second-site mutations and growth conditions that suppress LD lethality in the mutant background that support these conclusions. These results provide a mechanistic explanation as to why rpaA-null mutants die in the dark, further connect the clock to metabolism under diurnal growth, and indicate that RpaA likely has important unidentified functions during the day. PMID- 28074038 TI - Iconic photographs and the ebb and flow of empathic response to humanitarian disasters. AB - The power of visual imagery is well known, enshrined in such familiar sayings as "seeing is believing" and "a picture is worth a thousand words." Iconic photos stir our emotions and transform our perspectives about life and the world in which we live. On September 2, 2015, photographs of a young Syrian child, Aylan Kurdi, lying face-down on a Turkish beach, filled the front pages of newspapers worldwide. These images brought much-needed attention to the Syrian war that had resulted in hundreds of thousands of deaths and created millions of refugees. Here we present behavioral data demonstrating that, in this case, an iconic photo of a single child had more impact than statistical reports of hundreds of thousands of deaths. People who had been unmoved by the relentlessly rising death toll in Syria suddenly appeared to care much more after having seen Aylan's photograph; however, this newly created empathy waned rather quickly. We briefly examine the psychological processes underlying these findings, discuss some of their policy implications, and reflect on the lessons they provide about the challenges to effective intervention in the face of mass threats to human well being. PMID- 28074037 TI - Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex. AB - Working memory requires efficient excitatory drive to parvalbumin-positive (PV) interneurons in the primate dorsolateral prefrontal cortex (DLPFC). Developmental pruning eliminates superfluous excitatory inputs, suggesting that working memory maturation during adolescence requires pruning of excitatory inputs to PV interneurons. Therefore, we tested the hypothesis that excitatory synapses on PV interneurons are pruned during adolescence. The density of excitatory synapses, defined by overlapping vesicular glutamate transporter 1-positive (VGlut1+) and postsynaptic density 95-positive (PSD95+) puncta, on PV interneurons was lower in postpubertal relative to prepubertal monkeys. In contrast, puncta levels of VGlut1 and PSD95 proteins were higher in postpubertal monkeys and positively predicted activity-dependent PV levels, suggesting a greater strength of the remaining synapses after pruning. Because excitatory synapse number on PV interneurons is regulated by erb-b2 receptor tyrosine kinase 4 (ErbB4), whose function is influenced by alternative splicing, we tested the hypothesis that pruning of excitatory synapses on PV interneurons is associated with developmental shifts in ErbB4 expression and/or splicing. Pan-ErbB4 expression did not change, whereas the minor-to-major splice variant ratios increased with age. In cell culture, the major, but not the minor, variant increased excitatory synapse number on PV interneurons and displayed greater kinase activity than the minor variant, suggesting that the effect of ErbB4 signaling in PV interneurons is mediated by alternative splicing. Supporting this interpretation, in monkey DLPFC, higher minor-to-major variant ratios predicted lower PSD95+ puncta density on PV interneurons. Together, our findings suggest that ErbB4 splicing may regulate the pruning of excitatory synapses on PV interneurons during adolescence. PMID- 28074039 TI - CD34+ mesenchymal cells are a major component of the intestinal stem cells niche at homeostasis and after injury. AB - The intestinal epithelium is continuously renewed by intestinal epithelial stem cells (IESCs) positioned at the base of each crypt. Mesenchymal-derived factors are essential to maintain IESCs; however, the cellular composition and development of such mesenchymal niche remains unclear. Here, we identify pericryptal CD34+ Gp38+ alphaSMA- mesenchymal cells closely associated with Lgr5+ IESCs. We demonstrate that CD34+ Gp38+ cells are the major intestinal producers of the niche factors Wnt2b, Gremlin1, and R-spondin1, and are sufficient to promote maintenance of Lgr5+ IESCs in intestinal organoids, an effect mainly mediated by Gremlin1. CD34+ Gp38+ cells develop after birth in the intestinal submucosa and expand around the crypts during the third week of life in mice, independently of the microbiota. We further show that pericryptal CD34+gp38+ cells are rapidly activated by intestinal injury, up-regulating niche factors Gremlin1 and R-spondin1 as well as chemokines, proinflammatory cytokines, and growth factors with key roles in gut immunity and tissue repair, including IL-7, Ccl2, Ptgs2, and Amphiregulin. Our results indicate that CD34+ Gp38+ mesenchymal cells are programmed to develop in the intestine after birth to constitute a specialized microenvironment that maintains IESCs at homeostasis and contribute to intestinal inflammation and repair after injury. PMID- 28074040 TI - Potent neutralization of hepatitis A virus reveals a receptor mimic mechanism and the receptor recognition site. AB - Hepatitis A virus (HAV) infects ~1.4 million people annually and, although there is a vaccine, there are no licensed therapeutic drugs. HAV is unusually stable (making disinfection problematic) and little is known of how it enters cells and releases its RNA. Here we report a potent HAV-specific monoclonal antibody, R10, which neutralizes HAV infection by blocking attachment to the host cell. High resolution cryo-EM structures of HAV full and empty particles and of the complex of HAV with R10 Fab reveal the atomic details of antibody binding and point to a receptor recognition site at the pentamer interface. These results, together with our observation that the R10 Fab destabilizes the capsid, suggest the use of a receptor mimic mechanism to neutralize virus infection, providing new opportunities for therapeutic intervention. PMID- 28074041 TI - Transcription factor Xpp1 is a switch between primary and secondary fungal metabolism. AB - Fungi can produce a wide range of chemical compounds via secondary metabolism. These compounds are of major interest because of their (potential) application in medicine and biotechnology and as a potential source for new therapeutic agents and drug leads. However, under laboratory conditions, most secondary metabolism genes remain silent. This circumstance is an obstacle for the production of known metabolites and the discovery of new secondary metabolites. In this study, we describe the dual role of the transcription factor Xylanase promoter binding protein 1 (Xpp1) in the regulation of both primary and secondary metabolism of Trichoderma reesei Xpp1 was previously described as a repressor of xylanases. Here, we provide data from an RNA-sequencing analysis suggesting that Xpp1 is an activator of primary metabolism. This finding is supported by our results from a Biolog assay determining the carbon source assimilation behavior of an xpp1 deletion strain. Furthermore, the role of Xpp1 as a repressor of secondary metabolism is shown by gene expression analyses of polyketide synthases and the determination of the secondary metabolites of xpp1 deletion and overexpression strains using an untargeted metabolomics approach. The deletion of Xpp1 resulted in the enhanced secretion of secondary metabolites in terms of diversity and quantity. Homologs of Xpp1 are found among a broad range of fungi, including the biocontrol agent Trichoderma atroviride, the plant pathogens Fusarium graminearum and Colletotrichum graminicola, the model organism Neurospora crassa, the human pathogen Sporothrix schenckii, and the ergot fungus Claviceps purpurea. PMID- 28074042 TI - Different clades and traits yield similar grassland functional responses. AB - Plant functional traits are viewed as key to predicting important ecosystem and community properties across resource gradients within and among biogeographic regions. Vegetation dynamics and ecosystem processes, such as aboveground net primary productivity (ANPP), are increasingly being modeled as a function of the quantitative traits of species, which are used as proxies for photosynthetic rates and nutrient and water-use efficiency. These approaches rely on an assumption that a certain trait value consistently confers a specific function or response under given environmental conditions. Here, we provide a critical test of this idea and evaluate whether the functional traits that drive the well-known relationship between precipitation and ANPP differ between systems with distinct biogeographic histories and species assemblages. Specifically, we compared grasslands spanning a broad precipitation gradient (~200-1,000 mm/y) in North America and South Africa that differ in the relative representation and abundance of grass phylogenetic lineages. We found no significant difference between the regions in the positive relationship between annual precipitation and ANPP, yet the trait values underlying this relationship differed dramatically. Our results challenge the trait-based approach to predicting ecosystem function by demonstrating that different combinations of functional traits can act to maximize ANPP in a given environmental setting. Further, we show the importance of incorporating biogeographic and phylogenetic history in predicting community and ecosystem properties using traits. PMID- 28074043 TI - Correction: Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src. PMID- 28074044 TI - Diabetic Myonecrosis: A Rare Complication of Diabetes Mellitus Mimicking Deep Vein Thrombosis. AB - BACKGROUND Diabetic myonecrosis is an uncommon complication of long-standing poorly controlled diabetes mellitus. It presents as acute non-traumatic swelling and pain of the lower extremity, which can mimic deep vein thrombosis (DVT). The clinical course is usually self-limiting and patients respond well to supportive medical therapy. CASE REPORT A 54-year-old male with past medical history of poorly controlled diabetes mellitus type II, hyperlipidemia, gastroesophageal reflux disease (GERD), and remote history of DVT presented to our emergency department with 2-week history of progressively worsening left calf pain and swelling. On physical examination, the patient had increased warmth, edema, erythema, and tenderness in the left calf, with positive Homan's sign. A lower extremity venous Doppler was negative for DVT. His creatinine phosphokinase (CPK) level was normal, but hemoglobin A1C was 11.0%, reflective of poor glycemic control. Magnetic resonance imaging (MRI) of the left calf revealed a focus of non-enhancement in the gastrocnemius muscle along with increased enhancement of the rest of the muscle, suggestive of diabetic myonecrosis. CONCLUSIONS Diabetic myonecrosis is a rare complication of long-standing diabetes mellitus that can often mimic DVT. Diagnosis can be made on an MRI, and treatment involves strict glycemic control along with antiplatelet therapy and non-steroidal anti inflammatories (NSAIDs). PMID- 28074045 TI - High Expression of Stromal Cell-Derived Factor 1 (SDF-1) and NF-kappaB Predicts Poor Prognosis in Cervical Cancer. AB - BACKGROUND SDF-1 and NF-kappaB are associated with the prognosis of a wide range of cancers, but their value in cervical cancer remains controversial. The aim of this study was to investigate the expression of SDF-1and NF-kappaB in cervical cancer and their significance in clinical prognosis. MATERIAL AND METHODS The expression of SDF-1and NF-kappaB in 105 formalin-fixed, paraffin-embedded cervical cancer tissues and the adjacent tissues was examined by immunohistochemistry (IHC). The results were semi-quantitatively scored and analyzed by chi-square test. The overall survival times (OS) were collected by follow-up and analyzed by Kaplan-Meier analysis. RESULTS The expression level of both SDF-1and NF-kappaB in cervical cancer are higher than that in the adjacent tissues (P<0.05). SDF-1 expression are correlated with tumor size and FIGO histology grade (P<0.05). NF-kappaB expression are correlated with tumor size and FIGO histology grade, and lymph node metastasis (LNM) status (P<0.05). The patients with a positive expression of SDF-1or NF-kappaB tended to have much shorter survival time than patients with negative expression. In addition, multivariate Cox regression analysis demonstrated that SDF-1 expression and lymph node metastasis are independent predictors of the OS in cervical cancer patients. CONCLUSIONS The expression of SDF-1 is significantly associated with tumor size and FIGO histology grade. The expression of NF-kappaB is significantly associated with tumor size, FIGO histology grade, and lymph node metastasis. The positive SDF-1or NF-kappaB expression is significantly correlated with poor prognosis. These may be valuable biomarkers for the prognosis and the potential therapeutic targets of cervical cancer. PMID- 28074047 TI - Arabilin overcomes resistance to AR-targeted therapy. PMID- 28074048 TI - Elmenols C-H, new angucycline derivatives isolated from a culture of Streptomyces sp. IFM 11490. AB - Chemical investigations of the ethyl acetate extract of Streptomyces sp. IFM 11490 have led to the isolation of six new angucycline metabolites, named elmenols C-H (1-6), along with the previously reported elmonin (7) and elmenols A (8) and B (9). The known LS1924A (10), 6-deoxy-8-methylrabelomycin (11), tetrangulol methyl ether (12) and angucyclinone (13) were additionally identified. The structures of the isolated compounds were elucidated by means of spectroscopic methods including UV, IR, HRESIMS, and 1D and 2D NMR. Compounds 1-6 were evaluated for their abilities to overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in human gastric adenocarcinoma (AGS) cells. Compounds 5 (10 MUm) and 6 (50 MUm) in combination with TRAIL showed moderate activity in sensitizing TRAIL-resistant AGS cells. PMID- 28074050 TI - Enhanced dereplication of fungal cultures via use of mass defect filtering. AB - Effective and rapid dereplication is a hallmark of present-day drug discovery from natural sources. This project strove to both decrease the time and expand the structural diversity associated with dereplication methodologies. A 5 min liquid chromatographic run time employing heated electrospray ionization (HESI) was evaluated to determine whether it could be used as a faster alternative over the 10 min ESI method we reported previously. Results revealed that the 5 min method was as sensitive as the 10 min method and, obviously, was twice as fast. To facilitate dereplication, the retention times, UV absorption maxima, full-scan HRMS and MS/MS were cross-referenced with an in-house database of over 300 fungal secondary metabolites. However, this strategy was dependent upon the makeup of the screening in-house database. Thus, mass defect filtering (MDF) was explored as an additional targeted screening strategy to permit identification of structurally related components. The use of a dereplication platform incorporating the 5 min chromatographic method together with MDF facilitated rapid and effective identification of known compounds and detection of structurally related analogs in extracts of fungal cultures. PMID- 28074049 TI - In vitro antibacterial activity of alpha-methoxyimino acylide derivatives against macrolide-resistant pathogens and mutation analysis in 23S rRNA. AB - We characterized in vitro activities of alpha-methoxyimino acylides against macrolide-resistant clinical isolates of Streptococcus pneumoniae, Streptococcus pyogenes and Mycoplasma pneumoniae with ribosome modification or substitution and selected acylide-resistant mutants to clarify the binding point of the acylides. The acylides had low MICs against erm(B) gene-containing S. pneumoniae and S. pyogenes (MIC90s, 1-4 MUg ml-1). For M. pneumoniae, although they had poor potencies against macrolide-resistant strains with the A2058G (Escherichia coli numbering) mutation in 23S rRNA (MICs, >32 MUg ml-1), one of them showed in vitro activities against macrolide-resistant strains with the A2058U or A2059G mutations (MICs, 0.5-1 MUg ml-1). These A2058U and A2059G mutant strains were used for the selection of acylide-resistant mutants. A genetic analysis showed that new point mutations in acylide-resistant mutants were found at G2576 in domain V of 23S rRNA and at Lys90 in L22 ribosomal protein. Furthermore, a molecular modeling study revealed that G2505/C2610, which enables stacking with G2576, might interact with a pyridyl moiety or an alpha-methoxyimino group at the 3-position of acylides. The alpha-methoxyimino acylides were shown to possess a tertiary binding point at G2505/C2610 in 23S rRNA. Our results suggest that alpha methoxyimino acylides represent significant progress in macrolide antimicrobials. PMID- 28074051 TI - Anti-folates potentiate bactericidal effects of other antimicrobial agents. AB - Synergies between sulfonamides and other antimicrobial agents have long been reported, but the reason still remains unclear. Previously, Vilcheze et al. found that, sulfamethoxazole (SMX) could potentiate the bacterialcidal activity of isoniazid (INH) and rifampin (RIF) in Mycobacterium tuberculosis. To test if this was also the case in other bacteria, the ability to potentiate bactericidal effect of RIF by SMX was evaluated in Escherichia coli, Staphylococcus aureus, Salmonella typhimurium and Mycobacterium smegmatis. And the ability to potentiate bactericidal effect of streptomycin (SM) by SMX was also evaluated in E. coli and M. Smegmatis. Susceptibility tests and drug exposure experiments were performed for RIF and SM in the presence of sub-ICs of SMX. In drug exposure experiments, 10 mg l-1 of 7,8-dihydropteroic acid (DHP) was used to reverse the effect of SMX. In the presence of sub-ICs of SMX, MIC of RIF for E. coli and M. smegmatis decreased 2 and 16 fold, respectively. In the drug exposure experiments, addition of sub-ICs of SMX suppressed the growth of RIF and SM resistant population in a pool of susceptible bacteria, and the effects of SMX could be reversed by DHP. Besides, we also found that, sub-ICs of para-aminosalicylic acid (PAS) could bactericidal effects of INH, RIF and SM in M. tuberculosis. Taken together, our data suggest that, sub-ICs of anti-folates can potentiate bactericidal effects of other antimicrobial agents in various bacteria. PMID- 28074052 TI - Kribellosides, novel RNA 5'-triphosphatase inhibitors from the rare actinomycete Kribbella sp. MI481-42F6. AB - Yeast capping enzymes differ greatly from those of mammalian, both structurally and mechanistically. Yeast-type capping enzyme repressors are therefore candidate antifungal drugs. The 5'-guanine-N7 cap structure of mRNAs are an essential feature of all eukaryotic organisms examined to date and is the first co transcriptional modification of cellular pre-messenger RNA. Inhibitors of the RNA 5'-triphosphatase in yeast are likely to show fungicidal effects against pathogenic yeast such as Candida. We discovered a new RNA 5'-triphosphatase inhibitor, designated as the kribellosides, by screening metabolites from actinomycetes. Kribellosides belong to the alkyl glyceryl ethers. These novel compounds inhibit the activity of Cet1p (RNA 5'-triphosphatase) from Saccharomyces cerevisiae in vitro with IC50s of 5-8 MUM and show antifungal activity with MICs ranging from 3.12 to 100 MUg ml-1 against S. cerevisiae. PMID- 28074053 TI - Identification of pyripyropene A as a promising insecticidal compound in a microbial metabolite screening. AB - Approximately 300 microbial natural products in our library were screened for insecticidal activities against three species of agricultural pests, including aphids. Among the several compounds that showed insecticidal activities, pyripyropene A had high aphicidal activity in vivo. Furthermore, in advanced tests, pyripyropene A applications with foliar sprays and soil drenching controlled aphids on cabbage. On the basis of its unique and promising activities, we selected pyripyropene A as the active component of potential insecticides. PMID- 28074054 TI - Synergistic antifungal indolecarbazoles from Streptomyces sp. CNS-42 associated with traditional Chinese medicine Alisma orientale. PMID- 28074055 TI - Effects of two 6-quinolinyl chalcones on the integrity of plasma membrane of Paracoccidioides brasiliensis. AB - Paracoccidioidomycosis is the most prevalent systemic mycosis in Latin America, yet few therapeutic options exist. Our aim was to search for new compounds with high efficacy, low toxicity, shorter treatment time and affordable cost. We studied two synthetic 6-quinolinyl chalcones, 3b and 3e, to determine their effects on VERO cells, antifungal activity, survival curve, interaction with other drugs and phenotypic effects against several isolates of Paracoccidioides spp. In this study, we verified that the compounds were not toxic, exhibited superior in vitro activity compared with that shown by trimethoprim sulfamethoxazole, and after 5 days of treatment, decreased the fungal cell viability by approximately 70%. Additionally, no interactions were observed between the tested compounds and other drugs. We also found that these compounds induced morphological changes, such as shriveling of cells, fragmentation of the plasma membrane and cytoplasmic disorganization in vitro. The changes observed by microscopy assays corroborate the observation made with propidium iodide, where the number of cells stained with the compounds was higher than that observed after amphotericin B treatment. We observed an increase in the efflux of K+ and a loss of intracellular contents in cells treated with 3b and 3e, confirming their effects on fungal membranes. However, damage to the membrane was not associated with a decrease in membrane ergosterol levels. The experimental evidences showed no direct indications of cellular wall damage caused by these compounds. Thus, these results confirm the antifungal potential of 3b and 3e against Paracoccidioides spp. with possible action on the membrane. PMID- 28074056 TI - Biphenyl ether derivatives with protein tyrosine phosphatase 1B inhibitory activity from the freshwater fungus Phoma sp. PMID- 28074057 TI - Development of new polymyxin derivatives for multi-drug resistant Gram-negative infections. AB - Over the last decade, there has been a resurgence of interest in polymyxins owing to the rapid rise in multi-drug resistant Gram-negative bacteria against which polymyxins offer a last-resort treatment. Although having excellent antibacterial activity, the clinical utility of polymyxins is limited by toxicity, especially renal toxicity. There is much interest therefore in developing polymyxin analogues with an improved therapeutic index. This review describes recent work aimed at improving the activity and/or reducing the toxicity of polymyxins. Consideration to providing activity against emerging strains with reduced susceptibility to polymyxins is also made. PMID- 28074058 TI - Intracellular ATP in balance of pro- and anti-inflammatory cytokines in adipose tissue with and without tissue expansion. AB - OBJECTIVES: To understand the mechanism of white fat expansion in the presence of inflammation, we examined the balance of pro- and anti-inflammatory cytokines in epididymal fat during weight gain in diet-induced obese mice. METHODS: The pro- and anti-inflammatory cytokines were examined in white fat of diet-induced obese mice and lean mice. The mechanism of gene expression was investigated with a focus on intracellular ATP (iATP). ATP activity was tested in cellular and non cellular systems in activation of serine kinases (IKKbeta, JNK and ERK). RESULTS: The pro- (tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), IL-6, monocyte chemoattractant protein 1, interferon gamma and osteopontin) and the anti-inflammatory cytokines (IL-10, IL-1Ra, IL-13, soluble TNF receptor 2, pigment epithelium-derived factor and adiponectin) were increased at the same time during the weight gain. The balance was observed even in the absence of tissue expansion upon feeding in lean and obese mice. The iATP levels were positively associated with the cytokine elevation in the adipose tissue. In macrophages, induction of iATP with lauric acid stimulated the expression. Inhibition of iATP with beta-oxidation inhibitor (Etomoxir) or mitochondrial uncoupler (2,4-dinitrophenol, DNP) suppressed the expression. ATP exhibited an activity in the activation of inflammatory kinases (IKKbeta, JNK and ERK) in the living cells and cell lysate. The kinase activation was blocked in the cells by ATP inhibition. CONCLUSIONS: The data suggest that the pro- and anti-inflammatory cytokines are dynamically balanced in the white adipose tissue by iATP. PMID- 28074059 TI - School environment and policies, child eating behavior and overweight/obesity in urban China: the childhood obesity study in China megacities. AB - OBJECTIVES: Childhood obesity is rising rapidly in China, especially in urban areas. Knowledge about how school environment and policies (SEPs) may have contributed to the epidemic remains limited. We examined SEP and their associations with students' eating behaviors and overweight/obesity in urban China. METHODS: Data were collected from 1648 students (plus their parents and schools) in 16 primary and middle schools (4 schools per city) in four megacities across China: Beijing, Shanghai, Nanjing and Xi'an. We examined nutrition-related SEP such as unhealthy food restriction, healthy food promotion, price control and nutrition guideline in school cafeterias (SCs), campus food stores (CFS), school vicinity food stalls (SVFS); SEP on physical activity, physical education (PE) and physical examination. Cluster robust regression models were fit to assess associations of SEP with child eating behaviors and overweight/obesity (defined based on body mass index, from measured weight and height). RESULTS: All 16 schools had regular PE classes and annual physical examination. Most schools (n=12; 75%) had food policies in SC; few had policies on CFS (n=1; 6.25%) or SVFS (n=4; 25%). Local governments had a major role in regulating food prices, setting nutrition guidelines and regulating SVFS. Policies on CFS and SVFS were associated with less frequent intake of sugary beverage (odds ratio (OR)=0.54 (0.47-0.61); OR=0.70 (0.61-0.80)), snack (OR=0.84 (0.74-0.95); OR=0.78 (0.67 0.92)) and fast food (OR=0.58 (0.42-0.81); OR=0.56 (0.39-0.80)). The associations were stronger for boys. Policies on SC, CFS and SVFS were associated with lower likelihood for overweight/obesity (OR=0.60 (0.46-0.79); OR=0.74 (0.62-0.90); OR=0.51 (0.35-0.73)) and central obesity (OR=0.79 (0.70-0.89); OR=0.67 (0.48 0.92); OR=0.63 (0.48-0.84)) in boys. Policies on SC were associated with lower overweight/obesity odds (OR=0.48 (0.28-0.82)) for girls. CONCLUSIONS: SEP are heterogeneous in the four Chinese megacities, high-income areas. They affect child unhealthy eating and overweight/obesity, and are critical for fighting childhood obesity in China. PMID- 28074061 TI - Cell death: Pulling the apoptotic trigger for necrosis. PMID- 28074062 TI - Translation: Smoothening the coding sequence for translation. PMID- 28074060 TI - S100A8/A9 and S100A9 reduce acute lung injury. AB - S100A8 and S100A9 are myeloid cell-derived proteins that are elevated in several types of inflammatory lung disorders. Pro- and anti-inflammatory properties are reported and these proteins are proposed to activate TLR4. S100A8 and S100A9 can function separately, likely through distinct receptors but a systematic comparison of their effects in vivo are limited. Here we assess inflammation in murine lung following S100A9 and S100A8/A9 inhalation. Unlike S100A8, S100A9 promoted mild neutrophil and lymphocyte influx, possibly mediated in part, by increased mast cell degranulation and selective upregulation of some chemokine genes, particularly CXCL-10. S100 proteins did not significantly induce proinflammatory mediators including TNF-alpha, interleukin-1beta (IL-1beta), IL-6 or serum amyloid A3 (SAA3). In contrast to S100A8, neither preparation induced S100A8 or IL-10 mRNA/protein in airway epithelial cells, or in tracheal epithelial cells in vitro. Like S100A8, S100A9 and S100A8/A9 reduced neutrophil influx in acute lung injury provoked by lipopolysaccharide (LPS) challenge but were somewhat less inhibitory, possibly because of differential effects on expression of some chemokines, IL-1beta, SAA3 and IL-10. Novel common pathways including increased induction of an NAD+-dependent protein deacetylase sirtuin-1 that may reduce NF-kappaB signalling, and increased STAT3 activation may reduce LPS activation. Results suggest a role for these proteins in normal homeostasis and protective mechanisms in the lung. PMID- 28074065 TI - HDAC3 activity is required for initiation of leukemogenesis in acute promyelocytic leukemia. PMID- 28074063 TI - Direct in vivo evidence for increased proliferation of CLL cells in lymph nodes compared to bone marrow and peripheral blood. AB - Chronic lymphocytic leukemia (CLL) is a progressive malignancy of mature B-cells that involves the peripheral blood (PB), lymph nodes (LNs) and bone marrow (BM). Although the majority of CLL cells are in a resting state, small populations of proliferating cells exist; however, the anatomical site of active cell proliferation remains to be definitively determined. Based on findings that CLL cells in LNs have increased expression of B-cell activation genes, we tested the hypothesis that the fraction of 'newly born' cells would be highest in the LNs. Using a deuterium oxide (2H) in vivo labeling method in which patients consumed deuterated (heavy) water (2H2O), we determined CLL cell kinetics in concurrently obtained samples from LN, PB and BM. The LN was identified as the anatomical site harboring the largest fraction of newly born cells, compared to PB and BM. In fact, the calculated birth rate in the LN reached as high a 3.3% of the clone per day. Subdivision of the bulk CLL population by flow cytometry identified the subpopulation with the CXCR4dimCD5bright phenotype as containing the highest proportion of newly born cells within each compartment, including the LN, identifying this subclonal population as an important target for novel treatment approaches. PMID- 28074064 TI - O-GlcNAcylation of STAT5 controls tyrosine phosphorylation and oncogenic transcription in STAT5-dependent malignancies. AB - The signal transducer and activator of transcription 5 (STAT5) regulates differentiation, survival, proliferation and transformation of hematopoietic cells. Upon cytokine stimulation, STAT5 tyrosine phosphorylation (pYSTAT5) is transient, while in diverse neoplastic cells persistent overexpression and enhanced pYSTAT5 are frequently found. Post-translational modifications might contribute to enhanced STAT5 activation in the context of transformation, but the strength and duration of pYSTAT5 are incompletely understood. We found that O GlcNAcylation and tyrosine phosphorylation act together to trigger pYSTAT5 levels and oncogenic transcription in neoplastic cells. The expression of a mutated hyperactive gain-of-function (GOF) STAT5 without O-GlcNAcylation resulted in decreased tyrosine phosphorylation, oligomerization and transactivation potential and complete loss of oncogenic transformation capacity. The lack of O GlcNAcylation diminished phospho-ERK and phospho-AKT levels. Our data show that O GlcNAcylation of STAT5 is an important process that contributes to oncogenic transcription through enhanced STAT5 tyrosine phosphorylation and oligomerization driving myeloid transformation. O-GlcNAcylation of STAT5 could be required for nutrient sensing and metabolism of cancer cells. PMID- 28074066 TI - Preclinical targeting of aggressive T-cell malignancies using anti-CD5 chimeric antigen receptor. AB - The outlook for T-cell malignancies remain poor due to the lack of effective therapeutic options. Chimeric antigen receptor (CAR) immunotherapy has recently shown promise in clinical trials for B-cell malignancies, however, designing CARs for T-cell based disease remain a challenge due to the shared surface antigen pool between normal and malignant T-cells. Normal T-cells express CD5 but NK (natural killer) cells do not, positioning NK cells as attractive cytotoxicity cells for CD5CAR design. Additionally, CD5 is highly expressed in T-cell acute lymphoblastic leukemia (T-ALL) and peripheral T-cell lymphomas (PTCLs). Here, we report a robust anti-CD5 CAR (CD5CAR) transduced into a human NK cell line NK-92 that can undergo stable expansion ex vivo. We found that CD5CAR NK-92 cells possessed consistent, specific, and potent anti-tumor activity against a variety of T-cell leukemia and lymphoma cell lines as well as primary tumor cells. Furthermore, we were able to demonstrate significant inhibition and control of disease progression in xenograft mouse models of T-ALL. The data suggest that CAR redirected targeting for T-cell malignancies using NK cells may be a viable method for new and complementary therapeutic approaches that could improve the current outcome for patients. PMID- 28074067 TI - Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML. AB - It is unknown, why only a minority of chronic myeloid leukemia (CML) patients sustains treatment free remission (TFR) after discontinuation of tyrosine kinase inhibitor (TKI) therapy in deep molecular remission (MR). Here we studied, whether expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) affects relapse risk after TKI cessation. CML patients in MR displayed significantly higher CD86+pDC frequencies than normal donors (P<0.0024), whereas TFR patients had consistently low CD86+pDC (n=12). This suggested that low CD86+pDC might be predictive of TFR. Indeed, in a prospective analysis of 122 patients discontinuing their TKI within the EURO-SKI trial, the one-year relapse-free survival (RFS) was 30.1% (95% CI 15.6-47.9) for patients with >95 CD86+pDC per 105 lymphocytes, but 70.0% (95% CI 59.3-78.3) for patients with <95 CD86+pDC (hazard ratio (HR) 3.4, 95%-CI: 1.9-6.0; P<0.0001). Moreover, only patients with <95 CD86+pDC derived a significant benefit from longer (>8 years) TKI exposure before discontinuation (HR 0.3, 95% CI 0.1-0.8; P=0.0263). High CD86+pDC counts significantly correlated with leukemia-specific CD8+ T-cell exhaustion (Spearman correlation: 0.74, 95%-CI: 0.21-0.92; P=0.0098). Our data demonstrate that CML patients with high CD86+pDC counts have a higher risk of relapse after TKI discontinuation. PMID- 28074069 TI - Myelodysplastic syndromes and bone loss in mice and men. PMID- 28074070 TI - Gain of function in Jak2V617F-positive T-cells. PMID- 28074068 TI - A CpG island methylator phenotype in acute myeloid leukemia independent of IDH mutations and associated with a favorable outcome. AB - Genetic changes are infrequent in acute myeloid leukemia (AML) compared with other malignancies and often involve epigenetic regulators, suggesting that an altered epigenome may underlie AML biology and outcomes. In 96 AML cases including 65 pilot samples selected for cured/not-cured, we found higher CpG island (CGI) promoter methylation in cured patients. Expanded genome-wide digital restriction enzyme analysis of methylation data revealed a CGI methylator phenotype independent of IDH1/2 mutations we term AML-CGI methylator phenotype (CIMP) (A-CIMP+). A-CIMP was associated with longer overall survival (OS) in this data set (median OS, years: A-CIMP+=not reached, CIMP-=1.17; P=0.08). For validation we used 194 samples from The Cancer Genome Atlas interrogated with Illumina 450k methylation arrays where we confirmed longer OS in A-CIMP (median OS, years: A-CIMP+=2.34, A-CIMP-=1.00; P=0.01). Hypermethylation in A-CIMP+ favored CGIs (OR: CGI/non-CGI=5.21), and while A-CIMP+ was enriched in CEBPA (P=0.002) and WT1 mutations (P=0.02), 70% of cases lacked either mutation. Hypermethylated genes in A-CIMP+ function in pluripotency maintenance, and a gene expression signature of A-CIMP was associated with outcomes in multiple data sets. We conclude that CIMP in AML cannot be explained solely by gene mutations (for example, IDH1/2, TET2), and that curability in A-CIMP+ AML should be validated prospectively. PMID- 28074071 TI - Olaptesed pegol, an anti-CXCL12/SDF-1 Spiegelmer, alone and with bortezomib dexamethasone in relapsed/refractory multiple myeloma: a Phase IIa Study. PMID- 28074073 TI - Gut microbiota in 2016: A banner year for gut microbiota research. PMID- 28074074 TI - IBD in 2016: Biologicals and biosimilars in IBD - the road to personalized treatment. PMID- 28074072 TI - Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T cell acute lymphoblastic leukemia. AB - Inhibition of anti-apoptotic BCL-2 (B-cell lymphoma 2) has recently emerged as a promising new therapeutic strategy for the treatment of a variety of human cancers, including leukemia. Here, we used T-cell acute lymphoblastic leukemia (T ALL) as a model system to identify novel synergistic drug combinations with the BH3 mimetic venetoclax (ABT-199). In vitro drug screening in primary leukemia specimens that were derived from patients with high risk of relapse or relapse and cell lines revealed synergistic activity between venetoclax and the BET (bromodomain and extraterminal) bromodomain inhibitor JQ1. Notably, this drug synergism was confirmed in vivo using T-ALL cell line and patient-derived xenograft models. Moreover, the therapeutic benefit of this drug combination might, at least in part, be mediated by an acute induction of the pro-apoptotic factor BCL2L11 and concomitant reduction of BCL-2 upon BET bromodomain inhibition, ultimately resulting in an enhanced binding of BIM (encoded by BCL2L11) to BCL-2. Altogether, our work provides a rationale to develop a new type of targeted combination therapy for selected subgroups of high-risk leukemia patients. PMID- 28074075 TI - Primary biliary cholangitis in 2016: High-definition PBC: biology, models and therapeutic advances. PMID- 28074076 TI - A solid dielectric gated graphene nanosensor in electrolyte solutions. AB - This letter presents a graphene field effect transistor (GFET) nanosensor that, with a solid gate provided by a high-kappa dielectric, allows analyte detection in liquid media at low gate voltages. The gate is embedded within the sensor and thus is isolated from a sample solution, offering a high level of integration and miniaturization and eliminating errors caused by the liquid disturbance, desirable for both in vitro and in vivo applications. We demonstrate that the GFET nanosensor can be used to measure pH changes in a range of 5.3-9.3. Based on the experimental observations and quantitative analysis, the charging of an electrical double layer capacitor is found to be the major mechanism of pH sensing. PMID- 28074079 TI - Immunotherapeutic Targeting in Autoimmune Diseases. PMID- 28074077 TI - Identification of Gingival Crevicular Fluid Sampling, Analytical Methods, and Oral Biomarkers for the Diagnosis and Monitoring of Periodontal Diseases: A Systematic Review. AB - Background. Several studies in the last decades have focused on finding a precise method for the diagnosis of periodontal disease in its early stages. Aim. To evaluate from current scientific literature the most common and precise method for gingival crevicular fluid (GCF) sample collection, biomarker analytical methods, and the variability of biomarker quantification, even when using the same analytical technique. Methodology. An electronic search was conducted on in vivo studies that presented clinical data on techniques used for GCF collection and biomarker analysis. Results. The results showed that 71.1%, 24.7%, and 4.1% of the studies used absorption, microcapillary, and washing techniques, respectively, in their gingival crevicular fluid collection. 73.1% of the researchers analyzed their samples by using enzyme-linked immunosorbent assay (ELISA). 22.6%, 19.5%, and 18.5% of the researchers included interleukin-1 beta (IL-1beta), matrix metalloproteinase-8 (MMP-8), and tumor necrosis factor-alpha (TNF-alpha), respectively, in their studies as biomarkers for periodontal disease. Conclusion. IL-1beta can be considered among the most common biomarkers that give precise results and can be used as an indicator of periodontal disease progression. Furthermore, paper strips are the most convenient and accurate method for gingival crevicular fluid collection, while enzyme-linked immunosorbent assay can be considered the most conventional method for the diagnosis of biofluids. PMID- 28074078 TI - Pediatric Traumatic Brain Injury and Autism: Elucidating Shared Mechanisms. AB - Pediatric traumatic brain injury (TBI) and autism spectrum disorder (ASD) are two serious conditions that affect youth. Recent data, both preclinical and clinical, show that pediatric TBI and ASD share not only similar symptoms but also some of the same biologic mechanisms that cause these symptoms. Prominent symptoms for both disorders include gastrointestinal problems, learning difficulties, seizures, and sensory processing disruption. In this review, we highlight some of these shared mechanisms in order to discuss potential treatment options that might be applied for each condition. We discuss potential therapeutic and pharmacologic options as well as potential novel drug targets. Furthermore, we highlight advances in understanding of brain circuitry that is being propelled by improved imaging modalities. Going forward, advanced imaging will help in diagnosis and treatment planning strategies for pediatric patients. Lessons from each field can be applied to design better and more rigorous trials that can be used to improve guidelines for pediatric patients suffering from TBI or ASD. PMID- 28074081 TI - The Time Course of Markers of Neutrophil Extracellular Traps in Patients Undergoing Revascularisation for Acute Myocardial Infarction or Stable Angina Pectoris. AB - Background and Aims. Neutrophil extracellular traps (NETs) have been identified in acute myocardial infarction. We assessed the time profile and association with infarct size for NETs markers in ST-elevation myocardial infarction (STEMI) and stable angina pectoris (AP). Methods. In 20 patients with STEMI and 10 with AP undergoing percutaneous coronary intervention (PCI), blood samples were collected before PCI (only AP group) and after 3 and 12 hours, days 1, 3, 5, 7, and 14 for measurement of NETs markers. Results. Double-stranded deoxyribonucleic acid (dsDNA) and nucleosome levels were higher in STEMI than AP until day 3 and 12 hours (p < 0.03, all). DsDNA declined after day 5 in both groups (p < 0.04, all), while nucleosomes declined until day 3 only in the AP group (p < 0.05, all). DsDNA correlated with peak troponin T and creatine kinase MB (CKMB) at day 5 (r = 0.48, p = 0.03, both) and with MRI-measured infarct size at days 5 and 7 (r = 0.61, p = 0.01 and r = 0.52, p = 0.04, resp.), while nucleosomes correlated with infarct size at day 5 (r = 0.58, p = 0.02). Conclusions. High levels of NETs markers were observed in STEMI shortly after revascularisation and were partly associated with infarct size. The decline thereafter in both groups indicates a role for NETs in both acute and chronic atherothrombosis. PMID- 28074080 TI - Role of Mitochondria-Associated Endoplasmic Reticulum Membrane in Inflammation Mediated Metabolic Diseases. AB - Inflammation is considered to be one of the most critical factors involved in the development of complex metabolic diseases such as type 2 diabetes, cancer, and cardiovascular disease. A few decades ago, the discovery of mitochondria associated endoplasmic reticulum (ER) membrane (MAM) was followed by the identification of its roles in regulating cellular homeostatic processes, ranging from cellular bioenergetics to apoptosis. MAM provides an excellent platform for numerous signaling pathways; among them, inflammatory signaling pathways associated with MAM play a critical role in cellular defense during pathogenic infections and metabolic disorders. However, induction of MAM causes deleterious effects by amplifying mitochondrial reactive oxygen species generation through increased calcium transfer from the ER to mitochondria, thereby causing mitochondrial damage and release of mitochondrial components into the cytosol as damage-associated molecular patterns (DAMPs). These mitochondrial DAMPs rapidly activate MAM-resident inflammasome components and other inflammatory factors, which promote inflammasome complex formation and release of proinflammatory cytokines in pathological conditions. Long-term stimulation of the inflammasome instigates chronic inflammation, leading to the pathogenesis of metabolic diseases. In this review, we summarize the current understanding of MAM and its association with inflammation-mediated metabolic diseases. PMID- 28074082 TI - The Fate of the Tumor in the Hands of Microenvironment: Role of TAMs and mTOR Pathway. AB - Since 2000, written with elegance and accuracy, Hanahan and Weinberg have proposed six major hallmarks of cancer and, together, they provide great advances to the understanding of tumoral biology. Our knowledge about tumor behavior has improved and the investigators have now recognized that inflammatory microenvironment may be a new feature for the tumor entities. Macrophages are considered as an important component of tumoral microenvironment. Biologically, two forms of activated macrophages can be observed: classically activated macrophages (M1) and alternative activated macrophages (M2). Despite the canonical pathways that control this puzzle of macrophages polarization, recently, mTOR signaling pathway has been implicated as an important piece in determining the metabolic and functional differentiation of M1 and M2 profiles. Currently, it is believed that macrophages related to tumoral microenvironment present an "M2-like" feature promoting an immunosuppressive microenvironment enhancing tumoral angiogenesis, growth, and metastasis. In the present review we discuss the role of macrophages in the tumor microenvironment and the role of mTOR pathway in M1 and M2 differentiation. We also discuss the recent findings in M1 and M2 polarization as a possible target in the cancer therapy. PMID- 28074083 TI - Management of Malignant Pleural Effusion with ASEPT(r) Pleural Catheter: Quality of Life, Feasibility, and Patient Satisfaction. AB - Objective. The PleurX(r) IPC system has been used extensively in the past. Over time, management of MPE with the PleurX system can be costly. The new ASEPT pleural catheter, through advantages in design, may ultimately show cost savings. The primary outcome of this study was to evaluate safety and efficacy of the ASEPT system. Method. This single centre, prospective study enrolled 50 patients with MPE, who were followed for as long as they were alive with a catheter. Quality of Life (QoL) was assessed before, at 2 weeks, and 6 weeks after ASEPT catheter insertion using the EORTC QLQ-C30 and LC13 questionnaires. Ease of catheter use and complications were reported by physician and community nurses. Results. 50 patients with MPE with a mean age of 64.5 +/- 1.9, BDI of 2.8 +/- 0.9, and ECOG score of 3.0 +/- 0.7 were recruited. No immediate or long-term complications were reported during the study period. Compared to precatheter insertion, global health status (-18, p < 0.001), QLQ-C30 dyspnea (-39, p < 0.00001), and LC13 dyspnea (-11, p < 0.0005) significantly improved at 2 and 6 weeks after intervention. Provider surveys indicated favourable ease of use. Conclusion. The new ASEPT catheter offers a safe and effective option for the management of MPE. PMID- 28074085 TI - Erratum to: In vivo enhancement of the MAGE-specific cellular immune response by a recombinant MAGE1-MAGE3-TBHSP70 tumor vaccine. AB - [This corrects the article DOI: 10.1186/s12935-016-0317-2.]. PMID- 28074084 TI - Comparative Analysis of Methanogenic Communities in Different Laboratory-Scale Anaerobic Digesters. AB - Comparative analysis of methanogenic archaea compositions and dynamics in 11 laboratory-scale continuous stirred tank reactors fed with different agricultural materials (chicken manure, cattle manure, maize straw, maize silage, distillers grains, and Jatropha press cake) was carried out by analysis of the methyl coenzyme-M reductase alpha-subunit (mcrA) gene. Various taxa within Methanomicrobiales, Methanobacteriaceae, Methanosarcinaceae, Methanosaetaceae, and Methanomassiliicoccales were detected in the biogas reactors but in different proportions depending on the substrate type utilized as well as various process parameters. Improved coverage and higher taxonomic resolution of methanogens were obtained compared to a previous 16S rRNA gene based study of the same reactors. Some members of the genus Methanoculleus positively correlated with the relative methane content, whereas opposite correlations were found for Methanobacterium. Specific biogas production was found to be significantly correlating with Methanosarcinaceae. Statistical analysis also disclosed that some members of the genus Methanoculleus positively correlated with the ammonia level, whereas the prevalence of Methanocorpusculum, Methanobacterium, and Methanosaeta was negatively correlated with this parameter. These results suggest that the application of methanogenic archaea adapted to specific feedstock might enhance the anaerobic digestion of such waste materials in full-scale biogas reactors. PMID- 28074086 TI - Role of CYP2E1 polymorphisms in breast cancer: a systematic review and meta analysis. AB - BACKGROUND: CYP2E1 polymorphisms have been reported to influence individual's breast cancer susceptibility as a phase I enzyme, but the results of these previous studies remain controversial. We performed a comprehensive meta-analysis to assess their association. METHODS: A comprehensive search of literature included in various databases (PubMed, Web of Science and Google scholar), published before August 2016, was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) calculated in fixed or random-effects models were used to estimate the strength of the associations between three polymorphisms of CYP2E1 and breast cancer susceptibility. Subgroup analysis, sensitivity analysis and test for publication bias were also performed. A total of 11 separate comparisons involving 4311 cases and 4407 controls were included in the meta analysis. RESULTS: Our result showed that there was no significant association between the two common polymorphisms CYP2E1 rs2031920 C>T, CYP2E1*5 Rsa I/Rst I (c1/c2) and BC risk. For CYP2E1*6 Dra I (D/C) polymorphism, a significantly increased BC risk in the overall population was found in genetic model D/C vs. D/D (OR = 1.29, 95% CI = 1.04-1.61, P = 0.023) and C/C + D/C vs. D/D (OR = 1.25, 95% CI = 1.04-1.51, P = 0.019), together with subjects who have at least one C allele (C vs. D: OR = 1.46, 95% CI = 1.20-1.79, P < 0.001). Similar results were also found in subgroup analyses in Caucasians of these three comparison models. CONCLUSIONS: The present meta-analysis suggests that CYP2E1*6 Dra I (D/C) variation significantly associated with the risk of BC. Individuals with D/C and C/C + D/C genotypes or carried at least one C allele of CYP2E1*6 Dra I (D/C) polymorphism had a significant higher susceptibility to develop BC. PMID- 28074087 TI - The genetic variation rs6903956 in the novel androgen-dependent tissue factor pathway inhibitor regulating protein (ADTRP) gene is not associated with levels of plasma coagulation factors in the Singaporean Chinese. AB - BACKGROUND: Genome-wide association study (GWAS) has reported that rs6903956 within the first intron of androgen-dependent tissue factor pathway inhibitor (TFPI) regulating protein (ADTRP) gene is associated with coronary artery disease (CAD) risk in the Chinese population. Although ADTRP is believed to be involved in the upregulation of TFPI, the underlying mechanism involved is largely unknown. This study investigated the association of rs6903956 with plasma Factor VII coagulant activity (FVIIc) and fibrinogen levels, which are regulated by TFPI and are independent risk predictors for CAD. METHODS: We conducted the analysis in both Chinese adult (N = 309) and neonatal cohorts (N = 447). The genotypes of the rs6903956 single nucleotide polymorphism (SNP) were determined by the polymerase chain reaction restriction fragment length polymorphism method (PCR RFLP). FVIIc and fibrinogen level were measured from citrated plasma. The association between rs6903956 and coagulation factors was tested by linear regression with adjustment for possible confounders. Analysis was carried out in adults and neonates separately. RESULTS: No significant association was observed between rs6903956 and plasma FVIIc nor fibrinogen levels with adjustment for age, gender, body mass index (BMI) and cigarette smoking in adults (P for FVIIc = 0.464; P for fibrinogen = 0.349). The SNP was also not associated with these two coagulation factors in the neonates (P for FVIIc = 0.579; P for fibrinogen = 0.359) after adjusting for gestational age, gender and birth weight. CONCLUSIONS: SNP rs6903956 on ADTRP gene was not associated with plasma FVIIc nor fibrinogen levels. PMID- 28074088 TI - Accurate optimization of amino acid form factors for computing small-angle X-ray scattering intensity of atomistic protein structures. AB - Structure modelling via small-angle X-ray scattering (SAXS) data generally requires intensive computations of scattering intensity from any given biomolecular structure, where the accurate evaluation of SAXS profiles using coarse-grained (CG) methods is vital to improve computational efficiency. To date, most CG SAXS computing methods have been based on a single-bead-per-residue approximation but have neglected structural correlations between amino acids. To improve the accuracy of scattering calculations, accurate CG form factors of amino acids are now derived using a rigorous optimization strategy, termed electron-density matching (EDM), to best fit electron-density distributions of protein structures. This EDM method is compared with and tested against other CG SAXS computing methods, and the resulting CG SAXS profiles from EDM agree better with all-atom theoretical SAXS data. By including the protein hydration shell represented by explicit CG water molecules and the correction of protein excluded volume, the developed CG form factors also reproduce the selected experimental SAXS profiles with very small deviations. Taken together, these EDM-derived CG form factors present an accurate and efficient computational approach for SAXS computing, especially when higher molecular details (represented by the q range of the SAXS data) become necessary for effective structure modelling. PMID- 28074091 TI - Advances in Biliary Tract Disorders: Novel Biomarkers, Pharmacotherapies, Endoscopic Techniques, and Surgical Management. PMID- 28074089 TI - Antiviral activity of animal venom peptides and related compounds. AB - Viruses exhibit rapid mutational capacity to trick and infect host cells, sometimes assisted through virus-coded peptides that counteract host cellular immune defense. Although a large number of compounds have been identified as inhibiting various viral infections and disease progression, it is urgent to achieve the discovery of more effective agents. Furthermore, proportionally to the great variety of diseases caused by viruses, very few viral vaccines are available, and not all are efficient. Thus, new antiviral substances obtained from natural products have been prospected, including those derived from venomous animals. Venoms are complex mixtures of hundreds of molecules, mostly peptides, that present a large array of biological activities and evolved to putatively target the biochemical machinery of different pathogens or host cellular structures. In addition, non-venomous compounds, such as some body fluids of invertebrate organisms, exhibit antiviral activity. This review provides a panorama of peptides described from animal venoms that present antiviral activity, thereby reinforcing them as important tools for the development of new therapeutic drugs. PMID- 28074090 TI - Application of Machine Learning in Postural Control Kinematics for the Diagnosis of Alzheimer's Disease. AB - The use of wearable devices to study gait and postural control is a growing field on neurodegenerative disorders such as Alzheimer's disease (AD). In this paper, we investigate if machine-learning classifiers offer the discriminative power for the diagnosis of AD based on postural control kinematics. We compared Support Vector Machines (SVMs), Multiple Layer Perceptrons (MLPs), Radial Basis Function Neural Networks (RBNs), and Deep Belief Networks (DBNs) on 72 participants (36 AD patients and 36 healthy subjects) exposed to seven increasingly difficult postural tasks. The decisional space was composed of 18 kinematic variables (adjusted for age, education, height, and weight), with or without neuropsychological evaluation (Montreal cognitive assessment (MoCA) score), top ranked in an error incremental analysis. Classification results were based on threefold cross validation of 50 independent and randomized runs sets: training (50%), test (40%), and validation (10%). Having a decisional space relying solely on postural kinematics, accuracy of AD diagnosis ranged from 71.7 to 86.1%. Adding the MoCA variable, the accuracy ranged between 91 and 96.6%. MLP classifier achieved top performance in both decisional spaces. Having comprehended the interdynamic interaction between postural stability and cognitive performance, our results endorse machine-learning models as a useful tool for computer-aided diagnosis of AD based on postural control kinematics. PMID- 28074092 TI - Clinical Significance of UCA1 to Predict Metastasis and Poor Prognosis of Digestive System Malignancies: A Meta-Analysis. AB - Purpose. Urothelial carcinoma-associated 1 (UCA1) has been reported to be overexpressed and correlated with progression in various cancers. However, the association between UCA1 expression and some clinicopathological features of digestive system malignancies, such as metastasis and survival, remains inconclusive. Therefore, a meta-analysis was performed to investigate the clinical significance of UCA1 in digestive system malignancies. Methods. Relevant literatures were searched in PubMed, Web of Science, Cochrane Library, and Embase databases updated to May 2016. Results. A total of 1089 patients from 10 studies were included in this meta-analysis. Meta-analysis results showed that digestive system malignancy patients with UCA1 overexpression were significantly more susceptible to developing lymph node metastasis (LNM) (OR = 1.85, 95% CI: 1.28 2.67) and distant metastasis (DM) (OR = 3.14, 95% CI: 1.77-5.58) and suffer from poor overall survival (OS) (HR = 2.31, 95% CI: 1.89-2.82, univariate analysis; HR = 2.24, 95% CI: 1.69-2.98, multivariate analysis) and poor disease-free survival (DFS) (HR = 2.65, 95% CI: 1.59-4.43, univariate analysis; HR = 2.50, 95% CI: 1.62 3.86, multivariate analysis). Conclusion. UCA1 overexpression was correlated with LNM, DM, poor OS, and poor DFS. UCA1 may serve as an indicator for metastasis and poor prognosis in digestive system malignancies. PMID- 28074093 TI - Involvement of Reduced Microbial Diversity in Inflammatory Bowel Disease. AB - A considerable number of studies have been conducted to study the microbial profiles in inflammatory conditions. A common phenomenon in inflammatory bowel disease (IBD) is the reduction of the diversity of microbiota, which demonstrates that microbial diversity negatively correlates with disease severity in IBD. Increased microbial diversity is known to occur in disease remission. Species diversity plays an important role in maintaining the stability of the intestinal ecosystem as well as normal ecological function. A reduction in microbial diversity corresponds to a decrease in the stability of the ecosystem and can impair ecological function. Fecal microbiota transplantation (FMT), probiotics, and prebiotics, which aim to modulate the microbiota and restore its normal diversity, have been shown to be clinically efficacious. In this study, we hypothesized that a reduction in microbial diversity could play a role in the development of IBD. PMID- 28074094 TI - To Identify Predictors of Central Lymph Node Metastasis in Patients with Clinically Node-Negative Conventional Papillary Thyroid Carcinoma. AB - Objective. The aim of this study was to identify the risk factors associated with central lymph node metastasis (CLNM) in patients with clinically node-negative conventional papillary thyroid carcinoma (cN0 CPTC). Methods. A total of 190 cN0 CPTC patients who underwent thyroidectomy with prophylactic central neck dissection (pCND) in the Department of General Surgery at Guangdong General Hospital between March 2014 and December 2015 were assessed retrospectively. The relations of CLNM with clinicopathologic characteristics of cN0 CPTC were analyzed by univariate and multivariate logistic regression. Results. The incidence of CLNM in patients with cN0 CPTC was 63.2% (120 of 190 cases). Univariate analysis showed that age <45 years (P = 0.000), tumor size >2 cm (P = 0.009), multifocality (P = 0.001), and bilaterality (P = 0.000) were significantly associated with the increased incidence of CLNM in cN0 CPTC. No significant correlations were found between CLNM and other variables such as gender (P = 0.150), capsular invasion (P = 0.973), extrathyroidal invasion (P = 0.616), and lymphadenectomy (P = 0.062). Multivariate logistic regression analysis revealed that age <45 years (P = 0.000), tumor size >2 cm (P = 0.025), and bilaterality (P = 0.000) were independent risk factors of CLNM in patients with cN0 CPTC. Conclusions. Metastatic disease to central compartment lymph nodes is prevalent in patients with cN0 CPTC. Age <45 years, tumor size >2 cm, and bilaterality are independent risk factors of CLNM, which allow for selective CND in patients with cN0 CPTC. PMID- 28074095 TI - Multidisciplinary Management of Pituitary Apoplexy. AB - Pituitary apoplexy is a rare clinical syndrome due to ischemic or haemorrhagic necrosis of the pituitary gland which complicates 2-12% of pituitary tumours, especially nonfunctioning adenomas. In many cases, it results in severe neurological, ophthalmological, and endocrinological consequences and may require prompt surgical decompression. Pituitary apoplexy represents a rare medical emergency that necessitates a multidisciplinary approach. Modalities of treatment and times of intervention are still largely debated. Therefore, the management of patients with pituitary apoplexy is often empirically individualized and clinical outcome is inevitably related to the multidisciplinary team's skills and experience. This review aims to highlight the importance of a multidisciplinary approach in the management of pituitary apoplexy and to discuss modalities of presentation, treatment, and times of intervention. PMID- 28074096 TI - The Signaling Pathways Involved in Chondrocyte Differentiation and Hypertrophic Differentiation. AB - Chondrocytes communicate with each other mainly via diffusible signals rather than direct cell-to-cell contact. The chondrogenic differentiation of mesenchymal stem cells (MSCs) is well regulated by the interactions of varieties of growth factors, cytokines, and signaling molecules. A number of critical signaling molecules have been identified to regulate the differentiation of chondrocyte from mesenchymal progenitor cells to their terminal maturation of hypertrophic chondrocytes, including bone morphogenetic proteins (BMPs), SRY-related high mobility group-box gene 9 (Sox9), parathyroid hormone-related peptide (PTHrP), Indian hedgehog (Ihh), fibroblast growth factor receptor 3 (FGFR3), and beta catenin. Except for these molecules, other factors such as adenosine, O2 tension, and reactive oxygen species (ROS) also have a vital role in cartilage formation and chondrocyte maturation. Here, we outlined the complex transcriptional network and the function of key factors in this network that determine and regulate the genetic program of chondrogenesis and chondrocyte differentiation. PMID- 28074097 TI - Integrating Gene Correction in the Reprogramming and Transdifferentiation Processes: A One-Step Strategy to Overcome Stem Cell-Based Gene Therapy Limitations. AB - The recent advent of induced pluripotent stem cells (iPSCs) and gene therapy tools has raised the possibility of autologous cell therapy for rare genetic diseases. However, cellular reprogramming is inefficient in certain diseases such as ataxia telangiectasia, Fanconi anemia, LIG4 syndrome, and fibrodysplasia ossificans progressiva syndrome, owing to interference of the disease-related genes. To overcome these therapeutic limitations, it is necessary to fundamentally correct the abnormal gene during or prior to the reprogramming process. In addition, as genetic etiology of Parkinson's disease, it has been well known that induced neural stem cells (iNSCs) were progressively depleted by LRRK2 gene mutation, LRRK2 (G2019S). Thus, to maintain the induced NSCs directly derived from PD patient cells harboring LRRK2 (G2019S), it would be ideal to simultaneously treat the LRRK2 (G2019S) fibroblast during the process of TD. Therefore, simultaneous reprogramming (or TD) and gene therapy would provide the solution for therapeutic limitation caused by vulnerability of reprogramming or TD, in addition to being suitable for general application to the generation of autologous cell-therapy products for patients with genetic defects, thereby obviating the need for the arduous processes currently required. PMID- 28074098 TI - Human Cord Blood-Derived CD133+/C-Kit+/Lin- Cells Have Bipotential Ability to Differentiate into Mesenchymal Stem Cells and Outgrowth Endothelial Cells. AB - Recent evidence suggests that mononuclear cells (MNCs) derived from bone marrow and cord blood can differentiate into mesenchymal stem cells (MSCs) or outgrowth endothelial cells (OECs). However, controversy exists as to whether MNCs have the pluripotent capacity to differentiate into MSCs or OECs or are a mixture of cell lineage-determined progenitors of MSCs or OECs. Here, using CD133+/C-kit+/Lin- mononuclear cells (CKL- cells) isolated from human umbilical cord blood using magnetic cell sorting, we characterized the potency of MNC differentiation. We first found that CKL- cells cultured with conditioned medium of OECs or MSCs differentiated into OECs or MSCs and this differentiation was also induced by cell-to-cell contact. When we cultured single CKL- cells on OEC- or MSC conditioned medium, the cells differentiated morphologically and genetically into OEC- or MSC-like cells, respectively. Moreover, we confirmed that OECs or MSCs differentiated from CKL- cells had the ability to form capillary-like structures in Matrigel and differentiate into osteoblasts, chondrocytes, and adipocytes. Finally, using microarray analysis, we identified specific factors of OECs or MSCs that could potentially be involved in the differentiation fate of CKL- cells. Together, these results suggest that cord blood-derived CKL- cells possess at least bipotential differentiation capacity toward MSCs or OECs. PMID- 28074099 TI - A Network Pharmacology Approach to Explore the Pharmacological Mechanism of Xiaoyao Powder on Anovulatory Infertility. AB - Aim. To explore the pharmacological mechanism of Xiaoyao powder (XYP) on anovulatory infertility by a network pharmacology approach. Method. Collect XYP's active compounds by traditional Chinese medicine (TCM) databases, and input them into PharmMapper to get their targets. Then note these targets by Kyoto Encyclopedia of Genes and Genomes (KEGG) and filter out targets that can be noted by human signal pathway. Get the information of modern pharmacology of active compounds and recipe's traditional effects through databases. Acquire infertility targets by Therapeutic Target Database (TTD). Collect the interactions of all the targets and other human proteins via String and INACT. Put all the targets into the Database for Annotation, Visualization, and Integrated Discovery (DAVID) to do GO enrichment analysis. Finally, draw the network by Cytoscape by the information above. Result. Six network pictures and two GO enrichment analysis pictures are visualized. Conclusion. According to this network pharmacology approach some signal pathways of XYP acting on infertility are found for the first time. Some biological processes can also be identified as XYP's effects on anovulatory infertility. We believe that evaluating the efficacy of TCM recipes and uncovering the pharmacological mechanism on a systematic level will be a significant method for future studies. PMID- 28074101 TI - Evaluation of the Antioxidant Capacities and Cytotoxic Effects of Ten Parmeliaceae Lichen Species. AB - Parmeliaceae represents the largest and widespread family of lichens and includes species that attract much interest regarding pharmacological activities, due to their production of unique secondary metabolites. The current work aimed to investigate the in vitro antioxidant and cytotoxic activities of the methanol extracts of ten Parmeliaceae species, collected in different continents. Methanol extraction afforded high phenolic content in the extracts. The antioxidant activity displayed by lichens was evaluated through chemical assays, such as the ORAC (Oxygen Radical Absorbance Capacity) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities and the ferric reducing antioxidant power (FRAP). A moderately positive correlation was found between the phenolic content and the antioxidant properties for all the species: R: 0.7430 versus ORAC values, R: 0.7457 versus DPPH scavenging capacity, and R: 0.7056 versus FRAP reducing power. The methanol extract of Flavoparmelia euplecta exhibited the highest ORAC value, the extract of Myelochroa irrugans showed the maximum DPPH scavenging capacity, and Hypotrachyna cirrhata methanol extract demonstrated the highest reducing power. Further, the cytotoxic activity of the ten species was investigated on the human cancer cell lines HepG2 and MCF-7; Myelochroa irrugans exhibited the highest anticancer potential. The pharmacological activities shown here could be attributed to their phytochemical constituents. PMID- 28074100 TI - Antidepressant-Like Effect of Lipid Extract of Channa striatus in Chronic Unpredictable Mild Stress Model of Depression in Rats. AB - This study evaluated the antidepressant-like effect of lipid extract of C. striatus in chronic unpredictable mild stress (CUMS) model of depression in male rats and its mechanism of action. The animals were subjected to CUMS for six weeks by using variety of stressors. At the end of CUMS protocol, animals were subjected to forced swimming test (FST) and open field test followed by biochemical assay. The CUMS protocol produced depressive-like behavior in rats by decreasing the body weight, decreasing the sucrose preference, and increasing the duration of immobility in FST. The CUMS protocol increased plasma corticosterone and decreased hippocampal and prefrontal cortex levels of monoamines (serotonin, noradrenaline, and dopamine) and brain-derived neurotrophic factor. Further, the CUMS protocol increased interleukin-6 (in hippocampus and prefrontal cortex) and nuclear factor-kappa B (in prefrontal cortex but not in hippocampus). The lipid extract of C. striatus (125, 250, and 500 mg/kg) significantly (p < 0.05) reversed all the above parameters in rats subjected to CUMS, thus exhibiting antidepressant-like effect. The mechanism was found to be mediated through decrease in plasma corticosterone, increase in serotonin levels in prefrontal cortex, increase in dopamine and noradrenaline levels in hippocampus and prefrontal cortex, increase in BDNF in hippocampus and prefrontal cortex, and decrease in IL-6 and NF-kappaB in prefrontal cortex. PMID- 28074102 TI - Activation of p53/miR-34a Tumor Suppressor Axis by Chinese Herbal Formula JP-1 in A549 Lung Adenocarcinoma Cells. AB - Lung cancer is the leading cause of cancer death worldwide; the most common pathologic type is lung adenocarcinoma (LADC). In spite of the recent progress in targeted therapy, most LADC patients eventually expired due to the inevitable recurrence and drug resistance. New complementary agent with evidence-based molecular mechanism is urgently needed. MiR-34a is an important p53 downstream tumor suppressor, which regulates apoptosis, cell-cycle, EMT (epithelial mesenchymal transition), and so forth. Its expression is deficient in many types of cancers including LADC. Here, we show that a Chinese herbal formula JP-1 activates p53/miR-34a axis in A549 human LADC cells (p53 wild-type). Treatment with JP-1 induces p53 and its downstream p21 and BAX proteins as well as the miR 34a, resulting in growth inhibition, colony formation reduction, migration repression, and apoptosis induction. Accordingly, the decreases of miR-34a downstream targets such as CDK6, SIRT1, c-Myc, survivin, Snail, and AXL were observed. Moreover, JP-1 activates AMPKalpha and reduces mTOR activity, implying its inhibitory effect on the energy-sensitive protein synthesis and cell proliferation signaling. Our results show that JP-1 activates p53/miR-34a tumor suppressor axis and decreases proteins related to proliferation, apoptosis resistance, and metastasis, suggesting its potential as a complementary medicine for LADC treatment. PMID- 28074103 TI - Thai Fruits Exhibit Antioxidant Activity and Induction of Antioxidant Enzymes in HEK-293 Cells. AB - The cellular antioxidant enzymes play the important role of protecting the cells and organisms from the oxidative damage. Natural antioxidants contained in fruits have attracted considerable interest because of their presumed safety and potential nutritional value. Even though antioxidant activities of many fruits have been reported, the effects of phytochemicals contained in fruits on the induction of antioxidant enzymes in the cells have not been fully defined. In this study, we showed that extracts from Antidesma ghaesembilla, Averrhoa bilimbi, Malpighia glabra, Mangifera indica, Sandoricum koetjape, Syzygium malaccense, and Ziziphus jujuba inhibited H2O2-induced intracellular reactive oxygen species production in HEK-293 cells. Additionally, these Thai fruit extracts increased the mRNA and protein expressions of antioxidant enzymes, catalase, glutathione peroxidase-1, and manganese superoxide dismutase. The consumption of Thai fruits rich in phenolic compounds may reduce the risk of oxidative stress. PMID- 28074104 TI - Bufalin Inhibits Proliferation and Induces Apoptosis in Osteosarcoma Cells by Downregulating MicroRNA-221. AB - Bufalin, a major component of the Chinese medicine ChanSu, which is prepared from the skin and parotid venom glands of toads, has shown cytotoxicity in several malignant tumors. Here, we reported that bufalin inhibited proliferation and induced mitochondria-dependent apoptosis in U-2OS and Saos-2 osteosarcoma cells with intracellular reactive oxygen species (ROS) production. By microRNA (miR) array analysis and quantitative reverse transcription polymerase chain reaction, we found that miR-221 was downregulated after treatment with bufalin. In accordance with TargetScan prediction and luciferase reporter assay, Bcl2 binding component 3 (BBC3) was the direct target of miR-221. Furthermore, upregulating miR-221 by its MIMIC and suppressing BBC3 by small interfering RNA (siRNA) reversed the effects of bufalin on osteosarcoma cells. Collectively, our data indicate that bufalin inhibits cell proliferation and induces mitochondria dependent apoptosis in osteosarcoma cells through downregulating miR-221 and triggering BBC3 expression. PMID- 28074105 TI - Work-related exposures and disorders among physical therapists: experiences and beliefs of professional representatives assessed using a qualitative approach. AB - BACKGROUND: According to international study results, physical therapists are afflicted with work-related musculoskeletal, psychosocial and dermal disorders as well as infections. The few existing studies in German-speaking regions focus mainly on dermal and psychosocial exposures and resulting complaints. An overview of all relevant work-related exposures and complaints of physical therapists is currently lacking. We sought to identify work-related exposures based on the subjective experiences and beliefs of physiotherapeutic representatives, in order to identify relevant work-related complaints and diseases. Likewise we aimed to compare the international evidence with the actual situation of physical therapists in Germany. METHODS: Two complementary qualitative approaches were used: 1) a focus group discussion with representatives of professional physiotherapy associations as well as health and safety stakeholders and 2) qualitative semi-structured telephone interviews incorporating currently employed physical therapists. The group discussion was conducted applying a moderation technique, and interviews were analyzed using the content analysis approach by Mayring. RESULTS: The focus group discussion with five participants and the 40 semi-structured interviews with physical therapists identified comparable results. The main exposures of physiotherapeutic work were considered to be musculoskeletal (e.g., awkward body postures during treatment, patient transfers, passive mobilization), psychosocial (e.g., statutory audit of prescriptions and the associated conflicts with doctors and health insurance providers) and partly dermal and infectious (e.g., wet work and risk of infection) factors. Diseases of the spine, wrist or finger joints, burnout syndrome and infections were mentioned as possible consequences. CONCLUSIONS: The subjective data generated by both groups (focus group discussion and interviews) were comparable and consistent with the current state of research. The results provide new insight regarding work-related exposures and diseases of physical therapists working in Germany. These findings aided the design of a German-wide representative survey of practicing physical therapists. PMID- 28074106 TI - Factors that influence early breastfeeding of singletons and twins in Korea: a retrospective study. AB - BACKGROUND: This study aimed to evaluate the factors that influence breastfeeding throughout the hospital stay, including prenatal preparation, early skin-to-skin contact directly after delivery, rooming-in, feeding before the first breastfeed, time to first breastfeed, and postpartum support. This study also aimed to verify whether these factors were significant after adjusting for the mother's characteristics, the newborn's characteristics, and the delivery characteristics. METHODS: A retrospective survey was used to collect the data. Factors that influenced breastfeeding throughout the hospital stay, and differences between the types of newborns were analyzed. RESULTS: Among twins, a higher likelihood of breastfeeding throughout the hospital stay was associated with not feeding before the first breastfeeding and an earlier start time for the first breastfeeding. Among singletons, a higher likelihood of breastfeeding throughout the hospital stay was associated with early skin-to-skin contact, no other feeding before the first breastfeed, and an earlier commencement of the first breastfeed. CONCLUSIONS: Effort should encourage early breastfeeding, without restriction, to improve the breastfeeding rate among mothers of twins. Moreover, an individualized approach that addresses the factors that influence breastfeeding for each type of newborn may help improve the corresponding rates of breastfeeding throughout the hospital stay. PMID- 28074107 TI - Frequency of Chlamydia trachomatis infection in cervical intraepithelial lesions and the status of cytological p16/Ki-67 dual-staining. AB - BACKGROUND: Chlamydia trachomatis (Ct) is not a disease subject to mandatory reporting in Brazil, and the prevalence rate of this genital infection varies according to the region in which studies are conducted, as well as by the detection technique employed. Ct has been associated with persistence of Human papillomavirus (HPV) infection and the facilitation of cervical carcinoma development. We evaluated the Chlamydia trachomatis infection and its association with cytology, p16/Ki-67 dual-stained cytology and cervical intraepithelial lesions status in a screening cohort in Brazil. METHODS: This was a cross sectional study of 1481 cervical samples from asymptomatic women aged 18 to 64. Samples were collected for liquid-based cytology and Ct detection by polymerase chain reaction. p16/Ki-67 double staining was performed on samples with abnormal cytology. Statistical analysis was by chi-square and likelihood-ratio tests. Odds ratio (OR) and 95% confidence intervals (95% CI) were determined. RESULTS: The frequency of Ct was 15.6% and its presence was not associated with detection of p16/Ki-67 [OR = 1.35 (0.5-3.4)]. There was also no association between abnormal cervical cytology and Ct-positivity [OR = 1.21 (0.46-3.2)]. Associations were observed between p16/Ki-67 and high-grade lesions detected by cytology and in biopsies [OR = 3.55 (1.50-8.42) and OR = 19.00 (0.6-7.2), respectively]. CONCLUSIONS: The asymptomatic women in our study had a high frequency of Ct infection but this was not associated with p16/Ki-67 detection in samples with abnormal cytology. The expression of p16/Ki-67 was highest in women with high grade CIN (p = 0.003). PMID- 28074108 TI - Cellulolytic RoboLector - towards an automated high-throughput screening platform for recombinant cellulase expression. AB - BACKGROUND: Cellulases are key player in the hydrolyzation of cellulose. Unfortunately, this reaction is slow and a bottleneck in the process chain from biomass to intermediates and biofuels due to low activities of the enzymes. To overcome this draw back, a lot of effort is put into the area of protein engineering, to modify these enzymes by directed evolution or rational design. Huge clone libraries are constructed and have to be screened for improved variants. High-throughput screening is the method of choice to tackle this experimental effort, but up to now only a few process steps are adapted to automated platforms and little attention has been turned to the reproducibility of clone rankings. RESULTS: In this study, an extended robotic platform is presented to conduct automated high-throughput screenings of clone libraries including preculture synchronization and biomass specific induction. Automated upstream, downstream and analytical process steps are described and evaluated using E. coli and K. lactis as model organisms. Conventional protocols for media preparation, cell lysis, Azo-CMC assay and PAHBAH assay are successfully adapted to automatable high-throughput protocols. Finally, a recombinant E. coli celA2 clone library was screened and a reliable clone ranking could be realized. CONCLUSION: The RoboLector device is a suitable platform to perform all process steps of an automated high-throughput clone library screening for improved cellulases. On-line biomass growth measurement controlling liquid handling actions enables fair comparison of clone variants. PMID- 28074109 TI - Improvement of quality of life through glycemic control by liraglutide, a GLP-1 analog, in insulin-naive patients with type 2 diabetes mellitus: the PAGE1 study. AB - BACKGROUND: In addition to achieving good glycemic control, diabetes care management aims to improve the quality of life (QOL) in patients. Treatment associated difficulties and side effects frequently cause deterioration in QOL. Liraglutide, a GLP-1 receptor agonist, is a novel injection drug that promotes insulin secretion. It is a user-friendly, once-daily injection with fewer hypoglycemic events. In this study, we aimed to examine the effect of liraglutide therapy on QOL in patients. METHODS: In total, 304 insulin- and liraglutide-naive patients with type 2 diabetes were enrolled in this observational study; they received liraglutide therapy for 12 weeks. The main outcome measure was change in QOL from baseline, which was assessed using diabetes therapy-related QOL (DTR QOL). RESULTS: At week 12, liraglutide significantly decreased HbA1c levels (8.7 +/- 1.5 vs. 7.5 +/- 1.3, p < 0.001) and BMI (27.9 +/- 5.3 vs. 27.3 +/- 5.2, p < 0.001). According to the QOL scores, although the treatment modality had changed from non-injection to injection therapy, liraglutide improved patient satisfaction with treatment. Significant correlations were found between change in HbA1c level and satisfaction with treatment, as well as between change in body weight and burden on social and daily activities, anxiety and dissatisfaction with treatment, and hypoglycemia. CONCLUSIONS: Liraglutide significantly improved glycemic control and reduced the body weight without deteriorating QOL in obese patients with type 2 diabetes. Trial registration UMIN-CTR: UMIN000007159. PMID- 28074110 TI - An exploratory study on the impact of daily activities on the pleasure and physical activity of older adults. AB - BACKGROUND: Pleasure is one determinant of intrinsic motivation and yet a dimension often forgotten when promoting physical activity among the older population. In this study we investigate the relation between daily activities and physical activity, experience of pleasure, and the interaction between pleasure and physical activity in the daily lives of community-dwelling older adults. METHODS: Participants carried a hip-worn accelerometer during 30 consecutive days resulting in a total of 320 days of data collection. Current activity, location, companion and experience of pleasure during each activity were assessed through experience sampling on a smartphone every 1-2 h. Between- and within-individual differences were analysed with multi-level models and 10xN = 1 regression analysis. RESULTS: Outdoor activities were associated with higher physical activity than indoor activities (p < 0.001). Performing leisure activities, outdoors and not alone significantly predicted pleasure in daily life (all p's < 0.05). Being more active while performing leisure activities resulted in higher experiences of pleasure (p < 0.001). However, when performing basic activities of daily living (e.g. commuting or households) this relation was inverted. Results provide meaningful indication for individual variance. The 30 days of data collected from each participant allow for identification of individual differences. CONCLUSIONS: Daily activities and their contexts do influence the experience of pleasure and physical activity of older adults in daily life of older adults, although similar research with larger population is recommended. Results are in accordance with the literature, indicating that the method adopted (accelerometry combined with experience sampling) provides reliable representation of daily life. Identification of individual differences can eventually be automatically performed through data mining techniques. Further research could look at innovative approaches to promote Active Ageing using mobile technology in the daily life, by promoting physical activity through recommendation of pleasurable activities, and thus likely to increase the intrinsic motivation to become physically active. PMID- 28074111 TI - Absence of in vivo mutagenicity of multi-walled carbon nanotubes in single intratracheal instillation study using F344 gpt delta rats. AB - INTRODUCTION: It is known that fibrous particles of micrometer length, such as carbon nanotubes, which have same dimensions as asbestos, are carcinogenic. Carcinogenicity of nanomaterials is strongly related to inflammatory reactions; however, the genotoxicity mechanism(s) is unclear. Indeed, inconsistent results on genotoxicity of multi-walled carbon nanotubes (MWCNTs) have been shown in several reports. Therefore, we analyzed the in vivo genotoxicity induced by an intratracheal instillation of straight MWCNTs in rats using a different test system-the Pig-a gene mutation assay-that can reflect the genotoxicity occurring in the bone marrow. Since lungs were directly exposed to MWCNTs upon intratracheal instillation, we also performed the gpt assay using the lungs. FINDINGS: We detected no significant differences in Pig-a mutant frequencies (MFs) between the MWCNT-treated and control rats. Additionally, we detected no significant differences in gpt MFs in the lung between the MWCNT-treated and control rats. CONCLUSIONS: Our findings indicated that a single intratracheal instillation of MWCNTs was non-mutagenic to both the bone marrow and lung of rats. PMID- 28074112 TI - Isolation and characterization of antimutagenic components of Glycyrrhiza aspera against N-methyl-N-nitrosourea. AB - BACKGROUND: A powdered ethanolic extract of Glycyrrhiza aspera root exhibits antimutagenic activity against N-methyl-N-nitrosourea (MNU) based on the Ames assay with Salmonella typhimurium TA1535. The aim of this study was to identify the antimutagenic components of the powdered ethanolic extract of G. aspera root. RESULTS: The powdered ethanolic extract of G. aspera root was sequentially suspended in n-hexane, carbon tetrachloride, dichloromethane, ethyl acetate, and ethanol, and each solvent soluble fraction and the residue were assayed for antimutagenic activity against MNU in S. typhimurium TA1535. The dichloromethane soluble fraction exhibited the highest antimutagenicity and was fractionated several times by silica gel chromatography. The fraction with the highest antimutagenic activity was further purified using HPLC, and the fractions were assayed for antimutagenicity against MNU in S. typhimurium TA1535. Finally, five components with antimutagenic activity against MNU were identified as glyurallin A, glyasperin B, licoricidin, 1-methoxyphaseollin, and licoisoflavone B. CONCLUSIONS: The five components were demonstrated to possess an antigenotoxic effect against carcinogenic MNU for the first time. It is important to prevent DNA damage by N-nitrosamines for cancer chemoprevention. PMID- 28074113 TI - Genetic polymorphisms of human cytochrome P450 CYP1A1 in an Egyptian population and tobacco-induced lung cancer. AB - BACKGROUND: Cytochrome P450 CYP1A1 helps detoxify the potential carcinogens in tobacco smoke, it was reported that polymorphisms in the coding gene result in variation in the expression and activity levels which alter metabolism and clearance of carcinogens and therefore modify cancer risk. In this work, we aimed to identify CYP1A1 gene polymorphisms associated with lung cancer in Egyptian population and to examine the interaction effect with Tobacco smoking in modulating disease risk. METHODS: A case-control study was conducted on 150 unrelated lung cancer patients and 150 unrelated control subjects. Genomic DNA was extracted and sequencing analysis of CYP1A1 gene was performed on ABI PRISM 3100 genetic analyzer. RESULTS: Three variants in CYP1A1 gene were identified in heterozygous forms in lung cancer patients I462V, T461N and I286T. A combined variant T461N/ I462V associated with lung cancer and those who carried this variant were 2-times more likely to develop lung cancer (OR = 2.03, 95% CI = 1.81 2.29, P = 0.04), specially the non-small cell type (NSCLC) (OR = 2.20, 95% CI = 1.93-2.50, P = 0.02). Wild type was more frequent among smoker controls (83.3%) compared to smoker lung cancer patients (54.8%), P = 0.03. Association studies to examine the interaction effect of identified variants with Tobacco smoking in modulating disease risk showed no significant associations. Identified polymorphisms showed no significant implication on the stage or the prognosis of the disease. CONCLUSION: Our findings support that CYP1A1 polymorphisms play a role in the pathogenesis of lung cancer. In Egyptian population, CYP1A1 I462V, T461N and I286T variants were identified among lung cancer patients and combined T461N/ I462V was a risk variant for NSCLC in non smokers. PMID- 28074114 TI - Low-omega3 Fatty Acid and Soy Protein Attenuate Alcohol-Induced Fatty Liver and Injury by Regulating the Opposing Lipid Oxidation and Lipogenic Signaling Pathways. AB - Chronic ethanol-induced downregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha) and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1beta) affect hepatic lipid oxidation and lipogenesis, respectively, leading to fatty liver injury. Low-omega3 fatty acid (Low-omega3FA) that primarily regulates PGC1alpha and soy protein (SP) that seems to have its major regulatory effect on PGC1beta were evaluated for their protective effects against ethanol-induced hepatosteatosis in rats fed with Lieber-deCarli control or ethanol liquid diets with high or low omega3FA fish oil and soy protein. Low-omega3FA and SP opposed the actions of chronic ethanol by reducing serum and liver lipids with concomitant decreased fatty liver. They also prevented the downregulation of hepatic Sirtuin 1 (SIRT1) and PGC1alpha and their target fatty acid oxidation pathway genes and attenuated the upregulation of hepatic PGC1beta and sterol regulatory element-binding protein 1c (SREBP1c) and their target lipogenic pathway genes via the phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK). Thus, these two novel modulators attenuate ethanol-induced hepatosteatosis and consequent liver injury potentially by regulating the two opposing lipid oxidation and lipogenic pathways. PMID- 28074116 TI - Effects of Epigallocatechin Gallate on Tert-Butyl Hydroperoxide-Induced Mitochondrial Dysfunction in Rat Liver Mitochondria and Hepatocytes. AB - Epigallocatechin gallate (EGCG) is a green tea antioxidant with adverse effects on rat liver mitochondria and hepatocytes at high doses. Here, we assessed whether low doses of EGCG would protect these systems from damage induced by tert butyl hydroperoxide (tBHP). Rat liver mitochondria or permeabilized rat hepatocytes were pretreated with EGCG and then exposed to tBHP. Oxygen consumption, mitochondrial membrane potential (MMP), and mitochondrial retention capacity for calcium were measured. First, 50 MUM EGCG or 0.25 mM tBHP alone increased State 4 Complex I-driven respiration, thus demonstrating uncoupling effects; tBHP also inhibited State 3 ADP-stimulated respiration. Then, the coexposure to 0.25 mM tBHP and 50 MUM EGCG induced a trend of further decline in the respiratory control ratio beyond that observed upon tBHP exposure alone. EGCG had no effect on MMP and no effect, in concentrations up to 50 MUM, on mitochondrial calcium retention capacity. tBHP led to a decline in both MMP and mitochondrial retention capacity for calcium; these effects were not changed by pretreatment with EGCG. In addition, EGCG dose-dependently enhanced hydrogen peroxide formation in a cell- and mitochondria-free medium. Conclusion. Moderate nontoxic doses of EGCG were not able to protect rat liver mitochondria and hepatocytes from tBHP-induced mitochondrial dysfunction. PMID- 28074115 TI - Gamma-Glutamylcysteine Ethyl Ester Protects against Cyclophosphamide-Induced Liver Injury and Hematologic Alterations via Upregulation of PPARgamma and Attenuation of Oxidative Stress, Inflammation, and Apoptosis. AB - Gamma-glutamylcysteine ethyl ester (GCEE) is a precursor of glutathione (GSH) with promising hepatoprotective effects. This investigation aimed to evaluate the hepatoprotective effects of GCEE against cyclophosphamide- (CP-) induced toxicity, pointing to the possible role of peroxisome proliferator activated receptor gamma (PPARgamma). Wistar rats were given GCEE two weeks prior to CP. Five days after CP administration, animals were sacrificed and samples were collected. Pretreatment with GCEE significantly alleviated CP-induced liver injury by reducing serum aminotransferases, increasing albumin, and preventing histopathological and hematological alterations. GCEE suppressed lipid peroxidation and nitric oxide production and restored GSH and enzymatic antioxidants in the liver, which were associated with downregulation of COX-2, iNOS, and NF-kappaB. In addition, CP administration significantly increased serum proinflammatory cytokines and the expression of liver caspase-3 and BAX, an effect that was reversed by GCEE. CP-induced rats showed significant downregulation of PPARgamma which was markedly upregulated by GCEE treatment. These data demonstrated that pretreatment with GCEE protected against CP-induced hepatotoxicity, possibly by activating PPARgamma, preventing GSH depletion, and attenuating oxidative stress, inflammation, and apoptosis. Our findings point to the role of PPARgamma and suggest that GCEE might be a promising agent for the prevention of CP-induced liver injury. PMID- 28074117 TI - The Essential Oils of Rhaponticum carthamoides Hairy Roots and Roots of Soil Grown Plants: Chemical Composition and Antimicrobial, Anti-Inflammatory, and Antioxidant Activities. AB - The essential oils were isolated by hydrodistillation from the hairy roots (HR) and roots of soil-grown plants (SGR) of Rhaponticum carthamoides and were analyzed by GC-MS method. In the both essential oils 62 compounds were identified. The root essential oils showed the differences in the qualitative and quantitative composition. The sesquiterpene hydrocarbons (55-62%) dominated in both essential oils. The major compounds of HR essential oil were cyperene, 13 norcypera-1(5),11(12)-diene, and cadalene while aplotaxene, nardosina-1(10),11 diene, and dauca-4(11),8-diene dominated in SGR essential oil. Both essential oils showed antibacterial activity especially against Enterococcus faecalis (ATCC 29212) and Pseudomonas aeruginosa (ATCC 27853) (MIC value = 125 ug/mL). HR and SGR essential oils also decreased the expression of IL-1beta, IL-6, and TNF-alpha and the ROS level in LPS-treatment astrocytes. This is the first report to describe the chemical composition of R. carthamoides essential oil from hairy roots, its protective effect against LPS-induced inflammation and ROS production in astrocytes, and its antimicrobial potential. The results show that R. carthamoides hairy roots may be a valuable source of the essential oil and may be an alternative to the roots of soil-grown plants. PMID- 28074119 TI - Complete genome sequence of the salmonella enterica serovar enteritidis bacteriophages fSE1C and fSE4C isolated from food matrices. AB - Salmonella enterica serovar Enteritidis is one of the most common causes of Salmonellosis worldwide. Utilization of bacteriophages as prophylactic agents is a practical solution to prevent Salmonellosis in ready-to-eat products. Shelf stability is one of the desirable properties for prophylactic bacteriophages. Here, we describe the phenotype, genome, and phylogeny of fSE1C and fSE4S Salmonella bacteriophages. fSE1C and fSE4S were previously isolated from pickle sauce and ground beef respectively and selected for their significant shelf stability. fSE1C and fSE4S showed a broad S. enterica serovar range, infecting several Salmonella serovars. The viral particles showed an icosahedral head structure and flexible tail, a typical morphology of the Siphoviridae family. fSE1C and fSE4C genomes consists of dsDNA of 41,720 bp and 41,768 bp with 49.73% and 49.78% G + C, respectively. Comparative genomic analysis reveals a mosaic relationship between S. enterica serovar Enteritidis phages isolated from Valparaiso, Chile. PMID- 28074120 TI - Complete genome sequence of the heavy metal resistant bacterium Agromyces aureus AR33T and comparison with related Actinobacteria. AB - Agromyces aureus AR33T is a Gram-positive, rod-shaped and motile bacterium belonging to the Microbacteriaceae family in the phylum Actinobacteria that was isolated from a former zinc/lead mining and processing site in Austria. In this study, the whole genome was sequenced and assembled combining sequences obtained from Illumina MiSeq and Sanger sequencing. The assembly resulted in the complete genome sequence which is 4,373,124 bp long and has a GC content of 70.1%. Furthermore, we performed a comparative genomic analysis with other related organisms: 6 Agromyces spp., 4 Microbacteriaceae spp. and 2 other members of the class Actinobacteria. PMID- 28074118 TI - Behavior of Oxidative Stress Markers in Alcoholic Liver Cirrhosis Patients. AB - Alcohol is the most socially accepted addictive substance worldwide, and its metabolism is related with oxidative stress generation. The aim of this work was to evaluate the role of oxidative stress in alcoholic liver cirrhosis (ALC). This study included 187 patients divided into two groups: ALC, classified according to Child-Pugh score, and a control group. We determined the levels of reduced and oxidized glutathione (GSH and GSSG) and the GSH/GSSG ratio by an enzymatic method in blood. Also, protein carbonyl and malondialdehyde (MDA) content were estimated in serum. MDA levels increased in proportion to the severity of damage, whereas the GSH and GSSG levels decreased and increased, respectively, at different stages of cirrhosis. There were no differences in the GSH/GSSG ratio and carbonylated protein content between groups. We also evaluated whether the active consumption of or abstinence from alcoholic beverages affected the behavior of these oxidative markers and only found differences in the MDA, GSH, and GSSG determination and the GSH/GSSG ratio. Our results suggest that alcoholic cirrhotic subjects have an increase in oxidative stress in the early stages of disease severity and that abstinence from alcohol consumption favors the major antioxidant endogen: GSH in patients with advanced disease severity. PMID- 28074121 TI - Complete genome sequence and whole-genome phylogeny of Kosmotoga pacifica type strain SLHLJ1T from an East Pacific hydrothermal sediment. AB - Kosmotoga pacifica strain SLHLJ1T is a thermophilic chemoorganoheterotrophic bacterium isolated from a deep-sea hydrothermal sediment. It belongs to the physiologically homogeneous Thermotogaceae family. Here, we describe the phenotypic features of K. pacifica together with its genome sequence and annotation. The chromosome has 2,169,170 bp, organized in one contig. A total of 1897 candidate protein-encoding genes and 177 RNA genes were identified. The 16S rRNA gene sequence of this strain is distantly related to sequences of some relatives classified in the same genus (K. olearia 7.02% and K. shengliensis 7.83%), with dissimilarity percentages close to the threshold generally described for genus delineation. Nevertheless, the percentage of conserved proteins (POCP), which is much higher than 50% (around 70%), together with phenotypic features of the isolates, confirm the affiliation all Kosmotoga species described so far to the same genus. PMID- 28074122 TI - High quality draft genome of Nakamurella lactea type strain, a rock actinobacterium, and emended description of Nakamurella lactea. AB - Nakamurella lactea DLS-10T, isolated from rock in Korea, is one of the four type strains of the genus Nakamurella. In this study, we describe the high quality draft genome of N. lactea DLS-10T and its annotation. A summary of phenotypic data collected from previously published studies was also included. The genome of strain DLS-10T presents a size of 5.82 Mpb, 5100 protein coding genes, and a C + G content of 68.9%. Based on the genome analysis, emended description of N. lactea in terms of G + C content was also proposed. PMID- 28074123 TI - Role of autophagy in bone and muscle biology. AB - Autophagy in eukaryotic cells is a constitutive process and functions as a homeostatic mechanism; it is upregulated in response to specific stress stimuli such as starvation, hypoxia and as oxidative stress. In addition to playing a crucial role in adaptive responses to different stimuli, autophagy is also required for intracellular quality control. This second aspect is important to prevent the activation of pathological processes. Autophagy also plays a central role in cellular development and differentiation because it is involved in the regulation of energetic balance. This final aspect is critical for maintaining proper bone and muscle function as well as to prevent any pathological changes. Therefore, identifying new molecular targets involved in autophagy is critical to assure a good quality of life. PMID- 28074125 TI - Shiga (Vero)-toxin producing Escherichia coli isolated from the hospital foods; virulence factors, o-serogroups and antimicrobial resistance properties. AB - BACKGROUND: According to the presence of the weak, diabetic and immunosuppressive patients in hospitals, hospital foods should have a high quality and safety. Cooking a lot of foods higher than daily requirement, storage of cooked foods in an inappropriate condition and presence of nurses and servants in distribution of food to patients are the main reasons caused contamination of hospital foods. Shiga toxigenic Escherichia coli is one of the common cause of food poisoning in hospitals. The present research was carried out to study the distribution of virulence factors, O-serogroups and antibiotic resistance properties in STEC strains recovered from Iranian hospital food samples. METHODS: Five-hundred and eighty raw and cooked food samples were collected and immediately transferred to the laboratory. E. coli-positive strains were subjected to PCR and disk diffusion method. RESULTS: Thirty-nine out of 580 (6.72%) hospital food samples were contaminated with E. coli. Raw (20%) and cooked meat (6%) were the most commonly contaminated samples. Raw samples had the higher prevalence of E. coli (P <0.01). Samples which were collected in the summer season had the highest prevalence of bacteria (64.10%). Significant difference was seen between the prevalence of EHEC and AEEC subtypes (P <0.01). The most commonly detected virulence factors in both EHEC and AEEC subtypes were stx1 and eae. The most commonly detected serogroups were O26 (43.75%) and O157 (25%) and there were no positive results for O103, O145, O91, O113 and O128 serogroups. Aac (3)-IV (100%), CITM (100%) and tetA (62.50%) were the most commonly detected antibiotic resistance genes. STEC strains harbored the highest levels of resistance against ampicillin (93.75%), gentamycin (93.75%), tetracycline (87.50%) and ciprofloxacin (81.25%). All of the STEC strains were resistant to at least 3 antibiotics, while the prevalence of resistance against more than 12 antibiotics were 12.50%. CONCLUSIONS: High presence of O157 serogroups, EHEC strains and animal-based antibiotics in cooked foods showed insufficiency of cooking time and temperature in the kitchens of hospitals. Judicious prescription of antibiotics and attentions to the principles of food safety can reduce the risk of resistant and virulent strains of STEC in hospital foods. PMID- 28074124 TI - Involvement of blood mononuclear cells in the infertility, age-associated diseases and cancer treatment. AB - Blood mononuclear cells consist of T cells and monocyte derived cells. Beside immunity, the blood mononuclear cells belong to the complex tissue control system (TCS), where they exhibit morphostatic function by stimulating proliferation of tissue stem cells followed by cellular differentiation, that is stopped after attaining the proper functional stage, which differs among various tissue types. Therefore, the term immune and morphostatic system (IMS) should be implied. The TCS-mediated morphostasis also consists of vascular pericytes controlled by autonomic innervation, which is regulating the quantity of distinct tissues in vivo. Lack of proper differentiation of tissue cells by TCS causes either tissue underdevelopment, e.g., muscular dystrophy, or degenerative functional failures, e.g., type 1 diabetes and age-associated diseases. With the gradual IMS regression after 35 years of age the gonadal infertility develops, followed by a growing incidence of age-associated diseases and cancers. Without restoring an altered TCS function in a degenerative disease, the implantation of tissue specific stem cells alone by regenerative medicine can not be successful. Transfused young blood could temporarily restore fertility to enable parenthood. The young blood could also temporarily alleviate aging diseases, and this can be extended by substances inducing IMS regeneration, like the honey bee propolis. The local and/or systemic use of honey bee propolis stopped hair and teeth loss, regressed varicose veins, improved altered hearing, and lowered high blood pressure and sugar levels. Complete regression of stage IV ovarian cancer with liver metastases after a simple elaborated immunotherapy is also reported. PMID- 28074127 TI - Transfer of beta-hydroxy-beta-methylbutyrate from sows to their offspring and its impact on muscle fiber type transformation and performance in pigs. AB - BACKGROUND: Previous studies suggested that supplementation of lactating sows with beta-hydroxy-beta-methylbutyrate (HMB) could improve the performance of weaning pigs, but there were little information in the muscle fiber type transformation of the offspring and the subsequent performance in pigs from weaning through finishing in response to maternal HMB consumption. The purpose of this study was to determine the effect of supplementing lactating sows with HMB on skeletal muscle fiber type transformation and growth of the offspring during d 28 and 180 after birth. A total of 20 sows according to their body weight were divided into the control (CON, n = 10) or HMB groups (HMB, n = 10). Sows in the HMB group were supplemented with beta-hydroxy-beta-methylbutyrate calcium (HMB Ca) 2 g /kg feed during d 1 to 27 of lactation. After weaning, 48 mixed sex piglets were blocked by sow treatment and fed standard diets for post-weaning, growing, finishing periods. Growth performance was recorded during d 28 to 180 after birth. Pigs were slaughtered on d 28 (n = 6/treatment) and 180 (n = 6/treatment) postnatal, and the longissimus dorsi (LD) was collected, respectively. RESULTS: The HMB-fed sows during lactation showed increased HMB concentration (P < 0.05) in milk and LD of weaning piglets (P < 0.05). In addition, offsprings in HMB group had a higher finishing BW and lean percentage than did pigs in CON group (P < 0.05), meanwhile, compared with pigs from sows fed the CON diet, pigs from sows fed HMB diet showed higher type II muscle fiber cross-sectional area (CSA), elevated myosin heavy chain (MyHC) IIb and Sox6 mRNA, and fast-MyHC protein levels in LD (P < 0.05). CONCLUSIONS: HMB supplemented to sow diets throughout lactation increases the levels of HMB in maternal milk and skeletal muscle of pigs during d 28 after birth and promotes subsequent performance of pigs between d 28 and 180 of age by enhancing glycolytic muscle fiber transformation. PMID- 28074126 TI - The emergence of carbapenem resistant Klebsiella pneumoniae in Malaysia: correlation between microbiological trends with host characteristics and clinical factors. AB - BACKGROUND: Carbapenem resistant Enterobacteriaceae is a growing concern worldwide including Malaysia. The emergence of this pathogen is worrying because carbapenem is one of the 'last-line' antibiotics. The main objective of this study was to determine the prevalence of genetic mechanisms and clinical risk factors of carbapenem resistant Klebsiella pneumoniae (K. pneumoniae) in Malaysia. METHODS: In this study, seventeen carbapenem resistant K. pneumoniae strains isolated from a tertiary teaching hospital in 2013 were studied. Minimal inhibitory concentration (MIC) of the bacterial strains was determined and genes associated with carbapenemases and extended-spectrum-beta-lactamases (ESBLs) were sequenced and compared with the closest representatives published in public domains. All strains were also sub-typed using pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Statistical analyses were performed to determine the correlation between risk factors for acquiring carbapenem resistant K. pneumoniae and in-hospital mortality. RESULTS: The predominant carbapenemase was blaOXA-48, detected in 12 strains (70.59%). Other carbapenemases detected in this study were blaKPC-2, blaIMP-8, blaNMC-A and blaNDM-1. Nine different pulsotypes were identified and nine strains which were affiliated with ST101, the predominant sequence type had similar PFGE patterns (similarity index of 85%). Based on univariate statistical analysis, resistance to imipenem and usage of mechanical ventilation showed a statistically significant effect separately to in-hospital mortality. CONCLUSION: The diverse genetic mechanisms harbored by these carbapenem resistant K. pneumoniae facilitates its spread and complicates its detection. Thus, correlation between microbiological trends with host characteristics and clinical factors will provide a better insight of rational treatment strategies and pathogen control. PMID- 28074129 TI - Improving oxygen prescribing rates by tailoring interventions for specific healthcare professional groups. AB - Oxygen prescription remains a nationwide problem. The dangers associated with unregulated oxygen administration are well described in the literature with the potential for serious harm in patients with chronic hypercapnia, as well as potentially delaying discharge in patients who are administered it without a prescription. This project identifies poor compliance with regional and national standards and sets out to improve the frequency of oxygen prescribing on a cardiology ward. By studying the problem at a Somerset district general hospital we identified two main groups of professionals responsible for the poor compliance, nursing staff (who administer the oxygen) and junior doctors (who should prescribe it). A series of interventions was designed to firstly raise awareness of the problem within these two groups before going on to target each group with a further intervention over 24 weeks. At baseline we found only 11.3% of patients receiving oxygen had it prescribed. At the end of the project this had improved to 69.6%. We also found that following raised awareness in the nursing staff and introduction of a bedside warning the number of patients receiving oxygen on the ward fell by 35%. In conclusion, this project outlines a strategy for improving oxygen prescribing rates on a medical ward. By targeting different populations we had hoped to see a cumulative improvement after each improvement cycle, however, some resistance from junior doctors in engaging with our third intervention was reflected with a slight decrease in prescribing rates. Further work should address this issue and look to apply this strategy across a wider clinical area with a greater sample size to see if the results are replicable on a larger scale. PMID- 28074128 TI - Epidemic outbreak of Chikungunya in two neighboring towns in the Colombian Caribbean: a survival analysis. AB - BACKGROUND: The first autochthonous Chikungunya virus transmission in Colombia was reported in September 2014. Three months later, every town in the Caribbean region was affected, including the bordering towns of Ovejas and Corozal, in the department of Sucre. The objective of the study was to analyze and compare the temporal dynamics of the outbreak of Chikungunya in two towns of the department of Sucre. METHODS: Households with suspicious cases with clinical symptomatology for Chikungunya were enrolled. In each house an epidemiological questionnaire was applied to collect economic and social information and methods for vector control. RESULTS: The study analyzed data collected between 09/01/2014 and 01/31/2015; 458 families in Corozal and 516 families in Ovejas were identified with Chikungunya cases. Estimated attack rates were 10,621 cases and 1640 cases per 100,000 inhabitants, in Ovejas and Corozal, respectively. The 75-day survival curve was 27.2% lower (0.632, CI = 0.614-0.651) in Ovejas than in Corozal (0.904, CI = 0.891-0.917). After 120 days, both curves showed a stable horizontal slope, close to a survival probability of 0.54, indicating the end of the epidemic period. The log-rank test (X2 = 94.6, 1fd, p-value = 0.000) showed the improved survival of Chikungunya in the town of Corozal. The relative risk between the two towns was 0.863 (CI = 0.809-0.921; p-value < 0.001). CONCLUSIONS: The dynamics of the temporal distribution of CHIKV could be influenced by socioeconomic and preventable risk factors. Poor socioeconomic conditions such as the lack and poor efficiency of water supply and waste collection services could be determining factors in the proliferation of CHIKV. The survival analysis proved to be a suitable method for studying the presentation of CHIKV and can be applied to other prevalent vector-borne diseases such as the ZIKA and Dengue. PMID- 28074130 TI - Inbox Messaging: an effective tool for minimizing non-urgent paging related interruptions in hospital medicine provider workflow. AB - Communication is one of the foundations on which safe, high quality care is built.1, 3, 6, 17, 20 The nature of hospital medicine requires that nurses and providers be efficient and effective in communicating with multiple disciplines.17 This need for timely communication must continually be balanced with the need to minimize interruptions in workflow.1,2 3,4,6,7,9,13,15,17,18 Interruptions not only lead to distraction, they also add inefficiency to the care process and have been shown to contribute to an increased risk of medical error.2,3,4,7,17,18 A major source of interruptions are pagers that emit an audible tone with each message received.3,9,10,17,18 This interruptive nature makes pagers a less-than-ideal tool for communicating non-urgent (address within one hour) messages received.3,9,10,17,18 In addition to increasing interruptions, pagers do not facilitate closed loop communication, another feature that has been shown to improve safety.14,17,25 Inbox Messaging is intended to provide a less disruptive closed-loop method of communication for non-urgent messages. Inbox Messaging is an interface within the electronic health record (EHR) that functions similarly to e-mail. A multi-disciplinary communication workgroup identified this interface as having potential to not only decrease interruptions, but to also facilitate closed-loop communication. Inbox is currently utilized between the hours of 0700 and 1800 for non-urgent nurse-provider communication about patients on the hospital medicine service. The number of RN non-urgent pages per day was 103 (SD=19, n=97) prior to the Inbox intervention, with a significant decrease (p<.001) during follow-up to 38 (SD=14, n=354) pages per day. At the same time, the number of messages per day increased from 0 to 80 (SD=20, n=354) messages during follow-up. As desired, the mean number of RN urgent pages was unchanged from 13 per day to 13 per day (p=.52). Cerner Inbox Messaging decreases the frequency of non-urgent pager-related interruptions in workflow. PMID- 28074131 TI - Reducing the incidence of Obstetric Sphincter Injuries using a hands-on technique: an interventional quality improvement project. AB - A main concern for women giving birth is the risk of obstetric anal sphincter injuries. In our department the incidence of sphincter injuries was around 8 % among vaginally delivering first time mothers. We aimed to halve the incidence to 4 % or less. A prospective interventional program was instituted. We implemented a hands-on technique with four elements in a bundle of care together with a certification process for all staff on the delivery ward. The incidence of episiotomies served as a balancing indicator. The adherence to three of the four elements of the care bundle rose significantly while the all-or-nothing indicator leveled around 80 %. The median number of deliveries between cases with a sphincter injury increased from 9.5 in the baseline period to 20 during the intervention period. This corresponded with a reduction in the incidence from 7.0 % to 3.4 %. The rate of episiotomy remained low at 8.4 % in this group. By implementing the hands-on technique, we halved the risk of obstetric anal sphincter injuries. Our data suggest that further improvement may be anticipated. The study has demonstrated how implementation of a hands-on technique can be carried out within a quality improvement framework with rapid and sustainable results. PMID- 28074132 TI - Improving door-to-needle times for patients presenting with ST-elevation myocardial infarction at a rural district general hospital. AB - Acute coronary syndrome is a common condition with a major global impact on healthcare resources and expenditure. International guidelines are clear in specifying that patients with acute ST-elevation myocardial infarction (STEMI) should receive urgent coronary reperfusion with either primary percutaneous coronary intervention (PCI) or thrombolysis. Although PCI is the gold standard in the treatment of STEMI, this is not always achievable in a rural hospital with no cardiac catheterization service. Consequently, local recommendations on STEMI management exist to promote timely administration of thrombolysis within 30 minutes of patient arrival. However, translating updated clinical policy into practice is a challenging and complex task that requires a multi-faceted approach with sustained engagement from local stakeholders. Whilst working at a district general hospital in New Zealand, we noted a high incidence of patients presenting with STEMI receiving thrombolytic therapy outside the recommended 30 minutes door to-needle time. Although final treatment was often only delayed by 5-10 minutes, we were concerned by the seemingly inconsistent management of these patients, often leading to unnecessary delays in the initiation of rapid reperfusion therapy. We therefore championed a newly updated clinical guideline and promoted an early STEMI recognition and treatment algorithm in our hospital to raise awareness amongst staff and improve door-to-needle times. We introduced a number of simple low-cost interventions that included educational sessions for junior doctors and cardiac nursing staff, as well as posters and training on the use of a remote electronic ECG interpretation system to streamline out-of-hours management. Overall, we found there to a be a steady improvement in door-to needle times at our hospital, with 74% of patients receiving appropriate care within 30 minutes, compared to 43% prior to our interventions. This also translated to better patient outcomes. This project forms part of an ongoing process to instigate quality improvements in the management of STEMI within rural institutions. Whilst we have demonstrated improved utilisation of a local STEMI guideline and streamlining of out-of-hours services, the key challenge remains to ensure that momentum of this project continues and forms a platform for sustainable clinical improvement in the long term. PMID- 28074133 TI - A QI initiative: implementing a patient handoff checklist for pediatric hospitalist attendings. AB - Handoffs represent a critical transition point in patient care that play a key role in patient safety. Our quality improvement project was a descriptive observational study aimed at standardizing pediatric hospitalist handoffs via implementation of a handoff checklist, with the goal of improving handoff quality and physician satisfaction within six months. The handoff checklist was quickly adapted by hospitalists, with median compliance rate of 83% during the study. Handoff quality was assessed by trained observers using the validated Handoff Clinical Evaluation Exercise (CEX) tool at multiple time periods pre- and post implementation (at 2, 6, 12, and 24 months). Handoff quality improved during our study, with a significant decrease in the percentage of "unsatisfactory" handoffs from 9% to 0% (p-value 0.004), an effect which was sustained after initial project completion. The cumulative time required for verbal handoffs for different attending physicians paralleled patient census. However, our project identified wasted down time between individual physician handoffs, and an intervention to change shift times led to a decrease in the average total handoff process time from 86 minutes to 60 minutes, p-value <0.001. An average of 7.4 patient care items was identified during handoffs. A physician perception survey revealed improved situational awareness, efficiency, patient safety, and physician satisfaction as a result of our handoff improvement project. In conclusion, implementation of a checklist and standardized handoff process for pediatric hospitalists improved handoff efficiency and quality, as well as physician satisfaction. PMID- 28074134 TI - Managing complex respiratory patients in the community: an evaluation of a pilot integrated respiratory care service. AB - INTRODUCTION: In the UK, there is significant variation in respiratory care and outcomes. An integrated approach to the management of high-risk respiratory patients, incorporating specialist and primary care teams' expertise, is the basis for new integrated respiratory services designed to reduce this variation; however, this model needs evaluating. METHODS: To evaluate an integrated service managing high-risk respiratory patients, electronic searches for patients with asthma and chronic obstructive pulmonary disease at risk of poor outcomes were performed in two general practitioner (GP) practices in a local service development initiative. Patients were reviewed at joint clinics by primary and secondary care professionals. GPs also nominated patients for inclusion. Reviews were delivered to best standards of care including assessments of diagnosis, control, spirometry, self-management, education, medication, inhaler technique and smoking cessation support. Follow-up of routine clinical data collected at 9 months postclinic were compared with seasonally matched 9-months prior to integrated review. RESULTS: 82 patients were identified, 55 attended. 13 (23.6%) had their primary diagnosis changed. In comparison with the seasonally adjusted baseline period, in the 9-month follow-up there was an increase in inhaled corticosteroid prescriptions of 23.3%, a reduction in short-acting beta2-agonist prescription of 33.3%, a reduction in acute respiratory exacerbations of 67.6%, in unscheduled GP surgery visits of 53.3% and acute respiratory hospital admissions reduced from 3 to 0. Only 4 patients (7.3%) required referral to secondary care. Health economic evaluation showed respiratory-related costs per patient reduced by L231.86. CONCLUSIONS: Patients with respiratory disease in this region at risk of suboptimal outcomes identified proactively and managed by an integrated team improved outcomes without the need for hospital referral. PMID- 28074135 TI - Effect of aclidinium bromide on cough and sputum symptoms in moderate-to-severe COPD in three phase III trials. AB - BACKGROUND: Cough and sputum are troublesome symptoms in chronic obstructive pulmonary disease (COPD) and are associated with adverse outcomes. The efficacy of aclidinium bromide 400 ug twice daily in patients with stable COPD has been established in two phase III studies (ACCORD COPD I and ATTAIN) and a phase IIIb active-comparator study. This analysis evaluated cough-related symptoms across these studies. METHOD: Patients were randomised to placebo, aclidinium 200 ug or 400 ug twice daily in ACCORD (12 weeks) and ATTAIN (24 weeks), or to placebo, aclidinium 400 ug twice daily or tiotropium 18 ug once daily (6-week active comparator study). Analysed end points included changes from baseline in Evaluating Respiratory Symptoms (E-RS; formerly known as EXAcerbations of Chronic pulmonary disease Tool), total and cough/sputum scores and frequency/severity of morning and night-time cough and sputum symptoms. RESULTS: Data for 1792 patients were evaluated. E-RS cough/sputum domain scores were significantly reduced with aclidinium 400 ug versus placebo in ATTAIN (-0.7 vs -0.3, respectively; p<0.01) and the active-comparator study (-0.6 vs -0.2, respectively; p<0.01). In the active-comparator study, significantly greater improvements were observed with aclidinium versus placebo for severity of morning cough (-0.19 vs -0.02; p<0.01) and phlegm (-0.19 vs -0.02; p<0.05). In ACCORD, aclidinium reduced night-time cough frequency (-0.36 vs 0.1 for placebo; p<0.001) and severity (-0.24 vs -0.1 for placebo; p<0.05), and frequency of night-time sputum production (-0.37 vs 0.05 for placebo; p<0.001). CONCLUSIONS: Aclidinium 400 ug twice daily improves cough and sputum expectoration versus placebo in stable COPD. TRIAL REGISTRATION NUMBERS: NCT00891462; NCT01001494; NCT01462929. PMID- 28074136 TI - Clinical manifestations and outcomes of pulmonary aspergillosis: experience from Pakistan. AB - INTRODUCTION: Pulmonary aspergillosis has variable course of illness, severity and outcomes depending on underlying conditions. There is limited data available on the clinical manifestations and outcome of pulmonary aspergillosis from Pakistan. METHODS: To determine the clinical manifestations and outcome of pulmonary aspergillosis in a tertiary care hospital a retrospective study was conducted from 2004 to 2014 in patients admitted with pulmonary aspergillosis at the Aga Khan University Hospital Karachi, Pakistan. RESULTS: Of the 280 cases with provisional diagnosis of aspergillosis 69 met the inclusion criteria. The mean age was 45+/-15.7 years, 48 (69.6%) were men and 21 (30.4%) had diabetes mellitus (DM). The average length of hospital stay (LOS) was 10.61+/-9.08 days. Aspergillus fumigatus was the most common (42.0%), followed by Aspergillus flavus (28.9%). More than one-third of patients previously had tuberculosis (TB) (39.13%). The commonest pulmonary manifestation was chronic pulmonary aspergillosis (CPA) 47 (68.1%) followed by invasive pulmonary aspergillosis (IPA) 12 (17.4%) and subacute invasive aspergillosis (SAIA) 8 (11.6%). Surgical excision was performed in 28 patients (40.57%). Intensive care unit admission was required for 18 patients (26.08%). Case fatality rate was 14/69 (20.3%). DM, mean LOS and hypoxic respiratory failure were identified as independent risk factors of mortality on multivariate analysis. CONCLUSION: A. fumigatus was the most frequent species found especially in patients with prior TB. CPA was the commonest pulmonary manifestation seen as post TB sequel. Diabetes, hypoxic respiratory failure and increased LOS were independent predictors of poor outcomes. Overall patients had good outcome with CPA compared with SAIA and IPA. PMID- 28074137 TI - Pen needle design influences ease of insertion, pain, and skin trauma in subjects with type 2 diabetes. AB - OBJECTIVE: Pen needles used for subcutaneous injections have gradually become shorter, thinner and more thin walled, and thereby less robust to patient reuse. Thus, different needle sizes, alternative tip designs and needles resembling reuse were tested to explore how needle design influences ease of insertion, pain and skin trauma. RESEARCH DESIGN AND METHODS: 30 subjects with injection-treated type 2 diabetes and body mass index 25-35 kg/m2 were included in the single blinded study. Each subject received abdominal insertions with 18 different types of needles. All needles were tested twice per subject and in random order. Penetration force (PF) through the skin, pain perception on 100 mm visual analog scale, and change in skin blood perfusion (SBP) were quantified after the insertions. RESULTS: Needle diameter was positively related to PF and SBP (p<0.05) and with a positive pain trend relation. Lack of needle lubrication and small 'needle hooks' increased PF and SBP (p<0.05) but did not affect pain. Short tip, obtuse needle grinds affected PF and SBP, but pain was only significantly affected in extreme cases. PF in skin and in polyurethane rubber were linearly related, and pain outcome was dependent of SBP increase. CONCLUSIONS: The shape and design of a needle and the needle tip affect ease of insertion, pain and skin trauma. Relations are seen across different data acquisition methods and across species, enabling needle performance testing outside of clinical trials. TRIAL REGISTRATION NUMBER: NCT02531776; results. PMID- 28074138 TI - Undiagnosed diabetes and impaired fasting glucose in HFE C282Y homozygotes and HFE wild-type controls in the HEIRS Study. AB - OBJECTIVE: To determine prevalences and predictors of undiagnosed diabetes mellitus (UDM) and impaired fasting glucose (IFG) in non-Hispanic whites with HFE p.C282Y homozygosity and controls without common HFE mutations identified in population screening. RESEARCH DESIGN AND METHODS: We analyzed these observations in a postscreening examination: age; sex; body mass index; systolic/diastolic blood pressure; metacarpophalangeal joint hypertrophy; hepatomegaly; blood neutrophils; alanine and aspartate aminotransferase; elevated C reactive protein; transferrin saturation; serum ferritin; and Field Center. RESULTS: There were 223 p.C282Y homozygotes and 449 controls without diagnosed diabetes (43.9% men). Mean age of p.C282Y homozygotes was 52+/-13 years (controls 57+/-14 years; p<0.0001). Mean transferrin saturation in p.C282Y homozygotes was 67+/-26% (controls 34+/ 14%; p<0.0001). Mean serum ferritin in p.C282Y homozygotes was 607 pmol/L (95% CI 497 to 517; controls 274 pmol/L (247 to 301); p<0.0001). Overall prevalences of UDM (4.0% vs 4.2%) and IFG (23.8% vs 25.6%) did not differ significantly between p.C282Y homozygotes and wt/wt controls, respectively. In logistic regressions, male sex, body mass index, and alanine aminotransferase were significantly associated with UDM. ORs were 2.7 (1.2 to 2.8); 1.0 (1.0 to 1.1); and 1.0 (1.0 to 1.0), respectively. Age, male sex, and body mass index were significantly associated with IFG. ORs were 1.0 (1.0 to 1.1); 2.8 (1.9 to 4.2); and 1.0 (1.0 to 1.1), respectively. CONCLUSIONS: Prevalences of UDM and IFG were similar in p.C282Y homozygotes and controls in a postpopulation screening examination. Male sex was the strongest predictor of UDM and IFG. PMID- 28074139 TI - Egg ingestion in adults with type 2 diabetes: effects on glycemic control, anthropometry, and diet quality-a randomized, controlled, crossover trial. AB - BACKGROUND: The inclusion of eggs as part of a healthful diet for adults with diabetes is controversial. We examined the effects of including eggs in the diet of adults with type 2 diabetes on cardiometabolic risk factors. METHODS: Randomized, controlled, single-blind, crossover trial of 34 adults (mean age 64.5 years; 14 postmenopausal women, 20 men) with type 2 diabetes assigned to one of two possible sequence permutations of two different 12-week treatments (two eggs/day inclusion or egg exclusion), with 6-week washout periods. For the egg inclusion phase, participants received advice from a dietitian on how to preserve an isocaloric condition relative to the egg exclusion phase. The primary outcome was glycemic control as measured by glycated hemoglobin. Secondary measures included anthropometry, blood pressure, and diet quality. RESULTS: Compared with the exclusion of eggs in the habitual diet, the inclusion of eggs did not measurably affect glycated hemoglobin (0.01+/-0.5% vs -0.24+/-0.7%; p=0.115) and systolic blood pressure (-0.8+/-13.0 vs -3.0+/-10.0 mm Hg; p=0.438); and significantly reduced body mass index (0.06+/-0.8 vs -0.4+/-0.8 kg/m2; p=0.013) and visceral fat rating (0.2+/-1.1 vs -0.4+/-1.0; p=0.016). The inclusion of eggs in the habitual diet of diabetics significantly reduced waist circumference ( 0.4+/-1.2 cm; p=0.004) and percent body fat (-0.7+/-1.8; p=0.033) from baseline. CONCLUSIONS: Short-term daily inclusion of eggs in the habitual diet of adults with type 2 diabetes does not improve glycemic control but can improve anthropometric measures. TRIAL REGISTRATION NUMBER: NCT02052037; results. PMID- 28074140 TI - Disparities in recommended preventive care usage among persons living with diabetes in the Appalachian region. AB - OBJECTIVE: To examine disparities in the receipt of preventive care recommended by the American Diabetes Association (ADA) between Appalachian and non Appalachian counties and within Appalachian counties. RESEARCH DESIGN AND METHODS: Behavioral Risk Factor Surveillance System (BRFSS) data for 2008-2010 were used to identify individuals with diabetes and their preventive care usage. Each Appalachian respondent county of residence was categorised into one of the five economic levels: distressed, at-risk, transitional, competitive and attainment counties. Competitive and attainment counties were combined and designated as competitive counties. We used logistic regressions to compare receipt of ADA preventive care recommendations by county economic level, adjusting for respondent demographic, socioeconomic, health and access-to-care factors. RESULTS: Compared to the most affluent (competitive) counties, less affluent (distressed and at-risk) counties demonstrated equivalent or higher rates of self-care practices such as daily blood glucose monitoring and daily foot checks. But they showed 40-50% lower uptake of annual foot and eye examinations and 30% lower uptake of diabetes education and pneumococcal vaccinations compared to competitive counties. After adjusting for demographic factors, significant disparities still existed in the uptake of annual foot examinations, annual eye examinations, 2 or more A1c tests per year and pneumococcal vaccinations in distressed and at-risk counties compared to competitive counties. Appalachian counties as a whole were similar to non Appalachian counties in the uptake of all recommendations with the absolute differences of <=3%. CONCLUSIONS: Our results show that there are significant disparities in the uptake of many recommended preventive services between less and more affluent counties in the Appalachian region. PMID- 28074141 TI - Evaluation of exposure to pioglitazone and risk of prostate cancer: a nested case control study. AB - OBJECTIVES: Investigate potential association between pioglitazone exposure and risk of prostate cancer. RESEARCH DESIGN AND METHODS: Nested, matched case control study. UK primary care data (Clinical Practice Research Datalink (CPRD) GOLD) linked to inpatient (Hospital Episode Statistics (HES)) and cancer registry (National Cancer Information Network (NCIN)) data. English men aged >=40 years diagnosed with type 2 diabetes mellitus, January 1, 2001 to January 5, 2015. Cases, with prostate cancer diagnosis, matched with up to 4 controls by age, cohort entry date and region. ORs for association of exposure to pioglitazone to incident prostate cancer, adjusted for potential confounders. RESULTS: From a cohort of 47 772 men with 243 923 person-years follow-up, 756 definite cases of prostate cancer were identified. Incidence was 309.9/100 000 person-years (95% CI 288.6 to 332.8). Pioglitazone use was not associated with prostate cancer risk; adjusted OR 0.759, 95% CI 0.502 to 1.148. Analyses showed no difference when possible cases, prostate cancer in CPRD GOLD only, included (adjusted OR 0.726, 95% CI 0.510 to 1.034). No association when adjusted for channeling bias (OR 0.778, 95% CI 0.511 to 1.184) or limited to an index date prior to July 1, 2011 (adjusted OR 0.508, 95% CI 0.294 to 0.879), despite prostate-specific antigen screening occurring more frequently among cases than controls (81.6% of 756 definite cases cf. 24.2% of 2942 controls (p<0.01)). No association with duration of pioglitazone use, increasing pioglitazone dose or increasing time since initiation. CONCLUSIONS: In this real-world, nested matched case-control study, exposure to pioglitazone was not associated with increased risk of prostate cancer. PMID- 28074142 TI - Relationship between diabetic nephropathy and depression: a cross-sectional analysis using the Diabetes Study from the Center of Tokyo Women's Medical University (DIACET). AB - OBJECTIVE: We conducted this cross-sectional study to investigate the relationship between stage of diabetic nephropathy and likelihood or severity of depression in patients with diabetes. RESEARCH DESIGN AND METHODS: We studied 2212 patients with diabetes (mean age 60.9 years; 928 women; 1838 patients with type 2 diabetes). Presence and severity of depression was examined using the Patient Health Questionnaire-9 (PHQ-9). Patients were classified into 5 stages of nephropathy, according to albuminuria and estimated glomerular filtration rate (eGFR); patients in stage 5 undergoing dialysis and kidney transplantation were analyzed separately (stages 5D and 5T). The relationship between stage of nephropathy and depression was examined using analysis of covariance and multivariate logistic regression analysis. RESULTS: Both least square mean PHQ-9 scores and prevalence of patients with PHQ-9 scores >=5 points (mild depression) and >=10 points (moderate or severe depression) increased from stage 1 to 5D, and then declined in stage 5T. Multivariate ORs for mild or greater depression increased in patients in stages 3, 4, and 5D in reference to those in stage 1, which declined in patients in stage 5T. Albuminuria was significantly, but eGFR was not, associated with higher PHQ-9 scores and the PHQ-9 scores >=5 or >=10 after adjustment for clinical findings. CONCLUSIONS: In patients with diabetes, progression of nephropathy is likely to be associated with increased risk and severity of depression, which may be reduced after successful kidney transplantation. Albuminuria may be more strongly associated with depression than eGFR. PMID- 28074144 TI - Cattle are a potential reservoir of bubaline herpesvirus 1 (BuHV1). AB - In the present work, controlled experimental infection and transmission studies in domestic cattle (Bos taurus) and water buffaloes (Bubalus bubalis) were carried out to study the in vivo behaviour of bubaline herpesvirus 1 (BuHV1). Two bovine and two buffalo calves were infected with BuHV1 (20287N isolate) by intranasal aerosolisation. Two sentinel cattle did not receive the virus challenge, but were housed with infected buffaloes to evaluate horizontal transmission. All experimentally inoculated animals showed viral infection and respiratory clinical signs. BuHV1 experimentally infected calves showed intermittent viral excretion between 2 days and 18 days postinfection (dpi) with a maximum titre of excretion of 106 TCID50/ml and moderate rhinitis between 2 dpi and 20 dpi. BuHV1 experimentally inoculated buffaloes showed mild respiratory signs, which consisted mainly of serous nasal secretions during the infection period. Sentinel calves showed mucosal specific IgG1 antibodies at seven days postcontact. Viral DNA was detected by PCR and sequencing in both buffaloes and sentinel calves, which could be associated with latency. In conclusion, this study showed the susceptibility of cattle to BuHV1 after both experimental infection and contact with infected buffaloes. These data increase the scarce knowledge on the pathogenesis in natural host and the susceptibility of cattle to BuHV1 experimental infection. PMID- 28074143 TI - Gestational diabetes mellitus treatment reduces obesity-induced adverse pregnancy and neonatal outcomes: the St. Carlos gestational study. AB - BACKGROUND: Obesity and gestational diabetes mellitus (GDM) increase the morbidity of the mother and newborn, which could increase further should they coexist. We aimed to determine the risk of adverse pregnancy and neonatal outcomes associated with excess weight (EW), and within this group identify potential differences between those with and without GDM. METHODS: We carried out a post-hoc analysis of the St. Carlos Gestational Study which included 3312 pregnant women, arranged in 3 groups: normal-weight women (NWw) (2398/72.4%), overweight women (OWw) (649/19.6%) and obese women (OBw) (265/8%). OWw and OBw were grouped as EW women (EWw). We analyzed variables related to adverse pregnancy and neonatal outcomes. RESULTS: The relative risk (95% CI) for GDM was 1.82 (1.47 to 2.25; p<0.0001) for OWw, and 3.26 (2.45 to 4.35; p<0.0001) in OBw. Univariate analysis showed associations of EW to higher rates of prematurity, birth weight >90th centile, newborns admitted to neonatal intensive care unit (NICU), instrumental delivery and cesarean delivery (all p<0.005). Multivariate analysis, adjusted for parity and ethnicity, showed that EW increased the risk of prematurity, admission to NICU, cesarean and instrumental delivery, especially in EWw without GDM. NWw with GDM had a significantly lower risk of admission to NICU and cesarean delivery, compared with NWw without GDM. CONCLUSIONS: EW is detrimental for pregnancy and neonatal outcomes, and treatment of GDM contributes to lowering the risk in EWw and NWw. Applying the same lifestyle changes to all pregnant women, independent of their weight or GDM condition, could improve these outcomes. PMID- 28074145 TI - Genome-wide profiling identifies associations between lupus nephritis and differential methylation of genes regulating tissue hypoxia and type 1 interferon responses. AB - OBJECTIVE: Previous studies have shown that differential DNA methylation is associated with SLE susceptibility. How DNA methylation affects the clinical heterogeneity of SLE has not been fully defined. We conducted this study to identify differentially methylated CpG sites associated with nephritis among women with SLE. METHODS: The methylation status of 428 229 CpG sites across the genome was characterised for peripheral blood cells from 322 women of European descent with SLE, 80 of whom had lupus nephritis, using the Illumina HumanMethylation450 BeadChip. Multivariable linear regression adjusting for population substructure and leucocyte cell proportions was used to identify differentially methylated sites associated with lupus nephritis. The influence of genetic variation on methylation status was investigated using data from a genome wide association study of SLE. Pathway analyses were used to identify biological processes associated with lupus nephritis. RESULTS: We identified differential methylation of 19 sites in 18 genomic regions that was associated with nephritis among patients with SLE (false discovery rate q<0.05). Associations for four sites in HIF3A, IFI44 and PRR4 were replicated when examining methylation data derived from CD4+ T cells collected from an independent set of patients with SLE. These associations were not driven by genetic variation within or around the genomic regions. In addition, genes associated with lupus nephritis in a prior genome-wide association study were not differentially methylated in this epigenome-wide study. Pathway analysis indicated that biological processes involving type 1 interferon responses and the development of the immune system were associated with nephritis in patients with SLE. CONCLUSIONS: Differential methylation of genes regulating the response to tissue hypoxia and interferon mediated signalling is associated with lupus nephritis among women with SLE. These findings have not been identified in genetic studies of lupus nephritis, suggesting that epigenome-wide association studies can help identify the genomic differences that underlie the clinical heterogeneity of SLE. PMID- 28074146 TI - Assessing QT interval in patients with autoimmune chronic inflammatory diseases: perils and pitfalls. PMID- 28074147 TI - Cerebellar ataxia and sensory ganglionopathy associated with light-chain myeloma. AB - BACKGROUND: Cerebellar ataxia with sensory ganglionopathy is a rare neurological combination that can occur in some hereditary ataxias including mitochondrial diseases and in gluten sensitivity. Individually each condition can be a classic paraneoplastic neurological syndrome. We report a patient with this combination who was diagnosed with light-chain myeloma ten years after initial presentation. CASE PRESENTATION: A 65-year-old Caucasian lady was referred to our Ataxia Clinic because of a 6-year history of progressive unsteadiness and a 2-year history of slurred speech. Past medical history included arterial hypertension. The patient was a non-smoker was not consuming alcohol excessively. There was no family history of ataxia. Neurological examination revealed prominent gaze-evoked nystagmus, heel to shin ataxia, gait ataxia, reduced reflexes and loss of vibration sensation in the legs. Cerebellar ataxia was confirmed using magnetic resonance spectroscopy of the cerebellum and sensory ganglionopathy using neurophysiological assessments including blink reflex study. A muscle biopsy that was arranged to explore the possibility of mitochondrial disease revealed amyloidosis. Urinalysis confirmed the presence of light chains. A bone marrow biopsy confirmed the diagnosis of light chain multiple myeloma. CONCLUSIONS: Whilst it could be argued that this could simply be a coincidence, the rarity of these conditions and the absence of an alternative aetiology for the neurological dysfunction argue in favour of a paraneoplastic phenomenon. PMID- 28074148 TI - Apraxia of speech and cerebellar mutism syndrome: a case report. AB - BACKGROUND: Cerebellar mutism syndrome (CMS) or posterior fossa syndrome (PFS) consists of a constellation of neuropsychiatric, neuropsychological and neurogenic speech and language deficits. It is most commonly observed in children after posterior fossa tumor surgery. The most prominent feature of CMS is mutism, which generally starts after a few days after the operation, has a limited duration and is typically followed by motor speech deficits. However, the core speech disorder subserving CMS is still unclear. CASE PRESENTATION: This study investigates the speech and language symptoms following posterior fossa medulloblastoma surgery in a 12-year-old right-handed boy. An extensive battery of formal speech (DIAS = Diagnostic Instrument Apraxia of Speech) and language tests were administered during a follow-up of 6 weeks after surgery. Although the neurological and neuropsychological (affective, cognitive) symptoms of this patient are consistent with Schmahmann's syndrome, the speech and language symptoms were markedly different from what is typically described in the literature. In-depth analyses of speech production revealed features consistent with a diagnosis of apraxia of speech (AoS) while ataxic dysarthria was completely absent. In addition, language assessments showed genuine aphasic deficits as reflected by distorted language production and perception, wordfinding difficulties, grammatical disturbances and verbal fluency deficits. CONCLUSION: To the best of our knowledge this case might be the first example that clearly demonstrates that a higher level motor planning disorder (apraxia) may be the origin of disrupted speech in CMS. In addition, identification of non motor linguistic disturbances during follow-up add to the view that the cerebellum not only plays a crucial role in the planning and execution of speech but also in linguistic processing. Whether the cerebellum has a direct or indirect role in motor speech planning needs to be further investigated. PMID- 28074149 TI - Non-selective beta-blockers in advanced cirrhosis: a critical review of the effects on overall survival and renal function. AB - INTRODUCTION: Non-selective beta-blockers (NSBBs) are widely prescribed in patients with cirrhosis for primary and secondary prophylaxis of bleeding oesophageal varices. Furthermore, it has been suggested that the clinical benefits of NSBBs may extend beyond their haemodynamic effects. Recently, a potentially harmful effect has been described in patients with refractory ascites or spontaneous bacterial peritonitis. METHODOLOGY: A comprehensive literature search on beta-blockers and cirrhosis survival using the electronic databases PubMed/MEDLINE, AMED, CINAHL and the Cochrane Central Register of Controlled Trials. Full-text manuscripts published over more than 35 years, from 1980 to April 2016 were reviewed for relevance and reference lists were cross-checked for additional pertinent studies regarding potential NSBB effects, especially focused on those concerned with survival and/or acute kidney injury (AKI). DISCUSSION: The proposed review will be able to provide valuable evidence to help decision making in the use of NSBB for the treatment of advanced cirrhosis and highlights some limitations in existing evidence to direct future research. PMID- 28074150 TI - Colorectal cancer mortality 10 years after a single round of guaiac faecal occult blood test (gFOBT) screening: experiences from a Danish screening cohort. AB - BACKGROUND: In Denmark, colorectal cancer (CRC) is the third most frequent cancer. Randomised trials have shown that guaiac faecal occult blood test (gFOBT) screening can reduce CRC mortality, but a recent large randomised study from Finland did not find any effect. A feasibility study was carried out in Denmark in 2005-2006 where residents aged 50-74 years in 2 Danish counties were invited once to participate in gFOBT screening. We used the unique Danish registers to assess the impact of gFOBT screening in this group on CRC incidence and mortality. METHODS: In this cohort study, we followed a group comprising 166 277 individuals invited to screening and a reference group comprising the remaining 1 240 348 Danes of the same age. We linked the Danish population and health service registers to obtain information about colonoscopies, polypectomies, incident CRC and cause of death. RESULTS: After a median follow-up time of 8.9 years, the CRC mortality was significantly lower in the screening group than in the reference group with an adjusted HR (aHR) of 0.92 (95% CI 0.86 to 0.99), while the aHR for all-cause mortality was 0.95 (95% CI 0.94 to 0.96). For screening participants, the aHR for CRC mortality and all-cause mortality was 0.72 (0.64 to 0.80) and 0.59 (0.57 to 0.60), respectively. CONCLUSIONS: About 10 years after a single round of gFOBT screening, we found a significant 8% deficit in CRC mortality in the screening group compared with other Danes. We found almost the same deficit in all-cause mortality, and on this basis, it is not possible to conclude that one screening round had an effect on CRC mortality. Our study indicated that close monitoring of the outcome of CRC screening is warranted. PMID- 28074151 TI - Clinical and pH study characteristics in reflux patients with and without ineffective oesophageal motility (IEM). AB - BACKGROUND: The aetiology and clinical impact of ineffective oesophageal motility (IEM) remain poorly understood, but the condition is thought to worsen supine gastro-oesophageal acid reflux (GERD). AIMS: In this retrospective cohort analysis of symptomatic patients with abnormal oesophageal acid exposure, we sought to determine any clinical or functional characteristics that would distinguish those with normal peristalsis from those with IEM, defined using the Chicago classification. We hypothesised that the impaired oesophageal clearance in IEM would be contributing to more severe degrees of pathological acid exposure, as well as clinical and endoscopic GERD severity. METHODS: Consecutive symptomatic patients with GERD underwent clinical, endoscopic and functional evaluation that included high-resolution impedance manometry (HRIM) and ambulatory pH monitoring performed 'off' acid suppressive therapy. RESULTS: Of the 114 patients with abnormal oesophageal acid exposure, 71 had normal oesophageal motility by HRIM and 43 were diagnosed with IEM (38% prevalence). Age, gender and symptom duration were similar between the two groups. Both groups had similar magnitude and frequency of symptoms, making a distinction clinically impossible. Endoscopically, the two groups had similar rates of erosive disease, hiatal hernia and Barrett's oesophagus. Ambulatory pH, proton pump inhibitor (PPI) dosage and PPI response rates were also similar. Nevertheless, patients with IEM had significantly more impairment of oesophageal clearance (mean 56.9+/ 6.4) than those with normal motility (mean 32.4+/-5.0) (p<0.003). CONCLUSIONS: Symptomatic patients with IEM exhibit significant impairment of oesophageal clearance but are otherwise clinically indistinguishable from those with normal oesophageal motility and have a similar prevalence of erosive disease and pathological acid exposure. PMID- 28074152 TI - Optimal dosage of cefmetazole for intraoperative antimicrobial prophylaxis in patients undergoing surgery for colorectal cancer. AB - BACKGROUND: Few studies have reported the dosage of cefmetazole (CMZ) for intraoperative antimicrobial prophylaxis in patients underwent surgery for colorectal cancer. We therefore examined the optimal intraoperative dosage of CMZ according to pharmacokinetic/pharmacodynamic (PK/PD) theory in patients who undergoing surgery for colorectal cancer. METHODS: The study group comprised 23 patients with colorectal cancer who underwent surgery, using CMZ as antimicrobial treatment to prevent postoperative infection. CMZ was administered intravenously within 60 min before surgery. PK/PD analysis was performed by population pharmacokinetic analysis and Monte-Carlo simulation. RESULTS: The final population pharmacokinetic parameters of CMZ were as follows: CLCMZ = 0.0704 * creatinine clearance (Ccr) and VdCMZ = 0.163 * body weight (Bw). In patients with a Ccr of >=90 to <130 mL/min, the probability of achieving concentrations exceeding MIC was 52.9 to 82.2% at 2 h after the initial dose and less than 20% at 3 h after the initial dose. CONCLUSIONS: Additional doses of CMZ should be given every 2 h in patients with a Ccr of >=90 to <130 mL/min, every 3 h in those with a Ccr of >=50 to <90 mL/min, and every 4 to 5 h in those with a Ccr of >=10 to <50 mL/min. PMID- 28074153 TI - Effects of metabolic syndrome on aortic pulse wave velocity. AB - BACKGROUND: The purpose of this study was to compare the value and evaluate the validity of non-invasive methods for the detection of vascular stiffness in never treated individuals with metabolic syndrome (MetS). METHODS: A total of 59 subjects (mean age, 60 +/- 12 years; male:female = 35:24) were enrolled in the study and were categorized into the positive MetS (MetS[+]: N = 32) and negative group (MetS[-]: N = 27), according to the parameters set by the National Cholesterol Education Program's Adult Treatment Panel III. Pulse wave velocity (PWV) of the aorta, arm, and leg, Framingham risk score (FRS), ankle-brachial index (ABI), and carotid intima-media thickness (IMT) for vascular aging were measured for the two groups. RESULTS: Aortic PWV (PWVaor) was significantly higher in MetS(+) than MetS(-) group (7.0 +/- 1.4 m/s vs. 8.4 +/- 1.6 m/s, p < 0.01), while ABI was significantly lower in MetS(+) than MetS(-) group (1.2 +/- 0.1 vs. 1.1 +/- 0.2, p = 0.03), respectively. FRS was significantly higher in MetS(+) than MetS(-) group (11 +/- 5 vs. 14 +/- 4, p = 0.05). The both mean IMT was higher in MetS(+) than MetS(-) group (right: 0.94 +/- 0.20 mm vs. 0.81 +/- 0.20 mm, p = 0.03; left: 0.93 +/- 0.20 mm vs. 0.79 +/- 0.20 mm, p = 0.03, respectively). For predicting the probability of the presence of MetS, PWVaor was an independent tool (p = 0.04; odds ratio, 1.88; 95% confidence interval, 1.03 to 3.42) and a cut-off value of PWVaor of 7.4 m/s showed a sensitivity of 66.7% and a specificity of 47.6%. CONCLUSIONS: We suggest that PWVaor, combined with traditional tools, can play an important role as a complementary or alternative tool for the detection of vascular stiffness in never-treated individuals with MetS. PMID- 28074154 TI - Development of a feasible and responsive ultrasound inflammation score for rheumatoid arthritis through a data-driven approach. AB - OBJECTIVE: To develop and validate a responsive and feasible ultrasound inflammation score for rheumatoid arthritis (RA). METHODS: We used data from cohorts of early RA (development) and established RA starting/switching biologic therapy (validation). 4 tendons and 36 joints were examined by a grey scale (GSUS) and power Doppler semiquantitative ultrasound (PDUS) scoring system (full score). Ultrasound score components were selected based on factor analyses of 3 month change in the development cohort. Responsiveness was assessed by standardised response means (SRMs). We assessed the proportion of information retained from the full score by linear regression. RESULTS: 118 patients with early and 212 patients with established RA were included. The final ultrasound score included 8 joints (metacarpophalangeal 1-2-3, proximal interphalangeal 2-3, radiocarpal, metatarsophalangeal 2-3) and 1 tendon (extensor carpi ulnaris) examined bilaterally. The 6-month SRMs for the final score were -1.24 (95% CI 1.47 to -1.02) for GSUS, and -1.09 (-1.25 to -0.92) for PDUS in early RA, with 87% of total information retained for GSUS and 90% for PDUS. The new score performed somewhat better than formerly proposed scores in the validation cohort. CONCLUSIONS: The Ultrasound in Rheumatoid Arthritis 9 joint/tendon score (USRA9) inflammation score showed good responsiveness, retained most of the information from the original full score and overall performed better than previous scores in a validation cohort. TRIAL REGISTRATION NUMBERS: NCT01205854, ACTRN12610000284066; Post-results. PMID- 28074155 TI - An Automated Detection System for Microaneurysms That Is Effective across Different Racial Groups. AB - Patients without diabetic retinopathy (DR) represent a large proportion of the caseload seen by the DR screening service so reliable recognition of the absence of DR in digital fundus images (DFIs) is a prime focus of automated DR screening research. We investigate the use of a novel automated DR detection algorithm to assess retinal DFIs for absence of DR. A retrospective, masked, and controlled image-based study was undertaken. 17,850 DFIs of patients from six different countries were assessed for DR by the automated system and by human graders. The system's performance was compared across DFIs from the different countries/racial groups. The sensitivities for detection of DR by the automated system were Kenya 92.8%, Botswana 90.1%, Norway 93.5%, Mongolia 91.3%, China 91.9%, and UK 90.1%. The specificities were Kenya 82.7%, Botswana 83.2%, Norway 81.3%, Mongolia 82.5%, China 83.0%, and UK 79%. There was little variability in the calculated sensitivities and specificities across the six different countries involved in the study. These data suggest the possible scalability of an automated DR detection platform that enables rapid identification of patients without DR across a wide range of races. PMID- 28074156 TI - Laparoscopic Repair of Congenital Diaphragmatic Hernia in Adults. AB - Background, Aims, and Objectives. Congenital diaphragmatic hernia typically presents in childhood but in adults is extremely rare entity. Surgery is indicated for symptomatic and asymptomatic patients who are fit for surgery. It can be done by laparotomy, thoracotomy, thoracoscopy, or laparoscopy. With the advent of minimal access techniques, the open surgical repair for this hernia has decreased and results are comparable with early recovery and less hospital stay. The aim of this study is to establish that laparoscopic repair of congenital diaphragmatic hernia is a safe and effective modality of surgical treatment. Materials and Methods. A retrospective study of laparoscopic diaphragmatic hernia repair done during May 2011 to Oct 2014. Total n = 13 (M/F: 11/2) cases of confirmed diaphragmatic hernia on CT scan, 4 cases Bochdalek hernia (BH), 8 cases of left eventration of the diaphragm (ED), and one case of right-sided eventration of the diaphragm (ED) were included in the study. Largest defect found on the left side was 15 * 6 cm and on the right side it was 15 * 8 cm. Stomach, small intestine, transverse colon, and omentum were contents in the hernial sac. The contents were reduced with harmonic scalpel and thin sacs were usually excised. The eventration was plicated and hernial orifices were repaired with interrupted horizontal mattress sutures buttressed by Teflon pieces. A composite mesh was fixed with nonabsorbable tackers. All patients had good postoperative recovery and went home early with normal follow-up and were followed up for 2 years. Conclusion. The laparoscopic repair is a safe and effective modality of surgical treatment for congenital diaphragmatic hernia in experienced hands. PMID- 28074157 TI - The Efficiency of Sclerotherapy in the Treatment of Vascular Malformations: A Retrospective Study of 63 Patients. AB - Background and Aims. Vascular malformations are a vast group of congenital malformations that are present at birth. These malformations can cause pain, pressure, and cosmetic annoyance as well as downturn growth and development in a child in the case of high flow. Sclerotherapy has become an important tool in the treatment of vascular malformations. However, little is known about the success rate of sclerotherapy. Material and Methods. In this study, the efficiency of sclerotherapy in the treatment of vascular anomalies was investigated retrospectively in 63 patients treated in Turku University Hospital between 2003 and 2013. Results. Out of the 63 patients investigated, 83% (53) had venous malformations (VMs) and 9% (5) were defined as having arteriovenous malformations (AVMs). Patients with a VM were operated on, in 14% (8) out of all VM cases. Hence 86% (45) of patients with a VM received adequate help to their symptoms solely from sclerotherapy. The duration of treatment for the 14% of the VM patients that needed a surgical procedure was prolonged by 7-9 months, that is, by 41%. Conclusions. Sclerotherapy is an effective method in the treatment of VMs with a satisfactory clinical response in patients symptoms in 84% of cases. PMID- 28074158 TI - Visualization of Inflammation at Early Stage of Lung Cancer in Xenografted Temporally Immunosuppression Rats by Ferrioxamine Magnetic Resonance Imaging. AB - Physiological responses such as chronic inflammation and angiogenesis could be used as biomarkers for early detection of cancer with noninvasive imaging modalities. The present study reports the application of magnetic resonance imaging instrument to image the binding of ferrioxamine with hemin that allows visualizing the chronic inflammation foci of lung tissue of immunocompromised rats xenografted using small cell lung carcinoma. A low concentration of ferrioxamine (0.05 +/- 0.02 MUM.kg-1 of rat weight) deposited on tissue outside the vasculature was found to diffuse across the capillary walls to the interstitial space and inflammation foci, which provided a clear enhancement of T1-weighted gradient-echo sequence images. Ferrioxamine imaging allowed the determination of inflammatory sites and their localization in 3D fat-suppressed maximum intensity projections. The smallest dimension of foci that can be clearly determined is about 0.1 mm3. In concomitant to the in vivo imaging, analysis of histological tissue section showed the development of inflammatory sites. This study provides evidence that medical imaging instrument such as MRI scanner allows researchers to correlate images taken with MRI with those using high resolution microscopy. Moreover, ferrioxamine is a useful molecular probe for determining chronic inflammation particularly at the very early stages of cancer. PMID- 28074159 TI - A Comprehensive Review of Portosystemic Collaterals in Cirrhosis: Historical Aspects, Anatomy, and Classifications. AB - Portosystemic collateral formation in cirrhosis plays an important part in events that define the natural history in affected patients. A detailed understanding of collateral anatomy and hemodynamics in cirrhotics is essential to envisage diagnosis, management, and outcomes of portal hypertension. In this review, we provide detailed insights into the historical, anatomical, and hemodynamic aspects to portal hypertension and collateral pathways in cirrhosis with emphasis on the various classification systems. PMID- 28074160 TI - Resting-State Functional Connectivity and Cognitive Impairment in Children with Perinatal Stroke. AB - Perinatal stroke is a leading cause of congenital hemiparesis and neurocognitive deficits in children. Dysfunctions in the large-scale resting-state functional networks may underlie cognitive and behavioral disability in these children. We studied resting-state functional connectivity in patients with perinatal stroke collected from the Estonian Pediatric Stroke Database. Neurodevelopment of children was assessed by the Pediatric Stroke Outcome Measurement and the Kaufman Assessment Battery. The study included 36 children (age range 7.6-17.9 years): 10 with periventricular venous infarction (PVI), 7 with arterial ischemic stroke (AIS), and 19 controls. There were no differences in severity of hemiparesis between the PVI and AIS groups. A significant increase in default mode network connectivity (FDR 0.1) and lower cognitive functions (p < 0.05) were found in children with AIS compared to the controls and the PVI group. The children with PVI had no significant differences in the resting-state networks compared to the controls and their cognitive functions were normal. Our findings demonstrate impairment in cognitive functions and neural network profile in hemiparetic children with AIS compared to children with PVI and controls. Changes in the resting-state networks found in children with AIS could possibly serve as the underlying derangements of cognitive brain functions in these children. PMID- 28074161 TI - Direct Current-Induced Calcium Trafficking in Different Neuronal Preparations. AB - The influence of direct current (DC) stimulation on radioactive calcium trafficking in sciatic nerve in vivo and in vitro, spinal cord, and synaptosomes was investigated. The exposure to DC enhanced calcium redistribution in all of these preparations. The effect was dependent on the strength of the stimulation and extended beyond the phase of exposure to DC. The DC-induced increase in calcium sequestration by synaptosomes was significantly reduced by cobalt and rupture of synaptosomes by osmotic shock. Although both anodal and cathodal currents were effective, the experiments with two electrodes of different areas revealed that cathodal stimulation exerted stronger effect. The exposure to DC induced not only relocation but also redistribution of calcium within segments of the sciatic nerve. Enzymatic removal of sialic acid by preincubation of synaptosomes with neuroaminidase, or carrying out the experiments in sodium-free environment, amplified DC-induced calcium accumulation. PMID- 28074162 TI - Altered Effective Connectivity of Hippocampus-Dependent Episodic Memory Network in mTBI Survivors. AB - Traumatic brain injuries (TBIs) are generally recognized to affect episodic memory. However, less is known regarding how external force altered the way functionally connected brain structures of the episodic memory system interact. To address this issue, we adopted an effective connectivity based analysis, namely, multivariate Granger causality approach, to explore causal interactions within the brain network of interest. Results presented that TBI induced increased bilateral and decreased ipsilateral effective connectivity in the episodic memory network in comparison with that of normal controls. Moreover, the left anterior superior temporal gyrus (aSTG, the concept forming hub), left hippocampus (the personal experience binding hub), and left parahippocampal gyrus (the contextual association hub) were no longer network hubs in TBI survivors, who compensated for hippocampal deficits by relying more on the right hippocampus (underlying perceptual memory) and the right medial frontal gyrus (MeFG) in the anterior prefrontal cortex (PFC). We postulated that the overrecruitment of the right anterior PFC caused dysfunction of the strategic component of episodic memory, which caused deteriorating episodic memory in mTBI survivors. Our findings also suggested that the pattern of brain network changes in TBI survivors presented similar functional consequences to normal aging. PMID- 28074163 TI - Mycosis Fungoides of the Oral Cavity: Fungating Tumor Successfully Treated with Electron Beam Radiation and Maintenance Bexarotene. AB - Oral involvement in mycosis fungoides is unusual and portends a poor prognosis. The clinical findings of three new cases are described along with a differential diagnosis and review of the literature. For brevity, only one patient is discussed in detail below whereas the other two cases are solely described in table form. The patient had a four-year history of mycosis fungoides before developing an exophytic tongue tumor. He was treated with local electron beam radiation and is disease-free to date while being on maintenance therapy with oral bexarotene. Analysis of the data collected from our review of the literature and the present cases reveal key insights. PMID- 28074164 TI - Radiation-Induced Alopecia after Endovascular Embolization under Fluoroscopy. AB - Radiation-induced alopecia after fluoroscopically guided procedures is becoming more common due to an increasing use of endovascular procedures. It is characterized by geometric shapes of nonscarring alopecia related to the area of radiation. We report a case of a 46-year-old man presenting with asymptomatic, sharply demarcated rectangular, nonscarring alopecic patch on the occipital scalp following cerebral angiography with fistula embolization under fluoroscopy. His presentations were compatible with radiation-induced alopecia. Herein, we also report a novel scalp dermoscopic finding of blue-grey dots in a target pattern around yellow dots and follicles, which we detected in the lesion of radiation induced alopecia. PMID- 28074165 TI - Bamboo Leaf Sign as a Sensitive Magnetic Resonance Imaging Finding in Spinal Subependymoma: Case Report and Literature Review. AB - Background and Importance. Subependymoma occurs very rarely in the spinal cord. We report another case of spinal subependymoma along with a review of the literature and discussion of a radiological finding that is useful for preoperative diagnosis of this tumor. Clinical Presentation. A 51-year-old man presented with a 2-year history of progressive muscle weakness in the right lower extremity. Sagittal magnetic resonance imaging (MRI) showed spinal cord expansion at the Th7-12 vertebral level. Surgical resection was performed and the tumor was found to involve predominantly subpial growth. Histological diagnosis was subependymoma, classified as Grade I according to criteria of World Health Organization. We made an important discovery of what seems to be a characteristic appearance for spinal subependymoma on sagittal MRI. Swelling of the spinal cord is extremely steep, providing unusually large fusiform dilatation resembling a bamboo leaf. We have termed this characteristic MRI appearance as the "bamboo leaf sign." This characteristic was apparent in 76.2% of cases of spinal subependymoma for which MRI findings were reported. Conclusion. The bamboo leaf sign on spinal MRI is useful for differentiating between subependymoma and other intramedullary tumors. Neurosurgeons encountering the bamboo leaf sign on spinal MRI should consider the possibility of subependymoma. PMID- 28074166 TI - Can Cell Bound Complement Activation Products Predict Inherited Complement Deficiency in Systemic Lupus Erythematosus? AB - Activation of the classical pathway complement system has long been implicated in stimulating immune complex mediated tissue destruction in systemic lupus erythematosus (SLE). C3 and C4 complement levels are utilized as part of SLE diagnosis and monitoring criteria. Recently, cell bound complement activation products (CBCAPs) have shown increased sensitivity in diagnosing and monitoring lupus activity, compared to traditional markers. CBCAPs are increasingly utilized in rheumatology practice as additional serological markers in evaluating SLE patients. We report a case of a patient diagnosed with SLE that had chronically low C3 and C4, along with negative CBCAPs. We surmise that the patient has an inherited complement deficiency as the etiology of her SLE and that CBCAPs could be used to predict such deficiency. PMID- 28074167 TI - Delayed Tension Pneumocephalus following Gunshot Wound to the Head: A Case Report and Review of the Literature. AB - Tension pneumocephalus is a rare complication of head trauma and neurosurgical procedures, amongst other causes. It is defined by the combination of intracranial air, increased intracranial pressure, and mass effect. Although it often presents soon after surgery, it can also rarely present in a delayed fashion. We present a case of delayed tension pneumocephalus, occurring approximately 16 weeks after bifrontal craniectomy for a self-inflicted gunshot wound. Following a month of rhinorrhea, postnasal drip, and cough, the patient presented with a sensation of expansion in the area of the right forehead. As tension pneumocephalus is an emergency that can be fatal, this patient was treated expediently and avoided severe neurological deficits. The case recounted here is important as a demonstrative example that tension pneumocephalus does not always follow a defined course immediately after trauma or neurosurgery but rather can develop insidiously without obvious signs. PMID- 28074168 TI - Reconstruction of Abdominal Wall Defects Using a Pedicled Anterolateral Thigh Flap including the Vastus Lateralis Muscle: A Report of Two Cases. AB - The purpose of abdominal wall reconstruction is to prevent hernias and protect the abdominal viscera. In cases involving full-thickness defects of the rectus abdominis muscle, the muscle layer should be repaired. We present 2 cases in which full-thickness lower rectus abdominis muscle defects were reconstructed using vastus lateralis-anterolateral thigh flaps. The pedicled vastus lateralis anterolateral thigh flap provides skin, fascia, and muscle tissue. Furthermore, it has a long neurovascular pedicle and can reach up to the periumbilical area and cover large defects. We consider that this muscle flap is a good option for repairing full-thickness lower abdominal defects. PMID- 28074169 TI - Multilocular Cystic Renal Cell Carcinoma or Cystic Nephroma? AB - The incidence of Multilocular cystic renal cell carcinoma (MCRCC) in literature is very low and confounding MCRCC with cystic nephroma (CN) is even more unusual. The aim of this report is to present a case of MCRCC and emphasize the importance of the preoperative radiologic evaluation and immunohistochemical staining confirmation to obtain an accurate diagnosis. A 73-year-old woman presented with a history of 4-month right flank pain. CT showed a Bosniak type III renal mass. After laparoscopic partial nephrectomy the initial report was cystic nephroma. Immunohistochemical staining was performed being positive for Epithelial Membrane Antigen thus changing the diagnosis to MCRCC. Multilocular cystic renal cell carcinoma cannot reliably be distinguished from cystic nephroma neither by physical examination nor by radiologic evaluation; immunohistochemical staining assay is useful to differentiate between these conditions allowing an accurate diagnosis and proper follow-up. PMID- 28074170 TI - Nonobese Diabetic (NOD) Mice Lack a Protective B-Cell Response against the "Nonlethal" Plasmodium yoelii 17XNL Malaria Protozoan. AB - Background. Plasmodium yoelii 17XNL is a nonlethal malaria strain in mice of different genetic backgrounds including the C57BL/6 mice (I-Ab/I-Enull) used in this study as a control strain. We have compared the trends of blood stage infection with the nonlethal murine strain of P. yoelii 17XNL malaria protozoan in immunocompetent Nonobese Diabetic (NOD) mice prone to type 1 diabetes (T1D) and C57BL/6 mice (control mice) that are not prone to T1D and self-cure the P. yoelii 17XNL infection. Prediabetic NOD mice could not mount a protective antibody response to the P. yoelii 17XNL-infected red blood cells (iRBCs), and they all succumbed shortly after infection. Our data suggest that the lack of anti-P. yoelii 17XNL-iRBCs protective antibodies in NOD mice is a result of parasite-induced, Foxp3+ T regulatory (Treg) cells able to suppress the parasite specific antibody secretion. Conclusions. The NOD mouse model may help in identifying new mechanisms of B-cell evasion by malaria parasites. It may also serve as a more accurate tool for testing antimalaria therapeutics due to the lack of interference with a preexistent self-curing mechanism present in other mouse strains. PMID- 28074171 TI - Critical evaluation of reverse engineering tool Imagix 4D! AB - INTRODUCTION: The comprehension of legacy codes is difficult to understand. Various commercial reengineering tools are available that have unique working styles, and are equipped with their inherent capabilities and shortcomings. The focus of the available tools is in visualizing static behavior not the dynamic one. Therefore, it is difficult for people who work in software product maintenance, code understanding reengineering/reverse engineering. Consequently, the need for a comprehensive reengineering/reverse engineering tool arises. We found the usage of Imagix 4D to be good as it generates the maximum pictorial representations in the form of flow charts, flow graphs, class diagrams, metrics and, to a partial extent, dynamic visualizations. CASE DESCRIPTION AND EVOLUTION: We evaluated Imagix 4D with the help of a case study involving a few samples of source code. The behavior of the tool was analyzed on multiple small codes and a large code gcc C parser. Large code evaluation was performed to uncover dead code, unstructured code, and the effect of not including required files at preprocessing level. The utility of Imagix 4D to prepare decision density and complexity metrics for a large code was found to be useful in getting to know how much reengineering is required. At the outset, Imagix 4D offered limitations in dynamic visualizations, flow chart separation (large code) and parsing loops. CONCLUSION: The outcome of evaluation will eventually help in upgrading Imagix 4D and posed a need of full featured tools in the area of software reengineering/reverse engineering. It will also help the research community, especially those who are interested in the realm of software reengineering tool building. PMID- 28074172 TI - Non-allergic rhinitis in children: Epidemiological aspects, pathological features, diagnostic methodology and clinical management. AB - Chronic rhinitis is a very common disease, as the prevalence in the general population resulted to be 40%. Allergic rhinitis has been considered to be the most frequent form of chronic rhinitis, as non-allergic rhinitis has been estimated to account for 25%. However, several evidences suggested that non allergic rhinitis have been underrated, especially in children. In pediatrics, the diagnostic definition of non-allergic rhinitis has been often limited to the exclusion of an allergic sensitization. Actually, local allergic rhinitis has been often misdiagnosed as well as mixed rhinitis has not been recognized in most cases. Nasal cytology is a diagnostic procedure being suitable for routine clinical practice with children and could be a very useful tool to characterize and diagnose non-allergic rhinitis, providing important clues for epidemiological analysis and clinical management. PMID- 28074173 TI - Radiological clinical trials: Proposal of a problem-finding questionnaire to improve study success. AB - AIM: To develop a survey to help define the main problems in radiological clinical trials. METHODS: Since 2006, we have managed seven different radiological clinical trials recruiting patients in academic and non-academic centres. We developed a preliminary questionnaire using a four-round Delphi approach to identify problems occurring in radiological clinical trials run at our centre. We investigated the recruitment experience, involvement of all multi disciplinary team members and main obstacles to completing the projects. A final round of Delphi processes elucidated solutions to the identified problems. RESULTS: Among 19/20 (95%) respondents, 10 (53%) were young physicians (under 35 years old), and the respondents included non-faculty members, fellows, residents, and undergraduate students. Ninety-four percent (18/19) of respondents showed interest in conducting clinical trials. On a scale of 1 to 10, the problems with higher/worse scores (8-9) were related to technical or communication problems. The most frequent problems across all studies were technical problems related to clinical trial equipment, insufficient willingness to participate, obstacles to understanding the design of electronic-case report form and extra work. CONCLUSION: The developed questionnaire identified the main recurring problems in radiological clinical trials as perceived by end-users and helped define possible solutions that are mostly related to having dedicated clinical trial research staff. PMID- 28074174 TI - Colectomy Rates for Ulcerative Colitis Differ between Ethnic Groups: Results from a 15-Year Nationwide Cohort Study. AB - Introduction. Previous epidemiological studies suggest a higher rate of pancolonic disease in South Asians (SA) compared with White Europeans (WE). The aim of the study was to compare colectomy rates for ulcerative colitis (UC) in SA to those of WE. Methods. Patients with UC were identified from a national administrative dataset (Hospital Episode Statistics, HES) between 1997 and 2012 according to ICD-10 diagnosis code K51 for UC. The colectomy rate for each ethnic group was calculated as the proportion of patients who underwent colectomy from the total UC cases for that group. Results. Of 212,430 UC cases, 73,318 (35.3%) were coded for ethnicity. There was no significant difference in the colectomy rate between SA and WE (6.93% versus 6.90%). Indians had a significantly higher colectomy rate than WE (9.8% versus 6.9%, p < 0.001). Indian patients were 21% more likely to require colectomy for UC compared with WE group (OR: 1.21, 95% CI: 1.04-1.42, and p = 0.001). Conclusions. Given the limitations in coding, the colectomy rate in this cohort was higher in Indians compared to WE. A prospectively recruited ethnic cohort study will decipher whether this reflects a more aggressive phenotype or is due to other confounding factors. PMID- 28074175 TI - Gene Expression Analysis of Alfalfa Seedlings Response to Acid-Aluminum. AB - Acid-Aluminum (Al) is toxic to plants and greatly affects crop production worldwide. To understand the responses of plants to acid soils and Aluminum toxicity, we examined global gene expression using microarray data in alfalfa seedlings with the treatment of acid-Aluminum. 3,926 genes that were identified significantly up- or downregulated in response to Al3+ ions with pH 4.5 treatment, 66.33% of which were found in roots. Their functional categories were mainly involved with phytohormone regulation, reactive oxygen species, and transporters. Both gene ontology (GO) enrichment and KEGG analysis indicated that phenylpropanoid biosynthesis, phenylalanine metabolism, and flavonoid biosynthesis played a critical role on defense to Aluminum stress in alfalfa. In addition, we found that transcription factors such as the MYB and WRKY family proteins may be also involved in the regulation of reactive oxygen species reactions and flavonoid biosynthesis. Thus, the finding of global gene expression profile provided insights into the mechanisms of plant defense to acid-Al stress in alfalfa. Understanding the key regulatory genes and pathways would be advantageous for improving crop production not only in alfalfa but also in other crops under acid-Aluminum stress. PMID- 28074176 TI - Comparative Transcriptome Analysis Reveals Effects of Exogenous Hematin on Anthocyanin Biosynthesis during Strawberry Fruit Ripening. AB - Anthocyanin in strawberries has a positive effect on fruit coloration. In this study, the role of exogenous hematin on anthocyanin biosynthesis was investigated. Our result showed that the white stage of strawberries treated with exogenous hematin had higher anthocyanin content, compared to the control group. Among all treatments, 5 MUM of hematin was the optimal condition to promote color development. In order to explore the molecular mechanism of fruit coloring regulated by hematin, transcriptomes in the hematin- and non-hematin-treated fruit were analyzed. A large number of differentially expressed genes (DEGs) were identified in regulating anthocyanin synthesis, including the DEGs involved in anthocyanin biosynthesis, hormone signaling transduction, phytochrome signaling, starch and sucrose degradation, and transcriptional pathways. These regulatory networks may play an important role in regulating the color process of strawberries treated with hematin. In summary, exogenous hematin could promote fruit coloring by increasing anthocyanin content in the white stage of strawberries. Furthermore, transcriptome analysis suggests that hematin-promoted fruit coloring occurs through multiple related metabolic pathways, which provides valuable information for regulating fruit color via anthocyanin biosynthesis in strawberries. PMID- 28074177 TI - Pain Analysis in Patients with Pancreatic Carcinoma: Irreversible Electroporation versus Cryoablation. AB - The aim of this article is to evaluate and compare the postprocedure pain in patients with pancreatic carcinoma treated with irreversible electroporation (IRE) and cryoablation (CRYO). We compared 22 patients with 22 lesions in pancreas treated with IRE and 26 patients with 27 lesions treated with cryosurgery. All the patients in the two groups were under celiac plexus block (CPB) treatment to alleviate the postprocedure pain. A numerical rating scale (VAS) consisting of 11-point scales and the 24 h total hydromorphone use were recorded for the analysis of the pain level in the patients who underwent these two technologies separately. Other parameters, such as the complications and the ECOG performance status, were also noted. Statistical analysis was performed by Fisher's exact test, the Chi-square test, and Student's t-test. All the pancreatic carcinoma patients in our study were reported to have postprocedure pain in the two groups. But there was no significant difference in the mean pain score (4.95 (IRE) versus 4.85 (CRYO); P = 0.52) and 24 h total hydromorphone use (3.89 mg (IRE) versus 3.97 mg (CRYO); P = 0.30). IRE is comparable to cryotherapy in the amount of pain that patients with pancreatic carcinoma experience. PMID- 28074178 TI - Effects of Frequency and Acceleration Amplitude on Osteoblast Mechanical Vibration Responses: A Finite Element Study. AB - Bone cells are deformed according to mechanical stimulation they receive and their mechanical characteristics. However, how osteoblasts are affected by mechanical vibration frequency and acceleration amplitude remains unclear. By developing 3D osteoblast finite element (FE) models, this study investigated the effect of cell shapes on vibration characteristics and effect of acceleration (vibration intensity) on vibrational responses of cultured osteoblasts. Firstly, the developed FE models predicted natural frequencies of osteoblasts within 6.85 48.69 Hz. Then, three different levels of acceleration of base excitation were selected (0.5, 1, and 2 g) to simulate vibrational responses, and acceleration of base excitation was found to have no influence on natural frequencies of osteoblasts. However, vibration response values of displacement, stress, and strain increased with the increase of acceleration. Finally, stress and stress distributions of osteoblast models under 0.5 g acceleration in Z-direction were investigated further. It was revealed that resonance frequencies can be a monotonic function of cell height or bottom area when cell volumes and material properties were assumed as constants. These findings will be useful in understanding how forces are transferred and influence osteoblast mechanical responses during vibrations and in providing guidance for cell culture and external vibration loading in experimental and clinical osteogenesis studies. PMID- 28074179 TI - Integrative Evaluation of Automated Massage Combined with Thermotherapy: Physical, Physiological, and Psychological Viewpoints. AB - Various types of massages are reported to relieve stress, pain, and anxiety which are beneficial for rehabilitation; however, more comprehensive studies are needed to understand the mechanism of massage therapy. In this study, we investigated the effect of massage therapy, alone or in combination with infrared heating, on 3 different aspects: physical, physiological, and psychological. Twenty-eight healthy university students were subjected to 3 different treatment conditions on separate days, one condition per day: control, massage only, or massage with infrared heating. Physical (trunk extension [TE]; maximum power of erector spinae), physiological (heart-rate variability [HRV]; electroencephalogram [EEG]), and psychological (state-trait anxiety inventory [STAI]; visual analogue scale [VAS]) measurements were evaluated and recorded before and after each treatment condition. The results showed that massage therapy, especially when combined with infrared heating, significantly improved physical functioning, increased parasympathetic response, and decreased psychological stress and anxiety. In the current study, we observed that massage therapy contributes to various physical, physiological, and psychological changes, where the effect increases with thermotherapy. PMID- 28074180 TI - Horizontally Transferred Genetic Elements in the Tsetse Fly Genome: An Alignment Free Clustering Approach Using Batch Learning Self-Organising Map (BLSOM). AB - Tsetse flies (Glossina spp.) are the primary vectors of trypanosomes, which can cause human and animal African trypanosomiasis in Sub-Saharan African countries. The objective of this study was to explore the genome of Glossina morsitans morsitans for evidence of horizontal gene transfer (HGT) from microorganisms. We employed an alignment-free clustering method, that is, batch learning self organising map (BLSOM), in which sequence fragments are clustered based on the similarity of oligonucleotide frequencies independently of sequence homology. After an initial scan of HGT events using BLSOM, we identified 3.8% of the tsetse fly genome as HGT candidates. The predicted donors of these HGT candidates included known symbionts, such as Wolbachia, as well as bacteria that have not previously been associated with the tsetse fly. We detected HGT candidates from diverse bacteria such as Bacillus and Flavobacteria, suggesting a past association between these taxa. Functional annotation revealed that the HGT candidates encoded loci in various functional pathways, such as metabolic and antibiotic biosynthesis pathways. These findings provide a basis for understanding the coevolutionary history of the tsetse fly and its microbes and establish the effectiveness of BLSOM for the detection of HGT events. PMID- 28074181 TI - Transperitoneal Subcostal Access for Urologic Laparoscopy: Experience of a Large Chinese Center. AB - Objective. To present our experience of using transperitoneal subcostal access, Palmer's point (3 cm below the left costal margin in the midclavicular line), and its right corresponding site, in urologic laparoscopy. Methods. We used Palmer's point and the right corresponding site for initial access in 302 urologic surgeries (62 cases with prior surgeries). The record of these cases was reviewed. Results. Success rate of initial access is 99.4%, and complication rate of puncturing is only 3.4% with no serious complication. In the cases with prior surgeries, there were only two cases with access complication on the right side (minor laceration of liver). For people with BMI more than 30 kg/m2 (12, 3.9%), the success rate was also 100 percent. Conclusions. Palmer's point and the corresponding right location are feasible, effective, and safe for initial access in urologic laparoscopic surgeries. This entry technique should be used routinely in urologic laparoscopic surgeries. PMID- 28074182 TI - Current Computational Models for Prediction of the Varied Interactions Related to Noncoding RNAs. PMID- 28074183 TI - A Novel Assay for the Identification of NOTCH1 PEST Domain Mutations in Chronic Lymphocytic Leukemia. AB - Aims. To develop a fast and robust DNA-based assay to detect insertions and deletions mutations in exon 34 that encodes the PEST domain of NOTCH1 in order to evaluate patients with chronic lymphocytic leukemia (CLL). Methods. We designed a multiplexed allele-specific polymerase chain reaction (PCR) combined with a fragment analysis assay to detect specifically the mutation c.7544_7545delCT and possibly other insertions and deletions in exon 34 of NOTCH1. Results. We evaluated our assay in peripheral blood samples from two cohorts of patients with CLL. The frequency of NOTCH1 mutations was 8.4% in the first cohort of 71 unselected CLL patients. We then evaluated a second cohort of 26 CLL patients with known cytogenetic abnormalities that were enriched for patients with trisomy 12. NOTCH1 mutations were detected in 43.7% of the patients with trisomy 12. Conclusions. We have developed a fast and robust assay combining allele-specific PCR and fragment analysis able to detect NOTCH1 PEST domain insertions and deletions. PMID- 28074184 TI - Profiles of Inflammatory Cytokines in the Vitreous Fluid from Patients with Rhegmatogenous Retinal Detachment and Their Correlations with Clinical Features. AB - Purpose. To characterize the profiles for inflammatory cytokines in the vitreous fluid from patients with rhegmatogenous retinal detachment (RRD) by comparing those of other vitreoretinal diseases and to analyze the correlation between intravitreal cytokines and clinical features. Materials and Methods. Vitreous fluid was obtained at the time of surgery from 28 RRD eyes. Vitreous fluid was similarly collected from patients with macular hole (MH), epiretinal membrane, proliferative diabetic retinopathy (PDR), and retinal vein occlusion as controls. Twenty-seven cytokines were measured. Intravitreal cytokine profiles in RRD were characterized by comparing these with those in other vitreoretinal diseases. We also analyzed the correlations between vitreous cytokines and clinical features. Results. There were statistical differences in the MCP-1, MIP-1beta, and IP-10 between the RRD and MH, while the IL-6 and IL-8 exhibited levels that were between those for the PDR and MH. MIP-1beta was significantly correlated to both the extent and duration of the RRD, while IL-8 was significantly correlated to the extent of the RRD. Conclusions. MCP-1, MIP-1beta, and IP-10 may modify the pathologic features of RRD. The levels of these cytokines are related in part to the clinical features and the level of photoreceptor damage. PMID- 28074185 TI - Prevalence and Antimicrobial Resistance of Salmonella Isolated from Animal-Origin Food Items in Gondar, Ethiopia. AB - Salmonella has been found to be the major cause of foodborne diseases and a serious public health problem in the world, with an increasing concern for the emergence and spread of antimicrobial-resistant strains. A cross-sectional study was conducted between February 2014 and December 2015 on food items of animal origin to assess the prevalence and antimicrobial resistance profiles of Salmonella isolates using standard bacteriological methods. The overall prevalence rate of 5.5% was recorded from the total analyzed food items of animal origin. Salmonella isolates were detected from 12% of raw meat, 8% of minced meat, 2.9% of burger samples, 18% of raw eggs, and 6% of raw milk. Furthermore, antimicrobial susceptibility test identified 47.6% resistant Salmonella isolates, 28.6% intermediately sensitive isolates, and 23.8% susceptible isolates. Among Salmonella isolates tested, 42.6%, 28.6%, and 14.3% were found to be relatively resistant to tetracycline, sulfamethoxazole-trimethoprim, and ampicillin, respectively, while 9.5%-19% were intermediately resistant to tetracycline, amoxicillin, ampicillin, cephalothin, and nitrofurantoin. Therefore, our findings provide the prevalence and drug resistance of Salmonella from foods of animal origin and contribute information to scientists as well as public health researchers to minimize the prevalent and resistant foodborne Salmonella species in Ethiopia. PMID- 28074187 TI - Baseline Chronic Kidney Disease and Ischemic Method of Partial Nephrectomy Are Important Factors for the Short- and Long-Term Deterioration in Renal Function for Renal Cell Carcinoma Staged T1-T2: A Retrospective Single Center Study. AB - The renal functions of 215 patients (24 with benign renal mass, the rest with RCC staged T1-T2) who underwent partial nephrectomy (PN) between 2003 and 2014 were evaluated to identify predictors of short- and long-term deterioration in renal function after PN among renal cell carcinoma (RCC) patients with or without preoperative predisposition to chronic kidney disease (CKD) and among patients with benign renal mass. The 1- and 5-year predictive factors for de novo CKD were statistically analyzed. The incidence of de novo CKD differed significantly (p < 0.001) among patients with benign renal mass, those with RCC but no preoperative CKD predisposition, and those with RCC combined with preoperative CKD predisposition. Independent predictors for de novo CKD at 1 year postoperatively included intraoperative ischemic method, ECOG score, elevated albumin levels, male sex, and smoking exposure (in pack-years). Predictors for de novo CKD at 5 years postoperatively included hypertension, high preoperative albumin levels, De Ritis ratio (aspartate aminotransferase/alanine aminotransferase ratio), smoking exposure, and preoperative predisposition to CKD. Preoperative predisposition to CKD and ischemic method applied during PN, along with other preoperative parameters, were important factors affecting postoperative renal function deterioration in patients with T1-T2 RCC. PMID- 28074186 TI - TAMH: A Useful In Vitro Model for Assessing Hepatotoxic Mechanisms. AB - In vitro models for hepatotoxicity can be useful tools to predict in vivo responses. In this review, we discuss the use of the transforming growth factor alpha transgenic mouse hepatocyte (TAMH) cell line, which is an attractive model to study drug-induced liver injury due to its ability to retain a stable phenotype and express drug-metabolizing enzymes. Hepatotoxicity involves damage to the liver and is often associated with chemical exposure. Since the liver is a major site for drug metabolism, drug-induced liver injury is a serious health concern for certain agents. At the molecular level, various mechanisms may protect or harm the liver during drug-induced hepatocellular injury including signaling pathways and endogenous factors (e.g., Bcl-2, GSH, Nrf2, or MAPK). The interplay between these and other pathways in the hepatocyte can change upon drug or drug metabolite exposure leading to intracellular stress and eventually cell death and liver injury. This review focuses on mechanistic studies investigating drug-induced toxicity in the TAMH line and how alterations to hepatotoxic mechanisms in this model relate to the in vivo situation. The agents discussed herein include acetaminophen (APAP), tetrafluoroethylcysteine (TFEC), flutamide, PD0325901, lapatinib, and flupirtine. PMID- 28074188 TI - Effect of Negative Pressure on Proliferation, Virulence Factor Secretion, Biofilm Formation, and Virulence-Regulated Gene Expression of Pseudomonas aeruginosa In Vitro. AB - Objective. To investigate the effect of negative pressure conditions induced by NPWT on P. aeruginosa. Methods. P. aeruginosa was cultured in a Luria-Bertani medium at negative pressure of -125 mmHg for 24 h in the experimental group and at atmospheric pressure in the control group. The diameters of the colonies of P. aeruginosa were measured after 24 h. ELISA kit, orcinol method, and elastin-Congo red assay were used to quantify the virulence factors. Biofilm formation was observed by staining with Alexa Fluor(r) 647 conjugate of concanavalin A (Con A). Virulence-regulated genes were determined by quantitative RT-PCR. Results. As compared with the control group, growth of P. aeruginosa was inhibited by negative pressure. The colony size under negative pressure was significantly smaller in the experimental group than that in the controls (p < 0.01). Besides, reductions in the total amount of virulence factors were observed in the negative pressure group, including exotoxin A, rhamnolipid, and elastase. RT-PCR results revealed a significant inhibition in the expression level of virulence-regulated genes. Conclusion. Negative pressure could significantly inhibit the growth of P. aeruginosa. It led to a decrease in the virulence factor secretion, biofilm formation, and a reduction in the expression level of virulence-regulated genes. PMID- 28074189 TI - Ethnobotanical Research at the Kutuku Scientific Station, Morona-Santiago, Ecuador. AB - This work features the results of an ethnobotanical study on the uses of medicinal plants by the inhabitants of the region near to the Kutuku Scientific Station of Universidad Politecnica Salesiana, located in the Morona-Santiago province, southeast of Ecuador. In the surroundings of the station, one ethnic group, the Shuar, has been identified. The survey hereafter reports a total of 131 plant species, with 73 different therapeutic uses. PMID- 28074190 TI - Influence of Aluminium and EGCG on Fibrillation and Aggregation of Human Islet Amyloid Polypeptide. AB - The abnormal fibrillation of human islet amyloid polypeptide (hIAPP) has been implicated in the development of type II diabetes. Aluminum is known to trigger the structural transformation of many amyloid proteins and induce the formation of toxic aggregate species. The (-)-epigallocatechin gallate (EGCG) is considered capable of binding both metal ions and amyloid proteins with inhibitory effect on the fibrillation of amyloid proteins. However, the effect of Al(III)/EGCG complex on hIAPP fibrillation is unclear. In the present work, we sought to view insight into the structures and properties of Al(III) and EGCG complex by using spectroscopic experiments and quantum chemical calculations and also investigated the influence of Al(III) and EGCG on hIAPP fibrillation and aggregation as well as their combined interference on this process. Our studies demonstrated that Al(III) could promote fibrillation and aggregation of hIAPP, while EGCG could inhibit the fibrillation of hIAPP and lead to the formation of hIAPP amorphous aggregates instead of the ordered fibrils. Furthermore, we proved that the Al(III)/EGCG complex in molar ratio of 1 : 1 as Al(EGCG)(H2O)2 could inhibit the hIAPP fibrillation more effectively than EGCG alone. The results provide the invaluable reference for the new drug development to treat type II diabetes. PMID- 28074191 TI - Repeated Long-Term DT Application in the DEREG Mouse Induces a Neutralizing Anti DT Antibody Response. AB - Regulatory T (Tregs) cells play an important role in mediating tolerance to self antigens but can also mediate detrimental tolerance to tumours and pathogens in a Foxp3-dependent manner. Genetic tools exploiting the foxp3 locus including bacterial artificial chromosome- (BAC-) transgenic DEpletion of REGulatory T cells (DEREG) mice have provided essential information on Treg biology and the potential therapeutic modulation of tolerance. In DEREG mice, Foxp3+ Tregs selectively express enhanced green fluorescent protein (eGFP) and diphtheria toxin (DT) receptor, allowing for the specific depletion of Tregs through DT administration. We here provide a detailed overview about an important consideration that long-term administration of DT induces a humoral immune response with an appropriate production of anti-DT antibodies that can inactivate DT and thus abrogate its effect in the DEREG mouse. Additionally, we showed that anti-DT mouse serum partially neutralized DT-induced Foxp3 inhibition. PMID- 28074192 TI - Monocyte-Derived Macrophages Are Impaired in Myelodysplastic Syndrome. AB - Background. The myelodysplastic syndrome (MDS) comprises a group of clonal hematopoietic stem cell diseases characterized by cytopenia, dysplasia in one or more of the major myeloid lineages, ineffective hematopoiesis, and increased risk of development of acute myeloid leukemia (AML). Macrophages are innate immune cells that ingest and degrade abnormal cells, debris, and foreign material and orchestrate inflammatory processes. We analyzed the role of macrophages from MDS patients in vitro. Methods. Macrophages were induced from peripheral blood of patients with MDS via granulocyte macrophage colony-stimulating factor (GM-CSF). Phagocytic capacity of macrophages was measured with carboxyfluorescein succinimidyl ester and fluorescent microspheres. CD206 and signal regulatory protein alpha (SIRPalpha) on macrophages were detected by flow cytometry. Inducible nitric oxide synthase (iNOS) was measured by ELISA method. Results. Compared with normal control group, the number of monocytes increased in MDS patients. However, the monocytes showed impaired ability to induce macrophages and the number of macrophages induced from MDS samples was lower. Further, we demonstrated that the ex vivo phagocytic function of macrophages from MDS patients was impaired and levels of reorganization receptors CD206 and SIRPalpha were lower. Levels of iNOS secreted by macrophages in MDS were increased. Conclusions. Monocyte-derived macrophages are impaired in myelodysplastic syndromes. PMID- 28074195 TI - Harnessing the advantages of hard and soft colloids by the use of core-shell particles as interfacial stabilizers. AB - The ability of colloidal particles to penetrate fluid interfaces is a crucial factor in the preparation of particle stabilized disperse systems such as foams and emulsions. For hard micron-sized particles the insertion into fluid interfaces requires substantial energy input, but soft particles are known to adsorb spontaneously. Particle hardness, however, may also affect foam and emulsion stability. The high compliance of soft particles may compromise their ability to withstand the lateral compression associated with disproportionation. Hence, particles which can spontaneously adsorb onto fluid interfaces, and yet depict low compliance may be ideal as interfacial stabilizers. In the present work, we prepared core-shell particles comprising a hard, polystyrene core and a soft poly(N-isopropylacrylamide) based shell. We found that such core-shell particles adsorb spontaneously onto various fluid interfaces. The absence of a pronounced energy barrier for interfacial adsorption allowed the facile preparation of particle-stabilized bubbles as well as emulsion droplets. For bubbles, the stability was better than that of bubbles stabilized by entirely soft particles, but disproportionation was not stopped completely. Emulsion droplets, in contrast, showed excellent stability against both coalescence and disproportionation. Lateral compression of core-shell particles due to disproportionation was clearly limited by the presence of the polystyrene core, leading to long-lasting stability. For emulsions, we even observed non-spherical droplets, indicating a negligible Laplace pressure. Our results indicate that core-shell particles comprising a hard core and a soft shell combine the advantageous properties of hard and soft particles, namely spontaneous adsorption and limited compliance, and can therefore be superior materials for the preparation of particle-stabilized dispersions. PMID- 28074193 TI - Serum 25-Hydroxyvitamin D3 and BAFF Levels Are Associated with Disease Activity in Primary Sjogren's Syndrome. AB - The study investigated the association between disease activity and serum 25 hydroxyvitamin D3 (25(OH)-D3), B cell activation of the tumor necrosis factor family (BAFF), or beta2 microglobulin in patients with primary Sjogren's syndrome (SS). Sixty-nine primary SS patients and 22 sicca control patients were included in the study. Disease activity was measured with EULAR Sjogren's syndrome disease activity index (ESSDAI). Serum levels of 25(OH)-D3 and beta2 microglobulin were measured by radioimmunoassay and BAFF was measured by an enzyme-linked immunosorbent assay. Serum levels of 25(OH)-D3 were significantly lower in SS patients compared to the sicca controls (p = 0.036). Serum levels of BAFF tended to be higher (p = 0.225) and those of beta2 microglobulin were significantly higher in patients with SS than in sicca controls (p = 0.023). In univariate regression analyses, ESSDAI was significantly associated with serum levels of 25(OH)-D3, BAFF, and beta2 microglobulin. After stepwise backward multivariate linear regression analyses including age and acute phase reactants, ESSDAI was associated with 25(OH)-D3 (beta = -0.042, p = 0.015) and BAFF (beta = 0.001, p = 0.015) in SS patients. In SS patients, ESSDAI is negatively associated with serum levels of 25(OH)-D3 and positively associated with BAFF. PMID- 28074196 TI - Ionic Flash NanoPrecipitation (iFNP) for the facile, one-step synthesis of inorganic-organic hybrid nanoparticles in water. AB - Ionic Flash NanoPrecipitation (iFNP) was evaluated as a novel method for the synthesis of inorganic-organic hybrid nanomaterials and proved to be remarkably effective, fast and practical. To prove the potential of iFNP, various nanostructured GdPO4-based materials of biomedical imaging relevance were easily prepared in a one-step, tunable and highly controlled manner using only water as solvent. PMID- 28074194 TI - Returning for HIV Test Results: A Systematic Review of Barriers and Facilitators. AB - This systematic review aims to identify factors that facilitate or hinder the return for HIV test results. Four electronic databases were searched. Two independent reviewers selected eligible publications based on inclusion/exclusion criteria. Quantitative studies published since 1985 were included. Thirty-six studies were included in the final review. Individual level barriers included sociodemographic characteristics, such as being a male, of young age and low education level, risk behaviours such as injecting drugs, having multiple sexual partners, and psychosocial factors. Older age, higher education level, being a woman, having high self-esteem, having coping skills, and holding insurance coverage were identified as facilitators. Interpersonal barriers and facilitators were linked to risk behaviours of sexual partners. Contextual barriers included essentially the HIV testing center and its characteristics. This review identified the most important factors that need to be addressed to ensure that people return for their HIV test results. PMID- 28074197 TI - Azido- and amido-substituted gallium hydrides supported by N-heterocyclic carbenes. AB - Despite recent advances in main group N-heterocyclic carbene (NHC) coordination chemistry, gallium hydrides remain, in large part, an unexplored area of research. In this paper we outline efficient routes to azide- and amido functionalized gallium hydrides such as NHC.GaH2N3 and NHC.GaH2N(SiMe3)2 and explore these species as potential precursors to HGaNH complexes and bulk gallium nitride (GaN). PMID- 28074198 TI - Synergetic effect in heterogeneous acid catalysis by a porous ionic crystal based on Al(iii)-salphen and polyoxometalate. AB - A porous ionic crystal is synthesized with a cationic Al(iii)-salphen complex (Al(iii)-salphen) and a alpha-Keggin-type polyoxometalate (POM). The compound possesses stable three dimensional porous structure and shows high activity as a heterogeneous catalyst in pinacol rearrangement, which is a typical acid reaction. Notably, Al(iii)-salphen, POM, and a physical mixture of the two components are much less active, suggesting a synergetic effect of Al(iii) salphen and POM in a porous framework. PMID- 28074199 TI - Topological phase transformations and intrinsic size effects in ferroelectric nanoparticles. AB - Composite materials comprised of ferroelectric nanoparticles in a dielectric matrix are being actively investigated for a variety of functional properties attractive for a wide range of novel electronic and energy harvesting devices. However, the dependence of these functionalities on shapes, sizes, orientation and mutual arrangement of ferroelectric particles is currently not fully understood. In this study, we utilize a time-dependent Ginzburg-Landau approach combined with coupled-physics finite-element-method based simulations to elucidate the behavior of polarization in isolated spherical PbTiO3 or BaTiO3 nanoparticles embedded in a dielectric medium, including air. The equilibrium polarization topology is strongly affected by particle diameter, as well as the choice of inclusion and matrix materials, with monodomain, vortex-like and multidomain patterns emerging for various combinations of size and materials parameters. This leads to radically different polarization vs. electric field responses, resulting in highly tunable size-dependent dielectric properties that should be possible to observe experimentally. Our calculations show that there is a critical particle size below which ferroelectricity vanishes. For the PbTiO3 particle, this size is 2 and 3.4 nm, respectively, for high- and low-permittivity media. For the BaTiO3 particle, it is ~3.6 nm regardless of the medium dielectric strength. PMID- 28074200 TI - Hydrophenoxylation of internal alkynes catalysed with a heterobimetallic Cu NHC/Au-NHC system. AB - A straightforward method for the hydrophenoxylation of internal alkynes, using N heterocyclic carbene-based copper(i) and gold(i) complexes, is described. The heterobimetallic catalytic system proceeds via dual activation of the substrates to afford the desired vinylether derivatives. This methodology is shown to be highly efficient and tolerates a wide range of substituted phenols and alkynes. PMID- 28074201 TI - Metabolic stability of cells for extended metabolomical measurements using NMR. A comparison between lysed and additionally heat inactivated cells. AB - NMR measurements for metabolic characterization of biological samples like cells, biopsies or plasma, may take several hours for advanced methods. Preanalytical issues, such as sample preparation and stability over the measurement time, may have a high impact on metabolite content, and potentially lead to misinterpretation. The aim of this study was therefore to investigate by 1H HR MAS NMR the impact of different cell handling preparation protocols on the stability of the cell metabolite content over the measurement time. For this purpose, the metabolite content of fibroblasts and adrenal cells were measured at different time points after lysis and after additional heating. Interestingly the results showed similar metabolite concentrations between lysed and lysed-heated cells at the beginning of the measurement, but increasing differences after some hours of measurement. In lysed cells, metabolism was ongoing, producing metabolite changes over time, contrary to a stable metabolite content of the lysed-heated cells. These results were confirmed in both fibroblasts and adrenal cells. Therefore, in order to minimize metabolite content modifications over the measurement time, it is suggested to use cell lysis in combination with heat inactivation for extended HR-MAS NMR measurements. PMID- 28074202 TI - An Ising iron(ii) chain exhibits a large finite-size energy barrier and "hard" magnetic behaviour. AB - One-dimensional spin chains featuring strong axial anisotropic magnetism are promising candidates for isolatable and miniatured information storage materials, the so-called single-chain magnets (SCMs). Here we show a mixed azido/carboxylato bridged metamagnetic iron(ii) chain [Fe(N3)2(4-mpc)]n (4-mpc = N-methylpyridinium 4-carboxylate) with a large energy barrier of 150 K, a large remnant magnetization (1.55Nbeta) and coercivity (1.7 T at 2 K) for homo-spin SCMs. Heat capacity and Mossbauer spectroscopy studies corroborate the intrinsic nature of SCM behavior regardless of weak interchain magnetic interactions, which lead to the coexistence of metamagnetism but not long-range magnetic ordering. Moreover, detailed magnetic investigations indicate that the system is not only within the "Ising limit" but also in the "finite-size" regime. PMID- 28074203 TI - Multitopic ligand directed assembly of low-dimensional metal-chalcogenide organic frameworks. AB - Despite tremendous progress in metal-organic frameworks, only limited success has been achieved with metal-chalcogenide organic frameworks. Metal-chalcogenide organic frameworks are desirable because they offer a promising route towards tunable semiconducting porous frameworks. Here, four novel semiconducting chalcogenide-organic hybrid compounds have been synthesized through a solvothermal method. Multitopic organic molecules, i.e., 1,2-di-(4 pyridyl)ethylene (L1), 1,3,5-tris(4-pyridyl-trans-ethenyl)benzene (L2) and tetrakis(4-pyridyloxymethylene)methane (L3), have been used as linkers to assemble Zn(SAr)2 or Zn2(SAr)4 units to generate different patterns of spatial organizations. Single-crystal structural analyses indicate that compounds NTU-2, NTU-3 and NTU-4 possess two-dimensional layer structures, while compound NTU-1 adopts a one-dimensional coordination framework (NTU-n, where n is the number related to a specific structure). The diffuse-reflectance spectra demonstrate that these four compounds possess indirect bandgaps and their tunable bandgaps are correlated with their compositions and crystal structures. PMID- 28074204 TI - Surfactants adsorption on crossing stripes and steps. AB - Using coarse-grained dissipative particle dynamics (DPD) simulations, we systematically study the effect of surface heterogeneity on surfactant adsorption. Here we investigate the adsorption and aggregation of surfactants on hydrophobic stripes crossing each other perpendicularly (i.e., crossing stripes) and on hydrophobic steps. The results are compared with those obtained for isolated stripes. We find that on crossing stripes of moderate stripe widths (e.g., L = 0.61LS, 1.22LS and 1.83LS, where LS is the length of one surfactant molecule) the crossing region hinders the formation of defect-free adsorbed surfactant structures. By increasing the stripe width and/or by increasing the length of one of the two perpendicularly crossing stripes (i.e., lowering the surface density of defects/intersections), the crossing region is found to have a weaker effect on the features of the adsorbed structures. Regarding surfactant adsorption on steps, our simulation results show that the self-assembled aggregates can be stretched along the step corner, and the resultant elastic deformation can hinder adsorption. This qualitative observation can facilitate a description of surfactant adsorption that takes into consideration also the deformation of the self-assembled film. As suggested by such a general model, increasing the convex angle of the step, increasing the size of the surfactant head groups, and changing other physical parameters can reduce the elastic energy penalty, and yield larger amounts of surfactants adsorbed. The results presented could assist in understanding and sometimes predicting surfactant adsorption on heterogeneous surfaces, suggest methods to formulate surfactant mixtures to control surface coverage on heterogeneous surfaces, and perhaps facilitate new methods for the fabrication of nano-structured surfaces. PMID- 28074205 TI - Transport and adsorption under liquid flow: the role of pore geometry. AB - We study here the interplay between transport and adsorption in porous systems with complex geometries under fluid flow. Using a lattice Boltzmann scheme extended to take into account the adsorption at solid/fluid interfaces, we investigate the influence of pore geometry and internal surface roughness on the efficiency of fluid flow and the adsorption of molecular species inside the pore space. We show how the occurrence of roughness on pore walls acts effectively as a modification of the solid/fluid boundary conditions, introducing slippage at the interface. We then compare three common pore geometries, namely honeycomb pores, inverse opal, and materials produced by spinodal decomposition. Finally, we quantify the influence of those three geometries on fluid transport and tracer adsorption. This opens perspectives for the optimization of materials' geometries for applications in dynamic adsorption under fluid flow. PMID- 28074206 TI - Synthesis, reactivity and characterization of Pt(ii) complexes with N,N' chelating ligands; structure and dimethylsulfoxide reactivity relationship. AB - Platinum(ii) complexes of the formula PtLCl2 [L = 2-(2'-pyridyl)quinoxaline, (pqx) (1), 2,(2'-pyridyl)benzo[g]quinoxaline, (pbqx) (3) and 2,(2' pyridyl)quinoline, (pqn) (5)] were synthesized and characterized by spectroscopic and X-ray diffraction methods. Also, monodentate coordination of the ligands pqx and pbqx formed the complexes trans-Pt(DMSO)pqxCl2 (2) and trans-Pt(DMSO)pbqxCl2 (4) as it is indicated from X-ray crystal structure and NMR studies. The reaction of the complexes (1), (3) and (5) with DMSO-d6 revealed a ligand-release solvolysis, which was studied by means of NMR techniques. Correlation between the crystal structures of (1), (3), and (5) and the kinetic or thermodynamic parameters of the solvolysis reactions showed that the tendency of the ligands pqx, pbqx, and pqn to return to the anti-configuration in addition to their ability to form non-classical H-bonds are crucial factors for the ligand-release solvolysis. Instantaneous DMSO-d6 solvolysis for the complexes (1) and (3) and slow kinetics solvolysis for (5) (k = 10-4 +/- 6.4 * 10-6 s-1) reflect their structural differences in ligand planarity. Based on NMR techniques a two-step mechanism of the chelate ring opening was suggested with equilibrium constants of the overall reaction at 298 K, Keq = 4.1 +/- 0.2 * 10-4 M-1 (1) and Keq = 1.7 +/- 0.2 * 10-4 M-1 (2). PMID- 28074207 TI - Plutonium segregation in glassy aerodynamic fallout from a nuclear weapon test. AB - This study combines electron microscopy equipped with energy dispersive spectroscopy to probe major element composition and autoradiography to map plutonium in order to examine the spatial relationships between plutonium and fallout composition in aerodynamic glassy fallout from a nuclear weapon test. A sample set of 48 individual fallout specimens were interrogated to reveal that the significant chemical heterogeneity of this sample set could be described compositionally with a relatively small number of compositional endmembers. Furthermore, high concentrations of plutonium were never associated with several endmember compositions and concentrated with the so-called mafic glass endmember. This result suggests that it is the physical characteristics of the compositional endmembers and not the chemical characteristics of the individual component elements that govern the un-burnt plutonium distribution with respect to major element composition in fallout. PMID- 28074208 TI - Optomagnetic detection of DNA triplex nanoswitches. AB - We report on optomagnetic dose-dependent detection of DNA triplex-mediated and pH switchable clusters of functionalised magnetic nanoparticles. PMID- 28074209 TI - Cu(i) and Ag(i) complex formation with the hydrophilic phosphine 1,3,5-triaza-7 phosphadamantane in different ionic media. How to estimate the effect of a complexing medium. AB - The complexes of Cu(i) and Ag(i) with 1,3,5-triaza-7-phosphadamantane (PTA) are currently studied for their potential clinical use as anticancer agents, given the cytotoxicity they exhibited in vitro towards a panel of several human tumor cell lines. These metallodrugs are prepared in the form of [M(PTA)4]+ (M = Cu+, Ag+) compounds and dissolved in physiological solution for their administration. However, the nature of the species involved in the cytotoxic activity of the compounds is often unknown. In the present work, the thermodynamics of formation of the complexes of Cu(i) and Ag(i) with PTA in aqueous solution is investigated by means of potentiometric, spectrophotometric and microcalorimetric methods. The results show that both metal(i) ions form up to four successive complexes with PTA. The formation of Ag(i) complexes is studied at 298.15 K in 0.1 M NaNO3 whereas the formation of the Cu(i) one is studied in 1 M NaCl, where Cu(i) is stabilized by the formation of three successive chloro-complexes. Therefore, for this latter system, conditional stability constants and thermodynamic data are obtained. To estimate the affinity of Cu(i) for PTA in the absence of chloride, Density Functional Theory (DFT) calculations have been done to obtain the stoichiometry and the relative stability of the possible Cu/PTA/Cl species. Results indicate that one chloride ion is involved in the formation of the first two complexes of Cu(i) ([CuCl(PTA)] and [CuCl(PTA)2]) whereas it is absent in the successive ones ([Cu(PTA)3]+ and [Cu(PTA)4]+). The combination of DFT results and thermodynamic experimental data has been used to estimate the stability constants of the four [Cu(PTA)n]+ (n = 1-4) complexes in an ideal non-complexing medium. The calculated stability constants are higher than the corresponding conditional values and show that PTA prefers Cu(i) to the Ag(i) ion. The approach used here to estimate the hidden role of chloride on the conditional stability constants of Cu(i) complexes may be applied to any Cu(i)/ligand system, provided that the stoichiometry of the species in NaCl solution is known. The speciation for the two systems shows that the [M(PTA)4]+ (M = Cu+, Ag+) complexes present in the metallodrugs are dissociated into lower stoichiometry species when diluted to the micromolar concentration range, typical of the in vitro biological testing. Accordingly, [Cu(PTA)2]+, [Cu(PTA)3]+ and [Ag(PTA)2]+ are predicted to be the species actually involved in the cytotoxic activity of these compounds. PMID- 28074210 TI - Diagnostic value of additional 68Ga-PSMA-PET before 223Ra-dichloride therapy in patients with metastatic prostate carcinoma. AB - PURPOSE: Medical imaging plays an important role in selecting patients with metastatic castration-resistant prostate cancer for 223Ra-dichloride therapy of bone metastases. The purpose of this study was to investigate whether 68Ga-PSMA PET has incremental value over conventional imaging for selecting patients suitable for 223Ra-dichloride therapy. METHODS: In 27 consecutive patients referred for 223Ra-dichloride therapy additional 68Ga-PSMA-PET/CT was performed and tracer distribution was evaluated systematically with respect to the detection of visceral metastases and bone metastases with inadequate uptake on bone scintigraphy. RESULTS: In 4 patients (15 %) 68Ga-PSMA-PET revealed previously unknown visceral metastases (3 liver, 1 adrenal gland), which changed the therapeutic decision in 2 cases. PET revealed more extended tumour involvement in the bone compared to bone scintigraphy in 9 patients (33 %). In 3 of these, the mismatch was extensive enough to question suitability for 223Ra dichloride therapy. CONCLUSIONS: Additional 68Ga-PSMA-PET as a gatekeeper between conventional staging and 223Ra-dichloride therapy can provide valuable additional information with regard to visceral metastases and tumour manifestations without adequate bone mineral turnover. It may lead to a change in therapeutic management in a significant number of patients and should therefore be considered in future clinical trials. PMID- 28074211 TI - Safe Practices for Copy and Paste in the EHR. Systematic Review, Recommendations, and Novel Model for Health IT Collaboration. AB - BACKGROUND: Copy and paste functionality can support efficiency during clinical documentation, but may promote inaccurate documentation with risks for patient safety. The Partnership for Health IT Patient Safety was formed to gather data, conduct analysis, educate, and disseminate safe practices for safer care using health information technology (IT). OBJECTIVE: To characterize copy and paste events in clinical care, identify safety risks, describe existing evidence, and develop implementable practice recommendations for safe reuse of information via copy and paste. METHODS: The Partnership 1) reviewed 12 reported safety events, 2) solicited expert input, and 3) performed a systematic literature review (2010 to January 2015) to identify publications addressing frequency, perceptions/attitudes, patient safety risks, existing guidance, and potential interventions and mitigation practices. RESULTS: The literature review identified 51 publications that were included. Overall, 66% to 90% of clinicians routinely use copy and paste. One study of diagnostic errors found that copy and paste led to 2.6% of errors in which a missed diagnosis required patients to seek additional unplanned care. Copy and paste can promote note bloat, internal inconsistencies, error propagation, and documentation in the wrong patient chart. Existing guidance identified specific responsibilities for authors, organizations, and electronic health record (EHR) developers. Analysis of 12 reported copy and paste safety events was congruent with problems identified from the literature review. CONCLUSION: Despite regular copy and paste use, evidence regarding direct risk to patient safety remains sparse, with significant study limitations. Drawing on existing evidence, the Partnership developed four safe practice recommendations: 1) Provide a mechanism to make copy and paste material easily identifiable; 2) Ensure the provenance of copy and paste material is readily available; 3) Ensure adequate staff training and education; 4) Ensure copy and paste practices are regularly monitored, measured, and assessed. PMID- 28074212 TI - [Specific dermatoses of pregnancy]. AB - The specific dermatoses of pregnancy represent a heterogeneous group of inflammatory skin diseases related to pregnancy and/or the postpartum period. A clinically relevant classification has been well established over the past 10 years and includes pemphigoid gestationis, polymorphic eruption of pregnancy, intrahepatic cholestasis of pregnancy, and atopic eruption of pregnancy. The hallmark of all four entities is severe pruritus that is accompanied by characteristic skin changes. While some of these dermatoses are distressing only to the mother because of pruritus, others may be associated with significant fetal risks. Early diagnosis and prompt treatment are therefore essential. In this review, we discuss in detail pemphigoid gestationis, polymorphic and atopic eruptions of pregnancy whereas intrahepatic cholestasis of pregnancy is discussed in a separate article (Kremer A, Stander S, DOI 10.1007/s00105-016-3923-y ). Furthermore, we present a helpful algorithm for diagnosis and management of pruritus in pregnancy. PMID- 28074213 TI - [Intrahepatic cholestasis of pregnancy : Rare but important]. AB - Intrahepatic cholestasis of pregnancy (ICP) is a liver-specific disorder occurring in approximately 0.5-2.0% of all pregnancies with a considerable variation in certain ethnic groups. ICP usually runs a benign course for the mother and is characterized by maternal pruritus mainly in the third trimester, elevated transaminases and fasting total serum bile salts and increased fetal adverse events. The etiology of ICP is only partially understood but seems to be multifactorial. Cholestasis-inducing effects of certain female sex hormones and their metabolites play an important role in genetically susceptible women. The mechanisms resulting in fetal complications such as spontaneous preterm labour, antepartum passage of meconium, asphyxia events, still birth and fetal death are not well understood. Certain sulfated progesterone metabolites are likely to play a role in the pathogenesis of pruritus in ICP. In contrast to pregnancy-related dermatoses, pruritus does not present with primary skin alterations. However, intense scratching may cause secondary skin changes such as abrasions, excoriations and sometimes prurigo nodularis. Treatment is based on ursodeoxycholate treatment to reduce pruritus and hepatic impairment as well as elective delivery between gestation week 37-38 to pre-empt potential stillbirths. This article reviews clinical symptoms, diagnosis, treatment and in particular pathogenesis of pruritus in ICP. PMID- 28074214 TI - [Buschke-Lowenstein tumors]. AB - BACKGROUND: A giant condyloma acuminatum which shows destructive growth but lacking invasion is designated as a Buschke-Lowenstein tumor (BLT). OBJECTIVES: Classification of the BLT and therapeutic guidelines are provided. MATERIALS AND METHODS: A MEDLINE literature search from 2006-2016 was performed. RESULTS: Induction through low-risk mucosotropic human papillomavirus (HPV) infection separates BLT from verrucous carcinoma. In the last 10 years, slightly more than 100 new cases have been described. Invasion as a true sign of malignancy was described in 12% of cases. HIV infection was observed in 14%. As invasion often occurs only focally and may only be detected after complete resection, BLT must be treated and considered as a low grade in situ epithelial cancer that evolves from condylomata acuminata. Diagnosis is confirmed by HPV detection and typical histology. CT scans are recommended to rule out deeper invasion. Organ preservation surgery remains the recommended therapy. CONCLUSIONS: Buschke Lowenstein tumors represent low grade epithelial in situ carcinomas which evolved from condylomata acuminata. Focal invasion is frequent but metastases occur only rarely. Organ preservation surgery is recommended. PMID- 28074215 TI - [Management of dysphagia in acute stroke : A prospective study for validation of current recommendations]. AB - BACKGROUND: The German expert recommendations on the management of dysphagia in patients after acute stroke suggest an algorithm for clinical and technical investigations to identify patients at risk for aspiration and thus reduce the rate of aspiration pneumonia. The effectiveness of this algorithm has, however, not yet been prospectively validated . METHODS: In this study 144 consecutive stroke patients were assessed by a full bedside swallowing assessment including the screening procedures of standardized swallowing assessment (SSA) and 2 out of 6. Flexible endoscopic evaluation of swallowing (FEES) was performed in all patients. RESULTS: Aspiration was diagnosed in 25 patients (17.4%) by FEES. The SSA predicted aspiration with a sensitivity of 76% and a specificity of 55.5% and the 2 out of 6 screening with a sensitivity of 68.0% and a specificity of 61.0%. Of the patients 7 with negative screening for 2 out of 6 and 6 patients with negative SSA showed silent aspiration with the penetration aspiration scale (PAS 8) during FEES (28% of all patients with aspiration). Significant predictors for aspiration were dysarthria, dysphonia, abnormal volitional cough and cough after swallowing water; however, in multivariable analysis only dysarthria and cough after swallowing water were identified as independent predictors for aspiration. The rate of aspiration pneumonia was 2.8%. CONCLUSION: Clinical screening alone is not sufficient to identify patients at risk for aspiration pneumonia. The FEES should be used at a low threshold in cases of severe stroke and minor clinical abnormalities, especially concerning isolated dysarthria and cough after swallowing water; therefore, current recommendations should be correspondingly modified. PMID- 28074216 TI - Adenosine effectively restores endotoxin-induced inhibition of human neutrophil chemotaxis via A1 receptor-p38 pathway. AB - Neutrophil chemotaxis plays an essential role in recruiting neutrophils to sites of inflammation. Neutrophil chemotaxis is suppressed both after exposure to lipopolysaccharide (LPS) in vitro and during clinical and experimental endotoxemia, leading to serious consequences. Adenosine (ADO) is a potent anti inflammatory agent that acts on a variety of neutrophil functions. However, its effects on human neutrophil chemotaxis during infection have been less well characterized. In the present study, we investigated the effect of ADO and its receptor-specific antagonist and agonist on neutrophil chemotaxis in an in vitro LPS-stimulated model. The results showed that increasing the concentration of ADO effectively restored the LPS-inhibited neutrophil chemotaxis to IL-8. A similar phenomenon occurred after intervention with a selective A1 receptor agonist but not with a selective antagonist. Pre-treatment with cAMP antagonist failed to restore LPS-inhibited chemotaxis. Furthermore, protein array and western blot analysis showed that the activation of A1 receptor significantly decreased LPS induced p38 MAPK phosphorylation. However, the surface expression of the A1 receptor in LPS-stimulated neutrophils was not significantly changed. Taken together, these data indicated that ADO restored the LPS-inhibited chemotaxis via the A1 receptor, which downregulated the phosphorylation level of p38 MAPK, making this a promising new therapeutic strategy for infectious diseases. PMID- 28074217 TI - [Nutrition in dementia]. AB - BACKGROUND: In the course of dementia sooner or later nutritional problems appear, and the question arises which interventions are effective in ensuring adequate nutrition and thus may contribute to the maintenance of health, functionality and independence. OBJECTIVE: This overview presents the state of knowledge regarding nutrition in dementia. METHODS: This work is based on the present guidelines of the European Society for Clinical Nutrition and Metabolism (ESPEN) on nutrition in dementia, which systematically investigated relevant available evidence. RESULTS: Nutritional interventions should be an integral component of dementia treatment. They should be based on a routine screening for malnutrition, followed by assessment when appropriate, and periodic body weight control in order to recognize problems early. In all stages of dementia, adequate oral nutrition can be supported by attractive, high-quality food according to individual needs served in a pleasant ambience, by adequate nursing support and treatment of underlying causes of malnutrition. If nutritional requirements are not met by usual or enriched food, oral nutritional supplements are recommended in order to improve nutritional status. Beneficial effects of energy and/or nutrient supplementation on cognitive abilities are however not proven. Artificial nutrition is only rarely indicated, namely after careful weighing of individual benefits and risks considering the patients (presumed) will. In patients with advanced dementia and in the terminal phase of life artificial nutrition is not recommended. PMID- 28074218 TI - [Autoimmune diseases of the thyroid gland]. AB - Autoimmune diseases of the thyroid gland are considered to be the most frequent cause of thyroid gland disorders. Autoimmune thyroid diseases consist of two subgroups: autoimmune thyroiditis (AIT) and Graves' disease. The AIT is the most common human autoimmune disease. Infiltration of the thyroid gland with cytotoxic T-cells can lead to an initial thyrotoxicosis und during the course to hypothyroidism due to destruction of the thyroid gland. Substitution with Levothyroxine is indicated for manifest hypothyroidism and subclinical hypothyroidism with increased thyroid antibodies with the intention of normalizing the serum thyroid stimulating hormone (TSH). Graves' disease is characterized by the appearance of stimulating TSH receptor antibodies leading to hyperthyroidism. Endocrine ophthalmopathy may also occur. Ablative therapy with radioiodine therapy or thyroidectomy is administered to patients with Graves' disease without remission after at least 1 year of antithyroid drug therapy. PMID- 28074219 TI - Bioremediation of mercury: not properly exploited in contaminated soils! AB - Contamination of land and water caused by heavy metal mercury (Hg) poses a serious threat to biota worldwide. The seriousness of toxicity of this neurotoxin is characterized by its ability to augment in food chains and bind to thiol groups in living tissue. Therefore, different remediation approaches have been implemented to rehabilitate Hg-contaminated sites. Bioremediation is considered as cheaper and greener technology than the conventional physico-chemical means. Large-scale use of Hg-volatilizing bacteria are used to clean up Hg-contaminated waters, but there is no such approach to remediate Hg-contaminated soils. This review focuses on recent uses of Hg-resistant bacteria in bioremediation of mercury-contaminated sites, limitation and advantages of this approach, and identifies the gaps in existing research. PMID- 28074220 TI - Biology, dynamics, and applications of transposable elements in basidiomycete fungi. AB - The phylum Basidiomycota includes filamentous fungi and yeast species with different ecological and genomic characteristics. Transposable elements (TEs) are abundant components of most eukaryotic genomes, and their transition from being genomic parasites to key drivers of genomic architecture, functionality, and evolution is a subject receiving much attention. In light of the abundant genomic information released during the last decade, the aims of this mini-review are to discuss the dynamics and impact of TEs in basidiomycete fungi. To do this, we surveyed and explored data from 75 genomes, which encompass the phylogenetic diversity of the phylum Basidiomycota. We describe annotation approaches and analyze TE distribution in the context of species phylogeny and genome size. Further, we review the most relevant literature about the role of TEs in species lifestyle, their impact on genome architecture and functionality, and the defense mechanisms evolved to control their proliferation. Finally, we discuss potential applications of TEs that can drive future innovations in fungal research. PMID- 28074221 TI - Exploring the thermostable properties of halohydrin dehalogenase from Agrobacterium radiobacter AD1 by a combinatorial directed evolution strategy. AB - As a crucial factor for biocatalysts, protein thermostability often arises from a combination of factors that are often difficult to rationalize. In this work, the thermostable nature of halohydrin dehalogenase from Agrobacterium radiobacter AD1 (HheC) was systematically explored using a combinatorial directed evolution approach. For this, a mutagenesis library of HheC mutants was first constructed using error-prone PCR with low mutagenesis frequency. After screening approximately 2000 colonies, six mutants with eight mutation sites were obtained. Those mutation sites were subsequently combined by adopting several rounds of iterative saturation mutagenesis (ISM) approach. After four rounds of saturation mutagenesis, one best mutant ISM-4 with a 3400-fold improvement in half-life (t 1/2) inactivation at 65 degrees C, 18 degrees C increase in apparent T m value, and 20 degrees C increase in optimum temperature was obtained, compared to wild type HheC. To the best of our knowledge, the mutant represents the most thermostable HheC variant reported up to now. Moreover, the mutant was as active as wild-type enzyme for the substrate 1,3-dichloro-2-propanol, and they remained most enantioselectivity of wild-type enzyme in the kinetic resolution of rac-2 chloro-1-phenolethanol, exhibiting a great potential for industrial applications. Our structural investigation highlights that surface loop regions are hot spots for modulating the thermostability of HheC, the residues located at these regions contribute to the thermostability of HheC in a cooperative way, and protein rigidity and oligomeric interface connections contribute to the thermostability of HheC. All of these essential factors could be used for further design of an even more thermostable HheC, which, in turn, could greatly facilitate the application of the enzyme as a biocatalyst. PMID- 28074222 TI - Regulation of membrane fixation and energy production/conversion for adaptation and recovery of ZnO nanoparticle impacted Nitrosomonas europaea. AB - The ZnO nanoparticle (NP) effects on typical ammonia-oxidizing bacteria, Nitrosomonas europaea in a chemostat bioreactor, and the cells' toxicity adaptation and recovery potentials were explored. Hardly any inhibition was observed when the NP concentration was high up to 10 mg/L. The cells exposed to 50 mg/L ZnO NPs displayed time-dependent impairment and recovery potentials in terms of cell density, membrane integrity, nitrite production rate, and ammonia monooxygenase activity. The 6-h NP stress impaired cells were nearly completely restored during a 12-h recovery incubation, while the longer exposure time would cause irretrievable cell damage. Microarray analysis further indicated the transcriptional adaptation of N. europaea to NP stress. The regulations of genes encoding for membrane permeability or osmoprotectant, membrane integrity preservation, and inorganic ion transport during NP exposure and cell recovery revealed the importance of membrane fixation and the associated metabolisms for cells' self-protection and the following recovery from NP stress. The oxidative phosphorylation, carbon assimilation, and tricarboxylic acid (TCA) cycling pathways involved in the cells' antitoxicity activities and would promote the energy production/conversion efficiency for cell recovery. The heavy metal resistance, histidine metabolism, toxin-antitoxin defense, glycolysis, and sulfate reduction pathways were also suggested to participate in the cell detoxication and recovery processes. All these findings provided valuable insights into the mechanisms of cell-mediated ZnO NP cytotoxicity and their potential impacts on wastewater nitrogen removal system. PMID- 28074223 TI - Characterization and mechanism of anti-Aeromonas salmonicida activity of a marine probiotic strain, Bacillus velezensis V4. AB - The bacterium Aeromonas salmonicida is the causative agent of furunculosis, a systemic, ubiquitous disease of fish in the salmon family, characterized by high mortality and morbidity. Probiotics are a promising approach for prevention of furunculosis in aquaculture. A bacterial strain with anti-A. salmonicida properties, Bacillus velezensis V4, was isolated and the mechanisms underlying these properties were investigated. Anti-A. salmonicida compounds present in cell free supernatant of V4 were purified and structurally identified as members of the iturin, macrolactin, and difficidin groups. The compounds contributed jointly to inhibition of A. salmonicida, and the diversity of the compounds was related to the versatility of their mode of action. Addition of the compounds to A. salmonicida cell suspensions reduced cell density. Analyses by confocal microscopy and scanning electron microscopy revealed cell membrane disruption, deletion of cellular content, and cell lysis of A. salmonicida. The V4 genome was sequenced, and gene clusters involved in synthesis of anti-Aeromonas compounds were detected and identified. A possible probiotic effect on growth performance of Oncorhynchus mykiss (rainbow trout) was investigated by addition of 0, 1, and 3 % (v/w) V4. Relative to control, mortality was reduced 27.25 % in the 1 % addition group and 81.86 % in the 3 % addition group. Feed coefficient ratio was reduced 19.49 % and weight gain ratio was increased 71.22 % in the 1 % addition group. Our findings demonstrate that V4 is an effective probiotic strain in O. mykiss and has clear potential for both control of furunculosis and growth promotion of aquaculture animals. PMID- 28074224 TI - ARTP mutation and genome shuffling of ABE fermentation symbiotic system for improvement of butanol production. AB - Butanol is an ideal renewable biofuel which possesses superior fuel properties. Previously, butanol-producing symbiotic system TSH06 was isolated in our lab, with microoxygen tolerance ability. To boost butanol yield for large-scale industrial production, TSH06 was used as parental strain and subjected to atmospheric and room temperature plasma (ARTP) and four rounds of genome shuffling (GS). ARTP mutant and GS strain were co-cultured with facultative anaerobic Bacillus cereus TSH2 to form a symbiotic system with microoxygen tolerance, which was then subjected to fermentation. Relative messenger RNA (mRNA) level of key enzyme gene was measured by real-time PCR. The highest butanol titer of TS4-30 reached 15.63 g/L, which was 34% higher than TSH06 (12.19 g/L). Compared with parental strain, mRNA of acid-forming gene in TS4-30 decreased in acidogenesis phase, while solvent-forming gene increased in solventogenesis phase. This gene expression pattern was consistent with high butanol yield and low acid level in TS4-30. In summary, symbiotic system TS4-30 was obtained with butanol titer improvement and microoxygen tolerance. PMID- 28074225 TI - Recent advances in biotechnological applications of alcohol dehydrogenases. AB - Alcohol dehydrogenases (ADHs), which belong to the oxidoreductase superfamily, catalyze the interconversion between alcohols and aldehydes or ketones with high stereoselectivity under mild conditions. ADHs are widely employed as biocatalysts for the dynamic kinetic resolution of racemic substrates and for the preparation of enantiomerically pure chemicals. This review provides an overview of biotechnological applications for ADHs in the production of chiral pharmaceuticals and fine chemicals. PMID- 28074226 TI - Synergistic effects of host B7-H4 deficiency and gemcitabine treatment on tumor regression and anti-tumor T cell immunity in a mouse model. AB - B7-H4 (B7x/B7S1), a B7 family inhibitor of T cell activity, is expressed in multiple human cancers and correlates with decreased infiltrating lymphocytes and poor prognosis. In murine models, tumor-expressed B7-H4 enhances tumor growth and reduces T cell immunity, and blockade of tumor-B7-H4 rescues T cell activity and lowers tumor burden. This implicates B7-H4 as a target for cancer immunotherapy, yet limits the efficacy of B7-H4 blockade exclusively to patients with B7-H4+ tumors. Given the expression of B7-H4 on host immune cells, we have previously shown that BALB/c mice lacking host B7-H4 have enhanced anti-tumor profiles, yet similar 4T1 tumor growth relative to control. Given that T cell-mediated immunotherapies work best for tumors presenting tumor-associated neoantigens, we further investigated the function of host B7-H4 in the growth of a more immunogenic derivative, 4T1-12B, which is known to elicit strong anti-tumor CD8 T cell responses due to expression of a surrogate tumor-specific antigen, firefly luciferase. Notably, B7-H4 knockout hosts not only mounted greater tumor associated anti-tumor T cell responses, but also displayed reduced tumors. Additionally, B7-H4-deficiency synergized with gemcitabine to further inhibit tumor growth, often leading to tumor eradication and the generation of protective T cell immunity. These findings imply that inhibition of host B7-H4 can enhance anti-tumor T cell immunity in immunogenic cancers, and can be combined with other anti-cancer therapies to further reduce tumor burden regardless of tumor-B7-H4 positivity. PMID- 28074227 TI - Heavy Metals in Liver and Brain of Waterfowl from the Evros Delta, Greece. AB - The concentrations of six heavy metals (cadmium [Cd], chromium [Cr], copper [Cu], manganese [Mn], lead [Pb], and zinc [Zn]) were determined in liver and brain of nine species of waterfowl from the Evros Delta, one of the most important wetlands in Greece, to assess metal contamination and potential risk to waterfowl. Significant differences among species were found for hepatic Cr, Cu, Pb, and Zn; the highest levels of all metals were found in liver of mute swans. Cd increased significantly with age in both organs of wigeon; some differences were also observed between males and females of the same species. Feeding habits were found to significantly affect hepatic Cr, Zn, and Cu concentrations with greater concentrations found in herbivorous than omnivorous species. Several significant positive correlations between metals were detected mainly in liver samples, which were attributable either to their association to metallothioneins or to common routes of exposure of waterfowl. Hepatic and cerebral concentrations of Cd and Pb correlated positively. Given the discrepancies in the thresholds or critical levels of metals in tissues of waterfowl, our survey showed that environmental exposure to increased levels of heavy metals may threaten, at least to some degree, the populations of waterfowl wintering in the Evros Delta. In a small percentage of birds, values indicative of severe adverse effects were determined. Swans that had been found dead showed some of the highest values, whereas accumulation levels did not follow a consistent pattern among the ducks examined. PMID- 28074228 TI - Ventilation-induced lung injury exists in spontaneously breathing patients with acute respiratory failure: Yes. PMID- 28074229 TI - Ventilation-induced lung injury exists in spontaneously breathing patients with acute respiratory failure: We are not sure. PMID- 28074230 TI - Ventilation-induced lung injury exists in spontaneously breathing patients with acute respiratory failure: No. PMID- 28074231 TI - Development of a novel magnetic resonance imaging acquisition and analysis workflow for the quantification of shock wave lithotripsy-induced renal hemorrhagic injury. AB - The current accepted standard for quantifying shock wave lithotripsy (SWL) induced tissue damage is based on morphometric detection of renal hemorrhage in serial tissue sections from fixed kidneys. This methodology is time and labor intensive and is tissue destructive. We have developed a non-destructive magnetic resonance imaging (MRI) method that permits rapid assessment of SWL-induced hemorrhagic lesion volumes in post-mortem kidneys using native tissue contrast to reduce cycle time. Kidneys of anesthetized pigs were targeted with shock waves using the Dornier Compact S lithotripter. Harvested kidneys were then prepared for tissue injury quantification. T1 weighted (T1W) and T2 weighted (T2W) images were acquired on a Siemens 3T Tim Trio MRI scanner. Images were co-registered, normalized, difference (T1W - T2W) images generated, and volumes classified and segmented using a Multi-Spectral Neural Network (MSNN) classifier. Kidneys were then subjected to standard morphometric analysis for the measurement of lesion volumes. Classifications of T1W, T2W and difference image volumes were correlated with morphometric measurements of whole kidney and parenchymal lesion volumes. From these relationships, a mathematical model was developed that allowed predictions of the morphological parenchymal lesion volume from MRI whole kidney lesion volumes. Predictions and morphology were highly correlated (R = 0.9691, n = 20) and described by the relationship y = 0.84x + 0.09, and highly accurate with a sum of squares difference error of 0.79%. MRI and the MSNN classifier provide a semi-automated segmentation approach, which provide a rapid and reliable means to quantify renal injury lesion volumes due to SWL. PMID- 28074232 TI - Vasoactive actions of nitroxyl (HNO) are preserved in resistance arteries in diabetes. AB - Endothelial dysfunction is a major risk factor for the vascular complications of diabetes. Increased reactive oxygen species (ROS) generation, a hallmark of diabetes, reduces the bioavailability of endothelial vasodilators, including nitric oxide (NO.). The vascular endothelium also produces the one electron reduced and protonated form of NO., nitroxyl (HNO). Unlike NO., HNO is resistant to scavenging by superoxide anions (.O2?). The fate of HNO in resistance arteries in diabetes is unknown. We tested the hypothesis that the vasodilator actions of endogenous and exogenous HNO are preserved in resistance arteries in diabetes. We investigated the actions of HNO in small arteries from the mesenteric and femoral beds as they exhibit marked differences in endothelial vasodilator function following 8 weeks of streptozotocin (STZ)-induced diabetes mellitus. Vascular reactivity was assessed using wire myography and .O2? generation using lucigenin enhanced chemiluminescence. The HNO donor, Angeli's salt, and the NO. donor, DEA/NO, evoked relaxations in both arteries of control rats, and these responses were unaffected by diabetes. Nox2 oxidase expression and .O2? generation were upregulated in mesenteric, but unchanged, in femoral arteries of diabetic rats. Acetylcholine-induced endothelium-dependent relaxation was impaired in mesenteric but not femoral arteries in diabetes. The HNO scavenger, L-cysteine, reduced this endothelium-dependent relaxation to a similar extent in femoral and mesenteric arteries from control and diabetic animals. In conclusion, HNO and NO. contribute to the NO synthase (NOS)-sensitive component of endothelium-dependent relaxation in mesenteric and femoral arteries. The role of HNO is sustained in diabetes, serving to maintain endothelium-dependent relaxation. PMID- 28074233 TI - Microbial diversity in different compartments of an aquaponics system. AB - Aquaponics is a solution for sustainable production of fish and plants in a single semi-closed system, where nutrient-rich water from the aquaculture provides nutrients for plant growth. We examined the microbial communities within an experimental aquaponics system. Whereas the fish feces contained a separate community dominated by bacteria of the genus Cetobacterium, the samples from plant roots, biofilter, and periphyton were more similar to each other, while the communities were more diverse. Detailed examination of the data gave the first indications to functional groups of organisms in the different compartments of the aquaponic system. As other nitrifiers other than members of the genus Nitrospira were only present at low numbers, it was anticipated that Nitrospirae may perform the nitrification process in the biofilm. PMID- 28074234 TI - [Biological downsizing : Acetabular defect reconstruction in revision total hip arthroplasty]. AB - BACKGROUND: Periacetabular bony defects remain a great challenge in revision total hip arthroplasty. After assessment and classification of the defect and selection of a suitable implant the primary stable fixation and sufficient biological reconstitution of a sustainable bone stock are essential for long term success in acetabular revision surgery. Biological defect reconstruction aims for the down-sizing of periacetabular defects for later revision surgeries. TECHNIQUE: In the field of biological augmentation several methods are currently available. Autologous transplants feature a profound osseointegrative capacity. However, limitations such as volume restrictions and secondary complications at the donor site have to be considered. Structural allografts show little weight bearing potential in the long term and high failure rates. In clinical practice, the usage of spongious chips implanted via impaction bone grafting technique in combination with antiprotrusio cages for the management of contained defects have shown promising long time results. Nevertheless, when dealing with craniolateral acetabular and dorsal column defects, the additional implantation of macroporous metal implants or augments should be considered since biological augmentation has shown little clinical success in these particular cases. PROSPECT: This article provides an overview of the current clinically available biological augmentation methods of peri-acetabular defects. Due to the limitations of autologous and allogeneic bone transplants in terms of size and availability, the emerging field of innovative implantable tissue engineering constructs gains interest and will also be discussed in this article. PMID- 28074235 TI - Long-term brain structural magnetic resonance imaging and cognitive functioning in children treated for acute lymphoblastic leukemia with high-dose methotrexate chemotherapy alone or combined with CNS radiotherapy at reduced total dose to 12 Gy. AB - INTRODUCTION: The aim of this study was to assess the long-term side effects of central nervous system prophylaxis (high-dose chemotherapy alone vs chemotherapy and CNS radiotherapy) according to the ALL IC-BFM 2002. METHODS: Thirty-tree children aged 6.7-19.9 years have been studied. The control group consisted of 12 children newly diagnosed with acute lymphoblastic leukemia. We assessed subcortical gray matter volume using automatic MRI segmentation and cognitive performance to identify differences between two therapeutic schemes and patients prior to treatment. RESULTS: Patients treated with chemotherapy and CNS radiotherapy had smaller hippocampi than two other subgroups and lower IQ score than patients treated with chemotherapy alone. Both treated groups, whether with chemotherapy only or in combination with CNS radiotherapy, had significantly lower volumes of caudate nucleus and performed significantly worse on measures of verbal fluency in comparison with patients prior to treatment. There were no differences in the mean volumes of total white matter, total gray matter, thalamus, putamen, and amygdala between the studied groups. CONCLUSION: In all children treated according to the ALL IC-BFM 2002 with high-dose chemotherapy, both decreased volume of selected subcortical structures and cognitive impairment was observed, especially in children who received chemotherapy in combination with reduced dose CNS radiotherapy. In all children treated according to the ALL IC-BFM 2002 with high-dose chemotherapy, both decreased volume of selected subcortical structures and cognitive impairment were observed, especially in children who received chemotherapy in combination with CNS radiotherapy. PMID- 28074244 TI - Total synchronous fluorescence scan spectra of petroleum products. AB - Extending the two-dimensional synchronous fluorescence scan to a three dimensional total synchronous fluorescence scan (TSFS) spectral measurement gives the total synchronous fluorescence characteristics of a multifluorophoric sample at various possible wavelength intervals (Deltalambda), which could help to characterize multifluorophoric systems better. TSFS spectra of petroleum products such as diesel, kerosene, petrol, engine oil etc., available in the Indian market, are reported. Fluorescence in these samples is due to the presence of polycyclic aromatic hydrocarbons (PAHs) of various ring sizes. The TSFS contour plot profiles of the neat samples measured at right-angle geometry is a result of various energy-degrading photophysical processes such as inner filter effect, light attenuation, resonance energy transfer, collisional quenching etc. TSFS plots make it easy to obtain the optimized Deltalambda of an unknown sample of analytical interest. TSFS and the excitation-emission matrix (EEM) techniques are similar, but the contour profiles generated are different. The response of the TSFS contour profiles to dilution is different from that in the EEM contour profiles. Thus, TSFS can provide an alternative way of presenting the fluorescence response of concentrated multifluorophoric samples. PMID- 28074245 TI - Antifeedants Produced by Bacteria Associated with the Gut of the Pine Weevil Hylobius abietis. AB - The pine weevil, Hylobius abietis, is a severe forest pest insect as it feeds on newly planted conifer seedlings. To identify and develop an antifeedant could be one step towards the protection of seedlings from feeding damage by the pine weevil. With the aim to trace the origin of the antifeedants previously found in feces of the pine weevil, we investigated the culturable bacteria associated with the gut and identified the volatiles they produced. Bacterial isolates were identified by 16S ribosomal RNA gene analysis. The volatile emissions of selected bacteria, cultivated on NB media or on the grated phloem of Scots pine twigs dispersed in water, were collected and analyzed by solid-phase microextraction gas chromatography-mass spectrometry. The bacterial isolates released a variety of compounds, among others 2-methoxyphenol, 2-phenylethanol, 3-methyl-1-butanol, 1-octen-3-ol, 3-octanone, dimethyl disulfide, and dimethyl trisulfide. A strong antifeedant effect was observed by 2-phenylethanol, which could thus be a good candidate for use to protect planted conifer seedlings against feeding damage caused by H. abietis. PMID- 28074246 TI - Draft Genome of Scalindua rubra, Obtained from the Interface Above the Discovery Deep Brine in the Red Sea, Sheds Light on Potential Salt Adaptation Strategies in Anammox Bacteria. AB - Several recent studies have indicated that members of the phylum Planctomycetes are abundantly present at the brine-seawater interface (BSI) above multiple brine pools in the Red Sea. Planctomycetes include bacteria capable of anaerobic ammonium oxidation (anammox). Here, we investigated the possibility of anammox at BSI sites using metagenomic shotgun sequencing of DNA obtained from the BSI above the Discovery Deep brine pool. Analysis of sequencing reads matching the 16S rRNA and hzsA genes confirmed presence of anammox bacteria of the genus Scalindua. Phylogenetic analysis of the 16S rRNA gene indicated that this Scalindua sp. belongs to a distinct group, separate from the anammox bacteria in the seawater column, that contains mostly sequences retrieved from high-salt environments. Using coverage- and composition-based binning, we extracted and assembled the draft genome of the dominant anammox bacterium. Comparative genomic analysis indicated that this Scalindua species uses compatible solutes for osmoadaptation, in contrast to other marine anammox bacteria that likely use a salt-in strategy. We propose the name Candidatus Scalindua rubra for this novel species, alluding to its discovery in the Red Sea. PMID- 28074247 TI - Trends in Taxonomic and Functional Composition of Soil Microbiome Along a Precipitation Gradient in Israel. AB - The soil microbiome is important for the functioning of terrestrial ecosystems. However, the impacts of climate on taxonomic and functional diversity of soil microbiome are not well understood. A precipitation gradient along regional scale transects may offer a model setting for understanding the effect of climate on the composition and function of the soil microbiome. Here, we compared taxonomic and functional attributes of soil microorganisms in arid, semiarid, Mediterranean, and humid Mediterranean climatic conditions of Israel using shotgun metagenomic sequencing. We hypothesized that there would be a distinct taxonomic and functional soil community for each precipitation zone, with arid environments having lower taxonomic and functional diversity, greater relative abundance of stress response and sporulation-related genes, and lower relative abundance of genes related to nutrient cycling and degradation of complex organic compounds. As hypothesized, our results showed a distinct taxonomic and functional community in each precipitation zone, revealing differences in soil taxonomic and functional selection in the different climates. Although the taxonomic diversity remained similar across all sites, the functional diversity was-as hypothesized-lower in the arid environments, suggesting that functionality is more constrained in "extreme" environments. Also, with increasing aridity, we found a significant increase in genes related to dormancy/sporulation and a decrease in those related to nutrient cycling (genes related to nitrogen, potassium, and sulfur metabolism), respectively. However, relative abundance of genes related to stress response were lower in arid soils. Overall, these results indicate that climatic conditions play an important role in shaping taxonomic and functional attributes of soil microbiome. These findings have important implications for understanding the impacts of climate change (e.g., precipitation change) on structure and function of the soil microbiome. PMID- 28074248 TI - Pregnancy-associated osteoporosis: a case-control study. AB - : The etiology and underlying mechanisms of pregnancy-associated osteoporosis (PAO) are still unknown, since no systematic analyses exist. Our results indicate that PAO is a heterogeneous, rare but severe disease including a substantial number of fractures with a significant delay from first symptom to diagnose. INTRODUCTION: Pregnancy-associated osteoporosis (PAO) is a rare but severe type of premenopausal osteoporosis. Most common symptom includes acute lower back pain due to vertebral fracture predominantly occurring in the last trimester of pregnancy or immediately postpartum. The exact underlining mechanisms and risk factors of PAO are still unknown, and up to date, there are no published systematic analyses. METHODS: We identified 102 PAO patients and matched them with 102 healthy controls according to age, region, and gravidity to evaluate risk factors in a large and homogenous population of women. RESULTS: The baseline characteristics and anthropometric data of the two study groups were similar. Eighty-eight percent of the patients with PAO suffered from one or more fractures with a mean of 3.3 fractures per patient. The most common fracture site was the thoracolumbar spine, whereas 29, 37, 48, and 35% of the patients reported fractures at TH11, TH12, L1, and L2, respectively. PAO patients suffered more frequently from excessive dental problems in childhood (p < 0.001). The control group performed significantly more frequently sports both before (p < 0.002) and after puberty (p < 0.01). Compared to the controls, the patients with PAO reported twice as often severe diseases during pregnancy (p < 0.029). Hereby, the frequency of immobilization was twice as often in the PAO group compared to that in the control group (p < 0.005). CONCLUSIONS: Our results indicate that PAO is a heterogeneous, rare but severe disease including a substantial number of fractures with a significant delay from first symptom to diagnose. Increased awareness is warranted to immediately start effective treatment. PMID- 28074249 TI - Protein intake and risk of hip fractures in postmenopausal women and men age 50 and older. AB - : In this study, we followed postmenopausal women and men aged 50 and above for up to 32 years and found no evidence that higher protein intake increased the risk of hip fracture. Protein intake from specific sources was inversely associated with risk, but these associations appeared to differ by gender. INTRODUCTION: We examined the association between intakes of total and specific sources of protein and hip fracture risk in postmenopausal women and men over 50 years of age. Our hypothesis was that a higher protein intake would not be associated with a higher risk of hip fractures. METHODS: In this analysis, we followed 74,443 women in the Nurses' Health Study between 1980 and 2012 and 35,439 men from the Health Professionals Follow-up Study between 1986 and 2012. Health and lifestyle information and hip fractures were self-reported on biennial questionnaires. Protein was assessed approximately every 4 years with a food frequency questionnaire. Relative risks (RR) were computed for hip fracture by quintiles of total, animal, dairy, and plant protein intakes using Cox proportional hazard models, adjusting for potential confounders. RESULTS: During follow-up, we ascertained 2156 incident hip fractures in women and 595 fractures in men. Among men, we observed significant inverse associations for each 10 g increase of total protein (RR = 0.92, 95% CI = 0.85-0.99) and animal protein (RR = 0.91, 95% CI = 0.85-0.98) intakes. Total and animal proteins were not significantly associated with hip fractures in women. Both plant (RR = 0.88, 95% CI 0.79-0.99 per 10 g) and dairy protein (RR = 0.92, 95% CI 0.86-0.97) were associated with significantly lower risks of hip fracture when results for men and women were combined. None of these associations were modified by BMI, smoking, physical activity, age, or calcium intake. CONCLUSION: We found no evidence that higher protein intake increases risk of hip fracture in these Caucasian men and women. Protein intake from specific sources was inversely associated with risk, but these associations appeared to differ by gender. PMID- 28074251 TI - Hyponatremia and fractures: should hyponatremia be further studied as a potential biochemical risk factor to be included in FRAX algorithms? AB - The Fracture Risk Assessment Tool (FRAX(r)) was developed by the WHO Collaborating Centre for metabolic bone diseases to evaluate fracture risk of patients. It is based on patient models that integrate the risk associated with clinical variables and bone mineral density (BMD) at the femoral neck. The clinical risk factors included in FRAX were chosen to include only well established and independent variables related to skeletal fracture risk. The FRAX tool has acquired worldwide acceptance despite having several limitations. FRAX models have not included biochemical derangements in estimation of fracture risk due to the lack of validation in large prospective studies. Recently, there has been an increasing number of studies showing a relationship between hyponatremia and the occurrence of fractures. Hyponatremia is the most frequent electrolyte abnormality measured in the clinic, and serum sodium concentration is a very reproducible, affordable, and readily obtainable measurement. Thus, we think that hyponatremia should be further studied as a biochemical risk factor for skeletal fractures prediction, particularly those at the hip which carries the greatest morbidity and mortality. To achieve this will require the collection of large patient cohorts from diverse geographical locations that include a measure of serum sodium in addition to the other FRAX variables in large numbers, in both sexes, over a wide age range and with wide geographical representation. It would also require the inclusion of data on duration and severity of hyponatremia. Information will be required both on the risk of fracture associated with the occurrence and length of exposure to hyponatremia and to the relationship with the other risk variables included in FRAX and also the independent effect on the occurrence of death which is increased by hyponatremia. PMID- 28074250 TI - Cortical porosity exhibits accelerated rate of change in peri- compared with post menopausal women. AB - : The rate of change in bone density was not different between peri- and post menopausal women. Differences in rate of change were observed in bone microarchitecture, specifically cortical porosity (Ct.Po), where peri-menopausal women increased +9% per year compared with the +6% per year for post-menopausal women. INTRODUCTION: The purpose of this study was to compare changes in bone density and microarchitecture in peri- and post-menopausal women over 6 years. METHODS: Peri- (n = 26) and post- (n = 65) menopausal women were selected from the Canadian Multicenter Osteoporosis Study. Caucasian women were scanned on dual x-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and follow-up, an average 6 years later. To compare repeat scans, automated 3D image registration was conducted. At the radius and tibia, total volumetric BMD (Tt.BMD), total bone area (Tt.Ar) and cortical porosity (Ct.Po) were assessed, and finite element analysis estimated apparent bone strength. RESULTS: At the tibia, the rate of change for Ct.Po and Tt.Ar was different between groups. Peri-menopausal women had a + 9% per year increase in Ct.Po, but this increase was slower for post-menopausal women at +6% per year (p = 0.049). In addition, post-menopausal women had an increase in Tt.Ar of +0.13% per year compared with a slower increase of +0.06% per year for peri menopausal women (p = 0.017). The rate of change of density between groups was not significantly different and was approximately -1% per year at the hip by DXA, and -1% per year at the radius and -0.5% per year tibia by HR-pQCT. CONCLUSION: This is a 6-year prospective HR-pQCT study exploring rate of change in Caucasian peri- and post-menopausal women. The microarchitectural features represented by Ct.Po and Tt.Ar changed at a significantly different rate between groups, but group differences were not detected by density measures. PMID- 28074252 TI - High dietary sodium intake is associated with low bone mass in postmenopausal women: Korea National Health and Nutrition Examination Survey, 2008-2011. AB - : The present cross-sectional study performed using data from the Korea National Health and Nutrition Examination Survey in 9526 women older than 18 years of age demonstrates that high sodium intake is associated with lower bone mineral density and sodium intake >=2000 mg/day is a risk factor for osteoporosis in postmenopausal women. INTRODUCTION: Several studies have reported that large amount of dietary sodium intake is highly associated with elevated urinary calcium. However, the direct effect of excessive dietary sodium intake on bone mass, as a risk factor for osteoporosis, is still a controversial issue. The aim of the present study was to assess the relationship between high intake of sodium and lower bone mass and risk of osteoporosis in adult women. METHODS: This cross sectional study was performed using data from the Korea National Health and Nutrition Examination Survey (KNHANES), 2008-2011. Participants (n = 9526 women older than 18 years) were divided into a premenopausal (n = 4793) and postmenopausal (n = 4733) group. Both groups were subdivided into five groups according to quintiles of energy-adjusted sodium intake. Multiple regression analysis was performed to assess relationships between sodium intake and lower bone mass. RESULTS: Multivariate linear regression analysis showed that high sodium intake was negatively associated with bone mineral content (BMC) and bone mineral density (BMD) in postmenopausal women. After adjusting confounding factors, high sodium intake was negatively associated with BMC and BMD of the lumbar spine in postmenopausal women. Postmenopausal women, whose sodium intake was >=2000 mg/day (odds ratio 1.284, 95% CI 1.029-1.603, P = 0.027), were at risk of developing osteoporosis after adjustment of confounding variables. CONCLUSIONS: The present study suggested that high sodium intake could be a potential risk factor for low bone mass after adjusting for confounding factors in postmenopausal women. PMID- 28074253 TI - c-Abl inhibition mitigates diet-induced obesity through improving insulin sensitivity of subcutaneous fat in mice. AB - AIMS/HYPOTHESIS: High-energy diets are among the main causes of the global epidemic of metabolic disorders, including obesity and type 2 diabetes. The mechanisms of high-energy-diet-induced metabolic disorders are complex and largely unknown. The non-receptor tyrosine kinase c-Abl plays an important role in adipogenesis in vitro but its role in vivo in the regulation of metabolism is still elusive. Hence, we sought to address the role of c-Abl in diet-induced obesity and obesity-associated insulin resistance. METHODS: The expression of c Abl in different fat tissues from obese humans or mice fed a high-fat diet (HFD) were first analysed by western blotting and quantitative PCR. We employed conditional deletion of the c-Abl gene (also known as Abl1) in adipose tissue using Fabp4-Cre and 6-week-old mice were fed with either a chow diet (CD) or an HFD. Age-matched wild-type mice were treated with the c-Abl inhibitor nilotinib or with vehicle and exposed to either CD or HFD, followed by analysis of body mass, fat mass, glucose and insulin tolerance. Histological staining, ELISA and biochemical analysis were used to clarify details of changes in physiology and molecular signalling. RESULTS: c-Abl was highly expressed in subcutaneous fat from obese humans and HFD-induced obese mice. Conditional knockout of c-Abl in adipose tissue improved insulin sensitivity and mitigated HFD-induced body mass gain, hyperglycaemia and hyperinsulinaemia. Consistently, treatment with nilotinib significantly reduced fat mass and improved insulin sensitivity in HFD fed mice. Further biochemical analyses suggested that c-Abl inhibition improved whole-body insulin sensitivity by reducing HFD-triggered insulin resistance and increasing adiponectin in subcutaneous fat. CONCLUSIONS/INTERPRETATION: Our findings define a new biological role for c-Abl in the regulation of diet-induced obesity through improving insulin sensitivity of subcutaneous fat. This suggests it may become a novel therapeutic target in the treatment of metabolic disorders. PMID- 28074254 TI - The cardiovascular benefits of empagliflozin: SGLT2-dependent and -independent effects. PMID- 28074255 TI - Bortezomib-containing regimens (BCR) for the treatment of non-transplant eligible multiple myeloma. AB - In multiple myeloma (MM) patients ineligible for transplant, the selection of up front therapy needs to balance efficacy and toxicity. Recently, regimens with bortezomib, a proteasome inhibitor with anti-myeloma effects, have been reported. We aimed to evaluate the impact of different bortezomib-containing regimens (BCR) for the treatment of transplant-ineligible MM. All- consecutive patients treated with BCR at our institution from 01/05 to 02/16 were evaluated. With a median of 6 cycles, an overall response rate of 95.2, 80.9, and 76.3% was observed for patients treated with cyclophosphamide-bortezomib-dexamethasone (CyBorD), bortezomib-melphalan-prednisone (VMP), and bortezomib-dexamethasone (VD), respectively (p = 0.03). The median overall survival was similar between the three different BCR, but a trend for better progression-free survival was noted in favor of CyBorD. BCR are efficacious in the treatment of transplant-ineligible MM. Patients receiving continuous therapy (CT) exhibited better outcomes, suggesting that strategies to prevent toxicity and increase the cumulative dose are warranted. PMID- 28074256 TI - Erratum to: Visions of Restoration in Fire-Adapted Forest Landscapes: Lessons from the Collaborative Forest Landscape Restoration Program. PMID- 28074257 TI - Outcomes of dual mobility cups in a young Middle Eastern population and its influence on life style. AB - Dual mobility cups (DMC) in total hip arthroplasty (THA) are becoming popular among orthopaedic surgeons. Substantial benefit of their use has been reported among high risk patients, particularly in reducing post-operative hip instability (dislocation). Many reports stated some concern when implanted in young and active people where complications such as polyethylene wear and mechanical loosening could potentially be higher. This Middle Eastern study analyses a retrospective series of THA for any aetiology other than infection, using DMC for the acetabular component in 75 patients (85 implants) less than 70 years old. No instability, intra-prosthetic dislocation or mechanical failure was reported during a mean follow-up of five years. The only major complication was a post operative infection. The mean post- operative modified Harris hip score was 97.1 out of 100. All patients resumed their daily activities and all religious practicing patients were able to accomplish their prayer positions without pain. DMC is found to be an interesting option in reducing dislocation events in young patients. Those excellent short-term results would encourage surgeons to use DMC in an active and highly demanding population. Further research is necessary to confirm maintenance of such results at long term follow-up. PMID- 28074258 TI - The treatment options for posterior malleolar fractures in tibial spiral fractures. AB - PURPOSE: The posterior malleolar fracture (PMF) in tibial spiral fractures are a common type of complication that occurs in tibial fractures. However, the indication of fixation for posterior fractures is still under debate and varies between different surgeons'. It is not unusual to find the smaller PMF (<25%), which could be treated conservatively within guidelines, treated with internal fixation in clinic. The aim of this study is to evaluate the clinical outcomes of tibial spiral fractures with PMF and provide proper guidance for the treatment of this special fracture. METHODS: A total of 284 cases of spiral fractures combined with PMF were collected and analyzed. Demographic data, fragment size (classified by 25% involvement of ankle joint), time to weight-bearing and functional scores post-operatively were recorded. The ankle-hindfoot scale of the American Orthopaedic Foot and Ankle Society (AOFAS), a visual analogue scale (VAS) pain score, assessment of dorsiflexion restriction and arthritis scale were used as the main evaluations. RESULTS: Forty patients with a larger PMF (>=25%) and 72 with smaller ones (<25%) were fixed and categorized as the fixation group (FG). In the nonfixation group (NG), the corresponding numbers were four and 168 patients respectively. A total of 279 PMF were classified as large posterolateral triangular fragment carrying the posterior half of the fibular notch and intra incisural posterolateral fragment involving one-fourth to one-third of the fibular notch. However, no obvious differences were observed in terms of the clinical outcomes in PMF involving one-fourth to one-third of the fibular notch. In the treatment of smaller PMF (<25%) of this type, there were no obvious differences in the functional outcomes between fixed (SF) and nonfixed PMF (SN). CONCLUSIONS: Many patients with smaller PMFs were fixated, but functional outcomes of SF were not better than those of SN. There is no need to emphasize other factors guiding the treatment of PMF involving one-fourth to one-third of the fibular notch in spiral fractures. The traditional size of PMF may be only enough to guide the treatment of spiral fracture with PMF. But other types of PMF should still be treated considering morphology and fragment simultaneously. PMID- 28074260 TI - Accuracy and reproducibility of measurements on plaster models and digital models created using an intraoral scanner. AB - AIM: The purpose of the present study was to evaluate the accuracy and reproducibility of measurements made on digital models created using an intraoral color scanner compared to measurements on dental plaster models. METHODS: This study included impressions of 28 volunteers. Alginate impressions were used to make plaster models, and each volunteers' dentition was scanned with a TRIOS Color intraoral scanner. Two examiners performed measurements on the plaster models using a digital caliper and measured the digital models using Ortho Analyzer software. The examiners measured 52 distances, including tooth diameter and height, overjet, overbite, intercanine and intermolar distances, and the sagittal relationship. The paired t test was used to assess intra-examiner performance and measurement accuracy of the two examiners for both plaster and digital models. The level of clinically relevant differences between the measurements according to the threshold used was evaluated and a formula was applied to calculate the chance of finding clinically relevant errors on measurements on plaster and digital models. RESULTS: For several parameters, statistically significant differences were found between the measurements on the two different models. However, most of these discrepancies were not considered clinically significant. The measurement of the crown height of upper central incisors had the highest measurement error for both examiners. Based on the interexaminer performance, reproducibility of the measurements was poor for some of the parameters. CONCLUSIONS: Overall, our findings showed that most of the measurements on digital models created using the TRIOS Color scanner and measured with Ortho Analyzer software had a clinically acceptable accuracy compared to the same measurements made with a caliper on plaster models, but the measuring method can affect the reproducibility of the measurements. PMID- 28074261 TI - Perioperative chemotherapy in upper tract urothelial carcinoma: a comprehensive review. AB - PURPOSE: To evaluate the role of neoadjuvant (NAC) and adjuvant chemotherapy (AC) in patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). METHODS: A comprehensive review of the current literature was performed searching for all studies investigating NAC and AC in UTUC in MEDLINE and https://clinicaltrials.gov , prior to April 2016. The following keywords were used: "ureteral neoplasms," "urothelium," "ureter," "upper tract urothelial," "chemotherapy," "adjuvant," "neoadjuvant" and relevant variants. RESULTS: No randomized trials investigated the role of AC or NAC for UTUC. There was one prospective study with n = 36 patients investigating AC with carboplatin-paclitaxel. We included 14 retrospective studies (four in the NAC and ten in the AC setting), with a total of 694 patients receiving cisplatin-based or non-cisplatin-based AC after RNU and 1437 patients undergoing RNU alone. We found that the current literature, mainly based on retrospective studies, suggests significant overall and cancer-specific survival benefits for AC in UTUC. NAC appears promising, with favorable pathologic response rates up to 14%. CONCLUSIONS: Evidence is scarce for both NAC and AC use in UTUC. This comprehensive review suggests promising response rates for NAC and a survival benefit for patients treated with AC. Prospective randomized trials are needed to establish the role of AC and NAC in UTUC. PMID- 28074263 TI - Treatment options and outcome after bony avulsion of the flexor digitorum profundus tendon: a review of 29 cases. AB - INTRODUCTION: The objective of this retrospective review was to evaluate the functional and esthetic outcomes in patients with non- or minimally (<2 mm), and severely (>2 mm) displaced bony avulsions of the flexor digitorum profundus (FDP) tendon. MATERIALS AND METHODS: Between 1996 and 2010, 29 patients with a bony avulsion of the FDP tendon were treated. The displacement magnitude of the avulsed fragment determined, whether conservative or surgical treatment was performed. Persisting functional deficit, radiological findings, remaining disabilities using the Disability of the Arm, Shoulder, and Hand (DASH) score, as well as treatment-related deformities and complications were evaluated retrospectively and at a mean follow-up of 7 years. RESULTS: In 16 patients, conservative therapy by initial static splinting due to a fragment displacement of <2 mm was conducted. These patients reported no functional impairment at follow-up. In 13 cases, major displacement (>2 mm) of the bony fragment led to an open reconstruction of the avulsion injury either by screw fixation or a Lengemann pull-out wire. In a majority, an extension deficit in the DIP joint and a decrease of tip pinch strength by 25% was present at follow-up. In five patients, peri- or short-term postoperative complications occurred and in five, a nail deformity remained. DASH score revealed satisfying results after both therapeutic approaches. CONCLUSIONS: Conservative treatment in non- or minimally displaced avulsions leads to satisfying functional results. Patients receiving surgery after major fragment displacement need to be aware of a possible impaired ROM at the DIP joint. The use of the Lengemann pull-out wire may place patients at an increased complication risk and frequently induces nail deformities. LEVEL OF EVIDENCE: Therapeutic, level IV. PMID- 28074262 TI - Activated microglia induce the production of reactive oxygen species and promote apoptosis of co-cultured retinal microvascular pericytes. AB - PURPOSE: Pericyte apoptosis is a predominant feature of early diabetic retinopathy. In diabetic retinopathy, activated microglia migrate and release proinflammatory cytokines that contribute to disruption of the blood-retinal barrier, neuronal loss, and enhanced ROS production. Reactive oxygen species (ROS) are implicated in pericyte death; however, the mechanism by which activated microglia affect retinal microvascular pericytes is unclear. We hypothesized that activated microglia may promote pericyte apoptosis by enhancing ROS production. METHODS: Lipopolysaccharide (LPS)-activated microglia and pericytes were co cultured in a cell culture system. Pericyte ROS production and the mitochondrial membrane potential (DeltaPsim) were determined by flow cytometry. The pericyte protein expression levels of NADPH oxidase subunits, uncoupling protein 2, nuclear NF-kappaB-p65, and caspase-3 were determined by western blotting. One-way ANOVAs were used for statistical analysis. RESULTS: LPS successfully activated the microglia, as demonstrated by their morphological and phenotype changes and the significant increase in tumor necrosis factor secretion (P < 0.01). Co culture with activated microglia significantly up-regulated NADPH oxidase subunits (NOX4, NOX2, and NCF1; P < 0.01) and down-regulated uncoupling protein 2 expression (P < 0.01) in pericytes. Pericyte ROS production increased by 20% in the activated microglia co-cultured group, and was inhibited by pretreatment with diphenyleneiodonium, coenzyme Q10, and N-acetylcysteine. The proapoptotic pericyte changes induced by co-culture with activated microglia included a 9.50% decrease in pericyte DeltaPsim and significant increases in NF-kappaB-p65 nuclear translocation (P < 0.01) and activated caspase-3 (P < 0.01). These proapoptotic effects of activated microglia were inhibited by diphenyleneiodonium. CONCLUSIONS: Our results are consistent with our hypothesis that activated microglia may promote pericyte apoptosis by enhancing ROS production. Further studies are needed to examine retinal microglia activation and the corresponding changes in pericytes in a rat model of diabetes mellitus. PMID- 28074264 TI - NaCl stress induces CsSAMs gene expression in Cucumis sativus by mediating the binding of CsGT-3b to the GT-1 element within the CsSAMs promoter. AB - MAIN CONCLUSION: The CsSAMs promoter is a salt-stress-inducible promoter containing three GT-1 elements that are sufficient for the salt-stress response. The transcription factor CsGT-3b was found to bind to the GT-1 element. The S adenosyl-L-methionine synthase (SAMs) gene is among the functional genes induced during environmental stress. However, little is known about the regulatory mechanism and upstream regulators of this salt-inducible gene in cucumber plants. Thus, it is necessary to understand the characteristics of the SAMs gene by analyzing its promoter and transcription factors. In this study, we isolated and functionally analyzed a 1743-bp flanking fragment of the CsSAMs gene from Cucumis sativus. To examine promoter activity, the full-length promoter, as well as different promoter fragments, were fused to the beta-glucuronidase (GUS) reporter gene and introduced into the tobacco genome. The full-length promoter displayed maximal promoter activity, whereas the P4 promoter, containing 321 bp of upstream sequence, showed no basal promoter activity. In addition, the CsSAMs promoter exhibited stress-inducible regulation rather than tissue-specific activity in transgenic tobacco. Histochemical analysis revealed strong GUS staining in leaves, stems, and roots, especially in the veins of leaves, the vascular bundle of stems, and root tip zones following NaCl stress. A transient expression assay confirmed that the 242-bp region (-1743 to -1500) was sufficient for the NaCl stress response. Yeast one-hybrid assays further revealed interaction between the NaCl-response protein CsGT-3b and the GT-1 (GAAAAA) element within the 242-bp region. Taken together, we revealed the presence of four salt-stress-responsive elements (GT-1 cis-elements) in the CsSAMs promoter and identified a transcription factor, CsGT-3b, that specifically binds to this sequence. These results might help us better understand the intricate regulatory network of the cucumber SAMs gene. PMID- 28074265 TI - Pharmacokinetic and exposure-response analyses of pertuzumab in combination with trastuzumab and docetaxel during neoadjuvant treatment of HER2+ early breast cancer. AB - PURPOSE: The NeoSphere trial evaluated pertuzumab in the neoadjuvant setting [early breast cancer (EBC)] with pathological complete response (pCR) as the primary efficacy end point. This analysis of pertuzumab aimed to (1) compare its pharmacokinetics (PK) in patients with EBC versus advanced cancers, (2) to further evaluate PK drug-drug interactions (DDIs) when given in combination with trastuzumab, and (3) to assess the relationship between exposure and efficacy to assess the clinical dosing regimen in the EBC patients. METHODS: Pertuzumab serum concentration data from 180 patients in NeoSphere were compared to historical observations and potential DDI was assessed, by applying simulation techniques using a population PK model. The impact of pertuzumab exposure on pCR rate was evaluated using a logit response model (n = 88). RESULTS: The observed PK matched the population PK model simulations, confirming that the PK in neoadjuvant EBC appear to be in agreement with the historical observations. No evidence of a DDI effect of trastuzumab or docetaxel on pertuzumab was observed supporting the doses when given in combination. In NeoSphere >90% of EBC patients achieved the non-clinical target serum concentration. There was no association between the pertuzumab serum concentration and pCR within the range observed in this study (20-100 MUg/mL) supporting no dose adjustments needed for patients with lower exposure. CONCLUSIONS: This analysis further supports the lack of DDI between the two therapeutic proteins and the appropriateness of the approved fixed non-body weight-adjusted pertuzumab dose in the treatment of neoadjuvant EBC with pertuzumab in combination with trastuzumab and docetaxel. PMID- 28074266 TI - Fever of unknown origin, giant cell arteritis, and aortic dissection. AB - Giant cell arteritis is one of the most frequent causes of pyrexia of unknown origin after infectious or malignant causes have been ruled out. In this case report we describe a 66-year old female patient, who after five weeks of remitting fever developed a life-threatening, painless severe aortic dissection. The timely use of modern imaging technologies such as magnetic resonance angiography or positron emission computed tomography could in the future be of help to recognize aortic involvement early and to avoid this devastating complication in patients with fever of unknown origin. PMID- 28074267 TI - Reduced serum myostatin concentrations associated with genetic muscle disease progression. AB - Myostatin is a highly conserved protein secreted primarily from skeletal muscle that can potently suppress muscle growth. This ability to regulate skeletal muscle mass has sparked intense interest in the development of anti-myostatin therapies for a wide array of muscle disorders including sarcopenia, cachexia and genetic neuromuscular diseases. While a number of studies have examined the circulating myostatin concentrations in healthy and sarcopenic populations, very little data are available from inherited muscle disease patients. Here, we have measured the myostatin concentration in serum from seven genetic neuromuscular disorder patient populations using immunoaffinity LC-MS/MS. Average serum concentrations of myostatin in all seven muscle disease patient groups were significantly less than those measured in healthy controls. Furthermore, circulating myostatin concentrations correlated with clinical measures of disease progression for five of the muscle disease patient populations. These findings greatly expand the understanding of myostatin in neuromuscular disease and suggest its potential utility as a biomarker of disease progression. PMID- 28074268 TI - Cognitive deficits in patients with a chronic vestibular failure. AB - Behavioral studies in rodents and humans have demonstrated deficits of spatial memory and orientation in bilateral vestibular failure (BVF). Our aim was to explore the functional consequences of chronic vestibular failure on different cognitive domains including spatial as well as non-spatial cognitive abilities. Sixteen patients with a unilateral vestibular failure (UVF), 18 patients with a BVF, and 17 healthy controls (HC) participated in the study. To assess the cognitive domains of short-term memory, executive function, processing speed and visuospatial abilities the following tests were used: Theory of Visual Attention (TVA), TAP Alertness and Visual Scanning, the Stroop Color-Word, and the Corsi Block Tapping Test. The cognitive scores were correlated with the degree of vestibular dysfunction and the duration of the disease, respectively. Groups did not differ significantly in age, sex, or handedness. BVF patients were significantly impaired in all of the examined cognitive domains but not in all tests of the particular domain, whereas UVF patients exhibited significant impairments in their visuospatial abilities and in one of the two processing speed tasks when compared independently with HC. The degree of vestibular dysfunction significantly correlated with some of the cognitive scores. Neither the side of the lesion nor the duration of disease influenced cognitive performance. The results demonstrate that vestibular failure can lead to cognitive impairments beyond the spatial navigation deficits described earlier. These cognitive impairments are more significant in BVF patients, suggesting that the input from one labyrinth which is distributed into bilateral vestibular circuits is sufficient to maintain most of the cognitive functions. These results raise the question whether BVF patients may profit from specific cognitive training in addition to physiotherapy. PMID- 28074269 TI - Varied exposure to carcinogenic, mutagenic, and reprotoxic (CMR) chemicals in occupational settings in France. AB - PURPOSE: To explore varied exposure to carcinogenic, mutagenic, and reprotoxic chemicals (CMR) for French employees. METHODS: Our study assessed data from the French national cross-sectional survey of occupational risks (SUMER) that was conducted in 2010 in a national representative sample of employees. We selected 28 CMR agents that were classified by the International Agency for Research on Cancer or European Union as being known or presumed to have CMR potential in humans. The association of individual and job characteristics with exposure prevalence, duration, and intensity of the CMR agents during a 1-week period was examined using multilevel logistic regression analysis. RESULTS: Overall, 10.4% of employees in 2010 were exposed to one or more CMR agents at their workplace, and 3.4% were subjected to multiple CMR exposures. Blue-collar workers, night shift workers and workers with short-term employment contracts experienced higher exposure prevalence (p < 0.01) and intensity (p < 0.05). Blue-collar workers and shift workers experienced also longer exposure duration (p < 0.001). Conversely, managers, workers of large companies, and women were less exposed to CMR agents (p < 0.001). The presence of a Committee for Health, Safety, and Working Conditions, and intervention by Occupational Health and Safety officers were significantly associated with reduced exposure intensities (p < 0.001 and p < 0.05). Establishment of European CMR regulations and the existence of an applicable substitution principle reduced the exposure duration (p < 0.001) and intensity (p < 0.05). CONCLUSIONS: Our results point out disparities in CMR exposure and identify high-priority targets for prevention measures to help reducing social health discrepancies. PMID- 28074270 TI - Tree leaf litter composition drives temporal variation in aquatic beetle colonization and assemblage structure in lentic systems. AB - Tree leaf litter inputs to freshwater systems are a major resource and primary drivers of ecosystem processes and structure. Spatial variation in tree species distributions and forest composition control litter inputs across landscapes, but inputs to individual lentic habitat patches are determined by adjacent plant communities. In small, ephemeral, fishless ponds, resource quality and abundance can be the most important factor affecting habitat selection preferences of colonizing animals. We used a landscape of experimental mesocosms to assess how natural populations of aquatic beetles respond over time to variation in tree leaf litter composition (pine or hardwood). Patches with faster-decomposing hardwood leaf litter were initially colonized at higher rates than slower decomposing pine pools by most species of Hydrophilidae, but this pattern reversed later in the experiment with higher colonization of pine pools by hydrophilids. Colonization did not differ between pine and hardwood for dytiscids and the small hydrophilid Paracymus, but there were distinct beetle assemblages between pine and hardwood patches both early and late in the experiment. Our data support the importance of patch quality and habitat selection as determinants of species abundances, richness, and community structure in freshwater aquatic systems, not only when new habitat patches are formed and initial conditions set, but as patches change due to interactions of processes such as decomposition with time. PMID- 28074271 TI - [Erratum to: Optic disc swelling. A compilation of relevant differential diagnoses]. PMID- 28074272 TI - [Role of the aging visual system in glaucoma]. AB - BACKGROUND: Glaucoma is the second leading cause of blindness worldwide and is usually diagnosed in higher age groups. The goal was to survey how patient age influences the development of glaucoma. MATERIALS AND METHODS: A web-based search on aging of the visual system and its influence on glaucoma was performed and the most important results are summarized. RESULTS: The prevalence of glaucoma rises with age. Aging processes of the trabecular meshwork and the uveoscleral outflow pathway lead to a rise in the intraocular pressure. Chronically elevated intraocular pressure leads to remodelling of the lamina cribrosa and narrowing of its pores through which ganglion cell axons leave the eye. Age-dependent glia cell, mitochondria and immune system alterations are discussed to influence glaucoma. Patient age and further age-related nonophthalmological systemic diseases also influence adherence and persistence to the prescribed therapy. CONCLUSIONS: Aging is an important risk factor for developing glaucoma and is a main factor which influences therapy and course of the disease. At this point in time it remains unclear to which extent additional factors determine the development of glaucoma. PMID- 28074273 TI - Experimental models of neurological disease: neuropathology determines what is virtual reality, science or fiction. PMID- 28074275 TI - Crossover assessment of cardiolocomotor synchronization during running. AB - PURPOSE: This study aimed at testing the hypothesis that positive cardiolocomotor coordination (CLC) measure occurs by chance during a running task where the heart rate (HR) is approximated to the step frequency (StepF). METHODS: The electrocardiogram and electromyogram from the right gastrocnemius lateralis muscle were continuously recorded from ten healthy young men running at a paced rhythm of 152 step/min, to monitor HR and StepF. CLC was evaluated by phase synchrograms and the index of conditional probability (iCP). Results were validated with surrogate data and a crossover approach, where the HR of one subject was related to the StepF of another one, and comparisons were made combining subjects two by two. RESULTS: Six subjects showed synchrogram structures and high iCP values (>=0.8), suggesting the occurrence of physiological entrainment, when the HR reached the SF range. In crossover analysis, phase synchrograms and iCP presented similar behavior of original data when the HR from one subject was close enough to the SF from another one. Significant iCP values in 46 of 90 comparisons (51%) were observed, including all cases crossing signals among the six positive cases. CONCLUSION: Synchrogram and iCP tools currently employed for measuring CLC are not appropriate because they indicate the occurrence of this phenomenon even among subjects who ran on different days and times of each other. PMID- 28074274 TI - Glioma: experimental models and reality. AB - In theory, in vitro and in vivo models for human gliomas have great potential to not only enhance our understanding of glioma biology, but also to facilitate the development of novel treatment strategies for these tumors. For reliable prediction and validation of the effects of different therapeutic modalities, however, glioma models need to comply with specific and more strict demands than other models of cancer, and these demands are directly related to the combination of genetic aberrations and the specific brain micro-environment gliomas grow in. This review starts with a brief introduction on the pathological and molecular characteristics of gliomas, followed by an overview of the models that have been used in the last decades in glioma research. Next, we will discuss how these models may play a role in better understanding glioma development and especially in how they can aid in the design and optimization of novel therapies. The strengths and weaknesses of the different models will be discussed in light of genotypic, phenotypic and metabolic characteristics of human gliomas. The last part of this review provides some examples of how therapy experiments using glioma models can lead to deceptive results when such characteristics are not properly taken into account. PMID- 28074276 TI - In stage pT1 non-muscle-invasive bladder cancer (NMIBC), high KRT20 and low KRT5 mRNA expression identify the luminal subtype and predict recurrence and survival. AB - Differential expression of cytokeratins (CK) is a characteristic feature of chemoresistant luminal (KRT20) and chemosensitive intrinsic aggressive basal (KRT5) subtypes in muscle-invasive bladder cancer (MIBC). We investigated mRNA expression of KRT5 and KRT20 and its predictive value in stage pT1 bladder cancer. In retrospective analysis of clinical data and formalin-fixed paraffin embedded tissues (FFPE) of patients with stage pT1 NMIBC who underwent transurethral resection of the bladder, a single-step RT-qPCR was used to measure mRNA expression. Furthermore, immunohistochemical (IHC) staining of CK20, panCK, and MIB1 was performed. Valid measurements were obtained from 231 samples out of a series of 284 patients. Spearman correlation revealed significant associations between mRNA and protein expression of KRT20/CK20 (rho 0.6096, p < 0.0001) and MKI67/MIB1 (rho 0.5467, p < 0.0001). A positive correlation was found between MKI67 and KRT20 expression (rho 0.3492, p < 0.0001), while MKI67 and KRT5 were negatively correlated (rho -0.1693, p = 0.01). High KRT20 expression (>=40.26) was significantly associated with worse recurrence free survival (RFS) (p = 0.001), progression-free survival (PFS) (p = 0.0003), and cancer specific survival (CSS) (p = 0.0414). The combination of high KRT20 expression and low KRT5 expression (<36.83) was associated with unfavorable RFS (p = 0.0038) and PFS (p = 0.0003) and proved to be the only independent predictor for RFS (p = 0.0055) and PFS (p = 0.0023) in multivariate analysis. KRT20 mRNA determination was superior to CK20 protein estimation with regard to RFS and PFS prediction. KRT20 and KRT5 mRNA quantification can predict recurrence and progression of stage pT1 NMIBC reflecting basal and luminal subtypes of MIBC and is superior to CK20 protein expression determined by IHC. PMID- 28074277 TI - Patient-Reported Outcomes for Acute Gallstone Pathology. AB - BACKGROUND: A number of prominent surgical trials and clinical guidelines regard length of hospital stay and rates of daycase surgery as being of upmost importance following cholecystectomy. However, it is unclear whether these outcomes also matter to patients. This study aimed to identify the factors patients regard as most important when admitted with acute gallstone pathology. METHODS: A 41-item survey was produced by combining outcomes assessed in recent clinical trials with results from a preliminary patient questionnaire. This was then given out prospectively to patients presenting with acute gallstone pathology, prior to their cholecystectomy. Patients were asked to read an information sheet about laparoscopic cholecystectomy and then complete the survey, scoring each item out of 100 in terms of importance to them. RESULTS: Fifty-six patients completed the survey (43 females; median age 51 years). Diagnoses were: cholecystitis (28 patients), biliary colic (13), pancreatitis (10), common bile duct stones (3) and cholangitis (2). The top-scoring survey item was "long-term quality of life after surgery", with a median value of 97 out of 100. Other high-scoring items included "cleanliness of the ward environment" and "pain control after surgery" (both 96). The lowest-scoring item was "being treated as a daycase" (54). CONCLUSION: Patients with acute gallstone pathology view long-term quality of life after surgery as the most important factor and daycase surgery as the least important. These results should be considered when planning future surgical trials and clinical guidelines. PMID- 28074278 TI - Laparoscopic Appendectomy: Risk Factors for Postoperative Intraabdominal Abscess. AB - BACKGROUND: Laparoscopic appendectomy (LA) has obtained wide acceptance over the last two decades. However, some studies suggest that there is an increased rate of intraabdominal abscess (IAA) when is compared with open appendectomy. Since postoperative IAA is associated with high morbidity, identifying predictive factors of this complication may help to prevent it. The aim of this study was to identify preoperative and intraoperative risk factors for IAA after LA. METHODS: From January 2005 to June 2015, all charts of consecutive patients underwent to LA were revised. Demographics, clinical and intraoperative variables were analyzed. Independent risk factors for postoperative IAA were determined by logistic regression analysis. RESULTS: A total of 1300 LA were performed. The mean age was 34.7 (14-94) years. Two hundred and twenty-five patients (17.3%) had complicated appendicitis with perforation and peritonitis. The conversion rate was 2.3% (30 cases). The average hospital stay was 1.6 (0-27) days. There were 30 (2.3%) postoperative IAA. In the multivariate analysis, body mass index (BMI) >30 (p 0.01), leukocytosis >20,000/mm3 (p 0.02), perforated appendicitis (p < 0.001) and operative time >90 min (p 0.04) were associated with the development of postoperative IAA. There was no mortality in the series. CONCLUSION: Patients with obesity, leukocytosis >20,000/mm3, perforated appendicitis and surgical time longer than 90 min have a higher chance of having a postoperative IAA. A close postoperative follow-up would be necessary in these situations in order to prevent and identify IAA after LA. PMID- 28074280 TI - ? PMID- 28074279 TI - Identification and clinical course of 166 pediatric cardiac tumors. AB - : The aim of this study was to investigate the pathological classifications, clinical features, and natural history of pediatric cardiac tumors to provide a basis for the selection of an appropriate therapeutic method. The medical records of in- or outpatients with cardiac tumors at four hospitals were classified to analyze various types of tumor growth locations, clinical manifestations, surgical indications, and long-term follow-up results. There were 166 patients, including 158 with primary cardiac tumors, six with metastatic cardiac tumors, and two with unclassified cardiac tumors. Among the 158 cases of primary cardiac tumor, 150 were benign and eight were malignant. The rhabdomyoma, fibroma, and myxoma are the most common types of benign cardiac tumors. The major clinical manifestations of cardiac tumors include outflow tract obstruction, arrhythmia, dyspnea, pericardial effusion, heart failure, and seizures. Among the 59 patients who underwent surgery, 49 had primary benign cardiac tumors, eight had primary malignant tumors, and two had malignant metastatic tumors. Post-surgery, nine of the patients had residual tumor tissues that did not significantly affect their hemodynamics. Following surgery, there were two cases of recurrence and nine deaths, including four of benign and five of malignant tumors with mortality rates of 8.2 and 50.0 %, respectively. Of the remaining 107 cases of patients who did not undergo surgery, five (4.7 %) died. CONCLUSION: The primary benign cardiac tumors are the predominant pediatric cardiac tumors, of which rhabdomyoma, fibroma, and myxoma are the most common types. If severe symptoms are nonexistent and the hemodynamics is unaffected, most of the patients can survive in the long term despite the tumors. What is known: * Pediatric cardiac tumors are rare and are predominantly primary and benign. * The symptoms of heart failure, arrhythmia, and outflow obstruction are the most severe complications of cardiac tumors. What is new: * The rhabdomyoma, fibroma, and myxoma are the most common types of primary benign cardiac tumors. * If severe symptoms are not present and the hemodynamics are unaffected, most of the patients can survive in the long term despite the tumors. PMID- 28074281 TI - One-step CAD/CAM titanium cranioplasty after drilling template-assisted resection of intraosseous skull base meningioma: technical note. AB - INTRODUCTION: Cranial defects following intra-osseous tumor removal may be large and require adequate reconstruction. CAD/CAM implants have been used for years to achieve an optimal cosmetic result. The disadvantage is that such implants require a second surgery. A preoperative virtual planning of resection margins and the simultaneously fabrication of the cranioplasty could be a possibility to subsume the steps tumor resection and cosmetic restoration to a single procedure. METHODS: We present two cases of patients with complex intra-osseous spheno orbital meningioma. Tumor resection was performed with the help of a drilling template in form of a frame. The template also served as a negative for the computer-designed cranioplasty. The devices were manufactured by DMD GmbH - Digital Medical Design/DDI-Group, Dortmund, Germany. DISCUSSION: The usage of the template was highly practicable. Small adjustments in bone removal were necessary to achieve an optimal fitting of the implant. The 6-month follow-up showed for one patient a good and for one a satisfactory cosmetic result. No second surgery was necessary. CONCLUSIONS: Drilling template application could contribute to challenging cases of large fronto-basal meningiomas with the aim of minimizing operation time and achieving a good esthetic outcome. PMID- 28074283 TI - Diabetes and nephrotic syndrome: Questions. PMID- 28074282 TI - Unique findings of subependymal giant cell astrocytoma within cortical tubers in patients with tuberous sclerosis complex: a histopathological evaluation. AB - INTRODUCTION: Tuberous sclerosis is associated with three central nervous system pathologies: cortical/subcortical tubers, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs). Tubers are associated with epilepsy, which is often medication-resistant and often leads to resective surgery. Recently, mammalian target of rapamycin inhibitors (mTORi) have been shown to be effective reducing seizure burden in some patients with tuberous sclerosis complex (TSC)-related refractory epilepsy. mTORi have also been shown to be an alternative for surgery treating SEGAs. We describe several cases of resected tubers that contained SEGA tissue without an intraventricular SEGA. METHODS: After institutional review board (IRB) protocol approval, we retrospectively reviewed the surgical-pathological data for all TSC patients who underwent cortical resections for treatment of refractory epilepsy at NYU Langone Medical Center and Tel Aviv Medical Center between 2003 and 2013. Data included demographics, epilepsy type, MRI characteristics, epilepsy outcome, and histopathological staining. RESULTS: We reviewed cortical resections from 75 patients with complete pathological studies. In three patients, cortical lesions demonstrated histopathological findings consistent with a SEGA within the resected tuber tissue, with no intraventricular SEGA. All lesions were cortically based and none had any intraventricular extension. No patient had been treated before surgery with an mTORi. Two of the three patients remain Engel grade I-II. All lesions stained positive for glial fibrillary acidic protein (GFAP), synaptophysin, and neuronal nuclear antigen (NeuN). CONCLUSION: This is the first description of cortical tubers harboring SEGA tissue. This observation though preliminary may suggest a subgroup of patients with intractable epilepsy in whom mTORi may be considered before surgical intervention. PMID- 28074284 TI - High-affinity RNA binding by a hyperthermophilic single-stranded DNA-binding protein. AB - Single-stranded DNA-binding proteins (SSBs), including replication protein A (RPA) in eukaryotes, play a central role in DNA replication, recombination, and repair. SSBs utilise an oligonucleotide/oligosaccharide-binding (OB) fold domain to bind DNA, and typically oligomerise in solution to bring multiple OB fold domains together in the functional SSB. SSBs from hyperthermophilic crenarchaea, such as Sulfolobus solfataricus, have an unusual structure with a single OB fold coupled to a flexible C-terminal tail. The OB fold resembles those in RPA, whilst the tail is reminiscent of bacterial SSBs and mediates interaction with other proteins. One paradigm in the field is that SSBs bind specifically to ssDNA and much less strongly to RNA, ensuring that their functions are restricted to DNA metabolism. Here, we use a combination of biochemical and biophysical approaches to demonstrate that the binding properties of S. solfataricus SSB are essentially identical for ssDNA and ssRNA. These features may represent an adaptation to a hyperthermophilic lifestyle, where DNA and RNA damage is a more frequent event. PMID- 28074287 TI - Responses triggered in chloroplast of Chlorella variabilis NC64A by long-term association with Paramecium bursaria. AB - The unicellular green alga Chlorella variabilis NC64A is an endosymbiont of the ciliate Paramecium bursaria. The host's control, including the transfer of biochemical substrates from P. bursaria to C. variabilis, is involved in symbiotic relationships. C. variabilis NC64A that had been re-infected to P. bursaria for more than 1 year and isolated from the host showed higher chlorophyll levels compared to those in free-living cells. Unlike the host, the expression of C. variabilis NC64A heat shock 70 kDa protein was independent of establishment of endosymbiosis. In symbiotic cells, the levels of PII signal transduction protein (CvPII) that coordinate the central C/N anabolic metabolism were slightly higher than those in free-living cells. Furthermore, the environmental cues (light and host food bacteria availability) affected the abundance of CvPII, suggesting that synthesis of the protein was influenced by the host. Moreover, arginine concentrations in the symbiotic algae of P. bursaria were also controlled by the host's nutritional conditions. Together, our results imply that signal substrates and/or products of metabolism in host cells might act as messengers mediating the regulation of key events in symbiont cells. PMID- 28074286 TI - Regulation of microtubule nucleation mediated by gamma-tubulin complexes. AB - The microtubule cytoskeleton is critically important for spatio-temporal organization of eukaryotic cells. The nucleation of new microtubules is typically restricted to microtubule organizing centers (MTOCs) and requires gamma-tubulin that assembles into multisubunit complexes of various sizes. gamma-Tubulin ring complexes (TuRCs) are efficient microtubule nucleators and are associated with large number of targeting, activating and modulating proteins. gamma-Tubulin dependent nucleation of microtubules occurs both from canonical MTOCs, such as spindle pole bodies and centrosomes, and additional sites such as Golgi apparatus, nuclear envelope, plasma membrane-associated sites, chromatin and surface of pre-existing microtubules. Despite many advances in structure of gamma tubulin complexes and characterization of gammaTuRC interacting factors, regulatory mechanisms of microtubule nucleation are not fully understood. Here, we review recent work on the factors and regulatory mechanisms that are involved in centrosomal and non-centrosomal microtubule nucleation. PMID- 28074285 TI - T cell receptor repertoire usage in cancer as a surrogate marker for immune responses. AB - Characterizing the interaction of cancer cells with the host adaptive immune system is critical for understanding tumor immunology and the modus operandi of immunotherapeutic interventions to treat cancer. As the key cellular effectors of adaptive immunity, T cells are endowed with specialized receptors (the T cell receptor; TCR), to recognize and to eliminate cancer cells. The diversity of the TCR repertoire results from specialized genetic diversification mechanisms that generate an incredible variability allowing recognizing extensive collections of antigens. Based on the attainment and function of the TCR, the TCR repertoire is a mirror of the human immune response, and the dynamic changes of its usage can be assumed as a promising biomarker to monitor immunomodulatory therapies. Recent advances in multiplexed PCR amplification and massive parallel sequencing technologies have facilitated the characterization of TCR repertoires at high resolution even when only biomaterial of limited quantity and quality, such as formalin-fixed paraffin-embedded (FFPE) archived tissues, is available. Here, we review the concept framework and current experimental approaches to characterize the TCR repertoire usage in cancer including inherent technical and biological challenges. PMID- 28074288 TI - Clinical research participation among adolescent and young adults at an NCI designated Comprehensive Cancer Center and affiliated pediatric hospital. AB - PURPOSE: Minimal clinical trial participation among adolescents and young adults (AYAs) with cancer limits scientific progress and ultimately their clinical care and outcomes. These analyses examine the current state of AYA clinical research participation at a Midwestern comprehensive cancer center and affiliated pediatric hospital to advise program development and increase availability of trials and AYA participation. Enrollment is examined across all diagnoses, the entire AYA age spectrum (15-39), and both cancer therapeutic and supportive care protocols. METHODS: his study was a retrospective review of electronic medical records via existing databases and registries for all AYAs. Data were collected for AYAs seen by an oncologist at the adult outpatient cancer center or at the pediatric hospital between the years 2010 and 2014. Descriptive statistics and logistic regression analyses were conducted to characterize this sample. RESULTS: In the pediatric setting, 42.3% of AYAs were enrolled in a study compared to 11.2% in the adult setting. Regression analyses in the pediatric setting revealed that AYAs with private insurance or Caucasian race were more likely to participate. Within the adult setting, ethnicity, race, insurance, and diagnosis were associated with study participation; 54.8% of study enrollments were for cancer therapeutic and 43.4% for supportive care studies. CONCLUSIONS: These results are comparable to previously published data and support the need for new local and national AYA initiatives to increase the availability of and enrollment in therapeutic clinical trials. The same is true for supportive care studies which play a crucial role in improving quality of life. PMID- 28074290 TI - A trans-diagnostic approach to psychosis, psychiatric medication nomenclature and stigma. PMID- 28074289 TI - Anamorelin for cancer anorexia-cachexia syndrome: a systematic review and meta analysis. AB - PURPOSE: The aim of this study was to evaluate the therapeutic effects of Anamorelin on patients with cancer anorexia-cachexia syndrome (CACS) based on a meta-analysis of published randomized trials. METHODS: We searched PubMed, Embase, Medline, and the Cochrane Central Register of Controlled Trials databases. Data from each selected study were evaluated individually. All continuous outcomes were calculated by the mean difference or standardized mean difference with 95% confidence interval for each study. Heterogeneity was assessed by using the Chi2 test at a significance level of P < 0.1, in addition to the I 2 statistic (I 2 > 50% indicated substantial heterogeneity). RESULT: At last, four studies were included from 284 records. In three studies, lean body mass was reported and there was a significant difference between placebo and Anamorelin groups (P < 0.00001), without significant heterogeneity (I 2 = 0%). All the four studies reported the body weight change from baseline, and there was significant difference between placebo and Anamorelin groups (P = 0.007), but with high heterogeneity (I 2 = 97%). Two studies reported Anderson Symptom Assessment Scale (ASAS) score, and Anamorelin significantly increased the total ASAS score of CACS patients (P < 0.00001), without any heterogeneity (I 2 = 0%). Three studies reported non-dominant handgrip strength, and there was no significant difference between Anamorelin and placebo groups (P = 0.16). Three studies reported insulin-like growth factor-1 level, and there was significant difference between Anamorelin and placebo groups (P = 0.02), but with high heterogeneity (I 2 = 96%). Three studies reported IGF binding protein-3 concentration. Anamorelin significantly increased such concentration compared with placebo did (P < 0.00001). However, there was still higher heterogeneity (I 2 = 59%). All the included studies reported adverse events. Compared with placebo, Anamorelin induced fewer adverse events, but there was no significant difference between the two groups (RR = 0.07, P = 0.35). CONCLUSION: In the included studies, Anamorelin had some positive effects to relieve the symptoms and improved the quality of life. However, the heterogeneity was apparent, so the clinical effects of Anamorelin should be further validated by increasing the sample size, varying the range of doses during treatment, and observing other outcomes. We are still confident for the future application of Anamorelin in phase III clinical trials. PMID- 28074291 TI - Unaccompanied refugee minors in Germany: attitudes of the general population towards a vulnerable group. AB - Germany saw an increase in numbers of refugees in 2015, with nearly a third being below the age of 18. Unaccompanied refugee minors (URMs) present an especially vulnerable group. In addition to pre-flight and flight stress, the acculturation process can work as potential stressor, and we wanted to explore attitudes towards URM. We conducted a study in a representative sample (n = 2524) of the German population (ages 14 years or older) between January and March 2016. Only 22.8% of participants thought that Germany could accompany more URM. While few participants argued in support of immediate deportation of URM in general (38.6%) or of URM from the Middle East (35.3%), a majority advocated for immediate deportations of URM from the Balkan region (62%) or from Africa (51.1%). Difference in the variance regarding attitudes towards deportation was explained mostly by right-wing political attitudes as well as by islamophobic attitudes and general rejection of asylum seekers. High rates of approval were found for guaranteeing the same chances to schooling or apprenticeship for URM as to German children and for bestowing URM a right to permanent residence if they were able to complete school or apprenticeship. Education and qualification are key to integration. Studies about needs and wishes of URM consistently report a high motivation to learn the language of their new host country and attend school. At this point, hopes of URM and expectations of society meet, which underlines the importance of participation in education as key factor in integration. PMID- 28074292 TI - Reliability of the nociceptive blink reflex evoked by electrical stimulation of the trigeminal nerve in humans. AB - OBJECTIVE: The nociceptive blink reflex (nBR) can be useful to investigate trigeminal nociceptive function. The aim of this study was to estimate the reliability of the nBR evoked by electrical stimulation of the three branches of the trigeminal nerve under the following conditions: over time (test-retest and intrarater reliability) and by two examiners (interrater reliability). MATERIALS AND METHODS: Twenty-one healthy participants were evaluated in two sessions (24 h apart). The nBR was elicited by a so-called "nociceptive-specific" electrode placed over the entry zone of the right supraorbital (V1R), infraorbital (V2R), mental (V3R), and left infraorbital (V2L) nerve. The outcomes were individual electrical sensory (I 0) and pain thresholds (I P); root mean square (RMS), area under-the-curve (AUC), and onset latencies of R2 responses (determined twice after a recalibration session); and stimulus-evoked pain on a 0-10 numerical rating scale. Intraclass correlation coefficients (ICCs) and Kappa statistics were computed (alpha = 5%). RESULTS: ICCs were fair to excellent in 82% of the psychophysical measures (fair 21%, good 31%, excellent 30%) and in 86% of V1R, V2R, and V2L nBR parameters, whereas 52% of V3R showed poor reliability. ICCs for intrarater reliability were fair to good in 70% of measurements (fair 20%, good 50%) and in 75% of interrater measurements after the recalibration (fair 55%, good 20%). All kappa values showed at least fair agreement and the majority of the nBR measures (93%) presented moderate to excellent reliability. CONCLUSION: The nBR and its associated psychophysical measures can be considered a sufficiently reliable test. CLINICAL SIGNIFICANCE: The nBR can be recommended as an electrophysiological technique to assess trigeminal nociceptive function. PMID- 28074293 TI - [Management of NOAK administration during invasive or surgical interventions : When and how to pause and when to restart?] AB - Many patients under oral anticoagulation therapy need percutaneous or surgical interventions/operations. For vitamin K antagonists (VKA), there are recommendations regarding preoperative or postoperative administration. Management of the new oral anticoagulants (NOAC) was supposed to be easier - but some aspects must be considered. Due to the different pharmacokinetic profiles of substances such as dabigatran, rivaroxaban, apixaban, and edoxaban, different recommendations are given.Upon periprocedural management, thromboembolic risk has to be considered in patients treated with NOACs. NOACS have a pharmacokinetic advantage in terms of a rapid onset and rapid elimination via the liver and kidneys. Impaired renal function results in extended half-life of NOACs considerably.Surgical procedures under NOACS can be scheduled at the beginning of next dosing interval or omitted in low/minimal bleeding risk patients, so that only 2-3 NOAC doses are not administered. In patients with moderate and high risk of bleeding, there should be a NOAC break of 24-48 h prior to surgery in order to allow a corresponding decay of the active metabolite. In patients with low/intermediate risk for thromboembolism, no bridging is necessary if the "unprotected" time (NOAC break) is less than 4-5-(7) days. In patients at high risk of thromboembolism, individual consideration must be taken regarding bridging or extended NOAC break. Whether NOACs can be dispensed or bridging is necessary in these patients must be clarified in randomized trials for periprocedural management of NOACs patients. PMID- 28074294 TI - [Procedures on patients receiving NOACs : What's possible?] AB - Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used in patients with deep vein thrombosis (DVT), pulmonary embolism (PE) and atrial fibrillation (AF). However, there is insufficient data concerning the periinterventional, perioperative, and intensive care management of patients on NOACs. Therefore, the recommendations regarding this management rely on pharmacokinetics of the particular NOAC in combination with the individual patient's characteristics, bleeding risk of the planned intervention/surgery, and urgency of the procedure. This review summarizes evidence and recommendations regarding the optimal periinterventional/perioperative antithrombotic management of patients on NOACs. PMID- 28074295 TI - [Neuraxial anaesthesia and NOACs]. AB - BACKGROUND: Cardiovascular comorbidities in surgical patients are frequent and have a substantial impact on the postoperative outcome. Neuraxial blockades are able to reduce perioperative morbidity and mortality. The increasing use of new oral anticoagulants (NOAC) requires a high level of attention, especially in patients undergoing neuraxial blockades or requiring postoperative analgesia. OBJECTIVE: The goal of this article is to present the benefit of neuraxial anaesthesia and analgesia in patients with cardiovascular risks and perioperative management of NOAC in this setting. MATERIALS AND METHODS: Review of the respective literature in PubMed during the last 25 years as well as presentation of the S1 guideline "Neuraxial anaesthesia and thrombo-embolic prophylaxis/antithrombotic medication" of the German Society of Anaesthesiology and Intensive Care Medicine (DGAI). RESULTS: Thoracic epidural anaesthesia and analgesia contribute to an improved outcome in surgical patients with high cardiovascular risk. In order to avoid severe complications in patients on NOACs undergoing neuraxial blockades the S1 guideline of the DGAI must be respected and close interdisciplinary consultations between anaesthetist, cardiologist and surgeon are mandatory. CONCLUSION: In consideration of the respective guideline neuraxial blockades can be performed in cardiovascular risk patients on NOACs, since these techniques contribute to an improved postoperative outcome. PMID- 28074297 TI - [Delirium, analgesia, and sedation in intensive care medicine : Development of a protocol-based management approach]. AB - Intensive care treatment has long-term consequences that are often not immediately apparent to the health care providers. The combination of muscle weakness, cognitive damage, and psychological disorders is comprised under the term post-intensive care syndrome (PICS). Analgesia and sedation protocols, as well as nonpharmacological preventive and therapeutic approaches, are effective tools for avoiding complications and improving long-term survival. The principle of "early goal-directed therapy" is fundamental. Here, a treatment target is defined and continuously re-evaluated by validated monitoring methods. Evidence clearly supports a paradigm shift towards patients that are awake, attentive, and able to participate in their therapy. Individualized analgesia and (non)sedation approaches allow a Richmond Agitation-Sedation Scale (RASS) target value of 0/-1 for the majority of patients. Should sedation indeed be necessary, there must be a focus on avoiding oversedation, especially an early deep sedation. PMID- 28074298 TI - Effect of intraoperative radiotherapy in the treatment of retroperitoneal sarcoma. AB - BACKGROUND: Current National Comprehensive Cancer Network guidelines for the treatment of retroperitoneal sarcomas (RPS) endorse surgical resection, but the role of radiotherapy (RT) is less clear. We investigate the utilization and benefits of intraoperative RT (IORT) in the treatment of RPS. METHODS: We queried the Surveillance, Epidemiology and End Results (SEER) database (1988-2013) for the utilization of IORT and perioperative external beam RT (EBRT) in patients who underwent surgical resection of RPS. Groups were defined as any IORT (aIORT), IORT alone (IORT-), IORT with EBRT (IORT+) and preoperative and/or postoperative EBRT without IORT (EBRT). Demographics, tumor characteristics, extent of disease, and survival were compared between groups. RESULTS: We identified 908 patients with RPS who underwent surgical resection with perioperative RT. Demographics of age, sex, and race were similar between groups. There was no difference in baseline tumor characteristics of mean size, tumor grade, or histological subtype between groups. A higher percentage of patients receiving aIORT had tumors >20 cm in size, and extension beyond local tissues. Liposarcoma and leiomyosarcoma were the most common subtypes overall and in each subgroup. Patients with liposarcoma undergoing IORT and EBRT (IORT+) demonstrated a survival benefit over both IORT alone (IORT-) and EBRT alone. CONCLUSION: IORT was used infrequently for RPS but generated equivalent outcomes compared to EBRT, despite being utilized more often for larger tumors and those with peri-tumoral soft-tissue invasion. Patients with the most common subtype (liposarcoma) may benefit from combination IORT with adjuvant EBRT versus other regimens. PMID- 28074300 TI - Solving the crystal structure of human calcium-free S100Z: the siege and conquer of one of the last S100 family strongholds. AB - The X-ray structure of human apo-S100Z has been solved and compared with that of the zebrafish calcium-bound S100Z, which is the closest in sequence. Human apo S100A12, which shows only 43% sequence identity to human S100Z, has been used as template model to solve the crystallographic phase problem. Although a significant buried surface area between the two physiological dimers is present in the asymmetric unit of human apo-S100Z, the protein does not form the superhelical arrangement in the crystal as observed for the zebrafish calcium bound S100Z and human calcium-bound S100A4. These findings further demonstrate that calcium plays a fundamental role in triggering quaternary structure formation in several S100s. Solving the X-ray structure of human apo-S100Z by standard molecular replacement procedures turned out to be a challenge and required trying different models and different software tools among which only one was successful. The model that allowed structure solution was that with one of the lowest sequence identity with the target protein among the S100 family in the apo state. Based on the previously solved zebrafish holo-S100Z, a putative human holo-S100Z structure has been then calculated through homology modeling; the differences between the experimental human apo and calculated holo structure have been compared to those existing for other members of the family. PMID- 28074299 TI - Dioxygen activation by nonheme iron enzymes with the 2-His-1-carboxylate facial triad that generate high-valent oxoiron oxidants. AB - The 2-His-1-carboxylate facial triad is a widely used scaffold to bind the iron center in mononuclear nonheme iron enzymes for activating dioxygen in a variety of oxidative transformations of metabolic significance. Since the 1990s, over a hundred different iron enzymes have been identified to use this platform. This structural motif consists of two histidines and the side chain carboxylate of an aspartate or a glutamate arranged in a facial array that binds iron(II) at the active site. This triad occupies one face of an iron-centered octahedron and makes the opposite face available for the coordination of O2 and, in many cases, substrate, allowing the tailoring of the iron-dioxygen chemistry to carry out a plethora of diverse reactions. Activated dioxygen-derived species involved in the enzyme mechanisms include iron(III)-superoxo, iron(III)-peroxo, and high-valent iron(IV)-oxo intermediates. In this article, we highlight the major crystallographic, spectroscopic, and mechanistic advances of the past 20 years that have significantly enhanced our understanding of the mechanisms of O2 activation and the key roles played by iron-based oxidants. PMID- 28074302 TI - ENABLE (Exportable Notation and Bookmark List Engine): an Interface to Manage Tumor Measurement Data from PACS to Cancer Databases. AB - Oncologists evaluate therapeutic response in cancer trials based on tumor quantification following selected "target" lesions over time. At our cancer center, a majority of oncologists use Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 quantifying tumor progression based on lesion measurements on imaging. Currently, our oncologists handwrite tumor measurements, followed by multiple manual data transfers; however, our Picture Archiving Communication System (PACS) (Carestream Health, Rochester, NY) has the ability to export tumor measurements, making it possible to manage tumor metadata digitally. We developed an interface, "Exportable Notation and Bookmark List Engine" (ENABLE), which produces prepopulated RECIST v1.1 worksheets and compiles cohort data and data models from PACS measurement data, thus eliminating handwriting and manual data transcription. We compared RECIST v1.1 data from eight patients (16 computed tomography exams) enrolled in an IRB-approved therapeutic trial with ENABLE outputs: 10 data fields with a total of 194 data points. All data in ENABLE's output matched with the existing data. Seven staff were taught how to use the interface with a 5-min explanatory instructional video. All were able to use ENABLE successfully without additional guidance. We additionally assessed 42 metastatic genitourinary cancer patients with available RECIST data within PACS to produce a best response waterfall plot. ENABLE manages tumor measurements and associated metadata exported from PACS, producing forms and data models compatible with cancer databases, obviating handwriting and the manual re-entry of data. Automation should reduce transcription errors and improve efficiency and the auditing process. PMID- 28074301 TI - Tightrope fixation of syndesmotic injuries in Weber C ankle fractures: a multicentre case series. AB - BACKGROUND: No general consensus has yet been established for the gold standard treatment of ankle syndesmotic complex injuries. Recent literature has documented the success of ankle tightrope fixation for heterogeneous ankle fracture patterns, resulting in syndesmotic complex injuries. We present a multicentre case series assessing the clinical, radiological and functional outcomes of patients with Weber C ankle fractures treated with the Arthrex TightRope(r) fixation system. METHOD: We performed a retrospective analysis of all adult patients with Weber C ankle fractures who were treated with the Arthrex TightRope(r) fixation system at four centres over a 3-year period. All patients were followed up for a mean of 14 months (range 12-26). Outcomes measures were assessed subjectively using functional scores (AOFAS and Olerud and Molander) and objectively using radiological measurements, complication rates and revision surgery rates. RESULTS: Thirty-six patients met our eligibility criteria. The mean age at operation was 31 years (range 18-65). There were 20 males and 16 females. No patients were lost to follow-up. The ankle tightrope maintained satisfactory reduction in the ankle mortise in 97% of cases. Of these 35 successfully treated cases, no evidence of re-displacement on follow-up radiographs of the syndesmotic complex was observed at an average of 10.8 months (range 6-12). Post-operative mean medial clear space was 3.1 mm, and mean tibio fibular overlap was 10.1 mm. The mean American Orthopaedic Foot and Ankle Society (AOFAS) score was 88.8 (range 67-98) at a mean follow-up of 14 months (range 12 26). The overall complication rate was 6% (one failure requiring revision surgery and one medial sided skin irritation requiring removal of suture button). No infections or wound complications occurred. CONCLUSION: Tightrope fixation is a safe alternative to screw fixation for syndesmotic complex injuries in Weber C ankle fractures. We have shown that it has low complication rates and a high patient satisfaction. PMID- 28074304 TI - Evaluation of endothelial dysfunction in patients with familial Mediterranean fever: the relationship between the levels of asymmetric dimethylarginine and endocan with carotid intima-media thickness and endothelium-dependent vasodilation. AB - It has been suggested that there is an ongoing subclinical inflammation in familial Mediterranean fever (FMF) patients also in attack-free periods as well. Due to this ongoing inflammation, endothelial dysfunction (ED) may develop. Previously, ED has been suggested to increase the risk of the atherosclerosis and cardiovascular disease (CVD). Endocan is recognized as a specific molecule of the endothelium and has been shown to increase in some cases associated with inflammation. However, there is not sufficient data whether those with FMF could develop ED in the early period of life. In this study, we aimed to investigate ED and its relation with endocan in young FMF patients. A total of 57 male patients diagnosed with FMF according to the Tel Hashomer criteria and a total of 33 healthy males with similar characteristics to the patient group were included in this research. Complete blood count, erythrocyte sedimentation rate (ESR), fibrinogen, serum glucose, serum LDL cholesterol (LDL-C) and triglyceride (TG), asymmetric dimethylarginine (ADMA), and endocan levels were tested from fasting blood samples. Moreover, carotid intima-media thickness (CIMT) and flow-mediated dilatation (FMD) were measured. The endocan levels of the FMF patients during an attack-free period were significantly higher than those of the control group (p < 0.001). On the other hand, FMD measurements were significantly lower among FMF patients (p < 0.001). ADMA levels were higher in the patient group; however, this difference was similar (p > 0.05). CIMT values were similar among FMF patients and healthy controls (p > 0.05). These results have suggested that ED may develop in the patients with FMF who have no additional CVD risk, even during young adulthood, and endocan may be a favorable biomarker at demonstration of ED than ADMA among FMF patients. PMID- 28074305 TI - Clinical effectiveness of low-level laser treatment on peripheral somatosensory neuropathy. AB - Peripheral sensory neuropathy treatment is one of the common treatment problems and causes morbidity and mortality in people suffering from that. Although treatment depends on the underlying cause of the condition, nevertheless, in some cases, there is no cure for it, and it requires palliative and symptomatic treatment. In laboratory studies, low-level laser has been effective in the nerves protection and restoration. The aim of this article is to investigate the clinical efficacy of low-level laser on improvement of the peripheral somatosensory neuropathy. Search in the articles published up to 30 October 2015 (full text and abstracts) in databases PubMed (Medline), Cochrane library, Physiotherapy Evidence Database was performed. The studies of low-level laser trials on patients with peripheral neuropathy were carried out and evaluated in terms of the exclusion criteria. There are 35 articles among which 10 articles had the intended and required criteria. 1, 3, and 6 articles study the patients with diabetes, neuropathy caused by trauma, and carpal tunnel syndrome, respectively. In six studies, laser led to a reduction in sensory impairment and improvement of the physiological function of the sensory nerves. In these articles, lasers (Diode, GaAlAs, He-Ne) had wavelength range 660-860 nm, radiation power 20-250 mW, energy density 0.45-70 J/cm2. The intervention sessions range was 6-21 times and patient follow-up was 0-6 months. According to the results of these studies, low-level laser therapy can improve sensory function in patients with peripheral somatosensory neuropathy, although little research have not been done, laser treatment regimens are varied and do not recommend a specific treatment protocol. It seems it requires more research to sum up better, particularly in relation to diabetes. PMID- 28074306 TI - Second and Thirdhand Smoke Exposure, Attitudes and Protective Practices: Results from a Survey of Hispanic Residents in Multi-unit Housing. AB - Secondhand and third hand smoke (SHS, THS) exposure is prevalent in multi-unit housing (MUH). Minorities and low-income MUH residents are disproportionally exposed to SHS and THS compared to other populations. This study describes the characteristics, attitudes, knowledge, and behaviors related to SHS, THS and marijuana smoke exposure (MSHS) of a sample of Hispanic tenants in randomly selected MUH units in eastern metro Los Angeles (n = 402). Although most participants (97%) banned smoking inside their homes, 80% reported infiltration of SHS inside their apartments within the last year. Most (85%) favored a complete ban on smoking in apartment buildings. Twenty-eight percent did not know that marijuana (MSHS) smoke exposure is also harmful to their health. Knowledge scores were higher among Spanish-speakers (p < 0.05). Given the interpersonal barriers to advocating for change, widespread policy and communication interventions are also necessary to protect Hispanic MUH residents' rights to clean air in their living space. PMID- 28074307 TI - Clinical characteristics and long-term outcome of diarrhea-associated hemolytic uremic syndrome: a single center experience. AB - OBJECTIVES: To clarify the clinical characteristics and long-term outcomes of patients with diarrhea-associated hemolytic uremic syndrome (D + HUS) with a particular focus on time course. METHODS: We retrospectively analyzed the medical records of 61 patients with D + HUS who were admitted to Kobe University Hospital between 1995 and 2015. The onset of D + HUS was defined as day 1 of diarrhea. RESULTS: The age of onset was 4.1 (1.5-13.4) years, and the period between onset and diagnosis of D + HUS was 5 (3-18) days. The platelet count was lowest on day 7 (4-24), and the lactase dehydrogenase level was maximal on day 8 (4-25). Twenty three patients required dialysis for 13 (2-37) days, starting at day 5-9. Seventeen patients showed central nervous system (CNS) symptoms at day 4-18. They were followed up for 3.7 (0-18.4) years. At the final follow-up, estimated glomerular filtration rate was 113.7 (57.9-159.9) ml/min/1.73 m2 with five patients having chronic kidney disease. Three patients developed CNS sequelae. The time to diagnosis was significantly shorter in the group of patients receiving dialysis than without dialysis (p = 0.018) and in the group with CNS complications than without (p = 0.013). CONCLUSION: CNS complications were often apparent after blood examination results improved. Moreover, a shorter period between the onset of diarrhea and a diagnosis of D + HUS indicated a more severe clinical course or long-term sequelae, and it should be considered as a risk factor for poor prognosis. PMID- 28074308 TI - Influence of TS and ABCB1 gene polymorphisms on survival outcomes of 5-FU-based chemotherapy in a Chinese population of advanced gastric cancer patients. AB - To investigate the impacts of gene variations on survival outcomes of advanced gastric cancer (AGC) patients treated with 5-fluorouracil (5-FU)-based chemotherapy, we analyzed the associations of 2 indels of the TS gene rs34743033 (double or triple tandem repeats of a 28 bp sequence in 5'-UTR, denoted as 2R or 3R allele) and rs16430 (a 6 bp variation at 1494 bp in 3'-UTR, denoted as ins6 or del6 allele) and 2 single nucleotide polymorphisms (SNPs) of ABCB1gene rs2032582 in exon 21 and rs1045642 in exon 26, with clinical outcomes after 5-FU treatment. Generally, indels rs34743033 and rs16430 were genotyped by PCR and polyacrylamide gel electrophoresis assay and SNPs rs2032582 and rs1045642 were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in 110 Chinese AGC patients post-chemotherapy. Cox regression analysis was used to analyze the risk factors affecting patient survival. As a result, rs34743033, rs1045642 and rs2032582 were shown to be significantly associated with overall survival (P < 0.05), and associations between the four polymorphisms with disease-free survival were also observed (P < 0.05). Moreover, we found that genotypes rs34743033 3R/2R, rs16430 ins6/del6, rs1045642 CC or CT, and rs2032582 GG were beneficial predictors of clinical treatment outcome in AGC patients, suggesting some clinical implications in chemotherapy of a Chinese population. PMID- 28074309 TI - Helicobacter pylori-induced premature senescence of extragastric cells may contribute to chronic skin diseases. AB - Helicobacter pylori, one of the most frequently observed bacterium in the human intestinal flora, has been widely studied since Marshall and Warren documented a link between the presence of H. pylori in the gastrointestinal tract and gastritis and gastric ulcers. Interestingly, H. pylori has also been found in several other epithelial tissues, including the eyes, ears, nose and skin that may have direct or indirect effects on host physiology and may contribute to extragastric diseases, e.g. chronic skin diseases. More recently, it has been shown that H. pylori cytotoxin CagA expression induces cellular senescence of human gastric nonpolarized epithelial cells that may lead to gastrointestinal disorders and systemic inflammation. Here, we hypothesize that also chronic skin diseases may be promoted by stress-induced premature senescence (SIPS) of skin cells, namely fibroblasts and keratinocytes, stimulated with H. pylori cytotoxins. Future studies involving cell culture models and clinical specimens are needed to verify the involvement of H. pylori in SIPS-based chronic skin diseases. PMID- 28074310 TI - Recurrence of Lower Urinary Tract Symptoms Following Prostate Artery Embolization for Benign Hyperplasia: Single Center Experience Comparing Two Techniques. AB - PURPOSE: To compare recurrence of lower urinary tract symptoms (LUTS) recurrence at 12 months following original prostate artery embolization (oPAE) or "proximal embolization first, then embolize distal" (PErFecTED) PAE for benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: 105 consecutive patients older than 45 years, with prostate size greater than 30 cm3, International Prostate Symptom Score (IPSS) >= 8, quality of life (QoL) index >= 3, and refractory status or intolerance of medical management were prospectively enrolled between June 2008 and August 2013. The study was IRB-approved, and all patients provided informed consent. Patients underwent oPAE or PErFecTED PAE and were followed for at least 12 months. Technical success was defined as bilateral embolization and clinical success (non-recurrence) was defined as removal of the Foley catheter in patients with urinary retention, IPSS < 8 and QoL index < 3 at 12 months of follow-up. Nonparametric statistics were used to compare the study groups due to the size of the study population and distributions of clinical data. RESULTS: 97 patients had 12-month data and were categorized as oPAE without recurrence (n = 46), oPAE with recurrence (n = 13), PErFecTED without recurrence (n = 36), or PErFecTED with recurrence (n = 2). Recurrence was significantly more common in oPAE patients (chi 2, p = 0.026). Unilateral embolization was significantly associated with recurrence among patients who underwent oPAE (chi 2, p = 0.032). CONCLUSIONS: Both oPAE and PErFecTED PAE are safe and effective methods for treatment of LUTS, but PErFecTED PAE is associated with a significantly lower rate of symptom recurrence. PMID- 28074311 TI - Improving Maternal and Infant Child Health Outcomes with Community-Based Pregnancy Support Groups: Outcomes from Moms2B Ohio. AB - Objectives To describe temporal changes in maternal and child health outcomes in an impoverished urban community after the implementation of an innovative community-based pregnancy support program, named Moms2B. Methods Beginning in 2011, pregnant women in an urban impoverished community were recruited for participation in a community-based pregnancy support program focused on improving nutrition coupled with increasing social and medical support. The comprehensive program targeting pregnancy through the infants' first year of life was developed and staffed by a multidisciplinary team from an academic health system. As a preliminary effort to assess the effectiveness of Moms2B, we examined maternal and infant health characteristics in the community before and after implementation of the program. Results From 2011 to 2014, 195 pregnant women attended one or more Moms2B sessions at the Weinland Park (WP) location. Most (75%) were African American (AA) with incomes below $800 per month and significant medical and social stressors. Outcomes from the two WP census tracts before and after implementation of the Moms2B program were studied. From 2007 to 2010, there were 442 births in WP and 6 infant deaths for an infant mortality rate of 14.2/1000. In 2011-2014, the first four years of the Moms2B program there were 339 births and one infant death giving an IMR of 2.9/1000, nearly a five fold reduction in the rate of an infant death. Among pregnant women in WP who were covered by Medicaid, the breastfeeding initiation rate improved from 37.9 to 75.5% (p < .01) after the introduction of Moms2B. There were no infant deaths among Moms2B participants at the WP location in the first four years of the program. Conclusions Implementation of an innovative community-based pregnancy support program was associated with important improvements in maternal and infant health in an impoverished neighborhood. PMID- 28074312 TI - Barriers to and Facilitators of Adherence to Exclusive Breastfeeding Practices Among HIV Infected and Non-Infected Women in Jos, Nigeria. AB - Objectives In Nigeria adherence to exclusive breastfeeding (EBF) practices is currently suboptimal and a better understanding of the factors affecting adherence to EBF is needed. We sought to identify and delineate the barriers to and facilitators of adherence to EBF amongst HIV-infected and uninfected women in Nigeria. Methods We explored the barriers and facilitators to EBF amongst 37 (25 HIV-infected and 12 HIV-uninfected) pregnant women attending an antenatal clinic in Jos, Nigeria. In-depth interviews were conducted with each of the pregnant women in their third trimester of pregnancy and again 1 month after giving birth. Results The themes that emerged were mothers' feeding intentions, significant role players in the decision to breastfeed, perceived barriers (e.g. physiological issues, stigma, employment) and perceived facilitators (e.g. pleasure and enjoyment derived from breastfeeding, natural milk from God, disclosure and family support) associated with EBF. Conclusions Most women preferred EBF and offered it to their infants. However, more efforts are needed to improve support structures at home and at work to accommodate women who choose to do EBF. PMID- 28074313 TI - Characterizing Clinical Genetic Counselors' Countertransference Experiences: an Exploratory Study. AB - Countertransference (CT) refers to conscious and unconscious emotions, fantasies, behaviors, perceptions, and psychological defenses genetic counselors experience in response to any aspect of genetic counseling situations (Weil 2010). Some authors theorize about the importance of recognizing and managing CT, but no studies solely aim to explore genetic counselors' experiences of the phenomenon. This study examined the extent to which clinical genetic counselors' perceive themselves as inclined to experience CT, gathered examples of CT encountered in clinical situations, and assessed their CT management strategies. An anonymous online survey, sent to NSGC members, yielded 127 usable responses. Participants completed Likert-type items rating their CT propensities; 57 of these individuals also provided examples of CT they experienced in their practice. Factor analysis of CT propensities tentatively suggested four factors: Control, Conflict Avoidance, Directiveness, and Self-Regulation, accounting for 38.5% of response variance. Thematic analysis of CT examples yielded five common triggers: general similarity to patient, medical/genetic similarity, angry patients, patient behaves differently from counselor expectations, and disclosing bad news; six common manifestations: being self-focused, projecting feelings onto the patient, intense emotional reaction to patient, being overly invested, disengagement, and physical reaction; five CT effects: disruption in rapport building, repaired empathy, over-identification, conversation does not reach fullest potential, and counselor is drained emotionally; and three management strategies: recognizing CT as it occurs, self-reflection, and consultation. Results suggest CT is a common experience, occurring in both "routine" and emotionally complex cases. Training programs, continuing education, and peer supervision might include discussion of CT, informed by examples from the present study, to increase genetic counselor awareness and skills for managing the phenomenon. PMID- 28074314 TI - A Novel Effect of beta-Adrenergic Receptor on Mammary Branching Morphogenesis and its Possible Implications in Breast Cancer. AB - Understanding the mechanisms that govern normal mammary gland development is crucial to the comprehension of breast cancer etiology. beta-adrenergic receptors (beta-AR) are targets of endogenous catecholamines such as epinephrine that have gained importance in the context of cancer biology. Differences in beta2-AR expression levels may be responsible for the effects of epinephrine on tumor vs non-tumorigenic breast cell lines, the latter expressing higher levels of beta2 AR. To study regulation of the breast cell phenotype by beta2-AR, we over expressed beta2-AR in MCF-7 breast cancer cells and knocked-down the receptor in non-tumorigenic MCF-10A breast cells. In MCF-10A cells having knocked-down beta2 AR, epinephrine increased cell proliferation and migration, similar to the response by tumor cells. In contrast, in MCF-7 cells overexpressing the beta2-AR, epinephrine decreased cell proliferation and migration and increased adhesion, mimicking the response of the non-tumorigenic MCF-10A cells, thus underscoring that beta2-AR expression level is a key player in cell behavior. beta-adrenergic stimulation with isoproterenol induced differentiation of breast cells growing in 3-dimension cell culture, and also the branching of murine mammary epithelium in vivo. Branching induced by isoproterenol was abolished in fulvestrant or tamoxifen-treated mice, demonstrating that the effect of beta-adrenergic stimulation on branching is dependent on the estrogen receptor (ER). An ER independent effect of isoproterenol on lumen architecture was nonetheless found. Isoproterenol significantly increased the expression of ERalpha, Ephrine-B1 and fibroblast growth factors in the mammary glands of mice, and in MCF-10A cells. In a poorly differentiated murine ductal carcinoma, isoproterenol also decreased tumor growth and induced tumor differentiation. This study highlights that catecholamines, through beta-AR activation, seem to be involved in mammary gland development, inducing mature duct formation. Additionally, this differentiating effect could be resourceful in a breast tumor context. PMID- 28074315 TI - The roundworm Strongyloides stercoralis in children, dogs, and soil inside and outside a segregated settlement in Eastern Slovakia: frequent but hardly detectable parasite. AB - A comparative study was carried out to evaluate the Strongyloides stercoralis infections in children and dogs inside and outside the segregated settlement in Medzev, Eastern Slovakia, and a survey of the soil within the settlement was included. Applying the Koga agar plate (KAP) culture method and microscopy examination of stool samples collected from 60 Roma and 21 nonRoma children, no larvae of S. stercoralis were detected but eggs of three nematodes (Ascaris lumbricoides, Trichuris trichiura, and Enterobius vermicularis) and cysts of two protozoan endoparasites (Giardia duodenalis and Cryptosporidium spp.) were often found. However, immunoenzymatic assay (ELISA) for the evidence of IgG antibodies against S. stercoralis showed 33.3% seroprevalence in Roma children and 23.8% prevalence in children from the majority population, attending the same school. Eosinophilia was regularly present in children with exclusive infection of S. stercoralis (eight cases) as well as in individuals suffering from mixed infections of S. stercoralis and some of the above listed parasites (16 cases); high eosinophil counts sometimes, but not always, occurred in parasitized children lacking S. stercoralis antibodies. A comparison of S. stercoralis in dogs from the settlement (40 dogs) and from a distant dog shelter (20 dogs) did not reveal remarkable differences: the direct microscopy of faecal samples revealed rhabditiform larvae in 13.3% of the dogs from the settlement (4/30) and in 10.0% of the dogs from the shelter (2/20). Out of blood samples collected from the second dog group, 55% of the dogs contained antibodies against S. stercoralis. In the soil collected from 14 various locations within the settlement, S. stercoralis larvae were observed in two samples (14.3%); however, 13 samples (92.9%) were positive for human or dog endoparasites of the genera Ancylostoma, Ascaris, Toxocara, Toxascaris, Trichuris, and Hymenolepis. PMID- 28074316 TI - Familial Juvenile Idiopathic Arthritis. PMID- 28074317 TI - The First Everett Mendelsohn Prize. PMID- 28074318 TI - Boosted large-scale production and purification of a thermostable archaeal phosphotriesterase-like lactonase for organophosphate decontamination. AB - Thermostable phosphotriesterase-like lactonases (PLLs) from extremophile archaea, like SsoPox from Sulfolobus solfataricus, are attractive biotechnological tools with industrial applications as organophosphate decontaminants, but their manufacturing still remains an unresolved issue because of the high costs and the low production yields. In this paper, for the first time, an efficient biotechnological process for the production and purification of a recombinant, engineered PLL, SsoPox W263F, expressed in E. coli, has been set up by studying new induction strategies, by designing high cell density cultivations and a new membrane-based downstream process. In fed batches, the enzyme production was boosted of 69-fold up to 4660.0 U L-1 using galactose as inducer in the replacement of IPTG; the process was scalable from 2.5 up to 150 L. By coupling a single thermo-precipitation step and an ultrafiltration process, a total enzyme recovery of 77% with a purity grade of almost 80% was reached. PMID- 28074319 TI - Trans-Fatty Acid-Stimulated Mammary Gland Growth in Ovariectomized Mice is Fatty Acid Type and Isomer Specific. AB - We previously reported that the trans-18:2 fatty acid trans-10, cis-12 conjugated linoleic acid (t10,c12-CLA) stimulates mammary gland development independent of estrogen and its receptor. Given the negative consequences of dietary trans-fatty acids on various aspects of human health, we sought to establish whether other trans-fatty acids could similarly induce ovary-independent mammary gland growth in mice. Prepubertal BALB/cJ mice were ovariectomized at 21 days of age then were fed diets enriched with cis-9, trans-11 CLA (c9,t11-CLA), or mixtures of trans 18:1 fatty acids supplied by partially hydrogenated sunflower, safflower, or linseed oil. The resultant mammary phenotype was evaluated 3 weeks later and compared to the growth response elicited by t10,c12-CLA, or the defined control diet. Whereas partially hydrogenated safflower oil increased mammary gland weight, none of the partially hydrogenated vegetable oils promoted mammary ductal growth. Similarly, the c9,t11-CLA supplemented diet was without effect on mammary development. Taken together, our data emphasize a unique effect of t10,c12-CLA in stimulating estrogen-independent mammary gland growth manifest as increased mammary ductal area and elongation that was not recapitulated by c9,t11-CLA or the partially hydrogenated vegetable oil diets. PMID- 28074320 TI - Algorithmic three-dimensional analysis of tumor shape in MRI improves prognosis of survival in glioblastoma: a multi-institutional study. AB - In this retrospective, IRB-exempt study, we analyzed data from 68 patients diagnosed with glioblastoma (GBM) in two institutions and investigated the relationship between tumor shape, quantified using algorithmic analysis of magnetic resonance images, and survival. Each patient's Fluid Attenuated Inversion Recovery (FLAIR) abnormality and enhancing tumor were manually delineated, and tumor shape was analyzed by automatic computer algorithms. Five features were automatically extracted from the images to quantify the extent of irregularity in tumor shape in two and three dimensions. Univariate Cox proportional hazard regression analysis was performed to determine how prognostic each feature was of survival. Kaplan Meier analysis was performed to illustrate the prognostic value of each feature. To determine whether the proposed quantitative shape features have additional prognostic value compared with standard clinical features, we controlled for tumor volume, patient age, and Karnofsky Performance Score (KPS). The FLAIR-based bounding ellipsoid volume ratio (BEVR), a 3D complexity measure, was strongly prognostic of survival, with a hazard ratio of 0.36 (95% CI 0.20-0.65), and remained significant in regression analysis after controlling for other clinical factors (P = 0.0061). Three enhancing-tumor based shape features were prognostic of survival independently of clinical factors: BEVR (P = 0.0008), margin fluctuation (P = 0.0013), and angular standard deviation (P = 0.0078). Algorithmically assessed tumor shape is statistically significantly prognostic of survival for patients with GBM independently of patient age, KPS, and tumor volume. This shows promise for extending the utility of MR imaging in treatment of GBM patients. PMID- 28074321 TI - Predictive factors of early distant brain failure after gamma knife radiosurgery alone in patients with brain metastases of non-small-cell lung cancer. AB - The objective of this study was to elucidate the predictive factors for early distant brain failure in patients with brain metastases of non-small-cell lung cancer (NSCLC) who were treated with gamma knife radiosurgery (GKRS) without previous whole-brain radiotherapy (WBRT) or surgery. We retrospectively reviewed clinical and imaging data of 459 patients with brain metastases of NSCLC who underwent GKRS from June 2008 to December 2013. The primary end-point was early distant brain failure, defined as the detection of newly developed metastatic lesions on magnetic resonance imaging (MRI) 3 months after GKRS. Factors such as tumor pathology subtype, concurrent systemic chemotherapy, epidermal growth factor receptor (EGFR) mutation status, use of EGFR tyrosine kinase inhibitors (TKIs), systemic disease status, presence of a metastatic lesion only in delayed MRI, and volume and number of metastases were analyzed. There were no statistically significant differences with respect to pathologic subtype, concurrent systemic chemotherapy, EGFR mutation, and early distant brain failure. Patients treated with EGFR-TKIs (p = 0.004), with a stable systemic disease status (p = 0.028) and 3 or fewer brain lesions (p = 0.000) experienced a significantly lower incidence of early distant brain failure. This study suggests that GKRS alone could be considered for patients treated with EGFR-TKIs who have a stable systemic disease status and 3 or fewer brain lesions. WBRT should be considered for other patients. PMID- 28074322 TI - Decreased survival in glioblastomas is specific to contact with the ventricular subventricular zone, not subgranular zone or corpus callosum. AB - The clinical effect of radiographic contact of glioblastoma (GBM) with neurogenic zones (NZ)-the ventricular-subventricular (VSVZ) and subgranular (SGZ) zones-and the corpus callosum (CC) remains unclear and, in the case of the SGZ, unexplored. We investigated (1) if GBM contact with a NZ correlates with decreased survival; (2) if so, whether this effect is associated with a specific NZ; and (3) if radiographic contact with or invasion of the CC by GBM is associated with decreased survival. We retrospectively identified 207 adult patients who underwent cytoreductive surgery for GBM followed by chemotherapy and/or radiation. Age, preoperative Karnofsky performance status score (KPS), and extent of resection were recorded. Preoperative MRIs were blindly analyzed to calculate tumor volume and assess its contact with VSVZ, SGZ, CC, and cortex. Overall (OS) and progression free (PFS) survivals were calculated and analyzed with multivariate Cox analyses. Among the 207 patients, 111 had GBM contacting VSVZ (VSVZ+GBMs), 23 had SGZ+GBMs, 52 had CC+GBMs, and 164 had cortex+GBMs. VSVZ+, SGZ+, and CC+ GBMs were significantly larger in size relative to their respective non-contacting controls. Multivariate Cox survival analyses revealed GBM contact with the VSVZ, but not SGZ, CC, or cortex, as an independent predictor of lower OS, PFS, and early recurrence. We hypothesize that the VSVZ niche has unique properties that contribute to GBM pathobiology in adults. PMID- 28074323 TI - Changes in cerebral metabolism during ketogenic diet in patients with primary brain tumors: 1H-MRS study. AB - Normal brain cells depend on glucose metabolism, yet they have the flexibility to switch to the usage of ketone bodies during caloric restriction. In contrast, tumor cells lack genomic and metabolic flexibility and are largely dependent on glucose. Ketogenic-diet (KD) was suggested as a therapeutic option for malignant brain cancer. This study aimed to detect metabolic brain changes in patients with malignant brain gliomas on KD using proton magnetic-resonance-spectroscopy (1H MRS). Fifty MR scans were performed longitudinally in nine patients: four patients with recurrent glioblastoma (GB) treated with KD in addition to bevacizumab; one patient with gliomatosis-cerebri treated with KD only; and four patients with recurrent GB who did not receive KD. MR scans included conventional imaging and 1H-MRS acquired from normal appearing-white-matter (NAWM) and lesion. High adherence to KD was obtained only in two patients, based on high urine ketones; in these two patients ketone bodies, Acetone and Acetoacetate were detected in four MR spectra-three within the NAWM and one in the lesion area -4 and 25 months following initiation of the diet. No ketone-bodies were detected in the control group. In one patient with gliomatosis-cerebri, who adhered to the diet for 3 years and showed stable disease, an increase in glutamin + glutamate and reduction in N-Acetyl-Aspartate and myo-inositol were detected during KD. 1H MRS was able to detect ketone-bodies in patients with brain tumors who adhered to KD. Yet it remains unclear whether accumulation of ketone bodies is due to increased brain uptake or decreased utilization of ketone bodies within the brain. PMID- 28074324 TI - How to deal with giant pituitary adenomas: transsphenoidal or transcranial, simultaneous or two-staged? AB - Giant pituitary adenomas (diameter >4 cm) are a challenge to treat, and there is no consensus on the optimal surgical strategy. We report here our experience in surgical management of these lesions. Adult patients with giant pituitary adenomas (n = 62; 54 non-functioning and eight hormone-secreting adenomas) who underwent surgical resection at our hospital from 2009 to 2015 were retrospectively reviewed. Surgical and clinical outcomes were analyzed. Single transsphenoidal and transcranial approaches were used in 43 (69.4%) and four (6.5%) patients, respectively. A combined transsphenoidal and transcranial approach was used in 13 patients (20.9%) and in two patients (3.2%), a transcranial procedure was followed 3 months later by a transsphenoidal approach. Greater than 90% resection was achieved in 47 cases (75.8%). During a mean follow up period of 46.9 months, 49 patients (79%) showed improved visual impairment scores, while none experienced visual deterioration. There was no post-operative hemorrhage or mortality. A total of 27 patients (43.5%) received adjuvant medical and/or radiation therapy. At last follow-up, eight patients (12.9%) had recurrence. For giant pituitary adenoma, the transsphenoidal and transcranial approaches should be combined flexibly based on the characteristics of the tumor. In certain cases, a simultaneous combined approach can maximize tumor extirpation and lower the risk of swelling and bleeding of the residual tumor. PMID- 28074325 TI - Anticipatory Positive Urine Tests for Bladder Cancer. AB - PURPOSE: The aim of this study was to establish the criteria defining an anticipatory positive test for bladder cancer. METHODS: We reviewed all patients at our institution who underwent urine cytology or UroVysion fluorescence in situ hybridization (FISH) and cystoscopy from 2003 to 2012. Test performance and cancer anticipation was assessed using generalized linear mixed models, mixed effects proportional hazards models, and cumulative incidence curves using tests performed within 30 days of each other as well as within a lag time of 1 year. RESULTS: Overall, 6729 urine tests (4729 cytology and 2040 UroVysion FISH) were paired with gold-standard cystoscopies. Sensitivity and specificity were 63 and 41% for cytology, and 37 and 84% for UroVysion FISH, respectively. A 1-year lag time allowed for cancer anticipation and neither test improved. Among patients with positive cytology and initially negative cystoscopy, the hazard ratio of developing a bladder tumor at 1 year was 1.83; 76% of these patients developed a tumor within 1 year. Similarly, among patients with a positive FISH and initially negative cystoscopy, the hazard ratio of developing a bladder tumor at 1 year was 1.56; 40% of these patients developed a tumor within 1 year. CONCLUSIONS: Urine based tests for bladder cancer are frequently falsely positive. With further follow-up time, some of these false positive tests are vindicated as true (anticipatory) positive tests, although many will remain false positives. We developed statistical criteria to determine if a test anticipates future cancers or not. PMID- 28074326 TI - Minimally Invasive Staging Surgery in Women with Early-Stage Endometrial Cancer: Analysis of the National Cancer Data Base. AB - PURPOSE: The aim of this study was to determine factors associated with the adoption of minimally invasive surgery (MIS) compared with laparotomy in the treatment of endometrial cancer and to compare surgical outcomes and survival between these two surgical modalities. METHODS: We utilized the National Cancer Data Base (NCDB) to identify women diagnosed with presumed early-stage endometrial cancer between 2010 and 2012. We also identified factors associated with the performance of MIS and utilized propensity score matching to create a matched cohort of women who underwent minimally invasive staging surgery or laparotomy for surgical staging. RESULTS: Overall, 20,346 women were eligible for inclusion in the study; 12,604 (61.9%) had MIS, while 7742 (38.1%) had a laparotomy. African American race (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.49-0.60], Hispanic ethnicity (OR 0.70, 95% CI 0.61-0.80), Charlson score >2 (OR 0.79, 95% CI 0.69-0.91), high-grade histology (OR 0.63, 95% CI 0.59-0.68), presumed clinical stage II disease (OR 0.53, 95% CI 0.46-0.60), and surgery at a community cancer program (OR 0.46, 95% CI 0.39-0.55) or in the Midwest region (OR 0.70, 95% CI 0.64-0.76) were associated with a decreased likelihood of having MIS, while private insurance (OR 1.69, 95% CI 1.45-1.97) and highest quartile median household income (OR 1.13, 95% CI 1.03-1.24) were associated with an increased likelihood of having MIS. After propensity score matching, there was no association between minimally invasive staging surgery and 3-year overall survival (hazard ratio 1.03, 95% CI 0.92-1.16). CONCLUSION: There are notable racial, ethnic, socioeconomic, and geographic variations in the utilization of MIS for endometrial cancer staging in the US. After controlling for the aforementioned factors, MIS had a similar 3-year survival compared with laparotomy in women undergoing staging surgery for endometrial cancer. PMID- 28074327 TI - When Should Negative Endobronchial Ultrasonography Findings be Confirmed by a More Invasive Procedure? AB - The treatment of non-small cell lung cancer is largely dependent on accurate staging in order to determine appropriate therapy. Despite advances in imaging, such as computed tomography and positron emission tomography, invasive mediastinal staging is frequently needed to rule out mediastinal involvement prior to curative-intent stereotactic ablative radiotherapy or surgical resection. Surgical mediastinal staging with mediastinoscopy, or anterior mediastinotomy, were traditionally considered the gold standard for invasive mediastinal staging. Endobronchial and endoscopic ultrasound have emerged as modern techniques that are being used as first-line options instead of surgical staging. As experience is gained with these newer techniques, the need for confirmatory surgical staging continues to diminish. This article addresses the situations in which negative results should be confirmed by a more invasive procedure. PMID- 28074328 TI - LipidPioneer : A Comprehensive User-Generated Exact Mass Template for Lipidomics. AB - Lipidomics, the comprehensive measurement of lipid species in a biological system, has promising potential in biomarker discovery and disease etiology elucidation. Advances in chromatographic separation, mass spectrometric techniques, and novel substrate applications continue to expand the number of lipid species observed. The total number and type of lipid species detected in a given sample are generally indicative of the sample matrix examined (e.g., serum, plasma, cells, bacteria, tissue, etc.). Current exact mass lipid libraries are static and represent the most commonly analyzed matrices. It is common practice for users to manually curate their own lists of lipid species and adduct masses; however, this process is time-consuming. LipidPioneer, an interactive template, can be used to generate exact masses and molecular formulas of lipid species that may be encountered in the mass spectrometric analysis of lipid profiles. Over 60 lipid classes are present in the LipidPioneer template and include several unique lipid species, such as ether-linked lipids and lipid oxidation products. In the template, users can add any fatty acyl constituents without limitation in the number of carbons or degrees of unsaturation. LipidPioneer accepts naming using the lipid class level (sum composition) and the LIPID MAPS notation for fatty acyl structure level. In addition to lipid identification, user-generated lipid m/z values can be used to develop inclusion lists for targeted fragmentation experiments. Resulting lipid names and m/z values can be imported into software such as MZmine or Compound Discoverer to automate exact mass searching and isotopic pattern matching across experimental data. Graphical Abstract ?. PMID- 28074329 TI - Dietary adequacy of Egyptian children with autism spectrum disorder compared to healthy developing children. AB - Although the etiology and pathology of autism spectrum disorder (ASD) is still poorly understood, a number of environmental, anthropological, neurobiological and genetic factors have been related to the pathophysiology of ASD, even the impact of oxidative stress response related to the environment and nutrition intake. Usual recommended dietary habits are based on the combination of behavioral and dietary or nutraceutical interventions together with pharmacotherapy. Investigations about a reliable relationship between diet and ASD are still lacking. The present study aimed at comparing dietary regimens and habits of normally developing apparently healthy children, without diagnosed ASD, with a pediatric population of individuals affected by autistic disorder. Assessments of nutritional and anthropometric data, in addition to biochemical evaluation for nutrient deficiencies, were performed. A total of 80 children with autistic disorder and 80 healthy, normally developing pediatric individuals were enrolled in the study. Parents were asked to complete the standardized questionnaire regarding the different types of food and the proportion of a serving for their children. Biochemical analysis of micro- and macronutrients were also done. Plotting on the Egyptian sex-specific anthropometric growth (auximetric) chart, absolute weights as well as weight-related for age classes, were significantly higher in cases than healthy controls. No differences between groups were observed in regard to total kilocalories (kcal), carbohydrates, and fat intake. A total of 23.8% of children with autistic disorder vs. 11.3% in the healthy control group had a nutrient intake with features below the Recommended Dietary Allowance (RDA) of protein. Children with autistic disorder showed low dietary intake of some micronutrients; calcium (Ca), magnesium (Mg), iron (Fe), selenium (Se) and sodium (Na), also they had significantly high intake of potassium (K) and vitamin C compared to healthy controls. Serum Mg, Fe, Ca, folate and vitamin B12 in children with autistic disorder were significantly low compared with healthy children. Significant positive correlations between serum Mg, Fe, Ca, vitamin B12 and folate and their levels in food were present. These results confirmed that different nutritional inadequacy was observed in Egyptian children with autistic disorder. The evidence reported in the present study should recommend screening of the nutritional status of ASD children for nutrient adequacy to reduce these deficiencies by dietary means or by administering appropriate vitamin and mineral supplements. Nutritional intervention plan should be tailored to address specific needs. PMID- 28074330 TI - Comparison of Core Needle Biopsy and Excision Specimens for the Accurate Evaluation of Breast Cancer Molecular Markers: a Report of 1003 Cases. AB - In this study, we compared the accuracy of marker evaluation in core needle biopsy (CNB) specimens versus excision specimens (ESs) from breast cancer patients. This retrospective study used data collected from the breast cancer database at the West China Hospital, China. Immunohistochemistry (IHC) results from CNB specimens and ESs were compared, using estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 as markers. Molecular subtyping and endocrine therapy usage correlations based on CNB samples and ESs were evaluated. The results obtained from CNB samples and ESs exhibited substantial agreement for the detection of ER (kappa = 0.522), PR (kappa = 0.441), and HER2 (kappa = 0.451), and also influenced endocrine therapy usage. Fair and poor correlations were observed for Ki-67 staining and molecular subtyping (kappa = 0.195), respectively. This disagreement might be attributable to a combination of heterogeneity and large tumor size. This study indicates that the discordance rate in molecular marker staining between CNB specimens and ESs is significant enough that results obtained with CNB specimens should be used cautiously or verified using ESs. PMID- 28074331 TI - A Retrospective Analysis of the First 41 mCRPC Patients with Bone Pain Treated with Radium-223 at the National Institute of Oncology in Hungary. AB - Radium-223 dichloride is an alpha-emitting radiopharmaceutical which significantly prolongs overall survival in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases. This was a retrospective analysis of the efficacy and safety of Radium-223 in the first 41 patients treated at a single center in Hungary. Radium-223 was given at a dose of 50 kBq/kg intravenously every 4 weeks for up to 6 cycles. Between 23rd July 2014 and 23rd February 2016, 41 patients were treated. Patient demographics, laboratory values, treatment outcomes and adverse events were collected from medical records. The mean age was 72.2 years (SD: 7.1). 24 patients received Radium-223 as first-line treatment (58%), 7 patients as second (17%), 3 as third (7.3%), 6 as (14.6%), and 1 as fifth-line therapy (2.4%). The mean number of cycles administered was 5.5 (SD: 1.1). The most common side effects were anemia (32% grade 1-3), nausea (28%, grade 1), diarrhea (4%, grade 2), thrombocytopenia (4%, grade 3). The mean baseline PSA level was 307.2 ng/ml (SD: 525.7), which increased to a mean value of 728.5 ng/ml (SD: 1277) by the end of treatment. The baseline mean ALP of 521.1 U/L (SD: 728) decreased to 245.1 U/L (SD: 283.5). The majority of patients experienced a decrease (37%) or complete cessation (43%) of bone pain intensity. In our symptomatic prostate cancer patient population, Radium-223 proved to be efficient in terms of pain relief, with moderate side effects. No PSA response was detected, while alkaline phosphatase levels significantly decreased. PMID- 28074332 TI - Functional Analysis of Ribonucleotide Reductase from Cordyceps militaris Expressed in Escherichia coli. AB - Cordyceps militaris produces cordycepin (3'-deoxyadenosine), which has various activities, including anti-oxidant, anti-tumoral, anti-viral, and anti inflammatory. Ribonucleotide reductase (RNR) seems to be a candidate to produce cordycepin in C. militaris because RNR catalyzes the reduction of nucleotides to 2'-deoxynucleotides, whose structures are similar to that of cordycepin. However, the role of RNR has not been confirmed yet. In this study, complementary DNAs (cDNAs) of C. militaris RNR (CmRNR) large and small subunits (CmR1 and CmR2) were cloned from C. militaris NBRC9787 to investigate the function of CmRNR for its cordycepin production. C. militaris NBRC9787 began to produce cordycepin when grown in a liquid surface culture in medium composed of glucose and yeast extract for 15 days. CmR1 cDNA and CmR2 cDNA were obtained from its genomic DNA and from total RNA extracted from its mycelia after cultivation for 21 days, respectively. Recombinant CmR1 and CmR2 were expressed individually in Escherichia coli and purified. Purified recombinant CmR1 and CmR2 showed RNR activity toward adenosine diphosphate (ADP) only when two subunits were mixed but only show the reduction of ADP to 2'-deoxyADP. These results indicate that the pathway from ADP to 3'deoxyADP via CmRNR does not exist in C. militaris and cordycepin production in C. militaris may be mediated by other enzymes. PMID- 28074333 TI - Rosiglitazone Metabolism in Human Liver Microsomes Using a Substrate Depletion Method. AB - BACKGROUND: Elimination of rosiglitazone in humans is via hepatic metabolism. The existing studies suggest that CYP2C8 is the major enzyme responsible, with a minor contribution from CYP2C9; however, other studies suggest the involvement of additional cytochrome P450 enzymes and metabolic pathways. Thus a full picture of rosiglitazone metabolism is unclear. OBJECTIVE: This study aimed to improve the current understanding of potential drug-drug interactions and implications for therapy by evaluating the kinetics of rosiglitazone metabolism and examining the impact of specific inhibitors on its metabolism using the substrate depletion method. METHODS: In vitro oxidative metabolism of rosiglitazone in human liver microsomes obtained from five donors was determined over a 0.5-500 uM substrate range including the contribution of CYP2C8, CYP2C9, CYP3A4, CYP2E1, and CYP2D6. RESULTS: The maximum reaction velocity was 1.64 +/- 0.98 nmol.mg-1.min-1. The CYP2C8 (69 +/- 20%), CYP2C9 (42 +/- 10%), CYP3A4 (52 +/- 23%), and CEP2E1 (41 +/- 13%) inhibitors all significantly inhibited rosiglitazone metabolism. CONCLUSION: The results suggest that other cytochrome P450 enzymes, including CYP2C9, CYP3A4, and CEP2E1, in addition to CYP28, also play an important role in the metabolism of rosiglitazone. This example demonstrates that understanding the complete metabolism of a drug is important when evaluating the potential for drug-drug interactions and will assist to improve the current therapeutic strategies. PMID- 28074334 TI - Saliva Versus Plasma Bioequivalence of Azithromycin in Humans: Validation of Class I Drugs of the Salivary Excretion Classification System. AB - AIM: The aim of this study was to compare human pharmacokinetics and bioequivalence metrics in saliva versus plasma for azithromycin as a model class I drug of the Salivary Excretion Classification System (SECS). METHODS: A pilot, open-label, two-way crossover bioequivalence study was done, and involved a single 500-mg oral dose of azithromycin given to eight healthy subjects under fasting conditions, followed by a 3-week washout period. Blood and unstimulated saliva samples were collected over 72 h and deep frozen until analysis by a validated liquid chromatography with mass spectroscopy method. The pharmacokinetic parameters and bioequivalence metrics of azithromycin were calculated by non-compartment analysis using WinNonlin V5.2. Descriptive statistics and dimensional analysis of the pharmacokinetic parameters of azithromycin were performed using Microsoft Excel. PK-Sim V5.6 was used to estimate the effective intestinal permeability of azithromycin. RESULTS AND DISCUSSION: No statistical differences were shown in area under the concentration curves to 72 h (AUC0-72), maximum measured concentration (C max) and time to maximum concentration (T max) between test and reference azithromycin products (P > 0.05) in the saliva matrix and in the plasma matrix. Due to the high intra subject variability and low sample size of this pilot study, the 90% confidence intervals of AUC0-72 and C max did not fall within the acceptance range (80 125%). However, saliva levels were higher than that of plasma, with a longer salivary T max. The mean saliva/plasma concentration of test and reference were 2.29 and 2.33, respectively. The mean +/- standard deviation ratios of saliva/plasma of AUC0-72, C max and T max for test were 2.65 +/- 1.59, 1.51 +/- 0.49 and 1.85 +/- 1.4, while for the reference product they were 3.37 +/- 2.20, 1.57 +/- 0.77 and 2.6 +/- 1.27, respectively. A good correlation of R = 0.87 between plasma and saliva concentrations for both test and reference products was also observed. Azithromycin is considered a class I drug based on the SECS, since it has a high permeability and high fraction unbound, and saliva sampling could be used as an alternative to plasma sampling to characterize its pharmacokinetics and bioequivalence in humans when adequate sample size is used. PMID- 28074335 TI - Clinical Effects of Topiroxostat on Renal and Endothelial Function in A Patient with Chronic Kidney Disease and Hyperuricemic Arteriolopathy: A Case Report. AB - Hyperuricemia is associated with the progression of chronic kidney disease (CKD) and cardiovascular diseases. Topiroxostat, a selective xanthine oxidase inhibitor, effectively reduces serum uric acid (UA) levels and urinary albumin excretion (UAE) in CKD patients. A 50-year-old Japanese man was referred to our hospital due to albuminuria and hyperuricemia, and renal biopsy showed a typical hyperuricemic arteriolopathy. Treatment with topiroxostat decreased serum UA levels (9.2 mg/dL at baseline to 6.4 mg/dL after 6 months), UAE (388 to 88 mg/g.cr), and urinary level of liver-type fatty acid-binding protein (28.8 to 19.8 ug/g.cr). Interestingly, topiroxostat treatment was associated with a trend towards improved flow-mediated dilation (5.4 to 5.8%). These results suggested that topiroxostat in CKD patients with hyperuricemia is potentially effective, not only for ameliorating renal damages but also for improving endothelial function beyond its UA-lowering action. PMID- 28074337 TI - Economic Burden of Rheumatoid Arthritis in Italy: Possible Consequences on Anti Citrullinated Protein Antibody-Positive Patients. AB - BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease with a substantial medical and economic burden. In Italy, it affects approximately 280,000 people, therefore representing the musculoskeletal disease with the highest economic impact in terms of costs for the National Health Service and the social security system. OBJECTIVE: The aim of this study was to estimate the annual economic burden of RA in Italy and determine the potential cost reduction considering the most effective biologic treatment for early rapidly progressing RA (ERPRA) patients. METHODS: The model developed considers both direct costs that are mainly due to the pharmacological treatments, and indirect costs, which also include the productivity lost because of the disease. A systematic literature review provided the epidemiological and economic data used to inform the model. A one-way probabilistic sensitivity analysis based on 5000 Monte Carlo simulations was performed. Furthermore, specific scenario analyses were developed for those patients presenting an ERPRA, with the aim of evaluating the effectiveness of different biologic treatments for this subgroup of patients and estimating potential cost reduction. RESULTS: The total economic burden associated with RA was estimated to be ?2.0 billion per year (95% confidence interval [CI] ?1.8-2.3 billion). Forty-five percent of the expenditure was due to indirect costs (95% CI ?0.8-1.0 billion); 45% depended on direct medical costs (95% CI ?0.7-1.1 billion), and the residual 10% was determined by direct non-medical costs (95% CI ?0.16-0.25 billion). In particular, the costs estimated for ERPRA patients totalled ?76,171,181, of which approximately ?18 million was associated with patients with a high level of anti-citrullinated protein antibodies (ACPA). The results of the analysis outline how it is possible to obtain a cost reduction for ERPRA patients of between ?1 and ?3 million by varying the number of patients with a high level of immunoglobulin G treated with the most effective biologic drug. In fact, the latter may determine higher efficacy outcomes, especially for poor prognostic ERPRA patients, ensuing higher levels of productivity. CONCLUSIONS: This study presents a pioneering approach to estimate the direct and indirect costs of RA. The model developed is a useful tool for policy makers as it allows to understand the economic implications of RA treatment in Italy, identify the most effective allocation of resources, and select the most appropriate treatment for ERPRA patients. PMID- 28074338 TI - Erratum to: Histochemical changes of occlusal surface enamel of permanent teeth, where dental caries is questionable vs sound enamel surfaces. PMID- 28074336 TI - Small heat shock proteins in ageing and age-related diseases. AB - Small heat shock proteins (sHSPs) are gatekeepers of cellular homeostasis across species, preserving proteome integrity under stressful conditions. Nonetheless, recent evidence suggests that sHSPs are more than molecular chaperones with merely auxiliary role. In contrast, sHSPs have emerged as central lifespan determinants, and their malfunction has been associated with the manifestation of neurological disorders, cardiovascular disease and cancer malignancies. In this review, we focus on the role of sHSPs in ageing and age-associated diseases and highlight the most prominent paradigms, where impairment of sHSP function has been implicated in human pathology. PMID- 28074339 TI - Factors associated with dental anxiety in Brazilian children during the first transitional period of the mixed dentition. AB - AIMS: To determine the prevalence of dental anxiety in children during the first transitional period of the mixed dentition and associated factors. METHODS: A Cross-sectional study was performed with 1367 children of both genders aged 6-7 years old conducted in schools in Recife, Brazil in 2013. The data were collected through interviews and intra-oral examinations. Dental anxiety data were obtained using the dental anxiety questionnaire (DAQ). The associated factors considered were: age, gender, social group, child's experience with the dentist, history of dental pain, experience of caries and phase of exfoliation. RESULTS: The prevalence of children with some level of dental anxiety was 54.4%. Visit to the dentist and social group were associated with dental anxiety (p < 0.001). CONCLUSIONS: The prevalence of dental anxiety was high, although children attending private schools and those who had visited the dentist before had a lower prevalence of dental anxiety. PMID- 28074340 TI - Clinical significance of cathepsin L and cathepsin B in dilated cardiomyopathy. AB - Dysregulated expression of lysosomal cysteine cathepsins is associated with adverse cardiac remodeling, a characteristic of several cardiovascular diseases. However, the information regarding the role of cysteine cathepsin L (CTSL) and cathepsin B (CTSB) in dilated cardiomyopathy (DCM) is limited. The present study was aimed to investigate the expression of CTSL and CTSB in animal model of doxorubicin (doxo)-induced cardiomyopathy as well as in peripheral blood samples of DCM patients. Cardiac tissue sections from doxo-treated and control rats were used to study the expression of CTSL and CTSB by enzyme assay and immunohistochemistry (IHC). Peripheral blood mononuclear cells (PBMCs) isolated from DCM patients (n = 29) along with age-matched healthy controls (n = 28) were used to assay enzymatic activity of these cathepsins. Activities of these proteases were further correlated with echocardiographic parameters of DCM patients. A significant increase in CTSL activity and protein expression was observed with no changes in CTSB levels in doxo-treated rats as compared to controls. We also observed a drastic increase in the functional activity of cathepsin L+cathepsin B (CTSL+B), CTSL, and CTSB in DCM patients compared to controls (p <= 0.001). Increased levels of these proteases exhibited a statistically significant correlation with reduced left ventricular ejection fraction (LVEF) in DCM patients (rho = -0.58, p = 0.01). For the first time, this study demonstrates a correlation between increased expression of CTSL and CTSB in PBMCs with severity of left ventricular dysfunction in DCM patients. Thus, these proteases may serve as blood-based biomarker of DCM and prove useful in its management. PMID- 28074341 TI - Gap junction protein connexin43 deregulation contributes to bladder carcinogenesis via targeting MAPK pathway. AB - High expression of connexins was found in a variety of cancers, but their role is still controversial. We investigated whether connexin43 (Cx43) contributed to bladder carcinogenesis through MAPK activation. In this study, we found that Cx43 expression was significantly increased in bladder cancer tissues and cell line. Overexpression of Cx43 in bladder cancer 5637 cells increased cell proliferation, promoted cell cycle progression, and inhibited apoptosis. Western blot showed that JNK and ERK pathways were dramatically activated in Cx43-overexpressed cells. Conversely, knockdown of Cx43 inhibited cell proliferation by increasing apoptosis and causing cell cycle arrest, concomitant with inhibition of JNK and ERK signaling. In addition, JNK and ERK pathways were also activated in bladder cancer tissues. In conclusion, abnormal high expression and cytoplasmic localization of Cx43 contributed to bladder cancer. Inhibition of Cx43 activity could be a potential therapeutic strategy for preventing the progression of bladder cancer. PMID- 28074343 TI - Interspecies sexual behaviour between a male Japanese macaque and female sika deer. AB - Interspecies sexual behaviour or 'reproductive interference' has been reported across a wide range of animal taxa. However, most of these occurrences were observed in phylogenetically close species and were mainly discussed in terms of their effect on fitness, hybridization and species survival. The few cases of heterospecific mating in distant species occurred between animals that were bred and maintained in captivity. Only one scientific study has reported this phenomenon, describing sexual harassment of king penguins by an Antarctic fur seal. This is the first article to report mating behaviour between a male Japanese macaque (Macaca fuscata yakui) and female sika deer (Cervus nippon yakushimae) on Yakushima Island, Japan. Although Japanese macaques are known to ride deer, this individual showed clearly sexual behaviour towards several female deer, some of which tried to escape whilst others accepted the mount. This male seems to belong to a group of peripheral males. Although this phenomenon may be explained as copulation learning, this is highly unlikely. The most realistic hypothesis would be that of mate deprivation, which states that males with limited access to females are more likely to display this behaviour. Whatever the cause for this event may be, the observation of highly unusual animal behaviour may be a key to understanding the evolution of heterospecific mating behaviour in the animal kingdom. PMID- 28074342 TI - The presence of modified nucleosides in extracellular fluids leads to the specific incorporation of 5-chlorocytidine into RNA and modulates the transcription and translation. AB - Myeloperoxidase (MPO) is able to promote several kinds of damage and is involved in mechanisms leading to various diseases such as atherosclerosis or cancers. An example of these damages is the chlorination of nucleic acids, which is considered as a specific marker of the MPO activity. Since 5-chlorocytidine has been recently shown in healthy donor plasmas, this study aimed at discovering if these circulating modified nucleosides could be incorporated into RNA and DNA and if their presence impacts the ability of enzymes involved in the incorporation, transcription, and translation processes. Experimentations, which were carried out in vitro with endothelial and prostatic cells, showed a large penetration of all chloronucleosides but an exclusive incorporation of 5-chlorocytidine into RNA. However, no incorporation into DNA was observed. This specific incorporation is accompanied by an important reduction of translation yield. Although, in vitro, DNA polymerase processed in the presence of chloronucleosides but more slowly than in control conditions, ribonucleotide reductase could not reduce chloronucleotides prior to the replication. This reduction seems to be a limiting step, protecting DNA from chloronucleoside incorporation. This study shows the capacity of transcription enzyme to specifically incorporate 5-chlorocytidine into RNA and the loss of capacity-complete or partial-of different enzymes, involved in replication, transcription or translation, in the presence of chloronucleosides. Questions remain about the long-term impact of such specific incorporation in the RNA and such decrease of protein production on the cell viability and function. PMID- 28074344 TI - Multiple Oral Mucosal Hamartomas in a 34-Year Old Female. AB - A case of Cowden syndrome (CS) is described in a 34-year-old African American female who reported a history of breast and thyroid malignancies. Clinical examination demonstrated multiple soft, white-pink papules across multiple mucosal surfaces of the oral cavity. Microscopy of the lesions revealed hyperkeratotic surface squamous epithelium with papillomatosis and acanthosis along with elongated rete processes. A genomic polymerase chain reaction direct sequencing using the patient's blood was positive for mutations of the PTEN gene typical of CS. PMID- 28074345 TI - The Beneficial Effects of Physical Activity: Is It Down to Your Genes? A Systematic Review and Meta-Analysis of Twin and Family Studies. AB - BACKGROUND: There is evidence for considerable heterogeneity in the responsiveness to regular physical activity (PA) which might reflect the influence of genetic factors. The aim of this systematic review was to assess whether the response to a PA intervention for measures of body composition and cardiorespiratory fitness is (i) correlated within twin pairs and/or families and (ii) more correlated in monozygotic twins (MZ) compared to dizygotic twins (DZ), which would be consistent with genetic effects. METHODS: We performed electronic database searches, combining key words relating to "physical activity" and "genetics", in MEDLINE, CINAHL, EMBASE, SPORTS Discuss, AMED, PsycINFO, WEB OF SCIENCE, and SCOPUS from the earliest records to March 2016. Twin and family studies were included if they assessed body composition and/or cardiorespiratory fitness following a PA intervention, and provided a heritability estimate, maximal heritability estimate, or within MZ twin pair correlation (rMZ). Data on heritability (twin studies), maximal heritability (family studies), and the rMZ were extracted from included studies, although heritability estimates were not reported as small sample sizes made them uninformative. RESULTS: After screening 224 full texts, nine twin and five family studies were included in this review. The pooled rMZ in response to PA was significant for body mass index (rMZ = 0.69, n = 58), fat mass (rMZ = 0.58, n = 48), body fat percentage (rMZ = 0.55, n = 72), waist circumference (rMZ = 0.50, n = 27), and VO2max (rMZ = 0.39, n = 48), where "n" represents the total number of twin pairs from all studies. Maximal heritability estimates ranged from 0-21% for measures of body composition, and 22 57% for cardiorespiratory fitness. Twin studies differed in sample age, baseline values, and PA intervention, although the exclusion of any one study did not affect the results. CONCLUSIONS: Shared familial factors, including genetics, are likely to be a significant contributor to the response of body composition and cardiorespiratory fitness following PA. Genetic factors may explain individual variation in the response to PA. TRIAL REGISTRATIONS: PROSPERO Registration No CRD42015020056 . PMID- 28074346 TI - Actively Negotiating the Mind-Body Divide: How Clozapine-Treated Schizophrenia Patients Make Health for Themselves. AB - It is well recognised that antipsychotic treatments impact the whole body, not just the target area of the brain. For people with refractory schizophrenia on clozapine, the gold standard antipsychotic treatment in England and Australia, the separation of mental and physical regimes of health is particularly pronounced, resulting in multiple, compartmentalised treatment registers. Clinicians often focus on the mental health aspects of clozapine use, using physical indicators to determine whether treatment can continue. Our observations of 59 participants in England and Australia over 18 months revealed that patients did not observe this hierarchisation of mental treatments and physical outcomes. Patients often actively engaged in the management of their bodily symptoms, leading us to advance the figure of the active, rather than passive, patient. In our paper, we do not take the position that the facility for active management is a special one utilised only by these patients. We seek instead to draw attention to what is currently overlooked as an ordinary capacity to enact some sort of control over life, even under ostensibly confined and confining circumstances. We argue that clozapine-treated schizophrenia patients utilise the clinical dichotomy between mental and physical domains of health to rework what health means to them. This permits patients to actively manage their own phenomenological 'life projects' (Rapport, I am Dynamite: an Alternative Anthropology of Power, Routledge, London 2003), and forces us to reconsider the notion of clinical giveness of what health means. This making of one's own meanings of health may be critical to the maintenance of a sense of self. PMID- 28074348 TI - Challenges and Opportunities in the Development of HIV Medications in Pediatric Patients. AB - Successful management of pediatric HIV disease requires high therapeutic efficacy and adherence, which can be achieved by providing affordable, easy to store, and palatable antiretrovirals. Current challenges in pediatric antiretroviral drug development include poor palatability, large pill size, limited oral liquid formulations, and few incentives for development by drug manufacturers as the number of children with HIV continues to decline due to successful worldwide preventive interventions and improved access to antiretrovirals. This article summarizes the various challenges and opportunities with current pediatric antiretrovirals, recent and ongoing trials, new formulations, and suggestions that may expedite and provide incentives for the development of suitable pediatric formulations. PMID- 28074347 TI - Pattern- and motion-related visual evoked potentials in HIV-infected adults. AB - PURPOSE: The goal of the current study was to explore visual function in virally suppressed HIV patients undergoing combined antiretroviral therapy (cART) by using pattern-reversal and motion-onset visual evoked potentials (VEPs). METHODS: The pattern-reversal and motion-onset VEPs were recorded in 20 adult HIV+ patients with a mean age of 38 years and CD4 cell counts >=230 * 106 cells/L of blood. RESULTS: Nine out of 20 patients displayed VEP abnormalities. Pattern reversal VEPs pathology was observed in 20% of subjects, and 45% HIV patients had impaired motion-onset VEPs. Five out of 16 neurologically asymptomatic HIV patients had prolonged motion-onset VEP latencies in both eyes. Four neurologically symptomatic patients displayed simultaneously abnormal motion onset and pattern-reversal VEP latencies: monocular involvement was observed in two patients with Lyme and cytomegalovirus unilateral optic neuritis. Binocular involvement was noted in two patients with cognitive deficits. Correlation analysis between disease duration, CD4 cell count, HIV copies in plasma, MoCA and electrophysiological parameters did not show any significant relationships. CONCLUSIONS: The functional changes of the visual system in neurologically asymptomatic virally suppressed HIV patients displayed higher motion-onset VEP sensitivity than in standard pattern-reversal VEP examinations. This promising marker, however, has no significant association with clinical conditions. Further exploration is warranted. PMID- 28074349 TI - Second-Generation Antipsychotic Utilization and Metabolic Parameter Monitoring in an Inpatient Pediatric Population: A Retrospective Analysis. AB - BACKGROUND: Second-generation antipsychotics (SGAs) are prescribed for a variety of indications and are strongly associated with adverse metabolic effects. Studies of pediatric outpatients have revealed several deficiencies in monitoring practices for adverse effects associated with SGAs. OBJECTIVE: Our objective was to characterize SGA prescribing and metabolic parameter monitoring (MPM) in an inpatient pediatric population. METHODS: Patients aged <18 years and discharged on SGA treatment between 1 November 2013 and 30 April 2014 from an inpatient psychiatric institution in Pittsburgh, PA, USA were included. Electronic medical records (EMRs) were reviewed for patient age and weight and for parameters used by the International Diabetes Federation (IDF) to define metabolic syndrome: waist circumference, fasting blood glucose, triglycerides, high-density lipoprotein, and blood pressure. The primary outcome was the percent of patients with completed MPM, defined as all parameters being available within the patient's EMR in any form, except estimates. Secondary outcomes included percent of patients with existing metabolic syndrome or obesity according to IDF criteria, average total daily dose of individual SGAs, and frequency of individual SGA utilization. Data were analyzed utilizing univariate descriptive statistics. RESULTS: A total of 243 patients met inclusion criteria and were included in the analysis. For the primary outcome, 13.2% (n = 32) of patients had completed MPM for all parameters. Blood pressure was the most frequently documented parameter (n = 241; 99.2%), whereas waist circumference was the least (n = 67; 28%). Risperidone was the most commonly prescribed SGA (n = 99; 41%; average daily dose 1.92 mg). CONCLUSIONS: Compared with outpatient studies, rates of documented MPM for certain parameters (i.e., fasting blood glucose, lipids) is higher for pediatric inpatients treated with SGAs. However, several monitoring deficiencies are still noted. PMID- 28074350 TI - A Comparative Study of the Bone Regenerative Effect of Chemically Modified RNA Encoding BMP-2 or BMP-9. AB - Employing cost-effective biomaterials to deliver chemically modified ribonucleic acid (cmRNA) in a controlled manner addresses the high cost, safety concerns, and lower transfection efficiency that exist with protein and gene therapeutic approaches. By eliminating the need for nuclear entry, cmRNA therapeutics can potentially overcome the lower transfection efficiencies associated with non viral gene delivery systems. Here, we investigated the osteogenic potential of cmRNA-encoding BMP-9, in comparison to cmRNA-encoding BMP-2. Polyethylenimine (PEI) was used as a vector to increase in vitro transfection efficacy. Complexes of PEI-cmRNA (encoding BMP-2 or BMP-9) were fabricated at an amine (N) to phosphate (P) ratio of 10 and characterized for transfection efficacy in vitro using human bone marrow stromal cells (BMSCs). The osteogenic potential of BMSCs treated with these complexes was determined by evaluating the expression of bone specific genes as well as through the detection of bone matrix deposition. It was found that alkaline phosphatase (ALP) expression 3 days post transfection in the group treated with BMP-9-cmRNA was significantly higher than that in the group that received BMP-2-cmRNA treatment. Alizarin red staining and atomic absorption spectroscopy demonstrated enhanced osteogenic differentiation as evidenced by increased bone matrix production by the BMSCs treated with BMP-9-cmRNA when compared to cells treated with BMP-2-cmRNA. In vivo studies showed increased bone formation in calvarial defects treated with the BMP-9-cmRNA and BMP-2-cmRNA collagen scaffolds when compared to empty defects. The connectivity density of the regenerated bone was higher (2-fold-higher) in the group that received BMP-9 cmRNA compared to BMP-2-cmRNA. Together, these findings suggest that cmRNA activated matrix encoding osteogenic molecules can provide a powerful strategy for bone regeneration with significant clinical translational potential. PMID- 28074352 TI - Optshrink LR + S: accelerated fMRI reconstruction using non-convex optimal singular value shrinkage. AB - This paper presents a new accelerated fMRI reconstruction method, namely, OptShrink LR + S method that reconstructs undersampled fMRI data using a linear combination of low-rank and sparse components. The low-rank component has been estimated using non-convex optimal singular value shrinkage algorithm, while the sparse component has been estimated using convex l 1 minimization. The performance of the proposed method is compared with the existing state-of-the-art algorithms on real fMRI dataset. The proposed OptShrink LR + S method yields good qualitative and quantitative results. PMID- 28074351 TI - KRAS, NRAS and BRAF mutations in colorectal cancer and melanoma. AB - Cancers are the group of diseases, which arise because of the uncontrolled behavior of some of the genes in our cells. There are possibilities of gene amplifications, overexpressions, deletions and other anomalies which might lead to the development and spread of cancer. One of the most dangerous ways to the cancers is the mutations of the genes. The mutated genes can start unstoppable proliferation of cells, their uncontrolled motility, protection from apoptosis, the DNA mutation enhancement as well as other anomalies, leading to the cancer. This review focuses on the genes, which are frequently mutated in various cancers and are known to be important in the advance and progression of colorectal cancer and melanoma, namely KRAS, NRAS and BRAF. PMID- 28074353 TI - Language Skills of Males with Fragile X Syndrome or Nonsyndromic Autism Spectrum Disorder. AB - Despite the similarities observed between the fragile X syndrome (FXS) and autism spectrum disorder (ASD) phenotypes, few studies have compared their behavioral profiles outside of ASD symptomatology. In the present study, we sought to compare lexical and grammatical abilities in these two conditions. Comparisons of language abilities in both of these conditions are particularly interesting because both conditions are characterized by difficulties navigating social interactions. Results suggest that although both FXS and ASD are associated with language difficulties, there are important differences between the two conditions in terms of the language profiles observed and the factors influencing language when considering children of similar developmental levels. Theoretical implications are discussed. PMID- 28074354 TI - Parent-Reported Developmental Regression in Autism: Epilepsy, IQ, Schizophrenia Spectrum Symptoms, and Special Education. AB - Examined the psychiatric and clinical correlates of loss of previously acquired skills (regression) as reported by parents of youth with autism spectrum disorder (ASD). Study sample comprised 6- to 18-year old (N = 213) children and adolescents with ASD. Parents reported regression in 77 (36%) youth. A more homogeneous subgroup with regression between 18 and 36 months (n = 48) had higher rates of intellectual disability, epilepsy, and special education, more socially restrictive educational settings, and more severe ASD communication deficits and schizophrenia spectrum symptoms than non-regressed youth (n = 136). Similar results were obtained for a more inclusive definition of regression (n = 77). A brief parent report of developmental regression may be a useful clinical indicator of later general functioning. PMID- 28074355 TI - Evaluation of Visual Pedagogy in Dental Check-ups and Preventive Practices Among 6-12-Year-Old Children with Autism. AB - This study was aimed to evaluate the impact of visual pedagogy in dental check ups and preventive practices among children with autism aged 6-12. In this randomized double-blind clinical trial, the cooperation of 40 children with autism age 6-12. The selected children were equally divided into two groups of case and control (n = 20). The obtained data were analyzed by statistical tests, including Chi square and independent t test. The results of Cochran showed a significant increase in children's cooperation with regard to fluoride therapy in the case group by repeating the visit and training sessions (p <= 0.001). The findings of this study demonstrated, visual pedagogy was merely effective in the case of fluoride therapy in the case group. PMID- 28074356 TI - How Anxious Do You Think I Am? Relationship Between State and Trait Anxiety in Children With and Without ASD During Social Tasks. AB - Individuals with autism spectrum disorder (ASD) often exhibit increased anxiety, even in non-stressful situations. We investigate general anxiousness (anxiety trait) and responses to stressful situations (anxiety state) in 22 adolescents with ASD and 32 typically developing controls. We measured trait anxiety with standardized self- and parent-reported questionnaires. We used a Biopac system to capture state anxiety via skin conductance responses, mean heart rate and heart rate variability during high- and low-anxiety tasks. Results reveal higher trait anxiety in adolescents with ASD (p < 0.05) and no group difference in state anxiety. Increased parent-reported trait anxiety may predict decreased state anxiety during high-stress conditions. Together, these findings suggest that higher trait anxiety may result in dampened physical responses to stress. PMID- 28074357 TI - The Longitudinal Effects of Parenting on Adaptive Behavior in Children with Fragile X Syndrome. AB - Several studies have reported declines in adaptive behavior amongst children with fragile X syndrome (FXS) starting in middle childhood. We examined the effects of maternal responsivity on adaptive behavior in 55 children with FXS visited 5-6 times in their homes from early through middle childhood. Our analyses indicated that sustained maternal responsivity had a significant positive impact on the trajectories of communication and to a lesser extent other adaptive behavior domains through middle childhood with many effects remaining significant after controlling for autism symptoms and developmental level. For children who showed declines in adaptive behavior during middle childhood, sustained high levels of maternal responsivity minimized the amount of decline observed in the communication, socialization, and daily living domains. PMID- 28074358 TI - Genotype 3 Infection: The Last Stand of Hepatitis C Virus. AB - Hepatitis C virus (HCV) represents a significant global disease burden, with an estimated 130-150 million people worldwide living with chronic HCV infection. Within the six major clinical HCV genotypes, genotype 3 represents 22-30% of all infection and is described as a unique entity with higher rates of steatosis, faster progression to cirrhosis, and higher rates of hepatocellular carcinoma. Hepatic steatosis in the setting of hepatitis C genotype 3 (HCV-3) is driven by viral influence on three major pathways: microsomal triglyceride transfer protein, sterol regulatory element-binding protein-1c, and peroxisome proliferator-associated receptor-alpha. Historically with direct-acting antivirals, the rates of cure for HCV-3 therapies lagged behind the other genotypes. As current therapies for HCV-3 continue to close this gap, it is important to be cognizant of common drug interactions such as acid-suppressing medication and amiodarone. In this review, we discuss the rates of steatosis in HCV-3, the mechanisms behind HCV-3-specific steatosis, and current and future therapies. PMID- 28074360 TI - Exploring the stability of ligand binding modes to proteins by molecular dynamics simulations. AB - The binding mode prediction is of great importance to structure-based drug design. The discrimination of various binding poses of ligand generated by docking is a great challenge not only to docking score functions but also to the relatively expensive free energy calculation methods. Here we systematically analyzed the stability of various ligand poses under molecular dynamics (MD) simulation. First, a data set of 120 complexes was built based on the typical physicochemical properties of drug-like ligands. Three potential binding poses (one correct pose and two decoys) were selected for each ligand from self-docking in addition to the experimental pose. Then, five independent MD simulations for each pose were performed with different initial velocities for the statistical analysis. Finally, the stabilities of ligand poses under MD were evaluated and compared with the native one from crystal structure. We found that about 94% of the native poses were maintained stable during the simulations, which suggests that MD simulations are accurate enough to judge most experimental binding poses as stable properly. Interestingly, incorrect decoy poses were maintained much less and 38-44% of decoys could be excluded just by performing equilibrium MD simulations, though 56-62% of decoys were stable. The computationally-heavy binding free energy calculation can be performed only for these survived poses. PMID- 28074359 TI - Pharmacological Management of Chronic Pelvic Pain in Women. AB - Chronic pelvic pain (CPP) is a multifaceted condition that often has both peripheral and central generators of pain. An understanding of neurobiology and neuropsychology of CPP should guide management. Successful treatment of CPP is typically multimodal, and pharmacologic treatment strategies include analgesics, hormonal suppression, anesthetics, antidepressants, membrane stabilizers, and anxiolytics. Evidence for these and other emerging pharmacologic therapies is presented in this article. PMID- 28074361 TI - Partially-deuterated samples of HET-s(218-289) fibrils: assignment and deuterium isotope effect. AB - Fast magic-angle spinning and partial sample deuteration allows direct detection of 1H in solid-state NMR, yielding significant gains in mass sensitivity. In order to further analyze the spectra, 1H detection requires assignment of the 1H resonances. In this work, resonance assignments of backbone HN and Halpha are presented for HET-s(218-289) fibrils, based on the existing assignment of Calpha, Cbeta, C', and N resonances. The samples used are partially deuterated for higher spectral resolution, and the shifts in resonance frequencies of Calpha and Cbeta due to the deuterium isotope effect are investigated. It is shown that the deuterium isotope effect can be estimated and used for assigning resonances of deuterated samples in solid-state NMR, based on known resonances of the protonated protein. PMID- 28074362 TI - The determination and fate of disinfection by-products from ozonation chlorination of fulvic acid. AB - Ozonation of fulvic acid (FA) can result in diverse intermediate oxidation by products, significantly affecting disinfection by-product (DBP) formation following chlorination. The objective of this study was to provide insight into ozone reaction intermediates and reveal the possible formation pathway of DBPs from ozonation of FA due to the formation of intermediate oxidation by-products. Aldehydes, aromatic acids, short-chain acids, chloroform, and dichloroacetic acid were detected at various ozone dosage additions. Aromatic acids were studied by using solid-phase extraction-ultra high-performance liquid chromatography (SPE UPLC). This new analytical approach enables the extraction and analysis of highly polar carboxylic acids that are difficult to measure using conventional methods. The results showed that formaldehyde, acetaldehyde, glyoxal, methyl-glyoxal, fumaric, malonic protocatechuic, 3-hydroxybenzoic, and benzoic acid were predominant oxidation by-products. The yields of the four aldehydes increased steadily with ozone dosage. When ozone dosage was 2~2.5 mg/l, the amount of carboxylic acids was largest, and the total amount of the carboxylic acids was about 5~10 times higher than that of the aldehydes. Besides, hydroxybenzoic acids are the major precursor, although they have low content in ozone reaction solution, they have a great contribution to the DBP formation. This study provides a new perspective on ozonation natural organic matter, which contributes to understand the other sources of DBPs and thus broadens the knowledge of drinking water treatment. PMID- 28074363 TI - Risk assessment of agriculture impact on the Frio River watershed and Cano Negro Ramsar wetland, Costa Rica. AB - The Cano Negro Ramsar wetland is a conservation area of great natural and societal value, located in the lower part of the Frio River watershed in the north of Costa Rica. Its aquatic ecosystems may be considered vulnerable to pollution due to recent changes in land use toward agriculture. In 2011 and 2012, quarterly sampling was done at ten sites located in the middle and lower sections of the Frio River Basin that pass through crop areas and later drain into Cano Negro wetland. Pesticide residues, nitrates, sediment concentrations, and diversity of benthic macroinvertebrates and fish biomarkers were studied in the selected sites. Additionally, risk of toxicity was calculated in two different ways: (1) by using a ratio of MEC to hazard concentrations threshold for 5% of species (HC5) to calculate a risk quotient (RQ), and (2) by using a ratio of MEC to available ecotoxicity data of native fish and cladocera for diazinon and ethoprophos, to obtain a risk quotient for native species (RQns). Results indicated that three out of the ten sites (rivers Thiales, Monico, and Sabogal) showed variable levels of pollution including six different active ingredients (a.i.) of pesticide formulations (herbicides ametryn, bromacil, and diuron; insecticides cypermethrin, diazinon, and ethoprophos). Moreover, potential adverse effects on fishes in Thiales and Monico rivers were indicated by cholinesterase (ChE) inhibition and glutathione S-transferase (GST) enhancement. Risk evaluations indicated pesticide residues of ametryn, bromacil, and ethoprophos to be exceeding the limits set by MTR, also RQ was high (>1) in 70% of the positive samples for diuron (most frequently found pesticide in water samples), cypermethrin, diazinon, and ethoprophos, and RQns was high for diazinon. Therefore, these substances might be of major concern for the ecological health of aquatic ecosystems in the middle basin of the Frio River. The most critical site was Monico River, which had the highest pollution (75% detection samples with 3-5 a.i.) and highest calculated risk (RQ > 1 in 75% of the samples). This is also the river that most directly drains into the protected wetland. Even though pesticide pollution in this area is not as severe as in other parts of Costa Rica, it is imperative that measures are taken, particularly in the surroundings of Monico River, in order to diminish and mitigate possible detrimental effects to biota in Cano Negro Ramsar Site. PMID- 28074364 TI - Efficient photo-catalytic degradation of malachite green using nickel tungstate material as photo-catalyst. AB - The present study focused on the evaluation of photo-catalytic and photo electrochemical properties of the photo-catalyst based on nickel tungstate material prepared by a nitrate method through the degradation of malachite green (MG) dye's. The effect of catalyst loading and dye concentration was examined. Physico-chemical, optical, electrical, electrochemical, and photo-electrochemical properties of the prepared material were analyzed by X-ray diffraction (XRD), fourier transform-infrared spectroscopy (FTIR), BET analysis, optical reflectance diffuse (DR), scanning electron microscopy (SEM/EDX), electrical conductivity, cyclic voltammetry (CV), current intensity, mott-shottky, and nyquist. XRD revealed the formation of monoclinic structure with a small particle size. BET surface area of the sample was around 10 m2/g. The results show that the degradation of MG was more than 80%, achieved after 3 h of irradiation at pH 4.6 and with a catalyst loading of 75 mg. Also, it was found that the dye photo degradation obeyed the pseudo-first order kinetic via Langmuir Hinshelwood model. PMID- 28074366 TI - Improved slant drilling well for in situ remediation of groundwater and soil at contaminated sites. AB - Soil contamination has become a crucial issue in urban redevelopment. Japan has many contaminated sites on which manufacturing has been conducted over several decades. Site holders are now under pressure to manage chemical contamination; however, the use of heavy machinery is difficult in remedial operations on restricted sites, especially where there are still working factories. The slant well is a potentially useful technique in such settings, but its use is technically challenging because of the need for high drilling accuracy and the difficulty in sealing the slanted bores. In this study, we investigated an improved technique for slant drilling that can be used around existing structures to treat contaminated soil and groundwater. A key to this novel approach was the use of water-swelling materials as sealants. Research at a test site investigated the accuracy of drilling. Tracer tests were also conducted using sodium chloride and urea. The improved slant borings showed a deviation of less than 2% from the target bore. The spread of the two tracers at different depths was demonstrated. The proposed technique provides a useful approach to the treatment of brownfield sites in countries where in situ remediation has not yet been undertaken. PMID- 28074365 TI - Determination of cytostatic drugs in Besos River (NE Spain) and comparison with predicted environmental concentrations. AB - The number of cytostatic drugs used in cancer treatments is wide and increases every year; therefore, tools have been developed to predict their concentration in the environment to prioritize those for monitoring studies. In the present study, the predicted environmental concentrations (PECs) were calculated according to consumption data in Catalonia (NE Spain) for 2014. According to PECs and to the most widely reported compounds, 19 cytostatics were monitored in two sampling campaigns performed along the Besos River. A total of seven drugs were detected at levels between 0.5 and 656 ng L-1. PEC and measured environmental concentrations (MECs) were compared in order to validate PECs. The PEC/MEC ratio presented a good agreement between predicted and measured concentrations confirming the PEC estimations. Mycophenolic acid, prioritized as the compound with the highest PEC, was detected at the highest concentrations (8.5-656 ng L-1) but showed no risk for aquatic organisms (risk quotient <1) considering acute toxicity tests performed in Daphnia magna. PMID- 28074368 TI - Evaluation of 2D resistivity imaging technique for delineating subsurface seepage of hydrocarbon-contaminated water southeast of Karbala city, Iraq. AB - 2D imaging technique was applied in (8) transects near a pit of contaminated water near contaminated well southeast of Karbala city, Iraq. Each transect was 30 m long with 1 m electrode spacing. Data acquisition was fulfilled by using Wenner electrode array. The resistivity of water-contaminated zone is found less than 3Omega.m and the top dry zone recorded relatively high resistivity (more than 170Omega.m). It is found that the greatest amount of seepage was found moving towards northeast direction coincided with groundwater movement direction, whereas there was no movement towards northwest and southeast directions and restricted on the closest areas to the pit location. The outcomes suggested that the 2D imaging technique is a successful and powerful tool in separating contaminated zone from clear one and in detecting underground seepage depth and moving direction. PMID- 28074367 TI - Assessment of metal contamination in the Hun River, China, and evaluation of the fish Zacco platypus and the snail Radix swinhoei as potential biomonitors. AB - The Hun River is a major tributary of the Liao River in the northeast area of China and provides drinking water for 23 million local residents. This study was designed to assess the severity of metal contamination in the Hun River and the potential use of indigenous organisms (the fish Zacco platypus and the snail Radix swinhoei) as biomonitors of metal contamination. Water, sediment, and the native fish and snails were collected at four sampling sites that differed in their physicochemical characteristics and their contamination levels. The samples were analyzed for Cd, Cr, Cu, Ni, Pb, and Zn by ICP-MS. The results showed that although the overall potential ecological risks of the metals were low at our sampling sites, Cd posed a noteworthy ecological risk. Strong correlations were obtained between Cd concentrations in the organisms and in the environment. The results indicated that Z. platypus and R. swinhoei can be useful biomonitoring species for assessing Cd contamination. Biomonitoring with the snail may be most effective when focused on the gonad/digestive tissue (because of the high metal accumulation there), but further work is needed to confirm this. PMID- 28074369 TI - Mitigating cadmium accumulation in greenhouse lettuce production using biochar. AB - Greenhouse experiments were conducted to investigate the influence of rice straw biochar (RSB) on soil cadmium (Cd) availability and accumulation in lettuce. The RSB was applied either in bands or broadcast in the test site of four greenhouses with soil Cd concentrations ranging from 1.70-3.14 MUg g-1. Biochar doses applied in bands were half of those broadcast. The Cd levels in the shoots of lettuce were observed to be reduced by up to 57% with increasing RSB application rate (0, 6, 12, 18 t ha-1). Following RSB application, shoot Cd concentrations of lettuce were reduced to below the Chinese threshold value set for food, and hazard quotients for Cd associated with vegetable consumption were reduced from 0.70 1.11 to 0.42-0.65. A decrease in soil bulk density (11%) and increases in water holding capacity (16%), available phosphorus (30%), available potassium (197%), and lettuce yield (15%) were observed after RSB application. Multiple linear regression analysis suggested that the soil extractable Cd level (but not biomass dilution) and soil bulk density, as influenced by RSB addition, were the dominant contributors to the shoot Cd levels in lettuce and lettuce yield, respectively. These results highlight the potential for RSB to mitigate the phytoaccumulation of Cd and thereby to reduce human exposure from vegetable consumption. Application of biochar in band, rather than broadcasting over the entire area, represents an opportunity to halve the biochar cost while retaining a good remediation effect. PMID- 28074370 TI - Comparative toxicity of nano ZnO and bulk ZnO towards marine algae Tetraselmis suecica and Phaeodactylum tricornutum. AB - The wide use of ZnO nanoparticles in a number of products implies an increasing release into the marine environment, resulting in the need to evaluate the potential effects upon organisms, and particularly phytoplankton, being at the base of the throphic chain. To this aim, dose-response curves for the green alga Tetraselmis suecica and the diatom Phaeodactylum tricornutum derived from the exposure to nano ZnO (100 nm) were evaluated and compared with those obtained for bulk ZnO (200 nm) and ionic zinc. The toxic effects to both algae species were reported as no observable effect concentration (NOEC) of growth inhibition and as 1, 10, and 50% effect concentrations (EC1, EC10, and EC50). The toxicity decreased in the order nano ZnO > Zn2+ > bulk ZnO. EC50 values for nano ZnO were 3.91 [3.66-4.14] mg Zn/L towards the green microalgae and 1.09 [0.96-1.57] mg Zn/L towards the diatom, indicating a higher sensitivity of P. tricornutum. The observed diverse effects can be ascribed to the interaction occurring between different algae and ZnO particles. Due to algae motility, ZnO particles were intercepted in different phases of aggregation and sedimentation processes, while algae morphology and size can influence the level of entrapment by NP aggregates.This underlines the need to take into account the peculiarity of the biological system in the assessment of NP toxicity. PMID- 28074371 TI - Microbial flora analysis for the degradation of beta-cypermethrin. AB - In the Xinjiang region of Eurasia, sustained long-term and continuous cropping of cotton over a wide expanse of land is practiced, which requires application of high levels of pyrethroid and other classes of pesticides-resulting in high levels of pesticide residues in the soil. In this study, soil samples were collected from areas of long-term continuous cotton crops with the aim of obtaining microbial resources applicable for remediation of pyrethroid pesticide contamination suitable for the soil type and climate of that area. Soil samples were first used to culture microbial flora capable of degrading beta-cypermethrin using an enrichment culture method. Structural changes and ultimate microbial floral composition during enrichment were analyzed by high-throughput sequencing. Four strains capable of degrading beta-cypermethrin were isolated and preliminarily classified. Finally, comparative rates and speeds of degradation of beta-cypermethrin between relevant microbial flora and single strains were determined. After continuous subculture for 3 weeks, soil sample microbial flora formed a new type of microbial flora by rapid succession, which showed stable growth by utilizing beta-cypermethrin as the sole carbon source (GXzq). This microbial flora mainly consisted of Pseudomonas, Hyphomicrobium, Dokdonella, and Methyloversatilis. Analysis of the microbial flora also permitted separation of four additional strains; i.e., GXZQ4, GXZQ6, GXZQ7, and GXZQ13 that, respectively, belonged to Streptomyces, Enterobacter, Streptomyces, and Pseudomonas. Under culture conditions of 37 degrees C and 180 rpm, the degradation rate of beta-cypermethrin by GXzq was as high as 89.84% within 96 h, which exceeded that achieved by the single strains GXZQ4, GXZQ6, GXZQ7, and GXZQ13 and their derived microbial flora GXh. PMID- 28074372 TI - Tracking fluorescent components of dissolved organic matter from soils in large scale irrigated area. AB - Combination of fluorescence excitation-emission matrix spectroscopy with parallel factor analysis (PARAFAC) and principal component analysis (PCA) was engaged to track fluorescent components of dissolved organic matter (DOM) extracted from soils, to seek potential factors, and to reveal their correlations with physico chemical properties of soils. Soil samples at different depths were collected in Hetao irrigated area of Inner Mongolia, China. Five fluorescent components (C1 to C5) were identified by PARAFAC modeling of DOM extracted from the soil samples. C1 was referred as fulvic-like fluorescent component, by which DOM was dominated in the whole soil samples. C2 was associated with salinity and agriculture, which was similar to marine humic-like fluorescent component. C3 was assigned as traditional humic-like fluorescent component. The three components were of the terrestrial origin. C4 was involved in tryptophan-like fluorescent component, which was autochthonous productions of biological degradation. C5 might be a polycyclic aromatic hydrocarbon contaminant, which could be relative to anthropogenic sources of pesticides. The C1, C2, and C3 were the potential factors of characterizing DOM fractions using PCA on fluorescent components and physico-chemical parameters. Moreover, DOM might restrained by exchangeable sodium percentage, and its formation and decomposition might be influenced by soil moisture. PMID- 28074373 TI - Introduction to the Special Issue: Precarious Solidarity-Preferential Access in Canadian Health Care. AB - Systems of universal health coverage may aspire to provide care based on need and not ability to pay; the complexities of this aspiration (conceptual, practical, and ethical) call for normative analysis. This special issue arises in the wake of a judicial inquiry into preferential access in the Canadian province of Alberta, the Vertes Commission. I describe this inquiry and set out a taxonomy of forms of differential and preferential access. Papers in this special issue focus on the conceptual specification of health system boundaries (the concept of medical need) and on the normative questions raised by complex models of funding and delivery of care, where patients, providers, and services cross system boundaries. PMID- 28074374 TI - Can We Predict the Perioperative Pulmonary Complications Before Laparoscopic Sleeve Gastrectomy: Original Research. AB - BACKGROUND: The increasing prevalence of obesity in worldwide is one of the most serious chronic public health problems and is considered to be a global epidemic. Bariatric surgical procedures have also been applied more often with increased prevalence of obesity. As a result, the incidence of surgical complications has increased. Preoperative evaluation is quite important for these patients. AIMS: The aim of our study is to determine the predictors of perioperative pulmonary complications of laparoscopic sleeve gastrectomy. STUDY DESIGN: The study is a cross-sectional study. METHODS: One hundred eighty-three consecutive patients who received laparoscopic bariatric surgery were followed up during 3 months. Patients were divided into two groups A and B. Group A being the patients who had perioperative pulmonary complications (n = 28) and group B being patients who had not (n = 155). Pulmonary function test (PFT), body mass index (BMI), preoperative oxygen saturation, age, gender, comorbid diseases, and smoking history were compared between these groups. RESULTS: Mean age, size, weight, BMI, PFT parameters of groups A and B were close to each other. The strongest predictors of perioperative pulmonary complications were duration of smoking in current smokers and low baseline oxygen saturation. CONCLUSIONS: Preoperative oxygen saturation and smoking history may help to predict perioperative complications of laparoscopic sleeve gastrectomy. PMID- 28074375 TI - Identity Theft in the Academic World Leads to Junk Science. AB - In recent years, identity theft has been growing in the academic world. Cybercriminals create fake profiles for prominent scientists in attempts to manipulate the review and publishing process. Without permission, some fraudulent journals use the names of standout researchers on their editorial boards in the effort to look legitimate. This opinion piece, highlights some of the usual types of identity theft and their role in spreading junk science. Some general guidelines that editors and researchers can use against such attacks are presented. PMID- 28074376 TI - Synthetic Biology, Genome Editing, and the Risk of Bioterrorism. AB - The SynBioSecurity argument says that synthetic biology introduces new risks of intentional misuse of synthetic pathogens and that, therefore, there is a need for extra regulations and oversight. This paper provides an analysis of the argument, sets forth a new version of it, and identifies three developments that raise biosecurity risks compared to the situation earlier. The developments include (1) a spread of the required know-how, (2) improved availability of the techniques, instruments and biological parts, and (3) new technical possibilities such as "resurrecting" disappeared pathogens. It is first shown that the general argument from SynBioSecurity needs to be qualified and that many improvements to biosecurity have already been implemented, most notably in the United States. Second, I suggest a new strain of the argument: the situation that most branches of synthetic biology fall under the gene technology regulation in the European Union and that this regulation in its current form does not adequately address SynBioSecurity risks together provide a weighty reason to review and possibly refine the legislation as well as the supervisory practices. Ethically speaking, the rise in the relative risk of bioterrorism brings to the fore new extrinsic issues. PMID- 28074377 TI - Reflection on the Fazlul Sarkar versus PubPeer ("John Doe") Case. PMID- 28074378 TI - Neuroimaging findings of Zika virus infection : Emphasis of the emerging global threat. PMID- 28074379 TI - Neuroimaging findings of congenital Zika virus infection: a pictorial essay. AB - Zika virus (ZIKV) is a mosquito-borne arbovirus from the Flaviviridae family. It had caused several epidemics since its discovery in 1947, but there was no significant attention to this virus until the recent outbreak in Brazil in 2015. The main concern is the causal relationship between prenatal ZIKV infection and congenital microcephaly, which has been confirmed recently. Moreover, ZIKV may cause other central nervous system abnormalities such as brain parenchymal atrophy with secondary ventriculomegaly, intracranial calcification, malformations of cortical development (such as polymicrogyria, and lissencephaly pachygyria), agenesis/hypoplasia of the corpus callosum, cerebellar and brainstem hypoplasia, sensorineural hearing-loss, and ocular abnormalities as well as arthrogryposis in the infected fetuses. Postnatal (acquired) ZIKV infection usually has an asymptomatic or mildly symptomatic course, while prenatal (congenital) ZIKV infection has a more severe course and may cause severe brain anomalies that are described as congenital Zika syndrome. In this pictorial essay, we aim to illustrate the prenatal and postnatal neuroimaging findings that may be seen in fetuses and neonates with congenital Zika syndrome, and will discuss possible radiological differential diagnoses. A detailed knowledge of these findings is paramount for an early correct diagnosis, prognosis determination, and counseling of the affected children and families. PMID- 28074380 TI - Usefulness of diffusion-weighted MR imaging for differentiating between Warthin's tumor and oncocytoma of the parotid gland. AB - PURPOSE: To assess the efficacy of diffusion-weighted (DW) MR imaging for differentiating between Warthin's tumor and oncocytoma of the parotid gland. METHODS: Forty-five histopathologically confirmed parotid gland tumors (41 Warthin's tumors and 4 oncocytomas) were examined by MR imaging including DW imaging. 18F-fluorodeoxyglucose PET/CT was also performed in 9 Warthin's tumors and 3 oncocytomas. We retrospectively reviewed the images and compared the MR signal intensities, apparent diffusion coefficients (ADCs), and maximum standardized uptake values (SUVmax) of the solid components between the two pathologies. RESULTS: The signal intensity ratios (SIRs) on both T2-weighted images (0.92 +/- 0.18 vs 0.65 +/- 0.13, p < 0.01) and DW images (1.24 +/- 0.42 vs 0.43 +/- 0.16, p < 0.001) were higher in Warthin's tumors than in oncocytomas. ADCs (0.79 +/- 0.11 vs 1.06 +/- 0.06 * 10-3 mm2/s, p < 0.001) were lower in Warthin's tumors than in oncocytomas. No significant differences in the SIRs on T1-weighted images (1.09 +/- 0.12 vs. 0.99 +/- 0.07, p = 0.051) and SUVmax (8.22 +/- 3.86 vs. 8.11 +/- 1.33, p = 0.864) were found between Warthin's tumor and oncocytoma. CONCLUSION: DW imaging with ADC measurements is useful for the differentiation of Warthin's tumor from oncocytoma of the parotid gland. PMID- 28074381 TI - Adrenal hormones before and after venography during adrenal venous sampling: a self-controlled study. AB - OBJECTIVE: A stress reaction involving increased adrenal hormone release occurs when starting adrenal venous sampling (AVS). The purpose of the present study was to investigate the effect of single shot venography on adrenal hormone production during AVS. SUBJECTS AND METHODS: This was a prospective self-controlled study. We enrolled 54 consecutive patients (21 men, 33 women; mean age 52 +/- 11 years) with primary aldosteronism who underwent AVS from May 2014 to February 2015. Under non-stimulated conditions, blood samples were obtained from a common trunk of the left adrenal vein before and after single shot venography. The initial plasma aldosterone and cortisol concentration (PAC and PCC) were compared with those measured after venography for each patient. RESULTS: PAC and PCC were slightly but significantly decreased between before and after venography (after log transformation 2.12 +/- 0.73 vs 2.07 +/- 0.72, P = 0.00066, 1.89 +/- 0.52 vs 1.83 +/- 0.53, P = 0.00031, respectively). CONCLUSIONS: During non-stimulated left AVS, adrenal hormone secretion was slightly but significantly decreased after venography, similar to the normal time-related stress reaction. Venography did not increase the adrenal hormone secretion. PMID- 28074382 TI - Engaging Hmong adults in genomic and pharmacogenomic research: Toward reducing health disparities in genomic knowledge using a community-based participatory research approach. AB - Advancing precision medicine relies in part on examining populations that may exhibit unique genetic variants that impact clinical outcomes. Failure to include diverse populations in genomic-based research represents a health disparity. We implemented a community-based participatory research (CBPR) process with the Hmong community in Minnesota, who were refugees from Laos, in order to assess the feasibility of conducting genomic and pharmacogenomic-based research for genetic variants that are relevant to the Hmong community. Our Hmong Genomics Board, consisting of Hmong and non-Hmong professionals, used CBPR principles and built on previous formative research to create and implement culturally and linguistically appropriate informed consent processes for Hmong people at six community venues. The Board chose genetic variants for diabetes risk and warfarin response as relevant to the community. The Institutional Review Board approved aggregate but not individual return of results. Two hundred thirty-seven Hmong participants with mean (range) age of 30.2 (18-81) years and diverse levels of education (22% without and 75% with high-school education) provided saliva for genetic (DNA) analyses. Eighty-five percent of participants agreed to store DNA for future analyses, 82% agreed to share DNA with other researchers, and 78% agreed to be contacted for future studies. Twenty-five elders refused to participate because they wanted individual results. Aggregate results were shared with all participants. This CBPR approach proved highly successful to obtain informed consent and recruit a sample from the Hmong community for a genomic and pharmacogenomic study. Investment in the CBPR process may prove successful to address the gap of genomic information in under-represented communities. PMID- 28074383 TI - Poisoning the pika: must protection of grasslands be at the expense of biodiversity? PMID- 28074384 TI - Microfluidic Gut-liver chip for reproducing the first pass metabolism. AB - After oral intake of drugs, drugs go through the first pass metabolism in the gut and the liver, which greatly affects the final outcome of the drugs' efficacy and side effects. The first pass metabolism is a complex process involving the gut and the liver tissue, with transport and reaction occurring simultaneously at various locations, which makes it difficult to be reproduced in vitro with conventional cell culture systems. In an effort to tackle this challenge, here we have developed a microfluidic gut-liver chip that can reproduce the dynamics of the first pass metabolism. The microfluidic chip consists of two separate layers for gut epithelial cells (Caco-2) and the liver cells (HepG2), and is designed so that drugs go through a sequential absorption in the gut chamber and metabolic reaction in the liver chamber. We fabricated the chip and showed that the two different cell lines can be successfully co-cultured on chip. When the two cells are cultured on chip, changes in the physiological function of Caco-2 and HepG2 cells were noted. The cytochrome P450 metabolic activity of both cells were significantly enhanced, and the absorptive property of Caco-2 cells on chip also changed in response to the presence of flow. Finally, first pass metabolism of a flavonoid, apigenin, was evaluated as a model compound, and co-culture of gut and liver cells on chip resulted in a metabolic profile that is closer to the reported profile than a monoculture of gut cells. This microfluidic gut-liver chip can potentially be a useful platform to study the complex first pass metabolism of drugs in vitro. PMID- 28074385 TI - Use of a CD laser pickup head to fabricate microelectrodes in polymethylmethacrylate substrates for biosensing applications. AB - In this work, we report a simple fabrication method for microelectrodes on a polymethylmethacrylate substrate, using a low-cost laser platform based on a CD DVD unit for direct rapid-prototyping. We used this laser microfabrication technique to etch any desired design on polymethylmethacrylate substrates to produce microchannels with controlled geometry, with a highly repeatable micron scale resolution. Those shallow microchannels were then filled with a conductive paste of material of our choice that was converted into microelectrodes of desired shapes and geometries after drying. To validate our process, different geometries, sizes and materials were used as electrodes, and then tested for amperometry and impedance measurements. Development of these microelectrodes is motivated by their potential application in sensors and biosensors, such as glucose and cell counting, as demonstrated in this paper. PMID- 28074386 TI - The effect of ceramic thickness and resin cement shades on the color matching of ceramic veneers in discolored teeth. AB - The objective of this study was to analyze the effects of ceramic material thickness and resin cement shade on the color matching of ceramic veneers at the gray tooth structures. Seventy-two artificial maxillary right central incisor teeth (C2 shade) were prepared according to veneer tooth preparation in practice. Ceramic materials (LT, A2 shade, IPS e.max Press) were selected to fabricate the 0.50- and 0.75-mm thick veneers at the body region. The ceramic veneer specimens were bonded to the artificial teeth by the 6 shades of resin cements (Variolink Veneer: shades of HV+3, LV-2, LV-3; and RelyXTM Veneer: shades of WO, TR, A3). A clinical spectrophotometer (Crystaleye, Olympus) was used to measure the color parameters. The color differences (DeltaE values) of ceramic veneers and A2 shade tab (Vitapan Classical, Vita) and C* ab values were calculated. The results of three-way ANOVA indicated that the DeltaE values of ceramic veneer and A2 shade tab were significantly different in the thickness of ceramic materials, shades of resin cements, and measuring regions (p < 0.001). There were significant differences in 0.50-mm-thick ceramic veneers that exhibited higher DeltaE values compared with veneers that were 0.75-mm thick. Tukey's HSD test showed that the average DeltaE values in body region were significantly smaller than that in cervical and incisal regions. The color matching of ceramic veneers was significantly influenced not only by the ceramic thickness and the resin cement shades but also the tooth regions. PMID- 28074388 TI - Lactobacillus slpA promotes ESC growth through the ERK1/2 pathway. AB - Bacterial surface layers (S-layers) are cell envelope structures ubiquitously found in gram-negative and gram-positive bacteria, including Lactobacillus. S layers play a role in the determination and maintenance of cell shape as virulence factors, mediate cell adhesion, and regulate immature dendritic and T cells. In this study, we sought to understand the involvement of MAPK serine/threonine kinases in alterations in Endometrial epithelial cells (ESC) growth induced by Lactobacillus crispatus (L. crispatus) slpA, an S-layer protein. We applied various concentrations of L. crispatus to cultured ESCs and observed growth and changes in the phosphorylation status of ERK1/2, JNK, and p38. Similar experiments were conducted using L. crispatus lacking and overexpressing slpA. We found that ESC growth was altered by slpA primarily via ERK1/2. Our findings suggest that L. crispatus slpA promotes ESC growth mainly through an ERK1/2-dependent pathway. PMID- 28074387 TI - Epigenetic sampling effects: nephrectomy modifies the clear cell renal cell cancer methylome. AB - PURPOSE: Currently, it is unclear to what extent sampling procedures affect the epigenome. Here, this phenomenon was evaluated by studying the impact of artery ligation on DNA methylation in clear cell renal cancer. METHODS: DNA methylation profiles between vascularised tumour biopsy samples and devascularised nephrectomy samples from two individuals were compared. The relevance of significantly altered methylation profiles was validated in an independent clinical trial cohort. RESULTS: We found that six genes were differentially methylated in the test samples, of which four were linked to ischaemia or hypoxia (REXO1L1, TLR4, hsa-mir-1299, ANKRD2). Three of these genes were also found to be significantly differentially methylated in the validation cohort, indicating that the observed effects are genuine. CONCLUSION: Tissue ischaemia during normal surgical removal of tumour can cause epigenetic changes. Based on these results, we conclude that the impact of sampling procedures in clinical epigenetic studies should be considered and discussed, particularly after inducing hypoxia/ischaemia, which occurs in most oncological surgery procedures through which tissues are collected for translational research. PMID- 28074389 TI - Cochlear epithelial of dog fetuses: a new source of multipotent stem cells. AB - Hearing loss caused by the damage of cochlea sensory cells or neurons is a common human disease, but also affects dogs and other animals. To test their progenitor nature as potential value for future therapies, we characterized cells derived from the cochlear epithelium in dog fetuses. In total, 8 fetuses of 35-40 days of gestation, derived from castration campaigns, were investigated. Cells were analysed by the MTT colorimetric assay and in regard to cell cycle, differentiation capacities, immunophenotypes and qPCR analysis. In culture, cells had a fibroblast-like morphology. Phenotypic immunocharacterization showed positive staining for mesenchymal stem cell and pluripotency markers and were negative for hematopoietic cell markers. Cells possessed differentiation capacity for the three main cell lineages: osteogenic, adipogenic and chondrogenic, altogether indicating their nature as mesenchymal stem cells. Thus, cells derived from fetal cochlear tissues indeed may provide valuable sources of progenitor cells for cell therapy of canine deafness and other diseases. PMID- 28074390 TI - Anti-allergic triterpenes isolated from olive milled waste. AB - The degranulation of basophils stimulated by antigen is one of the allergic mechanisms of immediate hypersensitivity reactions. In a previous study, the beta hexosaminidase release of rat basophilic leukemia (RBL-2H3) cells stimulated by IgE cross-linking was specifically inhibited by ethanol extract of olive milled waste (OMW). OMW is a potential source of triterpenes, which show several biological activities. However, little is known about the effect of triterpenes in OMW on beta-hexosaminidase release. Here we investigated anti-allergic triterpenes from the ethanol extract of OMW, and we discuss the structure activity relationship. We subjected ethanol extract of OMW to activity-guided fractionation; this led to the isolation of five known triterpenes, i.e., maslinic acid (1), oleanolic acid (2), punicanolic acid (3), 2-O-acetylmaslinic acid (4), and epimaslinic acid (5) as well as one new triterpene, 11-oxo-maslinic acid (6). An anti-allergic assay revealed that 2-O-acetylmaslinic acid (4) and 11 oxo-maslinic acid (6) showed anti-allergic activity. Considering the structure activity relationship of these triterpenes, it appears that the existence of a ketone group at C-11 or an acetyl group at C-2 would influence the anti-allergic activity. PMID- 28074391 TI - Etiologic spectrum and functional outcome of the acute inflammatory myelitis. AB - Clinical, neuroimaging, and laboratory features are not specific enough to establish the etiological diagnosis of the acute inflammatory myelitis (AIM). Longitudinally extensive transverse myelitis (LETM) seen on magnetic resonance imaging (MRI) has been associated with a poor functional prognosis. The aim of this study was to assess the functional outcomes of a first AIM event comparing patients with LETM vs. no LETM on MRI and to report the differential diagnosis. Clinical, radiological, biochemical aspects were collected, and Winner-Hughes Functional Disability Scale (WHFDS) was performed after 3 and 6 months. Centromedullary lesions were associated with LETM, lateral lesions with partial lesion (PL), and brain MRI lesions with multiple sclerosis and acute encephalomyelitis disseminated. LETM patients were associated with a worse functional outcome as the need of a wheelchair after 3 and 6 months (OR = 7.61 p = 0.01; OR 4.8 p = 0.04, respectively), a walker or cane (OR = 11.0 p = 0.002, OR = 4.3 p = 0.03, respectively). In addition, we found a correlation between LETM and acute complete transverse myelitis and PL with acute partial transverse myelitis (83.3 and 90.9%, respectively; p < 0.0001). In conclusion, AIM is a heterogeneous syndrome from an etiological point of view and LETM patients had worse functional prognosis compared with PL after 3 and 6 months. PMID- 28074392 TI - Effect of cerebrolysin on gross motor function of children with cerebral palsy: a clinical trial. AB - Gross motor dysfunction is considered as the most challenging problem in cerebral palsy (CP). It is proven that improvement of gross motor function could reduce CP related disabilities and provide better quality of life in this group of patients. Therefore, the aim of this trial is to evaluate the effectiveness of cerebrolysin (CBL) on gross motor function of children with CP who are undergoing treatment. In this clinical trial study, paediatric patients aged 18-75 months with spastic diplegic or quadriplegic cerebral palsy, who were under rehabilitation therapy, were selected and randomly allocated in control and CBL groups. Patients in CBL group underwent treatment with standard rehabilitation therapy plus CBL. The latter was administrated intramuscularly as a single daily dose of 0.1 cc/kg for 10 days and then continued weekly for 4 months. Gross motor function of participants in the two studied groups, before and after trial, was evaluated and compared using the validated Persian version of gross motor function classification system-expanded and revised (GMFCS-E&R). During this trial, 108 patients with CP were evaluated for eligibility. From these, 50 patients were enrolled and randomly allocated in the CBL and control groups. Four months after trial, the mean level of GMFCS decreased significantly in the two groups (P < 0.05). However, it was significantly lower in the CBL group than in the control group (2.1 vs. 3.16, P < 0.05). The results of this trial indicated that CBL could improve gross motor function in patients with CP. This finding is consistent with neurotrophic and neuroprotective effects of CBL, which have been reported in various clinical trials in other neurological disorders. Further studies are recommended to establish the value of continued neuroprotection and to determine the pharmacokinetics/dynamics of CBL in this group of patients. PMID- 28074393 TI - 45th ESCP-NSF international symposium on clinical pharmacy: clinical pharmacy tackling inequalities and access to health care. Oslo, Norway, 5-7 October 2016. PMID- 28074394 TI - The Specificity of Women's Sexual Response and Its Relationship with Sexual Orientations: A Review and Ten Hypotheses. AB - Category-specific sexual response describes a pattern wherein the individual shows significantly greater responses to preferred versus nonpreferred categories of sexual stimuli; this pattern is described as gender specific for sexual orientation to gender, or gender nonspecific if lacking response differentiation by gender cues. Research on the gender specificity of women's sexual response has consistently produced sexual orientation effects, such that androphilic women (sexually attracted to adult males) typically show gender-nonspecific patterns of genital response and gynephilic women (sexually attracted to adult females) show more gender-specific responses. As research on the category specificity of sexual response has grown, this pattern has also been observed for other measures of sexual response. In this review, I use the Incentive Motivation and Information Processing Models as complementary frameworks to organize the empirical literature examining the gender specificity of women's sexual response at each stage of sexual stimulus processing and response. Collectively, these data disconfirm models of sexual orientation that equate androphilic women's sexual attractions with their sexual responses to sexual stimuli. I then discuss 10 hypotheses that might explain variability in the specificity of sexual response among androphilic and gynephilic women, and conclude with recommendations for future research on the (non)specificity of sexual response. PMID- 28074395 TI - Target-mediated drug disposition with drug-drug interaction, Part I: single drug case in alternative formulations. AB - Target-mediated drug disposition (TMDD) describes drug binding with high affinity to a target such as a receptor. In application TMDD models are often over parameterized and quasi-equilibrium (QE) or quasi-steady state (QSS) approximations are essential to reduce the number of parameters. However, implementation of such approximations becomes difficult for TMDD models with drug drug interaction (DDI) mechanisms. Hence, alternative but equivalent formulations are necessary for QE or QSS approximations. To introduce and develop such formulations, the single drug case is reanalyzed. This work opens the route for straightforward implementation of QE or QSS approximations of DDI TMDD models. The manuscript is the first part to introduce DDI TMDD models with QE or QSS approximations. PMID- 28074396 TI - Target mediated drug disposition with drug-drug interaction, Part II: competitive and uncompetitive cases. AB - We present competitive and uncompetitive drug-drug interaction (DDI) with target mediated drug disposition (TMDD) equations and investigate their pharmacokinetic DDI properties. For application of TMDD models, quasi-equilibrium (QE) or quasi steady state (QSS) approximations are necessary to reduce the number of parameters. To realize those approximations of DDI TMDD models, we derive an ordinary differential equation (ODE) representation formulated in free concentration and free receptor variables. This ODE formulation can be straightforward implemented in typical PKPD software without solving any non linear equation system arising from the QE or QSS approximation of the rapid binding assumptions. This manuscript is the second in a series to introduce and investigate DDI TMDD models and to apply the QE or QSS approximation. PMID- 28074397 TI - Anti-inflammatory effects of secondary metabolites isolated from the marine derived fungal strain Penicillium sp. SF-5629. AB - After the chemical investigation of the ethyl acetate extract of the marine derived fungal strain Penicillium sp. SF-5629, the isolation and structural elucidation of eight secondary metabolites, including (3R,4S)-6,8-dihydroxy-3,4,7 trimethylisocoumarin (1), (3S,4S)-sclerotinin A (2), penicitrinone A (3), citrinin H1 (4), emodin (5), omega-hydroxyemodin (6), 8-hydroxy-6-methyl-9-oxo-9H xanthene-1-carboxylate (7), and 3,8-dihydroxy-6-methyl-9-oxo-9H-xanthene-1 carboxylate (8) were carried out. Evaluation of the anti-inflammatory activity of these metabolites showed that 4 inhibited nitric oxide and prostaglandin E2 production in lipopolysaccharide-stimulated BV2 microglia, with IC50 values of 8.1 +/- 1.9 and 8.0 +/- 2.8 MUM, respectively. The inhibitory function of 4 was confirmed based on decreases in inducible nitric oxide synthesis and cyclooxygenase-2 gene expression. In addition, 4 was found to suppress the phosphorylation of inhibitor kappa B-alpha, interrupt the nuclear translocation of nuclear factor kappa B, and decrease the activation of p38 mitogen-activated protein kinase. PMID- 28074398 TI - Liquid chromatographic enantiomer separation of 1-naphthylamides of chiral acids using several amylose- and cellulose-derived chiral stationary phases. AB - The liquid chromatographic enantiomer separation of various chiral acids as 1 naphthylamides was performed using several chiral stationary phases (CSPs). The CSPs used in this study were six covalently bonded and four coated type CSPs derived from amylose and cellulose derivatives as chiral selectors. The degree of enantioseparation is affected by the structure of chiral acids and the CSPs used, which have different chiral selectors and types of immobilization. For the enantiomer resolution of chiral acids as 1-naphthylamide derivatives, the performance of the coated type Lux Cellulose-1 was superior to those of the other CSPs, except for 2-aryloxypropionic acid derivatives. Owing to the strong ultraviolet absorbance of the 1-naphthyl group, the convenient analytical method developed and validated in this study could be expected to be very useful for the enantiomer separation of various chiral acids as 1-naphthylamide derivatives using polysaccharide-derived CSPs. PMID- 28074399 TI - Evaluating the impact of lower resolutions of digital elevation model on rainfall runoff modeling for ungauged catchments. AB - Geomorphological instantaneous unit hydrograph (GIUH) usually uses geomorphologic parameters of catchment estimated from digital elevation model (DEM) for rainfall runoff modeling of ungauged watersheds with limited data. Higher resolutions (e.g., 5 or 10 m) of DEM play an important role in the accuracy of rainfall runoff models; however, such resolutions are expansive to obtain and require much greater efforts and time for preparation of inputs. In this research, a modeling framework is developed to evaluate the impact of lower resolutions (i.e., 30 and 90 m) of DEM on the accuracy of Clark GIUH model. Observed rainfall-runoff data of a 202-km2 catchment in a semiarid region was used to develop direct runoff hydrographs for nine rainfall events. Geographical information system was used to process both the DEMs. Model accuracy and errors were estimated by comparing the model results with the observed data. The study found (i) high model efficiencies greater than 90% for both the resolutions, and (ii) that the efficiency of Clark GIUH model does not significantly increase by enhancing the resolution of the DEM from 90 to 30 m. Thus, it is feasible to use lower resolutions (i.e., 90 m) of DEM in the estimation of peak runoff in ungauged catchments with relatively less efforts. Through sensitivity analysis (Monte Carlo simulations), the kinematic wave parameter and stream length ratio are found to be the most significant parameters in velocity and peak flow estimations, respectively; thus, they need to be carefully estimated for calculation of direct runoff in ungauged watersheds using Clark GIUH model. PMID- 28074400 TI - Peculiarities of the obese patient with cancer: a national consensus statement by the Spanish Society for the Study of Obesity and the Spanish Society of Medical Oncology. AB - The relationship between obesity and cancer is clear and is present at all times during course of the disease. The importance of obesity in increasing the risk of developing cancer is well known, and some of the most prevalent tumours (breast, colorectal, and prostate) are directly related to this risk increase. However, there is less information available on the role that obesity plays when the patient has already been diagnosed with cancer. Certain data demonstrate that in some types of cancer, obese patients tolerate the treatments more poorly. Obesity is also known to have an impact on the prognosis, favouring lower survival rates or the appearance of secondary tumours. In this consensus statement, we will analyse the scientific evidence on the role that obesity plays in patients already diagnosed with cancer, and the available data on how obesity control can improve the quality of daily life for the cancer patient. PMID- 28074401 TI - Adipsic diabetes insipidus in adult patients. AB - INTRODUCTION: Adipsic diabetes insipidus (ADI) is a very rare disorder, characterized by hypotonic polyuria due to arginine vasopressin (AVP) deficiency and failure to generate the sensation of thirst in response to hypernatraemia. As the sensation of thirst is the key homeostatic mechanism that prevents hypernatraemic dehydration in patients with untreated diabetes insipidus (DI), adipsia leads to failure to respond to aquaresis with appropriate fluid intake. This predisposes to the development of significant hypernatraemia, which is the typical biochemical manifestation of adipsic DI. METHODS: A literature search was performed to review the background, etiology, management and associated complications of this rare condition. RESULTS: ADI has been reported to occur in association with clipping of an anterior communicating artery aneurysm following subarachnoid haemorrhage, major hypothalamic surgery, traumatic brain injury and toluene exposure among other conditions. Management is very difficult and patients are prone to marked changes in plasma sodium concentration, in particular to the development of severe hypernatraemia. Associated hypothalamic disorders, such as severe obesity, sleep apnoea and thermoregulatory disorders are often observed in patients with ADI. CONCLUSION: The management of ADI is challenging and is associated with significant morbidity and mortality. Prognosis is variable; hypothalamic complications lead to early death in some patients, but recent reports highlight the possibility of recovery of thirst. PMID- 28074402 TI - Riparian rehabilitation planning in an urban-rural gradient: Integrating social needs and ecological conditions. AB - In the present context of global change and search for sustainability, we detected a gap between restoration and society: local communities are usually only considered as threats or disturbances when planning for restoration. To bridge this gap, we propose a landscape design framework for planning riparian rehabilitation in an urban-rural gradient. A spatial multi-criteria analysis was used to assess the priority of riversides by considering two rehabilitation objectives simultaneously-socio-environmental and ecological-and two sets of criteria were designed according to these objectives. The assessment made it possible to identify 17 priority sites for riparian rehabilitation that were associated with different conditions along the gradient. The double goal setting enabled a dual consideration of citizens, both as beneficiaries and potential impacts to rehabilitation, and the criteria selected incorporated the multi dimensional nature of the environment. This approach can potentially be adapted and implemented in any other anthropic-natural interface throughout the world. PMID- 28074403 TI - Commensal in conflict: Livestock depredation patterns by free-ranging domestic dogs in the Upper Spiti Landscape, Himachal Pradesh, India. AB - In human-populated landscapes worldwide, domestic dogs (Canis lupus familiaris) are the most abundant terrestrial carnivore. Although dogs have been used for the protection of livestock from wild carnivores, they have also been implicated as predators of livestock. We used a combination of methods (field surveys, interview surveys, and data from secondary sources) to examine the patterns and factors driving livestock depredation by free-ranging dogs, as well as economic losses to local communities in a Trans-Himalayan agro-pastoralist landscape in India. Our results show that livestock abundance was a better predictor of depredation in the villages than local dog abundance. Dogs mainly killed small bodied livestock and sheep were the most selected prey. Dogs were responsible for the majority of livestock losses, with losses being comparable to that by snow leopards. This high level of conflict may disrupt community benefits from conservation programs and potentially undermine the conservation efforts in the region through a range of cascading effects. PMID- 28074404 TI - A method for the assessment of long-term changes in carbon stock by construction of a hydropower reservoir. AB - Sustainability of hydropower reservoirs has been questioned since the detection of their greenhouse gas (GHG) emissions which are mainly composed of carbon dioxide and methane. A method to assess the impact on the carbon cycle caused by the transition from a natural river system into a reservoir is presented and discussed. The method evaluates the long term changes in carbon stock instead of the current approach of monitoring and integrating continuous short term fluxes. A case study was conducted in a subtropical reservoir in Brazil, showing that the carbon content within the reservoir exceeds that of the previous landuse. The average carbon sequestration over 43 years since damming was 895 mg C m[Formula: see text] and found to be mainly due to storage of carbon in sediments. These results demonstrate that reservoirs have two opposite effects on the balance of GHGs. By storing organic C in sediments, reservoirs are an important carbon sink. On the other hand, reservoirs increase the flux of methane into the atmosphere. If the sediments of reservoirs could be used for long term C storage, reservoirs might have a positive effect on the balance of GHGs. PMID- 28074405 TI - Big concerns with small projects: Evaluating the socio-ecological impacts of small hydropower projects in India. AB - Although Small Hydropower Projects (SHPs) are encouraged as sources of clean and green energy, there is a paucity of research examining their socio-ecological impacts. We assessed the perceived socio-ecological impacts of 4 SHPs within the Western Ghats in India by conducting semi-structured interviews with local respondents. Primary interview data were sequentially validated with secondary data, and respondent perceptions were subsequently compared against the expected baseline of assured impacts. We evaluated the level of awareness about SHPs, their perceived socio-economic impacts, influence on resource access and impacts on human-elephant interactions. The general level of awareness about SHPs was low, and assurances of local electricity and employment generation remained largely unfulfilled. Additionally most respondents faced numerous unanticipated adverse impacts. We found a strong relationship between SHP construction and increasing levels of human-elephant conflict. Based on the disparity between assured and actual social impacts, we suggest that policies regarding SHPs be suitably revised. PMID- 28074406 TI - Testosterone and Jamaican Fathers : Exploring Links to Relationship Dynamics and Paternal Care. AB - This paper investigates relationships between men's testosterone and family life in a sample of approximately 350 Jamaican fathers of children 18-24 months of age. The study recognizes the role of testosterone as a proximate mechanism coordinating and reflecting male life history allocations within specific family and cultural contexts. A sample of Jamaican fathers and/or father figures reported to an assessment center for an interview based on a standardized questionnaire and provided a saliva sample for measuring testosterone level. Outcomes measured include subject demographics such as age and relationship status as well as partnership quality and sexuality and paternal attitudes and behavior. The variation in these fathers' relationship status (e.g., married co residential fathers, fathers in new non-residential relationships) was not associated with men's testosterone. Too few stepfathers participated to enable a direct test of the prediction that stepfathers would have higher testosterone than biological fathers, although fathers who reported living with partners' (but not his own) children did not have higher testosterone than fathers not reporting residing with a non-biological child. Fathers' relationship quality was negatively related to their testosterone. Measures of paternal attitudes and behavior were not related to fathers' testosterone. Consistent with previous ethnography, this sample of Jamaican fathers exhibited variable life history profiles, including residential status. We discuss why fathers' relationship quality was found to be negatively related to their testosterone level, but other predictions were not upheld. PMID- 28074407 TI - Youth Views on Communication About ADHD and Medication Adherence. AB - The purpose of this study was to examine youth perceptions of attention deficit hyperactivity disorder (ADHD) communication with their pediatric providers, their reported adherence to their ADHD medications, and their desired location for an ADHD educational program. Youth ages 7 through 17 with an ADHD diagnosis were recruited. A research associate interviewed the youth. Parents completed demographic questionnaires. Seventy families participated. One-third of the youth wanted more discussion about ADHD with their providers during visits. The average youth had over eight questions about ADHD and its treatment. Most youth wanted to learn about ADHD at their provider's office. Non-white and older youth were significantly more likely to be less adherent to their ADHD medications. Youth want their providers to engage them more during visits. Providers should take advantage of this interest to engage youth more in discussions regarding ADHD and its treatment during pediatric ADHD visits. PMID- 28074408 TI - Pharmacologic stress myocardial perfusion imaging in patients with pulmonary hypertension: What do we know, and what remains to be learned? PMID- 28074409 TI - Management of Depression in Patients with Dementia: Is Pharmacological Treatment Justified? AB - Depression in the context of dementia is common and contributes to poorer outcomes in individuals and those who care for them. Non-pharmacological treatments are the preferred initial approach to managing these symptoms but data in support of these are scarce. There are a number of pharmacological treatment options available to clinicians but efficacy is uncertain and concern about potential side effects in an aging and vulnerable population needs to be taken into consideration. This review aims to provide a concise overview of pharmacological treatments for depression in dementia. Antidepressants are the mainstay of pharmacological treatment for clinically significant depression in the general population but evidence to support their use in dementia is mixed. Trials of antidepressants should generally be reserved for individuals with depression where the symptoms are distressing and surpass the threshold for major depression. Acetylcholinesterase inhibitors and memantine are effective in the symptomatic treatment of Alzheimer's disease but current evidence does not support their use to treat depressive symptoms in dementia. Similarly, antipsychotics and mood stabilizers have no proven efficacy for depression and the risk of adverse effects seems to outweigh any potential benefit. Pain can be a frequent problem in dementia and may have significant effects on behavior and mood. Preliminary evidence supports a role of adequate analgesia in improving mood in people with dementia. PMID- 28074410 TI - Improving Medication Adherence and Health Outcomes in Older Adults: An Evidence Based Review of Randomized Controlled Trials. AB - BACKGROUND: Poor medication adherence is a major public health problem in older adults often resulting in negative health outcomes. OBJECTIVE: The objective of this review was to provide an updated summary of evidence from randomized controlled studies to determine whether interventions aimed at improving medication adherence also improve the health outcomes of older adults residing in community-based settings. METHODS: Articles that assessed medication adherence interventions and related health outcomes in elderly individuals were identified through searches of MEDLINE (1970-June 2016), the Cochrane Database of Systematic Reviews (through to June 2016), and Google Scholar. Across the 12 included studies, interventions were grouped into three main categories: behavioral/educational (n = 3), pharmacist-led (n = 7), and reminder/simplification (n = 2). RESULTS: Among the behavioral/educational intervention studies, two showed improvements in both adherence and related health outcomes, whereas one found no changes in adherence or health outcomes. Among the pharmacist-led studies, three showed improvements in both adherence and related health outcomes, while three reported no changes in adherence or health outcomes. One found an improvement in adherence but not health outcomes. Among the reminder/simplification studies, both studies reported improvements in adherence without a significant impact on related health outcomes. CONCLUSION: This evidence-based review of medication adherence interventions in older adults revealed promising strategies in the larger context of a largely mixed body of literature. Future patient-centered and multidisciplinary interventions should be developed and tested using evidence-based principles to improve medication adherence and health outcomes in older adults. PMID- 28074411 TI - Biomass and terpenoids produced by mutant strains of Arthrospira under low temperature and light conditions. AB - The filamentous Cyanobacterium Arthrospira is commercially produced and is a functional, high-value, health food. We identified 5 low temperature and low light intensity tolerant strains of Arthrospira sp. (GMPA1, GMPA7, GMPB1, GMPC1, and GMPC3) using ethyl methanesulfonate mutagenesis and low temperature screening. The 5 Arthrospira strains grew rapidly below 14 degrees C, 43.75 MUmol photons m-2 s-1 and performed breed conservation at 2.5 degrees C, 8.75 MUmol photons m-2 s-1. We used morphological identification and molecular genetic analysis to identify GMPA1, GMPA7, GMPB1 and GMPC1 as Arthrospira platensis, while GMPC3 was identified as Arthrospira maxima. Growth at different culture temperatures was determined at regular intervals using dry biomass. At 16 degrees C and 43.75 MUmol photons m-2 s-1, the maximum dry biomass production and the mean dry biomass productivity of GMPA1, GMPB1, and GMPC1 were 2057 +/- 80 mg l-1, 68.7 +/- 2.5 mg l-1 day-1, 1839 +/- 44 mg l-1, 60.6 +/- 1.8 mg l-1 day-1, and 2113 +/- 64 mg l-1, 77.7 +/- 2.5 mg l-1 day-1 respectively. GMPB1 was chosen for additional low temperature tolerance studies and growth temperature preference. In winter, GMPB1 grew well at mean temperatures <10 degrees C, achieving 3258 mg dry biomass from a starting 68 mg. In summer, GMPB1 grew rapidly at mean temperatures more than 28 degrees C, achieving 1140 mg l-1 dry biomass from a starting 240 mg. Phytonutrient analysis of GMPB1 showed high levels of C-phycocyanin and carotenoids. Arthrospira metabolism relates to terpenoids, and the methyl-D-erythritol 4-phosphate pathway is the only terpenoid biosynthetic pathway in Cyanobacteria. The 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) gene from GMPB1 was cloned and phylogenetic analysis showed that GMPB1 is closest to the Cyanobacterium Oscillatoria nigro-viridis PCC711. Low temperature tolerant Arthrospira strains could broaden the areas suitable for cultivation, extend the seasonal cultivation time, and lower production costs. PMID- 28074412 TI - A Scientific Rationale to Improve Resistance Training Prescription in Exercise Oncology. AB - To date, the prevailing evidence in the field of exercise oncology supports the safety and efficacy of resistance training to attenuate many oncology treatment related adverse effects, such as risk for cardiovascular disease, increased fatigue, and diminished physical functioning and quality of life. Moreover, findings in the extant literature supporting the benefits of exercise for survivors of and patients with cancer have resulted in the release of exercise guidelines from several international agencies. However, despite research progression and international recognition, current exercise oncology-based exercise prescriptions remain relatively basic and underdeveloped, particularly in regards to resistance training. Recent publications have called for a more precise manipulation of training variables such as volume, intensity, and frequency (i.e., periodization), given the large heterogeneity of a cancer population, to truly optimize clinically relevant patient-reported outcomes. Indeed, increased attention to integrating fundamental principles of exercise physiology into the exercise prescription process could optimize the safety and efficacy of resistance training during cancer care. The purpose of this article is to give an overview of the current state of resistance training prescription and discuss novel methods that can contribute to improving approaches to exercise prescription. We hope this article may facilitate further evaluation of best practice regarding resistance training prescription, monitoring, and modification to ultimately optimize the efficacy of integrating resistance training as a supportive care intervention for survivors or and patients with cancer. PMID- 28074413 TI - Procoagulant activity of extracellular vesicles as a potential biomarker for risk of thrombosis and DIC in patients with acute leukaemia. AB - Haemostatic complication is common for patients with hematologic malignancies. Recent studies suggest that the procoagulant activity (PCA) of extracellular vesicles (EV) may play a major role in venous thromboembolism and disseminated intravascular coagulation (DIC) in acute leukaemia. To study the impact of EVs from leukaemic patients on thrombin generation and to assess EV-PCA as a potential biomarker for thrombotic complications in patients with acute leukaemia. Blood samples from a cohort of patients with newly diagnosed acute leukaemia were obtained before treatment (D-0), 3 and 7 days after treatment (D-3 and D-7). Extracellular vesicles were isolated and concentrated by ultracentrifugation. EV-PCA was assessed by thrombin generation assay, and EV associated tissue factor activity was measured using a commercial bio-immunoassay (Zymuphen MP-TF(r)). Of the 53 patients, 6 had increased EV-PCA at D-0 and 4 had a thrombotic event. Patients without thrombotic events (n = 47) had no elevated EV-PCA. One patient had increased EVs with procoagulant activity at D-3 and developed a DIC at D-5. This patient had no increased EVs-related tissue factor activity from D-0 to D-7 (<2 pg/ml). Eight patients had increased EVs with tissue factor activity (>2 pg/ml), of these, four had a thrombosis and two had haemorrhages. Procoagulant activity of extracellular vesicles could have a predictive value in excluding the risk of thrombotic events. Our findings also suggest a possible association between thrombotic events and EV-PCA. PMID- 28074414 TI - Spontaneous Remission of Subcutaneous Scedosporiosis Caused by Scedosporium dehoogii in a Psoriatic Patient. AB - To date, only one case of post-traumatic endophthalmitis caused by Scedosporium dehoogii has been reported, but its contamination or colonization might not be precluded due to the absence of pathogenic isolation and/or pathological examination. We report the first case to our knowledge of S. dehoogii-induced subcutaneous scedosporiosis in a psoriatic patient. A 58-year-old man with 5-year history of psoriasis vulgaris and immunosuppressant therapy developed pyrexia and multiple subcutaneous abscesses on both knees. Direct microscopy of the yellowish pus showed masses of bright green short spores. Skin biopsy revealed some branched septate hyphae within the granuloma. Two aspirated pus specimens collected at a 1-week interval produced white cottony colonies on Sabouraud dextrose agar. Bacterial cultures of one blood and two purulent samples were negative, and fungal culture of blood sample was not performed. The isolate was identified as S. dehoogii using beta-tubulin phylogeny and species-specific PCR with primer MSDE1/MSA2. Without addition of antifungal treatment, subcutaneous lesions disappeared spontaneously after immunosuppressant withdrawal and no relapse occurred during 64-month follow-up. The spontaneous recovery may result from immune reconstitution following immunosuppressant discontinuation. PMID- 28074417 TI - Influence of the marvelousTM three-way stopcock on the natural frequency and damping coefficient in blood pressure transducer kits. AB - Two types of PlanectaTM ports are commonly used as sampling ports in blood pressure transducer kits: a flat-type port (FTP) and a port with a three-way stopcock (PTS). Recently, a new type of three-way stopcock (MarvelousTM) has been released as a PlanectaTM counterpart, but its effects on the frequency characteristics and reliability of blood pressure monitoring have not been investigated. We assessed the influence of the MarvelousTM stopcock on the frequency characteristics of the pressure transducer kit. The basic pressure transducer kit, DT4812J, was modified by replacing one or two of the original three-way stopcocks with MarvelousTM stopcocks. The frequency characteristics (i.e., natural frequency and damping coefficient) of each kit were determined using wave parameter analysis software, and subsequently evaluated on a Gardner chart. Replacement of the original blood pressure transducer kit stopcocks with MarvelousTM stopcocks decreased the natural frequency (48.3 Hz) to 46.3 Hz or 44.8 Hz, respectively; the damping coefficient was not significantly changed. Plotting the data on a Gardner chart revealed that the changes fell within the adequate dynamic response region, indicating they were within the allowable range. Insertion of MarvelousTM stopcocks slightly affects the natural frequency of the pressure transducer kit, similar to inserting a PTS. The results indicate that the MarvelousTM stopcock is useful for accurate monitoring of arterial blood pressure, and may be recommended when insertion of two or more closed-loop blood sampling systems is necessary. PMID- 28074418 TI - Identification of low-molecular-weight vitellogenin 1 (Vg1)-like proteins as nucleotide excision repair (NER) factors in developing zebrafish (Danio rerio) using a transcription-based DNA repair assay. AB - Nucleotide excision repair (NER) removes helix-distorting DNA lesions such as UV induced pyrimidine dimers and cisplatin-induced strand crosslinking. Our earlier studies have identified low-molecular-weight proteins homologous to the 150-kDa vitellogenin 1 (Vg1) as UV-damaged DNA-binding factors expressed in developing zebrafish (Danio rerio). This present study explored if Vg1-like proteins also participated in NER in zebrafish. Immunoblot analysis of affinity-captured 12 h post-fertilization (hpf) zebrafish extract proteins showed a transient binding of a 30-kDa Vg1-like polypeptide to UV-damaged DNA. A transcription-based in vitro repair assay revealed a significant up-regulation of UVC or cisplatin-suppressed transcriptional activity of a marker cDNA driven by a SP6 RNA polymerase regulated promotor after incubating the damaged plasmid with the extracts of 12 hpf embryos or 96 hpf larvae. The up-regulation of UV or cisplatin-suppressed transcription was abolished in the presence of a monoclonal anti-zebrafish Vg1 antibody. The differential sensitivity of UV-induced repair in 12 and 96 hpf zebrafish extracts to exogenous ATP suggested a development-dependent expression of Vg1-like NER factors. A T4 endonuclease V digestion assay showed no inhibition of the anti-Vg1 antibody on the excision of UV-induced cyclobutane pyrimidine dimers. Our results identified the participation of Vg1-like factors in NER in developing zebrafish, and these factors may function at post-incison steps of NER. PMID- 28074419 TI - Deciphering the molecular mechanisms involved in HIV-associated lipoatrophy by transcriptomics: a pilot study. AB - HIV-associated lipoatrophy (LA) has considerable implications for risk of metabolic diseases, quality of life, and adherence to treatments. Although it has decreased in high-income countries, it is still very common in resource-limited countries. Understanding the pathophysiological mechanisms of LA can open the possibility to explore new ways to treat or prevent this condition. To identify new markers for an accurate and quick diagnosis will be also of interest. Thus, we aimed to examine functional classes of genes implicated in LA and to identify potential new markers for an accurate/quick diagnosis of LA and future complications. Eighteen participants were recruited: seven healthy volunteers, five non-LA-HIV patients, and six LA-HIV subjects. Clinical lipoatrophy was considered when changes in fat volume in the cheeks next to the nose, lateral aspect of the face, legs, arms, and buttocks were observed by the physicians. mRNA was isolated from peripheral blood mononuclear cells (PBMCs) to perform a transcriptomic and Gene Ontology analysis. To confirm RNA sequencing results, qPCRs were developed. A total of 55 genes were differentially expressed between LA and non-LA patients. Thirty-seven genes were overexpressed, whereas 18 genes were repressed. Functional analysis showed that overexpressed genes were involved in lymphocyte/neutrophil activation, inflammation, and atherogenesis. Several lymphoma markers and members of the lipocalin and aquaporin families were also found more expressed in LA patients. In contrast, most of the genes found less expressed in LA subjects were involved in angiogenesis and protection against myocardial infarction. Our results demonstrated a distinct transcriptomic signature in PBMCs of LA patients in comparison with non-LA-HIV subjects and, therefore, provided novel insights to the pathogenesis of HIV-associated lipoatrophy. Our study also highlights the potential usage of some of these genes as early markers of future complications. PMID- 28074420 TI - Efficacy of systemic diclofenac sodium on intravitreal concentration. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs), as an alternative, are replacing corticosteroids in ocular inflammatory diseases. Diclofenac has been used mainly topically, and recent focus has been on intravitreal delivery. Both of these methods have been shown to have complications in long-term application. PURPOSE: To assess the efficacy of slow release oral diclofenac sodium on intravitreal concentration in experimental model of chemically injured eyes. METHODS: In an experimental double-masked clinical trial, right eyes of 24 albino rabbits were chemically injured by 1 N NaOH. One hour after chemical injury, 10 cc suspension gavage containing 100 mg slow release diclofenac sodium was administered in all cases. 2, 4, 6, 12, 24, 48 h after gavage, vitreous samples were obtained in all cases. Intravitreal concentration of diclofenac sodium was evaluated in all samples using high-performance liquid chromatography (HPLC) method. RESULTS: Intravitreal diclofenac levels by oral intake were enhanced by the inflammation in all the measurements. In inflamed eyes, diclofenac concentration was ten times more than control eye (2.658 +/- 0.344 vs. 0.242 +/- 0.0279 and 1.617 +/- 0.527 vs. 0.148 +/- 0.095; in 2 and 4 h, respectively). After 6 h, diclofenac concentration was statistically different, although it reduced below 1 MUg/ml. CONCLUSION: Diclofenac is delivered to the inflamed eye more than healthy eye. It seems that by oral diclofenac consumption, it is possible to make a significant intravitreal concentration. PMID- 28074422 TI - Compacted Multiparticulate Systems for Colon-Specific Delivery of Ketoprofen. AB - Pellet-containing tablets for colon-specific drug delivery present higher targeting efficiency and lower costs when compared with monolithic tablets and pellet-filled capsules, respectively. In this study, pellets containing ketoprofen were coated with different acrylic polymers and submitted to compaction. The influence of formulation and process factors on film integrity was then evaluated. Pellets were prepared via extrusion-spheronization and coated using two acrylic polymers (Eudragit(r) FS 30 D and Opadry(r) 94 k28327, PMMA and PMA, respectively). The resulting pellets were mixed with placebo granules and compressed in a hydraulic press. Multiple regression showed that ketoprofen release from pellet-containing tablets is predominantly influenced by pellet content, hardness, friability, and disintegration time. PMA-containing tablets prepared under low compaction force or with low pellet content showed rapid disintegration (<1 min) and ketoprofen release similar to those of uncompressed coated pellets (~30% at 360 min of experiment). On the other hand, PMMA containing tablets showed a higher rupture level, and those prepared with higher pellet content gave rise to a non-disintegrating matrix. Coated pellets were shown to be able to target ketoprofen to the colonic region. Targeting capacity was dependent on the physicochemical characteristics of the tablets. PMID- 28074421 TI - Community-Based Accompaniment with Supervised Antiretrovirals for HIV-Positive Adults in Peru: A Cluster-Randomized Trial. AB - We conducted a cluster-randomized trial to estimate effects of directly observed combination antiretroviral therapy (DOT-cART) on retention with viral suppression among HIV-positive adults in Peru. We randomly allocated facilities to receive the 12-month intervention plus the standard of care, including adherence support provided through accompaniment. In the intervention arm, health workers supervised doses, twice daily, and accompanied patients to appointments. Among 356 patients, intention-to-treat analyses showed no statistically significant benefit of DOT, relative to no-DOT, at 12 or 24 months (adjusted probability of primary outcome: 0.81 vs. 0.73 and 0.76 vs. 0.68, respectively). A statistically significant benefit of DOT was found in per-protocol and as-treated analyses at 12 months (0.83 for DOT vs. 0.73 for no DOT, p value: 0.02 per-protocol, 0.01 as treated), but not 24 months. Rates of retention with viral suppression were high in both arms. Among adults receiving robust adherence support, the added effect of time-limited DOT, if any, is small-to-moderate. PMID- 28074423 TI - Effectiveness of Risk Evaluation and Mitigation Strategies (REMS) for Lenalidomide and Thalidomide: Patient Comprehension and Knowledge Retention. AB - INTRODUCTION: The effectiveness of patient education activities conducted within the lenalidomide and thalidomide risk evaluation and mitigation strategies (REMS) programs was evaluated by measuring understanding of serious risk and safe-use messages. METHODS: Results from mandatory knowledge, attitude, and behavior surveys and voluntary patient surveys completed between June 2012 and June 2013 were analyzed, and responses to questions relating to compliance with birth control measures and understanding of safe-use messages are presented by patient risk category. RESULTS: In total, 73,645 patients were enrolled into the REMS programs for lenalidomide and thalidomide and completed mandatory surveys prior to medication dispense. Of these, 2790 (3.8%) completed an additional voluntary survey. Among voluntary survey participants, for all patient pregnancy risk categories, reported compliance with birth control requirements was above 90% when starting therapy and at follow-up. At the beginning of therapy, complete compliance was 96.3%; 3 months later it was 96.4%. Patient understanding of safe use messages was very high in all pregnancy risk groups, notably for messages repeated at each physician visit. Overall, 98.2% of patients knew that lenalidomide and thalidomide could cause birth defects, which is part of the repeated educational messaging. In contrast, 87.1% recalled that unused product should be returned to their healthcare professional, which is not included in repeated messaging. CONCLUSION: The lenalidomide and thalidomide REMS programs enhance patient understanding of safe-use messages, resulting in high levels of compliance with the birth control precautions essential to prevent fetal exposure to these known and potential human teratogens. Overall compliance was maintained after 3 months of follow-up and throughout therapy. PMID- 28074424 TI - Signal Detection Based on Time to Onset Algorithm in Spontaneous Reporting System of China. AB - INTRODUCTION: The method of time-to-onset (TTO) has been proposed to overcome the drawbacks of traditional disproportionality analyses (DPAs), and it has been used for detecting safety signals of vaccines and some non-vaccine products in spontaneous reporting systems (SRSs). However, there is no consensus on its superiority over DPAs. Further, it is still not clear whether this novel approach can be generalized to the entire national SRS database. OBJECTIVE: The purpose of this study was to generalize the TTO method to the Chinese SRS and to identify suitable parameters for its optimal performance. METHODS: Reports submitted to the national SRS of China in 2014 were used as the data source for analysis. We evaluated the performance of TTO by using product labels as proxies for the gold standard. A series of values of significance level and time windows were explored to identify the most suitable parameters for TTO based on Youden's index, a statistic that summarizes the performance of a diagnostic test. Additionally, we compared TTO with traditional DPAs and explored the characteristics of signals detected by these methods. RESULTS: Compared with DPAs, TTO had a lower sensitivity, but higher specificity and positive predictive value. At a significance level of 0.2 and no restrictions on time windows, TTO had the highest Youden's index. The kappa coefficients between TTO and DPAs were rather low, indicating poor agreement between the two methods. More than 30% of the true signals detected by TTO were not identified by DPAs. Furthermore, TTO needed more number of reports to be able to detect signals. CONCLUSIONS: TTO can detect signals missed by traditional DPAs and could be an important complementary tool to the currently used DPAs in the SRS of China. We recommend a significance level of 0.2 and no restrictions on time windows for TTO. PMID- 28074425 TI - High wall shear stress and high-risk plaque: an emerging concept. AB - In recent years, there has been a significant effort to identify high-risk plaques in vivo prior to acute events. While number of imaging modalities have been developed to identify morphologic characteristics of high-risk plaques, prospective natural-history observational studies suggest that vulnerability is not solely dependent on plaque morphology and likely involves additional contributing mechanisms. High wall shear stress (WSS) has recently been proposed as one possible causative factor, promoting the development of high-risk plaques. High WSS has been shown to induce specific changes in endothelial cell behavior, exacerbating inflammation and stimulating progression of the atherosclerotic lipid core. In line with experimental and autopsy studies, several human studies have shown associations between high WSS and known morphological features of high risk plaques. However, despite increasing evidence, there is still no longitudinal data linking high WSS to clinical events. As the interplay between atherosclerotic plaque, artery, and WSS is highly dynamic, large natural history studies of atherosclerosis that include WSS measurements are now warranted. This review will summarize the available clinical evidence on high WSS as a possible etiological mechanism underlying high-risk plaque development. PMID- 28074427 TI - Erratum to: Functional identification and regulatory analysis of Delta6-fatty acid desaturase from the oleaginous fungus Mucor sp. EIM-10. PMID- 28074426 TI - Use of colour Doppler and M-mode ultrasonography to confirm the location of an epidural catheter - a retrospective case series. AB - PURPOSE: Epidural anesthesia and analgesia has a reported failure rate ranging from 13% to 32%. We describe a technique using colour Doppler and M-mode ultrasonography to determine the position of the epidural catheter after placement in adults. METHODS: This retrospective review included 37 adult patients who received postoperative epidural analgesia and underwent technically difficult epidural catheter placement. The demographic characteristics, type of surgery, use of ultrasonography, method of insertion, intervertebral level, and success of epidural localization using colour Doppler were noted for each patient. Pain scores on postoperative day 1 and the presence of a patchy block were also reviewed. RESULTS: Colour Doppler study helped to indicate the catheter's path from the skin to the epidural space during saline injection in 33 patients (89%). Saline flow within the epidural space (catheter tip confirmation) was successfully detected with colour Doppler in 25 patients (67.5%) and with M mode ultrasonography in 28 patients (75%). Appropriate dermatomal analgesia was noted in 35 patients (94.5%) during local anesthetic infusion. CONCLUSION: Our preliminary data suggest the feasibility of using colour Doppler and M-mode ultrasonography to confirm proper epidural catheter placement. PMID- 28074428 TI - Tat-DJ-1 enhances cell survival by inhibition of oxidative stress, NF-kappaB and MAPK activation in HepG2 cells. AB - OBJECTIVES: To identify the protective effect of DJ-1 protein against oxidative stress-induced HepG2 cell death, we used cell-permeable wild type (WT) and a mutant (C106A Tat-DJ-1) protein. RESULTS: By using western blotting and fluorescence microscopy, we observed WT and C106A Tat-DJ-1 proteins were efficiently transduced into HepG2 cells. Transduced WT Tat-DJ-1 proteins increased cell survival and protected against DNA fragmentation and intracellular ROS generation levels in H2O2-exposed HepG2 cells. At the same time, transduced WT Tat-DJ-1 protein significantly inhibited NF-kappaB and MAPK (JNK and p38) activation as well as regulated the Bcl-2 and Bax expression levels. However, C106A Tat-DJ-1 protein did not show any protective effect against cell death responses in H2O2-exposed HepG2 cells. CONCLUSIONS: Oxidative stress-induced HepG2 cell death was significantly reduced by transduced WT Tat-DJ-1 protein, not by C106A Tat-DJ-1 protein. Thus, transduction of WT Tat-DJ-1 protein could be a novel strategy for promoting cell survival in situations of oxidative stress induced HepG2 cell death. PMID- 28074429 TI - Longitudinal Associations between Change in Neighborhood Social Disorder and Change in Food Swamps in an Urban Setting. AB - Few studies have examined how neighborhood contextual features may influence the food outlet mix. We evaluated the relationship between changes in neighborhood crime and changes in the food environment, namely the relative density of unhealthy (or intermediate) food outlets out of total food outlets, or food swamp score, in Baltimore City from 2000 to 2012, using neighborhood fixed-effects linear regression models. Comparing neighborhoods to themselves over time, each unit increase in crime rate was associated with an increase in the food swamp score (b = 0.13; 95% CI, -0.00017 to 0.25). The association with food swamp score was in the same direction for violent crime and in the inverse direction for arrests related to juvenile crimes (proxy of reduced crime), but did not reach statistical significance when examined separately. Unfavorable conditions, such as crime, may deter a critical consumer base, diminishing the capacity of a community to attract businesses that are perceived to be neighborhood enhancing. Addressing these more distal drivers may be important for policies and programs to improve these food environments. PMID- 28074430 TI - The monomeric GTPase RabA2 is required for progression and maintenance of membrane integrity of infection threads during root nodule symbiosis. AB - KEY MESSAGE: Progression of the infection canal that conducts rhizobia to the nodule primordium requires a functional Rab GTPase located in Golgi/trans-Golgi that also participate in root hair polar growth. Common bean (Phaseolus vulgaris) symbiotically associates with its partner Rhizobium etli, resulting in the formation of root nitrogen-fixing nodules. Compatible bacteria can reach cortical cells in a tightly regulated infection process, in which the specific recognition of signal molecules is a key step to select the symbiotic partner. In this work, we show that RabA2, a monomeric GTPase from common bean, is required for the progression of the infection canal, referred to as the infection thread (IT), toward the cortical cells. Expression of miss-regulated mutant variants of RabA2 resulted in an increased number of abortive infection events, including bursting of ITs and a reduction in the number of nodules. Nodules formed in these plants were small and contained infected cells with disrupted symbiosome membranes, indicating either early senescence of these cells or defects in the formation of the symbiosome membrane during bacterial release. RabA2 localized to mobile vesicles around the IT, but mutations that affect GTP hydrolysis or GTP/GDP exchange modified this localization. Colocalization of RabA2 with ArfA1 and a Golgi marker indicates that RabA2 localizes in Golgi stacks and the trans-Golgi network. Our results suggest that RabA2 is part of the vesicle transport events required to maintain the integrity of the membrane during IT progression. PMID- 28074432 TI - Stereo- and region-specific biotransformation of physapubescin by four fungal strains. AB - Biotransformations of physapubescin (1) were performed by four fungal strains Mucor subtilissimus AS 3.2454, Mucor polymorphosporus AS 3.3443, Aspergillus niger AS 3.795, and Syncephalastrum racemosum AS 3.264. Four metabolites were prepared in the biotransformation process of 1, and their structures were elucidated as 15alpha-acetoxy-5,6beta:22,26:24,25-triepoxy-26alpha-hydroxy-3beta methoxy 4beta-hydroxyergost-1-one (2), 15alpha-acetoxy-5,6beta:22,26-diepoxy 4beta,24beta,25alpha,26(alpha, beta)-tetrahydroxyergost-3beta-methoxy-1-one (3a/3b), 15alpha-acetoxy-5,6beta:22,26-diepoxy-4beta,24beta,25alpha,26(alpha, beta)-tetrahydroxyergost-2-en-1-one (4a/4b), and physapubescin D (5), by spectroscopic data analysis. Among them, metabolites 2 and 3 are new. All of these fungal strains showed the ability to be highly stereo- and region-specific for the bioconversion of substrate (1). Our research provides a reference for the structural derivatization of withanolides or possibly even other natural products. PMID- 28074431 TI - Detection and Specific Elimination of EGFR+ Ovarian Cancer Cells Using a Near Infrared Photoimmunotheranostic Approach. AB - PURPOSE: Targeted theranostics is an alternative strategy in cancer management that aims to improve cancer detection and treatment simultaneously. This approach combines potent therapeutic and diagnostic agents with the specificity of different cell receptor ligands in one product. The success of antibody drug conjugates (ADCs) in clinical practice has encouraged the development of antibody theranostics conjugates (ATCs). However, the generation of homogeneous and pharmaceutically-acceptable ATCs remains a major challenge. The aim of this study is to detect and eliminate ovarian cancer cells on-demand using an ATC directed to EGFR. METHODS: An ATC with a defined drug-to-antibody ratio was generated by the site-directed conjugation of IRDye(r)700 to a self-labeling protein (SNAP tag) fused to an EGFR-specific antibody fragment (scFv-425). RESULTS: In vitro and ex vivo imaging showed that the ATC based on scFv-425 is suitable for the highly specific detection of EGFR+ ovarian cancer cell, human tissues and ascites samples. The construct was also able to eliminate EGFR+ cells and human ascites cells with IC50 values of 45-66 nM and 40-90 nM, respectively. CONCLUSION: Our experiments provide a framework to create a versatile technology platform for the development of ATCs for precise detection and treatment of ovarian cancer cells. PMID- 28074433 TI - Partial contribution of Rho-kinase inhibition to the bioactivity of Ganoderma lingzhi and its isolated compounds: insights on discovery of natural Rho-kinase inhibitors. AB - Recent studies identified Rho-kinase enzymes (ROCK-I and ROCK-II) as important targets that are involved in a variety of diseases. Synthetic Rho-kinase inhibitors have emerged as potential therapeutic agents to treat disorders such as hypertension, stroke, cancer, diabetes, glaucoma, etc. Our study is the first to screen the total ethanol extract of the medicinal mushroom Ganoderma lingzhi with thirty-five compounds for Rho-kinase inhibitory activity. Moreover, a molecular binding experiment was designed to investigate the binding affinity of the compounds at the active sites of Rho-kinase enzymes. The structure-activity relationship analysis was investigated. Our results suggest that the traditional uses of G. lingzhi might be in part due to the ROCK-I and ROCK-II inhibitory potential of this mushroom. Structure-activity relationship studies revealed some interesting features of the lanostane triterpenes that potentiate their Rho kinase inhibition. These findings would be helpful for further studies on the design of Rho-kinase inhibitors from natural sources and open the door for contributions from other researchers for optimizing the development of natural Rho-kinase inhibitors. PMID- 28074434 TI - Lessons learned from the world's first successful penis allotransplantation. AB - We performed a successful penis allotransplantation on 11 December 2014. Sharing the lessons learned might help more patients in need to be treated this way. We divided the project into manageable segments that was each overseen by an expert. The ethical review and conduct paved the way for a publically acceptable and successful project. Screening for a psychological stable recipient is important. The most difficult part of the project was finding a donor penis. This was successfully negotiated with the family of a brain dead donor by creating a neo phallus for the donor, thereby maintaining the dignity of the donor. Working with transplant coordinators that are sympathetic to aphallic men is crucial. Surgeons versed in microvascular techniques is a critical part of the team. Transplant immunologists have to adapt to treat composite tissue transplantation patients. PMID- 28074435 TI - Plk1 inhibition leads to a failure of mitotic division during the first mitotic division in pig embryos. AB - PURPOSE: This study was conducted to examine the dynamic distribution of polo like 1 kinase (Plk1) and the possible role it plays in first mitotic division during early porcine embryo development. METHODS: Indirect immunofluorescence and confocal microscopy imaging techniques combined with western blot analyses were used to study the dynamic expression and subcellular localization of Plk1 protein in pig parthenogenetic embryos. Finally, a selective Plk1 inhibitor, GSK461364, was used to evaluate the potential role of Plk1 during this special stage. RESULTS: The results showed that Plk1 upon expression exhibited specific dynamic intracellular localization, which closely correlated with the alpha-tubulin distribution during the first mitotic division. GSK461364 treatment resulted in cleavage failure, with majority of the GSK461364-treated embryos being arrested in prometaphase. Further results of the subcellular structure examination showed that GSK461364 treatment led to a significantly higher proportion of the treated embryos having abnormal spindles and misarranged chromosomes at the prometaphase stage. CONCLUSIONS: Thus, these results indicated that Plk1 is essential for porcine embryos to complete the first mitotic division. Furthermore, Plk1 regulation was associated with effects on spindle assembly and chromosome arrangement. PMID- 28074437 TI - Aberrant endometrial DNA methylome of homeobox A10 and catechol-O methyltransferase in endometriosis. AB - PURPOSE: Differential methylation of both HOXA10 and catechol-O-methyltransferase (COMT) has been reported in different endometrium disorders, and the two genes are linked through the estrogen pathway. The current study investigates the DNA methylation of HOXA10 and COMT in ectopic and eutopic endometrial tissues and its correlation with and the occurrence of endometriosis in women from Xinjiang province in China. METHODS: In the current study, 120 patients with endometriosis were recruited from our hospital between January 2011 and June 2014. The DNA methylation sites of HOXA10 and COMT were detected using a DNA methylation array. The methylation levels of specific sites were compared between ectopic and eutopic endometrial tissues via pyrosequencing. RESULTS: Five differentially expressed CpGs were localized in the promoter region of the COMT gene and expressed significantly higher in the ectopic endometrium than the eutopic endometrium (P < 0.001). Two out of the five differentially expressed CpGs in the HOXA10 gene located in the promoter region were both significantly lower (nearly half) in the ectopic endometrium than the eutopic endometrium (P < 0.001). CONCLUSIONS: To summarize, significant differential methylation of HOXA10 and COMT promoter regions was found between the ectopic and eutopic endometrial tissues. This is the first study investigating the methylation of HOXA10 and COMT genes and their linkage to endometriosis in Chinese patients. PMID- 28074436 TI - Intrafollicular inflammatory cytokines but not steroid hormone concentrations are increased in naturally matured follicles of women with proven endometriosis. AB - PURPOSE: The aim of this study was to assess whether the intrafollicular cytokine profile in naturally developed follicles is different in women with endometriosis, possibly explaining the lower reproductive outcome in endometriosis patients. METHODS: A matched case-control study was conducted at a university-based infertility and endometriosis centre. The study population included 17 patients with laparoscopically and histologically confirmed endometriosis (rAFS stages II-IV), each undergoing one natural cycle IVF (NC-IVF) treatment cycle between 2013 and 2015, and 17 age-matched NC-IVF women without diagnosed endometriosis (control group). Follicular fluid and serum was collected at the time of follicle aspiration. The concentrations of inflammatory cytokines (IL-1beta, IL-6, IL-8, IL-15, IL-18, TNF-alpha) and hormones (testosterone, estradiol, AMH) were determined in follicular fluid and serum by single or multiplexed immunoassay and compared between both groups. RESULTS: In the follicular fluid, IL-1beta and IL-6 showed significantly (P < 0.001 and 0.01, respectively) higher median concentrations in the endometriosis group than in the control group and a tendency towards endometriosis severity (rAFS stage) dependence. The levels of the interleukins detectable in follicular fluid were significantly higher than those in the serum (P < 0.01). Follicular estradiol concentration was lower in severe endometriosis patients than in the control group (P = 0.036). Follicular fluid IL-1beta and IL-6 levels were not correlated with estradiol in the same compartment in neither patient group. CONCLUSIONS: In women with moderate and severe endometrioses, some intrafollicular inflammatory cytokines are upregulated and not correlated with intrafollicular hormone concentrations. This might be due to the inflammatory microenvironment in endometriosis women, affecting follicular function and thereby possibly contributing to the reproductive dysfunction in endometriosis. PMID- 28074438 TI - Is There Variation in Procedural Utilization for Lumbar Spine Disorders Between a Fee-for-Service and Salaried Healthcare System? AB - BACKGROUND: Whether compensation for professional services drives the use of those services is an important question that has not been answered in a robust manner. Specifically, there is a growing concern that spine care practitioners may preferentially choose more costly or invasive procedures in a fee-for-service system, irrespective of the underlying lumbar disorder being treated. QUESTIONS/PURPOSES: (1) Were proportions of interbody fusions higher in the fee for-service setting as opposed to the salaried Department of Defense setting? (2) Were the odds of interbody fusion increased in a fee-for-service setting after controlling for indications for surgery? METHODS: Patients surgically treated for lumbar disc herniation, spinal stenosis, and spondylolisthesis (2006-2014) were identified. Patients were divided into two groups based on whether the surgery was performed in the fee-for-service setting (beneficiaries receive care at a civilian facility with expenses covered by TRICARE insurance) or at a Department of Defense facility (direct care). There were 28,344 patients in the entire study, 21,290 treated in fee-for-service and 7054 treated in Department of Defense facilities. Differences in the rates of fusion-based procedures, discectomy, and decompression between both healthcare settings were assessed using multinomial logistic regression to adjust for differences in case-mix and surgical indication. RESULTS: TRICARE beneficiaries treated for lumbar spinal disorders in the fee-for-service setting had higher odds of receiving interbody fusions (fee-for-service: 7267 of 21,290 [34%], direct care: 1539 of 7054 [22%], odds ratio [OR]: 1.25 [95% confidence interval 1.20-1.30], p < 0.001). Purchased care patients were more likely to receive interbody fusions for a diagnosis of disc herniation (adjusted OR 2.61 [2.36-2.89], p < 0.001) and for spinal stenosis (adjusted OR 1.39 [1.15-1.69], p < 0.001); however, there was no difference for patients with spondylolisthesis (adjusted OR 0.99 [0.84-1.16], p = 0.86). CONCLUSIONS: The preferential use of interbody fusion procedures was higher in the fee-for-service setting irrespective of the underlying diagnosis. These results speak to the existence of provider inducement within the field of spine surgery. This reality portends poor performance for surgical practices and hospitals in Accountable Care Organizations and bundled payment programs in which provider inducement is allowed to persist. LEVEL OF EVIDENCE: Level III, economic and decision analysis. PMID- 28074439 TI - CORR Insights(r): Racial Disparities in Above-knee Amputations after TKA: A National Database Study. PMID- 28074440 TI - Distal femoral extension and shortening osteotomy as a part of multilevel surgery in children with cerebral palsy. AB - BACKGROUND: There are several reports describing an increase in anterior pelvic tilt after hamstring lengthening in children with cerebral palsy (CP). Distal femoral extension and shortening osteotomy (DFESO) is an alternative treatment for correction of flexed knee gait, but investigations analyzing outcome and influence on adjacent joint are few in the literature. The purpose of this study was to analyze the influence of DFESO on knee and pelvis in children with CP. Furthermore, it was of interest if an additional patellar tendon advancement (PA) influences outcome. METHODS: In this retrospective study, 31 limbs of 22 children (GMFCS I-III; mean age: 12.1+/-3.1 years), who received DFESO were included and kinematic parameters (knee, pelvis) measured by 3-D-gait analysis were compared before and at least 1 year after surgery (mean follow-up period: 15.6 months). RESULTS: After surgery, during stance phase minimum knee flexion improved significantly by 20.5 degrees (P<0.001) and mean anterior pelvic tilt increased by 4.0 degrees (P=0.045). In 16 limbs, the postoperative increase in maximum anterior pelvic tilt was more than 5 degrees . Limbs who received an additional PA showed the biggest increase in anterior pelvic tilt. CONCLUSIONS: DFESO is an effective method for correction of flexed knee gait in children with CP. Furthermore, the results of this study indicate that DFESO may lead to an increase in anterior pelvic tilt, which may lead to a recurrence of flexed knee gait. In this context, PA seemed to aggravate the effect on the pelvis. PMID- 28074441 TI - Activation of Parvalbumin-Positive Neurons in Both Retina and Primary Visual Cortex Improves the Feature-Selectivity of Primary Visual Cortex Neurons. AB - Several recent studies using either viral or transgenic mouse models have shown different results on whether the activation of parvalbumin-positive (PV+) neurons expressing channelrhodopsin-2 (ChR2) in the primary visual cortex (V1) improves the orientation- and direction-selectivity of V1 neurons. Although this discrepancy was thoroughly discussed in a follow-up communication, the issue of using different models to express ChR2 in V1 was not mentioned. We found that ChR2 was expressed in retinal ganglion cells (RGCs) and V1 neurons in ChR2fl/+; PV-Cre mice. Our results showed that the activation of PV+ RGCs using white drifting gratings alone significantly decreased the firing rates of V1 neurons and improved their direction- and orientation-selectivity. Long-duration activation of PV+ interneurons in V1 further enhanced the feature-selectivity of V1 neurons in anesthetized mice, confirming the conclusions from previous findings. These results suggest that the activation of both PV+ RGCs and V1 neurons improves feature-selectivity in mice. PMID- 28074442 TI - Undifferentiated carcinoma of the liver: a case report with immunohistochemical analysis. AB - BACKGROUND: Undifferentiated carcinoma (UC) of the liver is extremely rare, and its clinicopathological characteristics have not been fully elucidated. CASE PRESENTATION: The present study reports the case of a 56-year-old male with UC of the liver. At 16 days post-admission, the patient suddenly succumbed due to intra abdominal bleeding resulting from a ruptured liver. Macroscopic examination revealed that the hepatic parenchyma was almost completely replaced by innumerable minute nodules. Microscopically, the tumor demonstrated a diffuse proliferation of anaplastic cells that were positive for epithelial membrane antigen and neuron-specific enolase, suggesting neuroendocrine differentiation. Grimelius and Fontana-Masson staining were negative. Neuroendocrine markers were also negative, including chromogranin A, synaptophysin, and S-100 protein. Cytokeratin markers and mesenchymal markers were all negative. Tumor markers, such as alpha-fetoprotein and carcinoembryonic antigen, were also negative. CONCLUSIONS: Although larger studies involving more patients are required to establish a therapeutic strategy, appropriate chemotherapy following an early diagnosis may be important to UC of the liver because the tumor behaves in an aggressive way. PMID- 28074443 TI - Knowledge, Behaviors, and Attitudes About Human Papilloma Virus Among Nursing Students in Izmir, Turkey. AB - Human papillomavirus (HPV) is transmitted through sexual contact and can cause cervical cancer. The aim of this study was to determine knowledge, behaviors, and attitudes about human papillomavirus (HPV) in nursing students in a baccalaureate program. This study was conducted with a sample of 624 students. Data were collected via questionnaires administered during the first class time. Students' knowledge about HPV was high; 90.5% knew HPV can cause cervical cancer; 94.6% recognized it as a sexually transmitted disease. Although; 87.7% stated a vaccine is available to protect women from HPV, nearly all participants (98.1%) had not received HPV vaccination. Findings show students' level of knowledge about HPV's risk factors and modes of transmission were high. However, this knowledge did not translate into engagement in health related behaviors such as being vaccinated against HPV. PMID- 28074444 TI - Effects of an Education Intervention about HPV Self-Testing for Healthcare Providers and Staff. AB - Human papillomavirus (HPV) self-testing is an emerging cervical cancer screening strategy, yet efforts to educate healthcare providers and staff about HPV self testing are lacking. We report the findings of a brief education intervention about HPV self-testing for healthcare providers and staff. We conducted education sessions during 2015 with healthcare providers and staff (n = 33) from five federally qualified health centers located in Appalachian Ohio. Participants attended a one-time session and completed pre- and post-intervention surveys. Analyses for paired data assessed changes in knowledge and beliefs about HPV, HPV related disease, and HPV self-testing. The intervention increased participants' knowledge and affected many of the beliefs examined. Participants answered an average of 4.67 of six knowledge items correctly on pre-intervention surveys and 5.82 items correctly on post-intervention surveys (p < 0.001). The proportion of participants who answered all six knowledge items correctly increased substantially (pre-intervention =9% vs. post-intervention =82%, p < 0.001). Compared to pre-intervention surveys, participants more strongly believed on post intervention surveys that it is important to examine HPV self-testing as a potential cervical cancer screening strategy, that their female patients would be willing to use an HPV self-test at home by themselves, and that they have the knowledge to talk with their patients about HPV self-testing (all p < 0.05). A brief education intervention can be a viable approach for increasing knowledge and affecting beliefs about HPV self-testing among healthcare providers and staff. Findings will be valuable for planning and developing future HPV self-test interventions that include an education component for healthcare providers and staff. PMID- 28074445 TI - Intrathoracic tumor of the chest wall: A case of Castleman's disease mimicking myositis of the lower extremities. AB - Castleman's disease refers to a group of uncommon lymphoproliferative disorders which exhibit common lymph-node histological features. A 72-year-old male patient presented with signs of lower limb myositis. Detailed work-up focused initially on evaluating hematological malignancies, the presence of a solid tumor, autoimmune diseases and degenerative disorders of the peripheral nerves. Finally, a PET-CT scan was performed to exclude paraneoplastic manifestations of a primary tumor, revealing however a tumor of the thoracic wall. The definite histological diagnosis confirmed the presence of unicentric Castleman's disease of the chest wall. The manifestations of the present case suggest that a systemic inflammation might occur in the unicentric form of the disease possibly due to cytokine hypersecretion. The unicentric manifestation of the disease should be well distinguished from the multicentric appearance. Unicentric disease is a surgical condition and warrants a follow-up based on the systemic inflammation that might occur. PMID- 28074447 TI - Seasonal Polyphenism and Behavioral Variations of Ceroplastes glomeratus Peronti (Hemiptera: Coccidae). AB - The wax scale Ceroplastes glomeratus Peronti shows seasonal behavioral and phenotypic differences. Individuals develop gregariously during autumn, whereas solitarily in spring. Besides such behavioral differences, spring ("isolated form") and autumn ("aggregated form") will also produce different morphotypes. We provide additional data on the morphological data of the species based on the microscopic and macroscopic characteristics of adult females and of first-instars of the two adult morphotypes of C. glomeratus. PMID- 28074448 TI - The importance of accurate sample size calculations in clinical trials. PMID- 28074446 TI - Efficacy and Safety of Switching to Ixekizumab in Etanercept Non-Responders: A Subanalysis from Two Phase III Randomized Clinical Trials in Moderate-to-Severe Plaque Psoriasis (UNCOVER-2 and -3). AB - BACKGROUND: Patients with psoriasis who have an inadequate response to one biologic may benefit from switching to a new biologic, such as ixekizumab, a high affinity monoclonal antibody that selectively targets interleukin (IL)-17A. OBJECTIVE: Our aim was to assess the response to ixekizumab in patients with moderate-to-severe plaque psoriasis who did not respond adequately to etanercept using a post-hoc analysis in two phase III studies. METHODS: For the subanalyses in two phase III trials (UNCOVER-2 and -3), non-response was defined by either failure to have a static physician global assessment (sPGA) of 0/1 in UNCOVER-2 or failure to have at least 75% improvement in psoriasis area and severity index (PASI 75) in UNCOVER-3 at Week 12 of each study. Non-responders treated with twice-weekly etanercept 50 mg in the first 12 weeks received two injections of placebo at Week 12 (4-week wash-out period), followed by ixekizumab every 4 weeks (Q4W) for Weeks 16-60. Non-responders to placebo in the first 12 weeks were administered ixekizumab 160 mg at Week 12, followed by ixekizumab Q4W for Weeks 16-60. RESULTS: After switching to ixekizumab Q4W, a substantial proportion of patients with moderate-to-severe psoriasis who did not respond to etanercept experienced rapid and durable improvement in all efficacy evaluations. Among sPGA 0/1 (UNCOVER-2) and PASI 75 (UNCOVER-3) non-responders to etanercept, 73.0% achieved sPGA 0/1 and 78.2% achieved PASI 75, respectively, after 12 weeks of ixekizumab treatment. Safety profiles in patients switched from etanercept to ixekizumab were similar to those in patients switched from placebo to ixekizumab. CONCLUSION: Patients who were non-responders to etanercept after 12 weeks, as defined by failure to meet sPGA 0/1 (UNCOVER-2) or PASI 75 (UNCOVER-3), achieved high levels of response 12 weeks after switching to ixekizumab. Studies are registered with ClinicalTrials.gov (NCT01597245 and NCT01646177). PMID- 28074449 TI - Effects of acupuncture on quality of life and pain in patients with osteoporosis a pilot randomized controlled trial: reply to comments by Moran et al. PMID- 28074451 TI - ERCP with stenting of traumatic pancreatic duct transection: A case report. AB - Pancreatic injuries, though rare, are associated with high morbidity because of location of pancreas adjacent to the various hollow and solid organs. Difficulty in early diagnosis adds to morbidity. Condition of the pancreatic duct is an important factor in grading the injury and deciding upon course of management. Conservative management is the line of treatment in lower grade injuries. Higher grades of pancreatic injuries are usually managed surgically. Endoscopic retrograde cholangiopancreaticography (ERCP) has recently emerged as an effective diagnostic as well as therapeutic modality for hepatobiliary and pancreatic pathologies. Presently described is case of a 12-year-old boy who presented with post-traumatic complete transection of pancreatic duct, which was successfully managed by ERCP-guided stenting of the duct. Therapeutic advantages of ERCP in trauma setting and difficulties involved are highlighted. PMID- 28074450 TI - Forget Me if You Can: Attentional capture by to-Be-remembered and to-Be-forgotten visual stimuli. AB - Previous studies on directed forgetting in visual working memory (VWM) have shown that, if people are cued to remember only a subset of the items currently held in VWM, they will completely forget the uncued, no longer relevant items. While this finding is indicative of selective remembering, it remains unclear whether directed forgetting can also occur in the absence of any concurrent to-be remembered information. In the current study, we addressed this matter by asking participants to memorize a single object that could be followed by a cue to forget or remember this object. Following the cue, we assessed the object's activation in VWM by determining whether a matching distractor would capture attention in a visual search task. The results showed that, compared to a cue to remember, a cue to forget led to a reduced likelihood of attentional capture by a matching distractor. In addition, we found that capture effects by to-be remembered and to-be-forgotten distractors remained stable as the interval between the onset of the cue and the search task increased from 700 ms to 3900 ms. We conclude that, in the absence of any to-be-remembered objects, an instruction to forget an object held in WM leads to a rapid but incomplete deactivation of the representation of that object, thus allowing it to continue to produce a weak biasing effect on attentional selection for several seconds after the instruction to forget. PMID- 28074452 TI - Hemoptysis caused by pulmonary sequestration in perforated appendicitis: A rare case report. AB - Pulmonary sequestration is a rare and usually asymptomatic congenital anomaly. Optimal management of this condition is still a subject of debate, including superiority of surgical resection or angiographic embolization of the aberrant arterial vessel. Presently described is rare case of a 51-year-old male who presented with hemoptysis related to pulmonary sequestration associated with acute right lower quadrant abdominal pain caused by perforated appendicitis. PMID- 28074453 TI - Laparoscopic resection and intracorporeal anastomosis of perforated small bowel caused by fish bone ingestion. AB - Presently described is case of a 52-year-old man who was admitted to the emergency department with 3-day history of epigastric pain. Abdominal examination revealed diffuse tenderness and muscle guarding. Plain abdominal X-ray showed free subdiaphragmatic air. The patient underwent diagnostic laparoscopy with presumptive diagnosis of peptic ulcer perforation. Laparoscopy showed several inflamed, edematous jejunal loops with proximal obstruction and perforation by an impacted fish bone. Completely intracorporeal resection and anastomosis using laparoscopic linear stapler was performed and segment of resected bowel was removed through trocar site. Postoperative period was uneventful, and the patient was discharged on fourth day. PMID- 28074454 TI - Obturator hernia should be considered in the differential diagnosis of hip and knee pain. AB - Obturator hernia is a rare disease usually occurring in debilitated elderly women. Pain radiating down the medial thigh and knee (Howship-Romberg sign) is a specific sign of the disease. Presently described is a case of obturator hernia in a 73-year-old female patient who presented with severe left hip pain radiating down the medial thigh and knee, nausea, and loss of appetite. Initially, vertebral disc herniation was thought to be cause, but abdomino-pelvic computed tomography scan revealed left strangulated obturator hernia. Diagnosis of obturator hernia can be challenging. Physicians should consider obturator hernia in the differential diagnosis of knee and hip pain, and investigate for Howship Romberg sign. Early diagnosis of the disease not only decreases morbidity and mortality, but also presents opportunity to treat with minimally invasive methods. PMID- 28074455 TI - Effect of medical treatment on histological findings in rabbits with acute appendicitis. AB - BACKGROUND: Acute appendicitis (AA) is the most common reason for abdominal surgery in the world. The aim of this study was to evaluate the effect of medical treatment on histological findings in rabbits with AA. METHODS: Twenty-one male New Zealand rabbits were divided into 3 groups: appendix ligation and medical treatment, appendix ligation and no treatment, and control group, which underwent only laparotomy. RESULTS: In appendix ligation without treatment group, AA findings were much more severe. CONCLUSION: Medical treatment reduced inflammation of AA. PMID- 28074456 TI - Therapeutic efficacy of tadalafil and eriythropoietin in experimental spinal cord injury. AB - BACKGROUND: This experimental study was an investigation of the efficacy of erythropoietin and tadalafil in rats with induced spinal cord injury (SCI). METHODS: Thirty-five Sprague Dawley rats were distributed into 5 groups. First group was used for normal biochemical values. Spinal cord injury was induced in 4 remaining groups with clip compression technique after laminectomy process to T10 vertebra. Second group was designated solvent group and received 1 cc physiological serum after injury. Third group was medicated with intraperitoneal 2000 u/kg single dose erythropoietin after injury. Orogastric 2 mg/kg single dose tadalafil was administered to fourth group after injury. Fifth group did not receive any treatment and was used for biochemical values with injury. All subjects were sacrificed 48 hours after application. Malondialdehyde (MDA) and total antioxidant capacity (TAOC) values were evaluated using blood and tissue samples. RESULTS: Lowest serum and tissue MDA values were found in group with erythropoietin intake. While highest serum TAOC values of all groups were seen in tadalafil group, highest tissue TAOC values were observed in group given erythropoietin. CONCLUSION: It was concluded that by decreasing oxidative stress, tadalafil and erythropoietin can inhibit secondary damage in SCI. PMID- 28074457 TI - The acute effects of thymoquinone on acute peripheral nerve injury: an experimental study. AB - BACKGROUND: The purpose of this study was to evaluate the acute effects of thymoquinone (TQ) on acute nerve injury. METHODS: A rat model of crush injury of the sciatic nerve was used. Animals were divided into 3 groups: control, trauma, and TQ treatment groups (n=6 per group). Seven days after injury, sciatic nerve specimens were obtained from the site of the injury and analyzed histologically and stereologically. Axon diameter, myelin thickness, and axon density were measured. RESULTS: There were no significant differences in axon diameter, myelin thickness, or axon density among groups. CONCLUSION: TQ has no acute therapeutic effect on acute nerve injury. PMID- 28074458 TI - Endovascular treatment of peripheral and visceral arterial injuries in patients with acute trauma. AB - BACKGROUND: The present study is an evaluation of the efficacy of endovascular treatment in emergency setting for patients with acute peripheral and visceral arterial injury secondary to penetrating or blunt trauma. METHODS: Twelve patients (11 men) aged 35.8+/-11.3 years (range: 18-56 years) with penetrating or blunt trauma who underwent endovascular treatment in our department between March 2010 and June 2014 for peripheral and visceral arterial injury were retrospectively reviewed. Selective coil embolization was performed on 11 patients and particle embolization of the injured vessel was performed on 1 patient. Criteria for endovascular treatment included active extravasation or pseudoaneurysm on contrast-enhanced computed tomography and decrease in hemoglobin level or temporary hemodynamic instability. RESULTS: Arterial injuries were secondary to penetrating injury due to gunshot wound in 4 patients and stab wound in 5, and blunt abdominal injury as result of traffic accident in 3 patients. Traumatic lesions were in the right hepatic artery (n=3), left hepatic (n=2), right hepatic and right renal (n=1), left inferior epigastric (n=2), left facial (n=1), anterior tibial (n=1), and deep femoral (n=1) arteries. Technical success with no procedural complications was seen in all cases. Two patients died due to coexisting injuries on 29th and 43rd days of hospitalization. Median hospitalization period was 6.0 days (range: 1-43 days) and mean intensive care unit hospitalization was 7.7 days (range: 0-43 days). CONCLUSION: In our experience, endovascular treatment was a safe and effective option for acute traumatic peripheral and visceral arterial lesions. PMID- 28074459 TI - Comparison of Revised Trauma Score, Injury Severity Score and Trauma and Injury Severity Score for mortality prediction in elderly trauma patients. AB - BACKGROUND: Trauma is the fifth leading cause of death in patients 65 years and older. This study is a comparison of results of Revised Trauma Score (RTS), Injury Severity Score (ISS), and Trauma and Injury Severity Score (TRISS) in prediction of mortality in cases of geriatric trauma. METHODS: This is a cross sectional study of records of 352 elderly trauma patients who were admitted to Pour-Sina Hospital in Rasht between 2010 and 2011. Injury scoring systems were compared in terms of specificity, sensitivity, and cut-off points using receiver operating characteristic curve of patient prognosis. RESULTS: Mean age of patients was 71.5 years. Most common mechanism of injury was traffic accident (53.7%). Of the total, 13.9% of patients died. Mean ISS was higher for patients who did not survive. Mean of TRISS and RTS scores in elderly survivors was higher than non-survivors and difference in all 3 scores was statistically significant (p<0.001). Best cut-off points for predicting mortality in elderly trauma patients in RTS, ISS, and TRISS systems were <=6, >=13.5, and <=2, with sensitivity of 99%, 84%, and 95% and specificity of 62%, 62%, and 72%, respectively. CONCLUSION: TRISS was the strongest predictor of mortality in elderly trauma patients as result of combination of both anatomical and physiological parameters. PMID- 28074460 TI - Gender does not affect the prognosis of Fournier's gangrene: a case-matched study. AB - BACKGROUND: Female gender is accepted as a poor prognostic factor for Fournier's gangrene (FG). However, there is a paucity of data in the literature regarding this matter. This case-matched study was designed to investigate the impact of gender on outcomes of FG. METHODS: Study patient data were retrieved from 120 patient, prospectively maintained database. Thirty-two female patients with FG were case-matched to 32 male patients based on symptom duration (days), FG severity index score, patient age, etiology, and presence of diabetes mellitus (DM) terms. Outcomes of FG were compared between the 2 groups. RESULTS: Median age was 57 years (range: 22-80 years), and 35 (54.7%) patients had DM. Patients underwent average of 3 debridement procedures (range: 1-9 debridements), and 15 (23.4%) received diverting stoma. Overall mortality rate was 28.1% (18 of 64 patients). Female gender was associated with widespread disease (p=0.009), increased need for consecutive debridements (p=0.005), prolonged length of intensive care unit stay (p=0.035), and increased requirement for split-thickness skin graft reconstruction (p=0.040). However, mortality rates were comparable between genders (p=0.264). CONCLUSION: FG is often more extensive in females and seems to be associated with anatomical features of female pelvis. However, female gender is not a factor affecting prognosis of patients with FG. PMID- 28074461 TI - Acute appendicitis during pregnancy: case series of 20 pregnant women. AB - BACKGROUND: Acute appendicitis (AA) is the most common cause of acute abdomen during pregnancy. Most of the signs of appendicitis are also found during normal pregnancy period, however, and diagnosis of appendicitis during pregnancy remains challenging. The aim of the current study was to report our clinical experience of AA during pregnancy and investigate optimal management of this difficult situation. METHODS: Records of 20 pregnant women with diagnosis of AA who underwent appendectomy between 2005 and 2015 were included in this study. Data were collected retrospectively. Patients were evaluated according to age, signs and symptoms, gestational age, physical findings, serum white blood cell count, ultrasound (US) findings, pathology reports, surgical technique, operation time, and complications. RESULTS: Of 20 patients, 16 (80%) underwent open appendectomy and 4 (20%) underwent laparoscopic appendectomy. Mean age of patients was 29.6+/ 5.6 years. Most common symptom was abdominal pain (95%). Six (30%) patients were in first trimester, 9 (45%) patients were in second trimester and 5 (25%) patients in were in third trimester. US findings consistent with AA were found in 12 (60%) patients. Negative appendectomy rate was 30%. Maternal complication was seen in only 1 (5%) patient. No fetal complication was observed. CONCLUSION: Accurate diagnosis and prompt surgical treatment of AA in pregnant women should be performed due to high rates of maternal and fetal complications. PMID- 28074462 TI - Contribution of MRI to clinically equivocal penile fracture cases. AB - BACKGROUND: Penile fracture is a surgical emergency defined as rupture of the tunica albuginea. Although most cases can be diagnosed with clinical evaluation, it has been stated in the literature that diagnosis in as many as 15% of cases can be challenging. In uncertain cases, imaging can help determine diagnosis. METHODS: Present study included 20 cases where diagnosis could not be made with certainty and magnetic resonance imaging (MRI) was performed. MR images were examined for tunical rupture and accompanying pathologies. When rupture was observed, localization and length of rupture were noted. All patients underwent degloving surgery. All imaging findings were compared to surgical findings. RESULTS: MRI revealed 19 tunical ruptures. In 1 case, hematoma was seen with no sign of penile fracture. No urethral injuries were found. All MRI findings were confirmed during surgery. CONCLUSION: Performing MRI in clinically equivocal cases can provide crucial data to make precise diagnosis and improve patient management. PMID- 28074463 TI - Importance of fixation of posterior malleolus fracture in trimalleolar fractures: A retrospective study. AB - BACKGROUND: The aim of this retrospective study was to evaluate treatment effect and importance of posterior malleolus (PM) fixation in surgically treated trimalleolar fractures. METHODS: A total of 57 cases of ankle joint fracture involving PM and treated with open reduction and internal fixation technique between 2004 and 2011 were evaluated. PM fixation was performed with cannulated screws in 46 cases, and in 11 cases, PM plate was used. All patients were assessed using American Orthopaedic Foot and Ankle Society (AOFAS) score, American Academy of Orthopedic Surgeons (AAOS) foot and ankle questionnaire, and Visual Analog Score (VAS) pain scale. Ankle joint mobility was also compared with unaffected side. RESULTS: Mean follow-up period was 44.6 months (range: 24-108 months). There were 36 female patients and 21 male patients between 23 and 85 years of age (mean: 55.9 years). Average time to surgery was 1.1 day (range: 1-3 days). According to AOFAS assessment, result was excellent in 21 patients and good in 26 patients. AAOS score was 92.4 (range: 32-100). Mean VAS score when resting was 1.1, and mean score was 1.3 when walking (range: 0-10). When compared with uninjured side, there was no significant difference in plantar flexion of ankle (p=0.325) but there was significant difference in dorsiflexion of ankle joint (p<0.001). CONCLUSION: Anatomical reduction and rigid internal fixation of PM provide satisfactory clinical and functional outcomes even in elderly patients where bone quality may make adequate fixation difficult. Fixation of even small PM fragments can facilitate rehabilitation by creating more stable construction. PMID- 28074464 TI - Investigation of hand function among children diagnosed with autism spectrum disorder with upper extremity trauma history. AB - BACKGROUND: The present study was designed to compare hand function in autistic children with history of upper extremity trauma with that of autistic children those who do not have history of trauma. METHODS: The study group included total of 65 children diagnosed with autism spectrum disorder (ASD) and was divided into 2 groups: children with trauma history (Group I) and control group (Group II) (Group I: n=28; Group II: n=37). Hand function was evaluated with 9-Hole Peg Test and Jebsen Hand Function Test. Somatosensory function was evaluated using somatosensory subtests of Sensory Integration and Praxis Test. Results were analyzed with Student's t-test and Mann-Whitney U test using SPSS version 20 software. RESULTS: Hand function and somatosensory perception test scores were statistically significantly better in children without upper extremity trauma history (p<0.05). When association between hand function tests and upper extremity somatosensory perception tests was taken into account, statistically significant correlations were found between all parameters of hand function tests and Manual Form Perception and Localization of Tactile Stimuli Test results (p<0.05). CONCLUSION: Autistic children with upper extremity trauma history had poor somatosensory perception and hand function. It is important to raise awareness among emergency service staff and inform them about strong relationship between somatosensory perception, hand function, and upper extremity trauma in children with ASD in order to develop appropriate rehabilitation process and prevent further trauma. PMID- 28074465 TI - Effects of alpha lipoic acid on ischemia-reperfusion injury in rat hindlimb ischemia model. AB - BACKGROUND: This study was performed to evaluate the effect of alpha lipoic acid (ALA) on prevention of ischemia-reperfusion (IR) injury in rat hindlimb ischemia model. METHODS: Forty male Sprague Dawley rats weighing between 250 and 300 g were divided into 4 groups of 10 rats. Hindlimb composite island flaps were raised in all rats. Clamps were applied to femoral vessels of all subjects, but immediately released without causing ischemia in Group 1. In Group 2, after 4 hours of ischemia, 24 hours of reperfusion was performed. Following 4 hours of ischemia, saline was administered to rats in Group 3 and flaps were reperfused for 24 hours. In Group 4, ALA was administered intraperitoneally after 4 hours of ischemia and flaps were reperfused for 24 hours. RESULTS: In Group 4, there was a significant decrease of liver malondialdehyde compared to Group 2 and decrease of muscle tumor necrosis factor-alpha compared to Group 3. There was also increase in levels of glutathione in erythrocytes compared to Group 3 and increase of plasma vitamin C compared to all groups. CONCLUSION: ALA was found to be effective in prevention of ischemia-reperfusion injury. Further studies are needed before clinical application. PMID- 28074466 TI - Anatomical organization of the brain of a diurnal and a nocturnal dung beetle. AB - To avoid the fierce competition for food, South African ball-rolling dung beetles carve a piece of dung off a dung-pile, shape it into a ball and roll it away along a straight line path. For this unidirectional exit from the busy dung pile, at night and day, the beetles use a wide repertoire of celestial compass cues. This robust and relatively easily measurable orientation behavior has made ball rolling dung beetles an attractive model organism for the study of the neuroethology behind insect orientation and sensory ecology. Although there is already some knowledge emerging concerning how celestial cues are processed in the dung beetle brain, little is known about its general neural layout. Mapping the neuropils of the dung beetle brain is thus a prerequisite to understand the neuronal network that underlies celestial compass orientation. Here, we describe and compare the brains of a day-active and a night-active dung beetle species based on immunostainings against synapsin and serotonin. We also provide 3D reconstructions for all brain areas and many of the fiber bundles in the brain of the day-active dung beetle. Comparison of neuropil structures between the two dung beetle species revealed differences that reflect adaptations to different light conditions. Altogether, our results provide a reference framework for future studies on the neuroethology of insects in general and dung beetles in particular. PMID- 28074468 TI - Do changes in mitochondrial quality contribute to increases in skeletal muscle oxidative capacity following endurance training? PMID- 28074467 TI - Systems pharmacology modeling of drug-induced hyperbilirubinemia: Differentiating hepatotoxicity and inhibition of enzymes/transporters. AB - Elevations in serum bilirubin during drug treatment may indicate global liver dysfunction and a high risk of liver failure. However, drugs also can increase serum bilirubin in the absence of hepatic injury by inhibiting specific enzymes/transporters. We constructed a mechanistic model of bilirubin disposition based on known functional polymorphisms in bilirubin metabolism/transport. Using physiologically based pharmacokinetic (PBPK) model-predicted drug exposure and enzyme/transporter inhibition constants determined in vitro, our model correctly predicted indinavir-mediated hyperbilirubinemia in humans and rats. Nelfinavir was predicted not to cause hyperbilirubinemia, consistent with clinical observations. We next examined a new drug candidate that caused both elevations in serum bilirubin and biochemical evidence of liver injury in rats. Simulations suggest that bilirubin elevation primarily resulted from inhibition of transporters rather than global liver dysfunction. We conclude that mechanistic modeling of bilirubin can help elucidate underlying mechanisms of drug-induced hyperbilirubinemia, and thereby distinguish benign from clinically important elevations in serum bilirubin. PMID- 28074469 TI - Development of cone photoreceptors and their synapses in the human and monkey fovea. AB - During retinal development, ribbon synapse assembly in the photoreceptors is a crucial step involving numerous molecules. While the developmental sequence of plexiform layers in human retina has been characterized, the molecular steps of synaptogenesis remain largely unknown. In the present study, we focused on the central rod-free region of primate retina, the fovea, to specifically investigate the development of cone photoreceptor ribbon synapses. Immunocytochemistry and electron microscopy were utilized to track the expression of photoreceptor transduction proteins and ribbon and synaptic markers in fetal human and Macaca retina. Although the inner plexiform layer appears earlier than the outer plexiform layer, synaptic proteins, and ribbons are first reliably recognized in cone pedicles. Markers first appear at fetal week 9. Both short (S) and medium/long (M/L) wavelength-selective cones express synaptic markers in the same temporal sequence; this is independent of opsin expression which takes place in S cones a month before M/L cones. The majority of ribbon markers, presynaptic vesicular release and postsynaptic neurotransduction-related machinery is present in both plexiform layers by fetal week 13. By contrast, two crucial components for cone to bipolar cell glutamatergic transmission, the metabotropic glutamate receptor 6 and voltage-dependent calcium channel alpha1.4, are not detected until fetal week 22 when bipolar cell invagination is present in the cone pedicle. These results suggest an intrinsically programmed but nonsynchronous expression of molecules in cone synaptic development. Moreover, functional ribbon synapses and active neurotransmission at foveal cone pedicles are possibly present as early as mid-gestation in human retina. PMID- 28074471 TI - The Probability of Hospitalizations for Mild-to-Moderate Injuries by Trauma Center Ownership Type. AB - OBJECTIVE: To corroborate anecdotal evidence with systematic evidence of a lower threshold for admission among for-profit hospitals. DATA SOURCES: The study used Florida emergency department and hospital discharge datasets for 2012 to 2014. The treatment variable of interest was for-profit-designated trauma center status. The dependent variable indicated whether a patient with mild-to-moderate injuries was admitted after presenting as a trauma alert and then discharged to home. A separate analysis was conducted of discharges that had a 1-day length of stay. STUDY DESIGN: Generalized estimation equations with logistic distribution models were used to control for the confounding influences and developed for four groups of patients: ICISS = 1 (no probability of mortality), ICISS >= 0.99, ICISS >= 0.95, and ICISS >= 0.85 (zero to 15 percent probability of mortality, which includes all mild and moderate injury patients). PRINCIPAL FINDINGS: For the ICISS = 1 and ICISS >= 0.99 models, the centers' for-profit status was the most important predictor. In the ICISS >= 0.95 and ICISS >= 0.85 models, injury type played a more important role, but for-profit status remained important. For patients with a 1-day stay, for-profit status was associated with an even higher probability of hospitalization. CONCLUSIONS: Considerable differences exist between for-profit and not-for-profit trauma centers concerning hospitalization among the study population, which may be explained by supplier-induced demand. PMID- 28074470 TI - Evidence that oxidative dephosphorylation by the nonheme Fe(II), alpha ketoglutarate:UMP oxygenase occurs by stereospecific hydroxylation. AB - LipL and Cpr19 are nonheme, mononuclear Fe(II)-dependent, alpha-ketoglutarate (alphaKG):UMP oxygenases that catalyze the formation of CO2 , succinate, phosphate, and uridine-5'-aldehyde, the last of which is a biosynthetic precursor for several nucleoside antibiotics that inhibit bacterial translocase I (MraY). To better understand the chemistry underlying this unusual oxidative dephosphorylation and establish a mechanistic framework for LipL and Cpr19, we report herein the synthesis of two biochemical probes-[1',3',4',5',5'-2 H]UMP and the phosphonate derivative of UMP-and their activity with both enzymes. The results are consistent with a reaction coordinate that proceeds through the loss of one 2 H atom of [1',3',4',5',5'-2 H]UMP and stereospecific hydroxylation geminal to the phosphoester to form a cryptic intermediate, (5'R)-5'-hydroxy-UMP. Thus, these enzyme catalysts can additionally be assigned as UMP hydroxylase phospholyases. PMID- 28074472 TI - Cost Evaluation of Irinotecan-Related Toxicities Associated With the UGT1A1*28 Patient Genotype. AB - The adoption of a preemptive UGT1A1*28 genotyping to increase irinotecan safety in clinical practice is still limited. This is the first actual study of costs associated with the management of irinotecan-related toxicities, and their association with UGT1A1*28 genotype. A retrospective analysis of the cost of toxicity management was conducted on 243 metastatic colorectal cancer patients enrolled in a clinical trial and treated with standard of care FOLFIRI (5 fluorouracil combined with irinotecan). The mean predicted cost per patient was higher for *28/*28 (?4,886), vs. *1/*1 (?812), (regression coefficient 1.79, 95% confidence interval (CI) = 1.31-2.28; P < 0.001) and for *1/*28 (?1,119) vs. *1/*1 (regression coefficient 0.32, 95% CI = 0.04-0.60; P = 0.024). This is consistent with a different grade 4 toxicity profile among the three genotypes, and a higher frequency of costly interventions like hospitalization among patients with the *28 allele. A differential toxicity management cost by *28 genotype is herein demonstrated, representing a first step towards the demonstration of the test clinical utility. PMID- 28074473 TI - Predicting CD4 T-Cell Reconstitution Following Pediatric Hematopoietic Stem Cell Transplantation. AB - Hematopoietic stem cell transplantation (HSCT) is an increasingly common treatment for children with a range of hematological disorders. Conditioning with cytotoxic chemotherapy and total body irradiation leaves patients severely immunocompromised. T-cell reconstitution can take several years due to delayed restoration of thymic output. Understanding T-cell reconstitution in children is complicated by normal immune system maturation, heterogeneous diagnoses, and sparse uneven sampling due to the long time spans involved. We describe here a mechanistic mathematical model for CD4 T-cell immune reconstitution following pediatric transplantation. Including relevant biology and using mixed-effects modeling allowed the factors affecting reconstitution to be identified. Bayesian predictions for the long-term reconstitution trajectories of individual children were then obtained using early post-transplant data. The model was developed using data from 288 children; its predictive ability validated on data from a further 75 children, with long-term reconstitution predicted accurately in 81% of the patients. PMID- 28074475 TI - What Makes You Feel Sick After Inflammation? Predictors of Acute and Persisting Physical Sickness Symptoms Induced by Experimental Endotoxemia. AB - We aimed to identify statistical predictor variables of lipopolysaccharide (LPS) induced physical sickness symptoms during the acute and late inflammatory phases using multivariate regression analyses. Data from N = 128 healthy volunteers who received i.v. LPS injection (0.4 or 0.8 ng/kg) or placebo were pooled for analyses. Physical sickness symptoms experienced during the acute (0-6h postinjection) and late (6-24h postinjection) phases were assessed with the validated General-Assessment-of-Side-Effects (GASE) questionnaire. LPS-treated subjects reported significantly more physical sickness symptoms. Physical symptoms during the acute phase were associated with LPS-induced mood impairments and interleukin (IL)-6 increases, explaining 28.5% of variance in GASE scores. During late phase, LPS-induced increases in cortisol and IL-6 plasma concentrations and baseline depression were significant predictor variables, explaining 38.5% of variance. In patients with recurrent or chronic inflammatory states, these factors may act as risk factors ultimately contributing to an exacerbation of sickness symptoms, and should be considered as potential targets for therapeutic strategies. PMID- 28074474 TI - Optimal defense theory explains deviations from latitudinal herbivory defense hypothesis. AB - The latitudinal herbivory defense hypothesis (LHDH) postulates that the prevalence of species interactions, including herbivory, is greater at lower latitudes, leading to selection for increased levels of plant defense. While latitudinal defense clines may be caused by spatial variation in herbivore pressure, optimal defense theory predicts that clines could also be caused by ecogeographic variation in the cost of defense. For instance, allocation of resources to defense may not increase plant fitness when growing seasons are short and plants must reproduce quickly. Here we use a common garden experiment to survey genetic variation for constitutive and induced phenylpropanoid glycoside (PPG) concentrations across 35 Mimulus guttatus populations over a ~13 degrees latitudinal transect. Our sampling regime is unique among studies of the LHDH in that it allows us to disentangle the effects of growing season length from those of latitude, temperature, and elevation. For five of the seven PPGs surveyed, we find associations between latitude and plant defense that are robust to population structure. However, contrary to the LHDH, only two PPGs were found at higher levels in low latitude populations, and total PPG concentrations were higher at higher latitudes. PPG levels are strongly correlated with growing season length, with higher levels of PPGs in plants from areas with longer growing seasons. Further, flowering time is positively correlated with the concentration of nearly all PPGs, suggesting that there may be a strong trade-off between development time and defense production. Our results reveal that ecogeographic patterns in plant defense may reflect variation in the cost of producing defense compounds in addition to variation in herbivore pressure. Thus, the biogeographic pattern predicted by the LHDH may not be accurate because the underlying factors driving variation in defense, in this case, growing season length, are not always associated with latitude in the same manner. Given these results, we conclude that LHDH cannot be interpreted without considering life history, and we recommend that future work on the LHDH move beyond solely testing the core LHDH prediction and place greater emphasis on isolating agents of selection that generate spatial variation in defense and herbivore pressure. PMID- 28074476 TI - Drug Development, Trial Design, and Endpoints in Oncology: Adapting to Rapidly Changing Science. AB - As a result of enhanced understanding of genetic and immunologic underpinnings of cancer, there has been progress in development of targeted and immunotherapies in oncology. The traditional linear sequential model of drug development has evolved. Early clinical trials of breakthrough therapies often include expansion cohorts, termed "seamless drug development." The US Food and Drug Administration (FDA) uses expedited programs, such as breakthrough designation and accelerated approval ensuring that transformative therapies are available to patients earlier in the cycle of evidence generation. PMID- 28074477 TI - Same but different: Comparative modes of information processing are implicated in the construction of perceptions of autonomy support. AB - An implicit assumption behind tenets of self-determination theory is that perceptions of autonomy support are a function of absolute modes of information processing. In this study, we examined whether comparative modes of information processing were implicated in the construction of perceptions of autonomy support. In an experimental study, we demonstrated that participants employed comparative modes of information processing in evaluating receipt of small, but not large, amounts of autonomy support. In addition, we found that social comparison processes influenced a number of outcomes that are empirically related to perceived autonomy support such as sense of autonomy, positive affect, perceived usefulness, and effort. Findings shed new light upon the processes underpinning construction of perceptions related to autonomy support and yield new insights into how to increase the predictive validity of models that use autonomy support as a determinant of motivation and psychological well-being. PMID- 28074479 TI - GDF8 inhibits bone formation and promotes bone resorption in mice. AB - Growth Differentiation Factor 8 (GDF8), also called myostatin, is a member of the transforming growth factor (TGF)-beta super-family. As a negative regulator of skeletal muscle growth, GDF8 is also associated with bone metabolism. However, the function of GDF8 in bone metabolism is not fully understood. Our study aimed to investigate the role of GDF8 in bone metabolism, both in vitro and in vivo. Our results showed that GDF8 had a negative regulatory effect on primary mouse osteoblasts, and promoted receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclastogenesis in vitro. Intraperitoneal injection of recombinant GDF8 repressed bone formation and accelerated bone resorption in mice. Furthermore, treatment of aged mice with a GDF8 neutralizing antibody stimulated new bone formation and prevented bone resorption. Thus, our study showed that GDF8 plays a significant regulatory role in bone formation and bone resorption, thus providing a potential therapeutic pathway for osteoporosis. PMID- 28074478 TI - Ultrastructural analysis of parvalbumin synapses in human dorsolateral prefrontal cortex. AB - Coordinated activity of neural circuitry in the primate dorsolateral prefrontal cortex (DLPFC) supports a range of cognitive functions. Altered DLPFC activation is implicated in a number of human psychiatric and neurological illnesses. Proper DLPFC activity is, in part, maintained by two populations of neurons containing the calcium-binding protein parvalbumin (PV): local inhibitory interneurons that form Type II synapses, and long-range glutamatergic inputs from the thalamus that form Type I synapses. Understanding the contributions of each PV neuronal population to human DLPFC function requires a detailed examination of their anatomical properties. Consequently, we performed an electron microscopic analysis of (1) the distribution of PV immunoreactivity within the neuropil, (2) the properties of dendritic shafts of PV-IR interneurons, (3) Type II PV-IR synapses from PV interneurons, and (4) Type I PV-IR synapses from long-range projections, within the superficial and middle laminar zones of the human DLPFC. In both laminar zones, Type II PV-IR synapses from interneurons comprised ~60% of all PV-IR synapses, and Type I PV-IR synapses from putative thalamocortical terminals comprised the remaining ~40% of PV-IR synapses. Thus, the present study suggests that innervation from PV-containing thalamic nuclei extends across superficial and middle layers of the human DLPFC. These findings contrast with previous ultrastructural studies in monkey DLPFC where Type I PV-IR synapses were not identified in the superficial laminar zone. The presumptive added modulation of DLPFC circuitry by the thalamus in human may contribute to species-specific, higher-order functions. PMID- 28074480 TI - Clonal reticulohistiocytosis of the skin and bone marrow associated with systemic mastocytosis and acute myeloid leukaemia. AB - AIMS: The aims of this study were to define whether diffuse cutaneous reticulohistiocytosis could be underpinned by somatic genetic alterations and represent a precursor of more aggressive forms of disease. METHODS AND RESULTS: A 59-year-old man with diffuse cutaneous reticulohistiocytosis experienced bone marrow localization of the disease, with associated systemic mastocytosis and acute myeloid leukaemia. Cytogenetic analyses of the bone marrow aspirate revealed the presence of a derivative chromosome giving rise to a partial trisomy of chromosome 1q and a partial monosomy of chromosome 9q. Therefore, we characterized the cutaneous lesions before and after chemotherapy by using an integrative approach combining histopathology, electron microscopy, and fluorescence in-situ hybridization. Histologically, the skin lesions belonged to the spectrum of diffuse cutaneous reticulohistiocytoses, as confirmed by immunohistochemistry and ultrastructural analyses. Fluorescence in-situ hybridization in the skin nodules confirmed the presence of the genetic alterations previously detected in the bone marrow. CONCLUSIONS: Here, we provide circumstantial evidence to suggest that at least a subset of cutaneous reticulohistiocytoses harbour clonal molecular alterations. Furthermore, we confirm that these lesions have the potential to arise in the setting of concurrent haematological disorders. In this hypothesis-generating study, two possible tumorigenesis models are proposed. PMID- 28074481 TI - Electronic structure of stoichiometric and reduced ZnO from periodic relativistic all electron hybrid density functional calculations using numeric atom-centered orbitals. AB - The atomic and electronic structure of stoichiometric and reduced ZnO wurtzite has been studied using a periodic relativistic all electron hybrid density functional (PBE0) approach and numeric atom-centered orbital basis set with quality equivalent to aug-cc-pVDZ. To assess the importance of relativistic effects, calculations were carried out without and with explicit inclusion of relativistic effects through the zero order regular approximation. The calculated band gap is ~0.2 eV smaller than experiment, close to previous PBE0 results including relativistic calculation through the pseudopotential and ~0.25 eV smaller than equivalent nonrelativistic all electron PBE0 calculations indicating possible sources of error in nonrelativistic all electron density functional calculations for systems containing elements with relatively high atomic number. The oxygen vacancy formation energy converges rather fast with the supercell size, the predicted value agrees with previously hybrid density functional calculations and analysis of the electronic structure evidences the presence of localized electrons at the vacancy site with a concomitant well localized peak in the density of states ~0.5 eV above the top of the valence band and a significant relaxation of the Zn atoms near to the oxygen vacancy. Finally, present work shows that accurate results can be obtained in systems involving large supercells containing up to ~450 atoms using a numeric atomic-centered orbital basis set within a full all electron description including scalar relativistic effects at an affordable cost. (c) 2017 Wiley Periodicals, Inc. PMID- 28074483 TI - Sample size calculations for randomised trials including both independent and paired data. AB - Randomised trials including a mixture of independent and paired data arise in many areas of health research, yet methods for determining the sample size for such trials are lacking. We derive design effects algebraically assuming clustering because of paired data will be taken into account in the analysis using generalised estimating equations with either an independence or exchangeable working correlation structure. Continuous and binary outcomes are considered, along with three different methods of randomisation: cluster randomisation, individual randomisation and randomisation to opposite treatment groups. The design effect is shown to depend on the intracluster correlation coefficient, proportion of observations belonging to a pair, working correlation structure, type of outcome and method of randomisation. The derived design effects are validated through simulation and example calculations are presented to illustrate their use in sample size planning. These design effects will enable appropriate sample size calculations to be performed for future randomised trials including both independent and paired data. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28074482 TI - Remote ischaemic preconditioning suppresses endogenous plasma nitrite during ischaemia-reperfusion: a randomized controlled crossover pilot study. AB - AIM: The aim of this article is to test the hypothesis that remote ischaemic preconditioning (RIPC) increases circulating endogenous local and systemic plasma (nitrite) during RIPC and ischaemia-reperfusion (IR) as a potential protective mechanism against ischaemia-reperfusion injury (IRI). METHODS: Six healthy male volunteers (mean age 29.5 +/- 7.6 years) were randomized in a crossover study to initially receive either RIPC (4 * 5 min cycles) to the left arm, or no RIPC (control), both followed by an ischaemia-reperfusion (IR) sequence (20 min cuff inflation to 200 mmHg, 20 min reperfusion) to the right arm. The volunteers returned at least 7 days later for the alternate intervention. The primary outcome was the effect of RIPC vs. control on local and systemic plasma (nitrite). RESULTS: RIPC did not significantly change plasma (nitrite) in either the left or the right arm during the RIPC sequence. However, compared to control, RIPC decreased plasma (nitrite) during the subsequent IR sequence by ~26% (from 118 +/- 9 to 87 +/- 5 nmol l-1 ) locally in the left arm (P = 0.008) overall, with an independent effect of -58.70 nmol l-1 (95% confidence intervals -116.1 to -1.33) at 15 min reperfusion, and by ~24% (from 109 +/- 9 to 83 +/- 7 nmol l-1 ) systemically in the right arm (P = 0.03). CONCLUSIONS: RIPC had no effect on plasma (nitrite) during the RIPC sequence, but instead decreased plasma (nitrite) by ~25% during IR. This would likely counteract the protective mechanisms of RIPC, and contribute to RIPC's lack of efficacy, as observed in recent clinical trials. A combined approach of RIPC with nitrite administration may be required. PMID- 28074484 TI - How to define successful transition? An exploration of consensus indicators and outcomes in young adults with chronic conditions. AB - BACKGROUND: In this short report, we use data from a previous cohort study to explore the relationship between five out of eight consensus indicators for successful transition and patient-reported outcomes in young adulthood. METHODS: Data came from a 6-year cohort study that consisted of a survey among 518 young adults with various chronic conditions and a review of their electronic patient records. Associations between five indicators for successful transition and background variables and patient-reported outcomes were explored with Spearman's r. Significant variables were included in stepwise (logistic) regression analyses with transition outcomes as dependent variables. RESULTS: The indicators relate to some extent to better healthcare-related transition outcomes, but not to autonomy in participation. The explained variance of the models varied from 9.7% to 26.4%. The change in explained variance after adding indicators varied from 2% to 16%. CONCLUSIONS: The challenge of translating the definition of transition into holistic indicators remains. The current consensus indicators are a good start, but there is more to transition than transfer. PMID- 28074485 TI - Light, temperature and tocopherol status influence foliar vascular anatomy and leaf function in Arabidopsis thaliana. AB - This study addressed whether the winter annual Arabidopsis thaliana can adjust foliar phloem and xylem anatomy both differentially and in parallel. In plants acclimated to hot vs cool temperature, foliar minor vein xylem-to-phloem ratio was greater, whereas xylem and phloem responded concomitantly to growth light intensity. Across all growth conditions, xylem anatomy correlated with transpiration rate, while phloem anatomy correlated with photosynthetic capacity for two plant lines (wild-type Col-0 and tocopherol-deficient vte1 mutant) irrespective of tocopherol status. A high foliar vein density (VD) was associated with greater numbers and cross-sectional areas of both xylem and phloem cells per vein as well as higher rates of both photosynthesis and transpiration under high vs low light intensities. Under hot vs cool temperature, high foliar VD was associated with a higher xylem-to-phloem ratio and greater relative rates of transpiration to photosynthesis. Tocopherol status affected development of foliar vasculature as dependent on growth environment. The most notable impact of tocopherol deficiency was seen under hot growth temperature, where the vte1 mutant exhibited greater numbers of tracheary elements (TEs) per vein, a greater ratio of TEs to sieve elements, with smaller individual sizes of TEs, and resulting similar total areas of TEs per vein and transpiration rates compared with Col-0 wild-type. These findings illustrate the plasticity of foliar vascular anatomy acclimation to growth environment resulting from independent adjustments of the vasculature's components. PMID- 28074486 TI - Introduction of steered molecular dynamics into UNRES coarse-grained simulations package. AB - In this article, an implementation of steered molecular dynamics (SMD) in coarse grain UNited RESidue (UNRES) simulations package is presented. Two variants of SMD have been implemented: with a constant force and a constant velocity. The huge advantage of SMD implementation in the UNRES force field is that it allows to pull with the speed significantly lower than the accessible pulling speed in simulations with all-atom representation of a system, with respect to a reasonable computational time. Therefore, obtaining pulling speed closer to those which appear in the atomic force spectroscopy is possible. The newly implemented method has been tested for behavior in a microcanonical run to verify the influence of introduction of artificial constrains on keeping total energy of the system. Moreover, as time dependent artificial force was introduced, the thermostat behavior was tested. The new method was also tested via unfolding of the Fn3 domain of human contactin 1 protein and the I27 titin domain. Obtained results were compared with Go-like force field, all-atom force field, and experimental results. (c) 2017 Wiley Periodicals, Inc. PMID- 28074487 TI - Higher 25-hydroxyvitamin D levels are associated with greater odds of remission with anti-tumour necrosis factor-alpha medications among patients with inflammatory bowel diseases. AB - BACKGROUND: Vitamin D has been linked to disease activity among patients with inflammatory bowel diseases (IBD). Prior investigation has also suggested that vitamin D levels may affect duration of therapy with anti-tumour necrosis factor alpha (anti-TNF-alpha) medications among patients with IBD. AIM: To evaluate the relationship between vitamin D levels and odds of reaching remission while on an anti-TNF-alpha medication. METHODS: A total of 521 IBD patients enrolled in the Brigham and Women's IBD Centre database were eligible for inclusion. Patients treated with anti-TNF-alpha therapy who had vitamin D levels drawn within 6 months prior or 2 weeks after initiation of anti-TNF-alpha medication and who had reported remission status at 3 months were included. A logistic regression model adjusting for age, gender, IBD diagnosis, anti-TNF-alpha medication (infliximab vs. adalimumab) and first or subsequent anti-TNF-alpha medication was used to identify the effect of vitamin D level on initial response to anti-TNF-alpha therapy. RESULTS: A total of 173 patients were included in the final analysis. On logistic regression, patients with normal vitamin D levels n = 122 at the time of anti-TNF-alpha medication initiation had a 2.64 increased odds of remission at 3 months compared to patients with low vitamin D levels n = 51 when controlling for age, gender, diagnosis, type of anti-TNF-alpha medication and first or subsequent anti-TNF-alpha medication (OR = 2.64, 95% CI = 1.31-5.32, P = 0.0067). CONCLUSIONS: These findings suggest that vitamin D levels may influence initial response to anti-TNF-alpha medication and that low vitamin D levels may pre dispose patients to decreased odds of remission. PMID- 28074488 TI - Molecular "Sameness" Is the Key Guiding Principle for Extrapolation to Multiple Indications. AB - Much has been made of biosimilars as a new regulatory concept, yet it is clear that misunderstandings are widespread, including the scientific justification for use in all indications of the reference product or "extrapolation." However, as this article shows, biosimilarity and extrapolation are not new concepts and most patients being treated with a branded biologic have already received a similar version of the original reference biologic based on changes in the manufacturing process. PMID- 28074490 TI - Rationally Designed Blue Triplet Emitting Gold(III) Complexes Based on a Phenylpyridine-Derived Framework. AB - A series of blue-emitting phosphorescent mono-cyclometalated AuIII complexes have been successfully synthesized. Tailoring the substitutions on the phenylpyridine (ppy) ligand scaffold with electron-withdrawing fluorine groups on the phenyl ring to achieve stabilization of the HOMO and an electron-donating dimethylamino group on the pyridine ring to destabilize the LUMO resulted in a large energy gap and bestowed on the gold(III) complexes high-energy emission and high quantum efficiencies. The results of cyclic voltammetry studies suggested a predominantly redox event localized on the cyclometalated ligand. Thermogravimetric analysis of selected complexes revealed a high stability up to 280 degrees C, thus the complexes are suitable for device fabrication through vacuum-deposition. Photophysical investigations performed on all the derivatives revealed phosphorescence emission in neat solid, solution, doped in poly(methyl methacrylate) (PMMA) films at room temperature as well as in rigidified glass media (2-MeTHF) at 77 K. A high photoluminescent quantum efficiency of 28 % was obtained for a complex in PMMA, the highest quantum yield reported for a blue emitting gold(III) complex. PMID- 28074489 TI - A Novel NF-kappaB Inhibitor, Edasalonexent (CAT-1004), in Development as a Disease-Modifying Treatment for Patients With Duchenne Muscular Dystrophy: Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics in Adult Subjects. AB - In Duchenne muscular dystrophy (DMD), NF-kappaB is activated in skeletal muscle from infancy regardless of the underlying dystrophin mutation and drives inflammation and muscle degeneration while inhibiting muscle regeneration. Edasalonexent (CAT-1004) is a bifunctional orally administered small molecule that covalently links 2 compounds known to inhibit NF-kappaB, salicylic acid and docosahexaenoic acid (DHA). Edasalonexent is designed to inhibit activated NF kappaB upon intracellular cleavage to these bioactive components. Preclinical data demonstrate disease-modifying activity in DMD animal models. Three placebo controlled studies in adult subjects assessed the safety, pharmacokinetics, and pharmacodynamics of single or multiple edasalonexent doses up to 6000 mg. Seventy nine adult subjects received edasalonexent, and 25 received placebo. Pharmacokinetic results were consistent with the intracellular cleavage of edasalonexent to its active components. Food increased plasma exposures of edasalonexent and salicyluric acid, an intracellularly formed metabolite of salicylic acid. The NF-kappaB pathway and proteosome gene expression profiles in peripheral mononuclear cells were significantly decreased (P = .02 and P = .002, respectively) after 2 weeks of edasalonexent treatment. NF-kappaB activity was inhibited following a single dose of edasalonexent but not by equimolar doses of salicylic acid and DHA. Edasalonexent was well tolerated, and the most common adverse events were mild diarrhea and headache. In first-in-human studies, edasalonexent was safe, well tolerated, and inhibited activated NF-kappaB pathways, suggesting potential therapeutic utility in DMD regardless of the causative dystrophin mutation, as well as other NF-kappaB-mediated diseases. PMID- 28074491 TI - Parental influences on weight-related health behaviors in western and eastern cultures. AB - BACKGROUND: Excessive bodyweight contributes to a myriad of risk factors for chronic diseases, and multiple reports have demonstrated that parents influence the development of their children's behaviors that contribute to bodyweight. However, studies that include considerations for cultural influences are limited, and methodology that considers direct reports from young adults and their parents across cultures does not exist. METHODS: A sample of young adults (N = 327) and their parents in the U.S. and in China were recruited and completed a series of questionnaires in two cycles (2010 and 2014). With correlation and multiple regression analyses, parents' characteristics, behaviors, and parental authority styles were examined and compared to weight-related health behaviors and bodyweight of their young-adult children. Additionally, similarities and differences of parental influences between the two cultures were explored. RESULTS: Parents' body mass indexes (BMIs) and dietary behaviors were positively associated with those of their young adult children in the mixed-culture sample (P < .001 for both). When controlling for gender, at high levels of authoritarian and permissive parental authority, the relationships between young adults' and their parents' BMIs were negative for U.S. participants and positive for Chinese participants (P < .05 for both). Further, at high levels of authoritarian parenting, the relationship between young adults' and their parents' dietary consumption behaviors was negative for U.S. participants and positive for Chinese participants (P < .001). CONCLUSIONS: This study provides evidence that the development of life-long health behaviors that contribute to BMI are significantly influenced by parents' behaviors and parenting styles. Moreover, an interaction of parental characteristics and cultural norms is indicated. PMID- 28074492 TI - Confirmation of resting-state BOLD fluctuations in the human brainstem and spinal cord after identification and removal of physiological noise. AB - PURPOSE: Resting-state functional MRI (rs-fMRI) has been used to investigate networks within the cortex, but its use in the brainstem (BS) and spinal cord (SC) has been limited. This region presents challenges for fMRI, partly because of sources of physiological noise. This study aims to quantify noise contributions to rs-fMRI, and to obtain evidence of resting-state blood oxygenation level-dependent (BOLD) fluctuations. METHODS: Resting-state-fMRI data were obtained from the BS/SC in 16 participants, at 3 Tesla, with T2 -weighted single-shot fast spin-echo imaging. The peripheral pulse, respiration, and expired CO2 were recorded continuously. Physiological noise was modeled from these recordings, movement parameters, and white matter regions. Model fits were then subtracted from the data. BOLD contributions were then investigated through connectivity. RESULTS: Bulk motion was the largest contributor to the signal variance (19% of the total), followed by cardiac-related motion (14%), nonspecific signal variations detected in white matter (10%), respiratory-related motion (2.6%), and end-tidal CO2 variations (0.7%). After noise was removed, significant left-right connectivity was detected in the SC dorsal horns and ventral horns. CONCLUSIONS: Resting-state BOLD fluctuations are demonstrated in the SC, as are the dominant noise contributions. These findings are an essential step toward establishing rs-fMRI in the BS/SC. Magn Reson Med 78:2149-2156, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28074494 TI - An Insight into the Interface through Excited-State Carrier Dynamics for Promising Enhancement of Power Conversion Efficiency in a Mn-Doped CdZnSSe Gradient Alloy. AB - To explore the significance of impurity doping in power conversion efficiency, quaternary gradient CdZnSSe alloy nanocrystals (NCs) and its Mn-doped analogues were synthesized by high-temperature pyrolysis. The undoped and Mn-doped CdZnSSe alloy NCs have been characterized by employing high-resolution TEM, X-ray diffraction, energy-dispersive X-ray spectroscopy, and electron paramagnetic resonance spectroscopy measurements. A low-temperature injection of chalcogens led to a gradient interface in the alloy, comprised of a CdSe/CdS/ZnSe/ZnS nanostructure. Both steady-state and ultrafast time-resolved absorption studies suggested the formation of a charge-transfer (CT) state due to the inner quasi type II CdSe/CdS part of the gradient CdZnSSe alloy NCs, in which electrons are delocalized throughout the conduction band (CB) of both CdSe and CdS. The CT state bleach recovery kinetics gave an additional slow electron cooling component (8 ps) in the undoped alloy NCs, which has been assigned to electron equilibration in the delocalized CB before recombination (or trapping). Interestingly, in the presence of dopant Mn, the slow electron cooling component became even more sluggish at 10 ps due to Mn-mediated electron cooling, in which Mn acts as an electron storage center. An unprecedented increase in the photocurrent conversion efficiency (PCE) of approximately 30 % from (3.3+/-0.11) to (4.29+/-0.07) % was observed in the Mn-doped gradient alloy compared with the undoped alloy. PMID- 28074493 TI - AMPK does not play a requisite role in regulation of PPARGC1A gene expression via the alternative promoter in endurance-trained human skeletal muscle. AB - NEW FINDINGS: What is the central question of this study? This study was designed to investigate the role of AMPK in the regulation of PGC-1alpha gene expression via the alternative promoter through a cAMP response element-binding protein-1 dependent mechanism in human skeletal muscle. What is the main finding and its importance? Low-intensity exercise markedly increased the expression of PGC 1alpha mRNA via the alternative promoter, without increases in ACCSer79/222 (a marker of AMPK activation) and AMPKThr172 phosphorylation. A single dose of the AMPK activator metformin indicated that AMPK was not involved in regulating PGC 1alpha mRNA expression via the alternative promoter in endurance-trained human skeletal muscle. In human skeletal muscle, PGC-1alpha is constitutively expressed via the canonical promoter. In contrast, the expression of PGC-1alpha mRNA via the alternative promoter was found to be highly dependent on the intensity of exercise and to contribute largely to the postexercise increase of total PGC 1alpha mRNA. This study investigated the role of AMPK in regulating PGC-1alpha gene expression via the alternative promoter through a cAMP response element binding protein-1-dependent mechanism in human skeletal muscle. AMPK activation and PGC-1alpha gene expression were assayed in skeletal muscle of nine endurance trained men before and after low-intensity exercise (38% of maximal oxygen uptake) and with or without administration of a single dose (2 g) of the AMPK activator metformin. Low-intensity exercise markedly and significantly increased (~100-fold, P < 0.05) the expression of PGC-1alpha mRNA via the alternative promoter, without increasing ACCSer79/222 (a marker of AMPK activation) and AMPKThr172 phosphorylation. Moreover, in contrast to placebo, metformin increased the level of ACCSer79/222 phosphorylation immediately after exercise (2.6-fold, P < 0.05). However postexercise expression of PGC-1alpha gene via the alternative promoter was not affected. This study was unable to confirm that AMPK plays a role in regulating PGC-1alpha gene expression via the alternative promoter in endurance-trained human skeletal muscle. PMID- 28074495 TI - Comparison of Medicaid Payments Relative to Medicare Using Inpatient Acute Care Claims from the Medicaid Program: Fiscal Year 2010-Fiscal Year 2011. AB - OBJECTIVE: To compare Medicaid fee-for-service (FFS) inpatient hospital payments to expected Medicare payments. DATA SOURCES: Medicaid and Medicare claims data, Medicare's MS-DRG grouper and inpatient prospective payment system pricer (IPPS pricer). STUDY DESIGN: Medicaid FFS inpatient hospital claims were run through Medicare's MS-DRG grouper and IPPS pricer to compare Medicaid's actual payment against what Medicare would have paid for the same claim. PRINCIPAL FINDINGS: Average inpatient hospital claim payments for Medicaid were 68.8 percent of what Medicare would have paid in fiscal year 2010, and 69.8 percent in fiscal year 2011. Including Medicaid disproportionate share hospital (DSH), graduate medical education (GME), and supplemental payments reduces a substantial proportion of the gap between Medicaid and Medicare payments. CONCLUSIONS: Medicaid payments relative to expected Medicare payments tend to be lower and vary by state Medicaid program, length of stay, and whether payments made outside of the Medicaid claims process are included. PMID- 28074496 TI - Passages 2017. PMID- 28074497 TI - In vivo imaging of the progression of acute lung injury using hyperpolarized [1 13 C] pyruvate. AB - PURPOSE: To investigate pulmonary metabolic alterations during progression of acute lung injury. METHODS: Using hyperpolarized [1-13 C] pyruvate imaging, we measured pulmonary lactate and pyruvate in 15 ventilated rats 1, 2, and 4 h after initiation of mechanical ventilation. Lung compliance was used as a marker for injury progression. 5 untreated rats were used as controls; 5 rats (injured-1) received 1 ml/kg and another 5 rats (injured-2) received 2 ml/kg hydrochloric acid (pH 1.25) in the trachea at 70 min. RESULTS: The mean lactate-to-pyruvate ratio of the injured-1 cohort was 0.15 +/- 0.02 and 0.15 +/- 0.03 at baseline and 1 h after the injury, and significantly increased from the baseline value 3 h after the injury to 0.23 +/- 0.02 (P = 0.002). The mean lactate-to-pyruvate ratio of the injured-2 cohort decreased from 0.14 +/- 0.03 at baseline to 0.08 +/- 0.02 1 h after the injury and further decreased to 0.07 +/- 0.02 (P = 0.08) 3 h after injury. No significant change was observed in the control group. Compliance in both injured groups decreased significantly after the injury (P < 0.01). CONCLUSIONS: Our findings suggest that in severe cases of lung injury, edema and hyperperfusion in the injured lung tissue may complicate interpretation of the pulmonary lactate-to-pyruvate ratio as a marker of inflammation. However, combining the lactate-to-pyruvate ratio with pulmonary compliance provides more insight into the progression of the injury and its severity. Magn Reson Med 78:2106-2115, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28074499 TI - Eye coloboma and complex cardiac malformations belong to the clinical spectrum of PUF60 variants. PMID- 28074498 TI - Imaging and T2 relaxometry of short-T2 connective tissues in the knee using ultrashort echo-time double-echo steady-state (UTEDESS). AB - PURPOSE: To develop a radial, double-echo steady-state (DESS) sequence with ultra short echo-time (UTE) capabilities for T2 measurement of short-T2 tissues along with simultaneous rapid, signal-to-noise ratio (SNR)-efficient, and high isotropic-resolution morphological knee imaging. METHODS: THe 3D radial UTE readouts were incorporated into DESS, termed UTEDESS. Multiple-echo-time UTEDESS was used for performing T2 relaxometry for short-T2 tendons, ligaments, and menisci; and for Dixon water-fat imaging. In vivo T2 estimate repeatability and SNR efficiency for UTEDESS and Cartesian DESS were compared. The impact of coil combination methods on short-T2 measurements was evaluated by means of simulations. UTEDESS T2 measurements were compared with T2 measurements from Cartesian DESS, multi-echo spin-echo (MESE), and fast spin-echo (FSE). RESULTS: UTEDESS produced isotropic resolution images with high SNR efficiency in all short-T2 tissues. Simulations and experiments demonstrated that sum-of-squares coil combinations overestimated short-T2 measurements. UTEDESS measurements of meniscal T2 were comparable to DESS, MESE, and FSE measurements while the tendon and ligament measurements were less biased than those from Cartesian DESS. Average UTEDESS T2 repeatability variation was under 10% in all tissues. CONCLUSION: The T2 measurements of short-T2 tissues and high-resolution morphological imaging provided by UTEDESS makes it promising for studying the whole knee, both in routine clinical examinations and longitudinal studies. Magn Reson Med 78:2136-2148, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28074500 TI - Level of environmental threat posed by horticultural trade in Cactaceae. AB - Ornamental horticulture has been identified as an important threat to plant biodiversity and is a major pathway for plant invasions worldwide. In this context, the family Cactaceae is particularly challenging because it is considered the fifth most threatened large taxonomic group in the world; several species are among the most widespread and damaging invasive species; and Cactaceae is one of the most popular horticultural plant groups. Based on the Convention on International Trade in Endangered Species of Wild Flora and Fauna and the 11 largest online auction sites selling cacti, we documented the international cactus trade. To provide an in-depth look at the dynamics of the industry, we surveyed the businesses involved in the cactus trade in South Africa (a hotspot of cactus trade and invasions). We purchased seeds of every available species and used DNA barcoding to identify species to the genus level. Although <20% of this trade involved threatened species and <3% involved known invasive species, many species were identified by a common name. However, only 0.02% of the globally traded cacti were collected from wild populations. Despite a large commercial network, all South African imports (of which 15% and 1.5% were of species listed as threatened and invasive, respectively) came from the same source. With DNA barcoding, we identified 24% of the species to genus level. Based on our results, we believe that if trade restrictions are placed on the small proportion of cacti that are invasive and there is no major increase in harvesting of native populations, then the commercial trade in cactus poses a negligible environmental threat. However, there are currently no effective methods for easily identifying which cacti are traded, and both the illicit harvesting of cacti from the wild and the informal trade in invasive taxa pose on going conservation challenges. PMID- 28074501 TI - Synthesis and Physical Properties of Strained Doubly Phosphorus-Bridged Biaryls and Viologens. AB - New P/N-containing pi-electron systems comprising fully planar biaryl arrays are synthesized by multiple radical phosphanylation. The biaryl moiety in these highly strained planar pi-systems is rigidified by double P-bridging. The electronic properties of the core biaryl entity are varied by introducing N-donor substituents or by installing N-atoms within the pi-system, thereby moving to the viologen core structure. The electrochemical and photophysical properties of these compounds are discussed and compared with those of related systems. PMID- 28074502 TI - Seedless Synthesis of Monodispersed Gold Nanorods with Remarkably High Yield: Synergistic Effect of Template Modification and Growth Kinetics Regulation. AB - Gold nanorods (AuNRs) are versatile materials due to their broadly tunable optical properties associated with their anisotropic feature. Conventional seed mediated synthesis is, however, not only limited by the operational complexity and over-sensitivity towards subtle changes of experimental conditions but also suffers from low yield (~15 %). A facile seedless method is reported to overcome these challenges. Monodispersed AuNRs with high yield (~100 %) and highly adjustable longitudinal surface plasmon resonance (LSPR) are reproducibly synthesized. The parameters that influence the AuNRs growth were thoroughly investigated in terms of growth kinetics and soft-template regulation, offering a better understanding of the template-based mechanism. The facile synthesis, broad tunability of LSRP, high reproducibility, high yield, and ease of scale-up make this method promising for the future mass production of monodispersed AuNRs for applications in catalysis, sensing, and biomedicine. PMID- 28074503 TI - Bioorthogonal Diversification of Peptides through Selective Ruthenium(II) Catalyzed C-H Activation. AB - Methods for the chemoselective modification of amino acids and peptides are powerful techniques in biomolecular chemistry. Among other applications, they enable the total synthesis of artificial peptides. In recent years, significant momentum has been gained by exploiting palladium-catalyzed cross-coupling for peptide modification. Despite major advances, the prefunctionalization elements on the coupling partners translate into undesired byproduct formation and lengthy synthetic operations. In sharp contrast, we herein illustrate the unprecedented use of versatile ruthenium(II)carboxylate catalysis for the step-economical late stage diversification of alpha- and beta-amino acids, as well as peptides, through chemo-selective C-H arylation under racemization-free reaction conditions. The ligand-accelerated C-H activation strategy proved water-tolerant and set the stage for direct fluorescence labelling as well as various modes of peptide ligation with excellent levels of positional selectivity in a bioorthogonal fashion. The synthetic utility of our approach is further demonstrated by twofold C-H arylations for the complexity-increasing assembly of artificial peptides within a multicatalytic C-H activation manifold. PMID- 28074504 TI - Letter: Helicobacter pylori-related non-alcoholic fatty liver disease with concomitant metabolic syndrome as risk factor for colorectal neoplasia. PMID- 28074505 TI - Letter: Helicobacter pylori-related non-alcoholic fatty liver disease with concomitant metabolic syndrome as risk factor for colorectal neoplasia - authors' reply. PMID- 28074506 TI - Editorial: treating the liver to treat the kidney in non-alcoholic steatohepatitis - authors' reply. PMID- 28074508 TI - Corrigendum. PMID- 28074507 TI - Letter: levofloxacin resistance - a challenge for the treatment of Helicobacter pylori infection. PMID- 28074509 TI - Editorial: volatile organic compounds in irritable bowel syndrome - technology for an accurate and reliable point-of-care test? PMID- 28074510 TI - Editorial: ultrasound surveillance of hepatocellular carcinoma in the 21st century - authors' reply. PMID- 28074511 TI - Editorial: direct acting antivirals - not the be-all and end-all in HIV/HCV co infection. Authors' reply. PMID- 28074512 TI - Editorial: ultrasound surveillance of hepatocellular carcinoma in the 21st century. PMID- 28074513 TI - Editorial: direct-acting anti-virals - not the be-all and end-all in HIV/HCV co infection. PMID- 28074514 TI - Editorial: increased expression of nerve growth factor correlates with visceral hypersensitivity and impaired gut barrier function in diarrhoea-predominant irritable bowel syndrome. PMID- 28074515 TI - Letter: need to re-evaluate non-invasive markers for staging fibrosis in chronic delta hepatitis. PMID- 28074516 TI - Letter: need to re-evaluate non-invasive markers for staging fibrosis in chronic delta hepatitis - authors' reply. PMID- 28074517 TI - Editorial: treating the liver to treat the kidney in non-alcoholic steatohepatitis. PMID- 28074518 TI - Editorial: increased expression of nerve growth factor correlates with visceral hypersensitivity and impaired gut barrier function in diarrhoea-predominant irritable bowel syndrome. Authors' reply. PMID- 28074519 TI - Letter: levofloxacin resistance - a challenge for treatment of Helicobacter pylori infection. Authors' reply. PMID- 28074520 TI - Assessing the accuracy of opioid overdose and poisoning codes in diagnostic information from electronic health records, claims data, and death records. AB - PURPOSE: The purpose of this study is to assess positive predictive value (PPV), relative to medical chart review, of International Classification of Diseases (ICD)-9/10 diagnostic codes for identifying opioid overdoses and poisonings. METHODS: Data were obtained from Kaiser Permanente Northwest and Northern California. Diagnostic data from electronic health records, submitted claims, and state death records from Oregon, Washington, and California were linked. Individual opioid-related poisoning codes (e.g., 965.xx and X42), and adverse effects of opioids codes (e.g., E935.xx) combined with diagnoses possibly indicative of overdoses (e.g., respiratory depression), were evaluated by comparison with chart audits. RESULTS: Opioid adverse effects codes had low PPV to detect overdoses (13.4%) as assessed in 127 charts and were not pursued. Instead, opioid poisoning codes were assessed in 2100 individuals who had those codes present in electronic health records in the period between the years 2008 and 2012. Of these, 10/2100 had no available information and 241/2100 were excluded potentially as anesthesia-related. Among the 1849 remaining individuals with opioid poisoning codes, 1495 events were accurately identified as opioid overdoses; 69 were miscodes or misidentified, and 285 were opioid adverse effects, not overdoses. Thus, PPV was 81%. Opioid adverse effects or overdoses were accurately identified in 1780 of 1849 events (96.3%). CONCLUSIONS: Opioid poisoning codes have a predictive value of 81% to identify opioid overdoses, suggesting ICD opioid poisoning codes can be used to monitor overdose rates and evaluate interventions to reduce overdose. Further research to assess sensitivity, specificity, and negative predictive value are ongoing. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28074521 TI - Assessment of the effectiveness of topical propranolol 4% gel for infantile hemangiomas. AB - BACKGROUND: Infantile hemangiomas (IHs) are the most common vascular tumors in children. Because of their benign character and natural involution, the vast majority of IHs do not require any treatment. In the past few years, topical beta blockers have been reported to be an effective treatment of superficial IHs. OBJECTIVE: We sought to evaluate the clinical effectiveness and safety profile of topical propranolol 4% gel for the treatment of IHs. METHODS: A retrospective study of all cases of IHs treated with topical propranolol 4% gel between 2013 and 2015 was performed. All patients were evaluated in a pediatric dermatology unit of a tertiary medical center. Epidemiologic, clinical, and treatment data, including effectiveness score and safety, were reviewed. RESULTS: The study included 63 patients with a total of 75 IHs. Of the total number of IHs, 43 (57.3%) showed a good response to treatment, 19 (25.3%) a partial response, and 13 (17.33%) poor or no response, thus 62 (82.6%) had good or partial response to treatment. Age at treatment initiation, treatment time, thickness of the superficial component, and size of the lesions were shown to predict response to therapy. Out of the entire examined group, only two patients reported minor local side effects manifested by irritation, redness, and scaling of the treated area. No systemic adverse effects were reported. LIMITATIONS: This is an uncontrolled retrospective study. CONCLUSION: Propranolol 4% gel is a safe and efficient topical therapy for IH. PMID- 28074522 TI - Protective effects of tacalcitol against oxidative damage in human epidermal melanocytes. AB - BACKGROUND: Oxidative damage may lead to the dysfunction of melanocytes (MCs) and is one of the causative mechanisms involved in the pathogenesis of vitiligo. OBJECTIVES: This study was designed to investigate the protective effects of the vitamin D3 analog tacalcitol on oxidative damage induced by hydrogen peroxide (H2 O2 ) in human epidermal MCs. METHODS: Human epidermal MCs were cultured and identified by l-DOPA staining and HMB-45 immunohistochemical staining. The model of oxidative damage induced by H2 O2 was established, and the cells were treated with tacalcitol. The viability of MCs was determined using an MTS assay. Morphological changes in cell dendrites were observed by microscopy, and the rate of change of dendrites was calculated. The reactive oxygen species (ROS) level in MCs was determined using immunofluorescence microscopy. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels in MCs were determined using the WST-1 and TBA methods, respectively. RESULTS: In comparison with the control group, the viability of MCs and SOD activity were significantly decreased in the H2 O2 group (P < 0.05) and significantly increased in the tacalcitol group (P < 0.05). In comparison with the control group, the rate of change of cell dendrites and levels of ROS and MDA were significantly increased in the H2 O2 group (P < 0.05) and significantly decreased in the tacalcitol group (P < 0.05). CONCLUSIONS: Tacalcitol can reduce oxidative damage induced by H2 O2 in MCs by inhibiting intracellular ROS overproduction, increasing SOD activity, and decreasing the level of MDA, thereby reducing cell apoptosis. PMID- 28074523 TI - Familial gastrointestinal stromal tumors, lentigines, and cafe-au-lait macules associated with germline c-kit mutation treated with imatinib. AB - BACKGROUND: Familial lentiginosis syndromes are characterized by a wide array of manifestations resulting from activation of molecular pathways which control growth, proliferation, and differentiation of a broad range of tissues. Familial gastrointestinal stromal tumors (GISTs) are often accompanied by additional features like hyperpigmentation, mastocytosis, and dysphagia. They have been described with mutations in c-kit (most commonly), platelet-derived growth factor receptor A, neurofibromatosis-1, and succinate dehydrogenase genes. MATERIALS AND METHODS: We report on molecular characterization and tumor histopathology of two siblings in whom lentigines and cafe-au-lait macules were present along with multifocal GIST. Immuhistochemical analysis of CD34 and CD117 was performed on GIST biopsy samples from both siblings, while c-kit mutational analysis was done by PCR and direct sequencing on DNA from peripheral blood leukocytes of all family members and from paraffin-embedded gastric biopsy specimens of affected siblings. RESULTS: Histopathology revealed positive expression of CD117 and CD34. Mutational analysis showed the germline c.1676T>C mutation in c-kit exon 11, (p.(Val559Ala)), in the peripheral blood of both siblings and a second exon 11 mutation, c.1669T>A (p.(Trp557Arg)) in the tumor biopsy of one of them. Initiation of imatinib treatment resulted in striking resolution of their hyperpigmentation and a stable gastrointestinal disease in one of them. CONCLUSIONS: A c-kit mutational test in familial GISTs is indicated before initiation of imatinib therapy, as it can help predict tumor response to treatment. PMID- 28074524 TI - Trichoscopic clues for diagnosis of alopecia areata and trichotillomania in Asians. AB - BACKGROUND: Trichoscopy has become a useful diagnostic tool for various hair and scalp diseases, including alopecia areata (AA) and trichotillomania (TTM), which are sometimes difficult to distinguish clinically. OBJECTIVES: To describe trichoscopic findings of AA and TTM in an Asian population and to establish diagnostic clues for these conditions. METHODS: Trichoscopy was performed with a handheld dermoscope in 52 patients diagnosed with AA and 23 patients diagnosed with TTM. Trichoscopic images were then blindly evaluated. RESULTS: The trichoscopic features more frequently observed in AA than in TTM included exclamation mark hairs (AA 59.6%, TTM 26.1%), tapered hairs (AA 59.6%, TTM 4.3%), yellow dots (AA 46.2%, TTM 21.7%), and angulated hairs (AA 26.9%, TTM 0%) (P < 0.05). On the other hand, broken hairs of different lengths (TTM 100%, AA 3.8%), trichoptilosis (TTM 78.3%, AA 5.8%), V-sign (TTM 43.5%, AA 3.8%), flame hairs (TTM 43.5%, AA 0%), and hair powder (TTM 13%, AA 1.9%) were more commonly demonstrated in TTM than in AA (P < 0.05). CONCLUSIONS: Exclamation mark hairs indicate a diagnosis of AA but not pathognomonic. In addition, angulated hairs, fractured hairs forming a sharp angle along the hair shaft, appear to be typical for AA in Asians when differentiating from TTM. It is important to consider various trichoscopic findings together to establish the diagnosis of AA or TTM. PMID- 28074525 TI - Efficacy of superficial cryotherapy on the eyebrows of patients with alopecia universalis also treated with contact immunotherapy on the scalp: a prospective, split-face comparative study. AB - BACKGROUND: Few treatment modalities are available for treating alopecia areata (AA) of the eyebrow. Due to the anatomical proximity of the eyebrows to the eyes, safety issues and side effects should always be taken into consideration when choosing the treatment modality. This study was designed to examine the efficacy of superficial cryotherapy on patients with AA of the eyebrow. METHODS: Superficial cryotherapy was performed every other week on the right eyebrow (SC treated) in a total of 20 patients who had been previously treated with diphenylcyclopropenone (DPCP) immunotherapy on the scalp. No specific treatment was performed on the left eyebrows as a control. The degree of eyebrow recovery was compared in 15 patients who continued to receive more than 10 superficial cryotherapy treatments (5 months of treatment) on their right eyebrow. RESULTS: Hair density was significantly increased on both treated and control eyebrows after 5 months of treatment compared with the pretreatment density; moreover, the SC-treated eyebrows exhibited a significantly greater increase in density than the control eyebrows. Although hair thickness in the control eyebrows did not change significantly over the treatment period, hair thickness of the SC-treated eyebrows showed a statistically significant increase at months 3 and 5. CONCLUSIONS: Superficial cryotherapy is associated with minimal to no adverse events and exhibits high compliance and relatively good efficacy. Thus, this treatment is an important additional option for patients with AA of the eyebrow. PMID- 28074526 TI - Risk factors for nonmelanoma skin cancer in renal transplant recipients: a case control study from a reference outpatient clinic in Southeast Brazil. AB - BACKGROUND: Nonmelanoma skin cancer (NMSC) is the most common tumor in humans, and its incidence increases among renal transplant recipients (RTRs). The aims of this study were to characterize the RTRs with NMSC, to identify risk factors, and to calculate the probability of this tumor in this population. METHODS: This was a hospital-based case-control study. Epidemiological and clinical variables were evaluated. Hierarchical logistic regression was used, and a mathematical model was built. RESULTS: In total, 245 subjects were included. Possible associations were identified using a univariate analysis. Multivariate analysis identified risk factors with respective odds ratios and confidence intervals (95% CI): males 2.5 (1.3-4.7), age over 50 years 5.4 (2.3-12.9), Fitzpatrick's skin phototypes I III 3.7 (1.6-8.7), occupational sun exposure 4.1 (2.1-8.1), timetable of recreational sun exposure all day 3.0 (1.4-6.1), and duration of transplantation (80 months or more) 3.3 (1.6-6.5). The Hosmer-Lemeshow test and the receiver operating characteristics curve showed a strong fit and accuracy, respectively. The probability of an NMSC ranged from less than 1 to 92.5%. CONCLUSIONS: This study characterized the RTRs with NMSC and identified risk factors. The multivariate analysis by hierarchical logistic regression proved to be a useful tool and allowed for the determination of the probability of NMSC in this population. PMID- 28074527 TI - Narcissus' reflection: toxic ingredients in cosmetics through the ages. PMID- 28074529 TI - Epigenetic-mediated immune suppression of positive co-stimulatory molecules in chemoresistant ovarian cancer cells. AB - The immunological response against cancer is a critical balance between immune activating and immune-suppressing mechanisms. Ovarian cancer creates a suppressive microenvironment to escape immune elimination; however, the molecular mechanisms are poorly understood, and it is unclear whether chemotherapeutic drugs exert an immunoreactive or immunosuppressive effect on the tumor microenvironment. 4-1BB ligand (4-1BBL/CD157) and OX-40 ligand (OX-40L/CD252) are important regulators of effector cytotoxic T-cells activity. This study demonstrates that expression of positive co-stimulatory molecules, OX-40L and 4 1BBL, is suppressed while expression of immunosuppressive molecule programmed death ligand-1 (PD-L1/CD274) is enhanced in chemoresistant cells compared to parental chemosensitive ovarian cancer cells. Here, the molecular mechanisms of silencing of OX-40L and 4-1BBL expression were investigated in chemoresistant A2780-AD ovarian cancer cells. The suppression of OX-40L and 4-1BBL are due to DNA hypermethylation and histone deacetylation, two important mechanisms that contribute to gene silencing during cancer progression. We identify important epigenetic regulators, histone deacetylase 1/3 (HDAC1/HDAC3) and DNA methyltransferase 1 (DNMT1), that exhibit aberrant association with OX-40L and 4 1BBL promoters in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1 expression, and pharmacological inhibition of DNMT or HDAC enzymatic activity, significantly increase OX-40L and 4-1BBL expression in chemoresistant cells. This study suggests that loss of histone acetylation and accumulation of DNA methylation correlates with suppressed expression of OX-40L and 4-1BBL in chemoresistant ovarian cancer cells. This study marks the first report of the regulation of these two molecules by histone deacetylation and DNA methylation in chemoresistant ovarian cancer cells. PMID- 28074528 TI - Respiratory motion prediction and prospective correction for free-breathing arterial spin-labeled perfusion MRI of the kidneys. AB - PURPOSE: Respiratory motion prediction using an artificial neural network (ANN) was integrated with pseudocontinuous arterial spin labeling (pCASL) MRI to allow free-breathing perfusion measurements in the kidney. In this study, we evaluated the performance of the ANN to accurately predict the location of the kidneys during image acquisition. METHODS: A pencil-beam navigator was integrated with a pCASL sequence to measure lung/diaphragm motion during ANN training and the pCASL transit delay. The ANN algorithm ran concurrently in the background to predict organ location during the 0.7-s 15-slice acquisition based on the navigator data. The predictions were supplied to the pulse sequence to prospectively adjust the axial slice acquisition to match the predicted organ location. Additional navigators were acquired immediately after the multislice acquisition to assess the performance and accuracy of the ANN. The technique was tested in eight healthy volunteers. RESULTS: The root-mean-square error (RMSE) and mean absolute error (MAE) for the eight volunteers were 1.91 +/- 0.17 mm and 1.43 +/- 0.17 mm, respectively, for the ANN. The RMSE increased with transit delay. The MAE typically increased from the first to last prediction in the image acquisition. The overshoot was 23.58% +/- 3.05% using the target prediction accuracy of +/- 1 mm. CONCLUSION: Respiratory motion prediction with prospective motion correction was successfully demonstrated for free-breathing perfusion MRI of the kidney. The method serves as an alternative to multiple breathholds and requires minimal effort from the patient. PMID- 28074530 TI - Slice profile and B1 corrections in 2D magnetic resonance fingerprinting. AB - PURPOSE: The goal of this study is to characterize and improve the accuracy of 2D magnetic resonance fingerprinting (MRF) scans in the presence of slice profile (SP) and B1 imperfections, which are two main factors that affect quantitative results in MRF. METHODS: The SP and B1 imperfections are characterized and corrected separately. The SP effect is corrected by simulating the radiofrequency pulse in the dictionary, and the B1 is corrected by acquiring a B1 map using the Bloch-Siegert method before each scan. The accuracy, precision, and repeatability of the proposed method are evaluated in phantom studies. The effects of both SP and B1 imperfections are also illustrated and corrected in the in vivo studies. RESULTS: The SP and B1 corrections improve the accuracy of the T1 and T2 values, independent of the shape of the radiofrequency pulse. The T1 and T2 values obtained from different excitation patterns become more consistent after corrections, which leads to an improvement of the robustness of the MRF design. CONCLUSION: This study demonstrates that MRF is sensitive to both SP and B1 effects, and that corrections can be made to improve the accuracy of MRF with only a 2-s increase in acquisition time. Magn Reson Med 78:1781-1789, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28074531 TI - Antibiotic use during infectious episodes in the first 6 months of anticancer treatment-A Swedish cohort study of children aged 7-16 years. AB - BACKGROUND: Children undergoing cancer therapy are at risk for infectious complications that require hospitalization and antimicrobial therapy. Host factors such as age and underlying disease may predict the risk of severe infections in these children. To describe the increased morbidity due to infections in children with cancer, we characterized the antibiotic use during the infectious complications in a national cohort of children 7-16 years of age with cancer. PROCEDURE: Data on infectious complications were prospectively collected from the medical records of all newly diagnosed children with cancer, aged 7-16 years, in Sweden between 2004 and 2006. An episode of infection was defined as a period of time when oral or intravenous antimicrobial treatment was prescribed because of symptoms of infection. RESULTS: A total of 230 infectious episodes occurred in 80 of the 101 patients. Pathogens were isolated in 15% of the blood cultures that showed a predominance of Gram-positive bacteria. Intravenous broad-spectrum antibiotics with cephalosporins and carbapenems were mostly used as single drugs but also in combination with aminoglycosides and glycopeptide. The median treatment length varied between 6 and 11 days depending on cancer diagnosis. CONCLUSION: Our data demonstrate that infectious complications contribute significantly to morbidity in children with cancer aged 7-16 years. At the time of this survey, antibiotic prescription patterns varied and cephalosporins and carbapenems were mostly used. With increasing antibiotic resistance, a more stringent antibiotic stewardship with less use of cephalosporins and carbapenems should be encouraged for children with cancer. Data on prescription patterns should be incorporated as a quality measurement in pediatric cancer care. PMID- 28074532 TI - Pathogenesis of developmental anomalies of the central nervous system induced by congenital cytomegalovirus infection. AB - In humans, the herpes virus family member cytomegalovirus (CMV) is the most prevalent mediator of intrauterine infection-induced congenital defect. Central nervous system (CNS) dysfunction is a distinguishing symptom of CMV infection, and characterized by ventriculoencephalitis and microglial nodular encephalitis. Reports on the initial distribution of CMV particles and its receptors on the blood brain barrier (BBB) are rare. Nevertheless, several factors are suggested to affect CMV etiology. Viral particle size is the primary factor in determining the pattern of CNS infections, followed by the expression of integrin beta1 in endothelial cells, pericytes, meninges, choroid plexus, and neural stem progenitor cells (NSPCs), which are the primary targets of CMV infection. After initial infection, CMV disrupts BBB structural integrity to facilitate the spread of viral particles into parenchyma. Then, the initial meningitis and vasculitis eventually reaches NSPC-dense areas such as ventricular zone and subventricular zone, where viral infection inhibits NSPC proliferation and differentiation and results in neuronal cell loss. These cellular events clinically manifest as brain malformations such as a microcephaly. The purpose of this review is to clearly delineate the pathophysiological basis of congenital CNS anomalies caused by CMV. PMID- 28074533 TI - Netrin G1: its downregulation in the nucleus accumbens of cocaine-conditioned mice and genetic association in human cocaine dependence. AB - Netrin G1 is a presynaptic ligand involved in axonal projection. Although molecular mechanisms underlying cocaine addiction are still poorly understood, Netrin G1 might have a role as a regulator of anxiety, fear and spatial memory, behavioural traits impaired in the context of cocaine exposure. In this study, the Netrin G1 (Ntng1) expression was investigated in the nucleus accumbens of mice primarily conditioned to cocaine using a place preference paradigm. A genetic association study was then conducted on 146 multiplex families of the Collaborative study on Genetics of Alcoholism, in which seven single nucleotide polymorphisms located in the NTNG1 gene were genotyped. NTNG1 expression levels were also quantified in BA10, BA46 and the cerebellum of healthy controls (with no Axis 1 psychopathology). Decreased Ntng1 expression was initially observed in the nucleus accumbens of mice conditioned to cocaine. Significant genetic family based associations were detected between NTNG1 polymorphisms and cocaine dependence. NTNG1 expression in BA10, BA46 and the cerebellum, however, were not significantly associated with any allele or haplotype of this gene. These results confirm that Ntng1 expression is disturbed in the nucleus accumbens of mice, after cocaine conditioning. A haplotype of NTNG1 was found to constitute a vulnerability factor for cocaine use disorder in patients, although none of its single nucleotide polymorphisms were associated with a differential expression pattern in healthy controls. The data suggest that change in the Ntng1 expression is a consequence of cocaine exposure, and that some of its genetic markers are associated with a greater risk for cocaine use disorder. PMID- 28074534 TI - Depolarizing gamma-aminobutyric acid contributes to glutamatergic network rewiring in epilepsy. AB - OBJECTIVE: Rewiring of excitatory glutamatergic neuronal circuits is a major abnormality in epilepsy. Besides the rewiring of excitatory circuits, an abnormal depolarizing gamma-aminobutyric acidergic (GABAergic) drive has been hypothesized to participate in the epileptogenic processes. However, a remaining clinically relevant question is whether early post-status epilepticus (SE) evoked chloride dysregulation is important for the remodeling of aberrant glutamatergic neuronal circuits. METHODS: Osmotic minipumps were used to infuse intracerebrally a specific inhibitor of depolarizing GABAergic transmission as well as a functionally blocking antibody toward the pan-neurotrophin receptor p75 (p75NTR ). The compounds were infused between 2 and 5 days after pilocarpine-induced SE. Immunohistochemistry for NKCC1, KCC2, and ectopic recurrent mossy fiber (rMF) sprouting as well as telemetric electroencephalographic and electrophysiological recordings were performed at day 5 and 2 months post-SE. RESULTS: Blockade of NKCC1 after SE with the specific inhibitor bumetanide restored NKCC1 and KCC2 expression, normalized chloride homeostasis, and significantly reduced the glutamatergic rMF sprouting within the dentate gyrus. This mechanism partially involves p75NTR signaling, as bumetanide application reduced SE-induced p75NTR expression and functional blockade of p75NTR decreased rMF sprouting. The early transient (3 days) post-SE infusion of bumetanide reduced rMF sprouting and recurrent seizures in the chronic epileptic phase. INTERPRETATION: Our findings show that early post-SE abnormal depolarizing GABA and p75NTR signaling fosters a long-lasting rearrangement of glutamatergic network that contributes to the epileptogenic process. This finding defines promising and novel targets to constrain reactive glutamatergic network rewiring in adult epilepsy. Ann Neurol 2017;81:251-265. PMID- 28074535 TI - Gene Ages, Nomenclatures, and Functional Diversification of the Methuselah/Methuselah-Like GPCR Family in Drosophila and Tribolium. AB - Affecting lifespan regulation and oxidative stress resistance, the G-protein coupled receptor (GPCR) gene methuselah (mth) plays important roles in the life history of Drosophila melanogaster. Substantial progress has been made in elucidating the molecular pathways by which mth affects these traits, yet conflicting ideas exist as to how old these genetic interactions are as well as how old the mth gene itself is. Root to these issues is the complex gene family history of the Mth/Mthl GPCR family, which experienced independent expansions in a variety of animal clades, leading to at least six subfamilies in insects. Within insects, drosophilid flies stand out by possessing up to three times more Mth/Mthl receptors due to the expansion of a single subfamily, the mth superclade subfamily, which contains an even younger subfamily introduced here as the melanogaster subgroup subfamily. As a result, most of the 16 Mth/Mthl receptors of D. melanogaster are characterized by n:1 orthology relationships to singleton mth superclade homologs in nondrosophilid species. This challenge is exacerbated by the inconsistent naming of Mth/Mthl orthologs across species. To consolidate this situation, we review established ortholog relationships among insect Mth/Mthl receptors, clarify the gene nomenclatures in two important satellite model species, the fruit fly relative D. virilis and the red flour beetle Tribolium castaneum, and discuss the genetic and functional evolution of the D. melanogaster Mth GPCR. PMID- 28074536 TI - Use of an intravenous sclerosing foam (3% sodium tetradecyl sulfate) for treatment of orbital varix in a dog. AB - A 6-month-old intact male Standard Dachshund was referred for evaluation of a soft tissue swelling above the right eye. Examination of the right eye revealed mild lateral deviation of the globe, normal vision, and a dorsonasal soft tissue swelling. Examination of the posterior segment was normal. Dual-phase computed tomography angiography was consistent with an orbital varix of the angularis oculi and right dorsal external ophthalmic veins with no evidence of arterial involvement. Treatment involved fluoroscopically guided coil embolization of the venous outflow with nine platinum microcoils, followed by sclerotherapy of the varix using 1.5 mL of 3% sodium tetradecyl sulfate foam. Moderate-to-marked swelling was noted at the treatment site in the weeks following therapy, which gradually resolved. At final reexamination 3 months post-therapy, complete sclerosis and resolution of the orbital varix were documented. To the authors' knowledge, this is the first reported case involving the use of a sclerotic agent for successful treatment of a venous malformation in a dog. PMID- 28074537 TI - Neuroblastoma causes alterations of the intestinal microbiome, gut hormones, inflammatory cytokines, and bile acid composition. AB - OBJECTIVE: To assess the effect of neuroblastoma (NB) on the intestinal microbiome, metabolism, and inflammatory parameters in a murine model. MATERIALS AND METHODS: Athymic Hsd:Fox1nu mice received subperitoneal implantation of human NB cells (MHH-NB11) (tumor group, TG) or culture medium (sham group). Following 10 weeks of tumor growth, all animals were sacrificed to collect total white adipose tissue (WAT). Luminex assays were performed for gut hormone and inflammation marker analysis. Bile acids were measured by high-performance liquid chromatography-mass spectrometry in feces and serum. The microbiome of the ileal content was determined by 16S rDNA next-generation sequencing. RESULTS: At 10 weeks, tumors masses in the TG reached a mean weight of 1.10 g (interquartile range 3.45 g) associated with a significant reduction in WAT. Furthermore, in the TG, there was a marked reduction in leptin and an increase in glucagon-like peptide 1 serum levels. Moreover, the TG mice displayed a pro-inflammatory profile, with significant increases in monocyte chemotactic protein 1, tumor necrosis factor alpha, and interleukin-10. Lithocholic acid, deoxycholic acid, and ursodeoxycholic acid were significantly decreased in the stool of TG mice. Significant alterations of the intestinal microbiome were found in the ileal contents of the TG. CONCLUSIONS: The present study provides a first glimpse that human NB in a murine model induces tumor cachexia associated with alterations in metabolic and inflammatory parameters, as well as changes in the intestinal microbiota. Since the intestinal microbiome is known to contribute to the host's ability to harvest energy, a favorable modulation of the intestinal microbiome in tumor patients could potentially represent a novel therapeutic target to prevent tumor-associated cachexia. PMID- 28074538 TI - Ultrasound biomicroscopy and tonometry in ophthalmologically normal pigeon eyes. AB - OBJECTIVE: To evaluate the feasibility of ultrasound biomicroscopy (UBM) and tonometry in pigeons and to provide biometric reference ranges for normal pigeon eyes. ANIMALS STUDIED: Ten pigeons (Columba livia var. domestica) with ophthalmologically normal eyes. PROCEDURES: Ophthalmic examinations, including slit-lamp biomicroscopy and tonometry, were performed to confirm that the eyes were normal. UBM was then performed on the left eye. On each obtained image, the ciliary cleft (CC) length, CC width, and CC area, and iridocorneal angle (ICA) were measured. RESULTS: Richly vascularized iris was observed in all pigeon eyes. Mean intraocular pressure was 11.7 +/- 1.6 mmHg, without any statistical difference between the left and right eyes. The UBM scanning procedure was well tolerated in all pigeons. Mean values of CC length, CC width, CC area, and ICA were 1.55 +/- 0.17 mm, 0.36 +/- 0.05 mm, 0.39 +/- 0.04 mm2 , and 15.17 +/- 1.06 degrees , respectively. CONCLUSIONS: Ultrasound biomicroscopy could be a useful diagnostic tool to evaluate anterior ocular segment of pigeons. PMID- 28074539 TI - Ritterostatin GN 1N , a Cephalostatin-Ritterazine Bis-steroidal Pyrazine Hybrid, Selectively Targets GRP78. AB - Natural products discovered by using agnostic approaches, unlike rationally designed leads or those obtained through high-throughput screening, offer the ability to reveal new biological pathways and, hence, serve as an important vehicle to unveil new avenues in drug discovery. The ritterazine-cephalostatin family of natural products displays robust and potent antitumor activities, with sub-nanomolar growth inhibition against multiple cell lines and potent activity in xenograft models. Herein, we used comparative cellular and molecular biological methods to uncover the ritterazine-cephalostatin cytotoxic mode of action (MOA) in human tumor cells. Our findings indicated that, whereas ritterostatin GN 1N , a cephalostatin-ritterazine hybrid, binds to multiple HSP70s, its cellular trafficking confines activity to the endoplasmic reticulum (ER)-based HSP70 isoform, GRP78. This targeting results in activation of the unfolding protein response (UPR) and subsequent apoptotic cell death. PMID- 28074541 TI - Comparison of respiratory motion suppression techniques for 4D flow MRI. AB - PURPOSE: The purpose of this work was to assess the impact of respiratory motion and to compare methods for suppression of respiratory motion artifacts in 4D Flow MRI. METHODS: A numerical 3D aorta phantom was designed based on an aorta velocity field obtained by computational fluid mechanics. Motion-distorted 4D Flow MRI measurements were simulated and several different motion-suppression techniques were evaluated: Gating with fixed acceptance window size, gating with different window sizes in inner and outer k-space, and k-space reordering. Additionally, different spatial resolutions were simulated. RESULTS: Respiratory motion reduced the image quality. All motion-suppression techniques improved the data quality. Flow rate errors of up to 30% without gating could be reduced to less than 2.5% with the most successful motion suppression methods. Weighted gating and gating combined with k-space reordering were advantageous compared with conventional fixed-window gating. Spatial resolutions finer than the amount of accepted motion did not lead to improved results. CONCLUSION: Respiratory motion affects 4D Flow MRI data. Several different motion suppression techniques exist that are capable of reducing the errors associated with respiratory motion. Spatial resolutions finer than the degree of accepted respiratory motion do not result in improved data quality. Magn Reson Med 78:1877-1882, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28074542 TI - Do cultural factors still exert an impact on the suicide rate in Japan? PMID- 28074540 TI - Complications of percutaneous liver biopsy with Klatskin needles: a 36-year single-centre experience. AB - BACKGROUND: Liver biopsy is the gold standard in evaluating liver diseases but is susceptible to complications. Safety data on aspiration needle biopsies remain limited. AIM: To evaluate the safety of percutaneous liver biopsy performed with Klatskin needle. METHODS: Clinical and biochemical data were retrospectively retrieved from sequential subjects who underwent liver biopsy with Klatskin needle from 1978 to 2015. Subjects with complications underwent thorough chart reviews for hospital course. RESULTS: Of 3357 biopsies performed, complications occurred in 135 (4%) biopsies with 33 (1%) resulting in major complications. Severe pain occurred in 78 (2.3%) subjects and bleeding occurred in 21 (0.6%) subjects. Biliary injury occurred in 8 (0.2%) biopsies. Three subjects died as a result of massive intraperitoneal bleeding. Compared to viral hepatitis, biopsies performed with certain diagnosis had significantly higher odds of major complications: NRH (OR: 17), DILI (OR: 20), GVHD (OR: 32) and HCC (OR: 34). Subjects with major complications had higher pre-biopsy median AP (153 vs. 78 U/L, P < 0.001), ALT (105 vs. 64 U/L, P < 0.05), AST (62 vs. 47 U/L, P < 0.02), along with marginally lower total bilirubin (1.0 vs. 0.7 mg/dL, P < 0.01) and albumin (3.7 vs. 4.0 g/dL, P < 0.001). By multivariate backward logistic regression, platelets <=100 K/MUL and aPTT >35 were independent risk factors of post-biopsy bleeding. CONCLUSION: Klatskin needle liver biopsies are safe with rare procedural morbidity. Our data suggests certain acutely ill subjects and those with systemic illnesses may be at higher risk of major complications. Clinicians should weigh the risks and benefits of liver biopsy in these patients with other alternative approaches. PMID- 28074543 TI - Low distress tolerance predicts heightened drug seeking and taking after extended abstinence from cocaine self-administration. AB - Distress tolerance (DT), defined as the ability to persist in goal-directed behavior while experiencing psychological distress, is associated with greater frequency of substance use and poor treatment outcomes. To examine a potential causal role substance use may play in DT, we developed a rodent model of DT in which rats had to press a lever within a continuously decreasing time window for reward while receiving negative feedback on failure trials. DT was defined as the time rats continued to seek reward before quitting the task. We assessed the relationship of DT with cocaine seeking/taking by measuring DT before cocaine self-administration (SA), and after 1 week and 1 month of drug abstinence. We found that DT prior to cocaine SA did not predict cocaine seeking/taking, yet DT measured after 1 month abstinence significantly predicted subsequent high levels of early session cocaine taking. Additionally, high DT measured after abstinence protected against high cocaine seeking, but this protective effect was blocked in rats with high impulsivity. Finally, while a decrease in 1 month-abstinent DT was observed following SA across treatment conditions, among cocaine-exposed rats, greater cocaine SA correlated with a steeper decrease in DT. These results show that low DT after drug abstinence is associated with heightened levels of cocaine seeking and taking behavior and that impulsivity influences this effect. Collectively, these results support the validity of our rodent DT model while extending the human literature and set the foundation for future animal studies designed to determine neural mechanisms underlying DT. PMID- 28074544 TI - A message from the new editor in chief. PMID- 28074545 TI - Development and testing of a database of NIH research funding of AAPM members: A report from the AAPM Working Group for the Development of a Research Database (WGDRD). AB - PURPOSE: To produce and maintain a database of National Institutes of Health (NIH) funding of the American Association of Physicists in Medicine (AAPM) members, to perform a top-level analysis of these data, and to make these data (hereafter referred to as the AAPM research database) available for the use of the AAPM and its members. METHODS: NIH-funded research dating back to 1985 is available for public download through the NIH exporter website, and AAPM membership information dating back to 2002 was supplied by the AAPM. To link these two sources of data, a data mining algorithm was developed in Matlab. The false-positive rate was manually estimated based on a random sample of 100 records, and the false-negative rate was assessed by comparing against 99 member supplied PI_ID numbers. The AAPM research database was queried to produce an analysis of trends and demographics in research funding dating from 2002 to 2015. RESULTS: A total of 566 PI_ID numbers were matched to AAPM members. False positive and -negative rates were respectively 4% (95% CI: 1-10%, N = 100) and 10% (95% CI: 5-18%, N = 99). Based on analysis of the AAPM research database, in 2015 the NIH awarded $USD 110M to members of the AAPM. The four NIH institutes which historically awarded the most funding to AAPM members were the National Cancer Institute, National Institute of Biomedical Imaging and Bioengineering, National Heart Lung and Blood Institute, and National Institute of Neurological Disorders and Stroke. In 2015, over 85% of the total NIH research funding awarded to AAPM members was via these institutes, representing 1.1% of their combined budget. In the same year, 2.0% of AAPM members received NIH funding for a total of $116M, which is lower than the historic mean of $120M (in 2015 USD). CONCLUSIONS: A database of NIH-funded research awarded to AAPM members has been developed and tested using a data mining approach, and a top-level analysis of funding trends has been performed. Current funding of AAPM members is lower than the historic mean. The database will be maintained by members of the Working group for the development of a research database (WGDRD) on an annual basis, and is available to the AAPM, its committees, working groups, and members for download through the AAPM electronic content website. A wide range of questions regarding financial and demographic funding trends can be addressed by these data. This report has been approved for publication by the AAPM Science Council. PMID- 28074547 TI - A Pharmacokinetic and Safety Study of Trebananib, an Fc-Fusion Peptibody, in Patients With Advanced Solid Tumors and Varying Degrees of Renal Dysfunction. AB - Clearance of trebananib (AMG 386), a 64-kD antiangiogenic peptibody, has been associated with estimated glomerular filtration rate (eGFR). We prospectively evaluated trebananib pharmacokinetics and safety/tolerability in advanced solid tumor patients with varying degrees of renal function. Patients were assigned to normal renal function, mild, moderate, or severe renal dysfunction cohorts based on eGFR, received trebananib 15 mg/kg i.v. weekly, and underwent week 1 and week 5 pharmacokinetic and weekly safety assessments. For 28 patients, trebananib clearance decreased from normal renal function (1.52 mL/hr/kg), to mild (1.20 mL/hr/kg), moderate (0.79 mL/hr/kg), and severe (0.53 mL/hr/kg) renal dysfunction (P <= 0.001). Treatment-related adverse events showed no association with clearance. Trebananib clearance was proportional to eGFR and unrelated to pretreatment protein excretion. These data confirm a role for renal clearance of a recombinant peptibody with molecular weight <69 kD and support a longer dosing interval for patients with severe renal dysfunction. PMID- 28074546 TI - Hypoxia and cellular metabolism in tumour pathophysiology. AB - Cancer cells are optimised for growth and survival via an ability to outcompete normal cells in their microenvironment. Many of these advantageous cellular adaptations are promoted by the pathophysiological hypoxia that arises in solid tumours due to incomplete vascularisation. Tumour cells are thus faced with the challenge of an increased need for nutrients to support the drive for proliferation in the face of a diminished extracellular supply. Among the many modifications occurring in tumour cells, hypoxia inducible factors (HIFs) act as essential drivers of key pro-survival pathways via the promotion of numerous membrane and cytosolic proteins. Here we focus our attention on two areas: the role of amino acid uptake and the handling of metabolic acid (CO2 /H+ ) production. We provide evidence for a number of hypoxia-induced proteins that promote cellular anabolism and regulation of metabolic acid-base levels in tumour cells including amino-acid transporters (LAT1), monocarboxylate transporters, and acid-base regulating carbonic anhydrases (CAs) and bicarbonate transporters (NBCs). Emphasis is placed on current work manipulating multiple CA isoforms and NBCs, which is at an interesting crossroads of gas physiology as they are regulated by hypoxia to contribute to the cellular handling of CO2 and pHi regulation. Our research combined with others indicates that targeting of HIF regulated membrane proteins in tumour cells will provide promising future anti cancer therapeutic approaches and we suggest strategies that could be potentially used to enhance these tactics. PMID- 28074548 TI - Annual Report of the Perinatology Committee, Japan Society of Obstetrics and Gynecology, 2015: Proposal of urgent measures to reduce maternal deaths. AB - Perinatal care in Japan has progressed rapidly in recent decades, remarkably reducing maternal, perinatal and neonatal mortality rates. This is attributable not only to the sustained efforts and dedication of past obstetricians and midwives, but also to the collective results achieved by the Japan Society of Obstetrics and Gynecology and healthcare administration, including research on advanced medical care, education, medical care improvements and establishing perinatal care centers. Although the maternal mortality rate was in steady decline until 2007 (3.1/100 000 births), it repeatedly fluctuated thereafter, plateauing at 3.4 per 100 000 births in 2013 and 2.7 per 100 000 births in 2014. Thus, the Perinatology Committee has analyzed the current situation of maternal deaths and has proposed countermeasures to reduce such death. The items deliberated upon by related subcommittees in 2015 are presented herein. The addition of indications for 'fibrinogen concentrate', 'eptacog alfa' and approval of the PGE2 vaginal tablet for cervical ripening were discussed in the subcommittee for unapproved drug review. Thus, a request for approval for health insurance coverage was submitted to the 'Evaluation committee on unapproved or off-label drugs with high medical needs' of the Ministry of Health, Labour and Welfare. Maternal and late-maternal deaths from suicide during the 10 years from 2005 to 2014 in Tokyo's 23 wards were jointly examined with the Tokyo Medical Examiner's Office. The suicide rate in the 23 wards is very high, at 8.7 per 100 000 births. Thus, the subcommittee for the reduction of maternal death discussed countermeasures for the eradication of maternal death and maternal suicide and the revision of death certificates. PMID- 28074549 TI - Systemic alterations and their oral manifestations in pregnant women. AB - The aims of this literature review are: to depict the main oral diseases that are related to pregnancy; to clarify some of the possible systemic mechanisms that are associated with these changes; and to address issues about oral care during pregnancy. A woman's organs undergo various physiological, neurological, and hormonal changes during pregnancy. Such changes occur gradually and are essential for the development of the fetus, providing what is needed for tissue formation and establishment of reserves for uterine and fetal life. In turn, the oral cavity shows some events during this period. Among the changes most frequently cited in the literature are pyogenic granuloma, gingivitis, and periodontitis. The inflammation of the periodontal tissues due to the formation of the biofilm increases dramatically in size and severity during the course of a normal pregnancy, even without changes in the amount of biofilm present. In addition, a decrease in salivary pH is observed in pregnant women and may lead to an increased incidence of dental caries in this period. PMID- 28074550 TI - Treatment strategy for urinary frequency in women. AB - The purpose of this paper is to discuss the differential diagnosis of the underlying etiologies of urinary frequency and the treatment strategies for urinary frequency in women. Urinary frequency is a symptom, a sign, and a condition of uncertainty and of multifactorial cause. Common causes of urinary frequency include psychosocial, medical, sexual, urological, gynecologic, endocrine, and pharmacological in origin. Hence, treatment of symptoms and possible cures need a high-level plan or strategy to overcome the multifactorial etiology. Proper investigation of the chief complaint, history and physical examinations, is needed to evaluate urinary frequency. Pregnancy test, wet smear, urinalysis, midstream urine culture, frequency-volume charts, cystourethroscopy, urodynamics, and genitourinary imaging are the basic routine of office investigations. These tools promote the accuracy of the differential diagnosis of the underlying cause of urinary frequency. It is then often helpful to adopt an algorithmic approach to the management of this complaint. Treatment of urinary frequency might be empirical, and it remains a clinical challenge to gynecologists. To cure the disease, it is important to listen to the patient and consider the condition in all its aspects and use proven techniques. PMID- 28074551 TI - Detection of a clone-specific GATA1 mutation to monitor treatment response and involvement of a monozygotic twin in myeloid leukemia of Down syndrome. PMID- 28074553 TI - Risk of bias in overviews of reviews: a scoping review of methodological guidance and four-item checklist. AB - OBJECTIVE: To assess the conditions under which employing an overview of systematic reviews is likely to lead to a high risk of bias. STUDY DESIGN: To synthesise existing guidance concerning overview practice, a scoping review was conducted. Four electronic databases were searched with a pre-specified strategy (PROSPERO 2015:CRD42015027592) ending October 2015. Included studies needed to describe or develop overview methodology. Data were narratively synthesised to delineate areas highlighted as outstanding challenges or where methodological recommendations conflict. RESULTS: Twenty-four papers met the inclusion criteria. There is emerging debate regarding overlapping systematic reviews; systematic review scope; quality of included research; updating; and synthesizing and reporting results. While three functions for overviews have been proposed identify gaps, explore heterogeneity, summarize evidence-overviews cannot perform the first; are unlikely to achieve the second and third simultaneously; and can only perform the third under specific circumstances. Namely, when identified systematic reviews meet the following four conditions: (1) include primary trials that do not substantially overlap, (2) match overview scope, (3) are of high methodological quality, and (4) are up-to-date. CONCLUSION: Considering the intended function of proposed overviews with the corresponding methodological conditions may improve the quality of this burgeoning publication type. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28074552 TI - Validation of microRNA pathway polymorphisms in esophageal adenocarcinoma survival. AB - Polymorphisms in miRNA and miRNA pathway genes have been previously associated with cancer risk and outcome, but have not been studied in esophageal adenocarcinoma outcomes. Here, we evaluate candidate miRNA pathway polymorphisms in esophageal adenocarcinoma prognosis and attempt to validate them in an independent cohort of esophageal adenocarcinoma patients. Among 231 esophageal adenocarcinoma patients of all stages/treatment plans, 38 candidate genetic polymorphisms (17 biogenesis, 9 miRNA targets, 5 pri-miRNA, 7 pre-miRNA) were genotyped and analyzed. Cox proportional hazard models adjusted for sociodemographic and clinicopathological covariates helped assess the association of genetic polymorphisms with overall survival (OS) and progression-free survival (PFS). Significantly associated polymorphisms were then evaluated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis, and median OS and PFS were 20 and 12 months, respectively. GEMIN3 rs197412 (aHR = 1.37, 95%CI: [1.04-1.80]; P = 0.02), hsa-mir 124-1 rs531564 (aHR = 0.60, 95% CI: [0.53-0.90]; P = 0.05), and KIAA0423 rs1053667 (aHR = 0.51, 95% CI: [0.28-0.96]; P = 0.04) were found associated with OS. Furthermore, GEMIN3 rs197412 (aHR = 1.33, 95% CI: [1.03-1.74]; P = 0.03) and KRT81 rs3660 (aHR = 1.29, 95% CI: [1.01-1.64]; P = 0.04) were found associated with PFS. Although none of these polymorphisms were significant in the second cohort, hsa-mir-124-1 rs531564 and KIAA0423 rs1053667 had trends in the same direction; when both cohorts were combined together, GEMIN3 rs197412, hsa-mir-124 1 rs531564, and KIAA0423 rs1053667 remained significantly associated with OS. We demonstrate the association of multiple miRNA pathway polymorphisms with esophageal adenocarcinoma prognosis in a discovery cohort of patients, which did not validate in a separate cohort but had consistent associations in the pooled cohort. Larger studies are required to confirm/validate the prognostic value of these polymorphisms in esophageal adenocarcinoma. PMID- 28074555 TI - Paediatric stress: from neuroendocrinology to contemporary disorders. AB - BACKGROUND: Stress is defined as a state of threatened or perceived as threatened homeostasis. A broad spectrum of extrinsic or intrinsic, real or perceived stressful stimuli, called 'stressors', activates a highly conserved system, the 'stress system', which adjusts homeostasis through central and peripheral neuroendocrine responses. Inadequate, excessive or prolonged adaptive responses to stress may underlie the pathogenesis of several disease states prevalent in modern societies. The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors and the timing of the stressful event(s), given that prenatal life, infancy, childhood and adolescence are critical periods characterized by increased vulnerability to stressors. MATERIALS AND METHODS: We conducted a systematic review of original articles and reviews published in MEDLINE from 1975 through June 2016. The search terms were 'childhood stress', 'pediatric stress', 'stress and disorders' and 'stress management'. RESULTS: In this review, we discuss the historical and neuroendocrine aspects of stress, and we present representative examples of paediatric stress system disorders, such as early-life adversity, obesity and bullying. We also discuss the adverse impact of a socio-economic crisis on childhood health. The tremendous progress of epigenetics has enabled us to have a deeper understanding of the molecular mechanisms underlying paediatric stress-related disorders. CONCLUSIONS: The need for early successful stress management techniques to decrease the incidence of paediatric stress-related diseases, as well as to prevent the development of several pathologic conditions in adolescence and adulthood, is imperative. PMID- 28074554 TI - Population genetic analysis of Giardia duodenalis: genetic diversity and haplotype sharing between clinical and environmental sources. AB - Giardia duodenalis is a flagellated intestinal protozoan responsible for infections in various hosts including humans and several wild and domestic animals. Few studies have correlated environmental contamination and clinical infections in the same region. The aim of this study was to compare groups of Giardia duodenalis from clinical and environmental sources through population genetic analyses to verify haplotype sharing and the degree of genetic similarity among populations from clinical and environmental sources in the metropolitan region of Campinas. The results showed high diversity of haplotypes and substantial genetic similarity between clinical and environmental groups of G. duodenalis. We demonstrated sharing of Giardia genotypes among the different populations studied. The comparison between veterinary and human sequences led us to identify new zoonotic genotypes, including human isolates from genetic assemblage C. The application of a population genetic analysis in epidemiological studies allows quantification of the degree of genetic similarity among populations of Giardia duodenalis from different sources of contamination. The genetic similarity of Giardia isolates among human, veterinary, and environmental groups reinforced the correlation between clinical and environmental isolates in this region, which is of great importance for public health. PMID- 28074557 TI - Microbiome and the future for food and nutrient security. AB - Microbiome and the future for food and nutrient security. PMID- 28074556 TI - QT Interval Shortening With Isavuconazole: In Vitro and In Vivo Effects on Cardiac Repolarization. AB - The effects of isavuconazole (active moiety of isavuconazonium sulfate) on cardiac ion channels in vitro and cardiac repolarization clinically were assessed in a phase I, randomized, double-blind study in healthy individuals who received isavuconazole (after 2-day loading dose), at therapeutic or supratherapeutic doses daily for 11 days, moxifloxacin (400 mg q.d.), or placebo. A post-hoc analysis of the phase III SECURE trial assessed effects on cardiac safety. L-type Ca2+ channels were most sensitive to inhibition by isavuconazole. The 50% inhibitory concentrations for ion channels were higher than maximum serum concentrations of nonprotein-bound isavuconazole in vivo. In the phase I study (n = 161), isavuconazole shortened the QT interval in a dose- and plasma concentration-related manner. There were no serious treatment-emergent adverse events; palpitations and tachycardia were observed in placebo and supratherapeutic isavuconazole groups; no cardiac safety signals were detected in the SECURE study (n = 257). Isavuconazole was associated with a shortened cardiac QT interval. PMID- 28074558 TI - Chelation for diabetes complications: A neglected approach? AB - ,Zou1 ,,?,,,,,2-4 ?,,,56 ,?2(T2D),,,7 ?1,,8 ?,,(TETA),,D-9 ? ,?,TETAT2D10 ;11 ,12 ?24,50T2D,EDTA,EDTA13 ?,1708EDTA,18%14 ,63341%, + 15 ,16 ;17 ? ?,,,,18 ?Zou1 ,?. PMID- 28074559 TI - Effects of traffic noise on tree frog stress levels, immunity, and color signaling. AB - During the last decade, many studies have focused on the detrimental effects of noise pollution on acoustic communication. Surprisingly, although it is known that noise exposure strongly influences health in humans, studies on wildlife remain scarce. In order to gain insight into the consequences of traffic noise exposure, we experimentally manipulated traffic noise exposure as well as the endocrine status of animals to investigate physiological and phenotypic consequences of noise pollution in an anuran species. We showed that noise exposure increased stress hormone level and induced an immunosuppressive effect. In addition, both traffic noise exposure and stress hormone application negatively impacted H. arborea vocal sac coloration. Moreover, our results suggest profound changes in sexual selection processes because the best quality males with initial attractive vocal sac coloration were the most impacted by noise. Hence, our study suggests that the recent increases in anthropogenic noise worldwide might affect a broader range of animal species than previously thought, because of alteration of visual signals and immunity. Generalizing these results to other taxa is crucial for the conservation of biodiversity in an increasingly noisy world. PMID- 28074560 TI - Experience of tailoring prophylaxis using factor VIII pharmacokinetic parameters estimated with myPKFiT(r) in patients with severe haemophilia A without inhibitors. PMID- 28074561 TI - Substance use outcomes of patients served by a large US implementation of Screening, Brief Intervention and Referral to Treatment (SBIRT). AB - AIMS: To estimate changes in the substance use behaviors of patients who received services as part of the US Substance Abuse and Mental Health Services Administration's (SAMHSA) Screening, Brief Intervention and Referral to Treatment (SBIRT) grant program. METHODS: We use a pre-post design and performance monitoring data collected by SBIRT organizations. For a sample of 17 575 patients, we compare pre-SBIRT substance use with substance use 6 months after receipt of SBIRT services. SBIRT's correlation with changes in substance use was estimated using generalized linear mixed models to account for the clustering of patients within health-care facility and US state. RESULTS: From pre- to post SBIRT we found large and statistically significant decreases for almost every measure of substance use. Model-adjusted means indicate that the prevalence of alcohol use was lower 6 months later by 35.6%, heavy drinking by 43.4% and illicit drug use by 75.8%. Greater intervention intensity was associated with larger decreases in substance use. The study design does not support causal conclusions and estimated decreases in reported substance use are due, at least in part, to a well-known set of confounders and natural substance use patterns that may be unrelated to any particular SBIRT intervention. CONCLUSIONS: Compared with previously published findings on the Screening, Brief Intervention and Referral to Treatment grant program, our estimates of substance use reduction were smaller, but still consistently large in absolute magnitude and within ranges of estimates from past trials of Screening, Brief Intervention and Referral to Treatment. PMID- 28074562 TI - The influence of state-level policy environments on the activation of the Medicaid SBIRT reimbursement codes. AB - AIMS: To examine how institutional constraints, comprising federal actions and states' substance abuse policy environments, influence states' decisions to activate Medicaid reimbursement codes for screening and brief intervention for risky substance use in the United States. METHODS: A discrete-time duration model was used to estimate the effect of institutional constraints on the likelihood of activating the Medicaid reimbursement codes. Primary constraints included federal Screening, Brief Intervention and Referral to Treatment (SBIRT) grant funding, substance abuse priority, economic climate, political climate and interstate diffusion. Study data came from publicly available secondary data sources. RESULTS: Federal SBIRT grant funding did not affect significantly the likelihood of activation (P = 0.628). A $1 increase in per-capita block grant funding was associated with a 10-percentage point reduction in the likelihood of activation (P = 0.003) and a $1 increase in per-capita state substance use disorder expenditures was associated with a 2-percentage point increase in the likelihood of activation (P = 0.004). States with enacted parity laws (P = 0.016) and a Democratic-controlled state government were also more likely to activate the codes. CONCLUSION: In the United States, the determinants of state activation of Medicaid Screening, Brief Intervention and Referral to Treatment (SBIRT) reimbursement codes are complex, and include more than financial considerations. Federal block grant funding is a strong disincentive to activating the SBIRT reimbursement codes, while more direct federal SBIRT grant funding has no detectable effects. PMID- 28074563 TI - A time and motion study of Screening, Brief Intervention, and Referral to Treatment implementation in health-care settings. AB - AIMS: Screening and brief intervention for harmful substance use in medical settings is being promoted heavily in the United States. To justify service provision fiscally, the field needs accurate estimates of the number and type of staff required to provide services, and thus the time taken to perform activities used to deliver services. This study analyzed the time spent in activities for the component services of the substance misuse Screening, Brief Intervention and Referral to Treatment (SBIRT) program implemented in emergency departments, in patient units and ambulatory clinics. DESIGN: Observers timed activities according to 18 distinct codes among SBIRT practitioners. SETTING: Twenty-six US sites within four grantees. PARTICIPANTS: Five hundred and one practitioner patient interactions; 63 SBIRT practitioners. MEASUREMENTS: Timing of practitioner activities. INTERVENTIONS: Delivery of component services of SBIRT. FINDINGS: The mean (standard error) time to deliver services was 1:19 (0:06) for a pre-screen (n = 210), 4:28 (0:24) for a screen (n = 97) and 6:51 (0:38) for a brief intervention (n = 66). Estimates of service duration varied by setting. Overall, practitioners spent 40% of their time supporting SBIRT delivery to patients and 13% of their time delivering services. CONCLUSIONS: In the United States, support activities (e.g. reviewing the patient's chart, locating the patient, writing case-notes) for substance abuse Screening, Brief Intervention and Referral to Treatment require more staff time than delivery of services. Support time for screens and brief interventions in the emergency department/trauma setting was high compared with the out-patient setting. PMID- 28074564 TI - Sustaining SBIRT in the wild: simulating revenues and costs for Screening, Brief Intervention and Referral to Treatment programs. AB - AIMS: To examine the conditions under which Screening, Brief Intervention and Referral to Treatment (SBIRT) programs can be sustained by health insurance payments. DESIGN: A mathematical model was used to estimate the number of patients needed for revenues to exceed costs. SETTING: Three medical settings in the United States were examined: in-patient, out-patient and emergency department. Components of SBIRT were delivered by combinations of health-care practitioners (generalists) and behavioral health specialists. PARTICIPANTS: Practitioners in seven SBIRT programs who received grants from the US Substance Abuse and Mental Health Services Administration (SAMHSA). MEASUREMENTS: Program costs and revenues were measured using data from grantees. Patient flows were measured from administrative data and adjusted with prevalence and screening estimates from the literature. FINDINGS: SBIRT can be sustained through health insurance reimbursement in out-patient and emergency department settings in most staffing mixes. To sustain SBIRT in in-patient programs, a patient flow larger than the national average may be needed; if that flow is achieved, the range of screens required to maintain a surplus is narrow. Sensitivity analyses suggest that the results are very sensitive to changes in the proportion of insured patients. CONCLUSIONS: Screening, Brief Intervention and Referral to Treatment programs in the United States can be sustained by health insurance payments under a variety of staffing models. Screening, Brief Intervention and Referral to Treatment programs can be sustained only in an in-patient setting with above average patient flow (more than 2500 screens). Screening, Brief Intervention and Referral to Treatment programs in out-patient and emergency department settings can be sustained with below-average patient flows (fewer than 125 000 out-patient visits and fewer than 27 000 emergency department visits). PMID- 28074565 TI - Sustaining Screening, Brief Intervention and Referral to Treatment (SBIRT) services in health-care settings. AB - AIMS: To assess the sustainability of Screening, Brief Intervention and Referral to Treatment (SBIRT) services after cessation of initial start-up funding. DESIGN: Descriptive study with quantitative and qualitative data collected from 34 staff participants from six grantees (comprising 103 sites) funded previously through a large, federally supported SBIRT program. SETTING: Primary care out patient clinics and hospitals in the United States. PARTICIPANTS: Thirty-four grantee-related staff members, including administrators, evaluators, key stakeholders and SBIRT service providers from six grantees. MEASUREMENTS: Changes to levels and types of service delivery activities after federal funding stopped, alternative sources of funding and obstacles to delivery of services. FINDINGS: Of the 103 original sites in the six SBIRT grantee programs, 69 sites continued providing services in some capacity (same as before, reduced, modified or expanded). Most of the 69 sites (67%) adapted and redesigned the delivery of SBIRT services post-initial grant funding. In addition, new sites were added after grant funding ended, bringing the total number of sites to 88. Analysis of participant responses identified four primary factors that influenced SBIRT sustainability: presence of champions, funding availability, systemic change and SBIRT practitioner characteristics. CONCLUSIONS: Almost 70% of the Screening, Brief Intervention and Referral to Treatment (SBIRT) services in the United States funded initially through a federal program were able to sustain operations after federal funding ceased and some expanded SBIRT services beyond the original sites. The key factors related to sustainability were securing new funding, having champions, adapting and making system changes and managing program staffing challenges. PMID- 28074566 TI - Screening, Brief Intervention and Referral to Treatment (SBIRT): rationale, program overview and cross-site evaluation. AB - AIMS: Since 2003, the US Substance Abuse and Mental Health Services Administration, Center for Substance Abuse Treatment (SAMHSA, CSAT) has awarded 32 Screening, Brief Intervention and Referral to Treatment (SBIRT) grants to states, territories and tribal organizations to enhance services for persons with, or at risk for, substance use disorders. The grants supported an expansion of the continuum of care to include screening, brief intervention, brief treatment and referral to treatment in general medical and community settings. This paper describes the SAMHSA SBIRT program in the context of the scientific research that motivated its development, as well as the two cross-site evaluations that are the subject of subsequent papers in this Supplement. METHODS: A narrative review of research evidence pertaining to SBIRT and of the cross-site evaluation design that made it possible to determine whether the SAMHSA SBIRT grant program achieved its intended aims. The 11 programs within the two cohorts of grant recipients that were the subject of the cross-site evaluations are described in terms of SBIRT service components, performance sites, providers, management structure/activities and patient/client characteristics. CONCLUSION: The US SAMHSA SBIRT program is an effective way to introduce a variety of new services that extend the continuum of care for substance-involved individuals, ranging from early intervention with non dependent substance users to referral of more serious cases to specialized substance abuse treatment. PMID- 28074567 TI - The cost-effectiveness of brief intervention versus brief treatment of Screening, Brief Intervention and Referral to Treatment (SBIRT) in the United States. AB - AIMS: To conduct a cost-effectiveness analysis (CEA) comparing the delivery of brief intervention (BI) with brief treatment (BT) within Screening, Brief Intervention and Referral to Treatment (SBIRT) programs. DESIGN: Quasi experimental differences in observed baseline characteristics between BI and BT patients were adjusted using propensity score techniques. Incremental comparison of costs and health outcomes associated with BI and BT. SETTING: Health-care settings in four US states participating in Substance Abuse and Mental Health Services Administration SBIRT grant programs. PARTICIPANTS: Ninety patients who received BT and 878 who received BI. MEASUREMENTS: Per-patient cost of SBIRT, patient demographics and six measures of substance use: proportion using alcohol, proportion using alcohol to intoxication, days of alcohol use, days of alcohol use to intoxication, proportion using drugs and days using drugs. FINDINGS: BI and BT were associated with better outcomes. The cost of SBIRT was significantly higher for BT patients ($75.54 versus 16.32, 95% confidence interval, P < 0.01). BT would be cost-effective if the decision-maker had a willingness to pay of $8.90 for a 1 percentage point reduction in the probability of using any alcohol. For the other five outcomes, BT was less effective and more costly, and BI would be a better use of resources. CONCLUSIONS: It might be cost-effective to offer brief treatment if the goal is to abstain from alcohol. However, the higher effectiveness of brief treatment for this outcome is associated with considerable uncertainty and, because both brief intervention and brief treatment improve all outcomes, brief treatment does not appear to be a good use of resources. PMID- 28074568 TI - The relative impact of brief treatment versus brief intervention in primary health-care screening programs for substance use disorders. AB - AIMS: To assess the relative impact of brief treatment (BT) compared with brief intervention (BI) on changes in substance use behavior in primary care screening programs for substance use disorders, overall and by patient severity. DESIGN AND PARTICIPANTS: A total of 9029 patients with both baseline and follow-up interviews were identified in the US Government Performance and Results Act (GPRA) data from October 2004 and February 2008. Using a propensity score framework, multiple generalized linear mixed models and a local linear matching method with a difference in difference estimator, patients from the BI group that resemble BT patients were used to determine the relative treatment effect of BT. A total of 3218 of these US patients with baseline and follow-up interviews were used in the final analysis sample after the propensity score-matching procedure (1448 patients assigned to a BI service category and 1770 assigned to a BT service category). SETTING: United States. MEASUREMENTS: Dependent variables were the number of days of use in the past 30 days of any alcohol, alcohol to intoxication, illicit drugs and marijuana. FINDINGS: The relative impact of BT was not significant for alcohol (0.269; P > 0.1) or alcohol to intoxication (0.462; P > 0.1). BT was found to reduce the frequency of use of illicit drugs at follow-up by 0.634 days more than BI (P < 0.05). Marijuana days were not affected significantly by assignment to BT (-0.128; P > 0.1). Higher severity patients assigned to BT had a decrease in days of illicit drug use of 1.765 (P < 0.05). CONCLUSIONS: In the United States, brief treatment appears to have a stronger impact on reducing illicit drug use than brief intervention but is similar to brief intervention for reducing alcohol use, alcohol to intoxication and marijuana use alone. PMID- 28074569 TI - Screening, Brief Intervention and Referral to Treatment: implications of SAMHSA's SBIRT initiative for substance abuse policy and practice. AB - AIMS: This paper describes the major findings and public health implications of a cross-site evaluation of a national Screening, Brief Intervention and Referral to Treatment (SBIRT) demonstration program funded by the US Substance Abuse and Mental Health Services Administration (SAMHSA). METHODS: Eleven multi-site programs in two cohorts of SAMHSA grant recipients were each funded for 5 years to promote the adoption and sustained implementation of SBIRT. The SBIRT cross site evaluation used a multi-method evaluation design to provide comprehensive information on the processes, outcomes and costs of SBIRT as implemented in a variety of medical and community settings. FINDINGS: SBIRT programs in the two evaluated SAMHSA cohorts screened more than 1 million patients/clients. SBIRT implementation was facilitated by committed leadership and the use of substance use specialists, rather than medical generalists, to deliver services. Although the quasi-experimental nature of the outcome evaluation does not permit causal inferences, pre-post differences were clinically meaningful and statistically significant for almost every measure of substance use. Greater intervention intensity was associated with larger decreases in substance use. Both brief intervention and brief treatment were associated with positive outcomes, but brief intervention was more cost-effective for most substances. Sixty-nine (67%) of the original performance sites adapted and redesigned SBIRT service delivery after initial grant funding ended. Four factors influenced SBIRT sustainability: presence of program champions, availability of funding, systemic change and effective management of SBIRT provider challenges. CONCLUSIONS: The US Substance Abuse and Mental Health Services Administration's Screening, Brief Intervention and Referral to Treatment (SBIRT) demonstration program was adapted successfully to the needs of early identification efforts for hazardous use of alcohol and illicit drugs. SBIRT is an innovative way to integrate the management of substance use disorders into primary care and general medicine. Screening, Brief Intervention and Referral to Treatment implementation was associated with improvements in treatment system equity, efficiency and economy. PMID- 28074570 TI - Development of the SBIRT checklist for observation in real-time (SCORe). AB - BACKGROUND AND AIMS: Screening, Brief Intervention and Referral to Treatment (SBIRT) programs have been implemented widely in medical settings, with little attention focused on how well providers adhere to evidence-based service delivery in everyday practice. The purposes of this paper were to: (1) introduce a flexible, relatively simple methodology, the SBIRT Checklist for Observation in Real-time (SCORe), to assess adherence to evidence-based practice and provide preliminary evidence supporting its criterion validity; and (2) illustrate the feasibility and potential utility of the SCORe by analyzing observations of providers within four large-scale SBIRT programs in the United States. METHODS: Eighteen potential adherence judges were trained to recognize SBIRT service elements presented in realistic taped portrayals constructed to serve as criterion coding standards. Across the four SBIRT programs, 76 providers were observed performing 388 services in three types of medical settings; emergency departments (n = 10), hospital out-patient/ambulatory clinics (n = 16) and hospital in-patient settings (n = 5). RESULTS: Across two exercises, trainees identified 81% of screening and 75% of brief intervention (BI) elements correctly; for the six FRAMES components (Feedback, Responsibility, Advice, Menu of options, Empathy, Self-efficacy), agreement ranged from 69% to 91%. Across programs, 56% of screening, 54% of brief intervention (BI) (81% of FRAMES) and 53% of referral to treatment elements were observed. Programs differed significantly in adherence [screening, P = 0.024; BI, P < 0.001; FRAMES, P < 0.001; referral to treatment (RT), P < 0.001]; medical setting differences were minimal. CONCLUSIONS: The Screening, Brief Intervention and Referral to Treatment Checklist for Observation in Real-time provides a flexible method for assessing adherence to evidence-based Screening, Brief Intervention and Referral to Treatment service protocols. Preliminary evidence supports the criterion validity, feasibility and potential utility of the Screening, Brief Intervention and Referral to Treatment Checklist for Observation in Real-time protocol. PMID- 28074571 TI - Screening, brief intervention and referral to treatment (SBIRT): implementation barriers, facilitators and model migration. AB - AIMS: To identify barriers and facilitators associated with initial implementation of a US alcohol and other substance use Screening, Brief Intervention, and Referral to Treatment (SBIRT) grant program, and to identify modifications in program design that addressed implementation challenges. DESIGN: A mixed-method approach used quantitative and qualitative data, including SBIRT provider ratings of implementation barriers and facilitators, staff interview responses and program documentation. SETTING: Multiple sites within the first seven programs funded in a national demonstration program in the United States. PARTICIPANTS: One hundred and two SBIRT providers were surveyed; 221 SBIRT stakeholders and staff were interviewed. MEASUREMENTS: Mean ratings of barriers and facilitators were calculated using provider survey responses. An inductive content analysis of interview responses identified factors perceived to support and challenge implementation; program modifications that occurred over time were recorded. FINDINGS: Providers rated pre-selected implementation facilitators higher than barriers. Content analysis of interview responses revealed six themes: committed leaders; intra- and inter-organizational communication/collaboration; provider buy-in and model acceptance; contextual factors; quality assurance; and grant requirements. Over time, programs tended to: adopt more efficient 'pre-screen' item sets; screen for risk factors in addition to alcohol/substance use; use contracted specialists to deliver SBIRT services; conduct services in high-volume emergency department and trauma center settings; and implement on-site and telephonic treatment delivery. CONCLUSIONS: Screening, Brief Intervention and Referral to Treatment program implementation in the United States is facilitated by committed leadership and the use of substance use specialists, rather than medical generalists, to deliver services. Many implementation challenges can be addressed by an adequate start-up phase focused on comprehensive education and training, and on the development of intra- and inter-organizational communication and collaboration; opinion leader support; and practitioner and host site buy-in. PMID- 28074572 TI - The SBIRT program matrix: a conceptual framework for program implementation and evaluation. AB - BACKGROUND AND AIMS: Screening, Brief Intervention and Referral to Treatment (SBIRT) is a comprehensive, integrated, public health approach to the delivery of services to those at risk for the adverse consequences of alcohol and other drug use, and for those with probable substance use disorders. Research on successful SBIRT implementation has lagged behind studies of efficacy and effectiveness. This paper (1) outlines a conceptual framework, the SBIRT Program Matrix, to guide implementation research and program evaluation and (2) specifies potential implementation outcomes. METHODS: Overview and narrative description of the SBIRT Program Matrix. RESULTS: The SBIRT Program Matrix has five components, each of which includes multiple elements: SBIRT services; performance sites; provider attributes; patient/client populations; and management structure and activities. Implementation outcomes include program adoption, acceptability, appropriateness, feasibility, fidelity, costs, penetration, sustainability, service provision and grant compliance. CONCLUSIONS: The Screening, Brief Intervention and Referral to Treatment Program Matrix provides a template for identifying, classifying and organizing the naturally occurring commonalities and variations within and across SBIRT programs, and for investigating which variables are associated with implementation success and, ultimately, with treatment outcomes and other impacts. PMID- 28074574 TI - Editorial for December JCD. PMID- 28074573 TI - Structural, Functional, and Clinical Characterization of a Novel PTPN11 Mutation Cluster Underlying Noonan Syndrome. AB - Germline mutations in PTPN11, the gene encoding the Src-homology 2 (SH2) domain containing protein tyrosine phosphatase (SHP2), cause Noonan syndrome (NS), a relatively common, clinically variable, multisystem disorder. Here, we report on the identification of five different PTPN11 missense changes affecting residues Leu261 , Leu262 , and Arg265 in 16 unrelated individuals with clinical diagnosis of NS or with features suggestive for this disorder, specifying a novel disease causing mutation cluster. Expression of the mutant proteins in HEK293T cells documented their activating role on MAPK signaling. Structural data predicted a gain-of-function role of substitutions at residues Leu262 and Arg265 exerted by disruption of the N-SH2/PTP autoinhibitory interaction. Molecular dynamics simulations suggested a more complex behavior for changes affecting Leu261 , with possible impact on SHP2's catalytic activity/selectivity and proper interaction of the PTP domain with the regulatory SH2 domains. Consistent with that, biochemical data indicated that substitutions at codons 262 and 265 increased the catalytic activity of the phosphatase, while those affecting codon 261 were only moderately activating but impacted substrate specificity. Remarkably, these mutations underlie a relatively mild form of NS characterized by low prevalence of cardiac defects, short stature, and cognitive and behavioral issues, as well as less evident typical facial features. PMID- 28074575 TI - The ACA from behind the "Veil of Ignorance". AB - John Rawls posited that we could determine the nature of justice if we imagined ourselves observing conditions in society from behind a hypothetical "veil of ignorance." Not knowing how or where we would end up-rich, poor, empowered, disabled-we would choose governing principles that did not leave one disadvantaged because of his or her circumstances. Rawls's concepts are implicitly embedded in the Affordable Care Act, which guarantees that vastly more Americans can obtain health insurance. The law effectively closed down the de facto lottery that awarded coverage to most but left out millions of others. PMID- 28074576 TI - Decisions and Authority. AB - This issue of the Hastings Center Report (January-February 2017) features three articles exploring aspects of decision-making for others. In the first two, the focus is on the limits of surrogate decision-makers' authority when the surrogates' judgments about a patient's treatment conflict with the physicians'. If a physician decides that a patient will not benefit from CPR, for example, but the patient's surrogate insists on it, is the physician obliged to proceed with the procedure? Or can the physician, pointing to a duty to provide good care to the patient and not to cause the patient to suffer, get a do-not-resuscitate order for the patient-even in the face of the surrogate's objections? These are the questions that animate the first article, in which a group of authors report on a policy implemented at Massachusetts General Hospital to help doctors who face this dilemma. The second article, by physician Jeffrey Berger, flips the questions. If a physician decides that a patient's intractable suffering requires palliative sedation, may the surrogate prevent it anyway? Or can the physician, pointing to a duty to alleviate the suffering, administer palliative sedation even in the face of the surrogate's objections? Such circumstances, says Berger, show the need for conceptual work delineating the limits of surrogates' authority and practical work on mechanisms for doing so-protecting patients and giving physicians a clear route to follow. PMID- 28074577 TI - Permanent Patients: Hospital Discharge Planning Meets Housing Insecurity. AB - Not all hospital inpatients need the level of care (including staffing, testing, monitoring, and treatment) uniquely available in the acute-care setting. In the United States, these longer-term, nonacute inpatients tend to be some combination of chronically ill, poor, homeless, undocumented, uninsured, and disabled-all groups who have struggled for health equity, political recognition, and voice. Even so, these "permanent patients" continue to receive care in one of the most expensive settings. This phenomenon is the result of federal legislation that creates an affirmative duty to care for all able to access our emergency departments without also making safe housing available to all. A handful of federal laws and policies as well as a potpourri of state laws and policies are involved. PMID- 28074578 TI - Managing Conflicts between Physicians and Surrogates. AB - Two articles in this issue of the Hastings Center Report explore two sides of the same problematic coin. In "The Limits of Surrogates' Moral Authority and Physician Professionalism," Jeffrey Berger discusses the moral problem of a surrogate refusing a treatment, palliative sedation, on behalf of a patient whose suffering is refractory to intensive palliative efforts provided by a multidisciplinary team. In "After the DNR: Surrogates Who Persist in Requesting Cardiopulmonary Resuscitation," Ellen Robinson and her colleagues analyze data from a study of cases in which physicians wished not to perform cardiopulmonary resuscitation on patients whom they thought it would harm. Both articles begin from the idea of a professional determination about a physician's duty to a patient that conflicted with a surrogate's determination about what should or should not be done for that patient. Berger's argument stops just short of a solution, however, because a physician's professional obligation to help patients, even within guidelines set by other professionals, is insufficient protection for patients. But if Berger's theory is right-that sometimes surrogates lack moral authority to make decisions on behalf of patients-then the Robinson team has developed a careful and public process for attending to that conflict. PMID- 28074579 TI - Bioethics in the law. AB - The role of law in bioethics is clear. Laws are enforcement tools: they govern which conditions qualify an individual for disability benefits, or what oversight is necessary for clinical trial protocols, or how patent applications for medical devices should be regulated. I initially studied the law in order to enhance my work in bioethics, but in examining how the law works, I have become convinced that the converse opportunity also exists: there are many areas of law that would benefit from greater input from those in the bioethics community. PMID- 28074580 TI - Employer Wellness Programs Challenged in Court. AB - Many employers faced with rising health care costs have adopted "voluntary" wellness programs that urge employees to engage in various health-promotion activities, such as smoking cessation and weight reduction. In the proper setting, measures to promote a more healthful lifestyle are difficult to question, but there is little compelling evidence that workplace wellness programs have significant, sustained health benefits or substantially reduce health care costs other than through cost-shifting to unhealthy employees. Congressional support for workplace wellness programs has persisted on a bipartisan basis for the last twenty years, and the incentives that current statutes allow employers to offer employees have become strong enough that the voluntariness of the programs has been called into question. In recent months, the battleground has shifted to the courts, where federal regulations and employer practices have been challenged. Three recent or pending cases raise questions about whether the incentives are coercing employees into the programs. PMID- 28074581 TI - Conflating Capacity & Authority: Why We're Asking the Wrong Question in the Adolescent Decision-Making Debate. AB - Whether adolescents should be allowed to make their own medical decisions has been a topic of discussion in bioethics for at least two decades now. Are adolescents sufficiently capacitated to make their own medical decisions? Is the mature-minor doctrine, an uncommon legal exception to the rule of parental decision-making authority, something we should expand or eliminate? Bioethicists have dealt with the curious liminality of adolescents-their being neither children nor adults-in a variety of ways. However, recently there has been a trend to rely heavily, and often exclusively, on emerging neuroscientific and psychological data to answer these questions. Using data from magnetic resonance imaging and functional MRI studies on the adolescent brain, authors have argued both that the adolescent brain isn't sufficiently mature to broadly confer capacity on this population and that the adolescent brain is sufficiently mature to assume adolescent capacity. Scholars then accept these data as sufficient for concluding that adolescents should or should not have decision-making authority. Two critical mistakes are being made here. The first is the expectation that neuroscience or psychology is or will be able to answer all our questions about capacity. The second, and more concerning, mistake is the conflation of decision making capacity with decision-making authority. PMID- 28074583 TI - Show Code. AB - "Let's get one thing straight: there is no such thing as a show code," my attending asserted, pausing for effect. "You either try to resuscitate, or you don't. None of this halfway junk." He spoke so loudly that the two off-service consultants huddled at computers at the end of the unit looked up... We did four rounds of compressions and pushed epinephrine twice. It was not a long code. We did good, strong compressions and coded this man in earnest until the end. Toward the final round, though, as I stepped up to do compressions, my attending looked at me in a deep way. It was a look in between willing me as some object under his command and revealing to me everything that lay within his brash, confident surface but could not be spoken. PMID- 28074584 TI - The Limits of Surrogates' Moral Authority and Physician Professionalism: Can the Paradigm of Palliative Sedation Be Instructive? AB - With narrow exception, physicians' treatment of incapacitated patients requires the consent of health surrogates. Although the decision-making authority of surrogates is appropriately broad, their moral authority is not without limits. Discerning these bounds is particularly germane to ethically complex treatments and has important implications for the welfare of patients, for the professional integrity of clinicians, and, in fact, for the welfare of surrogates. Palliative sedation is one such complex treatment; as such, it provides a valuable model for analyzing the scope of surrogates' moral authority. Guidelines for palliative sedation that present it as a "last-resort" treatment for severe and intractable suffering yet require surrogate consent in order to offer it are ethically untenable, precisely because the moral limits of surrogate authority have not been considered. PMID- 28074585 TI - A Good Death. AB - A good death is hard to find. Family members tell us that loved ones die in the wrong place-the hospital-and do not receive high-quality care at the end of life. This issue of the Hastings Center Report offers two articles from authors who strive to provide good end-of-life care and to prevent needless suffering. We agree with their goals, but we have substantial reservations about the approaches they recommend. Respect for the decisions of patients and their surrogates is a relatively new and still vulnerable aspect of medical care. For thousands of years, patients and surrogates had no say in medical decision-making. Today, standards support shared decision-making, but these articles both carve out exceptions to those standards, limiting the rights of patients and families in decisions about specific end-of-life treatments. As bioethics consultants in an acute care setting, we frequently confront conflicts similar to those described by Jeffrey Berger and by Ellen Robinson and colleagues. In such cases, our service emphasizes redoubled efforts at communication and mediation. Focusing on goals and values, rather than interventions, produces the best possible collaboration in health care decision-making. Cases in which we would overturn a surrogate's recommendations regarding palliative sedation or do-not-resuscitate orders are rare and require careful processes and clear evidence that the surrogate's choice is contrary to patient values. PMID- 28074586 TI - The Theory and Practice of Surrogate Decision-Making. AB - When a patient lacks decision-making capacity and has not left a clear advance directive, there is now widespread agreement that patient-designated and next-of kin surrogates should implement substituted judgment within a process of shared decision-making. Specifically, after discussing the "best scientific evidence available, as well as the patient's values, goals, and preferences" with the patient's clinicians, the patient-designated or next-of-kin surrogate should attempt to determine what decision the patient would have made in the circumstances. To the extent that this approach works, it seems to provide about as much respect for the autonomy of incapacitated patients as we could ask for. But, as articles in this issue of the Report by Jeffrey Berger and by Ellen Robinson and colleagues emphasize, reality presents challenges. PMID- 28074587 TI - After the DNR: Surrogates Who Persist in Requesting Cardiopulmonary Resuscitation. AB - Some health care organizations allow physicians to withhold cardiopulmonary resuscitation from a patient, despite patient or surrogate requests that it be provided, when they believe it will be more harmful than beneficial. Such cases usually involve patients with terminal diagnoses whose medical teams argue that aggressive treatments are medically inappropriate or likely to be harmful. Although there is state-to-state variability and a considerable judicial gray area about the conditions and mechanisms for refusals to perform CPR, medical teams typically follow a set of clearly defined procedures for these decisions. The procedures are based on the principle of nonmaleficence and typically include consultation with hospital ethics committees, reflecting the guidelines of relevant professional associations. Ethical debates about when CPR can and should be limited tend to rely more on discussions of theory, principles, and case studies than systematic empirical study of the situations in which such limitations are applied. Sociologists of bioethics call for empirical study, arguing that what ethicists and health professionals believe they are doing when they draft policies or invoke principles does not always mirror what is happening on the ground. In this article, we begin the task of modeling the empirical analyses sociologists call for, focusing on a cohort at Massachusetts General Hospital. We inductively analyzed ethics committee notes and medical records of nineteen patients whose surrogates did not accept the decision to withhold CPR. PMID- 28074588 TI - Care under the Influence. AB - A forty-year-old man is brought to the emergency room by his wife at five in the morning, two hours after he fell down the stairs at home, hitting his head and injuring his arm. He tells the ER physician that he got up to get a drink of water and tripped in the dark. His speech is slurred, and he smells strongly of alcohol. Lab results reveal elevated liver enzymes, and his blood alcohol level is 0.1. His medical history is unremarkable. When asked about his alcohol consumption, he says he usually has one or two drinks a night with dinner but that he drinks more on holidays and special occasions. He admits he had more to drink than usual last night because it had been a stressful day at work, but he is vague about how much he drank. His wife takes the ER physician aside and describes a very different situation. She says that her husband regularly has three or four drinks a night. She always goes to bed before he does and thinks he stays up later so he can continue to drink. She says that he often has no memory of conversations they had the night before and is concerned because he makes work related calls at night. When asked what he does for a living, she hesitates, and then answers that he is an internist. He does not work at this hospital but works at one of its affiliated clinics. The ER doctor is concerned that his patient is an impaired physician. Yet when the admitting hospitalist, to whom he explains the situation, asks if he really wants to "go there," he shrugs his shoulders. "I suppose," she replies, "you might as well call an ethics consult." PMID- 28074589 TI - On Patient Well-being and Professional Authority. AB - Two papers in this issue address the limits of surrogates' authority when making life-and-death decisions for dying family members or friends. Using palliative sedation as an example, Jeffrey Berger offers a conceptual argument for bounding surrogate authority. Since freedom from pain is an essential interest, when imminently dying, cognitively incapacitated patients are in duress and their symptoms are not manageable in any other way, clinicians should be free to offer palliative sedation without surrogate consent, although assent should be sought and every effort made to work with surrogates as harmoniously as possible. Ellen Robinson and her colleagues report on the implementation of a policy at Massachusetts General Hospital that supports do-not-resuscitate orders when cardiopulmonary resuscitation is likely to be ineffective or harmful, even if surrogates disagree. The "Doing No Harm" policy at MGH allows for what MGH calls a "medically indicated DNR" and what in some other places is called "a unilateral DNR"-the writing of an order not to provide cardiopulmonary resuscitation, regardless of surrogate disapproval. These kinds of DNR policies have emerged in some hospitals across the country and for much the same reason that Berger provides in his argument regarding palliative sedation. I support the reasoning and the policies in both the Berger and Robinson papers. However, as the authors would most likely agree, the problems they aim to remedy are not simply about the scope of surrogate and professional authority. They are also symptoms of inattention to professional obligations and system failures. PMID- 28074590 TI - Improving clinical handover in a paediatric ward: implications for nursing management. AB - AIM: To describe how nursing staff in a paediatric ward improved the conduct of clinical handover, using a practise development approach. BACKGROUND: ISBAR (Identify, Situation, Background, Assessment and Recommendation) is a mnemonic tool to aid the safe transfer of patient information in clinical handover. The nurses identified the need to improve the use of ISBAR, and other issues related to handover that could compromise patient safety and constrain family-centred care. METHOD: Sixty-one percent of nurses on the ward contributed to issue identification and the design of the educational material, including a set of written and video resources and incorporating the role of a handover coach. Staff performance was evaluated before and after access to the resources using self administered Likert scales, observation and a focus group. RESULTS: After the intervention, there was a stronger relationship between the participants' understanding of ISBAR and their application of it in handover. Further, there were statistically significant increases in improved handover practises, including family inclusion and safety checks. IMPLICATIONS FOR NURSING MANAGEMENT: A practise development approach is useful in the provision of education to guide clinical performance in patient handover. Nurse managers can use this approach to empower their staff to make positive changes to practise. PMID- 28074591 TI - Variations in crestal cortical bone thickness at dental implant sites in different regions of the jawbone. AB - BACKGROUND: Dental implants have become reliable and predictable tools for treating missing teeth. The survival rate of dental implants is markedly influenced by the host bone quality and quantity of the jawbone. A better host bone provides higher initial stability of the dental implant, resulting in better osseointegration and a higher success rate. Host bone quality and quantity are determined by the crestal cortical bone thickness and inner cancellous bone density. OBJECTIVE: The purpose of this study was to determine the crestal cortical bone thickness at dental implant sites in different regions of the jawbone through the use of dental cone-beam computed tomographic (CBCT) images. MATERIALS AND METHODS: A total of 661 dental implant sites (81 in the anterior mandible, 122 in the anterior maxilla, 224 in the posterior mandible, and 234 in the posterior maxilla) were obtained from the jawbones of 173 humans. The data were subjected to statistical analysis to determine any correlation between crestal cortical bone thicknesses and jawbone regions using one-way analysis of variance with Tukey's post-test. RESULTS: The crestal cortical bone thicknesses at dental implant sites in the four regions decreased in the following order: posterior mandible (1.07 +/- 0.47 mm, mean +/- SD) >anterior mandible (0.99 +/- 0.36 mm) >anterior maxilla (0.82 +/- 0.30 mm) >posterior maxilla (0.75 +/- 0.35 mm). CONCLUSION: The dental CBCT data demonstrate that crestal cortical bone thickness varies markedly between dental implant sites in the four regions of the jawbone. PMID- 28074592 TI - Birthweight and site of osteosarcoma development. PMID- 28074594 TI - Iridium-Catalyzed Intramolecular Asymmetric Allylic Dearomatization Reaction of Benzoxazoles, Benzothiazoles, and Benzimidazoles. AB - An iridium-catalyzed intramolecular asymmetric allylic dearomatization reaction of benzoxazoles, benzothiazoles, and benzimidazoles was developed. The reaction was found to be compatible with a wide range of five-membered-ring electron deficient heteroaromatic compounds and furnished the corresponding dearomatized heterocycles in high yield with excellent enantioselectivity. PMID- 28074593 TI - Microtubule-associated protein 1B: Novel paraneoplastic biomarker. AB - OBJECTIVE: To report the identification of microtubule-associated protein (MAP) 1B as the antigen of the previously described Purkinje cell cytoplasmic antibody type 2 (PCA-2) antibody, its frequency, and clinical, oncological, and serological associations. METHODS: Archival serum or cerebrospinal fluid (CSF) specimens were available from 96 of 118 consecutive PCA-2-IgG-seropositive patients identified during 1993-2016. The autoantigen, defined in mouse brain lysate by Western blot and mass spectrometry, was confirmed by dual immunohistochemical staining using commercial antibodies. The major antigenic region was defined by Western blot using recombinant protein fragments. RESULTS: IgG in 95 of 96 patients' serum or CSF (but in none of 98 healthy or disease control subjects' serum specimens) bound to recombinant MAP1B. A minority (17.5%) of patients' IgG also bound to MAP1A. PCA-2 was often accompanied by additional neural autoantibody markers of small-cell carcinoma, including collapsin response mediated protein 5 (CRMP5) IgG (26%) or antineuronal nuclear antibody type 1 (ANNA-1) IgG (also known as anti-Hu; 13%). Neurological manifestations in 95 patients were (in decreasing frequency): peripheral neuropathy, 53%; cerebellar ataxia, dysmetria, or dysarthria, 38%; and encephalopathy, 27%. Cancer (majority small-cell lung carcinoma [SCLC]) was detected in 66 of 84 evaluated patients (79%). The MAP1B (PCA-2) autoantibody detection rate, among approximately 70,000 patients undergoing service neural autoantibody evaluation in 2015, was 0.024%, equaling amphiphysin IgG (0.026%) and more common than ANNA-2 (also known as anti Ri; 0.016%) and PCA-Tr (also known as delta/notch-like epidermal growth factor related receptor [DNER]; 0.006%). INTERPRETATION: MAP1B, the PCA-2 autoantigen, represents a novel target in paraneoplastic neurological disorders and has high predictive value for SCLC. Its relatively high prevalence, compared with other recognized paraneoplastic neural autoantibodies, justifies its testing in comprehensive paraneoplastic neural autoantibody evaluation. Ann Neurol 2017;81:266-277. PMID- 28074595 TI - Providing opportunistic immunisations for at-risk inpatients in a tertiary paediatric hospital. AB - Attaining high immunisation coverage rates for children with medical conditions is vital. The Royal Children's Hospital (RCH) Immunisation Service has the opportunity to check each inpatient's immunisation status and provide opportunistic vaccines and/or bring the Australian Childhood Immunisation Register (ACIR) up-to-date. This paper highlights that during admission, one quarter of children were not up-to-date with routine scheduled immunisations and 42% of those inpatients due or overdue for immunisation were vaccinated. The model of establishing routine checking of immunisation records and reminding hospital staff about immunisation can result in improvements in vaccination coverage. Healthcare providers have a responsibility to check immunisation status and offer vaccines when necessary; however, often there are missed opportunities to immunise. This paper demonstrates that having a dedicated Immunisation Service, a partnership with a relevant government agency, and effective collaboration with inpatient clinical teams, opportunistic immunisation can be achieved for inpatients. PMID- 28074596 TI - Full-length sequence of 2 HLA-B alleles, B*52:01:01:01 and B*52:01:02:01, identified by cloning and sequencing. AB - Full-length sequence of HLA-B*52:01:01:01 and B*52:01:02:01, identified by cloning and sequencing in Chinese donors. PMID- 28074597 TI - Convergence of bark investment according to fire and climate structures ecosystem vulnerability to future change. AB - Fire regimes in savannas and forests are changing over much of the world. Anticipating the impact of these changes requires understanding how plants are adapted to fire. In this study, we test whether fire imposes a broad selective force on a key fire-tolerance trait, bark thickness, across 572 tree species distributed worldwide. We show that investment in thick bark is a pervasive adaptation in frequently burned areas across savannas and forests in both temperate and tropical regions where surface fires occur. Geographic variability in bark thickness is largely explained by annual burned area and precipitation seasonality. Combining environmental and species distribution data allowed us to assess vulnerability to future climate and fire conditions: tropical rainforests are especially vulnerable, whereas seasonal forests and savannas are more robust. The strong link between fire and bark thickness provides an avenue for assessing the vulnerability of tree communities to fire and demands inclusion in global models. PMID- 28074599 TI - Functionalization of C-H Bonds by Photoredox Catalysis. AB - Visible-light photoredox catalysis has been successfully used in the functionalization of inert C-H bonds including C(sp2 )-H bonds of arenes and C(sp3 )-H bonds of aliphatic compounds over the past decade. These transformations are typically promoted by the process of single-electron-transfer (SET) between substrates and photo-excited photocatalyst upon visible light irradiation (household bulbs or LEDs). Compared with other synthetic strategies, such as the transition-metal catalysis and traditional radical reactions, visible light photoredox approach has distinct advantages in terms of operational simplicity and practicability. Versatile direct functionalization of inert C(sp2 )-H and C(sp3 )-H bonds including alkylation, trifluoromethylation, arylation and amidation, has been achieved using this practical strategy. PMID- 28074600 TI - Analyzing multiple endpoints in a confirmatory randomized clinical trial-an approach that addresses stratification, missing values, baseline imbalance and multiplicity for strictly ordinal outcomes. AB - Confirmatory randomized clinical trials with a stratified design may have ordinal response outcomes, ie, either ordered categories or continuous determinations that are not compatible with an interval scale. Also, multiple endpoints are often collected when 1 single endpoint does not represent the overall efficacy of the treatment. In addition, random baseline imbalances and missing values can add another layer of difficulty in the analysis plan. Therefore, the development of an approach that provides a consolidated strategy to all issues collectively is essential. For a real case example that is from a clinical trial comparing a test treatment and a control for the pain management for patients with osteoarthritis, which has all aforementioned issues, multivariate Mann-Whitney estimators with stratification adjustment are applicable to the strictly ordinal responses with stratified design. Randomization based nonparametric analysis of covariance is applied to account for the possible baseline imbalances. Several approaches that handle missing values are provided. A global test followed by a closed testing procedure controls the family wise error rate in the strong sense for the analysis of multiple endpoints. Four outcomes indicating joint pain, stiffness, and functional status were analyzed collectively and also individually through the procedures. Treatment efficacy was observed in the combined endpoint as well as in the individual endpoints. The proposed approach is effective in addressing the aforementioned problems simultaneously and straightforward to implement. PMID- 28074598 TI - Prediction of skin sensitization potency using machine learning approaches. AB - The replacement of animal use in testing for regulatory classification of skin sensitizers is a priority for US federal agencies that use data from such testing. Machine learning models that classify substances as sensitizers or non sensitizers without using animal data have been developed and evaluated. Because some regulatory agencies require that sensitizers be further classified into potency categories, we developed statistical models to predict skin sensitization potency for murine local lymph node assay (LLNA) and human outcomes. Input variables for our models included six physicochemical properties and data from three non-animal test methods: direct peptide reactivity assay; human cell line activation test; and KeratinoSensTM assay. Models were built to predict three potency categories using four machine learning approaches and were validated using external test sets and leave-one-out cross-validation. A one-tiered strategy modeled all three categories of response together while a two-tiered strategy modeled sensitizer/non-sensitizer responses and then classified the sensitizers as strong or weak sensitizers. The two-tiered model using the support vector machine with all assay and physicochemical data inputs provided the best performance, yielding accuracy of 88% for prediction of LLNA outcomes (120 substances) and 81% for prediction of human test outcomes (87 substances). The best one-tiered model predicted LLNA outcomes with 78% accuracy and human outcomes with 75% accuracy. By comparison, the LLNA predicts human potency categories with 69% accuracy (60 of 87 substances correctly categorized). These results suggest that computational models using non-animal methods may provide valuable information for assessing skin sensitization potency. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28074601 TI - Boraformylation and Silaformylation of Allenes. AB - The boraformylation of allenes with B2 (pin)2 and a formate ester as boron and formyl source, respectively, proceeds in the presence of a copper catalyst. The reaction selectively affords the corresponding beta-boryl beta,gamma-unsaturated aldehydes in good to high yields. Furthermore, the silaformylation of allenes was achieved with a formate ester and PhMe2 Si-B(pin) as the silicon source. PMID- 28074602 TI - Direct MALDI-MS analysis of the disulfide bonds in peptide using thiosalicylic acid as a reactive matrix. AB - The ability of a thiol-containing molecule, thiosalicylic acid (TSA), to function as a reactive matrix for matrix-assisted laser desorption/ionization (MALDI) mass spectrometry analysis of peptides has been investigated. Although TSA has reducing characteristics, the use of TSA did not cause a reduction-induced MALDI in-source decay, probably because of the weak interactions between the thiol group in TSA and the carboxyl oxygen in the peptide. In contrast, when peptides containing disulfide bonds were analyzed by MALDI with TSA as the matrix, the disulfide bond was partially cleaved owing to the reaction with TSA, producing TSA-adducted peptides. The reaction between the disulfide bond and TSA was suggested to be occurred in solution. The comparison of the MALDI mass spectra obtained using conventional matrix and TSA allows us to count the number of disulfide bonds in the peptides. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28074603 TI - Supplementing diet with Manitoba lingonberry juice reduces kidney ischemia reperfusion injury. AB - BACKGROUND: Lingonberry (Vaccinium vitis-idaea L.) contains high levels of anthocyanins which are bioavailable in the kidney and may be protective against ischemia-reperfusion (IR)-induced acute kidney injury. This study investigated the effect of lingonberry juice on the IR-induced stress-activated signalling pathway and inflammatory response in the kidney. RESULTS: Sprague-Dawley rats subjected to kidney IR had significantly impaired kidney function, with increased activation of the JNK signalling pathway and increased inflammatory response, measured using a multiplex panel containing an extensive array of inflammatory biomarkers. In rats fed 1 mL lingonberry juice daily for 3 weeks prior to IR, kidney function was protected and attenuation of inflammatory response and JNK signalling was reflected in the reduction of the measured biomarkers. In vitro results in cultured HK-2 cells confirmed that lingonberry anthocyanins reduced JNK signalling and inflammatory gene expression after IR. CONCLUSION: This study shows, for the first time, that daily supplementation with lingonberry juice may protect against loss of kidney function induced by IR injury by modulating JNK signalling and inhibiting the subsequent inflammatory response. (c) 2017 Her Majesty the Queen in Right of Canada. Journal of the Science of Food and Agriculture (c) 2017 Society of Chemical Industry. PMID- 28074604 TI - Visible-Light-Triggered Activation of a Protein Kinase Inhibitor. AB - A photoresponsive small molecule undergoes a ring-opening reaction when exposed to visible light and becomes an active inhibitor of the enzyme protein kinase C. This "turning on" of enzyme inhibition with light puts control into the hands of the user, creating the opportunity to regulate when and where enzyme catalysis takes place. PMID- 28074605 TI - Eye-tracking-based assessment suggests preserved well-being in locked-in patients. AB - We assessed quality of life (QoL) and psychological well-being in patients with amyotrophic lateral sclerosis-induced locked-in state and their next of kin in a fully unbiased manner using eye-tracking computer systems. Eleven of 30 screened patients and 9 next of kin completed study procedures. Patients reported good QoL, which appeared to be at the cost of the QoL of their next of kin. Next of kin rated their own or patients' QoL similarly, but they identified different areas as important as compared with patients. Our results are of importance for the discussion of end-of-life decisions and the evaluation of patients' presumed wishes as well as for psychosocial interventions. Ann Neurol 2017;81:310-315. PMID- 28074606 TI - Assembly of Ring-Shaped Phosphorus within Carbon Nanotube Nanoreactors. AB - A phosphorus allotrope that has not been observed so far, ring-shaped phosphorus consisting of alternate P8 and P2 structural units, has been assembled inside multi-walled carbon nanotube nanoreactors with inner diameters of 5-8 nm by a chemical vapor transport and reaction of red phosphorus at 500 degrees C. The ring-shaped nanostructures with surrounding graphene walls are stable under ambient conditions. The nanostructures were characterized by high-resolution transmission electron microscopy, scanning transmission electron microscopy, energy-dispersive X-ray spectroscopy, Raman scattering, attenuated total reflectance Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. PMID- 28074607 TI - The use of intravenous pentamidine for the prophylaxis of Pneumocystis pneumonia in pediatric patients. AB - Pneumocystis jiroveci pneumonia was common in the immunocompromised host before the widespread use of prophylaxis. When trimethoprim-sulfamethoxazole is not tolerated, prophylaxis with intravenous pentamidine (IVP) may be initiated. We performed a retrospective analysis of all pediatric patients who received IVP regarding efficacy, safety, and reason for initiation. Of 106 patients included in our analysis, one patient tested positive for Pneumocystis DNA. Adverse events were reported in 18% of IVP courses, and main reason for initiation was cytopenia (59%). We found IVP to be effective and safe, and recommend the use of IVP in pediatric patients in whom first-line prophylaxis is contraindicated. PMID- 28074608 TI - Aged garlic extract suppresses the increase of plasma glycated albumin level and enhances the AMP-activated protein kinase in adipose tissue in TSOD mice. AB - SCOPE: In this study, we investigated the effect of aged garlic extract (AGE) on the high level of blood glucose in Tsumura Suzuki Obese-Diabetes (TSOD) mice. METHODS AND RESULTS: TSOD mice were fed standard diet with or without 2% AGE for 19 weeks. AGE treatment lowered the blood glucose level and significantly reduced the plasma level of glycated albumin in TSOD mice as compared with those without AGE treatment. In addition, AGE treatment increased the level of phosphorylated AMP-activated protein kinase (AMPK) in the adipose tissue, liver and muscle that played an important role in the maintenance of insulin sensitivity. Moreover, AGE treatment also suppressed the mRNA expression of fatty acid synthase, a known factor regulated by AMPK, and monocyte chemoattractant protein 1, one of the representative inflammatory chemokines, in the adipose tissue but not in the liver. CONCLUSION: AGE treatment suppresses the increase of plasma glycated albumin level in TSOD mice and this effect is accompanied by the activation of AMPK in adipose tissue, and suggests that AGE may play a potential role in the prevention and treatment of type 2 diabetes. PMID- 28074609 TI - Rapid chemical shift encoding with single-acquisition single-slab 3D GRASE. AB - PURPOSE: To investigate the feasibility of chemical shift encoded, single-slab 3D GRASE for rapid fat-water separation within a single acquisition. METHODS: The proposed method incorporates signal-to-noise-ratio-optimal chemical shift encoding into single-slab 3D GRASE with variable flip angles. Chemical shift induced phase information was encoded in succession to different positions in k space by inserting phase encoding blips between adjacent lobes of the oscillating readout gradients. To enhance imaging efficiency, signal prescription-based variable flip angles were used in the long refocusing pulse train. After echo independent phase correction, missing signals in k-echo space were interpolated using convolution kernels that span over all echoes. Fat-water separation in a single acquisition was performed using both multi-echo fast spin echo and GRASE as compared to conventional multiacquisition fast spin echo with echo shifts. RESULTS: The proposed single-slab 3D GRASE shows superior performance in accurately delineating cartilage structures compared to its counterpart, multi echo 3D fast spin echo. Compared with multiacquisition fast spin echo with three echo shifts (63 min), the proposed method substantially speeds up imaging time (7 min), and achieves 0.6 mm isotropic resolution in knee imaging with reduced artifacts and noise. CONCLUSION: We successfully demonstrated the feasibility of rapid chemical shift encoding and separation using the proposed, single acquisition single-slab 3D GRASE for high resolution isotropic imaging within clinically acceptable time. Magn Reson Med 78:1852-1861, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28074610 TI - An in vitro model yields 'importin' new insights into chronic traumatic encephalopathy: damaged astrocytes stop 'thrombospondin' to the injury: An Editorial Highlight for 'Defective synthesis and release of astrocytic thrombospondin-1 mediates the neuronal TDP-43 proteinopathy, resulting in defects in neuronal integrity associated with chronic traumatic encephalopathy: in vitro studies'. AB - Read the highlighted article 'Defective synthesis and release of astrocytic thrombospondin-1 mediates the neuronal TDP-43 proteinopathy, resulting in defects in neuronal integrity associated with chronic traumatic encephalopathy: in vitro studies' on page 645. PMID- 28074611 TI - Impact of physiologically based pharmacokinetic models on regulatory reviews and product labels: Frequent utilization in the field of oncology. AB - Physiologically based pharmacokinetic (PBPK) modeling can be used to predict drug pharmacokinetics in virtual populations using models that integrate understanding of physiological systems. PBPK models have been widely utilized for predicting pharmacokinetics in clinically untested scenarios during drug applications and regulatory reviews in recent years. Here, we provide a comprehensive review of the application of PBPK in new drug application (NDA) review documents from the US Food and Drug Administration (FDA) in the past 4 years. PMID- 28074612 TI - A New CuO-Fe2 O3 -Mesocarbon Microbeads Conversion Anode in a High-Performance Lithium-Ion Battery with a Li1.35 Ni0.48 Fe0.1 Mn1.72 O4 Spinel Cathode. AB - A ternary CuO-Fe2 O3 -mesocarbon microbeads (MCMB) conversion anode was characterized and combined with a high-voltage Li1.35 Ni0.48 Fe0.1 Mn1.72 O4 spinel cathode in a lithium-ion battery of relevant performance in terms of cycling stability and rate capability. The CuO-Fe2 O3 -MCMB composite was prepared by using high-energy milling, a low-cost pathway that leads to a crystalline structure and homogeneous submicrometrical morphology as revealed by XRD and electron microscopy. The anode reversibly exchanges lithium ions through the conversion reactions of CuO and Fe2 O3 and by insertion into the MCMB carbon. Electrochemical tests, including impedance spectroscopy, revealed a conductive electrode/electrolyte interface that enabled the anode to achieve a reversible capacity value higher than 500 mAh g-1 when cycled at a current of 120 mA g-1 . The remarkable stability of the CuO-Fe2 O3 -MCMB electrode and the suitable characteristics in terms of delivered capacity and voltage-profile retention allowed its use in an efficient full lithium-ion cell with a high-voltage Li1.35 Ni0.48 Fe0.1 Mn1.72 O4 cathode. The cell had a working voltage of 3.6 V and delivered a capacity of 110 mAh gcathode-1 with a Coulombic efficiency above 99 % after 100 cycles at 148 mA gcathode-1 . This relevant performances, rarely achieved by lithium-ion systems that use the conversion reaction, are the result of an excellent cell balance in terms of negative-to-positive ratio, favored by the anode composition and electrochemical features. PMID- 28074613 TI - Health benefits of methylxanthines in neurodegenerative diseases. AB - Methylxanthines (MTXs) are consumed by almost everybody in almost every area of the world. Caffeine, theophylline and theobromine are the most well-known members of this family of compounds; they are present, inter alia, in coffee, tea, cacao, yerba mate and cola drinks. MTXs are readily absorbed in the gastrointestinal tract and are able to penetrate into the central nervous system, where they exert significant psychostimulant actions, which are more evident in acute intake. Coffee has been paradigmatic, as its use was forbidden in many diseases, however, this negative view has radically changed; evidence shows that MTXs display health benefits in diseases involving cell death in the nervous system. This paper reviews data that appraise the preventive and even therapeutic potential of MTXs in a variety of neurodegenerative diseases. Future perspectives include the use of MTXs to advance the understanding the pathophysiology of, inter alia, Alzheimer's disease (AD) and Parkinson's disease (PD), and the use of the methylxanthine chemical moiety as a basis for the development of new and more efficacious drugs. PMID- 28074614 TI - Mutation analysis and gene expression profiling of ocular melanomas in cats. AB - Feline ocular melanomas show a high malignant behaviour, but adjunctive therapies are non-existent. The aim of this pilot study was to determine, whether feline ocular melanomas harbour mutations comparable to mutations in human melanomas and to evaluate the gene expression status of genes known to be involved in initiation and progression of human melanomas. Mutation hotspot regions of several genes of feline ocular melanomas were analysed by DNA sequencing and RNA expression levels of the respective genes and others were evaluated by quantitative real-time polymerase chain reaction (RT-qPCR). Common mutations found in human melanomas are not present in feline tumours. Gene expression analysis revealed a significant upregulation of KIT and LTA4H, as well as a downregulation of GNAQ, GNA11, BRAF and RASSF1 in feline ocular melanomas. As KIT seems to harbour a potential as target gene in human uveal melanomas, future studies should further investigate the potential of KIT as target for adjunctive therapy in feline ocular melanomas. PMID- 28074615 TI - Database of Optimized Proteomic Quantitative Methods for Human Drug Disposition Related Proteins for Applications in Physiologically Based Pharmacokinetic Modeling. AB - The purpose of this study was to create an open access repository of validated liquid chromatography tandem mass spectrometry (LC-MS/MS) multiple reaction monitoring (MRM) methods for quantifying 284 important proteins associated with drug absorption, distribution, metabolism, and excretion (ADME). Various in silico and experimental approaches were used to select surrogate peptides and optimize instrument parameters for LC-MS/MS quantification of the selected proteins. The final methods were uploaded to an online public database (QPrOmics; www.qpromics.uw.edu/qpromics/assay/), which provides essential information for facile method development in triple quadrupole mass spectrometry (MS) instruments. To validate the utility of the methods, the differential tissue expression of 107 key ADME proteins was characterized in the tryptic digests of the pooled subcellular fractions of human liver, kidneys, intestines, and lungs. These methods and the data are critical for development of physiologically based pharmacokinetic (PBPK) models to predict xenobiotic disposition. PMID- 28074616 TI - Is Hemodialysis Patient Survival Dependent upon Small Solute Clearance (Kt/V)?: If So How Can Kt/V be Adjusted to Prevent Under Dialysis in Vulnerable Groups? AB - Small solute clearance achieved during a single hemodialysis session has been traditionally evaluated by urea clearance, normalized for total body water (Kt/Vurea) for more than 30 years. By consensus, the target sessional KtVurea for thrice weekly treatments has been increased from 0.9 to 1.2 over the years. Although this is supported by observational studies, there is a fundamental lack of prospective studies to support this threshold target. In clinical practice achieving sessional Kt/Vurea targets are most closely followed in the US. Yet there appears to be a paradox in that by following Kt/Vurea targets in the US hemodialysis patient survival is better for men and the obese, the opposite of what is seen in the general population. Delivery of a lower dose of hemodialysis to women and smaller men can be explained by underestimation of total body water. The advent of bioimpedance techniques which can measure both body water and body composition will potentially allow a rescaling and re-evaluation of the importance of small solute clearances (Kt/Vurea) in the hemodialysis patient population. PMID- 28074617 TI - Soft drink intake and the risk of metabolic syndrome: A systematic review and meta-analysis. AB - BACKGROUND: It is unclear whether consumption of sugar- or artificially sweetened beverages is independently associated with the development of metabolic syndrome. A systematic review and meta-analysis was performed to evaluate whether soft drink consumption is associated with the development of metabolic syndrome. METHODS: Medline and EMBASE were searched in November 2015 for studies which considered soft drink (sugar-sweetened beverage [SSB] and artificially sweetened beverage [ASB]) intake and risk of metabolic syndrome. Pooled risk ratios for adverse outcomes were calculated using inverse variance with a random effects model, and heterogeneity was assessed using the I2 statistic. RESULTS: A total of 12 studies (eight cross-sectional, four prospective cohort studies) with 56 244 participants (age range 6-98 years) were included in the review. Our pooled analysis found that soft drink intake is associated with metabolic syndrome. This relationship is shown in cross-sectional studies of SSB consumption (RR 1.46, 95% CI 1.18-1.91) and both cross-sectional and prospective studies of ASB consumption (RR 2.45; 95% CI 1.15-5.14; RR 1.32, 95% CI 1.21-1.44, respectively). However, pooled results of prospective cohort studies of SSB consumption found no association between intake and risk of developing metabolic syndrome. CONCLUSIONS: Sugar-sweetened beverage and ASB intake are both associated with metabolic syndrome. This association may be driven by the fact that soft drink intake serves as a surrogate for an unhealthy lifestyle, or an adverse cardiovascular risk factor profile. PMID- 28074619 TI - Too busy to lead? Current challenges for German nurse leaders. PMID- 28074618 TI - Review article: dose optimisation of infliximab for acute severe ulcerative colitis. AB - BACKGROUND: Although optimal medical management of acute severe ulcerative colitis (UC) is ill-defined, infliximab has become a standard of care. Accumulating evidence suggests an increased rate of infliximab clearance in patients with acute severe UC and a reduced colectomy rate with an intensified infliximab induction regimen. AIM: To assess the strength of the current evidence for the relationship between infliximab pharmacokinetics, dosing strategies and disease behaviour in patients with acute severe UC. METHODS: We systematically searched MEDLINE and conference proceedings from 2000 to 2016 for relevant articles describing the pharmacokinetics of infliximab in acute severe UC and/or infliximab dose intensification strategies in acute severe UC. Eligible articles described randomised controlled trials, and cohort, cross-sectional, and case controlled studies. RESULTS: Of 400 citations identified, 76 studies were eligible. Increased infliximab clearance occurs in patients with acute severe UC, and is driven by the total inflammatory burden and leakage of drug into the colonic lumen. Several cohort studies suggest that infliximab dose intensification is beneficial to at least 50% of acute severe UC patients and the results of case-controlled studies indicate that an intensified infliximab dosing regimen with 1-2 additional infusions in the first 3 weeks of treatment could reduce the early (3-month) colectomy rate by up to 80%, although these data require prospective validation. CONCLUSIONS: Uncontrolled studies suggest a benefit for infliximab dose optimisation in patients with acute severe UC. A randomised controlled trial in acute severe UC patients comparing a personalised infliximab dose-optimisation strategy with conventional dosing is a research priority. PMID- 28074620 TI - Double immunostaining for maspin and p53 on cell blocks increases the diagnostic value of biliary brushing cytology. AB - Our objective is to elucidate the usefulness of maspin/p53 double immunostaining on biliary brushing cytology specimens. We first examined the expression of maspin in the biliary epithelium with variable degrees of dysplasia using surgically resected specimens (n = 56). Maspin appeared to be overexpressed in a stepwise manner from benign to malignant cholangiocytes: the reactive epithelium (20%), biliary intraepithelial neoplasia (~50%), and invasive cholangiocarcinomas (>90%). Next, an automated sequential double immunostaining protocol for maspin and p53 was applied to paraffin-embedded cell blocks of the biliary brushing cytology specimens obtained from 58 consecutive patients. Cell block preparation was successful in 44 cases (76%), which were morphologically diagnosed as adenocarcinoma (n = 16), atypical cells not diagnostic for malignancy (n = 10), and benign (n = 18). Double positive cells were observed in 14/16 (88%) morphologically malignant, 6/10 (60%) borderline, and 0/18 benign cases. All 20 positive cases were proven to have pancreatobiliary malignancies by subsequent imaging or pathological analyses. A similar staining protocol for S100P and p53 was also applied to the same cohort; however, the positive frequency was slightly lower than those of maspin and p53 (36% vs. 45%). In conclusion, Maspin/p53 double immunostaining on cell blocks contributes to the detection of malignant cells in biliary brushing cytology specimens. PMID- 28074621 TI - Total Synthesis of (-)-Tetrodotoxin and 11-norTTX-6(R)-ol. AB - The enantioselective total synthesis of (-)-tetrodotoxin [(-)-TTX] and 4,9 anhydrotetrodotoxin, which are selective blockers of voltage-gated sodium channels, was accomplished from the commercially available p-benzoquinone. This synthesis was based on efficient stereocontrol of the six contiguous stereogenic centers on the core cyclohexane ring through Ogasawara's method, [3,3] sigmatropic rearrangement of an allylic cyanate, and intramolecular 1,3-dipolar cycloaddition of a nitrile oxide. Our synthetic route was applied to the synthesis of the tetrodotoxin congeners 11-norTTX-6(R)-ol and 4,9-anhydro-11 norTTX-6(R)-ol through late-stage modification of the common intermediate. Neutral deprotection at the final step enabled easy purification of tetrodotoxin and 11-norTTX-6(R)-ol without competing dehydration to their 4,9-anhydro forms. PMID- 28074622 TI - "Holostei versus Halecostomi" Problem: Insight from Cytogenetics of Ancient Nonteleost Actinopterygian Fish, Bowfin Amia calva. AB - Bowfin belongs to an ancient lineage of nonteleost ray-finned fishes (actinopterygians) and is the only extant survivor of a once diverged group, the Halecomorphi or Amiiformes. Owing to the scarcity of extant nonteleost ray-finned lineages, also referred as "living fossils," their phylogenetic interrelationships have been the target of multiple hypotheses concerning their sister group relationships. Molecular and morphological data sets have produced controversial results; bowfin is considered as either the sister group to genome duplicated teleosts (together forming the group of Halecostomi) or to gars (Lepisosteiformes; together forming the group of Holostei). However, any detailed cytogenetic analysis of bowfin chromosomes has never been performed to address this issue. Here we examined bowfin chromosomes by conventional (Giemsa-staining, C-banding, base-specific fluorescence and silver staining) and molecular (FISH with rDNA probes) cytogenetic protocols. We identified diploid chromosome number 2n = 46 with a middle-sized submetacentric chromosome pair as the major ribosomal DNA-bearing (45S rDNA), GC-positive and silver-positive element. The minor rDNA (5S rDNA) sites were localized in the pericentromeric region of one middle-sized acrocentric chromosome pair. Comparison with available cytogenetic data of other nonteleost actinopterygians (bichirs, sturgeons, gars) and teleost species including representative of basally branching lineages showed bowfin chromosomal characteristics more similar to the teleost type than to any other nonteleosts. Particularly striking differences were identified between bowfin and gars, the latter of which were found to mimic mammalian AT/GC genomic organisation. Such conclusion however contradicts the most recent phylogenomic results and raises the question what states are ancestral and what are derived. PMID- 28074623 TI - Characterization and application of a self-aspirating electrospray source with pneumatic-assisted ionization. AB - A single gas-assisted electrospray ion source developed for ambient mass spectrometry is introduced in this paper. Simultaneous self-aspiration and electrospray could be achieved by using a constant sheath gas flow supplied from a mini air pump. A gas dynamic study of the spray module is carried out for structural optimization. The entire device exhibits a simplified design and has been systematically characterized through both simulated and experimental investigations. According to the results, the ion source exhibited satisfactory stability and the ability for quantitative operation in routine electrospray ionization mass spectrometry. Furthermore, the ion source can be operated as a desorption electrospray ionization source to perform direct desorption/ionization of the solid samples. The versatile source described here appears to provide a practical approach to perform ambient mass spectrometry analysis with unrestricted sampling operation, and the extensive gas dynamic studies together with the experimental characterization are believed to be helpful in building self-aspirating spray devices. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28074624 TI - Sustainability and comanagement of subsistence hunting in an indigenous reserve in Guyana. AB - Although hunting is a key component of subsistence strategies of many Amazonians, it is also one of the greatest threats to wildlife. Because indigenous reserves comprise over 20% of Amazonia, effective conservation often requires that conservation professionals work closely with indigenous groups to manage resource use. We used hunter-generated harvesting data in spatially explicit biodemographic models to assess the sustainability of subsistence hunting of indigenous Waiwai in Guyana. We collected data through a hunter self-monitoring program, systematic follows of hunters, and semistructured interviews. We used these data to predict future densities of 2 indicator species, spider monkeys (Ateles paniscus) and bearded sakis (Chiropotes sagulatus), under different scenarios of human population expansion and changing hunting technology. We used encounter rates from transect surveys and hunter catch-per-unit effort (CPUE) to validate model predictions. Paca (Cuniculus paca) (198 /year), Currosaw (Crax alector) (168), and spider monkey (117) were the most frequently harvested species. Predicted densities of spider monkeys were statistically indistinguishable from empirically derived transect data (Kolmogorov-Smirnov D = 0.67, p = 0.759) and CPUE (D = 0.32, p = 1.000), demonstrating the robustness of model predictions. Ateles paniscus and C. sagulatus were predicted to be extirpated from <13% of the Waiwai reserve in 20 years, even under the most intensive hunting scenarios. Our results suggest Waiwai hunting is currently sustainable, primarily due to their low population density and use of bow and arrow. Continual monitoring is necessary, however, particularly if human population increases are accompanied by a switch to shotgun-only hunting. We suggest that hunter self-monitoring and biodemographic modeling can be used effectively in a comanagement approach in which indigenous parabiologists continuously provide hunting data that is then used to update model parameters and validate model predictions. PMID- 28074625 TI - Heterocumulene Sulfinyl Radical OCNSO. AB - Neutral five-atomic cumulenes formally consisting of two pseudohalogens (e.g., NCO, NNN, NSO) by sharing the central nitrogen atom are exotic species that have been barely studied. Through flash vacuum pyrolysis of CF3 S(O)NCO at ca. 1200 K, sulfinyl isocyanate, bearing resonance structures of O=C-N=S=O and O=C=N-S=O, has been generated in the gas phase and subsequently characterized in cryogenic matrices (Ar and N2 ). Its reversible conformational (syn and anti) interconversion and photodecomposition were observed. PMID- 28074626 TI - Radio-cephalic fistula recovered with drainage to forearm basilic vein. AB - Dysfunction problems with vascular access are a concern to patients and dialysis units. The vascular surgeon should analyse such dysfunction and perform a careful assessment of the vascular network in order to find new fistula layouts. We introduce and discuss the case of creation of a radio-cephalic fistula with outflow into the forearm basilic vein through rotation of the forearm basilic vein toward the cephalic vein in the forearm of an 88-year-old hemodialysis male patient. This technique enables extending fistula patency and improves cost efficiency. PMID- 28074628 TI - S100A4 (metastasin) positive mesenchymal canine mammary tumour spheroids reduce Tenascin C synthesis under DMSO exposure in vitro. AB - In breast cancer research S100A4-positive tumour-associated stromal cells are assumed as primary source of Tenascin C (TNC) in the metastatic environment. Aim of the present study was to isolate and characterize S100A4/TNC positive stromal canine mammary tumour (CMT) cells. Cells grown as scaffold-free spheroids were investigated for S100A4, TNC, and proliferative activity under 1.8% DMSO stimulation by means of Western blot and immunohistochemistry. DMSO is a commonly used drug solvent despite well-known side effects on cells including TNC expression. DMSO did not affect proliferation, but TNC was significantly reduced under DMSO exposure for 7 and 14 days, whereby for S100A4 a reducing effect was only observed after 14 days. Without DMSO, cells stably expressed TNC and S100A4 which makes them suitable to be used in experimental approaches requiring S100A4/TNC expressing CMT stromal cells. Results show that 1.8% DMSO should not be used as solvent for experiments concerning TNC/S100A4 expression. PMID- 28074629 TI - A comparison of approaches for stratifying on the propensity score to reduce bias. AB - RATIONALE, AIMS, AND OBJECTIVES: Stratification is a popular propensity score (PS) adjustment technique. It has been shown that stratifying the PS into 5 quantiles can remove over 90% of the bias due to the covariates used to generate the PS. Because of this finding, many investigators partition their data into 5 quantiles of the PS without examining whether a more robust solution (one that increases covariate balance while potentially reducing bias in the outcome analysis) can be found for their data. Two approaches (referred to herein as PSCORE and PSTRATA) obtain the optimal stratification solution by repeatedly dividing the data into strata until balance is achieved between treatment and control groups on the PS. These algorithms differ in how they partition the data, and it is not known which is better, or if either is better than a 5-quantile default approach, for reducing bias in treatment effect estimates. METHOD: Monte Carlo simulations and empirical data are used to assess whether PS strata defined by PSCORE, PSTRATA, or 5 quantiles is best at reducing bias in treatment effect estimates, when used within a marginal mean weighting framework (MMWS). These estimates are further compared to results derived using inverse probability of treatment weights (IPTW). RESULTS: PSTRATA was slightly better than PSCORE in balancing covariates and reducing bias, while both approaches outperformed the 5 quantile approach. Overall MMWS using any stratification method outperformed IPTW. CONCLUSIONS: Investigators should routinely use stratification approaches that obtain the optimal stratification solution, rather than simply partitioning the data into 5 quantiles of the PS. Moreover, MMWS (in conjunction with an optimal stratification approach) should be considered as an alternative to IPTW in studies that use PS weights. PMID- 28074630 TI - Quantification of Phenotype Information Aids the Identification of Novel Disease Genes. AB - Next-generation sequencing led to the identification of many potential novel disease genes. The presence of mutations in the same gene in multiple unrelated patients is, however, a priori insufficient to establish that these genes are truly involved in the respective disease. Here, we show how phenotype information can be incorporated within statistical approaches to provide additional evidence for the causality of mutations. We developed a broadly applicable statistical model that integrates gene-specific mutation rates, cohort size, mutation type, and phenotype frequency information to assess the chance of identifying de novo mutations affecting the same gene in multiple patients with shared phenotype features. We demonstrate our approach based on the frequency of phenotype features present in a unique cohort of 6,149 patients with intellectual disability. We show that our combined approach can decrease the number of patients required to identify novel disease genes, especially for patients with combinations of rare phenotypes. In conclusion, we show how integrating genotype phenotype information can aid significantly in the interpretation of de novo mutations in potential novel disease genes. PMID- 28074631 TI - Transdifferentiation of Human Dermal Fibroblasts to Smooth Muscle-Like Cells to Study the Effect of MYH11 and ACTA2 Mutations in Aortic Aneurysms. AB - Mutations in genes encoding proteins of the smooth muscle cell (SMC) contractile apparatus contribute to familial aortic aneurysms. To investigate the pathogenicity of these mutations, SMC are required. We demonstrate a novel method to generate SMC-like cells from human dermal fibroblasts by transdifferentiation to study the effect of variants in genes encoding proteins of the SMC contractile apparatus (ACTA2 and MYH11) in patients with aortic aneurysms. Dermal fibroblasts from seven healthy donors and cells from seven patients with MYH11 or ACTA2 variants were transdifferentiated into SMC-like cells within a 2-week duration using 5 ng/ml TGFbeta1 on a scaffold containing collagen and elastin. The induced SMC were comparable to primary human aortic SMC in mRNA expression of SMC markers which was confirmed on the protein level by immunofluorescence quantification analysis and Western blotting. In patients with MYH11 or ACTA2 variants, the effect of intronic variants on splicing was demonstrated on the mRNA level in the induced SMC, allowing classification into pathogenic or nonpathogenic variants. In conclusion, direct conversion of human dermal fibroblasts into SMC-like cells is a highly efficient method to investigate the pathogenicity of variants in proteins of the SMC contractile apparatus. PMID- 28074632 TI - Gene expression profiles of the Southern house mosquito Culex quinquefasciatus during exposure to permethrin. AB - Insecticide resistance is a major obstacle to the management of disease-vectoring mosquitoes worldwide. The genetic changes and detoxification genes involved in insecticide resistance have been extensively studied in populations of insecticide-resistant mosquitoes, however few studies have focused on the resistance genes upregulated upon insecticide exposure and the possible regulation pathways involved in insecticide resistance. To characterize the changes in gene expression during insecticide exposure, and to investigate the possible connection of known regulation pathways with insecticide resistance, we conducted RNA-Seq analysis of a highly permethrin-resistant strain of Culex quinquefasciatus following permethrin exposure. Gene expression profiles revealed a total of 224 upregulated and 146 downregulated genes when compared to a blank acetone carrier treated control, respectively, suggesting that there were multiple, but specific genes involved in permethrin resistance. Functional enrichment analysis showed that the upregulated genes contained multiple detoxification genes including a glutathione S-transferase and multiple cytochrome P450 genes, as well as several immune-related genes, while the downregulated genes consisted primarily of proteases and carbohydrate metabolism and transport. Further analysis showed that permethrin exposure resulted in a decrease in the expression of serum storage proteins and likely represented a delay in the development of the fourth instar possibly due to a decrease in feeding. This effect was more pronounced in an insecticide-resistant strain than in an insecticide-susceptible strain and may represent a behavioral mechanism of insecticide resistance in Culex mosquitoes. PMID- 28074633 TI - A computational interactome for prioritizing genes associated with complex agronomic traits in rice (Oryza sativa). AB - Rice (Oryza sativa) is one of the most important staple foods for more than half of the global population. Many rice traits are quantitative, complex and controlled by multiple interacting genes. Thus, a full understanding of genetic relationships will be critical to systematically identify genes controlling agronomic traits. We developed a genome-wide rice protein-protein interaction network (RicePPINet, http://netbio.sjtu.edu.cn/riceppinet) using machine learning with structural relationship and functional information. RicePPINet contained 708 819 predicted interactions for 16 895 non-transposable element related proteins. The power of the network for discovering novel protein interactions was demonstrated through comparison with other publicly available protein-protein interaction (PPI) prediction methods, and by experimentally determined PPI data sets. Furthermore, global analysis of domain-mediated interactions revealed RicePPINet accurately reflects PPIs at the domain level. Our studies showed the efficiency of the RicePPINet-based method in prioritizing candidate genes involved in complex agronomic traits, such as disease resistance and drought tolerance, was approximately 2-11 times better than random prediction. RicePPINet provides an expanded landscape of computational interactome for the genetic dissection of agronomically important traits in rice. PMID- 28074634 TI - ARF2 coordinates with PLETHORAs and PINs to orchestrate ABA-mediated root meristem activity in Arabidopsis . AB - Multiple hormones, including abscisic acid (ABA) and auxin, regulate cell division and differentiation of Arabidopsis root meristems. AUXIN RESPONSE FACTOR 2 (ARF2) functions as a negative regulator of ABA responses, as seed germination and primary root growth of arf2 mutants are hypersensitive to ABA. In this study, we found that ABA treatment reduced the expression levels of the PIN-FORMEDs (PIN) auxin efflux carriers, PIN1, PIN3, PIN4, and PIN7, to a greater extent in the root meristems of arf2-101 mutant than in the wild type. Also, arf2-101 pin1 and arf2-101 pin4 double mutants show less ABA-induced inhibition of root meristem activity than the arf2-101 mutants. Furthermore, ARF2 positively mediates the transcripts of transcription factor PLETHORA 1 (PLT1) gene but negatively mediates PLT2 at protein level in root meristems. Using a dexamethasone (DEX)-inducible transgenic line, Pro35S:PLT2-GR, we showed that PLT2 greatly promotes cell division and completely inhibits cell differentiation in root meristems of the arf2-101 mutant once PLT2 is induced by DEX, which can be partially reversed by ABA treatment, suggesting that ABA regulates root meristem activity in both ARF2-dependent and independent pathways. Our results uncover a complex regulatory architecture in which ARF2 coordinates with PLTs and PINs to orchestrate ABA-mediated regulation of root meristem activity in Arabidopsis. PMID- 28074635 TI - Physician step prescription and monitoring to improve ARTERial health (SMARTER): A randomized controlled trial in patients with type 2 diabetes and hypertension. AB - AIMS: There are few proven strategies to enhance physical activity and cardiometabolic profiles in patients with type 2 diabetes and hypertension. We examined the effects of physician-delivered step count prescriptions and monitoring. METHODS: Participants randomized to the active arm were provided with pedometers and they recorded step counts. Over a 1-year period, their physicians reviewed their records and provided a written step count prescription at each clinic visit. The overall goal was a 3000 steps/day increase over 1 year (individualized rate of increase). Control arm participants were advised to engage in physical activity 30 to 60 min/day. We evaluated effects on step counts, carotid femoral pulse wave velocity (cfPWV, primary) and other cardiometabolic indicators including haemoglobin A1c in diabetes (henceforth abbreviated as A1c) and Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) in participants not receiving insulin therapy. RESULTS: A total of 79% completed final evaluations (275/347; mean age, 60 years; SD, 11). Over 66% of participants had type 2 diabetes and over 90% had hypertension. There was a net 20% increase in steps/day in active vs control arm participants (1190; 95% CI, 550-1840). Changes in cfPWV were inconclusive; active vs control arm participants with type 2 diabetes experienced a decrease in A1c (-0.38%; 95% CI, -0.69 to -0.06). HOMA IR also declined in the active arm vs the control arm (ie, assessed in all participants not treated with insulin; -0.96; 95% CI, -1.72 to -0.21). CONCLUSIONS: A simple physician-delivered step count prescription strategy incorporated into routine clinical practice led to a net 20% increase in step counts; however, this was below the 3000 steps/day targeted increment. While conclusive effects on cfPWV were not observed, there were improvements in both A1c and insulin sensitivity. Future studies will evaluate an amplified intervention to increase impact. PMID- 28074636 TI - Comment on: Juvenile granulosa cell ovarian tumor in a child with Beckwith Wiedemann syndrome. PMID- 28074638 TI - Clinical management of Candida albicans keratomycosis in a bottlenose dolphin (Tursiops truncatus). AB - OBJECTIVE: Corneal ulceration secondary to trauma commonly affects marine mammals, often with opportunistic secondary bacterial or fungal infections. This report characterizes the combined use of auriculopalpebral and ophthalmic nerve blocks, adipose-derived stem cells, and subconjunctival injections for successful treatment of corneal trauma and infection in dolphins. ANIMAL STUDIED: An 11-year old, female bottlenose dolphin (Tursiops truncatus) presented with bilateral diffuse corneal opacities, which progressed to keratomycosis caused by Candida albicans. PROCEDURE: Aggressive medical management was employed, including the use of subconjunctival injections of adipose-derived stem cells, plasma, topical and oral antifungals and antibiotics, and anti-inflammatory and pain medications. Anesthetic block of the auriculopalpebral and ophthalmic nerves was employed to evaluate the corneas. CONCLUSION: Subconjunctival injections were employed over 52 days, followed by topical drops for 5 months. At last evaluation, there was no evidence of blepharospasm bilaterally. Only a faint superficial gray corneal opacity remained OS. A temporal paraxial corneal opacity was present OD, with receding inactive vascularization and a small amount of melanosis temporally. PMID- 28074637 TI - Moderately elevated blood pressure during pregnancy and odds of hypertension later in life: the POUCHmoms longitudinal study. AB - OBJECTIVE: Hypertensive disorders in pregnancy signal an increased risk of cardiovascular disease for women. However, future hypertension risk among pregnant women with moderately elevated blood pressure (BP) is unknown. We examined associations among moderately elevated BP or hypertensive disorders during pregnancy and later prehypertension or hypertension. DESIGN: Longitudinal cohort study. SETTING: Five communities in Michigan, USA. SAMPLE: Data are from pregnant women enrolled in the Pregnancy Outcomes and Community Health Study. We included 667 women with gestational BP measurements who participated in the POUCHmoms Study follow-up 7-15 years later. METHODS: Moderately elevated BP was defined as two measures of systolic BP >= 120 mmHg or diastolic BP >=80 mmHg among women without a hypertensive disorder. Weighted multinomial logistic regression models estimated odds of prehypertension or hypertension at follow-up, adjusted for maternal confounders and time to follow-up. MAIN OUTCOME MEASURES: Prehypertension or hypertension. RESULTS: Women meeting the moderately elevated BP criteria (64%) had significantly higher odds of hypertension at follow-up (adjusted odds ratio 2.6; 95% confidence interval 1.2-5.5). These increased odds were observed for moderately elevated BP first identified before or after 20 weeks of gestation, and for elevated systolic BP alone or combined with elevated diastolic BP. CONCLUSIONS: Moderately elevated BP in pregnancy may be a risk factor for future hypertension. Pregnancy offers an opportunity to identify women at risk for hypertension who may not have been identified otherwise. TWEETABLE ABSTRACT: Moderately elevated blood pressure in pregnancy may be associated with hypertension later in life. PMID- 28074639 TI - Colloidal Synthesis of CH3 NH3 PbBr3 Nanoplatelets with Polarized Emission through Self-Organization. AB - We report a combined experimental and theoretical study of the synthesis of CH3 NH3 PbBr3 nanoplatelets through self-organization. Shape transformation from spherical nanodots to square or rectangular nanoplatelets can be achieved by keeping the preformed colloidal nanocrystals at a high concentration (3.5 mg mL-1 ) for 3 days, or combining the synthesis of nanodots with self-organization. The average thickness of the resulting CH3 NH3 PbBr3 nanoplatelets is similar to the size of the original nanoparticles, and we also noticed several nanoplatelets with circular or square holes, suggesting that the shape transformation experienced a self-organization process through dipole-dipole interactions along with a realignment of dipolar vectors. Additionally, the CH3 NH3 PbBr3 nanoplatelets exhibit excellent polarized emissions for stretched CH3 NH3 PbBr3 nanoplatelets embedded in a polymer composite film, showing advantageous photoluminescence properties for display backlights. PMID- 28074641 TI - Editorial: Methods and advances for systems and synthetic biology, nanobiotech and medicine. AB - Congratulations to the winners of our cover competition. The first prize goes to the cover of the October issue, which was provided by the authors of the article "Chlorella species as hosts for genetic engineering and expression of heterologous proteins: Progress, challenge and perspective" by Bo Yang, Jin Liu, Yue Jiang and Feng Chen (http://dx.doi.org/10.1002/biot.201500617). Very close by only very few votes followed the July issue cover showing a nice illustration of Aspergillus fungi, which was selected by BTJs Production manager Sigi Mehren and Technical editor Bernadette Gmeiner. The winner of the book voucher was already informed via email. Many thanks to the more than 1000 participants who were voting for these covers! PMID- 28074640 TI - Evaluation of Pharmacokinetic Interactions Between Lesinurad, a New Selective Urate Reabsorption Inhibitor, and Commonly Used Drugs for Gout Treatment. AB - Lesinurad is a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors (XOIs). Open-label pharmacokinetic studies were performed in volunteers or subjects with hyperuricemia (serum uric acid >= 8 mg/dL) to investigate interactions of lesinurad (with and without concurrent XOIs) with colchicine and 2 nonsteroidal anti-inflammatory drugs: naproxen and indomethacin. Colchicine studies included consecutive 7-day treatment periods of (1) allopurinol 300 mg, allopurinol 300 mg plus lesinurad 400 or 600 mg, and continued lesinurad 400 or 600 mg; or (2) febuxostat 40 or 80 mg, febuxostat 40 or 80 mg plus lesinurad 400 mg, and continued febuxostat 40 or 80 mg plus lesinurad 600 mg. Naproxen and indomethacin studies included lesinurad 400 mg on day 1, naproxen 250 mg twice daily or indomethacin 25 mg twice daily on days 2-6, and lesinurad 400 mg plus continued naproxen or indomethacin on days 7-13 and the morning of day 14. Lesinurad did not alter the pharmacokinetics of naproxen and modestly altered exposure to colchicine (AUC decrease of <= 25%) and indomethacin (AUC increase of ~35%). Indomethacin did not alter the pharmacokinetics of lesinurad, whereas naproxen modestly decreased the Cmax of lesinurad by ~27%. PMID- 28074642 TI - As dental hygienists, we should support WHO sugar tax recommendations! PMID- 28074643 TI - Ultraphotostable Mesoporous Silica-Coated Gap-Enhanced Raman Tags (GERTs) for High-Speed Bioimaging. AB - Surface-enhanced Raman scattering (SERS) tags can be utilized as optical labeling nanoprobes similar to fluorescent dyes and quantum dots for bioimaging with additional advantages of fingerprint vibrational signals as unique optical codes and ultranarrow line widths for multiplexing. However, the development of the SERS imaging technique is much less well-established compared to the devlopment of fluorescence imaging mainly because of speed limitations. An effective strategy for improving the SERS imaging speed and simultaneously maintaining the photostability of SERS tags has not, to the best of our knowledge, been reported. In this work, mesoporous silica- (MS-) coated gap-enhanced Raman tags (GERTs) were designed with built-in Raman reporters for off-resonance near-infrared laser excitation and reduced photothermal effects, leading to ultraphotostability during laser irradiation. Additionally, they achieve large amplification of Raman signals by combining the chemical (CHEM) and electromagnetic (EM) enhancement effects due to the subnanometer core-shell junction, so SERS imaging can be performed in a dramatically reduced duration. With these unique structural and optical advantages, MS GERTs exhibit high storage, pH, serum, and photostabilities; strong Raman enhancements; and favorable biocompatibility. Therefore, MS GERTs achieve long-term cell imaging that can last for 30 min without being photobleached and also maintain decent imaging effects. Furthermore, MS GERTs enable continuous and stable imaging in living tissues for more than 30 min. With these advantages, MS GERTs might potentially have more biomedical applications. PMID- 28074644 TI - Virus-Inspired Self-Assembled Nanofibers with Aggregation-Induced Emission for Highly Efficient and Visible Gene Delivery. AB - High-efficiency gene transfer and suitably low cytotoxicity are the main goals of gene transfection systems based on nonviral vectors. In addition, it is desirable to track the gene transfer process in order to observe and explain the mechanism. Herein, inspired by viral structures that are optimized for gene delivery, we designed a small-molecule gene vector (TR4) with aggregation-induced emission properties by capping a peptide containing four arginine residues with tetraphenylethene (TPE) and a lipophilic tail. This novel vector can self assemble with plasmid DNA to form nanofibers in solution with low cytotoxicity, high stability, and high transfection efficiency. pDNA@TR4 complexes were able to transfect a variety of different cell lines, including stem cells. The self assembly process induces bright fluorescence from TPE, which makes the nanofibers visible by confocal laser scanning microscopy (CLSM). This allows us for the tracking of the gene delivery process. PMID- 28074645 TI - Highly Sensitive Bendable and Foldable Paper Sensors Based on Reduced Graphene Oxide. AB - Over the past decade, the demand for high-performance wearable sensors has increased because of their capability for interaction with humans. Such sensors have typically been prepared on conventional substrates, such as silicon, PDMS, and copper mesh. In this work, we propose a class of wearable sensors fabricated from reduced graphene oxide (rGO) patterned paper substrates (rGO-paper). These rGO-paper sensors are highly sensitive to various deformations and capable of measuring bending and folding angles as small as 0.2 degrees and 0.1 degrees , respectively. We have demonstrated the applicability of these high-performance rGO-paper sensors by patterning rGO on kirigamis that can detect pulse and the motion of knees, wrists, and fingers. Finally, paper rings lined with rGO sensors were used to control a robotic hand, and an rGO-paper keyboard was used to light LEDs. PMID- 28074647 TI - Sustainable and Superior Heat-Resistant Alginate Nonwoven Separator of LiNi0.5Mn1.5O4/Li Batteries Operated at 55 degrees C. AB - High-voltage lithium-ion batteries have become a major research focus. As a major part of lithium batteries, the separator plays a critical role in the development of high-voltage lithium batteries. Herein, we demonstrated a sustainable and superior heat-resistant alginate nonwoven separator for high-voltage (5 V) lithium batteries. It was demonstrated that the resultant alginate nonwoven separator exhibited better mechanical property (37 MPa), superior thermal stability (up to 150 degrees C), and higher ionic conductivity (1.4 * 10-3 S/cm) as compared to commercially available polyolefin (PP) separator. More impressively, the 5 V class LiNi0.5Mn1.5O4 (LNMO)/Li cell with this alginate nonwoven separator delivered much better cycling stability (maintaining 79.6% of its initial discharge capacity) than that (69.3%) of PP separator after 200 cycles at an elevated temperature of 55 degrees C. In addition, the LiFePO4/Li cell assembled with such alginate nonwoven separator could still charge and discharge normally even at an elevated temperature of 150 degrees C. The above mentioned fascinating characteristics of alginate separator provide great probability for its application for high-voltage (5 V) lithium batteries at elevated temperatures. PMID- 28074646 TI - Differences in Protein Concentration Dependence for Nucleation and Elongation in Light Chain Amyloid Formation. AB - Light chain (AL) amyloidosis is a lethal disease characterized by the deposition of the immunoglobulin light chain into amyloid fibrils, resulting in organ dysfunction and failure. Amyloid fibrils have the ability to self-propagate, recruiting soluble protein into the fibril by a nucleation-polymerization mechanism, characteristic of autocatalytic reactions. Experimental data suggest the existence of a critical concentration for initiation of fibril formation. As such, the initial concentration of soluble amyloidogenic protein is expected to have a profound effect on the rate of fibril formation. In this work, we present in vitro evidence that fibril formation rates for AL light chains are affected by the protein concentration in a differential manner. De novo reactions of the proteins with the fastest amyloid kinetics (AL-09, AL-T05, and AL-103) do not present protein concentration dependence. Seeded reactions, however, exhibited weak protein concentration dependence. For AL-12, seeded and protein concentration dependence data suggest a synergistic effect for recruitment and elongation at low protein concentrations, while reactions of kappaI exhibited poor efficiency in nucleating and elongating preformed fibrils. Additionally, co aggregation and cross seeding of kappaI variable domain (VL) and the kappaI full length (FL) light chain indicate that the presence of the constant domain in kappaI FL modulates fibril formation, facilitating the recruitment of kappaI VL. Together, these results indicate that the dominant process in fibril formation varies among the AL proteins tested with a differential dependence of the protein concentration. PMID- 28074649 TI - Bio-Based Artificial Nacre with Excellent Mechanical and Barrier Properties Realized by a Facile In Situ Reduction and Cross-Linking Reaction. AB - Demands for high strength integrated materials have substantially increased across various kinds of industries. Inspired by the relationship of excellent integration of mechanical properties and hierarchical nano/microscale structure of the natural nacre, a simple and facile method to fabricate high strength integrated artificial nacre based on sodium carboxymethylcellulose (CMC) and borate cross-linked graphene oxide (GO) sheets has been developed. The tensile strength and toughness of cellulose-based hybrid material reached 480.5 +/- 13.1 MPa and 11.8 +/- 0.4 MJm-3 by a facile in situ reduction and cross-linking reaction between CMC and GO (0.7%), which are 3.55 and 6.55 times that of natural nacre. This hybrid film exhibits better thermal stability and flame retardancy. More interestingly, the hybrid material showed good water stability compared to that in the original water-soluble CMC. This type of hybrid has great potential applications in aerospace, artificial muscle, and tissue engineering. PMID- 28074648 TI - Mispacking and the Fitness Landscape of the Green Fluorescent Protein Chromophore Milieu. AB - The autocatalytic maturation of the chromophore in green fluorescent protein (GFP) was thought to require the precise positioning of the side chains surrounding it in the core of the protein, many of which are strongly conserved among homologous fluorescent proteins. In this study, we screened for green fluorescence in an exhaustive set of point mutations of seven residues that make up the chromophore microenvironment, excluding R96 and E222 because mutations at these positions have been previously characterized. Contrary to expectations, nearly all amino acids were tolerated at all seven positions. Only four point mutations knocked out fluorescence entirely. However, chromophore maturation was found to be slower and/or fluorescence reduced in several cases. Selected combinations of mutations showed nonadditive effects, including cooperativity and rescue. The results provide guidelines for the computational engineering of GFPs. PMID- 28074650 TI - Revisiting the Val/Ile Mutation in Mammalian and Bacterial Nitric Oxide Synthases: A Spectroscopic and Kinetic Study. AB - Nitric oxide is produced in mammals by the nitric oxide synthase (NOS) isoforms at a catalytic site comprising a heme associated with a biopterin cofactor. Through genome sequencing, proteins that are highly homologous to the oxygenase domain of NOSs have been identified, in particular in bacteria. The active site is highly conserved except for a valine residue in the distal pocket that is replaced with an isoleucine in bacteria. This switch was previously reported to influence the kinetics of the reaction. We have used the V346I mutant of the mouse inducible NOS (iNOS) as well as the I224V mutant of the NOS from Bacillus subtilis (bsNOS) to study their spectroscopic signatures in solution and look for potential structural differences compared to their respective wild types. Both mutants seem destabilized in the absence of substrate and cofactor. When both substrate and cofactor are present, small differences can be detected with Nomega hydroxy-l-arginine compared to arginine, which is likely due to the differences in the hydrogen bonding network of the distal pocket. Stopped-flow experiments evidence significant changes in the kinetics of the reaction due to the mutation as was already known. We found these effects particularly marked for iNOS. On the basis of these results, we performed rapid freeze-quench experiments to trap the biopterin radical and found the same results that we had obtained for the wild types. Despite differences in kinetics, a radical could be trapped in both steps for the iNOS mutant but only for the first step in the mutant of bsNOS. This strengthens the hypothesis that mammalian and bacterial NOSs may have a different mechanism during the second catalytic step. PMID- 28074651 TI - N-Heterocyclic Carbene-Catalyzed [4 + 2] Cyclization of Saturated Carboxylic Acid with o-Quinone Methides through in Situ Activation: Enantioselective Synthesis of Dihydrocoumarins. AB - An N-heterocyclic carbene (NHC)-catalyzed formal [4 + 2] synthesis of dihydrocoumarins was realized from saturated carboxylic acids and o-quinone methides via an in situ activation strategy. This protocol results in excellent diastereoselectivity and enantioselectivity and good yields and uses readily available and inexpensive starting materials. PMID- 28074652 TI - Trends in Methyl tert-Butyl Ether Concentrations in Private Wells in Southeast New Hampshire: 2005 to 2015. AB - In southeast New Hampshire, where reformulated gasoline was used from the 1990s to 2007, methyl tert-butyl ether (MtBE) concentrations >=0.2 MUg/L were found in water from 26.7% of 195 domestic wells sampled in 2005. Ten years later in 2015, and eight years after MtBE was banned, 10.3% continue to have MtBE. Most wells (140 of 195) had no MtBE detections (concentrations <0.2 MUg/L) in 2005 and 2015. Of the remaining wells, MtBE concentrations increased in 4 wells, decreased in 47 wells, and did not change in 4 wells. On average, MtBE concentrations decreased 65% among 47 wells whereas MtBE concentrations increased 17% among 4 wells between 2005 and 2015. The percent change in detection frequency from 2005 to 2015 (the decontamination rate) was lowest (45.5%) in high-population-density areas and in wells completed in the Berwick Formation geologic units. The decontamination rate was the highest (78.6%) where population densities were low and wells were completed in bedrock composed of granite, metamorphic, and mafic rocks. Wells in the Berwick Formation are characteristically deeper and have lower yields than wells in other rock types and have shallower overburden cover, which may allow for more rapid transport of MtBE from land-surface releases. Low yielding, deep bedrock wells may require large contributing areas to achieve adequate well yield, and thus have a greater chance of intercepting MtBE, in addition to diluting contaminants at a slower rate and thus requiring more time to decontaminate. PMID- 28074654 TI - Rhodium-Catalyzed Intramolecular Transannulation Reaction of Alkynyl Thiadiazole Enabled 5,n-Fused Thiophenes. AB - A method for the synthesis of a wide range of fused thiophenes, including those fused with lactams, lactones, or cyclic ethers, was developed from a rhodium catalyzed intramolecular transannulation reaction of alkynyl thiadiazoles. This transannulation reaction provides an efficient platform for the construction of a variety of 5,n-fused thiophenes from readily available starting materials together with the release of molecular nitrogen. PMID- 28074655 TI - Stereodivergent Coupling of Aldehydes and Alkynes via Synergistic Catalysis Using Rh and Jacobsen's Amine. AB - We report an enantioselective coupling between alpha-branched aldehydes and alkynes to generate vicinal quaternary and tertiary carbon stereocenters. The choice of Rh and organocatalyst combination allows for access to all possible stereoisomers with high enantio-, diastereo-, and regioselectivity. Our study highlights the power of catalysis to activate two common functional groups and provide access to divergent stereoisomers and constitutional structures. PMID- 28074653 TI - The Essential Medicinal Chemistry of Curcumin. AB - Curcumin is a constituent (up to ~5%) of the traditional medicine known as turmeric. Interest in the therapeutic use of turmeric and the relative ease of isolation of curcuminoids has led to their extensive investigation. Curcumin has recently been classified as both a PAINS (pan-assay interference compounds) and an IMPS (invalid metabolic panaceas) candidate. The likely false activity of curcumin in vitro and in vivo has resulted in >120 clinical trials of curcuminoids against several diseases. No double-blinded, placebo controlled clinical trial of curcumin has been successful. This manuscript reviews the essential medicinal chemistry of curcumin and provides evidence that curcumin is an unstable, reactive, nonbioavailable compound and, therefore, a highly improbable lead. On the basis of this in-depth evaluation, potential new directions for research on curcuminoids are discussed. PMID- 28074656 TI - Atomistic Modeling of Ion Conduction through the Voltage-Sensing Domain of the Shaker K+ Ion Channel. AB - Voltage-sensing domains (VSDs) sense changes in the membrane electrostatic potential and, through conformational changes, regulate a specific function. The VSDs of wild-type voltage-dependent K+, Na+, and Ca2+ channels do not conduct ions, but they can become ion-permeable through pathological mutations in the VSD. Relatively little is known about the underlying mechanisms of conduction through VSDs. The most detailed studies have been performed on Shaker K+ channel variants in which ion conduction through the VSD is manifested in electrophysiology experiments as a voltage-dependent inward current, the so called omega current, which appears when the VSDs are in their resting state conformation. Only monovalent cations appear to permeate the Shaker VSD via a pathway that is believed to be, at least in part, the same as that followed by the S4 basic side chains during voltage-dependent activation. We performed MUs time scale atomistic molecular dynamics simulations of a cation-conducting variant of the Shaker VSD under applied electric fields in an experimentally validated resting-state conformation, embedded in a lipid bilayer surrounded by solutions containing guanidinium chloride or potassium chloride. Our simulations provide insights into the Shaker VSD permeation pathway, the protein-ion interactions that control permeation kinetics, and the mechanism of voltage dependent activation of voltage-gated ion channels. PMID- 28074657 TI - Photocontrol of Anion Binding Affinity to a Bis-urea Receptor Derived from Stiff Stilbene. AB - Toward the development of photoresponsive anion receptors, a stiff-stilbene photoswitch has been equipped with two urea anion-binding motifs. Photoinduced E/Z isomerization has been studied in detail by UV-vis and NMR spectroscopy. Titration experiments (1H NMR) reveal strong binding of acetate and phosphate to the (Z)-isomer, in which the urea groups are closely together. Isomerization to the (E)-form separates the urea motifs, resulting in much weaker binding. Additionally, geometry optimizations by density functional theory (DFT) illustrate that oxo-anion binding to the (Z)-form involves four hydrogen bonds. PMID- 28074658 TI - Hyperglycemia as a prognosis predictor of length of stay and functional outcomes in patients with acute ischemic stroke. AB - BACKGROUND: Hyperglycemia has been shown to influence prognosis outcome of stroke. The objective of this study was to determine the correlation between hyperglycemia with length of stay (LOS) and functional outcomes in ischemic stroke patients. This is the first study to correlate hyperglycemia in ischemic stroke patients with their functional outcome as assessed by using Barthel index. METHODS: This is a prospective cohort study of patients admitted to the Stroke Unit of Dr. Sardjito General Hospital for ischemic stroke from January 2012 to June 2014. Subjects were selected in a consecutive manner until the required number of subjects was obtained. Data collected from medical records included the baseline social demographic variables and clinical variables. Bivariate and multivariate analyses with multiple linear regression analysis were used to identify correlation between hyperglycemia with LOS and functional outcomes. RESULTS: In total, 208 patients were included, of which 126 (60.6%) were men. The mean age was 61.18 (SD = 10.45), and the mean LOS in our study was 4.52 (SD = 5.89) d. For the univariate analysis, factors associated with LOS were history of diabetes (p = 0.003), urinary tract infection (p = 0.025), hyperglycemia (p < 0.001) and moderate to severe Barthel index on admission (p < 0.001), and the independent factor was hyperglycemia (beta: 6.212, p < 0.001) based on multivariate analysis. Furthermore, hyperglycemia was an independent factor of functional outcomes as measured with Barthel index (beta: 9.185, p < 0.001). CONCLUSIONS: Hyperglycemia is a prognosis predictor of LOS and functional outcomes of patients with acute ischemic stroke measured by discharge Barthel index. PMID- 28074659 TI - Ferulic acid (FA) abrogates gamma-radiation induced oxidative stress and DNA damage by up-regulating nuclear translocation of Nrf2 and activation of NHEJ pathway. AB - The present study was aimed to evaluate the radioprotective effect of ferulic acid (FA), a naturally occurring plant flavonoid in terms of DNA damage and damage related alterations of repair pathways by gamma radiation. FA was administered at a dose of 50 mg/kg body weight for five consecutive days prior to exposing the swiss albino mice to a single dose of 10 Gy gamma radiation. Ionising radiation induces oxidative damage manifested by decreased expression of Cu, Zn-SOD (SOD stands for super oxide dismutase), Mn-SOD and catalase. Gamma radiation promulgated reactive oxygen species (ROS) mediated DNA damage and modified repair pathways. ROS enhanced nuclear translocation of p53, activated ATM (ataxia telangiectasia-mutated protein), increased expression of GADD45a (growth arrest and DNA-damage-inducible protein) gene and inactivated Non homologous end joining (NHEJ) repair pathway. The comet formation in irradiated mice peripheral blood mononuclear cells (PBMC) reiterated the DNA damage in IR exposed groups. FA pretreatment significantly prevented the comet formation and regulated the nuclear translocation of p53, inhibited ATM activation and expression of GADD45a gene. FA promoted the nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and activated NHEJ repair pathway to overcome ROS mediated oxidative stress and DNA damage. Therefore, the current study stated that FA can challenge the oxidative stress by (i) inducing nuclear translocation of Nrf2, (ii) scavenging ROS, and (iii) activating NHEJ DNA repair process. PMID- 28074660 TI - Optimizing the management of children with latent tuberculosis infection. AB - INTRODUCTION: The management of latent tuberculosis (LTBI) in children represents an important issue for paediatricians because of the disease burden, the lack of a gold standard for the diagnosis and the high annual risk of progression to active disease. Areas covered: A review of English language articles on LTBI in children, published between the 1st of January 2010 and the 1st of July 2016, was conducted using multiple keywords and standardized terminology in PubMed database. This review provides an updated overview of the available tests for LTBI diagnosis in children, management strategies and treatment options. Expert commentary: Two tests are available for LTBI diagnosis: tuberculin skin test and interferon-gamma release assays, both with a suboptimal specificity and sensitivity, and both with the lack of capability in distinguishing between infection and disease. Several new markers have been identified but further studies are needed. Among all treatment regimes, because of the high safety and efficacy profile showed and to avoid the poor completion rate, the treatment with a three-month course of isoniazid and rifampicin is currently recommended. New vaccines are needed because of the spread of the disease despite BCG vaccination in high risk countries. Currently, 15 new vaccines are in the pipeline. PMID- 28074661 TI - Inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitors: a patent and scientific literature review (2002-2016). AB - INTRODUCTION: Inosine-5'-monophosphate dehydrogenase (IMPDH) is an enzyme involved in the de novo biosynthesis of guanine nucleotides. To date human IMPDH inhibitors have been approved for prevention of organ transplant rejection and as anti-viral agents. More recently, the use of IMPDH inhibitors for other indications including cancer and pathogenic microorganisms has been pursued. Areas covered: IMPDH inhibitors disclosed primarily in the patent and scientific literature from 2002 to the present are discussed. Several interesting chemotypes that have not been pursued by patent protection are also highlighted. Expert opinion: Progress has been made in the development of IMPDH inhibitors, particularly compounds that are structurally distinct from mycophenolic acid and nucleoside-based inhibitors. However, clinical progression has been hampered primarily by a limited understanding of the enzyme's role in disease pathophysiology. Finally, most of the IMPDH inhibitors developed over the past fourteen years fall within a relatively narrow set of chemotypes. This provides opportunities for expanding IMPDH inhibitor chemical space to further evaluate this class of molecular targets. PMID- 28074662 TI - Misuse of 2-(ethylamino)-1-(4-methylphenyl)-1-pentanone (4-MEAP), a synthetic cathinone. PMID- 28074664 TI - Recent advances in molecular biomarkers for diabetes mellitus: a systematic review. AB - CONTEXT: Diabetes is a growing global metabolic epidemic. Current research is focussing on exploring how the biological processes and clinical outcomes of diabetes are related and developing novel biomarkers to measure these relationships, as this can subsequently improve diagnostic, therapeutic and management capacity. OBJECTIVE: The objective of this study is to identify the most recent advances in molecular biomarkers of diabetes and directions that warrant further research. METHODS: Using a systematic search strategy, the MEDLINE, CINAHL and OVID MEDLINE databases were canvassed for articles that investigated molecular biomarkers for diabetes. Initial selections were made based on article title, whilst final inclusion was informed by a critical appraisal of the full text of each article. RESULTS: The systematic search returned 246 records, of which 113 were unique. Following screening, 29 records were included in the final review. Three main research strategies (the development of novel technologies, broad biomarker panels, and targeted approaches) identified a number of potential biomarkers for diabetes including miR-126, C-reactive protein, 2-aminoadipic acid and betatrophin. CONCLUSION: The most promising research avenue identified is the detection and quantification of micro RNA. Further, the utilisation of functionalised electrodes as a means to detect biomarker compounds also warrants attention. PMID- 28074663 TI - Primary graft dysfunction: pathophysiology to guide new preventive therapies. AB - INTRODUCTION: Primary graft dysfunction (PGD) is a common complication of lung transplantation characterized by acute pulmonary edema associated with bilateral pulmonary infiltrates and hypoxemia in the first 3 post-operative days. Development of PGD is a predictor of poor short- and long-term outcomes after lung transplantation, but there are currently limited tools to prevent its occurrence. Areas covered: Several potentially modifiable donor, recipient, and operative risk factors for PGD have been identified. In addition, basic and translational studies in animals and ex vivo lung perfusion systems have identified several biomarkers and mechanisms of injury in PGD. In this review, we outline the clinical and genetic risk factors for PGD and summarize experimental data exploring PGD mechanisms, with a focus on strategies to reduce PGD risk and on potential novel molecular targets for PGD prevention. Expert commentary: Because of the clinical importance of PGD, development of new therapies for prevention and treatment is critically important. Improved understanding of the pathophysiology of clinical PGD provides a framework to explore novel agents to prevent or reverse PGD. Ex vivo lung perfusion provides a new opportunity for rapid development of therapeutics that target this devastating complication of lung transplantation. PMID- 28074665 TI - Diterpenoid alkaloids from the root of Aconitum sinchiangense W. T. Wang with their antitumor and antibacterial activities. AB - A phytochemical study of the root barks of Aconitum sinchiangense W. T. Wang, a traditional Chinese herb medicine, led to the isolation of 15 diterpenoid alkaloids, including one new C19-diterpenoid alkaloid, sinchiangensine A (1), whose structure was determined by spectral methods including 2D NMR. Additionally, sinchiangensine A and its known analogue 3 were first reported as potential antitumor and antibacterial diterpenoid alkaloids, which showed significant antitumor activities against tumour cells (HL-60, A-549, SMCC-7721, MCF-7 and SW480), with IC50 comparable to cisplatin, and significant antibacterial activities against Staphylococcus aureus ATCC-25923 with MIC value of 0.147 and 0.144 MUmol/mL, respectively. PMID- 28074666 TI - Association between posttraumatic stress and acceptance of social changes: Findings from a general population study and proposal of a new concept. AB - BACKGROUND: There is a growing understanding of the importance of the social factors of posttraumatic stress disorder. AIMS: This study expands research on association between posttraumatic stress and social factors by introducing the measure of the acceptance of social changes and evaluating possible links between posttraumatic stress disorder symptoms and acceptance of social changes. METHODS: A general population sample ( n = 778) aged from 18 to 89 years ( M = 40.2) from Lithuania participated in our study, of whom 68% reported exposure to traumatic events. Posttraumatic stress reactions were measured with the Impact of Event Scale - Revised (IES-R), and acceptance of social changes was measured with the Acceptance of Social Changes Instrument (SOCHI) developed by the authors of this study. RESULTS: About 8% of the participants had a potential posttraumatic stress disorder (PTSD) diagnosis. Acceptance of social changes was negatively associated with posttraumatic stress. PTSD was related to lower acceptance of social changes ( d = .61). Structural equation model (SEM) revealed the mediating role of PTSD for acceptance of social changes following trauma exposure. CONCLUSION: Findings of our study indicate that the acceptance of social changes might be an important psychosocial factor of PTSD. PMID- 28074667 TI - A systematic analysis of methylene blue for drug-induced shock in humans. PMID- 28074668 TI - In-vivo evidence of nephrotoxicity and altered hepatic function in rats following administration of diglycolic acid, a metabolite of diethylene glycol. AB - CONTEXT: Diglycolic acid (DGA) is one of the two primary metabolites of diethylene glycol (DEG). DEG is an industrial solvent that has been implicated in mass poisonings resulting from product misuse in the United States and worldwide, with the hallmark toxicity being acute kidney injury, hepatotoxicity, encephalopathy and peripheral neuropathy. Our laboratory has generated in-vitro evidence suggesting that DGA is the metabolite responsible for the proximal tubule necrosis and decreased kidney function observed following DEG ingestion. Furthermore, we have shown that DGA specifically accumulates in kidney tissues (100* higher than peak blood concentrations) following DEG administration. OBJECTIVE: To examine renal and hepatic accumulation and dysfunction following direct administration of DGA in-vivo. We hypothesize that administration of DGA will result in renal and hepatic DGA accumulation, as well as proximal tubular necrosis and liver injury. MATERIALS AND METHODS: Adult male Wistar rats were divided into three groups dosed with 0, 100 or 300 mg/kg DGA via single oral gavage. Urine was collected every 6-12 h and blood, kidneys and liver were removed upon sacrifice at 48 h post-dosing for analysis. RESULTS: DGA accumulated significantly in both kidney and liver tissue only at 300 mg DGA/kg. DGA concentrations in the kidneys and liver correlated with renal and hepatic injury, respectively. Histopathological and clinical chemistry analysis revealed that DGA treated animals exhibited moderate liver fatty accumulation and marked renal injury, again only at 300 mg/kg. DISCUSSION: DGA-induced kidney injury demonstrated a steep dose response threshold, where severe damage occurred only in animals given 300 mg/kg DGA, while no toxicity was observed at 100 mg/kg. CONCLUSION: These results provide evidence for in-vivo toxicity following direct administration of DGA, a metabolite of DEG. The steep dose-response threshold for toxicity suggests mechanistically that there is likely a saturable step that results in DGA accumulation in target organs. PMID- 28074669 TI - Implementation of a novel ultra fast metabolic stability analysis method using exact mass TOF-MS. AB - AIM: Increasing numbers of compounds requiring stability data means highly optimized methods capable of rapid turnaround are desirable during early discovery. Materials and methods/results: An advanced, generic analytical workflow for metabolic stability has been developed that utilizing ballistic gradient LC (sub 1 min run times), exact mass TOF-MS (Waters Xevo-G2-XS Q-TOF) and automated data processing (Waters UNIFI software) allowed for rapid integration and interpretation of all data produced, eliminating the need for method development and manual processing. We can analyze and process 96 compounds across two species in quadruplicate in a 24-h period with no method development. CONCLUSION: An advanced bioanalytical workflow has increased our capacity threefold and reduced our instrument/processing needs threefold. PMID- 28074670 TI - Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance. AB - Psilocybin and psilocin are controlled substances in many countries. These are the two main hallucinogenic compounds of the "magic mushrooms" and both act as agonists or partial agonists at 5-hydroxytryptamine (5-HT)2A subtype receptors. During the last few years, psilocybin and psilocin have gained therapeutic relevance but considerable physiological variability between individuals that can influence dose-response and toxicological profile has been reported. This review aims to discuss metabolism of psilocybin and psilocin, by presenting all major and minor psychoactive metabolites. Psilocybin is primarily a pro-drug that is dephosphorylated by alkaline phosphatase to active metabolite psilocin. This last is then further metabolized, psilocin-O-glucuronide being the main urinary metabolite with clinical and forensic relevance in diagnosis. PMID- 28074671 TI - Effect of illusory kinesthesia on hand function in patients with distal radius fractures: a quasi-randomized controlled study. AB - OBJECTIVES: We investigated the effects of the illusion of motion through tendon vibration on hand function in patients with distal radius fractures. SETTING: Kawachi General Hospital, Japan. SUBJECTS: A total of 22 patients with distal radius fractures were divided into either an illusory kinesthesia group ( n = 11) or a control group ( n = 11). INTERVENTION: We performed the intervention for seven consecutive days after surgery. Evaluations were performed at one day, seven days, one month, and two months postsurgery. MAIN MEASURES: Data were collected on pain at rest and pain during movement. The Patient-Rated Wrist Evaluation and Pain Catastrophizing Scale were also used. RESULTS: The illusory kinesthesia group showed significantly better scores on Patient-Rated Wrist Evaluation ( p < 0.01) compared with the control group at seven days, one month, and two months postsurgery. The mean (SD) of the Patient-Rated Wrist Evaluation total score was 97.6 (2.2) at one day postsurgery and 9.1 (5.3) at seven days postsurgery in the illusory kinesthesia group, while the Patient-Rated Wrist Evaluation total score was 96.3 (4.4) at one day postsurgery and 20.1 (17.0) at seven days postsurgery in the control group. CONCLUSION: Our results indicate that illusory kinesthesia is an effective postsurgery management strategy not only for pain alleviation, but also hand function in patients with distal radius fractures. Furthermore, the significant improvements persisted for up to two months after intervention in the illusory kinesthesia group, but not in the control group. In addition, patients in the kinesthetic illusions group showed increased use of the affected limb in daily living. PMID- 28074672 TI - A power-assisted exercise intervention in people with profound intellectual and multiple disabilities living in a residential facility: a pilot randomised controlled trial. AB - OBJECTIVE: To assess the feasibility of conducting a randomised controlled trial to determine the effectiveness of a twenty-week power-assisted exercise intervention in people with profound intellectual and multiple disabilities and to evaluate the potential beneficial effects of this intervention. DESIGN: Pilot randomised controlled trial. SETTING: A large-scale twenty-four-hour residential facility in the Netherlands. SUBJECTS: Thirty-seven persons with profound intellectual and multiple disabilities. INTERVENTION: Participants in the intervention group received a power-assisted exercise intervention three times a week for thirty minutes over a twenty-week period. Participants in the control group received care as usual. MAIN MEASURES: Trial feasibility by recruitment process and outcomes completion rates; intervention feasibility by programme compliance rates; potential outcomes by functional abilities, alertness, body composition, muscle tone, oxygen saturation, cardiovascular fitness and quality of life. RESULTS: Thirty-seven participants were recruited ( M age = 32.1, SD = 14.6) and were randomly allocated to intervention ( n = 19) and control ( n = 18) groups. Programme compliance rates ranged from 54.2% to 97.7% with a mean (SD) of 81.5% (13.4). Oxygen saturation significantly increased in the intervention group. Standardised effect sizes on the difference between groups in outcome varied between 0.02 and 0.62. CONCLUSIONS: The power-assisted exercise intervention and the trial design were feasible and acceptable to people with profound intellectual and multiple disabilities living in a residential facility. This pilot study suggests that the intervention improves oxygen saturation, but further implementation with the aim of improving other outcomes should be considered with caution. PMID- 28074673 TI - One-hour rule-in and rule-out of acute myocardial infarction using high sensitivity cardiac troponin I. PMID- 28074674 TI - Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery. PMID- 28074675 TI - The Emergence of an Abstract Grammatical Category in Children's Early Speech. AB - How do children begin to use language to say things they have never heard before? The origins of linguistic productivity have been a subject of heated debate: Whereas generativist accounts posit that children's early language reflects the presence of syntactic abstractions, constructivist approaches instead emphasize gradual generalization derived from frequently heard forms. In the present research, we developed a Bayesian statistical model that measures the degree of abstraction implicit in children's early use of the determiners "a" and "the." Our work revealed that many previously used corpora are too small to allow researchers to judge between these theoretical positions. However, several data sets, including the Speechome corpus-a new ultra-dense data set for one child showed evidence of low initial levels of productivity and higher levels later in development. These findings are consistent with the hypothesis that children lack rich grammatical knowledge at the outset of language learning but rapidly begin to generalize on the basis of structural regularities in their input. PMID- 28074676 TI - Potential route of Th17/Treg cell dynamics in targeting type 1 diabetes and rheumatoid arthritis: an autoimmune disorder perspective. AB - Cytokines, small secreted proteins, have a specific effect on the interactions and communications between cells. They play a pivotal role in the pathogenesis of autoimmune diseases. Factors in the breakdown of self-tolerance and the subsequent events leading to the induction of pathogenic responses remain unclear for most of the autoimmune diseases. Large numbers of studies have revealed a general scheme in which pro-inflammatory cytokines contribute to the initiation and propagation of autoimmune inflammation, whereas anti-inflammatory cytokines facilitate the regression of inflammation and thereby recovery from the disease. The interleukin (IL)-17/IL-23 axis that emerged as the new paradigm has compelled us to critically re-examine the cytokine-driven immune events in the pathogenesis and treatment of autoimmunity. T-helper 17 cells and Regulatory T cells are two lymphocyte subsets with opposing action. In this review, we discuss the mechanism that promotes development of these cells from common precursors and specific factors that impact their cell numbers and function. Also presented are findings that suggest how the equilibrium between pre-inflammatory T helper and regulatory T-cell subsets might be pharmacologically restored for therapeutic benefit, emphasising type-1 diabetes and rheumatoid arthritis. Furthermore, the emerging clinical data showing anti-IL-17 and anti-IL-23 treatments for their efficacy in treating immune-mediated inflammatory diseases are presented. PMID- 28074677 TI - The effective tool for self-assessment of adherence to treatment in patients with benign prostatic obstruction and overactive bladder symptoms. AB - PURPOSE: Study of validity of the Medication Adherence Self-Report Inventory (MASRI) for use in clinical practice to treat patients with benign prostatic obstruction (BPO) accompanied with overactive bladder (OAB) symptoms. METHODS: During 12 weeks of the randomized study, 452 patients with BPO and OAB symptoms (mean age of 61.3 (12.7)) were studied for adherence to the treatment with Tamsulosin, Solifenacin and Trospium using the MASRI. External monitoring instruments included the Brief Medication Questionnaire (BMQ) and the visual remaining pill count. The state of the prostate gland and the lower urinary tract was monitored using questionnaires I-PSS, OAB Awareness Tool, uroflowmetry and voiding diaries. RESULT: Correlation between the percentage of men non-adherent to treatment (MASRI) and the percentage of patients having a belief barrier on the screen of the BMQ was r = 0.89, p <=0.05, r = 0.92, p <=0.01, r = 0.85, p <=0.05, a number of missed doses on the Regimen Screen of the BMQ was r = 0.79; p <=0.05; r = 0.81; p <=0.05; r = 0.75, p <=0.05, a number of non-adherent patients according to the BMQ was r = 0.83 (p <=0.05), r = 0.88 (p <=0.05), r = 0.79, p <=0.05, the results of the pill count were r = 0.65-0.76; p <=0.05-0.01. These data confirm high validity of the MASRI. CONCLUSION: The MASRI is a valid tool for rapid assessment of adherence to treatment of patients with BPO and OAB receiving Tamsulosin and antimuscarinic drugs and may be recommended for use in clinical practice. PMID- 28074678 TI - Prevention of Alzheimer's disease, cerebrovascular disease and dementia in women: the case for menopause hormone therapy. AB - Alzheimer's disease, cerebrovascular disease and aging-related cognitive impairment and dementia (ARCID) increase in prevalence in women with advancing age. The development of Alzheimer's disease, cerebrovascular disease and ARCID may be postponed or prevented by protective measures including the active treatment of vascular risk factors and continuing exercise and healthy lifestyle from early- and mid-life onward. Bilateral oophorectomy before the natural menopause is associated with an increased incidence of ARCID and the increased risk is significantly reduced by estrogen therapy. Recent advances in menopause hormone therapy including transdermal estrogen therapy have favorably influenced the balance of benefits and risks. A case can be made for menopause hormone therapy in healthy postmenopausal women for 5-10 years starting during the menopausal transition (the 'window of opportunity'), together with all other protective measures, to delay or prevent the development of ARCID in later life. PMID- 28074679 TI - Vitamin D treatment improves levels of sexual hormones, metabolic parameters and erectile function in middle-aged vitamin D deficient men. AB - BACKGROUND: The associations between serum vitamin D (VD), serum testosterone (TT) and metabolic syndrome are complex and with limited published research, particularly on the effects of VD treatment on sexual hormones, erectile function and the metabolic syndrome. OBJECTIVES: This study assessed whether a monthly high dose VD treatment for 12 months in VD deficient middle-aged men was associated with: changes in levels of sexual hormones, improvement of diabetes control and metabolic syndrome components, better erectile function [International Index of Erectile Function (IIEF)-5 questionnaire]; and changes in a prostate marker. MATERIALS AND METHODS: Descriptive research of a prospective study, conducted between October 2014 and September 2015, 102 male patients >=35 [(+/-SD: 53.2 +/- 10.5), (range 35-64)] years with deficient serum VD level (<30 ng/mL) were included in the study. Participants were followed up for one year, with monitoring at 3-, 6-, 9- and 12-months. At the initial baseline visit, a complete medical examination was conducted, and blood was drawn for laboratory tests for above biochemical and hormonal variables under examination. Participants received an initial VD (Ergocalciferol; oral solution 600 000 IU/1.5 ml), and followed a VD treatment regime thereafter. At the four follow up visits (3, 6, 9 and 12 months), blood was collected, and patients' erectile function was evaluated by IIEF-5 questionnaire. MAIN OUTCOME MEASURES: During the follow up visits, all the biochemical and hormonal (TT, estradiol and luteinizing hormones, HbA1c, serum lipids profile) were assessed, and patients' erectile function was evaluated by IIEF-5 questionnaire. RESULTS: Patients' mean age was 53.2 +/- 10.4 years. Serum VD exhibited significant increments (p <0.001) from baseline (15.16 +/- 4.64 ng/mL), to 3 (31.90 +/- 15.99 ng/mL), 6 (37.23 +/- 12.42 ng/mL), 9 (44.88 +/- 14.49 ng/mL) and 12 months (48.54 +/- 11.62 ng/mL), and there was significant stepladder increases in both serum TT level (12.46 +/- 3.30 to 15.99 +/- 1.84 nmol/L) and erectile function scores (13.88 +/- 3.96 to 20.25 +/- 3.24) (p <0.001 for both). We also observed significant stepladder decreases in estradiol (87.90 +/- 27.16 to 69.85 +/- 14.80 pmol/L, p = 0.001), PTH (from 58.52 +/- 28.99 to 38.33 +/- 19.44 pg/mL, p <0.001) and HbA1c levels (7.41 +/- 2.85 to 6.66 +/- 1.67%, p = 0.001). Mean BMI significantly decreased from 33.91 +/- 6.67 to 33.14 +/- 6.35 kg/m2 (p = 0.001); and PSA values significantly increased from 0.59 +/- 0.30 to 0.82 +/- 0.39 ng/mL (p <0.001) at the end of the 12 months' follow-up. There were no changes in LH levels. CONCLUSION: This study demonstrated that VD treatment improves testosterone levels, metabolic syndrome and erectile function in middle-aged men. More randomized placebo-controlled interventional trials of VD treatment in patients with the metabolic syndrome and low TT could assist in uncovering the putative roles of VD. PMID- 28074680 TI - Sero-discovering versus sero-cognisant: initial challenges and needs of HIV serodiscordant couples in Porto Alegre, Brazil. AB - This paper focuses on challenges faced by heterosexual couples of mixed HIV status in Porto Alegre, Brazil, and argues for more conceptual nuance in our understanding of 'serodiscordance'. Couples' stories, collected over 11 months of qualitative research, demonstrate how profoundly serodiscordance involves both partners and suggest that the timing of relationship formation relative to HIV diagnosis influenced the particular challenges they confronted. In recognition of this variation, we propose the distinction of 'sero-discovering' from 'sero cognisant' couples. Though Brazilian health policy strives to address the needs of individuals diagnosed with HIV, the needs of seronegative partners in this cohort received relatively little attention. In addition, the transformation of HIV from a death sentence to a chronic condition both facilitated the formation of serodiscordant unions and raised special challenges for such couples. Conceiving of any person receiving an HIV diagnosis as 'potentially partnered' may help address some of these lacunae while promoting primary prevention within mixed-status couples, and HIV testing more generally. More research with this population is needed. PMID- 28074681 TI - Community-Based Exercise in the Context of HIV: Factors to Consider when Developing and Implementing Community-Based Exercise Programs for People Living with HIV. AB - OBJECTIVE: To identify factors to consider for developing and implementing a community-based exercise (CBE) program for people living with HIV (PLWH). METHODS: We conducted a qualitative descriptive study using semi-structured interviews with PLWH, rehabilitation professionals, and recreation providers from Canada and the United Kingdom. We asked participants to describe their experience with exercise, facilitators, and barriers to accessing and participating in exercise, and factors to consider in developing a CBE program for PLWH. Interviews were analyzed using content analytical techniques. RESULTS: We developed a Framework of CBE in the Context of HIV that describes (1) exercise experiences of PLWH (nature of exercise, motivators for initiating or sustaining exercise, perceived benefits, and barriers and facilitators to exercise) and (2) 11 factors to consider in developing and implementing a CBE program for PLWH. CONCLUSION: Recommendations for the development and implementation of an accessible and feasible CBE program may enhance exercise participation among PLWH. PMID- 28074684 TI - Health and the Built Environment. PMID- 28074683 TI - Objectively measured sedentary behavior and brain volumetric measurements in multiple sclerosis. AB - AIM: This study examined the association between sedentary behavior patterns and whole brain gray matter (GM), white matter (WM) and subcortical GM structures in persons with multiple sclerosis (MS). METHODS: 36 persons with MS wore an accelerometer and underwent a brain MRI. Whole brain GM and WM and deep GM structures were calculated from 3D T1-weighted structural brain images. RESULTS: There were statistically significant (p < 0.01) and moderate or large associations between number of sedentary bouts/day and brain volume measures. The primary result was a consistent negative association between number of sedentary bouts/day and whole brain GM and WM, and deep GM structures. CONCLUSION: We provide novel evidence for decreased brain volume as a correlate of a sedentary behavior pattern in persons with MS. PMID- 28074685 TI - Waist measurement as an aid to type II diabetes screening among Asian Americans. PMID- 28074688 TI - Health and the built environment. PMID- 28074687 TI - The NHS Healthy New Towns programme. PMID- 28074689 TI - Refocusing upstream - three decades of public health: a personal reflection. PMID- 28074690 TI - Well Communities. PMID- 28074691 TI - Health, cities and planning: using universities to achieve place innovation. PMID- 28074692 TI - GoodSAM - how digital networks can revolutionise care in life-threatening emergencies. PMID- 28074693 TI - A green perspective: what good does it do? PMID- 28074694 TI - RSPH policy update. PMID- 28074695 TI - Diary. PMID- 28074698 TI - Crowd planning for public safety. PMID- 28074696 TI - Dr Fiona Sim, OBE - highlights of an outgoing Chair. PMID- 28074699 TI - RSPH Awards 2016: championing the public's health. PMID- 28074701 TI - Editors. PMID- 28074700 TI - Erratum. PMID- 28074702 TI - Operative technique and pitfalls in donor heart procurement. AB - We describe a simple and reproducible donor heart procurement technique in sequential steps. A detailed understanding of procurement and organ preservation techniques should be an essential part of a heart transplant training program. PMID- 28074703 TI - Early surgery after angiography in patients scheduled for valve replacement. AB - Background There are limited data regarding the risks of cardiac surgery early after coronary angiography in patients scheduled for isolated aortic and/or mitral valve replacement. Our aim was to evaluate the risk of early surgery after coronary angiography in these patients. Methods We retrospectively analyzed data of 1044 patients who underwent isolated aortic and/or mitral valve replacement from 2006 to 2014. Baseline, operative, and postoperative variables were collected. The patients were divided into 3 groups based on the interval between coronary angiography and surgery: <=3 days ( n = 216), 4-7 days ( n = 109), and >=8 days ( n = 719). We evaluated hospital mortality and postoperative acute kidney injury. Subgroup analysis was performed according to preoperative creatinine clearance. Results Postoperative creatinine clearance was lower in patients who underwent surgery <=3 days after coronary angiography (63.57 +/- 38.52 mL min-1) compared to >=8 days after coronary angiography (74.56 +/- 54.25 mL min-1, p = 0.015). Patients who underwent surgery <=3 days after coronary angiography had higher hospital mortality when preoperative creatinine clearance was <=60 mL min-1 (12% vs. 4% for creatinine clearance <=and >60 mL min-1, respectively; p = 0.039). Predictors of hospital mortality were New York Heart Association class and postoperative creatinine clearance. Conclusion Hospital mortality was higher in patients with decreased preoperative renal function who underwent surgery within the first 3 days after coronary angiography. Delaying surgery in this subgroup of patients could be a good strategy. PMID- 28074704 TI - The toxicology of zinc chloride smoke producing bombs and screens. AB - CONTEXT: Zinc chloride (ZnCl2)-based smoke bombs and screens are in use since the Second World War (1939-1945). Many case descriptions on ZnCl2 smoke inhalation incidents appeared since 1945. OBJECTIVE: We provide a comprehensive overview of the clinical symptoms and underlying pathophysiology due to exposure to fumes from ZnCl2 smoke producing bombs. In addition, we give a historical overview of treatment regimens and their outcomes. METHODOLOGY: We performed a literature search on Medline, Scopus and Google Scholar databases using combinations of the following search terms "smoke bomb", "smoke screen", "ZnCl2", "intoxication", "poisoning", "case report", "HE smoke", "hexachloroethane smoke", "smoke inhalation" and "white smoke". We retrieved additional reports based on the primary hits. We collected 30 case reports from the last seven decades encompassing 376 patients, 23 of whom died. Of all the patient descriptions, 31 were of sufficient detail for prudent analysis. RESULTS AND CONCLUSIONS: Intoxication with clinical signs mainly took place in war situations and in military and fire emergency training sessions in enclosed spaces. Symptoms follow a biphasic course mainly characterised by dyspnoea, coughing and lacrimation, related to irritation of the airways in the first six hours, followed by reappearance of early signs complemented with inflammation related signs and tachycardia from 24 h onwards. Acute respiratory stress syndrome developed in severely affected individuals. Chest radiographs did not always correspond with clinical symptoms. Common therapy comprises corticosteroids, antibiotics and supplemental oxygen or positive pressure ventilation in 64% of the cases. Of the 31 patients included, eight died, three had permanent lung damage and 15 showed complete recovery, whereas in five patients outcome was not reported. Early signs likely relate to caustic reactions in the airway lining, whereas inhaled ZnCl2 particles may trigger an inflammatory response and associated delayed fibrotic lung damage. Smoke bomb poisoning is a potentially lethal condition that can occur in large cohorts of victims simultaneously. PMID- 28074705 TI - An uncommon cause of sciatic pain: tuberculous osteomyelitis of the ischial tuberosity. AB - A 66-year-old Caucasian female presented with insidious sciatic pain leading to an uncommon diagnosis of tuberculous osteomyelitis with unknown portal entry. The patient did not report a history of a previous tuberculosis (TB) infection and her chest X-ray was negative for TB. Considering TB in the differential diagnosis of a 'bone abscess', it is of paramount importance to come to a correct diagnosis. Conventional radiographs still remain the first-line imaging modality for evaluation of skeletal symptomatology. However, biopsies or aspirates are often needed to yield the definitive diagnosis. The lack of awareness of the potential extrapulmonary involvement of TB leads to an important delay in diagnosis and treatment. Antituberculous drugs should be started at the time of biopsy and continued during 12-18 months, due to poor drug penetration into osseous and fibrous tissues. PMID- 28074706 TI - Christians' cut: popular religion and the global health campaign for medical male circumcision in Swaziland. AB - Swaziland faces one of the worst HIV epidemics in the world and is a site for the current global health campaign in sub-Saharan Africa to medically circumcise the majority of the male population. Given that Swaziland is also majority Christian, how does the most popular religion influence acceptance, rejection or understandings of medical male circumcision? This article considers interpretive differences by Christians across the Kingdom's three ecumenical organisations, showing how a diverse group people singly glossed as 'Christian' in most public health acceptability studies critically rejected the procedure in unity, but not uniformly. Participants saw medical male circumcision's promotion and messaging as offensive and circumspect, and medical male circumcision as confounding gendered expectations and sexualised ideas of the body in Swazi Culture. Pentecostal-charismatic churches were seen as more likely to accept medical male circumcision, while traditionalist African Independent Churches rejected the operation. The procedure was widely understood to be a personal choice, in line with New Testament-inspired commitments to metaphorical circumcision as a way of receiving God's grace. PMID- 28074708 TI - E. P. Pope Memorial Award to Dr. John M. Adaska. PMID- 28074707 TI - 2016 AAVLD Awards. PMID- 28074709 TI - A serosurvey for ruminant pestivirus exposure conducted using cattle sera collected for brucellosis surveillance in the United States. AB - Four species of ruminant pestivirus are currently circulating in the United States: Bovine viral diarrhea virus 1 and 2 (BVDV-1, -2; predominant host: cattle), Border disease virus (BDV; predominant host: sheep), and pronghorn virus (sporadically detected in wild ruminants). A third bovine pestivirus called HoBi like virus has been detected in cattle and water buffalo in South America, Asia, and Europe. To date, no isolations of HoBi-like viruses from U.S. cattle have been reported. To assess exposure, 2,000 cattle sera, collected between 2014 and 2015 as part of the U.S. brucellosis surveillance program, were tested for antibodies against BVDV-1, BVDV-2, and HoBi-like viruses. In addition, RNA was extracted and tested by reverse transcription-polymerase chain reaction for the presence of pestiviruses; all samples tested negative. The percent of VN-positive samples was 91.3% for BVDV-1, 89.3% for BVDV-2, and 84.9% for HoBi-like viruses. Because the 3 bovine pestiviruses are antigenically cross-reactive, the comparative level of antibody against each pestivirus species was determined. Based on comparative titers, samples were segregated into 6 categories: no titers (7.6%), titers clearly higher against BVDV-1 (22.2%), titers substantially higher against BVDV-2 (9.1%), BVDV-1 and BVDV-2 titers equivalent but substantially higher than HoBi titers (25.7%), titers substantially higher against HoBi-like viruses (0%), and equivocal (35.4%). Titers tended to be higher against BVDV-1 than BVDV-2. However, the overall percentage of animals with titers below levels considered protective against acute bovine pestivirus infection were ~11% for BVDV-1, 12% BVDV-2, and 18% for HoBi-like virus. PMID- 28074710 TI - Canine spinal cord glioma. AB - Spinal cord glioma is uncommonly reported in dogs. We describe the clinicopathologic and diagnostic features of 7 cases of canine spinal cord glioma and briefly review the veterinary literature on this topic. The median age at presentation was 7.2 y. Six females and 1 male were affected and 4 dogs were brachycephalic. The clinical course lasted from 3 d to 12 wk, and clinical signs were progressive and associated with multiple suspected neuroanatomic locations in the spinal cord. Magnetic resonance imaging of 6 cases revealed T2-weighted hyperintense lesions with variable contrast enhancement in the spinal cord. All dogs had a presumptive clinical diagnosis of intraparenchymal neoplasia or myelitis based on history, advanced imaging, and cerebrospinal fluid analysis. Euthanasia was elected in all cases because of poor outcome despite anti inflammatory or immunosuppressive treatment or because of poor prognosis at the time of diagnosis. Tumor location during autopsy ranged from C1 to L6, with no clear predilection for a specific spinal cord segment. The diagnosis was based on histopathology and the immunohistochemistry expression of glial fibrillary acidic protein, oligodendrocyte lineage transcription factor 2, 2',3'-cyclic-nucleotide 3'-phosphodiesterase, neuron-specific enolase, synaptophysin, and Ki-67. Diagnoses consisted of 4 cases of oligodendroglioma, 2 cases of gliomatosis cerebri, and 1 astrocytoma. This case series further defines the clinicopathologic features of canine spinal glioma and highlights the need for comprehensive immunohistochemistry in addition to routine histopathology to confirm the diagnosis of these tumors. PMID- 28074711 TI - A comparison of the reliability of two gene targets in loop-mediated isothermal amplification assays for detecting leptospiral DNA in canine urine. AB - We compared 2 novel loop-mediated isothermal amplification (LAMP) assays that target either the 16S ribosomal RNA ( rrs) gene or the gene encoding a 32-kDa leptospiral lipoprotein ( lipL32) in order to assess the effect of the target on the accuracy of the LAMP assays. The most sensitive assay was the rrs assay with a limit of detection (LOD) of 1.2 * 101 genome equivalents per reaction. The novel lipL32 assay showed an LOD of 1.2 * 102 genome equivalents per reaction. Both assays showed adequate specificity when tested against a collection of bacteria commonly found in voided canine urine. However, when field samples were assayed, the rrs assays gave many false-positive results and a poor positive predictive value of 8.33%. In conclusion, even if the LAMP assay is used in low prevalence areas, the lipL32 assay would be preferable. Conversely, the higher analytical sensitivity of the rrs assay could be effectively used as a screening test in endemic areas with high disease prevalence, followed by confirmation of the positive results using the lipL32 assay. PMID- 28074712 TI - High-throughput whole genome sequencing of Porcine reproductive and respiratory syndrome virus from cell culture materials and clinical specimens using next generation sequencing technology. AB - Next-generation sequencing (NGS) technologies have increasingly played crucial roles in biological and medical research, but are not yet in routine use in veterinary diagnostic laboratories. We developed and applied a procedure for high throughput RNA sequencing of Porcine reproductive and respiratory syndrome virus (PRRSV) from cell culture-derived isolates and clinical specimens. Ten PRRSV isolates with known sequence information, 2 mixtures each with 2 different PRRSV isolates, and 51 clinical specimens (19 sera, 16 lungs, and 16 oral fluids) with various PCR threshold cycle (Ct) values were subjected to nucleic acid extraction, cDNA library preparation (24-plexed), and sequencing. Whole genome sequences were obtained from 10 reference isolates with expected sequences and from sera with a PRRSV real-time reverse transcription PCR Ct <= 23.6, lung tissues with Ct <= 21, and oral fluids with Ct <= 20.6. For mixtures with PRRSV-1 and -2 isolates (57.8% nucleotide identity), NGS was able to distinguish them as well as obtain their respective genome sequences. For mixtures with 2 PRRSV-2 isolates (92.4% nucleotide identity), sequence reads with nucleotide ambiguity at numerous sites were observed, indicating mixed infection; however, individual virus sequences could only be separated when 1 isolate identity and sequence in the mixture is known. The NGS approach described herein offers the prospect of high-throughput sequencing and could be adapted to routine workflows in veterinary diagnostic laboratories, although further improvement of sequencing outcomes from clinical specimens with higher Ct values remains to be investigated. PMID- 28074713 TI - Pathogens, patterns of pneumonia, and epidemiologic risk factors associated with respiratory disease in recently weaned cattle in Ireland. AB - We examined the pathogens, morphologic patterns, and risk factors associated with bovine respiratory disease (BRD) in 136 recently weaned cattle ("weanlings"), 6 12 mo of age, that were submitted for postmortem examination to regional veterinary laboratories in Ireland. A standardized sampling protocol included routine microbiologic investigations as well as polymerase chain reaction and immunohistochemistry. Lungs with histologic lesions were categorized into 1 of 5 morphologic patterns of pneumonia. Fibrinosuppurative bronchopneumonia (49%) and interstitial pneumonia (48%) were the morphologic patterns recorded most frequently. The various morphologic patterns of pulmonary lesions suggest the involvement of variable combinations of initiating and compounding infectious agents that hindered any simple classification of the etiopathogenesis of the pneumonias. Dual infections were detected in 58% of lungs, with Mannheimia haemolytica and Histophilus somni most frequently recorded in concert. M. haemolytica (43%) was the most frequently detected respiratory pathogen; H. somni was also shown to be frequently implicated in pneumonia in this age group of cattle. Bovine parainfluenza virus 3 (BPIV-3) and Bovine respiratory syncytial virus (16% each) were the viral agents detected most frequently. Potential respiratory pathogens (particularly Pasteurella multocida, BPIV-3, and H. somni) were frequently detected (64%) in lungs that had neither gross nor histologic pulmonary lesions, raising questions regarding their role in the pathogenesis of BRD. The breadth of respiratory pathogens detected in bovine lungs by various detection methods highlights the diagnostic value of parallel analyses in respiratory disease postmortem investigation. PMID- 28074714 TI - Oncocytic carcinoma of the salivary gland in a dog. AB - A 3-y-old male miniature Dachshund was presented with an ~0.8 cm diameter mass in the right mandibular region. Fourteen months later, the mass was 5 * 4 * 3 cm. Grossly, the mass was encapsulated and was homogeneously gray-white on cut surface. Microscopically, the mass was composed of large, round to polygonal tumor cells that were arranged in solid nests and cords separated by a fibrovascular stroma. Tumor cells had large, round, hypochromatic nuclei containing large prominent nucleoli and abundant eosinophilic cytoplasm containing dark blue granules visible with phosphotungstic acid-hematoxylin stain. Metastasis was observed in the mandibular lymph node. Immunohistochemically, tumor cells were positive for CK AE1/AE3, low-molecular weight CK (CAM5.2), E-cadherin, mitochondria ATPase beta subunit, and S100, but were negative for vimentin, carcinoembryonic antigen, p63, CK14, CD10, and chromogranin A. Ultrastructurally, tumor cells contained numerous mitochondria. Therefore, the tumor was diagnosed as an oncocytic carcinoma of the mandibular gland. PMID- 28074715 TI - Comparison of three different primer sets for sexing birds. AB - Because many bird species are monomorphic or only sexually dimorphic in adult stages, it is difficult to determine their sexes, which may cause significant problems in population and conservation studies. DNA-based sexing relies on the chromodomain helicase DNA binding ( CHD) gene located on the W chromosome and its homolog on the Z chromosome, giving distinct banding patterns on agarose gel as a result of length differences in intronic regions within this gene. We used 3 specific primer sets, CHD1F/CHD1R, 2550F/2718R, and P2/P8, for sex determination of 230 samples from 77 avian species. We report here the records for 70 of those species analyzed using the CHD1F/CHD1R primer set, and 49 species using 2550F/2718R, and 46 species using P2/P8. CHD1F/CHD1R PCR products on agarose gel generally showed an apparent single band in males and 2 bands in females, but the products of 2550F/2718R (61%) and P2/P8 (42%) showed distinct banding patterns for separate bird orders. However, when PCR products of these last 2 primer pairs labeled with fluorescent dye were run in a capillary gel and detected using a DNA analyzer, P2/P8 gave 2 distinguishable peaks in females, whereas 2550F/2718R results remained the same. DNA sexing with any of those 3 primer sets can be used for all sexually monomorphic avian taxa although the primer sets should be compared before choosing the most efficient one for molecular sexing of the studied species. PMID- 28074716 TI - Semiquantitative immunohistochemical detection of progesterone receptors in male accessory sex glands as a screening assay for anabolic steroid use in bulls. AB - We investigated the immunohistochemical expression of progesterone receptors (PRs) in the prostate and bulbourethral glands of thirty-two 10-14-mo-old Charolais bulls following treatment with a low dosage of estrogens. Animals were divided into 2 groups: 16 animals (group T) were treated for 71 d with a therapeutic dose of trenbolone acetate and estradiol by subcutaneous implant, 16 animals (group C) received no treatment. Urine samples were collected both at the beginning of the trial and 9 times during the study. A semiquantitative analysis of immunohistochemistry (IHC) was performed by counting the number of positive cells in 10 randomly selected high-power fields (hpf). Both groups showed no significant histologic lesions. IHC examination showed positive cells in the epithelium of both glands, with different patterns of distribution between groups. In group C, IHC-positive cells per hpf varied from 0 to 40 in the prostate and from 0 to 32 in the bulbourethral gland. In group T, positive cells varied from 0 to 85 per hpf in the prostate and from 0 to 75 in the bulbourethral gland. The treated group showed significantly higher median numbers of positively stained cells in both organs than the controls ( p < 0.001). Chemical analysis of the urine samples confirmed that the experimental treatment mimics continuous, low-dose administration of anabolic steroids. IHC quantification showed good sensitivity with a high predictive power to correctly classify treated animals and could be used as a preliminary screening test in bulls. PMID- 28074717 TI - Endosulfan poisoning in canids and felids in the Calabria region of southern Italy. AB - Endosulfan, a highly toxic insecticide and acaricide, was globally banned under the Stockholm Convention in May 2011 because of its threats to human health and the environment. Despite the ban on its use, endosulfan is still present in the environment, causing poisoning events in domestic animals and wildlife. Toxicologic analysis of poisoned animals conducted by the Istituto Zooprofilattico Sperimentale del Mezzogiorno revealed that in the past 3 y, this pesticide has not disappeared in the regions of interest. More than 650 samples (baits and animal organs) collected from 2013 to 2015 were analyzed through solid phase extraction followed by gas chromatography-electron capture detection. This methodology allowed us to identify 45 positive samples from the Calabria region of southern Italy (10.2 % of the total samples). Most were samples of gastric content (alpha-endosulfan range: 1.27-3,800 mg/kg) and baits (alpha-endosulfan range: 92-1,497 mg/kg). Lower concentrations of pesticide were found in samples of stomach (alpha-endosulfan: 6.7-118 mg/kg) and liver (alpha-endosulfan: 0.38 14.2 mg/kg). PMID- 28074718 TI - Pyrolysis-catalysis of waste plastic using a nickel-stainless-steel mesh catalyst for high-value carbon products. AB - A stainless-steel mesh loaded with nickel catalyst was produced and used for the pyrolysis-catalysis of waste high-density polyethylene with the aim of producing high-value carbon products, including carbon nanotubes (CNTs). The catalysis temperature and plastic-to-catalyst ratio were investigated to determine the influence on the formation of different types of carbon deposited on the nickel stainless-steel mesh catalyst. Increasing temperature from 700 to 900 degrees C resulted in an increase in the carbon deposited on the nickel-loaded stainless steel mesh catalyst from 32.5 to 38.0 wt%. The increase in sample-to-catalyst ratio reduced the amount of carbon deposited on the mesh catalyst in terms of g carbon g-1 plastic. The carbons were found to be largely composed of filamentous carbons, with negligible disordered (amorphous) carbons. Transmission electron microscopy analysis of the filamentous carbons revealed them to be composed of a large proportion (estimated at ~40%) multi-walled carbon nanotubes (MWCNTs). The optimum process conditions for CNT production, in terms of yield and graphitic nature, determined by Raman spectroscopy, was catalysis temperature of 800 degrees C and plastic-to-catalyst ratio of 1:2, where a mass of 334 mg of filamentous/MWCNTs g-1 plastic was produced. PMID- 28074719 TI - [Ten tips for initial assessment and treatment of minor burns]. AB - The initial care of a patient with burns is a challenge for every doctor. After cooling the burn appropriately, a careful history and a good initial assessment are of essential importance for treatment. The burn should be inspected regularly for early detection of any infection and to evaluate wound healing. If healing has not occurred in two weeks, hypertrophic scarring may develop and surgical treatment should be considered. It is always possible to contact the burns centres in Beverwijk, Rotterdam and Groningen to discuss treatment of the burn, any infection of a wound, consideration of surgical treatment, or transfer of a patient to a burn centre. PMID- 28074720 TI - [Registration of assessments in orthopaedic residents' portfolios is falling short]. AB - OBJECTIVE: To evaluate of the number of registered competency assessments in the portfolios of orthopaedic residents in the Netherlands, for whom a competency based training programme is mandatory. DESIGN: National cohort study. METHOD: We collected data regarding the registered assessments of all orthopaedic residents who finished their training between 2012-2015. We determined the number of registered assessments of 'standard orthopaedic treatments' (evaluating residents' competency in 70 different orthopaedic treatments), objective structured clinical skills evaluations (OSCEs), critically appraised topics (CATs), and 360 degree feedback appraisals. We compared the number of registered assessments in the portfolios with the minimum requirements laid down by the training curriculum. RESULTS: A total of 196 residents finished their training between 2012 and 2015. These residents finished their training with a mean (i.e., percentage of minimally required number of assessments) of 17.0 (34%) 'standard orthopaedic treatments' (level 4 or 5), 13.6 (34%) OSCEs, 2.6 (33%) CATs and 0.2 (4%) 360 degree feedback. CONCLUSION: On average, only one-third of the minimally required number of assessments were registered in the portfolios of orthopaedic residents (OSCEs and standard orthopaedic treatments level 4 or 5). These revelations show that action is needed to improve the way in which the progress of residents is monitored. These findings are going to have an effect on the new curriculum which must be more practical and less complex. Additionally, external quality control will focus more on residents at the end of their training and on the training region involved. This information may serve as a framework for postgraduate training programmes in other scientific associations which also find themselves in the same process of modernisation. PMID- 28074721 TI - [Capecitabine-induced ventricular fibrillation]. AB - BACKGROUND: Capecitabine is an orally-administered chemotherapeutic agent used in the treatment of colorectal, gastric and breast carcinoma. Capecitabine has relatively mild side effects. Less known are its potential severe cardiotoxic effects. CASE DESCRIPTION: We report a case of a 61-year-old man recently diagnosed with rectal cancer. Six days after starting with capecitabine, he developed a cardiac arrest due to ventricular fibrillation (VF). Extensive additional diagnostics did not explain the cardiac arrest nor VF. Given the observed time relation between initiation of capecitabine administration and the occurrence of VF, combined with the absence of other causes for VF, we suspect that VF is a likely consequence of capecitabine-induced coronary vasospasm. CONCLUSION: Capecitabine-induced VF is a rare occurrence. With the increasing use of capecitabine for the treatment of various cancers, health professionals should be aware of these potential cardiotoxic side effects. PMID- 28074722 TI - [An adolescent with inability to bear weight on his knee after a jump]. AB - A 15-year-old boy sustained a left tuberositas tibiae avulsion fracture as a result of jumping. This type of fracture typically occurs in adolescent boys during sports. PMID- 28074723 TI - [A woman with excessive dynamic airway collapse]. AB - BACKGROUND: 'Excessive dynamic airway collapse' (EDAC) is a form of tracheamalacia, that does not affect the rings of cartilage on the anterior side of the trachea, but in which the posterior wall of the trachea collapses during inspiration and expiration. CASE DESCRIPTION: An 80 year-old woman presented to the accident and emergency department with dyspnoea and severe inspiratory and expiratory stridor, with sudden onset a few hours previously. Following a series of investigations, she was shown to have a narrowing of the trachea, radiating from the posterior wall. The diagnosis was EDAC. Because her saturation levels were acceptable and she was otherwise well she was admitted to the intensive care unit for observation only. The symptoms disappeared within 4 days, without intervention. CONCLUSION: EDAC is usually asymptomatic, but when symptoms arise the clinical picture is often confused with asthma, COPD or laryngeal oedema. The diagnostic gold standard is bronchoscopy. Therapy is chosen on the basis of severity of the symptoms. PMID- 28074724 TI - [Tasty food for cancer patients: the impact of smell and taste alterations on eating behaviour]. AB - - This article provides an overview of smell and taste changes in cancer patients and the influence of these changes on eating behaviour and food preferences.- Taste changes seem to be more common than alterations in the sense of smell.- The changes in taste and smell are often temporary; smell and taste functions mostly return to their previous level after treatment cessation.- The type of cancer and its treatment influence changes in the sense of smell and taste, making it challenging to give general advice.- Changes in taste and smell - which can lead to modified food preferences and decreased appetite - should be taken into consideration during the treatment of cancer patients to improve the nutritional status and the effectiveness of the treatment.- This requires a personal approach, a multidisciplinary team and validated methods. Moreover, it is important to involve the environment of the patient. PMID- 28074725 TI - [We are living longer, but in good health? Inequality in quality-adjusted life expectancy]. AB - OBJECTIVE: Quantifying trends in quality-adjusted life expectancy (QALE) by level of education in the Netherlands 2001-2011. DESIGN: Retrospective study. METHOD: For this study we used data from several sources. Using regression models we estimated mortality rates and quality of life as functions of age, gender, calendar year and educational level. Quality of life was measured using the SF-6D questionnaire. In order to calculate QALE we combined estimates of mortality rates and quality of life into Sullivan's life tables. RESULTS: Over the period 2001-2011 quality of life and survival increased at all educational levels. This resulted in an increase of QALE varying from 1.5 to 3 years depending on gender and education. QALE increased less strongly in people with lower education than in those with higher education, which to a large extent was due to widening inequalities in mortality. CONCLUSION: The Dutch are living longer and have a better quality of life but inequalities in QALE have increased. PMID- 28074726 TI - [Assessments during Medical Specialists Training: quantity or quality?] AB - Structured assessments form a mandatory part of Dutch Medical Specialist Training, but create administrative workload for both the staff and supervisors. One could argue that the quality of the narrative feedback is more important than the extensive reporting in learning portfolios, and that the focus should be on continuous on-the-job coaching. PMID- 28074727 TI - [Flank pain caused by a renal artery dissection]. AB - BACKGROUND: A spontaneous renal artery dissection is a very rare diagnosis. The clinical presentation can vary and its course can be atypical. There are no guidelines available regarding treatment; however, the options are a conservative (medication) or interventional (radiological or surgical) approach. CASE DESCRIPTION: A 45-year-old man presented to the emergency department with hypertensive urgency after earlier episodes of flank pain. The cause appeared to be a spontaneous bilateral renal artery dissection with infarction. After a multidisciplinary consultation, the decision was made to manage the patient conservatively since symptoms had subsided, blood pressure was acceptable and renal function remained stable. Eventually, kidney function restored to normal and CT images showed almost complete recovery of the previously damaged renal parenchyma. CONCLUSION: This case demonstrates that in the event of renal artery dissection, a conservative medication policy may be a good option in clinically stable patients with non-deteriorating renal function. Timely recognition and adequate follow-up are important to prevent serious complications, such as renal ischaemia or renal infarction that could necessitate a nephrectomy. PMID- 28074728 TI - [Relation between continuity of care and mortality]. AB - Continuity of care is one of the most important features of primary care. In this commentary we discuss the article by Maarsingh et al. regarding the relation between personal continuity (seeing the same care provider) and mortality. We raise some important points on the way continuity of care is measured and show how it affects the results. Our conclusion is that the relation between continuity of care and mortality is still weak. However, this does not alter the importance of having a personal care provider. It increases patient satisfaction and trust in the care provider, both of which are essential for a good doctor patient relationship. PMID- 28074729 TI - [A woman with episodes of abdominal pain]. AB - A 63-year-old woman was referred to the gastroenterology outpatient clinic with gallstones and a big liver mass on ultrasound. She had episodes of upper abdominal pain. Magnetic resonance imaging showed typical images for a giant liver haemangioma. We performed a surgical resection of the giant haemangioma and the gallbladder. PMID- 28074730 TI - [Thrombocytopenia]. AB - Thrombocytopenia can be caused by many different underlying disorders. The diagnostic approach to this haematological abnormality may, therefore, be challenging for physicians. Causes of thrombocytopenia may be classified according to decreased production, increased peripheral consumption or destruction, or abnormal distribution of platelets. Additionally, it is important to rule out pseudothrombocytopenia, a laboratory artefact caused in vitro by ethylenediaminetetraacetic acid (EDTA) anticoagulants. Here we discuss the clinical and laboratory evaluation of drug-induced thrombocytopenia based on the description of two patients, one with ceftriaxone-induced thrombocytopenia and the other with heparin-induced thrombocytopenia. Drug-induced thrombocytopenia is rare, but it is an important consideration in the differential diagnosis of thrombocytopenic patients. The aetiology is often not recognised or is ascribed to other complications such as disseminated intravascular coagulation (DIC) or immune thrombocytopenia (ITP). Misdiagnosis or late recognition may result in morbidity and mortality due to bleeding or thrombotic complications. PMID- 28074731 TI - [An older woman with dextrocardia and shortness of breath]. AB - A 73-year-old woman, who had a history of chronic sinusitis, presented to the emergency department with shortness of breath. Additional imaging demonstrated situs inversus totalis and multiple bronchiectases. The clinical triad of sinusitis, situs inversus totalis and bronchiectasis is often characteristic of Kartagener's syndrome, a subset of primary ciliary dyskinesia. PMID- 28074732 TI - [Acute abdominal pain in children caused by pneumonia]. AB - Three children presented with symptoms of an acute abdomen. In all three a diagnosis of pneumonia was subsequently established, and the patients made a full recovery following antibiotic therapy. When a paediatric patient presents with symptoms of an acute abdomen, the possibility of pneumonia should be considered. It can be difficult to differentiate between appendicitis and pneumonia because of the subtle clinical signs. Early recognition is, however, important in order to start the correct therapy and to avoid an unnecessary laparotomy. PMID- 28074733 TI - [Normoglycaemic ketoacidosis in pregnant patients with diabetes; early recognition is critical]. AB - Diabetic ketoacidosis (DKA) during pregnancy is a rare but very serious complication that requires early recognition and treatment to prevent severe complications. Here we present three cases in which DKA occurred during normoglycaemia, demonstrating the importance of early recognition. In pregnancy, DKA can occur at lower blood glucose levels than usual due to several pregnancy related factors, such as altered metabolism, increased insulin resistance, lower buffering capacity related to chronic hyperventilation and hunger. Symptoms that are common during pregnancy, such as vomiting, may be missed as a first sign of DKA. In patients with type 1 diabetes mellitus (especially those on continuous subcutaneous insulin infusion) insulin administration must never be discontinued, as this prevents lipolysis and ketone formation. Physicians and patients need to be aware of the risks and management of DKA in pregnancy. PMID- 28074734 TI - [A rare form of obstructive pulmonary disease]. AB - BACKGROUND: Lymphangioleiomyomatosis (LAM) is characterised by progressive dyspnoea, spontaneous pneumothorax and cystic pulmonary destruction. The disease may show similarities with emphysema clinically, radiologically and on lung function tests. CASE DESCRIPTION: A 44-year-old woman was referred for lung transplantation because of a 6-year history of dyspnoea and severe obstructive pulmonary function disorder with decreased diffusion capacity. Both her relatively young age and the fact that she had never smoked made us doubt the diagnosis 'COPD'. The pulmonary cysts seen on high-resolution CT (HRCT) suggested LAM. This was confirmed when we revised a pulmonary biopsy that had previously been performed. CONCLUSION: CT investigation should be carried out in patients with severe obstructive pulmonary disease without a risk profile appropriate for COPD. Diffuse, homogenous cysts on CT scan can indicate LAM, particularly in women. Conflict of interest and financial support: none declared. PMID- 28074735 TI - [Diagnostic delay of pulmonary embolism]. AB - OBJECTIVE: To quantify the different stages of diagnostic delay of pulmonary embolism (PE) in patients and to identify other clinical factors associated with this delay. DESIGN: Case series. METHOD: Medical records were reviewed for all patients diagnosed with PE in the period 1 January 2008 and 31 December 2009 in Isala Hospital in Zwolle (the Netherlands), and data was collated for: the dates of symptom onset, presentation to a GP, referral to secondary care, and diagnosis respectively. The relationship between diagnostic delay and other clinical parameters such as gender, age, risk factors, symptoms and co-morbidities was tested using multivariate logistic regression analysis. RESULTS: For the 261 patients included in the analysis, the average total delay was 8.6 days. Patient delay (4.2 days average) and delay in primary care (3.9 days) were the major contributors to this delay. Chest pain and symptoms of deep venous thrombosis were associated with an early diagnosis. Patient delay was shorter in patients with chest pain and longer in patients with dyspnoea. In primary care, chest pain and rales were associated with an early referral, whereas the presence of co morbidity led to a delayed referral. Delay in secondary care was shorter when the patient presented with dyspnoea. CONCLUSION: The diagnostic delay of PE is substantial, especially patient delay and delays originating in primary care. Further research is needed to identify clinical factors that raise suspicion of PE in primary care, to aid the development of improved diagnostic models. PMID- 28074736 TI - [An athletic man with a swollen arm]. AB - A 28-year-old male was referred to our emergency department with a swollen left arm after intensive exercise. Physical examination revealed distension of the superficial veins of his left arm and chest. Duplex ultrasound confirmed the diagnosis of Paget-Schroetter syndrome. He was successfully treated with thrombolysis and first rib resection. PMID- 28074737 TI - [An elderly, cachexic patient with a painful leg]. AB - A 68-year-old female presented with acute abdominal discomfort in the left lower quadrant and a painful left leg. Her medical history only revealed an eating disorder. Physical examination was insignificant. Diagnostic imaging showed an obturator hernia; subsequently, a laparotomy was performed. An obturator hernia, also known as little old ladies' disease, is associated with abdominal pain and a painful leg. PMID- 28074738 TI - [Do mental health nurses take over care from general practitioners?] AB - OBJECTIVE: The objective of this study was to examine mental health care provided by general practitioners and by mental health nurses working in general practices. DESIGN: Observational research. METHOD: We analysed how many consultations with patients with mental health problems were recorded in Dutch general practices in the period 2010-2014. General practices with and without a mental health nurse were compared, and we investigated which patients were mainly treated by mental health nurses. RESULTS: An increasing number of patients visited the GP for mental health problems in the period 2010-2014. GPs collaborating with a mental health nurse recorded a somewhat higher number of patients with mental health problems than GPs without a mental health nurse, but used as many consultations per patient. Mental health nurses mainly treat females, adult patients, and patients with common mental health problems. CONCLUSION: Mental health nurses do not take over care from GPs, but provide additional mental health care to patients with mental health problems. Collaborating with a mental health nurse might increase GPs' alertness to record mental health problems. PMID- 28074739 TI - [Power in the ICU: awareness and change]. AB - - Power is a charged issue but, when executed with integrity, a potent instrument to improve quality of care.- Execution of power has various manifestations, which have an important effect on several aspects of the care process including the doctor-patient relationship, primary responsible physician and the relationship with other team members.- Abuse of power is a source of conflicts and may also result in emotional exhaustion and burnout.- Various measures may stimulate the appropriate use of power. PMID- 28074741 TI - Efficiency of Rosemary and Basil Essential Oils on the Shelf-Life Extension of Atlantic Mackerel (Scomber scombrus) Fillets Stored at 2 degrees C. AB - The objective of the present study was to evaluate the impact of rosemary and basil essential oils (EOs) on the quality of Atlantic mackerel fillets stored at 2 degrees C up to 15 days. Atlantic mackerel (Scomber scombrus) fillets were periodically evaluated to assess their textural, color, physicochemical, and spectral characteristics. The results indicated that rosemary and basil treatments were effective for inhibiting the formation of total volatile basic nitrogen (TVB-N) and lipid oxidation products during storage. Based on TVB-N values, the shelf life of Atlantic mackerel fillets treated with rosemary and basil EOs was extended by 2 and 5 days, respectively, compared to the control group. Similar results were obtained with thiobarbituric acid-reactive substance analysis, which demonstrated an extended shelf life of Atlantic mackerel immersed with rosemary and basil EOs of 2 and 3 days, respectively, compared to the control group. The factorial discriminant analysis applied on the concatenated first five principal components corresponding to the physicochemical, textural, color, and fluorescence measurements allowed clear discrimination of the three groups, because a correct classification rate of 93.3% was obtained. Therefore, treatment with basil and rosemary EOs, as natural biopreservative compounds, could present a high-potential application in the seafood industry. PMID- 28074742 TI - Development and Validation of an RP-HPLC Method for the Determination of Vinpocetine and Folic Acid in the Presence of a Vinpocetine Alkaline Degradation Product in Bulk and in Capsule Form. AB - An alkaline-forced degradation hydrolytic product of vinpocetine was prepared and characterized by 1H-NMR, FTIR spectroscopy, and MS. Subsequently, a simple, selective, and validated reversed-phase HPLC method was developed for the simultaneous estimation of vinpocetine and folic acid in the presence of a vinpocetine alkaline degradation product. Chromatographic separation was achieved using an isocratic mobile phase consisting of acetonitrile-0.02 M KH2PO4 [containing 0.2% (v/v) triethylamine and adjusted to pH 6 with orthophosphoric acid; (80 + 20, v/v)] at a flow rate of 0.9 mL/min at ambient temperature on a Eurospher II C18 (250 * 4.6 mm, 5 MUm) column, with UV detection at 280 nm for folic acid and 230 nm for vinpocetine and its alkaline hydrolytic product. Linearity, accuracy, and precision were found to be acceptable over a concentration range of 12.5-200 MUg/mL for vinpocetine and 1-16 MUg/mL for folic acid. The proposed method was successfully applied for the determination of both drugs and a vinpocetine hydrolysis product in a laboratory-prepared mixture and in a capsule containing both drugs. PMID- 28074743 TI - Synthesis of Nanoporous Carbon for Fast Uptake of Cr(VI) and Ni(II) from Aqueous Solution. AB - Nanoporous carbon (NPC), based on organic xerogel compounds, was prepared at 650 degrees C pyrolysis temperature by sol-gel method from pyrogallol and formaldehyde (PF-650) mixtures in water using picric acid as a catalyst. The performance of NPC was characterized by scanning electron microscopy, transmission electron microscopy, X-ray diffraction and nitrogen porosimetry. The metal uptake characteristics were explored using effective parameters including pH, contact time, initial metal ion concentration, and temperature. Better adsorption of Cr(VI) and Ni(II) was observed at pH 2 and 4, respectively. The Langmuir model gave the better fit for Cr(VI), whereas for Ni(II), the Freundlich model is better than the other models. The kinetic studies revealed that the adsorption is fast and its data are well fitted by the pseudo-second-order kinetic model. The thermodynamic properties, i.e., DeltaG degrees , and DeltaS degrees , showed that adsorption of Cr(VI) and Ni(II) onto NPC was endothermic, spontaneous and feasible in the temperature range of 300 to 328 K. PMID- 28074744 TI - Being Ever Mindful. PMID- 28074745 TI - A Day in the Life of a Specialty Pharmacist. PMID- 28074746 TI - Oncology's Trojan Horse: Using Viruses to Battle Cancer. AB - : In 2016, the American health care system was faced with more than 1.6 million new cases of cancer, and individuals older than 65 years of age will be affected disproportionately. Many older individuals are poor candidates for traditional treatments (e.g., chemotherapy, radiation) because of actual or potential treatment-related adverse events. Researchers continuously look for novel therapeutic strategies, and an exciting new one is on the horizon: virotherapy. Viruses' ability to infect and kill human cells makes them promising cancer treatments. The greatest success has been seen in acute lymphocytic leukemia. To date, four genetically engineered oncolytic viruses have been approved globally by several countries' health regulatory agencies, but several challenges remain. Only one, talimogene laherparepvec (T-Vec), is available in the United States. Treatment-naive patients tend to respond better than patients receiving T-Vec as second-line therapy. Other good candidates for T-Vec include elderly patients who do not tolerate checkpoint inhibitors (the leading immunotherapy in advanced melanoma). Researchers continue to look for ways to increase oncolytic viruses' clinical potency. Once they do, these agents will become effective cancer therapy. ABBREVIATIONS: GM-CSF = Genetically modified colony-stimulating factor, HIV = Human immunodeficiency virus, HSV-1 = Herpes simplex virus, OV = Oncolytic virus. PMID- 28074747 TI - Liraglutide: A Glucagon-Like Peptide-1 Agonist for Chronic Weight Management. AB - OBJECTIVE: To review the efficacy and safety of liraglutide 3.0 mg for weight loss. DATA SOURCE: A literature search was performed using PubMed and MEDLINE from 2000 to 2016. The following key terms were used alone or in combination: glucagon-like peptide-1 agonist, liraglutide, obesity, overweight, and weight loss. Additional supporting literature was identified utilizing the reference lists of the preceding articles. STUDY SELECTION: Analyzed studies were published in English and investigated use of liraglutide and its impact on weight loss. DATA EXTRACTION: Clinical studies with a primary focus of liraglutide use in weight loss were included in this review. Author consensus determined final study inclusion. DATA SYNTHESIS: Management of obesity centers on behavior modification that includes diet and exercise; however, pharmacologic therapy may be used. Several studies have indicated that GLP-1 receptor agonists promote weight loss in patients with type 2 diabetes mellitus (T2DM). The efficacy of liraglutide 3.0 mg as a weight-loss agent in patients with and without T2DM was established in three SCALETM clinical trials. Liraglutide 3.0 mg was generally well tolerated during clinical trials. Common adverse events were typically related to the gastrointestinal system (i.e., nausea, vomiting). CONCLUSION: Based on available evidence, liraglutide 3.0 mg appears to be a safe and effective addition to the pharmacologic armamentarium available for chronic weight management in the general population. However, there are limited data within the geriatric population. Clinicians should consider liraglutide's cost, route of administration, and concomitant drug therapy when deciding which patients are appropriate candidates for liraglutide therapy. ABBREVIATIONS: AE = Adverse events, AHA/ACC/TOS = American Heart Association/American College of Cardiology/ The Obesity Society, BMI = Body mass index, CV = Cardiovascular, FDA = Food and Drug Administration, GI = Gastrointestinal, GLP-1 = Glucagon-like peptide-1, HbA1c = Hemoglobin A1c, Kcal = Kilocalorie, LCD = Low-calorie diet, MTC = Medullary thyroid carcinoma, NHLBI = National Heart Lung and Blood Institute, NNH = Number needed to harm, PYE = Patient years of exposure, REMS = Risk Evaluation and Mitigation Strategy, SCALETM = Satiety and Clinical Adiposity - Liraglutide Evidence in Non-diabetic and Diabetic individuals, T2DM = Type 2 diabetes mellitus. PMID- 28074748 TI - Possible Parkinson's Disease Induced by Chronic Manganese Supplement Ingestion. AB - OBJECTIVE: The objective is to report a case of possible neurotoxicity resulting from an incorrect dietary supplement for osteoporosis taken at a toxic dose. SUMMARY: The case study examined here is a 37-year-old African-American female who consumed excessive manganese over a period of years, resulting in Parkinson's disease (PD). This patient was referred to the pharmacist pharmacotherapy service by a neurology physician. PD has been shown in the medical literature to be caused by chronic exposure to high levels of manganese. It may be concluded that daily doses of manganese well above the upper limit of 9 mg per day were taken by this patient for an extended period of time, possibly causing PD via manganism. CONCLUSION: This case illustrates the unknown risks taken by patients who use excessive amounts of over-the-counter herbals and supplements and how pharmacists can assist patients and physicians in the proper use of these popular products. ABBREVIATIONS: AI = Adequate intake, EMS = Eosinophilia myalgia syndrome, MTM = Medication therapy management, UL = Tolerable upper limit. PMID- 28074749 TI - Students Use "STAMP-OUT" Program to Advance Seniors' Knowledge of Drug Misuse. AB - : This program assessed the impact of student presentations on 30 seniors and sought to improve their knowledge of prescription drug misuse and abuse. The six pharmacy students used the ASCP Foundation's "STAMP Out Prescription Drug Misuse and Abuse Tool Kit." Information presented to senior audiences included descriptions of drug misuse and abuse and preventive measures to uphold medication safety. Students assessed seniors' prior knowledge about the topics through audience participation. Afterwards, a self-assessment quiz was given that examined participants' learning about safe medication practices. Before the presentation, only 36% of participants recognized the difference between prescription drug misuse and abuse. The self-assessment quiz results showed that following the three presentations, all 30 participants received perfect scores: The results showed an improvement in knowledge after attending the student presentations. This program demonstrates advancement of the pharmacy profession through educating seniors on proper medication use to prevent drug abuse and improve medication safety. ABBREVIATION: OTC = Over-the-counter, UB SPPS: University at Buffalo School of Pharmacy and Pharmaceutical Sciences. PMID- 28074750 TI - Physician Perceptions of Consultant Pharmacist Services Associated with an Intervention for Adverse Drug Events in the Nursing Facility. AB - OBJECTIVE: To assess the importance and performance of consultant pharmacist services delivered before and after an intervention to detect and manage adverse drug events among nursing facility residents. DESIGN: Before and after intervention survey of physicians participating in a randomized, controlled trial. SETTING: Four nonprofit, academically affiliated nursing facilities. PARTICIPANTS: Attending physicians providing nursing facility care who were randomized to intervention or control groups. INTERVENTIONS: Within the intervention arm, consultant pharmacists provided academic detailing in which trained health care professionals visit practicing physicians in their offices and present the most up-to-date clinical information. Physicians responded to alerts from a medication monitoring system, adjudicated system alerts for adverse drug events (ADEs), and provided structured recommendations about ADE management. MAIN OUTCOME MEASURES: We compared physicians' assessments of the importance and performance of consultant pharmacist services before and after the trial intervention in the intervention and control groups. RESULTS: In the intervention group, ratings of importance increased for all 24 survey questions, and 5 of the changes were statistically significant (P < 0.05). In the control group, ratings of importance increased for 16 questions, and none of the changes were statistically significant. In the intervention group, ratings of performance increased for all 24 questions, and 20 of the changes were statistically significant. In the control group, ratings of performance increased for 16 questions, and none of the changes was statistically significant. CONCLUSION: A multifaceted, consultant pharmacist-led intervention comprising academic detailing, computerized decision support, and structured communication framework can improve physicians' assessment of importance and performance of consultant pharmacist services. ABBREVIATIONS: ADE = Adverse drug event, M = Statistically significant mean, RCT = Randomized controlled trial, SBAR = Situation, Background, Discussion, Recommendation, SD = Standard deviation. PMID- 28074751 TI - What Does the Future Hold Under President-Elect Trump? PMID- 28074752 TI - Removal of 17beta-estradiol in a Biological Active Carbon Reactor with Acetic Acid and Humic Acid. AB - The objective of this study is to characterize the removal of 17beta-estradiol (E2) and the microbial community of a biologically active carbon (BAC) reactor under acetic acid or humic acid as the primary carbon source. Influent E2 concentration was maintained at 20 MUg/L. Higher than 99% removal of E2 was achieved by the BAC reactor. The concentration of E2 increased from below detection limit (<5.8 ng/L) to 48 +/- 8 ng/L after switching the primary carbon source from acetic acid to humic acid in the reactor influent. Meanwhile, effluent estrone concentration increased from 50 +/- 15 to 55 +/- 15 ng/L after the switch of primary carbon source in the reactor influent. 17beta-estradiol degrading bacteria were isolated. Microbial community structures under different nutrient conditions were revealed by high throughput sequencing. The presence of readily biodegradable carbon source such as acetic acid benefited E2 removal in the BAC reactor. PMID- 28074753 TI - Conversion of Wastes to Bioelectricity, Bioethanol, and Fertilizer. AB - This research article presents production of bioelectricity, bioethanol, and fertilizer from different industrial wastewaters supplemented with waste fruit and vegetables. Bioelectricity was generated from wastewater through the development of different microbial fuel cells (MFCs). It was observed that the voltage was increased in series combination, whereas current was increased in parallel combinations. The series combination of four units of single-chamber and eight units of double-chamber MFCs produced the power output of 5.43 mW and 4.08 mW, respectively, which is sufficient to light up the light emitting diode (LED). Power output was increased by the addition of waste fruit and vegetables. The leftover filtrates of MFCs were used for the production of bioethanol using Saccharomyces cerevisiae, while residues were used as fertilizer to check the growth of okra plant. The result showed that minor amount of bioethanol is produced from different samples, which was confirmed by the preparation of ethylbenzoate derivative. PMID- 28074754 TI - Legal and Ethical Imperatives for Using Certified Sign Language Interpreters in Health Care Settings: How to "Do No Harm" When "It's (All) Greek" (Sign Language) to You. AB - Communication obstacles in health care settings adversely impact patient practitioner interactions by impeding service efficiency, reducing mutual trust and satisfaction, or even endangering health outcomes. When interlocutors are separated by language, interpreters are required. The efficacy of interpreting, however, is constrained not just by interpreters' competence but also by health care providers' facility working with interpreters. Deaf individuals whose preferred form of communication is a signed language often encounter communicative barriers in health care settings. In those environments, signing Deaf people are entitled to equal communicative access via sign language interpreting services according to the Americans with Disabilities Act and Executive Order 13166, the Limited English Proficiency Initiative. Yet, litigation in states across the United States suggests that individual and institutional providers remain uncertain about their legal obligations to provide equal communicative access. This article discusses the legal and ethical imperatives for using professionally certified (vs. ad hoc) sign language interpreters in health care settings. First outlining the legal terrain governing provision of sign language interpreting services, the article then describes different types of "sign language" (e.g., American Sign Language vs. manually coded English) and different forms of "sign language interpreting" (e.g., interpretation vs. transliteration vs. translation; simultaneous vs. consecutive interpreting; individual vs. team interpreting). This is followed by reviews of the formal credentialing process and of specialized forms of sign language interpreting-that is, certified deaf interpreting, trilingual interpreting, and court interpreting. After discussing practical steps for contracting professional sign language interpreters and addressing ethical issues of confidentiality, this article concludes by offering suggestions for working more effectively with Deaf clients via professional sign language interpreters. PMID- 28074755 TI - Attachment Theory and Neuroscience for Care Managers. AB - This article describes a model for care managers that is based on attachment theory supplemented by knowledge from neuroscience. Together, attachment theory and basic knowledge from neuroscience provide for both an organizing conceptual framework and a scientific, measureable approach to assessment and planning interventions in a care plan. PMID- 28074756 TI - Risk Factors and Effects of Care Management on Hospital Readmissions Among High Users at an Academic Medical Center. AB - Few studies have examined predictors of hospital readmission among high-using patients enrolled in a behaviorally oriented intensive care management program. The purpose of this case control study was to describe risk factors and the effectiveness of a complex care management program for hospital readmission among vulnerable patients at a large academic medical center. One hundred sixty-three patients enrolled in the University of Michigan Complex Care Management Program (UM CCMP) were hospitalized between January 2014 and March 2015. Sixty were readmitted within 30 days of discharge. Among all patients, the mean age was 51.1 years, 38.7% were non-White, 81.5% had Medicaid and/or Medicare, 50.3% were without stable housing, and 27.6% had significant psychiatric illnesses. Although mostly not statistically significant, multivariable risk of readmission was increased by having twice the mean number of hospitalizations in the last 6 months (odds ratio [OR] = 1.44, 95% CI [1.00, 2.06]), having chronic pain on a scheduled narcotic (OR = 1.49, 95% CI [0.67, 3.35]), and going to a primary care physician within 30 days of discharge (OR = 1.35, 95% CI [0.63, 2.89]). Risk was decreased by going to a specialist (OR = 0.54, 95% CI [0.23, 1.27]) and receiving moderate-intensity CCMP intervention (OR = 0.48, 95% CI [0.20, 1.19]). Among hospitalized high-using patients enrolled in the UM intensive care management program, readmission is likely significantly influenced by medical, behavioral, and social challenges. Care management appears most effective in preventing readmission among patients with mid- rather than high- or low-level needs. These findings at a single program should be explored in further, larger studies. PMID- 28074757 TI - Advanced Practice Nurse Transitional Care Model Promotes Healing in Wound Care. AB - : Optimally, transition in health care should be seamless and incorporate a well thought-out patient-centered discharge plan; yet, many hospitalized patients are unprepared for discharge, thereby compromising patient safety and quality of care. Transition of care should include a broad range of time-limited services designed to ensure health care continuity to avoid poor outcomes among at-risk populations. This case study demonstrates that advanced practice nurses (APNs) are in the perfect position to bridge the existing gap, reduce readmissions, and improve patient health. Transition from hospital to home is stressful under the best of circumstances. Naylor's transition of care model and Meleis's transition theory provides the foundation for APNs to manage patients' wounds across the continuum of care. The patient is educated and guided through the convoluted health care system, resulting in decreased discontinuity and improved outcomes and safety. CONCLUSION: A smooth transition between levels of care requires collaboration and care coordination of medical services and health care providers. The result of this continuity is improved patient outcomes, improved patient satisfaction, and reduced medical errors. APNs as care coordinators have the ability to bridge the existing gap between hospitalization and home while preventing readmission. PMID- 28074759 TI - ? PMID- 28074761 TI - ? PMID- 28074760 TI - ? PMID- 28074762 TI - [Ileus forarsaget af pille i blisterpakning]. PMID- 28074763 TI - [Dysfunctional breathing in patients with asthma]. AB - Dysfunctional breathing (DB) is a common comorbidity in adults with incomplete asthma control. The few available large-scale, randomized studies suggest efficacy of physiotherapy on symptom burden. In this article we discuss the current evidence including the need for systematic description of physiotherapeutic interventions. We also describe how access to physiotherapy service for DB (with or without asthma) is highly heterogeneous in Denmark, and that there is a need for increasing awareness of physiotherapy implementation for and research in DB (with or without concomitant asthma). PMID- 28074764 TI - [Chemoprevention of photocarcinogenesis using antioxidants]. AB - The skin is constantly exposed to reactive oxygen species (ROS) from both endogenous and exogenous sources. Ultraviolet irradiation is a well-known contributor of photocarcinogenesis and photoaging, as it - among other things - promotes the production of ROS which damage nucleic acids, proteins and lipids. Topical or oral administration of antioxidants is presumed to counteract the damaging effects of ROS to the skin, thus potentially lowering the risk of skin cancers and skin aging. We review the current literature on chemoprevention of photocarcinogenesis using antioxidants. PMID- 28074765 TI - [Osteoporosis treatment can be discontinued based on an individual assessment]. AB - In most patients, treatment of osteoporosis is a long-term challenge. Because alendronate and zoledronic acid accumulate in bone with some persistent antifracture efficacy after therapy, it is reasonable to consider a "drug holiday" for low-risk patients. It is recommended that the duration and length of drug holiday should be individualized for each patient. For all other bisphosphonates data are limited. For other antiresorptive and anabolic agents "drug holiday" is not recommended. PMID- 28074766 TI - [Herpes simplex encephalitis]. AB - Herpes simplex encephalitis (HSE) is a rare disease, although it is the most common form of sporadic encephalitis worldwide. Recently, studies have provided important new insight into the genetic and immunological basis of HSE. However, even in the presence of antiviral treatment, mortality and morbidity remain relatively high. Therefore, precise and early diagnosis together with basic and clinical studies to gain better insight into the pathogenesis of HSE is a prerequisite for the development of improved prophylaxis and treatment of this severe disease. PMID- 28074767 TI - [Diet consisting mainly of sunflower seeds and chicken as the cause of small bowel obstruction in a bodybuilder]. AB - Diet-induced small bowel obstruction is a rare condition in young, healthy patients. We describe a case of a 26-year-old man, who presented with acute small bowel obstruction. During a period of eight days prior to admission the patient had been eating an extremely restricted diet along with a regulated intake of fluids. The diet was part of a preparation for a major fitness contest. We chose a conservative treatment of IV fluids and laxatives, and the patient recovered uneventfully. PMID- 28074768 TI - [Erythema multiforme med svaer slimhindeinvolvering]. PMID- 28074769 TI - [Neuroradiological changes by suppression of tics]. AB - Tourette's syndrome is characterized by involuntary tics. First choice of treatment has been pharmacological, but recently, behavioural therapy teaching patients to suppress their tics has been introduced. Neuroimaging studies have shown an increased activity in the prefrontal cortex, temporal lobes and caudate nucleus, and a decreased activity in globus pallidus and putamen during inhibition of tics. The activity in the frontal lobes changes with age, probably caused by a lack of compensatory hypertrophy. In order to fully understand the mechanism behind behavioural therapy further studies are needed. PMID- 28074770 TI - [18F-FDG PET/CT contributes to diagnostics and therapy monitoring of radiation induced angiosarcoma]. AB - Angiosarcomas are rare, aggressive malignant mesenchymal tumours with a poor prognosis. Radiation therapy is an independent risk factor for the development of secondary angiosarcoma. The onset of angiosarcoma may resemble benign lesions, leading to delayed diagnosis. It has been suggested that 18F-fluorodeoxyglucose (FDG) PET/CT scan may be useful in the early diagnosis in differentiating angiosarcoma from benign lesions and in therapy monitoring. We report the utility of 18F-FDG PET/CT scan in the diagnosis and follow-up of radiation-induced angiosarcoma in a patient previously treated for uterine cancer. PMID- 28074771 TI - [Practical management of troponin screening after non-cardiac surgery]. AB - Myocardial injury after non-cardiac surgery (MINS) is associated with significant morbidity and mortality. Routine troponin screening is necessary to identify patients with MINS. Although some evidence indicates benefit with aspirin and statin therapy in these patients, a number of clinical considerations must be done in the practical management of MINS. This article describes current experience with identification and treatment in Denmark of patients with MINS. PMID- 28074772 TI - [Nuclear medicine techniques for selective internal radiotherapy of liver cancer]. AB - Selective internal radiation therapy (SIRT) of hepatocellular carcinoma has been introduced at Aarhus University Hospital. 90Y-microspheres are implanted in the tumour by catheterization of the tumour feeding liver artery. Pretreatment angiography and test treatment using 99mTc-labelled particles followed by scintigraphy ensure a feasible and effective treatment. Post-treatment imaging of radiation from 90Y visualize the localization of microspheres. Currently, SIRT is also applied for liver metastases of neuroendocrine tumours. Future indications may include other liver tumours and metastases. PMID- 28074773 TI - Low-dose dialysis combined with low protein intake can maintain nitrogen balance in peritoneal dialysis patients in poor economies?. AB - OBJECTIVE: Due to limited economic conditions, we tried to provide "fitted" dialysis doses instead of the doses recommended by the international guidelines to the individual patients. In the present cross-sectional study, we studied the dialysis adequacy and nutritional status of 5 peritoneal dialysis patients who had a low dialysis dose (2 bags, 4,000 mL/day). METHODS: The 3-day dietary records were reviewed to calculate patients' energy, protein, and nitrogen intake (NI). The nitrogen removal (NR) from urine and dialysate was measured by Kjeldahl technique. Fecal nitrogen was estimated as 0.0155 g/kg/day. Subjective global nutritional assessment was used to evaluate the nutritional status. RESULTS: Among the 5 patients, 1 male and 4 female, mean age was 59 (42 - 81) years, dialysis duration 43 (33 - 74) months, body weight 51.05 +/- 2.53 kg. The mean dietary protein intake was 0.66 g/kg/day, total weekly Kt/v was 1.25 (residual kidney Kt/v was 0.09), and total daily fluid removal was 699 mL. However, they achieved lower-level neutral nitrogen balance (NI 5.26 +/- 0.93 g/day vs. NR 5.33 +/- 0.81 g/day, N balance -0.07 +/- 0.60 g/day). All of them maintained good nutritional status (SGA "A") without symptoms of nitrogen retention (serum urea 22 +/- 4.18 mmol/L). CONCLUSIONS: Lower dialysis dose with lower daily protein intake can achieve a lower-level nitrogen balance and does not lead to malnutrition. It may be an effective approach to solve the dialysis problem for the economically week population in China, especially for people with a smaller body size with lower transport membrane.?. PMID- 28074774 TI - The DAIR (debridement, antibiotics and implant retention) procedure for infected total knee replacement - a literature review. AB - Prosthetic joint infection (PJI) is a devastating complication in total knee arthroplasty (TKA) and third most common cause of revision of TKA with significant morbidity and surgical challenges. Treatment options include non operative measures with long term antibiotic suppression, debridement and implant retention (DAIR), one- or two-stage revision arthroplasty, arthrodesis and amputation. Implant retention without infection is ideal and DAIR has been reported to have variable success rates depending on patient factors, duration of infection, infecting micro-organisms, choice of procedure, single or multiple debridement procedures, arthroscopic or open, antibiotic choice and duration of antibiotic use. We present a thorough literature review of DAIR for infected TKA. The important factors contributing to failure are presence of sinus, immunocompromised patient, delay between onset of infection and debridement procedure, Staphylococcal infection in particular Meticillin Resistant Staphylococcal aureus, multiple debridement procedures, retention of exchangeable components and short antibiotic duration. In conclusion DAIR can be successful procedure to eradicate infection in TKA in selective patients with factors contributing to failure taken into account. PMID- 28074775 TI - Axillary artery transection and bilateral pulmonary embolism after anterior shoulder dislocation: case report. AB - INTRODUCTION: Anterior shoulder dislocation can be associated with vascular and neurological complications. However, axillary artery injury associated with shoulder dislocation is rare and extremely rare without bone fracture. An early diagnosis of these complications allows predicting long-term functional outcomes. METHODS: This article reports the case of a 66-year-old patient who presented an anterior shoulder dislocation after a ski fall without any neurological dysfunction or pulse deficit. RESULTS: The first reduction attempts were unsuccessful and during the new attempt, we observed a hematoma. A CT scan showed a disruption of the axillary artery and a bilateral pulmonary embolism. CONCLUSION: Neurovascular injury must be systematically sought before and after reduction, and a multidisciplinary approach is always necessary. PMID- 28074776 TI - Morphological classification of acromial spur: correlation between Rockwood tilt view and arthroscopic finding. AB - : Purpose and hypothesis: Acromion spur is the extrinsic factor for impingement syndrome and rotator cuff tear. The Rockwood tilt view can be used to evaluate prominence of the anterior acromion, however no study has shown the correlation of findings between the Rockwood tilt view and the arthroscopic finding. METHODS: We developed the arthroscopic classification of acromion spur as type 1 flat spur, type 2 bump spur, type 3 heel spur, type 4 keel spur, and type 5 irregular spur. Patients with rotator cuff syndrome who underwent arthroscopic surgery were recruited. Two observers were asked to classify the type of spur from arthroscopic findings and Rockwood tilt views separately in random pattern. The prevalence of supraspinatus tendon tear was also recorded as no tear, partial thickness tear, and full-thickness tear. RESULTS: The keel spur (33.9%) was the most common finding followed by the heel spur (27.8%). The correlation was high especially for the heel, the keel, and the irregular spur (75.47%, 74.03%, and 72.73%, respectively.) These three types of spurs have a high prevalence of full thickness of supraspinatus tendon tear. CONCLUSION: The Rockwood tilt view can be used to evaluate the morphology of an acromion spur, especially the at-risk spur that correlates highly with the full-thickness supraspinatus tendon tear. The arthroscopic classification will also be a useful tool to improve communication between the surgeon and the guide for appropriate treatment in a rotator cuff tear patient when encountering the heel, keel, and irregular spur. PMID- 28074778 TI - "Thunderclap" headache in a patient with depression: Answer. PMID- 28074777 TI - Cell assemblies at multiple time scales with arbitrary lag constellations. AB - Hebb's idea of a cell assembly as the fundamental unit of neural information processing has dominated neuroscience like no other theoretical concept within the past 60 years. A range of different physiological phenomena, from precisely synchronized spiking to broadly simultaneous rate increases, has been subsumed under this term. Yet progress in this area is hampered by the lack of statistical tools that would enable to extract assemblies with arbitrary constellations of time lags, and at multiple temporal scales, partly due to the severe computational burden. Here we present such a unifying methodological and conceptual framework which detects assembly structure at many different time scales, levels of precision, and with arbitrary internal organization. Applying this methodology to multiple single unit recordings from various cortical areas, we find that there is no universal cortical coding scheme, but that assembly structure and precision significantly depends on the brain area recorded and ongoing task demands. PMID- 28074779 TI - "Thunderclap" headache in a patient with depression: Question. PMID- 28074781 TI - Mechanically tunable sub-10 nm metal gap by stretching PDMS substrate. AB - Manipulating light in sub-10 nm or subnanometer metal nanogaps is crucial to study the strong interaction between electromagnetic waves and matters. However, the fabrication of metallic nanogaps with precisely controlled size and high throughput still remains a challenge. Here, we developed an approach to actively control the gap distance between adjacent metal nanoparticles from 140 nm to sub 10 nm or even 0 nm via mechanical stretching process. To demonstrate this method, we manufactured the gold disk arrays in a square lattice on the polydimethylsiloxane (PDMS) substrate through interference lithography and gold deposition, and sub-10 nm interparticle gap was achieved as exerting a strain of 100% to the PDMS substrate. Transmission spectra show a remarkable red shift of the dipole resonance with narrowing gap from 140 nm to sub-10 nm. Importantly, a universal scaling law between the gap distance in nanoscale and the stretching amount of PDMS substrate in macroscopic scale were demonstrated experimentally and theoretically. Our method can tune the gap distance continuously and reversibly, suggesting potential applications in surface-enhanced Raman scattering, single photon emitter and quantum tunneling of electric charge. PMID- 28074780 TI - MRI-directed cognitive fusion-guided biopsy of the anterior prostate tumors. AB - PURPOSE: We aimed to evaluate the efficacy of magnetic resonance imaging (MRI) directed cognitive fusion transrectal ultrasonography (TRUS)-guided anterior prostate biopsy for diagnosis of anterior prostate tumors and to illustrate this technique. METHODS: A total of 39 patients with previous negative TRUS biopsy, but high clinical suspicion of occult prostate cancer, prospectively underwent prostate MRI including diffusion-weighted imaging (DWI). Patients with a suspicious anterior lesion on MRI underwent targeted anterior gland TRUS-guided biopsy with cognitive fusion technique using sagittal probe orientation. PIRADS version 1 scores (T2, DWI, and overall), lesion size, prostate-specific antigen (PSA), PSA density, and prostate gland volume were compared between positive and negative biopsy groups and between clinically significant cancer and remaining cases. Logistic regression analysis of imaging parameters and prostate cancer diagnosis was performed. RESULTS: Anterior gland prostate adenocarcinoma was diagnosed in 18 patients (46.2%) on targeted anterior gland TRUS-guided biopsy. Clinically significant prostate cancer was diagnosed in 13 patients (33.3%). MRI lesion size, T2, DWI, and overall PIRADS scores were significantly higher in patients with positive targeted biopsies and those with clinically significant cancer (P < 0.05). Biopsies were positive in 90%, 33%, and 29% of patients with overall PIRADS scores of 5, 4, and 3 respectively. Overall PIRADS score was an independent predictor of all prostate cancer diagnosis and of clinically significant prostate cancer diagnosis. CONCLUSION: Targeted anterior gland TRUS guided biopsy with MRI-directed cognitive fusion enables accurate sampling and may improve tumor detection yield of anterior prostate cancer. PMID- 28074782 TI - The need for a life-cycle based aging paradigm for nanomaterials: importance of real-world test systems to identify realistic particle transformations. AB - Assessing the risks of manufactured nanomaterials (MNM) has been almost exclusively focused on the pristine, as-produced materials with far fewer studies delving into more complex, real world scenarios. However, when considering a life cycle perspective, it is clear that MNM released from commercial products during manufacturing, use and disposal are far more relevant both in terms of more realistic environmental fate and transport as well as environmental risk. The quantity in which the particles are released and their (altered) physical and chemical form should be identified and it is these metrics that should be used to assess the exposure and hazard the materials pose. The goal of this review is to (1) provide a rationale for using a life-cycle based approach when dealing with MNM transformations, (2) to elucidate the different chemical and physical forces which age and transform MNM and (3) assess the pros and cons of current analytical techniques as they pertain to the measurement of aged and transformed MNM in these complex release scenarios. Specifically, we will describe the possible transformations common MNM may undergo during the use or disposal of nano-products based on how these products will be used by the consumer by taking stock of the current nano-enabled products on the market. Understanding the impact of these transformations may help forecast the benefits and/or risks associated with the use of products containing MNM. PMID- 28074783 TI - Automated extraction of single H atoms with STM: tip state dependency. AB - The atomistic structure of the tip apex plays a crucial role in performing reliable atomic-scale surface and adsorbate manipulation using scanning probe techniques. We have developed an automated extraction routine for controlled removal of single hydrogen atoms from the H:Si(100) surface. The set of atomic extraction protocols detect a variety of desorption events during scanning tunneling microscope (STM)-induced modification of the hydrogen-passivated surface. The influence of the tip state on the probability for hydrogen removal was examined by comparing the desorption efficiency for various classifications of STM topographs (rows, dimers, atoms, etc). We find that dimer-row-resolving tip apices extract hydrogen atoms most readily and reliably (and with least spurious desorption), while tip states which provide atomic resolution counter intuitively have a lower probability for single H atom removal. PMID- 28074784 TI - Electronic properties and transistors of the NbS2-MoS2-NbS2 NR heterostructure. AB - Based on density function theory and nonequilibrium Green's functions, we construct a NbS2-MoS2-NbS2 NR inplane heterostructure. The effects of channel length, width, chirality and vacancy of the heterostructure on transport properties are systematically investigated. The electron transport of the armchair-edge heterostructure device shows ballistic transport properties, while the zigzag-edge heterostructure device exhibits resonance tunneling transport properties. Further study indicates NbS2-MoS2-NbS2 field effect transistors (FETs) to be excellent ambipolar transistors. The FETs have high performances with current on/off ratio 4.7 * 105 and subthreshold swing 90 mV/decade with channel length m = 16 and width n = 6. Increases in the channel length sharply reduce the off-state current and enhance the performance of the devices significantly. PMID- 28074785 TI - Deformable registration of CT and cone-beam CT with local intensity matching. AB - Cone-beam CT (CBCT) is a widely used intra-operative imaging modality in image guided radiotherapy and surgery. A short scan followed by a filtered backprojection is typically used for CBCT reconstruction. While data on the mid plane (plane of source-detector rotation) is complete, off-mid-planes undergo different information deficiency and the computed reconstructions are approximate. This causes different reconstruction artifacts at off-mid-planes depending on slice locations, and therefore impedes accurate registration between CT and CBCT. In this paper, we propose a method to accurately register CT and CBCT by iteratively matching local CT and CBCT intensities. We correct CBCT intensities by matching local intensity histograms slice by slice in conjunction with intensity-based deformable registration. The correction-registration steps are repeated in an alternating way until the result image converges. We integrate the intensity matching into three different deformable registration methods, B spline, demons, and optical flow that are widely used for CT-CBCT registration. All three registration methods were implemented on a graphics processing unit for efficient parallel computation. We tested the proposed methods on twenty five head and neck cancer cases and compared the performance with state-of-the-art registration methods. Normalized cross correlation (NCC), structural similarity index (SSIM), and target registration error (TRE) were computed to evaluate the registration performance. Our method produced overall NCC of 0.96, SSIM of 0.94, and TRE of 2.26 -> 2.27 mm, outperforming existing methods by 9%, 12%, and 27%, respectively. Experimental results also show that our method performs consistently and is more accurate than existing algorithms, and also computationally efficient. PMID- 28074786 TI - Annals of Cardiac Anesthesia: Beacon journey toward excellence: 2015-2017. PMID- 28074787 TI - Anesthesiology and the difficult airway - Where do we currently stand? PMID- 28074788 TI - Comparison of two doses of heparin on outcome in off-pump coronary artery bypass surgery patients: A prospective randomized control study. AB - INTRODUCTION: While off pump coronary artery bypass surgery is practiced with an intention to reduce the morbidity associated with cardiopulmonary bypass, the resultant 'hypercoagulability' needs to be addressed. Complications such as cavitary thrombus possibly due to the hyper coagulability after off pump coronary artery bypass surgery have been described. Many clinicians use higher doses of heparin - up to 5 mg/kg in order to thwart this fear. Overall, there appears to be no consensus on the dose of heparin in off pump coronary artery bypass surgeries. AIM OF THE STUDY: The aim of the study was understand the differences in outcome of such as transfusion requirement, myocardial ischemia, and morbidity when two different doses were used for systemic heparinization. METHODS: Elective patients scheduled for off pump coronary artery bypass surgery were included. Ongoing anti platelet medication was not an exclusion criteria, however, anti platelet medications were ceased about a week prior to surgery when possible. Thoracic epidural anesthesia was administered as an adjunct in patients who qualified for it. By computer generated randomization chart, patients were chosen to receive either 2 or 3 mg/kg of intravenous unfractioned heparin to achieve systemic heparinization with activated clotting time targeted at >240 secs. Intraoperative blood loss, postoperative blood loss, myocardial ischemic episodes, requirement of intraaortic balloon counter pulsation and transfusion requirement were analyzed. RESULTS: Sixty two patients participated in the study. There was one conversion to cardiopulmonary bypass. The groups had comparable ACT at baseline (138.8 vs. 146.64 seconds, P = 0.12); 3 mg/kg group had significantly higher values after heparin, as expected. But after reversal with protamine, ACT and need for additional protamine was similar among the groups. Intraoperative (685.56 +/- 241.42 ml vs. 675.15 +/- 251.86 ml, P = 0.82) and postoperative blood loss (1906.29 +/- 611.87 ml vs 1793.65 +/- 663.54 ml , p value 0.49) were similar among the groups [Table 4]. The incidence of ECG changes of ischemia, arrhythmias, conversion to CPB, or need for intra-aortic balloon counter pulsation were not different. CONCLUSIONS: Use of either 2 or 3 mg/kg heparin for systemic heparinization in patients undergoing OPCAB did not affect the outcome. PMID- 28074789 TI - Extracorporeal membrane oxygenation in severe influenza infection with respiratory failure: A systematic review and meta-analysis. AB - INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) has been extensively used for potentially reversible acute respiratory failure associated with severe influenza A (H1N1) pneumonia; however, it remains an expensive, resource intensive therapy, with a high associated mortality. This systematic review and meta-analysis aims to summarize and pool outcomes data available in the published literature to guide clinical decision-making and further research. METHODS: We conducted a systematic search of MEDLINE (1966 to April 15, 2015), EMBASE (1980 to April 15, 2015), CENTRAL, and Google Scholar for patients with severe H1N1 pneumonia and respiratory failure who received ECMO. The study validity was appraised by Newcastle-Ottawa Scale. The primary outcome was all-cause mortality. The secondary outcomes were duration of ECMO therapy, mechanical ventilation, and Intensive Care Unit (ICU) length of stay. RESULTS: Of 698 abstracts screened and 142 full-text articles reviewed, we included 13 studies with a total of 494 patients receiving ECMO in our final review and meta-analysis. The study validity was satisfactory. The overall mortality was 37.1% (95% confidence interval: 30 45%) limited by underlying heterogeneity (I2 = 65%, P value of Q statistic = 0.006). The median duration for ECMO was 10 days, mechanical ventilation was 19 days, and ICU length of stay was 33 days. Exploratory meta-regression did not identify any statistically significant moderator of mortality (P < 0.05), except for the duration of pre-ECMO mechanical ventilation in days (coefficient 0.19, standard error: 0.09, Z = 2.01, P < 0.04, R2 = 0.16). The visual inspection of funnel plots did not suggest the presence of publication bias. CONCLUSIONS: ECMO therapy may be used as an adjunct or salvage therapy for severe H1N1 pneumonia with respiratory failure. It is associated with a prolonged duration of ventilator support, ICU length of stay, and high mortality. Initiating ECMO early once the patient has been instituted on mechanical ventilation may result in improved survival. PMID- 28074790 TI - Incidence and progression of cardiac surgery-associated acute kidney injury and its relationship with bypass and cross clamp time. AB - INTRODUCTION: Cardiac surgery-associated kidney injury (CSA-AKI) is common but relatively less is known about its progression. The present study is aimed at evaluating the incidence and course of CSA-AKI and its relationship with the different durations of cardiopulmonary bypass (CPB) and cross clamp times. MATERIALS AND METHODS: Occurrences of CSA-AKI are evaluated as per the Akin Kidney Injury Network (AKIN) criteria over the course of 5 postoperative day (POD) in 100 patients. The relationship of different durations of CPB and aortic cross clamp time with CSA-AKI is analyzed by Chi-squared test for trend and other appropriate tests using INSTAT software. RESULTS: One hundred (43 male, 57 female; mean age of 37.01 +/- 12.28 years, and baseline mean serum creatinine 0.99 +/- 0.20 mg %) patients undergone mostly valve replacement, and congenital heart disease correction was evaluated. Nearly 49% suffered CSA-AKI (81.63% AKIN Class I) with maximum numbers on 2 nd POD. Serum creatinine followed a falling trend 3 rd POD onward except in 8.16% cases of CSA-AKI. Oliguria was absent even in AKIN Class II. The CPB time >70 min and cross clamp time >60 min increase CSA AKI risk by an OR of 4.76 and 2.84, respectively (P < 0.05). CONCLUSION: CSA-AKI is very prevalent; mostly of AKIN Class I and increases with increasing CPB and cross clamp time. Urine output is not a reliable indicator of CSA-AKI. The AKIN Class II on the very 1 st POD or increasing trend of serum creatinine beyond 3 rd POD should alert for early intervention. PMID- 28074791 TI - Selection of an appropriate left-sided double-lumen tube size for one-lung ventilation among Asians. AB - CONTEXT: Selecting an appropriate size double-lumen tube (DLT) for one-lung ventilation has always been a challenge as most choose it based on experience or using the existing guidelines based on gender and height. AIMS: The aim of this study was to determine if the appropriate choice of this tube could be based on the patients' height, weight, tracheal diameter (TD), or the left main stem bronchus diameter (LMBD) and also to determine the relationship between height and depth of insertion among Asians. SUBJECTS AND METHODS: This was a retrospective review of 179 patients who were intubated with a left-sided DLT and also had a posterior-anterior view of a digital chest radiograph for tracheal and left main bronchus diameter measurements. Additional data collected included patients' demographics and DLT size used. RESULTS: There were 123 (68.7%) males and 56 (31.3%) females with an overall mean age of 33.3 +/- 16.3 years. Majority of the males (48.8%) used a size 39 Fr while females (46.4%) used a 35 Fr. There were weak correlations between DLT size with height (male: R2 = 0.222; female: R2 = 0.193), DLT size with weight (male: R2 = 0.109; female: R2 = 0.211), DLT size with TD (male: R2 = 0.027); female: R2 = 0.016), and DLT size with LMBD (male: R2 = 0.222; female: R2 = 0.193). There was a good correlation between depth of DLT inserted with patient's height for both genders. CONCLUSION: The appropriate size of the left-sided DLT could not be predicted based on patients' height, weight, tracheal or left main bronchus diameter alone in Asians; however, the depth of insertion of the tube was dependent on the height in both genders. PMID- 28074792 TI - Remifentanil prevents increases of blood glucose and lactate levels during cardiopulmonary bypass in pediatric cardiac surgery. AB - INTRODUCTION: Cardiopulmonary bypass (CPB) can cause stress response that increases levels of cytokine and catecholamine in plasma, resulting in hyperglycemia. In adults, it has been demonstrated that remifentanil infusion during CPB could prevent increases of cytokine, catecholamine, and blood glucose levels, but such effects of remifentanil in children have not been elucidated. AIM: In this study, we investigated the preventive effects of remifentanil on blood glucose and lactate levels during CPB in children. MATERIALS AND METHODS: This retrospective study included children who underwent ventricular septal defect or atrial septal defect closure. Data for patients who did not receive, during CPB period, remifentanil infusion (non-Remi group) and patients who received remifentanil infusion at 0.5 MUg/kg/min (Remi group) during CPB were used for analysis. Primary outcomes were lactate and blood glucose levels just before and after CPB. Data are presented as medians and interquartile ranges. Data were analyzed by the Mann-Whitney U-test and Chi-square test. A P < 0.05 was considered statistically significant. RESULTS: During CPB, 13 and 11 patients were allocated into Remi and non-Remi groups, respectively. Pre-CPB lactate and blood glucose levels were not significantly different between the two groups, but post-CPB lactate and blood glucose levels in the Remi group were significantly lower than that in the non-Remi group. CONCLUSION: 0.5 MUg/kg/min remifentanil infusion during CPB suppresses the increases of blood glucose and lactate levels in children. PMID- 28074793 TI - Assessment of limited chest x-ray technique in postcardiac surgery management. AB - OBJECTIVES: The objective of this study is to investigate the safety of elimination of chest radiography in the postcardiac surgery Intensive Care Unit (ICU). METHODS AND DESIGN: We compared patients in two different groups of routine CXR (RCXR) and limited CXR (LCXR) and their diagnostic and therapeutic outcome in a University hospital-based single center from 2014 to 2016. 3 CXR in the RCXR group and 1 CXR in the limited group was performed, in addition to on demand criteria. MEASUREMENT AND MAIN RESULTS: A total of 978 samples were acceptable for analysis which 55.21% of RCXR and 59.50% of LCXR were male patients. In total, 523 abnormalities in RCXR group and 154 occasions in LCXR group resulted in 26.73% diagnostic efficacy for RCXRs and 28.57% for LCXR. From 1956 CXR that was taken in RCXR group, 72 occasions required intervention (3.68%) and 84 cases out of 539 (15.58%) LCXR needed an action to therapy. This means a 14.40% in RCXRs' abnormalities and 56.00% of LCXRs' abnormalities were accompanied with some interventions. CONCLUSIONS: Abolishing routine CXR in the ICUs would not be harmful for the patients, and it can be managed based on their clinical status and other safer imaging techniques. PMID- 28074794 TI - Acute effect of treatment of mitral stenosis on left atrium function. AB - AIM: Peak atrial longitudinal strain (PALS) is used to evaluate left atrium (LA) function in patients with mitral stenosis (MS), before and after percutaneous transmitral commissurotomy (PTMC) and mitral valve replacement (MVR). METHODS: Patients with severe symptomatic MS, who were referred to our echocardiographic laboratory for a diagnostic examination before cardiac surgery or PTMC from October of 2014 to October of 2015, were included in the study. RESULT: The peak systolic global LA strain improved post-PTMC (P < 0.001) and post-MVR (P = 0.012). This difference was statistically highly significant. CONCLUSION: PALS is impaired in patients with severe symptomatic MS and improved acutely after treatment and may be a good indicator of LA function and may predict the right time for intervention on mitral valve. PMID- 28074795 TI - Comparative effect of grape seed extract (Vitis vinifera) and ascorbic acid in oxidative stress induced by on-pump coronary artery bypass surgery. AB - BACKGROUND: This study aimed to test the beneficial effect of grape seed extract (GSE) (Vitis vinifera) and Vitamin C in oxidative stress and reperfusion injury induced by cardiopulmonary bypass (CPB) in coronary artery bypass surgery. PATIENTS AND METHODS: In this randomized trial, 87 patients undergoing elective and isolated coronary bypass surgery included. The patients were randomly assigned into three groups (n = 29 each): (1) Control group with no treatment, (2) GSE group who received the extract 24 h before operation, 100 mg every 6 h, orally, (3) Vitamin C group who received 25 mg/kg Vitamin C through CPB during surgery. Blood samples were taken from coronary sinus at (T1) just before aortic cross clamp; (T2) just before starting controlled aortic root reperfusion; and (T3) 10 min after root reperfusion. Some clinical parameters and biochemical markers were compared among the groups. RESULTS: There were significant differences in tracheal intubation times, sinus rhythm return, and left ventricular function between treatment groups compared with control (P < 0.05). Total antioxidant capacity was higher (P < 0.05) in both grape seed and Vitamin C groups at T2 and T3 times. In reperfusion period, malondialdehyde level was increased in control group; however, it was significantly lower for the grape seed group (P = 0.04). The differences in the mean levels of superoxide dismutase and glutathione peroxidase among the three groups were not significant (P > 0.05 in all cases). CONCLUSIONS: In our patients, GSE and Vitamin C had antioxidative effects and reduced deleterious effects of CPB during coronary artery bypass grafting surgery. PMID- 28074796 TI - Low-intensity laser (660 NM) has analgesic effects on sternotomy of patients who underwent coronary artery bypass grafts. AB - BACKGROUND: The aim of this study was to evaluate the efficacy of low-level laser therapy for reducing the acute pain of sternotomy in patients who underwent a coronary artery bypass graft (CABG). METHODS: This study was conducted with ninety volunteers who electively submitted to CABG. The volunteers were randomly allocated into three groups of equal size (n = 30): control, placebo, and laser (lambda of 660 nm and spatial average energy fluency of 1.06 J/cm 2 ). Pain when coughing was assessed by a visual analog scale (VAS) and McGill Pain Questionnaire, according to sensory, affective, evaluative, and miscellaneous domains. The patients were followed for 1 month after the surgery. RESULTS: The laser group had a greater decrease in pain with analogous results, as indicated by both the VAS and the McGill questionnaire (P <= 0.05) on sensory and affective scores, on days 6 and 8 postsurgery compared to the placebo and control groups. CONCLUSION: Laser seems to be effective promoting pain reduction after coronary arterial bypass grafting. PMID- 28074797 TI - Minimally invasive compared to conventional approach for coronary artery bypass grafting improves outcome. AB - INTRODUCTION: Minimally invasive (MI) cardiac surgery is a rapidly gaining popularity, globally as well as in India. We aimed to compare the outcome of MI to the conventional approach for coronary artery bypass graft (CABG) surgery. METHODS: This prospective, comparative study was conducted at a tertiary care cardiac surgical center. All patients who underwent CABG surgery via MI approach (MI group) from July 2015 to December 2015 were enrolled and were compared against same number of EuroSCORE II matched patients undergoing CABG through conventional mid-sternotomy approach (CON group). Demographic, intra- and post operative variables were collected. RESULTS: In MI group, duration of the surgery was significantly longer (P = 0.029). Intraoperative blood loss lesser (P = 0.002), shorter duration of ventilation (P = 0.002), shorter Intensive Care Unit stay (P = 0.004), shorter hospital stay (P = 0.003), lesser postoperative analgesic requirements (P = 0.027), and lower visual analog scale scores on day of surgery (P = 0.032) and 1 st postoperative day (P = 0.025). No significant difference in postoperative blood loss, blood transfusion, or duration of inotrope requirement observed. There was no conversion to mid-sternotomy in any patients, 8% of patients had desaturation intraoperatively. There was no operative mortality. CONCLUSION: MI surgery is associated with lesser intraoperative blood loss, better analgesia, and faster recovery. PMID- 28074798 TI - ProSeal laryngeal mask airway as an alternative to standard endotracheal tube in securing upper airway in the patients undergoing beating-heart coronary artery bypass grafting. AB - BACKGROUND: ProSeal laryngeal mask airways (PLMAs) are routinely used after failed tracheal intubation as airway rescue, facilitating tracheal intubation by acting as a conduit and to secure airway during emergencies. In long duration surgeries, use of endotracheal tube (ETT) is associated with various hemodynamic complications, which are minimally affected during PLMA use. However, except for few studies, there are no significant data available that promote the use of laryngeal mask during cardiac surgery. This prospective study was conducted with the objective of demonstrating the advantages of PLMA over ETT in the patients undergoing beating-heart coronary artery bypass graft (CABG). METHODOLOGY: This prospective, interventional study was carried out in 200 patients who underwent beating-heart CABG. Patients were randomized in equal numbers to either ETT group or PLMA group, and various hemodynamic and respiratory parameters were observed at different time points. RESULTS: Patients in PLMA group had mean systolic blood pressure 126.10 +/- 5.31 mmHg compared to the patients of ETT group 143.75 +/- 6.02 mmHg. Pulse rate in the PLMA group was less (74.52 +/- 10.79 per min) (P < 0.05) compared to ETT group (81.72 +/- 9.8). Thus, hemodynamic changes were significantly lower (P < 0.05) in PLMA than in ETT group. Respiratory parameters such as oxygen saturation, pressure CO 2 (pCO 2 ), peak airway pressure, and lung compliance were similar to ETT group at all evaluation times. The incidence of adverse events was also lower in PLMA group. CONCLUSION: In experience hand, PLMA offers advantages over the ETT in airway management in the patients undergoing beating-heart CABG. PMID- 28074799 TI - Basic arterial blood gas biomarkers as a predictor of mortality in tetralogy of Fallot patients. AB - BACKGROUND: Serum lactate and base deficit have been shown to be a predictor of morbidity and mortality in critically ill patients. Poor preoperative oxygenation appears to be one of the significant factors that affects early mortality in tetralogy of Fallot (TOF). There is little published literature evaluating the utility of serum lactate, base excess (BE), and oxygen partial pressure (PO 2 ) as simple, widely available, prognostic markers in patients undergoing surgical repair of TOF. MATERIALS AND METHODS: This prospective, observational study was conducted in 150 TOF patients, undergoing elective intracardiac repair. PO 2 , BE, and lactate levels at three different time intervals were recorded. Arterial blood samples were collected after induction (T1), after cardiopulmonary bypass (T2), and 48 h (T3) after surgery in the Intensive Care Unit (ICU). To observe the changes in PO 2 , BE, and lactate levels over a period of time, repeated measures analysis was performed with Bonferroni method. The receiver operating characteristics (ROC) analysis was used to find area under curve (AUC) and cutoff values of various biomarkers for predicting mortality in ICU. RESULTS: The patients who could not survive showed significant elevated lactate levels at baseline (T1) and postoperatively (T2) as compared to patients who survived after surgery (P < 0.001). However, in nonsurvivors, the BE value decreased significantly in the postoperative period in comparison to survivors (-2.8 +/- 4.27 vs. 5.04 +/- 2.06) (P < 0.001). In nonsurvivors, there was a significant fall of PO 2 to a mean value of 59.86 +/- 15.09 in ICU (T3), whereas those who survived had a PO 2 of 125.86 +/- 95.09 (P < 0.001). The ROC curve analysis showed that lactate levels (T3) have highest mortality predictive value (AUC: 96.9%) as compared to BE (AUC: 94.5%) and PO 2 (AUC: 81.1%). CONCLUSION: Serum lactate and BE may be used as prognostic markers to predict mortality in patients undergoing TOF repair. The routine analysis of these simple, fast, widely available, and cost-effective biomarkers should be encouraged to predict prognosis of TOF patients. PMID- 28074800 TI - Effectiveness of ventilation of nondependent lung for a brief period in improving arterial oxygenation during one-lung ventilation: A prospective study. AB - BACKGROUND: Hypoxemia is common during one-lung ventilation(OLV), predominantly due to transpulmonary shunt. None of the strategies tried showed consistent results. We evaluated the effectiveness of ventilating the operated, non dependent lung (NDL) with small tidal volumes in improving the oxygenation during OLV. METHODS: 30 ASA 1 and 2 patients undergoing elective, open thoracotomy were studied. After standard induction of anesthesia, lung seperation was acheived with left sided DLT. The ventilatory settings for two lung ventilation (TLV) were: FiO 2 of 0.5, tidal volume of 8-10ml/kg and respiratory rate of 10-12/min. After initiating OLV, the dependent lung alone was ventilated with the above settings for 15 minutes and an arterial blood gas (ABG) analysis was done. Then the NDL was ventilated with a separate ventilator, with FiO 2 of 1, tidal volume of 70 ml, I:E ratio of 1:10 and respiratory rate of 6/min for 15 minutes. The NDL ventilation was started early if the patients desaturated to <95%. ABG was done at 5 and 15 mins of NDL ventilation. We compared the PaO 2 values. RESULTS: The mean PaO 2 decreased from 232.2 +/- 67.2 mm of Hg (TLV-ABG1) to 91.2 +/- 31.7 mm of Hg on OLV (OLV-ABG1). The ABG after 5 minutes and 15 minutes after institution of NDL ventilation during OLV showed a PaO2 of 145.7 +/- 50.2 mm of Hg and 170.6 +/- 50.4 mm of Hg which were significantly higher compared to the one lung ventilation values. PMID- 28074801 TI - Delirium after cardiac surgery: A pilot study from a single tertiary referral center. AB - BACKGROUND: Advances in cardiac surgery has shifted paradigm of management to perioperative psychological illnesses. Delirium is a state of altered consciousness with easy distraction of thoughts. The pathophysiology of this complication is not clear, but identification of risk factors is important for positive postoperative outcomes. The goal of the present study was to prospectively identify the incidence, motoric subtypes, and risk factors associated with development of delirium in cardiac surgical patients admitted to postoperative cardiac intensive care, using a validated delirium monitoring instrument. MATERIALS AND METHODS: This is a prospective, observational study. This study included 120 patients of age 18-80 years, admitted to undergo cardiac surgery after applying inclusion and exclusion criteria. Specific preoperative, intraoperative, and postoperative data for possible risk factors were obtained. Once in a day, assessment of delirium was done. Continuous variables were measured as mean +/- standard deviation, whereas categorical variables were described as proportions. Differences between groups were analyzed using Student's t-test, Mann-Whitney U-test, or Chi-square test. Variables with a P < 0.1 were then used to develop a predictive model using stepwise logistic regression with bootstrapping. RESULTS: Delirium was seen in 17.5% patients. The majority of cases were of hypoactive delirium type (85.72%). Multiple risk factors were found to be associated with delirium, and when logistic regression with bootstrapping applied to these risk factors, five independent variables were detected. History of hypertension (relative risk [RR] =6.7857, P = 0.0003), carotid artery disease (RR = 4.5000, P < 0.0001) in the form of stroke or hemorrhage, noninvasive ventilation (NIV) use (RR = 5.0446, P < 0.0001), Intensive Care Unit (ICU) stay more than 10 days (RR = 3.1630, P = 0.0021), and poor postoperative pain control (RR = 2.4958, P = 0.0063) was associated with postcardiac surgical delirium. CONCLUSIONS: Patients who developed delirium had systemic disease in the form of hypertension and cerebrovascular disease. Delirium was seen in patients who had higher postoperative pain scores, longer ICU stay, and NIV use. This study can be used to develop a predictive tool for diagnosing postcardiac surgical delirium. PMID- 28074802 TI - Goal-directed therapy improves the outcome of high-risk cardiac patients undergoing off-pump coronary artery bypass. AB - BACKGROUND: There has been a constant emphasis on developing management strategies to improve the outcome of high-risk cardiac patients undergoing surgical revascularization. The performance of coronary artery bypass surgery on an off-pump coronary artery bypass (OPCAB) avoids the risks associated with extra corporeal circulation. The preliminary results of goal-directed therapy (GDT) for hemodynamic management of high-risk cardiac surgical patients are encouraging. The present study was conducted to study the outcome benefits with the combined use of GDT with OPCAB as compared to the conventional hemodynamic management. MATERIAL AND METHOD: Patients with the European System for Cardiac Operative Risk Evaluation >=3 scheduled for OPCAB were randomly divided into two groups; the control and GDT groups. The GDT group included the monitoring and optimization of advanced parameters, including cardiac index (CI), systemic vascular resistance index, oxygen delivery index, stroke volume variation; continuous central venous oxygen saturation (ScVO 2 ), global end-diastolic volume, and extravascular lung water (EVLW), using FloTracTM , PreSepTM , and EV-1000 (r) monitoring panels, in addition to the conventional hemodynamic management in the control group. The hemodynamic parameters were continuously monitored for 48 h in Intensive Care Unit (ICU) and corrected according to GDT protocol. A total of 163 patients consented for the study. RESULT: Seventy-five patients were assigned to the GDT group and 88 patients were in the control group. In view of 9 exclusions from the GDT group and 12 exclusions from control group, 66 patients in the GDT group and 76 patients in control group completed the study. CONCLUSION: The length of stay in hospital (LOS-H) (7.42 +/- 1.48 vs. 5.61 +/- 1.11 days, P < 0.001) and ICU stay (4.2 +/- 0.82 vs. 2.53 +/- 0.56 days, P < 0.001) were significantly lower in the GDT group as compared to control group. The duration of inotropes (3.24 +/- 0.73 vs. 2.89 +/- 0.68 h, P = 0.005) was also significantly lower in the GDT group. The two groups did not differ in duration of ventilated hours, mortality, and other complications. The parameters such as ScVO 2 , CI, and EVLW had a strong negative and positive correlation with the LOS-H with r values of - 0.331, -0.319, and 0.798, respectively. The study elucidates the role of a goal-directed hemodynamic optimization for improved outcome in high-risk cardiac patients undergoing OPCAB. PMID- 28074803 TI - Prayer sign as a marker of increased ventilatory hours, length of intensive care unit and hospital stay in patients undergoing coronary artery bypass grafting surgery. AB - CONTEXT: Various predictors have been used to predict diabetic patients who are likely to have increased ventilatory hours and an increased length of stay (LOS) in the Intensive Care Unit (ICU) as well as in the hospital after undergoing coronary artery bypass grafting (CABG) surgery, for example, glycosylated hemoglobin (HbA1c). The authors propose a simple bed-side test, i.e., the prayer sign to predict increased ventilatory hours and increased length of ICU and hospital stay. AIMS: The aim of the present study was to assess whether any association exists between a positive prayer sign and increased ventilatory hours, length of ICU and hospital stay after CABG surgery in diabetic patients. SETTINGS AND DESIGN: This prospective observational study was conducted in a 650 bedded tertiary cardiac center. SUBJECTS AND METHODS: A total of 501 diabetic patients were recruited in the study over a period of 1 year. Group P consisted of 121 patients with prayer sign positive, whereas Group N consisted of 380 patients with prayer sign negative. HbA1c levels, ventilatory hours, LOS in the postoperative ICU and hospital were compared. STATISTICAL ANALYSIS USED: Unpaired Student's t-test was used to compare the data. RESULTS: The mean HbA1c levels in Group P were 8.01 +/- 2.28% as compared to 6.52 +/- 2.46% in Group N (P < 0.0001). The mean ventilatory hours in Group P were 9.52 +/- 6.46 h, and in Group N were 7.42 +/- 8.01 h (P = 0.013). Whereas, the mean length of ICU stay and hospital stay in Group P was 156.42 +/- 32.66 h (6.51 +/- 1.36 days) and 197.36 +/- 32.46 h (8.22 +/- 1.35 days), respectively, it was 121.12 +/- 29.48 h (5.04 +/- 1.22 days) and 178.52 +/- 28.52 h (7.43 +/- 1.18 days) in Group N (P < 0.0001). CONCLUSIONS: A positive prayer sign is a useful bedside test for predicting increased ventilatory hours and increased length of ICU and hospital stay after CABG surgery. PMID- 28074805 TI - Misdirected minitracheostomy tube. AB - We report a patient who after an uneventful coronary artery bypass graft surgery and left ventricular aneurysmorrhaphy developed intracerebral hemorrhage and subsequently required minitracheostomy. Chest X-ray showed misdirected minitracheostomy tube facing upward toward the laryngeal opening which was repositioned using bronchoscope. PMID- 28074804 TI - Outcome of four pretreatment regimes on hemodynamics during electroconvulsive therapy: A double-blind randomized controlled crossover trial. AB - CONTEXT: Electroconvulsive therapy (ECT) is associated with tachycardia and hypertension. AIMS: The aim of this study was to compare two doses of dexmedetomidine, esmolol, and lignocaine with respect to hemodynamics, seizure duration, emergence agitation (EA), and recovery profile. METHODOLOGY: Thirty patients undergoing ECT were assigned to each of the following pretreatment regimes over the course of five ECT sessions in a randomized crossover design: Group D1 (dexmedetomidine 1 MUg/kg), Group D0.5 (dexmedetomidine0.5 MUg/kg), Group E (esmolol 1 mg/kg), Group L (lignocaine 1 mg/kg), and Group C (saline as placebo) before induction. Heart rate (HR), mean arterial pressure (MAP), seizure duration, EA, and time to discharge were evaluated. RESULTS: Groups D1, D0.5, and esmolol had significantly reduced response of HR, MAP compared to lignocaine and control groups at 1, 3, 5 min after ECT (P < 0.05). Motor seizure duration was comparable in all groups except Group L (P = 0.000). Peak HR was significantly decreased in all groups compared to control. Total propofol requirement was reduced in D1 (P = 0.000) and D0.5 (P = 0.001) when compared to control. Time to spontaneous breathing was comparable in all the groups (P > 0.05). Time to eye opening and time to discharge were comparable in all groups (P > 0.05) except Group D1 (P = 0.001). EA score was least in Group D1 (P = 0.000). CONCLUSION: Dexmedetomidine 1 MUg/kg, 0.5 MUg/kg, and esmolol produced significant amelioration of cardiovascular response to ECT without affecting seizure duration, results being best with dexmedetomidine 1 MUg/kg. However, the latter has the shortcoming of delayed recovery. PMID- 28074806 TI - An unusual cause of postpartum heart failure. AB - Peripartum cardiomyopathy is a weakness of the heart muscle. It is an idiopathic cardiomyopathy that presents with heart failure secondary to left ventricular systolic dysfunction toward the end of pregnancy or in the months after delivery, in the absence of any other cause of heart failure. It is a rare condition that can carry mild or severe symptoms. PMID- 28074807 TI - Isolated persistent left superior vena cava: A case report and its clinical implications. AB - The venous anomaly of a persistent left superior vena cava (PLSVC) affects 0.3% 0.5% of the general population. PLSVC with absent right superior vena cava, also termed as "isolated PLSVC," is an extremely rare venous anomaly. Almost half of the patients with isolated PLSVC have cardiac anomalies in the form of atrial septal defect, endocardial cushion defects, or tetralogy of Fallot. Isolated PLSVC is usually innocuous. Its discovery, however, has important clinical implications. It can pose clinical difficulties with central venous access, cardiothoracic surgeries, and pacemaker implantation. When it drains to the left atrium, it may create a right to left shunt. In this case report, we present the incidental finding of isolated PLSVC in a patient who underwent aortic valve replacement. Awareness about this condition and its variations is important to avoid complications. PMID- 28074808 TI - Demonstration of blood flow by color doppler in the femoral artery distal to arterial cannula during peripheral venoarterial-extracorporeal membrane oxygenation. AB - In spite of distal perfusion of the limb using a cannula, the limb can have ischemic events if there is an undetected kink or clot anywhere in the line or thrombus in the artery. There are several ways to monitor and assess the limb ischemia. Monitoring for clinical signs of limb ischemia like temperature change and pallor is reliable and mandatory. We report a method where we used color Doppler to document the blood flow. Curvilinear vascular probe of an echo machine is used to identify the flow in the distal femoral artery of the lower limb. . As we have demonstrated in the video attached, once flow to the distal limb perfusion system is shut off by closing the three way stop cock, we can appreciate the immediate cessation of flow in the artery by Doppler. PMID- 28074809 TI - Holt-Oram syndrome: Anesthetic challenges and safe outcome. AB - Holt-Oram syndrome (HOS) is an autosomal dominant disease with skeletal and cardiac manifestations. We here are presenting a 31-year-old man and a diagnosed case of HOS, with an ulceroproliferative lesion on lateral border of the tongue, was posted for wide excision of lesion with primary closure and left side radical neck dissection. PMID- 28074810 TI - Nucleic acid-based methods for early detection of sepsis. PMID- 28074811 TI - Reliability and validity of perceived heart risk factors scale. PMID- 28074812 TI - Iatrogenic vocal cord paralysis after cardiac surgery: evocative note for surgeon and anesthesiologist. PMID- 28074814 TI - Percutaneous tracheostomy. PMID- 28074813 TI - Anesthetic management of a patient with Yamaguchi syndrome for laparoscopic radical nephroureterectomy. PMID- 28074815 TI - Effect of heparin and Bivalirudin on the kinetics of clot formation: Viscoelastic coagulation testing. PMID- 28074816 TI - Echocardiography in extracorporeal membrane oxygenation. PMID- 28074817 TI - Extracorporeal membrane oxygenation for refractory cardiac arrest. AB - Extracorporeal cardiopulmonary resuscitation (ECPR) is the use of rapid deployment venoarterial (VA) extracorporeal membrane oxygenation to support systemic circulation and vital organ perfusion in patients in refractory cardiac arrest not responding to conventional cardiopulmonary resuscitation (CPR). Although prospective controlled studies are lacking, observational studies suggest improved outcomes compared with conventional CPR when ECPR is instituted within 30-60 min following cardiac arrest. Adult and pediatric patients with witnessed in-hospital and out-of-hospital cardiac arrest and good quality CPR, failure of at least 15 min of conventional resuscitation, and a potentially reversible cause for arrest are candidates. Percutaneous cannulation where feasible is rapid and can be performed by nonsurgeons (emergency physicians, intensivists, cardiologists, and interventional radiologists). Modern extracorporeal systems are easy to prime and manage and are technically easy to manage with proper training and experience. ECPR can be deployed in the emergency department for out-of-hospital arrest or in various inpatient units for in hospital arrest. ECPR should be considered for patients with refractory cardiac arrest in hospitals with an existing extracorporeal life support program, able to provide rapid deployment of support, and with resources to provide postresuscitation evaluation and management. PMID- 28074818 TI - Cannulation strategies in adult veno-arterial and veno-venous extracorporeal membrane oxygenation: Techniques, limitations, and special considerations. AB - Extracorporeal membrane oxygenation (ECMO) refers to specific mechanical devices used to temporarily support the failing heart and/or lung. Technological advances as well as growing collective knowledge and experience have resulted in increased ECMO use and improved outcomes. Veno-arterial (VA) ECMO is used in selected patients with various etiologies of cardiogenic shock and entails either central or peripheral cannulation. Central cannulation is frequently used in postcardiotomy cardiogenic shock and is associated with improved venous drainage and reduced concern for upper body hypoxemia as compared to peripheral cannulation. These concerns inherent to peripheral VA ECMO may be addressed through so-called triple cannulation approaches. Veno-venous (VV) ECMO is increasingly employed in selected patients with respiratory failure refractory to more conventional measures. Newer dual lumen VV ECMO cannulas may facilitate extubation and mobilization. In summary, the pathology being addressed impacts the ECMO approach that is deployed, and each ECMO implementation has distinct virtues and drawbacks. Understanding these considerations is crucial to safe and effective ECMO use. PMID- 28074820 TI - Airway management of the cardiac surgical patients: Current perspective. AB - The difficult airway (DA) is a common problem encountered in patients undergoing cardiac surgery. However, the challenge is not only just establishment of airway but also maintaining a definitive airway for the safe conduct of cardiopulmonary bypass from initiation to weaning after surgical correction or palliation, de airing of cardiac chambers. This review describes the management of the DA in a cardiac theater environment. The primary aims are recognition of DA both anatomical and physiological, necessary preparations for (and management of) difficult intubation and extubation. All patients undergoing cardiac surgery should initially be considered as having potentially DA as many of them have poor physiologic reserve. Making the cardiac surgical theater environment conducive to DA management is as essential as it is to deal with low cardiac output syndrome or acute heart failure. Tube obstruction and/or displacement should be suspected in case of a new onset ventilation problem, especially in the recovery unit. Cardiac anesthesiologists are often challenged with DA while inducing general endotracheal anesthesia. They ought to be familiar with the DA algorithms and possess skill for using the latest airway adjuncts. PMID- 28074819 TI - Percutaneous tracheostomy. AB - Percutaneous dilatational tracheostomy (PDT) is a commonly performed procedure in critically sick patients. It can be safely performed bedside by intensivists.This has resulted in decline in the use of surgical tracheostomy in intensive care unit (ICU) except in few selected cases. Most common indication of tracheostomy in ICU is need for prolonged ventilation. About 10% of patients requiring at least 3 days of mechanical ventilator support get tracheostomised during ICU stay. The ideal timing of PDT remains undecided at present. Contraindications and complications become fewer with increase in experience. Various methods of performing PDT have been discovered in last two decades. Preoperative work up, patient selection and post tracheostomy care form key components of a successful PDT. Bronchoscopy and ultrasound have been found to be useful procedural adjuncts, especially in presence of unfavorable anatomy. This article gives a brief overview about the use of PDT in ICU. PMID- 28074821 TI - Acyanotic congenital heart disease and transesophageal echocardiography. AB - The spectrum of congenital heart disease (CHD) seen in the adult varies widely. Malformations range from mild anomalies requiring no intervention to extremely complex pathologies characterized by the presence of multiple coexistent defects. Echocardiography represents the primary noninvasive imaging modality in the assessment of these lesions. The transesophageal approach expands the applications of echocardiography by allowing the acquisition of anatomic and functional information that may not be obtainable by transthoracic imaging. PMID- 28074822 TI - Pleiotropic effects of statins in the perioperative setting. AB - Statins belong to a specific group of drugs that have been described for their ability to control hyperlipidemia as well as for other pleiotropic effects such as improving vascular endothelial function, inhibition of oxidative stress pathways, and anti-inflammatory actions. Accumulating clinical evidence strongly suggests that statins also have a beneficial effect on perioperative morbidity and mortality. Therefore, this review aims to present all recent and pooled data on statin treatment in the perioperative setting as well as to highlight considerations regarding their indications and therapeutic application. PMID- 28074823 TI - Pharmacological update: New drugs in cardiac practice: A critical appraisal. AB - Cardiac practice involves the application of a range of pharmacological therapies. An anesthesiologist needs to keep pace with the rampant drug developments in the field of cardiovascular medicine for appropriate management in both perioperative and intensive care set-up, to strengthen his/her role as a perioperative physician in practice. The article reviews the changing trends and the future perspectives in major classes of cardiovascular medicine. PMID- 28074824 TI - Studying diastology with speckle tracking echocardiography: The essentials. AB - Diastolic dysfunction is common in cardiac disease and an important finding independent of systolic function as it contributes to the signs and symptoms of heart failure. Tissue Doppler mitral early diastolic velocity (Ea) combined with peak transmitral early diastolic velocity (E) to obtain E/Ea ratio provides an estimate of the left ventricular (LV) filling pressure. However, E/Ea has a significant gray zone and less reliable in patients with preserved ejection fraction (>50%). Two-dimensional echocardiographic speckle tracking measure myocardial strain and strain rate (Sr) avoiding the Doppler-associated angulation errors and tethering artifacts. Global myocardial peak diastolic strain (Ds) and diastolic Sr (DSr) at the time of E and isovolumic relaxation combined with E (E/Ds and E/10 DSr) have been recently proposed as novel indices to determine LV filling pressure. The present article elucidates the methodology of studying diastology with strain echocardiography along with the advantages and limitations of the novel technique in light of the available literature. PMID- 28074825 TI - Goldenhar syndrome: Cardiac anesthesiologist's perspective. AB - Goldenhar syndrome or oculo-auriculo-vertebral dysplasia was defined by Goldenhar in 1952 and redefined by Grolin et al. later. As the name denotes, children with this syndrome present with craniofacial and vertebral anomalies which increase the risk of airway compromise. Neonates and infants with this syndrome often have premature internal organs, low birth weight, and airway disorders. For this reason, safe anesthesia in such infants requires a complete knowledge regarding metabolism and side effects of the drugs. The association of cardiovascular abnormalities is not uncommon and possesses additional challenge for anesthetic management. The aim of this review is to draw attention to the various perioperative problems that can be faced in these infants when they undergo surgery or the correction of the underlying cardiac problem. PMID- 28074826 TI - Extracorporeal membrane oxygenation for repair of tracheal injury during transhiatal esophagectomy. AB - Extracorporeal Membrane Oxygenation (ECMO) for repair of tracheal injury during transhiatal esophagectomy Tracheal injury is a rare but potentially fatal complication of esophagectomies requiring prompt recognition and treatment. We describe a case of tracheal injury recognized in the operative period of an open transhiatal esophagectomy for squamous cell carcinoma of the mid to distal esophagus. When injury was discovered, attempts to improve oxygenation and ventilation by conventional methods were unsuccessful. Therefore, peripheral ECMO was used to support oxygenation during the tracheal defect repair. The use of ECMO for the repair of a tracheal injury during esophagectomy is very uncommon but, in our case, provided adequate oxygenation and ventilation while the surgeon repaired the injury and the patient was able to be promptly weaned from ECMO support and extubated not long after. PMID- 28074827 TI - The perceval S aortic valve implantation in patients with porcelain aorta; is this ideal option? AB - We would like to present in this paper a patient with severe aortic valve stenosis referred to our department for surgical aortic valve replacement. In this patient, it was intraoperatively detected an unexpected heavily calcified porcelain ascending aorta. We present the treatment options in this situation, the difficulties affronted intraoperatively, the significance of the preoperative chest computed tomography scan and the use of the Perceval S aortic valve as ideal bioprosthesis implantation. This is a self-expanding, self-anchoring, and sutureless valve with a wide indication in all patients requiring aortic bioprosthesis. PMID- 28074828 TI - Three-dimensional transesophageal echocardiography-guided transcathetar closure of ruptured noncoronary sinus of valsalva aneurysm. AB - Sinus of Valsalva aneurysm accounts for only 1% of congenital cardiac anomalies. Sinus of Valsalva aneurysm can cause aortic insufficiency, coronary artery flow compromise, cardiac arrhythmia, or aneurysm rupture. Three-dimensional transesophageal echocardiography (3DTEE) represents an adjunctive tool to demonstrate the ruptured sinus of Valsalva with better delineation. We present an adult patient with rupture of noncoronary sinus of Valsalva aneurysm into the right atrium (RA). 3DTEE accurately delineated the site of rupture into the RA and showed the exact size and shape of the defect, which helped in the successful transcatheter closure of the defect with a duct occluder device. PMID- 28074829 TI - Large fault slip peaking at trench in the 2011 Tohoku-oki earthquake. AB - During the 2011 magnitude 9 Tohoku-oki earthquake, very large slip occurred on the shallowest part of the subduction megathrust. Quantitative information on the shallow slip is of critical importance to distinguishing between different rupture mechanics and understanding the generation of the ensuing devastating tsunami. However, the magnitude and distribution of the shallow slip are essentially unknown due primarily to the lack of near-trench constraints, as demonstrated by a compilation of 45 rupture models derived from a large range of data sets. To quantify the shallow slip, here we model high-resolution bathymetry differences before and after the earthquake across the trench axis. The slip is determined to be about 62 m over the most near-trench 40 km of the fault with a gentle increase towards the trench. This slip distribution indicates that dramatic net weakening or strengthening of the shallow fault did not occur during the Tohoku-oki earthquake. PMID- 28074830 TI - Tet1 in Nucleus Accumbens Opposes Depression- and Anxiety-Like Behaviors. AB - Depression is a leading cause of disease burden, yet current therapies fully treat <50% of affected individuals. Increasing evidence implicates epigenetic mechanisms in depression and antidepressant action. Here we examined a possible role for the DNA dioxygenase, ten-eleven translocation protein 1 (TET1), in depression-related behavioral abnormalities. We applied chronic social defeat stress, an ethologically validated mouse model of depression-like behaviors, and examined Tet1 expression changes in nucleus accumbens (NAc), a key brain reward region. We show decreased Tet1 expression in NAc in stress-susceptible mice only. Surprisingly, selective knockout of Tet1 in NAc neurons of adult mice produced antidepressant-like effects in several behavioral assays. To identify Tet1 targets that mediate these actions, we performed RNAseq on NAc after conditional deletion of Tet1 and found that immune-related genes are the most highly dysregulated. Moreover, many of these genes are also upregulated in the NAc of resilient mice after chronic social defeat stress. These findings reveal a novel role for TET1, an enzyme important for DNA hydroxymethylation, in the brain's reward circuitry in modulating stress responses in mice. We also identify a subset of genes that are regulated by TET1 in this circuitry. These findings provide new insight into the pathophysiology of depression, which can aid in future antidepressant drug discovery efforts. PMID- 28074832 TI - Correlation-driven transport asymmetries through coupled spins in a tunnel junction. AB - Spin-spin correlations can be the driving force that favours certain ground states and are key in numerous models that describe the behaviour of strongly correlated materials. While the sum of collective correlations usually lead to a macroscopically measurable change in properties, a direct quantification of correlations in atomic scale systems is difficult. Here we determine the correlations between a strongly hybridized spin impurity on the tip of a scanning tunnelling microscope and its electron bath by varying the coupling to a second spin impurity weakly hybridized to the sample surface. Electronic transport through these coupled spins reveals an asymmetry in the differential conductance reminiscent of spin-polarized transport in a magnetic field. We show that at zero field, this asymmetry can be controlled by the coupling strength and is related to either ferromagnetic or antiferromagnetic spin-spin correlations in the tip. PMID- 28074831 TI - RGS9-2 Modulates Responses to Oxycodone in Pain-Free and Chronic Pain States. AB - Regulator of G-protein signaling 9-2 (RGS9-2) is a striatal-enriched signal transduction modulator known to have a critical role in the development of addiction-related behaviors following exposure to psychostimulants or opioids. RGS9-2 controls the function of several G-protein-coupled receptors, including dopamine receptor and mu opioid receptor (MOR). We previously showed that RGS9-2 complexes negatively control morphine analgesia, and promote the development of morphine tolerance. In contrast, RGS9-2 positively modulates the actions of other opioid analgesics, such as fentanyl and methadone. Here we investigate the role of RGS9-2 in regulating responses to oxycodone, an MOR agonist prescribed for the treatment of severe pain conditions that has addictive properties. Using mice lacking the Rgs9 gene (RGS9KO), we demonstrate that RGS9-2 positively regulates the rewarding effects of oxycodone in pain-free states, and in a model of neuropathic pain. Furthermore, although RGS9-2 does not affect the analgesic efficacy of oxycodone or the expression of physical withdrawal, it opposes the development of oxycodone tolerance, in both acute pain and chronic neuropathic pain models. Taken together, these data provide new information on the signal transduction mechanisms that modulate the rewarding and analgesic actions of oxycodone. PMID- 28074833 TI - Shifting molecular localization by plasmonic coupling in a single-molecule mirage. AB - Over the last decade, two fields have dominated the attention of sub-diffraction photonics research: plasmonics and fluorescence nanoscopy. Nanoscopy based on single-molecule localization offers a practical way to explore plasmonic interactions with nanometre resolution. However, this seemingly straightforward technique may retrieve false positional information. Here, we make use of the DNA origami technique to both control a nanometric separation between emitters and a gold nanoparticle, and as a platform for super-resolution imaging based on single molecule localization. This enables a quantitative comparison between the position retrieved from single-molecule localization, the true position of the emitter and full-field simulations. We demonstrate that plasmonic coupling leads to shifted molecular localizations of up to 30 nm: a single-molecule mirage. PMID- 28074834 TI - Corrigendum: Differential transcriptional responses to Ebola and Marburg virus infection in bat and human cells. PMID- 28074835 TI - Topological Dirac nodal lines and surface charges in fcc alkaline earth metals. AB - In nodal-line semimetals, the gaps close along loops in k space, which are not at high-symmetry points. Typical mechanisms for the emergence of nodal lines involve mirror symmetry and the pi Berry phase. Here we show via ab initio calculations that fcc calcium (Ca), strontium (Sr) and ytterbium (Yb) have topological nodal lines with the pi Berry phase near the Fermi level, when spin-orbit interaction is neglected. In particular, Ca becomes a nodal-line semimetal at high pressure. Owing to nodal lines, the Zak phase becomes either pi or 0, depending on the wavevector k, and the pi Zak phase leads to surface polarization charge. Carriers eventually screen it, leaving behind large surface dipoles. In materials with nodal lines, both the large surface polarization charge and the emergent drumhead surface states enhance Rashba splitting when heavy adatoms are present, as we have shown to occur in Bi/Sr(111) and in Bi/Ag(111). PMID- 28074836 TI - Impact of interfacial coupling of oxygen octahedra on ferromagnetic order in La0.7Sr0.3MnO3/SrTiO3 heterostructures. AB - La0.7Sr0.3MnO3, a half-metallic ferromagnet with full spin polarization, is generally used as a standard spin injector in heterostructures. However, the magnetism of La0.7Sr0.3MnO3 is strongly modified near interfaces, which was addressed as "dead-layer" phenomenon whose origin is still controversial. Here, both magnetic and structural properties of La0.7Sr0.3MnO3/SrTiO3 heterostructures were investigated, with emphasis on the quantitative analysis of oxygen octahedral rotation (OOR) across interfaces using annular-bright-field imaging. OOR was found to be significantly altered near interface for both La0.7Sr0.3MnO3 and SrTiO3, as linked to the magnetism deterioration. Especially in La0.7Sr0.3MnO3/SrTiO3 superlattices, the almost complete suppression of OOR in 4 unit-cell-thick La0.7Sr0.3MnO3 results in a canted ferromagnetism. Detailed comparisons between strain and OOR relaxation and especially the observation of an unexpected La0.7Sr0.3MnO3 lattice c expansion near interfaces, prove the relevance of OOR for the magnetic properties. These results indicate the capability of tuning the magnetism by engineering OOR at the atomic scale. PMID- 28074837 TI - Two-Layer Elastographic 3-D Traction Force Microscopy. AB - Cellular traction force microscopy (TFM) requires knowledge of the mechanical properties of the substratum where the cells adhere to calculate cell-generated forces from measurements of substratum deformation. Polymer-based hydrogels are broadly used for TFM due to their linearly elastic behavior in the range of measured deformations. However, the calculated stresses, particularly their spatial patterns, can be highly sensitive to the substratum's Poisson's ratio. We present two-layer elastographic TFM (2LETFM), a method that allows for simultaneously measuring the Poisson's ratio of the substratum while also determining the cell-generated forces. The new method exploits the analytical solution of the elastostatic equation and deformation measurements from two layers of the substratum. We perform an in silico analysis of 2LETFM concluding that this technique is robust with respect to TFM experimental parameters, and remains accurate even for noisy measurement data. We also provide experimental proof of principle of 2LETFM by simultaneously measuring the stresses exerted by migrating Physarum amoeboae on the surface of polyacrylamide substrata, and the Poisson's ratio of the substrata. The 2LETFM method could be generalized to concurrently determine the mechanical properties and cell-generated forces in more physiologically relevant extracellular environments, opening new possibilities to study cell-matrix interactions. PMID- 28074838 TI - The effect of brumation on memory retention. AB - Long-term torpor is an adaptive strategy that allows animals to survive harsh winter conditions. However, the impact that prolonged torpor has on cognitive function is poorly understood. Hibernation causes reduced synaptic activity and experiments with mammals reveal that this can have adverse effects on memories formed prior to hibernation. The impact of brumation, the winter dormancy that is observed in ectotherms, on memory remains unknown. The aim of this study was to examine whether an amphibian, the fire salamander (Salamandra salamandra), was able to retain learned spatial information after a period of brumation. Twelve fire salamanders were trained to make a simple spatial discrimination using a T maze. All subjects learned the initial task. Upon reaching criterion, half of the subjects were placed into brumation for 100 days while the other half served as controls and were maintained under normal conditions. A post-brumation memory retention test revealed that animals from both conditions retained the learned response. Control tests showed that they solved the task using learned information and not olfactory cues. This finding contrasts with much of the mammalian research and suggests that the processes involved in prolonged torpor may have a fundamentally different impact on memory in mammals and amphibians. PMID- 28074839 TI - High-precision, non-invasive anti-microvascular approach via concurrent ultrasound and laser irradiation. AB - Antivascular therapy represents a proven strategy to treat angiogenesis. By applying synchronized ultrasound bursts and nanosecond laser irradiation, we developed a novel, selective, non-invasive, localized antivascular method, termed photo-mediated ultrasound therapy (PUT). PUT takes advantage of the high native optical contrast among biological tissues and can treat microvessels without causing collateral damage to the surrounding tissue. In a chicken yolk sac membrane model, under the same ultrasound parameters (1 MHz at 0.45 MPa and 10 Hz with 10% duty cycle), PUT with 4 mJ/cm2 and 6 mJ/cm2 laser fluence induced 51% (p = 0.001) and 37% (p = 0.018) vessel diameter reductions respectively. With 8 mJ/cm2 laser fluence, PUT would yield vessel disruption (90%, p < 0.01). Selectivity of PUT was demonstrated by utilizing laser wavelengths at 578 nm or 650 nm, where PUT selectively shrank veins or occluded arteries. In a rabbit ear model, PUT induced a 68.5% reduction in blood perfusion after 7 days (p < 0.001) without damaging the surrounding cells. In vitro experiments in human blood suggested that cavitation may play a role in PUT. In conclusion, PUT holds significant promise as a novel non-invasive antivascular method with the capability to precisely target blood vessels. PMID- 28074840 TI - Observational evidence for cloud cover enhancement over western European forests. AB - Forests impact regional hydrology and climate directly by regulating water and heat fluxes. Indirect effects through cloud formation and precipitation can be important in facilitating continental-scale moisture recycling but are poorly understood at regional scales. In particular, the impact of temperate forest on clouds is largely unknown. Here we provide observational evidence for a strong increase in cloud cover over large forest regions in western Europe based on analysis of 10 years of 15 min resolution data from geostationary satellites. In addition, we show that widespread windthrow by cyclone Klaus in the Landes forest led to a significant decrease in local cloud cover in subsequent years. Strong cloud development along the downwind edges of larger forest areas are consistent with a forest-breeze mesoscale circulation. Our results highlight the need to include impacts on cloud formation when evaluating the water and climate services of temperate forests, in particular around densely populated areas. PMID- 28074843 TI - Sexy males and sexless females: the origin of triploid apomicts. AB - Apomixis and polyploidy are closely associated in angiosperms, but the evolutionary reason for this association is unknown. Taraxacum officinale, the common dandelion, exists both as diploid sexuals and triploid apomicts. Here, in the context of T. officinale, we provide a model of the evolution of triploid apomicts from diploid sexuals. We posit an apomictic allele that arrests female meiosis in diploids, so that the plant produces diploid egg cells that can develop without fertilization, but haploid pollen. We propose occasional fertilization of diploid egg cells by haploid pollen, resulting in triploid apomicts that produce triploid egg cells but largely nonfunctional pollen. The irreversibility of this process renders diploid partial apomicts evolutionarily short-lived, and results in fixation of triploid apomicts except when they suffer extreme selective disadvantages. Our model can account for the high genetic diversity found in T. officinale triploid populations, because recombinant haploid pollen produced by diploids allows the apomictic allele to spread onto many genetic backgrounds. This leads to multiple clonal lineages in the newly apomictic population, and thereby alleviates some of the usual pitfalls of asexual reproduction. PMID- 28074841 TI - The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia. AB - Bacterial pneumonia is a significant healthcare burden worldwide. Failure to resolve inflammation after infection precipitates lung injury and an increase in morbidity and mortality. Gram-negative bacteria are common in pneumonia and increased levels of the mito-damage-associated molecular pattern (DAMP) cardiolipin can be detected in the lungs. Here we show that mice infected with Klebsiella pneumoniae develop lung injury with accumulation of cardiolipin. Cardiolipin inhibits resolution of inflammation by suppressing production of anti inflammatory IL-10 by lung CD11b+Ly6GintLy6CloF4/80+ cells. Cardiolipin induces PPARgamma SUMOylation, which causes recruitment of a repressive NCOR/HDAC3 complex to the IL-10 promoter, but not the TNF promoter, thereby tipping the balance towards inflammation rather than resolution. Inhibition of HDAC activity by sodium butyrate enhances recruitment of acetylated histone 3 to the IL-10 promoter and increases the concentration of IL-10 in the lungs. These findings identify a mechanism of persistent inflammation during pneumonia and indicate the potential of HDAC inhibition as a therapy. PMID- 28074842 TI - Analysis of the FGF gene family provides insights into aquatic adaptation in cetaceans. AB - Cetacean body structure and physiology exhibit dramatic adaptations to their aquatic environment. Fibroblast growth factors (FGFs) are a family of essential factors that regulate animal development and physiology; however, their role in cetacean evolution is not clearly understood. Here, we sequenced the fin whale genome and analysed FGFs from 8 cetaceans. FGF22, a hair follicle-enriched gene, exhibited pseudogenization, indicating that the function of this gene is no longer necessary in cetaceans that have lost most of their body hair. An evolutionary analysis revealed signatures of positive selection for FGF3 and FGF11, genes related to ear and tooth development and hypoxia, respectively. We found a D203G substitution in cetacean FGF9, which was predicted to affect FGF9 homodimerization, suggesting that this gene plays a role in the acquisition of rigid flippers for efficient manoeuvring. Cetaceans utilize low bone density as a buoyancy control mechanism, but the underlying genes are not known. We found that the expression of FGF23, a gene associated with reduced bone density, is greatly increased in the cetacean liver under hypoxic conditions, thus implicating FGF23 in low bone density in cetaceans. Altogether, our results provide novel insights into the roles of FGFs in cetacean adaptation to the aquatic environment. PMID- 28074844 TI - No signs of inbreeding despite long-term isolation and habitat fragmentation in the critically endangered Montseny brook newt (Calotriton arnoldi). AB - Endemic species with restricted geographic ranges potentially suffer the highest risk of extinction. If these species are further fragmented into genetically isolated subpopulations, the risk of extinction is elevated. Habitat fragmentation is generally considered to have negative effects on species survival, despite some evidence for neutral or even positive effects. Typically, non-negative effects are ignored by conservation biology. The Montseny brook newt (Calotriton arnoldi) has one of the smallest distribution ranges of any European amphibian (8 km2) and is considered critically endangered by the International Union for Conservation of Nature. Here we apply molecular markers to analyze its population structure and find that habitat fragmentation owing to a natural barrier has resulted in strong genetic division of populations into two sectors, with no detectable migration between sites. Although effective population size estimates suggest low values for all populations, we found low levels of inbreeding and relatedness between individuals within populations. Moreover, C. arnoldi displays similar levels of genetic diversity to its sister species Calotriton asper, from which it separated around 1.5 million years ago and which has a much larger distribution range. Our extensive study shows that natural habitat fragmentation does not result in negative genetic effects, such as the loss of genetic diversity and inbreeding on an evolutionary timescale. We hypothesize that species in such conditions may evolve strategies (for example, special mating preferences) to mitigate the effects of small population sizes. However, it should be stressed that the influence of natural habitat fragmentation on an evolutionary timescale should not be conflated with anthropogenic habitat loss or degradation when considering conservation strategies. PMID- 28074845 TI - Local coexistence and genetic isolation of three pollinator species on the same fig tree species. AB - Molecular tools increasingly reveal cryptic lineages and species that were previously unnoticed by traditional taxonomy. The discovery of cryptic species in sympatry prompts the question of how they coexist in the apparent absence of ecological divergence. However, this assumes first that the molecular taxonomy used to identify cryptic lineages delimits species boundaries accurately. This issue is important, because many diversity studies rely heavily or solely on data from mitochondrial DNA sequences for species delimitation, and several factors may lead to poor identification of species boundaries. We used a multilocus population genetics approach to show that three mtDNA-defined cryptic lineages of the fig wasp Pleistodontes imperialis Saunders, which pollinate Port Jackson figs (Ficus rubiginosa) in north-eastern Australia, represent reproductively isolated species. These species coexist locally, with about 13% of figs (where mating occurs) containing wasps from two or three species. However, there was no evidence for gene flow between them. Confirmed cases of coexisting cryptic species provide excellent opportunities for future studies of the ecological and evolutionary forces shaping both species coexistence and fig/pollinator coevolution. PMID- 28074847 TI - Nitrogen-doped porous carbon monoliths from polyacrylonitrile (PAN) and carbon nanotubes as electrodes for supercapacitors. AB - Nitrogen-doped porous activated carbon monoliths (NDP-ACMs) have long been the most desirable materials for supercapacitors. Unique to the conventional template based Lewis acid/base activation methods, herein, we report on a simple yet practicable novel approach to production of the three-dimensional NDP-ACMs (3D NDP-ACMs). Polyacrylonitrile (PAN) contained carbon nanotubes (CNTs), being pre dispersed into a tubular level of dispersions, were used as the starting material and the 3D-NDP-ACMs were obtained via a template-free process. First, a continuous mesoporous PAN/CNT based 3D monolith was established by using a template-free temperature-induced phase separation (TTPS). Second, a nitrogen doped 3D-ACM with a surface area of 613.8 m2/g and a pore volume 0.366 cm3/g was obtained. A typical supercapacitor with our 3D-NDP-ACMs as the functioning electrodes gave a specific capacitance stabilized at 216 F/g even after 3000 cycles, demonstrating the advantageous performance of the PAN/CNT based 3D-NDP ACMs. PMID- 28074846 TI - Novel blood-based microRNA biomarker panel for early diagnosis of chronic pancreatitis. AB - Chronic pancreatitis (CP) is an inflammatory disease characterized by progressive fibrosis of pancreas. Early diagnosis will improve the prognosis of patients. This study aimed to obtain serum miRNA biomarkers for early diagnosis of CP. In the current study, we analyzed the differentially expressed miRNAs (DEmiRs) of CP patients from Gene Expression Omnibus (GEO), and the DEmiRs in plasma of early CP patients (n = 10) from clinic by miRNA microarrays. Expression levels of DEmiRs were further tested in clinical samples including early CP patients (n = 20), late CP patients (n = 20) and healthy controls (n = 18). The primary endpoints were area under curve (AUC) and expression levels of DEmiRs. Four DEmiRs (hsa-miR 320a-d) were obtained from GEO CP, meanwhile two (hsa-miR-221 and hsa-miR-130a) were identified as distinct biomarkers of early CP by miRNA microarrays. When applied on clinical serum samples, hsa-miR-320a-d were accurate in predicting late CP, while hsa-miR-221 and hsa-miR-130a were accurate in predicting early CP with AUC of 100.0% and 87.5%. Our study indicates that miRNA expression profile is different in early and late CP. Hsa-miR-221 and hsa-miR-130a are biomarkers of early CP, and the panel of the above 6 serum miRNAs has the potential to be applied clinically for early diagnosis of CP. PMID- 28074848 TI - Crystal Structure of StnA for the Biosynthesis of Antitumor Drug Streptonigrin Reveals a Unique Substrate Binding Mode. AB - Streptonigrin methylesterase A (StnA) is one of the tailoring enzymes that modify the aminoquinone skeleton in the biosynthesis pathway of Streptomyces species. Although StnA has no significant sequence homology with the reported alpha/beta fold hydrolases, it shows typical hydrolytic activity in vivo and in vitro. In order to reveal its functional characteristics, the crystal structures of the selenomethionine substituted StnA (SeMet-StnA) and the complex (S185A mutant) with its substrate were resolved to the resolution of 2.71 A and 2.90 A, respectively. The overall structure of StnA can be described as an alpha-helix cap domain on top of a common alpha/beta hydrolase domain. The substrate methyl ester of 10'-demethoxystreptonigrin binds in a hydrophobic pocket that mainly consists of cap domain residues and is close to the catalytic triad Ser185-His349 Asp308. The transition state is stabilized by an oxyanion hole formed by the backbone amides of Ala102 and Leu186. The substrate binding appears to be dominated by interactions with several specific hydrophobic contacts and hydrogen bonds in the cap domain. The molecular dynamics simulation and site-directed mutagenesis confirmed the important roles of the key interacting residues in the cap domain. Structural alignment and phylogenetic tree analysis indicate that StnA represents a new subfamily of lipolytic enzymes with the specific binding pocket located at the cap domain instead of the interface between the two domains. PMID- 28074849 TI - Genetic Variants Identified from Epilepsy of Unknown Etiology in Chinese Children by Targeted Exome Sequencing. AB - Genetic factors play a major role in the etiology of epilepsy disorders. Recent genomics studies using next generation sequencing (NGS) technique have identified a large number of genetic variants including copy number (CNV) and single nucleotide variant (SNV) in a small set of genes from individuals with epilepsy. These discoveries have contributed significantly to evaluate the etiology of epilepsy in clinic and lay the foundation to develop molecular specific treatment. However, the molecular basis for a majority of epilepsy patients remains elusive, and furthermore, most of these studies have been conducted in Caucasian children. Here we conducted a targeted exome-sequencing of 63 trios of Chinese epilepsy families using a custom-designed NGS panel that covers 412 known and candidate genes for epilepsy. We identified pathogenic and likely pathogenic variants in 15 of 63 (23.8%) families in known epilepsy genes including SCN1A, CDKL5, STXBP1, CHD2, SCN3A, SCN9A, TSC2, MBD5, POLG and EFHC1. More importantly, we identified likely pathologic variants in several novel candidate genes such as GABRE, MYH1, and CLCN6. Our results provide the evidence supporting the application of custom-designed NGS panel in clinic and indicate a conserved genetic susceptibility for epilepsy between Chinese and Caucasian children. PMID- 28074851 TI - Corrigendum: Dynamics and genetics of a disease-driven species decline to near extinction: lessons for conservation. PMID- 28074850 TI - Juvenile hormone biosynthesis in adult Blattella germanica requires nuclear receptors Seven-up and FTZ-F1. AB - In insects, the transition from juvenile development to the adult stage is controlled by juvenile hormone (JH) synthesized from the corpora allata (CA) glands. Whereas a JH-free period during the last juvenile instar triggers metamorphosis and the end of the growth period, the reappearance of this hormone after the imaginal molt marks the onset of reproductive adulthood. Despite the importance of such transition, the regulatory mechanism that controls it remains mostly unknown. Here, using the hemimetabolous insect Blattella germanica, we show that nuclear hormone receptors Seven-up-B (BgSvp-B) and Fushi tarazu-factor 1 (BgFTZ-F1) have essential roles in the tissue- and stage-specific activation of adult CA JH-biosynthetic activity. Both factors are highly expressed in adult CA cells. Moreover, RNAi-knockdown of either BgSvp-B or BgFTZ-F1 results in adult animals with a complete block in two critical JH-dependent reproductive processes, vitellogenesis and oogenesis. We show that this reproductive blockage is the result of a dramatic impairment of JH biosynthesis, due to the CA-specific reduction in the expression of two key JH biosynthetic enzymes, 3-hydroxy-3 methylglutaryl coenzyme A synthase-1 (BgHMG-S1) and HMG-reductase (BgHMG-R). Our findings provide insights into the regulatory mechanisms underlying the specific changes in the CA gland necessary for the proper transition to adulthood. PMID- 28074852 TI - Initiation and growth kinetics of solidification cracking during welding of steel. AB - Solidification cracking is a key phenomenon associated with defect formation during welding. To elucidate the failure mechanisms, solidification cracking during arc welding of steel are investigated in situ with high-speed, high-energy synchrotron X-ray radiography. Damage initiates at relatively low true strain of about 3.1% in the form of micro-cavities at the weld subsurface where peak volumetric strain and triaxiality are localised. The initial micro-cavities, with sizes from 10 * 10-6 m to 27 * 10-6 m, are mostly formed in isolation as revealed by synchrotron X-ray micro-tomography. The growth of micro-cavities is driven by increasing strain induced to the solidifying steel. Cavities grow through coalescence of micro-cavities to form micro-cracks first and then through the propagation of micro-cracks. Cracks propagate from the core of the weld towards the free surface along the solidifying grain boundaries at a speed of 2-3 * 10-3 m s-1. PMID- 28074853 TI - Plasmonic plano-semi-cylindrical nanocavities with high-efficiency local-field confinement. AB - Plasmonic nanocavity arrays were achieved by producing isolated silver semi cylindrical nanoshells periodically on a continuous planar gold film. Hybridization between localized surface plasmon resonance (LSPR) in the Ag semi cylindrical nanoshells (SCNS) and surface plasmon polaritons (SPP) in the gold film was observed as split bonding and anti-bonding resonance modes located at different spectral positions. This led to strong local field enhancement and confinement in the plano-concave nanocavites. Narrow-band optical extinction with an amplitude as high as 1.5 OD, corresponding to 97% reduction in the transmission, was achieved in the visible spectrum. The resonance spectra of this hybrid device can be extended from the visible to the near infrared by adjusting the structural parameters. PMID- 28074854 TI - Facile Synthesis of Highly Crystalline and Large Areal Hexagonal Boron Nitride from Borazine Oligomers. AB - A novel and facile synthetic method for h-BN films from borazine oligomer (B3N3H4)x precursors has been developed. This method only includes spin-coating of borazine oligomer onto nickel catalysts and a subsequent annealing step. Large areal and highly crystalline h-BN films were obtained. The stoichiometric B/N ratio of borazine oligomer precursor was preserved in the final h-BN product such that it was close to 1 as revealed by XPS. Catalytic effect of nickel for h-BN formation was clearly demonstrated by lowering crystallization temperature compared to the growth condition in the absence of catalyst. The graphene field effect transistor (GFET) characterization has proved the high quality synthesis of h-BN films, showing the shift of neutrality point and the increase of the mobility. This method can also provide functional h-BN coating on various surfaces by annealing Ni-coated borazine oligomer films and subsequent removal of Ni catalyst. PMID- 28074855 TI - MiR-218 targets MeCP2 and inhibits heroin seeking behavior. AB - MicroRNAs (miRNAs) are a class of evolutionarily conserved, 18-25 nucleotide non coding sequences that post-transcriptionally regulate gene expression. Recent studies implicated their roles in the regulation of neuronal functions, such as learning, cognition and memory formation. Here we report that miR-218 inhibits heroin-induced behavioral plasticity. First, network propagation-based method was used to predict candidate miRNAs that played potential key roles in regulating drug addiction-related genes. Microarray screening was also carried out to identify miRNAs responding to chronic heroin administration in the nucleus accumbens (NAc). Among the collapsed miRNAs, top-ranked miR-218 was decreased after chronic exposure to heroin. Lentiviral overexpression of miR-218 in NAc could inhibit heroin-induced reinforcement in both conditioned place preference (CPP) test and heroin self-administration experiments. Luciferase activity assay indicated that miR-218 could regulate 3' untranslated regions (3' UTR) of multiple neuroplasticity-related genes and directly target methyl CpG binding protein 2 (Mecp2). Consistently, Mecp2308/y mice exhibited reduced heroin seeking behavior in CPP test. These data reveal a functional role of miR-218 and its target, MeCP2, in the regulation of heroin-induced behavioral plasticity. PMID- 28074856 TI - Local field potentials primarily reflect inhibitory neuron activity in human and monkey cortex. AB - The local field potential (LFP) is generated by large populations of neurons, but unitary contribution of spiking neurons to LFP is not well characterised. We investigated this contribution in multi-electrode array recordings from human and monkey neocortex by examining the spike-triggered LFP average (st-LFP). The resulting st-LFPs were dominated by broad spatio-temporal components due to ongoing activity, synaptic inputs and recurrent connectivity. To reduce the spatial reach of the st-LFP and observe the local field related to a single spike we applied a spatial filter, whose weights were adapted to the covariance of ongoing LFP. The filtered st-LFPs were limited to the perimeter of 800 MUm around the neuron, and propagated at axonal speed, which is consistent with their unitary nature. In addition, we discriminated between putative inhibitory and excitatory neurons and found that the inhibitory st-LFP peaked at shorter latencies, consistently with previous findings in hippocampal slices. Thus, in human and monkey neocortex, the LFP reflects primarily inhibitory neuron activity. PMID- 28074857 TI - Deubiquitylation of hepatitis B virus X protein (HBx) by ubiquitin-specific peptidase 15 (USP15) increases HBx stability and its transactivation activity. AB - Hepatitis B virus X protein (HBx) plays important roles in viral replication and the development of hepatocellular carcinoma. HBx is a rapid turnover protein and ubiquitin-proteasome pathway has been suggested to influence HBx stability as treatment with proteasome inhibitors increases the levels of HBx protein and causes accumulation of the polyubiquitinated forms of HBx. Deubiquitinases (DUBs) are known to act by removing ubiquitin moieties from proteins and thereby reverse their stability and/or activity. However, no information is available regarding the involvement of DUBs in regulation of ubiquitylation-dependent proteasomal degradation of HBx protein. This study identified the deubiquitylating enzyme USP15 as a critical regulator of HBx protein level. USP15 was found to directly interact with HBx via binding to the HBx region between amino acid residues 51 and 80. USP15 increased HBx protein levels in a dose-dependent manner and siRNA mediated knockdown of endogenous USP15 reduced HBx protein levels. Increased HBx stability and steady-state level by USP15 were attributable to reduced HBx ubiquitination and proteasomal degradation. Importantly, the transcriptional transactivation function of HBx is enhanced by overexpression of USP15. These results suggest that USP15 plays an essential role in stabilizing HBx and subsequently affects the biological function of HBx. PMID- 28074858 TI - Traces of an ancient immune system - how an injured arthropod survived 465 million years ago. AB - This report of a severely injured trilobite from the Middle Ordovician (~465 Ma) accords with a number of similar observations of healed lesions observed in trilobites. The uniqueness of the specimen described here is that the character of the repair-mechanisms is reflected by the secondarily built structures, which form the new surface of the ruptured compound eye. Smooth, repaired areas inside the visual surface advert to a clotting principle, rather similar to those of today, and the way in which broken parts of the exoskeleton fused during restoration seem to simulate modern samples. The irregularity and variance of newly inserted visual units indicate the severity of the injury, which, most probably, was caused by a predatory attack, presumably by a cephalopod; these were most likely, the top predators of the Ordovician. Furthermore, the state of the moulted cephalon tells the dramatic struggle of an organism that lived in the Palaeozoic, to survive. In sum the specimen analysed here is evidence of an ancient clotting mechanism not dissimilar to those of today, rapidly preventing any exsanguination and the breakdown of osmoregulation of this marine arthropod. PMID- 28074859 TI - Identifying a gene expression signature of cluster headache in blood. AB - Cluster headache is a relatively rare headache disorder, typically characterized by multiple daily, short-lasting attacks of excruciating, unilateral (peri )orbital or temporal pain associated with autonomic symptoms and restlessness. To better understand the pathophysiology of cluster headache, we used RNA sequencing to identify differentially expressed genes and pathways in whole blood of patients with episodic (n = 19) or chronic (n = 20) cluster headache in comparison with headache-free controls (n = 20). Gene expression data were analysed by gene and by module of co-expressed genes with particular attention to previously implicated disease pathways including hypocretin dysregulation. Only moderate gene expression differences were identified and no associations were found with previously reported pathogenic mechanisms. At the level of functional gene sets, associations were observed for genes involved in several brain-related mechanisms such as GABA receptor function and voltage-gated channels. In addition, genes and modules of co-expressed genes showed a role for intracellular signalling cascades, mitochondria and inflammation. Although larger study samples may be required to identify the full range of involved pathways, these results indicate a role for mitochondria, intracellular signalling and inflammation in cluster headache. PMID- 28074860 TI - Sex- and age-dependent patterns of survival and breeding success in a long-lived endangered avian scavenger. AB - In long-lived species, the age-, stage- and/or sex-dependent patterns of survival and reproduction determine the evolution of life history strategies, the shape of the reproductive value, and ultimately population dynamics. We evaluate the combined effects of age and sex in recruitment, breeder survival and breeding success of the globally endangered Egyptian vulture (Neophron percnopterus), using 31-years of exhaustive data on marked individuals in Spain. Mean age of first reproduction was 7-yrs for both sexes, but females showed an earlier median and a larger variance than males. We found an age-related improvement in breeding success at the population level responding to the selective appearance and disappearance of phenotypes of different quality but unrelated to within individual aging effects. Old males (>=8 yrs) showed a higher survival than both young males (<=7 yrs) and females, these later in turn not showing aging effects. Evolutionary trade-offs between age of recruitment and fitness (probably related to costs of territory acquisition and defense) as well as human-related mortality may explain these findings. Sex- and age-related differences in foraging strategies and susceptibility to toxics could be behind the relatively low survival of females and young males, adding a new concern for the conservation of this endangered species. PMID- 28074861 TI - Deployment of check-in nodes in complex networks. AB - In many real complex networks such as the city road networks and highway networks, vehicles often have to pass through some specially functioned nodes to receive check-in like services such as gas supplement at gas stations. Based on existing network structures, to guarantee every shortest path including at least a check-in node, the location selection of all check-in nodes is very essential and important to make vehicles to easily visit these check-in nodes, and it is still remains an open problem in complex network studies. In this work, we aim to find possible solutions for this problem. We first convert it into a set cover problem which is NP-complete and propose to employ the greedy algorithm to achieve an approximate result. Inspired by heuristic information of network structure, we discuss other four check-in node location deployment methods including high betweenness first (HBF), high degree first (HDF), random and low degree first (LDF). Finally, we compose extensive simulations in classical scale free networks, random networks and real network models, and the results can well confirm the effectiveness of the greedy algorithm. This work has potential applications into many real networks. PMID- 28074863 TI - Herb pair Danggui-Honghua: mechanisms underlying blood stasis syndrome by system pharmacology approach. AB - Herb pair Danggui-Honghua has been frequently used for treatment of blood stasis syndrome (BSS) in China, one of the most common clinical pathological syndromes in traditional Chinese medicine (TCM). However, its therapeutic mechanism has not been clearly elucidated. In the present study, a feasible system pharmacology model based on chemical, pharmacokinetic and pharmacological data was developed via network construction approach to clarify the mechanisms of this herb pair. Thirty-one active ingredients of Danggui-Honghua possessing favorable pharmacokinetic profiles and biological activities were selected, interacting with 42 BSS-related targets to provide potential synergistic therapeutic actions. Systematic analysis of the constructed networks revealed that these targets such as HMOX1, NOS2, NOS3, HIF1A and PTGS2 were mainly involved in TNF signaling pathway, HIF-1 signaling pathway, estrogen signaling pathway and neurotrophin signaling pathway. The contribution index of every active ingredient also indicated six compounds, including hydroxysafflor yellow A, safflor yellow A, safflor yellow B, Z-ligustilide, ferulic acid, and Z-butylidenephthalide, as the principal components of this herb pair. These results successfully explained the polypharmcological mechanisms underlying the efficiency of Danggui-Honghua for BSS treatment, and also probed into the potential novel therapeutic strategies for BSS in TCM. PMID- 28074864 TI - A novel monoclonal antibody targeting coxsackie virus and adenovirus receptor inhibits tumor growth in vivo. AB - To create a new anti-tumor antibody, we conducted signal sequence trap by retrovirus-meditated expression method and identified coxsackie virus and adenovirus receptor (CXADR) as an appropriate target. We developed monoclonal antibodies against human CXADR and found that one antibody (6G10A) significantly inhibited the growth of subcutaneous as well as orthotopic xenografts of human prostate cancer cells in vivo. Furthermore, 6G10A also inhibited other cancer xenografts expressing CXADR, such as pancreatic and colorectal cancer cells. Knockdown and overexpression of CXADR confirmed the dependence of its anti-tumor activity on CXADR expression. Our studies of its action demonstrated that 6G10A exerted its anti-tumor activity primarily through both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Moreover, 6G10A reacted with human tumor tissues, such as prostate, lung, and brain, each of which express CXADR. Although we need further evaluation of its reactivity and safety in human tissues, our results show that a novel anti-CXADR antibody may be a feasible candidate for cancer immunotherapy. PMID- 28074862 TI - Hypoxia activates Wnt/beta-catenin signaling by regulating the expression of BCL9 in human hepatocellular carcinoma. AB - The Wnt/beta-catenin signaling is abnormally activated in the progression of hepatocellular carcinoma (HCC). BCL9 is an essential co-activator in the Wnt/beta catenin signaling. Importantly, BCL9 is absent from tumors originating from normal cellular counterparts and overexpressed in many cancers including HCC. But the mechanism for BCL9 overexpression remains unknown. Ample evidence indicates that hypoxia inducible factors (HIFs) play a role in the development of HCC. It was found in our study that BCL9 was overexpressed in both primary HCC and bone metastasis specimens; loss of BCL9 inhibited the proliferation, migration and angiogenesis of HCC; and that that hypoxia mechanically induced the expression of BCL9. BCL9 induction under the hypoxic condition was predominantly mediated by HIF-1alpha but not HIF2alpha. In vitro evidence from xenograft models indicated that BCL9 promoter/gene knockout inhibited HCC tumor growth and angiogenesis. Notably, we found that BCL9 and HIF-1alpha were coordinately regulated in human HCC specimen. The above findings suggest that hypoxia may promote the expression of BCL9 and associate with the development of HCC. Specific regulation of BCL9 expression by HIF-1alpha may prove to be an underlying crosstalk between Wnt/beta catenin signaling and hypoxia signaling pathways. PMID- 28074865 TI - Bendable solid-state supercapacitors with Au nanoparticle-embedded graphene hydrogel films. AB - In this study, we fabricate bendable solid-state supercapacitors with Au nanoparticle (NP)-embedded graphene hydrogel (GH) electrodes and investigate the influence of the Au NP embedment on the internal resistance and capacitive performance. Embedding the Au NPs into the GH electrodes results in a decrease of the internal resistance from 35 to 21 Omega, and a threefold reduction of the IR drop at a current density of 5 A/g when compared with GH electrodes without Au NPs. The Au NP-embedded GH supercapacitors (NP-GH SCs) exhibit excellent capacitive performances, with large specific capacitance (135 F/g) and high energy density (15.2 W.h/kg). Moreover, the NP-GH SCs exhibit comparable areal capacitance (168 mF/cm2) and operate under tensile/compressive bending. PMID- 28074866 TI - "Mycobacterium massilipolynesiensis" sp. nov., a rapidly-growing mycobacterium of medical interest related to Mycobacterium phlei. AB - In French Polynesia, respiratory tract clinical isolate M26, displayed unusual phenotype and contradictory phylogenetic affiliations, suggesting a hitherto unidentified rapidly-growing Mycobacterium species. The phenotype of strain M26 was further characterized and its genome sequenced. Strain M26 genome consists in a 5,732,017-bp circular chromosome with a G + C% of 67.54%, comprising 5,500 protein-coding genes and 52 RNA genes (including two copies of the 16 S rRNA gene). One region coding for a putative prophage was also predicted. An intriguing characteristic of strain M26's genome is the large number of genes encoding polyketide synthases and nonribosomal peptide synthases. Phylogenomic analysis showed that strain M26's genome is closest to the Mycobacterium phlei genome with a 76.6% average nucleotide identity. Comparative genomics of 33 Mycobacterium genomes yielded 361 genes unique to M26 strain which functional annotation revealed 84.21% of unknown function and 3.88% encoding lipid transport and metabolism; while 48.87% of genes absent in M26 strain have unknown function, 9.5% are implicated in transcription and 19% are implicated in transport and metabolism. Strain M26's unique phenotypic and genomic characteristics indicate it is representative of a new species named "Mycobacterium massilipolynesiensis". Looking for mycobacteria in remote areas allows for the discovery of new Mycobacterium species. PMID- 28074867 TI - The role of macrophages in the susceptibility of Fc gamma receptor IIb deficient mice to Cryptococcus neoformans. AB - Dysfunctional polymorphisms of FcgammaRIIb, an inhibitory receptor, are associated with Systemic Lupus Erythaematosus (SLE). Cryptococcosis is an invasive fungal infection in SLE, perhaps due to the de novo immune defect. We investigated cryptococcosis in the FcgammaRIIb-/- mouse-lupus-model. Mortality, after intravenous C. neoformans-induced cryptococcosis, in young (8-week-old) and older (24-week-old) FcgammaRIIb-/- mice, was higher than in age-matched wild types. Severe cryptococcosis in the FcgammaRIIb-/- mice was demonstrated by high fungal burdens in the internal organs with histological cryptococcoma-like lesions and high levels of TNF-alpha and IL-6, but not IL-10. Interestingly, FcgammaRIIb-/- macrophages demonstrated more prominent phagocytosis but did not differ in killing activity in vitro and the striking TNF-alpha, IL-6 and IL-10 levels, compared to wild-type cells. Indeed, in vivo macrophage depletion with liposomal clodronate attenuated the fungal burdens in FcgammaRIIb-/- mice, but not wild-type mice. When administered to wild-type mice, FcgammaRIIb-/- macrophages with phagocytosed Cryptococcus resulted in higher fungal burdens than FcgammaRIIb+/+ macrophages with phagocytosed Cryptococcus. These results support, at least in part, a model whereby, in FcgammaRIIb-/- mice, enhanced C. neoformans transmigration occurs through infected macrophages. In summary, prominent phagocytosis, with limited effective killing activity, and high pro-inflammatory cytokine production by FcgammaRIIb-/- macrophages were correlated with more severe cryptococcosis in FcgammaRIIb-/- mice. PMID- 28074868 TI - Nucleoplasmin-like domain of FKBP39 from Drosophila melanogaster forms a tetramer with partly disordered tentacle-like C-terminal segments. AB - Nucleoplasmins are a nuclear chaperone family defined by the presence of a highly conserved N-terminal core domain. X-ray crystallographic studies of isolated nucleoplasmin core domains revealed a beta-propeller structure consisting of a set of five monomers that together form a stable pentamer. Recent studies on isolated N-terminal domains from Drosophila 39-kDa FK506-binding protein (FKBP39) and from other chromatin-associated proteins showed analogous, nucleoplasmin-like (NPL) pentameric structures. Here, we report that the NPL domain of the full length FKBP39 does not form pentameric complexes. Multi-angle light scattering (MALS) and sedimentation equilibrium ultracentrifugation (SE AUC) analyses of the molecular mass of the full-length protein indicated that FKBP39 forms homotetrameric complexes. Molecular models reconstructed from small-angle X-ray scattering (SAXS) revealed that the NPL domain forms a stable, tetrameric core and that FK506-binding domains are linked to it by intrinsically disordered, flexible chains that form tentacle-like segments. Analyses of full-length FKBP39 and its isolated NPL domain suggested that the distal regions of the polypeptide chain influence and determine the quaternary conformation of the nucleoplasmin like protein. These results provide new insights regarding the conserved structure of nucleoplasmin core domains and provide a potential explanation for the importance of the tetrameric structural organization of full-length nucleoplasmins. PMID- 28074869 TI - Urinary exosome-derived microRNAs reflecting the changes of renal function and histopathology in dogs. AB - MicroRNAs act as post-transcriptional regulators, and urinary exosome (UExo) derived microRNAs may be used as biomarkers. Herein, we screened for UExo-derived microRNAs reflecting kidney disease (KD) status in dogs. Examined dogs were divided into healthy kidney control (HC) and KD groups according to renal dysfunction. We confirmed the appearance of UExo having irregular globe-shapes in a dog by immunoblot detection of the exosome markers, TSG101 and CD9. Based on our previous data using KD model mice and the data obtained herein by next generation sequencing of UExo-derived microRNAs in dogs, miR-26a, miR-146a, miR 486, miR-21a, and miR-10a/b were selected as candidate microRNAs. In particular, UExo-derived miR-26a and miR-10a/b were significantly decreased in KD dogs, and miR-26a levels negatively correlated with deteriorated renal function compared to the other miRNAs. UExo-derived miR-21a levels corrected or not to that of internal control microRNAs in UExo, miR-26a and miR-191, significantly increased with renal dysfunction. In kidney tissues, the decrease of miR-26a and miR-10a/b in the glomerulus and miR-10b in the tubulointerstitium negatively correlated with deteriorated renal function and histopathology. Increased miR-21a in the tubulointerstitium rather than in the glomerulus correlated with deteriorated renal histopathology. In conclusion, microRNAs reflecting the changes in renal function and histopathology in dogs were identified in this study. PMID- 28074870 TI - MicroRNA-155 is upregulated in ascites in patients with spontaneous bacterial peritonitis. AB - MircoRNA's (miR) have been recognised as important modulators of gene expression and potential biomarkers. However, they have been rarely investigated in bio fluids apart from blood. We investigated the association of miR-125b and miR-155 with complications of cirrhosis. Ascites was prospectively collected from patients with cirrhosis undergoing paracentesis at our department. miR's were determined in the supernatant using qPCR and normalized by SV-40. Clinical parameters were assessed at paracentesis and during follow-up. 76 specimens from 72 patients were analysed. MiR's were not associated to age, sex or aetiology of cirrhosis. MiR-125b levels differed between patients with low and high MELD score, and miR-125b levels showed an inverse correlation to serum creatinine (r2 = -0.23; p = 0.05). MiR-155 was elevated in patients with spontaneous bacterial peritonitis (SBP) (n = 10; p = 0.04). MiR-155 levels differed between patients with and without 30-day survival (p = 0.02). No association of ascites levels of investigated miR's to size of varices, episodes of gastrointestinal bleeding or hepatorenal syndrome was observed. While miR-125b levels in ascites seem to be associated with liver and renal dysfunction, miR-155 might be implicated in local immune response in SBP. PMID- 28074871 TI - Long-term MODIS observations of cyanobacterial dynamics in Lake Taihu: Responses to nutrient enrichment and meteorological factors. AB - We developed and validated an empirical model for estimating chlorophyll a concentrations (Chla) in Lake Taihu to generate a long-term Chla and algal bloom area time series from MODIS-Aqua observations for 2003 to 2013. Then, based on the long-term time series data, we quantified the responses of cyanobacterial dynamics to nutrient enrichment and climatic conditions. Chla showed substantial spatial and temporal variability. In addition, the annual mean cyanobacterial surface bloom area exhibited an increasing trend across the entire lake from 2003 to 2013, with the exception of 2006 and 2007. High air temperature and phosphorus levels in the spring can prompt cyanobacterial growth, and low wind speeds and low atmospheric pressure levels favor cyanobacterial surface bloom formation. The sensitivity of cyanobacterial dynamics to climatic conditions was found to vary by region. Our results indicate that temperature is the most important factor controlling Chla inter-annual variability followed by phosphorus and that air pressure is the most important factor controlling cyanobacterial surface bloom formation followed by wind speeds in Lake Taihu. PMID- 28074872 TI - Corrigendum: Targeting High Dynamin-2 (DNM2) Expression by Restoring Ikaros Function in Acute Lymphoblastic Leukemia. PMID- 28074873 TI - The NAC-type transcription factor OsNAC2 regulates ABA-dependent genes and abiotic stress tolerance in rice. AB - Plants can perceive environmental changes and respond to external stressors. Here, we show that OsNAC2, a member of the NAC transcription factor family, was strongly induced by ABA and osmotic stressors such as drought and high salt. With reduced yields under drought conditions at the flowering stage, OsNAC2 overexpression lines had lower resistance to high salt and drought conditions. RNAi plants showed enhanced tolerance to high salinity and drought stress at both the vegetative and flowering stages. Furthermore, RNAi plants had improved yields after drought stress. A microarray assay indicated that many ABA-dependent stress related genes were down-regulated in OsNAC2 overexpression lines. We further confirmed that OsNAC2 directly binds the promoters of LATE EMBRYOGENESIS ABUNDANT 3 (OsLEA3) and Stress-Activated Protein Kinases 1 (OsSAPK1), two marker genes in the abiotic stress and ABA response pathways, respectively. Our results suggest that in rice OsNAC2 regulates both abiotic stress responses and ABA-mediated responses, and acts at the junction between the ABA and abiotic stress pathways. PMID- 28074874 TI - Modeling confirmation bias and polarization. AB - Online users tend to select claims that adhere to their system of beliefs and to ignore dissenting information. Confirmation bias, indeed, plays a pivotal role in viral phenomena. Furthermore, the wide availability of content on the web fosters the aggregation of likeminded people where debates tend to enforce group polarization. Such a configuration might alter the public debate and thus the formation of the public opinion. In this paper we provide a mathematical model to study online social debates and the related polarization dynamics. We assume the basic updating rule of the Bounded Confidence Model (BCM) and we develop two variations a) the Rewire with Bounded Confidence Model (RBCM), in which discordant links are broken until convergence is reached; and b) the Unbounded Confidence Model, under which the interaction among discordant pairs of users is allowed even with a negative feedback, either with the rewiring step (RUCM) or without it (UCM). From numerical simulations we find that the new models (UCM and RUCM), unlike the BCM, are able to explain the coexistence of two stable final opinions, often observed in reality. Lastly, we present a mean field approximation of the newly introduced models. PMID- 28074875 TI - From an indirect response pharmacodynamic model towards a secondary signal model of dose-response relationship between exercise training and physical performance. AB - The aim of this study was to test the suitability of using indirect responses for modeling the effects of physical training on performance. We formulated four different models assuming that increase in performance results of the transformation of a signal secondary to the primary stimulus which is the training dose. The models were designed to be used with experimental data with daily training amounts ascribed to input and performance measured at several dates ascribed to output. The models were tested using data obtained from six subjects who trained on a cycle ergometer over a 15-week period. The data fit for each subject was good for all of the models. Goodness-of-fit and consistency of parameter estimates favored the model that took into account the inhibition of production of training effect. This model produced an inverted-U shape graphic when plotting daily training dose against performance because of the effect of one training session on the cumulated effects of previous sessions. In conclusion, using secondary signal-dependent response provided a framework helpful for modeling training effect which could enhance the quantitative methods used to analyze how best to dose physical activity for athletic performance or healthy living. PMID- 28074876 TI - Scale-up of nature's tissue weaving algorithms to engineer advanced functional materials. AB - We are literally the stuff from which our tissue fabrics and their fibers are woven and spun. The arrangement of collagen, elastin and other structural proteins in space and time embodies our tissues and organs with amazing resilience and multifunctional smart properties. For example, the periosteum, a soft tissue sleeve that envelops all nonarticular bony surfaces of the body, comprises an inherently "smart" material that gives hard bones added strength under high impact loads. Yet a paucity of scalable bottom-up approaches stymies the harnessing of smart tissues' biological, mechanical and organizational detail to create advanced functional materials. Here, a novel approach is established to scale up the multidimensional fiber patterns of natural soft tissue weaves for rapid prototyping of advanced functional materials. First second harmonic generation and two-photon excitation microscopy is used to map the microscopic three-dimensional (3D) alignment, composition and distribution of the collagen and elastin fibers of periosteum, the soft tissue sheath bounding all nonarticular bone surfaces in our bodies. Then, using engineering rendering software to scale up this natural tissue fabric, as well as multidimensional weaving algorithms, macroscopic tissue prototypes are created using a computer controlled jacquard loom. The capacity to prototype scaled up architectures of natural fabrics provides a new avenue to create advanced functional materials. PMID- 28074877 TI - Microwave-synthesized freestanding iron-carbon nanotubes on polyester composites of woven Kevlar fibre and silver nanoparticle-decorated graphene. AB - We synthesized Ag nanoparticle-decorated multilayered graphene nanosheets (Ag graphene) from graphite nanoplatelets and silver nitrate through 90-100 s of microwave exposure, without the use of any mineral acids or harsh reducing agents. Fe nanoparticle-decorated carbon nanotubes (Fe-CNTs) were grown on polypyrrole (PPy) deposited on woven Kevlar fibre (WKF), using ferrocene as a catalyst, under microwave irradiation. Fe-CNTs grown on WKF and Ag-graphene dispersed in polyester resin (PES) were combined to fabricate Ag-graphene/Fe CNT/PPy-coated WKF/PES composites by vacuum-assisted resin transfer moulding. The combined effect of Fe-CNTs and Ag-graphene in the resulting composites resulted in a remarkable enhancement of tensile properties (a 192.56% increase in strength and 100.64% increase in modulus) as well as impact resistance (a 116.33% increase). The electrical conductivity significantly increased for Ag-graphene/Fe CNT/PPy-coated WKF/PES composites. The effectiveness of electromagnetic interference shielding, which relies strongly on the Ag-graphene content in the composites, was 25 times higher in Ag-graphene/Fe-CNT/PPy-coated WKF/PES than in neat WKF/PES composites. The current work offers a novel route for fabricating highly promising, cost effective WKF/PES composites through microwave-assisted synthesis of Fe-CNTs and Ag-graphene. PMID- 28074878 TI - Microscopic Evolution of Laboratory Volcanic Hybrid Earthquakes. AB - Characterizing the interaction between fluids and microscopic defects is one of the long-standing challenges in understanding a broad range of cracking processes, in part because they are so difficult to study experimentally. We address this issue by reexamining records of emitted acoustic phonon events during rock mechanics experiments under wet and dry conditions. The frequency spectrum of these events provides direct information regarding the state of the system. Such events are typically subdivided into high frequency (HF) and low frequency (LF) events, whereas intermediate "Hybrid" events, have HF onsets followed by LF ringing. At a larger scale in volcanic terranes, hybrid events are used empirically to predict eruptions, but their ambiguous physical origin limits their diagnostic use. By studying acoustic phonon emissions from individual microcracking events we show that the onset of a secondary instability-related to the transition from HF to LF-occurs during the fast equilibration phase of the system, leading to sudden increase of fluid pressure in the process zone. As a result of this squeezing process, a secondary instability akin to the LF event occurs. This mechanism is consistent with observations of hybrid earthquakes. PMID- 28074879 TI - Prediction of Local Quality of Protein Structure Models Considering Spatial Neighbors in Graphical Models. AB - Protein tertiary structure prediction methods have matured in recent years. However, some proteins defy accurate prediction due to factors such as inadequate template structures. While existing model quality assessment methods predict global model quality relatively well, there is substantial room for improvement in local quality assessment, i.e. assessment of the error at each residue position in a model. Local quality is a very important information for practical applications of structure models such as interpreting/designing site-directed mutagenesis of proteins. We have developed a novel local quality assessment method for protein tertiary structure models. The method, named Graph-based Model Quality assessment method (GMQ), explicitly considers the predicted quality of spatially neighboring residues using a graph representation of a query protein structure model. GMQ uses conditional random field as its core of the algorithm, and performs a binary prediction of the quality of each residue in a model, indicating if a residue position is likely to be within an error cutoff or not. The accuracy of GMQ was improved by considering larger graphs to include quality information of more surrounding residues. Moreover, we found that using different edge weights in graphs reflecting different secondary structures further improves the accuracy. GMQ showed competitive performance on a benchmark for quality assessment of structure models from the Critical Assessment of Techniques for Protein Structure Prediction (CASP). PMID- 28074880 TI - Tailoring Mechanically Robust Poly(m-phenylene isophthalamide) Nanofiber/nets for Ultrathin High-Efficiency Air Filter. AB - Effective promotion of air filtration applications proposed for fibers requires their real nanoscale diameter, optimized pore structure, and high service strength; however, creating such filter medium has proved to be a tremendous challenge. This study first establishes a strategy to design and fabricate novel poly(m-phenylene isophthalamide) nanofiber/nets (PMIA NF/N) air filter via electrospinning/netting. Our strategy results in generation of a bimodal structure including a scaffold of nanofibers and abundant two-dimensional ultrathin (~20 nm) nanonets to synchronously construct PMIA filters by combining solution optimization, humidity regulation, and additive inspiration. Benefiting from the structural features including the true nanoscale diameter, small pore size, high porosity, and nets bonding contributed by the widely distributed nanonets, our PMIA NF/N filter exhibits the integrated properties of superlight weight (0.365 g m-2), ultrathin thickness (~0.5 MUm), and high tensile strength (72.8 MPa) for effective air filtration, achieving the ultra-low penetration air filter level of 99.999% and low pressure drop of 92 Pa for 300-500 nm particles by sieving mechanism. The successful synthesis of PMIA NF/N would not only provide a promising medium for particle filtration, but also develop a versatile platform for exploring the application of nanonets in structural enhancement, separation and purification. PMID- 28074881 TI - Erratum: Discovery of a Carbazole-Derived Lead Drug for Human African Trypanosomiasis. PMID- 28074883 TI - Etalon Array Reconstructive Spectrometry. AB - Compact spectrometers are crucial in areas where size and weight may need to be minimized. These types of spectrometers often contain no moving parts, which makes for an instrument that can be highly durable. With the recent proliferation in low-cost and high-resolution cameras, camera-based spectrometry methods have the potential to make portable spectrometers small, ubiquitous, and cheap. Here, we demonstrate a novel method for compact spectrometry that uses an array of etalons to perform spectral encoding, and uses a reconstruction algorithm to recover the incident spectrum. This spectrometer has the unique capability for both high resolution and a large working bandwidth without sacrificing sensitivity, and we anticipate that its simplicity makes it an excellent candidate whenever a compact, robust, and flexible spectrometry solution is needed. PMID- 28074882 TI - Immunomagnetic separation of tumor initiating cells by screening two surface markers. AB - Isolating tumor initiating cells (TICs) often requires screening of multiple surface markers, sometimes with opposite preferences. This creates a challenge for using bead-based immunomagnetic separation (IMS) that typically enriches cells based on one abundant marker. Here, we propose a new strategy that allows isolation of CD44+/CD24- TICs by IMS involving both magnetic beads coated by anti CD44 antibody and nonmagnetic beads coated by anti-CD24 antibody (referred to as two-bead IMS). Cells enriched with our approach showed significant enhancement in TIC marker expression (examined by flow cytometry) and improved tumorsphere formation efficiency. Our method will extend the application of IMS to cell subsets characterized by multiple markers. PMID- 28074885 TI - First objective evaluation of taste sensitivity to 6-n-propylthiouracil (PROP), a paradigm gustatory stimulus in humans. AB - Practical and reliable methods for the objective measure of taste function are critically important for studying eating behavior and taste function impairment. Here, we present direct measures of human gustatory response to a prototypical bitter compound, 6-n-propyltiouracil (PROP), obtained by electrophysiological recordings from the tongue of subjects who were classified for taster status and genotyped for the specific receptor gene (TAS2R38), and in which taste papilla density was determined. PROP stimulation evoked negative slow potentials that represent the summated depolarization of taste cells. Depolarization amplitude and rate were correlated with papilla density and perceived bitterness, and associated with taster status and TAS2R38. Our study provides a robust and generalizable research tool for the quantitative measure of peripheral taste function, which can greatly help to resolve controversial outcomes on the PROP phenotype role in taste perception and food preferences, and be potentially useful for evaluating nutritional status and health. PMID- 28074884 TI - Actin-Interacting Protein 1 Contributes to Intranuclear Rod Assembly in Dictyostelium discoideum. AB - Intranuclear rods are aggregates consisting of actin and cofilin that are formed in the nucleus in consequence of chemical or mechanical stress conditions. The formation of rods is implicated in a variety of pathological conditions, such as certain myopathies and some neurological disorders. It is still not well understood what exactly triggers the formation of intranuclear rods, whether other proteins are involved, and what the underlying mechanisms of rod assembly or disassembly are. In this study, Dictyostelium discoideum was used to examine appearance, stages of assembly, composition, stability, and dismantling of rods. Our data show that intranuclear rods, in addition to actin and cofilin, are composed of a distinct set of other proteins comprising actin-interacting protein 1 (Aip1), coronin (CorA), filactin (Fia), and the 34 kDa actin-bundling protein B (AbpB). A finely tuned spatio-temporal pattern of protein recruitment was found during formation of rods. Aip1 is important for the final state of rod compaction indicating that Aip1 plays a major role in shaping the intranuclear rods. In the absence of both Aip1 and CorA, rods are not formed in the nucleus, suggesting that a sufficient supply of monomeric actin is a prerequisite for rod formation. PMID- 28074886 TI - Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases. AB - Sudden infant death syndrome (SIDS) is described as the sudden and unexplained death of an apparently healthy infant younger than one year of age. Genetic studies indicate that up to 35% of SIDS cases might be explained by familial or genetic diseases such as cardiomyopathies, ion channelopathies or metabolic disorders that remained undetected during conventional forensic autopsy procedures. Post-mortem genetic testing by using massive parallel sequencing (MPS) approaches represents an efficient and rapid tool to further investigate unexplained death cases and might help to elucidate pathogenic genetic variants and mechanisms in cases without a conclusive cause of death. In this study, we performed whole-exome sequencing (WES) in 161 European SIDS infants with focus on 192 genes associated with cardiovascular and metabolic diseases. Potentially causative variants were detected in 20% of the SIDS cases. The majority of infants had variants with likely functional effects in genes associated with channelopathies (9%), followed by cardiomyopathies (7%) and metabolic diseases (1%). Although lethal arrhythmia represents the most plausible and likely cause of death, the majority of SIDS cases still remains elusive and might be explained by a multifactorial etiology, triggered by a combination of different genetic and environmental risk factors. As WES is not substantially more expensive than a targeted sequencing approach, it represents an unbiased screening of the exome, which could help to investigate different pathogenic mechanisms within the genetically heterogeneous SIDS cohort. Additionally, re-analysis of the datasets provides the basis to identify new candidate genes in sudden infant death. PMID- 28074888 TI - A review of the carbohydrate-insulin model of obesity. AB - The carbohydrate-insulin model of obesity theorizes that diets high in carbohydrate are particularly fattening due to their propensity to elevate insulin secretion. Insulin directs the partitioning of energy toward storage as fat in adipose tissue and away from oxidation by metabolically active tissues and purportedly results in a perceived state of cellular internal starvation. In response, hunger and appetite increases and metabolism is suppressed, thereby promoting the positive energy balance associated with the development of obesity. Several logical consequences of this carbohydrate-insulin model of obesity were recently investigated in a pair of carefully controlled inpatient feeding studies whose results failed to support key model predictions. Therefore, important aspects of carbohydrate-insulin model have been experimentally falsified suggesting that the model is too simplistic. This review describes the current state of the carbohydrate-insulin model and the implications of its recent experimental tests. PMID- 28074887 TI - Association analysis of dyslexia candidate genes in a Dutch longitudinal sample. AB - Dyslexia is a common specific learning disability with a substantive genetic component. Several candidate genes have been proposed to be implicated in dyslexia susceptibility, such as DYX1C1, ROBO1, KIAA0319, and DCDC2. Associations with variants in these genes have also been reported with a variety of psychometric measures tapping into the underlying processes that might be impaired in dyslexic people. In this study, we first conducted a literature review to select single nucleotide polymorphisms (SNPs) in dyslexia candidate genes that had been repeatedly implicated across studies. We then assessed the SNPs for association in the richly phenotyped longitudinal data set from the Dutch Dyslexia Program. We tested for association with several quantitative traits, including word and nonword reading fluency, rapid naming, phoneme deletion, and nonword repetition. In this, we took advantage of the longitudinal nature of the sample to examine if associations were stable across four educational time-points (from 7 to 12 years). Two SNPs in the KIAA0319 gene were nominally associated with rapid naming, and these associations were stable across different ages. Genetic association analysis with complex cognitive traits can be enriched through the use of longitudinal information on trait development. PMID- 28074889 TI - Limitations and requirements for measuring metabolic rates: a mini review. AB - Metabolic measurement of humans and model animals is an important aspect of biomedicine. Particularly, in the case of model animals, the limitations of currently widely used metabolic measurement methods are not widely understood. In this mini-review, I explain the theoretical underpinnings of flow-through respirometry as a linear time-invariant system, and the (usually serious) distortions of metabolic data caused by the interaction of chamber volume and flow rate. These can be ameliorated by increasing the flow rate through the chamber, though this is at the expense of the magnitude of the O2 depletion and CO2 enhancement signals from which metabolic rates are calculated. If achieved, however, the improvement in temporal response that follows higher flow rates can be marked, and allows confident and accurate measurement of resting and active energy expenditure. Applications of this approach in multiplexing gas signals from multiple cages, and in human room calorimetry, are also discussed. PMID- 28074890 TI - Longitudinal association of leisure time physical activity and sedentary behaviors with body weight among Chinese adults from China Health and Nutrition Survey 2004-2011. AB - BACKGROUND/OBJECTIVES: Present study aims to longitudinally explore independent association of physical activity and sedentary behaviors with body weight. SUBJECTS/METHODS: This study included 15050 adults who have complete demographic and dietary data, leisure time physical activity (LTPA) and sedentary behavior evaluations, anthropometric measurements from longitudinal data of China Health and Nutrition Survey 2004-2011. Three-level mixed-effects linear and logistic regression models were performed for association analysis. RESULTS: Overweight and obesity prevalence in men and women progressively increased from 2004 to 2011. MET-h/week from LTPA declined, whereas time (h/day) spent in sedentary behaviors increased in men and women over 7 years. After adjustment for confounders, LTPA (MET-h/week) was linked with weight gain for moderate (beta=0.43, 95% confidence interval (CI): 0.16-0.60, P<0.01) and low (beta=0.52, 95% CI: 0.23-0.81, P<0.01) versus high LTPA in men; weight was increased by 0.7 kg (95% CI: 0.44-0.93, P<0.001) and 0.4 kg (95% CI: 0.12-0.68, P<0.01) among men and women without LTPA, respectively, compared with those with high LTPA. Sedentary behavior was associated with weight gain in men (beta=0.45, 95% CI: 0.14-0.76, P<0.01) and in women (beta=0.29, 95% CI: 0.11-0.49, P<0.05) for high versus low level. Moreover, overweight and obesity risk in men with low LTPA or without LTPA was 1.88 (95% CI: 1.15-2.51, P<0.05) and 2.01 (95% CI: 1.41-3.03, P<0.001) times higher than those with high LTPA, respectively. Odds of overweight and obesity were increased to 1.63 (95% CI: 1.29-2.21, P<0.01) times in women with low LTPA and 1.69 (95% CI: 1.37-2.27, P<0.001) times in women without LTPA compared with those with high LTPA. High level sedentary behavior was associated with 19% (OR=1.19, 95% CI: 1.04-1.35, P<0.05) greater odds of overweight and obesity against low level in men. CONCLUSIONS: LTPA and sedentary behaviors are independently and longitudinally associated with overweight and obesity, especially in men. PMID- 28074891 TI - Intake of vitamin C, vitamin E, selenium, zinc and polyunsaturated fatty acids and upper respiratory tract infection-a prospective cohort study. AB - BACKGROUND/OBJECTIVES: Antioxidants and polyunsaturated fatty acids (PUFAs) have a role in the human immune defense and may affect the susceptibility to upper respiratory tract infection (URTI). To examine dietary intake of vitamin C, vitamin E, selenium, zinc and PUFAs in relation to URTI incidence in a prospective cohort study. SUBJECTS/METHODS: A total of 1533 Swedish women and men aged 25-64 years were followed for nine months during 2011-2012. Information on dietary intake was assessed through a web-based food frequency questionnaire, and events of URTI were self-reported prospectively as they occurred. Cox proportional hazards regression was applied to obtain incidence rate ratios with 95% confidence intervals. RESULTS: The mean number of URTI events was 0.9 among all participants, 1.0 among women and 0.7 among men. In women, the incidence rate ratios (95% confidence interval) for high compared with low intake were 0.69 (0.55-0.88) for vitamin C, 0.77 (0.62-0.96) for vitamin E, 0.57 (0.39-0.83) for docosahexaenoic acid (DHA) and 0.80 (0.65-0.99) for arachidonic acid (AA). No association was found for selenium or zinc among women. In men, an increased URTI incidence was seen with medium vitamin E intake (1.42 (1.09-1.85)) and high zinc intake (1.50 (1.04-2.16)). No association was found for vitamin C, selenium or PUFAs among men. CONCLUSIONS: We found an inverse association of URTI incidence among women for vitamin C, vitamin E, DHA and AA intake and a positive association among men for vitamin E and zinc intake. The observed gender differences warrant further investigation. PMID- 28074892 TI - Are sleep duration, midpoint of sleep and sleep quality associated with dietary intake among Bavarian adults? AB - BACKGROUND/OBJECTIVES: Only few epidemiologic studies examined sleep characteristics in relation to dietary behaviour. Our aim was to analyse associations of sleep duration, midpoint of sleep and sleep quality with dietary intake among the Bavarian population. SUBJECTS/METHODS: Within the cross sectional Bavarian Food Consumption Survey II, 1050 subjects aged 13-81 years were recruited. Dietary intake was assessed with three 24-h dietary recalls by telephone (EPIC-Soft). In our study, 814 participants aged 18 years or older, who completed at least two 24-h dietary recalls and who had complete and plausible information on sleep characteristics were analysed. Dietary intake was described by the consumption of main food groups, energy-proving nutrients and energy intake. Sleep was measured by the Pittsburgh Sleep Quality Index Questionnaire, from which categories of self-reported usual sleep duration in half-h-steps per night, midpoint of sleep and overall sleep quality were derived. RESULTS: Sleep duration was associated with intake of non-alcoholic beverages (P<0.01), carbonated beverages (P=0.04), water (P=0.04) and coffee/black tea (P=0.01) with higher intake among short duration sleepers. No association was found between the consumption of other main food groups, energy-proving nutrients or total daily energy intake and sleep duration. Midpoint of sleep was associated with intake of carbonated beverages (P=0.02, highest intake among subjects with early midpoint of sleep). No association between sleep quality and dietary intake was detected. CONCLUSIONS: Our findings demonstrate only specific associations between sleep characteristics and dietary intake, and mainly sleep duration was associated with beverage intake. PMID- 28074893 TI - Understanding the molecular mechanism for the differential inhibitory activities of compounds against MTH1. AB - MTH1 can hydrolyze oxidized nucleotides and is required for cancer survival. The IC50 values were 0.8 nM for TH287 with a methyl substitution, 5.0 nM for TH588 with a cyclopropyl substitution, and 2.1 MUM for TH650 with an oxetanyl substitution. Thus, it is very significant to understand inhibitory mechanisms of these structurally similar compounds against MTH1 and influences of the substituent on the bioactivities. Our MD researches indicate that TH287 maintains significant hydrogen bonds with Asn33 and Asp119, stabilizes the binding site, and induces MTH1 adopt a closed motion, leading to a high inhibitory activity. When bound with TH588, the binding site can be partially stabilized and take a semi-closed state, which is because the cyclopropyl group in TH588 has larger steric hindrance than a methyl group in TH287. So TH588 has a slightly reduced inhibitory activity compared to TH287. TH650 induces greater conformation fluctuations than TH588 and the binding site adopts an opening state, which is caused by the large bulk of oxetanyl group and the interference of solvent on the oxetanyl substituent, leading to the lowest inhibitory activity. Thus, the inhibitory activity follows a TH287 > TH588 > TH650 trend, which well matches with the experimental finding. PMID- 28074894 TI - Characteristics of unilateral tibial plateau fractures among adult patients hospitalized at an orthopaedic trauma centre in China. AB - The aim of this study was to investigate the characteristics of unilateral tibial plateau fractures among hospitalized adult patients in Xijing Hospital, to evaluate the accuracy of Schatzker classification system and AO/OTA classification system to tibial plateau fractures. We retrospectively analysed clinical data on 274 patients admitted to Xijing Hospital between September 2006 and August 2015. The patients' demographic characteristics, admission periods and seasons, external causes and fracture types were recorded and summarized. Then the characteristics of tibial plateau fractures and the accuracy rate of these two classification systems were analysed. Schatzker type II fractures and AO/OTA type 41-B3 fractures were the most common types. The external causes differed between genders, types of employment, urban-rural residents and both two systems. In addition, some fractures were difficult to classify using Schatzker or AO/OTA classification system. Rural male physical labourers aged between 30-59 years-old were most likely to suffer from unilateral tibial plateau fractures, due to traffic accidents, falls and indoor activity injuries, or falls from height. We should pay more attention to the related people and professions, which contributed to the high occurrence of tibial plateau fractures. Besides that, further improvements are required for both Schatzker and AO/OTA classification systems. PMID- 28074895 TI - Multi-cellular natural killer (NK) cell clusters enhance NK cell activation through localizing IL-2 within the cluster. AB - Multi-cellular cluster formation of natural killer (NK) cells occurs during in vivo priming and potentiates their activation to IL-2. However, the precise mechanism underlying this synergy within NK cell clusters remains unclear. We employed lymphocyte-laden microwell technologies to modulate contact-mediated multi-cellular interactions among activating NK cells and to quantitatively assess the molecular events occurring in multi-cellular clusters of NK cells. NK cells in social microwells, which allow cell-to-cell contact, exhibited significantly higher levels of IL-2 receptor (IL-2R) signaling compared with those in lonesome microwells, which prevent intercellular contact. Further, CD25, an IL-2R alpha chain, and lytic granules of NK cells in social microwells were polarized toward MTOC. Live cell imaging of lytic granules revealed their dynamic and prolonged polarization toward neighboring NK cells without degranulation. These results suggest that IL-2 bound on CD25 of one NK cells triggered IL-2 signaling of neighboring NK cells. These results were further corroborated by findings that CD25-KO NK cells exhibited lower proliferation than WT NK cells, and when mixed with WT NK cells, underwent significantly higher level of proliferation. These data highlights the existence of IL-2 trans-presentation between NK cells in the local microenvironment where the availability of IL-2 is limited. PMID- 28074896 TI - The Neuropeptide Oxytocin Enhances Information Sharing and Group Decision Making Quality. AB - Groups can make better decisions than individuals when members cooperatively exchange and integrate their uniquely held information and insights. However, under conformity pressures group members are biased towards exchanging commonly known information, and away from exchanging unique information, thus undermining group decision-making quality. At the neurobiological level, conformity associates with the neuropeptide oxytocin. A double-blind placebo controlled study found no evidence for oxytocin induced conformity. Compared to placebo groups, three-person groups whose members received intranasal oxytocin, focused more on unique information (i) and repeated this information more often (ii). These findings reveal oxytocin as a neurobiological driver of group decision making processes. PMID- 28074897 TI - Prognostic factors in neuroendocrine carcinoma: biological markers are more useful than histomorphological markers. AB - Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are a very aggressive type of cancer, for which prognostic factors are lacking. We analysed clinical and histomorphological prognostic markers of overall survival (OS), completed with a record of biological and haematological data of patients diagnosed between December 2002 and December 2015. The median OS was 16 months (95% CI 13.9-18.1). After univariate analysis, performance status (PS) >= 2 and stage IV were associated with a worse outcome (9 months and 14 months, respectively), as well as patients with lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) levels >= 2 ULN (9 months and 8 months, respectively). After multivariate analysis, LDH and AST levels were the only factors that remained significantly associated with better survival: HR 0.36 (p = 0.04) and 0.31 (p = 0.03), respectively. When patients had elevated LDH and AST levels, OS was 20 months, when they had high LDH or AST levels, 13 months and 8 months in the group with low LDH and AST levels (p < 0.001). Therefore, biological data appeared to be more relevant prognostic factors than usual factors described in other studies (PS, stage, and Ki-67). Considering LDH and AST levels at diagnosis could help physicians to predict survival and to stratify patients for clinical trials. PMID- 28074898 TI - The "curved lead pathway" method to enable a single lead to reach any two intracranial targets. AB - Deep brain stimulation is an effective way to treat movement disorders, and a powerful research tool for exploring brain functions. This report proposes a "curved lead pathway" method for lead implantation, such that a single lead can reach in sequence to any two intracranial targets. A new type of stereotaxic system for implanting a curved lead to the brain of human/primates was designed, the auxiliary device needed for this method to be used in rat/mouse was fabricated and verified in rat, and the Excel algorithm used for automatically calculating the necessary parameters was implemented. This "curved lead pathway" method of lead implantation may complement the current method, make lead implantation for multiple targets more convenient, and expand the experimental techniques of brain function research. PMID- 28074899 TI - MOF-derived multifractal porous carbon with ultrahigh lithium-ion storage performance. AB - Porous carbon is one of the most promising alternatives to traditional graphite materials in lithium-ion batteries. This is not only attributed to its advantages of good safety, stability and electrical conductivity, which are held by all the carbon-based electrodes, but also especially ascribed to its relatively high capacity and excellent cycle stability. Here we report the design and synthesis of a highly porous pure carbon material with multifractal structures. This material is prepared by the vacuum carbonization of a zinc-based metal-organic framework, which demonstrates an ultrahigh lithium storage capacity of 2458 mAh g 1 and a favorable high-rate performance. The associations between the structural features and the lithium storage mechanism are also revealed by small-angle X-ray scattering (SAXS), especially the closed pore effects on lithium-ion storage. PMID- 28074900 TI - Physical controllability of complex networks. AB - A challenging problem in network science is to control complex networks. In existing frameworks of structural or exact controllability, the ability to steer a complex network toward any desired state is measured by the minimum number of required driver nodes. However, if we implement actual control by imposing input signals on the minimum set of driver nodes, an unexpected phenomenon arises: due to computational or experimental error there is a great probability that convergence to the final state cannot be achieved. In fact, the associated control cost can become unbearably large, effectively preventing actual control from being realized physically. The difficulty is particularly severe when the network is deemed controllable with a small number of drivers. Here we develop a physical controllability framework based on the probability of achieving actual control. Using a recently identified fundamental chain structure underlying the control energy, we offer strategies to turn physically uncontrollable networks into physically controllable ones by imposing slightly augmented set of input signals on properly chosen nodes. Our findings indicate that, although full control can be theoretically guaranteed by the prevailing structural controllability theory, it is necessary to balance the number of driver nodes and control cost to achieve physical control. PMID- 28074901 TI - Live visualization of genomic loci with BiFC-TALE. AB - Tracking the dynamics of genomic loci is important for understanding the mechanisms of fundamental intracellular processes. However, fluorescent labeling and imaging of such loci in live cells have been challenging. One of the major reasons is the low signal-to-background ratio (SBR) of images mainly caused by the background fluorescence from diffuse full-length fluorescent proteins (FPs) in the living nucleus, hampering the application of live cell genomic labeling methods. Here, combining bimolecular fluorescence complementation (BiFC) and transcription activator-like effector (TALE) technologies, we developed a novel method for labeling genomic loci (BiFC-TALE), which largely reduces the background fluorescence level. Using BiFC-TALE, we demonstrated a significantly improved SBR by imaging telomeres and centromeres in living cells in comparison with the methods using full-length FP. PMID- 28074902 TI - A reduced mechanical model for cAMP-modulated gating in HCN channels. AB - We developed an in silico mechanical model to analyze the process of cAMP-induced conformational modulations in hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which conduct cations across the membrane of mammalian heart and brain cells. The structural analysis reveals a quaternary twist in the cytosolic parts of the four subunits in the channel tetramer. This motion augments the intrinsic dynamics of the very same protein structure. The pronounced differences between the cAMP bound and unbound form include a mutual interaction between the C-linker of the cyclic nucleotide binding domain (CNBD) and the linker between the S4 and S5 transmembrane domain of the channel. This allows a mechanistic annotation of the twisting motion in relation to the allosteric modulation of voltage-dependent gating of this channel by cAMP. PMID- 28074903 TI - Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients. AB - Adenosine Deaminase (ADA) deficiency is an autosomal recessive variant of severe combined immunodeficiency (SCID) caused by systemic accumulation of ADA substrates. Neurological and behavioral abnormalities observed in ADA-SCID patients surviving after stem cell transplantation or gene therapy represent an unresolved enigma in the field. We found significant neurological and cognitive alterations in untreated ADA-SCID patients as well as in two groups of patients after short- and long-term enzyme replacement therapy with PEG-ADA. These included motor dysfunction, EEG alterations, sensorineural hypoacusia, white matter and ventricular alterations in MRI as well as a low mental development index or IQ. Ada-deficient mice were significantly less active and showed anxiety like behavior. Molecular and metabolic analyses showed that this phenotype coincides with metabolic alterations and aberrant adenosine receptor signaling. PEG-ADA treatment corrected metabolic adenosine-based alterations, but not cellular and signaling defects, indicating an intrinsic nature of the neurological and behavioral phenotype in ADA deficiency. PMID- 28074904 TI - Gd(III)-induced Supramolecular Hydrogelation with Enhanced Magnetic Resonance Performance for Enzyme Detection. AB - Here we report a supramolecular hydrogel based on Gd(III)-peptide complexes with dramatically enhanced magnetic resonance (MR) performance. The hydrogelations were formed by adding Gd(III) ion to the nanofiber dispersion of self-assembling peptides naphthalene-Gly-Phe-Phe-Tyr-Gly-Arg-Gly-Asp (Nap-GFFYGRGD) or naphthalene-Gly-Phe-Phe-Tyr-Gly-Arg-Gly-Glu (Nap-GFFYGRGE). We further showed that, by adjusting the molar ratio between Gd(III) and the corresponding peptide, the mechanical property of resulting gels could be fine-tuned. The longitudinal relaxivity (r1) of the Nap-GFFYGRGE-Gd(III) was 58.9 mM-1 S-1, which to our knowledge is the highest value for such peptide-Gd(III) complexes so far. Such an enhancement of r1 value could be applied for enzyme detection in aqueous solutions and cell lysates. PMID- 28074905 TI - MiR-488 inhibits proliferation and cisplatin sensibility in non-small-cell lung cancer (NSCLC) cells by activating the eIF3a-mediated NER signaling pathway. AB - Our previous studied indicated that eukaryotic translation initiation factor 3a (eIF3a) increases the sensitive of platinum-based chemotherapy in lung cancer. MiRNAs play an important role in lung carcinogenesis and drug response. In this study, we aimed to identify potential endogenous miRNAs that inhibit eIF3a expression and determine their influence of this inhibition on cisplatin resistance. Using bioinformatics analysis prediction and confirmation with dual luciferase reporter assays, we found that miRNA-488 inhibited eIF3a expression by directly binding to the 3'UTR of eIF3a. In addition, the overexpression of miRNA 488 inhibited cell migration and invasion in A549 cells, and also inhibited cell proliferation, cell cycle progression by elevated P27 expression. Compared to the parental cell line, A549/cisplatin (DDP) resistant cells exhibited a higher level of miRNA-488. Moreover, we found that miRNA-488 was associated with cisplatin resistance in three NSCLC cells (A549, H1299 and SK-MES-1). The mechanism of miRNA-488 induced cisplatin resistance was that miRNA-488 activated nucleotide excision repair (NER) by increasing the expression of Replication Protein A (RPA) 14 and Xeroderma pigmentosum group C (XPC). In conclusion, our results demonstrated that miRNA-488 is a tumor suppressor miRNA that acts by targeting eIF3a. Moreover, miRNA-488 also participates in eIF3a mediated cisplatin resistance in NSCLC cells. PMID- 28074906 TI - Antiproliferative Effects of 1alpha-OH-vitD3 in Malignant Melanoma: Potential Therapeutic implications. AB - Early detection and surgery represent the mainstay of treatment for superficial melanoma, but for high risk lesions (Breslow's thickness >0.75 mm) an effective adjuvant therapy is lacking. Vitamin D insufficiency plays a relevant role in cancer biology. The biological effects of 1alpha hydroxycholecalciferol on experimental melanoma models were investigated. 105 melanoma patients were checked for 25-hydroxycholecalciferol (circulating vitamin D) serum levels. Human derived melanoma cell lines and in vivo xenografts were used for studying 1alpha hydroxycholecalciferol-mediated biological effects on cell proliferation and tumor growth. 99 out of 105 (94%) melanoma patients had insufficient 25 hydroxycholecalciferol serum levels. Interestingly among the six with vitamin D in the normal range, five had a diagnosis of in situ/microinvasive melanoma. Treatment with 1alpha-hydroxycholecalciferol induced antiproliferative effects on melanoma cells in vitro and in vivo, modulating the expression of cell cycle key regulatory molecules. Cell cycle arrest in G1 or G2 phase was invariably observed in vitamin D treated melanoma cells. The antiproliferative activity induced by 1alpha-hydroxycholecalciferol in experimental melanoma models, together with the discovery of insufficient 25-hydroxycholecalciferol serum levels in melanoma patients, provide the rationale for using vitamin D in melanoma adjuvant therapy, alone or in association with other therapeutic options. PMID- 28074908 TI - Mapping curved spacetimes into Dirac spinors. AB - We show how to transform a Dirac equation in a curved static spacetime into a Dirac equation in flat spacetime. In particular, we show that any solution of the free massless Dirac equation in a 1 + 1 dimensional flat spacetime can be transformed via a local phase transformation into a solution of the corresponding Dirac equation in a curved static background, where the spacetime metric is encoded into the phase. In this way, the existing quantum simulators of the Dirac equation can naturally incorporate curved static spacetimes. As a first example we use our technique to obtain solutions of the Dirac equation in a particular family of interesting spacetimes in 1 + 1 dimensions. PMID- 28074907 TI - Insights into an evolutionary strategy leading to antibiotic resistance. AB - Metallo-beta-lactamases (MBLs) with activity towards a broad-spectrum of beta lactam antibiotics have become a major threat to public health, not least due to their ability to rapidly adapt their substrate preference. In this study, the capability of the MBL AIM-1 to evade antibiotic pressure by introducing specific mutations was probed by two alternative methods, i.e. site-saturation mutagenesis (SSM) of active site residues and in vitro evolution. Both approaches demonstrated that a single mutation in AIM-1 can greatly enhance a pathogen's resistance towards broad spectrum antibiotics without significantly compromising the catalytic efficiency of the enzyme. Importantly, the evolution experiments demonstrated that relevant amino acids are not necessarily in close proximity to the catalytic centre of the enzyme. This observation is a powerful demonstration that MBLs have a diverse array of possibilities to adapt to new selection pressures, avenues that cannot easily be predicted from a crystal structure alone. PMID- 28074909 TI - Extreme weather caused by concurrent cyclone, front and thunderstorm occurrences. AB - Phenomena such as cyclones, fronts and thunderstorms can cause extreme weather in various regions throughout the world. Although these phenomena have been examined in numerous studies, they have not all been systematically examined in combination with each other, including in relation to extreme precipitation and extreme winds throughout the world. Consequently, the combined influence of these phenomena represents a substantial gap in the current understanding of the causes of extreme weather events. Here we present a systematic analysis of cyclones, fronts and thunderstorms in combination with each other, as represented by seven different types of storm combinations. Our results highlight the storm combinations that most frequently cause extreme weather in various regions of the world. The highest risk of extreme precipitation and extreme wind speeds is found to be associated with a triple storm type characterized by concurrent cyclone, front and thunderstorm occurrences. Our findings reveal new insight on the relationships between cyclones, fronts and thunderstorms and clearly demonstrate the importance of concurrent phenomena in causing extreme weather. PMID- 28074910 TI - Myosin phosphatase and RhoA-activated kinase modulate arginine methylation by the regulation of protein arginine methyltransferase 5 in hepatocellular carcinoma cells. AB - Myosin phosphatase (MP) holoenzyme is a protein phosphatase-1 (PP1) type Ser/Thr specific enzyme that consists of a PP1 catalytic (PP1c) and a myosin phosphatase target subunit-1 (MYPT1). MYPT1 is an ubiquitously expressed isoform and it targets PP1c to its substrates. We identified the protein arginine methyltransferase 5 (PRMT5) enzyme of the methylosome complex as a MYPT1-binding protein uncovering the nuclear MYPT1-interactome of hepatocellular carcinoma cells. It is shown that PRMT5 is regulated by phosphorylation at Thr80 by RhoA associated protein kinase and MP. Silencing of MYPT1 increased the level of the PRMT5-specific symmetric dimethylation on arginine residues of histone 2 A/4, a repressing gene expression mark, and it resulted in a global change in the expression of genes affecting cellular processes like growth, proliferation and cell death, also affecting the expression of the retinoblastoma protein and c Myc. The phosphorylation of the MP inhibitory MYPT1T850 and the regulatory PRMT5T80 residues as well as the symmetric dimethylation of H2A/4 were elevated in human hepatocellular carcinoma and in other types of cancers. These changes correlated positively with the grade and state of the tumors. Our results suggest the tumor suppressor role of MP via inhibition of PRMT5 thereby regulating gene expression through histone arginine dimethylation. PMID- 28074911 TI - Further evidence for microtubule-independent dimerization of TPPP/p25. AB - Tubulin Polymerization Promoting Protein (TPPP/p25) is a brain-specific disordered protein that modulates the dynamics and stability of the microtubule network by its assembly promoting, cross-linking and acetylation enhancing activities. In normal brain it is expressed primarily in differentiated oligodendrocytes; however, at pathological conditions it is enriched in inclusions of both neurons and oligodendrocytes characteristic for Parkinson's disease and multiple system atrophy, respectively. The objective of this paper is to highlight a critical point of a recently published Skoufias's paper in which the crucial role of the microtubules in TPPP/p25 dimerization leading to microtubule bundling was suggested. However, our previous and present data provide evidence for the microtubule-independent dimerization of TPPP/p25 and its stabilization by disulphide bridges. In addition, our bimolecular fluorescence complementation experiments revealed the dimerization ability of both the full length and the terminal-free (CORE) TPPP/p25 forms, however, while TPPP/p25 aligned along the bundled microtubule network, the associated CORE segments distributed mostly homogeneously within the cytosol. Now, we identified a molecular model from the possible ones suggested in the Skoufias's paper that could be responsible for stabilization of the microtubule network in the course of the oligodendrocyte differentiation, consequently in the constitution of the myelin sheath. PMID- 28074912 TI - Influences of calcium silicate on chemical forms and subcellular distribution of cadmium in Amaranthus hypochondriacus L. AB - A pot experiment was conducted to investigate the effects of calcium silicate (CS) on the subcellular distribution and chemical forms of cadmium (Cd) in grain amaranths (Amaranthus hypochondriacus L. Cv. 'K112') grown in a Cd contaminated soil. Results showed that the dry weight and the photosynthetic pigments contents in grain amaranths increased significantly with the increasing doses of CS treatments, with the highest value found for the treatment of CS3 (1.65 g/kg). Compared with the control, application of CS4 (3.31 g/kg) significantly reduced Cd concentrations in the roots, stems and leaves of grain amaranths by 68%, 87% and 89%, respectively. At subcellular level, CS treatment resulted in redistribution of Cd, higher percentages of Cd in the chloroplast and soluble fractions in leaves of grain amaranths were found, while lower proportions of Cd were located at the cell wall of the leaves. The application of CS enhanced the proportions of pectate and protein integrated forms of Cd and decreased the percentages of water soluble Cd potentially associated with toxicity in grain amaranths. Changes of free Cd ions into inactive forms sequestered in subcellular compartments may indicate an important mechanism of CS for alleviating Cd toxicity and accumulation in plants. PMID- 28074913 TI - Auditory Localisation Biases Increase with Sensory Uncertainty. AB - Psychophysical studies have frequently found that adults with normal hearing exhibit systematic errors (biases) in their auditory localisation judgments. Here we tested (i) whether systematic localisation errors could reflect reliance on prior knowledge, as has been proposed for other systematic perceptual biases, and (ii) whether auditory localisation biases can be reduced following training with accurate visual feedback. Twenty-four normal hearing participants were asked to localise the position of a noise burst along the azimuth before, during, and after training with visual feedback. Consistent with reliance on prior knowledge to reduce sensory uncertainty, we found that auditory localisation biases increased when auditory localisation uncertainty increased. Specifically, participants mis-localised auditory stimuli as being more eccentric than they were, and did so more when auditory uncertainty was greater. However, biases also increased with eccentricity, despite no corresponding increase in uncertainty, which is not readily explained by use of a simple prior favouring peripheral locations. Localisation biases decreased (improved) following training with visual feedback, but the reliability of the visual feedback stimulus did not change the effects of training. We suggest that further research is needed to identify alternative mechanisms, besides use of prior knowledge, that could account for increased perceptual biases under sensory uncertainty. PMID- 28074914 TI - Hydroxysafflor yellow A attenuates the expression of inflammatory cytokines in acute soft tissue injury. AB - We examined the effect of hydroxysafflor yellow A (HSYA) on the inflammatory response to strike-induced acute soft tissue injury in rats. Soft tissue injury was induced in rat leg muscles using a strike hammer, followed by intraperitoneal administration of HSYA at 16, 32, or 64 mg/kg. After 24 h, the rats were anaesthetized, blood and muscle samples were taken. Plasma levels of interleukin (IL)-6, IL-1beta, and tumour necrosis factor (TNF)-alphawere measured by enzyme linked immunosorbent assay. Total RNA and protein were isolated from muscle tissue to determine the mRNA levels of IL-6, IL-1beta, TNF-alpha, vascular cell adhesion molecule (VCAM)-1, and intercellular adhesion molecule (ICAM)-1, and the protein level of phosphorylated p38 mitogen-activated protein kinase (MAPK). Nuclear factor (NF)-kappaB expression was determined by muscle histopathology and immunohistochemistry. HSYA attenuated pathologic changes instrike-induced soft tissue inflammation. Treatment with HSYA also alleviated strike-induced increases in TNF-alpha, IL-1beta, IL-6, VCAM-1, and ICAM-1mRNA levels and inhibited the increased activation of NF-kappaB and phosphorylation of p38 MAPK in muscle tissue. These findings suggest that HSYA effectively inhibits strike-induced inflammatory signal transduction in rats. PMID- 28074915 TI - Psychological distress and cancer pain: Results from a controlled cross-sectional survey in China. AB - We evaluated the pain associated with cancer and its impact on pain management, anxiety, and depression in Chinese patients using a controlled cross-sectional study. One hundred and twenty-six cancer outpatients were evaluated from January 2012 to June 2014; 64 reported pain and 62 did not. Patients with cancer eligible for this study were older than 18 years and able to effectively communicate with medical personnel. Patients were administered a questionnaire regarding their medical status. The information collected was used along with patient charts to complete a socio-demographic and clinical characteristic summary for each patient. Results showed that patients who reported pain had mean State-Trait Anxiety Inventory (STAI) scores of 46.38 for state anxiety and 44.64 for trait anxiety, as well as a mean BDI (Beck Depression Inventory) score of 19.17. The pain-free patient group had mean STAI scores of 40.73 for state anxiety and 42.87 for trait anxiety, and a mean BDI score of 15.35. In conclusion, patients who reported pain were more prone to anxiety and depression, with pain severity being a strong predictor of anxiety. Adequate pain assessment and adjustment proved necessary for pain management. PMID- 28074916 TI - Corrigendum: IL-17 Promotes Angiogenic Factors IL-6, IL-8, and Vegf Production via Stat1 in Lung Adenocarcinoma. PMID- 28074917 TI - Corrigendum: A unique peptide deformylase platform to rationally design and challenge novel active compounds. PMID- 28074918 TI - Regulation of plasma histamine levels by the mast cell clock and its modulation by stress. AB - At steady state, plasma histamine levels exhibit circadian variations with nocturnal peaks, which is implicated in the nighttime exacerbation of allergic symptoms. However, the regulatory mechanisms are largely unexplored. This study determined how steady-state plasma histamine levels are regulated and affected by environmental factors. We found that plasma histamine levels decreased in mast cell-deficient mice and their circadian variations were lost in mast cell deficient mice reconstituted with bone marrow-derived mast cells (BMMCs) harboring a mutation in the circadian gene Clock. Clock temporally regulates expression of organic cation transporter 3 (OCT3), which is involved in histamine transport, in mast cells; OCT inhibition abolished circadian variations in plasma histamine levels. Mice housed under aberrant light/dark conditions or suffering from restraint stress exhibited de-synchronization of the mast cell clockwork, concomitant with the loss of circadian variations in OCT3 expression and plasma histamine levels. The degree of compound 48/80-induced plasma extravasation in mice was correlated with plasma histamine levels. Collectively, the mast cell clock mediates circadian regulation of plasma histamine levels at steady state, in part by controlling OCT3 expression, which can be modulated by stress. Additionally, we propose that plasma histamine levels potentiate mast cell mediated allergic reactions. PMID- 28074919 TI - Development of microsatellite markers and estimation of inbreeding frequency in the parasitoid wasp Melittobia. AB - The parasitoid wasp Melittobia is an important insect for basic and applied biology. Specifically, their extremely female-biased sex ratios, which contrast to the prediction of pre-existing theories, are needed to be explained from the aspect of evolutionary biology. In this study, using next-generation sequencing, 20 microsatellite loci were developed and characterized for M. australica. The developed loci were used to analyze two populations, one from a mainland Japan and one from the Okinawa island region. Both populations showed a smaller observed heterozygosity than expected, and a high inbreeding coefficient. Deviations from Hardy-Weinberg equilibrium were recorded for the majority of the 20 loci, suggesting that both the populations are subdivided due to inbreeding as is expected by the reproductive biology in Melittobia. The sib-mating frequency in the two populations was calculated as 0.873 and 0.996, which is higher than the values estimated by the number of females observed in a host cocoon or cell, implying that closely related females lay eggs on a host. The microsatellite loci developed in this study can be used for more comprehensive analyses to identify genetic structure in natural populations for understanding their sex allocation behavior and for more generally evolutionary and population genetic studies. PMID- 28074921 TI - Heat-Related Hospitalizations in Older Adults: An Amplified Effect of the First Seasonal Heatwave. AB - Older adults are highly vulnerable to the detriment of extreme weather. The rapid non-linear increase in heat-related morbidity is difficult to quantify, hindering the attribution of direct effects of exposure on severe health outcomes. We examine the effects of ambient temperatures on heat-related hospitalizations (HH) among the elderly in presence of strong seasonality and by assessing the effects caused by the first and subsequent seasonal heatwaves. We empirically derived the thresholds for a heatwave episode in Boston MSA based on 16 years of daily observations. We compared the health risks of heatwaves using the proposed and four alternative definitions. 701 cases of HH in older residents of Boston area were examined using harmonic regression models, designed to capture the non linear effects of ambient temperatures and heatwave episodes when the night-time temperature is above 65.5 degrees F for 3 consecutive nights. The overall relative risk of HH associated with a heatwave episode was 6.9 [95%CI:4.8-9.8]. The relative risk of HH associated with the first heatwave increases up to 13.3 [95%CI:7.4-24.0]. The risk declined to 3.7 [95%CI:2.4-5.8] for the subsequent heatwave. Four other commonly used heatwave definitions confirmed these findings. Public health actions have to target the first heatwave to maximize the impact of preventive measures. PMID- 28074923 TI - Bacterial community composition in costal dunes of the Mediterranean along a gradient from the sea shore to the inland. AB - Sand dunes are unique ecosystems with distinct features which limited the accumulation of biomass. The distance from seashore affects both the physical properties of the sand dunes and the biota living above- and below ground. The goal of the present study was to determine the effects of the distance from shore to inland on soil bacterial community composition during wet and dry season. We studied a chronosequence of sites close to the eastern Mediterranean coast. Bacterial diversity was assessed using directly extracted DNA from soil samples and 16 S ribosomal RNA gene fingerprinting. Our data indicates a significant influence of season and site on bacterial community structure. We showed that during the wet season soil organic matter, pH and salinity strongly influence bacterial community composition, whereas during the dry period bacterial diversity was mainly driven by the shortage of water at all sites. Consequently diversity was lowest during dry season at dunes close to the shore, whereas during the wet season the higher water content and the reduced salinity at the dunes which are more at the inland induced an increase in diversity, which illustrates the pronounced dynamics of microbial communities in soil over a season mainly at inland dunes. PMID- 28074920 TI - A Comprehensive Evaluation of the Activity and Selectivity Profile of Ligands for RGD-binding Integrins. AB - Integrins, a diverse class of heterodimeric cell surface receptors, are key regulators of cell structure and behaviour, affecting cell morphology, proliferation, survival and differentiation. Consequently, mutations in specific integrins, or their deregulated expression, are associated with a variety of diseases. In the last decades, many integrin-specific ligands have been developed and used for modulation of integrin function in medical as well as biophysical studies. The IC50-values reported for these ligands strongly vary and are measured using different cell-based and cell-free systems. A systematic comparison of these values is of high importance for selecting the optimal ligands for given applications. In this study, we evaluate a wide range of ligands for their binding affinity towards the RGD-binding integrins alphavbeta3, alphavbeta5, alphavbeta6, alphavbeta8, alpha5beta1, alphaIIbbeta3, using homogenous ELISA-like solid phase binding assay. PMID- 28074922 TI - Soybean cyclophilin GmCYP1 interacts with an isoflavonoid regulator GmMYB176. AB - Cyclophilins (CYPs) belong to the immunophilin superfamily with peptidyl-prolyl cis-trans isomerase (PPIase) activity. They catalyze the interconversion of the cis- and trans-rotamers of the peptidyl-prolyl amide bond of peptides. A yeast two-hybrid screening using the isoflavonoid regulator GmMYB176 as bait identified GmCYP1 as one of the interacting proteins in soybean embryos. GmCYP1 localizes both in the nucleus and cytoplasm, and interacts in planta with GmMYB176, in the nucleus, and with SGF14l (a soybean 14-3-3 protein) in the nucleus and the cytoplasm. GmCYP1 contains a single cyclophilin-like domain and displays a high sequence identity with other plant CYPs that are known to have stress-specific function. Tissue-specific expression of GmCYP1 revealed higher expression in developing seeds compared to other vegetative tissues, suggesting their seed specific role. Furthermore, GmCYP1 transcript level was reduced in response to stress. Since isoflavonoids are involved in plant stress resistance against biotic and abiotic factors, the interaction of GmCYP1 with the isoflavonoid regulators GmMYB176 and 14-3-3 protein suggests its role in defense in soybean. PMID- 28074924 TI - Metabotyping Patients' Journeys Reveals Early Predisposition to Lung Injury after Cardiac Surgery. AB - Cardiovascular disease is the leading cause of death worldwide and patients with severe symptoms undergo cardiac surgery. Even after uncomplicated surgeries, some patients experience postoperative complications such as lung injury. We hypothesized that the procedure elicits metabolic activity that can be related to the disease progression, which is commonly observed two-three days postoperatively. More than 700 blood samples were collected from 50 patients at nine time points pre-, intra-, and postoperatively. Dramatic metabolite shifts were observed during and immediately after the intervention. Prolonged surgical stress was linked to an augmented anaerobic environment. Time series analysis showed shifts in purine-, nicotinic acid-, tyrosine-, hyaluronic acid-, ketone-, fatty acid, and lipid metabolism. A characteristic 'metabolic biosignature' was identified correlating with the risk of developing postoperative complications two days before the first clinical signs of lung injury. Hence, this study demonstrates the link between intra- and postoperative time-dependent metabolite changes and later postoperative outcome. In addition, the results indicate that metabotyping patients' journeys early, during or just after the end of surgery, may have potential impact in hospitals for the early diagnosis of postoperative lung injury, and for the monitoring of therapeutics targeting disease progression. PMID- 28074925 TI - Atomization of High-Viscosity Fluids for Aromatherapy Using Micro-heaters for Heterogeneous Bubble Nucleation. AB - The development of a novel lead-free microelectromechanical-system (MEMS)-based atomizer using the principle of thermal bubble actuation is presented. It is a low-cost, lead-free design that is environmentally friendly and harmless to humans. It has been tested to be applicable over a wide range of fluid viscosities, ranging from 1 cP (e.g., water) to 200 cP (e.g., oil-like fluid) at room temperature, a range that is difficult to achieve using ordinary atomizers. The results demonstrate that the average power consumption of the atomizer is approximately 1 W with an atomization rate of 0.1 to 0.3 mg of deionized (DI) water per cycle. The relationships between the micro-heater track width and the track gap, the size of the micro-cavities and the nucleation energy were studied to obtain an optimal atomizer design. The particle image velocimetry (PIV) results indicate that the diameter of the ejected droplets ranges from 30 to 90 MUm with a speed of 20 to 340 mm/s. In addition, different modes of spraying are reported for the first time. It is envisioned that the successful development of this MEMS-based atomizing technology will revolutionize the existing market for atomizers and could also benefit different industries, particularly in applications involving viscous fluids. PMID- 28074926 TI - Disrupted global metastability and static and dynamic brain connectivity across individuals in the Alzheimer's disease continuum. AB - As findings on the neuropathological and behavioral components of Alzheimer's disease (AD) continue to accrue, converging evidence suggests that macroscale brain functional disruptions may mediate their association. Recent developments on theoretical neuroscience indicate that instantaneous patterns of brain connectivity and metastability may be a key mechanism in neural communication underlying cognitive performance. However, the potential significance of these patterns across the AD spectrum remains virtually unexplored. We assessed the clinical sensitivity of static and dynamic functional brain disruptions across the AD spectrum using resting-state fMRI in a sample consisting of AD patients (n = 80) and subjects with either mild (n = 44) or subjective (n = 26) cognitive impairment (MCI, SCI). Spatial maps constituting the nodes in the functional brain network and their associated time-series were estimated using spatial group independent component analysis and dual regression, and whole-brain oscillatory activity was analyzed both globally (metastability) and locally (static and dynamic connectivity). Instantaneous phase metrics showed functional coupling alterations in AD compared to MCI and SCI, both static (putamen, dorsal and default-mode) and dynamic (temporal, frontal-superior and default-mode), along with decreased global metastability. The results suggest that brains of AD patients display altered oscillatory patterns, in agreement with theoretical premises on cognitive dynamics. PMID- 28074927 TI - Quaternary climate change drives allo-peripatric speciation and refugial divergence in the Dysosma versipellis-pleiantha complex from different forest types in China. AB - Subtropical China harbours the world's most diverse temperate flora, but little is known about the roles of geographical and eco-climatic factors underlying the region's exceptionally high levels of species diversity and endemism. Here we address this key question by investigating the spatio-temporal and ecological processes of divergence within the Dysosma versipellis-pleiantha species complex, endemic to subtropical China. Our cpDNA phylogeny showed that this monophyletic group of understory herbs is derived from a Late Pliocene ancestor of the Qinghai Tibetan Plateau (QTP)/Southwest China. Genetic and ENM data in conjunction with niche differentiation analyses support that the early divergence of D. versipellis and D. pleiantha proceeded through allo-peripatric speciation, possibly triggered by Early Pleistocene climate change, while subsequent climate induced cycles of range contractions/expansions enhanced the eco-geographical isolation of both taxa. Furthermore, modelling of population-genetic data indicated that major lineage divergences within D. versipellis likely resulted from long-term allopatric population isolation in multiple localized refugia over the last glacial/interglacial periods, and which in turn fostered endemic species formation (D. difformis, D. majoensis) from within D. versipellis in Southwest China. These findings point to an overriding role of Quaternary climate change in triggering essentially allopatric (incipient) speciation in this group of forest restricted plant species in subtropical China. PMID- 28074928 TI - Exocyst subunit SEC3A marks the germination site and is essential for pollen germination in Arabidopsis thaliana. AB - Arabidopsis exocyst subunit SEC3A has been reported to participate in embryo development. Here we report that SEC3A is involved during pollen germination. A T DNA insertion in SEC3A leads to an absolute, male-specific transmission defect that can be complemented by the expression of SEC3A coding sequence from the LAT52 promoter or SEC3A genomic DNA. No obvious abnormalities in the microgametogenesis are observed in the sec3a/SEC3A mutant, however, in vitro and in vivo pollen germination are defective. Further studies reveal that the callose, pectin, and cellulose are apparently not deposited at the germination site during pollen germination. SEC3A is expressed ubiquitously, including in pollen grains and pollen tubes. Notably, SEC3A-GFP fusion proteins are specifically recruited to the future pollen germination site. This particular localization pattern is independent of phosphatidylinositol 4,5-bisphosphate (PI 4,5P2), although SEC3-HIS fusion proteins are able to bind to several phosphoinositols in vitro. These results suggest that SEC3A plays an important role in the establishment of the polar site for pollen germination. PMID- 28074930 TI - Mechanism, reactivity, and regioselectivity in rhodium-catalyzed asymmetric ring opening reactions of oxabicyclic alkenes: a DFT Investigation. AB - The origin of the enantio- and regioselectivity of ring-opening reaction of oxabicyclic alkenes catalyzed by rhodium/Josiphos has been examined using M06-2X density functional theory(DFT). DFT calculations predict a 98% ee for the enantioselectivity and only the 1,2-trans product as one regio- and diastereomer, in excellent agreement with experimental results. The solvent tetrahydrofuran(THF) plays a key role in assisting nucleophilic attack. Orbital composition analysis of the LUMO and the NPA atomic charge calculations were conducted to probe the origins of the regioselectivity. The orbital composition analysis reveals two potential electrophilic sites of the Rh-pi-allyl intermediate M3 and the NPA atomic charges demonstrate that Calpha carries more positive charges than Cgamma, which suggests that Calpha is the electrophilic site. PMID- 28074929 TI - Evolution of protein N-glycosylation process in Golgi apparatus which shapes diversity of protein N-glycan structures in plants, animals and fungi. AB - Protein N-glycosylation (PNG) is crucial for protein folding and enzymatic activities, and has remarkable diversity among eukaryotic species. Little is known of how unique PNG mechanisms arose and evolved in eukaryotes. Here we demonstrate a picture of onset and evolution of PNG components in Golgi apparatus that shaped diversity of eukaryotic protein N-glycan structures, with an emphasis on roles that domain emergence and combination played on PNG evolution. 23 domains were identified from 24 known PNG genes, most of which could be classified into a single clan, indicating a single evolutionary source for the majority of the genes. From 153 species, 4491 sequences containing the domains were retrieved, based on which we analyzed distribution of domains among eukaryotic species. Two domains in GnTV are restricted to specific eukaryotic domains, while 10 domains distribute not only in species where certain unique PNG reactions occur and thus genes harboring these domains are supoosed to be present, but in other ehkaryotic lineages. Notably, two domains harbored by beta 1,3 galactosyltransferase, an essential enzyme in forming plant-specific Lea structure, were present in separated genes in fungi and animals, suggesting its emergence as a result of domain shuffling. PMID- 28074931 TI - EID3 directly associates with DNMT3A during transdifferentiation of human umbilical cord mesenchymal stem cells to NPC-like cells. AB - There has been recently been increased interest in the plasticity of human umbilical cord mesenchymal stem cells (UMSCs) and their potential in the treatment of neurological disorders. In this study, UMSCs were transdifferentiated into neural stem-like cells (uNSCL), these cells grow in neurosphere-like structures and express high levels of NSCs markers. Epigenetics related gene screening was here used to assess the relationship between E1A-like inhibitor of differentiation 3 (EID3), a p300 inhibitor, and DNA methyltransferase 3 A (DNMT3A) during the transdifferentiation of UMSCs into uNSCL in vitro. Before transdifferentiation of UMSCs into uNSCLs, high levels of EID3 and low levels of DNMT3A were detected; after transdifferentiation, low levels of EID3 and high levels of DNMT3A were detected. The current work showed that EID3 and DNMT3A co-localized in cell nuclei and EID3 interacted directly with DNMT3A in uNSCL. In summary, these results suggest that DNMT3A is probably directly regulated by EID3 during UMSC transdifferentiation into uNSCLs. These findings indicated a novel mechanism by which EID3, a p300 acetyltransferase inhibitor, could directly affect DNMT3A, this enzyme possesses dual methylation and demethylation abilities. These studies may be helpful for understanding a complex regulation mode of DNMT3A, which is a unique member of the methyltransferase family. PMID- 28074933 TI - Ultrafast carrier dynamics in Ge by ultra-broadband mid-infrared probe spectroscopy. AB - In this study, we carried out 800-nm pump and ultra-broadband mid-infrared (MIR) probe spectroscopy with high time-resolution (70 fs) in bulk Ge. By fitting the time-resolved difference reflection spectra [DeltaR(omega)/R(omega)] with the Drude model in the 200-5000 cm-1 region, the time-dependent plasma frequency and scattering rate have been obtained. Through the calculation, we can further get the time-dependent photoexcited carrier concentration and carrier mobility. The Auger recombination essentially dominates the fast relaxation of photoexcited carriers within 100 ps followed by slow relaxation due to diffusion. Additionally, a novel oscillation feature is clearly found in time-resolved difference reflection spectra around 2000 cm-1 especially for high pump fluence, which is the Lorentz oscillation lasting for about 20 ps due to the Coulomb force exerted just after the excitation. PMID- 28074932 TI - The Helicobacter cinaedi antigen CAIP participates in atherosclerotic inflammation by promoting the differentiation of macrophages in foam cells. AB - Recent studies have shown that certain specific microbial infections participate in atherosclerosis by inducing inflammation and immune reactions, but how the pathogens implicated in this pathology trigger the host responses remains unknown. In this study we show that Helicobacter cinaedi (Hc) is a human pathogen linked to atherosclerosis development since at least 27% of sera from atherosclerotic patients specifically recognize a protein of the Hc proteome, that we named Cinaedi Atherosclerosis Inflammatory Protein (CAIP) (n = 71). CAIP appears to be implicated in this pathology because atheromatous plaques isolated from atherosclerotic patients are enriched in CAIP-specific T cells (10%) which, in turn, we show to drive a Th1 inflammation, an immunopathological response typically associated to atherosclerosis. Recombinant CAIP promotes the differentiation and maintenance of the pro-inflammatory profile of human macrophages and triggers the formation of foam cells, which are a hallmark of atherosclerosis. This study identifies CAIP as a relevant factor in atherosclerosis inflammation linked to Hc infection and suggests that preventing and eradicating Hc infection could reduce the incidence of atherosclerosis. PMID- 28074934 TI - Disease-modifying effect of intravenous immunoglobulin in an experimental model of epilepsy. AB - Novel therapies that prevent or modify the development of epilepsy following an initiating brain insult could significantly reduce the burden of this disease. In light of evidence that immune mechanisms play an important role in generating and maintaining the epileptic condition, we evaluated the effect of a well established immunomodulatory treatment, intravenous immunoglobulin (IVIg), on the development of epilepsy in an experimental model of epileptogenesis. In separate experiments, IVIg was administered either before (pre-treatment) or after (post treatment) the onset of pilocarpine status epilepticus (SE). Our results show that both pre- and post-treatment with IVIg attenuated acute inflammation in the SE model. Specifically, IVIg reduced local activation of glial cells, complement system activation, and blood-brain barrier damage (BBB), which are all thought to play important roles in the development of epilepsy. Importantly, post-treatment with IVIg was also found to reduce the frequency and duration of subsequent spontaneous recurrent seizures as detected by chronic video electroencephalographic (video-EEG) recordings. This finding supports a novel application for IVIg, specifically its repurposing as a disease-modifying therapy in epilepsy. PMID- 28074935 TI - Neutrophil elastase cleavage of the gC1q domain impairs the EMILIN1-alpha4beta1 integrin interaction, cell adhesion and anti-proliferative activity. AB - The extracellular matrix glycoprotein EMILIN1 exerts a wide range of functions mainly associated with its gC1q domain. Besides providing functional significance for adhesion and migration, the direct interaction between alpha4beta1 integrin and EMILIN1-gC1q regulates cell proliferation, transducing net anti-proliferative effects. We have previously demonstrated that EMILIN1 degradation by neutrophil elastase (NE) is a specific mechanism leading to the loss of functions disabling its regulatory properties. In this study we further analysed the proteolytic activity of NE, MMP-3, MMP-9, and MT1-MMP on EMILIN1 and found that MMP-3 and MT1 MMP partially cleaved EMILIN1 but without affecting the functional properties associated with the gC1q domain, whereas NE was able to fully impair the interaction of gC1q with the alpha4beta1 integrin by cleaving this domain outside of the E933 integrin binding site. By a site direct mutagenesis approach we mapped the bond between S913 and R914 residues and selected the NE-resistant R914W mutant still able to interact with the alpha4beta1 integrin after NE treatment. Functional studies showed that NE impaired the EMILIN1-alpha4beta1 integrin interaction by cleaving the gC1q domain in a region crucial for its proper structural conformation, paving the way to better understand NE effects on EMILIN1-cell interaction in pathological context. PMID- 28074936 TI - Hygroscopic motions of fossil conifer cones. AB - Conifer cones represent natural, woody compliant structures which move their scales as passive responses to changes in environmental humidity. Here we report on water-driven opening and closing motions in coalified conifer cones from the Eemian Interglacial (approx. 126,000-113,000 years BP) and from the Middle Miocene (approx. 16.5 to 11.5 million years BP). These cones represent by far the oldest documented evidence of plant parts showing full functionality of such passive hydraulically actuated motion. The functional resilience of these structures is far beyond the biological purpose of seed dispersal and protection and is because of a low level of mineralization of the fossils. Our analysis emphasizes the functional-morphological integrity of these biological compliant mechanisms which, in addition to their biological fascination, are potentially also role models for resilient and maintenance-free biomimetic applications (e.g., adaptive and autonomously moving structures including passive hydraulic actuators). PMID- 28074938 TI - Sprayable superhydrophobic nano-chains coating with continuous self-jumping of dew and melting frost. AB - Spontaneous movement of condensed matter provides a new insight to efficiently improve condensation heat transfer on superhydrophobic surface. However, very few reports have shown the jumping behaviors on the sprayable superhydrophobic coatings. Here, we developed a sprayable silica nano-porous coating assembled by fluorinated nano-chains to survey the condensates' dynamics. The dewdrops were continuously removed by self- and/or trigger-propelling motion due to abundant nano-pores from random multilayer stacking of nano-chains. In comparison, the dewdrops just could be slipped under the gravity effect on lack of nano-pores coatings stacked by silica nano-spheres and nano-aggregates. More interestingly, the spontaneous jumping effect also occurred on micro-scale frost crystals under the defrosting process on nano-chains coating surfaces. Different from self jumping of dewdrops motion, the propelling force of frost crystals were provided by a sudden increase of the pressure under the frost crystal. PMID- 28074937 TI - Circulating T lymphocyte subsets, cytokines, and immune checkpoint inhibitors in patients with bipolar II or major depression: a preliminary study. AB - This study aimed to investigate the less known activation pattern of T lymphocyte populations and immune checkpoint inhibitors on immunocytes in patients with bipolar II disorder depression (BD) or major depression (MD). A total of 23 patients with BD, 22 patients with MD, and 20 healthy controls (HCs) were recruited. The blood cell count of T lymphocyte subsets and the plasma level of cytokines (IL-2, IL-4, IL-6, IL-10, TNF-alpha, and IFN-gamma) were selectively investigated. The expression of T-cell immunoglobulin and mucin-domain containing 3 (TIM-3), programmed cell death protein 1 (PD-1) and its ligands, PD-L1 and PD L2, on T lymphocytes and monocytes, was detected. In results, blood proportion of cytotoxic T cells significantly decreased in BD patients than in either MD patients or HCs. The plasma level of IL-6 increased in patients with BD and MD. The expression of TIM-3 on cytotoxic T cells significantly increased, whereas the expression of PD-L2 on monocytes significantly decreased in patients with BD than in HCs. These findings extended our knowledge of the immune dysfunction in patients with affective disorders. PMID- 28074939 TI - The influence of tip shape on bending force during needle insertion. AB - Steering of needles involves the planning and timely modifying of instrument tissue force interactions to allow for controlled deflections during the insertion in tissue. In this work, the effect of tip shape on these forces was studied using 10 mm diameter needle tips. Six different tips were selected, including beveled and conical versions, with or without pre-bend or pre-curve. A six-degree-of-freedom force/torque sensor measured the loads during indentations in tissue simulants. The increased insertion (axial) and bending (radial) forces with insertion depth - the force-displacement slopes - were analyzed. Results showed that the ratio between radial and axial forces was not always proportional. This means that the tip load does not have a constant orientation, as is often assumed in mechanics-based steering models. For all tip types, the tip-load assumed a more radial orientation with increased axial load. This effect was larger for straight tips than for pre-bent or pre-curved tips. In addition, the force-displacement slopes were consistently higher for (1) increased tip angles, and for (2) beveled tips compared to conical tips. Needles with a bent or curved tip allow for an increased bending force and a decreased variability of the tip load vector orientation. PMID- 28074942 TI - Chemistry at the square nanometer: reactivity at liquid/solid interfaces revealed with an STM. AB - For more than three decades the scanning tunnelling microscope (STM) has proven to be an indispensable tool to image molecules adsorbed at a surface at the highest detail possible. In addition to simply imaging molecules, STM can also be applied to monitor dynamic surface phenomena, including chemical reactions. By studying reactions at a surface at the single molecule level, unique information about reaction mechanisms can be obtained which remains hidden when conventional ensemble techniques are used. Many STM studies of chemical reactions have been performed in extreme environments like ultrahigh vacuum or high pressure chambers, but these are far removed from conditions in which most chemical and biological processes take place, i.e., in a liquid at ambient atmospheres. This feature paper highlights the developments in the relatively unexplored research area of investigating chemical reactions with an STM at a liquid/solid interface under ambient conditions. Covalent couplings between molecules, light-induced isomerisations, reactions under electrochemical control, and complex multistep processes and catalysis are discussed. PMID- 28074941 TI - Enhancing the Detection of Dysmorphic Red Blood Cells and Renal Tubular Epithelial Cells with a Modified Urinalysis Protocol. AB - Urinary sediment is used to evaluate patients with possible urinary tract diseases. Currently, numerous protocols are applied to detect dysmorphic red blood cells (RBCs) and renal tubular epithelial cells (RTECs) in urinary sediment. However, distinct protocols are used by nephrologists and medical technologists for specimen concentration and observation, which leads to major discrepancies in the differential counts of formed elements such as dysmorphic RBCs and RTECs and might interfere with an accurate clinical diagnosis. To resolve these problems, we first tested a modified urinalysis protocol with an increased relative centrifuge force and concentration factor in 20 biopsy confirmed glomerulonephritis patients with haematuria. We successfully improved the recovery ratio of dysmorphic RBCs in clinical specimens from 34.7% to 42.0% (P < 0.001). Furthermore, we confirmed the correlation between counts by the modified urinary protocol and Sysmex UF-1000i urinary flow cytometer (r >= 0.898, P < 0.001). A total of 28 types of isomorphic and dysmorphic RBCs were detected using a bright field microscope, with results comparable to those using a standard phase contrast microscope. Finally, we applied Sternheimer stain to enhance the contrast of RTECs in the urinary sediments. We concluded that this modified urinalysis protocol significantly enhanced the quality of urinalysis. PMID- 28074943 TI - The influence of flaxseed gum on the microrheological properties and physicochemical stability of whey protein stabilized beta-carotene emulsions. AB - The impact of flaxseed gum (FG) on the microrheological properties and physicochemical stability of whey protein isolate (WPI) stabilized beta-carotene emulsions at pH 3.0 was studied. A layer-by-layer electrostatic deposition method was used to prepare multilayered beta-carotene emulsions with interfacial membranes consisting of WPI and FG. The microrheological behavior of the multilayered beta-carotene emulsions was measured through the diffusive wave spectroscopy technique. WPI alone and WPI-FG (concentration of FG = 0.1, 0.2, 0.3 wt%) stabilized beta-carotene emulsions were purely viscous giving a mean square displacement that scaled linearly with decorrelation time (tau). The presence of 0.01, 0.02, and 0.05 wt% FG in the WPI-stabilized emulsions caused them to exhibit viscoelastic properties. Meanwhile, the increase in tau reflected the increase in the length scale of connectivity in the emulsions until a "cluster" was formed and the droplets were not free to move due to droplet-network interaction. The apparent increase in the macroscopic viscosity and elasticity index and decrease in the solid lipid balance and fluidity index of emulsions with lower concentrations (0.01, 0.02, 0.05 wt%) of FG indicated that the bridging flocculation of FG had a much more appreciable influence on the microrheological properties than depletion flocculation (higher concentrations, 0.1, 0.2, 0.3 wt%). Droplet size, zeta-potential, and transmission profiles using the centrifugal sedimentation technique and beta-carotene degradation during storage were also characterized. With the addition of FG, the zeta-potential of WPI coated beta-carotene droplets decreased from positive to negative, and an increase in the apparent droplet size was also noted. LUMISizer analysis exhibited an improvement in physical stability with the addition of 0.1 wt% FG. FG also helped to chemically stabilize the WPI emulsions against beta-carotene degradation mainly by slowing down the mobility of the droplets. PMID- 28074940 TI - Alpha7 nicotinic acetylcholine receptor is required for amyloid pathology in brain endothelial cells induced by Glycoprotein 120, methamphetamine and nicotine. AB - One of the most challenging issues in HIV-associated neurocognitive disorders (HAND) caused by HIV-1 virotoxins and drug abuse is the lack of understanding the underlying mechanisms that are commonly associated with disorders of the blood brain barrier (BBB), which mainly consists of brain microvascular endothelial cells (BMEC). Here, we hypothesized that Glycoprotein 120 (gp120), methamphetamine (METH) and nicotine (NT) can enhance amyloid-beta (Abeta) accumulation in BMEC through Alpha7 nicotinic acetylcholine receptor (alpha7 nAChR). Both in vitro (human BMEC) (HBMEC) and in vivo (mice) models of BBB were used to dissect the role of alpha7 nAChR in up-regulation of Abeta induced by gp120, METH and NT. Abeta release from and transport across HBMEC were significantly increased by these factors. Methyllycaconitine (MLA), an antagonist of alpha7 nAChR, could efficiently block these pathogenic effects. Furthermore, our animal data showed that these factors could significantly increase the levels of Abeta, Tau and Ubiquitin C-Terminal Hydrolase L1 (UCHL1) in mouse cerebrospinal fluid (CSF) and Abeta in the mouse brains. These pathogenicities were significantly reduced by MLA, suggesting that alpha7 nAChR may play an important role in neuropathology caused by gp120, METH and NT, which are the major pathogenic factors contributing to the pathogenesis of HAND. PMID- 28074944 TI - Synthesis and biophysical analysis of modified thymine-containing DNA oligonucleotides. AB - We report the synthesis of a 5-formyl-2'-deoxyuridine (5fU) phosphoramidite and the preparation of oligonucleotides comprising all known, naturally observed eukaryotic thymidine modifications. Biophysical characterization of the synthetic oligonucleotides indicates that 5fU, but not the other T-derivatives, can alter DNA structures. PMID- 28074945 TI - Solid-state NMR at natural isotopic abundance for the determination of conformational polymorphism - the case of designed beta-turn peptides containing di-prolines. AB - The proton double quantum-carbon single quantum correlation experiment has been applied to designed peptides in the solid state in natural isotopic abundance. Analogous to nOe studies in solution, through-space double-quantum connectivities have been exploited to obtain the cis-trans conformational polymorphism of diproline residues occurring at beta-turns in the peptides. PMID- 28074946 TI - Modulating the oxidation of cucurbit[n]urils. AB - The functionalisation of cucurbit[n]uril macrocycles carried out through an oxidative approach in water using ammonium persulfate was studied. Through complexation with a doubly-charged bisimidazolium guest we were able to detect, distinguish and quantify the presence of each CB[n]-(OH)x (where 1 <= x <= 2n) derivative for the first time. The impact of oxidation on each CB[n] (n = 6-8) was studied individually, as well as in the presence of other competing CB[n] species. We were able to understand the reactivity of the parent CB[n] alongside its hydroxylated derivatives, CB[n]-(OH)x, and show that the oxidation of CB[n] through a free-radical approach cannot result in stoichiometric hydroxylation despite previous literature reports by Bardelang, Ouari and co-workers, J. Am. Chem. Soc., 2015, 137, 10238. Furthermore, an in-depth study on hydroxylation of CB[7] was conducted. Through DFT calculations we were able to show that the second hydroxy substituent is preferentially located on the same glycoluril unit. Moreover, through optimisation of the reaction conditions we were able to access a protocol for controlled oxidation to yield a chemically monofunctional CB[7] derivative. PMID- 28074947 TI - Predicting the solubility of mixtures of sugars and their replacers using the Flory-Huggins theory. AB - In this paper we investigate whether the Flory-Huggins theory can describe the thermodynamics of solutions of simple carbohydrates, like sugars and polyols. In particular, we focus on the description of the solubility of the carbohydrates in water. This is investigated for both binary and ternary mixtures, having two types of these carbohydrates. This research question arises especially in the case of bakery products, where one seeks to replace sucrose with other simple carbohydrates - which are often polyols. Based on the model parameters obtained from fitting the theory to the experimental data of binary solutions, we show that the theory can predict (a) solubility data for ternary mixtures, over a broad range of concentrations and temperatures, and (b) the deliquescence point of binary mixtures of carbohydrate crystals as a function of temperature. The theory can even be applied to carbohydrates, which form hydrate crystals. Together with our earlier theories on the thermodynamics of complex food mixtures, we have now a complete thermodynamic framework to describe the phase and state transitions of food materials as confectionery and bakery products, where the question of sucrose replacement is urgent. PMID- 28074948 TI - Hot electron-driven photocatalytic water splitting. AB - We report measurements of photocatalytic water splitting using Au films with and without TiO2 coatings. In these structures, a thin (3-10 nm) film of TiO2 is deposited using atomic layer deposition (ALD) on top of a 100 nm thick Au film. We utilize an AC lock-in technique, which enables us to detect the relatively small photocurrents (~MUA) produced by the short-lived hot electrons that are photoexcited in the metal. Under illumination, the bare Au film produces a small AC photocurrent (<1 MUA) for both the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER) due to hot electrons and hot holes, respectively, that are photoexcited in the Au film. The samples with TiO2 produce a larger AC photocurrent indicating that hot electrons are being injected from the metal into the TiO2 semiconductor where they then reduce hydrogen ions in solution forming H2 (i.e., 2H+ + 2e- -> H2). The AC photocurrent exhibits a narrow peak when plotted as a function of reference potential, which is a signature of hot electrons. Here, we photoexcite a monoenergetic source of hot electrons, which produces a peak in the photocurrent, as the electrode potential is swept through the resonance with the redox potential of the desired half-reaction. This stands in contrast to conventional bulk semiconductor photocatalysts, whose AC photocurrent saturates beyond a certain potential (i.e., light limited photocurrent). The photocurrents produced at the metal-liquid interface are smaller than those of the metal-semiconductor system, mainly because, in the metal-semiconductor system, there is a continuum of energy and momentum states that each hot electron can be injected into, while for an ion in solution, the number of energy and momentum states are very small. PMID- 28074949 TI - New compounds from a hydrothermal vent crab-associated fungus Aspergillus versicolor XZ-4. AB - Three new quinazoline derivatives (1-3), one new oxepin-containing natural product (4) and four new cyclopenin derivatives (5-7 and 9) have been isolated from an EtOAc extract of the Taiwan Kueishantao hydrothermal vent crab-associated fungus Aspergillus versicolor XZ-4. Their planar structures were established by HRMS, 1D and 2D NMR spectroscopic data analyses. The absolute configurations for compounds 1 and 4 were determined by chiral phase HPLC analysis of their hydrolysis products. The absolute configurations of 2, 3 and 7 were defined mainly by comparison of the quantum chemical TDDFT calculated and the experimental ECD spectra, and the absolute configuration of 5 was deduced from comparison of the optical rotation values reported in the literature. The presence of two atropisomers of 5 was established by NOE analyses. The Ile & Val units in compounds 1-3 allowed the assignment of a new quinazoline skeleton and it's the first time the configuration of isoleucine in the quinazoline skeleton was defined. A series of 7-methoxy cyclopenin derivatives were reported for the first time in this study. The bioevaluation of compounds 5, 7, 8 and 9 revealed inhibitory activities against E. coli at MIC values around 32 MUg mL-1. PMID- 28074951 TI - Access to N-cyanosulfoximines by transition metal-free iminations of sulfoxides. AB - A transition metal-free synthesis of N-cyanosulfoximines from sulfoxides using N chlorosuccinimide (NCS) as oxidising agent and cyanamide as nucleophilic amine source is reported. The products are obtained in moderate to excellent yields. The protocol enables an easy access to N-cyanosulfoximines from readily available starting materials under inversion of configuration at a preexisting stereogenic center. PMID- 28074950 TI - Self-neutralizing oligonucleotides with enhanced cellular uptake. AB - There is tremendous potential for oligonucleotide (ON) therapeutics, but low cellular penetration due to their polyanionic nature is a major obstacle. We addressed this problem by developing a new approach for ON charge neutralization in which multiple branched charge-neutralizing sleeves (BCNSs) are attached to the internucleoside phosphates of ON by phosphotriester bonds. The BCNSs are terminated with positively charged amino groups, and are optimized to form ion pairs with the neighboring phosphate groups. The new modified ONs can be prepared by standard automated phosphoramidite chemistry in good yield and purity. They possess good solubility and hybridization properties, are not involved in non standard intramolecular aggregation, have low cytotoxicity, adequate chemical stability, improved serum stability, and above all, display significantly enhanced cellular uptake. Thus, the new ON derivatives exhibit properties that make them promising candidates for the development of novel therapeutics or research tools for modulation of the expression of target genes. PMID- 28074952 TI - Upregulation of caveolin-1 by mulberry leaf extract and its major components, chlorogenic acid derivatives, attenuates alcoholic steatohepatitis via inhibition of oxidative stress. AB - Excessive alcohol uptake exerts hepatocellular toxicity, ultimately leading to multiple liver diseases such as steatohepatitis and liver cirrhosis. Here, we aimed to explore the effects of mulberry leaf extract (MLE) and its major components chlorogenic acid (CGA) and neochlorogenic acid (nCGA) on alcoholic steatohepatitis. We determined the composition of MLE using liquid chromatography mass spectrometric (LC-MS) analysis, which showed that MLE consisted of mainly chlorogenic acid derivatives and other polyphenols. Next, we utilized a high alcohol-fed mouse model and demonstrated that MLE alleviated alcohol-induced hepatocellular disorders, resulting in lowered hepatic injury markers and lipid accumulation. In addition, MLE reduced lipid peroxidation and meanwhile elevated hepatic superoxide dismutase (SOD). Immunohistochemical (IHC) staining revealed that MLE elevated the expression of caveolin-1 but reduced the expressions of epidermal growth factor receptor (EGFR), signal transducer and activator of transcription (STAT), inducible nitric oxide synthase (iNOS) and receptor interacting protein (RIP) 1/3. Major components of MLE, CGA and nCGA, not only exerted a similar biological activity as MLE but also inhibited alcohol-induced pro-apoptotic signals. Involvement of caveolin-1 in MLE, CGA and nCGA was demonstrated by using specific small inhibitory RNA. In conclusion, MLE and its chlorogenic derivatives CGA and nCGA upregulate caveolin-1 expression and diminish EGFR/STAT3/iNOS signalling, which may contribute to lowered hepatic lipid accumulation and peroxidation and inhibited pro-apoptotic cascades. PMID- 28074953 TI - Gastrointestinal interactions, absorption, splanchnic metabolism and pharmacokinetics of orally ingested phenolic compounds. AB - The positive health effects of phenolic compounds (PCs) have been extensively reported in the literature. An understanding of their bioaccessibility and bioavailability is essential for the elucidation of their health benefits. Before reaching circulation and exerting bioactions in target tissues, numerous interactions take place before and during digestion with either the plant or host's macromolecules that directly impact the organism and modulate their own bioaccessibility and bioavailability. The present work is focused on the gastrointestinal (GI) interactions that are relevant to the absorption and metabolism of PCs and how these interactions impact their pharmacokinetic profiles. Non-digestible cell wall components (fiber) interact intimately with PCs and delay their absorption in the small intestine, instead carrying them to the large intestine. PCs not bound to fiber interact with digestible nutrients in the bolus where they interfere with the digestion and absorption of proteins, carbohydrates, lipids, cholesterol, bile salts and micronutrients through the inhibition of digestive enzymes and enterocyte transporters and the disruption of micelle formation. PCs internalized by enterocytes may reach circulation (through transcellular or paracellular transport), be effluxed back into the lumen (P glycoprotein, P-gp) or be metabolized by phase I and phase II enzymes. Some PCs can inhibit P-gp or phase I/II enzymes, which can potentially lead to drug nutrient interactions. The absorption and pharmacokinetic parameters are modified by all of the interactions within the digestive tract and by the presence of other PCs. Undesirable interactions have promoted the development of nanotechnological approaches to promote the bioaccessibility, bioavailability, and bioefficacy of PCs. PMID- 28074954 TI - A highly selective fluorescent probe for Fe3+ in living cells: a stress induced cell based model study. AB - A rhodamine-phenanthroline dyad based fluorescent probe 4 has been designed and synthesized which selectively monitors Fe3+ ions among the various metal ions tested. Furthermore, probe 4 has been explored for monitoring of dynamic changes in the Fe3+ ion level under aggressive Fenton reaction conditions using a cell based model study. More significantly, probe 4 has also been utilized for real time imaging of endogenous Fe3+ ions in living C6 cell lines, the results of which demonstrated that probe 4 acts as an efficient fluorescent tool for Fe3+ ion detection in biological systems. PMID- 28074955 TI - Total synthesis and biological activity of dolastatin 16. AB - The total synthesis of dolastatin 16, a macrocyclic depsipeptide first isolated from the sea hare Dolabella auricularia as a potential antineoplastic metabolite by Pettit et al., was achieved in a convergent manner. Dolastatin 16 was reported by Tan to exhibit strong antifouling activity, and thus shows promise for inhibiting the attachment of marine benthic organisms such as Amphibalanus amphitrite to ships and submerged artificial structures. Therefore, dolastatin 16 is a potential compound for a new, environmentally friendly antifouling material to replace banned tributyltin-based antifouling paints. The synthesis of dolastatin 16 involved the use of prolinol to prevent formation of a diketopiperazine composed of l-proline and N-methyl-d-valine during peptide coupling. This strategy for the elongation of peptide chains allowed the efficient and scalable synthesis of one segment, which was subsequently coupled with a second segment and cyclized to form the macrocyclic framework of dolastatin 16. The synthetic dolastatin 16 exhibited potent antifouling activity similar to that of natural dolastatin 16 toward cypris larvae of Amphibalanus amphitrite. PMID- 28074956 TI - Tunable superapolar Lotus-to-Rose hierarchical nanosurfaces via vertical carbon nanotubes driven electrohydrodynamic lithography. AB - The development of a robust, cost-effective, scalable and simple technique that enables the design and construction of well-controlled large area superhydrophobic surface structures which can be easily tuned from lotus-leaf to rose-petal state is essential to enable progress in realising the full applied potential of such surfaces. In this study, we introduce the tuneable carbon nanotubes-based electrohydrodynamic lithography (CNT-EHL) to fabricate unique multiscale structured cones and nanohair-like architectures with various periodicities and dimensions, successfully enabling surface energy minimization. The possibility of contact-less lithography via the CNT-EHL morphology replication combined with the electric field coupling to smaller self-assembled patterns within the film, provides a way for hierarchical structure control spanning many length scales along with tuneable wetting capabilities. By controlling the hierarchy of micro- to nano cones and spikes, these morphologies provide a range of architectures with sufficient roughness for very low wettability, with the highest contact angle achieved of 173 degrees and their properties can be easily switched between lotus-leaf to rose-petal behaviour. PMID- 28074957 TI - High-efficiency perovskite solar cells prepared by using a sandwich structure MAI PbI2-MAI precursor film. AB - Two-step deposition has been widely used in the perovskite layer preparation for perovskite solar cells due to its attractive morphology controllability. However, the limited diffusivity of CH3NH3I (MAI) might cause some PbI2 to remain in the perovskite film. The residual PbI2 in the perovskite film would lead to inferior performance of devices, such as, low power conversion efficiency (PCE), poor reproducibility and weak air stability. In this work, we developed a sandwich structure MAI-PbI2-MAI precursor film to prepare a PbI2-free CH3NH3PbI3 perovskite film. In comparison to the two-step approach, the MAI-PbI2-MAI precursor film with a typical sandwich structure formed a uniform and pinhole free perovskite film without any PbI2 residue, which could significantly improve the performance of the devices. Moreover, the bottom MAI layer of the MAI-PbI2 MAI precursor film could improve the interfacial contact of the porous TiO2 layer, leading to the promotion of the charge transfer and reduction of the recombination rate. Therefore, the devices fabricated from the sandwich structure MAI-PbI2-MAI precursor films showed dramatic improvements of open-circuit voltage (Voc), short-circuit current density (Jsc), fill factor (FF) and PCE. As a result, a promising PCE of 17.8% with good long-term air stability was achieved for the MAI-PbI2-MAI precursor film based PSC, which is better than that prepared by a two-step approach. PMID- 28074958 TI - Distant ultrafast energy transfer in a trimetallic {Ru-Ru-Cr} complex facilitated by hole delocalization. AB - Multi-metallic complexes based on {Ru-Cr}, {Ru-Ru} and {Ru-Ru-Cr} fragments are investigated for their light-harvesting and long-range energy transfer properties. We report the synthesis and characterization of [Ru(tpy)(bpy)(MU CN)Ru(py)4Cl]2+ and [Ru(tpy)(bpy)(MU-CN)Ru(py)4(MU-NC)Cr(CN)5]. The intercalation of {RuII(py)4} linked by cyanide bridges between {Ru(tpy)(bpy)} and {Cr(CN)5} results in efficient, distant energy transfer followed by emission from the Cr moiety. Characterization of the energy transfer process based on photophysical and ultrafast time-resolved absorption suggests the delocalization of holes in the excited state, providing a pathway for energy transfer between the end moieties. The proposed mechanism opens the door to utilize this family of complexes as an appealing platform for the design of antenna compounds as the properties of the fragments could be tuned independently. PMID- 28074959 TI - Partial hydrogenation induced interaction in a graphene-SiO2 interface: irreversible modulation of device characteristics. AB - The transformation of systematic vacuum and hydrogen annealing effects in graphene devices on the SiO2 surface is reported based on experimental and van der Waals interaction corrected density functional theory (DFT) simulation results. Vacuum annealing removes p-type dopants and reduces charged impurity scattering in graphene. Moreover, it induces n-type doping into graphene, leading to the improvement of the electron mobility and conductivity in the electron transport regime, which are reversed by exposing to atmospheric environment. On the other hand, annealing in hydrogen/argon gas results in smaller n-type doping along with a decrease in the overall conductivity and carrier mobility. This degradation of the conductivity is irreversible even the graphene devices are exposed to ambience. This was clarified by DFT simulations: initially, silicon dangling bonds were partially terminated by hydrogen, subsequently, the remaining dangling bonds became active and the distance between the graphene and SiO2 surface decreased. Moreover, both annealing methods affect the graphene channel including the vicinity of the metal contacts, which plays an important role in asymmetric carrier transport. PMID- 28074960 TI - Search for effective chemical quenching to arrest molecular assembly and directly monitor DNA nanostructure formation. AB - Structural DNA nanotechnology has demonstrated both versatility and potential as a molecular manufacturing tool; the formation and processing of DNA nanostructures has therefore been subject to much interest. Characterization of the formation process itself is vital to understanding the role of design in production yield. We present our search for a robust new technique, chemical quenching, to arrest molecular folding in DNA systems for subsequent characterization. Toward this end we will introduce two miniM13 origami designs based on a 2.4 kb scaffold, each with diametrically opposed scaffold routing strategies (maximized scaffold crossovers versus maximized staple crossovers) to examine the relevance of design in the folding process. By chemically rendering single strand DNA inert and unable to hybridize, we probe the folding pathway of several scaffolded DNA origami structures. PMID- 28074961 TI - Tunable electrical properties of multilayer HfSe2 field effect transistors by oxygen plasma treatment. AB - HfSe2 field effect transistors are systematically studied in order to selectively tune their electrical properties by optimizing layer thickness and oxygen plasma treatment. The optimized plasma-treated HfSe2 field effect transistors showed a high on/off ratio improvement of four orders of magnitude, from 27 to 105, a field effect mobility increase from 2.16 to 3.04 cm2 V-1 s-1, a subthreshold swing improvement from 30.6 to 4.8 V dec-1, and a positive threshold voltage shift between depletion mode and enhancement mode, from -7.02 to 11.5 V. The plasma-treated HfSe2 photodetector also demonstrates a reasonable photoresponsivity from the visible to the near-infrared region of light. PMID- 28074962 TI - Crossed flow microfluidics for high throughput screening of bioactive chemical cell interactions. AB - This paper describes the use of crossed laminar flow microfluidics for the selective capture of multiple cell types on-chip aiming for high throughput screening of various cell treatment compounds. Parallel laminar streams containing different cell types were perfused and captured on a cell adhesion protein-functionalized reaction area. Thereafter, parallel streams containing cell treatment solutions were delivered orthogonally over the captured cells. Multiple cell types and a range of cell treatment conditions could therefore be assessed in a single experiment. We were also able to sort mixed cell populations via antibody array clusters, and to further deliver treatments to subpopulations of cells. Moreover, using solutions with different tonicities, we successfully demonstrated the incorporation of a live/dead cell viability assessment on-chip for a direct read out assay following the treatments. This crossed laminar flow microfluidics for generation of a cell-based assay could therefore offer an interesting platform for high throughput screening of potential drug candidates, nanoparticle toxicity testing, or other cellular and molecular interventions. PMID- 28074964 TI - How the alignment of adsorbed ortho H pairs determines the onset of selective carbon nanotube etching. AB - Unlocking the enormous technological potential of carbon nanotubes strongly depends on our ability to specifically produce metallic or semiconducting tubes. While selective etching of both has already been demonstrated, the underlying reasons, however, remain elusive as yet. We here present computational and experimental evidence on the operative mechanisms at the atomic scale. We demonstrate that during the adsorption of H atoms and their coalescence, the adsorbed ortho hydrogen pairs on single-walled carbon nanotubes induce higher shear stresses than axial stresses, leading to the elongation of HC-CH bonds as a function of their alignment with the tube chirality vector, which we denote as the gamma-angle. As a result, the C-C cleavage occurs more rapidly in nanotubes containing ortho H-pairs with a small gamma-angle. This phenomenon can explain the selective etching of small-diameter semiconductor nanotubes with a similar curvature. Both theoretical and experimental results strongly indicate the important role of the gamma-angle in the selective etching mechanisms of carbon nanotubes, in addition to the nanotube curvature and metallicity effects and lead us to clearly understand the onset of selective synthesis/removal of CNT-based materials. PMID- 28074963 TI - Ultrahigh-capacity dynamic holographic displays via anisotropic nanoholes. AB - For the miniaturization of optical holographic and data recording devices, large information capacity or data density is indispensable but difficult to obtain using traditional technologies. In this paper, an ultrahigh-capacity metasurface hologram is proposed by encoding information in deep-subwavelength scale nanohole arrays, which can be reconstructed via a light beam with proper designed incident angles. The imaging information capacity of the two-dimensional (2D) hologram, defined by the distortion-free region, can be increased 11.5 times, which is experimentally demonstrated by focused ion beam (FIB) milling of an ultrathin metallic film. We also prove the feasibility of a three-dimensional (3D) hologram of spiral lines designed by using the point source algorithm. Benefitting from the ultrahigh capacity of the deep-subwavelength metasurface, dynamic holographic displays can be realized by controlling the incident angle. The method proposed here can also be leveraged to achieve large capacity optical storage, colorful holographic displays, lithography technology etc. PMID- 28074965 TI - N-Heterocyclic carbene-palladium(ii)-1-methylimidazole complex catalyzed direct C H bond arylation of imidazo[1,2-a]pyridines with aryl chlorides. AB - We herein reported the N-heterocyclic carbene-palladium(ii)-1-methylimidazole complex catalyzed direct C-H bond arylation of imidazo[1,2-a]pyridines with aryl chlorides. Under suitable conditions, all reactions between various imidazo[1,2 a]pyridines and aryl chlorides worked well to give the desired C3-H arylated products in acceptable to high yields, giving a convenient and alternative method for the direct C-H bond arylation of imidazo[1,2-a]pyridines, using economic and easily available aryl chlorides as the arylating reagents. PMID- 28074966 TI - The relationship between sun exposure and all-cause mortality. AB - We aimed to conduct a narrative review of the rapid advances in knowledge regarding sun exposure and all-cause mortality. Data support the hypothesis that sun exposure avoidance is a major risk factor for all-cause mortality in adjusted analysis (age, income, education, marital status, smoking, and comorbidity). This was caused by an increased risk of death due to cardiovascular disease (CVD) and noncancer/non-CVD. However, the increased life span among those with high sun exposure naturally results in an increased prevalence of cancer death. In addition, sun exposure increases the incidence, but is related to better prognosis of skin cancer. The new findings indicate that there is a need for modification of guidelines regarding sun exposure. They may also add to our knowledge regarding the increasing incidence of diabetes mellitus and increased mortality among non-Caucasians in western countries. According to the present knowledge, in a low solar intensity region we should aim for sound and safe sun exposure habits, especially for those at increased risk of CVD or noncancer/non CVD. PMID- 28074967 TI - Direct enantioselective C-acylation for the construction of a quaternary stereocenter catalyzed by a chiral bicyclic imidazole. AB - A direct enantioselective C-acylation of 3-substituted benzofuran-2(3H)-ones (with up to 97% ee) was developed using a chiral bicyclic imidazole catalyst OAc DPI and an achiral tertiary amine additive DIPEA. The reaction mechanism for the direct C-acylation has been investigated using both experimental and theoretical studies. PMID- 28074968 TI - Symmetry breaking above room temperature in an Fe(ii) spin crossover complex with an N4O2 donor set. AB - [Fe(qsal-Cl)2] is one of the few known Fe(ii) spin crossover compounds with an N4O2 donor atom environment. It shows an abrupt two-step spin transition at 308 and 316 K and importantly, symmetry breaking at the highest temperature reported, to date, in spin crossover compounds. PMID- 28074969 TI - Direct coordination of a germanium(ii) dicationic center to transition metals. AB - The germanium(ii) center of dicationic compound 1 donates an electron pair to transition metal Ag(i) and Au(i) cations, leading to complexes 2 and 3 respectively. Complex 3 is stabilized by [Ge:]2+->Au(i) sigma-donation and pi back donation from filled d-orbitals of Au(i) to the two sets of p-orbitals available on Ge(ii) centers. PMID- 28074970 TI - Synthesis of partially dextran-coated gold nanoworms and anisotropic structure based dual-strategic cargo conjugation for efficient combinational cancer therapy. AB - Partially dextran-coated gold nanoworms enabled the dual-strategic conjugation of peptides and genes. Combinational cancer therapy with photothermal conversion under near-infrared irradiation was shown to be a highly efficient cancer treatment. PMID- 28074971 TI - Bio-orthogonal "click-and-release" donation of caged carbonyl sulfide (COS) and hydrogen sulfide (H2S). AB - Hydrogen sulfide (H2S) is an important biomolecule with high therapeutic potential. Here we leverage the inverse-electron demand Diels-Alder (IEDDA) click reaction between a thiocarbamate-functionalized trans-cyclooctene and a tetrazine to deliver carbonyl sulfide (COS), which is quickly converted to H2S by the uniquitous enzyme carbonic anhydrase (CA), thus providing a new strategy for bio orthogonal COS/H2S donation. PMID- 28074972 TI - Correlated/non-correlated ion dynamics of charge-neutral ion couples: the origin of ionicity in ionic liquids. AB - Proton/fluoride spin-lattice (T1) nuclear magnetic relaxation dispersion (NMRD) measurements of 1-butyl-3-methyl-1H-imidazolium hexafluorophosphate, [C4mim][PF6], have been carried out using high field spectrometers and a fast field-cycling instrument at proton Larmor frequencies ranging from 10 kHz to 40 MHz, at different temperatures. The NMRD profiles are interpreted by means of a simple relaxation model based on the inter- and intra-ionic dipole-dipole relaxation mechanism. Using an atomic molecular-ion dynamic simulation at 323 K the relevant spin dipole-dipole (DD) correlation functions are calculated. The results indicate that the NMRD profiles can be rationalized using intra- and inter-ionic spin DD interactions, however, anions are mainly modulated by ionic reorientation because of temporary correlations with cations, where modulation by translational diffusion plays a minor role. Reorientational dynamics of charge neutral ion couples (i.e. [C4mim][PF6]) and [C4mim]+ ions are in the nano-second (ns) time range whereas the reorientation of [PF6]- is characterized by a reorientational correlation time in the pico-second (ps) regime. Based on the NMRD profiles we conclude that the main relaxation mechanism for [PF6]- is due to fast internal reorientational motion, a partially averaged F-F intra- and F-H inter-ionic DD coupling as the anion resides in close proximity to its temporary oppositely charged cation partner. The F-T1-NMRD data display a ns dispersion which is interpreted as being due to correlated reorientational modulations resulting from the H-containing charge-neutral ion couple [C4mim][PF6]. The analysis of ionicity is based on the free anion fraction, f, and it increases with temperature with f -> 1 at the highest temperatures investigated. The fraction is obtained from the H-F NMRD profiles as correlated-non-correlated dynamics of the ions. The analysis of T1 relaxation rates of C, H, F and P at high fields cannot generally give the fraction of ions but is consistent with the interpretation based on the NMRD profiles with relaxation contributions due to DD intra and -inter, CSA-intra (and -inter for C), including spin rotation for P. The investigation has led to a description of the mechanics governing ion transport in the title ionic liquid via identification of transient correlated/non-correlated ion dynamics. PMID- 28074973 TI - Fluorescence turn-on hairpin-probe PCR. AB - A new fluorescence turn-on type of PCR monitoring system (Hpro-PCR) using a hairpin probe and a primer having a tag sequence at the 5' end with the fluorescent molecule 2,7-diamino-1,8-naphthyridine derivative (DANP) has been developed. The Hpro-PCR exploited the modulation of the equilibrium states between the DANP-bound hairpin structure and probe-tag duplex, and the PCR progress alternated the equilibrium state, resulting in the change of fluorescent intensity. PMID- 28074974 TI - Ligand-assisted mechanochemical synthesis of ceria-based catalysts for the selective catalytic reduction of NO by NH3. AB - CeO2/TiO2 catalysts were fabricated by dry ball milling in the presence or absence of an organic ligand. It was found that the catalysts prepared by ligand assisted ball milling exhibited high NH3-SCR activities due to the interaction between cerium ions and ligand molecules resulting in good dispersion, a high Ce3+ ratio and high reducibility of cerium species. PMID- 28074975 TI - Accessing alternative reaction pathways of the intermolecular condensation between homo-propargyl alcohols and terminal alkynes through divergent gold catalysis. AB - An intermolecular condensation of alkynols and terminal alkynes is reported. Using IPrAuNTf2, an efficient Au-catalyzed cyclization-alkynylation strategy furnishes (2-arylalkynyl) cyclic ethers in moderate to excellent yields (up to 94%). This strategy is extended to the synthesis of functionalized 2,3 dihydrooxepines via the sequential Au-catalyzed ring expansion of the cyclic ether substrates. PMID- 28074976 TI - Utility of urinary markers in the assessment of renal dysfunction in canine babesiosis. AB - OBJECTIVE: Canine babesiosis is a common and clinically significant tick-borne disease caused by haemoprotozoan parasites of the genus Babesia. Acute renal failure is considered to be one of the most prevalent complications of canine babesiosis. This complication leads to a decrease in the glomerular filtration rate and in consequence causes azotemia and uremia. The objective of this study was to assess the localization and extent of renal damage in dogs infected with Babesia canis using an urinary marker for glomerular (urinary immunoglobulin G, uIgG), proximal tubular dysfunction (urinary retinol binding protein, uRBP) and distal tubular dysfunction (urinary Tamm-Horsfal protein, uTHP). Material und methods: In 10 dogs naturally infected with B. canis and 10 healthy control dogs the levels of urinary biomarkers were measured using commercially available ELISA tests. RESULTS: Higher concentrations of uIgG, uRBP and uTHP were found in the urine of all dogs with babesiosis than in those from the control group. This indicates that in the course of the disease, the glomeruli as well as the renal tubules become damaged. CONCLUSION AND CLINICAL RELEVANCE: The study results allow a better understanding of the pathogenesis of canine babesiosis. However, in order to fully determine the extent and the nature of the damage to the kidneys of the infected dogs, it is advisable to conduct additional histopathological examinations of these organs. PMID- 28074977 TI - [Association of C reactive protein levels with metabolic syndrome in adults: a population-based study]. AB - BACKGROUND: Metabolic syndrome is highly prevalent among adults in Chile and represents a health risk. AIM: To determine the relationship between metabolic syndrome (MetS) and its components, with C reactive protein levels (CRP) as an inflammation marker. MATERIAL AND METHODS: The population studied consisted of 736 individuals born in a hospital from Valparaiso Region, aged between 32-38 years at the time of the study. MetS was identified according to the Adult Treatment Panel (ATP) III guidelines and inflammation was measured using ultra sensitive CRP. This parameter was classified as normal for values from 0 to 3 mg/L, high for values from 3.01 to 10 mg/L and very high for values > 10 mg/L. RESULTS: Median CRP was in the normal range (1.9 mg/L, interquartile range 0.7 5.2) and was higher among women than men (2.2 and 1.4 mg/L respectively, p < 0.01). Twenty seven percent of participants had MetS. One-fourth had high blood glucose values, one-third had high triglyceride levels and 28% had blood pressure values over those established as normal in MetS. Elevated waist circumference (WC) and low HDL cholesterol were found among almost 50% of participants. A relationship between MetS and high CRP was only found among men with an Odds ratio (OR) of 2.04 (95% confidence intervals (CI): 1.11-3.73). The same association was observed for high triglyceride levels with an OR of 2.02 (CI: 1.17-3.49) and high WC with an OR of 3.89 (CI: 2.06-7.36). Among women, the only relationship observed was between abdominal obesity and very high CRP with an OR of 2. 65 (CI: 1.20-5.84). CONCLUSIONS: Metabolic syndrome, high triglyceride levels, and abdominal obesity were associated with inflammation only in men. PMID- 28074978 TI - [Effect of meal frequency and carbohydrate intake on the metabolic control of patients with type 2 diabetes mellitus]. AB - BACKGROUND: Increasing meal frequency is commonly used in the clinical practice as part of the nutritional treatment of patients with type 2 Diabetes Mellitus (DM2), although its effect on metabolic control parameters is controversial. AIM: To evaluate the association of energy intake, meal frequency, and amount of carbohydrates with fasting plasma glucose and glycosylated hemoglobin in a group of patients with DM2 without insulin therapy. MATERIAL AND METHODS: Dietary intake was evaluated in 60 subjects with DM2 through three-day food records. The meal frequency was estimated establishing the main meal times considering snacks. RESULTS: Meal frequency was 4.7 +/- 1.1 times per day. There was a positive association between glycosylated and fasting blood glucose levels (p <0.01). Meal frequency was associated with energy intake (p <0.01). When meal frequency, available carbohydrates and energy intake, body mass index and fasting plasma glucose were analyzed in a multiple linear regression model, fasting blood glucose was the variable that best predicted changes in glycosylated hemoglobin (45.5%). Meal frequency had no association with glycosylated hemoglobin. CONCLUSIONS: Meal frequency showed no association with metabolic control parameters in DM2 patients. PMID- 28074979 TI - [Effects of 12 sessions of high intensity intermittent training and nutrition counseling on body fat in obese and overweight participants]. AB - BACKGROUND: The search of efficient exercise alternatives to treat obesity is worthwhile. AIM: To demonstrate the effect of high intensity intermittent exercise on body fat reduction in overweight and obese subjects. MATERIAL AND METHODS: A group of 65 overweight and obese adult subjects (25 men), aged 18-65 years, participated during 12 sessions in a high intensity physical exercise program, 3 days/week. Weight, height and body fat was measured before and after the intervention by bioimpedance. Each session consisted of 1 min stationary cycling exercise at high intensity, followed by 2 min inactive rest. This cycle was repeated 10 times, thus the method is called 1*2*10. RESULTS: There was a significant reduction of body fat of -1.88 +/- 2.8 and -3.44 +/- 2.7 kg, in women and men, respectively (p < 0.05). CONCLUSIONS: The 1*2*10 training protocol lasting 12 weeks in association with nutrition counseling is effective in reducing body fat in overweight persons. PMID- 28074980 TI - [Implications of chilean legal framework in teen pregnancy prevention: conflict and insecurity in health professionals]. AB - BACKGROUND: Teenage pregnancy is a psychosocial and multifactorial problem described as a lack of exercise of rights in sexual and reproductive health. There are important aspects in the doctor-patient relationship and confidentiality that directly affect the continuity and quality of care. There are controversies in the laws relating to the provision of contraception and confidentiality, and those that protect the sexual indemnity, especially in adolescents under 14 years. AIM: To describe the implications of the legal framework for professional midwives in the care of adolescents younger than 14 years in sexual and reproductive health. MATERIAL AND METHODS: In-depth interviews were conducted to 13 female and 2 male midwives working at Primary Health Care Centers in the Metropolitan Region. RESULTS: The attention of adolescents younger than 14 years in sexual and reproductive health involves medical-legal issues for health professionals. All professionals recognize that mandatory reporting sexual activity is a complex situation. All professionals notify pregnancies. In relation to the delivery of contraception, clinical care is problematic since professionals should take shelter from a legal standpoint. CONCLUSIONS: The medical-legal context of pregnant women under 14 years of age care generates a context of uncertainty and fear for professionals and becomes a source of conflict and insecurity in the exercise of the profession. PMID- 28074981 TI - [Thrombolysis in stroke mimics: Experience in 10 cases]. AB - BACKGROUND: The effectiveness of intravenous thrombolysis (IVT) in cerebral ischemia is time dependent. Stroke mimics (SM) are frequent in emergency rooms. The effort to reduce door to needle time, can lead to administer thrombolytics to SM. AIM: To describe the frequency and prognosis of SM treated with IVT. MATERIAL AND METHODS: Prospective analysis of all patients evaluated in a Chilean private clinic between December 2004 and July 2015 with a suspected acute ischemic stroke (AIS). We calculated the number of SM that were treated with IVT. In these patients, we analyzed the presence of symptomatic cerebral hemorrhage defined as the presence of a neurological deterioration of four points or more on the National Institute of Health Stroke Scale, the presence of extracranial bleeding according to Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries criteria and the patient's functional status at three months by modified Rankin scale (MRS). RESULTS: We evaluated 1,417 patients with suspected AIS, of which 240 (16.9%) were finally diagnosed as SM. A total of 197 patients were treated with IVT, of these 10 (5%) corresponded to SM. All SM patients treated with thrombolytic drugs were functionally independent at 3 months and showed no bleeding complications. CONCLUSIONS: Occasionally SM patients were treated with IVT. This treatment was not associated with bleeding complications and the prognosis of these patients at three months was favorable. PMID- 28074982 TI - [Healthcare mistreatment attributed to discrimination among mapuche patients and discontinuation of diabetes care]. AB - BACKGROUND: The negative impact of perceived discrimination on health outcomes is well established. However, less attention has been directed towards understanding the effect of perceived discrimination on health behaviors relevant for the treatment of diabetes in ethnic minorities. AIM: To examine the effects of healthcare mistreatment attributed to discrimination on the continuity of Type 2 Diabetes (DM2) care among mapuche patients in a southern region of Chile. MATERIAL AND METHODS: A non-probabilistic sample of 85 mapuche DM2 patients were recruited from public and private health systems. Eligibility criteria included having experienced at least one incident of interpersonal healthcare mistreatment. All participants answered an instrument designed to measure healthcare mistreatment and continuity of diabetes care. RESULTS: Healthcare mistreatment attributed to ethnic discrimination was associated with the discontinuation of diabetes care. CONCLUSIONS: Healthcare mistreatment attributed to discrimination negatively impacted the continuity of diabetes care, a fact which may provide a better understanding of health disparities in ethnic minorities. PMID- 28074983 TI - [Role of coronary computed tomography angiography for the diagnosis of coronary anomalies]. AB - BACKGROUND: Coronary anomalies are rare heart diseases that can cause sudden cardiac death, especially in young individuals. Coronary computed tomography angiography delivers a three-dimensional view of excellent quality with information of the origin, course and anatomic relationships of the anomalous vessel, allowing differentiation between benign and malignant variants, entities that require different management and treatment. AIM: To show that coronary computed tomography angiography is the non-invasive technique of choice for the evaluation of a coronary anomaly due to its high diagnostic accuracy. MATERIAL AND METHODS: Between 2008 and 2014, 368 coronary computed tomography angiographies were carried out. Six (1.6%) patients had a coronary anomaly. RESULTS: The age of these six patients ranged from 38 to 82 years (five were women). The coronary computed tomography angiography was requested due to cardiac symptoms (angina and dyspnea) in two patients, after a selective coronary arteriography to obtain additional information of the coronary anomaly in three patients, and after a cardiorespiratory arrest in one patient. Three patients had an anomaly of the right coronary artery, two patients had an anomaly of the left coronary artery and one patient had absent left main coronary artery. In five patients the coronary anomaly was malignant. CONCLUSIONS: Coronary computed tomography angiography is a robust diagnostic method to evaluate patients with suspected coronary anomalies. PMID- 28074984 TI - [Wellbeing of Chilean older adults is associated with group participation]. AB - BACKGROUND: Subjective aspects such as personal growth and the development of their potential are relevant for the perception of wellbeing of older adults. These dimensions appear to be connected with meaningful group participation. AIM: To assess the perception of psychological wellbeing of older adults in a Chilean region and determine its association with socio-demographic variables and participation in organizations. MATERIAL AND METHODS: Ryff's scale of psychological wellbeing perception was applied to 101 adults (43 men) from Magallanes, aged 60 and 88 years. Sociodemographic data was also collected. RESULTS: Mean wellbeing scores reported were 193.7 +/- 20 (maximum score: 234). Those older adults who participated in organizations had higher scores than those who did not take part in them. Participation in organizations appeared to be specifically associated to positive relationships (p = 0.03) and personal growth (p < 0.01). The number of organizations in which older adults participated was positively correlated with the perception of wellbeing (p < 0.01). Greater personal wellbeing was associated with leadership roles in organizations (p = 0.01). Significant differences between level of schooling and personal growth (p = 0.01) were also observed found. There were no differences associated with sex, age and marital status. CONCLUSIONS: The perception of wellbeing of older adults is influenced by their participation in organizations. Leadership is associated with the highest levels of wellbeing. PMID- 28074985 TI - [Characteristics and evolution of patients admitted to a public hospital intensive care unit]. AB - BACKGROUND: The epidemiology of critical patients in Chile could differ from that reported in international studies. AIM: To describe the causes of admission and evolution of patients who were admitted to the ICU (Intensive Care Unit) of a general hospital in Chile in a two-year period (2012-2013). PATIENTS AND METHODS: A retrospective study was carried out using the ICU database. The following variables were registered: admission diagnosis, APACHE II (Acute Physiology and Chronic Health Evaluation), days of mechanical ventilation (MV), ICU length of stay and ICU and hospital survival. RESULTS: We analyzed data from 1075 aged 54 +/- 18 years (55% males), representing 75% of the admissions during the study period. The median ICU and MV lengths were 5 and 3 days respectively (92% of patients required MV). APACHE II was 20.5 +/- 8.2. The ICU and hospital mortality rate were 19.4% and 31%, respectively. Critical neurological diseases were the most common diagnoses requiring ICU, representing 26.8% of the admissions. No differences were found between 2012 and 2013 in age, APACHE II, ICU or hospital survival. A longer post ICU length of stay was found during 2013, both for patients who survived and those who died at the hospital. CONCLUSIONS: This study highlights the high percentage of patients that required MV and the high percentage critical neurological conditions requiring ICU admission. The characteristics and evolution of patients admitted to the ICU did not differ during 2012 and 2013. PMID- 28074987 TI - [Towards universal access to health care: incorporation of advanced practice nurses in primary care]. AB - To move towards universal access to health, the Pan American Health Organization recommends strengthening primary health care (PHC). One of the strategies is to increase the number qualified professionals, both medical and non-medical, working in PHC. In Chile there is a lack of professionals in this level of care, hampering the provision of health. Physicians still prefer secondary and tertiary levels of health. International experience has shown that advanced practice nurses (APN), specialists in PHC are cost-effective professionals able to deliver a complete and quality care to patients. Strong evidence demonstrates the benefits that APN could provide to the population, delivering nursing care that incorporates medical tasks, for example in patients with chronic diseases, allowing greater availability of medical hours for patients requiring more complex management. The success in the implementation of this new role requires the support of the health team, especially PHC physicians, endorsing and promoting the benefits of the APN for the population. PMID- 28074986 TI - [Recommendations for the management of pancreatic cancer type adenocarcinoma: A consensus statement reached during the 2015 Latin American Symposium on Gastroenterological Oncology]. AB - Pancreatic cancer is a malignancy of great impact in developed countries and is having an increasing impact in Latin America. Incidence and mortality rates are similar for this cancer. This is an important reason to offer to the patients the best treatments available. During the Latin American Symposium of Gastroenterology Oncology (SLAGO) held in Vina del Mar, Chile, in April 2015, a multidisciplinary group of specialists in the field met to discuss about this disease. The main conclusions of this meeting, where practitioners from most of Latin American countries participated, are listed in this consensus that seek to serve as a guide for better decision making for patients with pancreatic cancer in Latin America. PMID- 28074988 TI - [What is human infection with Zika virus?] PMID- 28074989 TI - [Antidepressants agents in breast cancer patients using tamoxifen: review of basic and clinical evidence]. AB - Tamoxifen (Tmf), is a standard of care for women with estrogen receptor positive (ER+) breast cancer. Endoxifen is a Tmf metabolite generated by cytochrome P450 2D6 (CYP2D6). Antidepressive agents (AD) are often prescribed to women with breast cancer not only for depression, but also for anxiety and hot flashes. Some AD are substrates or inhibitors of the Tmf metabolic pathway. Therefore there may be interactions when Tmf and AD are prescribed simultaneously. Oncologic protection afforded by Tmf may become less effective or null when AD are indicated, especially in poor metabolizing patients. We performed an update of the literature about the criteria for choosing AD in women receiving Tmf. Tricyclic AD, paroxetine and fluoxetine should be avoided in patients receiving Tmf, because they are strong inhibitors of CYP2D6. Bupropion, duloxetine and sertraline are only moderate inhibitors of the cytochrome and are not contraindicated. Citalopram, desvenlafaxine, escitalopram, milnacipran and venlafaxine are recommended, because they do not influence the metabolism and clinical efficacy of Tmf and have fewer drug interactions. However, other additional pharmacological and clinical issues should be considered when choosing an antidepressant in women with breast cancer. PMID- 28074990 TI - [Assessment of patients' capacity to give a valid consent]. AB - Autonomy is an inherent condition of every ethical act. This attribution is expressed, when decisions are made, as capacity. Physician-patient alliance is defied when there is a reasonable doubt of patients' ability to make a choice, an extraordinarily complex scenario. As a response, in the last few decades multiple tools have been developed aiming to determine in a standardized fashion whether capacity is present or not. In the present article, we present a classification of the most well-known tools and discuss their usefulness, the implications for standardization of capacity, and make recommendations for their use, based in evidence. PMID- 28074991 TI - [Factors affecting the educational environment in undergraduate medical schools]. AB - BACKGROUND: Educational environment has an important effect on the quality of learning and student satisfaction in medicine. Most of previous studies have been conducted using questionnaires that assess the phenomenon considering overall dimensions, without paying attention to the specific manifestations of this topic, especially those aspects that are related to the protagonists of the learning process: teachers and students. AIM: To describe factors that affect the educational environment in the preclinical Medical formation, according to Medical teachers in Concepcion, Chile. MATERIAL AND METHODS: Qualitative study, using the Grounded theory method. Semi-structured interviews were performed to 10 medical teachers in Concepcion, Chile. They were selected by theoretical sampling. Data were analyzed using open coding. RESULTS: Four emerging categories about the factors that affect the learning environment were identified: Personal factors of students, academic factors of students, personal factors of teachers and academic factors of teachers. CONCLUSIONS: According to interviewed teachers, both personal factors in teachers and students that promote a positive learning environment are related with an attitude oriented towards others and communication skills. Academic factors are related with the responsible exercise of student and teacher roles and with the promotion of participation in the educational process. PMID- 28074992 TI - [Antineutrophil cytoplasmic antibody (ANCA) associated renal vasculitis and pregnancy: Report of one case]. AB - ANCA mediated vasculitis mainly occur between the fourth and fifth decade of life; therefore, it is very uncommon to see pregnant patients with the disease. Vasculitis may affect significantly the course of pregnancy; in turn pregnancy can change the course of vasculitis. We report a 20 years old woman with ANCA mediated renal vasculitis lasting 10 years who consulted with a pregnancy of 15 weeks. She was in remission and had amenorrhea attributed to ovarian toxicity due to cyclophosphamide. Pregnancy had an uneventful course with spontaneous delivery at the 37th week, giving birth to a healthy newborn. Proteinuria increased during the course of pregnancy with a mild deterioration of kidney function. During the year after delivery, she had nephrotic proteinuria and a worsening of renal function. PMID- 28074993 TI - [Fatal interstitial lung disease associated with maximum androgen blockade]. AB - Maximum androgen blockade is the standard endocrine treatment for advanced prostate cancer. Interstitial lung disease in different degrees of severity, with low mortality and excellent response to treatment may appear with its use. We report a 77 years old patient with advanced prostate cancer who developed severe and progressive respiratory failure associated to bilateral pulmonary infiltrates, attributed to the direct effect of maximum androgen blockade. Despite the therapeutic efforts, the patient died. Lung pathology revealed Usual Interstitial Pneumonia. PMID- 28074994 TI - [Normoglycemic diabetic ketoacidosis in pregnancy: Report of one case]. AB - Normoglycemic diabetic ketoacidosis should be suspected in pregnant women presenting nausea, vomiting, abdominal pain and anorexia. We report a 39 years old woman with a 32 weeks pregnancy who sought emergency care due to hyperemesis. She was hospitalized with the following diagnoses: pregnancy hypertension syndrome, gestational diabetes, morbid obesity and poor prenatal control. The evaluation of the feto-placental unit showed perception of fetal movements, non reactive non-stress baseline record and a biophysical profile of 6/8. Fetal maturation was initiated. Laboratory tests showed a metabolic acidosis, a low pH, an increased Gap anion, elevated ketonemia and a blood glucose of 172 mg/dl. A diagnosis of normoglycemic diabetic ketoacidosis was formulated and treatment with hydration and regular insulin according to capillary blood glucose levels was started. An emergency caesarean section was performed. The newborn weighed 2.650 kg, had a length of 46 cm, was large for gestational age, had an Apgar score of 2.7, had perinatal asphyxia, convulsive syndrome and a possible congenital cardiopathy. Once the ketoacidosis was resolved during the immediate puerperium, slow acting insulin was initiated. PMID- 28074995 TI - [Chilean Healthcare Professionals? Perception of Knowledge about Dementia]. PMID- 28074996 TI - [Older adults and hiv: beyond risk perception]. PMID- 28074997 TI - [Classification of idiopathic generalised epilepsies in patients over 16 years of age]. AB - INTRODUCTION: Idiopathic generalised epilepsies (IGE) are a set of electroclinical syndromes with different phenotypes. Our aim is to analyse those phenotypes in patients over 16 years of age. PATIENTS AND METHODS: We conducted a retrospective analysis of a series of patients with IGE. They were classified as childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), epilepsy with tonic-clonic seizures only (TCSE), epilepsy with eyelid myoclonias and absences (EMA) and pure photogenic epilepsy (PE). RESULTS: We included 308 patients, the majority females (56.8%), in our study. JME was the most prevalent (40.9%), followed by TCSE (30%), JAE (10%), EMA (8.7%), CAE (7.7%) and PE (1.6%). The types of seizures presented by the most patients were tonic-clonic (89.6%), myoclonic (45.4%), absence (31.4%), reflex seizures (13.3%), eyelid myoclonias (12.6%), non-epileptic psychogenic seizures (3.6%) and status epilepticus (1.9%). They all had generalised spike-and-wave discharges in the electroencephalogram (EEG). 19.2% presented asymmetrical discharges and 28.2% showed a photoparoxysmal response. We observed differences between syndromes in polytherapy (p < 0.0001), withdrawal of therapy (p = 0.01) and being seizure-free beyond the age of 50 (p = 0.004). CONCLUSIONS: JME was the most frequent. Generalised tonic-clonic seizures were the type of seizures presented by the most patients, followed by myoclonic, absent and reflex seizures. The EEG showed a photoparoxysmal response in over a quarter of the patients, and one in five displayed asymmetrical anomalies. Differences were observed according to the syndrome in polytherapy, persistence of seizures and withdrawal of treatment. PMID- 28074998 TI - [Prognostic factors of functional recovery from a stroke at one year]. AB - INTRODUCTION: Recovery of the ability to walk and independence is fundamental for any patient who suffers a stroke, and it can be influenced by a number of factors. AIM: To determine what variables are more important to achieve a good functional recovery at one year after the stroke. PATIENTS AND METHODS: An observational, longitudinal prospective study was conducted with 231 patients diagnosed with a stroke in the year 2013. An analysis was performed of the clinical characteristics, socio-demographic data, neurological situation at the time of hospitalisation -National Institute of Health Stroke Scale (NIHSS)-, functional situation (Rankin Scale and Barthel Index) and ability to walk, both on hospitalisation and on discharge from rehabilitation and at one year. RESULTS: The mean age was 74.26 +/- 13.1 years, and 55.4% were males. The mean length of stay in hospital was 16.24 days. 68.9% followed rehabilitation therapy, with an average of 95.5 sessions. Good functional capacity was recovered by 51.7% at one year (Rankin < 2 and Barthel > 85), and 63.5% regained the ability to walk independently. The factors that had the most significant influence on functional and gait recovery at one year were: lower age, NIHSS score < 10 in the first week, the type of stroke (small vessel), the absence of atrial fibrillation and better previous functional situation. CONCLUSION: At one year of having suffered a stroke, most of the patients recover the capacity for independent gait and to a lesser extent independence in activities of daily living. PMID- 28074999 TI - [Predictive value of cerebellar growth and general movements assessments for neurodevelopment of very preterm infants at 18-24 months' corrected age]. AB - INTRODUCTION: Fidgety movements assessments is very sensitive predicting long term outcome or cerebral palsy of preterm, disrupted cerebellar growth has been reported in these patients. AIM: To compare the predictive value of cerebellar ultrasound growth and fidgety movements assessments, for neurodevelopment outcome of very preterm at 18-24 month's corrected age (CA). SUBJECTS AND METHODS: Prospective study of 88 infants cohort (<= 32 weeks' gestation), transverse cerebellar diameter was obtained by ultrasound via mastoid fontanel, in a weekly basis, until 40 weeks CA. Fidgety movements were assessed at 3 months CA. Neurodevelopment outcome at 18-24 month's CA was evaluated in 68 using Schedule of Growing Skills II Scale (SGS-II) and Amiel-Tison Neurologic Assessment (ATNA). RESULTS: At term age, cerebellar growth was under 3rd percentile in 11 (10.3%). Fidgety movements were normal in 42 (61.8%) and abnormal or absent in 7 (10.3%). At 18-24 months CA, 54 (79.4%) were normal by the SGS-II and in 6 (8.8%) ATNA classified as cerebral palsy. Cerebellar diameter under 3rd percentile at term was associated with abnormal motor outcome and normal fidgety movements correlated with normal neurodevelopment. CONCLUSION: Ultrasound cerebellar measurements and functional examinations (fidgety movements) have important complementary roles in predicting neurodevelopment of very preterm. PMID- 28075000 TI - [Bromocriptine: could it be the cure for post-surgical akinetic mutism?] AB - INTRODUCTION: Akinetic mutism is considered as an alteration of the motivational state of the person, which the patient is unable to initiate verbal or motor responses voluntary, even with preserved sensorimotor and surveillance functions. CASE REPORT: A 43 year-old male involved in a cerebellum arteriovenous fistula complicated with hydrocephalus, who responded dramatically to treatment with bromocriptine. CONCLUSION: Typically, akinetic mutism is described as a transient surgeries posterior fossa. However, it can also occur after multiple valvular failure in patients with hydrocephalus. PMID- 28075001 TI - [Proposed model of executive functions based on factorial analyses]. AB - INTRODUCTION: Since Lezak coined the term executive functions to refer to the mental capabilities that are considered essential for performing efficacious, creative and socially acceptable behaviour, they have gradually grown in importance in neuropsychological research. Different models have been proposed to explain their nature, but there is no general agreement as to whether we are dealing with a unitary construct or a multimodal processing system with independent, but interconnected, components. With the aim of gaining a deeper knowledge of the structure of this construct, researchers have conducted lesion, neuroimaging and, more recently, factorial analysis studies, the latter being seen as a promising methodology for expanding our knowledge about such a generic concept as the executive functions. DEVELOPMENT: The purpose of this study is to carry out a systematic review of factorial models of attention and executive control in adults, between the years 1991 and 2016, using the PubMed, OvidSP and PsycINFO databases. Altogether, 33 papers were reviewed. Based on the literature, an integrating proposal of the executive functions is put forward. CONCLUSIONS: Although we do not have just one single model that can account for the complexity of the executive functions, there does seem to be general agreement on their multidimensionality. In factorial analyses, there is strong evidence of updating, inhibition and alternation, although there are also studies that propose novel factors. Our integrating proposal aims to combine the executive processes found in the literature with their corresponding neuroanatomical correlates, and defends the stance that the ideal methodology should use information from lesion studies, neuroimaging techniques and psychometric-computational models. PMID- 28075003 TI - [XVIII Reunion Anual de la Sociedad Extremena de Neurologia. Communications]. PMID- 28075002 TI - [Why do we call the brain 'brain'?] AB - INTRODUCTION: Every day millions of professionals use a countless number of technical words to refer to the different structures inside the skull. But few of them would know how to explain their origin. In this study we take an in-depth look into the etymological origins of some of these neuroanatomical terms. DEVELOPMENT: The study takes an etymological tour of the central nervous system. It is in no way meant to be an exhaustive, detailed review of the terms currently in use, but instead a means to familiarise the reader with the linguistic past of words like brain, hippocampus, thalamus, claustrum, fornix, corpus callosum or limbic system. All of them come from either Greek or Latin, which were used for centuries as the lingua francas of science. The study also analyses the evolution of the word meninges, originally of Greco-Latin origin, although its current usages derive from Arabic. CONCLUSIONS: The neuroanatomical terms that are in use today do not come from words that associate a particular brain structure with its function, but instead from words that reflect the formal or conceptual similarity between a structure and a familiar or everyday entity (for example, an object or a part of the human body). In other cases, these words indicate the spatial location of the neuroanatomical structure with respect to a third, or they may be terms derived from characters in Greco-Latin mythology. PMID- 28075004 TI - [Trigeminal neuropathy with atypical pain as the presenting symptom of contralateral meningioma of the posterior fossa]. PMID- 28075005 TI - [Syringomyelias in paediatrics]. PMID- 28075006 TI - Georgiy Shulman 1929-2016. PMID- 28075007 TI - Transition to market economy promotes individualistic values: Analysing changes in frequencies of Russian words from 1980 to 2008. AB - Google Books Ngram was used to assess changes in frequency of usage in words corresponding to collectivistic and individualistic values in Russia during the time of economic changes. It was found that in many domains transition to market economy was associated with a rise in the use of words corresponding to individualistic values and a decrease in the use of words associated with collectivistic values. In several cases, words corresponding to collectivistic terms were used more often than words corresponding to individualistic values. The results suggest that economic changes lead to a change in values structure, but that individualistic and collectivistic values can co-exist because of the transitional sate of the Russian society. PMID- 28075008 TI - Promising anti-tumor properties of bisdemethoxycurcumin: A naturally occurring curcumin analogue. AB - Curcuminoids are turmeric-extracted phytochemicals with documented chemopreventive and anti-tumor activities against several types of malignancies. Curcuminoids can modulate several molecular pathways and cellular targets involved in different stages of tumor initiation, growth, and metastasis. Bisdemethoxycurcumin (BDMC) is a minor constituent (approximately 3%) of curcuminoids that has been shown to be more stable than the other two main curcuminoids, that is, curcumin and demthoxycurcumin. Recent studies have revealed that BDMC has anti-tumor effects exerted through a multimechanistic mode of action involving inhibition of cell proliferation, invasion and migration, metastasis and tumour growth, and induction of apoptotic death in cancer cells. The present review discusses the findings on the anti-tumor effects of BDMC, underlying mechanisms, and the relevance of finding for translational studies in human. PMID- 28075009 TI - The physiological costs of prey switching reinforce foraging specialization. AB - Sympatric speciation is thought to be strongly linked to resource specialization with alternative resource use acting as a fundamental agent driving divergence. However, sympatric speciation through niche expansion is dependent on foraging specialization being consistent over space and time. Standard metabolic rate is the minimal maintenance metabolic rate of an ectotherm in a post-absorptive and inactive state and can constitute a significant portion of an animal's energy budget; thus, standard metabolic rate and growth rate are two measures frequently used as an indication of the physiological performance of individuals. Physiological adaptations to a specific diet may increase the efficiency with which it is utilized, but may have an increased cost associated with switching diets, which may result in a reduced standard metabolic rate and growth rate. In this study, we use the diet specialization often seen in polymorphic Arctic charr (Salvelinus alpinus) populations to study the effects of different prey on standard metabolic rate and growth rate as well as the effects that early prey specialization may have on the ability to process other prey types efficiently. We found a significant effect of prey type on standard metabolic rate and growth rate. Furthermore, we found evidence of diet specialization with all fish maintaining a standard metabolic rate and growth rate lower than expected when fed on a diet different to which they were raised, possibly due to a maladaptation in digestion of alternative prey items. Our results show that early diet specialization may be reinforced by the elevated costs of prey switching, thus promoting the process of resource specialization during the incipient stages of sympatric divergence. PMID- 28075010 TI - Stimulatory actions of a novel thiourea derivative on large-conductance, calcium activated potassium channels. AB - In this study, we examine whether an anti-inflammatory thiourea derivative, compound #326, actions on ion channels. The effects of compound #326 on Ca2+ activated K+ channels were evaluated by patch-clamp recordings obtained in cell attached, inside-out or whole-cell configuration. In pituitary GH3 cells, compound #326 increased the amplitude of Ca2+ -activated K+ currents (IK(Ca) ) with an EC50 value of 11.6 MUM, which was reversed by verruculogen, but not tolbutamide or TRAM-34. Under inside-out configuration, a bath application of compound #326 raised the probability of large-conductance Ca2+ -activated K+ (BKCa ) channels. The activation curve of BKCa channels was shifted to less depolarised potential with no modification of the gating charge of the curve; consequently, the difference of free energy was reduced in the presence of this compound. Compound #326-stimulated activity of BKCa channels is explained by a shortening of mean closed time, despite its inability to alter single-channel conductance. Neither delayed-rectifier nor erg-mediated K+ currents was modified. Compound #326 decreased the peak amplitude of voltage-gated Na+ current with no clear change in the overall current-voltage relationship of this current. In HEK293T cells expressing alpha-hSlo, compound #326 enhanced BKCa channels effectively. Intriguingly, the inhibitory actions of compound #326 on interleukin 1beta in lipopolysaccharide-activated microglia were significantly reversed by verruculogen, whereas BKCa channel inhibitors suppressed the expressions of inducible nitric oxide synthase. The BKCa channels could be an important target for compound #326 if similar in vivo results occur, and the multi-functionality of BKCa channels in modulating microglial immunity merit further investigation. PMID- 28075011 TI - The changing contribution of top-down and bottom-up limitation of mesopredators during 220 years of land use and climate change. AB - Apex predators may buffer bottom-up driven ecosystem change, as top-down suppression may dampen herbivore and mesopredator responses to increased resource availability. However, theory suggests that for this buffering capacity to be realized, the equilibrium abundance of apex predators must increase. This raises the question: will apex predators maintain herbivore/mesopredator limitation, if bottom-up change relaxes resource constraints? Here, we explore changes in mesopredator (red fox Vulpes vulpes) abundance over 220 years in response to eradication and recovery of an apex predator (Eurasian lynx Lynx lynx), and changes in land use and climate which are linked to resource availability. A three-step approach was used. First, recent data from Finland and Sweden were modelled to estimate linear effects of lynx density, land use and winter temperature on fox density. Second, lynx density, land use and winter temperature was estimated in a 22 650 km2 focal area in boreal and boreo-nemoral Sweden in the years 1830, 1920, 2010 and 2050. Third, the models and estimates were used to project historic and future fox densities in the focal area. Projected fox density was lowest in 1830 when lynx density was high, winters cold and the proportion of cropland low. Fox density peaked in 1920 due to lynx eradication, a mesopredator release boosted by favourable bottom-up changes - milder winters and cropland expansion. By 2010, lynx recolonization had reduced fox density, but it remained higher than in 1830, partly due to the bottom-up changes. Comparing 1830 to 2010, the contribution of top-down limitation decreased, while environment enrichment relaxed bottom-up limitation. Future scenarios indicated that by 2050, lynx density would have to increase by 79% to compensate for a projected climate driven increase in fox density. We highlight that although top-down limitation in theory can buffer bottom-up change, this requires compensatory changes in apex predator abundance. Hence apex predator recolonization/recovery to historical levels would not be sufficient to compensate for widespread changes in climate and land use, which have relaxed the resource constraints for many herbivores and mesopredators. Variation in bottom-up conditions may also contribute to context dependence in apex predator effects. PMID- 28075012 TI - Rare ecomorphological convergence on a complex adaptive landscape: Body size and diet mediate evolution of jaw shape in squirrels (Sciuridae). AB - Convergence is widely regarded as compelling evidence for adaptation, often being portrayed as evidence that phenotypic outcomes are predictable from ecology, overriding contingencies of history. However, repeated outcomes may be very rare unless adaptive landscapes are simple, structured by strong ecological and functional constraints. One such constraint may be a limitation on body size because performance often scales with size, allowing species to adapt to challenging functions by modifying only size. When size is constrained, species might adapt by changing shape; convergent shapes may therefore be common when size is limiting and functions are challenging. We examine the roles of size and diet as determinants of jaw shape in Sciuridae. As expected, size and diet have significant interdependent effects on jaw shape and ecomorphological convergence is rare, typically involving demanding diets and limiting sizes. More surprising is morphological without ecological convergence, which is equally common between and within dietary classes. Those cases, like rare ecomorphological convergence, may be consequences of evolving on an adaptive landscape shaped by many-to-many relationships between ecology and function, many-to-one relationships between form and performance, and one-to-many relationships between functionally versatile morphologies and ecology. On complex adaptive landscapes, ecological selection can yield different outcomes. PMID- 28075013 TI - Prevalence, geographic distribution and phenotypic differences of Piscirickettsia salmonis EM-90-like isolates. AB - Early reports accounted for two main genotypes of Piscirickettsia salmonis, a fish pathogen and causative agent of piscirickettsiosis, placing the single isolate EM-90 apart from the prototypic LF-89 and related isolates. In this study, we provide evidence that, contrary to what has been supposed, the EM-90 like isolates are highly prevalent and disseminated across Chilean marine farms. Molecular analysis of 507 P. salmonis field isolates derived from main rearing areas, diverse hosts and collected over 6 years, revealed that nearly 50% of the entire collection were indeed typed as EM-90-like. Interestingly, these isolates showed a marked host preference, being recovered exclusively from Atlantic salmon (Salmo salar) samples. Although both strains produce undistinguishable pathological outcomes, differences regarding growth kinetics and susceptibility to the antibiotics and bactericidal action of serum could be identified. In sum, our results allow to conclude that the EM-90-like isolates represent an epidemiologically relevant group in the current situation of piscirickettsiosis. Based on the consistency between genotype and phenotype exhibited by this strain, we point out the need for genotypic studies that may be as important for the Chilean salmon industry as the continuous surveillance of antimicrobial susceptibility patterns. PMID- 28075014 TI - Knockdown of REV3 synergizes with ATR inhibition to promote apoptosis induced by cisplatin in lung cancer cells. AB - It has been demonstrated that REV3, the catalytic subunit of the translesion synthesis (TLS) polymerase zeta, play an important role in DNA damage response (DDR) induced by cisplatin, and Ataxia-telangietasia mutated and Rad-3-related (ATR) knase is a central player in activating cell cycle checkpoint, stabilizing replication forks, regulating DDR, and promoting repair of DNA damage caused by cisplatin. Cancer cells deficient in either one of REV3 and ATR are more sensitive to cisplatin. However, whether co-inhibition of REV3 and ATR can further increase sensitivity of non-small cell lung cancer (NSCLC) cells to cisplatin is not clear. In this study, we show that REV3 knockdown combined with ATR inhibition further enhance cytotoxicity of cisplatin in NSCLC cells, including cisplatin-sensitive and -resistant cell lines, compared to individual knockdown of REV3 or ATR, which are accompanied by markedly caspase-dependent apoptosis response, pronounced DNA damage accumulation and severe impediment of interstrand crosslink (ICL), and double strand break (DSB) repair. Our results suggest that REV3 knockdown synergize strongly with ATR inhibition to significantly increase sensitivity of cisplatin in NSCLC cells by inhibiting ICL and DSB repair. Thus simultaneously targeting REV3 and ATR may represent one approach to overcome cisplatin resistance and improve chemotherapeutic efficacy in NSCLC treatment. PMID- 28075015 TI - Leaf emergence (phyllochron index) and leaf expansion response to soil drying in cowpea genotypes. AB - Drought can result in severely decreased leaf area development, which impacts plant growth and yield. However, rarely is leaf emergence or leaf expansion separated to resolve the relative sensitivity to water-deficit of these two processes. Experiments were undertaken to impose drought over approximately 2 weeks for eight cowpea (Vigna unguiculata) genotypes grown in pots under controlled environmental conditions. Daily measures of phyllochron index (PI, leaf emergence) and leaf area increase (leaf expansion) were obtained. Each of these measures was referenced against volumetric soil water content, i.e. fraction transpirable soil water. Although there was no clear difference between leaf emergence and leaf expansion in sensitivity to drying soil, both processes were more sensitive to soil drying than plant transpiration rate. Genotypic differences in the soil water content at the initiation of the decline in PI were identified. However, no consistent difference in sensitivity to water-deficit in leaf expansion was found. The difference in leaf emergence among genotypes in sensitivity to soil drying can now be exploited to provide guidance for plant improvement and crop yield increase. PMID- 28075016 TI - Modulation of long-term endothelial-barrier integrity is conditional to the cross talk between Akt and Src signaling. AB - Although numerous studies have implicated Akt and Src kinases in vascular endothelial growth factor (VEGF) and Angiopoietin-1 (Ang-1)-induced endothelial barrier regulation, a link between these two pathways has never been demonstrated. We determined the long-term effects of Akt inhibition on Src activity and vice versa, and in turn, on the human microvascular endothelial cell (HMEC) barrier integrity at the basal level, and in response to growth factors. Our data showed that Akt1 gene knockdown increases gap formation in HMEC monolayer at the basal level. Pharmacological inhibition of Akt, but not Src resulted in exacerbated VEGF-induced vascular leakage and impaired Ang-1-induced HMEC-barrier protection in vitro at 24 hr. Whereas inhibition of Akt had no effect on VEGF-induced HMEC gap formation in the short term, inhibition of Src blunted this process. In contrast, inhibition of Akt disrupted the VEGF and Ang-1 stabilized barrier integrity in the long-term while inhibition of Src did not. Interestingly, both long-term Akt inhibition and Akt1 gene knockdown in HMECs resulted in increased Tyr416 phosphorylation of Src. Treatment of HMECs with transforming growth factor-beta1 (TGFbeta1) that inhibited Akt Ser473 phosphorylation in the long-term, activated Src through increased Tyr416 phosphorylation and decreased HMEC-barrier resistance. The effect of TGFbeta1 on endothelial-barrier breakdown was blunted in Akt1 deficient HMEC monolayers, where endothelial-barrier resistance was already impaired compared to the control. To our knowledge, this is the first report demonstrating a direct cross talk between Akt and Src in endothelial-barrier regulation. PMID- 28075017 TI - Intrapopulation variability in the timing of ontogenetic habitat shifts in sea turtles revealed using delta15 N values from bone growth rings. AB - Determining location and timing of ontogenetic shifts in the habitat use of highly migratory species, along with possible intrapopulation variation in these shifts, is essential for understanding mechanisms driving alternate life histories and assessing overall population trends. Measuring variations in multi year habitat-use patterns is especially difficult for remote oceanic species. To investigate the potential for differential habitat use among migratory marine vertebrates, we measured the naturally occurring stable nitrogen isotope (delta15 N) patterns that differentiate distinct ocean regions to create a 'regional isotope characterization', analysed the delta15 N values from annual bone growth layer rings from dead-stranded animals, and then combined the bone and regional isotope data to track individual animal movement patterns over multiple years. We used humeri from juvenile North Pacific loggerhead turtles (Caretta caretta), animals that undergo long migrations across the North Pacific Ocean (NPO), using multiple discrete regions as they develop to adulthood. Typical of many migratory marine species, ontogenetic changes in habitat use throughout their decades-long juvenile stage is poorly understood, but each potential habitat has unique foraging opportunities and spatially explicit natural and anthropogenic threats that could affect key life-history parameters. We found a bimodal size/age distribution in the timing that juveniles underwent an ontogenetic habitat shift from the oceanic central North Pacific (CNP) to the neritic east Pacific region near the Baja California Peninsula (BCP) (42.7 +/- 7.2 vs. 68.3 +/- 3.4 cm carapace length, 7.5 +/- 2.7 vs. 15.6 +/- 1.7 years). Important to the survival of this population, these disparate habitats differ considerably in their food availability, energy requirements and threats, and these differences can influence life-history parameters such as growth, survival and future fecundity. This is the first evidence of alternative ontogenetic shifts and habitat-use patterns for juveniles foraging in the eastern NPO. We combine two techniques, skeletochronology and stable isotope analysis, to reconstruct multi-year habitat use patterns of a remote migratory species, linked to estimated ages and body sizes of individuals, to reveal variable ontogeny during the juvenile life stage that could drive alternate life histories and that has the potential to illuminate the migration patterns for other species with accretionary tissues. PMID- 28075018 TI - C-Met as a potential target for the treatment of gastrointestinal cancer: Current status and future perspectives. AB - Aberrant activation of the HGF/c-Met signalling pathways is shown to be related with cell proliferation, progression, metastasis, and worse prognosis in several tumor types, including gastrointestinal cancers, suggesting its value as a stimulating-target for cancer-therapy. Several approaches have been developed for targeting HGF and/or c-Met, and one of them, crizotinib (dual c-Met/ALK inhibitor), is recently been approved by FDA for lung-cancers with ALK rearrangement. The main aim of current review is to give an overview on the role of c-Met/HGF pathway in gastrointestinal cancer, in preclinical and clinical trials. Although several important matters is still remained to be elucidated on the molecular pathways underlying the antitumor effects of this therapy in gastrointestinal-cancers. Further investigations are warranted to recognize the main determinants of the activity of c-Met inhibitors, for parallel targeting signalling pathway associated/activated via MET/HGF pathway or in response to the cell resistance to anti-c-Met agents. Additionally, identification of patients that might benefit from therapy could help to increase the selectivity and efficacy of the therapy. PMID- 28075019 TI - Differential Recruitment of Brain Regions During Response Inhibition in Children Prenatally Exposed to Alcohol. AB - BACKGROUND: Response inhibition is a distinct aspect of executive function that is frequently impaired in children with fetal alcohol spectrum disorders (FASD). We used a Go/NoGo (GNG) task in a functional MRI protocol to investigate differential activation of brain regions in the response inhibition network in children diagnosed with full or partial fetal alcohol syndrome (FAS/PFAS), compared with healthy controls. METHODS: A rapid, event-related task with 120 Go and 60 NoGo trials was used to study children aged 8 to 12 years-8 with FAS/PFAS, 17 controls. Letters were projected sequentially, with Go and NoGo trials randomly interspersed across the task. BOLD signal in the whole brain was contrasted for the correct NoGo minus correct Go trials between the FAS/PFAS and control groups. RESULTS: Compared to the FAS/PFAS group, controls showed greater activation of the inferior frontal and anterior cingulate network linked to response inhibition in typically developing children. By contrast, the FAS/PFAS group showed greater BOLD response in dorsolateral prefrontal cortex and other middle prefrontal regions, suggesting compensation for inefficient function of pathways that normally mediate inhibitory processing. All group differences were significant after control for potential confounding variables. None of the effects of prenatal alcohol exposure on activation of the regions associated with response inhibition were attributable to the effects of this exposure on IQ. CONCLUSIONS: This is the first FASD GNG study in which all participants in the exposed group met criteria for a diagnosis of full FAS or PFAS. Although FASD is frequently comorbid with attention deficit hyperactivity disorder, the pattern of brain activation seen in these disorders differs, suggesting that different neural pathways mediate response inhibition in FASD and that different interventions for FASD are, therefore, warranted. PMID- 28075021 TI - Ablative fractional laser resurfacing: A powerful tool to help restore form and function during international medical exchange. PMID- 28075020 TI - Adenosine receptors regulate gap junction coupling of the human cerebral microvascular endothelial cells hCMEC/D3 by Ca2+ influx through cyclic nucleotide gated channels. AB - KEY POINTS: Gap junction channels are essential for the formation and regulation of physiological units in tissues by allowing the lateral cell-to-cell diffusion of ions, metabolites and second messengers. Stimulation of the adenosine receptor subtype A2B increases the gap junction coupling in the human blood-brain barrier endothelial cell line hCMEC/D3. Although the increased gap junction coupling is cAMP-dependent, neither the protein kinase A nor the exchange protein directly activated by cAMP were involved in this increase. We found that cAMP activates cyclic nucleotide-gated (CNG) channels and thereby induces a Ca2+ influx, which leads to the increase in gap junction coupling. The report identifies CNG channels as a possible physiological link between adenosine receptors and the regulation of gap junction channels in endothelial cells of the blood-brain barrier. ABSTRACT: The human cerebral microvascular endothelial cell line hCMEC/D3 was used to characterize the physiological link between adenosine receptors and the gap junction coupling in endothelial cells of the blood-brain barrier. Expressed adenosine receptor subtypes and connexin (Cx) isoforms were identified by RT-PCR. Scrape loading/dye transfer was used to evaluate the impact of the A2A and A2B adenosine receptor subtype agonist 2-phenylaminoadenosine (2 PAA) on the gap junction coupling. We found that 2-PAA stimulated cAMP synthesis and enhanced gap junction coupling in a concentration-dependent manner. This enhancement was accompanied by an increase in gap junction plaques formed by Cx43. Inhibition of protein kinase A did not affect the 2-PAA-related enhancement of gap junction coupling. In contrast, the cyclic nucleotide-gated (CNG) channel inhibitor l-cis-diltiazem, as well as the chelation of intracellular Ca2+ with BAPTA, or the absence of external Ca2+ , suppressed the 2-PAA-related enhancement of gap junction coupling. Moreover, we observed a 2-PAA-dependent activation of CNG channels by a combination of electrophysiology and pharmacology. In conclusion, the stimulation of adenosine receptors in hCMEC/D3 cells induces a Ca2+ influx by opening CNG channels in a cAMP-dependent manner. Ca2+ in turn induces the formation of new gap junction plaques and a consecutive sustained enhancement of gap junction coupling. The report identifies CNG channels as a physiological link that integrates gap junction coupling into the adenosine receptor-dependent signalling of endothelial cells of the blood-brain barrier. PMID- 28075022 TI - The mechanistic basis for photobiomodulation therapy of neuropathic pain by near infrared laser light. AB - BACKGROUND AND OBJECTIVE: Various irradiances have been reported to be beneficial for the treatment of neuropathic pain with near infrared light. However, the mechanistic basis for the beneficial outcomes may vary based on the level of irradiance or fluence rate used. Using in vivo and in vitro experimental models, this study determined the mechanistic basis of photobiomodulation therapy (PBMT) for the treatment of neuropathic pain using a high irradiance. STUDY DESIGN/MATERIALS AND METHODS: In vitro experiments: Cultured, rat DRG were randomly assigned to control or laser treatment (LT) groups with different irradiation times (2, 5, 30, 60, or 120 seconds). The laser parameters were: output power = 960 mW, irradiance = 300 mW/cm2 , 808 nm wavelength, and spot size = 3 cm diameter/area = 7.07cm2 , with different fluences according to irradiation times. Mitochondrial metabolic activity was measured with the MTS assay. The DRG neurons were immunostained using a primary antibody to beta-Tubulin III. In vivo experiments: spared nerve injury surgery (SNI), an animal model of persistent peripheral neuropathic pain, was used. The injured rats were randomly divided into three groups (n = 5). (i) Control: SNI without LT; (ii) Short term: SNI with LT on day 7 and euthanized on day 7; (iii) Long term: SNI with LT on day 7 and euthanized on day 22. An 808 nm wavelength laser was used for all treatment groups. Treatment was performed once on day 7 post-surgery. The transcutaneous treatment parameters were: output power: 10 W, fluence rate: 270 mW/cm2 , treatment time: 120 seconds. The laser probe was moved along the course of the sciatic/sural nerve during the treatment. Within 1 hour of irradiation, behavior tests were performed to assess its immediate effect on sensory allodynia and hyperalgesia caused by SNI. RESULTS: In vitro experiments: Mitochondrial metabolism was significantly lower compared to controls for all LT groups. Varicosities and undulations formed in neurites of DRG neurons with a cell body diameter 30 um or less. In neurites of DRG neurons with a cell body diameter of greater than 30 um, varicosities formed only in the 120 seconds group. In vivo experiments: For heat hyperalgesia, there was a statistically significant reduction in sensitivity to the heat stimulus compared to the measurements done on day 7 prior to LT. A decrease in the sensitivity to the heat stimulus was found in the LT groups compared to the control group on days 15 and 21. For cold allodynia and mechanical hyperalgesia, a significant decrease in sensitivity to cold and pin prick was found within 1 hour after LT. Sensitivity to these stimuli returned to the control levels after 5 days post-LT. No significant difference was found in mechanical allodynia between control and LT groups for all time points examined. CONCLUSION: These in vitro and in vivo studies indicate that treatment with an irradiance/fluence rate at 270 mW/cm2 or higher at the level of the nerve can rapidly block pain transmission. A combination therapy is proposed to treat neuropathic pain with initial high irradiance/fluence rates for fast pain relief, followed by low irradiance/fluence rates for prolonged pain relief by altering chronic inflammation. Lasers Surg. Med. 49:516-524, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28075023 TI - Classifying Gestational Weight Gain Trajectories Using the SITAR Growth Model. AB - BACKGROUND: Gestational weight gain is often characterized by the total amount of weight gained during pregnancy, however, the pattern of gain may be an important determinant of health outcomes. The SITAR (Super Imposition by Translation And Rotation) model has been used to describe childhood growth trajectories and has appeal because of the biological interpretability of its parameters. The objective of this study was to determine the feasibility of applying this model to gestational weight gain trajectories. METHODS: The study cohort included 3470 normal-weight, overweight, and obese women delivering at Magee-Womens Hospital in Pittsburgh, Pennsylvania, 1998 to 2010. We applied the SITAR model, a non-linear mixed effects model, to serial prenatal weight gain measurements in each pre pregnancy body mass index (BMI) category. We fit models of varying complexity, and chose the best-fitting model to describe the pattern of weight gain (by its absolute amount, timing, and acceleration) for each BMI group. RESULTS: The most complex SITAR models failed to converge, but reduced models could successfully be fit by specifying fewer random effects and simplifying the modelling of gestational age. Best-fitting models for each BMI group explained between 95% and 97% of the variation in weight gain trajectories. Peak rates of weight gain were reached between the 20th and 22nd weeks, and were higher for normal and overweight women (0.59 kg/week and 0.57 kg/week, respectively) than obese women (0.46 kg/week). CONCLUSIONS: Following some modifications, the SITAR model can be used to characterize pregnancy weight gain patterns. PMID- 28075024 TI - Uncovering iron regulation with species-specific transcriptome patterns in Atlantic and coho salmon during a Caligus rogercresseyi infestation. AB - Salmon species cultured in Chile evidence different levels of susceptibility to the sea louse Caligus rogercresseyi. These differences have mainly been associated with specific immune responses. Moreover, iron regulation seems to be an important mechanism to confer immunity during the host infestation. This response called nutritional immunity has been described in bacterial infections, despite that no comprehensive studies involving in marine ectoparasites infestation have been reported. With this aim, we analysed the transcriptome profiles of Atlantic and coho salmon infected with C. rogercresseyi to evidence modulation of the iron metabolism as a proxy of nutritional immune responses. Whole transcriptome sequencing was performed in samples of skin and head kidney from Atlantic and coho salmon infected with sea lice. RNA-seq analyses revealed significant upregulation of transcripts in both salmon species at 7 and 14 dpi in skin and head kidney, respectively. However, iron regulation transcripts were differentially modulated, evidencing species-specific expression profiles. Genes related to heme degradation and iron transport such as hepcidin, transferrin and haptoglobin were primary upregulated in Atlantic salmon; meanwhile, in coho salmon, genes associated with heme biosynthesis were strongly transcribed. In summary, Atlantic salmon, which are more susceptible to infestation, presented molecular mechanisms to deplete cellular iron availability, suggesting putative mechanisms of nutritional immunity. In contrast, resistant coho salmon were less affected by sea lice, mainly activating pro-inflammatory mechanisms to cope with infestation. PMID- 28075025 TI - Warmer temperatures reduce the influence of an important keystone predator. AB - Predator-prey interactions may be strongly influenced by temperature variations in marine ecosystems. Consequently, climate change may alter the importance of predators with repercussions for ecosystem functioning and structure. In North eastern Pacific kelp forests, the starfish Pycnopodia helianthoides is known to be an important predator of the purple sea urchin Strongylocentrotus purpuratus. Here we investigated the influence of water temperature on this predator-prey interaction by: (i) assessing the spatial distribution and temporal dynamics of both species across a temperature gradient in the northern Channel Islands, California, and (ii) investigating how the feeding rate of P. helianthoides on S. purpuratus is affected by temperature in laboratory tests. On average, at sites where mean annual temperatures were <14 degrees C, P. helianthoides were common, S. purpuratus was rare and kelp was persistent, whereas where mean annual temperatures exceeded 14 degrees C, P. helianthoides and kelp were rare and S. purpuratus abundant. Temperature was found to be the primary environmental factor influencing P. helianthoides abundance, and in turn P. helianthoides was the primary determinant of S. purpuratus abundance. In the laboratory, temperatures >16 degrees C (equivalent to summer temperatures at sites where P. helianthoides were rare) reduced predation rates regardless of predator and prey sizes, although larger sea urchins were consumed only by large starfishes. These results clearly demonstrate that the effect of P. helianthoides on S. purpuratus is strongly mediated by temperature, and that the local abundance and predation rate of P. helianthoides on sea urchins will likely decrease with future warming. A reduction in top-down control on sea urchins, combined with other expected impacts of climate change on kelp, poses significant risks for the persistence of kelp forests in the future. PMID- 28075026 TI - Updating histological data on crown initiation and crown completion ages in southern Africans. AB - OBJECTIVES: To update histological data on crown initiation and completion ages in southern Africans. To evaluate implications of these data for studies that: (a) rely on these data to time linear enamel hypoplasias (LEHs), or, (b) use these data for comparison to fossil hominins. MATERIALS AND METHODS: Initiation ages were calculated on 67 histological sections from southern Africans, with sample sizes ranging from one to 11 per tooth type. Crown completion ages for southern Africans were calculated in two ways. First, actual derived initiation ages were added to crown formation times for each histological section to obtain direct information on the crown completion ages of individuals. Second, average initiation ages from this study were added to average crown formation times of southern Africans from the Reid and coworkers previous studies that were based on larger samples. RESULTS: For earlier-initiating tooth types (all anterior teeth and first molars), there is little difference in ages of initiation and crown completion between this and previous studies. Differences increase as a function of initiation age, such that the greatest differences between this and previous studies for both initiation and crown completion ages are for the second and third molars. DISCUSSION: This study documents variation in initiation ages, particularly for later-initiating tooth types. It upholds the use of previously published histological aging charts for LEHs on anterior teeth. However, this study finds that ages of crown initiation and completion in second and third molars for this southern African sample are earlier than previously estimated. These earlier ages reduce differences between modern humans and fossil hominins for these developmental events in second and third molars. PMID- 28075027 TI - A novel missense mutation in NR0B1 causes delayed-onset primary adrenal insufficiency in adults. AB - A novel missense mutation (c.775T>C; p.ser259Pro) in the NROBI gene cause a late onset adrenal insufficiency without hypogonadism. PMID- 28075028 TI - A recognizable type of syndromic short stature with arthrogryposis caused by bi allelic SEMA3A loss-of-function variants. AB - The semaphorins constitute a large family of secreted and membrane-associated proteins that regulate many developmental processes, including neural circuit assembly, bone formation and angiogenesis. Recently, bi-allelic loss-of-function variants in SEMA3A (semaphorin 3A) were identified in a single patient with a particular pattern of multiple congenital anomalies (MCA). Using homozygosity mapping combined with exome sequencing, we identified a homozygous SEMA3A variant causing a premature stop codon in an 8 year old boy with the same pattern of MCA. The phenotype of these patients is characterized by postnatal short stature, skeletal anomalies of the thorax, a minor congenital heart or vascular defect, camptodactyly, micropenis, and variable additional anomalies. Motor development is delayed in both patients, and intellectual development is delayed in one patient. Our observation of a second case supports the notion that bi-allelic mutations in SEMA3A cause an autosomal recessive type of syndromic short stature. PMID- 28075029 TI - Does cortical bone thickness in the last sacral vertebra differ among tail types in primates? AB - OBJECTIVES: The external morphology of the sacrum is demonstrably informative regarding tail type (i.e., tail presence/absence, length, and prehensility) in living and extinct primates. However, little research has focused on the relationship between tail type and internal sacral morphology, a potentially important source of functional information when fossil sacra are incomplete. Here, we determine if cortical bone cross-sectional thickness of the last sacral vertebral body differs among tail types in extant primates and can be used to reconstruct tail types in extinct primates. MATERIALS AND METHODS: Cortical bone cross-sectional thickness in the last sacral vertebral body was measured from high-resolution CT scans belonging to 20 extant primate species (N = 72) assigned to tail type categories ("tailless," "nonprehensile short-tailed," "nonprehensile long-tailed," and "prehensile-tailed"). The extant dataset was then used to reconstruct the tail types for four extinct primate species. RESULTS: Tailless primates had significantly thinner cortical bone than tail-bearing primates. Nonprehensile short-tailed primates had significantly thinner cortical bone than nonprehensile long-tailed primates. Cortical bone cross-sectional thickness did not distinguish between prehensile-tailed and nonprehensile long-tailed taxa. Results are strongly influenced by phylogeny. Corroborating previous studies, Epipliopithecus vindobonensis was reconstructed as tailless, Archaeolemur edwardsi as long-tailed, Megaladapis grandidieri as nonprehensile short-tailed, and Palaeopropithecus kelyus as nonprehensile short-tailed or tailless. CONCLUSIONS: Results indicate that, in the context of phylogenetic clade, measures of cortical bone cross-sectional thickness can be used to allocate extinct primate species to tail type categories. PMID- 28075030 TI - Erythropoietic protoporphyria a clinical and molecular study from Lebanon: Ferrochelatase a potential tumor suppressor gene in colon cancer. AB - Erythropoietic protoporphyria (EPP) is a rare cutaneous and systemic disease caused by mutations in the ferrochelatase gene (FECH). The molecular underpinnings of EPP in Middle Eastern populations and relative to other ethnic groups secondary to increased consanguinity are unknown. To understand the molecular pathogenesis of Middle Eastern EPP, we surveyed clinicopathological and molecular features in 6 large consanguineous families from Lebanon and Syria presenting with cutaneous and systemic features consistent with EPP. We observed 30% increased liver disease and 20% elevated end-stage liver complications in our EPP cohort compared to EPP patients previously reported elsewhere. In addition, Middle Eastern EPP patients in our cohort exhibited uniquely an increased incidence of colon cancer. Sequence analysis revealed 2 novel non-synonymous FECH mutations in the studied families designated p.M294T and p.I230M. In addition, FECH activity was significantly decreased (6%) in fibroblasts obtained from sun exposed sites in a patient with p.M294T mutation, whereas in sharp contrast, protected sites from the same patient exhibited 54% activity for the gene. We also found that sun-exposed fibroblasts, relative to sun-protected and control fibroblasts, exhibited suppressed growth and atypical morphology in vitro, and that these effects were alleviated when the cells were co-cultured with sun protected fibroblasts. Our findings on the increased incidence of colon cancer in EPP patients prompted us to survey FECH expression patterns in cancer. Using publicly available microarray datasets we found that FECH mRNA was largely significantly decreased in colon adenocarcinomas relative to normal colon tissues. Our findings suggest that families with autosomal recessive EPP should be screened more extensively for systemic involvement including liver diseases and colon cancer, and point to a previously unknown yet plausible tumor suppressor role for FECH in colon malignancy. PMID- 28075031 TI - Angiotropic syringomatous carcinoma. AB - Syringomatous carcinoma (SC) is a slow-growing malignant skin tumor that usually affects the face or scalp. An 83-year-old female developed SC on the sole, a rare location. Histopathologically, numerous ducts with few keratinizing cysts were seen in the upper dermis, and cords, strands and nests with sclerotic stroma were seen in the deep dermis and subcutis. In addition to the perineural and intraneural invasion of the tumor, the tumor cells had also invaded the vessel walls. There was no intravasation of tumor cells or interruption of the endothelium. Because melanoma with vascular wall invasion without intravasation of melanoma cells or interruption of the endothelium has been called angiotropic melanoma, we termed the present tumor angiotropic SC. Tumor cells showed wide local invasion. PMID- 28075032 TI - Microbiological findings and antibacterial therapy in Stevens-Johnson syndrome/toxic epidermal necrolysis patients from a Swedish Burn Center. AB - BACKGROUND: Superimposed infections/sepsis are the major cause of morbidity/mortality in Stevens-Johnson syndrome/Toxic Epidermal Necrolysis (SJS/TEN). It is a delicate balance between avoiding new pharmaceuticals and prophylactically treat an incipient infection. The objective of this study was to investigate the rates and types of infection-microbials and antibiotics involved in SJS/TEN patients. MATERIALS AND METHODS: Microbiology and clinical data were collected for SJS/TEN patients admitted to our Burn Center from January 2010 through January 2016. RESULTS: A total of 24 patients were admitted over the study period. There were 303 bacterial cultures taken whereof 113 (37.3%) were positive (median of 4.4 per patient). Twenty-two (91.7%) patients had at least 1 positive sample recorded. Fifteen (62.5%) patients had a confirmed episode of sepsis with skin being the most common source of colonization (77.8%). Eleven (45.8%) patients received empiric antibiotic therapy at referral facility/prior to admission to our Center. Patients who grew a higher number of different species were significantly less likely to have received early empiric antimicrobial therapy (P < .001). CONCLUSION: Secondary bacterial infection and sepsis were a highly common finding in our patient population. Despite the risk of resistance and further immunological provocation, empirical antibiotic treatment might have a place in clinical management. PMID- 28075033 TI - 3D Printing of Transparent and Conductive Heterogeneous Hydrogel-Elastomer Systems. AB - A hydrogel-dielectric-elastomer system, polyacrylamide and poly(dimethylsiloxane) (PDMS), is adapted for extrusion printing for integrated device fabrication. A lithium-chloride-containing hydrogel printing ink is developed and printed onto treated PDMS with no visible signs of delamination and geometrically scaling resistance under moderate uniaxial tension and fatigue. A variety of designs are demonstrated, including a resistive strain gauge and an ionic cable. PMID- 28075034 TI - Abdominal lean muscle is associated with lower mortality among kidney waitlist candidates. AB - Morphometric assessments, such as muscle density and body fat distribution, have emerged as strong predictors of cardiovascular risk and postoperative morbidity and mortality. To date, no study has examined morphometric mortality risk prediction among kidney transplant (KT) candidates. KT candidates, waitlisted 2008-2009, were identified (n=96) and followed to the earliest of transplant, death, or administrative end of study. Morphometric measures, including abdominal adipose tissue, paraspinous and psoas muscle composition, and aortic calcification, were measured from CTs. Risk of waitlist mortality was examined using Cox proportional hazard regression. On adjusted analyses, radiologic measures remained independently and significantly associated with lower waitlist mortality; the addition of radiologic measures significantly improved model predictive ability over models containing traditional risk factors alone (net reclassification index: 0.56, 95% CI: 0.31-0.75). Higher psoas muscle attenuation (indicative of leaner muscle) was associated with decreased risk of death (aHR: 0.93, 95% CI: 0.91-0.96, P<.001), and for each unit increase in lean paraspinous volume, there was an associated 2% decreased risk for death (aHR: 0.98, 95% CI: 0.96-0.99, P=.03). Radiologic measures of lean muscle mass, such as psoas muscle attenuation and paraspinous lean volume, may improve waitlist mortality risk prediction and candidate selection. PMID- 28075035 TI - Direct Observations of Nanofilament Evolution in Switching Processes in HfO2 Based Resistive Random Access Memory by In Situ TEM Studies. AB - Resistive switching processes in HfO2 are studied by electron holography and in situ energy-filtered imaging. The results show that oxygen vacancies are gradually generated in the oxide layer under ramped electrical bias, and finally form several conductive channels connecting the two electrodes. It also shows that the switching process occurs at the top interface of the hafnia layer. PMID- 28075036 TI - Double trouble: A case of periprocedural detection of intracardiac thrombus and aortic root dissection during emergent transfemoral TAVR. AB - We report a case of emergency transcatheter aortic valve replacement (TAVR) in a 65-year-old patient presenting with decompensated severe aortic stenosis. Transesophageal echocardiography (TEE) was used effectively to obtain measurements of the aortic annulus and for intra-procedural guidance. At baseline, we detected a left atrial appendage thrombus and a localized aortic root dissection after balloon valvuloplasty. The case highlights the important role that TEE may play during TAVR procedures. PMID- 28075037 TI - Gauging the response to cardiac resynchronization therapy: The important interplay between predictor variables and definition of a favorable outcome. AB - AIMS: Selection of patients who are viable candidates for cardiac resynchronization therapy (CRT), prediction of the response to CRT as well as an optimal definition of a favorable response, all require further exploration. The purpose of this study was to evaluate the interplay between the prediction of the response to CRT and the definition of a favorable outcome. METHODS: Seventy patients who received CRT were included. All patients met current guideline criteria for CRT. Forty-three echocardiographic parameters were evaluated before CRT and at 1, 3, 6, and 12 months. M-mode, 2D echocardiography, and Doppler imaging were used to quantify left ventricular (LV) systolic and diastolic function, mitral regurgitation, right ventricular systolic function, pulmonary artery pressure, and myocardial mechanical dyssynchrony. The following definitions of a favorable CRT response were used: left ventricular ejection fraction (LVEF) improvement more >5% acutely following CRT, LVEF improvement >20% at 12-month follow-up, and a LV end-systolic volume (LVESV) decrease >15% at 12 month follow-up. RESULTS: For the LVEF improvement >5%, the best predictor was isovolumetric relaxation time (IVRT; P=.035). For improvement of LVEF >20%, the best predictors were left ventricular stroke index (LVSI; P=.044) and left ventricular fractional shortening (LVFS; P=.031). For the drop in left ventricular systolic volume (LVESV >15%), the best predictor was septal-to lateral wall delay (DeltaT) (P=.043, RR=1.023, 95% CI for RR=1.001-1.045). CONCLUSION: The definition of a favorable CRT response influenced the optimal predictor variable(s). Standardization of defining a favorable response to CRT is needed to guide clinical decision making processes. PMID- 28075038 TI - Effect of aerobic exercise on cancer-associated cognitive impairment: A proof-of concept RCT. AB - BACKGROUND: Change in cognitive ability is a commonly reported adverse effect by breast cancer survivors. The underlying etiology of cognitive complaints is unclear and to date, there is limited evidence for effective intervention strategies. Exercise has been shown to improve cognitive function in older adults and animal models treated with chemotherapy. This proof-of-concept randomized controlled trial tested the effect of aerobic exercise versus usual lifestyle on cognitive function in postmenopausal breast cancer survivors. METHODS: Women, aged 40 to 65 years, postmenopausal, stages I to IIIA breast cancer, and who self reported cognitive dysfunction following chemotherapy treatment, were recruited and randomized to a 24-week aerobic exercise intervention (EX; n = 10) or usual lifestyle control (CON; n = 9). Participants completed self-report measures of the impact of cognitive issues on quality of life (Functional Assessment of Cancer Therapy-Cognitive version 3), objective neuropsychological testing, and functional magnetic resonance imaging at baseline and 24 weeks. RESULTS: Compared to CON, EX had a reduced time to complete a processing speed test (trail making test-A) (-14.2 seconds, P < .01; effect size 0.35). Compared to CON, there was no improvement in self-reported cognitive function and effect sizes were small. Interestingly, lack of between-group differences in Stroop behavioral performance was accompanied by functional changes in several brain regions of interest in EX compared to CON at 24 weeks. CONCLUSION: These findings provide preliminary proof of-concept results for the potential of aerobic exercise to improve cancer related cognitive impairment and will serve to inform the development of future trials. PMID- 28075039 TI - Using DNA barcoding to track seafood mislabeling in Los Angeles restaurants. AB - Seafood mislabeling is common in both domestic and international markets. Studies on seafood fraud often report high rates of mislabeling (e.g., >70%), but these studies have been limited to a single sampling year, which means it is difficult to assess the impact of stricter governmental truth-in-labeling regulations. We used DNA barcoding to assess seafood labeling in 26 sushi restaurants in Los Angeles over 4 years. Seafood from 3 high-end grocery stores were also sampled (n = 16) in 2014. We ordered 9 common sushi fish from menus, preserved tissue samples in 95% ethanol, extracted the genomic DNA, amplified and sequenced a portion of the mtDNA COI gene, and identified the resulting sequence to known fish sequences from the National Center for Biotechnology Information nucleotide database. We compared DNA results with the U.S. Food and Drug Administration (FDA) list of acceptable market names and retail names. We considered sushi sample labels that were inconsistent with FDA names mislabeled. Sushi restaurants had a consistently high percentage of mislabeling (47%; 151 of 323) from 2012 to 2015, yet mislabeling was not homogenous across species. Halibut, red snapper, yellowfin tuna, and yellowtail had consistently high (<77%) occurrences of mislabeling on menus, whereas mislabeling of salmon and mackerel were typically low (>15%). All sampled sushi restaurants had at least one case of mislabeling. Mislabeling of sushi-grade fish from high-end grocery stores was also identified in red snapper, yellowfin tuna, and yellowtail, but at a slightly lower frequency (42%) than sushi restaurants. Despite increased regulatory measures and media attention, we found seafood mislabeling continues to be prevalent. PMID- 28075040 TI - N-acetyl-seryl-aspartyl-lysyl-proline mediates the anti-fibrotic properties of captopril in unilateral ureteric obstructed BALB/C mice. AB - AIM: Angiotensin-converting enzyme inhibitors (ACEi) are widely used to deter the progression of chronic kidney disease (CKD). Besides controlling hypertension and reduction of intra-glomerular pressure, ACEi appear to have anti-fibrotic effects in the renal cortex. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), an endogenous tetrapeptide that is degraded by ACE, has also been shown to ameliorate the pro-fibrotic phenotype displayed in CKD in our recent study. Whether the anti-fibrotic properties of ACEi are mediated by Ac-SDKP has not been fully investigated. METHODS: To delineate the role of Ac-SDKP in ACE blockade, 12 week-old male BALB/c mice underwent sham operation or unilateral ureteric obstruction (UUO). UUO mice were subjected to: (i) vehicle; (ii) captopril or (iii) captopril in conjunction with S17092, a prolyl oligopeptidase inhibitor. After 7 days, mice were sacrificed and kidneys harvested for analyses. RESULTS: After UUO, there were heightened expressions of collagen I, collagen III, fibronectin and alpha-SMA associated with significant levels of tubulointerstitial injury on histological examination. Furthermore, p44/42 mitogen-activated protein kinase (MAPK) and transforming growth factor beta 1(TGF beta1) signalling were upregulated. These were significantly ameliorated by captopril treatment alone but unaffected by co-administration of captopril with S17092. Captopril treatment had resulted in elevated urinary Ac-SDKP levels, an effect that was eliminated by the co-administration with S17092. CONCLUSION: This study allowed the investigation of the renoprotective property of ACEi in the absence of Ac-SDKP and proved conclusively that Ac-SDKP is the prime anti fibrotic mediator of captopril, acting via p44/42 MAPK and TGF-beta1 signalling pathways. Future research to expand CKD armamentarium should explore the utility of augmenting Ac-SDKP levels. PMID- 28075041 TI - Engineering matrix-free laser desorption ionization mass spectrometry using glancing angle deposition films. AB - RATIONALE: Thin, nanoporous films fabricated using Glancing Angle Deposition (GLAD) technology are demonstrated for solid matrix laser desorption/ionization mass spectrometry (SMALDI-MS). GLAD allows facile engineering of nanoporosity, film thickness, post alignment, and material composition, as demonstrated here by the fabrication of Co-GLAD and Si-GLAD films for SMALDI, and by exploration of the SMALDI performance as a function of thickness, post density, and angle of the post relative to surface normal. METHODS: GLAD films were prepared by electron beam evaporation onto silicon substrates, using steep angles of incidence for the vacuum deposition, with computer controlled substrate rotation. LDI from the GLAD films was evaluated using an MDS-Sciex time-of-flight (TOF) MALDI mass spectrometer. RESULTS: Co-GLAD films give a limit of quantitation of 6 fmol for complex carbohydrate derivatives, and slanted-post Si-GLAD films show up to three times higher sensitivity than vertical post structures. Reproducibility of both Si and Co films is much higher than conventional MALDI methods for m/z below at least 2100 Da. Both reproducibility and detection limits are comparable to or better than other nano-structured materials. Co-GLAD films are significantly better in performance than Co powders or Co thin films on silicon substrates previously evaluated. CONCLUSIONS: The flexibility of GLAD for thin film fabrication of LDI materials is demonstrated by the range of nanoporous materials that can be grown, and the fine control over structural conformation, thickness and porosity. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28075042 TI - Protein induced by vitamin K absence or antagonist II (PIVKA-II) producing large cell neuroendocrine carcinoma (LCNEC) of lung with multiple liver metastases: A case report. AB - A 78-year-old man was admitted to our hospital for multiple lung and liver tumors. Initial clinical diagnosis was hepatocellular carcinoma (HCC) with lung metastases because of a high value of serum protein induced by vitamin K absence or antagonist II (PIVKA-II) (6,705 mAU/mL). However, a review of a prior CT showed the lung tumor had existed 6 months before liver tumors were detected. The tumors progressed rapidly and the patient died 37 days after admission. Autopsy revealed that both lung and liver tumors exhibited the histology of large cell neuroendocrine carcinoma (LCNEC). Immunohistochemistry revealed that the tumor cells expressed not only neuroendocrine markers but also PIVKA-II diffusely. Hepatoid differentiation was not detected. Background liver did not show any chronic liver disease. The final diagnosis was PIVKA-II producing LCNEC of the lung with multiple liver metastases. PIVKA-II producing tumors other than HCC are extremely rare. To our best knowledge, this is the first case report of PIVKA-II producing neuroendocrine tumors of the lung. PMID- 28075043 TI - All-Organic Rechargeable Battery with Reversibility Supported by "Water-in-Salt" Electrolyte. AB - Rechargeable batteries with organic electrodes are preferred to those with transition-metal-containing electrodes for their environmental friendliness, and resource availability, but all such batteries reported to date are based on organic electrolytes, which raise concerns of safety and performance. Here an aqueous-electrolyte all-organic rechargeable battery is reported, with a maximum operating voltage of 2.1 V, in which polytriphenylamine (PTPAn) and 1,4,5,8 naphthalenetetracarboxylic dianhydride (NTCDA)-derived polyimide (PNTCDA) serve as cathode and anode material, respectively. A key feature of the design is use of a "water-in-salt" electrolyte to bind "free" water; this impedes the side reaction of water oxidation, thereby enabling excellent reversibility in aqueous solution. The battery can deliver a maximum energy density of 52.8 Wh kg-1 , which is close to most of the all-organic batteries with organic electrolytes. The battery exhibits a supercapacitor-like high power of 32 000 W kg-1 and a long cycle life (700 cycles with capacity retention of 85 %), due to the kinetics not being limited by ion diffusion at either electrode. PMID- 28075044 TI - Population impacts in white sucker (Catostomus commersonii) exposed to oil sands derived contaminants in the Athabasca River. AB - Biological and chemical endpoints were measured in white sucker collected downstream of Athabasca oil sands developments (AB, Canada) and compared with those at Calling Lake (AB, Canada), a reference location upstream of the Athabasca oil sands deposit. Naphthenic acid concentrations were also measured at 14 sites in the Athabasca River watershed. Concentrations of naphthenic acids were elevated in tributaries adjacent to oil sands mining developments. Tributary naphthenic acid profiles were more similar to aged oil sands process water than samples from the Athabasca River, suggesting an influence of tailings in the tributaries. White sucker showed higher energy storage in the Athabasca River as indicated by significantly higher condition and liver size. White sucker were not investing that energy into reproductive effort as measured by gonad size and fecundity, which were significantly reduced relative to the reference location. White sucker showed increased exposure to polycyclic aromatic hydrocarbons as indicated by hepatic cytochrome P4501A (CYP1A) activity and fluorescent bile metabolites, as well as higher concentrations of naphthenic acids in bile. Cadmium, copper, nickel, and selenium were also elevated in white sucker liver tissue compared with the reference location. Based on the exposure profile and response pattern observed, effects on energy storage and utilization in white sucker from the Athabasca River most likely resulted from exposure to polycyclic aromatic hydrocarbons derived from petrogenic and pyrolytic sources. Environ Toxicol Chem 2017;36:2058-2067. (c) 2017 SETAC. PMID- 28075045 TI - Interplay Between Long Noncoding RNA ZEB1-AS1 and miR-200s Regulates Osteosarcoma Cell Proliferation and Migration. AB - In our previous study, we found long noncoding RNA ZEB1-AS1 is upregulated and functions as an oncogene in osteosarcoma. MiR-200 family (miR-200s) functions as tumor suppressor via directly targeting ZEB1 in various cancers. In this study, we further investigate the potential interplay between ZEB1-AS1, miR-200s, and ZEB1 in osteosarcoma. Our results showed that ZEB1-AS1 functions as a molecular sponge for miR-200s and relieves the inhibition of ZEB1 caused by miR-200s. ZEB1 AS1 and miR-200s reciprocally negatively regulate each other. MiR-200s are downregulated in osteosarcoma tissues, and negatively correlated with ZEB1-AS1 and ZEB1 expression levels in osteosarcoma. Functional experiments showed that consistent with ZEB1-AS1 depletion, miR-200s overexpression and ZEB1 depletion both inhibit osteosarcoma cell proliferation and migration. Overexpression of miR 200s partially abolished the effects of ZEB1-AS1 on osteosarcoma cell proliferation and migration. Moreover, the combination of ZEB1-AS1 depletion and miR-200s overexpression significantly inhibits osteosarcoma cell proliferation and migration. In conclusion, this study revealed a novel regulatory mechanism between ZEB1-AS1, miR-200s, and ZEB1. The interplay between ZEB1-AS1 and miR-200s contributes to osteosarcoma cell proliferation and migration, and targeting this interplay could be a promising strategy for osteosarcoma treatment. J. Cell. Biochem. 118: 2250-2260, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28075046 TI - Standardized fluoroscopy-based technique to measure intraoperative cup anteversion. AB - Direct anterior approach (DAA) with the patient lying supine has facilitated the use of intraoperative fluoroscopy and allows for standardized positioning of the patient. The current study presents a new technique to measure acetabular component anteversion using intraoperative fluoroscopy. The current paper describes a mathematical formula to calculate true acetabular component anteversion based on the acetabular component abduction angle and the c-arm tilt angle (CaT). The CaT is determined by tilting the c-arm until an external pelvic oblique radiograph with the equatorial plane of the acetabular component perpendicular to the fluoroscopy receptor is obtained. CaT is determined by direct reading on the C-arm device. The technique was validated using a radiopaque synbone model comparing the described technique to computed tomography anteversion measurement. The experiment was repeated 25 times. The difference in anteversion between the two measuring techniques was on average 0.2 degrees (range -3.0-3.1). The linear regression coefficients evaluating the agreement between the experimental and control methods were 0.99 (95%CI 0.88-1.10, p < 0.001) and 0.33 (95%CI -1.53-2.20, p = 0.713) for the slope and intercept, respectively. The current study confirms that the described three-step c-arm acetabular cup measuring technique can reproducibly and reliably assess acetabular component anteversion in the supine position, as compared to CT imaging. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2307-2312, 2017. PMID- 28075047 TI - Growing larger with domestication: a matter of physiology, morphology or allocation? AB - Domestication might affect plant size. We investigated whether herbaceous crops are larger than their wild progenitors, and the traits that influence size variation. We grew six crop plants and their wild progenitors under common garden conditions. We measured the aboveground biomass gain by individual plants during the vegetative stage. We then tested whether photosynthesis rate, biomass allocation to leaves, leaf size and specific leaf area (SLA) accounted for variations in whole-plant photosynthesis, and ultimately in aboveground biomass. Despite variations among crops, domestication generally increased the aboveground biomass (average effect +1.38, Cohen's d effect size). Domesticated plants invested less in leaves and more in stems than their wild progenitors. Photosynthesis rates remained similar after domestication. Variations in whole plant C gains could not be explained by changes in leaf photosynthesis. Leaves were larger after domestication, which provided the main contribution to increases in leaf area per plant and plant-level C gain, and ultimately to larger aboveground biomass. In general, cultivated plants have become larger since domestication. In our six crops, this occurred despite lower investment in leaves, comparable leaf-level photosynthesis and similar biomass costs of leaf area (i.e. SLA) than their wild progenitors. Increased leaf size was the main driver of increases in aboveground size. Thus, we suggest that large seeds, which are also typical of crops, might produce individuals with larger organs (i.e. leaves) via cascading effects throughout ontogeny. Larger leaves would then scale into larger whole plants, which might partly explain the increases in size that accompanied domestication. PMID- 28075048 TI - The STI and UBA Domains of UBQLN1 Are Critical Determinants of Substrate Interaction and Proteostasis. AB - There are five Ubiquilin proteins (UBQLN1-4, UBQLN-L), which are evolutionarily conserved and structurally similar. UBQLN proteins have three functional domains: N-terminal ubiquitin-like domain (UBL), C-terminal ubiquitin-associated domain (UBA), and STI chaperone-like regions in the middle. Alterations in UBQLN1 gene have been detected in a variety of disorders ranging from Alzheimer's disease to cancer. UBQLN1 has been largely studied in neurodegenerative disorders in the context of protein quality control. Several studies have hypothesized that the UBA domain of UBQLN1 binds to poly-ubiquitin chains of substrate and shuttles it to the proteasome via its UBL domain for degradation. UBQLN1 either facilitates degradation (Ataxin3, EPS15) or stabilizes (PSEN1/2, BCLb) substrates it binds to. The signal that determines this fate is unknown and there is conflicting data to support the existing working model of UBQLN1. Using BCLb as a model substrate, we characterized UBQLN1-substrate interaction. We identified the first two STI domains of UBQLN1 as critical for binding to BCLb. Interaction of UBQLN1 with BCLb is independent of ubiquitination of BCLb, but interaction with ubiquitin via UBA domain is required for stabilization of BCLb. Similarly, we showed that UBQLN1 interacts with IGF1R and ESYT2 through the STI domains and stabilizes these proteins through its UBA domain. Interactions that are not dependent on STI domains, for example, UBL mediated interaction with PSMD4 and BAG6, do not appear to be stabilized by UBQLN1. We conclude that fate of substrates that UBQLN1 associates with, is interaction domain specific. J. Cell. Biochem. 118: 2261 2270, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28075049 TI - Src Homology 2 Domain-Containing Inositol 5'-Phosphatase Ameliorates High Glucose Induced Extracellular Matrix Deposition via the Phosphatidylinositol 3 Kinase/Protein Kinase B Pathway in Renal Tubular Epithelial Cells. AB - A typical hallmark of diabetic kidney disease (DKD) is an excessive deposition of extracellular matrix (ECM) in the glomerulus and renal tubulointerstitium, leading to glomerulosclerosis and tubular interstitial fibrosis. Src homology 2 domain-containing inositol 5'-phosphatase (SHIP) is a negative regulator of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling. Here, we investigated the effect of SHIP on ECM deposition in diabetic mice and high glucose-stimulated human renal tubular epithelial cells (HK2 cells). The decreased SHIP and increased phospho-Akt (Ser 473, Thr 308) were found in the renal tubular cells of diabetic mice, which were accompanied by overexpression of transforming growth factor-beta1 (TGF-beta1), alpha-smooth muscle actin (alpha SMA), and secreted collagen type 3 (Col 3) and a low expression of E-cadherin compared to that in normal mice. In vitro research revealed that high glucose attenuated SHIP expression accompanied the activation of the PI3K/Akt signaling and ECM production. Knocking down SHIP in HK2 cells caused an increase in the levels of phospho-Akt (Ser 473), phospho-Akt (Thr 308), TGF-beta1, alpha-SMA, and secreted Col 3 and a decrease in E-cadherin. Again, either the M90-SHIP plasmid or the PI3K/Akt pathway inhibitor LY294002 could significantly prevent the high glucose-induced increase in TGF-beta1, alpha-SMA, and secreted Col 3 and decreased E-cadherin. Furthermore, we confirmed that inhibition of the TGF-beta1 pathway with SB431542 blocked the effect of SHIP knockdown on ECM production in HK2 cells. In summary, our study suggests that decreased SHIP mediates high glucose-induced TGF-beta1 upregulation and ECM deposition through activation of the PI3K/Akt pathway in renal tubular cells. J. Cell. Biochem. 118: 2271-2284, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28075050 TI - Formyl Peptide Receptors in Cellular Differentiation and Inflammatory Diseases. AB - Formyl peptide receptors (FPRs) are a family of classical chemoattractant receptors. Although FPRs are mainly expressed in phagocytic innate immune cells including monocytes/macrophages and neutrophils, recent reports demonstrated that additional different cell types such as T-lymphocytes and several non-immune cells also express functional FPRs. FPRs were first reported as a specific receptor to detect bacteria-derived N-formyl peptides. However, accumulating evidence has shown that FPRs can recognize various ligands derived from pathogens, mitochondria, and host. This review summarizes studies on some interesting endogenous agonists for FPRs. Here, we discuss functional roles of FPRs and their ligands concerning the regulation of cellular differentiation focusing on myeloid lineage cells. Accumulating evidence also suggests that FPRs may contribute to the control of inflammatory diseases. Here, we briefly review the current understanding of the functional role of FPRs and their ligands in inflammatory disorders in some animal disease models. J. Cell. Biochem. 118: 1300 1307, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28075051 TI - Bilateral multifocal upper extremity atypical granular cell tumors presenting as long-standing right wrist and left hand masses in a 15-year-old African-American female. AB - Granular cell tumor (GrCT) is a benign nerve sheath tumor. Atypical and malignant variants of GrCT are rare but have been well described. We report a case of multifocal symmetric atypical GrCT in the bilateral hand/wrists of a 15-year-old African-American female. The initial clinical impression for both masses was favored to be ganglion cysts. Ultrasound findings of both masses revealed hypoechoic soft tissue lesions with some internal echogenicity favoring complex cysts. On excision, both masses were histologically circumscribed, lobulated and attached to tendon. Large epithelioid cells with abundant granular eosinophilic cytoplasm arranged in syncytial cords and trabeculae percolated through collagen. Many cells had pleomorphism and/or prominent nucleoli. Mitotic figures, spindling, high nuclear-to-cytoplasmic ratio and necrosis were absent. Both masses showed diffuse S100 protein but negative desmin and pancytokeratin expression. Ki-67 index was 1% to 2%. p53 was positive in 5% to 10% of nuclei. Both masses met criteria for atypical (but not malignant) GrCT. Our case shows that atypical GrCT may be not only multifocal but also symmetric. We speculate that migration of defective neural crest stem cells along both upper limb buds during embryogenesis may have allowed these essentially identical tumors to arise in similar locations bilaterally simultaneously. PMID- 28075052 TI - Functional characterisation and cell specificity of BvSUT1, the transporter that loads sucrose into the phloem of sugar beet (Beta vulgaris L.) source leaves. AB - Sugar beet (Beta vulgaris L.) is one of the most important sugar-producing plants worldwide and provides about one third of the sugar consumed by humans. Here we report on molecular characterisation of the BvSUT1 gene and on the functional characterisation of the encoded transporter. In contrast to the recently identified tonoplast-localised sucrose transporter BvTST2.1 from sugar beet taproots, which evolved within the monosaccharide transporter (MST) superfamily, BvSUT1 represents a classical sucrose transporter and is a typical member of the disaccharide transporter (DST) superfamily. Transgenic Arabidopsis plants expressing the beta-GLUCURONIDASE (GUS) reporter gene under control of the BvSUT1 promoter showed GUS histochemical staining of their phloem; an anti-BvSUT1 antiserum identified the BvSUT1 transporter specifically in phloem companion cells. After expression of BvSUT1 cDNA in bakers' yeasts (Saccharomyces cerevisiae) uptake characteristics of the BvSUT1 protein were studied. Moreover, the sugar beet transporter was characterised as a proton-coupled sucrose symporter in Xenopus laevis oocytes. Our findings indicate that BvSUT1 is the sucrose transporter that is responsible for loading of sucrose into the phloem of sugar beet source leaves delivering sucrose to the storage tissue in sugar beet taproot sinks. PMID- 28075053 TI - Synthesis, Characterization and Immunological Evaluation of Self-Adjuvanting Group A Streptococcal Vaccine Candidates Bearing Various Lipidic Adjuvanting Moieties. AB - Four group A streptococcal glycolipopeptide vaccine candidates with different lipidic adjuvanting moieties were prepared and characterized. The immunogenicity of the compounds was evaluated by macrophage and dendritic cell uptake studies and by in vivo quantification of systemic IgG antibody by ELISA. Three of the candidates showed significant induction of the IgG response. PMID- 28075054 TI - Inkjet-Printed Lithium-Sulfur Microcathodes for All-Printed, Integrated Nanomanufacturing. AB - Improved thin-film microbatteries are needed to provide appropriate energy storage options to power the multitude of devices that will bring the proposed "Internet of Things" network to fruition (e.g., active radio-frequency identification tags and microcontrollers for wearable and implantable devices). Although impressive efforts have been made to improve the energy density of 3D microbatteries, they have all used low energy-density lithium-ion chemistries, which present a fundamental barrier to miniaturization. In addition, they require complicated microfabrication processes that hinder cost-competitiveness. Here, inkjet-printed lithium-sulfur (Li-S) cathodes for integrated nanomanufacturing are reported. Single-wall carbon nanotubes infused with electronically conductive straight-chain sulfur (S@SWNT) are adopted as an integrated current collector/active-material composite, and inkjet printing as a top-down approach to achieve thin-film shape control over printed electrode dimensions is used. The novel Li-S cathodes may be directly printed on traditional microelectronic semicoductor substrates (e.g., SiO2 ) or on flexible aluminum foil. Profilometry indicates that these microelectrodes are less than 10 um thick, while cyclic voltammetry analyses show that the S@SWNT possesses pseudocapacitive characteristics and corroborates a previous study suggesting the S@SWNT discharge via a purely solid-state mechanism. The printed electrodes produce ~800 mAh g-1 S initially and ~700 mAh g-1 after 100 charge/discharge cycles at C/2 rate. PMID- 28075056 TI - M1 aminopeptidases as drug targets: broad applications or therapeutic niche? AB - M1 aminopeptidase enzymes are a diverse family of metalloenzymes characterized by conserved structure and reaction specificity. Excluding viruses, M1 aminopeptidases are distributed throughout all phyla, and have been implicated in a wide range of functions including cell maintenance, growth and development, and defense. The structure and catalytic mechanism of M1 aminopeptidases are well understood, and make them ideal candidates for the design of small-molecule inhibitors. As a result, many research groups have assessed their utility as therapeutic targets for both infectious and chronic diseases of humans, and many inhibitors with a range of target specificities and potential therapeutic applications have been developed. Herein, we have aimed to address these studies, to determine whether the family of M1 aminopeptidases does in fact present a universal target for the treatment of a diverse range of human diseases. Our analysis indicates that early validation of M1 aminopeptidases as therapeutic targets is often overlooked, which prevents the enzymes from being confirmed as drug targets. This validation cannot be neglected, and needs to include a thorough characterization of enzymes' specific roles within complex physiological pathways. Furthermore, any chemical probes used in target validation must be carefully designed to ensure that specificity over the closely related enzymes has been achieved. While many drug discovery programs that target M1 aminopeptidases remain in their infancy, certain inhibitors have shown promise for the treatment of a range of conditions including malaria, hypertension, and cancer. PMID- 28075055 TI - Argonaute 2 immunoprecipitation revealed large tumor suppressor kinase 1 as a novel proapoptotic target of miR-21 in T cells. AB - MicroRNA (miR)-21 is an important suppressor of T-cell apoptosis that is also overexpressed in many types of cancers. The exact mechanisms underlying the antiapoptotic effects of miR-21 are not well understood. In this study, we used the Jurkat T-cell line as a model to identify apoptosis-associated miR-21 target genes. We showed that expression of miR-21 rapidly increases upon alphaCD3/alphaCD28 activation of Jurkat cells. Inhibition of miR-21 reduced cell growth which could be explained by an increase in apoptosis. MicroRNA target gene identification by AGO2 RNA-immunoprecipitation followed by gene expression microarray (RIP-Chip) resulted in the identification of 72 predicted miR-21 target genes that were at least twofold enriched in the AGO2-IP fraction of miR 21 overexpressing cells. Of these, 71 were at least twofold more enriched in the AGO2-IP fraction of miR-21 overexpressing cells as compared to AGO2-IP fraction of control cells. The target gene for which the AGO2-IP enrichment was most prominently increased upon miR-21 overexpression was the proapoptotic protein LATS1. Luciferase reporter assays and western blot analysis confirmed targeting of LATS1 by miR-21. qRT-PCR analysis in primary T cells showed an inverse expression pattern between LATS1 transcript levels and miR-21 upon T-cell stimulation. Finally, LATS1 knockdown partially rescued the miR-21 inhibition induced impaired cell growth. Collectively, these data identify LATS1 as a miR-21 target important for the antiapoptotic function of miR-21 in T cells and likely also in many types of cancer. PMID- 28075057 TI - Two-Dimensional Nanomaterials for Cancer Nanotheranostics. AB - Emerging nanotechnologies show unprecedented advantages in accelerating cancer theranostics. Among them, two-dimensional nanomaterials (2DNMs) represent a novel type of material with versatile physicochemical properties that have enabled a new horizon for applications in both cancer diagnosis and therapy. Studies have demonstrated that 2DNMs may be used in diverse aspects, including i) cancer detection due to their high propensity towards tumor markers; ii) molecular imaging for guided tumor therapies, and iii) drug and gene loading, photothermal and photodynamic cancer therapies. However, their biomedical applications raise concerns due to the limited understanding of their in vivo metabolism, transformation and possible toxicities. In this comprehensive review, the state of-the-art development of 2DNMs and their implications for cancer nanotheranostics are presented. The modification strategies to enhance the biocompatibility of 2DNMs are also reviewed. PMID- 28075058 TI - MOF-Derived Hollow Cage Nix Co3-x O4 and Their Synergy with Graphene for Outstanding Supercapacitors. AB - Highly optimized nickel cobalt mixed oxide has been derived from zeolite imidazole frameworks. While the pure cobalt oxide gives only 178.7 F g-1 as the specific capacitance at a current density of 1 A g-1 , the optimized Ni:Co 1:1 has given an extremely high and unprecedented specific capacitance of 1931 F g-1 at a current density of 1 A g-1 , with a capacitance retention of 69.5% after 5000 cycles in a three electrode test. This optimized Ni:Co 1:1 mixed oxide is further used to make a composite of nickel cobalt mixed oxide/graphene 3D hydrogel for enhancing the electrochemical performance by virtue of a continuous and porous graphene conductive network. The electrode made from GNi:Co 1:1 successfully achieves an even higher specific capacitance of 2870.8 F g-1 at 1 A g-1 and also shows a significant improvement in the cyclic stability with 81% capacitance retention after 5000 cycles. An asymmetric supercapacitor is also assembled using a pure graphene 3D hydrogel as the negative electrode and the GNi:Co 1:1 as the positive electrode. With a potential window of 1.5 V and binder free electrodes, the capacitor gives a high specific energy density of 50.2 Wh kg 1 at a high power density of 750 W kg-1 . PMID- 28075059 TI - Photochemically Driven Polymeric Network Formation: Synthesis and Applications. AB - Polymeric networks have been intensely investigated and a large number of applications have been found in areas ranging from biomedicine to materials science. Network fabrication via light-induced reactions is a particularly powerful tool, since light provides ready access to temporal and spatial control, opening an array of synthetic access routes for structuring the network geometry as well as functionality. Herein, the most recent light-induced modular reactions and their use in the formation of precision polymeric networks are collated. The synthetic strategies including photoinduced thiol-based reactions, Diels-Alder systems, and photogenerated reactive dipoles, as well as photodimerizations, are discussed in detail. Importantly, applications of the fabricated networks via the aforementioned reactions are highlighted with selected examples. Concomitantly, we provide future directions for the field, emphasizing the most critically required advances. PMID- 28075060 TI - Self-Templated Synthesis of Co- and N-Doped Carbon Microtubes Composed of Hollow Nanospheres and Nanotubes for Efficient Oxygen Reduction Reaction. AB - A facile, self-templated strategy for the synthesis of Co- and N-doped carbon microtubular structures composed of nanoscale hollow spheres and nanotubes is proposed. Cobalt oxalate microtubes serve simultaneously as the solid cobalt precursor for the in situ conversion reaction to metal-organic framework and self templates for the 1D tubular structure. PMID- 28075061 TI - Constructing Post-Permeation Method to Fabricate Polymer/Nanocrystals Hybrid Solar Cells with PCE Exceeding 6. AB - A post-permeation method is constructed for fabricating bulk-heterojunction hybrid solar cells. Porous CdTe film is prepared by annealing the mixture solution of aqueous CdTe nanocrystals and cetyltrimethyl ammonium bromide, after which the post-permeation of polymer is employed. By this method, kinds of polymers can be applied regardless of the intermiscibility with the nanoparticles. The inorganic nanocrystals and the polymer can be treated under respective optimized annealing temperatures, which can facilitate the growth of nanocrystals without damaging the polymers. A high power conversion efficiency of 6.36% in the polymer/nanocrystals hybrid solar cells is obtained via systematical optimization. PMID- 28075063 TI - Well-Covered. PMID- 28075062 TI - Specific Arabidopsis thaliana malic enzyme isoforms can provide anaplerotic pyruvate carboxylation function in Saccharomyces cerevisiae. AB - NAD(P)-malic enzyme (NAD(P)-ME) catalyzes the reversible oxidative decarboxylation of malate to pyruvate, CO2 , and NAD(P)H and is present as a multigene family in Arabidopsis thaliana. The carboxylation reaction catalyzed by purified recombinant Arabidopsis NADP-ME proteins is faster than those reported for other animal or plant isoforms. In contrast, no carboxylation activity could be detected in vitro for the NAD-dependent counterparts. In order to further investigate their putative carboxylating role in vivo, Arabidopsis NAD(P)-ME isoforms, as well as the NADP-ME2del2 (with a decreased ability to carboxylate pyruvate) and NADP-ME2R115A (lacking fumarate activation) versions, were functionally expressed in the cytosol of pyruvate carboxylase-negative (Pyc- ) Saccharomyces cerevisiae strains. The heterologous expression of NADP-ME1, NADP ME2 (and its mutant proteins), and NADP-ME3 restored the growth of Pyc- S. cerevisiae on glucose, and this capacity was dependent on the availability of CO2 . On the other hand, NADP-ME4, NAD-ME1, and NAD-ME2 could not rescue the Pyc- strains from C4 auxotrophy. NADP-ME carboxylation activity could be measured in leaf crude extracts of knockout and overexpressing Arabidopsis lines with modified levels of NADP-ME, where this activity was correlated with the amount of NADP-ME2 transcript. These results indicate that specific A. thaliana NADP-ME isoforms are able to play an anaplerotic role in vivo and provide a basis for the study on the carboxylating activity of NADP-ME, which may contribute to the synthesis of C4 compounds and redox shuttling in plant cells. PMID- 28075065 TI - Sulfur-Immobilized, Activated Porous Carbon Nanotube Composite Based Cathodes for Lithium-Sulfur Batteries. AB - Activated highly porous carbon nanotubes are synthesized with a facile dual nozzle co-electrospinning and a redox process to apply the framework of a sulfur immobilized composite as a high-performance cathode in lithium-sulfur batteries. PMID- 28075064 TI - Efficacy of nebivolol-valsartan single-pill combination in obese and nonobese patients with hypertension. AB - Antihypertensive efficacy of single-pill combinations (SPCs) consisting of a beta1 -selective adrenergic blocker with vasodilatory properties via beta3 agonism (nebivolol) and an angiotensin II receptor blocker (valsartan) was demonstrated in an 8-week phase 3 trial (NCT01508026). In this post hoc analysis, seated blood pressure, heart rate, 24-hour ambulatory blood pressure monitoring, plasma aldosterone, estimated glomerular filtration rate, and safety measures were assessed in obese (body mass index >32 kg/m2 ; n=1823) and nonobese (body mass index <27 kg/m2 ; n=847) adults with hypertension (stage I or II) treated with nebivolol-valsartan SPCs, nebivolol or valsartan monotherapy, or placebo. At week 8, reductions from baseline in blood pressure and ambulatory blood pressure monitoring were greater with SPCs and most nebivolol and valsartan monotherapy doses vs placebo regardless of obesity status. Aldosterone declined with all active treatments and estimated glomerular filtration rate remained steady. The nebivolol-valsartan 5/80 mg/d SPC was efficacious regardless of degree of obesity. PMID- 28075067 TI - National implementation of a mental health service model: A survey of Crisis Resolution Teams in England. AB - In response to pressures on mental health inpatient beds and a perceived 'crisis in acute care', Crisis Resolution Teams (CRTs), acute home treatment services, were implemented nationally in England following the NHS Plan in the year 2000: an unprecedentedly prescriptive policy mandate for three new types of functional community mental health team. We examined the effects of this mandate on implementation of the CRT service model. Two hundred and eighteen CRTs were mapped in England, including services in all 65 mental health administrative regions. Eighty-eight percent (n = 192) of CRT managers in England participated in an online survey. CRT service organization and delivery was highly variable. Nurses were the only professional group employed in all CRT staff teams. Almost no teams adhered fully to government implementation guidance. CRT managers identified several aspects of CRT service delivery as desirable but not routinely provided. A national policy mandate and government guidance and standards have proved insufficient to ensure CRT implementation as planned. Development and testing of resources to support implementation and monitoring of a complex mental health intervention is required. PMID- 28075068 TI - Binding and processing of beta-lactam antibiotics by the transpeptidase LdtMt2 from Mycobacterium tuberculosis. AB - : beta-lactam antibiotics represent a novel direction in the chemotherapy of tuberculosis that brings the peptidoglycan layer of the complex mycobacterial cell wall in focus as a therapeutic target. Peptidoglycan stability in Mycobacterium tuberculosis, especially during infection, relies on the nonconventional peptide cross-links formed by l,d-transpeptidases. These enzymes are known to be inhibited by beta-lactams, primarily carbapenems, leading to a stable covalent modification at the enzyme active site. A panel of 16 beta-lactam antibiotics was characterized by inhibition kinetics, mass spectrometry, and x ray crystallography to identify efficient compounds and study their action on the essential transpeptidase, LdtMt2 . Members of the carbapenem class displayed fast binding kinetics, but faropenem, a penem type compound showed a three to four time higher rate in the adduct formation. In three cases, mass spectrometry indicated that carbapenems may undergo decarboxylation, while faropenem decomposition following the acylation step results in a small 87 Da beta-OH butyryl adduct bound at the catalytic cysteine residue. The crystal structure of LdtMt2 at 1.54 A resolution with this fragment bound revealed that the protein adopts a closed conformation that shields the thioester bond from the solvent, which is in line with the high stability of this dead-end complex observed also in biochemical assays. DATABASE: Structural data are available in Protein Data Bank under the accession numbers 5LB1 and 5LBG. PMID- 28075066 TI - Efficacy and safety of fixed-dose combination therapy, alogliptin plus metformin, in Asian patients with type 2 diabetes: A phase 3 trial. AB - This study evaluated the efficacy and safety of 26 weeks of twice-daily (BID) alogliptin + metformin fixed-dose combination (FDC) therapy in Asian patients with type 2 diabetes. Patients aged 18 to 75 years with hemoglobin A1c (HbA1c) of 7.5% to 10.0% after >=2 months of diet and exercise and a 4-week placebo run-in were enrolled. Eligible patients were randomized (1:1:1:1) to placebo, alogliptin 12.5 mg BID, metformin 500 mg BID or alogliptin 12.5 mg plus metformin 500 mg FDC BID. The primary endpoint was change in HbA1c from baseline to end of treatment (Week 26). In total, 647 patients were randomized. The least-squares mean change in HbA1c from baseline to Week 26 was -0.19% with placebo, -0.86% with alogliptin, -1.04% with metformin and -1.53% with alogliptin + metformin FDC. Alogliptin + metformin FDC was significantly more effective ( P < .0001) in lowering HbA1c than either alogliptin or metformin alone. The safety profile of alogliptin + metformin FDC was similar to that of the individual components alogliptin and metformin. The study demonstrated that treatment with alogliptin + metformin FDC BID resulted in better glycaemic control than either monotherapy and was well tolerated in Asian patients with type 2 diabetes. PMID- 28075069 TI - Ebola Vaccination Using a DNA Vaccine Coated on PLGA-PLL/gammaPGA Nanoparticles Administered Using a Microneedle Patch. AB - Ebola DNA vaccine is incorporated into PLGA-PLL/gammaPGA nanoparticles and administered to skin using a microneedle (MN) patch. The nanoparticle delivery system increases vaccine thermostability and immunogenicity compared to free vaccine. Vaccination by MN patch produces stronger immune responses than intramuscular administration. PMID- 28075070 TI - Celebrating 5 years of Advanced Healthcare Materials! PMID- 28075071 TI - Multitarget selection of catalytic antibodies with beta-lactamase activity using phage display. AB - beta-lactamase enzymes responsible for bacterial resistance to antibiotics are among the most important health threats to the human population today. Understanding the increasingly vast structural motifs responsible for the catalytic mechanism of beta-lactamases will help improve the future design of new generation antibiotics and mechanism-based inhibitors of these enzymes. Here we report the construction of a large murine single chain fragment variable (scFv) phage display library of size 2.7 * 109 with extended diversity by combining different mouse models. We have used two molecularly different inhibitors of the R-TEM beta-lactamase as targets for selection of catalytic antibodies with beta lactamase activity. This novel methodology has led to the isolation of five antibody fragments, which are all capable of hydrolyzing the beta-lactam ring. Structural modeling of the selected scFv has revealed the presence of different motifs in each of the antibody fragments potentially responsible for their catalytic activity. Our results confirm (a) the validity of using our two target inhibitors for the in vitro selection of catalytic antibodies endowed with beta lactamase activity, and (b) the plasticity of the beta-lactamase active site responsible for the wide resistance of these enzymes to clinically available inhibitors and antibiotics. PMID- 28075073 TI - Resolving the relationships of Paleocene placental mammals. AB - The 'Age of Mammals' began in the Paleocene epoch, the 10 million year interval immediately following the Cretaceous-Palaeogene mass extinction. The apparently rapid shift in mammalian ecomorphs from small, largely insectivorous forms to many small-to-large-bodied, diverse taxa has driven a hypothesis that the end Cretaceous heralded an adaptive radiation in placental mammal evolution. However, the affinities of most Paleocene mammals have remained unresolved, despite significant advances in understanding the relationships of the extant orders, hindering efforts to reconstruct robustly the origin and early evolution of placental mammals. Here we present the largest cladistic analysis of Paleocene placentals to date, from a data matrix including 177 taxa (130 of which are Palaeogene) and 680 morphological characters. We improve the resolution of the relationships of several enigmatic Paleocene clades, including families of 'condylarths'. Protungulatum is resolved as a stem eutherian, meaning that no crown-placental mammal unambiguously pre-dates the Cretaceous-Palaeogene boundary. Our results support an Atlantogenata-Boreoeutheria split at the root of crown Placentalia, the presence of phenacodontids as closest relatives of Perissodactyla, the validity of Euungulata, and the placement of Arctocyonidae close to Carnivora. Periptychidae and Pantodonta are resolved as sister taxa, Leptictida and Cimolestidae are found to be stem eutherians, and Hyopsodontidae is highly polyphyletic. The inclusion of Paleocene taxa in a placental phylogeny alters interpretations of relationships and key events in mammalian evolutionary history. Paleocene mammals are an essential source of data for understanding fully the biotic dynamics associated with the end-Cretaceous mass extinction. The relationships presented here mark a critical first step towards accurate reconstruction of this important interval in the evolution of the modern fauna. PMID- 28075072 TI - Use of erythrocyte indicators of health and condition in vertebrate ecophysiology: a review and appraisal. AB - We review evidence for and against the use of erythrocyte indicators of health status and condition, parasite infection level and physiological stress in free living vertebrates. The use of indicators that are measured directly from the blood, such as haemoglobin concentration, haematocrit and erythrocyte sedimentation rate, and parameters that are calculated from multiple measured metrics, such as mean cell volume, mean cell haemoglobin content or mean cell haemoglobin concentration is evaluated. The evidence for or against the use of any given metric is equivocal when the relevant research is considered in total, although there is sometimes strong support for using a particular metric in a particular taxon. Possibly the usefulness of these metrics is taxon, environment or condition specific. Alternatively, in an uncontrolled environment where multiple factors are influencing a metric, its response to environmental change will sometimes, but not always, be predictable. We suggest that (i) researchers should validate a metric's utility before use, (ii) multiple metrics should be used to construct an overall erythrocyte profile for an individual or population, (iii) there is a need for researchers to compile reference ranges for free-living species, and (iv) some metrics which are useful under controlled, clinical conditions may not have the same utility or applicability for free-living vertebrates. Erythrocyte metrics provide useful information about health and condition that can be meaningfully interpreted in free-living vertebrates, but their use requires careful forethought about confounding factors. PMID- 28075075 TI - Ten Sins of Office Medicine. PMID- 28075074 TI - Should We Fear the Unintended Consequences of MACRA? PMID- 28075076 TI - New Codes, New Payment Opportunities for 2017. PMID- 28075077 TI - Making Sense of MACRA, Part 2: Value-Based Payment and Your Future. PMID- 28075078 TI - Why Best Practices Fail to Spread. PMID- 28075080 TI - Reduce faxed requests for Rx renewals. PMID- 28075079 TI - The State of Family Medicine: 2017. PMID- 28075081 TI - Create improvement that lasts. PMID- 28075082 TI - Rethink how you store patient records. PMID- 28075083 TI - Vital signs. PMID- 28075084 TI - Noncontributory documentation. PMID- 28075085 TI - Preoperative exam. PMID- 28075086 TI - FX modifier for x-ray. PMID- 28075088 TI - AFP Online: We're on a Mission. PMID- 28075090 TI - Carpal Tunnel Syndrome: Diagnosis and Management. AB - Carpal tunnel syndrome, the most common entrapment neuropathy of the upper extremity, is caused by compression of the median nerve as it travels through the carpal tunnel. Classically, patients with the condition experience pain and paresthesias in the distribution of the median nerve, which includes the palmar aspect of the thumb, index and middle fingers, and radial half of the ring finger. Additional clues include positive physical examination findings, such as the flick sign, Phalen maneuver, and median nerve compression test. Although patients with typical symptoms and signs of carpal tunnel syndrome do not need additional testing, ultrasonography and electrodiagnostic studies are useful to confirm the diagnosis in atypical cases and rule out other causes. If surgical decompression is planned, electrodiagnostic studies should be obtained to determine severity and surgical prognosis. Conservative treatment may be offered initially to patients with mild to moderate carpal tunnel syndrome. Options include splinting, corticosteroids, physical therapy, therapeutic ultrasound, and yoga. Nonsteroidal anti-inflammatory drugs, diuretics, and vitamin B6 are not effective therapies. Local corticosteroid injection can provide relief for more than one month and delay the need for surgery at one year. Patients with severe carpal tunnel syndrome or whose symptoms have not improved after four to six months of conservative therapy should be offered surgical decompression. Endoscopic and open techniques are equally effective, but patients return to work an average of one week earlier with endoscopic repair. PMID- 28075089 TI - Autism Spectrum Disorder: Primary Care Principles. AB - Autism spectrum disorder is characterized by difficulty with social communication and restricted, repetitive patterns of behavior, interest, or activities. The Diagnostic and Statistical Manual of Mental Disorders, 5th ed., created an umbrella diagnosis that includes several previously separate conditions: autistic disorder, Asperger syndrome, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified. There is insufficient evidence to recommend screening for autism spectrum disorder in children 18 to 30 months of age in whom the disorder is not suspected; however, there is a growing body of evidence that early intensive behavioral intervention based on applied behavior analysis improves cognitive ability, language, and adaptive skills. Therefore, early identification of autism spectrum disorder is important, and experts recommend the use of a validated screening tool at 18- and 24-month well-child visits. Medications can be used as adjunctive treatment for maladaptive behaviors and comorbid psychiatric conditions, but there is no single medical therapy that is effective for all symptoms of autism spectrum disorder. Prognosis is heavily affected by the severity of diagnosis and the presence of intellectual disability. Children with optimal outcomes receive earlier, more intensive behavioral interventions and less pharmacologic treatment. PMID- 28075091 TI - Empagliflozin (Jardiance) for Type 2 Diabetes Mellitus. PMID- 28075092 TI - Diabetes Mellitus: Management of Gastrointestinal Complications. AB - Gastrointestinal disorders are common complications of diabetes mellitus and include gastroparesis, nonalcoholic fatty liver disease, gastroesophageal reflux disease, and chronic diarrhea. Symptoms of gastroparesis include early satiety, postprandial fullness, nausea, vomiting of undigested food, bloating, and abdominal pain. Gastroparesis is diagnosed based on clinical symptoms and a delay in gastric emptying in the absence of mechanical obstruction. Gastric emptying scintigraphy is the preferred diagnostic test. Treatment involves glucose control, dietary changes, and prokinetic medications when needed. Nonalcoholic fatty liver disease and its more severe variant, nonalcoholic steatohepatitis, are becoming increasingly prevalent in persons with diabetes. Screening for nonalcoholic fatty liver disease is not recommended, and most cases are diagnosed when steatosis is found incidentally on imaging or from liver function testing followed by diagnostic ultrasonography. Liver biopsy is the preferred diagnostic test for nonalcoholic steatohepatitis. Clinical scoring systems are being developed that, when used in conjunction with less invasive imaging, can more accurately predict which patients have severe fibrosis requiring biopsy. Treatment of nonalcoholic fatty liver disease involves weight loss and improved glycemic control; no medications have been approved for treatment of this condition. Diabetes is also a risk factor for gastroesophageal reflux disease. Patients may be asymptomatic or present with atypical symptoms, including globus sensation and dysphagia. Diabetes also may exacerbate hepatitis C and pancreatitis, resulting in more severe complications. Glycemic control improves or reverses most gastrointestinal complications of diabetes. PMID- 28075093 TI - Screening for Lipid Disorders in Children and Adolescents: Recommendation Statement. PMID- 28075094 TI - Prognosis Following Mild Head Injury in Children. PMID- 28075095 TI - Needle Phobia: A Vasovagal Response During Acupuncture. PMID- 28075096 TI - A Pedunculated Mass on the Thigh. PMID- 28075098 TI - Autism Spectrum Disorder. PMID- 28075099 TI - Carpal Tunnel Syndrome. PMID- 28075100 TI - ADA Updates Standards of Medical Care for Patients with Diabetes Mellitus. PMID- 28075101 TI - The CDC's Recommendations to Help Prevent Fetal Alcohol Spectrum Disorders. PMID- 28075102 TI - Interventions to Facilitate Shared Decision Making to Address Antibiotic Use for Acute Respiratory Tract Infections in Primary Care. PMID- 28075103 TI - Extended-Release Bupropion for Preventing Seasonal Affective Disorder in Adults. PMID- 28075104 TI - Esophageal Cancer. AB - Esophageal cancer has a poor prognosis and high mortality rate, with an estimated 16,910 new cases and 15,910 deaths projected in 2016 in the United States. Squamous cell carcinoma and adenocarcinoma account for more than 95% of esophageal cancers. Squamous cell carcinoma is more common in nonindustrialized countries, and important risk factors include smoking, alcohol use, and achalasia. Adenocarcinoma is the predominant esophageal cancer in developed nations, and important risk factors include chronic gastroesophageal reflux disease, obesity, and smoking. Dysphagia alone or with unintentional weight loss is the most common presenting symptom, although esophageal cancer is often asymptomatic in early stages. Physicians should have a low threshold for evaluation with endoscopy if any symptoms are present. If cancer is confirmed, integrated positron emission tomography and computed tomography should be used for initial staging. If no distant metastases are found, endoscopic ultrasonography should be performed to determine tumor depth and evaluate for nodal involvement. Localized tumors can be treated with endoscopic mucosal resection, whereas regional tumors are treated with esophagectomy, neoadjuvant chemotherapy, chemoradiotherapy, or a combination of modalities. Nonresectable tumors or tumors with distant metastases are treated with palliative interventions. Specific prevention strategies have not been proven, and there are no recommendations for esophageal cancer screening. PMID- 28075105 TI - Heart Failure Due to Reduced Ejection Fraction: Medical Management. AB - Heart failure is an increasingly common condition resulting in high rates of morbidity and mortality. For patients who have heart failure and reduced ejection fraction, randomized clinical trials demonstrate consistent mortality benefit from angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, direct-acting vasodilators, beta blockers, and aldosterone antagonists. Additionally, some data show benefits from two new classes of drugs: angiotensin receptor blocker/neprilysin inhibitor and sinus node modulator. Diuretics and digoxin can be used as needed for symptom control. Statins are not recommended solely for treatment of heart failure. Implantable cardioverter-defibrillators and biventricular pacemakers improve mortality and function in selected patients. For patients who have been hospitalized for heart failure, disease management programs and telemonitoring can reduce hospitalizations and mortality. PMID- 28075106 TI - Membrane Sweeping to Decrease Rates of Postdate Induction. PMID- 28075108 TI - Alpha-adrenergic Agonists for the Management of Opioid Withdrawal. PMID- 28075109 TI - Patient-Centered Communication: Basic Skills. AB - Communication skills needed for patient-centered care include eliciting the patient's agenda with open-ended questions, especially early on; not interrupting the patient; and engaging in focused active listening. Understanding the patient's perspective of the illness and expressing empathy are key features of patient-centered communication. Understanding the patient's perspective entails exploring the patient's feelings, ideas, concerns, and experience regarding the impact of the illness, as well as what the patient expects from the physician. Empathy can be expressed by naming the feeling; communicating understanding, respect, and support; and exploring the patient's illness experience and emotions. Before revealing a new diagnosis, the patient's prior knowledge and preferences for the depth of information desired should be assessed. After disclosing a diagnosis, physicians should explore the patient's emotional response. Shared decision making empowers patients by inviting them to consider the pros and cons of different treatment options, including no treatment. Instead of overwhelming the patient with medical information, small chunks of data should be provided using repeated cycles of the "ask-tell-ask" approach. Training programs on patient-centered communication for health care professionals can improve communication skills. PMID- 28075110 TI - Rash in a U.S. Marine After Predeployment Vaccinations. PMID- 28075111 TI - Esophageal Cancer: What You Should Know. PMID- 28075112 TI - Heart Failure: What You Should Know. PMID- 28075113 TI - Pseudomonas aeruginosa LasR.DNA Binding Is Directly Inhibited by Quorum Sensing Antagonists. AB - Inhibition of quorum sensing in Pseudomonas aeruginosa is of interest as a possible antivirulence strategy for this pathogenic bacterium. The LasR regulator protein is important in coordinating gene expression in response to quorum sensing signaling molecules. One predominant strategy for LasR inhibition is the development of small-molecule antagonists that mimic the native autoinducer, though the mechanism by which they inactivate LasR is not known. This work reveals that multiple antagonists function by binding to and stabilizing LasR in a conformation that renders it unable to bind DNA. Further analysis of purified LasR complexed with known antagonists indicates that DNA binding can be recovered with the addition of native autoinducer, providing insights into the reversibility of ligand binding for this transcription factor. This in vitro assay could be used to assess future promising antagonists and complements existing cell-based reporter assays. PMID- 28075114 TI - Unveiling the Critical Role of Polymeric Binders for Silicon Negative Electrodes in Lithium-Ion Full Cells. AB - Because of its natural abundance and high theoretical specific capacity (3579 mAh g-1, based on Li15Si4), silicon and its composites have been extensively studied as the negative electrode for future high energy density lithium-ion batteries. While rapid failure due to the significant volumetric strain of lithium-silicon reactions makes bulk silicon unsuitable for practical applications, silicon nanoparticles can sustain the large volume changes without fracturing. However, polymeric binders are usually required to maintain the structural integrity of electrodes made of particles. Recent lithium-ion half-cell tests have shown that lithium ion-exchanged Nafion (designated as Li-Nafion) and sodium alginate are highly promising binders for nanoparticle silicon electrodes. Nevertheless, there is scant information on the performance and durability of these electrodes in full cell tests which are likely to reveal the role of binders under more realistic conditions. This work focuses on understanding the role of various binders in lithium-ion full cells consisting of Si negative electrode and LiNi1/3Mn1/3Co1/3O2 positive electrode. This study demonstrates, possibly for the first time, that silicon nanoparticles with either Li-Nafion or sodium alginate as binder can maintain a constant capacity of 1200 mAh g-1 for more than 100 cycles. In addition, during deep charge/discharge cycling, silicon electrodes containing Li-Nafion, Nafion, and sodium alginate can exhibit better capacity retention and higher specific capacity than that of silicon electrodes using polyvinylidene fluoride (PVDF) as a binder. PMID- 28075115 TI - Recent Methodologies That Exploit C-C Single-Bond Cleavage of Strained Ring Systems by Transition Metal Complexes. AB - In this review, synthetic and mechanistic aspects of key methodologies that exploit C-C single-bond cleavage of strained ring systems are highlighted. The focus is on transition-metal-catalyzed processes that are triggered by C-C bond activation and beta-carbon elimination, with the review concentrating on developments from mid-2009 to mid-2016. PMID- 28075116 TI - Metal-Organic Frameworks for Thin-Layer Chromatographic Applications. AB - Preparation of thin-layer chromatographic (TLC) plates based on metal-organic frameworks (MOFs) as porous stationary phases is described. DUT-67 (DUT = Dresden University of Technology), a zirconium based MOF, was used in combination with a fluorescent indicator as stationary phase for analyzing a small selection of a wide spectrum of relevant analytes. The successful separation of benzaldehyde from trans-cinnamaldehyde and 4-aminophenol from 2-aminotoluene is reported as a model system using optimized eluent mixtures containing acetic acid. PMID- 28075117 TI - Decoding Proton-Coupled Electron Transfer with Potential-pKa Diagrams. AB - Aqueous potential-pH diagrams, commonly called Pourbaix diagrams, were originally developed to study metal corrosion in the 1930s and 1940s. Pourbaix diagrams have since been widely adopted for use across chemistry disciplines, particularly for the study of aqueous proton-coupled electron transfer reactions. Despite this enormous versatility, a clear extension of analogous diagrams to nonaqueous solvents is lacking. The problem hinges on the difficulty of defining the nonaqueous solution pH. Here, we address this issue by reporting the development of diagrams based on nonaqueous pKa scales. We experimentally construct diagrams for two transition-metal complexes that undergo proton-coupled electron transfer reactivity by recording their reduction potentials in the presence of acids with varying pKa values. These experimental diagrams validate the potential-pKa theory and provide valuable thermochemical information for proton-coupled electron transfer reactions, including for fleetingly stable species. PMID- 28075118 TI - Uranyl Peroxide Cage Cluster Solubility in Water and the Role of the Electrical Double Layer. AB - Uranium concentrations as high as 2.94 * 105 parts per million (1.82 mol of U/1 kg of H2O) occur in water containing nanoscale uranyl cage clusters. The anionic cage clusters, with diameters of 1.5-2.5 nm, are charge-balanced by encapsulated cations, as well as cations within their electrical double layer in solution. The concentration of uranium in these systems is impacted by the countercations (K, Li, Na), and molecular dynamics simulations have predicted their distributions in selected cases. Formation of uranyl cages prevents hydrolysis reactions that would result in formation of insoluble uranyl solids under alkaline conditions, and these spherical clusters reach concentrations that require close packing in solution. PMID- 28075119 TI - Bubble-Driven Detachment of Bacteria from Confined Microgeometries. AB - Moving air-liquid interfaces, for example, bubbles, play a significant role in the detachment and transport of colloids and microorganisms in confined systems as well as unsaturated porous media. Moreover, they can effectively prevent and/or postpone the development of mature biofilms on surfaces that are colonized by bacteria. Here we demonstrate the dynamics and quantify the effectiveness of this bubble-driven detachment process for the bacterial strain Staphylococcus aureus. We investigate the effects of interface velocity and geometrical factors through microfluidic experiments that mimic some of the confinement features of pore-scale geometries. Depending on the bubble velocity U, at least three different flow regimes are found. These operating flow regimes not only affect the efficiency of the detachment process but also modify the final distribution of the bacteria on the surface. We organize our results according to the capillary number, [Formula: see text], where MU and gamma are the viscosity and the surface tension, respectively. Bubbles at very low velocities, corresponding to capillary numbers Ca < 5 * 10-5, exhibit detachment efficiencies of up to 80% at the early stage of bacterial adhesion. In contrast, faster bubbles at capillary numbers Ca > 10-3, have lower detachment efficiencies and cause significant nonuniformities in the final distribution of the cells on the substrate. This effect is associated with the formation of a thin liquid film around the bubble at higher Ca. In general, at higher bubble velocities bacterial cells in the corners of the geometry are less influenced by the bubble passage compared to the central region. PMID- 28075120 TI - Femtosecond Study of Dimolybdenum Paddlewheel Compounds with Amide/Thioamide Ligands: Symmetry, Electronic Structure, and Charge Distribution in the 1MLCT S1 State. AB - Four photophysically interesting dimolybdenum paddlewheel compounds are synthesized and characterized: I and II contain amide ligand (N,3-diphenyl-2 propynamide), and III and IV contain thioamide ligand (N,3-diphenyl-2 propynethioamide). I and III are trans-Mo2L2(O2C-TiPB)2-type compounds, and II and IV are Mo2L4-type compounds, where O2C-TiPB is 2,4,6-triisopropylbenzoate. I IV display strong light absorption due to metal to ligand charge transfer (MLCT) transitions from molybdenum to the amide/thioamide ligands. Charge transfer dynamics in the MLCT excited states of I-IV have been examined using femtosecond transient absorption (fs-TA) spectroscopy and femtosecond time-resolved infrared (fs-TRIR) spectroscopy. The asymmetric amide/thioamide ligands show two forms of regioarrangements in the paddlewheel compounds. Analyses of the nu(C=C) bands in the fs-TRIR spectra of I and II show similar electron density distribution over ligands in their 1MLCT S1 states where only two amide ligands are involved and the transferred electron is mainly localized on one of them. The fs-TRIR spectra of III and IV, however, show different charge distribution patterns where the transferred electron is fully delocalized over two thioamide ligands in III and partially delocalized in IV. Fast interligand electron transfer (ILET) was recognized as the explanation for the various charge distribution patterns, and ILET was shown to be influenced by both the ligands and the ligand arrangements. PMID- 28075121 TI - Computationally-Guided Assignment of Unexpected Signals in the Raman Spectra of Uranyl Triperoxide Complexes. AB - Combination of uranium, peroxide, and mono- (Na, K) or divalent (Mg, Ca, Sr) cations under alkaline aqueous conditions results in the rapid formation of anionic uranyl triperoxide monomers (UTs), (UO2(O2)3)4-, exhibiting unique Raman signatures. Electronic structure calculations were decisive for the interpretation of the spectra and assignment of unexpected signals associated with vibrations of the uranyl and peroxide ions. Assignments were verified by 18O isotopic labeling of the uranyl ions supporting the computational-based interpretation of the experimentally observed peaks and the assignment of a novel asymmetric vibration of the peroxide ligands, v2(O22-). PMID- 28075122 TI - Acetylene Fuels TCE Reductive Dechlorination by Defined Dehalococcoides/Pelobacter Consortia. AB - Acetylene (C2H2) can be generated in contaminated groundwater sites as a consequence of chemical degradation of trichloroethene (TCE) by in situ minerals, and C2H2 is known to inhibit bacterial dechlorination. In this study, we show that while high C2H2 (1.3 mM) concentrations reversibly inhibit reductive dechlorination of TCE by Dehalococcoides mccartyi isolates as well as enrichment cultures containing D. mccartyi sp., low C2H2 (0.4 mM) concentrations do not inhibit growth or metabolism of D. mccartyi. Cocultures of Pelobacter SFB93, a C2H2-fermenting bacterium, with D. mccartyi strain 195 or with D. mccartyi strain BAV1 were actively sustained by providing acetylene as the electron donor and carbon source while TCE or cis-DCE served as the electron acceptor. Inhibition by acetylene of reductive dechlorination and methanogenesis in the enrichment culture ANAS was observed, and the inhibition was removed by adding Pelobacter SFB93 into the consortium. Transcriptomic analysis of D. mccartyi strain 195 showed genes encoding for reductive dehalogenases (e.g., tceA) were not affected during the C2H2-inhibition, while genes encoding for ATP synthase, biosynthesis, and Hym hydrogenase were down-regulated during C2H2 inhibition, consistent with the physiological observation of lower cell yields and reduced dechlorination rates in strain 195. These results will help facilitate the optimization of TCE bioremediation at contaminated sites containing both TCE and C2H2. PMID- 28075123 TI - Nitrogen-Doped Yolk-Shell-Structured CoSe/C Dodecahedra for High-Performance Sodium Ion Batteries. AB - In this work, nitrogen-doped, yolk-shell-structured CoSe/C mesoporous dodecahedra are successfully prepared by using cobalt-based metal-organic frameworks (ZIF-67) as sacrificial templates. The CoSe nanoparticles are in situ produced by reacting the cobalt species in the metal-organic frameworks with selenium (Se) powder, and the organic species are simultaneously converted into nitrogen-doped carbon material in an inert atmosphere at temperatures between 700 and 900 degrees C for 4 h. For the composite synthesized at 800 degrees C, the carbon framework has a relatively higher extent of graphitization, with high nitrogen content (17.65%). Furthermore, the CoSe nanoparticles, with a size of around 15 nm, are coherently confined in the mesoporous carbon framework. When evaluated as novel anode materials for sodium ion batteries, the CoSe/C composites exhibit high capacity and superior rate capability. The composite electrode delivers the specific capacities of 597.2 and 361.9 mA h g-1 at 0.2 and 16 A g-1, respectively. PMID- 28075124 TI - PtNi/NiO Clusters Coated by Hollow Sillica: Novel Design for Highly Efficient Hydrogen Production from Ammonia-Borane. AB - Ammonia-borane (NH3.BH3; AB) has been considered as an excellent chemical material for hydrogen storage. However, developing highly efficient catalysts for continuous hydrogen generation from AB is still a challenge for future fuel cell applications. The combination of Pt with Ni is an effective strategy to achieve active bimetallic nanocatalyst, and the particle size has proved to play a crucial role in determining its final activity. However, the synthesis of PtNi bimetallic catalyst in the size of highly dispersed clusters has always been a challenge. In this report, PtNi/NiO clusters coated by small-sized hollow silica (R-PtNi/NiO@SiO2) were designed for efficient hydrogen generation from the hydrolysis of ammonia-borane. The newly designed catalysis system showed extremely high activity with the initial turnover frequency value reaching 1240.3 mol of H2.mol-1 of Pt.min-1, which makes it one the most active Pt-based catalysts for this reaction. Detailed characterization by means of scanning transmission electron microscopy, X-ray photoelectron spectroscopy, energy dispersive X-ray spectroscopy element mapping, etc. revealed that the excellent performance of R-PtNi/NiO@SiO2 is derived from the highly dispersed PtNi/NiO clusters and the reduction of extra Pt4+ on the surface of PtNi/NiO clusters to Pt0 at relatively low temperature. PMID- 28075125 TI - Multifunctional Nanoparticles by Coordinative Self-Assembly of His-Tagged Units with Metal-Organic Frameworks. AB - Self-assembly of individual units into multicomponent complexes is a powerful approach for the generation of functional superstructures. We present the coordinative interaction of oligohistidine-tags (His-tags) with metal-organic framework nanoparticles (MOF NPs). By this novel concept, different molecular units can be anchored on the outer surface of MOF NPs in a self-assembly process generating multifunctional nanosystems. The article focuses on two main objectives: first, the detailed investigation of the assembly process and fundamental establishment of the novel functionalization concept; and second, its subsequent use for the development of biomacromolecule (e.g., peptides and proteins) delivery vehicles. Three exemplary MOF structures, MIL-88A, HKUST-1, and Zr-fum, based on different metal components, were selected for the external binding of various His-tagged synthetic peptides and recombinant or chemically H6 modified proteins. Evidence for simultaneous assembly of different functional units with Zr-fum MOF NPs as well as their successful transport into living cells illustrate the promising potential of the self-assembly approach for the generation of multifunctional NPs and future biological applications. Taking the high number of possible MOF NPs and different functional units into account, the reported functionalization approach opens great flexibility for the targeted synthesis of multifunctional NPs for specific purposes. PMID- 28075126 TI - Cell-Conditioned Protein Coronas on Engineered Particles Influence Immune Responses. AB - A protein corona, which forms on engineered particles as soon as they are introduced into biological environments, is known to provide particles with a "biological identity". Protein coronas derived from various biological environments have been demonstrated to alter the cell internalization mechanism, to diminish targeting ability and to induce nanoparticle aggregation. So far, most of these studies have challenged engineered particles with a static biological environment. However, the extracellular environment is highly dynamic due to the process termed "cell-conditioning", in which cells deplete and secrete biomolecules. In this work, we demonstrate that protein coronas formed on engineered particles from such cell-conditioned media affect the biophysical particle properties and protein adsorption differently to protein coronas derived from an unconditioned environment. When investigating particles with protein coronas formed in various biologically relevant environments for their interaction with immune cells, we observed differences in pro-inflammatory cytokine secretion and immune cell apoptosis. We found that the particles either increased or mitigated the secretion of a specific cytokine, depending on the environment where the protein corona was formed. Our study suggests that the use of protein coronas could be useful to engineer drug carriers for elongated circulation, enhanced biocompatibility, and lower toxicity by triggering a specific immune response. PMID- 28075127 TI - Homeomorphic Isomerization as a Design Element in Container Molecules; Binding, Displacement, and Selective Transport of MCl2 Species (M = Pt, Pd, Ni). AB - The dibridgehead diphosphine ((CH2)14)3 P (1) can rapidly turn inside-out (homeomorphic isomerization) to give a mixture of in,in and out,out isomers. The exo directed lone pairs in the latter are able to scavenge Lewis acidic MCl2; cagelike adducts of the in,in isomer, trans- Cl2(P((CH2)14)3 P) (M = 2/Pt, 3/Pd, 4/Ni), then form. The NiCl2 unit in 4 may be replaced by PtCl2 or PdCl2, but 2 and 3 do not give similar substitutions. U-tubes are charged with CH2Cl2 solutions of 1 (lower phase), an aqueous solution of K2MCl4 (charging arm; M = Pt, Pd), and an aqueous solution of excess KCl (receiving arm). The MCl2 units are then transported to the receiving arm until equilibrium is reached (up to 22 d). When the receiving arm is charged with KCN, transport is much faster (ca. 100 h) and higher K2MX4 equilibrium ratios are obtained (>=96<=4). Analogous experiments with K2PtCl4/K2PdCl4 mixtures show PdCl2 transport to be more rapid. A similar diphosphine with longer methylene chains, P((CH2)18)3P, is equally effective. No transport occurs in the absence of 1, and other diphosphines or monophosphines assayed give only trace levels. PMID- 28075128 TI - Pursuit of Record Breaking Energy Barriers: A Study of Magnetic Axiality in Diamide Ligated DyIII Single-Molecule Magnets. AB - DyIII single-ion magnets (SIMs) with strong axial donors and weak equatorial ligands are attractive model systems with which to harness the maximum magnetic anisotropy of DyIII ions. Utilizing a rigid ferrocene diamide ligand (NNTBS), a DyIII SIM, (NNTBS)DyI(THF)2, 1-Dy (NNTBS = fc(NHSitBuMe2)2, fc = 1,1' ferrocenediyl), composed of a near linear arrangement of donor atoms, exhibits a large energy barrier to spin reversal (770.8 K) and magnetic blocking (14 K). The effects of the transverse ligands on the magnetic and electronic structure of 1 Dy were investigated through ab initio methods, eliciting significant magnetic axiality, even in the fourth Kramers doublet, thus demonstrating the potential of rigid diamide ligands in the design of new SIMs with defined magnetic axiality. PMID- 28075129 TI - Substituted Diarylnorbornadienes and Quadricyclanes: Synthesis, Photochemical Properties, and Effect of Substituent on the Kinetic Stability of Quadricyclanes. AB - In this Article, we present a new method for the synthesis of diarylnorbornadiene derivatives. Through the use of a two-step procedure consisting of a tandem alkene insertion-Suzuki coupling reaction followed by a DDQ dehydrogenation, we have been able to synthesize derivatives with a wide variety of substituents. We also present the results of UV-visible spectroscopy studies and kinetics experiments that show the effect of substituent on light absorption properties of the norbornadienes as well as the kinetic stability of the quadricyclanes that result from their photochemical conversion. While substitution on the aromatic rings had comparatively little effect on quadricyclane lability, substitution at a bridgehead position with a methyl group produced a quadricyclane that thermally reverted to the norbornadiene at a rate that was significantly slower than that for the quadricyclane without the methyl substituent. From the results of the kinetics experiments, we determined that the reversion of the quadricyclanes occurs via a free radical mechanism with very little contribution from polar effects. This observation led us to speculate as to whether our data may form the basis for a free radical substituent constant, sigmaQ*, analogous to the traditional Hammett sigma parameter. PMID- 28075130 TI - Expression and Characterization of Levansucrase from Clostridium acetobutylicum. AB - The Clostridium acetobutylicum gene Ca-SacB encoding levansucrase was cloned and expressed in Escherichia coli. Ca-SacB is composed of 1287 bp and encodes 428 amino acid residues, which could convert 150 mmol/L sucrose to levan with the liberation of glucose. The optimum pH and temperature of this enzyme for levan formation were pH 6 and 60 degrees C, respectively. Levansucrase activity of Ca SacB was completely abolished by 5 mmol/L Ag+ and Hg2+. The Km and Vmax values for levansucrase were calculated to be 64 mmol/L and 190 MUmol/min/mg, respectively. Interestingly, Ca-SacB was found to have high product specificity, and no fructooligosaccharide was identified in the product, indicating that Ca SacB may be valuable for industrial production of levan. In addition, Ca-SacB is the first characterized levansucrase isolated from an anaerobic bacterium, which should be valuable for exploring new enzyme resources and deepening the understanding of the catalytic mechanisms of levansucrases. PMID- 28075131 TI - Classical Galactosemia: Insight into Molecular Pathomechanisms by Differential Membrane Proteomics of Fibroblasts under Galactose Stress. AB - Classical galactosemia, a hereditary metabolic disease caused by the deficiency of galactose-1-phosphate uridyltransferase (GALT; EC 2.7.712), results in an impaired galactose metabolism and serious long-term developmental affection of the CNS and ovaries, potentially related in part to endogenous galactose-induced protein dysglycosylation. In search for galactose-induced changes in membrane raft proteomes of GALT-deficient cells, we performed differential analyses of lipid rafts from patient-derived (Q) and sex- and age-matched control fibroblasts (H) in the presence or absence of the stressor. Label-based proteomics revealed of the total 454 (female) or 678 (male) proteins a proportion of ~12% in at least one of four relevant ratios as fold-changed. GALT(-) cell-specific effects in the absence of stressor revealed cell-model-dependent affection of biological processes related to protein targeting to the plasma membrane (female) or to cellular migration (male). However, a series of common galactose-induced effects were observed, among them the strongly increased ER-stress marker GRP78 and calreticulin involved in N-glycoprotein quality control. The membrane-anchored N glycoprotein receptor CD109 was concertedly decreased under galactose-stress together with cadherin-13, GLIPR1, glypican-1, and semaphorin-7A. A series of proteins showed opposite fold-changes in the two cell models, whereas others fluctuated in only one of the two models. PMID- 28075133 TI - Phosphine Supported Ruthenium Nanoparticle Catalyzed Synthesis of Substituted Pyrazines and Imidazoles from alpha-Diketones. AB - A new methodology has been developed for the synthesis of highly substituted nitrogen heterocycles such as pyrazines and imidazoles starting from alpha diketones using phosphine supported ruthenium nanoparticles (RuNPs) as catalysts. Ruthenium nanoparticles Ru1-Ru4 supported with different phosphines such as dbdocphos, dppp, DPEphos, and Xantphos are screened, of which Ru1 and Ru4 are found to be the most active. Interestingly, aryl-substituted and alkyl substituted alpha-diketones produced different products: namely, pyrazine and imidazoles, respectively. This reaction methodology has been applied to the synthesis of a key intermediate (2m) of the marine cytotoxic natural product Dragmacidin B and an estrogen receptor (2l). This work represents the first examples of pyrazines prepared by RuNPs. PMID- 28075134 TI - Dynamic Optical Switching of Polymer/Plasmonic Nanoparticle Hybrids with Sparse Loading. AB - Responsive nanomaterials composed of gold nanoparticles (AuNPs) and temperature responsive poly(N-isopropylacrylamide) (PNIPAM) hydrogels offer the promise of designing smart materials that can change color in response to varying thermal or photothermal stimuli. Typical PNIPAM/AuNP hybrids are heavily loaded with AuNPs. Here, we demonstrate that hybrids with an average loading of three to five AuNPs per PNIPAM sphere exhibit peak extinction shifts of over 150 nm and color change from red to purple to gray as the temperature increases from 25 to 50 degrees C. We observe that the time scale for spectral shifts is offset from that for hydrophobic collapse of the PNIPAM spheres. Facilitated by the low loading density, we combine kinetic studies of the changes in the extinction spectra with finite-difference time-domain simulations to show that the location of AuNPs relative to the PNIPAM sphere at different stages of collapse is a key variable accounting for the time and temperature dependence of the experimental data. PMID- 28075132 TI - Discovery of Imidazo[1,2-a]pyridine Ethers and Squaramides as Selective and Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthesis. AB - The approval of bedaquiline to treat tuberculosis has validated adenosine triphosphate (ATP) synthase as an attractive target to kill Mycobacterium tuberculosis (Mtb). Herein, we report the discovery of two diverse lead series imidazo[1,2-a]pyridine ethers (IPE) and squaramides (SQA) as inhibitors of mycobacterial ATP synthesis. Through medicinal chemistry exploration, we established a robust structure-activity relationship of these two scaffolds, resulting in nanomolar potencies in an ATP synthesis inhibition assay. A biochemical deconvolution cascade suggested cytochrome c oxidase as the potential target of IPE class of molecules, whereas characterization of spontaneous resistant mutants of SQAs unambiguously identified ATP synthase as its molecular target. Absence of cross resistance against bedaquiline resistant mutants suggested a different binding site for SQAs on ATP synthase. Furthermore, SQAs were found to be noncytotoxic and demonstrated efficacy in a mouse model of tuberculosis infection. PMID- 28075135 TI - Access to Enantiopure alpha-Hydrazino Acids for N-Amino Peptide Synthesis. AB - Backbone N-methylation of alpha-peptides has been widely employed to enhance the bioavailability and bioactivity of parent sequences. Heteroatomic peptide amide substituents have received less attention due, in part, to the lack of practical synthetic strategies. Here, we report the synthesis of alpha-hydrazino acids derived from 19 out of the 20 canonical proteinogenic amino acids and demonstrate their use in the solid-phase synthesis of N-amino peptide derivatives. PMID- 28075136 TI - Theoretical Investigation of the Interfaces and Mechanisms of Induced Spin Polarization of 1D Narrow Zigzag Graphene- and h-BN Nanoribbons on a SrO Terminated LSMO(001) Surface. AB - The structure of the interfaces and the mechanisms of induced spin polarization of 1D infinite and finite narrow graphene- and h-BN zigzag nanoribbons placed on a SrO-terminated La1-xSrxMnO3 (LSMO) (001) surface were studied using density functional theory (DFT) electronic structure calculations. It was found that the pi-conjugated nanofragments are bonded to the LSMO(001) surface by weak disperse interactions. The types of coordination of the fragments, the strength of bonding, and the rate of spin polarization depend upon the nature of the fragments. Infinite and finite graphene narrow zigzag nanoribbons are characterized by the lift of the spin degeneracy and strong spin polarization caused by interface-induced structural asymmetry and oxygen-mediated indirect exchange interactions with Mn ions of LSMO support. Spin polarization changes the semiconducting nature of infinite graphene nanoribbons to half-metallic state with visible spin-up density of states at the Fermi level. The h-BN nanoribbon binding energy is weaker than graphene nanoribbon ones with noticeably shorter interlayer distance. The asymmetry effect and indirect exchange interactions cause spin polarization of h-BN nanoribbon as well with formation of embedded states inside the band gap. The results show a possibility to use one-atom thick nanofragments to design LSMO-based heterostructures for spintronic nanodevices with h-BN as an inert spacer to develop different potential barriers. PMID- 28075138 TI - Control of Chemo-, Regio-, and Enantioselectivity in Copper Hydride Reductions of Morita-Baylis-Hillman Adducts. AB - Nonracemically ligated copper hydride can be used to effect tandem SN2'/1,2 reductions of racemic Morita-Baylis-Hillman (MBH) acetates to access enantioenriched chiral allylic alcohols with defined olefin geometry. MBH esters, including those with beta-substitution, can be transformed to stereodefined enoates by taking advantage of a bulky, oligomeric, in situ generated trialkoxysiloxane leaving group. Finally, an atypical conversion of easily arrived at MBH alcohol derivatives to nonracemic allylic alcohols is disclosed. PMID- 28075137 TI - Anisotropic Electroless Deposition on DNA Origami Templates To Form Small Diameter Conductive Nanowires. AB - An improved method for the metallization of DNA origami is examined in this work. DNA origami, a simple and robust method for creating a wide variety of nanostructured shapes and patterns, provides an enabling template for bottom-up fabrication of next-generation nanodevices. Selective metallization of these DNA templates is needed to make nanoelectronic devices. Here, we demonstrate a metallization process that uses gold nanorod seeds followed by anisotropic plating to provide improved morphology and greater control of the final metallized width of the structure. In our approach, gold nanorods are attached to an origami template to create a seed layer. Electroless gold deposition is then used to fill the gaps between seeds in order to create continuous, conductive nanowires. Importantly, growth during electroless deposition occurs preferentially in the length direction at a rate that is approximately 4 times the growth rate in the width direction, which enables fabrication of narrow, continuous wires. The electrical properties of 49 nanowires with widths ranging from 13 to 29 nm were characterized, and resistivity values as low as 8.9 * 10-7 Omega.m were measured. The anisotropic metallization process presented here represents important progress toward the creation of nanoelectronic devices by molecularly directed placement of functional components onto self-assembled biological templates. PMID- 28075140 TI - Impact of blood collection method on first-trimester dried blood free Beta hCG and PAPP-A. AB - Background Analysis of dried blood specimens has been an integral part of laboratory medicine dating back to the early 1960s when they were introduced as part of neonatal screening programs. More recently, they have been used in Down syndrome screening programmes. Dried blood spot specimens can be collected either by finger-stick or by traditional venipuncture and spotted onto filter paper. We sought to evaluate whether first-trimester free Beta hCG and PAPP-A multiples of the median (MoMs) were different in dried blood specimens collected via finger stick compared to specimens collected via venipuncture. Methods A total of 2786 consecutive dried blood specimens were evaluated including 2144 collected using finger-stick and 644 specimens collected using venipuncture and spotted onto filter paper. Linear regression was used to assess the overall impact of collection method on dried blood free Beta hCG and PAPP-A and the impact of collection method on the trend of dried blood free Beta hCG and PAPP-A with transport time. Results For finger-stick and venipuncture, the median for free Beta hCG MoM was 0.99 and 1.04, respectively while the median PAPP-A MoM was 1.00 and 1.01, respectively. The regression formula for free Beta hCG was ln(MoM) = 0.00918 + 0.05112*Venipuncture + 0.00299*Days -0.00983*Days*Venipuncture and for PAPP-A the formula was ln(MoM) = -0.01000 + 0.04779*Venipuncture -0.00051*Days 0.02117*Days*Venipuncture. None of the coefficients were significant. Conclusions Collection method does not impact MoM values. Thus, centres have flexibility in the collection method utilized while being able to use a single reference database for all dried blood specimens. PMID- 28075141 TI - Distinct injury markers for the early detection and prognosis of incident acute kidney injury in critically ill adults with preserved kidney function. PMID- 28075142 TI - Predicting late recurrence in surgically treated patients with Cushing's disease. PMID- 28075143 TI - Contemporary bloodletting in cardiac surgical care. PMID- 28075144 TI - Comparison of a direct enzymatic assay and polyacrylamide tube gel electrophoresis for measurement of small, dense low-density lipoprotein cholesterol. PMID- 28075145 TI - Knee-to-Ankle Mosaicplasty for the Treatment of Osteochondral Lesions of the Ankle Joint. AB - BACKGROUND: Osteochondral lesions are frequently seen in athletes after ankle injuries. At this time, osteochondral autologous transplantation (OATS, mosaicplasty) is the only surgical treatment that replaces the entire osteochondral unit in symptomatic lesions. PURPOSE: To evaluate the clinical and radiological midterm to long-term outcome of ankles treated with knee-to-ankle mosaicplasty. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Clinical evaluation consisted of patient satisfaction, pain evaluation (visual analog scale [VAS]), American Orthopaedic Foot and Ankle Society (AOFAS) ankle score, sports activity score, range of motion, the radiological evaluation of magnetic resonance imaging (MRI), and single photon emission computed tomography-computed tomography (SPECT-CT) analysis of both the ankle and the knee joint. RESULTS: Twelve of 21 patients (mean age, 43 years; male, 8; female, 4) were available for latest follow-up (mean, 72 months). At follow-up, patients reported a satisfaction rate of good to excellent in 92% (n 5 11) and poor in 8% (n 5 1). The average VAS pain score was 3.9 (preoperative, 5.9; P 5 .02), AOFAS ankle score significantly increased from 45.9 to 80.2 points (P< .0001), sports activity score remained significantly decreased with 1.25 (preinjury level, 2.3; P 5 .035), and ankle dorsiflexion was significantly reduced (P 5 .003). Knee pain was reported in 6 patients (50%). Radiologically, recurrent lesions were found in 10 of 10 cases (100%) and some degree of cartilage degeneration and discontinuity of the subchondral bone plate in 100%. CONCLUSION: Indications for mosaicplasty with a plug transfer from the knee to the talus must be considered carefully, as at midterm, moderate outcome and considerable donor-site morbidity may be found. PMID- 28075146 TI - Five Near Full-Length Hepatitis C Virus Sequences Were Identified from HIV Coinfected Injection Drug Users of China. AB - HIV and hepatitis C virus (HCV) share transmission routes, including contaminated blood transfusion, sexual intercourse, and needle-sharing in injection drug users (IDUs). We obtained five near full-length genome sequences of HCV isolated from five HIV-1-coinfected IDUs in Sichuan and Xinjiang provinces, China. By conducting reconstruction of neighbor-joining phylogenetic tree, our results revealed that the five isolates are of four different genotypes (1b, 3a, 6a, and 6n). The amino acid substitutions (170I) in XJN0021 related to resistant to protease inhibitors (grazoprevir) were also identified. The genetic diversity of these sequences uncovered more complicated transmission situation of HCV among IDUs in China. PMID- 28075147 TI - Evaluating the Efficacy of the Feeding Exercise Randomized Trial in Overweight and Obese Adolescents. AB - BACKGROUND: The Feeding Exercise Trial in Adolescents (FETA) aimed to evaluate whether a community-based, parents-involving, combined physical activity and nutritional education program was effective in improving adiposity profiles in overweight and obese adolescents. METHODS: A total of 181 overweight and obese adolescents aged 13-15 years old were randomized in the three study groups ("Diet & Activity," "Activity," and Control). The Activity intervention included a 45 minute, 3-day per week supervised training program, while the Diet & Activity intervention included a supplementary 15 minutes of group-based sessions attended by the parents. The intervention lasted 3 months and the participants were followed for another 3 months after the intervention. The participants were assessed for anthropometric measures and activity and fulfilled the modified version of the questionnaire "Family Eating and Activity Habits Questionnaire" (FEAHQ). RESULTS: Both "Activity" only and "Diet & Activity" groups reduced significantly (p < 0.001) their mean body mass index (BMI) (-1.1, 95% CI -1.3, 0.8, and -1.4, 95% CI -1.7, -1.2, respectively), waist circumference, systolic and diastolic blood pressure, pulses per minute, and 50 m sprint run test at 3 months, while greater reductions in BMI were observed at 6 months (-2.3, 95% CI 2.6, -2.0, and -3.1, 95% CI -3.3, -2.8). Significant changes in the total FEAHQ score were achieved only in the "Diet & Activity" group both at 3 months and at 6 months. CONCLUSIONS: FETA resulted in significant effects on improving adiposity profiles in overweight and obese adolescents, as well as family activity and feeding habits, maintained at 3 months follow-up. PMID- 28075150 TI - 2016-2017 Conferences. PMID- 28075149 TI - Journal Watch. PMID- 28075152 TI - CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders. PMID- 28075151 TI - Multilevel Correlates of Healthy BMI Maintenance and Return to a Healthy BMI among Children in Massachusetts. AB - OBJECTIVES: To examine predictors of healthy BMI maintenance (HBM) or return to a healthy BMI (RHB) among children. METHODS: We studied 33,272 children in Massachusetts between 2008 and 2012. We used multinomial logistic regression to examine associations of individual- and neighborhood-level factors with the odds of: (1) HBM: maintenance of a healthy BMI >=5th to <85th percentile and (2) RHB: transition to a healthy BMI range from an initial BMI >=85th percentile between two clinic visits spanning an average of 3.5 years. RESULTS: Racial/ethnic minorities had lower odds of HBM and RHB than non-Hispanic white children. Higher neighborhood educational attainment was associated with an increased odds of HBM and RHB. Higher neighborhood median household income, proximity to a supermarket, and access to more open recreational space were associated with a higher odds of HBM. Children of ages 2-5 years at baseline had higher odds of RHB and HBM than children 13 years and older. CONCLUSIONS: Early childhood interventions and efforts to create health-promoting neighborhoods including improving access to supermarkets and open recreational space could have important effects on obesity prevention and management. PMID- 28075154 TI - Survivorship After Meniscal Allograft Transplantation According to Articular Cartilage Status. AB - BACKGROUND: Clinical outcomes after meniscal allograft transplantation (MAT) in arthritic knees are unclear, and objective estimates of graft survival according to the articular cartilage status have not been performed. HYPOTHESIS: MAT should provide clinical benefits in knees with high-grade cartilage damage, but their graft survivorship should be inferior to that in knees with low-grade chondral degeneration after MAT. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: The records of 222 consecutive patients who underwent primary MAT were reviewed to compare clinical outcomes and graft survivorship. The patients were grouped according to the degree and location of articular cartilage degeneration: low-grade chondral lesions (International Cartilage Repair Society [ICRS] grade <=2) on both the femoral and tibial sides (ideal indication), high-grade lesions (ICRS grade 3 or 4) on either the femoral or tibial side (relative indication), and high-grade lesions on both sides (salvage indication). Kaplan-Meier survival analysis with the log-rank test was performed to compare the clinical survival rates and graft survival rates between the groups. A Lysholm score of <65 was considered a clinical failure, and graft failure was defined as a meniscal tear or meniscectomy of greater than one-third of the allograft, objectively evaluated by magnetic resonance imaging (MRI) and second-look arthroscopic surgery. RESULTS: The mean (+/-SD) Lysholm score significantly improved from 63.1 +/- 15.1 preoperatively to 85.1 +/- 14.3 at the latest follow-up of a mean 44.6 +/- 19.7 months ( P < .001). However, the postoperative scores were not significantly different between the 3 groups (85.7 +/- 14.2 for ideal indication, 84.7 +/- 17.0 for relative indication, and 84.7 +/- 14.2 for salvage indication; P = .877). On MRI at the latest follow-up of a mean 23.0 +/- 19.9 months and second-look arthroscopic surgery of a mean 19.3 +/- 20.7 months, there were 25 (11.3%) failed MAT procedures (4 medial, 21 lateral); of these, 5 lateral MAT procedures (2.3%) went on to allograft removal. Clinical survival rates were not significantly different between the groups ( P = .256). However, on objective evaluation, the estimated cumulative graft survival rate at 5 years in the salvage indication group (62.2% [95% CI, 41.6-82.8]) was significantly lower than that in the other 2 groups (ideal indication: 93.8% [95% CI, 88.5-99.1]; relative indication: 90.9% [95% CI, 81.1-100.0]) ( P = .006). CONCLUSION: Our findings showed that MAT was an effective symptomatic treatment in knees with advanced bipolar chondral lesions. However, better graft survival can be expected when articular cartilage is intact or if chondral damage is limited to a unipolar lesion. MAT should be considered before the progression of chondral damage to a bipolar lesion for better graft survivorship and should be performed cautiously in arthritic knees. PMID- 28075157 TI - Visual Occlusion During Minimally Invasive Surgery: A Contemporary Review of Methods to Reduce Laparoscopic and Robotic Lens Fogging and Other Sources of Optical Loss. AB - BACKGROUND: Maintenance of optimal vision during minimally invasive surgery is crucial to maintaining operative awareness, efficiency, and safety. Hampered vision is commonly caused by laparoscopic lens fogging (LLF), which has prompted the development of various antifogging fluids and warming devices. However, limited comparative evidence exists in contemporary literature. Despite technologic advancements there remains no consensus as to superior methods to prevent LLF or restore visual acuity once LLF has occurred. We performed a review of literature to present the current body of evidence supporting the use of numerous techniques. METHODS: A standardized Preferred Reporting Items for Systematic Reviews and Meta-Analysis review was performed, and PubMed, Embase, Web of Science, and Google Scholar were searched. Articles pertaining to mechanisms and prevention of LLF were reviewed. We applied no limit to year of publication or publication type and all articles encountered were included in final review. Limited original research and heterogenous outcome measures precluded meta-analytical assessment. RESULTS: Vision loss has a multitude of causes and although scientific theory can be applied to in vivo environments, no authors have completely characterized this complex problem. No method to prevent or correct LLF was identified as superior to others and comparative evidence is minimal. Robotic LLF was poorly investigated and aside from a single analysis has not been directly compared to standard laparoscopic fogging in any capacity. CONCLUSIONS: Obscured vision during surgery is hazardous and typically caused by LLF. The etiology of LLF despite application of scientific theory is yet to be definitively proven in the in vivo environment. Common methods of prevention of LLF or restoration of vision due to LLF have little evidence-based data to support their use. A multiarm comparative in vivo analysis is required to formally assess these commonly used techniques in both standard and robotic laparoscopes. PMID- 28075155 TI - A Qualitative Study Exploring Community Yoga Practice in Adults with Rheumatoid Arthritis. AB - OBJECTIVE: Yoga may improve physical function and reduce disease symptoms in adults with rheumatoid arthritis (RA). However, little is known about how patients with RA are practicing yoga in the community. The objective of this qualitative study was to explore community yoga practice characteristics and thoughts about yoga practice for adults with RA. DESIGN: Participants completed a semi-structured telephone interview with open-ended questions. Thematic analysis was used to analyze interview transcripts. PARTICIPANTS: A convenience sample of 17 adults with rheumatologist-diagnosed RA who had participated in yoga within the past year were asked about the decision to start, continue, and stop yoga; the perceived benefits of yoga; components of yoga sessions; and general thoughts about yoga as it relates to RA. RESULTS: Although eight different styles of yoga were practiced, commonalities in yoga class components (such as stretching, strengthening, deep breathing, meditation, and positive messaging from the instructor) reveal examples of preferred types of yoga for patients with RA. Three main themes emerged, each with multiple subthemes: (1) motivators (physical fitness, influence of others, reduced price), (2) barriers (cost, symptom burden, class difficulty), and (3) benefits of yoga practice (mind-body, a tool for coping, pride/achievement, social, and "yoga meets you where you are"). CONCLUSION: In this study, patients with RA described how yoga practice helped improve physical and psychosocial symptoms related to their disease. Yoga practice, a dynamic exercise, encompassing many different styles, can provide many benefits for adults with RA; however, yoga may not be beneficial for every adult with RA. PMID- 28075160 TI - Can We Accomplish Better Oncological Results with Robot-Assisted Radical Prostatectomy? AB - Surgical removal with radical prostatectomy has been a cornerstone for the treatment of prostate cancer and is associated with level 1 evidence for survival advantage compared with watchful waiting. Since the first structured robotic program was launched in 2000, robot-assisted radical prostatectomy (RARP) has had a rapid diffusion and surpassed its open radical prostatectomy (ORP) and laparoscopic radical prostatectomy (LRP) counterparts in the United States and is progressively expanding in other countries. Interestingly, this common acceptance of RARP was initially driven in the paucity of robust clinical evidence. There is still lack of level 1 evidence with prospective randomized trials on the oncologic outcomes of RARP. In that scenario, the clinician has to rely on retrospective data and systemic and meta-analyses. In comparison with ORP and LRP, RARP has proven to reach at least equivalent oncological outcomes. Lower rate of positive surgical margins may probably be achieved with RARP in pT2 patients. Although urologists were initially reluctant to embrace RARP in high risk patients and lymph node yield was low, contemporary series have revealed that RARP and extended lymphadenectomy may be safely performed with obtaining similar (or better) nodal yields compared with ORP. Surgeon experience is universally of utmost importance in obtaining good outcomes. We will need to wait for long-term results of contemporary series to comprehend the impact of RARP on cancer-specific survival and overall survival. Using novel imaging before surgery and frozen section analysis during surgery may allow for superior oncological outcomes. PMID- 28075162 TI - Cognitive development in congenital hypothyroidism: is overtreatment a greater threat than undertreatment? PMID- 28075163 TI - Endocrine assays and pitfalls. PMID- 28075169 TI - Corrigendum. AB - Redmond JM, El Bitar YF, Gupta A, Stake CE, Domb BG. Arthroscopic acetabuloplasty and labral refixation without labral detachment. Am J Sports Med. 2015;43(1):105 112. (Original DOI: 10.1177/0363546514555330 ) In the above article, an author was inadvertently omitted: S. Pavan Vemula, MA (Hinsdale Orthopaedics, American Hip Institute in Chicago, Westmont, Illinois, USA). The corrected citation information is as follows: Redmond JM, El Bitar YF, Gupta A, Stake CE, Vemula SP, Domb BG. Arthroscopic acetabuloplasty and labral refixation without labral detachment. Am J Sports Med. 2015;43(1):105-112. PMID- 28075166 TI - The predictive value of Ki-67 before neoadjuvant chemotherapy for breast cancer: a systematic review and meta-analysis. AB - AIM: To review the predictive values of Ki-67 before neoadjuvant chemotherapy (NAC) for breast cancer patients. METHODS: PubMed and EMBASE were searched. Random-effect model meta-analysis was conducted using Revman software. RESULTS: High Ki-67 was associated with more pathological complete responses (pCRs) events (odds ratio: 3.10; 95% CI: 2.52-3.81; 53 studies, 10,848 patients) regardless of HR+, HER2+ and triple-negative breast cancer types, the definitions of pCR and cut-off points for Ki-67. Ki-67 could predict pCR in those who received anthracyclines plus taxanes, and anthracyclines only, and those from Asia and Europe. CONCLUSION: High Ki-67 before NAC was a predictor for pCR in neoadjuvant setting for breast cancer patients. PMID- 28075171 TI - The role of tumor microenvironment in collective tumor cell invasion. AB - For many cancer types, cancer cells invade into surrounding tissues by collective movement of cell groups that remain connected via cell-cell junctions. This migration is completely distinguished from single-cell migration, in which cancer cells disrupt the tight intercellular junctions and gain a mesenchymal phenotype. Recently, emerging evidence has revealed that collective cell invasion depends on not only cell-intrinsic mechanisms but also on extracellular mechanisms by bidirectional interplay between the tumor cell and the tumor environment. Herein, in this review we discuss the role and underline mechanisms of tumor microenvironment in collective tumor cell invasion, particularly focusing on extracellular matrix remodeling and cross-talk between tumor and stromal cells. PMID- 28075172 TI - Clinical News. PMID- 28075173 TI - TGFbeta1-Induced LncRNA UCA1 Upregulation Promotes Gastric Cancer Invasion and Migration. AB - According to recent studies, long noncoding RNA urothelial carcinoma associated 1 (UCA1) is involved in the development and progression of many malignant tumors, including gastric cancer (GC). We validated the detailed role of UCA1 in human GC cell lines and GC tissues so as to determine its exact function and the underlying mechanism of GC invasion and migration. In our research, lncRNA-UCA1 was specifically upregulated in GC tissues and cell lines, and augmented GC cell proliferation, and invasive and migratory capabilities. High UCA1 expression in GC was related with poorer prognosis (poorer invasion depth, lymph node metastasis, advanced TNM [T is for the original (primary) tumor, N for nearby (regional) lymph nodes that are involved, and M for distant metastasis] stage, and shorter overall survival). Epithelial mesenchymal transition (EMT), associated with malignancy of cancers, was reported to be responsible for invasion and migration of cancer cells. Transforming growth factor beta1 (TGFbeta1)-induced EMT was well evaluated. UCA1 silence reduced the protein levels of EMT-related factors, vimentin and snail, while promoted E-cadherin and zonula occludens-1 protein levels in GC cells; the effect of UCA1 could be partly restored by TGFbeta1 treatment. Taken together, UCA1 might regulate the tumor proliferation, invasion, and metastasis under TGFbeta1 induction. Taken together, UCA1 might present a potential oncogenic factor by promoting GC cell proliferation, invasion, and migration. UCA1 could serve as a novel biomarker for prognosis and a novel therapeutic target of GC treatment. PMID- 28075175 TI - Racial group categorization in minority drug use studies. PMID- 28075174 TI - Analysis of SIVmac Envelope-Specific Antibodies Selected Through Phage Display. AB - We have constructed a single chain fragment variable (scFv) phage display library from a simian immunodeficiency virus (SIV)-infected rhesus macaque that developed unusually high-titer neutralizing antibody responses against tier-3, neutralization-resistant SIVmac239. The library was screened using trimeric (gp140) and monomeric (gp120) forms of the SIVmac239 envelope (Env) glycoprotein. We also cloned variable-heavy and variable-light (VH-VL) antibody fragments from seven previously described rhesus macaque B-cell lines (BLCLs) that produce SIV gp120-specific monoclonal antibodies (mAbs). Thirty-two gp140-specific mAbs were selected along with 20 gp120-specific ones. gp120-specific mAbs were only from the VH4 family, while gp41-specific mAbs were primarily from VH1, followed by VH4 and VH3. Rhesus macaque BLCL-derived mAbs belonged primarily to the VH4 family of antibodies followed by VH3 and a smaller number of VH1s. A preferential VH combination with Vlambda light chain was observed with phage display-selected SIV Env-specific mAbs (gp120 and gp140), but not with BLCL-derived antibodies or the unpanned library. None of the tested antibodies had detectable neutralizing activity against tier-3 SIVmac239. The majority of gp120-specifc mAbs potently neutralized tier-1 SIVmac316 with 50% inhibitory concentration (IC50) values below 1 MUg/ml. For gp140-specific antibodies, which were all specific for the gp41-subunit, 2 out of 11 tested neutralized SIVmac316 (IC50 of 7 and 5 MUg/ml, respectively). These data suggest an order of preferential VH segment usage for SIV-specific antibodies in rhesus macaques. These antibodies will be useful in assessing the contribution of non-neutralizing antibodies to inhibition of SIV infection in vitro and in vivo. PMID- 28075176 TI - The ADAPP trial: a two-year longitudinal multidisciplinary intervention study for prostate cancer frail patients on androgen deprivation associated to curative radiotherapy. AB - BACKGROUND: Androgen deprivation (AD) therapy combined to radiotherapy (RT) is a curative therapeutic option for patients with non-metastatic locally advanced or aggressive intermediate prostate cancer (PC), though with a range of nutritional, physical, and psychological side effects. A multidisciplinary care program was created to help frail patients to prevent and manage those side effects. MATERIAL AND METHODS: We conducted a longitudinal interventional study in frail patients, presenting either cardiovascular/pulmonary comorbidities, old age (>=75 years), vulnerability ratings, or balance impairment. Patients were treated by AD and RT and, benefited from nutritional coaching, supervised biweekly 45 minute physical training, and psychological counseling for two years. Treatment outcomes included PC-related quality of life (QoL), body mass index, fat mass index, and fat-free mass index derived from bioelectrical impedance analysis, Six-Minute Walk Test, Timed Up&Go, handgrip strength, Hospital Anxiety and Depression scale, Mini Mental State Examination. Measures were repeated after zero, three, six, nine, 12, 18, 24 months, and 12-months post-study follow-up. A prospective mixed-model design was used to assess longitudinal outcome. RESULTS: Regression analyses revealed no significant change over the two years, including post-study follow up. Means of QoL, nutritional, physical, as well as psychological variables remained stable over more than two years in the 35 men aged 74 (range 68-76) years. CONCLUSION: The expected side effects of AD and RT were not observed in frail PC patients who followed this multidisciplinary care program. PMID- 28075178 TI - The scope of physiotherapy services provided in public ICUs in Greece: A pilot study. AB - The aim of the present study was to determine the scope of physiotherapy services provided in Greek ICUs in Athens. A cross-sectional study was conducted with two postal questionnaires administered separately, one for ICU directors and one for ICU physiotherapists. Responses were received from 19 ICU directors and 103 physiotherapists employed in all the adult public mixed medical and surgical ICUs across Athens. The response rate for the survey completion was 100% for ICU directors and 68.7% for physiotherapists. The results showed a 1:50 to 1:12 range in the ratio of physiotherapists to ICU beds. Among the 19 ICUs, 15 (78.9%) employed physiotherapists on a rotational basis, while four (21.0%) retained them exclusively. On weekdays, all surveyed ICUs were covered by physiotherapists in the morning and 10/19 (52.6%) during the afternoon. On weekends, 12/19 (63.2%) of the surveyed ICUs reported physiotherapy care during the morning and 4/19 (21.0%) during both morning and afternoon. All 103 physiotherapists conducted airway clearance techniques and progressive mobilization, 92/103 (89.3%) were involved in extubating patients, 102/103 (99.0%) in passive and active range of motion exercises, and 61/103 (59.2%) in walking. In conclusion, all Greek ICUs in Athens surveyed had physiotherapy cover. The physiotherapists working in these ICUs in Athens were involved in respiratory care and mobilization. PMID- 28075179 TI - Informatics and Computing. PMID- 28075177 TI - Function and origin of mistranslation in distinct cellular contexts. AB - Mistranslation describes errors during protein synthesis that prevent the amino acid sequences specified in the genetic code from being reflected within proteins. For a long time, mistranslation has largely been considered an aberrant cellular process that cells actively avoid at all times. However, recent evidence has demonstrated that cells from all three domains of life not only tolerate certain levels and forms of mistranslation, but actively induce mistranslation under certain circumstances. To this end, dedicated biological mechanisms have recently been found to reduce translational fidelity, which indicates that mistranslation is not exclusively an erroneous process and can even benefit cells in particular cellular contexts. There currently exists a spectrum of mistranslational processes that differ not only in their origins, but also in their molecular and cellular effects. These findings suggest that the optimal degree of translational fidelity largely depends on a specific cellular context. This review aims to conceptualize the basis and functional consequence of the diverse types of mistranslation that have been described so far. PMID- 28075181 TI - Accelerated or conventional whole brain irradiation of malignant melanoma. PMID- 28075183 TI - Systematic evaluation of lung tumor motion using four-dimensional computed tomography. AB - BACKGROUND: Respiratory-induced lung tumor motion may decrease robustness and outcome of radiation therapy (RT) if not accounted for. This study provides detailed information on the motion distribution of lung tumors for a group of 126 patients treated with stereotactic body RT. MATERIAL AND METHODS: Four dimensional computed tomography scans were reviewed to assess lung tumor motion. The tumor motion was determined by the center of mass shift based on a rigid registration of the breathing phases containing the largest positional differences in the inferior-superior (IS), left-right (LR), and anterior posterior (AP) directions. The patients were divided into subgroups depending on tumor diameter (phi < 2.0 cm, 2.0 <= phi <= 5.0 cm, phi > 5.0 cm) and tumor location within the lung (upper, middle, or lower lobe). The observed motion distributions were evaluated for each group separately to assess the dependence on tumor size and location. For each tumor size, the motion pattern in each direction (IS, LR, and AP) was analyzed for every tumor moving >5 mm. Sinusoidal trigonometric functions were fitted to the measured data using the least mean square method to determine which type of function best describes the motion pattern. Tumor volumes between 1.6 and 52.3 cm3 were evaluated. Mann-Whitney statistical tests were used for statistical analyses. RESULTS: The mean amplitude for the tumors in this study was 1.5 mm (LR), 2.5 mm (AP), and 6.9 mm (IS) while the maximum amplitude was 11.0 mm (LR), 9.0 mm (AP), and 53.0 mm (IS). In total, 95% of the tumors moved <=20 mm in the IS direction, <=3 mm in the LR direction, and <=6 mm in the AP direction. The observed motion distributions showed no statistically significant correlation with tumor size or location within the lung except for motion in the IS direction, where the mean and maximum amplitudes significantly increased for tumors located in the middle and lower parts of the lung. The motion pattern of a tumor in any direction was best described using a squared trigonometric function of the type [Formula: see text], where A is the maximum amplitude of the motion in the current direction, t is the time of measurement, T is the total time of the breathing cycle and B is a constant used to synchronize the starting point of the breathing cycle. CONCLUSION: Lung tumor movements were generally larger in the IS direction and the motion amplitude in this direction increased for tumors located in the middle and lower parts of the lungs. Motions in LR or AP showed no such relation. Tumor size was not found to have any correlation with the motion amplitude in any direction. The motion pattern of a lung tumor in any direction is best described with a squared sinusoidal function independently of the tumor size or tumor location. PMID- 28075182 TI - Dispersing the Mists: An Experimental History of Medicine Study into the Quality of Volatile Inhalations. AB - BACKGROUND: Dr. Nelson's Improved Inhaler was first marketed with an advertisement in The Lancet in 1865. Revolutionary at the time for its ease of use and patient-friendliness, the inhaler is still in use for self-treatment by many all over the world. On the occasion of its 150th anniversary, this study reports an experimental historical medicine approach to identify evidence for the quality of vapor inhalers. METHODS: Through accessing reviews of the device's use by the contemporary medical establishment, it was established that Dr. Nelson's Inhaler enjoyed a reputation of quality and efficacy among reputable physicians generating empirical evidence of clinical performance. There was a general absence of product performance tests during this period. Therefore, modern inhalation performance testing was applied to test the aerosol delivery performance for Friars' Balsam, and its key chemical constituent, benzoic acid (BA). RESULTS: A respirable dose of 59.9 +/- 9.0 MUg of BA was aerosolized in a 10 minutes period from a dose of 3.3 mL Friars' Balsam (equivalent to 35.1 +/- 0.2 mg of BA) in 375 mL of steaming water using the glass twin stage impinger at a flow rate of 60 L.min-1. The respirable dose from a standardized aqueous BA inhalation formulation increased from 115.9 +/- 10.6 to 200.2 +/- 19.9 MUg by increasing the simulated inhalation period from 5 to 10 minutes. When tested with a simulated inhalation maneuver (500 mL tidal volume, 13 minutes-1 respiration rate, 1:2 inspiratory:expiratory ratio) a respirable dose of 112.8 +/- 40.3 MUg was produced. CONCLUSIONS: This work has highlighted the potential for aerosol drug delivery using steam inhalers that are popular with patients. Physicians should therefore be aware of the potential for lung dosing with irritants when patients self-medicate using the Nelson Inhaler with vaporizing formulations such as Friars' Balsam. PMID- 28075184 TI - Elucidation of Formulation and Delivery Device-Related Effects on In Vitro Performance of Nasal Spray with Implication to Rational Product Specification Identification. AB - BACKGROUND: The aim of this work is to use an experimental design approach to identify and study influential formulation and delivery device properties, which can be controlled by final product manufacturer, to establish design space, within which desired in vitro performance can be reached. METHODS: Combining three factors, viscosity of suspension, nozzle orifice diameter (OD), and shot weight (SW), at three levels resulted in D-optimal experimental design with 20 runs. Responses within this study were droplet size distribution (DSD) and spray pattern (SP) in vitro tests. In addition, the amount of mechanical work needed for actuation was integrated from force profiles and used as a response. Results were fit to quadratic model by regression, which allowed also for determination of second-order and interaction effects between factors. Models were further optimized by keeping significant terms only. Optimized models were used to create response surfaces and design space with confidence levels. RESULTS: Viscosity has a dominant effect on DSD and modest effect on SP, with lower viscosities related to generation of smaller DSD and larger SP. Orifice diameter was found to have the highest impact on SP, with larger diameter resulting in larger SP. This effect was additionally confirmed by results of Plume Geometry in vitro test. Shot weight factor exerts significant influence on all tested metrics. Work, however, did not vary greatly with suspension viscosity or orifice diameter. Shot weight is the most dominant factor for work and important for DSD having a positive effect on both responses. In the case of SP, its relationship with shot weight is described by second-order polynomial fit. Inspection of raw data revealed that density of droplets within SP area is different for different shot weights. CONCLUSION: Presented study elucidated an inherent relationship between factors and responses and established mathematical models (response surfaces) for predictive purposes to target specific in vitro performance of nasal sprays by appropriate specification of factors, taking into account control space with included risk and uncertainty analysis. PMID- 28075185 TI - Cerebellar heterogeneity and its impact on PET data quantification of 5-HT receptor radioligands. AB - In the quantification of positron emission tomography (PET) radiotracer binding, a commonly used method is reference tissue modeling (RTM). RTM necessitates a proper reference and a ubiquitous choice for G-protein coupled receptors is the cerebellum. We investigated regional differences in uptake within the grey matter of the cerebellar hemispheres (CH), the cerebellar white matter (CW), and the cerebellar vermis (CV) for five PET radioligands targeting the serotonin system. Furthermore, we evaluated the impact of choosing different reference regions when quantifying neocortical binding. The PET and MR images are part of the Cimbi database: 5-HT1AR ([11C]CUMI-101, n = 8), 5-HT1BR ([11C]AZ10419369, n = 36), 5 HT2AR ([11C]Cimbi-36, n = 29), 5-HT4R ([11C]SB207145, n = 59), and 5-HTT ([11C]DASB, n = 100). We employed SUIT and FreeSurfer to delineate CV, CW, and CH and quantified mean standardized uptake values (SUV) and nondisplaceable neocortical binding potential (BPND). Statistical difference was assessed with paired nonparametric two-sided Wilcoxon signed-rank tests and multiple comparison corrected via false discovery rate. We demonstrate significant radioligand specific regional differences in cerebellar uptake. These differences persist when using different cerebellar regions for RTM, but the influence on the neocortical BPND is small. Nevertheless, our data highlight the importance of validating each radioligand carefully for defining the optimal reference region. PMID- 28075188 TI - Automated Systems. PMID- 28075186 TI - Performance on tasks of visuospatial memory and ability: A cross-sectional study in 330 adolescents aged 11 to 20. AB - Cognitive functions mature at different points in time between birth and adulthood. Of these functions, visuospatial skills, such as spatial memory and part-to-whole organization, have often been tested in children and adults but have been less frequently evaluated during adolescence. We studied visuospatial memory and ability during this critical developmental period, as well as the correlation between these abilities, in a large group of 330 participants (aged 11 to 20 years, 55% male). To assess visuospatial memory, the participants were asked to memorize and reproduce sequences of random locations within a grid using a computer. Visuospatial ability was tested using a variation of the Design Organization Test (DOT). In this paper-and-pencil test, the participants had one minute to reproduce as many visual patterns as possible using a numerical code. On the memory task, compared with younger participants, older participants correctly reproduced more locations overall and longer sequences of locations, made fewer mistakes and needed less time to reproduce the sequences. In the visuospatial ability task, the number of correctly reproduced patterns increased with age. We show that both visuospatial memory and ability improve significantly throughout adolescence and that performance on both tasks is significantly correlated. PMID- 28075189 TI - 11 analytically confirmed cases of mexedrone use among polydrug users. AB - INTRODUCTION: Mexedrone, 3-methoxy-2-(methylamino)-1-(4-methylphenyl)propan-1 one, is the alpha-methoxy-derivative of mephedrone (4-methyl-N-methyl cathinone). Mexedrone inhibits the re-uptake of serotonin and dopamine in a dose-dependent manner and has affinity for serotonin and dopamine membrane transporters and receptors (5-HT2 and D2 receptors), producing sympathomimetic effects similar to amfetamines. To date there are no published clinical reports on mexedrone use that are analytically confirmed. OBJECTIVE: To characterise the features of mexedrone use in patients who presented to our hospital after using a variety of psychoactive substances including mexedrone, with analytical confirmation in each case. METHODS: This is an observational case series. Urine toxicological screening using ultra-performance liquid chromatography with tandem mass spectrometry and exact mass time of flight was employed in all patients. RESULTS: A total of 305 cases were screened and mexedrone was identified in 11 urine samples. Agitation was the most common presenting feature in 10 of 11 patients. This was marked to the extent of aggression in some cases, with six patients requiring sedation and/or physical restraint. Delusions and hallucinations, often with paranoia, were observed in three cases with a prominent supernatural/demonic theme. None of these individuals had a history of psychosis. Seven of 11 patients were tachycardic >100 bpm. The median length of stay was 20 hours (range 2-77; IQR 4-33). Mexedrone alone is only likely to have been responsible for these clinical features in 2 cases; in two others mexedrone was found in high concentration along with substantial amounts of other stimulants. In 7 other cases other stimulants detected more likely explained the features. However, comprehensive analytical data enabled us to identify the full complement of agents contributing to the clinical presentation. CONCLUSIONS: Agitation was the predominant clinical feature in this case series and was often accompanied by a sinus tachycardia; mexedrone was primarily responsible in 2 patients but contributed substantially in two others. Patients typically recovered fully within 24 hours, unless they required sedation. PMID- 28075190 TI - Gestational age within normal range and infants' health and temperament at 3 months of age. AB - OBJECTIVE: To examine the association between gestational age (GA) at birth across the normal GA spectrum (37-41 weeks) and the temperament and health of 3 month old infants. METHODS: The sample comprised 242 "low-risk" mothers and infants without chronic illnesses or severe pregnancy complications. Infant temperament was defined by three constructs: Negative Affectivity (NA), Extraversion, and Regulation, assessed by parents' reports on the Infant Behavior Questionnaire. Infants' health was defined as the number of nonroutine doctors' visits attended by the infants since their release from the hospital after birth. Analyses employed a continuous measure of GA to assess outcomes across GAs and a categorical measure (37, 38, 39-41 weeks GA) to examine contrasts. RESULTS: Extraversion was positively related to GA primarily due to the lower scores of infants born at 37 weeks compared to infants born at 39-41 weeks GA. NA showed a similar effect. The odds of infants born at 37 weeks attending a nonroutine medical visit were 2.8 times that of infants born full-term. DISCUSSION: Infants born at 37 weeks GA express less affect and use more nonroutine medical services than do infants born at 39-41 weeks GA. The findings underscore the importance of considering the risks of pregnancy prolongation with the developmental risk associated with early-term delivery. PMID- 28075191 TI - Reduction mammaplasty improves levels of anxiety, depression and body image satisfaction in patients with symptomatic macromastia in the short and long term. AB - OBJECTIVE: To evaluate the psychological consequences (anxiety, depression and body image dissatisfaction) of symptomatic macromastia and the effectiveness of breast reduction surgery in re-establishing the mental health of the patient in the short and long term. METHOD: 119 patients over 18 years old who had been diagnosed with symptomatic macromastia were assessed, before surgery, one month after the operation and one year later. Patients completed the Hospital Anxiety and Depression Scale (HADS) and the Body Image Dissatisfaction subscale of the Eating Disorders Inventory (EDI-2). Participants were also asked about their physical appearance, social relationships and their satisfaction with regards to clothing and dress. RESULTS: The average age of the patients was 40.7 (SD = 12.02), 80.2% had a body mass index >=25 kg/m2. Before surgery, we found psychological distress with values indicating clinical anxiety and body image dissatisfaction. Younger women (< 36 years old) were more psychologically affected. At one month after surgery, there were significant improvements: there were lower scores for anxiety (p < 0.001), depression (p < 0.001) and body image dissatisfaction (p < 0.001). When compared with the pre-surgery scores, all these results showed improvement one year after the intervention (p < 0.001). There were also improvements in social relationships (p < 0.001) and satisfaction with clothing and dress. CONCLUSION: Reduction mammaplasty can alleviate the psychological impact of symptomatic macromastia. PMID- 28075192 TI - Loss of monocyte chemoattractant protein-1 expression delays mammary tumorigenesis and reduces localized inflammation in the C3(1)/SV40Tag triple negative breast cancer model. AB - Monocyte chemoattractant protein 1 (MCP-1) has been implicated as a major modulator in the progression of mammary tumorigenesis, largely due to its ability to recruit macrophages to the tumor microenvironment. Macrophages are key mediators in the connection between inflammation and cancer progression and have been shown to play an important role in tumorigenesis. Thus, MCP-1 may be a potential therapeutic target in inflammatory and difficult-to-treat cancers such as triple negative breast cancer (TNBC). We examined the effect of MCP-1 depletion on mammary tumorigenesis in a model of TNBC. Tumor measurements were conducted weekly (until 22 weeks of age) and at sacrifice (23 weeks of age) in female C3(1)/SV40Tag and C3(1)/SV40Tag MCP-1 deficient mice to determine tumor numbers and tumorvolumes. Histopathological scoring was performed at 12 weeks of age and 23 weeks of age. Gene expression of macrophage markers and inflammatory mediators were measured in the mammary gland and tumor microenvironment at sacrifice. As expected, MCP-1 depletion resulted in decreased tumorigenesis, indicated by reduced primary tumor volume and multiplicity, and a delay in tumor progression represented by histopathological scoring (12 weeks of age). Deficiency in MCP-1 significantly downregulated expression of macrophage markers in the mammary gland (Mertk and CD64) and the tumor microenvironment (CD64), and also reduced expression of inflammatory cytokines in the mammary gland (TNFalpha and IL-1beta) and the tumor microenvironment (IL-6). These data support the hypothesis that MCP-1 expression contributes to increased tumorigenesis in a model of TNBC via recruitment of macrophages and subsequent increase in inflammatory mediators. PMID- 28075193 TI - Workshop Report: Aerosol Delivery to Spontaneously Breathing Tracheostomized Patients. AB - The number of pediatric and adult patients requiring tracheostomy has increased. Many of them require aerosol therapy as part of their treatment. Practitioners have little guidance on how to optimize drug delivery in this population. The following is a report of a workshop dedicated to review the current status of aerosol delivery to spontaneously breathing tracheostomized patients and to provide practice recommendations. PMID- 28075196 TI - Typhlitis (neutropenic enterocolitis) in patients with acute leukemia: a review. AB - INTRODUCTION: Typhlitis is an abdominal complication of cancer chemotherapy, affecting mostly patients receiving intensive chemotherapeutic regimens with high potential to induce mucosal damage, such as patients with acute leukemia. Despite being relatively frequent, there are no randomized trials or high-quality cohort studies addressing important aspects of the diagnosis and management of the disease. Areas covered: In this review we discuss the gaps in the literature, acknowledging that the evidences for recommendations regarding the management of typhlitis are mostly expert opinion. We performed a computerized search of the MEDLINE database (PubMed version) for appropriate articles published from 1963 through July, 2016 in English language. Thereafter the reference lists of all identified studies were screened, reviewing the abstracts of all potentially pertinent articles for inclusion. Expert commentary: The diagnosis of typhlitis still relies on clinical and radiologic features consisting of fever, abdominal pain and thickness of a segment of the bowel wall, as seen by ultrasonography or CT scan. The treatment consists in antimicrobial therapy with a regimen that covers the most frequent pathogens, taking into consideration the local epidemiology. Other measures include bowel rest, and the use of G-CSF. Surgery is indicated only in selected situations. PMID- 28075194 TI - Aerosol Drug Delivery During Noninvasive Positive Pressure Ventilation: Effects of Intersubject Variability and Excipient Enhanced Growth. AB - BACKGROUND: Nebulized aerosol drug delivery during the administration of noninvasive positive pressure ventilation (NPPV) is commonly implemented. While studies have shown improved patient outcomes for this therapeutic approach, aerosol delivery efficiency is reported to be low with high variability in lung deposited dose. Excipient enhanced growth (EEG) aerosol delivery is a newly proposed technique that may improve drug delivery efficiency and reduce intersubject aerosol delivery variability when coupled with NPPV. MATERIALS AND METHODS: A combined approach using in vitro experiments and computational fluid dynamics (CFD) was used to characterize aerosol delivery efficiency during NPPV in two new nasal cavity models that include face mask interfaces. Mesh nebulizer and in-line dry powder inhaler (DPI) sources of conventional and EEG aerosols were both considered. RESULTS: Based on validated steady-state CFD predictions, EEG aerosol delivery improved lung penetration fraction (PF) values by factors ranging from 1.3 to 6.4 compared with conventional-sized aerosols. Furthermore, intersubject variability in lung PF was very high for conventional aerosol sizes (relative differences between subjects in the range of 54.5%-134.3%) and was reduced by an order of magnitude with the EEG approach (relative differences between subjects in the range of 5.5%-17.4%). Realistic in vitro experiments of cyclic NPPV demonstrated similar trends in lung delivery to those observed with the steady-state simulations, but with lower lung delivery efficiencies. Reaching the lung delivery efficiencies reported with the steady-state simulations of 80% 90% will require synchronization of aerosol administration during inspiration and reducing the size of the EEG aerosol delivery unit. CONCLUSIONS: The EEG approach enabled high-efficiency lung delivery of aerosols administered during NPPV and reduced intersubject aerosol delivery variability by an order of magnitude. Use of an in-line DPI device that connects to the NPPV mask appears to be a convenient method to rapidly administer an EEG aerosol and synchronize the delivery with inspiration. PMID- 28075197 TI - Validation of an established prognostic score after re-irradiation of recurrent glioma. AB - BACKGROUND: Re-irradiation (Re-RT) is offered widely in clinical routine, and has been established as a key element in the treatment of recurrent gliomas. At our center, generally re-resection is performed widely by an experienced neurosurgical team. Thus, Re-RT mostly offered to patients with macroscopic residuals or irresectable lesions, is applied later compared to other centers. Therefore, we sought to validate the Combs Prognostic Score developed in 2012 using our independent patient cohort. PATIENTS AND METHODS: We included 199 patients treated from 2002 until April 2016 for recurrent glioma at the Department of Radiation Oncology at the Klinikum Rechts der Isar, Munich. Different concepts of Re-RT were applied. RESULTS: Median follow-up after Re-RT was 2.5 months. Median overall survival (OS) after Re-RT was 7.9 months for WHO IV gliomas, 11.3 months for WHO III gliomas, and 13.6 months for low-grade gliomas (WHO I/II). Univariate analyses confirmed the prognostic factors primary histology (p = 0.001), age (p = 0.002), and time between primary radiotherapy and Re-RT (p < 0.001). We also tested Karnofsky Performance Score (KPS), gender, and neurological symptoms before Re-RT as well as planning target volume and found only KPS also significant at p < 0.001. Comparing the prognostic score groups, the outcome was highly statistically significant at p < 0.001. CONCLUSION: In our analysis, we validated the Combs Prognostic Score. Validation in this independent large patient cohort confirms the significance of the score for glioma recurrences. Thus, the role of the Combs Prognostic Score might be an essential component of future clinical decision making and patient stratification. PMID- 28075198 TI - Impact of a history of maternal depression and anxiety on asthma control during pregnancy. AB - OBJECTIVE: To determine the impact of self-reported maternal depression/anxiety on asthma control during pregnancy. METHOD: Pregnant women with a doctor diagnosis of asthma (n = 189) were prospectively recruited at their antenatal booking visit, and the presence of maternal depression and anxiety was identified using self-report and routine questionnaire assessments. Data on exacerbations and asthma control were collected during gestation. Asthma control was assessed using the Juniper Asthma Control Questionnaire (ACQ) and women were classified as having recurrent uncontrolled asthma if their ACQ score was >1.5 during two or more consecutive study visits. Exacerbations were defined as events that led to increased treatment requirements, and doctor or hospital visits. RESULTS: There were 85 women with self-reported depression/anxiety and 104 women without self reported depression/anxiety. The presence of depression/anxiety was associated with an increased likelihood (adjusted hazard ratio (HR) 1.67: 95% confidence interval (CI) 1.03-2.72) and incidence (adjusted incidence rate ratio (IRR) 1.71: 95% CI 1.13-2.58) of uncontrolled asthma during pregnancy, as well as an increased risk of recurrent uncontrolled asthma during 2 or more study visits (adjusted relative risk (RR) 1.98: 95% CI 1.00-3.91). No impact of depression/anxiety was observed with respect to the likelihood (adjusted HR 0.70: 95% CI 0.35-1.41) or incidence of exacerbations during pregnancy (adjusted IRR 0.66: 95% CI 0.35-1.26). CONCLUSIONS: This study provides evidence that the presence of maternal depression/anxiety is associated with an increased likelihood and incidence of uncontrolled asthma during pregnancy. Given the high prevalence of co-morbid depression/anxiety among asthmatics, further research investigating such associations is urgently required. PMID- 28075200 TI - In response to: "Gautam N, Singh R, Agarwal A, et al. Pattern of Pediatric Uveitis at a Tertiary Referral Institute in North India". PMID- 28075199 TI - An epigenome-wide association analysis of cardiac autonomic responses among a population of welders. AB - DNA methylation is one of the potential epigenetic mechanisms associated with various adverse cardiovascular effects; however, its association with cardiac autonomic dysfunction, in particular, is unknown. In the current study, we aimed to identify epigenetic variants associated with alterations in cardiac autonomic responses. Cardiac autonomic responses were measured with two novel markers: acceleration capacity (AC) and deceleration capacity (DC). We examined DNA methylation levels at more than 472,506 CpG probes through the Illumina Infinium HumanMethylation450 BeadChip assay. We conducted separate linear mixed models to examine associations of DNA methylation levels at each CpG with AC and DC. One CpG (cg26829071) located in the GPR133 gene was negatively associated with DC values after multiple testing corrections through false discovery rate. Our study suggests the potential functional importance of methylation in cardiac autonomic responses. Findings from the current study need to be replicated in future studies in a larger population. PMID- 28075204 TI - Automated Systems. PMID- 28075201 TI - Corrigendum. PMID- 28075205 TI - A Genomic and Protein-Protein Interaction Analyses of Nonsyndromic Hearing Impairment in Cameroon Using Targeted Genomic Enrichment and Massively Parallel Sequencing. AB - Hearing impairment (HI) is one of the leading causes of disability in the world, impacting the social, economic, and psychological well-being of the affected individual. This is particularly true in sub-Saharan Africa, which carries one of the highest burdens of this condition. Despite this, there are limited data on the most prevalent genes or mutations that cause HI among sub-Saharan Africans. Next-generation technologies, such as targeted genomic enrichment and massively parallel sequencing, offer new promise in this context. This study reports, for the first time to the best of our knowledge, on the prevalence of novel mutations identified through a platform of 116 HI genes (OtoSCOPE(r)), among 82 African probands with HI. Only variants OTOF NM_194248.2:c.766-2A>G and MYO7A NM_000260.3:c.1996C>T, p.Arg666Stop were found in 3 (3.7%) and 5 (6.1%) patients, respectively. In addition and uniquely, the analysis of protein-protein interactions (PPI), through interrogation of gene subnetworks, using a custom script and two databases (Enrichr and PANTHER), and an algorithm in the igraph package of R, identified the enrichment of sensory perception and mechanical stimulus biological processes, and the most significant molecular functions of these variants pertained to binding or structural activity. Furthermore, 10 genes (MYO7A, MYO6, KCTD3, NUMA1, MYH9, KCNQ1, UBC, DIAPH1, PSMC2, and RDX) were identified as significant hubs within the subnetworks. Results reveal that the novel variants identified among familial cases of HI in Cameroon are not common, and PPI analysis has highlighted the role of 10 genes, potentially important in understanding HI genomics among Africans. PMID- 28075206 TI - Hydrogel rectum-prostate spacers mitigate the uncertainties in proton relative biological effectiveness associated with anterior-oblique beams. AB - AIM: Anterior-oblique (AO) proton beams can form an attractive option for prostate patients receiving external beam radiotherapy (EBRT) as they avoid the femoral heads. For a cohort with hydrogel prostate-rectum spacers, we asked whether it was possible to generate AO proton plans robust to end-of-range elevations in linear energy transfer (LET) and modeled relative biological effectiveness (RBE). Additionally we considered how rectal spacers influenced planned dose distributions for AO and standard bilateral (SB) proton beams versus intensity-modulated radiotherapy (IMRT). MATERIAL AND METHODS: We studied three treatment strategies for 10 patients with rectal spacers: (A) AO proton beams, (B) SB proton beams and (C) IMRT. For strategy (A) dose and LET distributions were simulated (using the TOPAS Monte Carlo platform) and the McNamara model was used to calculate proton RBE as a function of LET, dose per fraction, and photon alpha/beta. All calculations were performed on pretreatment scans: inter- and intra-fractional changes in anatomy/set-up were not considered. RESULTS: For 9/10 patients, rectal spacers enabled generation of AO proton plans robust to modeled RBE elevations: rectal dose constraints were fulfilled even when the variable RBE model was applied with a conservative alpha/beta = 2 Gy. Amongst a subset of patients the proton rectal doses for the planning target volume plans were remarkably low: for 2/10 SB plans and 4/10 AO plans, <=10% of the rectum received >=20 Gy. AO proton plans delivered integral doses a factor of approximately three lower than IMRT and spared the femoral heads almost entirely. CONCLUSION: Typically, rectal spacers enabled the generation of anterior beam proton plans that appeared robust to modeled variation in RBE. However, further analysis of day-to-day robustness would be required prior to a clinical implementation of AO proton beams. Such beams offer almost complete femoral head sparing, but their broader value relative to IMRT and SB protons remains unclear. PMID- 28075208 TI - Corrigendum. AB - The authors would like to apologise for errors made in ECTRIMS, Supplement 4, October 2012, 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis; 10-13 October 2012, Lyon, France. PMID- 28075207 TI - Perceived needs for different components in a rehabilitation program among cancer survivors with chronic fatigue compared to survivors without chronic fatigue. AB - BACKGROUND: Knowledge about the user' needs is important to develop targeted rehabilitation for cancer patients with chronic fatigue (CF). The aims of the study were to examine prevalence of CF in cancer survivors attending an one-week inpatient educational program (IEP) and to identify characteristics of those with CF. Further to examine the perceived needs for different components in a rehabilitation program, need of complex rehabilitation (at least two components) and aspects of health-related quality of life (HRQoL) among survivors with CF versus those without CF. MATERIAL AND METHODS: Cancer survivors >=18 years, diagnosed with different types of cancer within the last 10 years and attending a one-week IEP were invited to this cross-sectional study. CF was assessed by the Fatigue Questionnaire, perceived needs by asking a question about needs for different components in a rehabilitation program and HRQoL was assessed by The Medical Outcomes Study Short Form 36. RESULTS: Of 564 participants, 45% reported CF. Breast cancer, mixed cancer types (including small groups with different cancer types) and comorbidities increased the risk for having CF. Compared to participants without CF, the participants with CF reported more frequently need for physical training (86% vs. 65%, p < 0.001), physiotherapy (71% vs. 55%, p < 0.001) and nutrition counseling (68% vs. 53%, p = 0.001). Among participants with CF, 75% reported need for three or more components whereas 54% reported need for the same number of components among those without CF (p < 0.001). CONCLUSION: Almost half of the cancer survivors attending the IEP had CF. Physical training, physiotherapy and nutrition counseling were the most frequently reported needs and significantly more often observed in participants with CF than without CF. A higher percentage of those with CF reported need for a complex rehabilitation compared to those without CF. More research is necessary to obtain more knowledge to further make targeted programs to better match cancer survivors' needs. PMID- 28075209 TI - Abstracts from PACTRIMS. PMID- 28075212 TI - Response to Letter to the Editor 'Simvastatin improves final visual outcome in acute optic neuritis, a randomized study'. PMID- 28075213 TI - American Academy of Neurology (AAN) response to Goodin and Reder letter. PMID- 28075215 TI - Reviewers in 2011. PMID- 28075216 TI - Abstracts from PACTRIMS. PMID- 28075214 TI - Intralipid Vehicle Does Not Interfere with the Efficacy of Progesterone in Attenuating Edema following Traumatic Brain Injury. AB - The recent disappointing results of phase III trials for progesterone (PROG) in traumatic brain injury (TBI) have triggered speculation about reasons for the negative outcomes. One confounding factor may have been the vehicle used to administer PROG. Virtually all of the many pre-clinical experiments informing the clinical trials and reporting beneficial PROG effects used more soluble 2 hydroxypropyl-b-cyclodextrin as a vehicle given intraperitoneally or subcutaneously rather than a lipid formulation given intravenously (IV). The present investigation compared the effect of PROG infusion with that of lipid emulsion (Intralipid(r)) as a carrier/vehicle on edema following TBI in rats. Eight-mg/kg doses of PROG with 20% Intralipid were given IV via central venous catheter beginning 1 h post-injury over a 1 h duration (1.2 mL/h). Animals were killed and brains removed at 24 h post-injury. All the brain-injured groups showed more edema compared with the control group. However, PROG+Intralipid significantly attenuated cerebral swelling compared with Intralipid alone. No difference was observed between the TBI-alone and Intralipid groups. Although this study used much a smaller volume and shorter duration of Intralipid infusion than the clinical trials (up to 5 days of continuous infusion), our results suggest that the use of Intralipid in rats did not prevent or mask the beneficial effect of PROG. PMID- 28075218 TI - The relationship between stroke survivors' perceived identity and mood, self esteem and quality of life. AB - OBJECTIVES: To examine change in identity after stroke and to elucidate its relationship with mood and quality of life. To test Higgins' theory of the impact of identity (self-discrepancy) on anxiety and depression. To examine the role of self-esteem in mediating the relationship between identity and outcomes. METHOD: Sixty-five community-living first-time stroke survivors, mean age 61.58 and time since stroke 5.60 years, were recruited from stroke charities. A cross-sectional study used the Head Injury Semantic Differential Scale, the Hospital Anxiety and Depression Scale, the Rosenberg Self-Esteem Scale, the Stroke-Specific Quality of Life Questionnaire (adapted) and the Barthel Index. RESULTS: Identity was rated more negatively after stroke than before (t(64) = 6.46, p < .00). Greater discrepancy in identity was associated with anxiety (r = .38, p < .00), depression (r = .59, p < .00), self-esteem (r = -.48, p < .00) and quality of life (r = -.54, p < .00). Overall positivity of identity after stroke predicted outcomes even better than discrepancy. The association between discrepancy and mood and quality of life was mediated by self-esteem (beta = .30, p < .01; beta = -.24, p < .01, respectively). Specific types of discrepancy defined by Higgins did not show differential relationships with anxiety and depression as predicted. CONCLUSIONS: Identity changes after stroke and identity and self-esteem are associated with important outcomes for stroke survivors. PMID- 28075217 TI - Endoscopy-Assisted Laparoscopic Resections for Gastric Gastrointestinal Stromal Tumors: A Retrospective Study. AB - OBJECTIVE: To explore the safety, feasibility, and clinical curative effect of endoscopy-assisted laparoscopic resections for gastric gastrointestinal stromal tumors (GISTs). MATERIALS AND METHODS: We retrospectively compared the general condition of 41 GIST patients undergoing endoscopy-assisted laparoscopic resections (n = 41, combined group) with those undergoing traditional open gastrectomy (n = 43, open surgery group). RESULTS: All patients survived during the surgery. The average operation time of the combined group and the open surgery group was 90 +/- 40 minutes and 120 +/- 60 minutes, respectively, and no significant difference (P = .088) was observed. Bleeding volume during operation was significantly lower [(50 +/- 20 versus 150 +/- 40) mL, P < .001] and recovery time of the gastrointestinal function was significantly shorter in the combined group [(2.02 +/- 0.99) days versus (3.02 +/- 1) days, P < .001]. No statistical difference was found in the postoperative complications (5% versus 12%, P = .442) or GIST recurrence (2.44% versus 2.33%, P = 1.000) between the two groups. Follow up visit showed no death. CONCLUSION: For GIST patients who attempted to receive gastrectomy, endoscopy-assisted laparoscopic resections showed advantages on the operation time, bleeding volume, and recovery time and are suggested as a better alternative for GISTs. PMID- 28075219 TI - How do assessments of activities of daily living address executive functions: A scoping review. AB - : Executive functions (EF) allow persons to adapt to situations arising in daily life and can be affected following acquired brain injury (ABI). Measuring the impact of EF impairments on the accomplishment of activities of daily living (ADL) requires specific assessment tools, but choosing the right tool may be difficult. PURPOSE: To conduct a scoping review on how assessments of ADL address EF and EF impairments in persons with ABI. METHOD: A scoping review of literature (peer-reviewed and grey literature) published until August 2014 was conducted. Using a systematic procedure, literature was selected, results were charted, and tools were analysed with respect to their goals, underlying models, psychometric properties and applicability. The analysis also included how tools considered components of EF according to Lezak's model. RESULTS: 12 tools, developed either to assess EF in ADL, independence in ADL considering EF or ADL capacities, were identified and analysed according to multiple criteria. CONCLUSIONS: This review provides important information about existing tools to assist in tool selection and clinical decision-making related to ABI and EF. PMID- 28075220 TI - The contribution of assessing cognitive impairment in radiologically-isolated syndrome (RIS): A single case report follow-up study. PMID- 28075221 TI - Editorial comment. AB - Owing to errors made by the authors, Gavin Giovannoni and Tove Christensen, the editorial 'HERVs: have we been here before?' Multiple Sclerosis Journal 18(12): 1670-1672, (DOI: 10.1177/1352458512469331 )1 is incorrect. This editorial addressing the article written by Perron and colleagues2 in the same issue, contained a number of errors identified by both the authors of the editorial and the authors of the article. The latter are outlined in the letter from Herve Perron et al to follow, (DOI: 10.1177/1352458513485051) with additional supplemental information. The authors of the editorial suggested that they rewrite the entire piece to address many of the issues raised and this has also been published on the following pages. PMID- 28075223 TI - [Formula: see text]The statistical crisis in science: how is it relevant to clinical neuropsychology? AB - There is currently increased attention to the statistical (and replication) crisis in science. Biomedicine and social psychology have been at the heart of this crisis, but similar problems are evident in a wide range of fields. We discuss three examples of replication challenges from the field of social psychology and some proposed solutions, and then consider the applicability of these ideas to clinical neuropsychology. In addition to procedural developments such as preregistration and open data and criticism, we recommend that data be collected and analyzed with more recognition that each new study is a part of a learning process. The goal of improving neuropsychological assessment, care, and cure is too important to not take good scientific practice seriously. PMID- 28075222 TI - Expression of MYD88 in Adipose Tissue of Obese People: Is There Some Role in the Development of Metabolic Syndrome? AB - BACKGROUND: The mechanism leading to the development of metabolic complications in obese individuals is not fully understood. Thus, the objective of this study was to examine differences in insulin resistance, inflammation, cytokine and adipokine levels, and expression of selected genes across obese individuals with different number of metabolic syndrome (MetS) components. METHODS: Forty obese individuals who underwent bariatric surgery, divided in three groups based on the number of components of MetS, in addition to abdominal obesity (0, 1, and 2-3 additional components), were studied. Levels of inflammatory proteins, insulin resistance, cytokines, adipokines, and gene expression in subcutaneous (SAT) and visceral adipose tissue (VAT) were compared. RESULTS: There was a significantly higher expression of MYD88 in SAT among those with more components of MetS (P = 0.008). In SAT, but not in VAT, MYD88 expression was significantly correlated with toll-like receptor 4 expression (r = 0.7, P < 0.05). Expression of adipsin in SAT was also associated with the presence of more components of MetS, but with borderline statistical significance (P = 0.05). There were no significant differences in insulin resistance, inflammation, and cytokine and adipokine levels by the number of components of MetS. CONCLUSIONS: Our study suggests that MYD88 expression in SAT of obese subjects could be associated with the development of components of MetS. PMID- 28075224 TI - Integrating Approaches Requires More Than a Division of Labor. PMID- 28075225 TI - Plants contain small families of UPF0016 proteins including the PHOTOSYNTHESIS AFFECTED MUTANT71 transporter. AB - PHOTOSYNTHESIS AFFECTED MUTANT71 (PAM71) is an integral thylakoid membrane protein that functions in manganese uptake into the lumen. Manganese is needed in the thylakoid lumen to build up the inorganic Mn4CaO5 cluster, the catalytic center for water oxidation, and is hence indispensable for oxygen evolution. A recent study revealed that PAM71 is well conserved in plants and shares homology to GCR1 DEPENDENT TRANSLATION FACTOR1 (GDT1) and TRANSMEMBRANE PROTEIN 165 (TMEM165) in Saccharomyces cerevisiae and Homo sapiens, respectively. In most eukaryotes only single members of this family, designated "Uncharacterized Protein Family 0016" (UPF0016), are present; however, plant genomes contain genes for several UPF0016 proteins. In Arabidopsis thaliana, this protein family comprises 5 members, which mainly differ in their N-terminal regions. PAM71 and its closest homolog PAM71-HL possess chloroplast transit peptides at their N terminus. Two of the remaining 3 members are derived from a segmental chromosomal duplication event and lack an N-terminal extension. Thus, plants have evolved UPF0016 members residing in various compartments of the cell, whereas in non plant eukaryotes just a Golgi localization occurs. The identification of PAM71 as a candidate Mn2+ transporter opens the question on the function of the remaining plant members. Here we resume briefly our current knowledge of UPF0016 members in Arabidopsis in comparison to their yeast and human UPF0016 members. PMID- 28075228 TI - Impacts of a population-based prostate cancer screening programme on excess total mortality rates in men with prostate cancer: a randomized controlled trial. AB - Objectives To assess the effect of screening in terms of excess mortality in the European Randomized Study of Screening for Prostate Cancer (ERSPC). Methods A total of 141,578 men aged 55-69 were randomized to systematic screening or usual care in ERSPC sections in Finland, Italy, the Netherlands and Sweden. The excess number of deaths was defined as the difference between the observed number of deaths in the prostate cancer (PC) patients and the expected number of deaths up to 31 December 2006. The expected number was derived from mortality of all study participants before a diagnosis with PC adjusted for study centre, study arm and study attendance. The excess mortality rates were compared between the two study arms. Results The PC incidence was 9.25 per 1000 person-years in the intervention arm and 5.49 per 1000 person-years in the control arm, relative risk (RR) 1.69 (95% confidence interval [CI] 1.62-1.76). The excess mortality among men with PC was 0.29 per 1000 person-years in the intervention arm and 0.37 per 1000 person years in the control arm; the RR for excess mortality was 0.77 (95% CI 0.55 1.08). The absolute risk reduction in the excess mortality was 0.08 per 1000 person-years. The overall mortality was not significantly different between the intervention and the control arms of the study: RR 0.99 (95% CI 0.96-1.01). Conclusions Although the reduction in excess mortality was not statistically significant, the between-arm reduction in excess mortality rate was in line with the previously reported 20% reduction in the disease-specific mortality. This finding indicates that the reduction in PC mortality in the ERSPC trial cannot be due to a bias in cause of death adjudication. PMID- 28075231 TI - Presumptive granulocytic leukemia in a hognose snake (Heterodon platirhinos). PMID- 28075229 TI - Altered mitochondrial dynamics as a consequence of Venezuelan Equine encephalitis virus infection. AB - Mitochondria are sentinel organelles that are impacted by various forms of cellular stress, including viral infections. While signaling events associated with mitochondria, including those activated by pathogen associated molecular patterns (PAMPs), are widely studied, alterations in mitochondrial distribution and changes in mitochondrial dynamics are also beginning to be associated with cellular insult. Cells of neuronal origin have been demonstrated to display remarkable alterations in several instances, including neurodegenerative disorders. Venezuelan Equine Encephalitis Virus (VEEV) is a New World alphavirus that infects neuronal cells and contributes to an encephalitic phenotype. We demonstrate that upon infection by the vaccine strain of VEEV (TC-83), astrocytoma cells experience a robust drop in mitochondrial activity, which corresponds with an increased accumulation of reactive oxygen species (ROS) in an infection-dependent manner. Infection status also corresponds with a prominent perinuclear accumulation of mitochondria. Cellular enzymatic machinery, including PINK1 and Parkin, appears to be enriched in mitochondrial fractions as compared with uninfected cells, which is indicative of mitochondrial damage. Dynamin related protein 1 (Drp1), a protein that is associated with mitochondrial fission, demonstrated a modest enrichment in mitochondrial fractions of infected cells. Treatment with an inhibitor of mitochondrial fission, Mdivi-1, led to a decrease in caspase cleavage, suggesting that mitochondrial fission was likely to contribute to apoptosis of infected cells. Finally, our data demonstrate that mitophagy ensues in infected cells. In combination, our data suggest that VEEV infection results in significant changes in the mitochondrial landscape that may influence pathological outcomes in the infected cell. PMID- 28075232 TI - Records of Aedes albopictus (Skuse, 1894) (Diptera; Culicidae) and Culex tritaeniorhynchus (Diptera; Culicidae) Expansion in Areas in Mainland Greece and Islands. AB - Annual entomological surveillance programs aiming to monitor mosquito populations and record presence and absence of mosquito species have been performed in Greece. We report, in this study, new records and expansion of Aedes albopictus in the islands of Lesvos (region of North Aegean), Crete (region of Crete), and the regional units of Rodopi in East Macedonia-Thrace. Furthermore, Culex tritaeniorhynchus was recorded for the first time in Arta (region of Epirus) in northwestern Greece. PMID- 28075234 TI - Different Outcomes Require Different Explanations. PMID- 28075235 TI - Staphylococcus pseudintermedius Human Infection Cases in Spain: Dog-to-Human Transmission. AB - Staphylococcus pseudintermedius is an opportunistic pathogen that has been identified as infectious agent or colonizer mainly in dogs. S. pseudintermedius has been also detected in humans and more specifically in people in contact with dogs. In this study, the possible S. pseudintermedius pet-to-human transmission was analyzed in four clinical human cases. Two patients were dog owners and S. pseudintermedius was also detected as colonizer in these healthy animals. S. pseudintermedius isolates from patients and dogs of the same household showed identical pulsed-field gel electrophoresis patterns, sequence types (STs), and antimicrobial resistance phenotypes and genotypes, and were methicillin susceptible. Resistance to erythromycin, clindamycin, tetracycline, trimetoprim sulfamethoxazole, and/or ciprofloxacin was identified among S. pseudintermedius strains. The lineages ST241 and the new ST521 were detected in the strains of the two dog-owner patients, respectively. The strains from the other two patients presented two new STs, ST719 and ST720. To our knowledge, this is the first description of human infections caused by S. pseudintermedius in Spain. PMID- 28075236 TI - First Serological Evidence of West Nile Virus in Horses and Dogs from Corsica Island, France. AB - West Nile virus (WNV) is widely distributed over the world, including Europe, Africa, and Asia and spread over the past two decades to North and South America. In the south of France, sporadic cases are frequently described and the virus is endemic in Italy with frequent cases and outbreaks. The aim of this study was to identify a possible WNV circulation in Corsica (French island in the Mediterranean Sea) in sheep, horses, and dogs as sentinel animals for the virus surveillance. In 2014, 386 blood samples were collected from 219 sheep, 96 horses, and 71 dogs, in 12 localities in Corsica, in the oriental coast of Corsica. Each sample was systematically tested for WNV immunoglobulin G using an in-house enzyme-linked immunosorbent assay (ELISA) with inactivated WNV as antigen. The result of the ELISA for the WNV antibody test on the sheep sera was all negative, whereas 9 of 96 horses (9.4%) and 6 of 71 dogs (8.4%) presented WNV antibodies. All the positive samples from horses and dogs were confirmed by serum neutralization test. Although no clinical case in humans and horses was reported to date, this report highlights the necessity to improve WNV surveillance in animals and humans, as well as in blood donors in Corsica. PMID- 28075238 TI - Safety of stationary grinding machines - impact resistance of work zone enclosures. AB - Guards on machine tools are intended to protect persons from being injured by parts ejected with high kinetic energy from the work zone of the machine. Stationary grinding machines are a typical example. Generally such machines are provided with abrasive product guards closely enveloping the grinding wheel. However, many machining tasks do not allow the use of abrasive product guards. In such cases, the work zone enclosure has to be dimensioned so that, in case of failure, grinding wheel fragments remain inside the machine's working zone. To obtain data for the dimensioning of work zone enclosures on stationary grinding machines, which must be operated without an abrasive product guard, burst tests were conducted with vitrified grinding wheels. The studies show that, contrary to widely held opinion, narrower grinding wheels can be more critical concerning the impact resistance than wider wheels although their fragment energy is smaller. PMID- 28075242 TI - Erratum. PMID- 28075239 TI - Hantavirus Strains in East Africa Related to Western African Hantaviruses. AB - Hantaviruses are RNA viruses primarily carried by rodents, soricomorphs, and bats. The data about the distribution and genetic diversity of these viruses are often limited, especially in most regions of sub-Saharan Africa. Moreover, the majority of representatives were identified in western African localities, while only three hantaviruses have been reported in East Africa to date. In this study, a total of 1866 small mammals captured between 2009 and 2014 in various countries of Eastern Africa (Ethiopia, Zambia, Mozambique, Kenya, and Tanzania) were molecularly screened for the presence of hantaviruses. Hantavirus RNA was detected in dried blood samples of the Cape pipistrelle bat (Neoromicia capensis) captured in Ethiopia and the African wood mouse (Hylomyscus endorobae) from Kenya. Phylogenetic analysis of partial genomic segments revealed that the Ethiopian sample represents a sister lineage of the Mouyassue virus (reported previously from the congeneric bat in Cote d'Ivoire), and the Kenyan sample is a sister lineage of the Sangassou virus (described from the same mouse genus in Guinea). PMID- 28075243 TI - Mouse HistoArt. PMID- 28075248 TI - Evaluation of vibrant muscles over the shoulder region among workers of the hand screen printing industry. AB - This study focuses on evaluation of the muscle activities associated with shoulder pain among workers of the hand screen printing (HSP) industry. Activities of three major muscles which showed higher muscle activity for a HSP job were observed for fatigue using surface electromyography (SEMG). The anatomical sites were chosen on the basis of a statistical survey and a visual inspection conducted before the experiment. Activities of the deltoid, teres major and infraspinatus were recorded using SEMG and the nature of muscle activities was studied for about 50 m of cloth printing. Data collected were processed using LabVIEW 2014 and the activities were analyzed using statistical tests and regression analyses. The results showed an increased risk of shoulder disorders with an increase in working time. Some of the risks which might cause disorders were predicted from the results; inspection and possible mitigations were suggested. PMID- 28075251 TI - The Spatial Variation of the Weekday/Weekend Differences in the Baltimore Area. AB - This study examined the spatial distribution of the weekday/weekend difference in Baltimore, MD, and vicinity. The difference in Baltimore was characterized by having ~39% more NOx , ~59% more CO, and ~27% more volatile organic compounds (VOCs) on the average weekday, but there was ~13% more O3 on the weekend day. Spatially, the difference was elongated in the northeast-southwest direction. It decreased from 13% more O3 in Baltimore to 6% at ~20 km west of Baltimore and to 4% at ~40 km south of Baltimore. It also appeared to decrease to the east, but the magnitude of the decrease could not be determined because of the lack of data east of the Chesapeake Bay. However, the difference increased to the north, reaching a value of almost 18% at a northern Delaware site. PMID- 28075249 TI - Cost-effectiveness analysis of AS04-adjuvanted human papillomavirus 16/18 vaccine compared with human papillomavirus 6/11/16/18 vaccine in the Philippines, with the new 2-dose schedule. AB - Cervical cancer (CC) is the second leading cause of cancer death among Filipino women. Human papillomavirus (HPV) vaccination protects against CC. Two vaccines (AS04-HPV-16/18 and 4vHPV) are approved in the Philippines; they were originally developed for a 3-dose (3D) administration and have recently been approved in a 2 dose schedule (2D). This study aims to evaluate the cost-effectiveness of HPV vaccination of 13-year-old Filipino girls, in addition to current screening, in the new 2D schedule. An existing static lifetime, one-year cycle Markov cohort model was adapted to the Philippine settings to simulate the natural history of low-risk and oncogenic HPV infection, the effects of screening and vaccination of a 13-year-old girls cohort vaccinated with either the 2D-AS04-HPV-16/18 or 2D 4vHPV assuming a 100% vaccination coverage. Incremental cost, quality-adjusted life year (QALY) and cost-effectiveness were derived from these estimates. Input data were obtained from published sources and Delphi panel, using country specific data where possible. Sensitivity analyses were performed to assess the robustness of the model. The model estimated that 2D-AS04-HPV-16/18 prevented 986 additional CC cases and 399 CC deaths (undiscounted), as well as 555 increased QALY (discounted), and save 228.1 million Philippine pesos (PHP) compared with the 2D-4vHPV. In conclusion, AS04-HPV-16/18 is shown to be dominant over 4vHPV in the Philippines, with greater estimated health benefits and lower costs. PMID- 28075252 TI - Characterization of PM25 and PM10 in the South Coast Air Basin of Southern California: Part 1-Spatial Variations. AB - In December 1994, the South Coast Air Quality Management District (SCAQMD) initiated a comprehensive program, the PM10 Technical Enhancement Program (PTEP), to characterize fine PM in the South Coast Air Basin (SCAB). A 1-year special particulate monitoring project was conducted from January 1995 to February 1996 as part of the PTEP. Under this enhanced monitoring, HNO3, NH3, and speciated PM10 and PM2.5 concentrations were measured at five stations (Anaheim, downtown Los Angeles, Diamond Bar, Fontana, and Rubidoux) in the SCAB and at one background station at San Nicolas Island. PM2.5 and PM10 mass and 43 individual species were analyzed for a full chemical speciation of the particle data. The PTEP data indicate that the most abundant chemical components of PM10 and PM25 in the SCAB are NH4+ (8-9% of PM10 and 14-17% of PM25), NO3- (23-26% of PM10 and 28 41% of PM25), SO4= (6-11% of PM10 and 9-18% of PM2 5), organic carbon (OC) (15 19% of PM10 and 18-26% of PM2.5), and elemental carbon (EC) (5-8% of PM10 and 8 13% of PM25). On an annual average basis, PM25 comprises 52-59% of the SCAB PM10. Annual average PM10 and PM2.5 concentrations showed strong spatial variations, low at coastal sites and high at inland sites. Annual average PM10 concentrations varied from 40.8 ug/m3 at Anaheim to 76.8 ug/m3 at Rubidoux, while annual average PM2.5 concentrations varied from 21.7 ug/m3 at Anaheim to 39.8 ug/m3 at Rubidoux. The chemical characterizations of the PM2.5 and PM10 concentrations, as well as their spatial variations, were examined; the important findings are summarized in this paper, and the temporal variations are discussed in the companion paper.1. PMID- 28075253 TI - Characterization of PM25 and PM10 in the South Coast Air Basin of Southern California: Part 2-Temporal Variations. AB - The South Coast Air Quality Management District (SCAQMD) conducted a 1-year special particulate monitoring study from January 1995 to February 1996. This monitoring data indicates that high PM10 and PM2 5 concentrations were observed in the fall (October, November, and December), with November concentrations being the highest. During the rest of the year, PM2.5 and PM10 masses gradually increased from January to September. Monthly PM10 mass varied from 20 to 120 |ig/m3, and monthly PM25 mass varied from 13 to 63 |j.g/m3. The PM2.5-to-PM10 ratio varied daily and ranged between 22 and 96%. Two types of high-PM days were observed. The first type was observed under fall stagnation conditions, which lead to high secondary species concentrations. The second type was observed under high wind conditions, which lead to high primary coarse particles of crustal components. The highest 24-hr average PM10 concentration (226.3 |ig/m3) was observed at the Fontana station, while the highest PM25 concentration (129.3 |ig/m3) was observed at the Diamond Bar station. PMID- 28075254 TI - Modeling Traffic-Related Air Pollution in Street Canyons of Beijing. AB - It is important to develop a general model to accurately simulate the air pollution in urban street areas. In this paper, the Operational Street Pollution Model (OSPM) initially developed in Denmark is tested with measured data from a relatively wide and open street in Beijing. Major factors influencing the dispersion, such as emission factors, stationary source emissions, and solar radiation, are analyzed. Results show that the model can reflect the basic dispersion pattern in the street but gives systematically higher concentrations. After modifications to estimate street-level wind speed in the model, performance is obviously improved. PMID- 28075255 TI - Performance Characteristics of a Regenerative Catalytic Oxidizer for Treating VOC Contaminated Airstreams. AB - A pilot apparatus of a regenerative catalytic oxidizer (RCO) equipped with two electrical heaters and two 20-cm i.d. * 200-cm height regenerative beds was used to treat methyl ethyl ketone (MEK) and toluene, respectively, in an airstream. The regenerative beds were packed with gravel (approximate particle size 1.25 cm, specific area 205 m2/m3, and specific heat capacity 840 J/kg degrees C) as a solid regenerative material and K-type thermal couples for measuring solid and gas temperatures, respectively. The catalyst bed temperature was kept around 400 degrees C and the gas superficial velocity was operated at 0.234 m/sec. This investigation measured and analyzed distributions of solid and gas temperatures with operating time and variations of volatile organic compound (VOC) concentrations in the regenerative beds. The overall VOC removal efficiency exceeded 98% for MEK and 95% for toluene. Degradation of VOCs will exist for MEK on the surface of solid material (gravel) in the temperature range of 330-400 degrees C, but toluene does not exhibit this phenomenon. PMID- 28075256 TI - Use of Two Different Acidic Aerosol Samplers To Measure Acidic Aerosols in Hsinchu, Taiwan. AB - Acidic aerosol concentrations measured by an annular denuder system (ADS) and a honeycomb denuder system (HDS) in Hsinchu, Taiwan, were compared. Aerosols were also sampled by a MOUDI (micro-orifice uniform deposit impactor) and analyzed by an ion chromatograph to determine the size distributions of different species. Using the measured aerosol size distribution, theoretical analysis showed that positive HNO3 artifact due to volatiliza-tion of NH4NO3 is generally negligible for both samplers.4 3Comparing two different denuder samplers, the average concentration of HNO3 measured by the ADS was found3to be lower than that measured by the HDS, while the difference between the two samplers for the average concentration of other species was found to be within +/-15%. A possible cause of the difference in HNO3 con-3centrations is due to a greater loss of HNO3 in the cyclone3 used by the ADS than in the impactor used by the HDS. The study also showed incomplete absorption of the evaporated HCl and HNO3 from the particles on the Teflon3filter by the first nylon filter in the filter pack of the ADS. Collection efficiency and capacity of HCl and HNO3 by3the nylon filters need further investigation. PMID- 28075257 TI - Emission Factors for Gasoline Light-Duty Vehicles: Experimental Program in Santiago, Chile. AB - The emission inventory of the city of Santiago, Chile, related to mobile sources was built up using constant emission factors extracted from international literature. To improve the estimate of mobile source emissions, an experimental program was designed, consisting of transient tests on a chassis dynamometer over a sample of about 166 vehicles, applying 9 local driving cycles with average speeds of 3-80 km/hr, and experimentally determined in previous research carried out by the authors. An analysis of the influence of fuel inlet technology, and a year time-length model over emissions, was undertaken. We proposed emission factors as a function of average speed and of CO, THC, and NOx for catalytic and noncatalytic light-duty gasoline vehicles, disaggregated on commercial and private cars. A comparative analysis with emission factors obtained for the application of the COPERT II and AP-42 models was also presented. Our current analysis gives solid evidence indicating that to obtain a reasonable accuracy on emission estimates and calculations, local emission factors must be used. PMID- 28075258 TI - The Use of Ambient Measurements To Identify which Precursor Species Limit Aerosol Nitrate Formation. AB - A thermodynamic equilibrium model was used to investigate the response of aerosol NO3 to changes in concentrations of HNO3, NH3, and H2SO4. Over a range of temperatures and relative humidities (RHs), two parameters provided sufficient information for indicating the qualitative response of aerosol NO3. The first was the excess of aerosol NH4+ plus gas-phase NH3 over the sum of HNO3, particulate NO3, and particulate SO42- concentrations. The second was the ratio of particulate to total NO3 concentrations. Computation of these quantities from ambient measurements provides a means to rapidly analyze large numbers of samples and identify cases in which inorganic aerosol NO3 formation is limited by the availability of NH3. Example calculations are presented using data from three field studies. The predictions of the indicator variables and the equilibrium model are compared. PMID- 28075260 TI - Introduction to the Air & Waste Management Association's 28th Annual Critical Review. PMID- 28075259 TI - Systematic Evaluation and Uncertainty Analysis of the Refuse-Derived Fuel Process in Taiwan. AB - In the last few years, Taiwan has set a bold agenda in solid waste recycling and incineration programs. Not only were the recycling activities and incineration projects promoted by government agencies, but the related laws and regulations were continuously promulgated by the Legislative Yen. The solid waste presorting process that is to be considered prior to the existing incineration facilities has received wide attention. This paper illustrates a thorough evaluation for the first refuse-derived fuel pilot process from both quantitative and qualitative aspects. The process is to be installed and integrated with a large-scale municipal incinerator. This pilot process, developed by an engineering firm in Tainan County, consists of standard unit operations of shredding, magnetic separation, trommel screening, and air classification. A series of sampling and analyses were initialized in order to characterize its potentials in the solid waste management system. The probabilistic modeling for various types o f waste pro perties derived in this analysis may provide a basic understanding of system reliability. PMID- 28075262 TI - Real-World Emissions from Conventional Passenger Cars. AB - It has long been recognized that vehicles emit more pollutants than allowed under the new car emission standards. Further tightening of the certification standards based on existing test procedures does not directly address the largest sources of emissions. This study attempts to quantify vehicle emissions by source, in order to prioritize future policymaking. Several new sets of data are used in conjunction with regulatory emission models to characterize the lifetime emissions from the average Model Year (MY)93 vehicle. Special attention is paid to two of the largest sources of real-world emissions: (1) high-power driving by cars with properly functioning emissions controls, and (2) cars with malfunctioning emissions controls. Emissions are projected to MY2000 and 2010, based on estimates of the effectiveness of recently adopted and proposed regulatory policies. These new policies are projected to reduce total emissions substantially. PMID- 28075263 TI - Feasibility Testing of Biofiltration Technology for Remediating Air Contaminated by a Boat Manufacturing Facility. AB - This research investigated and compared the use of both bench- and pilot-scale biofilters to determine the effectiveness of controlling styrene, methyl ethyl ketone (MEK), and acetone emissions from an industrial gas waste stream. Critical operating parameters, including contaminant loading rate, temperature, and empty bed contact time, were manipulated in both the laboratory and field. At steady state conditions, the bench and pilot-scale biofilters showed a 99% removal efficiency for styrene when the contaminant loading rate was less than 50 g m-3hr 1 and 40 g m-3hr-1, respectively. Although few data points were collected in the pilot-scale reactor where the styrene load was greater than 40 g m-3hr-1, the total organic contaminant load including both MEK and acetone typically ranged between 50 g m-3hr-1 and 80 g m-3hr-1. Greater than 99% removal efficiencies were observed for acetone and MEK in the pilot-scale biofilter at all evaluated loading rates. Also studied were biofilter acclimation and re-acclimation periods. In inoculated bench and pilot biofilter systems, microbial acclimation to styrene was achieved in less than five days. In comparison, no MEK degrading microbial inoculum was added, so during the first months of pilot-scale biofilter operation, MEK removal efficiencies lagged behind those noted with styrene. PMID- 28075264 TI - Use of Tracer Gas for Direct Calibration of Emission-Factor Measurements in a Traffic Tunnel. AB - Pollutant measurements in traffic tunnels have been used to estimate motor vehicle emissions for several decades. The objective in this type of study is to use the traffic tunnel as a tool for characterizing motor vehicles rather than seeking a tunnel design with acceptably low pollutant concentrations. In the past, very simple aerodynamic models have been used to relate measured concentrations to vehicle emissions. Typically, it is assumed that velocities and concentrations are uniform across the tunnel cross section. In the present work, a vehicle emitting a known amount of sulfur hexafluoride (SF6) was driven repeatedly through a 730-m-long traffic tunnel in Vancouver, Canada. Comparing the measured SF6 concentrations to the known emission rates, it is possible to directly assess the accuracy of the simple tunnel aerodynamic models typically used to interpret tunnel data. Correction factors derived from this procedure were then applied to measurements of carbon monoxide and other pollutants to obtain gram-per-kilometer emission factors for vehicles. Although the specific correction factors measured here are valid only for the tunnel tested, the magnitude of the factors (up to two or more) suggests that the phenomena observed here should be considered when interpreting data from other tunnels. PMID- 28075265 TI - Musculoskeletal Load Assessment of the Upper Limb Positions Subjectively Chosen as the Most Convenient. AB - Work posture is determined by interdependence between work stand design, the necessity to perform given activities, and the anthropometric dimensions of the worker, but it also depends on individual preferences. The aim of the study was to compare the musculoskeletal load of the right upper extremity under conditions of imposed (standard) upper limb position and subjectively chosen ones, and to assess the influence of the changes in magnitude of the external force on the musculoskeletal load in the examined limb positions. Ten healthy male participants took part in the study. Muscular load associated with different upper extremity positions with and without external load were assessed. Musculoskeletal load for standard and subjectively chosen limb positions and two different values of external load were compared by means of theoretical and experimental methods. Results indicate that differences in musculoskeletal load between imposed and subjectively chosen limb positions were not high enough to show statistically significant differences, and the upper limb position chosen by the participant does not always cause the lowest musculoskeletal load. PMID- 28075266 TI - A Comparison of VDT Workstation Adjustment Methods by Evaluating and Optimizing VDT Operator's Seated Posture. AB - Three methods of visual display terminal (VDT) workstation adjustment were compared in this study in order to investigate their effects on the operator's seated posture. The first two methods were adjustments made both with and without any suggestion on the correct seated posture. The third method was an adjustment after which the workstation settings were initially set according to the results recommended by the IntelAd computer program. Ten male and 5 female participants were asked to readjust a VDT workstation until their most comfortable seated posture was obtained. When comparing the final seated postures to the ones ergonomically recommended, it was found that the workstation adjustment assisted by the computer program yielded the best result, followed by the adjustment without any suggestion on the seated posture, and then the adjustment with a suggestion on the seated posture. Furthermore, factors such as gender and typing skill level were not found to have any significant influence on the results. PMID- 28075267 TI - Morphology-Related Isometric Trunk Strength of South African Manual Workers: Implications for Prevention of Occupational Low-Back Stress. AB - Occupational back stress among manual workers in South Africa is now a cause of governmental concern. Yet no data on the back strength of the South African workforce have been published. This study represents a first step in reporting the trunk strength of Xhosa workers in South Africa, in absolute and size relative terms. Thirty-five male manual workers were tested isometrically while making maximal extension and flexion efforts at 0 degrees , 23 degrees , 46 degrees , 69 degrees , and 92 degrees of stoop. The results show nonlinearity of the extensor-to-flexor (E/F) ratio of the trunk musculature. The E/F ratio increases in deep stoop because of a drop in flexor torques. The data suggest that predictions of flexor from extensor torques or vice versa can confidently be made so long as testing is done away from the fully flexed position. Significant differences between morphologically gracile and robust workers in this sample are discussed. The study has implications for occupational rehabilitation and for prophylaxis, for whereas muscular strength alone may not protect the spine from occupational injury, muscular weakness certainly predisposes it. PMID- 28075268 TI - Footedness and Mounting-Short Review and Two Case Studies. AB - Footedness is a personal quality like handedness. Footedness may be associated with moving ability during mounting, dismounting, and jumping movements. Occupational accidents have occurred during movement at different working levels, during the use of access and exit systems, and during the mounting of vehicles. Aging can also affect accident risk and body laterality. For example, falling accidents on stairs are common among the elderly. One reason for accidents may be that the structure of the access system or stair system is unsuitable for individual moving patterns depending partly on body laterality. Footedness and the way the feet are used may be contradictory to the demands of the moving situation, especially during uncommon or rapid situations. This contradiction may trigger disturbance during moving. The aims of this pilot study were (a) to review the literature briefly and (b) to describe the use of the dominant and nondominant foot by farmers and the elderly when mounting a tractor and stairs, respectively. The study also gives ideas for future studies based on both (a) and (b). PMID- 28075269 TI - Work-Related Accidents Among Young Workers in Finland. AB - The aim of this study was to discover accident factors specific to young workers, using two accident data sets gathered at the same time but with different methods. The first data set consisted of 99 serious occupational accidents, which occured in Southern Finland in 1988 and 1989. The second data set was based on the interview study of over 13,000 people of whom 792 were involved in an accident at work. Both data sets showed consistently that the accident frequency of young workers was higher than that of older workers. The accidents of young workers, however, were less severe. Young accident victims hurt themselves more often when feeding or cleaning machines. Incautiousness contributed more often to accidents of young workers. In order to prevent occupational accidents of young workers, companies should introduce training programmes for new employees. PMID- 28075271 TI - Children in low-income countries have higher risk of death from emergency surgery. AB - The likelihood of dying after emergency abdominal surgery is seven times higher for children in poor countries than those in rich nations, a study suggests. PMID- 28075270 TI - Defending the Wrist Deviation Test for Carpal Tunnel Syndrome Screening: A Comparison of Vibration Thresholds and Distal Motor Latency. AB - This research used distal motor latency (DML) and vibration thresholds (VT) to evaluate 84 hand activity and wrist deviation combinations to determine the best association with carpal tunnel syndrome (CTS). Female volunteers, 2 healthy and 2 CTS diagnosed, were age matched and operated a keyboard for 4 hrs a day. Room temperature was 28 degrees C(+/-2). Beginning DML and VT were taken with a relaxed neutral posture hand. The wrist was deviated in a randomly selected combination, and determinations were taken at 5-min intervals. The trial ended at 20 min or when discomfort was felt. The CTS conditions were discriminated by pain four times, DML once, and VT 14 times. Vibrometry was the most consistent CTS discriminator. The best VT results for wrist positions were obtained with wrist extension and extended extension, whereas the unclenched, clenched, and loaded power grip activities proved to be the most consistent hand activities. PMID- 28075272 TI - Measuring peak expiratory flow rate: what the nurse needs to know. AB - Rationale and key points This article provides information on monitoring a patient's peak expiratory flow rate. It explains the rationale for measuring the peak expiratory flow rate, provides guidance for nurses to undertake this investigation and offers advice on how to instruct patients in the use of this technique. " Measuring the peak expiratory flow rate is an inexpensive, straightforward and useful clinical investigation that enables fluctuations in the patient's respiratory effort to be monitored over time. " The peak expiratory flow rate is used for the diagnosis, monitoring and assessment of the severity of respiratory compromise, particularly in patients with asthma. " The nurse can enable significant improvements in patient care by providing patient education on the correct technique, and by accurate assessment and recording of the peak expiratory flow rate. " The nurse should advise the patient on the action required if variation between readings occurs, where the patient is required to monitor their condition at home. PMID- 28075273 TI - Ensuring fair care for people with multiple sclerosis. AB - In November 2016, the MS Trust published the MS Forward View: a consensus for the future of multiple sclerosis (MS) services. PMID- 28075274 TI - Student life - When does compassion become caring too much? AB - The decision to become a nurse is often driven by a desire to help people, and many nurses are prepared to go the extra mile to support their patients. But for some, particularly those just starting out in their careers, it can be hard to know how involved to get in patients' lives. PMID- 28075275 TI - The perils of alcohol. AB - Listening to some of the older generation reminisce about the good old days, I was transported back to my childhood and a vow I made that when I grew up, alcohol would never sully my lips. PMID- 28075276 TI - Readers' panel - Is nursing in the UK losing its appeal as a profession? AB - Our experts consider a hot topic of the day. PMID- 28075278 TI - Antipsychotic drug use raises risk of death in people with Alzheimer's disease. AB - The prescription of psychotropic drugs is associated with a sharply higher risk of falling among residents of nursing homes. PMID- 28075277 TI - Social isolation linked to higher mortality rates in breast cancer. AB - Women with breast cancer who are more socially isolated have higher rates of recurrence and mortality than women with larger social networks, new study results suggest. PMID- 28075279 TI - Focus on workplace safety as staff injury bill tops L47m. AB - The overall bill for compensation payments and legal costs for NHS staff injuries last year was L47.5 million, Nursing Standard can reveal. PMID- 28075280 TI - Making the big move. AB - One reason Josie Gilday wanted to study nursing was the exciting opportunities it offered to work abroad. PMID- 28075281 TI - Nursing associates. AB - I think this role will give people a brilliant opportunity to enter the care service, obtain qualifications and develop a career. The degree pathway prevents some individuals from entering nursing. We must encourage people into the profession and support this - we need more people bedside with patients. PMID- 28075282 TI - Learning together. AB - Even as a newbie to medical education, I'm aware of how we doctors rely heavily on nursing colleagues and their monitoring of patients. PMID- 28075283 TI - Dorset trust offers nurses L5,000 relocation package to 'leave London behind'. AB - A trust is offering a relocation package of up to L5,000 to tempt nurses away from London. PMID- 28075284 TI - After 43 years, I'm still enthusiastic about nursing. AB - I have been nursing for 43 years in an acute area. I was not a nurse at 18 so had other jobs before starting as a nursing auxiliary. I am now registered and still enthusiastic about my job. PMID- 28075285 TI - Narcolepsy drug could help food addicts lose weight. AB - A drug used to treat the sleep disorder narcolepsy could help people addicted to food to lose weight, say UK researchers. PMID- 28075286 TI - Heavy alcohol use in adolescence alters brain development. AB - Young people who drink heavily throughout their teenage years risk altering the development of the brain, say Finnish researchers. PMID- 28075287 TI - Nursing in the Trump era. AB - Do nurses in the US know what to expect from President Trump? The predominant mood at the moment is one of uncertainty, according to editor-in-chief of the American Journal of Nursing Shawn Kennedy. While presidential candidate Trump had a lot to say about health care, it is far from clear what President Trump will do. One reason for this is that he has been inconsistent in his views. He was pro choice in 1999, for example, and antiabortion afterwards. Another reason is that the reality of politics may limit his power. PMID- 28075288 TI - Trust makes Twitter plea for off-duty staff to help in A&E. AB - Emergency department pressures caused by an influx of patients to a hospital trust prompted a plea on social media and radio for off-duty nurses to work an extra shift. PMID- 28075289 TI - 'My daughter's rheumatology nurse took away all of her fear'. AB - My daughter Isabella was diagnosed with juvenile arthritis at the age of one. She was unable to walk and in pain constantly. PMID- 28075291 TI - Board game helps hone new nurses' management skills on the ward. AB - New nurses and students are learning about management skills thanks to a board game featuring a miniature ward. PMID- 28075293 TI - Take the lead and get involved in research. AB - Trends in health and social care are changing how care is delivered. This is creating new roles for nurses, who are needed to supervise and coordinate work in many settings, including hospitals, care homes and the community. PMID- 28075294 TI - Nursing is stronger when we work together. AB - There are some striking similarities between Brexit and the election of Donald Trump as president of the United States: anger with an out-of-touch establishment, a desire to take back control and many people feeling left behind by globalisation. PMID- 28075295 TI - The high cost of cataracts. AB - A report from the Royal National Institute of Blind People (RNIB) has revealed that in some parts of the UK, patients with sight loss wait up to 15 months for cataract surgery, increasing their risk of falls, social isolation and depression. PMID- 28075296 TI - A dangerous game. AB - The government's ending of the cap on nurse training places in 2017 in England was a calculated gamble. The hope was to contain public funding for nurse education while encouraging growth in nursing student numbers by using other funding models. In short, more nurses are being trained, but someone else is picking up the tab. PMID- 28075297 TI - Physical health of people in prison. AB - Essential facts Since 2013, NHS England has commissioned health services for prisoners in England. The National Institute for Health and Care Excellence (NICE) says health care in prison plays an important role in identifying health needs, including chronic conditions. PMID- 28075299 TI - Prevention is better than compensation. AB - It has become rather fashionable to blame 'health and safety' for many of the nation's ills. Most of us have heard colleagues complain - or joke - that routine tasks can no longer be completed without first undertaking a cumbersome risk assessment. PMID- 28075300 TI - Leading clinic reports 40% drop in HIV diagnoses. AB - A nurse-led sexual health clinic has reported a 'significant' 40% fall in HIV diagnoses. PMID- 28075301 TI - Revalidation. AB - What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The article discussed the Nursing and Midwifery Council (NMC) revalidation process, which replaced the post registration education and practice requirements in April 2016. It stated that nurses and midwives must undertake revalidation every three years to renew their NMC registration. PMID- 28075302 TI - Using mentorship activities to assist nurses and midwives with their revalidation requirements. AB - Before the Nursing and Midwifery Council (NMC) introduced revalidation in 2016, the proposed model for revalidation was piloted in 19 healthcare organisations in the UK. Aneurin Bevan University Health Board (ABUHB) was among the pilot sites, and invited more than 1,000 registered nurses and midwives to take part. One of these participants, a member of the ABUHB practice facilitator team, used this experience to identify links between mentorship activities and the NMC requirements for revalidation. This article discusses how becoming a mentor and maintaining mentor status can provide registered nurses and midwives with evidence to assist them in their revalidation. PMID- 28075304 TI - We must help BME staff to whistleblow. AB - There are two main reasons why people do not raise concerns about wrongdoing - the belief that nothing will be done about what they report and the fear of retaliation. Indeed, there is more evidence of reprisals being suffered than of 'successful' whistleblowing. PMID- 28075306 TI - Coping with a patient's death. AB - During my clinical placement in a hospice in my first year of training, a patient with bowel cancer was admitted. PMID- 28075308 TI - Pulmonary Nodule Risk. AB - This app aims to help nurses, doctors and technicians assess the risk of lung cancer in people with lung nodules. PMID- 28075307 TI - Chronic heart failure part 2: treatment and management. AB - Chronic heart failure is a common and complex clinical syndrome that results from impaired cardiac relaxation or contraction. There have been considerable advances in the management of chronic heart failure; however, the mortality rate remains high. Patients with chronic heart failure may experience multiple debilitating symptoms, such as fatigue, pain, and peripheral oedema. However, breathlessness may be considered the most debilitating symptom. The management of chronic heart failure aims to improve the patient's quality of life by reducing symptoms and supporting the patient to manage their condition. Treatment of patients with chronic heart failure may involve a combination of pharmacological therapy, device implantation and cardiac rehabilitation. This is the second of two articles on chronic heart failure. Part 1 discussed the pathophysiology of chronic heart failure, its causes, assessment, signs and symptoms. Part 2 outlines the treatment and management of patients with the condition, including pharmacological strategies, device implantation, lifestyle modification, cardiac rehabilitation and palliative care. PMID- 28075309 TI - BME staff less likely to raise concerns in the workplace. AB - Asian and black healthcare staff are significantly less likely to whistleblow than their white British colleagues, research shows. PMID- 28075312 TI - Pay petition nearing 100,000 signatures. AB - The RCN has renewed its appeal for nurses to sign a petition urging the government to scrap the 1% cap on annual pay rises for NHS staff. PMID- 28075313 TI - Stories of Dignity within Healthcare: Research, Narratives and Theories Tranvag Oscar Synnes Oddgeir and McSherry Wilf Stories of Dignity within Healthcare: Research, Narratives and Theories 212pp L35 M & K Publishers 9781905539970 1905539975 [Formula: see text]. AB - Dignity is fundamental to us all. It is reflected in what we do every day and includes respect, attitudes and behaviour. It applies to the worth we see in ourselves and how we see and treat others. As healthcare professionals, we have our own dignity and also need to ensure we preserve the dignity of others. PMID- 28075314 TI - Sickness absence halved in trial of six-hour day. AB - Assistant nurses taking part in a trial of six-hour working days in Sweden reported higher rates of good health, calmness and alertness. PMID- 28075315 TI - Age and experience. AB - I enjoyed the online article, How to stay enthusiastic after years of nursing (December 27). PMID- 28075316 TI - A portrait of compassion. AB - The film Ethel & Ernest - an animation based on the Raymond Briggs book about the lives of his parents, from marriage to death - should be compulsory viewing for all involved in health care. PMID- 28075318 TI - Deserving Desire: Women's Stories of Sexual Evolution. PMID- 28075317 TI - 'Respect everyone around you'. AB - Estephanie Dunn qualified as a nurse at London's King's College Hospital. She has held clinical, managerial and academic roles, including health visitor, lecturer in nurse education at the University of Northumbria, and director of nursing for South Tyneside Primary Care Trust. She was appointed operational manager for the RCN Northern region in 2009 and has been in her current role as RCN North West regional director since 2014. PMID- 28075319 TI - Couple Relationships in the Middle and Later Years: Their Nature, Complexity, and Role in Health and Illness. PMID- 28075320 TI - Evidence-Based Approaches to Sexuality Education: A Global Perspective. PMID- 28075322 TI - Pathology in Context. PMID- 28075321 TI - Effects of exercise and lifestyle intervention on oxidative stress in chronic kidney disease. AB - OBJECTIVES: Determine the effects of a 12-month exercise and lifestyle intervention program on changes in plasma biomarkers of oxidative stress in pre dialysis chronic kidney disease (CKD) patients. METHODS: A total of 136 stage 3-4 CKD patients were randomized to receive standard nephrological care with (N = 72) or without (N = 64) a lifestyle and exercise intervention for 12 months. Plasma total F2-isoprostanes (IsoP), glutathione peroxidase (GPX) activity, total antioxidant capacity (TAC), anthropometric and biochemical data were collected at baseline and at 12 months. RESULTS: There were no significant differences between groups at baseline. There were no significant differences in changes for standard care and lifestyle intervention, respectively, in IsoP (p = 0.88), GPX (p = 0.87), or TAC (p = 0.56). Patients identified as having high IsoP at baseline (>250 pg/mL) had a greater decrease in IsoP with lifestyle intervention compared to standard care; however, the difference was not statistically significant (p = 0.06). There was no difference in the change in kidney function (eGFR) between standard care and lifestyle intervention (p = 0.33). DISCUSSION: Exercise and lifestyle modification in stage 3-4 CKD did not produce changes in systemic biomarkers of oxidative stress over a 12-month period, but patients with high IsoP may benefit most from the addition of intervention to standard care. PMID- 28075325 TI - Detection of Zika Virus in Desiccated Mosquitoes by Real-Time Reverse Transcription PCR and Plaque Assay. AB - We assayed Zika virus-infected mosquitoes stored at room temperature for <30 days for live virus by using plaque assay and virus RNA by using real-time reverse transcription PCR. Viable virus was detected in samples stored <10 days, and virus RNA was detected in samples held for 30 days. PMID- 28075327 TI - Orbital driven impurity spin effect on the magnetic order of quasi-3D cupric oxide. AB - Density functional calculations are performed to study the magnetic order of the severely distorted square planar cupric oxide (CuO) and local spin disorder in it in the presence of the transition metal impurities M (=Cr, Mn, Fe, Co and Ni). The distortion in the crystal structure, arisen to reduce the band energy by minimizing the covalent interaction, creates two crisscrossing zigzag spin-1/2 chains. From the spin dimer analysis we find that while the spin chain along [Formula: see text] has strong Heisenberg type antiferromagnetic coupling (J ~ 127 meV), along [Formula: see text] it exhibits weak, but robust, ferromagnetic coupling (J ~ 9 meV) mediated by reminiscent p-d covalent interactions. The impurity effect on the magnetic ordering is independent of M and purely orbital driven. If the given spin-state of M is such that the [Formula: see text] orbital is spin-polarized, then the original long-range ordering is maintained. However, if [Formula: see text] orbital is unoccupied, the absence of corresponding covalent interaction breaks the weak ferromagnetic coupling and a spin-flip takes place at the impurity site leading to breakdown of the long range magnetic ordering. PMID- 28075328 TI - Magnetization at the interface of Cr2O3 and paramagnets with large stoner susceptibility. AB - From the Cr 2p3/2 x-ray magnetic circular dichroism signal, there is clear evidence of interface polarization with overlayers of both Pd and Pt on chromia (Cr2O3). The residual boundary polarization of chomia is stronger for a Pt overlayer than in the case of a Pd overlayer. The reduction of chromia boundary magnetization with a paramagnetic metal overlayer, compared to the free surface, is interpreted as a response to the induced spin polarization in Pt and Pd. Magnetization induced in a Pt overlayer, via proximity to the chromia boundary magnetization, is evident in the polar magneto-optical Kerr measurements. These results are essential to explainations why Pt and Pd are excellent spacer layers for voltage controlled exchange bias, in the [Pd/Co] n /Pd/Cr2O3 and [Pt/Co] n /Pt/Cr2O3 perpendicular magneto-electric exchange bias systems. The findings pave the way to realize ultra-fast reversal of induced magnetization in a free moment paramagnetic layer, with possible application in voltage-controlled magnetic random access memory. PMID- 28075329 TI - Fano-Andreev effect in a T-shape double quantum dot in the Kondo regime. AB - In the present work, we investigate the electronic transport through a T-shape double quantum dot system coupled to two normal leads and to one superconducting lead. We explore the interplay between Kondo and Andreev states due to proximity effects. We find that Kondo resonance is modified by the Andreev bound states, which manifest through Fano antiresonances in the local density of states of the embedded quantum dot and normal transmission. This means that there is a correlation between Andreev bound states and Fano resonances that is robust under the influence of high electronic correlation. We have also found that the dominant couplings at the quantum dots are characterized by a crossover region that defines the range where the Fano-Kondo and the Andreev-Kondo effect prevail in each quantum dot. Likewise, we find that the interaction between Kondo and Andreev bound states has a notable influence on the Andreev transport. PMID- 28075326 TI - Transformation of spatiotemporal dynamics in the macaque vestibular system from otolith afferents to cortex. AB - Sensory signals undergo substantial recoding when neural activity is relayed from sensors through pre-thalamic and thalamic nuclei to cortex. To explore how temporal dynamics and directional tuning are sculpted in hierarchical vestibular circuits, we compared responses of macaque otolith afferents with neurons in the vestibular and cerebellar nuclei, as well as five cortical areas, to identical three-dimensional translational motion. We demonstrate a remarkable spatio temporal transformation: otolith afferents carry spatially aligned cosine-tuned translational acceleration and jerk signals. In contrast, brainstem and cerebellar neurons exhibit non-linear, mixed selectivity for translational velocity, acceleration, jerk and position. Furthermore, these components often show dissimilar spatial tuning. Moderate further transformation of translation signals occurs in the cortex, such that similar spatio-temporal properties are found in multiple cortical areas. These results suggest that the first synapse represents a key processing element in vestibular pathways, robustly shaping how self-motion is represented in central vestibular circuits and cortical areas. PMID- 28075330 TI - Building an open-source simulation platform of acoustic radiation force-based breast elastography. AB - Ultrasound-based elastography including strain elastography, acoustic radiation force impulse (ARFI) imaging, point shear wave elastography and supersonic shear imaging (SSI) have been used to differentiate breast tumors among other clinical applications. The objective of this study is to extend a previously published virtual simulation platform built for ultrasound quasi-static breast elastography toward acoustic radiation force-based breast elastography. Consequently, the extended virtual breast elastography simulation platform can be used to validate image pixels with known underlying soft tissue properties (i.e. 'ground truth') in complex, heterogeneous media, enhancing confidence in elastographic image interpretations. The proposed virtual breast elastography system inherited four key components from the previously published virtual simulation platform: an ultrasound simulator (Field II), a mesh generator (Tetgen), a finite element solver (FEBio) and a visualization and data processing package (VTK). Using a simple message passing mechanism, functionalities have now been extended to acoustic radiation force-based elastography simulations. Examples involving three different numerical breast models with increasing complexity-one uniform model, one simple inclusion model and one virtual complex breast model derived from magnetic resonance imaging data, were used to demonstrate capabilities of this extended virtual platform. Overall, simulation results were compared with the published results. In the uniform model, the estimated shear wave speed (SWS) values were within 4% compared to the predetermined SWS values. In the simple inclusion and the complex breast models, SWS values of all hard inclusions in soft backgrounds were slightly underestimated, similar to what has been reported. The elastic contrast values and visual observation show that ARFI images have higher spatial resolution, while SSI images can provide higher inclusion-to background contrast. In summary, our initial results were consistent with our expectations and what have been reported in the literature. The proposed (open source) simulation platform can serve as a single gateway to perform many elastographic simulations in a transparent manner, thereby promoting collaborative developments. PMID- 28075331 TI - Predictive modeling of respiratory tumor motion for real-time prediction of baseline shifts. AB - Baseline shifts in respiratory patterns can result in significant spatiotemporal changes in patient anatomy (compared to that captured during simulation), in turn, causing geometric and dosimetric errors in the administration of thoracic and abdominal radiotherapy. We propose predictive modeling of the tumor motion trajectories for predicting a baseline shift ahead of its occurrence. The key idea is to use the features of the tumor motion trajectory over a 1 min window, and predict the occurrence of a baseline shift in the 5 s that immediately follow (lookahead window). In this study, we explored a preliminary trend-based analysis with multi-class annotations as well as a more focused binary classification analysis. In both analyses, a number of different inter-fraction and intra fraction training strategies were studied, both offline as well as online, along with data sufficiency and skew compensation for class imbalances. The performance of different training strategies were compared across multiple machine learning classification algorithms, including nearest neighbor, Naive Bayes, linear discriminant and ensemble Adaboost. The prediction performance is evaluated using metrics such as accuracy, precision, recall and the area under the curve (AUC) for repeater operating characteristics curve. The key results of the trend-based analysis indicate that (i) intra-fraction training strategies achieve highest prediction accuracies (90.5-91.4%); (ii) the predictive modeling yields lowest accuracies (50-60%) when the training data does not include any information from the test patient; (iii) the prediction latencies are as low as a few hundred milliseconds, and thus conducive for real-time prediction. The binary classification performance is promising, indicated by high AUCs (0.96-0.98). It also confirms the utility of prior data from previous patients, and also the necessity of training the classifier on some initial data from the new patient for reasonable prediction performance. The ability to predict a baseline shift with a sufficient look-ahead window will enable clinical systems or even human users to hold the treatment beam in such situations, thereby reducing the probability of serious geometric and dosimetric errors. PMID- 28075332 TI - Ab initio calculations of the elastic and thermodynamic properties of gold under pressure. AB - The paper presents first-principles FP-LMTO calculations on the relative stability of fcc, bcc, hcp and dhcp gold under pressure. They were done in local density approximation (LDA), as well as in generalized gradient approximation (GGA) with and without spin-orbit interaction. Phonon spectra for the considered gold structures were obtained from LDA calculations within linear response theory and the contribution of lattice vibrations to the free energy of the system was determined in quasiharmonic approximation. Our thorough adjustment of FP-LMTO internal parameters (linearization and tail energies, the MT-sphere radius) helped us to obtain results that agree well with the available experimental phase relation Dubrovinsky et al (2007 Phys. Rev. Lett. 98 045503) between fcc and hcp structures of gold under pressure. The calculations suggest that gold compressed at room temperature successively undergoes the following structural changes: [Formula: see text]. The paper also presents the calculated elastic constants of fcc, bcc and hcp Au, the principal Hugoniot and the melting curve. Calculated results were used to construct the PT-diagram which describes the relative stability of the gold structures under study up to 500 GPa. PMID- 28075333 TI - Magnetic resonance study of bulk and thin film EuTiO3. AB - Magnetic resonance spectra of EuTiO3 in both bulk and thin film form were taken at temperatures from 3-350 K and microwave frequencies from 9.2-9.8 and 34 GHz. In the paramagnetic phase, magnetic resonance spectra are determined by magnetic dipole and exchange interactions between Eu2+ spins. In the film, a large contribution arises from the demagnetization field. From detailed analysis of the linewidth and its temperature dependence, the parameters of spin-spin interactions were determined: the exchange frequency is 10.5 GHz and the estimated critical exponent of the spin correlation length is ~0.4. In the bulk samples, the spectra exhibited a distinct minimum in the linewidth at the Neel temperature, T N ~ 5.5 K, while the resonance field practically does not change even on cooling below T N. This is indicative of a small magnetic anisotropy ~320 G in the antiferromagnetic phase. In the film, the magnetic resonance spectrum is split below T N into several components due to excitation of the magnetostatic modes, corresponding to a non-uniform precession of magnetization. Moreover, the film was observed to degrade over two years. This was manifested by an increase of defects and a change in the domain structure. The saturated magnetization in the film, estimated from the magnetic resonance spectrum, was about 900 emu cm-3 or 5.5 u B/unit cell at T = 3.5 K. PMID- 28075334 TI - Spin and valley-dependent electron transport through arrays of ferromagnet on monolayer MoS2. AB - We theoretically study ballistic transport of Dirac fermions in MoS2 junction through arrays of barriers, of width [Formula: see text], in the presence of a tunable potential of height [Formula: see text] and an exchange field [Formula: see text]. The charge conductance as functions of [Formula: see text] and [Formula: see text], exhibits more conspicuous and sharpened oscillation as the number of barriers increase, due to the contribution of evanescent modes near the edges of the extremum conductance which are exponentially suppressed or enhanced. Furthermore, we found the valley-resolved conductance exhibits a similar oscillating behavior as the charge conductance for multiple barriers, but with inverse oscillatory phases for [Formula: see text] and [Formula: see text], accordingly, a high-efficiency fully valley polarized device is proposed in our system. Also, a perfect 100% spin polarized conductance is observed for 4 barriers and the polarized direction can be switched by changing the direction of exchange field. These findings not only benefit understanding of basic physics in monolayers MoS2, but also provide us a new way to generate a pure and high efficiency spintronics and valleytronics. PMID- 28075335 TI - Towards standardization of x-ray beam filters in digital mammography and digital breast tomosynthesis: Monte Carlo simulations and analytical modelling. AB - In digital breast tomosynthesis and digital mammography, the x-ray beam filter material and thickness vary between systems. Replacing K-edge filters with Al was investigated with the intent to reduce exposure duration and to simplify system design. Tungsten target x-ray spectra were simulated with K-edge filters (50 um Rh; 50 um Ag) and Al filters of varying thickness. Monte Carlo simulations were conducted to quantify the x-ray scatter from various filters alone, scatter-to primary ratio (SPR) with compressed breasts, and to determine the radiation dose to the breast. These data were used to analytically compute the signal-difference to-noise ratio (SDNR) at unit (1 mGy) mean glandular dose (MGD) for W/Rh and W/Ag spectra. At SDNR matched between K-edge and Al filtered spectra, the reductions in exposure duration and MGD were quantified for three strategies: (i) fixed Al thickness and matched tube potential in kilovolts (kV); (ii) fixed Al thickness and varying the kV to match the half-value layer (HVL) between Al and K-edge filtered spectra; and, (iii) matched kV and varying the Al thickness to match the HVL between Al and K-edge filtered spectra. Monte Carlo simulations indicate that the SPR with and without the breast were not different between Al and K-edge filters. Modelling for fixed Al thickness (700 um) and kV matched to K-edge filtered spectra, identical SDNR was achieved with 37-57% reduction in exposure duration and with 2-20% reduction in MGD, depending on breast thickness. Modelling for fixed Al thickness (700 um) and HVL matched by increasing the kV over (0,4) range, identical SDNR was achieved with 62-65% decrease in exposure duration and with 2-24% reduction in MGD, depending on breast thickness. For kV and HVL matched to K-edge filtered spectra by varying Al filter thickness over (700, 880) um range, identical SDNR was achieved with 23-56% reduction in exposure duration and 2-20% reduction in MGD, depending on breast thickness. These simulations indicate that increased fluence with Al filter of fixed or variable thickness substantially decreases exposure duration while providing for similar image quality with moderate reduction in MGD. PMID- 28075336 TI - Multilevel Analysis of Factors Associated with Wasting and Underweight among Children Under-Five Years in Nigeria. AB - Wasting and underweight reflect poor nutrition, which in children leads to retarded growth. The aim of this study is to determine the factors associated with wasting and underweight among children aged 0-59 months in Nigeria. A sample of 24,529 children aged 0-59 months from the 2013 Nigeria Demographic and Health Survey (NDHS) was used. Multilevel logistic regression analysis that adjusted for cluster and survey weights was used to identify significant factors associated with wasting/severe wasting and underweight/severe underweight. The prevalence of wasting was 18% (95% Confidence Interval (CI): 17.1, 19.7) and severe wasting 9% (95% CI: 7.9, 9.8). The prevalence of underweight was 29% (95% CI: 27.1, 30.5) and severe underweight 12% (95% CI: 10.6, 12.9). Multivariable analysis revealed that the most consistent factors associated with wasting/severe wasting and underweight/severe underweight are: geopolitical zone (North East, North West and North Central), perceived birth size (small and average), sex of child (male), place/mode of delivery (home delivery and non-caesarean) and a contraction of fever in the two weeks prior to the survey. In order to meet the WHO's global nutrition target for 2025, interventions aimed at improving maternal health and access to health care services for children especially in the northern geopolitical zones of Nigeria are urgently needed. PMID- 28075337 TI - Implementation of Point-of-Care Diagnostics in Rural Primary Healthcare Clinics in South Africa: Perspectives of Key Stakeholders. AB - INTRODUCTION: Key stakeholders' involvement is crucial to the sustainability of quality point-of-care (POC) diagnostics services in low-and-middle income countries. The aim of this study was to explore key stakeholder perceptions on the implementation of POC diagnostics in rural primary healthcare (PHC) clinics in South Africa. METHOD: We conducted a qualitative study encompassing in-depth interviews with multiple key stakeholders of POC diagnostic services for rural and resource-limited PHC clinics. Interviews were digitally recorded and transcribed verbatim prior to thematic content analysis. Thematic content analysis was conducted using themes guided by the World Health Organisation (WHO) quality-ASSURED (Affordable, Sensitive, Specific, User friendly, Rapid and to enable treatment at first visit and Robust, Equipment free and Delivered to those who need it) criteria for POC diagnostic services in resource-limited settings. RESULTS: 11 key stakeholders participated in the study. All stakeholders perceived the main advantage of POC diagnostics as enabling access to healthcare for rural patients. Stakeholders perceived the current POC diagnostic services to have an ability to meet patients' needs, but recommended further improvement of the following areas: research on cost-effectiveness; improved quality management systems; development of affordable POC diagnostic and clinic-based monitoring and evaluation. CONCLUSIONS: Key stakeholders of POC diagnostics in rural PHC clinics in South Africa highlighted the need to assess affordability and ensure quality assurance of current services before adopting new POC diagnostics and scaling up current POC diagnostics. PMID- 28075338 TI - Maternal Exposure to Pyrethroid Insecticides during Pregnancy and Infant Development at 18 Months of Age. AB - The possible association between maternal exposure to pyrethroid insecticides (PYRs) during pregnancy and infant development was explored. Levels of exposure to PYRs was assessed by metabolite (3-phenoybenzoic acid, 3-PBA) concentration in maternal spot urine sampled in the first trimester of index pregnancy, and infant development was assessed at 18 months of age using the Kinder Infants Development Scale (KIDS), which is based on a questionnaire to the caretaker. The relationship between KIDS score and maternal urinary 3-PBA levels was examined by a stepwise multiple regression analysis using biological attributes of the mother and infant, breast feeding, and nursing environment as covariates. The analysis extracted 3-PBA and the nursing environment as significant to explain the KIDS score at 18 months of age with positive partial regression coefficients. Inclusion of fish consumption frequency of the mother during pregnancy as an independent variable resulted in the selection of fish consumption as significant, while the two variables were marginally insignificant but still with a positive coefficient with the KIDS score. The result suggested a positive effect of maternal PYR exposure on infant development, the reason for which is not clear, but an unknown confounding factor is suspected. PMID- 28075339 TI - NO Exchange for a Water Molecule Favorably Changes Iontophoretic Release of Ruthenium Complexes to the Skin. AB - Ruthenium (Ru) complexes have been studied as promising anticancer agents. Ru nitrosyl complex (Ru-NO) is one which acts as a pro-drug for the release of nitric oxide (NO). The Ru-aqueous complex formed by the exchange of NO for a water molecule after NO release could also possess therapeutic effects. This study evaluates the influence of iontophoresis on enhancing the skin penetration of Ru-NO and Ru-aqueous and assesses its applicability as a tool in treating diverse skin diseases. Passive and iontophoretic (0.5 mA.cm-2) skin permeation of the complexes were performed for 4 h. The amount of Ru and NO in the stratum corneum (SC), viable epidermis (VE), and receptor solution was quantified while the influence of iontophoresis and irradiation on NO release from Ru-NO complex was also evaluated. Iontophoresis increased the amount of Ru-NO and Ru-aqueous recovered from the receptor solution by 15 and 400 times, respectively, as compared to passive permeation. Iontophoresis produced a higher accumulation of Ru-aqueous in the skin layers as compared to Ru-NO. At least 50% of Ru-NO penetrated the SC was stable after 4 h. The presence of Ru-NO in this skin layer suggests that further controlled release of NO can be achieved by photo stimulation after iontophoresis. PMID- 28075341 TI - A Non-Invasive Multichannel Hybrid Fiber-Optic Sensor System for Vital Sign Monitoring. AB - In this article, we briefly describe the design, construction, and functional verification of a hybrid multichannel fiber-optic sensor system for basic vital sign monitoring. This sensor uses a novel non-invasive measurement probe based on the fiber Bragg grating (FBG). The probe is composed of two FBGs encapsulated inside a polydimethylsiloxane polymer (PDMS). The PDMS is non-reactive to human skin and resistant to electromagnetic waves, UV absorption, and radiation. We emphasize the construction of the probe to be specifically used for basic vital sign monitoring such as body temperature, respiratory rate and heart rate. The proposed sensor system can continuously process incoming signals from up to 128 individuals. We first present the overall design of this novel multichannel sensor and then elaborate on how it has the potential to simplify vital sign monitoring and consequently improve the comfort level of patients in long-term health care facilities, hospitals and clinics. The reference ECG signal was acquired with the use of standard gel electrodes fixed to the monitored person's chest using a real-time monitoring system for ECG signals with virtual instrumentation. The outcomes of these experiments have unambiguously proved the functionality of the sensor system and will be used to inform our future research in this fast developing and emerging field. PMID- 28075342 TI - Trunk Motion System (TMS) Using Printed Body Worn Sensor (BWS) via Data Fusion Approach. AB - Human movement analysis is an important part of biomechanics and rehabilitation, for which many measurement systems are introduced. Among these, wearable devices have substantial biomedical applications, primarily since they can be implemented both in indoor and outdoor applications. In this study, a Trunk Motion System (TMS) using printed Body-Worn Sensors (BWS) is designed and developed. TMS can measure three-dimensional (3D) trunk motions, is lightweight, and is a portable and non-invasive system. After the recognition of sensor locations, twelve BWSs were printed on stretchable clothing with the purpose of measuring the 3D trunk movements. To integrate BWSs data, a neural network data fusion algorithm was used. The outcome of this algorithm along with the actual 3D anatomical movements (obtained by Qualisys system) were used to calibrate the TMS. Three healthy participants with different physical characteristics participated in the calibration tests. Seven different tasks (each repeated three times) were performed, involving five planar, and two multiplanar movements. Results showed that the accuracy of TMS system was less than 1.0 degrees , 0.8 degrees , 0.6 degrees , 0.8 degrees , 0.9 degrees , and 1.3 degrees for flexion/extension, left/right lateral bending, left/right axial rotation, and multi-planar motions, respectively. In addition, the accuracy of TMS for the identified movement was less than 2.7 degrees . TMS, developed to monitor and measure the trunk orientations, can have diverse applications in clinical, biomechanical, and ergonomic studies to prevent musculoskeletal injuries, and to determine the impact of interventions. PMID- 28075343 TI - A Fast Synthetic Aperture Radar Raw Data Simulation Using Cloud Computing. AB - Synthetic Aperture Radar (SAR) raw data simulation is a fundamental problem in radar system design and imaging algorithm research. The growth of surveying swath and resolution results in a significant increase in data volume and simulation period, which can be considered to be a comprehensive data intensive and computing intensive issue. Although several high performance computing (HPC) methods have demonstrated their potential for accelerating simulation, the input/output (I/O) bottleneck of huge raw data has not been eased. In this paper, we propose a cloud computing based SAR raw data simulation algorithm, which employs the MapReduce model to accelerate the raw data computing and the Hadoop distributed file system (HDFS) for fast I/O access. The MapReduce model is designed for the irregular parallel accumulation of raw data simulation, which greatly reduces the parallel efficiency of graphics processing unit (GPU) based simulation methods. In addition, three kinds of optimization strategies are put forward from the aspects of programming model, HDFS configuration and scheduling. The experimental results show that the cloud computing based algorithm achieves 4_ speedup over the baseline serial approach in an 8-node cloud environment, and each optimization strategy can improve about 20%. This work proves that the proposed cloud algorithm is capable of solving the computing intensive and data intensive issues in SAR raw data simulation, and is easily extended to large scale computing to achieve higher acceleration. PMID- 28075344 TI - Pull-In Effect of Suspended Microchannel Resonator Sensor Subjected to Electrostatic Actuation. AB - In this article, the pull-in instability and dynamic characteristics of electrostatically actuated suspended microchannel resonators are studied. A theoretical model is presented to describe the pull-in effect of suspended microchannel resonators by considering the electrostatic field and the internal fluid. The results indicate that the system is subjected to both the pull-in instability and the flutter. The former is induced by the applied voltage which exceeds the pull-in value while the latter occurs as the velocity of steady flow get closer to the critical velocity. The statically and dynamically stable regions are presented by thoroughly studying the two forms of instability. It is demonstrated that the steady flow can remarkably extend the dynamic stable range of pull-in while the applied voltage slightly decreases the critical velocity. It is also shown that the dc voltage and the steady flow can adjust the resonant frequency while the ac voltage can modulate the vibrational amplitude of the resonator. PMID- 28075345 TI - Software Defined Doppler Radar as a Contactless Multipurpose Microwave Sensor for Vibrations Monitoring. AB - A vibration sensor based on the use of a Software-Defined Radio (SDR) platform is adopted in this work to provide a contactless and multipurpose solution for low cost real-time vibrations monitoring. In order to test the vibration detection ability of the proposed non-contact method, a 1 GHz Doppler radar sensor is simulated and successfully assessed on targets at various distances, with various oscillation frequencies and amplitudes. Furthermore, an SDR Doppler platform is practically realized, and preliminary experimental validations on a device able to produce a harmonic motion are illustrated to prove the effectiveness of the proposed approach. PMID- 28075340 TI - Bioactive Nutrients and Nutrigenomics in Age-Related Diseases. AB - The increased life expectancy and the expansion of the elderly population are stimulating research into aging. Aging may be viewed as a multifactorial process that results from the interaction of genetic and environmental factors, which include lifestyle. Human molecular processes are influenced by physiological pathways as well as exogenous factors, which include the diet. Dietary components have substantive effects on metabolic health; for instance, bioactive molecules capable of selectively modulating specific metabolic pathways affect the development/progression of cardiovascular and neoplastic disease. As bioactive nutrients are increasingly identified, their clinical and molecular chemopreventive effects are being characterized and systematic analyses encompassing the "omics" technologies (transcriptomics, proteomics and metabolomics) are being conducted to explore their action. The evolving field of molecular pathological epidemiology has unique strength to investigate the effects of dietary and lifestyle exposure on clinical outcomes. The mounting body of knowledge regarding diet-related health status and disease risk is expected to lead in the near future to the development of improved diagnostic procedures and therapeutic strategies targeting processes relevant to nutrition. The state of the art of aging and nutrigenomics research and the molecular mechanisms underlying the beneficial effects of bioactive nutrients on the main aging related disorders are reviewed herein. PMID- 28075346 TI - Automated Surveillance of Fruit Flies. AB - Insects of the Diptera order of the Tephritidae family cause costly, annual crop losses worldwide. Monitoring traps are important components of integrated pest management programs used against fruit flies. Here we report the modification of typical, low-cost plastic traps for fruit flies by adding the necessary optoelectronic sensors to monitor the entrance of the trap in order to detect, time-stamp, GPS tag, and identify the species of incoming insects from the optoacoustic spectrum analysis of their wingbeat. We propose that the incorporation of automated streaming of insect counts, environmental parameters and GPS coordinates into informative visualization of collective behavior will finally enable better decision making across spatial and temporal scales, as well as administrative levels. The device presented is at product level of maturity as it has solved many pending issues presented in a previously reported study. PMID- 28075347 TI - SDTCP: Towards Datacenter TCP Congestion Control with SDN for IoT Applications. AB - The Internet of Things (IoT) has gained popularity in recent years. Today's IoT applications are now increasingly deployed in cloud platforms to perform Big Data analytics. In cloud data center networks (DCN), TCP incast usually happens when multiple senders simultaneously communicate with a single receiver. However, when TCP incast happens, DCN may suffer from both throughput collapse for TCP burst flows and temporary starvation for TCP background flows. In this paper, we propose a software defined network (SDN)-based TCP congestion control mechanism, referred to as SDTCP, to leverage the features, e.g., centralized control methods and the global view of the network, in order to solve the TCP incast problems. When we detect network congestion on an OpenFlow switch, our controller can select the background flows and reduce their bandwidth by adjusting the advertised window of TCP ACK packets of the corresponding background flows so as to reserve more bandwidth for burst flows. SDTCP is transparent to the end systems and can accurately decelerate the rate of background flows by leveraging the global view of the network gained via SDN. The experiments demonstrate that our SDTCP can provide high tolerance for burst flows and achieve better flow completion time for short flows. Therefore, SDTCP is an effective and scalable solution for the TCP incast problem. PMID- 28075348 TI - A Novel Monopulse Technique for Adaptive Phased Array Radar. AB - The monopulse angle measuring technique is widely adopted in radar systems due to its simplicity and speed in accurately acquiring a target's angle. However, in a spatial adaptive array, beam distortion, due to adaptive beamforming, can result in serious deterioration of monopulse performance. In this paper, a novel constrained monopulse angle measuring algorithm is proposed for spatial adaptive arrays. This algorithm maintains the ability to suppress the unwanted signals without suffering from beam distortion. Compared with conventional adaptive monopulse methods, the proposed algorithm adopts a new form of constraint in forming the difference beam with the merit that it is more robust in most practical situations. At the same time, it also exhibits the simplicity of one dimension monopulse, helping to make this algorithm even more appealing to use in adaptive planar arrays. The theoretical mean and variance of the proposed monopulse estimator is derived for theoretical analysis. Mathematical simulations are formulated to demonstrate the effectiveness and advantages of the proposed algorithm. Both theoretical analysis and simulation results show that the proposed algorithm can outperform the conventional adaptive monopulse methods in the presence of severe interference near the mainlobe. PMID- 28075349 TI - Transthyretin: A Transporter Protein Essential for Proliferation of Myoblast in the Myogenic Program. AB - Irregularities in the cellular uptake of thyroid hormones significantly affect muscle development and regeneration. Herein, we report indispensable role of transthyretin (TTR) in maintaining cellular thyroxine level. TTR was found to enhance recruitment of muscle satellite cells to the site of injury, thereby regulating muscle regeneration. Fluorescence-activated cell sorting (FACS) and immunofluorescence analysis of TTRwt (TTR wild type) and TTRkd (TTR knock-down) cells revealed that TTR controlled cell cycle progression by affecting the expression of Cyclin A2. Deiodinase 2 (D2) mediated increases in triiodothyronine levels were found to regulate the expression of myogenic marker, myogenin (MYOG). Moreover, use of a coumarin derivative (CD) revealed a significant reduction in cellular thyroxine, thereby indicating that TTR play a role in the transport of thyroxine. Taken together, these findings suggest that TTR mediated transport of thyroxine represents a survival mechanism necessary for the myogenic program. The results of this study will be highly useful to the strategic development of novel therapeutics to combat muscular dystrophies. PMID- 28075350 TI - Hydroxypyridinone Chelators: From Iron Scavenging to Radiopharmaceuticals for PET Imaging with Gallium-68. AB - Derivatives of 3,4-hydroxypyridinones have been extensively studied for in vivo Fe3+ sequestration. Deferiprone, a 1,2-dimethyl-3,4-hydroxypyridinone, is now routinely used for clinical treatment of iron overload disease. Hexadentate tris(3,4-hydroxypyridinone) ligands (THP) complex Fe3+ at very low iron concentrations, and their high affinities for oxophilic trivalent metal ions have led to their development for new applications as bifunctional chelators for the positron emitting radiometal, 68Ga3+, which is clinically used for molecular imaging in positron emission tomography (PET). THP-peptide bioconjugates rapidly and quantitatively complex 68Ga3+ at ambient temperature, neutral pH and micromolar concentrations of ligand, making them amenable to kit-based radiosynthesis of 68Ga PET radiopharmaceuticals. 68Ga-labelled THP-peptides accumulate at target tissue in vivo, and are excreted largely via a renal pathway, providing high quality PET images. PMID- 28075352 TI - A Case Study of Upper-Room UVGI in Densely-Occupied Elementary Classrooms by Real Time Fluorescent Bioaerosol Measurements. AB - Recently, the requirement to continuously collect bioaerosol samples using shorter response times has called for the use of real-time detection. The decreased cost of this technology makes it available for a wider application than military use, and makes it accessible to pharmaceutical and academic research. In this case study, real-time bioaerosol monitors (RBMs) were applied in elementary school classrooms-a densely occupied environment-along with upper-room ultraviolet germicidal irradiation (UVGI) devices. The classrooms were separated into a UVGI group and a non-UVGI control group. Fluorescent bioaerosol counts (FBCs) were monitored on 20 visiting days over a four-month period. The classroom with upper-room UVGI showed significantly lower concentrations of fine size (<3 MUm) and total FBCs than the control classroom during 13 of the 20 visiting days. The results of the study indicate that the upper-room UVGI could be effective in reducing FBCs in the school environment, and RBMs may be applicable in reflecting the transient conditions of the classrooms due to the dynamic activity levels of the students and teachers. PMID- 28075351 TI - Circulating Nucleosomes and Nucleosome Modifications as Biomarkers in Cancer. AB - Traditionally the stratification of many cancers involves combining tumour and clinicopathological features (e.g., patient age; tumour size, grade, receptor status and location) to inform treatment options and predict recurrence risk and survival. However, current biomarkers often require invasive excision of the tumour for profiling, do not allow monitoring of the response to treatment and stratify patients into broad heterogeneous groups leading to inconsistent treatment responses. Here we explore and describe the benefits of using circulating biomarkers (nucleosomes and/or modifications to nucleosomes) as a non invasive method for detecting cancer and monitoring response to treatment. Nucleosomes (DNA wound around eight core histone proteins) are responsible for compacting our genome and their composition and post-translational modifications are responsible for regulating gene expression. Here, we focus on breast and colorectal cancer as examples where utilizing circulating nucleosomes as biomarkers hold real potential as liquid biopsies. Utilizing circulating nucleosomes as biomarkers is an exciting new area of research that promises to allow both the early detection of cancer and monitoring of treatment response. Nucleosome-based biomarkers combine with current biomarkers, increasing both specificity and sensitivity of current tests and have the potential to provide individualised precision-medicine based treatments for patients. PMID- 28075353 TI - Biochemical and Structural Insights into a Novel Thermostable beta-1,3 Galactosidase from Marinomonas sp. BSi20414. AB - A novel beta-1,3-galactosidase, designated as MaBGA (beta-galactosidase from Marinomonas sp. BSi20414), was successfully purified to homogeneity from Marinomonas sp. BSi20414 isolated from Arctic sea ice by ammonium sulfate precipitation and anion exchange chromatography, resulting in an 8.12-fold increase in specific activity and 9.9% recovery in total activity. MaBGA displayed its maximum activity at pH 6.0 and 60 degrees C, and maintained at least 90% of its initial activity over the pH range of 5.0-8.0 after incubating for 1 h. It also exhibited considerable thermal stability, which retained 76% of its initial activity after incubating at 50 degrees C for 6 h. In contrast to other beta-galactosidases, MaBGA displayed strict substrate specificity, not only for the glycosyl group, but also for the linkage type. To better understand the structure-function relationship, the encoding gene of MaBGA was obtained and subject to bioinformatics analysis. Multiple alignments and phylogenetic analysis revealed that MaBGA belonged to the glycoside hydrolase family 42 and had closer genetic relationships with thermophilic beta-galactosidases of extremophiles. With the aid of homology modeling and molecular docking, we proposed a reasonable explanation for the linkage selectivity of MaBGA from a structural perspective. On account of the robust stability and 1,3-linkage selectivity, MaBGA would be a promising candidate in the biosynthesis of galacto-oligosaccharide with beta1-3 linkage. PMID- 28075354 TI - The State of the Art of Lethal Oviposition Trap-Based Mass Interventions for Arboviral Control. AB - The intensifying expansion of arboviruses highlights the need for effective invasive Aedes control. While mass-trapping interventions have long been discredited as inefficient compared to insecticide applications, increasing levels of insecticide resistance, and the development of simple affordable traps that target and kill gravid female mosquitoes, show great promise. We summarize the methodologies and outcomes of recent lethal oviposition trap-based mass interventions for suppression of urban Aedes and their associated diseases. The evidence supports the recommendation of mass deployments of oviposition traps to suppress populations of invasive Aedes, although better measures of the effects on disease control are needed. Strategies associated with successful mass-trap deployments include: (1) high coverage (>80%) of the residential areas; (2) pre intervention and/or parallel source reduction campaigns; (3) direct involvement of community members for economic long-term sustainability; and (4) use of new generation larger traps (Autocidal Gravid Ovitrap, AGO; Gravid Aedes Trap, GAT) to outcompete remaining water-holding containers. While to the best of our knowledge all published studies so far have been on Ae. aegypti in resource-poor or tropical settings, we propose that mass deployment of lethal oviposition traps can be used for focused cost-effective control of temperate Ae. albopictus pre empting arboviral epidemics and increasing participation of residents in urban mosquito control. PMID- 28075355 TI - The CSIRO Healthy Diet Score: An Online Survey to Estimate Compliance with the Australian Dietary Guidelines. AB - There are few dietary assessment tools that are scientifically developed and freely available online. The Commonwealth Scientific and Industrial Research Organisation (CSIRO) Healthy Diet Score survey asks questions about the quantity, quality, and variety of foods consumed. On completion, individuals receive a personalised Diet Score-reflecting their overall compliance with the Australian Dietary Guidelines. Over 145,000 Australians have completed the survey since it was launched in May 2015. The average Diet Score was 58.8 out of a possible 100 (SD = 12.9). Women scored higher than men; older adults higher than younger adults; and normal weight adults higher than obese adults. It was most common to receive feedback about discretionary foods (73.8% of the sample), followed by dairy foods (55.5%) and healthy fats (47.0%). Results suggest that Australians' diets are not consistent with the recommendations in the guidelines. The combination of using technology and providing the tool free of charge has attracted a lot of traffic to the website, providing valuable insights into what Australians' report to be eating. The use of technology has also enhanced the user experience, with individuals receiving immediate and personalised feedback. This survey tool will be useful to monitor population diet quality and understand the degree to Australians' diets comply with dietary guidelines. PMID- 28075357 TI - Correlations between Endomyocardial Biopsies and Cardiac Manifestations in Taiwanese Patients with the Chinese Hotspot IVS4+919G>A Mutation: Data from the Fabry Outcome Survey. AB - We retrospectively evaluated correlations between cardiac manifestations and globotriaosylceramide (Gb3) accumulation in cardiomyocytes from Taiwanese patients with Fabry disease and the IVS4+919G>A (IVS4) mutation who underwent endomyocardial biopsy (Shire; Fabry Outcome Survey data; extracted January 2015). Of 24 males and six females (median age [Q1; Q3] at biopsy 60.4 [57.4; 64.1] and 61.3 [60.4; 65.1] years, respectively), 13 males (54.2%) and five females (83.3%) received agalsidase alfa enzyme replacement therapy (ERT) before biopsy. Median left ventricular mass indexed to height (LVMI) within +/-6 months of biopsy was 65.3 (52.7; 93.1) in males and 53.2 (42.0; 55.0) g/m2.7 in females. A moderate, positive, statistically significant correlation was found between the percentage area Gb3 accumulation in cardiomyocytes and LVMI (Spearman's rho, 0.45; p = 0.014); a smaller, positive, non-statistically significant correlation was observed between cardiomyocyte diameter and LVMI (Spearman's rho 0.16, p = 0.394). Moderate, statistically significant, negative correlations were found between Gb3 accumulation and ERT duration (Spearman's rho, -0.49, p = 0.007) and between cardiomyocyte size and ERT duration (Spearman's rho, -0.37, p = 0.048). Longer ERT duration was associated with smaller amounts of Gb3 accumulation and smaller cardiomyocyte size. Further follow-up is recommended to confirm these trends in a larger sample size. PMID- 28075356 TI - Targeting MicroRNAs in Cancer Gene Therapy. AB - MicroRNAs (miRNAs) are a kind of conserved small non-coding RNAs that participate in regulating gene expression by targeting multiple molecules. Early studies have shown that the expression of miRNAs changes significantly in different tumor tissues and cancer cell lines. It is well acknowledged that such variation is involved in almost all biological processes, including cell proliferation, mobility, survival and differentiation. Increasing experimental data indicate that miRNA dysregulation is a biomarker of several pathological conditions including cancer, and that miRNA can exert a causal role, as oncogenes or tumor suppressor genes, in different steps of the tumorigenic process. Anticancer therapies based on miRNAs are currently being developed with a goal to improve outcomes of cancer treatment. In our present study, we review the function of miRNAs in tumorigenesis and development, and discuss the latest clinical applications and strategies of therapy targeting miRNAs in cancer. PMID- 28075358 TI - Diet Quality during Infancy and Early Childhood in Children with and without Risk of Type 1 Diabetes: A DEDIPAC Study. AB - Previous studies have indicated that mothers of children at increased risk of type 1 diabetes (T1D) may modify their child's diet following risk notification. Our aim was to investigate the diet quality after notified of T1D risk in at-risk children compared to not-at-risk children. The quality of nutrient intake (PANDiet score) and food intake (analyzed by a newly developed score and the HuSKY score) were assessed using three-day dietary records collected for at-risk children (BABYDIET study, n = 109) and a matched sample of not-at-risk children (DONALD study, n = 205) at nine and 24 months of age. Nutrient and food intake quality were lower at nine months of age and food intake quality was lower at 24 months of age in at-risk than in not-at-risk children (p = 0.01 and p < 0.0001, respectively). The amount of added sugar was higher in at-risk children at both ages (p < 0.0001). In at-risk children, dietary quality was similar between children who were first exposed to gluten at six or 12 months of age. Despite being notified about their child's risk of T1D, the child's mother did not switch to healthier diets compared with not-at-risk mothers. PMID- 28075359 TI - Development of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining. AB - Protein kinase CK2, initially designated as casein kinase 2, is an ubiquitously expressed serine/threonine kinase. This enzyme, implicated in many cellular processes, is highly expressed and active in many tumor cells. A large number of compounds has been developed as inhibitors comprising different backbones. Beside others, structures with an indeno[1,2-b]indole scaffold turned out to be potent new leads. With the aim of developing new inhibitors of human protein kinase CK2, we report here on the generation of common feature pharmacophore model to further explain the binding requirements for human CK2 inhibitors. Nine common chemical features of indeno[1,2-b]indole-type CK2 inhibitors were determined using MOE software (Chemical Computing Group, Montreal, Canada). This pharmacophore model was used for database mining with the aim to identify novel scaffolds for developing new potent and selective CK2 inhibitors. Using this strategy several structures were selected by searching inside the ZINC compound database. One of the selected compounds was bikaverin (6,11-dihydroxy-3,8-dimethoxy-1 methylbenzo[b]xanthene-7,10,12-trione), a natural compound which is produced by several kinds of fungi. This compound was tested on human recombinant CK2 and turned out to be an active inhibitor with an IC50 value of 1.24 uM. PMID- 28075360 TI - Design and Integration for High Performance Robotic Systems Based on Decomposition and Hybridization Approaches. AB - Currently, the uses of robotics are limited with respect to performance capabilities. Improving the performance of robotic mechanisms is and still will be the main research topic in the next decade. In this paper, design and integration for improving performance of robotic systems are achieved through three different approaches, i.e., structure synthesis design approach, dynamic balancing approach, and adaptive control approach. The purpose of robotic mechanism structure synthesis design is to propose certain mechanism that has better kinematic and dynamic performance as compared to the old ones. For the dynamic balancing design approach, it is normally accomplished based on employing counterweights or counter-rotations. The potential issue is that more weight and inertia will be included in the system. Here, reactionless based on the reconfiguration concept is put forward, which can address the mentioned problem. With the mechanism reconfiguration, the control system needs to be adapted thereafter. One way to address control system adaptation is by applying the "divide and conquer" methodology. It entails modularizing the functionalities: breaking up the control functions into small functional modules, and from those modules assembling the control system according to the changing needs of the mechanism. PMID- 28075362 TI - Transparency of Mandatory Information Disclosure and Concerns of Health Services Providers and Consumers. AB - BACKGROUND: This study analyzed differences between transparency of information disclosure and related demands from the health service consumer's perspective. It also compared how health service providers and consumers are associated by different levels of mandatory information disclosure. METHODS: We obtained our research data using a questionnaire survey (health services providers, n = 201; health service consumers, n = 384). RESULTS: Health service consumers do not have major concerns regarding mandatory information disclosure. However, they are concerned about complaint channels and settlement results, results of patient satisfaction surveys, and disclosure of hospital financial statements (p < 0.001). We identified significant differences in health service providers' and consumers' awareness regarding the transparency of information disclosure (p < 0.001). CONCLUSIONS: It may not be possible for outsiders to properly interpret the information provided by hospitals. Thus, when a hospital discloses information, it is necessary for the government to consider the information's applicability. Toward improving medical expertise and information asymmetry, the government has to reduce the burden among health service consumers in dealing with this information, and it has to use the information effectively. PMID- 28075361 TI - Role of IRE1alpha/XBP-1 in Cystic Fibrosis Airway Inflammation. AB - Cystic fibrosis (CF) pulmonary disease is characterized by chronic airway infection and inflammation. The infectious and inflamed CF airway environment impacts on the innate defense of airway epithelia and airway macrophages. The CF airway milieu induces an adaptation in these cells characterized by increased basal inflammation and a robust inflammatory response to inflammatory mediators. Recent studies have indicated that these responses depend on activation of the unfolded protein response (UPR). This review discusses the contribution of airway epithelia and airway macrophages to CF airway inflammatory responses and specifically highlights the functional importance of the UPR pathway mediated by IRE1/XBP-1 in these processes. These findings suggest that targeting the IRE1/XBP 1 UPR pathway may be a therapeutic strategy for CF airway disease. PMID- 28075363 TI - Maternal and Child Health of Internally Displaced Persons in Ukraine: A Qualitative Study. AB - Due to the conflict that started in spring 2014 in Eastern Ukraine, a total of 1.75 million internally displaced persons (IDPs) fled the area and have been registered in government-controlled areas of the country. This paper explores perceived health, barriers to access to healthcare, caring practices, food security, and overall financial situation of mothers and young children displaced by the conflict in Ukraine. This is a qualitative study, which collected data through semi-structured in-depth interviews with nine IDP mothers via Skype and Viber with a convenience sample of participants selected through snowball technique. Contrary to the expectations, the perceived physical health of mothers and their children was found not to be affected by conflict and displacement, while psychological distress was often reported. A weak healthcare system, Ukraine's proneness to informal payments, and heavy bureaucracy to register as an IDP were reported in our study. A precarious social safety net to IDP mothers in Ukraine, poor dietary diversity, and a generalized rupture of vaccine stocks, with halted or delayed vaccinations in children were identified. Increasing social allowances and their timely delivery to IDP mothers might be the most efficient policy measure to improve health and nutrition security. Reestablishment and sustainability of vaccine stocks in Ukraine is urgent to avoid the risks of a public health crisis. Offering psychological support for IDP mothers is recommended. PMID- 28075364 TI - A Social Potential Fields Approach for Self-Deployment and Self-Healing in Hierarchical Mobile Wireless Sensor Networks. AB - Autonomous mobile nodes in mobile wireless sensor networks (MWSN) allow self deployment and self-healing. In both cases, the goals are: (i) to achieve adequate coverage; and (ii) to extend network life. In dynamic environments, nodes may use reactive algorithms so that each node locally decides when and where to move. This paper presents a behavior-based deployment and self-healing algorithm based on the social potential fields algorithm. In the proposed algorithm, nodes are attached to low cost robots to autonomously navigate in the coverage area. The proposed algorithm has been tested in environments with and without obstacles. Our study also analyzes the differences between non hierarchical and hierarchical routing configurations in terms of network life and coverage. PMID- 28075365 TI - A Two-Phase Coverage-Enhancing Algorithm for Hybrid Wireless Sensor Networks. AB - Providing field coverage is a key task in many sensor network applications. In certain scenarios, the sensor field may have coverage holes due to random initial deployment of sensors; thus, the desired level of coverage cannot be achieved. A hybrid wireless sensor network is a cost-effective solution to this problem, which is achieved by repositioning a portion of the mobile sensors in the network to meet the network coverage requirement. This paper investigates how to redeploy mobile sensor nodes to improve network coverage in hybrid wireless sensor networks. We propose a two-phase coverage-enhancing algorithm for hybrid wireless sensor networks. In phase one, we use a differential evolution algorithm to compute the candidate's target positions in the mobile sensor nodes that could potentially improve coverage. In the second phase, we use an optimization scheme on the candidate's target positions calculated from phase one to reduce the accumulated potential moving distance of mobile sensors, such that the exact mobile sensor nodes that need to be moved as well as their final target positions can be determined. Experimental results show that the proposed algorithm provided significant improvement in terms of area coverage rate, average moving distance, area coverage-distance rate and the number of moved mobile sensors, when compare with other approaches. PMID- 28075366 TI - Stepwise, Protecting Group Free Synthesis of [4]Rotaxanes. AB - Despite significant advances in the last three decades towards high yielding syntheses of rotaxanes, the preparation of systems constructed from more than two components remains a challenge. Herein we build upon our previous report of an active template copper-catalyzed azide-alkyne cycloaddition (CuAAC) rotaxane synthesis with a diyne in which, following the formation of the first mechanical bond, the steric bulk of the macrocycle tempers the reactivity of the second alkyne unit. We have now extended this approach to the use of 1,3,5 triethynylbenzene in order to successively prepare [2]-, [3]- and [4]rotaxanes without the need for protecting group chemistry. Whilst the first two iterations proceeded in good yield, the steric shielding that affords this selectivity also significantly reduces the efficacy of the active template (AT)-CuAAC reaction of the third alkyne towards the preparation of [4]rotaxanes, resulting in severely diminished yields. PMID- 28075367 TI - High-Performance Anti-Retransmission Deception Jamming Utilizing Range Direction Multiple Input and Multiple Output (MIMO) Synthetic Aperture Radar (SAR). AB - Retransmission deception jamming seriously degrades the Synthetic Aperture Radar (SAR) detection efficiency and can mislead SAR image interpretation by forming false targets. In order to suppress retransmission deception jamming, this paper proposes a novel multiple input and multiple output (MIMO) SAR structure range direction MIMO SAR, whose multiple channel antennas are vertical to the azimuth. First, based on the multiple channels of range direction MIMO SAR, the orthogonal frequency division multiplexing (OFDM) linear frequency modulation (LFM) signal was adopted as the transmission signal of each channel, which is defined as a sub band signal. This sub-band signal corresponds to the transmission channel. Then, all of the sub-band signals are modulated with random initial phases and concurrently transmitted. The signal form is more complex and difficult to intercept. Next, the echoes of the sub-band signal are utilized to synthesize a wide band signal after preprocessing. The proposed method will increase the signal to interference ratio and peak amplitude ratio of the signal to resist retransmission deception jamming. Finally, well-focused SAR imagery is obtained using a conventional imaging method where the retransmission deception jamming strength is degraded and defocused. Simulations demonstrated the effectiveness of the proposed method. PMID- 28075369 TI - Validation of a Dish-Based Semiquantitative Food Questionnaire in Rural Bangladesh. AB - A locally validated tool was needed to evaluate long-term dietary intake in rural Bangladesh. We assessed the validity of a 42-item dish-based semi-quantitative food frequency questionnaire (FFQ) using two 3-day food diaries (FDs). We selected a random subset of 47 families (190 participants) from a longitudinal arsenic biomonitoring study in Bangladesh to administer the FFQ. Two 3-day FDs were completed by the female head of the households and we used an adult male equivalent method to estimate the FD for the other participants. Food and nutrient intakes measured by FFQ and FD were compared using Pearson's and Spearman's correlation, paired t-test, percent difference, cross-classification, weighted Kappa, and Bland-Altman analysis. Results showed good validity for total energy intake (paired t-test, p < 0.05; percent difference <10%), with no presence of proportional bias (Bland-Altman correlation, p > 0.05). After energy adjustment and de-attenuation for within-person variation, macronutrient intakes had excellent correlations ranging from 0.55 to 0.70. Validity for micronutrients was mixed. High intraclass correlation coefficients (ICCs) were found for most nutrients between the two seasons, except vitamin A. This dish-based FFQ provided adequate validity to assess and rank long-term dietary intake in rural Bangladesh for most food groups and nutrients, and should be useful for studying dietary disease relationships. PMID- 28075368 TI - Critical Windows of Prenatal Exposure to Cadmium and Size at Birth. AB - Prenatal cadmium (Cd) exposure has been associated with adverse birth outcomes, but the findings of previous studies are inconsistent. We measured Cd concentrations in urine samples at or near 13, 24, and 35 gestational weeks from 282 women in Wuhan, China. We used generalized estimating equation models to assess the associations between maternal creatinine adjusted urinary Cd concentrations at each trimester and birth size. A significant inverse association was observed between higher maternal Cd levels measured during the 1st trimester and birth size in girls. For each log unit increase in Cd (ug/g creatinine) levels from the 1st trimester, there was a decrease in birth weight by 116.99 g (95% confidence interval (CI): -208.87, -25.11 g). The Cd levels from the 1st and 2nd trimesters were also borderline significantly associated with ponderal index in girls. Joint estimation of trimester-specific effects suggested that associations with Cd levels for ponderal index (pint = 0.02) were significantly different across trimesters, and differences for effects across trimesters for birth weight were marginally significant (pint = 0.08) in girls. No significant associations were observed between Cd levels from any trimester and birth size in boys. Maternal Cd exposure during earlier periods of pregnancy may have a larger impact on delayed fetal growth. PMID- 28075371 TI - Dynamic Oil-in-Water Concentration Acquisition on a Pilot-Scaled Offshore Water Oil Separation Facility. AB - This article is a feasibility study on using fluorescence-based oil-in-water (OiW) monitors for on-line dynamic efficiency measurement of a deoiling hydrocyclone. Dynamic measurements are crucial in the design and validation of dynamic models of the hydrocyclones, and to our knowledge, no dynamic OiW analysis of hydrocyclones has been carried out. Previous studies have extensively studied the steady state efficiency perspective of hydrocyclones, and have related them to different key parameters, such as the pressure drop ratio (PDR), inlet flow rate, and the flow-spilt. Through our study, we were able to measure the dynamics of the hydrocyclone's efficiency ( epsilon ) response to step changes in the inlet flow rate with high accuracy. This is a breakthrough in the modelling, control, and monitoring of hydrocyclones. PMID- 28075370 TI - Effect of Carotenoid Supplemented Formula on Carotenoid Bioaccumulation in Tissues of Infant Rhesus Macaques: A Pilot Study Focused on Lutein. AB - Lutein is the predominant carotenoid in the developing primate brain and retina, and may have important functional roles. However, its bioaccumulation pattern during early development is not understood. In this pilot study, we investigated whether carotenoid supplementation of infant formula enhanced lutein tissue deposition in infant rhesus macaques. Monkeys were initially breastfed; from 1 to 3 months of age they were fed either a formula supplemented with lutein, zeaxanthin, beta-carotene and lycopene, or a control formula with low levels of these carotenoids, for 4 months (n = 2/group). All samples were analyzed by high pressure liquid chromatography (HPLC). Final serum lutein in the supplemented group was 5 times higher than in the unsupplemented group. All brain regions examined showed a selective increase in lutein deposition in the supplemented infants. Lutein differentially accumulated across brain regions, with highest amounts in occipital cortex in both groups. beta-carotene accumulated, but zeaxanthin and lycopene were undetectable in any brain region. Supplemented infants had higher lutein concentrations in peripheral retina but not in macular retina. Among adipose sites, abdominal subcutaneous adipose tissue exhibited the highest lutein level and was 3-fold higher in the supplemented infants. The supplemented formula enhanced carotenoid deposition in several other tissues. In rhesus infants, increased intake of carotenoids from formula enhanced their deposition in serum and numerous tissues and selectively increased lutein in multiple brain regions. PMID- 28075372 TI - Distributed Sensor Nodes Charged by Mobile Charger with Directional Antenna and by Energy Trading for Balancing. AB - Provision of energy to wireless sensor networks is crucial for their sustainable operation. Sensor nodes are typically equipped with batteries as their operating energy sources. However, when the sensor nodes are sited in almost inaccessible locations, replacing their batteries incurs high maintenance cost. Under such conditions, wireless charging of sensor nodes by a mobile charger with an antenna can be an efficient solution. When charging distributed sensor nodes, a directional antenna, rather than an omnidirectional antenna, is more energy efficient because of smaller proportion of off-target radiation. In addition, for densely distributed sensor nodes, it can be more effective for some undercharged sensor nodes to harvest energy from neighboring overcharged sensor nodes than from the remote mobile charger, because this reduces the pathloss of charging signal due to smaller distances. In this paper, we propose a hybrid charging scheme that combines charging by a mobile charger with a directional antenna, and energy trading, e.g., transferring and harvesting, between neighboring sensor nodes. The proposed scheme is compared with other charging scheme. Simulations demonstrate that the hybrid charging scheme with a directional antenna achieves a significant reduction in the total charging time required for all sensor nodes to reach a target energy level. PMID- 28075373 TI - Visual Object Tracking Based on Cross-Modality Gaussian-Bernoulli Deep Boltzmann Machines with RGB-D Sensors. AB - Visual object tracking technology is one of the key issues in computer vision. In this paper, we propose a visual object tracking algorithm based on cross-modality featuredeep learning using Gaussian-Bernoulli deep Boltzmann machines (DBM) with RGB-D sensors. First, a cross-modality featurelearning network based on aGaussian Bernoulli DBM is constructed, which can extract cross-modality features of the samples in RGB-D video data. Second, the cross-modality features of the samples are input into the logistic regression classifier, andthe observation likelihood model is established according to the confidence score of the classifier. Finally, the object tracking results over RGB-D data are obtained using aBayesian maximum a posteriori (MAP) probability estimation algorithm. The experimental results show that the proposed method has strong robustness to abnormal changes (e.g., occlusion, rotation, illumination change, etc.). The algorithm can steadily track multiple targets and has higher accuracy. PMID- 28075374 TI - A Point Mutation in a Herpesvirus Co-Determines Neuropathogenicity and Viral Shedding. AB - A point mutation in the DNA polymerase gene in equine herpesvirus type 1 (EHV-1) is one determinant for the development of neurological disease in horses. Three recently conducted infection experiments using domestic horses and ponies failed to detect statistically significant differences in viral shedding between the neuropathogenic and non-neuropathogenic variants. These results were interpreted as suggesting the absence of a consistent selective advantage of the neuropathogenic variant and therefore appeared to be inconsistent with a systematic increase in the prevalence of neuropathogenic strains. To overcome potential problems of low statistical power related to small group sizes in these infection experiments, we integrated raw data from all three experiments into a single statistical analysis. The results of this combined analysis showed that infection with the neuropathogenic EHV-1 variant led to a statistically significant increase in viral shedding. This finding is consistent with the idea that neuropathogenic strains could have a selective advantage and are therefore systematically increasing in prevalence in domestic horse populations. However, further studies are required to determine whether a selective advantage indeed exists for neuropathogenic strains. PMID- 28075375 TI - An Approach to Biometric Verification Based on Human Body Communication in Wearable Devices. AB - In this paper, an approach to biometric verification based on human body communication (HBC) is presented for wearable devices. For this purpose, the transmission gain S21 of volunteer's forearm is measured by vector network analyzer (VNA). Specifically, in order to determine the chosen frequency for biometric verification, 1800 groups of data are acquired from 10 volunteers in the frequency range 0.3 MHz to 1500 MHz, and each group includes 1601 sample data. In addition, to achieve the rapid verification, 30 groups of data for each volunteer are acquired at the chosen frequency, and each group contains only 21 sample data. Furthermore, a threshold-adaptive template matching (TATM) algorithm based on weighted Euclidean distance is proposed for rapid verification in this work. The results indicate that the chosen frequency for biometric verification is from 650 MHz to 750 MHz. The false acceptance rate (FAR) and false rejection rate (FRR) based on TATM are approximately 5.79% and 6.74%, respectively. In contrast, the FAR and FRR were 4.17% and 37.5%, 3.37% and 33.33%, and 3.80% and 34.17% using K-nearest neighbor (KNN) classification, support vector machines (SVM), and naive Bayesian method (NBM) classification, respectively. In addition, the running time of TATM is 0.019 s, whereas the running times of KNN, SVM and NBM are 0.310 s, 0.0385 s, and 0.168 s, respectively. Therefore, TATM is suggested to be appropriate for rapid verification use in wearable devices. PMID- 28075377 TI - Complex Messages in Long-Term Monitoring of Regal Fritillary (Speyeria idalia) (Lepidoptera: Nymphalidae) in the State of Wisconsin, USA, 1988-2015. AB - The regal fritillary ("regal") (Speyeria idalia) is endangered in Wisconsin, USA, and declining and at risk range-wide. During 1988-2015, we surveyed 24 known regal sites and >100 areas of potential habitat in Wisconsin. We recorded 9037 individuals in 742.7 km on the peak survey per year at occupied sites. At six sites surveyed over 5-25 years, we found regal fritillaries in only one year, mostly in the latter half of the study. The three populations in the state with more favorable trends than the median had a never-burned refugium and/or infrequent fire management. They also all had substantial amounts of grazing, haying, and/or mowing managements. Sites with trends below the regional median trend had frequent or moderate fire management, and either a diminishing never burned refugium or none at all. Regal populations at sites with <=15 ha of grassland have become undetectable. Nonetheless, Hogback, a slightly larger than 15 ha site, had the most favorable trend, a significant increase. Nearly all Wisconsin Regal populations known before 1990 declined to consistent non findability, even though these were conserved sites. More favorable trends at more recently discovered populations may be attributable to species-specific habitat management protocols implemented in the 1990s. Two sites with better than median long-term trends represent the longest consistent land ownership of known Regal populations in the state. This wide range of population outcomes illustrates both the need for long-term monitoring and the challenges of explaining the outcomes. Despite evidence of increasing Regal dispersal, this species remains very localized, indicating the unsuitability of the wider landscape as regal habitat. The number of significantly declining or no longer detectable populations in Wisconsin indicates an ever more adverse landscape for this species. Sites will need to have habitat characteristics that are ever more optimal in a wide range of climatic conditions for Regal populations to persist. PMID- 28075376 TI - The New High Resolution Crystal Structure of NS2B-NS3 Protease of Zika Virus. AB - Zika virus (ZIKV) is the cause of a significant viral disease affecting humans, which has spread throughout many South American countries and has also become a threat to Southeastern Asia. This commentary discusses the article "Crystal structure of unlinked NS2B-NS3 protease from Zika virus" published recently in the journal Science by Zhang et al. of Nanyang Technological University, Singapore. They resolved a 1.58 A resolution structure of the NS2B-NS3 protease of ZIKV and demonstrated how peptide and non-peptide inhibitors interact with this structure, along with the different conformational states that were observed. This protease crystal structure offers new opportunities for the design and development of novel antiviral drugs used for the treatment and control of ZIKV. PMID- 28075379 TI - Veterinary Compounding: Regulation, Challenges, and Resources. AB - The spectrum of therapeutic need in veterinary medicine is large, and the availability of approved drug products for all veterinary species and indications is relatively small. For this reason, extemporaneous preparation, or compounding, of drugs is commonly employed to provide veterinary medical therapies. The scope of veterinary compounding is broad and focused primarily on meeting the therapeutic needs of companion animals and not food-producing animals in order to avoid human exposure to drug residues. As beneficial as compounded medical therapies may be to animal patients, these therapies are not without risks, and serious adverse events may occur from poor quality compounds or excipients that are uniquely toxic when administered to a given species. Other challenges in extemporaneous compounding for animals include significant regulatory variation across the global veterinary community, a relative lack of validated compounding formulas for use in animals, and poor adherence by compounders to established compounding standards. The information presented in this article is intended to provide an overview of the current landscape of compounding for animals; a discussion on associated benefits, risks, and challenges; and resources to aid compounders in preparing animal compounds of the highest possible quality. PMID- 28075380 TI - Splenic Immune Response Is Down-Regulated in C57BL/6J Mice Fed Eicosapentaenoic Acid and Docosahexaenoic Acid Enriched High Fat Diet. AB - Dietary n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are associated with reduction of inflammation, although the mechanisms are poorly understood, especially how the spleen, as a secondary lymphoid organ, is involved. To investigate the effects of EPA and DHA on spleen gene expression, male C57BL/6J mice were fed high fat diets (HFD) differing in fatty acid composition, either based on corn oil (HFD-CO), or CO enriched with 2 g/100 g EPA and DHA (HFD-ED), for eight weeks. Spleen tissue was analyzed using transcriptomics and for fatty acids profiling. Biological processes (BPs) related to the immune response, including T-cell receptor signaling pathway, T-cell differentiation and co-stimulation, myeloid dendritic cell differentiation, antigen presentation and processing, and the toll like receptor pathway were downregulated by HFD-ED compared with control and HFD-CO. These findings were supported by the down-regulation of NF-kappaB in HFD-ED compared with HFD-CO fed mice. Lower phospholipid arachidonic acid levels in HFD-ED compared with HFD-CO, and control mice suggest attenuation of pathways via prostaglandins and leukotrienes. The HFD-ED also upregulated BPs related to erythropoiesis and hematopoiesis compared with control and HFD-CO fed mice. Our findings suggest that EPA and DHA down-regulate the splenic immune response induced by HFD-CO, supporting earlier work that the spleen is a target organ for the anti inflammatory effects of these n-3 fatty acids. PMID- 28075381 TI - The n-3 Polyunsaturated Fatty Acids Supplementation Improved the Cognitive Function in the Chinese Elderly with Mild Cognitive Impairment: A Double-Blind Randomized Controlled Trial. AB - OBJECTIVE: Intake of n-3 polyunsaturated fatty acids (n-3 PUFAs) may protect against mild cognitive impairment (MCI). However, there is still a lack of the n 3 PUFAs intervention in the elderly with MCI in China. The aim of the present study was to investigate the effect of n-3 PUFA supplementation on cognitive function in the Chinese elderly with MCI. METHODS: Eighty six MCI individuals aged 60 years or older were randomly assigned to receive either n-3 PUFAs (480 mg DHA and 720 mg EPA per day, n = 44) or placebo (olive oil, n = 42) capsules. The changes of cognitive functions were assessed using Basic Cognitive Aptitude Tests (BCAT). RESULTS: The mean age of participants was 71 years old, and 59% of the participants were men. n-3 PUFA supplementation was associated with improved total BCAT scores, perceptual speed, space imagery efficiency, and working memory (p < 0.01), but not with mental arithmetic efficiency or recognition memory (p > 0.05). Subgroup analysis by sex showed that n-3 PUFAs significantly improved perceptual speed (p = 0.001), space imagery efficiency (p = 0.013), working memory (p = 0.018), and total BCAT scores (p = 0.000) in males. However, in females, the significant beneficial effects can only be observed in perceptual speed (p = 0.027), space imagery efficiency (p = 0.006), and total BCAT scores (p = 0.015)-not working memory (p = 0.113). CONCLUSION: n-3 PUFAs can improve cognitive function in people with MCI. Further studies with different fish oil dosages, longer intervention periods, and larger sample sizes should be investigated before definite recommendations can be made. PMID- 28075382 TI - B-Vitamin Intake and Biomarker Status in Relation to Cognitive Decline in Healthy Older Adults in a 4-Year Follow-Up Study. AB - Advancing age can be associated with an increase in cognitive dysfunction, a spectrum of disability that ranges in severity from mild cognitive impairment to dementia. Folate and the other B-vitamins involved in one-carbon metabolism are associated with cognition in ageing but the evidence is not entirely clear. The hypothesis addressed in this study was that lower dietary intake or biomarker status of folate and/or the metabolically related B-vitamins would be associated with a greater than expected rate of cognitive decline over a 4-year follow-up period in healthy older adults. Participants (aged 60-88 years; n = 155) who had been previously screened for cognitive function were reassessed four years after initial investigation using the Mini-Mental State Examination (MMSE). At the 4 year follow-up assessment when participants were aged 73.4 +/- 7.1 years, mean cognitive MMSE scores had declined from 29.1 +/- 1.3 at baseline to 27.5 +/- 2.4 (p < 0.001), but some 27% of participants showed a greater than expected rate of cognitive decline (i.e., decrease in MMSE > 0.56 points per year). Lower vitamin B6 status, as measured using pyridoxal-5-phosphate (PLP; <43 nmol/L) was associated with a 3.5 times higher risk of accelerated cognitive decline, after adjustment for age and baseline MMSE score (OR, 3.48; 95% CI, 1.58 to 7.63; p < 0.05). Correspondingly, lower dietary intake (0.9-1.4 mg/day) of vitamin B6 was also associated with a greater rate of cognitive decline (OR, 4.22; 95% CI, 1.28 13.90; p < 0.05). No significant relationships of dietary intake or biomarker status with cognitive decline were observed for the other B-vitamins. In conclusion, lower dietary and biomarker status of vitamin B6 at baseline predicted a greater than expected rate of cognitive decline over a 4-year period in healthy older adults. Vitamin B6 may be an important protective factor in helping maintain cognitive health in ageing. PMID- 28075383 TI - Soluble Fibre Meal Challenge Reduces Airway Inflammation and Expression of GPR43 and GPR41 in Asthma. AB - Short chain fatty acids (SCFAs) are produced following the fermentation of soluble fibre by gut bacteria. In animal models, both dietary fibre and SCFAs have demonstrated anti-inflammatory effects via the activation of free fatty acid receptors, such as G protein-coupled receptor 41 and 43 (GPR41 and GPR43). This pilot study examined the acute effect of a single dose of soluble fibre on airway inflammation-including changes in gene expression of free fatty acid receptors-in asthma. Adults with stable asthma consumed a soluble fibre meal (n = 17) containing 3.5 g inulin and probiotics, or a control meal (n = 12) of simple carbohydrates. Exhaled nitric oxide (eNO) was measured and induced sputum was collected at 0 and 4 h for differential cell counts, measurement of interleukin-8 (IL-8) protein concentration, and GPR41 and GPR43 gene expression. At 4 h after meal consumption, airway inflammation biomarkers, including sputum total cell count, neutrophils, macrophages, lymphocytes, sputum IL-8, and eNO significantly decreased compared to baseline in the soluble fibre group only. This corresponded with upregulated GPR41 and GPR43 sputum gene expression and improved lung function in the soluble fibre group alone. Soluble fibre has acute anti inflammatory effects in asthmatic airways. Long-term effects of soluble fibre as an anti-inflammatory therapy in asthma warrants further investigation. PMID- 28075384 TI - Monitoring Lead (Pb) Pollution and Identifying Pb Pollution Sources in Japan Using Stable Pb Isotope Analysis with Kidneys of Wild Rats. AB - Although Japan has been considered to have little lead (Pb) pollution in modern times, the actual pollution situation is unclear. The present study aims to investigate the extent of Pb pollution and to identify the pollution sources in Japan using stable Pb isotope analysis with kidneys of wild rats. Wild brown (Rattus norvegicus, n = 43) and black (R. rattus, n = 98) rats were trapped from various sites in Japan. Mean Pb concentrations in the kidneys of rats from Okinawa (15.58 mg/kg, dry weight), Aichi (10.83), Niigata (10.62), Fukuoka (8.09), Ibaraki (5.06), Kyoto (4.58), Osaka (4.57), Kanagawa (3.42), and Tokyo (3.40) were above the threshold (2.50) for histological kidney changes. Similarly, compared with the previous report, it was regarded that even structural and functional kidney damage as well as neurotoxicity have spread among rats in Japan. Additionally, the possibility of human exposure to a high level of Pb was assumed. In regard to stable Pb isotope analysis, distinctive values of stable Pb isotope ratios (Pb-IRs) were detected in some kidney samples with Pb levels above 5.0 mg/kg. This result indicated that composite factors are involved in Pb pollution. However, the identification of a concrete pollution source has not been accomplished due to limited differences among previously reported values of Pb isotope composition in circulating Pb products. Namely, the current study established the limit of Pb isotope analysis for source identification. Further detailed research about monitoring Pb pollution in Japan and the demonstration of a novel method to identify Pb sources are needed. PMID- 28075391 TI - AAC as a Potential Target Gene to Control Verticillium dahliae. AB - Verticillium dahliae invades the roots of host plants and causes vascular wilt, which seriously diminishes the yield of cotton and other important crops. The protein AAC (ADP, ATP carrier) is responsible for transferring ATP from the mitochondria into the cytoplasm. When V. dahliae protoplasts were transformed with short interfering RNAs (siRNAs) targeting the VdAAC gene, fungal growth and sporulation were significantly inhibited. To further confirm a role for VdAAC in fungal development, we generated knockout mutants (DeltaVdACC). Compared with wild-type V. dahliae (Vd wt), DeltaVdAAC was impaired in germination and virulence; these impairments were rescued in the complementary strains (DeltaVdAAC-C). Moreover, when an RNAi construct of VdAAC under the control of the 35S promoter was used to transform Nicotiana benthamiana, the expression of VdAAC was downregulated in the transgenic seedlings, and they had elevated resistance against V. dahliae. The results of this study suggest that VdAAC contributes to fungal development, virulence and is a promising candidate gene to control V. dahliae. In addition, RNAi is a highly efficient way to silence fungal genes and provides a novel strategy to improve disease resistance in plants. PMID- 28075392 TI - A Distance Detector with a Strip Magnetic MOSFET and Readout Circuit. AB - This paper presents a distance detector composed of two separated metal-oxide semiconductor field-effect transistors (MOSFETs), a differential polysilicon cross-shaped Hall plate (CSHP), and a readout circuit. The distance detector was fabricated using 0.18 MUm 1P6M Complementary Metal-Oxide Semiconductor (CMOS) technology to sense the magnetic induction perpendicular to the chip surface. The differential polysilicon CSHP enabled the magnetic device to not only increase the magnetosensitivity but also eliminate the offset voltage generated because of device mismatch and Lorentz force. Two MOSFETs generated two drain currents with a quadratic function of the differential Hall voltages at CSHP. A readout circuit composed of a current-to-voltage converter, a low-pass filter, and a difference amplifier-was designed to amplify the current difference between two drains of MOSFETs. Measurements revealed that the electrostatic discharge (ESD) could be eliminated from the distance sensor by grounding it to earth; however, the sensor could be desensitized by ESD in the absence of grounding. The magnetic influence can be ignored if the magnetic body (human) stays far from the magnetic sensor, and the measuring system is grounded to earth by using the ESD wrist strap (Strap E-GND). Both 'no grounding' and 'grounding to power supply' conditions were unsuitable for measuring the induced Hall voltage. PMID- 28075389 TI - Control of Initiation of DNA Replication in Bacillus subtilis and Escherichia coli. AB - Initiation of DNA Replication is tightly regulated in all cells since imbalances in chromosomal copy number are deleterious and often lethal. In bacteria such as Bacillus subtilis and Escherichia coli, at the point of cytokinesis, there must be two complete copies of the chromosome to partition into the daughter cells following division at mid-cell during vegetative growth. Under conditions of rapid growth, when the time taken to replicate the chromosome exceeds the doubling time of the cells, there will be multiple initiations per cell cycle and daughter cells will inherit chromosomes that are already undergoing replication. In contrast, cells entering the sporulation pathway in B. subtilis can do so only during a short interval in the cell cycle when there are two, and only two, chromosomes per cell, one destined for the spore and one for the mother cell. Here, we briefly describe the overall process of DNA replication in bacteria before reviewing initiation of DNA replication in detail. The review covers DnaA directed assembly of the replisome at oriC and the multitude of mechanisms of regulation of initiation, with a focus on the similarities and differences between E. coli and B. subtilis. PMID- 28075394 TI - Coffee Intake Is Associated with a Lower Liver Stiffness in Patients with Non Alcoholic Fatty Liver Disease, Hepatitis C, and Hepatitis B. AB - There is emerging evidence for the positive effects or benefits of coffee in patients with liver disease. We conducted a retrospective cross-sectional study on patients with non-alcoholic fatty liver disease (NAFLD), hepatitis C virus (HCV), and hepatitis B virus (HBV) infection to determine the effects of coffee intake on a non-invasive marker of liver fibrosis: liver stiffness assessed by transient elastography (TE). We assessed coffee and tea intake and measured TE in 1018 patients with NAFLD, HCV, and HBV (155 with NAFLD, 378 with HCV and 485 with HBV). Univariate and multivariate regression models were performed taking into account potential confounders. Liver stiffness was higher in males compared to females (p < 0.05). Patients with HBV had lower liver stiffness than those with HCV and NAFLD. After adjustment for age, gender, smoking, alcohol consumption, M or XL probe, and disease state (NAFLD, HCV, and HBV status), those who drank 2 or more cups of coffee per day had a lower liver stiffness (p = 0.044). Tea consumption had no effect (p = 0.9). Coffee consumption decreases liver stiffness, which may indicate less fibrosis and inflammation, independent of disease state. This study adds further evidence to the notion of coffee maybe beneficial in patients with liver disease. PMID- 28075395 TI - Disability Weights for Chronic Mercury Intoxication Resulting from Gold Mining Activities: Results from an Online Pairwise Comparisons Survey. AB - In artisanal small-scale gold mining, mercury is used for gold-extraction, putting miners and nearby residents at risk of chronic metallic mercury vapor intoxication (CMMVI). Burden of disease (BoD) analyses allow the estimation of the public health relevance of CMMVI, but until now there have been no specific CMMVI disability weights (DWs). The objective is to derive DWs for moderate and severe CMMVI. Disease-specific and generic health state descriptions of 18 diseases were used in a pairwise comparison survey. Mercury and BoD experts were invited to participate in an online survey. Data were analyzed using probit regression. Local regression was used to make the DWs comparable to the Global Burden of Disease (GBD) study. Alternative survey (visual analogue scale) and data analyses approaches (linear interpolation) were evaluated in scenario analyses. A total of 105 participants completed the questionnaire. DWs for moderate and severe CMMVI were 0.368 (0.261-0.484) and 0.588 (0.193-0.907), respectively. Scenario analyses resulted in higher mean values. The results are limited by the sample size, group of interviewees, questionnaire extent, and lack of generally accepted health state descriptions. DWs were derived to improve the data basis of mercury-related BoD estimates, providing useful information for policy-making. Integration of the results into the GBD DWs enhances comparability. PMID- 28075397 TI - The Sulfur Metabolite Lanthionine: Evidence for a Role as a Novel Uremic Toxin. AB - Lanthionine is a nonproteinogenic amino acid, composed of two alanine residues that are crosslinked on their beta-carbon atoms by a thioether linkage. It is biosynthesized from the condensation of two cysteine molecules, while the related compound homolanthionine is formed from the condensation of two homocysteine molecules. The reactions can be carried out by either cystathionine-beta-synthase (CBS) or cystathionine-gamma-lyase (CSE) independently, in the alternate reactions of the transsulfuration pathway devoted to hydrogen sulfide biosynthesis. Low plasma total hydrogen sulfide levels, probably due to reduced CSE expression, are present in uremia, while homolanthionine and lanthionine accumulate in blood, the latter several fold. Uremic patients display a derangement of sulfur amino acid metabolism with a high prevalence of hyperhomocysteinemia. Uremia is associated with a high cardiovascular mortality, the causes of which are still not completely explained, but are related to uremic toxicity, due to the accumulation of retention products. Lanthionine inhibits hydrogen sulfide production in hepatoma cells, possibly through CBS inhibition, thus providing some basis for the biochemical mechanism, which may significantly contribute to alterations of metabolism sulfur compounds in these subjects (e.g., high homocysteine and low hydrogen sulfide). We therefore suggest that lanthionine is a novel uremic toxin. PMID- 28075402 TI - Comment on Neiser et al. Assessment of Dextran Antigenicity of Intravenous Iron Preparations with Enzyme-Linked Immunosorbent Assay (ELISA). Int. J. Mol. Sci. 2016, 17, 1185. AB - All IV iron complexes carry a risk of potentially fatal allergic type hypersensitivity reactions. The mechanism(s) behind these reactions is unknown but the limited data available suggests that classic IgE mediated allergy is exceedingly rare, if ever occurring. Iron-carbohydrate molecules are complex nano particles and trying to reduce the risk of serious hypersensitivity to antibody binding of an artificial antibody seems meaningless. A recently published analysis of safety data from randomized clinical trials confirms the method reported by Neiser to be useless to predict reaction risk. In conclusion, the study by Neiser et al. is biased, contains no new information, and has no clinical relevance. We are concerned that the association of the authors with a commercial entity has caused a conflict of interest that biases not only the results, but the entire experimental setup against competitors. (Comment on Neiser et al. Int. J. Mol. Sci. 2016, 17, 1185, doi:10.3390/ijms17071185). PMID- 28075401 TI - Anti-Neuroblastoma Properties of a Recombinant Sunflower Lectin. AB - According to their sugar recognition specificity, plant lectins are proposed as bioactive proteins with potential in cancer treatment and diagnosis. Helja is a mannose-specific jacalin-like lectin from sunflower which was shown to inhibit the growth of certain fungi. Here, we report its recombinant expression in a prokaryotic system and its activity in neurobalstoma cells. Helja coding sequence was fused to the pET-32 EK/LIC, the enterokinase/Ligation-independent cloning vector and a 35 kDa protein was obtained in Escherichia coli representing Helja coupled to thioredoxin (Trx). The identity of this protein was verified using anti-Helja antibodies. This chimera, named Trx-rHelja, was enriched in the soluble bacterial extracts and was purified using Ni+2-Sepharose and d-mannose agarose chromatography. Trx-rHelja and the enterokinase-released recombinant Helja (rHelja) both displayed toxicity on human SH-SY5Y neuroblastomas. rHelja decreased the viability of these tumor cells by 75% according to the tetrazolium reduction assay, and microscopic analyses revealed that the cell morphology was disturbed. Thus, the stellate cells of the monolayer became spheroids and were isolated. Our results indicate that rHelja is a promising tool for the development of diagnostic or therapeutic methods for neuroblastoma cells, the most common solid tumors in childhood. PMID- 28075403 TI - Reply to "Comment on Neiser et al. Assessment of Dextran Antigenicity of Intravenous Iron Preparations with Enzyme-Linked Immunosorbent Assay (ELISA). Int. J. Mol. Sci. 2016, 17, 1185." AB - n/a. PMID- 28075396 TI - Translesion Synthesis: Insights into the Selection and Switching of DNA Polymerases. AB - DNA replication is constantly challenged by DNA lesions, noncanonical DNA structures and difficult-to-replicate DNA sequences. Two major strategies to rescue a stalled replication fork and to ensure continuous DNA synthesis are: (1) template switching and recombination-dependent DNA synthesis; and (2) translesion synthesis (TLS) using specialized DNA polymerases to perform nucleotide incorporation opposite DNA lesions. The former pathway is mainly error-free, and the latter is error-prone and a major source of mutagenesis. An accepted model of translesion synthesis involves DNA polymerase switching steps between a replicative DNA polymerase and one or more TLS DNA polymerases. The mechanisms that govern the selection and exchange of specialized DNA polymerases for a given DNA lesion are not well understood. In this review, recent studies concerning the mechanisms of selection and switching of DNA polymerases in eukaryotic systems are summarized. PMID- 28075404 TI - Advanced Oxidation Protein Products-Modified Albumin Induces Differentiation of RAW264.7 Macrophages into Dendritic-Like Cells Which Is Modulated by Cell Surface Thiols. AB - Local accumulation of Advanced Oxidation Protein Products (AOPP) induces pro inflammatory and pro-fibrotic processes in kidneys and is an independent predictor of renal fibrosis and of rapid decline of eGFR in patients with chronic kidney disease (CKD). In addition to kidney damage, circulating AOPP may be regarded as mediators of systemic oxidative stress and, in this capacity, they might play a role in the progression of atherosclerotic damage of arterial walls. Atherosclerosis is a chronic inflammatory disease that involves activation of innate and adaptive immunity. Dendritic cells (DCs) are key cells in this process, due to their role in antigen presentation, inflammation resolution and T cell activation. AOPP consist in oxidative modifications of proteins (such as albumin and fibrinogen) that mainly occur through myeloperoxidase (MPO)-derived hypochlorite (HOCl). HOCl modified proteins have been found in atherosclerotic lesions. The oxidizing environment and the shifts in cellular redox equilibrium trigger inflammation, activate immune cells and induce immune responses. Thus, surface thiol groups contribute to the regulation of immune functions. The aims of this work are: (1) to evaluate whether AOPP-proteins induce activation and differentiation of mature macrophages into dendritic cells in vitro; and (2) to define the role of cell surface thiol groups and of free radicals in this process. AOPP-proteins were prepared by in vitro incubation of human serum albumin (HSA) with HOCl. Mouse macrophage-like RAW264.7 were treated with various concentrations of AOPP-HSA with or without the antioxidant N-acetyl cysteine (NAC). Following 48 h of HSA-AOPP treatment, RAW264.7 morphological changes were evaluated by microscopic observation, while markers of dendritic lineage and activation (CD40, CD86, and MHC class II) and allogeneic T cell proliferation were evaluated by flow cytometry. Cell surface thiols were measured by AlexaFluor maleimide binding, and ROS production was assessed as DCF fluorescence by flow cytometry. HSA-AOPP induced the differentiation of RAW264.7 cells into a dendritic-like phenotype, as shown by morphological changes, by increased CD40, CD86 and MHC class II surface expression and by induction of T cell proliferation. The cell surface thiols dose dependently decreased following HSA AOPP treatment, while ROS production increased. NAC pre-treatment enhanced the amount of cell surface thiols and prevented their reduction due to treatment with AOPP. Both ROS production and RAW264.7 differentiation into DC-like cells induced by HSA-AOPP were reduced by NAC. Our results highlight that oxidized plasma proteins modulate specific immune responses of macrophages through a process involving changes in the thiol redox equilibrium. We suggest that this mechanism may play a role in determining the rapid progression of the atherosclerotic process observed in CKD patients. PMID- 28075406 TI - Molecular Signals in Nodulation Control. AB - Our world is facing major problems relating to food production. According to an August 30, 2015 program of LANDLINE (Australian Broadcasting Corporation, Australia),we lose 120,000,000 hectares of agricultural land per year due to population growth, associated urbanisation, and desertification. PMID- 28075405 TI - The Role of Reactive Oxygen Species (ROS) in the Biological Activities of Metallic Nanoparticles. AB - Nanoparticles (NPs) possess unique physical and chemical properties that make them appropriate for various applications. The structural alteration of metallic NPs leads to different biological functions, specifically resulting in different potentials for the generation of reactive oxygen species (ROS). The amount of ROS produced by metallic NPs correlates with particle size, shape, surface area, and chemistry. ROS possess multiple functions in cellular biology, with ROS generation a key factor in metallic NP-induced toxicity, as well as modulation of cellular signaling involved in cell death, proliferation, and differentiation. In this review, we briefly explained NP classes and their biomedical applications and describe the sources and roles of ROS in NP-related biological functions in vitro and in vivo. Furthermore, we also described the roles of metal NP-induced ROS generation in stem cell biology. Although the roles of ROS in metallic NP related biological functions requires further investigation, modulation and characterization of metallic NP-induced ROS production are promising in the application of metallic NPs in the areas of regenerative medicine and medical devices. PMID- 28075407 TI - Diagnostic Value of Serum Angiogenesis Markers in Ovarian Cancer Using Multiplex Immunoassay. AB - As cancer development involves pathological vessel formation, 16 angiogenesis markers were evaluated as potential ovarian cancer (OC) biomarkers. Blood samples collected from 172 patients were divided based on histopathological result: OC (n = 38), borderline ovarian tumours (n = 6), non-malignant ovarian tumours (n = 62), healthy controls (n = 50) and 16 patients were excluded. Sixteen angiogenesis markers were measured using BioPlex Pro Human Cancer Biomarker Panel 1 immunoassay. Additionally, concentrations of cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) were measured in patients with adnexal masses using electrochemiluminescence immunoassay. In the comparison between OC vs. non OC, osteopontin achieved the highest area under the curve (AUC) of 0.79 (sensitivity 69%, specificity 78%). Multimarker models based on four to six markers (basic fibroblast growth factor-FGF-basic, follistatin, hepatocyte growth factor-HGF, osteopontin, platelet-derived growth factor AB/BB-PDGF-AB/BB, leptin) demonstrated higher discriminatory ability (AUC 0.80-0.81) than a single marker (AUC 0.79). When comparing OC with benign ovarian tumours, six markers had statistically different expression (osteopontin, leptin, follistatin, PDGF-AB/BB, HGF, FGF-basic). Osteopontin was the best single angiogenesis marker (AUC 0.825, sensitivity 72%, specificity 82%). A three-marker panel consisting of osteopontin, CA125 and HE4 better discriminated the groups (AUC 0.958) than HE4 or CA125 alone (AUC 0.941 and 0.932, respectively). Osteopontin should be further investigated as a potential biomarker in OC screening and differential diagnosis of ovarian tumours. Adding osteopontin to a panel of already used biomarkers (CA125 and HE4) significantly improves differential diagnosis between malignant and benign ovarian tumours. PMID- 28075408 TI - Time Course Exo-Metabolomic Profiling in the Green Marine Macroalga Ulva (Chlorophyta) for Identification of Growth Phase-Dependent Biomarkers. AB - The marine green macroalga Ulva (Chlorophyta) lives in a mutualistic symbiosis with bacteria that influence growth, development, and morphogenesis. We surveyed changes in Ulva's chemosphere, which was defined as a space where organisms interact with each other via compounds, such as infochemicals, nutrients, morphogens, and defense compounds. Thereby, Ulva mutabilis cooperates with bacteria, in particular, Roseovarius sp. strain MS2 and Maribacter sp. strain MS6 (formerly identified as Roseobacter sp. strain MS2 and Cytophaga sp. strain MS6). Without this accompanying microbial flora, U. mutabilis forms only callus-like colonies. However, upon addition of the two bacteria species, in effect forming a tripartite community, morphogenesis can be completely restored. Under this strictly standardized condition, bioactive and eco-physiologically-relevant marine natural products can be discovered. Solid phase extracted waterborne metabolites were analyzed using a metabolomics platform, facilitating gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) analysis, combined with the necessary acquisition of biological metadata. Multivariate statistics of the GC-MS and LC-MS data revealed strong differences between Ulva's growth phases, as well as between the axenic Ulva cultures and the tripartite community. Waterborne biomarkers, including glycerol, were identified as potential indicators for algal carbon source and bacterial-algal interactions. Furthermore, it was demonstrated that U. mutabilis releases glycerol that can be utilized for growth by Roseovarius sp. MS2. PMID- 28075411 TI - Tamaractam, a New Bioactive Lactam from Tamarix ramosissima, Induces Apoptosis in Rheumatoid Arthritis Fibroblast-Like Synoviocytes. AB - Chemical investigation of Tamarix ramosissima Ledeb, a traditional herbal medicine used for rheumatoid arthritis (RA) treatment in northwest China, led to the discovery of a new phenolic aromatic rings substituted lactam, tamaractam (1), together with the previously reported compounds cis-N-feruloyl-3-O methyldopamine (2) and trans-N-feruloyl-3-O-methyldopamine (3). The structures of the compounds were determined by high resolution electrospray ionization mass spectroscopy (HRESIMS) and 1D and 2D-NMR experiments, as well as comparison with the literature data. The effects of the three compounds on the viability of RA fibroblast-like synoviocytes (RA-FLS) were assessed by 3-(4,5-dimethyl-2 thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Pro-apoptosis effect of compound 1 in RA-FLS was further investigated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, activated caspase-3/7 level assessment using luminescence assay, and sub-G1 fraction measurement using flow cytometry. It was found that these three compounds displayed variable proliferation inhibitory activity in RA-FLS, and compound 1 exhibited the strongest effect. Compound 1 could remarkably induce cellular apoptosis of RA FLS, increase activated caspase-3/7 levels, and significantly increase sub-G1 fraction in the cell cycle. The results suggested that compound 1 may inhibit the proliferation of RA-FLS through apoptosis-inducing effect, and these compounds may contribute to the anti-RA effect of T. ramosissima. PMID- 28075409 TI - The HIV-1 Vpr Protein: A Multifaceted Target for Therapeutic Intervention. AB - The human immunodeficiency virus type 1 (HIV-1) Vpr protein is an attractive target for antiretroviral drug development. The conservation both of the structure along virus evolution and the amino acid sequence in viral isolates from patients underlines the importance of Vpr for the establishment and progression of HIV-1 disease. While its contribution to virus replication in dividing and non-dividing cells and to the pathogenesis of HIV-1 in many different cell types, both extracellular and intracellular forms, have been extensively studied, its precise mechanism of action nevertheless remains enigmatic. The present review discusses how the apparently multifaceted interplay between Vpr and host cells may be due to the impairment of basic metabolic pathways. Vpr protein modifies host cell energy metabolism, oxidative status, and proteasome function, all of which are likely conditioned by the concentration and multimerization of the protein. The characterization of Vpr domains along with new laboratory tools for the assessment of their function has become increasingly relevant in recent years. With these advances, it is conceivable that drug discovery efforts involving Vpr-targeted antiretrovirals will experience substantial growth in the coming years. PMID- 28075410 TI - Is Toxoplasma gondii a Trigger of Bipolar Disorder? AB - Toxoplasma gondii, a ubiquitous intracellular parasite, has a strong tropism for the brain tissue, where it forms intracellular cysts within the neurons and glial cells, establishing a chronic infection. Although latent toxoplasmosis is generally assumed to be asymptomatic in immunocompetent individuals, it is now clear that it can induce behavioral manipulations in mice and infected humans. Moreover, a strong relation has emerged in recent years between toxoplasmosis and psychiatric disorders. The link between T. gondii and schizophrenia has been the most widely documented; however, a significant association with bipolar disorder (BD) and suicidal/aggressive behaviors has also been detected. T. gondii may play a role in the etiopathogenesis of psychiatric disorders affecting neurotransmitters, especially dopamine, that are implicated in the emergence of psychosis and behavioral Toxoplasma-induced abnormalities, and inducing brain inflammation by the direct stimulation of inflammatory cytokines in the central nervous system. Besides this, there is increasing evidence for a prominent role of immune dysregulation in psychosis and BD. The aim of this review is to describe recent evidence suggesting a link between Toxoplasma gondii and BD, focusing on the interaction between immune responses and this infectious agent in the etiopathogenesis of psychiatric symptoms. PMID- 28075412 TI - The Antagonistic Effect of Mycotoxins Deoxynivalenol and Zearalenone on Metabolic Profiling in Serum and Liver of Mice. AB - Metabolic profiling in liver and serum of mice was studied for the combined toxic effects of deoxynivalenol (DON) and zearalenone (ZEN), through gas chromatography mass spectrum. The spectrum of serum and liver sample of mice, treated with individual 2 mg/kg DON, 20 mg/kg ZEN, and the combined DON + ZEN with final concentration 2 mg/kg DON and 20 mg/kg ZEN for 21 days, were deconvoluted, aligned and identified with MS DIAL. The data matrix was processed with univariate analysis and multivariate analysis for selection of metabolites with variable importance for the projection (VIP) > 1, t-test p value < 0.05. The metabolic pathway analysis was performed with MetaMapp and drawn by CytoScape. Results show that the combined DON and ZEN treatment has an obvious "antagonistic effect" in serum and liver tissue metabolic profiling of mice. The blood biochemical indexes, like alkaline phosphatase, alanine transaminase, and albumin (ALB)/globulin (GLO), reveal a moderated trend in the combined DON + ZEN treatment group, which is consistent with histopathological examination. The metabolic pathway analysis demonstrated that the combined DON and ZEN treatment could down-regulate the valine, leucine and isoleucine biosynthesis, glycine, serine and threonine metabolism, and O-glycosyl compounds related glucose metabolism in liver tissue. The metabolic profiling in serum confirmed the finding that the combined DON and ZEN treatment has an "antagonistic effect" on liver metabolism of mice. PMID- 28075414 TI - Atom-Economic Synthesis of 4-Pyrones from Diynones and Water. AB - Transition-metal-free synthesis of 4-pyrones via TfOH-promoted nucleophilic addition/cyclization of diynones and water has been developed. This transformation is simple, atom economical and environmentally benign, providing rapid and efficient access to substituted 4-pyrones. PMID- 28075415 TI - Inhibitory Effects of Probiotic Lactobacillus on the Growth of Human Colonic Carcinoma Cell Line HT-29. AB - This study was conducted to investigate the inhibitory effect of Lactobacillus cells and supernatants on the growth of the human colon cancer cell line HT-29. Our study results indicated that the PM153 strain exhibits the best adhesion ability and the highest survival in the gastrointestinal tract simulation experiment. Furthermore, after an 8-h co-culture of PM153 and HT-29 cells, the PM153 strain can induce the secretion of nitric oxide from the HT-29 cells. In addition, after the co-culture of the BCRC17010 strain (108 cfu/mL) and HT-29 cells, the Bax/Bcl-2 ratio in the HT-29 cells was 1.19, which showed a significant difference from the other control and LAB groups (p < 0.05), which therefore led to the inference that the BCRC17010 strain exerts a pro-apoptotic effect on the HT-29 cells. Upon co-culture with HT-29 cells for 4, 8 and 12 h, the BCRC14625 strain (108 cfu/mL) demonstrated a significant increase in lactate dehydrogenase (LDH) activity (p < 0.05), causing harm to the HT-29 cell membrane; further, after an 8-h co-culture with the HT-29 cells, it induced the secretion of nitric oxide (NO) from the HT-29 cells. Some lactic acid bacteria (LAB) strains have ability to inhibit the growth of the colorectal cancer cell line HT 29 Bax/Bcl-2 pathway or NO production. In summary, we demonstrated that the BCRC17010 strain, good abilities of adhesion and increased LDH release, was the best probiotic potential for inhibition of HT-29 growth amongst the seven LAB strains tested in vitro. PMID- 28075416 TI - Phosphorylated Radix Cyathulae officinalis Polysaccharides Act as Adjuvant via Promoting Dendritic Cell Maturation. AB - The aim of this study was to investigate whether phosphorylated Radix Cyathulae officinalis Kuan polysaccharides (pRCPS) used as adjuvant with foot-and-mouth disease vaccine (FMDV) can stimulate specific humoral and cellular immune responses in ICR mice. The results demonstrated that pRCPS significantly up regulated FMDV-specific IgG, IgG1, IgG2b and IgG2a antibody levels and splenocyte proliferation. pRCPS also promoted the killing activities of cytotoxic T lymphocytes (CTL) and natural killer cells (NK). In addition, pRCPS enhanced the expression levels of IL-2, IL-4, and IFN-gamma in CD4+ T cells and the level of IFN-gamma in CD8+ T cells. Importantly, pRCPS enhanced the expression of MHCII, CD40+, CD86+, and CD80+ in dendritic cells (DCs). This study indicated that phosphorylation modification could increase immune-enhancing activities of RCPS, and pRCPS could promote humoral and cellular immune responses through facilitating DC maturation. PMID- 28075417 TI - Enriching Mental Health Mobile Assessment and Intervention with Situation Awareness. AB - Current mobile devices allow the execution of sophisticated applications with the capacity for identifying the user situation, which can be helpful in treatments of mental disorders. In this paper, we present SituMan, a solution that provides situation awareness to MoodBuster, an ecological momentary assessment and intervention mobile application used to request self-assessments from patients in depression treatments. SituMan has a fuzzy inference engine to identify patient situations using context data gathered from the sensors embedded in mobile devices. Situations are specified jointly by the patient and mental health professional, and they can represent the patient's daily routine (e.g., "studying", "at work", "working out"). MoodBuster requests mental status self assessments from patients at adequate moments using situation awareness. In addition, SituMan saves and displays patient situations in a summary, delivering them for consultation by mental health professionals. A first experimental evaluation was performed to assess the user satisfaction with the approaches to define and identify situations. This experiment showed that SituMan was well evaluated in both criteria. A second experiment was performed to assess the accuracy of the fuzzy engine to infer situations. Results from the second experiment showed that the fuzzy inference engine has a good accuracy to identify situations. PMID- 28075418 TI - Serum Polychlorinated Biphenyls Increase and Oxidative Stress Decreases with a Protein-Pacing Caloric Restriction Diet in Obese Men and Women. AB - The purposes were to compare the effects of a: (1) 12-week P-CR weight loss (WL) diet (Phase 1) between obese men and women and; (2) 52-week modified P-CR (mP-CR) vs. heart healthy (HH) weight maintenance (WM) diet (Phase 2) on serum PCBs and oxidative stress biomarkers (thiobarbituric acid reactive substances, TBARS; total antioxidant capacity, TAC) in 40 obese participants (men, n = 21; women, n = 19). Participants received dietary counseling and monitoring of compliance. PCBs, TBARS, and TAC were assessed at weeks -1 (CON), 12 (WL), and 64 (WM). Following WL (Week 12), concomitant with reductions in TBARS (0.24 +/- 0.15 vs. 0.18 +/- 0.11 uM; p < 0.01), PCB serum concentrations (86.7 +/- 45.6 vs. 115.6 +/ 65.9 ng/g lipid; p < 0.01) and TAC (18.9 +/- 2.6 vs. 19.9 +/- 2.3 nmol/mL; p < 0.02) were increased similarly in men and women. At the end of WM (Week 64), a significant effect of time * group interaction was observed for % change in PCB 170 and 187; whereby mP-CR values were higher compared to HH (PCB170: 19.31% +/- 26.48% vs. -6.61% +/- 28.88%, p = 0.02; PCB187: -3.04% +/- 17.78% vs. -21.4% +/- 27.31%, p = 0.04). PCB changes were positively correlated with TBARS levels (r > 0.42, p < 0.05) and negatively correlated with body weight, fat mass, and abdominal fat (r < -0.46, p < 0.02). Our results support mobilization of stored PCBs as well as enhanced redox status following a 12-week P-CR WL diet. Additionally, a 52-week mP-CR WM diet demonstrated an advantage in preventing weight gain relapse accompanied by an increase in circulating PCBs compared to a traditional HH diet. PMID- 28075420 TI - The Trend of Voluntary Warnings in Electronic Nicotine Delivery System Magazine Advertisements. AB - Some manufacturers of electronic nicotine delivery systems (ENDS) voluntarily carried health warnings in their advertisements. This study examined these voluntary warnings in magazine ads and plotted their trends between 2012 and early 2015. ENDS magazine ads were obtained through Kantar media and warnings were collected from the Chicago Public Library or the Trinkets and Trash surveillance system. The prevalence of voluntary warnings, warnings with the specific capitalized word "WARNING", and MarkTen warnings were examined after being weighted using factors related to exposure between January 2012 and March 2015. Five brands (MarkTen, NJOY, MISTIC, and some Blu) carried warnings during the study period. The prevalence of warnings post 2012 that contained a description of nicotine did not significantly increase until the launch of MarkTen, which also happened several months before April 2014 when the U.S. food and drug administration (FDA) published its proposed deeming rule. In addition, none of these warnings met the criteria required by the FDA in the final rules. Voluntary warnings, particularly MarkTen warnings, significantly increased in ENDS magazine ads between 2014 and 2015. It is important to monitor how ENDS manufacturers will comply with the FDA regulation related to warnings and how this regulation will ultimately impact ENDS risk perceptions and use. PMID- 28075419 TI - Surveillance of Clostridium difficile Infections: Results from a Six-Year Retrospective Study in Nine Hospitals of a North Italian Local Health Authority. AB - Clostridium difficile is an emerging cause of healthcare associated infections. In nine hospitals of an Italian Local Health Authority the episodes of C. difficile infection (CDI) were identified using the data registered by the centralized Laboratory Information System, from 2010 to 2015. CDI incidence (positive patients for A and/or B toxins per patients-days) was analysed per year, hospital, and ward. A number of cases approximately equivalent to the mean of identified cases per year were studied retrospectively to highlight the risk factors associated to CDI and their severity. Nine hundred and forty-two patients affected by CDI were identified. The overall incidence was 3.7/10,000 patients days, with a stable trend across the six years and the highest rates observed in smaller and outlying hospitals (up to 17.8/10,000), where the admitted patients were older and the wards with the highest incidences (long-term-care: 7.6/10,000, general medicine: 5.7/10,000) were more represented. The mean age of patients in each hospital was correlated with CDI rates. Of the 101 cases selected for the retrospective study, 86.1% were healthcare associated, 10.9% community acquired; 9.1% met the criteria for recurrent case and 23.8% for severe case of CDI. The overall mortality rate was 28.7%. Comorbidity conditions occurred in 91.1%, previous exposure to antibiotics in 76.2%, and proton pump inhibitors in 77.2%. Recurrent and severe cases were significantly associated with renal insufficiency and creatinine levels >=2 mg/dL. The survey based on the centralized laboratory data was useful to study CDI epidemiology in the different centres in order to identify possible weaknesses and plan control strategies, in particular the reinforcement of staff training, mainly targeted at compliance with contact precautions and hand hygiene. PMID- 28075421 TI - Mx Is Not Responsible for the Antiviral Activity of Interferon-alpha against Japanese Encephalitis Virus. AB - Mx proteins are interferon (IFN)-induced dynamin-like GTPases that are present in all vertebrates and inhibit the replication of myriad viruses. However, the role Mx proteins play in IFN-mediated suppression of Japanese encephalitis virus (JEV) infection is unknown. In this study, we set out to investigate the effects of Mx1 and Mx2 expression on the interferon-alpha (IFNalpha) restriction of JEV replication. To evaluate whether the inhibitory activity of IFNalpha on JEV is dependent on Mx1 or Mx2, we knocked down Mx1 or Mx2 with siRNA in IFNalpha treated PK-15 cells and BHK-21 cells, then challenged them with JEV; the production of progeny virus was assessed by plaque assay, RT-qPCR, and Western blotting. Our results demonstrated that depletion of Mx1 or Mx2 did not affect JEV restriction imposed by IFNalpha, although these two proteins were knocked down 66% and 79%, respectively. Accordingly, expression of exogenous Mx1 or Mx2 did not change the inhibitory activity of IFNalpha to JEV. In addition, even though virus-induced membranes were damaged by Brefeldin A (BFA), overexpressing porcine Mx1 or Mx2 did not inhibit JEV proliferation. We found that BFA inhibited JEV replication, not maturation, suggesting that BFA could be developed into a novel antiviral reagent. Collectively, our findings demonstrate that IFNalpha inhibits JEV infection by Mx-independent pathways. PMID- 28075422 TI - Inflammation, cardiometabolic markers, and functional changes in men with prostate cancer. A randomized controlled trial of a 12-month exercise program. AB - INTRODUCTION Previous studies have shown that physical exercise in cancer patients during radiation therapy (RT) and androgen deprivation therapy (ADT) improves cardiac fitness and quality of life (QoL), as well as reduces fatigue, but it is still not entirely known how it affects inflammation or metabolic factors and what its consequences are in patients with prostate cancer (PCa). OBJECTIVES The aim of the study was to assess the effect of a 12-month physical exercise program on inflammatory and cardiometabolic parameters, as well as on functional status in patients with PCa undergoing RT and ADT. PATIENTS AND METHODS This was a randomized controlled clinical trial including 72 men with high-risk and intermediate-risk PCa, allocated to 2 groups before RT. The physical exercise group trained 5 days/ wk during RT and then 3 days/wk. The control group received usual care according to recommendations. Measurements were performed at baseline, after RT (8 weeks), and after 10 months. The parameters assessed were proinflammatory cytokine levels, lipid profile, aerobic capacity, body mass index (BMI), waist-to-hip ratio (WHR), and functional status (FACT-F and EORTC questionnaires). RESULTS We observed an significant improvement in functional capacity, BMI, and WHR, and a decrease in the levels of proinflammatory cytokines and fatigue in the exercise group compared with controls after 12 months. The level of fatigue was significantly higher in controls than in the exercise group, especially after RT. CONCLUSIONS Long-term supervised exercise training is more effective than educational materials on physical activity in terms of a decrease in cardiovascular risk and improvement in functional status in patients with PCa during RT and ADT. PMID- 28075423 TI - Effects of device-guided slow breathing training on exercise capacity, cardiac function, and respiratory patterns during sleep in male and female patients with chronic heart failure. AB - INTRODUCTION Slow breathing training (SBT) has been proposed as a new nonpharmacologic treatment in patients with chronic heart failure (CHF). OBJECTIVES The aim of this study was to assess the effects of SBT on exercise capacity, hemodynamic parameters, and sleep respiratory patterns in a relatively large sample of CHF patients. PATIENTS AND METHODS A crossover open study was conducted. Patients completed, in a random order, 10- to 12-week SBT, with 2 15 minute sessions of device-guided SBT each day, reaching 6 breaths/ min, and a 10- to 12-week follow-up under standard care. Clinical data collection, polysomnography, echocardiography, 6-minute walk test (6MWT), and laboratory tests were performed. RESULTS A total of 96 patients (74 men, 22 women) in New York Heart Association classes I-III, with an average age of 65 years and an ejection fraction (EF) of 31%, completed the study. Home-based SBT was safe. After training, EF and 6MWT distance improved (EF: 31.3% +/-7.3% vs 32.3% +/ 7.7%; P = 0.030; 6MWT: 449.9 +/-122.7 m vs 468.3 +/-121.9 m; P <0.001), and the apnea-hypopnea index decreased (5.6 [interquartile range (IQR), 2.1; 12.8] vs. 5.4 [IQR, 2.0; 10.8]; P = 0.043). CONCLUSIONS SBT improved physical capacity and systolic heart function; it also diminished sleep disturbances. The results support the benefits of SBT as a novel component of cardiorespiratory rehabilitation programs in patients with CHF. PMID- 28075424 TI - Managing challenging patients with venous thromboembolism: a practical, case based approach. AB - The management of patients with venous thromboembolism (VTE) is a common clinical scenario that, for the most part, involves well-established, evidence-based treatment pathways. However, important unanswered clinical questions remain that are the focus of ongoing research. The aim of this narrative review is to provide a practical, case-based approach to the following clinical scenarios in which therapeutic management pathways are less well established: How long to administer anticoagulation to patients with a first unprovoked VTE? How to manage complex patients with cancer-associated VTE? When and how to treat patients with splanchnic vein thrombosis? When to use thrombolytic therapy for deep vein thrombosis? PMID- 28075425 TI - Management of fibromyalgia: practical guides from recent evidence-based guidelines. AB - Fibromyalgia (FM) is a prevalent and costly condition worldwide, affecting approximately 2% of the general population. Recent evidence- and consensus-based guidelines from Canada, Germany, Israel, and the European League Against Rheumatism aim to support physicians in achieving a comprehensive diagnostic workup of patients with chronic widespread (generalized) pain (CWP) and to assist patients and physicians in shared decision making on treatment options. Every patient with CWP requires, at the first medical evaluation, a complete history, medical examination, and some laboratory tests (complete blood count, measurement of C-reactive protein, serum calcium, creatine phosphokinase, thyroid-stimulating hormone, and 25-hydroxyvitamin D levels) to screen for metabolic or inflammatory causes of CWP. Any additional laboratory or radiographic testing should depend on red flags suggesting some other medical condition. The diagnosis is based on the history of a typical cluster of symptoms (CWP, nonrestorative sleep, physical and/or mental fatigue) that cannot be sufficiently explained by another medical condition. Optimal management should begin with education of patients regarding the current knowledge of FM (including written materials). Management should be a graduated approach with the aim of improving health-related quality of life. The initial focus should ensure active participation of patients in applying healthy lifestyle practices. Aerobic and strengthening exercises should be the foundation of nonpharmacologic management. Cognitive behavioral therapies should be considered for those with mood disorder or inadequate coping strategies. Pharmacologic therapies may be considered for those with severe pain (duloxetine, pregabalin, tramadol) or sleep disturbance (amitriptyline, cyclobenzaprine, pregabalin). Multimodal programs should be considered for those with severe disability. PMID- 28075426 TI - Age-adjusted plasma D-dimer levels in suspected acute pulmonary embolism: a retrospective, single-center study. AB - INTRODUCTION The conventional D-dimer threshold (CDD) is characterized by high sensitivity and low specificity in diagnosing acute pulmonary embolism (PE) in older patients. A higher cut-off level for D-dimer has been proposed, aiming at increasing the specificity while maintaining high sensitivity. It is calculated by multiplying the patient's age in years by a coefficient of 10 (YADD10). OBJECTIVES The aim of this study was to validate the clinical value of YADD10 in patients with suspected acute PE and to optimize this threshold to achieve increased specificity paired with high sensitivity. PATIENTS AND METHODS The medical records of 1022 patients with suspected acute PE, hospitalized between the years 2014 and 2016, were retrospectively analyzed. Patients older than 50 years, with complete medical records and good quality of multislice computed tomography (CT) scans were enrolled. The sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of the proposed thresholds were calculated and compared with those of the CCD. The number of computed tomography scans that could have been avoided with higher thresholds was determined. RESULTS The final analysis included 321 patients (176 women; mean age, 74.2 years; range, 51-101 years). Acute PE was confirmed in 135 patients. The sensitivity of CDD was 100%, and specificity-5.4%. The use of the YADD10 and YADD11 thresholds (obtained by multiplying by the coefficients of 10 and 11, respectively) resulted in maintaining high sensitivity, with increased specificity of 8.6% (YADD10) and 12.4% (YADD11). The number of unnecessary CT scans was reduced by 7%. CONCLUSIONS The YADD thresholds are characterized by high sensitivity and increased specificity when compared with CDD, thus allowing for a safe reduction of the number of CT scans. A prospective study should be conducted to validate these results. PMID- 28075427 TI - Evaluation of sudomotor function in adult patients with long-lasting type 1 diabetes. AB - INTRODUCTION The function of the sweat glands appears to be impaired in patients with diabetic complications. OBJECTIVES The aim of the study was to evaluate sudomotor function in adult patients with type 1 diabetes (DM1) and healthy controls and its relationship with metabolic control and diabetic complications. PATIENTS AND METHODS The study group included 404 patients with DM1 (194 women), aged 41 years (interquartile range [IQR], 32-51 years) and with disease duration of 23 years (IQR, 18-31 years). The control group included 84 healthy volunteers. Electrochemical skin conductance (ESC) in the feet and hands was measured in both groups. RESULTS Patients with DM1 had lower ESC than controls (feet: 80 MUS [IQR, 65-85 MUS] vs 83 MUS [IQR, 78.5-87 MUS], P <0.001; hands: 63 MUS (IQR, 51-75 MUS) vs 69 MUS (IQR, 61.5-78.5 MUS), P <0.001). In the study group, there was a negative correlation between ESC and patients' age, duration of diabetes, waist to-hip ratio, skin autofluorescence, vibration perception threshold, as well as hemoglobin A1c and triglyceride levels, and a positive correlation with estimated glomerular filtration rate. Microvascular complications were diagnosed in 73.3% of the patients. Patients with retinopathy, diabetic kidney disease, peripheral neuropathy, and cardiac autonomic neuropathy had lower ESC in the feet and hands compared with those without complications. In multivariate logistic regression models, ESC was associated with the presence of any microvascular complications independently of potential confounders. CONCLUSIONS Diabetic microangiopathy, and in particular neuropathy, is related with reduced sudomotor function in DM1. A longer duration of diabetes, worse metabolic control, and reduced renal function are associated with greater sudomotor dysfunction. PMID- 28075428 TI - Balanced secretion of anti-CEA * anti-CD3 diabody chains using the 2A self cleaving peptide maximizes diabody assembly and tumor-specific cytotoxicity. AB - Adoptive transfer of genetically engineered human cells secreting bispecific T cell engagers has shown encouraging therapeutic effects in preclinical models of cancer. However, reducing the toxicity and improving the effectiveness of this emerging immunotherapeutic strategy will be critical to its successful application. We have demonstrated that for gene-based bispecific antibody strategies, two-chain diabodies have a better safety profile than single-chain tandem scFvs (single-chain variable fragments), because their reduced tendency to form aggregates reduces the risk of inducing antigen-independent T-cell activation. Here, we demonstrate that the incorporation of a 2A self-processing peptide derived from foot-and-mouth disease virus conveying co-translational cleavage into a two-chain anti-CD3 * anti-CEA diabody gene enables near-equimolar expression of diabody chains 1 and 2, and thus increases the final amount of assembled diabody. This was found to maximize diabody-mediated T-cell activation and cytotoxicity against carcinoembryonic antigen-positive tumor cells. PMID- 28075430 TI - Correction: Inhibition of TLR1/2 dimerization by enantiomers of metal complexes. AB - Correction for 'Inhibition of TLR1/2 dimerization by enantiomers of metal complexes' by Li-Juan Liu et al., Chem. Commun., 2016, 52, 12278-12281. PMID- 28075429 TI - Telomerase-specific oncolytic adenovirus expressing TRAIL suppresses peritoneal dissemination of gastric cancer. AB - Peritoneal dissemination is the most common condition of metastasis in gastric cancer. The survival duration of a patient with advanced stage gastric cancer, may be improved by gene therapy. In this study, we used an oncolytic adenovirus vector (Ad/TRAIL-E1) that expresses both the TRAIL and E1A genes under the control of a tumor-specific promoter. We evaluated the anti-tumor effect of Ad/TRAIL-E1 on gastric cancer cells in vitro, as well as in vivo in a xenograft peritoneal carcinomatosis mouse model. Our data showed that Ad/TRAIL-E1 induced TRAIL-mediated apoptosis in gastric cancer cell lines, but not in the normal cell lines. In addition, Ad/TRAIL-E1 significantly inhibited peritoneal metastasis and prolonged the survival of mice without treatment-related toxicity. Therefore, tumor-specific TRAIL expression from an oncolytic adenovirus vector may provide a novel therapeutic approach for the treatment of advance stage gastric cancer with peritoneal dissemination. PMID- 28075431 TI - Influencing colloidal formation with optical traps. AB - We present a novel concept where optical traps are used to influence an ongoing polymerization process of emulsion droplets. By directed coalescence and partial fusion of intermediate nucleation sites, spherical and elongated colloids with specific dimensions are formed. The strength of this approach lies in its versatility and ease of making various changes to the end product without the need for chemical modifications. PMID- 28075432 TI - Aggregation and deposition of in situ formed colloidal particles in the presence of polyelectrolytes. AB - In this work, aggregation and deposition of in situ formed magnesium hydroxide (IFM) in the presence of hydrolyzed polyacrylamide (HPAM) were investigated. Relative concentrations of interactants, as well as other experimental conditions, were changed to elucidate the interaction mechanisms from microscopic to macroscopic levels. Light scattering measurements were used to investigate the aggregation kinetics, fractal dimension, and collision efficiency of the aggregates on a microscopic level. Electrophoretic mobility and TEM were utilized to measure the charging properties and morphologies of aggregates, respectively. Adsorption and rheology experiments were performed to determine the deposition mechanism at higher concentrations of interactants on a macroscopic level. The results demonstrate that the initial rapid aggregation of IFM in the presence of HPAM is due to an electrostatic patch mechanism. In addition, the deposition was accelerated by flocculation with different mechanisms. When more IFM is involved, bridging flocculation dominates; when more HPAM is added, depletion flocculation plays a leading role. The results of this work may provide further insight into understanding the aggregation and deposition of in situ formed natural/engineered particles in the presence of oppositely charged polyelectrolytes, as well as provide new possibilities for produced water treatment, biomedical applications, biomineralization, etc. PMID- 28075433 TI - [Effects of morphine, butorphanol and levomethadone in different doses on thermal nociceptive thresholds in horses]. AB - OBJECTIVE: Various opioids are available for use in equine medicine. Studies directly comparing their analgesic effects and side effects are rare. Therefore, the aim of this study was to compare the antinociceptive effect and the duration of analgesia of two different doses of morphine, butorphanol and levomethadone in horses. MATERIAL AND METHODS: Eight adult, healthy horses were used for this randomized, placebo-controlled, blinded cross-over trail. Each horse received placebo (P = 0.9% saline) and morphine (M0.1 = 0.1 mg/kg; M0.2 = 0.2 mg/kg), butorphanol (B0.1 = 0.1 mg/kg; B0.2 = 0.2 mg/kg) and levomethadone (L0.1 = 0.1 mg/kg; L0.2 = 0.2 mg/kg) in a low and a high dose and with a wash-out period of 14 days. Thermal thresholds were determined by incremental contact heat applied to the skin at the withers. Single stimulations were performed 15 minutes prior and 10, 30, 60, 90, 120, 180, 240, 300, 360, 420, 540 and 1350 minutes after treatment. Threshold values, gastrointestinal auscultation score and horses' behavior were recorded. Data were analyzed with analysis of variance for repeated measurements (p < 0.05). RESULTS: In group M0.1, changes in thermal thresholds did not reach significance. Thermal threshold increased significantly in the groups M0.2, B0.1, B0.2, L0.1 and L0.2 for 240, 90, 90, 60 and 300 minutes, respectively. Behavioural changes, increased locomotion and decreased bowel sounds as well as delayed time until defecation were noticed in all groups. CONCLUSIONS: Levomethadone induced a dose-dependent increase and prolongation of analgesia, whereas with butorphanol there was no difference between dosages regarding duration and intensity of analgesia. Morphine provided detectable analgesia only in the high dose of 0.2 mg/kg. CLINICAL RELEVANCE: Levomethadone and morphine in the low dose (0.1 mg/kg) produced only minor and short lived anti nociception and further studies are necessary to give a profound dose recommendation for the use of these drugs in horses. PMID- 28075434 TI - Diagnosis and surgical correction of congenital bilateral patellar luxation in two dwarf zebu calves. AB - This case study presents two female dwarf zebu calves with permanent bilateral flexion of the stifle joint secondary to bilateral congenital lateral patellar luxation. The patella could be manually repositioned bilaterally in the first calf (14 days old), but re-luxated immediately with release of manual pressure (luxation grade III). In the second calf (28 days old) both patellae were permanently luxated laterally (grade IV). The right and left stifles of each calf were operated in a staged procedure with approximately 14 days between surgery of the two sides. While a lateral release and a medial imbrication were sufficient for correction in the left stifle of the younger calf, a trochlear wedge resection was required in the other three stifle joints with hypo- to aplastic trochleas in order to stabilize the patella. Postoperatively each stifle was immobilized for 10 days with a cast. The younger calf regained full function of the hind limbs during the complete gait cycle in walk and in trot one month after the procedure. The older calf regained full function in the hind limbs in walk but in trot there was some degree of lameness due to a reduced extension of approximately 20 degrees . PMID- 28075435 TI - Cardiac Biomarkers Predict 1-Year Mortality in Elderly Patients Undergoing Hip Fracture Surgery. AB - This prospective study included 152 elderly patients (mean age, 80 years; range, 72-88 years) with a hip fracture treated surgically. Comorbidities were evaluated, and B-type natriuretic peptide was measured at baseline and at postoperative days 4 and 5 in addition to troponin I. Major cardiac events were recorded, and 1-year mortality was assessed. Comorbidity models with the important multivariate predictors of 1-year mortality were analyzed. Overall, 9 patients (6%) experienced major cardiac events postoperatively during their hospitalization. Three patients (2%) died postoperatively, at days 5, 7, and 10, from autopsy-confirmed myocardial infarction. Three patients (2%) experienced a nonfatal myocardial infarction, and 3 patients (2%) experienced acute heart failure. At 1-year follow-up, 37 patients (24%) had died. Age older than 80 years (P=.000), renal failure (P=.016), cardiovascular disease (P=.003), respiratory disease (P=.010), Parkinson disease (P=.024), and dementia (P=.000) were univariate predictors of 1-year mortality. However, in the multivariate model, only age older than 80 years (P=.000) and dementia (P=.024) were important predictors of 1-year mortality. In all comorbidity models, age older than 80 years and dementia were important predictors of 1-year mortality. Postoperative increase in B-type natriuretic peptide was the most important predictor of 1-year mortality. Receiver operating characteristic curve analysis showed a threshold of 90 ng/mL of preoperative B-type natriuretic peptide (area under the curve=0.773, 95% confidence interval, 0.691-0.855, P<.001) had 82% sensitivity and 62% specificity to predict 1-year mortality. Similarly, a threshold of 190 ng/mL of postoperative B-type natriuretic peptide (area under the curve=0.753, 95% confidence interval, 0.662-0.844, P<.001) had 70% sensitivity and 77% specificity to predict the study endpoint. [Orthopedics. 2017; 40(3):e417-e424.]. PMID- 28075436 TI - Gait Kinematic Deviations in Patients With Developmental Dysplasia of the Hip Treated With Total Hip Arthroplasty. AB - Comprehensive gait analysis of patients with Crowe type II and III developmental dysplasia of the hip (DDH) after successful total hip arthroplasty (THA) is lacking in the literature. This study evaluated gait function in joint kinematics after unilateral and bilateral THA in patients with DDH. In addition, the effect of high cup position on gait function was investigated. A total of 16 unilateral and 15 bilateral cementless THA patients due to DDH and 10 healthy participants comprised the study population. Levels of superior displacement of the acetabular cup and leg-length discrepancy after THA were measured. Three-dimensional gait analysis for patients who underwent THA was performed at least 1 year postoperatively. Range of motion (ROM), particularly sagittal (flexion/extension) and frontal (adduction/abduction) hip joint ROM, was significantly lower in both the unilateral and bilateral groups than in healthy participants. Sagittal (flexion/extension) hip ROM in patients with DDH was greater in the unilateral group than in the bilateral group. A significant influence of high acetabular cup position on hip joint kinematics was not observed in the unilateral subgroups (mean level of cup superior displacement was 11.8 mm). In contrast, a significant influence of high acetabular cup position on hip joint kinematics was observed in the bilateral subgroups (mean level of cup superior displacement was 21.3 mm). The functional symmetry and cup superior displacement within 12 mm in patients with DDH after unilateral THA contributed to the restoration of normal hip biomechanics. [Orthopedics. 2017; 40(3):e425-e431.]. PMID- 28075437 TI - Comparison of Irrigation Times Using Gravity and High-Pressure Lavage. AB - The benefits of high-pressure pulsatile lavage for open fracture irrigation have been controversial based on conflicting experimental animal research. Recently published data definitively demonstrated that irrigation pressure does not affect the incidence of reoperation for the treatment of open fractures. However, proponents of pulsatile lavage argue a faster irrigation time is an important benefit of the high-pressure treatment. The purpose of this study was to determine the difference in irrigation time between gravity and high-pressure lavage. The experimental setup was designed to mimic clinical practice and compared mean irrigation flow times for high-pressure pulsatile lavage and gravity flow with 2 commonly used tube diameters. Each irrigation setup was tested 5 times at 3 different irrigation bag heights. Analysis of variance and Student's t tests were used to compare the mean flow times of 3 irrigation methods at each height and among the 3 heights for each irrigation method. The mean irrigation flow time in the various experimental models ranged from 161 to 243 seconds. Gravity irrigation with wide tubing was significantly faster than pulsatile lavage or gravity with narrow tubing (P<.001). Increasing irrigation bag height had only a marginal effect on the overall flow times (<9% difference). The difference in mean flow time among the testing techniques was slightly longer than 1 minute, which is unlikely to have a material impact on procedural costs, operating times, and subsequent gains in patient safety. [Orthopedics. 2017; 40(3):e413-e416.]. PMID- 28075438 TI - Quantitative Anatomical Differences in the Shoulder. AB - This study explored the radiographic and anatomical differences in normal shoulders between men and women, as well as factors such as race, height, weight, and age. A total of 205 patients with documented normal anatomical radiographs comprised the study population. Five fellowship-trained orthopedic surgeon reviewers measured head diameter, humeral head size, head to tuberosity distance, greater tuberosity width, neck-shaft angle, surface-arc angle, glenoid neck length, and distance from the lateral acromion process to the greater tuberosity on anteroposterior radiographs with the shoulder in external rotation. After the reviewers identified and marked defined anatomical landmarks, a comprehensive automated calculator was used to compute all parameters. Between men and women, head diameter (P<.001), humeral head size (P<.001), greater tuberosity width (P<.001), distance from the lateral acromion process to the greater tuberosity (P<.001), and glenoid neck length (P<.001) were significantly different, whereas race was not significantly different for any anatomical parameter. Using Spearman's rho, there was a strong correlation between head diameter/humeral head height and height (rs=0.77/rs=0.68), weight (rs =0.62), and greater tuberosity width (rs=0.66/rs= 0.61); there also was a strong negative correlation between head to tuberosity distance and neck-shaft angle (rs=-0.80). This study demonstrated precisely defined proximal humeral anatomical relationships and sizes using an advanced standardized imaging software program. With these data, orthopedic surgeons and implant designers can better understand the anatomy and glenohumeral relationships to re-create when performing total shoulder arthroplasty. [Orthopedics. 2017; 40(3):155-160.]. PMID- 28075439 TI - Effects of S100A6 gene silencing on the biological features of eutopic endometrial stromal cells and beta-catenin expression. AB - Protein expression levels of S100 calcium binding protein A6 (S100A6) are increased in various malignancies and are associated with tumor behavior; however, the association between S100A6 and endometriosis remains to be elucidated. In order to investigate the influence of S100A6 protein, recombinant lentivirus siS100A6 was used to transfect the eutopic endometrial stromal cells. CCK-8 assay was performed to identify the proliferation ability of cell and the cell migration was detected by Transwell assay. Flow cytometry was performed to detect cell apoptosis, and western blotting and reverse transcription quantitative polymerase chain reaction were performed to identify the expression of beta-catenin. The present study investigated the role of S100A6 in endometriosis and its interaction with beta-catenin by transfecting eutopic endometrial stromal cells with a recombinant lentivirus containing S100A6 specific small interfering RNA. Inhibition of S100A6 expression had a significant antiproliferative effect and reduced the migratory ability of eutopic endometrial stromal cells, and induced their apoptosis. In addition, inhibition of S100A6 expression suppressed beta-catenin expression. These results suggested that inhibition of S100A6 may represent a promising novel approach for the targeted therapy of endometriosis. PMID- 28075440 TI - The metastasis suppressor gene KISS-1 regulates osteosarcoma apoptosis and autophagy processes. AB - The expression of the metastasis suppressor gene KISS-1 in osteosarcoma cells during apoptosis and autophagy was evaluated. MG-63 osteosarcoma cells were transfected with either KISS-1 overexpression or KISS-1 knockdown expression vector in vitro, and compared with cell lines transfected with empty vector. After 12, 24, 48 and 72 h of cell culture, the cell proliferation was examined. The MTT method was used to detect apoptosis by flow cytometry, and the mRNA levels of apoptosis and autophagy markers caspase-3, Bcl-2, Bax, LC3 and Beclin1 were assessed by RT-PCR. Our results showed that cells in the control and low expression group kept proliferating during the cell culture period of 72 h, while the cells in the overexpression group progressively decreased in number. Also, the proliferation rate of the low expression group was significantly higher than that of the control group. The relative mRNA expression levels of caspase-3 and Bax mRNA in the control and low expression group showed no change (the expression was lowest in the low expression group). Moreover, the mRNA level of Bcl-2 increased in both cell groups. The mRNA expression levels of caspase-3 and Bax in the overexpression group were increased, and the level of Bcl-2 was reduced significantly. At the same time, the relative expression level of LC3 and Beclin1 mRNA in the control and low expression groups remained the same, and that of the overexpression group increased. The mRNA levels of LC3 and Beclin1 in the overexpression group were the highest, and that of the low expression group the lowest. The differences were statistically significant (P<0.05). Based on these results, we showed that KISS-1 inhibited the proliferation of osteosarcoma in vitro, probably by accelerating the processes of apoptosis and autophagy in the cells. PMID- 28075441 TI - miR-34c-3p acts as a tumor suppressor gene in osteosarcoma by targeting MARCKS. AB - Previous studies have demonstrated that microRNA (miR)-34c-3p is important in human cancer progression. However, the function of miR-34c-3p in osteosarcoma (OS) remains to be elucidated. In the present study, miR-34c-3p level was measured by reverse transcription-quantitative polymerase chain reaction in OS tissues and the associated prognostic value for overall survival was determined. The function of miR-34c-3p was examined in vitro and in vivo. A luciferase reporter assay was used to identify the targets of miR-34c-3p. The results of the present study revealed that miR-34c-3p was downregulated in OS tissues and cell lines, and decreased levels of miR-34c-3p were associated with a high mortality rate in patients with OS. Furthermore, restoration of miR-34c-3p expression reduced cell growth in vitro and suppressed tumorigenesis in vivo. Conversely, inhibition of miR-34c-3p stimulated OS cell growth in vitro and in vivo. Myristoylated alanine-rich protein kinase C substrate (MARCKS) was identified as a direct target of miR-34c-3p and its overexpression partly reversed the suppressive effects of miR-34c-3p. Furthermore, MARCKS was revealed to be upregulated and inversely correlated with miR-34c-3p levels in OS tissues. These data suggested that miR-34c-3p acts as a tumor suppressor via regulation of MARCKS expression in OS progression and miR-34c-3p may be a promising therapeutic target for this type of cancer. PMID- 28075442 TI - Increased expression of PD-L1 by the human papillomavirus 16 E7 oncoprotein inhibits anticancer immunity. AB - Cytotoxic T lymphocyte dysfunction is frequently associated with PD-L1/PD-1 pathway activation, and is a principal obstacle in cancer therapy. In the present study, the mechanisms underlying the human papillomavirus (HPV)-induced evasion of cervical cancer cells to the host immune system via the programmed death ligand 1/programmed death 1 (PD-L1/PD-1) signaling pathway was investigated. A significant increase in the expression of the HPV16E7 viral protein and PD-L1 in cervical tissues was observed when compared with normal cervical tissues. In addition, a positive correlation between HPV16E7 and PD-L1 expression was observed by immunohistochemical staining and reverse transcription-polymerase chain reaction. Overexpressing HPV16E7 oncoprotein in the epithelial carcinoma of PC3 cells increased the expression level of the PD-L1 protein and inhibited peripheral blood mononuclear cell (PBMC) proliferation and cytotoxic T lymphocyte (CTL) activity. Upon knockdown of HPV16E7 in HPV16-associated CaSki cervical cancer cells with a relevant siRNA, a reduction in PD-L1 protein expression was observed, as well as a significant increase in PBMC proliferation and CTL activity. A recombinant plasmid, MSCVPIG-soluble PD-1, was constructed and transfected into the CaSki cell line, and was co-cultured with PBMCs. PBMC proliferation and CTL activity were observed to increase significantly. In conclusion, the results presented in the current study suggest that overexpression of PD-L1, induced by HPV16E7, may be responsible for lymphocyte dysfunction. In addition, soluble PD-1 may restore the function of tumor infiltrating lymphocytes by inhibiting the PD-L1/PD-1 signaling pathway. These results may provide a novel insight for immunotherapeutic approaches in the treatment of cervical cancer. PMID- 28075443 TI - MicroRNA expression signature and the therapeutic effect of the microRNA-21 antagomir in hypertrophic scarring. AB - Hypertrophic scars (HS) area fibroproliferative disorder of the skin, which causes aesthetic and functional impairment. However, the molecular pathogenesis of this disease remains largely unknown and currently no efficient treatment exists. MicroRNAs (miRNAs) are involved in a variety of pathophysiological processes, however the role of miRNAs in HS development remains unclear. To investigate the miRNA expression signature of HS, microarray analysis was performed and 152 miRNAs were observed to be differentially expressed in HS tissue compared with normal skin tissues. Of the miRNAs identified, miRNA-21 (miR 21) was significantly increased in HS tissues and hypertrophic scar fibroblasts (HSFBs) as determined by reverse transcription-quantitative polymerase chain reaction analysis. It was also observed that, when miR-21 in HSFBs was blocked through use of an antagomir, the phenotype of fibrotic fibroblasts in vitro was reversed, as demonstrated by growth inhibition, induction of apoptosis and suppressed expression of fibrosis-associated genes collagen type I alpha 1 chain (COL1A1), COL1A2 and fibronectin. Furthermore, miR-21 antagomir administration significantly reduced the severity of HS formation and decreased collagen deposition in a rabbit ear HS model. The total scar area and scar elevation index were calculated and were demonstrated to be significantly decreased in the treatment group compared with control rabbits. These results indicated that the miR-21 antagomir has a therapeutic effect on HS and suggests that targeting miRNAs may be a successful and novel therapeutic strategy in the treatment of fibrotic diseases that are difficult to treat with existing methods. PMID- 28075444 TI - The role of lncRNA MALAT1 in the regulation of hepatocyte proliferation during liver regeneration. AB - Exploring the biological functions of long non-coding RNAs (lncRNAs) has come to the foreground in recent years. Studies have indicated that the lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) not only regulates tumorigenesis in hepatocellular carcinoma, but also controls cell cycle progression in hematopoietic cells. The present study was designed to investigate the biological role of lncRNA MALAT1 in liver regeneration. We carried out a series of assays during liver regeneration following 2/3 partial hepatectomy in mice. We explored the functions of lncRNA MALAT1 with a series of functional analyses in vitro. We found that MALAT1 was upregulated during liver regeneration. Moreover, MALAT1 accelerated hepatocyte proliferation by stimulating cell cycle progression from the G1 to the S phase and inhibiting apoptosis in vitro. In addition, our findings also demonstrated that MALAT1 was regulated by p53 during liver regeneration, and that p53 may be a key upstream regulator of MALAT1 activity. Mechanistically, we found that MALAT1 activated the Wnt/beta-catenin pathway by inhibiting the expression of Axin1 and adenomatous polyposis coli (APC), and subsequently promoting the expression of cyclin D1. On the whole, the findings of this study suggest that MALAT1 is a critical molecule for liver regeneration. Pharmacological interventions targeting MALAT1 may thus prove to be therapeutically beneficial in liver failure or liver transplantation by promoting liver regeneration. PMID- 28075445 TI - A clinical and molecular analysis of a patient with Emanuel syndrome. AB - Emanuel syndrome (ES) is the most frequent type of recurrent non-Robertsonian translocation that is characterized by numerous anomalies. Over 100 patients with ES have been described in the literature. The phenotype of this syndrome varies but often consists of facial dysmorphism, microcephaly, severe intellectual disability, developmental retardation, congenital heart disease and genital anomalies. The present study describes a 2-year-old boy with multiple malformations, including facial dysmorphism, severe intellectual disability, growth retardation, congenital heart disease, cleft lip and palate, genital malformation (micropenis), amblyopia, thymic dysplasia and hearing impairment. The karyotype of the patient was 47,XY,+del(22)(q13), and the maternal karyotype was 46,XX,t(11;22)(q25;q13),9qh-,15p+. Single-nucleotide polymorphism-array analysis of the proband indicated a partial duplication of chromosomes 22 and 11 at 22q11.1-q11.21 and 11q23.3-q25, respectively, which confirmed the diagnosis of ES. To date, no cases of ES have been reported in mainland China. The present case further emphasizes the necessity and importance of high-resolution techniques for genetic diagnosis and for subsequent genetic counseling. The present study contributed to the phenotypic delineation of ES and confirmed the first ES patient in mainland China. PMID- 28075446 TI - NF-kappaB inhibition is associated with OPN/MMP-9 downregulation in cutaneous melanoma. AB - The development of cutaneous melanoma is influenced by genetic factors, including BRAF mutations and environmental factors, such as ultraviolet exposure. Its progression has been also associated with the involvement of several tumour microenvironmental molecules. Among these, nuclear factor-kappaB (NF-kappaB) has been indicated as a key player of osteopontin (OPN) and matrix metalloproteinase 9 (MMP-9) activation. However, whether NF-kappaB plays a role in the development and progression of melanoma in association with the OPN/MMP-9 axis according to the BRAFV600E mutation status has not been investigated in detail to date. Thus, in the present study, in order to shed light on this matter, 148 patients with melanoma and 53 healthy donors were recruited for the analysis of OPN, MMP-9 and NF-kappaB. Significantly higher circulating levels of OPN and MMP-9 were observed in the patients with melanoma when compared to the healthy donors. Similar data were obtained for NF-kappaB p65 activity. The OPN levels did not differ significantly between melanomas with or without BRAFV600E mutation. However, as regards NF-kappaB and MMP-9, significant differences were observed between the melanomas with or without BRAFV600E mutation. To determine whether NF-kappaB inhibition is associated with a decrease in the levels of OPN and MMP-9, peripheral blood mononuclear cells from 29 patients with melanoma were treated with the NF-kappaB inhibitor, dehydroxymethylepoxyquinomycin (DHMEQ), with or without OPN. As expected, the inhibition of NF-kappaB induced a marked decrease in both the OPN and MMP-9 levels. Furthermore, the decrease in MMP-9 levels was higher among melanomas harbouring the BRAFV600E mutation. Overall, our data suggest that the activation of MMP-9 is associated with the BRAFV600E mutation status. Furthermore, such an activation is mediated by NF-kappaB, suggesting its role as therapeutic target in patients with melanoma. PMID- 28075447 TI - Anti-metastatic effect of rhodomyrtone from Rhodomyrtus tomentosa on human skin cancer cells. AB - This study focused on the inhibitory effect of rhodomyrtone, a bioactive compound isolated from the leaves of Rhodomyrtus tomentosa (Aiton) Hassk., on cancer metastasis in epidermoid carcinoma A431 cells and on the verification of the underlying related molecular mechanisms of this event. We demonstrated that rhodomyrtone at the subcytotoxic concentration (0.5 and 1.5 ug/ml) exhibited pronounced inhibition of cancer metastasis by reducing cell migration, cell adhesive ability and cell invasion of A431 cells in a dose-dependent manner. Data demonstrated that rhodomyrtone could inhibit the focal adhesion kinase (FAK) and phosphorylation of protein kinase B (AKT), c-Raf, extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 MAPK involved in the downregulation the enzyme activities and protein expression of matrix metalloproteinase-2 (MMP-2) and MMP 9. Moreover, we found that rhodomyrtone increased the expression of TIMP-1 and TIMP-2, which are inhibitors of MMP-9 and MMP-2, respectively. Rhodomyrtone also inhibited the expression of NF-kappaB and phosphorylation of NF-kappaB in a dose dependent manner. These results suggested that rhodomyrtone inhibited A431 cell metastasis by reducing MMP-2/9 activities and expression through inhibiting ERK1/2, p38 and FAK/Akt signaling pathways via NF-kappaB activities. This finding suggested that rhodomyrtone may be a novel antimetastasis agent for treatment of skin cancer cells. PMID- 28075448 TI - Microarray analysis of circular RNA expression patterns in polarized macrophages. AB - Circular RNAs (circRNAs) are generated from diverse genomic locations and are a new player in the regulation of post-transcriptional gene expression. Recent studies have revealed that circRNAs play a crucial role in fine-tuning the level of microRNA (miRNA)-mediated regulation of gene expression by sequestering miRNAs. The interaction of circRNAs with disease-associated miRNAs suggests that circRNAs are important in the pathology of disease. However, the effects and roles of circRNAs in macrophage polarization have yet to be explored. In the present study, we performed a circRNA microarray to compare the circRNA expression profiles of bone marrow-derived macrophages (BMDMs) under two distinct polarizing conditions (M1 macrophages induced by interferon-gamma and LPS stimulation, and M2 macrophages induced by interleukin-4 stimulation). Our results showed that a total of 189 circRNAs were differentially expressed between M1 and M2 macrophages. Differentially expressed circRNAs with a high fold-change were selected for validation by RT-qPCR: circRNA-003780, circRNA-010056, and circRNA-010231 were upregulated and circRNA-003424, circRNA-013630, circRNA 001489 and circRNA-018127 were downregulated (fold-change >4, P<0.05) in M1 compared to M2, which was found to correlate with the microarray data. Furthermore, the most differentially expressed circRNAs within all the comparisons were annotated in detail with circRNA/miRNA interaction information using miRNA target prediction software. In conclusion, the present study provides novel insight into the role of circRNAs in macrophage differentiation and polarization. PMID- 28075449 TI - Construction of an miRNA-regulated drug-pathway network reveals drug repurposing candidates for myasthenia gravis. AB - Myasthenia gravis (MG) is a rare debilitating autoimmune neuromuscular disorder. Many studies have focused on the mechanism and treatment strategies of MG. However, the exact pathogenesis of MG and effective treatment strategies remain unclear. Recent studies have indicated that microRNAs (miRNAs or miRs) can regulate the pathological pathways of MG, suggesting their potential role in novel treatments. In the present study, we created a comprehensive catalog of experimentally confirmed MG risk genes and miRNAs by manually mining published literature and public databases. Based on these genes and miRNAs, we identified 41 MG risk pathways and 105 approved drugs that can affect these pathways. Some important MG-related pathways, such as hsa04060 (cytokine-cytokine receptor interaction) and hsa05200 (pathway in cancer), were found to be regulated by MG risk miRNAs and drugs. Furthermore, we constructed an miRNA-regulated drug pathway network and identified miRNAs and drugs that synergistically regulate key MG pathways and biological processes. We developed a drug repurposing strategy to identify 25 drug repurposing candidates for MG; several of these drugs, such as rituximab, adalimumab, sunitinib, and muromonab, have the potential to be novel MG treatment drugs. This study provides novel insight into the pathogenesis of MG and potential drug candidates for MG were identified. PMID- 28075450 TI - Integrated analysis of differentially expressed genes and pathways in triple negative breast cancer. AB - Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by an aggressive phenotype and reduced survival. The aim of the present study was to investigate the molecular mechanisms involved in the carcinogenesis of TNBC and to identify novel target molecules for therapy. The differentially expressed genes (DEGs) in TNBC and normal adjacent tissue were assessed by analyzing the GSE41970 microarray data using Qlucore Omics Explorer, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes. Pathway enrichment analyses for DEGs were performed using the Database for Annotation, Visualization and Integrated Discovery online resource. A protein-protein interaction (PPI) network was constructed using Search Tool for the Retrieval of Interacting Genes, and subnetworks were analyzed by ClusterONE. The PPI network and subnetworks were visualized using Cytoscape software. A total of 121 DEGs were obtained, of which 101 were upregulated and 20 were downregulated. The upregulated DEGs were significantly enriched in 14 pathways and 83 GO biological processes, while the downregulated DEGs were significantly enriched in 18 GO biological processes. The PPI network with 118 nodes and 1,264 edges was constructed and three subnetworks were extracted from the entire network. The significant hub DEGs with high degrees were identified, including TP53, glyceraldehyde-3-phosphate dehydrogenase, cyclin D1, HRAS and proliferating cell nuclear antigen, which were predominantly enriched in the cell cycle pathway and pathways in cancer. A number of critical genes and pathways were revealed to be associated with TNBC. The present study may provide an improved understanding of the pathogenesis of TNBC and contribute to the development of therapeutic targets for TNBC. PMID- 28075452 TI - A novel pathway in NSCLC cells: miR-191, targeting NFIA, is induced by chronic hypoxia, and promotes cell proliferation and migration. AB - MicroRNAs (miRs) have emerged as being important in cancer biology. miR-191 is a conserved miRNA, which has been investigated in detail and is reported to be induced by hypoxia-inducible factor (HIF)-1alpha and has an contributory action in the progression of breast, hepatic and pancreatic cancer. However, the effects of miR-191 in the progression of lung cancer are a subject of debate. In the present study, it was found that the expression of miR-191 was significantly upregulated in non-small cell lung cancer (NSCLC) cells in patients in vivo. However, the levels of miR-191 remained unchanged in SK-MES-1, A549 and NCI-H460 NSCLC cell lines, compared with the level in the normal HBE lung cell line, however, the levels were markedly upregulated in these NSCLC cell lines under conditions of chronic hypoxia. Subsequently, an miR-191 mimic was transfected into the NSCLC cell lines to examine its effect on the progression of the NSCLC cells in vitro. The data obtained using MTT and Cell counting kit-8 assays revealed that miR-191 had no effect on the proliferation of the cells under normal condition, however, their proliferation was promoted under mild hypoxic conditions. In addition, the results of a Transwell migration assay showed that miR-191 had a promoting effect on NSCLC cell migration under the conditions of chronic hypoxia. Furthermore, the TargetScan bioinformatics server and 3' untranslated region luciferase reporter assay indicated that the transcription factor, nuclear factor 1alpha (NFIA) was a target of miR-191. Subsequent western blot analysis showed that, in chronic-hypoxia, the protein levels of NFIA and the tumor suppressor, CCAAT-enhancer-binding protein alpha, were sharply reduced in A549 cells. In conclusion, miR-191 was induced by chronic hypoxia and promoted the proliferation and migration of NSCLC cells under chronic hypoxic conditions. This promotion may be associated with its targeting of NFIA. The present findings may provide a potential molecular target for the therapeutic treatment of NSCLC. PMID- 28075451 TI - The role of sphingolipid signalling in diabetes-associated pathologies (Review). AB - Sphingosine kinase (SphK) is an important signalling enzyme that catalyses the phosphorylation of sphingosine (Sph) to form sphingosine-1-phosphate (S1P). The multifunctional lipid, S1P binds to a family of five G protein-coupled receptors (GPCRs). As an intracellular second messenger, S1P activates key signalling cascades responsible for the maintenance of sphingolipid metabolism, and has been implicated in the progression of cancer, and the development of other inflammatory and metabolic diseases. SphK and S1P are critical molecules involved in the regulation of various cellular metabolic processes, such as cell proliferation, survival, apoptosis, adhesion and migration. There is strong evidence supporting the critical roles of SphK and S1P in the progression of diabetes mellitus, including insulin sensitivity and insulin secretion, pancreatic beta-cell apoptosis, and the development of diabetic inflammatory state. In this review, we summarise the current state of knowledge for SphK/S1P signalling effects, associated with the development of insulin resistance, pancreatic beta-cell death and the vascular complications of diabetes mellitus. PMID- 28075453 TI - miR-375 inhibits cancer stem cell phenotype and tamoxifen resistance by degrading HOXB3 in human ER-positive breast cancer. AB - Cancer stem cell (CSC) formation and epithelial-mesenchymal transition (EMT) are pivotal events in tumor cell invasion and metastasis. They have been shown to occur in resistance to tamoxifen. Moreover, microRNAs (miRNAs) have been associated with CSCs, EMT as well as tamoxifen resistance. Studying molecular mechanism of CSCs, EMT as well as tamoxifen resistance will help us to further understand the pathogenesis and progression of the disease and offer new targets for effective therapies. In the present study, we showed that miR-375 inhibits CSC traits in breast cancer MCF-7 cells. Bioinformatics analysis and experimental validation identified HOXB3 as a direct target of miR-375. Overexpressing miR-375 degraded HOXB3 mRNA in MCF-7 cells. Moreover, overexpression of HOXB3 induced formation of CSC phenotypes, EMT and tamoxifen-resistance as well as enhanced ability of migration and invasion in MCF-7 cells. Most ER-positive breast cancer related deaths occur, because of resistance to standard therapies and metastasis, restoring miR-375 or targeting HOXB3 might serve as potential therapeutic approaches for the treatment of tamoxifen-resistant breast cancer. PMID- 28075454 TI - Expression of glia maturation factor gamma is associated with colorectal cancer metastasis and its downregulation suppresses colorectal cancer cell migration and invasion in vitro. AB - Glia maturation factor gamma (GMFG) functions to reorganize the actin cytoskeleton and appears to play a causative role in cell migration and adherence. The present study assessed GMFG expression in colorectal cancer cells and tissue specimens and then explored the role of GMFG in colorectal cancer progression in vitro. GMFG protein was highly expressed in colorectal cancer tissues and a metastatic colon cancer cell line. Knockdown of GMFG expression using GMFG siRNA or anti-GMFG antibody decreased the capacity of colon cancer LoVo cell migration and invasion in vitro, while recombinant GMFG treatment induced LoVo cell migration. Furthermore, GMFG knockdown also decreased expression of MMP2 protein and reversed epithelial-mesenchymal transition (EMT) phenotypes in LoVo cells. Co-culture of LoVo cells with human umbilical vein endothelial cells (HUVECs) and exogenous GMFG treatment promoted LoVo cell migration and invasion. The data from the present study indicate that GMFG should be further evaluated as a biomarker for detection of colorectal cancer metastasis and that the targeting of GMFG expression or function could be a novel strategy in the future control of colorectal cancer. PMID- 28075455 TI - TNF-alpha regulates apoptosis of human vascular smooth muscle cells through gap junctions. AB - Inflammatory cytokines are released by immune cells and are able to induce vascular smooth muscle cells (VSMCs) to undergo apoptosis, causing atherosclerotic plaque rupture. Changes in the expression levels of connexins (Cxs) have been demonstrated in VSMCs to be involved in the pathogenesis of atherosclerotic progression. The present study examined the effect of tumor necrosis factor-alpha (TNF-alpha) on Cx43 expression levels and apoptosis in human VSMCs. Overexpression of Cx43 plasmids notably stimulated VSMC proliferation. TNF-alpha directly inhibited Cx43 expression levels in a dose- and time-dependent manner in VSMCs, however this was blocked by c-Jun N-terminal kinase inhibitor. TNF-alpha also increased caspase-3 activity and apoptosis of VSMCs through the inhibition of Cx43. These data suggested that TNF-alpha induced the apoptosis of VMSCs and prompted the destabilization of atherosclerotic plaques by downregulating Cx43. PMID- 28075456 TI - HPIP silencing inhibits TGF-beta1-induced EMT in lung cancer cells. AB - Epithelial-mesenchymal transition (EMT) has been reported to play an important role in the migration and invasion of tumor cells. Hematopoietic pre-B-cell leukemia transcription factor (PBX)-interacting protein (HPIP/PBXIP1) has emerged as an important regulator of the development of cancer. However, the role of HPIP in lung cancer is unclear. Thus, in the present study, we investigated the role of HPIP in transforming growth factor (TGF)-beta1-induced EMT in A549 lung cancer cells in vitro. Our data demonstrated that HPIP was overexpressed in the lung cancer cell lines. TGF-beta1 increased the expression of HPIP in the A549 cells. In addition, HPIP silencing significantly attenuated TGF-beta1-induced EMT and migration/invasion in the A549 cells. Furthermore, knockdown of HPIP greatly inhibited TGF-beta1-induced phosphorylation of Smad2 in the A549 cells. In conclusion, we demonstrated that HPIP silencing suppressed TGF-beta1-induced EMT in lung cancer cells by inhibiting Smad2 activation. Therefore, HPIP may be a new therapeutic target for the treatment of lung cancer. PMID- 28075457 TI - High-resolution melting analysis for rapid and sensitive NOTCH1 screening in chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is a biological and clinical heterogeneous disease. Activating mutations of NOTCH1 have been implicated to be associated with adverse prognosis in CLL. The objective of the present study was to develop an effective high-resolution melting (HRM) assay for detecting NOTCH1 mutations. Genomic DNA (gDNA) extracted from 133 CLL patients was screened by HRM assay, and the results were compared with the data obtained using direct sequencing. The relative sensitivity of the HRM assay and direct sequencing was evaluated using diluted gDNA with different NOTCH1 mutational frequencies. The HRM assay was able to detect and discriminate samples with NOTCH1 mutations from the wild-type template in CLL. Eight of the 133 CLL patients (6.02%) were scored positively for NOTCH1 mutations in the HRM assay. The results of the NOTCH1 mutations detected by HRM analysis achieved 100% concordance with those determined from direct sequencing. HRM had a higher sensitivity (1%) and shorter turn-around time (TAT), compared to direct sequencing. In conclusion, the HRM assay developed by us was confirmed to be a rapid, sensitive, and promising approach for high-throughput prognostic NOTCH1 screening in CLL. It enables real-time NOTCH1 evaluation, which is of great significance in clinical practice and may facilitate the decision making of clinicians in CLL. PMID- 28075458 TI - Silencing of Forkhead box D1 inhibits proliferation and migration in glioma cells. AB - Despite the extensive role of Forkhead box transcription factors in the development and progression of various cancers, little is known about their role in glioma. We examined the expression and function of Forkhead box D1 (FOXD1) in glioma cell behavior and found that FOXD1 was upregulated and directly correlated with the glioma grade. Data analysis also revealed significant differences in FOXD1 expression for both gene expression profiles (GSE4290 and GSE7696) and the TCGA datasets. Additionally, decreased FOXD1 expression in U251 and U87 glioma cells caused a delay in cell growth and a disruption in colony formation. FOXD1 silencing also promoted generation of apoptotic bodies containing nuclear fragments. Cells with suppressed expression of FOXD1 markedly reduced glioma cell migration. Our results suggest that FOXD1 may serve as a novel regulator of glioblastoma cell behavior that may offer a novel target for gene targeted glioma therapies. PMID- 28075459 TI - Death-associated protein kinase 3 controls the tumor progression of A549 cells through ERK MAPK/c-Myc signaling. AB - Death-associated protein kinases (DAPKs) are members of the serine/threonine protein kinase family, which regulate cell death. Although DAPK3 has been implicated as a tumor suppressor, a recent study revealed an oncogenic role of DAPK3. However, the role of DAPK3 in non-small cell lung cancer (NSCLC) remains unclear. Therefore, we examined whether DAPK3 controls the progression of NSCLC using the NSCLC cell line, A549. We generated A549 cells stably expressing small hairpin RNA (shRNA) targeting DAPK3. In the A549 cells, the protein level of DAPK3 was decreased and the cell proliferation was inhibited. DAPK3 knockdown caused G1/G0 cell cycle arrest as assessed by flow cytometric assay and reduced cyclin D1 expression in A549 cells. Phosphorylation of ERK and c-Myc, but not Akt and JNK, was inhibited by DAPK3 knockdown. Cell migration and invasion were also inhibited by DAPK3 knockdown as determined by a Boyden chamber assay and an invasion assay, respectively. Moreover, DAPK3 knockdown inhibited anchorage independent cell growth as determined by soft-agar colony formation assay. In a mouse xenograft model, tumors derived from DAPK3-knockdown cells exhibited reduced tumor growth. The present results demonstrated for the first time that DAPK3 controls proliferation, migration, invasion, soft-agar colony formation and tumor growth through activation of ERK/c-Myc signaling in A549 cells. These findings indicate that DAPK3 may be a novel target for the treatment of NSCLC. PMID- 28075460 TI - Roles of oncogenes and tumor-suppressor genes in osteoclastogenesis (Review). AB - Osteoporosis is a bone disease that poses a tremendous burden to health care. The receptor activator of nuclear factor-kappaB (RANK) and its ligand (RANKL) have been a major focus of this research field. RANKL signaling not only activates a variety of downstream signaling pathways required for osteoclast development, but crosstalk with other signaling pathways also adjusts bone homeostasis both in normal physiology and in bone disease. Consequently, novel drugs specifically targeting RANK-RANKL and their signaling pathways in osteoclasts are expected to revolutionize the treatment of various bone diseases such as osteoporosis. Osteoclasts are the exclusive cells involved in bone resorption. Abnormal activation of osteoclasts can lead to reduced bone density, resulting in osteopenia, osteoporosis and other bone disorders. To date, the mechanism of how osteoclast precursors differentiate into mature osteoclasts remains elusive. Cell proliferation and cell death may be key processes in the progression as well as other cell types. Oncogene products and tumor-suppressor molecules play a pivotal role in regulating the processes, which are important in regulating the configuration of bone disorders. Based on the understanding of these processes, promising alternatives to the use of medications against osteoporosis include specific diets with plant-derived supplements to modulate the expression and/or activity of these molecules. In this review, we summarize the progress of research with a focus on the modulatory roles of oncogene products and tumor suppressor molecules and suggest the scope of further research concerning the prevention of osteoporosis in this field. PMID- 28075461 TI - Resistance of interleukin-6 to the extracellular inhibitory environment promotes axonal regeneration and functional recovery following spinal cord injury. AB - Interleukin-6 (IL)-6 was originally discovered as a factor that contributes to the secondary pathological and inflammatory response in the central nervous system (CNS) following injury. However, accumulating evidence suggests that IL-6 is also involved in functional and structural recovery following CNS injury by promoting axonal sprou-ting. This suggests a potential dual role of IL-6 in CNS injury. However, the definitive function of IL-6 in neural injury and the corresponding underlying mechanisms are still topics of controversy. The present study was carried out to examine the potential function of IL-6 in resistance to neurite growth-inhibitory effects via regulation of the expression of growth associated protein-43 (GAP-43), myelin-associated neurite outgrowth inhibitor (Nogo-A) and its receptor (NgR). Rat dorsal root ganglion (DRG) neurons cultured in an inhibitory microenvironment mimicking injured CNS were used to investigate the effects of IL-6 on the outgrowth of neuronal processes. Additionally, IL-6 was subarachnoidally injected into rats to establish a spinal cord injury (SCI) model, and the neurobehavioral manifestations and neural morphology were subsequently evaluated to determine the effect of IL-6 on neural regeneration. Finally, the potential molecular mechanisms of IL-6-mediated rege-neration and functional recovery following CNS injury are discussed. The results of the present study demonstrated that the in vitro administration of IL-6 enhanced the neurite outgrowth of DRG neurons in a dose-dependent manner via resisting the inhibitory function of myelin proteins. All doses of the IL-6 subarachnoid injection improved the Basso, Beattie and Bresnahan scores following SCI, with a large number of axonal sproutings observed at the spinal lesion site, and several sprouting fibers being elongated and bypassing the lesion and entered the caudal spinal cord. Additionally, a significantly increased density area of diaminobenzidine-labeled neural fiber was observed in rats that received a subarachnoid injection of IL-6, and the rats exhibited increased expression of GAP-43 and decreased expression of Nogo-A. In conclusion, the results of the present study indicated that IL-6 interferes with the inhibitory functions of myelin proteins by upregulating the expression of GAP-43 and simultaneously downregulating the expression of Nogo-A and NgR to promote axonal sprouting and functional recovery following SCI. PMID- 28075462 TI - DNALK2 inhibits the proliferation and invasiveness of breast cancer MDA-MB-231 cells through the Smad-dependent pathway. AB - Breast cancer is one of the most common malignant neoplasms diagnosed in females worldwide. Bone morphogenetic proteins (BMPs), which belong to the TGF-beta superfamily, regulate a wide range of cellular responses including cell proliferation, differentiation, adhesion, migration and apoptosis in breast cancer. BMPs can bind to type I and II serine/threonine kinase receptors to regulate cell proliferation, invasion, migration, and apoptosis. Type I receptors are expressed in various breast cancer cell lines and primary tumor samples. Activin-like kinase 2 (ALK2) is generally expressed in breast cancer cells (MDA MB-231, MCF7, SK-BR-3 and MDA-MB-468); however, the effect of ALK2 on the proliferation and metastasis of breast cancer cells remains unknown. We used a dominant-negative mutant of ALK2 to research the function of ALK2. We aimed to ascertain whether dominant-negative mutant ALK2 adenovirus vector (DNALK2) receptors can compete with wild-type ALK2 receptors. The present study showed that DNALK2 inhibited the growth, migration and metastasis of breast cancer cells by inhibiting the SMAD-dependent pathway and downregulating connective tissue growth factor and inhibitor of differentiation 1 expression, in vivo and in vitro. These observations indicate that ALK2 is a potential therapeutic agent for the treatment of breast cancer. PMID- 28075463 TI - Expression of the promyelocytic leukemia protein without the nuclear localization signal as a novel diagnostic marker for acute promyelocytic leukemia. AB - Promyelocytic leukemia-retinoic acid receptor alpha (PML-RARalpha) is a fusion protein generated by the t(15;17)(q22;q12) translocation associated with acute promyelocytic leukemia (APL). PML-RARalpha is cleaved by neutrophil elastase, an early myeloid-specific serine protease, leading to translocation of the nuclear localization signal (NLS) of the PML protein to the N-terminal of RARalpha, and the mutational product PML(NLS-). The present study was designed to analyze the role of the NLS in mediating PML transport into the nucleus and to evaluate the value of measuring NLS translocation in the early diagnosis of APL. PML and PML(NLS-) localization was examined by immunofluorescence (IF). The interaction between PML/PML(NLS-) and importin alpha was detected by an in vivo binding assay using co-immunoprecipitation and double IF labeling. Twenty-seven untreated APL patients with PML-RARalpha and 22 non-APL controls were evaluated. PML(NLS-) was detected in primary APL, but not non-APL cells. IF showed that PML was localized to the nucleus, interacted with importin alpha in vivo, and co-localized in the PML nuclear bodies. PML(NLS-) was primarily localized in the cytoplasm and the interaction with importin alpha was lost. IF had a sensitivity and specificity of 92.6 and 77.3%, respectively, for diagnosing APL. These data suggest that PML(NLS ) may be a novel diagnostic biomarker for APL. PMID- 28075464 TI - Downregulation of the N-myc downstream regulated gene 1 is related to enhanced proliferation, invasion and migration of pancreatic cancer. AB - The N-myc downstream regulated gene 1 (NDRG1) is differently expressed in human malignancies according to the tumor type. We investigated the expression of NDRG1 in pancreatic cancer tissues and cell lines as well as how it affects tumor growth, invasion and migration in pancreatic cancer cells. Experimental groups included NDRG1 overexpression and knockdown pancreatic cancer cell lines. Lentivirus-based empty vector transfected cells (NC group) were considered control groups. Proliferation, invasion and migration related proteins such as STAT3, MMPs, PTEN, PI3K/AKT were assessed by CCK-8, Transwell assay and western blotting. Efficient NDRG1 overexpression results in reduced cell proliferation, invasion and migration. Inversely, downregulation of NDRG1 promoted proliferation, invasion and migration. We also found NDRG1 could deactivate p STAT3, PI3K, p-AKT, MMP2, MMP9 and activate PTEN. NDRG1 is a potential anti oncogene. Its upregulation significantly decreases pancreatic cancer tumorigenesis, likely by inhibiting STAT3 and the PI3K/AKT signaling pathway. PMID- 28075465 TI - Monoclonal antibody Zt/g4 targeting RON receptor tyrosine kinase enhances chemosensitivity of bladder cancer cells to Epirubicin by promoting G1/S arrest and apoptosis. AB - Epirubicin (EPI) is one of the most used intravesical chemotherapy agents after transurethral resection to non-muscle invasive bladder tumors (NMIBC) to prevent cancer recurrence and progression. However, even after resection of bladder tumors and intravesical chemotherapy, half of them will recur and progress. RON is a membrane tyrosine kinase receptor usually overexpressed in bladder cancer cells and associated with poor pathological features. This study aims to investigate the effects of anti-RON monoclonal antibody Zt/g4 on the chemosensitivity of bladder cells to EPI. After Zt/g4 treatment, cell cytotoxicity was significantly increased and cell invasion was markedly suppressed in EPI-treated bladder cancer cells. Further investigation indicated that combing Zt/g4 with EPI promoted cell G1/S-phase arrest and apoptosis, which are the potential mechanisms that RON signaling inhibition enhances chemosensitivity of EPI. Thus, combing antibody-based RON targeted therapy enhances the therapeutic effects of intravesical chemotherapy, which provides new strategy for further improvement of NMIBC patient outcomes. PMID- 28075466 TI - Co-delivery of doxorubicin and pH-sensitive curcumin prodrug by transferrin targeted nanoparticles for breast cancer treatment. AB - The natural product curcumin and the chemotherapeutic agent doxorubicin have been used in the treatment of many cancers, including breast cancer. However, fast clearance and unspecific distribution in the body after intravenous injection are still challenges to be overcome by an ideal nano-sized drug delivery system in cancer treatment. In this study we design transferrin (Tf) decorated nanoparticles (NPs) to co-deliver CUR and DOX for breast cancer treatment. A pH sensitive prodrug, transferrin-poly(ethylene glycol)-curcumin (Tf-PEG-CUR), was synthesized and used for the self-assembling of NPs (Tf-PEG-CUR NPs). DOX is incorporated into the Tf-PEG-CUR NPs to obtain Tf-PEG-CUR/DOX NPs. In vitro cytotoxicity studies and in vivo antitumor activity were carried out using MCF-7 cells and mice bearing MCF-7 cells, respectively. Tf-PEG-CUR/DOX NPs has a particle size of 89 nm and a zeta potential of -15.6 mV. This system displayed remarkably higher efficiency than other systems both in vitro and in vivo. DOX and CUR were successfully loaded into nanocarriers. The in vitro cell viability assays revealed the combination of Tf-PEG-CUR and DOX NPs exhibited higher cytotoxicity in vitro in MCF-7 cells compared with Tf-PEG-CUR NPs alone. Using the breast cancer xenograft mouse model, we demonstrate that this co encapsulation approach resulted in an efficient tumor-targeted drug delivery, decreased cytotoxic effects and exhibited stronger antitumor effect. PMID- 28075467 TI - Resveratrol suppresses human hepatocellular carcinoma via targeting HGF-c-Met signaling pathway. AB - Resveratrol, one of the major polyphenols found in red wine, is suggested to have a role as a chemo-prevention or chemotherapy agent in various human cancer models. Herein, we report that resveratrol has a profound antitumor effect on human hepatocellular carcinoma (HCC) cells by down-regulation of the HGF-c-Met signaling pathway. Resveratrol inhibited anchorage-dependent and -independent growth of HCC cells in a dose-dependent manner. Short-term resveratrol exposure substantially decreased HGF-induced c-Met signaling pathway activation, and long term exposure to resveratrol markedly inhibited c-Met expression on the cell membrane. Additionally, resveratrol suppressed HGF-induced cell invasion, and knockdown of c-Met decreased the sensitivity of HCC cells to resveratrol treatment. Finally, the antitumor activity of resveratrol was validated in xenograft model and resveratrol prominently restrained tumor growth in vivo. In summary, our results suggested that c-Met offers a candidate molecular target for hepatocellular carcinoma management. PMID- 28075468 TI - MicroRNA-138-5p controls sensitivity of nasopharyngeal carcinoma to radiation by targeting EIF4EBP1. AB - Radiation therapy is the standard treatment for primary nasopharyngeal carcinoma (NPC). MicroRNA regulates cancer responsiveness to radiation therapy by controlling the genes involved in radiation responses. Recent studies suggested that downregulation of microRNA-138-5p was clinically significant in NPC. Here, we evaluated the effect of miR-138-5p on radiosensitivity of NPC cells and explored the underlying mechanisms by identifying its target gene that impacted sensitivity to radiation. Our results revealed that overexpression of miR-138-5p reduced the ability to form colonies, inhibited proliferation, and enhanced radiation-induced DNA damage and autophagy in NPC cells upon radiation treatment. By integrating predicted targets with the transcripts downregulated by miR-138 5p, EIF4EBP1 was identified to be a target gene of miR-138-5p. Results from luciferase reporter assay demonstrated that miR-138-5p downregulated the expression of EIF4EBP1 by binding to the 3'-UTR. Silence of EIF4EBP1 enhanced radiosensitivity of NPC cells as evidenced by reduced ability to form colonies after radiation exposure. In summary, our results indicated that miR-138-5p enhanced radiosensitivity of NPC cells by targeting EIF4EBP1. Further studies are warranted to investigate the potential use of miR-138-5p in the clinical management and treatment prediction of NPC patients. PMID- 28075469 TI - Urinary kidney injury molecule-1 as an early diagnostic biomarker of obstructive acute kidney injury and development of a rapid detection method. AB - The aim of the present study was to investigate whether urinary kidney injury molecule-1 (KIM-1) presents a suitable early diagnostic biomarker of obstructive nephropathy-induced acute kidney injury (AKI), and to develop a rapid detection method for urinary KIM-1. Obstructive AKI was induced in an experimental rat model by a unilateral ureteral obstruction (UUO) operation. Macro- and micromorphological kidney alterations were determined by visual observation and hematoxylin and eosin (HE) staining, respectively. Kidney functions were evaluated by detecting urea nitrogen and creatinine levels in rat urine and blood. Urinary KIM-1 levels were measured using an enzyme-linked immunosorbent assay, and the protein expression levels of KIM-1, alpha-smooth muscle actin (alpha-SMA) and vimentin in kidney tissues were detected using immunohistochemical assays. In order to measure KIM-1 levels, colloidal gold immunochromatographic strips were developed based on the colloidal gold immunochromatographic assay. The results indicated that KIM-1 levels were significantly higher in the UUO group when compared with the Sham group. KIM-1 levels in the urine and kidney tissues exhibited a time-dependent increase, together with increasing obstructive AKI in the UUO group. In addition, KIM-1 levels were demonstrated to be a more sensitive biomarker of early obstructive AKI, when compared with alpha-SMA and vimentin. A colloidal gold-based immunochromatographic strip was developed, whereby the detection of urinary KIM-1 could be completed within 5-10 min. In conclusion, results of the present study demonstrated that urinary KIM-1 may be a valuable biomarker for the early diagnosis of obstructive AKI, and the use of a colloidal gold immunochromatographic strip may be a promising method for the rapid detection of urinary KIM-1. PMID- 28075470 TI - Combined effects of atorvastatin and aspirin on growth and apoptosis in human prostate cancer cells. AB - Epidemiologic studies indicate the use of either statins or aspirin have beneficial effects in prostate cancer patients. The present study was undertaken to evaluate the effects and mechanisms of atorvastatin and aspirin alone or in combination in human prostate cancer cells cultured in vitro and grown as xenograft tumors in severe combined immune-deficient (SCID) mice. The growth and apoptosis in prostate cancer cells were determined by the trypan blue exclusion and propidium iodide staining assays. Activation of the nuclear factor kappaB (NF kappaB) was measured by luciferase reporter assay, and the levels of phospho signal transducer and activator of transcription (Stat)3 and phospho extracellular signal-regulated kinase (Erk)1/2 were determined by western blot analysis. Mice were injected subcutaneously with PC-3 cells in Matrigel. After 4 6 weeks, mice with PC-3 tumors received i.p. injections of vehicle, atorvastatin (5 mg/kg), aspirin (80 mg/kg), or atorvastatin (5 mg/kg) + aspirin (80 mg/kg) three times a week for 30 days. Our results demonstrated the combination of atorvastatin and aspirin had more potent effects on growth inhibition and apoptosis stimulation in prostate cancer cells than either drug alone. Mechanistic studies indicated the induction of apoptosis in PC-3 cells was associated with strong inhibition of NF-kappaB and decreases in the levels of phospho-Stat3 and phospho-Erk1/2. Results of the present study demonstrated a strong combined effect of atorvastatin and aspirin on inhibiting the growth of prostate cancer cells in vitro and in vivo. The findings provide a strong rationale for clinical evaluation of the combination of atorvastatin and aspirin in patients with prostate cancer. PMID- 28075471 TI - Alterations in splenic function and gene expression in mice with depressive-like behavior induced by exposure to corticosterone. AB - Depressed patients present with increased cortisol levels and attenuated immune responses. However, little is known about the association between depression and the spleen, as this is the largest peripheral immune organ. In this study, we examined alterations in splenic function and gene expression in mice with depressive-like behavior, well as the expression of certain proteins in related pathways. A mouse model of depression was established with the use of corticosterone. Splenic function and histopathology were assessed using Wright and H&E staining. The Agilent Whole Mouse Genome Oligo Microarray containing >41,174 transcript probes was used to measure the levels of gene-expression in the spleens from control and model mice, and the levels of certain proteins associated with depression were measured by western blot analysis in the brain and spleen separately. We found that splenic function and immunity in the mice with depressive-like behavior were markedly impaired. A total of 53 genes exhibited a differential response in the mice with depressive-like behavior, 11 of which were more notable, including collagen, type VI, alpha5 (Col6a5), immunoglobulin superfamily, member 11 (Igsf11), D site albumin promoter binding protein (Dbp), tachykinin 2 (Tac2) and gamma-aminobutyric acid B receptor 2 (Gabbr2). Pathway analysis revealed that the amino acid biosynthesis and the clock gene pathways were more meaningful among these genes. The levels of GABBR2, DBP and substance P (SP; encoded by the Tac2 gene) related proteins in the brain were markedly downregulated, and similar results were observed in the spleen. The anti-depressant, fluoxetine, reversed the changes in the levels of these proteins. The findings of our study regarding changes occurring in the spleen during depression may indirectly elucidate and shed light into the pathogenesis of depression and depressive-like behavior. PMID- 28075472 TI - Suppression of PTEN/AKT signaling decreases the expression of TUBB3 and TOP2A with subsequent inhibition of cell growth and induction of apoptosis in human breast cancer MCF-7 cells via ATP and caspase-3 signaling pathways. AB - The aim of the present study was to evaluate the effects of PTEN/AKT signaling on TUBB3 and TOP2A expression and on the subsequent cell growth of human breast cancer MCF-7 cells. We found that the disease-free survival (DFS) and overall survival (OS) of breast cancer patients with TUBB3-positive tumors were lower than these rates in the patients with TUBB3-negative tumors. Meanwhile, DFS and OS of breast cancer patients with TOP2A-positive tumors were also lower than these rates in patients with TOP2A-negative tumors. Suppression of PTEN reduced the protein expression of TUBB3 and TOP2A in MCF-7 cells. Suppression of PTEN also reduced cell proliferation and induced apoptosis and caspase-3 activity in MCF-7 cells. Moreover, an increase in ATP also reduced TUBB3 and TOP2A protein expression, reduced cell proliferation and induced apoptosis and caspase-3 activity in the MCF-7 cells following suppression of PTEN. Suppression of phosphorylation-AKT (p-AKT) reduced the protein expression of TUBB3 and TOP2A in the MCF-7 cells. Suppression of p-AKT also reduced cell proliferation and induced apoptosis and caspase-3 activity in the MCF-7 cells. Then, ATP also reduced TUBB3 and TOP2A protein expression, reduced cell proliferation and induced apoptosis and caspase-3 activity in MCF-7 cells following suppression of p-AKT. These results suggest that PTEN/AKT signaling affects the expression of TUBB3 and TOP2A reducing cell growth and inducing apoptosis of human breast cancer MCF-7 cells through ATP and caspase-3 signaling pathways. TUBB3 and TOP2A may be promising prognostic markers for the efficacy of adjuvant cisplatin-based chemotherapy. PMID- 28075474 TI - Isomahanine induces endoplasmic reticulum stress and simultaneously triggers p38 MAPK-mediated apoptosis and autophagy in multidrug-resistant human oral squamous cell carcinoma cells. AB - Advanced oral squamous cell carcinoma (OSCC) is typically aggressive and closely correlated with disease recurrence and poor survival. Multidrug resistance (MDR) is the most critical problem leading to therapeutic failure. Investigation of novel anticancer candidates targeting multidrug-resistant OSCC cells may provide a basis for developing effective strategies for OSCC treatment. In the present study, we investigated the cytotoxic mechanism of a carbazole alkaloid, namely isomahanine, in a multidrug-resistant OSCC cell line CLS-354/DX. We demonstrated that CLS-354/DX cells overexpressing multidrug resistance-associated protein 1 (MRP1) were resistant to anticancer drugs cisplatin and camptothecin. Isomahanine effectively induced cytotoxicity against CLS-354/DX cells regardless of resistance. Apoptosis as determined by FITC-Annexin V/PI staining and western blot analysis of cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP) was significantly induced in a time-dependent manner upon isomahanine treatment. Isomahanine-induced caspase-dependent apoptosis was determined using z-VAD-fmk. The effects on autophagy in isomahanine-treated cells were investigated via conversion of LC3B and degradation of p62/SQSTM1 (p62). Isomahanine obviously induced autophagic flux as shown by an increase in punctate GFP-LC3B and the LC3B II/LC3B-I ratio with a concomitant decrease in p62 levels. Autophagy inhibitors 3 methyladenine (3-MA) and chloroquine (CQ) protected isomahanine-induced cell death, indicating the activation of autophagic cell death. Endoplasmic reticulum (ER) stress and MAPK activation were examined to elucidate the mechanism underlying cell death. The expression levels of PERK, CHOP and phosphorylated MAPK (p38, ERK1/2 and JNK1/2) were upregulated following isomahanine treatment. We found that p38 MAPK inhibitor (SB203580) significantly attenuated isomahanine induced apoptosis and autophagic flux and this prevented cell death. Collectively, the present study demonstrated that isomahanine was able to induce ER stress and trigger p38 MAPK-mediated apoptosis and autophagic cell death in multidrug-resistant OSCC cells. The potential cytotoxic action of isomahanine may provide the development of anticancer candidates for treating multidrug-resistant cancer. PMID- 28075473 TI - Spirulina lipopolysaccharides inhibit tumor growth in a Toll-like receptor 4 dependent manner by altering the cytokine milieu from interleukin-17/interleukin 23 to interferon-gamma. AB - Th17 cells and the cytokine they produce, interleukin (IL)-17, play an important role in tumor progression in humans and in mice. IL-6 and IL-23 are critical cytokines for the differentiation and propagation of Th17 cells, respectively. Bacterial lipopolysaccharides (LPS) are known to stimulate immune cells to produce such inflammatory cytokines. Contrary to Escherichia coli (E. coli) LPS, LPS from Spirulina has low toxicity and barely induces in vivo production of IL-6 and IL-23 in mice. We examined the antitumor effects of Spirulina LPS compared to E. coli LPS in an MH134 hepatoma model. Administration of Spirulina LPS suppressed tumor growth in C3H/HeN mice, but not in Toll-like receptor 4 (TLR4) mutant C3H/HeJ mice, by reducing serum levels of IL-17 and IL-23, while increasing interferon (IFN)-gamma levels. The antitumor activity and IFN-gamma production were mediated by T cells. Moreover, in vitro experiments showed that Spirulina LPS impaired the antigen-presenting function that supports the generation of IL-17-producing cells in a toll-like receptor (TLR)4-dependent manner. Of note, injection of anti-IL-17 antibody in tumor-bearing C3H/HeN mice in the absence of Spirulina LPS markedly suppressed tumor growth and augmented IFN-gamma responses. Thus, our results support the notion that IFN-gamma and IL 17/IL-23 mutually regulate Th17 and Th1 responses in tumor-bearing hosts, and Spirulina LPS modulates the balance of the IFN-gamma-IL-17/IL-23 axis towards IFN gamma production, which leads to tumor inhibition. Furthermore, Spirulina LPS effectively inhibited the spontaneous development of mammary tumors. This study has important implications for the exploitation of TLR-based immunomodulators for cancer immunotherapy. PMID- 28075475 TI - miR-134 suppresses the migration and invasion of non-small cell lung cancer by targeting ITGB1. AB - Most cancer-related deaths are caused by the development of metastatic disease. Thus, investigation of the underlying mechanisms of metastasis is urgent to design more effective targeted drugs and to treat metastatic disease more effectively. MicroRNAs (miRNAs) have emerged as potential targets for cancer treatment. In the present study, we aimed to identify the roles of miR-134 in non small cell lung cancer (NSCLC) cell migration and invasion. We demonstrated that overexpression of miR-134 inhibited migration and invasion of A549 and H1299 cells. Further mechanistic investigations revealed that miR-134 inhibited epithelial-to-mesenchymal transition (EMT) evidenced by upregulation of E cadherin expression and downregulation of vimentin expression. Using luciferase assays, we identified integrin beta1 (ITGB1) as a direct target of miR-134. Performing RNAi and rescue experiments, we confirmed that miR-134 exerted its migratory and invasive suppressive role partly by downregulating ITGB1. Finally, an in vivo experiment also, to some extent, suggested that miR-134 may function as a suppressor of metastasis. Taken together, our findings suggest that miR-134 suppresses migration and invasion of NSCLC by targeting ITGB1. PMID- 28075476 TI - Silencing of GP73 inhibits invasion and metastasis via suppression of epithelial mesenchymal transition in hepatocellular carcinoma. AB - Epithelial-mesenchymal transition (EMT) is associated with invasion and metastasis of cancer cells. Golgi protein 73 (GP73) is a serum biomarker for hepatocellular carcinoma (HCC) and our previous study demonstrated that the expression of GP73 correlated with aggressive behavior and EMT molecules in HCC. However, its role in metastatic mechanism of HCC is not clear. The aim of this study was to investigate the effect of GP73 on invasion and migration, and underlying mechanism of GP73 involved in EMT of HCC. The expression of GP73 was downregulated by small interfering RNA (siRNA). The metastatic and invasive abilities were analyzed using scratch assay and Transwell assay. Changes in EMT related molecules were evaluated by western blot and qRT-PCR analyses, and epithelial-mesenchymal phenotype changes were also observed. Expression of GP73 was upregulated in the more metastatic HCC cell lines. Knockdown of GP73 by siRNA resulted in a significant decrease in migratory and invasive abilities in both MHCC97H and Bel-7404 cell lines. Importantly, EMT-related markers and morphological phenotypes significantly changed following by the inhibition of GP73. Silencing GP73 contributed to the reduction of invasion and metastasis via suppressing EMT in HCC. GP73 may serve as a novel molecular target against EMT in HCC metastasis therapy. PMID- 28075477 TI - Escin induces apoptosis in human renal cancer cells through G2/M arrest and reactive oxygen species-modulated mitochondrial pathways. AB - Escin, a natural pentacyclic triterpenoid compound, exhibits antitumor effects on various types of human cancer cells, but its effect on human renal cancer cells has not been fully elucidated. In the present study, we demonstrated that escin elicits cytotoxic effects on human renal cancer cells (786-O and Caki-1) in a dose-dependent manner, as determined by MTT assay. Escin induced G2/M arrest, and then increased the sub-G1 population, Annexin V binding, activation of caspase-9/ 3, cleavage of poly(ADP-ribose) polymerase (PARP) and Bax protein. Escin also decreased the anti-apoptotic protein levels of Bcl-2, X-linked inhibitor of apoptosis protein and survivin. In addition, escin induced reactive oxygen species (ROS) generation, leading to mitochondrial membrane potential dysfunction and inducing apoptosis in 786-O renal cancer cells, which were suppressed by antioxidants, such as NAC. Collectively, our results suggest that escin induces apoptosis via the intrinsic-mitochondrial apoptosis pathway through G2/M arrest and ROS generation in human renal cancer cells. Escin appears to have potential as a clinically useful chemotherapeutic agent for human renal cancer. PMID- 28075478 TI - High expression of RAB43 predicts poor prognosis and is associated with epithelial-mesenchymal transition in gliomas. AB - The Ras-related GTP-binding protein (RAB) family plays an important role in regulating signal transduction and cellular processes including vesicle transport, cytoskeleton formation and membrane trafficking. More recently, several RAB members have been reported to promote tumorigenesis in many types of cancers. However, the clinical significance and potential function of RAB43 in gliomas remain unclear. Herein, we found that RAB43 was upregulated and positively correlated with the grade of progression in glioma patients by in silico analysis and immunohistochemistry (IHC). Patients with high RAB43 displayed worse clinical outcomes in comparison to those with low RAB43. RAB43 was also highly expressed in mesenchymal and G3 subtypes, and isocitrate dehydrogenase 1 (IDH1) wild-type gliomas. Moreover, transcriptomic analyses via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed that RAB43-related gene sets were mainly involved in the regulation of cell adhesion and cell migration processes. Further investigation indicated that RAB43 downregulation significantly suppressed the migratory and invasive ability of glioma cells, as well as decreased the expression of epithelial-mesenchymal transition (EMT) markers (N-cadherin, vimentin and Snail). In conclusion, a high level of RAB43 was significantly associated with the malignant phenotypes of gliomas, which suggests that RAB43 may serve as a novel biomarker and a potential therapeutic target for gliomas. PMID- 28075479 TI - Different contributions of local- and distant-regulatory changes to transcriptome divergence between stickleback ecotypes. AB - Differential gene expression can play an important role in phenotypic evolution and divergent adaptation. Although differential gene expression can be caused by both local- and distant-regulatory changes, we know little about their relative contribution to transcriptome evolution in natural populations. Here, we conducted expression quantitative trait loci (eQTL) analysis to investigate the genetic architecture underlying transcriptome divergence between marine and stream ecotypes of threespine sticklebacks (Gasterosteus aculeatus). We identified both local and distant eQTLs, some of which constitute hotspots, regions with a disproportionate number of significant eQTLs relative to the genomic background. The majority of local eQTLs including those in the hotspots caused expression changes consistent with the direction of transcriptomic divergence between ecotypes. Genome scan analysis showed that many local eQTLs overlapped with genomic regions of high differentiation. In contrast, nearly half of the distant eQTLs including those in the hotspots caused opposite expression changes, and few overlapped with regions of high differentiation, indicating that distant eQTLs may act as a constraint of transcriptome evolution. Finally, a comparison between two salinity conditions revealed that nearly half of eQTL hotspots were environment specific, suggesting that analysis of genetic architecture in multiple conditions is essential for predicting response to selection. PMID- 28075480 TI - Costs of selfing prevent the spread of a self-compatibility mutation that causes reproductive assurance. AB - In flowering plants, shifts from outcrossing to partial or complete self fertilization have occurred independently thousands of times, yet the underlying adaptive processes are difficult to discern. Selfing's ability to provide reproductive assurance when pollination is uncertain is an oft-cited ecological explanation for its evolution, but this benefit may be outweighed by costs diminishing its selective advantage over outcrossing. We directly studied the fitness effects of a self-compatibility mutation that was backcrossed into a self incompatible (SI) population of Leavenworthia alabamica, illuminating the direction and magnitude of selection on the mating-system modifier. In array experiments conducted in two years, self-compatible (SC) plants produced 17-26% more seed, but this advantage was counteracted by extensive seed discounting-the replacement of high-quality outcrossed seeds by selfed seeds. Using a simple model and simulations, we demonstrate that SC mutations with these attributes rarely spread to high frequency in natural populations, unless inbreeding depression falls below a threshold value (0.57 <= deltathreshold <= 0.70) in SI populations. A combination of heavy seed discounting and inbreeding depression likely explains why outcrossing adaptations such as self-incompatibility are maintained generally, despite persistent input of selfing mutations, and frequent limits on outcross seed production in nature. PMID- 28075481 TI - Diagnosis of Spinocerebellar Ataxias Caused by Trinucleotide Repeat Expansions. AB - Spinocerebellar ataxias (SCAs) are a group of disorders that are both clinically and genetically heterogeneous. They usually demonstrate onset in adulthood, but some forms may have juvenile or infantile onset. There are many different types of SCA, demonstrating different modes of inheritance and types of mutation. The most common forms are due to dominantly inherited expansions in trinucleotide repeat sequences located within the coding region of the relevant genes, and these are readily identifiable by molecular genetic testing. In general, it is possible to test for these disorders using PCR-based assays, amplifying across the trinucleotide repeat regions and sizing the PCR products to determine the number of repeats. Larger expansions are generally associated with a more severe presentation of the disorder, and alternative methods may be necessary to detect these alleles. This protocol describes methods for detecting normal and expanded triplet repeat alleles in the most common SCA genes. (c) 2017 by John Wiley & Sons, Inc. PMID- 28075482 TI - Human Induced Pluripotent Stem (hiPS) Cells from Urine Samples: A Non-Integrative and Feeder-Free Reprogramming Strategy. AB - Human induced pluripotent stem (hiPS) cell technology has already revolutionized some aspects of fundamental and applied research such as study of disease mechanisms and pharmacology screening. The first clinical trial using hiPS cell derived cells began in Japan, only 10 years after the publication of the proof-of concept article. In this exciting context, strategies to generate hiPS cells have evolved quickly, tending towards non-invasive protocols to sample somatic cells combined with "safer" reprogramming strategies. In this unit, we describe a protocol combining both of these advantages to generate hiPS cells with episomal plasmid transfection from urine samples of individuals carrying the desired genotype. Based on previous published works, this simplified protocol requires minimal equipment and reagents, and is suitable both for scientists familiar with the hiPS cells technology and neophytes. HiPS cells displaying classical features of pluripotency and suitable for all desired downstream applications are generated rapidly (<10 weeks) and with high efficiency. (c) 2017 by John Wiley & Sons, Inc. PMID- 28075483 TI - Detecting APC Gene Mutations in Familial Adenomatous Polyposis (FAP). AB - Hereditary forms of colorectal cancer (CRC) account for up to 5% of total cases. Familial adenomatous polyposis (FAP) is an autosomal dominant condition affecting nearly 1 in 5000 people and accounts for only about 1% of all CRCs. It is characterized by the progressive development of hundreds to thousands of adenomatous colon polyps. The gene associated with FAP (APC) contains 15 coding exons. The mutation spectrum of the APC gene is broad in that 87% of causative mutations are point mutations (including other sequence variants) and around 10% to 15% are intragenic deletions and duplications. The strategy for molecular diagnostic testing for FAP involves initial full sequence analysis of APC for sequence variants followed by screening for deletion/duplications using microarray-based comparative genomic hybridization (array CGH) or Multiplex Ligation-dependent Probe Amplification (MLPA). Recently, next generation sequencing (NGS)-based targeted gene analysis has become clinically available for detection of point mutations and other sequence variants. This unit discusses detailed protocols for an NGS-based sequencing assay, PCR-based Sanger sequencing, and array CGH. (c) 2017 by John Wiley & Sons, Inc. PMID- 28075484 TI - Assay for Transposase-Accessible Chromatin Using Sequencing (ATAC-seq) Data Analysis. AB - The study of epigenetic properties of the human genome, including structural modifications of DNA and chromatin, has increased tremendously as mounting evidence has demonstrated how much epigenetics affects human gene expression. Buenrostro et al. have developed a rapid method, requiring low numbers of living cells as input, for examining chromatin accessibility across the epigenome, known as the assay for transposase-accessible chromatin using sequencing (ATAC-seq). The overall goal of this unit is to provide a thorough ATAC-seq data analysis plan, as well as describe how primary human blood samples can be processed for use in ATAC-seq. In addition, a number of quality control parameters are discussed to ensure the integrity and confidence in the ATAC-seq data. (c) 2017 by John Wiley & Sons, Inc. PMID- 28075485 TI - Culturing and Neuronal Differentiation of Human Dental Pulp Stem Cells. AB - A major issue in studying human neurogenetic disorders, especially rare syndromes affecting the nervous system, is the ability to grow neuronal cultures that accurately represent these disorders for analysis. Although there has been some success in generating induced pluripotent stem (iPS) cells from both skin and blood, there are still limitations to the collection and production of iPS cells from these biospecimens. We have had significant success in collecting and growing human dental pulp stem (DPS) cells from exfoliated teeth sent to our laboratory by the parents of children with a variety of rare neurogenetic syndromes. This protocol outlines our current methods for the growth and expansion of DPS cells from exfoliated (baby) teeth. These DPS cells can be differentiated into a variety of cell types including osteoblasts, chondrocytes, and mixed neuron and glial cultures. Here we provide our protocol for the differentiation of early passage DPS cell cultures into neurons for molecular studies. (c) 2017 by John Wiley & Sons, Inc. PMID- 28075487 TI - Molecular Analysis of Gene Rearrangements and Mutations in Acute Leukemias and Myeloid Neoplasms. AB - A subset of acute leukemias and other myeloid neoplasms contains specific genetic alterations, many of which are associated with unique clinical and pathologic features. These alterations include chromosomal rearrangements leading to oncogenic fusion proteins or alteration of gene expression by juxtaposing oncogenes to enhancer elements, as well as mutations leading to aberrant activation of a variety of proteins critical to hematopoietic progenitor cell proliferation and differentiation. Molecular analysis is central to diagnosis and clinical management of leukemias, permitting genetic confirmation of a clinical and histologic impression, providing prognostic and predictive information, and facilitating detection of minimal residual disease. This unit will outline approaches to the molecular diagnosis of the most frequent and clinically relevant genetic alterations in acute leukemias and myeloid neoplasms. (c) 2017 by John Wiley & Sons, Inc. PMID- 28075486 TI - Highly Expandable Human iPS Cell-Derived Neural Progenitor Cells (NPC) and Neurons for Central Nervous System Disease Modeling and High-Throughput Screening. AB - Reprogramming of human somatic cells into induced pluripotent stem (iPS) cells has greatly expanded the set of research tools available to investigate the molecular and cellular mechanisms underlying central nervous system (CNS) disorders. Realizing the promise of iPS cell technology for the identification of novel therapeutic targets and for high-throughput drug screening requires implementation of methods for the large-scale production of defined CNS cell types. Here we describe a protocol for generating stable, highly expandable, iPS cell-derived CNS neural progenitor cells (NPC) using multi-dimensional fluorescence activated cell sorting (FACS) to purify NPC defined by cell surface markers. In addition, we describe a rapid, efficient, and reproducible method for generating excitatory cortical-like neurons from these NPC through inducible expression of the pro-neural transcription factor Neurogenin 2 (iNgn2-NPC). Finally, we describe methodology for the use of iNgn2-NPC for probing human neuroplasticity and mechanisms underlying CNS disorders using high-content, single-cell-level automated microscopy assays. (c) 2017 by John Wiley & Sons, Inc. PMID- 28075488 TI - Generating Exome Enriched Sequencing Libraries from Formalin-Fixed, Paraffin Embedded Tissue DNA for Next-Generation Sequencing. AB - This unit describes a technique for generating exome-enriched sequencing libraries using DNA extracted from formalin-fixed paraffin-embedded (FFPE) samples. Utilizing commercially available kits, we present a low-input FFPE workflow starting with 50 ng of DNA. This procedure includes a repair step to address damage caused by FFPE preservation that improves sequence quality. Subsequently, libraries undergo an in-solution-targeted selection for exons, followed by sequencing using the Illumina next-generation short-read sequencing platform. (c) 2017 by John Wiley & Sons, Inc. PMID- 28075489 TI - Cough augmentation techniques for extubation or weaning critically ill patients from mechanical ventilation. AB - BACKGROUND: There are various reasons why weaning and extubation failure occur, but ineffective cough and secretion retention can play a significant role. Cough augmentation techniques, such as lung volume recruitment or manually- and mechanically-assisted cough, are used to prevent and manage respiratory complications associated with chronic conditions, particularly neuromuscular disease, and may improve short- and long-term outcomes for people with acute respiratory failure. However, the role of cough augmentation to facilitate extubation and prevent post-extubation respiratory failure is unclear. OBJECTIVES: Our primary objective was to determine extubation success using cough augmentation techniques compared to no cough augmentation for critically-ill adults and children with acute respiratory failure admitted to a high-intensity care setting capable of managing mechanically-ventilated people (such as an intensive care unit, specialized weaning centre, respiratory intermediate care unit, or high-dependency unit).Secondary objectives were to determine the effect of cough augmentation techniques on reintubation, weaning success, mechanical ventilation and weaning duration, length of stay (high-intensity care setting and hospital), pneumonia, tracheostomy placement and tracheostomy decannulation, and mortality (high-intensity care setting, hospital, and after hospital discharge). We evaluated harms associated with use of cough augmentation techniques when applied via an artificial airway (or non-invasive mask once extubated/decannulated), including haemodynamic compromise, arrhythmias, pneumothorax, haemoptysis, and mucus plugging requiring airway change and the type of person (such as those with neuromuscular disorders or weakness and spinal cord injury) for whom these techniques may be efficacious. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 4, 2016), MEDLINE (OvidSP) (1946 to April 2016), Embase (OvidSP) (1980 to April 2016), CINAHL (EBSCOhost) (1982 to April 2016), and ISI Web of Science and Conference Proceedings. We searched the PROSPERO and Joanna Briggs Institute databases, websites of relevant professional societies, and conference abstracts from five professional society annual congresses (2011 to 2015). We did not impose language or other restrictions. We performed a citation search using PubMed and examined reference lists of relevant studies and reviews. We contacted corresponding authors for details of additional published or unpublished work. We searched for unpublished studies and ongoing trials on the International Clinical Trials Registry Platform (apps.who.int/trialsearch) (April 2016). SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials that evaluated cough augmentation compared to a control group without this intervention. We included non-randomized studies for assessment of harms. We included studies of adults and of children aged four weeks or older, receiving invasive mechanical ventilation in a high-intensity care setting. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts identified by our search methods. Two review authors independently evaluated full text versions, independently extracted data and assessed risks of bias. MAIN RESULTS: We screened 2686 citations and included two trials enrolling 95 participants and one cohort study enrolling 17 participants. We assessed one randomized controlled trial as being at unclear risk of bias, and the other at high risk of bias; we assessed the non-randomized study as being at high risk of bias. We were unable to pool data due to the small number of studies meeting our inclusion criteria and therefore present narrative results rather than meta analyses. One trial of 75 participants reported that extubation success (defined as no need for reintubation within 48 hours) was higher in the mechanical insufflation-exsufflation (MI-E) group (82.9% versus 52.5%, P < 0.05) (risk ratio (RR) 1.58, 95% confidence interval (CI) 1.13 to 2.20, very low-quality evidence). No study reported weaning success or reintubation as distinct from extubation success. One trial reported a statistically significant reduction in mechanical ventilation duration favouring MI-E (mean difference -6.1 days, 95% CI -8.4 to 3.8, very low-quality evidence). One trial reported mortality, with no participant dying in either study group. Adverse events (reported by two trials) included one participant receiving the MI-E protocol experiencing haemodynamic compromise. Nine (22.5%) of the control group compared to two (6%) MI-E participants experienced secretion encumbrance with severe hypoxaemia requiring reintubation (RR 0.25, 95% CI 0.06 to 1.10). In the lung volume recruitment trial, one participant experienced an elevated blood pressure for more than 30 minutes. No participant experienced new-onset arrhythmias, heart rate increased by more than 25%, or a pneumothorax.For outcomes assessed using GRADE, we based our downgrading decisions on unclear risk of bias, inability to assess consistency or publication bias, and uncertainty about the estimate of effect due to the limited number of studies contributing outcome data. AUTHORS' CONCLUSIONS: The overall quality of evidence on the efficacy of cough augmentation techniques for critically-ill people is very low. Cough augmentation techniques when used in mechanically-ventilated critically-ill people appear to result in few adverse events. PMID- 28075490 TI - Soluble transferrin receptor and risk of type 2 diabetes in the obese and nonobese. AB - BACKGROUND: Studies evaluating the relationship between soluble transferrin receptor (sTfR), a biomarker inversely related to body iron stores, and risk of type 2 diabetes mellitus (T2DM) are scarce and inconclusive. Furthermore, sTfR concentrations have been observed to be significantly higher in obese than in nonobese individuals. Therefore, the aim of this study was to assess the relationship between sTfR and the risk of T2DM in obese and nonobese subjects. DESIGN: A nested case-control study of 153 cases of newly diagnosed diabetic subjects, 73 obese and 80 nonobese, and 306 individually matched controls, 138 obese and 166 nonobese, who did not develop T2DM for a median 6-year follow-up (interquartile range: 3.9-6.5) was conducted using data from the PREvention with MEDiterranean Diet (PREDIMED) cohort (http://www.controlled trials.com/ISRCTN35739639). Cases and controls were matched for age (<= 67 vs. > 67 years), gender, dietary intervention group and BMI (<= 27 vs. > 27 kg/m2 ). RESULTS: Waist circumference is the main determinant of sTfR concentrations in the whole sample (beta = 0.476, P < 0.001), in the obese (beta = 0.802, P < 0.001) and the nonobese (beta = 0.455, P = 0.003). Furthermore, sTfR is directly associated with the risk of T2DM in obese individuals (OR = 2.79; 95% CI: 1.35 5.77, P = 0.005) and inversely associated in nonobese individuals (OR = 0.40; 95% CI: 0.20-0.79, P = 0.015). CONCLUSIONS: The association between sTfR levels and risk of T2DM in a population at high cardiovascular risk depend on the presence or absence of obesity. While in nonobese subjects elevated sTfR levels are associated with a decreased risk of developing T2DM, in obese subjects the risk increases. This suggests that obesity alters the relationship between sTfR and T2DM incidence. PMID- 28075491 TI - Integrated classification of inflammatory myopathies. AB - Inflammatory myopathies comprise a multitude of diverse diseases, most often occurring in complex clinical settings. To ensure accurate diagnosis, multidisciplinary expertise is required. Here, we propose a comprehensive myositis classification that incorporates clinical, morphological and molecular data as well as autoantibody profile. This review focuses on recent advances in myositis research, in particular, the correlation between autoantibodies and morphological or clinical phenotypes that can be used as the basis for an 'integrated' classification system. PMID- 28075492 TI - A thematic content analysis of #cheatmeal images on social media: Characterizing an emerging dietary trend. AB - Despite the pervasive social endorsement of "cheat meals" within pro-muscularity online communities, there is an absence of empirical work examining this dietary phenomenon. The present study aimed to characterize cheat meals, and explore the meaning ascribed to engagement in this practice. Thematic content analysis was employed to code the photographic and textual elements of a sample (n = 600) that was extracted from over 1.6 million images marked with the #cheatmeal tag on the social networking site, Instagram. Analysis of the volume and type of food revealed the presence of very large quantities (54.5%) of calorie-dense foods (71.3%) that was rated to qualify as an objective binge episode. Photographic content of people commonly portrayed highly-muscular bodies (60.7%) in the act of intentional body exposure (40.0%). Meanwhile, textual content exemplified the idealization of overconsumption, a strict commitment to fitness, and a reward based framework around diet and fitness. Collectively, these findings position cheat meals as goal-oriented dietary practices in the pursuit of physique-ideals, thus underscoring the potential clinical repercussions of this socially-endorsed dietary phenomenon. PMID- 28075493 TI - Joint stability after canine cranial cruciate ligament graft reconstruction varies among femoral fixation sites. AB - OBJECTIVE: To quantify stability in cranial cruciate ligament (CrCL) deficient canine stifles with hamstring grafts affixed at 3 femoral locations. STUDY DESIGN: Canine stifle motion study using a multi-cohort, repeated measures design. SAMPLE POPULATION: 27 canine cadaver stifles. METHODS: Hamstring grafts (HG) were affixed at the gracilis-semitendinosus insertion and on the lateral femur (1) proximal trochlear ridge (TR), (2) craniodistal to fabella (F), or (3) condyle center (CC). Total, cranial, and caudal tibial translation and total, medial, and lateral angular displacement, with and without translational load, were quantified with the CrCL intact, transected, and reconstructed. Angular displacement was quantified from points on the distal femur and proximal tibia. Graft strain was calculated from tissue displacement measured at joint angles of 30 degrees , 60 degrees , 90 degrees , and 120 degrees . RESULTS: Tibial translation was lowest in F constructs, which also achieved the least difference in tibial translation from intact stifles. Tibial translation was lower in intact stifles than in CrCL transected or reconstructed stifles. Less angular displacement of the proximal tibia was detected in the medial than in the lateral direction, and tibial displacement was lower in the cranial than the caudal direction. Angular displacement was lowest in the F treatment group. F constructs had the lowest graft strain at joint angles greater than 30 degrees . CONCLUSIONS: Femoral fixation of a canine hamstring graft craniodistal to the lateral fabella conferred the best joint stability and lowest graft strain in vitro. No fixation method restored joint stability of the intact CrCL. PMID- 28075494 TI - Geographic access to dental care varies in Missouri and Wisconsin. AB - OBJECTIVE: To examine geographic access to dental providers for the general population and children with public insurance in Missouri and Wisconsin. METHODS: Using a newly constructed dentist office database from the American Dental Association master file and other sources, we use the two-step floating area catchment area method to calculate population to provider ratios at the census block group level. These ratios are used to determine potential geographic dentist shortage areas. We utilize street network data to estimate travel times and catchment areas between population centers and dental offices. This methodology accounts for the actual spatial distribution of dental providers and potential dental patients. RESULTS: Within and across Missouri and Wisconsin, there is some variation in geographic access to dental offices for the general population and publicly insured children. More than 90 percent of publicly insured children have access to dental providers within 30 minutes. Among the states examined, Missouri has more geographic disparities to dental care. CONCLUSION: The Health Resources and Services Administration, which designates dental health professional shortage areas, relies on administrative boundaries to calculate population to dental provider ratios. These boundaries may not reflect actual or "real-time" dental care markets. The methods employed in this paper may give policymakers a template to better determine geographic dentist shortage areas. PMID- 28075495 TI - Oral tactile sensitivity and masticatory performance are impaired in stroke patients. AB - Oro-facial impairment following stroke frequently involves reduced chewing performance, that is oral phase dysphagia. The aim was to investigate the sensitivity of oral tissues following stroke and its potential impact on masticatory function. Therefore, hospitalised post-stroke patients were recruited and compared to healthy controls. Outcome measures comprised masticatory performance employing a colour-mixing ability, that is a bolus-kneading test, maximum lip- and bite force and the one-point and two-point tactile thresholds. Food hoarding and prevalence of dry mouth were evaluated with ordinal scales. Twenty-seven stroke patients (age 64.3 +/- 14.1 years) and 27 healthy controls (age 60.8 +/- 14.3 years, P = 0.254) participated in this study. The groups had similar numbers of occluding units. Stroke patients reported more frequently dry mouth sensations and food hoarding. The intra-oral tactile sensitivity on the contra-lesional side was significantly lower in stroke patients compared to controls (0.0001 < P < 0.0002), and significant intra-group side differences were found only in the stroke group (0.0001 < P < 0.0010). For the lip, both sides were less sensitive in the stroke group compared with controls. The experiments confirmed lower masticatory performance and lip force in the stroke group, but the bite force was similar compared to healthy controls. Oral sensitivity was correlated with masticatory performance when a global correlation model was applied. A stroke may affect the sensitivity of the intra-oral tissues contra lesionally, thus potentially affecting chewing function. Rehabilitation should therefore not only focus on motor impairment, but equally stimulate the sensitivity of the oral tissues, employing dry ice application or similar specific treatments. PMID- 28075496 TI - Effect of dorsal laminectomy and dorsal annulectomy with partial lumbosacral discectomy on the volume of the lateral intervertebral neuroforamina in dogs when the lumbosacral junction is extended. AB - OBJECTIVE: To determine the effect of dorsal annulectomy and partial discectomy on the volume of the lumbosacral lateral intervertebral neurovascular foramina (intervertebral foramina) in canine cadavers during extension of the lumbosacral junction. STUDY DESIGN: Ex vivo experiment. SAMPLE POPULATION: Lumbosacral specimens from 10 large breed dogs euthanatized for reasons unrelated to lumbosacral disease. METHODS: The lumbosacral specimens were clamped in a wooden jig and scanned using computed tomography (CT) with the lumbosacral junction in a neutral position and loaded in extension using a tensioning device. The 3 dimensional volumes of the lumbosacral intervertebral neurovascular foramina were measured and the extent of any disc degeneration was determined from the CT data. A limited dorsal laminectomy of S1 and a dorsal LS annulectomy and partial discectomy were then performed. The lumbosacral specimens were remounted into the jig and loaded into extension at the same tension and were re-scanned. Measurements of intervertebral foraminal volume were then repeated. RESULTS: The mean volume of the lumbosacral foramina (n = 20) was 381 mm3 in neutral (unloaded) positioning and 137 mm3 when loaded in extension. Following dorsal annulectomy, the mean volume was significantly reduced by a mean of 28% to 98 mm3 (P < .01). The foraminal volume was reduced in 19/20 lumbosacral foramen, with the post-annulectomy volume ranging from 31% to 97% of the pre-annulectomy volume (3%-69% reduction). CONCLUSIONS: This study suggests that a dorsal annulectomy with partial discectomy may induce further dynamic collapse of the lumbosacral articulation in the dog. PMID- 28075497 TI - Computed tomographic evaluation of dynamic alteration of the canine lumbosacral intervertebral neurovascular foramina. AB - OBJECTIVE: To develop a computed tomographic (CT) method to measure the volume of the lumbosacral intervertebral neurovascular foramina (IVF) in dogs, and determine the effect of the range of motion of the lumbosacral (LS) junction on this measurement in German shepherd dogs (GSDs) with degenerative lumbosacral stenosis (DLSS) compared to unaffected controls. STUDY DESIGN: In vivo analysis and retrospective case series. SAMPLE POPULATION: Twenty-four working Police GSDs, 12 diagnosed with DLSS and 12 unaffected by DLSS were compared to 10 Greyhounds without DLSS. METHODS: Three-dimensional renderings of CT data were used to measure the lumbosacral foraminal volume of dogs positioned in dorsal recumbency with the LS junction alternately positioned in extension, neutral position, and flexion. RESULTS: Volumetric analysis of the IVF was found repeatable for the extended and neutral positions (interclass correlation coefficient of 0.89 and 0.8, respectively). The mean lumbosacral IVF volume was decreased by 74% between LS flexion and extension in Greyhounds, compared to 79 and 85% reductions in GSDs unaffected and affected by DLSS, respectively. The lumbosacral IVF volume was decreased by 23% when comparing extended to neutral LS positions in Greyhounds, 29% in unaffected GSDs, and 31% in affected GSDs. IVF volumes were smaller in affected GSDs compared to unaffected GSDs (P < .05) and Greyhounds (P < .01). CONCLUSIONS: Positioning the LS junction in full extension decreases the volume of the lumbosacral IVF. This dynamic narrowing was more pronounced in GSDs with signs of DLSS than in GSDs not overtly affected by DLSS. PMID- 28075498 TI - Tamoxifen and its active metabolites inhibit dopamine transporter function independently of the estrogen receptors. AB - As one of the primary mechanisms by which dopamine signaling is regulated, the dopamine transporter (DAT) is an attractive pharmacological target for the treatment of diseases based in dopaminergic dysfunction. In this work we demonstrate for the first time that the commonly prescribed breast cancer therapeutic tamoxifen and its major metabolites, 4-hydroxytamoxifen and endoxifen, inhibit DAT function. Tamoxifen inhibits [3 H]dopamine uptake into human DAT (hDAT)-N2A cells via an uncompetitive or mixed mechanism. Endoxifen, an active metabolite of tamoxifen, asymmetrically inhibits DAT function in hDAT-N2A cells, showing a preference for the inhibition of amphetamine-stimulated dopamine efflux as compared to dopamine uptake. Importantly, we demonstrate that the effects of tamoxifen and its metabolites on the DAT occur independently of its activity as selective estrogen receptor modulators. This work suggests that tamoxifen is inhibiting DAT function through a previously unidentified mechanism. PMID- 28075499 TI - Long-term outcome following remote ischemic postconditioning during percutaneous coronary interventions-the RIP-PCI trial long-term follow-up. AB - The clinical value of ischemic conditioning during percutaneous coronary intervention (PCI) and mode of administration is controversial. Our aim was to assess the long-term effect of remote ischemic postconditioning among patients undergoing PCI. We randomized 360 patients undergoing PCI who presented with a negative troponin T at baseline into 3 groups: 2 groups received remote ischemic postconditioning (with ischemia applied to the arm in 1 group and to the thigh in the other group), and the third group acted as a control group. Remote ischemic postconditioning was applied during PCI immediately following stent deployment, by 3, 5-minute cycles of blood pressure cuff inflation to >200 mm Hg on the arm or thigh (20 mm Hg to the arm in the control), with 5-minute breaks between each cycle. There were no differences in baseline characteristics among the 3 groups. Periprocedural myocardial injury occurred in 33% (P = 0.64). After 1 year, there was no difference between groups in death (P = 0.91), myocardial infarction (P = 0.78), or repeat revascularization (P = 0.86). During 3 years of follow-up, there was no difference in death, myocardial infarction, and revascularization among the groups (P = 0.45). Remote ischemic postconditioning during PCI did not affect long-term cardiovascular outcome. A similar effect was obtained when remote ischemia was induced to the upper or lower limb. ClinicalTrials.gov Identifier: NCT00970827. PMID- 28075500 TI - Very short/short-term benefit of inpatient/outpatient cardiac rehabilitation programs after coronary artery bypass grafting surgery. AB - BACKGROUND: Exercise-based rehabilitation is an important part of treatment patients following coronary artery bypass graft (CABG) surgery. HYPOTHESIS: To evaluate effect of very short/short-term exercise training on cardiopulmonary exercise testing (CPET) parameters. METHODS: We studied 54 consecutive patients with myocardial infarction (MI) treated with CABG surgery referred for rehabilitation. The study population consisted of 50 men and 4 women (age 57.72 +/- 7.61 years, left ventricular ejection fraction 55% +/- 5.81%), who participated in a 3-week clinical and 6-month outpatient cardiac rehabilitation program. The Inpatient program consisted of cycling 7 times/week and daily walking for 45 minutes. The outpatient program consisted mainly of walking 5 times/week for 45 minutes and cycling 3 times/week. All patients performed symptom-limited CPET on a bicycle ergometer with a ramp protocol of 10 W/minute at the start, for 3 weeks, and for 6 months. RESULTS: After 3 weeks of an exercise-based cardiac rehabilitation program, exercise tolerance improved as compared to baseline, as well as peak respiratory exchange ratio. Most importantly, peak VO2 (16.35 +/- 3.83 vs 17.88 +/- 4.25 mL/kg/min, respectively, P < 0.05), peak VCO2 (1.48 +/- 0.40 vs 1.68 +/- 0.43, respectively, P < 0.05), peak ventilatory exchange (44.52 +/- 11.32 vs 52.56 +/- 12.37 L/min, respectively, P < 0.05), and peak breathing reserve (52.00% +/- 13.73% vs 45.75% +/- 14.84%, respectively, P < 0.05) were also improved. The same improvement trend continued after 6 months (respectively, P < 0.001 and P < 0.0001). No major adverse cardiac events were noted during the rehabilitation program. CONCLUSIONS: Very short/short-term exercise training in patients with MI treated with CABG surgery is safe and improves functional capacity. PMID- 28075501 TI - A Recoverable Ruthenium Aqua Complex Supported on Silica Particles: An Efficient Epoxidation Catalyst. AB - The preparation and characterization of complexes with a phosphonated terpyridine (trpy) ligand (trpy-P-Et) and a bidentate pyridylpyrazole (pypz-Me) ligand, with formula [RuII (trpy-P-Et)(pypz-Me)X]n+ (2: X=Cl, n=1; 3: X=H2 O, n=2), is described, together with the anchoring of 3 on two types of supports: mesoporous silica particles (SP) and silica-coated magnetic particles (MSP). Aqua complex 3 is easily obtained by heating 2 in refluxing water and exhibits a two-electron RuIV/II redox process. It was anchored on SP and MSP supports by two different synthetic strategies, yielding the heterogeneous systems SP@3 and MSP@3, which were fully characterized by IR and UV/Vis spectroscopy, SEM, cyclic voltammetry, and differential pulse voltammetry. Catalytic olefin epoxidation was tested with molecular complex 3 and its SP@3 and MSP@3 heterogeneous counterparts, including reuse of the heterogeneous systems. The MSP@3 material can be easily recovered by a magnet, which facilitates its reusability. PMID- 28075502 TI - Antibody and cytokine levels in humans fed on by the common bedbug, Cimex lectularius L. AB - Little is known about cimicosis, the resultant dermal reaction from feeding activity by the common bedbug, Cimex lectularius L. We fed C. lectularius on human study subjects four times over four weeks and measured serum cytokine and antibody levels, and subjects recorded any cimicosis. The average time for subjects to develop cimicosis decreased with each feeding from 8.4, to 2.1, 1.5 and 1.3 days, respectively. There were no significant changes in total IgG, IgG1, IgG2, IgG4 or IgE levels between the first and fourth bedbug feedings, but there was a significant decrease in total IgG3 levels (P<.001). IgG4 was not required for cimicosis. Higher IgG2 and IgG4 levels at study visit 4 were associated with an increased duration of cimicosis (P=.04) and lower pruritis (P=.03), respectively. There were no significant changes in serum TNF-alpha, IL-1beta, IL 4, IL-5, IL-6, IL-10, IFN-gamma and IL-17A levels before and one hour after the C. lectularius feeding. Lower post-C. lectularius feeding IL-6 levels were associated with increased pruritis (P=.001) and the time to maximum pruritis (P=.04), respectively. Higher post-C. lectularius feeding IL-5 levels were associated with a longer duration of pruritis (P=.05). PMID- 28075503 TI - Correlation between cardiac rhythm, left atrial appendage flow velocity, and CHA2 DS2 -VASc score: Study based on transesophageal echocardiography and 2 dimensional speckle tracking. AB - BACKGROUND: The CHA2 DS2 -VASc score is a classic predictor of stroke in patients with atrial fibrillation (AF). Decreased left atrial appendage flow velocity (LAA FV) reflects the blood stasis, and left atrial (LA) strain is a manifestation of atrial remodeling. This study aimed to explore the effects of AF rhythm and CHA2 DS2 -VASc score in the development of thrombogenesis and their potential correlation with LAA-FV and LA strain. HYPOTHESIS: AF rhythm and high CHA2 DS2 VASc score correlate independently with decreased LAA-FV, which can be predicted by LA strain. METHODS: In 98 AF patients, LAA-FV was measured by transesophageal echocardiography and LA strain was measured by transthoracic echocardiography. RESULTS: LAA-FV decreased sharply in the AF rhythm group (26.22 vs 61.87 mm/s; P < 0.001), and CHA2 DS2 -VASc score did not differ between the decreased and normal LAA-FV groups in all patients (P = 0.289). However, in sinus rhythm (SR), LAA-FV was associated with CHA2 DS2 -VASc score (coefficient = -0.317, P = 0.013), and the CHA2 DS2 -VASc score differed between the normal and decreased LAA-FV groups (2 [0-7] vs 3 [0-6], respectively; P = 0.038). Moreover, LA strain was a predictor of LAA-FV in both AF rhythm and SR, whereas a peak positive systolic strain divided by LA volume index <0.744 predicted decreased LAA-FV. CONCLUSIONS: AF rhythm caused a sharp decrease in LAA-FV independent of CHA2 DS2 VASc score. In SR, the CHA2 DS2 -VASc score correlated negatively with LAA-FV. LA strain was a predictor of LAA-FV in both SR and AF rhythm. PMID- 28075504 TI - Anxiety and burnout in young athletes: The mediating role of cognitive appraisal. AB - This study tested the relationship between trait anxiety, cognitive appraisal, and athletes' burnout proposing two hypotheses: (a) there is a direct relationship between athletes' trait anxiety and cognitive appraisal and burnout, and (b) cognitive appraisal mediates the relationship between trait anxiety and burnout, and this mediation occurs despite the competitive level and sport records of athletes. The study included 673 young athletes and provided measures of trait anxiety, cognitive appraisal, and burnout. Structural equation modeling indicated that cognitive appraisal mediates the relationship between trait anxiety and burnout, confirming hypothesis 2, and this model provided better fit than the direct model of hypothesis 1. However, the mediation also indicated that the direct relationship between trait anxiety and burnout should be considered. The mediating model was invariant according to competitive levels and sport records. In conclusion, cognitive appraisal is an important variable in explaining athletes' burnout. PMID- 28075505 TI - Terminal Uranium(V/VI) Nitride Activation of Carbon Dioxide and Carbon Disulfide: Factors Governing Diverse and Well-Defined Cleavage and Redox Reactions. AB - The reactivity of terminal uranium(V/VI) nitrides with CE2 (E=O, S) is presented. Well-defined C=E cleavage followed by zero-, one-, and two-electron redox events is observed. The uranium(V) nitride [U(TrenTIPS )(N)][K(B15C5)2 ] (1, TrenTIPS =N(CH2 CH2 NSiiPr3 )3 ; B15C5=benzo-15-crown-5) reacts with CO2 to give [U(TrenTIPS )(O)(NCO)][K(B15C5)2 ] (3), whereas the uranium(VI) nitride [U(TrenTIPS )(N)] (2) reacts with CO2 to give isolable [U(TrenTIPS )(O)(NCO)] (4); complex 4 rapidly decomposes to known [U(TrenTIPS )(O)] (5) with concomitant formation of N2 and CO proposed, with the latter trapped as a vanadocene adduct. In contrast, 1 reacts with CS2 to give [U(TrenTIPS )(kappa2 -CS3 )][K(B15C5)2 ] (6), 2, and [K(B15C5)2 ][NCS] (7), whereas 2 reacts with CS2 to give [U(TrenTIPS )(NCS)] (8) and "S", with the latter trapped as Ph3 PS. Calculated reaction profiles reveal outer-sphere reactivity for uranium(V) but inner-sphere mechanisms for uranium(VI); despite the wide divergence of products the initial activation of CE2 follows mechanistically related pathways, providing insight into the factors of uranium oxidation state, chalcogen, and NCE groups that govern the subsequent divergent redox reactions that include common one-electron reactions and a less-common two-electron redox event. Caution, we suggest, is warranted when utilising CS2 as a reactivity surrogate for CO2 . PMID- 28075506 TI - Efficacy of chlorhexidine for the prevention and treatment of oral mucositis in cancer patients: a systematic review with meta-analyses. AB - BACKGROUND: Oral mucositis occurs in patients undergoing chemoradiation for cancer treatment. It is believed that colonization of ulcerated mucosa by bacteria, fungi, and virus results in secondary infections. The effect of chlorhexidine on the incidence and severity of oral mucositis in patients with cancer was evaluated in this review. METHODS: Studies were limited to randomized placebo-controlled trials. Three databases were searched: MEDLINE (via PubMed), Web of Science, and the Cochrane Library up to May 25, 2016. RESULTS: Ninety eight abstracts were evaluated by three independent reviewers. Twelve studies met the criteria for inclusion. Four of these studies were assessed at unclear risk of bias and eight of them at high risk. Of the 12 studies, nine were included in two meta-analyses. Pooled results showed that chlorhexidine did not significantly reduce incidence of mucositis compared to placebo (P = 0.129), nor chlorhexidine did significantly reduce the severity of mucositis (P = 0.127), although subgroup analysis in the chemotherapy group showed a trend toward significance (P = 0.054). Side effects reported in the included studies were teeth staining and altered taste perception. CONCLUSIONS: This systematic review found that chlorhexidine is not significantly effective in reducing the severity of mucositis (moderate quality of evidence) nor in preventing the incidence of mucositis (low quality of evidence). However, more studies are needed in patients receiving chemotherapy only, as a positive trend toward significance was found (P = 0.054). PMID- 28075507 TI - Labour induction near term for women aged 35 or over: an economic evaluation. AB - OBJECTIVE: Induction of labour at 39 weeks for nulliparous women aged 35 years and over may prevent stillbirths and does not increase caesarean births, so it may be popular. But the overall costs and benefits of such a policy have not been compared. DESIGN: A cost-utility analysis alongside a randomised controlled trial (the 35/39 trial). SETTING: Obstetric departments of 38 UK National Health Service hospitals and one UK primary-care trust. POPULATION: Nulliparous women aged 35 years or over on their expected due date, with a singleton live fetus in a cephalic presentation. METHODS: Costs were estimated from the National Health Service and Personal Social Services perspective and quality-adjusted life-years (QALYs) were calculated based on patient responses to the EQ-5D at baseline and 4 weeks. MAIN OUTCOME MEASURES: Data on antenatal care, mode of delivery, analgesia in labour, method of induction, EQ-5D (baseline and 4 weeks postnatal) and participant-administered postnatal health resource use data were collected. RESULTS: The intervention was associated with a mean cost saving of L263 and a small additional gain in QALYs (though this was not statistically significant), even without considering any possible QALY gains from stillbirth prevention. CONCLUSION: A policy of induction of labour at 39 weeks for women of advanced maternal age would save money. TWEETABLE ABSTRACT: A policy of induction of labour at 39 weeks of gestation for women of advanced maternal age would save money. PMID- 28075508 TI - Differences in Access to and Use of Electronic Personal Health Information Between Rural and Urban Residents in the United States. AB - PURPOSE: The increase in use of health information technologies (HIT) presents new opportunities for patient engagement and self-management. Patients in rural areas stand to benefit especially from increased access to health care tools and electronic communication with providers. We assessed the adoption of 4 HIT tools over time by rural or urban residency. METHODS: Analyses were conducted using data from 7 iterations of the National Cancer Institute's Health Information National Trends Survey (HINTS; 2003-2014). Rural/urban residency was based on the USDA's 2003 Rural-Urban Continuum Codes. Outcomes of interest included managing personal health information online; whether providers maintain electronic health records (EHRs); e-mailing health care providers; and purchasing medicine online. Bivariate analyses and logistic regression were used to assess relationships between geography and outcomes, controlling for sociodemographic characteristics. FINDINGS: In total, 6,043 (17.6%, weighted) of the 33,749 respondents across the 7 administrations of HINTS lived in rural areas. Rural participants were less likely to report regular access to Internet (OR = 0.70, 95% CI = 0.61-0.80). Rural respondents were neither more nor less likely to report that their health care providers maintained EHRs than were urban respondents; however, they had decreased odds of managing personal health information online (OR = 0.59, 95% CI = 0.40-0.78) and e-mailing health care providers (OR = 0.62, 95% CI = 0.49-0.77). CONCLUSIONS: The digital divide between rural and urban residents extends to HIT. Additional investigation is needed to determine whether the decreased use of HIT may be due to lack of Internet connectivity or awareness of these tools. PMID- 28075509 TI - Complexation and Electronic Communication between Corannulene-Based Buckybowls and a Curved Truxene-TTF Donor. AB - The association behavior of an electron-donating, bowl-shaped, truxene-based tetrathiafulvalene (truxTTF) with two corannulene-based fullerene fragments, C32 H12 and C38 H14 , is investigated in several solvents. Formation of 1:1 complexes is followed by absorption titrations and complemented by density functional theory (DFT) calculations. The binding constants are in the range log Ka =2.9 3.5. DFT calculations reveal that the most stable arrangement is the conformation in which the 1,3-dithiole ring of truxTTF is placed inside the concave cavity of the corannulene derivative. This arrangement is confirmed experimentally by NMR measurements, and implies that a combination of pi-pi and CH-pi interactions is the driving force for association. Time-dependent DFT calculations reproduce the experimental UV/Vis titrations and provide a detailed understanding of the spectral changes observed. Femtosecond transient absorption studies reveal the processes occurring after photoexcitation of either C32 H12 or C38 H14 and their supramolecular associates with truxTTF. In the case of truxTTF?C38 H14 , photoexcitation yields the charge-separated state truxTTF.+ ?C38 H14.- with a lifetime of approximately 160 ps. PMID- 28075510 TI - Development of a voided urine assay for detecting prostate cancer non-invasively: a pilot study. AB - OBJECTIVE: To validate a hypothesis that prostate cancer can be detected non invasively by a simple and reliable assay by targeting genomic VPAC receptors expressed on malignant prostate cancer cells shed in voided urine. PATIENTS/SUBJECTS AND METHODS: VPAC receptors were targeted with a specific biomolecule, TP4303, developed in our laboratory. With an Institutional Review Board exempt approval of use of de-identified discarded samples, an aliquot of urine collected as a standard of care, from patients presenting to the urology clinic (207 patients, 176 men and 31 women, aged >=21 years) was cytospun. The cells were fixed and treated with TP4303 and 4,6-diamidino-2-phenylindole (DAPI). The cells were then observed under a microscope and cells with TP4303 orange fluorescence around the blue (DAPI) nucleus were considered 'malignant' and those only with a blue nucleus were regarded as 'normal'. VPAC presence was validated using receptor blocking assay and cell malignancy was confirmed by prostate cancer gene profile examination. RESULTS: The urine specimens were labelled only with gender and presenting diagnosis, with no personal health identifiers or other clinical data. The assay detected VPAC positive cells in 98.6% of the men with a prostate cancer diagnosis (141), and none of the 10 men with benign prostatic hyperplasia. Of the 56 'normal' patients, 62.5% (35 patients, 10 men and 25 women) were negative for VPAC cells; 19.6% (11, 11 men and no women) had VPAC positive cells; and 17.8% (10, four men and six women) were uninterpretable due to excessive crystals in the urine. Although data are limited, the sensitivity of the assay was 99.3% with a confidence interval (CI) of 96.1-100% and the specificity was 100% with a CI of 69.2-100%. Receptor blocking assay and fluorescence-activated cell sorting (FACS) analyses demonstrated the presence of VPAC receptors and gene profiling examinations confirmed that the cells expressing VPAC receptors were malignant prostate cancer cells. CONCLUSION: These preliminary data are highly encouraging and warrant further evaluation of the assay to serve as a simple and reliable tool to detect prostate cancer non invasively. PMID- 28075511 TI - Postoperative iodine-125 interstitial brachytherapy for the early stages of minor salivary gland carcinomas of the lip and buccal mucosa with positive or close margins. AB - BACKGROUND: The purpose of this study was to present our preliminary exploration of safety and efficacy of postoperative low-dose-rate brachytherapy for the early clinical stages of minor salivary gland carcinomas of the lip and buccal mucosa. METHODS: Twenty-seven patients with the early stages of minor salivary gland carcinomas of the lip and buccal mucosa received postoperative 125 I seed interstitial brachytherapy from March 2005 to May 2015. Actuarial likelihood estimates for local control, overall survival, and disease-free survival were calculated by Kaplan-Meier method. RESULTS: The actuarial 3-year, 5-year, and 10 year local control rates were 94.7%, 82.9%, and 82.9%, respectively. The actuarial 3-year, 5-year, and 10-year overall survival rates were 93.3%, 93.3%, and 77.8%, respectively. No patient experienced toxicity above grade 2. CONCLUSION: Postoperative 125 I seed interstitial brachytherapy is an alternative to radical surgery for early stages of minor salivary gland carcinomas of the lip and buccal mucosa, which offers satisfactory cosmetic and functional outcomes. (c) 2017 Wiley Periodicals, Inc. Head Neck 39: 572-577, 2017. PMID- 28075512 TI - Alkyl Formate Ester Synthesis by a Fungal Baeyer-Villiger Monooxygenase. AB - We investigated Baeyer-Villiger monooxygenase (BVMO)-mediated synthesis of alkyl formate esters, which are important flavor and fragrance products. A recombinant fungal BVMO from Aspergillus flavus was found to transform a selection of aliphatic aldehydes into alkyl formates with high regioselectivity. Near complete conversion of 10 mm octanal was achieved within 8 h with a regiomeric excess of ~80 %. Substrate concentration was found to affect specific activity and regioselectivity of the BVMO, as well as the rate of product autohydrolysis to the primary alcohol. More than 80 % conversion of 50 mm octanal was reached after 72 h (TTN nearly 20 000). Biotransformation on a 200 mL scale under unoptimized conditions gave a space-time yield (STY) of 4.2 g L-1 d-1 (3.4 g L-1 d-1 extracted product). PMID- 28075513 TI - Regio- and Enantioselective Rhodium-Catalyzed Addition of 1,3-Diketones to Allenes: Construction of Asymmetric Tertiary and Quaternary All Carbon Centers. AB - An unprecedented highly regio- and enantioselective rhodium-catalyzed addition of 1,3-diketones to terminal and 1,1-disubstituted allenes furnishing asymmetric tertiary and quaternary all-carbon centers is reported. By applying a RhI /phosphoramidite/TFA catalytic system under mild conditions, the desired chiral branched alpha-allylated 1,3-diketones could be obtained in good to excellent yields, with perfect regioselectivity and in high enantioselectivity. The reaction shows a broad functional-group tolerance on both reaction partners highlighting its synthetic potential. PMID- 28075514 TI - TANGO - a screening tool to identify comorbidities on the causal pathway of nocturia. AB - OBJECTIVES: To develop a robust screening metric for use in identifying non-lower urinary tract comorbidities pertinent to the multidisciplinary assessment of patients with nocturia. METHODS: Variables having a significant risk association with nocturia of greater than once per night were identified. Discriminating items from validated and reliable tools measuring these comorbidities were identified. A self-completed 57-item questionnaire was developed and a medical checklist and pertinent clinical measures added. Pre-determined criteria were applied to retain or remove items in the development of the Short-Form (SF) screening tool. The tool was administered to 252 individuals with nocturia who were attending either a tertiary level Sleep, Continence, Falls or Rehabilitation service for routine care. Data collected were subjected to descriptive analysis; criteria were applied to reduce the number of items. Using pre-determined domains, a nocturia screening metric, entitled TANGO, was generated. The acronym TANGO stands for Targeting the individual's Aetiology of Nocturia to Guide Outcomes. RESULTS: The demographic characteristics of the sample are described, along with item endorsement levels. The statistical and structural framework to justify deleting or retaining of items from the TANGO Long-Form to the SF is presented. The resultant TANGO-SF patient-completed nocturia screening tool is reported. CONCLUSIONS: A novel all-cause diagnostic metric for identifying co existing morbidities of clinical relevance to nocturia in patients who present across disciplines and medical specialties has been developed. TANGO has the potential to improve practice and smooth inequalities associated with a siloed approach to assessment and subsequent care of patients with nocturia. PMID- 28075515 TI - The limitations of pulse oximetry for critical congenital heart disease screening in the neonatal intensive care units. PMID- 28075516 TI - Quantifying severe urinary complications after radical prostatectomy: the development and validation of a surgical performance indicator using hospital administrative data. AB - OBJECTIVES: To develop and validate a surgical performance indicator based on severe urinary complications that require an intervention within 2 years of radical prostatectomy (RP), identified in hospital administrative data. PATIENTS AND METHODS: Men who underwent RP between 2008 and 2012 in England were identified using hospital administrative data. A transparent coding framework based on procedure codes was developed to identify severe urinary complications which were grouped into 'stricture', 'incontinence' and 'other'. Their validity as a performance indicator was assessed by evaluating the consistency with diagnosis codes and association with patient and surgical characteristics. Kaplan Meier methods were used to assess time to first occurrence and multivariable logistic regression was used to estimate adjusted odds ratios (ORs) for patient and surgical characteristics. RESULTS: A total of 17 299 men were included, of whom 2695 (15.6%) experienced at least one severe urinary complication within 2 years. High proportions of men with a complication had relevant diagnosis codes: 86% for strictures and 93% for incontinence. Urinary complications were more common in men from poorer socio-economic backgrounds (OR comparing lowest with highest quintile: 1.45; 95% confidence interval [CI] 1.26-1.67) and in those with prolonged length of hospital stay (OR 1.54, 95% CI 1.40-1.69), and were less common in men who underwent robot-assisted surgery (OR 0.65, 95% CI 0.58-0.74). CONCLUSION: These results show that severe urinary complications identified in administrative data provide a medium-term performance indicator after RP. They can be used for research assessing outcomes of treatment methods and for service evaluation comparing performance of prostate cancer surgery providers. PMID- 28075517 TI - Neutrophil-to-lymphocyte ratio: Prognostic indicator for head and neck squamous cell carcinoma. AB - BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) has prognostic significance for many cancers, with higher values correlating with poor outcomes. The purpose of this study was to determine the prognostic significance of this inflammatory marker for patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Univariate logistic regression and multivariate Cox regression analyses were performed on a retrospective cohort of 123 patients treated with primary chemoradiotherapy. RESULTS: The NLR is an indicator of both recurrence-free and overall survival, but the NLR does not have independent prognostic significance when the favorable prognostic influence of human papillomavirus (HPV) status is incorporated into multivariate models. CONCLUSION: The interaction between NLR and HPV status suggests that HPV status may be a determining factor in the favorable prognosis associated with a decreased NLR in HNSCC; these findings also suggest that HPV status may interact with the prognostic associations of indicators of systemic inflammation in HNSCC. (c) 2017 Wiley Periodicals, Inc. Head Neck 39: 662-667, 2017. PMID- 28075518 TI - Rapid Asymmetric Synthesis of Disubstituted Allenes by Coupling of Flow-Generated Diazo Compounds and Propargylated Amines. AB - We report herein the asymmetric coupling of flow-generated unstabilized diazo compounds and propargylated amine derivatives, using a new pyridinebis(imidazoline) ligand, a copper catalyst and base. The reaction proceeds rapidly, generating chiral allenes in 10-20 minutes with high enantioselectivity (89-98 % de/ee), moderate yields and a wide functional group tolerance. PMID- 28075519 TI - An update of management of insomnia in patients with chronic orofacial pain. AB - In this review, we discuss the management of chronic orofacial pain (COFP) patients with insomnia. Diagnostic work-up and follow-up routines of COFP patients should include assessment of sleep problems. Management is based on a multidisciplinary approach, addressing the factors that modulate the pain experience as well as insomnia and including both non-pharmacological and pharmacological modalities. Parallel to treatment, patients should receive therapy for comorbid medical and psychiatric disorders, and possible substance abuse that may be that may trigger or worsen the COFP and/or their insomnia. Insomnia treatment should begin with non-pharmacological therapy, to minimize potential side effects, drug interactions, and risk of substance abuse associated with pharmacological therapy. Behavioral therapies for insomnia include the following: sleep hygiene, cognitive behavioral therapy for insomnia, multicomponent behavioral therapy or brief behavioral therapy for insomnia, relaxation strategies, stimulus control, and sleep restriction. Approved U.S. Food and Drug Administration medications to treat insomnia include the following: benzodiazepines (estazolam, flurazepam, temazepam, triazolam, and quazepam), non benzodiazepine hypnotics (eszopiclone, zaleplon, zolpidem), the melatonin receptor agonist ramelteon, the antidepressant doxepin, and the orexin receptor antagonist suvorexant. Chronic orofacial pain can greatly improve following treatment of the underlying insomnia, and therefore, re-evaluation of COFP is advised after 1 month of treatment. PMID- 28075520 TI - Long-term enhanced winter soil frost alters growing season CO2 fluxes through its impact on vegetation development in a boreal peatland. AB - At high latitudes, winter climate change alters snow cover and, consequently, may cause a sustained change in soil frost dynamics. Altered winter soil conditions could influence the ecosystem exchange of carbon dioxide (CO2 ) and, in turn, provide feedbacks to ongoing climate change. To investigate the mechanisms that modify the peatland CO2 exchange in response to altered winter soil frost, we conducted a snow exclusion experiment to enhance winter soil frost and to evaluate its short-term (1-3 years) and long-term (11 years) effects on CO2 fluxes during subsequent growing seasons in a boreal peatland. In the first 3 years after initiating the treatment, no significant effects were observed on either gross primary production (GPP) or ecosystem respiration (ER). However, after 11 years, the temperature sensitivity of ER was reduced in the treatment plots relative to the control, resulting in an overall lower ER in the former. Furthermore, early growing season GPP was also lower in the treatment plots than in the controls during periods with photosynthetic photon flux density (PPFD) >=800 MUmol m-2 s-1 , corresponding to lower sedge leaf biomass in the treatment plots during the same period. During the peak growing season, a higher GPP was observed in the treatment plots under the low light condition (i.e. PPFD 400 MUmol m-2 s-1 ) compared to the control. As Sphagnum moss maximizes photosynthesis at low light levels, this GPP difference between the plots may have been due to greater moss photosynthesis, as indicated by greater moss biomass production, in the treatment plots relative to the controls. Our study highlights the different responses to enhanced winter soil frost among plant functional types which regulate CO2 fluxes, suggesting that winter climate change could considerably alter the growing season CO2 exchange in boreal peatlands through its effect on vegetation development. PMID- 28075521 TI - Association between adolescent sport activities and lumbar disk degeneration among young adults. AB - The relationship between different sport activities and lumbar intervertebral disk degeneration (DD) is largely unknown. We evaluated whether adolescent participation in different sports is associated with lumbar DD in a population based birth cohort of young adults. A total of 558 young adults (325 females and 233 males) underwent magnetic resonance imaging (MRI, 1.5-T scanner). A DD sum score, based on the Pfirrmann grading, was calculated for all lumbar levels. The sum score was categorized into no DD, 1, 2, or at least 3. Participation in different sport activities was self-reported by postal surveys at 16, 18, and 19 years, and three groups were formed based on participation frequency in 11 sports: (a) highly active (at least twice a week), (b) moderately active (2-4 times a month), and (c) inactive (maximum once a month). Cumulative odds ratios (COR) and their 95% confidence intervals (CI) were obtained for each sport by ordinal logistic regression, adjusting for gender, body mass index, age, socioeconomic status, smoking, and other sports. Highly active participation in jogging/running and swimming was associated with a higher DD sum score (COR: 3.0; 95% CI: 1.4-6.3 and 5.0; 1.7-15.2, respectively) compared to inactive participation, whereas highly active participation in skating showed low COR. In conclusion, running and swimming at least twice a week in early adulthood are potentially associated with lumbar DD. Follow-up studies with MRI are needed to show whether frequent exposure to running or swimming has further effect on the integrity of lumbar intervertebral disks. PMID- 28075523 TI - Extreme rainfall and snowfall alter responses of soil respiration to nitrogen fertilization: a 3-year field experiment. AB - Extreme precipitation is predicted to be more frequent and intense accompanying global warming and may have profound impacts on soil respiration (Rs) and its components, that is, autotrophic (Ra) and heterotrophic (Rh) respiration. However, how natural extreme rainfall or snowfall events affect these fluxes are still lacking, especially under nitrogen (N) fertilization. In this study, extreme rainfall and snowfall events occurred during a 3-year field experiment, allowing us to examine their effects on the response of Rs, Rh, and Ra to N supply. In normal rainfall years of 2011/2012 and 2012/2013, N fertilization significantly stimulated Rs by 23.9% and 10.9%, respectively. This stimulation was mainly due to the increase of Ra because of N-induced increase in plant biomass. In the record wet year of 2013/2014, however, Rs was independent on N supply because of the inhibition effect of the extreme rainfall event. Compared with those in other years, Rh and Ra were reduced by 36.8% and 59.1%, respectively, which were likely related to the anoxic stress on soil microbes and decreased photosynthates supply. Although N supply did not affect annual Rh, the response ratio (RR) of Rh flux to N fertilization decreased firstly during growing season, increased in nongrowing season and peaked during spring thaw in each year. Nongrowing season Rs and Rh contributed 5.5-16.4% to their annual fluxes and were higher in 2012/2013 than other years due to the extreme snowfall inducing higher soil moisture during spring thaw. The RR of nongrowing season Rs and Rh decreased in years with extreme snowfall or rainfall compared to those in normal years. Overall, our results highlight the significant effects of extreme precipitation on responses of Rs and its components to N fertilization, which should be incorporated into models to improve the prediction of carbon-climate feedbacks. PMID- 28075522 TI - Crucial role of carbonic anhydrase IX in tumorigenicity of xenotransplanted adult T-cell leukemia-derived cells. AB - Carbonic anhydrase IX (CA9) is a membrane-associated carbonic anhydrase that regulates cellular pH, is upregulated in various solid tumors, and is considered to be a therapeutic target. Here, we describe the essential role of CA9 in the tumorigenicity of cells derived from human adult T-cell leukemia/lymphoma (ATL). We previously established the highly tumorigenic ST1-N6 subline from the ATL derived ST1 cell line by serial xenotransplantation in NOG mice. In the present study, we first show that CA9 expression is strongly enhanced in ST1-N6 cells. We then sorted ST1 cells by high or low CA9 expression and established ST1-CA9high and ST1-CA9low sublines. ST1-CA9high cells, like ST1-N6 cells, were more strongly tumorigenic than ST1-CA9low or parental ST1 cells when injected into NOG mice. Knockdown of CA9 with shRNAs suppressed the ability of ST1-CA9high cells to initiate tumors, and the tumorigenicity of ST1 cells was significantly enhanced by introducing wild-type CA9 or a CA9 mutant with deletion of an intracytoplasmic domain. However, a CA9 with point mutations in the catalytic site did not increase the tumorigenicity of ST1 cells. Furthermore, we detected a small population of CA9+ CD25+ cells in lymph nodes of ATL patients. These findings suggest that CA9, and particularly its carbonic anhydrase activity, promotes the tumorigenicity of ATL-derived cells and may be involved in malignant development of lymphoma-type ATL. PMID- 28075524 TI - TOPK (T-LAK cell-originated protein kinase) inhibitor exhibits growth suppressive effect on small cell lung cancer. AB - T-lymphokine-activated killer cell-originated protein kinase (TOPK) plays critical roles in cancer cell proliferation as well as maintenance of cancer stem cells (CSC). Small cell lung cancer (SCLC) has highly aggressive phenotype, reveals early spread to distant sites, and results in dismal prognosis with little effective treatment. In this study, we demonstrate that TOPK expression was highly upregulated in both SCLC cell lines and primary tumors. Similar to siRNA-mediated TOPK knockdown effects, treatment with a potent TOPK inhibitor, OTS514, effectively suppressed growth of SCLC cell lines (IC50 ; 0.4-42.6 nM) and led to their apoptotic cell death. TOPK inhibition caused cell morphologic changes in SCLC cells, elongation of intercellular bridges caused by cytokinesis defects or neuronal protrusions induced by neuronal differentiation in a subset of CSC-like SCLC cells. Treatment with OTS514 suppressed forkhead box protein M1 (FOXM1) activity, which was involved in stemness of CSC. Furthermore, OTS514 treatment reduced CD90-positive SCLC cells and showed higher cytotoxic effect against lung sphere-derived CSC-like SCLC cells. Collectively, our results suggest that targeting TOPK is a promising approach for SCLC therapy. PMID- 28075525 TI - Dynamic remodeling of arteriolar collaterals after acute occlusion in chick chorioallantoic membrane. AB - OBJECTIVE: After arteriolar occlusion, collaterals enlarge and initially elevated WSS normalizes. While most previous studies focused on endpoints of such adaptive changes in larger collaterals, the present investigation aimed to continuously determine the relation between WSS and diameter in microvascular collaterals during adaptive reactions. METHODS: In Hamburger-Hamilton stage 40 CAMs, junction points between arteriolar segments were identified and the third upstream segment on one side was occluded. Intravital microscopy recordings were taken for 24 hours post-occlusion. Segment diameter and blood velocity were measured: WSS and capillary density were calculated. RESULTS: After occlusion, vascular diameters exhibited an immediate decrease, then increased with a time constant of 2.5 +/- 0.8 hours and reached a plateau of up to 60% above baseline after about 7 hours. Vascular tone showed no significant change. WSS exhibited an immediate increase post-occlusion and linearly returned to baseline after about 12 hours. Local WSS change and diameter change rate showed similar patterns during the initial but not the later phase of post-occlusive adaptation. CONCLUSIONS: CAM collaterals undergo fast structural remodeling within 24 hours post-occlusion. This remodeling might be driven by local WSS and by other regulators within the vascular network. PMID- 28075527 TI - Recent Development of the Second and Third Generation Irreversible Epidermal Growth Factor Receptor Inhibitors. AB - Recent reports suggested that essential directions for new lung cancer, breast carcinoma therapies, as well as the roomier realm of targeted cancer therapies were provided through targeting the epidermal growth factor receptor (EGFR). Patients who carrying non-small cell lung carcinoma (NSCLC) with activating mutations in EGFR initially respond well to the EGFR inhibitors erlotinib and gefitinib, which were located the active site of the EGFR kinase and designed to act as competitive inhibitors of combining with the ATP. However, patients who were treated with the erlotinib and gefitinib will relapse because of the emergence of drug-resistant mutations, with T790M mutations accounting for approximately 60% of all resistance. In order to overcome drug resistance, Pharmaceutical chemistry experts recently devoted great endeavors to the development of second-generation irreversible selective inhibitors which covalently modify Cys797 or Cys773 at the ATP binding cleft. Nevertheless, these inhibitors have not reached ideal effect of experts in patients with T790M positive mutation and apparently because of the dose-limiting toxicities associated with inhibition of wild type EGFR. A novel class of 'third generation' EGFR TKIs have been developed that is sensitising and T790M mutant-specific whilst sparing WT EGFR, representing a significant breakthrough in the treatment in NSCLC patients with acquired resistance harboring these genotypes. Herein, we provides an overview of the second and third generation inhibitors currently approved, in clinical trial and also encompasses novel structures of discovery. This review mainly focuses on drug resistance, their mechanisms of action, development of structure-activity relationships and binding modes. PMID- 28075526 TI - Cetuximab strongly enhances immune cell infiltration into liver metastatic sites in colorectal cancer. AB - Cetuximab has activity against colorectal cancers. Recent studies demonstrated that cetuximab induces antibody-dependent cell-mediated cytotoxicity via immune cells, and a new immune-related mechanism of inducing immunogenic cell death. This study aimed to evaluate the immune responses induced by cetuximab in tumor microenvironments at liver metastasis sites of metastatic colorectal cancer patients. We assessed immune cell infiltration in the liver metastatic sites of 53 colorectal cancer patients. These patients were divided into three groups according to the treatment before operation: chemotherapy with cetuximab, chemotherapy without cetuximab, and no chemotherapy. The inflammatory cells in the liver metastatic sites were assessed by hematoxylin-eosin staining, focusing on the invasive margin. The overall inflammatory reaction and number of lymphoid cells were assessed with a four-point scoring system. We then assessed immune cell infiltration (CD3, CD8 and CD56) in 15 liver metastatic sites. Hematoxylin eosin staining demonstrated more inflammatory cells in the chemotherapy with cetuximab group than in the other groups (P < 0.001). Of note, inflammatory cells were found in intratumoral areas, and the destruction of cancer cell foci was observed in the chemotherapy with cetuximab group. Moreover, a higher infiltration of CD3+ (P = 0.003), CD8+ (P = 0.003) and CD56+ (P = 0.001) cells was observed in the chemotherapy with cetuximab group than in the other groups. These results suggest that cetuximab might have an immune-enhancing effect. As such, the immune-related mechanism of action of cetuximab may enhance the efficacy of combination therapy, such as chemotherapy and immunotherapy using therapeutic peptides. PMID- 28075528 TI - Prospective Evaluation of Genetic Variation in Platelet Endothelial Aggregation Receptor 1 Reveals Aspirin-Dependent Effects on Platelet Aggregation Pathways. AB - Genetic variation in the platelet endothelial aggregation receptor 1 (PEAR1) gene, most notably rs12041331, is implicated in altered on-aspirin platelet aggregation and increased cardiovascular event risk. We prospectively tested the effects of aspirin administration at commonly prescribed doses (81, 162, and 324 mg/day) on agonist-induced platelet aggregation by rs12041331 genotype in 67 healthy individuals. Prior to aspirin administration, rs12041331 minor allele carriers had significantly reduced adenosine diphosphate (ADP)-induced platelet aggregation compared with noncarriers (P = 0.03) but was not associated with other platelet pathways. In contrast, rs12041331 was significantly associated with on-aspirin platelet aggregation when collagen and epinephrine were used to stimulate platelet aggregation (P < 0.05 for all associations), but not ADP. The influence of PEAR1 rs12041331 on platelet aggregation is pathway-specific and is altered by aspirin at therapeutic doses, but not in a dose-dependent manner. Additional studies are needed to determine the impact of PEAR1 on cardiovascular events in aspirin-treated patients. PMID- 28075531 TI - Three-dimensional imaging flow cytometry through light-sheet fluorescence microscopy. AB - Flow cytometry is the tool of choice for high-speed acquisition and analysis of large cell populations, with the tradeoff of lacking intracellular spatial information. Although in the last decades flow cytometry systems that can actually acquire two-dimensional spatial information were developed, some of the limitations remained though, namely constrains related to sample size and lack of depth or dynamic information. The combination of fluidics and light-sheet illumination has the potential to address these limitations. By having cells travelling with the flowing sheath one can, in a controlled fashion, force them at constant speed through the light-sheet enabling the synchronized acquisition of several optical sections, that is, three-dimensional imaging. This approach has already been used for imaging cellular spheroids, plankton, and zebra-fish embryos. In this review, we discuss the known solutions and standing challenges of performing three-dimensional high-throughput imaging of multicellular biological models using fluidics, while retaining cell and organelle-level resolution. (c) 2017 International Society for Advancement of Cytometry. PMID- 28075529 TI - Diabetes, hypertension, obesity, and long-term risk of renal disease mortality: Racial and socioeconomic differences. AB - AIMS/INTRODUCTION: Diabetes, hypertension, and obesity increase the risk of chronic kidney disease and associated mortality. Race and socioeconomic status (SES) differences in the effects of these risk factors are, however, still unknown. The current study aimed to investigate whether or not race and SES alter the effects of diabetes, hypertension, and obesity on mortality due to renal disease. MATERIALS AND METHODS: Data came from the Americans' Changing Lives Study, 1986-2011, a nationally representative prospective cohort of adults with 25 years of follow up. The study included 3,361 adults aged 25 years and older who were followed for up to 25 years. The outcome was death from renal disease. Diabetes, hypertension, and obesity were the main predictors. Race and SES (education, income, and employment) were moderators. Health behaviors and health status at baseline were covariates. We used Cox proportional hazards models for data analysis. RESULTS: In separate models, diabetes, hypertension, and obesity at baseline were associated with a higher risk of death from renal disease. From our SES indicators, education and income interacted with diabetes, hypertension, and obesity on death from renal disease. In a consistent pattern, diabetes, hypertension, and obesity showed stronger effects on the risk of death from renal disease among high-SES groups compared with low-SES individuals. Race and employment did not alter the effects of diabetes, hypertension and obesity on the risk of death from renal disease. CONCLUSIONS: Social groups differ in how diabetes, hypertension, and obesity influence health outcomes over long-term periods. Elimination of disparities in renal disease mortality in the USA requires understanding of the complex and non-linear effects of socioeconomic and medical risk factors on health outcomes. Multidisciplinary programs and policies are required to reduce social inequality in renal disease burden caused by diabetes, hypertension, and obesity. PMID- 28075530 TI - Dysregulation of PLDN (pallidin) is a mechanism for platelet dense granule deficiency in RUNX1 haplodeficiency. AB - : Essentials Platelet dense granule (DG) deficiency is a major abnormality in RUNX1 haplodeficiency patients. The molecular mechanisms leading to the platelet DG deficiency are unknown. Platelet expression of PLDN (BLOC1S6, pallidin), involved in DG biogenesis, is regulated by RUNX1. Downregulation of PLDN is a mechanism for DG deficiency in RUNX1 haplodeficiency. SUMMARY: Background Inherited RUNX1 haplodeficiency is associated with thrombocytopenia and platelet dysfunction. Dense granule (DG) deficiency has been reported in patients with RUNX1 haplodeficiency, but the molecular mechanisms are unknown. Platelet mRNA expression profiling in a patient previously reported by us with a RUNX1 mutation and platelet dysfunction showed decreased expression of PLDN (BLOC1S6), which encodes pallidin, a subunit of biogenesis of lysosome-related organelles complex 1 (BLOC-1) involved in DG biogenesis. PLDN mutations in the pallid mouse and Hermansky-Pudlak syndrome-9 are associated with platelet DG deficiency. Objectives We postulated that PLDN is a RUNX1 target, and that its decreased expression leads to platelet DG deficiency in RUNX1 haplodeficiency. Results Platelet pallidin and DG levels were decreased in our patient. This was also observed in two siblings from a different family with a RUNX1 mutation. Chromatin immunoprecipitation and electrophoretic mobility shift assays with phorbol ester treated human erythroleukemia (HEL) cells showed RUNX1 binding to RUNX1 consensus sites in the PLDN1 5' upstream region. In luciferase reporter studies, mutation of RUNX1 sites in the PLDN promoter reduced activity. RUNX1 overexpression enhanced and RUNX1 downregulation decreased PLDN1 promoter activity and protein expression. RUNX1 downregulation resulted in impaired handling of mepacrine and mislocalization of the DG marker CD63 in HEL cells, indicating impaired DG formation, recapitulating findings on PLDN downregulation. Conclusions These studies provide the first evidence that PLDN is a direct target of RUNX1 and that its dysregulation is a mechanism for platelet DG deficiency associated with RUNX1 haplodeficiency. PMID- 28075533 TI - Corrigendum. PMID- 28075532 TI - Clinical and biochemical characterization of the prothrombin Belgrade mutation in a large Serbian pedigree: new insights into the antithrombin resistance mechanism. AB - : Essentials Prothrombin Belgrade mutation leads to antithrombin resistance. Clinical and biochemical phenotypes in a large family with this mutation were investigated. In carriers, we detected decreased factor II activity and increased endogenous thrombin potential. Prothrombin Belgrade mutation represents a strong prothrombotic risk factor. SUMMARY: Background The recently reported c.1787G>A mutation in the prothrombin gene leads to Arg596Gln replacement in the protein molecule (prothrombin Belgrade). This substitution impairs binding of antithrombin to thrombin and results in inherited thrombophilia, known as antithrombin resistance. Objectives We aimed to elucidate the clinical and biochemical characteristics of thrombophilia associated with antithrombin resistance in a large Serbian family with the prothrombin Belgrade mutation. Patients and methods Nineteen family members were investigated, among whom 10 were carriers of the c.1787G>A mutation. In all subjects the clinical phenotype was determined and laboratory investigations of hemostatic parameters were performed. Results Six out of the 10 mutation carriers developed thromboembolic events, mainly deep venous and mesenteric vein thrombosis. The median age of the first thrombotic event was 26.5 (12-41) years, whereas the incidence rate of first thrombosis was 2.2% per year. In all mutation carriers prothrombin activity was significantly decreased in comparison with non-carriers, clearly distinguishing each group. However, the presence of the mutation did not affect the prothrombin antigen level in plasma. The endogenous thrombin potential was significantly increased in all carriers in comparison with non-carriers, indicating the presence of blood hypercoagulability. Interestingly, levels of D dimer and the F1+2 fragment were similar in both groups. Conclusions Although rare, the prothrombin Belgrade mutation represents strong thrombophilia with early onset of thrombosis in the investigated family. According to our results, decreased prothrombin activity may be a simple screening test for detection of this mutation in thrombotic patients. PMID- 28075534 TI - Commentary on Wilson et al. (2016): The meaning of success in failure. PMID- 28075535 TI - Response to Smith and Brogly et al. commentaries on Zedler et al. PMID- 28075536 TI - Commentary on Greenland (2016): Tobacco companies' response to plain packaging in Australia and implications for tobacco control. PMID- 28075537 TI - The comparative safety of buprenorphine versus methadone in pregnancy-what about confounding? PMID- 28075539 TI - Commentary on Nardone et al. (2016): Satisfaction, dissatisfaction and complicating the nicotine-reduction strategy with more nicotine. PMID- 28075540 TI - Zero is an important number. PMID- 28075542 TI - Considering marijuana legalization carefully: insights for other jurisdictions from analysis for Vermont. AB - BACKGROUND AND AIMS: In 2014 the legislature of Vermont, USA passed a law requiring the Secretary of Administration to report on the consequences of legalizing marijuana. The RAND Corporation was commissioned to write that report. This paper summarizes insights from that analysis that are germane to other jurisdictions. METHOD: Translation of key findings from the RAND Corporation report to the broader policy debate. RESULTS: Marijuana legalization encompasses a wide range of possible regimes, distinguished along at least four dimensions: which organizations are allowed to produce and supply the drug, the regulations under which they operate, the nature of the products that can be distributed and taxes and prices. Vermont's decriminalization had already cut its costs of enforcing marijuana prohibition against adults to about $1 per resident per year. That is probably less than the cost of regulating a legal market. Revenues from taxing residents' purchases after legalization could be many times that amount, so the main fiscal cost of prohibition after decriminalization relative to outright legalization may be foregone tax revenues, not enforcement costs. Approximately 40 times as many users live within 200 miles of Vermont's borders as live within the state; drug tourism and associated tax revenues will be important considerations, as will be the response of other states. Indeed, if another state legalized with lower taxes, that could undermine the ability to collect taxes on even Vermont residents' purchases. CONCLUSIONS: Analysis of possible outcomes if Vermont, USA, legalized marijuana reveal that choices about how, and not just whether, to legalize a drug can have profound consequences for the effects on health and social wellbeing, and the choices of one jurisdiction can affect the options and incentives available to other jurisdictions. PMID- 28075543 TI - Prognostic value of tissue-based biomarker signature in clear cell renal cell carcinoma. AB - OBJECTIVE: To improve risk stratification for recurrence prognostication in patients with localised clear cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS: In all, 367 patients with non-metastatic ccRCC were included. The cohort was divided into a training and validation set. Using tissue microarrays, immunostaining was performed for 24 biomarkers representative of key pathways in ccRCC. Using Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression, we identified several markers that were used to construct a risk classifier for risk of disease recurrence. RESULTS: The median (interquartile range) follow-up was 63.5 (24.0-85.3) months. Five out of 24 markers were selected by LASSO Cox regression for the risk classifier: N-cadherin, E-cadherin, Ki67, cyclin D1 and phosphorylated eukaryotic initiation factor 4E binding protein-1 (p-4EBP1). Patients were classified as either low, intermediate or high risk of disease recurrence by tertiles of risk score. The 5-year recurrence-free survival (RFS) was 93.8%, 87.7% and 70% for patients with low-, intermediate- and high-risk scores, respectively (P < 0.001). Patients with a high marker score had worse RFS on multivariate analysis adjusted for age, gender, race and the Mayo Clinic Stage, Size, Grade, and Necrosis (SSIGN) score (hazard ratio 3.66, 95% confidence interval 1.58-8.49, P = 0.003 for high vs low marker score in the overall cohort). The five-marker classifier increased the concordance index of the clinical model in both the training and validation sets. CONCLUSION: We developed a five-marker-based prognostic tool that can effectively classify patients with ccRCC according to risk of disease recurrence after surgery. This tool, if prospectively validated, could provide individualised risk estimation for patients with ccRCC. PMID- 28075545 TI - Fetal growth and parental cardiovascular risk: preterm birth matters. PMID- 28075544 TI - The impact of Type 2 diabetes prevention programmes based on risk-identification and lifestyle intervention intensity strategies: a cost-effectiveness analysis. AB - AIMS: To develop a cost-effectiveness model to compare Type 2 diabetes prevention programmes targeting different at-risk population subgroups with a lifestyle intervention of varying intensity. METHODS: An individual patient simulation model was constructed to simulate the development of diabetes in a representative sample of adults without diabetes from the UK population. The model incorporates trajectories for HbA1c , 2-h glucose, fasting plasma glucose, BMI, systolic blood pressure, total cholesterol and HDL cholesterol. Patients can be diagnosed with diabetes, cardiovascular disease, microvascular complications of diabetes, cancer, osteoarthritis and depression, or can die. The model collects costs and utilities over a lifetime horizon. The perspective is the UK National Health Service and personal social services. We used the model to evaluate the population-wide impact of targeting a lifestyle intervention of varying intensity to six population subgroups defined as high risk for diabetes. RESULTS: The intervention produces 0.0003 to 0.0009 incremental quality-adjusted life years and saves up to L1.04 per person in the general population, depending upon the subgroup targeted. Cost-effectiveness increases with intervention intensity. The most cost-effective options are to target individuals with HbA1c > 42 mmol/mol (6%) or with a high Finnish Diabetes Risk (FINDRISC) probability score (> 0.1). CONCLUSION: The model indicates that diabetes prevention interventions are likely to be cost-effective and may be cost-saving over a lifetime. In the model, the criteria for selecting at-risk individuals differentially impact upon diabetes and cardiovascular disease outcomes, and on the timing of benefits. These findings have implications for deciding who should be targeted for diabetes prevention interventions. PMID- 28075546 TI - Matrix pathobiology-central roles for proteoglycans and heparanase in health and disease. AB - This thematic minireview series highlights new concepts in matrix pathobiology. The reviews in this series cover the roles of the two matrix proteoglycans, decorin and biglycan, in inflammation and autophagy, the various functions of syndecans in cancer development and prognosis and the recently discovered mechanisms underlying the multiple roles of heparanase in cancer progression, inflammation, and autophagy. PMID- 28075548 TI - Triindole-Tris-Alkynyl-Bridged Trinuclear Gold(I) Complexes for Cooperative Supramolecular Self-Assembly and Small-Molecule Solution-Processable Resistive Memories. AB - A novel class of luminescent trinuclear alkynylgold(I) complexes with N-alkyl substituted triindole ligands has been synthesized and characterized. They are found to exhibit rich photophysical and electrochemical properties. The complexes have been demonstrated to display interesting supramolecular assembly with spherical nanostructures in aqueous THF solution through a cooperative growth mechanism. The self-assembly process is shown to be mediated by the pi-pi stacking interactions and hydrophobic-hydrophobic interactions of the triindole moieties upon solvent modulation. These gold(I) complexes have been employed as active materials in the fabrication of solution-processable resistive memory devices, showing promising binary memory performances with low switching threshold voltages of ca. 1.5 V, high ON/OFF current ratio of up to 105, long retention time of over 104 s, and excellent stability. The present work opens up a new avenue for the future design of versatile organogold(I) complexes that could serve as multifunctional materials. PMID- 28075549 TI - Solvent-Morphology-Property Relationship of PTB7:PC71BM Polymer Solar Cells. AB - The influence of three different solvents and a solvent additive on the morphology and photovoltaic performance of bulk heterojunction films made of the copolymer based on thieno[3,4-b]thiophene-alt-benzodithiophene unit PTB7-F40 blended with [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM) is investigated. Optical microscopy and atomic force microscopy are combined with X-ray reflectivity and grazing incidence small and wide-angle X-ray scattering (GISAXS and GIWAXS, respectively), enabling the characterization of the morphology of the whole photoactive film. The detailed study reveals that different length scales of PCBM clusters are observed using different solvents, while adding a solvent additive results in the PCBM clusters being selectively dissolved. Vertical and lateral phase separation occurs during spin coating and depends on the solvent used. A hierarchical morphology is detected within the bulk film through GISAXS measurements. Furthermore, GIWAXS shows that a rather amorphous film with low crystallinity was probed, which substantiates that high crystallinity is not necessarily required for high performance organic solar cells. Different models for the morphology are proposed through the combination of all the findings and correlated with the corresponding device properties. Consequently, the solvent induced different device performance is mainly ascribed to the varied lateral structure sizes, whereas the highest device performance is a result of the smallest average multilength scale lateral structure sizes with the smallest length scale matching the exciton diffusion length. PMID- 28075550 TI - Vascularization in Engineered Tissue Construct by Assembly of Cellular Patterned Micromodules and Degradable Microspheres. AB - Tissue engineering aims to generate functional tissue constructs in which proper extracellular matrix (ECM) for cell survival and establishment of a vascular network are necessary. A modular approach via the assembly of modules mimicking the complex tissues' microarchitectural features and establishing a vascular network represents a promising strategy for fabricating larger and more complex tissue constructs. Herein, as a model for this modular tissue engineering, engineered bone-like constructs were developed by self-assembly of osteon-like modules and fast degradable gelatin microspheres. The collagen microspheres acting as osteon-like modules were developed by seeding human umbilical vein endothelial cells (HUVECs) onto collagen microspheres laden with human osteoblast like cells (MG63) and collagenase. Both HUVECs and MG63 cells were well spatially patterned in the modules, and collagen as ECM well supported cell adhesion, spreading, and functional expression due to its native RGD domains and enzymatic degradation activity. The patterned modules facilitated both the cellular function expression of osteogenic MG63 cells and vasculogenic HUVECs; that is, the osteon-like units were successfully achieved. The assembly of the osteon-like modules and fast degradable gelatin microspheres promoted the vascularization, thus facilitating the osteogenic function expression. The study provides a highly efficient approach to engineering complex 3D tissues with micropatterned cell types and interconnected channels. PMID- 28075551 TI - Cucurbit[n]uril-Based Microcapsules Self-Assembled within Microfluidic Droplets: A Versatile Approach for Supramolecular Architectures and Materials. AB - Microencapsulation is a fundamental concept behind a wide range of daily applications ranging from paints, adhesives, and pesticides to targeted drug delivery, transport of vaccines, and self-healing concretes. The beauty of microfluidics to generate microcapsules arises from the capability of fabricating monodisperse and micrometer-scale droplets, which can lead to microcapsules/particles with fine-tuned control over size, shape, and hierarchical structure, as well as high reproducibility, efficient material usage, and high-throughput manipulation. The introduction of supramolecular chemistry, such as host-guest interactions, endows the resultant microcapsules with stimuli-responsiveness and self-adjusting capabilities, and facilitates hierarchical microstructures with tunable stability and porosity, leading to the maturity of current microencapsulation industry. Supramolecular architectures and materials have attracted immense attention over the past decade, as they open the possibility to obtain a large variety of aesthetically pleasing structures, with myriad applications in biomedicine, energy, sensing, catalysis, and biomimicry, on account of the inherent reversible and adaptive nature of supramolecular interactions. As a subset of supramolecular interactions, host-guest molecular recognition involves the formation of inclusion complexes between two or more moieties, with specific three-dimensional structures and spatial arrangements, in a highly controllable and cooperative manner. Such highly selective, strong yet dynamic interactions could be exploited as an alternative methodology for programmable and controllable engineering of supramolecular architectures and materials, exploiting reversible interactions between complementary components. Through the engineering of molecular structures, assemblies can be readily functionalized based on host-guest interactions, with desirable physicochemical characteristics. In this Account, we summarize the current state of development in the field of monodisperse supramolecular microcapsules, fabricated through the integration of traditional microfluidic techniques and interfacial host-guest chemistry, specifically cucurbit[n]uril (CB[n])-mediated host-guest interactions. Three different strategies, colloidal particle-driven assembly, interfacial condensation-driven assembly and electrostatic interaction-driven assembly, are classified and discussed in detail, presenting the methodology involved in each microcapsule formation process. We highlight the state-of-the-art in design and control over structural complexity with desirable functionality, as well as promising applications, such as cargo delivery stemming from the assembled microcapsules. On account of its dynamic nature, the CB[n]-mediated host-guest complexation has demonstrated efficient response toward various external stimuli such as UV light, pH change, redox chemistry, and competitive guests. Herein, we also demonstrate different microcapsule modalities, which are engineered with CB[n] host-guest chemistry and also can be disrupted with the aid of external stimuli, for triggered release of payloads. In addition to the overview of recent achievements and current limitations of these microcapsules, we finally summarize several perspectives on tunable cargo loading and triggered release, directions, and challenges for this technology, as well as possible strategies for further improvement, which will lead to substainitial progress of host-guest chemistry in supramolecular architectures and materials. PMID- 28075552 TI - Nanoparticles Coated with Neutrophil Membranes Can Effectively Treat Cancer Metastasis. AB - The dissemination, seeding, and colonization of circulating tumor cells (CTCs) serve as the root of distant metastasis. As a key step in the early stage of metastasis formation, colonization of CTCs in the (pre-)metastatic niche appears to be a valuable target. Evidence showed that inflammatory neutrophils possess both a CTC- and niche-targeting property by the intrinsic cell adhesion molecules on neutrophils. Inspired by this mechanism, we developed a nanosize neutrophil mimicking drug delivery system (NM-NP) by coating neutrophils membranes on the surface of poly(latic-co-glycolic acid) nanoparticles (NPs). The membrane associated protein cocktails on neutrophils membrane were mostly translocated to the surface of NM-NP via a nondisruptive approach, and the biobinding activity of neutrophils was highly preserved. Compared with uncoated NP, NM-NP exhibited enhanced cellular association in 4T1 cell models under shear flow in vitro, much higher CTC-capture efficiency in vivo, and improved homing to the premetastatic niche. Following loading with carfilzomib, a second generation of proteasome inhibitor, the NM-NP-based nanoformulation (NM-NP-CFZ) selectively depleted CTCs in the blood, prevented early metastasis and potentially inhibited the progress of already-formed metastasis. Our NP design can neutralize CTCs in the circulation and inhibit the formation of a metastatic niche. PMID- 28075553 TI - Double-Layer Graphene Outperforming Monolayer as Catalyst on Silicon Photocathode for Hydrogen Production. AB - Photoelectrochemical cells are used to split hydrogen and oxygen from water molecules to generate chemical fuels to satisfy our ever-increasing energy demands. However, it is a major challenge to design efficient catalysts to use in the photoelectochemical process. Recently, research has focused on carbon-based catalysts, as they are nonprecious and environmentally benign. Interesting advances have also been made in controlling nanostructure interfaces and in introducing new materials as catalysts in the photoelectrochemical cell. However, these catalysts have as yet unresolved issues involving kinetics and light transmittance. In this work, we introduce high-transmittance graphene onto a planar p-Si photocathode to produce a hydrogen evolution reaction to dramatically enhance photon-to-current efficiency. Interestingly, double-layer graphene/Si exhibits noticeably improved photon-to-current efficiency and modifies the band structure of the graphene/Si photocathode. On the basis of in-depth electrochemical and electrical analyses, the band structure of graphene/Si was shown to result in a much lower work function than Si, accelerating the electron to-hydrogen production potential. Specifically, plasma-treated double-layer graphene exhibited the best performance and the lowest work function. We electrochemically analyzed the mechanism at work in the graphene-assisted photoelectrode. Atomistic calculations based on the density functional theory were also carried out to more fully understand our experimental observations. We believe that investigation of the underlying mechanism in this high-performance electrode is an important contribution to efforts to develop high-efficiency metal-free carbon-based catalysts for photoelectrochemical cell hydrogen production. PMID- 28075554 TI - An Engineered Allele of afsQ1 Facilitates the Discovery and Investigation of Cryptic Natural Products. AB - New approaches to antimicrobial discovery are needed to address the growing threat of antibiotic resistance. The Streptomyces genus, a proven source of antibiotics, is recognized as having a large reservoir of untapped secondary metabolic genes, many of which are likely to produce uncharacterized compounds. However, most of these compounds are currently inaccessible, as they are not expressed under standard laboratory conditions. Here, we present a novel methodology for activating these "cryptic" metabolites by heterologously expressing a constitutively active pleiotropic regulator. By screening wild Streptomyces isolates, we identified the antibiotic siamycin-I, a lasso peptide that we show is active against multidrug pathogens. We further revealed that siamycin-I interferes with cell wall integrity via lipid II. This new technology has the potential to be broadly applied for use in the discovery of additional "cryptic" metabolites. PMID- 28075555 TI - Familial Mutations May Switch Conformational Preferences in alpha-Synuclein Fibrils. AB - The pathogenesis of Parkinson's disease is closely associated with the aggregation of the alpha-synuclein protein. Several familial mutants have been identified and shown to affect the aggregation kinetics of alpha-synuclein through distinct molecular mechanisms. Quantitative evaluation of the relative stabilities of the wild type and mutant fibrils is crucial for understanding the aggregation process and identifying the key component steps. In this work, we examined two topologically different alpha-synuclein fibril structures that are either determined by solid-state NMR method or modeled based on solid-state NMR data, and characterized their conformational properties and thermodynamic stabilities using molecular dynamics simulations. We show that the two fibril morphologies have comparable size, solvent exposure, secondary structures, and similar molecule/peptide binding modes; but different stabilities. Familial mutations do not significantly alter the overall fibril structures but shift their relative stabilities. Distinct mutations display altered fibril conformational behavior, suggesting different propagation preferences, reminiscent of cross-seeding among prion strains and tau deletion mutants. The simulations quantify the hydrophobic and electrostatic interactions, as well as N terminal dynamics, that may contribute to the divergent aggregation kinetics that has been observed experimentally. Our results indicate that small molecule and peptide inhibitors may share the same binding region, providing molecular recognition that is independent of fibril conformation. PMID- 28075557 TI - Facile Synthesis of Magnetic Covalent Organic Framework with Three-Dimensional Bouquet-Like Structure for Enhanced Extraction of Organic Targets. AB - A facile strategy for the fabrication of novel bouquet-shaped magnetic porous nanocomposite via grafting a covalent organic framework (COF, TpPa-1) onto the surface-modified Fe3O4 nanoparticles (Fe3O4 NPs) was reported. The magnetic TpPa 1 (a COF synthesized from 1,3,5-triformylphloroglucinol (Tp) and p phenylenediamine (Pa-1)) contains clusters of core-shell magnetic nanoparticles and interconnected porous TpPa-1 nanofibers. Thus, it possesses larger specific surface area, higher porosity, and supermagnetism, making it an ideal sorbent for enrichment of trace analytes. Its performance was evaluated by the magnetic solid phase extraction (MSPE) of trace polycyclic aromatic hydrocarbons (PAHs) from environmental samples prior to high-performance liquid chromatographic analysis. The results indicated that the magnetic TpPa-1 possessed superior enrichment capacity of such organic compounds. PMID- 28075556 TI - Biosynthesis of the Methylthioxylose Capping Motif of Lipoarabinomannan in Mycobacterium tuberculosis. AB - Lipoarabinomannan (LAM) is a lipoglycan found in abundant quantities in the cell envelope of all mycobacteria. The nonreducing arabinan termini of LAM display species-specific structural microheterogeneity that impacts the biological activity of the entire molecule. Mycobacterium tuberculosis, for instance, produces mannoside caps made of one to three alpha-(1 -> 2)-Manp-linked residues that may be further substituted with an alpha-(1 -> 4)-linked methylthio-d-xylose (MTX) residue. While the biological functions and catalytic steps leading to the formation of the mannoside caps of M. tuberculosis LAM have been well established, the biosynthetic origin and biological relevance of the MTX motif remain elusive. We here report on the discovery of a five-gene cluster dedicated to the biosynthesis of the MTX capping motif of M. tuberculosis LAM, and on the functional characterization of two glycosyltransferases, MtxS and MtxT, responsible, respectively, for the production of decaprenyl-phospho-MTX (DP-MTX) and the transfer of MTX from DP-MTX to the mannoside caps of LAM. Collectively, our NMR spectroscopic and mass spectrometric analyses of mtxS and mtxT overexpressors and knockout mutants support a biosynthetic model wherein the conversion of 5'-methylthioadenosine, which is a ubiquitous byproduct of spermidine biosynthesis, into 5'-methylthioribose-1-phosphate precedes the formation of a 5'-methylthioribose nucleotide sugar, followed by the epimerization at C-3 of the ribose residue, and the transfer of MTX from the nucleotide sugar to decaprenyl-phosphate yielding the substrate for transfer onto LAM. The conservation of the MTX biosynthetic genes in a number of Actinomycetes suggests that this discrete glycosyl substituent may be more widespread in prokaryotes than originally thought. PMID- 28075558 TI - Immunological Principles Guiding the Rational Design of Particles for Vaccine Delivery. AB - Despite the immense public health successes of immunization over the past century, effective vaccines are still lacking for globally important pathogens such as human immunodeficiency virus, malaria, and tuberculosis. Exciting recent advances in immunology and biotechnology over the past few decades have facilitated a shift from empirical to rational vaccine design, opening possibilities for improved vaccines. Some of the most important advancements include (i) the purification of subunit antigens with high safety profiles, (ii) the identification of innate pattern recognition receptors (PRRs) and cognate agonists responsible for inducing immune responses, and (iii) developments in nano- and microparticle fabrication and characterization techniques. Advances in particle engineering now allow highly tunable physicochemical properties of particle-based vaccines, including composition, size, shape, surface characteristics, and degradability. Enhanced collaborative efforts between researchers in immunology and materials science are expected to rise to next generation vaccines. This process will be significantly aided by a greater understanding of the immunological principles guiding vaccine antigenicity, immunogenicity, and efficacy. With specific emphasis on PRR-targeted adjuvants and particle physicochemical properties, this review aims to provide an overview of the current literature to guide and focus rational particle-based vaccine design efforts. PMID- 28075560 TI - Multilayer-Grown Ultrathin Nanostructured GaAs Solar Cells as a Cost-Competitive Materials Platform for III-V Photovoltaics. AB - Large-scale deployment of GaAs solar cells in terrestrial photovoltaics demands significant cost reduction for preparing device-quality epitaxial materials. Although multilayer epitaxial growth in conjunction with printing-based materials assemblies has been proposed as a promising route to achieve this goal, their practical implementation remains challenging owing to the degradation of materials properties and resulting nonuniform device performance between solar cells grown in different sequences. Here we report an alternative approach to circumvent these limitations and enable multilayer-grown GaAs solar cells with uniform photovoltaic performance. Ultrathin single-junction GaAs solar cells having a 300-nm-thick absorber (i.e., emitter and base) are epitaxially grown in triple-stack releasable multilayer assemblies by molecular beam epitaxy using beryllium as a p-type impurity. Microscale (~500 * 500 MUm2) GaAs solar cells fabricated from respective device layers exhibit excellent uniformity (<3% relative) of photovoltaic performance and contact properties owing to the suppressed diffusion of p-type dopant as well as substantially reduced time of epitaxial growth associated with ultrathin device configuration. Bifacial photon management employing hexagonally periodic TiO2 nanoposts and a vertical p-type metal contact serving as a metallic back-surface reflector together with specialized epitaxial design to minimize parasitic optical losses for efficient light trapping synergistically enable significantly enhanced photovoltaic performance of such ultrathin absorbers, where ~17.2% solar-to-electric power conversion efficiency under simulated AM1.5G illumination is demonstrated from 420-nm-thick single-junction GaAs solar cells grown in triple-stack epitaxial assemblies. PMID- 28075559 TI - One-Component Supramolecular Filament Hydrogels as Theranostic Label-Free Magnetic Resonance Imaging Agents. AB - Gadolinium (Gd)-based compounds and materials are the most commonly used magnetic resonance imaging (MRI) contrast agents in the clinic; however, safety concerns associated with their toxicities in the free ionic form have promoted the development of new generations of metal-free contrast agents. Here we report a supramolecular strategy to convert an FDA-approved anticancer drug, Pemetrexed (Pem), to a molecular hydrogelator with inherent chemical exchange saturation transfer (CEST) MRI signals. The rationally designed drug-peptide conjugate can spontaneously associate into filamentous assemblies under physiological conditions and consequently form theranostic supramolecular hydrogels for injectable delivery. We demonstrated that the local delivery and distribution of Pem-peptide nanofiber hydrogels can be directly assessed using CEST MRI in a mouse glioma model. Our work lays out the foundation for the development of drug constructed theranostic supramolecular materials with an inherent CEST MRI signal that enables noninvasive monitoring of their in vivo distribution and drug release. PMID- 28075561 TI - Selective Tuning of Elastin-like Polypeptide Properties via Methionine Oxidation. AB - We have designed and prepared a recombinant elastin-like polypeptide (ELP) containing precisely positioned methionine residues, and performed the selective and complete oxidation of its methionine thioether groups to both sulfoxide and sulfone derivatives. Since these oxidation reactions substantially increase methionine residue polarity, they were found to be a useful means to precisely adjust the temperature responsive behavior of ELPs in aqueous solutions. In particular, lower critical solution temperatures were found to be elevated in oxidized sample solutions, but were not eliminated. These transition temperatures were found to be further tunable by the use of solvents containing different Hofmeister salts. Overall, the ability to selectively and fully oxidize methionine residues in ELPs proved to be a convenient postmodification strategy for tuning their transition temperatures in aqueous media. PMID- 28075563 TI - Particulate Formation from a Copper Oxide-Based Oxygen Carrier in Chemical Looping Combustion for CO2 Capture. AB - Attrition behavior and particle loss of a copper oxide-based oxygen carrier from a methane chemical looping combustion (CLC) process was investigated in a fluidized bed reactor. The aerodynamic diameters of most elutriated particulates, after passing through a horizontal settling duct, range between 2 and 5 MUm. A notable number of submicrometer particulates are also identified. Oxygen carrier attrition was observed to lead to increased CuO loss resulting from the chemical looping reactions, i.e., Cu is enriched in small particles generated primarily from fragmentation in the size range of 10-75 MUm. Cyclic reduction and oxidation reactions in CLC have been determined to weaken the oxygen carrier particles, resulting in increased particulate emission rates when compared to those of oxygen carriers without redox reactions. The generation rate for particulates <10 MUm was found to decrease with progressive cycles over as-prepared oxygen carrier particles and then reach a steady state. The surface of the oxygen carrier is also found to be coarsened due to a Kirkendall effect, which also explains the enrichment of Cu on particle surfaces and in small particles. PMID- 28075562 TI - Evidence for a Di-MU-oxo Diamond Core in the Mn(IV)/Fe(IV) Activation Intermediate of Ribonucleotide Reductase from Chlamydia trachomatis. AB - High-valent iron and manganese complexes effect some of the most challenging biochemical reactions known, including hydrocarbon and water oxidations associated with the global carbon cycle and oxygenic photosynthesis, respectively. Their extreme reactivity presents an impediment to structural characterization, but their biological importance and potential chemical utility have, nevertheless, motivated extensive efforts toward that end. Several such intermediates accumulate during activation of class I ribonucleotide reductase (RNR) beta subunits, which self-assemble dimetal cofactors with stable one electron oxidants that serve to initiate the enzyme's free-radical mechanism. In the class I-c beta subunit from Chlamydia trachomatis, a heterodinuclear Mn(II)/Fe(II) complex reacts with dioxygen to form a Mn(IV)/Fe(IV) intermediate, which undergoes reduction of the iron site to produce the active Mn(IV)/Fe(III) cofactor. Herein, we assess the structure of the Mn(IV)/Fe(IV) activation intermediate using Fe- and Mn-edge extended X-ray absorption fine structure (EXAFS) analysis and multifrequency pulse electron paramagnetic resonance (EPR) spectroscopy. The EXAFS results reveal a metal-metal vector of 2.74-2.75 A and an intense light-atom (C/N/O) scattering interaction 1.8 A from the Fe. Pulse EPR data reveal an exchangeable deuterium hyperfine coupling of strength |T| = 0.7 MHz, but no stronger couplings. The results suggest that the intermediate possesses a di-MU-oxo diamond core structure with a terminal hydroxide ligand to the Mn(IV). PMID- 28075564 TI - Spatiotemporal Trends of Heavy Metals in Indo-Pacific Humpback Dolphins (Sousa chinensis) from the Western Pearl River Estuary, China. AB - We assessed the spatiotemporal trends of the concentrations of 11 heavy metals (HMs) in the liver and kidney of Indo-Pacific humpback dolphins (Sousa chinensis) from western Pearl River Estuary (PRE) during 2004-2015. The hepatic levels of Cr, As, and Cu in these dolphins were among the highest reported for cetaceans globally, and the levels of Zn, Cu, and Hg were sufficiently high to cause toxicological effects in some of the animals. Between same age-sex groups, dolphins from Lingdingyang were significantly more contaminated with Hg, Se, and V than those from the West-four region, while the opposite was true for Cd. Generalized additive mixed models showed that most metals had significant but dissimilar temporal trends over a 10-year period. The concentrations of Cu and Zn increased significantly in recent years, corresponding to the high input of these metals in the region. Body-length-adjusted Cd levels peaked in 2012, accompanied by the highest annual number of dolphin stranding events. In contrast to the significant decrease in HM levels in the dolphins in Hong Kong waters (the eastern reaches of the PRE), the elevated metal exposure in the western PRE raises serious concerns. PMID- 28075565 TI - Redox Couple Involving NOx in Aerobic Pd-Catalyzed Oxidation of sp3-C-H Bonds: Direct Evidence for Pd-NO3-/NO2- Interactions Involved in Oxidation and Reductive Elimination. AB - NaNO3 is used in oxidative Pd-catalyzed processes as a complementary co-catalyst to common oxidants, e.g., CuII salts, in C-H bond activation and Wacker oxidation processes. NaNO3 and NaNO2 (with air or O2) assist the sp3-C-H bond acetoxylation of substrates bearing an N-directing group. It has been proposed previously that a redox couple is operative. The role played by NOx anions is examined in this investigation. Evidence for an NOx anion interaction at PdII is presented. Palladacyclic complexes containing NOx anions are competent catalysts for acetoxylation of 8-methylquinoline, with and without exogenous NaNO3. The oxidation of 8-methylquinoline to the corresponding carboxylic acid has also been noted at PdII. 18O-Labeling studies indicate that oxygen derived from nitrate appears in the acetoxylation product, the transfer of which can only occur by interaction of 18O at Pd with a coordinating-acetate ligand. Nitrated organic intermediates are formed under catalytic conditions, which are converted to acetoxylation products, a process that occurs with (50 degrees C) and without Pd (110 degrees C). A catalytically competent palladacyclic dimer intermediate has been identified. Head-space analysis measurements show that NO and NO2 gases are formed within minutes on heating catalytic mixtures to 110 degrees C from room temperature. Measurements by in situ infrared spectroscopy show that N2O is formed in sp3-C-H acetoxylation reactions at 80 degrees C. Studies confirm that cyclopalladated NO2 complexes are rapidly oxidized to the corresponding NO3 adducts on exposure to NO2(g). The investigation shows that NOx anions act as participating ligands at PdII in aerobic sp3-C-H bond acetoxylation processes and are involved in redox processes. PMID- 28075566 TI - Chilling Stress Upregulates alpha-Linolenic Acid-Oxidation Pathway and Induces Volatiles of C6 and C9 Aldehydes in Mango Fruit. AB - Mango-fruit storage period and shelf life are prolonged by cold storage. However, chilling temperature induces physiological and molecular changes, compromising fruit quality. In our previous transcriptomic study of mango fruit, cold storage at suboptimal temperature (5 degrees C) activated the alpha-linolenic acid metabolic pathway. To evaluate changes in fruit quality during chilling, we analyzed mango "Keitt" fruit peel volatiles. GC-MS analysis revealed significant modulations in fruit volatiles during storage at suboptimal temperature. Fewer changes were seen in response to the time of storage. The mango volatiles related to aroma, such as delta-3-carene, (Z)-beta-ocimene, and terpinolene, were downregulated during the storage at suboptimal temperature. In contrast, C6 and C9 aldehydes and alcohols-alpha-linolenic acid derivatives 1-hexanal, (Z)-3 hexenal, (Z)-3-hexenol, (E)-2-hexenal, and nonanal-were elevated during suboptimal-temperature storage, before chilling-injury symptoms appeared. Detection of those molecules before chilling symptoms could lead to a new agro technology to avoid chilling injuries and maintain fruit quality during cold storage at the lowest possible temperature. PMID- 28075567 TI - Facile Syntheses of Ba2[B4O7(OH)2] and Na[B5O7(OH)2](H2O) Borate Salts Exhibiting Nonlinear Optical Activity in the Ultraviolet. AB - Two novel noncentrosymmetric metal borates, Ba2[B4O7(OH)2] (1) and Na[B5O7(OH)2](H2O) (2), have been obtained by hydrothermal and surfactant-thermal means. Compound 1 consists of novel one-dimensional borate chains formed by B3O9 and B3O8 rings, assembled into a three-dimensional (3D) framework by Ba2+ cations. The structure of 2 exhibits double-helical chains constructed from B5O10 primary building units, which are interconnected via Na+ cations and H-bonding interactions to generate a 3D framework. Second-harmonic-generation (SHG) measurements show that 1 shows a phase-matching powder SHG response of ~2.2 * KH2PO4 (KDP), while 2 exhibits a weak SHG response. The cutoff edges of 1 and 2 are ~242 and ~221 nm, respectively, which suggests that they are potential ultraviolet nonlinear optical (NLO) materials. Band structures and NLO properties have also been theoretically studied. PMID- 28075568 TI - Reaction Pathways and Kinetics of a Cyanobacterial Neurotoxin beta-N-Methylamino L-Alanine (BMAA) during Chlorination. AB - beta-N-Methylamino-L-alanine (BMAA), a probable cause of the amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC), or Alzheimer's disease, has been identified in more than 20 cyanobacterial genera. However, its removal and fate in drinking water has never been reported before. In this study, the reaction of BMAA with chlorine, a common drinking-water oxidant/disinfectant, was investigated. A liquid chromatograph coupled with a triple quadrupole mass spectrometer was employed to quantify BMAA and its intermediates. Upon chlorination, four chlorinated intermediates, each with one or two chlorines, were identified. The disappearance of BMAA caused by chlorine follows a second order reaction, with the rate constant k1 is 5.0 * 104 M-1 s-1 at pH ~7.0. The chlorinated intermediates were found to further react with free chlorine, exhibiting a second-order rate constant k3 = 16.8 M-1 s-1. After all free chlorine was consumed, the chlorinated intermediates autodecomposed slowly with a first order rate constant k2 = 0.003 min-1; when a reductant was added, these chlorinated intermediates were then reduced back to BMAA. The results as described shed a useful light on the reactivity, appearance, and removal of BMAA in the chlorination process of a drinking-water system. PMID- 28075570 TI - Contrasting Behavior of the Z Bonds in X-Z...Y Weak Interactions: Z = Main Group Elements Versus the Transition Metals. AB - In contrast to the increasing family of weak intermolecular interactions in main group compounds (X-Z...Y, Z = main-group elements), an analysis of the Cambridge Structural Database indicates that electron-saturated (18-electron) transition metal complexes show reluctance toward weak M bond formation (X-M...Y, M = transition metal). In particular, weak M bonds involving electron-saturated (18 electron) complexes of transition metals with partially filled d-orbitals are not found. We propose that the nature of valence electron density distribution in transition-metal complexes is the primary reason for this reluctance. A survey of the interaction of selected electron-saturated transition-metal complexes with electron-rich molecules (Y) demonstrates the following: shielding the possible sigma-hole on the metal center by the core electron density in 3d series, and enhanced electronegativity and relativistic effects in 4d and 5d series, hinders the formation of the M bond. A balance in all the destabilizing effects has been found in the 4d series due to its moderate polarizability and primogenic repulsion from inner core d-electrons. A changeover in the donor-acceptor nature of the metal center toward different types of incoming molecules is also unveiled here. The present study confirms the possibility of M bond as a new supramolecular force in designing the crystal structures of electron-saturated transition-metal complexes by invoking extreme ligand conditions. PMID- 28075569 TI - Inlet Particle-Sorting Cyclone for the Enhancement of PM2.5 Separation. AB - Many cities are suffering from severe air pollution from fine particulate matter. Cyclone is an effective separator for particulate pollutant but has low efficiency for those with an aerodynamic diameter of 2.5 MUm or less (PM2.5). In this research, four novel inlet particle-sorting cyclones were first developed to enhance the separation of PM2.5. The energy consumption, overall separation efficiency, particle grade efficiency,outlet particle concentration and size distribution were compared with common cyclone (CM-C). It was found that the vertical reverse rotation cyclone (VRR-C), which made the smaller particles enter cyclone from radially outer side and axially lower side at the rectangular inlet, had the best separation performance, especially for PM2.5 separation. The mean diameter of inlet particles was 15.7 MUm and the particle concentration was 2000 mg/m3, the overall separation efficiency of the VRR-C reached 98.3%, which was 6.4% higher than that of CM-C. PM2.5 grade efficiency of the VRR-C exceeded 80%, which was 15~20% higher than that of CM-C. The PM2.5 content at the VRR-C outlet was 30.8 mg/m3, while that of CM-C was still 118.4 mg/m3. The novel inlet particle-sorting cyclone is an effective separation enhancement for PM2.5 source control in the process of industrial production and environment protection. PMID- 28075571 TI - Editorial. PMID- 28075572 TI - Effect of Protein Corona on Silver Nanoparticle Stabilization and Ion Release Kinetics in Artificial Seawater. AB - In parallel with the growing use of nanoparticle-containing products, their release into the environment over the coming years is expected to increase significantly. With many large population centers located in near-coastal areas, and increasing evidence that various nanoparticles may be toxic to a range of organisms, biota in estuarine and coastal waters may be particularly vulnerable. While size effects may be important in cases, silver nanoparticles have been found to be toxic in large part due to their release of silver ions. However, there is relatively little data available on how nanoparticle coatings can affect silver ion release in estuarine or marine waters. We have found that albumin, as a model for biocorona-forming macromolecules which nanoparticles may encounter in wastewater streams, stabilizes silver colloids from agglomeration in high salinity marine waters by electrosteric repulsion for long time periods. A minimum mass ratio of about 130 for albumin:silver nanoparticles (40 nm) was required for stable dispersion in seawater. Increasing albumin concentration was also found to reduce dissolution of nanoparticles in seawater with up to 3.3 times lower concentrations of silver ions noted. Persistent colloids and slow sustained ion release may have important consequences for biota in these environmental compartments. PMID- 28075573 TI - Functional Graphene Nanomaterials Based Architectures: Biointeractions, Fabrications, and Emerging Biological Applications. AB - Functional graphene nanomaterials (FGNs) are fast emerging materials with extremely unique physical and chemical properties and physiological ability to interfere and/or interact with bioorganisms; as a result, FGNs present manifold possibilities for diverse biological applications. Beyond their use in drug/gene delivery, phototherapy, and bioimaging, recent studies have revealed that FGNs can significantly promote interfacial biointeractions, in particular, with proteins, mammalian cells/stem cells, and microbials. FGNs can adsorb and concentrate nutrition factors including proteins from physiological media. This accelerates the formation of extracellular matrix, which eventually promotes cell colonization by providing a more beneficial microenvironment for cell adhesion and growth. Furthermore, FGNs can also interact with cocultured cells by physical or chemical stimulation, which significantly mediate their cellular signaling and biological performance. In this review, we elucidate FGNs-bioorganism interactions and summarize recent advancements on designing FGN-based two dimensional and three-dimensional architectures as multifunctional biological platforms. We have also discussed the representative biological applications regarding these FGN-based bioactive architectures. Furthermore, the future perspectives and emerging challenges will also be highlighted. Due to the lack of comprehensive reviews in this emerging field, this review may catch great interest and inspire many new opportunities across a broad range of disciplines. PMID- 28075575 TI - Correction to "Electrocatalytic Currents from Single Enzyme Molecules". PMID- 28075574 TI - Visualization of mycobacterial membrane dynamics in live cells. AB - Mycobacteria are endowed with a highly impermeable mycomembrane that confers intrinsic resistance to many antibiotics. Several unique mycomembrane glycolipids have been isolated and structurally characterized, but the underlying organization and dynamics of glycolipids within the cell envelope remain poorly understood. We report here a study of mycomembrane dynamics that was enabled by trehalose-fluorophore conjugates capable of labeling trehalose glycolipids in live actinomycetes. We identified fluorescein-trehalose analogues that are metabolically incorporated into the trehalose mycolates of representative Mycobacterium, Corynebacterium, Nocardia, and Rhodococcus species. Using these probes, we studied the mobilities of labeled glycolipids by time-lapse microscopy and fluorescence recovery after photobleaching experiments and found that mycomembrane fluidity varies widely across species and correlates with mycolic acid structure. Finally, we discovered that treatment of mycobacteria with ethambutol, a front-line tuberculosis (TB) drug, significantly increases mycomembrane fluidity. These findings enhance our understanding of mycobacterial cell envelope structure and dynamics and have implications for development of TB drug cocktails. PMID- 28075576 TI - Proton Coupled Electronic Rearrangement within the H-Cluster as an Essential Step in the Catalytic Cycle of [FeFe] Hydrogenases. AB - The active site of [FeFe] hydrogenases, the H-cluster, consists of a [4Fe-4S] cluster connected via a bridging cysteine to a [2Fe] complex carrying CO and CN- ligands as well as a bridging aza-dithiolate ligand (ADT) of which the amine moiety serves as a proton shuttle between the protein and the H-cluster. During the catalytic cycle, the two subclusters change oxidation states: [4Fe-4S]H2+ <=> [4Fe-4S]H+ and [Fe(I)Fe(II)]H <=> [Fe(I)Fe(I)]H thereby enabling the storage of the two electrons needed for the catalyzed reaction 2H+ + 2e- ? H2. Using FTIR spectro-electrochemistry on the [FeFe] hydrogenase from Chlamydomonas reinhardtii (CrHydA1) at different pH values, we resolve the redox and protonation events in the catalytic cycle and determine their intrinsic thermodynamic parameters. We show that the singly reduced state Hred of the H-cluster actually consists of two species: Hred = [4Fe-4S]H+ - [Fe(I)Fe(II)]H and HredH+ = [4Fe-4S]H2+ - [Fe(I)Fe(I)]H (H+) related by proton coupled electronic rearrangement. The two redox events in the catalytic cycle occur on the [4Fe-4S]H subcluster at similar midpoint-potentials (-375 vs -418 mV); the protonation event (Hred/HredH+) has a pKa ~ 7.2. PMID- 28075577 TI - Reversible Unfolding and Folding of the Metalloprotein Ferredoxin Revealed by Single-Molecule Atomic Force Microscopy. AB - Plant type [2Fe-2S] ferredoxins function primarily as electron transfer proteins in photosynthesis. Studying the unfolding-folding of ferredoxins in vitro is challenging, because the unfolding of ferredoxin is often irreversible due to the loss or disintegration of the iron-sulfur cluster. Additionally, the in vivo folding of holo-ferredoxin requires ferredoxin biogenesis proteins. Here, we employed atomic force microscopy-based single-molecule force microscopy and protein engineering techniques to directly study the mechanical unfolding and refolding of a plant type [2Fe-2S] ferredoxin from cyanobacteria Anabaena. Our results indicate that upon stretching, ferredoxin unfolds in a three-state mechanism. The first step is the unfolding of the protein sequence that is outside and not sequestered by the [2Fe-2S] center, and the second one relates to the force-induced rupture of the [2Fe-2S] metal center and subsequent unraveling of the protein structure shielded by the [2Fe-2S] center. During repeated stretching and relaxation of a single polyprotein, we observed that the completely unfolded ferredoxin can refold to its native holo-form with a fully reconstituted [2Fe-2S] center. These results demonstrate that the unfolding refolding of individual ferredoxin is reversible at the single-molecule level, enabling new avenues of studying both folding-unfolding mechanisms, as well as the reactivity of the metal center of metalloproteins in vitro. PMID- 28075578 TI - Probing Structural Perturbation in a Bent Molecular Crystal with Synchrotron Infrared Microspectroscopy and Periodic Density Functional Theory Calculations. AB - The range of unit cell orientations generated at the kink of a bent single crystal poses unsurmountable challenges with diffraction analysis and limits the insight into the molecular-scale mechanism of bending. On a plastically bent crystal of hexachlorobenzene, it is demonstrated here that spatially resolved microfocus infrared spectroscopy using synchrotron radiation can be applied in conjunction with periodic density functional theory calculations to predict spectral changes or to extract information on structural changes that occur as a consequence of bending. The approach reproduces well the observed trends, such as the wall effects, and provides estimations of the vibrational shifts, unit cell deformations, and intramolecular parameters. Generally, expansion of the lattice induces red-shift while compression induces larger blue-shift of the characteristic nu(C-C) and nu(C-Cl) modes. Uniform or non-uniform expansion or contraction of the unit cell of 0.1 A results in shifts of several cm-1, whereas deformation of the cell of 0.5 degrees at the unique angle causes shifts of <0.5 cm-1. Since this approach does not include parameters related to the actual stimulus by which the deformation has been induced, it can be generalized and applied to other mechanically, photochemically, or thermally bent crystals. PMID- 28075579 TI - Human Health and Economic Impacts of Ozone Reductions by Income Group. AB - Low-income households may be disproportionately affected by ozone pollution and ozone policy. We quantify how three factors affect the relative benefits of ozone policies with household income: (1) unequal ozone reductions; (2) policy delay; and (3) economic valuation methods. We model ozone concentrations under baseline and policy conditions across the full continental United States to estimate the distribution of ozone-related health impacts across nine income groups. We enhance an economic model to include these impacts across household income categories, and present its first application to evaluate the benefits of ozone reductions for low-income households. We find that mortality incidence rates decrease with increasing income. Modeled ozone levels yield a median of 11 deaths per 100 000 people in 2005. Proposed policy reduces these rates by 13%. Ozone reductions are highest among low-income households, which increases their relative welfare gains by up to 4% and decreases them for the rich by up to 8%. The median value of reductions in 2015 is either $30 billion (in 2006 U.S. dollars) or $1 billion if reduced mortality risks are valued with willingness-to pay or as income from increased life expectancy. Ozone reductions were relatively twice as beneficial for the lowest- compared to the highest-income households. The valuation approach affected benefits more than a policy delay or differential ozone reductions with income. PMID- 28075581 TI - Antagonizing NOD2 Signaling with Conjugates of Paclitaxel and Muramyl Dipeptide Derivatives Sensitizes Paclitaxel Therapy and Significantly Prevents Tumor Metastasis. AB - A noncleavable paclitaxel (PTX) and N-acetylmuramyl-l-alanyl-d-isoglutamine (MDP) derivative conjugate, 22 (DY-16-43), and its analogues were prepared and characterized as antagonists of NOD2 signaling. This conjugate enhanced the antitumor and antimetastatic efficacy of PTX in Lewis lung carcinoma (LLC) tumor bearing mice. This work first describes a molecular strategy that enables the sensitization of a chemotherapeutic response via antagonizing NOD2 inflammatory signaling and suggests NOD2 antagonist as potential adjunct in treating non-small cell lung cancer (NSCLC). PMID- 28075580 TI - Antibacterial and Cytotoxic Phenolic Metabolites from the Fruits of Amorpha fruticosa. AB - Fourteen new natural products, namely, 2-[(Z)-styryl]-5-geranylresorcin-1 carboxylic acid (1), amorfrutin D (2), 4-O-demethylamorfrutin D (3), 8-geranyl 3,5,7-trihydroxyflavanone (4), 8-geranyl-5,7,3'-trihydroxy-4'-methoxyisoflavone (5), 6-geranyl-5,7,3'-trihydroxy-4'-methoxyisoflavone (6), 8-geranyl-7,3' dihydroxy-4'-methoxyisoflavone (7), 3-O-demethyldalbinol (8), 6a,12a-dehydro-3-O demethylamorphigenin (9), (6aR,12aR,5'R)-amorphigenin (10), amorphispironones B and C (11 and 12), resokaempferol 3-O-beta-d-glucopyranosyl-(1->2)-beta-d glucopyranoside-7-O-alpha-l-rhamnopyranoside (13), and daidzein 7-O-beta-d glucopyranosyl-(1->2)-beta-d-glucopyranoside (14), together with 40 known compounds, were isolated from the fruits of Amorpha fruticosa. The structures of the new compounds were elucidated by 1D and 2D NMR spectroscopic analysis as well as from the mass spectrometry data. ECD calculations were performed to determine the absolute configurations of 11 and 15. Compounds 1, 4-6, and 16-23 showed potent to moderate antibacterial activities against several Gram-positive bacteria with MIC values ranging from 3.1 to 100 MUM. In addition, compounds 11 and 24-33 were significantly cytotoxic against the L5178Y mouse lymphoma cell line and exhibited IC50 values from 0.2 to 10.2 MUM. PMID- 28075582 TI - The Form in Which Nitrogen Is Supplied Affects the Polyamines, Amino Acids, and Mineral Composition of Sweet Pepper Fruit under an Elevated CO2 Concentration. AB - We investigated the effect of supplying nitrogen, as NO3- or as NO3-/NH4+, on the composition of fruits of sweet pepper (Capsicum annuum L. cv. Melchor) plants grown with different CO2 concentrations ([CO2]): ambient or elevated (800 MUmol mol-1). The results show that the application of NH4+ and high [CO2] affected the chroma related to the concentrations of chlorophylls. The concentrations of Ca, Cu, Mg, P, and Zn were significantly reduced in the fruits of plants nourished with NH4+, the loss of Fe being more dramatic at increased [CO2], which was also the case with the protein concentration. The concentration of total phenolics was increased by NH4+, being unaffected by [CO2]. Globally, the NH4+ was the main factor that affected fruit free amino acid concentrations. Polyamines were affected differently: putrescine was increased by elevated [CO2], while the response of cadaverine depended on the form of N supplied. PMID- 28075583 TI - Amyloid Fibril Polymorphism: Almost Identical on the Atomic Level, Mesoscopically Very Different. AB - Amyloid polymorphism of twisted and straight beta-endorphin fibrils was studied by negative-stain transmission electron microscopy, scanning transmission electron microscopy, and solid-state nuclear magnetic resonance spectroscopy. Whereas fibrils assembled in the presence of salt formed flat, striated ribbons, in the absence of salt they formed mainly twisted filaments. To get insights into their structural differences at the atomic level, 3D solid-state NMR spectra of both fibril types were acquired, allowing the detection of the differences in chemical shifts of 13C and 15N atoms in both preparations. The spectral fingerprints and therefore the chemical shifts are very similar for both fibril types. This indicates that the monomer structure and the molecular interfaces are almost the same but that these small differences do propagate to produce flat and twisted morphologies at the mesoscopic scale. This finding is in agreement with both experimental and theoretical considerations on the assembly of polymers (including amyloids) under different salt conditions, which attribute the mesoscopic difference of flat versus twisted fibrils to electrostatic intermolecular repulsions. PMID- 28075585 TI - Acidity of M(VI)O2(OH)2 for M = Group 6, 16, and U as Central Atoms. AB - Gas-phase acidities and aqueous solution pKa's are predicted for MO2(OH)2, where the center atom M is a main Group 6, 16, and U atom using the Feller-Peterson Dixon approach based on coupled cluster CCSD(T) calculations with additional corrections. The gas-phase acidities of the MO2(OH)2 compounds are essentially the same for elements (M) of the same group, 304-310 kcal/mol at 298 K. All of the Group 6 compounds are 5-6 kcal/mol less acidic in the gas phase than H2SO4. The gas-phase acidity of UO2(OH)2 is calculated to be up to 338.0 kcal/mol, ~10% less acidic in the gas phase than the other MO2(OH)2 acids. The most acidic molecule in aqueous solution is predicted to be H2SO4. Overall, for the Group 16 compounds, the pKa's increase going down the group, with H2PoO4 predicted to be slightly more acidic than nitric acid. H2CrO4 is the most acidic of the Group 6 transition metal compounds. The aqueous acidities of H2MoO4 and H2WO4 are comparable and about 3 pKa units less acidic than H2CrO4 and comparable in acidity to HNO3. H2UO4 is not acidic at all in aqueous solution with a pKa near 20 pKa units and is also not predicted to readily undergo hydrolysis reactions. PMID- 28075586 TI - Determining Substrate Specificities of beta1,4-Endogalactanases Using Plant Arabinogalactan Oligosaccharides Synthesized by Automated Glycan Assembly. AB - Pectin is a structurally complex plant polysaccharide with many industrial applications in food products. The structural elucidation of pectin is aided by digestion assays with glycosyl hydrolases. We report the automated glycan assembly of oligosaccharides related to the arabinogalactan side chains of pectin as novel biochemical tools to determine the substrate specificities of endogalactanases. Analysis of the digestion products revealed different requirements for the lengths and arabinose substitution pattern of the oligosaccharides to be recognized and hydrolyzed by the galactanases. PMID- 28075587 TI - Design and Synthesis of Novel Nonsteroidal Anti-Inflammatory Drugs and Carbonic Anhydrase Inhibitors Hybrids (NSAIDs-CAIs) for the Treatment of Rheumatoid Arthritis. AB - We report the synthesis of a series of hybrid compounds incorporating 6- and 7 substituted coumarins (carbonic anhydrase, CA inhibitors) derivatized with clinically used NSAIDs (indomethacin, sulindac, ketoprofen, ibuprofen, diclofenac, ketorolac, etc., cyclooxygenase inhibitors) as agents for the management of rheumatoid arthritis (RA). Most compounds were effective in inhibiting the RA overexpressed hCA IX and XII, with KI values in the low nanomolar-subnanomolar ranges. The antihyperalgesic activity of such compounds was assessed by means of the paw-pressure and incapacitance tests using an in vivo RA model. Among all tested compounds, the 7-coumarine hybrid with ibuprofen showed potent and persistent antihyperalgesic effect up to 60 min after administration. PMID- 28075588 TI - Accurate Reference Data for the Nonadditive, Noninteracting Kinetic Energy in Covalent Bonds. AB - The nonadditive, noninteracting kinetic energy (NAKE) is calculated numerically for fragments of H2, Li2, Be2, C2, N2, F2, and Na2 within partition density functional theory (PDFT). The resulting fragments are uniquely determined, and their sum reproduces the Kohn-Sham molecular density of the corresponding XC functional. We present the NAKE of these unique fragments as a function of internuclear separation and compare the use of fractional orbital occupation to the usual PDFT ensemble method for treating the fragment energies and densities. We also compare Thomas-Fermi and von Weizsacker approximate kinetic energy functionals to the numerically exact solutions and find significant regions where the von Weizsacker functional is nearly exact. In addition, we find that the von Weizsacker approximation can provide accurate NAKE in stretched covalent bonds, especially in the cases of Li2 and Na2. PMID- 28075589 TI - Water-Soluble Ruthenium (II) Chiral Heteroleptic Complexes with Amoebicidal in Vitro and in Vivo Activity. AB - Three water-soluble Ru(II) chiral heteroleptic coordination compounds [Ru(en)(pdto)]Cl2 (1), [Ru(gly)(pdto)]Cl (2), and [Ru(acac)(pdto)]Cl (3), where pdto = 2,2'-[1,2-ethanediylbis-(sulfanediyl-2,1-ethanediyl)]dipyridine, en = ethylendiamine, gly = glycinate, and acac = acetylacetonate, have been synthezised and fully characterized. The crystal structures of compounds 1-3 are described. The IC50 values for compounds 1-3 are within nanomolar range (14, 12, and 6 nM, respectively). The cytotoxicity for human peripheral blood lymphocytes is extremely low (>100 MUM). Selectivity indexes for Ru(II) compounds are in the range 700-1300. Trophozoites exposed to Ru(II) compounds die through an apoptotic pathway triggered by ROS production. The orally administration to infected mice induces a total elimination of the parasite charge in mice faeces 1-2-fold faster than metronidazole. Besides, all compounds inhibit the trophozoite proliferation in amoebic liver abscess induced in hamster. All our results lead us to propose these compounds as promising candidates as antiparasitic agents. PMID- 28075590 TI - Nanometer-Sized Water Bridge and Pull-Off Force in AFM at Different Relative Humidities: Reproducibility Measurement and Model Based on Surface Tension Change. AB - This article deals with the analysis of the relationship between the pull-off force measured by atomic force microscopy and the dimensions of water bridge condensed between a hydrophilic silicon oxide tip and a silicon oxide surface under ambient conditions. Our experiments have shown that the pull-off force increases linearly with the radius of the tip and nonmonotonically with the relative humidity (RH). The latter dependence generally consists of an initial constant part changing to a convex-concave-like increase of the pull-off force and finally followed by a concave-like decrease of this force. The reproducibility tests have demonstrated that the precision limits have to be taken into account for comparing these measurements carried out under atmospheric conditions. The results were fitted by a classical thermodynamic model based on water-bridge envelope calculations using the numerical solution of the Kelvin equation in the form of axisymmetric differential equations and consequent calculation of adhesive forces. To describe the measured data more precisely, a decrease of the water surface tension for low RH was incorporated into the calculation. Such a decrease can be expected as a consequence of the high surface curvature in the nanometer-sized water bridge between the tip and the surface. PMID- 28075591 TI - Discovery of Potent Cyclophilin Inhibitors Based on the Structural Simplification of Sanglifehrin A. AB - Cyclophilin inhibition has been a target for the treatment of hepatitis C and other diseases, but the generation of potent, drug-like molecules through chemical synthesis has been challenging. In this study, a set of macrocyclic cyclophilin inhibitors was synthesized based on the core structure of the natural product sanglifehrin A. Initial compound optimization identified the valine-m tyrosine-piperazic acid tripeptide (Val-m-Tyr-Pip) in the sanglifehrin core, stereocenters at C14 and C15, and the hydroxyl group of the m-tyrosine (m-Tyr) residue as key contributors to compound potency. Replacing the C18-C21 diene unit of sanglifehrin with a styryl group led to potent compounds that displayed a novel binding mode in which the styrene moiety engaged in a pi-stacking interaction with Arg55 of cyclophilin A (Cyp A), and the m-Tyr residue was displaced into solvent. This observation allowed further simplifications of the scaffold to generate new lead compounds in the search for orally bioavailable cyclophilin inhibitors. PMID- 28075592 TI - Total Syntheses and Biological Activities of Vinylamycin Analogues. AB - Natural depsipeptide vinylamycin was reported to be an antibiotic previously. Herein we report vinylamycin to be active against K562 leukemia cells (IC50 = 4.86 MUM) and be unstable in plasma (t1/2 = 0.54 h). A total of 24 vinylamycin analogues with modification of the OH group and chiral centers were generated via a combinatorial approach. The lead compound 1a was subsequently characterized as having the following: no antimicrobial activity, significantly higher plasma stability (t1/2 = 14.3 h), improved activity against K562 leukemia cells (IC50 = 0.64 MUM), and up to 75% cell inhibition without significant toxicities in K562 cells xenograft zebrafish model. Furthermore, compound 1a maintained its activity against the breast cancer cell line MCF-7 under hypoxic conditions. In comparison, the activity of gemcitabine in the same hypoxic in vitro model of MCF 7 cells was 15-fold lower. Therefore, the present results demonstrate that 1a has great potential as an anticancer agent. PMID- 28075593 TI - Formation of Nickel Clusters Wrapped in Carbon Cages: Toward New Endohedral Metallofullerene Synthesis. AB - Despite the high potential of endohedral metallofullerenes (EMFs) for application in biology, medicine and molecular electronics, and recent efforts in EMF synthesis, the variety of EMFs accessible by conventional synthetic methods remains limited and does not include, for example, EMFs of late transition metals. We propose a method in which EMF formation is initiated by electron irradiation in aberration-corrected high-resolution transmission electron spectroscopy (AC-HRTEM) of a metal cluster surrounded by amorphous carbon inside a carbon nanotube serving as a nanoreactor and apply this method for synthesis of nickel EMFs. The use of AC-HRTEM makes it possible not only to synthesize new, previously unattainable nanoobjects but also to study in situ the mechanism of structural transformations. Molecular dynamics simulations using the state-of-the art approach for modeling the effect of electron irradiation are performed to rationalize the experimental observations and to link the observed processes with conditions of bulk EMF synthesis. PMID- 28075594 TI - High-Curvature Nanostructuring Enhances Probe Display for Biomolecular Detection. AB - High-curvature electrodes facilitate rapid and sensitive detection of a broad class of molecular analytes. These sensors have reached detection limits not attained using bulk macroscale materials. It has been proposed that immobilized DNA probes are displayed at a high deflection angle on the sensor surface, which allows greater accessibility and more efficient hybridization. Here we report the first use of all-atom molecular dynamics simulations coupled with electrochemical experiments to explore the dynamics of single-stranded DNA immobilized on high curvature versus flat surfaces. We find that high-curvature structures suppress DNA probe aggregation among adjacent probes. This results in conformations that are more freely accessed by target molecules. The effect observed is amplified in the presence of highly charged cations commonly used in electrochemical biosensing. The results of the simulations agree with experiments that measure the degree of hybridization in the presence of mono-, di-, and trivalent cations. On high-curvature structures, hybridization current density increases as positive charge increases, whereas on flat electrodes, the trivalent cations cause aggregation due to electrostatic overscreening, which leads to decreased current density and less sensitive detection. PMID- 28075595 TI - Adsorption of Small Cationic Nanoparticles onto Large Anionic Particles from Aqueous Solution: A Model System for Understanding Pigment Dispersion and the Problem of Effective Particle Density. AB - The present study focuses on the use of copolymer nanoparticles as a dispersant for a model pigment (silica). Reversible addition-fragmentation chain transfer (RAFT) alcoholic dispersion polymerization was used to synthesize sterically stabilized diblock copolymer nanoparticles. The steric stabilizer block was poly(2-(dimethylamino)ethyl methacrylate) (PDMA) and the core-forming block was poly(benzyl methacrylate) (PBzMA). The mean degrees of polymerization for the PDMA and PBzMA blocks were 71 and 100, respectively. Transmission electron microscopy (TEM) studies confirmed a near-monodisperse spherical morphology, while dynamic light scattering (DLS) studies indicated an intensity-average diameter of 30 nm. Small-angle X-ray scattering (SAXS) reported a volume-average diameter of 29 +/- 0.5 nm and a mean aggregation number of 154. Aqueous electrophoresis measurements confirmed that these PDMA71-PBzMA100 nanoparticles acquired cationic character when transferred from ethanol to water as a result of protonation of the weakly basic PDMA chains. Electrostatic adsorption of these nanoparticles from aqueous solution onto 470 nm silica particles led to either flocculation at submonolayer coverage or steric stabilization at or above monolayer coverage, as judged by DLS. This technique indicated that saturation coverage was achieved on addition of approximately 465 copolymer nanoparticles per silica particle, which corresponds to a fractional surface coverage of around 0.42. These adsorption data were corroborated using thermogravimetry, UV spectroscopy and X-ray photoelectron spectroscopy. TEM studies indicated that the cationic nanoparticles remained intact on the silica surface after electrostatic adsorption, while aqueous electrophoresis confirmed that surface charge reversal occurred below pH 7. The relatively thick layer of adsorbed nanoparticles led to a significant reduction in the effective particle density of the silica particles from 1.99 g cm-3 to approximately 1.74 g cm-3, as judged by disk centrifuge photosedimentometry (DCP). Combining the DCP and SAXS data suggests that essentially no deformation of the PBzMA cores occurs during nanoparticle adsorption onto the silica particles. PMID- 28075596 TI - Yeast Microcapsule-Mediated Targeted Delivery of Diverse Nanoparticles for Imaging and Therapy via the Oral Route. AB - Targeting of nanoparticles to distant diseased sites after oral delivery remains highly challenging due to the existence of many biological barriers in the gastrointestinal tract. Here we report targeted oral delivery of diverse nanoparticles in multiple disease models, via a "Trojan horse" strategy based on a bioinspired yeast capsule (YC). Diverse charged nanoprobes including quantum dots (QDs), iron oxide nanoparticles (IONPs), and assembled organic fluorescent nanoparticles can be effectively loaded into YC through electrostatic force driven spontaneous deposition, resulting in different diagnostic YC assemblies. Also, different positive nanotherapies containing an anti-inflammatory drug indomethacin (IND) or an antitumor drug paclitaxel (PTX) are efficiently packaged into YC. YCs containing either nanoprobes or nanotherapies may be rapidly endocytosed by macrophages and maintained in cells for a relatively long period of time. Post oral administration, nanoparticles packaged in YC are first transcytosed by M cells and sequentially endocytosed by macrophages, then transported to neighboring lymphoid tissues, and finally delivered to remote diseased sites of inflammation or tumor in mice or rats, all through the natural route of macrophage activation, recruitment, and deployment. For the examined acute inflammation model, the targeting efficiency of YC-delivered QDs or IONPs is even higher than that of control nanoprobes administered at the same dose via intravenous injection. Assembled IND or PTX nanotherapies orally delivered via YCs exhibit remarkably potentiated efficacies as compared to nanotherapies alone in animal models of inflammation and tumor, which is consistent with the targeting effect and enhanced accumulation of drug molecules at diseased sites. Consequently, through the intricate transportation route, nanoprobes or nanotherapies enveloped in YC can be preferentially delivered to desired targets, affording remarkably improved efficacies for the treatment of multiple diseases associated with inflammation. PMID- 28075597 TI - A Class of Electron-Transporting Vinylogous Tetrathiafulvalenes Constructed by the Dimerization of Core-Expanded Naphthalenediimides. AB - The combination of the (1,3-dithiol-2-ylidene)malononitrile (DTYM) and/or (1,3 dithiol-2-ylidene)acetonitrile (DTYA) moieties with naphthalenediimide (NDI) core affords two singly linked NDI-based dimers, (DTYM-NDI-DTYA)2 (D1) and (NDI-DTYA)2 (D2), which both contain a dicyano-substituted vinylogous tetrathiafulvalene (TTF) unit. The synthesis, thermal/optical/electrochemical properties of D1 and D2, and their primary applications in n-channel organic thin film transistors are studied. The results demonstrate that these NDI-fused vinylogous TTFs are excellent electron acceptors, and their further applications are promising. PMID- 28075598 TI - Organocatalytic Regioselective Concomitant Thiocyanation and Acylation of Oxiranes Using Aroyl Isothiocyanates. AB - A regioselective and concomitant transfer of thiocyanate (-SCN) and aroyl/acyl ( COR) groups from aroyl/acyl isothiocyanates onto oxiranes was achieved, giving thiocyanato benzoates in 100% atom economy. In this biomimetic organocatalytic process, one part (-SCN) of aroyl/acyl isothiocyanates acts as the nucleophile whereas the other half (-COR) serves as an electrophilic partner. PMID- 28075599 TI - Enhancing Cation Diffusion and Suppressing Anion Diffusion via Lewis-Acidic Polymer Electrolytes. AB - Solid polymer electrolytes (SPEs) have the potential to increase both the energy density and stability of lithium-based batteries, but low Li+ conductivity remains a barrier to technological viability. SPEs are designed to maximize Li+ diffusivity relative to the anion while maintaining sufficient salt solubility. It is thus remarkable that poly(ethylene oxide) (PEO), the most widely used SPE, exhibits Li+ diffusivity that is an order of magnitude smaller than that of typical counterions at moderate salt concentrations. We show that Lewis-basic polymers like PEO favor slow cation and rapid anion diffusion, while this relationship can be reversed in Lewis-acidic polymers. Using molecular dynamics, polyboranes are identified that achieve up to 10-fold increases in Li+ diffusivities and significant decreases in anion diffusivities, relative to PEO in the dilute-ion regime. These results illustrate a general principle for increasing Li+ diffusivity and transference number with chemistries that exhibit weaker cation and stronger anion coordination. PMID- 28075600 TI - A Synthesis of "Dual Warhead" beta-Aryl Ethenesulfonyl Fluorides and One-Pot Reaction to beta-Sultams. AB - Herein, we report an operationally simple, ligand- and additive-free oxidative boron-Heck coupling that is compatible with the ethenesulfonyl fluoride functional group. The protocol proceeds at room temperature with chemoselectivity and E-isomer selectivity and offers facile access to a wide range of beta aryl/heteroaryl ethenesulfonyl fluorides from commercial boronic acids. Furthermore, we demonstrate a "one-pot click" reaction to directly transform the products to aryl-substituted beta-sultams. PMID- 28075601 TI - Nitrogen-Doped Mesoporous Carbons as Counter Electrodes in Quantum Dot Sensitized Solar Cells with a Conversion Efficiency Exceeding 12. AB - The exploration of catalyst materials for counter electrodes (CEs) in quantum dot sensitized solar cells (QDSCs) that have both high electrocatalytic activity and low charge transfer resistance is always significant yet challenging. In this work, we report the incorporation of nitrogen heteroatoms into carbon lattices leading to nitrogen-doped mesoporous carbon (N-MC) materials with superior catalytic activity when used as CEs in Zn-Cu-In-Se QDSCs. A series of N-MC materials with different nitrogen contents were synthesized by a colloidal silica nanocasting method. Electrochemical measurements revealed that the N-MC with a nitrogen content of 8.58 wt % exhibited the strongest activity in catalyzing the reduction of a polysulfide redox couple (Sn2-/S2-), and therefore, the corresponding QDSC device showed the best photovoltaic performance with an average power conversion efficiency (PCE) of 12.23% and a certified PCE of 12.07% under one full sun illumination, which is a new PCE record for quantum dot based solar cells. PMID- 28075602 TI - Enantioselective Hydrophosphonylation of in Situ Generated N-Acyl Ketimines Catalyzed by BINOL-Derived Phosphoric Acid. AB - An efficient route to pharmacologically interesting isoindolinone-based alpha amino phosphonates is described via asymmetric hydrophosphonylation of in situ generated ketimines catalyzed by BINOL-derived phosphoric acid. The reaction proceeds smoothly at ambient temperature affording a variety of alpha-amino phosphonates with a quaternary stereogenic center embedded in isoindolinone motif in high yields with excellent enantiomeric ratios (up to 98.5:1.5 er). Several interesting transformations of the products into valuable synthetic intermediates are also depicted. PMID- 28075603 TI - Mobility and Oxidation of Adsorbed CO on Shape-Controlled Pt Nanoparticles in Acidic Medium. AB - The knowledge about how CO occupies and detaches from specific surface sites on well-structured Pt surfaces provides outstanding information on both dynamics/mobility of COads and oxidation of this molecule under electrochemical conditions. This work reports how the potentiostatic growth of different coverage CO adlayers evolves with time on both cubic and octahedral Pt nanoparticles in acidic medium. Data suggest that during the growth of the CO adlayer, COads molecules slightly shift toward low coordination sites only on octahedral Pt nanoparticles, so that these undercoordinated sites are the first filled on octahedral Pt nanoparticles. Conversely, on cubic Pt nanoparticles, adsorbed CO behaves as an immobile species, and low coordinated sites as well as (100) terraces are apparently filled uniformly and simultaneously. However, once the adlayer is complete, irrespectively of whether the CO is oxidized in a single step or in a sequence of different potential steps, results suggest that COads behaves as an immobile species during its oxidation on both octahedral and cubic Pt nanoparticles. PMID- 28075604 TI - High-Level ab Initio Predictions for the Ionization Energies, Bond Dissociation Energies, and Heats of Formation of Titanium Oxides and Their Cations (TiOn/TiOn+, n = 1 and 2). AB - The ionization energies (IEs) of TiO and TiO2 and the 0 K bond dissociation energies (D0) and the heats of formation at 0 K (DeltaH degrees f0) and 298 K (DeltaH degrees f298) for TiO/TiO+ and TiO2/TiO2+ are predicted by the wave function-based CCSDTQ/CBS approach. The CCSDTQ/CBS calculations involve the approximation to the complete basis set (CBS) limit at the coupled cluster level up to full quadruple excitations along with the zero-point vibrational energy (ZPVE), high-order correlation (HOC), core-valence (CV) electronic, spin-orbit (SO) coupling, and scalar relativistic (SR) effect corrections. The present calculations yield IE(TiO) = 6.815 eV and are in good agreement with the experimental IE value of 6.819 80 +/- 0.000 10 eV determined in a two-color laser pulsed field ionization-photoelectron (PFI-PE) study. The CCSDT and MRCI+Q methods give the best predictions to the harmonic frequencies: omegae (omegae+) = 1013 (1069) and 1027 (1059) cm-1 and the bond lengths re (re+) = 1.625 (1.587) and 1.621 (1.588) A, for TiO (TiO+) compared with the experimental values. Two nearly degenerate, stable structures are found for TiO2 cation: TiO2+(C2v) structure has two equivalent TiO bonds, while the TiO2+(Cs) structure features a long and a short TiO bond. The IEs for the TiO2+(C2v)<-TiO2 and TiO2+(Cs)<-TiO2 ionization transitions are calculated to be 9.515 and 9.525 eV, respectively, giving the theoretical adiabatic IE value in good agreement with the experiment IE(TiO2) = 9.573 55 +/- 0.000 15 eV obtained in the previous vacuum ultraviolet (VUV)-PFI-PE study of TiO2. The potential energy surface of TiO2+ along the normal vibrational coordinates of asymmetric stretching mode (omega3+) is nearly flat and exhibits a double-well potential with the well of TiO2+ (Cs) situated around the central well of TiO2+(C2v). This makes the theoretical calculation of omega3+ infeasible. For the symmetric stretching (omega1+), the current theoretical predictions overestimate the experimental value of 829.1 +/- 2.0 cm-1 by more than 100 cm-1. This work together with the previous experimental and theoretical investigations supports the conclusion that the CCSDTQ/CBS approach is capable of providing reliable IE and D0 predictions for TiO/TiO+ and TiO2/TiO2+ with error limits less than or equal to 60 meV. The CCSDTQ/CBS calculations give the predictions of D0(Ti+-O) - D0(Ti-O) = 0.004 eV and D0(O TiO) - D0(O-TiO+) = 2.699 eV, which are also consistent with the respective experimental determination of 0.008 32 +/- 0.000 10 and 2.753 75 +/- 0.000 18 eV. PMID- 28075605 TI - Pyrazolofluostatins A-C, Pyrazole-Fused Benzo[a]fluorenes from South China Sea Derived Micromonospora rosaria SCSIO N160. AB - Pyrazolofluostatins A-C (1-3), three new benzo[a]fluorenes with an unprecedented carbon skeleton, were obtained from the South China Sea-derived Micromonospora rosaria SCSIO N160. Their structures were elucidated by extensive spectroscopic analyses. The structure of pyrazolofluostatin A (1) was confirmed by X-ray crystallographic analysis. Notably, 1-3 possessed a benzo[cd]indeno[2,1-f]indazol skeleton with a pyrazole-fused 6/5/6/6/5 pentacyclic ring system. Pyrazolofluostatin A (1) showed moderate antioxidation activity (EC50 48.6 MUM). PMID- 28075606 TI - Potential Application of Dual-Energy CT in Gynecologic Cancer: Initial Experience. AB - OBJECTIVE: The purpose of this article is to review the use of dual-energy CT (DECT) in the assessment of gynecologic cancer. CONCLUSION: DECT has the potential to improve diagnostic performance, may improve the ability to differentiate between simple cystic lesions and primary ovarian cancer, and may also improve the detection of musculoskeletal and liver metastases. Additional studies will be needed to determine the direction of future developments and the degree to which DECT will affect the imaging and management of gynecologic cancer. PMID- 28075608 TI - Sonographic Appearance of Lesions Diagnosed as Lobular Neoplasia at Sonographically Guided Biopsies. AB - OBJECTIVE: The objective of our study was to review the sonographic features of breast lesions yielding lobular neoplasia (LN) at sonographically guided biopsy, evaluate the surgical pathology outcome of these lesions, and determine if imaging findings or clinical features can be used to predict an upgrade to malignancy. MATERIALS AND METHODS: Of the 8205 sonographically guided breast biopsies (14-gauge cores) performed from 2007 through 2014, 22 yielded a diagnosis of LN, which means that LN was the most severe pathologic lesion. Imaging features were analyzed in consensus by two radiologists. Correlation of biopsy findings with definitive pathologic results was performed when available. RESULTS: Twenty-two LN lesions (20 patients [mean age +/- SD, 52.05 +/- 13.66 years]) were diagnosed at biopsy. Of the LN lesions that were seen on mammography (6/22, 27.3%), most lesions appeared as masses (3/6, 50%). On sonography, LN lesions (mean size, 8.10 mm) appeared as masses (15/22, 68.2%) with oval shape (10/15, 66.7%), well-circumscribed or microlobulated margins (11/15, 73.3%), hypoechoic echotexture (10/15, 66.7%), posterior enhancement (73.3%, 11/15), and parallel orientation (8/15, 53.3%). Most of the masses were categorized as BI RADS category 4 (21/22, 95.5%). Seven lesions (7/22, 31.8%) appeared as areas of shadowing or distortion without discrete masses. Twenty (20/22, 90.9%) lesions were excised surgically, and pathology results led to an upgrade in five lesions (5/20, 25% [one nonmass lesion and four masses]). Neither mammographic nor sonographic features were associated with malignant outcome (p > 0.05). CONCLUSION: LN diagnosed at sonographically guided 14-gauge core needle biopsy does not show any specific features according to the BI-RADS lexicon and is associated with a 25% underestimation rate. No clinical or imaging characteristic is predictive of malignancy. PMID- 28075607 TI - Efficacy of an Escherichia coli O157:H7 SRP Vaccine in Orally Challenged Goats and Strain Persistence Over Time. AB - Small ruminants have been implicated in outbreaks of Escherichia coli O157:H7 at livestock exhibitions throughout the United States. Additionally, goat meat or milk may serve as a reservoir for foodborne transmission of the organism. These associations highlight the public health importance of an effective strategy to reduce E. coli O157:H7 shedding in goats. We examined the efficacy of the SRP(r) vaccine in goats orally challenged with E. coli O157:H7. Mixed-breed goats (n = 14) were randomly allocated into vaccinated and unvaccinated treatments (n = 7 per treatment). Goats were housed with a vaccinated and unvaccinated animal in each pen. Feces were collected for 3 weeks, then at necropsy, gastrointestinal contents were collected to determine the concentration of E. coli O157:H7. Three isolates per positive sample were saved and evaluated by pulsed-field gel electrophoresis (PFGE) to assess strain persistence over time. The mean concentration of E. coli O157:H7 in the feces of goats was numerically reduced in the vaccinated treatment; however, it was not statistically significant. In addition, the total number of days goats were fecal positive for E. coli O157:H7 were not different between vaccinated and unvaccinated treatments. Pulsotypes of isolates revealed that goats initially shed two of the four challenge strains of E. coli O157:H7, after which there was a distinct shift to two different strains. Further work is needed to evaluate cost-effective intervention strategies that reliably reduce E. coli O157:H7 shedding in goats, particularly those that may reduce the risk of transmission at public events, including petting zoos and fairs. PMID- 28075609 TI - Female Smokers Are at Greater Risk of Airflow Obstruction Than Male Smokers. UK Biobank. AB - RATIONALE: The prevalence of chronic obstructive pulmonary disease (COPD) is increasing faster among women than among men. OBJECTIVES: To examine sex differences in the risk of airflow obstruction (a COPD hallmark) in relation to smoking history. METHODS: We analyzed 149,075 women and 100,252 men taking part in the UK Biobank who had provided spirometry measurements and information on smoking. The association of airflow obstruction with smoking characteristics was assessed by sex using regression analysis. The shape of this relationship was examined using restricted cubic splines. MEASUREMENTS AND MAIN RESULTS: The association of airflow obstruction with smoking status was stronger in women (odds ratio for ex-smokers [ORex], 1.44; ORcurrent, 3.45) than in men (ORex, 1.25; ORcurrent, 3.06) (P for interaction = 5.6 * 10-4). In both sexes, the association of airflow obstruction with cigarettes per day, smoking duration, and pack-years did not follow a linear pattern, with the increase in risk at lower doses being steeper among women. For equal doses of exposure, sex differences were present in both ex-smokers and current smokers for cigarettes per day (P for interactionex = 6.0 * 10-8; P for interactioncurrent = 1.1 * 10-5), smoking duration (P for interactionex = 7.9 * 10-4; P for interactioncurrent = 0.004), and pack-years (P for interactionex = 6.6 * 10-18; P for interactioncurrent = 1.3 * 10-6). Overall, those who started smoking before age 18 years were more likely to have airflow obstruction, but a sex difference in this association was not clear. For equal time since quitting, the reduction in risk among women seemed less marked than among men. CONCLUSIONS: Exposed to the same dose of smoking, women showed a higher risk of airflow obstruction than men. This could partly explain the increasingly smaller sex difference in the prevalence of COPD, especially in countries where smoking patterns have become similar between women and men. PMID- 28075610 TI - Factors affecting lactoferrin concentration in human milk: how much do we know? AB - Lactoferrin (LF) is a breast milk glycoprotein with antimicrobial and anti inflammatory effects. Its beneficial properties in infants, especially in those born preterm, are currently being studied in clinical trials. However, the maternal and nursing infant factors that may affect LF concentration in breast milk are still not clear. We conducted a systematic review to investigate the factors that may affect the concentration of LF in breast milk. We used a 2-step approach to identify the eligible studies according to inclusion/exclusion criteria, and to determine which studies would be considered. We included 70 qualified articles from 29 countries with publication dates ranging from 1976 to 2015. We described the correlation between LF concentration in breast milk and lactation stage; 10 maternal factors, such as race, parity, among others; and 2 infant factors: infections and prematurity. Colostrum has the highest LF levels, but they decrease with days postpartum. No other factor has been consistently associated with LF concentration. A major limitation of the majority of the published studies is the small sample size and the different methods used to measure LF concentration. Therefore, there is a need for large, multicenter studies with standardized study design, sample collection, and LF measurement methods to identify clinically significant factors associated with LF expression in breast milk, which will help promote exclusive breastfeeding in preterm infants. PMID- 28075611 TI - What the Radiologist Should Know About Treatment of Peritoneal Malignancy. AB - OBJECTIVE: The purpose of this article is to discuss the role of the radiologist in the treatment of peritoneal cancer, with focus placed on advanced treatment options and selection of patients with resectable disease for whom complete cytoreduction can be achieved. CONCLUSION: Peritoneal cancers traditionally have been associated with significant morbidity and universal mortality; however, the management of such cancers has evolved substantially. Advanced treatment options, including cytoreductive surgery and intraperitoneal chemotherapy, are associated with significantly improved long-term patient survival. To ensure that patients benefit from aggressive multimodality treatments, the radiologist plays a pivotal role in the multidisciplinary team to ensure careful patient selection, identifying individuals with resectable disease for whom complete cytoreduction can be achieved. PMID- 28075612 TI - Comparison of Mechanical Versus Hand Administration of IV Contrast Agents for Pediatric Pulmonary CT Angiography. AB - OBJECTIVE: The purpose of this study was to assess the difference between mechanical versus hand administration of IV contrast agents on the diagnostic quality of pediatric pulmonary CT angiography (CTA). MATERIALS AND METHODS: A retrospective review of the medical records was performed to detect pediatric patients (<= 18 years) with pulmonary CTA performed between September 2012 and March 2015. Patients were placed into two cohorts on the basis of the method of contrast administration (mechanical vs hand). Additional information obtained included IV size or gauge, IV site, amount and type of contrast agent administered, and rate of administration (mL/s). The quality of the CT images was independently evaluated by two pediatric radiologists using a qualitative 4-point visual assessment scale and quantitatively with attenuation (HU). An ANOVA controlling for age compared the contrast enhancement in the central pulmonary arteries between the cohorts. RESULTS: One hundred forty-eight consecutive pediatric patients (71 boys and 77 girls; mean age, 11.1 years; age range, 8 days 17.9 years) were identified between September 2012 and March 2015. Mechanical administration of contrast material was performed in 117 patients (79.1%; mean age [+/- SD], 13.7 +/- 3.7 years), and hand administration of contrast material was performed in 31 patients (20.9%; mean age, 1.6 +/- 1.8 years). After adjusting for age, the degree of enhancement within the pulmonary arteries was not statistically different between the two IV contrast administration methods at the main pulmonary artery (mechanical vs hand administration: mean attenuation, 310 +/- 128 vs 338 +/- 142 HU, respectively, p = 0.505), right pulmonary artery (305 +/- 124 vs 329 +/- 146 HU, p = 0.556), and left pulmonary artery (303 +/- 125 vs 340 +/- 151 HU, p = 0.349). CONCLUSION: It is possible to perform diagnostic-quality pulmonary CTA for the assessment of the central pulmonary arteries with hand administration of IV contrast material in pediatric patients with small-gauge IV catheters. PMID- 28075613 TI - Vertebral Venous Congestion Mimicking Sclerotic Metastasis in the Absence of Venous Obstruction. PMID- 28075614 TI - Peritoneal Insufflation Facilitates CT-Guided Percutaneous Jejunostomy Replacement. AB - OBJECTIVE: The purpose of this report was to examine whether peritoneal insufflation can facilitate CT-guided percutaneous jejunostomy replacement. CONCLUSION: Peritoneal insufflation allowed clear differentiation of the adherent jejunum from adjacent bowel, permitting confident direct puncture into the adherent jejunum without the need for jejunopexy anchors. PMID- 28075615 TI - Ignorance=Fear. PMID- 28075617 TI - Medicolegal-Malpractice and Ethical Issues in Radiology. PMID- 28075616 TI - Role of CXC chemokine receptor type 4 as a lactoferrin receptor. AB - Lactoferrin exerts its biological activities by interacting with receptors on target cells, including LDL receptor-related protein-1 (LRP-1/CD91), intelectin-1 (omentin-1), and Toll-like receptor 4 (TLR4). However, the effects mediated by these receptors are not sufficient to fully explain the many functions of lactoferrin. C-X-C-motif cytokine receptor 4 (CXCR4) is a ubiquitously expressed G-protein coupled receptor for stromal cell-derived factor-1 (SDF-1/CXCL12). Lactoferrin was found to be as capable as SDF-1 in blocking infection by an HIV variant that uses CXCR4 as a co-receptor (X4-tropic HIV), suggesting that lactoferrin interacts with CXCR4. We addressed whether CXCR4 acts as a lactoferrin receptor using HaCaT human keratinocytes and Caco-2 human intestinal cells. We found that bovine lactoferrin interacted with CXCR4-containing lipoparticles, and that this interaction was not antagonized by SDF-1. In addition, activation of Akt in response to lactoferrin was abrogated by AMD3100, a small molecule inhibitor of CXCR4, or by a CXCR4-neutralizing antibody, suggesting that CXCR4 functions as a lactoferrin receptor able to mediate activation of the PI3K-Akt signaling pathway. Lactoferrin stimulation mimicked many aspects of SDF-1-induced CXCR4 activity, including receptor dimerization, tyrosine phosphorylation, and ubiquitination. Cycloheximide chase assays indicated that turnover of CXCR4 was accelerated in response to lactoferrin. These results indicate that CXCR4 is a potent lactoferrin receptor that mediates lactoferrin-induced activation of Akt signaling. PMID- 28075618 TI - Rodent models of glaucoma and their applicability for drug discovery. AB - INTRODUCTION: Rodents have widely been used to represent glaucomatous changes both in the presence and absence of elevated intraocular pressure (IOP) as they offer clear advantages over other animal species. IOP elevation is commonly achieved by creating an obstruction in the aqueous outflow pathways, consequently leading to retinal ganglion cell and optic nerve (ON) damage, the hallmark of glaucoma. These changes may also be achieved in the absence of elevated IOP by directly inflicting injury to retina or ON. Areas covered: This paper presents a summary of currently used rodent models of glaucoma. The characteristics of these models from several studies are summarized. The benefits and shortcomings of these models are also discussed. Expert opinion: The choice of animal model that closely represents human disease is key for successful translational of preclinical research to clinical practice. Rodent models of rapid IOP elevation are likely to be least representative, whereas models such as steroid-induced glaucoma models more closely resemble the trabecular meshwork changes seen in glaucomatous human eyes. However, this model needs further characterization. Rodent models based on direct retinal and ON injury are also useful tools to investigate molecular mechanisms involved at the site of final common pathology and neuroprotective strategies. PMID- 28075619 TI - Role of CT in the Diagnosis of Nonspecific Abdominal Pain: A Multicenter Analysis. AB - OBJECTIVE: The objective of our study was to determine whether specific patient and physician factors-known before CT-are associated with a diagnosis of nonspecific abdominal pain (NSAP) after CT in the emergency department (ED). MATERIALS AND METHODS: We analyzed data originally collected in a prospective multicenter study. In the parent study, we identified ED patients referred to CT for evaluation of abdominal pain. We surveyed their physicians before and after CT to identify changes in leading diagnoses, diagnostic confidence, and admission decisions. In the current study, we conducted a multiple regression analysis to identify whether the following were associated with a post-CT diagnosis of NSAP: patient age; patient sex; physicians' years of experience; physicians' pre-CT diagnostic confidence; and physicians' pre-CT admission decision if CT had not been available. We analyzed patients with and those without a pre-CT diagnosis of NSAP separately. For the sensitivity analysis, we excluded patients with different physicians before and after CT. RESULTS: In total, 544 patients were included: 10% (52/544) with a pre-CT diagnosis of NSAP and 90% (492/544) with a pre-CT diagnosis other than NSAP. The leading diagnoses changed after CT in a large proportion of patients with a pre-CT diagnosis of NSAP (38%, 20/52). In regression analysis, we found that physicians' pre-CT diagnostic confidence was inversely associated with a post-CT diagnosis of NSAP in patients with a pre-CT diagnosis other than NSAP (p = 0.0001). No other associations were significant in both primary and sensitivity analyses. CONCLUSION: With the exception of physicians' pre-CT diagnostic confidence, the factors evaluated were not associated with a post-CT diagnosis of NSAP. PMID- 28075620 TI - Diagnostic Efficacy of Structural MRI in Patients With Mild-to-Moderate Alzheimer Disease: Automated Volumetric Assessment Versus Visual Assessment. AB - OBJECTIVE: The purpose of this study was to compare the diagnostic efficacies of an automated volumetric assessment tool and visual assessment in the evaluation of medial temporal lobar atrophy in mild-to-moderate Alzheimer disease (AD). MATERIALS AND METHODS: This retrospective study included 30 patients with mild-to moderate AD and 25 age-matched healthy control subjects undergoing MRI with a 3D fast spoiled gradient recalled-echo sequence at 3 T. The images were processed with fully automated volumetric analysis software. To assess medial temporal lobe (MTL) atrophy, two MTL indexes, which took into account the volumes of the hippocampus and the inferior lateral ventricle, were calculated with the automated volumetric assessment software. In addition, two neuroradiologists assessed MTL atrophy visually using the Scheltens scale. ROC curve analysis was used to compare the diagnostic performances of the two methods. The weighted kappa statistic was used to assess the intrarater and interrater reliability of visual inspection. RESULTS: The automated volumetric assessment tool had moderate sensitivity (63.3%) and high specificity (100%) in differentiating patients with mild-to-moderate AD from control subjects. Visual inspection showed sensitivity of 63.3% and specificity of 92.0%. The diagnostic performance was not significantly different between the two methods (p = 0.536-0.906). Intraobserver reliability for visual inspection was 0.858 and 0.902 for the two reviewers, and interobserver reliability was 0.692-0.780. CONCLUSION: Both the automated volumetric assessment tool and visual inspection can be used to evaluate MTL atrophy and differentiate patients with AD from healthy individuals with good diagnostic accuracy. Thus, the automated tool can be a useful and efficient adjunct in clinical practice for evaluating MTL atrophy in the diagnosis of AD. PMID- 28075621 TI - Key Principles in Quality and Safety in Radiology. AB - OBJECTIVE: The purpose of this article is to introduce the reader to basic concepts of quality and safety in radiology. CONCLUSION: Concepts are introduced that are keys to identifying, understanding, and utilizing certain quality tools with the aim of making process improvements. Challenges, opportunities, and change drivers can be mapped from the radiology quality perspective. Best practices, informatics, and benchmarks can profoundly affect the outcome of the quality improvement initiative we all aim to achieve. PMID- 28075623 TI - Identifying Hidden Zones of the Far Posterior Cartilage of the Femoral Condyles Not Visible During Knee Arthroscopy. AB - OBJECTIVE: The purpose of this study was to compare standard knee arthroscopic and MRI findings and measurements for visualization of the femoral condyle articular cartilage. The hypothesis was that certain posterior cartilage defects identified with MRI may not be accessible with routine arthroscopy. MATERIALS AND METHODS: Six cadaveric knees were examined by routine arthroscopy through standard inferomedial and inferolateral portals. Suture anchors were inserted into the femoral condyles at 30 degrees , 60 degrees , 90 degrees , and 120 degrees of flexion as markers of the cartilage surface at the most posterior aspect of the condyle that could be accessed at each degree of flexion. Each specimen was then examined with 3-T MRI and gross dissection. Measurements were obtained and compared. RESULTS: During arthroscopy at 90 degrees of knee flexion, only 5.83 mm of the medial femoral condyle and 6.83 mm of the lateral femoral condyle were visualized posterior to the anchor placed at 90 degrees of flexion. These arthroscopic measurements were statistically significant underestimates of the actual amount of cartilage identified posterior to the 90 degrees anchor at gross dissection (medial condyle, 44.20 mm; lateral condyle, 37.50 mm) and MRI (medial, 41.33 mm; lateral, 38.87 mm). This indicates that 85.9% of the medial and 81.8% of the lateral posterior articular cartilage of the femoral condyle seen at MRI were not visualized during arthroscopy. CONCLUSION: More than 80% of the articular cartilage proximal to the menisci seen at MRI is not visible during routine arthroscopy. This far posterior articular cartilage should be called the hidden zone. PMID- 28075624 TI - Use of Preprocedural MDCT for Cardiac Implantable Electric Device Lead Extraction: Frequency of Findings That Change Management. AB - OBJECTIVE: Five percent of cardiac implantable electric devices (CIEDs) are removed each year. Percutaneous extraction is preferred but can be complicated if the leads adhere to the vasculature or perforate. The goal of this study is to assess the frequency of findings on dedicated MDCT that alter preprocedural planning for percutaneous CIED extraction. MATERIALS AND METHODS: One hundred patients with CIEDs who underwent MDCT before percutaneous lead extraction were analyzed. Major findings that could preclude percutaneous removal, including lead course and termination, were distinguished from moderately significant findings that could alter but not preclude percutaneous removal, including endofibrosis of leads to the vasculature, lead termination abnormalities, central vein stenosis, or thrombus. Incidental findings were characterized separately. Findings were correlated with preprocedural decisions, the extraction procedure performed, and procedural outcomes. RESULTS: Twenty-six women and 74 men with 125 right ventricular leads, 84 right atrial leads, and 26 coronary venous leads were evaluated. Major findings were present in 7% of patients, including six patients with lead perforation and one with a lead coursing outside a tricuspid annuloplasty ring. Moderately significant findings of endothelial fibrosis were found in 78% of patients. The central veins were narrowed or occluded in 42% of patients, and thrombus was present in 2% of patients. Thirty-six percent of patients had incidental findings, and 4% of patients had unexpected findings requiring immediate inpatient attention. CONCLUSION: MDCT performed before CIED lead extraction is able to identify major and moderately significant findings that can alter either percutaneous extraction or preprocedural planning. The use of dedicated preprocedural MDCT can help to stratify patient risk, guide decision making by the proceduralist, and identify non-catheter-related findings that affect patient management. PMID- 28075622 TI - Imaging Surveillance After Primary Breast Cancer Treatment. AB - OBJECTIVE: Current clinical guidelines are consistent in supporting annual mammography for women after treatment of primary breast cancer. Surveillance imaging beyond standard digital mammography, including digital breast tomosynthesis (DBT), breast ultrasound, and MRI, may improve outcomes. This article reviews the evidence on the performance and effectiveness of breast imaging modalities available for surveillance after treatment of sporadic unilateral primary breast cancer and identifies additional factors to be considered when selecting an imaging surveillance regimen. CONCLUSION: Evidence review supports the use of mammography for surveillance after primary breast cancer treatment. Variability exists in guideline recommendations for surveillance initiation, interval, and cessation. DBT offers the most promise as a potential modality to replace standard digital mammography as a front-line surveillance test; a single published study to date has shown a significant decrease in recall rates compared with standard digital mammography alone. Most guidelines do not support the use of whole-breast ultrasound in breast cancer surveillance, and further studies are needed to define the characteristics of women who may benefit from MRI surveillance. The emerging evidence about surveillance imaging outcomes suggests that additional factors, including patient and imaging characteristics, tumor biology and gene expression profile, and choice of treatment, warrant consideration in selecting personalized posttreatment imaging surveillance regimens. PMID- 28075625 TI - Unenhanced and Contrast-Enhanced MR Angiography and Perfusion Imaging for Suspected Pulmonary Thromboembolism. AB - OBJECTIVE: This article discusses the basics of unenhanced MR angiography (MRA) and MR venography (MRV), time-resolved contrast-enhanced (CE) MRA and dynamic first-pass CE perfusion MRI, and unenhanced and CE MRV, in addition to assessing the clinical relevance of these techniques for evaluating patients with suspected pulmonary thromboembolism and deep venous thrombosis. CONCLUSION: Since the 1990s, the efficacy of MRA or MRV and dynamic perfusion MRI for patients with suspected pulmonary thromboembolism and deep venous thrombosis has been evaluated. On the basis of the results of single-center trials, comprehensive MRI protocols, including pulmonary unenhanced and CE MRA, perfusion MRI, and MRV, promise to be safe and time effective for assessing patients with suspected pulmonary thromboembolism, although future multicenter trials are required to assess the real clinical value of MRI. PMID- 28075626 TI - Could the President and Congress Precipitate a Public Health Crisis? PMID- 28075627 TI - Sokolow et al. Respond. PMID- 28075628 TI - How Will Public Health Fare in a Trump Administration? PMID- 28075630 TI - A Public Health of Consequence: Review of the February 2017 Issue of AJPH. PMID- 28075631 TI - Universal Health Coverage and Public Health: Ensuring Parity and Complementarity. PMID- 28075632 TI - Transgender Population Size in the United States: a Meta-Regression of Population Based Probability Samples. AB - BACKGROUND: Transgender individuals have a gender identity that differs from the sex they were assigned at birth. The population size of transgender individuals in the United States is not well-known, in part because official records, including the US Census, do not include data on gender identity. Population surveys today more often collect transgender-inclusive gender-identity data, and secular trends in culture and the media have created a somewhat more favorable environment for transgender people. OBJECTIVES: To estimate the current population size of transgender individuals in the United States and evaluate any trend over time. SEARCH METHODS: In June and July 2016, we searched PubMed, Cumulative Index to Nursing and Allied Health Literature, and Web of Science for national surveys, as well as "gray" literature, through an Internet search. We limited the search to 2006 through 2016. SELECTION CRITERIA: We selected population-based surveys that used probability sampling and included self reported transgender-identity data. DATA COLLECTION AND ANALYSIS: We used random effects meta-analysis to pool eligible surveys and used meta-regression to address our hypothesis that the transgender population size estimate would increase over time. We used subsample and leave-one-out analysis to assess for bias. MAIN RESULTS: Our meta-regression model, based on 12 surveys covering 2007 to 2015, explained 62.5% of model heterogeneity, with a significant effect for each unit increase in survey year (F = 17.122; df = 1,10; b = 0.026%; P = .002). Extrapolating these results to 2016 suggested a current US population size of 390 adults per 100 000, or almost 1 million adults nationally. This estimate may be more indicative for younger adults, who represented more than 50% of the respondents in our analysis. AUTHORS' CONCLUSIONS: Future national surveys are likely to observe higher numbers of transgender people. The large variety in questions used to ask about transgender identity may account for residual heterogeneity in our models. Public health implications. Under- or nonrepresentation of transgender individuals in population surveys is a barrier to understanding social determinants and health disparities faced by this population. We recommend using standardized questions to identify respondents with transgender and nonbinary gender identities, which will allow a more accurate population size estimate. PMID- 28075634 TI - The Health of the Transgender Community: Out, Proud, and Coming Into Their Own. PMID- 28075636 TI - How Has Legal Recreational Cannabis Affected Adolescents in Your State? A Window of Opportunity. PMID- 28075637 TI - Eliminating Coverage Discrimination Through the Essential Health Benefit's Anti Discrimination Provisions. PMID- 28075638 TI - Children Need Sufficient Time to Eat School Lunch. PMID- 28075639 TI - Enhancing Transgender Health Care. PMID- 28075640 TI - Toward Developing Clinical Competence: Improving Health Care of Gender Diverse People. PMID- 28075641 TI - The Transgender Women of Color Initiative: Implementing and Evaluating Innovative Interventions to Enhance Engagement and Retention in HIV Care. AB - To improve health outcomes among transgender women of color living with HIV, the Health Resources and Services Administration's Special Programs of National Significance program funded the Enhancing Engagement and Retention in Quality HIV Care for Transgender Women of Color Initiative in 2012. Nine demonstration projects in four US urban areas implemented innovative, theory-based interventions specifically targeting transgender women of color in their jurisdictions. An evaluation and technical assistance center was funded to evaluate the outcomes of the access to care interventions, and these findings will yield best practices and lessons learned to improve the care and treatment of transgender women of color living with HIV infection. PMID- 28075642 TI - Shaping a New Field: Three Key Challenges for Population Health Science. PMID- 28075644 TI - Carbon Footprint of Water in California. PMID- 28075646 TI - AJPH Global News. PMID- 28075645 TI - Lessons From a 2016 Large-Scale Contamination of Cereals With Salmonella altona in Israel. PMID- 28075647 TI - More States Should Regulate Pain Management Clinics to Promote Public Health. PMID- 28075648 TI - Leveraging Housing Vouchers to Address Health Disparities. PMID- 28075649 TI - Polls, the Election, and Public Health Research: Reaching the Hard to Reach. PMID- 28075650 TI - Pharmacokinetic evaluation of pregabalin for the treatment of generalized anxiety disorder. AB - INTRODUCTION: Pregabalin is an alternative compound to SSRIs and SNRIs for the first-line treatment of generalized anxiety disorder (GAD). Areas covered: We describe the pharmacokinetic properties of pregabalin and their implications for the treatment of GAD. A search in the main database sources (Medline, ISI, Web of Knowledge and Medscape) was performed in order to obtain a comprehensive and balanced evaluation about the clinical implications of the pharmacokinetic properties of pregabalin in the treatment of GAD. The word "pregabalin" was associated with "pharmacokinetics", "interactions"', "GAD", "anxiety" and "tolerability". No restriction criteria were established in relation to methodology or publication year. Only English-language articles were selected. Expert opinion: Pregabalin is a safe and efficacious compound for GAD treatment. Short half-life (preventing persistence of side effects), absence of active metabolites and no interactions with CYP450 enzymatic system are all favorable pharmacokinetic properties for the treatment of GAD patients, including those with comorbid depressive symptoms or medical conditions. On the other hand, prescription of pregabalin should be handled with caution to minimize the incidence of renal impairment (especially in elderly patients), where a history of substance misuse or concomitant medications (e.g. anti-hypertensives or some antibiotics) are risk factors that can affect renal function. PMID- 28075651 TI - Imaging Characteristics of Prostate Cancer Patients Who Discontinued Active Surveillance on 3-T Multiparametric Prostate MRI. AB - OBJECTIVE: Early-stage prostate cancer may be followed with active surveillance to avoid overtreatment. Our institution's active surveillance regimen uses annual MRI in place of serial biopsies, and biopsies are performed only when clinically necessary. The objective of our study was to report the multiparametric MRI characteristics of prostate cancer patients who discontinued active surveillance at our institution after repeat imaging revealed possible evidence of tumor upgrading. MATERIALS AND METHODS: The Department of Urology at Winthrop University Hospital prospectively maintains a database of prostate cancer patients who are monitored with active surveillance. At the time of this study, there were 200 prostate cancer patients being monitored with active surveillance. Of those patients, 114 patients had an initial multiparametric MRI study that was performed before active surveillance started and at least one follow-up multiparametric MRI study that was performed after active surveillance began. The MRI findings were evaluated and correlated with pathology results, if available. RESULTS: Fourteen patients discontinued active surveillance because changes on follow-up MRI suggested progression of cancer. Follow-up MRI showed an enlarged or more prominent lesion compared with the appearance on a previous MRI in three (21.4%) patients, a new lesion or lesions suspicious for cancer in two (14.3%) patients, and findings suspicious for or confirming extracapsular extension in nine (64.3%) patients. Seven of the 14 (50.0%) patients had a biopsy after follow up multiparametric MRI, and biopsy results led to tumor upgrading in six of the 14 (42.9%) patients. The duration of active surveillance ranged from 4 to 110 months. All patients received definitive treatment. CONCLUSION: The small number of patients with follow-up multiparametric MRI findings showing worsening disease supports the role of MRI in patients with early-stage prostate cancer. Multiparametric MRI is useful in monitoring patients on active surveillance and may identify patients with clinically significant cancer amenable to definitive treatment. PMID- 28075652 TI - Parent-Adolescent Cross-Informant Agreement in Clinically Referred Samples: Findings From Seven Societies. AB - To conduct international comparisons of parent-adolescent cross-informant agreement in clinical samples, we analyzed ratings on the Child Behavior Checklist (CBCL) and Youth Self-Report (YSR) for 6,762 clinically referred adolescents ages 11-18 from 7 societies (M = 14.5 years, SD = 2.0 years; 51% boys). Using CBCL and YSR data, we asked the following questions: (a) Do parents report more problems for their adolescent children than the adolescents report about themselves? (b) How do cross-informant correlations (rs) for scale scores differ by problem type and by society? (c) How well do parents and adolescents, on average, agree regarding which problems they rate as low, medium, or high? (d) How does within-dyad item agreement vary within and between societies? (e) How do societies vary in dichotomous cross-informant agreement with respect to the deviance status of the adolescents? CBCL and YSR scores were quite similar, with small and inconsistent informant effects across societies. Cross-informant rs averaged .47 across scales and societies. On average, parents and adolescents agreed well regarding which problem items received low, medium, or high ratings (M r = .87). Mean within-dyad item agreement was moderate across all societies, but dyadic agreement varied widely within every society. In most societies, adolescent noncorroboration of parent-reported deviance was more common than parental noncorroboration of adolescent-reported deviance. Overall, somewhat better parent-adolescent agreement and more consistency in agreement patterns across diverse societies were found in these seven clinical samples than in population samples studied using the same methods. PMID- 28075653 TI - Serum creatine kinase elevations in ultramarathon runners at high altitude. AB - OBJECTIVES: Creatine kinase (CK) is a sensitive enzyme marker for muscle damage in athletes. Elevated CK levels have been reported in many endurance physical activities. The consequence and possible long-term sequela of the CK elevation in athletes is unknown. There is a paucity of literature stating actual numerical values of CK associated with competing in an ultramarathon with extreme environmental conditions. Our hypothesis was that the serum CK levels increase significantly as a result of running a 161 km ultramarathon at high altitude. METHODS: This was a prospective observational study of participants of the Leadville 100 ultramarathon race in Leadville, Colorado at high altitude (2800 3840 m) in August 2014. We collected blood samples from sixty-four volunteer runners before and eighty-three runners immediately after the race. RESULTS: Out of 669 athletes who started the race, 352 successfully completed the race in less than the 30-hour cut-off time (52%). The majority of runners were male (84%). We were able to collect both pre- and post-race blood samples from 36 runners. Out of these 36 runners, the mean pre-race CK was increased from 126 +/- 64 U/L to 14,569 +/- 14,729 U/L (p < 0.001). There was a weak linear correlation between lower sodium levels and higher CK levels post-race (p = 0.003; R2 = 0.10). Using a multiple regression model, other than a negative correlation between sodium and CK levels (p = 0.001), there were no statistically significant correlations between post-race CK levels and athletes' age, BMI, or finishing time. CONCLUSIONS: Significant elevation of CK level occurs as a result of running ultramarathons. The majority of athletes with significantly elevated CK levels were asymptomatic and required no major medical attention. PMID- 28075654 TI - ZSOLT SZABO MD, PhD. PMID- 28075655 TI - Experiences and Preferences for End-of-Life Care for Young Adults with Cancer and Their Informal Carers: A Narrative Synthesis. AB - To review the qualitative literature on experiences of and preferences for end-of life care of people with cancer aged 16-40 years (young adults) and their informal carers. A systematic review using narrative synthesis of qualitative studies using the 2006 UK Economic and Social Research Council research methods program guidance. Seven electronic bibliographic databases, two clinical trials databases, and three relevant theses databases were searched from January 2004 to October 2015. Eighteen articles were included from twelve countries. The selected studies included at least 5% of their patient sample within the age range 16-40 years. The studies were heterogeneous in their aims, focus, and sample, but described different aspects of end-of-life care for people with cancer. Positive experiences included facilitating adaptive coping and receiving palliative home care, while negative experiences were loss of "self" and nonfacilitative services and environment. Preferences included a family-centered approach to care, honest conversations about end of life, and facilitating normality. There is little evidence focused on the end-of-life needs of young adults. Analysis of reports including some young adults does not explore experience or preferences by age; therefore, it is difficult to identify age-specific issues clearly. From this review, we suggest that supportive interventions and education are needed to facilitate open and honest communication at an appropriate level with young people. Future research should focus on age-specific evidence about the end-of life experiences and preferences for young adults with cancer and their informal carers. PMID- 28075658 TI - Labware, Lab Supplies, and Microplates. PMID- 28075656 TI - Intimate Partner Violence and 5-Year Weight Change in Young Women: A Longitudinal Study. AB - BACKGROUND: Intimate partner violence (IPV) and obesity are national public health problems that are potentially associated. We examined the association between IPV exposure and 5-year weight gain in young women. We also examined whether depressive mood conferred additional increases in weight gain. MATERIALS AND METHODS: Analyses were conducted among women in Project EAT, a longitudinal cohort study of weight-related health, which has collected data at three 5-year survey waves: "EAT I" (mean age 15 years), "EAT II" (mean age 19 years), and "EAT III" (mean age 25 years). Height and body weight were self-reported at each survey wave. IPV victimization and depressive mood were assessed on the EAT II survey. The study comprised women with data on IPV and body mass index (BMI) (N = 619). Linear regression analyses examined (1) 5-year (EAT II to EAT III) BMI change as a function of IPV exposure and (2) 5-year BMI change as a function of depressive mood at EAT II in women with and without IPV exposure. RESULTS: Almost 20% of the study sample reported IPV. Women exposed to both physical and sexual IPV at EAT II gained 1.1 kg/m2 (95% CI -0.2 to 2.4) more, over 5 years, than women unexposed to IPV, although this did not reach statistical significance. Among those with IPV exposure, depressive mood at EAT II was associated with an additional increase in BMI of 1.8 kg/m2 (95% CI 0.2-3.4) relative to no depressive mood. CONCLUSION: Survivors of IPV with depressive mood may have accelerated weight gain. Trauma-informed obesity prevention strategies may be warranted in this group. PMID- 28075662 TI - Centriolin, a centriole-appendage protein, regulates peripheral spindle migration and asymmetric division in mouse meiotic oocytes. AB - Unlike somatic cells mitosis, germ cell meiosis consists of 2 consecutive rounds of division that segregate homologous chromosomes and sister chromatids, respectively. The meiotic oocyte is characterized by an absence of centrioles and asymmetric division. Centriolin is a relatively novel centriolar protein that functions in mitotic cell cycle progression and cytokinesis. Here, we explored the function of centriolin in meiosis and showed that it is localized to meiotic spindles and concentrated at the spindle poles and midbody during oocyte meiotic maturation. Unexpectedly, knockdown of centriolin in oocytes with either siRNA or Morpholino micro-injection, did not affect meiotic spindle organization, cell cycle progression, or cytokinesis (as indicated by polar body emission), but led to a failure of peripheral meiotic spindle migration, large polar body emission, and 2-cell like oocytes. These data suggest that, unlike in mitotic cells, the centriolar protein centriolin does not regulate cytokinesis, but plays an important role in regulating asymmetric division of meiotic oocytes. PMID- 28075666 TI - The European Board of Hand Surgery Diploma Examination 2014. PMID- 28075670 TI - The Indian Society For Surgery of the Hand Executive Committee. PMID- 28075663 TI - Comparative study of Her-2, p53, Ki-67 expression and clinicopathological characteristics of breast cancer in a cohort of northern China female patients. AB - The objective was to study the relationship among Her-2, Ki-67, p53 expression and the clinicopathologic characteristics of breast cancer in the patients of northern China. Expression of Her-2, Ki-67, p53 and clinical characteristics of 260 breast cancer patients were retrospectively studied. Her-2 overexpression led to higher incidence rates of infiltrating ductal carcinoma and axillary lymph node metastasis, bigger diameters of the primary tumors, later pTNM staging, and a lower incidence rate of ductal carcinoma in situ (p < 0.05). High expression of ER and PR led to fewer patients classified histologically in higher grade (p = 0.001), while high expression of Ki-67 and p53 caused more patients classified histologically in higher grade (p = 0.001). In patients histologically classified in grade 1 and 2, the expression of Ki-67 and p53 was significantly (p = 0.001) higher, and the expression of ER and PR was significantly lower, in Her-2 positive patients than Her-2 negative patients. Breast cancer with Her-2 overexpression was more likely to recur and metastasize than Her-2 negative breast cancer. Higher coincidence of high expression of p53 and Ki-67 with Her-2 overexpression and more progressed tumors suggested that in addition to p53, Ki 67 might also be a prognostic biomarker of breast cancer. PMID- 28075669 TI - Editorial. PMID- 28075671 TI - Hospitalization rates for intussusception in children aged 0-59 months from 2009 to 2014 in Italy. AB - The real cause of intussusception is not fully understood and a variety of conditions have been associated with it (Meckel diverticulum, polyps, duplication cysts, parasites, Henoch-Schonlein purpura, cystic fibrosis, hemolytic-uremic syndrome and infectious gastroenteritis). Furthermore few European countries, following WHO recommendation to monitor baseline incidence of intussusception before implementation of immunization program for rotavirus, used intussusception rate as a baseline value to compare the same figures in the period before and after introduction of vaccination. In this study, data of intussusception hospitalizations occurred among Italian children aged 0 through 59 months from 2009 to 2014 were analyzed. A total amount of 3,088 children were included, accounting for a hospitalization rate of 20.2 per 100,000. Overall, the hospitalization rate for intussusception had a slight increase in trend from 2009 to 2014 (18%). In particular children 0-11 months had a hospitalization rate higher than 12-59 months with an aggregate value of 36 Vs. 16 per 100,000 respectively. Among all children hospitalized for intussusception a total of 239 (7.7%) had also a previous or concomitant hospitalization for gastroenteritis. This study demonstrates that Italian hospitalizations for intussusception are increasing by time and the role played by different risk factors, including acute gastroenteritis, have to be investigated in the future. These data could be useful to monitor intussusception hospitalization in the perspective of anti rotavirus vaccination introduction in Italy. PMID- 28075672 TI - Application Areas. PMID- 28075673 TI - Introducing the 2014 JALA Ten Honorees. PMID- 28075679 TI - Presentation To the Best Candidate in the European Diploma in Hand Surgery Examination 2009. PMID- 28075680 TI - Re: Salem et al. Analysis of rewarming curves in Raynaud's phenomenon of various aetiologies. J Hand Surg Eur. 2009, 34: 621-6. PMID- 28075682 TI - Lab Automation Services. PMID- 28075687 TI - Automated Systems. PMID- 28075688 TI - Genome editing of crops: A renewed opportunity for food security. AB - Genome editing of crop plants is a rapidly advancing technology whereby targeted mutations can be introduced into a plant genome in a highly specific manner and with great precision. For the most part, the technology does not incorporate transgenic modifications and is far superior to conventional chemical mutagenesis. In this study we bring into focus some of the underlying differences between the 3 existing technologies: classical plant breeding, genetic modification and genome editing. We discuss some of the main achievements from each area and highlight their common characteristics and individual limitations, while emphasizing the unique capabilities of genome editing. We subsequently examine the possible regulatory mechanisms which governments may be inclined to use in assessing the status of genome edited products. If assessed on the basis of their phenotype rather than the process by which they are obtained, these products will be categorized as equivalent to those produced by classical mutagenesis. This would mean that genome edited products will not be subject to the restrictions imposed on genetically modified products, except in some cases where the mutation involves a large sequence insertion into the genome. We conclude by examining the potential of societal acceptance of genome editing technology, reinforced by a scientific perspective on promoting such acceptance. PMID- 28075691 TI - Complexity of brain signals is associated with outcome in preterm infants. AB - A characteristic feature of complex healthy biological systems is the ability to react and adapt to minute changes in the environment. This 'complexity' manifests itself in highly irregular patterns of various physiological measurements. Here, we apply Multiscale Entropy (MSE) analysis to assess the complexity of systemic and cerebral near-infrared spectroscopy (NIRS) signals in a cohort of 61 critically ill preterm infants born at median (range) gestational age of 26 (23 31) weeks, before 24 h of life. We further correlate the complexity of these parameters with brain injury and mortality. Lower complexity index (CoI) of oxygenated haemoglobin (HbO2), deoxygenated haemoglobin (Hb) and tissue oxygenation index (TOI) were observed in those infants who developed intraventricular haemorrhage (IVH) compared to those who did not (P = 0.002, P = 0.010 and P = 0.038, respectively). Mean CoI of HbO2, Hb and total haemoglobin index (THI) were lower in those infants who died compared to those who survived (P = 0.012, P = 0.004 and P = 0.003, respectively). CoI-HbO2 was an independent predictor of IVH (P = 0.010). Decreased complexity of brain signals was associated with mortality and brain injury. Measurement of brain signal complexity in preterm infants is feasible and could represent a significant advance in the brain-oriented care. PMID- 28075692 TI - Comparing Emergency Department Use Among Medicaid and Commercial Patients Using All-Payer All-Claims Data. AB - The high rate of emergency department (ED) use by Medicaid patients is not fully understood. The objective of this paper is (1) to provide context for ED service use by comparing Medicaid and commercial patients' differences across ED and non ED health service use, and (2) to assess the extent to which Medicaid-commercial differences in ED use can be explained by observable factors in administrative data. Statistical decomposition methods were applied to ED, mental health, and inpatient care using 2011-2013 Medicaid and commercial insurance claims from the Oregon All Payer All Claims database. Demographics, comorbidities, health services use, and neighborhood characteristics accounted for 44% of the Medicaid commercial difference in ED use, compared to 83% for mental health care and 75% for inpatient care. This suggests that relative to mental health and inpatient care, a large portion of ED use cannot be explained by administrative data. Models that further accounted for patient access to different primary care physicians explained an additional 8% of the Medicaid-commercial difference in ED use, suggesting that the quality of primary care may influence ED use. The remaining unexplained difference suggests that appropriately reducing ED use remains a credible target for policy makers, although success may require knowledge about patients' perceptions and behaviors as well as social determinants of health. PMID- 28075693 TI - Making the Paradigm Shift from Siloed Population Health Management to an Enterprise-Wide Approach. AB - Health systems across the United States have started their journeys toward population health management and the future of accountable care. Models of population health management include patient-centered medical homes and private sector accountable care organizations (ACOs). Other models include public sector efforts, such as Physician Group Practice Transition Demonstrations, Medicare Health Care Quality Demonstration Programs, Beacon Communities, Medicare Shared Savings Program, and Pioneer ACOs. As a result, health care organizations often have pockets of population health initiatives that lack an enterprise-wide strategy. The next steps are to build on these efforts, leverage the learnings from these experiences, and incorporate the initiatives into an overarching framework and a road map for the future. This paper describes the current challenge many organizations face to implement an enterprise solution, describes how to transition from existing siloed initiatives, and shares a case study of how Mayo Clinic launched its Mayo Model of Community Care. PMID- 28075694 TI - Cutaneous Eruption in a U.S. Woman with Locally Acquired Zika Virus Infection. PMID- 28075695 TI - Lessons from Launching the Diabetes Prevention Program in a Large Integrated Health Care Delivery System: A Case Study. AB - There is urgent need for health systems to prevent diabetes. To date, few health systems have implemented the evidence-based Diabetes Prevention Program (DPP), and the few that have mostly partnered with community-based organizations to implement the program. Given the recent decision by the Centers for Medicare & Medicaid Services to reimburse for diabetes prevention, there is likely much interest in how such programs can be implemented within large health systems or how community partnerships can be expanded to support DPP implementation. Beginning in 2010, Montefiore Health System (MHS), a large health care system in the Bronx, NY, partnered with the Young Men's Christian Association (YMCA) of Greater New York to deliver the YMCA's DPP. Over 4 years, 1390 referrals to YMCA's DPP were made; 287 participants attended >=3 classes, and average weight loss was 3.4%. Because of increased patient demand and internal capacity, MHS assumed responsibility for DPP implementation in May 2015. Fully integrating the program within the health system took 5-6 months, including configuring electronic health record templates/reports, hiring a coordinator, and creating clinical referral workflows/training guides. Billing workflows were designed for risk-based contracts. In the first 11 months of implementation, 1277 referrals were made, and referrals increased over time. Twenty-four class cycles were initiated, and 282 patients began attending classes. Average weight loss among 61 graduates from the Summer/Fall 2015 wave of MDPP classes was 3.8%. Additional opportunities for expansion include training allied health staff, providing patient incentives, increasing master trainer capacity, offering DPP to employees, and securing reimbursement. PMID- 28075696 TI - Dual Eligibles' Experience of Care with North Carolina's Patient-Centered Medical Home. AB - Although individuals enrolled in both Medicare and Medicaid (dual eligibles) are among those with the nation's greatest need, at $300 billion per year, their care is also expensive and beset by quality problems. Previous research found problems associated with inadequate coordination of benefits and services; however, these studies have largely used quantitative approaches and focused on providers-few studies have explored the perspective of dual eligible patients. In an effort to improve care and reduce costs, North Carolina (NC) developed a Patient-Centered Medical Home (PCMH) model centered on a continuous relationship with a primary care provider who is responsible for coordination of services and addressing patients' health care needs by providing direct services or arranging care with other qualified professionals. This article presents the history of the NC PCMH model and describes results of an in-depth qualitative investigation of dual eligible patients' experience of care with this model. Experience of care was captured through 11 focus groups with 61 dual eligible patients. Focus groups were audio recorded and analyzed using NVivo 9 software, which supported the categorization of data into themes based on frequency and intensity of discussions. Findings indicate that dual eligible patients were generally satisfied by the care received through the NC PCMH program. However, many patients reported continuity of care issues, problems accessing necessary prescription drugs, and difficulties navigating the health care delivery system. Findings also revealed that conflicting state and federal Medicaid drug co-pay policies confused and limited access for some patients. PMID- 28075699 TI - Outcome and Impact Evaluation of a Transgender Health Course for Health Profession Students. AB - PURPOSE: Being transgender is associated with numerous health disparities, and transgender individuals face mistreatment and discrimination in healthcare settings. At the same time, healthcare professionals report inadequate preparation to care for transgender people, and patients often have to teach their own medical providers about transgender care. Our study aimed to evaluate the impact of an elective course for health profession students in transgender health that was implemented to address these gaps in provider knowledge. METHODS: Students participated in a 10-session, lunch-hour elective course during the spring of 2015. To evaluate impact, course participants completed pre-, immediately post-, and 3-month postcourse questionnaires, including a previously validated nine-item transphobia scale, to determine the course's effect on knowledge, attitudes, and beliefs about transgender health. RESULTS: Forty-six students completed the pre- and immediately postelective questionnaire (74% response rate). Compared with pre-elective surveys, immediately postelective scores demonstrated increased knowledge in most domains and reduced transphobia. Specific knowledge domains with improvements included terminology, best practices for collecting gender identity, awareness of the DSM-V gender dysphoria diagnosis, medications used for gender affirmation, and relevant federal policies. A previously validated transphobia scale was found to have good reliability in the current sample. CONCLUSION: This elective course led to positive short-term changes in measures of multiple knowledge domains and reduced measures of transphobia among health profession students. Further study is needed to assess the long-term impact. Our methods and findings, including the demonstration of reliability of a previously validated nine-item transphobia scale, serve as formative data for the future development of theory-based transgender medicine curricula and measures. PMID- 28075698 TI - Older Adults and Management of Medical Devices in the Home: Five Requirements for Appropriate Use. AB - Medical devices, or instruments or tools to manage disease, are increasingly used in the home, yet there have been limited evaluations of how older adults and caregivers safely use these devices. This study concerns a qualitative evaluation of (1) barriers and facilitators of appropriate use, and (2) outcomes of inappropriate use, among older adults at the transition from hospital to home with skilled home health care (SHHC). Guided by a human factors engineering work system model, the authors (1) conducted direct observations with contextual inquiry of the start-of-care or resumption-of-care SHHC provider visit, and (2) semi-structured interviews with 24 older adults and their informal caregivers, and 39 SHHC providers and administrators. Five requirements for the appropriate use of home medical devices were identified. A systems approach integrating the hospital with the SHHC agency is needed to make the use of home medical devices safer. PMID- 28075701 TI - Expression Analysis of Genes Associated with Prolificacy in FecB Carrier and Noncarrier Indian Sheep. AB - The effect of FecB mutation on the gene expression in FecB carrier and noncarrier estrous synchronized ewes, has been analyzed. For this study the whole ovarian tissues and Graafian follicles were collected from estrus synchronized FecB carrier Garole, and non-carrier Deccani Indian sheep, showing remarkable differences in the numbers of preovulatory follicles among two groups. Eleven potential candidate genes (BMP15, GDF9, BMP4, BMP7, BMPR1B, BMPR1A, SMAD9, LHCGR, FSHR, IGF1R, and STAT5) were selected for their expression analysis by SybrGreen based real-time PCR, across ovaries and Graafian follicles of different fecundity groups, for having better insights into the effect of FecB genotypes on follicular development. Variable expression was observed for almost all the genes included in the present study among high and low fecundity groups that was most significant for the BMP7, BMP4, LHCGR, and FSHR transcripts in the ovarian follicles of high and low fecundity ewes, indicating their importance in governing the fecundity in FecB carrier, Indian Garole sheep. BMP4 expression among the genes studied was significantly higher in FecB carrier Garole sheep. This study confirms the changes in mRNA expression of the genes implicated in follicular development in FecB carrier and noncarrier Indian sheep breeds. PMID- 28075702 TI - Features of Patient-Centered Primary Care and the Use of Ambulatory Care. AB - This study explores the association between patients' use of ambulatory care resources and features of patient-centered primary care (PCPC), specifically clinic-level National Committee for Quality Assurance (NCQA) recognition of PCPC, continuity of care, and care team communication. Data for this study were compiled from the electronic health records of a large multispecialty group practice in California, covering the period between 2009 and 2010 for 37,042 nonelderly patients under capitated managed care plans. Regression analysis of these data was performed using a generalized linear model, comparing measures of patient-level annual resource use (in total relative value units [tRVUs]) against measures of both clinic- and patient-level PCPC, and patient-level risk (eg, age, comorbidities). Patients linked to NCQA Recognition Level III versus Level II clinics used 4.8% (P < 0.001) fewer ambulatory care tRVUs. Patients with a 1 standard deviation increase in primary care continuity used 3.9% (P < 0.001) fewer ambulatory care tRVUs. Patients who switched primary care physicians used 17.4% (P < 0.001) more ambulatory care tRVUs. These results indicate that PCPC is associated with reductions in resource use related to both clinic- and patient level features. The patient-level associations document within-clinic heterogeneity in PCPC. Based on these findings, practices can be encouraged to perform consistent with high NCQA recognition, promote primary care continuity, and be mindful of differences at an individual patient level. PMID- 28075704 TI - Changes in Cardiorespiratory Responses and Kinematics With Hippotherapy in Youth With and Without Cerebral Palsy. AB - PURPOSE: The purpose of this study was to characterize pelvic displacement and cardiorespiratory responses to simulated horseback riding and walking in youth with cerebral palsy and to compare responses to youth without cerebral palsy before and after 8 weeks of hippotherapy. METHOD: Eight youth with cerebral palsy (Mage = 10 +/- 4 years; Mheight = 137 +/- 24 cm; Mweight = 32 +/- 16 kg) and 8 youth without cerebral palsy (Mage = 11 +/- 2 years; Mheight = 149 +/- 14 cm; Mweight = 48 +/- 15 kg) underwent a hippotherapy intervention. Participants completed simulated horseback riding at an intensity approximating a fast walk (0.65 Hz) and walked on a treadmill (1 mph, 0% grade) before and after hippotherapy. Pelvic displacement along the anterior-posterior, vertical, and medial-lateral axes, heart rate, oxygen consumption, ventilation, and blood pressure were measured at rest and during steady-state exercise in both exercise modes. RESULTS: Kinematics and cardiorespiratory responses were similar between the 2 groups during simulated horseback riding (p > .05 for all) before the intervention. Significantly greater cardiorespiratory responses were observed in the youth with cerebral palsy compared with the group without cerebral palsy while walking before and after the intervention (p < .05, effect sizes 26% to 237% greater). Eight weeks of hippotherapy did not alter responses, but anecdotal improvements in gait, balance, posture, and range of motion were observed in those with cerebral palsy. CONCLUSION: These results contribute to our understanding regarding the efficacy of hippotherapy as an intervention to improve functional abilities in those with cerebral palsy. PMID- 28075705 TI - Tracking of Gross Motor Coordination From Childhood Into Adolescence. AB - PURPOSE: The purpose of this study was to analyze tracking and stability of motor coordination in children from age 6 years to ages 9 and 13 years. METHOD: Data were from the Copenhagen School Child Intervention Study. Motor coordination (MC) was measured using the korperkoordinationstest fur Kinder (KTK) test. The crude performance score on every item was converted into a standardized "score" based on the original German reference study, which was used to generate a total standardized motor coordination (MQ) score. The MQ scores, which represented children's level of gross MC, were classified as low (MQ score < 85), normal (MQ score = 85-115), or high (MQ score>115). Pearson correlation was used to calculate the tracking coefficients of each KTK element and MQ score, and weighted kappa was used to analyze maintenance in MC classification groups. Mixed effects logistic regression analyses were performed to examine the odds of remaining in the low MC group over time based on body mass index (BMI), weight, and height tertiles. RESULTS: Tracking coefficients among the MQ score and each KTK element at different ages were moderate (r>.35). Children in the highest BMI and weight tertiles had a 5.44 and 5.15 times greater chance to be in the lower MC classification group during the 7-year follow-up, respectively, in comparison with children in their lowest tertiles. CONCLUSION: MC tracked moderately through childhood to early adolescence. Because heavier children had a greater chance to be in the lower MC group at older ages, intervention may be useful at earlier ages for those with lower MC and disadvantageous weight status. PMID- 28075707 TI - Is Flibanserin Meaningfully Superior to Placebo? PMID- 28075708 TI - Conflict Resolution in Chinese Adolescents' Friendship: Links with Regulatory Focus and Friendship Satisfaction. AB - It is generally acknowledged that people adopt different resolution strategies when facing conflicts with others. However, the mechanisms of conflict resolution are still unclear and under researched, in particular within the context of Chinese adolescents' same-sex friendship relations. Thus, the present study investigated the mediator role of conflict resolution strategies in the relationship between regulatory foci and friendship satisfaction for the first time. 653 Chinese adolescents completed the regulatory foci, conflict resolution style, and friendship satisfaction measures. The results of the structure equation modeling showed that while promotion focus was positively associated with problem-solving and compliance, prevention focus was positively associated with withdrawal and conflict engagement. In addition, problem-solving mediated the relationship between promotion focus and friendship satisfaction, and conflict engagement mediated the relationship between prevention focus and friendship satisfaction. These findings contribute to understanding Chinese adolescents' use of conflict resolution strategies as well as the relationship between regulatory foci and behavioral strategies in negative situations. PMID- 28075709 TI - The Influence of Exercise Intensity on Postexercise Baroreflex Sensitivity. AB - PURPOSE: The purpose of this study was to investigate the influence of exercise intensity on postexercise supine and tilt baroreflex sensitivity (BRS). METHOD: Nine healthy, active men performed 2 conditions of interval cycling of 40% maximal work rate (WRmax) and 75% WRmax of matched work done and a control condition of no exercise in a counterbalanced order. BRS outcome measures were determined at preexercise and postexercise up to +24 hr in supine and tilt positions. R-R interval and blood pressure data were collected over consecutive 10-min periods and were analyzed by Fast Fourier transformation analysis. RESULTS: A fully repeated analysis of variance revealed a significant interaction (p < .05) between time and condition in supine for BRSalphaLF, F(3, 134) = 5.19, p < .05, ES = .39, and BRSTFTG, F(3, 134) = 5.65, p < .05, ES = .41, and in tilt for BRSUpUp, F(3, 134) = 3.54, p < .05, ES = .31, BRSDownDown, F(3, 134) = 5.94, p < .05, ES = .43, BRSalphaLF, F(4, 134) = 6.23, p < .05, ES = .44, and BRSTFTG, F(4, 134) = 9.22, p < .05, ES = .54. There were significant differences (p < .05) between condition comparisons at +15 min and between control and 75% WRmax and between the 40% WRmax and 75% WRmax conditions at +60 min. At +15 min, BRS was lower in the 75% WRmax condition compared with the 40% WRmax condition and the control condition, and it was lower in the 40% WRmax condition than in the control condition. CONCLUSION: The findings demonstrate an intensity-dependent relationship in the BRS response following exercise. PMID- 28075710 TI - Corrigendum. AB - Camp CL, Stuart MJ, Krych AJ. Current concepts of articular cartilage restoration techniques in the knee. Sports Health. 2014;6(3):265-273. Original DOI: 10.1177/1941738113508917 In the above article, a citation was omitted on pages 266 and 267 in the discussion of the treatment algorithm. The algorithm, and Figure 2, were adapted from Cole et al. and should have been cited as such. The online version of the article has been updated as follows. PMID- 28075713 TI - An Activist Approach to Sport Meets Youth From Socially Vulnerable Backgrounds: Possible Learning Aspirations. AB - PURPOSE: This study was a 2-phase activist research project aimed at co-creating a prototype pedagogical model for working with youth from socially vulnerable backgrounds in a sport context. This article addresses the learning aspirations (learning outcomes) that emerged when we created spaces for youth to develop strategies to manage the risks they face in their community. METHOD: This study took place in a socially and economically disadvantaged neighborhood in a Brazilian city where we worked with a group of 17 boys aged 13 to 15 years old, 4 coaches, a pedagogic coordinator, and a social worker. During a 6-month period, we collected multiple sources of data including field journal entries/observations (38) and audio records of youth work sessions (18), coaches' work sessions (16), combined coaches and youth work sessions (3), and meetings between the lead and the 2nd author for debriefing and planning sessions (36). RESULTS: By using an activist approach, 4 learning aspirations emerged: becoming responsible/committed, learning from mistakes, valuing each other's knowledge, and communicating with others. CONCLUSION: Findings suggest there is a need for more sports programs that start from young people's concrete needs and life situations and look to create places for youth to see alternative possibilities and take action. PMID- 28075715 TI - Abstracts of the 18th Annual Meeting of the International Society of Addiction Medicine (ISAM)-2016. PMID- 28075716 TI - Factors Predicting the Provision of Smoking Cessation Services Among Occupational Health Nurses in Thailand. AB - The purpose of this study was to identify factors predicting occupational health nurses' provision of smoking cessation services. Data were collected via a self administered questionnaire distributed to 254 occupational health nurses in Thailand. Analysis by structural equation modeling revealed that self-efficacy directly and positively influenced smoking cessation services, and mediated the relationship between workplace factors, nurse factors, and smoking cessation services. The final model had good fit to the data, accounting for 20.4% and 38.0% of the variance in self-efficacy and smoking cessation services, respectively. The findings show that self-efficacy is a mediator that influences provision of smoking cessation services by occupational health nurses. Interventions to enhance nurses' self-efficacy in providing smoking cessation services are expected to promote provision of smoking cessation services to workers. PMID- 28075717 TI - Reviewing Manuscripts for JAPNA. PMID- 28075718 TI - Whole Health Begins With Mental Health. PMID- 28075720 TI - Transferred bank staff to lose out on NHS pensions. AB - Bank nurses who worked for a trust that has transferred staff to a private provider are to lose access to the NHS pension scheme from this week. PMID- 28075721 TI - Treasury puts selective increments on review body's agenda. AB - The body that makes recommendations on NHS pay increases has been asked to look into offering more generous rises to some staff than others. PMID- 28075722 TI - Council members question trusts' regional pay plans as dispute widens. AB - Local authorities have intervened in a row over moves by 20 NHS trusts in the south west of England to cut nurses' pay, terms and conditions. PMID- 28075725 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28075728 TI - Call for funding of nursing placements. AB - An independent commission examining how nurse education and training can be improved is likely to call for funding for employers who offer nursing students clinical placements. PMID- 28075729 TI - Concern over centralisation of specialist care services. AB - RCN Wales has expressed concerns about plans to concentrate specialist services such as neonatal care at four or five hospital sites in south Wales. PMID- 28075732 TI - People with disabilities need new champion like the late alf morris. AB - I welcome Stephen Wright's tribute to the late Lord Morris of Manchester (September 12). PMID- 28075731 TI - E-learning is an exciting way to broaden our horizons. AB - Many thanks to Heather Bain for her article highlighting the potential for e learning to build international links and extend our access to learning (careers September 12). PMID- 28075733 TI - Our experience of psychological difficulties and mental illness. AB - Steve Flatt seems to take issue with the notion of mental illness (reflections September 12), referring to 'psychological distress' and 'psychological difficulties', but without defining what he means by these terms. PMID- 28075734 TI - Losing person-centred care to more technical approaches. AB - I welcome Jennifer Trueland's article on compassion (features September 12), especially given the ongoing criticisms of nursing care. I too am concerned that the profession is losing the skill of compassion in favour of more technical and medical approaches. PMID- 28075735 TI - Workforce. AB - A recent report from the National Audit Office (NAO) gave an insight into how the NHS looks in the four UK countries. Its publication also showed us how the media and politicians spin the results selectively. PMID- 28075736 TI - Medicines management. AB - I am a first-year nursing student. What medicines management advice can you give me? PMID- 28075737 TI - Constant reorganisation of the NHS is pointless and counterproductive. AB - The first paragraph of the editorial (September 12) summarises the state of the NHS over the past 20 to 30 years, with new names and logos, and managers being made redundant, only to be re-engaged. PMID- 28075738 TI - Guidelines must be underpinned by compassion and empathy. AB - It is refreshing to read that the Leadership in Compassionate Care programme is benefiting from L1 million of funding from former nurse Ann Gloag (features September 12). PMID- 28075739 TI - Deconstruction is easy, the hard part is offering alternatives. AB - Jane Wright's article (Art & Science September 19) is a decent academic exercise that highlights the shortcomings of clinical supervision, but offers little by way of advancing our thinking. What is offered by Ms Wright to take its place? Sadly she offers no alternative. PMID- 28075740 TI - Leaders need to show more courage. AB - Since I wrote the editorial for Black History Month in 2011, the NHS has changed almost beyond recognition. The 'no major change' promised by Andrew Lansley on taking office as health secretary in 2010 has turned into a huge, organisational and economic restructuring. It has culminated in an entirely new ministerial team and the appointment of Jane Cummings as chief nursing officer and Viv Bennett as director of nursing at the Department of Health. PMID- 28075741 TI - Our experience - the good and the bad - of working in the health service. AB - 'I spent 13 years working in an older people's care ward before coming out into the community. PMID- 28075742 TI - 'I have rarely experienced discrimination in the NHS'. AB - Robert Nicholls (pictured), deputy chief nurse at Great Western Hospitals NHS Foundation Trust in Swindon, has been a nurse for 19 years. During his varied career he has been a pharmaceutical company nurse adviser, clinical nurse specialist, matron, head of clinical governance and head of nursing. PMID- 28075743 TI - Exercise scheme reduces risk of falls. AB - An exercise programme devised by a Nursing Standard award winner has improved older people's balance and reduced their risk of falling, according to research. PMID- 28075745 TI - Leading champions of bme health care priorities. AB - Members of the BME advisory group for England's chief nursing officer Jane Cummings include. PMID- 28075744 TI - 'Having the views of BME nurses is vital to improve patient care'. AB - When Joan Myers was three years old she received a nursing outfit for Christmas, and by the time she was 11 she was determined to join the profession. PMID- 28075746 TI - Hands up who's opposed to local pay for NHS workers. AB - Liberal Democrats overwhelmingly backed a party conference motion calling on the coalition to rule out regional pay last week. PMID- 28075747 TI - Equality is our aim. AB - When the Afi ya Trust was set up in 1997, one of the charity's main goals was to improve access to health and social care services for people from black and minority ethnic (BME) communities in the UK. PMID- 28075748 TI - Patients taking certain psychotropic medications should be advised not to drive. AB - Newer drugs prescribed to treat anxiety, depression and insomnia may increase patients' risk of being involved in a motor vehicle accident, according to a study in Taiwan. PMID- 28075749 TI - Hunger games. AB - Excuse the pun, but it is 'fast' becoming the nation's favourite health trend. If I had a Kit Kat for everyone I know who has embraced the idea with vigour, I would be the size of a house. I am talking about fasting, which was featured on a television programme a few weeks ago. PMID- 28075751 TI - Voices- the open working culture in the us should be copied here, says yvonne coghill. AB - I am writing this from the state of Massachusetts in the US, where I have come to work with colleagues from the Institute of Health Improvement (IHI) on their diversity strategy. PMID- 28075752 TI - Conference notes. AB - 'There is nothing like making people share a kettle to get them off their professional high horse,' according to Liberal Democrat health spokesperson in the Lords, Baroness Liz Barker. PMID- 28075753 TI - Coalition will be urged to make mental health services a priority. AB - Stricter checks on NHS organisations are required to ensure money earmarked for mental health is actually spent on that area, Liberal Democrat members agreed. PMID- 28075754 TI - World in brief. AB - What's happening in nursing across the globe. PMID- 28075755 TI - By giving L2, you could make a big difference. AB - Many nurses and midwives throughout history have made a difference, and Mary Seacole was one such person. However, as a profession we lag behind our medical colleagues in remembering the historical giants on whose shoulders we stand. PMID- 28075757 TI - Webwise. AB - A language system involving signs and graphic symbols, Makaton is used alongside the spoken word. It was devised in the 1970s and 1980s for people who cannot communicate easily, such as children with Down's syndrome and those with cognitive impairment. PMID- 28075756 TI - Lack of training means patients are lest waiting. AB - Cannulation, phlebotomy and IV administration are extended skills that qualified nurses are only able to practise once they have attended the appropriate training. PMID- 28075758 TI - Readers panel. AB - Our experts consider a hot topic of the day. PMID- 28075759 TI - Starting out - Health visitor role has opened my time to eyes to childhood obesity problem. AB - When I decided on a career change and began my nurse training, I had clear ideas of what I considered 'good parenting' to be, and what constituted a suitable environment in which to raise a child. PMID- 28075760 TI - Hormonal changes in pregnancy may influence cancer tumour growth. AB - The increasing rate of pregnancy-associated cancer is only partly explained by the rise in older mothers, suggests a large Australian study. PMID- 28075761 TI - Nurse support is most effective follow-up for heart failure patients. AB - Nurse-led follow-up of heart failure patients following discharge from hospital reduces the risk of mortality, suggests a review of case management interventions. PMID- 28075762 TI - Study findings support case for rotavirus vaccinations in high income countries. AB - A rotavirus vaccination programme in Belgium has proved effective in preventing hospital admissions for gastroenteritis among young children, according to the first study to examine the effectiveness of such a programme in a European country. PMID- 28075763 TI - Inhaled pain relief is more efficient and safer in early stage of labour. AB - Analgesia that can be inhaled appear to be effective in reducing pain intensity in the first stage of labour, according to a review of the evidence by Cochrane researchers. PMID- 28075764 TI - Old age giggles. AB - It might come as a surprise to anyone under 50, but getting older can actually be fun. Whoever would have thought it? PMID- 28075765 TI - Double-sole socks help to stop falls. AB - Socks designed to reduce patient falls have been introduced by nurses following a successful trial. PMID- 28075767 TI - Bursary restrictions will hit recruitment. AB - EDUCATION AND nursing representatives are dismayed by government moves to push through changes in the rules that determine which diploma students qualify for bursaries. PMID- 28075766 TI - Corrigendum. PMID- 28075768 TI - Overseas staff badly treated. AB - UNETHICAL recruitment of nurses from overseas was slated at last week's RCN Congress. PMID- 28075770 TI - Support for whistle-blowers. AB - THE PERSONAL and professional anguish suffered by people who blow the whistle on poor care standards was spelled out in an RCN Congress debate. PMID- 28075769 TI - Outside in. AB - We are having a baby. I announced that to a friend and was almost laughed off the train. 'Good heavens,' he yelped. 'You don't still use politically correct expressions like that, do you?' Empathy is out of fashion. PMID- 28075771 TI - Public access to the register could put nurses in danger. AB - NURSES COULD be put at further risk of attack and harassment under government proposals for the new Nursing and Midwifery Council (NMC), it has been claimed. PMID- 28075772 TI - Give it up. AB - Faced with an emotional crisis, not everyone will go to a therapist or counsellor. Happiness is the Best Revenge (1997) is a self- help programme for those who need to let go of attachment and heartbreak. PMID- 28075773 TI - Foot and mouth trauma sparks mental health crisis. AB - FARMERS AND their families face incalculable risks of mental health problems and suicide because the foot and mouth crisis has cost them their livelihoods, RCN Congress heard. PMID- 28075774 TI - Blooming marvellous. AB - Bristol-based community nurse Catherine Le Roy was last week named Marie Curie's nurse of the year for England. She received her award from the Prince of Wales at a ceremony in St James' Palace, London. PMID- 28075775 TI - Last chance for action. AB - Polling day is fast approaching and in these last days before the general election all the parties will make a final push to snag votes. PMID- 28075776 TI - Jobs website stalled by High Court challenge. AB - HEALTH DEPARTMENT plans for the NHS Executive to advertise all health service jobs on the internet have suffered a set back after a successful High Court challenge. PMID- 28075777 TI - Ask the experts. AB - I work in a satellite hospital in a medical I elderly directorate. Many of the patients received onto our wards are confused, often agitated and aggressive, and tend to wander. Some of my colleagues believe that locks should be fitted to the doors, preventing patients from leaving the ward. I feel that this impinges on patients' human rights, but no one seems to be able to offer any guidance. Surely this is a form of restraint? PMID- 28075778 TI - Follow the leader. AB - NORTH AND WEST Devon has been severely affected by foot and mouth disease. It has hit everyone, not just the farmers. Everything in a rural area is allied to agriculture, from businesses to social circles. At one point we had 178,000 dead animals lying in farmyards and fields, many of which had been there for several weeks, waiting to be disposed of. PMID- 28075779 TI - Debate on CHC abolition needed. AB - THE PLANNED abolition of community health councils would leave patients without an independent voice, RCN congress agreed by an overwhelming majority. PMID- 28075780 TI - Call for national living cost help. AB - COST OF LIVING supplements currently handed out only in southern England should be given to nurses all over the UK, eight in ten nurses have said. PMID- 28075781 TI - Labour launches plan for NHS University. AB - NURSES IN England will be able to undertake post-registration courses at a new University of the NHS, the Labour party promised last week. PMID- 28075782 TI - Agencies to be 'kitemarked'. AB - NURSING AGENCIES should be 'kitemarked' to show whether they comply with NHS guidance on overseas recruitment, according to a three-point plan published by the Liberal Democrats last week. PMID- 28075783 TI - Fury at long-term care charges. AB - THE FUNDING of long-term care proved the dominant theme of this year's RCN Congress. PMID- 28075784 TI - New era dawns as Malone addresses her first congress. AB - RCN MEMBERS paid tribute to their retiring general secretary, Christine Hancock, last week and gave a warm welcome to her successor, Beverly Malone. PMID- 28075785 TI - Congress rejects prescribing limit. AB - THE RCN is to call a meeting of nursing organisations in a bid to challege the government's latest move on nurse prescribing. The college wants to forge a joint initiative that will demand a more radical extension to the nurse prescribing formulary. PMID- 28075786 TI - At least Mr Mullet has put some swing in the election. AB - If you ask me, anyone who sports a mullet haircut in this day and age is asking for a fat lip. Combine this hair-like-a-burst-sofa with a propensity to throw eggs at people, and you double your chances of getting walloped. PMID- 28075788 TI - State of play. AB - With the party manifestos published ' and the politicians hitting the campaign trail hard, the election is well and truly under way. Nurses have just two weeks to make up their minds how to cast their votes. PMID- 28075787 TI - Let's shout about our new image. AB - I'M HALFWAY through my adult nursing diploma and have worked hard every spare minute in the hope that, at the end of the three years, I will be the best nurse I possibly can. PMID- 28075789 TI - What's on: the best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28075790 TI - Missing the positive in the new code of conduct. AB - As chair of the UKCC's recent consultative conference in Belfast on the new code of professional conduct (news May 23), I was disappointed with Nursing Standard's coverage. PMID- 28075791 TI - Benefits are for basic needs, not takeaways. AB - I would like to reply to Fo Ettinger's article 'Ask and you might receive' (perspectives May 23). PMID- 28075792 TI - Domestic life can lead to chronic weariness. AB - Female employees obviously take more sick leave because of their domestic responsibilities (letters May 23). PMID- 28075793 TI - Strong induction needed for fairness in new code. AB - Further to your coverage of the recent UKCC consultative conference in Belfast on the new Code of Professional Conduct (news May 23), the point I wished to make about the role of lay members in professional conduct cases is that a strong induction programme will be needed for all those who will sit in judgement on such cases brought before the Nursing and Midwifery Council. PMID- 28075794 TI - Research shows foramen ovale link with migraine. AB - The most severe forms of migraine might be the result of a patent foramen ovale, say UK researchers. PMID- 28075795 TI - Desire to see new century led to mortality peak. AB - Although January 1 2000 came and went quite uneventfully in the electronic world, its influence on mortality might have been overlooked. PMID- 28075796 TI - Home chemotherapy can improve compliance. PMID- 28075797 TI - independent sector has made huge advances. AB - In her address to RCN Congress, outgoing general secretary Christine Hancock criticised the NHS for the past practice of providing care in open wards with no curtains and no dignity. In the next breath she said there is no evidence to suggest the independent sector does it any better. PMID- 28075799 TI - Atopic eczema halved with Lactobacillus rhammosus use. AB - Probiotics might prevent atopic disease in infants at high risk, Finnish researchers report. PMID- 28075798 TI - Assessment charges are a backward step. AB - Do nurses realise that the single assessment process for long-term care will be introduced in October this year for older people and in April 2002 for all other care groups? NHS nurses will be expected to assess nursing and personal needs using purely financial criteria and with a charging limit of L100 per week for nursing interventions. PMID- 28075800 TI - Give cancer service framework time to work. AB - It is fairly obvious that cancer initiatives in the NHS cancer plan will have an impact on other services, but this doesn't have to be a negative one. Some are concerned that the two-week wait from GP to consultation could lead to longer waiting times for those without a malignancy. But could the funding for this and similar initiatives enhance the speed of diagnosis for everyone? PMID- 28075801 TI - Practical solutions. AB - The experiences of black staff in the workplace are well known: inequality of treatment; lack of opportunities for advancement; exodus when they fail to gain promotion; and little representation on trust decision-making boards. PMID- 28075802 TI - Qualified nurses who are barred from practice. AB - There are a significant number of highly skilled registered learning disability nurses working in non-NHS settings who are currently unable to practise because of Section 31 of the NHS Act (1999). PMID- 28075803 TI - Be choosy. AB - WHAT STRATEGIES can you use to identify a good employer? A starting point when applying U If for a new job is the job W W advert and application pack. Look for symbols indicating initiatives such as Investors in People, Positive about Disabled People or the Charter Mark. Is there an equal opportunities statement or mention of employee- friendly policies? Does the material contain an indication of the organisation's mission? If so, do you identify with it? How positive is the advert? Visit the organisation's website, if there is one, to find out more information. PMID- 28075804 TI - Tories slam 'offensive' overseas recruitment. AB - THE CONSERVATIVES will keep more nurses in the health service than Labour by giving them a greater say in the decision making process, party leader William Hague said last week. PMID- 28075805 TI - The answer lies with long-term care. AB - FOR THE SECOND year running, the topic that aroused most passion at RCN Congress was funding of long-term care. If party leaders are wondering why nurses appear disillusioned with the political process, they need look no further. Hopes were raised when the new Labour government set up a Royal Commission. At last something would be done about this injustice. PMID- 28075806 TI - Floating voters make waves. AB - NURSES GAVE politicians a rough ride at the RCN Congress in Harrogate last week and that message is reinforced with the publication of our MTS telephone survey today. PMID- 28075807 TI - Oil's well that ends well. AB - So there I was - 3am on a cold December morning walking around the pontoons of an oil rig, seawater swirling over my boots, torch in one hand, lead in the other and on the end of the lead.., a diver. How did this happen to a nurse and why wasn't I in a nice warm hospital? PMID- 28075809 TI - On with the plan. AB - Alan Milburn was well received at RCN Congress a year ago and a clear majority said they had more confidence in the Labour Party than any other when the future of the NHS was debated. PMID- 28075808 TI - Boys like to make noise. AB - I work as a part-time school nurse in a special needs school. Last summer provided a few days respite care for a student who has a tracheostomy, so I was pleased to find the article on tracheostomy care. PMID- 28075810 TI - Sexist, outdated...matron rejected for modem NHS. AB - CALLS FOR the return of matron, modern or otherwise, were rejected at RCN Congress last week, with college members agreeing the title was sexist and the role outdated. PMID- 28075811 TI - TV distorting survival rates. AB - TELEVISION VIEWERS are receiving an inaccurate impression of the success rate of cardiopulmonary resuscitation (CPR), congress heard. PMID- 28075813 TI - Mixed wards 'of no clinical benefit'. AB - MIXED-SEX wards have no clinical benefit in acute settings, six out of ten members at RCN Congress agreed. PMID- 28075814 TI - Struggling in silence. PMID- 28075815 TI - Mortality increases in patients who are depressed after coronary stent implantation. AB - Depression increases the risk of death in patients who have had a coronary stent implanted, suggests research. PMID- 28075816 TI - No agreement between ambulance services on how to respond to falls. AB - The ambulance service response to emergency calls for older people who have fallen varies widely across the UK, reveals a national survey. PMID- 28075817 TI - Under deconstruction - employers chip away at agenda for change. AB - Nurses' entitlement to paid annual leave, incremental pay progression and sick leave, all covered by Agenda for Change, is being threatened by employers across England. PMID- 28075819 TI - Trust loses legal bid to save its children's heart unit from closure. AB - A decision on which four or five of England's ten children's heart units could close will be made in July following a high court ruling into the consultation process. PMID- 28075818 TI - Student life - Wheel of learning support. AB - There are many reasons why nursing students drop out of pre-registration courses, but a known contributory factor is the quality of support and learning experiences on practice placements. PMID- 28075820 TI - Findings from mid staffs inquiry to be reported in october, chair announces. AB - The chair of the public inquiry set up to investigate failings at Mid Staffordshire NHS Foundation Trust has announced he will report his findings in October. PMID- 28075821 TI - Loopy lingual. AB - The word burst through the foggy mass that is my early morning brain. 'Euroneurology', said the report on my bedside radio. PMID- 28075822 TI - Voices -The NHS reforms offer opportunities for nurses, explains Viv Bennett. AB - My new position as director of nursing at the Department of Health offers me the opportunity to provide strong national leadership to nurses, midwives and health visitors. PMID- 28075824 TI - Student lobbying to screen women at 20. AB - A nursing student diagnosed with cervical cancer when she was 20 is campaigning to get the age of cervical screening lowered from 25 to 20. PMID- 28075823 TI - Age-old values. AB - It can be no accident that the recent high profile cases of uncaring nurses focused on the care, or lack of it, of older patients. PMID- 28075825 TI - Conclusions about circumcision and prostate cancer are dubious. AB - The Wright study of circumcision and the risk of prostate cancer (clinical digest April 11 and letters April 18) is a boon for those wishing to promote the circumcision of infants. PMID- 28075826 TI - Nurses need the right to strike to protect patients. AB - Four of your readers panellists were asked if the RCN should be affiliated to the Trades Union Congress (reflections April 4). One of them said the RCN needs to modernise and join the wider trade union movement, but 'should keep the "no strike" policy that has always served it so well'. PMID- 28075828 TI - Never underestimate the pure pleasure of caring for patients. AB - Second-year nursing student Antonia Kitching has captured all that is good about nursing in her Starting Out article (reflections April 18). PMID- 28075827 TI - Learning zone article helped me appreciate asthma/ rhinitis link. AB - Thank you for the excellent learning zone article (April 11) on the management of patients with asthma and allergic rhinitis. Dave Burns notes that the two conditions frequently co-exist, have similar aetiologies and genetic and environmental influences. PMID- 28075829 TI - The gloves should have been off before recording a procedure. AB - I was surprised to see a photograph (analysis April 4) showing a nurse with gloved hands using a ballpoint pen. PMID- 28075830 TI - Malaria death risk higher in older people of european origin. AB - Older tourists from the UK who have visited a country where malaria is endemic are ten times more likely to die from the disease than travellers aged 35 or younger. PMID- 28075831 TI - Eating less saturated fat and more omega-3 oils may benefit men's fertility. AB - A diet high in saturated fats has been linked to reduced sperm quality in a small study of men attending a fertility clinic in the United States. PMID- 28075832 TI - Link between antidepressant use in pregnancy and high blood pressured identified. AB - Women who take antidepressants during pregnancy appear to be at increased risk of high blood pressure. PMID- 28075834 TI - Cameron spells out quality forum's. AB - The new Nursing and Care Quality Forum will identify ways for nurses to have more time to show care and compassion towards patients with existing staffing levels, according to health secretary Andrew Lansley. PMID- 28075833 TI - Combine practice with theory. AB - For many nurses, a career in clinical research might seem like an impossible dream. Unlike medicine, where it is accepted that most senior doctors will be involved in clinical work as well as in research, nurses have found that they must choose one or the other. PMID- 28075835 TI - Compassion tests may be introduced. AB - Assessing potential nurses' values will be a focus of the Nursing and Care Quality Forum, according to one of its members. PMID- 28075837 TI - I am fed up with agency nurses being unfairly stereotyped. AB - I read with interest the obituary of Dorothy Gardiner (letters April 11), who worked tirelessly to raise the profile of the agency nurse. PMID- 28075840 TI - Web wise. AB - It was not only sailors, soldiers and air crew who set sail with the task force to the Falkland Islands 30 years ago. The hospital ship Uganda had a contingent of nurses and sisters from Queen Alexandra's Royal Naval Nursing Service. PMID- 28075841 TI - Clock watch. AB - I equate punctuality with being conscientious and reliable, and I always try to turn up on time. So it is hardly surprising that, during my recent visit to Pakistan, the total disregard for time set my teeth on edge. PMID- 28075842 TI - Commission could help shape a better workforce. AB - The way nursing students are prepared for practice has been a hot topic for years. Debates about modern professional standards are usually characterised by vociferous arguments about whether students are leaving their courses with an appropriate mix of practical and academic skills. PMID- 28075843 TI - Political notebook. AB - Deputy prime minister Nick Clegg has rejected claims that an elected House of Lords would remove members with expert knowledge, such as senior nurses and doctors. PMID- 28075844 TI - Left speechless. AB - The firm that runs my commuter service likes to chat. 'I would ask you to take time to read the safety notices displayed around the train,' repeats our driver, and there are other notices advertising the firm's Twitter feed and Facebook site. PMID- 28075845 TI - Tweeting does not preclude the ability to communicate. AB - I share the frustration of your correspondent (letters April 11) who deplores the use of mobile phones and social networking sites such as Twitter and Facebook in the workplace. I also agree that their use should be restricted in the clinical area. PMID- 28075846 TI - Readers panel- A test of temperament. AB - Our experts consider a hot topic of the day. PMID- 28075847 TI - The arts should be central in the lives of people with dementia. AB - Further to the art&science article on the benefits of creative therapy for people with dementia (April 18), who among us does not need to belong, have fun and contact with others? PMID- 28075849 TI - World in brief. AB - What's happening in nursing across the globe. PMID- 28075848 TI - Texting patients on the ward is the next step for the twitterati. AB - Following on from the letter (April 11) about Twitter-obsessed nurses, my colleagues and I thought we could go one step further. PMID- 28075850 TI - Broadmoor jobs cut after closure of unit. AB - A total of 78 staff, including 33 nurses, at the high-security psychiatric Broadmoor Hospital in Berkshire have taken voluntary redundancy following the closure of its personality disorder service. PMID- 28075851 TI - Starting out - Transition to staff nurse can be a a test of daunting, but positive experience. AB - In my final weeks at university, the daunting prospect of leaving behind my comfortable nursing student status to become a qualified nurse started to dawn on me. PMID- 28075853 TI - Benefits of using the liverpool care pathway in end of life care. AB - The Liverpool Care Pathway (LCP) is an integrated care pathway used to manage terminally ill patients in their final days or hours of life. It was developed by the Marie Curie Palliative Care Institute Liverpool to incorporate 'gold standard' care associated with the hospice setting into mainstream healthcare. The LCP has been advocated by the National Institute for Health and Clinical Excellence and the Department of Health for use in the care of dying patients. A literature review was undertaken to determine whether there is sufficient evidence that the LCP represents best practice in end of life care and whether patients cared for using the LCP receive better end of life care. Eight research articles were selected for inclusion in the review. The key themes of symptom management, communication and documentation were identified, and the research surrounding these themes was analysed. The analysis showed that use of the LCP promotes better care for patients in the terminal stage of illness; however, some weaknesses in the research were identified and recommendations have been made for further research and future practice. PMID- 28075854 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28075855 TI - Colleges rule out joining day of action over pension reforms. AB - RCN and Royal College of Midwives members will not be asked to take part in industrial action planned for next month in opposition to pension reforms. PMID- 28075856 TI - Advice published on how to defend pay. AB - Employers proposing changes to NHS terms and conditions should be asked to provide a written copy of their plans, according to guidance for local healthcare union representatives. PMID- 28075858 TI - Pressure ulcer tool brings incidence to zero. AB - A system that has reduced pressure ulcers at a Welsh health board has been rolled out across England, Wales and Denmark. PMID- 28075859 TI - Leading figures spearhead recruitment initiative. AB - The government has enlisted senior nurses to spearhead a recruitment campaign that aims to enlist and train thousands of health visitors. PMID- 28075861 TI - Nurse calls for famine fund donors. AB - A leading humanitarian nurse has urged the public to donate funds to help the millions of people affected by famine in east Africa. PMID- 28075860 TI - Minister claims to have heard no dissent over control of budgets. AB - Plans to give local authorities far greater control of public health have received widespread support, health minister Anne Milton told the House of Commons health committee. PMID- 28075862 TI - Remembering a wonderful matron and friend to many. AB - I would like to thank Laurence Dopson for his obituary of Moyra Yates (letters June 29). She died aged 57, the week before she was due to receive a Norfolk Community Health and Care NHS Trust award for being an inspirational role model. PMID- 28075863 TI - Trust faces grievance as unions battle pay penalty for sickness. AB - Unions have challenged a foundation trust's decision to penalise staff for taking sick leave. PMID- 28075866 TI - Separate talks agreed for NHS pension scheme. AB - The RCN and other health unions are to take part in talks about how public sector pension reforms will specifically affect the NHS scheme. PMID- 28075864 TI - New end of life care pathway will surely benefit everyone. AB - It is good to see that end of life care is being addressed in a systematic way through a clear six-step pathway outlining the actions nurses need to take at each stage (analysis July 6). PMID- 28075867 TI - Ann Young. AB - Ann Young, who has died aged 65, was a nurse, author and academic who pioneered the teaching of law to nurses. PMID- 28075870 TI - 'Nurses lead at every level here'. AB - Five million hours are donated each year by 40,000 St John Ambulance volunteers, and the organisation's recently retired chief nurse Alison Leary offered 4,200 of them over her three-year term of office. PMID- 28075868 TI - Letter. AB - Further to the news story (July 6) on the stained glass window to be installed in the Jenny Lind Chapel of the old Worcester Royal Infirmary (WRI), only the newer parts of the former hospital have been demolished. PMID- 28075871 TI - High-profile cases cause NMC backlog. AB - The Nursing and Midwifery Council's caseload of fitness to practise cases has been swollen by the large number of alleged high profile failures of care. PMID- 28075872 TI - 'We will be burnt out in three years'. AB - Unions fear nursing students in England will be forced to take second jobs throughout their studies after the government revealed they will receive a L1,000 a-year grant. PMID- 28075874 TI - Position of trust. AB - The Royal College of Physicians, the Royal College of General Practitioners and the British Medical Association (BMA) are unanimous in their opposition to the legalisation of 'assisted dying' - the euphemism for physician-assisted suicide. The RCN is the odd one out: two years ago it shifted its position from opposition to neutrality. PMID- 28075875 TI - Webwise. AB - There are sections on the importance of attractive surroundings, physical comfort, hygiene, food, communication, children, activities, waiting rooms and waiting lists, long-term care, bereavement, going home and volunteering. PMID- 28075876 TI - Outside in. AB - Good news, said the woman on the telly. The rate of inflation has fallen. But then the bad news: the fall was due to retailers having to slash the price of electronic goods. Meanwhile, food prices were still rising. PMID- 28075878 TI - Pulmonary tuberculosis: clinical features and patient management. PMID- 28075879 TI - Re-registration process 'is unfit for purpose'. AB - The Nursing and Midwifery Council's system for checking that nurses are keeping their skills up to date is 'wholly inadequate', according to MPs. PMID- 28075880 TI - Travelling should not cost the earth. AB - In the current financial climate many nurses will be considering a stay-at-home or local holiday break to save money. Those still keen to travel overseas this year should consider these tips to make their holiday funds go further. PMID- 28075881 TI - One-page patient passport for people with learning disabilities. PMID- 28075882 TI - A fair deal in retirement. AB - The hard sell against nurses and other public sector workers receiving modest, but reasonable pensions during their retirement continues. However, last week there was a chink of light as the chances increased of NHS staff winning their case for a fair deal. The government announced that it would hold separate talks with health unions over the future of the NHS pension scheme, rather than lumping all the public sector schemes together in a single set of negotiations. PMID- 28075884 TI - People who sleep a lot or a little are at risk of heart disease. AB - Both short and long duration of sleep are predictors, or markers, of cardiovascular disease. PMID- 28075883 TI - Voices. AB - In June I visited Londonderry/ Derry and Perth to hear from nurses and midwives about the issues that matter to them. PMID- 28075885 TI - Blood pressure unaffected by level of coffee consumption. AB - Habitual consumption of more than three cups of coffee a day is not associated with an increased risk of hypertension compared with less than one cup a day, but there is a slightly higher risk associated with the consumption of one to three cups. PMID- 28075886 TI - Law change on smoking in cars would protect children. AB - As well cared for and much loved children, my brother and I were driven to the seaside or countryside regularly for exercise and fresh air. PMID- 28075887 TI - For the good of the patients-Should nurses support hospital closures? We asked our readers panel. AB - Our experts consider a hot topic of the day. PMID- 28075889 TI - Managers put on alert across the NHS over bogus advertising bills. AB - Nurses involved in recruitment advertising have been put on their guard against a scam that has already tricked some employers out of thousands of pounds. PMID- 28075888 TI - Pack gives details of dementia services. AB - A resource to help NHS commissioners design and purchase high quality dementia services was published by the Department of Health last week. PMID- 28075890 TI - Demon doris. AB - Twice recently I have known patients who have been prescribed pretty vital medication, one for angina and the other for hypertension. And in both cases a well-meaning friend or neighbour has regaled the person with horror stories about that particular drug. PMID- 28075892 TI - Incentives to improve health are unpopular with the public. AB - There are negative attitudes among the public both in the UK and United States towards the use of financial incentives - rewards as well as penalties in improving health outcomes. PMID- 28075891 TI - Night operations had no worse survival outcomes than those performed in the day. AB - There is no significant link between the time of day thoracic transplant surgery is performed and survival at one year. PMID- 28075894 TI - Letter. AB - NHS Direct consistently receives patient satisfaction ratings of 90 per cent or higher and we are determined to maintain this level of service (letters July 20). We believe that the savings we need to make at NHS Direct can be done effectively without jeopardising the quality and clinical effectiveness of our services. PMID- 28075895 TI - Three cycles of single embryo IVF are economically viable. AB - I agree with Jane Denton about the lack of equity in the provision of NHS fertility treatment (reflections July 20). It has long been inadequate, despite strong messages of support from successive health ministers and prime ministers from the time of the first Blair government. PMID- 28075896 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28075897 TI - Starting out - Disengagement can be a way of maintaining professionalism. AB - As a nanny, I built up a series of close relationships with the children and families that I worked with. It was always difficult when it was time to leave, and this worried me when I began my training in children's nursing. PMID- 28075898 TI - Saline solution deaths will tarnish nurses' reputation. AB - The problem with incidents such as the contaminated saline solution at Stepping Hill Hospital in Stockport is that they often cause knee-jerk responses. Whatever the outcome of this particular case, there will inevitably be a spotlight on nurses. But people should not question the professionalism of the vast majority of nurses and nursing students. PMID- 28075899 TI - School nurses are being forgotten in the rush to recruit health visitors. AB - As a school nurse I was most interested in your news story, 'School nurses being "poached" in rush to recruit health visitors' (July 6). I am saddened that this follows the failure of the previous government's pledge to have one qualified school nurse per school cluster by 2010. PMID- 28075900 TI - Nurses reduce catheter use. AB - Catheter use on a hospital ward fell by around a third in one year after nurses introduced a policy to remove the device 48 hours after surgery. PMID- 28075901 TI - Nurses take tea at the palace. AB - RCN members and staff enjoyed tea and cakes as guests of the Queen at a Buckingham Palace garden party. PMID- 28075903 TI - RCN concern over proposed regulators. AB - RCN Scotland has expressed concern about the creation of two regulators for health and social care instead of one overall body, believing it will confuse the public. PMID- 28075905 TI - Airline drops charge for supplementary oxygen. AB - Nurses are hoping all airlines will follow the lead of Thomson Airways, which has decided to scrap charges for customers who require supplementary oxygen on its flights. PMID- 28075904 TI - A gift of hope to people with HIV. PMID- 28075906 TI - Identifying and assessing anxiety in pre-operative patients. PMID- 28075907 TI - Leadership training aims to create more nursing directors. AB - An ambitious leadership programme has been developed to create assertive and politically astute nurses. PMID- 28075908 TI - Standard uniform colours could be a big help in cases of mistaken identity. AB - I was interested to read your news story (August 19) on the new uniforms being introduced at the Heart of England NHS Foundation Trust as part of its Start of Our Journey to World Class Nursing Care initiative. PMID- 28075909 TI - Why return a day's pay when we already give too much? AB - Is Janet Smith (reflections August 19) serious when she suggests that we help the NHS by giving back a day's pay? Perhaps as a clinical nurse specialist she has lost touch with how things really are in the NHS. PMID- 28075910 TI - Improving standards of care for patients: A pilot project. PMID- 28075911 TI - Teaching carers the tricks of the trade. AB - Britain's silent army of carers delivers a self-sacrificing service that saves the NHS an estimated L87 billion every year, but with precious little training or support. That situation is changing thanks to a nurse-led initiative set up by St John Ambulance. PMID- 28075912 TI - Nurses need support to care. AB - Broadmoor high security hospital managers have announced an open day to recruit 100 registered mental health nurses, a significant boost to the current team of 550. PMID- 28075913 TI - PCTs poaching staff from other services to bridge swine flu gaps. AB - Specialist nurses are being diverted during some shifts to cope with the outbreak of swine flu because their work is considered 'non-essential'. PMID- 28075914 TI - Foreign nurses disadvantaged by migration rules on diplomas. AB - Failure to clarify whether the nursing diploma and degree have equal status in migration rules could limit the recruitment of overseas nurses to the UK, it is claimed. PMID- 28075916 TI - Health visitors make baby safety film. AB - Nurses are enlisting students to help them make a film warning young people about the risks of shaking babies. PMID- 28075915 TI - Crowds gather to defend the NHS. AB - Protesters gathered in London to defend the NHS against a barrage of criticism during the debate on healthcare reform in the United States. PMID- 28075917 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28075920 TI - 'If you want to eat an elephant, do it one bite at a time'. AB - We have a new nurse starting, at last, after months of struggling with inadequate cover and filling in on days when we had somewhere better to go. PMID- 28075918 TI - Screening men for abdominal aneurysm is cost effective. AB - The mortality benefit of screening men aged 65-74 for abdominal aortic aneurysm is maintained up to ten years and cost effectiveness becomes more favourable over time. PMID- 28075921 TI - Rocky road to recovery. AB - In February last year I was struck down by a mystery illness. The next few weeks were a spiral of pain, fever, sleepless nights, loss of mobility and anxiety. PMID- 28075922 TI - Introduction to stoma care. AB - Venue Online learning resource. Run by Nurse Learning, via CancerNursing.org.in collaboration with SecuriCare Medical. Summary of content Introduction to stoma care and related issues; anatomy and physiology; types of stoma; description of nursing roles in the specialty; and the practical management of a stoma. PMID- 28075923 TI - Opportunity knocks. AB - Recognising and acting on opportunities for career development is a skill that can help you climb the career ladder. PMID- 28075924 TI - Bed of nails. AB - Glancing idly over a list of procedures while I was damp-dusting our theatre, I reeled in shock. 'Operation on the nail bed,' it read. PMID- 28075926 TI - Webwise. AB - The Infant and Toddler Forum gives healthcare professionals practical help and information on infant and toddler nutrition and development. PMID- 28075927 TI - Little progress with staff development. AB - Around four out of ten nurses have not received an annual appraisal in the past year, preliminary findings from the RCN's employment survey show. PMID- 28075929 TI - Delays or freeze in recruitment masks true deficit in personnel. AB - Official figures on nurse vacancies severely underestimate the number of posts that are currently unfilled, according to the RCN. PMID- 28075930 TI - Studies link migraine with pathological changes in brain. AB - Migraine is considered to be an episodic condition with no long-term consequences. However, recent studies suggest that migraine attacks may be associated with pathological changes in the brain, particularly in the cerebellum. PMID- 28075931 TI - Orthopaedic plaster casting: nurse and patient education. PMID- 28075932 TI - Starting out - Even when pushed for time, it is vital to keep up routine checks. AB - During my first week on a male orthopaedic ward I participated in a drug round while being supervised by my mentor. PMID- 28075934 TI - Voices-strong nursing leaders are role models for students, says elizabeth anionwu. AB - Last month United States and UK national nursing organisations hit the headlines with their positions on highly controversial policies. The RCN took a neutral stance on assisted suicide, while the American Nurses Association strongly reaffirmed its support of president Barack Obama's healthcare reform proposals. PMID- 28075933 TI - The nut crackers. PMID- 28075935 TI - Patients with faith should know their needs will be met. AB - I am a nurse and I am also a Roman Catholic. My faith is an important part of who I am. PMID- 28075936 TI - Readers panel - Donor incentivesl. AB - Our experts consider a hot topic of the day. PMID- 28075937 TI - Big response to ideal nurse consultation. AB - The consultation on what makes the ideal nurse by the prime minister's Commission on the Future of Nursing and Midwifery received more than 2,000 responses. PMID- 28075938 TI - Otitis more likely to recur in children given antibiotics. AB - Children treated with antibiotics for acute otitis media are more likely to get a recurrence of the condition. PMID- 28075939 TI - RCN calls for improvements in career progress. AB - The RCN is calling for a post-registration curriculum that helps qualified nurses to move towards advanced and consultant-level practice. PMID- 28075940 TI - Extra cleaner on wards reduces MRSA infections. AB - MRSA infections Having one extra cleaner on a ward can apparently benefit patients with regard to meticillin-resistant Staphylococcus aureus (MRSA). PMID- 28075941 TI - Negative stereotypes prevent men from entering profession. AB - The image of nursing needs to be bolstered to encourage more people into the profession, according to the union that represents health visitors and community nurses. PMID- 28075942 TI - A timely article from Belgium shows the way forward here. AB - The RCN policy unit put together a balanced briefing paper on assisted suicide and I believe the feedback on the consultation is a fair reflection of the range of opinion in the profession. The latest RCN position of being neutral on assisted suicide is a sensible one. PMID- 28075943 TI - NHS and public libraries are a real boon for free materials. AB - Bridget Ryan complains about having to pay for health articles (letters August 19). Has she never used her local NHS library? PMID- 28075944 TI - Nurses returning from sick leave too soon - survey. AB - Nurses are forcing themselves back to work while still feeling unwell, risking harm to themselves, colleagues and patients, according to a major study. PMID- 28075945 TI - Life worth living. PMID- 28075946 TI - Congratulations should be in order for academic scheme. AB - It was with familiar disappointment that I read Julie Scholes's letter 'Drive to meet targets may undermine learning aims' (August 12). PMID- 28075947 TI - More postgraduate study can only have a positive impact. AB - In response to Julie Scholes's comments in relation to boosting the number of nurses with degrees (letters August 12), I find it surprising that she cannot see the broader picture. PMID- 28075948 TI - Time for the RCN to review literature on assisted suicide. AB - Gay Lee is correct to suggest that many responses to the debate on assisted suicide and euthanasia are emotive and illogical (letters August 19). This holds true for both sides. PMID- 28075949 TI - Power to the patient. AB - For UK nurses, holistic care, patient empowerment and multidisciplinary approaches to care are constant themes in our professional codes, as well as health policies and funding principles. PMID- 28075950 TI - Intravenous therapy. AB - As a newly qualified nurse working in an oncology and haematology unit, my role includes undertaking intravenous (IV) therapy. The article has raised my awareness of the legal implications of my actions and/or omissions in relation to IV therapy. PMID- 28075951 TI - Broadmoor's recruitment drive looks to add an extra 100 staff. AB - Broadmoor high security hospital is recruiting up to 100 mental health nurses as part of moves to increase the nurse to patient ratio. PMID- 28075952 TI - Scottish board meets to start community plan of action. AB - Plans to modernise community nursing in Scotland have taken a step forward with the first meeting of the board that will lead the way forward. PMID- 28075954 TI - From my perspective, the private sector is thriving. AB - Many people may be under the impression that the private healthcare sector is suffering during the recession (analysis August 12). But as a former nurse and now doctor liaison manager with BMI Healthcare but, from my perspective, the private sector is doing well. PMID- 28075955 TI - Should dying prisoners be given their freedom for a more dignified end? AB - While train robber Ronnie Biggs prepared to spend his final weeks in a London nursing home, Lockerbie bomber Abdelbaset Ali al-Megrahi travelled home to Libya after being released from jail on compassionate grounds. PMID- 28075956 TI - ?Como es la promocion de la salud mundial? PMID- 28075957 TI - A quoi ressemble la promotion de la sante mondiale ? PMID- 28075962 TI - What you need to know about the new approach. AB - A rapid response report (RRR) issued in March says that all organisations in the NHS and independent sector where nasogastric feeding tubes are placed and used for feeding patients must comply with the following by September 12. PMID- 28075959 TI - Iniciativas escolares y deportivas lideradas desde la Federation Internationale de Football Association (FIFA): revision sistematica. AB - Introduccion: Los programas iniciados por la Federation Internationale de Football Association (FIFA) consisten en la difusion de mensajes relacionados con el cuidado de la salud y como estrategia de prevencion de lesiones deportivas entre los ninos y jovenes. El objetivo de esta revision sistematica fue resumir los resultados de la implementacion de los programas "FIFA 11 para la salud" y "FIFA 11+". Metodos: Se realizo una busqueda sistematica en las bases de datos electronicos de MEDLINE, EMBASE y Scopus, identificando los estudios que evaluaran la implementacion de los programas "FIFA 11 para la salud" y "FIFA 11+", durante los ultimos 10 anos (1 enero 2003 a 1 diciembre 2013). Resultados: Incluimos 17 estudios. Dos estudios evaluaron la implementacion del programa "FIFA 11 para la salud" y encontraron un aumento significativo en el conocimiento de los mensajes de promocion de la salud; 15 estudios evaluaron los efectos del programa "FIFA 11+", reportando una reduccion en el riesgo de lesiones deportivas y mejorias en el rendimiento deportivo. Discusion: Los programas "FIFA 11 para la salud" y "FIFA 11+" han demostrado resultados positivos para la salud, en el ambito escolar y deportivo. Conclusiones: Dichos programas del FIFA representan una oportunidad para crear habitos protectores y fomentar modos de vida saludables en ninos y jovenes. PMID- 28075963 TI - Nurses and patients describe inpatient anorexia wards in terms of incarceration. AB - A small study of an inpatient unit for adolescents with anorexia has found that patients and nurses viewed the treatment programme as a form of incarceration. PMID- 28075964 TI - Study reveals that inactivity is a threat to health on a par with smoking and obesity. AB - Physical inactivity is responsible for one in ten premature deaths worldwide and is a public health threat on a level with smoking and obesity, suggests an analysis of the evidence by international researchers. PMID- 28075965 TI - Overdiagnosis of malaria means other life-threatening infections are missed. AB - Substantial overdiagnosis and mistreatment of malaria is taking place, wasting resources and leaving people vulnerable to other serious non-malarial infections. PMID- 28075966 TI - Skin cancer risk from indoor sunbed use is higher than estimated. AB - People who use indoor sunbeds to get a tan increase their risk of skin cancer by 20 per cent, according to an analysis of 27 European studies between 1981 and 2012. PMID- 28075967 TI - Procedures and training review aims to bring an end to 'never event'. AB - Deaths from misplaced nasogastric tubes are listed among the Department of Health's 'never events' - incidents considered unacceptable and preventable. PMID- 28075969 TI - Course prompts optimistic outlook. AB - Nurses who took a module on mental health problems in primary care as part of their master's degree were more likely to believe that intervention would improve patient outcomes after taking the course than before. PMID- 28075968 TI - Planning for your retirement. AB - The new NHS pension scheme is due to come into effect in 2015. In this scheme, pensions will be calculated on the basis of earnings averaged over the length of a career rather than the worker's final salary amount, as it is now. The amount by which pensions increase each year as employer and employee contributions are added to the pension pot (known as the accrual rate) will be 1/54th of each year's earnings. PMID- 28075970 TI - Occupational clinic sessions could help people with back pain take more control. AB - A counselling intervention for people with low back pain, focused on overcoming the barriers to getting back to work and being physically active, can help people to 'transform', suggests a Danish trial. PMID- 28075972 TI - Rules of engagement. AB - When researchers at Birmingham's Aston University compared the NHS Staff Survey and Patient Survey two years ago, they made an important observation: in organisations where staff reported higher levels of engagement, patients were more satisfied with their care. PMID- 28075971 TI - Voices - The battle for reform of us health care rages on, writes Jean Gray. AB - Dr Russell Dohner is seen as something of a hero by the people of Rushville, Illinois. Patients visiting the GP's practice are charged only $5 per consultation, the same price they would have paid in the 1970s. PMID- 28075973 TI - Load of hot air. AB - One of the worst aspects of travelling must be hotel hairdryers. They are so feeble that they hardly produce any air current at all - you might as well be coughed at by a baby. PMID- 28075975 TI - Study highlights influence of drug company gifts. AB - Nurse practitioners are more likely to prescribe a drug after hearing about it at an event sponsored by a pharmaceutical company, according to research conducted in Canada. PMID- 28075976 TI - Are NHS trusts merely paying lip service to wage equality? AB - The equality delivery statements of NHS trusts in England state: 'Levels of pay and related terms and conditions are fairly determined for all posts, with staff doing the same work in the same job being remunerated equally.' PMID- 28075978 TI - Survey reveals use of prescribing powers. AB - Independent prescribers working in general practice prescribe an average of 39 items a week, a survey of more than 800 non-medical prescribers has revealed. PMID- 28075977 TI - Help us to develop a vaccine that will prevent meningitis. AB - I read with interest Louise Rowland's practice profile on meningococcal B disease and the importance of early detection (learning zone August 1). PMID- 28075979 TI - Students urged to publish more research papers. AB - Nursing students at a United States university must submit a study paper to a journal as part of moves to bolster nurse research, conference delegates heard. PMID- 28075981 TI - Pay Cartel will damage nurse morale and local economies. AB - Unions have written to the chief executives of trusts in south west England urging them to abandon plans to introduce a 'cartel' to drive down nurses' pay (news August 22). PMID- 28075982 TI - Carter slams loss of almost 5,000 nurses since 2010. AB - RCN general secretary Peter Carter has condemned the 'slash and burn' approach to nurse jobs after fi gures were released showing the loss of more than 4,800 posts in two years. PMID- 28075983 TI - Anger at trust's attempts to claw back parking fees. AB - Almost 600 NHS staff have received a bill for one year of car parking that employers forgot to deduct from their monthly wages last year. PMID- 28075988 TI - Mentors need support to assess students on their placements. AB - Bob Price provides a pragmatic and welcome approach for mentors when undertaking practice-based assessments (learning zone August 8). PMID- 28075984 TI - Webwise. AB - The International Paralympic Committee website - the offi cial site of the paralympic movement - is a tremendous resource. PMID- 28075989 TI - Starting out - Treating a patient with pressure ulcers has taught me compassion. AB - While on an acute placement at the end of my second year of training, I helped to look after a patient who was admitted to hospital from her home following gradual deterioration of health and reduced mobility. PMID- 28075990 TI - Shortage of funds behind delay in salary payments. AB - Nurses employed at a private hospital had their pay withheld for three weeks because of cash-flow problems. PMID- 28075991 TI - Women who miscarry need to be looked after by skilled nurses. AB - When working as a midwife in Nigeria I encountered many women who had miscarried, so I was interested to read staff nurse Rachel Evans's article, 'Emotional care for women who experience miscarriage' (art&science June 20). PMID- 28075993 TI - The life-saving care received by my godson deserves a gold medal. AB - The Paralympic Games are here, so it is a good time to express my pride and respect for all those in the NHS and other public services who helped to save the life of my godson Alistair Patrick-Heselton. PMID- 28075992 TI - Get up, stand up. AB - I read a newspaper article recently that said the 'labor movement' in the United States - their version of trade unions - is being 'pummelled into insignificance by economic forces beyond its control'. PMID- 28075994 TI - Better drug monitoring will reduce risk and benefit patients. AB - I read with interest the news story on a specialised drug prescribing system that aims to improve surveillance in hospitals and highlight patients at risk of harm resulting from clinical error or criminal activity (news August 8). PMID- 28075995 TI - Wards in good cheer. AB - Over the past year a West Midlands trust has introduced activities to improve the experience of patients in a co-ordinated and sustainable way. The initiative is spreading to other settings across the country. PMID- 28075997 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28075996 TI - All in the curves. AB - The man on the food programme was talking about shapes. Tests have shown that food tastes sweeter in round bowls, he said, while angular shapes enhance sharp, sour and salty flavours. PMID- 28075999 TI - 'Outrage, disgust and distress' at proposed 58 per cent NMC fee hike. AB - Tens of thousands of nurses have overwhelmingly rejected Nursing and Midwifery Council proposals to increase fees from L76 to L120. PMID- 28076000 TI - Local pay plans set alarm bells ringing. AB - Nursing staff in south west England must feel under siege. Their managers have embarked on an unprecedented attack on pay, terms and conditions that will leave them fearful for their futures. Nurses throughout the UK have reason to be concerned because, as Nursing Standard revealed recently, employers in other areas are preparing to follow suit. PMID- 28076001 TI - Smoother, faster. PMID- 28076002 TI - Readers panel - a fragmented approach to pay. AB - Our experts consider a hot topic of the day. PMID- 28076003 TI - Reducing Functional MR Imaging Acquisition Times by Optimizing Workflow. AB - Functional magnetic resonance (MR) imaging is a complex, specialized examination that is able to noninvasively measure information critical to patient care such as hemispheric language lateralization ( 1 ). Diagnostic functional MR imaging requires extensive patient interaction as well as the coordinated efforts of the entire health care team. We observed in our practice at an academic center that the times to perform functional MR imaging examinations were excessively lengthy, making scheduling of the examination difficult. The purpose of our project was to reduce functional MR imaging acquisition times by increasing the efficiency of our workflow, using specific quality tools to drive improvement of functional MR imaging. We assembled a multidisciplinary team and retrospectively reviewed all functional MR imaging examinations performed at our institution from January 2013 to August 2015. We identified five key drivers: (a) streamlined protocols, (b) consistent patient monitoring, (c) clear visual slides and audio, (d) improved patient understanding, and (e) minimized patient motion. We then implemented four specific interventions over a period of 10 months: (a) eliminating intravenous contrast medium, (b) reducing repeated language paradigms, (c) updating technologist and physician checklists, and (d) updating visual slides and audio. Our mean functional MR imaging acquisition time was reduced from 76.3 to 53.2 minutes, while our functional MR imaging examinations remained of diagnostic quality. As a result, we reduced our routine scheduling time for functional MR imaging from 2 hours to 1 hour, improving patient comfort and satisfaction as well as saving time for additional potential MR imaging acquisitions. Our efforts to optimize functional MR imaging workflow constitute a practice quality improvement project that is beneficial for patient care and can be applied broadly to other functional MR imaging practices. (c)RSNA, 2017. PMID- 28076004 TI - Fetal Cardiac Screening Sonography: Methodology: Women's Imaging. PMID- 28076005 TI - A Review of 2016 and a Look Forward to 2017 and Beyond: Editor's Page. PMID- 28076006 TI - David A. Bluemke, MD, PhD, Named Editor of Radiology. PMID- 28076008 TI - Pictorial Review of False-Positive Results on Radioiodine Scintigrams of Patients with Differentiated Thyroid Cancer. AB - Radioiodine has served an important role in the diagnostic workup and treatment of patients with differentiated thyroid cancer for more than 6 decades. The interpretation of radioiodine scintigraphic studies should be performed in conjunction with a comprehensive history, histopathologic correlation, and pertinent laboratory values, as well as correlation with available anatomic images and the findings from physical examination. A thorough understanding of the physiology and biodistribution of radioiodine is critical when interpreting radioiodine scintigraphic studies to avoid misinterpretation of physiologic and nonthyroid pathologic variants as thyroid cancer metastases. Differentiating a false-positive finding from a true metastasis on pretherapy radioiodine scintigrams is important to determine the appropriate radioiodine treatment dose. The correct interpretation of posttherapy radioiodine scintigraphic studies is also important to determine if repeat radioiodine treatment will be necessary and for the future clinical and imaging followup of the patient. A variety of different factors, such as the presence of the sodium-iodide symporter and the passive diffusion or retention of radioiodine in normal and pathologic structures, can result in false-positive results on radioiodine scintigrams. Numerous false-positive findings have been reported in the literature and are further demonstrated with the increasing availability of single photon emission computed tomography (SPECT) integrated with computed tomography (CT) as true dual modality imaging (SPECT/CT). SPECT/CT has been documented to be of incremental value in the accurate anatomic localization and characterization of radioiodine uptake as false-positive findings, particularly in cases with discordant findings of a low serum thyroglobulin level but positive findings on radioiodine whole body planar scintigrams. The objectives of this review are to describe the physiology and biodistribution of radioiodine and to provide examples of false positive results on radioiodine scintigrams, with clinical and anatomic correlation, in the following categories of radioiodine uptake: functional uptake secondary to sodium-iodide symporter expression, radioiodine retention, nonthyroid neoplasms, inflammatory or infectious uptake, contamination, and other causes. (c)RSNA, 2017. PMID- 28076009 TI - Delineating Extramammary Findings at Breast MR Imaging. AB - Breast magnetic resonance (MR) imaging is the only breast imaging modality that consistently encompasses extramammary structures in the thorax and upper abdomen. Incidental extramammary findings on breast MR images of patients with a history of breast cancer or other malignancies are significantly more likely to be malignant and may affect staging and treatment. An understanding of the frequency, distribution, and context of extramammary findings on breast MR images and a familiarity with common and uncommon sites of breast cancer metastasis inform the differential diagnosis and prompt the appropriate diagnostic next step, to differentiate benign from malignant findings. High-yield organ systems on breast MR images, as reflected by a high positive predictive value for malignancy, are correlated with known distant sites of breast cancer metastasis in the bone, lung, liver, and lymph nodes. Staging is considered when disease involves the skin and chest wall. Unusual sites of breast cancer metastasis from invasive lobular carcinoma are discussed, including the gastrointestinal tract, peritoneum, and adrenal glands. Nonmalignant clinically important findings involving the cardiovascular and gastrointestinal systems are reviewed, and potential pitfalls in diagnosis and interpretation are highlighted. A consistently systematic diagnostic approach is emphasized for identifying extramammary abnormalities on breast MR images. All things considered, the radiologist should be able to improve diagnostic sensitivity and specificity while interpreting extramammary findings on breast MR images. (c)RSNA, 2017. PMID- 28076010 TI - Foreign Bodies on Lateral Neck Radiographs in Adults: Imaging Findings and Common Pitfalls. AB - Foreign-body (FB) ingestion is less common in adults than in children, but still occurs. Diagnostic management of patients with suspected FB ingestion in emergency departments depends on FB type and location, both of which are related to the patient profile. In adults, fish and chicken bones are the most common FB types, and the oropharynx and cricopharyngeal muscle are the most common locations. Once accidentally swallowed, an FB may become lodged in the oropharynx, and in such cases indirect or fiberoptic laryngoscopy is the first clinical management option. For FBs that have passed beyond this location, radiologic study is recommended, including anteroposterior and lateral neck radiographs (LNRs) using the soft-tissue technique. This is a quick and simple imaging method that in emergency departments achieves detection rates of 70%-80% in assessing FBs in the hypopharynx and upper cervical esophagus. Careful initial evaluation using LNRs can determine the presence and nature of an FB, which helps with predicting the location and risk assessment, making further imaging including computed tomography-unnecessary. Prevertebral soft-tissue swelling is a nonspecific indirect sign, which in the appropriate clinical context raises suspicion of a radiolucent FB or related complications. LNRs can sometimes be difficult to interpret due to the presence of multiple overlapping soft-tissue structures and variable patterns of laryngeal cartilage calcification in adults. Adequate performance in interpreting LNRs along with familiarity with the full diagnostic process in these patients will enable radiologists to use the right imaging technique for the right patient, as described in the clinical algorithm proposed by the authors. (c)RSNA, 2017. PMID- 28076011 TI - Pulmonary Tuberculosis: Role of Radiology in Diagnosis and Management. AB - Tuberculosis is a public health problem worldwide, including in the United States particularly among immunocompromised patients and other high-risk groups. Tuberculosis manifests in active and latent forms. Active disease can occur as primary tuberculosis, developing shortly after infection, or postprimary tuberculosis, developing after a long period of latent infection. Primary tuberculosis occurs most commonly in children and immunocompromised patients, who present with lymphadenopathy, pulmonary consolidation, and pleural effusion. Postprimary tuberculosis may manifest with cavities, consolidations, and centrilobular nodules. Miliary tuberculosis refers to hematogenously disseminated disease that is more commonly seen in immunocompromised patients, who present with miliary lung nodules and multiorgan involvement. The principal means of testing for active tuberculosis is sputum analysis, including smear, culture, and nucleic acid amplification testing. Imaging findings, particularly the presence of cavitation, can affect treatment decisions, such as the duration of therapy. Latent tuberculosis is an asymptomatic infection that can lead to postprimary tuberculosis in the future. Patients who are suspected of having latent tuberculosis may undergo targeted testing with a tuberculin skin test or interferon-gamma release assay. Chest radiographs are used to stratify for risk and to assess for asymptomatic active disease. Sequelae of previous tuberculosis that is now inactive manifest characteristically as fibronodular opacities in the apical and upper lung zones. Stability of radiographic findings for 6 months distinguishes inactive from active disease. Nontuberculous mycobacterial disease can sometimes mimic the findings of active tuberculosis, and laboratory confirmation is required to make the distinction. Familiarity with the imaging, clinical, and laboratory features of tuberculosis is important for diagnosis and management. (c)RSNA, 2017. PMID- 28076012 TI - Imaging of Creutzfeldt-Jakob Disease: Imaging Patterns and Their Differential Diagnosis. AB - Diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) remains a challenge because of the large variability of the clinical scenario, especially in its early stages, which may mimic several reversible or treatable disorders. The molecular basis of prion disease, as well as its brain propagation and the pathogenesis of the illness, have become better understood in recent decades. Several reports have listed recognizable clinical features and paraclinical tests to supplement the replicable diagnostic criteria in vivo. Nevertheless, we lack specific data about the differential diagnosis of CJD at imaging, mainly regarding those disorders evolving with similar clinical features (mimicking disorders). This review provides an update on the neuroimaging patterns of sCJD, emphasizing the relevance of magnetic resonance (MR) imaging, summarizing the clinical scenario and molecular basis of the disease, and highlighting clinical, genetic, and imaging correlations in different subtypes of prion diseases. A long list of differential diagnoses produces a comprehensive pictorial review, with the aim of enabling radiologists to identify typical and atypical patterns of sCJD. This review reinforces distinguishable imaging findings and confirms diffusion-weighted imaging (DWI) features as pivotal in the diagnostic workup of sCJD, as these findings enable radiologists to reliably recognize this rare but invariably lethal disease. A probable diagnosis is justified when expected MR imaging patterns are demonstrated and CJD-mimicking disorders are confidently ruled out. (c)RSNA, 2017. PMID- 28076013 TI - Exercise Oximetry and Exercise Near-infrared Spectroscopy to Assess Peripheral Artery Disease. PMID- 28076014 TI - Ankle-Brachial Index for Diagnosing Peripheral Arterial Disease. PMID- 28076015 TI - US and MR Imaging of Pectoralis Major Injuries. AB - During the past 2 decades, the frequency of pectoralis major muscle injuries has increased in association with the increased popularity of bench press exercises. Injury of the pectoralis major can occur at the muscle origin, muscle belly, musculotendinous junction, intratendinous region, and/or humeral insertion-with or without bone avulsion. The extent of the tendon injury ranges from partial to complete tears. Treatment may be surgical or conservative, depending on the clinical scenario and anatomic characteristics of the injury. The radiologist has a critical role in the patient's treatment-first in detecting and then in characterizing the injury. In this article, the authors review the normal anatomy and anatomic variations of the pectoralis major muscle, classifications and typical patterns of pectoralis major injuries, and associated treatment considerations. The authors further provide an instructive guide for ultrasonographic (US) and magnetic resonance (MR) imaging evaluation of pectoralis major injuries, with emphasis on a systematic approach involving the use of anatomic landmarks. After reviewing this article, the reader should have an understanding of how to perform-and interpret the findings of-US and MR imaging of the pectoralis major. The reader should also understand how to classify pectoralis major injuries, with emphasis on the key findings used to differentiate injuries for which surgical management is required from those for which nonsurgical management is required. Familiarity with the normal but complex anatomy of the pectoralis major is crucial for performing imaging-based evaluation and understanding the injury findings. (c)RSNA, 2017 Online supplemental material is available for this article. PMID- 28076016 TI - Herpes Simplex Encephalitis. PMID- 28076017 TI - Morel-Lavallee Lesion: AIRP Best Cases in Radiologic-Pathologic Correlation. PMID- 28076018 TI - Invited Commentary on "Tumor-Vessel Relationships in Pancreatic Ductal Adenocarcinoma at Multidetector CT," with Response from Dr Zaky and Colleagues. PMID- 28076019 TI - Viral and Prion Infections of the Central Nervous System: Radiologic-Pathologic Correlation: From the Radiologic Pathology Archives. AB - Viral infections of the central nervous system (CNS) range in clinical severity, with the most severe proving fatal within a matter of days. Some of the more than 100 different viruses known to affect the brain and spinal cord are neurotropic with a predilection for producing CNS infection. The host response to viral infection of the CNS is responsible for the pathophysiology and imaging findings seen in affected patients. Viral CNS infections can take the form of meningitis, encephalitis, encephalomyelitis, or, when involving the spinal cord and nerve roots, encephalomyeloradiculitis. In 1982, an infectious particle termed a prion that lacked nucleic acid and therefore was not a virus was reported to produce the fatal neurodegenerative disease Creutzfeldt-Jakob disease and related disorders. These prion diseases produce characteristic neuroimaging findings that are distinct from those seen in most viral infections. The clinical and imaging findings associated with viral CNS infection are often nonspecific, with microbiologic analysis of cerebrospinal fluid the most useful single test allowing for diagnosis of a specific viral infection. This review details the spectrum of viral CNS infections and uses case material from the archives of the American Institute for Radiologic Pathology, with a focus on the specific clinical characteristics and magnetic resonance imaging features seen in these infections. Where possible, the imaging features that allow distinction of these infections from other CNS inflammatory conditions are highlighted. PMID- 28076021 TI - Radiologic Assessment of Native Renal Vasculature: A Multimodality Review. AB - A wide range of clinically important anatomic variants and pathologic conditions may affect the renal vasculature, and radiologists have a pivotal role in the diagnosis and management of these processes. Because many of these entities may not be suspected clinically, renal artery and vein assessment is an essential application of all imaging modalities. An understanding of the normal vascular anatomy is essential for recognizing clinically important anatomic variants. An understanding of the protocols used to optimize imaging modalities also is necessary. Renal artery stenosis is the most common cause of secondary hypertension and is diagnosed by using both direct ultrasonographic (US) findings at the site of stenosis and indirect US findings distal to the stenosis. Fibromuscular dysplasia, while not as common as atherosclerosis, remains an important cause of renal artery hypertension, especially among young female individuals. Fibromuscular dysplasia also predisposes individuals to renal artery aneurysms and dissection. Although most renal artery dissections are extensions of aortic dissections, on rare occasion they occur in isolation. Renal artery aneurysms often are not suspected clinically before imaging, but they can lead to catastrophic outcomes if they are overlooked. Unlike true aneurysms, pseudoaneurysms are typically iatrogenic or posttraumatic. However, multiple small pseudoaneurysms may be seen with underlying vasculitis. Arteriovenous fistulas also are commonly iatrogenic, whereas arteriovenous malformations are developmental (ie, congenital). Both of these conditions involve a prominent feeding artery and draining vein; however, arteriovenous malformations contain a nidus of tangled vessels. Nutcracker syndrome should be suspected when there is distention of the left renal vein with abrupt narrowing as it passes posterior to the superior mesenteric artery. Filling defects in a renal vein can be due to a bland or tumor thrombus. A tumor thrombus is most commonly an extension of renal cell carcinoma. When an enhancing mass is located predominantly within a renal vein, leiomyosarcoma of the renal vein should be suspected. (c)RSNA, 2017. PMID- 28076020 TI - Structure of the Medullary Veins of the Cerebral Hemisphere and Related Disorders. AB - Deep medullary veins drain into subependymal veins with four convergence zones and show parallel distribution patterns adjacent to the body or inferior horn and a radial pattern in the frontal horn or trigon of the lateral ventricle. As white matter imaging develops such as diffusion tensor imaging or susceptibility weighted imaging, requirements for understanding of white matter structures are increasing, not only for understanding of neuronal tracts but also for that of other structures including the fine anatomy of white matter vessels. Some disorders are related to deep medullary veins and show characteristic distributions of the lesions indicating the relationship to the medullary veins. When lesions show a parallel or radial distribution pattern in the certebral deep white matter, disorders related to deep medullary veins should be considered for differential diagnosis. In this review, we discuss disorders related to deep medullary veins, including (a) anomalies of the medullary veins, (b) hemorrhagic disorders related to the medullary veins (diffuse vascular injury due to high energy trauma, deep medullary vein engorgement/thrombosis in neonates), (c) inflammatory changes that spread along the medullary veins, (d) neoplasms within the medullary veins, and (e) metabolic changes that lead to altered visualization of medullary veins. Understanding the anatomic structure of medullary veins in the cerebral hemisphere and becoming familiar with disorders in which the medullary veins play a major role in disease development may be helpful in the interpretation of brain images. (c)RSNA, 2017. PMID- 28076023 TI - Outside in. AB - Nigel in the health food shop was amused at my ignorance. 'I thought you were a child of the sixties,' he said. Wrong, I told him, I was a child in the sixties. Which is why I missed out on all the swinging. PMID- 28076022 TI - Renal Papillary and Calyceal Lesions at CT Urography: Genitourinary Imaging. PMID- 28076024 TI - Down tools. AB - Poor Saint George. I think of him every time I see the St George's Forceps in our store room. Have you ever seen a pair? They are about six inches long and used for biopsies somewhere where the sun does not shine. PMID- 28076025 TI - People who sit for long periods have higher mortality rate. AB - People who spend a lot of time sitting down have higher rates of mortality, regardless of overall physical activity levels. PMID- 28076026 TI - Us nurses inspired by nightingale. AB - Florence Nightingale revolutionised military nursing practice and transformed negative attitudes towards female nurses during the American Civil War, conference-goers heard last week. PMID- 28076027 TI - Delaying gratification helps children avoid gaining weight. AB - Boys and girls who exercise self-control are less likely to become overweight by the time they reach adolescence. PMID- 28076028 TI - Voices - Being newly qualified is daunting, but guidance is available, says Tony Hazell. AB - This autumn more than 8,000 newly qualified nurses and midwives will bid farewell to student life and join our register for the first time. Their years of hard work will finally be rewarded. PMID- 28076029 TI - Fitness to practise targets not met despite 179 extra panellists. AB - Almost one third of the 4,000 fitness to practise (FtP) cases on the books of the Nursing and Midwifery Council (NMC) have not been completed. PMID- 28076030 TI - Unions join forces to fight pay freezes for sickness absences. AB - Health unions and employers met last week to discuss moves by several NHS trusts to freeze annual pay increments for underperforming nurses and those absent from work through sickness. PMID- 28076031 TI - Readers panel. AB - Our experts consider a hot topic of the day. PMID- 28076032 TI - Mentoring scheme deals effectively with issue of job 'fatigue'. AB - A scheme giving all new staff two mentors rather than one has improved staff retention and helped treble the number of mentors. PMID- 28076033 TI - Initiative helps bolster staff confidence. AB - Ward sisters and charge nurses are being trained to deal with staff conflict, hospital-acquired infections and budgets as part of an initiative to improve staff retention in Jersey. PMID- 28076036 TI - Ninety years strong for Dame Sheila. AB - Dame Sheila Quinn, one of the UK's most influential nurses in the 20th century, celebrated her 90th birthday with family and friends last week. PMID- 28076034 TI - Over-reliance on technology is bad news for care. AB - I teach pre-registration nursing students clinical skills. Here in Shropshire, hospitals use an automated data collection system designed to alert nurses when the patient's condition is deteriorating. The dominance of such technology sometimes makes me think about hanging up my uniform for good. PMID- 28076037 TI - Nursing and medical students benefit from training together. AB - Communication and respect between nursing and medical students improved when they were taught alongside each other on wards as part of a project to improve working relations. PMID- 28076039 TI - Greater risk of death in people with cystic fibrosis and MRSA. AB - Detection of meticilin-resistant staphylococcus aureus (MRSA) in patients with cystic fibrosis is associated with lower survival rates. PMID- 28076040 TI - Chance of a heart attack is higher in a colder climate. AB - Increases in the risk of myocardial infarction at colder ambient temperatures may be one driver of cold-related increases of overall mortality. An increased risk of myocardial infarction at higher temperatures has not been found. PMID- 28076041 TI - Working conditions in care homes are ideal for student placements. AB - I agree with Stuart Keeling (career development September 8) that care homes offer tremendous opportunities for nursing students and those thinking of going into nursing and medicine. PMID- 28076042 TI - Webwise. AB - Independent Living Alternatives (ILA) advocates the rights of people with disabilities. Run by the clients it serves, the organisation provides a comprehensive range of personal assistance services. PMID- 28076043 TI - A more complete picture of mental health legislation. AB - As research and development officer for mental health at NHS Grampian, I was interested to read Ian Harvey's article on the implementation of the Mental Health Act 2007 in England and Wales (art&science August 25). PMID- 28076047 TI - Five hand hygiene elements may be useful audit tools. AB - I was pleased that Dinah Gould's learning zone article on auditing hand hygiene practice (September 15) referred to the guidelines on hand hygiene issued last year by the World Health Organization (WHO). PMID- 28076045 TI - Therapeutic touch is good, but technology cannot be ignored. AB - While I agree that nurses should rely more on their sense of touch, sight and hearing when assessing patients (features September 8), this should be in conjunction with state-of-the-art technology and monitoring devices. We need to nurse in the 21st century, not the 19th. PMID- 28076048 TI - Midwife shortage is at its most acute in inner cities. AB - Further to Christian Duffin's interview with Cathy Warwick, general secretary of the Royal College of Midwives (career development September 8), I fear for the future of maternity services. PMID- 28076049 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28076051 TI - Scots look south for jobs. AB - Newly qualified nurses struggling to find jobs in Scotland are searching for work in England. PMID- 28076052 TI - Doctors demand better training for nurses in continence care. AB - Inconsistent training for nursing staff in bladder and bowel problems is leading to variable standards in continence care, according to a major audit by the Royal College of Physicians. PMID- 28076053 TI - Public health campaign launched to promote safe sex for over-50s. AB - A campaign urging people over 50 years old to use condoms has been launched by the Family Planning Association (FPA) after its nurse advisers noticed a surge in calls from the age group. PMID- 28076055 TI - An ambitious agenda. AB - The Nursing and Midwifery Council (NMC) revealed its new standards for pre registration education last week. They have been endorsed by professional leaders from the four corners of the UK and will be in place by the time all students are being prepared to degree level. PMID- 28076054 TI - New NMC standards place more emphasis on community learning. AB - Pre-registration education standards to be introduced at the same time as the move to all-graduate entry into nursing were published by the Nursing and Midwifery Council (NMC) last week. PMID- 28076056 TI - Reader's practice profile gunshot wounds. AB - As a newly qualified nurse who has just joined the Royal Air Force, I believe it is important to have an understanding of the complicated nature of gunshot wounds, including the importance of effective record keeping and the role this may have in any court action involving the perpetrator. PMID- 28076057 TI - Starting out - Medical terminology confuses patients and nursing staff. AB - On my second placement I worked in a medical ward. I helped to care for a patient who was prone to falling, had multiple conditions and was generally frail. A care of the elderly review was required for this patient as he was unable to carry out most activities of living without some assistance, particularly mobilising, personal cleansing and dressing. PMID- 28076059 TI - More talking therapy would improve care, say mental health patients. AB - Almost all people with mental health problems who are seen by a community psychiatric nurse in England feel they have been listened to, according to a survey by the healthcare regulator. PMID- 28076058 TI - Outreach project targets sex workers. AB - Nurses are visiting up to 60 flats in central London per month and screening sex workers for sexually transmitted infections (STIs) as part of a project to increase access to health care. PMID- 28076060 TI - Learning from each other to improve dementia care. PMID- 28076062 TI - Expert advice when you need it is only a phone call away. AB - David James (pictured) has been a nurse information scientist at the Regional Drug and Therapeutics Centre for the past eight years, and for the next six months he will be seconded as information manager. PMID- 28076061 TI - Advice helps women after termination. AB - A nurse-led telephone service for women who have undergone an abortion has increased uptake and awareness of contraception, results of a pilot show. PMID- 28076063 TI - Nurses as information scientists. AB - Nurses at the Regional Drug and Therapeutics Centre (RDTC) in Newcastle upon Tyne are helping in efforts to provide health professionals with the information they need about the safe use of medicines. PMID- 28076064 TI - Pope's visit boosts care home staff. AB - The Pope greeted 80 members of staff, including about 40 HCAs, who work at St Peter's Residence for Older People in Vauxhall. PMID- 28076065 TI - Health visitors' caseloads 'way too high' and a risk to families. AB - Nearly half of health visitors have more than 400 children on their books, according to preliminary results from a Community Practitioners' and Health Visitors' Association (CPHVA) survey. PMID- 28076067 TI - An opportunity to influence politicians in uncertain times. AB - As well as the continuing economic challenges, there is a new coalition government, public sector pensions are being reviewed as part of a comprehensive spending review, and the NHS has been told to make L20 billion of efficiency savings. Thousands of nursing posts are being lost all over the country. PMID- 28076066 TI - Fast, honest feedback. PMID- 28076068 TI - The future of health care relies on motivated people. AB - I read with interest Rose-Marie Gilbert's experience of negative comments when mentioning community nursing as a career choice (letters September 8). PMID- 28076069 TI - Training should include community placements. AB - I agree with RCN education adviser Dame Betty Kershaw that we desperately need more community placements (analysis September 1). PMID- 28076070 TI - New nurses need to be urged to apply for various posts. AB - Jemma Rhodes' letter (September 15) gives the impression that I endured an unsatisfactory placement in a nursing home, when this was not the case. PMID- 28076071 TI - Present and correct - Student Life. AB - Some universities pursue a policy of enforced attendance at lectures to ensure grade attainment, to encourage what is described as discipline and professionalism and to meet Nursing and Midwifery Council (NMC) requirements. PMID- 28076072 TI - Patient assessment. AB - Patient consultation and history taking are important aspects of nursing. Reading this article enabled me to recognise the essential factors that need to be considered. PMID- 28076074 TI - Starting out-Patient's cash gift to my mentor made me feel uncomfortable. AB - Before he left the ward, Mr D walked to the nurses' station, said goodbye to the team and discreetly slipped some money under the planner on the desk where my mentor was sitting. My mentor, who had just discharged him, said 'thank you' and took the money. PMID- 28076073 TI - Experiences of stress among nurses in acute mental health settings. AB - Aim To explore occupational stressors, the lived experience of stress and the meaning of this experience for staff working in acute mental health care. Method The study adopted a hermeneutic phenomenological approach to ascertain the lived experience of stress among eight qualified staff working in a mental health NHS trust in London. A semi-structured interview format was used. Interviews were transcribed verbatim and analysed using an interpretative phenomenological analysis framework. Findings The occupational experience of nurses in this study indicates that staff are frequently subjected to violent and aggressive behaviour from patients. Such experiences adversely affect patient outcomes in that staff may be reluctant to engage with such individuals because of anxiety about being hurt or experiencing further intimidation. Environmental pressures coupled with high activity levels mean that staff have little time to focus on the task at hand or to plan future activities. As a result they find that when they go home they are unable to switch off from work. Conclusion Further investment is needed in acute mental health settings and in staff who work in this area. If this does not happen, it is likely that the quality of service provision will deteriorate and nurses' health and wellbeing will suffer. PMID- 28076075 TI - Readers panel - No MMR, no free education. PMID- 28076076 TI - Voices-Politicians beware - cuts in health spending hurt even more during a recession. AB - Over the past few weeks the latest row between the main political parties has concerned the slashing of public spending. Will they? Won't they? Who would do it more? And perhaps most importantly, how much will be cut? PMID- 28076077 TI - Opinions split on minimum age for cervical smears. AB - Nurse opinion is divided over a decision to keep the minimum cervical screening age of women at 25 in England. PMID- 28076078 TI - Generic community role to be scrapped. AB - The way community nursing care is delivered in Scotland will be re-examined after plans to create a generic community role were scrapped. PMID- 28076081 TI - Newborn babies might benefit from having music played to them. AB - Playing music to neonates may have physiological and behavioural benefits and might reduce pain and improve feeding, according to the preliminary findings of researchers in Canada who investigated the effects of music played to term or premature infants. PMID- 28076080 TI - CBT plus medication for initial treatment of insomnia, then CBT. AB - In patients with persistent insomnia, the addition of medication to cognitive behavioural therapy (CBT) produces added benefits during acute therapy. But long term outcome is optimal when medication is discontinued during maintenance CBT. PMID- 28076082 TI - Developing a community matron service:a neighbourhood model. AB - NHS Blackburn with Darwen Provider Services Unit has adopted an innovative team approach to improve patient access to its community matron service. This article reviews the national picture and local development of the community matrons role. PMID- 28076083 TI - The cruellest cuts of all. AB - Gill Donovan and Michele Pengelly are special nurses whose work is highly valued by their patients. Ms Donovan set up a round-the-clock telephone callback system to give cancer patients support, advice and guidance. One of her patients, Sheila Bevins, says the nurse's help was invaluable in her successful battle with breast cancer. PMID- 28076084 TI - On the cover - using coaching interventions to develop clinical skills. AB - This article contributes to the development of senior nurse coaching interventions to help colleagues develop their clinical skills. It introduces a practice skill analysis framework as a recommended tool and examines the challenges that can arise in its use. PMID- 28076085 TI - Nurses at troubled trust 'should be given chance to speak out'. AB - Nurses at an NHS trust where 'catastrophic failures' in care led to the deaths of at least 400 patients should be called to give evidence on why problems were not picked up sooner, MPs told ministers last week. PMID- 28076086 TI - Heat sends wimbledon fans to a&e. AB - Emergency nurses at the south London hospital that serves Wimbledon treated an influx of tennis fans suffering the effects of heatstroke last week. St George's in Tooting reported that the numbers were up on previous years. PMID- 28076087 TI - Anna's living legacy. AB - Megs and Bob Wilson set up a charity to help young adults with life-threatening illnesses after losing their daughter Anna, a nurse, to cancer. PMID- 28076089 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28076091 TI - Health-check drive boosts access to care. AB - Practice nurses are carrying out health checks on people with learning disabilities in a bid to ensure they have equal access to health care. PMID- 28076090 TI - Metric mania. AB - 'What's that in old money?' patients ask after they have been coerced on to the scales and we tell them their weight in kilograms. PMID- 28076092 TI - Recession forces charity to close, leaving cancer nurses out of work. AB - Specialist nurses were left feeling 'shocked and devastated' after a cancer charity that employed them was forced to fold due to the economic downturn. PMID- 28076093 TI - A genderless cancer. AB - Breast cancer in men accounts for less than 1 per cent of all breast cancers in the UK, but for each man diagnosed it is devastating and life threatening. As a man with breast cancer, I know how awful it is. PMID- 28076095 TI - Outsidein-New research has forced David Newnham to make sure he knows his left from his right. AB - When the phone rings, I pick it up with my left hand and hold it to my left ear. This leaves my right hand free to hold a pen or drink coffee. I have done it that way since the phone was invented. Is that wrong? PMID- 28076098 TI - As healthcare assistants take on more responsibility, should they be regulated? AB - The expanding role of the healthcare assistant (HCA) in primary, acute and independent settings has intensified the debate about whether the workforce should be regulated. PMID- 28076096 TI - Webwise. AB - The Child Accident Prevention Trust (CAPT) is the UK's leading charity working to reduce the number of children and young people killed, disabled or seriously injured in accidents. Its aim is to see children leading active, healthy lives - not 'wrapped in cotton wool'. PMID- 28076099 TI - Graduate diploma in aesthetic medicine. PMID- 28076101 TI - Antiretroviral programme cuts HIV birth rate in South Africa. AB - A nurse-led programme in which pregnant women with HIV are administered antiretroviral drugs has dramatically reduced the number of babies born with HIV. PMID- 28076100 TI - Complaints against nurses go up but number struck off is down. AB - The number of complaints about nurses from members of the public doubled last year compared with the previous 12 months, latest figures from the Nursing and Midwifery Council (NMC) reveal. PMID- 28076103 TI - Maternal mortality group lobbies PM. AB - RCN midwifery forum chair Gill Barber presented prime minister Gordon Brown with a petition last week highlighting the number of women dying needlessly in childbirth. PMID- 28076104 TI - UK ranks highly in 'work happiness' global survey. AB - The world's happiest nurses are those working in Canada, according to a global survey released last week. PMID- 28076105 TI - Safety remains concern in crime capital. AB - Violence and sexual harassment is one of the main problems faced by healthcare staff in South Africa, according to nurses at an International Council of Nurses congress debate. PMID- 28076106 TI - Internal damage to bronchoscopes could pose infection risk. AB - Periodic engineering maintenance of bronchoscopes may be needed to prevent contamination that is resistant to high-level disinfection. PMID- 28076107 TI - Medication concordance not caused by social factors. AB - Europeans' drug concordance increases with age but decreases with education. PMID- 28076108 TI - RCN joins colourful parade to celebrate worldwide gathering of nurses in Durban. AB - The International Council of Nurses (ICN) 24th congress opened in South Africa last week with a procession of nurse leaders from across the world. PMID- 28076109 TI - 'Emigration of nurses is crippling Africa's embattled health system'. AB - The migration of African-trained nurses to developed countries such as the UK is 'crippling' health systems for the world's most needy, the former president of Botswana told an event attended by 5,000 nurses last week. PMID- 28076110 TI - Promoting christianity is unacceptable in health care. AB - Offering to say a prayer is a warm and kind thought (letters June 10). Most patients will accept it as such. It is no more offensive than being offered a sleeping pill. If they do not like the idea, they can simply say: 'Thanks, but no thanks.' 'Thanks, but no thanks.' PMID- 28076112 TI - A suitable case for treatment. PMID- 28076111 TI - Nail care feature gets to the heart of core nursing skills. AB - Thank you for drawing attention to the importance of personal hygiene in nail care (art&science June 17). Authors Bridget Malkin and Pat Berridge discuss the subject in depth and address the confusion over who should perform nail care for patients. PMID- 28076113 TI - Epilepsy article will help me improve patient outcomes. AB - As a practice nurse with a special interest in epilepsy, I very much enjoyed Rebecca Walsh and Sarah Kerley's clear, thorough and comprehensive article 'Nursing patients with epilepsy in secondary care settings' (learning zone May 13). PMID- 28076114 TI - Now the UK knows how it feels to lose trained nurses. AB - In your report on nurse migration to Australia (news June 17), James Buchan identifies the weakening pound, pay, and limitations on continuing professional development and pensions as drivers of migration. PMID- 28076115 TI - Report of increase in NMC fees was pure speculation. AB - I wish to correct the misleading report about Nursing and Midwifery Council (NMC) registration fees (news July 1). The NMC recently held a briefing for journalists on our trustees' report and accounts. Due to careful financial management and prudent investment, the NMC has cleared the historical debt inherited from its predecessor, the UKCC. PMID- 28076116 TI - NHS direct turns to band 5 nurses after success in scotland. AB - An evaluation of band 5 nurses working for an NHS helpline has been launched to determine the effectiveness of the group in handling calls and supporting colleagues. PMID- 28076117 TI - Guidance is needed on storing drugs during a heatwave. AB - DRUGS DURING A HEATWAVE The recent heatwave prompted a number of health warnings. One possible consequence that does not seem to have been considered is the effect of heat on drug stability. PMID- 28076118 TI - 'Fat suit' innovation AIDS staff training. AB - A former healthcare assistant has invented a 'fat suit' to train healthcare professionals in safely moving and handling obese patients. PMID- 28076119 TI - Let's keep things in perspective in terms of relationships with patients. AB - I do not believe sexual relationships between nurses and patients or former patients are always wrong (readers panel July 1). As Jane Scullion says: 'It depends on the relationship, the setting, the participants and the integrity of the nurse.' PMID- 28076120 TI - DH insists pay award will be honoured. AB - Next year's 2.25 per cent pay deal will be honoured by the government, the Department of Health (DH) assured Nursing Standard readers this week. PMID- 28076121 TI - Corrections. AB - Our report about the plans by the Nursing and Midwifery Council (NMC) to collect new data (news July 1) incorrectly stated that personal information about registrants' ethnicity, sexual orientation and religious beliefs would be published on the nursing register next year. PMID- 28076122 TI - Student life - The two sides of stress. AB - Training to be a nurse involves exposure to many stressors. Whatever they are studying, most students face the stresses of leaving home and adjusting to university life with the attendant financial worries, time pressures and anxieties associated with examinations and assessments. But nursing students face additional pressures. PMID- 28076123 TI - Nurses with diplomas are as worthy as those with degrees. AB - Mandy Dervis (readers panel June 17) states that nurse training should be to degree level. She adds: 'Those who do not feel up to it because they are too busy or only have a "handful of GCSEs" can undertake further education or work as nursing assistants.' PMID- 28076125 TI - 'Personal experience taught me about grief'. AB - Dawn Chaplin, pictured, is head of bereavement services at the Heart of England NHS Foundation Trust, vice chair of the Bereavement Services Association and a member of the steering group of the Bereavement Pathways project. PMID- 28076124 TI - Stroke units benefit from work of nutrition assistants. AB - As a support service manager in the stroke and rehabilitation unit at Addenbrooke's Hospital, Cambridge, I manage a team of band 3 nutrition assistants working effectively to meet the nutritional needs of all our patients (letters July 1). PMID- 28076126 TI - Cultural shift cultural shif. AB - THE HEALTH service is a major employer of minority ethnic groups, although it has not always been an equal opportunities employer. NHS trusts are now required to ensure that their employee profile more accurately reflects the local population ( NHSE 2000 ). PMID- 28076127 TI - Appeals expected after care home assessments. AB - NURSING HOME residents expecting to receive the maximum L110 a week contribution to their care costs are being left disappointed, emerging evidence suggests. PMID- 28076129 TI - Sign of change. AB - Department of Health nursing officer Anna Maslin has edited a book about how well known women have overcome challenges on the road to success. Royal College of Midwives president Lorna Muirhead is among those featured in Women at Work: Perspectives and Experiences. For details, call Kerry Veitch on 0191 227 4018. PMID- 28076128 TI - 100,000 patients get private care. AB - SPARE CAPACITY in the independent healthcare sector means private hospitals could treat 100,000 NHS patients a year, health minister John Hutton said last week. PMID- 28076130 TI - Who'll join me in backing the modest bumbag? AB - On watching the weekly episode of ER, I noticed that the nurses were equipped with bumbags to hold some of their necessary equipment. PMID- 28076131 TI - ? AB - What a superb suggestion by Chris Buswell for nurses to have bumbags to keep basic equipment on hand. Why this has not been thought of before I do not know. A roll-down pouch is already available from St John Ambulance Supplies at L12.95 (empty). Or there is a roll-down bumbag from SP Services. Nurses could kit themselves out to suit their own particular needs. PMID- 28076132 TI - Less whingeing on pay or we alienate the public. AB - I am fed up with hearing nurses whingeing about an above-inflation pay rise of 3.6 per cent. The vast majority of the public do not get yearly pay rises. If nurses really want wages that are comparable with other public sector employees they should ensure that their unions agree a pay structure with the government through Agenda for Change. PMID- 28076135 TI - Cardiac nursing: a comprehensive guide Richard Hatchet Cardiac nursing: a comprehensive guide and David Thompson Churchill Livingstone 603pp; L59.95 0 443 06346 X 044306346X. AB - This book deals with all aspects of care, prevention and management of heart disease. Contents are listed at the beginning of each chapter, making everything easy to find. PMID- 28076133 TI - It's a lonely job for our strategic thinkers. AB - Nurses who really want to influence health policy may be disappointed if they think Strategic Health Authorities (StHAs) will have much influence over national or local government, at least for the first year or two. PMID- 28076136 TI - Whats on: the best of the week's Health related tv and Radio. AB - Our roundup of what's on. PMID- 28076137 TI - The gift of 'the gap' that appears unwanted. AB - As a member of the audience at the 7th European Mental Health Conference, it was good to hear Beverly Malone talk of the 'gift' of mental health nursing to the profession. PMID- 28076138 TI - Enema suggestion works every time. AB - I read Jane Bates's recollections of 'high, hot and hell of a lot' enemas with great amusement (perspectives February 13). I would add that they still have the power to instil fear in those who remember. I sometimes use the memory of them to good effect! PMID- 28076139 TI - Dorothy Clifford, OBE (nee white). AB - As deputy chief nursing officer at the Department of Health, Dorothy White OBE was a high flyer with an atypical career. An unobtrusive nurse with an artistic temperament, she had wide experience in nursing administration, but relatively little experience at ward level. PMID- 28076140 TI - The naked truth about my classical nude figures. AB - The story 'Concerns raised over nudes at cancer clinic' (news February 13) does not truly reflect the situation. Although the hospital authorities had concerns about placing the classical nude figures in the hospital environment, the overwhelming response from the public has been positive. Moreover, considerable support for the figures has come from cancer patients. PMID- 28076141 TI - MRI scans show benefits of fluoxetine after stroke. AB - The antidepressant fluoxetine might improve functional recovery in people who have had a stroke, French researchers say. PMID- 28076143 TI - Listings. PMID- 28076142 TI - Sugar fragments could target specific cancer cells. AB - Tiny sugar fragments might herald a new approach to treating cancer, according to research from the US. PMID- 28076144 TI - Fusidic acid cream proved effective against impetigo. AB - Topical fusidic acid should be considered the first choice of treatment for impetigo, researchers from the Netherlands say. PMID- 28076145 TI - Transplanting liver cells for inherited metabolic disease. AB - Transplanting hepatocytes might be an alternative to liver transplantation in some people with inherited liver disorders. PMID- 28076146 TI - Tea and toast combats dangers in the night. AB - I would like to dispute the findings reported in Lynne Wallis's article, 'Dangers in the night' (features February 13). I believe heart problems found in night nurses are due to disrupted coping strategies. I have worked nights for more than 30 years and my heart is perfect. PMID- 28076147 TI - No degrees - and no pressure areas either. AB - The articles by Stephen Wright (perspectives February 13) and Miles Maylor (tissue viability supplement) struck a note with me. I have no problem with degrees or, for that matter, any training that will improve patient care but, as a matron/manager of a nursing home, I am dismayed at the condition of the pressure areas of some patients who are admitted from hospitals. PMID- 28076148 TI - Reluctance to refer sexual health cases. AB - SCHOOL NURSES have come under fire from doctors for failing to refer more youngsters to genito-urinary medicine (GUM) clinics. PMID- 28076149 TI - Durex sponsors university course. AB - DUREX IS part-funding a university sexual health course for nurses, providing, among other things, guest speakers and free condoms. PMID- 28076150 TI - Add up the benefits benefits. AB - Health secretary Alan Milburn wants ward sisters to manage their own budgets, typically worth hundreds of thousands of pounds, so that they can make decisions about how money is spent on the front line. I was appointed to my current post as a G grade sister four years ago. Of all the areas of responsibility in my job description - clinical standards, professional development of staff, effective skill mix, daily organisation and management of clinics across specialities - it was the words 'will be responsible for managing the outpatient budget' that made me wince. PMID- 28076151 TI - A thrifty vicar' son could teach the NHS a thing or two about cutting costs. AB - Awarm glow sweeps over me whenever I find a bargain, so when Poundland had a half price sale recently - well, I glowed like a nuclear accident. If you don't shop there, you don't know what you are missing: toiletries, big pants, six-pack socks and sets of bendy spanners all at a quid each. PMID- 28076152 TI - Children's champion lines up next battle. AB - THE RCN's new adviser in paediatric nursing has been caring for children for as long as she can remember. Fiona Smith grew up as the oldest of eight children and used to help her mother care for her siblings. 'I can recall, as a little tot, putting flannels on my sister's forehead in the middle of the night when she had mumps,' she says. PMID- 28076153 TI - Itchy business. AB - Over the past six years I have come across a number of patients with scabies. I have tried to find out as much as I can on the subject through talking to colleagues, searching the internet and by reading the CPD article ( Hadfield-Law 2001 ). PMID- 28076154 TI - A team dame. AB - A BRIGHT PURPLE nursing uniform hangs in Dame Catherine Elcoat's office. The chief nurse of a major teaching hospital, she has just been awarded a DBE for her work on clinical governance at the Department of Health (DoH). But when she goes into a clinical area, she wants colleagues and the public to identify her as one of the nursing staff. PMID- 28076155 TI - Most staff seem to be feeling that if things are getting better it's not in their neck of the healthcare woods '. AB - If you saw the Tonight programme on television last week, your heart must have gone out to the A&E staff whose department was being secretly filmed. PMID- 28076156 TI - Prime minister vows to raise public sector pay. AB - PRIME MINISTER Tony Blair has admitted that nurses' pay is too low and vowed to increase it. He said that wages were especially inadequate in London and areas where house prices are high. PMID- 28076157 TI - Welsh equal pay guidelines. AB - NEW GUIDELINES to give practice nurses in Wales the same pay awards as their colleagues working elsewhere in the health service have been issued to GPs and health authorities. PMID- 28076158 TI - Safe to use the 'T' word. AB - IT IS POSSIBLE, of course, that things will have changed by the time you read this, but as Nursing Standard went to press this week, it seemed that politicians were finally getting some- where on health service funding. PMID- 28076159 TI - NHS statistics at a glance. AB - DATA REVEALED in the NHS performance tables for England include. PMID- 28076160 TI - That's what you call a thank-you gesture. AB - SHOULD LONG-SERVING health service staff be paid loyalty bonuses? This was one of the suggestions put to Tony Blair last week in a letter signed by a number of public service leaders, including RCN general secretary Beverly Malone. PMID- 28076161 TI - Nursing leaders say NHS indicators are confusing. AB - MINISTERS HAVE come under fire from nursing leaders for the way they are measuring performance in the health service. PMID- 28076162 TI - Co-operation key to timely discharge. AB - NURSES HAVE expressed frustration at the way thousands of patients are still being discharged too early to free up beds or too late because there is nowhere for them to go. PMID- 28076163 TI - On the move. AB - Promotions/new appointments. PMID- 28076164 TI - Prescription-only medicines added to formulary. AB - THE NEW nurse prescribers will be able to prescribe all general sales list and pharmacy list medicines available to GPs, together with the following prescription-only medicines. PMID- 28076165 TI - Go-ahead for more MS nurses. AB - AN ADDITIONAL 20 to 25 specialist nursing posts are being created to speed up the prescription and monitoring of MS drugs. PMID- 28076166 TI - Lessons have been learned from Victoria Climbie case. AB - TWO NHS TRUSTS accused of failing to protect murdered eight-year-old Victoria Climbie say they have learnt important lessons from the case and updated their policies. PMID- 28076167 TI - Out of the ashes. AB - September 11 2001 has been hailed as 'the day that changed the world'. In a series of articles I wrote last year for Nursing Standard I offered evidence that a cultural shift, in the western world at least, is under way. People are turning away from materialistic lifestyles towards global, personal and spiritual wellbeing and concerns. Ground zero may have accelerated this, prompting people to ask themselves: 'If I were facing death, could I say that I have done everything I wanted?' ( Arlidge et al 2001 ). No one ever died wishing they had spent more time at the office. PMID- 28076168 TI - Funding campaign. AB - Nursing students from Unison led a march in London last week calling for better financial support. They are unhappy that diploma nursing students receive bursaries worth L2.70 an hour and are not entitled to certain benefits. Unison is campaigning for students to be paid 'a living wage', while the RCN prefers a sharp increase in bursaries. PMID- 28076169 TI - Ask the experts. AB - W hat can I do with my RCN continuing education points? I have collected more than 200 points over the past three years through attendance at conferences and writing practice profiles based on Nursing Standard continuing professional development articles. Is it worth my while keeping a record of them and do they have any currency elsewhere? PMID- 28076170 TI - Doubt over reliability of nursing vacancy figures. AB - THE PUBLICATION of performance indicators relating to nurse vacancy rates has been met with disbelief by managers and staff in some NHS trusts. PMID- 28076171 TI - Sharp contrasts in suicide levels. AB - HEALTH AUTHORITY performance tables reveal sharp contrasts in suicide rates. PMID- 28076173 TI - Cost of living keeps London rates high. AB - NURSES IN London were far from surprised to discover that vacancy rates are a lot higher in the capital than elsewhere in England. PMID- 28076172 TI - Can celebrity chefs crack it? AB - What became of the splendid idea to involve celebrity chefs in hospital catering? (No doubt they were offered a larger budget than the paltry 10p per patient per day that is allocated to our poor cooks.) Our worthy founder Florence Nightingale engaged the help of top chefs to nourish her charges in the Crimea. She recognised the importance of appetising food for sick patients, not just for nutritional purposes, but also as a psychological aid to recovery. PMID- 28076174 TI - Executive decision. AB - Nursing underpins the NHS - without us, the structure collapses. And nurses feel that even the most perceptive of non-nurse chief executives cannot fully understand the clinical issues that prevent them from working adequately or to their satisfaction. Nurses will have greater respect for managers with a nursing background and will accept proposals for change from them more readily. PMID- 28076175 TI - Research notes. AB - In a culture where randomised controlled trials are considered the 'gold standard', qualitative research suffers from the 'stigma of the small n'. A small number of cases are studied, the cases are not statistically representative of the population and the data collected are unstructured and difficult to analyse. Consequently, some NHS staff may see the study as not worthwhile, and indeed as a waste of money and resources. PMID- 28076176 TI - Network. AB - I was recently appointed health adviser to a local council community and housing directorate, with a remit for older people. I am interested in hearing from other nurses working in similar posts throughout the UK and would like to know if there is a national group that represents this type of nursing practice. PMID- 28076178 TI - Hay fever relief seven jabs away. AB - THE MISERY suffered by people with hay fever could be reduced thanks to a new treatment being tested by an allergy research nurse specialist. PMID- 28076177 TI - Outside in. AB - I always thought it was tough for children who couldn't go to school because of chronic illness, but having met Emma, I am not so sure. Emma was diagnosed with diabetes when she was ten, and her problem is that she does go to school. Well, that is probably a bit simplistic. But the fact is that, at 16, she is finding it all a bit much. PMID- 28076179 TI - Union fears shift to local pay at NHS Professionals. AB - NURSES EMPLOYED by NHS Professionals, the government's national staff agency, are receiving vastly differing sums depending on where in the country they work. PMID- 28076181 TI - Type 2 diabetes trend 'worrying'. AB - THE NUMBER of children with adult-type diabetes will continue to rise unless youngsters are encouraged to change their lifestyles, a nurse who specialises in the condition said this week. PMID- 28076183 TI - Markov Influence Diagrams. AB - Markov influence diagrams (MIDs) are a new type of probabilistic graphical model that extends influence diagrams in the same way that Markov decision trees extend decision trees. They have been designed to build state-transition models, mainly in medicine, and perform cost-effectiveness analyses. Using a causal graph that may contain several variables per cycle, MIDs can model various patient characteristics without multiplying the number of states; in particular, they can represent the history of the patient without using tunnel states. OpenMarkov, an open-source tool, allows the decision analyst to build and evaluate MIDs including cost-effectiveness analysis and several types of deterministic and probabilistic sensitivity analysis-with a graphical user interface, without writing any code. This way, MIDs can be used to easily build and evaluate complex models whose implementation as spreadsheets or decision trees would be cumbersome or unfeasible in practice. Furthermore, many problems that previously required discrete event simulation can be solved with MIDs; i.e., within the paradigm of state-transition models, in which many health economists feel more comfortable. PMID- 28076186 TI - LETTERS TO THE EDITOR. PMID- 28076192 TI - In Memoriam. PMID- 28076182 TI - Promoting healthy transition to college through mindfulness training with first year college students: Pilot randomized controlled trial. AB - OBJECTIVE: Given the importance of developmental transitions on young adults' lives and the high rates of mental health issues among U.S. college students, first-year college students can be particularly vulnerable to stress and adversity. This pilot study evaluated the effectiveness and feasibility of mindfulness training aiming to promote first-year college students' health and wellbeing. PARTICIPANTS: 109 freshmen were recruited from residential halls (50% Caucasian, 66% female). Data collection was completed in November 2014. METHODS: A randomized control trial was conducted utilizing the Learning to BREATHE (L2B) program, a universal mindfulness program adapted to match the developmental tasks of college transition. RESULTS: Participation in the pilot intervention was associated with significant increase in students' life satisfaction, and significant decrease in depression and anxiety. Marginally significant decrease was found for sleep issues and alcohol consequences. CONCLUSIONS: Mindfulness based programs may be an effective strategy to enhance a healthy transition into college. PMID- 28076196 TI - Impacts of Lowered Urban Air Temperatures on Precursor Emission and Ozone Air Quality. AB - Meteorological, photochemical, building-energy, and power plant simulations were performed to assess the possible precursor emission and ozone air quality impacts of decreased air temperatures that could result from implementing the "cool communities" concept in California's South Coast Air Basin (SoCAB). Two pathways are considered. In the direct pathway, a reduction in cooling energy use translates into reduced demand for generation capacity and, thus, reduced precursor emissions from electric utility power plants. In the indirect pathway, reduced air temperatures can slow the atmospheric production of ozone as well as precursor emission from anthropogenic and biogenic sources. The simulations suggest small impacts on emissions following implementation of cool communities in the SoCAB. In summer, for example, there can be reductions of up to 3% in NOx emissions from in-basin power plants. The photochemical simulations suggest that the air quality impacts of these direct emission reductions are small. However, the indirect atmospheric effects of cool communities can be significant. For example, ozone peak concentrations can decrease by up to 11% in summer and population-weighted exceedance exposure to ozone above the California and National Ambient Air Quality Standards can decrease by up to 11 and 17%, respectively. The modeling suggests that if these strategies are combined with others, such as mobile-source emission control, the improvements in ozone air quality can be substantial. PMID- 28076197 TI - A Method for the Removal of Chromium from Tanned Leather Wastes. AB - The separation of Cr(III) from collagen in chromium-tanned leather (wet-blue) is achieved by a combination of the protein (collagen) stabilization (protective cross-linking) and a subsequent labilization of the Cr(III) species bound to the protein. During the separation collagen retains the tertiary triple helical and higher (fibril) structures. The model proposed for the protective cross-linking involves inter- rather than intramolecular bridging, that is, a supramolecular bridging. The process of chromium removal takes place in a restricted aqueous environment, and it can be characterized as semihomogeneous or semiheterogeneous. PMID- 28076198 TI - Performance of a Suspended-Growth Bioscrubber for the Control of Methanol. AB - An experimental study is presented on the control of methanol emissions using a single-stage, laboratory-scale, suspended-growth bioscrubber. The inlet concentration was 50 or 100 ppmv. The bioscrubber was operated for over 80 days at a solids residence time of either one or two days. The overall removal efficiency of the scrubber with biomass ranged from 69.0 to 81.0%. The efficiency increased with the liquid flow rate. Model simulations were in good agreement with the data. PMID- 28076200 TI - The Relationship between Historic Industrial Site Use and Environmental Contamination. AB - A methodology is presented for estimating the probability that particular classes of environmental contaminants will be of concern at brownfield redevelopment sites. These probabilities are predicted by a logistics model that is based on qualitative information about site history and status. This qualitative information comprises data that would be collected through a Phase I Environmental Site Assessment (ESA), including historic site use, current use and ownership status, and the nature of adjacent properties. The model is fit and demonstrated using a set of 59 former industrial sites in southwestern Pennsylvania that were collected from the files of the Pennsylvania Department of Environmental Protection (PADEP). Predictive models are developed for exceedances of contaminants as grouped into the following classes: metals, chlorinated hydrocarbons, fuel hydrocarbons, and PCBs. A procedure for estimating the parametric uncertainty of the model predictions is also illustrated. This method can serve as a starting point for more effective usage of existing Phase I ESA information and for evaluation of the benefit of obtaining additional site information. By increasing the decision-making value of existing (or inexpensive) data, this method can help to reduce the information asymmetry that may be an obstacle to redevelopment. PMID- 28076202 TI - Sources of SO2, SO42-, NOx, and NO3- in the Air of Four Spanish Remote Stations. AB - In this study we have analyzed the sources of SO2, SO42-, Nox, and NO3- in the air of four remote Spanish stations belonging to the European Monitoring and Evaluation Programme (EMEP) network. Information about trajectories has been used together with the conditional probability functions (CPFs).1 The most remarkable result is that the Mediterranean area is the main source of these pollutants in the air of the Spanish EMEP stations. Northern Africa and Central Europe are also important sources while the Atlantic Ocean and British Islands are, in general terms, low sources of these pollutants. The role of the Iberian Peninsula as a source of pollutants in one of the stations, Logrono, is analyzed with more details using smaller regions to define CPFs. PMID- 28076203 TI - Sulfur Dioxide Emissions and Market Effects under the Clean Air Act Acid Rain Program. AB - The Clean Air Act Amendments of 1990 (CAAA90) established a national program to control sulfur dioxide (SO2) emissions from electricity generation. CAAA90's market-based approach includes trading and banking of Soumissions allowances. We analyzed data describing electric utility SO2 emissions in 1995, the first year of the program's Phase I, and market effects over the 1990-1995 period. Fuel switching and flue-gas desulfurization were the dominant means used in 1995 by targeted generators to reduce emissions to 51% of 1990 levels. Flue-gas desulfur ization costs, emissions allowance prices, low-sulfur coal prices, and average sulfur contents of coals shipped to electric utilities declined over the 1990 1995 period. Projections indicate that 13-15 million allowances will have been banked during the program's Phase I, which ends in 1999, a quantity expected to last through the first decade of the program's stricter Phase II controls. In 1995, both allowance prices and SO2 emissions were below pre-CAAA90 expectations. The reduction of SO2 emissions beyond pre-CAAA90 expectations, combined with lower-than-expected allowance prices and declining compliance costs, can be viewed as a success for market-based environmental controls. PMID- 28076205 TI - Letters To The Editor. PMID- 28076204 TI - Ozone and Its Precursors in the Atmosphere of Mexico City. AB - The relative apportionment of hydrocarbons (HCs) coming from mobile, fixed, and other sources (not correlated either to carbon monoxide [CO] or sulfur dioxide [SO2] emissions as solvent evaporation and biogenic sources) is calculated as previously proposed by Riveros et al.1 through the linear approximation [HC]tol = [HC]0 + m1 [CO] + m2 [SO2], where m1 and m2 are fitted constants. The obtained apportionment with air samples taken in 1993 is consistent with the earlier published apportionment with air samples taken in 1992, validating the previous procedure. This analysis suggests that 75% of HC originate from mobile sources, 5 18% from fixed sources, and 7-20% from other sources (mainly solvents and bio genic sources). A similar analysis was employed to estimate the relative contribution of HCs and nitric oxides (NO2) to ozone (O3) formation, the most important air pollutant in Mexico City. In this way, through a local lineation of O3 isopleths, simultaneous measurements of HC and NO2 in the atmosphere were fitted to the equation-[O3]peak = [O3]0 + ma [HC] + mb [NO2]-to predict O3 peak. With these data, the adjusted parameters show that NO2, not HC as was proposed previously, is the most important contributor to O3 formation. PMID- 28076206 TI - Processing older persons as clients in elderly care: A study of the micro processes of care management practice. AB - Elder care has undergone a marketization in recent years in which various models for care management have been introduced with the aim of making assessments efficient. This article investigates the effects the care management model has on resource allocation for home care when handling the requests of older persons in the needs assessment process. Sixteen tape-recorded assessment conversations with associated case-file texts were analyzed through discourse analysis. The results show that a managerialist thinking has had a partial impact on the assessment process where the documentation requirements have entailed bureaucratization in terms of the transfer that occurs from talk to text. The findings from the study nevertheless indicate that the assessment conversations have clear elements of an individual-centred perspective in which there is room for a care rational dialogue. This constitutes a welfare policy dilemma today. Providing for older people's requests should be on the basis of quality and an individual-centred perspective and care management has had a contrary effect in which focus is directed instead towards needs assessment and bureaucratic processes. PMID- 28076208 TI - Introduction to the Air & Waste Management Association's 30th Annual Critical Review. AB - This marks the 30th year of the Air & Waste Management Association's Critical Review Program. The Critical Review is a feature of A&WMA's Annual Conference, and is directed by the Critical Review Committee. The committee evaluates several topics each year, selects the best for presentation, and invites an individual (or group) to prepare the Critical Review Paper. This paper is thoroughly reviewed by the committee members and a panel of experts. After presentation of the review by the authors (typically on the Wednesday of the Annual Conference), there is a panel discussion and question-and-answer session. Panel members are invited to prepare their comments on the Critical Review, which, along with audience comments and the author's closing statements, are published in the Journal. PMID- 28076211 TI - Vitrification Process for Treatment of Sewage Sludge and Incineration Ash. AB - Vitrification processes, in which the operating temperature is higher than the melting point of the silica compounds contained in sewage sludge that turns into slag, are studied in this paper. The dried sludge and the incineration ash are injected into a furnace with auxiliary fuel and flux. The flux is the material used to control basicity of the ash content. Crushed limestone is used as the flux in this test. Almost all ashes in the sludge are vitrificated into slag. The flow of molten slag from the tap is smooth. After the slag is treated, it can be used as wall tile, interlocking tile, insulating material, and slag wool. This technology conforms to resource recycling. PMID- 28076213 TI - In Situ Reduction of Hexavalent Chromium in Alkaline Soils Enriched with Chromite Ore Processing Residue. AB - In investigating chromium sites in New Jersey, it has been observed that an organic-rich 0.5- to 4-foot-thick layer of decayed vegetation (locally known as "meadowmat") underlying the chromium-containing material acts as a natural barrier to the migration of Cr(VI). The groundwater in a sand layer directly beneath the meadowmat has been shown to contain low or nondetectable levels of chromium. The meadowmat is under highly reduced conditions due to bacterial activity associated with the organic material. Based on the observed ability of the meadowmat to reduce Cr(VI) to Cr(III), the feasibility of in situ reduction of Cr(VI) to Cr(III) at chromite ore processing residue (COPR) sites was investigated in biologically-active, laboratory-scale test columns. COPR typically has a high pH (in excess of 12) and may contain total chromium concentrations as high as 70,000 mg/kg. Experimental results demonstrated that the addition of a mineral acid (to lower the pH to between 7.0 and 9.5) and a bacteria-rich organic substrate (fresh manure) resulted in the reduction of Cr(VI) to the less toxic and less mobile trivalent form. Pore water Cr(VI) was reduced from approximately 800 mg/L to less than 0.05 mg/L over a period of eight months. This is less than the U.S. Environmental Protection Agency's (EPA) Maximum Contaminant Level (MCL) for chromium in drinking water of 0.1 mg/L. Solid phase Cr(VI) concentrations decreased from approximately 2,000 mg/kg to less than 10 mg/kg in the columns over a period of 11 months while the total chromium concentrations remained unchanged. Toxicity Characteristic Leaching Procedure (TCLP) extract from the treated columns met the regulatory limit of 5 mg/L of Cr, whereas the untreated samples had TCLP extract concentrations greater than 40 mg/L. This study demonstrated the potential applicability of in situ reduction to soils contaminated with Cr(VI) by adjusting the pH to between 7.0 and 9.5 and mixing in a bacteria-rich organic substrate. PMID- 28076219 TI - Children's Risk from Multimedia Exposure to Environmental Chemicals. PMID- 28076215 TI - National Annual Dioxin Emissions Estimate for Hazardous Waste Incinerators. AB - Reducing emissions of polychlorinated dibenzo-p-di-oxins and dibenzofurans, commonly known as di-oxins, is a high priority for environmental regulatory bodies throughout much of the world. In the United States, Section 112 (c)(6) of the Clean Air Act (CAA) requires the Environmental Protectio n Agency (EPA) to identify and control emissions from sources that are responsible for at least 90% of the overall emissions of seven targeted hazardous air pollutants, including dioxins.1 On April 19, 1996, the EPA proposed Maximum Achievable Control Technology (MACT) Standards for Hazardous Waste Combustors2 (HWCs). In that preamble, the EPA estimated annual dioxin emissions from the nation's hazardous waste incinerators (HWIs) to be 79 grams expressed as 2,3,7,8 tetrachloro dibenzo p-dioxins (TCDD) international toxic equivalents (ITEQs). However, early EPA dioxin emission estimates from medical waste incinerators and cement kilns were significantly overestimated;3-5 so, the following independent national dioxin emissions estimate for HWIs was prepared. This estimate corrects the errors in the EPA's HWI emissions database, uses an updated inventory of HWIs in the United States, and applies statistical imputation techniques that take maximum advantage of the limited dioxin emissions data for HWIs. PMID- 28076221 TI - Evaluation of a Portable Fourier Transform Infrared Gas Analyzer for Measurements of Air Toxics in Pollution Prevention Research. AB - A portable Fourier transform infrared gas analyzer with a photoacoustic detector performed reliably during pollution prevention research at two industrial facilities. It exhibited good agreement (within approximately 6%) with other analytical instruments (dispersive infrared and flame ionization) when analyte concentrations were high and relatively steady. It did not show good agreement when analyte concentrations were low (approximately 10 parts per million [ppm]) or were varying rapidly (less than 1.5 min). The precision for total acetates measurements was estimated to be approximately 40 ppm for measurements in the 0- to 700-ppm region. The precision for styrene measurements was estimated to be approximately 10 ppm for measurements in the 0- to 90-ppm region. PMID- 28076222 TI - Modeling Powdered Activated Carbon Injection for the Uptake of Elemental Mercury Vapors. AB - Batch kinetic experiments were performed to assess the rate of elemental mercury uptake by virgin activated carbon at 25 and 140 degrees C, and the homogeneous surface diffusion model (HSDM) was used to obtain Langmuir isotherm constants, the film mass transfer coefficient, and the surface diffusion coefficient for this adsorbent-adsor-bate pair. The adsorptive capacity of the carbon decreased, while the adsorption kinetics improved, with an increase in temperature. Simulations showed that the adsorptive capacity, particle size, and activated carbon dose, as well as the contact time influenced the removal of elemental mercury under conditions that may be encountered in the flue gases of coal-fired power plants. When adsorption equilibrium was achieved, the adsorptive capacity determined the carbon dose required to attain a certain percentage of mercury removal. When the system was mass-transfer limited, smaller particle size resulted in beter mercury removal. Although increasing the adsorptive capacity also led to better mercury removal for mass-transfer-limited systems, the magnitude of the improvement depended on the carbon particle size. Longer contact times resulted in the system approaching equilibrium and a more efficient use of the adsorptive capacity of activated carbon. Design nomo-grams were developed to estimate the carbon dose required to attain 80 and 90% removals of elemental mercury from nitrogen atmosphere for various process conditions and carbon properties. PMID- 28076224 TI - A Method for Removal of CO from Exhaust Gas Using Pulsed Corona Discharge. AB - An experimental study of the oxidation of CO in exhaust gas from a motorcycle has been carried out using plasma chemical reactions in a pulsed corona discharge. In the process, some main parameters, such as the initial CO concentration, amplitude and frequency of pulses, residence time, reactor volume, and relative humidity (RH), as well as their effects on CO removal characteristics, were investigated. O3, which is beneficial to reducing CO, was produced during CO removal . When the exhaust gas was at ambient temperature, more than 80% CO removal efficiency was realized at an initial concentration of 288 ppm in a suitable range of the parameters. PMID- 28076227 TI - An Evaluation of Flare Combustion Efficiency Using Open-Path Fourier Transform Infrared Technology. AB - Open-path Fourier transform infrared (OP-FTIR) technology was used to evaluate the combustion efficiency of a flare for comparison to several combustion models. Most flares have been considered an effective method for destroying organic compounds and anything that burns. As the Btu content of the flare gas is reduced, the combustion efficiency may also be reduced. Recent studies have suggested that lower Btu flares may have efficiencies as low as 65%. In addition, models have been developed to predict the effect of wind speed and stack discharge velocity on the combustion efficiency. This study was conducted on a low-Btu flare gas that is primarily CO. While the models would predict efficiencies as low as 30%, the sampling using OP-FTIR showed most combustion efficiencies well above 90%. Three methods were used to track combustion efficiency: monitoring the ratio of CO to CO2, monitoring the ratio of CO to tracer gas, and dispersion modeling. This study was complicated by the presence of two flare stacks, thus two tracer gases were used-SF6 and CF4. A method was developed for distinguishing between the two stacks and quantifying the efficiency in each stack. PMID- 28076229 TI - The Fate of Hydrogen Peroxide as an Oxygen Source for Bioremediation Activities within Saturated Aquifer Systems. AB - In situ bioremediation is an innovative technique for the remediation of contaminated aquifers that involves the use of microorganisms to remediate soils and groundwaters polluted by hazardous substances. During its application, this process may require the addition of nutrients and/or electron acceptors to stimulate appropriate biological activity. Hydrogen peroxide has been commonly used as an oxygen source because of the limited concentrations of oxygen that can be transferred into the groundwater using above-ground aeration followed by reinjection of the oxygenated groundwater into the aquifer or subsurface air sparging of the aquifer. Because of several potential interactions of H2O2 with various aquifer material constituents, its decomposition may be too rapid, making effective introduction of the H2O2 into targeted treatment zones extremely difficult and costly. Therefore, a bench-scale study was conducted to determine the fate of H2O2 within subsurface aquifer environments. The purpose of this investigation was to identify those aquifer constituents, both biotic and abiotic, that are most active in controlling the fate of H2O2. The decomposition rates of H2O2 were determined using both equilibrated water samples and soil slurries. Results showed H2O2 decomposition to be effected by several commonly found inorganic soil components; however, biologically mediated catalytic reactions were determined to be the most substantial. PMID- 28076230 TI - Characterization of Emissions from Diffusion Flare Systems. AB - Emissions from flares typical of those found at oil-field battery sites in Alberta, Canada, were investigated to determine the degree to which the flared gases were burned and to characterize the products of combustion in the emissions. The study consisted of laboratory, pilot-scale, and field-scale investigations. Combustion of all hydrocarbon fuels in both laboratory and pilot scale tests produced a complex variety of hydrocarbon products within the flame, primarily by pyrolytic reactions. Acetylene, eth-ylene, benzene, styrene, ethynyl benzene, and naphthalene were some of the major constituents produced by conversion of more than 10% of the methane within the flames. The majority of the hydrocarbons produced within the flames of pure gas fuels were effectively destroyed in the outer combustion zone, resulting in combustion efficiencies greater than 98% as measured in the emissions. The addition of liquid hydrocarbon fuels or condensates to pure gas streams had the largest effect on impairing the ability of the resulting flame to destroy the pyrolytically produced hydrocarbons, as well as the original hydrocarbon fuels directed to the flare. Crosswinds were also found to reduce the combustion efficiency (CE) of the co flowing gas/condensate flames by causing more unburned fuel and the pyrolytically produced hydrocarbons to escape into the emissions. Flaring of solution gas at oil-field battery sites was found to burn with an efficiency of 62-82%, depending on either how much fuel was directed to flare or how much liquid hydrocarbon was in the knockout drum. Benzene, styrene, ethynyl benzene, ethynyl-methyl benzenes, toluene, xylenes, acenaphthalene, biphenyl, and fluorene were, in most cases, the most abundant compounds found in any of the emissions examined in the field flare testing. The emissions from sour solution gas flaring also contained reduced sulfur compounds and thiophenes. PMID- 28076231 TI - Development and Preliminary Evaluation of a Particulate Matter Emission Factor Model for European Motor Vehicles. AB - Although modeling of gaseous emissions from motor vehicles is now quite advanced, prediction of particulate emissions is still at an unsophisticated stage. Emission factors for gasoline vehicles are not reliably available, since gasoline vehicles are not included in the European Union (EU) emission test procedure. Regarding diesel vehicles, emission factors are available for different driving cycles but give little information about change of emissions with speed or engine load. We have developed size-specific speed-dependent emission factors for gasoline and diesel vehicles. Other vehicle-generated emission factors are also considered and the empirical equation for re-entrained road dust is modified to include humidity effects. A methodology is proposed to calculate modal (accelerating, cruising, or idling) emission factors. The emission factors cover particle size ranges up to 10 um, either from published data or from user-defined size distributions. A particulate matter emission factor model (PMFAC), which incorporates virtually all the available information on particulate emissions for European motor vehicles, has been developed. PMFAC calculates the emission factors for five particle size ranges [i.e., total suspended particulates (TSP), PM10, PM5, PM25, and PM1] from both vehicle exhaust and nonexhaust emissions, such as tire wear, brake wear, and re-entrained road dust. The model can be used for an unlimited number of roads and lanes, and to calculate emission factors near an intersection in user-defined elements of the lane. PMFAC can be used for a variety of fleet structures. Hot emission factors at the user-defined speed can be calculated for individual vehicles, along with relative cold-to-hot emission factors. The model accounts for the proportions of distance driven with cold engines as a function of ambient temperature and road type (i.e., urban, rural, or motorway). A preliminary evaluation of PMFAC with an available dispersion model to predict the airborne concentration in the urban environment is presented. The trial was on the A6 trunk road where it passes through Loughborough, a medium-size town in the English East Midlands. This evaluation for TSP and PM10 was carried out for a range of traffic fleet compositions, speeds, and meteorological conditions. Given the limited basis of the evaluation, encouraging agreement was shown between predicted and measured concentrations. PMID- 28076232 TI - A Life-Cycle Comparison of Alternative Automobile Fuels. AB - We examine the life cycles of gasoline, diesel, compressed natural gas (CNG), and ethanol (C2H5OH)-fueled internal combustion engine (ICE) automobiles. Port and direct injection and spark and compression ignition engines are examined. We investigate diesel fuel from both petroleum and biosources as well as C2H5OH from corn, herbaceous bio-mass, and woody biomass. The baseline vehicle is a gasoline fueled 1998 Ford Taurus. We optimize the other fuel/powertrain combinations for each specific fuel as a part of making the vehicles comparable to the baseline in terms of range, emissions level, and vehicle lifetime. Life-cycle calculations are done using the economic input-output life-cycle analysis (EIO-LCA) software; fuel cycles and vehicle end-of-life stages are based on published model results. We find that recent advances in gasoline vehicles, the low petroleum price, and the extensive gasoline infrastructure make it difficult for any alternative fuel to become commercially viable. The most attractive alternative fuel is compressed natural gas because it is less expensive than gasoline, has lower regulated pollutant and toxics emissions, produces less greenhouse gas (GHG) emissions, and is available in North America in large quantities. However, the bulk and weight of gas storage cylinders required for the vehicle to attain a range comparable to that of gasoline vehicles necessitates a redesign of the engine and chassis. Additional natural gas transportation and distribution infrastructure is required for large-scale use of natural gas for transportation. Diesel engines are extremely attractive in terms of energy efficiency, but expert judgment is divided on whether these engines will be able to meet strict emissions standards, even with reformulated fuel. The attractiveness of direct injection engines depends on their being able to meet strict emissions standards without losing their greater efficiency. Biofuels offer lower GHG emissions, are sustainable, and reduce the demand for imported fuels. Fuels from food sources, such as biodiesel from soybeans and C2H5OH from corn, can be attractive only if the co products are in high demand and if the fuel production does not diminish the food supply. C2H5OH from herbaceous or woody biomass could replace the gasoline burned in the light-duty fleet while supplying electricity as a co-product. While it costs more than gasoline, bioethanol would be attractive if the price of gasoline doubled, if significant reductions in GHG emissions were required, or if fuel economy regulations for gasoline vehicles were tightened. PMID- 28076240 TI - Effects of bariatric surgery on gout incidence in the Swedish Obese Subjects study: a non-randomised, prospective, controlled intervention trial. AB - OBJECTIVES: To assess the long-term effect of bariatric surgery on the incidence of gout and hyperuricaemia in participants of the Swedish Obese Subjects (SOS) study. METHODS: This report includes 1982 subjects who underwent bariatric surgery and 1999 obese controls from the SOS study, a prospective intervention trial designed to assess the effect of bariatric surgery compared with conventional treatment. None of the subjects had gout at baseline. An endpoint on gout incidence was created based on information on gout diagnosis and use of gout medications through national registers and questionnaires. Median follow-up for the incidence of gout was about 19 years for both groups. Moreover, the incidence of hyperuricaemia over up to 20 years was examined in a subgroup of participants having baseline uric acid levels <6.8 mg/dL. RESULTS: Bariatric surgery was associated with a reduced incidence of gout compared with usual care (adjusted HR 0.60, 95% CI 0.48 to 0.75, p<0.001). The difference in absolute risk between groups was 3 percentage points at 15 years, and the number of subjects needed to be treated by bariatric surgery to prevent one incident gout event was 32 (95% CI 22 to 59). The effect of bariatric surgery on gout incidence was not influenced by baseline risk factors, including body mass index. During follow-up, the surgery group had a lower incidence of hyperuricaemia (adjusted HR 0.47, 95% CI 0.39 to 0.58, p<0.001). The difference in absolute risk between groups was 12 percentage points at 15 years, and the number of participants needed to be treated by bariatric surgery to prevent hyperuricaemia was 8 (95% CI 6 to 13). CONCLUSIONS: Bariatric surgery prevents gout and hyperuricaemia in obese subjects. TRIAL REGISTRATION NUMBER: NCT01479452; Results. PMID- 28076242 TI - Bread and Butter of Family Medicine: Guidelines, Population Screening, Diagnostic Evaluations, and Practice Models. AB - This issue of JABFM is full of evidence and thoughtful articles on topics central to family medicine. These articles critically examine what family physicians do on a daily basis. Reports in this issue provide new evidence regarding guidelines, screening programs, evaluation procedures, and practice models. Clinical articles report that the sensitivity of mailed Fecal Immunochemical Testing changes with the weather; a dermatoscope and a simple algorithm can help differentiate malignant from benign skin lesions; and that a few almonds can alter blood glucose levels in response to a glucose tolerance test. Readers will find an excellent discussion about whether, and how, the growing number of clinical guidelines should be overseen going forward. We also have a first-hand account of the Inaugural Starfield Summit, a meeting of family medicine leaders working to improve primary care for all. These topics, and plenty of additional new evidence pertinent to the daily practice of family physicians can be found in this issue. PMID- 28076243 TI - Clinical Practice Guidelines-Is "Regulation" the Answer? PMID- 28076241 TI - Phenotypic and functional characteristics of HLA-DR+ neutrophils in Brazilians with cutaneous leishmaniasis. AB - The protozoan Leishmania braziliensis causes cutaneous leishmaniasis (CL) in endemic regions. In murine models, neutrophils (PMNs) are recruited to the site of infection soon after parasite inoculation. However, the roles of neutrophils during chronic infection and in human disease remain undefined. We hypothesized that neutrophils help maintain a systemic inflammatory state in subjects with CL. Lesion biopsies from all patients with CL tested contained neutrophils expressing HLA-DR, a molecule thought to be restricted to professional antigen-presenting cells. Although CL is a localized disease, a subset of patients with CL also had circulating neutrophils expressing HLA-DR and the costimulatory molecules CD80, CD86, and CD40. PMNs isolated from a low-density leukocyte blood fraction (LD PMNs) contained a higher percentage of HLA-DR+ PMNs than did normal-density PMNs. In vitro coculture experiments suggested LD-PMNs do not suppress T cell responses, differentiating them from MDSCs. Flow-sorted HLA-DR+ PMNs morphologically resembled conventional PMNs, and they exhibited functional properties of PMNs. Compared with conventional PMNs, HLA-DR+ PMNs showed increased activation, degranulation, DHR123 oxidation, and phagocytic capacity. A few HLA-DR+ PMNs were observed in healthy subjects, and that proportion could be increased by incubation in either inflammatory cytokines or in plasma from a patient with CL. This was accompanied by an increase in PMN hladrb1 mRNA, suggesting a possible connection between neutrophil "priming" and up-regulation of HLA-DR. These data suggest that PMNs that are primed for activation and that also express surface markers of antigen-presenting cells emerge in the circulation and infected tissue lesions of patients with CL. PMID- 28076244 TI - The Need to Systematically Evaluate Clinical Practice Guidelines. AB - Clinical practice guidelines abound. The recommendations contained in these guidelines are used not only to make decisions about the care of individual patients but also as practice standards to rate physician "quality." Physicians' confidence in guidelines is based on the supposition that there is a rigorous, objective process for developing recommendations based on the best available evidence. Though voluntary standards for the development of guidelines exist, the process of guideline development is unregulated and the quality of many guidelines is low. In addition, the few tools available to assess the quality of guidelines are time consuming and designed for researchers, not clinicians. Few guidelines are evaluated, either before or after their dissemination, for their impact on patient outcomes. Just as with pharmaceuticals and other products that can affect patients for better or worse, perhaps it is time to develop more standardized ways to evaluate the development and dissemination of clinical practice guidelines to ensure a similar balance between risk and benefit. PMID- 28076245 TI - Care Coordination for Primary Care Practice. PMID- 28076246 TI - Care Coordination and Population Management Services Are More Prevalent in Large Practices and Patient-centered Medical Homes. AB - Despite efforts to better coordinate health care and improve population health, primary care practices may face difficulty dedicating an individual to provide these services. Using data from the American Board of Family Medicine, we found that the presence of care coordinators or population health managers was higher in larger practices and those with patient-centered medical home certification. PMID- 28076247 TI - 5-Day versus 10-Day Course of Fluoroquinolones in Outpatient Males with a Urinary Tract Infection (UTI). AB - INTRODUCTION: Current guidelines classify urinary tract infections (UTIs) in males as complicated and recommend longer treatment than for UTIs in females. The objective of this study is to demonstrate that males with UTIs may be successfully treated with an outpatient 5-day course of levofloxacin. METHODS: Data were obtained from a previously conducted clinical trial (www.clinicaltrials.gov identifier NCT00210886), a multicenter, double-blind, randomized, noninferiority study comparing levofloxacin 750 mg intravenously/by mouth once daily for 5 days and ciprofloxacin 400/500 mg intravenously/by mouth twice daily for 10 days in complicated UTI (cUTI). The current study was a post hoc, subgroup analysis of male and female subjects with cUTI. Subjects were stratified into groups based on sex and antibiotic received. The subjects were analyzed at the end of therapy (EOT) and post therapy (PT) for clinical success rates, defined as no further need for antimicrobial treatment. RESULTS: Totals of 427 patients (224 male, 203 female) and 350 patients (189 male, 161 female) were included in the modified intent-to-treat (mITT) population and microbiologically evaluable (ME) populations, respectively. Clinical success rates between males and females were not statistically different between antibiotic groups in either the mITT or ME populations at EOT or PT. CONCLUSION: This study demonstrates that males with UTI may be treated with a shorter course of antimicrobial therapy for UTI than previously recommended. PMID- 28076248 TI - Prediabetes Screening and Treatment in Diabetes Prevention: The Impact of Physician Attitudes. AB - PURPOSE: Detection and treatment of prediabetes is an effective strategy in diabetes prevention. However, most patients with prediabetes are not identified. Our objective was to evaluate the relationship between attitudes toward prediabetes as a clinical construct and screening/treatment behaviors for diabetes prevention among US family physicians. METHODS: An electronic survey of a national sample of academic family physicians (n 1248) was conducted in 2016. Attitude toward prediabetes was calculated using a summated scale assessing agreement with statements regarding prediabetes as a clinical construct. Perceived barriers to diabetes prevention, current strategies for diabetes prevention, and perceptions of peers were also examined. RESULTS: Physicians who have a positive attitude toward prediabetes as a clinical construct are more likely to follow national guidelines for screening (58.4% vs 44.4; P < .0001) and recommend metformin to their patients for prediabetes (36.4% vs 20.9%; P < .0001). Physicians perceived a number of barriers to treatment, including a patient's economic resources (71.9%), sustaining patient motivation (83.2%), a patient's ability to modify his or her lifestyle (75.3%), and time to educate patient (75.3%) as barriers to diabetes prevention. CONCLUSIONS: How physicians view prediabetes varies significantly, and this variation is related to treatment/screening behaviors for diabetes prevention. PMID- 28076249 TI - Fecal Immunochemical Test (FIT) for Colon Cancer Screening: Variable Performance with Ambient Temperature. AB - INTRODUCTION: Fecal immunochemical tests (FITs) are widely used in colorectal cancer (CRC) screening, but hemoglobin degradation, due to exposure of the collected sample to high temperatures, could reduce test sensitivity. We examined the relation of ambient temperature exposure with FIT positivity rate and sensitivity. METHODS: This was a retrospective cohort study of patients 50 to 75 years in Kaiser Permanente Northern California's CRC screening program, which began mailing FIT kits annually to screen-eligible members in 2007. Primary outcomes were FIT positivity rate and sensitivity to detect CRC. Predictors were month, season, and daily ambient temperatures of test result dates based on US National Oceanic and Atmospheric Administration data. RESULTS: Patients (n = 472,542) completed 1,141,162 FITs. Weekly test positivity rate ranged from 2.6% to 8.0% (median, 4.4%) and varied significantly by month (June/July vs December/January rate ratio [RR] = 0.79, 95% confidence interval [CI], 0.76 to 0.83) and season. FIT sensitivity was lower in June/July (74.5%; 95% CI, 72.5 to 76.6) than January/December (78.9%; 95% CI, 77.0 to 80.7). CONCLUSIONS: FITs completed during high ambient temperatures had lower positivity rates and lower sensitivity. Changing kit design, specimen transportation practices, or avoiding periods of high ambient temperatures may help optimize FIT performance, but may also increase testing complexity and reduce patient adherence, requiring careful study. PMID- 28076250 TI - Patient-Reported Offers of Alcohol Treatment for Primary Care Patients at High Risk for an Alcohol Use Disorder. AB - BACKGROUND: This study assessed patient-reported alcohol treatment offers by health care providers following routine annual screening for alcohol use in primary care. METHODS: A telephone interview within 30 days of the annual screen assessed demographics, alcohol and other drug use, mental health symptoms, and offers of formal treatment for alcohol by a Veterans Affairs health care provider. We included male patients (n = 349) at high risk for an alcohol use disorder (AUD) who had not received alcohol treatment in the past 3 months. We assessed self-reported receipt of any offers of formal treatment for alcohol use and associations of offers of formal treatment for alcohol with demographic and clinical variables. RESULTS: A total of 145 patients (41.5%) reported an offer of at least 1 type of formal treatment for alcohol use. More severe alcohol misuse (odds ratio, 1.07; 95% confidence interval, 1.03-1.11) and younger age (odds ratio, 0.97, 95% confidence interval, 0.95-0.99) were associated with reporting an offer of formal treatment. CONCLUSION: Most primary care patients at high risk for an AUD were not offered treatment following annual screening. Our results highlight the importance of training primary care providers in what constitutes appropriate medical treatment for this population and the most effective ways of offering treatment. PMID- 28076251 TI - Comparison of Medical Diagnoses among Same-Sex and Opposite-Sex-Partnered Patients. AB - BACKGROUND: Health disparities for gay and lesbian individuals are well documented in survey research. However, a limitation throughout the existing literature is the reliance on self-reported health conditions. This study used medical record diagnoses for gay and lesbian patients seen in primary care clinics. METHODS: This study used medical records of primary care patients (n = 31,569) seen at Midwestern, university-affiliated primary care clinics. First, all records with information about the sexual partnering of the patient were identified (n = 13,509). Then, opposite-sex-partnered and same-sex-partnered (SSP) patients were compared for prevalence of common chronic conditions and clinic utilization. RESULTS: Only 44.20% of medical records included information about patients' sexual partners. Both male and female SSP patients were more likely to be lower socioeconomic status, be a current or former smoker, and be diagnosed with substance abuse/dependence and depression. CONCLUSIONS: The findings suggest the need for more consistent screening of the sexual partnering of patients for identifying patients who are at greater risk of poorer health outcomes. However, identifying the sexual partnering of patients may not occur systematically in primary care, and there may be a lack of disclosure by SSP patients to their physicians given the social stigma about same-sex relationships. PMID- 28076253 TI - Presenting Signs of Multiple Myeloma and the Effect of Diagnostic Delay on the Prognosis. AB - BACKGROUND: Presenting symptoms of multiple myeloma (MM) are vague and nonspecific. Early detection poses a diagnostic challenge in primary care. We assessed whether clinical and laboratory data could provide early clues to MM diagnosis and whether time to detection affects survival. METHODS: A retrospective population-based study, including 110 men and women diagnosed with MM between 2002 and 2011, and matched cancer-free controls presenting with back pain. Clinical and laboratory data were extracted from medical records for the 2 year period prior to diagnosis of MM/back pain complaint. RESULTS: During the two years prior to diagnosis 64 (58%) of MM patients complained of back pain, and 37 (34%) suffered from fatigue or weight loss. Case-control comparisons did not reveal any significant differences in the number of pain complaints or infections in the two-year prediagnostic period. However, fatigue or weight loss, anemia, elevated ESR and creatinine (p < 0.001 for all) occurred more frequently in MM patients than controls and were confirmed as independent predictors in multivariated analysis. TTD did not impact stage at diagnosis, survival, or mortality. CONCLUSIONS: Back pain accompanied by fatigue, weight loss or abnormal lab results should raise a "red flag" warning of MM. Nonetheless, we did not find evidence that TTD influences the initial stage or the prognosis of MM. PMID- 28076252 TI - A Clinical Aid for Detecting Skin Cancer: The Triage Amalgamated Dermoscopic Algorithm (TADA). AB - PURPOSE: Family physicians (FPs) frequently evaluate skin lesions but may not have the necessary training to accurately and confidently identify lesions that require skin biopsy or specialist referral. We evaluated the diagnostic performance of a new, simplified dermoscopy algorithm for skin cancer detection. METHODS: In this cross-sectional, observation study, attendees of a dermoscopy course evaluated 50 polarized dermoscopy images of skin lesions (27 malignant and 23 benign) using the Triage Amalgamated Dermoscopic Algorithm (TADA). The dermoscopic criteria of TADA include architectural disorder (ie, disorganized or asymmetric distribution of colors and/or structures), starburst pattern, blue black or gray color, white structures, negative network, ulcer, and vessels. The study occurred after 1 day of basic dermoscopy training. Clinical information related to palpation (ie, firm, dimpling) was provided when relevant. RESULTS: Of 200 course attendees, 120 (60%) participated in the study. Participants included 64 (53.3%) dermatologists and 41 (34.2%) primary care physicians, 19 (46.3%) of whom were FPs. Fifty-two (43%) individuals had no previous dermoscopy training. Overall, the sensitivity and specificity of TADA for malignant skin lesions was 94.8% and 72.3%, respectively. Previous dermoscopy training and years of dermoscopy experience were not associated with diagnostic sensitivity (P = .13 and P = .05, respectively) or specificity (P = .36 and P = .21, respectively). Specialty type was not associated with sensitivity (P = .37) but dermatologists had a higher specificity than nondermatologists (79% v. 72%, P = .008). CONCLUSIONS: After basic instruction, TADA may be a useful dermoscopy algorithm for FPs who examine skin lesions as it has a high sensitivity for detecting skin cancer. PMID- 28076254 TI - Watchful Waiting Strategy May Reduce Low-Value Diagnostic Testing. AB - BACKGROUND: PCPs need effective communication strategies to address patient requests for low-value testing while sustaining patient-provider partnerships. Watchful waiting - allowing a negotiated period of time to pass before making a firm testing decision - shows promise as a tool for addressing patient requests for low-value testing. METHODS: Observational analysis of data from a randomized controlled trial of a communication intervention designed to boost patient centeredness and reduce low-value test ordering among 61 resident primary care physicians. Intervention effectiveness was assessed during follow-up encounters of unannounced standardized patients (SPs) who requested low-value tests. We examined associations between five physician counseling behaviors and overall patient-centeredness (Measure of Patient-Centered Communication) and requested test ordering. RESULTS: During 155 SP encounters, residents most commonly used reassurance (96% of encounters), evidence-based recommendations (97%), and watchful waiting (68 %). Resident advice to pursue watchful waiting was associated with 39% lower likelihood of test ordering (adjusted marginal effect of -38.6% [95% CI -43.6 to -33.6]). When all communication behaviors were examined together, only watchful waiting was significantly associated with test ordering (marginal effect of -38% [95% CI -44.3% to -31.7%]). Overall patient centeredness was not associated with low-value testing. CONCLUSION: Resident physician counseling to pursue watchful waiting was associated with less ordering of requested low-value diagnostic tests, while overall patient-centeredness was not. PMID- 28076255 TI - Problem Drug-related Behavior and Discontinuation of Opioids Following the Introduction of an Opioid Management Program. AB - PURPOSE: Problem drug-related behavior (PDB) among patients on chronic opioid therapy may reflect an opioid use disorder. This study assessed PDB prevalence and the relationship between PDB and ongoing prescription of opioids at a primary care clinic that implemented a multifaceted opioid management program. METHODS: A chart review of patients in a chronic opioid registry assessed prevalence of different types of PDB over 2 years, and whether opioids were prescribed during the last 3 months of the 2-year study period among patients with different levels of PDB. RESULTS: Among 233 registry patients, 84.1% exhibited PDB; 45.5% exhibited >=3 types of PDB. At the end of 2 years, most registry patients were still prescribed opioids, though patients with >=3 types of PDB were less likely than those without PDB to be prescribed opioids (62.3% vs. 78.4%, P = 0.016). CONCLUSIONS: PDB was pervasive in this population of patients on chronic opioid therapy. Those with the most PDB, and thus with the greatest likelihood of opioid use disorder and its social and medical consequences, were the least likely to be prescribed opioids by the clinic after 2 years. Given the rising rates of illicit opioid use in the U.S., it is important that clinics work closely with their patients who display PDB, systematically assess them for opioid use disorder, and offer evidence-based treatment. PMID- 28076256 TI - Statin Therapy as Primary Prevention in Exercising Adults: Best Evidence for Avoiding Myalgia. AB - INTRODUCTION: This review aims to determine whether active adults who begin statins and develop myalgia reduce or stop activity to become less symptomatic. If this occurs, strategies to mitigate symptoms are explored. Should these strategies fail, the question of whether exercise is an adequate alternative to statin therapy is addressed. METHODS: PubMed, Google Scholar, and the Cochrane Database were searched with keywords designed to retrieve information on statin myopathy in exercising adults. RESULTS: Statins are well tolerated by most people who exercise; however, caution is warranted in those who exercise at high levels, in the elderly, and in those receiving high-dose therapy. Several strategies improve statin tolerance while maintaining exercise levels, based on low-quality evidence. If statins are not tolerated, a continuing physical activity program can provide equivalent or superior cardiometabolic protection. CONCLUSIONS: Statins may occasionally present a barrier to physical activity. A number of strategies exist that can reduce the risk of myopathy. If a choice between exercise and statins becomes necessary, exercise provides equal benefit in terms of cardiovascular protection and superior mortality reduction, with improved quality of life. PMID- 28076257 TI - Physician Advice for e-Cigarette Use. AB - PURPOSE: To determine characteristics of smokers discussing e-cigarette use with their physician and receiving recommendations from their physician to use e cigarettes for smoking cessation. METHODS: US adult smokers who had visited a physician in the previous 12 months (n = 2671) were surveyed. Logistic generalized estimating equation models were used to assess the characteristics of smokers who (1) talked to a physician about e-cigarettes, and (2) received physician advice to use e-cigarettes for smoking cessation. RESULTS: 15% (n = 406) of smokers who visited a physician talked with their physician about e cigarettes. Among those asked whether their physician recommend e-cigarettes for smoking cessation (n = 257), 61% responded affirmatively. Current e-cigarette users were more likely to talk to their physicians about e-cigarettes (nondaily users vs never users: OR, 2.70; 95% CI, 1.79-4.05; daily users vs never users: OR, 4.29; 95% CI, 2.34-7.84) and have their physician recommend e-cigarettes for smoking cessation (daily users vs never users: OR, 9.40; 95% CI, 2.54-34.71). CONCLUSIONS: The majority of smokers who talk to their physician about e cigarettes report that they received advice to use e-cigarettes to quit smoking, despite limited evidence for their efficacy. More studies are needed to better understand e-cigarette recommendations in clinical settings. PMID- 28076258 TI - Perspectives of Primary Care Providers Toward Palliative Care for Their Patients. AB - PURPOSE: The need for all providers to deliver basic palliative care has emerged as patients' needs outstrip the capacity of specialty palliative care. Many patients with complex illnesses have unmet needs and are seen in primary care more than other settings. We explore primary care providers' willingness and perceived capacity to provide basic palliative care, and their concerns and perceived barriers. METHODS: We performed semistructured telephone interviews with 20 primary care providers about their perceptions of palliative care, including needs, practices, experiences, access, and what would be helpful for their practices to systematically provide basic palliative care. RESULTS: We identified 3 major themes: (1) Participants recognize palliative needs in patients with complex problems. (2) They reactively respond to those needs using practice and community resources, believing that meeting those needs at a basic level is within the scope of primary care. (3) They can identify opportunities to improve the delivery of a basic palliative approach in primary care through practice change and redesign strategies used in enhanced primary care environments. CONCLUSIONS: Systematic attention along the multidimensional domains of basic palliative care might allow practices to address unmet needs in patients with complex illnesses by using existing practice improvement models, strategies, and prioritization. PMID- 28076259 TI - Almond "Appetizer" Effect on Glucose Tolerance Test (GTT) Results. AB - BACKGROUND: The extent to which glucose intolerance can be acutely improved with dietary modification is unclear. The purpose of this study was to test the effect of ingesting a low-calorie almond preload ("appetizer") 30 minutes before oral glucose tolerance testing in glucose-intolerant individuals without diabetes. METHODS: Twenty adults with prediabetes or isolated 1-hour glucose >=160 mg/dL underwent 2 fasting oral glucose tolerance tests (GTTs)-1 standard GTT and 1 GTT 30 minutes after eating a half ounce (12) of dry-roasted almonds. Fourteen participants met 1 or more prediabetes diagnostic criteria; 6 had only elevated 1 hour glucose >=160 mg/dL. RESULTS: The mean 1-hour plasma glucose after the almond preload was 37.1 mg/dL (19.4%) lower (154.6 vs 191.7; P < .001) than in the standard GTT. The almond preload reduced the area under the glucose curve by 15.5% (P < .001). Eight individuals had a marked hypoglycemic effect (glucose reduced by 45 to 110 mg/dL); 4 had a moderate hypoglycemic effect (22-32 mg/dL). CONCLUSION: A low-calorie almond "appetizer" showed promise as an option for decreasing postprandial hyperglycemia in individuals with prediabetes or isolated 1-hour postprandial hyperglycemia. Further study is needed to confirm and refine the role of such a premeal appetizer in the self-care of prediabetes. PMID- 28076260 TI - Medical Home Implementation in Small Primary Care Practices: Provider Perspectives. AB - BACKGROUND: CareFirst BlueCross BlueShield of Maryland implemented a voluntary patient-centered medical home (PCMH) program in 2011 that did not require formal certification to participate. This study assessed attitudes and awareness of PCMH programs among participating providers in Maryland and Northern Virginia. METHODS: This qualitative study used information from 13 focus groups. In addition, 39 telephone interviews were conducted. An experienced facilitator moderated the focus groups. Written transcripts were analyzed using NVivo software. RESULTS: Several cross-cutting themes emerged. First, the payment bump of 12% was a motivating factor to participate but did not have long-term effects on participation. Second, nurse care coordinators were perceived as the key element of the PCMH program. Third, providers had limited awareness of an external data portal. Finally, small practices were generally receptive to the externally supported program elements. CONCLUSIONS: Implementation of PCMH program elements can be facilitated in small primary care practices even if third party certification is not a requirement. Participating providers viewed having an external nurse care coordinator as the key element of the PCMH program. Small practices were receptive to external supports, but a lack of trust was viewed as a barrier to implementing a payer-based medical home program. PMID- 28076261 TI - "How Can We Talk about Patient-centered Care without Patients at the Table?" Lessons Learned from Patient Advisory Councils. AB - CONTEXT AND OBJECTIVE: Patient advisory councils (PACs) are a strategy for primary care clinics to engage patients in practice improvement. However, there is scant research on how PACs function. This study aimed to understand how PACs are organized and identify common challenges and perceived benefits of high functioning PACs. SETTING AND POPULATION: Key informants identified 8 primary care clinics in California with high-functioning PACs. Leaders from each of the 8 clinics nominated 1 clinic staff member and 1 PAC patient member to be interviewed. STUDY DESIGN: Semistructured, one-on-one interviews were conducted at each clinic site or by phone. Interviews were dual-coded using modified grounded theory. Common themes were identified that would be pertinent to the development of future best practices for running PACs. RESULTS: Common characteristics of high-functioning PACs included careful attention to participant recruitment, facilitation strategies guiding diverse personalities toward a common purpose, and assigning accountability for practice improvement projects. Interviewees identified a variety of positive outcomes that ranged from tangible improvements to the waiting area to a more patient-centered staff culture. CONCLUSIONS: PACs show potential for promoting patient-centered practice improvements in primary care. Lessons learned from high-functioning PACs can inform a common set of strategies to assist practices in creating and sustaining effective advisory councils. PMID- 28076262 TI - Physician Cost Consciousness and Use of Low-Value Clinical Services. AB - PURPOSE: Choosing WiselyTM engaged medical specialties, creating "top 5 lists" of low-value services. We describe primary care physicians' (PCPs') self-reported use of these services and perceived barriers to guideline adherence. We quantify physician cost consciousness and determine associations with use. METHODS: PCP attendees of a continuing medical education conference completed a survey. For each Family Medicine Choosing Wisely behavior, participants reported clinical adherence. Likert scale items assessed perceived barriers. Low-value service frequency was the dependent variable. A validated Cost Consciousness Scale created the predictor variable. We hypothesized that participants with greater cost consciousness would report less frequent use of low-value services. RESULTS: Of 199 PCP attendees, 143 (72%) participated. Papanicolaou test after hysterectomy was performed least (0.2 mean services performed/10 patients). Provider knowledge of sinusitis treatment guidelines was greatest but provided most frequently (3.9 mean services performed/10 patients). Practice related barriers were perceived most frequently for adhering to sinusitis treatment guidelines. Attitudinal barriers were greatest for avoiding osteoporosis screening in low risk patients. Greater cost consciousness was associated with less use of low-value services (P = .03), greater knowledge of guidelines (P = .001), and fewer perceived attitudinal and practice behavior-related barriers (P < .001 for each). Greater knowledge of guidelines was not associated with less use of low-value services (P = .58). Familiarity with Choosing Wisely was associated with both greater cost consciousness (P = .004) and less use of low value services (P = .03). CONCLUSIONS: Greater PCP cost consciousness was associated with less use of low-value services. Interventions to decrease perceived barriers and increase cost consciousness, perhaps by increasing awareness of Choosing Wisely, may translate into improved performance. PMID- 28076263 TI - "A Paradox Persists When the Paradigm Is Wrong": Pisacano Scholars' Reflections from the Inaugural Starfield Summit. AB - The inaugural Starfield Summit was hosted in April 2016 by the Robert Graham Center for Policy Studies in Family Medicine and Primary Care with additional partners and sponsors, including the Pisacano Leadership Foundation (PLF). The Summit addressed critical topics in primary care and health care delivery, including payment, measurement, and team-based care. Invited participants included an interdisciplinary group of pediatricians, family physicians, internists, behaviorists, trainees, researchers, and advocates. Among the family physicians invited were both current and past PLF (Pisacano) scholars. After the Summit, a small group of current and past Pisacano scholars formed a writing group to reflect on and summarize key lessons and conclusions from the Summit. A Summit participant's statement, "a paradox persists when the paradigm is wrong," became a repeated theme regarding the paradox of primary care within the context of the health care system in the United States. The Summit energized participants to renew their commitment to Dr. Starfield's 4 C's of Primary Care (first contact access, continuity, comprehensiveness, and care coordination) and to the Quadruple Aim (quality, value, and patient and physician satisfaction) and to continue to explore how primary care can best shape the future of the nation's health care system. PMID- 28076264 TI - Researchers' Experience with Clinical Data Sharing. AB - The topic of transparency in industry-sponsored clinical trials has gathered the attention of researchers in medicine. Patient-level data from recently completed clinical trials is now available for investigators to reanalyze or perform new analyses. In this Special Communication, the authors discuss their experience using this type of research and provide recommendations for success. PMID- 28076265 TI - Nonbacterial Causes of Lymphangitis with Streaking. AB - BACKGROUND: Lymphangitic streaking, characterized by linear erythema on the skin, is most commonly observed in the setting of bacterial infection. However, a number of nonbacterial causes can result in lymphangitic streaking. We sought to elucidate the nonbacterial causes of lymphangitic streaking that may mimic bacterial infection to broaden clinicians' differential diagnosis for patients presenting with lymphangitic streaking. METHODS: We performed a review of the literature, including all available reports pertaining to nonbacterial causes of lymphangitic streaking. RESULTS: Various nonbacterial causes can result in lymphangitic streaking, including viral and fungal infections, insect or spider bites, and iatrogenic etiologies. CONCLUSION: Awareness of potential nonbacterial causes of superficial lymphangitis is important to avoid misdiagnosis and delay the administration of appropriate care. PMID- 28076266 TI - Re: Social Justice as the Moral Core of Family Medicine: A Perspective from the Keystone IV Conference. PMID- 28076267 TI - Response: Re: Social Justice as the Moral Core of Family Medicine: A Perspective from the Keystone IV Conference. PMID- 28076268 TI - Re: Over Half of Graduating Family Medicine Residents Report More Than $150,000 in Educational Debt. PMID- 28076269 TI - A Message from the President of the American Board of Family Medicine (ABFM). PMID- 28076270 TI - Correction to "The Performance of Fertility Awareness-based Method Apps Marketed to Avoid Pregnancy". AB - In the above-mentioned article,1 the electronic version differs from the print version due to typos in Table 2. The only data affected were the apps that did not predict the fertile window. The electronic version on the Journal of the American Board of Family Medicine website has been corrected. We apologize for the error, and we regret any confusion or inconvenience it may have caused. PMID- 28076271 TI - Correction to "Family Physicians with a Certificate of Added Qualifications (CAQs) in Sports Medicine Spend the Majority of Their Time Practicing Sports Medicine". AB - In the above-mentioned article,1 the electronic version differs from the print version due to data errors in the figure. Consequently, the original title no longer accurately reflects the findings after correcting the data errors and has been changed to: "Family Physicians with a Certificate of Added Qualifications in Sports Medicine Spend an Increasing Amount of Time Practicing Sports Medicine." The electronic version on the Journal of the American Board of Family Medicine website has been corrected. We apologize for the error, and we regret any confusion or inconvenience it may have caused. PMID- 28076272 TI - Correction to "Reported Practice Patterns Among Family Physicians With a Geriatrics Certificate of Added Qualifications". AB - In the above-mentioned article,1 the electronic version differs from the print version due to data reporting errors. The electronic version on the Journal of the American Board of Family Medicine website has been corrected. We apologize for the error, and we regret any confusion or inconvenience it may have caused. PMID- 28076275 TI - Atmospheric fine particulate matter and breast cancer mortality: a population based cohort study. AB - OBJECTIVES: Atmospheric fine particulate matter (PM2.5) has multiple adverse effects on human health. Global atmospheric levels of PM2.5 increased by 0.55 MUg/m3/year (2.1%/year) from 1998 through 2012. There is evidence of a causal relationship between atmospheric PM2.5 and breast cancer (BC) incidence, but few studies have investigated BC mortality and atmospheric PM2.5. We investigated BC mortality in relation to atmospheric PM2.5 levels among patients living in Varese Province, northern Italy. METHODS: We selected female BC cases, archived in the local population-based cancer registry, diagnosed at age 50-69 years, between 2003 and 2009. The geographic coordinates of each woman's place of residence were identified, and individual PM2.5 exposures were assessed from satellite data. Grade, stage, age at diagnosis, period of diagnosis and participation in BC screening were potential confounders. Kaplan-Meir and Nelson-Aalen methods were used to test for mortality differences in relation to PM2.5 quartiles. Multivariable Cox proportional hazards modelling estimated HRs and 95% CIs of BC death in relation to PM2.5 exposure. RESULTS: Of 2021 BC cases, 325 died during follow-up to 31 December 2013, 246 for BC. Risk of BC death was significantly higher for all three upper quartiles of PM2.5 exposure compared to the lowest, with HRs of death: 1.82 (95% CI 1.15 to 2.89), 1.73 (95% CI 1.12 to 2.67) and 1.72 (95% CI 1.08 to 2.75). CONCLUSIONS: Our study indicates that the risk of BC mortality increases with PM2.5 exposure. Although additional research is required to confirm these findings, they are further evidence that PM2.5 exposure is harmful and indicate an urgent need to improve global air quality. PMID- 28076276 TI - Analysis of Acquisition and Titer of Maize Mosaic Rhabdovirus in Its Vector, Peregrinus maidis (Hemiptera: Delphacidae). AB - The corn planthopper, Peregrinus maidis (Ashmead) (Hemiptera: Delphacidae), transmits Maize mosaic rhabdovirus (MMV), an important pathogen of maize and sorghum, in a persistent propagative manner. To better understand the vectorial capacity of P. maidis, we determined the efficiency of MMV acquisition by nymphal and adult stages, and characterized MMV titer through development. Acquisition efficiency, i.e., proportion of insects that acquired the virus, was determined by reverse transcriptase polymerase chain reaction (RT-PCR) and virus titer of individual insects was estimated by quantitative RT-PCR. Acquisition efficiency of MMV differed significantly between nymphs and adults. MMV titer increased significantly over time and throughout insect development from nymphal to adult stage, indication of virus replication in the vector during development. There was a positive association between the vector developmental stage and virus titer. Also, the average titer in male insects was threefold higher than female titers, and this difference persisted up to 30 d post adult eclosion. Overall, our findings indicate that nymphs are more efficient than adults at acquiring MMV and virus accumulated in the vector over the course of nymphal development. Furthermore, sustained infection over the lifespan of P. maidis indicates a potentially high capacity of this vector to transmit MMV. PMID- 28076277 TI - The Combined Effect of Methyl- and Ethyl-Paraben on Lifespan and Preadult Development Period of Drosophila melanogaster (Diptera: Drosophilidae). AB - Parabens are widely used as preservative substances in foods, pharmaceuticals, industrial products, and cosmetics. But several studies have cautioned that parabens have estrogenic or endocrine-disrupting properties. Drosophila melanogaster is an ideal model in vivo to detect the toxic effects of chemistry. The study was designed to assess the potential additive toxic effects of methylparaben (MP) and ethylparaben (EP) mixture (MP + EP) on lifespan and preadult development period in D. melanogaster The data revealed that the MP + EP can reduce the longevity of flies compared with the control group, consistent with a significant reduction in malondialdehyde levels and an increase in superoxide dismutase activities. Furthermore, MP + EP may have a greater toxic effect on longevity of flies than separate using with the same concentration. Additionally, parabens had a nonmonotonic dose-response effect on D. melanogaster preadult development period, showing that MP + EP delayed preadult development period compared with control group while individual MP or EP significantly shortened (P < 0.01) at low concentration (300 mg/l). In conclusion, MP + EP had the potential additive toxicity on lifespan and preadult development period for D. melanogaster. PMID- 28076278 TI - Characterization of the Ryanodine Receptor Gene With a Unique 3'-UTR and Alternative Splice Site From the Oriental Fruit Moth. AB - The ryanodine receptor (RyR), the largest calcium channel protein, has been studied because of its key roles in calcium signaling in cells. Insect RyRs are molecular targets for novel diamide insecticides. The target has been focused widely because of the diamides with high activity against lepidopterous pests and safety for nontarget organisms. To study our understanding of effects of diamides on RyR, we cloned the RyR gene from the oriental fruit moth, Grapholita molesta, which is the most serious pest of stone and pome tree fruits throughout the world, to investigate the modulation of diamide insecticides on RyR mRNA expression in G. molesta (GmRyR). The full-length cDNAs of GmRyR contain a unique 3'-UTR with 625 bp and an open reading frame of 15,402 bp with a predicted protein consisting of 5,133 amino acids. GmRyR possessed a high level of overall amino acid homology with insect and vertebrate isoforms, with 77-92% and 45-47% identity, respectively. Furthermore, five alternative splice sites were identified in GmRyR. Diagnostic PCR showed that the inclusion frequency of one optional exon (f) differed between developmental stages, a finding only found in GmRyR. The lowest expression level of GmRyR mRNA was in larvae, the highest was in male pupae, and the relative expression level in male pupae was 25.67 times higher than that of in larvae. The expression level of GmRyR in the male pupae was 8.70 times higher than in female pupae, and that in male adults was 5.70 times higher than female adults. PMID- 28076279 TI - Identification and Validation of Reference Genes for the Normalization of Gene Expression Data in qRT-PCR Analysis in Aphis gossypii (Hemiptera: Aphididae). AB - To obtain accurate and reliable results from quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) analysis, it is necessary to select suitable reference genes as standards for normalizing target gene expression data. QRT-PCR is a popular analytical methodology for studying gene expression and it has been used widely in studies of Aphis gossypii Glover in recent years. However, there is absence of study on the stability of the expression of reference genes in A. gossypii. In this study, eight commonly used candidate reference genes, including 18S, 28S, beta-ACT, GAPDH, EF1alpha, RPL7, alpha-TUB, and TBP, were evaluated under various experimental conditions to assess their suitability for use in the normalization of qRT-PCR data. The optimal number of reference genes was determined using the geNorm program, and the suitability of particular reference genes was empirically validated by performing normalizations of expression data for the HSP70 gene. The results showed the most suitable combinations of reference genes for the different experimental conditions. For experiments based on divergent developmental stages, EF1alpha, beta-ACT, and RPL7 are the optimal reference gene combination, both EF1alpha and beta-ACT are the optimal combination used in the experiments of different geographical populations, whereas for experiments of the temperature changes, the combination of GAPDH and RPL7 is optimal, both 18S and beta-ACT are an optimal combination for feeding assay experiments. These research results should be useful for the selection of the suitable reference genes to obtain reliable qRT-PCR data in the gene expression study of A. gossypii. PMID- 28076280 TI - The Effect of Organic Fertilizers and Flowering Plants on Sheet-Web and Wolf Spider Populations (Araneae: Lycosidae and Linyphiidae) and Its Importance for Pest Control. AB - The main goal of this study was to identify the treatment that increases the populations of spiders, which are effective predators in agroecosystems. In 2013 and 2014 the experimental eggplant (Solanum melongena L.) field was two different treatments, organic fertilizers and chemical fertilizer treatment, and in 2014 we surrounded organic fertilizer plots with the flowering plants mealy cup sage (Salvia farinacea Benth.), spearmint (Mentha spicata L.), and basil (Ocimum basilicum L.). Analysis using repeated measures ANOVA revealed significant influences of fertilizer type on the numbers of linyphiid spiders and Collembola in 2013. In 2014, the numbers of Collembola, thrips, and lycosid and linyphiid spider were higher in organic fertilizer with flowering plants treatment comparing with the chemical fertilizer treatment. Moreover, the numbers of Henosepilachna vigintioctopunctata (F.) were significantly lower in the organic fertilizer with flowering plants treatment than in chemical fertilizers treatment. Finally, we expect that Thysanoptera and Collembola were important alternative prey for linyphiid and lycosid spiders and the use of organic fertilizer and flowering plants enhanced the density of these spiders, and may increase their effectiveness in suppressing the populations of H. vigintioctopunctata (F.). PMID- 28076281 TI - Transcriptome and Gene Expression Analysis of Cylas formicarius (Coleoptera: Brentidae) During Different Development Stages. AB - The sweet potato weevil, Cylas formicarius (F.) (Coleoptera: Brentidae), is an important pest of sweet potato worldwide. However, there is limited knowledge on the molecular mechanisms underlying growth and differentiation of C. formicarius The transcriptomes of the eggs, second instar larvae, third instar larvae (L3), pupae, females, and males of C. formicarius were sequenced using Illumina sequencing technology for obtaining global insights into developing transcriptome characteristics and elucidating the relative functional genes. A total of 54,255,544 high-quality reads were produced, trimmed, and de novo assembled into 115,281 contigs. 61,686 unigenes were obtained, with an average length of 1,009 nt. Among these unigenes, 17,348 were annotated into 59 Gene Ontology (GO) terms and 12,660 were assigned to 25 Cluster of Orthologous Groups classes, whereas 24,796 unigenes were mapped to 258 pathways. Differentially expressed unigenes between various developmental stages of C. formicarius were detected. Higher numbers of differentially expressed genes (DEGs) were recorded in the eggs versus L3 and eggs versus male samples (2,141 and 2,058 unigenes, respectively) than the others. Genes preferentially expressed in each stage were also identified. GO and pathway-based enrichment analysis were used to further investigate the functions of the DEGs. In addition, the expression profiles of ten DEGs were validated by quantitative real-time PCR. The transcriptome profiles presented in this study and these DEGs detected by comparative analysis of different developed stages of C. formicarius will facilitate the understanding of the molecular mechanism of various living process and will contribute to further genome-wide research. PMID- 28076282 TI - Enzyme Activity, Cold Hardiness, and Supercooling Point in Developmental Stages of Acrosternum arabicum (Hemiptera: Pentatomidae). AB - Several species of pentatomid bugs feed on pistachio fruits in Iran. Acrosternum arabicum Wagner (Hemiptera: Pentatomidae) is one of the most important pests of pistachio in Rafsanjan, Iran. This study was carried out to investigate the carbohydrase activities, supercooling points, and cold hardiness profiles of different developmental stages of A. arabicum under laboratory conditions. The midgut amylolytic of A. arabicum showed an optimal pH at 7.0. The highest amylolytic activity was found in the female adults (35.41 +/- 0.90 nmol/min/gut). The mean amylolytic activity measured in first instar nymph was 6.75 +/- 0.54 nmol/min/gut. Midgut alpha- and beta-glucosidase showed an optimal activity at pH 5 and 7, respectively. These activities increased from first (83 +/- 5 and 54 +/- 5 nmol/min, respectively) to fifth (881 +/- 17 and 237 +/- 14 nmol/min, respectively) instar nymphs. The enzyme activities increased in the adults. Midgut alpha- and beta-galactosidase showed an optimal activity at pH 5. alpha- and beta-galactosidase activities were low in the first instar nymphs (73 +/- 5 and 21 +/- 3 nmol/min, respectively). The level of alpha- and beta-galactosidase activities in the female adults (533 +/- 18 and 246 +/- 6 nmol/min, respectively) was higher than the nymphs. The lowest super cooling points (-19 and -18.2 degrees C, respectively) and the highest cold hardiness (22 and 18% following 24 h exposure at - 20 degrees C, respectively) were recorded for the eggs and adult females. PMID- 28076283 TI - Potential Distribution Map of Culicoides insignis (Diptera: Ceratopogonidae), Vector of Bluetongue Virus, in Northwestern Argentina. AB - Culicoides insignis Lutz is incriminated as a vector of bluetongue virus (BTV) to ruminants in America. In South America, almost all countries have serological evidence of BTV infections, but only four outbreaks of the disease have been reported. Although clinical diseases have never been cited in Argentina, viral activity has been detected in cattle. In this study, we developed a potential distribution map of Culicoides insignis populations in northwestern Argentina using Maximum Entropy Modeling (Maxent). For the analyses, information regarding both data of specimen collections between 2003 and 2013, and climatic and environmental variables was used. Variables selection was based on the ecological relevance in relation to Culicoides spp. biology and distribution in the area. The best Maxent model according to the Jackknife test included 53 C. insignis presence records and precipitation of the warmest quarter, altitude, and precipitation of the wettest month. Accuracy was evaluated by the area under the curve (AUC = 0.97). These results provide an important analytical resource of high potential for both the development of suitable control strategies and the assessment of disease transmission risk in the region. PMID- 28076284 TI - Abnormal Development of Haemaphysalis qinghaiensis (Acari: Ixodidae). AB - A single Haemaphysalis qinghaiensis specimen exhibiting abnormal morphology was collected from a tick laboratory colony. The tick had a heart-shaped body with partial twinning of the posterior region (with two anal orifices and two genital grooves). To the best of our knowledge, this is the first report of teratological changes in H. qinghaiensis The abnormal morphological features are described herein. PMID- 28076285 TI - Ephemera danica (Ephemeroptera: Ephemeridae) As a Resource for Two Commensals: Ciliated Protozoans (Sessilida) and Chironomids (Diptera). AB - The distribution and coexistence of two unrelated commensals, the chironomid Epoicocladius ephemerae (Kieffer 1924) and ciliate Carchesium polypinum L. 1758, on one host species, Ephemera danica Muller 1764, sampled in two small lowland rivers in 2009, 2010 and 2011, were investigated. We analyzed 288 mayfly specimens from the Bzura River and 101 from the Mroga River. The number of commensals on a single mayfly specimen varied between 0 and 18 chironomids, and from 0 to 46 colonies of ciliates. Prevalences were >48% for chironomids and ~30% for ciliates, whereas mean intensities were low (4.01+/-6.04 commensals on one host). The spatial distribution of each commensal species was investigated on different parts of the host body. Neither chironomids nor ciliates infected the whole mayfly body. The co-occurrence of these two commensals was not random and showed a negative association. Chironomids were most frequent on two or three parts of the body (two parts of the abdomen, with gills and without gills, and legs), whereas ciliates were found on two parts (the whole abdomen). Coexistence of the two commensal species led to partitioning of resources that was host body size dependent: small mayflies (optimal size 11.63 mm) were primarily settled by ciliated protozoans while larger specimens (optimal size 28.77 mm) were settled by chironomids. PMID- 28076287 TI - Erratum. PMID- 28076286 TI - Spinosad Induces Antioxidative Response and Ultrastructure Changes in Males of Red Palm Weevil Rhynchophorus ferrugineus (Coleoptera: Dryophthoridae). AB - The red palm weevil, Rhynchophorus ferrugineus, is of great concern worldwide, especially in the Middle East, where dates are a strategic crop. Despite their ecological hazard, insecticides remain the most effective means of control. A bioinsecticide of bacterial origin, spinosad is effective against several pests, and its efficacy against male R. ferrugineus was assessed in the present study. The antioxidative responses of key enzymes including catalase (CAT), superoxide dismutase (SOD), and glutathione-S-transferase (GST) to spinosad were investigated in the midgut and testes, and the effects of this insecticide on the cell ultrastructure of the midgut, Malpighian tubules, and testes were also determined. The lethal concentration 50 of spinosad was measured at 58.8 ppm, and the insecticide inhibited the activities of CAT, SOD, and GST in the midgut. However, no significant changes in the activities of these enzymes were observed in the testes. Spinosad treatment resulted in concentration-dependent changes in the cellular organelles of the midgut, Malpighian tubules, and testes of R. ferrugineus, and some of these effects were similar to those exerted by other xenobiotics. However, specific changes were observed as a result of spinosad treatment, including an increase in the number and size of concretions in Malpighian tubule cells and the occasional absence of the central pair of microtubules in the axonemes of sperm tails. This study introduces spinosad for potential use as an insecticide within an integrated control program against male red palm weevils. Additionally, the study provides biochemical and ultrastructural evidence for use in the development of bioindicators. PMID- 28076289 TI - From bacteria to chloroplasts: evolution of the chloroplast SRP system. AB - Chloroplasts derive from a prokaryotic symbiont that lost most of its genes during evolution. As a result, the great majority of chloroplast proteins are encoded in the nucleus and are posttranslationally imported into the organelle. The chloroplast genome encodes only a few proteins. These include several multispan thylakoid membrane proteins which are synthesized on thylakoid-bound ribosomes and cotranslationally inserted into the membrane. During evolution, ancient prokaryotic targeting machineries were adapted and combined with novel targeting mechanisms to facilitate post- and cotranslational protein transport in chloroplasts. This review focusses on the chloroplast signal recognition particle (cpSRP) protein transport system, which has been intensively studied in higher plants. The cpSRP system derived from the prokaryotic SRP pathway, which mediates the cotranslational protein transport to the bacterial plasma membrane. Chloroplasts contain homologs of several components of the bacterial SRP system. The function of these conserved components in post- and/or cotranslational protein transport and chloroplast-specific modifications of these transport mechanisms are described. Furthermore, recent studies of cpSRP systems in algae and lower plants are summarized and their impact on understanding the evolution of the cpSRP system are discussed. PMID- 28076288 TI - Transfer RNAs with novel cloverleaf structures. AB - We report the identification of novel tRNA species with 12-base pair amino-acid acceptor branches composed of longer acceptor stem and shorter T-stem. While canonical tRNAs have a 7/5 configuration of the branch, the novel tRNAs have either 8/4 or 9/3 structure. They were found during the search for selenocysteine tRNAs in terabytes of genome, metagenome and metatranscriptome sequences. Certain bacteria and their phages employ the 8/4 structure for serine and histidine tRNAs, while minor cysteine and selenocysteine tRNA species may have a modified 8/4 structure with one bulge nucleotide. In Acidobacteria, tRNAs with 8/4 and 9/3 structures may function as missense and nonsense suppressor tRNAs and/or regulatory noncoding RNAs. In delta-proteobacteria, an additional cysteine tRNA with an 8/4 structure mimics selenocysteine tRNA and may function as opal suppressor. We examined the potential translation function of suppressor tRNA species in Escherichia coli; tRNAs with 8/4 or 9/3 structures efficiently inserted serine, alanine and cysteine in response to stop and sense codons, depending on the identity element and anticodon sequence of the tRNA. These findings expand our view of how tRNA, and possibly the genetic code, is diversified in nature. PMID- 28076290 TI - Tailored interactive sequences for continuous MR-image-guided freehand biopsies of different organs in an open system at 1.0 tesla (T) - Initial experience. AB - OBJECTIVES: To assess the feasibility, image quality, and accuracy of freehand biopsies of liver, bone, muscle, vertebral disc, soft tissue, and other lesions using balanced steady-state free precession (SSFP, balanced fast field echo: bFFE), spoiled and nonspoiled gradient echo (FFE), and turbo spin echo (TSE) sequences for interactive continuous navigation in an open magnetic resonance imaging (MRI) system at 1.0 tesla (T). METHODS: Twenty-six MR-guided biopsies (five liver, five bone, four muscle, four vertebral disc, one lung, one kidney, one suprarenal gland, and five soft or other tissue) were performed in 23 patients in a 1.0-T open magnetic resonance (MR) scanner (Panorama HFO, Philips Healthcare, Best, the Netherlands). A total of 42 samples were obtained. Depending on lesion size and location, 14-18-gauge MR-compatible biopsy sets with a length of 100 or 200 mm (Somatex Medical, Teltow, Germany), 14-18-gauge MR compatible semiautomatic biopsy guns with a length of 100 or 150 mm (Invivo, Schwerin, Germany), or 11-gauge MR-compatible bone marrow biopsy needles with a length of 100 mm (Somatex Medical, Teltow, Germany) were employed. RESULTS: All lesions were visible with continuous interactive imaging. Our initial results indicate that bFFE is particularly suitable for fast-moving organs (pulmonary, paracardial); moving organs are targeted better with T1-weighted (T1W) TSE, T1W FFE (liver) or T2-weighted (T2W) TSE (complicated cysts, adrenal glands), and static organs are successfully approached with proton density (PD) (spine) or T1W TSE (peripheral bones, musculoskeletal system). No adverse events related to the use of MRI were obtained. No complications occurred according to the Society of Interventional Radiology (SIR) clinical practice guidelines. CONCLUSION: Applying tailored interactive dynamic imaging sequences for continuous navigation to liver, bone, muscle, vertebral disc, soft tissue, and other lesions can improve the feasibility, image quality, and interventional accuracy of freehand MR-guided biopsies and may hence reduce the risk of complications. PMID- 28076291 TI - Individual construction of freeform-fabricated polycaprolactone scaffolds for osteogenesis. AB - The construction of engineered bone mostly focuses on simulating the extracellular matrix (ECM) for proper biological activity. However, the complexity of architecture and the variability of the mechanical properties of natural bones are related to individual differences in age, nutritional state, mechanical loading and disease status. Defect substitutions should be normed with the host natural bone, balancing architectural and mechanical adaption, as well as biological activity. Using a freeform fabrication (FFF) method, we prepared polycaprolactone (PCL) scaffolds with different architectures. With simulation of structural and mechanical parameters of rabbit femur cancellous bone, individual defect substitution with the characteristics of the rabbit femur was obtained with high porosity and connectivity. Biological adaption in vitro was examined and osteoid formation in vivo was assessed by implantation in situ. Simulating the femur cancellous bone, 300-MUm FFF PCL scaffolds had better architectural and mechanical properties. The protocol produced an architecturally, mechanically and biologically adaptive construction of an individual model for rapid-prototype PCL scaffolds. A guide system was developed to accurately reproduce virtually individual defect substitutions of the bone. PMID- 28076292 TI - 445-nm diode laser-assisted debonding of self-ligating ceramic brackets. AB - OBJECTIVES: This study determined the influence of irradiation on aesthetic ceramic brackets with a novel 445-nm diode laser prior to debonding on the bracket failure mode. MATERIALS AND METHODS: Thirty ceramic brackets (In Ovation(r) C, GAC) were standard-bonded to the oral and buccal planed and polished enamel surfaces of 15 caries-free human 3rd molars. Prior to study blinded debonding, the brackets in the laser group were irradiated with the diode laser (SIROLaser Blue(r), Sirona), while the irradiation was simulated within the conventional group. To determine the degree of enamel fractures and the adhesive remnant index (ARI) before debonding (T0), after debonding (T1) and after removal of the remaining composite using a rotating fraise (red ring, Comet) (T2), micrographs of the enamel surface at 10-fold and 20-fold magnifications were taken. Additionally, the enamel surface was investigated using seven randomly chosen samples from each group at every time point by SEM at 200-fold and 500 fold magnifications. RESULTS: In the laser group, the ARI-score was statistically significantly reduced (p<0.05) at 10-fold and 20-fold magnifications compared to the conventional group, while enamel fractures were not found at any magnification in either group at T1. Enamel fractures and grinding marks were increasingly found in the conventional group by SEM at T2. CONCLUSION: Irradiation with the novel diode laser prior to debonding of ceramic brackets significantly changes bonding failure in terms of less remaining adhesive. This is of clinical importance as the risk of enamel fractures and chair time can be reduced. PMID- 28076293 TI - Electromyographic classification of effort in muscle strength assessment. AB - Dual-channel evaluation of surface electromyogram (SEMG) signals acquired from amputee subjects using computational techniques for classification of arm motions is presented in this study. SEMG signals were classified by the neural network (NN) and interpretation was done using statistical techniques to extract the effectiveness of the recorded signals. From the results, it was observed that there exists a calculative difference in amplitude gain across different motions and that SEMG signals have great potential to classify arm motions. The outcomes indicated that the NN algorithm performs significantly better than other algorithms, with a classification rate (CR) of 96.40%. Analysis of variance (ANOVA) presents the results to validate the effectiveness of the recorded data to discriminate SEMG signals. The results are of significant thrust in identifying the operations that can be implemented for classifying upper-limb movements suitable for prostheses' design. PMID- 28076294 TI - Simulation of effects of the electrode structure and material in the density measuring system of the peripheral nerve based on micro-electrical impedance tomography. AB - The electrode structure in micro-electrical impedance tomography (MEIT) highly influences the measurement sensitivity and therefore the reconstructed image quality. Hence, optimizing the electrode structure leads to the improvement of image quality in the reconstruction procedure. Although there have been many investigations on electrical impedance tomography (EIT) electrodes, there is no comprehensive study on their influence on images of the peripheral nerve. In this paper, we present a simulation method to study the effects of the electrode structure in the density measurement system of the peripheral nerve based on MEIT. The influence of the electrode structure such as dimensions, material and the number of electrodes and also the recognition feature of different radii of fascicle and different locations of fascicles has been studied. Data were reconstructed from the real and imaginary parts of complex conductivity data, respectively. It has been shown that the material of the electrodes had no effect on the reconstructed images, while the dimensions of the electrodes significantly affected the image sensitivity and thus the image quality. An increase in the number of electrodes increased the amount of data and information content. However, as the number of electrodes increased due to the given perimeter of the peripheral nerve, the area of the electrodes was reduced. This reduction affects the reconstructed image quality. The real and imaginary parts of the data were separately reconstructed for each case. Although, in real EIT systems, the reconstructed images using the real part of the signal have a better signal-to noise ratio (SNR), this study proved that for a density measuring system of the peripheral nerve, the reconstructed images using the imaginary part of the signal had better quality. This simulation study proposes the effects of the electrode size and material and obtained spatial resolution that was high enough to reconstruct fascicles in a peripheral nerve. PMID- 28076295 TI - Convolutive blind source separation of surface EMG measurements of the respiratory muscles. AB - Electromyography (EMG) has long been used for the assessment of muscle function and activity and has recently been applied to the control of medical ventilation. For this application, the EMG signal is usually recorded invasively by means of electrodes on a nasogastric tube which is placed inside the esophagus in order to minimize noise and crosstalk from other muscles. Replacing these invasive measurements with an EMG signal obtained non-invasively on the body surface is difficult and requires techniques for signal separation in order to reconstruct the contributions of the individual respiratory muscles. In the case of muscles with small cross-sectional areas, or with muscles at large distances from the recording site, solutions to this problem have been proposed previously. The respiratory muscles, however, are large and distributed widely over the upper body volume. In this article, we describe an algorithm for convolutive blind source separation (BSS) that performs well even for large, distributed muscles such as the respiratory muscles, while using only a small number of electrodes. The algorithm is derived as a special case of the TRINICON general framework for BSS. To provide evidence that it shows potential for separating inspiratory, expiratory, and cardiac activities in practical applications, a joint numerical simulation of EMG and ECG activities was performed, and separation success was evaluated in a variety of noise settings. The results are promising. PMID- 28076296 TI - Efficiency test of current carotid embolic protection devices. AB - Embolic protection devices were developed to reduce the risk of stroke during carotid artery stenting. The aim of this study was to test the capture efficiency of five embolic protection devices under reproducible in vitro conditions. The setup consisted of silicone tubes representing the vessel modeling round and oval cross sections. Spherical polystyrene particles (150 MUm, COOH-coating) were used to simulate the plaque. The particles were inserted in a clean water circuit and either captured by the device or collected in a glass filter. The missed particles were counted by laser obscuration as a measure of device leakage. The systems Angioguard RX, RX Accunet, FiberNet, FilterWire EZ and EmboshieldNAV were analyzed. At the round cross section, FilterWire EZ demonstrated the highest capture efficiency (0% of missed particles) and RX Accunet the lowest, at 34%. The amount of leaked particles increased to 22% for FilterWire EZ and 89% for Angioguard RX during the test with the oval cross profile. PMID- 28076298 TI - Comparison of Abbott RealTime genotype II, GeneMatrix restriction fragment mass polymorphism and Sysmex HISCL HCV Gr assays for hepatitis C virus genotyping. AB - BACKGROUND: Hepatitis C virus (HCV) genotype is a predictive marker for treatment response. We sequentially evaluated the performances of two nucleic acid amplification tests (NAATs) and one serology assay for HCV genotype: Abbott RealTime genotype II (RealTime II), GeneMatrix restriction fragment mass polymorphism (RFMP), and Sysmex HISCL HCV Gr (HISCL Gr). METHODS: We examined 281 clinical samples with three assays. The accuracy was assessed using the HCV Genotype Performance Panel PHW204 (SeraCare Life Sciences) for two NAATs. Discrepant cases were re-genotyped by the Versant HCV v.2.0 (line probe 2.0) assay. RESULTS: With the RealTime II assay, clinic samples were analyzed as follows: genotypes 1b (43.1%), 2 (40.2%), 1 subtypes other than 1a and 1b (12.5%), 3 (1.8%), 4 (1.4%), 1a (0.7%), 6 (0.4%), and mixed (1.1%). The RealTime II and RFMP assays showed a type concordance rate of 97.5% (274/281) (kappa=0.80) and no significant discordance (p=0.25). Both assays accurately genotyped all samples in the Performance Panel by the subtype level. The HISCL Gr assay showed concordance rates of about 91% (kappa<0.40) and statistically significant discordances with two NAATs (p<0.05). In confirmation tests, the results of RFMP assay were the most consistent with those of Versant 2.0 assay. CONCLUSIONS: The three HCV assays provided genotyping and serotyping results with good concordance rates. The two NAATs (RealTime II and RFMP) showed comparable performance and good agreement. However, the results of the HISCL Gr assay showed statistically significant differences with those of the NAATs. PMID- 28076297 TI - Dynamics of the cardiovascular autonomic regulation during orthostatic challenge is more relaxed in women. AB - Linear dynamic analysis of cardiovascular and respiratory time series was performed in healthy subjects with respect to gender by shifted short-term segments throughout a head-up tilt (HUT) test. Beat-to-beat intervals (BBI), systolic (SYS) and diastolic (DIA) blood pressure and respiratory interval (RESP) time series were acquired in 14 men and 15 women. In time domain (TD), the descending slope of the auto-correlation function (ACF) (BBI_a31cor) was more pronounced in women than in men (p<0.05) during the HUT test and considerably steeper (p<0.01) at the end of orthostatic phase (OP). The index SYS_meanNN was slightly but significantly lower (p<0.05) in women during the complete test, while higher respiratory frequency and variability (RESP_sdNN) were found in women (p<0.05), during 10-20 min after tilt-up. In frequency domain (FD), during baseline (BL), BBI-normalized low frequency (BBI_LFN) and BBI_LF/HF were slightly but significantly lower (p<0.05), while normalized high frequency (BBI_HFN) was significantly higher in women. These differences were highly significant from the first 5 min after tilt-up (p<0.01) and highly significant (p<0.001) during 10-14 min of OP. Findings revealed that men showed instantaneously a pronounced and sustained increase in sympathetic activity to compensate orthostatism. In women, sympathetic activity was just increased slightly with delayed onset without considerably affecting sympatho-vagal balance. PMID- 28076299 TI - Association between plasma proANP and hyperuricemia in Chinese Han women: a cross sectional study. AB - BACKGROUND: Association between pro-atrial natriuretic peptide (proANP) and hyperuricemia has not yet been investigated in population. This study aimed to examine the association in Chinese Han women. METHODS: We measured plasma proANP, serum uric acid, and other traditional biomarkers in 1360 women older than 30 years residing in the Gusu district of Suzhou City. Association between plasma proANP and hyperuricemia was analyzed in women aged >=45 years and those aged <45 years, respectively. RESULTS: In women aged >=45 years, the odds ratio (OR) [95% confidence interval (CI)] of hyperuricemia with high proANP (over the median) was 0.57 (0.34-0.97) compared to those with low proANP (p=0.040). After adjustment for age and other potential covariates, a high plasma proANP was associated with a decreased risk of hyperuricemia in women aged >=45 years (OR 0.40; 95% CI, 0.19 0.84), when the highest and lowest categories were compared. In contrast, there was no association between plasma proANP and hyperuricemia in women aged <45 years. We did not observe a significant interaction between age and proANP (pinteraction=0.113). Sensitivity analyses further confirmed these age-specific findings. CONCLUSIONS: Plasma proANP was significantly and inversely associated with hyperuricemia in Chinese Han women aged >=45 years. This study suggests that an increased plasma proANP should be a protective factor of hyperuricemia among middle-aged and old women. PMID- 28076300 TI - Usefulness of maternal red cell antibodies to predict hemolytic disease of the fetus and newborn and significant neonatal hyperbilirubinemia: a retrospective study. PMID- 28076301 TI - Clinical use of targeted high-throughput whole-genome sequencing for a dengue virus variant. PMID- 28076303 TI - Implementation and application of moving average as continuous analytical quality control instrument demonstrated for 24 routine chemistry assays. AB - BACKGROUND: General application of a moving average (MA) as continuous analytical quality control (QC) for routine chemistry assays has failed due to lack of a simple method that allows optimization of MAs. A new method was applied to optimize the MA for routine chemistry and was evaluated in daily practice as continuous analytical QC instrument. METHODS: MA procedures were optimized using an MA bias detection simulation procedure. Optimization was graphically supported by bias detection curves. Next, all optimal MA procedures that contributed to the quality assurance were run for 100 consecutive days and MA alarms generated during working hours were investigated. RESULTS: Optimized MA procedures were applied for 24 chemistry assays. During this evaluation, 303,871 MA values and 76 MA alarms were generated. Of all alarms, 54 (71%) were generated during office hours. Of these, 41 were further investigated and were caused by ion selective electrode (ISE) failure (1), calibration failure not detected by QC due to improper QC settings (1), possible bias (significant difference with the other analyzer) (10), non-human materials analyzed (2), extreme result(s) of a single patient (2), pre-analytical error (1), no cause identified (20), and no conclusion possible (4). CONCLUSIONS: MA was implemented in daily practice as a continuous QC instrument for 24 routine chemistry assays. In our setup when an MA alarm required follow-up, a manageable number of MA alarms was generated that resulted in valuable MA alarms. For the management of MA alarms, several applications/requirements in the MA management software will simplify the use of MA procedures. PMID- 28076302 TI - Detecting paraprotein interference on a direct bilirubin assay by reviewing the photometric reaction data. AB - BACKGROUND: The direct bilirubin (D-Bil) assay on the AU Beckman Coulter instrumentation can be interfered by paraproteins, which may result in spurious D Bil results. In a previous work, we took advantage of this fact to detect this interference, thus helping with the identification of patients with unsuspected monoclonal gammopathies. In this work, we investigate the possibility to detect interference based on the review of the photometric reactions, regardless of the D-Bil result. METHODS: The D-Bil assay was carried out in a set of 2164 samples. It included a group of 164 samples with paraproteins (67 of which caused interference on the assay), as well as different groups of samples for which high absorbance background readings could also be expected (i.e. hemolyzed, lipemic, or icteric samples). Photometric reaction data were reviewed and receiver operating characteristics (ROC) curves were used to establish a cut-off for absorbance that best discriminates interference. RESULTS: The best cut-off was 0.0100 for the absorbance at the first photometric point of the complementary wavelength in the blank cuvette. Once the optimal cut-off for probable interference was selected, all samples analyzed in our laboratory that provided absorbance values above this cut-off were further investigated to try to discover paraproteins. During a period of 6 months, we detected 44 samples containing paraproteins, five of which belonged to patients with non-diagnosed monoclonal gammopathies. CONCLUSIONS: Review of the photometric reaction data permits the systematic detection of paraprotein interference on the D-Bil AU assay, even for samples for which reasonable results are obtained. PMID- 28076304 TI - The use of liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring of antibiotics in cancer patients. AB - Cancer remains a leading cause of mortality and morbidity worldwide. In addition to organ failure, the most frequent reasons for admission of cancer patients to intensive care units (ICU) are: infections and sepsis. As critically ill, the complexity of the health situation of cancer patients renders the standard antimicrobial regimen more complex and even inadequate which results in increased mortality rates. This is due to pathophysiological changes in the volume of distribution, increased clearance, as well as to organ dysfunction. While in the former cases a decrease in drug efficacy is observed, the hallmark of the latter one is overdosing leading to increased toxicity at the expense of efficacy. Furthermore, an additional risk factor is the potential drug-drug interaction between antibiotics and antineoplastic agents. Therefore, therapeutic drug monitoring (TDM) is a necessity to improve the clinical outcome of antimicrobial therapy in cancer patients. To be applied in routine analysis the method used for TDM should be cheap, fast and highly accurate/sensitive. Furthermore, as ICU patients are treated with a cocktail of antibiotics the method has to cover the simultaneous analysis of antibiotics used as a first/second line of treatment. The aim of the current review is to briefly survey the pitfalls in the current antimicrobial therapy and the central role of TDM in dose adjustment and drug drug interaction's evaluation. A major section is dedicated to summarize the currently published analytical methods and to shed light on the difficulties and potential problems that can be encountered during method development. PMID- 28076305 TI - Analytical and diagnostic performance of two automated fecal calprotectin immunoassays for detection of inflammatory bowel disease. AB - BACKGROUND: We evaluated the (pre-)analytical and diagnostic performance of two automated fecal calprotectin (FC) immunoassays, Liaison(r) Calprotectin (Diasorin) on Liaison(r) XL and fCALTM turbo (Buhlmann laboratories AG) on Cobas C501 (Roche Diagnostics), and compared it with our established Buhlmann ELISA method. METHODS: Our study comprised 229 consecutive patients with clinical suspicion of inflammatory bowel disease (IBD). RESULTS: All assay related stool extraction procedures showed excellent correlation with the established method, but the new stool extraction devices tend to give higher results as compared with stool weight methods. Both automated assays demonstrated good performance in terms of precision (CVt<=8.1%), accuracy (bias<=6.7%) and total error (<=16.4%). Method comparison with established enzyme linked immunosorbent assay (ELISA) showed good correlation (rs>0.925), but regression analysis showed significant proportional differences. Diagnostic performance characteristics with regard to diagnosis of IBD were good and in line with other reports. In addition, we were able to show that optimization of manufacturer's cut-off and moreover, the introduction of a gray zone resulted in a significant increase of post-test probability. CONCLUSIONS: In conclusion, the newly developed stool extraction device protocols showed acceptable and comparable performance to the stool weight method. Overall, the automated Liaison(r) Calprotectin and fCALTM turbo assay showed good analytical and diagnostic performance for detection of IBD. PMID- 28076306 TI - Parallel diurnal fluctuation of testosterone, androstenedione, dehydroepiandrosterone and 17OHprogesterone as assessed in serum and saliva: validation of a novel liquid chromatography-tandem mass spectrometry method for salivary steroid profiling. AB - BACKGROUND: Salivary androgen testing represents a valuable source of biological information. However, the proper measurement of such low levels is challenging for direct immunoassays, lacking adequate accuracy. In the last few years, many conflicting findings reporting low correlation with the serum counterparts have hampered the clinical application of salivary androgen testing. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) makes it possible to overcome previous analytical limits, providing new insights in endocrinology practice. METHODS: Salivary testosterone (T), androstenedione (A), dehydroepiandrosterone (DHEA) and 17OHprogesterone (17OHP) were extracted from 500uL of saliva, separated in 9.5 min LC-gradient and detected by positive electrospray ionization - multiple reaction monitoring. The diurnal variation of salivary and serum androgens was described by a four paired collection protocol (8 am, 12 am, 4 pm and 8 pm) in 19 healthy subjects. RESULTS: The assay allowed the quantitation of T, A, DHEA and 17OHP down to 3.40, 6.81, 271.0 and 23.7 pmol/L, respectively, with accuracy between 83.0 and 106.1% for all analytes. A parallel diurnal rhythm in saliva and serum was observed for all androgens, with values decreasing from the morning to the evening time points. Salivary androgen levels revealed a high linear correlation with serum counterparts in both sexes (T: R>0.85; A: R>0.90; DHEA: R>0.73 and 17OHP: R>0.89; p<0.0001 for all). CONCLUSIONS: Our LC-MS/MS method allowed a sensitive evaluation of androgen salivary levels and represents an optimal technique to explore the relevance of a comprehensive androgen profile as measured in saliva for the study of androgen secretion modulation and activity in physiologic and pathologic states. PMID- 28076307 TI - Evaluation of the Greiner Bio-One serum separator BCA Fast Clot tube. AB - BACKGROUND: Current commercial tubes have difficulties in producing "true" serum from all blood samples even within the recommended clotting times. Hence, Becton Dickinson (BD) and now Greiner have produced tubes containing thrombin as the procoagulant to reduce the clotting time and increase the possibility of producing serum from anticoagulated blood samples. METHODS: The Greiner BCA Fast Clot (GBBCAFC) tube was evaluated in a hospital environment using 40 participants, (30 healthy and 10 undergoing renal dialysis) for 32 analytes against the Greiner lithium heparin tube and the BD Rapid Serum Tubes (BD RST) tube measured on Beckman DxC 800 and DxI 800 analyzers. Clotting strength was also examined using thromboelastography (TEG). RESULTS: The analytes results showed there was a very close agreement between the BD RST tube and GBBCAFC tube in comparison with lithium heparin plasma. The result comparison data showed equivalent performance with lower levels of hemolysis. The prolonged storage study also showed very similar agreement between the BD RST and the GBBCAFC tubes. Likewise, the TEG data showed there was very little difference in clotting ability between the tubes, and neither was capable of producing true serum from blood spiked with 2 U heparin/mL of blood. CONCLUSIONS: The study showed the GBBCAFC tube with the combination of the two procoagulants blood clotting activator and thrombin produced comparable performance with the lithium heparin plasma and the BD RST serum samples. PMID- 28076308 TI - Measurements of serum non-ceruloplasmin copper by a direct fluorescent method specific to Cu(II). AB - BACKGROUND: Meta-analyses indicated the breakdown of copper homeostasis in the sporadic form of Alzheimer's disease (AD), comprising copper decreases within the brain and copper increases in the blood and the pool not bound to ceruloplasmin (non-Cp Cu, also known in the literature as "free" copper). The calculated non-Cp Cu (Walshe's) index has many limitations. METHODS: A direct fluorescent method for non-Cp Cu detection has been developed and data are presented herein. The study included samples from 147 healthy subjects, 36 stable mild cognitive impairment (MCI) and 89 AD patients, who were tested for non-Cp Cu through the direct method, total serum copper, ceruloplasmin concentration and o-dianisidine ceruloplasmin activity. The indirect non-Cp Cu Walshe's index was also calculated. RESULTS: The direct method was linear (0.9-5.9 MUM), precise (within laboratory coefficient variation of 9.7% for low and 7.1% for high measurements), and had a good recovery. A reference interval (0-1.9 MUM) was determined parametrically in 147 healthy controls (27-84 years old). The variation of non-Cp Cu was evaluated according to age and sex. Non-Cp Cu was 1.5 times higher in AD patients (regarding the upper value of the reference interval) than in healthy controls. Healthy, MCI and AD subjects were differentiated through the direct non Cp Cu method [areas under the curve (AUC)=0.755]. Considering a 95% specificity and a 1.91 MUmol/L cut-off, the sensitivity was 48.3% (confidence interval 95%: 38%-58%). The likelihood ratio (LR) was 9.94 for positive test results (LR+) and 0.54 for negative test result (LR-). CONCLUSIONS: The direct fluorescent test reliably and accurately measures non-Cp Cu, thereby determining the probability of having AD. PMID- 28076309 TI - Activation of the tryptophan/serotonin pathway is associated with severity and predicts outcomes in pneumonia: results of a long-term cohort study. AB - BACKGROUND: As part of the immune defense during infection, an increase in enzyme activity of indoleamine 2,3-dioxygenase (IDO) leads to a breakdown of tryptophan to kynurenine. In previous animal studies, therapeutic antagonism of IDO resulted in reduced sepsis mortality. We investigated the prognostic ability of tryptophan, serotonin, kynurenine and IDO (represented by the ratio of kynurenine/tryptophan) to predict adverse clinical outcomes in patients with community-acquired pneumonia (CAP). METHODS: We measured tryptophan, serotonin and kynurenine on admission plasma samples from CAP patients included in a previous multicenter trial by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). We studied their association with inflammation (C reactive protein), infection (procalcitonin) and clinical outcome. RESULTS: Mortality in the 268 included patients was 45% within 6 years of follow-up. IDO and kynurenine showed a strong positive correlation with markers of infection (procalcitonin) and inflammation (C-reactive protein) as well as sepsis and CAP severity scores. Tryptophan showed similar, but negative correlations. In a multivariate regression analysis adjusted for age and comorbidities, higher IDO activity and lower tryptophan levels were strongly associated with short-term adverse outcome defined as death and/or ICU admission within 30 days with adjusted odds ratios of 9.1 [95% confidence interval (CI) 1.4-59.5, p=0.021] and 0.11 (95% CI 0.02-0.70, p=0.021). Multivariate analysis did not reveal significant associations for kynurenine and serotonin. CONCLUSIONS: In hospitalized CAP patients, higher IDO activity and lower tryptophan levels independently predicted disease severity and short-term adverse outcome. Whether therapeutic modulation of IDO has positive effects on outcome needs further investigation. PMID- 28076310 TI - The serum concentrations of leptin and MCP-1 independently predict low back pain duration. AB - BACKGROUND: Low back pain (LBP) is a very frequent condition, affecting most people at some point throughout their life. This cross-sectional study was aimed to investigate a selected panel of cytokines and inflammatory biomarkers in patients with or without LBP. METHODS: The study population consisted of 104 patients diagnosed with LBP (52 non-persistent and 52 persistent) and 52 healthy subjects with no LBP. Blood samples were collected for assessment of adiponectin, leptin, monocyte chemoattractant protein-1 (MCP-1) and C reactive protein (CRP). The duration of LBP was categorized as "no pain", "non-persistent LBP" and "persistent LBP". RESULTS: Higher values of CRP and lower concentrations of both leptin and MCP-1 were found in LBP patients compared to controls, whereas adiponectin did not differ among groups. MCP-1 was also lower in patients with non-persistent than in those with persistent LBP. Age, leptin (relative risk, 11.8; 95% CI, 3.9-35.8) and MCP-1 (relative risk, 2.7; 95% CI, 1.7-4.4) were independently associated with presence and duration of LBP. The combination of age, leptin and MCP-1 predicted 61% of the risk of LBP duration. The area under the curve of MCP-1 for distinguishing persistent from non-persistent LBP was 0.65 (95% CI, 0.54-0.76). CONCLUSIONS: Then results of our study suggest that leptin and MCP-1 may be promising biomarkers for diagnosis of acute LBP and its risk to become chronic. PMID- 28076311 TI - Biomarkers of acute kidney injury: the pathway from discovery to clinical adoption. AB - Acute kidney injury (AKI) is a common complication of critical illnesses and has a significant impact on outcomes, including mortality and morbidities. Unfortunately, apart from prophylactic measures, no effective treatment for this syndrome is known. Therefore, early recognition of AKI not only can provide better opportunities for preventive interventions, but also opens many gates for research and development of effective therapeutic options. Over the last few years, several new AKI biomarkers have been discovered and validated to improve early detection, differential diagnosis, and differentiation of patients into risk groups for progressive renal failure, need for renal replacement therapy (RRT), or death. These novel AKI biomarkers complement serum creatinine (SCr) and urine output, which are the standard diagnostic tools for AKI detection. In this article, we review the available literature on characteristics of promising AKI biomarkers that are currently the focus of preclinical and clinical investigations. These biomarkers include neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), liver-type fatty acid-binding protein, interleukin 18 (lL-18), insulin-like growth factor-binding protein 7, tissue inhibitor of metalloproteinase 2 (TIMP-2), calprotectin, urine angiotensinogen (AGT), and urine microRNA. We then describe the clinical performance of these biomarkers for diagnosis and prognostication. We also appraise each AKI biomarker's advantages and limitations as a tool for early AKI recognition and prediction of clinical outcomes after AKI. Finally, we review the current and future states of implementation of biomarkers in the clinical practice. PMID- 28076312 TI - Implausible elevation of peripheral thyroid hormones during therapy with a protein supplement. PMID- 28076313 TI - Ethnopharmacological investigation of the aerial part of Phragmites karka (Poaceae). AB - BACKGROUND: In this ethnopharmacological study, methanolic extract of the aerial plant parts of Phragmites karka (Family: Poaceae) and its petroleum ether and carbon tetrachloride fractions were investigated for bioactivities in Swiss albino mice, namely, analgesic, central nervous system (CNS) depressant, hypoglycemic, and antidiarrheal activity. METHODS: The cold methanolic extract of the aerial plant parts of Phragmites karka (MEPK) was first prepared, and it was then further fractionated as petroleum ether (PEFMEPK) and carbon tetrachloride (CTFMEPK) fractions. Analgesic activity was performed employing acidic acid induced writhing test, central analgesic effect by radiant heat tail-flick method. CNS depressant activity was evaluated by phenobarbitone-induced sleeping time test. Hypoglycemic activity was tested by glucose tolerance test (GTT). Antidiarrheal activity was evaluated by castor oil-induced diarrhea method. For all in vivo tests, doses of 200 and 400 mg/kg body weight were used. RESULTS: In the mice model, the MEPK, PEFMEPK, and CTFMEPK fractions showed significant peripheral analgesic activity at a dose of 400 mg/kg body weight with percentage of inhibition of acetic acid-induced writhing 77.67 (p<0.001), 33.50 (p<0.001), and 40.29 (p<0.001), respectively, compared to the standard dichlofenac (60.68%, p<0.001) group. The hypoglycemic properties of MEPK, PEFMEPK, and CTFMEPK extracts were evaluated in normoglycemic mice where the reduction of blood glucose level after 30 min of glucose load were 69.85%, 78.91%, and 72.73%, respectively, and for standard glibenclamide, the reduction was 72.85%. All results were significant (p<0.05). In the case of the CNS depressant activity by phenobarbitone-induced sleeping time test, the crude ME significantly reduced sleep latency by 57.14% and increased the duration of sleep by 63.29% compared to the control, which were comparable to that of standard diazepam (65.71% and 77.62%, respectively). Among all the extract and fractions, methanolic extract showed the maximum antidiarrheal effect. The methanolic extract at 200 mg/kg dose induced a significant decrease in the total number of defecation in 4 h (69.05% of inhibition, p<0.001) and at 400 mg/kg dose showed 76.19% of inhibition (p<0.001). CONCLUSIONS: In light of the available literature, these findings represent the first experimental investigation of biological activities of P. karka in the perspective of their traditional use. PMID- 28076314 TI - In vivo sedative and hypnotic activities of methanol extract from the leaves of Jacquemontia paniculata (Burm.f.) Hallier f. in Swiss Albino mice. AB - BACKGROUND: The superior genus Jacquemontia belongs to Convolvulaceae, with around 120 species, and is also considered taxonomically difficult. The aim of this experiment was to assess the sedative and hypnotic activities of methanol extract from the leaves of Jacquemontia paniculata (Burm.f.) Hallier f. METHODS: The sedative and hypnotic activities were evaluated by hole-cross, open field, hole-board, elevated plus maze (EPM), and thiopental sodium-induced sleeping time determination tests in mice at doses of 200 and 400 mg/kg. RESULTS: In this investigation, we found that methanol extract of Jacquemontia paniculata (MEJP) produced a significant dose-dependent inhibition of spontaneous activity of mice both in hole-cross and open field tests. In addition, it also decreased the number of head dips in hole-board test. In the case of EPM test, this crude extract induced an anxiogenic-like effect rather than anxiolytic effect in mice. Moreover, MEJP significantly decreased the induction time to sleep and prolonged the duration of sleeping, induced by thiopental sodium. CONCLUSIONS: To conclude, these results suggest that the MEJP leaves possess potent sedative and hypnotic activities, which supported its therapeutic use for sleep disorders like insomnia. PMID- 28076315 TI - Meteorological parameters and pollutants on asthma exacerbation in Bangalore, India - an ecological retrospective time-series study. AB - BACKGROUND: Literature has shown a significant association between asthma exacerbations and pollutant levels during that time. There is very limited evidence in India, especially Bangalore, for impacts of meteorological changes and pollution on asthma hospital admissions in adults. The objective was to study the impact of air pollution and meteorological parameters on asthma exacerbation in Bangalore. METHODS: This study quantitatively analyzed the relation between acute exacerbations of asthma and related admissions to the hospital with the air pollution and the meteorological conditions during that time. Data regarding the daily hospital admissions in about 13 tertiary care centers in Bangalore, Karnataka and air pollutant levels and the meteorological conditions prevailing during each day over a year were collected from the Karnataka State pollution control board and meteorology departments, respectively. RESULTS: An average daily asthma admission of 4.84+/-2.91, with clear seasonal variation and autocorrelations between meteorological parameters and pollutants was observed. Multiple linear regression analysis revealed that average temperature (p=0.005) and nitrogen dioxide (NO2) (p=0.034) were the two factors that were affecting the number of admissions. Quasi-poisson regression analysis using multi-pollutants and meteorological variables showed that particulate matter and NO2 had significant lag effect for up to 5 days (p<0.05) and rainfall for 1 day (p<0.001). CONCLUSIONS: In Bangalore city, levels of NO2 and particulate matter, temperature, rainfall, and season increase asthma exacerbations. PMID- 28076316 TI - Changes of thyroid hormonal status in patients receiving ketogenic diet due to intractable epilepsy. AB - BACKGROUND: Ketogenic diet (KD), which is high in fat and low in carbohydrates, mimics the metabolic state of starvation and is used therapeutically for pharmacoresistant epilepsy. It is known that generation of triiodothyronine (T3) from thyroxine (T4) decreases during fasting periods. The aim of this study was to evaluate the thyroid function of children receiving KD for at least 1 year due to drug-resistant epilepsy. METHODS: A total of 120 patients [63 males, 52.5%; mean age 7.3+/-4.3 years, median interquartile range (IQR): 7.0 (4-10 years)] treated with KD for at least 1 year were enrolled. Seizure control, side effects, and compliance with the diet were recorded, and free T3, free T4, and thyroid stimulating hormone (TSH) levels were measured at baseline and at post-treatment months 1, 3, 6, and 12. The Mann-Whitney U-test, repeated measures analysis of variance (ANOVA) with post-hoc Bonferroni correction, and logistic regression analysis were used for data analysis. RESULTS: Hypothyroidism was diagnosed and L thyroxine medication was initiated for eight, seven and five patients (20 patients in total, 16.7%) at 1, 3, and 6 months of KD therapy, respectively. Logistic regression analysis showed that baseline TSH elevation [odds ratio (OR): 26.91, 95% confidence interval (CI) 6.48-111.76, p<0.001] and female gender (OR: 3.69, 95% CI 1.05-12.97, p=0.042) were independent risk factors for development of hypothyroidism during KD treatment in epileptic children. CONCLUSIONS: KD causes thyroid malfunction and L-thyroxine treatment may be required. This is the first report documenting the effect of KD treatment on thyroid function. Thyroid function should be monitored regularly in epileptic patients treated with KD. PMID- 28076317 TI - High predictability of impaired glucose tolerance by combining cardiometabolic screening parameters in obese children. AB - BACKGROUND: There is debate on which overweight and obese children should be screened for the presence of impaired glucose tolerance (IGT) by oral glucose tolerance testing (OGTT). The objective of the study was to identify risk factors predictive of the presence of IGT. METHODS: In a cohort of overweight children, who underwent OGTT, we determined the association of anthropometric and laboratory parameters with IGT and whether combining parameters improved the sensitivity of screening for IGT. RESULTS: Out of 145 patients, IGT was present in 11, of whom two had impaired fasting glucose (IFG). Elevated blood pressure (p=0.025) and elevated liver enzymes (p=0.003) were associated with IGT, whereas IFG was not (p=0.067), screening patients with either one of these parameters predicted IGT with a high sensitivity of 1.00, and a number needed to screen of 5.7. CONCLUSIONS: Screening all patients with either IFG, presence of elevated blood pressure and elevated liver enzymes, significantly increases predictability of IGT compared to using IFG alone. PMID- 28076318 TI - Beta cell function and clinical course in three siblings with thiamine-responsive megaloblastic anemia (TRMA) treated with thiamine supplementation. AB - Three siblings with thiamine-responsive megaloblastic anemia (TRMA) with a homozygous c.454delGGCATinsAT mutation in SLC19A2 are described. The index case presented at 14 months' old with severe non-ketotic hyperglycemia, dehydration, seizures and sinovenous thrombosis. She was started on insulin and developed sensorineural hearing loss around 2 years old. Two siblings were found to have the same mutation and were started on thiamine. One sibling developed transient hyperglycemia after several years of thiamine supplementation of 12 mg/kg that resolved with an increased thiamine dose (23 mg/kg). A younger sibling continues to remain diabetes-free on thiamine (24 mg/kg). The clinical course in this family suggests that there is an effect of thiamine on pancreatic beta cell function in patients with TRMA given the resolution of impaired fasting glucose with increasing thiamine dose in one sibling and the lack of diabetes to date in the siblings that were treated early with thiamine. PMID- 28076320 TI - Solid waste management in Thailand: an overview and case study (Tha Khon Yang sub district). AB - Due to rapid urbanization, solid waste management (SWM) has become a significant issue in several developing countries including Thailand. Policies implemented by the Central Thai Government to manage SWM issues have had only limited success. This article reviews current municipal waste management plans in Thailand and examines municipal waste management at the local level, with focus on the Tha Khon Yang sub-district surrounding Mahasarakham University in Mahasarakham Province. Within two decades this area has been converted from a rural to an urban landscape featuring accommodation for over 45,000 university students and a range of business facilities. This development and influx of people has outpaced the government's ability to manage municipal solid waste (MSW). There are significant opportunities to improve local infrastructure and operational capacity; but there are few mechanisms to provide and distribute information to improve community participation in waste management. Many community-based waste management projects, such as waste recycling banks, the 3Rs (reduce, reuse and recycle), and waste-to-biogas projects have been abandoned. Additionally, waste from Tha Kon Yang and its surrounding areas has been transferred to unsanitary landfills; there is also haphazard dumping and uncontrolled burning of waste, which exacerbate current pollution issues. PMID- 28076319 TI - Impact of nutrition on pollutant toxicity: an update with new insights into epigenetic regulation. AB - Exposure to environmental pollutants is a global health problem and is associated with the development of many chronic diseases, including cardiovascular disease, diabetes and metabolic syndrome. There is a growing body of evidence that nutrition can both positively and negatively modulate the toxic effects of pollutant exposure. Diets high in proinflammatory fats, such as linoleic acid, can exacerbate pollutant toxicity, whereas diets rich in bioactive and anti inflammatory food components, including omega-3 fatty acids and polyphenols, can attenuate toxicant-associated inflammation. Previously, researchers have elucidated direct mechanisms of nutritional modulation, including alteration of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signaling, but recently, increased focus has been given to the ways in which nutrition and pollutants affect epigenetics. Nutrition has been demonstrated to modulate epigenetic markers that have been linked either to increased disease risks or to protection against diseases. Overnutrition (i.e. obesity) and undernutrition (i.e. famine) have been observed to alter prenatal epigenetic tags that may increase the risk of offspring developing disease later in life. Conversely, bioactive food components, including curcumin, have been shown to alter epigenetic markers that suppress the activation of NF-kappaB, thus reducing inflammatory responses. Exposure to pollutants also alters epigenetic markers and may contribute to inflammation and disease. It has been demonstrated that pollutants, via epigenetic modulations, can increase the activation of NF-kappaB and upregulate microRNAs associated with inflammation, cardiac injury and oxidative damage. Importantly, recent evidence suggests that nutritional components, including epigallocatechin gallate (EGCG), can protect against pollutant-induced inflammation through epigenetic regulation of proinflammatory target genes of NF-kappaB. Further research is needed to better understand how nutrition can modulate pollutant toxicity through epigenetic regulation. Therefore, the objective of this review is to elucidate the current evidence linking epigenetic changes to pollutant-induced diseases and how this regulation may be modulated by nutrients allowing for the development of future personalized lifestyle interventions. PMID- 28076321 TI - Secretion modification region-derived peptide blocks exosome release and mediates cell cycle arrest in breast cancer cells. AB - PURPOSE: Discovery and development of a novel anticancer PEG-SMR-Clu peptide to prevent breast cancer metastasis. How breast cancer cells and primary mammary epithelial cells interact and communicate with each other to promote tumorigenesis and how to prevent tumor metastasis has long been a concern of researchers. Cancer cells secrete exosomes containing proteins and RNA. These factors can influence tumor development by directly targeting cancer cells and tumor stroma. In this study, we determined the effects of a peptide as an inhibitor of exosome secretion on breast tumors. We developed a peptide derived from the Secretion Modification Region (SMR) of HIV-1 Nef protein that was modified with PEG on the N-terminus and with a Clusterin (Clu)-binding peptide on the C-terminus. Attachment of PEG to the SMR peptide, termed PEGylation, offers improved water solubility and stability as well as reduced clearance through the kidneys, leading to a longer circulation time. The 12-mer Clu-binding peptide plays multiple roles in tumor development and metastasis. The Clu peptide can be detected by antibody in vivo, thus it has the potential to be used to monitor tumor status and treatment efficacy in animal studies and eventually in cancer patients. RESULTS: PEG-SMRwt-Clu and PEG-SMRwt peptides inhibited the growth of both of MCF-7 (estrogen responsive, ER+) and MDA-MD-231 (estrogen non-responsive, ER-) human breast cancer cells in a dose and time-dependent manner, without inducing cytotoxic effects. The SMRwt peptide, combined with paclitaxel, induced G2/M phase cell cycle arrest on MCF-7 and MDA-MB-231 cells but did not promote apoptosis. PEG-SMRwt-Clu peptide treatment blocked exosome release from both MCF 7 and MDA-MB-231 cells. This effect was blocked by knockdown of the chaperone protein mortalin by either antibody or siRNA. MATERIALS AND METHODS: MCF-7 and MDA-MB-231 breast tumor cells were treated with PEG-SMR-Clu peptide alone and in combination with paclitaxel and cisplatin. Cell proliferation and viabilty were determined via cell cycle analysis using Cellometer imaging cytometry, Annexin V and MTT assays. The effects of the PEG-SMR-Clu peptide on tumor exosome release were determined by testing isolated exosome fractions, for (i) expression of CD63 and Alix proteins by Western blotting, (ii) NanoSight nanoparticle tracking analysis (NTA 10) to measure exosomes size and concentration, and (iii) measurement of acetylcholinesterase (AchE) for exosome specific enzyme activity. CONCLUSIONS: PEG-SMRwt-CLU peptides inhibited the growth of human breast cancer cells and blocked tumor exosome release in vitro. The peptide alone did not cause increased cytotoxicity or apoptosis induction, but did cause cell cycle G2/M phase arrest in both estrogen responsive and non-responsive breast cancer cells. These data suggest a potential therapeutic value of SMR to prevent breast cancer metastasis and as an adjuvant for the chemotherapeutic treatment of human breast cancer. PMID- 28076322 TI - Aeroallergen Der p 2 promotes motility of human non-small cell lung cancer cells via toll-like receptor-mediated up-regulation of urokinase-type plasminogen activator and integrin/focal adhesion kinase signaling. AB - House dust mite (HDM) allergens are one of the major causes leading to respiratory hypersensitiveness and airway remodeling. Here we hypothesized that a major HDM allergen Der p 2 could increase cell motility and invasiveness of non small cell lung cancer (NSCLC) cells. Our results showed that low dose (1 and 3 MUg/mL) recombinant Der p 2 protein (DP2) enhanced the migration and invasiveness of human NSCLC cell A549, H1299 and CL1-5, but nonsignificantly altered their growth. Further investigation revealed that integrin alphaV level was increased and its downstream signaling including focal adhesion kinase (FAK) and paxillin were activated in A549 cells exposed to DP2. In parallel, DP2 also activated the FAK-associated signaling effectors such as Src, phosphatidyl inositol 3-kinase (PI3K), AKT, p38 mitogen-activated protein kinase (P38), extracellular signal regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK). Our findings also revealed that DP2 increased expression level of urokinase type plasminogen activated kinase (uPA) and uPA receptor (uPAR), and subsequently enhanced the binding of uPAR to integrin alphaV. Moreover, the involvement of toll-like receptor 2/4 (TLR2/4)-triggered ERK1/2 activation in the increased expression of uPA and uPAR was also demonstrated. Collectively, these findings indicate that DP2 can enhance cell motility and invasiveness of NSCLC cells, attributing to TLR2/4-ERK1/2 activation, increased uPA and uPAR expression, enhanced binding of uPAR to integrin alphaV, and the consequent FAK signaling cascades. Thus, we suggest that DP2 may exacerbate NSCLC via promoting metastatic ability of carcinoma cell. PMID- 28076324 TI - Poly(C)-binding protein 1 mediates drug resistance in colorectal cancer. AB - Oxaliplatin (L-OHP) is standard treatment for colorectal cancer. However, resistance to L-OHP often leads to treatment failure or cancer relapse. Understanding of the mechanism underlying L-OHP resistance is important to overcome the resistance and improve colorectal cancer treatment. This study aimed to identify new proteins that mediates L-OHP resistance in colorectal cancer and elucidate their mode of function. HT-29 cells were exposed to gradually increased concentration of L-OHP to select L-OHP resistant HT-29/L-OHP cell line. Proteomic analysis of HT-29 and HT-29/L-OHP cells were performed to identify differentially expressed proteins, including Poly(C)-binding protein 1 (PCBP1). PCBP1 expression level in 20 cases of L-OHP sensitive patients and 20 cases of L-OHP refractory patients was analyzed by immunohistochemistry. Chemoresistance and Akt activation in HT-29 and HT-29/L-OHP cells were analyzed by MTT assay and Western blot analysis. We identified 37 proteins showing differential expression in HT-29/L OHP and HT-29 cells. In particular, PCBP1 protein level increased 15.6 fold in HT 29/L-OHP cells compared to HT-29 cells. Knockdown of PCBP1 sensitized HT-29/L-OHP and HT-29 cells to L-OHP, while overexpression of PCBP1 increased L-OHP resistance in HT-29 cells. In addition, PCBP1 expression was significantly higher in tumor samples from L-OHP refractory patients than in those from L-OHP responsive patients. Furthermore, we found that knockdown of PCBP1 inhibited the activation of Akt in HT-29/L-OHP and HT-29 cells. In conclusion, our findings suggest that PCBP1 is a molecular marker of L-OHP resistance in colorectal cancer and a promising target for colorectal cancer therapy. PMID- 28076323 TI - Clinical outcome of tyrosine kinase inhibitors alone or combined with radiotherapy for brain metastases from epidermal growth factor receptor (EGFR) mutant non small cell lung cancer (NSCLC). AB - This study compared treatment outcomes between TKI monotherapy and TKI administration combined with brain radiotherapy (TKI + RT) in 133 non-small cell lung cancer (NSCLC) patients with brain metastasis (BM). We also evaluated the association of different epidermal growth factor receptor (EGFR) mutation subtypes with treatment outcome. To screen for potential variables affecting cranial progression free survival (PFS) and overall survival (OS), we performed univariate and multivariate analysis based on Cox proportional-hazards models. Median cranial PFS and OS were longer for the TKI + RT group (n = 67) than TKI alone group (n = 66). Intracranial metastasis correlated with a better median OS than extracranial metastasis. For patients with exon 21 mutations, TKI + RT yielded a better median OS and cranial PFS than TKI alone. However, there were no significant differences in median OS and cranial PFS between the two treatment groups for patients with exon 19 deletions. Thus EGFR-mutant NSCLC patients with BM could benefit more from TKI + RT than from TKI monotherapy, especially when they suffer from exon 21 mutations. However, TKI + RT confers no advantage over TKI treatment alone for patients with exon 19 deletions. These results underscore the urgent need to develop individualized disease management strategies in clinical practice. PMID- 28076325 TI - Identification of long noncoding RNAs for the detection of early stage lung squamous cell carcinoma by microarray analysis. AB - The aberrant expressions of long noncoding RNAs have been reported in numerous cancers, which have facilitated the cancer diagnosis. However, the expression profile of lncRNAs in early stage lung squamous cell carcinoma has not been well discussed. The present study aimed to examine the expression profile of lncRNAs in early stage lung squamous cell carcinoma and identify lncRNA biomarkers for diagnosis. Through high-throughput lncRNA microarray, we screened thousands of aberrantly expressed lncRNAs and mRNAs in early stage lung squamous cell carcinoma tissues compared to their corresponding adjacent nontumorous tissues. Bioinformatics analyses were used to investigate the functions of aberrantly expressed mRNAs and their associated lncRNAs. After that, in order to identify lncRNA biomarkers for early detection, candidate lncRNA biomarkers were selected based on our established filtering pipeline and validated by real-time quantitative polymerase chain reaction on a total of 63 pairs of tumor samples. Five lncRNAs were finally identified which were able to distinguish early stage tumor and normal samples with high sensitivity (92%) and specificity (83%). These results imply that lncRNAs may be powerful biomarker for early diagnosis. PMID- 28076326 TI - Cytosolic THUMPD1 promotes breast cancer cells invasion and metastasis via the AKT-GSK3-Snail pathway. AB - Human THUMP domain-containing protein 1 (THUMPD1) is a specific adaptor protein that modulates tRNA acetylation through interaction with NAT10. Immunohistochemical analysis of 146 breast cancer specimens (82 triple-negative and 64 non-triple-negative cases) indicated THUMPD1 expression is higher in breast cancer tissues (60.9%, 89/146) than normal breast tissues (28.3%, 15/53; p < 0.001). Overall and cytosolic, but not nuclear, THUMPD1 expression in breast cancer correlated with advanced TNM stage (p = 0.003 and p < 0.001, respectively), lymph node metastasis (p = 0.001 and p < 0.001, respectively), and poor patient prognosis (p = 0.001 and p < 0.001, respectively). THUMPD1 interacted and co-localized with YAP, but did not affect Hippo pathway activity. THUMPD1 overexpression enhanced breast cancer cells invasion and migration in vivo and in vitro, possibly through activation of AKT, GSK3beta and Snail, and inhibition of E-cadherin. Treatment with the AKT inhibitor, LY294002, reduced the effects of THUMPD1 overexpression in breast cancer cells. These results indicate that THUMPD1 promotes breast cancer cells invasion and migration via the AKT GSK3beta-Snail pathway. PMID- 28076327 TI - MiR-410 induces stemness by inhibiting Gsk3beta but upregulating beta-catenin in non-small cells lung cancer. AB - Our previous research indicated miR-410 played a critical role in promoting the tumorigenesis and development of NSCLC (non-small cells lung cancer). MiR-410 has been recently reported to be crucial for development and differentiation of embryonic stem cells. But it remains elusive whether miR-410 stimulates the stemness of cancer until now. Herein, we identify miR-410 induces the stemness and is associated with the progression of NSCLC. We demonstrate miR-410 increases the levels of stem cells marker Sox2, Oct4, Nanog, CXCR4 as well as lung cancer stem cells surface marker CD44 and CD166. MiR-410 promotes stem cells-like properties such as proliferation, sphere formation, metastasis and chemoresistance. Moreover, Gsk3beta is directly targeted and post transcriptionally downregulated by miR-410. Also, the expression levels of miR 410 and Gsk3beta may be correlated to clinicopathological differentiation in NSCLC tumor specimens. Additionally, we demonstrate miR-410 induces stemness through inhibiting Gsk3beta but increasing Sox2, Oct4, Nanog and CXCR4, which binds to beta-catenin signaling. In conclusion, our findings identify the miR 410/Gsk3beta/beta-catenin signaling axis is a novel molecular circuit in inducing stemness of NSCLC. PMID- 28076328 TI - Albumin to gamma-glutamyltransferase ratio as a prognostic indicator in intrahepatic cholangiocarcinoma after curative resection. AB - The prognosis of intrahepatic cholangiocarcinoma (ICC) remains poor whereas predictive models for survival prediction in ICC patients following curative resection are limited. Herein, we established a novel inflammation-based score derived from preoperative albumin to gamma-glutamyltransferase ratio (AGR) and evaluated its prognostic significance in ICC patients underwent curative resection. Prognostic value of AGR was retrospectively studied in a cohort comprising 206 ICC patients following curative resection. The predictive performance of AGR was compared with other inflammation-based scores and serological tumor markers in terms of concordance index (C-index). Further, prognostic nomograms incorporating AGR into the tumor-node-metastasis (TNM) staging systems were established to achieve a better discriminatory ability. The optimal cut-off value of AGR was 0.6. Multivariate analysis showed that AGR was an independent predictor for overall survival (OS; P = 0.003) and recurrence-free survival (RFS; P = 0.046). The C-index of AGR was superior to other inflammation based scores and serological tumor markers in OS and RFS prediction. The established nomograms showed improved predictive accuracy compared with the TNM staging systems alone. These results indicate that AGR is an independent prognostic indicator for ICC underwent curative resection. The incorporation of AGR into the existing TNM staging systems achieved improved predictive accuracy. PMID- 28076329 TI - Feasibility of abbreviated cycles of immunochemotherapy for completely resected limited-stage CD20+ diffuse large B-cell lymphoma (CISL 12-09). AB - BACKGROUND: The appropriate number of chemotherapy cycles for limited stage diffuse large B-cell lymphoma (DLBCL) patients without gross residual lesions after complete resection, has not been specifically questioned. We performed a multicenter, single-arm, phase 2 study to investigate the feasibility of 3 cycles of abbreviated R-CHOP chemotherapy in low-risk patients with completely resected localized CD20+ DLBCL. RESULTS: Between December 2010 and May 2013, we recruited 23 patients. One was excluded due to ineligibility, and hence, 22 were included in the final analysis. The primary sites comprised the intestine (n = 15), cervical lymph nodes (n = 4), stomach (n = 1), tonsil (n = 1), and spleen (n = 1). All patients successfully completed the 3 cycles of planned R-CHOP chemotherapy. Over a median follow-up of 39.5 months (95% confidence interval, 29.9-47.1 months), both the estimated 2-year disease-free survival and overall survival rates was 95% confidence interval, 85.9-104.1%. Only one patient with an international prognostic index of 2 experienced relapse and died. The most common grade 3 or 4 toxicity condition included neutropenia (n = 8, 36.4%). Three patients experienced grade 3 febrile neutropenia, but no grade 3 or 4 non hematologic toxicity was observed. MATERIALS AND METHODS: DLBCL patients without residual lesions after resection were enrolled and R-CHOP chemotherapy was repeated at 3-week-intervals over 3 cycles. The primary endpoint was 2-year disease-free survival. CONCLUSIONS: Three cycles of abbreviated R-CHOP immunochemotherapy is feasible for completely resected low risk localized DLBCL. PMID- 28076330 TI - The correlation of age with chemotherapy-induced ovarian function failure in breast cancer patients. AB - PURPOSE: To assess the incidence of chemotherapy-induced ovarian function failure (COFF) based on estradiol and follicle stimulating hormone (FSH) monitoring in premenopausal women with hormone-receptor positive breast cancer treated with second and third generation (neo-)adjuvant chemotherapy. RESULTS: We identified 115 eligible women. Two years after start of chemotherapy, COFF was significantly more often present in women >= 40 years (85.6%) as compared to women < 40 years (8.7%). Only age was significantly associated with COFF two years after start of chemotherapy (HR 12.26; 95% CI 5.21-28.86). In 50% of the patients, premenopausal hormone levels were the first or only evidence of ovarian function recovery (OFR). MATERIALS AND METHODS: We included all premenopausal women with hormone receptor positive breast cancer treated with anthracycline-based chemotherapy, with or without taxanes, in our university hospital in the Netherlands in the years 2005-2013. Patients were 3-monthly monitored for ovarian function. Cox proportional hazards model was used to determine the predictive impact of various parameters on the occurrence of COFF. CONCLUSIONS: After second- or third generation (neo-)adjuvant chemotherapy, COFF was still present in 8.7% of patients < 40 years after two years. FSH and estradiol monitoring may be relevant for those in whom ovarian function suppression is considered an additional effective endocrine treatment. PMID- 28076331 TI - A short-term intervention with selenium affects expression of genes implicated in the epithelial-to-mesenchymal transition in the prostate. AB - In parallel with the inconsistency in observational studies and chemoprevention trials, the mechanisms by which selenium affects prostate cancer risk have not been elucidated. We conducted a randomized, placebo-controlled trial to examine the effects of a short-term intervention with selenium on gene expression in non malignant prostate tissue. Twenty-three men received 300 ug selenium per day in the form of selenized yeast (n=12) or a placebo (n=11) during 5 weeks. Prostate biopsies collected from the transition zone before and after intervention were analysed for 15 participants (n=8 selenium, n=7 placebo). Pathway analyses revealed that the intervention with selenium was associated with down-regulated expression of genes involved in cellular migration, invasion, remodeling and immune responses. Specifically, expression of well-established epithelial markers, such as E-cadherin and epithelial cell adhesion molecule EPCAM, was up regulated, while the mesenchymal markers vimentin and fibronectin were down regulated after intervention with selenium. This implies an inhibitory effect of selenium on the epithelial-to-mesenchymal transition (EMT). Moreover, selenium was associated with down-regulated expression of genes involved in wound healing and inflammation; processes which are both related to EMT. In conclusion, our explorative data showed that selenium affected expression of genes implicated in EMT in the transition zone of the prostate. PMID- 28076332 TI - Lysosomal acid phosphatase 2 is an unfavorable prognostic factor but is associated with better survival in stage II colorectal cancer patients receiving chemotherapy. AB - Colorectal cancer (CRC) is one of the leading cancers worldwide. Surgery is the main therapeutic modality for stage II CRC. However, the implementation of adjuvant chemotherapy remains controversial and is not universally applied so far. In this study, we found that the protein expression of lysosomal acid phosphatase 2 (ACP2) was increased in CRC and that stage II CRC patients with high ACP2 expression showed a poorer outcome than those with low ACP2 expression (p = 0.004). To investigate this discrepancy, we analyzed the relation between ACP2 expression and several clinical cofactors.Among patients who received chemotherapy, those with an high expression of ACP2 showed better survival in both stage II and III CRC than those with low ACP2 expression. In stage II CRC patients, univariate analysis showed ACP2 expression and T stage to be cofactors significantly associated with overall survival (ACP2: p = 0.006; T stage: p = 0.034). Multivariate Cox proportion hazard model analysis also revealed ACP2 to be an independent prognostic factor for overall survival (ACP2: p = 0.006; T stage: p = 0.041). Furthermore, ACP2-knockdown CRC cells showed an increase in chemoresistance to 5-FU treatment and increased proliferation marker in the ACP2 knockdown clone.Taken together, our results suggested that ACP2 is an unfavorable prognostic factor for stage II CRC and may serve as a potential chemotherapy sensitive marker to help identify a subset of stage II and III CRC patients for whom chemotherapy would improve survival.Highlights1. To the best of our knowledge, the study is the first report to show ACP2 overexpression in human colorectal cancer (CRC) and its association with poor outcome in stage II CRC.2. Patients with stage II and III CRCs with high expression of ACP2 were more sensitive to chemotherapy than those with a low expression.3. ACP2 expression may serve as a marker for CRC patients receiving chemotherapy and help identify the subset of CRC patients who would benefit from chemotherapy. PMID- 28076333 TI - Surgical debulking promotes recruitment of macrophages and triggers glioblastoma phagocytosis in combination with CD47 blocking immunotherapy. AB - Surgical resection is a standard component of treatment in the clinical management of patients with glioblastoma multiforme (GBM). However, experimental therapies are rarely investigated in the context of tumor debulking in preclinical models. Here, a surgical debulking GBM xenograft model was developed in nude rats, and was used in combination with CD47 blocking immunotherapy, a novel treatment strategy that triggers phagocytosis of tumor cells by macrophages in diverse cancer types including GBM. Orthotopic patient-derived xenograft tumors expressing CD47 were resected at 4 weeks after implantation and immediately thereafter treated with anti-CD47 or control antibodies injected into the cavity. Debulking prolonged survival (median survival, 68.5 vs 42.5 days, debulking and non-debulking survival times, respectively; n = 6 animals/group; P = 0.0005). Survival was further improved in animals that underwent combination treatment with anti-CD47 mAbs (median survival, 81.5 days vs 69 days, debulking + anti-CD47 vs debulking + control IgG, respectively; P = 0.0007). Immunohistochemistical staining of tumor sections revealed an increase in recruitment of cells positive for CD68, a marker for macrophages/immune cell types, to the surgical site (50% vs 10%, debulking vs non-debulking, respectively). Finally, analysis of tumor protein lysates on antibody microarrays demonstrated an increase in pro-inflammatory cytokines, such as CXCL10, and a decrease in angiogenic proteins in debulking + anti-CD47 vs non-debulking + IgG tumors. The results indicated that surgical resection combined with anti-CD47 blocking immunotherapy promoted an inflammatory response and prolonged survival in animals, and is therefore an attractive strategy for clinical translation. PMID- 28076334 TI - Establishment of a normal-derived estrogen receptor-positive cell line comparable to the prevailing human breast cancer subtype. AB - Understanding human cancer increasingly relies on insight gained from subtype specific comparisons between malignant and non-malignant cells. The most frequent subtype in breast cancer is the luminal. By far the most frequently used model for luminal breast cancer is the iconic estrogen receptor-positive (ERpos) MCF7 cell line. However, luminal specific comparisons have suffered from the lack of a relevant non-malignant counterpart. Our previous work has shown that transforming growth factor-beta receptor (TGFbetaR) inhibition suffices to propagate prospectively isolated ERpos human breast luminal cells from reduction mammoplasties (HBEC). Here we demonstrate that transduction of these cells with hTERT/shp16 renders them immortal while remaining true to the luminal lineage including expression of functional ER (iHBECERpos). Under identical culture conditions a major difference between MCF7 and normal-derived cells is the dependence of the latter on TGFbetaR inhibition for ER expression. In a breast fibroblast co-culture model we further show that whereas MCF7 proliferate concurrently with ER expression, iHBECERpos form correctly polarized acini, and segregate into proliferating and ER expressing cells. We propose that iHBECERpos may serve to shed light on hitherto unappreciated differences in ER regulation and function between normal breast and breast cancer. PMID- 28076335 TI - Infrequent development of drug resistance in HIV-1-infected treatment-naive subjects after 96 weeks of treatment with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate. AB - BACKGROUND: Tenofovir alafenamide (TAF) is a novel prodrug of the nucleotide reverse transcriptase inhibitor tenofovir (TFV) that loads lymphocytes with TFV diphosphate more efficiently than tenofovir disoproxil fumarate (TDF). The single tablet regimen (STR) comprising elvitegravir, cobicistat, emtricitabine and TAF (E/C/F/TAF) has demonstrated non-inferiority to the STR of E/C/F/TDF in clinical studies, with high proportions of subjects achieving HIV-1 RNA <50 copies/ml at week 48 that were maintained through week 96. A resistance analysis of the combined Phase III clinical studies through 96 weeks is described here. METHODS: Genotypic and phenotypic susceptibility to antiretrovirals (ARVs) was evaluated for subjects with HIV-1 RNA >=400 copies/ml at time of virological failure (VF) or early discontinuation. RESULTS: Through week 96, VF resistance analyses were conducted for 24 subjects in each arm (2.8%, 24/866 and 2.8%, 24/867; for E/C/F/TAF and E/C/F/TDF arms, respectively). Primary resistance development to ARVs of the regimen occurred in 10 of 24 subjects in the E/C/F/TAF arm, and 8 of 24 subjects in the E/C/F/TDF arm (E/C/F/TAF: M184V/I, n=9; integrase strand transfer inhibitor resistance-associated mutations [INSTI-RAMs], n=8; K65R/N, n=2; E/C/F/TDF: M184V/I, n=6; INSTI-RAMs, n=5; K65R/N, n=3). The emergent resistance mutations were similar between the treatment arms. CONCLUSIONS: E/C/F/TAF achieved a high level of virological suppression in HIV-1 treatment naive subjects through 96 weeks of treatment, with infrequent resistance development and comparable genotypic changes across both the E/C/F/TAF and E/C/F/TDF treatment groups. PMID- 28076336 TI - A theoretical framework to predict the most likely ion path in particle imaging. AB - In this work, a generic rigorous Bayesian formalism is introduced to predict the most likely path of any ion crossing a medium between two detection points. The path is predicted based on a combination of the particle scattering in the material and measurements of its initial and final position, direction and energy. The path estimate's precision is compared to the Monte Carlo simulated path. Every ion from hydrogen to carbon is simulated in two scenarios, (1) where the range is fixed and (2) where the initial velocity is fixed. In the scenario where the range is kept constant, the maximal root-mean-square error between the estimated path and the Monte Carlo path drops significantly between the proton path estimate (0.50 mm) and the helium path estimate (0.18 mm), but less so up to the carbon path estimate (0.09 mm). However, this scenario is identified as the configuration that maximizes the dose while minimizing the path resolution. In the scenario where the initial velocity is fixed, the maximal root-mean-square error between the estimated path and the Monte Carlo path drops significantly between the proton path estimate (0.29 mm) and the helium path estimate (0.09 mm) but increases for heavier ions up to carbon (0.12 mm). As a result, helium is found to be the particle with the most accurate path estimate for the lowest dose, potentially leading to tomographic images of higher spatial resolution. PMID- 28076337 TI - Coded excitation for diverging wave cardiac imaging: a feasibility study. AB - Diverging wave (DW) based cardiac imaging has gained increasing interest in recent years given its capacity to achieve ultrahigh frame rate. However, the signal-to-noise ratio (SNR), contrast, and penetration depth of the resulting B mode images are typically low as DWs spread energy over a large region. Coded excitation is known to be capable of increasing the SNR and penetration for ultrasound imaging. The aim of this study was therefore to test the feasibility of applying coded excitation in DW imaging to improve the corresponding SNR, contrast and penetration depth. To this end, two types of codes, i.e. a linear frequency modulated chirp code and a set of complementary Golay codes were tested in three different DW imaging schemes, i.e. 1 angle DW transmit without compounding, 3 and 5 angles DW transmits with coherent compounding. The performances (SNR, contrast ratio (CR), contrast-to-noise ratio (CNR), and penetration) of different imaging schemes were investigated by means of simulations and in vitro experiments. As for benchmark, corresponding DW imaging schemes with regular pulsed excitation as well as the conventional focused imaging scheme were also included. The results showed that the SNR was improved by about 10 dB using coded excitation while the penetration depth was increased by 2.5 cm and 1.8 cm using chirp code and Golay codes, respectively. The CNR and CR gains varied with the depth for different DW schemes using coded excitations. Specifically, for non-compounded DW imaging schemes, the gain in the CR was about 5 dB and 3 dB while the gain in the CNR was about 4.5 dB and 3.5 dB at larger depths using chirp code and Golay codes, respectively. For compounded imaging schemes, using coded excitation, the gain in the penetration and contrast were relatively smaller compared to non-compounded ones. Overall, these findings indicated the feasibility of coded excitation in improving the image quality of DW imaging. Preliminary in vivo cardiac images of a healthy volunteer were presented finally, and higher SNR and deeper penetration depth can be achieved by coded schemes. PMID- 28076338 TI - Quantification of confounding factors in MRI-based dose calculations as applied to prostate IMRT. AB - Magnetic resonance (MR)-only radiotherapy treatment planning requires pseudo-CT (pCT) images to enable MR-based dose calculations. To verify the accuracy of MR based dose calculations, institutions interested in introducing MR-only planning will have to compare pCT-based and computer tomography (CT)-based dose calculations. However, interpreting such comparison studies may be challenging, since potential differences arise from a range of confounding factors which are not necessarily specific to MR-only planning. Therefore, the aim of this study is to identify and quantify the contribution of factors confounding dosimetric accuracy estimation in comparison studies between CT and pCT. The following factors were distinguished: set-up and positioning differences between imaging sessions, MR-related geometric inaccuracy, pCT generation, use of specific calibration curves to convert pCT into electron density information, and registration errors. The study comprised fourteen prostate cancer patients who underwent CT/MRI-based treatment planning. To enable pCT generation, a commercial solution (MRCAT, Philips Healthcare, Vantaa, Finland) was adopted. IMRT plans were calculated on CT (gold standard) and pCTs. Dose difference maps in a high dose region (CTV) and in the body volume were evaluated, and the contribution to dose errors of possible confounding factors was individually quantified. We found that the largest confounding factor leading to dose difference was the use of different calibration curves to convert pCT and CT into electron density (0.7%). The second largest factor was the pCT generation which resulted in pCT stratified into a fixed number of tissue classes (0.16%). Inter-scan differences due to patient repositioning, MR-related geometric inaccuracy, and registration errors did not significantly contribute to dose differences (0.01%). The proposed approach successfully identified and quantified the factors confounding accurate MRI-based dose calculation in the prostate. This study will be valuable for institutions interested in introducing MR-only dose planning in their clinical practice. PMID- 28076339 TI - Drugs for type 2 diabetes. PMID- 28076340 TI - Telomere Length Assessment for Prediction of Organ Transplantation Outcome. Future or Failure: A Review of the Literature. AB - Telomeres are located at each end of eukaryotic chromosomes. Their functional role is genomic stability maintenance. The protective role of telomeres depends on various factors, including number of nucleotides repeats, telomere-binding proteins, and telomerase activity. Organ transplantation is the preferred replacement therapy in the case of chronic kidney disease and the only possibility of sustaining recipients' life in the case of advanced liver failure. While the prevalence of acute rejection is constantly decreasing, prevention of transplanted organ long-term function loss is still challenging. It has been demonstrated that post-transplant stressors accelerate aging of the allografts manifested through telomere shortening. The aim of this paper was to evaluate the importance of telomere length assessment for prediction of organ transplantation outcome. Literature review included the 10 most important studies regarding linkage between allograft function and telomere erosion, including 2 of our own reports. Telomere length assessment is useful to predict organ transplantation outcome. The importance of telomere length as a prediction marker depends on the analyzed material. To obtain reliable results, both graft cells (donor material) and lymphocytes (recipient material) should be examined. In the case of kidney transplantation, assessment of telomere length in the early post-transplant period allows prediction of the long-term function of the transplanted organ. To increase the accuracy of transplantation outcome prediction, telomere length assessment should be combined with evaluation of other aging biomarkers, like CDKN2A (p16). Large-scale clinical studies regarding telomere length measurement, including genome wide association analysis introducing relevant genetic factors, are needed for the future. PMID- 28076341 TI - Risk factors for post coronary artery bypass graft atrial fibrillation: role of obstructive sleep apnea. AB - In this chapter, we start by discussing coronary artery bypass grafting and the most common complication after surgery ? post coronary artery bypass grafting atrial fibrillation (PCAF). We then discuss the major risk factors for PCAF, and subsequently conduct an in-depth discussion of obstructive sleep apnea as a risk factor. In this endeavor, we outline how obstructive sleep apnea is diagnosed, its pathophysiological relationship to PCAF, and recent clinical studies investigating the association between obstructive sleep apnea and PCAF. We conclude with prevention and treatment strategies for PCAF, and a discussion of future research recommendations. PMID- 28076342 TI - Knowledge, beliefs and attitudes report on patient care and safety in undergraduate students: validating the modified APSQ-III questionnaire. AB - INTRODUCTION: Patient safety aims to achieve healthcare free of damage. The World Health Organization indicates that this objective is achieved through communication, analysis, and prevention of adverse events in patients. Organizational culture has been identified as one of the main factors for interventions aimed to reduce medical errors; and an essential component of safety culture is the attitude of health professionals towards medical error. Attitudes can be improved through appropriate education in biomedical careers but its inclusion in Argentina is scarce. The Attitudes Questionnaire for Patient Safety, measures knowledge, beliefs, and attitudes about patient safety and could be a useful tool in our country. OBJECTIVES: To validate the modified attitudes for patient safety questionnaire to measure knowledges, beliefs, and attitudes of medical students at CEMIC University Institute. To describe the level of knowledges, beliefs, and attitudes in patient safety of medical students at CEMIC University Institute in 2012, 2015 and 2016. METHODS: Design: descriptive study. Scope: Exploratory. Setting: the CEMIC University Institute in Buenos Aires, Argentina. Population: medical students of 4th and 5th year. Sampling: a sample size of 100 participants was estimated to derive meaningful estimates as per a Cronbach's alpha> 0.60. RESULTS: The reliability of the instrument (internal consistency) by Cronbach's alpha showed an overall correlation of 0.695. Suitable Cronbach's alpha values were obtained in all categories, except in two: importance of patient safety in the curriculum and the inevitability of error. The responses on knowledge, attitudes and perceptions about patient safety in the three cohorts showed that 57% of students believe they understand concepts about patient safety, 53% consider their training prepares them to understand the cause of medical errors, only 59% believe that human error is inevitable and 98% believe that real professionals do not make mistakes. Lastly, 64% believe that this knowledge is only acquired from clinical experience. CONCLUSION: This study shows that the APSQ-III modified survey is valid and could be used in Argentina and the region to measure the impact of incorporating patient safety topics in the medical curriculum. PMID- 28076343 TI - Pigmented basal cell carcinoma mimicking a superficial spreading melanoma. AB - Basal cell carcinoma is the most common form of skin cancer, especially in elderly people. Pigmented basal cell carcinoma is a rare subtype and has been described in the literature as a nodular and hyperpigmented lesion; rarely, it can appear as an extensive pigmented plate, which may be clinically indistinguishable from superficial spreading melanoma and Bowen disease. Dermatoscopy has a high sensitivity in the diagnosis of basal cell carcinoma. When Menzies criteria are used; however, the final diagnosis is made by histopathology. The objective of the present report is to analyze the case of a patient with pigmented basal cell carcinoma simulating a superficial spreading melanoma. PMID- 28076344 TI - Qualitative aspects of the process of Neonatal Hearing Screening Program in Mexico evaluated from the parental perspective. AB - INTRODUCTION: The Universal Newborn Hearing Screening Program in Mexico began in 2010. Its results, published in 2013 by the National Council for the Development and Inclusion of Persons with Disabilities (CONADIS), report low coverage and, currently, there is a dearth of information about its activities. This study describes the process of the program from the epistemological perspective of women whose children participated in the program, evaluating it under the sustenance of the constructivist-respondent model in search of aspects that could help explain its results. METHODS: Descriptive study with a qualitative approach based on the constructivist?respondent paradigm. We elected the 14 women who participated in the study through trial and number until theoretical saturation. After signing an informed consent form and respecting the confidentiality and anonymity, these women underwent semi-structured interviews that were audio recorded and transcribed as were conducted. The researchers separately analyzed and coded categories and conjointly summarized categories and subcategories. Validity and reliability were obtained through the credibility, transferability and triangulation. RESULTS: From the speeches, we obtained the general profile of the interviewed, evolution of their children in the program process and four categories with 15 subcategories related to the reconstruction of the process: knowledge, needs, feelings and attitudes. One was evaluated as favorable, six without agreement and eight as unfavorable. The latter refer to our own context. CONCLUSIONS: The epistemological perspective of the interviewed women showed aspects that could help explain the low coverage of the program. Attention from public policies could improve this feature. With the establishment of the program, children with deafness are diagnosed and treated at a lower age than before the program. PMID- 28076345 TI - Structure of a spliceosome remodelled for exon ligation. AB - The spliceosome excises introns from pre-mRNAs in two sequential transesterifications-branching and exon ligation-catalysed at a single catalytic metal site in U6 small nuclear RNA (snRNA). Recently reported structures of the spliceosomal C complex with the cleaved 5' exon and lariat-3'-exon bound to the catalytic centre revealed that branching-specific factors such as Cwc25 lock the branch helix into position for nucleophilic attack of the branch adenosine at the 5' splice site. Furthermore, the ATPase Prp16 is positioned to bind and translocate the intron downstream of the branch point to destabilize branching specific factors and release the branch helix from the active site. Here we present, at 3.8 A resolution, the cryo-electron microscopy structure of a Saccharomyces cerevisiae spliceosome stalled after Prp16-mediated remodelling but before exon ligation. While the U6 snRNA catalytic core remains firmly held in the active site cavity of Prp8 by proteins common to both steps, the branch helix has rotated by 75 degrees compared to the C complex and is stabilized in a new position by Prp17, Cef1 and the reoriented Prp8 RNase H-like domain. This rotation of the branch helix removes the branch adenosine from the catalytic core, creates a space for 3' exon docking, and restructures the pairing of the 5' splice site with the U6 snRNA ACAGAGA region. Slu7 and Prp18, which promote exon ligation, bind together to the Prp8 RNase H-like domain. The ATPase Prp22, bound to Prp8 in place of Prp16, could interact with the 3' exon, suggesting a possible basis for mRNA release after exon ligation. Together with the structure of the C complex, our structure of the C* complex reveals the two major conformations of the spliceosome during the catalytic stages of splicing. PMID- 28076346 TI - Cryo-EM structure of a human spliceosome activated for step 2 of splicing. AB - Spliceosome rearrangements facilitated by RNA helicase PRP16 before catalytic step two of splicing are poorly understood. Here we report a 3D cryo-electron microscopy structure of the human spliceosomal C complex stalled directly after PRP16 action (C*). The architecture of the catalytic U2-U6 ribonucleoprotein (RNP) core of the human C* spliceosome is very similar to that of the yeast pre Prp16 C complex. However, in C* the branched intron region is separated from the catalytic centre by approximately 20 A, and its position close to the U6 small nuclear RNA ACAGA box is stabilized by interactions with the PRP8 RNase H-like and PRP17 WD40 domains. RNA helicase PRP22 is located about 100 A from the catalytic centre, suggesting that it destabilizes the spliced mRNA after step two from a distance. Comparison of the structure of the yeast C and human C* complexes reveals numerous RNP rearrangements that are likely to be facilitated by PRP16, including a large-scale movement of the U2 small nuclear RNP. PMID- 28076347 TI - Spatiotemporal Feedback and Network Structure Drive and Encode Caenorhabditis elegans Locomotion. AB - Using a computational model of the Caenorhabditis elegans connectome dynamics, we show that proprioceptive feedback is necessary for sustained dynamic responses to external input. This is consistent with the lack of biophysical evidence for a central pattern generator, and recent experimental evidence that proprioception drives locomotion. The low-dimensional functional response of the Caenorhabditis elegans network of neurons to proprioception-like feedback is optimized by input of specific spatial wavelengths which correspond to the spatial scale of real body shape dynamics. Furthermore, we find that the motor subcircuit of the network is responsible for regulating this response, in agreement with experimental expectations. To explore how the connectomic dynamics produces the observed two-mode, oscillatory limit cycle behavior from a static fixed point, we probe the fixed point's low-dimensional structure using Dynamic Mode Decomposition. This reveals that the nonlinear network dynamics encode six clusters of dynamic modes, with timescales spanning three orders of magnitude. Two of these six dynamic mode clusters correspond to previously-discovered behavioral modes related to locomotion. These dynamic modes and their timescales are encoded by the network's degree distribution and specific connectivity. This suggests that behavioral dynamics are partially encoded within the connectome itself, the connectivity of which facilitates proprioceptive control. PMID- 28076349 TI - Mechanical Control of Whole Body Shape by a Single Cuticular Protein Obstructor-E in Drosophila melanogaster. AB - Body shapes are much more variable than body plans. One way to alter body shapes independently of body plans would be to mechanically deform bodies. To what extent body shapes are regulated physically, or molecules involved in physical control of morphogenesis, remain elusive. During fly metamorphosis, the cuticle (exoskeleton) covering the larval body contracts longitudinally and expands laterally to become the ellipsoidal pupal case (puparium). Here we show that Drosophila melanogaster Obstructor-E (Obst-E) is a protein constituent of the larval cuticle that confers the oriented contractility/expandability. In the absence of obst-E function, the larval cuticle fails to undergo metamorphic shape change and finally becomes a twiggy puparium. We present results indicating that Obst-E regulates the arrangement of chitin, a long-chain polysaccharide and a central component of the insect cuticle, and directs the formation of supracellular ridges on the larval cuticle. We further show that Obst-E is locally required for the oriented shape change of the cuticle during metamorphosis, which is associated with changes in the morphology of those ridges. Thus, Obst-E dramatically affects the body shape in a direct, physical manner by controlling the mechanical property of the exoskeleton. PMID- 28076348 TI - Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders. AB - Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs) in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies), we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (P = 0.02). We then screened genome-wide for interactors with RASopathy gene SNPs and showed strong enrichment in ASD-affected individuals (P < 2.2 x 10-16), with a number of pairwise interactions meeting genome-wide criteria for significance. Finally, we utilized quantitative measures of ASD symptoms in RASopathy-affected individuals to perform modifier mapping via GWAS. One top region overlapped between these independent approaches, and we showed dysregulation of a gene in this region, GPR141, in a RASopathy neural cell line. We thus used orthogonal approaches to provide strong evidence for a contribution of epistasis to ASDs, confirm a role for the Ras/MAPK pathway in idiopathic ASDs, and to identify a convergent candidate gene that may interact with the Ras/MAPK pathway. PMID- 28076350 TI - Emergence of Rare Species of Nontuberculous Mycobacteria as Potential Pathogens in Saudi Arabian Clinical Setting. AB - BACKGROUND: Clinical relevance of nontuberculous mycobacteria (NTM) is increasing worldwide including in Saudi Arabia. A high species diversity of NTM's has been noticed in a recent study. However, the identification in diagnostic laboratories is mostly limited to common species. The impact of NTM species diversity on clinical outcome is so far neglected in most of the clinical settings. METHODOLOGY/PRINCIPAL FINDINGS: During April 2014 to September 2015, a nationwide collection of suspected NTM clinical isolates with clinical and demographical data were carried out. Primary identification was performed by commercial line probe assays. Isolates identified up to Mycobacterium species level by line probe assays only were included and subjected to sequencing of 16S rRNA, rpoB, hsp65 and 16S-23S ITS region genes. The sequence data were subjected to BLAST analysis in GenBank and Ez-Taxon databases. Male Saudi nationals were dominated in the study population and falling majorly into the 46-59 years age group. Pulmonary cases were 59.3% with a surprising clinical relevance of 75% based on American Thoracic Society guidelines. Among the 40.7% extra-pulmonary cases, 50% of them were skin infections. The identification revealed 16 species and all of them are reporting for the first time in Saudi Arabia. The major species obtained were Mycobacterium monascence (18.5%), M. cosmeticum (11.1%), M. kubicae (11.1%), M. duvalli (7.4%), M.terrae (7.4%) and M. triplex (7.4%). This is the first report on clinical relevance of M. kubicae, M. tusciae, M.yongonense, M. arupense and M.iranicum causing pulmonary disease and M. monascence, M. duvalli, M. perigrinum, M. insubricum, M. holsaticum and M. kyorinense causing various extra pulmonary diseases in Saudi Arabia. Ascites caused by M. monascence and cecum infection by M. holsaticum were the rarest incidents. CONCLUSIONS/SIGNIFICANCE: To the first time in the country, clinical significance of various rare NTM's are well explored and the finding warrants a new threat to the Saudi Arabian clinical settings. PMID- 28076351 TI - Ultra-Fine Scale Spatially-Integrated Mapping of Habitat and Occupancy Using Structure-From-Motion. AB - Organisms respond to and often simultaneously modify their environment. While these interactions are apparent at the landscape extent, the driving mechanisms often occur at very fine spatial scales. Structure-from-Motion (SfM), a computer vision technique, allows the simultaneous mapping of organisms and fine scale habitat, and will greatly improve our understanding of habitat suitability, ecophysiology, and the bi-directional relationship between geomorphology and habitat use. SfM can be used to create high-resolution (centimeter-scale) three dimensional (3D) habitat models at low cost. These models can capture the abiotic conditions formed by terrain and simultaneously record the position of individual organisms within that terrain. While coloniality is common in seabird species, we have a poor understanding of the extent to which dense breeding aggregations are driven by fine-scale active aggregation or limited suitable habitat. We demonstrate the use of SfM for fine-scale habitat suitability by reconstructing the locations of nests in a gentoo penguin colony and fitting models that explicitly account for conspecific attraction. The resulting digital elevation models (DEMs) are used as covariates in an inhomogeneous hybrid point process model. We find that gentoo penguin nest site selection is a function of the topography of the landscape, but that nests are far more aggregated than would be expected based on terrain alone, suggesting a strong role of behavioral aggregation in driving coloniality in this species. This integrated mapping of organisms and fine scale habitat will greatly improve our understanding of fine scale habitat suitability, ecophysiology, and the complex bi-directional relationship between geomorphology and habitat use. PMID- 28076352 TI - High-Intensity Interval Training Elicits Higher Enjoyment than Moderate Intensity Continuous Exercise. AB - : Exercise adherence is affected by factors including perceptions of enjoyment, time availability, and intrinsic motivation. Approximately 50% of individuals withdraw from an exercise program within the first 6 mo of initiation, citing lack of time as a main influence. Time efficient exercise such as high intensity interval training (HIIT) may provide an alternative to moderate intensity continuous exercise (MICT) to elicit substantial health benefits. This study examined differences in enjoyment, affect, and perceived exertion between MICT and HIIT. Twelve recreationally active men and women (age = 29.5 +/- 10.7 yr, VO2max = 41.4 +/- 4.1 mL/kg/min, BMI = 23.1 +/- 2.1 kg/m2) initially performed a VO2max test on a cycle ergometer to determine appropriate workloads for subsequent exercise bouts. Each subject returned for two additional exercise trials, performing either HIIT (eight 1 min bouts of cycling at 85% maximal workload (Wmax) with 1 min of active recovery between bouts) or MICT (20 min of cycling at 45% Wmax) in randomized order. During exercise, rating of perceived exertion (RPE), affect, and blood lactate concentration (BLa) were measured. Additionally, the Physical Activity Enjoyment Scale (PACES) was completed after exercise. Results showed higher enjoyment (p = 0.013) in response to HIIT (103.8 +/- 9.4) versus MICT (84.2 +/- 19.1). Eleven of 12 participants (92%) preferred HIIT to MICT. However, affect was lower (p<0.05) and HR, RPE, and BLa were higher (p<0.05) in HIIT versus MICT. Although HIIT is more physically demanding than MICT, individuals report greater enjoyment due to its time efficiency and constantly changing stimulus. TRIAL REGISTRATION: NCT:02981667. PMID- 28076353 TI - A Topological Criterion for Filtering Information in Complex Brain Networks. AB - In many biological systems, the network of interactions between the elements can only be inferred from experimental measurements. In neuroscience, non-invasive imaging tools are extensively used to derive either structural or functional brain networks in-vivo. As a result of the inference process, we obtain a matrix of values corresponding to a fully connected and weighted network. To turn this into a useful sparse network, thresholding is typically adopted to cancel a percentage of the weakest connections. The structural properties of the resulting network depend on how much of the inferred connectivity is eventually retained. However, how to objectively fix this threshold is still an open issue. We introduce a criterion, the efficiency cost optimization (ECO), to select a threshold based on the optimization of the trade-off between the efficiency of a network and its wiring cost. We prove analytically and we confirm through numerical simulations that the connection density maximizing this trade-off emphasizes the intrinsic properties of a given network, while preserving its sparsity. Moreover, this density threshold can be determined a-priori, since the number of connections to filter only depends on the network size according to a power-law. We validate this result on several brain networks, from micro- to macro-scales, obtained with different imaging modalities. Finally, we test the potential of ECO in discriminating brain states with respect to alternative filtering methods. ECO advances our ability to analyze and compare biological networks, inferred from experimental data, in a fast and principled way. PMID- 28076354 TI - Where Have All the Giants Gone? How Animals Deal with the Problem of Size. AB - The survival of both the hunter and the hunted often comes down to speed. Yet how fast an animal can run is intricately linked to its size, such that the fastest animals are not the biggest nor the smallest. The ability to maintain high speeds is dependent on the body's capacity to withstand the high stresses involved with locomotion. Yet even when standing still, scaling principles would suggest that the mechanical stress an animal feels will increase in greater demand than its body can support. So if big animals want to be fast, they must find solutions to overcome these high stresses. This article explores the ways in which extant animals mitigate size-related increases in musculoskeletal stress in an effort to help understand where all the giants have gone. PMID- 28076355 TI - Multiple Choice Neurodynamical Model of the Uncertain Option Task. AB - The uncertain option task has been recently adopted to investigate the neural systems underlying the decision confidence. Latterly single neurons activity has been recorded in lateral intraparietal cortex of monkeys performing an uncertain option task, where the subject is allowed to opt for a small but sure reward instead of making a risky perceptual decision. We propose a multiple choice model implemented in a discrete attractors network. This model is able to reproduce both behavioral and neurophysiological experimental data and therefore provides support to the numerous perspectives that interpret the uncertain option task as a sensory-motor association. The model explains the behavioral and neural data recorded in monkeys as the result of the multistable attractor landscape and produces several testable predictions. One of these predictions may help distinguish our model from a recently proposed continuous attractor model. PMID- 28076356 TI - The Limitations of the GRE in Predicting Success in Biomedical Graduate School. AB - Historically, admissions committees for biomedical Ph.D. programs have heavily weighed GRE scores when considering applications for admission. The predictive validity of GRE scores on graduate student success is unclear, and there have been no recent investigations specifically on the relationship between general GRE scores and graduate student success in biomedical research. Data from Vanderbilt University Medical School's biomedical umbrella program were used to test to what extent GRE scores can predict outcomes in graduate school training when controlling for other admissions information. Overall, the GRE did not prove useful in predicating who will graduate with a Ph.D., pass the qualifying exam, have a shorter time to defense, deliver more conference presentations, publish more first author papers, or obtain an individual grant or fellowship. GRE scores were found to be moderate predictors of first semester grades, and weak to moderate predictors of graduate GPA and some elements of a faculty evaluation. These findings suggest admissions committees of biomedical doctoral programs should consider minimizing their reliance on GRE scores to predict the important measures of progress in the program and student productivity. PMID- 28076357 TI - Soil, Leaf and Root Ecological Stoichiometry of Caragana korshinskii on the Loess Plateau of China in Relation to Plantation Age. AB - Caragana korshinskii, a leguminous shrub, a common specie, is widely planted to prevent soil erosion on the Loess Plateau. The objective of this study was to determine how the plantation ages affected soil, leaf and root nutrients and ecological stoichiometry. The chronosequence ages of C. korshinskii plantations selected for this study were 10, 20 and 30 years. Soil organic carbon (SOC) and soil total nitrogen (STN) of C. korshinskii plantations significantly increased with increase in the chronosequence age. However, soil total phosphorous (STP) was not affected by the chronosequence age. The soil C: N ratio decreased and the soil C: P and N: P ratios increased with increasing plantation age. The leaf and root concentrations of C, N, and P increased and the ratios C: N, C: P, and N: P decreased with age increase. Leaf N: P ratios were >20, indicating that P was the main factor limiting the growth of C. korshinskii. This study also demonstrated that the regeneration of natural grassland (NG) effectively preserved and enhanced soil nutrient contents. Compared with NG, shrub lands (C. korshinskii) had much lower soil nutrient concentrations, especially for long (>20 years) chronosequence age. Thus, the regeneration of natural grassland is an ecologically beneficial practice for the recovery of degraded soils in this area. PMID- 28076358 TI - A Randomized Trial Examining Housing First in Congregate and Scattered Site Formats. AB - OBJECTIVE: No previous experimental trials have investigated Housing First (HF) in both scattered site (SHF) and congregate (CHF) formats. We hypothesized that CHF and SHF would be associated with a greater percentage of time stably housed as well as superior health and psychosocial outcomes over 24 months compared to treatment as usual (TAU). METHODS: Inclusion criteria were homelessness, mental illness, and high need for support. Participants were randomised to SHF, CHF, or TAU. SHF consisted of market rental apartments with support provided by Assertive Community Treatment (ACT). CHF consisted of a single building with supports equivalent to ACT. TAU included existing services and supports. RESULTS: Of 800 people screened, 297 were randomly assigned to CHF (107), SHF (90), or TAU (100). The percentage of time in stable housing over 24 months was 26.3% in TAU (reference; 95% confidence interval (CI) = 20.5, 32.0), compared to 74.3% in CHF (95% CI = 69.3, 79.3, p<0.001) and 74.5% in SHF (95% CI = 69.2, 79.7, p<0.001). Secondary outcomes favoured CHF but not SHF compared to TAU. CONCLUSION: HF in scattered and congregate formats is capable of achieving housing stability among people experiencing major mental illness and chronic homelessness. Only CHF was associated with improvement on select secondary outcomes. REGISTRATION: Current Controlled Trials: ISRCTN57595077. PMID- 28076359 TI - Environmental Factors Affecting Survival of Immature Ixodes scapularis and Implications for Geographical Distribution of Lyme Disease: The Climate/Behavior Hypothesis. AB - Recent reports suggest that host-seeking nymphs in southern populations of Ixodes scapularis remain below the leaf litter surface, while northern nymphs seek hosts on leaves and twigs above the litter surface. This behavioral difference potentially results in decreased tick contact with humans in the south, and fewer cases of Lyme disease. We studied whether north-south differences in tick survival patterns might contribute to this phenomenon. Four month old larvae resulting from a cross between Wisconsin males and South Carolina females died faster under southern than under northern conditions in the lab, as has previously been reported for ticks from both northern and southern populations. However, newly-emerged larvae from Rhode Island parents did not differ consistently in mortality under northern and southern conditions, possibly because of their younger age. Survival is lower, and so the north-south survival difference might be greater in older ticks. Larval survival was positively related to larval size (as measured by scutal area), while survival was positively related to larval fat content in some, but not all, trials. The difference in larval survival under northern vs. southern conditions might simply result from faster metabolism under warmer southern conditions leading to shorter life spans. However, ticks consistently died faster under southern than under northern conditions in the laboratory when relative humidity was low (75%), but not under moderate (85%) or high (95%) RH. Therefore, mortality due to desiccation stress is greater under southern than under northern conditions. We hypothesize that mortality resulting from the greater desiccation stress under southern conditions acts as a selective pressure resulting in the evolution of host-seeking behavior in which immatures remain below the leaf litter surface in southern I. scapularis populations, so as to avoid the desiccating conditions at the surface. If this hypothesis is correct, it has implications for the effect of climate change on the future distribution of Lyme disease. PMID- 28076360 TI - Consequences of Global Warming of 1.5 degrees C and 2 degrees C for Regional Temperature and Precipitation Changes in the Contiguous United States. AB - The differential warming of land and ocean leads to many continental regions in the Northern Hemisphere warming at rates higher than the global mean temperature. Adaptation and conservation efforts will, therefore, benefit from understanding regional consequences of limiting the global mean temperature increase to well below 2 degrees C above pre-industrial levels, a limit agreed upon at the United Nations Climate Summit in Paris in December 2015. Here, we analyze climate model simulations from the Coupled Model Intercomparison Project Phase 5 (CMIP5) to determine the timing and magnitude of regional temperature and precipitation changes across the contiguous United States (US) for global warming of 1.5 and 2 degrees C and highlight consensus and uncertainties in model projections and their implications for making decisions. The regional warming rates differ considerably across the contiguous US, but all regions are projected to reach 2 degrees C about 10-20 years before the global mean temperature. Although there is uncertainty in the timing of exactly when the 1.5 and 2 degrees C thresholds will be crossed regionally, over 80% of the models project at least 2 degrees C warming by 2050 for all regions for the high emissions scenario. This threshold based approach also highlights regional variations in the rate of warming across the US. The fastest warming region in the contiguous US is the Northeast, which is projected to warm by 3 degrees C when global warming reaches 2 degrees C. The signal-to-noise ratio calculations indicate that the regional warming estimates remain outside the envelope of uncertainty throughout the twenty-first century, making them potentially useful to planners. The regional precipitation projections for global warming of 1.5 degrees C and 2 degrees C are uncertain, but the eastern US is projected to experience wetter winters and the Great Plains and the Northwest US are projected to experience drier summers in the future. The impact of different scenarios on regional precipitation projections is negligible throughout the twenty-first century compared to uncertainties associated with internal variability and model diversity. PMID- 28076361 TI - Synergy and Order Effects of Antibiotics and Phages in Killing Pseudomonas aeruginosa Biofilms. AB - In contrast to planktonic cells, bacteria imbedded biofilms are notoriously refractory to treatment by antibiotics or bacteriophage (phage) used alone. Given that the mechanisms of killing differ profoundly between drugs and phages, an obvious question is whether killing is improved by combining antibiotic and phage therapy. However, this question has only recently begun to be explored. Here, in vitro biofilm populations of Pseudomonas aeruginosa PA14 were treated singly and with combinations of two phages and bactericidal antibiotics of five classes. By themselves, phages and drugs commonly had only modest effects in killing the bacteria. However some phage-drug combinations reduced bacterial densities to well below that of the best single treatment; in some cases, bacterial densities were reduced even below the level expected if both agents killed independently of each other (synergy). Furthermore, there was a profound order effect in some cases: treatment with phages before drugs achieved maximum killing. Combined treatment was particularly effective in killing in Pseudomonas biofilms grown on layers of cultured epithelial cells. Phages were also capable of limiting the extent to which minority populations of bacteria resistant to the treating antibiotic ascend. The potential of combined antibiotic and phage treatment of biofilm infections is discussed as a realistic way to evaluate and establish the use of bacteriophage for the treatment of humans. PMID- 28076362 TI - Temporal Dependency and the Structure of Early Looking. AB - Although looking time is used to assess infant perceptual and cognitive processing, little is known about the temporal structure of infant looking. To shed light on this temporal structure, 127 three-month-olds were assessed in an infant-controlled habituation procedure and presented with a pre-recorded display of a woman addressing the infant using infant-directed speech. Previous individual look durations positively predicted subsequent look durations over a six look window, suggesting a temporal dependency between successive infant looks. The previous look duration continued to predict the subsequent look duration after accounting for habituation-linked declines in look duration, and when looks were separated by an inter-trial interval in which no stimulus was displayed. Individual differences in temporal dependency, the strength of associations between consecutive look durations, are distinct from individual differences in mean infant look duration. Nevertheless, infants with stronger temporal dependency had briefer mean look durations, a potential index of stimulus processing. Temporal dependency was evident not only between individual infant looks but between the durations of successive habituation trials (total looking within a trial). Finally, temporal dependency was evident in associations between the last look at the habituation stimulus and the first look at a novel test stimulus. Thus temporal dependency was evident across multiple timescales (individual looks and trials comprised of multiple individual looks) and persisted across conditions including brief periods of no stimulus presentation and changes from a familiar to novel stimulus. Associations between consecutive look durations over multiple timescales and stimuli suggest a temporal structure of infant attention that has been largely ignored in previous work on infant looking. PMID- 28076363 TI - Effects of Loading Duration and Short Rest Insertion on Cancellous and Cortical Bone Adaptation in the Mouse Tibia. AB - The skeleton's osteogenic response to mechanical loading can be affected by loading duration and rest insertion during a series of loading events. Prior animal loading studies have shown that the cortical bone response saturates quickly and short rest insertions between load cycles can enhance cortical bone formation. However, it remains unknown how loading duration and short rest insertion affect load-induced osteogenesis in the mouse tibial compressive loading model, and particularly in cancellous bone. To address this issue, we applied cyclic loading (-9 N peak load; 4 Hz) to the tibiae of three groups of 16 week-old female C57BL/6 mice for two weeks, with a different number of continuous load cycles applied daily to each group (36, 216 and 1200). A fourth group was loaded under 216 daily load cycles with a 10 s rest insertion after every fourth cycle. We found that as few as 36 load cycles per day were able to induce osteogenic responses in both cancellous and cortical bone. Furthermore, while cortical bone area and thickness continued to increase through 1200 cycles, the incremental increase in the osteogenic response decreased as load number increased, indicating a reduced benefit of the increasing number of load cycles. In the proximal metaphyseal cancellous bone, trabecular thickness increased with load up to 216 cycles. We also found that insertion of a 10 s rest between load cycles did not improve the osteogenic response of the cortical or cancellous tissues compared to continuous loading in this model given the age and sex of the mice and the loading parameters used here. These results suggest that relatively few load cycles (e.g. 36) are sufficient to induce osteogenic responses in both cortical and cancellous bone in the mouse tibial loading model. Mechanistic studies using the mouse tibial loading model to examine bone formation and skeletal mechanobiology could be accomplished with relatively few load cycles. PMID- 28076364 TI - IFNgamma Regulates Activated Vdelta2+ T Cells through a Feedback Mechanism Mediated by Mesenchymal Stem Cells. AB - gammadelta T cells play a role in a wide range of diseases such as autoimmunity and cancer. The majority of circulating human gammadelta T lymphocytes express a Vgamma9Vdelta2+ (Vdelta2+) T cell receptor (TCR) and following activation release pro-inflammatory cytokines. In this study, we show that IFNgamma, produced by Vdelta2+ cells, activates mesenchymal stem cell (MSC)-mediated immunosupression, which in turn exerts a negative feedback mechanism on gammadelta T cell function ranging from cytokine production to proliferation. Importantly, this modulatory effect is limited to a short period of time (<24 hours) post-T cell activation, after which MSCs can no longer exert their immunoregulatory capacity. Using genetically modified MSCs with the IFNgamma receptor 1 constitutively silenced, we demonstrate that IFNgamma is essential to this process. Activated gammadelta T cells induce expression of several factors by MSCs that participate in the depletion of amino acids. In particular, we show that indolamine 2,3-dioxygenase (IDO), an enzyme involved in L-tryptophan degradation, is responsible for MSC mediated immunosuppression of Vdelta2+ T cells. Thus, our data demonstrate that gammadelta T cell responses can be immuno-modulated by different signals derived from MSC. PMID- 28076365 TI - Gene Expression Profiling in Slow-Type Calf Soleus Muscle of 30 Days Space-Flown Mice. AB - Microgravity exposure as well as chronic disuse are two main causes of skeletal muscle atrophy in animals and humans. The antigravity calf soleus is a reference postural muscle to investigate the mechanism of disuse-induced maladaptation and plasticity of human and rodent (rats or mice) skeletal musculature. Here, we report microgravity-induced global gene expression changes in space-flown mouse skeletal muscle and the identification of yet unknown disuse susceptible transcripts found in soleus (a mainly slow phenotype) but not in extensor digitorum longus (a mainly fast phenotype dorsiflexor as functional counterpart to soleus). Adult C57Bl/N6 male mice (n = 5) flew aboard a biosatellite for 30 days on orbit (BION-M1 mission, 2013), a sex and age-matched cohort were housed in standard vivarium cages (n = 5), or in a replicate flight habitat as ground control (n = 5). Next to disuse atrophy signs (reduced size and myofiber phenotype I to II type shift) as much as 680 differentially expressed genes were found in the space-flown soleus, and only 72 in extensor digitorum longus (only 24 genes in common) compared to ground controls. Altered expression of gene transcripts matched key biological processes (contractile machinery, calcium homeostasis, muscle development, cell metabolism, inflammatory and oxidative stress response). Some transcripts (Fzd9, Casq2, Kcnma1, Ppara, Myf6) were further validated by quantitative real-time PCR (qRT-PCR). Besides previous reports on other leg muscle types we put forth for the first time a complete set of microgravity susceptible gene transcripts in soleus of mice as promising new biomarkers or targets for optimization of physical countermeasures and rehabilitation protocols to overcome disuse atrophy conditions in different clinical settings, rehabilitation and spaceflight. PMID- 28076366 TI - Plum Fruit Development Occurs via Gibberellin-Sensitive and -Insensitive DELLA Repressors. AB - Fruit growth depends on highly coordinated hormonal activities. The phytohormone gibberellin (GA) promotes growth by triggering degradation of the growth repressing DELLA proteins; however, the extent to which such proteins contribute to GA-mediated fruit development remains to be clarified. Three new plum genes encoding DELLA proteins, PslGAI, PslRGL and PslRGA were isolated and functionally characterized. Analysis of expression profile during fruit development suggested that PslDELLA are transcriptionally regulated during flower and fruit ontogeny with potential positive regulation by GA and ethylene, depending on organ and developmental stage. PslGAI and PslRGL deduced proteins contain all domains present in typical DELLA proteins. However, PslRGA exhibited a degenerated DELLA domain and subsequently lacks in GID1-DELLA interaction property. PslDELLA overexpression in WT Arabidopsis caused dramatic disruption in overall growth including root length, stem elongation, plant architecture, flower structure, fertility, and considerable retardation in development due to dramatic distortion in GA-metabolic pathway. GA treatment enhanced PslGAI/PslRGL interaction with PslGID1 receptors, causing protein destabilization and relief of growth restraining effect. By contrast, PslRGA protein was not degraded by GA due to its inability to interact with PslGID1. Relative to other PslDELLA-mutants, PslRGA plants displayed stronger constitutive repressive growth that was irreversible by GA application. The present results describe additional complexities in GA signalling during plum fruit development, which may be particularly important to optimize successful reproductive growth. PMID- 28076367 TI - A Chemogenomic Screen Reveals Novel Snf1p/AMPK Independent Regulators of Acetyl CoA Carboxylase. AB - Acetyl-CoA carboxylase (Acc1p) is a key enzyme in fatty acid biosynthesis and is essential for cell viability. To discover new regulators of its activity, we screened a Saccharomyces cerevisiae deletion library for increased sensitivity to soraphen A, a potent Acc1p inhibitor. The hits identified in the screen (118 hits) were filtered using a chemical-phenotype map to exclude those associated with pleiotropic drug resistance. This enabled the identification of 82 ORFs that are genetic interactors of Acc1p. The main functional clusters represented by these hits were "transcriptional regulation", "protein post-translational modifications" and "lipid metabolism". Further investigation of the "transcriptional regulation" cluster revealed that soraphen A sensitivity is poorly correlated with ACC1 transcript levels. We also studied the three top unknown ORFs that affected soraphen A sensitivity: SOR1 (YDL129W), SOR2 (YIL092W) and SOR3 (YJR039W). Since the C18/C16 ratio of lipid acyl lengths reflects Acc1p activity levels, we evaluated this ratio in the three mutants. Deletion of SOR2 and SOR3 led to reduced acyl lengths, suggesting that Acc1p is indeed down regulated in these strains. Also, these mutants showed no differences in Snf1p/AMPK activation status and deletion of SNF1 in these backgrounds did not revert soraphen A sensitivity completely. Furthermore, plasmid maintenance was reduced in sor2Delta strain and this trait was shared with 18 other soraphen A sensitive hits. In summary, our screen uncovered novel Acc1p Snf1p/AMPK independent regulators. PMID- 28076368 TI - Functional Laterality of Task-Evoked Activation in Sensorimotor Cortex of Preterm Infants: An Optimized 3 T fMRI Study Employing a Customized Neonatal Head Coil. AB - BACKGROUND: Functional magnetic resonance imaging (fMRI) in neonates has been introduced as a non-invasive method for studying sensorimotor processing in the developing brain. However, previous neonatal studies have delivered conflicting results regarding localization, lateralization, and directionality of blood oxygenation level dependent (BOLD) responses in sensorimotor cortex (SMC). Amongst the confounding factors in interpreting neonatal fMRI studies include the use of standard adult MR-coils providing insufficient signal to noise, and liberal statistical thresholds, compromising clinical interpretation at the single subject level. PATIENTS / METHODS: Here, we employed a custom-designed neonatal MR-coil adapted and optimized to the head size of a newborn in order to improve robustness, reliability and validity of neonatal sensorimotor fMRI. Thirteen preterm infants with a median gestational age of 26 weeks were scanned at term-corrected age using a prototype 8-channel neonatal head coil at 3T (Achieva, Philips, Best, NL). Sensorimotor stimulation was elicited by passive extension/flexion of the elbow at 1 Hz in a block design. Analysis of temporal signal to noise ratio (tSNR) was performed on the whole brain and the SMC, and was compared to data acquired with an 'adult' 8 channel head coil published previously. Task-evoked activation was determined by single-subject SPM8 analyses, thresholded at p < 0.05, whole-brain FWE-corrected. RESULTS: Using a custom-designed neonatal MR-coil, we found significant positive BOLD responses in contralateral SMC after unilateral passive sensorimotor stimulation in all neonates (analyses restricted to artifact-free data sets = 8/13). Improved imaging characteristics of the neonatal MR-coil were evidenced by additional phantom and in vivo tSNR measurements: phantom studies revealed a 240% global increase in tSNR; in vivo studies revealed a 73% global and a 55% local (SMC) increase in tSNR, as compared to the 'adult' MR-coil. CONCLUSIONS: Our findings strengthen the importance of using optimized coil settings for neonatal fMRI, yielding robust and reproducible SMC activation at the single subject level. We conclude that functional lateralization of SMC activation, as found in children and adults, is already present in the newborn period. PMID- 28076369 TI - Novel Inflammation-Based Prognostic Score for Predicting Survival in Patients with Metastatic Urothelial Carcinoma. AB - PURPOSE: We developed a novel inflammation-based model (NPS), which consisted of a neutrophil to lymphocyte ratio (NLR) and platelet count (PC), for assessing the prognostic role in patients with metastatic urothelial carcinoma (UC). MATERIALS AND METHODS: We performed a retrospective analysis of patients with metastatic UC who underwent systemic chemotherapy between January 1997 and December 2014 in Kaohsiung Chang Gung Memorial Hospital. The defined cutoff values for the NLR and PC were 3.0 and 400 * 103/MUL, respectively. Patients were scored 1 for either an elevated NLR or PC, and 0 otherwise. The NPS was calculated by summing the scores, ranging from 0 to 2. The primary endpoint was overall survival (OS) by using Kaplan-Meier analysis. Multivariate Cox regression analysis was used to identify the independent prognostic factors for OS. RESULTS: In total, 256 metastatic UC patients were enrolled. Univariate analysis revealed that patients with either a high NLR or PC had a significantly shorter survival rate compared with those with a low NLR (P = .001) or PC (P < .0001). The median OS in patients with NPS 0, 1, and 2 was 19.0, 12.8, and 9.3 months, respectively (P < .0001). Multivariate analysis revealed that NPS, along with the histologic variant, liver metastasis, age, and white cell count, was an independent factor facilitating OS prediction (hazard ratio 1.64, 95% confidence interval 1.20-2.24, P = .002). CONCLUSION: The NLR and PC are independent prognostic factors for OS in patients with metastatic UC. The NPS model has excellent discriminant ability for OS. PMID- 28076370 TI - Dizziness and Falls in Obese Inpatients Undergoing Metabolic Rehabilitation. AB - AIM: The relationship between dizziness and falls in the obese population is a relatively unexplored issue. The aims of the present study were to define the 1 year prevalence of dizziness in an obese inpatient population undergoing metabolic rehabilitation and to investigate possible correlations with fall events. MATERIALS AND METHODS: We recruited 329 obese subjects: 203 female (BMI 43,74 kg/m2 +/- 0.5 SE; age 17-83 years, 58.33 +/- 0.9 SE) and 126 male (BMI 44,27kg/m2 +/- 0.7 DE age 27-79 years, 58.84 +/- 1 SE). To assess dizziness we used the validated Italian version (38) of the Dizziness Handicap Inventory (DHI). RESULTS: Out of the experimental sample, 100 subjects did not complain of dizziness and felt confident about their balance control, while 69.6% reported some degree of dizziness. Their mean DHI score was 22.3, which corresponds to mild dizziness. Twenty-one percent reported more severe dizziness (DHI score > 40). The majority of our sample reported minor dizziness and its perception appears to be independent from BMI: DHI scores were consistent across classes of obesity. DISCUSSION: The rate of dizziness and falls (30.1%) in an this obese population was higher than that previously reported in a general matched population. However, obese subjects, in our sample, seem to underestimate their risk of fall and DHI score does not appear a reliable predictor of falls. Since complications associated with falls in obese persons generally require longer treatments than in lean individuals, our findings should be taken into account in order to identify other predictors, including cognitive and perceptual, of risk of fall and to implement fall prevention programs. PMID- 28076371 TI - Meta-Analysis of the Long Term Success Rate of Different Interventions in Benign Biliary Strictures. AB - BACKGROUND: Benign biliary stricture is a rare condition and the majority of the cases are caused by operative trauma or chronic inflammation based on various etiology. Although the initial results of endoscopic, percutaneous and surgical treatment are impressive, no comparison about long term stricture resolution is available. AIMS: The goal of this study was to compare the long term disease free survival in benign biliary strictures with various etiology after surgery, percutaneous transhepatic-and endoscopic treatment. METHODS: PubMed, Embase, and Cochrane Library were searched by computer and manually for published studies. The investigators selected the publications according to the inclusion and exclusion criteria, processed the data and assessed the quality of the selected studies. Meta-analysis of data of 24 publications was performed to compare long term disease free survival of different treatment groups. RESULTS: Compared the subgroups surgery resulted in the highest long term stricture resolution rate, followed by the percutaneous transhepatic treatment, the multiple plastic stent insertion and covered self-expanding metal stents (SEMS), however the difference was not significant. All compared methods are significantly superior to the single plastic stent placement. Long term stricture resolution rate irrespectively of any therapy is still not more than 84%. CONCLUSIONS: In summary, the use of single plastic stent is not recommended. Further randomized studies and innovative technical development are required for improving the treatment of benign biliary strictures. PMID- 28076372 TI - Bad to the Bone: On In Vitro and Ex Vivo Microbial Biofilm Ability to Directly Destroy Colonized Bone Surfaces without Participation of Host Immunity or Osteoclastogenesis. AB - Bone infections are a significant public health burden associated with morbidity and mortality in patients. Microbial biofilm pathogens are the causative agents in chronic osteomyelitis. Research on the pathogenesis of osteomyelitis has focused on indirect bone destruction by host immune cells and cytokines secondary to microbial insult. Direct bone resorption by biofilm pathogens has not yet been seriously considered. In this study, common osteomyelitis pathogens (Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Streptococcus mutans) were grown as biofilms in multiple in vitro and ex vivo experiments to analyze quantitative and qualitative aspects of bone destruction during infection. Pathogens were grown as single or mixed species biofilms on the following substrates: hydroxyapatite, rat jawbone, or polystyrene wells, and in various media. Biofilm growth was evaluated by scanning electron microscopy and pH levels were monitored over time. Histomorphologic and quantitative effects of biofilms on tested substrates were analyzed by microcomputed tomography and quantitative cultures. All tested biofilms demonstrated significant damage to bone. Scanning electron microscopy indicated that all strains formed mature biofilms within 7 days on all substrate surfaces regardless of media. Experimental conditions impacted pH levels, although this had no impact on biofilm growth or bone destruction. Presence of biofilm led to bone dissolution with a decrease of total volume by 20.17+/-2.93% upon microcomputed tomography analysis, which was statistically significant as compared to controls (p <0.05, ANOVA). Quantitative cultures indicated that media and substrate did not impact biofilm formation (Kruskall-Wallis test, post-hoc Dunne's test; p <0.05). Overall, these results indicate that biofilms associated with osteomyelitis have the ability to directly resorb bone. These findings should lead to a more complete understanding of the etiopathogenesis of osteomyelitis, where direct bone resorption by biofilm is considered in addition to the well-known osteoclastic and host cell destruction of bone. PMID- 28076373 TI - Larvae and Nests of Aculeate Hymenoptera (Hymenoptera: Aculeata) Nesting in Reed Galls Induced by Lipara spp. (Diptera: Chloropidae) with a Review of Species Recorded. Part II. AB - The ability of aculeate Hymenoptera to utilize wetlands is poorly understood, and descriptions of their nests and developmental stages are largely absent. Here we present results based on our survey of hymenopterans using galls induced by Lipara spp. flies on common reed Phragmites australis in the years 2015-2016. We studied 20,704 galls, of which 9,446 were longitudinally cut and the brood from them reared in the laboratory, while the remaining 11,258 galls reared in rearing bags also in laboratory conditions. We recorded eight species that were previously not known to nest in reed galls: cuckoo wasps Chrysis rutilans and Trichrysis pumilionis, solitary wasps Stenodynerus chevrieranus and Stenodynerus clypeopictus, and bees Pseudoanthidium tenellum, Stelis punctulatissima, Hylaeus communis and Hylaeus confusus. Forty five species of Hymenoptera: Aculeata are known to be associated with reed galls, of which 36 make their nests there, and the other are six parasitoids of the family Chrysididae and three cuckoo bees of the genus Stelis. Of these species, Pemphredon fabricii and in southern Europe also Heriades rubicola are very common in reed galls, followed by Hylaeus pectoralis and two species of the genus Trypoxylon. We also found new host parasite associations: Chrysis angustula in nests of Pemphredon fabricii, Chrysis rutilans in nests of Stenodynerus clypeopictus, Trichrysis pumilionis in nests of Trypoxylon deceptorium, and Stelis breviuscula in nests of Heriades rubicola. We provide new descriptions of the nests of seven species nesting in reed galls and morphology of mature larvae of eight species nesting in reed galls and two parasitoids and one nest cleptoparasite. The larvae are usually very similar to those of related species but possess characteristics that make them easy to distinguish from related species. Our results show that common reeds are not only expansive and harmful, but very important for many insect species associated with habitats dominated by this plant species. PMID- 28076374 TI - A Burgeoning Crisis? A Nationwide Assessment of the Geography of Water Affordability in the United States. AB - While basic access to clean water is critical, another important issue is the affordability of water access for people around the globe. Prior international work has highlighted that a large proportion of consumers could not afford water if priced at full cost recovery levels. Given growing concern about affordability issues due to rising water rates, and a comparative lack of work on affordability in the developed world, as compared to the developing world, more work is needed in developed countries to understand the extent of this issue in terms of the number of households and persons impacted. To address this need, this paper assesses potential affordability issues for households in the United States using the U.S. EPA's 4.5% affordability criteria for combined water and wastewater services. Analytical results from this paper highlight high-risk and at-risk households for water poverty or unaffordable water services. Many of these households are clustered in pockets of water poverty within counties, which is a concern for individual utility providers servicing a large proportion of customers with a financial inability to pay for water services. Results also highlight that while water rates remain comparatively affordable for many U.S. households, this trend will not continue in the future. If water rates rise at projected amounts over the next five years, conservative projections estimate that the percentage of U.S. households who will find water bills unaffordable could triple from 11.9% to 35.6%. This is a concern due to the cascading economic impacts associated with widespread affordability issues; these issues mean that utility providers could have fewer customers over which to spread the large fixed costs of water service. Unaffordable water bills also impact customers for whom water services are affordable via higher water rates to recover the costs of services that go unpaid by lower income households. PMID- 28076375 TI - SensibleSleep: A Bayesian Model for Learning Sleep Patterns from Smartphone Events. AB - We propose a Bayesian model for extracting sleep patterns from smartphone events. Our method is able to identify individuals' daily sleep periods and their evolution over time, and provides an estimation of the probability of sleep and wake transitions. The model is fitted to more than 400 participants from two different datasets, and we verify the results against ground truth from dedicated armband sleep trackers. We show that the model is able to produce reliable sleep estimates with an accuracy of 0.89, both at the individual and at the collective level. Moreover the Bayesian model is able to quantify uncertainty and encode prior knowledge about sleep patterns. Compared with existing smartphone-based systems, our method requires only screen on/off events, and is therefore much less intrusive in terms of privacy and more battery-efficient. PMID- 28076376 TI - Increased Natural Killer Cell Activation in HIV-Infected Immunologic Non Responders Correlates with CD4+ T Cell Recovery after Antiretroviral Therapy and Viral Suppression. AB - The role of natural killer (NK) cell function in HIV disease especially in the setting of long-term antiretroviral therapy (ART) and viral suppression is not fully understood. In the current study, we have investigated NK cell activation in healthy controls and aviremic ART-treated HIV+ subjects with different degrees of immune restoration. We performed a cross sectional study in 12 healthy controls and 24 aviremic ART-treated HIV-infected subjects including 13 HIV+ subjects with CD4+ T cells above 500 cells/MUL defined as "immunologic responders" and 11 HIV+ subjects with CD4+ T cells below 350 cells/MUL defined as "immunologic non-responders". We analyzed NK cell number, subset, and activation by expression of CD107a and NKG2D and co-expression of CD38 and HLA-DR. NK cell mediated cytotoxicity against uninfected CD4+ T cells was tested in vitro. We found that NK cell absolute number, percentage of NK cells, and percentage of NK cell subsets were similar in the three study groups. The increased NK cell activation was found predominantly in CD56dimCD16+ subset of immunologic non responders but not immunologic responders compared to healthy controls. The activation of NK cells was inversely correlated with the peripheral CD4+ T cell count in HIV+ subjects, even after controlling for chronic T cell activation, sex, and age, potential contributors for CD4+ T cell counts in HIV disease. Interestingly, NK cells from immunologic non-responders mediated cytotoxicity against uninfected CD4+ T cells ex vivo. NK cells may play a role in blunted CD4+ T cell recovery in ART-treated HIV disease. PMID- 28076377 TI - Comparative Analysis of Vertebrate Diurnal/Circadian Transcriptomes. AB - From photosynthetic bacteria to mammals, the circadian clock evolved to track diurnal rhythms and enable organisms to anticipate daily recurring changes such as temperature and light. It orchestrates a broad spectrum of physiology such as the sleep/wake and eating/fasting cycles. While we have made tremendous advances in our understanding of the molecular details of the circadian clock mechanism and how it is synchronized with the environment, we still have rudimentary knowledge regarding its connection to help regulate diurnal physiology. One potential reason is the sheer size of the output network. Diurnal/circadian transcriptomic studies are reporting that around 10% of the expressed genome is rhythmically controlled. Zebrafish is an important model system for the study of the core circadian mechanism in vertebrate. As Zebrafish share more than 70% of its genes with human, it could also be an additional model in addition to rodent for exploring the diurnal/circadian output with potential for translational relevance. Here we performed comparative diurnal/circadian transcriptome analysis with established mouse liver and other tissue datasets. First, by combining liver tissue sampling in a 48h time series, transcription profiling using oligonucleotide arrays and bioinformatics analysis, we profiled rhythmic transcripts and identified 2609 rhythmic genes. The comparative analysis revealed interesting features of the output network regarding number of rhythmic genes, proportion of tissue specific genes and the extent of transcription factor family expression. Undoubtedly, the Zebrafish model system will help identify new vertebrate outputs and their regulators and provides leads for further characterization of the diurnal cis-regulatory network. PMID- 28076378 TI - p62 Pathology Model in the Rat Substantia Nigra with Filamentous Inclusions and Progressive Neurodegeneration. AB - One of the proteins most frequently found in neuropathological lesions is the ubiquitin binding protein p62 (sequestosome 1). Post-mortem analysis of p62 is a defining diagnostic marker in several neurodegenerative diseases including amyotrophic lateral sclerosis and inclusion body myositis. Since p62 functions in protein degradation pathways including autophagy, the build-up of p62-positive inclusions suggests defects in protein clearance. p62 was expressed unilaterally in the rat substantia nigra with an adeno-associated virus vector (AAV9) in order to study p62 neuropathology. Inclusions formed within neurons from several days to several weeks after gene transfer. By electron microscopy, the inclusions were found to contain packed 10 nm thick filaments, and mitochondria cristae structure was disrupted, resulting in the formation of empty spaces. In corollary cell culture transfections, p62 clearly impaired mitochondrial function. To probe for potential effects on macroautophagy, we co-expressed p62 with a double fluorescent tagged reporter for the autophagosome protein LC3 in the rat. p62 induced a dramatic and specific dissociation of the two tags. By 12 weeks, a rotational behavior phenotype manifested, consistent with a significant loss of dopaminergic neurons analyzed post-mortem. p62 overexpression resulted in a progressive and robust pathology model with neuronal inclusions and neurodegeneration. p62 gene transfer could be a novel methodological probe to disrupt mitochondrial function or autophagy in the brain and other tissues in vivo. PMID- 28076379 TI - Upregulation of Far Upstream Element-Binding Protein 1 (FUBP1) Promotes Tumor Proliferation and Tumorigenesis of Clear Cell Renal Cell Carcinoma. AB - OBJECTIVE: The far upstream element (FUSE)-binding protein 1 (FUBP1) is a transactivator of human c-myc proto-oncogene transcription, with important roles in carcinogenesis. However, the expression pattern and potential biological function of FUBP1 in clear cell renal cell carcinoma (ccRCC) is yet to be established. METHODS: FUBP1 expression was detected in ccRCC tissues and cell lines by real-time RT-PCR, Western blot analysis, and immunohistochemistry. The correlations of FUBP1 mRNA expression levels with clinicopathological factors were evaluated. The biological function of FUBP1 during tumor cell proliferation was studied by MTS, colony formation, and soft-agar colony formation. The effects of FUBP1 on cell cycle distribution and apoptosis were analyzed by flow cytometry. Western blot analysis was used to identify the potential mechanism of FUBP1 regulating cell cycle and apoptosis. RESULTS: The levels of FUBP1 mRNA and protein expression were upregulated in human ccRCC tissues compared with adjacent noncancerous tissues. High levels of FUBP1 mRNA expression were associated with higher tumor stage and tumor size. FUBP1 knockdown inhibited cell proliferation and induced cell cycle arrest and apoptosis. Meanwhile, the expression levels of c-myc and p21 mRNA were correlated with that of FUBP1 mRNA. CONCLUSIONS: FUBP1 acts as a potential oncogene in ccRCC and may be considered as a novel biomarker or an attractive treatment target of ccRCC. PMID- 28076380 TI - A Device-Independent Evaluation of Carbonyl Emissions from Heated Electronic Cigarette Solvents. AB - OBJECTIVES: To investigate how the two main electronic (e-) cigarette solvents propylene glycol (PG) and glycerol (GL)-modulate the formation of toxic volatile carbonyl compounds under precisely controlled temperatures in the absence of nicotine and flavor additives. METHODS: PG, GL, PG:GL = 1:1 (wt/wt) mixture, and two commercial e-cigarette liquids were vaporized in a stainless steel, tubular reactor in flowing air ranging up to 318 degrees C to simulate e-cigarette vaping. Aerosols were collected and analyzed to quantify the amount of volatile carbonyls produced with each of the five e-liquids. RESULTS: Significant amounts of formaldehyde and acetaldehyde were detected at reactor temperatures >=215 degrees C for both PG and GL. Acrolein was observed only in e-liquids containing GL when reactor temperatures exceeded 270 degrees C. At 318 degrees C, 2.03+/ 0.80 MUg of formaldehyde, 2.35+/-0.87 MUg of acetaldehyde, and a trace amount of acetone were generated per milligram of PG; at the same temperature, 21.1+/-3.80 MUg of formaldehyde, 2.40+/-0.99 MUg of acetaldehyde, and 0.80+/-0.50 MUg of acrolein were detected per milligram of GL. CONCLUSIONS: We developed a device independent test method to investigate carbonyl emissions from different e cigarette liquids under precisely controlled temperatures. PG and GL were identified to be the main sources of toxic carbonyl compounds from e-cigarette use. GL produced much more formaldehyde than PG. Besides formaldehyde and acetaldehyde, measurable amounts of acrolein were also detected at >=270 degrees C but only when GL was present in the e-liquid. At 215 degrees C, the estimated daily exposure to formaldehyde from e-cigarettes, exceeded United States Environmental Protection Agency (USEPA) and California Office of Environmental Health Hazard Assessment (OEHHA) acceptable limits, which emphasized the need to further examine the potential cancer and non-cancer health risks associated with e-cigarette use. PMID- 28076381 TI - Stain Deconvolution Using Statistical Analysis of Multi-Resolution Stain Colour Representation. AB - Stain colour estimation is a prominent factor of the analysis pipeline in most of histology image processing algorithms. Providing a reliable and efficient stain colour deconvolution approach is fundamental for robust algorithm. In this paper, we propose a novel method for stain colour deconvolution of histology images. This approach statistically analyses the multi-resolutional representation of the image to separate the independent observations out of the correlated ones. We then estimate the stain mixing matrix using filtered uncorrelated data. We conducted an extensive set of experiments to compare the proposed method to the recent state of the art methods and demonstrate the robustness of this approach using three different datasets of scanned slides, prepared in different labs using different scanners. PMID- 28076382 TI - Deregulated Expression of Mitochondrial Proteins Mfn2 and Bcnl3L in Placentae from Sheep Somatic Cell Nuclear Transfer (SCNT) Conceptuses. AB - In various animal species, the main cause of pregnancy loss in conceptuses obtained by somatic cell nuclear transfer (SCNT) are placental abnormalities. Most abnormalities described in SCNT pregnancies (such as placentomegaly, reduced vascularisation, hypoplasia of trophoblastic epithelium) suggest that placental cell degeneration may be triggered by mitochondrial failure. We hypothesized that placental abnormalities of clones obtained by SCNT are related to mitochondrial dysfunction. To test this, early SCNT and control (CTR, from pregnancies obtained by in vitro fertilization) placentae were collected from pregnant ewes (at day 20 and 22 of gestation) and subjected to morphological, mRNA and protein analysis. Here, we demonstrated swollen and fragmented mitochondria and low expression of mitofusin 2 (Mfn2), the protein which plays a crucial role in mitochondrial functionality, in SCNT early placentae. Furthermore, reduced expression of the Bcnl3L/Nix protein, which plays a crucial role in selective elimination of damaged mitochondria, was observed and reflected by the accumulation of numerous damaged mitochondria in SCNT placental cells. Likely, this accumulation of damaged organelles led to uncontrolled apoptosis in SCNT placentae, as demonstrated by the high number of apoptotic bodies, fragmented cytoplasm, condensed chromatin, lack of integrity of the nuclear membrane and the perturbed mRNA expression of apoptotic genes (BCL2 and BAX). In conclusion, our data indicate that deregulated expression of Mfn2 and Bcnl3L is responsible for placental abnormalities in SCNT conceptuses. Our results suggest that some nuclear genes, that are involved in the regulation of mitochondrial function, do not work well and consequently this influence the function of mitochondria. PMID- 28076383 TI - Time-Varying Transition Probability Matrix Estimation and Its Application to Brand Share Analysis. AB - In a product market or stock market, different products or stocks compete for the same consumers or purchasers. We propose a method to estimate the time-varying transition matrix of the product share using a multivariate time series of the product share. The method is based on the assumption that each of the observed time series of shares is a stationary distribution of the underlying Markov processes characterized by transition probability matrices. We estimate transition probability matrices for every observation under natural assumptions. We demonstrate, on a real-world dataset of the share of automobiles, that the proposed method can find intrinsic transition of shares. The resulting transition matrices reveal interesting phenomena, for example, the change in flows between TOYOTA group and GM group for the fiscal year where TOYOTA group's sales beat GM's sales, which is a reasonable scenario. PMID- 28076384 TI - Anti-Epileptic Drug Combination Efficacy in an In Vitro Seizure Model - Phenytoin and Valproate, Lamotrigine and Valproate. AB - In this study, we investigated the relative efficacy of different classes of commonly used anti-epileptic drugs (AEDs) with different mechanisms of action, individually and in combination, to suppress epileptiform discharges in an in vitro model. Extracellular field potential were recorded in 450 MUm thick transverse hippocampal slices prepared from juvenile Wistar rats, in which "epileptiform discharges" (ED's) were produced with a high-K+ (8.5 mM) bicarbonate-buffered saline solution. Single and dual recordings in stratum pyramidale of CA1 and CA3 regions were performed with 3-5 MOmega glass microelectrodes. All drugs-lamotrigine (LTG), phenytoin (PHT) and valproate (VPA) were applied to the slice by superfusion at a rate of 2 ml/min at 32 degrees C. Effects upon frequency of ED's were assessed for LTG, PHT and VPA applied at different concentrations, in isolation and in combination. We demonstrated that high-K+ induced ED frequency was reversibly reduced by LTG, PHT and VPA, at concentrations corresponding to human therapeutic blood plasma concentrations. With a protocol using several applications of drugs to the same slice, PHT and VPA in combination displayed additivity of effect with 50MUM PHT and 350MUM VPA reducing SLD frequency by 44% and 24% individually (n = 19), and together reducing SLD frequency by 66% (n = 19). 20MUM LTG reduced SLD frequency by 32% and 350MUM VPA by 16% (n = 18). However, in combination there was a supra-linear suppression of ED's of 64% (n = 18). In another independent set of experiments, similar results of drug combination responses were also found. In conclusion, a combination of conventional AEDs with different mechanisms of action, PHT and VPA, displayed linear additivity of effect on epileptiform activity. More intriguingly, a combination of LTG and VPA considered particularly efficacious clinically showed a supra-additive suppression of ED's. This approach may be useful as an in vitro platform for assessing drug combination efficacy. PMID- 28076385 TI - The Effect of a Novel c.820C>T (Arg274Trp) Mutation in the Mitofusin 2 Gene on Fibroblast Metabolism and Clinical Manifestation in a Patient. AB - Charcot-Marie-Tooth disease type 2A (CMT2A) is an autosomal dominant axonal peripheral neuropathy caused by mutations in the mitofusin 2 gene (MFN2). Mitofusin 2 is a GTPase protein present in the outer mitochondrial membrane and responsible for regulation of mitochondrial network architecture via the fusion of mitochondria. As that fusion process is known to be strongly dependent on the GTPase activity of mitofusin 2, it is postulated that the MFN2 mutation within the GTPase domain may lead to impaired GTPase activity, and in turn to mitochondrial dysfunction. The work described here has therefore sought to verify the effects of MFN2 mutation within its GTPase domain on mitochondrial and endoplasmic reticulum morphology, as well as the mtDNA content in a cultured primary fibroblast obtained from a CMT2A patient harboring a de novo Arg274Trp mutation. In fact, all the parameters studied were affected significantly by the presence of the mutant MFN2 protein. However, using the stable model for mitofusin 2 obtained by us, we were next able to determine that the Arg274Trp mutation does not impact directly upon GTP binding. Such results were also confirmed for GTP-hydrolysis activity of MFN2 protein in patient fibroblast. We therefore suggest that the biological malfunctions observable with the disease are not consequences of impaired GTPase activity, but rather reflect an impaired contribution of the GTPase domain to other MFN2 activities involving that region, for example protein-protein interactions. PMID- 28076386 TI - Neutrophil-to-Lymphocyte Ratio for Predicting Loss of Response to Infliximab in Ulcerative Colitis. AB - OBJECTIVES: Neutrophil-to-lymphocyte ratio (NLR) has been used to determine the outcome in malignancies and coronary heart disease. Some reports considered the value of NLR as a predictor of response to infliximab in patients with Crohn's disease or rheumatoid arthritis; however, no similar studies have been reported for ulcerative colitis (UC). This study aimed to evaluate the clinical significance of the baseline NLR in patients with UC treated by infliximab. MATERIALS AND METHODS: Patients with moderate-to-severe active UC who received the first infliximab infusion in our hospital between 2010 and 2015, who showed clinical response during the induction period, were retrospectively evaluated for long-term outcomes and risk factors for loss of response (LOR) during infliximab maintenance therapy. Baseline inflammatory markers including NLR were measured within one week before the initiation of infliximab. RESULTS: Fifty-nine patients with moderate-to-severe active UC started treatment with infliximab and 37 patients (62.7%) experienced clinical response after induction therapy. Fourteen of 37 patients on maintenance therapy lost the response during follow-up. Baseline NLR of patients with LOR was significantly higher than in patients with sustained response. The NLR cut-off value of 4.488 was predictive of LOR, using receiver operating characteristic analysis (sensitivity: 78.6%, specificity: 78.3%). A univariate analysis revealed a significant relationship between relapse free survival and the NLR (P = 0.018). Multivariate analysis indicated the NLR as an independent prognostic factor for LOR (hazard ratio = 3.86, 95% confidence interval: 1.20-12.4, P = 0.023). CONCLUSIONS: Baseline NLR is a useful prognostic marker in patients with moderate-to-severe active UC treated with infliximab, and may contribute to appropriate use of infliximab. PMID- 28076387 TI - Distinct Subtypes of Apathy Revealed by the Apathy Motivation Index. AB - Apathy is a debilitating but poorly understood disorder characterized by a reduction in motivation. As well as being associated with several brain disorders, apathy is also prevalent in varying degrees in healthy people. Whilst many tools have been developed to assess levels of apathy in clinical disorders, surprisingly there are no measures of apathy suitable for healthy people. Moreover, although apathy is commonly comorbid with symptoms of depression, anhedonia and fatigue, how and why these symptoms are associated is unclear. Here we developed the Apathy-Motivation Index (AMI), a brief self-report index of apathy and motivation. Using exploratory factor analysis (in a sample of 505 people), and then confirmatory analysis (in a different set of 479 individuals), we identified subtypes of apathy in behavioural, social and emotional domains. Latent profile analyses showed four different profiles of apathy that were associated with varying levels of depression, anhedonia and fatigue. The AMI is a novel and reliable measure of individual differences in apathy and might provide a useful means of probing different mechanisms underlying sub-clinical lack of motivation in otherwise healthy individuals. Moreover, associations between apathy and comorbid states may be reflective of problems in different emotional, social and behavioural domains. PMID- 28076388 TI - Risk Factors for Multi-Drug Resistant Pathogens and Failure of Empiric First-Line Therapy in Acute Cholangitis. AB - BACKGROUND: Acute cholangitis (AC) requires the immediate initiation of antibiotic therapy in addition to treatment for biliary obstruction. Against a background of an increasing prevalence of multi-drug resistant (MDR) bacteria, the risk factors for the failure of empiric therapy must be defined. METHODS: Using a pathogen-based approach, 1764 isolates from positive bile duct cultures were retrospectively analyzed to characterize the respective pathogen spectra in two German tertiary centers. Using a patient-based approach, the clinical and laboratory data for 83 patients with AC were assessed to identify risk factors for AC with pathogens resistant to the applied empiric therapy. RESULTS: Bile cultures were predominantly polymicrobial, and empiric antibiotic therapies did not cover the full biliary pathogen spectrum in 78% of cases. MDR bacteria were isolated from the bile of 24/83 (29%) patients. The univariate risk factors for biliary MDR bacteria were male sex, nosocomial AC, prior antibiotic exposure and prior biliary stenting, of which biliary stenting was the only independent risk factor according to multivariate analysis (OR = 3.8; 95% CI 1.3-11.0, P = 0.013). Although there were no significant differences in survival or hospital stay in AC patients with and without detected biliary MDR pathogens, the former more often had a concomitant bloodstream infection (58% vs. 24%; P = 0.019), including those involving MDR pathogens or fungi (21% vs. 2%; P = 0.007). CONCLUSION: Patients with biliary stents who develop AC should receive empiric therapy covering enterococci and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. These patients are at an increased risk for bloodstream infections by MDR pathogens or fungi. PMID- 28076389 TI - A Computational Study on the Relation between Resting Heart Rate and Atrial Fibrillation Hemodynamics under Exercise. AB - AIMS: Clinical data indicating a heart rate (HR) target during rate control therapy for permanent atrial fibrillation (AF) and assessing its eventual relationship with reduced exercise tolerance are lacking. The present study aims at investigating the impact of resting HR on the hemodynamic response to exercise in permanent AF patients by means of a computational cardiovascular model. METHODS: The AF lumped-parameter model was run to simulate resting (1 Metabolic Equivalent of Task-MET) and various exercise conditions (4 METs: brisk walking; 6 METs: skiing; 8 METs: running), considering different resting HR (70 bpm for the slower resting HR-SHR-simulations, and 100 bpm for the higher resting HR-HHR simulations). To compare relative variations of cardiovascular variables upon exertion, the variation comparative index (VCI)-the absolute variation between the exercise and the resting values in SHR simulations referred to the absolute variation in HHR simulations-was calculated at each exercise grade (VCI4, VCI6 and VCI8). RESULTS: Pulmonary venous pressure underwent a greater increase in HHR compared to SHR simulations (VCI4 = 0.71, VCI6 = 0.73 and VCI8 = 0.77), while for systemic arterial pressure the opposite is true (VCI4 = 1.15, VCI6 = 1.36, VCI8 = 1.56). CONCLUSIONS: The computational findings suggest that a slower, with respect to a higher resting HR, might be preferable in permanent AF patients, since during exercise pulmonary venous pressure undergoes a slighter increase and systemic blood pressure reveals a more appropriate increase. PMID- 28076390 TI - IL-37 Confers Protection against Mycobacterial Infection Involving Suppressing Inflammation and Modulating T Cell Activation. AB - Interleukin-37 (IL-37), a novel member of the IL-1 family, plays fundamental immunosuppressive roles by broadly reducing both innate inflammation and acquired immunity, but whether it is involved in the pathogenesis of tuberculosis (TB) has not been clearly elucidated. In this study, single nucleotide polymorphism (SNP) analysis demonstrated an association of the genetic variant rs3811047 of IL-37 with TB susceptibility. In line with previous report, a significant elevated IL 37 abundance in the sera and increased expression of IL-37 protein in the peripheral blood mononuclear cells (PBMC) were observed in TB patients in comparison to healthy controls. Moreover, release of IL-37 were detected in either macrophages infected with Mycobacterium tuberculosis (Mtb) or the lung of BCG-infected mice, concurrent with reduced production of proinflammatory cytokines including IL-6 and TNF-alpha. Furthermore, in contrast to wild-type mice, BCG-infected IL-37-Tg mice manifested with reduced mycobacterial burden and tissue damage in the lung, accompanied by higher frequency of Th1 cell and less frequencies of regulatory T cells and Th17 cells in the spleen. Taken together, our findings demonstrated that IL-37 conferred resistance to Mtb infection possibly involving suppressing detrimental inflammation and modulating T cell responses. These findings implicated that IL-37 may be employed as a new molecular target for the therapy and diagnosis of TB. PMID- 28076391 TI - Assessing Sexual Dicromatism: The Importance of Proper Parameterization in Tetrachromatic Visual Models. AB - Perceptual models of animal vision have greatly contributed to our understanding of animal-animal and plant-animal communication. The receptor-noise model of color contrasts has been central to this research as it quantifies the difference between two colors for any visual system of interest. However, if the properties of the visual system are unknown, assumptions regarding parameter values must be made, generally with unknown consequences. In this study, we conduct a sensitivity analysis of the receptor-noise model using avian visual system parameters to systematically investigate the influence of variation in light environment, photoreceptor sensitivities, photoreceptor densities, and light transmission properties of the ocular media and the oil droplets. We calculated the chromatic contrast of 15 plumage patches to quantify a dichromatism score for 70 species of Galliformes, a group of birds that display a wide range of sexual dimorphism. We found that the photoreceptor densities and the wavelength of maximum sensitivity of the short-wavelength-sensitive photoreceptor 1 (SWS1) can change dichromatism scores by 50% to 100%. In contrast, the light environment, transmission properties of the oil droplets, transmission properties of the ocular media, and the peak sensitivities of the cone photoreceptors had a smaller impact on the scores. By investigating the effect of varying two or more parameters simultaneously, we further demonstrate that improper parameterization could lead to differences between calculated and actual contrasts of more than 650%. Our findings demonstrate that improper parameterization of tetrachromatic visual models can have very large effects on measures of dichromatism scores, potentially leading to erroneous inferences. We urge more complete characterization of avian retinal properties and recommend that researchers either determine whether their species of interest possess an ultraviolet or near ultraviolet sensitive SWS1 photoreceptor, or present models for both. PMID- 28076392 TI - Arthropod Pest Control for UK Oilseed Rape - Comparing Insecticide Efficacies, Side Effects and Alternatives. AB - Oilseed rape (Brassica napus) is an important combinable break crop in the UK, which is largely protected from arthropod pests by insecticidal chemicals. Despite ongoing debate regarding the use of neonicotinoids, the dominant seed treatment ingredients used for this crop, there is little publicly available data comparing the efficacy of insecticides in controlling key arthropod pests or comparing the impacts on non-target species and the wider environment. To provide an insight into these matters, a UK-wide expert survey targeting agronomists and entomologists was conducted from March to June 2015. Based on the opinions of 90 respondents, an average of 20% yield loss caused by the key arthropod pests was expected to have occurred in the absence of insecticide treatments. Relatively older chemical groups were perceived to have lower efficacy for target pests than newer ones, partly due to the development of insecticide resistance. Without neonicotinoid seed treatments, a lack of good control for cabbage stem flea beetle was perceived. Wide spectrum foliar insecticide sprays were perceived to have significantly greater negative impacts than seed treatments on users' health, natural enemies, pollinators, soil and water, and many foliar active ingredients have had potential risks for non-target arthropod species in UK oilseed rape fields for the past 25 years. Overall, 72% of respondents opposed the neonicotinoid restriction, while 10% supported it. Opposition and support of the restriction were largely based on concerns for pollinators and the wider environment, highlighting the uncertainty over the side effects of neonicotinoid use. More people from the government and research institutes leaned towards neutrality over the issue, compared to those directly involved in growing the crop. Neonicotinoid restriction was expected to result in greater effort and expenditure on pest control and lower production (0-1 t/ha less). Alternatives for future oilseed rape protection were then discussed. PMID- 28076393 TI - Alder, Nitrogen, and Lake Ecology: Terrestrial-Aquatic Linkages in the Postglacial History of Lone Spruce Pond, Southwestern Alaska. AB - Diatoms, combined with a multiproxy study of lake sediments (organic matter, N, delta15N, delta13C, biogenic silica, grain size, Cladocera and chironomids, Alnus pollen) from Lone Spruce Pond, Alaska detail the late-glacial to Holocene history of the lake and its response to regional climate and landscape change over the last 14.5 cal ka BP. We show that the immigration of alder (Alnus viridis) in the early Holocene marks the rise of available reactive nitrogen (Nr) in the lake as well as the establishment of a primarily planktonic diatom community. The later establishment of diatom Discostella stelligera is coupled to a rise of sedimentary delta15N, indicating diminished competition for this nutrient. This terrestrial-aquatic linkage demonstrates how profoundly vegetation may affect soil geochemistry, lake development, and lake ecology over millennial timescales. Furthermore, the response of the diatom community to strengthened stratification and N levels in the past confirms the sensitivity of planktonic diatom communities to changing thermal and nutrient regimes. These past ecosystem dynamics serve as an analogue for the nature of threshold-type ecological responses to current climate change and atmospheric nitrogen (Nr) deposition, but also for the larger changes we should anticipate under future climate, pollution, and vegetation succession scenarios in high-latitude and high-elevation regions. PMID- 28076394 TI - Correction: Electrode Mass Balancing as an Inexpensive and Simple Method to Increase the Capacitance of Electric Double-Layer Capacitors. AB - [This corrects the article DOI: 10.1371/journal.pone.0163146.]. PMID- 28076395 TI - Mapping and Genetic Structure Analysis of the Anthracnose Resistance Locus Co-1HY in the Common Bean (Phaseolus vulgaris L.). AB - Anthracnose is a destructive disease of the common bean (Phaseolus vulgaris L.). The Andean cultivar Hongyundou has been demonstrated to possess strong resistance to anthracnose race 81. To study the genetics of this resistance, the Hongyundou cultivar was crossed with a susceptible genotype Jingdou. Segregation of resistance for race 81 was assessed in the F2 population and F2:3 lines under controlled conditions. Results indicate that Hongyundou carries a single dominant gene for anthracnose resistance. An allele test by crossing Hongyundou with another resistant cultivar revealed that the resistance gene is in the Co-1 locus (therefore named Co-1HY). The physical distance between this locus and the two flanking markers was 46 kb, and this region included four candidate genes, namely, Phvul.001G243500, Phvul.001G243600, Phvul.001G243700 and Phvul.001G243800. These candidate genes encoded serine/threonine-protein kinases. Expression analysis of the four candidate genes in the resistant and susceptible cultivars under control condition and inoculated treatment revealed that all the four candidate genes are expressed at significantly higher levels in the resistant genotype than in susceptible genotype. Phvul.001G243600 and Phvul.001G243700 are expressed nearly 15-fold and 90-fold higher in the resistant genotype than in the susceptible parent before inoculation, respectively. Four candidate genes will provide useful information for further research into the resistance mechanism of anthracnose in common bean. The closely linked flanking markers identified here may be useful for transferring the resistance allele Co 1HY from Hongyundou to elite anthracnose susceptible common bean lines. PMID- 28076396 TI - Neutrophil Interactions Stimulate Evasive Hyphal Branching by Aspergillus fumigatus. AB - Invasive aspergillosis (IA), primarily caused by Aspergillus fumigatus, is an opportunistic fungal infection predominantly affecting immunocompromised and neutropenic patients that is difficult to treat and results in high mortality. Investigations of neutrophil-hypha interaction in vitro and in animal models of IA are limited by lack of temporal and spatial control over interactions. This study presents a new approach for studying neutrophil-hypha interaction at single cell resolution over time, which revealed an evasive fungal behavior triggered by interaction with neutrophils: Interacting hyphae performed de novo tip formation to generate new hyphal branches, allowing the fungi to avoid the interaction point and continue invasive growth. Induction of this mechanism was independent of neutrophil NADPH oxidase activity and neutrophil extracellular trap (NET) formation, but could be phenocopied by iron chelation and mechanical or physiological stalling of hyphal tip extension. The consequence of branch induction upon interaction outcome depends on the number and activity of neutrophils available: In the presence of sufficient neutrophils branching makes hyphae more vulnerable to destruction, while in the presence of limited neutrophils the interaction increases the number of hyphal tips, potentially making the infection more aggressive. This has direct implications for infections in neutrophil-deficient patients and opens new avenues for treatments targeting fungal branching. PMID- 28076397 TI - When Viruses Don't Go Viral: The Importance of Host Phylogeographic Structure in the Spatial Spread of Arenaviruses. AB - Many emerging infections are RNA virus spillovers from animal reservoirs. Reservoir identification is necessary for predicting the geographic extent of infection risk, but rarely are taxonomic levels below the animal species considered as reservoir, and only key circumstances in nature and methodology allow intrinsic virus-host associations to be distinguished from simple geographic (co-)isolation. We sampled and genetically characterized in detail a contact zone of two subtaxa of the rodent Mastomys natalensis in Tanzania. We find two distinct arenaviruses, Gairo and Morogoro virus, each spatially confined to a single M. natalensis subtaxon, only co-occurring at the contact zone's centre. Inter-subtaxon hybridization at this centre and a continuum of quality habitat for M. natalensis show that both viruses have the ecological opportunity to spread into the other substaxon's range, but do not, strongly suggesting host intrinsic barriers. Such barriers could explain why human cases of another M. natalensis-borne arenavirus, Lassa virus, are limited to West Africa. PMID- 28076398 TI - Identification of a Novel Mutation in BRD4 that Causes Autosomal Dominant Syndromic Congenital Cataracts Associated with Other Neuro-Skeletal Anomalies. AB - Congenital cataracts can occur as a non-syndromic isolated ocular disease or as a part of genetic syndromes accompanied by a multi-systemic disease. Approximately 50% of all congenital cataract cases have a heterogeneous genetic basis. Here, we describe three generations of a family with an autosomal dominant inheritance pattern and common complex phenotypes, including bilateral congenital cataracts, short stature, macrocephaly, and minor skeletal anomalies. We did not find any chromosomal aberrations or gene copy number abnormalities using conventional genetic tests; accordingly, we conducted whole-exome sequencing (WES) to identify disease-causing genetic alterations in this family. Based on family WES data, we identified a novel BRD4 missense mutation as a candidate causal variant and performed cell-based experiments by ablation of endogenous BRD4 expression in human lens epithelial cells. The protein expression levels of connexin 43, p62, LC3BII, and p53 differed significantly between control cells and cells in which endogenous BRD4 expression was inhibited. We inferred that a BRD4 missense mutation was the likely disease-causing mutation in this family. Our findings may improve the molecular diagnosis of congenital cataracts and support the use of WES to clarify the genetic basis of complex diseases. PMID- 28076399 TI - Epidemiology of Injury-Related Death in Children under 5 Years of Age in Hunan Province, China, 2009-2014. AB - BACKGROUND: Injury is an important cause of childhood mortality in China. We described the epidemiology and trends of injury-related deaths of children <5 years of age in Hunan province, and discussed several policy implications. METHODS: Injury-related deaths of children <5 years of age in 2009-2014 were identified from surveillance data. All specific injury mortality and mortality rates in urban and rural area were calculated from census data; Cochran-armitage trend test was used to assess the time trends. RESULTS: Injury was the leading cause of death in children <5 years of age. Overall injury mortality was 48.96 per 100,000 persons, gradually declined with the year (Z = -18.75, P<0.001), and accounted for 27.14% of all deaths. Injury mortality in rural areas was 64.66 per 100,000 persons, which was more than 3.73 times higher than the rate in urban areas. The three leading causes of injury-related death were drowning (43.63%), suffocation (27.57%), and traffic accidents (14.34%). Suffocation was the leading cause in children <1 year of age (79.49%). Suffocation has high incidence in the winter and spring, and drowning has high incidence in the summer season. Drowning was the leading cause in children 1-4 years of age (62.80%). Drowning and suffocation accounted for 67.74% and 65.11%, of injury-related deaths that occurred at home; while the traffic injury deaths (54.12%) occurred mainly in transit. CONCLUSIONS: Injury-related fatalities in children <5 years of age followed time trends that were different in rural and urban areas. Effective childhood injury prevention may require different prevention policies combination depending on epidemiological characteristics such as development of injury surveillance and public education on injury knowledge. There is a need for evidence-based surveillance of risk factors for development of effective injury prevention programs. PMID- 28076400 TI - Mandarin-English Bilinguals Process Lexical Tones in Newly Learned Words in Accordance with the Language Context. AB - Previous research has mainly considered the impact of tone-language experience on ability to discriminate linguistic pitch, but proficient bilingual listening requires differential processing of sound variation in each language context. Here, we ask whether Mandarin-English bilinguals, for whom pitch indicates word distinctions in one language but not the other, can process pitch differently in a Mandarin context vs. an English context. Across three eye-tracked word-learning experiments, results indicated that tone-intonation bilinguals process tone in accordance with the language context. In Experiment 1, 51 Mandarin-English bilinguals and 26 English speakers without tone experience were taught Mandarin compatible novel words with tones. Mandarin-English bilinguals out-performed English speakers, and, for bilinguals, overall accuracy was correlated with Mandarin dominance. Experiment 2 taught 24 Mandarin-English bilinguals and 25 English speakers novel words with Mandarin-like tones, but English-like phonemes and phonotactics. The Mandarin-dominance advantages observed in Experiment 1 disappeared when words were English-like. Experiment 3 contrasted Mandarin-like vs. English-like words in a within-subjects design, providing even stronger evidence that bilinguals can process tone language-specifically. Bilinguals (N = 58), regardless of language dominance, attended more to tone than English speakers without Mandarin experience (N = 28), but only when words were Mandarin like-not when they were English-like. Mandarin-English bilinguals thus tailor tone processing to the within-word language context. PMID- 28076401 TI - Exploring Nurses', Preschool Teachers' and Parents' Perspectives on Information Sharing Using SDQ in a Swedish Setting - A Qualitative Study Using Grounded Theory. AB - Evidence-based methods to identify behavioural problems among children are not regularly used within the Swedish Child healthcare. A new procedure was therefore introduced to assess children through parent- and preschool teacher reports using the Strengths and Difficulties Questionnaire (SDQ). This study aims to explore nurses', preschool teachers' and parents' perspectives of this new information sharing model. Using the grounded theory methodology, semi-structured interviews with nurses (n = 10) at child health clinics, preschool teachers (n = 13) and parents (n = 11) of 3-, 4- and 5-year-old children were collected and analysed between March 2014 and June 2014. The analysis was conducted using constant comparative method. The participants were sampled purposively within a larger trial in Sweden. Results indicate that all stakeholders shared a desire to have a complete picture of the child's health. The perceptions that explain why the stakeholders were in favour of the new procedure-the 'causal conditions' in a grounded theory model-included: (1) Nurses thought that visits after 18-months were unsatisfactory, (2) Preschool teachers wanted to identify children with difficulties and (3) Parents viewed preschool teachers as being qualified to assess children. However, all stakeholders had doubts as to whether there was a reliable way to assess children's behaviour. Although nurses found the SDQ to be useful for their clinical evaluation, they noticed that not all parents chose to participate. Both teachers and parents acknowledged benefits of information sharing. However, the former had concerns about parental reactions to their assessments and the latter about how personal information was handled. The theoretical model developed describes that the causal conditions and current context of child healthcare in many respects endorse the introduction of information sharing. However, successful implementation requires considerable work to address barriers: the tension between normative thinking versus helping children with developmental problems for preschool teachers and dealing with privacy issues and inequity in participation for parents. PMID- 28076402 TI - Non-Orthogonal Random Access in MIMO Cognitive Radio Networks: Beamforming, Power Allocation, and Opportunistic Transmission. AB - We study secondary random access in multi-input multi-output cognitive radio networks, where a slotted ALOHA-type protocol and successive interference cancellation are used. We first introduce three types of transmit beamforming performed by secondary users, where multiple antennas are used to suppress the interference at the primary base station and/or to increase the received signal power at the secondary base station. Then, we show a simple decentralized power allocation along with the equivalent single-antenna conversion. To exploit the multiuser diversity gain, an opportunistic transmission protocol is proposed, where the secondary users generating less interference are opportunistically selected, resulting in a further reduction of the interference temperature. The proposed methods are validated via computer simulations. Numerical results show that increasing the number of transmit antennas can greatly reduce the interference temperature, while increasing the number of receive antennas leads to a reduction of the total transmit power. Optimal parameter values of the opportunistic transmission protocol are examined according to three types of beamforming and different antenna configurations, in terms of maximizing the cognitive transmission capacity. All the beamforming, decentralized power allocation, and opportunistic transmission protocol are performed by the secondary users in a decentralized manner, thus resulting in an easy implementation in practice. PMID- 28076403 TI - Correction: Virtual Morality: Transitioning from Moral Judgment to Moral Action? AB - [This corrects the article DOI: 10.1371/journal.pone.0164374.]. PMID- 28076404 TI - Combined Inhibition of the Renin-Angiotensin System and Neprilysin Positively Influences Complex Mitochondrial Adaptations in Progressive Experimental Heart Failure. AB - BACKGROUND: Inhibitors of the renin angiotensin system and neprilysin (RAS-/NEP inhibitors) proved to be extraordinarily beneficial in systolic heart failure. Furthermore, compelling evidence exists that impaired mitochondrial pathways are causatively involved in progressive left ventricular (LV) dysfunction. Consequently, we aimed to assess whether RAS-/NEP-inhibition can attenuate mitochondrial adaptations in experimental heart failure (HF). METHODS AND RESULTS: By progressive right ventricular pacing, distinct HF stages were induced in 15 rabbits, and 6 animals served as controls (CTRL). Six animals with manifest HF (CHF) were treated with the RAS-/NEP-inhibitor omapatrilat. Echocardiographic studies and invasive blood pressure measurements were undertaken during HF progression. Mitochondria were isolated from LV tissue, respectively, and further worked up for proteomic analysis using the SWATH technique. Enzymatic activities of citrate synthase and the electron transfer chain (ETC) complexes I, II, and IV were assessed. Ultrastructural analyses were performed by transmission electron microscopy. During progression to overt HF, intricate expression changes were mainly detected for proteins belonging to the tricarboxylic acid cycle, glucose and fat metabolism, and the ETC complexes, even though ETC complex I, II, or IV enzymatic activities were not significantly influenced. Treatment with a RAS-/NEP inhibitor then reversed some maladaptive metabolic adaptations, positively influenced the decline of citrate synthase activity, and altered the composition of each respiratory chain complex, even though this was again not accompanied by altered ETC complex enzymatic activities. Finally, ultrastructural evidence pointed to a reduction of autophagolytic and degenerative processes with omapatrilat-treatment. CONCLUSIONS: This study describes complex adaptations of the mitochondrial proteome in experimental tachycardia-induced heart failure and shows that a combined RAS-/NEP-inhibition can beneficially influence mitochondrial key pathways. PMID- 28076405 TI - Development and Validation of a New Reliable Method for the Diagnosis of Avian Botulism. AB - Liver is a reliable matrix for laboratory confirmation of avian botulism using real-time PCR. Here, we developed, optimized, and validated the analytical steps preceding PCR to maximize the detection of Clostridium botulinum group III in avian liver. These pre-PCR steps included enrichment incubation of the whole liver (maximum 25 g) at 37 degrees C for at least 24 h in an anaerobic chamber and DNA extraction using an enzymatic digestion step followed by a DNA purification step. Conditions of sample storage before analysis appear to have a strong effect on the detection of group III C. botulinum strains and our results recommend storage at temperatures below -18 degrees C. Short-term storage at 5 degrees C is possible for up to 24 h, but a decrease in sensitivity was observed at 48 h of storage at this temperature. Analysis of whole livers (maximum 25 g) is required and pooling samples before enrichment culturing must be avoided. Pooling is however possible before or after DNA extraction under certain conditions. Whole livers should be 10-fold diluted in enrichment medium and homogenized using a Pulsifier(r) blender (Microgen, Surrey, UK) instead of a conventional paddle blender. Spiked liver samples showed a limit of detection of 5 spores/g liver for types C and D and 250 spores/g for type E. Using the method developed here, the analysis of 268 samples from 73 suspected outbreaks showed 100% specificity and 95.35% sensitivity compared with other PCR-based methods considered as reference. The mosaic type C/D was the most common neurotoxin type found in examined samples, which included both wild and domestic birds. PMID- 28076406 TI - The Development and Validation of the Empathy Components Questionnaire (ECQ). AB - Key research suggests that empathy is a multidimensional construct comprising of both cognitive and affective components. More recent theories and research suggest even further factors within these components of empathy, including the ability to empathize with others versus the drive towards empathizing with others. While numerous self-report measures have been developed to examine empathy, none of them currently index all of these wider components together. The aim of the present research was to develop and validate the Empathy Components Questionnaire (ECQ) to measure cognitive and affective components, as well as ability and drive components within each. Study one utilized items measuring cognitive and affective empathy taken from various established questionnaires to create an initial version of the ECQ. Principal component analysis (PCA) was used to examine the underlying components of empathy within the ECQ in a sample of 101 typical adults. Results revealed a five-component model consisting of cognitive ability, cognitive drive, affective ability, affective drive, and a fifth factor assessing affective reactivity. This five-component structure was then validated and confirmed using confirmatory factor analysis (CFA) in an independent sample of 211 typical adults. Results also showed that females scored higher than males overall on the ECQ, and on specific components, which is consistent with previous findings of a female advantage on self-reported empathy. Findings also showed certain components predicted scores on an independent measure of social behavior, which provided good convergent validity of the ECQ. Together, these findings validate the newly developed ECQ as a multidimensional measure of empathy more in line with current theories of empathy. The ECQ provides a useful new tool for quick and easy measurement of empathy and its components for research with both healthy and clinical populations. PMID- 28076407 TI - Medicinal Plant Diversity and Inter-Cultural Interactions between Indigenous Guarani, Criollos and Polish Migrants in the Subtropics of Argentina. AB - Numerous studies highlight the importance of phytotherapy for indigenous and non indigenous people in different parts of the world. In this work we analyze the richness (number of species), diversity (plant identity and the number of illnesses for which it is used) and similarity of plant species and illnesses treated with them, in order to contribute new data and insight into the importance of plant medicines to the local medical systems of people living in Misiones province, in the subtropics of Argentina. Three sympatric groups were compared: Guarani Indians, Criollos (mestizos) and Polish migrants. Quantitative scrutiny was focused on both primary and secondary sources. The similarity and diversity of medicinal plants and uses between groups was calculated by applying the Sorensen quantitative coefficient and the Shannon-Wiener index, respectively. In order to identify the characteristic plant species used by each group, the Cultural Importance and Prevalence Value (CIPV) was calculated based on the species Indicator Value (IndVal), which combines a species relative abundance with its relative frequency of occurrence in the various groups, and modified according to the type of the analyzed data. The important finding is a great variation in the number of species used by the study groups. Altogether, 509 botanical species were registered: Guarani (397), Criollos (243) and Polish migrants (137). For all groups, the use of native medicinal plants prevailed. The Guarani appear to be the local experts in use of medicinal plants. There is the significant difference in the number of treated illnesses by each taxon among three groups. Criollos and Polish migrants exhibit the greatest similarity in illnesses treated with medicinal plants. These groups share a corpus of knowledge related to illness nosology, and have a symptomatic approach to illness treatment. The Guarani have an etiological approach to illness diagnosis and healing, which may be viewed as a barrier to the exchange of knowledge about home medicine with other ethnic groups of Misiones. PMID- 28076408 TI - Development of a Novel Enzyme-Linked Immunosorbent Assay Targeting a Neo-Epitope Generated by Cathepsin-Mediated Turnover of Type III Collagen and Its Application in Chronic Obstructive Pulmonary Disease. AB - A high level of extracellular matrix (ECM) turnover characterizes several lung diseases with fibrotic features. Type III collagen is one of the most abundant collagens in lung parenchyma, and cathepsins play a role in lung pathology, being responsible for tissue remodeling. In this study, we explore the diagnostic features of neo-epitope fragments of type III collagen generated by cathepsins that could reflect the pathological tissue turnover in patients with different diseases. A novel enzyme-linked immunosorbent assay (ELISA) measuring cathepsins B, L, S and K -generated type III collagen fragments (C3C) was developed for assessment in serum and plasma. The assay was biologically validated in serum from patients with chronic obstructive pulmonary disease (COPD). Serological levels of C3C were significantly elevated in patients with COPD compared to healthy controls (p = 0.0006). Levels of C3C in serum and heparin plasma of COPD patients had a highly significant correlation (R2 = 0.86, p<0.0001). The data suggests that the C3C fragment is elevated in patients with COPD compared to healthy controls. PMID- 28076409 TI - An Efficient Antioxidant System in a Long-Lived Termite Queen. AB - The trade-off between reproduction and longevity is known in wide variety of animals. Social insect queens are rare organisms that can achieve a long lifespan without sacrificing fecundity. The extended longevity of social insect queens, which contradicts the trade-off, has attracted much attention because it implies the existence of an extraordinary anti-aging mechanism. Here, we show that queens of the termite Reticulitermes speratus incur significantly lower oxidative damage to DNA, protein and lipid and have higher activity of antioxidant enzymes than non-reproductive individuals (workers and soldiers). The levels of 8-hydroxy-2' deoxyguanosine (oxidative damage marker of DNA) were lower in queens than in workers after UV irradiation. Queens also showed lower levels of protein carbonyls and malondialdehyde (oxidative damage markers of protein and lipid, respectively). The antioxidant enzymes of insects are generally composed of catalase (CAT) and peroxiredoxin (Prx). Queens showed more than two times higher CAT activity and more than seven times higher expression levels of the CAT gene RsCAT1 than workers. The CAT activity of termite queens was also markedly higher in comparison with other solitary insects and the queens of eusocial Hymenoptera. In addition, queens showed higher expression levels of the Prx gene RsPRX6. These results suggested that this efficient antioxidant system can partly explain why termite queens achieve long life. This study provides important insights into the evolutionary linkage of reproductive division of labor and the development of queens' oxidative stress resistance in social insects. PMID- 28076411 TI - Participatory Online Surveillance as a Supplementary Tool to Sentinel Doctors for Influenza-Like Illness Surveillance in Italy. AB - The monitoring of seasonal influenza yearly epidemics remains one of the main activity of national syndromic surveillance systems. The development of internet based surveillance tools has brought an innovative approach to seasonal influenza surveillance by directly involving self-selected volunteers among the general population reporting their health status on a weekly basis throughout the flu season. In this paper, we explore how Influweb, an internet-based monitoring system for influenza surveillance, deployed in Italy since 2008 has performed during three years from 2012 to 2015 in comparison with data collected during the same period by the Italian sentinel doctors surveillance system. PMID- 28076412 TI - Significant Local-Scale Plant-Insect Species Richness Relationship Independent of Abiotic Effects in the Temperate Cape Floristic Region Biodiversity Hotspot. AB - Globally plant species richness is a significant predictor of insect richness. Whether this is the result of insect diversity responding directly to plant diversity, or both groups responding in similar ways to extrinsic factors, has been much debated. Here we assess this relationship in the Cape Floristic Region (CFR), a biodiversity hotspot. The CFR has higher plant diversity than expected from latitude (i.e., abiotic conditions), but very little is known about the diversity of insects residing in this region. We first quantify diversity relationships at multiple spatial scales for one of the dominant plant families in the CFR, the Restionaceae, and its associated insect herbivore community. Plant and insect diversity are significantly positively correlated at the local scales (10-50 m; 0.1-3 km), but not at the regional scales (15-20 km; 50-70 km). The local scale relationship remains significantly positively correlated even when accounting for the influence of extrinsic variables and other vegetation attributes. This suggests that the diversity of local insect assemblages may be more strongly influenced by plant species richness than by abiotic variables. Further, vegetation age and plant structural complexity also influenced insect richness. The ratio of insect species per plant species in the CFR is comparable to other temperate regions around the world, suggesting that the insect diversity of the CFR is high relative to other areas of the globe with similar abiotic conditions, primarily as a result of the unusually high plant diversity in the region. PMID- 28076410 TI - Role for Egr1 in the Transcriptional Program Associated with Neuronal Differentiation of PC12 Cells. AB - PC12 cells are a well-established model to study how differences in signal transduction duration can elicit distinct cell behaviors. Epidermal growth factor (EGF) activates transient ERK signaling in PC12 cells that lasts 30-60 min, which in turn promotes proliferation; nerve growth factor (NGF) activates more sustained ERK signaling that lasts 4-6 h, which in turns induces neuronal differentiation. Data presented here extend a previous study by Mullenbrock et al. (2011) that demonstrated that sustained ERK signaling in response to NGF induces preferential expression of a 69-member gene set compared to transient ERK signaling in response to EGF and that the transcription factors AP-1 and CREB play a major role in the preferential expression of several genes within the set. Here, we examined whether the Egr family of transcription factors also contributes to the preferential expression of the gene set in response to NGF. Our data demonstrate that NGF causes transient induction of all Egr family member transcripts, but a corresponding induction of protein was detected for only Egr1 and 2. Chromatin immunoprecipitation experiments provided clearest evidence that, after induction, Egr1 binds 12 of the 69 genes that are preferentially expressed during sustained ERK signaling. In addition, Egr1 expression and binding upstream of its target genes were both sustained in response to NGF versus EGF within the same timeframe that its targets are preferentially expressed. These data thus provide evidence that Egr1 contributes to the transcriptional program activated by sustained ERK signaling in response to NGF, specifically by contributing to the preferential expression of its target genes identified here. PMID- 28076413 TI - Dynamic Characteristics of Ventilatory and Gas Exchange during Sinusoidal Walking in Humans. AB - Our present study investigated whether the ventilatory and gas exchange responses show different dynamics in response to sinusoidal change in cycle work rate or walking speed even if the metabolic demand was equivalent in both types of exercise. Locomotive parameters (stride length and step frequency), breath-by breath ventilation (VE) and gas exchange (CO2 output (VCO2) and O2 uptake (VO2)) responses were measured in 10 healthy young participants. The speed of the treadmill was sinusoidally changed between 3 km.h-1 and 6 km.h-1 with various periods (from 10 to 1 min). The amplitude of locomotive parameters against sinusoidal variation showed a constant gain with a small phase shift, being independent of the oscillation periods. In marked contrast, when the periods of the speed oscillations were shortened, the amplitude of VE decreased sharply whereas the phase shift of VE increased. In comparing walking and cycling at the equivalent metabolic demand, the amplitude of VE during sinusoidal walking (SW) was significantly greater than that during sinusoidal cycling (SC), and the phase shift became smaller. The steeper slope of linear regression for the VE amplitude ratio to VCO2 amplitude ratio was observed during SW than SC. These findings suggested that the greater amplitude and smaller phase shift of ventilatory dynamics were not equivalent between SW and SC even if the metabolic demand was equivalent between both exercises. Such phenomenon would be derived from central command in proportion to locomotor muscle recruitment (feedforward) and muscle afferent feedback. PMID- 28076414 TI - A MRI-Compatible Combined Mechanical Loading and MR Elastography Setup to Study Deformation-Induced Skeletal Muscle Damage in Rats. AB - Deformation of skeletal muscle in the proximity of bony structures may lead to deep tissue injury category of pressure ulcers. Changes in mechanical properties have been proposed as a risk factor in the development of deep tissue injury and may be useful as a diagnostic tool for early detection. MRE allows for the estimation of mechanical properties of soft tissue through analysis of shear wave data. The shear waves originate from vibrations induced by an external actuator placed on the tissue surface. In this study a combined Magnetic Resonance (MR) compatible indentation and MR Elastography (MRE) setup is presented to study mechanical properties associated with deep tissue injury in rats. The proposed setup allows for MRE investigations combined with damage-inducing large strain indentation of the Tibialis Anterior muscle in the rat hind leg inside a small animal MR scanner. An alginate cast allowed proper fixation of the animal leg with anatomical perfect fit, provided boundary condition information for FEA and provided good susceptibility matching. MR Elastography data could be recorded for the Tibialis Anterior muscle prior to, during, and after indentation. A decaying shear wave with an average amplitude of approximately 2 MUm propagated in the whole muscle. MRE elastograms representing local tissue shear storage modulus Gd showed significant increased mean values due to damage-inducing indentation (from 4.2 +/- 0.1 kPa before to 5.1 +/- 0.6 kPa after, p<0.05). The proposed setup enables controlled deformation under MRI-guidance, monitoring of the wound development by MRI, and quantification of tissue mechanical properties by MRE. We expect that improved knowledge of changes in soft tissue mechanical properties due to deep tissue injury, will provide new insights in the etiology of deep tissue injuries, skeletal muscle damage and other related muscle pathologies. PMID- 28076416 TI - The CCR2 Inhibitor Propagermanium Attenuates Diet-Induced Insulin Resistance, Adipose Tissue Inflammation and Non-Alcoholic Steatohepatitis. AB - BACKGROUND AND AIM: Obese patients with chronic inflammation in white adipose tissue (WAT) have an increased risk of developing non-alcoholic steatohepatitis (NASH). The C-C chemokine receptor-2 (CCR2) has a crucial role in the recruitment of immune cells to WAT and liver, thereby promoting the inflammatory component of the disease. Herein, we examined whether intervention with propagermanium, an inhibitor of CCR2, would attenuate tissue inflammation and NASH development. METHODS: Male C57BL/6J mice received a high-fat diet (HFD) for 0, 6, 12 and 24 weeks to characterize the development of early disease symptoms of NASH, i.e. insulin resistance and WAT inflammation (by hyperinsulinemic-euglycemic clamp and histology, respectively) and to define the optimal time point for intervention. In a separate study, mice were pretreated with HFD followed by propagermanium treatment (0.05% w/w) after 6 weeks (early intervention) or 12 weeks (late intervention). NASH was analyzed after 24 weeks of diet feeding. RESULTS: Insulin resistance in WAT developed after 6 weeks of HFD, which was paralleled by modest WAT inflammation. Insulin resistance and inflammation in WAT intensified after 12 weeks of HFD, and preceded NASH development. The subsequent CCR2 intervention experiment showed that early, but not late, propagermanium treatment attenuated insulin resistance. Only the early treatment significantly decreased Mcp-1 and CD11c gene expression in WAT, indicating reduced WAT inflammation. Histopathological analysis of liver demonstrated that propagermanium treatment decreased macrovesicular steatosis and tended to reduce lobular inflammation, with more pronounced effects in the early intervention group. Propagermanium improved the ratio between pro-inflammatory (M1) and anti-inflammatory (M2) macrophages, quantified by CD11c and Arginase-1 gene expression in both intervention groups. CONCLUSIONS: Overall, early propagermanium administration was more effective to improve insulin resistance, WAT inflammation and NASH compared to late intervention. These data suggest that therapeutic interventions for NASH directed at the MCP-1/CCR2 pathway should be initiated early. PMID- 28076417 TI - Colonization of Wheat, Maize and Cucumber by Paenibacillus polymyxa WLY78. AB - Paenibacillus polymyxa WLY78 is a nitrogen fixer and it can be potentially applied to biofertilizer in agriculture. In this study, P. polymyxa WLY78 is labelled with gfp gene. The GFP-labelled P. polymyxa WLY78 is used to inoculate wheat, maize and cucumber seedlings grown in the gnotobiotic system and in soil, respectively. Observation by confocal laser scanning microscope reveals that the GFP-labeled bacterial cells are mainly located on the root surface and epidermis of wheat, and only a few cells are present within cortical cells. In maize and cucumber seedlings, bacterial cells were colonized in epidermal and cortical cells, intercellular spaces and vascular system of root, stem and leaf tissue interiors besides on root surfaces. Higher densities of the bacterial cells in roots, stems and leaves indicated that P. polymyxa WLY78 cells could migrate from roots to stems and leaves of maize and cucumber. This study will provide insight into interaction between P. polymyxa WLY78 and host cells. PMID- 28076415 TI - Structure and Recognition of a Novel HIV-1 gp120-gp41 Interface Antibody that Caused MPER Exposure through Viral Escape. AB - A comprehensive understanding of the regions on HIV-1 envelope trimers targeted by broadly neutralizing antibodies may contribute to rational design of an HIV-1 vaccine. We previously identified a participant in the CAPRISA cohort, CAP248, who developed trimer-specific antibodies capable of neutralizing 60% of heterologous viruses at three years post-infection. Here, we report the isolation by B cell culture of monoclonal antibody CAP248-2B, which targets a novel membrane proximal epitope including elements of gp120 and gp41. Despite low maximum inhibition plateaus, often below 50% inhibitory concentrations, the breadth of CAP248-2B significantly correlated with donor plasma. Site-directed mutagenesis, X-ray crystallography, and negative-stain electron microscopy 3D reconstructions revealed how CAP248-2B recognizes a cleavage-dependent epitope that includes the gp120 C terminus. While this epitope is distinct, it overlapped in parts of gp41 with the epitopes of broadly neutralizing antibodies PGT151, VRC34, 35O22, 3BC315, and 10E8. CAP248-2B has a conformationally variable paratope with an unusually long 19 amino acid light chain third complementarity determining region. Two phenylalanines at the loop apex were predicted by docking and mutagenesis data to interact with the viral membrane. Neutralization by CAP248-2B is not dependent on any single glycan proximal to its epitope, and low neutralization plateaus could not be completely explained by N- or O-linked glycosylation pathway inhibitors, furin co-transfection, or pre-incubation with soluble CD4. Viral escape from CAP248-2B involved a cluster of rare mutations in the gp120-gp41 cleavage sites. Simultaneous introduction of these mutations into heterologous viruses abrogated neutralization by CAP248-2B, but enhanced neutralization sensitivity to 35O22, 4E10, and 10E8 by 10-100-fold. Altogether, this study expands the region of the HIV-1 gp120-gp41 quaternary interface that is a target for broadly neutralizing antibodies and identifies a set of mutations in the gp120 C terminus that exposes the membrane-proximal external region of gp41, with potential utility in HIV vaccine design. PMID- 28076418 TI - Sensorless Modeling of Varying Pulse Width Modulator Resolutions in Three-Phase Induction Motors. AB - A sensorless algorithm was developed to predict rotor speeds in an electric three phase induction motor. This sensorless model requires a measurement of the stator currents and voltages, and the rotor speed is predicted accurately without any mechanical measurement of the rotor speed. A model of an electric vehicle undergoing acceleration was built, and the sensorless prediction of the simulation rotor speed was determined to be robust even in the presence of fluctuating motor parameters and significant sensor errors. Studies were conducted for varying pulse width modulator resolutions, and the sensorless model was accurate for all resolutions of sinusoidal voltage functions. PMID- 28076419 TI - Stability of A Coevolving Host-parasite System Peaks at Intermediate Productivity. AB - Habitat productivity may affect the stability of consumer-resource systems, through both ecological and evolutionary mechanisms. We hypothesize that coevolving consumer-resource systems show more stable dynamics at intermediate resource availability, while very low-level resource supply cannot support sufficiently large populations of resource and consumer species to avoid stochastic extinction, and extremely resource-rich environments may promote escalatory arms-race-like coevolution that can cause strong fluctuations in species abundance and even extinction of one or both trophic levels. We tested these ideas by carrying out an experimental evolution study with a model bacterium-phage system (Pseudomonas fluorescens SBW25 and its phage SBW25Phi2). Consistent with our hypothesis, this system was most stable at intermediate resource supply (fewer extinction events and smaller magnitude of population fluctuation). In our experiment, the rate of coevolution between bacterial resistance and phage infectivity was correlated with the magnitude of population fluctuation, which may explain the different in stability between levels of resource supply. Crucially, our results are consistent with a suggestion that, among the two major modes of antagonistic coevolution, arms race is more likely than fluctuation selection dynamics to cause extinction events in consumer resource systems. This study suggests an important role of environment-dependent coevolutionary dynamics for the stability of consumer-resource species systems, therefore highlights the importance to consider contemporaneous evolutionary dynamics when studying the stability of ecosystems, particularly those under environmental changes. PMID- 28076420 TI - Chaperone-Mediated Autophagy Protein BAG3 Negatively Regulates Ebola and Marburg VP40-Mediated Egress. AB - Ebola (EBOV) and Marburg (MARV) viruses are members of the Filoviridae family which cause outbreaks of hemorrhagic fever. The filovirus VP40 matrix protein is essential for virus assembly and budding, and its PPxY L-domain motif interacts with WW-domains of specific host proteins, such as Nedd4 and ITCH, to facilitate the late stage of virus-cell separation. To identify additional WW-domain-bearing host proteins that interact with VP40, we used an EBOV PPxY-containing peptide to screen an array of 115 mammalian WW-domain-bearing proteins. Using this unbiased approach, we identified BCL2 Associated Athanogene 3 (BAG3), a member of the BAG family of molecular chaperone proteins, as a specific VP40 PPxY interactor. Here, we demonstrate that the WW-domain of BAG3 interacts with the PPxY motif of both EBOV and MARV VP40 and, unexpectedly, inhibits budding of both eVP40 and mVP40 virus-like particles (VLPs), as well as infectious VSV-EBOV recombinants. BAG3 is a stress induced protein that regulates cellular protein homeostasis and cell survival through chaperone-mediated autophagy (CMA). Interestingly, our results show that BAG3 alters the intracellular localization of VP40 by sequestering VP40 away from the plasma membrane. As BAG3 is the first WW-domain interactor identified that negatively regulates budding of VP40 VLPs and infectious virus, we propose that the chaperone-mediated autophagy function of BAG3 represents a specific host defense strategy to counteract the function of VP40 in promoting efficient egress and spread of virus particles. PMID- 28076422 TI - Monoclonal Antibody against G Glycoprotein Increases Respiratory Syncytial Virus Clearance In Vivo and Prevents Vaccine-Enhanced Diseases. AB - Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract illness in infants, young children, and the elderly. The G glycoprotein plays a role in host cell attachment and also modulates the host immune response, thereby inducing disease pathogenesis. We generated two monoclonal antibodies (mAbs; 5H6 and 3A5) against G protein core fragment (Gcf), which consisted of amino acid residues 131 to 230 from RSV A2 G protein. Epitope mapping study revealed that 5H6 specifically binds to the G/164-176 peptide that includes conserved sequences shared by both RSV A and B subtypes, and 3A5 binds to the G/190-204 peptide. Studies with mutant Gcf proteins in which cysteine residues were substituted with alanine revealed that 5H6 requires four cysteines for binding and 3A5 binds to Gcf variants with alanine substitutions better than wild-type. To determine if these mAbs reduce pulmonary viral infection, BALB/c mice were administered mAb and subsequently challenged with RSV. On day 4 post-infection, lung viral titers were reduced by up to 93% with the 5H6 injection and 90% with the 3A5 injection, indicating that prophylactic injection of these mAbs contributes to RSV clearance in vivo. Importantly, 5H6 injection reduced vaccine-enhanced diseases. Overall, our results suggest that this novel anti-G mAb could be used as a prophylactic regimen against RSV diseases. PMID- 28076421 TI - Oscillatory Dynamics Supporting Semantic Cognition: MEG Evidence for the Contribution of the Anterior Temporal Lobe Hub and Modality-Specific Spokes. AB - The "hub and spoke model" of semantic representation suggests that the multimodal features of objects are drawn together by an anterior temporal lobe (ATL) "hub", while modality-specific "spokes" capture perceptual/action features. However, relatively little is known about how these components are recruited through time to support object identification. We used magnetoencephalography to measure neural oscillations within left ATL, lateral fusiform cortex (FC) and central sulcus (CS) during word-picture matching at different levels of specificity (employing superordinate vs. specific labels) for different categories (manmade vs. animal). This allowed us to determine (i) when each site was sensitive to semantic category and (ii) whether this was modulated by task demands. In ATL, there were two phases of response: from around 100 ms post-stimulus there were phasic bursts of low gamma activity resulting in reductions in oscillatory power, relative to a baseline period, that were modulated by both category and specificity; this was followed by more sustained power decreases across frequency bands from 250 ms onwards. In the spokes, initial power increases were not stronger for specific identification, while later power decreases were stronger for specific-level identification in FC for animals and in CS for manmade objects (from around 150 ms and 200 ms, respectively). These data are inconsistent with a temporal sequence in which early sensory-motor activity is followed by later retrieval in ATL. Instead, knowledge emerges from the rapid recruitment of both hub and spokes, with early specificity and category effects in the ATL hub. The balance between these components depends on semantic category and task, with visual cortex playing a greater role in the fine-grained identification of animals and motor cortex contributing to the identification of tools. PMID- 28076423 TI - Unique Features of Germline Variation in Five Egyptian Familial Breast Cancer Families Revealed by Exome Sequencing. AB - Genetic predisposition increases the risk of familial breast cancer. Recent studies indicate that genetic predisposition for familial breast cancer can be ethnic-specific. However, current knowledge of genetic predisposition for the disease is predominantly derived from Western populations. Using this existing information as the sole reference to judge the predisposition in non-Western populations is not adequate and can potentially lead to misdiagnosis. Efforts are required to collect genetic predisposition from non-Western populations. The Egyptian population has high genetic variations in reflecting its divergent ethnic origins, and incident rate of familial breast cancer in Egypt is also higher than the rate in many other populations. Using whole exome sequencing, we investigated genetic predisposition in five Egyptian familial breast cancer families. No pathogenic variants in BRCA1, BRCA2 and other classical breast cancer-predisposition genes were present in these five families. Comparison of the genetic variants with those in Caucasian familial breast cancer showed that variants in the Egyptian families were more variable and heterogeneous than the variants in Caucasian families. Multiple damaging variants in genes of different functional categories were identified either in a single family or shared between families. Our study demonstrates that genetic predisposition in Egyptian breast cancer families may differ from those in other disease populations, and supports a comprehensive screening of local disease families to determine the genetic predisposition in Egyptian familial breast cancer. PMID- 28076424 TI - Sensitization of TRPA1 by Protein Kinase A. AB - The TRPA1 ion channel is expressed in nociceptive (pain-sensitive) somatosensory neurons and is activated by a wide variety of chemical irritants, such as acrolein in smoke or isothiocyanates in mustard. Here, we investigate the enhancement of TRPA1 function caused by inflammatory mediators, which is thought to be important in lung conditions such as asthma and COPD. Protein kinase A is an important kinase acting downstream of inflammatory mediators to cause sensitization of TRPA1. By using site-directed mutagenesis, patch-clamp electrophysiology and calcium imaging we identify four amino acid residues, S86, S317, S428, and S972, as the principal targets of PKA-mediated phosphorylation and sensitization of TRPA1. PMID- 28076425 TI - The Fatty Acid Profile and Oxidative Stability of Meat from Turkeys Fed Diets Enriched with n-3 Polyunsaturated Fatty Acids and Dried Fruit Pomaces as a Source of Polyphenols. AB - The aim of this study was to determine the efficacy of different dietary fruit pomaces in reducing lipid oxidation in the meat of turkeys fed diets with a high content of n-3 polyunsaturated fatty acids (PUFAs). Over a period of 4 weeks before slaughter, turkeys were fed diets with the addition of 5% dried apple, blackcurrant, strawberry and seedless strawberry pomaces (groups AP, BP, SP and SSP, respectively) and 2.5% linseed oil. Pomaces differed in the content (from 5.5 in AP to 43.1 mg/g in SSP) and composition of polyphenols Proanthocyanidins were the main polyphenolic fraction in all pomaces, AP contained flavone glycosides and dihydrochalcones, BP contained anthocyanins, and SP and SSP ellagitannins. The n-6/n-3 PUFA ratio in all diets was comparable and lower than 2:1. In comparison with groups C and AP, the percentage of n-3 PUFAs in the total fatty acid pool of white meat from the breast muscles of turkeys in groups BP, SP and SSP was significantly higher, proportionally to the higher content of alpha linolenic acid in berry pomaces. The fatty acid profile of dark meat from thigh muscles, including the n-6/n-3 PUFA ratio, was similar and lower than 3:1 in all groups. Vitamin A levels in raw breast muscles were higher in group AP than in groups C and BP (P<0.05). The addition of fruit pomaces to turkey diets lowered vitamin E concentrations (P = 0.001) in raw breast muscles relative to group C. Diets supplemented with fruit pomaces significantly lowered the concentration of thiobarbituric acid reactive substances (TBARS) in raw, frozen and cooked meat. Our results indicate that the dietary application of dried fruit pomaces increases the oxidative stability of meat from turkeys fed linseed oil, and strawberry pomace exerted the most desirable effects due to its highest polyphenol content and antioxidant potential. PMID- 28076426 TI - Evidence of a Vocalic Proto-System in the Baboon (Papio papio) Suggests Pre Hominin Speech Precursors. AB - Language is a distinguishing characteristic of our species, and the course of its evolution is one of the hardest problems in science. It has long been generally considered that human speech requires a low larynx, and that the high larynx of nonhuman primates should preclude their producing the vowel systems universally found in human language. Examining the vocalizations through acoustic analyses, tongue anatomy, and modeling of acoustic potential, we found that baboons (Papio papio) produce sounds sharing the F1/F2 formant structure of the human [i ae alpha o u] vowels, and that similarly with humans those vocalic qualities are organized as a system on two acoustic-anatomic axes. This confirms that hominoids can produce contrasting vowel qualities despite a high larynx. It suggests that spoken languages evolved from ancient articulatory skills already present in our last common ancestor with Cercopithecoidea, about 25 MYA. PMID- 28076427 TI - Biting Midges (Diptera: Ceratopogonidae) from Cambay Amber Indicate that the Eocene Fauna of the Indian Subcontinent Was Not Isolated. AB - India's unique and highly diverse biota combined with its unique geodynamical history has generated significant interest in the patterns and processes that have shaped the current distribution of India's flora and fauna and their biogeographical relationships. Fifty four million year old Cambay amber from northwestern India provides the opportunity to address questions relating to endemism and biogeographic history by studying fossil insects. Within the present study seven extant and three fossil genera of biting midges are recorded from Cambay amber and five new species are described: Eohelea indica Stebner & Szadziewski n. sp., Gedanohelea gerdesorum Stebner & Szadziewski n. sp., Meunierohelea cambayana Stebner & Szadziewski n. sp., Meunierohelea borkenti Stebner & Szadziewski n. sp., and Meunierohelea orientalis Stebner & Szadziewski n. sp. Fossils of species in the genera Leptoconops Skuse, 1889, Forcipomyia Meigen, 1818, Brachypogon Kieffer, 1899, Stilobezzia Kieffer, 1911, Serromyia Meigen, 1818, and Mantohelea Szadziewski, 1988 are recorded without formal description. Furthermore, one fossil belonging to the genus Camptopterohelea Wirth & Hubert, 1960 is included in the present study. Our study reveals faunal links among Ceratopogonidae from Cambay amber and contemporaneous amber from Fushun, China, Eocene Baltic amber from Europe, as well as the modern Australasian and the Oriental regions. These findings imply that faunal exchange between Europe, Asia and India took place before the formation of Cambay amber in the early Eocene. PMID- 28076429 TI - Turning Simulation into Estimation: Generalized Exchange Algorithms for Exponential Family Models. AB - The Single Variable Exchange algorithm is based on a simple idea; any model that can be simulated can be estimated by producing draws from the posterior distribution. We build on this simple idea by framing the Exchange algorithm as a mixture of Metropolis transition kernels and propose strategies that automatically select the more efficient transition kernels. In this manner we achieve significant improvements in convergence rate and autocorrelation of the Markov chain without relying on more than being able to simulate from the model. Our focus will be on statistical models in the Exponential Family and use two simple models from educational measurement to illustrate the contribution. PMID- 28076428 TI - Does Measles Vaccination Reduce the Risk of Acute Respiratory Infection (ARI) and Diarrhea in Children: A Multi-Country Study? AB - BACKGROUND: Pneumonia and diarrhea occur either as complications or secondary infections in measles affected children. So, the integrated Global Action Plan for Pneumonia and Diarrhea (GAPPD) by WHO and UNICEF includes measles vaccination as preventive measure in children. The objective of the study is to examine the effect of measles vaccination on Acute Respiratory Infection (ARI) and diarrhea in children in the Democratic Republic of Congo, Ethiopia, India, Nigeria, and Pakistan. METHODS: We analyzed data from the most recent rounds of Demographic and Health Surveys (DHS) in the selected countries. We included children age 12 59 months in the analysis. We used multivariable binary logistic regression to examine the effect of measles vaccination on ARI and diarrhea in children. We also estimated Vaccination Effectiveness (VE). FINDINGS: More than 60 percent of the children age 12-59 months were given measles vaccine before the survey in the Democratic Republic of Congo, Ethiopia, India and Pakistan. Children who were given the measles vaccine were less likely to suffer from ARI than unvaccinated children in India and Pakistan. Children who were given the measles vaccine had a lower risk of diarrhea than those who did not receive it in all the selected countries except Ethiopia. Measles vaccination was associated with reduction in ARI cases by 15-30 percent in India and Pakistan, and diarrhea cases by 12-22 percent in the Democratic Republic of Congo, India, Nigeria and Pakistan. CONCLUSION: The receipt of the measles vaccine was associated with decrease in ARI and diarrhea in children. The immunization program must ensure that each child gets the recommended doses of measles vaccine at the appropriate age. The measles vaccination should be given more attention as a preventive intervention under the Global Action Plan for Pneumonia and Diarrhea (GAPPD) in all low and middle-income countries. PMID- 28076430 TI - Effects of Zn Deficiency and Bicarbonate on the Growth and Photosynthetic Characteristics of Four Plant Species. AB - Calcareous soils are characterized by low nutrient contents, high bicarbonate (HCO3-) content, and high alkalinity. The effects of HCO3- addition under zinc sufficient (+Zn) and zinc-deficient (-Zn) conditions on the growth and photosynthetic characteristics of seedlings of two Moraceae species (Broussonetia papyrifera and Morus alba) and two Brassicaceae species (Orychophragmus violaceus and Brassica napus) were investigated. These four species were hydroponically grown in nutrient solution with 0 mM Zn (-Zn) or 0.02 mM Zn (+Zn) and 0 mM or 10 mM HCO3-. The photosynthetic response to HCO3- treatment, Zn deficiency, or both varied according to plant species. Of the four species, Broussonetia papyrifera showed the best adaptability to Zn deficiency for both the 0 mM and 10 mM HCO3- treatments due to its strong growth and minimal inhibition of photosynthesis and photosystem II (PS II). Brassica napus was sensitive to Zn deficiency, HCO3- treatment, or both as evidenced by the considerable inhibition of photosynthesis and high PS II activity. The results indicated different responses of various plant species to Zn deficiency and excess HCO3-. Broussonetia papyrifera was shown to have potential as a pioneer species in karst regions. PMID- 28076432 TI - Development of a Humane Slaughter Device for Green Turtles for Use by Traditional Owners in the Torres Strait Islands, Australia. AB - Marine turtles are caught and slaughtered for consumption as part of traditional indigenous community harvest in Australia as well as in many countries in which marine turtles can be found. However, changes to the Animal Care and Protection Act 2001 in 2012 resulted in Australian indigenous hunters becoming potentially liable to prosecution for using traditional practices to slaughter marine turtles. To provide indigenous hunters with an alternative scientifically tested method to hunt, we developed and tested a humane method as an option to use in indigenous communities. Between 2012 and 2015, a device was developed, tested on 11 carcasses to determine effectiveness and repeatability, used on 5 anaesthetised animals independently diagnosed as candidates for euthanasia, and ultimately used on 2 healthy, conscious animals as part of normal indigenous community subsistence harvesting under observation before being left with the communities for use. Feedback was sought from the communities on the suitability and potential adoption of the device. The device effectively ablated the hind brain and severed the spinal cord when deployed in 81% (9/11) of the tested carcasses, with death in 100% (5/5) of turtles, on average, within 78 seconds of deployment on anaesthetised turtles and death in 100% (2/2) of turtles, on average, within 144 seconds when deployed on healthy turtles within community. Failure to ablate the hindbrain and sever the spinal cord in the cadaver cases was due to incorrect deployment of the device. This device showed promise as an alternative euthanasia method available to indigenous communities of the Torres Straits. Further work is required to encourage acceptance by hunters. PMID- 28076431 TI - Knee Cartilage Thickness, T1rho and T2 Relaxation Time Are Related to Articular Cartilage Loading in Healthy Adults. AB - Cartilage is responsive to the loading imposed during cyclic routine activities. However, the local relation between cartilage in terms of thickness distribution and biochemical composition and the local contact pressure during walking has not been established. The objective of this study was to evaluate the relation between cartilage thickness, proteoglycan and collagen concentration in the knee joint and knee loading in terms of contact forces and pressure during walking. 3D gait analysis and MRI (3D-FSE, T1rho relaxation time and T2 relaxation time sequence) of fifteen healthy subjects were acquired. Experimental gait data was processed using musculoskeletal modeling to calculate the contact forces, impulses and pressure distribution in the tibiofemoral joint. Correlates to local cartilage thickness and mean T1rho and T2 relaxation times of the weight-bearing area of the femoral condyles were examined. Local thickness was significantly correlated with local pressure: medial thickness was correlated with medial condyle contact pressure and contact force, and lateral condyle thickness was correlated with lateral condyle contact pressure and contact force during stance. Furthermore, average T1rho and T2 relaxation time correlated significantly with the peak contact forces and impulses. Increased T1rho relaxation time correlated with increased shear loading, decreased T1rho and T2 relaxation time correlated with increased compressive forces and pressures. Thicker cartilage was correlated with higher condylar loading during walking, suggesting that cartilage thickness is increased in those areas experiencing higher loading during a cyclic activity such as gait. Furthermore, the proteoglycan and collagen concentration and orientation derived from T1rho and T2 relaxation measures were related to loading. PMID- 28076433 TI - Enhanced Rb/E2F and TSC/mTOR Pathways Induce Synergistic Inhibition in PDGF Induced Proliferation in Vascular Smooth Muscle Cells. AB - Platelet-derived growth factor (PDGF) plays an essential role in proliferation of vascular smooth muscle cells (VSMCs). The Rb/E2F and TSC/mTOR pathways contribute to the proliferation of VSMCs, but its exact roles in PDGF-induced proliferation are unclear. In this study, we demonstrated the roles of Rb/E2F and TSC/mTOR pathways in PDGF-induced proliferation in VSMCs. We found that PDGF stimulates the activity of E2F and mTOR pathways, and knockdown of either Rb or TSC2 increases PDGF-induced proliferation in VSMCs. More interestingly, we revealed that enhancing both E2F and mTOR activity leads to synergistic inhibition of PDGF induced proliferation in VSMCs. We further identified that the synergistic inhibition effect is caused by the induced oxidative stress. Summarily, these data suggest the important regulations of Rb/E2F and TSC/mTOR pathways in PDGF induced proliferation in VSMCs, and also present a promising way to limit deregulated proliferation by PDGF induction in VSMCs. PMID- 28076435 TI - Walking Ahead: The Headed Social Force Model. AB - Human motion models are finding an increasing number of novel applications in many different fields, such as building design, computer graphics and robot motion planning. The Social Force Model is one of the most popular alternatives to describe the motion of pedestrians. By resorting to a physical analogy, individuals are assimilated to point-wise particles subject to social forces which drive their dynamics. Such a model implicitly assumes that humans move isotropically. On the contrary, empirical evidence shows that people do have a preferred direction of motion, walking forward most of the time. Lateral motions are observed only in specific circumstances, such as when navigating in overcrowded environments or avoiding unexpected obstacles. In this paper, the Headed Social Force Model is introduced in order to improve the realism of the trajectories generated by the classical Social Force Model. The key feature of the proposed approach is the inclusion of the pedestrians' heading into the dynamic model used to describe the motion of each individual. The force and torque representing the model inputs are computed as suitable functions of the force terms resulting from the traditional Social Force Model. Moreover, a new force contribution is introduced in order to model the behavior of people walking together as a single group. The proposed model features high versatility, being able to reproduce both the unicycle-like trajectories typical of people moving in open spaces and the point-wise motion patterns occurring in high density scenarios. Extensive numerical simulations show an increased regularity of the resulting trajectories and confirm a general improvement of the model realism. PMID- 28076434 TI - Diabetes and Breast Cancer Subtypes. AB - BACKGROUND: Women with diabetes have a worse survival after breast cancer diagnosis compared to women without diabetes. This may be due to a different etiological profile, leading to the development of more aggressive breast cancer subtypes. Our aim was to investigate whether insulin and non-insulin treated women with diabetes develop specific clinicopathological breast cancer subtypes compared to women without diabetes. METHODS AND FINDINGS: This cross-sectional study included randomly selected patients with invasive breast cancer diagnosed in 2000-2010. Stratified by age at breast cancer diagnosis (<=50 and >50 years), women with diabetes were 2:1 frequency-matched on year of birth and age at breast cancer diagnosis (both in 10-year categories) to women without diabetes, to select ~300 patients with tumor tissue available. Tumor MicroArrays were stained by immunohistochemistry for estrogen and progesterone receptor (ER, PR), HER2, Ki67, CK5/6, CK14, and p63. A pathologist scored all stains and revised morphology and grade. Associations between diabetes/insulin treatment and clinicopathological subtypes were analyzed using multivariable logistic regression. Morphology and grade were not significantly different between women with diabetes (n = 211) and women without diabetes (n = 101), irrespective of menopausal status. Premenopausal women with diabetes tended to have more often PR negative (OR = 2.44(95%CI:1.07-5.55)), HER2-negative (OR = 2.84(95%CI:1.11 7.22)), and basal-like (OR = 3.14(95%CI:1.03-9.60) tumors than the women without diabetes, with non-significantly increased frequencies of ER-negative (OR = 2.48(95%CI:0.95-6.45)) and triple negative (OR = 2.60(95%CI:0.88-7.67) tumors. After adjustment for age and BMI, the associations remained similar in size but less significant. We observed no evidence for associations of clinicopathological subtypes with diabetes in postmenopausal women, or with insulin treatment in general. CONCLUSIONS: We found no compelling evidence that women with diabetes, treated with or without insulin, develop different breast cancer subtypes than women without diabetes. However, premenopausal women with diabetes tended to develop breast tumors that do not express hormonal receptors, which are typically associated with poor prognosis. PMID- 28076436 TI - Correction: A Network-Based Data Integration Approach to Support Drug Repurposing and Multi-Target Therapies in Triple Negative Breast Cancer. AB - [This corrects the article DOI: 10.1371/journal.pone.0162407.]. PMID- 28076438 TI - The Roles of Sea-Ice, Light and Sedimentation in Structuring Shallow Antarctic Benthic Communities. AB - On polar coasts, seasonal sea-ice duration strongly influences shallow marine environments by affecting environmental conditions, such as light, sedimentation, and physical disturbance. Sea-ice dynamics are changing in response to climate, but there is limited understanding of how this might affect shallow marine environments and benthos. Here we present a unique set of physical and biological data from a single region of Antarctic coast, and use it to gain insights into factors shaping polar benthic communities. At sites encompassing a gradient of sea-ice duration, we measured temporal and spatial variation in light and sedimentation and hard-substrate communities at different depths and substrate orientations. Biological trends were highly correlated with sea-ice duration, and appear to be driven by opposing gradients in light and sedimentation. As sea-ice duration decreased, there was increased light and reduced sedimentation, and concurrent shifts in community structure from invertebrate to algal dominance. Trends were strongest on shallower, horizontal surfaces, which are most exposed to light and sedimentation. Depth and substrate orientation appear to mediate exposure of benthos to these factors, thereby tempering effects of sea-ice and increasing biological heterogeneity. However, while light and sedimentation both varied spatially with sea-ice, their dynamics differed temporally. Light was sensitive to the site-specific date of sea-ice breakout, whereas sedimentation fluctuated at a regional scale coincident with the summer phytoplankton bloom. Sea-ice duration is clearly the overarching force structuring these shallow Antarctic benthic communities, but direct effects are imposed via light and sedimentation, and mediated by habitat characteristics. PMID- 28076437 TI - Mutations in Splicing Factor Genes Are a Major Cause of Autosomal Dominant Retinitis Pigmentosa in Belgian Families. AB - PURPOSE: Autosomal dominant retinitis pigmentosa (adRP) is characterized by an extensive genetic heterogeneity, implicating 27 genes, which account for 50 to 70% of cases. Here 86 Belgian probands with possible adRP underwent genetic testing to unravel the molecular basis and to assess the contribution of the genes underlying their condition. METHODS: Mutation detection methods evolved over the past ten years, including mutation specific methods (APEX chip analysis), linkage analysis, gene panel analysis (Sanger sequencing, targeted next-generation sequencing or whole exome sequencing), high-resolution copy number screening (customized microarray-based comparative genomic hybridization). Identified variants were classified following American College of Medical Genetics and Genomics (ACMG) recommendations. RESULTS: Molecular genetic screening revealed mutations in 48/86 cases (56%). In total, 17 novel pathogenic mutations were identified: four missense mutations in RHO, five frameshift mutations in RP1, six mutations in genes encoding spliceosome components (SNRNP200, PRPF8, and PRPF31), one frameshift mutation in PRPH2, and one frameshift mutation in TOPORS. The proportion of RHO mutations in our cohort (14%) is higher than reported in a French adRP population (10.3%), but lower than reported elsewhere (16.5-30%). The prevalence of RP1 mutations (10.5%) is comparable to other populations (3.5%-10%). The mutation frequency in genes encoding splicing factors is unexpectedly high (altogether 19.8%), with PRPF31 the second most prevalent mutated gene (10.5%). PRPH2 mutations were found in 4.7% of the Belgian cohort. Two families (2.3%) have the recurrent NR2E3 mutation p.(Gly56Arg). The prevalence of the recurrent PROM1 mutation p.(Arg373Cys) was higher than anticipated (3.5%). CONCLUSIONS: Overall, we identified mutations in 48 of 86 Belgian adRP cases (56%), with the highest prevalence in RHO (14%), RP1 (10.5%) and PRPF31 (10.5%). Finally, we expanded the molecular spectrum of PRPH2, PRPF8, RHO, RP1, SNRNP200, and TOPORS-associated adRP by the identification of 17 novel mutations. PMID- 28076439 TI - Predictors of Student Productivity in Biomedical Graduate School Applications. AB - Many US biomedical PhD programs receive more applications for admissions than they can accept each year, necessitating a selective admissions process. Typical selection criteria include standardized test scores, undergraduate grade point average, letters of recommendation, a resume and/or personal statement highlighting relevant research or professional experience, and feedback from interviews with training faculty. Admissions decisions are often founded on assumptions that these application components correlate with research success in graduate school, but these assumptions have not been rigorously tested. We sought to determine if any application components were predictive of student productivity measured by first-author student publications and time to degree completion. We collected productivity metrics for graduate students who entered the umbrella first-year biomedical PhD program at the University of North Carolina at Chapel Hill from 2008-2010 and analyzed components of their admissions applications. We found no correlations of test scores, grades, amount of previous research experience, or faculty interview ratings with high or low productivity among those applicants who were admitted and chose to matriculate at UNC. In contrast, ratings from recommendation letter writers were significantly stronger for students who published multiple first-author papers in graduate school than for those who published no first-author papers during the same timeframe. We conclude that the most commonly used standardized test (the general GRE) is a particularly ineffective predictive tool, but that qualitative assessments by previous mentors are more likely to identify students who will succeed in biomedical graduate research. Based on these results, we conclude that admissions committees should avoid over-reliance on any single component of the application and de-emphasize metrics that are minimally predictive of student productivity. We recommend continual tracking of desired training outcomes combined with retrospective analysis of admissions practices to guide both application requirements and holistic application review. PMID- 28076440 TI - Application of a Cloud Model-Set Pair Analysis in Hazard Assessment for Biomass Gasification Stations. AB - Because a biomass gasification station includes various hazard factors, hazard assessment is needed and significant. In this article, the cloud model (CM) is employed to improve set pair analysis (SPA), and a novel hazard assessment method for a biomass gasification station is proposed based on the cloud model-set pair analysis (CM-SPA). In this method, cloud weight is proposed to be the weight of index. In contrast to the index weight of other methods, cloud weight is shown by cloud descriptors; hence, the randomness and fuzziness of cloud weight will make it effective to reflect the linguistic variables of experts. Then, the cloud connection degree (CCD) is proposed to replace the connection degree (CD); the calculation algorithm of CCD is also worked out. By utilizing the CCD, the hazard assessment results are shown by some normal clouds, and the normal clouds are reflected by cloud descriptors; meanwhile, the hazard grade is confirmed by analyzing the cloud descriptors. After that, two biomass gasification stations undergo hazard assessment via CM-SPA and AHP based SPA, respectively. The comparison of assessment results illustrates that the CM-SPA is suitable and effective for the hazard assessment of a biomass gasification station and that CM SPA will make the assessment results more reasonable and scientific. PMID- 28076441 TI - Effects of an Integrated 'Fast Track' Rehabilitation Service for Multi-Trauma Patients: A Non-Randomized Clinical Trial in the Netherlands. AB - OBJECTIVES: The effects on health related outcomes of a newly-developed rehabilitation program, called 'supported Fast Track multi-trauma rehabilitation service' (Fast Track), were evaluated in comparison with conventional trauma rehabilitation service (Care as Usual). METHODS: Prospective, multi-center, non randomized controlled study. Between 2009 and 2012, 132 adult multi-trauma patients were included: 65 Fast Track and 67 Care as Usual patients with an Injury Severity Score >=16, complex multiple injuries in several extremities or complex pelvic and/or acetabulum fractures. The Fast Track program involved: integrated coordination between trauma surgeon and rehabilitation physician, shorter stay in hospital with faster transfer to a specialized trauma rehabilitation unit, earlier start of multidisciplinary treatment and 'non-weight bearing' mobilization. Primary outcomes were functional status (FIM) and quality of life (SF-36) measured through questionnaires at baseline, 3, 6, 9 and 12 months post-trauma. Outcomes were analyzed using a linear mixed-effects regression model. RESULTS: The FIM scores significantly increased between 0 and 3 months (p<0.001) for both groups showing that they had improved overall, and continued to improve between 3 and 6 months for Fast Track (p = 0.04) and between 3 and 9 months for Care as Usual (p = 0.03). SF-36 scores significantly improved in both groups between 3 and 6 months (Fast Track, p<0.001; Care as Usual, p = 0.01). At 12 months, SF-36 scores were still below (self-reported) baseline measurements of patient health prior to the accident. However, the FIM and SF-36 scores differed little between the groups at any of the measured time points. CONCLUSION: Both Fast Track and Care as Usual rehabilitation programs were effective in that multi-trauma patients improved their functional status and quality of life. A faster (maximum) recovery in functional status was observed for Fast Track at 6 months compared to 9 months for Care as Usual. At twelve months follow-up no differential effects between treatment conditions were found. TRIAL REGISTRATION: ISRCTN68246661. PMID- 28076442 TI - Subfoveal Choroidal Thickness in Central Serous Chorioretinopathy: A Meta Analysis. AB - PURPOSE: To evaluate the relationship between subfoveal choroidal thickness (SFCT) and eyes with central serous chorioretinopathy (CSC) versus fellow or control eyes. METHODS: We performed a meta-analysis using databases including PubMed, Embase and ISI Web of Science to find relevant studies. Weighted mean difference (WMD) was calculated for the SFCT in CSC eyes, the unaffected fellow eyes and normal controls. RESULTS: Twelve studies were selected for this meta analysis, including 1108 eyes (397 CSC eyes, 228 unaffected fellow eyes and 483 eyes of normal controls). The meta-analysis clearly demonstrated that the subfoveal choiroid of eyes with a clinical presentation of CSC was thickened compared to unaffected fellow eyes (WMD = 52.81, 95% confidence interval (CI), 39.13-66.49, P<0.00001) and was thickened compared to control eyes (WMD = 145.03, 95%CI, 121.33-168.73, P<0.00001). The mean SFCT measurement of the unaffected fellow eyes showed also significantly increased choroidal thickness compared to that of normal control eyes (WMD = 77.20, 95% CI, 44.98-109.42, P<0.00001). Similar results were obtained in a sub-analysis based on the same instrument. CONCLUSION: It is demonstrated that SFCT is significantly increased in eyes with clinical manifestation of CSC, and in the clinically non-manifested fellow eyes. These results support the hypothesis that CSC is a bilateral disorder with an initial unilateral clinical presentation. PMID- 28076443 TI - Predicting Reoffending Using the Structured Assessment of Violence Risk in Youth (SAVRY): A 5-Year Follow-Up Study of Male Juvenile Offenders in Hunan Province, China. AB - BACKGROUND: Juvenile violent offending is a serious worldwide public health issue. OBJECTIVE: The study examined whether the Structured Assessment of Violence Risk in Youth (SAVRY) can be used to predict violent reoffending in Chinese male juvenile offenders, and to determine which risk/protective domains (items) are associated with violent recidivism. METHODS: A total of 246 male juvenile offenders were recruited. SAVRY domains were scored by trained raters based on file review and interviews with participants and their legal guardians. Information on further arrests, charges, or convictions for violent offences were collected from police records over a five year follow-up. RESULTS: Over the course of the five year follow-up periods, 63 (25.6%) juvenile offenders were re arrested for a further violent reoffence. Receiver Operating Characteristic (ROC) analyses showed Areas Under the Curve (AUCs) ranging from 0.60 to 0.68 for the SAVRY total, risk and protective score domains. Univariate logistic regression analysis showed that 7 of the 30 SAVRY items were significantly associated with reoffending; explaining 36.2% of the variance. Backward stepwise multiple logistic regression analysis showed the independently predictive items were items 2 ('history of non-violent offending'), 17 ('negative attitudes'), 18 ('risk taking/impulsivity'), and 20 ('anger management problems'). Together these four items explained 25.0% of the variance in reoffending. CONCLUSIONS: The results suggested that the SAVRY can be meaningfully used to inform the development and evaluation of effective violence risk assessment and management approaches for male juvenile offenders detained in a Youth Detention Center in Hunan province, China. PMID- 28076444 TI - WiseEye: Next Generation Expandable and Programmable Camera Trap Platform for Wildlife Research. AB - The widespread availability of relatively cheap, reliable and easy to use digital camera traps has led to their extensive use for wildlife research, monitoring and public outreach. Users of these units are, however, often frustrated by the limited options for controlling camera functions, the generation of large numbers of images, and the lack of flexibility to suit different research environments and questions. We describe the development of a user-customisable open source camera trap platform named 'WiseEye', designed to provide flexible camera trap technology for wildlife researchers. The novel platform is based on a Raspberry Pi single-board computer and compatible peripherals that allow the user to control its functions and performance. We introduce the concept of confirmatory sensing, in which the Passive Infrared triggering is confirmed through other modalities (i.e. radar, pixel change) to reduce the occurrence of false positives images. This concept, together with user-definable metadata, aided identification of spurious images and greatly reduced post-collection processing time. When tested against a commercial camera trap, WiseEye was found to reduce the incidence of false positive images and false negatives across a range of test conditions. WiseEye represents a step-change in camera trap functionality, greatly increasing the value of this technology for wildlife research and conservation management. PMID- 28076445 TI - Emerging Bordetella pertussis Strains Induce Enhanced Signaling of Human Pattern Recognition Receptors TLR2, NOD2 and Secretion of IL-10 by Dendritic Cells. AB - Vaccines against pertussis have been available for more than 60 years. Nonetheless, this highly contagious disease is reemerging even in countries with high vaccination coverage. Genetic changes of Bordetella pertussis over time have been suggested to contribute to the resurgence of pertussis, as these changes may favor escape from vaccine-induced immunity. Nonetheless, studies on the effects of these bacterial changes on the immune response are limited. Here, we characterize innate immune recognition and activation by a collection of genetically diverse B. pertussis strains isolated from Dutch pertussis patients before and after the introduction of the pertussis vaccines. For this purpose, we used HEK-Blue cells transfected with human pattern recognition receptors TLR2, TLR4, NOD2 and NOD1 as a high throughput system for screening innate immune recognition of more than 90 bacterial strains. Physiologically relevant human monocyte derived dendritic cells (moDC), purified from peripheral blood of healthy donors were also used. Findings indicate that, in addition to inducing TLR2 and TLR4 signaling, all B. pertussis strains activate the NOD-like receptor NOD2 but not NOD1. Furthermore, we observed a significant increase in TLR2 and NOD2, but not TLR4, activation by strains circulating after the introduction of pertussis vaccines. When using moDC, we observed that the recently circulating strains induced increased activation of these cells with a dominant IL-10 production. In addition, we observed an increased expression of surface markers including the regulatory molecule PD-L1. Expression of PD-L1 was decreased upon blocking TLR2. These in vitro findings suggest that emerging B. pertussis strains have evolved to dampen the vaccine-induced inflammatory response, which would benefit survival and transmission of this pathogen. Understanding how this disease has resurged in a highly vaccinated population is crucial for the design of improved vaccines against pertussis. PMID- 28076446 TI - Downscaling Global Emissions and Its Implications Derived from Climate Model Experiments. AB - In climate change research, future scenarios of greenhouse gas and air pollutant emissions generated by integrated assessment models (IAMs) are used in climate models (CMs) and earth system models to analyze future interactions and feedback between human activities and climate. However, the spatial resolutions of IAMs and CMs differ. IAMs usually disaggregate the world into 10-30 aggregated regions, whereas CMs require a grid-based spatial resolution. Therefore, downscaling emissions data from IAMs into a finer scale is necessary to input the emissions into CMs. In this study, we examined whether differences in downscaling methods significantly affect climate variables such as temperature and precipitation. We tested two downscaling methods using the same regionally aggregated sulfur emissions scenario obtained from the Asian-Pacific Integrated Model/Computable General Equilibrium (AIM/CGE) model. The downscaled emissions were fed into the Model for Interdisciplinary Research on Climate (MIROC). One of the methods assumed a strong convergence of national emissions intensity (e.g., emissions per gross domestic product), while the other was based on inertia (i.e., the base-year remained unchanged). The emissions intensities in the downscaled spatial emissions generated from the two methods markedly differed, whereas the emissions densities (emissions per area) were similar. We investigated whether the climate change projections of temperature and precipitation would significantly differ between the two methods by applying a field significance test, and found little evidence of a significant difference between the two methods. Moreover, there was no clear evidence of a difference between the climate simulations based on these two downscaling methods. PMID- 28076447 TI - Lower Methane Emissions from Yak Compared with Cattle in Rusitec Fermenters. AB - Globally methane (CH4) emissions from ruminant livestock account for 29% of total CH4 emissions. Inherited variation about CH4 emissions of different animal species might provide new opportunity for manipulating CH4 production. Six rumen simulating fermenters (Rusitec) were set up for this study lasting for 16 d. The diet consisted of forage to concentrate ratio of 50:50 with barley straw as the forage. Treated vessels were supplied with rumen fluid from yak or cattle (3 vessels per animal species). Microbial growth was measured using 15N as a marker. The microbial community structure from liquid- and solid-fraction of each vessel was determined based on the 16S rRNA genes targeting both bacteria and archaea with MiSeq platform. CH4 yield was lower when the inoculum used from yak than that from cattle (0.26 and 0.33 mmol CH4/g dry matter intake, respectively). Lower H2 production was observed in Rusitec fermenters with rumen fluid from yak compare with that from cattle (0.28 and 0.86 mmol/d, respectively). The apparent digestibility of neutral detergent fiber, the isovalerate percentage with respect to the total amount of volatile fatty acids, the hydrogen recovery, and the proportion of liquid-associated microbial nitrogen derived from ammonia-nitrogen were higher in Rusitec fermenters incubated with rumen fluid from cattle than that from yak. The relative abundances of methanogens were no difference between two animal species. We hypothesize that more H2 production contributes to the higher methane emissions in cattle compare with yak. PMID- 28076448 TI - IGF-1 Induces GHRH Neuronal Axon Elongation during Early Postnatal Life in Mice. AB - Nutrition during the perinatal period programs body growth. Growth hormone (GH) secretion from the pituitary regulates body growth and is controlled by Growth Hormone Releasing Hormone (GHRH) neurons located in the arcuate nucleus of the hypothalamus. We observed that dietary restriction during the early postnatal period (i.e. lactation) in mice influences postnatal growth by permanently altering the development of the somatotropic axis in the pituitary gland. This alteration may be due to a lack of GHRH signaling during this critical developmental period. Indeed, underfed pups showed decreased insulin-like growth factor I (IGF-I) plasma levels, which are associated with lower innervation of the median eminence by GHRH axons at 10 days of age relative to normally fed pups. IGF-I preferentially stimulated axon elongation of GHRH neurons in in vitro arcuate explant cultures from 7 day-old normally fed pups. This IGF-I stimulating effect was selective since other arcuate neurons visualized concomitantly by neurofilament labeling, or AgRP immunochemistry, did not significantly respond to IGF-I stimulation. Moreover, GHRH neurons in explants from age-matched underfed pups lost the capacity to respond to IGF-I stimulation. Molecular analyses indicated that nutritional restriction was associated with impaired activation of AKT. These results highlight a role for IGF-I in axon elongation that appears to be cell selective and participates in the complex cellular mechanisms that link underfeeding during the early postnatal period with programming of the growth trajectory. PMID- 28076449 TI - Long-Term Follow-Up of Patients after Percutaneous Coronary Intervention with Everolimus-Eluting Bioresorbable Vascular Scaffold. AB - Background:: Bioresorbable vascular scaffolds (BVS) were developed to improve the long-term results of percutaneous coronary intervention, restoring vasomotion. Objectives:: To report very late follow-up of everolimus-eluting Absorb BVS (Abbott Vascular, Santa Clara, USA) in our center. Methods:: Observational retrospective study, in a single Brazilian center, from August 2011 to October 2013, including 49 patients submitted to Absorb BVS implantation. Safety and efficacy outcomes were analyzed in the in-hospital and very late follow-up phases (> 2 years). Results:: All 49 patients underwent a minimum follow-up of 2.5 years and a maximum of 4.6 years. Mean age was 56.8 +/- 7.6 years, 71.4% of the patients were men, and 26.5% were diabetic. Regarding clinical presentation, the majority (94%) had stable angina or silent ischemia. Device success was achieved in 100% of cases with 96% overall procedure success rate. Major adverse cardiovascular events rate was 4% at 30 days, 8.2% at 1 year, and 12.2% at 2 years, and there were no more events until 4.6 years. There were 2 cases of thrombosis (1 subacute and 1 late). Conclusions:: In this preliminary analysis, Absorb BVS showed to be a safe and effective device in the very late follow-up. Establishing the efficacy and safety profiles of these devices in more complex scenarios is necessary. Fundamento:: Os suportes vasculares bioabsorviveis (SVB) foram desenvolvidos com o intuito de melhorar os resultados da intervencao coronaria percutanea a longo prazo, restabelecendo-se a vasomotricidade. Objetivos:: Reportar o seguimento muito tardio do implante do SVB eluidor de everolimus Absorb(r) (Abbot Vascular, Santa Clara, EUA) em nosso centro. Metodos:: Estudo observacional, retrospectivo, em um unico centro brasileiro, que incluiu 49 pacientes submetidos ao implante do SVB Absorb(r) entre agosto/2011 e outubro/2013. Foram analisados os desfechos de seguranca e eficacia na fase hospitalar e bastante tardia (> 2 anos). Resultados:: Todos os 49 pacientes completaram um seguimento minimo de 2,5 anos, sendo o maximo de 4,6 anos. A media de idade foi 56,8 +/- 7,6 anos, sendo 71,4% da populacao estudada do sexo masculino e 26,5% composta por diabeticos. Considerando a apresentacao clinica, a grande maioria (94%) tinha angina estavel ou isquemia silenciosa. Obteve-se sucesso do dispositivo em 100% dos casos e do procedimento, em 96%. A taxa de eventos cardiovasculares maiores foi de 4% aos 30 dias, de 8,2% em 1 ano, e de 12,2% em 2 anos, sem mais eventos ate 4,6 anos. Houve 2 casos de trombose (1 subaguda e 1 tardia) ate o ultimo seguimento. Conclusoes:: Nesta analise preliminar, o uso do SVB Absorb(r) mostrou-se seguro e eficaz no seguimento bastante tardio. Faz-se necessario estabelecer o perfil de eficacia e seguranca destes dispositivos em cenarios de maior complexidade. PMID- 28076450 TI - Time course of changes in heart rate and blood pressure variability in rats with myocardial infarction. AB - Our aim was to determine the time course of changes in autonomic balance in the acute (1 and 3 days), sub-acute (7 days) and chronic (28 days) phases of myocardial infarction (MI) in rats. Autonomic balance was assessed by temporal and spectral analyses of blood pressure variability (BPV) and heart rate variability (HRV). Pulsatile blood pressure (BP) recordings (30 min) were obtained in awake and unrestrained male Wistar rats (N = 77; 8-10 weeks old) with MI (coronary ligature) or sham operation (SO). Data are reported as means+/-SE. The high frequency (HF) component (n.u.) of HRV was significantly lower in MI-1- (P<0.01) and MI-3-day rats (P<0.05) than in their time-control groups (SO-1=68+/ 4 vs MI-1=35.3+/-4.3; SO-3=71+/-5.8 vs MI-3=45.2+/-3.8), without differences thereafter (SO-7=69.2+/-4.8 vs MI-7=56+/-5.8; SO-28=73+/-4 vs MI-28=66+/-6.6). A sharp reduction (P<0.05) of BPV (mmHg2) was observed in the first week after MI (SO-1=8.55+/-0.80; SO-3=9.11+/-1.08; SO-7=7.92+/-1.10 vs MI-1=5.63+/-0.73; MI 3=5.93+/-0.30; MI-7=5.30+/-0.25). Normal BPV, however, was observed 4 weeks after MI (SO-28=8.60+/-0.66 vs MI-28=8.43+/-0.56 mmHg2; P>0.05). This reduction was mainly due to attenuation of the low frequency (LF) band of BPV in absolute and normalized units (SO-1=39.3+/-7%; SO-3=55+/-4.5%; SO-7=46.8+/-4.5%; SO-28=45.7+/ 5%; MI-1=13+/-3.5%; MI-3=35+/-4.7%; MI-7=25+/-2.8%; MI-28=21.4+/-2.8%). The results suggest that the reduction in HRV was associated with decrease of the HF component of HRV suggesting recovery of the vagal control of heartbeats along the post-infarction healing period. The depression of BPV was more dependent on the attenuation of the LF component, which is linked to the baroreflex modulation of the autonomic balance. PMID- 28076451 TI - Survival benefits of interferon-based therapy in patients with recurrent hepatitis C after orthotopic liver transplantation. AB - Recurrent hepatitis C after orthotopic liver transplantation (OLT) is universal and can lead to graft failure and, consequently, reduced survival. Hepatitis C treatment can be used to prevent these detrimental outcomes. The aim of this study was to describe rates of hepatitis C recurrence and sustained virological response (SVR) to interferon-based treatment after OLT and its relationship to survival and progression of liver disease through retrospective analysis of medical records of 127 patients who underwent OLT due to cirrhosis or hepatocellular carcinoma secondary to chronic hepatitis C between January 2002 and December 2013. Fifty-six patients were diagnosed with recurrent disease, 42 started interferon-based therapy and 37 completed treatment. Demographic, treatment- and outcome-related variables were compared between SVR and non responders (non-SVR). There was an overall 54.1% SVR rate with interferon-based therapies. SVR was associated with longer follow-up after treatment (median 66.5 vs 37 months for non-SVR, P=0.03) and after OLT (median 105 vs 72 months, P=0.074), and lower rates of disease progression (15 vs 64.7%, P=0.0028) and death (5 vs 35.3%, P=0.033). Regardless of the result of therapy (SVR or non SVR), there was a significant difference between treated and untreated patients regarding the occurrence of death (P<0.001) and months of survival (P<0.001). Even with suboptimal interferon-based therapies (compared to the new direct acting antivirals) there is a 54.1% SVR rate to treatment. SVR is associated with improved survival and reduced risks of clinical decompensation, loss of the liver graft and death. PMID- 28076452 TI - Angiotensin-(1-7) relieved renal injury induced by chronic intermittent hypoxia in rats by reducing inflammation, oxidative stress and fibrosis. AB - We aimed to study the renal injury and hypertension induced by chronic intermittent hypoxia (CIH) and the protective effects mediated by angiotensin 1-7 [Ang(1-7)]. We randomly assigned 32 male Sprague-Dawley rats (body weight 180-200 g) to normoxia control, CIH, Ang(1-7)-treated normoxia, and Ang(1-7)-treated CIH groups. Systolic blood pressure (SBP) was monitored at the start and end of each week. Renal sympathetic nerve activity (RSNA) was recorded. CTGF and TGF-beta were detected by immunohistochemistry and western blotting. Tissue parameters of oxidative stress were also determined. In addition, renal levels of interleukin 6, tumor necrosis factor-alpha, nitrotyrosine, and hypoxia-inducible factor 1alpha were determined by immunohistochemistry, immunoblotting, and ELISA. TUNEL assay results and cleaved caspase 3 and 12 were also determined. Ang(1-7) induced a reduction in SBP together with a restoration of RSNA in the rat model of CIH. Ang(1-7) treatment also suppressed the production of reactive oxygen species, reduced renal tissue inflammation, ameliorated mesangial expansion, and decreased renal fibrosis. Thus, Ang(1-7) treatment exerted renoprotective effects on CIH induced renal injury and was associated with a reduction of oxidative stress, inflammation and fibrosis. Ang(1-7) might therefore represent a promising therapy for obstructive sleep apnea-related hypertension and renal injury. PMID- 28076453 TI - Ferulic acid lowers body weight and visceral fat accumulation via modulation of enzymatic, hormonal and inflammatory changes in a mouse model of high-fat diet induced obesity. AB - Previous studies have reported on the glucose and lipid-lowering effects of ferulic acid (FA) but its anti-obesity potential has not yet been firmly established. This study investigated the possible anti-obesitogenic effects of FA in mice fed a high-fat diet (HFD) for 15 weeks. To assess the antiobesity potential of FA, 32 male Swiss mice, weighing 20-25 g (n=6-8 per group) were fed a normal diet (ND) or HFD, treated orally or not with either FA (10 mg/kg) or sibutramine (10 mg/kg) for 15 weeks and at the end of this period, the body weights of animals, visceral fat accumulation, plasma levels of glucose and insulin hormone, amylase and lipase activities, the satiety hormones ghrelin and leptin, and tumor necrosis factor-alpha (TNF-alpha) and monocyte chemoattractant protein-1 (MCH-1) were analyzed. Results revealed that FA could effectively suppress the HFD-associated increase in visceral fat accumulation, adipocyte size and body weight gain, similar to sibutramine, the positive control. FA also significantly (P<0.05) decreased the HFD-induced elevations in serum lipid profiles, amylase and lipase activities, and the levels of blood glucose and insulin hormone. The markedly elevated leptin and decreased ghrelin levels seen in HFD-fed control mice were significantly (P<0.05) reversed by FA treatment, almost reaching the values seen in ND-fed mice. Furthermore, FA demonstrated significant (P<0.05) inhibition of serum levels of inflammatory mediators TNF alpha, and MCH-1. These results suggest that FA could be beneficial in lowering the risk of HFD-induced obesity via modulation of enzymatic, hormonal and inflammatory responses. PMID- 28076454 TI - A broad pH range and processive chitinase from a metagenome library. AB - Chitinases are hydrolases that degrade chitin, a polymer of N-acetylglucosamine linked beta(1-4) present in the exoskeleton of crustaceans, insects, nematodes and fungal cell walls. A metagenome fosmid library from a wastewater-contaminated soil was functionally screened for chitinase activity leading to the isolation and identification of a chitinase gene named metachi18A. The metachi18A gene was subcloned and overexpressed in Escherichia coli BL21 and the MetaChi18A chitinase was purified by affinity chromatography as a 6xHis-tagged fusion protein. The MetaChi18A enzyme is a 92-kDa protein with a conserved active site domain of glycosyl hydrolases family 18. It hydrolyses colloidal chitin with an optimum pH of 5 and temperature of 50 degrees C. Moreover, the enzyme retained at least 80% of its activity in the pH range from 4 to 9 and 98% at 600 mM NaCl. Thin layer chromatography analyses identified chitobiose as the main product of MetaChi18A on chitin polymers as substrate. Kinetic analysis showed inhibition of MetaChi18A activity at high concentrations of colloidal chitin and 4-methylumbelliferyl N,N' diacetylchitobiose and sigmoid kinetics at low concentrations of colloidal chitin, indicating a possible conformational change to lead the chitin chain from the chitin-binding to the catalytic domain. The observed stability and activity of MetaChi18A over a wide range of conditions suggest that this chitinase, now characterized, may be suitable for application in the industrial processing of chitin. PMID- 28076455 TI - Decreased platelet responsiveness to clopidogrel correlates with CYP2C19 and PON1 polymorphisms in atherosclerotic patients. AB - Clopidogrel and aspirin are the most commonly used medications worldwide for dual antiplatelet therapy after percutaneous coronary intervention. However, clopidogrel hyporesponsiveness related to gene polymorphisms is a concern. Populations with higher degrees of genetic admixture may have increased prevalence of clopidogrel hyporesponsiveness. To assess this, we genotyped CYP2C19, ABCB1, and PON1 in 187 patients who underwent percutaneous coronary intervention. Race was self-defined by patients. We also performed light transmission aggregometry with adenosine diphosphate (ADP) and arachidonic acid during dual antiplatelet therapy. We found a significant difference for presence of the CYP2C19*2 polymorphism between white and non-white patients. Although 7% of patients had platelet resistance to clopidogrel, this did not correlate with any of the tested genetic polymorphisms. We did not find platelet resistance to aspirin in this cohort. Multivariate analysis showed that patients with PON1 and CYP2C19 polymorphisms had higher light transmission after ADP aggregometry than patients with native alleles. There was no preponderance of any race in patients with higher light transmission aggregometry. In brief, PON1 and CYP2C19 polymorphisms were associated with lower clopidogrel responsiveness in this sample. Despite differences in CYP2C19 polymorphisms across white and non-white patients, genetic admixture by itself was not able to identify clopidogrel hyporesponsiveness. PMID- 28076456 TI - Propofol inhibits lung cancer cell viability and induces cell apoptosis by upregulating microRNA-486 expression. AB - Propofol is a frequently used intravenous anesthetic agent. Recent studies show that propofol exerts a number of non-anesthetic effects. The present study aimed to investigate the effects of propofol on lung cancer cell lines H1299 and H1792 and functional role of microRNA (miR)-486 in these effects. H1299 and/or H1792 cells were treated with or without propofol and transfected or not with miR-486 inhibitor, and then cell viability and apoptosis were analyzed by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry. The expression of miR-486 was determined by quantitative real-time polymerase chain reaction (qRT-PCR) with or without propofol treatment. Western blot was performed to analyze the protein expression of Forkhead box, class O (FOXO) 1 and 3, Bcl-2 interacting mediator of cell death (Bim), and pro- and activated caspases-3. Results showed that propofol significantly increased the miR-486 levels in both H1299 and H1792 cells compared to untreated cells in a dose dependent manner (P<0.05 or P<0.01). Propofol statistically decreased cell viability but increased the percentages of apoptotic cells and protein expressions of FOXO1, FOXO3, Bim, and pro- and activated caspases-3; however, miR 486 inhibitor reversed the effects of propofol on cell viability, apoptosis, and protein expression (P<0.05 or P<0.01). In conclusion, propofol might be an ideal anesthetic for lung cancer surgery by effectively inhibiting lung cancer cell viability and inducing cell apoptosis. Modulation of miR-486 might contribute to the anti-tumor activity of propofol. PMID- 28076457 TI - Removal of calcium hydroxide from Weine Type II systems using photon-induced photoacoustic streaming, passive ultrasonic, and needle irrigation: a microcomputed tomography study. AB - Objective: This study compared the effectiveness of Er:YAG laser-activated irrigation (PIPS), passive ultrasonic irrigation (PUI) with EndoUltra and standard needle irrigation (SNI) in the removal of calcium hydroxide [Ca(OH)2] from the mesial roots of Weine Type II mandibular molars. Material and Methods: Thirty mandibular molars were screened by uCT for the presence of mesial roots with complex intra-canal anatomy and a common apical foramen. The teeth were enlarged to a standardized 25/.06 preparation and filled with Ca(OH)2 paste. Specimens were divided into three groups (n=10) according to the technique used for Ca(OH)2 removal: PIPS, at 15 Hz and 20 mJ using a 9 mm long, 600 um diameter tip; PUI using a 15/.02 tip; and SNI (30 Ga. side-vented needle). Equal volumes of 8.25% NaOCl and 17% EDTA were used in all groups. uCT was used to measure the initial amount of Ca(OH)2 present and to assess the residual volume of Ca(OH)2 following each irrigation protocol. Data were analyzed using Tukey HSD and Kruskal-Wallis tests (alpha=5%). Results: The mean volume of Ca(OH)2 before removal was significantly higher in the coronal third than in the middle and apical third (p<0.001). Ca(OH)2 was similarly removed from the coronal and middle thirds with the three methods used (p>0.05). PIPS (median 0%; IQR: 0-0) showed significant higher Ca(OH)2 removal in the apical third than PUI (median 100%, IQR: 85-100) and SNI (median 47%; IQR: 16-72) (p<0.001). Conclusions: PIPS laser activation was more effective for the removal of Ca(OH)2 from mesial roots of mandibular molars with Weine Type II canal configurations than PUI with EndoUltra and SNI. PMID- 28076458 TI - Risk of developing palatally displaced canines in patients with early detectable dental anomalies: a retrospective cohort study. AB - Objective: To estimate the risk of PDC occurrence in children with dental anomalies identified early during mixed dentition. Material and Methods: The sample comprised 730 longitudinal orthodontic records from children (448 females and 282 males) with an initial mean age of 8.3 years (SD=1.36). The dental anomaly group (DA) included 263 records of patients with at least one dental anomaly identified in the initial or middle mixed dentition. The non-dental anomaly group (NDA) was composed of 467 records of patients with no dental anomalies. The occurrence of PDC in both groups was diagnosed using panoramic and periapical radiographs taken in the late mixed dentition or early permanent dentition. The prevalence of PDC in patients with and without early diagnosed dental anomalies was compared using the chi-square test (p<0.01), relative risk assessments (RR), and positive and negative predictive values (PPV and NPV). Results: PDC frequency was 16.35% and 6.2% in DA and NDA groups, respectively. A statistically significant difference was observed between groups (p<0.01), with greater risk of PDC development in the DA group (RR=2.63). The PPV and NPV was 16% and 93%, respectively. Small maxillary lateral incisors, deciduous molar infraocclusion, and mandibular second premolar distoangulation were associated with PDC. Conclusion: Children with dental anomalies diagnosed during early mixed dentition have an approximately two and a half fold increased risk of developing PDC during late mixed dentition compared with children without dental anomalies. PMID- 28076459 TI - Evaluation of phenyl-propanedione on yellowing and chemical-mechanical properties of experimental dental resin-based materials. AB - Objective: To evaluate the influence of phenyl-propanedione on yellowing and chemical-mechanical properties of experimental resin-based materials photoactivated using different light curing units (LCUs). Material and Methods: Experimental resin-based materials with the same organic matrix (60:40 wt% BisGMA:TEGDMA) were mechanically blended using a centrifugal mixing device. To this blend, different photoinitiator systems were added in equimolar concentrations with aliphatic amine doubled by wt%: 0.4 wt% CQ; 0.38 wt% PPD; or 0.2 wt% CQ and 0.19 wt% PPD. The degree of conversion (DC), flexural strength (FS), Young's modulus (YM), Knoop hardness (KNH), crosslinking density (CLD), and yellowing (Y) were evaluated (n=10). All samples were light cured with the following LCUs: a halogen lamp (XL 2500), a monowave LED (Radii), or a polywave LED (Valo) with 16 J/cm2. The results were analysed by two-way ANOVA and Tukey's test (alpha=0.05). Results: No statistical differences were found between the different photoinitiator systems to KNH, CLS, FS, and YM properties (p>=0.05). PPD/CQ association showed the higher DC values compared with CQ and PPD isolated systems when photoactivated by a polywave LED (p<=0.05). Y values were highest for the CQ compared with the PPD systems (p<=0.05). Conclusion: PPD isolated system promoted similar chemical and mechanical properties and less yellowing compared with the CQ isolated system, regardless of the LCU used. PMID- 28076460 TI - The accuracy of fine-needle aspiration cytology for diagnosis of parotid gland masses: a clinicopathological study of 114 patients. AB - Objective: Fine-needle aspiration cytology is a valuable method for preoperative assessment of head and neck tumors. However, its accuracy in detection of salivary gland masses is controversial compared with other methods. The aim of this work was to evaluate the effectiveness and accuracy of fine-needle aspiration cytology (FNAC) in the diagnosis of parotid gland masses. Material and Methods: Over a 10-year period, 126 parotid gland masses were resected. Retrospective chart reviews of 114 patients were performed. The results of FNAC and final histological diagnosis were compared and the accuracy of FNAC was determined. Results: Final histological evaluation revealed 11 malignant tumors and 103 benign lesions. Pleomorphic adenoma was the most common neoplasm (63%), followed by Warthin's tumor (17.5%). The sensitivity of FNAC in detecting malignant tumors was 73% and the specificity was 97%. Positive predictive value (PPV) was 73% and negative predictive value (NPV) was 97%. The overall accuracy of FNAC in detecting parotid masses was 95%. False-negative diagnosis was found in mucoepidermoid carcinoma, acinic cell carcinoma, and epithelial-myoepithelial carcinoma whereas there was false-positive diagnosis in cases of pleomorphic adenoma and normal parotid gland tissue. Conclusion: FNAC is a reliable minimally invasive diagnostic method with a high sensitivity in diagnosis of lesions in parotid glands. The sensitivity of detection of malignant tumors in parotid glands was low due to the biopsy technique used, and depended on tumor location. Postoperative complications decreased after superficial parotidectomy. PMID- 28076461 TI - An in vitro evaluation of various irrigation techniques for the removal of double antibiotic paste from root canal surfaces. AB - Objective: The aim of this study was to investigate the effectiveness of conventional syringe irrigations, passive ultrasonic irrigation (PUI), Vibringe, CanalBrush, XP-endo Finisher, and laser-activated irrigation (LAI) systems in removing double antibiotic paste (DAP) from root canals. Material and Methods: One hundred five extracted single-rooted teeth were instrumented. The roots were split longitudinally. Three standard grooves were created and covered with DAP. The roots were distributed into seven groups: Group 1, beveled needle irrigation; Group 2, double side-vented needle irrigation; Group 3, CanalBrush; Group 4, XP endo Finisher; Group 5, Vibringe; Group 6, PUI; Group 7, LAI. The amount of remaining DAP was scored under a stereomicroscope. Results: Group 4, Group 6, and Group 7 removed significantly more DAP than the other protocols in the coronal region. Group 7 was more efficient in the middle region; however, no significant difference was found between Group 7 and Group 6. No differences were found between groups in the apical region either, except for the comparisons between groups 7 and 2, and groups 2 and 3. Conclusions: None of the investigated protocols were able to completely remove the DAP from the grooves. The Vibringe and XP-endo Finisher systems showed results similar to those of conventional needle irrigation. PMID- 28076462 TI - Effect of ultrasonic streaming on intra-dentinal disinfection and penetration of calcium hydroxide paste in endodontic treatment. AB - Objective: The antimicrobial effect of ultrasonic agitation of calcium hydroxide (CH) pastes in infected bovine dentin and their penetrability were evaluated using confocal laser scanning microscopy (CLSM) and microbiological culture. Material and Methods: Fifty-two bovine teeth were infected with Enterococcus faecalis using a new contamination protocol; then they received CH paste and were divided into groups with or without ultrasound. Ultrasonic agitation was conducted for 1 min with a plain point insert. After 15 d, the CLSM analyzed the viable and dead bacteria with Live and Dead assay. The dentinal wall debris was collected by burs, and the colony forming units (CFU/mL) were counted. The penetrability of the paste inside dentinal tubules was tested using the B rodamine dye. Results: The calcium hydroxide paste showed better results with the use of ultrasonic agitation (p<0.05). Conclusion: The ultrasonic agitation of CH paste increased its antimicrobial action and was responsible for intradentinal penetration with the fulfilment of the tubules. PMID- 28076463 TI - In vitro effects of Melaleuca alternifolia essential oil on growth and production of volatile sulphur compounds by oral bacteria. AB - Objective: Halitosis can be caused by microorganisms that produce volatile sulphur compounds (VSCs), which colonize the surface of the tongue and subgingival sites. Studies have reported that the use of natural products can reduce the bacterial load and, consequently, the development of halitosis. The aim of this study was to evaluate the antimicrobial activity of the essential oil of Melaleuca alternifolia on the growth and volatile sulphur compound (VSC) production of oral bacteria compared with chlorhexidine. Material and Methods: The effects of these substances were evaluated by the Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) in planktonic cultures of Porphyromonas gingivalis and Porphyromonas endodontalis. In addition, gas chromatography analyses were performed to measure the concentration of VSCs from bacterial cultures and to characterize M. alternifolia oil components. Results: The MIC and MBC values were as follows: M. alternifolia - P. gingivalis (MIC and MBC=0.007%), P. endodontalis (MIC and MBC=0.007%=0.5%); chlorhexidine - P. gingivalis and P. endodontalis (MIC and MBC=1.5 mg/mL). M. alternifolia significantly reduced the growth and production of hydrogen sulfide (H2S) by P. gingivalis (p<0.05, ANOVA-Dunnet) and the H2S and methyl mercaptan (CH3SH) levels of P. endodontalis (p<0.05, ANOVA-Dunnet). Chlorhexidine reduced the growth of both microorganisms without altering the production of VSC in P. endodontalis. For P. gingivalis, the production of H2S and CH3SH decreased (p<0.05, ANOVA Dunnet). Conclusion: M. alternifolia can reduce bacterial growth and VSCs production and could be used as an alternative to chlorhexidine. PMID- 28076464 TI - Silver nanoparticle incorporation effect on mechanical and thermal properties of denture base acrylic resins. AB - Objective: The aim of the present study was to evaluate the mechanical and thermal characteristics of two denture base acrylic resins containing silver nanoparticles (AgNPs). Material and Methods: Two different acrylic denture base resins (heat-polymerized and microwave polymerized) containing 0.3, 0.8 and 1.6 wt% AgNPs were evaluated for flexural strength, elastic modulus and impact strength. The glass transition temperature (Tg) and relative heat capacity (Cp) of the samples were determined from the Differential Scanning Calorimetry (DSC) results. For statistical analysis, two-way ANOVA and Tukey-HSD tests were performed. Results: Addition of 0.8% and 1.6% AgNPs in microwave-polymerized resin significantly decreased the transverse strength and elastic modulus. In terms of impact strength, the addition of AgNPs has no effect on both resin groups. Glass transition temperature (Tg) was decreased with the addition of AgNPs for both denture base resins. Conclusions: The incorporation of AgNPs, generally used for antimicrobial efficiency, affected the transverse strength of the denture base acrylic resins depending on the concentration of nanoparticles. Tg was decreased with the addition of AgNPs for both denture base resins. PMID- 28076465 TI - The effect of capsaicin on expression patterns of CGRP in trigeminal ganglion and trigeminal nucleus caudalis following experimental tooth movement in rats. AB - Objectives: The aim of this study was to explore the effect of capsaicin on expression patterns of calcitonin gene-related peptide (CGRP) in the trigeminal ganglion (TG) and trigeminal subnucleus caudalis (Vc) following experimental tooth movement. Material and Methods: Male Sprague-Dawley rats were used in this study and divided into small-dose capsaicin+force group, large-dose capsaicin+force group, saline+force group, and no force group. Closed coil springs were used to mimic orthodontic forces in all groups except for the no force group, in which springs were inactivated. Capsaicin and saline were injected into periodontal tissues. Rats were euthanized at 0 h, 12 h, 1 d, 3 d, 5 d, and 7 d following experimental tooth movement. Then, TG and Vc were obtained for immunohistochemical staining and western blotting against CGRP. Results: Immunohistochemical results indicated that CGRP positive neurons were located in the TG, and CGRP immunoreactive fibers were distributed in the Vc. Immunohistochemical semiquantitative analysis and western blotting analysis demonstrated that CGRP expression levels both in TG and Vc were elevated at 12 h, 1 d, 3 d, 5 d, and 7 d in the saline + force group. However, both small-dose and large-dose capsaicin could decrease CGRP expression in TG and Vc at 1 d and 3 d following experimental tooth movement, as compared with the saline + force group. Conclusions: These results suggest that capsaicin could regulate CGRP expression in TG and Vc following experimental tooth movement in rats. PMID- 28076466 TI - Ozone therapy as an adjuvant for endondontic protocols: microbiological - ex vivo study and citotoxicity analyses. AB - Objectives: This study evaluated the antimicrobial efficacy of ozone therapy in teeth contaminated with Pseudomonas aeruginosa, Enterococcus faecalis, and Staphylococcus aureus using a mono-species biofilm model. Parallel to this, the study aimed to evaluate the cytotoxicity of ozone for human gingival fibroblasts. Material and Methods: One hundred and eighty single-root teeth were contaminated with a mono-species biofilm of Enterococcus faecalis, Pseudomonas aeruginosa, and Staphylococcus aureus. Groups were formed: Group I - control; Group II - standard protocol; Group III - standard protocol + ozone gas at 40 ug/mL; and Group IV - standard protocol + aqueous ozone at 8 ug/mL. In parallel, human gingival fibroblasts were submitted to the MTT test. Cells were plated, then ozone was applied as follows: Group I (control) - broth medium; Group II - aqueous ozone at 2 ug/mL; Group III - aqueous ozone at 5 ug/mL; and Group IV - aqueous ozone at 8 ug/mL. Data were submitted to the Kruskal Wallis test and Bonferroni post hoc analyses to assess microbiology and cytotoxicity, respectively (p<0.05%). Results: The results revealed antimicrobial efficacy by Group IV with no CFU count. The cytotoxicity assay showed Groups III and IV to be the most aggressive, providing a decrease in cell viability at hour 0 from 100% to 77.3% and 68.6%, respectively. Such a decrease in cell viability was reverted, and after 72 hours Groups III and IV provided the greatest increase in cell viability, being statistically different from Groups I and II. Conclusion: According to the applied methodology and the limitations of this study, it was possible to conclude that ozone therapy improved the decontamination of the root canal ex vivo. Ozone was toxic to the cells on first contact, but cell viability was recovered. Thus, these findings suggest that ozone might be useful to improve root canal results. PMID- 28076467 TI - The search for novel insecticide targets in the post-genomics era, with a specific focus on G-protein coupled receptors. AB - Insects are considered pests globally, implicated in the destruction of agricultural fields and transmission of pathogens that cause deadly human diseases, such as dengue, Zika and malaria. The diversity of the insecticide arsenal has remained stagnant for decades, but the recent rise of insecticide resistance fueled the discovery of novel modes of action, and the power of genomics has reinvigorated this search. This review discusses the importance of comparative and functional insect genomics in the identification of potential gene targets for an insecticidal mode of action with low off-target toxicity. Due to the global participation in the sequencing and annotation of insect genomes, the targeting of specific genes with molecular tools like RNAi and CRISPR/Cas9 for genome engineering and consequent functional identification and validation has become more efficient. While there are multiple avenues to explore for insecticidal candidates, this review identifies G-protein coupled receptors as attractive targets, and hones in on the octopamine and dopamine receptors due to their potential. PMID- 28076468 TI - Phenotypic diversity and selection maintain Leishmania amazonensis infectivity in BALB/c mouse model. AB - Leishmania are protozoan parasites that show remarkable diversity, as revealed by the various clinical forms of leishmaniasis, which can range from mild skin lesions to severe metastatic cutaneous/mucosal lesions. The exact nature and extent of Leishmania phenotypic diversity in establishing infection is not fully understood. In order to try to understand some aspects of this diversity, we subcutaneously infected BALB/c mice with first and second generation subclones of a L. amazonensis strain isolated from a patient (BA125) and examined in vivo lesion growth rate and antimony susceptibility. In vivo fast-, medium- and slow growing subclones were obtained; moreover, fast-growing subclones could generate slow-growing subclones and inversely, revealing the continuous generation of diversity after passage into mice. No antimony-resistant subclone appeared, probably a rare occurrence. By tagging subclone cells with a L. amazonensis genomic cosmid library, we found that only a very small number of founding cells could produce lesions. Leishmania clones transfected with in vivo selected individual cosmids were also diverse in terms of lesion growth rate, revealing the cosmid-independent intrinsic characteristics of each clone. Our results suggest that only a few of the infecting parasites are able to grow and produce lesions; later, within the cell mixture of each lesion, there coexist several parasite populations with different potentialities to grow lesions during the next infection round. This may reflect a sort of programmed heterogeneity of individual parasites, favoring the survival of some individuals in various environmental conditions. PMID- 28076469 TI - Scoring clinical signs can help diagnose canine visceral leishmaniasis in a highly endemic area in Brazil. AB - Canine visceral leishmaniasis (CVL) diagnosis is still a challenge in endemic areas with limited diagnostic resources. This study proposes a score with the potential to distinguish positive CVL cases from negative ones. We studied 265 dogs that tested positive for CVL on ELISA and parasitological tests. A score ranging between 0 and 19 was recorded on the basis of clinical signs. Dogs with CVL had an overall higher positivity of the majority of clinical signs than did dogs without CVL or with ehrlichiosis. Clinical signs such as enlarged lymph nodes (83.93%), muzzle/ear lesions (55.36%), nutritional status (51.79%), bristle condition (57.14%), pale mucosal colour (48.21%), onychogryphosis (58.93%), skin lesion (39.28%), bleeding (12.50%), muzzle depigmentation (41.07%), alopecia (39.29%), blepharitis (21.43%), and keratoconjunctivitis (42.86%) were more frequent in dogs with CVL than in dogs with ehrlichiosis or without CVL. Moreover, the clinical score increased according to the positivity of all diagnostic tests (ELISA, p < 0.001; parasite culture, p = 0.0021; and smear, p = 0.0003). Onychogryphosis (long nails) [odds ratio (OR): 3.529; 95% confidence interval (CI): 1.832-6.796; p < 0.001], muzzle depigmentation (OR: 4.651; 95% CI: 2.218-9.750; p < 0.001), and keratoconjunctivitis (OR: 5.400; 95% CI: 2.549 11.441; p < 0.001) were highly associated with CVL. Interestingly, a score cut off value >= 6 had an area under the curve of 0.717 (p < 0.0001), sensitivity of 60.71%, and specificity of 73.64% for CVL diagnosis. The clinical sign-based score for CVL diagnosis suggested herein can help veterinarians reliably identify dogs with CVL in endemic areas with limited diagnostic resources. PMID- 28076470 TI - First description of Leishmania (Viannia) infection in Evandromyia saulensis, Pressatia sp. and Trichophoromyia auraensis (Psychodidae: Phlebotominae) in a transmission area of cutaneous leishmaniasis in Acre state, Amazon Basin, Brazil. AB - Studies on the sandfly fauna to evaluate natural infection indexes are still limited in the Brazilian Amazon, a region with an increasing incidence of cutaneous leishmaniasis. Here, by using a multiplex polymerase chain reaction directed to Leishmania kDNA and hybridisation, we were able to identify L. (Viannia) subgenus in 12 out of 173 sandflies captured in the municipality of Rio Branco, Acre state, revealing a positivity of 6.94%. By sequencing the Leishmania 234 bp-hsp70 amplified products from positive samples, infection by L. (V.) braziliensis was confirmed in five sandflies: one Evandromyia saulensis, three Trichophoromyia auraensis and one Pressatia sp. The finding of L. (Viannia) DNA in two Ev. saulensis corresponds to the first record of possible infection associated with this sandfly. Moreover, our study reveals for the first time in Brazil, Th. auraensis and Pressatia sp. infected by L. (Viannia) parasites. PMID- 28076471 TI - Genomic information on multidrug-resistant livestock-associated methicillin resistant Staphylococcus aureus ST398 isolated from a Brazilian patient with cystic fibrosis. AB - Alarmingly, the isolation of methicillin-resistant Staphylococcus aureus (MRSA) has been increasing among patients with cystic fibrosis (CF). During a previous molecular characterisation of MRSA isolates obtained from patients with CF from Rio de Janeiro, Brazil, one isolate was identified as the ST398 clone, a livestock-associated (LA) MRSA. In this study, we report the draft genome sequence of an LA-MRSA ST398 clone isolated from a patient with CF. PMID- 28076472 TI - EVALUATION OF LYMPHATIC SPREAD, VISCERAL METASTASIS AND TUMORAL LOCAL INVASION IN ESOPHAGEAL CARCINOMAS. AB - Background: : Knowing esophageal tumors behavior in relationship to lymph node involvement, distant metastases and local tumor invasion is of paramount importance for the best esophageal tumors management. Aim: : To describe lymph node involvement, distant metastases, and local tumor invasion in esophageal carcinoma, according to tumor topography and histology. Methods: : A total of 444 patients with esophageal squamous cell carcinoma and 105 adenocarcinoma were retrospectively analyzed. They were divided into four groups: adenocarcinoma and squamous cell carcinoma in the three esophageal segments: cervical, middle, and distal. They were compared based on their CT scans at the time of the diagnosis. Results: : Nodal metastasis showed great relationship with of primary tumor site. Lymph nodes of hepatogastric, perigastric and peripancreatic ligaments were mainly affected in distal tumors. Periaortic, interaortocaval and portocaval nodes were more commonly found in distal squamous carcinoma; subcarinal, paratracheal and subaortic nodes in middle; neck chains were more affected in cervical squamous carcinoma. Adenocarcinoma had a higher frequency of peritoneal involvement (11.8%) and liver (24.5%) than squamous cell carcinoma. Considering the local tumor invasion, the more cranial neoplasia, more common squamous invasion of airways, reaching 64.7% in the incidence of cervical tumors. Middle esophageal tumors invade more often aorta (27.6%) and distal esophageal tumors, the pericardium and the right atrium (10.4%). Conclusion: : Esophageal adenocarcinoma and squamous cell carcinoma in different topographies present peculiarities in lymph node involvement, distant metastasis and local tumor invasion. These differences must be taken into account in esophageal cancer patients' care. Racional: : Conhecer o comportamento das neoplasias esofagicas em relacao a disseminacao linfonodal, distribuicao de metastases e invasao local do tumor, pode auxiliar o manejo dos pacientes. Objetivo: : Descrever o envolvimento linfonodal, disseminacao metastatica e invasao local dos carcinomas esofagicos, de acordo com a topografia e o tipo histologico do tumor. Metodo: : Pacientes com diagnostico de carcinoma espinocelular de esofago (n=444) e adenocarcinoma de esofago (n=105) foram retrospectivamente analisados. Foram divididos em quatro grupos: adenocarcinoma e carcinoma espinocelular do segmento cervical, medio e distal. Tais grupos foram comparados baseando-se em tomografias computadorizadas realizadas no momento do diagnostico. Resultados: : Disseminacao linfonodal mostrou grande associacao com topografia do tumor. Linfonodos do ligamento hepatogastrico, perigastricos e peripancreaticos foram acometidos principalmente por tumores de esofago distal; linfonodos periaorticos, interaortocavais, portocavais no carcinoma espinocelular de esofago distal; e linfonodos subcarinais, paratraqueais, subaorticos nos tumores de esofago medio. Cadeias cervicais foram acometidas por espinocelulares cervicais. Adenocarcinoma teve maior frequencia de acometimento peritoneal (11,8%) e hepatico (24,5%) do que carcinoma espinocelular. Considerando invasao tumoral local, quanto mais cranial a neoplasia, mais comum a invasao do espinocelular em vias aereas, chegando a incidencia de 64,7% nos tumores cervicais. Tumores de esofago medio invadem mais frequentemente aorta (27,6%) e tumores de esofago distal, o pericardio e atrio direito (10,4%). Conclusoes: : Adenocarcinoma e carcinoma espinocelular de esofago em diferentes topografias apresentam peculiaridades na disseminacao linfatica, metastases a distancia e invasao local do tumor. Tais diferencas devem ser consideradas no manejo do paciente com carcinoma esofagico. PMID- 28076473 TI - INFLUENCE OF TOBACCO, ALCOHOL AND DIABETES ON THE COLLAGEN OF CREMASTER MUSCLE IN PATIENTS WITH INGUINAL HERNIAS. AB - Background: : New findings point out that the mechanism of formation of the hernias can be related to the collagenous tissues, under activity of aggressive agents such as the tobacco, alcohol and diabetes. Aim: : To analyze the collagen present in the cremaster muscle in patients with inguinal hernias, focusing the effect of tobacco, alcohol, and diabetes. Methods: : Fifteen patients with inguinal hernia divided in three groups were studied: group I (n=5) was control; group II (n=5) were smokers and/or drinkers; and group III (n=5) had diabetes mellitus. All subjects were underwent to surgical repair of the inguinal hernias obeying the same pre, intra and postoperative conditions. During surgery, samples of the cremaster muscle were collected for analysis in polarized light microscopy, collagen morphometry and protein. Results: : The area occupied by the connective tissue was higher in groups II and III (p<0.05). The collagen tissue occupied the majority of the samples analyzed in comparison to the area occupied by muscle cells. The content of total protein was higher in groups II and III compared to the control group (p<0.05). Conclusion: : The tobacco, alcohol and diabetes cause a remodel the cremaster muscle, leading to a loss of support or structural change in this region, which may enhance the occurrences and damage related to inguinal hernias. Racional: : Estudos recentes sinalizam que o mecanismo de formacao das hernias pode estar relacionado aos tecidos colagenosos, sob a acao de agentes agressores como o tabaco, o alcool e o diabete. Objetivo: : Avaliar o colageno presente no musculo cremaster em pacientes com hernias inguinais enfocando o efeito do tabaco, alcool e diabete. Metodos: : Foram estudados 15 pacientes com hernias inguinais divididos em: grupo I (n=5) controles; grupo II (n=5) individuos fumantes e/ou etilistas; e grupo III (n=5) individuos que apresentavam diabete melito. Todos foram submetidos a correcao cirurgica das hernias inguinais obedecendo as mesmas condicoes pre, intra e pos operatorias. Durante o procedimento cirurgico, amostras do musculo cremaster foram coletadas para analises em microscopia de luz polarizada, morfometria do colageno e de proteinas. Resultados: : A area ocupada por tecido conjuntivo foi maior nos grupos II e III (p<0,05). O tecido colageno ocupou a maior parte das amostras analisadas, em comparacao a area ocupada pelas celulas musculares. O conteudo de proteinas totais foi maior nos grupos II e III, quando comparado com o grupo controle (p<0,05). Conclusao: : O tabaco, o alcool e o diabete ocasionam remodelacao no musculo cremaster, levando a perda de suporte ou alteracao estrutural nesta regiao, podendo intensificar as ocorrencias e os danos relacionados as hernias inguinais. PMID- 28076474 TI - GROWTH FACTORS AND COX2 IN WOUND HEALING: AN EXPERIMENTAL STUDY WITH EHRLICH TUMORS. AB - Background:: Healing is an innate biological phenomenon, and carcinogenesis acquired, but with common humoral and cellular elements. Carcinogenesis interferes negatively in healing. Aim: : To evaluate the histological changes in laparotomy scars of healthy Balb/c mice and with an Ehrlich tumor in its various forms of presentation. Methods:: Fifty-four mice were divided into three groups of 18 animals. First group was the control; the second had Ehrlich tumor with ascites; and the third had the subcutaneous form of this tumor. Seven days after tumor inoculation, all 54 mice were submitted to laparotomy. All of the animals in the experiment were operated on again on 7th day after surgery, with resection of the scar and subsequent euthanasia of the animal. The scars were sent for histological assessment using immunohistochemical techniques to evaluate Cox-2 (cyclooxygenase 2), VEGF (vascular endothelial growth factor) and FGF (fibroblast growth factor). Semi-quantitatively analysis was done in the laparotomy scars and in the abdominal walls far away from the site of the operation. Results:: Assessing the weight of the animals, the correct inoculation of the tumor and weight gain in the group with tumoral ascites was observed. The histological studies showed that groups with the tumor showed a statistically significant higher presence of Cox-2 compared to the control. In the Cox-2 analysis of the abdominal wall, the ascites group showed the most significant difference. VEGF did not present any significant differences between the three groups, regardless of the site. The FGF showed a significant increase in animals with the tumor. Conclusion: : Histological findings in both laparotomy scar and the abdominal wall showed that with Ehrlich's neoplasia there was an exacerbated inflammatory response, translated by more intense expression of Cox-2 and greater fibroblast proliferation, translated by more intense expression of FGF, that is, it stimulated both the immediate inflammatory reactions, observed with Cox-2 reactions, and late scarring by fibroblasts and FGF. Racional:: A cicatrizacao e fenomeno biologico inato, e a carcinogenese adquirido, mas com elementos humorais e celulares comuns. A carcinogenese interfere de forma negativa na cicatrizacao. Objetivo: : Avaliar as modificacoes histologicas nas cicatrizes laparotomicas de camundongos Balb/c sadios como controles, e com a neoplasia de Ehrlich, em suas diferentes formas de apresentacao. Metodos: : Foram utilizados 54 camundongos, divididos em tres grupos de 18 animais cada um. O primeiro era controle; o segundo com a neoplasia de Ehrlich em sua forma ascitica; e o terceiro na forma subcutanea. Sete dias apos a inoculacao do tumor, todos os 54 camundongos foram submetidos a laparotomia e reoperados no setimo dia de pos-operatorio, com resseccao da cicatriz e posterior eutanasia. As cicatrizes foram encaminhadas para estudo histologico com tecnicas imunoistoquimicas para avaliar Cox-2 (ciclo oxigenase 2), VEGF (fator de crescimento do endotelio vascular) e FGF (fator de crescimento dos fibroblastos) e analisadas de forma semiquantitativana tanto na cicatriz laparotomica como na parede abdominal mais distante do local operado. Resultados: : Avaliando o peso, observou-se a correta inoculacao do tumor e o aumento de peso no grupo com a neoplasia na modalidade ascitica. Os estudos histologicos mostraram que os grupos com a neoplasia apresentaram maior presenca da Cox-2 em relacao ao controle, estatisticamente significante. No estudo da Cox 2 da parede abdominal foi o local em que o grupo ascitico apresentou a diferenca mais expressiva. O VEGF nao apresentou diferencas significantes entre os tres grupos, independentemente do local estudado. O FGF teve aumento significante nos animais com neoplasia. Conclusao:: Os achados histologicos encontrados tanto na cicatriz das laparotomias quanto na parede abdominal mostraram que com a neoplasia de Ehrlich houve resposta inflamatoria exacerbada, traduzida por expressao mais intensa da Cox-2 e maior proliferacao fibroblastica, traduzida por expressao mais intensa do FGF, ou seja, estimulou tanto as reacoes inflamatorias imediatas, observadas nas reacoes da Cox-2, como nas cicatriciais tardias com os fibroblastos e o FGF. PMID- 28076475 TI - EXPRESSION OF E-CADHERIN AND WNT PATHWAY PROTEINS BETACATENIN, APC, TCF-4 AND SURVIVIN IN GASTRIC ADENOCARCINOMA: CLINICAL AND PATHOLOGICAL IMPLICATION. AB - Background:: Gastric cancer is the fifth most frequent cancer and the third most common cause of cancer-related deaths worldwide.It has been reported that Wnt/ betacatenin pathway is activated in 30-50% of these tumors. However,the deregulation of this pathway has not been fully elucidated. Aim:: To determine the expression of E-cadherin, betacatenin, APC, TCF-4 and survivin proteins in gastric adenocarcinoma tissues and correlate with clinical and pathological parameters. Method:: Seventy-one patients with gastric adenocarcinoma undergoing gastrectomy were enrolled. The expression of E-cadherin, betacatenin, APC, TCF-4 and survivin proteins was detected by immunohistochemistryand related to the clinical and pathological parameters. Results:: The expression rates of E cadherin in the membrane was 3%; betacatenin in the cytoplasm and nucleus were 23,4% and 3,1% respectively; APC in the cytoplasm was 94,6%; TCF-4 in the nucleus was 19,4%; and survivin in the nucleus 93,9%. The expression rate of E-cadherin was correlated with older patients (p=0,007), while betacatenin with tumors <5 cm (p=0,041) and APC with proximal tumors (p=0,047). Moreover, the expression of TCF 4 was significantly higher in the diffuse type (p=0,017) and T4 tumors (p=0,002). Conclusion:: The Wnt/betacatenin is not involved in gastric carcinogenesis. However, the high frequency of survivin allows to suggest that other signaling pathways must be involved in the transformation of gastric tissue. Racional:: O cancer gastrico encontra-se entre as principais neoplasias malignas do mundo sendo o quinto mais incidente e o terceiro em relacao ao indice de mortalidade. Acredita-se que a via Wnt/betacatenina esteja ativada em 30-50% desses tumores, porem a desregulacao dela ainda nao esta completamente esclarecida. Objetivo:: Avaliar a imunoexpressao das proteinas E-caderina, betacatenina, APC, TCF-4 e survivina em tecidos de adenocarcinoma gastrico e correlaciona-las com as variaveis clinicas dos doentes e anatomopatologicas do tumor. Metodo:: Foram coletados os dados clinicos e anatomopatologicos dos prontuarios de 71 doentes com adenocarcinoma gastrico submetidos a gastrectomia. O material obtido na operacao foi submetido a analise imunoistoquimica e a frequencia da expressao de cada proteina pode ser analisada de acordo com a sua localizacao na celula e relacionada com as variaveis clinicopatologicas. Resultados:: A graduacao percentualda expressao e da localizacao das proteinas foi a seguinte: E-caderina em 3% na membrana; betacatenina em 23,4% no citoplasma e 3,1% no nucleo; APC em 94,6% no citoplasma; TCF-4 em19,4% no nucleo; e survivina em 93,9% no nucleo. Houve relacao entre expressao da proteina E-caderina com a idade mais avancada (p=0,007); betacatenina com tumores <5 cm de diametro (p=0,041);APC com tumores proximais (p=0,047); e TCF-4 com tipo difuso da classificacao de Lauren (p=0,017) e com o grau de penetracao tumoral (p=0,002). Conclusao:: A via Wnt/betacatenina nao esta envolvida na carcinogenese gastrica. Porem, a frequencia elevada de survivina permite sugerir que outras vias sinalizadoras devam estar envolvidas na transformacao do tecido gastrico. PMID- 28076476 TI - DO PROXIMAL AND DISTAL GASTRIC TUMOURS BEHAVE DIFFERENTLY? AB - Background:: Although the incidence of gastric (adenocarcinoma) cancer has been decreasing over time, it is still one of the most common malignancies worldwide, and proximal tumours tend to have a worse prognosis. Aim:: To compare surgical outcomes and prognosis between proximal - excluding tumours of the cardia - and distal gastric cancer. Methods:: Out of 293 cases reviewed - 209 with distal and 69 with proximal gastric cancer - were compared for clinical and pathological features, stage, surgical outcome, mortality and survival. Results:: Statistically, there was no significant difference between patients in both groups regarding mortality (p=0.661), adjuvant chemotherapy (p 0.661), and radiation (p=1.000). However, there was significant difference in the degree of lymph node dissection employed (p=0.002) and the number of positive lymph nodes resected (p=0.038) between the two groups. The odds of death at five years for patients who had a D0 dissection was three times greater (odds ratio 2.78; (95%CI 1.33-5.82) than that for patients who had a D2 dissection, while for patients who had a D1 dissection the odds ratio was only 1.41 (95%CI 0.71-2.83) compared to D2 dissected patients. Conclusion:: Although no significant differences were found between proximal and distal gastric cancer, the increased risk of death in D0- and D1-dissected patients clearly suggests an important role of radical D2 lymph node dissection in survival. Racional: : Embora a incidencia do cancer gastrico esteja diminuindo nas ultimas decadas, ele ainda aparece como uma das neoplasias malignas mais comuns, e tumores proximais tendem a ter pior prognostico. Objetivo:: Comparar os resultados cirurgicos e o prognostico entre o cancer gastrico proximal, excluindo os tumores da cardia e juncao esofagogastrica, e o distal. Metodos: : De 293 casos revistos - 209 distais e 69 proximais - foram comparados quanto aos achados clinicos e patologicos, estagio, resultados cirurgicos, mortalidade e sobrevida. Resultados: : Estatisticamente nao houve diferenca entre pacientes em ambos os grupos quanto a mortalidade (p=0.661), emprego de quimioterapia adjuvante (p=0.661) e de radioterapia (p=1.000). Entretanto, houve diferenca significativa no grau de disseccao linfonodal empregada (p=0.002) e no numero de linfonodos positivos ressecados (p=0.038) entre os dois grupos. A razao de chances para morte em cinco anos nos casos de disseccao D0 foi tres vezes maior (2,78; IC95% de 1,33 a 5,82) do que a D2, enquanto que para disseccao D1, ela foi apenas 1,41 vezes maior (95%CI 0.71-2.83) quando comparado a D2. Conclusao: : Ainda que nao se tenha observado diferencas significativas entre o cancer gastrico proximal e o distal, o risco de morte aumentado nos casos de D0 e D1, claramente demonstra o papel preponderante da linfadenectomia radical D2 no tratamento dessa doenca. PMID- 28076477 TI - PEDIATRIC LIVER TRANSPLANTATION WITH EX-SITU LIVER TRANSECTION AND THE APPLICATION OF THE HUMAN FIBRINOGEN AND THROMBIN SPONGE IN THE WOUND AREA. AB - Background: : Surgical strategy to increase the number of liver transplants in the pediatric population is the ex-situ liver transection (reduction or split). However, it is associated with complications such as hemorrhage and leaks. The human fibrinogen and thrombin sponge is useful for improving hemostasis in liver surgery. Aim:: Compare pediatric liver transplants with ex-situ liver transection (reduction or split) with or without the human fibrinogen and thrombin sponge. Methods:: Was performed a prospective analysis of 21 patients submitted to liver transplantation with ex-situ liver transection with the application of the human fibrinogen and thrombin sponge in the wound area (group A) and retrospective analysis of 59 patients without the sponge (group B). Results:: The characteristics of recipients and donors were similar. There were fewer reoperations due to bleeding in the wound area in group A (14.2%) compared to group B (41.7%, p=0.029). There was no difference in relation to the biliary leak (group A: 17.6%, group B: 5.1%, p=0.14). Conclusion:: There was a lower number of reoperations due to bleeding of the wound area of the hepatic graft when the human fibrinogen and thrombin sponge were used. Racional: : Estrategia cirurgica para aumentar o numero de transplantes hepaticos na populacao pediatrica e a transeccao hepatica ex-situ (reducao ou split). No entanto, ela esta associada com complicacoes, tais como hemorragia e fistulas. A esponja de fibrinogenio e trombina humana e util para melhorar a hemostasia nas operacoes hepaticas. Objetivo:: Comparar transplantes hepaticos pediatricos com transeccao hepatica ex situ (reducao ou split) com ou sem a esponja de fibrinogenio e trombina humana. Metodos:: Foi realizada analise prospectiva de 21 pacientes submetidos ao transplante de figado com transeccao hepatica ex-situ com a aplicacao da esponja de fibrinogenio e trombina humana na area cruenta (grupo A) e analise retrospectiva de 59 pacientes sem a esponja (grupo B). Resultados:: As caracteristicas dos receptores e doadores eram semelhantes. Observou-se menor numero de reoperacoes devido a hemorragia na area da cruenta no grupo A (14,2%) em comparacao com o grupo B (41,7%, p=0,029). Nao houve diferenca em relacao a fistula biliar (grupo A: 17,6%, grupo B: 5,1%, p=0,14). Conclusao:: Houve menor numero de reoperacoes por sangramento da area cruenta do enxerto hepatico quando a esponja de fibrinogenio e trombina humana foi utilizada. PMID- 28076478 TI - LIVER TRANSPLANTATION FOR CARCINOMA HEPATOCELLULAR IN SAO PAULO: 414 CASES BY THE MILAN/BRAZIL CRITERIA. AB - Background:: The criterion of Milan (CM) has been used as standard for indication of liver transplantation (LTx) for hepatocellular carcinoma (HCC) worldwide for nearly 20 years. Several centers have adopted criteria expanded in order to increase the number of patients eligible to liver transplantation, while maintaining good survival rates. In Brazil, since 2006, the criterion of Milan/Brazil (CMB), which disregards nodules <2 cm, is adopted, including patients with a higher number of small nodules. Aim:: To evaluate the outcome of liver transplantation within the CMB. Methods:: The medical records of patients with HCC undergoing liver transplantation in relation to recurrence and survival by comparing CM and CMB, were analyzed. Results:: 414 LTx for HCC, the survival at 1 and 5 years was 84.1 and 72.7%. Of these, 7% reached the CMB through downstaging, with survival at 1 and 5 years of 93.1 and 71.9%. The CMB patient group that exceeded the CM (8.6%) had a survival rate of 58.1% at five years. There was no statistical difference in survival between the groups CM, CMB and downstaging. Vascular invasion (p<0.001), higher nodule size (p=0.001) and number of nodules >2 cm (p=0.028) were associated with relapse. The age (p=0.001), female (p<0.001), real MELD (p<0.001), vascular invasion (p=0.045) and number of nodes >2 cm (p<0.014) were associated with worse survival. Conclusions:: CMB increased by 8.6% indications of liver transplantation, and showed survival rates similar to CM. Racional:: O criterio de Milao (CM) vem sendo utilizado como padrao para indicacao do transplante hepatico (TxH) por hepatocarcinoma (HCC) em todo mundo ha quase 20 anos. Diversos centros tem adotado criterios expandidos com intuito de aumentar o numero de pacientes candidatos ao transplante, mantendo bons indices de sobrevida. No Brasil, desde 2006, o criterio de Milao/Brasil (CMB), que desconsidera nodulos <2 cm, e adotado, incluindo pacientes com maior numero de nodulos pequenos. Objetivo:: Avaliar o resultado do transplante hepatico dentro do CMB. Metodos:: Foram analisados os prontuarios dos pacientes com HCC submetidos ao TxH em relacao a recidiva e sobrevida atraves da comparacao entre CM e CMB. Resultados:: Em 414 TxH por HCC, a sobrevida em 1 e 5 anos foi de 84,1 e 72,7%. Destes, 7% atingiram o CMB atraves de downstaging, com sobrevida em 1 e 5 anos de 93,1 e 71,9%. O grupo de pacientes do CMB que excederam o CM (8,6%) teve sobrevida de 58,1% em cinco anos. Nao houve diferenca estatistica na sobrevida entre os grupos CM, CMB e downstaging. A invasao vascular (p<0,001), tamanho do maior nodulo (p=0,001) e numero de nodulos >2 cm (p=0,028) associaram se com recidiva. A idade (p=0,001), sexo feminino (p<0,001), MELD real (p<0,001), invasao vascular (p=0,045) e o numero de nodulos >2 cm (p<0,014) estiveram associados com a piora na sobrevida. Conclusoes:: O CMB aumentou em 8,6% as indicacoes de TxH e apresentou indices de sobrevida semelhantes ao CM. PMID- 28076479 TI - DIETARY MANAGEMENT FOR DYSLIPIDEMIA IN LIVER TRANSPLANT RECIPIENTS. AB - Background: : Dyslipidemia occurs in approximately 70% of all liver transplant (LT) recipients, and no prior control studies have demonstrated any dietary intervention to change it. Aim: : To analyze the effects of a dietary intervention on the lipid profile of dyslipidemic LT recipients. Methods: : All LT recipients with dyslipidemia on clinical follow-up were enrolled. Anthropometric evaluation, food history, body composition (bioimpedance) and assessment of basal metabolism through indirect calorimetry were performed. Patients met with a dietitian and an individualized diet based on estimate of basal metabolism and consisting of 25% of the total energy value in total fat and <200 mg/day of cholesterol was prescribed. Total cholesterol (TC), HDL cholesterol (HDL), LDL-cholesterol (LDL), triglycerides (TG) and anthropometric measures were measured at baseline and six months after intervention. Results:: Fifty-thee out of 56 patients concluded follow-up; age was 59+/-10 years; 29 were men (51.8%). The analysis pre- and post-intervention were, respectively: TC 238.9+/-30 and 165.1+/-35, p<0.001; LDL 154+/-33 and 90+/-29, p<0.001; and TG 168 (IQR=51-200) and 137 (IQR=94-177), p=<0.001. They were all modified at six months following intervention. At baseline, none of the patients had normal TC, and only 12 (22.7%) had optimal/near optimal LDL. Following dietary intervention, 45 patients (84.9%) reached normal TC and 50 (94.4%) had optimal/near optimal LDL. HDL and anthropometric measures were not modified. Conclusions:: Dietary counseling with prescription of individualized diet based on estimate of basal metabolism through indirect calorimetry was able to manage dyslipidemia in most LT recipients; so, all dyslipidemic LT recipients must be enrolled on a dietary program. Racional:: A dislipidemia ocorre em aproximadamente 70% de todos os pacientes transplantados de figado em acompanhamento ambulatorial. Nao ha relato previo de qualquer intervencao dietetica que houvesse controlado a dislipidemia nesse grupo de pacientes. Objetivo:: Analisar os efeitos de uma intervencao dietetica no perfil lipidico de pacientes transplantados hepaticos dislipidemicos em acompanhamento ambulatorial. Metodos:: Foram incluidos todos os pacientes adultos transplantados hepaticos com dislipidemia e em acompanhamento ambulatorial em nossa instituicao. Avaliacao antropometrica, anamnese alimentar, composicao corporal (bioimpedancia) e calculo do metabolismo basal (calorimetria indireta) foram realizados. Pacientes foram atendidos por uma nutricionista e uma dieta individualizada baseada no metabolismo basal e consistindo de 25% do valor energetico em gorduras totais e menos de 200 mg/dia de colesterol foi prescrita. Colesterol total (CT), HDL-colesterol (HDL), LDL-colesterol (LDL), triglicerideos (TG) e medidas antropometricas foram medidos antes do inicio da dieta, sendo repetidos seis meses apos o inicio da intervencao dietetica. Resultados:: Cinquenta e tres pacientes concluiram o seguimento e tinham idade 59+/-10 anos e 29 eram homens (51,8%). CT pre-intervencao=238,9+/-30; pos-intervencao=165,1+/ 35, p<0.001; LDL pre-intervencao=154+/-33; pos-intervencao=90+/-29, p<0.001 e TG pre-intervencao=168, IQR=151-200; pos-intervencao=137, IQR=94-177, p=<0.001 sofreram modificacoes significativas seis meses apos a intervencao. Antes do estudo, nenhum dos pacientes apresentava niveis sericos normais para o CT, e apenas 12 pacientes (22,7%) tinham niveis sericos otimo ou quase otimos para o LDL. Seis meses apos o inicio da intervencao, 45 pacientes (84,9%) alcancaram niveis sericos normais de CT e 50 (94,4%) niveis sericos otimos ou quase otimos de LDL. Os niveis sericos de HDL e as medidas antropometricas nao sofreram modificacoes significativas. Conclusoes:: Aconselhamento dietetico com prescricao de dieta individualizada baseada no calculo do metabolismo basal mostrou-se efetivo no manejo da dislipidemia em pacientes transplantados hepaticos em seguimento ambulatorial. Assim, todos os pacientes transplantados hepaticos com dislipidemia devem ser incluidos em um programa de intervencao dietetica sob orientacao de nutricionista. PMID- 28076480 TI - PRELIMINARY ANALYSIS OF INTERLEUKIN-6 CHANGES IN PRE- AND POSTOPERATIVE IN DIABETIC PATIENTS WITH BMI<35 SUBMITTED TO PARTIAL DUODENAL SWITCH. AB - Background:: Studies related to obesity have shown association with metabolic syndrome. Data showing that obesity is capable to cause low grade chronic inflammation, without its classic signs and symptoms, call attention to researches to study different cells types and the mechanism of the inflammatory process. Aim:: To evaluate the variation of glycated hemoglobin (HbA1c) and the pro-inflammatory cytokine interleukin-6 (IL6) in diabetic patients with BMI <35 kg/m2 in the pre and postoperative of partial duodenal switch. Method:: Nine patients were studied before and one year after the operation and the variation of the serum IL6 was measured by Elisa. The changes of HbA1c were also registered. Results:: The pre-operative IL6 levels reached 65,50436+/-2,911993 pg/ml and one year after de operation 39,47739+/-3,410057 and the HbA1c average of 10,67 and 5.8 in the same period. Conclusion:: The partial duodenal switch was efficient to control one year after the procedure the chronic inflammatory process caused by the diabetes mellitus type 2 with BMI <35 by dropping the IL6 levels and bringing the HbA1c to normal. Racional:: Os estudos relacionados a obesidade tem evidenciado sua associacao com a sindrome metabolica. A descoberta que a obesidade e capaz de promover inflamacao, sem os sinais classicos, tem levado varios grupos de pesquisa a caracterizar os tipos celulares que agem e o mecanismo envolvido neste processo. Objetivo:: Avaliar a variacao da hemoglobina glicada e a secrecao da citocina inflamatoria, interleucina-6, em individuos diabeticos com IMC<35 kg/m2 no pre e pos-operatorio da tecnica de desvio duodenal parcial. Metodos:: Nove pacientes foram avaliados antes e um ano apos a operacao e a variacao da concentracao da interleucina-6 foi avaliada pela metodologia de Elisa. Tambem foi avaliada a variacao da HbA1c. Resultados: : A quantificacao de interleucina-6 apresentou no pre-operatorio valor de 65,50436+/-2,911993 pg/ml e de 39,47739+3,410057 pg/ml apos um ano da operacao e a hemoglobina glicada apresentou media de 10,67 no pre-operatorio e de 5,8 apos um ano da operacao. Conclusao: : O desvio duodenal parcial foi capaz de, um ano apos o procedimento, diminuir os efeitos da inflamacao cronica demonstrada pela diminuicao da concentracao da interleucina-6 plasmatica e normalizar a hemoglobina glicada em pacientes diabeticos com IMC<35 kg/m2. PMID- 28076481 TI - CORRELATION BETWEEN PRE AND POSTOPERATIVE LEVELS OF GLP-1/GLP-2 AND WEIGHT LOSS AFTER ROUX-EN-Y GASTRIC BYPASS: A PROSPECTIVE STUDY. AB - Background:: The role of gut hormones in glucose homeostasis and weight loss achievement and maintenance after bariatric surgery appears to be a key point in the understanding of the beneficial effects observed following these procedures. Aim:: To determine whether there is a correlation between the pre and postoperative levels of both GLP-1 and GLP-2 and the excess weight loss after Roux-en-Y gastric bypass (RYGB). Methods:: An exploratory prospective study which enrolled 11 individuals who underwent RYGB and were followed-up for 12 months. GLP-1 and GLP-2 after standard meal tolerance test (MTT) were determined before and after surgery and then correlated with the percentage of excess loss (%EWL). Results:: GLP-2 AUC presented a significant postoperative increase (945.3+/-449.1 vs.1787.9+/-602.7; p=0.0037); GLP-1 AUC presented a non-significant trend towards increase after RYGB (709.6+/-320.4 vs. 1026.5+/-714.3; p=0.3808). Mean %EWL was 66.7+/-12.2%. There was not any significant correlation between both the pre and postoperative GLP-1 AUCs and GLP-2 AUCs and the %EWL achieved after one year. Conclusion:: There was no significant correlation between the pre and postoperative levels of the areas under the GLP-1 and GLP-2 curves with the percentage of weight loss reached after one year. Racional:: O papel de hormonios gastrointestinais sobre a homeostase glicemica e a obtencao e manutencao da perda de peso apos a cirurgia bariatrica parece ser elemento fundamental na compreensao dos beneficios observados apos estes procedimentos. Objetivo:: Determinar se ha correlacao entre os niveis pre e pos-operatorios de GLP-1 e GLP-2 com a perda do excesso de peso apos o bypass gastrico em Y-de-Roux. Metodos:: Estudo prospectivo exploratorio que envolveu 11 individuos submetidos ao bypass gastrico, acompanhados por 12 meses. Os niveis GLP-1 e GLP-2 apos um teste de refeicao padrao foram determinados antes e 12 meses apos a operacao e entao foram correlacionados com o percentual de perda do excesso de peso. Resultados:: Houve aumento significativo da area sob a curva do GLP-2 apos a operacao (945,3+/-449,1 vs. 1787,9+/-602,7; p=0,0037); a area sob a curva do GLP-1 apresentou tendencia nao-significativa a elevacao apos o procedimento (709,6+/-320,4 vs. 1026,5+/ 714,3; p=0,3808). O percentual medio de perda de peso foi 66,7+/-12,2%. Conclusao:: Nao houve nenhuma correlacao significativa entre os niveis pre e pos operatorios das areas sob as curvas de GLP-1 e GLP-2 com o percentual de perda de peso atingido apos um ano. PMID- 28076482 TI - CORRELATION OF NON-ALCOHOLIC FATTY LIVER DISEASE AND FEATURES OF METABOLIC SYNDROME IN MORBIDLY OBESE PATIENTS IN THE PREOPERATIVE ASSESSMENT FOR BARIATRIC SURGERY. AB - Background:: Obesity is an epidemic and chronic disease that can bring other comorbidities to the patient. Non-alcoholic fatty liver disease is present in up to 90% of these patients and can progress to hepatitis and hepatocarcinoma. The relationship of this liver disease and obesity is already well known; however, it is possible that some parameters of the comorbidities are more related than others in the pathophysiology of the disease. Aim:: Was analyzed the relationship between non-alcoholic fatty liver disease (NAFLD) and the comorbidities of metabolic syndrome in morbidly obese patients. Methods:: Was involved ultrasonography and laboratory assessment of obese patients before bariatric surgery. NAFLD was assessed using the same sonography parameters for all patients. Based on the results, the patients were divided into groups with and without NAFLD. Comparisons between them involved clinical and laboratory variables such as fasting blood glucose, insulin, HOMA-IR (homeostasis model assessment - insulin resistance), glycated hemoglobin, total cholesterol and fractions, triglycerides, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, C-reactive protein, albumin and ferritin. Patients who reported alcohol abuse (defined as the consumption of >14 drinks per week) or who had hepatitis were excluded. Results:: Eighty-two patients (74 women and 8 men) were studied, of whom 53 (64.6%) had NAFLD and 29 (35.4%) did not. The levels of glycated hemoglobin (p=0.05) and LDL cholesterol (p=0.01) were significantly altered in patients with NAFLD. However, weight, body mass index and excess weight did not differ significantly between the groups (p=0.835, p=0.488 and p=0.727, respectively). Conclusions:: Altered LDL cholesterol and glycated hemoglobin levels were related to the presence of NAFLD. Racional: : A obesidade e doenca epidemica e cronica que pode trazer outras comorbidades ao paciente. A doenca hepatica gordurosa nao alcoolica esta presente em ate 90% desses pacientes e pode evoluir para hepatite e hepatocarcinoma. A relacao desta hepatopatia e a obesidade ja e bem conhecida; porem, e possivel que alguns parametros das comorbidades estejam mais relacionados do que outros na fisiopatogenia da doenca. Objetivo:: Correlacionar a doenca hepatica gordurosa nao alcoolica (DHGNA) com as comorbidades da sindrome metabolica em pacientes obesos morbidos em pre-operatorio de cirurgia bariatrica. Metodos:: Avaliacao ultrassonografica e laboratorial de pacientes obesos em pre-operatorio para cirurgia bariatrica. Durante o preparo para a operacao em todos os pacientes foi avaliada DHGNA atraves de ultrassonografia. De acordo com o resultado, os pacientes foram separados em dois grupos: sem DHGNA e com DHGNA. Para analise entre os grupos, avaliaram-se as seguintes variaveis clinicas e laboratoriais: insulina, HOMA-IR, hemoglobina glicada, colesterol total e fracoes, triglicerideos, transaminase piruvica, transaminase glutamico oxalacetica, gama glutamil transferase, proteina C reativa, albumina, ferritina. Os pacientes que relataram uso de bebida alcoolica ou que apresentaram hepatite foram excluidos do estudo. Resultados:: Avaliou-se um total de 82 pacientes (74 mulheres e 8 homens), sendo 53 (64.6%) com DHGNA e 29 (35.4%) sem. Os niveis de hemoglobina glicada (p=0.05) e de LDL (p=0.01) mostraram-se mais relacionados no grupo de pacientes com DHGNA. Conclusao:: A hemoglobina glicada e o LDL tiveram relacao com a presenca de DHGA. PMID- 28076483 TI - SEDATION IN COLONOSCOPY BY USING THREE DIFFERENT PROPOFOL INFUSION METHODS AND ANALYSIS OF PLASMA CONCENTRATION LEVELS: A PROSPECTIVE COMPARATIVE STUDY. AB - Background: : The propofolemia becomes directly linked to the clinical effects of this anesthetic and is the focus for studies comparing propofol clinical use, in different administration methods routinely used in endoscopy units where sedation is widely administered to patients. Aim: : To evaluate the effects of three different regimens of intravenous propofol infusion in colonoscopies. Methods: : A total of 50 patients that underwent colonoscopies were consecutively assigned to three groups: 1) intermittent bolus infusion; 2) continuous manually controlled infusion; 3) continuous automatic infusion. Patients were monitored with Bispectral IndexTM (BIS) and propofol serum levels were collected at three different timepoints. The development of an original dilution of propofol and an inventive capnography catheter were necessary. Results: : Regarding clinical outcomes, statistical differences in agitation (higher in group 1, p=0.001) and initial blood pressure (p=0.008) were found. As for propofol serum levels, findings were similar in consumption per minute (p=0.748) and over time (p=0.830). In terms of cost analysis, group 1 cost was R$7.00 (approximately US$2,25); group2, R$17.50 (approximately US$5,64); and group 3, R$112.70 (approximately US$36,35, p<0.001). Capnography was able to predict 100% of the oxygen saturation drop (below 90%). Conclusion: : The use of propofol bolus administration for colonoscopies, through continuous manually controlled infusion or automatic infusion are similar regarding propofolemia and the clinical outcomes evaluated. The use of an innovative capnography catheter is liable and low-cost solution for the early detection of airway obstruction. Racional: : A propofolemia esta diretamente relacionada com os efeitos clinicos desse anestesico e e foco de diversos estudos comparando os usos clinicos do propofol e os diferentes metodos de administracao, como realizado amplamente nos centros de endoscopia. Objetivo: : Avaliar os efeitos de tres diferentes regimes de infusao de propofol intravenoso em colonoscopias. Metodos: : Ao todo 50 pacientes que foram submetidos a colonoscopia foram consecutivamente divididos em tres grupos: 1) infusao em bolus intermitente; 2) perfusao continua controlada manualmente; 3) infusao automatica continua. Os pacientes foram monitorados com Bispectral IndexTM (BIS) e os niveis sericos de propofol foram coletados em tres momentos diferentes. Foi necessario a preparacao de uma diluicao especifica de propofol e o desenvolvimento de um cateter de capnografia original manufaturado para a realizacao do estudo. Resultados: : Em relacao aos desfechos clinicos, houve diferenca estatistica na agitacao (maior no grupo 1, p=0,001) e pressao arterial inicial (p=0,008). Com relacao aos niveis sericos de propofol, os resultados foram semelhantes no consumo por minuto (p=0,748) e ao longo do tempo (p=0,830). Em termos de analise de custo, no grupo 1 o custo foi de R$ 7,00 (aproximadamente US$ 2,25); grupo 2, R$ 17,50 (aproximadamente US$ 5,64); e grupo 3, R$ 112,70 (cerca de US$ 36,35, p<0,001). A capnografia foi capaz de diagnosticar 100% das dessaturacoes de oxigenio (abaixo de 90%). Conclusao: : O uso de propofol em bolus para colonoscopias, por meio de infusao continua controlada manualmente ou infusao automatica sao semelhantes quanto a propofolemia e os resultados clinicos avaliados. Alem disso, o uso de um cateter de capnografia inovador e solucao de baixo custo para a deteccao precoce da obstrucao da via aerea. PMID- 28076484 TI - AN INNOVATIVE EX-VIVO MODEL FOR RAPID CHANGE OF THE PAPILLA FOR TEACHING ADVANCED ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY PROCEDURES. AB - Background:: Models for endoscopic retrograde cholangiopancreatography training allow practice with an expert feedback and without risks. A method to rapidly exchange the papilla can be time saving and accelerate the learning curve. Aim:: To demonstrate a newly method of rapid exchange papilla in ex-vivo models to teach retrograde cholangiopancreatography advanced procedures. Methods:: A new model of ex-vivo papilla was developed in order to resemble live conditions of procedures as cannulation, papilotomy or fistula-papilotomy, papiloplasty, biliary dilatation, plastic and metallic stentings. Results:: The ex-vivo model of papilla rapid exchange is feasible and imitates with realism conditions of retrograde cholangiopancreatography procedures. Conclusion:: This model allows an innovative method of advanced endoscopic training. Racional:: Nas ultimas decadas os simuladores de colangiopancreatografia retrograda tiveram grande evolucao. Atualmente dispoem-se de varios metodos para realizar o treinamento minimizando os riscos de complicacoes e tornando a curva de aprendizagem muito rapida. Objetivo:: Demonstrar uma variacao dos modelos ex-vivos desenvolvidos para o treinamento avancado em colangiopancreatografia retrograda. Metodo:: Foi criado um modelo ex-vivo simulando fatores e condicoes reais para o treinamento avancado de colangiopancreatografia retrograda como canulacao, papilotomia, fistulotomia, papiloplastia e uso de proteses plasticas e metalicas. Resultados:: Esse modelo ex-vivo, com a possibilidade de troca rapida da papila, mostrou-se viavel e no treinamento simula condicoes muito proximas as reais. Conclusao:: Neste modelo ha grande inovacao para o treinamento de novos endoscopistas em procedimento avancados na colangiopancreatografia retrograda. PMID- 28076485 TI - GLP-2: A POORLY UNDERSTOOD MEDIATOR ENROLLED IN VARIOUS BARIATRIC/METABOLIC SURGERY-RELATED PATHOPHYSIOLOGIC MECHANISMS. AB - Introduction:: Glucagon-like peptide-2 (GLP-2) is a gastrointestinal hormone whose effects are predominantly trophic on the intestinal mucosa. Aim:: Critically evaluate the current literature on the influence of bariatric/metabolic surgery on the levels of GLP-2 and its potential clinical implications. Method: s: Narrative review through online research on the databases Medline and Lilacs. There were six prospective human studies, two cross sectional human studies, and three experimental animal studies selected. Results:: There is evidence demonstrating significant increase in the levels of GLP-2 following gastric bypass, Scopinaro operation, and sleeve gastrectomy. There are no differences between gastric bypass and sleeve gastrectomy in regards to the increase in the GLP-2 levels. There is no correlation between the postoperative levels of GLP-2 and the occurrence of adequate or insufficient postoperative weight loss. Conclusion:: GLP-2 plays significant roles on the regulation of nutrient absorption, permeability of gut mucosa, control of bone resorption, and regulation of satiety. The overall impact of these effects potentially exerts a significant adaptive or compensatory effect within the context of varied bariatric surgical techniques. Introducao:: O peptideo semelhante ao glucagon-2 (GLP-2) e hormonio gastrointestinal com efeitos predominantemente troficos sobre a mucosa intestinal. Objetivo:: Avaliar criticamente a literatura atual a respeito da cirurgia bariatrica/metabolica sobre os niveis de GLP-2 e suas potenciais implicacoes clinicas. Metodos:: Revisao narrativa realizada atraves de pesquisa on-line nas bases de dados Medline e LILACS. Foram selecionados seis estudos prospectivos em humanos, dois transversais em humanos e tres experimentais em animais. Resultados:: Existem evidencias demonstrando aumento significativo nos niveis de GLP-2 apos o bypass gastrico, a operacao de Scopinaro e a gastrectomia vertical. Nao foram observadas diferencas entre o bypass gastrico e a gastrectomia vertical em relacao ao aumento do GLP-2. Nao ha correlacao entre os niveis de GLP-2 e a ocorrencia de perda de peso pos-operatoria adequada ou insuficiente. Conclusao:: O GLP-2 desempenha importantes papel sobre a regulacao da absorcao de nutrientes, permeabilidade da mucosa intestinal, controle da reabsorcao ossea e regulacao da saciedade. O impacto combinado destes efeitos potencialmente exerce efeito adaptativo ou compensatorio importante no contexto das diferentes tecnicas bariatricas. PMID- 28076486 TI - SERUM LEPTIN LEVENS AND HEPATOCELLULAR CARCINOMA: REVIEW ARTICLE. AB - Introduction: : Hepatocellular carcinoma is one of the most frequent types of malignant tumors in the world. There is growing evidence of the relationship between it development and obesity. The mechanism that links obesity to cancer is still not fully understood; however, it is essential to the understanding the adipose tissue in metabolic changes related to obesity and hepatocellular carcinoma. Objective:: To review the influence of serum leptin levels in patients with hepatocelular carcinoma. Method:: Systematic review of the literature based on the methodology of the Cochrane Institute. The search for articles was in the database: Science Direct, Scielo, Medline, Lilacs e Pubmed. The key words used were hepatocellular carcinoma, leptin, adipokine. Results:: After evaluation of individual studies, were selected seven studies. The results previously studied are still inconsistent and contradictory, and leptin can be effectively involved in the occurrence and development of hepatocellular carcinoma. Conclusion:: Therefore, it is necessary to develop prospective, well-designed and conducted focusing on the role and specific mechanisms of this hormone in patients with hepatocellular carcinoma, so that new correlations can be properly supported. Introducao: : O carcinoma hepatocelular e um dos tipos mais frequentes de tumores malignos no mundo. Ha crescentes evidencias da relacao entre o seu desenvolvimento e a obesidade. O mecanismo que os relaciona ainda nao e completamente entendido. Entretanto e essencial a compreensao do tecido adiposo nas alteracoes metabolicas relacionadas a obesidade e ao cancer. Objetivo:: Revisar a influencia dos niveis sericos de leptina em pacientes com carcinoma hepatocelular. Metodo:: Trata-se de revisao bibliografica baseada na metodologia do Instituto Cochrane; a busca de dados foi realizada na base de dados Science Direct, Scielo, Medline, Lilacs e Pubmed, empregando as seguintes descritores: hepatocellular carcinoma, leptin, adipokine. Resultado:: Apos avaliacao individual dos artigos selecionaram-se sete estudos. Os resultados ainda sao inconsistentes e contraditorios, e a leptina pode estar efetivamente envolvida na ocorrencia e no desenvolvimento do carcinoma hepatocelular. Conclusao:: Faz-se necessario o desenvolvimento de estudos prospectivos, bem desenhados e conduzidos sobre o papel e mecanismos especificos deste hormonio em pacientes com carcinoma hepatocelular para que novas correlacoes sejam devidamente comprovadas. PMID- 28076487 TI - TECHNOLOGICAL INFORMATION REGARDING PREBIOTICS AND PROBIOTICS NUTRITION VERSUS THE PATENT REGISTERS: WHAT IS NEW? AB - Introduction:: Food is a key factor both in prevention and in promoting human health. Among the functional food are highlighted probiotics and prebiotics. Patent databases are the main source of technological information about innovation worldwide, providing extensive library for research sector. Objective:: Perform mapping in the main patent databases about pre and probiotics, seeking relevant information regarding the use of biotechnology, nanotechnology and genetic engineering in the production of these foods. Method: : Electronic consultation was conducted (online) in the main public databases of patents in Brazil (INPI), United States (USPTO) and the European Patent Bank (EPO). The research involved the period from January 2014 to July 2015, being used in the title fields and summary of patents, the following descriptors in INPI "prebiotic", "prebiotic" "probiotics", "probiotic" and the USPTO and EPO: "prebiotic", "prebiotics", "probiotic", "probiotics". Results:: This search haven't found any deposit at the brazilian patents website (INPI) in this period; US Patent &Trademark Office had registered 60 titles in patents and the European Patent Office (EPO) showed 10 documents on the issue. Conclusion:: Information technology offered by genetic engineering, biotechnology and nanotechnology deposited in the form of titles and abstracts of patents in relation to early nutritional intervention as functional foods, has increasingly required to decrease the risks and control the progression of health problems. But, the existing summaries, although attractive and promising in this sense, are still incipient to recommend them safely as a therapeutic tool. Therefore, they should be seen more as diet elements and healthy lifestyles. Introducao: : A alimentacao e fator primordial tanto na prevencao quanto na promocao para a saude humana. Dentre os alimentos funcionais destacam-se os probioticos e prebioticos. Os bancos de dados de patentes representam a maior fonte de informacao tecnologica acerca de inovacao em nivel mundial, provendo vasta biblioteca para o setor de pesquisa. Objetivo:: Realizar mapeamento nas principais bases de dados de patentes relacionada aos pre e probioticos buscando informacoes relevantes com relacao ao uso da biotecnologia, nanotecnologia e engenharia genetica na producao desses alimentos. Metodo:: Foi realizada consulta eletronica (online) nas principais bases de dados publicas de patentes do Brasil (INPI), Estados Unidos da America (USPTO) e o Banco de Patentes Europeu (EPO). A pesquisa envolveu o periodo de janeiro de 2014 a julho 2015, sendo utilizado nos campos de titulo e resumo das patentes, os seguintes descritores no INPI: "prebiotico", "prebioticos" "probiotico", "probioticos" e no USPTO e EPO: "prebiotic", "prebiotics", "probiotic", "probiotics". Resultados:: Nao foram observados, no INPI, depositos de residentes (empresas ou universidades). Ja no USPTO foram detectados 60 depositos e no EPO 10 titulos de interesse a pesquisa. Conclusao:: A tecnologia da informacao ofertada pela engenharia genetica, biotecnologia e nanotecnologia depositada na forma de titulos e resumos das patentes em relacao a intervencao nutricional precoce como alimentos funcionais, tem cada vez mais pretendido diminuir os riscos e controlar a progressao de agravos a saude. Mas, os resumos existentes, embora atraentes e promissores neste sentido, ainda sao incipientes para recomenda-los de forma segura como ferramenta terapeutica. Portanto, devem ser encarados mais como integrantes de dieta e estilos de vida saudaveis. PMID- 28076488 TI - USE OF TRANEXAMIC ACID IN TRAUMA PATIENTS: AN ANALYSIS OF COST-EFFECTIVENESS FOR USE IN BRAZIL. AB - Introduction:: Use of tranexamic acid (TXA) in trauma has been the subject of growing interest by researchers and health professionals. However, there are still several open questions regarding its use. In some aspects medical literature is controversial. The points of disagreement among experts include questions such as: Which patients should receive TXA in trauma? Should treatment be performed in the pre-hospital environment? Is there any need for laboratory parameters before starting TXA treatment? What is the drug safety profile? The main issue on which there is still no basis in literature is: What is the indication for treatment within massive transfusion protocols? Objective:: Answer the questions proposed based on critical evaluation of the evidence gathered so far and carry out a study of cost-effectiveness of TXA use in trauma adapted to the Brazilian reality. Methods:: A literature review was performed through searching Pubmed.com, Embase and Cab Abstract by headings "tranexamic AND trauma", in all languages, yielding 426 articles. Manuscripts reporting on TXA utilization for elective procedures were excluded, remaining 79 articles. Fifty five articles were selected, and critically evaluated in order to answer study questions. The evaluation of cost effectiveness was performed using CRASH-2 trial data and Brazilian official population data. Results:: TXA is effective and efficient, and should be administered to a wide range of patients, including those with indication evaluated in research protocols and current indication criteria for TXA should be expanded. As for the cost-effectiveness, the TXA proved to be cost-effective with an average cost of R$ 61.35 (currently US$16) per year of life saved. Conclusion:: The use of TXA in trauma setting seems to be effective, efficient and cost-effective in the various groups of polytrauma patients. Its use in massive transfusion protocols should be the subject of further investigations. Introducao:: O uso do acido tranexamico (TXA) no trauma tem sido alvo de interesse crescente por parte de pesquisadores e profissionais de saude. No entanto, seus beneficios ainda nao foram completamente definidos. Os pontos de divergencia entre especialistas incluem questoes como: quais pacientes devem receber TXA no trauma? O tratamento deve ser realizado em ambiente pre hospitalar? Ha necessidade de exames laboratoriais para indicar o tratamento? Qual o perfil de seguranca da droga? A principal questao para a qual ainda nao existe qualquer embasamento na literatura e: qual a indicacao do tratamento dentro de protocolos de transfusao macica? Objetivo:: Responder as questoes propostas, com base em avaliacao critica da evidencia reunida ate o momento e realizar estudo de custo-efetividade do uso do TXA no trauma adaptado a realidade brasileira. Metodos:: Foi realizada revisao da literatura atraves de estrategia de busca: PubMed.com, Embase e no Cab Abstract pelos descritores "tranexamic AND trauma", em todos idiomas, resultando em 426 artigos. Foram excluidos aqueles relativos as operacoes eletivas, restando 79 artigos. Cinquenta e cinco foram selecionados e avaliados criticamente com vistas a responder as questoes em estudo. A avaliacao de custo-efetividade foi realizada utilizando dados do estudo CRASH-2 e populacionais oficiais brasileiros. Resultados:: Atraves da analise da evidencia disponivel chegou-se a conclusao de que o acido tranexamico e tratamento eficaz e efetivo, devendo ser administrado a ampla gama de pacientes, incluindo todos aqueles com indicacao ja avaliada nos protocolos de pesquisa publicados e provavelmente devam-se expandir os criterios de indicacao. Quanto a avaliacao de custo-efetividade, o TXA mostrou-se bastante custo-eficaz com gasto medio de R$ 61,35 por ano de vida salvo. Conclusao:: O uso do acido tranexamico no trauma parece ser eficaz, efetivo e custo-eficaz nos diversos grupos de pacientes politraumatizados. Seu uso em protocolos de transfusao macica ainda deve ser objeto de futuras investigacoes. PMID- 28076489 TI - ROBOTIC SURGERY: BIOETHICAL ASPECTS. AB - Introduction: : The use of robots in surgery has been increasingly common today, allowing the emergence of numerous bioethical issues in this area. Objective:: To present review of the ethical aspects of robot use in surgery. Method:: Search in Pubmed, SciELO and Lilacs crossing the headings "bioethics", "surgery", "ethics", "laparoscopy" and "robotic". Results:: Of the citations obtained, were selected 17 articles, which were used for the preparation of the article. It contains brief presentation on robotics, its inclusion in health and bioethical aspects, and the use of robots in surgery. Conclusion:: Robotic surgery is a reality today in many hospitals, which makes essential bioethical reflection on the relationship between health professionals, automata and patients. Introducao: : A utilizacao de robos em procedimentos cirurgicos tem sido cada vez mais frequente na atualidade, o que permite a emergencia de inumeras questoes bioeticas nesse ambito. Objetivo:: Apresentar revisao sobre os aspectos eticos dos usos de robos em cirurgia. Metodo:: Realizou-se revisao nas bases de dados Pubmed, SciELO e Lilacs cruzando-se os descritores "bioetica", "cirurgia", "etica", "laparoscopia" e "robotica". Resultados:: Do total de citacoes obtidas, selecionou-se 17 artigos, os quais foram utilizados para a elaboracao do artigo. Ele contem breve apresentacao sobre a robotica, sua insercao na saude e os aspectos bioeticos da utilizacao dos robos em procedimentos cirurgicos. Conclusao:: A cirurgia robotica e uma realidade, hoje, em muitas unidades hospitalares, o que torna essencial a reflexao bioetica sobre as relacoes entre profissionais da saude, automatos e pacientes. PMID- 28076490 TI - COMPLEX PANCREATIC RESSECTIONS WITH VASCULAR INVOLVEMENT IN JEHOVAH'S WITNESSES: HOW TO APPROACH? PMID- 28076491 TI - SYNCHRONOUS ANAL MELANOMA AND COLON ADENOCARCINOMA: CASE REPORT AND REVIEW OF DIAGNOSIS AND MANAGEMENT. PMID- 28076492 TI - CENTRAL HEPATECTOMY FOR BILIARY CYSTADENOMA: PARENCHYMA-SPARING APPROACH FOR BENIGN LESIONS. PMID- 28076493 TI - COMMENT: HOSPITALIZATIONS FOR CHOLECYSTITIS AND CHOLELITHIASIS IN THE STATE OF RIO GRANDE DO SUL, BRAZILREPLY. PMID- 28076494 TI - Accuracy of mandibular measurements of sexual dimorphism using stabilizer equipment. AB - The objective of this investigation was to compare the accuracy of mandibular measurements using a stabilizer (MS) with gold standard computed tomography (GS) images. Sixty mandibles were studied. Werth TomoScope HV Compact(r) was used to obtain CT images (GS), and the MS was also used. Analysis of the CT scans was performed using the VG Studio Max software(r) (Volume Graphics GmbH, Heidelberg, Germany), and MS was used after the proper positioning of the mandible. Descriptive and paired t test measures were used, and a ROC curve was calculated, as well as sensibility and specificity. MedCalc and STATA 13.0(r) were used (95% level of significance). Bicondylar breadth, bicoronoid breadth and minimum ramus breadth reached the highest concordance correlation coefficients at 0.99 (0.99 1.00), 0.99 (0.99-1.00) and 1.00 (0.99-1.00), respectively. Comparing observers with GS, the lowest accuracy was noted for the maximum mandibular length [0.59 (0.45-0.69), 0.64 (0.51-0.74)], the breadth of the right (0.14 (0.04-0.23), 0.14 (0.004-0.24)) and left mandibular body [0.14 (0.03-0.24), 0.16 (0.05-0.26)], and the right [0.58 (0.45-0.69), 0.63 (0.51-0.73) and left (0.59 (0.45-0.70), 0.59 (0.46-0.69)] mandibular angle. Various measurements exhibited good sensibility for males using MS: maximum mandibular length (78.12), bicondylar breadth (78.12), left mandibular notch breadth (84.37), and the left height of the mandibular body at the mental foramen (75.00). High specificity in discriminating females was observed for the left maximal ramus height (85.19), mandibular length (85.71), bicoronoid breadth (96.43), right height of the mandibular body at the mental foramen (82.19), bimental breadth (78.57), breadth right (92.86) and left (96.43) mandibular body, minimum ramus breadth (89.29), and left mandibular angle (85.71). MS was able to discriminate sexual dimorphism. PMID- 28076495 TI - Antimicrobial activity of ozone and NaF-chlorhexidine on early childhood caries. AB - An early childhood carie (ECC) is an extremely destructive form of tooth decay. The aim of this study was to investigate the action of ozone (O3), and the association of sodium fluoride (NaF) with chlorhexidine (CHX) on bacteria related to ECC. Overnight culture of the bacteria was performed. On exponential phase the suspension was adjusted (101-108 CFU/mL). A drop (10MUL) of each concentration of bacteria was applied on sheep blood agar plates and treated with O3 (2, 20, 200, and 2,000 ppm); after 18 hours, recovery analysis of CFU verified the reduction of bacterial activity. For NaF-CHX, sterile 96-well plates were prepared and divided into groups: G1 (150 uL TSB); G2 (20 uL of bacteria + 25 uL CHX + 25 uL NaF); and G3 (150 uL TSB + 20 uL of bacteria + 50 uL water). The plates were verified by analysis of the optical density (0, 12, 14, 16, and 18 hours). The data from O3 test were submitted to ANOVA and Tukey's test (p < 0.05). For the data from NaF-CHX, the ANOVA 2-way and Bonferroni's test (p < 0.05) were used. The number of CFU/mL showed death > 3log10 (99.9%) for all bacteria (ozone >= 20ppm), while the combination of NaF-CHX was more effective (p < 0.001) compared to each substance tested alone and the control group. The antimicrobial agents tested were able to inhibit all bacteria tested; O3 seemed to be a good alternative for controlling progression of carious lesions, while the association of NaF-CHX showed to be a good antimicrobial with easy and inexpensive application. PMID- 28076496 TI - Evaluation of dentin hypersensitivity treatment with glass ionomer cements: A randomized clinical trial. AB - A randomized, double-blind, split-mouth clinical trial was performed compared the desensitizing efficacy of the resin-modified glass ionomer cement (GIC) ClinproTM XT (3M ESPE, Minnesota, USA) and the conventional GIC Vidrion R (SS White, Gloucester, UK) in a 6-month follow-up. Subjects were required to have at least two teeth with dentin hypersensitivity. Teeth were divided at random into 2 groups, one group received Clinpro XT and the other conventional GIC Vidrion R. Treatments were assessed by tactile and air blast tests using Visual Analogue Scale (VAS) at baseline, after 20 minutes, and at 7, 15, 21, 30, 90 and 180 days post-treatment. Twenty subjects (152 teeth) were included. Both tests (tactile and air blast) showed a significant reduction of dentin hypersensitivity immediately after the application of Vidrion R and Clinpro XT (20 min). VAS scores obtained along the 6-month follow-up were statistically lower when compared to initial rates (p < 0.05). Both GIC were able to reduce dentin hypersensitivity up to 6-month post-treatment period without statistically significant differences among them (p > 0.05). Both cements provided satisfactory results in long-term dental sensitivity reduction. PMID- 28076497 TI - One-year aging effects on microtensile bond strengths of composite and repairs with different surface treatments. AB - The present study aimed to evaluate effects of different surface treatments and aging of composite cylinders on bond strength of composite resin repair. Thirty two composite cylinders were produced and divided into four groups according to type of surface treatment and storage time of composite cylinder and repair. Cylinder surface of control group (Gcontrol) received no treatment before composite repair. Other groups were sandblasted with aluminum oxide (GAl2O3), followed by silane (GAl2O3sil) or adhesive (GAl2O3ad). Composite cylinders were stored in artificial saliva for either 24 hours or 1 year. Repairs were performed and stored in artificial saliva for 24 hours or 1 year and repair strength was evaluated using microtensile bond strength test. Data were submitted to Student's t test, two-way ANOVA, and post hoc test for storage time and treatment (alpha = 0.05). Gcontrol group showed lower values of aging of composite cylinder and storage time of repair (24 hours or 1 year for both) compared with other groups (p < 0.05). GAl2O3ad and GAl2O3sil groups did not exhibit decreased microtensile bond strength with aged repairs (1 year; p > 0.05). Polymer degradation was significant for composite cylinders during the first year of storage in Gcontrol, GAl2O3, and GAl2O3ad groups (p < 0.05). In GAl2O3sil group, storage time of composite cylinders was not significant (p > 0.05). Aging of composite resin influenced bond strength of restoration repair for up to 1 year. Sandblasting with Al2O3, followed by application of silane layer, produced high bond strength after composite or repair aging. PMID- 28076498 TI - The efficacy of low-level 940 nm laser therapy with different energy intensities on bone healing. AB - The aim of this study was to evaluate the efficacy of low-level 940 nm laser therapy with energy intensities of 5, 10 and 20 J/cm2 on bone healing in an animal model. A total of 48 female adult Wistar rats underwent surgery to create bone defects in the right tibias. Low-level laser therapy (LLLT) was applied immediately after surgery and on post-operative days 2, 4, 6, 8, 10 and 12 in three study groups with energy intensities of 5 J/cm2, 10 J/cm2 and 20 J/cm2 using a 940 nm Gallium-Aluminium-Arsenide (Ga-Al-As) laser, while one control group underwent only the tibia defect surgery. All animals were sacrificed 4 or 8 weeks post-surgery. Fibroblasts, osteoblasts, osteocytes, osteoclasts and newly formed vessels were evaluated by a histological examination. No significant change was observed in the number of osteocytes, osteoblasts, osteoclasts and newly formed vessels at either time period across all laser groups. Although LLLT with the 10 J/cm2 energy density increased fibroblast activity at the 4th week in comparison with the 5 and 20 J/cm2 groups, no significant change was observed between the laser groups and the control group. These results indicate that low level 940 nm laser with different energy intensities may not have marked effects on the bone healing process in both phases of bone formation. PMID- 28076499 TI - Association between the clinical severity of oral lichen planus and anti-TPO level in thyroid patients. AB - This study considered a possible relationship between the severity of oral lichen planus (OLP), serum anti-TPO autoantibodies (TPOAb) titer and thyroid disease in OLP patients. Forty-six OLP patients with positive TPOAb results (> 35 IU/ml) who had also been diagnosed with thyroid disease were included in the study group. The control group consisted of 46OLP patients with no thyroid disease. The study and control groups (92) were divided to two subgroups of erosive OLP (EOLP) and non-erosive OLP (NEOLP). Serum TPOAb levels and IL-8 (to measure OLP severity) were evaluated using the independent t-test, chi-square and conditional logistic regression analysis (alpha = 0.05). A significant positive correlation was found between serum IL-8 and TPOAb levels in the study group (r = 0.783; p = 0.001). The positive blood levels of TPOAb were significantly associated with an increased risk of EOLP (OR = 4.02 at 95%CI; 1.21-13.4; p = 0.023). It is possible to used positive serum TPOAb levels in patients with OLP as in indicator of possible undetected thyroid disorders in those patients. Because erosive OLP has been associated with TPOAb in thyroid patients, it may be useful to determine TPOAb levels of such patients to diagnose a possible undetected thyroid disorders and follow-up for malignancy. PMID- 28076500 TI - Histological evaluation of capsules formed by silicon implants coated with polyurethane foam and with a textured surface in rats. AB - PURPOSE: : To assess the capsules formed by silicone implants coated with polyurethane foam and with a textured surface. METHODS: : Sixty-four Wistar albinus rats were divided into two groups of 32 each using polyurethane foam and textured surface. The capsules around the implants were analyzed for 30, 50, 70 and 90 days. Were analyzed the following parameters: foreign body reaction, granulation tissue, presence of myofibroblasts, neoangiogenesis, presence of synovial metaplasia, capsular thickness, total area and collagen percentage of type I and III, in capsules formed around silicone implants in both groups. RESULTS: : The foreign body reaction was only present in the four polyurethane subgroups. The formation of granulation tissue and the presence of myofibroblasts were higher in the four polyurethane subgroups. Regarding to neoangiogenesis and synovial metaplasia, there was no statistical difference between the groups. Polyurethane group presented (all subgroups) a greater capsule thickness, a smaller total area and collagen percentage of type I and a higher percentage area of type III, with statistical difference. CONCLUSION: : The use of polyurethane coated implants should be stimulated by the long-term results in a more stable capsule and a lower incidence of capsular contracture, despite developing a more intense and delayed inflammatory reaction in relation to implants with textured surface. PMID- 28076501 TI - Evaluating the best time to intervene acute liver failure in rat models induced by d-galactosamine. AB - PURPOSE:: To describe an animal model for acute liver failure by intraperitoneal d-galactosamine injections in rats and to define when is the best time to intervene through King's College and Clichy's criteria evaluation. METHODS:: Sixty-one Wistar female rats were distributed into three groups: group 1 (11 rats received 1.4 g/kg of d-galactosamine intraperitoneally and were observed until they died); group 2 (44 rats received a dose of 1.4 g/kg of d-galactosamine and blood and histological samples were collected for analysis at 12 , 24, 48 , 72 and 120 hours after the injection); and the control group as well (6 rats) . RESULTS:: Twelve hours after applying d-galactosamine, AST/ALT, bilirubin, factor V, PT and INR were already altered. The peak was reached at 48 hours. INR > 6.5 was found 12 hours after the injection and factor V < 30% after 24 hours. All the laboratory variables presented statistical differences, except urea (p = 0.758). There were statistical differences among all the histological variables analyzed. CONCLUSION:: King's College and Clichy's criteria were fulfilled 12 hours after the d-galactosamine injection and this time may represent the best time to intervene in this acute liver failure animal model. PMID- 28076502 TI - Carcinogenesis in rats subjected to a new model ureterosigmoidostomy and treated with L-lysine. AB - PURPOSE: : To evaluate the effects of L-lysine on the intestinal and urothelial epithelium of rats subjected to ureterosigmoidostomy (new model for surgical carcinogenesis). METHODS: : Forty-two rats, 9 weeks of age, were divided into 6 groups. Animals in groups A, B, C were subjected to ureterosigmoidostomy (US) and treated with L-lysine, celecoxib and H2O, respectively. Groups D, E and F (non operated controls) received L-lysine, celecoxib and H2O, respectively. The L lysine dose was 150 mg/kg and that of celecoxib was 20 mg/kg. The colon was analyzed for the presence of aberrant crypt foci (ACF) under a stereomicroscope.The tissue was stained with hematoxylin and eosin and PAS alcian blue. RESULTS: : There were rare ACF, and there was no statistically significant difference between the groups. Histopathologic study of the ureteral epithelium identified moderate to severe urothelial hyperplasia in rats with ureterosigmoidostomy. Transitional hyperplasia in the ureters of animals receiving L-lysine (A) showed an apparent difference compared to the control (C) (P=0.2424). There was no dysplasia or atypia. CONCLUSION: : L-lysine does not promote carcinogenesis of the intestinal and urethelial epithelium of rats subjected to ureterosigmoidostomy at the doses and times studied. PMID- 28076504 TI - The role of bradykinin in lung ischemia-reperfusion injury in a rat lung transplantation model. AB - PURPOSE: : To investigate the role of bradykinin in a rat lung transplantation (LTx) model and preliminarily discuss the relationship between bradykinin and CD26/DPP-4. METHODS: : Rats were randomly divided into four groups: Control (CON), Sham, low potassium dextranglucose (LPD), and AB192 (n=15/group). Orthotopic single LTx was performed in the LPD and AB192 groups. The donor lungs were flush-perfused and preserved with low potassium dextranglucose (LPD) or LPD+CD26/DPP-4 catalytic inhibitor (AB192). LTx was performed after 18 h cold ischemia time and harvested two days post-LTx. Blood gas analysis (PO2), wet/dry weight ratio (W/D), myeloperoxidase activity (MPO), and lipid peroxidation (MDA) were analyzed at 48 hr after transplantation. Immunohistochemical (IHC) analysis was performed in the same sample and validated by Western-Blot. RESULTS: : Compared to the LPD group, the AB192 group showed higher PO2, lower W/D ratio, and decreased MPO and MDA. IHC studies showed strong bradykinin beta2 receptor (B2R) staining in the LPD group, especially in inflammatory cells, alveolar macrophages, and respiratory epithelial cells. Expression of B2R by Western-Blot was significantly different between the AB192 and LPD groups. CONCLUSION: : Bradykinin may be a competitive substrate of DPP-4, and decreased bradykinin levels may enhance protective effects against ischemia/reperfusion injury during LTx. PMID- 28076503 TI - Effect of silymarin on oxidative stress and liver histopathology in experimental obstructive jaundice model. AB - PURPOSE:: To investigate the effect of silymarin on oxidative stress and hepatic injury induced by obstructive jaundice in an experimental model. METHODS:: Thirty Wistar-Albino type female rats were divided into 3 groups each including 10 rats. Only laparotomy was performed in group 1. Bile duct ligation was performed in group 2. In group 3, bile duct ligation was performed and orogastic silymarin 300 mg/kg/day dose was given for seven days. At the end of seven days, rats were sacrificed. The blood and liver tissue samples were taken to be examined biochemically and histopathologically. RESULTS:: The plasma and liver levels of malondialdehyde were significantly lower in silymarin group than in the bile duct ligated group. Although liver levels of GSH were significantly higher in silymarin group than in the bile duct ligated group, there was no significant difference between the plasma GSH levels of these groups. In silymarin group; the enlargement of hepatocytes, dilatation of canaliculi and the edema were regressed. CONCLUSION:: Silymarin diminished the harmful effects of obstructive jaundice on liver. PMID- 28076505 TI - Therapeutic effect of low molecular weight chitosan containing sepia ink on ethanol-induced gastric ulcer in rats. AB - PURPOSE: : To evaluate the role of low molecular chitosan containing sepia ink (LMCS) in ethanol-induced (5 ml/kg) gastric ulcer in rats. METHODS: : Animals were divided into four groups (n = 12): normal group (Normal), negative control group (Con), experiment group (LMCS) and positive control Omeprazole group (OMZ). Gastric empty rate was detected in the first 7 days. Rats were sacrificed at 7, 14 and 21 day for histology and ELISA detections. RESULTS: : Gastric empty was no significant differences among the groups (P > 0.05). Histological observation showed gastric mucosal LMCS treated had better healing effect. Hydroxyproline (Hyp) was significantly increased from 7 day (P < 0.05). LMCS significantly inhibited malondialdehyde (MDA) generation for lipid peroxidation from 7 day (P < 0.05). LMCS significantly promoted the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) at the earlier stage (P < 0.05). OMZ had the similar effects above. As for myeloperoxidase (MPO), LMCS significantly decreased and restored it to normal levels from 7 day (P < 0.05), it is earlier than OMZ which is from 14 day. CONCLUSION: : LMCS can improve gastric mucosa tissue repair, exert significant influences on oxidative and antioxidant enzyme activities and neutrophil infiltration. PMID- 28076506 TI - Stem cells from adipose tissue improve the time of wound healing in rats. AB - PURPOSE: : To evaluate the Adipose Stem Cells (ACS) therapy efficacy on the time and quality of wound healing process in rats. METHODS: : Nine male Wistar rats were randomly distributed into three groups I) 7 days of healing; II) 14 days of healing; III) 21 days of healing. Four incisions were made on the dorsal surface of each rat and then treated with intralesional ACS, meloxicam, and no treatment and ACS+meloxicam. Macroscopic evaluation was measured by percentage of healing and histopathological by hematoxylin-eosin was performed. RESULTS: : All groups have the wound reduced during the three weeks (p<0.001) and after 14 days of healing had greater reduction than others. Wounds treated with ASC had accelerated healing in relation to no treatment and only meloxicam (p<0.001), excepting the ASC+Meloxicam that was similar (p=0.13). There was no difference in histopathological analysis between lesions. CONCLUSION: : Adipose stem cell have benefits in reducing time of healing of experimental model of wound in rats, observed 7 days of after application. PMID- 28076507 TI - Effects of cococonut water and simvastatin in the treatment of sepsis and hemorrhagic shock in rats. AB - PURPOSE:: To evaluate the effects of modified coconut water as fluid of resuscitation combined with simvastatin in hemorrhagic shock and sepsis model in rats. METHODS:: Four groups of Wistar rats with hemorrhagic shock and abdominal sepsis were studied (n=8/group). Rats were bled and maintained at a mean blood pressure 35mmHg for 60min. They were then resuscitated with: 1) saline 0.9%; 2) coconut water+3% NaCl; 3) coconut water+NaCl 3%+simvastatin microemulsion (10 mg/kg i.v.; 4) normal coconut water. At 8h post-resuscitation, blood and lungs were collected for exams. RESULTS:: Clinical scores, TNF-alpha, IL-1beta, liver/kidney proof levels, and lung injury were significantly reduced in coconut water+NaCl 3%+simvastatin group treated rats, comparing with the other resuscitation treatments. CONCLUSIONS:: Resuscitation with coconut water with Nacl 3%+simvastatin had a significant beneficial effect on downregulating cytokines and decreasing lung injury in a rat model of abdominal sepsis and hemorrhagic shock. We also demonstrated that coconut water with Nacl 3%+simvastatin administration clearly made liver and kidney function better and improved clinical score. PMID- 28076508 TI - Swing mesh versus Modified Kugel mesh for primary inguinal hernia repair. A prospective randomized clinical trial. AB - PURPOSE: To evaluate the safety and efficacy of a new mesh in the pre-peritoneal repair of inguinal hernia. METHODS: We randomly divided 120 patients undergoing pre-peritoneal repair into 2 groups between March 2012 and December 2013. The patients were randomized to receive the Swing mesh (n=60; study group) or the Modified Kugel mesh (n=60; control group). The primary end point of this study was to compare postoperative groin pain of the two groups. Complications, recurrence and analgesic use were also recorded. RESULTS: There were no recurrent cases in either group throughout the study period. There was no significant difference between the groups with respect to postoperative complications. The VAS of early postoperative pain was 1.32+/-1.69 in study group and 1.52+/-1.93 in control group, with the difference being not statistically significant (p = 0.547). Concerning chronic pain, no remarkable statistically significant difference was observed between the two groups at 3-month, 6-month, 12- and 18 month follow-up period. CONCLUSION: Swing mesh can be safely and effectively used in inguinal hernia repair with the same advantage compared to the Modified Kugel mesh. PMID- 28076509 TI - Animal models of obesity in rodents. An integrative review. AB - PURPOSE:: To perform an integrative review of the main animal disease models in rodents used for obesity. METHODS:: Research was conducted in the CAPES Portal database using the following keywords "obesity animal models, diet and rodents", published between the years 2010 to 2016. We found 108 articles, of which 19 were selected and analyzed in full for this study. RESULTS:: Larger part of publications occurred in the last 6 years, the rats (n = 10) were used in the same proportion mice (n = 10). The choice of male animals (n = 18) and age greater than 21 days (n = 17) showed a major highlight. The greater than 5 week follow-up period (n = 18) was the most applied. A High Fat Diet was the most used in studies (n = 18) . CONCLUSIONS:: Male rodents continue to be considered the species most used in experimental studies to induce obesity, also was found variations of age to the beginning of the experiment. For the most part are follow-up time studies along with the use of High Fat Diet. PMID- 28076510 TI - Writing scientific articles like a native English speaker: concise writing for Portuguese speakers. PMID- 28076511 TI - Passive acquisition of anti-Staphylococcus aureus antibodies by newborns via transplacental transfer and breastfeeding, regardless of maternal colonization. AB - OBJECTIVE:: To investigate the transmission of anti-Staphylococcus aureus (Sa) IgG, IgG1 and IgG2 via placental transfer and the transfer of IgA via the colostrum according to maternal Sa carrier status at delivery. METHODS:: We evaluated anti-Sa IgG, IgG1 and IgG2 in maternal and cord sera and IgA in colostrum from a case (n=49, Sa+) and a control group (n=98, Sa-). RESULTS:: Of the 250 parturients analyzed for this study, 49 were nasally colonized with S. aureus (prevalence of 19.6%). Ninety-eight non-colonized subjects were selected for the control group. The anti-Sa IgG, IgG1 and IgG2 levels and the IgG avidity indexes in the maternal and cord sera did not differ between the groups, with a low transfer ratio of anti-Sa IgG to the newborns in both groups. The anti-Sa IgG2 titers were significantly higher than the IgG1 titers in the maternal and cord sera. Inversely, the transfer ratios were higher for anti-Sa IgG1 compared with IgG2; however, no differences between the groups were detected. The Sa specific IgA levels and avidity indexes in the colostrum were equivalent between groups. CONCLUSIONS:: Maternal Sa nasal colonization at delivery is not associated with higher antibody levels in the mother or newborns. The high titers of anti-Sa IgG2 found in the cord serum indicate a greater reactivity with non protein antigens, which may further contribute to the susceptibility to staphylococcal infections at birth. The presence of IgA in the colostrum with avidity to S. aureus reinforces the importance of breastfeeding shortly after birth. PMID- 28076512 TI - Mutation analysis of NANOS3 in Brazilian women with primary ovarian failure. AB - OBJECTIVES:: Primary ovarian failure is a rare disorder, and approximately 90% of cases are of unknown etiology. The aim of this study was to search for mutations in NANOS3, a gene that was recently related to the etiology of primary ovarian failure, in a group of Brazilian women. METHODS:: We screened for NANOS3 DNA variants in 30 consecutive women who were previously diagnosed with primary ovarian failure, of unknown etiology and compared the results with those from 185 women with normal fertility. The NANOS3 gene was amplified by polymerase chain reaction using pairs of specific primers and then sequenced. The resulting sequences were compared with control sequences available in the National Center for Biotechnology and Information database. RESULTS:: No mutations in NANOS3 were found in primary ovarian failure patients, but four previously described polymorphisms were identified at a similar frequency in the control and primary ovarian failure groups. CONCLUSIONS:: Mutations in NANOS3 were not associated with primary ovarian failure in the present cohort. PMID- 28076513 TI - Serum concentration of vascular endothelial growth factor and depth of trophoblastic invasion in ampullary ectopic pregnancy. AB - OBJECTIVE:: To evaluate the association between the depth of trophoblastic infiltration and serum vascular endothelial growth factorconcentration in patients with an ampullary pregnancy. METHODS:: This prospective cross sectionalstudy involved 34 patients with an ampullary ectopic pregnancy who underwent salpingectomy between 2012 and 2013. Maternal serum vascular endothelial growth factor concentrations were measured using Luminex technology. Trophoblastic invasion was classified histologically as follows: stage I, limited to the tubal mucosa; stage II, reaching the muscle layer; and stage III,involving the full thickness. The qualitative data were compared using Fisher's exact test. The nonparametric Kruskal-Wallis and Mann-Whitney tests were used to evaluate differences in serum vascular endothelial growth factor among the degrees of trophoblastic invasion. ROC curves were constructed to determine vascular endothelial growth factor cut-off values that predict the degree of tubal invasion based on the best sensitivity and specificity. RESULTS:: Eight patients had stage I trophoblastic invasion, seven had stage II, and 19 had stage III. The median serum vascular endothelial growth factorconcentration was 69.88 pg/mL for stage I, 14.53 pg/mL for stage II and 9.08 pg/mL for stage III, with a significant difference between stages I and III. Based on the ROC curve, a serum vascular endothelial growth factor concentration of 25.9 pg/mL best differentiated stage I from stages II and III with asensitivity of 75.0%, specificity of 76.9%, and area under the curve of 0.798. CONCLUSIONS:: The depth of trophoblastic penetration into the tubal wall isassociated with serum vascular endothelial growth factor concentration in ampullary pregnancies. PMID- 28076514 TI - Evaluation of embolization for periuterine varices involving chronic pelvic pain secondary to pelvic congestion syndrome. AB - OBJECTIVES:: To evaluate the clinical response and success rate after periuterine varices embolization in patients with chronic pelvic pain secondary to pelvic congestion syndrome and to report the safety of endovascular treatment and its rate of complications. METHODS:: Retrospective cohort of patients undergoing endovascular treatment of pelvic congestion syndrome in our department from January 2012 to November 2015. Data were analyzed based on patient background, imaging findings, embolized veins, rate of complications, and clinical response as indicated by the visual analog pain scale. RESULTS:: We performed periuterine varices embolization in 22 patients during the study, four of which required a second embolization. Seventeen patients reported a reduction in pelvic pain after the first embolization and three patients reported a reduction in pelvic pain after the second embolization. Minor complications were observed in our patients, such as postural hypotension, postoperative pain, and venous perforation during the procedure, without clinical repercussion. CONCLUSION:: Periuterine varices embolization in patients with chronic pelvic pain secondary to pelvic congestion syndrome appears to be an effective and safe technique. PMID- 28076515 TI - Serum adipocytokine profile and metabolic syndrome in young adult female dermatomyositis patients. AB - OBJECTIVES:: To analyse the frequency of metabolic syndrome in young adult female dermatomyositis patients and its possible association with clinical and laboratory dermatomyositis-related features and serum adipocytokines. METHOD:: This cross-sectional study included 35 dermatomyositis patients and 48 healthy controls. Metabolic syndrome was defined according to the 2009 Joint Interim Statement. RESULTS:: Patient age was comparable in the dermatomyositis and control groups, and the median disease duration was 1.0 year. An increased prevalence of metabolic syndrome was detected in the dermatomyositis group (34.3% vs. 6.3%; p=0.001). In addition, increased serum adiponectin and resistin levels were noted in contrast to lower leptin levels. In dermatomyositis patients, adipocytokine levels were correlated with the levels of total cholesterol, low density cholesterol, triglycerides and muscle enzymes. A comparison of dermatomyositis patients with (n=12) and without (n=23) syndrome metabolic revealed that adipocytokine levels were also correlated with age, and that dermatomyositis patients with metabolic syndrome tended to have more disease activity despite similar adipocytokine levels. CONCLUSIONS:: Metabolic syndrome is highly prevalent in young adult female dermatomyositis patients and is related to age and disease activity. Moreover, increased serum adiponectin and resistin levels were detected in dermatomyositis patients, but lower serum leptin levels were observed. PMID- 28076516 TI - Septic arthritis of the knee: clinical and laboratory comparison of groups with different etiologies. AB - OBJECTIVES:: To clinically and epidemiologically characterize a population diagnosed with and treated for septic arthritis of the knee, to evaluate the treatment results and to analyze the differences between patients with positive and negative culture results, patients with Gram-positive and Gram-negative bacterial isolates and patients with S. aureus- and non-S. aureus-related infections. METHODS:: One hundred and five patients with septic knee arthritis were included in this study. The clinical and epidemiological data were evaluated. Statistical analysis was performed to compare patients with and without an isolated causative agent, patients with Gram-positive and Gram negative pathogens and patients with S. aureus-related and non S. aureus-related infections. RESULTS:: Causative agents were isolated in 81 patients. Gram positive bacteria were isolated in 65 patients and Gram-negative bacteria were isolated in 16 patients. The most commonly isolated bacterium was S. aureus. Comparing cases with an isolated pathogen to cases without an isolated pathogen, no differences between the studied variables were found except for the longer hospital stays of patients in whom an etiological agent was identified. When comparing Gram-positive bacteria with Gram-negative bacteria, patients with Gram positive-related infections exhibited higher leukocyte counts. Patients with S. aureus-related infections were more frequently associated with healthcare-related environmental encounters. CONCLUSION:: S. aureus is the most common pathogen of septic knee arthritis. Major differences were not observed between infections with isolated and non-isolated pathogens and between infections with Gram positive and Gram-negative bacteria. S. aureus infections were more likely to be associated with a prior healthcare environment exposure. PMID- 28076517 TI - Standardization of the face-hand test in a Brazilian multicultural population: prevalence of sensory extinction and implications for neurological diagnosis. AB - OBJECTIVE:: The face-hand test is a simple, practical, and rapid test to detect neurological syndromes. However, it has not previously been assessed in a Brazilian sample; therefore, the objective of the present study was to standardize the face-hand test for use in the multi-cultural population of Brazil and identify the sociodemographic factors affecting the results. METHODS:: This was a cross sectional study of 150 individuals. The sociodemographic variables that were collected included age, gender, race, body mass index and years of education. Standardization of the face-hand test occurred in 2 rounds of 10 sensory stimuli, with the participant seated to support the trunk and their vision obstructed in a sound-controlled environment. The face-hand test was conducted by applying 2 rounds of 10 sensory stimuli that were applied to the face and hand simultaneously. The associations between the face-hand test and sociodemographic variables were analyzed using Mann-Whitney tests and Spearman correlations. Binomial models were adjusted for the number of face-hand test variations, and ROC curves evaluated sensitivity and specificity of sensory extinction. RESULTS:: There was no significant relationship between the sociodemographic variables and the number of stimuli perceived for the face-hand test. There was a high relative frequency of detection, 8 out of 10 stimuli, in this population. Sensory extinction was 25.3%, which increased with increasing age (OR=1.4[1:01-1:07]; p=0.006) and decreased significantly with increasing education (OR=0.82[0.71-0.94]; p=0.005). CONCLUSION:: In the Brazilian population, a normal face-hand test score ranges between 8-10 stimuli, and the results indicate that sensory extinction is associated with increased age and lower levels of education. PMID- 28076518 TI - Serum Klotho (but not haplotypes) associate with the post-myocardial infarction status of older adults. AB - OBJECTIVES:: The number of deaths from vascular diseases is incredibly high worldwide, and reliable markers for major events are still needed. The current cross-sectional study investigated the association of Klotho haplotypes and Klotho serum levels with classic risk factors and a clinical history of vascular events. METHODS:: Clinical, anthropometric, biochemical and nutritional assessments were conducted with 168 older adults, complemented by genotyping (rs9536314 and rs9527025) and the detection of serum Klotho (ELISA). RESULTS:: Klotho levels and haplotypes did not associate with most classic risk factors for vascular events, including markers such as C-reactive protein and homocysteine. A positive association was only found between Klotho levels and the previous occurrence of a myocardial infarction by both correlational (p=0.006) and variance analyses (p<0.001), and these associations were independent of the context. CONCLUSION:: Our results suggest that serum Klotho is higher in individuals with a clinical history of myocardial infarction but not with a history of coronary artery disease or stroke. None of the Klotho haplotypes were associated with the variables investigated herein. PMID- 28076520 TI - Qualitative research in medicine. PMID- 28076521 TI - Knowledge references: analysis of Brazilian health journal instructions to authors. AB - Health researchers refer to the difficulty in publishing which is a barrier to conducting qualitative studies. We sought to identify which Brazilian publications indexed in SciELO in the area of health sciences include instructions to authors that allow the publication of original studies based on qualitative methods. Of the 88 current titles analyzed, more than half (52) impose conditions that are incompatible with the qualitative research, most of them medical publications. Some publications (19) do not provide information on the type of study, but do not present typical requirements of quantitative research, such as statistical tests and reproducibility. Magazines demonstrating the acceptance of qualitative research (17) allow longer texts, study designs that include interviews, and some even specifically state acceptance of studies with qualitative approaches. In general, these publications belong to the collective health or nursing areas and have higher scores in CAPES. The lack of clear instructions for qualitative manuscripts and the need for quantification are barriers to the publishing of qualitative studies, which does not favor the expansion of the clinical look to the human phenomena related to health. The scientific and accuracy criteria should be reviewed. PMID- 28076519 TI - Detection value of free cancer cells in peritoneal washing in gastric cancer: a systematic review and meta-analysis. AB - Intraperitoneal free cancer cells in gastric adenocarcinoma are associated with a poor outcome. However, the true prognostic value of intraperitoneal free cancer cells is still unclear, leading to a lack of consensus in the management of gastric cancer. The aim of the present study is to perform a systematic review and meta-analysis to analyze intraperitoneal free cancer cells-positive patients with regard to tumor oncologic stage, recurrence, grade of cellular differentiation, and survival rates and to analyze the clinical significance of intraperitoneal free cancer cells with regard to prognosis. Databases were searched up to January 2016 for prognostic factors associated with intraperitoneal free cancer cells, including oncologic stage, depth of neoplasm invasion, lymph nodal spread, differentiation grade of the tumor, and recurrence and survival rates. A total of 100 studies were identified. Meta-analysis revealed a clear association between intraperitoneal free cancer cells and a poor prognosis. intraperitoneal free cancer cells -positive patients had higher rates of nodal spread (risk difference: 0.29; p<0.01), serosal invasion (risk difference: 0.43; p<0.01), recurrence (after 60 months of follow-up, risk difference: 0.44; p<0.01), and mortality (after 60 months of follow-up, risk difference: 0.34; p<0.01). Intraperitoneal free cancer cells are associated with a poor outcome in gastric cancer. This surrogate biomarker should be used to guide therapy both prior to and after surgery. PMID- 28076522 TI - A dialogue between scientific health editors and scientists responsible for qualitative studies. PMID- 28076523 TI - Scientificity, generalization and dissemination of qualitative studies. PMID- 28076524 TI - Science or sciences? Interdisciplinary dialogues in the crossroads. PMID- 28076525 TI - The authors respond. PMID- 28076526 TI - Perception of pre- and post-HIV test counseling among patients diagnosed with aids in adolescence HIV test counseling for adolescents. AB - Pre- and post-HIV test counseling has singular importance in adolescence, since it is a phase of great changes, and AIDS is an incurable chronic disease. In order to comprehend the perception of young people with AIDS diagnosed in adolescence regarding the counseling received upon testing, we conducted 39 in depth interviews, with 23 in female patients and 16 male patients, and then analyzed the data with extensive reading, categorization and interpretation on a comprehensive basis. The results revealed that less than one third received pre test counseling (30.8%), which often was limited to the explanation of the reason of the test, and 51.2% were counseled post-test. We found that most patients were unaccompanied when receiving the communication of their seropositivity, some of which were later informed by the adolescent's guardian. Some patients felt secure after counseling, realizing that the disease is something that would not change their lives, if they properly followed the guidelines. On the other hand, the feelings of desperation and suicide expressed by some of the patients may have been influenced by the lack of adequate counseling. We have concluded that, for the improved management of the epidemic, there is a need to enhance the communications of health professionals, especially those that are in primary care, pre-natal services, gynecology and family health strategy. PMID- 28076527 TI - [On the sidelines of society: crack use, deviation, criminalization and social exclusion - a narrative review]. AB - The article comprises a narrative review of the scientific literature, aiming to identify and discuss the contexts of vulnerability and social exclusion faced by users of crack cocaine and other substances who live on the sidelines of society in the Brazilian and international context. The paper summarizes insights from different theoretical frameworks, focusing on an integrated perspective of substance use and abuse, with an emphasis on the use of crack and its inter relationships with social vulnerability, marginalization, social exclusion and deviation. In a first step, broad aspects of qualitative research on drugs are outlined. The subsequent section highlights issues associated with exclusion and social vulnerability of crack users, followed by an assessment of the main associations mentioned in the literature on drug use and criminal involvement. Finally, the concept of "sidelines of society" is discussed, as exemplified by situations and events experienced by users of crack and other substances, as mentioned in the literature. PMID- 28076528 TI - The brief life of Norplant(r) in Brazil: controversies and reassemblages between science, society and State. AB - Norplant(r) is the brand name of the world's first registered subdermal hormonal contraceptive implant, developed by the laboratories of the Population Council, an international organisation working in the area of fertility and population growth. The article revisits the trajectory of this contraceptive in Brazil from its arrival through clinical trials to its eventual ban in 1986 by the Brazilian regulatory agency responsible for approving medications at the time. Its circulation generated controversies related to research practices, side effects and political uses of the drug as a birth control method. This article focuses its analysis on the divergences related to research practices. It uses a controversy analysis technique, reviewing the versions of those involved, investigating their understandings and the effects that this object generated in their networks. Norplant(r) provoked displacements and associations between civil society groups, State authorities, scientists and physicians, industry, pharmaceutical products, research procedures, bureaucratic instruments, and the female users of the contraceptives. Scientific styles of medical thought were shaken up and new forms of thinking about scientific autonomy began to be discussed in the country. PMID- 28076529 TI - Relationships between oncohematopediatrics, mothers and children in communicating bad news. AB - We present a study about the relations between pediatric oncological haematologists, mothers, and children in sharing bad news (BN) in a public hospital in Rio de Janeiro. The text emphasizes the intertwining of technique and emotions for the treatment of children with diagnoses in which the fatal outcome is always a probability. We used a qualitative approach, privileging participant observation and open interviews with oncologists (at this service all professionals were female) and mothers. We sought to understand the importance of communication which includes expressions and control of emotions; bioethical issues that require sensitivity, serenity, and truth about approaching the end of life; and how the professionals balance proximity to children and families and objectivity in their activity. The main results showed: intense exchanges on BN among professionals; relapse of children who were evolving positively as the most difficult news; constant update of BN facing terminally ill children; quality of communication influencing the treatment; professionals permanently balancing between closeness and distance from patients and evidence of the their irreplaceable role to secure the family and the child. PMID- 28076530 TI - Factors associated with Chronic Obstructive Pulmonary Disease among the elderly. AB - This study aimed to identify factors associated with Chronic Obstructive Pulmonary Disease (COPD) among non-institutionalized elderly people. It involved a cross-sectional study conducted on the basis of a household survey, followed by spirometry. People diagnosed with COPD were compared with those with normal spirometry, through bivariate analysis, followed by multivariate regression analysis. We identified 53 elderly people were identified with COPD. After multivariate analysis, the following factors associated with COPD were identified: past or current smoking (OR: 3.74; 95% CI: 1.65-8.46), presence of chronic sputum (OR: 4.92; 95% CI: 2.03-11.95), pulse oximetry at rest <= 90% (OR: 8.74; 95%CI: 1.27-60.07), self-reported asthma (OR: 3.41; 95% CI: 1.01-11.57). The results reveal associated factors that highlight the need to review the selection criteria for patients at risk of COPD among the elderly. PMID- 28076532 TI - [Trajectories of women living with HIV/AIDS in Brazil. Progress and permanence of the response to the epidemic]. AB - This article analyzes the trajectories of 85 women living with HIV/AIDS in six Brazilian cities: Belem, Sao Paulo, Ribeirao Preto, Goiania, Recife and Pelotas, to understand some specific aspects of their experiences before and after diagnosis. It is based on in-depth interviews conducted in 2009 addressing women diagnosed with HIV between 1 and 20 years previously. The results show a profile characterized by limited access to school, health services and labor and a marked presence of violence. The reasons for applying HIV tests vary over time and there is an increase in prenatal testing, although no modifications in the context of the infection are apparent. For some women, the diagnosis determines changes in lifestyle. However, for the majority, social and labor experiences and the decisions about love, sexuality and reproduction seem to respond to their immediate demands and opportunities. The management of the diagnosis and the support received influence living with HIV/AIDS. These results show the need for actions for prevention and testing not restricted to pregnant women, even in the context of a concentrated epidemic. Studies adopting a biographical perspective can contribute to prevent or improve living with HIV/AIDS appropriate to the different moments of the womens' trajectories. PMID- 28076531 TI - Anxious and depressed women's experiences of emotional suffering and help seeking in a Rio de Janeiro favela. AB - Taking into consideration issues such as stigma and the mental health gap, this study explores narratives of anxious and depressed women treated in a community based primary care service in a Rio de Janeiro favela about their suffering and care. We analysed 13 in-depth interviews using questions from Kadam's study. Framework analysis studied Access, Gateway, Trust, Psychosocial Issues, and Primary Mental Health Care, as key-concepts. Vulnerability and accessibility were the theoretical references. Thematic analysis found "suffering category", highlighting family and community problems, and "help seeking category", indicating how these women have coped with their emotional problems and addressed their needs through health services, community resources and self-help. Women's language patterns indicated links between implicit social rules and constraints to talk about suffering, especially if related to local violence. High medical turnover and overload are barriers for establishing a positive relationship with family physicians and continuity of care is a facilitator that promotes trust, security and adherence. Concluding, to plan community-based primary mental health care of this population, cultural and social factors must be comprehended as well as the work health teams conditions. PMID- 28076533 TI - Similarities and differences in crack cocaine use patterns in Santa Catarina, Brazil: Capital vs. Midwest. AB - Crack cocaine has been a major public health problem in Brazil due to the individual and social harms and risks deriving from its use. This article aims to assess the characteristics of drug scenes in the capital and Midwest of Santa Catarina state. The project used the Time-Location Sampling. Between January and June 2011, 41 crack cocaine scenes were mapped in capital of Santa Catarina, whereas 33 were mapped in the Midwest of that state. Such scenes were randomly selected to be observed, as well as their days and shifts (time periods/day) for in-depth observation. Overall, 98 scenes/shifts were observed in the capital and 62 in the Midwest. First-hand reports were logged as field notes into notebooks. Analyses of the empirical material were based on Bardin's content analysis, and findings were compared and contrasted with Brazilian and international literature. Most crack cocaine users were adult males. In the capital, a substantial fraction of the users lived in the streets, but in both settings most interviewees have used multiple substances. In the Midwest, most scenes occurred at night, whereas in the capital scenes occurred in all shifts. Risk practices associated with the use of crack cocaine were: association of multiple drugs, prostitution, pipe sharing and sexual favors in exchange for the substance. PMID- 28076534 TI - Absorption and metabolization of sex hormones and their transformation into contraceptive technologies: the paths taken by medical thought in Brazil. AB - The article analyses knowledge assimilation and the development of clinical and research practices relating to sex hormones among Brazilian gynaecologists. It discusses the paths taken by medical thought from the reception of the hormones to their transformation into contraceptives. Our objective is to comprehend styles of introducing and disseminating medical technologies in the area of reproductive health in Brazil. It uses methods of historical analysis and takes as its source the Anais Brasileiros de Ginecologia, a journal published between 1936 and 1970. From the outset, the accompaniment of scientific breakthroughs in relation to sex hormones and their use to treat diverse female illnesses played a key role in the rapid medical acceptance of hormonal contraception. Scientific and technical questions (side effects, dosages) and the demographic issue formed part of the majority of the debates. Objections from the Catholic Church were considered but did not set the agenda of medical thought on contraceptives. The quest to consolidate gynaecology as a scientific, modern and cosmopolitan area of expertise, along with sanitary and demographic motives that allowed contraceptives to be classed as ethical drugs, are identified as processes underlying the assimilation and metabolization of sex hormones as hormonal contraceptives. PMID- 28076535 TI - [Femicides in ethnic and racialized groups: syntheses]. AB - The text entitled "Femicides in ethnic and racialized groups: syntheses" presents some of the discussions that took place during a seminar on this topic in Buenaventura. Buenaventura is the main Colombian port on the Pacific, a region rich in minerals and a corridor for the movement of goods, which makes it a strategic territory and a center for disputes. At the seminar, the social and political determinants of femicide were discussed, understanding it as a tactic of waging war against women. The forum provided a space for academic discussion, but also for grievances over inter-personal violence, the manifestation of feelings and the elaboration of pain and grief through the medium of art. We believe that the dissemination of this experience to the Brazilian public, in a country with ethnic, social and racial vulnerability similar to that in Colombia, will be of value to social and health workers. The scope of this paper is therefore to provide the opinion of its authors on the determinants of femicides and on actions to tackle them, in addition to a synthesis of the discussions and debates that permeated the event. PMID- 28076536 TI - [Quality of life of family caregivers of adults with spinal cord injury: a systematic review]. AB - The scope of this study was to analyze the quality of life of family caregivers of adults with spinal cord injury. Two researchers conducted a systematic review independently, based on articles published between 2000 to 2014, using the key words quality of life and caregivers or family and spinal cord, in Portuguese, English and Spanish. The search was conducted in the Virtual Health Library (BVS) and the United States National Library of Medicine (PubMED) databases. Caregivers of tetraplegics have a worse quality of life than caregivers of paraplegics. Changes in the quality of life for the caregivers were not significant over time. Different results were observed when comparing caregivers of adults with spinal cord injury and healthy subjects. Factors that negatively influence the quality of life of caregivers were the presence of chronic disease; greater care time, age and number of children; and lower schooling level of caregivers. There is a need for public health policy development and preparation of more comprehensive intervention strategies that include not only the patient but also the caregiver. PMID- 28076537 TI - Risk factors of breast cancer and knowledge about the disease: an integrative revision of Latin American studies. AB - The aim of this integrative review was to compare Latin American literature about risk and knowledge on breast cancer. Of 47 studies selected, 20 were about knowledge or awareness and 27 about risk of breast cancer. English was the dominant language in studies about risk, whereas studies about knowledge were mainly written in Spanish or Portuguese. Studies about knowledge were all cross- sectional, whereas case- control studies dominated authors' interest about risk of breast cancer. Studies about knowledge were mainly focused on early detection of the disease and the most common study objective was breast self- examination (N = 14). In contrast, few studies about risk of breast cancer focused on early detection (N = 5). Obesity and overweight (N = 14), family history (N = 13), decreased parity (N = 12), and short breastfeeding duration (N = 10) were among the most frequent identified risk factors. Socio- economic factors such as income and educational level had variable effects on breast cancer risk and affected also knowledge of women about risk factors and early detection. Present results indicated that studies about risk of breast cancer were more often based on a better sound analytical background, compared to studies about knowledge, which were mostly descriptive. PMID- 28076538 TI - Comparative study of satisfaction of users and health professionals with the public dental service. AB - The objective was to confront the view of users and health professionals about the satisfaction with the public dental service. Interviews were conducted with users, professionals considered directly (ESB) and indirectly (ACS) involved in oral health. Variables were evaluated individually and grouped into domains. A score was created for the analysis and the Kruskal-Wallis test was applied. The respondents positively assessed the quality of the dental services. The ACS demonstrated less satisfaction compared to users regarding general satisfaction in the Physical Structure and Medical Care domains and the variables: quality of clinical care; guidance to the patient after treatment performed in the specialty; and period of dental care. The ESB professionals expressed greater satisfaction than the users in the Medical Care domain and in the variables related to the provision of guidance, answering questions, attention solvability and consultation scheduling. It is concluded that the ESB professionals demonstrated a high degree of similarity to the satisfaction displayed by users, although positively expanded, and the ACS expressed more critically discrepant opinions in relation to users. PMID- 28076539 TI - Comparative study on mortality due to cardiovascular diseases in Sao Caetano do Sul, Sao Paulo, Brazil, between 1980 and 2010. AB - Analysis of the mortality due to cardiovascular diseases (CVD) can provide subsidies for preventive and control measures. The goal of this article is to compare CVD mortality rates in Sao Caetano do Sul, the state of Sao Paulo and the country as a whole. Standardized mortality and mortality due to CVD were calculated for the 1980-2010 period. We found a significant reduction in cardiovascular mortality in all three study units during this period, with the largest reduction in CVD in Sao Caetano do Sul. The largest mortality rate was found in the state of Sao Paulo. In adults 30 to 59, the CVD mortality rate in Sao Caetano do Sul was three times as high in men as in women, yet among adults 60 and older, CVD mortality was higher in women than in men. The lower rate is the result of implementing different healthcare policies. However, specific interventions are required that focus on changes in lifestyle, especially among adult men and the elderly. PMID- 28076540 TI - Self-reported occupational accidents among Brazil's adult population based on data from the 2013 National Health Survey. AB - Objective:: to provide an overview of occupational accidents among Brazil's adult population. Methods:: descriptive study using data from the 2013 National Health Survey. Results:: A total of 4.9 million workers mentioned having suffered some kind of work-related accident, which is equivalent to 3.4% (CI95% 4.6-5.6) of Brazil's adult population. Prevalence rates were higher among men, young adults aged between 18 and 39 years, and black people and in the North Region of the country. Prevalence was highest in the State of Para and lowest in the State of Rio de Janeiro State. Around one third of all accidents were commuting accidents, 50.4% (CI95% 45.3-55.5) of people who had suffered an occupational accident were prevented from carrying out some kind of routine activity due to the accident, 8.8% (CI95% 6.4-11.2) were hospitalized and 19% (CI95% 15.3-22.7) had sequelae resulting from occupational accidents. Conclusion:: the data provided by the National Health Survey comprises an unprecedented and invaluable source of information on these issues in Brazil. The results of the survey confirm that occupational accidents are underreported, since official figures do not cover individuals working in the informal sector. PMID- 28076541 TI - Private Health Care Coverage in the Brazilian population, according to the 2013 Brazilian National Health Survey. AB - This study aims to present the percentages of the Brazilian population holding health insurance plans, itemized by social-demographic characteristics, based on the data of the National Health Survey carried out in 2013, and to compare this information with the administrative data of the National Supplementary Health Agency for the same year. Data from the National Health Survey, and from the Beneficiaries Information System of the National Health Agency for the year 2013, were used. The percentage of people having a health plan was described according to stratification for: all of Brazil, urban/rural, Brazilian official Regions, Brazilian States and state capitals, gender, age group, level of schooling, position in the workforce, ethnic classification, and self-assessed state of health. Results include the following: The percentage of people saying they had some health plan in Brazil was 27.9% (CI 95%: 27.1-28.8). A significant difference was found relating to level of schooling - the percentage being highest for those who stated they had complete secondary education (68.8% CI 95%: 67.2-70.4) and for those who said they were currently in work (32.5% CI 95%: 31.5 33.5). The increase in health plan coverage in the Brazilian population reflects the improvement of the suply of employment and the growth in the country's economy. PMID- 28076542 TI - [Dental decay in 5-year-old children: sociodemographic factors, monitoring points and parental attitudes]. AB - Dental decay affects many children, especially those from the lower socioeconomic classes. In this cross-sectional study designed to investigate the role played by sociodemographic factors, parental attitudes, and monitoring points, which are an indicator of personal perception of what controls individual health, on the prevalence of tooth decay among 5-year-old pre-school children living in a midsized city in Sao Paulo, Brazil. The ceo-d index of 426 children was assessed; the parents reported sociodemographic characteristics and completed two questionnaires concerning monitoring points and parental attitudes. The results show that 52.35% of the children had decay; higher levels of severe decay were observed among lower E-F socioeconomic classes. Higher socioeconomic status and low externality appear to be protective factors. Low parental internality emerged as a risk factor for decay in primary teeth, possibly because the mother expects or delegates the action to others, delaying care. Parental perceptions of control over a child's health seem to impact preventive care and, consequently, the level of tooth decay among children. PMID- 28076543 TI - Oral Health in the Children's Preventive Health Care Initiative: indicators and goals in a Primary Health Care Service. AB - The objective of this study is to assess fulfillment of the oral health goals of the Children's Preventive Health Care Initiative in 12 Health Units (HU) of a Primary Health Care Service, in Porto Alegre, in the state of Rio Grande do Sul, through a cross-sectional analytical study on the annual dental visit coverage in early childhood. The study was comprised of 660 children born in 2010. In relation to the coverage of dental visits for each year of life of children, the health units did not achieve the set targets (100%). However, a considerable number of children (35%) had their first dental visit during the first year of life. In relation to the total number of visits, 22% of the children had never gone to the dentist and only 8% did the recommended four visits. There was a positive correlation between the ratio of the total population and children from ages 0 to 4 years in the area enrolled in the initiative, on the one hand, and the number of dental professionals and coverage in the first year of life in each health unit, on the other. Although few children had adequate follow-up visits in relation to the set targets, the percentage of coverage was higher than that found in the literature. PMID- 28076544 TI - The process of defining the hospital care profile in federal hospitals in the city of Rio de Janeiro, Brazil. AB - This article analyzes the process of shaping the care profile of federal hospitals in the city of Rio de Janeiro. This is a qualitative, descriptive study that draws on semi-structured interviews with hospital administrators. Data analysis used the Collective Subject Discourse approach. Managers believe this process is the result of a set of emerging strategies, proposals and need for change, which result in adaptive reactions that hospitals develop with no coordination between them to resolve problems identified by professionals and managers. The process is analyzed much more from a political point of view than from a rational and systemic one. Some of the experience with the hospital mission, such as the focus on a strategic approach, already signals a more collegiate approach to defining the profile of care, where the hospital is one component of an integrated network of services, with a decision process that is less incremental and more integrating. PMID- 28076545 TI - Economic evaluation of the Programs Rede Farmacia de Minas do SUS versus Farmacia Popular do Brasil. AB - We conducted an economic assessment of the Pharmaceutical Assistance - Rede Farmacia de Minas Gerais-RFMG and Farmacia Popular do Brasil-FPB to ascertain which of the two models stands out as the most efficient. To do this, a model, which consisted of a study of incurred costs in both programs, up to the dispensing of medicine to citizens, was developed. The uncertainties of the proposed model were tested using the Monte Carlo method. If the entire population initially estimated in the RFMG were attended in the FPB, there would be an additional cost of R$ 139,324,050.19. The sensitivity analysis appeared to be favorable to the RFMG. A total of 10000 simulations were carried out, resulting in a median value of R$ 114,053,709.99 for the RFMG and R$ 254,106,120.65 for the FPB. The current National Drug Policy emphasizes the need to strengthen pharmaceutical services beyond the mere acquisition and delivery of pharmaceutical products. The public healthcare service model, consistent with the principles and guidelines of the SUS, seems to be more appropriate in ensuring complete and universal quality healthcare services to the citizens. The economic study conducted reinforces this fact, as it appears to be a more efficient alternative of the direct use of resources in the public health network. PMID- 28076546 TI - Pharmacist's contribution to the promotion of access and rational use of essential medicines in SUS. AB - Objective:: to describe the pharmaceutical inclusion process in a Basic Health Unit multidisciplinary team and evaluate results related to rational use and promotion of access to essential medicines. Methods:: This is a descriptive, cross-sectional study conducted in a primary care health unit in the city of Sao Paulo. Pharmacist's activities were evaluated regarding the service structure and organization and prescribing quality improvement, guidance method creation, and implementation of clinical pharmacy service. Data measured before and after the interventions and between 2010 and 2011 were analyzed using Pearson's chi-square test with a significance level of 5%, and odds ratio. Results:: Pharmacist's activities had statistically significant result in drug shortage reduction; prescribing quality improvement associated with an increased proportion of prescriptions met; decrease in the total of prescribed drugs among patients receiving pharmacotherapeutic follow-up and, comparing the years 2010 and 2011, changes in the pharmacotherapy recommendations have gained increased acceptance level. Conclusions:: Pharmacist's activities may effectively provide rational use and promotion of access to essential medicines. PMID- 28076547 TI - [Spatial distribution of biomass burning and mortality among the elderly in a Brazilian Amazon region, 2001 - 2012]. AB - The burning of biomass has a significant impact on the Amazon ecosystem in the dry season due to the emissions of air pollutants. The effects on the health of the population, especially in the region of the arc of deforestation, has been the subject of recent studies. The scope of this study was to evaluate the spatial distribution of biomass burning and mortality from respiratory and cardiovascular diseases among the elderly in the state of Rondonia in the period from 2001 to 2012. Mortality data were obtained through the Mortality Information System of the Ministry of Health. Biomass burning data were provided by the National Institute for Space Research. The Kernel estimator was used. The highest mortality rates were observed in the central-east and south-east of Rondonia. The focuses of the fires were concentrated in the northern part of the state, though with a significant amount in other regions. The spatial distribution of the hot areas of mortality and fires were not directly associated. However, fires were observed in all municipalities in the state. Pollutants emitted from biomass burning can be transported thousands of kilometers from the source areas and influence the health of the elderly. PMID- 28076548 TI - Recruitment rate and retention of stroke subjects in cross-sectional studies. AB - This article aimed to determine the recruitment rate of chronic stroke survivors to cross-sectional studies and to determine their retention at the two days of assessments. Participants after six months of a unilateral stroke were screened for eligibility and invited to participate in two cross-sectional studies, by telephone. The number of people who were screened, eligible, and successfully recruited was recorded. Retention at the two days of assessments was also recorded. From a list of 654 individuals, 87 were ineligible. Of the 567 left, 216 had wrong contact numbers, 144 refused to participate, and 12 had died. A total of 165 subjects participated in both studies. Out of the 56 who agreed to attend to the second day of assessment, eight did not return. The results showed that individuals with chronic stroke had low rates of recruitment and retention. PMID- 28076549 TI - Training of pharmacy technicians for dispensing drugs in Primary Health Care. AB - Few Brazilian articles discuss the importance of pharmacy technicians who offer direct assistance to patients. This paper describes an experience of the training of pharmacy technicians in drug dispensing. A descriptive, cross-sectional study was conducted in the primary healthcare setting. The technicians were trained by the pharmacist to advise patients at the time of drug dispensing and to screen cases that needed pharmaceutical consultation. Problems were identified by verifying the prescription and return date for dispensing the medication as well as through direct questioning of the patients. Flowcharts for problem identification and intervention were created for use by the technicians. After training, pharmacy technicians identified 3944 problems, the most common of which were the use of a lower dosage than that prescribed (26%) and non-adherence to pharmacological treatment. The findings of the present study demonstrate the importance of training pharmacy technicians with regard to dispensing drugs so that they can assist pharmacists in the process of identifying and solving drug related problems, thereby making them active members of the care process in the public health system. PMID- 28076550 TI - Suicide in University students in Bogota, Colombia, 2004-2014. AB - We report the results of a retrospective, descriptive, qualitative study of suicide among university students in Bogota, Colombia. The objective of this study was to document the magnitude, principal characteristics, and impact of this phenomenon in the selected population. A semi-structured survey was employed to collect information from 66 individuals linked to the universities. A total of 45 cases of suicide were documented in the study period (2004 - 2014). Of these, 69% occurred in males and 31% in females. The age range was 17 - 27 years, with 62% of the cases in the 19 - 22 year-old group. The most common mechanisms employed were suffocation and poisoning, followed by intentional falls, use of a firearm, and drug overdose. The selected location was the place of residence in 52% of cases and the university campus in 16% of cases. The distribution of students by area of knowledge showed a predominance of social and human science (44%) followed by engineering (22%). A history of difficulties in family and affective relationships was common among victims, as was a history of exposure to intolerance of differences in sexual orientation. The individuals surveyed expressed a wide range of interpretations of the significance of suicide, both positive (courage, self-affirmation, autonomy) and negative (defeat, despair, and an inability to adapt). PMID- 28076551 TI - Prevalence and factors associated with the use of public health services for adult men. AB - The aim of this study was to identify prevalence and factors associated with use of public health services by adult males residing in the city of Maringa, Parana. A household survey was carried out with 410 men aged 20 to 59 years old. Analysis was performed by means of descriptive statistics and multiple logistic regression models. The prevalence of use of public services stood at 56.3%. Men who used public health services most often were those with little education, no health plan, no partner, unemployed, who had more contact with nurses and other professionals, sought the services due to disease/symptoms/emergency, had difficulties with the service, rated health services as regular and chose attention and promptness as the most important aspects of health services - variables adjusted for family income, economic class and need for treatment. Men's health care should be reorganized according to factors linked to the use of health services by them, with the promotion of greater contact between health services and men and the centering of assistance on users, expanding men's participation in promotional and preventive practices. PMID- 28076552 TI - Perceptions about men's health in a gender relational perspective, Brazil, 2014. AB - The goal of this article is to assess the perception of male health from the viewpoint of men and women. The study drew from a random sample of men aged 20 to 59 who were SUS (Unified Healthcare System) users and resided in the capitals of Brazilian states and the Federal District. Participants were interviewed by phone. Sociodemographic variables and variables related to perception of healthcare services, health status and health care were recorded. Logistic regression was used to assess failure to seek service and good and very good self care. The majority of the study population considers it has no health problem, especially men. The main reason for failure to seek treatment is no access to services, although both men and women claim the healthcare services receive them adequately. Over 40% of men and almost 30% of women self-medicate. Men believe they are taking good care of their health, while women have a different perception of this. Perceptions differ when we take into consideration age, years of schooling, ethnicity and occupation. PMID- 28076553 TI - Acupuncture in Brazil's Unified Health System - an analysis based on different health management tools. AB - The integration of Integrative and Complementary Practices into public health systems has been the subject of national and international debate. In Brazil, the National Policy on Integrative and Complementary Practices guides the integration of acupuncture into the Unified Health System (UHS). This article explored the availability and/or accessibility of acupuncture in the UHS in 26 municipalities in the XIII Health Region of the State of Sao Paulo between 2001 and 2011, based on the analysis of Municipal Health Plans, Annual Management Reports and complementary data obtained from Information Systems. The data was analyzed using a framework for policy analysis based on: context, process, content and actors. Results show that the legislative framework provides a favorable environment; however public funding for these activities is particularly limited. Only government actors participated in the decision-making processes; the plans and reports contained inconsistencies both in structure and in the references made to acupuncture; the process showed that the policy helped to describe the organization of the provision of acupuncture services. The study concludes that the integration of acupuncture and use of health management and planning tools is limited in the 26 municipalities and that this precludes monitoring and maintains these practices on the periphery of the system. PMID- 28076554 TI - [Training of health professionals in breastfeeding and its association with knowledge, skills and practices]. AB - A cross-sectional study was conducted in the 15 hospitals with over 1000 deliveries/year in Rio de Janeiro, Brazil, to verify the association between training of health professionals in breastfeeding and professional knowledge, skills and practices. Interviews were staged with 215 health professionals, 48.4% working in Baby-Friendly Hospitals, by means of a questionnaire adapted from the revalidation instrument of the initiative. The three dichotomized outcomes were subjected to bivariate and multivariate analysis. Adjusted prevalence ratios were obtained by the Poisson regression model: 48.1% of the professionals had adequate knowledge, 58.9% adequate skills and 74.9% reported adequate practice. Theoretical and practical training >= 18 hours considered adequate (by 65.6% of the professionals) showed a significant association with professional knowledge (aPR = 1.575), skills (aPR = 1.530) and practices (aPR = 1.312). Less working experience was associated with less knowledge (aPR = 0.723), but with better practices (aPR = 1.183). Nursing staff reported better practices than physicians (aPR = 0.808) and other categories (aPR = 0.658). The study concludes that training contributes to improved breastfeeding knowledge, skills and practices that are essential for maternal and child care. PMID- 28076555 TI - [Qualitative research as a vocation?Resposta dos autores]. PMID- 28076556 TI - [Is it possible to generalize in qualitative studies?] PMID- 28076557 TI - ? AB - [This corrects the article doi: 10.1590/1413-812320152112.17532016]. PMID- 28076558 TI - Visual impairment and autism in children: when the ophthalmologist makes the difference. PMID- 28076559 TI - Anti-inflammatory effect of lycopene on endotoxin-induced uveitis in rats. AB - Purpose:: We evaluated the efficacy of lycopene, a dietary carotenoid and potent antioxidant, against ocular inflammation and oxidative stress in an experimental uveitis model. Methods:: Endotoxin-induced uveitis (EIU) was induced in Sprague Dawley rats by a single subcutaneous injection of 200 MUg lipopolysaccharide (LPS). Induction of EIU was preceded by daily intraperitoneal injection of 10 mg/kg lycopene for three consecutive days (Lycopene + LPS group) or equivolume vehicle (Vehicle + LPS group). A positive control group received 1 mg/kg dexamethasone pretreatment (DEX + LPS), and a negative control group received daily vehicle injection but no LPS (Vehicle Control). Twenty-four hours after LPS or final vehicle administration, eyes were enucleated, and aqueous humor was collected for measurement of the number of infiltrating cells, total protein concentration, and levels of nitric oxide (NO), tumor necrosis factor-alpha (TNF alpha), interleukin-6 (IL-6), and oxidative stress markers. Inflammatory response severity was compared among groups clinically and histopathologically. Results:: Infiltrating cell number, total protein concentration, and NO, TNF-alpha, and IL 6 levels were significantly elevated in the aqueous humor of Vehicle + LPS group rats compared to Vehicle Controls. Compared to the Vehicle + LPS group, lycopene pretreatment significantly reduced aqueous humor concentrations of oxidative stress markers, NO (0.29 +/- 0.1 MUM vs. 0.19 +/- 0.1 MUM, p=0.003), TNF-alpha (71.0 +/- 22.3 ng/ml vs. 50.1 +/- 2.1 ng/ml, p=0.043), and IL-6 (121.6 +/- 3.0 pg/ml vs. 111.1 +/- 5.6 pg/ml, p=0.008). Inflammatory score was also reduced (2.0 +/- 0.0 vs. 0.4 +/- 0.5, p=0.001). Lycopene reduced the infiltrating cell count and protein concentration, but differences did not reach significance. Most lycopene effects were equivalent to dexamethasone. Conclusions:: Lycopene may aid in the clinical management of uveitis by suppressing inflammation and oxidative stress. PMID- 28076560 TI - Evaluation of anterior segment parameters using Scheimpflug technology during the Valsalva maneuver in patients with keratoconus. AB - Purpose:: This study aimed to explore the effects of the Valsalva maneuver (VM) on ectatic corneas during anterior segment tomography scans using a Scheimpflug camera. Methods:: This prospective observational study included 100 eyes of 50 patients with bilateral keratoconus (KC). Anterior segment tomography was first performed when the patients were in a resting position and immediately repeated as the participant performed VM. Scheimpflug images were taken using a Pentacam(r). Results:: The mean age of the participants was 24.14 +/- 6.59 years. Of the 100 eyes included in the study, 7% had stage 1 KC, 47% had stage 2 KC, 32% had stage 3 KC, and 14% had stage 4 KC. The indices of KC were not significantly affected by VM. Similarly, no statistically significant differences were found between the stages of KC, or with the mean pachymetric progression index during VM. Pupil diameter showed a statistically significant increase during VM (p=0.017). There was a statistically significant decrease in the anterior chamber angle measurement during VM (p=0.001). Maximum curvature power in the front of the cornea decreased more during VM in stage 4 KC than for the other stages (p=0.014). Conclusions:: No changes associated with VM were found in the KC indices or the stage of the disease. However, an increase in pupil diameter and a decrease in anterior chamber angle value were found. These changes were comparable to values obtained from previous studies performed on normal corneas. PMID- 28076561 TI - Visual outcomes after deep anterior lamellar keratoplasty using donor corneas without removal of Descemet membrane and endothelium. AB - Purpose:: The optical quality of the interface after deep anterior lamellar keratoplasty (DALK) using the big-bubble technique has been shown to be excellent, leading to results comparable to penetrating keratoplasty. However, there is little in the literature with respect to the controversy surrounding the preparation of the donor cornea. The purpose of this study was to evaluate visual acuity (VA) in patients with keratoconus who underwent DALK without removal of the donor graft endothelium. Methods:: The records of 90 patients who underwent DALK without the removal of the Descemet membrane (DM) and endothelium were retrospectively reviewed. Data collected included uncorrected VA (UCVA) and spectacle-corrected VA (SCVA) at 7, 30, 180 days, and 1 year postoperatively. Contact lens-corrected visual acuity (CLVA) was evaluated after 1 year of the procedure. Results:: UCVA was significantly better than preoperative values at 7 days (p<0.001), 30 days (p<0.001), 180 days (p<0.001), and 1 year (p<0.001) after surgery. The 1-year postoperative mean SCVA and CLVA also improved when compared with preoperative SCVA (p<0.001 for both). Conclusions:: DALK utilizing donor corneas with attached Descemet membrane and endothelium results in satisfactory VA in patients with keratoconus. PMID- 28076562 TI - Mycophenolate mofetil as an immunomodulator in refractory noninfectious uveitis. AB - Purpose:: To evaluate the efficacy and tolerance of mycophenolate mofetil (MMF) for the treatment of noninfectious uveitis using the methods advocated by the Standardization of Uveitis Nomenclature (SUN) Working Group and to compare this with other studies of immunosuppression in ocular inflammation. Methods:: Retrospective case series. Patients with noninfectious uveitis, followed at a tertiary Uveitis Service in Sao Paulo, Brazil, from 2007 to 2014 and receiving oral MMF for a minimum of 6 months, were retrospectively reviewed. After reaching an optimal dose of MMF, patients were evaluated after 6 (T6), 12 (T12), and 24 months (T24). The optimal dose varied for each patient (medium 2.2 g/day, range 1.0-3.0 g/day). The main outcome measures were: 1) success on achieving complete control of inflammation in both eyes and/or oral prednisone dosage reduction to <=10 mg per day, and 2) the length of time required to reduce oral prednisone to <=10 mg/day, partial control of ocular inflammation, and side effects. Results:: In a cohort of 16 patients with refractory noninfectious uveitis, 67% reached the ideal prednisone dose after 1 year of MMF treatment and 83% after 2 years of MMF treatment. Complete or partial inflammation control was achieved in 43.7% at T12. Two patients (14%) had disease remission after 4.7 years of MMF treatment. Adverse effects were gastrointestinal disturbances, infection, insomnia, and liver function abnormalities at a rate of 0.03 patient-year each. Conclusions:: This small retrospective case series is consistent with the literature concerning the high efficacy and moderate tolerability of MMF in noninfectious uveitis. Observation of patients should be continued for at least 1 year to clearly determine MMF efficacy. PMID- 28076563 TI - Influence of the epiretinal membrane on ranibizumab therapy outcomes in patients with diabetic macular edema. AB - Purpose:: To investigate the influence of the epiretinal membrane (ERM) on intravitreal ranibizumab (IVR) therapy for diabetic macular edema (DME). Methods:: This retrospective study included 56 eyes of 48 patients with DME divided into two groups: the DME with ERM (study) and only DME (control) groups. Changes in the central macular thickness (CMT) and best-corrected visual acuity (BCVA) were evaluated. Results:: In the study group, although the CMT was significantly reduced following the first injection (p<0.001), BCVA did not improve significantly (p=0.296). However, after the first injection, the control group exhibited both a significant decrease in CMT (p<0.001) and improvement in BCVA (p<0.001). However, the improvement in BCVA in the control group was not significantly different from the outcome of the study group. Conclusions:: We observed a negative short-term influence of the ERM on IVR treatment for DME. PMID- 28076564 TI - Atopic keratoconjunctivitis: long-term results of medical treatment and penetrating keratoplasty. AB - Purpose:: To evaluate the long-term outcomes of medically or surgically treated patients with atopic keratoconjunctivitis (AKC). Methods:: Charts of 16 patients with AKC (32 eyes) observed between 1996 and 2013 were reviewed retrospectively. Outcome measures included demographic features, follow-up duration, and biomicroscopic findings at the first and most recent visits. The corrected distance visual acuity (CDVA; in decimal units) was evaluated at the initial visit and the 1-, 6-, and 12-month follow-up visits. Results:: In the medically treated group (25 eyes of 15 patients), the median follow-up duration was 3 (range, 1-9) years, and the median CDVA values were 0.01 (0.001-1.0) at the first visit and 0.01 (0.001-0.8) at the most recent visit (p=0.916). In the penetrating keratoplasty (PK) group (7 eyes of 6 patients), the median follow-up duration was 7 years (range, 1-11), and the median CDVA increased from 0.01 (0.001-0.01) to 0.2 (0.001-0.7) postoperatively (p=0.043). Conclusion:: Whereas most AKC patients maintained a useful CDVA with medical treatment, PK may be required in some cases. Despite the frequent occurrence of complications, PK can significantly improve the CDVA. PMID- 28076565 TI - Effect of corneal biomechanical properties on surgically-induced astigmatism and higher-order aberrations after cataract surgery. AB - Purpose:: To investigate the relationship between biomechanical properties of the cornea and postoperative refractive changes in patients with low-level astigmatism after cataract surgery. Methods:: This prospective study recruited patients undergoing cataract surgery involving 2.8-mm superior incisions. Biomechanical properties of the cornea were evaluated preoperatively using the Ocular Response Analyzer, and corneal profiles were evaluated using a Scheimpflug system (Pentacam HR). Topographic astigmatism, total corneal aberrations (TCA) and higher-order corneal aberrations (HOCA) analyses were performed preoperatively and during 1- and 3-month postoperative exams. The incidences of surgically-induced astigmatism (SIA) and HOCAs were calculated using vector analyses. Associations of the preoperative biomechanical properties of the cornea with SIA and HOCAs were evaluated. Results:: This study included 28 eyes of 28 patients. The preoperative corneal hysteresis (CH) was 8.68 +/- 1.86 mmHg, and the corneal resistance factor (CRF) was 8.66 +/- 1.61 mmHg. At the 1-month postoperative evaluation, significant changes were observed in HOCAs (p=0.023), TCAs (p=0.05), astigmatism (p=0.02), and trefoil (p=0.033); in contrast, differences in coma (p=0.386) and spherical aberration (SA) were not significant (p=0.947). At the 3-month visit, significant changes were only observed in TCAs (p=0.02) and HOCAs (p=0.012). No relationships between the preoperative corneal hysteresis and corneal resistance factor and postoperative SIA and HOCA were identified, other than a positive correlation between the 3-month postoperative incidence of corneal hysteresis and spherical aberration. Conclusions:: Despite the observed lack of relationships of preoperative biomechanical properties of the cornea with SIA and postoperative aberrations (except for SA), further studies involving larger patient groups are needed to explore the unexpected refractive deviations after cataract surgery. PMID- 28076566 TI - Efficacy of aflibercept on exudative age-related macular degeneration in patients exhibiting complete ranibizumab resistance and tachyphylaxis. AB - Purpose:: The present study compared the efficacy of aflibercept for neovascular age-related macular degeneration (NV-AMD) in patients with complete ranibizumab resistance and tachyphylaxis. Methods:: Forty-four eyes of 38 neovascular age related macular degeneration patients were evaluated. Eyes were divided into a complete resistance group (n=23 eyes) and tachyphylaxis group (n=21 eyes). Results:: After three injections, eight (38.1%) patients in the tachyphylaxis group and nine (39.1%) in the complete resistance group presented with macular dryness. After the first injection of aflibercept, the mean visual acuity improved significantly in the tachyphylaxis group (p=0.018) but remained unchanged in the complete resistance group (p=0.37). There was a non-significant trend towards improved mean visual acuity in both groups after the second and third injections relative to the acuity at the final visit for ranibizumab treatment. In the tachyphylaxis group, the presence of subfoveal pigmented epithelium detachment (PED) decreased significantly after intravitreal aflibercept treatment. Conclusions:: Although treatment with aflibercept yielded generally positive anatomical results in both groups, no significant increase in visual acuity was achieved. PMID- 28076567 TI - Full-field electroretinogram recorded with skin electrodes in normal adults. AB - Purpose:: Alternative recording methods have been tested to allow the electroretinogram (ERG) recording in uncooperative patients and/or patients with palpebral alterations, including recordings with skin electrodes. The purpose of this study was to compare ERG recorded with skin electrodes and well-established microfiber electrodes and to determine normative values of ERG parameters for recording with skin electrodes. Methods:: Fifty healthy volunteers (17-26 years; mean 20.63 +/- 2.01 years) participated in the study. A gold disk skin electrode was placed on the lower orbital rim of a randomly chosen eye. On the contralateral eye, a microfiber electrode was positioned in the lower conjunctival sac. Gold disc electrodes were positioned at the ipsilateral outer canthus of both eyes acting as reference electrodes for the creation of a potential difference. Two ground electrodes were placed on the lobe of each ear. ERGs were recorded according to the International Society of Clinical Electrophysiology Visual (ISCEV) protocol using the VERIS 5.1.9 system for data acquisition and analysis. Results:: Both types of electrodes showed similar wave response morphologies. The implicit time of responses between the two electrodes was comparable. On peak-to-peak amplitude, skin electrode recordings showed an amplitude reduction of 61.4% for rod responses, 61.5% for maximal responses, 46.2% for oscillatory potentials, 57.4% for cone responses, and 54.4% for 30Hz flicker responses, when compared with microfiber electrode recordings. Based on these findings, normative values for peak-to-peak amplitude and implicit time to be used as a reference for ERGs recorded with skin electrodes were determined. Conclusions:: ERGs recorded with skin electrodes presented lower peak-to-peak amplitude compared with microfiber electrodes. However, using appropriate normative values, skin electrodes may be useful for specific target populations such as uncooperative infants and/or patients with ocular surface alterations. PMID- 28076568 TI - Immunohistochemical analysis of retinoblastoma cell phenotype using neuronal and glial cell markers. AB - Purpose:: The cellular origin of retinoblastoma is uncertain as constituent tumor cells heterogeneously express markers of both immature and mature retinal cells. An immunohistochemical analysis of cellular origin may yield valuable insights into disease progression and treatment options. This study aimed to determine the cellular origin of retinoblastoma in a large case series and correlate these findings with histopathological prognostic factors. Methods:: Thirty-nine retinoblastoma cases were histopathologically diagnosed and analyzed by immunohistochemistry using monoclonal antibodies against the immature neural cell marker SRY-box containing gene 2 (SOX-2), the mature neuronal cell marker microtubule-associated protein 2 (MAP2), and the mature glial cell marker glial fibrillary acidic protein (GFAP). Histopathological features were also evaluated, including patterns of growth, differentiation, vitreous seeding, and choroidal/scleral, optic nerve, and anterior chamber invasion. Two retinoblastoma cell lines, WERI-1 and Y79, were studied by immunocytochemistry using the same antibodies. Results:: Expression of SOX-2 was strong in 97.4% of retinoblastoma cases, while MAP-2 was expressed in 59% of cases. Immunostaining for GFAP was positive only in reactive stromal astrocytes interspersed amongst tumor cells and in peritumoral tissue. There was no correlation between histopathological prognostic factors and immunohistochemical markers. Retinoblastoma cell lines showed strong positivity for SOX2 (90% of WERI-1 cells and 70% of Y79 cells) and MAP2 (90% of cells in both lines). GFAP was completely negative in both cell lines. Conclusion:: The majority of retinoblastomas and both RB cell lines expressed an immature neural and/or a mature neuronal cell marker, but not a glial marker. These results indicate a typical neuroblast or neuronal origin and eliminate astrocyte differentiation from neural stem cells as the source of retinoblastoma. PMID- 28076569 TI - Optical coherence tomography of macular atrophy associated with microcephaly and presumed intrauterine Zika virus infection. AB - This case report describes the retinal optical coherence tomography (OCT) findings in a microcephalic infant with macular atrophy presumably caused by intrauterine Zika virus infection. OCT demonstrated atrophy of the outer retinal layers and choriocapillaris, including the outer nuclear layer and ellipsoid zone, associated with retinal pigment epithelium hyper-reflectivity and increased OCT penetration into deeper layers of the choroid and sclera. A major concern associated with this infection is the apparent increased incidence of microcephaly in fetuses born to mothers infected with the Zika virus. It is becoming increasingly difficult to ignore the upsurge in congenital microcephaly observed in Brazil. Recently, ocular findings in infants with microcephaly associated with intrauterine Zika virus infection have been described. This is the first report of OCT imaging of macular atrophy in a child with presumed Zika virus infection-associated microcephaly. PMID- 28076570 TI - Bilateral retinal vasculitis in a patient with lichen planus. AB - Lichen planus (LP) is an autoimmune, inflammatory disease of unknown etiology that commonly affects the skin and mucous membranes. Retinal vasculitis is a group of vision-threatening disorders, in which autoimmunity is thought to play a role in pathogenesis. We present the case of a patient who was diagnosed with retinal vasculitis and who was followed up for mucosal LP. LP has not been reported as a cause of retinal vasculitis in the literature. We believe that the retinal vasculitis in this case was related to LP because cellular immunity plays a role in the pathogenesis of both entities. PMID- 28076571 TI - Pupilloplasty in a patient with true polycoria: a case report. AB - Here we report a case of surgical pupilloplasty in an adult with true polycoria. A 44-year old man was referred to our clinic with a best-corrected visual acuity (BCVA) of 0.5 diopters (D) in his left eye. Biomicroscopy revealed two pupils within a 2.5-mm central zone, with diameters of 1.2 and 1.1 mm. Both pupils had real iris sphincters and responded to light and chemical stimulation. Therefore, we surgically cut the bridge between the two pupils without any intraoperative or postoperative complications. One month after the surgery, BCVA had improved to 0.9 D, and the final pupil was almost round, measuring 2.7 mm in diameter. PMID- 28076572 TI - Iris metastases from systemic cancer: a report of three cases. AB - Ocular metastasis is relatively uncommon, with a reported incidence of approximately 8%, according to the results of autopsy evaluation. The majority of ocular metastases are located within the choroid, while metastatic tumors affecting the iris are rare. Metastatic tumors may manifest as stromal nodules or ill-defined iris thickening, or they may present with nonspecific features such as pain, iridocyclitis, and hyphema. Here, we describe three patients with iris metastasis and discuss the diagnostic challenges and unusual findings associated with these cases. PMID- 28076573 TI - Dacryoliths causing intermittent epiphora associated with a patent lacrimal system. AB - We present two patients with dacryoliths and patent lacrimal drainage with intermittent tearing and without infection. Dacryoliths can be present in the lacrimal sac or lacrimal duct without acute or chronic inflammation. In these cases, we believe dacryolith formation was a causative factor of intermittent epiphora even with a patent drainage system, and we propose that dacryoliths and even fungal colonization formation may be the first event before dacryocystitis and should be considered as a cause of epiphora. PMID- 28076574 TI - Macular hemorrhage after roller coaster riding in a single-eyed patient with congenital glaucoma. AB - A 21-year-old female presented with a 4-day history of decreased vision in her only functional eye (right eye, OD). She had a history of multiple ocular surgeries in both eyes because of congenital glaucoma and had lost light perception in her left eye several years prior. Ophthalmological examination revealed 0.15 Snellen visual acuity, and fundoscopy revealed nearly total cupping and pallor of the optic disc and multiple retinal hemorrhagic foci in the macula in OD. Lesions spontaneously resolved over a few months. Gravitational forces during a roller coaster ride may have caused this macular hemorrhage. PMID- 28076575 TI - Selective laser trabeculoplasty as an initial treatment option for open-angle glaucoma. AB - Although eye drops are frequently used as an initial treatment option for open angle glaucoma (OAG), side effects, and poor adherence, among others, may compromise treatment efficacy. In this scenario, laser trabeculoplasty is an interesting therapeutic option for open angle glaucoma cases. Commonly used for many years as a last alternative prior to glaucoma incisional surgery, laser trabeculoplasty has been changing its indication after the advent of selective laser trabeculoplasty (SLT). In the current review, we critically evaluated the published data regarding the use of laser trabeculoplasty as a first treatment option for open angle glaucoma patients. Studies using SLT as a first-line treatment have encouraging findings. One-year efficacy results are comparable to those obtained with prostaglandin analogues, with a good safety profile. Although the laser's effect is known to be transitory, recent data suggest it can be successfully repeated in cases with good response to the first SLT treatment. PMID- 28076576 TI - [Optimization of registry of deaths from chronic kidney disease in agricultural communities in Central America]. AB - Several Central American countries are seeing continued growth in the number of deaths from chronic kidney disease of nontraditional causes (CKDnT) among farm workers and there is underreporting. This report presents the results of a consensus process coordinated by the Pan American Health Organization/World Health Organization (PAHO/WHO), the United States Centers for Disease Control and Prevention (CDC), and the Latin American Society of Nephrology and Hypertension (SLANH). This consensus seeks to increase the probability of detecting and recording deaths from these causes. There has been recognition of the negative impact of the lack of a standardized instrument and the lack of training in the medical profession for adequate registration of the cause or causes of death. As a result of the consensus, the following has been proposed: temporarily use a code from the Codes for Special Purposes in the International Classification of Diseases (ICD-10); continue to promote use of the WHO international standardized instrument for recording causes and preceding events related to death; increase training of physicians responsible for filling out death certificates; take action to increase the coverage and quality of information on mortality; and create a decision tree to facilitate selection of CKDnT as a specific cause of death, while presenting the role that different regional and subregional mechanisms in the Region of the Americas should play in order to improve CKD and CKDnT mortality records. PMID- 28076577 TI - Chronic kidney disease of nontraditional etiology in Central America: a provisional epidemiologic case definition for surveillance and epidemiologic studies. AB - SYNOPSIS Over the last two decades, experts have reported a rising number of deaths caused by chronic kidney disease (CKD) along the Pacific coast of Central America, from southern Mexico to Costa Rica. However, this specific disease is not associated with traditional causes of CKD, such as aging, diabetes, or hypertension. Rather, this disease is a chronic interstitial nephritis termed chronic kidney disease of nontraditional etiology (CKDnT). According to the Pan American Health Organization (PAHO) mortality database, there are elevated rates of deaths related to kidney disease in many of these countries, with the highest rates being reported in El Salvador and Nicaragua. This condition has been identified in certain agricultural communities, predominantly among male farmworkers. Since CKD surveillance systems in Central America are under development or nonexistent, experts and governmental bodies have recommended creating standardized case definitions for surveillance purposes to monitor and characterize this epidemiological situation. A group of experts from Central American ministries of health, the U.S. Centers for Disease Control and Prevention (CDC), and PAHO held a workshop in Guatemala to discuss CKDnT epidemiologic case definitions. In this paper, we propose that CKD in general be identified by the standard definition internationally accepted and that a suspect case of CKDnT be defined as a person age < 60 years with CKD, without type 1 diabetes mellitus, hypertensive diseases, and other well-known causes of CKD. A probable case of CKDnT is defined as a suspect case with the same findings confirmed three or more months later. PMID- 28076578 TI - Confirmed clinical case of chronic kidney disease of nontraditional causes in agricultural communities in Central America: a case definition for surveillance. AB - Over the last 20 years, many reports have described an excess of cases of chronic kidney disease (CKD) in the Pacific coastal area of Central America, mainly affecting male farmworkers and signaling a serious public health problem. Most of these cases are not associated with traditional risk factors for CKD, such as aging, diabetes mellitus, and hypertension. This CKD of nontraditional causes (CKDnT) might be linked to environmental and/or occupational exposure or working conditions, limited access to health services, and poverty. In response to a resolution approved by the Directing Council of the Pan American Health Organization (PAHO) in 2013, PAHO, the U.S. Centers for Disease Control and Prevention, and the Latin American Society of Nephrology and Hypertension (SLANH) organized a consultation process in order to expand knowledge on the epidemic of CKDnT and to develop appropriate surveillance instruments. The Clinical Working Group from SLANH was put in charge of finding a consensus definition of a confirmed clinical case of CKDnT. The resulting definition establishes mandatory criteria and exclusion criteria necessary for classifying a case of CKDnT. The definition includes a combination of universally accepted definitions of CKD and the main clinical manifestations of CKDnT. Based on the best available evidence, the Clinical Working Group also formulated general recommendations about clinical management that apply to any patient with CKDnT. Adhering to the definition of a confirmed clinical case of CKDnT and implementing it appropriately is expected to be a powerful instrument for understanding the prevalence of the epidemic, evaluating the results of interventions, and promoting appropriate advocacy and planning efforts. PMID- 28076579 TI - Factors that influence career choice in primary care among medical students starting social service in Honduras. AB - Objective: To 1) describe patterns of specialty choice; 2) investigate relationships between career selection and selected demographic indicators; and 3) identify salary perception, factors that influence career choice in primary care, and factors that influence desired location of future medical practice. Methods: The study used a mixed-methods approach that included a cross-sectional questionnaire survey applied to 234 last-year medical students in Honduras (September 2014), and semi-structured interviews with eight key informants (October 2014). Statistical analysis included chi-square and factor analysis. An alpha level of 0.05 was used to determine significance. Results: In the qualitative analysis, several codes were associated with each other, and five major themes emerged. Primary care careers were the preferred choice for 8.1% of students, who preferred urban settings for future practice location. The perceived salary of specialties other than primary care was significantly higher than those of general practitioners, family practitioners, and pediatricians (P < 0.001). Participants considered "making a difference," income, teaching, prestige, and challenging work the most important factors influencing career choice. Practice in ambulatory settings was significantly associated with a preference for primary care specialties (P = < 0.05). Logistic regression analysis found that factors related to patient-based care were statistically significant for selecting primary care (P = 0.006). The qualitative analysis further endorsed the survey findings, identifying additional factors that influence career choice (future work option; availability of residency positions; and social factors, including violence). Rationales behind preference of a specialty appeared to be based on a combination of ambition and prestige, and on personal and altruistic considerations. Conclusions: Most factors that influence primary care career choice are similar to those found in the literature. There are several factors distinctive to medical students in Honduras-most of them barriers to primary care career choice. PMID- 28076580 TI - [(CAG)n polymorphism of the ATXN2 gene, a new marker of susceptibility for type 2 diabetes mellitus]. AB - Objective: Estimate whether there is an association between the (CAG)n repeat in the ATXN2 gene in the Mexican population and type 2 diabetes mellitus (DM). Methods: Epidemiological case-control study, including healthy people and diabetics. (CAG)n expansion was detected by end-point polymerase chain reaction (PCR). PCR outputs were analyzed by electrophoresis (PAGE 8%) and silver nitrate staining. Results: (CAG)n nucleotide allele distribution in the study population was similar to that reported in central Mexico. The 22-repeat allele is the most frequent; however, there is an association with carriers of long repeats in the normal range with diabetes. Conclusions: The results suggest that the (CAG)n repeat of the ATXN2 gene could be a causal factor for type 2 DM. PMID- 28076581 TI - [Social determinants of health and convergence in health agendas of regional agencies in South America]. AB - Objective: Characterize areas of interinstitutional cooperation and converging health agendas of the Pan American Health Organization/World Health Organization (PAHO/WHO), the Health Council of the Union of South American Nations (UNASUR), and the Amazon Cooperation Treaty Organization (ACTO) in South America based on social determinants of health. Methods: A qualitative study based on official documentary sources from the three organizations, using a comparative analysis of the health agendas of these agencies and the Rio Political Declaration on Social Determinants of Health (2011). Information was systematized using an analytical matrix that identifies convergences in the respective agendas. Results: Development of the health agendas of these agencies is influenced by various international forces such as Member States' foreign policy, international cooperation strategies and models, and the institutions' political and strategic guidelines. These agendas reveal efforts to strengthen blocs, cooperation mechanisms, and coordinated programmatic actions. Conclusions: The agendas of PAHO/WHO, the UNASUR Health Council, and ACTO point towards opportunities for convergence in various programmatic areas, emphasizing social determinants of health. Based on the overall agreements of the Rio Declaration as an analytical framework with recommendations in five decision-making spheres, structural cooperation actions can be carried out in the region's countries, jointly mediated by these agencies. PMID- 28076582 TI - Interventions that facilitate sustainable jobs and have a positive impact on workers' health: an overview of systematic reviews. AB - Objective: To identify interventions that facilitate sustainable jobs and have a positive impact on the health of workers in health sector workplaces. Methods: This overview utilized systematic review methods to synthesize evidence from multiple systematic reviews and economic evaluations. A comprehensive search was conducted based on a predefined protocol, including specific inclusion criteria. To be classified as "sustainable," interventions needed to aim (explicitly or implicitly) to 1) have a positive impact on at least two key dimensions of the integrated framework for sustainable development and 2) include measures of health impact. Only interventions conducted in, or applicable to, health sector workplaces were included. Results: Fourteen systematic reviews and no economic evaluations met the inclusion criteria for the overview. The interventions that had a positive impact on health included 1) enforcement of occupational health and safety regulations; 2) use of the "degree of experience rating" feature of workers' compensation; 3) provision of flexible working arrangements that increase worker control and choice; 4) implementation of certain organizational changes to shift work schedules; and 5) use of some employee participation schemes. Interventions with negative impacts on health included 1) downsizing/restructuring; 2) temporary and insecure work arrangements; 3) outsourcing/home-based work arrangements; and 4) some forms of task restructuring. Conclusions: What is needed now is careful implementation, in health sector workplaces, of interventions likely to have positive impacts, but with careful evaluation of their effects including possible adverse impacts. Well evaluated implementation of the interventions (including those at the pilot-study stage) will contribute to the evidence base and inform future action. Interventions with negative health impacts should be withdrawn from practice (through regulation, where possible). If use of these interventions is necessary, for other reasons, considerable care should be taken to ensure an appropriate balance between business needs and human health and well-being. PMID- 28076583 TI - [Social factors associated with use of prenatal care in Ecuador]. AB - Objectives: Prenatal care is a pillar of public health, enabling access to interventions including prevention of mother-to-child transmission of HIV and congenital syphilis. This paper describes social factors related to use of prenatal care in Ecuador. Methods: In 2011 and 2012, participant clinical history and interview information was analyzed from a national probability sample of 5 998 women presenting for delivery or miscarriage services in 15 healthcare facilities in Ecuador, to estimate prevalence of HIV, syphilis, and Chagas disease, and prenatal care coverage. Results: The study found that 94.1% of women had attended at least one prenatal visit, but that attendance at no less than four visits was 73.1%. Furthermore, lower educational level, greater number of pregnancies, occupation in the agriculture or livestock sector, and membership in ethnic indigenous, Afro-Ecuadorian, or other minority groups were factors associated with lack of use (no prenatal visits) or insufficient use of prenatal care (fewer than four visits or first visit at >20 weeks gestation) in Ecuador. Conclusions: These results point to persistence of marked inequalities in access to and use of prenatal health services attributable to socioeconomic factors and to the need to strengthen strategies to address them, to reach the goal of universal prenatal care coverage. PMID- 28076584 TI - Impact of bullying victimization on suicide and negative health behaviors among adolescents in Latin America. AB - Objective: To compare the prevalence of bullying victimization, suicidal ideation, suicidal attempts, and negative health behaviors (current tobacco use, recent heavy alcohol use, truancy, involvement in physical fighting, and unprotected sexual intercourse) in five different Latin American countries and determine the association of bullying victimization with these outcomes, exploring both bullying type and frequency. Methods: Study data were from Global School-based Student Health Surveys from Bolivia, Costa Rica, Honduras, Peru, and Uruguay, which covered nationally representative samples of school-going adolescents. The surveys used a two-stage clustered sample design, sampling schools and then classrooms. Logistic regression models were run to determine the statistical significance of associations with bullying. Results: Among the 14 560 school-going adolescents included in this study, the prevalence of any bullying victimization in the past 30 days was 37.8%. Bullying victimization was associated with greater odds of suicidal ideation with planning (adjusted odds ratio (AOR): 3.12; P < 0.0001) and at least one suicide attempt (AOR: 3.07; P < 0.0001). An increasing exposure-response effect of increasing days of bullying victimization on suicide outcomes was also observed. Bullying victimization was associated with higher odds of current tobacco use (AOR: 2.14; P < 0.0001); truancy (AOR: 1.76; P < 0.0001); physical fighting (AOR: 2.40; P < 0.0001); and unprotected sexual intercourse (AOR: 1.77; P < 0.0001). Conclusions: Although the prevalence of bullying victimization varied by country, its association with suicidal ideation and behavior and negative health behaviors remained relatively consistent. Addressing bullying needs to be made a priority in Latin America, and an integrated approach that also includes mental and physical health promotion is needed. PMID- 28076585 TI - [Priorities of clinical drug trials in Brazil and neglected diseases of poverty]. AB - Objective: To identify clinical drug trials performed in Brazil between 2012 and 2015, with emphasis on those focusing on neglected diseases of poverty. Method: Two clinical trial registries, ReBEC (Brazilian registry) and ClinicalTrials.gov were surveyed. The following aspects were investigated: distribution of clinical trials in relation to the burden of disease in Brazil, distribution of trials regarding their focus on diseases of poverty vs. diseases not linked to poverty, phase of trials, performing institution, and type of funding (private, public, or mixed). Results: The search revealed 866 eligible trials, 88 registered in ReBEC and 778 in ClinicalTrials.gov. Of these, 73 (8.5%) were phase I trials, 610 (70.5%) were phase II and III trials, and 183 (21%) were phase IV trials. There were 38 trials (4%) focusing on neglected diseases of poverty. Regarding the burden of disease, 734 (84.8%) trials focused on noncommunicable diseases, which in fact represent the largest burden of disease in Brazil. Most trials were carried out by pharmaceutical companies (55.3%), with predominance of private funding (57.1%); however, if only the diseases of poverty are considered, 63.1% were financed by public resources. Conclusions: The clinical drug trials carried out in Brazil in the study period are in agreement with the proportional burden of disease for the country. However, the neglected diseases of poverty were not prioritized. More effective action is necessary to redirect clinical research on drug development to meet national needs. PMID- 28076586 TI - Predictors of readiness for oral rapid HIV testing by Chilean health care providers. AB - Objective: This study identified the personal characteristics that affect Chilean health care providers' readiness to adopt HIV Oral Rapid Testing (ORT) in Chile as a new clinical evidence-based practice (EBP). Methods: Using a cross-sectional research design, the study sampled 150 nurses, midwives, and physicians employed at four clinics within the Pontificia Universidad Catolica de Chile Health Network in Santiago. Participants completed a self-administered survey asking about their demographic background, EBP attitudes and experience, personal beliefs related to HIV, the importance of HIV testing, and perceived self-comfort in performing a rapid HIV test. Results: Of the participants, 90% believed that incorporating ORT would make a positive difference in their practice and said that they would be willing to adopt the technology for that reason. Nonetheless, the providers reported a mean "readiness to implement ORT" score of 15.1 out of a possible value of 20, suggesting only moderate self-perceived readiness to adopt the EBP. Education, beliefs about evidence-based practice, perceived comfort in performing ORT, and perceived importance of HIV testing explained 43.6% of the variance in readiness to adopt ORT. Conclusion: The findings of this first ORT pre-implementation study in Chile can help guide policy makers and HIV stakeholders to prepare for and increase primary health care providers' readiness to successfully adopt this evidence-based technology. Successful adoption of ORT could increase Chile's capacity to reach HIV-vulnerable Chileans for testing and referral to care if infected, thus helping the country to reduce further transmission of the virus and its medical complications. PMID- 28076587 TI - [Interventions to improve access to health services by indigenous peoples in the Americas]. AB - Objective: Synthesize evidence on effectiveness of interventions designed to improve access to health services by indigenous populations. Methods: Review of systematic reviews published as of July 2015, selecting and analyzing only studies in the Region of the Americas. The bibliographic search encompassed MEDLINE, Lilacs, SciELO, EMBASE, DARE, HTA, The Cochrane Library, and organization websites. Two independent reviewers selected studies and analyzed their methodological quality. A narrative summary of the results was produced. Results: Twenty-two reviews met the inclusion criteria. All selected studies were conducted in Canada and the United States of America. The majority of the interventions were preventive, to surmount geographical barriers, increase use of effective measures, develop human resources, and improve people's skills or willingness to seek care. Topics included pregnancy, cardiovascular risk factors, diabetes, substance abuse, child development, cancer, mental health, oral health, and injuries. Some interventions showed effectiveness with moderate or high quality studies: educational strategies to prevent depression, interventions to prevent childhood caries, and multicomponent programs to promote use of child safety seats. In general, results for chronic non-communicable diseases were negative or inconsistent. Conclusions: Interventions do exist that have potential for producing positive effects on access to health services by indigenous populations in the Americas, but available studies are limited to Canada and the U.S. There is a significant research gap on the topic in Latin America and the Caribbean. PMID- 28076588 TI - [Essential competencies in training in obstetrics]. AB - Objective: Analyze international reports related to training in obstetrics and present guidelines to help leading educational institutions to develop curriculum guidelines for the teaching of obstetrics and advanced nursing practice in this specialty. Methods: A narrative review was conducted of documents from the World Health Organization and the International Confederation of Midwives. The search used the descriptors midwifery and education. All official reports that guide midwife education policies, published from 2009 to 2015 in English and Spanish, and available online, were included. Reports that did not specifically refer to training were excluded. Results: Five reports were selected. Analysis and synthesis of their respective objectives and contents were based on three themes: requirements for professional qualification, continuing education, and guidelines for skilled training in obstetrics, taking into account accepted core competencies for this specialty. Conclusions: Analysis of reports related to training in obstetrics identified that key tasks are being implemented for both educators and midwives. The reports represent a solid basis to develop educational policies that can contribute to universal access and coverage in health and to reducing maternal and neonatal mortality, and potentially can be used to guide international policies. PMID- 28076589 TI - Time volunteered on community health activities by brigadistas in Nicaragua. AB - Objective: To report on how brigadistas ("health brigadiers") in Nicaragua volunteer their time before the introduction of expanded responsibilities (beyond the scope of integrated community case management (iCCM)) for sick children 2-59 months old. Methods: Three complete teams of brigadistas (n = 12 brigadistas total) were selected from remote communities in the department of Matagalpa. Each respondent brigadista was interviewed privately regarding the frequency and duration (i.e., preparation, round-trip travel, and implementation time) of 13 separate activities. The correlation between their overall estimates and summed times of individual activities were measured. Results: Brigadista mean density was 1 per 156 total population (range: 120-217). Each team had one encargado/a ("manager") with an iCCM drug box plus two to four asistentes ("assistants"). All resided in the community they served. Eight reported competing time demands during one to nine months of the year. Brigadistas volunteered an average of 75 hours per month (range: 35-131). Encargados were busier than asistentes (98 versus 68 hours per month). Three activities accounted for 70% of their time: 1) iCCM (30%: treatment (11%), follow-up (19%)); 2) receiving training (21%); and 3) promoting birth planning (19%). Brigadistas' time was divided among preparation (12%), travel (27%), and implementation (61%). Overall estimates were highly correlated (+0.70) with summed implementation time. Conclusions: Brigadistas from these remote Nicaraguan communities were busy with different activities, levels of effort, and patterns of task-sharing. These findings, plus an ongoing job satisfaction survey and a follow-on time study after the introduction of the new interventions, will inform policy for this valuable volunteer cadre. PMID- 28076590 TI - Effect of maternal exercises on biophysical fetal and maternal parameters: a transversal study. AB - Objective: To evaluate the acute effects of maternal and fetal hemodynamic responses in pregnant women submitted to fetal Doppler and an aerobic physical exercise test according to the degree of effort during the activity and the impact on the well-being. Methods: Transversal study with low risk pregnant women, obtained by convenience sample with gestational age between 26 to 34 weeks. The participants carry out a progressive exercise test. Results: After the exercise session, reduced resistance (p=0.02) and pulsatility indices (p=0.01) were identified in the umbilical artery; however, other Doppler parameters analyzed, in addition to cardiotocography and fetal biophysical profile did not achieve significant change. Maternal parameters obtained linear growth with activity, but it was not possible to establish a standard with the Borg scale, and oxygen saturation remained stable. Conclusion: A short submaximal exercise had little effect on placental blood flow after exercise in pregnancies without complications, corroborating that healthy fetus maintains homeostasis even in situations that alter maternal hemodynamics. Objetivo: Avaliar os efeitos agudos de respostas hemodinamicas maternas e fetais em gestantes submetidas a Doppler fetal e a um teste de exercicio fisico aerobio, de acordo com o grau de esforco durante a atividade e o impacto sobre o bem-estar. Metodos: Estudo transversal desenvolvido com gestantes de baixo risco, por amostra de conveniencia com idade gestacional entre 26 e 34 semanas. As participantes realizam um teste de esforco progressivo. Resultados: Na arteria umbilical, apos sessao de exercicio fisico, identificou-se a reducao do indice de resistencia (p=0,02) e do indice de pulsatilidade (p=0,01), mas os demais parametros Doppler analisados, alem da cardiotocografia e do perfil biofisico fetal, nao obtiveram alteracao significativa. Os parametros maternos obtiveram crescimento linear com a atividade, mas nao foi possivel estabelecer padrao com a escala de Borg, e a saturacao de oxigenio se manteve estavel. Conclusao: O esforco submaximo curto teve pouco efeito sobre o fluxo de sangue da placenta apos o exercicio em gestacoes sem complicacoes, corroborando que o feto higido mantem a homeostase mesmo em situacoes que alterem a hemodinamica materna. PMID- 28076591 TI - Urban versus rural lifestyle in adolescents: associations between environment, physical activity levels and sedentary behavior. AB - Objective: To analyze the levels of physical activity and sedentary behavior in adolescents living in urban and rural areas. Methods: An epidemiological, cross section study with quantitative design, carried out at the regional level. The sample comprised 6,234 students aged 14 to 19 years, selected using random cluster sampling. The chi2 test and binary logistic regression were used in the analysis. Results: A total of 74.5% of adolescents lived in urban areas. After adjustment, rural residents spent less time watching television (odds ratio - OR: 0.45; 95% confidence interval - 95%CI: 0.39-0.52), using a computer and/or playing video games (OR: 0.30; 95%CI: 0.22-0.42), or sitting down (OR: 0.66; 95%CI: 0.54-0.80); chose passive leisure less often (OR: 0.83; 95%IC: 0.72-0.95) and were less likely to be classified as insufficiently active (OR: 0.88; 95%IC: 0.78-0.99) when compared to urban residents, regardless of sex or age. The fact that adolescents living in rural areas who did not work were more likely to be classified as insufficiently active (OR: 2.59; 95%CI: 2.07-3.24) emphasized the significant role of occupation in physical activity levels in this group. Conclusion: Adolescents living in rural areas were less exposed to the sedentary behaviors, chose more active leisure, and had higher levels of physical activity. Place of residence and occupation may play a major role in youth lifestyle. Objetivo: Analisar os niveis de atividade fisica e o comportamento sedentario em adolescentes das areas urbanas e rurais. Metodos: Estudo epidemiologico, transversal, com abordagem quantitativa e abrangencia estadual, cuja amostra foi constituida por 6.234 estudantes (14 a 19 anos), selecionados por meio de uma estrategia de amostragem aleatoria de conglomerados. As analises foram realizadas por meio do teste chi2 e da regressao logistica binaria. Resultados: Na amostra, 74,5% dos adolescentes eram residentes em area urbana. Apos o ajuste, constatou se que os adolescentes oriundos da area rural usavam menos televisao (odds ratio OR: 0,45; intervalo de confianca de 95% - IC95%: 0,39-0,52), computador e/ou videogame (OR: 0,30; IC95%: 0,22-0,42), passavam menos tempo sentados (OR: 0,66; IC95%: 0,54-0,80), optaram menos pelo lazer passivo (OR: 0,83; IC95%: 0,72-0,95) e tinham menos chances de serem classificados como insuficientes ativos (OR: 0,88; IC95%: 0,78-0,99), quando comparados aqueles que residiam na area urbana, independentemente do sexo e da idade. Os adolescentes da area rural que nao trabalhavam apresentaram mais chances de serem classificados como insuficientemente ativos (OR: 2,59; IC95%: 2,07-3,24), mostrando que a ocupacao tinha um papel importante no nivel de atividade fisica deste grupo. Conclusao: Os adolescentes residentes na area rural estiveram menos expostos aos comportamentos sedentarios, optaram mais por um lazer ativo e apresentaram um melhor nivel de atividade fisica, podendo a zona de domicilio e a ocupacao influenciar no estilo de vida deles. PMID- 28076592 TI - Assessment of laparoscopic skills of Gynecology and Obstetrics residents after a training program. AB - Objective: To evaluate laparoscopic skills of third-year Gynecology and Obstetrics residents after training at a training and surgical experimentation center. Methods: Use of a prospective questionnaire analyzing demographic data, medical residency, skills, competences, and training in a box trainer and in pigs. Results: After the training, there was significant improvement in laparoscopic skills according to the residents (before 1.3/after 2.7; p=0.000) and preceptors (before 2.1/after 4.8; p=0.000). There was also significant improvement in the feeling of competence in surgeries with level 1 and 2 of difficulty. All residents approved the training. Conclusion: The training was distributed into 12 hours in the box trainer and 20 hours in animals, and led to better laparoscopic skills and a feeling of more surgical competence in laparoscopic surgery levels 1 and 2. Objetivo: Avaliar a habilidade laparoscopica dos residentes do terceiro ano de residencia medica em Ginecologia e Obstetricia apos treinamento em um centro de treinamento e experimentacao cirurgica. Metodos: Aplicacao de questionario de forma prospectiva analisando dados demograficos, da residencia medica, da habilidade, da competencia e do treinamento em caixa preta e em porcas. Resultados: Apos o treinamento, houve melhora da habilidade em laparoscopia de forma significativa na avaliacao dos residentes (antes 1,3/depois 2,7; p=0,000) e preceptores (antes 2,1/depois 4,8; p=0,000). Houve melhora significativa na sensacao de competencia em cirurgias de niveis 1 e 2 de dificuldade. Todos os residentes aprovaram o treinamento. Conclusao: O treinamento dividido em 12 horas de caixa preta e 20 horas em animais trouxe melhora na habilidade em laparoscopia e na sensacao de melhora na competencia cirurgica em cirurgias laparoscopicas de niveis 1 e 2. PMID- 28076593 TI - Brachial insertion of fully implantable venous catheters for chemotherapy: complications and quality of life assessment in 35 patients. AB - Objective: To prospectively evaluate the perioperative safety, early complications and satisfaction of patients who underwent the implantation of central catheters peripherally inserted via basilic vein. Methods: Thirty-five consecutive patients with active oncologic disease requiring chemotherapy were prospectively followed up after undergoing peripheral implantation of indwelling venous catheters, between November 2013 and June 2014. The procedures were performed in the operating room by the same team of three vascular surgeons. The primary endpoints assessed were early postoperative complications, occurring within 30 days after implantation. The evaluation of patient satisfaction was based on a specific questionnaire used in previous studies. Results: In all cases, ultrasound-guided puncture of the basilic vein was feasible and the procedure successfully completed. Early complications included one case of basilic vein thrombophlebitis and one case of pocket infection that did not require device removal. Out of 35 patients interviewed, 33 (94.3%) would recommend the device to other patients. Conclusion: Implanting brachial ports is a feasible option, with low intraoperative risk and similar rates of early postoperative complications when compared to the existing data of the conventional technique. The patients studied were satisfied with the device and would recommend the procedure to others. Objetivo: Avaliar prospectivamente seguranca perioperatoria, complicacoes precoces e grau de satisfacao de pacientes submetidos ao implante de cateteres centrais de insercao periferica pela veia basilica. Metodos: Foram acompanhados prospectivamente e submetidos ao implante de cateteres de longa permanencia de insercao periferica, entre novembro de 2013 e junho de 2014, 35 pacientes consecutivos com doenca oncologica ativa necessitando de quimioterapia. Os procedimentos foram realizados em centro cirurgico por uma mesma equipe composta por tres cirurgioes vasculares. Os desfechos primarios avaliados foram as complicacoes pos-operatorias precoces, ocorridas em ate 30 dias apos o implante. A avaliacao do grau de satisfacao foi realizada com base na aplicacao de um questionario especifico ja utilizado em estudos previos. Resultados: Em todos os casos, a puncao ecoguiada da veia basilica foi possivel, e o procedimento foi concluido com sucesso. As complicacoes precoces observadas incluiram um caso de tromboflebite de basilica e um de infeccao de bolsa, ambos tratados clinicamente sem necessidade de retirada do dispositivo. Dos 35 pacientes interrogados, 33 (94,3%) recomendariam o dispositivo para outras pessoas. Conclusao: A implantacao do port braquial e uma opcao factivel, com baixo risco intraoperatorio e taxas semelhantes de complicacoes pos-operatorias imediatas quando comparada a dados ja existentes da tecnica convencional. Os pacientes estudados apresentaram-se satisfeitos com o dispositivo e recomendariam o procedimento para outras pessoas. PMID- 28076594 TI - Predictive factors of atrial fibrillation after coronary artery bypass grafting. AB - Objective: To analyze predictive demographic and perioperative variables of postoperative atrial fibrillation in patients who underwent exclusively coronary artery bypass grafting. Methods: This was a retrospective cohort. We randomly selected 105 medical records of patients who underwent exclusively coronary artery bypass grafting in 2014. Demographic, clinical (preoperative and immediate postoperative) data and related with surgical procedure were collected from medical records. The occurrence of postoperative atrial fibrillation was considered until the third day after the surgery. Variables were analyzed using descriptive and inferential statistics. To identify predictive factors of postoperative atrial fibrillation we used a decision tree model with Classification and Regression Trees algorithm. Results: Atrial fibrillation incidence was 19.0% (n=20). Patients with left atrial >40.5mm and aged >64.5 years were more likely to develop the arrhythmia during the post-surgical period. Conclusion: Left atrial diameter and advanced age were predictive factors of atrial fibrillation in patients who underwent exclusively coronary artery bypass grafting. Objetivo: Analisar as variaveis demograficas e perioperatorias preditivas de fibrilacao atrial pos-operatoria em pacientes brasileiros submetidos exclusivamente a cirurgia de revascularizacao do miocardio. Metodos: Trata-se de coorte retrospectiva. A amostra foi constituida de 105 prontuarios de pacientes submetidos exclusivamente a revascularizacao do miocardio no ano de 2014, selecionados aleatoriamente. Dados demograficos, clinicos (preoperatorios e do pos-operatorio imediato) e relacionados ao procedimento cirurgico foram coletados por meio de consulta ao prontuario. A ocorrencia de fibrilacao atrial no pos-operatorio foi considerada ate o terceiro dia apos a cirurgia. As variaveis foram analisadas por estatistica descritiva e inferencial. Para identificar os fatores preditivos de fibrilacao atrial no pos-operatorio, utilizou-se um modelo de arvore de decisao com algoritmo Classification and Regression Trees. Resultados: A incidencia de fibrilacao atrial pos-operatoria foi de 19,0% (n=20). Pacientes com atrio esquerdo >40,5mm e idade >64,5 anos foram aqueles com mais chance de desenvolver a arritmia no pos-operatorio. Conclusao: Tamanho do atrio esquerdo e idade avancada foram fatores preditivos de fibrilacao atrial em pacientes submetidos exclusivamente a cirurgia de revascularizacao do miocardio. PMID- 28076595 TI - Short version of the Depression Anxiety Stress Scale-21: is it valid for Brazilian adolescents? AB - Objective: To evaluate the interday reproducibility, agreement and validity of the construct of short version of the Depression Anxiety Stress Scale-21 applied to adolescents. Methods: The sample consisted of adolescents of both sexes, aged between 10 and 19 years, who were recruited from schools and sports centers. The validity of the construct was performed by exploratory factor analysis, and reliability was calculated for each construct using the intraclass correlation coefficient, standard error of measurement and the minimum detectable change. Results: The factor analysis combining the items corresponding to anxiety and stress in a single factor, and depression in a second factor, showed a better match of all 21 items, with higher factor loadings in their respective constructs. The reproducibility values for depression were intraclass correlation coefficient with 0.86, standard error of measurement with 0.80, and minimum detectable change with 2.22; and, for anxiety/stress: intraclass correlation coefficient with 0.82, standard error of measurement with 1.80, and minimum detectable change with 4.99. Conclusion: The short version of the Depression Anxiety Stress Scale-21 showed excellent values of reliability, and strong internal consistency. The two-factor model with condensation of the constructs anxiety and stress in a single factor was the most acceptable for the adolescent population. Objetivo: Avaliar a reprodutibilidade interdias, a concordancia e a validade do construto da versao reduzida da Depression Anxiety Stress Scale-21 aplicada a adolescentes. Metodo: A amostra foi composta por adolescentes de ambos os sexos, com idades entre 10 e 19 anos, recrutados de escolas e centros esportivos. A validade de construto foi realizada por analise fatorial exploratoria, e a confiabilidade foi calculada para cada construto, por meio de coeficiente de correlacao intraclasse, erro padrao de medida e mudanca minima detectavel. Resultados: A analise fatorial combinando os itens correspondentes a ansiedade e estresse em um unico fator, e depressao em um segundo fator apresentou melhor adequacao de todos os 21 itens, com cargas fatoriais mais altas em seus respectivos construtos. Os valores de reprodutibilidade para a depressao foram coeficiente de correlacao intraclasse com 0,86, erros padrao de medida com 0,80 e mudanca minima detectavel com 2,22 e, para a ansiedade/estresse, foram coeficiente de correlacao intraclasse com 0,82, erro padrao de medida com 1,80 e mudanca minima detectavel com 4,99. Conclusao: A versao reduzida da Depression Anxiety Stress Scale-21 apresentou excelentes valores de confiabilidade e tambem uma forte consistencia interna. O modelo de dois fatores com a condensacao dos construtos ansiedade e estresse em um unico fator foi o mais aceitavel para a populacao adolescente. PMID- 28076596 TI - Prevalence of inter-hemispheric asymetry in children and adolescents with interdisciplinary diagnosis of non-verbal learning disorder. AB - Objective: To describe clinical and epidemiological features of children and adolescents with interdisciplinary diagnosis of non-verbal learning disorder and to investigate the prevalence of inter-hemispheric asymmetry in this population group. Methods: Cross-sectional study including children and adolescents referred for interdisciplinary assessment with learning difficulty complaints, who were given an interdisciplinary diagnosis of non-verbal learning disorder. The following variables were included in the analysis: sex-related prevalence, educational system, initial presumptive diagnoses and respective prevalence, overall non-verbal learning disorder prevalence, prevalence according to school year, age range at the time of assessment, major family complaints, presence of inter-hemispheric asymmetry, arithmetic deficits, visuoconstruction impairments and major signs and symptoms of non-verbal learning disorder. Results: Out of 810 medical records analyzed, 14 were from individuals who met the diagnostic criteria for non-verbal learning disorder, including the presence of inter hemispheric asymmetry. Of these 14 patients, 8 were male. Conclusion: The high prevalence of inter-hemispheric asymmetry suggests this parameter can be used to predict or support the diagnosis of non-verbal learning disorder. Objetivo: Descrever as caracteristicas clinicas e epidemiologicas de criancas e adolescentes com transtorno de aprendizagem nao verbal, e investigar a prevalencia de assimetria inter-hemisferica neste grupo populacional. Metodos: Estudo transversal que incluiu criancas e adolescentes encaminhados para uma avaliacao interdisciplinar, com queixas de dificuldades de aprendizagem e que receberam diagnostico interdisciplinar de transtorno de aprendizagem nao verbal. As variaveis avaliadas foram prevalencia por sexo, sistema de ensino, hipoteses diagnosticas iniciais e respectivas prevalencias, prevalencia de condicoes em relacao a amostra total, prevalencia geral do transtorno de aprendizagem nao verbal, prevalencia de acordo com ano escolar, faixa etaria no momento da avaliacao, principais queixas familiares, presenca assimetria inter-hemisferica, dificuldade em aritmetica, alteracoes em visuoconstrucao, e principais sinais e sintomas do transtorno de aprendizagem nao verbal. Resultados: Dos 810 prontuarios medicos analisados, 14 eram de individuos que preencheram os criterios diagnosticos para transtorno de aprendizagem nao verbal, incluindo a assimetria inter-hemisferica. Destes 14 pacientes, 8 eram do sexo masculino. Conclusao: A alta prevalencia de assimetria inter-hemisferica sugere que este parametro possa ser usado como preditor ou reforcador para diagnostico de transtorno de aprendizagem nao verbal. PMID- 28076597 TI - Oral health evaluation in special needs individuals. AB - Objective: To identify the prevalence of the main oral problems present in special needs children and to relate the underlying conditions with the clinical and demographic variables. Methods: The study was based on the physical examination of 47 students from the Associacao de Pais e Amigos dos Excepcionais diagnosed as Down syndrome, cerebral palsy and intellectual deficit. For data collection, we used a self-administered questionnaire that included indices of dental caries and oral hygiene, Angle classification, malposition of dental groups and oral hygiene habits. Results: The predominant age group was 12-25 years (46.8%) and most patients were male (55.3%). Regarding daily brushing, 63.8% reported brushing their teeth three times a day, and 85.1% did it by themselves. A total of 48.9% were rated as Angle class I, and 25.5% had no type of malocclusion. A high dental carries index (decayed, missing, filled >10) was observed in 44.7%, and 53.2% had inadequate oral hygiene (zero to 1.16). There was a statistically significant difference between cerebral palsy and the act of the participants brushing their teeth by themselves. Conclusion: There was a high decayed-missing-filled teeth index and malocclusion class I, as well as inadequate oral hygiene. The type of underlying condition of the participants influenced the act of brushing teeth by themselves. Objetivo: Conhecer a prevalencia dos principais problemas bucais em criancas com necessidades especiais, e relacionar as doencas de base com variaveis clinicas e demograficas. Metodos: O estudo foi realizado a partir de exame clinico em 47 alunos da Associacao de Pais e Amigos dos Excepcionais com diagnostico medico de sindrome de Down, paralisia cerebral e deficit intelectual. Para a coleta de dados, foi utilizado um questionario autoaplicativo com indices de carie dentaria e higiene oral, classificacao de Angle, malposicao de grupos dentarios e habitos de higiene oral. Resultados: A faixa etaria predominante foi de 12 a 25 anos (46,8%) e a maioria era do sexo masculino (55,3%). Em relacao a escovacao dentaria, 63,8% relataram escovar os dentes tres vezes ao dia, sendo que 85,1% realizavam-na sozinhos. Constatou-se que 48,9% dos examinados apresentavam uma classificacao de Angle tipo I e 25,5% nao apresentavam qualquer tipo de maloclusao. Os avaliados (44,7%) apresentaram alto indice de carie dentaria (cariados, perdidos e obturados >10) e 53,2% apresentaram higiene oral inadequada (zero a 1,16). Houve diferenca estatisticamente significativa entre a paralisia cerebral e o ato de escovar os dentes sozinho. Conclusao: Constataram-se altos indices de carie e de maloclusao classe I, alem de inadequada higiene oral. Houve influencia do tipo de patologia de base na realizacao do ato de escovar os dentes sozinhos. PMID- 28076598 TI - Minor intraoral salivary gland tumors: a clinical-pathological study. AB - Objective: To evaluate the clinical-pathological profile of patients with minor salivary gland neoplasms. Methods: A retrospective study of specific cases diagnosed as benign and malignant tumors of the minor salivary glands was performed. The data were collected from medical records of patients seen at a hospital over a period of 15 years. The sample was made up of 37 cases. For the pathological study, slides containing 5MUm thick sections stained with hematoxylin and eosin were used. The data were tabulated using descriptive statistics. Results: Malignant neoplasms represented 70.3% of cases. The mucoepidermoid carcinoma was the most common neoplasm (45.9%), followed by pleomorphic adenoma (24.4%). Most patients were female (70.3%), aged between 71 and 80 years. The palate (67.6%) and the retromolar region (10.8%) were the most affected sites. Conclusion: Mucoepidermoid carcinoma was the most common tumor in minor salivary glands. These tumors are more common in females aged over 40 years. The palate was the most common affected site. Objetivo: Avaliar o perfil clinico-patologico de pacientes com neoplasias de glandula salivar menor. Metodos: Foi realizado um estudo retrospectivo de casos especificos diagnosticados como neoplasias benignas ou malignas de glandula salivar menor. Os dados foram coletados dos prontuarios dos pacientes atendidos em um hospital no periodo de 15 anos. A amostra final foi de 37 casos. Para o estudo histopatologico, foram usadas laminas contendo seccoes com 5MUm de espessura, coradas pela tecnica de hematoxilina e eosina. Os dados foram tabulados de forma descritiva. Resultados: As neoplasias malignas representaram 70,3% dos casos. O tipo histologico mais prevalente foi o carcinoma mucoepidermoide (45,9%), seguido do adenoma pleomorfico (24,4%). A maioria dos pacientes era do sexo feminino (70,3%), com idade entre 71 e 80 anos. O palato (67,6%) e a regiao retromolar (10,8%) foram os sitios mais acometidos. Conclusao: O carcinoma mucoepidermoide foi o tumor mais comum das glandulas salivares menores. Estes tumores foram mais comuns em mulheres com mais de 40 anos. O palato foi o sitio mais acometido. PMID- 28076599 TI - Applicability of the Spoken Knowledge in Low Literacy Patients with Diabetes in Brazilian elderly. AB - Objective: To translate, adapt and evaluate the properties of a Brazilian Portuguese version of the Spoken Knowledge in Low Literacy Patients with Diabetes, which is a questionnaire that evaluate diabetes knowledge. Methods: A cross-sectional study with type 2 diabetes patients aged >=60 years, seen at a public healthcare organization in the city of Sao Paulo (SP). After the development of the Portuguese version, we evaluated the psychometrics properties and the association with sociodemographic and clinical variables. The regression models were adjusted for sociodemographic data, functional health literacy, duration of disease, use of insulin, and glycemic control. Results: We evaluated 129 type 2 diabetic patients, with mean age of 75.9 (+/-6.2) years, mean scholling of 5.2 (+/-4.4) years, mean glycosylated hemoglobin of 7.2% (+/-1.4), and mean score on Spoken Knowledge in Low Literacy Patients with Diabetes of 42.1% (+/-25.8). In the regression model, the variables independently associated to Spoken Knowledge in Low Literacy Patients with Diabetes were schooling (B=0.193; p=0.003), use of insulin (B=1.326; p=0.004), duration of diabetes (B=0.053; p=0.022) and health literacy (B=0.108; p=0.021). The determination coefficient was 0.273. The Cronbach a was 0.75, demonstrating appropriate internal consistency. Conclusion: This translated version of the Spoken Knowledge in Low Literacy Patients with Diabetes showed to be adequate to evaluate diabetes knowledge in elderly patients with low schooling levels. It presented normal distribution, adequate internal consistency, with no ceiling or floor effect. The tool is easy to be used, can be quickly applied and does not depend on reading skills. Objetivo: Traduzir, adaptar e avaliar as propriedades de uma versao, em portugues do Brasil, do Spoken Knowledge in Low Literacy Patients with Diabetes, um questionario que avalia conhecimento em diabetes. Metodos: Estudo transversal, em diabeticos tipo 2, com idade >=60 anos de uma instituicao publica de saude, em Sao Paulo (SP). Apos o desenvolvimento da versao na lingua portuguesa, foram avaliadas suas propriedades psicometricas e associacao com variaveis sociodemograficas e clinicas. Os modelos de regressao foram ajustados para dados sociodemograficos, alfabetismo funcional em saude, tempo de doenca, uso de insulina e controle glicemico. Resultados: Foram avaliados 129 diabeticos, com media de idade de 75,9 (+/-6,2) anos, escolaridade media de 5,2 (+/-4,4) anos, hemoglobina glicada media de 7,2% (+/-1,4) e valor medio do Spoken Knowledge in Low Literacy Patients with Diabetes de 42,1% (+/-25,8). No modelo de regressao, as variaveis associadas de forma independente ao Spoken Knowledge in Low Literacy Patients with Diabetes foram escolaridade (B=0,193; p=0,003), uso de insulina (B=1,326; p=0,004), tempo de doenca (B=0,053; p=0,022) e alfabetismo em saude (B=0,108; p=0,021). O coeficiente de determinacao foi de 0,273. O a de Cronbach apresentou valor de 0,75, revelando consistencia interna adequada. Conclusao: Esta versao traduzida do Spoken Knowledge in Low LiteraFcy Patients with Diabetes mostrou-se adequada para avaliar conhecimentos em diabetes em idosos de baixa escolaridade, apresentando distribuicao normal, consistencia interna adequada, sem a presenca de efeito teto ou chao. O instrumento teve boa aplicabilidade, ja que pode ser administrado de maneira rapida e nao depende da capacidade de leitura. PMID- 28076600 TI - Use of cuff tear arthroplasty head prosthesis for rotator cuff arthropathy treatment in elderly patients with comorbidities. AB - Objective: To evaluate the clinical and functional behavior of patients undergoing cuff tear arthroplasty at different stages of the disease. Methods: Cuff tear arthroplasty hemiarthroplasties were performed in 34 patients with rotator cuff arthropathy and associated comorbidities, classified according to Seebauer. The mean age was 76.3 years, and the sample comprised 23 females (67.6%) and 11 males (32.4%). The mean follow-up period was 21.7 months, and evaluations were performed using the Visual Analog Scale for pain and the Constant scale. Results: There were no statistically significant differences in the mean reduction in the Visual Analog Scale or in the Constant scale increase between the female and male groups. The variation between the pre- and postoperative Visual Analog Scale and Constant scale evaluations was significant. There was also no statistically significant difference between the Seebauer classification groups regarding the mean Visual Analog Scale reduction, or the mean Constant scale increase. Conclusion: Cuff tear arthroplasty shoulder hemiarthroplasty is a good option for rotator cuff arthropathy in patients with comorbidities. Objetivo: Avaliar o comportamento clinico e funcional dos pacientes submetidos a artroplastia do tipo cuff tear arthroplasty para o tratamento da artropatia do manguito rotador em diferentes estagios da afeccao. Metodos: Foram realizadas 34 hemiartroplastias do tipo cuff tear arthroplasty em 34 pacientes com artropatia do manguito rotador e comorbidades associadas, classificadas de acordo com Seebauer. A media de idade foi de 76,3 anos, sendo 23 pacientes do sexo feminino (67,6%) e 11 do sexo masculino (32,4%). O seguimento medio foi de 21,7 meses e a avaliacao foi realizada por meio da Escala Visual Analogica da dor e pela escala de Constant. Resultados: Nao houve diferenca estatisticamente significante entre os grupos feminino e masculino, tanto nas medias de reducao na Escala Visual Analogica quanto nas de aumento na escala de Constant. A variacao entre as avaliacoes da Escala Visual Analogica e da escala de Constant pre e pos-operatorias foi significante. Nao houve diferenca estatisticamente significante entre os grupos de classificacao de Seebauer quanto as medias de reducao na Escala Visual Analogica e nem quanto as medias de aumento na escala de Constant, e nao houve casos de infeccao. Conclusao: A hemiartroplastia do ombro tipo cuff tear arthroplasty e boa uma opcao nos pacientes com artropatia do manguito rotador, especialmente em pacientes com comorbidades. PMID- 28076601 TI - Retrospective analysis of a case series of patients with traumatic injuries to the craniocervical junction. AB - Objective: To evaluate the correlation between the treatment, the characteristics of the lesions and the clinical outcome of patients with traumatic injuries to the craniocervical junction. Methods: This was a retrospective study of patients treated conservatively or surgically between 2010 and 2013 with complete data sets. Results: We analyzed 37 patients, 73% were men with mean age of 41.7 years. Of these, 32% were submitted to initial surgical treatment and 68% received conservative treatment. Seven (29%) underwent surgery subsequently. In the surgical group, there were seven cases of odontoid type II fractures, two cases of fracture of posterior elements of the axis, one case of C1-C2 dislocation with associated fractured C2, one case of occipitocervical dislocation, and one case of combined C1 and C2 fractures, and facet dislocation. Only one patient had neurological deficit that improved after treatment. Two surgical complications were seen: a liquoric fistula and one surgical wound infection (reaproached). In the group treated conservatively, odontoid fractures (eight cases) and fractures of the posterior elements of C2 (five cases) were more frequent. In two cases, in addition to the injuries of the craniocervical junction, there were fractures in other segments of the spine. None of the patients who underwent conservative treatment presented neurological deterioration. Conclusion: Although injuries of craniocervical junction are relatively rare, they usually involve fractures of the odontoid and the posterior elements of the axis. Our results recommend early surgical treatment for type II odontoid fractures and ligament injuries, the conservative treatment for other injuries. Objetivo: Avaliar a correlacao entre o tratamento, as caracteristicas das lesoes e o resultado clinico em pacientes com lesoes traumaticas na juncao craniocervical. Metodos: Estudo retrospectivo de pacientes maiores de 18 anos tratados de forma conservadora ou cirurgica, entre 2010 e 2013. Resultados: Foram analisados 37 pacientes, 73% eram do sexo masculino e a media de idade foi de 41,7 anos. Inicialmente 32% dos pacientes foram submetidos a tratamento cirurgico, e 68% foram submetidos a tratamento conservador. Sete pacientes (29%) do grupo conservador foram submetidos posteriormente a cirurgia. No grupo cirurgico, houve sete casos de fratura de odontoide tipo II, dois casos de fratura de elementos posteriores do axis, um caso de luxacao C1-C2, um caso de deslocamento occipito-cervical e um caso de fraturas de C1 e C2 e luxacao facetaria. Um paciente apresentava deficit neurologico, melhorando apos o tratamento. Houve duas complicacoes pos cirurgicas, uma fistula liquorica e uma infeccao de ferida operatoria (reabordada). No grupo conservador, predominaram as fraturas do odontoide (oito) e dos elementos posteriores de C2 (cinco). Em dois casos, havia tambem fraturas em outros segmentos da coluna. Nenhum dos pacientes deste grupo apresentou deterioracao neurologica. Conclusao: As lesoes da juncao craniocervical sao raras, sendo mais frequentes as fraturas do odontoide e dos elementos posteriores do axis. Nossos resultados recomendam o tratamento cirurgico precoce para os pacientes com fraturas do odontoide tipo II e lesoes ligamentares, e tratamento conservador para os demais pacientes. PMID- 28076602 TI - Incidence of Y-chromosome microdeletions in children whose fathers underwent vasectomy reversal or in vitro fertilization with epididymal sperm aspiration: a case-control study. AB - Objective: To evaluate the incidence of Y-chromosome microdeletions in individuals born from vasectomized fathers who underwent vasectomy reversal or in vitro fertilization with sperm retrieval by epididymal aspiration (percutaneous epididymal sperm aspiration). Methods: A case-control study comprising male children of couples in which the man had been previously vasectomized and chose vasectomy reversal (n=31) or in vitro fertilization with sperm retrieval by percutaneous epididymal sperm aspiration (n=30) to conceive new children, and a Control Group of male children of fertile men who had programmed vasectomies (n=60). Y-chromosome microdeletions research was performed by polymerase chain reaction on fathers and children, evaluating 20 regions of the chromosome. Results: The results showed no Y-chromosome microdeletions in any of the studied subjects. The incidence of Y-chromosome microdeletions in individuals born from vasectomized fathers who underwent vasectomy reversal or in vitro fertilization with spermatozoa recovered by percutaneous epididymal sperm aspiration did not differ between the groups, and there was no difference between control subjects born from natural pregnancies or population incidence in fertile men. Conclusion: We found no association considering microdeletions in the azoospermia factor region of the Y chromosome and assisted reproduction. We also found no correlation between these Y-chromosome microdeletions and vasectomies, which suggests that the assisted reproduction techniques do not increase the incidence of Y-chromosome microdeletions. Objetivo: Avaliar a incidencia de microdelecoes do cromossomo Y em individuos nascidos de pais vasectomizados submetidos a reversao de vasectomia ou fertilizacao in vitro com recuperacao de espermatozoides por aspiracao do epididimo (aspiracao percutanea de espermatozoides do epididimo). Metodos: Estudo caso-controle que compreende criancas do sexo masculino de casais em que o homem havia sido previamente vasectomizado e escolheu reversao da vasectomia (n=31) ou fertilizacao in vitro com recuperacao espermatica por aspiracao percutanea de espermatozoides do epididimo (n=30) para obtencao de novos filhos, e um Grupo Controle de criancas do sexo masculino de homens ferteis com vasectomia programada (n=60). A pesquisa de microdelecoes do cromossomo Y foi realizada por reacao em cadeia da polimerase nos pais e filhos, avaliando 20 regioes do cromossomo. Resultados: O resultado nao revelou microdelecoes do cromossomo Y em qualquer individuo estudado. A incidencia de microdelecoes do cromossomo Y em individuos nascidos de pais vasectomizados que sofreram reversao de vasectomia ou fertilizacao in vitro com espermatozoides recuperados pela aspiracao percutanea de espermatozoides do epididimo nao diferiu entre os grupos, e nao houve nenhuma diferenca entre individuos controle nascidos de gestacoes naturais ou incidencia populacional em homens ferteis. Conclusao: Nao foi encontrada nenhuma associacao considerando microdelecoes da regiao do fator de azoospermia no cromossomo Y e reproducao assistida. Nao houve correlacao entre microdelecoes do cromossomo Y e vasectomia, o que sugere que as tecnicas de reproducao assistida nao aumentam a incidencia de microdelecoes do cromossomo Y. PMID- 28076603 TI - Extracellular adenosine 5'-triphosphate concentrations changes in rat spinal cord associated with the activation of urinary bladder afferents. A microdialysis study. AB - Objective: To determine adenosine 5'-triphosphate levels in the interstice of spinal cord L6-S1 segment, under basal conditions or during mechanical and chemical activation of urinary bladder afferents. Methods: A microdialysis probe was transversally implanted in the dorsal half of spinal cord L6-S1 segment in female rats. Microdialysate was collected at 15 minutes intervals during 135 minutes, in anesthetized animals. Adenosine 5'-triphosphate concentrations were determined with a bioluminescent assay. In one group of animals (n=7) microdialysate samples were obtained with an empty bladder during a 10-minutes bladder distension to 20 or 40cmH2O with either saline, saline with acetic acid or saline with capsaicin. In another group of animals (n=6) bladder distention was performed and the microdialysis solution contained the ectonucleotidase inhibitor ARL 67156. Results: Basal extracellular adenosine triphosphate levels were 110.9+/-35.34fmol/15 minutes, (mean+/-SEM, n=13), and bladder distention was associated with a significant increase in adenosine 5'-triphosphate levels which was not observed after bladder distention with saline solution containing capsaicin (10uM). Microdialysis with solution containing ARL 67156 (1mM) was associated with significantly higher extracellular adenosine 5'-triphosphate levels and no further increase in adenosine 5'-triphosphate was observed during bladder distension. Conclusion: Adenosine 5'-triphosphate was present in the interstice of L6-S1 spinal cord segments, was degraded by ectonucleotidase, and its concentration increased following the activation of bladder mechanosensitive but not of the chemosensitive afferents fibers. Adenosine 5'-triphosphate may originate either from the central endings of bladder mechanosensitive primary afferent neurons, or most likely from intrinsic spinal neurons, or glial cells and its release appears to be modulated by capsaicin activated bladder primary afferent or by adenosine 5'-triphosphate itself. Objetivo: Determinar as concentracoes extracelulares do 5'-trifosfato de adenosina no intersticio dos segmentos medulares L6-S1, em condicoes basais ou durante a ativacao mecanica e quimica das fibras aferentes vesicais. Metodos: Um cateter de microdialise foi implantado no sentido transversal na parte dorsal da medula espinal, entre os segmentos L6-S1 de ratas. O microdialisado foi coletado em intervalos de 15 minutos, durante 135 minutos, com os animais anestesiados. A concentracao de 5' trifosfato de adenosina nas amostras foi determinada mediante ensaio de bioluminescencia. Em um grupo de animais (n=7), as amostras de microdialisado foram obtidas com a bexiga vazia, com distensao da bexiga para volume de 20 ou 40cmH2O, com solucao salina, solucao salina com acido acetico, ou solucao salina com capsaicina. Em outro grupo (n=6), foi realizada com a bexiga distendida, e a solucao para microdialise continha o inibidor de ectonucleotidase ARL 67156. Resultados: Os niveis extracelulares de trifosfato de adenosina no inicio do estudo foram 110,9+/-35,36fmol/15 minutos (media+/-EPM, n=13), e a distensao da bexiga causou um aumento nos niveis de 5'-trifosfato de adenosina, o que nao foi observado apos a distensao da bexiga com solucao salina contendo capsaicina (10uM). A microdialise com solucao contendo ARL 67156 (1mM) foi associada com significante aumento dos niveis de trifosfato de adenosina extracelular, e nenhum aumento do trifosfato de adenosina foi observado durante a distensao da bexiga. Conclusao: O 5'-trifosfato de adenosina esta presente no intersticio do segmento L6-S1 da medula espinal, e degradado por ectonucleotidases, e sua concentracao aumentou com a ativacao das fibras aferentes mecanossensiveis da bexiga, mas nao das quimiossensiveis. O 5'-trifosfato de adenosina pode ter sido liberado das terminacoes centrais dos neuronios aferentes primarios mecanossensiveis ou, mais provavelmente, de neuronios espinais intrinsecos, ou ainda de celulas gliais. Sua liberacao parece ser modulada por fibras aferentes primarias da bexiga ativadas pela capsaicina ou pelo proprio 5'-trifosfato de adenosina. PMID- 28076604 TI - Quality Program: what influences the opinion of nursing team. AB - Objective: To analyze the major impact variables in the opinion of nursing staff about the Quality Program of a teaching hospital. Methods: An exploratory descriptive study was performed with 72 nursing staff. Data were collected through self-administered questionnaire containing 24 statements about the Quality Program; and the degree of agreement of the participants was expressed in a Likert scale. The collected data were analyzed by factor analysis and Pearson's correlation coefficient. Results: The analysis grouped the statements in six factors. The Pearson's correlation coefficient defined a scale of influence of the variables within each factor, whose variable with the greatest impact in each factor is the priority issue for improving worker opinion about the Quality Program. The priority variables were to believe the Quality Program contributes to the hospital; to understand the program orientations; interest in hospital quality direction; and do not feel exhausted due to the program. Conclusion: These variables must be focused during the implementation and execution of Quality Program, as they have greater impact on improving opinion regarding the Quality Program and thus helping to increase compliance of the nursing staff to the program. Objetivo: Analisar as variaveis de maior impacto na opiniao dos trabalhadores de enfermagem sobre um Programa de Qualidade de um hospital de ensino. Metodos: Estudo exploratorio-descritivo, desenvolvido com 72 trabalhadores de enfermagem, com dados coletados por meio de questionario autoaplicavel, contendo 24 afirmacoes com escala Likert sobre o Programa de Qualidade. Para analise dos dados, foram utilizados analise fatorial e coeficiente de correlacao de Pearson. Resultados: A analise agrupou as afirmacoes em seis fatores. O coeficiente de correlacao de Pearson definiu uma escala de influencia das variaveis dentro de cada fator, cuja variavel de maior impacto em cada fator representa a questao prioritaria para a melhoria da opiniao do trabalhador sobre o Programa de Qualidade. As variaveis prioritarias foram: acreditar que o Programa de Qualidade contribui para o hospital; compreender as orientacoes do programa; interessar-se pelos rumos de qualidade do hospital; e nao se sentir desgastado em funcao do programa. Conclusao: Estas variaveis devem ser focadas durante a implantacao e a execucao de um Programa de Qualidade, pois possuem maior impacto na melhoria da opiniao em relacao a ele, contribuindo para aumentar a adesao dos trabalhadores de enfermagem. PMID- 28076605 TI - Isolated primary amyloidosis of the inferior rectus muscle mimicking Graves' orbitopathy. AB - The diagnosis of Graves' orbitopathy is usually straightforward. However, orbital diseases that mimick some clinical signs of Graves' orbitopathy may cause diagnostic confusion, particularly when associated to some form of thyroid dysfunction. This report describes the rare occurrence of localized inferior rectus muscle amyloidosis in a patient with autoimmune hypothyroidism, who was misdiagnosed as Graves' orbitopathy. A 48-year-old man complained of painless progressive proptosis on the left side and intermittent vertical diplopia for 6 months. The diagnosis of Graves' orbitopathy was entertained after magnetic resonance imaging revealing a markedly enlarged, tendon-sparing inferior rectus enlargement on the left side, and an autoimmune hypothyroidism was disclosed on systemic medical workup. After no clinical improvement with treatment, the patient was referred to an ophthalmologist and further investigation was performed. The presence of calcification in the inferior rectus muscle on computed tomography, associated with the clinical findings led to a diagnostic biopsy, which revealed amyloid deposition. This report emphasizes that a careful evaluation of atypical forms of Graves' orbitopathy may be crucial and should include, yet with rare occurrence, amyloidosis in its differential diagnosis. RESUMO O diagnostico de orbitopatia de Graves usualmente e facil de ser estabelecido. No entanto, doencas da orbita que simulam alguns sinais clinicos da orbitopatia de Graves podem levar a confusao diagnostica, particularmente quando associada a alguma forma de disfuncao tireoidiana. Relatamos a ocorrencia rara de amiloidose localizada no musculo reto inferior em paciente com hipotireoidismo autoimune, que recebeu inicialmente o diagnostico erroneo de orbitopatia de Graves. Paciente masculino, 48 anos, com queixa de proptose progressiva e indolor do lado esquerdo e diplopia vertical intermitente ha 6 meses. O diagnostico de orbitopatia de Graves foi considerado apos a realizacao de ressonancia magnetica, que revelou aumento importante do musculo reto inferior esquerdo, sem acometimento do tendao, e uma propedeutica sistemica detectou hipotireoidismo autoimune. Como nao houve melhora com o tratamento clinico, o paciente foi encaminhado a um oftalmologista, que realizou nova investigacao. A presenca de calcificacao no musculo reto inferior na tomografia computadorizada, associada aos achados clinicos, levou a uma biopsia da lesao, que demonstrou a deposicao de material amiloide. Este relato enfatiza como uma avaliacao minuciosa das formas atipicas de orbitopatia de Graves e essencial e deve incluir a ocorrencia, embora rara, de amiloidose no diagnostico diferencial da orbitopatia de Graves. PMID- 28076606 TI - Giant gastric lipossarcoma: case report and review of the literature. AB - Liposarcoma is one of the most common soft tissue sarcomas in adults, occurring in 15 to 20% of all patients with sarcoma. Primary liposarcoma of the stomach is rare. We report a case of patient with giant gastric liposarcoma who underwent surgery after a gastrointestinal bleeding. Preoperative hystopathological diagnosis was not established, even after three biopsy attempts. We discuss differential diagnosis, genetic causes, diagnosis strategies and treatment. RESUMO O lipossarcoma e um tipo comum de sarcomas em adultos, com incidencia entre 15 e 20% entre os sarcomas. No entanto, o acometimento do estomago e raro. Relatamos um caso de um lipossarcoma primario gastrico gigante com apresentacao clinica de hemorragia digestiva. Foi submetido a tratamento cirurgico sem diagnostico definitivo, apesar de tres biopsias realizadas. Revisamos diagnosticos diferenciais, influencia genetica e estrategias diagnosticas e terapeuticas. PMID- 28076608 TI - Dental chromatic alteration caused by neonatal cholestasis. PMID- 28076607 TI - Vascular access: the impact of ultrasonography. AB - Vascular punctures are often necessary in critically ill patients. They are secure, but not free of complications. Ultrasonography enhances safety of the procedure by decreasing puncture attempts, complications and costs. This study reviews important publications and the puncture technique using ultrasound, bringing part of the experience of the intensive care unit of the Hospital Israelita Albert Einstein, Sao Paulo (SP), Brazil, and discussing issues that should be considered in future studies. RESUMO Puncoes vasculares sao muitas vezes necessarias em pacientes gravemente enfermos. Sao seguras, mas nao isentas de complicacoes. A ultrassonografia associada a tecnica de puncao gera diminuicao do numero de tentativas, de complicacoes e de custos. O presente artigo revisou importantes publicacoes sobre o tema, bem como tecnicas de puncoes, trazendo parte da experiencia do centro de terapia intensiva de adultos do Hospital Israelita Albert Einstein, em Sao Paulo (SP) e discutindo topicos que devem ser melhor explorados em estudos futuros. PMID- 28076609 TI - Rotation of the second cervical vertebra in pediatric patient. PMID- 28076610 TI - Intraoperative near-infrared fluorescent imaging during robotic operations. AB - The intraoperative identification of certain anatomical structures because they are small or visually occult may be challenging. The development of minimally invasive surgery brought additional difficulties to identify these structures due to the lack of complete tactile sensitivity. A number of different forms of intraoperative mapping have been tried. Recently, the near-infrared fluorescence imaging technology with indocyanine green has been added to robotic platforms. In addition, this technology has been tested in several types of operations, and has advantages such as safety, low cost and good results. Disadvantages are linked to contrast distribution in certain clinical scenarios. The intraoperative near infrared fluorescent imaging is new and promising addition to robotic surgery. Several reports show the utility of this technology in several different procedures. The ideal dose, time and site for dye injection are not well defined. No high quality evidence-based comparative studies and long-term follow-up outcomes have been published so far. Initial results, however, are good and safe. RESUMO A identificacao intraoperatoria de certas estruturas anatomicas, por seu tamanho ou por elas serem ocultas a visao, pode ser desafiadora. O desenvolvimento da cirurgia minimamente invasiva trouxe dificuldades adicionais, pela falta da sensibilidade tatil completa. Diversas formas de deteccao intraoperatoria destas estruturas tem sido tentadas. Recentemente, a tecnologia de fluorescencia infravermelha com verde de indocianina foi associada as plataformas roboticas. Alem disso, essa tecnologia tem sido testada em uma variedade de cirurgias, e suas vantagens parecem estar ligadas a baixo custo, seguranca e bons resultados. As desvantagens estao associadas a ma distribuicao do contraste em determinados cenarios. A imagem intraoperatoria por fluorescencia infravermelha e uma nova e promissora adicao a cirurgia robotica. Diversas series mostram a utilidade da tecnologia em diferentes procedimentos. Dose ideal, local e tempo da injecao do corante ainda nao estao bem estabelecidos. Estudos comparativos de alta qualidade epidemiologica baseados em evidencia ainda nao estao disponiveis. No entanto, os resultados iniciais sao bons e seguros. PMID- 28076612 TI - Einstein Sao Paulo: its metrics and some related issues. PMID- 28076611 TI - Sarcopenia and chemotherapy-mediated toxicity. AB - This narrative review focuses on the role of sarcopenia and chemotherapy-induced toxicity in cancer patients. Consistent evidence shows that sarcopenia in cancer patients leads to decreased overall survival by influencing treatment discontinuation and dose reduction. Therefore, sarcopenia should be considered a robust prognostic factor of negative outcome as well as a determinant of increased healthcare costs. RESUMO Esta revisao narrativa descreve o papel da sarcopenia e a toxicidade mediada pela quimioterapia em pacientes com cancer. Diversas evidencias consistentes mostram que a sarcopenia em pacientes com cancer induz a menor sobrevida global, por influenciar na interrupcao do tratamento e na reducao da dose. Portanto, a sarcopenia pode ser considerada um importante fator de prognostico de desfecho negativo, alem de um determinante de maiores custos em saude. PMID- 28076613 TI - The role of dietary fatty acid intake in inflammatory gene expression: a critical review. AB - CONTEXT AND OBJECTIVE:: Diet is an important modifiable factor involved in obesity-induced inflammation. We reviewed clinical trials that assessed the effect of consumption of different fatty acids on the expression of inflammation related genes, such as cytokines, adipokines, chemokines and transcription factors. DESIGN AND SETTING:: Narrative review study conducted at a research center. METHODS:: This was a review on the effect of fat intake on inflammatory gene expression in humans. RESULTS:: Consumption of saturated fatty acids (SFAs) was related to postprandial upregulation of genes associated with pro inflammatory pathways in peripheral blood mononuclear cells (PBMCs), in comparison with monounsaturated fatty acid (MUFA) or polyunsaturated fatty acid (PUFA) intake. In addition, acute intake of a high-SFA meal also induced a postprandial pro-inflammatory response for several inflammatory genes in subcutaneous adipose tissue. Both high-MUFA and high-PUFA diets showed anti inflammatory profiles, or at least a less pronounced pro-inflammatory response than did SFA consumption. However, the results concerning the best substitute for SFAs were divergent because of the large variability in doses of MUFA (20% to 72% of energy intake) and n3 PUFA (0.4 g to 23.7% of energy intake) used in interventions. CONCLUSIONS:: The lipid profile of the diet can modulate the genes relating to postprandial and long-term inflammation in PBMCs and adipose tissue. Identifying the optimal fat profile for inflammatory control may be a promising approach for treating chronic diseases such as obesity. PMID- 28076614 TI - Association between asthma and female sex hormones. AB - CONTEXT AND OBJECTIVE:: The relationship between sex hormones and asthma has been evaluated in several studies. The aim of this review article was to investigate the association between asthma and female sex hormones, under different conditions (premenstrual asthma, use of oral contraceptives, menopause, hormone replacement therapy and pregnancy). DESIGN AND SETTING:: Narrative review of the medical literature, Universidade Federal do Tocantins (UFT) and Universidade Federal de Sao Paulo (Unifesp). METHODS:: We searched the CAPES journal portal, a Brazilian platform that provides access to articles in the MEDLINE, PubMed, SciELO, and LILACS databases. The following keywords were used based on Medical Subject Headings: asthma, sex hormones, women and use of oral contraceptives. RESULTS:: The associations between sex hormones and asthma remain obscure. In adults, asthma is more common in women than in men. In addition, mortality due to asthma is significantly higher among females. The immune system is influenced by sex hormones: either because progesterone stimulates progesterone-induced blocking factor and Th2 cytokines or because contraceptives derived from progesterone and estrogen stimulate the transcription factor GATA-3. CONCLUSIONS:: The associations between asthma and female sex hormones remain obscure. We speculate that estrogen fluctuations are responsible for asthma exacerbations that occur in women. Because of the anti-inflammatory action of estrogen, it decreases TNF-alpha production, interferon-gamma expression and NK cell activity. We suggest that further studies that highlight the underlying physiopathological mechanisms contributing towards these interactions should be conducted. PMID- 28076615 TI - Lichen amyloidosis associated with rheumatoid arthritis: unique presentation in a Bulgarian patient. PMID- 28076616 TI - New Year - New Challenges - New Achievements. PMID- 28076617 TI - Radiation Exposure in Endovascular Infra-Renal Aortic Aneurysm Repair and Factors that Influence It. AB - Objective: The endovascular repair of aortic abdominal aneurysms exposes the patients and surgical team to ionizing radiation with risk of direct tissue damage and induction of gene mutation. This study aims to describe our standard of radiation exposure in endovascular aortic aneurysm repair and the factors that influence it. Methods: Retrospective analysis of a prospective database of patients with abdominal infra-renal aortic aneurysms submitted to endovascular repair. This study evaluated the radiation doses (dose area product (DAP)), fluoroscopy durations and their relationships to the patients, aneurysms, and stent-graft characteristics. Results: This study included 127 patients with a mean age of 73 years. The mean DAP was 4.8 mGy.m(2), and the fluoroscopy time was 21.8 minutes. Aortic bilateral iliac aneurysms, higher body mass index, aneurysms with diameters larger than 60 mm, necks with diameters larger than 28 mm, common iliac arteries with diameters larger than 20 mm, and neck angulations superior to 50 degrees were associated with an increased radiation dose. The number of anatomic risk factors present was associated with increased radiation exposure and fluoroscopy time, regardless of the anatomical risk factors. Conclusion: The radiation exposure during endovascular aortic aneurysm repair is significant (mean DAP 4.8 mGy.m(2)) with potential hazards to the surgical team and the patients. The anatomical characteristics of the aneurysm, patient characteristics, and the procedure's technical difficulty were all related to increased radiation exposure during endovascular aortic aneurysm repair procedures. Approximately 40% of radiation exposure can be explained by body mass index, neck angulation, aneurysm diameter, neck diameter, and aneurysm type. PMID- 28076618 TI - Aortic Valve Replacement: Treatment by Sternotomy versus Minimally Invasive Approach. AB - Objective: To compare the results of aortic valve replacement with access by sternotomy or minimally invasive approach. Methods: Retrospective analysis of medical records of 37 patients undergoing aortic valve replacement by sternotomy or minimally invasive approach, with emphasis on the comparison of time of cardiopulmonary bypass and aortic clamping, volume of surgical bleeding, time of mechanical ventilation, need for blood transfusion, incidence of atrial fibrillation, length of stay in intensive care unit, time of hospital discharge, short-term mortality and presence of surgical wound infection. Results: Sternotomy was used in 22 patients and minimally invasive surgery in 15 patients. The minimally invasive approach had significantly higher time values of cardiopulmonary bypass (114.3+/-23.9 versus 86.7+/-19.8min.; P=0.003), aortic clamping (87.4+/-19.2 versus 61.4+/-12.9 min.; P<0.001) and mechanical ventilation (287.3+/-138.9 versus 153.9+/-118.6 min.; P=0.003). No difference was found in outcomes surgical bleeding volume, need for blood transfusion, incidence of atrial fibrillation, length of stay in intensive care unit and time of hospital discharge. No cases of short-term mortality or surgical wound infection were documented. Conclusion: The less invasive approach presented with longer times of cardiopulmonary bypass, aortic clamping and mechanical ventilation than sternotomy, however without prejudice to the length of stay in intensive care unit, time of hospital discharge and morbidity. PMID- 28076619 TI - Oxidative Stress in Human Aorta of Patients with Advanced Aortoiliac Occlusive Disease. AB - Introduction: Oxidative stress seems to be a role in the atherosclerosis process, but research in human beings is scarce. Objective: To evaluate the role of oxidative stress on human aortas of patients submitted to surgical treatment for advanced aortoiliac occlusive disease. Methods: Twenty-six patients were divided into three groups: control group (n=10) formed by cadaveric organ donors; severe aortoiliac stenosis group (patients with severe aortoiliac stenosis; n=9); and total aortoiliac occlusion group (patients with chronic total aortoiliac occlusion; n=7). We evaluated the reactive oxygen species concentration, nicotinamide adenine dinucleotide phosphate-oxidase, superoxide dismutase and catalase activities as well as nitrite levels in samples of aortas harvested during aortofemoral bypass for treatment of advanced aortoiliac occlusive disease. Results: We observed a higher level of reactive oxygen species in total aortoiliac occlusion group (48.3+/-9.56 pmol/mg protein) when compared to severe aortoiliac stenosis (33.5+/-7.4 pmol/mg protein) and control (4.91+/-0.8 pmol/mg protein) groups (P<0.05). Nicotinamide adenine dinucleotide phosphate oxidase activity was also higher in total aortoiliac occlusion group when compared to the control group (3.81+/-1.7 versus 1.05+/-0.31 umol/min.mg protein; P<0.05). Furthermore, superoxide dismutase and catalase activities were significantly higher in the severe aortoiliac stenosis and total aortoiliac occlusion groups when compared to the control cases (P<0.05). Nitrite concentration was smaller in the severe aortoiliac stenosis group in comparing to the other groups. Conclusion: Our results indicated an increase of reactive oxygen species levels and nicotinamide adenine dinucleotide phosphate-oxidase activity in human aortic samples of patients with advanced aortoiliac occlusive disease. The increase of antioxidant enzymes activities may be due to a compensative phenomenon to reactive oxygen species production mediated by nicotinamide adenine dinucleotide phosphate oxidase. This preliminary study offers us a more comprehensive knowledge about the role of oxidative stress in advanced aortoiliac occlusive disease in human beings. PMID- 28076621 TI - Experimental Model for Sutureless Proximal Anastomosis by the Viabahn Open Revascularization TEChnique (VORTEC). AB - Introduction: In the treatment of complex aneurysms, debranching is an extra anatomical revascularization of visceral arteries followed by endograft coverage of the thoracoabdominal aorta. It eliminates the need for a thoracotomy and aortic clamping, but requires the performance of several technically demanding visceral anastomosis. In 2008, Lachat described visceral revascularization with the use of a sutureless distal anastomosis, performed by the telescoping of an endograft in the visceral branch, named VORTEC (Viabahn Open Revascularization TEChnique). Objective: An experimental model was created to test the feasibility and short term results of performing a telescoped proximal anastomosis to the abdominal aorta. Methods: Swine model. The abdominal aorta was dissected and ligated between the renal arteries and the iliac vessels. Three centimeters bellow the renal arteries a Viabahn endograft was telescoped for 2 cm into the proximal aorta. The other extremity was conventionally anastomosed to the distal aorta. Patency, sealing and tensile strength of the anastomosis were tested. Results: Time for performing the telescoped anastomosis was shorter (5.4+/-2.8 min versus 10.3+/-3.4 min, P<0.05). All grafts were patent and both types of anastomosis presented no bleeding. Immediate tensile strength showed a higher strength of the conventional suture (22.7 x 14.3 N, P<0.09). After 30 days there was no pseudo-aneurysms and the strength of the conventional and VORTEC anastomosis were similar (37.3 x 40.8 N, respectively, P=0.17). Conclusion: Telescoped proximal anastomosis by the technique of VORTEC is feasible. After 30 days the tensile strength of the both anastomosis were similar. PMID- 28076620 TI - Intraperitoneal Administration of Silymarin Protects End Organs from Multivisceral Ischemia/Reperfusion Injury in a Rat Model. AB - Objective: To determine whether intraperitoneal silymarin administration has favorable effects on the heart, lungs, kidney, and liver and on oxidative stress in a rat model of supraceliac aorta ischemia/reperfusion injury. Methods: Thirty male Wistar albino rats were divided equally into three groups: sham, control, and silymarin. The control and silymarin groups underwent supraceliac aortic occlusion for 45 min, followed by a 60 min period of reperfusion under terminal anesthesia. In the silymarin group, silymarin was administered intraperitoneally during ischemia at a dose of 200 mg/kg. Rats were euthanized using terminal anesthesia, and blood was collected from the inferior vena cava for total antioxidant capacity, total oxidative status, and oxidative stress index measurement. Lungs, heart, liver and kidney tissues were histologically examined. Results: Ischemia/reperfusion injury significantly increased histopathological damage as well as the total oxidative status and oxidative stress index levels in the blood samples. The silymarin group incurred significantly lesser damage to the lungs, liver and kidneys than the control group, while no differences were observed in the myocardium. Furthermore, the silymarin group had significantly lower total oxidative status and oxidative stress index levels than the control group. Conclusion: Intraperitoneal administration of silymarin reduces oxidative stress and protects the liver, kidney, and lungs from acute supraceliac abdominal aorta ischemia/reperfusion injury in the rat model. PMID- 28076622 TI - Impact of Surgeon Experience During Carotid Endarterectomy Operation and Effects on Perioperative Outcomes. AB - Objective: We evaluated the effect of surgeon experience on complication and mortality rates of carotid endarterectomy operation. Methods: Fifty-nine consecutive patients who underwent carotid endarterectomy between January 2013 and February 2016 were divided into two groups. Patients who had been operated by surgeons performing carotid endarterectomy for more than 10 years were allocated to group 1 (experienced surgeons; n=34). Group 2 (younger surgeons; n=25) consisted of patients operated by surgeons independently performing carotid endarterectomy for less than 2 years. Both groups were compared in respect of operative results and postoperative complications. Results: No intergroup difference was found for laterality of the lesion or concomitant coronary artery disease. In group 1, signs of local nerve damage (n=2; 5.9%) were detected, whereas in group 2 no evidence of local nerve damage was observed. Surgeons in group 1 used local and general anesthesia in 3 (8.8%) and 31 (91.2%) patients, respectively, while surgeons in group 2 preferred to use local and general anesthesia in 1 (4%) and 24 (96%) patients, respectively. Postoperative stroke was observed in group 1 (n=2; 5.9%) and group 2 (n=2; 5.8%). Conclusion: Younger surgeons perform carotid endarterectomy with similar techniques and have similar results compared to experienced surgeons. Younger surgeons rarely prefer using shunt during carotid endarterectomy. The experience and the skills gained by these surgeons during their training, under the supervision of experienced surgeons, will enable them to perform successful carotid endarterectomy operations independently after completion of their training period. PMID- 28076623 TI - Low Cost Simulator for Heart Surgery Training. AB - Objective: Introduce the low-cost and easy to purchase simulator without biological material so that any institution may promote extensive cardiovascular surgery training both in a hospital setting and at home without large budgets. Methods: A transparent plastic box is placed in a wooden frame, which is held by the edges using elastic bands, with the bottom turned upwards, where an oval opening is made, "simulating" a thoracotomy. For basic exercises in the aorta, the model presented by our service in the 2015 Brazilian Congress of Cardiovascular Surgery: a silicone ice tray, where one can train to make aortic purse-string suture, aortotomy, aortorrhaphy and proximal and distal anastomoses. Simulators for the training of valve replacement and valvoplasty, atrial septal defect repair and aortic diseases were added. These simulators are based on sewage pipes obtained in construction material stores and the silicone trays and ethyl vinyl acetate tissue were obtained in utility stores, all of them at a very low cost. Results: The models were manufactured using inert materials easily found in regular stores and do not present contamination risk. They may be used in any environment and maybe stored without any difficulties. This training enabled young surgeons to familiarize and train different surgical techniques, including procedures for aortic diseases. In a subjective assessment, these surgeons reported that the training period led to improved surgical techniques in the surgical field. Conclusion: The model described in this protocol is effective and low-cost when compared to existing simulators, enabling a large array of cardiovascular surgery training. PMID- 28076625 TI - Endoscopic or No-Touch Vein Harvesting for CABG: What is Best for the Patient? PMID- 28076624 TI - Quadricuspid Aortic Valve: A Comprehensive Review. AB - Quadricuspid aortic valve (QAV) is a rare congenital heart disease. The functional status of QAV is predominantly a pure aortic regurgitation. Clinical manifestations of patients with a QAV depend on the functional status of the QAV and the associated disorders. Significant valvular regurgitation and (or) stenosis is often present with subsequent operation performed at the fifth to sixth decade of life. The functional status of QAV is predominantly regurgitant; whereas pure stenotic QAV can be as few as in only 0.7% of the patients. QAV is usually an isolated anomaly, but other congenital heart defects can be present in 18-32% of the patients. About one-fifth of them require a surgical operation. Tricuspidalization is a preferred technique for QAV repair. As not all the patients with a QAV necessarily warrant a surgical operation, decision-making in patient selection and surgical procedure of choice are crucial. Antibiotic prophylaxis against infective endocarditis is necessary in the QAV patients with unequal-sized cusps. PMID- 28076626 TI - Development of a Multifunctional Needle for Percutaneous Heart Biopsy and Cell Therapy. A Technical Note. AB - Validation of transendocardial injection as a method for delivering therapeutic agents to the diseased heart is increasing. Puncture heart biopsies should re emerge as a possible alternative method to allow access to the myocardium and implantable biomaterial for cell therapy. Therefore, this work aims to present a percutaneous puncture device for biopsy and intramyocardial biomaterial injection, standardize the technique and attest to the safety of the method. The adaptation consists of creating myocardial microlesions that allow for better fixation of stem cells. The objective of this technical note covers only the development of the needle and the histological quality of the biopsies. It has not been used in humans yet. PMID- 28076627 TI - PetCO2, VCO2 and CorPP Values in the Successful Prediction of the Return of Spontaneous Circulation: An Experimental Study on Unassisted Induced Cardiopulmonary Arrest. PMID- 28076628 TI - Knowing for whom the bell tolls: acting locally and thinking globally. Brazil, Latin America and the Global Burden of Diseases, 2015. PMID- 28076629 TI - Acoustic radiation force impulse (ARFI) elastography compared with biopsy for evaluating hepatic fibrosis after liver transplantation: a cross-sectional diagnostic study. AB - CONTEXT AND OBJECTIVE:: Biopsies are used after liver transplantation to evaluate fibrosis. This study aimed to evaluate the elasticity of transplanted livers by means of a non-invasive examination, acoustic radiation force imaging (ARFI) elastography, correlating the results with the histological analysis. DESIGN AND SETTING:: Cross-sectional study in a public university hospital. METHODS:: All patients consecutively operated between 2002 and 2010 with an indication for biopsy were evaluated by means of elastography. The radiologist evaluating ARFI and the pathologist doing anatomopathological examinations were blinded to each other's evaluations. RESULTS:: During the study period, 33 patients were included. The indication for transplantation was cirrhosis due to hepatitis C in 21 cases (63%). Liver biopsies showed absence of fibrosis (F0) in 10 patients, F1 in 11, F2 in 8 and F3 in 4. There were no cases of F4 (cirrhosis). The difference in ARFI values (degree of fibrosis) was 0.26 (95% confidence interval, CI: 0.07 0.52) between the groups F0-F1 and F2-F4 (P = 0.04). An area under the curve of 0.74 (CI: 0.55-0.94) and a cutoff of 1.29 m/s between the groups resulted in the best relationship between sensitivity and specificity. Sensitivity (0.66; CI: 0.50-0.83) was lower than specificity (0.85; CI: 0.72-0.97). There was no significant difference in ARFI between patients with hepatitis C and those with other diseases. CONCLUSIONS:: The values obtained from elastography were not affected by inflammatory reaction or anatomical alterations. A cutoff point of 1.29 m/s separating patients with or without significant fibrosis was identified. PMID- 28076630 TI - Cutoffs and cardiovascular risk factors associated with neck circumference among community-dwelling elderly adults: a cross-sectional study. AB - CONTEXT AND OBJECTIVE:: In elderly people, measurement of several anthropometric parameters may present complications. Although neck circumference measurements seem to avoid these issues, the cutoffs and cardiovascular risk factors associated with this parameter among elderly people remain unknown. This study was developed to identify the cutoff values and cardiovascular risk factors associated with neck circumference measurements among elderly people. DESIGN AND SETTING:: Cross-sectional study conducted in two community centers for elderly people. METHODS:: 435 elderly adults (371 women and 64 men) were recruited. These volunteers underwent morphological evaluations (body mass index and waist, hip, and neck circumferences) and hemodynamic evaluations (blood pressure values and heart rate). Receiver operating characteristic curve analyses were used to determine the predictive validity of cutoff values for neck circumference, for identifying overweight/obesity. Multivariate analysis was used to identify cardiovascular risk factors associated with large neck circumference. RESULTS:: Cutoff values for neck circumference (men = 40.5 cm and women = 35.7 cm), for detection of obese older adults according to body mass index, were identified. After a second analysis, large neck circumference was shown to be associated with elevated body mass index in men; and elevated body mass index, blood pressure values, prevalence of type 2 diabetes and hypertension in women. CONCLUSION:: The data indicate that neck circumference can be used as a screening tool to identify overweight/obesity in older people. Moreover, large neck circumference values may be associated with cardiovascular risk factors. PMID- 28076631 TI - Targeting stroke risk and improving outcomes in patients with atrial fibrillation in Latin America. AB - CONTEXT AND OBJECTIVE:: To examine stroke risk factors, including atrial fibrillation, management and prevention, and stroke outcomes across Latin America. DESIGN AND SETTING:: Narrative review conducted at Piedmont Heart Institute, United States. METHODS:: The PubMed, Embase and Cochrane databases were searched for stroke AND "Latin America" AND epidemiology (between January 2009 and March 2015). Further studies in the SciELO, World Health Organization and Pan-American Health Organization databases were used to address specific points. RESULTS:: Countries categorized as low or middle-income nations by the World Bank, which includes most of Latin America, account for two-thirds of all strokes. Globally, fewer than half of patients (median treatment level: 43.9%) with atrial fibrillation receive adequate anticoagulation to reduce stroke risk, which correlates with data from Latin America, where 46% of outpatients did not receive guideline-compliant anticoagulation, ranging from 41.8% in Brazil to 54.8% in Colombia. CONCLUSIONS:: Atrial fibrillation-related stroke carries a heavy burden. Non-vitamin K antagonist oral anti-coagulants provide options for reducing the risk of atrial fibrillation-related stroke. However, cost effectiveness comparisons with warfarin are warranted before observational health economics study results can be applied clinically. Initiatives to remedy inequalities and improve access to care across Latin America should accompany risk factor modification and guideline-based prevention. PMID- 28076632 TI - "EMMA Study: a Brazilian community-based cohort study of stroke mortality and morbidity". AB - CONTEXT AND OBJECTIVE:: Stroke has a high burden of disability and mortality. The aim here was to evaluate epidemiology, risk factors and prognosis for stroke in the EMMA Study (Study of Stroke Mortality and Morbidity). DESIGN AND SETTINGS:: Prospective community-based cohort carried out in Hospital Universitario, University of Sao Paulo, 2006-2014. METHODS:: Stroke data based on fatal and non fatal events were assessed, including sociodemographic data, mortality and predictors, which were evaluated by means of logistic regression and survival analyses. RESULTS:: Stroke subtype was better defined in the hospital setting than in the local community. In the hospital phase, around 70% were first events and the ischemic subtype. Among cerebrovascular risk factors, the frequency of alcohol intake was higher in hemorrhagic stroke (HS) than in ischemic stroke (IS) cases (35.4% versus 12.3%, P < 0.001). Low education was associated with higher risk of death, particularly after six months among IS cases (odds ratio, OR, 4.31; 95% confidence interval, CI, 1.34-13.91). The risk of death due to hemorrhagic stroke was greater than for ischemic stroke and reached its maximum 10 days after the event (OR: 3.31; 95% CI: 1.55-7.05). Four-year survival analysis on 665 cases of first stroke (82.6% ischemic and 17.4% hemorrhagic) showed an overall survival rate of 48%. At four years, the highest risks of death were in relation to ischemic stroke and illiteracy (hazard ratio, HR: 1.83; 95% CI: 1.26-2.68) and diabetes (HR: 1.45; 95% CI: 1.07-1.97). Major depression presented worse one-year survival (HR: 4.60; 95% CI: 1.36-15.55). CONCLUSION:: Over the long term, the EMMA database will provide additional information for planning resources destined for the public healthcare system. PMID- 28076633 TI - Statins for aortic valve stenosis. AB - BACKGROUND:: Aortic valve stenosis is the most common type of valvular heart disease in the USA and Europe. Aortic valve stenosis is considered similar to atherosclerotic disease. Some studies have evaluated statins for aortic valve stenosis. OBJECTIVES:: To evaluate the effectiveness and safety of statins in aortic valve stenosis. METHODS:: Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS - IBECS, Web of Science and CINAHL Plus. These databases were searched from their inception to 24 November 2015. We also searched trials in registers for ongoing trials. We used no language restrictions.Selection criteria: Randomized controlled clinical trials (RCTs) comparing statins alone or in association with other systemic drugs to reduce cholesterol levels versus placebo or usual care. Data collection and analysis: Primary outcomes were severity of aortic valve stenosis (evaluated by echocardiographic criteria: mean pressure gradient, valve area and aortic jet velocity), freedom from valve replacement and death from cardiovascular cause. Secondary outcomes were hospitalization for any reason, overall mortality, adverse events and patient quality of life.Two review authors independently selected trials for inclusion, extracted data and assessed the risk of bias. The GRADE methodology was employed to assess the quality of result findings and the GRADE profiler (GRADEPRO) was used to import data from Review Manager 5.3 to create a 'Summary of findings' table. MAIN RESULTS:: We included four RCTs with 2360 participants comparing statins (1185 participants) with placebo (1175 participants). We found low-quality evidence for our primary outcome of severity of aortic valve stenosis, evaluated by mean pressure gradient (mean difference (MD) -0.54, 95% confidence interval (CI) -1.88 to 0.80; participants = 1935; studies = 2), valve area (MD -0.07, 95% CI -0.28 to 0.14; participants = 127; studies = 2), and aortic jet velocity (MD -0.06, 95% CI -0.26 to 0.14; participants = 155; study = 1). Moderate-quality evidence showed no effect on freedom from valve replacement with statins (risk ratio (RR) 0.93, 95% CI 0.81 to 1.06; participants = 2360; studies = 4), and no effect on muscle pain as an adverse event (RR 0.91, 95% CI 0.75 to 1.09; participants = 2204; studies = 3; moderate-quality evidence). Low- and very low-quality evidence showed uncertainty around the effect of statins on death from cardiovascular cause (RR 0.80, 95% CI 0.56 to 1.15; participants = 2297; studies = 3; low-quality evidence) and hospitalization for any reason (RR 0.84, 95% CI 0.39 to 1.84; participants = 155; study = 1; very low-quality evidence). None of the four included studies reported on overall mortality and patient quality of life. AUTHORS CONCLUSIONS:: Result findings showed uncertainty surrounding the effect of statins for aortic valve stenosis. The quality of evidence from the reported outcomes ranged from moderate to very low. These results give support to European and USA guidelines (2012 and 2014, respectively) that so far there is no clinical treatment option for aortic valve stenosis. PMID- 28076634 TI - Immediate versus delayed treatment for recently symptomatic carotid artery stenosis. AB - BACKGROUND:: The timing of surgery for recently symptomatic carotid artery stenosis remains controversial. Early cerebral revascularization may prevent a disabling or fatal ischemic recurrence, but it may also increase the risk of hemorrhagic transformation, or of dislodging a thrombus. This review examined the randomized controlled evidence that addressed whether the increased risk of recurrent events outweighed the increased benefit of an earlier intervention. OBJECTIVES:: To assess the risks and benefits of performing very early cerebral revascularization (within two days) compared with delayed treatment (after two days) for people with recently symptomatic carotid artery stenosis. METHODS:: Search methods: We searched the Cochrane Stroke Group Trials Register in January 2016, the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2016, issue 1), MEDLINE (1948 to 26 January 2016), EMBASE (1974 to 26 January 2016), LILACS (1982 to 26 January 2016), and trial registers (from inception to 26 January 2016). We also handsearched conference proceedings and journals, and searched reference lists. There were no language restrictions. We contacted colleagues and pharmaceutical companies to identify further studies and unpublished trials Selection criteria: All completed, truly randomized trials (RCT) that compared very early cerebral revascularization (within two days) with delayed treatment (after two days) for people with recently symptomatic carotid artery stenosis.Data collection and analysis: We independently selected trials for inclusion according to the above criteria, assessed risk of bias for each trial, and performed data extraction. We utilized an intention-to-treat analysis strategy. MAIN RESULTS:: We identified one RCT that involved 40 participants, and addressed the timing of surgery for people with recently symptomatic carotid artery stenosis. It compared very early surgery with surgery performed after 14 days of the last symptomatic event. The overall quality of the evidence was very low, due to the small number of participants from only one trial, and missing outcome data. We found no statistically significant difference between the effects of very early or delayed surgery in reducing the combined risk of stroke and death within 30 days of surgery (risk ratio (RR) 3.32; confidence interval (CI) 0.38 to 29.23; very low-quality evidence), or the combined risk of perioperative death and stroke (RR 0.47; CI 0.14 to 1.58; very low-quality evidence). To date, no results are available to confirm the optimal timing for surgery. AUTHORS CONCLUSIONS:: There is currently no high-quality evidence available to support either very early or delayed cerebral revascularization after a recent ischemic stroke. Hence, further randomized trials to identify which patients should undergo very urgent revascularization are needed. Future studies should stratify participants by age group, sex, grade of ischemia, and degree of stenosis. Currently, there is one ongoing RCT that is examining the timing of cerebral revascularization. PMID- 28076635 TI - Prevalence of vitamin B12 deficiency in type 2 diabetic patients using metformin: a cross-sectional study. AB - CONTEXT AND OBJECTIVE:: The prevalence of vitamin B12 deficiency varies from 5.8% to 30% among patients undergoing long-term treatment with metformin. Because of the paucity of data on Brazilian patients, this study aimed to determine the frequency of B12 deficiency and related factors among Brazilian patients with type 2 diabetes mellitus (T2DM) using metformin. DESIGN AND SETTING:: Cross sectional study at a public university hospital. METHODS:: Patients with T2DM and a control group of non-diabetics were included. Serum B12 levels were measured and biochemical B12 deficiency was defined as serum levels < 180 pg/ml. Associations between B12 deficiency and age, duration of T2DM, duration of use and dosage of metformin, and use of proton pump inhibitors (PPIs) or histamine H2 antagonists were determined. RESULTS:: 231 T2DM patients using metformin (T2DM met) and 231 controls were included. No difference in the frequency of PPI or H2 antagonist use was seen between the groups. B12 deficiency was more frequent in the T2DM-met group (22.5% versus 7.4%) and this difference persisted after excluding PPI/H2-antagonist users (17.9% versus 5.6%). The factors that interfered with serum B12 levels were PPI/H2-antagonist use and duration of metformin use >= 10 years. Use of PPI/H2-antagonists was associated with B12 deficiency, with an odds ratio of 2.60 (95% confidence interval, 1.34-5.04). CONCLUSIONS:: Among T2DM patients, treatment with metformin and concomitant use of PPI/H2-antagonists are associated with a higher chance of developing B12 deficiency than among non-diabetics. PMID- 28076636 TI - Body Dysmorphic Symptoms Scale for patients seeking esthetic surgery: cross cultural validation study. AB - CONTEXT AND OBJECTIVE:: Rhinoplasty is one of the most sought-after esthetic operations among individuals with body dysmorphic disorder. The aim of this study was to cross-culturally adapt and validate the Body Dysmorphic Symptoms Scale. DESIGN AND SETTING:: Cross-cultural validation study conducted in a plastic surgery outpatient clinic of a public university hospital. METHODS:: Between February 2014 and March 2015, 80 consecutive patients of both sexes seeking rhinoplasty were selected. Thirty of them participated in the phase of cultural adaptation of the instrument. Reproducibility was tested on 20 patients and construct validity was assessed on 50 patients, with correlation against the Yale Brown Obsessive Compulsive Scale for Body Dysmorphic Disorder. RESULTS:: The Brazilian version of the instrument showed Cronbach's alpha of 0.805 and excellent inter-rater reproducibility (intraclass correlation coefficient, ICC = 0.873; P < 0.001) and intra-rater reproducibility (ICC = 0.939; P < 0.001). Significant differences in total scores were found between patients with and without symptoms (P < 0.001). A strong correlation (r = 0.841; P < 0.001) was observed between the Yale-Brown Obsessive Compulsive Scale for Body Dysmorphic Disorder and the Body Dysmorphic Symptoms Scale. The area under the receiver operating characteristic curve was 0.981, thus showing good accuracy for discriminating between presence and absence of symptoms of body dysmorphic disorder. Forty-six percent of the patients had body dysmorphic symptoms and 54% had moderate to severe appearance-related obsessive-compulsive symptoms. CONCLUSIONS:: The Brazilian version of the Body Dysmorphic Symptoms Scale is a reproducible instrument that presents face, content and construct validity. PMID- 28076637 TI - A five-year review of vertical HIV transmission in a specialized service: cross sectional study. AB - CONTEXT AND OBJECTIVE:: Healthcare professionals need to instill the process of prevention, control and treatment of people infected with HIV into care practice. Through maintaining preventive treatment among HIV-infected pregnant women, it has been demonstrated that prophylactic antiretroviral therapy, scheduled cesarean section and the prohibition of breastfeeding significantly reduce vertical HIV transmission. This study aimed to assess the rates of vertical HIV transmission in a specialized service and identify the factors associated with it. DESIGN AND SETTING:: Cross-sectional study developed at the University Hospital of Santa Maria (RS), Brazil. METHODS:: A cross-sectional study was conducted on a sample of 198 notification forms and medical records of HIV positive pregnant women and exposed children. RESULTS:: The vertical transmission rate was 2.4%, and three children had been infected by vertical HIV transmission. The statistically significant risk factor was the use of injectable drugs. Delayed reporting of pregnancy, absence of antiretroviral therapy during pregnancy, lack of proper prenatal care, incapacity to perform viral load detection tests and CD4+ T cell counts and obstetric and maternal clinical complications were reported. CONCLUSIONS:: The vertical transmission rate was high and the recommended intervention measures were not adopted in full. Adequate prophylactic measures need to be implemented in HIV-positive pregnant women prenatally and during the antenatal, delivery and postpartum periods. PMID- 28076638 TI - The future of psychiatric research. AB - Psychiatric disorders place considerable burden on individuals and on public health. Funding for research in psychiatry is less than ideal, but even so high quality research is being conducted at many centers. However, these studies have not impacted clinical practice as much as expected. The complexity of psychiatric disorders is one of the reasons why we face difficulties in translating research results to patient care. New technologies and improved methodologies are now available and must be incorporated to deal with this complexity and to accelerate the translational process. I discuss the application of modern techniques for data acquisition and analysis and also the new possibilities for performing trials in virtual models of biological systems. Adoption of new technologies is necessary, but will not reduce the importance of some of the fundamentals of all psychiatry research, such as the developmental and translational perspectives. Psychiatrists wishing to integrate these novelties into their research will need to work with contributors with whom they are unaccustomed to working, such as computer experts, a multidisciplinary team, and stakeholders such as patients and caregivers. This process will allow us to further understand and alleviate the suffering and impairment of people with psychiatric disorders. PMID- 28076639 TI - Transcranial magnetic stimulation for treatment of major depression during pregnancy: a review. AB - Introduction:: Pregnancy is characterized by a high prevalence of mental disorders. Depression is the most common of these disorders and it is a risk factor for negative maternal and child development outcomes. Psychotherapy and pharmacotherapy are conventional and well-established therapeutic options, but some clients fail to respond and the safety of using some pharmacological agents during pregnancy is unclear. Some neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), have been studied in depressed pregnant women. Objective:: To evaluate the safety and efficacy of rTMS for major depression in pregnant women. Methods:: The LILACS and PubMed databases were reviewed using the search terms depression, pregnancy and magnetic stimulation. Texts including primary data, published in Portuguese, Spanish, or English, between 1995 and 2014, that evaluated depressed pregnant women and used rTMS as the intervention were selected. Papers lacking sufficient data were excluded. Twenty-two texts were initially identified; after applying the inclusion criteria, 12 were selected and analyzed. Results:: The studies reviewed reported satisfactory responses to rTMS in acute depressive episodes, as measured using depressive symptom scales. Remission of symptoms was achieved in many cases. The procedure was well tolerated and there were no reports of damage/complications to unborn children. Conclusion:: The data available at this time support the efficacy and tolerability of rTMS for depression in pregnant women. Controlled studies should corroborate this conclusion. This review only included studies in three languages and the resulting sample size was not large enough to conduct a meta-analysis. PMID- 28076640 TI - Frontal lobe alterations in schizophrenia: a review. AB - Objective:: To highlight the changes in the frontal lobe of the human brain in people with schizophrenia. Methods:: This was a qualitative review of the literature. Results:: Many schizophrenic patients exhibit functional, structural, and metabolic abnormalities in the frontal lobe. Some patients have few or no alterations, while some have more functional and structural changes than others. Magnetic resonance imaging (MRI) shows structural and functional changes in volume, gray matter, white matter, and functional activity in the frontal lobe, but the mechanisms underlying these changes are not yet fully understood. Conclusion:: When schizophrenia is studied as an essential topic in the field of neuropsychiatry, neuroscientists find that the frontal lobe is the most commonly involved area of the human brain. A clear picture of how this lobe is affected in schizophrenia is still lacking. We therefore recommend that further research be conducted to improve understanding of the pathophysiology of this psychiatric dilemma. PMID- 28076641 TI - Cross-cultural adaptation of the Posttraumatic Stress Disorder Checklist 5 (PCL 5) and Life Events Checklist 5 (LEC-5) for the Brazilian context. AB - Objective:: To describe the process of cross-cultural adaptation of the Posttraumatic Stress Disorder Checklist 5 (PCL-5) and the Life Events Checklist 5 (LEC-5) for the Brazilian sociolinguistic context. Method:: The adaptation process sought to establish conceptual, semantic, and operational equivalence between the original items of the questionnaire and their translated versions, following standardized protocols. Initially, two researchers translated the original version of the scale into Brazilian Portuguese. Next, a native English speaker performed the back-translation. Quantitative and qualitative criteria were used to evaluate the intelligibility of items. Five specialists compared the original and translated versions and assessed the degree of equivalence between them in terms of semantic, idiomatic, cultural and conceptual aspects. The degree of agreement between the specialists was measured using the content validity coefficient (CVC). Finally, 28 volunteers from the target population were interviewed in order to assess their level of comprehension of the items. Results:: CVCs for items from both scales were satisfactory for all criteria. The mean comprehension scores were above the cutoff point established. Overall, the results showed that the adapted versions' items had adequate rates of equivalence in terms of concepts and semantics. Conclusions:: The translation and adaptation processes were successful for both scales, resulting in versions that are not only equivalent to the originals, but are also intelligible for the population at large. PMID- 28076642 TI - Activity/rest rhythm of depressed adolescents undergoing therapy: case studies. AB - Introduction:: Disorders of circadian rhythms have been reported in studies of both depressed children and of depressed adolescents. The aim of this study was to evaluate whether there is a relationship between the 24-hour spectral power (24h SP) of the activity/rest rhythm and the clinical course of depression in adolescents. Methods:: Six 14 to 17-year-old adolescents were recruited for the study. They were all suffering from major depressive disorder, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria, as identified by the Schedule for Affective Disorders and Schizophrenia for School Aged Children: Present and Lifetime Version (K-SADS-PL). Depressive symptoms were assessed using the Children's Depression Rating Scale - Revised (CDRS-R) and clinical evaluations. Locomotor activity was monitored over a period of 13 consecutive weeks. Activity was measured for 10-minute periods using wrist worn activity monitors. All patients were prescribed sertraline from after the first week up until the end of the study. Results:: We found a relationship between high CDRS values and low 24-hour spectral power. Conclusions:: The 24h SP of the activity/rest rhythm correlated significantly (negatively) with the clinical ratings of depression. PMID- 28076643 TI - Translation and cross-cultural adaptation of the Rating Scale for Countertransference (RSCT) to American English. AB - Introduction:: The Rating Scale for Countertransference (RSCT) - originally, Escala para Avaliacao de Contratransferencia (EACT) - is a self-administered instrument comprising questions that assess 23 feelings (divided into three blocs, closeness, distance, and indifference) that access conscious countertransferential emotions and sentiments. This paper describes the process of translation and cross-cultural adaptation of the RSCT into American English. Methods:: This study employed the guidelines proposed by the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Task Force for Translation and Cultural Adaptation which define 10 steps for translation and cross-cultural adaptation of self-report instruments. Additionally, semantic equivalence tools were employed to select the final versions of terms used. The author of the RSCT gave permission for translation and took part in the process. The instrument is available for use free of charge. Results:: Analysis of the back-translation showed that just seven of the 23 terms needed to be adjusted to arrive at the final version in American English. Conclusions:: This study applied rigorous standards to construct a version of the RSCT in American English. This version of the RSCT translated and adapted into American English should be of great use for accessing and researching countertransferential feelings that are part of psychodynamic treatment. PMID- 28076644 TI - Main mental disorders in crack-cocaine users treated at Psychosocial Care Centers for Alcohol and Drugs in the city of Recife, Brazil. AB - Introduction:: Brazil's Northeast region has the highest crack-cocaine consumption in the country. Crack-cocaine has more intense effects than cocaine powder and can cause greater chemical dependence. Psychosocial Care Centers for Alcohol and Drugs (CAPSad) are public health services that provide treatment for drug dependence. It is common for drug users, and particularly crack-cocaine users, to develop mental disorders. Objective: To evaluate the most common mental disorders in crack-cocaine dependents in treatment at CAPSad in the city of Recife, Brazil. Methods:: The research database "Between rocks and shots: user profiles, consumption strategies, and social impact of crack cocaine" (CEP/CCS/UFPE no. 206/11) was consulted to establish the areas of crack cocaine consumption in the city of Recife. Results:: There were 885 patients in treatment for crack-cocaine use, with a mean age of 29.8+/-9.4 years. The mean duration of drug use was 6.1+/-4.6 years. Most of the patients were males (80.3%), had left school at some point between the 1st and 9th grades (45.6%), were unemployed and/or seeking employment (52%) and used drugs daily (56.4%). Cocaine chemical dependence was more significant when correlated with use of crack-cocaine and other drugs such as medications and hallucinogens (p = 0.01). Conclusions:: Data from this study showed strong associations between crack-cocaine uses and development of mental disorders, particularly when abuse of multiple substances occurs. Based on these data, there is a clear need for coordination of related public policies for support and social reintegration to provide these people with comprehensive care. PMID- 28076645 TI - Is there a correlation between physicians' clinical impressions and patients' perceptions of change? Use of the Perceived Change Scale with inpatients with mental disorders. AB - Introduction:: Assessment of the results of treatment for mental disorders becomes more complete when the patient's perspective is incorporated. Here, we aimed to evaluate the psychometric properties and application of the Perceived Change Scale - Patient version (PCS-P) in a sample of inpatients with mental disorders. Methods:: One hundred and ninety-one psychiatric inpatients answered the PCS-P and the Patients' Satisfaction with Mental Health Services Scale (SATIS) and were evaluated in terms of clinical and sociodemographic data. An exploratory factor analysis (EFA) was performed and internal consistency was calculated. The clinical impressions of the patient, family, and physician were correlated with the patient's perception of change. Results:: The EFA indicated a psychometrically suitable four-factor solution. The PCS-P exhibited a coherent relationship with SATIS and had a Cronbach's alpha value of 0.856. No correlations were found between the physician's clinical global impression of improvement and the patient's perception of change, although a moderate positive correlation was found between the patients' clinical global impression of improvement and the change perceived by the patient. Conclusions:: The PCS-P exhibited adequate psychometric proprieties in a sample of inpatients with mental disorders. The patient's perception of change is an important dimension for evaluation of outcomes in the treatment of mental disorders and differs from the physician's clinical impression of improvement. Evaluation of positive and negative perceptions of the various dimensions of the patient's life enables more precise consideration of the patient's priorities and interests. PMID- 28076646 TI - Cocaine addiction: treatments and future perspectives. PMID- 28076648 TI - Latent class profile of psychiatric symptoms and treatment utilization in a sample of patients with co-occurring disorders. AB - OBJECTIVE: To identify symptom-based subgroups within a sample of patients with co-occurring disorders (CODs) and to analyze intersubgroup differences in mental health services utilization. METHODS: Two hundred and fifteen patients with COD from an addiction clinic completed the Symptom Checklist 90-Revised. Subgroups were determined using latent class profile analysis. Services utilization data were collected from electronic records during a 3-year span. RESULTS: The five class model obtained the best fit (Bayesian information criteria [BIC] = 3,546.95; adjusted BIC = 3,363.14; bootstrapped likelihood ratio test p < 0.0001). Differences between classes were quantitative, and groups were labeled according to severity: mild (26%), mild-moderate (28.8%), moderate (18.6%), moderate-severe (17.2%), and severe (9.3%). A significant time by class interaction was obtained (chi-square [chi2[15]] = 30.05, p = 0.012); mild (chi2[1] = 243.90, p < 0.05), mild-moderate (chi2[1] = 198.03, p < 0.05), and moderate (chi2[1] = 526.77, p < 0.05) classes displayed significantly higher treatment utilization. CONCLUSION: The classes with more symptom severity (moderate-severe and severe) displayed lower utilization of services across time when compared to participants belonging to less severe groups. However, as pairwise differences in treatment utilization between classes were not significant between every subgroup, future studies should determine whether subgroup membership predicts other treatment outcomes. PMID- 28076649 TI - Suicide attempts in bipolar I patients: impact of comorbid personality disorders. AB - Objective: To evaluate the association between personality disorders (PDs) and suicide attempts (SAs) in euthymic patients with type I bipolar disorder (BD). Methods: One-hundred twenty patients with type I BD, with and without history of SA, were evaluated during euthymia. The assessment included a clinical and sociodemographic questionnaire, the Hamilton Depression Rating Scale, the Young Mania Rating Scale, the Barratt Impulsiveness Scale, and Structured Clinical Interviews for DSM-IV Axis I and II Disorders. Logistic regression was employed to determine associations between history of SA and patient characteristics. Results: History of SA was significantly associated with comorbid axis I disorder, rapid cycling, high impulsivity (attentional, motor, non-planning, and total), having any PD, and cluster B and C PDs. Only cluster B PDs, high attentional impulsivity, and lack of paid occupation remained significant after multivariate analysis. Conclusions: Cluster B PDs were significantly associated with SA in patients with type I BD. High attentional impulsivity and lack of gainful employment were also associated with SA, which suggests that some cluster B clinical and social characteristics may exacerbate suicidal behavior in this population. This finding offers alternatives for new therapeutic interventions. PMID- 28076650 TI - Chronotype and anxiety are associated in patients with chronic primary insomnia. AB - Objective:: To assess the interaction of chronotype with anxiety in patients with chronic primary insomnia. Methods:: Sixty-four patients (50 women) with mean age 43.9+/-8.1 years were investigated with the Horne and Ostberg Morningness Eveningness Questionnaire (MEQ) and State-Trait Anxiety Inventory (STAI). Results:: Significant negative correlations of chronotype-MEQ score with STAI state-anxiety (r = -0.40, p < 0.05), STAI trait-anxiety (r = -0.40, p < 0.05), and STAI pre-sleep state anxiety (r = -0.30, p < 0.05) were observed. Eveningness preference was associated with higher trait, state, and pre-sleep state anxiety. Conclusions:: These results suggest that chronotype may be an important parameter to identifying the origin and significance of a vicious anxiety-insomnia depression cycle in patients with chronic primary insomnia. PMID- 28076651 TI - Controlled release of chlorhexidine from a mesoporous silica-containing macroporous titanium dental implant prevents microbial biofilm formation. AB - Roughened surfaces are increasingly being used for dental implant applications as the enlarged contact area improves bone cell anchorage, thereby facilitating osseointegration. However, the additional surface area also entails a higher risk for the development of biofilm associated infections, an etiologic factor for many dental ailments, including peri-implantitis. To overcome this problem, we designed a dental implant composed of a porous titanium-silica (Ti/SiO2) composite material and containing an internal reservoir that can be loaded with antimicrobial compounds. The composite material consists of a sol-gel derived mesoporous SiO2 diffusion barrier integrated in a macroporous Ti load-bearing structure obtained by powder metallurgical processing. The antimicrobial compounds can diffuse through the porous implant walls, thereby reducing microbial biofilm formation on the implant surface. A continuous release of uM concentrations of chlorhexidine through the Ti/SiO2 composite material was measured, without initial burst effect, over at least 10 days and using a 5 mM chlorhexidine solution in the implant reservoir. Metabolic staining, CFU counting and visualisation by scanning electron microscopy confirmed that Streptococcus mutans biofilm formation on the implant surface was almost completely prevented due to chlorhexidine release (preventive setup). Moreover, we demonstrated efficacy of released chlorhexidine against mature Streptococcus mutans biofilms (curative setup). In conclusion, we provide a proof of concept of the sustained release of chlorhexidine, one of the most widely used oral antiseptics, through the Ti/SiO2 material thereby preventing and eradicating biofilm formation on the surface of the dental implant. In principle, our flexible design allows for the use of any bioactive compound, as discussed. PMID- 28076653 TI - Recent advances in primate nutritional ecology. AB - Nutritional ecology seeks to explain, in an ecological and evolutionary context, how individuals choose, acquire, and process food to satisfy their nutritional requirements. Historically, studies of primate feeding ecology have focused on characterizing diets in terms of the botanical composition of the plants consumed. Further, dietary studies have demonstrated how patch and food choice in relation to time spent foraging and feeding are influenced by the spatial and temporal distribution of resources and by social factors such as feeding competition, dominance, or partner preferences. From a nutritional perspective, several theories including energy and protein-to-fiber maximization, nutrient mixing, and toxin avoidance, have been proposed to explain the food choices of non-human primates. However, more recently, analytical frameworks such as nutritional geometry have been incorporated into primatology to explore, using a multivariate approach, the synergistic effects of multiple nutrients, secondary metabolites, and energy requirements on primate food choice. Dietary strategies associated with nutrient balancing highlight the tradeoffs that primates face in bypassing or selecting particular feeding sites and food items. In this Special Issue, the authors bring together a set of studies focusing on the nutritional ecology of a diverse set of primate taxa characterized by marked differences in dietary emphasis. The authors present, compare, and discuss the diversity of strategies used by primates in diet selection, and how species differences in ecology, physiology, anatomy, and phylogeny can affect patterns of nutrient choice and nutrient balancing. The use of a nutritionally explicit analytical framework is fundamental to identify the nutritional requirements of different individuals of a given species, and through its application, direct conservation efforts can be applied to regenerate and protect specific foods and food patches that offer the opportunity of a nutritionally balanced diet. PMID- 28076652 TI - Estimation of Benchmark Dose of Lifetime Cadmium Intake for Adverse Renal Effects Using Hybrid Approach in Inhabitants of an Environmentally Exposed River Basin in Japan. AB - The aim of this study is to estimate the reference level of lifetime cadmium intake (LCd) as the benchmark doses (BMDs) and their 95% lower confidence limits (BMDLs) for various renal effects by applying a hybrid approach. The participants comprised 3,013 (1,362 men and 1,651 women) and 278 (129 men and 149 women) inhabitants of the Cd-polluted and nonpolluted areas, respectively, in the environmentally exposed Kakehashi River basin. Glucose, protein, aminonitrogen, metallothionein, and beta2 -microglobulin in urine were measured as indicators of renal dysfunction. The BMD and BMDL that corresponded to an additional risk of 5% were calculated with background risk at zero exposure set at 5%. The obtained BMDLs of LCd were 3.7 g (glucose), 3.2 g (protein), 3.7 g (aminonitrogen), 1.7 g (metallothionein), and 1.8 g (beta2 -microglobulin) in men and 2.9 g (glucose), 2.5 g (protein), 2.0 g (aminonitrogen), 1.6 g (metallothionein), and 1.3 g (beta2 -microglobulin) in women. The lowest BMDL was 1.7 g (metallothionein) and 1.3 g (beta2 -microglobulin) in men and women, respectively. The lowest BMDL of LCd (1.3 g) was somewhat lower than the representative threshold LCd (2.0 g) calculated in the previous studies. The obtained BMDLs may contribute to further discussion on the health risk assessment of cadmium exposure. PMID- 28076654 TI - Estimating varying coefficients for partial differential equation models. AB - Partial differential equations (PDEs) are used to model complex dynamical systems in multiple dimensions, and their parameters often have important scientific interpretations. In some applications, PDE parameters are not constant but can change depending on the values of covariates, a feature that we call varying coefficients. We propose a parameter cascading method to estimate varying coefficients in PDE models from noisy data. Our estimates of the varying coefficients are shown to be consistent and asymptotically normally distributed. The performance of our method is evaluated by a simulation study and by an empirical study estimating three varying coefficients in a PDE model arising from LIDAR data. PMID- 28076655 TI - Fecal total iron concentration is inversely associated with fecal Lactobacillus in preschool children. AB - BACKGROUND AND AIM: Iron deficiency is associated with stunting and poor performance in children. Oral iron supplementation is widely promoted to correct iron deficiency. However, excess iron may be toxic to beneficial luminal gut bacteria and could support growth of pathobionts. The aim of this study is to analyze the fecal total iron concentration and fecal Lactobacillus levels in a cohort of stunted and normal children. METHODS: The study was undertaken in two different locations. One of them is a rural area, and the other is a semi-urban slum area; both areas are located in the Vellore district of Tamilnadu state. Twenty children (10 stunted and 10 normal growth) aged 2 to 5 years from each area were recruited. Both groups were nearly identical demographically. Fecal samples were collected. Fecal total iron was estimated, and fecal DNA was extracted and subjected to 16S rDNA-targeted real-time PCR to determine the relative predominance of Lactobacillus and Escherichia coli. RESULTS: The fecal total iron concentration in rural children (3656 MUg/g wet wt. of feces) was significantly higher when compared with semi-urban-slum children (114.9 MUg/g wet wt. of feces, P < 0.005). Inversely, fecal Lactobacillus in rural children (median 3.18 * 10-3 relative difference compared with total bacteria) was significantly lower when compared with semi-urban-slum children (median 59.33 * 10-3 , p < 0.005). There was no significant change observed between normal and stunted children. E. coli levels remained unaffected. CONCLUSION: The present study documents an inverse relationship between fecal iron concentration and fecal Lactobacillus concentration in children belonging to two different localities independent of their nutritional status. PMID- 28076657 TI - Geophysics Is Not a Silver Bullet, but Worth a Shot. PMID- 28076656 TI - Combined inhaled beta-agonist and anticholinergic agents for emergency management in adults with asthma. AB - BACKGROUND: Inhaled short-acting anticholinergics (SAAC) and short-acting beta2 agonists (SABA) are effective therapies for adult patients with acute asthma who present to the emergency department (ED). It is unclear, however, whether the combination of SAAC and SABA treatment is more effective in reducing hospitalisations compared to treatment with SABA alone. OBJECTIVES: To conduct an up-to-date systematic search and meta-analysis on the effectiveness of combined inhaled therapy (SAAC + SABA agents) vs. SABA alone to reduce hospitalisations in adult patients presenting to the ED with an exacerbation of asthma. SEARCH METHODS: We searched MEDLINE, Embase, CINAHL, SCOPUS, LILACS, ProQuest Dissertations & Theses Global and evidence-based medicine (EBM) databases using controlled vocabulary, natural language terms, and a variety of specific and general terms for inhaled SAAC and SABA drugs. The search spanned from 1946 to July 2015. The Cochrane Airways Group provided search results from the Cochrane Airways Group Register of Trials which was most recently conducted in July 2016. An extensive search of the grey literature was completed to identify any other potentially relevant studies. SELECTION CRITERIA: Included studies were randomised or controlled clinical trials comparing the effectiveness of combined inhaled therapy (SAAC and SABA) to SABA treatment alone to prevent hospitalisations in adults with acute asthma in the emergency department. Two independent review authors assessed studies for inclusion using pre-determined criteria. DATA COLLECTION AND ANALYSIS: For dichotomous outcomes, we calculated individual and pooled statistics as risk ratios (RR) or odds ratios (OR) with 95% confidence intervals (CI) using a random-effects model and reporting heterogeneity (I2). For continuous outcomes, we reported individual trial results using mean differences (MD) and pooled results as weighted mean differences (WMD) or standardised mean differences (SMD) with 95% CIs using a random-effects model. MAIN RESULTS: We included 23 studies that involved a total of 2724 enrolled participants. Most studies were rated at unclear or high risk of bias.Overall, participants receiving combination inhaled therapy were less likely to be hospitalised (RR 0.72, 95% CI 0.59 to 0.87; participants = 2120; studies = 16; I2 = 12%; moderate quality of evidence). An estimated 65 fewer patients per 1000 would require hospitalisation after receiving combination therapy (95% 30 to 95), compared to 231 per 1000 patients receiving SABA alone. Although combination inhaled therapy was more effective than SABA treatment alone in reducing hospitalisation in participants with severe asthma exacerbations, this was not found for participants with mild or moderate exacerbations (test for difference between subgroups P = 0.02).Participants receiving combination therapy were more likely to experience improved forced expiratory volume in one second (FEV1) (MD 0.25 L, 95% CI 0.02 to 0.48; participants = 687; studies = 6; I2 = 70%; low quality of evidence), peak expiratory flow (PEF) (MD 36.58 L/min, 95% CI 23.07 to 50.09; participants = 1056; studies = 12; I2 = 25%; very low quality of evidence), increased percent change in PEF from baseline (MD 24.88, 95% CI 14.83 to 34.93; participants = 551; studies = 7; I2 = 23%; moderate quality of evidence), and were less likely to return to the ED for additional care (RR 0.80, 95% CI 0.66 to 0.98; participants = 1180; studies = 5; I2 = 0%; moderate quality of evidence) than participants receiving SABA alone.Participants receiving combination inhaled therapy were more likely to experience adverse events than those treated with SABA agents alone (OR 2.03, 95% CI 1.28 to 3.20; participants = 1392; studies = 11; I2 = 14%; moderate quality of evidence). Among patients receiving combination therapy, 103 per 1000 were likely to report adverse events (95% 31 to 195 more) compared to 131 per 1000 patients receiving SABA alone. AUTHORS' CONCLUSIONS: Overall, combination inhaled therapy with SAAC and SABA reduced hospitalisation and improved pulmonary function in adults presenting to the ED with acute asthma. In particular, combination inhaled therapy was more effective in preventing hospitalisation in adults with severe asthma exacerbations who are at increased risk of hospitalisation, compared to those with mild-moderate exacerbations, who were at a lower risk to be hospitalised. A single dose of combination therapy and multiple doses both showed reductions in the risk of hospitalisation among adults with acute asthma. However, adults receiving combination therapy were more likely to experience adverse events, such as tremor, agitation, and palpitations, compared to patients receiving SABA alone. PMID- 28076658 TI - The Development of Groundwater Modeling: The End of an Era. PMID- 28076659 TI - An Empirical Agent-Based Model to Simulate the Adoption of Water Reuse Using the Social Amplification of Risk Framework. AB - Water reuse can serve as a sustainable alternative water source for urban areas. However, the successful implementation of large-scale water reuse projects depends on community acceptance. Because of the negative perceptions that are traditionally associated with reclaimed water, water reuse is often not considered in the development of urban water management plans. This study develops a simulation model for understanding community opinion dynamics surrounding the issue of water reuse, and how individual perceptions evolve within that context, which can help in the planning and decision-making process. Based on the social amplification of risk framework, our agent-based model simulates consumer perceptions, discussion patterns, and their adoption or rejection of water reuse. The model is based on the "risk publics" model, an empirical approach that uses the concept of belief clusters to explain the adoption of new technology. Each household is represented as an agent, and parameters that define their behavior and attributes are defined from survey data. Community-level parameters-including social groups, relationships, and communication variables, also from survey data-are encoded to simulate the social processes that influence community opinion. The model demonstrates its capabilities to simulate opinion dynamics and consumer adoption of water reuse. In addition, based on empirical data, the model is applied to investigate water reuse behavior in different regions of the United States. Importantly, our results reveal that public opinion dynamics emerge differently based on membership in opinion clusters, frequency of discussion, and the structure of social networks. PMID- 28076660 TI - Influenza A virus NS1 protein-induced JNK activation and apoptosis are not functionally linked. AB - Expression of the influenza A virus (IAV) nonstructural protein (NS1) results in the activation of c-Jun N-terminal kinase (JNK). Both NS1 and JNK are involved in apoptosis induction. To investigate their interrelationship, we stably expressed a tamoxifen inducible NS1 oestrogen receptor fusion-protein (NS1ERT) in mammalian cells. Upon tamoxifen stimulation, NS1ERT-expressing cells partially rescued the attenuated replication of NS1-deficient IAVs and also inhibited interferon up regulation, confirming the functional competence of NS1ERT. Tamoxifen-induced NS1ERT created a cytopathic phenotype and led to the activation of JNK and apoptosis. Induction of NS1F103SERT mutant failed to activate JNK, but induced apoptosis, whereas the induction of NS1M106IERT led to JNK phosphorylation, but not apoptosis, indicating that JNK activation and apoptosis induction are not functionally linked. Further mutational analysis highlighted that apoptosis induction is a function of the C-terminal effector domain of NS1. Finally, IAVs encoding mutant NS1 revealed a modulating effect of NS1 on apoptosis induction in a genuine infection. With respect to apoptogenicity, an NS1 mutant virus that results in a super activation of JNK behaves similarly to the JNK nonactivating virus expressing NS1F103S, thus confirming that NS1-mediated JNK activation and apoptosis induction are also functionally independent from each other in vivo. PMID- 28076661 TI - Impression Techniques Used for Single-Unit Crowns: Findings from the National Dental Practice-Based Research Network. AB - PURPOSE: To: (1) determine which impression and gingival displacement techniques practitioners use for single-unit crowns on natural teeth; and (2) test whether certain dentist and practice characteristics are significantly associated with the use of these techniques. MATERIALS AND METHODS: Dentists participating in the National Dental Practice-Based Research Network were eligible for this survey study. The study used a questionnaire developed by clinicians, statisticians, laboratory technicians, and survey experts. The questionnaire was pretested via cognitive interviewing with a regionally diverse group of practitioners. The survey included questions regarding gingival displacement and impression techniques. Survey responses were compared by dentist and practice characteristics using ANOVA. RESULTS: The response rate was 1777 of 2132 eligible dentists (83%). Regarding gingival displacement, most clinicians reported using either a single cord (35%) or dual cord (35%) technique. About 16% of respondents preferred an injectable retraction technique. For making impressions, the most frequently used techniques and materials are: poly(vinyl siloxane), 77%; polyether, 12%; optical/digital, 9%. A dental auxiliary or assistant made the final impression 2% of the time. Regarding dual-arch impression trays, 23% of practitioners report they typically use a metal frame tray, 60% use a plastic frame, and 16% do not use a dual-arch tray. Clinicians using optical impression techniques were more likely to be private practice owners or associates. CONCLUSIONS: This study documents current techniques for gingival displacement and making impressions for crowns. Certain dentist and practice characteristics are significantly associated with these techniques. PMID- 28076662 TI - Vps13F links bacterial recognition and intracellular killing in Dictyostelium. AB - Bacterial sensing, ingestion, and killing by phagocytic cells are essential processes to protect the human body from infectious microorganisms. The cellular mechanisms involved in intracellular killing, their relative importance, and their specificity towards different bacteria are however poorly defined. In this study, we used Dictyostelium discoideum, a phagocytic cell model amenable to genetic analysis, to identify new gene products involved in intracellular killing. A random genetic screen led us to identify the role of Vps13F in intracellular killing of Klebsiella pneumoniae. Vps13F knock-out (KO) cells exhibited a delayed intracellular killing of K. pneumoniae, although the general organization of the phagocytic and endocytic pathway appeared largely unaffected. Transcriptomic analysis revealed that vps13F KO cells may be functionally similar to previously characterized fspA KO cells, shown to be defective in folate sensing. Indeed, vps13F KO cells showed a decreased chemokinetic response to various stimulants, suggesting a direct or indirect role of Vps13F in intracellular signaling. Overstimulation with excess folate restored efficient killing in vps13F KO cells. Finally, genetic inactivation of Far1, the folate receptor, resulted in inefficient intracellular killing of K. pneumoniae. Together, these observations show that stimulation of Dictyostelium by bacterial folate is necessary for rapid intracellular killing of K. pneumoniae. PMID- 28076663 TI - Synthesis and Biological Evaluation of Amidinourea and Triazine Congeners as Inhibitors of MDA-MB-231 Human Breast Cancer Cell Proliferation. AB - A series of novel amidinourea derivatives was synthesized, and the compounds were evaluated as inhibitors of MDA-MB-231 human breast cancer cell proliferation. In addition, a second series of triazine derivatives designed as rigid congeners of the amidinoureas was synthesized, and the compounds were evaluated for their antiproliferative activity. Among the two series, amidinourea 3 d (N-[N-[8-[[N (morpholine-4-carbonyl)carbamimidoyl]amino]octyl]carbamimidoyl]morpholine-4 carboxamide) emerged as a potent anticancer hit compound with an IC50 value of 0.76 MUm, similar to that of tamoxifen. PMID- 28076664 TI - Sensitization predicts asthma development among wheezing toddlers in secondary healthcare. AB - INTRODUCTION: Some wheezing toddlers develop asthma later in childhood. Sensitization is known to predict asthma in birth cohorts. However, its predictive value in secondary healthcare is uncertain. AIM: This study examines the predictive value of sensitization to inhalant allergens among wheezing toddlers in secondary healthcare for the development of asthma at school age (>=6 years). METHODS: Preschool children (1-3 years) who presented with wheezing in secondary healthcare were screened on asthma at school age with the International Study of Asthma and Allergies in Childhood questionnaire. The positive and negative predictive value (PPV and NPV) of specific IgE to inhalant allergens (cut-off concentration 0.35 kU/L) and several non-invasive variables from a child's history (such as hospitalization, eczema, and parental atopy) were calculated. The additional predictive value of sensitization when combined with non-invasive predictors was examined in multivariate analysis and by ROC curves. RESULTS: Of 116 included children, 63% developed asthma at school age. Sensitization to inhalant allergens was a strong asthma predictor. The odds ratio (OR), PPV and NPV were 7.4%, 86%, and 55%, respectively. Eczema (OR 3.4) and hospital admission (OR 2.6) were significant non-invasive determinants. Adding sensitization to these non-invasive predictors in multivariate analysis resulted in a significantly better asthma prediction. The area under the ROC curve increased from 0.70 with only non-invasive predictors to 0.79 after adding sensitization. CONCLUSION: Sensitization to inhalant allergens is a strong predictor of school age asthma in secondary healthcare and has added predictive value when combined with non-invasive determinants. Pediatr Pulmonol. 2017;52:729 736. (c) 2017 Wiley Periodicals, Inc. PMID- 28076665 TI - Carbohydrate-Lectin Interactions: An Unexpected Contribution to Affinity. AB - Uropathogenic E. coli exploit PapG-II adhesin for infecting host cells of the kidney; the expression of PapG-II at the tip of bacterial pili correlates with the onset of pyelonephritis in humans, a potentially life-threatening condition. It was envisaged that blocking PapG-II (and thus bacterial adhesion) would provide a viable therapeutic alternative to conventional antibiotic treatment. In our search for potent PapG-II antagonists, we observed an increase in affinity when tetrasaccharide 1, the natural ligand of PapG-II in human kidneys, was elongated to hexasaccharide 2, even though the additional Siaalpha(2-3)Gal extension is not in direct contact with the lectin. ITC studies suggest that the increased affinity results from partial desolvation of nonbinding regions of the hexasaccharide; this is ultimately responsible for perturbation of the outer hydration layers. Our results are in agreement with previous observations and suggest a general mechanism for modulating carbohydrate-protein interactions based on nonbinding regions of the ligand. PMID- 28076666 TI - The global incidence of lip, oral cavity, and pharyngeal cancers by subsite in 2012. AB - By using data from the International Agency for Research on Cancer publication Cancer Incidence in 5 Continents and GLOBOCAN, this report provides the first consolidated global estimation of the subsite distribution of new cases of lip, oral cavity, and pharyngeal cancers by country, sex, and age for the year 2012. Major geographically based, sex-based, and age-based variations in the incidence of lip, oral cavity, and pharyngeal cancers by subsite were observed. Lip cancers were highly frequent in Australia (associated with solar radiation) and in central and eastern Europe (associated with tobacco smoking). Cancers of the oral cavity and hypopharynx were highly common in south-central Asia, especially in India (associated with smokeless tobacco, bidi, and betel-quid use). Rates of oropharyngeal cancers were elevated in northern America and Europe, notably in Hungary, Slovakia, Germany, and France and were associated with alcohol use, tobacco smoking, and human papillomavirus infection. Nasopharyngeal cancers were most common in northern Africa and eastern/southeast Asia, indicative of genetic susceptibility combined with Epstein-Barr virus infection and early life carcinogenic exposures (nitrosamines and salted foods). The global incidence of lip, oral cavity, and pharyngeal cancers of 529,500, corresponding to 3.8% of all cancer cases, is predicted to rise by 62% to 856,000 cases by 2035 because of changes in demographics. Given the rising incidence of lip, oral cavity, and pharyngeal cancers and the variations in incidence by subsites across world regions and countries, there is a need for local, tailored approaches to prevention, screening, and treatment interventions that will optimally reduce the lip, oral cavity, and pharyngeal cancer burden in future decades. CA Cancer J Clin 2017;67:51-64. (c) 2016 American Cancer Society. PMID- 28076667 TI - Effectiveness of Antipsychotic Drugs for 24-Month Maintenance Treatment in First Episode Schizophrenia: Evidence From a Community-Based "Real-World" Study. AB - OBJECTIVE: Maintenance treatment of schizophrenia with antipsychotic medications has become a standard for the prevention of psychotic relapse. However, little is known about the effectiveness of antipsychotic drugs for maintenance treatment in "real-world" populations with schizophrenia. We carried out a prospective study to assess the effectiveness of the most frequently prescribed antipsychotic drugs in the maintenance treatment of schizophrenia from 2 community settings. METHODS: This study was conducted from October 2011 to December 2014. All participants were diagnosed with schizophrenia according to DSM-IV, were treated with an antipsychotic monotherapy, and were registered in a case management program with monthly monitoring for 24 months. The primary outcome measure, Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales were used to evaluate symptom severity and treatment response. The Personal and Social Performance scale (PSP) was used to evaluate the patients' social functioning. The Medication Adherence Rating Scale (MARS) was used to assess medication adherence behavior. On the basis of antipsychotic used at baseline, patients were clustered into 7 groups: aripiprazole (n = 21), clozapine (n = 84), chlorpromazine (n = 61), olanzapine (n = 34), perphenazine (n = 21), quetiapine (n = 27), and risperidone (n = 99). RESULTS: Of the 347 patients enrolled in the study, 312 completed the 24-month follow-up. There were no significant differences among the treatment groups in the PANSS total and subscale scores or the CGI-S and CGI-I scores over 24 months (all P values > .05). There were also no significant differences in interactions between PSP scores and antipsychotic drugs (P = .17). The remission rates increased as the follow-time lapsed in all groups, but no significant difference was observed in remission rates at each time point among the 7 groups (P values > .05). At the endpoint, MARS total scores were over 6, but did not significantly differ among the studied drugs (P = .24). CONCLUSIONS: These findings suggest that antipsychotic drugs can achieve equivalent effectiveness in maintenance treatment of first-episode schizophrenia through a well-organized case management program and family participation. PMID- 28076668 TI - US Veterans and PTSD: Who Are They, and How Did It Happen? PMID- 28076669 TI - Medication Discrepancies at Outpatient Departments for Mood and Anxiety Disorders in the Netherlands: Risks and Clinical Relevance. AB - OBJECTIVE: To identify discrepancies between actual drug use by outpatients with mood and anxiety disorders and medication overviews from health care providers as well as to investigate the clinical relevance of those discrepancies. METHODS: A cross-sectional study in adults visiting 1 of 4 participating outpatient departments for mood and anxiety disorders was conducted between March and November 2014. DSM-5 criteria were used to assign the psychiatric diagnosis. The primary outcome was the number of discrepancies between the actual medication use, as determined by medication reconciliation with the patient, and the medication overview from the outpatient department, general practitioner, and community pharmacy. Our secondary outcome was the clinical relevance of discrepancies, as assessed by an expert panel that reviewed all discrepancies for their potential to cause patient harm. RESULTS: Of 367 patients included, 94.8% had at least 1 discrepancy in the medication overview from the outpatient department. A mean of 3.9 discrepancies existed per patient. Most discrepancies (74.5%) related to omitted drugs (drugs taken regularly by patients but absent from the medication overview). Of all discrepancies at the outpatient departments, 22.7% had the potential to cause moderate to severe discomfort or clinical deterioration, affecting 49.3% of the patients. Both total number and number of clinically relevant discrepancies were lower in medication overviews from general practitioners and pharmacies. CONCLUSION: Patients from outpatient departments for mood and anxiety disorders may be at substantial risk for medication discrepancies that are often clinically relevant. Medication reconciliation at mental health care outpatient departments is in need of improvement. PMID- 28076670 TI - Introduction. PMID- 28076671 TI - A Randomized Trial of Collaborative Care for Perinatal Depression in Socioeconomically Disadvantaged Women: The Impact of Comorbid Posttraumatic Stress Disorder. AB - OBJECTIVE: The comorbidity of posttraumatic stress disorder (PTSD) with antenatal depression poses increased risks for postpartum depression and may delay or diminish response to evidence-based depression care. In a secondary analysis of an 18-month study of collaborative care for perinatal depression, the authors hypothesized that pregnant, depressed, socioeconomically disadvantaged women with comorbid PTSD would show more improvement in the MOMCare intervention providing Brief Interpersonal Psychotherapy and/or antidepressants, compared to intensive public health Maternity Support Services (MSS-Plus). METHODS: A multisite randomized controlled trial with blinded outcome assessment was conducted in the Seattle-King County Public Health System, July 2009-January 2014. Pregnant women were recruited who met criteria for a probable diagnosis of major depressive disorder (MDD) on the Patient Health Questionnaire-9 and/or dysthymia on the MINI International Neuropsychiatric Interview (5.0.0). The primary outcome was depression severity at 3-, 6-, 12-and 18-month follow-ups; secondary outcomes included functional improvement, PTSD severity, depression response and remission, and quality of depression care. RESULTS: Sixty-five percent of the sample of 164 met criteria for probable comorbid PTSD. The treatment effect was significantly associated with PTSD status in a group-by-PTSD severity interaction, controlling for baseline depression severity (Wald chi21 = 4.52, P = .03). Over the 18-month follow-up, those with comorbid PTSD in MOMCare (n = 48), versus MSS-Plus (n = 58), showed greater improvement in depression severity (Wald chi21 = 8.51, P < .004), PTSD severity (Wald chi21 = 5.55, P < .02), and functioning (Wald chi21 = 4.40, P < .04); higher rates of depression response (Wald chi21 = 4.13, P < .04) and remission (Wald chi21 = 5.17, P < .02); and increased use of mental health services (Wald chi21 = 39.87, P < .0001) and antidepressant medication (Wald chi21 = 8.07, P < .005). Participants without comorbid PTSD in MOMCare (n = 33) and MSS-Plus (n = 25) showed equivalent improvement on these outcomes. CONCLUSIONS: Collaborative depression care had a greater impact on perinatal depressive outcomes for socioeconomically disadvantaged women with comorbid PTSD than for those without PTSD. Findings suggest that a stepped care treatment model for high-risk pregnant women with both MDD and PTSD could be integrated into public health systems in the United States. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01045655. PMID- 28076672 TI - Prenatal Psychostimulant and Antidepressant Exposure and Risk of Hypertensive Disorders of Pregnancy. AB - OBJECTIVE: To investigate the association, if any, of prenatal mental illness and psychotropic exposure with the risk of hypertensive disorders of pregnancy (HDP). METHODS: A case-cohort analysis was conducted of 686 pregnant women participating in prospective, longitudinal observational studies in a tertiary referral center between January 1998 and May 2012. Risk estimates were produced using multivariate logistic regression modeling. Medication- and diagnosis-specific data were utilized to conduct post hoc confirmatory analyses of the risk estimates. RESULTS: After adjustment for confounders, HDP were significantly associated with psychostimulant (odds ratio [OR] = 6.11; 95% CI, 1.79-20.9) and serotonin-norepinephrine reuptake inhibitor (SNRI) (OR = 2.57; 95%, 1.34-4.93) exposure following the 20th week of gestation and lifetime histories of cocaine dependence (OR = 2.99; 95% CI, 1.12-7.98) and panic disorder (OR = 1.78; 95% CI, 1.06-2.98) using DSM-IV diagnostic criteria. HDP risk was not associated with prenatal selective serotonin reuptake inhibitor exposure or other psychiatric disorders. Post hoc analyses demonstrated an increased risk for HDP with higher maternal daily doses of amphetamine psychostimulants and the SNRI venlafaxine. CONCLUSIONS: These data indicate that psychostimulant and SNRI exposure following the 20th week of gestation conveys considerable risk for the emergence of HDP. Overall, the findings suggest that heightened vascular reactivity to noradrenergic, rather than serotonergic, stimulation may be pivotal to HDP risk among women with psychiatric illness. PMID- 28076673 TI - An Infanticide Trial: US Infanticide Laws Fall Well Short of International Standards. PMID- 28076674 TI - Trajectories of Perinatal Depressive and Anxiety Symptoms in a Community Cohort. AB - OBJECTIVE: The evidence on trajectories of perinatal depression is mostly based on studies composed of women at high risk for poor mental health. Research on maternal anxiety trajectories is also scarce. Using a large community cohort, the All Our Babies study, in Alberta, Canada, we examined trajectories of perinatal depressive and anxiety symptoms and compared characteristics of women across trajectories. METHODS: Anxiety and depressive symptoms were measured at the second and third trimesters and at 4 and 12 months postpartum among 1,445 women recruited between May 2008 and December 2010. The state subscale of the Spielberger State-Trait Anxiety Inventory was used to measure anxiety symptoms, and depressive symptoms were measured with the Edinburgh Postnatal Depression Scale. Semiparametric group-based mixed modeling was performed to identify the optimal trajectory shape, number of groups, and proportion of the sample belonging to each trajectory. Model fit was evaluated using the Bayesian information criterion. Multinomial logistic regression analysis was conducted to compare characteristics across the trajectories. RESULTS: Five distinct trajectory groups with constant and variable patterns were identified for both depressive and anxiety symptoms: minimal, mild, antepartum, postpartum, and chronic. Common risk factors of depression and anxiety across groups with elevated symptoms were history of mental health issues (odds ratios [ORs] varied from 1.83 to 7.64), history of abuse/neglect (ORs varied from 1.67 to 8.97), and low social support (ORs varied from 1.64 to 11.37). The magnitude of the influence of the psychosocial risk factors was greater in the chronic group compared to others, suggesting a dose-related relationship. CONCLUSIONS: Heterogeneity of anxiety and depressive symptoms highlights the importance of multiple mental health assessments during the perinatal period. The patterns and intensity of postpartum depression differed between community and high-risk samples, underlining the significance of defining suitable cutoffs. Research to examine the impact of these trajectories on child outcomes is needed. PMID- 28076676 TI - Use of Metformin for Cardiometabolic Risks in Psychiatric Practice: Need-to-Know Safety Issues. AB - Metformin, a biguanide drug, is emerging as an important treatment option for the prevention or treatment of weight gain, type 2 diabetes mellitus, and the metabolic syndrome in psychiatric patients, especially those who require or receive antipsychotic drugs. Metformin treatment is commonly associated with gastrointestinal adverse effects; the risk of these is reduced by gradual dose uptitration, administration of the drug with meals, and use of a time-release formulation. Lactic acidosis, a potentially fatal complication of biguanide therapy, is very rare with metformin; the risk can be reduced by avoidance of its prescription in patients with impaired renal function, impaired liver function, cardiac failure, and certain other conditions. Long-term metformin use is associated with decreased vitamin B12 levels, and even with biochemical B12 deficiency; this complication can detected early by annual assessments of serum B12 levels and prevented by annual intramuscular B12 administration. PMID- 28076675 TI - Low Fasting Oxytocin Levels Are Associated With Psychopathology in Anorexia Nervosa in Partial Recovery. AB - OBJECTIVE: Anorexia nervosa (AN), a psychiatric disorder characterized by restriction of food intake despite severe weight loss, is associated with increased comorbid anxiety and depression. Secretion of oxytocin, an appetite regulating neurohormone with anxiolytic and antidepressant properties, is abnormal in AN. The link between oxytocin levels and psychopathology in AN has not been well explored. METHODS: We performed a cross-sectional study of 79 women aged 18-45 years (19 AN, 26 AN in partial recovery [ANPR], and 34 healthy controls [HC]) investigating the relationship between basal oxytocin levels and disordered eating psychopathology, anxiety, and depressive symptoms. AN diagnoses were based on DSM-5 criteria. Data acquisition took place between December 2008 and March 2014. Fasting serum oxytocin levels were obtained, and the following self-report measures were used to assess psychopathology: Eating Disorder Examination Questionnaire, State-Trait Anxiety Inventory, and Beck Depression Inventory-II. RESULTS: Fasting oxytocin levels were low in ANPR compared to HC (P = .0004). In ANPR but not AN, oxytocin was negatively associated with disordered eating psychopathology (r = -0.39, P = .0496) and anxiety symptoms (state anxiety: r = -0.53, P = .006; trait anxiety: r = -0.49, P = .01). Furthermore, ANPR with significant disordered eating psychopathology, anxiety symptoms, or depressive symptoms had lower oxytocin levels compared to those with minimal or no symptoms (P = .04, .02, and .007, respectively). CONCLUSIONS: We speculate that a dysregulation of oxytocin pathways may contribute to persistent psychopathology after partial weight recovery from anorexia nervosa. PMID- 28076677 TI - A Call to Action: The Active Role Psychiatrists and the DEA Must Take to Decrease Harm from Psychotropic Drugs Acquired via the Internet. PMID- 28076678 TI - Managing Medical Comorbidities in Patients With Depression to Improve Overall Prognosis. AB - Clinicians should weigh potential adverse effects of antidepressant medications when treating patients with medical comorbidities. Consider an example of the choices that sometimes must be made through the case of Tony, a 64-year-old man whose current diagnosis of hypertension and increased risk of diabetes influence his treatment for depression. PMID- 28076680 TI - Regulating the Master Regulator: Controlling Ubiquitination by Thinking Outside the Active Site. AB - The labeling of proteins with ubiquitin/ubiquitin-like (Ubl) proteins is crucial for several physiological processes and in the onset of various diseases. Recently, targeting ubiquitin protein labeling has shifted toward the use of allosteric mechanisms over classical activity-based approaches. Allosteric enzyme regulation offers the potential for greater selectivity and has demonstrated less susceptibility to acquired resistance often associated with active site inhibitors. Furthermore, the isoform diversity among E1 activating, E2 conjugating, E3 ligase, and deubiquitinating (DUB) enzymes offers an ideal platform for modulating activity via allostery. Herein, we have reviewed allosteric inhibitors of the ubiquitin E1-E2-E3 and DUB enzymatic cascade developed over the past decade with a focus on their mechanisms of action. We have highlighted the advantages as well as the challenges associated with designing allosteric modulators of the ubiquitin labeling machinery, and the future promise in targeting these systems using allosteric approaches. PMID- 28076679 TI - Molecular Dynamics Simulations for Deciphering the Structural Basis of Recognition of Pre-let-7 miRNAs by LIN28. AB - LIN28 protein inhibits biogenesis of miRNAs belonging to the let-7 family by binding to precursor forms of miRNAs. Overexpression of LIN28 and low levels of let-7 miRNAs are associated with several forms of cancer cells. We have performed multiple explicit solvent molecular dynamics simulations ranging from 200 to 500 ns in length on different isoforms of preE-let-7 in complex with LIN28 and also in isolation to identify structural features and key specificity-determining residues (SDRs) that are important for the inhibitory role of LIN28. Our simulations suggest that a conserved structural feature of the loop regions of preE-let-7 miRNAs is more important for LIN28 recognition than sequence conservation among members of the let-7 family or the presence of the GGAG motif in the 3' region. The loop region consisting of a minimum of five nucleotides helps pre-miRNAs to acquire a conformation ideal for binding to LIN28, but pre let-7c-2 prefers a conformation with a three-nucleotide loop. Thus, our simulations provide a theoretical rationale for the recent experimental observation of the escape of LIN28-mediated repression by pre-let-7c-2. The essential structural and sequence features highlighted in this study might aid in designing synthetic small molecule inhibitors for modulating LIN28-let-7 interaction in malignant cells. We have also identified crucial SDRs of the LIN28 preE-let-7 complex involving 13 residues of LIN28 and 10 residues of the pre miRNA. On the basis of the conservation profile of these 13 SDRs, we have identified 10 novel proteins that are not annotated as LIN28 like but are similar in sequence, domain, or fold level to LIN28. PMID- 28076682 TI - Effect of Maternal +/-Citalopram Exposure on P11 Expression and Neurogenesis in the Mouse Fetal Brain. AB - Fetal exposure to selective serotonin reuptake inhibitors (SSRI) has been associated with increased risk of adverse neurodevelopmental outcomes. In the adult brain, SSRI therapy regulates p11 (s100a10) expression and alters neurogenesis. The protein p11 indirectly regulates 5-HT signaling through 5 HT1B/D receptors. In the fetal brain, signaling through these receptors modulates axonal circuit formation. We determined whether p11 is expressed in the fetal mouse brain, and whether maternal SSRI exposure affects fetal p11 expression and neurogenesis. The SSRI +/- citalopram was administered to pregnant mice from gestational day 8 to 17. Results show that p11 is expressed in fetal thalamic neurons and thalamocortical axons. Furthermore, p11 protein expression is significantly decreased in the fetal thalamus after in utero +/-citalopram exposure compared to untreated controls, and neurogenesis is significantly decreased in specific fetal brain regions. These findings reveal differential regulation of p11 expression and altered neurogenesis in the fetal brain as a result of maternal SSRI exposure. PMID- 28076683 TI - Modulation of Cytotoxicity by Transcription-Coupled Nucleotide Excision Repair Is Independent of the Requirement for Bioactivation of Acylfulvene. AB - Bioactivation as well as DNA repair affects the susceptibility of cancer cells to the action of DNA-alkylating chemotherapeutic drugs. However, information is limited with regard to the relative contributions of these processes to the biological outcome of metabolically activated DNA alkylating agents. We evaluated the influence of cellular bioactivation capacity and DNA repair on cytotoxicity of the DNA alkylating agent acylfulvene (AF). We compared the cytotoxicity and RNA synthesis inhibition by AF and its synthetic activated analogue iso-M0 in a panel of fibroblast cell lines with deficiencies in transcription-coupled (TC NER) or global genome nucleotide excision repair (GG-NER). We related these data to the inherent bioactivation capacity of each cell type on the basis of mRNA levels. We demonstrated that specific inactivation of TC-NER by siRNA had the largest positive impact on AF activity in a cancer cell line. These findings establish that transcription-coupled DNA repair reduces cellular sensitivity to AF, independent of the requirement for bioactivation. PMID- 28076681 TI - Computational Modeling of Neurotransmitter Release Evoked by Electrical Stimulation: Nonlinear Approaches to Predicting Stimulation-Evoked Dopamine Release. AB - Neurochemical changes evoked by electrical stimulation of the nervous system have been linked to both therapeutic and undesired effects of neuromodulation therapies used to treat obsessive-compulsive disorder, depression, epilepsy, Parkinson's disease, stroke, hypertension, tinnitus, and many other indications. In fact, interest in better understanding the role of neurochemical signaling in neuromodulation therapies has been a focus of recent government- and industry sponsored programs whose ultimate goal is to usher in an era of personalized medicine by creating neuromodulation therapies that respond to real-time changes in patient status. A key element to achieving these precision therapeutic interventions is the development of mathematical modeling approaches capable of describing the nonlinear transfer function between neuromodulation parameters and evoked neurochemical changes. Here, we propose two computational modeling frameworks, based on artificial neural networks (ANNs) and Volterra kernels, that can characterize the input/output transfer functions of stimulation-evoked neurochemical release. We evaluate the ability of these modeling frameworks to characterize subject-specific neurochemical kinetics by accurately describing stimulation-evoked dopamine release across rodent (R2 = 0.83 Volterra kernel, R2 = 0.86 ANN), swine (R2 = 0.90 Volterra kernel, R2 = 0.93 ANN), and non-human primate (R2 = 0.98 Volterra kernel, R2 = 0.96 ANN) models of brain stimulation. Ultimately, these models will not only improve understanding of neurochemical signaling in healthy and diseased brains but also facilitate the development of neuromodulation strategies capable of controlling neurochemical release via closed-loop strategies. PMID- 28076684 TI - Radiographic Differentiation of Advanced Fibrocystic Lung Diseases. AB - The concept of end-stage lung disease suggests a final common pathway for most diffuse parenchymal lung diseases. In accordance with this concept, end-stage disease is characterized radiographically and pathologically by the presence of extensive honeycombing. However, sequential computed tomographic (CT) scans obtained from patients with chronic diffuse lung disease evolve over time to show various advanced lung disease patterns other than honeycombing. In addition, several radiographically distinct honeycomb patterns, including microcystic, macrocystic, mixed, and combined emphysema and honeycombing, differentiate one advanced lung disease from another. For example, usual interstitial pneumonia (IP) usually shows mixed microcystic and macrocystic honeycombing. In contrast, CT images of long-standing fibrotic nonspecific IP typically show only small, scattered foci of honeycombing; instead, most enlarged airspaces observed in the advanced stage of this disease represent dilatation of bronchioles. In desquamative IP and pulmonary Langerhans cell histiocytosis, focal opacities typically evolve into emphysema-like lesions seen on CT imaging. In combined pulmonary fibrosis and emphysema and sarcoidosis, the cysts tend to be larger than those observed in usual IP. Sequential CT scans in other chronic, diffuse lung diseases also show various distinctive changes. This article highlights radiographic patterns of lung destruction that belie a single common pathway to end-stage lung disease. Recognition of distinct radiographic patterns of lung destruction can help differentiate diffuse parenchymal lung diseases, even in advanced stages of disease evolution. PMID- 28076686 TI - Small-molecule HIV-1 entry inhibitors targeting gp120 and gp41: a patent review (2010-2015). AB - INTRODUCTION: It is essential to discover and develop small-molecule HIV-1 entry inhibitors with suitable pharmaceutical properties. Areas covered: We review the development of small-molecule HIV-1 entry inhibitors as evidenced in patents, patent applications, and related research articles published between 2010 and 2015. Expert opinion: HIV-1 Env gp120 and gp41 are important targets for development of HIV-1 entry inhibitors. The Phe43 pocket in gp120 and the highly conserved hydrophobic pocket on gp41 NHR-trimer are important targets for identification of HIV-1 attachment and fusion inhibitors, respectively. Compounds that bind to Phe43 pocket can block viral gp120 binding to CD4 on T cells, thus inhibiting HIV-1 attachment. However, most compounds targeting Phe43 pocket identified so far are HIV-1 entry agonists with the ability to enhance infectivity of HIV-1 in CD4-negative cells. Therefore, it is essential to identify HIV-1 entry antagonist-based HIV-1 attachment/entry inhibitors. Compounds binding to the gp41 hydrophobic pocket may inhibit CHR binding to the gp41 NHR trimer, thus blocking six-helix bundle formation and gp41-mediated virus cell fusion. However, most lead compounds targeting this pocket have low potency, possibly because the pocket is too big or too deep. Therefore, it is necessary to identify other pockets in gp41 for developing HIV-1 fusion/entry inhibitors. PMID- 28076685 TI - Diffusion of Evidence-based Intensive Care Unit Organizational Practices. A State Wide Analysis. AB - RATIONALE: Several intensive care unit (ICU) organizational practices have been associated with improved patient outcomes. However, the uptake of these evidence based practices is unknown. OBJECTIVES: To assess diffusion of ICU organizational practices across the state of Pennsylvania. METHODS: We conducted two web-based, cross-sectional surveys of ICU organizational practices in Pennsylvania acute care hospitals, in 2005 (chief nursing officer respondents) and 2014 (ICU nurse manager respondents). MEASUREMENTS AND MAIN RESULTS: Of 223 eligible respondents, nurse managers from 136 (61%) medical, surgical, mixed medical-surgical, cardiac, and specialty ICUs in 98 hospitals completed the 2014 survey, compared with 124 of 164 (76%) chief nursing officers in the 2005 survey. In 2014, daytime physician staffing models varied widely, with 23 of 136 (17%) using closed models and 33 (24%) offering no intensivist staffing. Nighttime intensivist staffing was used in 37 (27%) ICUs, 38 (28%) used nonintensivist attending staffing, and 24 (18%) had no nighttime attending physicians. Daily multidisciplinary rounds occurred in 93 (68%) ICUs. Regular participants included clinical pharmacists in 68 of 93 (73%) ICUs, respiratory therapists in 62 (67%), and advanced practitioners in 37 (39%). Patients and family members participated in rounds in 36 (39%) ICUs. Clinical protocols or checklists for mechanically ventilated patients were available in 128 of 133 (96%) ICUs, low tidal volume ventilation for acute respiratory distress syndrome in 54 of 132 (41%) ICUs, prone positioning for severe acute respiratory distress syndrome in 37 of 134 (28%) ICUs, and family meetings in 19 of 134 (14%) ICUs. Among 61 ICUs that responded to both surveys, there was a significant increase in the proportion of ICUs using nighttime in-ICU attending physicians (23 [38%] in 2005 vs. 30 [49%] in 2014; P = 0.006). CONCLUSIONS: The diffusion of evidence-based ICU organizational practices has been variable across the state of Pennsylvania. Only half of Pennsylvania ICUs have intensivists dedicated to the ICU. Variable numbers use clinical protocols for life-saving therapies, and few use structured family engagement strategies. In contrast, the diffusion of non-evidence-based practices, including overnight ICU attending physician staffing, is increasing. Future research should focus on promoting implementation of organizational evidence to promote high quality ICU care. PMID- 28076688 TI - Exploring an Emotional Intelligence Model With Psychiatric Mental Health Nurses. AB - BACKGROUND: A lack of emotional skills may affect a nurse's personal well-being and have negative effects on patient outcomes. OBJECTIVE: To compare psychiatric mental health nurses' (PMHN) scores on the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) to a normed population and compare the emotional intelligence (EI) scores of PMHNs using two tools, MSCEIT and Self-Rated Emotional Intelligence Scale (SREIS). DESIGN: Comparative descriptive and correlational study. RESULTS: PMHNs in the study had a higher mean EI compared with that of 5,000 participants in the normed MSCEIT sample. Significant weak correlations were seen between the perceiving and understanding emotion branches of the MSCEIT and SREIS. CONCLUSION: The current study added data about a sample of PMHN's EI levels in the United States, which may encourage dialog about EI among PMHNs. Future research is needed to examine the relationship between self report EI tools (e.g., SREIS) and performance tools (e.g., MSCEIT) to determine if they are measuring the same construct. PMID- 28076687 TI - Parent and Family Processes Related to ADHD Management in Ethnically Diverse Youth. AB - BACKGROUND: Previous research has shown major disparities in attention deficit hyperactivity disorder (ADHD) for diverse youth across America. We do not fully understand, however, how parent and family processes are related to the identification, care-seeking approaches, treatment preferences, and engagement with care systems and services for youth with ADHD. OBJECTIVES: The present study aimed to explore parent and family processes related to the management of ADHD in racially and ethnically diverse youth. DESIGN: This integrative review was structured with the methodology proposed by Whittemore and Knafl. RESULTS: Three major electronic databases yielded a final sample of 32 articles (24 quantitative, 6 qualitative, and 2 mixed methods). Nine themes emerged within three overarching meta-themes. CONCLUSIONS: Understanding the unique perspectives of families from diverse backgrounds is essential for clinicians, researchers, and policymakers, who are dedicated to understanding racial and ethnic perspectives and developing ecologically appropriate and family-based interventions for youth with ADHD. PMID- 28076689 TI - National Organization of Nurse Practitioner Faculties. AB - BACKGROUND: No data exist about how directors of psychiatric mental health (PMH) graduate nurse practitioner (NP) programs have dealt with moving their programs to a lifespan model. It is equally unclear as to how many programs have changed to a doctor of nursing practice (DNP) level of clinical education. OBJECTIVES: The purpose of this survey was to gather data on the state of graduate PMH NP education as they align with regulatory models. DESIGN: A brief survey was sent via e-mail to 118 program directors of PMH NP programs. RESULTS: Seventy-six program directors responded (64% return rate). Their responses indicate all programs have transitioned to a PMH NP lifespan model and about a third to the DNP level. Securing child clinical placements is a significant issue. CONCLUSION: Significant challenges exist to growing the PMH NP lifespan workforce including how to assist PMH clinical nurse specialists, Adult PMH NPs, and other NPs wanting to obtain the PMH NP lifespan degree. PMID- 28076690 TI - Effect of intermittent aeration strategies on treatment performance and microbial community of an IFAS reactor treating municipal waste water. AB - This study investigated the effect of various intermittent aeration (IA) cycles on organics and nutrient removal, and microbial communities in an integrated fixed-film activated sludge (IFAS) reactor treating municipal waste water. Average effluent biological oxygen demand (BOD), chemical oxygen demand (COD), total suspended solids, total nitrogen (TN) and total phosphorus (TP) values were noted as 20, 50, 30, 12 and 1.5 mgL-1, respectively, in continuous aeration mode. A total of four operational conditions (run 1, continuous aeration; run 2, 150/30 min aeration on/off time; run 3, 120/60 min aeration on/off time and run 4, 90/60 min aeration on/off time) were investigated in IFAS reactor assessment. Among the all examined IA cycles, IA phase 2 gave the maximum COD and BOD removals with values recorded as 97% and 93.8%, respectively. With respect to nutrient removal (TN and TP), IA phase 1 was found to be optimum. Pathogen removal efficiency of present system was recorded as 90-95% during the three phases. With regard to settling characteristics, pilot showed poor settling during IA schedules, which was also evidenced by high sludge volume index values. Overall, IA could be used as a feasible way to improve the overall performance of IFAS system. PMID- 28076691 TI - Removal of copper from aqueous solutions by rhizofiltration using genetically modified hairy roots expressing a bacterial Cu-binding protein. AB - : The aim of this work was to develop a biotechnological tool to hyperaccumulate high copper (Cu) concentrations from wastewaters. Transgenic tobacco hairy roots were obtained by expressing, either the wild-type version of the gene copC from Pseudomonas fluorescens in the cytoplasm of plant cells (CuHR), or a modified version targeted to the vacuole (CuHR-V). Control hairy roots transformed with the empty vector (HR) were also generated. The roots were incubated in the presence of solutions containing Cu (from 1 to 50 mM). At 5 mM external copper, transgenic hairy roots accumulated twice the amount of copper accumulated by control hairy roots. However, at 50 mM Cu, accumulation in both transgenic and control roots reached similar values. Maximum Cu accumulation achieved by transgenic hairy roots was 45,000 ug g-1 at 50 mM external Cu. Despite the high Cu accumulation, transgenic hairy roots, particularly CuHR-V, showed less toxicity symptoms, in correlation with lower activity of several antioxidant enzymes and lower malondialdehyde (MDA) levels. Moreover, CuHR-V roots displayed low values of the oxidative stress index (OSI) - a global parameter proposed for oxidative stress - indicating that targeting CopC to the vacuole could alleviate the oxidative stress caused by Cu. Our results suggest that expressing copC in transgenic hairy roots is a suitable strategy to obtain Cu-hyperaccumulator hairy roots with less toxicity stress symptoms. ABBREVIATIONS: APX: ascorbate peroxidase; ATSDR: Agency for Toxic Substances and Disease Registry (U.S.); BCF: bioconcentration factor; CuHR: copper-hairy roots; EDTA: ethylenediamine tetracetic acid; EPA: Environmental Protection Agency (U.S.); GSH: glutathione; HM: heavy metals; HR: control hairy roots; ICP-OES: Inductively Coupled Plasma/Optical Emission Spectrometry; MDA: malondialdehyde; NBT: nitroblue tetrazolium; OD: optical density; OSI: oxidative stress index; PCR: polymerase chain reaction; PVP: polyvynilpirrolidone; PX: peroxidase; ROS: reactive oxygen species; SOD: superoxide dismutase. PMID- 28076694 TI - Free Communications. PMID- 28076692 TI - The effects of ultrasound-guided corticosteroid injection for the treatment of hemiplegic shoulder pain on depression and anxiety in patients with chronic stroke. AB - PURPOSE: We attempted to investigate whether ultrasound (US)-guided intra articular or subacromial bursa corticosteroid injections can potentially influence the severity of depression and anxiety in patients with chronic stroke with hemiplegic shoulder pain (HSP). METHODS: Thirty patients with chronic stroke with HSP received US-guided corticosteroid injections. Numeric rating scale (NRS) scores, passive shoulder range of motion (ROM), Beck Depression Inventory (BDI) scores and Spielberger State-Trait Anxiety Inventory (STAI) scores were evaluated before the injection, and one and two months after the injection. RESULTS: NRS, passive shoulder ROM, BDI and STAI scores were significantly lower one and two months following the injection. Changes in NRS scores were significantly correlated with changes in psychological outcomes (BDI and STAI). CONCLUSION: US guided intra-articular or subacromial bursa corticosteroid injections might be a beneficial treatment option for relieving depression and anxiety symptoms in patients with chronic stroke with HSP. Also, US-guided injections appear to be helpful for reducing shoulder pain and increasing shoulder ROM. PMID- 28076695 TI - Deacetylase inhibitors: an advance in myeloma therapy? AB - INTRODUCTION: A significant unmet need exists in patients with relapsed or refractory multiple myeloma (MM), which remains an incurable disease despite recent advances in the field. One such development was the use of deacetylase inhibitors (DACi), which exert unique antimyeloma effects through targeting of epigenetic and protein metabolism pathways. The pan-DACi panobinostat was recently approved in combination with bortezomib and dexamethasone for use in patients with relapsed or relapsed and refractory MM. Results of a phase 3 trial showed that the panobinostat-containing regimen improved the overall response rate and progression-free survival. Panobinostat-associated adverse events included thrombocytopenia, diarrhea, fatigue, and peripheral neuropathy. Research into how to maintain the benefits of DACi while improving tolerability is ongoing. Areas covered: This review focuses on the efficacy and safety of panobinostat and panobinostat-based combinations for MM. Early data from clinical trials investigating the HDAC6 inhibitor ricolinostat are also discussed. Expert commentary: DACi are a unique and effective new class of agents for the treatment of MM, with panobinostat being the first to have clinically meaningful benefit for patients with relapsed or refractory MM. Optimization of dose and schedule, novel combination strategies, and introduction of selective DACi may improve the risk-benefit profile of DACi-based regimens. PMID- 28076696 TI - Proton pump inhibitors for preventing non-steroidal anti-inflammatory drug induced gastrointestinal toxicity: a systematic review. AB - OBJECTIVE: Proton pump inhibitors (PPIs) are recommended for preventing gastrointestinal lesions induced by non-steroidal anti-inflammatory drugs (NSAIDs). We performed this study: (1) to evaluate the effectiveness and safety of PPIs, (2) to explore the association between effectiveness and potential influential factors, and (3) to investigate the comparative effect of different PPIs. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched to identify randomized controlled trials comparing different classes of PPIs, or comparing PPIs with placebo, H2 receptor antagonists or misoprostol in NSAIDs users. Both pairwise meta-analysis and Bayesian network meta-analysis were performed. RESULTS: Analyses were based on 12,532 participants from 31 trials. PPIs were significantly more effective than placebo in reducing ulcer complications (relative risk [RR] = 0.29; 95% confidence interval [CI], 0.20 to 0.42) and endoscopic peptic ulcers (RR = 0.27; 95% CI, 0.22 to 0.33), with no subgroup differences according to class of NSAIDs, ulcer risk, history of previous ulcer disease, Helicobacter pylori infection, or age. To prevent one ulcer complication, 10 high risk patients and 268 moderate risk patients need PPI therapy. Network meta-analysis indicated that the effectiveness of different PPIs in reducing ulcer complications and endoscopic peptic ulcers is generally similar. PPIs significantly reduced gastrointestinal adverse events and the related withdrawals compared to placebo; there is no difference in safety between different PPIs. CONCLUSIONS: PPIs are effective and safe in preventing peptic ulcers and complications in a wide spectrum of patients requiring NSAID therapy. There is no major difference in the comparative effectiveness and safety between different PPIs. PMID- 28076697 TI - Development and characterization of a mucoadhesive sublingual formulation for pain control: extemporaneous oxycodone films in personalized therapy. AB - OBJECTIVE: The aim of this work was the development of mucoadhesive sublingual films, prepared using a casting method, for the administration of oxycodone. MATERIALS AND METHODS: A solvent casting method was employed to prepare the mucoadhesive films. A calibrated pipette was used to deposit single aliquots of different polymeric solutions on a polystyrene plate lid. Among the various tested polymers, hydroxypropylcellulose at low and medium molecular weight (HPC) and pectin at two different degrees of esterification (PC) were chosen for preparing solutions with good casting properties, capable of producing films suitable for mucosal application. RESULTS AND DISCUSSION: The obtained films showed excellent drug content uniformity and stability and rapid drug release, which, at 8 min, ranged from 60% to 80%. All films presented satisfactory mucoadhesive and mechanical properties, also confirmed by a test on healthy volunteers, who did not experience irritation or mucosa damages. Pectin films based on pectin at lower degrees of esterification have been further evaluated to study the influence of two different amounts of drug on the physicochemical properties of the formulation. A slight reduction in elasticity has been observed in films containing a higher drug dose; nevertheless, the formulation maintained satisfactory flexibility and resistance to elongation. CONCLUSIONS: HPC and PC sublingual films, obtained by a simple casting method, could be proposed to realize personalized hospital pharmacy preparations on a small scale. PMID- 28076698 TI - Emerging role of SETDB1 as a therapeutic target. AB - INTRODUCTION: Epigenetic changes lead to aberrant gene expression in cancer. SETDB1, a histone lysine methyltransferase plays an important role in methylation and gene silencing. Aberrant histone methylation at H3K9 by SETDB1 promotes silencing of tumor suppressor genes and thus contributes to carcinogenesis. Recent studies indicate that SETDB1 is abnormally expressed in various human cancer conditions which contributed to enhanced tumor growth and metastasis. Hence, SETDB1 appears to be a promising epigenetic target for therapeutic intervention. Areas covered: In this article, the structural features, localization and functions of SETDB1 are reviewed. Also, an overview of the role of SETDB1 in cancer and other disease mechanisms, the currently studied inhibitors for SETDB1 are mentioned. Expert opinion: Silencing of tumor suppressor genes due to excessive trimethylation at H3K9 by amplified SETDB1 levels is found in various cancerous conditions. Since epigenetic changes are reversible, SETDB1 holds promise as an important therapeutic target for cancer. Therefore, a better understanding of the role of SETDB1 and its interaction with various proteins in cancer-related mechanisms along with therapeutic interventions specific for SETDB1 may improve targeted cancer therapy. PMID- 28076699 TI - Infective endocarditis prophylaxis: a review. AB - INTRODUCTION: Guidelines for prophylaxis against infective endocarditis (IE) have changed significantly due to a lack of evidence for its efficacy and increasing concerns about safety and antibiotic resistance. The impact of these changes on clinical practice and IE hospitalisation trends and outcomes has become a focus of research. Areas covered: We review the rationale for and against IE prophylaxis, highlight significant changes in guidelines since 2002, and discuss literature examining the impact of these changes on antibiotic prescription rates for IE prophylaxis, IE incidence, morbidity, and mortality. We included English articles published since 2002 relevant to IE prophylaxis. Expert commentary: Existing guidelines recommend limited to no prophylaxis against IE but differ on which patient populations would benefit most. Antibiotic prescription rates for IE prophylaxis have declined as a result of newer restrictive guidelines, most significantly in the UK where IE prophylaxis is not recommended. However, conflicting data exists on the impact of these changes on the trends of IE hospitalisation and clinical outcomes. Definitive studies to resolve this controversy do not seem feasible in the near future but well designed prospective observational studies may provide novel information on the long term impact of the new guidelines. PMID- 28076700 TI - Correlation between acute toxicity for Daphnia magna, Aliivibrio fischeri and physicochemical variables of the leachate produced in landfill simulator reactors. AB - Due to the diversified nature of municipal solid waste and the different stages of its decomposition, the formed leachates result in a complex chemical mixture with toxic potential. These chemicals can cause environmental problems, such as the contamination of surface or groundwater, thus affecting the balance of aquatic ecosystems. The aim of our study was to evaluate the acute toxicity of leachates in Daphnia magna and Aliivibrio fischeri and to identify the main physicochemical variables that influence the toxicity of the landfill leachates produced in reactors within pilot simulations. Acute toxicity tests carried out on D. magna and A. fischeri showed that the leachates produced inside the reactors are highly toxic, presenting EC5048h < 1% for D. magna and EC5015min < 12% for A. fischeri. This result indicates that microcrustaceans are more sensitive to leachates, making them more suitable to our study. Pb showed the highest correlation with EC5048h, suggesting that Pb is the main chemical variable indicative of toxicity for the conditions of the experiment. In smaller scale, phosphate (PO43-) and nitrate (NO3-) were the macronutrients that most influenced the toxicity. Clearly, this correlation should be viewed with caution because the synergistic effects of this complex mixture are difficult to observe. PMID- 28076702 TI - Lasmiditan for the treatment of migraine. AB - INTRODUCTION: Migraine is one of the most common diseases in the world, with high economical and subjective burden. Migraine acute therapy is nowadays based on specific and non-specific drugs but up to 40% of episodic migraineurs still have unmet treatment needs and over 35% do not benefit from triptans administration. Serotonin-1F receptors have been identified in trigeminal system and became an ideal target for anti-migraine drug development as potential trigeminal neural inhibitors. Lasmiditan, a novel serotonin1F receptor agonist, showed specific affinity in vitro for the receptor without any vasoconstrictive action and inhibited markers associated with electrical stimulation of trigeminal ganglion in migraine animal models. Areas covered: This article reviews both preclinical and clinical studies on lasmiditan as a potential acute therapy for migraine, as well as pharmacokinetic and pharmacodynamic features. It also summarizes safety and tolerability data gathered in the various human studies. Expert opinion: The absence of vasoconstrictive effects makes lasmiditan a promising novel migraine acute therapy. Although preclinical and Phase I and II studies established a significant efficacy, the limited knowledge about pharmacokinetics and metabolism, the high rate of non-serious central nervous system side effects and the lack of larger studies remain still a matter of concern that should be addressed in future studies. PMID- 28076703 TI - A systematic review to assess adherence and persistence with statins. AB - OBJECTIVE: To identify and assess studies published over a 10 year period up to February 2016 which measure adherence or persistence with statins, to summarize their methods, strengths and weaknesses and to summarize evidence linking statin adherence/persistence with risk of cardiovascular events. METHODS: Electronic databases and abstracts from four major cardiovascular disease conferences were searched from January 2005 to February 2016. The study selection process was performed by two reviewers working independently. Studies were included if they reported data regarding patient adherence or persistence with statins in adults with primary hypercholesterolemia, using any type of study design or length of follow-up. One reviewer extracted the study data and assessed study quality, which was checked by a second reviewer independently. Given the heterogeneity between the included studies a narrative critique and summary is presented. RESULTS: We report on 84 real world studies which aimed to assess adherence or persistence with statins. The majority of studies concluded that good adherence/persistence was associated with reduction in cardiovascular events and mortality. In two studies high intensity statin regimens were associated with poorer patient adherence when compared to low intensity statins. Adherence and persistence with statin therapy also has an impact on hospitalization costs and other cardiovascular disease (CVD) related costs. CONCLUSIONS: Adherence and persistence are associated with a reduction in CVD events and mortality. There was limited evidence to suggest that high intensity statin regimens are associated with poorer treatment adherence when compared to lower intensity regimens. Hence, more robust studies are required to establish this association. As recommended by the 2013 ACC/AHA, 2016 ESC and several other clinical guidelines, clinicians and pharmacy managers should regularly monitor statin therapy adherence. PMID- 28076701 TI - Reduced Expiratory Flow Rate among Heavy Smokers Increases Lung Cancer Risk. Results from the National Lung Screening Trial-American College of Radiology Imaging Network Cohort. AB - RATIONALE: Although epidemiological studies consistently show that chronic obstructive pulmonary disease is associated with an increased risk of lung cancer, debate exists as to whether there is a linear relationship between the severity of airflow limitation and lung cancer risk. OBJECTIVES: We examined this in a large, prospective study of older heavy smokers from the American College of Radiology Imaging Network subcohort of the National Lung Screening Trial (ACRIN). Airflow limitation was defined by prebronchodilator spirometry subgrouped according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 1-4. METHODS: In the National Lung Screening Trial-ACRIN cohort of 18,473 screening participants, 6,436 had airflow limitation (35%) and 12,037 (65%) had no airflow limitation. From these groups, 758 lung cancer cases were prospectively identified. Participants with airflow limitation were stratified according to GOLD groups 1 (n = 1,607), 2 (n = 3,528), 3 (n = 1,083), and 4 (n = 211). Lung cancer incidence at study end (mean follow-up, 6.4 yr) was compared between the GOLD groups and those with no airflow limitation (referent group). MEASUREMENTS AND MAIN RESULTS: Compared with those with no airflow limitation, where lung cancer incidence was 3.78/1,000 person years, incidence rates increased in a simple linear relationship: GOLD 1 (6.27/1,000 person yr); GOLD 2 (7.86/1,000 person yr); GOLD 3 (10.71/1,000 person yr); and GOLD 4 (13.25/1,000 person yr). All relationships were significant versus the reference group at a P value of 0.0001 or less. CONCLUSIONS: In a large prospective study of high-risk cigarette smokers, we report a strong linear relationship between increasing severity of airflow limitation and risk of lung cancer. PMID- 28076704 TI - TARGT Gene Therapy Platform for Correction of Anemia in End-Stage Renal Disease. PMID- 28076705 TI - Improving the Accuracy of Prenatal Screening with DNA Copy-Number Analysis. PMID- 28076706 TI - Circinate Balanitis. PMID- 28076707 TI - Adjunctive Azithromycin Prophylaxis for Cesarean Delivery. PMID- 28076708 TI - Patient-Reported Outcomes - Harnessing Patients' Voices to Improve Clinical Care. PMID- 28076710 TI - Graves' Disease. PMID- 28076712 TI - Hepatic Encephalopathy. PMID- 28076711 TI - Case 1-2017. A 70-Year-Old Woman with Gradually Progressive Loss of Language. PMID- 28076709 TI - Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. AB - BACKGROUND: Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. METHODS: We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. RESULTS: At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. CONCLUSIONS: Treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .). PMID- 28076713 TI - Fibromuscular Dysplasia of the Brachial Artery. PMID- 28076714 TI - Mental Illness and the Criminal Justice System. PMID- 28076715 TI - Preserved Renal-Allograft Function and the PD-1 Pathway Inhibitor Nivolumab. PMID- 28076716 TI - 10-Year Outcomes in Localized Prostate Cancer. PMID- 28076717 TI - 10-Year Outcomes in Localized Prostate Cancer. PMID- 28076718 TI - Chronic Cough. PMID- 28076719 TI - Pediatric Migraine Headache - Still Searching for Effective Treatments. PMID- 28076720 TI - Screening for Colorectal Neoplasia. PMID- 28076721 TI - Effect of Tumor Complexity and Technique on Efficacy and Complications after Percutaneous Microwave Ablation of Stage T1a Renal Cell Carcinoma: A Single Center, Retrospective Study. AB - Purpose To evaluate the effects of tumor complexity and technique on early and midterm oncologic efficacy and rate of complications for 100 consecutive biopsy proved stage T1a renal cell carcinomas (RCCs) treated with percutaneous microwave ablation. Materials and Methods This HIPAA-compliant, single-center retrospective study was approved by the institutional review board. The requirement to obtain informed consent was waived. Ninety-six consecutive patients (68 men, 28 women; mean age, 66 years +/- 9.4) with 100 stage T1a N0M0 biopsy-proved RCCs (median diameter, 2.6 cm +/- 0.8) underwent percutaneous microwave ablation between March 2011 and June 2015. Patient and procedural data were collected, including body mass index, comorbidities, tumor histologic characteristics and grade, RENAL nephrometry score, number of antennas, generator power, and duration of ablation. Technical success, local tumor progression, and presence of complications were assessed at immediate and follow-up imaging. The Kaplan-Meier method was used for survival analyses. Results Technical success was achieved for all 100 tumors (100%), including 47 moderately and five highly complex RCCs. Median clinical and imaging follow-up was 17 months (range, 0-48 months) and 15 months (range, 0-44 months), respectively. No change in estimated glomerular filtration rate was noted after the procedure (P = .49). There were three (3%) procedure-related complications and six (6%) delayed complications, all urinomas. One case of local tumor progression (1%) was identified 25 months after the procedure. Three-year local progression-free survival, cancer-specific survival, and overall survival were 88% (95% confidence interval: 0.52%, 0.97%), 100% (95% confidence interval: 1.0%, 1.0%), and 91% (95% confidence interval: 0.51%, 0.99%), respectively. Conclusion Percutaneous microwave ablation is an effective and safe treatment option for stage T1a RCC, regardless of tumor complexity. Long-term follow-up is needed to establish durable oncologic efficacy and survival relative to competing ablation modalities and surgery. (c) RSNA, 2017. PMID- 28076723 TI - Adaptation to a New Workplace According to Reactivity and Values-Motives Coherence at Work. AB - A new workplace is a result of changing a work post or undertaking a new job. Direct indices of adaptation to this situation (average mood at the workplace and job satisfaction) and the indirect ones (costs like health complaints and the level of depressing or facilitating anxiety) are analysed with regard to reactivity and values-motives coherence at work. Sixty bank workers were investigated. The obtained results confirm that mood and costs depend on reactivity, but satisfaction with work depends on coherence. Only achievement values-motives coherence at work differentiates direct and indirect indicators of adaptation. Considering both kinds of variables modifies dependencies. Some theoretical and practical conclusions resulting from the research are included. PMID- 28076722 TI - Is There Long-term Signal Intensity Increase in the Central Nervous System on T1 weighted Images after MR Imaging with the Hepatospecific Contrast Agent Gadoxetic Acid? A Cross-sectional Study in 91 Patients. AB - Purpose To evaluate whether there is T1-weighted signal intensity (SI) increase in the dentate nucleus (DN) and globus pallidus (GP) in relation to the middle cerebellar peduncle (MCP), pons, and thalamus after repeated administration of the liver-specific contrast agent gadoxetic acid. Materials and Methods This was an institutional review board-approved, prospectively conducted (written informed consent acquired), cross-sectional study performed in a consecutively selected patient group (n = 91; patients received one to 37 doses of gadoxetic acid) and a control group (n = 52; subjects had never received injections of gadolinium-based contrast agent) examined with a standard T1-weighted two-dimensional spin-echo pulse sequence of the brain at 1.5 T. DN/MCP, DN-to-pons, GP-to thalamus, and GP to-cerebrospinal fluid ratios were measured and compared by using the nonparametric Kruskal-Wallis test, corresponding pairwise tests, and Spearman correlation. Results DN/MCP (rho = 0.51, P < .0001) and DN-to-pons (rho = 0.41, P = .0001) ratios correlated positively with the number of previous administrations of gadoxetic acid. DN/MCP and DN-to-pons ratios were significantly different between control subjects (medians of 1.016 and 1.034, respectively) and patients with more than 10 gadoxetic acid administrations (1.038 [P < .0001] and 1.053 [P = .0100], respectively), whereas no significant difference was found in the groups with five to 10 (1.029 [P = .053] and 1.044 [P = .072], respectively) and fewer than five (1.014 [P = .420] and 1.030 [P = .595], respectively) gadoxetic acid administrations. GP-to-thalamus ratios differed significantly between the study and control groups (P < .0001), whereas no significant correlation was found for GP-to-thalamus ratios and number of gadoxetic acid administrations (rho = 0.13, P = .2304). Conclusion Results show a significant correlation between the number of gadoxetic acid administrations and the increase of SI in the DN, which is likely due to gadolinium retention. (c) RSNA, 2017. PMID- 28076724 TI - An Observation Method for Analyzing Operators' Routine Activity in Computerized Control Rooms. AB - An activity analysis method was developed for studying the structure and dynamics of control room operators' activity during normal operation based on directly observable elements of the operators' behavior. The method assesses current activity along three dimensions in each 5-min period of the shift. Intensity characterizes arousal level, direction shows whether the activity is directed predominantly at the process control task, at something else, or miscellaneous. Motivation reflects if the activity is driven by intrinsic or extrinsic motivation. A case study is presented, in which 3 morning, 3 afternoon, and 3 night shifts of a Nuclear Power Plant operator crew are involved. The obtained results gave a deeper understanding of the operators' activity and also revealed an "arousal compensation" tendency. PMID- 28076725 TI - Clogging of Filtering Material Systems Used for Disposable Respirators. AB - The article shows the problem of clogging in connection with the parameters of filtering materials used in respiratory protective equipment. The results of investigations of airflow resistance changes during the depositing of dust inside the filtering material are presented. The configuration of layers differing in mass per unit area and the number of layers, were taken into consideration. For each configuration, the clogging abilities and the changes of airflow resistance as a reason of loading with dust were assessed. The analysis of tested materials confirms the hypothesis that there is an important coincidence between the properties of the material used in filtering equipment and the clogging coefficient. The results show that the filter should have a layered structure and that the outer layer should be made of a nonwoven of relatively high surface density. PMID- 28076726 TI - Towards revalidation in Australia: a discussion. PMID- 28076727 TI - A game changer for eye care for diabetes. PMID- 28076729 TI - Diffraction spikes. PMID- 28076728 TI - Bringing competencies closer to day-to-day clinical work through entrustable professional activities. PMID- 28076730 TI - Encouraging early treatment of suspected heart attack: it's OK to call 000. PMID- 28076731 TI - The challenge of discharge: combining medication reconciliation and discharge planning. PMID- 28076732 TI - Centralising care for patients with pancreatic cancer: a hybrid model approach. PMID- 28076733 TI - Pancreatectomy is underused in NSW regions with low institutional surgical volumes: a population data linkage study. AB - OBJECTIVE: To examine differences in the proportions of people diagnosed with pancreatic cancer who underwent pancreatectomy, post-operative outcomes and 5 year survival in different New South Wales administrative health regions of residence. DESIGN, SETTING AND PARTICIPANTS: Retrospective analysis of NSW data on pancreatic cancer incidence and surgery, 2005-2013. MAIN OUTCOME MEASURES: The proportion of newly diagnosed patients with pancreatic cancer who were resected in each region; 90-day post-operative mortality; one-year post-operative survival; 5-year post-diagnosis survival. RESULTS: 14% of people diagnosed with pancreatic cancer during 2010-2013 (431 of 3064) underwent pancreatectomy, an average of 108 resections per year. After adjusting for age, sex and comorbidities, the proportion that underwent resection varied significantly between regions, ranging between 8% and 21% (P<0.001). Higher resection rates were not associated with higher post-operative 90-day mortality or lower one-year survival (unadjusted and risk-adjusted analyses). Higher resection rates were associated with higher 5-year post-diagnosis survival: the mean survival in regions with resection rates below 10% was 3.4%, compared with 7.2% in regions with rates greater than 15% (unadjusted and adjusted survival analyses; P<0.001). There was a positive association between regional resection rate and the pancreatectomy volume of hospitals during 2005-2009. An additional 32 people would be resected annually if resection rates in low rate regions were increased to the 80th percentile regional resection rate (18%). CONCLUSION: There is significant geographic variation in the proportion of people with pancreatic cancer undergoing pancreatectomy, and the 5-year survival rate is higher in regions where this proportion is higher. PMID- 28076734 TI - Effect of a mass media campaign on ambulance use for chest pain. AB - OBJECTIVES: To evaluate the impact of comprehensive public awareness campaigns by the National Heart Foundation of Australia on emergency medical service (EMS) use by people with chest pain. DESIGN, SETTING AND PARTICIPANTS: A retrospective analysis of 253428 emergency ambulance attendances for non-traumatic chest pain in Melbourne, January 2008 - December 2013. Time series analyses, adjusted for underlying trend and seasonal effects, assessed the impact of mass media campaigns on EMS use. MAIN OUTCOME MEASURE: Monthly ambulance attendances. RESULTS: The median number of monthly ambulance attendances for chest pain was 3609 (IQR, 3011-3891), but was higher in campaign months than in non-campaign months (3880 v 3234, P<0.001). After adjustments, campaign activity was associated with a 10.7% increase (95% CI, 6.5-14.9%; P<0.001) in monthly ambulance use for chest pain, and a 15.4% increase (95% CI, 10.1-20.9%; P<0.001) when the two-month lag periods were included. Clinical presentations for suspected acute coronary syndromes, as determined by paramedics, increased by 11.3% (95% CI, 6.9-15.9%; P<0.001) during campaigns. Although the number of patients transported to hospital by ambulance increased by 10.0% (95% CI, 6.1 14.2%; P<0.001) during campaign months, the number of patients not transported to hospital also increased, by 13.9% (95% CI, 8.3-19.8%; P<0.001). CONCLUSION: A public awareness campaign about responding to prodromal acute myocardial infarction symptoms was associated with an increase in EMS use by people with chest pain and suspected acute coronary syndromes. Campaign activity may also lead to increased EMS use in low risk populations. PMID- 28076735 TI - Reducing medication errors in hospital discharge summaries: a randomised controlled trial. AB - OBJECTIVES: To evaluate whether pharmacists completing the medication management plan in the medical discharge summary reduced the rate of medication errors in these summaries. DESIGN: Unblinded, cluster randomised, controlled investigation of medication management plans for patients discharged after an inpatient stay in a general medical unit. SETTING: The Alfred Hospital, an adult major referral hospital in metropolitan Melbourne, with an annual emergency department attendance of about 60000 patients. PARTICIPANTS: The evaluation included patients' discharge summaries for the period 16 March 2015 - 27 July 2015. INTERVENTIONS: Patients randomised to the intervention arm received medication management plans completed by a pharmacist (intervention); those in the control arm received standard medical discharge summaries (control). MAIN OUTCOME MEASURES: The primary outcome variable was a discharge summary including a medication error identified by an independent assessor. RESULTS: At least one medication error was identified in the summaries of 265 of 431 patients (61.5%) in the control arm, compared with 60 of 401 patients (15%) in the intervention arm (P<0.01). The absolute risk reduction was 46.5% (95% CI, 40.7-52.3%); the number needed to treat (NNT) to avoid one error was 2.2 (95% CI, 1.9-2.5). The absolute risk reduction for a high or extreme risk error was 9.6% (95% CI, 6.4 12.8%), with an NNT of 10.4 (95% CI, 7.8-15.5). CONCLUSIONS: Pharmacists completing medication management plans in the discharge summary significantly reduced the rate of medication errors (including errors of high and extreme risk) in medication summaries for general medical patients.Australia New Zealand Clinical Trials Registry number: ACTRN12616001034426. PMID- 28076736 TI - Australian Institute of Sport and Australian Medical Association position statement on concussion in sport. AB - Sport-related concussion is a growing health concern in Australia. Public concern is focused on the incidence and potential long term consequences of concussion. Children may be more prone to concussion and take longer to recover. The Australian Institute of Sport and the Australian Medical Association have collaborated to present the most contemporary evidence-based information in a format appropriate for all stakeholders. This position statement aims to ensure that participant safety and welfare is paramount when dealing with concussion in sport.First aid principles apply in the management of the athlete with suspected concussion, including protection of the cervical spine. Tools exist for use by members of the community, allowing identification of key symptoms and signs that raise the suspicion of concussion. Medical professionals should use the Sport Concussion Assessment Tool 3, in conjunction with clinical assessment for the diagnosis of concussion. Clinical assessment includes mechanism of injury, symptoms and signs, cognitive functioning, and neurological assessment including balance testing. In any situation where concussion is suspected, the athlete must be immediately removed from sport and not be allowed to return to activity until they have been assessed by a medical practitioner. "If in doubt, sit them out."A diagnosis of concussion requires immediate physical and cognitive rest, followed by a structured, graduated return to physical activity. Children require a longer period of recovery from concussion. Algorithms are provided for use by medical and non-medically trained stakeholders in the recognition and management of concussion. PMID- 28076737 TI - Absolute risk of cardiovascular disease events and blood pressure- and lipid lowering therapy in Australia. PMID- 28076738 TI - Lost in translation: the gap between what we know and what we do about cardiovascular disease. PMID- 28076739 TI - Retraction notice. PMID- 28076740 TI - Overcoming cardiovascular disease in Indigenous Australians. PMID- 28076742 TI - Cloudless. PMID- 28076741 TI - Introducing a new series on innovations in medical education. PMID- 28076743 TI - Australia Day 2016: alcohol-related presentations to emergency departments. PMID- 28076744 TI - Modern management of acne. AB - Acne is a chronic inflammatory disease of the pilosebaceous unit resulting from androgen-induced increased sebum production; altered keratinisation; bacterial colonisation of hair follicles on the face, neck, chest and back by Propionibacterium acnes; and an inflammatory response in the skin. The exact way these processes interact and the order in which they occur in the pathogenesis of acne are still unclear. Scarring that occurs from acne, particularly severe acne, can persist a lifetime and have long lasting psychosocial effects. Depression, social isolation and suicidal ideation are frequent comorbidities in acne. Despite the plethora of topical and systemic treatments available for acne, there is a relative lack of quality evidence for its application. Of the systemic treatments available, oral isotretinoin remains the most effective well established treatment for acne that targets all the aetiological factors. Current guidelines for the treatment of acne are based largely on expert consensus and advocate a combination of topical agents in mild to moderate cases and reserve the use of systemic therapies for moderate to severe or refractory cases of acne. However, given the psychosocial impacts of acne, there is a strong argument for early, effective treatment with systemic therapy when topical and general measures have failed. PMID- 28076745 TI - Absolute risk of cardiovascular disease events, and blood pressure- and lipid lowering therapy in Australia. PMID- 28076746 TI - Characteristics of patients presenting to an after-hours clinic: results of a MAGNET analysis. AB - After-hours access to general practice (GP) is critical to supporting accessibility and reducing emergency department demand. To understand who utilises after-hours GP services, this study examined the characteristics of presentations to an Eastern Melbourne after-hours clinic between 2005 and 2014. Descriptive analyses of patient and presentation characteristics, diagnoses, medications and pathology were conducted. Across the study period, 39.1% of presentations to the clinic (N=64,800) were by patients under 18 years of age. Females were found to attend more often than males, and nearly 79% of patients attended only once. The most common diagnoses were respiratory system diseases (13.4%), gastrointestinal system diseases (12.6%) and eye and ear problems (11.6%). Antibacterial medications accounted for over half (53.0%) of all prescriptions, with 34% of antibiotics prescribed to patients under 18 years of age. Seasonal variation in GP demand was also observed. Presenting patients differed from the wider GP patient population, with more young patients, and a higher proportion of prescriptions for antibacterial medications compared to other predominantly non-after-hours practices. Further research is required to understand the health-seeking, decision-making of patients who utilise after hours GPs over predominantly non-after-hours primary care services, to inform service promotion and delivery strategies. PMID- 28076747 TI - A preliminary investigation of the Partners in Health scale measurement properties in patients with end stage renal disease. AB - End-stage renal disease (ESRD) is becoming more prevalent in Australia. As a result, strategies to improve quality of life when living with ESRD are becoming increasingly important. The Flinders Program has been developed to help support and increase the self-management capacity of people living with chronic disease. The Partners in Health (PIH) scale is a self-management capacity assessment tool, which is an integral element of the Flinders Program. The primary aim of this study was to investigate the preliminary measurement properties of the PIH scale within the ESRD population. Forty participants took part in the study, which involved survey assessments at baseline and follow up and a semi-structured interview. Results indicated that the PIH scale had good internal reliability (alpha=0.85), moderate test-retest reliability (r=0.33) and face validity in ESRD patients. Areas for improving the instrument or data collection process were identified through qualitative interviews, and implications are discussed specific to ESRD patients. PMID- 28076749 TI - Epigenetic changes of hepatic glucocorticoid receptor in sheep male offspring undernourished in utero. AB - The aim of this study was to characterise the effects of maternal undernutrition during gestation on hepatic gluconeogenic enzyme gene expression and to determine whether such effects are mediated through epigenetic changes in the glucocorticoid receptor (GR). Pregnant ewes were fed a 50% nutrient-restricted diet from Day 0 to 30 (R1) or from Day 31 to 100 of gestation (R2) or a 100% diet throughout gestation (Control). After parturition lambs were fed to appetite. At 10 months of age offspring were euthanised and livers were removed. Maternal undernutrition did not affect offspring bodyweight at birth or at 10 months of age. However, liver weight of males of the R2 group was lower (P<0.05) in relation to other groups. A significant (P<0.05) hypomethylation of the hepatic GR promoter was revealed in males of the R2 group and a tendency towards the same in the R1 group, along with increased (P<0.001) GR gene expression in both restricted groups. A significant increase (P<0.05) in hepatic phosphoenolpyruvate carboxykinase (PEPCK) gene expression was found in male lambs of both undernourished groups, accompanied by increased (P<0.01) protein levels, while no differences were detected for glucose-6-phosphatase (G6Pase) mRNA abundance and protein levels. In female lambs, no differences between groups were observed for any parameter studied. These data represent potential mechanisms by which insults in early life may lead to persistent physiological changes in the offspring. PMID- 28076748 TI - Are low-to-middle-income households experiencing food insecurity in Victoria, Australia? An examination of the Victorian Population Health Survey, 2006-2009. AB - Food insecurity affects health and wellbeing. Little is known about the relationship between food insecurity across income levels. This study aims to investigate the prevalence and frequency of food insecurity in low-to-middle income Victorian households over time and identify factors associated with food insecurity in these households. Prevalence and frequency of food insecurity was analysed across household income levels using data from the cross-sectional 2006 09 Victorian Population Health Surveys (VPHS). Respondents were categorised as food insecure, if in the last 12 months they had run out of food and were unable to afford to buy more. Multivariable logistic regression was used to describe factors associated with food insecurity in low-to-middle-income households (A$40000-$80000 in 2008). Between 4.9 and 5.5% for total survey populations and 3.9-4.8% in low-to-middle-income respondents were food insecure. Food insecurity was associated with limited help from friends, home ownership status, inability to raise money in an emergency and cost of some foods. Food insecurity exists in households beyond those on a very low income. Understanding the extent and implications of household food insecurity across all income groups in Australia will inform effective and appropriate public health responses. PMID- 28076751 TI - Salter-Harris type IV fracture of the proximal phalanx of the thumb with rotation of the epiphysis: Outcome 10 years following open reduction and K-wire fixation. AB - INTRODUCTION: Salter-Harris type IV fracture of the proximal phalanx with 90 degrees rotation of the epiphysis is very rare. We report on a case of Salter Harris type IV fracture of the proximal phalanx of the thumb with rotation of the epiphysis and document the outcome 10 years after surgery. PRESENTATION OF CASE: A 5-year old boy presented with Salter-Harris type IV fracture of the thumb with 90 degrees rotation of the epiphysis. Open reduction and K-wire fixation was done. Ten years later, the injured thumb was smaller in width when compared to the contralateral thumb, although there was no length discrepancy. Clinically, there was full range of motion. Radiologically, the physis was still open but there were minor irregularities at the adjacent metaphyseal base and epiphysis. The diaphysis of the injured proximal phalanx had a constricted appearance when compared to the contralateral normal side. DISCUSSION: After an extensive literature review, we found one reported case which was similar to our case and had long term assessment. At skeletal maturity, there was complete remodeling and full range of motion of the digit with no shortening. The X-ray showed a constricted diaphysis of the proximal phalanx with an identical appearance to our case. CONCLUSION: We present a rare case of Salter-Harris type IV fracture of the proximal phalanx of the thumb with rotation of the epiphysis. Long term outcome was satisfactory but there was diaphyseal constriction leading to a narrower thumb. PMID- 28076750 TI - A giant multi-lobed osteochondroma of the phalanx in an adult: A case report. AB - INTRODUCTION: Solitary osteochondromas of the adult hand are extremely rare. We present a case of a giant multi-lobed osteochondroma of the phalanx in an adult. No similar cases were found in the literature. PRESENTATION OF CASE: A 25-year old male presented with a giant multi-lobed osteochondroma arising from the base of the middle phalanx; causing limitations of motion of the proximal interphalangeal joint (PIPJ). The patient refused complete excision, bone grafting and possible fusion of the PIPJ. Marginal resection resulted in recovery of almost full range of motion. There was no recurrence up to the 8-month follow up visit. DISCUSSION: The case was compared to previously reported cases of ostechondroma of the hand. The management is discussed along with differentiating large osteochondromas from Nora's lesions in the hand. CONCLUSION: A rare case of a large multi-lobed osteochondroma of the phalanx in an adult is presented and the management is discussed. PMID- 28076752 TI - Methotrexate-associated primary hepatic malignant lymphoma following hepatectomy: A case report. AB - INTRODUCTION: Recently, immunosuppressant-associated malignant lymphoma (ML) cases have been increasing along with the development of several effective immunosuppressant drugs for rheumatoid arthritis (RA). Among methotrexate (MTX) associated lymphoproliferative disorders, primary hepatic lymphoma (PHL) in patients with RA following surgical resection has not been reported previously. PRESENTATION OF CASE: A 65-year-old woman who is a hepatitis B virus carrier with a history of RA was admitted. MTX was introduced seven years prior as an RA treatment. Her laboratory data showed no elevation of several tumor markers, and liver function test results were normal. On contrasted computed tomography (CT) scanning, a slightly enhanced tumor was detected at the early phase, and tumor staining was sustained at the delayed phase. Further, subsegmentectomy of the S6 was performed. The pathological diagnosis was diffuse large B-cell lymphoma. However, positron emission tomography-CT and bone marrow aspiration sample showed no resident sign of ML. DISCUSSION: Diagnosis of PHL before surgery is difficult. If the mass lesion was solitary and had a certain degree of size, then resection could be performed for its treatment and diagnosis. The treatment for ML requires a diagnosis of the subtypes to select a therapeutic agent and determine the prognosis. Once a precise preoperative diagnosis was made, withdrawing MTX could be the first treatment in case of MTX-related ML. CONCLUSION: Long-term usage of immunosuppressant drugs could cause proliferative ML. Considering the increasing occurrence of MTX-related ML, withdrawing MTX should be considered, especially in patients with long-term immunosuppressant usage for RA. PMID- 28076753 TI - CD25 targeted therapy of chemotherapy resistant leukemic stem cells using DR5 specific TRAIL peptide. AB - Chemotherapy resistant leukemic stem cells (LSCs) are being targeted as a modern therapeutic approach to prevent disease relapse. LSCs isolated from methotrexate resistant side population (SP) of leukemic cell lines HL60 and MOLT4 exhibited high levels of CD25 and TRAIL R2/DR5 which are potential targets. Recombinant immunotoxin conjugating IL2alpha with TRAIL peptide mimetic was constructed for DR5 receptor specific targeting of LSCs and were tested in total cell population and LSCs. IL2-TRAIL peptide induced apoptosis in drug resistant SP cells from cell lines and showed potent cytotoxicity in PBMCs derived from leukemic patients with an efficacy of 81.25% in AML and 100% in CML, ALL and CLL. IL2-TRAIL peptide showed cytotoxicity in relapsed patient samples and was more effective than TRAIL or IL2-TRAIL proteins. Additionally, DR5 specific IL2-TRAIL peptide was effective in targeting and killing LSCs purified from cell lines [IC50: 952nM in HL60, 714nM in MOLT4] and relapsed patient blood samples with higher efficacy (85%) than IL2-TRAIL protein (46%). Hence, CD25 and DR5 specific targeting by IL2-TRAIL peptide may be an effective strategy for targeting drug resistant leukemic cells and LSCs. PMID- 28076754 TI - Transcriptome analysis of the potential roles of FOXL2 in chicken pre hierarchical and pre-ovulatory granulosa cells. AB - Forkheadbox L2 (FOXL2) is a transcription factor involved in mammalian ovarian development, especially in granulosa cell differentiation. However, this factor's function in mature chicken ovary is unclear. To explore the function of FOXL2 in chicken granulosa cells, we performed RNA-seq to compare the transcriptomes of pre-hierarchical (phGCs) and pre-ovulatory granulosa cells (poGCs) by FOXL2 overexpression. We observed that focal adhesion might be one of the key pathways activated during the differentiation of granulosa cells, and FOXL2 might be involved in follicle selection by regulating the expression of cytokines and the concentration of cyclic adenosine monophosphate (cAMP). Interestingly, we observed that FOXL2 played different roles in phGCs and poGCs, which might contribute to homeostasis in the chicken follicle by inducing differentiation of granulosa cells in pre-hierarchal follicles and preventing premature ovulation in pre-ovulatory follicles. Taken together, the results of our study establish a framework for understanding the potential functions of FOXL2 in the chicken granulosa cell. PMID- 28076755 TI - RAD51 Is a Selective DNA Repair Target to Radiosensitize Glioma Stem Cells. AB - Patients with glioblastoma die from local relapse despite surgery and high-dose radiotherapy. Resistance to radiotherapy is thought to be due to efficient DNA double-strand break (DSB) repair in stem-like cells able to survive DNA damage and repopulate the tumor. We used clinical samples and patient-derived glioblastoma stem cells (GSCs) to confirm that the DSB repair protein RAD51 is highly expressed in GSCs, which are reliant on RAD51-dependent DSB repair after radiation. RAD51 expression and RAD51 foci numbers fall when these cells move toward astrocytic differentiation. In GSCs, the small-molecule RAD51 inhibitors RI-1 and B02 prevent RAD51 focus formation, reduce DNA DSB repair, and cause significant radiosensitization. We further demonstrate that treatment with these agents combined with radiation promotes loss of stem cells defined by SOX2 expression. This indicates that RAD51-dependent repair represents an effective and specific target in GSCs. PMID- 28076756 TI - Dissociation of Survival, Proliferation, and State Control in Human Hematopoietic Stem Cells. AB - The role of growth factors (GFs) in controlling the biology of human hematopoietic stem cells (HSCs) remains limited by a lack of information concerning the individual and combined effects of GFs directly on the survival, Mitogenesis, and regenerative activity of highly purified human HSCs. We show that the initial input HSC activity of such a purified starting population of human cord blood cells can be fully maintained over a 21-day period in serum-free medium containing five GFs alone. HSC survival was partially supported by any one of these GFs, but none were essential, and different combinations of GFs variably stimulated HSC proliferation. However, serial transplantability was not detectably compromised by many conditions that reduced human HSC proliferation and/or survival. These results demonstrate the dissociated control of these three human HSC bio-responses, and set the stage for future improvements in strategies to modify and expand human HSCs ex vivo. PMID- 28076757 TI - iPSC-Derived Retina Transplants Improve Vision in rd1 End-Stage Retinal Degeneration Mice. AB - Recent success in functional recovery by photoreceptor precursor transplantation in dysfunctional retina has led to an increased interest in using embryonic stem cell (ESC) or induced pluripotent stem cell (iPSC)-derived retinal progenitors to treat retinal degeneration. However, cell-based therapies for end-stage degenerative retinas that have lost the outer nuclear layer (ONL) are still a big challenge. In the present study, by transplanting mouse iPSC-derived retinal tissue (miPSC retina) in the end-stage retinal-degeneration model (rd1), we visualized the direct contact between host bipolar cell terminals and the presynaptic terminal of graft photoreceptors by gene labeling, showed light responsive behaviors in transplanted rd1 mice, and recorded responses from the host retina with transplants by ex vivo micro-electroretinography and ganglion cell recordings using a multiple-electrode array system. Our data provides a proof of concept for transplanting ESC/iPSC retinas to restore vision in end stage retinal degeneration. PMID- 28076758 TI - Polysaccharides from Ganoderma lucidum Promote Cognitive Function and Neural Progenitor Proliferation in Mouse Model of Alzheimer's Disease. AB - Promoting neurogenesis is a promising strategy for the treatment of cognition impairment associated with Alzheimer's disease (AD). Ganoderma lucidum is a revered medicinal mushroom for health-promoting benefits in the Orient. Here, we found that oral administration of the polysaccharides and water extract from G. lucidum promoted neural progenitor cell (NPC) proliferation to enhance neurogenesis and alleviated cognitive deficits in transgenic AD mice. G. lucidum polysaccharides (GLP) also promoted self-renewal of NPC in cell culture. Further mechanistic study revealed that GLP potentiated activation of fibroblast growth factor receptor 1 (FGFR1) and downstream extracellular signal-regulated kinase (ERK) and AKT cascades. Consistently, inhibition of FGFR1 effectively blocked the GLP-promoted NPC proliferation and activation of the downstream cascades. Our findings suggest that GLP could serve as a regenerative therapeutic agent for the treatment of cognitive decline associated with neurodegenerative diseases. PMID- 28076759 TI - Quantitative in-situ TEM nanotensile testing of single crystal Ni facilitated by a new sample preparation approach. AB - Twin-jet electro-polishing and Focused Ion Beam (FIB) were combined to produce small size Nickel single crystal specimens for quantitative in-situ nanotensile experiments in the transmission electron microscope. The combination of these techniques allows producing samples with nearly defect-free zones in the centre in contrast to conventional FIB-prepared samples. Since TEM investigations can be performed on the electro-polished samples prior to in-situ TEM straining, specimens with desired crystallographic orientation and initial microstructure can be prepared. The present results reveal a dislocation nucleation-controlled plasticity, in which small loops induced by FIB near the edges of the samples play a central role. PMID- 28076760 TI - Enriching the Circadian Proteome. AB - Circadian clocks regulate most aspects of physiology and metabolism. Genome-wide approaches have uncovered widespread circadian rhythms in the transcriptome, cistrome, and epigenome of mice, and now two proteomics studies in this issue (Robles et al., 2016; Wang et al., 2016) reveal extensive circadian regulation of the nuclear and phosphoproteome. PMID- 28076761 TI - Timing Is Everything. AB - In a recent issue of Cancer Cell, Kettner and colleagues (2016) link disruption of normal circadian rhythms to NASH and associated liver cancer, suggesting that molecular clocks, as well as their regulators and target genes, might provide novel therapeutic targets in these diseases. PMID- 28076763 TI - Osteocalcin Signaling in Myofibers Is Necessary and Sufficient for Optimum Adaptation to Exercise. PMID- 28076762 TI - A Leptin Analog Locally Produced in the Brain Acts via a Conserved Neural Circuit to Modulate Obesity-Linked Behaviors in Drosophila. AB - Leptin, a typically adipose-derived "satiety hormone," has a well-established role in weight regulation. Here we describe a functionally conserved model of genetically induced obesity in Drosophila by manipulating the fly leptin analog unpaired 1 (upd1). Unexpectedly, cell-type-specific knockdown reveals upd1 in the brain, not the adipose tissue, mediates obesity-related traits. Disrupting brain derived upd1 in flies leads to all the hallmarks of mammalian obesity: increased attraction to food cues, increased food intake, and increased weight. These effects are mediated by domeless receptors on neurons expressing Drosophila neuropeptide F, the orexigenic mammalian neuropeptide Y homolog. In vivo two photon imaging reveals upd1 and domeless inhibit this hedonic signal in fed animals. Manipulations along this central circuit also create hypersensitivity to obesogenic conditions, emphasizing the critical interplay between biological predisposition and environment in overweight and obesity prevalence. We propose adipose- and brain-derived upd/leptin may control differing features of weight regulation through distinct neural circuits. PMID- 28076764 TI - SnapShot: Non-coding RNAs and Metabolism. AB - In recent years, understanding the crucial role played by cellular homeostasis in disease initiation and progression became the focus of scientists and clinicians. This SnapShot sketches the involvement of both short microRNAs and long ncRNAs in the major metabolic pathways altered in diseases. To view this SnapShot, open or download the PDF. PMID- 28076765 TI - Building a Beautiful Beast: Mammalian Respiratory Complex I. AB - Understanding the mammalian respiratory complex I assembly has been an arduous task due to the lack of appropriate techniques and the complexity of the process. In this issue, a new tour de force based on complexome profiling provides an encyclopedic description of the process (Guerrero-Castillo et al., 2017). PMID- 28076766 TI - Are Gut Microbes Responsible for Post-dieting Weight Rebound? AB - One of the dieting conundrums in the age of the obesity epidemic is the cycle of weight loss and regain known as the "yo-yo effect." Thaiss et al. (2016) demonstrate that the microbiome plays a key role in this phenomenon and that simple dietary supplementations can reset the weight-rebound clock. PMID- 28076767 TI - (S)Pot on Mitochondria: Cannabinoids Disrupt Cellular Respiration to Limit Neuronal Activity. AB - Classical views posit G protein-coupled cannabinoid receptor 1s (CB1Rs) at the cell surface with cytosolic Gialpha-mediated signal transduction. Hebert Chatelain et al. (2016) instead place CB1Rs at mitochondria limiting neuronal respiration by soluble adenylyl cyclase-dependent modulation of complex I activity. Thus, neuronal bioenergetics link to synaptic plasticity and, globally, learning and memory. PMID- 28076768 TI - Microscopic solvation environments in a prototype room-temperature ionic liquid as elucidated by resonance Raman spectroscopy of iodine and bromine. AB - Microscopic solvation environments in a prototype ionic liquid, bmimTf2N; 1-butyl 3-methyl-imidazolium-bis(trifluoromethanesulfonyl)imide, have been studied with the use of halides, X2 and Xn- (X=I, Br; n=3,5), as molecular probes. Resonance Raman spectroscopy has been used to detect these halogen species existing in bmimTf2N as well as in reference solvents including heptane, cyclohexane, KX/H2O and benzene. In heptane and cyclohexane, only free X2 species are detected. In KX/H2O, only Xn- and, in benzene, only benzene-X2 complexes are detected. On the contrary, free X2 and Xn- are concomitantly detected in bmimTf2N, indicating that there are two distinct solvation environments in bmimTf2N, non-polar environments that solvate free X2 and polar environments that stabilize Xn-. These two distinct solvation environments are most likely to arise from microscopic structural heterogeneity of ionic liquids. PMID- 28076769 TI - Synthesis of Cu/Cu2O hydrides for enhanced removal of iodide from water. AB - In order to improve the removal capacity of Cu2O for I- anions from water, Cu/Cu2O hybrids have been synthesized through a facile hydrothermal route, characterized by using SEM, XRD, XPS, and applied to remove I- anions under different experimental environments. The results demonstrate that the Cu content and morphology of samples can be tuned by the adding amount of ammonia. Meanwhile, the possible crystalline mechanism, Cu2O formed firstly and then metallic Cu generated, was presented. With the increasing of Cu doped amount, the removal capacity of Cu/Cu2O hybrids increased significantly from 0.02mmolg-1 to 0.18mmolg-1. Furthermore, a reaction mechanism of I- anions and Cu2O, which generated from the disproportionation reaction of metallic Cu and CuO, has been proposed according to the characterization analyses of the composites before and after adsorption, explaining the highly efficient removal of I- anions. In addition, Cu/Cu2O hybrids showed excellent selectivity for I- anions in the presence of large concentrations of competitive anions such as SO42- and NO3- and could work in an acidic and neutral environment. This study is hopefully to prompt Cu2O to grow up to be a new and highly efficient adsorbent for the removal of iodide from solutions. PMID- 28076770 TI - Gamma irradiation-induced complete degradation and mineralization of phenol in aqueous solution: Effects of reagent. AB - This study aims to gain new insight into phenol degradation and mineralization in aqueous solution using ionizing radiation to control its radiolytic elimination under various experimental conditions and to present the different radical reactions involved in water radiolysis. The most obvious finding of this study is that the combination of a reagent, i.e., O3, H2O2, N2O, O2, or S2O82-, with gamma rays effectively enhances the radiolytic system for phenol degradation or mineralization. Radiolytic yield is higher with H2O2 than with S2O82-. For the gamma-ray/free O2, gamma-ray/H2O2, gamma-ray/S2O82-, gamma-ray/N2O, and gamma ray/N2 systems, the absorbed doses for 90% phenol elimination are 1.7, 0.85, 1.65, 1.2, and 6.4kGy, respectively; in contrast, phenol can be decomposed totally and directly via reaction with molecular ozone. The lowest dose constant for phenol removal is determined for gamma-ray/HCO3-. 89% of mineralization is reached for an absorbed dose of 10kGy with a gamma-ray/S2O82- combination. PMID- 28076772 TI - Impact of dairy manure pre-application treatment on manure composition, soil dynamics of antibiotic resistance genes, and abundance of antibiotic-resistance genes on vegetables at harvest. AB - Manuring ground used for crop production is an important agricultural practice. Should antibiotic-resistant enteric bacteria carried in the manure be transferred to crops that are consumed raw, their consumption by humans or animals will represent a route of exposure to antibiotic resistance genes. Treatment of manures prior to land application is a potential management option to reduce the abundance of antibiotic resistance genes entrained with manure application. In this study, dairy manure that was untreated, anaerobically digested, mechanically dewatered or composted was applied to field plots that were then cropped to lettuce, carrots and radishes. The impact of treatment on manure composition, persistence of antibiotic resistance gene targets in soil following application, and distribution of antibiotic resistance genes and bacteria on vegetables at harvest was determined. Composted manure had the lowest abundance of antibiotic resistance gene targets compared to the other manures. There was no significant difference in the persistence characteristics of antibiotic resistance genes following land application of the various manures. Compared to unmanured soil, antibiotic resistance genes were detected more frequently in soil receiving raw or digested manure, whereas they were not in soil receiving composted manure. The present study suggests that vegetables grown in ground receiving raw or digested manure are at risk of contamination with manure-borne antibiotic resistant bacteria, whereas vegetables grown in ground receiving composted manure are less so. PMID- 28076771 TI - Screening and prioritization of micropollutants in wastewaters from on-site sewage treatment facilities. AB - A comprehensive screening of micropollutants was performed in wastewaters from on site sewage treatment facilities (OSSFs) and urban wastewater treatment plants (WWTPs) in Sweden. A suspect screening approach, using high resolution mass spectrometry, was developed and used in combination with target analysis. With this strategy, a total number of 79 micropollutants were successfully identified, which belong to the groups of per- and polyfluoroalkyl substances (PFASs), pesticides, phosphorus-containing flame retardants (PFRs) and pharmaceuticals and personal care products (PPCPs). Results from this screening indicate that concentrations of micropollutants are similar in influents and effluents of OSSFs and WWTPs, respectively. Removal efficiencies of micropollutants were assessed in the OSSFs and compared with those observed in WWTPs. In general, removal of PFASs and PFRs was higher in package treatment OSSFs, which are based on biological treatments, while removal of PPCPs was more efficient in soil bed OSSFs. A novel comprehensive prioritization strategy was then developed to identify OSSF specific chemicals of environmental relevance. The strategy was based on the compound concentrations in the wastewater, removal efficiency, frequency of detection in OSSFs and on in silico based data for toxicity, persistency and bioaccumulation potential. PMID- 28076773 TI - Thymol detection and quantitation by solid-phase microextraction in faeces and egg yolk of Japanese quail. AB - To measure bioavailability of the active ingredients of phytogenic feed additives in poultry products and subproducts is a key element for developing a rational understanding of its mode of action and biological effects. Hence, we validated a headspace solid phase microextraction (HS-SPME) technique followed by gas chromatography-mass spectrometry as an analytical extraction procedure and as method for detection and quantitation of 2-Isopropyl-5-methylphenol (thymol) in faeces and egg yolk of quail. The suitability of this method for thymol analysis in both matrices was first proved via linearity, limit of detection, limit of quantification, and recovery using m-cresol as internal standard. The optimal HS SPME extraction conditions were obtained at 40 degrees C for 5min in faeces and 60 degrees C for 30min in egg yolk. This procedure was found to be precise, sensitive and linear in the range of 2.5-100ng/gr for faeces and 20-800ng/gr for the egg yolk. Limits of detection were 0.5ng/g and 5ng/g for faeces and yolk, respectively, and the limits of quantitation were 1ng/g and 10ng/g for faeces and yolk, respectively. The method was successfully used for measuring thymol in fecal and egg yolk samples, from quails supplemented with thymol in their diets. Thus, in fresh faeces and egg yolk samples obtained from a supplemented group (80mg thymol per bird per day) were determined as 31.51ng/g for faeces and 11.83ng/g for the egg yolk. PMID- 28076774 TI - Chromatographic efficiency and selectivity in top-down proteomics of histones. AB - Histones are involved in epigenetic control of a wide variety of cellular processes through their multiple post-translational modifications. Their strongly cationic nature makes them challenging to separate with reversed-phase liquid chromatography coupled to mass spectrometry (RPLC-MS), where trifluoroacetic acid is avoided due to adduct formation. Columns with higher resolution are needed. In this work, RPLC-MS is performed on a histone sample using difluoroacetic acid and a 20-min gradient. Columns with C18 surfaces are compared for two different types of particle morphologies: 1) fully porous particles of 5MUm in diameter, 2) superficially porous particles of 3MUm in diameter with a shell of 0.2MUm. The resolution for the histone separation is better for the latter column, but only when the modifier is trifluoroacetic acid, which is used with UV absorbance detection. When difluoroacetic acid is used for LCMS, the peaks broaden enough to erase the advantage in efficiency for the superficially porous particles. The fully porous and superficially porous cases show similar performance in RPLC-MS, with slightly higher resolution for the fully porous particles. The expected advantage of the shorter diffusion distances for the superficially porous particles is shown to be outweighed by the lower selectivity of its bonded phase. PMID- 28076775 TI - Nutritional Programming of Lifespan by FOXO Inhibition on Sugar-Rich Diets. AB - Consumption of unhealthy diets is exacerbating the burden of age-related ill health in aging populations. Such diets can program mammalian physiology to cause long-term, detrimental effects. Here, we show that, in Drosophila melanogaster, an unhealthy, high-sugar diet in early adulthood programs lifespan to curtail later-life survival despite subsequent dietary improvement. Excess dietary sugar promotes insulin-like signaling, inhibits dFOXO-the Drosophila homolog of forkhead box O (FOXO) transcription factors-and represses expression of dFOXO target genes encoding epigenetic regulators. Crucially, dfoxo is required both for transcriptional changes that mark the fly's dietary history and for nutritional programming of lifespan by excess dietary sugar, and this mechanism is conserved in Caenorhabditis elegans. Our study implicates FOXO factors, the evolutionarily conserved determinants of animal longevity, in the mechanisms of nutritional programming of animal lifespan. PMID- 28076776 TI - Ptc7p Dephosphorylates Select Mitochondrial Proteins to Enhance Metabolic Function. AB - Proper maintenance of mitochondrial activity is essential for metabolic homeostasis. Widespread phosphorylation of mitochondrial proteins may be an important element of this process; yet, little is known about which enzymes control mitochondrial phosphorylation or which phosphosites have functional impact. We investigate these issues by disrupting Ptc7p, a conserved but largely uncharacterized mitochondrial matrix PP2C-type phosphatase. Loss of Ptc7p causes respiratory growth defects concomitant with elevated phosphorylation of select matrix proteins. Among these, Deltaptc7 yeast exhibit an increase in phosphorylation of Cit1p, the canonical citrate synthase of the tricarboxylic acid (TCA) cycle, that diminishes its activity. We find that phosphorylation of S462 can eliminate Cit1p enzymatic activity likely by disrupting its proper dimerization, and that Ptc7p-driven dephosphorylation rescues Cit1p activity. Collectively, our work connects Ptc7p to an essential TCA cycle function and to additional phosphorylation events that may affect mitochondrial activity inadvertently or in a regulatory manner. PMID- 28076777 TI - Antagonistic Functions of MBP and CNP Establish Cytosolic Channels in CNS Myelin. AB - The myelin sheath is a multilamellar plasma membrane extension of highly specialized glial cells laid down in regularly spaced segments along axons. Recent studies indicate that myelin is metabolically active and capable of communicating with the underlying axon. To be functionally connected to the neuron, oligodendrocytes maintain non-compacted myelin as cytoplasmic nanochannels. Here, we used high-pressure freezing for electron microscopy to study these cytoplasmic regions within myelin close to their native state. We identified 2,'3'-cyclic nucleotide 3'-phosphodiesterase (CNP), an oligodendrocyte specific protein previously implicated in the maintenance of axonal integrity, as an essential factor in generating and maintaining cytoplasm within the myelin compartment. We provide evidence that CNP directly associates with and organizes the actin cytoskeleton, thereby providing an intracellular strut that counteracts membrane compaction by myelin basic protein (MBP). Our study provides a molecular and structural framework for understanding how myelin maintains its cytoplasm to function as an active axon-glial unit. PMID- 28076778 TI - Axl Mediates ZIKA Virus Entry in Human Glial Cells and Modulates Innate Immune Responses. AB - ZIKA virus (ZIKV) is an emerging pathogen responsible for neurological disorders and congenital microcephaly. However, the molecular basis for ZIKV neurotropism remains poorly understood. Here, we show that Axl is expressed in human microglia and astrocytes in the developing brain and that it mediates ZIKV infection of glial cells. Axl-mediated ZIKV entry requires the Axl ligand Gas6, which bridges ZIKV particles to glial cells. Following binding, ZIKV is internalized through clathrin-mediated endocytosis and traffics to Rab5+ endosomes to establish productive infection. During entry, the ZIKV/Gas6 complex activates Axl kinase activity, which downmodulates interferon signaling and facilitates infection. ZIKV infection of human glial cells is inhibited by MYD1, an engineered Axl decoy receptor, and by the Axl kinase inhibitor R428. Our results highlight the dual role of Axl during ZIKV infection of glial cells: promoting viral entry and modulating innate immune responses. Therefore, inhibiting Axl function may represent a potential target for future antiviral therapies. PMID- 28076779 TI - Transcription Dynamics Prevent RNA-Mediated Genomic Instability through SRPK2 Dependent DDX23 Phosphorylation. AB - Genomic instability is frequently caused by nucleic acid structures termed R loops that are formed during transcription. Despite their harmful potential, mechanisms that sense, signal, and suppress these structures remain elusive. Here, we report that oscillations in transcription dynamics are a major sensor of R-loops. We show that pausing of RNA polymerase II (RNA Pol II) initiates a signaling cascade whereby the serine/arginine protein kinase 2 (SRPK2) phosphorylates the DDX23 helicase, culminating in the suppression of R-loops. We show that in the absence of either SRPK2 or DDX23, accumulation of R-loops leads to massive genomic instability revealed by high levels of DNA double-strand breaks (DSBs). Importantly, we found DDX23 mutations in several cancers and detected homozygous deletions of the entire DDX23 locus in 10 (17%) adenoid cystic carcinoma (ACC) samples. Our results unravel molecular details of a link between transcription dynamics and RNA-mediated genomic instability that may play important roles in cancer development. PMID- 28076780 TI - DET1 and HY5 Control PIF4-Mediated Thermosensory Elongation Growth through Distinct Mechanisms. AB - Plant growth and development are defined by environmental cues. The transcription factor PHYTOCHROME INTERACTING FACTOR 4 (PIF4) is the central signaling hub that integrates environmental cues, including light and temperature, to regulate growth and development. The thermosensory mechanisms controlling the PIF4 mediated temperature response, and its integration with other environmental responses, remain poorly understood. DE-ETIOLATED 1 (DET1) and CONSTITUTIVE PHOTOMORPHOGENESIS 1 (COP1), key regulators of light signaling, have been proposed to control thermosensory growth by transcriptional regulation of PIF4, through ELONGATED HYPOCOTYL 5 (HY5). Here, we show that DET1/COP1 and HY5 regulate thermosensory elongation through distinct mechanisms. DET1 and COP1 are essential for promoting PIF4 expression and stabilizing PIF4 protein. Furthermore, HY5 inhibits elongation growth through competitive chromatin binding to PIF4 targets, not through transcriptional regulation of PIF4. Our findings reveal a mechanistic framework in which DET1/COP1 and HY5 regulatory modules act independently to regulate growth through the environmental signal integrator PIF4. PMID- 28076782 TI - GFRalpha1 Regulates Purkinje Cell Migration by Counteracting NCAM Function. AB - During embryonic development of the cerebellum, Purkinje cells (PCs) migrate away from the ventricular zone to form the PC plate. The mechanisms that regulate PC migration are incompletely understood. Here, we report that the neurotrophic receptor GFRalpha1 is transiently expressed in developing PCs and loss of GFRalpha1 delays PC migration. Neither GDNF nor RET, the canonical GFRalpha1 ligand and co-receptor, respectively, contribute to this process. Instead, we found that the neural cell adhesion molecule NCAM is co-expressed and directly interacts with GFRalpha1 in embryonic PCs. Genetic reduction of NCAM expression enhances wild-type PC migration and restores migration in Gfra1 mutants, indicating that NCAM restricts PC migration in the embryonic cerebellum. In vitro experiments indicated that GFRalpha1 can function both in cis and trans to counteract NCAM and promote PC migration. Collectively, our studies show that GFRalpha1 contributes to PC migration by limiting NCAM function. PMID- 28076781 TI - CRTC1 Nuclear Translocation Following Learning Modulates Memory Strength via Exchange of Chromatin Remodeling Complexes on the Fgf1 Gene. AB - Memory is formed by synapse-to-nucleus communication that leads to regulation of gene transcription, but the identity and organizational logic of signaling pathways involved in this communication remain unclear. Here we find that the transcription cofactor CRTC1 is a critical determinant of sustained gene transcription and memory strength in the hippocampus. Following associative learning, synaptically localized CRTC1 is translocated to the nucleus and regulates Fgf1b transcription in an activity-dependent manner. After both weak and strong training, the HDAC3-N-CoR corepressor complex leaves the Fgf1b promoter and a complex involving the translocated CRTC1, phosphorylated CREB, and histone acetyltransferase CBP induces transient transcription. Strong training later substitutes KAT5 for CBP, a process that is dependent on CRTC1, but not on CREB phosphorylation. This in turn leads to long-lasting Fgf1b transcription and memory enhancement. Thus, memory strength relies on activity-dependent changes in chromatin and temporal regulation of gene transcription on specific CREB/CRTC1 gene targets. PMID- 28076783 TI - CDYL Deficiency Disrupts Neuronal Migration and Increases Susceptibility to Epilepsy. AB - During brain development, the correct migration of newborn neurons is one of the determinants of circuit formation, and neuronal migration defects may lead to neurological and psychiatric disorders. The molecular mechanisms underlying neuronal migration and related disorders are poorly understood. Here, we report that Chromodomain Y-like (CDYL) is critical for neuronal migration in mice. Knocking down CDYL caused neuronal migration defects and disrupted both mobility and multipolar-to-bipolar transition of migrating neurons. We find that CDYL regulates neuronal migration by transcriptionally repressing RhoA. In addition, CDYL deficiency increased the excitability of cortical pyramidal neurons and the susceptibility of mice to convulsant-induced seizures. These results demonstrate that CDYL is a regulator of neuronal migration and shed light on the pathogenesis of seizure-related neurodevelopmental disorders. PMID- 28076784 TI - Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain. AB - Microglia play key roles in brain development, homeostasis, and function, and it is widely assumed that the adult population is long lived and maintained by self renewal. However, the precise temporal and spatial dynamics of the microglial population are unknown. We show in mice and humans that the turnover of microglia is remarkably fast, allowing the whole population to be renewed several times during a lifetime. The number of microglial cells remains steady from late postnatal stages until aging and is maintained by the spatial and temporal coupling of proliferation and apoptosis, as shown by pulse-chase studies, chronic in vivo imaging of microglia, and the use of mouse models of dysregulated apoptosis. Our results reveal that the microglial population is constantly and rapidly remodeled, expanding our understanding of its role in the maintenance of brain homeostasis. PMID- 28076785 TI - Infection Programs Sustained Lymphoid Stromal Cell Responses and Shapes Lymph Node Remodeling upon Secondary Challenge. AB - Lymph nodes (LNs) are constructed of intricate networks of endothelial and mesenchymal stromal cells. How these lymphoid stromal cells (LSCs) regulate lymphoid tissue remodeling and contribute to immune responses remains poorly understood. We performed a comprehensive functional and transcriptional analysis of LSC responses to skin viral infection and found that LSC subsets responded robustly, with different kinetics for distinct pathogens. Recruitment of cells to inflamed LNs induced LSC expansion, while B cells sustained stromal responses in an antigen-independent manner. Infection induced rapid transcriptional responses in LSCs. This transcriptional program was transient, returning to homeostasis within 1 month of infection, yet expanded fibroblastic reticular cell networks persisted for more than 3 months after infection, and this altered LN composition reduced the magnitude of LSC responses to subsequent heterologous infection. Our results reveal the complexity of LSC responses during infection and suggest that amplified networks of LN stromal cells support successive immune responses. PMID- 28076786 TI - Porphyromonas gingivalis Promotes Unrestrained Type I Interferon Production by Dysregulating TAM Signaling via MYD88 Degradation. AB - Whereas type I interferons (IFNs-I) were proposed to be elevated in human periodontitis, their role in the disease remains elusive. Using a bacterial induced model of murine periodontitis, we revealed a prolonged elevation in IFN-I expression. This was due to the downregulation of TAM signaling, a major negative regulator of IFN-I. Further examination revealed that the expression of certain TAM components was reduced as a result of prolonged degradation of MYD88 by the infection. As a result of such prolonged IFN-I production, innate immunological functions of the gingiva were disrupted, and CD4+ T cells were constitutively primed by dendritic cells, leading to elevated RANKL expression and, subsequently, alveolar bone loss (ABL). Blocking IFN-I signaling restored proper immunological function and prevented ABL. Importantly, a loss of negative regulation on IFN-I expression by TAM signaling was also evident in periodontitis patients. These findings thus suggest a role for IFN-I in the pathogenesis of periodontitis. PMID- 28076787 TI - IMPDH2 Is an Intracellular Target of the Cyclophilin A and Sanglifehrin A Complex. AB - Natural products have demonstrated utility in the clinic and can also act as probes to understand complex cellular pathways. Sanglifehrin A (SFA) is a mixed polyketide and non-ribosomal peptide synthase natural product with sub-nano-molar affinity for its receptor cyclophilin A (PPIA). It has been shown to behave in vitro as an immune suppressant. Here, we identify inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) as an intracellular target of the PPIA-SFA binary complex. The formation of this ternary complex does not inhibit the enzymatic activity of IMPDH2. Rather, ternary complex formation modulates cell growth through interaction with the cystathionine-beta-synthase (CBS) domain of IMPDH2. We further demonstrate that the SFA complex is highly isoform selective for IMPDH2 (versus IMPDH1). This work reveals a role for the CBS domains of IMPDH2 in cellular proliferation, suggesting a more complex role than previously suspected for IMPDH2 in T cell activation and proliferation. PMID- 28076788 TI - Dynamin-2 Stabilizes the HIV-1 Fusion Pore with a Low Oligomeric State. AB - One of the key research areas surrounding HIV-1 concerns the regulation of the fusion event that occurs between the virus particle and the host cell during entry. Even if it is universally accepted that the large GTPase dynamin-2 is important during HIV-1 entry, its exact role during the first steps of HIV-1 infection is not well characterized. Here, we have utilized a multidisciplinary approach to study the DNM2 role during fusion of HIV-1 in primary resting CD4 T and TZM-bl cells. We have combined advanced light microscopy and functional cell based assays to experimentally assess the role of dynamin-2 during these processes. Overall, our data suggest that dynamin-2, as a tetramer, might help to establish hemi-fusion and stabilizes the pore during HIV-1 fusion. PMID- 28076789 TI - Reduced Insulin/IGF-1 Signaling Restores the Dynamic Properties of Key Stress Granule Proteins during Aging. AB - Low-complexity "prion-like" domains in key RNA-binding proteins (RBPs) mediate the reversible assembly of RNA granules. Individual RBPs harboring these domains have been linked to specific neurodegenerative diseases. Although their aggregation in neurodegeneration has been extensively characterized, it remains unknown how the process of aging disturbs RBP dynamics. We show that a wide variety of RNA granule components, including stress granule proteins, become highly insoluble with age in C. elegans and that reduced insulin/insulin-like growth factor 1 (IGF-1) daf-2 receptor signaling efficiently prevents their aggregation. Importantly, stress-granule-related RBP aggregates are associated with reduced fitness. We show that heat shock transcription factor 1 (HSF-1) is a main regulator of stress-granule-related RBP aggregation in both young and aged animals. During aging, increasing DAF-16 activity restores dynamic stress-granule related RBPs, partly by decreasing the buildup of other misfolded proteins that seed RBP aggregation. Longevity-associated mechanisms found to maintain dynamic RBPs during aging could be relevant for neurodegenerative diseases. PMID- 28076790 TI - The Anti-Warburg Effect Elicited by the cAMP-PGC1alpha Pathway Drives Differentiation of Glioblastoma Cells into Astrocytes. AB - Glioblastoma multiforme (GBM) is among the most aggressive of human cancers. Although differentiation therapy has been proposed as a potential approach to treat GBM, the mechanisms of induced differentiation remain poorly defined. Here, we established an induced differentiation model of GBM using cAMP activators that specifically directed GBM differentiation into astroglia. Transcriptomic and proteomic analyses revealed that oxidative phosphorylation and mitochondrial biogenesis are involved in induced differentiation of GBM. Dibutyryl cyclic AMP (dbcAMP) reverses the Warburg effect, as evidenced by increased oxygen consumption and reduced lactate production. Mitochondrial biogenesis induced by activation of the CREB-PGC1alpha pathway triggers metabolic shift and differentiation. Blocking mitochondrial biogenesis using mdivi1 or by silencing PGC1alpha abrogates differentiation; conversely, overexpression of PGC1alpha elicits differentiation. In GBM xenograft models and patient-derived GBM samples, cAMP activators also induce tumor growth inhibition and differentiation. Our data show that mitochondrial biogenesis and metabolic switch to oxidative phosphorylation drive the differentiation of tumor cells. PMID- 28076791 TI - MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia. AB - Understanding the underlying molecular mechanisms of defined cancers is crucial for effective personalized therapies. Translocations of the mixed-lineage leukemia (MLL) gene produce fusion proteins such as MLL-AF4 that disrupt epigenetic pathways and cause poor-prognosis leukemias. Here, we find that at a subset of gene targets, MLL-AF4 binding spreads into the gene body and is associated with the spreading of Menin binding, increased transcription, increased H3K79 methylation (H3K79me2/3), a disruption of normal H3K36me3 patterns, and unmethylated CpG regions in the gene body. Compared to other H3K79me2/3 marked genes, MLL-AF4 spreading gene expression is downregulated by inhibitors of the H3K79 methyltransferase DOT1L. This sensitivity mediates synergistic interactions with additional targeted drug treatments. Therefore, epigenetic spreading and enhanced susceptibility to epidrugs provides a potential marker for better understanding combination therapies in humans. PMID- 28076792 TI - The Mre11-Nbs1 Interface Is Essential for Viability and Tumor Suppression. AB - The Mre11 complex (Mre11, Rad50, and Nbs1) is integral to both DNA repair and ataxia telangiectasia mutated (ATM)-dependent DNA damage signaling. All three Mre11 complex components are essential for viability at the cellular and organismal levels. To delineate essential and non-essential Mre11 complex functions that are mediated by Nbs1, we used TALEN-based genome editing to derive Nbs1 mutant mice (Nbs1mid mice), which harbor mutations in the Mre11 interaction domain of Nbs1. Nbs1mid alleles that abolished interaction were incompatible with viability. Conversely, a 108-amino-acid Nbs1 fragment comprising the Mre11 interface was sufficient to rescue viability and ATM activation in cultured cells and support differentiation of hematopoietic cells in vivo. These data indicate that the essential role of Nbs1 is via its interaction with Mre11 and that most of the Nbs1 protein is dispensable for Mre11 complex functions and suggest that Mre11 and Rad50 directly activate ATM. PMID- 28076793 TI - Chloroquine-Inducible Par-4 Secretion Is Essential for Tumor Cell Apoptosis and Inhibition of Metastasis. AB - The induction of tumor suppressor proteins capable of cancer cell apoptosis represents an attractive option for the re-purposing of existing drugs. We report that the anti-malarial drug, chloroquine (CQ), is a robust inducer of Par-4 secretion from normal cells in mice and cancer patients in a clinical trial. CQ inducible Par-4 secretion triggers paracrine apoptosis of cancer cells and also inhibits metastatic tumor growth. CQ induces Par-4 secretion via the classical secretory pathway that requires the activation of p53. Mechanistically, p53 directly induces Rab8b, a GTPase essential for vesicle transport of Par-4 to the plasma membrane prior to secretion. Our findings indicate that CQ induces p53- and Rab8b-dependent Par-4 secretion from normal cells for Par-4-dependent inhibition of metastatic tumor growth. PMID- 28076794 TI - BRCA1 Directs the Repair Pathway to Homologous Recombination by Promoting 53BP1 Dephosphorylation. AB - BRCA1 promotes homologous recombination (HR) by activating DNA-end resection. By contrast, 53BP1 forms a barrier that inhibits DNA-end resection. Here, we show that BRCA1 promotes DNA-end resection by relieving the 53BP1-dependent barrier. We show that 53BP1 is phosphorylated by ATM in S/G2 phase, promoting RIF1 recruitment, which inhibits resection. 53BP1 is promptly dephosphorylated and RIF1 released, despite remaining unrepaired DNA double-strand breaks (DSBs). When resection is impaired by CtIP/MRE11 endonuclease inhibition, 53BP1 phosphorylation and RIF1 are sustained due to ongoing ATM signaling. BRCA1 depletion also sustains 53BP1 phosphorylation and RIF1 recruitment. We identify the phosphatase PP4C as having a major role in 53BP1 dephosphorylation and RIF1 release. BRCA1 or PP4C depletion impairs 53BP1 repositioning, EXO1 recruitment, and HR progression. 53BP1 or RIF1 depletion restores resection, RAD51 loading, and HR in PP4C-depleted cells. Our findings suggest that BRCA1 promotes PP4C dependent 53BP1 dephosphorylation and RIF1 release, directing repair toward HR. PMID- 28076795 TI - Hangover Links Nuclear RNA Signaling to cAMP Regulation via the Phosphodiesterase 4d Ortholog dunce. AB - The hangover gene defines a cellular stress pathway that is required for rapid ethanol tolerance in Drosophila melanogaster. To understand how cellular stress changes neuronal function, we analyzed Hangover function on a cellular and neuronal level. We provide evidence that Hangover acts as a nuclear RNA binding protein and we identified the phosphodiesterase 4d ortholog dunce as a target RNA. We generated a transcript-specific dunce mutant that is impaired not only in ethanol tolerance but also in the cellular stress response. At the neuronal level, Dunce and Hangover are required in the same neuron pair to regulate experience-dependent motor output. Within these neurons, two cyclic AMP (cAMP) dependent mechanisms balance the degree of tolerance. The balance is achieved by feedback regulation of Hangover and dunce transcript levels. This study provides insight into how nuclear Hangover/RNA signaling is linked to the cytoplasmic regulation of cAMP levels and results in neuronal adaptation and behavioral changes. PMID- 28076797 TI - Major Shifts in Glial Regional Identity Are a Transcriptional Hallmark of Human Brain Aging. AB - Gene expression studies suggest that aging of the human brain is determined by a complex interplay of molecular events, although both its region- and cell-type specific consequences remain poorly understood. Here, we extensively characterized aging-altered gene expression changes across ten human brain regions from 480 individuals ranging in age from 16 to 106 years. We show that astrocyte- and oligodendrocyte-specific genes, but not neuron-specific genes, shift their regional expression patterns upon aging, particularly in the hippocampus and substantia nigra, while the expression of microglia- and endothelial-specific genes increase in all brain regions. In line with these changes, high-resolution immunohistochemistry demonstrated decreased numbers of oligodendrocytes and of neuronal subpopulations in the aging brain cortex. Finally, glial-specific genes predict age with greater precision than neuron specific genes, thus highlighting the need for greater mechanistic understanding of neuron-glia interactions in aging and late-life diseases. PMID- 28076796 TI - Ribosomal Proteins Rpl22 and Rpl22l1 Control Morphogenesis by Regulating Pre-mRNA Splicing. AB - Most ribosomal proteins (RP) are regarded as essential, static components that contribute only to ribosome biogenesis and protein synthesis. However, emerging evidence suggests that RNA-binding RP are dynamic and can influence cellular processes by performing "extraribosomal," regulatory functions involving binding to select critical target mRNAs. We report here that the RP, Rpl22, and its highly homologous paralog Rpl22-Like1 (Rpl22l1 or Like1) play critical, extraribosomal roles in embryogenesis. Indeed, they antagonistically control morphogenesis through developmentally regulated localization to the nucleus, where they modulate splicing of the pre-mRNA encoding smad2, an essential transcriptional effector of Nodal/TGF-beta signaling. During gastrulation, Rpl22 binds to intronic sequences of smad2 pre-mRNA and induces exon 9 skipping in cooperation with hnRNP-A1. This action is opposed by its paralog, Like1, which promotes exon 9 inclusion in the mature transcript. The nuclear roles of these RP in controlling morphogenesis represent a fundamentally different and paradigm shifting mode of action for RP. PMID- 28076799 TI - Adenylyl cyclase type 9 gene polymorphisms are associated with asthma and allergy in Brazilian children. AB - Asthma is a chronic inflammatory disease of the respiratory tract. This heterogeneous disease is caused by the interaction of interindividual genetic variability and environmental factors. The gene adenylyl cyclase type 9 (ADCY9) encodes a protein called adenylyl cyclase (AC), responsible for producing the second messenger cyclic AMP (cAMP). cAMP is produced by T regulatory cells and is involved in the down-regulation of T effector cells. Failures in cAMP production may be related to an imbalance in the regulatory immune response, leading to immune-mediated diseases, such as allergic disorders. The aim of this study was to investigate how polymorphisms in the ADCY9 are associated with asthma and allergic markers. The study comprised 1309 subjects from the SCAALA (Social Changes Asthma and Allergy in Latin America) program. Genotyping was accomplished using the Illumina 2.5 Human Omni bead chip. Logistic regression was used to assess the association between allergy markers and ADCY9 variation in PLINK 1.07 software with adjustments for sex, age, helminth infection and ancestry markers. The ADCY9 candidate gene was associated with different phenotypes, such as asthma, specific IgE, skin prick test, and cytokine production. Among 133 markers analyzed, 29 SNPs where associated with asthma and allergic markers in silico analysis revealed the functional impact of the 6 SNPs on ADCY9 expression. It can be concluded that polymorphisms in the ADCY9 gene are significantly associated with asthma and/or allergy markers. We believe that such polymorphisms may lead to increased expression of adenylyl cyclase with a consequent increase in immunoregulatory activity. Therefore, these SNPs may offer an impact on the occurrence of these conditions in admixture population from countries such as Brazil. PMID- 28076798 TI - Neonatal Transplantation Confers Maturation of PSC-Derived Cardiomyocytes Conducive to Modeling Cardiomyopathy. AB - Pluripotent stem cells (PSCs) offer unprecedented opportunities for disease modeling and personalized medicine. However, PSC-derived cells exhibit fetal-like characteristics and remain immature in a dish. This has emerged as a major obstacle for their application for late-onset diseases. We previously showed that there is a neonatal arrest of long-term cultured PSC-derived cardiomyocytes (PSC CMs). Here, we demonstrate that PSC-CMs mature into adult CMs when transplanted into neonatal hearts. PSC-CMs became similar to adult CMs in morphology, structure, and function within a month of transplantation into rats. The similarity was further supported by single-cell RNA-sequencing analysis. Moreover, this in vivo maturation allowed patient-derived PSC-CMs to reveal the disease phenotype of arrhythmogenic right ventricular cardiomyopathy, which manifests predominantly in adults. This study lays a foundation for understanding human CM maturation and pathogenesis and can be instrumental in PSC-based modeling of adult heart diseases. PMID- 28076800 TI - The Making and Breaking of a Substrate Trap. PMID- 28076801 TI - MSMBuilder: Statistical Models for Biomolecular Dynamics. AB - MSMBuilder is a software package for building statistical models of high dimensional time-series data. It is designed with a particular focus on the analysis of atomistic simulations of biomolecular dynamics such as protein folding and conformational change. MSMBuilder is named for its ability to construct Markov state models (MSMs), a class of models that has gained favor among computational biophysicists. In addition to both well-established and newer MSM methods, the package includes complementary algorithms for understanding time series data such as hidden Markov models and time-structure based independent component analysis. MSMBuilder boasts an easy to use command-line interface, as well as clear and consistent abstractions through its Python application programming interface. MSMBuilder was developed with careful consideration for compatibility with the broader machine learning community by following the design of scikit-learn. The package is used primarily by practitioners of molecular dynamics, but is just as applicable to other computational or experimental time series measurements. PMID- 28076802 TI - PELDOR Spectroscopy Reveals Two Defined States of a Sialic Acid TRAP Transporter SBP in Solution. AB - The tripartite ATP-independent periplasmic (TRAP) transporters are a widespread class of membrane transporters in bacteria and archaea. Typical substrates for TRAP transporters are organic acids including the sialic acid N-acetylneuraminic acid. The substrate binding proteins (SBP) of TRAP transporters are the best studied component and are responsible for initial high-affinity substrate binding. To better understand the dynamics of the ligand binding process, pulsed electron-electron double resonance (PELDOR, also known as DEER) spectroscopy was applied to study the conformational changes in the N-acetylneuraminic acid specific SBP VcSiaP. The protein is the SBP of VcSiaPQM, a sialic acid TRAP transporter from Vibrio cholerae. Spin-labeled double-cysteine mutants of VcSiaP were analyzed in the substrate-bound and -free state and the measured distances were compared to available crystal structures. The data were compatible with two clear states only, which are consistent with the open and closed forms seen in TRAP SBP crystal structures. Substrate titration experiments demonstrated the transition of the population from one state to the other with no other observed forms. Mutants of key residues involved in ligand binding and/or proposed to be involved in domain closure were produced and the corresponding PELDOR experiments reveal important insights into the open-closed transition. The results are in excellent agreement with previous in vivo sialylation experiments. The structure of the spin-labeled Q54R1/L173R1 R125A mutant was solved at 2.1 A resolution, revealing no significant changes in the protein structure. Thus, the loss of domain closure appears to be solely due to loss of binding. In conclusion, these data are consistent with TRAP SBPs undergoing a simple two-state transition from an open-unliganded to closed-liganded state during the transport cycle. PMID- 28076803 TI - Drunken Membranes: Short-Chain Alcohols Alter Fusion of Liposomes to Planar Lipid Bilayers. AB - Although the effects of ethanol on protein receptors and lipid membranes have been studied extensively, ethanol's effect on vesicles fusing to lipid bilayers is not known. To determine the effect of alcohols on fusion rates, we utilized the nystatin/ergosterol fusion assay to measure fusion of liposomes to a planar lipid bilayer (BLM). The addition of ethanol excited fusion when applied on the cis (vesicle) side, and inhibited fusion on the trans side. Other short-chain alcohols followed a similar pattern. In general, the inhibitory effect of alcohols (trans) occurs at lower doses than the excitatory (cis) effect, with a decrease of 29% in fusion rates at the legal driving limit of 0.08% (w/v) ethanol (IC50 = 0.2% v/v, 34 mM). Similar inhibitory effects were observed with methanol, propanol, and butanol, with ethanol being the most potent. Significant variability was observed with different alcohols when applied to the cis side. Ethanol and propanol enhanced fusion, butanol also enhanced fusion but was less potent, and low doses of methanol mildly inhibited fusion. The inhibition by trans addition of alcohols implies that they alter the planar membrane structure and thereby increase the activation energy required for fusion, likely through an increase in membrane fluidity. The cis data are likely a combination of the above effect and a proportionally greater lowering of the vesicle lysis tension and hydration repulsive pressure that combine to enhance fusion. Alternate hypotheses are also discussed. The inhibitory effect of ethanol on liposome-membrane fusion is large enough to provide a possible biophysical explanation of compromised neuronal behavior. PMID- 28076804 TI - 3D Protein Dynamics in the Cell Nucleus. AB - The three-dimensional (3D) architecture of the cell nucleus plays an important role in protein dynamics and in regulating gene expression. However, protein dynamics within the 3D nucleus are poorly understood. Here, we present, to our knowledge, a novel combination of 1) single-objective based light-sheet microscopy, 2) photoconvertible proteins, and 3) fluorescence correlation microscopy, to quantitatively measure 3D protein dynamics in the nucleus. We are able to acquire >3400 autocorrelation functions at multiple spatial positions within a nucleus, without significant photobleaching, allowing us to make reliable estimates of diffusion dynamics. Using this tool, we demonstrate spatial heterogeneity in Polymerase II dynamics in live U2OS cells. Further, we provide detailed measurements of human-Yes-associated protein diffusion dynamics in a human gastric cancer epithelial cell line. PMID- 28076805 TI - Regulation of Active ICAM-4 on Normal and Sickle Cell Disease RBCs via AKAPs Is Revealed by AFM. AB - Human healthy (wild-type (WT)) and homozygous sickle (SS) red blood cells (RBCs) express a large number of surface receptors that mediate cell adhesion between RBCs, and between RBCs and white blood cells, platelets, and the endothelium. In sickle cell disease (SCD), abnormal adhesion of RBCs to endothelial cells is mediated by the intercellular adhesion molecule-4 (ICAM-4), which appears on the RBC membrane and binds to the endothelial alphavbeta3 integrin. This is a key factor in the initiation of vaso-occlusive episodes, the hallmark of SCD. A better understanding of the mechanisms that control RBC adhesion to endothelium may lead to novel approaches to both prevention and treatment of vaso-occlusive episodes in SCD. One important mechanism of ICAM-4 activation occurs via the cyclic adenosine monophosphate-protein kinase A (cAMP-PKA)-dependent signaling pathway. Here, we employed an in vitro technique called single-molecule force spectroscopy to study the effect of modulation of the cAMP-PKA-dependent pathway on ICAM-4 receptor activation. We quantified the frequency of active ICAM-4 receptors on WT-RBC and SS-RBC membranes, as well as the median unbinding force between ICAM-4 and alphavbeta3. We showed that the collective frequency of unbinding events in WT-RBCs is not significantly different from that of SS-RBCs. This result was confirmed by confocal microscopy experiments. In addition, we showed that incubation of normal RBCs and SS-RBCs with epinephrine, a catecholamine that binds to the beta-adrenergic receptor and activates the cAMP PKA-dependent pathway, caused a significant increase in the frequency of active ICAM-4 receptors in both normal RBCs and SS-RBCs. However, the unbinding force between ICAM-4 and the corresponding ligand alphavbeta3 remained the same. Furthermore, we demonstrated that forskolin, an adenylyl cyclase activator, significantly increased the frequency of ICAM-4 receptors in WT-RBCs and SS-RBCs, confirming that the activation of ICAM-4 is regulated by the cAMP-PKA pathway. Finally, we showed that A-kinase anchoring proteins play an essential role in ICAM-4 activation. PMID- 28076806 TI - Measurement of Slow Spontaneous Release of 11-cis-Retinal from Rhodopsin. AB - The vertebrate visual photoreceptor rhodopsin (Rho) is a unique G protein-coupled receptor as it utilizes a covalently tethered inverse agonist (11-cis-retinal) as the native ligand. Previously, electrophysiological studies showed that ligand binding of 11-cis-retinal in dark-adapted Rho was essentially irreversible with a half-life estimated to be 420 years, until after thermal isomerization to all trans-retinal, which then slowly dissociates. This long lifetime of 11-cis retinal binding was considered to be physiologically important for minimizing background signal (dark noise) of the visual system. However, in vitro biochemical studies on the thermal stability of Rho showed that Rho decays with a half-life on the order of days. In this study, we resolve the discrepancy by measuring the chromophore exchange rate of the bound 11-cis-retinal chromophore with free 9-cis-retinal from Rho in an in vitro phospholipid/detergent bicelle system. We conclude that the thermal decay of Rho primarily proceeds through spontaneous breaking of the covalent linkage between opsin and 11-cis-retinal, which was overlooked in the electrophysiological recording. We estimate that this slow spontaneous release of 11-cis-retinal from Rho should result in 104 to 105 free opsin molecules in a dark-adapted rod cell-a number that is three orders of magnitude higher than previously expected. We also discuss the physiological implications of these findings on the basal activity of opsins and the associated dark noise in the visual system. PMID- 28076807 TI - CIDER: Resources to Analyze Sequence-Ensemble Relationships of Intrinsically Disordered Proteins. AB - Intrinsically disordered proteins and regions (IDPs) represent a large class of proteins that are defined by conformational heterogeneity and lack of persistent tertiary/secondary structure. IDPs play important roles in a range of biological functions, and their dysregulation is central to numerous diseases, including neurodegeneration and cancer. The conformational ensembles of IDPs are encoded by their amino acid sequences. Here, we present two computational tools that are designed to enable rapid and high-throughput analyses of a wide range of physicochemical properties encoded by IDP sequences. The first, CIDER, is a user friendly webserver that enables rapid analysis of IDP sequences. The second, localCIDER, is a high-performance software package that enables a wide range of analyses relevant to IDP sequences. In addition to introducing the two packages, we demonstrate the utility of these resources using examples where sequence analysis offers biophysical insights. PMID- 28076808 TI - Spatiotemporal Modeling of Triggering and Amplifying Pathways in GLP-1 Secreting Intestinal L Cells. AB - Glucagon-like peptide 1 (GLP-1) is secreted by intestinal L-cells, and augments glucose-induced insulin secretion, thus playing an important role in glucose control. The stimulus-secretion pathway in L-cells is still incompletely understood and a topic of debate. It is known that GLP-1 secreting cells can sense glucose to promote electrical activity either by the electrogenic sodium glucose cotransporter SGLT1, or by closure of ATP-sensitive potassium channels after glucose metabolism. Glucose also has an effect on GLP-1 secretion downstream of electrical activity. An important aspect to take into account is the spatial organization of the cell. Indeed, the glucose transporter GLUT2 is located at the basolateral, vascular side, while SGLT1 is exposed to luminal glucose at the apical side of the cell, suggesting that the two types of transporters play different roles in glucose sensing. Here, we extend our recent model of electrical activity in primary L-cells to include spatiotemporal glucose and Ca2+ dynamics, and GLP-1 secretion. The model confirmed that glucose transportation into the cell through SGLT1 cotransporters can induce Ca2+ influx and release of GLP-1 as a result of electrical activity, while glucose metabolism alone is insufficient to depolarize the cell and evoke GLP-1 secretion in the model, suggesting a crucial role for SGLT1 in triggering GLP-1 release in agreement with experimental studies. We suggest a secondary, but participating, role of GLUT2 and glucose metabolism for GLP-1 secretion via an amplifying pathway that increases the secretion rate at a given Ca2+ level. PMID- 28076809 TI - A Model for the Transient Subdiffusive Behavior of Particles in Mucus. AB - In this study we have applied a model to explain the reported subdiffusion of particles in mucus, based on the measured mean squared displacements (MSD). The model considers Brownian diffusion of particles in a confined geometry, made from permeable membranes. The applied model predicts a normal diffusive behavior at very short and long time lags, as observed in several experiments. In between these timescales, we find that the "subdiffusive" regime is only a transient effect, MSD?taualpha,alpha<1. The only parameters in the model are the diffusion coefficients at the limits of very short and long times, and the distance between the permeable membranes L. Our numerical results are in agreement with published experimental data for realistic assumptions of these parameters. Finally, we show that only particles with a diameter less than 40 nm are able to pass through a mucus layer by passive Brownian motion. PMID- 28076810 TI - DNA Occupancy of Polymerizing Transcription Factors: A Chemical Model of the ETS Family Factor Yan. AB - Transcription factors use both protein-DNA and protein-protein interactions to assemble appropriate complexes to regulate gene expression. Although most transcription factors operate as monomers or dimers, a few, including the E26 transformation-specific family repressors Drosophila melanogaster Yan and its human homolog TEL/ETV6, can polymerize. Although polymerization is required for both the normal and oncogenic function of Yan and TEL/ETV6, the mechanisms by which it influences the recruitment, organization, and stability of transcriptional complexes remain poorly understood. Further, a quantitative description of the DNA occupancy of a polymerizing transcription factor is lacking, and such a description would have broader applications to the conceptually related area of polymerizing chromatin regulators. To expand the theoretical basis for understanding how the oligomeric state of a transcriptional regulator influences its chromatin occupancy and function, we leveraged the extensive biochemical characterization of E26 transformation-specific factors to develop a mathematical model of Yan occupancy at chemical equilibrium. We find that spreading condensation from a specific binding site can take place in a path independent manner given reasonable values of the free energies of specific and non-specific DNA binding and protein-protein cooperativity. Our calculations show that polymerization confers upon a transcription factor the unique ability to extend occupancy across DNA regions far from specific binding sites. In contrast, dimerization promotes recruitment to clustered binding sites and maximizes discrimination between specific and non-specific sites. We speculate that the association with non-specific DNA afforded by polymerization may enable regulatory behaviors that are well-suited to transcriptional repressors but perhaps incompatible with precise activation. PMID- 28076811 TI - Modeling the Effect of Curvature on the Collective Behavior of Cells Growing New Tissue. AB - The growth of several biological tissues is known to be controlled in part by local geometrical features, such as the curvature of the tissue interface. This control leads to changes in tissue shape that in turn can affect the tissue's evolution. Understanding the cellular basis of this control is highly significant for bioscaffold tissue engineering, the evolution of bone microarchitecture, wound healing, and tumor growth. Although previous models have proposed geometrical relationships between tissue growth and curvature, the role of cell density and cell vigor remains poorly understood. We propose a cell-based mathematical model of tissue growth to investigate the systematic influence of curvature on the collective crowding or spreading of tissue-synthesizing cells induced by changes in local tissue surface area during the motion of the interface. Depending on the strength of diffusive damping, the model exhibits complex growth patterns such as undulating motion, efficient smoothing of irregularities, and the generation of cusps. We compare this model with in vitro experiments of tissue deposition in bioscaffolds of different geometries. By including the depletion of active cells, the model is able to capture both smoothing of initial substrate geometry and tissue deposition slowdown as observed experimentally. PMID- 28076812 TI - Spermine Condenses DNA, but Not RNA Duplexes. AB - Interactions between the polyamine spermine and nucleic acids drive important cellular processes. Spermine condenses DNA and some RNAs, such as poly(rA):poly(rU). A large fraction of the spermine present in cells is bound to RNA but apparently does not condense it. Here, we study the effect of spermine binding to short duplex RNA and DNA, and compare our findings with predictions of molecular-dynamics simulations. When small numbers of spermine are introduced, RNA with a designed sequence containing a mixture of 14 GC pairs and 11 AU pairs resists condensation relative to DNA of an equivalent sequence or to 25 bp poly(rA):poly(rU) RNA. A comparison of wide-angle x-ray scattering profiles with simulation results suggests that spermine is sequestered deep within the major groove of mixed-sequence RNA. This prevents condensation by limiting opportunities to bridge to other molecules and stabilizes the RNA by locking it into a particular conformation. In contrast, for DNA, simulations suggest that spermine binds externally to the duplex, offering opportunities for intermolecular interaction. The goal of this study is to explain how RNA can remain soluble and available for interaction with other molecules in the cell despite the presence of spermine at concentrations high enough to precipitate DNA. PMID- 28076813 TI - Signatures of Mechanosensitive Gating. AB - The question of how mechanically gated membrane channels open and close is notoriously difficult to address, especially if the protein structure is not available. This perspective highlights the relevance of micropipette-aspirated single-particle tracking-used to obtain a channel's diffusion coefficient, D, as a function of applied membrane tension, sigma-as an indirect assay for determining functional behavior in mechanosensitive channels. While ensuring that the protein remains integral to the membrane, such methods can be used to identify not only the gating mechanism of a protein, but also associated physical moduli, such as torsional and dilational rigidity, which correspond to the protein's effective shape change. As an example, three distinct D-versus-sigma "signatures" are calculated, corresponding to gating by dilation, gating by tilt, and gating by a combination of both dilation and tilt. Both advantages and disadvantages of the approach are discussed. PMID- 28076814 TI - GsMTx4: Mechanism of Inhibiting Mechanosensitive Ion Channels. AB - GsMTx4 is a spider venom peptide that inhibits cationic mechanosensitive channels (MSCs). It has six lysine residues that have been proposed to affect membrane binding. We synthesized six analogs with single lysine-to-glutamate substitutions and tested them against Piezo1 channels in outside-out patches and independently measured lipid binding. Four analogs had ~20% lower efficacy than the wild-type (WT) peptide. The equilibrium constants calculated from the rates of inhibition and washout did not correlate with the changes in inhibition. The lipid association strength of the WT GsMTx4 and the analogs was determined by tryptophan autofluorescence quenching and isothermal calorimetry with membrane vesicles and showed no significant differences in binding energy. Tryptophan fluorescence-quenching assays showed that both WT and analog peptides bound superficially near the lipid-water interface, although analogs penetrated deeper. Peptide-lipid association, as a function of lipid surface pressure, was investigated in Langmuir monolayers. The peptides occupied a large fraction of the expanded monolayer area, but that fraction was reduced by peptide expulsion as the pressure approached the monolayer-bilayer equivalence pressure. Analogs with compromised efficacy had pressure-area isotherms with steeper slopes in this region, suggesting tighter peptide association. The pressure-dependent redistribution of peptide between "deep" and "shallow" binding modes was supported by molecular dynamics (MD) simulations of the peptide-monolayer system under different area constraints. These data suggest a model placing GsMTx4 at the membrane surface, where it is stabilized by the lysines, and occupying a small fraction of the surface area in unstressed membranes. When applied tension reduces lateral pressure in the lipids, the peptides penetrate deeper acting as "area reservoirs" leading to partial relaxation of the outer monolayer, thereby reducing the effective magnitude of stimulus acting on the MSC gate. PMID- 28076815 TI - Fluorescent Labeling Preserving OCP Photoactivity Reveals Its Reorganization during the Photocycle. AB - Orange carotenoid protein (OCP), responsible for the photoprotection of the cyanobacterial photosynthetic apparatus under excessive light conditions, undergoes significant rearrangements upon photoconversion and transits from the stable orange to the signaling red state. This is thought to involve a 12-A translocation of the carotenoid cofactor and separation of the N- and C-terminal protein domains. Despite clear recent progress, the detailed mechanism of the OCP photoconversion and associated photoprotection remains elusive. Here, we labeled the OCP of Synechocystis with tetramethylrhodamine-maleimide (TMR) and obtained a photoactive OCP-TMR complex, the fluorescence of which was highly sensitive to the protein state, showing unprecedented contrast between the orange and red states and reflecting changes in protein conformation and the distances from TMR to the carotenoid throughout the photocycle. The OCP-TMR complex was sensitive to the light intensity, temperature, and viscosity of the solvent. Based on the observed Forster resonance energy transfer, we determined that upon photoconversion, the distance between TMR (donor) bound to a cysteine in the C terminal domain and the carotenoid (acceptor) increased by 18 A, with simultaneous translocation of the carotenoid into the N-terminal domain. Time resolved fluorescence anisotropy revealed a significant decrease of the OCP rotation rate in the red state, indicating that the light-triggered conversion of the protein is accompanied by an increase of its hydrodynamic radius. Thus, our results support the idea of significant structural rearrangements of OCP, providing, to our knowledge, new insights into the structural rearrangements of OCP throughout the photocycle and a completely novel approach to the study of its photocycle and non-photochemical quenching. We suggest that this approach can be generally applied to other photoactive proteins. PMID- 28076816 TI - Mutation G1629E Increases von Willebrand Factor Cleavage via a Cooperative Destabilization Mechanism. AB - The large multimeric glycoprotein von Willebrand Factor (VWF) plays a pivotal adhesive role during primary hemostasis. VWF is cleaved by the protease ADAMTS13 as a down-regulatory mechanism to prevent excessive VWF-mediated platelet aggregation. For each VWF monomer, the ADAMTS13 cleavage site is located deeply buried inside the VWF A2 domain. External forces in vivo or denaturants in vitro trigger the unfolding of this domain, thereby leaving the cleavage site solvent exposed and ready for cleavage. Mutations in the VWF A2 domain, facilitating the cleavage process, cause a distinct form of von Willebrand disease (VWD), VWD type 2A. In particular, the VWD type 2A Gly1629Glu mutation drastically accelerates the proteolytic cleavage activity, even in the absence of forces or denaturants. However, the effect of this mutation has not yet been quantified, in terms of kinetics or thermodynamics, nor has the underlying molecular mechanism been revealed. In this study, we addressed these questions by using fluorescence correlation spectroscopy, molecular dynamics simulations, and free energy calculations. The measured enzyme kinetics revealed a 20-fold increase in the cleavage rate for the Gly1629Glu mutant compared with the wild-type VWF. Cleavage was found cooperative with a cooperativity coefficient n = 2.3, suggesting that the mutant VWF gives access to multiple cleavage sites of the VWF multimer at the same time. According to our simulations and free energy calculations, the Gly1629Glu mutation causes structural perturbation in the A2 domain and thereby destabilizes the domain by ~10 kJ/mol, promoting its unfolding. Taken together, the enhanced proteolytic activity of Gly1629Glu can be readily explained by an increased availability of the ADAMTS13 cleavage site through A2-domain-fold thermodynamic destabilization. Our study puts forward the Gly1629Glu mutant as a very efficient enzyme substrate for ADAMTS13 activity assays. PMID- 28076817 TI - Elucidation of Single Hydrogen Bonds in GTPases via Experimental and Theoretical Infrared Spectroscopy. AB - Time-resolved Fourier transform infrared (FTIR) spectroscopy is a powerful tool to elucidate label-free the reaction mechanisms of proteins. After assignment of the absorption bands to individual groups of the protein, the order of events during the reaction mechanism can be monitored and rate constants can be obtained. Additionally, structural information is encoded into infrared spectra and can be decoded by combining the experimental data with biomolecular simulations. We have determined recently the infrared vibrations of GTP and guanosine diphosphate (GDP) bound to Galphai1, a ubiquitous GTPase. These vibrations are highly sensitive for the environment of the phosphate groups and thereby for the binding mode the GTPase adopts to enable fast hydrolysis of GTP. In this study we calculated these infrared vibrations from biomolecular simulations to transfer the spectral information into a computational model that provides structural information far beyond crystal structure resolution. Conformational ensembles were generated using 15 snapshots of several 100 ns molecular-mechanics/molecular-dynamics (MM-MD) simulations, followed by quantum mechanics/molecular-mechanics (QM/MM) minimization and normal mode analysis. In comparison with other approaches, no time-consuming QM/MM-MD simulation was necessary. We carefully benchmarked the simulation systems by deletion of single hydrogen bonds between the GTPase and GTP through several Galphai1 point mutants. The missing hydrogen bonds lead to blue-shifts of the corresponding absorption bands. These band shifts for alpha-GTP (Galphai1-T48A), gamma-GTP (Galphai1 R178S), and for both beta-GTP/gamma-GTP (Galphai1-K46A, Galphai1-D200E) were found in agreement in the experimental and the theoretical spectra. We applied our approach to open questions regarding Galphai1: we show that the GDP state of Galphai1 carries a Mg2+, which is not found in x-ray structures. Further, the catalytic role of K46, a central residue of the P-loop, and the protonation state of the GTP are elucidated. PMID- 28076818 TI - One-Way Allosteric Communication between the Two Disulfide Bonds in Tissue Factor. AB - Tissue factor (TF) is a transmembrane glycoprotein that plays distinct roles in the initiation of extrinsic coagulation cascade and thrombosis. TF contains two disulfide bonds, one each in the N-terminal and C-terminal extracellular domains. The C-domain disulfide, Cys186-Cys209, has a -RHStaple configuration in crystal structures, suggesting that this disulfide carries high pre-stress. The redox state of this disulfide has been proposed to regulate TF encryption/decryption. Ablating the N-domain Cys49-Cys57 disulfide bond was found to increase the redox potential of the Cys186-Cys209 bond, implying an allosteric communication between the domains. Using molecular dynamics simulations, we observed that the Cys186 Cys209 disulfide bond retained the -RHStaple configuration, whereas the Cys49 Cys57 disulfide bond fluctuated widely. The Cys186-Cys209 bond featured the typical -RHStaple disulfide properties, such as a longer S-S bond length, larger C-S-S angles, and higher bonded prestress, in comparison to the Cys49-Cys57 bond. Force distribution analysis was used to sense the subtle structural changes upon ablating the disulfide bonds, and allowed us to identify a one-way allosteric communication mechanism from the N-terminal to the C-terminal domain. We propose a force propagation pathway using a shortest-pathway algorithm, which we suggest is a useful method for searching allosteric signal transduction pathways in proteins. As a possible explanation for the pathway being one-way, we identified a pronounced lower degree of conformational fluctuation, or effectively higher stiffness, in the N-terminal domain. Thus, the changes of the rigid domain (N terminal domain) can induce mechanical force propagation to the soft domain (C terminal domain), but not vice versa. PMID- 28076819 TI - Full-Spectral Multiplexing of Bioluminescence Resonance Energy Transfer in Three TRPV Channels. AB - Multiplexed bioluminescence resonance energy transfer (BRET) assays were developed to monitor the activation of several functional transient receptor potential (TRP) channels in live cells and in real time. We probed both TRPV1 intramolecular rearrangements and its interaction with Calmodulin (CaM) under activation by chemical agonists and temperature. Our BRET study also confirmed that: (1) capsaicin and heat promoted distinct transitions, independently coupled to channel gating, and that (2) TRPV1 and Ca2+-bound CaM but not Ca2+-free CaM were preassociated in resting live cells, while capsaicin activation induced both the formation of more TRPV1/CaM complexes and conformational changes. The BRET assay, based on the interaction with Calmodulin, was successfully extended to TRPV3 and TRPV4 channels. We therefore developed a full-spectral three-color BRET assay for analyzing the specific activation of each of the three TRPV channels in a single sample. Such key improvement in BRET measurement paves the way for the simultaneous monitoring of independent biological pathways in live cells. PMID- 28076821 TI - 2017 Ushers in New Editorial Board Members and More. PMID- 28076820 TI - Probing Conformational Changes during the Gating Cycle of a Potassium Channel in Lipid Bilayers. AB - Ion conduction across the cellular membrane requires the simultaneous opening of activation and inactivation gates of the K+ channel pore. The bacterial KcsA channel has served as a powerful system for dissecting the structural changes that are related to four major functional states associated with K+ gating. Yet, the direct observation of the full gating cycle of KcsA has remained structurally elusive, and crystal structures mimicking these gating events require mutations in or stabilization of functionally relevant channel segments. Here, we found that changes in lipid composition strongly increased the KcsA open probability. This enabled us to probe all four major gating states in native-like membranes by combining electrophysiological and solid-state NMR experiments. In contrast to previous crystallographic views, we found that the selectivity filter and turret region, coupled to the surrounding bilayer, were actively involved in channel gating. The increase in overall steady-state open probability was accompanied by a reduction in activation-gate opening, underscoring the important role of the surrounding lipid bilayer in the delicate conformational coupling of the inactivation and activation gates. PMID- 28076822 TI - An in vitro analysis of the size and shape of cryolesions for facet joint denervation. AB - OBJECTIVES: Lumbar facet joint syndrome (LFJS) is the cause of lower back pain in 15-54% of the patients. Clinical studies of cryotherapy for LFJS have reported promising outcomes. However, few studies have focused on the technical aspects of cryoneurolysis for LFJS. The aim of the study was to determine the size and shape of cryolesions in vitro and to determine how they are affected by the duration of freezing, size of the cryoprobe and distance and angulation to an osseous boundary layer. MATERIALS AND METHODS: Two different cryolesion generators were used. Cryolesions were generated in tempered physiologic NaCl solution in the vicinity of an osseous surface. The size of the cryoprobes, duration of freezing, distance to the bone surface and angulation of the probe were studied. Cryolesions were recorded with a video camera during their emergence. Images at distinct time points were analysed using digital image processing software. RESULTS: The probe size, the system in use and the duration of the freezing cycle were the main determinants for the size of the cryolesion. The vicinity of the osseous boundary resulted in a modest increase in the size of the cryolesion. Angulation of the cryoprobe towards the osseous boundary is of minor importance for the size of the contact area to the nerve. CONCLUSION: For cryoneurolysis of LFJS, duration of freezing, temperature and probe size are the main determinants of lesion size and thus the probability of success of the procedure. A tangential approach of the probe is not essential. PMID- 28076823 TI - Guazuma ulmifolia bark-synthesized Ag, Au and Ag/Au alloy nanoparticles: Photocatalytic potential, DNA/protein interactions, anticancer activity and toxicity against 14 species of microbial pathogens. AB - In the present study, we focused on a quick and green method to fabricate Ag, Au and Ag/Au alloy nanoparticles (NPs) using the bark extract of Guazuma ulmifolia L. Green synthesized metal NPs were characterized using different techniques, including UV-Vis spectroscopy, FT-IR, XRD, AFM and HR-TEM analyses. The production of Ag, Au and Ag/Au alloy NPs was observed monitoring color change from colorless to brown, followed by pink and dark brown, as confirmed by UV-Vis spectroscopy characteristic peaks at 436, 522 and 510nm, respectively. TEM shed light on the spherical shapes of NPs with size ranges of 10-15, 20-25 and 10 20nm. Biosynthesized NPs showed good catalytic activity reducing two organic dyes, 4-nitrophenol (4-NP) and Congo red (CR). UV-vis spectroscopy, fluorescence, circular dichroism spectroscopy and viscosity analyses were used to investigate the NP binding with calf thymus DNA. The binding constant of NPs with DNA calculated in UV-Vis absorption studies were 1.18*104, 1.83*104 and 2.91*104M-1, respectively, indicating that NPs were able to bind DNA with variable binding affinity: Ag/Au alloy NPs>Ag NPs>Au NPs. Ag/Au alloy NPs also showed binding activity to bovine serum albumin (BSA) over the other NPs. Ag and Ag/Au alloy NPs exhibited good antimicrobial activity on 14 species of microbial pathogens. In addition, the cytotoxic effects of Ag/Au alloy NPs were studied on human cervical cancer cells (HeLa) using MTT assay. Overall, our work showed the promising potential of bark-synthesized Ag and Ag/Au alloy NPs as cheap sources to develop novel and safer photocatalytic, antimicrobial and anticancer agents. PMID- 28076824 TI - Discovery of new nanomolar inhibitors of GPa: Extension of 2-oxo-1,2 dihydropyridinyl-3-yl amide-based GPa inhibitors. AB - Glycogen Phosphorylase (GP) is a functionally active dimeric enzyme, which is a target for inhibition of the conversion of glycogen to glucose-1-phosphate. In this study we report the design and synthesis of 14 new pyridone derivatives, and seek to extend the SAR analysis of these compounds. The SAR revealed the minor influence of the amide group, importance of the pyridone ring both spatially around the pyridine ring and for possible pi-stacking, and confirmed a preference for inclusion of 3,4-dichlorobenzyl moieties, as bookends to the pyridone scaffold. Upon exploring a dimer strategy as part of the SAR analysis, the first extended 2-oxo-dihydropyridinyl-3-yl amide nanomolar based inhibitors of GPa (IC50 = 230 and 260 nM) were identified. PMID- 28076825 TI - Polar aromatic periphery increases agonist potency of spirocyclic free fatty acid receptor (GPR40) agonists inspired by LY2881835. AB - A series of spirocyclic compounds inspired by Eli Lilly's phase 1 antidiabetic FFA1 receptor agonist LY2881835 was designed to include polar aromatic periphery groups and explore a possibility of building additional contacts with the target near the agonist binding site. The frontrunner compound in the series (9i) was shown to be a potent (EC50 = 260 nM) FFA1 agonist with excellent aqueous (PBS) solubility and good Caco-2 permeability. The observed structure-activity relationships were rationalized by a docking study. The new series significantly expands the ligand landscape for the ongoing quest for new potent and more polar FFA1 agonists as fundamentally new class of therapeutic agents against type 2 diabetes mellitus. PMID- 28076826 TI - Identification of new pyrrolo[2,3-d]pyrimidines as Src tyrosine kinase inhibitors in vitro active against Glioblastoma. AB - In the last few years, several pyrrolo-pyrimidine derivatives have been either approved by the US FDA and in other countries for the treatment of different diseases or are currently in phase I/II clinical trials. Herein we present the synthesis and the characterization of a novel series of pyrrolo[2,3 d]pyrimidines, compounds 8a-j, and their activity against Glioblastoma multiforme (GBM). Docking studies and MM-GBSA analysis revealed the ability of such compounds to efficiently interact with the ATP binding site of Src. Enzymatic assays against a mini-panel of kinases (Src, Fyn, EGFR, Kit, Flt3, Abl, AblT315I) have been performed, showing an unexpected selectivity of our pyrrolo[2,3 d]pyrimidines for Src. Finally, the derivatives were tested for their antiproliferative potency on U87 GBM cell line. Compound 8h showed a considerable cytotoxicity effect against U87 cell line with an IC50 value of 7.1 MUM. PMID- 28076827 TI - New diphenylmethane derivatives as peroxisome proliferator-activated receptor alpha/gamma dual agonists endowed with anti-proliferative effects and mitochondrial activity. AB - We screened a short series of new chiral diphenylmethane derivatives and identified potent dual PPARalpha/gamma partial agonists. As both enantiomers of the most active compound 1 displayed an unexpected similar transactivation activity, we performed docking experiments to provide a molecular understanding of their similar partial agonism. We also evaluated the ability of both enantiomers of 1 and racemic 2 to inhibit colorectal cancer cells proliferation: (S)-1 displayed a more robust activity due, at least in part, to a partial inhibition of the Wnt/beta-catenin signalling pathway that is upregulated in the majority of colorectal cancers. Finally, we investigated the effects of (R)-1, (S)-1 and (R,S)-2 on mitochondrial function and demonstrated that they activate the carnitine shuttle system through upregulation of carnitine/acylcarnitine carrier (CAC) and carnitine-palmitoyl-transferase 1 (CPT1) genes. Consistent with the notion that these are PPARalpha target genes, we tested and found that PPARalpha itself is regulated by a positive loop. Moreover, these compounds induced a significant mitochondrial biogenesis. In conclusion, we identified a new series of dual PPARalpha/gamma agonists endowed with novel anti-proliferative properties associated with a strong activation of mitochondrial functions and biogenesis, a potential therapeutic target of the treatment of insulin resistance. PMID- 28076828 TI - Perinatal risk factors for low and moderate five-minute Apgar scores at term. AB - OBJECTIVE: To evaluate the specific maternal and perinatal variables associated with a low (<=3) or moderate (4-6) Apgar score, compared to a high (>=7) score. STUDY DESIGN: This was a retrospective, cohort study of 58429 term singleton babies born at the Mater Mother's Hospital in Brisbane, Australia in 2007-2013. Maternal demographics, socio-economic status using the Australian Socioeconomic Index for Areas (SEIFA) score, obstetric factors, and birth outcomes were compared for neonates grouped into three categories based on their five-minute Apgar: low (<=3), moderate (4-6) and high (>=7). The low- and moderate-score cohorts were individually compared to the high-score cohort using both univariate and multivariate analysis. RESULTS: Logistic regression analysis confirmed that of the variables analysed, only maternal public insurance status (OR 2.1, 95% CI 1.5-3.1), breech presentation (OR 2.4, 95% CI 1.1-4.6), other non-cephalic presentation (OR 9.5, 95% CI 2.2-25.4), intramuscular narcotic use (OR 2.3, 95% CI 1.5-3.5), and presence of meconium (OR 3.7, 95% CI 2.5-5.4) were significantly associated with low Apgar scores. Variables significantly associated with a moderate score were: SEIFA <=50th centile (OR 1.6, 95% CI 1.2-2.0) and 61st to 70th centile (OR 1.31, 95% CI 0.9-1.8) categories, maternal public insurance status (OR 2.7, 95% CI 2.2-3.3), nulliparity (OR 2.0, 95% CI 1.7-2.5), emergency caesarean birth (OR 2.6, 95% CI 2.1-3.2), instrumental birth (OR 2.3, 95% CI 1.9 2.9), and presence of meconium (OR 2.6, 95% CI 2.1-3.2). CONCLUSIONS: Factors associated with low and moderate Apgar scores vary in type and degree of influence. Distinctions in the perinatal background can help predict newborn compromise and accelerate delivery of care. PMID- 28076829 TI - Comparing the effect of aromatase inhibitor (letrozole) + cabergoline (Dostinex) and letrozole alone on uterine myoma regression,a randomized clinical trial. AB - OBJECTIVE: To evaluate the effect of letrozole in combination with cabergoline and letrozole alone on regression of symptomatic uterine myomas in women of reproductive age. DESIGN: Randomized controlled clinical trial. SETTING: University hospital. PATIENTS: Ninety-one women of reproductive age were enrolled in the study and 88 women were eligible. Eight participants were excluded from the study. INTERVENTIONS: Eighty women of reproductive age with symptomatic myomas >4cm were evaluated in two groups. Participants in Group 1 received 2.5mg letrozole once daily and cabergoline 0.5mg/week from the first day of the menstrual cycle for 12 weeks, and participants in Group 2 received letrozole alone. MAIN OUTCOME MEASURES: Changes in uterine size and volume; myoma size, volume and number; and side effects of treatment. RESULTS: Overall, 76 patients completed the study. Compared with baseline values, mean uterine volume was reduced significantly in both groups (p=0.01), and there was no significant difference between groups (p=0.99). The mean number of dominant myomas was reduced significantly in both groups (p=0.03), with no significant difference between groups (p=0.6). The mean volume of myomas was reduced significantly in both groups (p=0.01), with no significant difference between groups (p=0.45). Although a significant decrease in number and volume of myomas was documented in each group (p<0.05), the intergroup analyses did not reveal significant differences between the two groups in terms of the change in number (p=0.28) and volume (p=0.96) of myomas. Headache was significantly more common in the letrozole+cabergoline group (nine vs two cases, p=0.02), but the two groups were comparable for the remaining minor side effects. CONCLUSION: This study showed that 12 weeks of treatment with letrozole with and without cabergoline improved the size and volume of the uterus and myomas, led to symptom improvement, and could be used for short-term treatment prior to surgery or fertility programmes. CONDENSATION: Condensation letrozole in combination with cabergoline in the management of uterine fibroids. PMID- 28076830 TI - Rosuvastatin improves myocardial and neurological outcomes after asphyxial cardiac arrest and cardiopulmonary resuscitation in rats. AB - Rosuvastatin, a potent HMG-CoA reductase inhibitor, is cholesterol-lowering drugs and reduce the risk of myocardial infarction and stroke. This study is to explore whether rosuvastatin improves outcomes after cardiac arrest in rats. Male Sprague Dawley rats were subjected to 8min of cardiac arrest (CA) by asphyxia and randomly assigned to three experimental groups immediately following successful resuscitation: Sham; Control; and Rosuvastatin. The survival, hemodynamics, myocardial function, neurological outcomes and apoptosis were assessed. The 7-d survival rate was greater in the rosuvastatin treated group compared to the Control group (P=0.019 by log-rank test). Myocardial function, as measured by cardiac output and ejection fraction, was significantly impaired after CA and notably improved in the animals treated with rosuvastatin beginning at 60min after return of spontaneous circulation (ROSC) (P<0.05). Moreover, rosuvastatin treatment significantly ameliorated brain injury after ROSC, which was characterized by the increase of neurological function scores, and reduction of brain edema in cortex and hippocampus (P<0.05). Meanwhile, the levels of cardiac troponin T and neuron-specific enolase and the caspase-3 activity were significantly decreased in the Rosuvastatin group when compared with the Control group (P<0.05). In conclusion, rosuvastatin treatment substantially improves the 7-d survival rate as well as myocardial function and neurological outcomes after ROSC. PMID- 28076831 TI - Dosing-time dependent oxidative effects of an immunosuppressive drug "Mycophenolate Mofetil" on rat kidneys. AB - This study investigates whether the toxicity in kidneys as well as oxidative stress varied according to the dosing time of an immunosuppressive agent "mycophenolate mofetil (MMF)" in Wistar Rat. 300mg/kg of MMF was injected by intraperitonal at four different circadian stages (1, 7, 13 and 19h after light onset, HALO). Rats were sacrificed after 3days, and the kidneys were removed for determination of oxidative stress and histological analysis. Biochemical variable (creatinine, urea) was performed. Statistical analysis showed that MMF administration at 7 HALO produced a renal toxicity assessed by the significant increase in both blood creatinine and urea and antioxidant activity assessed by malondialdehyde and protein carbonyl levels indicating an induction of lipid peroxidation in oxidative damage. Whereas, at this time MMF induced a decrease the enzyme activities of renal catalase and superoxide dismutase, with a renal histopathology alterations (glomerular atrophy and lesions within proximal tubules). However, when MMF was injected in the middle of the dark-activity phase it produced a very mild renal toxicity and low oxidative stress. The obtained data indicate that the maximum of renal toxicity is observed when MMF was injected in the middle of the light- rest span in rats. PMID- 28076832 TI - Dietary supplementation of grape seed and skin flour mitigates brain oxidative damage induced by a high-fat diet in rat: Gender dependency. AB - It is unknown whether gender has an impact on brain injury in obesity, and, if so, whether treatment with grape seed and skin flour could exert a protective effect. Both male and female rats were fed a standard diet (SD) or a high fat diet (HFD) during eight weeks and treated with high dosage grape seed and skin flour (GSSF). Fat-induced oxidative stress was evaluated into the brain with a special emphasis on transition metals determination. HFD induced male-cholesterol overload (+78.12%) and an oxidative stress status characterized by increased lipoperoxidation (+68.97%), carbonylation (+40.28%), decreased antioxidant enzyme activities as glutathione peroxidase (-61.07%) and manganese-superoxide dismutase (-35.47%) but not catalase. Additionally HFD depleted the brain from manganese ( 71.31%) and dropped glutamine synthetase activity (-36.16%), without affecting copper nor iron nor their associated enzymes. HFD also altered intracellular mediators as superoxide anion (+36.12%), calcium (+44.41%) and also calpain (+76.54%) a calcium dependent protease. Importantly all these alterations were detected exclusively in male brain and were efficiently corrected upon GSSF treatment. In conclusion, GSSF has the potential to alleviate the deleterious lipotoxic effect of HFD treatment that occurred in male brain and perhaps in post menauposal female brain. PMID- 28076833 TI - 7-O-Geranylquercetin induces apoptosis in gastric cancer cells via ROS-MAPK mediated mitochondrial signaling pathway activation. AB - 7-O-Geranylquercetin (GQ) is a novel O-alkylated derivate of quercetin. In this study, we evaluated its apoptosis induction effects in human gastric cancer cell lines SGC-7901 and MGC-803 and explored the potential molecular mechanisms. The results demonstrated that GQ lowered viability of SGC-7901 and MGC-803 cells in a dose- and time-dependent manner without apparent cytotoxicity to human gastric epithelial cell line GES-1. GQ could induce apoptosis in SGC-7901 and MGC 803cells, and arrest the gastric cancer cells at G2/M phase. Mechanism study showed that GQ triggered generation of reactive oxygen species (ROS), then activated p38 and JNK signaling pathways, subsequently led to mitochondrial impairment by regulating the expression of Bcl-2, Bcl-xl and Bax, and finally promoted the release of cytochrome c and the activation of caspases to induce apoptosis. In addition, Z-VAD-FMK (caspase inhibitor) could reverse GQ-induced apoptosis. SB203580 (p38 inhibitor) and SP600125 (JNK inhibitor) could rescue GQ induced cell death and attenuate mitochondrial signal pathway activation. Furthermore, NAC (ROS inhibitor) could rescue GQ-induced cell death, reduce ROS generation, decrease the phosphorylation of p38 and JNK, and then attenuate the activation of mitochondrial signal pathway. Taken together, GQ induces caspase dependent apoptosis in gastric cancer cells through activating ROS-MAPK mediated mitochondrial signal pathway. This study highlights the potential use of GQ as a gastric cancer therapeutic agent. PMID- 28076834 TI - Risk factors for posttraumatic epilepsy: A systematic review and meta-analysis. AB - OBJECTIVE: A systematic review and meta-analysis was performed to identify risk factors for posttraumatic epilepsy (PTE). METHODS: Two electronic databases (Medline and Embase) were searched to identify studies with a cohort, case control, or cross-sectional design reporting on epidemiologic evidence regarding risk factors for PTE. RESULTS: Men had a higher risk of developing PTE than women [relative ratio (RR), 1.32; 95% confidence interval (CI), 1.10-1.59]. A history of alcohol abuse (RR, 2.18; 95% CI, 1.26-3.79), posttraumatic amnesia (RR, 1.31; 95% CI, 1.12-1.53), focal neurologic signs (RR, 1.42; 95% CI, 1.16-1.74), and loss of consciousness at initial traumatic brain injury (TBI) (RR, 1.62; 95% CI, 1.13-2.32) were associated with a greater risk of PTE. TBI-related abnormal neuroimaging findings, including skull fracture (RR, 2.27; 95% CI, 1.49-3.44), midline shift (RR, 1.46; 95% CI, 1.14-1.87), brain contusion (RR, 2.35; 95% CI, 1.69-3.28), subdural hemorrhage (RR, 2.00; 95% CI, 1.33-3.01), and intracranial hemorrhage (RR, 2.65; 95% CI, 1.83-3.82) were strong risk factors for PTE. The risk of developing PTE after skull fracture, mild brain injury, and severe brain injury peaked within the first year after TBI, and then gradually decreased. However, a high risk of PTE was sustained for >10years. CONCLUSION: The current meta-analysis identified potential risk factors for PTE. The results may contribute to better prevention strategies and treatments for PTE. PMID- 28076835 TI - The functional polymorphisms of LIS1 are associated with acute myeloid leukemia risk in a Han Chinese population. AB - There is increasing evidence that the human lissencephaly-1 gene, LIS1, plays an important role in carcinogenesis of several malignancies including leukemia. However, little is known about the relationship between single nucleotide polymorphisms (SNPs) in LIS1 and the susceptibility to myeloid leukemia. In the present study, we systematically screened 5 potentially functional polymorphisms in LIS1, and conducted a case-control study including 660 acute myeloid leukemia (AML) patients and 1034 cancer-free controls in a Chinese population, to assess the association between these SNPs and AML risk. We found that the variant alleles of rs4790348, rs4790353, and rs7209748 could significantly increase the AML risk (rs4790348: adjusted OR=1.31, 95%CI=1.13-1.53 in additive model; rs4790353: adjusted OR=4.97, 95%CI=1.59-15.50 in recessive model; rs7209748: adjusted OR=2.34, 95%CI=1.11-4.94 in recessive model). These findings indicated that genetic variants in LIS1 may contribute to AML risk in Chinese population. PMID- 28076836 TI - The metabolic syndrome and 10-year cognitive and functional decline in very old men. A population-based study. AB - OBJECTIVES: To describe longitudinal relationships of metabolic syndrome (MetS) to cognitive decline and functional disability in a sample of older non institutionalized men. METHODS: data from 1991 to 2000 of the Italian cohorts of the Finland, Italy, the Netherlands, Elderly (FINE) study, were used. Global cognitive function and functional disability, defined as limitations in mobility, basic (ADLs) and instrumental activities of daily living (IADLs) were screened in 1991 and 2000. MetS was defined according to the NCEP ATP-III criteria. RESULTS: The study sample consisted of 195 men, baseline age 76.1+/-3.1years. Baseline MetS was prospectively associated with greater 10-year cognitive and functional decline in ADLs and IADLs. After multiple adjustment including age, education, marital status, ApoE epsilon4 allele, cerebrovascular disease and initial cognitive and depressive status, MetS predicted cognitive decline (B=-1.684, 95%CI=-2.202 to -1.167, p<0.001) and risk of IADLs (OR=1.09, 95% CI=1.01-1.20, p=0.048) and ADLs disability (OR=1.35, 95%CI=1.12-1.62, p<0.001). Interestingly, such associations were not attributable to individual altered components of MetS nor to their sum. Incident disability in ADLs and IADLs were not explained by parallel decline in cognitive function. CONCLUSIONS: MetS as an entity was associated with accelerated cognitive and functional decline in a population based sample of very old men. PMID- 28076837 TI - Possible influences on bullet trajectory deflection in ballistic gelatine. AB - The influence of the distance to the top and bottom of a gelatine block and to bullet tracks from previously fired shots on a bullet's trajectory, when passing through ballistic gelatine, was studied. No significant difference in deflection was found when trajectories of 9mm Luger bullets, fired at a 3.5cm distance to the top and bottom of a gelatine block and to bullet tracks from previously fired shots, were compared to trajectories of bullets fired 7cm or more away from any of the aforementioned aspects. A surprisingly consistent 6.5 degrees absolute deflection angle was found when these bullets passed through 22.5 to 23.5cm of ballistic gelatine. The projection angle, determined by the direction of the deflection, appeared to be random. The consistent absolute angle, in combination with the random projection angle, resulted in a cone-like deflection pattern. PMID- 28076838 TI - Identification of MDMB-FUBINACA in commercially available e-liquid formulations sold for use in electronic cigarettes. AB - MDMB-FUBINACA (aka MDMB(N)-Bz-F), chemical name Methyl (S)-2-(1-(4-fluorobenzyl) 1H-indazole-3-carboxamido)-3,3-dimethylbutanoate, a designer drug or a new psychoactive substance (NPS), was identified in three commercially available e liquids formulated for electronic cigarette use. The e-liquids were evaluated using direct analysis in real time ion source attached to a time of flight mass spectrometer (DART-MS) and gas chromatograph mass spectrometer (GC-MS) to identify active ingredients/drugs, flavorants, and other possible constituents. The e-liquids were also evaluated for alcohol content by headspace gas chromatography with flame ionization detector (HS-GC-FID). The aerosol produced from the e-liquids by use of an e-cigarette was analyzed by solid phase micro extraction gas chromatography mass spectrometry (SPME-GC-MS) to ensure delivery of the active ingredient/drug. Propylene glycol, vegetable glycerin, MDMB FUBINACA, alcohol content and a flavor profile were determined for each of the e liquids. MDMB-FUBINACA was determined to be the major active ingredient in all three e-liquids and was successfully detected by SPME-GC-MS in the aerosol generated by a KangerTech Aerotank clearomizer/electronic cigarette. PMID- 28076840 TI - HIF-1alpha induces the epithelial-mesenchymal transition in gastric cancer stem cells through the Snail pathway. AB - Substantial evidence suggests that the epithelial-mesenchymal transition (EMT) phenotype is associated with the invasive characteristics of cancer stem cells (CSCs),which possess an EMT phenotype that may predominate in tumor invasion and metastasis. However, the mechanisms for the generation and regulation of these CSCs have not been clearly defined. As hypoxia and EMT-related factors may have important functions in EMT-like CSCs, the aim of this study was to investigate the effects of hypoxia on these cells. CSCs were established from the gastric cancer cell lines MGC-803 and SGC7901, and the relationship between hypoxia and EMT-like CSCs was investigated in gastric cancer. After hypoxia treatment, some gastric CSCs exhibited a marked increase in hypoxia-inducible factor-1alpha (HIF 1alpha)expression and increased migration and invasion capabilities compared with the normoxic control. These CSCs were defined by activation of the mesenchymal cell marker Vimentin and by inhibition of the epithelial cell marker E-cadherin. Our analyses also show that HIF-1alpha was responsible for activating EMT via increased expression of the transcription factor Snail in gastric CSCs. Moreover, inhibition of Snail by shRNA reduced HIF-1alpha-induced EMT in gastric CSCs. The results demonstrated that hypoxia-induced EMT-like CSCs rely on HIF-1alphato activate Snail, which may result in recurrence and metastasis of gastric cancer. PMID- 28076839 TI - Chemotherapy can induce weight normalization of morbidly obese mice despite undiminished ingestion of high fat diet. AB - Morbidly obese patients who accomplish substantial weight loss often display a long-term decline in their resting metabolism, causing even relatively restrained caloric intake to trigger a relapse to the obese state. Paradoxically, we observed that morbidly obese mice receiving chemotherapy for cancer experienced spontaneous weight reduction despite unabated ingestion of their high fat diet (HFD). This response to chemotherapy could also be achieved in morbidly obese mice without cancer. Optimally dosed methotrexate (MTX) or cyclophosphamide (CY) enabled the mice to completely and safely normalize their body weight despite continued consumption of obesogenic quantities of HFD. Weight reduction was not attributable to decreased HFD intake, enhanced energy expenditure or malabsorption. MTX or CY dosing significantly depleted both adipose tissue and preadipocyte progenitors. Remarkably, however, despite continued high fat feeding, a compensatory increase in hepatocyte lipid storage was not observed, but rather the opposite. Gene microarray liver analyses demonstrated that HFD mice receiving MTX or CY experienced significantly inhibited lipogenesis and lipid storage, whereas Enho (energy homeostasis) gene expression was significantly upregulated. Further metabolic studies employing a human hepatocellular line revealed that MTX treatment preserved robust oxidative phosphorylation, but also promoted mitochondrial uncoupling with a surge in proton leak. This is the first report that certain optimally dosed chemotherapeutic agents can induce weight loss in morbidly obese mice without reduced dietary intake, apparently by depleting stores of adipocytes and their progenitors, curtailment of lipogenesis, and inconspicuous disposal of incoming dietary lipid via a steady state partial uncoupling of mitochondrial oxidative phosphorylation. PMID- 28076841 TI - Clonal evolution in therapy-related neoplasms. AB - Therapy-related myeloid neoplasms (t-MN) may occur as a late effect of cytotoxic therapy for a primary malignancy or autoimmune diseases in susceptible individuals. We studied the development of somatic mutations in t-MN, using a collection of follow-up samples from 14 patients with a primary hematologic malignancy, who developed a secondary leukemia (13 t-MN and 1 t-acute lymphoblastic leukemia), at a median latency of 73 months (range 18-108) from primary cancer diagnosis.Using Sanger and next generation sequencing (NGS) approaches we identified 8 mutations (IDH1 R132H, ASXL1 Y591*, ASXL1 S689*, ASXL1 R693*, SRSF2 P95H, SF3B1 K700E, SETBP1 G870R and TP53 Y220C) in seven of thirteen t-MN patients (54%), whereas the t-ALL patient had a t(4,11) translocation, resulting in the KMT2A/AFF1 fusion gene. These mutations were then tracked backwards in marrow samples preceding secondary leukemia occurrence, using pyrosequencing and a NGS protocol that allows the detection of low variant allele frequencies (>=0.1%).Somatic mutations were detectable in the BM harvested at the primary diagnosis, prior to any cytotoxic treatment in three patients, while they were not detectable and apparently acquired by the t-MN clone in five patients.These data show that clonal evolution in t-MN is heterogeneous, with some somatic mutations preceding cytotoxic treatment and possibly favoring leukemic development. PMID- 28076842 TI - Systemically identifying and prioritizing risk lncRNAs through integration of pan cancer phenotype associations. AB - LncRNAs have emerged as a major class of regulatory molecules involved in normal cellular physiology and disease, our knowledge of lncRNAs is very limited and it has become a major research challenge in discovering novel disease-related lncRNAs in cancers. Based on the assumption that diverse diseases with similar phenotype associations show similar molecular mechanisms, we presented a pan cancer network-based prioritization approach to systematically identify disease specific risk lncRNAs by integrating disease phenotype associations. We applied this strategy to approximately 2800 tumor samples from 14 cancer types for prioritizing disease risk lncRNAs. Our approach yielded an average area under the ROC curve (AUC) of 80.66%, with the highest AUC (98.14%) for medulloblastoma. When evaluated using leave-one-out cross-validation (LOOCV) for prioritization of disease candidate genes, the average AUC score of 97.16% was achieved. Moreover, we demonstrated the robustness as well as the integrative importance of this approach, including disease phenotype associations, known disease genes and the numbers of cancer types. Taking glioblastoma multiforme as a case study, we identified a candidate lncRNA gene SNHG1 as a novel disease risk factor for disease diagnosis and prognosis. In summary, we provided a novel lncRNA prioritization approach by integrating pan-cancer phenotype associations that could help researchers better understand the important roles of lncRNAs in human cancers. PMID- 28076843 TI - Pax-5 is a potent regulator of E-cadherin and breast cancer malignant processes. AB - Pax-5, an essential transcription factor for B lymphocyte development, has been linked with the development and progression of lymphoid cancers and carcinoma. In contrast to B-cell cancer lesions, the specific expression signatures and roles of Pax-5 in breast cancer progression are relatively unknown. In the present study, we set out to profile Pax-5 expression in mammary tissues and elucidate the cellular and molecular roles of Pax-5 in breast cancer processes. Using immunohistology on mammary tissue arrays, Pax-5 was detected in a total of 298/306 (97.6%) samples tested. Interestingly, our studies reveal that Pax-5 inhibits aggressive features and confers anti-proliferative effects in breast carcinoma cells in contrast to its oncogenic properties in B cell cancers. More precisely, Pax-5 suppressed breast cancer cell migration, invasion and tumor spheroid formation while concomitantly promoting cell adhesion properties. We also observed that Pax-5 inhibited and reversed breast cancer epithelial to mesenchymal phenotypic transitioning. Mechanistically, we found that the Pax-5 transcription factor binds and induces gene expression of E-cadherin, a pivotal regulator of epithelialisation. Globally, we demonstrate that Pax-5 is predominant expressed factor in mammary epithelial cells. We also present an important role for Pax-5 in the phenotypic transitioning processes and aggressive features associated with breast cancer malignancy and disease progression. PMID- 28076844 TI - Sulforaphane inhibits cancer stem-like cell properties and cisplatin resistance through miR-214-mediated downregulation of c-MYC in non-small cell lung cancer. AB - We herein report that sulforaphane (SFN), a potent anti-cancer and well-tolerated dietary compound, inhibits cancer stem-like cell (CSC) properties and enhances therapeutic efficacy of cisplatin in human non-small cell lung cancer (NSCLC). SFN exerted these functions through upregulation of miR-214, which in turn targets the coding region of c-MYC. This finding was further corroborated by our observations that plasmid or lentiviral vector-mediated expression of 3'UTR-less c-MYC cDNA and cisplatin- or doxorubicin-induced endogenous c-MYC accumulation was similarly suppressed by either SFN or miR-214. Further, we showed that the reported inhibitory effects of SFN on beta-catenin are also mediated by miR-214. SFN/miR-214 signaling inhibited CSC properties and enhanced the cytotoxicity of chemotherapeutic drugs in vitro. Experiments with nude mice carrying xenograft tumors showed that SFN sensitized NSCLC cells to cisplatin's efficacy, which is accompanied by inhibition of cisplatin-induced c-MYC accumulation in tumor tissues. Our results provided strong evidence and mechanisms to support consideration of SFN or synthetic derivatives as a therapeutic agent in combination with cisplatin for the treatment of patients with NSCLC and, potentially, other types of c-MYC-addicted tumors. PMID- 28076845 TI - Molecular dynamics simulation reveals how phosphorylation of tyrosine 26 of phosphoglycerate mutase 1 upregulates glycolysis and promotes tumor growth. AB - Phosphoglycerate mutase 1 (PGAM1) catalyzes the eighth step of glycolysis and is often found upregulated in cancer cells. To test the hypothesis that the phosphorylation of tyrosine 26 residue of PGAM1 greatly enhances its activity, we performed both conventional and steered molecular dynamics simulations on the binding and unbinding of PGAM1 to its substrates, with tyrosine 26 either phosphorylated or not. We analyzed the simulated data in terms of structural stability, hydrogen bond formation, binding free energy, etc. We found that tyrosine 26 phosphorylation enhances the binding of PGAM1 to its substrates through generating electrostatic environment and structural features that are advantageous to the binding. Our results may provide valuable insights into computer-aided design of drugs that specifically target cancer cells with PGAM1 tyrosine 26 phosphorylated. PMID- 28076846 TI - Effect of Trp53 gene deficiency on brain injury after neonatal hypoxia-ischemia. AB - Hypoxia-ischemia (HI) can result in permanent life-long injuries such as motor and cognitive deficits. In response to cellular stressors such as hypoxia, tumor suppressor protein p53 is activated, potently initiating apoptosis and promoting Bax-dependent mitochondrial outer membrane permeabilization. The aim of this study was to investigate the effect of Trp53 genetic inhibition on injury development in the immature brain following HI. HI (50 min or 60 min) was induced at postnatal day 9 (PND9) in Trp53 heterozygote (het) and wild type (WT) mice. Utilizing Cre-LoxP technology, CaMK2alpha-Cre mice were bred with Trp53-Lox mice, resulting in knockdown of Trp53 in CaMK2alpha neurons. HI was induced at PND12 (50 min) and PND28 (40 min). Extent of brain injury was assessed 7 days following HI. Following 50 min HI at PND9, Trp53 het mice showed protection in the posterior hippocampus and thalamus. No difference was seen between WT or Trp53 het mice following a severe, 60 min HI. Cre-Lox mice that were subjected to HI at PND12 showed no difference in injury, however we determined that neuronal specific CaMK2alpha-Cre recombinase activity was strongly expressed by PND28. Concomitantly, Trp53 was reduced at 6 weeks of age in KO-Lox Trp53 mice. Cre-Lox mice subjected to HI at PND28 showed no significant difference in brain injury. These data suggest that p53 has a limited contribution to the development of injury in the immature/juvenile brain following HI. Further studies are required to determine the effect of p53 on downstream targets. PMID- 28076847 TI - Programmed cell death-ligand 1 expression predicts survival in patients with gastric carcinoma with microsatellite instability. AB - Programmed death-ligand 1 (PD-L1) is expressed in a subgroup of gastric cancers that may benefit from immunotherapy. Microsatellite instability-high (MSI-H) is a potential predictive factor for response to immunotherapy targeting the PD-1 or its ligand PD-L1. The relationship between PD-L1 expression and MSI-H status remains poorly understood. In this study, we investigated PD-L1 expression in patients with MSI-H gastric cancer. We analyzed PD-L1 expression in 78 MSI-H gastric cancer tissue samples using immunohistochemistry. PD-L1 expression was classified as expression on tumor cells or on immune cells. We observed PD-L1 expression in 48 gastric cancer samples (61.5%), consisting of 7 (9.0%) cases with tumor PD-L1 expression and 47 (60.3%) cases with immune cell PD-L1 expression. Immune cell PD-L1 expression was frequently associated with intestinal type cancer by the Lauren classification (p = 0.015), with a lower risk of lymph node metastasis (p = 0.027) and lower tumor stages (p = 0.029) compared to MSI-H gastric cancers without PD-L1 expression. Moreover, immune cell PD-L1 expression was an independent favorable prognostic factor for overall survival (versus PD-L1 negative; hazard ratio, 3.451; 95% confidence interval, 1.172-12.745; p = 0.025). In MSI-H gastric cancer, PD-L1 expression was observed to be independently associated with a longer survival. PMID- 28076848 TI - Endovascular brachytherapy combined with portal vein stenting and transarterial chemoembolization improves overall survival of hepatocellular carcinoma patients with main portal vein tumor thrombus. AB - Hepatocellular carcinoma (HCC) patients with main portal vein tumor thrombus have a median survival time of only about 4 months. We therefore compared the safety and efficacy of endovascular brachytherapy (EVBT) and sequential three dimensional conformal radiotherapy (3-DCRT). From a cohort of 176 patients, we treated 123 with EVBT using iodine-125 seed strands (group A) and the remaining 53 with sequential 3-DCRT (group B). Overall survival, progression free survival and stent patency characteristics were compared between the two groups. Our analysis demonstrated a median survival of 11.7 +/- 1.2 months in group A versus 9.5 +/- 1.8 months in group B (p = 0.002). The median progression free survival was 5.3 +/- 0.7 months in groupA versus 4.4 +/- 0.4 months in group B (p = 0.010). The median stent patency period was 10.3 +/- 1.1 months in group A versus 8.7 +/- 0.7 months in group B (p = 0.003). Therefore, as compared to sequential 3 DCRT, EVBT combined with portal vein stenting and TACE improved overall survival of HCC patients with main portal vein tumor thrombus. PMID- 28076849 TI - A plasma metabolomic signature discloses human breast cancer. AB - PURPOSE: Metabolomics is the comprehensive global study of metabolites in biological samples. In this retrospective pilot study we explored whether serum metabolomic profile can discriminate the presence of human breast cancer irrespective of the cancer subtype. METHODS: Plasma samples were analyzed from healthy women (n = 20) and patients with breast cancer after diagnosis (n = 91) using a liquid chromatography-mass spectrometry platform. Multivariate statistics and a Random Forest (RF) classifier were used to create a metabolomics panel for the diagnosis of human breast cancer. RESULTS: Metabolomics correctly distinguished between breast cancer patients and healthy control subjects. In the RF supervised class prediction analysis comparing breast cancer and healthy control groups, RF accurately classified 100% both samples of the breast cancer patients and healthy controls. So, the class error for both group in and the out of-bag error were 0. We also found 1269 metabolites with different concentration in plasma from healthy controls and cancer patients; and basing on exact mass, retention time and isotopic distribution we identified 35 metabolites. These metabolites mostly support cell growth by providing energy and building stones for the synthesis of essential biomolecules, and function as signal transduction molecules. The collective results of RF, significance testing, and false discovery rate analysis identified several metabolites that were strongly associated with breast cancer. CONCLUSIONS: In breast cancer a metabolomics signature of cancer exists and can be detected in patient plasma irrespectively of the breast cancer type. PMID- 28076850 TI - Transforming growth factor-beta1 suppresses hepatocellular carcinoma proliferation via activation of Hippo signaling. AB - In this study, we examined the expression of core proteins of the Hippo signaling pathway in hepatocellular carcinoma (HCC) cells treated with transforming growth factor-beta 1(TGF-beta1) and investigated the relationship between TGF-beta1 and the Hippo signaling pathway, in order to better understand their roles in HCC and their potential implications for cancer therapy. We prove that the Hippo signaling pathway is involved in the TGF-beta1-induced inhibition of the growth of HCC cells. Large tumor suppressor expression (LATS1) was overexpression and yes association protein 1(YAP1) translocated from the nucleus to the cytoplasm in HCC cells treated with TGF-beta1. Overexpression of LATS1 and the nucleocytoplasmic translocation of YAP1 play an anti-oncogenetic role in the occurrence and development of liver cancer. Our findings provide new insight into strategies for liver cancer therapy. PMID- 28076851 TI - Pse-Analysis: a python package for DNA/RNA and protein/ peptide sequence analysis based on pseudo components and kernel methods. AB - To expedite the pace in conducting genome/proteome analysis, we have developed a Python package called Pse-Analysis. The powerful package can automatically complete the following five procedures: (1) sample feature extraction, (2) optimal parameter selection, (3) model training, (4) cross validation, and (5) evaluating prediction quality. All the work a user needs to do is to input a benchmark dataset along with the query biological sequences concerned. Based on the benchmark dataset, Pse-Analysis will automatically construct an ideal predictor, followed by yielding the predicted results for the submitted query samples. All the aforementioned tedious jobs can be automatically done by the computer. Moreover, the multiprocessing technique was adopted to enhance computational speed by about 6 folds. The Pse-Analysis Python package is freely accessible to the public at http://bioinformatics.hitsz.edu.cn/Pse-Analysis/, and can be directly run on Windows, Linux, and Unix. PMID- 28076852 TI - miR-874-3p is down-regulated in hepatocellular carcinoma and negatively regulates PIN1 expression. AB - PIN1 is a peptidyl-prolyl cis/trans isomerase (PPIase) that regulates multiple signaling pathways to control cell fate and is found to be over-expressed in cancers, including hepatocellular carcinoma (HCC). However, the regulation of PIN1 in HCC remains poorly defined. Micro-RNAs (miRNAs) have been reported to play a pivotal role in oncogenesis by targeting the 3'-untranslated region (UTR) of mRNAs encoded by oncogenes and tumour suppressor genes, thereby suppressing the levels of both oncoproteins and tumour suppressors. In this report, we aimed to identify miRNAs that suppress PIN1 expression and to determine their role in HCC. By searching the TargetScan database, miR-874-3p was identified as a potential negative regulator of PIN1. miR-874-3p was demonstrated to bind the 3'UTR of PIN1 mRNA directly to suppress expression of PIN1. Functionally, over expression of miR-874-3p in HCC cell line PLC/PRF/5 inhibited cell growth and colony formation in-vitro, and promoted cellular apoptosis. Furthermore, these tumour suppressive functions conferred by miR-874-3p were abrogated by over expression of PIN1. Similarly, expression of miR-874-3p in PLC/PRF/5 with PIN1 knocked-down did not further suppress cellular proliferation, suggesting that PIN1 was a major target of miR-874-3p. More importantly, miR-874-3p was found to be down-regulated in HCC tissues and its expression was negatively correlated with that of PIN1. Down-regulation of miR-874-3p was also associated with poorly differentiated tumour cells, more advanced staging, and inferior patient outcomes. In addition, over-expression of miR-874-3p suppressed tumour growth in vivo. Taken together, our data suggested that miR-874-3p plays a tumour suppressive role in HCC through down-regulation of PIN1. PMID- 28076854 TI - Open-Angle Glaucoma: Drug Development Pipeline during the Last 20 Years (1995 2015). AB - OBJECTIVES: To analyse drug development for open-angle glaucoma during the last 20 years. METHODS: Research was performed by referring to clinical trials registered at the International Clinical Trials Registry Platform (ICTRP). A search for the condition "open-angle glaucoma" with the intervention "drug" was performed. We included trials registered from 01/01/1995 to 01/01/2015, only involving studies in phases 1, 2, and 3. Only studies resorting to novel treatment strategies (either novel drugs or yet-untested fixed associations of approved medication) were considered. RESULTS: We recorded 158 studies for the condition of open-angle glaucoma with a drug-based intervention; 65 of the studies reported phase 2 trials and 74 reported phase 3 trials. Pharmaceutical companies were the primary sponsors of 95.3% of the trials. Most of the studies (66.5%, n = 105) involved a new drug, and the remainder (33.5%, n = 53) tested fixed drug associations. The bulk of the trials (n = 99, 62.7%) involved the use of prostaglandin analogues, either as a comparator or a study drug. In descending order of frequency, the studies conducted involved Rho-kinase inhibitors (n = 15), carbonic anhydrase inhibitors (n = 14), beta-blockers (n = 7), angiostatic steroids (n = 6), alpha2-adrenergic agonists (n = 4), 5-HT2A receptor agonists (n = 4), and NMDA receptor antagonists (n = 2). A cyclin-dependent kinase inhibitor, an LIM-domain kinase 2 inhibitor, an A1 adenosine receptor agonist, catechin, macrolide, saffron, and seawater were each tested in 1 clinical trial. CONCLUSION: Research into the medical treatment of glaucoma indicates the use of prostaglandin analogues. However, there are a significant number of trials testing other drug classes, particularly Rho-kinase inhibitors. This new focus could lead to a potential increase in the number of therapeutical options for the management of glaucoma in the future. PMID- 28076853 TI - Pyruvate dehydrogenase expression is negatively associated with cell stemness and worse clinical outcome in prostate cancers. AB - Cells generate adenosine-5'-triphosphate (ATP), the major currency for energy consuming reactions, through mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis. One of the remarkable features of cancer cells is aerobic glycolysis, also known as the "Warburg Effect", in which cancer cells rely preferentially on glycolysis instead of mitochondrial OXPHOS as the main energy source even in the presence of high oxygen tension. One of the main players in controlling OXPHOS is the mitochondrial gatekeeperpyruvate dehydrogenase complex (PDHc) and its major subunit is E1alpha (PDHA1). To further analyze the function of PDHA1 in cancer cells, it was knock out (KO) in the human prostate cancer cell line LnCap and a stable KO cell line was established. We demonstrated that PDHA1 gene KO significantly decreased mitochondrial OXPHOS and promoted anaerobic glycolysis, accompanied with higher stemness phenotype including resistance to chemotherapy, enhanced migration ability and increased expression of cancer stem cell markers. We also examined PDHA1 protein expression in prostate cancer tissues by immunohistochemistry and observed that reduced PDHA1 protein expression in clinical prostate carcinomas was significantly correlated with poor prognosis. Collectively, our results show that negative PDHA1 gene expressionis associated with significantly higher cell stemness in prostate cancer cells and reduced protein expression of this gene is associated with shorter clinical outcome in prostate cancers. PMID- 28076855 TI - MicroRNA-126 Reduces Blood-Retina Barrier Breakdown via the Regulation of VCAM-1 and BCL2L11 in Ischemic Retinopathy. AB - To evaluate the role of microRNA-126 (miR-126) in maintaining the integrity of the blood-retina barrier (BRB), we established a mouse model of oxygen-induced retinopathy (OIR) and measured the retinal levels of miR-126 using recombinant plasmid pCMV-MIR or pCMV-MIR-126 intravitreal injections. We also detected VCAM-1 and BCL2L11 levels. Retinal vaso-obliteration, VCAM-1 localization on retinal endothelial cells, the blood-retina vascular permeability or albumin leakage in retinas, TUNEL histology, Evans blue assays, or Western blotting for detecting albumin or tight junction levels in the retina was performed. We also detected the effect of miR-126 on the survival of Muller cells in a mouse model using vimentin fluorescence staining. Our results suggested that miR-126 may not only regulate the overexpression of VCAM-1 or BCL2L11 and lead to the reduction of retinal endothelial cell apoptosis, retinal vascular leakage, or retinal permeability in the OIR mouse model, but may also protect hypoxic retinal Muller cells via the STAT3 signaling pathway. We believe that miR-126 could also be a potential therapeutic agent to maintain the stability of the BRB in ischemic retinopathy. PMID- 28076856 TI - MRI Differences Associated with Intrauterine Growth Restriction in Preterm Infants. AB - BACKGROUND: Preterm infants are at risk for neurodevelopmental impairment. Intrauterine growth restriction (IUGR) further increases this risk. Brain imaging studies are often utilized at or near term-equivalent age to determine later prognosis. OBJECTIVE: To evaluate the association between intrauterine growth and regional brain volume on MRI scans performed in preterm infants at or near term equivalent age. METHODS: This is a retrospective case-control study of 24 infants born at gestational age <=30 weeks and cared for in a large, inner-city, academic neonatal intensive-care unit from 2012 to 2013. Each IUGR infant was matched with 1-2 appropriate for gestational age (AGA) infants who served as controls. Predischarge MRI scans routinely obtained at >=36 weeks' adjusted age were analyzed for regional brain volumetric differences. We examined the association between IUGR and thalamic, basal ganglion, and cerebellar brain volumes in these preterm infants. RESULTS: Compared to AGA infants, IUGR infants had a smaller thalamus (7.88 vs. 5.87 mL, p = 0.001) and basal ganglion (8.87 vs. 6.92 mL, p = 0.002) volumes. There was no difference in cerebellar volumes between the two study groups. Linear regression analyses revealed similar trends in the associations between IUGR and brain volumes after adjusting for sex, gestational age at birth, and postconceptual age and weight at MRI. CONCLUSIONS: Thalamus and basal ganglion volumes are reduced in growth-restricted preterm infants. These differences may preferentially impact neurodevelopmental outcomes. Further research is needed to explore these relationships. PMID- 28076857 TI - The Journey of "Geographic Atrophy" through Past, Present, and Future. AB - "Geographic atrophy" is a concise term that has been firmly established for the description of the end-stage manifestation of nonexudative age-related macular degeneration (AMD). "Geographic lesions" resembling sharply demarcated continents on a map have been originally described in the German literature in 1854 (landkartenartiger/inselformiger Zungenfratt) for a manifestation later called "geographic tongue" in English. In 1970, Gass was the first to describe "geographic areas of atrophy" in "senile macular choroidal degeneration." Within a decade, the disease itself was named "geographic atrophy." Today, various meanings of the term are used in parallel both in research and in routine clinical care. Currently, we are on the verge of better understanding the different forms of atrophy development, manifestation, and progression in AMD, which will pave the way for a more rational approach to their nomenclature and classification. PMID- 28076860 TI - Efficacy and Survival of Systemic Psoriasis Treatments: An Analysis of the Swiss Registry SDNTT. AB - BACKGROUND: The Swiss psoriasis registry SDNTT (Swiss Dermatology Network for Targeted Therapies) records the long-term safety and effectiveness of systemic treatment regimens for psoriasis. PATIENTS AND METHODS: Patients with moderate to severe psoriasis are included in the SDNTT when treatment with a conventional systemic agent or biologic is initiated that was not previously used by the respective patient. Patients are followed over a 5-year period. Clinical data are obtained every 3-6 months using standardized case report forms. Here, baseline data and follow-up data for 1 year of patients included from October 2011 until December 2014 were analyzed. RESULTS: Within 39 months, 323 patients from 7 tertiary dermatology centers in Switzerland were recruited in the SDNTT; 165 patients received biologics and 158 conventional systemic therapies. Patients treated with biologics had a significantly higher severity (PASI 11.3 vs. 9.2, BSA 15.6 vs.11.9, psoriatic arthritis 36.4 vs. 10.8%; p <= 0.005, p <= 0.013, p <= 0.001) and a longer duration of illness (19.2 vs. 14.4 years, p <= 0.003) compared to patients starting a conventional systemic treatment. PASI reduction was satisfying in both treatment groups, with 60.6% of patients treated with biologics achieving PASI75 after 1 year compared to 54.2% of patients receiving conventional systemic drugs (nonsignificant). On average, the drug survival in patients receiving a biologic therapy was significantly longer than those receiving conventional systemic treatments (30.5 vs. 19.2 months, p <= 0.001). CONCLUSIONS: In the real-world setting of a prospective national therapy registry, the application of current therapeutic guidelines for patients with moderate to severe psoriasis resulted in a PASI reduction of approximately 70% within the first year of treatment, but current therapeutic targets of PASI75 and PASI90 were reached in only 58 and 36% of patients, respectively, at 1 year, highlighting a gap in efficacy between selective clinical trials and the real world setting. PMID- 28076858 TI - Non-Coding Loss-of-Function Variation in Human Genomes. AB - Whole-genome and exome sequencing in human populations has revealed the tolerance of each gene for loss-of-function variation. By understanding this tolerance, it has become increasingly possible to identify genes that would make safe therapeutic targets and to identify rare genetic risk factors and phenotypes at the scale of individual genomes. To date, the vast majority of surveyed loss-of function variants are in protein-coding regions of the genome mainly due to the focus on these regions by exome-based sequencing projects and their relative ease of interpretability. As whole-genome sequencing becomes more prevalent, new strategies will be required to uncover impactful variation in non-coding regions of the genome where the architecture of genome function is more complex. In this review, we investigate recent studies of loss-of-function variation and emerging approaches for interpreting whole-genome sequencing data to identify rare and impactful non-coding loss-of-function variants. PMID- 28076861 TI - Potential Applications of Smart Multifunctional Wearable Materials to Gerontology. AB - Smart multifunctional materials can play a constructive role in addressing some very important aging-related issues. Aging affects the ability of older adults to continue to live safely and economically in their own residences for as long as possible. Thus, there will be a greater need for preventive, acute, rehabilitative, and long-term health care services for older adults as well as a need for tools to enable them to function independently during daily activities. The objective of this paper is, thus, to present a comprehensive review of some potential smart materials and their areas of applications to gerontology. Thus, brief descriptions of various currently available multifunctional smart materials and their possible applications to aging-related problems are presented. It is concluded that some of the most important applications to geriatrics may be in various sensing scenarios to collect health-related feedback or information and provide personalized care. Further described are the applications of wearable technologies to aging-related needs, including devices for home rehabilitation, remote monitoring, social well-being, frailty monitoring, monitoring of diabetes and wound healing and fall detection or prediction. It is also concluded that wearable technologies, when combined with an appropriate application and with appropriate feedback, may help improve activities and functions of older patients with chronic diseases. Finally, it is noted that methods developed to measure what one collectively manages in this population may provide a foundation to establish new definitions of quality of life. PMID- 28076862 TI - Prognostic Value of the Pretreatment Advanced Lung Cancer Inflammation Index (ALI) in Diffuse Large B Cell Lymphoma Patients Treated with R-CHOP Chemotherapy. AB - BACKGROUND: The Advanced Lung Cancer Inflammation Index (ALI, body mass index * albumin/neutrophil-to-lymphocyte ratio) has been demonstrated to be a prognostic factor of survival in some solid cancers. We retrospectively investigated the usefulness of the ALI to predict chemotherapy response and survival in 212 patients with diffuse large B cell lymphoma (DLBCL) treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy. METHODS: Patients were allocated to a low ALI group (n = 82, 38.7%) or a high ALI group (n = 130, 61.3%) according to an optimal pretreatment ALI cut off value of 15.5 as determined by receiver operating curve analysis. RESULTS: The low ALI group displayed more adverse clinical characteristics, lower rates of complete remission (54.9 vs. 75.4%, p = 0.008), and poorer 5-year progression free (PFS, 58.1 vs. 77.3%, p = 0.006) and overall (OS, 64.2 vs. 80.2%, p = 0.008) survival. Multivariate analysis showed that low ALI was found to independently predict shorter PFS and OS. Interestingly, a low ALI reverted to a high ALI during treatment in 58 patients (27.4%), and the 5-year OS of these patients was better than that of patients whose ALI remained low (n = 24, 72.5 vs. 24%, p < 0.001). CONCLUSIONS: ALI might be an easily available marker for predicting clinical outcomes in DLBCL patients treated with R-CHOP chemotherapy. PMID- 28076863 TI - Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review. AB - BACKGROUND: Cancer immunotherapy, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death 1 (PD-1), has revolutionized the treatment of malignancies by engaging the patient's own immune system against the tumor rather than targeting the cancer directly. These therapies have demonstrated a significant benefit in the treatment of melanomas and other cancers. SUMMARY: In order to provide an extensive overview of the renal toxicities induced by these agents, a Medline search was conducted of published literature related to ipilimumab-, pembrolizumab-, and nivolumab-induced kidney toxicity. In addition, primary data from the initial clinical trials of these agents and the FDA adverse reporting system database were also reviewed to determine renal adverse events. Acute interstitial nephritis (AIN), podocytopathy, and hyponatremia were toxicities caused by ipilimumab. The main adverse effect associated with both the PD-1 inhibitors was AIN. The onset of kidney injury seen with PD-1 inhibitors is usually late (3-10 months) compared to CTLA-4 antagonists related renal injury, which happens earlier (2-3 months). PD-1 as opposed to CTLA-4 inhibitors has been associated with kidney rejection in transplantation. Steroids appear to be effective in treating the immune-related adverse effects noted with these agents. Key Message: Although initially thought to be rare, the incidence rates of renal toxicities might be higher (9.9-29%) as identified by recent studies. As a result, obtaining knowledge about renal toxicities of immune checkpoint inhibitors is extremely important. PMID- 28076864 TI - Inflammatory Biomarkers in Diffuse Large B-Cell Lymphoma: Time for Extending the Established Prognosis Scores? PMID- 28076865 TI - Gene Mapping in Admixed Families: A Cautionary Note on the Interpretation of the Transmission Disequilibrium Test and a Possible Solution. AB - A family-based study design is commonly used in gene mapping studies of complex human diseases. Most family-based studies use the transmission of alleles to assess evidence of association. It is generally believed that the transmission disequilibrium test (TDT) is robust against spurious association due to population stratification or admixture. While this is true when population stratification is due to discrete population structure, one should use the TDT type methods with caution when they are applied to admixed populations in which population structure exists in local genomic regions. In a recently admixed population, such as African Americans and Hispanic Americans, the linkage disequilibrium coefficient between a marker and disease loci in the parental generation contains a spurious component from the admixture process. In this paper, we show that the general belief that family-based design would guard against spurious association caused by population stratification does not always hold in admixed populations. It is safe to use the TDT as a test of association when population stratification is due to global genome ancestry difference. However, when population stratification is due to local ancestry difference in certain genomic regions, the use of the TDT as a test of association can lead to spurious association. Second, we present a statistical framework for fine mapping of disease-associated genetic variants in admixed families. Unlike the TDT and other family-based association tests, this method does not rely on transmission disequilibrium and therefore can control local ancestry difference between transmitted and untransmitted alleles. Through simulations, we show that this method can control type I error rates under a wide range of population stratification mechanisms. PMID- 28076866 TI - Biophysically Motivated Regulatory Network Inference: Progress and Prospects. AB - Thanks to the confluence of genomic technology and computational developments, the possibility of network inference methods that automatically learn large comprehensive models of cellular regulation is closer than ever. This perspective focuses on enumerating the elements of computational strategies that, when coupled to appropriate experimental designs, can lead to accurate large-scale models of chromatin state and transcriptional regulatory structure and dynamics. We highlight 4 research questions that require further investigation in order to make progress in network inference: (1) using overall constraints on network structure such as sparsity, (2) use of informative priors and data integration to constrain individual model parameters, (3) estimation of latent regulatory factor activity under varying cell conditions, and (4) new methods for learning and modeling regulatory factor interactions. We conclude that methods combining advances in these 4 categories of required effort with new genomic technologies will result in biophysically motivated dynamic genome-wide regulatory network models for several of the best-studied organisms and cell types. PMID- 28076867 TI - Identifying Host Genetic Variants Associated with Microbiome Composition by Testing Multiple Beta Diversity Matrices. AB - OBJECTIVES: Host genetics have been recently reported to affect human microbiome composition. We previously developed a statistical framework, microbiomeGWAS, to identify host genetic variants associated with microbiome composition by testing a distance matrix. However, statistical power depends on the choice of a microbiome distance matrix. To achieve more robust statistical power, we aim to extend microbiomeGWAS to test the association with many distance matrices, which are defined based on multilevel taxa abundances and phylogenetic information. METHODS: The main challenge is to accurately and rapidly evaluate the significance for millions of SNPs. We propose methods for approximating p values by correcting for the multiple testing introduced by testing many distance matrices and by correcting for the skewness and kurtosis of score statistics. RESULTS: The accuracy of p value approximation was verified by simulations. We applied our method to a set of 147 lung cancer patients with 16S rRNA microbiome profiles from nonmalignant lung tissues. We show that correcting for skewness and kurtosis eliminated dramatic deviations in the quantile-quantile plot. CONCLUSION: We developed computationally efficient methods for identifying host genetic variants associated with microbiome composition by testing many distance matrices. The algorithms are implemented in the package microbiomeGWAS (https://github.com/lsncibb/microbiomeGWAS). PMID- 28076868 TI - SAGES 2015. Symposium of Advances in Genomics, Epidemiology and Statistics 2015: Abstracts. PMID- 28076870 TI - ? PMID- 28076871 TI - ? PMID- 28076872 TI - ? PMID- 28076869 TI - Computational Prediction of the Global Functional Genomic Landscape: Applications, Methods, and Challenges. AB - Technological advances have led to an explosive growth of high-throughput functional genomic data. Exploiting the correlation among different data types, it is possible to predict one functional genomic data type from other data types. Prediction tools are valuable in understanding the relationship among different functional genomic signals. They also provide a cost-efficient solution to inferring the unknown functional genomic profiles when experimental data are unavailable due to resource or technological constraints. The predicted data may be used for generating hypotheses, prioritizing targets, interpreting disease variants, facilitating data integration, quality control, and many other purposes. This article reviews various applications of prediction methods in functional genomics, discusses analytical challenges, and highlights some common and effective strategies used to develop prediction methods for functional genomic data. PMID- 28076873 TI - ? PMID- 28076874 TI - ? PMID- 28076875 TI - ? PMID- 28076876 TI - ? PMID- 28076877 TI - Ultrasound Imaging for Ovarian and Deep Infiltrating Endometriosis. AB - The main challenges of imaging for endometriosis are the detection of nonovarian disease and the evaluation of the extension of the disease into pelvic structures. Transvaginal ultrasonography (TVS) has been proposed as the first line imaging technique because it allows extensive exploration of the pelvis. The "typical" endometrioma is a unilocular cyst with homogeneous low-level echogenicity (ground glass echogenicity) of the cyst fluid. The use of color Doppler helps avoid classifying malignancies as endometriomas, defining the presence of vascular flow in papillations. The real-time dynamic TVS examination of adhesions and pouch of Douglas (POD) obliteration, using the sliding sign technique, seems to be useful in the identification of women at increased risk for bowel endometriosis. Transvaginal ultrasound allows an accurate assessment of the vagina, particularly the areas of the posterior and lateral vaginal fornixes, the retrocervical area with torus uterinum and uterosacral ligaments, and the rectovaginal septum. The slightly filled bladder permits an evaluation of the bladder walls and the presence of endometriotic nodules which appear as hypoechoic linear or spherical lesions bulging toward the lumen, involving the serosa, muscularis, or (sub)mucosa of the bladder. Deep nodules of the rectum appear as hypoechoic lesions, linear or nodular retroperitoneal thickening with irregular borders, penetrating into the intestinal wall distorting its normal structure with the presence of few vessels observed with power Doppler evaluation. Adenomyosis can be observed with the two-dimensional (2D) TVS showing the typical myometrial features and 3D evaluation of the junctional zone. Although the sensitivity and specificity of TVS in the prediction of deeply infiltrating endometriosis and adenomyosis is high, their assessment by TVS is difficult and needs a great expertise. PMID- 28076878 TI - Sumatriptan, an Antimigraine Drug, Inhibits Pentylenetetrazol-induced Seizures in NMRI Mice. AB - Sumatriptan has been used for the acute treatment of migraine attacks. There are many similarities between migraine and epilepsy and the medications used to treat one of these disorders can effectively be used to treat the other. The purpose of this study was to evaluate and compare the anticonvulsant effects of sumatriptan with sodium valproate in NMRI mice. 62 male NMRI mice were divided into 8 groups. The groups consisted of a saline (control) group, 4 intraperitoneally (ip) administered sumatriptan groups (1, 10, 50, and 100 mg/kg, ip), and 3 sodium valproate groups (50, 150, and 300 mg/kg, ip). 20-min after the injection of either saline or one of the drug doses, pentylenetetrazol (100 mg/kg, ip) was injected and seizure parameters were evaluated. The results showed that 300 mg/kg sodium valproate markedly inhibited the seizure stage, whereas none of the sumatriptan doses had any significant effect on this parameter. The latency to stages 2 and 4 of the seizures and the interval between the pentylenetetrazol injection to death was significantly increased by both sodium valproate and sumatriptan.Sumatriptan is commonly used for the treatment of migraine and also has a protective effect against seizures induced by pentylenetetrazol in mice. PMID- 28076880 TI - Repeatability, consistency, and accuracy of hand-held dynamometry with and without fixation for measuring ankle plantarflexion strength in healthy adolescents and adults. AB - INTRODUCTION: Hand-held dynamometry (HHD) is commonly used to measure ankle plantarflexion strength but has variable reliability measuring higher forces. Fixed HHD is suggested to improve reliability. We, therefore, compared the reliability, consistency, and accuracy of measuring plantarflexion strength. METHODS: Plantarflexion strength was measured in 25 healthy individuals with fixed HHD and HHD alone. Intraclass correlation coefficients (ICC2,2 ), SEM, minimal detectable change, and Spearman correlation coefficients were calculated to assess inter-trial repeatability, consistency, agreement, and accuracy. RESULTS: Both methods were repeatable (ICC2,2 0.96 to 0.98) and highly correlated (Spearman rho = 0.815; P < 0.01). Fixed HHD produced significantly higher force outputs. HHD alone provided more consistent force values. CONCLUSIONS: Both methods of measuring ankle plantarflexion force were reliable. Force measured with fixed HHD will likely be more accurate for adults and individuals with greater strength, while HHD alone will be more consistent for individuals with lower strength. Muscle Nerve 56: 896-900, 2017. PMID- 28076879 TI - Immunoglobulin (Ig)M antibodies to proteinase 3 in granulomatosis with polyangiitis and microscopic polyangiitis. AB - Anti-neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme-linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)-ANCA], which we applied to two large, clinically well-characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3-ANCA occurred with a frequency of 15.0%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (29.6 versus 15.7%, P = 0.10). Analysis of follow-up samples in this cohort showed that the presence of IgM PR3 ANCA was transient, but could recur. In the second cohort, IgM PR3-ANCA occurred with a frequency of 41.1%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3-ANCA (45.3 versus 15.8%; P < 0.001). The association of transient IgM PR3-ANCA with an acute respiratory manifestation of AAV suggests a possible link between an infectious trigger and AAV disease activity. PMID- 28076881 TI - Constitutive NOS uncoupling and NADPH oxidase upregulation in the penis of type 2 diabetic men with erectile dysfunction. AB - Erectile dysfunction (ED) associated with type 2 diabetes mellitus (T2DM) involves dysfunctional nitric oxide (NO) signaling and increased oxidative stress in the penis. However, the mechanisms of endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS) dysregulation, and the sources of oxidative stress, are not well defined, particularly at the human level. The objective of this study was to define whether uncoupled eNOS and nNOS, and NADPH oxidase upregulation, contribute to the pathogenesis of ED in T2DM men. Penile erectile tissue was obtained from 9 T2DM patients with ED who underwent penile prosthesis surgery for ED, and from six control patients without T2DM or ED who underwent penectomy for penile cancer. The dimer-to-monomer protein expression ratio, an indicator of uncoupling for both eNOS and nNOS, total protein expressions of eNOS and nNOS, as well as protein expressions of NADPH oxidase catalytic subunit gp91phox (an enzymatic source of oxidative stress) and 4-hydroxy-2-nonenal [4 HNE] and nitrotyrosine (markers of oxidative stress) were measured by western blot in this tissue. In the erectile tissue of T2DM men, eNOS and nNOS uncoupling and protein expressions of NADPH oxidase subunit gp91phox, 4-HNE- and nitrotyrosine-modified proteins were significantly (p < 0.05) increased compared to control values. Total eNOS and nNOS protein expressions were not significantly different between the groups. In conclusion, mechanisms of T2DM-associated ED in the human penis may involve uncoupled eNOS and nNOS and NADPH oxidase upregulation. Our description of molecular factors contributing to the pathogenesis of T2DM-associated ED at the human level is relevant to advancing clinically therapeutic approaches to restore erectile function in T2DM patients. PMID- 28076882 TI - Characterization of Salmonella typhi OmpC and OmpF porins engineered with HIV gp41 epitope on the surface loops. AB - Porins form trimers in the outer membrane and help transport nutrients and waste products across the bacterial cell membrane. Porin loops are suitable candidates as display systems due to their high immunogenicity and presentation at the bacterial cell surface. In this study, Salmonella typhi porins (OmpC and OmpF) engineered with the Kennedy peptide from gp41 of HIV were characterised. The chimeric OmpC carrying the Kennedy peptide in loop7 did not trimerise, whereas the chimeric OmpF with the epitope in loop5 formed trimers and also was recognised by the antibodies in the HIV patient serum. The results suggest that chimeric S. typhi OmpF may be taken further as a potential candidate to develop as an epitope display system. Proteins 2017; 85:657-664. (c) 2016 Wiley Periodicals, Inc. PMID- 28076884 TI - Impact of fludarabine-based induction therapy on outcome of FLT3-/NPM1+ cytogenetically normal acute myeloid leukemia. PMID- 28076883 TI - In vivo feasibility test using transparent carbon nanotube-coated polydimethylsiloxane sheet at brain tissue and sciatic nerve. AB - Carbon nanotubes, with their unique and outstanding properties, such as strong mechanical strength and high electrical conductivity, have become very popular for the repair of tissues, particularly for those requiring electrical stimuli. Polydimethylsiloxane (PDMS)-based elastomers have been used in a wide range of biomedical applications because of their optical transparency, physiological inertness, blood compatibility, non-toxicity, and gas permeability. In present study, most of artificial nerve guidance conduits (ANGCs) are not transparent. It is hard to confirm the position of two stumps of damaged nerve during nerve surgery and the conduits must be cut open again to observe regenerative nerves after surgery. Thus, a novel preparation method was utilized to produce a transparent sheet using PDMS and multiwalled carbon nanotubes (MWNTs) via printing transfer method. Characterization of the PDMS/MWNT (PM) sheets revealed their unique physicochemical properties, such as superior mechanical strength, a certain degree of electrical conductivity, and high transparency. Characterization of the in vitro and in vivo usability was evaluated. PM sheets showed high biocompatibility and adhesive ability. In vivo feasibility tests of rat brain tissue and sciatic nerve revealed the high transparency of PM sheets, suggesting that it can be used in the further development of ANGCs. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1736-1745, 2017. PMID- 28076885 TI - Cross-linking of porcine acellular dermal matrices negatively affects induced neovessel formation using platelet-rich plasma in a rat model of hernia repair. AB - The degree of cross-linking within acellular dermal matrices (ADM) seems to correlate to neovascularization when used in ventral hernia repair (VHR). Platelet-rich plasma (PRP) enhances wound healing through several mechanisms including neovascularization, but research regarding its effect on soft tissue healing in VHR is lacking. We sought to study the effect of cross-linking on PRP induced neovascularization in a rodent model of bridging VHR. We hypothesized that ADM cross-linking would negatively affect PRP-induced neovessel formation. PRP was extracted and characterized from pooled whole blood. Porcine cross-linked (cADM) and non-cross-linked ADMs (ncADM) were implanted in a rat model of chronic VHR after treatment with saline (control) or PRP. Neovascularization of samples at 2, 4, and 6 weeks was assessed by hematoxylin and eosin and immunohistochemical staining of CD 31. Adhesion severity at necropsy was compared using a previously validated scale. Addition of PRP increased neovascularization in both cADM and ncADM at 2- and 4-week time points but appeared to do so in a dependent fashion, with significantly greater neovascularization in the PRP treated ncADMs compared to cADMs. Omental adhesions were increased in all PRP treated groups. Results indicate that, for 2-week measurements when compared with the cADM group without PRP therapy, the mean change in neovascularization due to ncADM was 3.27 (Z = 2.75, p = 0.006), PRP was 17.56 (Z = 14.77, p < 0.001), and the combined effect of ncADM and PRP was 9.41 (Z = 5.6, p < 0.001). The 4-week data indicate that the average neovascularization change due to ncADM was 0.676 (Z = 0.7, p = 0.484), PRP was 7.69 (Z = 7.95, p < 0.001), and combined effect of ncADM and PRP was 5.28 (Z = 3.86, p < 0.001). These findings validate PRP as a clinical adjunct to enhance the native tissue response to implantable biomaterials and suggest that ncADM is more amenable than cADM to induced neovascularization. PRP use could be advantageous in patients undergoing VHR where poor incorporation is anticipated and early-enhanced neovascularization is desired. PMID- 28076886 TI - The ectomycorrhizal basidiomycete Hebeloma cylindrosporum undergoes early waves of transcriptional reprogramming prior to symbiotic structures differentiation. AB - To clarify the early molecular interaction between ectomycorrhizal partners, we performed a RNA-Seq study of transcriptome reprogramming of the basidiomycete Hebeloma cylindrosporum before symbiotic structure differentiation with Pinus pinaster. Mycorrhiza transcriptome was studied for comparison. By reference to asymbiotic mycelium, 47 and 46 genes were specifically upregulated over fivefold (p <= 0.05) upon rhizosphere colonization and root adhesion respectively. Other 45 were upregulated throughout the symbiotic interaction, from rhizosphere colonization to differentiated mycorrhizas, whereas 274 were specifically upregulated in mycorrhizas. Although exoproteome represents 5.6% of H. cylindrosporum proteome, 38.5% of the genes upregulated upon pre-infectious root colonization encoded extracellular proteins. The proportion decreased to 23.5% in mycorrhizas. At all studied time points, mycorrhiza-induced small secreted proteins (MiSSPs), representing potential effectors, were over-represented among upregulated genes. This was also the case for carbohydrate-active enzymes (CAZymes). Several CAZymes were upregulated at all studied stages of the interaction. Consistent with a role in fungal morphogenesis and symbiotic interface differentiation, CAZymes over-expressed before and upon root attachment targeted fungal and both fungal and plant polysaccharides respectively. Different hydrophobins were upregulated upon early root adhesion, in mycorrhizas or throughout interaction. The functional classification of genes upregulated only in mycorrhizas pointed to intense metabolic activity and nutritional exchanges. PMID- 28076887 TI - In vivo bone tunnel evaluation of nanoparticle-grafts using an ACL reconstruction rabbit model. AB - Acellular human gracilis tendons conjugated with gold nanoparticles (AuNP) and hydroxyapatite nanoparticles (nano-HAp) were used as a graft in an anterior cruciate ligament (ACL) reconstruction rabbit model. The ACLs of 11 New Zealand rabbits were reconstructed using grafts conjugated without nanoparticles, with AuNP only, and with both AuNP and nano-HAp. Semi-quantitative histological scoring of bone tunnel portion of grafts was performed after 14 weeks. Bone tunnels were scored for graft degeneration, graft remodeling, percentage of new host fibrous connective, collateral connection, head-to-head connection, graft collagen fiber organization, new host fibrous connective tissue organization, and graft and interface vascularity. All grafts were intact at 14 weeks. Results of bone tunnel scoring indicate remodeling in all graft types with new organized host fibrous connective tissue, head-to-head connection to bone and mild inflammation associated with remodeling. Components of the 20 nm AuNP grafts have significantly more graft degeneration, more new host fibrous connective tissue, and more vascularity compared to crosslinked grafts. Comparison between femoral and tibial tunnel scores indicate more degeneration in femoral tunnels compared to tibial tunnels. Overall results indicated potentially enhanced remodeling from the use of 20 nm AuNP grafts. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1071-1082, 2017. PMID- 28076888 TI - Caspase mediated beclin-1 dependent autophagy tuning activity and apoptosis promotion by surface modified hausmannite nanoparticle. AB - Hidden effects of nano-materials to induced autophagy, a lysosomal degradative pathway, remain an exciting topic, in the level of material-protein interaction and subsequent cellular signaling features. Here, our studies show that surface modified hausmannite nanoparticles (Mn3 O4 NPs) can uniformly cleave/splice Beclin-1 protein and alter cellular mechanism on the emphasis of tuning autophagy and subsequently promote enhancement of apoptosis. Details investigation of Beclin-1 dependency and its uniform cleavage/splice pattern by surface modified Mn3 O4 NPs, shows tuning of cellular mechanism on emphasis of caspase mediated autophagy tuning. Our findings will also clarify the conflict between apoptosis autophagy on the basis of its unique property derived from surface chemistry modulation, in context of Beclin-1 eminent cleavage/splice which remarks novel effect of Beclin-1 dependent tuning of autophagosomes formation and switch to enhance apoptotic index, mediates by PI3KC3 cleavage and caspase activation. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1299-1310, 2017. PMID- 28076889 TI - Polyurethane conjugating TGF-beta on surface impacts local inflammation and endoplasmic reticulum stress in skeletal muscle. AB - The synthesized short peptide-polymers would provide key functions for tissue regeneration and repair, through enriching bioactive molecules on polymers or releasing these molecules pre-conjugated on the materials. We have developed a degradable polyurethane (PU) bearing HSNGLPL peptide, which has affinity binding ability to transforming growth factor-betas (TGF-beta). For deeply understanding spatial release of TGF-beta from the PU polymers and its localized bioactivity, quartz crystal microbalance (QCM) and Elisa test were used to verify TGF-beta binding capacities in vitro and in vivo. The PU polymers, with or without pre conjugating of TGF-beta, were implanted into gastronomies muscle (GN) of C57BL/6 mice, for addressing TGF-beta release from the polymers and its bio-regulating function in vivo. QCM result shows that PU bearing HSNGLPL peptide has affinity binding ability to TGF-beta in vitro. Intramuscular implanting experiment further supports the enrichment efficiency of TGF-beta on PU polymers in vivo. The detecting data involving intramuscular inflammatory infiltration triggered by the implants, myofiber regeneration, muscular fibrosis degree, and activation of endoplasmic reticulum stress (ER stress), evidence TGF-beta can be released from PU polymers, and exerts regulating effects on the material-induced inflammation. Thus, our present results suggest it is feasible to improve biocompatibility of PU polymers in vivo, by pre-bearing bioactive molecules on materials before the implanting. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1156-1165, 2017. PMID- 28076890 TI - Suppression of osteogenic activity by regulation of WNT and BMP signaling during titanium particle induced osteolysis. AB - Periprosthetic osteolysis remains the leading obstacle for total joint replacements. Primarily, it was thought that aseptic loosening is mainly caused by macrophage mediated inflammatory process arising from production of wear debris. The role of osteoclasts and its sequential bone resorption ability has been extensively studied, but little is known about impaired osteogenesis during osteolysis. In the current study, we have tried to delineate the regulatory mechanism of osteogenic signals by Ti particles in osteoprogenitor cells as well its participatory role in wear debris induced osteolysis. Implantation of Ti particles on mice calvaria induced pro-inflammatory response, elevated expression of COX2 and reduced the expression of Osterix. Treatment of Ti particles to MC3T3 E-1 cells displayed decreased osteogenic activity including ALP activity, mineralization and mRNA levels several osteogenic genes. Moreover, the basal activity of WNT and BMP signaling pathways was suppressed in MC3T3 E-1 cells treated with Ti particles. As an early response to Ti particles, MC3T3 E-1 cells showed activation of ERK and JNK. Co-inhibition of ERK and JNK with their specific inhibitors resulted in partial recovery of WNT and BMP signaling activity as well as ALP activity and collagen synthesis. Finally, LiCl mediated activation of WNT signaling pathway demonstrated rescue of Ti particle facilitated suppression of Osterix expression in mice calvaria. Our results provide evidences that WNT signaling pathway is regulated by ERK, JNK, and BMP signaling pathway during wear debris induced inflammatory osteolysis and may be considered as suitable therapeutic targets for the treatment. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 912-926, 2017. PMID- 28076891 TI - Comparative genomics of Mortierella elongata and its bacterial endosymbiont Mycoavidus cysteinexigens. AB - Endosymbiosis of bacteria by eukaryotes is a defining feature of cellular evolution. In addition to well-known bacterial origins for mitochondria and chloroplasts, multiple origins of bacterial endosymbiosis are known within the cells of diverse animals, plants and fungi. Early-diverging lineages of terrestrial fungi harbor endosymbiotic bacteria belonging to the Burkholderiaceae. We sequenced the metagenome of the soil-inhabiting fungus Mortierella elongata and assembled the complete circular chromosome of its endosymbiont, Mycoavidus cysteinexigens, which we place within a lineage of endofungal symbionts that are sister clade to Burkholderia. The genome of M. elongata strain AG77 features a core set of primary metabolic pathways for degradation of simple carbohydrates and lipid biosynthesis, while the M. cysteinexigens (AG77) genome is reduced in size and function. Experiments using antibiotics to cure the endobacterium from the host demonstrate that the fungal host metabolism is highly modulated by presence/absence of M. cysteinexigens. Independent comparative phylogenomic analyses of fungal and bacterial genomes are consistent with an ancient origin for M. elongata - M. cysteinexigens symbiosis, most likely over 350 million years ago and concomitant with the terrestrialization of Earth and diversification of land fungi and plants. PMID- 28076892 TI - Impact of achievement of complete cytogenetic response on outcome in patients with myelodysplastic syndromes treated with hypomethylating agents. AB - Two hundred and sixteen consecutive patients with MDS and abnormal karyotype treated with hypomethylating agents between 4/04 and 10/12 were reviewed. Median follow-up was 17 months. Using IWG criteria, best responses were complete response (CR) in 79 patients (37%), partial response (PR) in 4 (2%), and hematologic improvement (HI) in 10 (5%). Cytogenetic response (CyR) was achieved in 78 patients (36%): complete (CCyR) in 62 (29%) and partial in 16 (7%). CyR was achieved in 48 of 79 patients (61%) with CR, 1 of 14 (7%) with PR/HI, and in 29 of the 123 (24%) with no morphologic response. Median overall survival (OS) and leukemia-free survival (LFS) for patients with and without CCyR were 21 and 13 months (P = .007), and 16 and 9 months (P = .001), respectively. By multivariate analysis, the achievement of CCyR was predictive for better OS (HR = 2.1; P < .001). In conclusion, CyR occurs at a rate of 36% (complete in 29%) in patients with MDS treated with HMA and is not always associated with morphological response. The achievement of CCyR is associated with survival improvement and constitutes a major predictive factor for outcome particularly in patients without morphologic response. Therefore, the achievement of CCyR should be considered a milestone in the management of patients with MDS. PMID- 28076893 TI - Pseudofeeders on fetal magnetic resonance imaging predict outcome in vein of Galen malformations. AB - OBJECTIVE: Although vein of Galen aneurysmal malformations (VGAM) can be diagnosed in the fetus, the challenge is predicting the occurrence of its 2 major complications: cardiopulmonary failure and encephalomalacia. This study attempts to determine which fetal brain magnetic resonance imaging (MRI) features might be used to predict the development of these complications at birth. METHODS: The cohort was extracted from a prospectively assembled database of VGAM cases managed at a single referral center from 2000 to 2014. Of 251 patients with VGAM, 83 cases were diagnosed prenatally. A total of 58 patient charts having at least 1 fetal MRI were reviewed. Patterns of brain parenchyma, hydrocephalus, and so called middle cerebral artery (MCA) "pseudofeeders" were correlated with cardiac failure, pulmonary hypertension, and encephalomalacia at birth. RESULTS: The median gestational age at fetal MRI was 32.3 weeks of pregnancy (+/-2.3). Nine fetuses (16%) had encephalomalacia. Thirty-one fetuses (53%) had MCA pseudofeeders. Twenty-six fetuses (45%) had prenatal hydrocephalus. Prenatal MCA pseudofeeders were a risk factor for encephalomalacia at birth (p = 0.001). MCA pseudofeeders and hydrocephalus were risk factors for both severe cardiac failure (p = 0.01 and p = 0.04, respectively) and severe pulmonary hypertension (p = 0.014 and p = 0.05, respectively) at birth. INTERPRETATION: MCA pseudofeeders are the result of impaired cerebral blood flow, and are thus a risk factor for further brain melting at birth. Their presence can be used for informing parents and as an aid in management decisions. Ann Neurol 2017;81:278-286. PMID- 28076894 TI - Electrical impedance myography for assessment of Duchenne muscular dystrophy. AB - OBJECTIVE: Sensitive, objective, and easily applied methods for evaluating disease progression and response to therapy are needed for clinical trials in Duchenne muscular dystrophy (DMD). In this study, we evaluated whether electrical impedance myography (EIM) could serve this purpose. METHODS: In this nonblinded study, 36 boys with DMD and 29 age-similar healthy boys underwent multifrequency EIM measurements for up to 2 years on 6 muscles unilaterally along with functional assessments. A linear mixed-effects model with random intercept and slope terms was used for the analysis of multifrequency EIM values and functional measures. Seven DMD boys were initiated on corticosteroids; these data were analyzed using a piecewise linear mixed-effects model. RESULTS: In boys > 7.0 years old, a significant difference in the slope of EIM phase ratio trajectories in the upper extremity was observed by 6 months of -0.074/month, p = 0.023, 95% confidence interval (CI) = -0.013, -0.14; at 2 years, this difference was 0.048/month, p < 0.0001, 95% CI = -0.028, -0.068. In boys <= 7.0 years old, differences appeared at 6 months in gastrocnemius (EIM phase slope = -0.83 degrees /kHz/mo, p = 0.007, 95% CI = -0.26, -1.40). EIM outcomes showed significant differences earlier than functional tests. Initiation of corticosteroids significantly improved the slope of EIM phase ratio (0.057/mo, p = 0.00019, 95% CI = 0.028, 0.086) and EIM phase slope (0.14 degrees /kHz/mo, p = 0.013, 95% CI = 0.028, 0.25), consistent with corticosteroids' known clinical benefit. INTERPRETATION: EIM detects deterioration in muscles of both younger and older boys by 6 months; it also identifies the therapeutic effect of corticosteroid initiation. Because EIM is rapid to apply, painless, and requires minimal operator training, the technique deserves to be further evaluated as a biomarker in DMD clinical therapeutic trials. Ann Neurol 2017;81:622-632. PMID- 28076895 TI - Implantation of left ventricular assist device in a patient with left ventricular non-compaction. AB - Left ventricular noncompaction (LVNC) may result in systolic left ventricular (LV) failure resulting in the need for heart transplantation. LV assist devices (LVAD) have been used to bridge these patients to transplantation; however, the extensive trabeculations found in these patients predispose them to thromboembolic events and pump thrombosis. We describe a patient with LVNC in whom an aggressive surgical approach was used to debride the LV cavity of trabeculations to successfully implant an LVAD. PMID- 28076896 TI - Comment on "esophageal balloon tamponade vs. esophageal stent in controlling acute refractory variceal bleeding: A multicenter RCT". PMID- 28076898 TI - Characterization of the Hog1 MAPK pathway in the entomopathogenic fungus Beauveria bassiana. AB - High-osmolarity glycerol (HOG) pathway required for yeast osmoregulation relies upon the mitogen-activated protein kinase (MAPK) Hog1 cascade that comprise the MAPKKKs Ssk2/Ssk22 and Ste11 converging on the MAPKK Pbs2. Here we show a Hog1 cascade with the unique MAPKKK Ssk2 acting in Beauveria bassiana. Hypersensitivity to high osmolarity and high resistance to fludioxonil fungicide appeared in Deltassk2, Deltapbs2 and Deltahog1 mutants whereas the two hallmark phenotypes were reversed in Deltaste11. Increased sensitivity to heat shock and decreased sensitivity to cell wall perturbation also occurred in the three mutants but not in Deltaste11 although antioxidant phenotypes were different in all deletion mutants. Intriguingly, signals of Hog1 phosphorylation induced by osmotic, oxidative and thermal cues were present in Deltaste11 but absent in Deltassk2 and Deltapbs2. Moreover, vegetative growth on minimal media with different carbon/nitrogen sources was much more suppressed in Deltaste11 and Deltassk2 than in Deltapbs2 and Deltahog1 although all mutants suffered similar, but severe, conidiation defects on a standard medium. Normal host infection was abolished in Deltaste11 while virulence was differentially attenuated in other mutants. Our findings exclude Ste11 from the Hog1 cascade that regulates multiple stress responses and environmental adaptation of B. bassiana and perhaps other filamentous fungi. PMID- 28076897 TI - MicroRNA Expression Shows Inflammatory Dysregulation and Tumor-Like Proliferative Responses in Joints of Patients With Postinfectious Lyme Arthritis. AB - OBJECTIVE: Lyme arthritis (LA) is caused by infection with Borrelia burgdorferi and usually resolves following spirochetal killing with antibiotics. However, in some patients, arthritis persists after antibiotic therapy. To provide insights into underlying pathogenic processes associated with antibiotic-refractory LA (postinfectious LA), we analyzed differences in microRNA (miRNA) expression between LA patients with active infection and those with postinfectious LA. METHODS: MicroRNA expression was assayed in synovial fluid (SF) from LA patients before and after oral and intravenous antibiotic therapy, and in synovial tissue obtained months after antibiotic therapy from patients with postinfectious LA. SF and tissue from patients with other forms of arthritis, such as rheumatoid arthritis (RA) and osteoarthritis, were used for comparison. RESULTS: SF from LA patients during active infection had marked elevations of white blood cells, particularly polymorphonuclear leukocytes, accompanied by elevated levels of microRNA-223 (miR-223). In contrast, SF from postantibiotic LA patients contained greater percentages of lymphocytes and mononuclear cells. SF from postantibiotic LA patients also exhibited marked inflammatory (miR-146a, miR-155), wound repair (miR-142), and proliferative (miR-17-92) miRNA signatures, and higher levels of these miRNAs correlated with longer arthritis duration. Levels of miR-146a, miR 155, miR-142, miR-223, and miR-17-92 were also elevated in synovial tissue in late postinfectious LA, and levels of let-7a were reduced, similar to RA. CONCLUSION: During active infection, miRNA expression in SF reflected an immune response associated with bacterial killing, while in postinfectious LA, miRNA expression in SF and synovial tissue reflected chronic inflammation, synovial proliferation, and breakdown of wound repair processes, showing that the nature of the arthritis was altered after spirochetal killing. PMID- 28076900 TI - Childhood autoimmune necrotizing myopathy with anti-signal recognition particle antibodies. AB - INTRODUCTION: The aim of this study was to describe the therapeutic effects of immunomodulatory therapy in 3 patients with childhood autoimmune necrotizing myopathy with anti-signal recognition particle antibodies (SRP-ANM). METHODS: Before treatment, data on clinical features, muscle pathology, and thigh MRIs were obtained. After definitive diagnoses, all 3 patients were treated with intravenous immunoglobulin and corticosteroids, and thigh MRIs were performed. RESULTS: Clinical improvements were associated with declines in serum creatine kinase levels. Pretreatment thigh MRIs revealed diffuse, but uneven or focal edema, mostly in the posterior thigh muscles, which was alleviated after immunomodulatory therapy. DISCUSSION: Childhood SRP-ANM responded well to immunomodulatory therapy. The extent of edema, as monitored by thigh MRI, appears to be a useful marker of disease severity and therapeutic benefit. Muscle Nerve 56: 1181-1187, 2017. PMID- 28076899 TI - Genome-Wide Association Analysis Reveals Genetic Heterogeneity of Sjogren's Syndrome According to Ancestry. AB - OBJECTIVE: The Sjogren's International Collaborative Clinical Alliance (SICCA) is an international data registry and biorepository derived from a multisite observational study of participants in whom genotyping was performed on the Omni2.5M platform and who had undergone deep phenotyping using common protocol directed methods. The aim of this study was to examine the genetic etiology of Sjogren's syndrome (SS) across ancestry and disease subsets. METHODS: We performed genome-wide association study analyses using SICCA subjects and external controls obtained from dbGaP data sets, one using all participants (1,405 cases, 1,622 SICCA controls, and 3,125 external controls), one using European participants (585, 966, and 580, respectively), and one using Asian participants (460, 224, and 901, respectively) with ancestry adjustments via principal components analyses. We also investigated whether subphenotype distributions differ by ethnicity, and whether this contributes to the heterogeneity of genetic associations. RESULTS: We observed significant associations in established regions of the major histocompatibility complex (MHC), IRF5, and STAT4 (P = 3 * 10-42 , P = 3 * 10-14 , and P = 9 * 10-10 , respectively), and several novel suggestive regions (those with 2 or more associations at P < 1 * 10-5 ). Two regions have been previously implicated in autoimmune disease: KLRG1 (P = 6 * 10-7 [Asian cluster]) and SH2D2A (P = 2 * 10-6 [all participants]). We observed striking differences between the associations in Europeans and Asians, with high heterogeneity especially in the MHC; representative single-nucleotide polymorphisms from established and suggestive regions had highly significant differences in the allele frequencies in the study populations. We showed that SSA/SSB autoantibody production and the labial salivary gland focus score criteria were associated with the first worldwide principal component, indicative of higher non-European ancestry (P = 4 * 10-15 and P = 4 * 10-5 , respectively), but that subphenotype differences did not explain most of the ancestry differences in genetic associations. CONCLUSION: Genetic associations with SS differ markedly according to ancestry; however, this is not explained by differences in subphenotypes. PMID- 28076901 TI - Nuclear factor one transcription factors as epigenetic regulators in cancer. AB - Tumour heterogeneity poses a distinct obstacle to therapeutic intervention. While the initiation of tumours across various physiological systems is frequently associated with signature mutations in genes that drive proliferation and bypass senescence, increasing evidence suggests that tumour progression and clonal diversity is driven at an epigenetic level. The tumour microenvironment plays a key role in driving diversity as cells adapt to demands imposed during tumour growth, and is thought to drive certain subpopulations back to a stem cell-like state. This stem cell-like phenotype primes tumour cells to react to external cues via the use of developmental pathways that facilitate changes in proliferation, migration and invasion. Because the dynamism of this stem cell like state requires constant chromatin remodelling and rapid alterations at regulatory elements, it is of great therapeutic interest to identify the cell intrinsic factors that confer these epigenetic changes that drive tumour progression. The nuclear factor one (NFI) family are transcription factors that play an important role in the development of many mammalian organ systems. While all four family members have been shown to act as either oncogenes or tumour suppressors across various cancer models, evidence has emerged implicating them as key epigenetic regulators during development and within tumours. Notably, NFIs have also been shown to regulate chromatin accessibility at distal regulatory elements that drive tumour cell dissemination and metastasis. Here we summarize the role of the NFIs in cancer, focusing largely on the potential mechanisms associated with chromatin remodelling and epigenetic modulation of gene expression. PMID- 28076902 TI - Decellularized extracellular matrix of human umbilical vein endothelial cells promotes endothelial differentiation of stem cells from exfoliated deciduous teeth. AB - Dental stem cells can serve as a potential source of functional endothelial cells for tissue engineering applications, but the endothelial-lineage differentiation efficiency is rather low even with growth factors and mechanical stimuli, which greatly limits their clinical applications. This is partly due to the deficiency of standard two-dimensional (2-D) culture systems, which is unable to recapitulate the three-dimensional (3-D) in vivo milieu that is rich in extracellular matrix. Hence, we extracted decellularized extracellular matrix from human umbilical vein endothelial cells (HUVECs-DECM) to provide a bioactive substratum conducive to the endothelial differentiation of dental stem cells. Compared to cells plated on tissue culture polystyrene (TCP), stem cells from exfoliated deciduous teeth (SHED) cultured on the HUVECs-DECM demonstrated more regular arrangement and elongated morphology. HUVECs-DECM significantly enhanced the rapid adhesion and proliferation rates of SHED, as demonstrated by WST-8 assay and immunocytochemistry indicating higher expression levels of vinculin by newly adherent SHED on HUVECs-DECM versus TCP. In addition, there was twofold to fivefold higher mRNA expression levels of endothelial-specific markers CD31 and VEGFR-2 in SHED after seven days of culture on DECM versus TCP. Functional testing with in vitro matrigel angiogenesis assay identified more capillary-like structure formation with significantly higher tubule length in SHED induced by DECM versus TCP. Hence, the results of this study provide a better understanding of the unique characteristics of cell-specific ECM and demonstrated the potential use of HUVECs-DECM as a culture substratum conducive for stimulating the endothelial differentiation of SHED for therapeutic angiogenic applications. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1083-1093, 2017. PMID- 28076904 TI - Report on outpatient management of patients with neutropenic fever in a tertiary hospital. PMID- 28076903 TI - Signaling Lymphocytic Activation Molecule Family Member 7 Engagement Restores Defective Effector CD8+ T Cell Function in Systemic Lupus Erythematosus. AB - OBJECTIVE: Effector CD8+ T cell function is impaired in systemic lupus erythematosus (SLE) and is associated with a compromised ability to fight infections. Signaling lymphocytic activation molecule family member 7 (SLAMF7) engagement has been shown to enhance natural killer cell degranulation. This study was undertaken to characterize the expression and function of SLAMF7 on CD8+ T cell subsets isolated from the peripheral blood of SLE patients and healthy subjects. METHODS: CD8+ T cell subset distribution, SLAMF7 expression, and expression of cytolytic enzymes (perforin, granzyme A [GzmA], and GzmB) on cells isolated from SLE patients and healthy controls were analyzed by flow cytometry. CD107a expression and interferon-gamma (IFNgamma) production in response to viral antigenic stimulation in the presence or absence of an anti SLAMF7 antibody were assessed by flow cytometry. Antiviral cytotoxic activity in response to SLAMF7 engagement was determined using a flow cytometry-based assay. RESULTS: The distribution of CD8+ T cell subsets was altered in the peripheral blood of SLE patients, with a decreased effector cell subpopulation. Memory CD8+ T cells from SLE patients displayed decreased amounts of SLAMF7, a surface receptor that characterizes effector CD8+ T cells. Ligation of SLAMF7 increased CD8+ T cell degranulation capacity and the percentage of IFNgamma-producing cells in response to antigen challenge in SLE patients and healthy controls. Moreover, SLAMF7 engagement promoted cytotoxic lysis of target cells in response to stimulation with viral antigens. CONCLUSION: CD8+ T cell activation in response to viral antigens is defective in SLE patients. Activation of SLAMF7 through a specific monoclonal antibody restores CD8+ T cell antiviral effector function to normal levels and thus represents a potential therapeutic option in SLE. PMID- 28076906 TI - 2016 IMJ Reviewers. PMID- 28076905 TI - Paroxysmal atrial fibrillation cured through surgical repair of a large paraoesophageal hernia. PMID- 28076907 TI - Corrigendum. PMID- 28076909 TI - Corrigendum. PMID- 28076908 TI - Aceruloplasminaemia: a disorder of diabetes and neurodegeneration. AB - Aceruloplasminaemia is an autosomal recessive disorder of iron metabolism which is characterised by diabetes, neurodegeneration and anaemia. It should be considered in the differential diagnosis of adult onset, antibody-negative diabetes associated with persistent mild anaemia and hyperferritinaemia and/or progressive neuropsychiatric impairments. PMID- 28076911 TI - Gentamicin in pregnancy: seeing past the drug categorisation in pregnancy. PMID- 28076912 TI - The Journal in 2016. PMID- 28076910 TI - Treatment of patients with Waldenstrom macroglobulinaemia: clinical practice guidelines from the Myeloma Foundation of Australia Medical and Scientific Advisory Group. AB - Waldenstrom macroglobulinaemia (WM) is an indolent B-cell malignancy characterised by the presence of immunoglobulin M (IgM) paraprotein and bone marrow infiltration by clonal small B lymphocytes, plasmacytoid lymphocytes and plasma cells. The symptoms of WM are protean, often follow an asymptomatic phase and may include complications related to the paraneoplastic effects of IgM paraprotein. The revised 2016 World Health Organization classification includes the MYD88 L265P mutation, which is seen in >90% of cases, within the diagnostic criteria for WM. While treatment of WM has often been considered together with other indolent B cell lymphomas, there are unique aspects of WM management that require specific care. These include the unreliability of IgM and paraprotein measurements in monitoring patients prior to and after treatment, the lack of correlation between disease burden and symptoms and rituximab-induced IgM flare. Moreover, while bendamustine and rituximab has recently been approved for reimbursed frontline use in WM in Australia, other regimens, including ibrutinib- and bortezomib-based treatments, are not funded, requiring tailoring of treatment to the regional regulatory environment. The Medical and Scientific Advisory Group of the Myeloma Foundation Australia has therefore developed clinical practice guidelines with specific recommendations for the work-up and therapy of WM to assist Australian clinicians in the management of this disease. PMID- 28076913 TI - Use of intravenous immunoglobulin therapy for myositis: an audit in South Australian patients. AB - In South Australia, between 2000 and 2014, 57 patients with idiopathic inflammatory myositis (IIM) were treated with intravenous immunoglobulin (IVIg). We reviewed disease characteristics to determine predictors of response to therapy and IVIg dosing and duration to identify opportunities to rationalise IVIg use. Patients with dermatomyositis/polymyositis had a response rate of 77% and were more likely than inclusion body myositis to respond to therapy. Consideration should be given to the use of the lowest possible dose of IVIg and to the undertaking of trials of cessation of IVIg in patients with stable IIM. PMID- 28076914 TI - Absence of evidence: antimicrobial prescribing in neonates, elderly and pregnant women. PMID- 28076915 TI - Towards equality. PMID- 28076916 TI - False positive hepatitis B virus core and surface antibodies due to intravenous immunoglobulin. PMID- 28076917 TI - Multi-organ dysfunction due to bath salts: are we aware of this entity? AB - Methylenedioxypyrovalerone (MDPV) is a synthetic, cathinone-derivative, central nervous system stimulant taken to produce a cocaine- or methamphetamine-like high. Physical manifestations include tachycardia, hypertension, arrhythmias, hyperthermia, sweating, rhabdomyolysis, hyperkalaemia, disseminated intravascular coagulation, oliguria and seizures. We report a patient who presented with severe metabolic acidosis, multi-organ dysfunction, rhabdomyolysis, hyperkalaemia and seizures. This case highlights that even though a urine drug screen for routine psychostimulant drugs is negative, clinicians need to be vigilant about the adverse effects of MDPV as a possible cause of multi-organ dysfunction. Substances such as this can only be detected by special tests, such as gas/liquid chromatography mass spectrometry. This is the first reported case of MDPV toxicity successfully treated in Australia to the best of our knowledge. PMID- 28076918 TI - Disparities in Supports for Student Wellness Promotion Efforts Among Secondary Schools in Minnesota. AB - BACKGROUND: We examined whether there are differences in the presence of supports for student wellness promotion (1) between schools in city, suburban and rural locations and, (2) among rural schools, according to distance from a metropolitan center. METHODS: The analysis was conducted in a sample of 309 secondary schools using 2012 Minnesota School Health Profiles surveys and National Center for Educational Statistics Common Core Data. Scores for overall support addressed school health improvement coordination (range: 0-29), collaboration on health education activities (range: 0-5), and teachers' professional preparation (range: 0-7). RESULTS: Mean overall scores for health improvement coordination (10.5 +/- 7.3), collaboration on health education activities (3.0 +/- 1.5) and professional preparation (4.0 +/- 1.9) indicated supports are lacking in schools across city, suburban, and rural locations. Comparison of overall scores did not identify disparities; however, weaknesses and strengths of particular relevance for rural schools were identified in examining specific aspects of support. For example, the proportion of rural schools having a written school improvement plan was 54.8% compared to 84.6% of city schools and 64.3% of suburban schools (p = .01). CONCLUSIONS: Tailored training and technical assistance are needed to better support schools in implementing recommended wellness policies and practices. PMID- 28076919 TI - Use of Treatment and Counseling Services and Mind-Body Techniques by Students With Emotional and Behavioral Difficulties. AB - BACKGROUND: School-based treatment and counseling services (TCSs) can integrate mind-body techniques (MBTs) to improve children's health, wellness, and academic performance. We aimed to describe the effect of school-based TCS on MBT-use among students experiencing difficulties with concentration, emotions, behaviors, and getting along (DCEBG). METHODS: National Health Interview Survey data were utilized (N2007 = 1225; N2012 = 1835). Logistic regression examined associations between TCS-type and MBT-use, while propensity score matching controlled for confounders in the prematch sample. RESULTS: Compared with children without DCEBG, MBT-use was higher among children with DCEBG, but it decreased from 2007 (9.7%) to 2012 (5.1%). Receipt of school-based TCS increased from 2007 (11.3%) to 2012 (33.9%). Receipt of school-only TCS, compared with nonschool-only TCS, was associated with lower MBT-use (OR2007 = 0.20; OR2012 = 0.54). After matching, this difference remained for 2007 (tprematch = -2.77; tpostmatch = -2.00), but not 2012 (tprematch = -2.53; tpostmatch = -0.88). School-only TCS-use increased with family activity limitations; in 2012, it decreased with higher parental education. Mind-body techniques-use was higher in girls and associated with higher parental education and family activity limitations. CONCLUSIONS: While the relative increase of MBT integration by school-based TCS is commendable and further encouraged, school mental health practitioners should account for the differential effects of family-level factors on TCS-choice and MBT-use. PMID- 28076920 TI - Effectiveness of IMPACT:Ability to Improve Safety and Self-Advocacy Skills in Students With Disabilities-Follow-Up Study. AB - BACKGROUND: Research shows that individuals with disabilities are more likely to experience abuse than their peers without disabilities. Yet, few evidenced-based abuse prevention interventions exist. This study examines whether positive outcomes identified previously in an evaluation of IMPACT:Ability were maintained 1 year later. METHODS: A survey measuring safety and self-advocacy knowledge, confidence, and behaviors among special education high-school students was administered 12 months post-training. Paired samples t-tests were used to compare baseline to follow up and postsurvey to follow up and repeated measures analyses were conducted to test the effect of time across the 3 time points (baseline, post, and 1-year follow up) (N = 47). RESULTS: Follow-up study participants had a range of disabilities, just over half were boys, and most were either black or Latino/Hispanic. Difference between scores at baseline and follow-up for all the measures of interest represented gains from baseline. Statistically significant post-training improvements in participants' safety and self-advocacy knowledge and confidence were maintained 1-year later. CONCLUSIONS: These results provide additional support for the case that IMPACT:Ability is a promising safety and self-advocacy training program for diverse groups of students with disabilities. PMID- 28076921 TI - Classroom Nutrition Education Combined With Fruit and Vegetable Taste Testing Improves Children's Dietary Intake. AB - BACKGROUND: We tested the effectiveness of the Go Wild With Fruits and Veggies! (GWWFV) Extension curriculum on increasing fruit and vegetable (FV) intake of third graders. METHODS: An intervention study was used testing self-reported FV intake pre/post GWWFV. Recruited schools were randomized to control (12 schools, N = 369, third grade children) or intervention (14 schools, N = 378, third grade children). Measures included items from a validated FV food frequency survey. Access to the federal Fresh Fruit and Vegetable Snack Program (FFVSP), and taste testing within GWWFV were also measured. Between-group differences in FV intake were evaluated using 1-way ANOVA for unadjusted models and 1-way ANCOVA for baseline adjusted models. The Tukey-Kramer test was employed for post hoc comparisons. RESULTS: Students with access to the FFVSP consumed more fruits (p < .01) and vegetables (p < .0001). Students who participated in the FFVSP and GWWFV with taste testing consumed more fruits and vegetables (p < .05) compared with students who participated in the FFVSP and GWWFV without taste testing, along with the control group. CONCLUSIONS: The FFVSP and GWWFV with taste testing demonstrated a positive influence on FV intake in third grade children. Leveraging environmental approaches with interactive learning experiences create desired outcomes. PMID- 28076922 TI - Evaluating Active Parental Consent Procedures for School Programming: Addressing the Sensitive Topic of Suicide Prevention. AB - BACKGROUND: Suicide is the second leading cause of death for adolescents. Whereas school-based prevention programs are effective, obtaining active consent for youth participation in public health programming concerning sensitive topics is challenging. We explored several active consent procedures for improving participation rates. METHODS: Five active consent methods (in-person, students taking forms home, mailing, mailing preceded by primers, mailing followed by reminder calls) were compared against passive consent procedures to evaluate recruitment success, as determined by participation (proportion who responded yes) and response (proportion who returned any response) rates. RESULTS: Participation acceptance rates ranged from 38 to 100% depending on consent method implemented. Compared with passive consent, active consent procedures were more variable in response and participation rates. In-person methods provided higher rates than less interpersonal methods, such as mailing or students taking consents home. Mailed primers before or reminder calls after consent forms were mailed increased response but not participation rates. Students taking consents home resulted in the lowest rates. CONCLUSIONS: Although passive consent produces the highest student participation, these methods are not always appropriate for programs addressing sensitive topics in schools. In-person active consent procedures may be the best option when prioritizing balance between parental awareness and successful student recruitment. PMID- 28076923 TI - How Schools Can Promote Healthy Development for Newly Arrived Immigrant and Refugee Adolescents: Research Priorities. AB - BACKGROUND: The US education system must find creative and effective ways to foster the healthy development of the approximately 2 million newly arrived immigrant and refugee adolescents, many of whom contend with language barriers, limited prior education, trauma, and discrimination. We identify research priorities for promoting the school success of these youth. METHODS: The study used the 4-phase priority-setting method of the Child Health and Nutrition Research Initiative. In the final stage, 132 researchers, service providers, educators, and policymakers based in the United States were asked to rate the importance of 36 research options. RESULTS: The highest priority research options (range 1 to 5) were: evaluating newcomer programs (mean = 4.44, SD = 0.55), identifying how family and community stressors affect newly arrived immigrant and refugee adolescents' functioning in school (mean = 4.40, SD = 0.56), identifying teachers' major stressors in working with this population (mean = 4.36, SD = 0.72), and identifying how to engage immigrant and refugee families in their children's education (mean = 4.35, SD = 0.62). CONCLUSION: These research priorities emphasize the generation of practical knowledge that could translate to immediate, tangible benefits for schools. Funders, schools, and researchers can use these research priorities to guide research for the highest benefit of schools and the newly arrived immigrant and refugee adolescents they serve. PMID- 28076924 TI - Healthy Concessions: High School Students' Responses to Healthy Concession Stand Changes. AB - BACKGROUND: A previous sales data analysis demonstrated success in selling healthier items at a concession stand. Questions remained regarding student satisfaction and whether the intervention reached non-health-conscious students. METHODS: Cross-sectional anonymous samples of students at a large midwestern high school were surveyed before and after an intervention improved the number of healthier items available at the concession stand. RESULTS: The survey was completed by 301 students preintervention and 314 students postintervention. Satisfaction remained good (3.7 preintervention and 3.6 postintervention). Satisfaction with the variety and taste of foods increased. We compared students who felt having healthy items were important at the concessions to those who did not. Overall satisfaction with concessions did not differ between groups. The latter group (healthy items not important) reported improved satisfaction with food variety (2.8 to 3.1, p = .02) and the former reported improved satisfaction with healthy foods (2.5 to 2.9, p = .03) and overall taste (3.2 to 3.4, p = .02). Of the healthy items not important students 76% reported purchasing at least 1 new healthier food. CONCLUSIONS: Adding healthier foods to school concession stands has positive effects on student satisfaction, sales, and reaches all students whether or not they care about having healthy items available. PMID- 28076925 TI - The Association Between Electronic Bullying and School Absenteeism Among High School Students in the United States. AB - BACKGROUND: We examined the relationship between exposure to electronic bullying and absenteeism as a result of being afraid. METHODS: This multivariate, multinomial regression analysis of the 2013 Youth Risk Behavior Survey data assessed the association between experiencing electronic bullying in the past year and how often students were absent in the last month due to feeling unsafe at/in transit to school. The model controlled for other predictors of school absence including demographics, physical/behavioral health, and risk factors. Missing data were multiply imputed. RESULTS: Electronic bullying was significantly associated with absences. Controlling for model covariates, the relative risk of missing 1 day of school was 1.77 times higher, the relative risk of missing 2 to 3 days of school per month increased by a factor of 2.08, and the relative risk of missing 4 or more days of school per month increased by a factor of 1.77 for those who experienced electronic bullying in the past year compared with those who were not electronically bullied. CONCLUSIONS: Electronic bullying's association with absenteeism places it among already recognized negative influences such as depression and binge drinking, necessitating schools to implement policies to mediate the resulting harmful effects. PMID- 28076927 TI - Gender differences in suicide in Sri Lanka - what does it tell us? PMID- 28076926 TI - Yoga treatment for chronic non-specific low back pain. AB - BACKGROUND: Non-specific low back pain is a common, potentially disabling condition usually treated with self-care and non-prescription medication. For chronic low back pain, current guidelines state that exercise therapy may be beneficial. Yoga is a mind-body exercise sometimes used for non-specific low back pain. OBJECTIVES: To assess the effects of yoga for treating chronic non-specific low back pain, compared to no specific treatment, a minimal intervention (e.g. education), or another active treatment, with a focus on pain, function, and adverse events. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, five other databases and four trials registers to 11 March 2016 without restriction of language or publication status. We screened reference lists and contacted experts in the field to identify additional studies. SELECTION CRITERIA: We included randomized controlled trials of yoga treatment in people with chronic non specific low back pain. We included studies comparing yoga to any other intervention or to no intervention. We also included studies comparing yoga as an adjunct to other therapies, versus those other therapies alone. DATA COLLECTION AND ANALYSIS: Two authors independently screened and selected studies, extracted outcome data, and assessed risk of bias. We contacted study authors to obtain missing or unclear information. We evaluated the overall certainty of evidence using the GRADE approach. MAIN RESULTS: We included 12 trials (1080 participants) carried out in the USA (seven trials), India (three trials), and the UK (two trials). Studies were unfunded (one trial), funded by a yoga institution (one trial), funded by non-profit or government sources (seven trials), or did not report on funding (three trials). Most trials used Iyengar, Hatha, or Viniyoga forms of yoga. The trials compared yoga to no intervention or a non-exercise intervention such as education (seven trials), an exercise intervention (three trials), or both exercise and non-exercise interventions (two trials). All trials were at high risk of performance and detection bias because participants and providers were not blinded to treatment assignment, and outcomes were self assessed. Therefore, we downgraded all outcomes to 'moderate' certainty evidence because of risk of bias, and when there was additional serious risk of bias, unexplained heterogeneity between studies, or the analyses were imprecise, we downgraded the certainty of the evidence further.For yoga compared to non exercise controls (9 trials; 810 participants), there was low-certainty evidence that yoga produced small to moderate improvements in back-related function at three to four months (standardized mean difference (SMD) -0.40, 95% confidence interval (CI) -0.66 to -0.14; corresponding to a change in the Roland-Morris Disability Questionnaire of mean difference (MD) -2.18, 95% -3.60 to -0.76), moderate-certainty evidence for small to moderate improvements at six months (SMD -0.44, 95% CI -0.66 to -0.22; corresponding to a change in the Roland-Morris Disability Questionnaire of MD -2.15, 95% -3.23 to -1.08), and low-certainty evidence for small improvements at 12 months (SMD -0.26, 95% CI -0.46 to -0.05; corresponding to a change in the Roland-Morris Disability Questionnaire of MD 1.36, 95% -2.41 to -0.26). On a 0-100 scale there was very low- to moderate certainty evidence that yoga was slightly better for pain at three to four months (MD -4.55, 95% CI -7.04 to -2.06), six months (MD -7.81, 95% CI -13.37 to -2.25), and 12 months (MD -5.40, 95% CI -14.50 to -3.70), however we pre-defined clinically significant changes in pain as 15 points or greater and this threshold was not met. Based on information from six trials, there was moderate-certainty evidence that the risk of adverse events, primarily increased back pain, was higher in yoga than in non-exercise controls (risk difference (RD) 5%, 95% CI 2% to 8%).For yoga compared to non-yoga exercise controls (4 trials; 394 participants), there was very-low-certainty evidence for little or no difference in back-related function at three months (SMD -0.22, 95% CI -0.65 to 0.20; corresponding to a change in the Roland-Morris Disability Questionnaire of MD 0.99, 95% -2.87 to 0.90) and six months (SMD -0.20, 95% CI -0.59 to 0.19; corresponding to a change in the Roland-Morris Disability Questionnaire of MD 0.90, 95% -2.61 to 0.81), and no information on back-related function after six months. There was very low-certainty evidence for lower pain on a 0-100 scale at seven months (MD -20.40, 95% CI -25.48 to -15.32), and no information on pain at three months or after seven months. Based on information from three trials, there was low-certainty evidence for no difference in the risk of adverse events between yoga and non-yoga exercise controls (RD 1%, 95% CI -4% to 6%).For yoga added to exercise compared to exercise alone (1 trial; 24 participants), there was very-low-certainty evidence for little or no difference at 10 weeks in back related function (SMD -0.60, 95% CI -1.42 to 0.22; corresponding to a change in the Oswestry Disability Index of MD -17.05, 95% -22.96 to 11.14) or pain on a 0 100 scale (MD -3.20, 95% CI -13.76 to 7.36). There was no information on outcomes at other time points. There was no information on adverse events.Studies provided limited evidence on risk of clinical improvement, measures of quality of life, and depression. There was no evidence on work-related disability. AUTHORS' CONCLUSIONS: There is low- to moderate-certainty evidence that yoga compared to non-exercise controls results in small to moderate improvements in back-related function at three and six months. Yoga may also be slightly more effective for pain at three and six months, however the effect size did not meet predefined levels of minimum clinical importance. It is uncertain whether there is any difference between yoga and other exercise for back-related function or pain, or whether yoga added to exercise is more effective than exercise alone. Yoga is associated with more adverse events than non-exercise controls, but may have the same risk of adverse events as other back-focused exercise. Yoga is not associated with serious adverse events. There is a need for additional high quality research to improve confidence in estimates of effect, to evaluate long term outcomes, and to provide additional information on comparisons between yoga and other exercise for chronic non-specific low back pain. PMID- 28076929 TI - Non-invasive imaging demonstrates clinical features of ankylosing spondylitis in a rat adjuvant model: a case study. AB - Ankylosing spondylitis is a common rheumatic disease involving both inflammatory erosive osteopenia and bony overgrowth. Main disease features are recapitulated in small rodents challenged with complete Freund's adjuvant. MRI was used to follow longitudinally in vivo changes induced in the rat spine and micro-CT as terminal assessment of bone damage. Histochemistry methods were used to validate these imaging modalities in view of preclinical drug testing and translational applications of spine imaging. Animals were examined using a 3D fat-suppressed gradient-echo sequence, following the injection of gadolinium. At the end of the study, spines were excised for micro-CT and histological examination. Signals reflecting inflammation were detected at levels L5-L6 of the lumbar spine throughout the experimental period, peaking at day 27 after adjuvant. At day 14 the inflammatory response occurred along ligaments but it expanded to nearby soft tissues at later time points. From day 27 onwards inflammation was also detected within the bone, in areas where erosion occurred, and bone-like structures were formed. Micro-CT showed bone remodeling. Histology of isolated spines confirmed the inflammation and bone remodeling observed in vivo. The present study including three complementary approaches clearly demonstrates the potential of imaging for longitudinal assessments of changes in the spine in this animal model in view of preclinical pharmacological studies. The excellent correlation seen between the in vivo images and the histology underlines its fundamental role in the validation of non-invasive imaging readouts. PMID- 28076928 TI - RXRalpha is upregulated in first trimester endometrial glands of spontaneous abortions unlike LXR and PPARgamma. AB - Nuclear receptors are necessary for uterine invasion of the trophoblast and therefore important for maintaining a viable pregnancy. The aim of this study was to investigate the expression pattern and frequency of LXR, PPARgamma and RXRalpha under physiological circumstances and in spontaneous abortions in endometrial glands and decidual tissue cells. A total of 28 (14 physiologic pregnancies/14 spontaneous abortion) human pregnancies in first trimester were analysed for expression of the nuclear receptors LXR, RXRalpha and PPARgamma. Expression changes were evaluated by immunohistochemistry in decidual tissue and endometrial glands of the decidua. RXRalpha expression was up-regulated in the endometrial glands of spontaneous abortion (P<0.015). Similar up regulation of RXRalpha was found in decidual tissue (P<0.05). LXR and PPARgamma expression was unchanged in spontaneous abortion. Via Correlation analysis we found a trend to positive correlation of LXR and PPARgamma (Spearman correlation coefficient r=0.56 P=0.07) in endometrial glands. In decidual tissue, we found significant negative correlation in the control group, for the combination of RXRalpha and PPARgamma (Spearman correlation coefficient r=0.913, P=0.03). Our data show that RXRalpha expression is increased in miscarriage in endometrial glands and correlation analysis showed that negative correlation between RXRalpha and PPARgamma disappears in miscarriage. This shift is supposable responsible for the loss of regular function in trophoblast and embryonic tissue. PMID- 28076930 TI - Hormone receptor expression in human fascial tissue. AB - Many epidemiologic, clinical, and experimental findings point to sex differences in myofascial pain in view of the fact that adult women tend to have more myofascial problems with respect to men. It is possible that one of the stimuli to sensitization of fascial nociceptors could come from hormonal factors such as estrogen and relaxin, that are involved in extracellular matrix and collagen remodeling and thus contribute to functions of myofascial tissue. Immunohistochemical and molecular investigations (real-time PCR analysis) of relaxin receptor 1 (RXFP1) and estrogen receptor-alpha (ERalpha) localization were carried out on sample of human fascia collected from 8 volunteers patients during orthopedic surgery (all females, between 42 and 70 yrs, divided into pre- and post-menopausal groups), and in fibroblasts isolated from deep fascia, to examine both protein and RNA expression levels. We can assume that the two sex hormone receptors analyzed are expressed in all the human fascial districts examined and in fascial fibroblasts culture cells, to a lesser degree in the post menopausal with respect to the pre-menopausal women. Hormone receptor expression was concentrated in the fibroblasts, and RXFP1 was also evident in blood vessels and nerves. Our results are the first demonstrating that the fibroblasts located within different districts of the muscular fasciae express sex hormone receptors and can help to explain the link between hormonal factors and myofascial pain. It is known, in fact, that estrogen and relaxin play a key role in extracellular matrix remodeling by inhibiting fibrosis and inflammatory activities, both important factors affecting fascial stiffness and sensitization of fascial nociceptors. PMID- 28076931 TI - Varying effects of EGF, HGF and TGFbeta on formation of invadopodia and invasiveness of melanoma cell lines of different origin. AB - The understanding of melanoma malignancy mechanisms is essential for patient survival, because melanoma is responsible for ca. 75% of deaths related to skin cancers. Enhanced formation of invadopodia and extracellular matrix (ECM) degradation are two important drivers of cell invasion, and actin dynamics facilitate protrusive activity by providing a driving force to push through the ECM. We focused on the influence of epidermal growth factor (EGF), hepatocyte growth factor (HGF) and transforming growth factor beta (TGFbeta) on melanoma cell invasiveness, since they are observed in the melanoma microenvironment. All three factors stimulated invasion of A375 and WM1341D cells derived from primary tumor sites. In contrast, only EGF and HGF stimulated invasion of WM9 and Hs294T cells isolated from lymph node metastases. Enhanced formation of invadopodia and ECM degradation underlie the increased amount of invasive cells after stimulation with the tested agents. Generally, a rise in invasive potential was accompanied by a decrease in actin polymerization state (F:G ratio). The F:G ratio remained unchanged or was even increased in metastatic cell lines treated with TGFbeta. Our findings indicate that the effects of stimulation with EGF, HGF and TGFbeta on melanoma cell invasiveness could depend on melanoma cell progression stage. PMID- 28076932 TI - Aortic dissection is associated with reduced polycystin-1 expression, an abnormality that leads to increased ERK phosphorylation in vascular smooth muscle cells. AB - The vascular smooth muscle cell (VSMC) phenotypic switch is a key pathophysiological change in various cardiovascular diseases, such as aortic dissection (AD), with a high morbidity. Polycystin-1 (PC1) is significantly downregulated in the VSMCs of AD patients. PC1 is an integral membrane glycoprotein and kinase that regulates different biological processes, including cell proliferation, apoptosis, and cell polarity. However, the role of PC1 in intracellular signaling pathways remains poorly understood. In this study, PC1 downregulation in VSMCs promoted the expression of SM22alpha, ACTA2 and calponin 1 (CNN1) proteins. Furthermore, PC1 downregulation in VSMCs upregulated phospho MEK, phospho-ERK and myc, but did not change phospho-JNK and phospho-p38. These findings suggest that the MEK/ERK/myc signaling pathway is involved in PC1 mediated human VSMC phenotypic switch. Opposite results were observed when an ERK inhibitor was used in VSMCs downregulated by PC1. When the C-terminal domain of PC1 (PC1 C-tail) was overexpressed in VSMCs, the expression levels of phosphor ERK, myc, SM22alpha, ACTA2 and CNN1 proteins were downregulated. The group with the overexpressed mutant protein (S4166A) in the PC1 C-tail showed similar results to the group with the downregulated PC1 in VSMCs. These results suggest that the Ser at the 4166 site in PC1 is crucial in the PC1 mediated MEK/ERK/myc signaling pathway, which might be the key pathophysiological cause of AD. PMID- 28076933 TI - 3-hydroxi-anthranilic acid is early expressed in stroke. AB - Using an immunohistochemical technique, we have studied the distribution of 3-OH anthranilic acid (3-HAA) in the rat brain. Our study was carried out in control animals and in rats in which a stroke model (single transient middle cerebral artery occlusion) was performed. A monoclonal antibody directed against 3-HAA was also developed. 3-HAA was exclusively observed in the infarcted regions (ipsilateral striatum/cerebral cortex), 2, 5 and 21 days after the induction of stroke. In control rats and in the contralateral side of the stroke animals, no immunoreactivity for 3-HAA was visualized. Under pathological conditions (from early phases of stroke), we reported for the first time the presence of 3-HAA in the mammalian brain. By double immunohistochemistry, the coexistence of 3-HAA and GFAP was observed in astrocytes. The distribution of 3-HAA matched perfectly with the infarcted regions. Our findings suggest that, in stroke, 3-HAA could be involved in the tissue damage observed in the infarcted regions, since it is well known that 3-HAA exerts cytotoxic effects. PMID- 28076934 TI - The injury of serotonin on intestinal epithelium cell renewal of weaned diarrhoea mice. AB - Diarrhoea is a common cause of death in children and weaned animals. Recent research has found that serotonin (5-HT) in the gastrointestinal tract plays an important role in regulating growth and the maintenance of mucosa, which protect against diarrhoea. To determine the influence of 5-HT on intestinal epithelium cell renewal under weaned stress diarrhoea, a weaned-stress diarrhoea mouse model was established with senna infusion (15 mL/Kg) via intragastric administration and stress restraint (SR). Mice with an increase in 5-HT were induced by intraperitoneal injection with citalopram hydrobromide (CH, 10 mg/Kg). The results demonstrated that compared with the control animals, diarrhoea appeared in weaned stress mice and the 5-HT content in the small intestine was significantly increased (P<0.05). Further, the caspase-3 cells and cells undergoing apoptosis in the small intestine were significantly increased, but the VH (villus height), V/C (villus height /crypt depth), and PCNA-positive rate significantly decreased. Compared with the control animals, CH increased the intestinal 5-HT content, caspase-3 cells and cells undergoing apoptosis but decreased the VH and V/C. Compared with both control and weaned stress animals, weaned stress animals that were pre-treated with CH showed higher 5-HT concentrations, positive caspase-3 cells and cells undergoing apoptosis but lower VH, V/C and PCNA-positive rate. In vitro, a low concentration of 5-HT inhibit, IEC-6 cell line apoptosis but a higher concentration of 5-HT promoted it. Therefore, weaned stress diarrhoea mice were accompanied by a 5-HT increase in the small intestine and vice versa, and the increase in 5-HT induced by CH caused diarrhoea. In brief, 5-HT and diarrhoea slowed the intestinal epithelium cell renewal and injured the abortion function and mucosal barrier by decreasing VH, V/C and proliferation and increasing epithelium cell apoptosis. PMID- 28076935 TI - High temperature requirement A1 and fibronectin: two possible players in placental tissue remodelling. AB - High temperature requirement A1 (HtrA1) is a secreted protease involved in placental development. Fibronectin (FN) is involved in important process such as wound healing, cell adhesion and spreading, growth, migration, and differentiation. The purpose of this study was to analyse the expression patterns of HtrA1 in relationship to FN and to the key growth zones of placenta such as mesenchymal villi as well as cell islands and cell columns. We demonstrated that FN and HtrA1 are localized in the placental key growth zones suggesting a pivotal role in maintaining the balance among the molecules involved in the placental development and differentiation. PMID- 28076936 TI - Histochemical and morphological aspects of fresh frozen bone: a preliminary study. AB - Bone graft are used in dentistry for the reconstruction of severely atrophic jaws. Fresh frozen bone has no osteogenic property but it has osteoconductive and osteoinductive properties because its matrix contains growth factors such as vascular endothelial growth factor. The purpose of the present study was to evaluate morphological and protein expression characteristics of fresh frozen bone before graft and after six months of graft in patients who needed maxillary reconstruction. After 6 month of graft we observed the presence of viable bone as evidenced by full osteocyte lacunae and by the presence of RANKR, osteocalcin positive cells and vascular endothelial growth factor. In conclusion, our findings show that the fresh frozen bone after six month of graft is for the most part viable bone, encouraging its use as an alternative to autogenous bone for reconstructing maxillary bone defects prior to implant. PMID- 28076937 TI - In vivo imaging techniques: a new era for histochemical analysis. AB - In vivo imaging techniques can be integrated with classical histochemistry to create an actual histochemistry of water. In particular, Magnetic Resonance Imaging (MRI), an imaging technique primarily used as diagnostic tool in clinical/preclinical research, has excellent anatomical resolution, unlimited penetration depth and intrinsic soft tissue contrast. Thanks to the technological development, MRI is not only capable to provide morphological information but also and more interestingly functional, biophysical and molecular. In this paper we describe the main features of several advanced imaging techniques, such as MRI microscopy, Magnetic Resonance Spectroscopy, functional MRI, Diffusion Tensor Imaging and MRI with contrast agent as a useful support to classical histochemistry. PMID- 28076938 TI - Transmission electron microscopy for nanomedicine: novel applications for long established techniques. AB - During the last twenty years, the research in nanoscience and nanotechnology has dramatically increased and, in the last decade, the interest has progressively been oriented towards biomedical applications, giving rise to a new field termed nanomedicine. Transmis - sion electron microscopy is a valuable technique not only for the thorough physico-chemical characterization of newly synthesized nanoparticulates, but especially to explore the effects of nanocomposites on biological systems, providing essential information for the development of efficient therapeutic and diagnostic strategies. Thus, for the progress of nanotechnology in the biomedical field, experts in cell biology, histochemistry and ultramicroscopy should always support the chemists, physicists and pharmacologists engaged in the synthesis and characterization of innovative nanoconstructs. PMID- 28076940 TI - Cervical ripening with self administered iso sorbide mononitrate vaginally, in uncomplicated singleton pregnancies at 39 weeks gestation: a double blind randomised controlled trial AB - Introduction: Vaginal iso sorbide mononitrate (ISMN) is effective in pre induction cervical ripening in post dated pregnancies. Objectives: To determine the effectiveness and acceptability of ISMN self-administered vaginally at home, in causing cervical ripening in uncomplicated singleton pregnancies at 39 weeks gestation. Methods: Consecutive women with uncomplicated singleton pregnancies, presenting between 01 October 2013 and 31 March 2014, with a modified Bishop score (MBS) of < 5 at a gestational age (GA) of 273 days to the University Obstetric Unit of Teaching Hospital Mahamodera Galle, were allocated by stratified (primip/multip) block randomisation to self-administer vaginally at home every other day, five doses of 60 mg of sustained release form of ISMN (ISMN SR); (n = 72, cases), or pyridoxine 10 mgs (n=72, controls), from GA 273 to 282 days. Results: The mean MBS and the mean change of MBS at 282 days, and the proportions with spontaneous onset of labour (SOL) by GA 282 days, were not significantly different between the two groups. A vast majority were satisfied with outpatient therapy (80% cases vs.76% controls), were happy to use it in a subsequent preg-nancy (89% cases vs. 86% controls) and would recom-mend it to a friend (93% cases vs. 90% controls). Conclusions: Home adminstrated vaginal ISMN therapy from GA 39 weeks was not effective in causing significant cervical ripening or promoting SOL, but it was acceptable to women. PMID- 28076939 TI - Is there still room for novelty, in histochemical papers? AB - Histochemistry continues to be widely applied in biomedical research, being nowadays mostly addressed to detect and locate single molecules or molecular complexes inside cells and tissues, and to relate structural organization and function at the high resolution of the more advanced microscopical techniques. In the attempt to see whether histochemical novelties may be found in the recent literature, the articles published in the European Journal of Histochemistry in the period 2014-2016 have been reviewed. In the majority of the published papers, standardized methods have been preferred by scientists to make their results reliably comparable with the data in the literature, but many papers (approximately one fourth of the published articles) described novel histochemical methods and procedures. It is worth noting that there is a growing interest for minimally-invasive in vivo techniques (magnetic resonance imaging, autofluorescence spectroscopy) which may parallel conventional histochemical analyses to obtain information not only on the morphological features of living organs and tissues, but also on their functional, biophysical and molecular characteristics. Thanks to this unceasing methodological refinement, histochemistry will continue to provide innovative applications in the biomedical field. PMID- 28076941 TI - Double-Balloon Endoscopy in Overt and Occult Small Bowel Bleeding: Results, Complications, and Correlation with Prior Videocapsule Endoscopy in a Tertiary Referral Center. AB - BACKGROUND/AIMS: Videocapsule endoscopy (VCE) and double-balloon endoscopy (DBE) allow deep exploration in patients with suspected small bowel pathology. VCE is often performed as an initial small bowel examination to explore whether an intervention by DBE is indicated and to determine insertion route. The study aim was to evaluate the correlation between DBE and VCE in patients with obscure or overt bleeding or anemia, as well as intervention frequency, and complications. METHODS: Retrospective observational study. RESULTS: DBE procedures (n=205) showed small bowel lesions in 64% cases. Antegrade DBE showed positive results in 79% cases, mostly angiodysplasias (63%). Retrograde DBE showed positive results in 22% cases. An intervention was performed in 64% of DBE procedures. The major complication rate was 0.5%, which was one case of perforation. Pancreatitis did not occur. The overall diagnostic agreement was 66% among the 134 DBEs with preceded VCE. CONCLUSIONS: In cases of overt or occult bleeding or anemia, DBE was positive in 64%, with only a few complications. Positive correlation was 66% among initially performed VCEs and DBEs. Owing to the time-consuming and invasive character of DBE, performing VCE before DBE might still be clinically relevant. PMID- 28076942 TI - Prevalence of gestational diabetes mellitus in a Suburban District in Sri Lanka: a population based study AB - Introduction: GDM is a leading metabolic cause of morbidity to mother and offspring. Determining its prevalence is important for health planning and implementation. Objective: Assess prevalence of GDM in the District of Gampaha. Method: Community based cross-sectional study was conducted in women attending field-based ante-natal clinics in two Medical Officer of Health (MOH) areas between January 2014 to March 2015. Consecutive women were recruited by cluster sampling with probability proportionate to size using strict exclusion criteria. GDM diagnosis was based on fasting 75 g OGTT, WHO 1999. All responders underwent 2 hr PPBS in first trimester- >200 mg/dl with symptoms identified as abnormal, probably diabetes in pregnancy (DIP); those >120 and <200 mg/dl proceeded to OGTT before 16 weeks POA; all negatives were tested by OGTT between 24-28 weeks. Negatives for GDM at 24-28 weeks underwent OGTT between 32-36 weeks; venous plasma glucose tested by accredited laboratory. Results: Sample consistedof 160, non-response 4.2% (67); 1533 underwent 2 hr PPBS with 40 exceeding 120mg: 4 >200 mg diagnosed as GDM / DIP, 36 (PPBS >120 < 200 mg) underwent OGTT before 16 weeks with 15 GDM. One hundred and thirty four (8.38%) miscarried including one with early abnormal OGTT. Of 1381 eligible for OGTT (24- 28 weeks) 150 had GDM (10.86%). Only 344 (27.94% of normal 1231) consented for third trimester OGTT, of whom 25 had GDM- yielding a total of 194 with GDM (13.9%). Conclusions: The current community prevalence of GDM in the suburban Gampaha District, Sri Lanka is high. PMID- 28076943 TI - Repetition rate after non-fatal self-poisoning in Sri-Lanka: a one year prospective longitudinal study AB - Introduction: Attempted or non-fatal self-poisoning is an important public health problem in Sri Lanka. Current evidence from Sri Lanka suggests that this phenomenon is more common among young people, and females, and is associated with a recent interpersonal conflict. International studies indicate that recent non fatal selfharm is associated with an increased risk of repetition and completed suicide. Prospective follow-up data regarding rates of repetition of self-harm in Sri Lanka is limited. Objectives: The aim of this study was to describe the rate of repetition, and rate of suicidal ideation, at one-year follow up among those who have survived an act of selfpoisoning. Methods: Participants who presented to the toxicology unit, Teaching Hospital Peradeniya over a 14-month period, for medical management of non-fatal self-poisoning, were contacted by telephone one year following the initial presentation. Results: A total of 949 persons were included in the study, of which 35.3% (n=335) were contactable at one-year follow up. The rate of repetition of self-harm after one year was 2.5% and 2.7% of participants had suicidal ideation at one-year follow-up. Conclusions: The rate of repetition of self-harm in Sri Lanka is lower than the rate reported in the West (15%). PMID- 28076944 TI - Rice variety and processing: contribution to glycaemic response AB - Introduction: Glycaemic index (GI) of different varieties of rice (Oryza sativa L.) commonly consumed in Sri Lanka are not widely studied even though it is the staple food. Objectives: To determine the proximate compositions and the GI of three different rice meals, namely Bg 360 Samba (raw), Basmati At 405 (raw) and parboiled Nadu Bg 352. Methods: The study was a randomised cross over study using healthy volunteers (n=11). GI was determined as the ratio between the incremental areas under curve obtained for the test food and the standard glucose (WHO/FAO method). Proximate compositions were determined by standard methods. Results: The GI value so obtained were, 66+/-8 (medium GI) for Bg 360 Samba, 73+/-7 (high GI) for Basmati At 405 and 40+/-4 (low GI) for Nadu Bg 352. Parboiled variety had a significantly low GI and the lowest peak glucose concentration. Significant differences were observed in insoluble dietary fibre (IDF), total dietary fibre (TDF) and moisture contents of the rice varieties. Non significant negative correlations between IDF (r = -0.94, p = >0.05, n = 3) and TDF (r = - 0.90, p = >0.05, n = 3) and GI of the rice varieties were observed. Conclusions: Parboiled Nadu Bg 352 and Bg 360 Samba (raw) are of nutritional significance to individuals seeking to control the energy intake and glycaemic response. PMID- 28076945 TI - Effect of body mass index on pulmonary function in children AB - Introduction: The relationship between obesity or overweight and pulmonary functions has not been investigated in Sri Lankan children previously. Therefore, we aimed to study the effects of obesity/overweight on dynamic lung functions in healthy school children in Sri Lanka. Methods: Results: Of 275 children 55 (20%) were 'obese/overweight'. BMI has no significant relationship to any ofthe pulmonary function parameters. However, in contrastto what is expected, mean values of FVC, FEV1 and FEF25-75% were lower in 'normal weight' group (Table 2). Conclusions: No significant difference was detected in spirometry parameters between obese/overweight and normal weight school children in our study. PMID- 28076946 TI - Validation of the Sinhala version of the Repeatable Battery for Assessment of Neuropsychological Status (RBANS) AB - Introduction: Only the Mini mental state examination (MMSE) and Montreal Cognitive Assessment scale have been validated in a Sri Lankan population for the assessment of cognitive functions. Both tests are deficient in the number of domains assessed. Therefore validation of Repeatable Battery for Assessment of Neuropsychological Status is important as it assesses most of the cognitive domains. Objectives: To culturally adapt RBANS and investigate the validity and reliability of culturally adapted RBANS (RBANS-S). Methods: Fifty four participants with major neurocognitive disorder and 60 normal controls aged >50 were administered with RBANS-S at the Cognitive Assessment Unit, Faculty of Medicine, Colombo and National Hospital of Sri Lanka. The participants were selected after a detailed clinical assessment according to Diagnostic and Statistical Manual - 5 criteria. Data were analysed using SPSS data package. Results: The mean age of the sample was 69.5 years. RBANS-S total scale correlated highly with MMSE total score, (Pearson correlational coefficient = 0.793 p=0.01). Criterion validity was assessed using receiver operating curve characteristic analysis and the area under the curve was 0.937. RBANS-S showed strong concurrent validity us indicated by its significant correlations with the MMSE. All of the RBANS-S subtests demonstrated significant correlations with the MMSE subsets. The sensitivity and specificity for RBANS-S was 89% and 85% respectively at a totals score of 80.5. The RBANS-S yielded a reliability coefficient of 0.929. Conclusions: Culturally adapted RBANS-S is a valid and reliable instrument which can be used in assessment of cognitive functions. PMID- 28076947 TI - Asymmetric Volcano Trend in Oxygen Reduction Activity of Pt and Non-Pt Catalysts: In Situ Identification of the Site-Blocking Effect. AB - Proper understanding of the major limitations of current catalysts for oxygen reduction reaction (ORR) is essential for further advancement. Herein by studying representative Pt and non-Pt ORR catalysts with a wide range of redox potential (Eredox) via combined electrochemical, theoretical, and in situ spectroscopic methods, we demonstrate that the role of the site-blocking effect in limiting the ORR varies drastically depending on the Eredox of active sites; and the intrinsic activity of active sites with low Eredox have been markedly underestimated owing to the overlook of this effect. Accordingly, we establish a general asymmetric volcano trend in the ORR activity: the ORR of the catalysts on the overly high Eredox side of the volcano is limited by the intrinsic activity; whereas the ORR of the catalysts on the low Eredox side is limited by either the site-blocking effect and/or intrinsic activity depending on the Eredox. PMID- 28076948 TI - Cerium(IV) Imido Complexes: Structural, Computational, and Reactivity Studies. AB - A series of alkali metal capped cerium(IV) imido complexes, [M(solv)x][Ce?N(3,5 (CF3)2C6H3)(TriNOx)] (M = Li, K, Rb, Cs; solv = TMEDA, THF, Et2O, or DME), was isolated and fully characterized. An X-ray structural investigation of the cerium imido complexes demonstrated the impact of the alkali metal counterions on the geometry of the [Ce?N(3,5-(CF3)2C6H3)(TriNOx)]- moiety. Substantial shortening of the Ce?N bond was observed with increasing size of the alkali metal cation. The first complex featuring an unsupported, terminal multiple bond between a Ce(IV) ion and a ligand fragment was also isolated by encapsulation of a Cs+ counterion with 2.2.2-cryptand. This complex shows the shortest recorded Ce?N bond length of 2.077(3) A. Computational investigation of the cerium imido complexes using DFT methods showed a relatively larger contribution of the cerium 5d orbital than the 4f orbital to the Ce?N bonds. The [K(DME)2][Ce?N(3,5-(CF3)2C6H3)(TriNOx)] complex cleaves the Si-O bond in (Me3Si)2O, yielding the [(Me3SiO)CeIV(TriNOx)] adduct. The reaction of the rubidium capped imido complex with benzophenone resulted in the formation of a rare Ce(IV)-oxo complex, that was stabilized by a supramolecular, tetrameric oligomerization of the Ce?O units with rubidium cations. PMID- 28076949 TI - Arsenic Methyltransferase is Involved in Arsenosugar Biosynthesis by Providing DMA. AB - Arsenic is an ubiquitous toxic element in the environment, and organisms have evolved different arsenic detoxification strategies. Studies on arsenic biotransformation mechanisms have mainly focused on arsenate (As(V)) reduction, arsenite (As(III)) oxidation, and arsenic methylation; little is known, however, about the pathway for the biosynthesis of arsenosugars, which are significant arsenic transformation products. Here, the involvement of As(III) S Adenosylmethionine methyltransferase (ArsM) in arsenosugar synthesis is demonstrated for the first time. Synechocystis sp. PCC 6803 incubated with As(III) or monomethylarsonic acid (MMA(V)) produced dimethylarsinic acid (DMA(V)) and arsenosugars, as determined by high performance liquid chromatography inductively coupled plasma mass spectrometry (HPLC/ICPMS). Arsenosugars were also detected in the cells when they were exposed to DMA(V). A mutant strain Synechocystis DeltaarsM was constructed by disrupting arsM in Synechocystis sp. PCC 6803. Methylation of arsenic species was not observed in the mutant strain after exposure to arsenite or MMA(V); when Synechocystis DeltaarsM was incubated with DMA(V), arsenosugars were detected in the cells. These results suggest that ArsM is a required enzyme for the methylation of inorganic arsenicals, but not required for the synthesis of arsenosugars from DMA, and that DMA is the precursor of arsenosugar biosynthesis. The findings will stimulate more studies on the biosynthesis of complex organoarsenicals, and lead to a better understanding of the bioavailability and function of the organoarsenicals in biological systems. PMID- 28076951 TI - Multiscale Study of Plasmonic Scattering and Light Trapping Effect in Silicon Nanowire Array Solar Cells. AB - Nanometallic structures that support surface plasmons provide new ways to confine light at deep-subwavelength scales. The effect of light scattering in nanowire array solar cells is studied by a multiscale approach combining classical electromagnetic (EM) and quantum mechanical simulations. A photovoltaic device is constructed by integrating a silicon nanowire array with a plasmonic silver nanosphere. The light scatterings by plasmonic element and nanowire array are obtained via classical EM simulations, while current-voltage characteristics and optical properties of the nanowire cells are evaluated quantum mechanically. We found that the power conversion efficiency (PCE) of photovoltaic device is substantially improved due to the local field enhancement of the plasmonic effect and light trapping by the nanowire array. In addition, we showed that there exists an optimal nanowire number density in terms of optical confinement and solar cell PCE. PMID- 28076950 TI - Single Amino Acid Variant Profiles of Subpopulations in the MCF-7 Breast Cancer Cell Line. AB - Cancers are initiated and developed from a small population of stem-like cells termed cancer stem cells (CSCs). There is heterogeneity among this CSC population that leads to multiple subpopulations with their own distinct biological features and protein expression. The protein expression and function may be impacted by amino acid variants that can occur largely due to single nucleotide changes. We have thus performed proteomic analysis of breast CSC subpopulations by mass spectrometry to study the presence of single amino acid variants (SAAVs) and their relation to breast cancer. We have used CSC markers to isolate pure breast CSC subpopulation fractions (ALDH+ and CD44+/CD24- cell populations) and the mature luminal cells (CD49f-EpCAM+) from the MCF-7 breast cancer cell line. By searching the Swiss-CanSAAVs database, 374 unique SAAVs were identified in total, where 27 are cancer-related SAAVs. 135 unique SAAVs were found in the CSC population compared with the mature luminal cells. The distribution of SAAVs detected in MCF-7 cells was compared with those predicted from the Swiss-CanSAAVs database, where we found distinct differences in the numbers of SAAVs detected relative to that expected from the Swiss-CanSAAVs database for several of the amino acids. PMID- 28076952 TI - Compactness of the Lithium Peroxide Thin Film Formed in Li-O2 Batteries and Its Link to the Charge Transport Mechanism: Insights from Stochastic Simulations. AB - We simulated the discharge process of Li-O2 batteries and the growth of Li2O2 thin films at the mesoscale with a novel kinetic Monte Carlo model, which combined a stochastic description of mass transport and detailed elementary reaction kinetics. The simulation results show that the ordering of the Li2O2 thin film is determined by the interplay between diffusion and reaction kinetics. Due to the fast reaction kinetics on the catalyst, the Li2O2 formed in the presence of catalyst (cat-CNF) shows a low degree of ordering and is more likely to be amorphous. Moreover, the mobility of the LiO2 ion pair, which depends largely on the nature of the electrolyte, also impacts the homogeneity of the compactness of the Li2O2 thin film. These results are of high importance for understanding the role of the catalyst and reaction kinetics in Li-O2 batteries. PMID- 28076953 TI - Effects of Lithium and Other Monovalent Ions on Palmitoyl Oleoyl Phosphatidylcholine Bilayer. AB - Interactions of monovalent salts with lipid membranes are explored with molecular dynamics (MD) simulations. The simulations included the monovalent ions Na+ and K+, for their importance in physiology, Li+ for its small size and importance in several medical conditions including bipolar disorder, and Rb+ for its large size. All simulations included Cl- as counterions. One bilayer was simulated without salt as a control. Palmitoyl oleoyl phosphatidylcholine (POPC) bilayers experienced reductions in area per lipid with the addition of salt; the smaller the ion the smaller the area, with the exception of Li+. Li+ exhibited unique binding affinities between phosphates and sn-2 carbonyls that lowered the order of the top part of sn-2 chain, which increased the area per lipid, compared to other ionic simulations. Further, we observe that monovalent salts alter bilayer properties through structural changes and not so much through the changes in surface potential. PMID- 28076954 TI - Identification of Genes Associated with Breast Cancer Metastasis to Bone on a Protein-Protein Interaction Network with a Shortest Path Algorithm. AB - Tumor metastasis is defined as the spread of tumor cells from one organ or part to another that is not directly connected to it, which significantly contributes to the progression and aggravation of tumorigenesis. Because it always involves multiple organs, the metastatic process is difficult to study in its entirety. Complete identification of the genes related to this process is an alternative way to study metastasis. In this study, we developed a computational method to identify such genes. To test our method, we selected breast cancer bone metastasis. A large network was constructed using human protein-protein interactions. On the basis of the validated genes related to breast and bone cancer, a shortest path algorithm was applied to the network to search for novel genes that may mediate breast cancer metastasis to bone. In addition, further rules constructed using the permutation FDR, the betweenness ratio, and the max min interaction score were also employed in the method to make the inferred genes more reliable. Eighteen putative genes were identified by the method and were extensively analyzed. The confirmation results indicate that these genes participate in metastasis. PMID- 28076955 TI - Post-translational Modifications of Trypanosoma cruzi Canonical and Variant Histones. AB - Chagas disease, caused by Trypanosoma cruzi, still affects millions of people around the world. No vaccines nor treatment for chronic Chagas disease are available, and chemotherapy for the acute phase is hindered by limited efficacy and severe side effects. The processes by which the parasite acquires infectivity and survives in different hosts involve tight regulation of gene expression, mainly post-transcriptionally. Nevertheless, chromatin structure/organization of trypanosomatids is similar to other eukaryotes, including histone variants and post-translational modifications. Emerging evidence suggests that epigenetic mechanisms also play an important role in the biology/pathogenesis of these parasites, making epigenetic targets suitable candidates to drug discovery. Here, we present the first comprehensive map of post-translational modifications of T. cruzi canonical and variant histones and show that its histone code can be as sophisticated as that of other eukaryotes. A total of 13 distinct modification types were identified, including rather novel and unusual ones such as alternative lysine acylations, serine/threonine acetylation, and N-terminal methylation. Some histone marks correlate to those described for other organisms, suggesting that similar regulatory mechanisms may be in place. Others, however, are unique to T. cruzi or to trypanosomatids as a group and might represent good candidates for the development of antiparasitic drugs. PMID- 28076956 TI - SBOLme: a Repository of SBOL Parts for Metabolic Engineering. AB - The Synthetic Biology Open Language (SBOL) is a community-driven open language to promote standardization in synthetic biology. To support the use of SBOL in metabolic engineering, we developed SBOLme, the first open-access repository of SBOL 2-compliant biochemical parts for a wide range of metabolic engineering applications. The URL of our repository is http://www.cbrc.kaust.edu.sa/sbolme . PMID- 28076958 TI - Editorial for January 2017 for JPC A/B/C. PMID- 28076957 TI - Collapse Precedes Folding in Denaturant-Dependent Assembly of Ubiquitin. AB - The folding of small protein ubiquitin (Ub), which plays an indispensable role in targeting proteins for degradation and DNA damage response, is complex. A number of experiments on Ub folding have reached differing conclusions regarding the relation between collapse and folding, and whether intermediates are populated. In order to resolve these vexing issues, we elucidate the denaturant-dependent thermodynamics and kinetics of Ub folding at low and neutral pH as a function of guanidinium chloride and urea using coarse-grained molecular simulations. The changes in the fraction of the folded Ub, and the radius of gyration (Rg) as a function of the denaturant concentration, [C], are in quantitative agreement with experiments. Under conditions used in experiments, Rg of the unfolded state at neutral pH changes only by ~17% as the [GdmCl] decreases from 6 to 0 M. We predict that the extent of compaction of the unfolded state increases as temperature decreases. A two-dimensional folding landscape as a function of Rg and a measure of similarity to the folded state reveals unambiguously that the native state assembly is preceded by collapse, as discovered in fast mixing experiments on several proteins. Analyses of the folding trajectories, under mildly denaturing conditions ([GdmCl] = 1.0 M or [Urea] = 1.0 M), shows that Ub folds by collision between preformed secondary structural elements involving kinetic intermediates that are primarily stabilized by long-range contacts. Our work explains the results of small angle X-ray scattering (SAXS) experiments on Ub quantitatively, and establishes that evolved globular proteins in the unfolded ensemble are poised to collapse as the solvent conditions for the biopolymer changes from good solvent to Theta-solvent like conditions on denaturant dilution. In the process, we explain the discrepancy between SAXS and single molecule fluorescent resonant energy transfer (smFRET) experiments, which have arrived at a contradicting conclusion concerning the collapse of polypeptide chains. PMID- 28076959 TI - Journal of Medicinal Chemistry, Technological Advances: Highlights 2015-2016. PMID- 28076960 TI - Editorial for January 2017 for JPC A/B/C. PMID- 28076961 TI - Total arch replacement through a median sternotomy for Kommerell's diverticulum. AB - Kommerell's diverticulum with a right aortic arch and aberrant left subclavian artery is a rare anomaly, and the optimal operative strategy has not yet been established. In particular, the approach to the diverticulum is controversial, with the greatest concern being whether or not to add a right thoracotomy to the median sternotomy for distal anastomosis. We successfully performed total arch replacement through a median sternotomy only, by referring to preoperative computed tomography. We think that if the aneurysm is in a shallow position from the tracheal bifurcation, total arch replacement is possible with a midline incision only. PMID- 28076962 TI - Role of post-mapping computed tomography in virtual-assisted lung mapping. AB - Background Virtual-assisted lung mapping is a novel bronchoscopic preoperative lung marking technique in which virtual bronchoscopy is used to predict the locations of multiple dye markings. Post-mapping computed tomography is performed to confirm the locations of the actual markings. This study aimed to examine the accuracy of marking locations predicted by virtual bronchoscopy and elucidate the role of post-mapping computed tomography. Methods Automated and manual virtual bronchoscopy was used to predict marking locations. After bronchoscopic dye marking under local anesthesia, computed tomography was performed to confirm the actual marking locations before surgery. Discrepancies between marking locations predicted by the different methods and the actual markings were examined on computed tomography images. Forty-three markings in 11 patients were analyzed. Results The average difference between the predicted and actual marking locations was 30 mm. There was no significant difference between the latest version of the automated virtual bronchoscopy system (30.7 +/- 17.2 mm) and manual virtual bronchoscopy (29.8 +/- 19.1 mm). The difference was significantly greater in the upper vs. lower lobes (37.1 +/- 20.1 vs. 23.0 +/- 6.8 mm, for automated virtual bronchoscopy; p < 0.01). Despite this discrepancy, all targeted lesions were successfully resected using 3-dimensional image guidance based on post-mapping computed tomography reflecting the actual marking locations. Conclusions Markings predicted by virtual bronchoscopy were dislocated from the actual markings by an average of 3 cm. However, surgery was accurately performed using post-mapping computed tomography guidance, demonstrating the indispensable role of post mapping computed tomography in virtual-assisted lung mapping. PMID- 28076963 TI - Long-term consequences of atrial fibrillation after aortic valve replacement. AB - Background Atrial fibrillation is a common complication after cardiac surgery, but the risk factors and long-term outcome after primary isolated aortic valve replacement remains to be clarified. Methods A single-center retrospective study was conducted on 157 patients who underwent first-time isolated aortic valve replacement between April 1999 and February 2015. Fifty-eight patients developed new-onset atrial fibrillation within 6 months postoperatively, and they were compared with patients who remained in sinus rhythm. Multivariate analyses, which incorporated the propensity score patient matching technique, were conducted to evaluate the long-term outcome of new-onset postoperative atrial fibrillation and identify patients at risk of developing this arrhythmia. Results At a mean follow up of 52.4 months (range 8.4-200.7 months), mortality was significantly higher in patients who developed atrial fibrillation compared to those who remained in sinus rhythm (2.8%/patient-year vs. 0.2%/patient-year, respectively; p < 0.05). Patients developing atrial fibrillation were also at an independently increased risk of stroke and readmission during follow-up. Risk analysis revealed that advanced age (>70 years) and absence of a postoperative beta-blocker were predictors of atrial fibrillation. Conclusions New-onset atrial fibrillation after first-time isolated aortic valve replacement correlated significantly with late morbidity and mortality. Advanced age and absence of a postoperative beta blocker may increase the incidence of atrial fibrillation. PMID- 28076964 TI - Trigeminal neuralgia - diagnosis and treatment. AB - Introduction Trigeminal neuralgia (TN) is characterized by touch-evoked unilateral brief shock-like paroxysmal pain in one or more divisions of the trigeminal nerve. In addition to the paroxysmal pain, some patients also have continuous pain. TN is divided into classical TN (CTN) and secondary TN (STN). Etiology and pathophysiology Demyelination of primary sensory trigeminal afferents in the root entry zone is the predominant pathophysiological mechanism. Most likely, demyelination paves the way for generation of ectopic impulses and ephaptic crosstalk. In a significant proportion of the patients, the demyelination is caused by a neurovascular conflict with morphological changes such as compression of the trigeminal root. However, there are also other unknown etiological factors, as only half of the CTN patients have morphological changes. STN is caused by multiple sclerosis or a space-occupying lesion affecting the trigeminal nerve. Differential diagnosis and treatment Important differential diagnoses include trigeminal autonomic cephalalgias, posttraumatic or postherpetic pain and other facial pains. First line treatment is prophylactic medication with sodium channel blockers, and second line treatment is neurosurgical intervention. Future perspectives Future studies should focus on genetics, unexplored etiological factors, sensory function, the neurosurgical outcome and complications, combination and neuromodulation treatment as well as development of new drugs with better tolerability. PMID- 28076965 TI - Predictors of burnout and health status in Samaritans' listening volunteers. AB - Samaritan listening volunteers provide emotional support to people in distress or suicidal. Samaritans' has high volunteer turnover, which may be due to burnout. This study evaluated the role of demographic and psychosocial factors in predicting Samaritans listening volunteers' burnout and health status. Samaritans' listening volunteers (n = 216) from seven branches across UK completed an online survey to assess their levels of burnout (emotional exhaustion, depersonalisation, personal accomplishment), subjective health status, coping, empathy and social support. Overall, listeners showed low levels of burnout and good health. Regression analysis revealed that higher emotional exhaustion was predicted by younger age and avoidant coping style; higher depersonalisation was predicted by lower empathy fantasy and higher avoidant coping style; lower personal accomplishment scores were predicted by higher empathy personal distress and worse health status was predicted by more hours per week spent on listening duties, lower social support and higher avoidant coping style. Overall, different factors influenced different facets of burnout. However, higher use of avoidant coping style consistently predicted higher burnout and worse health status, suggesting avoidant coping is an important target for intervention. PMID- 28076967 TI - Fine particulate matter on hospital admissions for acute exacerbation of chronic obstructive pulmonary disease in southwestern Taiwan during 2006-2012. AB - This study explored the effects of PM2.5 on hospital admissions (HAs) for acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in southwestern Taiwan. Data on HAs for AECOPD, pollutants, and meteorological variables were obtained from the National Health Insurance Research Database and Environmental Protection Administration. The relative risks (RRs) of HAs for AECOPD was estimated using the Quasi-Poisson generalized additive model. A total of 38,715 HAs for AECOPD were recorded. The average daily HAs for AECOPD and mean 24-h average level of PM2.5 were 15.2 and 38.8 ug/m3, respectively. For both single and multiple pollutant (adjusted for O3 and NO2) models, increased AECOPD admissions were significantly associated with PM2.5 during cold season, with the RRs for every 10 ug/m3 increase in PM2.5 being 1.02 (95% CI = 1.007-1.040) at lag 0-1 in single-pollutant, and 1.02 (95 % CI = 1.001-1.042) at lag 0 day in multiple pollutant model. People 65 years of age and older had higher risk of HAs for AECOPD after PM2.5 exposure. The RRs of PM2.5 on HAs for AECOPD were robust after adjusting for O3 and NO2. Findings reveal an association between PM2.5 and HAs for AECOPD in southwestern Taiwan, particularly during cold season. PMID- 28076966 TI - EVESOR, a model-based, multiparameter, Phase I trial to optimize the benefit/toxicity ratio of everolimus and sorafenib. AB - AIM: This novel multiparameter Phase I study aimed to optimize doses/dosing schedules of everolimus and sorafenib drug combination, based on modeling/simulation (NCT01932177). PATIENTS & METHODS: About 26 patients with solid tumors were treated in four different dosing schedules. Everolimus once daily + sorafenib twice daily were given continuously in arms A and B, and intermittently in arms C (alternating every other week) and D (everolimus continuous and sorafenib 3 days on/4 days off). RESULTS: Continuous schedules exhibited higher toxicity risks than intermittent schedules (64.1 vs 35.9%; p < 0.0001), and trends for lower disease control rates (80 vs 100%). No significant pharmacokinetic interaction was identified. CONCLUSION: Feasibility of EVESOR trial is demonstrated. Intermittent schedules might provide better tolerance and efficacy than continuous schedules. PMID- 28076968 TI - Influence of southwest monsoons in the Kashmir Valley, western Himalayas. AB - The regional climate of the Himalayas is predominated by the southwest monsoons and the western disturbances. The uplift of the Pir Panjal to its present height is believed to restrict the southwest monsoons from entering into the Kashmir Valley in the western Himalayas. In the present study, monthly precipitation samples were collected across the Kashmir Valley from June 2013 to May 2014 for delta18O and delta2H analyses to constrain the influence of southwest monsoons in the valley. Except in August, the precipitation is enriched in 18O and 2H from June to September and depleted from October to May. The sharp depletion of 18O in precipitation along with the decrease in d-excess in August confirm the maximum intrusion of southwest monsoons into the valley. A significant temperature - delta18O relationship was found during October and May (westerlies period) decreasing during June and September (southwest monsoon period). The local meteoric water line for the whole Kashmir Valley based on the precipitation weighted monthly samples is [Formula: see text] [Formula: see text]. Higher intercept of the regression equation suggested dominant contribution of precipitation from western disturbances. The study suggested that the southwest monsoons enter the Kashmir Valley from southwest through the mountainous passes. PMID- 28076969 TI - The Successful Immediate Neonatal Transition to Extrauterine Life. AB - PURPOSE: To define and describe the processes underlying the successful neonatal transition to extrauterine life and methods to assess the transition. METHOD: Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, Web of Science, and Google Scholar were searched using a combination of the key words neonate, neonatal, newborn, transition, respiratory OR pulmonary, cardiac, metabolic, pH, umbilical cord, and assessment. Articles in English and German were reviewed. The final sample of articles consisted of one randomized controlled trial, 30 observational studies using human neonates, one observational study using rabbit pups, one secondary analysis, three systematic reviews, and 23 review articles. MAJOR FINDINGS: The pertinent findings in regard to normal events in the respiratory, cardiovascular, and metabolic transitions are reviewed and summarized. We address the underlying factors necessary for the transition to extrauterine life, specify the consequences of a successful transition, and review common assessment approaches. CONCLUSION: Available evidence indicates that the successful immediate transition to extrauterine life should be completed within 1-3 hr after birth, though some adaptive processes can fail as late as 24-48 hr after birth. Further research is necessary to identify a feasible, easily used, noninvasive method to assess the status of a neonate's transition to extrauterine life. PMID- 28076970 TI - Future Directions for Work on Refinement of ADHD Assessment in Young Adults. AB - Sibley, Coxe, and Molina provide a thoughtful discussion of the implications of our study and highlight important future directions in this line of work. They helpfully amplify several themes that space did not allow discussion of in our article. In particular, they correctly emphasize the importance of theoretical as well as statistical considerations in model selection. We also agree that clinical tests of sensitivity and specificity, taking into account different base rates and types of samples, are essential before a final algorithm would be ready for dissemination. However, we are not convinced that such tests should be limited to populations of individuals with attention-deficit/hyperactivity disorder (ADHD). Rather, they should include those with and without diagnosed ADHD in order to provide comprehensive tests of reporter sensitivity and specificity across the entire continuum of ADHD symptomatology and in relation to different populations, including other disorders and typically developing populations. PMID- 28076971 TI - Corrigendum. AB - Mall NA, Buchowski J, Zebala L, Brophy RH, Wright RW, Matava MJ. Spine and axial skeleton injuries in the National Football League. Am J Sports Med. 2012;40(8):1755-1761. (Original DOI: 10.1177/0363546512448355). PMID- 28076972 TI - Society News and Announcements. PMID- 28076976 TI - Measuring Parenting Throughout Adolescence. AB - This study examined the structural validity of the parenting concept throughout adolescence. First, we examined whether an established five-dimension parenting model including support, proactive control, punitive control, harsh punitive control, and psychological control, showed longitudinal invariance across time (i.e., early, middle, and late adolescence) and measurement invariance across informants (i.e., mothers, fathers, and adolescents). Second, patterns of continuity and discontinuity in these dimensions were examined from the perspective of the different informants. In a four-wave accelerated longitudinal study with 1,111 adolescents and their parents, a multigroup structural equation modelling showed partial scalar invariance across adolescence and across informants. Subsequent growth modelling indicated that parenting was relatively stable over time and that similar patterns were present for mother, father, and adolescent ratings of parenting. Future research on associations between parenting and adolescent development can build on the findings of this study, given that comparing perspectives on parenting by different informants and over time seems to be valid. PMID- 28076974 TI - Topological Organization of Whole-Brain White Matter in HIV Infection. AB - Infection with human immunodeficiency virus (HIV) is associated with neuroimaging alterations. However, little is known about the topological organization of whole brain networks and the corresponding association with cognition. As such, we examined structural whole-brain white matter connectivity patterns and cognitive performance in 29 HIV+ young adults (mean age = 25.9) with limited or no HIV treatment history. HIV+ participants and demographically similar HIV- controls (n = 16) residing in South Africa underwent magnetic resonance imaging (MRI) and neuropsychological testing. Structural network models were constructed using diffusion MRI-based multifiber tractography and T1-weighted MRI-based regional gray matter segmentation. Global network measures included whole-brain structural integration, connection strength, and structural segregation. Cognition was measured using a neuropsychological global deficit score (GDS) as well as individual cognitive domains. Results revealed that HIV+ participants exhibited significant disruptions to whole-brain networks, characterized by weaker structural integration (characteristic path length and efficiency), connection strength, and structural segregation (clustering coefficient) than HIV- controls (p < 0.05). GDSs and performance on learning/recall tasks were negatively correlated with the clustering coefficient (p < 0.05) in HIV+ participants. Results from this study indicate disruption to brain network integrity in treatment-limited HIV+ young adults with corresponding abnormalities in cognitive performance. PMID- 28076977 TI - Combining Microfractures, Autologous Bone Graft, and Autologous Matrix-Induced Chondrogenesis for the Treatment of Juvenile Osteochondral Talar Lesions. AB - BACKGROUND: The purpose of this study was to evaluate the clinical and radiologic outcomes of patients younger than 20 years, treated with the arthroscopic-talus autologous matrix-induced chondrogenesis (AT-AMIC) technique and autologous bone graft for osteochondral lesion of the talus (OLT). METHODS: Eleven patients under 20 years (range 13.3-20.0) underwent the AT-AMIC procedure and autologous bone graft for OLTs. Patients were evaluated preoperatively (T0) and at 6 (T1), 12 (T2), and 24 (T3) months postoperatively, using the American Orthopaedic Foot & Ankle Society Ankle and Hindfoot (AOFAS) score, the visual analog scale and the SF-12 respectively in its Mental and Physical Component Scores. Radiologic assessment included computed tomographic (CT) scan, magnetic resonance imaging (MRI) and intraoperative measurement of the lesion. A multivariate statistical analysis was performed. RESULTS: Mean lesion size measured during surgery was 1.1 cm3 +/- 0.5 cm3. We found a significant difference in clinical and radiologic parameters with analysis of variance for repeated measures ( P < .001). All clinical scores significantly improved ( P < .05) from T0 to T3. Lesion area significantly reduced from 119.1 +/- 29.1 mm2 preoperatively to 77.9 +/- 15.8 mm2 ( P < .05) at final follow-up as assessed by CT, and from 132.2 +/- 31.3 mm2 to 85.3 +/- 14.5 mm2 ( P < .05) as assessed by MRI. Moreover, we noted an important correlation between intraoperative size of the lesion and body mass index (BMI) ( P = .011). CONCLUSIONS: The technique can be considered safe and effective with early good results in young patients. Moreover, we demonstrated a significant correlation between BMI and lesion size and a significant impact of OLTs on quality of life. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 28076978 TI - Abortion services at hospitals in Istanbul. AB - OBJECTIVE: Despite the existence of a liberal law on abortion in Turkey, there is growing evidence that actually securing an abortion in Istanbul may prove difficult. This study aimed to determine whether or not state hospitals and private hospitals that accept state health insurance in Istanbul are providing abortion services and for what indications. METHOD: Between October and December 2015, a mystery patient telephone survey of 154 hospitals, 43 public and 111 private, in Istanbul was conducted. RESULTS: 14% of the state hospitals in Istanbul perform abortions without restriction as to reason provided in the current law while 60% provide the service if there is a medical necessity. A quarter of state hospitals in Istanbul do not provide abortion services at all. 48.6% of private hospitals that accept the state health insurance also provide for abortion without restriction while 10% do not provide abortion services under any circumstances. KEY CONCLUSIONS: State and private hospitals in Istanbul are not providing abortion services to the full extent allowed under the law. The low numbers of state hospitals offering abortions without restriction indicates a de facto privatization of the service. This same trend is also visible in many private hospitals partnering with the state that do not provide abortion care. While many women may choose a private provider, the lack of provision of abortion care at state hospitals and those private hospitals working with the state leaves women little option but to purchase these services from private providers at some times subtantial costs. PMID- 28076979 TI - Strategies for identifying pulmonary sarcoidosis patients at risk for severe or chronic disease. AB - INTRODUCTION: Most of the morbidity and mortality resulting from pulmonary sarcoidosis relates to complications of fibrotic disease. Because the fibrosis related to pulmonary sarcoidosis is often of minimal clinical importance, pharmacotherapy is not mandated. However, a small fraction of pulmonary sarcoidosis patients develop significant lung fibrosis, and they could potentially benefit from anti-sarcoidosis therapy. A reliable algorithm to determine the likelihood of a pulmonary sarcoidosis patient developing fibrosis would minimize the toxicity of therapy and potentially prevent serious complications of the disease. Areas covered: The mechanisms of fibrosis in pulmonary sarcoidosis are discussed. Granulomatous inflammation is the major cause of fibrosis in pulmonary sarcoidosis. Known risk factors for the development of persistent and fibrotic sarcoidosis, including genetic risk factors are explored. Expert opinion/commentary: Currently, methods to determine the propensity of a pulmonary sarcoidosis to develop significant fibrosis are unreliable. This is an important unmet medical need. PMID- 28076980 TI - Status of sperm-born oocyte activating factors (PAWP, PLCzeta) and sperm chromatin in uncapacitated, capacitated and acrosome-reacted conditions. AB - The aim of this study was to investigate the value of sperm factors PAWP and PLCzeta involved in oocyte activation and sperm chromatin status, as indicators of sperm quality during uncapacitated, capacitated and acrosome-reacted conditions. Semen samples collected from 10 normozoospermic men and sperm factors PAWP, PLCzeta, protamine deficiency and DNA fragmentation evaluated in fresh samples, processed sample by DGC (density gradient centrifugation), capacitated and acrosome reacted sperm, using immunofluorescence and flow cytometry. The status of capacitation and the acrosome reaction were confirmed by tyrosine kinase phosphorylation and CD46 markers, respectively. The proportion of sperm expressing weak or zero levels of PLCzeta and PAWP were significantly reduced after DGC processing. There were no significant differences among processed DGC, capacitated and acrosome-reacted samples. The proportions of DNA fragmented and protamine-deficient spermatozoa were decreased after DGC and maintained during capacitation and the acrosome reaction. DGC processing, therefore, improved the quality of sperm in terms of chromatin and DNA integrity, and removed sperm which may have had a lower potential to induce oocyte activation and undergo capacitation and the acrosome reaction. PMID- 28076981 TI - Prenatal drainage of fetal urinoma with polyhydramnios: a case report and literature review. AB - The appearance of fetal urinoma is rare in prenatal care, especially when associated with polyhydramnions. Many previous reports have concluded that the visualization of a prenatal urinoma is probably a sign of underlying renal dysplasia or poor function. Thus, the management of the reported cases, conservative treatment or uniroma drainage, has not been unified. In this paper, we present two cases of prenatally detected urinoma with prenatal drainage to improve the prognosis. PMID- 28076982 TI - From Structure to Activity: Using Centrality Measures to Predict Neuronal Activity. AB - It is clear that the topological structure of a neural network somehow determines the activity of the neurons within it. In the present work, we ask to what extent it is possible to examine the structural features of a network and learn something about its activity? Specifically, we consider how the centrality (the importance of a node in a network) of a neuron correlates with its firing rate. To investigate, we apply an array of centrality measures, including In-Degree, Closeness, Betweenness, Eigenvector, Katz, PageRank, Hyperlink-Induced Topic Search (HITS) and NeuronRank to Leaky-Integrate and Fire neural networks with different connectivity schemes. We find that Katz centrality is the best predictor of firing rate given the network structure, with almost perfect correlation in all cases studied, which include purely excitatory and excitatory inhibitory networks, with either homogeneous connections or a small-world structure. We identify the properties of a network which will cause this correlation to hold. We argue that the reason Katz centrality correlates so highly with neuronal activity compared to other centrality measures is because it nicely captures disinhibition in neural networks. In addition, we argue that these theoretical findings are applicable to neuroscientists who apply centrality measures to functional brain networks, as well as offer a neurophysiological justification to high level cognitive models which use certain centrality measures. PMID- 28076983 TI - Multidimensional Family Therapy Reduces Self-Reported Criminality Among Adolescents With a Cannabis Use Disorder. AB - Multidimensional family therapy (MDFT) is an established treatment program for youth displaying multiproblem behavior. We examined whether MDFT decreased criminal offending among cannabis abusing adolescents, as compared with individual psychotherapy (IP). In a Western European randomized controlled trial comparing MDFT with IP, a sample of 169 adolescents with a cannabis disorder completed self-reports on criminal offending. Half indicated they had committed one or more criminal offenses in the 90 days before the baseline assessment. Follow-up assessments were at 6 and 12 months after randomization. The proportion of adolescents reporting nondelinquency increased during the study period, most so in the MDFT condition. In addition, MDFT lowered the number of violent offenses more than IP. This difference was not seen for property crimes. In cannabis abusing adolescents, MDFT is an effective treatment to prevent and reduce criminal offending. MDFT outperforms IP for violent crimes. PMID- 28076984 TI - Percutaneous endoscopic gastrostomy, body weight loss and survival in amyotrophic lateral sclerosis: a population-based registry study. AB - OBJECTIVE: To assess the role of percutaneous endoscopic gastrostomy (PEG) insertion, and its timing, on ALS survival, and to study prognostic factors of survival before and after PEG placement in a population-based setting. METHODS: In this observational population-based, registry study, we enrolled patients with newly- diagnosed ALS, according to the El Escorial revised criteria, who were resident in the Emilia Romagna Region, and who developed severe dysphagia needing enteral nutritional support. The primary outcome measure was tracheostomy-free survival after PEG recommendation. RESULTS: There were 210 patients needing PEG, out of an incident cohort of 545 patients from the Emilia Romagna Registry for ALS, who were diagnosed between 2009 and 2013. One hundred and ninety-three patients were included in the study, and 17 were excluded because they were already tracheostomized at the time of PEG placement. Of the 193 patients included in the study, 152 underwent PEG, whereas 41 did not undergo the procedure. Patients who did not undergo PEG, among the eligible ones, had the same tracheostomy-free survival from onset as patients who did (25 vs. 32 months, p = 0.21). Tracheostomy-free survival from PEG recommendation was greater in patients who underwent PEG placement than in patients who did not (6 vs. 2 months, p = 0.008). Median tracheostomy-free survival from PEG insertion was eight months (95% CI5-12); 30 days after PEG placement, survival was 89.60%. At Cox multivariable analysis, the hazard of death or tracheostomy after PEG insertion was significantly influenced by the difference between BMI at the time of the PEG procedure and BMI at diagnosis (HR 1.05, 95% CI 1.02-1.08; p = 0.002). The hazard of death or tracheostomy was not affected by the timing of PEG insertion. CONCLUSIONS: The present study, although it has some limitations, suggests a gain of tracheostomy-free survival from the time of PEG recommendation for patients who undergo PEG placement, and, among patients who undergo PEG, a greater survival if PEG is inserted before a significant weight loss occurs, and if nutritional support avoids further weight loss. Should this association between prevention of weight loss and better clinical outcome be confirmed by further studies, it would have important implications for disease management. PMID- 28076985 TI - Two new diketopiperazines from the tin mine tailings-derived fungus Schizophyllum commune YIM DT 10058. AB - Two new diketopiperazines, named diphenylalazine C (1) and epicoccin U (2), together with six known compounds (3-8) were isolated from the EtOAc extract of the fermentation broth of the tin mine tailings-derived fungus Schizophyllum commune YIM DT 10058. Their structures were elucidated by detailed analysis of spectroscopic data and comparison with related known compounds. Compounds 1 and 2 exhibited weak antibacterial and cytotoxic activities. PMID- 28076986 TI - Utilising exhaled nitric oxide information to enhance diagnosis and therapy of respiratory disease - current evidence for clinical practice and proposals to improve the methodology. AB - INTRODUCTION: A non-invasive tool to diagnose respiratory diseases and to follow treatment has long been looked-for. Exhaled nitric oxide (NO) is a promising marker of inflammation in asthma but nearly 25-years of research has shown that it works in only certain endotypes of asthma. The modelling of NO dynamics of the lung can give more information than a single FENO value. Areas covered: The estimation of the NO production in the conducting airways and in the gas exchange area has given new insight of the NO production in diseases beyond asthma. In this article, we discuss the importance of methodology for NO measurement in the exhaled breath and the indication of applying this technique to detect respiratory disorders. This narrative review is an attempt to examine and discuss the physiological basis underlying exhaled NO measurements and the clinical evidence of the usefulness of this method in asthma and various other respiratory disorders. Expert commentary: Estimation of the NO parameters would aid in our understanding of the NO dynamics of the lung and thereby give more knowledge how to interpret the measured FENO value in clinical practice. PMID- 28076987 TI - Antioxidant activity and cholinesterase inhibition studies of four flavouring herbs from Alentejo. AB - Essential oils (EOs) and aqueous extracts of aerial parts of four aromatic species, Calamintha nepeta, Foeniculum vulgare, Mentha spicata and Thymus mastichina, from southwest of Portugal were characterised chemically and analysed in order to evaluate their antioxidant potential and cholinesterase inhibitory activities. The main components of EOs were oxygenated monoterpenes, and aqueous extracts were rich in phenol and flavonoid compounds. EOs and aqueous extracts presented a high antioxidant potential, with ability to protect the lipid substrate, free radical scavenging and iron reducing power. Furthermore, EOs and extracts showed AChE and BChE inhibitory activities higher than rivastigmine, the standard drug. Results suggested the potential use of EOs and aqueous extracts of these flavouring herbs as nutraceutical or pharmaceutical preparations to minimise the oxidative stress and the progression of degenerative diseases. PMID- 28076988 TI - Ischemic stroke risk in East Asian patients with CHA2DS2-VASc score of 1: systematic review and meta-analysis. AB - BACKGROUND: The use of anticoagulation for stroke prevention in patients with atrial fibrillation (AF) and CHA2DS2-VASc score of 1 has been debated, partially due to limited data on ischemic stroke risk and specific clinical trials in these patients. East Asian patients have a different stroke risk profile compared to non-East Asians. We performed a systematic review and meta-analysis of ischemic stroke risk in AF patients with a CHA2DS2-VASc score of 1 in East Asian countries. METHODS: A comprehensive literature search for studies evaluating ischemic stroke risk related with AF with CHA2DS2-VASc score of 1 was conducted by two reviewers. We used a fixed-effect model first, then a random-effect model if heterogeneity was assessed with I2. RESULTS: After pooling 6 studies, the annual rate of ischemic stroke in East Asian patients with AF and a CHA2DS2-VASc score of 1 was 1.66% (95% CI: 0.71%-2.61%, I2 = 98.4%). There was a wide range in reported pooled rates between countries, from 0.59% to 3.13%. Significant difference existed not only in the community-based studies (Chinese: 2.10% vs. Japanese: 0.60%), but also from the hospital-based studies (Chinese: 3.55% vs. Japanese: 0.42%). Confining the analysis to those on no antithrombotic treatment had limited effect on the summary estimate (eg. Chinese: 4.28% vs. Japanese: 0.6%). In Chinese studies, ischemic stroke rate was lower in females than males (female: 1.40% vs. male: 1.79%). However, the low event rate in Japanese studies may reflect unrecorded anticoagulation status at follow-up. CONCLUSIONS: Some regional differences between East Asian countries were observed for ischemic stroke risk in patients with a CHA2DS2-VASc score of 1. This may reflect methodological differences in studies and unrecorded anticoagulation use at followup, but further prospective studies are required to ascertain ischemic stroke risks, as well as the differences and reasons for this between East Asians and non-East Asians. PMID- 28076989 TI - Improvement of patient eligibility with the use of new generation endografts for the treatment of abdominal aortic aneurysms. A comparison study among currently used endografts and literature review. AB - BACKGROUND: Newer generation devices have attempted to accommodate a wider range of aortoiliac anatomies offering endovascular aneurysm repair (EVAR) to more patients with abdominal aortic aneurysms (AAAs). We aim to examine the anatomic suitability for the ultra-low profile Ovation endograft in our AAA patients and to compare them with other contemporary devices. METHODS: 158 consecutive AAA patients treated with EVAR or open surgical repair (OSR) were tested for EVAR eligibility according to the most commonly used endografts' instructions for use. RESULTS: 106 patients underwent EVAR and 52 OSR. EVAR eligibility was higher for the Ovation system (72%) compared to the rest of the devices (Incraft: 63%, Nellix: 60%, Endurant-II: 59%, Excluder: 55%, Zenith-Flex: 36%, Aorfix: 35%, P value<0.001). Non-suitable proximal neck anatomy followed by access vessel inadequacy were the primary reasons for ineligibility. CONCLUSION: New generation aortic endografts with innovative proximal sealing mechanisms and ultra-low profile delivery systems are increasing patient eligibility for EVAR. PMID- 28076990 TI - Outcomes in the absence of the ductus venosus diagnosed in the first trimester. AB - PURPOSE: To clarify the outcomes of the absence of the ductus venosus (DV) diagnosed in fetuses suspected to have a structural abnormality during a morphological assessment in the first trimester. METHODS: Infants in whom ultrasound fetal morphological assessments were attempted in the first trimester (11 to 13-6 weeks of gestation) and who were subsequently delivered between 2013 and 2015 at Showa University Hospital were enrolled. In cases in which the absence of the DV was diagnosed in the first trimester, the prognosis was assessed. RESULTS: First-trimester ultrasound screening was performed in a total of 2610 cases between 2013 and 2015. Fetal edema (n = 38), hydrops (n = 16), abnormal four-chamber view findings (n = 2), and tricuspid regurgitation (n = 1) were observed in a total of 52 cases (2.0%). In 4 of the 52 cases with abnormal ultrasound findings, the absence of the DV was detected. CONCLUSION: If fetal edema or hydrops in early pregnancy is found without any other structural abnormalities, not only chromosomal abnormalities should be suspected but also an evaluation for the absence of the DV should be included. In addition, absence of the DV with fetal edema may be associated with the outcomes of cardiac dysfunction, chromosome abnormalities, and intrauterine sudden death. Severe fetal edema is associated with a poor prognosis, and the family must be carefully informed of the potential outcomes. PMID- 28076991 TI - Type-2 diabetes mellitus: does prenatal care affect outcomes? AB - OBJECTIVE: To determine if prenatal care affects adverse perinatal outcomes in pregnant women with Type-2 diabetes mellitus (T2DM). STUDY DESIGN: This was a retrospective cohort study of pregnant women with pregestational diabetes mellitus pregnancies in the state of California between 1997 and 2006, using vital statistics data linked to birth certificates. Women were stratified by time of presentation to care and we compared those who presented in the first trimester, third trimester, and those who had no prenatal care prior to delivery. Perinatal outcomes looked at included: preeclampsia, macrosomia, preterm delivery, cesarean delivery, and intrauterine fetal demise (IUFD). The two groups were compared with chi-squared testing to determine statistical significance. RESULTS: In women with pregestational diabetes those who presented at time of delivery had an 11.3% risk of IUFD compared to 0.9% in those who presented in the first trimester. There was also an increased rate of preterm birth in the late presentation cohort (29.4% at time of delivery versus 21.0% in the first trimester). After adjusting for possible confounding variables using logistic regression models, rates of IUFD and preterm delivery were still found to be statistically significant with adjusted odds ratios of 11.37 (95% CI: 6.10-21.16) and 1.55 (95% CI: 1.03-2.32), respectively. There were no differences in rates of macrosomia or preeclampsia between the three cohorts. CONCLUSIONS: Treatment of T2DM throughout pregnancy leads to improved maternal and neonatal outcomes. PMID- 28076992 TI - The issue of delivery room infections in the Italian law. A brief comparative study with English and French jurisprudence. AB - Delivery room infections are frequent, and many of them could be avoided through higher standards of care. The authors examine this issue by comparing it to English and French reality. Unlike England, in Italy and France the relationship established between health facility, physician and patient is outlined in a contract. In England, the judges' decisions converge toward a better and higher protection of the patient-the actor-and facilitate the probative task. In case of infections, including those occurring in the delivery room, three issues are evaluated: the hospital's negligent conduct, damages if any and causal nexus. Therefore, the hospital must demonstrate to have taken the appropriate asepsis measures according to current scientific knowledge concerning not only treatment, but also diagnosis, previous activities, surgery and post-surgery. In order to avoid a negative sentence, both physicians and hospital have to demonstrate their correct behavior and that the infection was caused by an unforeseeable event. The authors examine the most significant rulings by the Courts and the Supreme Court. They show that hospitals can avoid being accused of negligence and recklessness only if they can demonstrate to have implemented all the preventive measures provided for in the guidelines or protocols. PMID- 28076993 TI - Evaluation of clinical and serological findings for diagnosis of cutaneous anthrax infection after an outbreak. AB - PURPOSE: Anthrax, caused by the bacterium Bacillus anthracis, is one of the oldest documented infectious diseases in both livestock and humans. We aimed to evaluate clinical findings and risk factors of patients with cutaneous anthrax infection and report anti-lethal factor (LF) IgG and anti-protective antigen (PA) IgG titers in the serologic diagnosis of disease. METHODS: In this study, serum samples of 18 cutaneous anthrax patients were collected and anti-LF IgG and anti PA IgG titers were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Twelve (67%) males and 6 (33%) females, with a mean age of 36.06 +/- 16.58 years were included in the study. Risk factors identified in the patient population studied were slaughtering (28%), flaying (56%), chopping meat (67%), burying diseased animal corpses (17%) and milking (6%) livestock. Black eschar formation (94%), pruritus (78%) and painful lymphadenopathy (61%) were first three common clinical signs and symptoms, respectively. Fourteen (78%) patients produced a positive IgG response against PA, 11 (61%) patients produced against LF. Three (17%) patients had no response to either antigen. CONCLUSIONS: A detailed history of contact with sick animals or animal products along with clinical findings should be taken at the first step for the diagnosis of cutaneous anthrax infection. Serologic detection of anti-LF IgG and anti-PA IgG with ELISA may be useful auxillary method for establishing the diagnosis. PMID- 28076994 TI - Adapted dexamethasone delivery polyethylene oxide and poly(E-caprolactone) construct promote mesenchymal stem cells chondrogenesis. AB - Issues associated with tissue transplantation and shortage of donors has always been a concern, whereas tissue engineering has provided the hopeful opportunities. The aim of this study was to investigate the chondrogenic differentiation potential of mesenchymal stem cells (MSCs) in the presence of embedded Dexamethasone into electrospun Poly(ethyleneoxide) nanofibers composited with Poly(E-caprolactone) nanofibers. Electrospun-fabricated scaffolds were characterized by SEM, tensile, contact angle, release profile, MTT assay, and chonderogenic differentiation of stem cells. Results demonstrated Poly(E caprolactone) properties improved by composite with a Poly(ethyleneoxide). Overall, stem cells seeded on nanofibers content drug showed highest chondrogenic potential in comparison to the other groups. PMID- 28076995 TI - Biosurfactants in cosmetic formulations: trends and challenges. AB - Cosmetic products play an essential role in everyone's life. People everyday use a large variety of cosmetic products such as soap, shampoo, toothpaste, deodorant, skin care, perfume, make-up, among others. The cosmetic industry encompasses several environmental, social and economic impacts that are being addressed through the search for more efficient manufacturing techniques, the reduction of waste and emissions and the promotion of personal hygiene, contributing to an improvement of public health and at the same time providing employment opportunities. The current trend among consumers is the pursuit for natural ingredients in cosmetic products, as many of these products exhibit equal, better or additional benefits in comparison with the chemical-based products. In this sense, biosurfactants are natural compounds with great potential in the formulation of cosmetic products given by their biodegradability and impact in health. Indeed, many of these biosurfactants could exhibit a "prebiotic" character. This review covers the current state-of-the-art of biosurfactant research for cosmetic purposes and further discusses the future challenges for cosmetic applications. PMID- 28076996 TI - A serious case of anthrax associated with compartment syndrome. AB - Compartment syndrome linked to skin anthrax is a rare complication that may develop and it should be noted that the disease may progress in spite of medical drug treatment. Our case was a farmer who was exposed after slaughtering a dead animal, a time delay for treatment hided this history and then developed compartment syndrome. In anthrax cases with delayed treatment and aggressive progression, circulation in the extremities should be carefully noted. We believe that the cases with compartment syndrome progressing in spite of medical drug treatment may be assessed for fasciotomy as a treatment approach. PMID- 28076997 TI - Surgical treatment of severe multilevel circumferential compressive myelopathy of the cervical spine: is circumferential procedure necessary? AB - OBJECTIVE: To determine the necessity of circumferential decompression and fusion in patients with severe multilevel cervical spondylotic myelopathy with circumferential cord compression. METHODS: This prospective study involved 51 patients with severe multilevel circumferential cervical myelopathy underwent two stage circumferential procedure between July 2008 and June 2010. VAS scores, satisfaction surveys and JOA scores and imaging studies were obtained. Twenty three patients (45.1%) underwent two-stage surgery (group A); the other 28 patients (54.9%) were satisfied with the outcomes after first-stage surgery, and the second-stage surgery was avoided (group B). Age, sex and symptom duration did not differ between the groups. RESULTS: Patients were followed up for 3-5 years (mean, 42.5 months). In group A, VAS and JOA scores significantly improved from 63.3 and 7.9 to 38.3 and 10.4, respectively, at 3 months after the first-stage operation and 10.2 and 12.7, respectively, at 3 months after the second-stage operation. In group B, the VAS and JOA scores significantly improved from 62.7 and 7.9 to 31.1 and 11.2 respectively, at 3 months and 18.2 and 12.4, respectively at 6 months. Patient satisfaction rate significantly increased from 43.5% after the first-stage operation to 82.6% after the second-stage operation in group A. In group B, this rate was 89.3%. In group A, cervical spine lordosis increased from 12.8 degrees preoperatively to 18.5 degrees (p < .0001) and 19.1 degrees (p > .05) at 3 months after the first-stage and second-stage operations, respectively. In group B, lordosis significantly increased from 12.5 degrees preoperatively to 18.8 degrees at 3 months. The total complication rate did not significantly differ from the rates after a single surgery (either anterior or posterior). CONCLUSION: Only 45.1% patients required surgery via both approaches. Therefore, a two-stage procedure is a rational choice and safe procedure. If outcomes are unsatisfactory after the first-stage operation, a second-stage operation can be performed. PMID- 28076998 TI - Phosphate, phytate and phytases in plants: from fundamental knowledge gained in Arabidopsis to potential biotechnological applications in wheat. AB - Phosphorus (P) is an essential macronutrient for all living organisms. In plants, P is taken up from the rhizosphere by the roots mainly as inorganic phosphate (Pi), which is required in large and sufficient quantities to maximize crop yields. In today's agricultural society, crop yield is mostly ensured by the excessive use of Pi fertilizers, a costly practice neither eco-friendly or sustainable. Therefore, generating plants with improved P use efficiency (PUE) is of major interest. Among the various strategies employed to date, attempts to engineer genetically modified crops with improved capacity to utilize phytate (PA), the largest soil P form and unfortunately not taken up by plants, remains a key challenge. To meet these challenges, we need a better understanding of the mechanisms regulating Pi sensing, signaling, transport and storage in plants. In this review, we summarize the current knowledge on these aspects, which are mainly gained from investigations conducted in Arabidopsis thaliana, and we extended it to those available on an economically important crop, wheat. Strategies to enhance the PA use, through the use of bacterial or fungal phytases and other attempts of reducing seed PA levels, are also discussed. We critically review these data in terms of their potential for use as a technology for genetic manipulation of PUE in wheat, which would be both economically and environmentally beneficial. PMID- 28077000 TI - Specificity rates for non-clinical, bilingual, Mexican Americans on three popular performance validity measures. AB - OBJECTIVE: To measure specificity as failure rates for non-clinical, bilingual, Mexican Americans on three popular performance validity measures: (a) the language format Reliable Digit Span; (b) visual-perceptual format Test of Memory Malingering; and (c) visual-perceptual format Dot Counting, using optimal/suboptimal effort cut scores developed for monolingual, English-speakers. METHODS: Participants were 61 consecutive referrals, aged between 18 and 65 years, with <16 years of education who were subjectively bilingual (confirmed via formal assessment) and chose the language of assessment, Spanish or English, for the performance validity tests. RESULTS: Failure rates were 38% for Reliable Digit Span, 3% for the Test of Memory Malingering, and 7% for Dot Counting. For Reliable Digit Span, the failure rates for Spanish (46%) and English (31%) languages of administration did not differ significantly. CONCLUSIONS: Optimal/suboptimal effort cut scores derived for monolingual English-speakers can be used with Spanish/English bilinguals when using the visual-perceptual format Test of Memory Malingering and Dot Counting. The high failure rate for Reliable Digit Span suggests it should not be used as a performance validity measure with Spanish/English bilinguals, irrespective of the language of test administration, Spanish or English. PMID- 28076999 TI - Iridoids and anti-inflammatory properties of n-butanol extract of Linaria tingitana Boiss. & Reut. AB - The analysis of the n-butanol extract of Linaria tingitana (BELT) by HPLC-DAD ESI/MS allowed the identification of four iridoids structurally confirmed by NMR and ESI-MS/MS extensive experiments data. The subjection of BELT to the anti inflammatory activity showed that it exhibited a concentration dependent stabilisation of HRBC membrane, inhibition of protein denaturation and nitric oxide scavenging effect in the in vitro process. These results were confirmed in the in vivo experiments which showed that BELT was found to be most pronounced at 200 mg/kg after carrageenan injection which significantly reduced the swelling in both early and late phases of carrageenan-evoked oedema, as well as a significant reduce at the accumulation of infiltrating cells, inhibition of the myeloperoxidase activity and suppressed the lipid peroxidation. These results were supported by the histological analysis which revealed the reduction of oedema and cells infiltration, this might be influenced by the synergistic action of the above isolated compounds. PMID- 28077001 TI - Non-visualized aorta in abdominal aortic aneurysm screening: Screening outcomes and the influence of subject and programme characteristics. AB - Objectives To compare abdominal aortic aneurysm screening outcomes of men with non-visualized aorta at original scan with subsequent scans and to determine predictors of non-visualized aorta. Methods In the Northern Ireland Abdominal Aortic Aneurysm screening programme, outcomes (discharge, annual surveillance, three-monthly surveillance, or vascular referral) and patient and programme characteristics (age, deprivation quintile, family history, technician experience, and screening location) for men with non-visualized aorta were investigated at original scan, and first and second rescans. Results Non visualized aorta proportions were 2.9, 11.4, and 4.7% at original, first, and second rescan, respectively. There were no differences in screening outcomes between scanning stages (98.4, 97.6, and 97.4% <3 cm). There were 42 men (0.13%) with aortas >=5.5 cm at original scan, but none at first and second rescan. A significantly greater proportion with non-visualized aorta were from more deprived (5.0%) than less deprived areas (1.7%). Deprivation quintile and staff role were significant independent non-visualized aorta predictors at original scan, and staff role at first rescan. Men from less deprived areas were three times as likely to have aortas visualized than those from more deprived areas (OR = 3.0, CI = 2.4-3.8) at original scan. A man scanned by screening technician compared with lead sonographer was 51% less likely to have aorta visualized at original scan and 94% less likely at first rescan. Conclusions The risk of abdominal aortic aneurysm in men with non-visualized aorta on first or subsequent rescans is no more than for those with visualized aorta on original scanning. Men from deprived areas are much more likely to have non-visualized aorta at original scan. PMID- 28077002 TI - Pupil size behavior during online processing of sentences. AB - In the present work we analyzed the pupil size behavior of 40 subjects while they read well-defined sentences with different contextual predictability (i.e., regular sentences and proverbs). In general, pupil size increased when reading regular sentences, but when readers realized that they were reading proverbs their pupils strongly increase until finishing proverbs' reading. Our results suggest that an increased pupil size is not limited to cognitive load (i.e., relative difficulty in processing) because when participants accurately recognized words during reading proverbs, theirs pupil size increased too. Our results show that pupil size dynamics may be a reliable measure to investigate the cognitive processes involved in sentence processing and memory functioning. PMID- 28077003 TI - Influence of extrinsic inputs and synaptic gains on dynamics of Wendling's neural mass model: A bifurcation analysis. AB - We analyze the neurodynamics attributed by a model proposed by Wendling and co workers (2002) [Wendling, F., Bartolomei, F., Bellanger, J.J. & Chauvel, P. (2002) Epileptic fast activity can be explained by a model of impaired GABAergic dendritic inhibition. Eur. J. Neurosci., 15, 1499.] to explain several different types of electroencephalographic activities. We could find three principal types of steady states when the system parameters change slowly: (i) the model produce a constant output when it is under a state of stable equilibrium point with a constant input. If a small perturbation is introduced (e.g., noisy input), the output changes into noise without oscillatory components, which is related to the normal background activity or low-voltage rapid activity, (ii) Hopf bifurcations lead to stable limit cycles, which we call Hopf cycles. The model generates a rhythmic oscillating output when it is under a state of Hopf cycles, which is related to slow rhythmic activity or slow quasi-sinusoidal activity, (iii) global bifurcations lead to homoclinic limit cycles that appear suddenly at high amplitude, which we call spike cycles. In general, the spike cycles are not harmonic but they have a spike-like appearance (anharmonic oscillation). The model produces a spike-like output when it is under a state of spike cycles, which is related to the sustained discharge of spikes. Finally, the bifurcation analysis demonstrates the influence of the interaction between the excitatory and inhibitory synaptic gains on the dynamics. PMID- 28077005 TI - Corrigendum. PMID- 28077004 TI - Endoplasmic Reticulum Stress Modulation as a Target for Ameliorating Effects of Blast Induced Traumatic Brain Injury. AB - Blast traumatic brain injury (bTBI) has been shown to contribute to progressive neurodegenerative disease. Recent evidence suggests that endoplasmic reticulum (ER) stress is a mechanistic link between acute neurotrauma and progressive tauopathy. We propose that ER stress contributes to extensive behavioral changes associated with a chronic traumatic encephalopathy (CTE)-like phenotype. Targeting ER stress is a promising option for the treatment of neurotrauma related neurodegeneration, which warrants investigation. Utilizing our validated and clinically relevant Sprague-Dawley blast model, we investigated a time course of mechanistic changes that occur following bTBI (50 psi) including: ER stress activation, iron-mediated toxicity, and tauopathy via Western blot and immunohistochemistry. These changes were associated with behavioral alterations measured by the Elevated Plus Maze (EPM), Forced Swim Test (FST), and Morris Water Maze (MWM). Following characterization, salubrinal, an ER stress modulator, was given at a concentration of 1 mg/kg post-blast, and its mechanism of action was determined in vitro. bTBI significantly increased markers of injury in the cortex of the left hemisphere: p-PERK and p-eIF2alpha at 30 min, p-T205 tau at 6 h, and iron at 24 h. bTBI animals spent more time immobile on the FST at 72 h and more time in the open arm of the EPM at 7 days. Further, bTBI caused a significant learning disruption measured with MWM at 21 days post-blast, with persistent tau changes. Salubrinal successfully reduced ER stress markers in vivo and in vitro while significantly improving performance on the EPM. bTBI causes robust biochemical changes that contribute to neurodegeneration, but these changes may be targeted with ER stress modulators. PMID- 28077006 TI - Longitudinal Assessment of Health-Related Quality of Life following Adolescent Sports-Related Concussion. AB - To examine initial and longitudinal health-related quality of life (HRQOL) in adolescent sports-related concussion (SRC) patients, a prospective observational case-series study was conducted among adolescent SRC patients who were evaluated at a multi-disciplinary pediatric concussion program. Health-related quality of life was measured using the child self-report Pediatric Quality of Life Inventory (PedsQL) generic score scale (age 13-18 version) and the PedsQL Cognitive Functioning scale. Initial and longitudinal HRQOL outcomes were compared between patients who did and did not develop post-concussion syndrome (PCS). A total of 63 patients met the inclusion criteria during the study period. The mean age of the cohort was 14.57 years (standard deviation, 1.17) and 61.9% were male. The median time from injury to initial consultation was 6.5 days (interquartile range, 5, 11). At initial consultation, impairments in physical and cognitive HRQOL but not social or emotional HRQOL were observed. Initial symptom burden and length of recovery were associated with greater impairment in physical and cognitive HRQOL. Patients who went on to develop PCS had significantly worse physical and cognitive HRQOL at initial consultation and demonstrated a slower rate of recovery in these domains, compared with those who recovered in less than 30 days. Adolescent SRC was associated with HRQOL impairments that correlated with clinical outcomes. No persistent impairments in HRQOL were detected among patients who achieved physician-documented clinical recovery. Future studies are needed to evaluate the clinical utility of HRQOL measurement in the longitudinal management of adolescent SRC and PCS patients. PMID- 28077007 TI - Accurate and fast urinalysis in febrile patients by flow cytometry. AB - BACKGROUND: The urine culture is worldwide accepted as the gold standard in diagnosing urinary tract infections, but is time consuming and costly, other methods are fast but moderately reliable. We investigated whether counting the number of bacteria by flow cytometry could be a fast and accurate method to analyze urine samples in febrile patients at the emergency department (ED). METHODS: Urine samples were obtained from 140 febrile patients at the ED. Urinalysis was performed according to standard procedures. Flow cytometric analysis for bacteria was performed with the Accuri C6 flow cytometer. Diagnostic values were determined at various cut-off points by using urine culture as the gold standard. RESULTS: The highest diagnostic accuracy of urinalysis of bacteria was obtained with flow cytometric analysis (AUC of 0.96). The best cut-off value for bacteria counted by flow cytometry based on the ROC-curve was 3.72 * 106 bacteria/mL, this resulted in a sensitivity of 94.7% and a specificity of 88.2%. CONCLUSIONS: Counting bacteria by flow cytometry has the highest diagnostic accuracy and is superior to other methods in urinalysis in febrile patients in the ED when using urine culture as the gold standard. PMID- 28077008 TI - Is decreasing mortality in total hip and knee arthroplasty patients dependent on patients' comorbidity? AB - Background and purpose - Mortality after primary total hip and knee arthroplasty (THA and TKA) has declined, and the proportion of THA and TKA patients with comorbid conditions has increased. We therefore wanted to examine changes in comorbidity burden over time and the impact of comorbid on mortality following primary total hip and knee arthroplasty in patients with osteoarthritis. Patients and methods - We used the Danish arthroplasty registers to identify THA and TKA patients from 1996 through 2013. From administrative databases, we collected data on pre-surgery hospital history for all patients, which were used to calculate the Charlson comorbidity index (CCI). Patients were divided into 4 groups: CCI none, CCI-low, CCI-moderate, and CCI-high. We calculated the relative risk (RR) of mortality within 90 days after surgery with a 95% confidence interval (CI), with stratification according to CCI group and year of surgery. Results - 99,962 THAs and 63,718 TKAs were included. The proportion of THAs with comorbidity increased by 3-4% in CCI-low, CCI-moderate, and CCI-high patients, from 1996-1999 to 2010-2013. The overall 90-day mortality risk declined for both procedures. Compared to CCI-none, THA patients with low, moderate, and high comorbidity burdens had an RR of 90-day mortality of 1.9 (95% CI: 1.6-2.4), 1.9 (CI: 1.5 2.5), and 3.3 (CI: 2.6-4.2), respectively. Similar increases in proportions and RRs were observed in TKAs. Interpretation - Despite the fact that the proportion of THA and TKA patients with comorbidities has increased over the past 18 years, the overall mortality has declined. The mortality risk depended on the comorbidity burden and did not decline during the study period for THA and TKA patients with a moderate or high comorbidity burden at the time of surgery. PMID- 28077009 TI - Cognitive Decline, Body Mass Index, and Waist Circumference in Community-Dwelling Elderly Participants. AB - OBJECTIVE: The aim of this study was to explore the association of body mass index (BMI), waist circumference (WC), and BMI and WC changes over time with cognitive decline in a nationally representative sample. METHODS: A total of 5239 participants (>=65 years) were followed for 3 years as part of the National Health and Aging Trends Study. Cox proportional hazard regression was applied to model the risk of cognitive decline. RESULTS: BMI, after adjusting for WC and main confounders, was associated with reduced risk of cognitive decline (hazard ratio [HR] 0.97 for each unit BMI increase, 0.95-0.99). After stratifying by gender and age, this effect remained significant among females and young elders <=80 years. A BMI decrease and WC increase >10% over the study period were associated with increased risk of cognitive decline (HR 1.98, 1.16-3.38; HR 1.30, 1.04-1.62, respectively). CONCLUSION: In the elderly individuals, lean mass, as measured by BMI adjusted for WC, was associated with reduced risk of cognitive decline. Loss of lean mass and gain of fat mass, as measured by WC adjusted for BMI, were associated with elevated risk of cognitive decline. PMID- 28077010 TI - Positive Aspects of Caregiving Questionnaire. AB - OBJECTIVE: The potential role of positive aspects of caregiving in enhancing caregivers' health is an important issue. The aim of this study was to develop and validate Positive Aspects of Caregiving Questionnaire (PACQ) in caregivers of patients with dementia in Iran. METHODS: Content validation process was used to content valid development. Cronbach alpha and intraclass correlation coefficient (ICC) were calculated as reliability indices. We used exploratory factor analysis to extract potential latent factors and evaluate the factor structure of PACQ. We assess correlation between PACQ and caregiver burden for divergent validity. For convergent validity, correlation between PACQ and self-rated health was specified. RESULTS: Content validity indices (CVIs), internal consistency, and test-retest reliability were CVI > 0.80, alpha = 0.785, and ICC = 0.905, respectively. Moreover, item-total correlations confirmed good reliability of PACQ. Two factors were identified by factor analysis in this 10-item measure: patient and caregiver relationship and caregiver's psychological well-being. Divergent validity and convergent validity were established by high negative correlation between positive aspect of caregiving (PAC) and caregiver burden along with significant positive correlation between PAC and self-rated health, respectively. While Cronbach alpha for the entire scale was 0.785, Cronbach alphas for both of the scale components were 0.71. CONCLUSION: The PACQ demonstrated acceptable psychometric properties of reliability and performs well in preliminary tests of validity as a measure of positive aspects of caregiving. This measure can be used to determine the outcome of interventional programs on positive, not only negative, aspect of caregiving. PMID- 28077011 TI - Mourning and Grief on Facebook: An Examination of Motivations for Interacting With the Deceased. AB - Facebook not only changed the way we communicate but also the way we mourn and express grief. The social networking site allows users to interact with deceased users' walls after death. This study utilized textual analysis to categorize Facebook posts ( N = 122) on 30 deceased users' walls according to uses and gratifications theory. Most posts were found to be motivated by entertainment, followed by integration and social interaction. Facebook users posted memories, condolences, and interacted with friends and family members in the deceased user's network. Implications and potential future research are discussed. PMID- 28077012 TI - Phonological Working Memory Deficits in ADHD Revisited. AB - OBJECTIVE: The current study dissociates lower level information-processing abilities (visual registration/encoding, visual-to-phonological conversion, and response output) and examines their contribution to ADHD-related phonological working memory (PHWM) deficits. METHOD: Twenty children with ADHD and 15 typically developing (TD) children completed tasks assessing PHWM, visual registration/encoding, visual-to-phonological conversion, and response output. RESULTS: Relative to TD children, children with ADHD exhibited deficient visual registration/encoding ( d = 0.60), visual-to-phonological conversion ( d = 0.56), and PHWM ( d = 0.72) but faster response output ( d = -0.66). Bias-corrected, bootstrapped mediation analyses revealed that visual registration/encoding, but not visual-to-phonological conversion, partially mediated ADHD-related PHWM impairments. In contrast, faster response output in children with ADHD served as a suppressor variable, such that greater PHWM deficits were observed in children with ADHD after controlling for their faster response output ( d = 0.72 vs. 0.85). CONCLUSION: Results implicate both lower level (visual registration/encoding) and higher order (PHWM) impairments in ADHD. Implications for designing educationally relevant cognitive interventions are discussed. PMID- 28077013 TI - Disgust-Related Olfactory Processing: The Role of Gender and Trait Disgust. AB - For the rejection of disgusting and potentially health-threatening food, the sense of smell plays a critical role. We conducted two experiments in order to investigate the role of gender and trait disgust (the temporally stable tendency to experience disgust across different situations) on disgust-related olfactory processing. A total of 40 men and women (Study 1), as well as a group of women divided according to high versus low trait disgust (Study 2, n = 59), were compared with regard to their odor thresholds for carbon disulfide (which smells like spoiled food) and a control stimulus ( n-butanol). The stimuli were rated for experienced arousal, negative valence, and familiarity. In addition, all participants underwent the "Sniffin' Sticks" battery assessing general olfactory performance. We found that women had a lower carbon disulfide threshold and rated this odorant as more unpleasant than men. Trait disgust was neither associated with the detection of the odorant signaling spoilage, nor with general olfactory function. The latter finding questions the role of this personality trait for olfactory-driven food-rejection responses, at least for normosmic individuals. PMID- 28077014 TI - Factors associated with reduced functional outcome and quality of life in patients having limb-sparing surgery for soft tissue sarcomas - a national multicenter study of 128 patients. AB - BACKGROUND: Limb-sparing surgery for sarcomas has become possible in most cases. However, the impact of the procedure on the functional outcome has only been investigated in a few studies. The aim of this study has been to identify tumor- and patient-related factors associated with reduced functional outcome and quality of life after limb-sparing surgery in soft tissue sarcoma patients. MATERIAL AND METHODS: In total, 128 patients (mean age = 58, female/male = 54/74) who were treated with limb-sparing surgery without bone resection for soft tissue sarcomas in Denmark during the period 1 January 2009 to 31 December 2011 were included. Patients were asked to participate at least one year after surgery, and patients who had experienced local recurrence or metastatic disease were excluded. The Toronto Extremity Salvage Score (TESS) measured functional disability, while the Musculoskeletal Tumor Society Score (MSTS) measured functional impairment. European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 measured quality of life. Tumor- and patient-related factors (age, gender, tumor depth, tumor size, malignancy, comorbidity, location, and radiotherapy) were extracted from the Danish National Sarcoma Database. Wilcoxon rank-sum test and Kruskal-Wallis were used for univariable analysis. Adjusted odds ratios were estimated by using multiple logistic regression models. RESULTS: In the multiple regression analysis, it was found that female gender (p = 0.03), lower extremity tumors (p < 0.01) and radiotherapy (p = 0.02) resulted in an increased risk of a lower TESS score. Initial reduced postoperative function was found to be associated with a lower functional outcome. Patients with reduced functional outcome have increased risk for reduced quality of life (p < 0.01). CONCLUSION: The results of this study show that patient- and tumor-related factors have an important role in the functional outcome. PMID- 28077015 TI - Atypical femoral fractures mimicking metastatic lesions in 2 patients taking denosumab. PMID- 28077016 TI - Bone mineral density is close to normal for age in long-term lymphoma survivors treated with high-dose therapy with autologous stem cell transplantation. AB - BACKGROUND: Few studies have assessed bone health in lymphoma survivors treated with high-dose therapy with autologous stem cell transplantation (HDT-ASCT). Therefore, we aimed to assess bone mineral density (BMD) at six different skeletal sites and to investigate associations between clinical factors and BMD in these survivors. MATERIAL AND METHODS: Eligible lymphoma survivors were aged >=18 years at diagnosis and at HDT-ASCT given between 1987 and 2008. Participants responded to questionnaires, blood samples were drawn, and a dual energy X-ray absorptiometry (DXA) was performed. Mean Z-score was applied for assessment of BMD in relation to age. Prevalence of Z-scores >=-1, between -1 and -2, and <=-2 is reported for each measurement site and for the lumbar spine, femoral neck, and hip in combination. Likewise, T-scores were applied to assess the prevalence of normal BMD (>=-1), osteopenia (between -1 and -2.5), and osteoporosis (<=-2.5). RESULTS: We included 228 lymphoma survivors, of whom 62% were males. The median age at survey was 56 years, and median observation time from HDT-ASCT was eight years. Among males, Z-scores were lower at the left femoral neck and higher at the ultra-distal (UD) radius and whole body compared to the Lunar reference database. In females, Z-scores were lower at UD radius and one-third (33%) radius and higher at the whole body. Using a classification based on Z-scores at the lumbar spine, femoral neck, and hip in combination, 25% of males and 16% of females had Z-scores <-1 and >-2, while 8% and 6% had Z-scores <=-2. According to T-scores, 35% of males and 41% of females had osteopenia, while 8% and 13% had osteoporosis, respectively. CONCLUSION: BMD was close to normal for age in this population of long-term lymphoma survivors treated with HDT-ASCT. PMID- 28077017 TI - Adolescent and young adult (AYA) lymphoma survivors report lower health-related quality of life compared to a normative population: results from the PROFILES registry. AB - BACKGROUND: Trying to simultaneously achieve developmental milestones and cope with a life-threatening disease may place adolescents and young adults (AYAs) at risk for impaired health-related quality of life (HRQoL) later in life. The aim of this study was to examine differences in HRQoL between AYA lymphoma survivors and a normative population and to determine sociodemographic, clinical and long term symptom-related factors associated with HRQoL. MATERIAL AND METHODS: This study was part of a longitudinal, population-based survey among lymphoma survivors diagnosed between 1999 and 2012. The AYA survivor sample (18-39 years at time diagnosis) was compared to a sex- and age-matched normative population on HRQoL (EORTC-QLQ-C30) and psychological distress (HADS). Multiple linear regression analyses were conducted to determine factors associated with HRQoL among survivors. RESULTS: One hundred and ninety-eight AYA lymphoma survivors (58%) responded to the study invitation. Compared to an age- and sex-matched normative population (N = 380), significantly and clinically relevant poorer HRQoL was observed for AYA lymphoma survivors in seven specific domains of HRQoL: physical, role, cognitive, emotional, social functioning, fatigue and financial difficulties (all p < 0.05). In addition, AYA lymphoma survivors less often had a spouse/partner and more often had a lower educational level compared to the normative population. Linear regression analyses showed that being unemployed, female gender, having one or more comorbid conditions, high levels of fatigue and psychological distress were most strongly associated with HRQoL. CONCLUSIONS: These findings identify specific domains of life in which cancer has a significant and long-term impact for AYA lymphoma survivors. Future investigations are needed to identify and test administrations and timing of psychosocial support interventions having potential to reduce long-term late effects in specific HRQoL domains and promote function and adaptability after cancer treatment. PMID- 28077018 TI - Patient factors and quality of life outcomes differ among four subgroups of oncology patients based on symptom occurrence. AB - CONTEXT: Reviews of the literature on symptoms in oncology patients undergoing curative treatment, as well as patients receiving palliative care, suggest that they experience multiple, co-occurring symptoms and side effects. OBJECTIVES: The purposes of this study were to determine if subgroups of oncology patients could be identified based on symptom occurrence rates and if these subgroups differed on a number of demographic and clinical characteristics, as well as on quality of life (QoL) outcomes. METHODS: Latent class analysis (LCA) was used to identify subgroups (i.e. latent classes) of patients with distinct symptom experiences based on the occurrence rates for the 13 most common symptoms from the Memorial Symptom Assessment Scale. RESULTS: In total, 534 patients with breast, head and neck, colorectal, or ovarian cancer participated. Four latent classes of patients were identified based on probability of symptom occurrence: all low class [i.e. low probability for all symptoms (n = 152)], all high class (n = 149), high psychological class (n = 121), and low psychological class (n = 112). Patients in the all high class were significantly younger compared with patients in the all low class. Furthermore, compared to the other three classes, patients in the all high class had lower functional status and higher comorbidity scores, and reported poorer QoL scores. Patients in the high and low psychological classes had a moderate probability of reporting physical symptoms. Patients in the low psychological class reported a higher number of symptoms, a lower functional status, and poorer physical and total QoL scores. CONCLUSION: Distinct subgroups of oncology patients can be identified based on symptom occurrence rates. Patient characteristics that are associated with these subgroups can be used to identify patients who are at greater risk for multiple co-occurring symptoms and diminished QoL, so that these patients can be offered appropriate symptom management interventions. PMID- 28077019 TI - Independence: proposing an initial framework for occupational therapy. AB - BACKGROUND: The concept of independence is common in occupational therapy theory and practice but has rarely been clearly defined or conceptualized within in occupational therapy literature and there seems to be no standard definition. This can result in ambiguity, which potentially jeopardizes client-centred practice. AIM: This paper proposes an occupational therapy independence framework (OTIF) that synthesizes the range of characterizations of independence in a practically useful and occupation-centred manner. METHODS: A review of literature, clinical experience, doctoral research and conversations with occupational therapists and disabled people, in particular those involved in a disability activism group and people with physical disabilities, has led to the development of the OTIF. RESULTS: Independence and interdependence, as characterized in the OTIF, occur when an individual exerts choice over occupational performance and can engage in occupations in a manner acceptable to the individual. Interdependence results when occupations are performed with another person whereas independence involves solitary occupational performance. Dependence typically results from inability to choose occupations or a mismatch between performance capacity and environmental factors. SIGNIFICANCE: The OTIF has the potential to clarify the conceptualization of independence within occupational therapy theory and practice. This initial proposal is presented to stimulate debate and discussion. PMID- 28077021 TI - Mainlandization, the ICAC, and the Seriousness Attached by Local Politicians to Corruption in Post-1997 Hong Kong. AB - To date, few studies have focused on how the public has perceived the effectiveness of the Independent Commission Against Corruption (ICAC). Furthermore, little is known about how the public has assessed the functions of the ICAC during the political-economic convergence between Hong Kong and mainland China since 1997. This study attempts to explore local politicians' perceptions towards the ICAC in post-1997 Hong Kong. The quantitative data show that the important historical juncture of mainlandization has been politicized in Hong Kong and has deeply influenced the seriousness attached by local politicians to corruption. Moreover, a mediating path of the effect of "Conflict of Interest" on the "Perceived Seriousness of Corruption" has been found, that is, mainlandization is found to have brought about increased levels of conflict of interest among government officials, which has weakened the symbolic anti corruption function of the ICAC and, in turn, has affected the perceived seriousness attached to corruption. PMID- 28077020 TI - Relationship between 18F-Flutemetamol uptake and RBANS performance in non demented community-dwelling older adults. AB - OBJECTIVE: The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has been used extensively for clinical care and in research for patients with mild cognitive impairment and Alzheimer's disease (AD); however, relatively few studies have evaluated the relationship between RBANS performance and AD imaging biomarkers. The purpose of the current study was to evaluate the association between a relatively new amyloid positron emission tomography imaging biomarker and performance on the RBANS. METHODS: Twenty-seven nondemented community-dwelling adults over the age of 65 underwent 18F-Flutemetamol amyloid- positron emission tomography imaging, along with cognitive testing using the RBANS and select behavioral measures. Partial correlation coefficients were used to identify relationships between the imaging and behavioral markers. RESULTS: After controlling for age and education, amyloid deposition and RBANS Indexes of Immediate Memory, Delayed Memory, and Total Scale score were significantly correlated (p's < .001, r's = -.73 to -.77, d's = 2.13-2.39), with greater amyloid burden being associated with lower RBANS scores. The Delayed Memory Index was particularly highly associated with 18F-Flutemetamol binding (r2 = .59, p < .001, d = 2.39). Neither 18F-Flutemetamol binding nor RBANS performance was significantly correlated with levels of depression, subjective cognitive difficulties, or premorbid intellect. CONCLUSIONS: Because of the limited use of amyloid imaging in clinical settings due to high cost and lack of reimbursement, these findings suggest that in particular RBANS Delayed Memory Index may be a cost-efficient tool to identify early signs of AD pathology, and its use may enlighten clinical decision-making regarding potential progression to dementia due to AD. PMID- 28077022 TI - Feasibility of a novel multispot nanoarray for antibiotic screening in honey. AB - Practical solutions for multiple antibiotic determination in food are required by the food industry and regulators for cost-effective screening purposes. This study describes the feasibility in development and preliminary performance of a novel multispot nanoarray for antibiotic screening in honey. Using a multiplex approach, the metabolites of the four main nitrofuran antibiotics, including morpholinomethyl-2-oxazolidone (AMOZ), 3-amino-2-oxazolidinone (AOZ), semicarbazide (SEM), 1-aminohydantoin (AHD) and chloramphenicol (CAP), were simultaneously detected. Antibodies specific to the five antibiotics were nano spotted onto microtitre plate wells and a direct competitive assay format was employed. The assay characteristics and performance were evaluated for feasibility as a screening tool for antibiotic determination in honey to replace traditional ELISAs. Optimisation of the spotting and assay parameters was undertaken with both individual and multiplex calibration curves generated in PBS and a honey matrix. The limits of detection as determined by the 20% inhibitory concentrations (IC20) were determined as 0.19, 0.83, 0.09, 15.2 and 35.9 ng ml-1 in PBS, 0.34, 0.87, 0.17, 42.1 and 90.7 ng ml-1 in honey (fortified at the start of the extraction), and 0.23, 0.98, 0.24, 24.8 and 58.9 ng ml-1 in honey (fortified at the end of the extraction) for AMOZ, AOZ, CAP, SEM and AHD respectively. This work has demonstrated the potential of multiplex analysis for antibiotics with results available for 40 samples within a 90-min period for antibiotics sharing a common sample preparation. Although both the SEM and AHD assay do not show the required sensitivity with the antibodies available for use to meet regulatory limits, with further improvements in these particular antibodies this multiplex format has the potential to show a reduction in cost with reduced labour time in combination with the high-throughput screening of samples. This is the first 96-well spotted microtitre plate nanoarray for the semi-quantitative and simultaneous analysis of antibiotics. PMID- 28077023 TI - HIV-associated sub-acute sclerosing panencephalitis - an emerging threat? AB - Earlier age of measles virus infection predisposes to development of sub-acute sclerosing panencephalitis (SSPE) and this risk is heightened in HIV-infected children. We describe a HIV-infected young adult on antiretroviral therapy, presenting with a non-classical, fulminant form of SSPE to highlight the unpredictable nature of measles presentation. The recent spate of measles outbreaks due to virus introduction in populations with sub-optimal vaccine coverage or waning immunity and co-existing paediatric HIV cohorts is a cause for concern. PMID- 28077024 TI - Localization of functional beta-xylosidases, encoded by the same single gene, xlsIV (xlnD), from Aspergillus niger E-1. AB - Cell wall-associated beta-xylosidase was isolated from Aspergillus niger E-1 and identified as XlsIV, corresponding to the extracellular enzyme XlnD reported previously. xlsIV was transcribed only in the early cultivation period. Cell wall associated enzyme activity gradually decreased, but extracellular activity increased as the strain grew. These results indicate that XlsIV (XlnD) was secreted into culture after localizing at cell wall. PMID- 28077025 TI - Total mercury levels in commercial fish species from Italian fishery and aquaculture. AB - Total mercury levels were measured in 42 commercial fish species caught off the Central Adriatic and Tyrrhenian coasts of Italy and in 6 aquaculture species. The study on wild fish covered species differing in living habitat and trophic level. The study on farmed fish covered marine and freshwater species from intensive and extensive aquaculture and their feed. Mercury levels were analysed by thermal decomposition-amalgamation-atomic absorption spectrophotometry. Total mercury concentrations in the muscle of wild fish showed a high variability among species (0.025-2.20 mg kg-1 wet weight). The lowest levels were detected in low trophic level demersal and pelagic-neritic fish and in young individuals of high trophic level species. Levels exceeding the European Commission limits were found in large-size specimens of high trophic-level pelagic and demersal species. Fish from intensive farming showed low levels of total mercury (0.008-0.251 mg kg-1). Fish from extensive rearing showed variable contamination levels, depending on the area of provenience. An estimation of the human intake of mercury associated to the consumption of the studied fish and its comparison with the tolerable weekly intake is provided. PMID- 28077026 TI - A case-control study of risk factors of chronic venous ulceration in patients with varicose veins. AB - Background/objectives Venous ulcers carry psychological and high financial burden for patients, causing depression, pain, and limitation of mobility. The study aimed to identify factors associated with an increased risk of venous ulceration in patients with varicose veins in Armenia. Methods A case-control study design was utilized enrolling 80 patients in each group, who underwent varicose treatment surgery in two specialized surgical centers in Armenia during 2013-2014 years. Cases were patients with varicose veins and venous leg ulcers. Controls included patients with varicose veins but without venous leg ulcers. Data were collected using interviewer-administered telephone interviews and medical record abstraction. Multiple logistic regression analysis was used to identify the risk factors of venous ulceration. Results There were more females than males in both groups (72.5% of cases and 85.0 % of controls). Cases were on average older than controls (53.9 vs. 39.2 years old, p <= 0.001). After adjusting for potential confounders, the estimated odds of developing venous ulcer was higher in patients with history of post thrombotic syndrome (odds ratio = 14.90; 95% confidence interval: 3.95-56.19; p = 0.001), with higher average sitting time (odds ratio = 1.32 per hour of sitting time; 95% confidence interval: 1.08-1.61; p = 0.006), those with reflux in deep veins (odds ratio = 3.58; 95% confidence interval: 1.23 10.31; p = 0.019) and history of leg injury (odds ratio = 3.12; 95% confidence interval: 1.18-8.23; p = 0.022). Regular exercise in form of walking (>=5 days per week) was found to be a protective factor from venous ulceration (odds ratio = 0.26; 95% confidence interval: 0.08-0.90; p = 0.034). Conclusion We found that reflux in deep veins, history of leg injury, history of post thrombotic syndrome, and physical inactivity were significant risk factors for venous ulceration in patients with varicose veins, while regular physical exercise mitigated that risk. Future studies should investigate the relationships between the duration and type of regular exercise and the risk of venous ulceration to make more specific recommendations on preventing ulcer development. PMID- 28077027 TI - Probabilistic acute risk assessment of cumulative exposure to organophosphorus and carbamate pesticides from dietary vegetables and fruits in Shanghai populations. AB - Organophosphorus pesticides (OPs) and carbamate pesticides (CPs) are among the most widely used pesticides in China, playing a major role in protecting agricultural commodities. In this study, we determined the cumulative acute exposure to OPs and CPs of Shanghai residents from vegetables and fruits (VFs). The food consumption data were obtained from the Shanghai Food Consumption Survey (SHFCS) of 2012-14 including a total of 1973 participants aged 2-90 years. The pesticide residue data were obtained from the Shanghai monitoring programme during 2008-11 with 34 organophosphates and 11 carbamates analysed in a total of 5335 samples of VFs. A probabilistic approach was performed as recommended by the EFSA, using the optimistic model with non-detects set as zero and with processing factors (PFs) being used and the pessimistic model with non-detects replaced by limit of detection (LOD) and without PFs. We used the relative potency factor (RPF) method to normalise the various pesticides to the index compound (IC) of methamidophos and chlorpyrifos separately. Only in the pessimistic model using methamidophos as the IC was there was small risk of exposure exceeding the ARfD (3 ug kg-1 bw day-1) in the populations of preschool children (0.029%), school age children (0.022%) and adults (0.002%). There were no risk of exposure exceeding the ARfD of methamidophos in the optimistic model and of chlorpyrifos (100 ug kg-1 bw day-1) in both optimistic and pessimistic models in all three populations. Considering the Chinese habits of overwhelmingly eating processed food (vegetables being cooked, and fruits being washed or peeled), we conclude that little acute risk was found for the exposure to VF-sourced OPs and CPs in Shanghai. PMID- 28077029 TI - The behavior of mobile genetic elements (MGEs) in different environments. AB - Mobile genetic elements (MGEs) including plasmids have an important role in the rapid evolution and adaptation of bacteria. Here, the behavior of MGEs in different environments is reviewed, in particular, behavior of the plasmid pCAR1, a carbazole-degradative plasmid isolated from Pseudomonas resinovorans CA10. pCAR1 belongs to incompatibility P-7 group and is self-transmissible among different bacteria. Comparisons of changes in the transcriptome of different host strains caused by carrying pCAR1 revealed common responses in the hosts and host specific responses. Monitoring the survival of the host and transfer of the plasmid in artificial and natural environmental samples revealed several environmental factors, including cations and water content, which changed the behavior of both the host and its plasmid. Single-cell level analysis to detect the transconjugants of different plasmids successfully determined the transfer range of the plasmids. Three nucleoid-associated proteins encoded on pCAR1 are important factors affecting its genetic stability, maintenance, and transfer. PMID- 28077028 TI - Ferulic acid suppresses expression of tryptophan metabolic key enzyme indoleamine 2, 3-dioxygenase via NFkappaB and p38 MAPK in lipopolysaccharide-stimulated microglial cells. AB - Ferulic acid (FA) is a phenol compound found in plants that has anti-inflammatory properties. Indoleamine 2, 3-dioxygenase (IDO) is a tryptophan catabolic enzyme induced in immune cells, including glial cells, during inflammation. Enhanced IDO expression leads to reduced tryptophan levels and increased levels of toxic metabolites, including quinolinic acid. Therefore, inhibition of IDO expression may be effective in suppressing progression of neurodegenerative diseases. In this study, we examined the effect of FA in microglial cells on IDO expression levels and related inflammatory signal molecules. FA suppressed LPS-induced IDO mRNA expression and also suppressed nuclear translocation of NF-kappaB and phosphorylation of p38 MAPK. However, FA did not affect the production of LPS induced inflammatory mediators and phosphorylation of JNK. Our results indicate that FA suppresses LPS-induced IDO mRNA expression, which may be mediated by inhibition of the NF-kappaB and p38 MAPK pathways in microglial cells. PMID- 28077030 TI - Mortality rates in OECD countries converged during the period 1990-2010. AB - AIMS: Since the scientific revolution of the 18th century, human health has gradually improved, but there is no unifying theory that explains this improvement in health. Studies of macrodeterminants have produced conflicting results. Most studies have analysed health at a given point in time as the outcome; however, the rate of improvement in health might be a more appropriate outcome. METHODS: Twenty-eight OECD member countries were selected for analysis in the period 1990-2010. The main outcomes studied, in six age groups, were the national rates of decrease in mortality in the period 1990-2010. The effects of seven potential determinants on the rates of decrease in mortality were analysed in linear multiple regression models using least squares, controlling for country specific history constants, which represent the mortality rate in 1990. RESULTS: The multiple regression analyses started with models that only included mortality rates in 1990 as determinants. These models explained 87% of the intercountry variation in the children aged 1-4 years and 51% in adults aged 55-74 years. When added to the regression equations, the seven determinants did not seem to significantly increase the explanatory power of the equations. CONCLUSIONS: The analyses indicated a decrease in mortality in all nations and in all age groups. The development of mortality rates in the different nations demonstrated significant catch-up effects. Therefore an important objective of the national public health sector seems to be to reduce the delay between international research findings and the universal implementation of relevant innovations. PMID- 28077032 TI - Iodine-responsive poly (HEMA-PVP) hydrogel for self-regulating burst-free extended release. AB - Swollen hydrogels with extended iodine release kinetics is highly desirable for burn and scald treatment. In this paper semi-interpenetrating poly (HEMA-PVP) hydrogels were prepared by radical polymerization followed by thermo-treatment to crosslink its PVP component. Incorporation of PVP component endows the hydrogels responsive to loaded iodine undergoing a reversible shrunken/swollen volume transition. This resulted in a self-regulating iodine release model, in which shrunken hydrogel at high iodine loading decreased drug diffusion thereby reducing burst release, and then gradually swollen hydrogel as drug release ensures rapid release of dissociated drug from strong affinity sites on hydrogel backbone, achieving a burst-free extended release. The hydrogels demonstrated 11.5-fold higher iodine loading than pure pHEMA hydrogel and showed a highest 40% volume shrink. Initial burst release of iodine was efficiently decreased from 12,894 MUg/day of pure pHEMA hydrogel to 2570 MUg/day of pHEMA/PVP hydrogel with 37% PVP content. Iodine-loaded hydrogels showed zero-order release at three time periods of 0-15 h, 15 h-3.5 days and 3.5-23.5 days corresponding to release rate of 2570, 776 and 493 MUg/day. The work gained a new insight into swollen hydrogel drug delivery system with burst-free extended drug release kinetics. PMID- 28077033 TI - Governing health equity in Scandinavian municipalities: The inter-sectorial challenge. AB - AIMS: Local governments in the Scandinavian countries are increasingly committed to reduce health inequity through 'health equity in all policies' (HEiAP) governance. There exists, however, only very sporadic implementation evidence concerning municipal HEiAP governance, which is the focus of this study. METHODS: Data are based on qualitative thematic network analysis of 20 interviews conducted from 2014 to 2015 with Scandinavian political and administrative practitioners. RESULTS: We identify 24 factors located within three categories; political processes, where insufficient political commitment to health equity goals outside of the health sector and inadequate economic prioritization budget curbs implementation. Concerning evidence, there is a lack of epidemiological data, detailed evidence of health equity interventions as well as indicators relevant for monitoring implementation. Concerted administrative action relates to a lack of vertical support and alignment from the national and the regional level to the local level. Horizontally within the municipality, insufficient coordination across policy sectors inhibits effective health equity governance. CONCLUSIONS: A shift away from 'health in all policies' based on a narrow health concept towards 'health equity for all policies' based on a broader concept such as 'sustainability' can improve ownership of health equity policy goals across municipal sectors. PMID- 28077034 TI - Written reflection in assessment and appraisal: GP and GP trainee views. AB - BACKGROUND: In the UK, evidence of written reflection is part of licensing and revalidation for general practitioners (GPs). However, there is little evidence of specific benefits compared to other forms of reflective practice. AIM: To seek GPs' and general practice (GP) trainees' views on the role of written reflection in learning and assessment. DESIGN AND SETTING: An online survey of 1005 GPs and GP trainees (GPTs) in the UK. METHOD: An anonymous questionnaire containing 38 attitudinal items was administered. Descriptive statistics were used to analyse Likert scale responses, thematic analysis for free-text responses. RESULTS: In total 544 GPs and 461 GPTs completed the survey, with 842 (83.8%) agreeing they find verbal reflection with a colleague more useful than written reflection. Three quarters disagreed that written reflection is a way of identifying poorly performing GPs. Over 70% of respondents stated that summative, written reflection is a time-consuming, box-ticking exercise which distracts from other learning. They question its validity as part of assessment and state that its use may contribute to current difficulties with recruitment and retention to GP. CONCLUSIONS: For many GPs, written reflection is an onerous process rather than beneficial to their learning, indicating its continued use in assessment needs to be critically examined. PMID- 28077035 TI - Nurses' online behaviour: lessons for the nursing profession. AB - Social networking is popular online activity; however, like many activities on the internet, there are some privacy risks and concerns associated with its use. Recently, an increasing number of nurses have been censured or asked to appear before regulatory or registering authorities for unprofessional behaviour on social media sites. Problem behaviours identified include: inappropriate content and postings, crossing professional boundaries and breaching patient privacy and confidentiality. This discussion paper aims to give the nursing profession an understanding of how their online behaviour can impact on their professionalism, and how they can avoid problematic situations when using social media (Facebook). This exploratory discussion paper will inform a study researching nurses' online behaviour. Social media is here to stay and nurses need to navigate the complexities of the boundaries between the personal and the professional. Nurses need to learn to balance the growing usefulness of social media, with the legalities and etiquette of the online environment. PMID- 28077038 TI - Policy. PMID- 28077036 TI - Mass media narratives of women's cardiovascular disease: a qualitative meta synthesis. AB - Cardiovascular disease is the leading cause of death and disability among women worldwide. Narratives circulated by the media regarding women's identities and health constitute one source of meanings by which conceptualisations about risk, risk reduction, and disease prevention are formed and framed. An interpretive and integrative meta-synthesis of qualitative research was done to examine the representations of women's cardiovascular disease in traditional and user generated Canadian and US media narratives, and explore the implications of these for gendered identities and health promotion for women. After a literature search of electronic databases, 29 qualitative peer-reviewed journal articles published since 2000 met the eligibility criteria and were included for review. The findings revealed three overarching themes: (a) the construction of who is at risk for cardiovascular disease; (b) the portrayal of certain risk-reducing strategies and acute events; and (c) the delegation of responsibility for maintaining female cardiovascular health. These meta-synthesis findings contribute towards novel understandings about the culture of women's cardiovascular disease risk and the feminisation of healthism/individual responsibility, which may limit awareness among marginalised female demographics (those from lower socio-economic and minority racial backgrounds). PMID- 28077041 TI - Policy News. PMID- 28077040 TI - Diary. PMID- 28077044 TI - Reducing health disparities for women through use of the medical home model. AB - BACKGROUND: Healthcare services can be difficult to access, particularly for low income or underinsured women. One way of overcoming the barriers to quality, patient-centered care is through the use of the Medical Home Model (MHM). The MHM is a cost-effective approach to care that improves patient outcomes and improves access. AIM: The purpose of this article is to discuss barriers to healthcare, with an emphasis on reducing healthcare disparities for women. METHOD: Extant, contemporary literature has been reviewed and synthesized to develop this theoretical paper on the benefits of using the MHM to reduce disparities in the provision of healthcare for women. CONCLUSIONS: The MHM provides an example of how healthcare can be provided in a more coordinated and effective manner. Extension of this model into the area of women's health may be one way to reduce barriers to quality, accessible care for women. PMID- 28077045 TI - Association of time to antibiotics and clinical outcomes in adult hematologic malignancy patients with febrile neutropenia. AB - Objective The objective of this study was to determine the clinical impact of time to antibiotic administration in adult inpatients who have hematologic malignancies and develop febrile neutropenia. Methods A retrospective chart review was conducted to screen for all febrile neutropenia events amongst adult hematologic malignancy patients between 1 January 2010 and 1 September 2014. All included patients were admitted to the hospital at the time of fever onset, having been admitted for a diagnosis other than febrile neutropenia. Descriptive statistics and logistic generalized estimated equations were used to analyze the data. Results Two hundred forty-four neutropenic fever events met inclusion criteria. Thirty-five events (14.34%) led to negative clinical outcomes (in hospital mortality, intensive care unit transfer, or vasopressor requirement), with an in-house mortality rate of 7.4%. The time to antibiotics ranged from 10 min to 1495 min. The median time to antibiotics in the events that led to negative outcomes was 120 min compared to 102 min in the events that did not lead to the negative outcome ( p = 0.93). Conditional order sets were used to order empiric antibiotics in 176 events (72.1%) and significantly reduced time to antibiotics from 287 min to 143 min ( p = 0.0019). Conclusion Prolonged time to antibiotic administration in hematologic malignancy patients who develop neutropenic fever was not shown to be associated with negative clinical outcomes. PMID- 28077046 TI - Rational use of rasburicase for the treatment and management of tumor lysis syndrome. AB - Purpose There is a lack of high-level evidence identifying meaningful outcomes and the optimal place in therapy of rasburicase in patients with, or at high risk for tumor lysis syndrome. The primary objective of this study was to evaluate and characterize outcomes resulting from an institution-specific guideline emphasizing supportive care, xanthine oxidase inhibitors, and lower doses of rasburicase. Methods In this retrospective chart review, we compared conservative rasburicase dosing, in accordance with newly developed UMHS tumor lysis syndrome guidelines, with aggressive rasburicase in adult patients (>= 18 years of age) with hematological or solid tumor malignancies, and a uric acid level between 8 and 15 mg/dL. The primary efficacy outcome assessed the difference in the proportion of patients achieving a uric acid level <8 mg/dL within 48 h using a one-sided noninferiority test. The principle safety outcomes analyzed included incidence of acute kidney injury and hemodialysis requirement. Results One hundred sixty-one patients met inclusion criteria and were included in the study. Within 48 h of an elevated uric acid level, treatment was successful in 97.03% of patients in the conservative group, as compared with 98.33% in the aggressive group (difference, 1.3 percentage points; 95% confidence interval [CI], -3.33 to 5.93). Furthermore, there was no difference in the proportion of patients requiring hemodialysis (2.97% vs. 10.0%, p-value 0.079), or incidence of acute kidney injury (4.0% vs. 12.5%, p-value 1.00) between the treatment group and control group, respectively. Conclusions Conservative rasburicase use was noninferior to aggressive rasburicase use in patients with or at high risk for tumor lysis syndrome. PMID- 28077047 TI - Extended infusion compared to standard infusion cefepime as empiric treatment of febrile neutropenia. AB - Background Extended infusion (EI) dosing provides a longer time above the minimum inhibitory concentration, which is important for the clinical success of beta lactam antibiotics, especially for patients with impaired immunity. The aim of this study was to determine the feasibility and clinical impact of administering cefepime by EI as treatment of febrile neutropenia. Methods This was a prospective, randomized, comparative pilot study. All patients received cefepime 2 g IV every 8 h, with the first dose administered using a 30-min infusion. After the first dose, patients were randomized to receive cefepime over 30 min as a standard infusion (SI) or 3 h (EI). Patients were >18 years old with febrile neutropenia (neutrophil count <500 cells/mm3 and temperature >38.0oC) and received chemotherapy or stem cell transplant as treatment for malignancy. Patients were excluded for the following: allergy to a cephalosporin, creatinine clearance (CrCl) < 50 mL/min, receipt of concurrent Gram-negative antimicrobial, sepsis, or solid tumor malignancy. The primary outcome was defervescence by 72 h. Secondary outcomes included time to defervescence, clinical success, in-hospital mortality, hospital length of stay, and need for additional antimicrobials. Main results Sixty-three patients were enrolled: 33 in the SI arm and 30 in the EI arm. The groups were similar with regard to age, gender, weight, estimated creatinine clearance, and duration of neutropenia. None of the patients in the EI arm withdrew due to practical complications of receiving EI cefepime. Twenty three patients in the SI arm and 20 patients in the EI arm defervesced by 72 h ( p = 0.99). There were no differences in secondary outcome measures; however, patients in the EI arm appeared to have defervesced more rapidly (median 19 vs. 41 h, p = 0.305). Conclusion Administration of cefepime by EI for the treatment of febrile neutropenia is feasible. Larger clinical trials are necessary to determine if EI cefepime imparts a clinical benefit in the treatment of febrile neutropenia. PMID- 28077048 TI - Baxter elastomeric pumps: Weighing as an alternative to visual inspection. AB - Purpose Elastomeric pumps are used to administer 46-hour infusions of 5 fluorouracil (5FU). Baxter suggests patients visually monitor their pumps to ensure that infusions are proceeding correctly. This can be confusing and lead to concerns about under- or over-dosing. Baxter has not considered weighing pumps as a validated method for monitoring. This study aims to validate weighing as a more accurate method for patients and healthcare professionals, and describe real life Baxter InfusorTM variability. Methods Patients who had been started on a 46-hour 5FU infusion returned to the clinic approximately 24 h after starting treatment. The pump was weighed on a StarFrit kitchen scale, and date, time, and weights recorded. Patients were asked if they had a preference for weighing or visually inspecting their pump. Results Pumps ( n = 103) were weighed between 17.25 and 27.5 h after connection. The average weight of a pump was 189 g. Of 103 pumps weighed, 99 weighed less than expected, corresponding to average flow rates of 5.69 mL/h over the elapsed time. The expected flow rate is 5 mL/h with 10% variability. Average flow rates within the 17.25- to 27.5-hour window were 4.561 mL/h, which is 8.78% slower than expected, but within the 10% known variability. Forty-seven percent of patients didn't have a preference for either method, but for those who did have a preference, more than twice as many preferred weighing. Conclusion With proper education, weighing Baxter Infusors at home with kitchen scales can be an accepted and objective alternative to the current recommendation of visual inspection. PMID- 28077049 TI - Evaluation on biological compatibility of carboxymethyl chitosan as biomaterials for antitumor drug delivery. AB - Carboxymethyl-chitosan, a water-soluble derivative of chitosan, has emerged as a promising candidate for biomedical applications due to its excellent water solubility, biodegradation, biocompatibility, hydrating, antimicrobial, and nontoxicity. In this paper, the antitumor proliferation and metastasis was studied in vitro and in vivo to evaluate biocompatibility of carboxymethyl chitosan as biomaterials for antitumor drug delivery. The results showed that carboxymethyl-chitosan could significantly reduce the clone formation and tumor migration of human cancer cells including kidney cancer cell line OS-RC-2, gastric cancer cell line SGC-7901, colon cancer cell line HT-29, and nonsmall cell lung cancer cell line NCI-H1650 in vitro. Through Lewis tumor-bearing C57BL/6 mouse model, carboxymethyl-chitosan was proved to be able to inhibit solid tumor growth and tumor metastasis to the liver and lung, meanwhile increase the level of tissue inhibitor of metalloproteinase 1 and E-cadherin, and decrease the level of mice blood serum matrix metalloproteinase 9. This study suggested that carboxymethyl-chitosan had certain antimetastasis effect and good biocompatibility and may have a potential application as a synergic antitumor reagent. PMID- 28077050 TI - A novel human-like collagen hemostatic sponge with uniform morphology, good biodegradability and biocompatibility. AB - Biodegradable sponges, as a promising hemostatic biomaterial, has been clinically required over the past decades. Current hemostatic sponges are generally prepared by crosslinking and freeze-drying, but the quality control or biocompatibility is often unsatisfactory due to the freezing-caused morphological non-uniformity and the toxicity of raw materials or cross-linkers. The crosslinking often greatly retards the degradation of the sponges and thus affects the healing of the wound. In this work, we prepared a novel hemostatic sponge using human-like collagen and glutamine transaminase (non-toxic cross-linker) and optimized its morphology via "two-step" freezing instead of conventional "one-step" freezing. The resulting sponge showed a good biocompatibility in cytotoxicity and implantation tests and had a significant hemostatic effect in ear artery and liver injury models. Moreover, the sponge could be degraded high efficiently by several common enzymes in organisms (e.g. I collagenase, trypsase, and lysozyme), which means that the sponge can be easily digested by metabolism and can facilitate seamless healing. Finally, both the front and back of the sponge prepared via two-step freezing was more uniform in morphology than that prepared via one-step freezing. More importantly, two-step freezing can be used as a universal approach for preparation of diverse uniform biomaterials. PMID- 28077051 TI - Facile preparation of antibacterial, highly elastic silvered polyurethane nanofiber fabrics using silver carbamate and their dermal wound healing properties. AB - In this study, polycarbonate diol/isosorbide-based antibacterial polyurethane nanofiber fabrics containing Ag nanoparticles were prepared by electrospinning process. Bio-based highly elastic polyurethane was prepared from hexamethylene diisocyanate and isosorbide/polycarbonate diol (8/2) by a simple one-shot bulk polymerization. Ag nanoparticles were formed using simple thermal reduction of silver 2-ethylhexylcarbamate at 120C. The structural and morphological properties of polyurethane/Ag nanofibers were characterized by X-ray diffraction and scanning electron microscopy. The polyurethane nanofiber fabrics were flexible, with breaking strains from 355% to 950% under 7.28 to 23.1 MPa tensile stress. The antibacterial effects of the treated polyurethane/Ag fabrics against Staphylococcus aureus and methicillin resistant Staphylococcus aureus were examined and found to be excellent. Cell proliferation using the immortalized human keratinocyte HaCaT cell line was performed in order to determine cell viability in the presence of polyurethane and polyurethane/Ag fabrics, showing cytocompatiblility and a lack of toxicity. PMID- 28077052 TI - Examinations of a new long-term degradable electrospun polycaprolactone scaffold in three rat abdominal wall models. AB - Alternative approaches to reinforce native tissue in reconstructive surgery for pelvic organ prolapse are warranted. Tissue engineering combines the use of a scaffold with the regenerative potential of stem cells and is a promising new concept in urogynecology. Our objective was to evaluate whether a newly developed long-term degradable polycaprolactone scaffold could provide biomechanical reinforcement and function as a scaffold for autologous muscle fiber fragments. We performed a study with three different rat abdominal wall models where the scaffold with or without muscle fiber fragments was placed (1) subcutaneously (minimal load), (2) in a partial defect (partial load), and (3) in a full thickness defect (heavy load). After 8 weeks, no animals had developed hernia, and the scaffold provided biomechanical reinforcement, even in the models where it was subjected to heavy load. The scaffold was not yet degraded but showed increased thickness in all groups. Histologically, we found a massive foreign body response with numerous large giant cells intermingled with the fibers of the scaffold. Cells from added muscle fiber fragments could not be traced by PKH26 fluorescence or desmin staining. Taken together, the long-term degradable polycaprolactone scaffold provided biomechanical reinforcement by inducing a marked foreign-body response and attracting numerous inflammatory cells to form a strong neo-tissue construct. However, cells from the muscle fiber fragments did not survive in this milieu. Properties of the new neo-tissue construct must be evaluated at the time of full degradation of the scaffold before its possible clinical value in pelvic organ prolapse surgery can be evaluated. PMID- 28077054 TI - Synthetic biology: taking a look at a field in the making. PMID- 28077053 TI - Patient empowerment: a systematic review of questionnaires measuring empowerment in cancer patients. AB - BACKGROUND: There is an increased attention to and demand for patient empowerment in cancer treatment and follow-up programs. Patient empowerment has been defined as feeling in control of or having mastery in relation to cancer and cancer care. This calls for properly developed questionnaires assessing empowerment from the user perspective. The aim of this review was to identify questionnaires and subscales measuring empowerment and manifestations of empowerment among cancer patients. MATERIALS AND METHODS: We conducted a systematic search of the PubMed, PsycINFO and CINAHL databases. Empowerment and multiple search terms associated with empowerment were included. We included peer-reviewed articles published in English, which described questionnaires measuring empowerment or manifestations of empowerment in a cancer setting. In addition, the questionnaire had to be a patient-reported outcome measure for adult cancer patients. RESULTS: Database searches identified 831 records. Title and abstract screening resulted in 482 records being excluded. The remaining 349 full text articles were retrieved and assessed for eligibility. This led to the inclusion of 33 individual instruments measuring empowerment and manifestations of empowerment. Of these, only four were specifically developed to measure empowerment, and two were originally developed for the cancer setting, whereas the remaining two were developed elsewhere, but adapted to the cancer setting. The other 29 questionnaires were not intended to measure the concept of empowerment, but focused on patient-centered care, patient competence, self-efficacy, etc. However, they were included because part of the instrument (at least five items) was considered to measure empowerment or manifestations of empowerment. CONCLUSION: Our study provides an overview of the available questionnaires, which can be used by researchers and practitioners who wish to measure the concept of empowerment among cancer patients. Very few questionnaires were explicitly developed to explore empowerment, and the review brings to light a significant lack of questionnaires that measure patient empowerment comprehensively. PMID- 28077058 TI - Imaging investigations before referral to a sarcoma center delay the final diagnosis of musculoskeletal sarcoma. AB - Background and purpose - The use of point-of-care or local investigations before referral to specialist sarcoma centers as part of a fast-track diagnostic pathway varies, and may affect the time to diagnosis. We wanted to investigate differences in time intervals and proportion of malignancy in patients who were referred after initial diagnostic investigations were performed locally and in patients who were referred without these investigations. Patients and methods - We included 545 consecutive patients who were referred to Aarhus Sarcoma Center for suspected musculoskeletal sarcoma. Data on time intervals and investigations performed were collected from questionnaires and patient records. Patients who were referred from outside Aarhus uptake area after initial MRI/CT or histology performed locally were compared with patients who were referred from Aarhus uptake area without these investigations. Results - The median total interval from first symptom to diagnosis was 166 days for outside patients referred with MRI/CT or histology, which was 91 (95% CI: 76-106) days longer than for local patients who were referred without MRI/CT or histology. Comparing the same groups, the median diagnostic interval was 41 (95% CI: 30-51) days longer for outside patients including both primary care and hospital intervals. Both the proportion of malignancies (38% vs. 14%) and the proportion of sarcomas (24% vs. 7%) were higher in the outside group referred with MRI/CT or histology than in the local group without MRI/CT or histology. Interpretation - Pre-referral investigations at a local hospital increased the diagnostic interval by at least 1 month for 50% of the patients, and the proportion of malignancy was more than doubled-to almost 40%. If investigations are to be performed before referral to a sarcoma center, they should be part of the fast-track pathway in order to ensure timely diagnosis. PMID- 28077059 TI - Ignorance is not bliss: The effect of systematic information on immigrants' knowledge of and satisfaction with the Danish healthcare system. AB - AIMS: Suboptimal healthcare utilisation and lower satisfaction with the patient doctor encounter among immigrants has been documented. Immigrants' lack of familiarity with the healthcare system has been proposed as an explanation for this. This study investigated whether a systematic delivery of information affected immigrants' knowledge of and satisfaction with the Danish healthcare system. METHODS: A prospective, randomised intervention study of 1158 adult immigrants attending two language schools in Copenhagen was conducted. Two intervention groups received written information or a 12-hour course on the Danish healthcare system, while a control group received nothing. Survey data included self-assessed knowledge, true/false questions on access and questions relating to satisfaction with the healthcare system. Data were linked to socioeconomic registry data. Logistic regression analyses were performed. RESULTS: The course improved knowledge of who to contact in the event of an accident (odds ratio (OR) = 2.67, 95% confidence interval (CI) = 1.56-4.59) but not in the event of illness. Further, it positively affected correct answers for nine out of 11 questions on the healthcare system (varying from OR = 1.87, 95% CI = 1.08-3.24 to OR = 3.11, 95% CI = 1.58-6.11). Written information positively affected correct answers for three out of 11 questions, but negatively affected one out of 11 compared with the control group. Neither intervention affected immigrants' satisfaction with the healthcare system. CONCLUSIONS: Knowledge of the healthcare system is necessary for optimal healthcare-seeking behaviour. The results may form the basis of national and international changes in immigrant reception and optimise immigrants' contact with the healthcare system. PMID- 28077062 TI - Diary. PMID- 28077060 TI - Methods to characterize the structure of food powders - a review. AB - Food powders can exist in amorphous, crystalline or mixed structure depending on the order of molecular arrangement in the powder particle matrices. In food production, the structure of powders has a greatly effect on their stability, functionality, and applicability. The undesirable structure of powders can be accidentally formed during production. Therefore, characterization of powder structure as well as quantification of amorphous-crystalline proportions presenting in the powders are essential to control the quality of products during storage and further processing. For these purposes, many analytical techniques with large differences in the degree of selectivity and sensitivity have been developed. In this review, differences in the structure of food powders are described with a focus being placed on applications of amorphous powders. Essentially, applicability of common analytical techniques including X-ray, microscopic, vapor adsorption, thermal, and spectroscopic approaches for quantitative and qualitative structural characterization of food powders is also discussed. PMID- 28077063 TI - Gendered health inequalities in mental well-being? The Nordic countries in a comparative perspective. AB - AIMS: The aims of this study were to: (a) compare gender differences in mental well-being in the Nordic countries with gender differences in 28 other countries around the world; and (b) evaluate whether gender differences in the Nordic countries remain when other social and lifestyle factors are taken into account. METHODS: Data were obtained from 32 countries around the world that participated in the 2011 health module of the International Social Survey Programme. Ordered logit regression models were used to evaluate whether gender differences remained significant when other social and lifestyle factors were considered. RESULTS: Gender differences in mental well-being in the Nordic countries are not particularly small and the four countries do not cluster together. The gender differences remain when other social and lifestyle factors are taken into account. CONCLUSIONS: There appears to be a similar Nordic health paradox for mental well-being outcomes as for physical health outcomes. Although there may be multiple reasons for this, continued gender equality, including sex segregation in the labour market and gendered expectations, are considered to play a part. PMID- 28077064 TI - An internet-based bioinformatics toolkit for plant biosecurity diagnosis and surveillance of viruses and viroids. AB - BACKGROUND: Detection and preventing entry of exotic viruses and viroids at the border is critical for protecting plant industries trade worldwide. Existing post entry quarantine screening protocols rely on time-consuming biological indicators and/or molecular assays that require knowledge of infecting viral pathogens. Plants have developed the ability to recognise and respond to viral infections through Dicer-like enzymes that cleave viral sequences into specific small RNA products. Many studies reported the use of a broad range of small RNAs encompassing the product sizes of several Dicer enzymes involved in distinct biological pathways. Here we optimise the assembly of viral sequences by using specific small RNA subsets. RESULTS: We sequenced the small RNA fractions of 21 plants held at quarantine glasshouse facilities in Australia and New Zealand. Benchmarking of several de novo assembler tools yielded SPAdes using a kmer of 19 to produce the best assembly outcomes. We also found that de novo assembly using 21-25 nt small RNAs can result in chimeric assemblies of viral sequences and plant host sequences. Such non-specific assemblies can be resolved by using 21-22 nt or 24 nt small RNAs subsets. Among the 21 selected samples, we identified contigs with sequence similarity to 18 viruses and 3 viroids in 13 samples. Most of the viruses were assembled using only 21-22 nt long virus-derived siRNAs (viRNAs), except for one Citrus endogenous pararetrovirus that was more efficiently assembled using 24 nt long viRNAs. All three viroids found in this study were fully assembled using either 21-22 nt or 24 nt viRNAs. Optimised analysis workflows were customised within the Yabi web-based analytical environment. We present a fully automated viral surveillance and diagnosis web based bioinformatics toolkit that provides a flexible, user-friendly, robust and scalable interface for the discovery and diagnosis of viral pathogens. CONCLUSIONS: We have implemented an automated viral surveillance and diagnosis (VSD) bioinformatics toolkit that produces improved viruses and viroid sequence assemblies. The VSD toolkit provides several optimised and reusable workflows applicable to distinct viral pathogens. We envisage that this resource will facilitate the surveillance and diagnosis viral pathogens in plants, insects and invertebrates. PMID- 28077065 TI - Structure alignment-based classification of RNA-binding pockets reveals regional RNA recognition motifs on protein surfaces. AB - BACKGROUND: Many critical biological processes are strongly related to protein RNA interactions. Revealing the protein structure motifs for RNA-binding will provide valuable information for deciphering protein-RNA recognition mechanisms and benefit complementary structural design in bioengineering. RNA-binding events often take place at pockets on protein surfaces. The structural classification of local binding pockets determines the major patterns of RNA recognition. RESULTS: In this work, we provide a novel framework for systematically identifying the structure motifs of protein-RNA binding sites in the form of pockets on regional protein surfaces via a structure alignment-based method. We first construct a similarity network of RNA-binding pockets based on a non-sequential-order structure alignment method for local structure alignment. By using network community decomposition, the RNA-binding pockets on protein surfaces are clustered into groups with structural similarity. With a multiple structure alignment strategy, the consensus RNA-binding pockets in each group are identified. The crucial recognition patterns, as well as the protein-RNA binding motifs, are then identified and analyzed. CONCLUSIONS: Large-scale RNA-binding pockets on protein surfaces are grouped by measuring their structural similarities. This similarity network-based framework provides a convenient method for modeling the structural relationships of functional pockets. The local structural patterns identified serve as structure motifs for the recognition with RNA on protein surfaces. PMID- 28077066 TI - The essential requirement of an animal heme peroxidase protein during the wing maturation process in Drosophila. AB - BACKGROUND: Thus far, a handful of genes have been shown to be related to the wing maturation process in insects. A novel heme peroxidase enzyme known as curly suppressor (Cysu)(formerly CG5873), have been characterized in this report because it is involved in wing morphogenesis. Using bioinformatics tools we found that Cysu is remarkably conserved in the genus Drosophila (>95%) as well as in invertebrates (>70%), although its vertebrate orthologs show poor homology. Time lapse imaging and histochemical analyses have confirmed that the defective wing phenotype of Cysu is not a result of any underlying cellular alterations; instead, its wings fail to expand in mature adults. RESULTS: The precise requirement of Cysu in wings was established by identifying a bona fide mutant of Cysu from the Bloomington Drosophila Stock Centre collection. Its requirement in the wing has also been shown by RNA knockdown of the gene. Subsequent transgenic rescue of the mutant wing phenotype with the wild-type gene confirmed the phenotype resulting from Cysu mutant. With appropriate GAL4 driver like engrailed GAL4, the Cysu phenotype was compartmentalized, which raises a strong possibility that Cysu is not localized in the extracellular matrix (ECM); hence, Cysu is not engaged in bonding the dorsal and ventral cuticular layers. Finally, shortened lifespan of the Cysu mutant suggests it is functionally essential for other biological processes as well. CONCLUSION: Cysu, a peroxinectin-like gene, is required during the wing maturation process in Drosophila because as a heme peroxidase, Cysu is capable of utilizing H2O2, which plays an essential role in post-eclosion wing morphogenesis. PMID- 28077067 TI - Use of antidepressants during pregnancy in the Netherlands: observational study into postpartum interventions. AB - BACKGROUND: Psychiatric disorders and use of selective antidepressants during pregnancy can have negative effects on mother and infant postpartum. This study aimed to provide evidence-based recommendations on observation of antidepressant exposed mother-infant dyads. METHODS: In this observational study, mother-infant dyads were observed for possible consequences of either the maternal psychiatric disorder or fetal exposure to selective antidepressants during pregnancy. These possible complications can lead to medical interventions, including 1. adjustment of antidepressants 2. admission to the psychiatric department 3. additional investigations due to indistinctness about the origin of neonatal symptoms 4. treatment of poor neonatal adaptation and 5. consultation of an external organization for additional care. The type, number and time to medical interventions were analyzed. RESULTS: In 61% of the 324 included mother-infant dyads one or more intrventions were performed. Adjustment of antidepressants and treatment of poor neonatal adaptation were most prevalent. In 75% of dyads the final intervention was performed within 48 h. CONCLUSIONS: The high prevalence and type of medical interventions requires professional observation of all mother infant dyads exposed to selective antidepressants. In the absence of specialized home care, hospital admission is indicated whereby an observational period of 48 h seems sufficient for most dyads. PMID- 28077068 TI - Structure and evolution of the filaggrin gene repeated region in primates. AB - BACKGROUND: The evolutionary dynamics of repeat sequences is quite complex, with some duplicates never having differentiated from each other. Two models can explain the complex evolutionary process for repeated genes-concerted and birth and-death, of which the latter is driven by duplications maintained by selection. Copy number variations caused by random duplications and losses in repeat regions may modulate molecular pathways and therefore affect phenotypic characteristics in a population, resulting in individuals that are able to adapt to new environments. In this study, we investigated the filaggrin gene (FLG), which codes for filaggrin-an important component of the outer layers of mammalian skin and contains tandem repeats that exhibit copy number variation between and within species. To examine which model best fits the evolutionary pathway for the complete tandem repeats within a single exon of FLG, we determined the repeat sequences in crab-eating macaque (Macaca fascicularis), orangutan (Pongo abelii), gorilla (Gorilla gorilla), and chimpanzee (Pan troglodytes) and compared these with the sequence in human (Homo sapiens). RESULTS: In this study we compared concerted and birth-and-death evolution models, commonly used for gene copies. We found that there is high nucleotide diversity between filaggrin repeat regions, which fits the birth-and-death model. Phylogenetic analyses also suggested that independent duplication events created the repeat sequences in crab-eating macaques and orangutans, while different duplication and loss events created the repeats in gorillas, chimpanzees, and humans. Comparison of the repeat sequences detected purifying selection within species and lineage-specific duplications across species. We also found variation in the length of the repeated region within species such as chimpanzee and crab-eating macaque. CONCLUSIONS: We conclude that the copy number variation in the repeat sequences of FLG between primates may be a consequence of species-specific divergence and expansion. PMID- 28077069 TI - A pilot study of brisk walking in sedentary combination antiretroviral treatement (cART)- treated patients: benefit on soluble and cell inflammatory markers. AB - BACKGROUND: Chronic HIV infection is associated with low-level inflammation and increased risk of chronic diseases and mortality. The objective was to assess the effects of moderate intensity exercise on metabolic and inflammatory markers in HIV-infected treated persons. METHODS: This was a pilot study enrolling cART treated, sedentary persons with metabolic complications in a 12-week protocol, consisting of three sessions per week of 60 min brisk walking with (strength-walk group) or without (walk group) 30 min circuit-training. Assessments at baseline and week 12 (W12) included body morphometrics and total body dual-energy X-ray absorptiometry; lipid and glucose blood profile; plasma level of high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), D-dimer, interleukin-18 (IL 18), soluble CD14, and CD38 and HLA-DR expression on CD4+ and CD8+ T-cells. RESULTS: Forty-nine patients were included and 35 (71%) completed the program: 21 in the walk and 14 in the strength-walk group. At W12, significant improvements were observed of body mass index, waist and hip circumference, and total cholesterol both overall and in the walk group, and of LDL cholesterol in both training groups. In the whole group, significant reductions were observed in hsCRP, IL-6, D-dimer, IL-18, and of CD8+/CD38+/HLA-DR+ cell frequencies. HsCRP and CD8+/CD38+/HLA-DR+ frequency decreased significantly in both training groups when examined separately whereas IL-6 and D-dimer in the walk group only. CONCLUSIONS: Brisk walking, with or without strength exercise, could improve lipid profile and inflammatory markers in chronic HIV infection. TRIAL REGISTRATION: ACTRN12615001258549, registered 17 November 2015, "retrospectively registered" Web address of trial: http://www.ANZCTR.org.au/ACTRN12615001258549.aspx. PMID- 28077070 TI - SCOPA and META-SCOPA: software for the analysis and aggregation of genome-wide association studies of multiple correlated phenotypes. AB - BACKGROUND: Genome-wide association studies (GWAS) of single nucleotide polymorphisms (SNPs) have been successful in identifying loci contributing genetic effects to a wide range of complex human diseases and quantitative traits. The traditional approach to GWAS analysis is to consider each phenotype separately, despite the fact that many diseases and quantitative traits are correlated with each other, and often measured in the same sample of individuals. Multivariate analyses of correlated phenotypes have been demonstrated, by simulation, to increase power to detect association with SNPs, and thus may enable improved detection of novel loci contributing to diseases and quantitative traits. RESULTS: We have developed the SCOPA software to enable GWAS analysis of multiple correlated phenotypes. The software implements "reverse regression" methodology, which treats the genotype of an individual at a SNP as the outcome and the phenotypes as predictors in a general linear model. SCOPA can be applied to quantitative traits and categorical phenotypes, and can accommodate imputed genotypes under a dosage model. The accompanying META-SCOPA software enables meta analysis of association summary statistics from SCOPA across GWAS. Application of SCOPA to two GWAS of high-and low-density lipoprotein cholesterol, triglycerides and body mass index, and subsequent meta-analysis with META-SCOPA, highlighted stronger association signals than univariate phenotype analysis at established lipid and obesity loci. The META-SCOPA meta-analysis also revealed a novel signal of association at genome-wide significance for triglycerides mapping to GPC5 (lead SNP rs71427535, p = 1.1x10-8), which has not been reported in previous large-scale GWAS of lipid traits. CONCLUSIONS: The SCOPA and META-SCOPA software enable discovery and dissection of multiple phenotype association signals through implementation of a powerful reverse regression approach. PMID- 28077071 TI - An integrated analysis of QTL mapping and RNA sequencing provides further insights and promising candidates for pod number variation in rapeseed (Brassica napus L.). AB - BACKGROUND: As the most important yield component in rapeseed (Brassica napus L.), pod number is determined by a series of successive growth and development processes. Pod number shows extensive variation in rapeseed natural germplasm, which is valuable for genetic improvement. However, the genetic and especially the molecular mechanism for this kind of variation are poorly understood. In this study, we conducted QTL mapping and RNA sequencing, respectively, using the BnaZNRIL population and its two parental cultivars Zhongshuang11 and No.73290 which showed significant difference in pod number, primarily due to the difference in floral organ number. RESULT: A total of eight QTLs for pod number were identified using BnaZNRIL population with a high-density SNP linkage map, each was distributed on seven linkage groups and explained 5.8-11.9% of phenotypic variance. Then, they were integrated with those previously detected in BnaZNF2 population (deriving from same parents) and resulted in 15 consensus QTLs. Of which, seven QTLs were identical to other studies, whereas the other eight should be novel. RNA sequencing of the shoot apical meristem (SAM) at the formation stage of floral bud primordia identified 9135 genes that were differentially expressed between the two parents. Gene ontology (GO) analysis showed that the top two enriched groups were S-assimilation, providing an essential nutrient for the synthesis of diverse metabolites, and polyamine metabolism, serving as second messengers that play an essential role in flowering genes initiation. KEGG analysis showed that the top three overrepresented pathways were carbohydrate (707 genes), amino acid (390 genes) and lipid metabolisms (322 genes). In silico mapping showed that 647 DEGs were located within the confidence intervals of 15 consensus QTLs. Based on annotations of Arabidopsis homologs corresponding to DEGs, nine genes related to meristem growth and development were considered as promising candidates for six QTLs. CONCLUSION: In this study, we discovered the first repeatable major QTL for pod number in rapeseed. In addition, RNA sequencing was performed for SAM in rapeseed, which provides new insights into the determination of floral organ number. Furthermore, the integration of DEGs and QTLs identified promising candidates for further gene cloning and mechanism study. PMID- 28077072 TI - Diabetes mellitus medication use and catastrophic healthcare expenditure among adults aged 50+ years in China and India: results from the WHO study on global AGEing and adult health (SAGE). AB - BACKGROUND: Expenditure on medications for highly prevalent chronic conditions such as diabetes mellitus (DM) can result in financial impoverishment. People in developing countries and in low socioeconomic status groups are particularly vulnerable. China and India currently hold the world's two largest DM populations. Both countries are ageing and undergoing rapid economic development, urbanisation and social change. This paper assesses the determinants of DM medication use and catastrophic expenditure on medications in older adults with DM in China and India. METHODS: Using national standardised data collected from adults aged 50 years and above with DM (self-reported) in China (N = 773) and India (N = 463), multivariable logistic regression describes: 1) association between respondents' socio-demographic and health behavioural characteristics and the dependent variable, DM medication use, and 2) association between DM medication use (independent variable) and household catastrophic expenditure on medications (dependent variable) (China: N = 630; India: N = 439). The data source is the World Health Organization (WHO) Study on global AGEing and adult health (SAGE) Wave 1 (2007-2010). RESULTS: Prevalence of DM medication use was 87% in China and 71% in India. Multivariable analysis indicates that people reporting lifestyle modification were more likely to use DM medications in China (OR = 6.22) and India (OR = 8.45). Women were more likely to use DM medications in China (OR = 1.56). Respondents in poorer wealth quintiles in China were more likely to use DM medications whereas the reverse was true in India. Almost 17% of people with DM in China experienced catastrophic healthcare expenditure on medications compared with 7% in India. Diabetes medication use was not a statistically significant predictor of catastrophic healthcare expenditure on medications in either country, although the odds were 33% higher among DM medications users in China (OR = 1.33). CONCLUSIONS: The country comparison reflects major public policy differences underpinned by divergent political and ideological frameworks. The DM epidemic poses huge public health challenges for China and India. Ensuring equitable and affordable access to medications for DM is fundamental for healthy ageing cohorts, and is consistent with the global agenda for universal healthcare coverage. PMID- 28077073 TI - Student midwives' perceptions on the organisation of maternity care and alternative maternity care models in the Netherlands - a qualitative study. AB - BACKGROUND: A major change in the organisation of maternity care in the Netherlands is under consideration, going from an echelon system where midwives provide primary care in the community and refer to obstetricians for secondary and tertiary care, to a more integrated maternity care system involving midwives and obstetricians at all care levels. Student midwives are the future maternity care providers and they may be entering into a changing maternity care system, so inclusion of their views in the discussion is relevant. This study aimed to explore student midwives' perceptions on the current organisation of maternity care and alternative maternity care models, including integrated care. METHODS: This qualitative study was based on the interpretivist/constructivist paradigm, using a grounded theory design. Interviews and focus groups with 18 female final year student midwives of the Midwifery Academy Amsterdam Groningen (AVAG) were held on the basis of a topic list, then later transcribed, coded and analysed. RESULTS: Students felt that inevitably there will be a change in the organisation of maternity care, and they were open to change. Participants indicated that good collaboration between professions, including a shared system of maternity notes and guidelines, and mutual trust and respect were important aspects of any alternative model. The students indicated that client-centered care and the safeguarding of the physiological, normalcy approach to pregnancy and birth should be maintained in any alternative model. Students expressed worries that the role of midwives in intrapartum care could become redundant, and thus they are motivated to take on new roles and competencies, so they can ensure their own role in intrapartum care. CONCLUSIONS: Final year student midwives recognise that change in the organisation of maternity care is inevitable and have an open attitude towards changes if they include good collaboration, client-centred care and safeguards for normal physiological birth. The graduating midwives are motivated to undertake an expanded intrapartum skill set. It can be important to involve students' views in the discussion, because they are the future maternity care providers. PMID- 28077074 TI - Single- and multiple viral respiratory infections in children: disease and management cannot be related to a specific pathogen. AB - BACKGROUND: The number of viral pathogens associated with pediatric acute respiratory tract infection (ARI) has grown since the introduction of reverse transcription real-time polymerase chain reaction (RT-PCR) assays. Multiple viruses are detected during a single ARI episode in approximately a quarter of all cases. The clinical relevance of these multiple detections is unclear, as is the role of the individual virus. We therefore investigated the correlation between clinical data and RT-PCR results in children with single- and multiple viral ARI. METHODS: Data from children with ARI were prospectively collected during two winter seasons. RT-PCR testing for 15 viruses was performed in 560 ARI episodes. In the patients with a single-viral etiology, clinical data, laboratory findings, patient management- and outcome data were compared between the different viruses. With this information, we compared data from children of whom RT-PCR data were negative, with children with single- and multiple viral positive results. RESULTS: The viral detection rate was 457/560 (81.6%) of which 331/560 (59.1%) were single infections and 126/560 (22.5%) were multiple infections. In single viral infections, some statistically significant differences in demographics, clinical findings, disease severity and outcome were found between children with different viral etiologies. However, no clinically recognizable pattern was established to be virus-specific. In a multivariate analysis, the only variables that were correlated with longer hospital stay were the use of oxygen and nebulizer therapy, irrespective of the viral pathogen. Children with RT-PCR positive test results had a significant higher disease severity, fever, length of hospital stay, days of extra oxygen supply, and days of antibiotic treatment than children with a negative RT-PCR test result. For children with single- versus children with multiple positive RT-PCR test results, these differences were not significant. CONCLUSIONS: Disease (severity), management and outcome in pediatric ARI are not associated with a specific virus. Single- and multiple viral ARI do not significantly differ with regard to clinical outcome and patient management. For general pediatrics, RT-PCR assays should be restricted to pathogens for which therapy is available or otherwise may have clinical consequences. Further research with an extended panel of RT-PCR assays and a larger number of inclusions is necessary to further validate our findings. PMID- 28077075 TI - Protection via a ROM4 DNA vaccine and peptide against Toxoplasma gondii in BALB/c mice. AB - BACKGROUND: Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan parasite with a broad host range including most warm-blooded animals, including humans. T. gondii surface antigen 1 (SAG1) is a well-characterized T. gondii antigen. T. gondii expresses five nonmitochondrial rhomboid intramembrane proteases, TgROM1-5. TgROM4 is uniformly distributed on the surface of T. gondii and involved in regulating MIC2, MIC3, MIC6, and AMA1 during T. gondii invasion of host cells. Bioinformatics have predicted ROM4 B-cell and T-cell epitopes. Immunization strategy is also a key factor in determining the effectiveness of the immune response and has gained increasing attention in T. gondii vaccine research. In this study, we used a DNA prime-peptide boost vaccination regimen to assess the protective efficacy of various vaccination strategies using TgROM4. METHODS: We identified a polypeptide (YALLGALIPYCVEYWKSIPR) using a bioinformatics approach, and immunized mice using a DNA-prime and polypeptide boost regimen. BALB/c mice were randomly divided into six groups, including three experimental groups (peptide, pROM4 and pROM4/peptide) and three control groups (PBS, pEGFP-C1 and pSAG1). Mice were then immunized intramuscularly four times. After immunization, IgG and cytokine productions were determined using enzyme linked immunosorbent assays. The survival time of mice was evaluated after challenge with tachyzoites of T. gondii RH strain. Additionally, the number of cysts in the brain was determined after intragastric challenge with cysts of T. gondii PRU strain. RESULTS: Mice vaccinated with different immunization regimens (peptide, pROM4 and pROM4/peptide) elicited specific humoral and cellular responses, with high levels of IgG, IgG2a, and interferon (IFN)-gamma. Moreover, IgG, IgG2a and IFN-gamma levels were highest in the pROM4/peptide group. Immunized mice, especially those in the pROM4/peptide group, had prolonged survival times after challenge with tachyzoites and reduced numbers of brain cysts after infection compared with negative controls. CONCLUSION: A DNA prime peptide boost regimen based on ROM4 elicited the highest level of humoral and cellular immune responses among immunization regimens, and may be a promising approach to increase the efficacy of DNA immunization. PMID- 28077076 TI - Estimating a population cumulative incidence under calendar time trends. AB - BACKGROUND: The risk of a disease or psychiatric disorder is frequently measured by the age-specific cumulative incidence. Cumulative incidence estimates are often derived in cohort studies with individuals recruited over calendar time and with the end of follow-up governed by a specific date. It is common practice to apply the Kaplan-Meier or Aalen-Johansen estimator to the total sample and report either the estimated cumulative incidence curve or just a single point on the curve as a description of the disease risk. METHODS: We argue that, whenever the disease or disorder of interest is influenced by calendar time trends, the total sample Kaplan-Meier and Aalen-Johansen estimators do not provide useful estimates of the general risk in the target population. We present some alternatives to this type of analysis. RESULTS: We show how a proportional hazards model may be used to extrapolate disease risk estimates if proportionality is a reasonable assumption. If not reasonable, we instead advocate that a more useful description of the disease risk lies in the age-specific cumulative incidence curves across strata given by time of entry or perhaps just the end of follow-up estimates across all strata. Finally, we argue that a weighted average of these end of follow-up estimates may be a useful summary measure of the disease risk within the study period. CONCLUSIONS: Time trends in a disease risk will render total sample estimators less useful in observational studies with staggered entry and administrative censoring. An analysis based on proportional hazards or a stratified analysis may be better alternatives. PMID- 28077077 TI - Estimating genomic diversity and population differentiation - an empirical comparison of microsatellite and SNP variation in Arabidopsis halleri. AB - BACKGROUND: Microsatellite markers are widely used for estimating genetic diversity within and differentiation among populations. However, it has rarely been tested whether such estimates are useful proxies for genome-wide patterns of variation and differentiation. Here, we compared microsatellite variation with genome-wide single nucleotide polymorphisms (SNPs) to assess and quantify potential marker-specific biases and derive recommendations for future studies. Overall, we genotyped 180 Arabidopsis halleri individuals from nine populations using 20 microsatellite markers. Twelve of these markers were originally developed for Arabidopsis thaliana (cross-species markers) and eight for A. halleri (species-specific markers). We further characterized 2 million SNPs across the genome with a pooled whole-genome re-sequencing approach (Pool-Seq). RESULTS: Our analyses revealed that estimates of genetic diversity and differentiation derived from cross-species and species-specific microsatellites differed substantially and that expected microsatellite heterozygosity (SSR-H e) was not significantly correlated with genome-wide SNP diversity estimates (SNP-H e and theta Watterson) in A. halleri. Instead, microsatellite allelic richness (A r) was a better proxy for genome-wide SNP diversity. Estimates of genetic differentiation among populations (F ST) based on both marker types were correlated, but microsatellite-based estimates were significantly larger than those from SNPs. Possible causes include the limited number of microsatellite markers used, marker ascertainment bias, as well as the high variance in microsatellite-derived estimates. In contrast, genome-wide SNP data provided unbiased estimates of genetic diversity independent of whether genome- or only exome-wide SNPs were used. Further, we inferred that a few thousand random SNPs are sufficient to reliably estimate genome-wide diversity and to distinguish among populations differing in genetic variation. CONCLUSIONS: We recommend that future analyses of genetic diversity within and differentiation among populations use randomly selected high-throughput sequencing-based SNP data to draw conclusions on genome-wide diversity patterns. In species comparable to A. halleri, a few thousand SNPs are sufficient to achieve this goal. PMID- 28077078 TI - Transcriptomic evidence for the control of soybean root isoflavonoid content by regulation of overlapping phenylpropanoid pathways. AB - BACKGROUND: Isoflavonoids are a class of specialized metabolites found predominantly in legumes. They play a role in signaling for symbiosis with nitrogen-fixing bacteria and inhibiting pathogen infection. RESULTS: A transcriptomic approach using soybean cultivars with high (Conrad and AC Colombe) and low (AC Glengarry and Pagoda) root isoflavonoid content was used to find elements that underlie this variation. Two genes, encoding the flavonoid metabolizing enzymes, flavonoid 3'-hydroxylase (GmF3'H) and dihydroflavonol 4 reductase (GmDFR), had lower expression levels in high isoflavonoid cultivars. These enzymes compete with isoflavonoid biosynthetic enzymes for the important branch-point substrate naringenin and its derivatives. Differentially expressed genes, between the two sets of cultivars, encode transcription factors, transporters and enzymatic families of interest, such as oxidoreductases, hydrolases and transferases. In addition, genes annotated with stress and disease response were upregulated in high isoflavonoid cultivars. CONCLUSIONS: Coordinated regulation of genes involved in flavonoid metabolism could redirect flux into the isoflavonoid branch of the phenylpropanoid pathway, by reducing competition for the flavanone substrate. These candidate genes could help identify mechanisms to overcome the endogenous bottleneck to isoflavonoid production, facilitate biosynthesis in heterologous systems, and enhance crop resistance against pathogenic infections. PMID- 28077079 TI - A double SIMEX approach for bivariate random-effects meta-analysis of diagnostic accuracy studies. AB - BACKGROUND: Bivariate random-effects models represent a widely accepted and recommended approach for meta-analysis of test accuracy studies. Standard likelihood methods routinely used for inference are prone to several drawbacks. Small sample size can give rise to unreliable inferential conclusions and convergence issues make the approach unappealing. This paper suggests a different methodology to address such difficulties. METHODS: A SIMEX methodology is proposed. The method is a simulation-based technique originally developed as a correction strategy within the measurement error literature. It suits the meta analysis framework as the diagnostic accuracy measures provided by each study are prone to measurement error. SIMEX can be straightforwardly adapted to cover different measurement error structures and to deal with covariates. The effortless implementation with standard software is an interesting feature of the method. RESULTS: Extensive simulation studies highlight the improvement provided by SIMEX over likelihood approach in terms of empirical coverage probabilities of confidence intervals under different scenarios, independently of the sample size and the values of the correlation between sensitivity and specificity. A remarkable amelioration is obtained in case of deviations from the normality assumption for the random-effects distribution. From a computational point of view, the application of SIMEX is shown to be neither involved nor subject to the convergence issues affecting likelihood-based alternatives. Application of the method to a diagnostic review of the performance of transesophageal echocardiography for assessing ascending aorta atherosclerosis enables overcoming limitations of the likelihood procedure. CONCLUSIONS: The SIMEX methodology represents an interesting alternative to likelihood-based procedures for inference in meta-analysis of diagnostic accuracy studies. The approach can provide more accurate inferential conclusions, while avoiding convergence failure and numerical instabilities. The application of the method in the R programming language is possible through the code which is made available and illustrated using the real data example. PMID- 28077080 TI - Should patients older than 65 years be offered a second kidney transplant? AB - BACKGROUND: Age and number of recipients in need of kidney re-transplantation are increasing. Re-transplantation practices and outcomes in elderly recipients are not previously explored. We aimed to retrospectively evaluate the outcomes of recipients 65 years and older receiving their second deceased donor allograft. METHODS: The study was designed as a retrospective registry based study. All recipients 65 years or older who received a deceased donor kidney transplant at Oslo University Hospital between 2000 and 2014 were included in the study. Survival outcomes were compared between recipients of first (TX1) and second (TX2) allograft. Survival analyses were performed using the Kaplan-Meier method and Cox proportional hazard models with patient survival, uncensored graft survival and death-censored graft survival as outcomes in the analyses. RESULTS: Seven hundred and thirty-tree recipients > 65 years received a first (n = 687) or second (n = 46) deceased donor kidney transplant. Five years uncensored graft survival rates were 64% in TX 2 and 67% in TX 1 (P= 0.789). Estimated five years graft survival rates censored for death with functioning graft were 88% in TX2 and 90% in TX1 (P=0.475). Adjusted hazard ratio for uncensored graft loss (TX2 vs. TX1) was 1.24 (95% CI 0.77 - 2.00). Adjusted hazard ratio for graft loss censored for death with functioning graft (TX2 vs. TX1) was 1.70 (0.72-4.02). CONCLUSIONS: Older recipients of second transplants have outcomes that are comparable to the outcomes of age-matched first transplant recipients, and far better than previously documented for older transplant candidates remaining on dialysis treatment. Advanced age by itself should not be a contraindication for re-transplantation. Best results are achieved with short time on dialysis before re-transplantation. PMID- 28077081 TI - Antigen presenting capacity of murine splenic myeloid cells. AB - BACKGROUND: The spleen is an important site for hematopoiesis. It supports development of myeloid cells from bone marrow-derived precursors entering from blood. Myeloid subsets in spleen are not well characterised although dendritic cell (DC) subsets are clearly defined in terms of phenotype, development and functional role. Recently a novel dendritic-like cell type in spleen named 'L-DC' was distinguished from other known dendritic and myeloid cells by its distinct phenotype and developmental origin. That study also redefined splenic eosinophils as well as resident and inflammatory monocytes in spleen. RESULTS: L-DC are shown to be distinct from known splenic macrophages and monocyte subsets. Using a new flow cytometric procedure, it has been possible to identify and isolate L-DC in order to assess their functional competence and ability to activate T cells both in vivo and in vitro. L-DC are readily accessible to antigen given intravenously through receptor-mediated endocytosis. They are also capable of CD8+ T cell activation through antigen cross presentation, with subsequent induction of cytotoxic effector T cells. L-DC are MHCII- cells and unable to activate CD4+ T cells, a property which clearly distinguishes them from conventional DC. The myeloid subsets of resident monocytes, inflammatory monocytes, neutrophils and eosinophils, were found to have varying capacities to take up antigen, but were uniformly unable to activate either CD4+ T cells or CD8+ T cells. CONCLUSION: The results presented here demonstrate that L-DC in spleen are distinct from other myeloid cells in that they can process antigen for CD8+ T cell activation and induction of cytotoxic effector function, while both L-DC and myeloid subsets remain unable to activate CD4+ T cells. The L-DC subset in spleen is therefore distinct as an antigen presenting cell. PMID- 28077082 TI - The Arabidopsis paralogs, PUB46 and PUB48, encoding U-box E3 ubiquitin ligases, are essential for plant response to drought stress. AB - BACKGROUND: Plants respond to abiotic stress on physiological, biochemical and molecular levels. This includes a global change in their cellular proteome achieved by changes in the pattern of their protein synthesis and degradation. The ubiquitin-proteasome system (UPS) is a key player in protein degradation in eukaryotes. Proteins are marked for degradation by the proteasome by coupling short chains of ubiquitin polypeptides in a three-step pathway. The last and regulatory stage is catalyzed by a member of a large family of substrate-specific ubiquitin ligases. RESULTS: We have identified AtPUB46 and AtPUB48-two paralogous genes that encode ubiquitin ligases (E3s)-to have a role in the plant environmental response. The AtPUB46, -47, and -48 appear as tandem gene copies on chromosome 5, and we present a phylogenetic analysis that traces their evolution from an ancestral PUB-ARM gene. Single homozygous T-DNA insertion mutants of AtPUB46 and AtPUB48 displayed hypersensitivity to water stress; this was not observed for similar mutants of AtPUB47. Although the three genes show a similar spatial expression pattern, the steady state levels of their transcripts are differentially affected by abiotic stresses and plant hormones. CONCLUSIONS: AtPUB46 and AtPUB48 encode plant U-Box E3s and are involved in the response to water stress. Our data suggest that despite encoding highly homologous proteins, AtPUB46 and AtPUB48 biological activity does not fully overlap. PMID- 28077083 TI - Evaluation of the line probe assay for the rapid detection of bacterial meningitis pathogens in cerebrospinal fluid samples from children. AB - BACKGROUND: The aim of this study is to compare the diagnostic performance of the line probe assay (LPA) with conventional multiplex polymerase chain reaction (PCR) for Streptococcus pneumoniae as well as real-time PCR for Neisseria meningitidis and Haemophilus influenzae type b (Hib) in cerebrospinal fluid (CSF) samples from children during the multicenter national surveillance of bacterial meningitis between the years 2006 and 2009 in Turkey. RESULTS: During the study period 1460 subjects were enrolled and among them 841 (57%) met the criteria for probable bacterial meningitis. The mean age of subjects was 51 +/- 47 months (range, 1-212 months). We performed the line probe assay in 751 (89%) CSF samples of 841 probable bacterial meningitis cases, of whom 431 (57%) were negative, 127 (17%) were positive for S. pneumoniae, 53 (7%) were positive for H. influenzae type b, and 41 (5%) were positive for N. meningitidis. The LPA was positive in 19 of 23 (82%) S. pneumoniae samples, 4 of 6 (67%) N. meningitidis samples and 2 of 2 (100%) Hib samples in CSF culture-positive cases. The specificity of the LPA for all of S. pneumoniae, H. influenzae type b, and N. meningitidis was 88% (95% CI: 85-91%), when using the standard PCR as a reference. The specificity of LPA for each of S. pneumoniae, H. influenzae type b, and N. meningitidis was 93% (95% CI: 89-95%), 96% (95% CI: 94-98%), and 99% (95% CI: 97-99%), respectively. For all of S. pneumoniae, H. influenzae type b and N. meningitidis the sensitivity of the LPA was 76% (95% CI: 70-82%) and for each of S. pneumoniae, H. influenzae type b and N. meningitidis was 72% (95% CI:63-79%), 88% (95% CI: 73-95%), and 81% (95% CI:67-92%), respectively. CONCLUSIONS: The LPA assay can be used to detect common bacterial meningitis pathogens in CSF samples, but the assay requires further improvement. PMID- 28077084 TI - Erratum to: Power estimation and sample size determination for replication studies of genome-wide association studies. PMID- 28077085 TI - Erythropoiesis stimulating agents and reno-protection: a meta-analysis. AB - BACKGROUND: Erythropoiesis stimulating agents (ESAs) were proposed to enhance survival of renal tissues through direct effects via activation of EPO receptors on renal cells resulting in reduced cell apoptosis, or indirect effects via increased oxygen delivery due to increased numbers of Hb containing red blood cells. Thus through several mechanisms there may be benefit of ESA administration on kidney disease progression and kidney function in renal patients. However conflicting ESA reno-protection outcomes have been reported in both pre-clinical animal studies and human clinical trials. To better understand the potential beneficial effects of ESAs on renal-patients, meta-analyses of clinical trials is needed. METHODS: Literature searches and manual searches of references lists from published studies were performed. Controlled trials that included ESA treatment on renal patients with relevant renal endpoints were selected. RESULTS: Thirty two ESA controlled trials in 3 categories of intervention were identified. These included 7 trials with patients who had a high likelihood of AKI, 7 trials with kidney transplant patients and 18 anemia correction trials with chronic kidney disease (predialysis) patients. There was a trend toward improvement in renal outcomes in the ESA treated arm of AKI and transplant trials, but none reached statistical significance. In 12 of the anemia correction trials, meta-analyses showed no difference in renal outcomes with the anemia correction but both arms received some ESA treatment making it difficult to assess effects of ESA treatment alone. However, in 6 trials the low Hb arm received no ESAs and meta analysis also showed no difference in renal outcomes, consistent with no benefit of ESA/ Hb increase. CONCLUSIONS: Most ESA trials were small with modest event rates. While trends tended to favor the ESA treatment arm, these meta-analyses showed no reduction of incidence of AKI, no reduction in DGF or improvement in 1 year graft survival after renal transplantation and no significant delay in progression of CKD. These results do not support significant clinical reno protection by ESAs. PMID- 28077086 TI - The measure of success: geographic isolation promotes diversification in Pachydactylus geckos. AB - BACKGROUND: Geckos of the genus Pachydactylus and their close relatives comprise the most species-rich clade of lizards in sub-Saharan Africa. Many explanations have been offered to explain species richness patterns of clades. In the Pachydactylus group, one possible explanation is a history of diversification via geographic isolation. If geographic isolation has played a key role in facilitating diversification, then we expect species in more species-rich subclades to have smaller ranges than species in less diverse subclades. We also expect traits promoting geographic isolation to be correlated with small geographic ranges. In order to test these expectations, we performed phylogenetic analyses and tested for correlations among body size, habitat choice, range sizes, and diversification rates in the Pachydactylus group. RESULTS: Both body size and habitat use are inferred to have shifted multiple times across the phylogeny of the Pachydactylus group, with large size and generalist habitat use being ancestral for the group. Geographic range size is correlated with both of these traits. Small-bodied species have more restricted ranges than large-bodied species, and rock-dwelling species have more restricted ranges than either terrestrial or generalist species. Rock-dwelling and small body size are also associated with higher rates of diversification, and subclades retaining ancestral conditions for these traits are less species rich than subclades in which shifts to small body size and rocky habitat use have occurred. The phylogeny also illustrates inadequacies of the current taxonomy of the group. CONCLUSIONS: The results are consistent with a model in which lineages more likely to become geographically isolated diversify to a greater extent, although some patterns also resemble those expected of an adaptive radiation in which ecological divergence acts as a driver of speciation. Therefore, the Pachydactylus group may represent an intermediate between clades in which radiation is adaptive versus those in which it is non-adaptive. PMID- 28077087 TI - Embryogenesis in the parasitic nematode Heterodera glycines is independent of host-derived hatching stimulation. AB - BACKGROUND: Many parasites regulate their development to synchronize their life cycle with a compatible host. The parasitic nematode Heterodera glycines displays incomplete host-mediated hatching behavior wherein some H. glycines individuals hatch only in the presence of a host-derived cue while others hatch in water alone. Furthermore, H. glycines shows variable hatching behavior based on oviposition location. The mechanisms regulating this hatching variability are unknown. In this study, we established a detailed timeline of the H. glycines pre hatch development from early embryogenesis to the pre-hatched J2. These descriptive data were then used to test hypotheses regarding the effect of host stimulus and oviposition location on pre-hatch development. RESULTS: We found that H. glycines develops from a single-cell egg to a fully formed J2 in approximately 172 hours. The stylet-based mouthpart, which is used to pierce the eggshell during hatching, is not completely formed until late in pre-hatch J2 development and is preceded by the formation of stylet protractor muscles. We also found that the primary motor nervous system of H. glycines did not complete development until late in pre-hatch J2 development. These data suggest possible structural requirements for H. glycines hatching. As expected, exposure of H. glycines eggs to host-derived cues increased the percentage of nematodes that hatched. However, exposure to hatching cues did not affect pre-hatch development. Similarly, we found no obvious differences in the pre-hatch developmental timeline between eggs laid in an egg sac or retained within the mother. CONCLUSIONS: The pattern of early embryonic development in H. glycines was very similar to that recently described in the related parasitic nematode Meloidogyne incognita. However, the speed of H. glycines pre-hatch development was approximately three times faster than reported for M. incognita. Our results suggest that hatching stimulants do not affect embryogenesis itself but only influence the hatching decision once J2 development is complete. Similarly, the oviposition location does not alter the rate of embryogenesis. These results provide insight into the primary survival mechanism for this important parasite. PMID- 28077088 TI - Integrated RNA-seq and DNase-seq analyses identify phenotype-specific BMP4 signaling in breast cancer. AB - BACKGROUND: Bone morphogenetic protein 4 (BMP4) plays an important role in cancer pathogenesis. In breast cancer, it reduces proliferation and increases migration in a cell line-dependent manner. To characterize the transcriptional mediators of these phenotypes, we performed RNA-seq and DNase-seq analyses after BMP4 treatment in MDA-MB-231 and T-47D breast cancer cells that respond to BMP4 with enhanced migration and decreased cell growth, respectively. RESULTS: The RNA-seq data revealed gene expression changes that were consistent with the in vitro phenotypes of the cell lines, particularly in MDA-MB-231, where migration-related processes were enriched. These results were confirmed when enrichment of BMP4 induced open chromatin regions was analyzed. Interestingly, the chromatin in transcription start sites of differentially expressed genes was already open in unstimulated cells, thus enabling rapid recruitment of transcription factors to the promoters as a response to stimulation. Further analysis and functional validation identified MBD2, CBFB, and HIF1A as downstream regulators of BMP4 signaling. Silencing of these transcription factors revealed that MBD2 was a consistent activator of target genes in both cell lines, CBFB an activator in cells with reduced proliferation phenotype, and HIF1A a repressor in cells with induced migration phenotype. CONCLUSIONS: Integrating RNA-seq and DNase-seq data showed that the phenotypic responses to BMP4 in breast cancer cell lines are reflected in transcriptomic and chromatin levels. We identified and experimentally validated downstream regulators of BMP4 signaling that relate to the different in vitro phenotypes and thus demonstrate that the downstream BMP4 response is regulated in a cell type-specific manner. PMID- 28077089 TI - Control beliefs and risk for 4-year mortality in older adults: a prospective cohort study. AB - BACKGROUND: Control beliefs are important psychological factors that likely contribute to heterogeneity in health outcomes for older adults. We evaluated whether control beliefs are associated with risk for 4-year mortality, after accounting for established "classic" biomedical risk factors. We also determined if an enhanced risk model with control beliefs improved identification of individuals with low vs. high mortality risk. METHODS: We used nationally representative data from the Health and Retirement Study (2006-2012) for adults 50 years or older in 2006 (n = 7313) or 2008 (n = 6301). We assessed baseline perceived global control (measured as 2 dimensions-"constraints" and "mastery"), and health-specific control. We also obtained baseline data for 12 established biomedical risk factors of 4-year mortality: age, sex, 4 medical conditions (diabetes mellitus, cancer, lung disease and heart failure), body mass index less than 25 kg/m2, smoking, and 4 functional difficulties (with bathing, managing finances, walking several blocks and pushing or pulling heavy objects). Deaths within 4 years of follow-up were determined through interviews with respondents' family and the National Death Index. RESULTS: After accounting for classic biomedical risk factors, perceived constraints were significantly associated with higher mortality risk (third quartile scores odds ratio [OR] 1.37, 95% CI 1.03 1.81; fourth quartile scores OR 1.45, 95% CI, 1.09-1.92), while health-specific control was significantly associated with lower risk (OR 0.69-0.78 for scores above first quartile). Higher perceived mastery scores were not consistently associated with decreased risk. The enhanced model with control beliefs found an additional 3.5% of participants (n = 222) with low predicted risk of 4-year mortality (i.e., 4% or less); observed mortality for these individuals was 1.8% during follow-up. Compared with participants predicted to have low mortality risk only by the classic biomedical model, individuals identified by only the enhanced model were older, had higher educational status, higher income, and higher prevalence of diabetes mellitus and cancer. CONCLUSION: Control beliefs were significantly associated with risk for 4-year mortality; accounting for these factors improved identification of low-risk individuals. More work is needed to determine how assessment of control beliefs could enable targeting of clinical interventions to support at-risk older adults. PMID- 28077090 TI - GBS-based single dosage markers for linkage and QTL mapping allow gene mining for yield-related traits in sugarcane. AB - BACKGROUND: Sugarcane (Saccharum spp.) is predominantly an autopolyploid plant with a variable ploidy level, frequent aneuploidy and a large genome that hampers investigation of its organization. Genetic architecture studies are important for identifying genomic regions associated with traits of interest. However, due to the genetic complexity of sugarcane, the practical applications of genomic tools have been notably delayed in this crop, in contrast to other crops that have already advanced to marker-assisted selection (MAS) and genomic selection. High throughput next-generation sequencing (NGS) technologies have opened new opportunities for discovering molecular markers, especially single nucleotide polymorphisms (SNPs) and insertion-deletion (indels), at the genome-wide level. The objectives of this study were to (i) establish a pipeline for identifying variants from genotyping-by-sequencing (GBS) data in sugarcane, (ii) construct an integrated genetic map with GBS-based markers plus target region amplification polymorphisms and microsatellites, (iii) detect QTLs related to yield component traits, and (iv) perform annotation of the sequences that originated the associated markers with mapped QTLs to search putative candidate genes. RESULTS: We used four pseudo-references to align the GBS reads. Depending on the reference, from 3,433 to 15,906 high-quality markers were discovered, and half of them segregated as single-dose markers (SDMs) on average. In addition to 7,049 non-redundant SDMs from GBS, 629 gel-based markers were used in a subsequent linkage analysis. Of 7,678 SDMs, 993 were mapped. These markers were distributed throughout 223 linkage groups, which were clustered in 18 homo(eo)logous groups (HGs), with a cumulative map length of 3,682.04 cM and an average marker density of 3.70 cM. We performed QTL mapping of four traits and found seven QTLs. Our results suggest the presence of a stable QTL across locations. Furthermore, QTLs to soluble solid content (BRIX) and fiber content (FIB) traits had markers linked to putative candidate genes. CONCLUSIONS: This study is the first to report the use of GBS for large-scale variant discovery and genotyping of a mapping population in sugarcane, providing several insights regarding the use of NGS data in a polyploid, non-model species. The use of GBS generated a large number of markers and still enabled ploidy and allelic dosage estimation. Moreover, we were able to identify seven QTLs, two of which had great potential for validation and future use for molecular breeding in sugarcane. PMID- 28077091 TI - Transradial versus transfemoral approach for coronary angiography and angioplasty - A prospective, randomized comparison. AB - BACKGROUND: PCI has been done traditionally through transfemoral route. But now transradial and transbrachial routes are also coming up in practice. We compared transradial versus transfemoral routes for ease of operability, time for procedure, complications, and failure rates through a prospective study. METHODS: Four hundred Patients admitted in department of cardiology for percutaneous interventions were enrolled in the study. 200 patients were assigned to each group randomly. A single team did all the procedures. Pre procedure, intra procedure and post procedure data of all the patients was collected, tabulated and analysed properly. RESULTS: Access time (6.0 +/- 1vs 4.2 +/- 0.7; P =0.001); Fluoroscopy time and overall procedure time (29 +/- 11.3 Vs. 27.3 +/- 12.4 min) were more with trans radial than transfemoral route, respectively. The most common post procedure complication, ecchymosis was seen in 20.5% in transfemoral group compared to 12.5% in transradial group (P 0.031). Thrombophelibites (17.5 VS 8%, P0.004); Hematoma (14.5 Vs 0%, P 0.005); post procedure access bleed (7 VS 3%, P 0.039) were seen in transfemoral than transradial group, respectively. Failure rates were almost similar. None of our patients had post procedure myocardial infarction, stroke, acute renal failure and infections. CONCLUSION: Transradial approach of PCI is better than transfemoral route with respect to complications like bleeding, haematoma formation, thrombophelebites and ecchymosis is concerned. However access and fluoroscopic time is more with the former. We recommend the transradial route for PCI. TRIAL REGISTRATION: Trial is retrospectively registered in ClinicalTrials.gov with the Identifier: NCT02983721 , Date of registration is December 2, 2016. PMID- 28077092 TI - Phylogenetic analysis of ionotropic L-glutamate receptor genes in the Bilateria, with special notes on Aplysia californica. AB - BACKGROUND: The neurotransmitter L-Glutamate (L-Glu) acting at ionotropic L-Glu receptors (iGluR) conveys fast excitatory signal transmission in the nervous systems of all animals. iGluR-dependent neurotransmission is a key component of the synaptic plasticity that underlies learning and memory. During learning, two subtypes of iGluR, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) and N-methyl-D-aspartate receptors (NMDAR), are dynamically regulated postsynaptically in vertebrates. Invertebrate organisms such as Aplysia californica (Aplysia) are well-studied models for iGluR-mediated function, yet no studies to date have analyzed the evolutionary relationships between iGluR genes in these species and those in vertebrates, to identify genes that may mediate plasticity. We conducted a thorough phylogenetic analysis spanning Bilateria to elucidate these relationships. The expression status of iGluR genes in the Aplysia nervous system was also examined. RESULTS: Our analysis shows that ancestral genes for both NMDAR and AMPAR subtypes were present in the common bilaterian ancestor. NMDAR genes show very high conservation in motifs responsible for forming the conductance pore of the ion channel. The number of NMDAR subunits is greater in vertebrates due to an increased number of splice variants and an increased number of genes, likely due to gene duplication events. AMPAR subunits form an orthologous group, and there is high variability in the number of AMPAR genes in each species due to extensive taxon specific gene gain and loss. qPCR results show that all 12 Aplysia iGluR subunits are expressed in all nervous system ganglia. CONCLUSIONS: Orthologous NMDAR subunits in all species studied suggests conserved function across Bilateria, and potentially a conserved mechanism of neuroplasticity and learning. Vertebrates display an increased number of NMDAR genes and splice variants, which may play a role in their greater diversity of physiological responses. Extensive gene gain and loss of AMPAR genes may result in different physiological properties that are taxon specific. Our results suggest a significant role for L-Glu mediated responses throughout the Aplysia nervous system, consistent with L-Glu's role as the primary excitatory neurotransmitter. PMID- 28077093 TI - Evaluation of the point-of-care Becton Dickinson VeritorTM Rapid influenza diagnostic test in Kenya, 2013-2014. AB - BACKGROUND: We evaluated the performance of the Becton Dickinson VeritorTM System Flu A + B rapid influenza diagnostic test (RIDT) to detect influenza viruses in respiratory specimens from patients enrolled at five surveillance sites in Kenya, a tropical country where influenza seasonality is variable. METHODS: Nasal swab (NS) and nasopharyngeal (NP)/oropharyngeal (OP) swabs were collected from patients with influenza like illness and/or severe acute respiratory infection. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the RIDT using NS specimens were evaluated against nasal swabs tested by real time reverse transcription polymerase chain reaction (rRT-PCR). The performance parameter results were expressed as 95% confidence intervals (CI) calculated using binomial exact methods, with P < 0.05 considered significant. Two-sample Z tests were used to test for differences in sample proportions. Analysis was performed using SAS software version 9.3. RESULTS: From July 2013 to July 2014, 3,569 patients were recruited, of which 78.7% were aged <5 years. Overall, 14.4% of NS specimens were influenza-positive by RIDT. RIDT overall sensitivity was 77.1% (95% CI 72.8-81.0%) and specificity was 94.9% (95% CI 94.0-95.7%) compared to rRT-PCR using NS specimens. RIDT sensitivity for influenza A virus compared to rRT-PCR using NS specimens was 71.8% (95% CI 66.7 76.4%) and was significantly higher than for influenza B which was 43.8% (95% CI 33.8-54.2%). PPV ranged from 30%-80% depending on background prevalence of influenza. CONCLUSION: Although the variable seasonality of influenza in tropical Africa presents unique challenges, RIDTs may have a role in making influenza surveillance sustainable in more remote areas of Africa, where laboratory capacity is limited. PMID- 28077094 TI - The cut-off value of tumor size and appropriate timing of follow-up for management of minimal EUS-suspected gastric gastrointestinal stromal tumors. AB - BACKGROUD: The detectable rate of minimal gastric GISTs has continuously increased. While the surveillance and management of GIST <2 cm have been deemed controversial or lack evidence-based approaches. The aim of the current study is to propose a cut-off value of tumor size for treatment policy and the appropriate timing for endoscopic ultrasonography (EUS) follow-up in the minimal EUS suspected gastric GIST patients. METHODS: A single-institution retrospective study was performed. 69 patients with EUS-suspected gastric GISTs were studied from November 2008 to March 2015. 69 patients with minimal gastric GISTs <=2 cm diagnosed by EUS were followed for a mean period of 29 months (range, 12 to 70). An at least 20% increase of the maximal diameter of the tumors was set as a significant change. RESULTS: During follow-up, Of the 69 minimal EUS-suspected GISTs, 16 (23.2%) showed significant changes in size. 11 out of 69 GISTs (15.9%), 6 out of 43 GISTs (14.0%), 7 out of 30 GISTs (23.3%) showed significant changes in size, at 1 year, 2 years, and more than 3 years respectively. The receiver operating characteristic curve analysis showed that the tumor size cut-off was 9.5 mm. Only 4.7 and 3.7% of gastric EUS-suspected GISTs of <9.5 mm in size showed significant changes at 1 year and 2 years, while 9.5% at more than 3 years. 34.6, 31.3 and 55.6% of gastric EUS-suspected GISTs of >= 9.5 mm in size showed significant changes at 1 year, 2 years and more than 3 years. CONCLUSIONS: Minimal EUS-suspected GISTs, larger than 9.5 mm may be associated with significant progression. The patients with a >= 9.5 mm GIST should have a EUS 6 12months, while <9.5 mm GIST may have a EUS extended to every 2-3 years. PMID- 28077096 TI - Rates and trends in cesarean sections between 2008 and 2012 in Iraq. AB - BACKGROUND: The prevalence of cesarean sections is increasing globally; however, it can lead to significant increases in maternal and infant morbidity and mortality. This study aimed to determine the rates and trends of cesarean sections in Iraq. METHODS: The cesarean section rates of all births and public and private hospital-based births were calculated from the data on births provided by the annual reports of the Iraqi Ministry of Health for the years 2008 and 2012. The comparable rates for the Center/South and Kurdistan Region and the individual governorates were determined. The cesarean section rates for all births in 2008 were computed and compared with the 2012 rates. RESULTS: The cesarean section rate for all births in Iraq was 24.4% in 2012, which was similar to the rates in the Iraqi Kurdistan Region (25.4%) and the Center/South of Iraq (24.3%). The cesarean section rates were specifically high in the governorates containing a larger number of private hospitals, and there was a significant positive relationship between the number of private hospitals and the cesarean section rate (beta = 0.671; r = 0.671; P < 0.002). The hospital-based cesarean section rate was 34.7%. The cesarean section rate in private hospitals (77.9%) was remarkably higher than the rate in public hospitals (29.3%). The overall rate of cesarean sections in Iraq increased from 18.0% in 2008 to 24.4% in 2012. CONCLUSIONS: The cesarean section rate in Iraq is far above the recommended rate. Iraq witnessed a rapid upward trend in the cesarean section rate from 2008 to 2012, with most of this trend attributable to the Kurdistan Region. There is a potential relationship between the expansion of the private health sector and the increasing cesarean section rate, and further studies of this relationship are necessary. Future research should consider an audit of the indications for a cesarean section rather than measuring the cesarean section rate alone. PMID- 28077095 TI - Geographic information system for improving maternal and newborn health: recommendations for policy and programs. AB - This correspondence argues and offers recommendations for how Geographic Information System (GIS) applied to maternal and newborn health data could potentially be used as part of the broader efforts for ending preventable maternal and newborn mortality. These recommendations were generated from a technical consultation on reporting and mapping maternal deaths that was held in Washington, DC from January 12 to 13, 2015 and hosted by the United States Agency for International Development's (USAID) global Maternal and Child Survival Program (MCSP). Approximately 72 participants from over 25 global health organizations, government agencies, donors, universities, and other groups participated in the meeting.The meeting placed emphases on how improved use of mapping could contribute to the post-2015 United Nation's Sustainable Development Goals (SDGs), agenda in general and to contribute to better maternal and neonatal health outcomes in particular. Researchers and policy makers have been calling for more equitable improvement in Maternal and Newborn Health (MNH), specifically addressing hard-to-reach populations at sub-national levels. Data visualization using mapping and geospatial analyses play a significant role in addressing the emerging need for improved spatial investigation at subnational scale. This correspondence identifies key challenges and recommendations so GIS may be better applied to maternal health programs in resource poor settings. The challenges and recommendations are broadly grouped into three categories: ancillary geospatial and MNH data sources, technical and human resources needs and community participation. PMID- 28077097 TI - What patients really think about asthma guidelines: barriers to guideline implementation from the patients' perspective. AB - BACKGROUND: Treatment of asthma does not always comply with asthma guidelines (AG). This may be rooted in direct or indirect resistance on the doctors' and/or patients' side or be caused by the healthcare system. To assess whether patients' concepts and attitudes are really an implementation barrier for AG, we analysed the patients' perspective of a "good asthma therapy" and contrasted their wishes with current recommendations. METHODS: Using a qualitative exploratory design, topic centred focus group (FG) discussions were performed until theoretical saturation was reached. Inclusion criteria were an asthma diagnosis and age above 18. FG sessions were recorded audio-visually and analysed via a mapping technique and content analysis performed according to Mayring (supported by MAXQDA(r)). Participants' speech times and the proportion of time devoted to different themes were calculated using the Videograph System(r) and related to the content analysis. RESULTS: Thirteen men and 24 women aged between 20 and 77 from rural and urban areas attended five FG. Some patients had been recently diagnosed with asthma, others years previously or in childhood. The following topics were addressed: (a) concern about or rejection of therapy components, particularly corticosteroids, which sometimes resulted in autonomous uncommunicated medication changes, (b) lack of time or money for optimal treatment, (c) insufficient involvement in therapy choices and (d) a desire for greater empowerment, (e) suboptimal communication between healthcare professionals and (f) difficulties with recommendations conflicting with daily life. Primarily, (g) participants wanted more time with doctors to discuss difficulties and (h) all aspects of living with an impairing condition. CONCLUSIONS: We identified some important patient driven barriers to implementing AG recommendations. In order to advance AG implementation and improve asthma treatment, the patients' perspective needs to be considered before drafting new versions of AG. These issues should be addressed at the planning stage. TRIAL REGISTRATION: DRKS00000562 (German Clinical Trials Registry). PMID- 28077098 TI - Validity of gestational age estimates by last menstrual period and neonatal examination compared to ultrasound in Vietnam. AB - BACKGROUND: Accurate estimation of gestational age is important for both clinical and public health purposes. Estimates of gestational age using fetal ultrasound measurements are considered most accurate but are frequently unavailable in low- and middle-income countries. The objective of this study was to assess the validity of last menstrual period and Farr neonatal examination estimates of gestational age, compared to ultrasound estimates, in a large cohort of women in Vietnam. METHODS: Data for this analysis come from a randomized, placebo controlled micronutrient supplementation trial in Vietnam. We analyzed 912 women with ultrasound and prospectively-collected last menstrual period estimates of gestational age and 685 women with ultrasound and Farr estimates of gestational age. We used the Wilcoxon signed rank sum test to assess differences in gestational age estimated by last menstrual period or Farr examination compared to ultrasound and computed the intraclass correlation coefficient (ICC) and concordance correlation coefficient (CCC) to quantify agreement between methods. We computed the Kappa coefficient (kappa) to quantify agreement in preterm, term and post-term classification. RESULTS: The median gestational age estimated by ultrasound was 273.9 days. Gestational age was slightly overestimated by last menstrual period (median 276.0 days, P < 0.001) and more greatly overestimated by Farr examination (median 286.7 days, P < 0.001). Gestational age estimates by last menstrual period and ultrasound were moderately correlated (ICC = 0.78) and concordant (CCC = 0.63), whereas gestational age estimates by Farr examination and ultrasound were weakly correlated (ICC = 0.26) and concordant (CCC = 0.05). Last menstrual period and ultrasound estimates of gestational age were within +/- 14 days for 88.4% of women; Farr and ultrasound estimates were within +/- 14 days for 55.8% of women. Last menstrual period and ultrasound estimates of gestational age had higher agreement in term classification (kappa = 0.41) than Farr and ultrasound (kappa = 0.05). CONCLUSION: In this study of women in Vietnam, we found last menstrual period provided a more accurate estimate of gestational age than the Farr examination when compared to ultrasound. These findings provide useful information about the utility and accuracy of different methods to estimate gestational age and suggest last menstrual period may be preferred over Farr examination in settings where ultrasound is unavailable. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.Gov as NCT01665378 on August 13, 2012. PMID- 28077099 TI - A prospective study on the characteristics and subjects of pediatric palliative care case management provided by a hospital based palliative care team. AB - BACKGROUND: Case management is a subject of interest within pediatric palliative care. Detailed descriptions of the content of this type of case management are lacking. We aim to describe the contents of care provided, utilization of different disciplines, and times of usage of a pediatric palliative care case management program compared for patients with malignant disease (MD) and non malignant disease (NMD). METHODS: A three-month prospective study, with questionnaires filled in by members of a pediatric palliative care team (PPCT) for each contact with parents. RESULTS: Four hundred fifty-five contacts took place with parents of 70 patients (27MD, 43NMD). Sixty-two percent of all contacts were with the specialized nurse. The child life specialists, psychologist and social worker were also regularly consulted, the chaplain was not consulted. Ninety-five percent of all contacts took place between 8 am and 6 pm during weekdays, a limited number between 6 pm and 9 pm. Twenty-five percent of all contacts were proactively initiated by the PPCT, 25 % were initiated by parents. In these care characteristics, no differences were seen for MD and NMD patients. Psychosocial topics were addressed most frequently. MD patients consulted the PPCT more often about school and NMD patients about socio-economic issues. CONCLUSIONS: All different disciplines of the PPCT were regularly consulted, except for the chaplain. With an easy accessible team with a highly pro-active approach, availability from 8 am to 9 pm seems sufficient to accommodate patient's and parent's needs. More anticipation seems required for socio-economic topics. This insight in pediatric palliative case management can provide guidance in the development of a new PPCT. PMID- 28077101 TI - Erratum to: Does acupuncture have a role in the treatment of threatened miscarriage? Findings from a feasibility randomised trial and semi-structured participant interviews. PMID- 28077100 TI - Incidence of solitary pulmonary nodules in Northeastern France: a population based study in five regions. AB - BACKGROUND: The discovery of a solitary pulmonary nodule (SPN) on a chest imaging exam is of major clinical concern. However, the incidence rates of SPNs in a general population have not been estimated. The objective of this study was to provide incidence estimates of SPNs in a general population in 5 northeastern regions of France. METHODS: This population-based study was undertaken in 5 regions of northeastern France in May 2002-March 2003 and May 2004-June 2005. SPNs were identified by chest CT reports collected from all radiology centres in the study area by trained readers using a standardised procedure. All reports for patients at least 18 years old, without a previous history of cancer and showing an SPN between 1 and 3 cm, were included. RESULTS: A total of 11,705 and 20,075 chest CT reports were collected for the 2002-2003 and 2004-2005 periods, respectively. Among them, 154 and 297 reports showing a SPN were included, respectively for each period. The age-standardised incidence rate (IR) was 10.2 per 100,000 person-years (95% confidence interval 8.5-11.9) for 2002-2003 and 12.6 (11.0-14.2) for 2004-2005. From 2002 to 2005, the age-standardised IR evolved for men from 16.4 (13.2-19.6) to 17.7 (15.0-20.4) and for women from 4.9 (3.2-6.6) to 8.2 (6.4-10.0). In multivariate Poisson regression analysis, gender, age, region and period were significantly associated with incidence variation. CONCLUSIONS: This study provides reference incidence rates of SPN in France. Incidence was higher for men than women, increased with age for both gender and with time for women. Trends in smoking prevalence and improvement in radiological equipment may be related to incidence variations. PMID- 28077102 TI - Effects of aqueous extracts of Taraxacum Officinale on expression of tumor necrosis factor-alpha and intracellular adhesion molecule 1 in LPS-stimulated RMMVECs. AB - BACKGROUND: Mastitis gives rise to big financial burden to farm industry (mainly dairy production) and public health. Its incidence is currently high and therefore, highly effective treatments for therapy, especially with natural products are required. Taraxacum officinale has been reported to use for anti inflammation. However, its effect on endothelium during mastitis has not been reported. METHODS: We firstly established inflammation experimental model of rat mammary microvascular endothelial cells (RMMVECs). We evaluated the effects of dandelion leaf aqueous extracts (DAE) on LPS-induced production of inflammatory mediators in RMMVECs by enzyme-linked immunosorbent assay and Western blot. We treated RMMVECs with 1 MUg/ml LPS for 4 h and then incubated with 10, 100 and 200 MUg/mL DAE for 4, 8, 12 and 24 h. The expression (mRNA and protein level) of targets (tumor necrosis factor-alpha (TNF- alpha) and Intracellular Adhesion Molecule 1 (ICAM1) was analyzed by employing real-time PCR and Western blots. The in vivo anti-inflammatory effect of DAE on mastitis within an Staphylococcus aureus-induced mouse model was also determined. RESULTS: The obtained results showed that dandelion extracts at the concentration of 100 and 200 MUg/mL could significantly inhibit both TNF-alpha and ICAM-1 expression in all time points checked while 10 MUg/mL of dandelion only suppress both expression at 8 and 12 h post-treatment. The in vivo tests showed that the DAE inhibited the expression of TNF-alpha and ICAM-1 in a time-dependent manner. CONCLUSIONS: All results suggest that the endothelium may use as as a possible target of dandelion for anti inflammation. PMID- 28077103 TI - Determinants of quality of shared sanitation facilities in informal settlements: case study of Kisumu, Kenya. AB - BACKGROUND: Shared facilities are not recognised as improved sanitation due to challenges of maintenance as they easily can be avenues for the spread of diseases. Thus there is need to evaluate the quality of shared facilities, especially in informal settlements, where they are commonly used. A shared facility can be equated to a common good whose management depends on the users. If users do not work collectively towards keeping the facility clean, it is likely that the quality may depreciate due to lack of maintenance. This study examined the quality of shared sanitation facilities and used the common pool resource (CPR) management principles to examine the determinants of shared sanitation quality in the informal settlements of Kisumu, Kenya. METHODS: Using a multiple case study design, the study employed both quantitative and qualitative methods. In both phases, users of shared sanitation facilities were interviewed, while shared sanitation facilities were inspected. Shared sanitation quality was a score which was the dependent variable in a regression analysis. Interviews during the qualitative stage were aimed at understanding management practices of shared sanitation users. Qualitative data was analysed thematically by following the CPR principles. RESULTS: Shared facilities, most of which were dirty, were shared by an average of eight households, and their quality decreased with an increase in the number of households sharing. The effect of numbers on quality is explained by behaviour reflected in the CPR principles, as it was easier to define boundaries of shared facilities when there were fewer users who cooperated towards improving their shared sanitation facility. Other factors, such as defined management systems, cooperation, collective decision making, and social norms, also played a role in influencing the behaviour of users towards keeping shared facilities clean and functional. CONCLUSION: Apart from hardware factors, quality of shared sanitation is largely due to group behaviour of users. The CPR principles form a crucial lens through which the dynamics of shared sanitation facilities in informal settlements can be understood. Development and policy efforts should incorporate group behaviour as they determine the quality of shared sanitation facilities. PMID- 28077104 TI - Effects of treadmill exercise versus Flutter(r) on respiratory flow and sputum properties in adults with cystic fibrosis: a randomised, controlled, cross-over trial. AB - BACKGROUND: Treadmill exercise and airway clearance with the Flutter(r) device have previously been shown to improve mucus clearance mechanisms in people with cystic fibrosis (CF) but have not been compared. It is therefore not known if treadmill exercise is an adequate form of airway clearance that could replace established airway clearance techniques, such as the Flutter(r). The aim of this study was to evaluate respiratory flow, sputum properties and subjective responses of treadmill exercise and Flutter(r) therapy, compared to resting breathing (control). METHODS: Twenty-four adults with mild to severe CF lung disease (FEV1 28-86% predicted) completed a three-day randomised, controlled, cross-over study. Interventions consisted of 20 min of resting breathing (control), treadmill exercise at 60% of the participant's peak oxygen consumption and Flutter(r) therapy. Respiratory flow was measured during the interventions. Sputum properties (solids content and mechanical impedance) and subjective responses (ease of expectoration and sense of chest congestion) were measured before, immediately after the interventions and after 20 min of recovery. RESULTS: Treadmill exercise and Flutter(r) resulted in similar significant increases in peak expiratory flow, but only Flutter(r) created an expiratory airflow bias (i.e. peak expiratory flow was at least 10% higher than peak inspiratory flow). Treadmill exercise and Flutter(r) therapy resulted in similar significant reductions in sputum mechanical impedance, but only treadmill exercise caused a transient increase in sputum hydration. Treadmill exercise improved ease of expectoration and Flutter(r) therapy improved subjective sense of chest congestion. CONCLUSIONS: A single bout of treadmill exercise and Flutter(r) therapy were equally effective in augmenting mucus clearance mechanisms in adults with CF. Only longer term studies, however, will determine if exercise alone is an adequate form of airway clearance therapy that could replace other airway clearance techniques. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry, Registration number # ACTRN12609000168257 , Retrospectively registered (Date submitted to registry 26/2/2009, First participant enrolled 27/2/2009, Date registered 6/4/2009). PMID- 28077105 TI - The prevalence of the metabolic syndrome in a farm worker community in the Boland district, South Africa. AB - BACKGROUND: In South Africa, not much is known about MetS in farm working communities. This study aimed to describe the prevalence of the MetS in a farm working population from the Boland winelands district of the Western Cape, South Africa. METHODS: A cross-sectional study was followed among farm workers (aged 20 60 years) from surrounding wine estates. The questionnaires used described socio demographic status, ethnic background, alcohol consumption, smoking, exercise and daily medication. Anthropometric assessments were performed and blood pressure measurements taken prior to blood sampling for serum insulin, glucose and fasting lipogram profiles. RESULTS: The prevalence of the MetS was higher in women (46.3 vs 29.3%). Both men and women in the MetS group had a significantly higher waist circumferences (WC; p < 0.001 for both), whilst higher glucose levels were only significantly higher in the women (p < 0.001). Correlations showed significant differences between body mass index (BMI), WC and waist to hip ratio (W:H) and the different MetS risk factors. CONCLUSIONS: The female population in this study showed higher prevalence rates for the individual risk factors and the MetS overall. There is an urgent need to develop culturally sensitive health promotion programs addressing risk factors for metabolic syndrome among farm workers. PMID- 28077106 TI - Age of onset of substance use and psychosocial problems among individuals with substance use disorders. AB - BACKGROUND: Substance use is generally initiated in adolescence or early adulthood and is commonly associated with several physical, psychological, emotional and social problems. The objective of this study is to assess the age of onset of substance use differences on psychosocial problems among individuals with substance use disorders (SUDs) residing in drug rehabilitation centers. METHODS: A descriptive cross sectional research design was carried out. Probability Proportional to Size (PPS) sampling technique was used to select the drug rehabilitation centers and all the respondents meeting the inclusion criteria of the selected seven rehabilitation centers were taken as a sample and comprised of 221 diagnosed individuals with SUDs. A semi structured self administered questionnaires were used to collect the information regarding demographic and substance use related characteristics. A standard tool Drug Use Screening Inventory-Revised (DUSI-R) was used to assess the psychosocial problems among individuals with SUDs. Data were analyzed using both descriptive and inferential statistics. Multivariate general linear model (MANOVA and MANCOVA) was used to evaluate differences in psychosocial problems between early vs late onset substance users. RESULT: The age of onset of substance use was significantly associated with psychosocial problems. The mean psychosocial problem scores were higher in early onset substance user (17 years or younger) than late onset substance user (18 years or higher) in various domains of DUSI-R even after controlling confounding factors. The two groups (early vs late) differed significantly in relation to age, gender, occupational status, current types of substance use, frequency of use, mode of substance use and relapse history. CONCLUSION: The study indicated that early onset substance users are at higher risk for psychosocial problems in various areas of life such as Behavior Pattern, Psychiatric disorder, Family system, Peer relationship, Leisure/Recreation and Work adjustment compared to late onset substance users. It highlights the need for early prevention, screening, and timely intervention among those individuals. PMID- 28077108 TI - Wasting, underweight and stunting among children with congenital heart disease presenting at Mulago hospital, Uganda. AB - BACKGROUND: Children with congenital heart disease are at increased risk of malnutrition. The aim of this study was to describe the prevalence of wasting, underweight and stunting among children with congenital heart disease attending Mulago National Referral Hospital, Uganda. METHODS: A cross-sectional study among 194 children aged 0-15 years was conducted between August 2013 and March 2014. Anthropometric measurements and clinical assessments were carried out on all children. Anthropometric z-scores based on WHO 2007 reference ranges were generated for each child. Weight-for-height z-scores were generated for children 0-5 years, weight-for-age z-scores for children 0-10 years, and height-for-age and BMI-for-age z-scores for all children. Risk factors associated with malnutrition were determined by Poisson regression. RESULTS: One hundred and forty five (74.7%) children were aged 0-5 years; and 111 of 194 (57.2%) were female. Forty five of 145 (31.5%) children aged 0-5 years were wasted; 77 of 181 (42.5%) children aged 0-10 years were underweight; 88 of 194 (45.4%) children were stunted; and 53 of 194 (27.3%) children were thin (BMI for age z score < 2). Moderate to severe anaemia (RR 1.11, 95% CI: 1.01-1.22) and moderate to severe heart failure (RR 1.24, 95% CI: 1.13-1.36) were associated with wasting and underweight respectively. Stunting was associated with moderate to severe heart failure (RR 1.11, 95% CI: 1.01-1.21) while thinness was associated with moderate to severe heart failure (RR 1.12, 95% CI: 1.04-1.21) and moderate to severe anaemia (RR 1.15, 95% CI: 1.06-1.25). CONCLUSION: Malnutrition is common in children with congenital heart disease, and is associated with anaemia and heart failure. There is need to integrate strategies to identify and manage malnutrition during the care of children with congenital heart disease. PMID- 28077107 TI - Recurrent pneumonia among Japanese adults: disease burden and risk factors. AB - BACKGROUND: In Japan and other societies with rapidly aging populations, recurrent pneumonia (RP) is a major clinical problem yet only limited information exists regarding the burden of this disease. METHODS: A prospective study of adult pneumonia was conducted to investigate the incidence of RP and potential risk factors. From February 1, 2012 to January 31, 2013, patients aged >= 15 years who were diagnosed with pneumonia were prospectively enrolled in a representative community hospital located in central Japan. Patients were followed for one-year to evaluate the recurrence of pneumonia and characteristics associated with RP. Cox proportional hazards models were constructed to compute adjusted hazard ratios (aHR) and ascertain risk factors significantly associated with RP. RESULTS: In total, 841 patients with a median age of 73 years (range 15 101 years) were enrolled totaling 1,048 person-years of observation with a median follow-up time of 475 days. A total of 137 patients had at least one recurrent episode with an incidence rate of 13.1 per 100 person-years (95% confidence interval: 11.1-15.5). In multivariate analysis, a past history of pneumonia (aHR 1.95, 95% CI: 1.35-2.8), chronic pulmonary disease (aHR 1.86, 1.24-2.78) and inhaled corticosteroid usage (aHR 1.78, 1.12-2.84) and hypnotic/sedative medication usage (aHR 2.06, 1.28-3.31) were identified as independent risk factors for recurrent pneumonia, whereas angiotensin converting enzyme-inhibitors usage was associated with a reduction of the risk of RP (aHR 0.22, 0.05-0.91). The detection of P. aeruginosa was significantly associated with RP even after adjusting for chronic pulmonary diseases (aHR = 2.37). CONCLUSIONS: Recurrent pneumonia constitutes a considerable proportion of the pneumonia burden in Japan. A past history of pneumonia, chronic pulmonary disease, inhaled corticosteroid and hypnotic/sedative medication usage and detection of P. aeruginosa were identified as independent risk factors for recurrent pneumonia and special attention regarding the use of medications in this vulnerable population is needed to reduce the impact of this disease in aging populations. PMID- 28077109 TI - Cause of neonatal deaths in Northern Ethiopia: a prospective cohort study. AB - BACKGROUND: Despite the significant reduction in childhood mortality, neonatal mortality has shown little or no concomitant decline worldwide. The dilemma arises in that the lack of documentation of cause of death in developing countries, where registration of vital events is virtually nonexistent. Understanding of the causes of death in neonates is important to guide public health interventions. The present study identifies the common causes of neonatal death in Ethiopia. METHODS: A prospective cohort study was conducted among neonates born between April 2014 and July 2014 in seven hospitals, in Tigray region, Ethiopia. Mothers were interviewed by midwifes respecting risk factors and infant survival. For neonates who died in hospital, causes of death were extracted from medical records, whereas a verbal autopsy method provided presumptive assignment of cause of death for those infants who died at home. RESULTS: Of the1152 live births, there were 68 deaths (63 per 1000 live births). Two thirds of deaths were attributable to prematurity 23 (34%) or asphyxia 21 (31%). Slight variance was seen between the morality patterns in early and late neonatal periods. In the early neonatal period, 37% were due to prematurity, while asphyxia (35%) was more common in the late neonatal period. All infection related deaths occurred in neonate-mother dyads from rural areas. CONCLUSION: Prematurity, asphyxia, and infections were the leading causes of neonatal deaths in Tigray region during the study period. Causes of deaths identified during early and late neonatal mortality differed, which clearly indicates the need for responsive and evidence-based interventions and policies. PMID- 28077110 TI - The first rib hypoplasia and the aberrant pulmonary artery branch detected by three-dimensional computed tomography in a surgical case with apical lung cancer, a case report. AB - BACKGROUND: The complete resection is one of the most crucial requirements to achieve favorable outcomes in oncologic surgery. The apex of the lung is surrounded complicatedly by the clavicle, the first rib, the subclavian artery and vein, and the brachial plexus. Therefore, the image information especially about the infiltration of adjacent anatomic structures, facilitates the surgery in the apical lung cancer. CASE PRESENTATION: A 70-year-old man presented at our hospital with a computed tomography (CT) scan showing a tumor at the left lung apex that infiltrated the chest wall. Two anatomical anomalies were found, which were the first rib hypoplasia and the aberrant pulmonary artery branch. The three dimensional (3D) CT enhanced with using bolus tracking method, simultaneously revealed that the subclavian vessels existed between the clavicle and the second rib, and the left lingual pulmonary artery and the ventrobasal pulmonary artery diverged from the left main pulmonary artery as the first branch. We diagnosed the tumor as a primary lung squamous cell carcinoma that infiltrated the second rib, because sputum cytology suggested squamous cell carcinoma. Left lung upper lobectomy with lymph node dissection and chest wall resection (the second and third ribs) were performed with caution for the anatomical anomalies. The pathological diagnosis was pleomorphic carcinoma (5.0 * 3.0 * 1.9 cm) that invaded the second costal bone, and the pathological stage was confirmed to be pT3N0M0. Pathologically curative resection was accomplished. The patient was discharged from the hospital on 10 days after surgery. CONCLUSION: The 3D-CT precisely detected the anomalous structure consisted with the clavicle, the second rib, the subclavian artery and vein, the aberrant pulmonary artery branch. In the present case with the apical lung cancer, the evaluation of the anatomical structure via 3D-CT facilitated to achieve a pathological complete resection. PMID- 28077111 TI - Cumulative exposure to shift work and sickness absence: associations in a five year historic cohort. AB - BACKGROUND: Exposure to shift work has been associated with negative health consequences, although the association between shift work and sickness absence remains unclear. The aim of this study is to investigate associations between cumulative exposure to shift work and sickness absence among ground staff employees of an airline company. METHODS: This study used data from the MORE (Monitoring Occupational Health Risks in Employees) cohort, which is a 5-year historic cohort. The population of the present study consisted of 7562 ground staff employees. For each employee, work schedules and sickness absence days between 2005 and 2009 were obtained from company records. For the exposure to different shift schedule types and to the cumulative number of night shifts, the association with long-term sickness absence (>7 consecutive sickness absence days) and the number of sickness absence episodes during 2009, was calculated using logistic and Poisson regression analyses. Socio-demographic variables, work related variables, job classification variables, and previous sickness absence days were regarded as confounders. RESULTS: After adjusting for previous sickness absence and job classification variables, only the group of employees that switched into working in a three-shift schedule, showed a significantly increased risk for long-term sickness absence (OR = 1.31, 95%CI 1.02-1.69). Night shift exposure was not significantly associated with long-term sickness absence. Exposure to shift work was negatively associated with more sickness absence episodes. Employees who were exposed to more than 46 night shifts also showed a lower risk for more sickness absence episodes. Subgroup analyses showed that single employees and employees without children had an increased risk for long term sickness absence when exposed to a three-shift schedule, and when they had changed between shift schedule types. CONCLUSIONS: Cumulative exposure to shift work proved to be negatively associated with more sickness absence episodes, and was not associated with more long-term sickness absence, although selection bias could not be ruled out. Future research should explore the influence of household composition, and take into account both previous sickness absence and psychosocial and physical work factors to obtain a better estimation of the association between shift work and sickness absence. PMID- 28077112 TI - Prevalence and factors associated with hypertension in Burkina Faso: a countrywide cross-sectional study. AB - BACKGROUND: High blood pressure (HBP) is an increasing public health issue for developing countries. HBP is an important contributing factor to many non communicable diseases that were until very recently thought to be rare in developing countries. There is not enough evidence on its burden and risk factors in Africa. We report in this study on the prevalence and factors associated with HBP in the adult and active population of Burkina Faso from a nationally representative sample. METHODS: We conducted a secondary analysis of data from the World Health Organization (WHO) Stepwise approach to Surveillance(STEPS) survey on the prevalence of major risk factors for non-communicable diseases in Burkina Faso. This survey was conducted between September 26 and November 18, 2013 and involved a nationally representative sample of 4,800 adults aged 25 to 64 years. The risk factors were identified using a binary logistic regression in STATA Version 13.1 software. RESULTS: The analysis was conducted on a sample of 4629 participants of whom 72.18% lived in rural areas. The overall prevalence of hypertension in Burkina Faso was 18% (95% CI: 16.19%-19.96%). In urban areas the prevalence was 24.81% (95% CI 20.21%-30.07%) and 15.37% (95% CI 13.67%-17.24%) in rural areas. Increased Body Mass Index (BMI) and older age were consistently associated with higher odds of HBP in both residential areas. In addition, being of male sex, fat intake, family history of HBP and low level of HDL cholesterol were significantly associated with increased odds of HBP in rural residents. CONCLUSION: The prevalence of hypertension is high in Burkina Faso with roughly one person in five affected. There is a predominant burden in urban areas with prevalence of ten-point percent higher compared to rural area. Modifiable risk factors should be targeted with appropriate and effective strategies to curb the rising burden of hypertension and its consequences. PMID- 28077113 TI - A possible dose-response association between distance to farmers' markets and roadside produce stands, frequency of shopping, fruit and vegetable consumption, and body mass index among customers in the Southern United States. AB - BACKGROUND: The association between farmers' market characteristics and consumer shopping habits remains unclear. Our objective was to examine associations among distance to farmers' markets, amenities within farmers' markets, frequency of farmers' market shopping, fruit and vegetable consumption, and body mass index (BMI). We hypothesized that the relationship between frequency of farmers' market shopping and BMI would be mediated by fruit and vegetable consumption. METHODS: In 15 farmers' markets in northeastern North Carolina, July-September 2015, we conducted a cross-sectional survey among 263 farmers' market customers (199 provided complete address data) and conducted farmers' market audits. To participate, customers had to be over 18 years of age, and English speaking. Dependent variables included farmers' market shopping frequency, fruit and vegetable consumption, and BMI. Analysis of variance, adjusted multinomial logistic regression, Poisson regression, and linear regression models, adjusted for age, race, sex, and education, were used to examine associations between distance to farmers' markets, amenities within farmers' markets, frequency of farmers' market shopping, fruit and vegetable consumption, and BMI. RESULTS: Those who reported shopping at farmers' markets a few times per year or less reported consuming 4.4 (standard deviation = 1.7) daily servings of fruits and vegetables, and those who reported shopping 2 or more times per week reported consuming 5.5 (2.2) daily servings. There was no association between farmers' market amenities, and shopping frequency or fruit and vegetable consumption. Those who shopped 2 or more times per week had a statistically significantly lower BMI than those who shopped less frequently. There was no evidence of mediation of the relationship between frequency of shopping and BMI by fruit and vegetable consumption. CONCLUSIONS: More work should be done to understand factors within farmers' markets that encourage fruit and vegetable purchases. PMID- 28077114 TI - Using nudging and social marketing techniques to create healthy worksite cafeterias in the Netherlands: intervention development and study design. AB - BACKGROUND: The worksite cafeteria is a suitable setting for interventions focusing on changing eating behavior, because a lot of employees visit the worksite cafeteria regularly and a variety of interventions could be implemented there. The aim of this paper is to describe the intervention development and design of the evaluation of an intervention to make the purchase behavior of employees in the worksite cafeteria healthier. The developed intervention called "the worksite cafeteria 2.0" consists of a set of 19 strategies based on theory of nudging and social marketing (marketing mix). The intervention will be evaluated in a real-life setting, that is Dutch worksite cafeterias of different companies and with a number of contract catering organizations. METHODS/DESIGN: The study is a randomized controlled trial (RCT), with 34 Dutch worksite cafeterias randomly allocated to the 12-week intervention or to the control group. Primary outcomes are sales data of selected products groups like sandwiches, salads, snacks and bread topping. Secondary outcomes are satisfaction of employees with the cafeteria and vitality. DISCUSSION: When executed, the described RCT will provide better knowledge in the effect of the intervention "the worksite cafeteria 2.0" on the purchasing behavior of Dutch employees in worksite cafeterias. TRIAL REGISTRATION: Dutch Trial register: NTR5372 . PMID- 28077115 TI - Local mandate improves equity of paid sick leave coverage: Seattle's experience. AB - BACKGROUND: Paid sick leave allows workers to take time off work for personal or family health needs, improving health and potentially limiting infectious diseases. The U.S. has no national sick leave mandate, and many American workers particularly those at lower income levels - have no right to paid time off for their own or family members' health needs. This article reports on outcomes of a local mandate, the City of Seattle Paid Sick and Safe Time Ordinance, which requires certain employers to provide paid sick leave to eligible workers. METHODS: Survey collectors contacted a stratified random sample of Seattle employers before the Ordinance went into effect and one year later. Pre- and post analysis draws on responses to survey items by 345 employers who were subject to the paid sick leave mandate. RESULTS: Awareness of the policy and provision of paid leave grew significantly over the year after the Ordinance was enacted. More employers offered leave to full-time workers (80.8 to 93.9%, p < .001) and part time workers (47.1 to 66.7%, p < .001) with particularly large increases in the hospitality sector, which includes food workers (coverage of any hospitality employee: 27.5 to 85.0%, p < .001). CONCLUSIONS: Absent a federal policy, local paid sick time mandates can increase paid sick leave coverage, an important social determinant of health. PMID- 28077116 TI - Quality of life and functional outcome after infravesical desobstruction and HIFU treatment for localized prostate cancer. AB - BACKGROUND: To evaluate quality of life, functional and oncological outcome after infravesical desobstruction and HIFU treatment for localized prostate cancer. METHODS: One hundred thirty-one patients, treated with TURP and HIFU in a single institution were followed up for oncological and functional outcome. Oncological outcome was quantified by biochemical recurrence free survival using the Stuttgart and Phoenix criteria. Quality of life was assessed by usage of standardized QLQ-C30 and QLQ-PR25 questionnaires. In addition, functional questionnaires such as IPSS and IIEF-5 were used. Complications were assessed by the Clavien-Dindo classification. RESULTS: One hundred thirty-one patients with a mean age of 72.8 years (SD: 6.0) underwent HIFU for prostate cancer (29.0% low risk, 58.8% intermediate risk, 12.2% high risk). PSA nadir was 0.6 ng/ml (SD: 1.2) after a mean of 4.6 months (SD: 5.7). Biochemical recurrence free survival defined by Stuttgart criteria was 73.7%, 84.4% and 62.5% for low-, intermediate- and high-risk patients after 22.2 months. Complications were grouped according to Clavien-Dindo and occurred in 10.7% (grade II) and 11.5% (grade IIIa) of cases. 35.1% of patients needed further treatment for bladder neck stricture. Regarding incontinence, 14.3%, 2.9% and 0% of patients had de novo urinary incontinence grade I degrees , II degrees and III degrees and 3.8% urge incontinence due to HIFU treatment. Patients were asked for the ability to have intercourse: 15.8%, 58.6% and 66.7% of patients after non-, onesided and bothsided nervesparing procedure were able to obtain sufficient erection for intercourse, respectively. Regarding quality of life, mean global health score according to QLQ-C30 was 69.4%. CONCLUSION: HIFU treatment for localized prostate cancer shows acceptable oncological safety. Quality of life after HIFU is better than in the general population and ranges within those of standard treatment options compared to literature. HIFU seems a safe valuable treatment alternative for patients not suitable for standard treatment. PMID- 28077117 TI - Topoisomerase I copy number alterations as biomarker for irinotecan efficacy in metastatic colorectal cancer. AB - BACKGROUND: No biomarker exists to guide the optimal choice of chemotherapy for patients with metastatic colorectal cancer. We examined the copy numbers (CN) of topoisomerase I (TOP1) as well as the ratios of TOP1/CEN-20 and TOP1/CEN-2 as biomarkers for irinotecan efficacy in patients with metastatic colorectal cancer. METHODS: From a national cohort, we identified 163 patients treated every third week with irinotecan 350 mg/m2 as second-line therapy. Among these 108 were eligible for analyses and thus entered the study. Primary tumors samples were collected and tissue microarray (TMA) blocks were produced. FISH analysis was performed using two probe-mixes: TOP1/CEN-20 and TOP1/CEN-2. Only samples harboring all three signals (TOP1, CEN-20 and CEN-2) using FISH were included in the analyses. RESULTS: In the TOP1/CEN-20 probe-mix the median TOP1- and CEN-20 CN were 4.46 (range: 1.5-9.5) and 2.00 (range: 0.55-4.55), respectively. The median TOP1- and CEN-2 CN in the TOP1/CEN-2 probe-mix, were 4.57 (range: 1.82 10.43) and 1.98 (range: 1.22-6.14), respectively. The median TOP1/CEN-20 ratio and TOP1/CEN-2 ratio were 1.25 (range: 0.92-2.90) and 2.05 (range: 1.00-6.00), respectively. None of the markers TOP1 CN, TOP1/CEN-20-ratio or TOP1/CEN-2-ratio were associated with progression free survival, overall survival or baseline characteristics. Yet, we observed a borderline association for a stepwise increase of the TOP1 CN in relation to objective response as hazard ratio were 1.35 (95% CI 0.96-1.90; p = 0.081). CONCLUSIONS: We verified a borderline significant association between increasing TOP1 CN and objective response as previously reported. Applying the probes representing CEN-20 and CEN-2, in order to investigate the ratios of TOP1/CEN-20 and TOP1/CEN-2 provided no further information in search of a biomarker driven patient stratification. Other biomarkers to be paired with TOP1 CN are therefore highly warranted. PMID- 28077118 TI - MALAT1 promoted invasiveness of gastric adenocarcinoma. AB - BACKGROUND: Gastric cancer is the second leading cause of cancer globally, and the mechanism of its pathogenesis is still largely unknown. Recently, non-coding RNAs have been recognized to promote metastasis in various cancers, including gastric cancer. METHODS: We found that metastasis associated lung adenocarcinoma transcript-1 (MALAT1) is upregulated in gastric cancer tissue compared to adjacent normal tissue, as determined by microarray and subsequent qRT-PCR, then investigated the impact of MALAT1 on apoptosis, cell proliferation, and the cell cycle to dissect the carcinogenesis of gastric cancer, and examined mechanisms of invasion and metastasis. Expression of MALAT1 and U6 was determined by SYBR qRT PCR in nine-teen gastric cancer cell lines and fifty fresh samples of cancer tissue and adjacent tissues. Downregulation of MALAT1 was accomplished with two different siRNAs. Cell proliferation was determined after treatment with these siRNAs. FACS using PI/Annexin-V staining was carried out. To analyze the invasiveness, a scratch wound-healing assay and a Matrigel invasion assay were performed. Cancer related gene expression assay was done after transfection of siR- MALAT1. RESULTS: The expression of MALAT1 was significantly elevated in various gastric cancer cell lines and gastric cancer tissues compared to normal cell lines and tissues (p < 0.01). siR-MALAT1 significantly reduced viable AGS cell numbers and induced apoptosis (p < 0.05). Deep invasion of tumor (advanced T stages) was more common in the high MALAT1-level group (p = 0.039). siR-MALAT1 significantly decreased AGS cell invasiveness and migration. siR-MALAT1 reduced expression of snail and N-cadherin, and elevated E-cadherin. The Wnt/beta-catenin related genes were significantly decreased by transfection of siRNA MALAT1. MALAT1 is involved in gastric carcinogenesis via inhibition of apoptosis and promotes invasiveness via the epithelial-to-mesenchymal transition. CONCLUSIONS: In our study, we found that deregulation of MALAT1 could be involved in both tumorigenesis and invasiveness in gastric cancer cells. PMID- 28077119 TI - Physical activity levels and associated socio-demographic factors in Bangladeshi adults: a cross-sectional study. AB - BACKGROUND: Low level of physical activity (PA) has become an important public health problem even in low-income countries. The objectives of this study were to measure PA levels, determine the prevalence of low PA and identify socio demographic factors associated with it in Bangladeshi adults. METHODS: Data from 792 (urban, 395; rural, 397) Bangladeshi adults (25-64 years) were included in this population-based cross-sectional study conducted in 2011. Global Physical Activity Questionnaire version 2 (GPAQ-2) was used to measure PA. The metabolic equivalent task (MET) in minutes per week was calculated to determine total PA. Participants were categorized into low, moderate and high PA groups. Logistic regression was used to assess socio-demographic factors associated with low level of PA. RESULTS: Median MET-minute of total PA per week was almost double in the rural area (1720) than the urban area (960). The overall prevalence of low PA was 50.3% (95% CI: 46.8-53.8), urban 59.5% (54.7-64.3) and rural 41.9% (37.0-46.8). Women in general were more inactive (women 63.1% [58.3-67.9], men 39.3% [34.6 44.0]). The main contributions to total PA were from work (urban 40.0%, rural 77.0%) and active commute (57.0%, 21.0%). Leisure-time PA represented a very small proportion (<3.0%). Multiple logistic regressions found a significant association of urban residence (OR = 2.2; 95% CI: 1.5-3.2), women (2.1; 1.4-3.9), oldest age group 55-64 years (15.6; 7.5-32.2) compared to youngest age group 25 34 years, graduation or further education (8.6; 4.1-17.7), and higher socio economic class (2.4; 1.4-4.2) compared to poor with insufficient PA. CONCLUSIONS: This study identifies low PA in a rural and urban population in Bangladesh and that further large-scale population studies are warranted. PMID- 28077120 TI - Altered fractional amplitude of low frequency fluctuation associated with cognitive dysfunction in first-episode drug-naive major depressive disorder patients. AB - BACKGROUND: Previous studies have demonstrated that abnormities of both resting state brain activity and cognitive dysfunction are frequently observed in patients with major depressive disorder (MDD). However, the underlying relationship between these two aspects is less investigated. In this context, the aim of the present study was to investigate the association between cognitive dysfunction and altered resting-state brain function in first-episode drug-naive MDD patients. METHODS: Twenty-five drug-naive MDD patients and twenty-six age-, sex-, and education-matched normal controls were recruited in this study. Cognitive function was evaluated by using a series of validated test procedures. The resting-state functional magnetic resonance imaging data were obtained on a Philips 3.0 Tesla scanner and analysed using the fractional amplitude of low frequency fluctuation (fALFF) method. Correlations of fALFF values with cognitive dysfunction were further analysed. RESULTS: Compared with healthy controls, MDD patients showed significantly fewer completed categories in the Wisconsin Card Sorting Test (WCST) and decreased scores in the first and second subtests of the Continuous Performance Test (CPT). However, the two groups did not differ in their performance on the Stroop Colour Word Test and Trail-making Test. MDD patients exhibited significantly decreased fALFF values in the left superior frontal gyrus (SFG), left middle frontal gyrus, and left inferior frontal gyrus, as well as increased fALFF values in the left inferior temporal gyrus (ITG), bilateral parahippocampal gyrus, and the right caudate. Finally, the correlation analyses revealed that fALFF values in the left SFG and left ITG were associated with the number of WSCT completed categories and scores on the second subtest of the CPT in MDD, respectively. CONCLUSIONS: The present findings suggest that there is little evidence of an association between regional abnormalities in resting-state brain function and cognitive deficits in MDD. PMID- 28077121 TI - Awareness of food allergies: a survey of pediatricians in Kuwait. AB - BACKGROUND: Early diagnosis of food allergies (FA) is important for a favorable prognosis. This study aimed to determine the level of awareness of FA among pediatricians in Kuwait. METHOD: A 43-item self-administered questionnaire was designed and distributed to pediatricians working at 4 government hospitals in Kuwait. RESULTS: A total of 140 pediatricians completed the questionnaire, with a participation rate of 51.1% (81 males and 59 females). The mean age of participants was 40.81 years, and the mean number of years working in pediatrics was 13.94 years. The mean overall knowledge score was 22.2. The pediatricians' overall knowledge scores were found to be significantly associated with their age (older pediatricians had higher overall scores) and years of experience as a pediatrician but were independent from hospital site, gender, or rank. A multiple linear regression revealed pediatrician age and gender were the only variables that were significantly associated with the overall knowledge score. Only 16.4% of the participants answered at least 2/3 of the survey questions correctly. The questions that were correctly answered by <= 2/3 of the participants constituted 80% of clinical presentation questions, 66.6% of diagnostics questions, 77.7% of treatment questions, and 42.8% of prevention questions. Interestingly, among 68 pediatricians (48.5%) who determined that they felt comfortable evaluating and treating patients with FA, only 12 (17.6%) passed the questionnaire. CONCLUSIONS: This survey demonstrates that there is a noteworthy deficiency of pediatricians' awareness about FA. The implementation of strategies to improve pediatricians' awareness is critical to diagnose food allergy patients early and improve their health and outcomes. PMID- 28077122 TI - Relationship between risk assessment and payment models in Swedish Public Dental Service: a prospective study. AB - BACKGROUND: To a) compare risk categories in patients selecting a capitation payment (CP) model with those in fee-for-service (FFS), b) determine the 3-year caries increment in the two groups, and c) compare the amount of delivered preventive care in the two groups. METHODS: A comprehensive risk assessment was carried out in 1295 young adults attending eight Public Dental Clinics in the Scania region and 75% could be re-examined after 3 years; 615 had selected the CP model and 310 the traditional FFS. Caries was scored according to WHO and data concerning preventive care was extracted from the dental records. RESULTS: More patients in the low risk category preferred the CP model (74% vs. 26%) while >80% with high risk selected FFS. The baseline caries level was significantly higher in the FFS group as well as the 3-year caries increment (1.6 vs. 0.8 DFS: p < 0.05). The amount of additional preventive care delivered to each patient was generally lower in the FFS model; it was most frequent among patients with "some" risk in the CP model (83.8%) while the lowest delivery rates were found among low risk patients in the FFS system (32.4%). CONCLUSIONS: Young adults in public dental care with low risk preferred the prepaid model while those in the higher risk categories selected fee-for-service. As more additional preventive care was delivered to patients in the subscribed care, oral health planners and decision makers should be aware of the fact that capitation payment models may enhance inequalities in dental health over time. PMID- 28077123 TI - Daily actions, challenges, and needs among Dutch parents while supporting the participation of their child with a physical disability at home, at school, and in the community: a qualitative diary study. AB - BACKGROUND: Parents have a vital influence on the participation of their child with a physical disability. The aim of this study is to gain insight into parents' own daily actions, challenges, and needs while supporting their child with a physical disability at home, at school, and in the community. An additional objective of this study is to refine the preliminary thematic framework previously identified in a scoping review. METHODS: A qualitative research inquiry was performed based on using a diary over a 7-day period to gather data. To systematically organise data into a structured format, content analysis has been applied using both inductive and deductive reasoning guided by the existing preliminary thematic framework. RESULTS: Analysis of the eligible diaries shows that the actions mentioned by the 47 parents describe several efforts to enhance participation of their children with a physical disability by using, enabling, or changing the social and physical environment, or by supporting their child to perform or engage in meaningful activities. Those parents' actions are primarily a result of challenges caused by restrictions in social and physical environments. Parental responses highlighted, above all, the need for environments designed for all people. Based on the findings a redefined thematic framework is presented. CONCLUSIONS: Parents' actions, challenges, and needs are mainly directed towards the social or/and physical environment. The presented thematic framework can offer practitioners knowledge to support parents. More work is necessary to provide tailored approaches. Paediatric rehabilitation may need to address the importance of the environment on the participation of a child with a physical disability. PMID- 28077124 TI - Important patient characteristics differ prior to total knee arthroplasty and total hip arthroplasty between Switzerland and the United States. AB - BACKGROUND: Outcomes after total knee (TKA) and hip (THA) arthroplasty are often generalized internationally. Patient-dependent factors and preoperative symptom levels may differ across countries. We compared preoperative patient and clinical characteristics from two large cohorts, one in Switzerland, the other in the US. METHODS: Patient characteristics were collected prospectively on all elective primary TKAs and THAs performed at a large Swiss hospital and in a US national sample. Data included age, sex, education level, BMI, diagnosis, medical co morbidities, PROMs (WOMAC pain/function), global health (SF-12). RESULTS: Six thousand six hundred eighty primary TKAs (US) and 823 TKAs (Swiss) were evaluated. US vs. Switzerland TKA patients were younger (mean age 67 vs. 72 years.), more obese (BMI >=30 55% vs. 43%), had higher levels of education, more cardiac disease. Swiss patients had lower preoperative WOMAC pain scores (41 vs. 52) but pre-operative physical disability were comparable. 4,647 primary THAs (US) and 1,023 THAs (Swiss) were evaluated. US vs. Switzerland patients were younger (65 vs. 68 years.), more obese (BMI >=30: 38% vs. 24%), had higher levels of education, more diabetes. Swiss patients had lower preoperative WOMAC pain scores (40 vs. 48 points). Physical disability was reported comparable, but Swiss patients indicated lower mental health scores. CONCLUSION: We found substantial differences between US and Swiss cohorts in pre-operative patient characteristics and pain levels, which has potentially important implications for cross-cultural comparison of TKA/THA outcomes. Reports from national registries lack detailed patient information while these data suggest the need for adequate risk adjustment of patient factors. PMID- 28077125 TI - Spatiotemporal epidemic characteristics and risk factor analysis of malaria in Yunnan Province, China. AB - BACKGROUND: Malaria remains an important public health concern in China and is particularly serious in Yunnan, a China's provincial region of high malaria burden with an incidence of 1.79/105 in 2012. This study aims to examine the epidemiologic profile and spatiotemporal aspects of epidemics of malaria, and to examine risk factors which may influence malaria epidemics in Yunnan Province. METHODS: The data of malaria cases in 2012 in 125 counties of Yunnan Province was used in this research. The epidemical characteristics of cases were revealed, and time and space clusters of malaria were detected by applying scan statistics method. In addition, we applied the geographically weighted regression (GWR) model in identifying underlying risk factors. RESULTS: There was a total of 821 cases of malaria, and male patients accounted for 83.9% (689) of the total cases. The incidence in the group aged 20-30 years was the highest, at 3.00/105. The majority (84.1%) of malaria cases occurred in farmers and migrant workers, according to occupation statistics. On a space-time basis, epidemics of malaria of varying severity occurred in the summer and autumn months, and the high risk regions were mainly distributed in the southwest counties. Annual average temperature, annual cumulative rainfall, rice yield per square kilometer and proportion of rural employees mainly showed a positive association with the malaria incidence rate, according to the GWR model. CONCLUSIONS: Malaria continues to be one of serious public health issues in Yunnan Province, especially in border counties in southwestern Yunnan. Temperature, precipitation, rice cultivation and proportion of rural employees were positively associated with malaria incidence. Individuals, and disease prevention and control departments, should implement more stringent preventative strategies in locations with hot and humid environmental conditions to control malaria. PMID- 28077126 TI - What do we know about the effects of exposure to 'Low alcohol' and equivalent product labelling on the amounts of alcohol, food and tobacco people select and consume? A systematic review. AB - BACKGROUND: Explicit labelling of lower strength alcohol products could reduce alcohol consumption by attracting more people to buy and drink such products instead of higher strength ones. Alternatively, it may lead to more consumption due to a 'self-licensing' mechanism. Equivalent labelling of food or tobacco (for example "Low fat" or "Low tar") could influence consumption of those products by similar mechanisms. This systematic review examined the effects of 'Low alcohol' and equivalent labelling of alcohol, food and tobacco products on selection, consumption, and perceptions of products among adults. METHODS: A systematic review was conducted based on Cochrane methods. Electronic and snowball searches identified 26 eligible studies. Evidence from 12 randomised controlled trials (all on food) was assessed for risk of bias, synthesised using random effects meta-analysis, and interpreted in conjunction with evidence from 14 non randomised studies (one on alcohol, seven on food and six on tobacco). Outcomes assessed were: quantities of the product (i) selected or (ii) consumed (primary outcomes - behaviours), (iii) intentions to select or consume the product, (iv) beliefs associated with it consumption, (v) product appeal, and (vi) understanding of the label (secondary outcomes - cognitions). RESULTS: Evidence for impacts on the primary outcomes (i.e. amounts selected or consumed) was overall of very low quality, showing mixed effects, likely to vary by specific label descriptors, products and population characteristics. Overall very low quality evidence suggested that exposure to 'Low alcohol' and equivalent labelling on alcohol, food and tobacco products can shift consumer perceptions of products, with the potential to 'self-licence' excess consumption. CONCLUSIONS: Considerable uncertainty remains about the effects of labels denoting low alcohol, and equivalent labels, on alcohol, food and tobacco selection and consumption. Independent, high-quality studies are urgently needed to inform policies on labelling regulations. PMID- 28077127 TI - Navigating social and ethical challenges of biobanking for human microbiome research. AB - BACKGROUND: Biobanks are considered to be key infrastructures for research development and have generated a lot of debate about their ethical, legal and social implications (ELSI). While the focus has been on human genomic research, rapid advances in human microbiome research further complicate the debate. DISCUSSION: We draw on two cystic fibrosis biobanks in Toronto, Canada, to illustrate our points. The biobanks have been established to facilitate sample and data sharing for research into the link between disease progression and microbial dynamics in the lungs of pediatric and adult patients. We begin by providing an overview of some of the ELSI associated with human microbiome research, particularly on the implications for the broader society. We then discuss ethical considerations regarding the identifiability of samples biobanked for human microbiome research, and examine the issue of return of results and incidental findings. We argue that, for the purposes of research ethics oversight, human microbiome research samples should be treated with the same privacy considerations as human tissues samples. We also suggest that returning individual microbiome-related findings could provide a powerful clinical tool for care management, but highlight the need for a more grounded understanding of contextual factors that may be unique to human microbiome research. CONCLUSIONS: We revisit the ELSI of biobanking and consider the impact that human microbiome research might have. Our discussion focuses on identifiability of human microbiome research samples, and return of research results and incidental findings for clinical management. PMID- 28077128 TI - Treatment planning comparison of IMPT, VMAT and 4pi radiotherapy for prostate cases. AB - BACKGROUND: Intensity-modulated proton therapy (IMPT), non-coplanar 4pi intensity modulated radiation therapy (IMRT), and volumetric-modulated arc therapy (VMAT) represent the most advanced treatment methods based on heavy ion and X-rays, respectively. Here we compare their performance for prostate cancer treatment. METHODS: Ten prostate patients were planned using IMPT with robustness optimization, VMAT, and 4pi to an initial dose of 54 Gy to a clinical target volume (CTV) that encompassed the prostate and seminal vesicles, then a boost prescription dose of 25.2 Gy to the prostate for a total dose of 79.2 Gy. The IMPT plans utilized two coplanar, oblique scanning beams 10 degrees posterior of the lateral beam positions. Range uncertainties were taken into consideration in the IMPT plans. VMAT plans used two full, coplanar arcs to ensure sufficient PTV coverage. 4pi plans were created by inversely selecting and optimizing 30 beams from 1162 candidate non-coplanar beams using a greedy column generation algorithm. CTV doses, bladder and rectum dose volumes (V40, V45, V60, V65, V70, V75, and V80), R100, R50, R10, and CTV homogeneity index (D95/D5) were evaluated. RESULTS: Compared to IMPT, 4pi resulted in lower anterior rectal wall mean dose as well as lower rectum V40, V45, V60, V65, V70, and V75. Due to the opposing beam arrangement, IMPT resulted in significantly (p < 0.05) greater femoral head doses. However, IMPT plans had significantly lower bladder, rectum, and anterior rectal wall max dose. IMPT doses were also significantly more homogeneous than 4pi and VMAT doses. CONCLUSION: Compared to the VMAT and 4pi plans, IMPT treatment plans are superior in CTV homogeneity and maximum point organ-at-risk (OAR) doses with the exception of femur heads. IMPT is inferior in rectum and bladder volumes receiving intermediate to high doses, particularly to the 4pi plans, but significantly reduced low dose spillage and integral dose, which are correlated to secondary cancer for patients with expected long survival. The dosimetric benefits of 4pi plans over VMAT are consistent with the previous publication. PMID- 28077129 TI - Hypoglycemic and pancreatic protective effects of Portulaca oleracea extract in alloxan induced diabetic rats. AB - BACKGROUND: Diabetes is a major public health concern. In spite of continuous new drug development to treat diabetes, herbal remedies remain a potential adjunct therapy to maintain better glycemic control while also imparting few side effects. Portulaca oleracea has been traditionally used to manage several diseases due to the anti-oxidant and anti-atherogenic effects it imparts. To better understand the mechanisms associated with potential protective effect of P. oleracea extract against diabetes, alloxan-induced diabetic rats were used in this study. METHODS: Forty Wistar rats (male, 7-8-wk-old, 140-160 g) were divided into four groups (n = 10/group): Group I (control), Group II (P. oleracea treated; gavaged with P. oleracea extract daily [at 250 mg/kg] for 4 weeks), Group III (diabetic control; daily IP injection of alloxan [at 75 mg/kg] for 5 days) and Group IV (P. oleracea-pre-treated diabetic; gavaged with P. oleracea extract daily [at 250 mg/kg] for 4 weeks and then daily IP injection of alloxan [at 75 mg/kg] for 5 days). Body weight, food consumption, blood (serum) levels of glucose, C peptide, Hb A1C, insulin, tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were determined for all groups. RESULTS: The results indicated that while Hb A1C, serum levels of glucose, TNF-alpha and IL-6 were all significantly decreased in the P. oleracea-pre-treated diabetic rats, these hosts also had significant increases in C peptide and insulin compared to levels in the counterpart diabetic rats. These results were confirmed by the histopathological assessments which showed marked improvement of the destructive effect on pancreatic islet cells induced by alloxan. CONCLUSION: P. oleracea extract is a general tissue protective and regeneartive agent, as evidenced by increasing beta cell mass and therefore improved the glucose metabolism. Thus, stimulation of Portulaca oleracea signaling in beta- cells may be a novel therapeutic strategy for diabetes prevention. PMID- 28077130 TI - The case of value-based healthcare for people living with complex long-term conditions. AB - BACKGROUND: There is a trend towards value-based health service, striving to cut costs while generating value for the patient. The overall objective comprises higher-quality health services and improved patient safety and cost efficiency. The approach could align with patient-centred care, as it entails a focus on the patient's experience of her or his entire cycle of care, including the use of well-defined outcome measurements. Challenges arise when the approach is applied to health services for people living with long-term complex conditions that require support from various healthcare services. The aim of this work is to critically discuss the value-based approach and its implications for patients with long-term complex conditions. Two cases from clinical practice and research form the foundation for our reasoning, illustrating several challenges regarding value-based health services for people living with long-term complex conditions. DISCUSSION: Achieving value-based health services that provide the health outcomes that matter to patients and providing greater patient-centredness will place increased demands on the healthcare system. Patients and their informal caregivers must be included in the development and establishment of outcome measures. The outcome measures must be standardized to allow evaluation of specific conditions at an aggregated level, but they must also be sensitive enough to capture each patient's individual needs and goals. Healthcare systems that strive to establish value-based services must collaborate beyond the organizational boundaries to create clear patient trajectories in order to avoid fragmentation. The shift towards value-based health services has the potential to align healthcare-service delivery with patient-centred care if serious efforts to take the patient's perspective into account are made. This is especially challenging in fragmented healthcare systems and for patients with long-term- and multi-setting-care needs. PMID- 28077131 TI - Granulocyte colony-stimulating factor (G-CSF) promotes spermatogenic regeneration from surviving spermatogonia after high-dose alkylating chemotherapy. AB - BACKGROUND: The lifesaving chemotherapy and radiation treatments that allow patients to survive cancer can also result in a lifetime of side-effects, including male infertility. Infertility in male cancer survivors is thought to primarily result from killing of the spermatogonial stem cells (SSCs) responsible for producing spermatozoa since SSCs turn over slowly and are thereby sensitive to antineoplastic therapies. We previously demonstrated that the cytokine granulocyte colony-stimulating factor (G-CSF) can preserve spermatogenesis after alkylating chemotherapy (busulfan). METHODS: Male mice were treated with G-CSF or controls before and/or after sterilizing busulfan treatment and evaluated immediately or 10-19 weeks later for effects on spermatogenesis. RESULTS: We demonstrated that the protective effect of G-CSF on spermatogenesis was stable for at least 19 weeks after chemotherapy, nearly twice as long as previously shown. Further, G-CSF treatment enhanced spermatogenic measures 10 weeks after treatment in the absence of a cytotoxic insult, suggesting G-CSF acts as a mitogen in steady-state spermatogenesis. In agreement with this conclusion, G-CSF treatment for 3 days before busulfan treatment exacerbated the loss of spermatogenesis observed with G-CSF alone. Reciprocally, spermatogenic recovery was modestly enhanced in mice treated with G-CSF for 4 days after busulfan. These results suggested that G-CSF promoted spermatogonial proliferation, leading to enhanced spermatogenic regeneration from surviving SSCs. Similarly, there was a significant increase in proportion of PLZF+ undifferentiated spermatogonia that were Ki67+ (proliferating) 1 day after G-CSF treatment. CONCLUSIONS: Together, these results clarify that G-CSF protects spermatogenesis after alkylating chemotherapy by stimulating proliferation of surviving spermatogonia, and indicate it may be useful as a retrospective fertility-restoring treatment. PMID- 28077132 TI - FOXN1 deficient nude severe combined immunodeficiency. AB - Nude severe combined immunodeficiency is a rare inherited disease caused by autosomal recessive loss-of-function mutations in FOXN1. This gene encodes a transcription factor essential for the development of the thymus, the primary lymphoid organ that supports T-cell development and selection. To date nine cases have been reported presenting with the clinical triad of absent thymus resulting in severe T-cell immunodeficiency, congenital alopecia universalis and nail dystrophy. Diagnosis relies on testing for FOXN1 mutations, which allows genetic counselling and guides therapeutic management. Options for treating the underlying immune deficiency include HLA-matched genoidentical haematopoietic cell transplantation containing mature donor T-cells or thymus tissue transplantation. Experience from other severe combined immune deficiency syndromes suggests that early diagnosis, supportive care and definitive management result in better patient outcomes. Without these the prognosis is poor due to early-onset life threatening infections. PMID- 28077133 TI - T1 and T2 mapping for evaluation of myocardial involvement in patients with ANCA associated vasculitides. AB - BACKGROUND: Myocardial involvement in AAV patients might be silent, presenting with no or nonspecific symptoms, normal ECG, and preserved left-ventricular ejection fraction (LV-EF). Since up to 50% of deaths in these patients may be due to myocardial involvement, a reliable diagnostic tool is warranted. In contrast to LGE-CMR, which has its strengths in detecting focal inflammatory or fibrotic processes, recent mapping techniques are able to detect even subtle, diffuse inflammatory or fibrotic processes. Our study sought to investigate ANCA (antineutrophil cytoplasmic antibody) associated vasculitides (AAV) patients for myocardial involvement by a cardiovascular magnetic resonance (CMR) protocol, including late gadolinium enhancement (LGE) and mapping sequences. METHODS: Thirty seven AAV patients were prospectively enrolled and underwent CMR imaging. Twenty healthy volunteers served as controls. RESULTS: Mean LV-EF was 64%; LGE prevalence of the AAV patients was 43%. AAV patients had higher median native T1 (988 vs. 952 ms, p < 0.001), lower post-contrast T1 (488 vs. 524 ms, p = 0.03), expanded extracellular volume (ECV) (27.5 vs. 24.5%, p < 0.001), and higher T2 (53 vs. 49 ms, p < 0.001) compared to controls, with most parameters independent of the LGE status. Native T1 and T2 in AAV patients showed the highest prevalence of abnormally increased values beyond the 95% percentile of controls. CONCLUSION: AAV patients demonstrated increased T1, ECV, and T2 values, with native T1 and T2 showing the highest prevalence of values beyond the 95% percentile of normal. Since these findings seem to be independent of LGE, mapping techniques may provide complementary information to LGE-CMR in the assessment of myocardial involvement in patients with AAV. PMID- 28077134 TI - Endoscopy-assisted surgery for the management of benign breast tumors: technique, learning curve, and patient-reported outcome from preliminary 323 procedures. AB - BACKGROUND: Endoscopy-assisted breast surgery (EABS), a technique that optimizes cosmetic outcome because it is performed through small wounds hidden in inconspicuous areas, could be an alternative surgical technique for benign breast tumors. In this study, we report the preliminary results of 323 EABS procedures performed at our institution for the management of benign breast tumors. METHODS: The medical records of patients who underwent EABS for benign breast lesions during the periods August 2010 to December 2015 were collected from the Changhua Christian Hospital EABS database. Data on clinicopathologic characteristics, type of surgery, hospital stay, and complications were analyzed to determine the effectiveness of the procedure for benign breast tumors. The operating time with the number of procedure performed was analyzed for learning curve evaluation. Patient satisfaction with cosmetic outcome was evaluated with a self-report questionnaire. RESULTS: A total of 323 EABS procedures were performed in 286 patients with benign breast lesions, including 249 (90.5%) patients with unilateral lesions. The mean age was 36 years, the mean tumor size was 2.2 cm, and the mean distance from the nipple to the tumor was 5.2 cm. Most (93.8%, 303/323) of these tumors were excised through a transareolar wound, 2.4% (8/323) through an axillary wound, and 0.3% (1/323) through the infra-mammary fold. Histopathologic analysis revealed that 63.5% (202/318) of the tumors were fibroadenoma-related lesions. The mean operative time was 81.4 min (59~89 min), which was decreased with experience increased. The overall rate of complications was 6.5%, and all were minor and wound-related. Among the 110 patients who participated in the self-report cosmetic outcome evaluation, 85.4% reported being satisfied with the cosmetic result, and almost all were satisfied with breast symmetry. Of the patients interviewed, 92.7% reported that they would choose the same procedure if they had to undergo the operation again. CONCLUSIONS: Our preliminary results show that transareolar video-assisted breast surgery is a safe and effective procedure with good cosmetic outcome and that it could be appropriate for patients with moderate to large peripherally located breast tumors. TRIAL REGISTRATION: CCH-IRB No.15115. Registered 14 December 2015 (retrospectively registered). PMID- 28077135 TI - Comorbidity study of borderline personality disorder: applying association rule mining to the Taiwan national health insurance research database. AB - BACKGROUND: Borderline personality disorder (BPD) is a complex clinical state with highly polymorphic symptoms and signs. Studies have demonstrated that people with a BPD diagnosis are likely to have numerous co-occurring psychiatric disorders and physical comorbidities. The aim of our study was to obtain further insight about the associations among comorbidities of BPD and to demonstrate the practicality of using association rule mining (ARM) technique in clinical databases. METHODS: A retrospective case-control study was conducted on information of 1460 patients (292 BPD patients and 1168 control patients) selected from the Taiwan National Health Insurance Research Database. Information on physical and psychiatric comorbidities, which were diagnosed within 3 years before and after enrollment, was collected. A logistic regression model was used to calculate the odds ratios of comorbidities between patients with and without BPD. ARM technique was used to study the associations of BPD and two or more psychiatric comorbidities. RESULTS: We classified physical comorbidities into 13 categories according to the International Classification of Diseases, Ninth Revision, Clinical Modification system, and the results indicated that the 12 categories were more common in the BPD patients than in the control patients (except congenital anomalies). However, psychiatric comorbidities, including depressive disorder, bipolar disorder, anxiety disorder, sleep disorder, substance use disorder, and mental retardation were more common in the BPD patients than in the control patients. Furthermore, the associations of BPD and two or more comorbidities were evaluated. CONCLUSION: Most physical and psychiatric disorders were more common in the BPD patients than in the control patients. Because the failure to remit from BPD is associated with suffering from chronic physical conditions and because psychiatric comorbidities may lead to delays in diagnosis of BPD, clinicians caring for people with BPD should be aware of possible comorbidities. PMID- 28077136 TI - Increased leptin/adiponectin ratio relates to low-normal thyroid function in metabolic syndrome. AB - BACKGROUND: Low-normal thyroid function within the euthyroid range may contribute to increased atherosclerosis susceptibility. The leptin/adiponectin (L/A) ratio is associated with cardiovascular disease and reflects adipose tissue dysfunction. Relationships of the L/A ratio with low-normal thyroid function are unknown. METHODS: Relationships of thyroid stimulating hormone (TSH) and free thyroxine (free T4) with leptin, adiponectin and the L/A ratio in euthyroid subjects were documented in 67 fasting subjects with metabolic syndrome (Mets) and 86 euthyroid subjects without MetS (TSH and free T4 levels within the institutional reference range). RESULTS: Neither plasma leptin nor adiponectin was significantly correlated with TSH or free T4 in subjects with and without MetS. In the whole group, high sensitivity C-reactive protein (hs-CRP) was positively correlated with the L/A ratio (r = 0.485, P < 0.001). Notably, the L/A ratio was positively correlated with TSH in subjects with MetS (r = 0.252, P = 0.040) but not in subjects without MetS (r = -0.068, P = 0.54; interaction term, P = 0.027). In MetS subjects, the L/A ratio remained positively related with TSH after adjustment for age, sex, diabetes status, hs-CRP and the use of antihypertensive and glucose lowering medication (beta = 0.283, P = 0.018), as well as after adjustment for individual MetS components (beta = 0.294, P = 0.020). CONCLUSIONS: In the context of MetS, a higher TSH within the euthyroid range confers an increased L/A ratio, a proposed marker of atherosclerosis susceptibility and adipocyte dysfunction. PMID- 28077137 TI - Aberrant methylation of DACT1 and DACT2 are associated with tumor progression and poor prognosis in esophageal squamous cell carcinoma. AB - BACKGROUND: The DACT (Dishevelled-associated antagonist of beta-catenin) family of scaffold proteins may play important roles in tumorigenesis. However, the epigenetic changes of DACT1, 2, 3 and their effect on esophageal squamous cell carcinoma (ESCC) have not been investigated so far. The aim of this study was to investigate the promoter methylation and expression of DACT family, in order to elucidate more information on the role of DACT with regard to the progression and prognosis of ESCC. METHODS: MSP and BGS methods were respectively applied to examine the methylation status of DACT; RT-PCR, Western blot and immunohistochemistry methods were respectively used to determine the mRNA and protein expression of DACT; MTT, Colony-formation and Wound-healing assay were performed to assess the effect of DACT1 and DACT2 on proliferation and migration of esophageal cancer cells. RESULTS: Frequent reduced expression of DACT1, DACT2 and DACT3 were found in esophageal cancer cell lines and the expression levels of DACT1 and DACT2 were reversed by 5-Aza-Dc. Decreased mRNA and protein expression of DACT1 and DACT2 were observed in ESCC tumor tissues and were associated with the methylation status of transcription start site (TSS) region. The hypermethylation of CpG islands (CGI) shore region in DACT1 was observed both in tumor and corresponding adjacent tissues but wasn't related to the transcriptional inhibition of DACT1. The methylation status of TSS region in DACT1 and DACT2 and the protein expression of DACT2 were independently associated with ESCC patients' prognosis. CONCLUSIONS: The TSS region hypermethylation may be one of the main mechanisms for reduced expression of DACT1 and DACT2 in ESCC. The simultaneous methylation of DACT1 and DACT2 may play important roles in progression of ESCC and may serve as prognostic methylation biomarkers for ESCC patients. PMID- 28077138 TI - Fish intake and the risk of brain tumor: a meta-analysis with systematic review. AB - BACKGROUND: Fish, rich in omega-3 polyunsaturated fatty acids, has been found to be associated with lower risk of several types of cancer risk, and beneficial for brain development. However, the association between fish intake and brain tumor risk is still inconsistent. Therefore, we conducted a meta-analysis to clarify the association. METHODS: Relevant studies were identified from PubMed and EMBASE databases. The pooled relative risks were obtained by the fixed-effects model when no substantial heterogeneity was observed. Otherwise, the random-effects model was employed. Subgroup and publication bias analyses were also performed. RESULTS: Nine observational studies were included in the meta-analysis. The pooled relative risk of brain cancer for the highest vs. lowest category of fish intake was 0.83 (95% confidence interval [CI]: 0.70-0.99). No significant heterogeneity was detected. Dose-response analysis showed that the RR per 100 g/day increase in fish intake was 0.95 (95% CI: 0.91-0.98). The results remained unchanged in subgroup and sensitivity analyses. CONCLUSIONS: The results of our meta-analysis suggest that fish intake might be associated with lower risk of brain cancer risk. The finding should be further confirmed by future cohort studies with validated questionnaires and strict control of confounders. PMID- 28077139 TI - Assessment of coping: a new french four-factor structure of the brief COPE inventory. AB - BACKGROUND: The Brief Coping Orientation to Problems Experienced (Brief COPE) inventory is the most usual measure to identify the nature of coping strategies implemented by individuals and explore 14 coping strategies. The availability of a structure with fewer factors rather than the initial 14-factor structure may be of interest for both healthcare professionals and researchers. We report the validation process of a 4-factor structure of the French version of the Brief COPE in a French sample of individuals facing a singular life event, such as cancer, including patients and their caregivers. METHODS: The cross-sectional study included cancer patients and their caregivers. Self-administered data were collected including: socio-demographic (age, gender, marital status, employment status, and education level), coping strategies using the French version of the Brief COPE, quality of life (QoL) using the French version of the short form health survey questionnaire (SF36). Construct validity, internal consistency, reliability, and external validity were tested. RESULTS: The sample included 398 individuals. The principal component factor analysis identified a 4-factor structure. The dimensions were labeled according to their constitutive items: social support (8 items), problem solving (4), avoidance (10), and positive thinking (6). The 4-factor structure was supported by different theoretical models of coping and showed satisfactory psychometric properties. CONCLUSION: The 4-factor structure of the French version of the Brief COPE, validated in a sample of individuals facing a singular stressful event, including cancer patients and their caregivers, makes the instrument easier to use both in clinical practice and clinical research. PMID- 28077140 TI - Indacaterol and glycopyrronium versus indacaterol on body plethysmography measurements in COPD-a randomised controlled study. AB - BACKGROUND: Dual bronchodilator therapy is recommended for symptomatic patients with chronic obstructive pulmonary disease (COPD). There are limited data on effects of a combination of two long-acting bronchodilators on lung function including body plethysmography. METHODS: This multicentre, randomised, double blind, single-dose, cross-over, placebo-controlled study evaluated efficacy and safety of the free combination of indacaterol maleate (IND) and glycopyrronium bromide (GLY) versus IND alone on spirometric and body plethysmography parameters, including inspiratory capacity (IC), forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), total lung capacity (TLC) and airway resistance (Raw) in moderate-to-severe COPD patients. RESULTS: Seventy-eight patients with FEV1 % pred. (mean +/- SD) 56 +/- 13% were randomised. The combination of IND + GLY versus IND presented a numerically higher peak-IC (Delta = 0.076 L, 95% confidence interval [CI]: -0.010 - 0.161 L; p = 0.083), with a statistically significant difference in mean IC over 4 h (Delta = 0.054 L, 95%CI 0.022 - 0.086 L; p = 0.001). FEV1, FVC and Raw, but not TLC, were consistently significantly improved by IND + GLY compared to IND alone. Safety profiles of both treatments were comparable. CONCLUSION: The free combination of IND + GLY improved lung function parameters as evaluated by spirometry and body plethysmography, with a similar safety profile compared to IND alone. TRIAL REGISTRATION: NCT01699685. PMID- 28077141 TI - Determinants of and socio-economic disparities in self-rated health in China. AB - BACKGROUND: Self-rated health (SRH) is not only used to measure health status and health inequalities, but also as a strong predictor of morbidity and mortality. The purpose of this study was to: 1) evaluate the factors that account for variations in self-rated health among Chinese citizens; and to 2) explore the process through which socio-economic status may impact self-rated health. METHODS: Data were derived from the Chinese General Social Survey (CGSS) (2013). Determinants of self-rated health were analyzed along four main dimensions: demographic characteristics, socio-economic status, lifestyle, and psychosocial factors. Multivariate odds ratios for good self-rated health were calculated for different variables in order to analyze the determinants. Binary logistic regression analysis was performed to assess the extent to which lifestyle and psychosocial factors explained the association between socio-economic status and self-rated health. RESULTS: About 65% of the survey respondents reported good self-rated health. Women, the elderly, married or single respondents and residents of Western China were less likely to report good self-rated health. Respondents who were engaged in work, had higher household income, reported high social class and higher socio-economic status compared with peers were more likely to report good self-rated health. Normal weight and physically active respondents along with those reporting a happy life, no depression, and good relationships with families and friends were related to good self-rated health. We also found the effect of socio-economic status on self-rated health was partly explained by lifestyle and psychosocial factors. CONCLUSION: The present findings support the notion that both socio-economic status and lifestyle as well as psychosocial factors were related with good self-rated health. The interventions targeting these factors could improve the health status of the population. The depression was the most influential predictor of self-rated health, especially for the women and the elderly. Although lifestyle and psychosocial factors explained partly the the association between socio-economic status and health, the reason why socio-economic difference exists in health must be further explored. What's more, it needs to be further studied why the same determinant has different influence strengths on the health of different groups of people. PMID- 28077142 TI - Steroid withdrawal after renal transplantation: a retrospective cohort study. AB - BACKGROUND: Immunosuppressive regimens in renal transplantation frequently contain corticosteroids, but many centers withdraw steroids as a consequence of unwanted side effects of steroids. The optimal timing to withdraw steroids after transplantation, however, remains unclear. The aim of this study was to determine an optimal time point following kidney transplantation that is associated with reduced mortality without jeopardizing the allograft to allow safe discontinuation of steroids. METHODS: We conducted a retrospective cohort study and computed a concatenated landmark-stratified Cox supermodel to estimate hazard ratios and 95% confidence intervals for mortality and graft loss using dynamic propensity score matching to adjust for confounding by indication. RESULTS: A total of 6070 first kidney transplant recipients in the Austrian Dialysis and Transplant Registry who were transplanted between 1990 and 2012 were evaluated and classified according to steroid treatment status throughout follow-up after kidney transplantation; 2142 patients were withdrawn from steroids during the study period. Overall, 1131 patients lost their graft and 821 patients in the study cohort died. Steroid withdrawal within 18 months after transplantation was associated with an increased rate of graft loss compared to steroid maintenance during that time (6 months after transplantation: HR = 1.8; 95% CI, 1.3 to 2.6; 18 months after transplantation: HR = 1.3; 95% CI, 1.1 to 1.6; 24 months after transplantation: HR = 1.2; 95% CI, 0.9 to 1.5), while mortality was not different between groups. CONCLUSIONS: Our findings suggest that steroid withdrawal after anti-IL-2 induction in the first 18 months after transplantation is associated with an increased risk of allograft loss. PMID- 28077143 TI - Pregnant women carrying microcephaly foetuses and Zika virus contain potentially pathogenic microbes and parasites in their amniotic fluid. AB - BACKGROUND: Microcephaly has become a major public health problem in Brazil. The total number of newborns with microcephaly was reported to be >4000 in June 2016. Studies suggest that Zika Virus is a major cause of new microcephaly cases in Brazil. Inside the uterus, the foetus is surrounded by the Amniotic Fluid, a proximal fluid that contains foetal and maternal cells as well as microorganisms and where Zika Virus was already found. CASE PRESENTATION: A previous study reported the presence of the Zika Virus in the amniotic fluid (collected in the 28th gestational week) of two pregnant women carrying microcephaly foetuses in Brazil. The virus was detected by means of real-time PCR and metatranscriptomic analysis. We compared the microbiome of these two cases with metatranscriptomic sequences from 16 pregnant women collected at various times in their pregnancies CONCLUSION: Several strains of bacteria (e.g., Streptococcus and Propionibacterium) found in Amniotic Fluid may be involved in neurological diseases. When the foetus is infected by the Zika Virus, due to neurological damage, they do not move inside the uterus, thus changing the Amniotic Fluid environment, potentially leading to secondary problems. Zika infection could also lead to an immunodeficient state, making bacterial colonization of the foetuses easier. An altered microbial composition during pregnancy may also result in harmful secondary metabolite production from certain microbes that further impair foetal brain development. However, these observations of potentially harmful microbial species are correlations and thus cannot be assumed to be causative agents of (microcephaly) disease. In our study, microbial and parasitic diversity of the Amniotic Fluid was lower in patients infected by ZIKV, compared to that of Prenatal and Preterm controls. The present study was a first attempt to shed light on the microbial and parasitic diversity associated with ZIKV-infected pregnant women bearing microcephaly foetuses, and the presence of diverse microbial and parasite communities in the Amniotic Fluid suggests a poor health status of both the pregnant women and the foetuses they carry. PMID- 28077144 TI - Intraoperative radiation therapy for colon and rectal cancers: a clinical review. AB - Although there have been significant advances in the adjuvant therapy of colorectal cancer, results for patients have historically been poor when complete resection is unlikely or not possible. Similarly, locally recurrent colorectal cancer patients often experience significant tumor related morbidity and disease control and long term survival have historically been poor with standard therapies. Intraoperative radiation therapy (IORT) has been proposed as a possible tool for dose escalation in patients with locally advanced colorectal cancer.For patients with locally advanced primary or recurrent colon cancer, the absence of prospective controlled trials limits the ability to draw definitive conclusions in completely resected patients. In subtotally resected patients, the available evidence is consistent with marked improvements in disease control and survival compared to historical controls. For patients with locally advanced primary or recurrent rectal cancer, a relatively large body of evidence suggests improved disease control and survival, especially in subtotally resected patients, with the addition of IORT to moderate dose external beam radiation (EBRT) and chemotherapy. The most important prognostic factor in nearly all series is the completeness of surgical resection. Many previously irradiated patients may be carefully re-treated with radiation and IORT in addition to chemotherapy resulting in long term survival in more than 25% of patients. Peripheral nerve is dose limiting for IORT and patients receiving 15 Gy or more are at higher risk.IORT is a useful tool when dose escalation beyond EBRT tolerance limits is required for acceptable local control in patients with locally advanced primary or recurrent colorectal cancer. Previously irradiated patients should not be excluded from treatment consideration. PMID- 28077145 TI - Perceptions and experiences of the mistreatment of women during childbirth in health facilities in Guinea: a qualitative study with women and service providers. AB - BACKGROUND: Every woman is entitled to respectful care during childbirth; so it is concerning to hear of informal reports of mistreatment during childbirth in Guinea. This study sought to explore the perceptions and experiences of mistreatment during childbirth, from the perspectives of women and service providers, and the analysis presents findings according to a typology of mistreatment during childbirth. METHODS: This study used qualitative methods (in depth interviews (IDIs) and focus group discussions (FGDs)) and was conducted with four groups of participants: women of reproductive age, midwives, doctors, and administrators. The study took place in two sites in Guinea, an urban area (Mamou) and peri-urban (Pita). Data collection was conducted in two health facilities for providers and administrators, and in the health facility catchment area for women. Data were collected in local languages (Pular and Malinke), then transcribed and analyzed in French. We used a thematic analysis approach and coded transcripts manually. RESULTS: A total of 64 IDIs and eight FGDs were conducted and are included in this analysis, including 40 IDIs and eight FGDs with women of reproductive age, 5 IDIs with doctors, 13 IDIs with midwives, and 6 IDIs with administrators. Participants described their own personal experiences, experiences of women in their communities and perceptions regarding mistreatment during childbirth. Results were organized according to a typology of mistreatment during childbirth, and included instances of physical abuse, verbal abuse, abandonment and neglect. Women described being slapped by providers, yelled at for noncompliance with provider requests, giving birth on the floor and without skilled attendance in the health facility. Poor physical conditions of health facilities and health workforce constraints contributed to experiences of mistreatment. CONCLUSIONS: These results are important because they demonstrate that the mistreatment of women during childbirth exists in Guinea and occurs in multiple forms. These data should be used by the Ministry of Health and other stakeholders to develop strategies to reduce and prevent the mistreatment of women during childbirth. PMID- 28077146 TI - Childhood Arthritis and Rheumatology Research Alliance consensus clinical treatment plans for juvenile dermatomyositis with skin predominant disease. AB - BACKGROUND: Juvenile dermatomyositis (JDM) is the most common form of the idiopathic inflammatory myopathies in children. A subset of children have the rash of JDM without significant weakness, and the optimal treatments for these children are unknown. The goal of this study was to describe the development of consensus clinical treatment plans (CTPs) for children with JDM who have active skin rashes, without significant muscle involvement, referred to as skin predominant JDM in this manuscript. METHODS: The Children's Arthritis and Rheumatology Research Alliance (CARRA) is a North American consortium of pediatric rheumatology health care providers. CARRA members collaborated to determine consensus on typical treatments for JDM patients with skin findings without significant weakness, to develop CTPs for this subgroup of patients. We used a combination of Delphi surveys and nominal group consensus meetings to develop these CTPs. RESULTS: Consensus was reached on patient characteristics and outcome assessment, and CTPs were developed and finalized for patients with skin predominant JDM. Treatment option A included hydroxychloroquine alone, Treatment option B included hydroxychloroquine and methotrexate, and Treatment option C included hydroxychloroquine, methotrexate and corticosteroids. CONCLUSIONS: Three CTPs were developed for use in children with skin predominant JDM, which reflect typical treatment approaches. These are not considered to be specific recommendations or standard of care. Using the CARRA network and prospective data collection, we will be able to apply statistical methods in the future to allow comparisons of JDM patients following these consensus treatment plans. PMID- 28077147 TI - The political and scientific challenges in evaluating compulsory drug treatment centers in Southeast Asia. AB - BACKGROUND: In Vietnam, like many countries in Southeast Asia, the commonly used approach of center-based compulsory drug treatment (CCT) has been criticized on human rights ground. Meanwhile, community-based voluntary methadone maintenance treatment (MMT) has been implemented for nearly a decade with promising results. Reform-minded leaders have been seeking empirical evidence of the costs and effectiveness associated with these two main treatment modalities. Conducting evaluations of these treatments, especially where randomization is not ethical, presents challenges. The aim of this paper is to discuss political challenges and methodological issues when conducting cost-effectiveness studies within the context of a non-democratic Southeast Asian country. METHODS: A retrospective analysis of the political and scientific challenges that were experienced in the study design, sample size determination, government approval and ethics approvals, participant recruitment, data collection, and determination of sources, and quantification of cost and effectiveness data was undertaken. As a consequence of the non-randomized design, analysis of patient characteristics for both treatment types was undertaken to identify the magnitude of baseline group differences. Concordance between self-reported heroin use and urine drug testing was undertaken to determine the reliability of self-report data in a politically challenging environment. RESULTS: We demonstrate that conducting research around compulsory treatment in a non-democratic society is feasible, yet it is politically challenging and requires navigation between science and politics. We also demonstrate that engagement with the government decision makers in the research conception, implementation, and dissemination of the results increases the likelihood of research evidence being considered for change in a contentious drug policy area. CONCLUSIONS: Local empirical evidence on the comparative cost effectiveness of CCT and MMT in a Southeast Asian setting is critical to consideration of more holistic, humane, and effective drug-dependence treatment approaches, but the garnering of such evidence is very challenging. PMID- 28077149 TI - Plasmodium falciparum malaria co-infection with tick-borne relapsing fever in Dakar. AB - BACKGROUND: West African tick-borne relapsing fever (TBRF) due to Borrelia crocidurae and malaria are co-endemics in Senegal. Although expected to be high, co-infections are rarely reported. A case of falciparum malaria and B. crocidurae co-infection in a patient from Velingara (South of Senegal) is discussed. CASE: A 28 year-old-male patient presented to Aristide Le Dantec Hospital for recurrent fever. He initially presented to a local post health of Pikine (sub-urban of Dakar) and was diagnosed for malaria on the basis of positive malaria rapid diagnostic test (RDT) specific to Plamodium falciparum. The patient was treated as uncomplicated falciparum malaria. Four days after admission the patient was referred to Le Dantec Hospital. He presented with fever (39 degrees C), soreness, headache and vomiting. The blood pressure was 120/80 mmHg. The rest of the examination was normal. A thick film from peripheral blood was performed and addressed to the parasitology laboratory of the hospital. Thick film was stained with 10% Giemsa. Trophozoite of P. falciparum was identified at parasite density of 47 parasites per microlitre. The presence of Borrelia was also observed, concluding to malaria co-infection with borreliosis. CONCLUSIONS: Signs of malaria can overlap with signs of borreliosis leading to the misdiagnosis of the latter. Thick and thin smear or QBC test or molecular method may be helpful to detect both Plamodium species and Borrelia. In addition, there is a real need to consider co-infections with other endemics pathogens when diagnosing malaria. PMID- 28077148 TI - Linking communities to formal health care providers through village health teams in rural Uganda: lessons from linking social capital. AB - BACKGROUND: Community-based programmes, particularly community health workers (CHWs), have been portrayed as a cost-effective alternative to the shortage of health workers in low-income countries. Usually, literature emphasises how easily CHWs link and connect communities to formal health care services. There is little evidence in Uganda to support or dispute such claims. Drawing from linking social capital framework, this paper examines the claim that village health teams (VHTs), as an example of CHWs, link and connect communities with formal health care services. METHODS: Data were collected through ethnographic fieldwork undertaken as part of a larger research program in Luwero District, Uganda, between 2012 and 2014. The main methods of data collection were participant observation in events organised by VHTs. In addition, a total of 91 in-depth interviews and 42 focus group discussions (FGD) were conducted with adult community members as part of the larger project. After preliminary analysis of the data, we conducted an additional six in-depth interviews and three FGD with VHTs and four FGD with community members on the role of VHTs. Key informant interviews were conducted with local government staff, health workers, local leaders, and NGO staff with health programs in Luwero. Thematic analysis was used during data analysis. RESULTS: The ability of VHTs to link communities with formal health care was affected by the stakeholders' perception of their roles. Community members perceive VHTs as working for and under instructions of "others", which makes them powerless in the formal health care system. One of the challenges associated with VHTs' linking roles is support from the government and formal health care providers. Formal health care providers perceived VHTs as interested in special recognition for their services yet they are not "experts". For some health workers, the introduction of VHTs is seen as a ploy by the government to control people and hide its inability to provide health services. Having received training and initial support from an NGO, VHTs suffered transition failure from NGO to the formal public health care structure. As a result, VHTs are entangled in power relations that affect their role of linking community members with formal health care services. We also found that factors such as lack of money for treatment, poor transport networks, the attitudes of health workers and the existence of multiple health care systems, all factors that hinder access to formal health care, cannot be addressed by the VHTs. CONCLUSIONS: As linking social capital framework shows, for VHTs to effectively act as links between the community and formal health care and harness the resources that exist in institutions beyond the community, it is important to take into account the power relationships embedded in vertical relationships and forge a partnership between public health providers and the communities they serve. This will ensure strengthened partnerships and the improved capacity of local people to leverage resources embedded in vertical power networks. PMID- 28077150 TI - The equity of China's emergency medical services from 2010-2014. AB - BACKGROUND: With the depth development of health care system reform in China, emergency medical services (EMS) is confronted with challenges as well as opportunities. This study aimed to analyze the equity of China's EMS needs, utilization, and resources distribution, and put forward proposal to improve the equity. METHOD: Three emergency needs indicators (mortality rate of cardiovascular and cerebrovascular diseases, harm, and digestive system disease), two utilization indicators (emergency outpatient visits and rate of utilization) and one resource allocation indicator (number of EMS facilities) were collected after the review of the China Statistical Yearbook and the National Disease Surveillance System. Next, EMS related indicators were compared among 31 provinces from the eastern, central, and western regions of the country. Concentration Index (CI) were used to measure the equity of EMS needs and utilization among the western, central, and eastern regions. The Gini coefficient of demographic and geographic distribution of facilities represented the equity of resource allocation. RESULT: During 2010-2014, the CI of cardiovascular and cerebrovascular disease mortality changed from positive to negative, which indicates that the concentrated trend transferred from richer regions to the poorer area. Injury mortality (CI: range from - 0.1241to -0.1504) and digestive disease mortality (CI: range from - 0.1921 to - 0.2279) consistently concentrated in the poorer region, and the inequity among regions became more obviously year by-year. The utilization of EMS (CI: range from 0.1074 to 0.0824) showed an improvement; however, the inequity reduced gradually. The EMS facilities distribution by population (Gini coefficient: range from 0.0922 to 0.1200) showed high equitability but the EMS facilities distribution by geography (Gini coefficient: range from 0.0922 to 0.1200) suggested a huge gap between regions because the Gini coefficients were greater than 0.5 in the past 5 years. CONCLUSION: There are some inequities of needs, utilization, and resource allocation in the China EMS. The government needs to stick to the principle of increasing investment in poorer regions, perfecting ambulance configuration and improving health workers' professional skills to improve the equity and quality of EMS. PMID- 28077151 TI - Multi-strategic intervention to enhance implementation of healthy canteen policy: a randomised controlled trial. AB - BACKGROUND: Internationally, governments have implemented school-based nutrition policies to restrict the availability of unhealthy foods from sale. The aim of the trial was to assess the effectiveness of a multi-strategic intervention to increase implementation of a state-wide healthy canteen policy. The impact of the intervention on the energy, total fat, and sodium of children's canteen purchases and on schools' canteen revenue was also assessed. METHODS: Australian primary schools with a canteen were randomised to receive a 12-14-month, multi-strategic intervention or to a no intervention control group. The intervention sought to increase implementation of a state-wide healthy canteen policy which required schools to remove unhealthy items (classified as 'red' or 'banned') from regular sale and encouraged schools to 'fill the menu' with healthy items (classified as 'green'). The intervention strategies included allocation of a support officer to assist with policy implementation, engagement of school principals and parent committees, consensus processes with canteen managers, training, provision of tools and resources, academic detailing, performance feedback, recognition and marketing initiatives. Data were collected at baseline (April to September, 2013) and at completion of the implementation period (November, 2014 to April, 2015). RESULTS: Seventy schools participated in the trial. Relative to control, at follow-up, intervention schools were significantly more likely to have menus without 'red' or 'banned' items (RR = 21.11; 95% CI 3.30 to 147.28; p <= 0.01) and to have at least 50% of menu items classified as 'green' (RR = 3.06; 95% CI 1.64 to 5.68; p <= 0.01). At follow-up, student purchases from intervention school canteens were significantly lower in total fat (difference = -1.51 g; 95% CI -2.84 to -0.18; p = 0.028) compared to controls, but not in energy (difference = -132.32 kJ; 95% CI -280.99 to 16.34; p = 0.080) or sodium (difference = -46.81 mg; 95% CI -96.97 to 3.35; p = 0.067). Canteen revenue did not differ significantly between groups. CONCLUSION: Poor implementation of evidence-based school nutrition policies is a problem experienced by governments internationally, and one with significant implications for public health. The study makes an important contribution to the limited experimental evidence regarding strategies to improve implementation of school nutrition policies and suggests that, with multi-strategic support, implementation of healthy canteen policies can be achieved in most schools. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( ACTRN12613000311752 ). PMID- 28077152 TI - Gender bias and sex-based differences in health care efficiency in Polish regions. AB - BACKGROUND: Health differences between sexes are relatively well recognized, though less is known about the specificity of women's and men's health responsiveness to medical care. Applying data from Polish regions, this study identifies sex-based differences in medical care efficiency and investigates the reasons for these disparities in the gender bias context. METHODS: The study estimates sex-specific health production functions for regional data from Poland (1999-2013). Using panel-data regression, male and female life expectancies at ages 0, 15, 30, 45, 60 and 65 are regressed on a set of socioeconomic factors, with the primary interest in medical care proxied by doctor density. RESULTS: The results show that in Poland the association between life expectancy and doctor density was positive for both men and women; however, the coefficients for medical care were insignificant for those at birth and at the age of 30 for both sexes. The magnitude of health care for longevity was higher for men comparing to women at every age, though the difference between sexes was not statistically significant. The sex-based disparities in medical care efficiency were more pronounced at younger ages and they diminished with age. The inspection of data on the health system in Poland shows that male patients seemed to be in an advantageous position: the mean reimbursement per service for men was higher in most medical care areas; men reported less problems with access to health care; and their mortality trend exhibited more favorable evolution over time. Additionally, the association between other socioeconomic factors and health also differed across sexes, and several of these factors were more important for life expectancy than health care. CONCLUSION: Polish medical care suffers from gender bias, which possibly makes men more responsive to medical care. The disparities in the operation of medical care in Poland should be challenged to achieve more equal access to services between sexes and possibly to gain more health from the treatment of female patients. PMID- 28077153 TI - Detection of Strongylus vulgaris in equine faecal samples by real-time PCR and larval culture - method comparison and occurrence assessment. AB - BACKGROUND: Strongylus vulgaris has become a rare parasite in Germany during the past 50 years due to the practice of frequent prophylactic anthelmintic therapy. To date, the emerging development of resistance in Cyathostominae and Parascaris spp. to numerous equine anthelmintics has changed deworming management and the frequency of anthelmintic usage. In this regard, reliable detection of parasitic infections, especially of the highly pathogenic S. vulgaris is essential. In the current study, two diagnostic methods for the detection of infections with S. vulgaris were compared and information on the occurrence of this parasite in German horses was gained. For this purpose, faecal samples of 501 horses were screened for S. vulgaris with real-time PCR and an additional larval culture was performed in samples of 278 horses. A subset of 26 horses underwent multiple follow-up examinations with both methods in order to evaluate both the persistence of S. vulgaris infections and the reproducibility of each diagnostic method. RESULTS: The real-time PCR revealed S. vulgaris-DNA in ten of 501 investigated equine samples (1.9%). The larval culture demonstrated larvae of S. vulgaris in three of the 278 samples (1.1%). A direct comparison of the two methods was possible in 321 samples including 43 follow-up examinations with the result of 11 S. vulgaris-positive samples by real-time PCR and 4 S. vulgaris positive samples by larval culture. The McNemar's test (p-value = 0.016) revealed a significant difference and the kappa values (0.525) showed a moderate agreement between real-time PCR and larval culture. CONCLUSIONS: The real-time PCR detected a significantly higher proportion of positives of S. vulgaris compared to larval culture and should thus be considered as a routine diagnostic method for the detection of S. vulgaris in equine samples. PMID- 28077154 TI - Incremental decreases in quality-adjusted life years (QALY) associated with higher levels of depressive symptoms for U.S. Adults aged 65 years and older. AB - BACKGROUND: Quality-adjusted life years (QALY) is a single value index that quantifies the overall burden of disease. It reflects all aspects of heath, including nonfatal illness and mortality outcomes by weighting life-years lived with health-related quality of life (HRQOL) scores. This study examine the burden of disease due to increasing levels of depressive symptoms by examining the association between the 9-item Patient Health Questionnaire (PHQ-9) scores and QALY for U.S. adults aged 65 years and older. METHODS: We ascertained respondents' HRQOL scores and mortality status from the 2005-2006, 2007-2008, and 2009-2010 cohorts of the National Health and Nutrition Examination Survey (NHANES) with mortality follow-up data through December 31, 2011. This analysis included respondents aged 65 years and older (n = 3,680). We estimated the mean QALY throughout the remaining lifetime according to participants' depression severity categories: none or minimal (PHQ-9 score 0-4), mild (5-9), moderate (10 14), and moderately severs and severe (15 or higher). We estimated QALY loss due to major depressive disorder (PHQ-9 score 10 or higher) and to mild depression (5 9). RESULTS: The QALY for persons with none/minimal, mild, moderate, and moderately severe/severe depression were 14.0, 7.8, 4.7, and 3.3 years, respectively. Compared to persons without major depressive disorder, persons with major depressive disorder had 8.3 fewer QALY (12.7 vs. 4.4), or a 65% loss. Compared to persons who reported "none" or minimal depressive symptoms, persons who reported mild depressive symptoms had 6.2 fewer QALY (14.0 vs. 7.8), or a 44% loss. The same patterns were noted in demographic and socioeconomic subgroups and according to number of comorbidities. CONCLUSIONS: This study not only confirmed the significant burden of disease for major depressive disorder among the U.S. elderly, but also showed an incremental decrease in QALY with an increasing severity of depressive symptoms as well as significant QALY loss due to mild depression. Specifically, individuals with higher (or more impaired) PHQ-9 scores had significantly fewer QALYs and our findings of fewer years of QALY for persons with major depressive disorder and mild depression were not only statistically significant but also clinically important. PMID- 28077155 TI - MODEM: A comprehensive approach to modelling outcome and costs impacts of interventions for dementia. Protocol paper. AB - BACKGROUND: The MODEM project (A comprehensive approach to MODelling outcome and costs impacts of interventions for DEMentia) explores how changes in arrangements for the future treatment and care of people living with dementia, and support for family and other unpaid carers, could result in better outcomes and more efficient use of resources. METHODS: MODEM starts with a systematic mapping of the literature on effective and (potentially) cost-effective interventions in dementia care. Those findings, as well as data from a cohort, will then be used to model the quality of life and cost impacts of making these evidence-based interventions more widely available in England over the period from now to 2040. Modelling will use a suite of models, combining microsimulation and macrosimulation methods, modelling the costs and outcomes of care, both for an individual over the life-course from the point of dementia diagnosis, and for individuals and England as a whole in a particular year. Project outputs will include an online Dementia Evidence Toolkit, making evidence summaries and a literature database available free to anyone, papers in academic journals and other written outputs, and a MODEM Legacy Model, which will enable local commissioners of services to apply the model to their own populations. DISCUSSION: Modelling the effects of evidence-based cost-effective interventions and making this information widely available has the potential to improve the health and quality of life both of people with dementia and their carers, while ensuring that resources are used efficiently. PMID- 28077156 TI - Interventions following a high violence risk assessment score: a naturalistic study on a Finnish psychiatric admission ward. AB - BACKGROUND: Patient aggression and violence against staff members and other patients are common concerns in psychiatric units. Many structured clinical risk assessment tools have recently been developed. Despite their superiority to unaided clinical judgments, staff has shown ambivalent views towards them. A constant worry of staff is that the results of risk assessments would not be used. The aims of the present study were to investigate what were the interventions applied by the staff of a psychiatric admission ward after a high risk patient had been identified, how frequently these interventions were used and how effective they were. METHODS: The data were collected in a naturalistic setting during a 6-month period in a Finnish psychiatric admission ward with a total of 331 patients with a mean age of 42.9 years (SD 17.39) suffering mostly from mood, schizophrenia-related and substance use disorders. The total number of treatment days was 2399. The staff assessed the patients daily with the Dynamic Appraisal of Situational Aggression (DASA), which is a structured violence risk assessment considering the upcoming 24 h. The interventions in order to reduce the risk of violence following a high DASA total score (>=4) were collected from the patients' medical files. Inductive content analysis was used. RESULTS: There were a total of 64 patients with 217 observations of high DASA total score. In 91.2% of cases, at least one intervention aiming to reduce the violence risk was used. Pro re nata (PRN)-medication, seclusion and focused discussions with a nurse were the most frequently used interventions. Non-coercive and non pharmacological interventions like daily activities associated significantly with the decrease of perceived risk of violence. CONCLUSION: In most cases, a high score in violence risk assessment led to interventions aiming to reduce the risk. Unfortunately, the most frequently used methods were psychopharmacological or coercive. It is hoped that the findings will encourage the staff to use their imagination when choosing violence risk reducing intervention techniques. PMID- 28077157 TI - Clinical, biochemical and molecular characteristics of Filipino patients with mucopolysaccharidosis type II - Hunter syndrome. AB - BACKGROUND: Mucopolysaccharidosis type II, an X-linked recessive disorder is the most common lysosomal storage disease detected among Filipinos. This is a case series involving 23 male Filipino patients confirmed to have Hunter syndrome. The clinical and biochemical characteristics were obtained and mutation testing of the IDS gene was done on the probands and their female relatives. RESULTS: The mean age of the patients was 11.28 (SD 4.10) years with an average symptom onset at 1.2 (SD 1.4) years. The mean age at biochemical diagnosis was 8 (SD 3.2) years. The early clinical characteristics were developmental delay, joint stiffness, coarse facies, recurrent respiratory tract infections, abdominal distention and hernia. Majority of the patients had joint contractures, severe intellectual disability, error of refraction, hearing loss and valvular regurgitation on subspecialists' evaluation. The mean GAG concentration was 506.5 mg (SD 191.3)/grams creatinine while the mean plasma iduronate-2-sulfatase activity was 0.86 (SD 0.79) nmol/mg plasma/4 h. Fourteen (14) mutations were found: 6 missense (42.9%), 4 nonsense (28.6%), 2 frameshift (14.3%), 1 exon skipping at the cDNA level (7.1%), and 1 gross insertion (7.1%). Six (6) novel mutations were observed (43%): p.C422F, p.P86Rfs*44, p.Q121*, p.L209Wfs*4, p.T409R, and c.1461_1462insN[710]. CONCLUSION: The age at diagnosis in this series was much delayed and majority of the patients presented with severe neurologic impairment. The results of the biochemical tests did not contribute to the phenotypic classification of patients. The effects of the mutations were consistent with the severe phenotype seen in the majority of the patients. PMID- 28077158 TI - CCL2-driven inflammation increases mammary gland stromal density and cancer susceptibility in a transgenic mouse model. AB - BACKGROUND: Macrophages play diverse roles in mammary gland development and breast cancer. CC-chemokine ligand 2 (CCL2) is an inflammatory cytokine that recruits macrophages to sites of injury. Although CCL2 has been detected in human and mouse mammary epithelium, its role in regulating mammary gland development and cancer risk has not been explored. METHODS: Transgenic mice were generated wherein CCL2 is driven by the mammary epithelial cell-specific mouse mammary tumour virus 206 (MMTV) promoter. Estrous cycles were tracked in adult transgenic and non-transgenic FVB mice, and mammary glands collected at the four different stages of the cycle. Dissected mammary glands were assessed for cyclical morphological changes, proliferation and apoptosis of epithelium, macrophage abundance and collagen deposition, and mRNA encoding matrix remodelling enzymes. Another cohort of control and transgenic mice received carcinogen 7,12 Dimethylbenz(a)anthracene (DMBA) and tumour development was monitored weekly. CCL2 protein was also quantified in paired samples of human breast tissue with high and low mammographic density. RESULTS: Overexpression of CCL2 in the mammary epithelium resulted in an increased number of macrophages, increased density of stroma and collagen and elevated mRNA encoding matrix remodelling enzymes lysyl oxidase (LOX) and tissue inhibitor of matrix metalloproteinases (TIMP)3 compared to non-transgenic controls. Transgenic mice also exhibited increased susceptibility to development of DMBA-induced mammary tumours. In a paired sample cohort of human breast tissue, abundance of epithelial-cell-associated CCL2 was higher in breast tissue of high mammographic density compared to tissue of low mammographic density. CONCLUSIONS: Constitutive expression of CCL2 by the mouse mammary epithelium induces a state of low level chronic inflammation that increases stromal density and elevates cancer risk. We propose that CCL2-driven inflammation contributes to the increased risk of breast cancer observed in women with high mammographic density. PMID- 28077159 TI - Concurrent chemoradiotherapy combined with enteral nutrition support: a radical treatment strategy for esophageal squamous cell carcinoma patients with malignant fistulae. AB - BACKGROUND: Concurrent chemoradiotherapy (CCRT) significantly increases the survival rate of esophageal squamous cell carcinoma (ESCC) patients with malignant fistulae. Recent clinical evidence has shown the benefits of enteral nutrition for malnourished cancer patients. In this study, we aimed to validate that, with the support of enteral nutrition, ESCC patients who develop malignant fistulae might be able to complete CCRT and achieve long-term survival. METHODS: We reviewed the medical records of 652 patients with ESCC who received definitive CCRT at Sun Yat-sen University Cancer Center between January 2010 and December 2012. Treatment outcome and toxicity were retrospectively evaluated in 40 ESCC patients with malignant fistulae. All the 40 patients were treated with CCRT and evaluated by clinical nutritionists using nutrition risk screening (NRS) before, during, and after treatment. Twenty-two patients received a nasogastric tube, and 18 underwent percutaneous endoscopic gastrostomy feeding. The median energy intake was 2166 kcal/day. Treatment response was evaluated at 3 months after the completion of CCRT. RESULTS: With a median follow-up of 18 months (range, 3-39 months), patients' 1-year overall survival (OS) rate was 62.5%, and the estimated OS time was 25.5 months. Univariate analysis showed that the NRS score (P = 0.003), increase in NRS score (P = 0.024), fistula closure (P = 0.011), and response to treatment (P < 0.001) were significantly associated with OS. Multivariate analysis showed that tumor response (P = 0.044) and increase in NRS score (P = 0.044) were independent predictors of OS. Grade 3 vomiting was observed in 8 patients (20.0%), grade 3 neutropenia was observed in 11 patients (27.5%), and grade 3 cough was observed in 13 patients (32.5%); 2 patients (5.0%) died of massive bleeding during treatment. CONCLUSIONS: CCRT combined with enteral nutrition support is effective for ESCC patients with malignant fistulae. Patients have an increased potential to be cured, especially those who experience complete response and have an increase in NRS score. Careful observation and nutrition support are required for patients with advanced T-category ESCC who undergo CCRT. PMID- 28077160 TI - Indatuximab ravtansine (BT062) combination treatment in multiple myeloma: pre clinical studies. AB - Indatuximab ravtansine is a monoclonal antibody-linked cytotoxic agent that specifically targets CD138-expressing cells. Monotherapy has been shown to significantly inhibit multiple myeloma tumour growth in vivo and improve host survival. Here, we show that in most cell lines tested, indatuximab ravtansine acts additively or even synergistically with clinically approved therapies for treatment of multiple myeloma. In addition, in vivo mouse xenograft models confirmed the activity of indatuximab ravtansine in combination with lenalidamide and lenalidomide/dexamethasone. Indatuximab ravtansine may therefore be a suitable combination partner for multiple myeloma, and a clinical study is ongoing. PMID- 28077161 TI - Mathematical modelling of Echinococcus multilocularis abundance in foxes in Zurich, Switzerland. AB - BACKGROUND: In Europe, the red fox (Vulpes vulpes) is the main definitive host of Echinococcus multilocularis, the aetiological agent of a severe disease in humans called alveolar echinococcosis. The distribution of this zoonotic parasite among the fox population is remarkably aggregated with few heavily infected animals harbouring much of the parasite burdens and being responsible for most of the environmental parasitic egg contamination. Important research questions explored were: (i) spatial differences in parasite infection pressure related to the level of urbanization; (ii) temporal differences in parasite infection pressure in relation to time of the year; (iii) is herd immunity or an age-dependent infection pressure responsible for the observed parasite abundance; (iv) assuming E. multilocularis infection is a clumped process, how many parasites results from a regular infection insult. METHODS: By developing and comparing different transmission models we characterised the spatio-temporal variation of the infection pressure, in terms of numbers of parasites that foxes acquired after exposure per unit time, in foxes in Zurich (Switzerland). These included the variations in infection pressure with age of fox and season and the possible regulating effect of herd immunity on parasite abundance. RESULTS: The model fitting best to the observed data supported the existence of spatial and seasonal differences in infection pressure and the absence of parasite-induced host immunity. The periodic infection pressure had different amplitudes across urbanization zones with higher peaks during autumn and winter. In addition, the model indicated the existence of variations in infection pressure among age groups in foxes from the periurban zone. CONCLUSIONS: These heterogeneities in infection exposure have strong implications for the implementation of targeted control interventions to lower the intensity of environmental contamination with parasite eggs and, ultimately, the infection risk to humans. PMID- 28077162 TI - A fixed inhaled nitrous oxide/oxygen mixture as an analgesic for adult cancer patients with breakthrough pain: study protocol for a randomized controlled trial. AB - BACKGROUND: The management of breakthrough pain in cancer patients is always a challenge for medical professions. Occurring in 80% of cancer patients with advanced disease, breakthrough pain significantly decreases both patient's and caregiver's quality of life. The aim of this study is to assess the analgesic efficacy of a fixed inhaled nitrous oxide/oxygen mixture for adult cancer patients with breakthrough pain. METHODS/DESIGN: This is a randomized, placebo controlled, double-blind study; it will be conducted in the General Hospital of Ningxia Medical University. The target study subjects are at least 18 years old, and are hospitalized cancer patients who are receiving routine opioids to control cancer-related pain but still experience breakthrough pain. A total of 240 patients will be recruited and randomly allocated between three treatment groups (A, B, C) and a control group (group D) in a ratio of 3:1. All treatment groups (A, B, C) will receive standard pain treatment (oral immediate-release morphine) plus a pre-prepared nitrous oxide/oxygen mixture, and the control group (D) will receive the standard pain treatment plus oxygen. Patients, doctors, nurses, and data collectors are all blind to the experiment. Assessments will be taken before treatment (T0), at 5 min (T1) and 15 min (T2) during treatment, and at 5 min after treatment (T3). The primary endpoint measures will be the percentage of patients whose pain is relieved at T1, T2, and T3. Secondary outcome measures will include the safety of treatment, adverse events, and satisfaction from both health professionals and patients. DISCUSSION: This study aims to provide an effective and practical intervention for a fast breakthrough pain relief and to improve cancer patients' quality of life significantly. The Evidence-Based Medicine Working Group claim that a randomized, double-blind, placebo-controlled experimental intervention is the most appropriate design to demonstrate its efficacy, so this study could give a new approach to controlling breakthrough pain episodes. TRIAL REGISTRATION: ChiCTR-INC-16008075 . Registered on 8 March 2016. PMID- 28077164 TI - Erratum to: Novel sorafenib analogues induce apoptosis through SHP-1 dependent STAT3 inactivation in human breast cancer cells. PMID- 28077163 TI - The efficacy of varenicline in achieving abstinence among waterpipe tobacco smokers - study protocol for a randomized controlled trial. AB - BACKGROUND: Waterpipe tobacco smoking has increased among youth across the globe including in the US, and it continues as a common and traditional form of smoking tobacco in Pakistan. A range of behavioral and pharmacological therapies are available to support people in quitting cigarette smoking; however, little evidence exists for the efficacy of these therapies in achieving abstinence among waterpipe tobacco smokers. The objective of this study is to assess the efficacy of varenicline when added to behavioral support for waterpipe tobacco smoking cessation, by measuring biochemically validated continuous abstinence in waterpipe tobacco smokers. METHODS/DESIGN: This is a two-arm, double-blind, placebo-controlled randomized trial conducted in four districts in Punjab, Pakistan. Study participants include adults using a waterpipe (with or without concomitant cigarette, bidi or other forms of tobacco smoking) on a daily basis for at least 6 months and who are willing to quit. We will individually randomize 510 participants to one of the two arms of the trial. Participants in the intervention arm will receive varenicline and behavioral support and those in the control arm will receive placebo and behavioral support. The primary outcome will be continuous abstinence for at least 6 months (week 25) which is biochemically verified by a carbon monoxide level of <10 ppm. Secondary outcomes will include biochemically verified 7-day point abstinence at 5, 12 and 25 weeks and any lapses and relapses between the different assessment points. Tertiary outcomes will include assessment of withdrawal symptoms using the Mood and Physical Symptoms Scale (MPSS), smoking dependency using the Lebanon Waterpipe Dependency Scale (LWDS-11) and monitoring adverse outcomes. DISCUSSION: This is an efficacy trial and would require a subsequent effectiveness trial for a definitive evaluation of the intervention. TRIAL REGISTRATION: ISRCTN, ISRCTN94103375 . Registered on 1 December 2015. PMID- 28077165 TI - Malignant transformation of a long-standing submental dermoid cyst to a carcinosarcoma: a case report. AB - BACKGROUND: Submental dermoid cysts are uncommon midline cysts which occur due to entrapment of ectoderm between the second and third branchial arches during embryogenesis. Most dermoid cysts of the head and neck are benign, but rarely malignant transformation may occur. To the best of our knowledge, this is the first report of a carcinosarcoma arising in a submental dermoid cyst. CASE PRESENTATION: A 42-year-old Sri Lankan Tamil man presented with a large cystic swelling in his submental region which was diagnosed as an extensive submental dermoid cyst. The cyst had been asymptomatic for 11 years but there was sudden enlargement and pain during the past 2 months. On surgical removal, a primary carcinosarcoma arising from part of the cyst wall was identified. After completion of radiotherapy, the disease was well controlled and he was disease free at 18 months. CONCLUSIONS: Although extremely rare, a dermoid cyst of the submental region can undergo malignant transformation. It can be successfully treated with surgical excision and radiotherapy. PMID- 28077166 TI - Threonine175, a novel pathological phosphorylation site on tau protein linked to multiple tauopathies. AB - Microtubule associated protein tau (tau) deposition is associated with a spectrum of neurodegenerative diseases collectively termed tauopathies. We have previously shown that amyotrophic lateral sclerosis (ALS) with cognitive impairment (ALSci) is associated with tau phosphorylation at Thr175 and that this leads to activation of GSK3beta which then induces phosphorylation at tau Thr231. This latter step leads to dissociation of tau from microtubules and pathological tau fibril formation. To determine the extent to which this pathway is unique to ALS, we have investigated the expression of pThr175 tau and pThr231 tau across a range of frontotemporal degenerations. Representative sections from the superior frontal cortex, anterior cingulate cortex (ACC), amygdala, hippocampal formation, basal ganglia, and substantia nigra were selected from neuropathologically confirmed cases of Alzheimer's disease (AD; n = 3), vascular dementia (n = 2), frontotemporal lobar degeneration (FTLD; n = 4), ALS (n = 5), ALSci (n = 6), Parkinson's disease (PD; n = 5), corticobasal degeneration (CBD; n = 2), diffuse Lewy body dementia (DLBD; n = 2), mixed DLBD (n = 3), multisystem atrophy (MSA; n = 6) and Pick's disease (n = 1) and three neuropathologically-normal control groups aged 50-60 (n = 6), 60-70 (n = 6) and 70-80 (n = 8). Sections were examined using a panel of phospho-tau antibodies (pSer208,210, pThr217, pThr175, pThr231, pSer202 and T22 (oligomeric tau)). Across diseases, phospho-tau load was most prominent in layers II/III of the entorhinal cortex, amygdala and hippocampus. This is in contrast to the preferential deposition of phospho-tau in the ACC and frontal cortex in ALSci. Controls showed pThr175 tau expression only in the 7th decade of life and only in the presence of tau pathology and tau oligomers. With the exception of DLBD, we observed pThr175 co-localizing with pThr231 in the same cell populations as T22 positivity. This suggests that this pathway may be a common mechanism of toxicity across the tauopathies. PMID- 28077167 TI - Role of Anopheles (Cellia) rufipes (Gough, 1910) and other local anophelines in human malaria transmission in the northern savannah of Cameroon: a cross sectional survey. AB - BACKGROUND: As part of a study to determine the impact of insecticide resistance on the effectiveness of long-lasting insecticide treated nets (LLINs) in the north of Cameroon, the unexpectedly high density and anthropophilic behaviour of Anopheles rufipes lead us to investigate this species bionomics and role in human malaria parasite transmission. METHODS: For four consecutive years (2011-2014), annual cross-sectional sampling of adult mosquitoes was conducted during the peak malaria season (September-October) in three health districts in northern Cameroon. Mosquitoes sampled by human landing catch and pyrethrum spray catch methods were morphologically identified, their ovaries dissected for parity determination and Anopheles gambiae siblings were identified by molecular assay. Infection with P. falciparum and blood meal source in residual fauna of indoor resting anopheline mosquitoes were determined by enzyme-linked-immunosorbent assays. RESULTS: Anopheles gambiae (sensu lato) (s.l.) comprised 18.4% of mosquitoes collected with An. arabiensis representing 66.27% of the sibling species. The proportion of An. rufipes (2.7%) collected was high with a human biting rate ranging between 0.441 and 11.083 bites/person/night (b/p/n) and an anthropophagic rate of 15.36%. Although overall the members of An. gambiae complex were responsible for most of the transmission with entomological inoculation rates (EIR) reaching 1.221 infective bites/person/night (ib/p/n), An. arabiensis and An. coluzzii were the most implicated. The roles of An. funestus, An. pharoensis and An. paludis were minor. Plasmodium falciparum circumsporozoite protein rate in Anopheles rufipes varied from 0.6 to 5.7% with EIR values between 0.010 and 0.481 ib/p/n. CONCLUSIONS: The study highlights the epidemiological role of An. rufipes alongside the members of the An. gambiae complex, and several other sympatric species in human malaria transmission during the wet season in northern Cameroon. For the first time in Cameroon, An. rufipes has been shown to be an important local malaria vector, emphasising the need to review the malaria entomological profile across the country as pre-requisite to effective vector management strategies. PMID- 28077168 TI - Towards precision medicine for sepsis patients. PMID- 28077169 TI - Distinct 5-methylcytosine profiles in poly(A) RNA from mouse embryonic stem cells and brain. AB - BACKGROUND: Recent work has identified and mapped a range of posttranscriptional modifications in mRNA, including methylation of the N6 and N1 positions in adenine, pseudouridylation, and methylation of carbon 5 in cytosine (m5C). However, knowledge about the prevalence and transcriptome-wide distribution of m5C is still extremely limited; thus, studies in different cell types, tissues, and organisms are needed to gain insight into possible functions of this modification and implications for other regulatory processes. RESULTS: We have carried out an unbiased global analysis of m5C in total and nuclear poly(A) RNA of mouse embryonic stem cells and murine brain. We show that there are intriguing differences in these samples and cell compartments with respect to the degree of methylation, functional classification of methylated transcripts, and position bias within the transcript. Specifically, we observe a pronounced accumulation of m5C sites in the vicinity of the translational start codon, depletion in coding sequences, and mixed patterns of enrichment in the 3' UTR. Degree and pattern of methylation distinguish transcripts modified in both embryonic stem cells and brain from those methylated in either one of the samples. We also analyze potential correlations between m5C and micro RNA target sites, binding sites of RNA binding proteins, and N6-methyladenosine. CONCLUSION: Our study presents the first comprehensive picture of cytosine methylation in the epitranscriptome of pluripotent and differentiated stages in the mouse. These data provide an invaluable resource for future studies of function and biological significance of m5C in mRNA in mammals. PMID- 28077170 TI - Prosodic processing post traumatic brain injury - a systematic review. AB - BACKGROUND: Traumatic brain injury (TBI) survivors often report difficulties with understanding and producing paralinguistic cues, as well as understanding and producing basic communication tasks. However, a large range of communicative deficits in this population cannot be adequately explained by linguistic impairment. The review examines prosodic processing performance post-TBI, its relationship with injury severity, brain injury localization, recovery and co occurring psychiatric or mental health issues post-TBI METHODS: A systematic review using several databases including MEDLINE, EMBASE, Cochrane, LLBA (Linguistics and Language Behaviour Abstract) and Web of Science (January 1980 to May 2015), as well as a manual search of the cited references of the selected articles and the search cited features of PubMed was performed. The search was limited to comparative analyses between individuals who had a TBI and non-injured individuals (control). The review included studies assessing prosodic processing outcomes after TBI has been formally diagnosed. Articles that measured communication disorders, prosodic impairments, aphasia, and recognition of various aspects of prosody were included. Methods of summary included study characteristics, sample characteristics, demographics, auditory processing task, age at injury, brain localization of the injury, time elapsed since TBI, reports between TBI and mental health, socialization and employment difficulties. There were no limitations to the population size, age or gender. Results were reported according to the PRISMA guidelines. Two raters evaluated the quality of the articles in the search, extracted data using data abstraction forms and assessed the external and internal validity of the studies included using STROBE criteria. Agreement between the two raters was very high (Cohen's kappa = .89, P < 0.001). Results are reported according to the PRISMA guidelines. RESULTS: A systematic review of 5212 records between 1980 and 2015 revealed 206 potentially eligible studies and 8 case-control studies (3 perspective and 5 retrospective) met inclusion and exclusion criteria for content and quality. Performance on prosodic processing tasks was found to be impaired among all participants with a history of TBI (ages ranged from 8 to 70 years old), compared to those with no history of TBI, in all eight studies examined. Compared with controls, individuals with a history of TBI had statistically significantly slower reaction time in identifying emotions from prosody and impaired processing of prosodic information that is muffled, non-sense, competing, or in conflict (prosody versus semantics). Heterogeneous findings on correlations between specific brain locations and prosodic processing impairment were reported. Psychiatric issues, employment status or social integration post-TBI were scarcely reported but, when reported, they co-occurred with a history of TBI and prosodic impairments. CONCLUSIONS: The current review confirms the relationship between impaired prosodic processing and history of TBI. Future studies should collect and report comprehensive details about severity of TBI, location of brain injury and time elapsed since injury, as they could key influence factors to the extent of prosodic processing impairments and recovery from auditory processing impairments post-TBI. The exploration of prosodic processing tasks as a possible neuropsychological marker of TBI diagnosis and recovery is warranted. PMID- 28077171 TI - Prostate-specific IL-6 transgene autonomously induce prostate neoplasm through amplifying inflammation in the prostate and peri-prostatic adipose tissue. AB - BACKGROUND: The causative role of the pro-inflammatory cytokine IL-6 in prostate cancer progression has been well established at molecular level. However, whether and how IL-6 may play a role in prostate cancer risk and development is not well defined. One limitation factor to acquiring this knowledge is the lack of appropriate animal models. METHODS: We generated a novel line of prostate specific IL-6 transgenic mouse model. We compared the prostate pathology, tumorigenic signaling components, and prostate tumor microenvironment of the IL-6 transgenic mice with wild type littermates. RESULTS: With this model, we demonstrate that IL-6 induces prostate neoplasm autonomously. We further demonstrate that transgenic expression of IL-6 in the prostate activates oncogenic pathways, induces autocrine IL-6 secretion and steadily-state of STAT3 activation in the prostate tissue, upregulates paracrine insulin-like growth factor (IGF) signaling axis, reprograms prostate oncogenic gene expression, and more intriguingly, amplifies inflammation in the prostate and peri-prostatic adipose tissue. CONCLUSIONS: The pro-inflammatory IL-6 is autonomous oncogene for the prostate. IL-6 induces prostate oncogenesis through amplifying local inflammation. We also presented a valuable animal model to study inflammation and prostate cancer development. PMID- 28077172 TI - Promoting effect of hepatitis B virus on the expressoin of phospholipase A2 group IIA. AB - BACKGROUND: Hepatitis B virus (HBV) infection causes acute and chronic liver disease, ultimately leading to the development of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Phospholipase A2 group IIA (PLA2G2A) plays important roles in the development and progression of many tumors. Thus far, there have been no reports on the association between HBV and PLA2G2A. The present study investigated the effect of HBV infection on PLA2G2A expression and its application in the diagnosis of HBV-related diseases. METHODS: Serum levels of PLA2G2A in 308 HBV-infected patients and 185 healthy controls were measured using an enzyme-linked immunosorbent assay (ELISA). The difference in serum levels of PLA2G2A was analyzed among chronic hepatitis B (CHB), LC, and HCC patients. PLA2G2A mRNA and protein expression in HepG2 and HepG2.2.15 cells carrying the integrated HBV genome were measured using reverse transcription polymerase chain reaction (RT-PCR) and western blot assays. The HBV infectious clone pHBV1.3, the control plasmid pBlue-ks and PLA2G2A gene promoter were transfected into HepG2 and HepG2.2.15 cells. After transfection, the luciferase activity was measured in the cells. PLA2G2A mRNA and protein expression levels were examined using RT-PCR and western blot assays. RESULTS: The serum levels of PLA2G2A were 258.3 +/- 20.3ng/dl in the healthy controls and 329.0 +/- 22.5ng/dl, 385.4 +/- 29.3ng/dl and 459.2 +/- 38.6ng/dl in the CHB, LC, and HCC patients, respectively. Statistical analyses revealed significantly higher serum levels of PLA2G2A in CHB, LC, and HCC patients than in the healthy controls (P < 0.05), and PLA2G2A levels were elevated in the order of HCC > LC > CHB group. High serum PLA2G2A levels in HCC patients were associated with a lower prevalence of lymph node metastasis and a lower TNM stage. HepG2.2.15 cells carrying the HBV genome expressed higher levels of PLA2G2A mRNA and protein than the HepG2 cells. In addition, HBV triggered PLA2G2A promoter activity and enhanced PLA2G2A mRNA and protein expression compared to the empty vector pBlue-ks. CONCLUSION: HBV can upregulate the expression of PLA2G2A, and serum levels of PLA2G2A are associated with the progression of HBV-related diseases. PMID- 28077173 TI - Is CD47 an innate immune checkpoint for tumor evasion? AB - Cluster of differentiation 47 (CD47) (also known as integrin-associated protein) is a ubiquitously expressed glycoprotein of the immunoglobulin superfamily that plays a critical role in self-recognition. Various solid and hematologic cancers exploit CD47 expression in order to evade immunological eradication, and its overexpression is clinically correlated with poor prognoses. One essential mechanism behind CD47-mediated immune evasion is that it can interact with signal regulatory protein-alpha (SIRPalpha) expressed on myeloid cells, causing phosphorylation of the SIRPalpha cytoplasmic immunoreceptor tyrosine-based inhibition motifs and recruitment of Src homology 2 domain-containing tyrosine phosphatases to ultimately result in delivering an anti-phagocytic-"don't eat me" signal. Given its essential role as a negative checkpoint for innate immunity and subsequent adaptive immunity, CD47-SIRPalpha axis has been explored as a new target for cancer immunotherapy and its disruption has demonstrated great therapeutic promise. Indeed, CD47 blocking antibodies have been found to decrease primary tumor size and/or metastasis in various pre-clinical models. In this review, we highlight the various functions of CD47, discuss anti-tumor responses generated by both the innate and adaptive immune systems as a consequence of administering anti-CD47 blocking antibody, and finally elaborate on the clinical potential of CD47 blockade. We argue that CD47 is a checkpoint molecule for both innate and adaptive immunity for tumor evasion and is thus a promising target for cancer immunotherapy. PMID- 28077175 TI - Structural correlates of trait impulsivity in patients with bipolar disorder and healthy controls: a surface-based morphometry study. AB - BACKGROUND: Patients with bipolar disorder (BD) frequently exhibit impulsive behaviors independent of their mood state, and trait impulsivity is increasingly recognized as a crucial BD biomarker. This study aimed to investigate structural correlates of trait impulsivity measured using the Barratt Impulsiveness Scale (BIS) in healthy controls (HCs) and patients with BD. METHOD: We recruited 59 patients diagnosed with BD I or BD II (35.3 +/- 8.5 years) and 56 age- and sex matched HCs (33.9 +/- 7.4 years). Participants underwent structural magnetic resonance imaging and clinical evaluations, and their BIS scores were evaluated. An automated surface-based method (FreeSurfer) was used to measure cortical thickness and generate thickness maps for each participant. Brain-wise regression analysis of the association between cortical thickness and BIS scores was performed separately for BD and HC groups by using a general linear model. RESULTS: Patients with BD obtained significantly higher BIS scores than HCs. In HCs, higher BIS scores were associated with a thinner cortex in the left inferior, middle and medial frontal cortices. By contrast, in BD patients, higher BIS scores were associated with a thicker cortex in the right insula. Patients with BD showed a thinner cortex than HCs in all these four structures. CONCLUSIONS: The findings indicate that the left prefrontal cortex plays a cardinal role in trait impulsivity of healthy individuals. Patients with BD have a different structural correlate of trait impulsivity in the right insula. However, the use of various psychotropics in patients with BD may limit our interpretation of BD findings. PMID- 28077176 TI - Main pulmonary artery cross-section ratio is low in fetuses with tetralogy of Fallot and ductus arteriosus-dependent pulmonary circulation. AB - OBJECTIVES: This study aimed to determine fetal echocardiographic features of tetralogy of Fallot in association with postnatal outcomes. METHODS: The Z-scores of the main and bilateral pulmonary arteries and the aorta were measured, and the following variables were calculated in 13 fetuses with tetralogy of Fallot: pulmonary artery-to-aorta ratio and main pulmonary artery cross-section ratio - the main pulmonary artery diameter squared divided by the sum of the diameter squared of the left and right pulmonary arteries. Fetuses were classified as having ductus arteriosus-dependent or ductus arteriosus-independent pulmonary circulation. RESULTS: We included two infants with pulmonary atresia and six infants with ductus-dependent pulmonary circulation, who underwent systemic-to pulmonary shunt surgeries at ?1 month of age. The Z-scores of the main pulmonary artery and the pulmonary artery-to-aorta ratio in fetuses with ductus-dependent pulmonary circulation were lesser than those in fetuses with ductus independence, but not significantly. The main pulmonary artery cross-section ratio in fetuses with ductus dependence was significantly lesser (0.65+/-0.44 versus 1.56+/-0.48, p<0.005). Besides, the flow of the ductus arteriosus was directed from the aorta to the pulmonary artery in the ductus arteriosus-dependent group during the fetal period. CONCLUSIONS: The main pulmonary artery cross-section ratio was the most significant variable for predicting postnatal outcomes in fetuses with tetralogy of Fallot. PMID- 28077177 TI - Transcatheter closure of secundum atrial septal defects: has fear of device erosion altered outcomes? AB - BACKGROUND: Transcatheter device closure has become the established standard of care for suitable atrial septal defects. Device erosion has been a recent focus and has prompted changes in the Instructions for Users documentation released by device companies. We reviewed our entire local experience with atrial septal defect device closure, focussing on the evolution of this procedure in our centre and particularly on complications. METHODS: We carried out a retrospective review of 581 consecutive patients undergoing attempted transcatheter device closure of an atrial septal defect in Auckland from December 1997 to June 2014. We reviewed all complications recorded and compared our outcomes with the current literature. We sought to understand the impact of the evolution in recommendations and clinical practice on patient outcomes in our programme. RESULTS: There were a total of 24 complications (4.1%), including 10 device embolisations (1.7%), nine arrhythmias (1.5%), two significant vascular access-related complications (0.3%), one device erosion (0.2%), one malposed device (0.2%), and one probable wire perforation of the left atrial appendage (0.2%). There was one mortality related to device embolisation. All device embolisations occurred following the change in Instructions for Users after publication of the first device erosion report in 2004. This increase in embolisation rate was statistically significant (p-value 0.015). CONCLUSIONS: In our series, the incidence of device embolisation was higher than that anticipated, with a significant increase following changes to the Instructions for Users. This highlights the need for ongoing data collection on complication incidence and for ongoing review of the impact of changes in clinical practice on complication rates. PMID- 28077174 TI - Mutant HSPB1 causes loss of translational repression by binding to PCBP1, an RNA binding protein with a possible role in neurodegenerative disease. AB - The small heat shock protein HSPB1 (Hsp27) is an ubiquitously expressed molecular chaperone able to regulate various cellular functions like actin dynamics, oxidative stress regulation and anti-apoptosis. So far disease causing mutations in HSPB1 have been associated with neurodegenerative diseases such as distal hereditary motor neuropathy, Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. Most mutations in HSPB1 target its highly conserved alpha-crystallin domain, while other mutations affect the C- or N-terminal regions or its promotor. Mutations inside the alpha-crystallin domain have been shown to enhance the chaperone activity of HSPB1 and increase the binding to client proteins. However, the HSPB1-P182L mutation, located outside and downstream of the alpha crystallin domain, behaves differently. This specific HSPB1 mutation results in a severe neuropathy phenotype affecting exclusively the motor neurons of the peripheral nervous system. We identified that the HSPB1-P182L mutant protein has a specifically increased interaction with the RNA binding protein poly(C)binding protein 1 (PCBP1) and results in a reduction of its translational repressive activity. RNA immunoprecipitation followed by RNA sequencing on mouse brain lead to the identification of PCBP1 mRNA targets. These targets contain larger 3'- and 5'-UTRs than average and are enriched in an RNA motif consisting of the CTCCTCCTCCTCC consensus sequence. Interestingly, next to the clear presence of neuronal transcripts among the identified PCBP1 targets we identified known genes associated with hereditary peripheral neuropathies and hereditary spastic paraplegias. We therefore conclude that HSPB1 can mediate translational repression through interaction with an RNA binding protein further supporting its role in neurodegenerative disease. PMID- 28077178 TI - PTSD or not PTSD? Comparing the proposed ICD-11 and the DSM-5 PTSD criteria among young survivors of the 2011 Norway attacks and their parents. AB - BACKGROUND: The conceptualization of post-traumatic stress disorder (PTSD) in the upcoming International Classification of Diseases (ICD)-11 differs in many respects from the diagnostic criteria in the Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5). The consequences of these differences for individuals and for estimation of prevalence rates are largely unknown. This study investigated the concordance of the two diagnostic systems in two separate samples at two separate waves. METHOD: Young survivors of the 2011 Norway attacks (n = 325) and their parents (n = 451) were interviewed at 4-6 months (wave 1) and 15-18 months (wave 2) after the shooting. PTSD was assessed with the UCLA PTSD Reaction Index for DSM-IV adapted for DSM-5, and a subset was used as diagnostic criteria for ICD-11. RESULTS: In survivors, PTSD prevalence did not differ significantly at any time point, but in parents, the DSM-5 algorithm produced significantly higher prevalence rates than the ICD-11 criteria. The overlap was fair for survivors, but amongst parents a large proportion of individuals met the criteria for only one of the diagnostic systems. No systematic differences were found between ICD-11 and DSM-5 in predictive validity. CONCLUSIONS: The proposed ICD-11 criteria and the DSM-5 criteria performed equally well when identifying individuals in distress. Nevertheless, the overlap between those meeting the PTSD diagnosis for both ICD 11 and DSM-5 was disturbingly low, with the ICD-11 criteria identifying fewer people than the DSM-5. This represents a major challenge in identifying individuals suffering from PTSD worldwide, possibly resulting in overtreatment or unmet needs for trauma-specific treatment, depending on the area of the world in which patients are being diagnosed. PMID- 28077179 TI - Scared behind the wheel: what impact does driving anxiety have on the health and well-being of young older adults? AB - BACKGROUND: Driving anxiety can range from driving reluctance to driving phobia, and 20% of young older adults experience mild driving anxiety, whereas 6% report moderate to severe driving anxiety. However, we do not know what impact driving anxiety has on health and well-being, especially among older drivers. This is problematic because there is a growing proportion of older adult drivers and a potential for driving anxiety to result in premature driving cessation that can impact on health and mortality. The purpose of the current study was to examine the impact of driving anxiety on young older adults' health and well-being. METHOD: Data were taken from a longitudinal study of health and aging that included 2,473 young older adults aged 55-70 years. The outcome measures were mental and physical health (SF-12) and quality of life (WHOQOL-8). RESULTS: Hierarchical multiple regression analyses demonstrated that driving anxiety was associated with poorer mental health, physical health, and quality of life, over and above the effect of socio-demographic variables. Sex moderated the effect of driving anxiety on mental health and quality of life in that, as driving anxiety increased, men and women were more likely to have lower mental health and quality of life, but women were more likely to have higher scores compared to men. CONCLUSION: Further research is needed to investigate whether driving anxiety contributes to premature driving cessation. If so, self-regulation of driving and treating driving anxiety could be important in preventing or reducing the declines in health and quality of life associated with driving cessation for older adults affected by driving anxiety. PMID- 28077180 TI - Understanding transmissibility patterns of Chagas disease through complex vector host networks. AB - Chagas disease is one of the most important vector-borne zoonotic diseases in Latin America. Control strategies could be improved if transmissibility patterns of its aetiologic agent, Trypanosoma cruzi, were better understood. To understand transmissibility patterns of Chagas disease in Mexico, we inferred potential vectors and hosts of T. cruzi from geographic distributions of nine species of Triatominae and 396 wild mammal species, respectively. The most probable vectors and hosts of T. cruzi were represented in a Complex Inference Network, from which we formulated a predictive model and several associated hypotheses about the ecological epidemiology of Chagas disease. We compiled a list of confirmed mammal hosts to test our hypotheses. Our tests allowed us to predict the most important potential hosts of T. cruzi and to validate the model showing that the confirmed hosts were those predicted to be the most important hosts. We were also able to predict differences in the transmissibility of T. cruzi among triatomine species from spatial data. We hope our findings help drive efforts for future experimental studies. PMID- 28077181 TI - At what age should tetralogy of Fallot be corrected? AB - Tetralogy of Fallot can be corrected with very low mortality at any age, even in neonates, but this does not necessarily mean that it should be corrected in the neonatal period. Although there are many advantages to early correction, a high proportion of these neonates have residual stenosis or pulmonary regurgitation that impairs ventricular function and may require further surgery or implantation of a pulmonary valve. Before we had the ability to correct this anomaly with low mortality in small children, a variety of palliative procedures had to be performed. Today, with better understanding of the anatomy of tetralogy of Fallot, we should consider what forms of palliation will increase growth of the right ventricular outflow tract in order to reduce the complications of very early surgery. PMID- 28077182 TI - Functional tricuspid stenosis: a rare presentation of suspected rhabdomyoma as congenital cyanotic heart disease. AB - Cardiac tumours in newborns are often asymptomatic and can be sporadically detected on routine screening unless they result in intractable arrhythmias or haemodynamically significant obstructions causing heart failure. Their presentation as a cause of congenital cyanosis is never anticipated. We report a rare case of a newborn presenting with congenital cyanosis consequent to suspected cardiac rhabdomyoma causing tricuspid inflow obstruction. Our experience with this patient with two large cardiac masses illustrates the significance of its inclusion in the differential diagnosis of perinatal cyanosis, as early detection and surgical management might be the only lifesaving options, if performed well in time. PMID- 28077183 TI - The prevalence of Aphanomyces astaci in invasive signal crayfish from the UK and implications for native crayfish conservation. AB - The crayfish plague agent, Aphanomyces astaci, has spread throughout Europe, causing a significant decline in native European crayfish. The introduction and dissemination of this pathogen is attributed to the spread of invasive North American crayfish, which can act as carriers for A. astaci. As native European crayfish often succumb to infection with A. astaci, determining the prevalence of this pathogen in non-native crayfish is vital to prioritize native crayfish populations for managed translocation. In the current study, 23 populations of invasive signal crayfish (Pacifastacus leniusculus) from the UK were tested for A. astaci presence using quantitative PCR. Altogether, 13 out of 23 (56.5%) populations were found to be infected, and pathogen prevalence within infected sites varied from 3 to 80%. Microsatellite pathogen genotyping revealed that at least one UK signal crayfish population was infected with the A. astaci genotype group B, known to include virulent strains. Based on recent crayfish distribution records and the average rate of signal crayfish population dispersal, we identified one native white-clawed crayfish (Austropotamobius pallipes) population predicted to come into contact with infected signal crayfish within 5 years. This population should be considered as a priority for translocation. PMID- 28077184 TI - Abnormalities in the effective connectivity of visuothalamic circuitry in schizophrenia. AB - BACKGROUND: Sensory-processing deficits appear crucial to the clinical expression of symptoms of schizophrenia. The visual cortex displays both dysconnectivity and aberrant spontaneous activity in patients with persistent symptoms and cognitive deficits. In this paper, we examine visual cortex in the context of the remerging notion of thalamic dysfunction in schizophrenia. We examined specific regional and longer-range abnormalities in sensory and thalamic circuits in schizophrenia, and whether these patterns are strong enough to discriminate symptomatic patients from controls. METHOD: Using publicly available resting fMRI data of 71 controls and 62 schizophrenia patients, we derived conjunction maps of regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuations (fALFF) to inform further seed-based Granger causality analysis (GCA) to study effective connectivity patterns. ReHo, fALFF and GCA maps were entered into a multiple kernel learning classifier, to determine whether patterns of local and effective connectivity can differentiate controls from patients. RESULTS: Visual cortex shows both ReHo and fALFF reductions in patients. Visuothalamic effective connectivity in patients was significantly reduced. Local connectivity (ReHo) patterns discriminated patients from controls with the highest level of accuracy of 80.32%. CONCLUSIONS: Both the inflow and outflow of Granger causal information between visual cortex and thalamus is affected in schizophrenia; this occurs in conjunction with highly discriminatory but localized dysconnectivity and reduced neural activity within the visual cortex. This may explain the visual-processing deficits that are present despite symptomatic remission in schizophrenia. PMID- 28077185 TI - Rapidly progressive mitral valve stenosis in patients with acromelic dysplasia. AB - Acromelic dysplasias are a group of skeletal dysplasias characterised by short limbed short stature with other distinctive phenotypic features including small hands and feet and stiff joints. Geleophysic dysplasia is an acromelic dysplasia that is associated with characteristic facial features, progressive cardiac valvular thickening, and tracheal stenosis. Owing to overlapping clinical features with other types of short-limbed skeletal dysplasias, it is important to make a precise diagnosis as they have different cardiac morbidity and mortality. We present the cases of three patients with geleophysic dysplasia and progressive mitral valve disease to emphasise the natural history of this disorder and provide guidance regarding cardiac health supervision in these individuals. PMID- 28077186 TI - Antenatal diagnosis of double-outlet left atrium. AB - In this study, we describe a fetus with double-outlet atrium associated with complex arrangement of the ventricles and the great vessels. Various presentations of this malformation not described antenatally are discussed. PMID- 28077187 TI - Lysosome-like compartments of Trypanosoma cruzi trypomastigotes may originate directly from epimastigote reservosomes. AB - Trypanosoma cruzi epimastigote reservosomes store nutrients taken up during the intense endocytic activity exhibited by this developmental form. Reservosomes were classified as pre-lysosomal compartments. In contrast, trypomastigote forms are not able to take up nutrients from the medium. Interestingly, trypomastigotes also have acidic organelles with the same proteases contained in epimastigote reservosomes. Nevertheless, the origin and function of these organelles have not been disclosed so far. Given the similarities between the compartments of epimastigotes and trypomastigotes, the present study aimed to investigate the origin of metacyclic trypomastigote protease-containing organelles by tracking fluorospheres or colloidal gold particles previously stored in epimastigotes' reservosomes throughout metacyclogenesis. Using three-dimensional reconstruction of serial electron microscopy images, it was possible to find trypomastigote compartments containing the tracer. Our observations demonstrate that the protease-containing compartments from metacyclic trypomastigotes may originate directly from the reservosomes of epimastigotes. PMID- 28077188 TI - Point catheter ablation of macro-re-entrant ventricular tachycardia in a patient after surgical repair for double-outlet right ventricle. AB - Catheter ablation of ventricular tachycardia is often difficult in patients after surgery for CHD. In patients with a ventricular septal defect patch, it is necessary to decide which ventricular side is appropriate for catheter ablation. In this article, we report a case of successful point catheter ablation of re entrant ventricular tachycardia. Identification of the ventricular septal defect patch using intra-cardiac echocardiography was useful. PMID- 28077189 TI - Cardiac haemangioma associated with a duct-dependent congenital heart disease in a newborn infant. AB - Cardiac haemangiomas are exceedingly rare; however, they can cause significant haemodynamic impairment and disturbances in heart rhythm. Rarely, cardiac tumours may also coexist with congenital heart lesions. We present an extremely unusual case of a cardiac haemangioma in the setting of complex transposition of the great arteries that caused functional tricuspid atresia. To our knowledge, this is the first such case described in the literature. PMID- 28077190 TI - Measures of the DSM-5 mixed-features specifier of major depressive disorder. AB - During the past two decades, a number of studies have found that depressed patients frequently have manic symptoms intermixed with depressive symptoms. While the frequency of mixed syndromes are more common in bipolar than in unipolar depressives, mixed states are also common in patients with major depressive disorder. The admixture of symptoms may be evident when depressed patients present for treatment, or they may emerge during ongoing treatment. In some patients, treatment with antidepressant medication might precipitate the emergence of mixed states. It would therefore be useful to systematically inquire into the presence of manic/hypomanic symptoms in depressed patients. We can anticipate that increased attention will likely be given to mixed depression because of changes in the DSM-5. In the present article, I review instruments that have been utilized to assess the presence and severity of manic symptoms and therefore could be potentially used to identify the DSM-5 mixed-features specifier in depressed patients and to evaluate the course and outcome of treatment. In choosing which measure to use, clinicians and researchers should consider whether the measure assesses both depression and mania/hypomania, assesses all or only some of the DSM-5 criteria for the mixed-features specifier, or assesses manic/hypomanic symptoms that are not part of the DSM-5 definition. Feasibility, more so than reliability and validity, will likely determine whether these measures are incorporated into routine clinical practice. PMID- 28077191 TI - Genome-wide analysis in endangered populations: a case study in Barbaresca sheep. AB - Analysis of genomic data is becoming increasingly common in the livestock industry and the findings have been an invaluable resource for effective management of breeding programs in small and endangered populations. In this paper, with the goal of highlighting the potential of genomic analysis for small and endangered populations, genome-wide levels of linkage disequilibrium, measured as the squared correlation coefficient of allele frequencies at a pair of loci, effective population size, runs of homozygosity (ROH) and genetic diversity parameters, were estimated in Barbaresca sheep using Illumina OvineSNP50K array data. Moreover, the breed's genetic structure and its relationship with other breeds were investigated. Levels of pairwise linkage disequilibrium decreased with increasing distance between single nucleotide polymorphisms. An average correlation coefficient <0.25 was found for markers located up to 50 kb apart. Therefore, these results support the need to use denser single nucleotide polymorphism panels for high power association mapping and genomic selection efficiency in future breeding programs. The estimate of past effective population size ranged from 747 animals 250 generations ago to 28 animals five generations ago, whereas the contemporary effective population size was 25 animals. A total of 637 ROH were identified, most of which were short (67%) and ranged from 1 to 10 Mb. The genetic analyses revealed that the Barbaresca breed tended to display lower variability than other Sicilian breeds. Recent inbreeding was evident, according to the ROH analysis. All the investigated parameters showed a comparatively narrow genetic base and indicated an endangered status for Barbaresca. Multidimensional scaling, model-based clustering, measurement of population differentiation, neighbor networks and haplotype sharing distinguished Barbaresca from other breeds, showed a low level of admixture with the other breeds considered in this study, and indicated clear genetic differences compared with other breeds. Attention should be given to the conservation of Barbaresca due to its critical conservation status. In this context, genomic information may have a crucial role in management of small and endangered populations. PMID- 28077192 TI - Dietary probiotic supplementation improves growth and the intestinal morphology of Nile tilapia. AB - Probiotic administration can be a nutritional strategy to improve the immune response and growth performance of fish. The current study aimed to evaluate the effects of a probiotic blend (Bacillus sp., Pediococcus sp., Enterococcus sp., Lactobacillus sp.) as a dietary supplement on growth performance, feed utilization, innate immune and oxidative stress responses and intestinal morphology in juvenile Nile tilapia (Oreochromis niloticus). The probiotic was incorporated into a basal diet at three concentrations: 0 g/kg (A0: control), 3 g/kg (A1: 1.0*106 colony forming unit (CFU)/g) and 6 g/kg (A2: 2.3*106 CFU/g diet). After 8 weeks of probiotic feeding, weight and specific growth rate where significantly higher in fish-fed A1 diet than in fish-fed A0. Alternative complement in plasma was significantly enhanced in fish-fed A2 when compared with A0. The hepatic antioxidant indicators were not affected by probiotic supplementation. Villi height and goblet cell counts increased significantly in the intestine of fish-fed A1 and A2 diets compared with A0. The dietary probiotic supplementation was maintained until 20 weeks of feeding. Then the selected immune parameters, digestive enzymes and apparent digestibility of diets were studied. No effect of probiotic feeding was observed after that longer period supplementation. The dietary supplementation of mixed species probiotic may constitute a valuable nutritional approach towards a sustainable tilapia aquaculture. The improvement of the immune responses and intestinal morphology play an important role in increasing growth performance, nutrient absorption and disease resistance in fish, important outcomes in such a competitive and developing aquaculture sector. PMID- 28077193 TI - Caring for Cancer Patients After the Italian Earthquakes: A Proposal From the Field. PMID- 28077194 TI - The response of weaned piglets to dietary valine and leucine. AB - Valine (Val) is considered to be the fifth-limiting amino acid in a maize soyabean meal diet for pigs. Excess leucine (Leu) levels often occur in commercial diets, which may attenuate the effect of Val deficiency because of an increased oxidation of Val. The objective of the present experiment was to determine the effect of increasing concentrations of Leu on the response of young piglets to dietary Val. In all, 75 Large White*Landrace entire male pigs, 44 days of age and with a mean starting weight of 13.5 kg, were used. Three of these were sacrificed at the start to determine their mean initial chemical composition. A summit feed first limiting in Val was serially diluted with a non-protein diluent to produce a series of five digestible Val concentrations of 11.9, 10.1, 8.3, 6.6 and 4.8 g/kg, with a sixth treatment being added to test that the feeds were limiting in Val. Three identical Val series, each with six levels of Val, were supplemented with increasing amounts of Leu (23, 45 and 67 g/kg), thus 18 treatments in total. All pigs were killed at the end of the trial after 18 days for analysis of water, protein, lipid and ash in the carcass. The levels of Val and Leu and their interaction significantly influenced all the measurements taken in the trial. Daily gain in liveweight, water and protein, and feed conversion efficiency all increased with dietary Val content, whereas feed intake decreased as both Val and Leu contents increased. The deleterious effect of increased Leu on feed intake and growth was more marked at lower levels of Val. Supplementing the feed with the lowest Val content with additional Val largely overcame the effect of excess Leu. The efficiency of utilisation of Val for protein growth was unaffected by the level of Leu in the feed, the primary response to excess Leu being a reduction in feed intake. An intake of around 9 g Val/day yielded maximal protein growth during the period from 44 to 62 days of age in pigs of the genotype used in this trial. PMID- 28077195 TI - Evidence-based medicine in the era of social media: Scholarly engagement through participation and online interaction. AB - The integration of new knowledge into clinical practice continues to lag behind discovery. The use of Free Open Access Medical education (FOAM) has disrupted communication between emergency physicians, making it easy for practicing clinicians to interact with colleagues from around the world to discuss the latest and highest impact research. FOAM has the potential to decrease the knowledge translation gap, but the concerns raised about its growing influence are 1) research that is translated too quickly may cause harm if its findings are incorrect; 2) there is little editorial oversight of online material; and 3) eminent online individuals may develop an outsized influence on clinical practice. We propose that new types of scholars are emerging to moderate the changing landscape of knowledge translation: 1) critical clinicians who critically appraise research in the same way that lay reviewers critique restaurants; 2) translational teachers adept with these new technologies who will work with researchers to disseminate their findings effectively; and 3) interactive investigators who engage with clinicians to ensure that their findings resonate and are applied at the bedside. The development of these scholars could build on the promise of evidence-based medicine by enhancing the appraisal and translation of research in practice. PMID- 28077196 TI - Brief assessment of delirium subtypes: Psychometric evaluation of the Delirium Motor Subtype Scale (DMSS)-4 in the intensive care setting. AB - OBJECTIVE: The management of and prognosis for delirium are affected by its subtype: hypoactive, hyperactive, mixed, and none. The DMSS-4, an abbreviated version of the Delirium Motor Symptom Scale, is a brief instrument for the assessment of delirium subtypes. However, it has not yet been evaluated in an intensive care setting. METHOD: We performed a prospective/descriptive cohort study in order to determine the internal consistency, reliability, and validity of the relevant items of the DMSS-4 versus the Delirium Rating Scale-Revised-98 (DRS-R-98) and the original DMSS in a surgical intensive care setting. RESULTS: A total of 289 elderly, predominantly male patients were screened for delirium, and 122 were included in our sample. The internal consistency of the DMSS-4 items was excellent (Cronbach's alpha = 0.92), and between the DMSS-4 and DRS-R-98 the overall concurrent validity was substantial (Cramer's V = 0.67). Within individual motor subtypes, concurrent validity remained at least substantial (Cohen's kappa = 0.65-0.81) and sensitivity high (69.8 to 82.2%), in contrast to those of the no-motor subtype, with less validity and sensitivity (kappa = 0.28, 22%). Similarly, total concurrent validity between the DMSS-4 and the original DMSS reached perfection (Cramer's V = 0.83), as did agreement between the subtypes (kappa = 0.83-0.92), while sensitivity remained high (88.2-100%). Only in those with delirium with no-motor subtype was agreement moderate (kappa = 0.56) and sensitivity lower (67%). Specificity was high across all subtypes (91.2 99.1%). The DMSS-4 yielded very sensitive ratings, particularly for hypoactive and hyperactive motor symptoms, and interrater agreement was excellent (Fleiss's kappa = 0.83). SIGNIFICANCE OF RESULTS: We found the DMSS-4 to be a most reliable and valid brief assessment of delirium in characterizing the subtypes of delirium in an intensive care setting, with increased sensitivity to hypoactive and hyperactive motor alterations. PMID- 28077197 TI - Personal Disaster and Emergency Support Networks of Older Adults in a Rural Community: Changes After Participation in a Preparedness Program. AB - OBJECTIVE: Personal disaster and emergency support networks of rural older adults are described before and after participation in a disaster preparedness intervention, PrepWise. METHODS: At baseline, a total of 194 disaster support network members were identified by 27 older adults in a rural Midwest community. After the intervention, these participants identified 232 support network members. Multilevel logistic regression models were constructed to identify characteristics of the network members and social interactions associated with support providers at baseline as well as newly added support sources after the PrepWise intervention. RESULTS: Member and interaction characteristics associated with being identified as emergency support sources at baseline were as follows: family, lived in close proximity, weekly or more frequent contact, and being someone whom participants shared concerns with, trusted, and exchanged emotional support with. After receiving PrepWise, participants on average identified 3 new sources of emergency support within their networks. Support sources added at follow-up tended to be nonfamily members and those participants trusted. CONCLUSIONS: Enhancements in personal emergency support networks occurred after the intervention. Understanding characteristics of the network members and social interactions may assist in identifying additional emergency support sources. Larger studies investigating the impacts of enhanced support networks on disaster related behaviors and outcomes will be beneficial. (Disaster Med Public Health Preparedness. 2017;11:110-119). PMID- 28077198 TI - Association of BMI with risk of CVD mortality and all-cause mortality. AB - OBJECTIVE: To determine the relationship between BMI and risk of CVD mortality and all-cause mortality among Malaysian adults. DESIGN: Population-based, retrospective cohort study. Participants were followed up for 5 years from 2006 to 2010. Mortality data were obtained via record linkages with the Malaysian National Registration Department. Multiple Cox regression was applied to compare risk of CVD and all-cause mortality between BMI categories adjusting for age, gender and ethnicity. Models were generated for all participants, all participants the first 2 years of follow-up, healthy participants, healthy never smokers, never smokers, current smokers and former smokers. SETTING: All fourteen states in Malaysia. SUBJECTS: Malaysian adults (n 32 839) aged 18 years or above from the third National Health and Morbidity Survey. RESULTS: Total follow-up time was 153 814 person-years with 1035 deaths from all causes and 225 deaths from CVD. Underweight (BMI<18.5 kg/m2) was associated with a significantly increased risk of all-cause mortality, while obesity (BMI >=30.0 kg/m2) was associated with a heightened risk of CVD mortality. Overweight (BMI=25.0-29.9 kg/m2) was inversely associated with risk of all-cause mortality. Underweight was significantly associated with all-cause mortality in all models except for current smokers. Overweight was inversely associated with all-cause mortality in all participants. Although a positive trend was observed between BMI and CVD mortality in all participants, a significant association was observed only for severe obesity (BMI>=35.0 kg/m2). CONCLUSIONS: Underweight was associated with increased risk of all-cause mortality and obesity with increased risk of CVD mortality. Therefore, maintaining a normal BMI through leading an active lifestyle and healthy dietary habits should continue to be promoted. PMID- 28077199 TI - Legume consumption and CVD risk: a systematic review and meta-analysis. AB - OBJECTIVE: The aim of the present study was to systematically review and perform a meta-analysis of prospective cohort studies exploring the association between dietary legume consumption and CVD risk, including CHD and stroke. DESIGN: The PubMed and EMBASE databases were searched up to December 2015. A meta-analysis of the highest v. lowest (reference) category of dietary legume consumption was performed through random-effects models. RESULTS: Fourteen studies conducted on eleven cohorts and accounting for a total of 367 000 individuals and 18 475 cases of CVD (7451 CHD and 6336 stroke cases) were considered for the analyses. Compared with lower legume consumption, the highest category of exposure was associated with a decreased risk of 10 % in both CVD and CHD (relative risk=0.90; 95 % CI 0.84, 0.97) with no or little evidence of heterogeneity and no publication bias. Null results were found regarding legume consumption and stroke risk. No substantial confounding factors were evident in stratified analyses. CONCLUSIONS: Legume consumption was associated with lower risk of CVD. Legumes' intrinsic characteristics, because they are often part of an overall healthy diet, or because they are a substitute for unhealthy sources of protein may potentially explain the current findings. PMID- 28077200 TI - Expression of heat shock protein 70 in transport-stressed broiler pectoralis major muscle and its relationship with meat quality. AB - Omics research has indicated that heat shock protein 70 (HSP70) is a potential biomarker of meat quality. However, the specific changes and the potential role of HSP70 in postmortem meat quality development need to be further defined. In this study, Arbor Acres broiler chickens (n=126) were randomly categorized into three treatment groups of unstressed control (C), 0.5-h transport (T) and subsequent water shower spray following transport (T/W). Each treatment consisted of six replicates with seven birds each. The birds were transported according to a designed protocol. The pectoralis major (PM) muscles of the transport-stressed broilers were categorized as normal and pale, soft and exudative (PSE)-like muscle samples according to L* and pH24 h values to test the expression and location of HSP70. Results revealed that the activities of plasma creatine kinase and lactate dehydrogenase increased significantly (P<0.05) in normal and PSE-like muscle samples after transportation. The mRNA expression of HSP70 in normal muscle samples increased significantly (P<0.05) compared with that in the controls after stress. The protein expression of HSP70 increased significantly in normal muscle samples and decreased significantly (P<0.05) in PSE-like muscles. Immuno-fluorescence showed that HSP70 was present in the cytoplasm and on surface membranes of PM muscle cells in the normal samples following stress. Meanwhile, HSP70 was present on the surface membranes and extracellular matrix but was barely visible in the cytoplasm of the PSE-like samples. Principal component analysis showed high correlations between HSP70 and meat quality and stress indicators. In conclusion, this research suggests that the variation in HSP70 expression may provide a novel insight into the pathways underlying meat quality development. PMID- 28077201 TI - Last Year's Big Story: Antibiotic Stewardship. PMID- 28077202 TI - Long-Term Care and Cultural Competence. AB - The United States has historically been a melting pot of cultures. Today the population has changed because many immigrants are now older than past immigrants, are frequently retired, and have chronic diseases that need careful management. Health care providers need to be culturally competent to deliver effective health care to these diverse populations. Over the years, health care systems and providers have become much more aware of the needs of minority populations. They accommodate language differences and individuals' ingrained beliefs that may affect health care and learn how to ask the questions that will elicit the information they need to treat patients. Today, while the American health care system meets more of the needs of minority populations, the needs of smaller minority populations may languish or be overshadowed by the unique needs of individual groups or difficult experiences or immigration histories, such as Cambodian immigrants, Indian Asians, and even veterans of U.S. conflicts. This article makes the case for greater cultural competence and offers ideas and suggestions that can be applied to any small minority population. PMID- 28077203 TI - Clostridium difficile Infection in Older Adults: Systematic Review of Efforts to Reduce Occurrence and Improve Outcomes. AB - OBJECTIVE: Provide a systematic review of the primary literature on efforts to reduce Clostridium difficile infection (CDI) occurrence and improve outcomes in older adults. DATA SOURCES, STUDY SELECTION, DATA EXTRACTION: PubMed and CINAHL databases were searched for research studies using search terms CDI, CDI prevention, reduction, control, management, geriatric, elderly, adults 65 years of age and older. The MeSH categories Aged and Aged, 80 and older, were used. A second search of PubMed, CINAHL, National Guideline Clearinghouse, and TRIP databases was conducted for primary, secondary, and tertiary literature for CDI epidemiology, burden, and management in adults of all ages, and prevention and management guidelines. Of the 2,263 articles located, 105 were selected for full review: 55 primary and 50 secondary, tertiary. Primary literature selected for full review included studies of interventions to prevent, reduce occurrence, control, manage, or improve outcomes in adults 65 years of age and older. Patient settings included the community, assisted living, nursing facility, subacute care, or hospital. DATA SYNTHESIS: The main outcome measures for research studies were whether the studied intervention prevented, reduced occurrence, controlled, managed, or improved outcomes. Studies were conducted in acute or long-term hospitals, with a few in nursing facilities. Interventions that prevented or reduced CDI included antibiotic policy changes, education, procedure changes, infection control, and multi-intervention approaches. There were few management studies for adults 65 years of age and older or for all adults with results stratified by age. Treatments studied included efficacy of fidaxomicin, metronidazole, vancomycin, and fecal microbiota transplant. Though clinical outcomes were slightly less robust in those 65 years of age and older, age was not an independent predictor of success or failure. The current prevention and management guidelines for adults of all ages, as well as special considerations in skilled nursing facilities, extracted from the secondary/tertiary literature selected, are summarized. CONCLUSION: There are a limited number of studies designed for older adults. Our findings suggest that guideline recommendations for adults are adequate and appropriate for older adults. Exposure to antibiotics and Clostridium difficile remain the two major risk factors for CDI, reinforcing the importance of antibiotic stewardship and infection control. PMID- 28077204 TI - Review of the Next Generation of Long-Acting Basal Insulins: Insulin Degludec and Insulin Glargine. AB - Older adults are at an increased risk of developing type 2 diabetes mellitus (T2DM). Although oral agents (i.e., metformin) are the preferred first-line therapy, older adults often eventually require the addition of insulin to control their blood glucose. Long-acting insulin analogues are the preferred insulin products for older adults with T2DM. Insulin degludec and insulin glargine U-300 are both new generation long-acting insulins. When compared with the standard of care, long-acting insulin product insulin glargine U-100, insulin degludec, and insulin glargine U-300 had similar glucose-lowering effects, longer half-lives and durations of action, and a more even distribution over a 24-hour period. Additionally, the new generation insulins were superior with regard to rates and severity of nocturnal hypoglycemia. The long-term cardiovascular safety of these products has not been established yet. Although the new generation long-acting insulins will not revolutionize diabetes management, they appear to be an improvement over previous long-acting insulins. PMID- 28077205 TI - Impact of Pharmacists in Optimizing Geriatric Pharmacotherapy in Primary Care Within a Veterans Affairs Medical Center. AB - OBJECTIVE: To assess pharmacists' impact on optimizing pharmacotherapy among geriatric patients. DESIGN: Single-site, prospective, quality-improvement project. SETTING: Primary care at a Veterans Affairs medical center. PARTICIPANTS: Thirteen males 75 years of age and older were included. INTERVENTIONS: Recommendations were made by pharmacists to optimize prescribing. MAIN OUTCOME MEASURES: Differences between specific instances of suboptimal prescribing before and after pharmacists' recommendations, the percentage of pharmacists' recommendations accepted, and the top most commonly prescribed psychotropic medications and their most common indications. RESULTS: Sixty-three recommendations were made by pharmacists, and 48% of these recommendations were accepted by providers. There was a 27% reduction of the use of high-risk medications, a 44% reduction of omissions of care, and a 74% reduction of incomplete medication monitoring after pharmacists' recommendations. The most commonly prescribed psychotropic medications were zolpidem (31%), lorazepam (23%), and clonazepam and temazepam (each 15%). The most common indications for these medications were anxiety and insomnia (each 46%), with 8% of patients having an indication for both. CONCLUSION: Pharmacists' recommendations improved geriatric pharmacotherapy by decreasing the overall instances of suboptimal prescribing. PMID- 28077206 TI - Predictions on Health Care Policy? Unlikely. PMID- 28077207 TI - Proposal to reclassify Roseivirga ehrenbergii (Nedashkovskaya et al., 2008) as Roseivirga seohaensis comb. nov., description of Roseivirga seohaensis subsp. aquiponti subsp. nov. and emendation of the genus Roseivirga. AB - The genus Roseivirga currently includes five species: Roseivirga ehrenbergii, R. echinicomitans, R. spongicola, R. marina and R. maritima. Marinicola seohaensis SW-152T was renamed as Roseivirgaseohaensis SW-152T and then reclassified again as a later heterotypic synonym of R. ehrenbergii KMM 6017T. In this study, based on average nucleotide identity and digital DNA-DNA hybridization values obtained from in silico methods, together with fatty acid analyses and biochemical tests, we propose to reclassify R. ehrenbergii SW-152 as Roseivirga seohaensis comb. nov. (type strain SW-152T=KCTC 1231T=JCM 12600T). In this work, a Gram-negative, rod-shaped, aerobic and pink-pigmented strain designated as D-25T was isolated from seawater (Desaru Beach, Johor, Malaysia). The 16S rRNA gene analysis revealed that strain D-25T was related to the genus Roseivirga. Strain D-25T was found most closely related to R. seohaensis SW-152T based on average nucleotide identity and digital DNA-DNA hybridization values, phenotypic and chemotaxonomic analyses, indicating that these strains belong to the same species. Thus, it is proposed to split the species R.oseivirga seohaensis into two novel subspecies, Roseivirga seohaensissubsp. seohaensis subsp. nov. (type strain SW-152T=KCTC 12312T=JCM 12600T) and Roseivirga seohaensissubsp. aquiponti subsp. nov. (type strain D-25T=KCTC 42709T=DSM 101709T) and to emend the description of the genus Roseivirga. PMID- 28077208 TI - Aerobic denitrification and biomineralization by a novel heterotrophic bacterium, Acinetobacter sp. H36. AB - A novel aerobic denitrification and biomineralization strain H36 was isolated from the Qu Jiang artificial lake. Based on phylogenetic characteristics, the isolated strain was identified as Acinetobacter species. Strain H36 was confirmed to have the ability to perform simultaneous denitrification and biomineralization. Results showed the strain H36 had the capability to completely reduce 96.29% of NO3--N and 78.59% of Ca2+ over 112h under aerobic condition. Response surface methodology (RSM) analysis demonstrated the highest removal ratio of Ca2+ was 74.24% with hardness concentration of 350mg/L, pH of 8.5, organic concentration of 0.75g/L and inoculum size of 15%. The highest removal ratio of nitrate was 77.00% with hardness concentration of 350mg/L, pH of 7.5, organic concentration of 0.75g/L and inoculum size of 10%. Besides, X-ray diffraction (XRD) analysis showed calcium carbonate could be formed in the process of biomineralization. PMID- 28077210 TI - Spatial-temporal and multi-media variations of polycyclic aromatic hydrocarbons in a highly urbanized river from South China. AB - Comprehensive studies on polycyclic aromatic hydrocarbons (PAHs) within an urban river are urgently needed to carry out strategies to limit their contamination and dispersal. Here, we analyzed 16 PAH occurrences in water, suspended particulate matter (SPM), and sediment monthly for a year in the Maozhou River mainstream (Shenzhen, South China). Monthly rainfall positively correlated with both total PAH concentrations in filtered water (water PAHs) and SPM. Sediment PAH concentration increased from the river source to estuary. Compared to the earlier record, the sediment PAHs decreased at almost all sites due to the high molecular-weight PAH (>=4 rings; especially the 4-ring PAH) degradation, except the estuary site that accumulated more low-molecular-weight PAHs (<4 rings). Results suggest that the water and SPM PAHs had similar and recent sources (e.g., rainfall and storm runoff) and actively exchanged with each other. The sediment PAHs had relatively different and complicated sources (fossil fuel combustion: 44.0%; oil pollution: 28.4%; biomass burning: 27.6%), and showed a long-term accumulation effect and increasingly weaker source-sink relation with both water and SPM PAHs from river source to estuary. This study highlights a disconnection in the source and migration mechanism between the water body (including water and SPM) and sediment PAHs. PMID- 28077209 TI - Residual compressive surface stress increases the bending strength of dental zirconia. AB - OBJECTIVE: To assess the influence of surface treatment and thermal annealing on the four-point bending strength of two ground dental zirconia grades. METHODS: Fully-sintered zirconia specimens (4.0*3.0*45.0mm3) of Y-TZP zirconia (LAVA Plus, 3M ESPE) and Y-TZP/Al2O3 zirconia (ZirTough, Kuraray Noritake) were subjected to four surface treatments: (1) 'GROUND': all surfaces were ground with a diamond coated grinding wheel on a grinding machine; (2) 'GROUND+HEAT': (1) followed by annealing at 1100 degrees C for 30min; (3) 'GROUND+Al2O3 SANDBLASTED': (1) followed by sandblasting using Al2O3; (4) 'GROUND+CoJet SANDBLASTED': (1) followed by tribochemical silica (CoJet) sandblasting. Micro-Raman spectroscopy was used to assess the zirconia-phase composition and potentially induced residual stress. The four-point bending strength was measured using a universal material-testing machine. RESULTS: Weibull analysis revealed a substantially higher Weibull modulus and slightly higher characteristic strength for ZirTough (Kuraray Noritake) than for LAVA Plus (3M ESPE). For both zirconia grades, the 'GROUND' zirconia had the lowest Weibull modulus in combination with a high characteristic strength. Sandblasting hardly changed the bending strength but substantially increased the Weibull modulus of the ground zirconia, whereas a thermal treatment increased the Weibull modulus of both zirconia grades but resulted in a significantly lower bending strength. Micro-Raman analysis revealed a higher residual compressive surface stress that correlated with an increased bending strength. SIGNIFICANCE: Residual compressive surface stress increased the bending strength of dental zirconia. Thermal annealing substantially reduced the bending strength but increased the consistency (reliability) of 'GROUND' zirconia. PMID- 28077211 TI - The effect of socio-economic status on non-fatal outcome after injury: A systematic review. AB - BACKGROUND: Over the past decades, the number of survivors of injuries has rapidly grown. It has become important to focus more on the determinants of non fatal outcome. Although socio-economic status (SES) is considered to be a fundamental determinant of health in general, the role of SES as a determinant of non-fatal outcome after injury is largely unknown. METHODS: An online search was conducted in November 2015 using Embase, Medline, Web of Science, Cinahl, Cochrane, Google scholar and PubMed. Studies examining the relation between SES and a physical or psychological outcome measure, or using SES as a confounder in a general trauma population were included. There were no restrictions regarding study design. The 'Quality in Prognostic Studies tool' was used to assess the methodological quality of the included studies. RESULTS: The 24 included studies showed large variations in methodological quality. The number of participants ranged from 56 to 4639, and assessments of the measures ranged from immediately to 6year post-injury. Studies used a large number of variables as indicators of SES. Participant's educational level was used most frequently. The majority of the studies used a multivariable technique to analyse the relation between SES and non-fatal outcome after injury. All studies found a positive association (80% of studies significant, n=19) between increased SES and better non-fatal outcome after injury. CONCLUSION: Although an adequate and valid measure of SES is lacking, the results of this review showed that SES is an important determinant of non-fatal outcome after injury. Future research should focus on the definition and measurement of SES and should further underpin the effect of SES on non-fatal outcome after injury. PMID- 28077212 TI - Decoding the content of recollection within the core recollection network and beyond. AB - Recollection - retrieval of qualitative information about a past event - is associated with enhanced neural activity in a consistent set of neural regions (the 'core recollection network') seemingly regardless of the nature of the recollected content. Here, we employed multi-voxel pattern analysis (MVPA) to assess whether retrieval-related functional magnetic resonance imaging (fMRI) activity in core recollection regions - including the hippocampus, angular gyrus, medial prefrontal cortex, retrosplenial/posterior cingulate cortex, and middle temporal gyrus - contain information about studied content and thus demonstrate retrieval-related 'reinstatement' effects. During study, participants viewed objects and concrete words that were subjected to different encoding tasks. Test items included studied words, the names of studied objects, or unstudied words. Participants judged whether the items were recollected, familiar, or new by making 'remember', 'know', and 'new' responses, respectively. The study history of remembered test items could be reliably decoded using MVPA in most regions, as well as from the dorsolateral prefrontal cortex, a region where univariate recollection effects could not be detected. The findings add to evidence that members of the core recollection network, as well as at least one neural region where mean signal is insensitive to recollection success, carry information about recollected content. Importantly, the study history of recognized items endorsed with a 'know' response could be decoded with equal accuracy. The results thus demonstrate a striking dissociation between mean signal and multi-voxel indices of recollection. Moreover, they converge with prior findings in suggesting that, as it is operationalized by classification-based MVPA, reinstatement is not uniquely a signature of recollection. PMID- 28077213 TI - Inhibition of dopamine receptor D3 signaling in dendritic cells increases antigen cross-presentation to CD8+ T-cells favoring anti-tumor immunity. AB - Dendritic cells (DCs) display the unique ability for cross-presenting antigens to CD8+ T-cells, promoting their differentiation into cytotoxic T-lymphocytes (CTLs), which play a pivotal role in anti-tumor immunity. Emerging evidence points to dopamine receptor D3 (D3R) as a key regulator of immunity. Accordingly, we studied how D3R regulates DCs function in anti-tumor immunity. The results show that D3R-deficiency in DCs enhanced expansion of CTLs in vivo and induced stronger anti-tumor immunity. Co-culture experiments indicated that D3R inhibition in DCs potentiated antigen cross-presentation and CTLs activation. Our findings suggest that D3R in DCs constitutes a new therapeutic target to strengthen anti-tumor immunity. PMID- 28077214 TI - Intervention Effectiveness of The Incredible Years: New Insights Into Sociodemographic and Intervention-Based Moderators. AB - We tested the effectiveness of the preventive behavioral parent training (BPT) program, The Incredible Years (IY), and the independent effects of previously suggested sociodemographic and intervention-based moderator variables (i.e., initial severity of externalizing problem behavior, child gender, social economic status, family composition, and number of sessions parents attended), in a large scale randomized controlled trial. Questionnaire and observation data from 387 parents and children ages 4-8 years (Mage= 6.21, SD = 1.33, 55.30% boys) across pretest, posttest, and 4-month follow-up were analyzed, using full intention-to treat analyses and correcting for multiple testing. IY was successful in decreasing parent-reported child externalizing behavior (Cohen's d = 0.20 at posttest, d = 0.08 at follow-up), increasing parent-reported (d = 0.49, d = 0.45) and observed (d = 0.06, d = 0.02) positive parenting behavior, and decreasing parent-reported negative parenting behavior (d = 0.29, d = 0.25). No intervention effects were found for reported and observed child prosocial behavior, observed child externalizing behavior, and observed negative parenting behavior. Out of 40 tested moderation effects (i.e., 8 Outcomes * 5 Moderators), only three significant moderation effects appeared. Thus, no systematic evidence emerged for moderation of IY effects. The present multi-informant trial demonstrated that many previously suggested moderators might not be as potent in differentiating BPT effects as once thought. PMID- 28077215 TI - Analyzing Therapeutic Change Using Modified Brinley Plots: History, Construction, and Interpretation. AB - The paper reviews the history, construction, and interpretation of modified Brinley plots, a scatter plot used in therapy outcome research to compare each individual participant's scores on the same dependent variable at Time 1 (normally pretreatment baseline; x-axis), with scores at selected times during or after treatment (y-axis). Since 1965 eponymously named Brinley plots have occasionally been used in experimental psychology to display group mean data. Between 1979 and 1995 a number of clinical researchers modified Brinley plots to show individuals' data but these plots have received little subsequent use. When constructed with orthogonal axes having the same origin and scale values, little or no change over time is shown by individuals' data points lying on or closely about the diagonal (450o) while the magnitude and direction of any improvement (or deterioration), outliers, and the extent of replication across cases shows via dispersion of points away from 450o. Interpretation is aided by displaying reliable change boundaries, clinical cutoffs, means, variances, confidence intervals, and effect sizes directly on the graph. Modified Brinley plots are directly informative about individual change during therapy in the context of concurrent change in others in the same (or a different) condition, clearly show if outcomes are replicated and if they are clinically significant, and make nomothetic group information, notably effect sizes, directly available. They usefully complement other forms of analysis in therapy outcome research. PMID- 28077216 TI - Current Definitions of "Transdiagnostic" in Treatment Development: A Search for Consensus. AB - Research in psychopathology has identified psychological processes that are relevant across a range of Diagnostic and Statistical Manual (DSM) mental disorders, and these efforts have begun to produce treatment principles and protocols that can be applied transdiagnostically. However, review of recent work suggests that there has been great variability in conceptions of the term "transdiagnostic" in the treatment development literature. We believe that there is value in arriving at a common understanding of the term "transdiagnostic." The purpose of the current paper is to outline three principal ways in which the term "transdiagnostic" is currently used, to delineate treatment approaches that fall into these three categories, and to consider potential advantages and disadvantages of each approach. PMID- 28077217 TI - Corrigendum to "Assessing Decentering: Validation, Psychometric Properties, and Clinical Usefulness of the Experiences Questionnaire in a Spanish Sample" [Behavior Therapy 45 (2014) 863- 871]. PMID- 28077218 TI - A Person-by-Situation Account of Why Some People More Frequently Engage in Upward Appearance Comparison Behaviors in Everyday Life. AB - Although the influence of stable, trait-like factors (such as trait body dissatisfaction and appearance internalization) on instances of appearance comparison has been well documented, the additive and interactive influence of contextual factors (such as one's current body satisfaction) on comparison behaviors is unknown. Therefore, the present study tested a Person*Situation model in which both state and trait body image variables interacted to predict engagement in various forms of comparison (upward, downward, and lateral). Participants included 161 women who completed a baseline measure of trait body dissatisfaction and internalization, and then completed, via an iPhone app, an ecological momentary assessment phase in which they reported momentary experiences of mood and comparison behaviors at up to 6 random times per day for 7days. Multilevel analyses revealed that upward comparisons (comparisons against more attractive people) were more likely for individuals with heightened trait and/or state negative body image, but these predictive effects of state and trait on appearance comparisons appear largely independent of each other. Furthermore, neither state nor trait body image variables were related to the other forms of comparison, and time lag at the state-level between predictor and outcome did not seem to influence the strength of these associations. Present findings are consistent with the notion that how an individual feels in the moment about their appearance may influence engagement in deleterious appearance behaviors. However, further testing is needed to confirm these causal hypotheses. PMID- 28077220 TI - Examining the Impact of Suicide Attempt Function and Perceived Effectiveness in Predicting Reattempt for Emergency Medicine Patients. AB - While previous studies have examined motivational aspects of self-directed violence, few studies have included specific motivations in predictive models for future suicide attempts. The current study utilized a sample of 160 individuals treated in an acute emergency setting following a suicide attempt who completed an interview battery that included an assessment of functional aspects of the index suicide attempt. A follow-up interview was conducted at 6 months to ascertain subsequent suicide attempts. The functional domains of suicide attempts were labeled as reduction-of-distress, communication, perceived better alternative to living, and self-loathing. Above and beyond other known risk factors, including history and highest lethality of previous self-injury, suicide attempts that served a communication function (OR = 0.18, p = .02, CI = 0.04, 0.73) and higher ratings of clinical dysfunction (OR = 3.41, p = .05, CI = 1.02, 11.36) were associated with a significant reduction in likelihood to engage in a suicide attempt during the 6-month follow-up window. Including the perceived effectiveness of the index suicide attempt in getting one's needs met strengthened the overall model predicting a suicide attempt in the follow-up window and was an independent risk factor above and beyond other variables in the model OR = 1.75, p = .04, CI = 1.02, 3.01). Assessment of functional aspects of suicide attempt is feasible and may improve formulation of risk in a population where typical risk factors for suicide are ubiquitous. PMID- 28077219 TI - Cognitive-Behavioral Therapy for Depression Using Mind Over Mood: CBT Skill Use and Differential Symptom Alleviation. AB - Cognitive-behavioral therapy (CBT) for depression is highly effective. An essential element of this therapy involves acquiring and utilizing CBT skills; however, it is unclear whether the type of CBT skill used is associated with differential symptom alleviation. Outpatients (N = 356) diagnosed with a primary mood disorder received 14 two-hour group sessions of CBT for depression, using the Mind Over Mood protocol. In each session, patients completed the Beck Depression Inventory and throughout the week they reported on their use of CBT skills: behavioral activation (BA), cognitive restructuring (CR), and core belief (CB) strategies. Bivariate latent difference score (LDS) longitudinal analyses were used to examine patterns of differential skill use and subsequent symptom change, and multigroup LDS analyses were used to determine whether longitudinal associations differed as a function of initial depression severity. Higher levels of BA use were associated with a greater subsequent decrease in depressive symptoms for patients with mild to moderate initial depression symptoms relative to those with severe symptoms. Higher levels of CR use were associated with a greater subsequent decrease in depressive symptoms, whereas higher levels of CB use were followed by a subsequent increase in depressive symptoms, regardless of initial severity. Results indicated that the type of CBT skill used is associated with differential patterns of subsequent symptom change. BA use was associated with differential subsequent change as a function of initial severity (patients with less severe depression symptoms demonstrated greater symptom improvement), whereas CR use was associated with symptom alleviation and CB use with an increase in subsequent symptoms as related to initial severity. PMID- 28077222 TI - Prediction of Relapse After Cognitive-Behavioral Treatment of Gambling Disorder in Individuals With Chronic Schizophrenia: A Survival Analysis. AB - Gambling disorder (GD) in individuals with chronic schizophrenia is relevant because there are higher rates of GD in schizophrenic populations (10%) than in the nonschizophrenic population (1%-5%). In addition, these patients have more severe alcohol use disorder (i.e., meeting at least 6 of the DSM-5 11 criteria for diagnosis of this disorder), higher depression scores, a poor adherence to treatment, and more frequent use of outpatient mental health care. One of the main problems in GD is therapeutic failure (defined as three or more lapse episodes during treatment) or relapse (three or more lapse episodes in the follow up period). Predicting a relapse of GD in individuals with chronic schizophrenia can be useful in targeting the patients for aftercare services. The main aim of this study was to estimate the time to a GD relapse (survival rate) and to evaluate some of the qualitative and quantitative variables related to a GD relapse by a survival analysis. The sample consisted of 35 patients with chronic schizophrenia and GD who were treated with pharmacological and cognitive behavioral therapy. The therapeutic failure rate in the treatment period was 43%, and it was associated with the number of episodes of schizophrenia, the age of gambling onset, and the age of the patients. The relapse rate in the follow-up period was 32%, and it was associated with the patients' age, educational level, and weekly allowance. The implications of this study for future research are discussed. PMID- 28077221 TI - Interpersonal Problems Predict Differential Response to Cognitive Versus Behavioral Treatment in a Randomized Controlled Trial. AB - OBJECTIVE: We examined dimensional interpersonal problems as moderators of cognitive behavioral therapy (CBT) versus its components (cognitive therapy [CT] and behavioral therapy [BT]). We predicted that people with generalized anxiety disorder (GAD) whose interpersonal problems reflected more dominance and intrusiveness would respond best to a relaxation-based BT compared to CT or CBT, based on studies showing that people with personality features associated with a need for autonomy respond best to treatments that are more experiential, concrete, and self-directed compared to therapies involving abstract analysis of one's problems (e.g., containing CT). METHOD: This was a secondary analysis of Borkovec, Newman, Pincus, and Lytle (2002). Forty-seven participants with principal diagnoses of GAD were assigned randomly to combined CBT (n = 16), CT (n = 15), or BT (n = 16). RESULTS: As predicted, compared to participants with less intrusiveness, those with dimensionally more intrusiveness responded with greater GAD symptom reduction to BT than to CBT at posttreatment and greater change to BT than to CT or CBT across all follow-up points. Similarly, those with more dominance responded better to BT compared to CT and CBT at all follow-up points. Additionally, being overly nurturant at baseline was associated with GAD symptoms at baseline, post, and all follow-up time-points regardless of therapy condition. CONCLUSIONS: Generally anxious individuals with domineering and intrusive problems associated with higher need for control may respond better to experiential behavioral interventions than to cognitive interventions, which may be perceived as a direct challenge of their perceptions. PMID- 28077223 TI - An Exploratory Randomized Controlled Trial of Personalized Lifestyle Advice and Tandem Skydives as a Means to Reduce Anhedonia. AB - Anhedonia is a major public health concern and has proven particularly difficult to counteract. It has been hypothesized that anhedonia can be deterred by engagement in rewarding social and physical events. The aims of the present study were to examine (1) the effects of personalized lifestyle advice based on observed individual patterns of lifestyle factors and experienced pleasure in anhedonic young adults; and (2) whether a tandem skydive can enhance the motivation to carry out the recommended lifestyle changes. Participants (N = 69; Mage = 21.5, SD = 2.0; 79.7% female) were selected through an online screening survey among young adults. Inclusion criteria were persistent anhedonia and willingness to perform a tandem skydive. Participants filled out questionnaires on their smartphones for 2 consecutive months (3 times per day). After the first month, they were randomly assigned to one of three groups: (1) no intervention, (2) lifestyle advice, and (3) lifestyle advice and tandem skydive. The momentary questionnaire data were analyzed using interrupted time series analyses (ITSA) in a multilevel model and monthly pleasure and depression questionnaires by repeated measures ANOVA. No group differences were found in monthly depression and pleasure scores, but the momentary data showed higher positive affect (PA) and pleasure ratings in the month following the intervention in the two intervention groups than in the control group. The tandem skydive did not have any effects above the effects of the lifestyle advice. Our results indicate that providing personalized lifestyle advice to anhedonic young adults can be an effective way to increase PA and pleasure. PMID- 28077224 TI - Recommendations for Choosing Single-Case Data Analytical Techniques. AB - The current paper responds to the need to provide guidance to applied single-case researchers regarding the possibilities of data analysis. The amount of available single-case data analytical techniques has been growing during recent years and a general overview, comparing the possibilities of these techniques, is missing. Such an overview is provided that refers to techniques that yield results in terms of a raw or standardized difference and procedures related to regression analysis, as well as nonoverlap and percentage change indices. The comparison is provided in terms of the type of quantification provided, data features taken into account, conditions in which the techniques are appropriate, possibilities for meta-analysis, and evidence available on their performance. Moreover, we provide a set of recommendations for choosing appropriate analysis techniques, pointing at specific situations (aims, types of data, researchers' resources) and the data analytical techniques that are most appropriate in these situations. The recommendations are contextualized using a variety of published single-case data sets in order to illustrate a range of realistic situations that researchers have faced and may face in their investigations. PMID- 28077225 TI - Age does matter: Younger pPCI patients profit more from cardiac rehabilitation than older patients. AB - BACKGROUND: Cardiac rehabilitation (CR) is recommended as secondary prevention in primary percutaneous coronary intervention (pPCI) patients. This study was conducted to expand the knowledge about age-effects of CR in pPCI patients. The aim of this study was to compare changes in subjective health status (SHS) during and after CR between patients <60years and patients >=60years, who underwent pPCI after myocardial infarction. METHODS: Between 2009 and 2011, in total 282 pPCI patients who participated in CR were included. Patients completed the Short Form 12 (SF-12) questionnaire at baseline (pre-CR), 3months (post-CR) and 12months follow-up. Patients were divided into two age-groups, <60years versus >=60years. To compare improvements in SHS between groups, Generalized Estimating Equations (GEE) analyses were performed. RESULTS: The mean physical component summary (PCS) score improved over time in both groups and even reached mean levels of the normative Dutch population. The improvement on the PCS score was equal in both age groups. The mental component summary (MCS) score also improved in both groups. Patients <60years reported on average more improvement on the MCS score than patients >=60years (Exp(B) 1.019; 95%CI 1.009-1.030; P<0.001). However, mean levels of the normative Dutch population were not reached by patients <60years. CONCLUSION: Even though pPCI patients <60years reported more improvement on the MCS score, mean levels of the normative Dutch population were not reached. Therefore, a tailored CR program with more focus on their mental status, may be beneficial in younger patients. PMID- 28077226 TI - Response to the letter to editor: Cardiac or renal protection by delayed remote ischemic preconditioning in the clinical practice: Potential additive effect from concurrent medications with pharmacological mimicking conditioning. PMID- 28077227 TI - Impact of nutritional assessment and body mass index on cardiovascular outcomes in patients with stable coronary artery disease. AB - BACKGROUND: An inverse association between obesity, as defined by body mass index (BMI) and prognosis has been reported in patients with cardiovascular disease ("obesity paradox"). The aim of this study was to investigate whether adding nutritional information to BMI provides better risk assessment in patients undergoing elective percutaneous coronary intervention (PCI). METHOD: This study comprised 1004 patients undergoing elective PCI. We calculated each patient's controlling nutritional status (CONUT) score for nutritional screening at baseline. Patients were divided into 4 groups based on CONUT score (low, 0-1 [<75th percentile]; or high, >=2 [>=75th percentile]) and BMI (normal, 18.5 24.9kg/m2; or high, >=25kg/m2). The endpoint was major adverse cardiac events (MACE) defined as cardiac death and/or myocardial infarction. RESULTS: Low CONUT score+normal BMI, low CONUT score+high BMI, high CONUT score+normal BMI, and high CONUT score+high BMI were determined in 374, 242, 275, and 113 patients, respectively. During a median follow-up of 1779 days, 73 events occurred. High CONUT score+normal BMI showed a 2.72-fold increase in the incidence of MACE (95% CI 1.46-5.08, p=0.002) compared with low CONUT score+normal BMI after adjusting for confounding factors. On the other hand, no significant difference in the incidence of MACE was observed in the other three groups. CONCLUSION: The combination of CONUT score and BMI was a useful predictor of MACE in this population. Using BMI to assess the cardiovascular risk may be misleading unless the nutritional information is considered. PMID- 28077228 TI - Levers for addressing medical underuse and overuse: achieving high-value health care. AB - The preceding papers in this Series have outlined how underuse and overuse of health-care services occur within a complex system of health-care production, with a multiplicity of causes. Because poor care is ubiquitous and has considerable consequences for the health and wellbeing of billions of people around the world, remedying this problem is a morally and politically urgent task. Universal health coverage is a key step towards achieving the right care. Therefore, full consideration of potential levers of change must include an upstream perspective-ie, an understanding of the system-level factors that drive overuse and underuse, as well as the various incentives at work during a clinical encounter. One example of a system-level factor is the allocation of resources (eg, hospital beds and clinicians) to meet the needs of a local population to minimise underuse or overuse. Another example is priority setting using tools such as health technology assessment to guide the optimum diffusion of safe, effective, and cost-effective health-care services. In this Series paper we investigate a range of levers for eliminating medical underuse and overuse. Some levers could operate effectively (and be politically viable) across many different health and political systems (eg, increase patient activation with decision support) whereas other levers must be tailored to local contexts (eg, basing coverage decisions on a particular cost-effectiveness ratio). Ideally, policies must move beyond the purely incremental; that is, policies that merely tinker at the policy edges after underuse or overuse arises. In this regard, efforts to increase public awareness, mobilisation, and empowerment hold promise as universal methods to reset all other contexts and thereby enhance all other efforts to promote the right care. PMID- 28077229 TI - Avoiding overuse-the next quality frontier. PMID- 28077230 TI - Addressing overuse and underuse around the world. PMID- 28077231 TI - From universal health coverage to right care for health. PMID- 28077232 TI - Evidence for underuse of effective medical services around the world. AB - Underuse-the failure to use effective and affordable medical interventions-is common and responsible for substantial suffering, disability, and loss of life worldwide. Underuse occurs at every point along the treatment continuum, from populations lacking access to health care to inadequate supply of medical resources and labour, slow or partial uptake of innovations, and patients not accessing or declining them. The extent of underuse for different interventions varies by country, and is documented in countries of high, middle, and low income, and across different types of health-care systems, payment models, and health services. Most research into underuse has focused on measuring solutions to the problem, with considerably less attention paid to its global prevalence or its consequences for patients and populations. Although focused effort and resources can overcome specific underuse problems, comparatively little is spent on work to better understand and overcome the barriers to improved uptake of effective interventions, and methods to make them affordable. PMID- 28077233 TI - Vikas Saini: leading activist in the Right Care Alliance. PMID- 28077235 TI - Drivers of poor medical care. AB - The global ubiquity of overuse and underuse of health-care resources and the gravity of resulting harms necessitate an investigation of drivers to inform potential solutions. We describe the network of influences that contribute to poor care and suggest that it is driven by factors that fall into three domains: money and finance; knowledge, bias, and uncertainty; and power and human relationships. In each domain the drivers operate at the global, national, regional, and individual level, and are modulated by the specific contexts within which they act. We discuss in detail drivers of poor care in each domain. PMID- 28077236 TI - High-resolution ultrahigh-pressure long column reversed-phase liquid chromatography for top-down proteomics. AB - Separation of proteoforms for global intact protein analysis (i.e. top-down proteomics) has lagged well behind what is achievable for peptides in traditional bottom-up proteomic approach and is becoming a true bottle neck for top-down proteomics. Herein, we report use of long (>=1M) columns containing short alkyl (C1-C4) bonded phases to achieve high-resolution RPLC for separation of proteoforms. At a specific operation pressure limit (i.e., 96.5MPa or 14Kpsi used in this work), column length was found to be the most important factor for achieving maximal resolution separation of proteins when 1.5-5MUm particles were used as packings and long columns provided peak capacities greater than 400 for proteoforms derived from a global cell lysate with molecular weights below 50kDa. Larger proteoforms (50-110kDa) were chromatographed on long RPLC columns and detected by MS; however, they cannot be identified yet by tandem mass spectrometry. Our experimental data further demonstrated that long alkyl (e.g., C8 and C18) bonded particles provided high-resolution RPLC for <10kDa proteoforms, not efficient for separation of global proteoforms. Reversed-phase particles with porous, nonporous, and superficially porous surfaces were systematically investigated for high-resolution RPLC. Pore size (200-400A) and the surface structure (porous and superficially porous) of particles was found to have minor influences on high-resolution RPLC of proteoforms. RPLC presented herein enabled confident identification of ~900 proteoforms (1% FDR) for a low microgram quantity of proteomic samples using a single RPLC-MS/MS analysis. The level of RPLC performance attained in this work is close to that typically realized in bottom-up proteomics, and broadly useful when applying e.g., the single-stage MS accurate mass tag approach, but less effective when combined with current tandem MS. Our initial data indicate that MS detection and fragmentation inefficiencies provided by current high-resolution mass spectrometers are key challenges for characterization of larger proteoforms. PMID- 28077234 TI - Evidence for overuse of medical services around the world. AB - Overuse, which is defined as the provision of medical services that are more likely to cause harm than good, is a pervasive problem. Direct measurement of overuse through documentation of delivery of inappropriate services is challenging given the difficulty of defining appropriate care for patients with individual preferences and needs; overuse can also be measured indirectly through examination of unwarranted geographical variations in prevalence of procedures and care intensity. Despite the challenges, the high prevalence of overuse is well documented in high-income countries across a wide range of services and is increasingly recognised in low-income countries. Overuse of unneeded services can harm patients physically and psychologically, and can harm health systems by wasting resources and deflecting investments in both public health and social spending, which is known to contribute to health. Although harms from overuse have not been well quantified and trends have not been well described, overuse is likely to be increasing worldwide. PMID- 28077239 TI - The versatility of the Karapandzic flap: A review of 65 cases with patient reported outcomes. AB - OBJECTIVE: The Karapandzic flap is an established technique for reconstruction of large lip defects and in our experience is particularly valuable in repair of the upper lateral lip and the commissures as well. We present our experience in a case series of 65 patients under one consultant. METHOD: This is a retrospective study of patients who underwent Karapandzic flap repair for lip defects following cancer resection from 2007 to 2014 in North Yorkshire. A data collection tool was used which incorporated patient demographics, tumour location, histology, complications, resection margins and recurrence including functional and aesthetic outcomes. The Patient and Observer Scar Assessment Scale (POSAS) was used to assess postoperative outcome at more than 1 year. RESULTS: The clearance rate was 98.4%. For those with a follow-up greater than 1 year, there was no recurrence or surgical revision, whilst the most common concern was temporary lip paraesthesia. The mean POSAS scores were low for both patients and observers reflecting a high satisfaction rate. CONCLUSION: The technique of Karapandzic flap reconstruction for defects in both upper and lower lip allows adequate margin clearance with a low level of complications. The advantages of this technique include preservation of both function and sensation utilising local tissue to allow successful aesthetic outcomes. PMID- 28077238 TI - Patterns of Care and Clinical Outcomes in Patients With Metastatic Renal Cell Carcinoma-Results From a Tertiary Cancer Center in India. AB - INTRODUCTION: The current treatment of metastatic renal cell carcinoma (mRCC) revolves around targeted agents, which have resulted in a median overall survival of 22 to 26 months in registration trials. However, the outcomes in a non-trial, real-world Indian population have not yet been evaluated. MATERIALS AND METHODS: The present study was a part of a prospective Clinical Trials Registry-India registered study, the Kidney Cancer Registry, a prospectively maintained kidney cancer registry. The data of patients with a diagnosis of mRCC from February 2007 to August 2015 who were potential candidates for systemic therapy were extracted from the database and analyzed for treatment patterns and outcomes. RESULTS: The data from 212 patients were eligible for analysis. Of these 212 patients, 204 (96.2%) received first-line systemic treatment with sunitinib (40.6%), sorafenib (37.7%), pazopanib (2.8%), temsirolimus (2.8%), or everolimus (1.9%). The risk status of 91% of the patients could be stratified using the Heng criteria into favorable (18.9%), intermediate (43.9%), and poor risk (28.3%) categories. The response rate, clinical benefit rate, median progression-free survival, and median overall survival with first-line targeted therapy were 22.5%, 60.7%, 7.09 months, and 12.87 months, respectively. The common adverse events seen included skin rash (31.7%), hypertension (29.4%), grade 3 hand-foot syndrome (27.4%), mucositis (26.4%), dyslipidemia (20%), and hyperglycemia (17.6%). Patients receiving second-line therapy (22.6%) had superior overall survival to patients who had not (16.46 vs. 10.67 months; P = .032). CONCLUSION: The present registry based study is the first, to the best of our knowledge, of its type from India and showed that the overall outcomes in this real-world cohort appear comparable to non-trial data worldwide. An increased incidence of metabolic adverse events that require monitoring during treatment was also found. PMID- 28077240 TI - Association between community pharmacy loyalty and persistence and implementation of antipsychotic treatment among individuals with schizophrenia. AB - BACKGROUND: Non-adherence is a major obstacle to optimal treatment of schizophrenia. Community pharmacists are in a key position to detect non adherence and put in place interventions. Their role is likely to be more efficient when individuals are loyal to a single pharmacy. OBJECTIVE: To assess the association between the level of community pharmacy loyalty and persistence with and implementation of antipsychotic drug treatment among individuals with schizophrenia. METHODS: A cohort study using databases from the Quebec health insurance board (Canada) was conducted among new antipsychotic users insured by Quebec's public drug plan. Level of community pharmacy loyalty was assessed as the number of pharmacies visited in the year after antipsychotics initiation. Persistence was defined as having an antipsychotic supply in the user's possession on the 730th day after its initiation and implementation as having antipsychotics in the user's possession for >=80% of the days in the second year after antipsychotics initiation (among persistent only). Generalized linear models were used to estimate adjusted prevalence ratios (aPR) and 95% confidence intervals (95%CI). RESULTS: 6,251 individuals were included in the cohort and 54.1% had their drug prescriptions filled in >1 pharmacy. When compared to those who had their prescriptions filled in a single pharmacy, those who had their prescriptions filled in >=4 different pharmacies were 22% more likely to be non persistent (aPR = 1.22; 95%CI = 1.10-1.37) and 49% more likely to have an antipsychotic for <80% of the days (aPR = 1.49; 95%IC = 1.28-1.74). CONCLUSION: This first exploration of community pharmacy loyalty in the context of severe mental illness indicates that this healthcare organisation factor might be associated with antipsychotics persistence and implementation. Identification of individuals with low community pharmacy loyalty and initiatives to optimize community pharmacy loyalty could contribute to enhanced persistence and implementation. PMID- 28077241 TI - The role of splenectomy in autoimmune hematological disorders: Outdated or still worth considering? PMID- 28077237 TI - Interplay of extracellular matrix and leukocytes in lung inflammation. AB - During inflammation, leukocytes influx into lung compartments and interact with extracellular matrix (ECM). Two ECM components, versican and hyaluronan, increase in a range of lung diseases. The interaction of leukocytes with these ECM components controls leukocyte retention and accumulation, proliferation, migration, differentiation, and activation as part of the inflammatory phase of lung disease. In addition, bronchial epithelial cells from asthmatic children co cultured with human lung fibroblasts generate an ECM that is adherent for monocytes/macrophages. Macrophages are present in both early and late lung inflammation. Matrix metalloproteinase 10 (MMP10) is induced in alveolar macrophages with injury and infection and modulates macrophage phenotype and their ability to degrade collagenous ECM components. Collectively, studies outlined in this review highlight the importance of specific ECM components in the regulation of inflammatory events in lung disease. The widespread involvement of these ECM components in the pathogenesis of lung inflammation make them attractive candidates for therapeutic intervention. PMID- 28077242 TI - Outbreak of Elizabethkingia meningoseptica sepsis with meningitis in a well-baby nursery. AB - Between March and May 2012, three neonates born at a regional maternity hospital developed Elizabethkingia meningoseptica (previously Chryseobacterium meningosepticum) sepsis with meningitis aged <10 days, and were treated successfully with intravenous ciprofloxacin plus vancomycin or piperacillin tazobactam for three to six weeks. Four (16.6%) of 24 environmental specimens obtained from the nursery and delivery room were positive for this organism. All of the clinical isolates and two isolates from storage boxes for pacifiers and pacifier covers were genetically identical. After changing the storage boxes to stainless steel boxes that underwent regular autoclave sterilization, there were no further cases of infection with E. meningoseptica. PMID- 28077243 TI - Effective use of oral ribavirin for respiratory syncytial viral infections in allogeneic haematopoietic stem cell transplant recipients. AB - BACKGROUND: Respiratory syncytial virus (RSV) is a frequent cause of respiratory viral infections, increasing the morbidity and mortality in allogeneic haematopoietic stem cell transplantation (HSCT) recipients. Little is known about the best management strategy in this immunocompromised group and there are very few data on oral ribavirin treatment. AIM: To evaluate the effectiveness of oral ribavirin in allogeneic HSCT patients with RSV infection. METHODS: Twenty-three RSV cases treated with oral ribavirin were analysed retrospectively. RSV diagnosis was established by polymerase chain reaction assay. Oral ribavirin was initiated at 15 mg/kg/day in three divided doses for 10 days, with no subsequent dose escalation, as per centre policy. FINDINGS: At diagnosis, seven patients presented with lower respiratory tract infection (RTI), whereas 16 had upper RTI. Oral ribavirin was well tolerated with minor adverse effects. The median treatment duration was 10 days (range: 5-47). After a median follow-up of 17 months (range: 4-48), 17 patients are alive. We recorded one RSV-related and five non-related deaths. CONCLUSION: To our knowledge, this is the largest single centre study yet performed on adult allogeneic HSCT recipients with RSV infection treated with oral ribavirin. Prompt initiation of treatment is essential and may avoid hospital admission. Our experience supports the use of oral ribavirin, but large prospective studies are needed to determine the optimal therapy in this patient group. PMID- 28077244 TI - The CatSper channel modulates boar sperm motility during capacitation. AB - The cation channel of sperm (CatSper) comprises four transmembrane subunits specifically expressed in human, equine, murine and ovine spermatozoa, apparently implicated in capacitation, hyperactivation and acrosome exocytosis. Western blotting and immunocytochemistry showed hereby that CatSper subunits are also present in boar spermatozoa, primarily over the sperm neck, tail and cytoplasmic droplets; albeit CatSper -1 presented in addition some distribution over the membrane of the acrosome and CatSper -2 and -4 over the membrane of the post acrosome. The role of the Catsper channel in boar spermatozoa was investigated by extending the spermatozoa in media containing different calcium (Ca2+) availability and exposure to the capacitation-trigger bicarbonate, to progesterone or CatSper inhibitors (Mibefradil and NNC 55-0396), separately or sequentially, at physiological and toxicological doses. Extracellular Ca2+ availability, combined with bicarbonate exposure (capacitation-inducing conditions) decreased sperm motility, similarly to when spermatozoa incubated in capacitation-inducing conditions was exposed to Mibefradil and NNC 55-0396. Exposure of these spermatozoa to progesterone did not cause significant changes in sperm motility and nor did it revert its decrease induced by CatSper antagonists. In conclusion, the CatSper channel regulates sperm motility during porcine capacitation-related events in vitro. PMID- 28077245 TI - A systematic review of adrenarche as a sensitive period in neurobiological development and mental health. AB - Substantial hormonal and neurobiological changes occur during puberty, and are widely argued to render this period of life a sensitive period in terms of risk for mental health problems. However, there is a paucity of research focusing on adrenarche, the earlier phase of pubertal development. Furthermore, there is a limited understanding of the association between adrenarche and neural development during this phase of life. We systematically reviewed research examining human adrenarcheal development as operationalized by hormonal levels of DHEA and DHEA-S, in relation to indices of mental health (Systematic Review 1). We then reviewed the limited amount of literature that has examined the association between adrenarcheal development and brain structure or function (Systematic Review 2). In general, studies showed that earlier timing of adrenarche was associated with greater mental health symptoms, and there is emerging support that brain development plays a role in this relationship. However, several methodological inconsistencies were noted. We propose that future research in this area test a theoretical model of adrenarche as a sensitive period of neurobiological development, whereby timing of exposure to hormones interacts with brain development, biological sex, and psychosocial stress to influence environmental sensitivity and risk for mental health problems through adolescence. PMID- 28077246 TI - Testing of a palatable bait and compatible vaccine carrier for the oral vaccination of European badgers (Meles meles) against tuberculosis. AB - The oral vaccination of wild badgers (Meles meles) with live Bacillus Calmette Guerin (BCG) is one of the tools being considered for the control of bovine tuberculosis (caused by Mycobacterium bovis) in the UK. The design of a product for oral vaccination requires that numerous, and often competing, conditions are met. These include the need for a highly palatable, but physically stable bait that will meet regulatory requirements, and one which is also compatible with the vaccine formulation; in this case live BCG. In collaboration with two commercial bait companies we have developed a highly attractive and palatable bait recipe designed specifically for European badgers (Meles meles) that meets these requirements. The palatability of different batches of bait was evaluated against a standardised palatable control bait using captive badgers. The physical properties of the bait are described e.g. firmness and colour. The microbial load in the bait was assessed against European and US Pharmacopoeias. The bait was combined with an edible vaccine carrier made of hydrogenated peanut oil in which BCG vaccine was stable during bait manufacture and cold storage, demonstrating <0.5 log10 reduction in titre after 117weeks' storage at -20 degrees C. BCG stability in bait was also evaluated at +4 degrees C and under simulated environmental conditions (20 degrees C, 98% Relative Humidity; RH). Finally, iophenoxic acid biomarkers were utilised as a surrogate for the BCG vaccine, to test variants of the vaccine-bait design for their ability to deliver biomarker to the gastrointestinal tract of individual animals. These data provide the first detailed description of a bait-vaccine delivery system developed specifically for the oral vaccination of badgers against Mycobacterium bovis using live BCG. PMID- 28077247 TI - Mouse DNA polymerase iota lacking the forty-two amino acids encoded by exon-2 is catalytically inactive in vitro. AB - In 2003, we reported that 129-derived strains of mice carry a naturally occurring nonsense mutation at codon 27 of the Poli gene that would produce a poliota peptide of just 26 amino acids, rather then the full-length 717 amino acid wild type polymerase. In support of the genomic analysis, no poliota protein was detected in testes extracts from 129X1/SvJmice, where wild-type poliota is normally highly expressed. The early truncation in poliota occurs before any structural domains of the polymerase are synthesized and as a consequence, we reasoned that 129-derived strains of mice should be considered as functionally defective in poliota activity. However, it has recently been reported that during the maturation of the Poli mRNA in 129-derived strains, exon- 2 is sometimes skipped and that an exon-2-less poliota protein of 675 amino acids is synthesized that retains catalytic activity in vitro and in vivo. From a structural perspective, we found this idea untenable, given that the amino acids encoded by exon-2 include residues critical for the coordination of the metal ions required for catalysis, as well as the structural integrity of the DNA polymerase. To determine if the exon-2-less poliota isoform possesses catalytic activity in vitro, we have purified a glutathione-tagged full-length exon-2-less (675 amino acid) poliota protein from baculovirus infected insect cells and compared the activity of the isoform to full-length (717 amino acid) GST-tagged wild-type mouse poliota in vitro. Reaction conditions were performed under a range of magnesium or manganese concentrations, as well as different template sequence contexts. Wild-type mouse poliota exhibited robust characteristic properties previously associated with human poliota's biochemical properties. However, we did not detect any polymerase activity associated with the exon-2-less poliota enzyme under the same reaction conditions and conclude that exon-2-less poliota is indeed rendered catalytically inactive in vitro. PMID- 28077248 TI - Alternative splicing at exon 2 results in the loss of the catalytic activity of mouse DNA polymerase iota in vitro. AB - Y-family DNA polymerase iota (Pol iota) possesses both DNA polymerase and dRP lyase activities and was suggested to be involved in DNA translesion synthesis and base excision repair in mammals. The 129 strain of mice and its derivatives have a natural nonsense codon mutation in the second exon of the Pol iota gene resulting in truncation of the Pol iota protein. These mice were widely used as a Pol iota-null model for in vivo studies of the Pol iota function. However whether 129-derived strains of mice are fully deficient in the Pol iota functions was a subject of discussion since Pol iota mRNA undergoes alternative splicing at exon 2. Here we report purification of mouse Pol iota lacking the region encoded by exon 2, which includes several conserved residues involved in catalysis. We show that the deletion abrogates both the DNA polymerase and dRP lyase activities of Pol iota in the presence of either Mg2+ or Mn2+ ions. Thus, 129-derived strains of mice express catalytically inactive alternatively spliced Pol iota variant, whose cellular functions, if any exist, remain to be established. PMID- 28077249 TI - Altered mucosal expression of microRNAs in pediatric patients with inflammatory bowel disease. AB - INTRODUCTION: MicroRNAs (miRs) came recently into focus as promising novel research targets offering new insights into the pathogenesis of inflammatory bowel diseases (IBD). AIMS: The aim of our study was to identify a pediatric IBD (pIBD) characteristic miR profile serving as potential Crohn's disease (CD) and ulcerative colitis (UC) specific diagnostic pattern and to further analyze the related target genes. METHODS: Small RNA sequencing was performed on inflamed and intact colonic biopsies of CD, and control patients. Selected miRs were further investigated by RT-PCR, complemented with an UC group, in order to address the differential diagnostic potential of miRs in the two IBD subtypes. To analyze network connection of differentially expressed miRs and their target genes MiRTarBase database and previous transcriptome sequencing data from pediatric patient groups were used. RESULTS: Sequencing analysis identified 170 miRs with altered expression. RT-PCR analysis revealed altered expression of miR-31, -125a, -142-3p, and -146a discriminating between the inflamed mucosa of CD and UC. In the intact mucosa of CD patients the expression of miR-18a, -20a, -21, -31, -99a, -99b, -100, -125a, -126, -142-5p, -146a, -185, -204, -221, and -223 was elevated compared to the controls. The expression of miR-20a, -204 and -221 was elevated exclusively in the intact region of CD patients compared to the controls. Enrichment analysis identified main IBD-related functional groups. CONCLUSIONS: We demonstrated a characteristic colonic miR pattern in pIBD that could facilitate deeper understanding of the pathomechanism of IBD and may serve as a diagnostic tool. PMID- 28077250 TI - Role of video-head impulse test in lateralization of vestibulopathy: Comparative study with caloric test. AB - OBJECTIVE: To evaluate the lateralization value of video head-impulse test (vHIT) for the diagnosis of vestibulopathy and to analyze cases showing dissociated results with caloric test. METHODS: In total, 19 healthy volunteers and 92 dizzy patients who underwent both a caloric test and a vHIT were enrolled. Patients were divided into two groups depending on their fluctuating pattern of vertigo. The vestibulo-ocular reflex (VOR) gain and gain asymmetry (GA) of a vHIT as well as unilateral weakness (UW) and the sum of the slow-phase velocities (SPVs) of warm and cold irrigation of the same side were compared. A cutoff value of VOR gain of a vHIT was also calculated using a receiver-operating characteristic curve. RESULTS: A VOR gain in an affected ear and GA of a vHIT showed a statistically significant correlation with UW in a caloric test. The cutoff value of a vHIT was determined to be 0.875, derived under the assumption that UW of a caloric test <=25% is normal. However, the parameters of the two tests were dissociated in 18%. CONCLUSION: A VOR gain of vHIT is a valuable objective parameter with a lateralization value determining vestibular hypofunction. However, considering substantial dissociation between a vHIT and a caloric test, these tests can be complementary tools for the lateralization of vestibular impairment for the comprehensive evaluation of patients' VOR. PMID- 28077251 TI - Theoretical Implications of a Pre-Erythrocytic Plasmodium vivax Vaccine for Preventing Relapses. AB - Preventing malaria infection through vaccination requires preventing every sporozoite inoculated by mosquito bite: a major challenge for Plasmodium falciparum. Plasmodium vivax sporozoites consist of tachysporozoites causing primary infection and bradysporozoites leading to relapses. We hypothesise that a candidate P. vivax vaccine with low efficacy against primary infection may substantially reduce transmission by preventing relapses. PMID- 28077252 TI - Incorporating body-type (apple vs. pear) in STOP-BANG questionnaire improves its validity to detect OSA. AB - STUDY OBJECTIVE: The aim of this study is to evaluate whether adding the item of "apple body type" to the STOP-BANG questionnaire enhances diagnostic performance of the questionnaire for detecting obstructive sleep apnea (OSA). DESIGN: Cross sectional study. SETTING: Sleep center setting. PATIENTS: Two hundred and eight subjects who were referred for an evaluation of possible OSA at Tulane Comprehensive Sleep Center. The exclusion criteria were age<18years old, incomplete or absent questionnaire, incomplete body type identification, polysomnography (PSG) refusal, and pregnant women. INTERVENTIONS: STOP-BANG items and body type data were collected on the initial clinic visit. An overnight PSG was performed on every participant. MEASUREMENTS: Descriptive analyses of the demographic data and PSG variables were performed. The predictive parameters of STOP and STOP-BANG without and with body type score (STOP-Apple and STOPBANG Apple) were compared. MAIN RESULTS: The STOP questionnaire's sensitivity/specificity/positive likelihood ratio (+LR) (cut-off=2) was 96%/11%/1.1, respectively whereas the STOP-Apple questionnaire (cut-off=3) was 88%/39%/1.5. The STOP-BANG's sensitivity/specificity/+LR (cut-off=3) was 96%/19%/1.2, respectively whereas the STOP-BANG-Apple questionnaire (cut-off=4) was 90%/39%/1.5. The area under the Receiver Operating Characteristic (ROC) curve of STOP-Apple was comparable to the STOP-BANG (P=0.25). The addition of the apple body type item to the STOP-BANG questionnaire in participants with a score>=3 led to increased specificity (67.4%), increased the odds ratio of having OSA of 2.5 (95% CI, 1.2-5.3) and odds ratio of having moderate-severe OSA of 4.7 (95% CI, 2.5-8.7). CONCLUSION: In the sleep center setting, adding the body type item to the STOP-BANG questionnaire improves not only clinical prediction for PSG confirmed OSA but also predicts moderate to severe of OSA. PMID- 28077253 TI - A survey of patients with bed bugs in the emergency department. AB - Bed bugs are one of the most important human ectoparasites in the United States, and a growing problem in the emergency department. We evaluated 40 emergency department (ED) patients found with a bed bug. The data show that ED patients with bed bugs are statistically more likely to be male, older, more likely to be admitted to the hospital, have higher triage emergency severity index (ESI) scores, and arrive by ambulance than the general ED patient population (p<0.05). On average bed bugs were found 108min after a patient arrived to the ED, after 35% of subjects had already received a blood draw, and after 23% had already received a radiology study; putting other ED patients and staff at risk for acquiring the infestation. We found that 13% and 18% of subjects had wheezing and a papular rash, respectively on physical exam. Of those patients found with a bed bug in the ED, 42% reported having bed bugs at home and 21% reporting having a possible home infestation. PMID- 28077254 TI - Use of the smartphone for end vertebra selection in scoliosis. AB - OBJECTIVES: The aim of our study was to develop a smartphone-aided end vertebra selection method and to investigate its effectiveness in Cobb angle measurement. METHODS: Twenty-nine adolescent idiopathic scoliosis patients' pre-operative posteroanterior scoliosis radiographs were used for end vertebra selection and Cobb angle measurement by standard method and smartphone-aided method. Measurements were performed by 7 examiners. The intraclass correlation coefficient was used to analyze selection and measurement reliability. Summary statistics of variance calculations were used to provide 95% prediction limits for the error in Cobb angle measurements. A paired 2-tailed t test was used to analyze end vertebra selection differences. RESULTS: Mean absolute Cobb angle difference was 3.6 degrees for the manual method and 1.9 degrees for the smartphone-aided method. Both intraobserver and interobserver reliability were found excellent in manual and smartphone set for Cobb angle measurement. Both intraobserver and interobserver reliability were found excellent in manual and smartphone set for end vertebra selection. But reliability values of manual set were lower than smartphone. Two observers selected significantly different end vertebra in their repeated selections for manual method. CONCLUSION: Smartphone aided method for end vertebra selection and Cobb angle measurement showed excellent reliability. We can expect a reduction in measurement error rates with the widespread use of this method in clinical practice. LEVEL OF EVIDENCE: Level III, Diagnostic study. PMID- 28077255 TI - The problem with incidental and chronic portal vein thrombosis. PMID- 28077256 TI - Montivipera bornmuelleri venom selectively exhibits high cytotoxic effects on keratinocytes cancer cell lines. AB - CONTEXT: The Viperidae family venom is a rich source of bioactive compounds such as many proteases, which cause tissue necrosis and affect mostly the vascular system. However, the venom exhibits therapeutic potentials and has contributed to the development of some medical drugs. Specifically, the Montivipera bornmuelleri venom has shown to exhibit antibacterial, pro-inflammatory and antifungal activities. OBJECTIVE: This work evaluates the cytotoxic effect of the M. bornmuelleri venom on human-derived keratinocytes including the non-tumorigenic HaCaT, the benign A5 and the low-grade malignant II4 cells. MATERIALS AND METHODS: The toxicity of different venom concentrations (0.9, 1.87, 3.75, 7.5, 15, 30 and 60MUg/mL) and their effect on the viability of the cells lines were assessed using the Lactate Dehydrogenase (LDH) activity and the Trypan blue tests after 24h of incubation. RESULTS: The venom was able to reduce the viability of all cell lines in a dose dependent manner with the HaCat cells being the least affected. For example, the 60MUg/mL dose induced a more significant decrease the viability of A5 (44%) and II4 (21.33%) keratinocytes as compared to HaCaT cells (70.63%). Also, this venom showed a higher cytotoxic activity on the A5 (52.45%) and II4 (98.67%) cells as compared to HaCaT cells (30.14%) with an IC50 estimated at 10MUg/mL on II4 and at 60MUg/mL on benign A5. DISCUSSION AND CONCLUSION: Those differential cytotoxic effects of the M. bornmuelleri venom pave the road for more advanced studies which might unravel the potential anticancer effects of this venom. PMID- 28077257 TI - Real-world effectiveness and safety of dapagliflozin therapy added to a GLP1 receptor agonist in patients with type 2 diabetes. AB - BACKGROUND AND AIM: To evaluate the effectiveness and safety of a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, dapagliflozin, in patients with type 2 diabetes mellitus (T2DM) and background glucagon-like peptide-1 receptor agonist (GLP1-RA) therapy. METHODS AND RESULTS: This is a 12-month, real-world observational study, which assessed the effectiveness and safety of dapagliflozin in patients with T2DM and background GLP1-RA therapy. The main outcome measures were changes in A1C and weight at 6 and 12 months from baseline. Secondary outcomes were differences in A1C and weight reduction between this cohort and another group of patients with T2DM treated with dapagliflozin but without background GLP1-RA therapy. In total, 109 patients with GLP1-RA and 104 patients without GLP1-RA were included. Baseline mean A1C and weight in the GLP1-RA and non-GLP1-RA groups were 7.4% vs. 7.3% and 96.2 kg vs. 95.1 kg, respectively. A significant reduction in A1C was seen with dapagliflozin in both cohorts at 6 and 12 months (GLP1-RA: -0.51% and -0.34%, non-GLP1-RA: -0.69% and -0.62%, respectively, p < 0.0001 in all analyses). Weight was significantly reduced in both groups at 6 and 12 months (GLP1-RA: -2.3 kg and -2.4 kg, non-GLP1-RA: -3.9 kg and -4.8 kg, respectively, p < 0.0001 in all analyses). A1C reduction and weight loss were significantly lower in patients with GLP1-RA than in patients without GLP1-RAs. Drug discontinuation rates were similar in both cohorts. CONCLUSIONS: Dapagliflozin, when added in real life to patients with T2DM treated with GLP1-RAs, induced a further significant, albeit modest improvement in A1C and a further weight loss. PMID- 28077258 TI - Discovery of new MurA inhibitors using induced-fit simulation and docking. AB - We report on the successful application of ProBiS-CHARMMing web server in the discovery of new inhibitors of MurA, an enzyme that catalyzes the first committed cytoplasmic step of bacterial peptidoglycan synthesis. The available crystal structures of Escherichia coli MurA in the Protein Data Bank have binding sites whose small volume does not permit the docking of drug-like molecules. To prepare the binding site for docking, the ProBiS-CHARMMing web server was used to simulate the induced-fit effect upon ligand binding to MurA, resulting in a larger, more holo-like binding site. The docking of a filtered ZINC compound library to this enlarged binding site was then performed and resulted in three compounds with promising inhibitory potencies against MurA. Compound 1 displayed significant inhibitory potency with IC50 value of 1MUM. All three compounds have novel chemical structures, which could be used for further optimization of small molecule MurA inhibitors. PMID- 28077259 TI - The growth of language: Universal Grammar, experience, and principles of computation. AB - Human infants develop language remarkably rapidly and without overt instruction. We argue that the distinctive ontogenesis of child language arises from the interplay of three factors: domain-specific principles of language (Universal Grammar), external experience, and properties of non-linguistic domains of cognition including general learning mechanisms and principles of efficient computation. We review developmental evidence that children make use of hierarchically composed structures ('Merge') from the earliest stages and at all levels of linguistic organization. At the same time, longitudinal trajectories of development show sensitivity to the quantity of specific patterns in the input, which suggests the use of probabilistic processes as well as inductive learning mechanisms that are suitable for the psychological constraints on language acquisition. By considering the place of language in human biology and evolution, we propose an approach that integrates principles from Universal Grammar and constraints from other domains of cognition. We outline some initial results of this approach as well as challenges for future research. PMID- 28077260 TI - Third-party social evaluations of humans by monkeys and dogs. AB - Developmental psychologists are increasingly interested in young children's evaluations of individuals based on third-party interactions. Studies have shown that infants react negatively to agents who display harmful intentions toward others, and to those who behave unfairly. We describe experimental studies of capuchin monkeys' and pet dogs' differential reactions to people who are helpful or unhelpful in third-party contexts, and monkeys' responses to people who behave unfairly in exchanges of objects with a third party. We also present evidence that capuchin monkeys monitor the context of failures to help and violations of reciprocity, and that intentionality is one factor underlying their social evaluations of individuals whom they see interacting with others. We conclude by proposing some questions for studies of nonhuman species' third party-based social evaluations. PMID- 28077261 TI - Ventral medullary control of rapid eye movement sleep and atonia. AB - Discrete populations of neurons at multiple levels of the brainstem control rapid eye movement (REM) sleep and the accompanying loss of postural muscle tone, or atonia. The specific contributions of these brainstem cell populations to REM sleep control remains incompletely understood. Here we show in rats that viral vector-based lesions of the ventromedial medulla at a level rostral to the inferior olive (pSOM) produced violent myoclonic twitches and abnormal electromyographic spikes, but not complete loss of tonic atonia, during REM sleep. Motor tone during non-REM (NREM) sleep was unaffected in these same animals. Acute chemogenetic activation of pSOM neurons in rats robustly and selectively suppressed REM sleep but not NREM sleep. Similar lesions targeting the more rostral ventromedial medulla (RVM) did not affect sleep or atonia, while chemogenetic stimulation of the RVM produced wakefulness and reduced sleep. Finally, selective activation of vesicular GABA transporter (VGAT) pSOM neurons in mice produced complete suppression of REM sleep whereas their loss increased EMG spikes during REM sleep. These results reveal a key contribution of the pSOM and specifically the VGAT+ neurons in this region in REM sleep and motor control. PMID- 28077262 TI - Virus Innexins induce alterations in insect cell and tissue function. AB - Polydnaviruses are dsDNA viruses that induce immune and developmental alterations in their caterpillar hosts. Characterization of polydnavirus gene families and family members is necessary to understand mechanisms of pathology and evolution of these viruses, and may aid to elucidate the role of host homologues if present. For example, the polydnavirus vinnexin gene family encodes homologues of insect gap junction genes (innexins) that are expressed in host immune cells (hemocytes). While the roles of Innexin proteins and gap junctions in insect immunity are largely unclear, we previously demonstrated that Vinnexins form functional gap junctions and alter the junctional characteristics of a host Innexin when co-expressed in paired Xenopus oocytes. Here, we test the effect of ectopic vinnexin expression on host cell physiology using both a lepidopteran cell culture model and a dipteran whole organism model. Vinnexin expression in the cell culture system resulted in gene-specific alterations in cell morphology and a slight, but non-statistically significant, reduction in gap junction activity as measured by dye transfer, while ectopic expression of a lepidopteran innexin2 gene led to morphological alterations and increase in gap junction activity. Global ectopic expression in the model dipteran, Drosophila melanogaster, of one vinnexin (vinnexinG) or D. melanogaster innexin2 (Dm-inx2) resulted in embryonic lethality, while expression of the other vinnexin genes had no effect. Furthermore, ectopic expression of vinnexinG, but not other vinnexin genes or Dm-inx2, in D. melanogaster larval gut resulted in developmental arrest in the pupal stage. These data indicate the vinnexins likely have gene-specific roles in host manipulation. They also support the use of Drosophila in further analysis of the role of Vinnexins and other polydnavirus genes in modifying host physiological processes. Finally, our findings suggest the vinnexin genes may be useful to perturb and characterize the physiological functions of insect Innexins. PMID- 28077263 TI - Learning in mosquito larvae (Aedes aegypti): Habituation to a visual danger signal. AB - In spite of the mosquito Aedes aegypti being a vector of several infectious diseases, a limited number of studies has been undertaken on learning in this species. Moreover, larval stages have been neglected as model organisms, although they are active, aquatic and perform stereotyped behavioural responses, e.g. the escape response when disturbed. To study the learning abilities of mosquito larvae, we focused on habituation, a form of non-associative learning widely studied in vertebrates and invertebrates. Habituation was defined as the progressive and reversible decrease in response to a reiterative stimulus. We first aimed at confirming habituation of the escape response in mosquito larvae (4th instar). Then, we determined whether a mnesic trace was established. Larvae were individually stimulated with a visual danger stimulus inducing the escape response. We set up a protocol for testing larvae individually, allowing the control of different parameters that are crucial for the study of cognitive abilities. After 15 trials, the escape response of mosquitoes was significantly lower. A disturbance stimulus presented after the 15th trial, induced the escape response and reversed habituation. Retention was confirmed up to 1h after the last habituation trial. This original bioassay can be adapted for studying the physiology of learning and memory in mosquito larvae, for analysing the effects of chemicals in the water, the characterisation of the cognitive abilities related to the life history of different mosquito species across preimaginal stages. PMID- 28077264 TI - Self-assembly of green tea catechin derivatives in nanoparticles for oral lycopene delivery. AB - Lycopene is a natural anti-oxidant that has attracted much attention due to its varied applications such as protection against loss of bone mass, chronic diseases, skin cancer, prostate cancer, and cardiovascular disease. However, high instability and extremely low oral bioavailability limit its further clinical development. We selected a green tea catechin derivative, oligomerized (-) epigallocatechin-3-O-gallate (OEGCG) as a carrier for oral lycopene delivery. Lycopene-loaded OEGCG nanoparticles (NPs) were prepared by a nano-precipitation method, followed by coating with chitosan to form a shell. This method not only can easily control the size of the NP to be around 200nm to improve its bioavailability, but also can effectively protect the lycopene against degradation due to EGCG's anti-oxidant property. OEGCG was carefully characterized with nuclear magnetic resonance spectroscopy and mass spectrometry. Lycopene-loaded polylactic-co-glycolic acid (PLGA) NPs were prepared by the same method. Chitosan-coated OEGCG/lycopene NPs had a diameter of 152+/-32nm and a zeta-potential of 58.3+/-4.2mv as characterized with transmission electron microscopy and dynamic light scattering. The loading capacity of lycopene was 9% and encapsulation efficiency was 89%. FT-IR spectral analysis revealed electrostatic interaction between OEGCG and chitosan. Freeze drying of the NPs was also evaluated as a means to improve shelf life. Dynamic light scattering data showed that no aggregation occurred, and the size of the NP increased 1.2 times (Sf/Si ratio) in the presence of 10% sucrose after freeze drying. The in vitro release study showed slow release of lycopene in simulated gastric fluid at acidic pH and faster release in simulated intestinal fluid. In an in vivo study in mice, lycopene pharmacokinetic parameters were improved by lycopene/OEGCG/chitosan NPs, but not improved by lycopene/PLGA/chitosan NPs. The self-assembled nanostructure of OEGCG combined with lycopene may be a promising application in oral drug delivery in various indications. PMID- 28077265 TI - A smart aminoglycoside hydrogel with tunable gel degradation, on-demand drug release, and high antibacterial activity. AB - Aminoglycosides are a family of critically important antibiotics for the treatment of serious infections including multidrug-resistant pathogens. However, clinical use of aminoglycoside antibiotics is compromised by bacterial biofilm formation at subinhibitory concentrations or adverse side effects such as ototoxicity and nephrotoxicity at high antibiotic doses. Preparation of aminoglycoside formulation that allows on-demand drug delivery is a solution to this sticky issue. Here, we designed a new type of aminoglycoside hydrogels by cross-linking oxidized polysaccharides such as dextran, carboxymethyl cellulose, alginate, and chondroitin using aminoglycosides as cross-linkers. The hydrogel modulus, degradation rate and release kinetics can be precisely modulated by tailoring the aminoglycoside dose during gel formation. The aminoglycoside hydrogel showed fast gelation, self-healing and on-demand drug release behaviors, and high antibacterial activities in vitro and in vivo against both Gram-positive and Gram-negative bacteria. This study provides a facile and promising strategy to develop smart hydrogels for topical administration of aminoglycoside antibiotics. PMID- 28077266 TI - ASP0028 in combination with suboptimal-dose of tacrolimus in Cynomolgus monkey renal transplantation model. AB - FTY720, a S1P-receptor modulator, has shown to be effective in several transplant and autoimmune disease models, via modulating lymphocyte homing into secondary lymphoid organs (SLOs), and thereby reducing these cells in peripheral blood. ASP0028, a newly developed S1P1/S1P5-selective agonist, presented comparable efficacy to FTY720 and wider safety margins than FTY720. In this study, we assessed the efficacy and safety of ASP0028 co-administered with suboptimal-dose of tacrolimus in the Cynomolgus monkey renal transplantation model. Seven animals in group-1 or group-2 received mono-tacrolimus 1.0mg/kg once a day (QD), or ASP0028 0.6mg/kg plus tacrolimus 1.0mg/kg QD, respectively. Eight animals in group-3 received ASP0028 1.2mg/kg plus tacrolimus 1.0mg/kg QD. The allograft median survival time (MST) in group-2 and group-3 were significantly extended to 41 and 61.5days, versus that of 28days in group-1 (p=0.036 and 0.001, respectively). ASP0028 administration remarkably reduced absolute numbers of peripheral lymphocytes, particularly subsets of CD4+/ or CD8+/naive and central memory cells, CD4+/Treg cells, and to a lesser extent on B cells, but not CD4+/ or CD8+/effector memory cells and NK cells. These data show ASP0028 combined with suboptimal-dose of tacrolimus effectively prolongs renal allograft survival in nonhuman primates (NHPs) with well tolerated safety, supporting its further investigation to optimize CNI-sparing regimens. PMID- 28077267 TI - Rapid whole brain myelin water content mapping without an external water standard at 1.5T. AB - The objective of this study is to develop rapid whole brain mapping of myelin water content (MWC) at 1.5T. The Fast Acquisition with Spiral Trajectory and T2prep (FAST-T2) pulse sequence originally developed for myelin water fraction (MWF) mapping was modified to obtain fast mapping of T1 and receiver coil sensitivity needed for MWC computation. The accuracy of the proposed T1 mapping was evaluated by comparing with the standard IR-FSE method. Numerical simulations were performed to assess the accuracy and reliability of the proposed MWC mapping. We also compared MWC values obtained with either cerebrospinal fluid (CSF) or an external water tube attached to the subject's head as the water reference. Our results from healthy volunteers show that whole brain MWC mapping is feasible in 7min and provides accurate brain T1 values. Regional brain WC and MWC measurements obtained with the internal CSF-based water standard showed excellent correlation (R>0.99) and negligible bias within narrow limits of agreement compared to those obtained with an external water standard. PMID- 28077269 TI - Association of an individual's ability to overcome desire to fall asleep with a higher anterior-posterior gradient in electroencephalographic indexes of sleep pressure. AB - Individual differences in ability to overcome desire to fall asleep cannot be accurately predicted from subjective and objective measurements of sleepiness level. Previously, we showed that an exponential buildup of sleep pressure during prolonged wakefulness can be accurately traced with electroencephalographic (EEG) indexes, such as Spectral Sleep Pressure Component (SSPC) score and score on the 2nd principal component (2PC) of the EEG spectrum. The anterior-posterior gradients in SSPC and 2PC scores were calculated as the differences between frontal and occipital scores and examined as possible correlates of individual's ability to overcome desire of falling asleep. Fifteen young and 15 older adults participated in two identically designed sleep deprivation experiments. After, at least, 12hours of wakefulness, resting EEG recordings were obtained from frontal and occipital derivations with 2-h intervals during 26-50hours. Due to irresistible desire to sleep, 11 young and 5 older adults completed <25 required EEG recordings. SSPC and 2PC scores were computed and, by subtracting occipital scores from frontal scores, the anterior-posterior gradients in SSPC and 2PC scores were calculated on one-min intervals of 5-min eyes closed EEG records. The analysis of these anterior-posterior gradients revealed their age-related difference and association with the number of completed EEG recording sessions (13-25). This association remained significant after accounting for age, alertness-sleepiness level, minute of eyes closed recording, and day of experiment. It seems that the anterior-posterior gradients in the EEG indexes of sleep pressure are the objective correlates of individual's ability to overcome desire to fall asleep. PMID- 28077270 TI - Instructions to suppress semantic memory enhances or has no effect on P300 in a concealed information test (CIT). AB - The present study investigated the extent to which people can suppress semantic memory as indexed with the P300 ERP and the autobiographical implicit association test (aIAT). In EXP 1, participants (22) were run in a counterbalanced repeated measures study in both simply knowledgeable (SK) and knowledgeable with suppression (SP) conditions. A P300-based, concealed information test ("Complex Trial Protocol"; CTP) with a 50/50 Target/Nontarget (T/NT) ratio was given both with and without instructions to suppress semantic memories. The results showed increased P300s to probe name stimuli, reduced (but still high positive) aIAT d scores, and increased simple reaction times to all stimuli used in ERP tests in the SP condition. EXP 2 was similar, but with SP and SK in two separate groups, and a 20/80 T/NT ratio. Again, ERP and aIAT results failed to show a suppression effect for semantic memory. The behavioral data suggest some task demand effects under suppression instructions, and that EXP 1 was more demanding than EXP 2. PMID- 28077268 TI - Development of high resolution 3D hyperpolarized carbon-13 MR molecular imaging techniques. AB - The goal of this project was to develop and apply techniques for T2 mapping and 3D high resolution (1.5mm isotropic; 0.003cm3) 13C imaging of hyperpolarized (HP) probes [1-13C]lactate, [1-13C]pyruvate, [2-13C]pyruvate, and [13C,15N2]urea in vivo. A specialized 2D bSSFP sequence was implemented on a clinical 3T scanner and used to obtain the first high resolution T2 maps of these different hyperpolarized compounds in both rats and tumor-bearing mice. These maps were first used to optimize timings for highest SNR for single time-point 3D bSSFP acquisitions with a 1.5mm isotropic spatial resolution of normal rats. This 3D acquisition approach was extended to serial dynamic imaging with 2-fold compressed sensing acceleration without changing spatial resolution. The T2 mapping experiments yielded measurements of T2 values of >1s for all compounds within rat kidneys/vasculature and TRAMP tumors, except for [2-13C]pyruvate which was ~730ms and ~320ms, respectively. The high resolution 3D imaging enabled visualization the biodistribution of [1-13C]lactate, [1-13C]pyruvate, and [2 13C]pyruvate within different kidney compartments as well as in the vasculature. While the mouse anatomy is smaller, the resolution was also sufficient to image the distribution of all compounds within kidney, vasculature, and tumor. The development of the specialized 3D sequence with compressed sensing provided improved structural and functional assessments at a high (0.003cm3) spatial and 2s temporal resolution in vivo utilizing HP 13C substrates by exploiting their long T2 values. This 1.5mm isotropic resolution is comparable to 1H imaging and application of this approach could be extended to future studies of uptake, metabolism, and perfusion in cancer and other disease models and may ultimately be of value for clinical imaging. PMID- 28077271 TI - Occupational exposure to pesticides, reproductive hormone levels and sperm quality in young Brazilian men. AB - The association of occupational exposure to current-use pesticides with reproductive hormones, semen quality, and genital measures was investigated among young men in the South of Brazil. A cross-sectional study was conducted in 99 rural and 36 urban men aged 18-23 years. Information on pesticide use was obtained through questionnaire. Serum and semen samples were analyzed for sex hormones and sperm parameters, respectively, and measurement of anogenital distance (AGD) and testis volume (TV) were performed. Associations were explored using multivariate linear regression. Rural men had poorer sperm morphology, higher sperm count, and lower LH levels relative to urban subjects. Lifetime use of pesticides, especially herbicides and fungicides, was associated with poorer morphology and reduced LH and prolactin, with evidence of a linear pattern. Maternal farming during pregnancy was associated with larger AGD and TV. Chronic occupational exposure to modern pesticides may affect reproductive outcomes in young men. PMID- 28077272 TI - Evaluation of sodium arsenite exposure on reproductive competence in pregnant and postlactational dams and their offspring. AB - We investigated arsenite exposure on the reproductive axis of dams (during pregnancy and at cyclicity resumption) and their offspring. Pregnant rats were exposed to 5 (A5) or 50ppm (A50) of sodium arsenite in drinking water from gestational day 1 (GD1) until sacrifice at GD18 or two months postpartum. Offspring were exposed to the same treatment as their mothers from weaning to adulthood. A50-pregnant rats gained less weight, showed increased testosterone and estradiol but pregnancy was unaffected. After lactation, arsenic-exposed dams presented compromised cyclicity, decreased estradiol, increased follicle stimulating hormone (FSH), less preovulatory follicles and presence of ovarian cysts, suggesting impaired reproduction. A50-offspring presented lower body weight; A50-female-offspring showed elevated gonadotropin releasing hormone (GnRH), FSH and testosterone, while A50-males showed diminished GnRH/FSH, but normal testosterone. We conclude that arsenite at the present exposure levels did not compromise pregnancy outcome while it negatively affected reproductive physiology in postpartum dams and their offspring. PMID- 28077273 TI - Reevaluating the mechanism of excitation energy regulation in iron-starved cyanobacteria. AB - This paper presents spectroscopic investigations of IsiA, a chlorophyll a-binding membrane protein produced by cyanobacteria grown in iron-deficient environments. IsiA, if associated with photosystem I, supports photosystem I in light harvesting by efficiently transferring excitation energy. However, if separated from photosystem I, IsiA exhibits considerable excitation quenching observed as a substantial reduction of protein-bound chlorophyll a fluorescence lifetime. Previous spectroscopic studies suggested that carotenoids are involved in excitation energy dissipation and in addition play a second role in this antenna complex by supporting chlorophyll a in light harvesting by absorbing in the spectral range inaccessible for chlorophyll a and transferring excitation to chlorophylls. However, this investigation does not support these proposed roles of carotenoids in this light harvesting protein. This study shows that carotenoids do not transfer excitation energy to chlorophyll a. In addition, our investigations do not support the hypothesis that carotenoids are quenchers of the excited state of chlorophyll a in this protein complex. We propose that quenching of chlorophyll a fluorescence in IsiA is maintained by pigment-protein interaction via electron transfer from an excited chlorophyll a to a cysteine residue, an excitation quenching mechanism that was recently proposed to regulate the light harvesting capabilities of the bacteriochlorophyll a-containing Fenna Mathews-Olson protein from green sulfur bacteria. PMID- 28077274 TI - The role and regulation of the peroxisome proliferator activated receptor alpha in human liver. AB - The peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand activated transcription factor that is abundantly expressed in liver. PPARalpha is activated by fatty acids and various other lipid species, as well as by a class of chemicals referred to as peroxisome proliferators. Studies in mice have shown that PPARalpha serves as the master regulator of hepatic lipid metabolism during fasting. In addition, PPARalpha suppresses inflammation and the acute phase response. Comparatively little is known about PPARalpha in human liver. Here, an overview is provided of the role and regulation of PPARalpha in human liver. The main outcomes are: 1) the level of PPARA mRNA expression in human and mouse liver is similar. 2) Expression of PPARA in human liver is reduced in patients with non-alcoholic steatohepatitis or infected with the hepatitis C virus. 3) PPARalpha in human liver is able to effectively induce the expression of numerous genes involved in numerous lipid metabolic pathways, including microsomal, peroxisomal and mitochondrial fatty acid oxidation, fatty acid binding and activation, fatty acid elongation and desaturation, synthesis and breakdown of triglycerides and lipid droplets, lipoprotein metabolism, gluconeogenesis, bile acid metabolism, and various other metabolic pathways and genes. 4) PPARalpha activation in human liver causes the down-regulation of a large number of genes involved in various immunity-related pathways. 5) Peroxisome proliferators do not promote tumour formation in human liver as opposed to mouse liver because of structural and functional differences between human and mouse PPARalpha. 6) In addition to helping to correct dyslipidemia, PPARalpha agonists may hold promise as a therapy for patients with cholestatic liver diseases, non-alcoholic fatty liver disease, and/or type 2 diabetes. PMID- 28077275 TI - Investigations of blood ammonia analysis: Test matrices, storage, and stability. AB - An assessment of blood ammonia concentration is common medical practice in the evaluation of an individual with an unexplained mental status change or coma. The determination of a blood ammonia level is most commonly done using a glutamate dehydrogenase (GLDH)-based assay, although there are many potential sources of artifact and the literature is inconsistent regarding key preanalytic issues. Using a GLDH-based assay, we first investigated matrix effects using three anticoagulants: heparin, EDTA and oxalate. Heparin-anticoagulated plasma was substantially less precise than EDTA- and oxalate-anticoagulated plasma. Oxalate anticoagulated plasma showed a greater baseline of apparent ammonia than either heparin- or EDTA-derived plasma, presumably due to interferants. We then evaluated the stability of EDTA-anticoagulated plasma for assessment of ammonia when stored at 4 degrees C,-14 degrees C or -70 degrees C. There was a linear increase of ammonia with storage at both 4 degrees C and -14 degrees C. Plasma kept at -70 degrees C for up to three weeks showed no change in measured ammonia relative to the baseline determination. This work clarifies preanalytic conditions for which a precise determination of ammonia can be accomplished using a GLDH-based assay. PMID- 28077276 TI - In vitro prediction of gastrointestinal absorption of novel beta-hydroxy-beta arylalkanoic acids using PAMPA technique. AB - Prediction of gastrointestinal absorption of thirteen newly synthesized beta hydroxy-beta-arylalkanoic acids (HAA) and ibuprofen was performed using PAMPA test. The highest values of PAMPA parameters (%T and Papp) were calculated for 1C, 1B and 2C and these parameters were significantly lower in comparison to ibuprofen. QSPR analysis was performed in order to identify molecular descriptors with the highest influence on %T and -logPapp and to create models which could be used for the design of novel HAA with improved gastrointestinal absorption. Obtained results indicate that introduction of branched side chain, as well as introduction of substituents on one phenyl ring (which disturb symmetry of the molecule) could have positive impact on gastrointestinal absorption. On the basis of these results, six novel HAA were designed and PAMPA parameters %T and logPapp were predicted by use of selected QSPR models. Designed derivatives should have better gastrointestinal absorption than HAA tested in this study. PMID- 28077277 TI - Berberine protects against ischemia/reperfusion injury after orthotopic liver transplantation via activating Sirt1/FoxO3alpha induced autophagy. AB - The effects and mechanism of berberine (BBR) on hepatic injury after orthotopic liver transplantation (OLT) have not been well characterized. We examined the role of Sirt1/FoxO3alpha axis in the protective effect of BBR on ischemia/reperfusion injury after OLT. Adult male Wistar rats were randomly allocated into four groups: Sham, OLT, OLT with BBR pretreatment (BBR), OLT with BBR and Sirt1 inhibitor (EX527) pretreatment group (EX527). The liver function and oxidative stress level were measured by biochemical and histopathologic examinations. The formation of autophagosome was observed by transmission electron microscopy. The apoptotic rate was determined by TUNEL analysis and the apoptotic mRNA expression. The expression of Sirt1, FoxO3alpha, Beclin-1, LC3 II/LC3-I, p62 and the acetylation of FoxO3alpha were assayed by western blot assay and immunoprecipitation. Compared with the OLT group, BBR dramatically attenuated the histopathologic damage, restored the liver function, and decreased the oxidative stress level. Simultaneously, BBR significantly ameliorated apoptosis by decreasing the apoptotic rate and the expression of apoptotic mRNA in rats subjected to OLT. The level of Beclin-1 and LC3-II/LC3-I were upregulated with the inhibition of p62. The deacetylation of FoxO3alpha by Sirt1 was enhanced in the nuclear of liver after pretreated with BBR. However, the inhibition of Sirt1 by EX527 counteracted the protective effects of BBR. Thus, BBR preconditioning promotes liver transplant ischemia/reperfusion injury partly via activating Sirt1/FoxO3alpha mediated autophagy. PMID- 28077279 TI - Homology analysis detects topological changes of Iba1 localization accompanied by microglial activation. AB - The state of microglial activation provides important information about the central nervous system. However, a reliable index of microglial activation in histological samples has yet to be established. Here, we show that microglial activation induces topological changes of Iba1 localization that can be detected by analysis based on homology theory. Analysis of homology was applied to images of Iba1-stained tissue sections, and the 0-dimentional Betti number (b0: the number of solid components) and the 1-dimentional Betti number (b1: the number of windows surrounded by solid components) were obtained. We defined b1/b0 as the Homology Value (HV), and investigated its validity as an index of microglial activation using cerebral ischemia model mice. Microglial activation was accompanied by changes to Iba1 localization and morphology of microglial processes. In single microglial cells, the change of Iba1 localization increased b1. Conversely, thickening or retraction of microglial processes decreased b0. Consequently, microglial activation increased the HV. The HV of a tissue area increased with proximity to the ischemic core and showed a high degree of concordance with the number of microglia expressing activation makers. Furthermore, the HV of human metastatic brain tumor tissue also increased with proximity to the tumor. These results suggest that our index, based on homology theory, can be used to correctly evaluate microglial activation in various tissue images. PMID- 28077278 TI - Oscillatory EEG activity induced by conditioning stimuli during fear conditioning reflects Salience and Valence of these stimuli more than Expectancy. AB - Imaging studies have described hemodynamic activity during fear conditioning protocols with stimulus trains in which a visual conditioned stimulus (CS+) is paired with an aversive unconditioned stimulus (US, painful laser pulse) while another visual stimulus is unpaired (CS-). We now test the hypothesis that CS Event Related Spectral Perturbations (ERSPs) are related to ratings of CS Expectancy (likelihood of pairing with the US), Valence (unpleasantness) and Salience (ability to capture attention). ERSP windows in EEG were defined by both time after the CS and frequency, and showed increased oscillatory power (Event Related Synchronization, ERS) in the Delta/Theta Windows (0-8Hz) and the Gamma Window (30-55Hz). Decreased oscillatory power (Event Related Desynchronization - ERD) was found in Alpha (8-14Hz) and Beta Windows (14-30Hz). The Delta/Theta ERS showed a differential effect of CS+ versus CS- at Prefrontal, Frontal and Midline Channels, while Alpha and Beta ERD were greater at Parietal and Occipital Channels early in the stimulus train. The Gamma ERS Window increased from habituation to acquisition over a broad area from frontal and occipital electrodes. The CS Valence and Salience were greater for CS+ than CS-, and were correlated with each other and with the ERD at overlapping channels, particularly in the Alpha Window. Expectancy and CS Skin Conductance Response were greater for CS+ than CS- and were correlated with ERSP at fewer channels than Valence or Salience. These results suggest that Alpha ERSP activity during fear conditioning reflects Valence and Salience of the CSs more than conditioning per se. PMID- 28077280 TI - Engineering out the noise. AB - The US Navy, through an Office of Naval Research (ONR) lead effort on Noise Induced Hearing Loss (NIHL), is investigating methods and techniques to mitigate hearing loss for the crews and warfighters. Hearing protection is a viable and increasingly popular method of reducing hearing exposure for many ship crew members; however, it has limitations on comfort and low frequency effectiveness. Furthermore, Personal Hearing Protection (PHP) is often used improperly. Proper vessel planning, programmatic changes and advances in noise control engineering can also have significant impacts by inherently reducing noise exposure through ship design and use of noise control treatments. These impacts go beyond hearing loss mitigation since they can improve quality of life onboard vessels and provide enhanced warfighter performance. Such approaches also can be made to work in the lower frequency range where hearing protection is not as effective. This paper describes non-hearing protection methods being implemented to mitigate and control noise within the US Navy and US Marine Corps. These approaches reflect the latest changes to Mil-Std 1474E, Appendix F. PMID- 28077281 TI - Does acute or habitual protein deprivation influence liking for monosodium glutamate? AB - The umami flavour generated by monosodium glutamate (MSG) has been proposed as the marker for the presence of protein in foods. As protein is the most closely regulated macronutrient in the diet, the present study addressed whether acute protein deprivation, habitual protein intake or a combination of the two influenced liking for the taste of MSG. 24 low-restraint male participants (mean age: 22; BMI: 23) consumed either their habitual breakfast (baseline), a low protein breakfast (breakfast meal with low protein milk and milkshake) or a high protein breakfast (breakfast meal with high protein milk and milkshake) on three different days, and then evaluated the acceptability of umami (MSG), salty (NaCl) or sweet (Acesulphame K) tastes at low or high concentrations in a soup context at lunchtime. Participants also completed a habitual protein intake questionnaire (39-item protein Food Frequency Questionnaire). Liking for all tastes was higher on the low than on the high protein day, and NaCl and Acesulphame K were liked less on both protein manipulation days when compared to the no added flavour control. Habitual protein intake was not related to liking for MSG stimuli alone but habitual high protein consumers rated a high concentration of MSG as more pleasant than any other taste when in protein deficit. Overall, these findings suggest that liking for high MSG concentrations may be moderated by nutritional need in high protein consumers. PMID- 28077282 TI - The changing face of bacteraemia in an HIV-1 positive cohort in the United Kingdom. PMID- 28077284 TI - Structural Biology of the Cvt Pathway. AB - Macroautophagy is a degradation process in which autophagosomes are generated to isolate and transport various materials, including damaged organelles and protein aggregates, as cargos to the lysosomes or vacuoles. Bulk autophagy is one of the two types of macroautophagy, which is triggered by starvation and targets non specific cargos. The second type, that is, selective autophagy, identifies and preferentially degrades specific cargos via receptor recognition. Cytoplasm-to vacuole targeting (Cvt) is a selective autophagy pathway that specifically transports vacuolar hydrolases into the vacuole in budding yeast cells and has been extensively studied as a model of selective autophagy. In the present review, we focused on the Cvt pathway, especially on the recent structural insights into cargo assembly, receptor recognition, and recruitment mechanisms of the Cvt machinery. Elucidating the Cvt pathway would help in understanding the basic molecular mechanisms of various types of selective autophagy. PMID- 28077283 TI - Aetiology of febrile pharyngitis in children: Potential of myxovirus resistance protein A (MxA) as a biomarker of viral infection. AB - OBJECTIVES: Besides group A streptococcus (GAS), microbial causes of pharyngitis in children are not well known. We aimed to document the viral and bacterial aetiology of pharyngitis and to assess the pathogenic role of viruses by determining the myxovirus resistance protein A (MxA) in the blood as a marker of interferon response. METHODS: In this prospective observational study, throat swabs and blood samples were collected from children (age 1-16 years) presenting to the emergency department with febrile pharyngitis. Microbial cause was sought by bacterial culture, polymerase chain reaction, and serology. Blood MxA level was determined. RESULTS: A potential pathogen was detected in 88% of 83 patients: GAS alone in 10%, GAS and viruses in 13%, group C or G streptococci alone in 2% and together with viruses in 3%, and viruses alone in 59% of cases. Enteroviruses, rhinoviruses, and adenoviruses were the most frequently detected viruses. Blood MxA levels were higher in children with viral (880 [245-1250] MUg/L; median [IQR]) or concomitant GAS-viral (340 [150-710] MUg/L) than in those with sole GAS (105 [80-160] MUg/L) infections. CONCLUSIONS: Detection of respiratory viruses simultaneously with elevated blood MxA levels supports the causative role of viruses in the majority of children with pharyngitis. PMID- 28077285 TI - A Fluorophore Fusion Construct of Human Profilin I with Non-Compromised Poly(L Proline) Binding Capacity Suitable for Imaging. AB - Profilin is vital for actin organisation in eukaryotic cells. It controls actin filament formation by binding monomeric actin and numerous proteins involved in polarised actin assembly. Important for the latter is the interaction surface formed by the N- and C-terminal helices, which pack close to each other on one side of the molecule at a distance from the actin site and mediate binding to poly-proline sequences present in many of the targeted proteins. Via these interactions, profilin contributes to the spatiotemporal control of actin filament growth. Studies of profilin dynamics in living cells by imaging techniques have been hampered by problems to generate fusion constructs with fluorophore proteins without negatively impacting on its poly-proline binding. With the object to circumvent this problem, we have generated an internal fusion of profilin with the green fluorescent variant citrine, here referred to as citrine-profilin. The characterisation of citrine-profilin (CIT-Pfn) demonstrates that it has full capacity to interact with poly-proline and also binds phosphatidylinositol lipids and actin, albeit with 10 times reduced affinity for the latter. Imaging of living cells expressing CIT-Pfn showed a distribution of the fusion protein similar to endogenous profilin. Furthermore, CIT-Pfn rescued the phenotypes observed after the Crispr/Cas9 knockout of the profilin 1 gene, including the lost migratory capacity characterising the knockout cells. Based on this, we conclude that the CIT-Pfn construct will be useful as a tool for displaying profilin localisation in living cells and obtaining information on its dynamic organisation under different conditions and activations of the actin microfilament and microtubule systems. PMID- 28077286 TI - Assessment of neuroanatomical and behavioural effects of in ovo methylmercury exposure in zebra finches (Taeniopygia guttata). AB - Methylmercury (MeHg) readily crosses the blood brain barrier and is a known neuro toxicant. MeHg accumulation in the brain causes histopathological alterations, neurobehavioral changes, and impairments to cognitive motor functions in mammalian models. However, in birds the neurotoxic effects of MeHg on the developing pre-hatching brain and consequent behavioral alterations in adult birds have not received much attention. Moreover, passerine birds are poorly represented in MeHg neurotoxicology studies in comparison to other avian orders. Hence in this study, we used the egg injection method to investigate the long term effects of in ovo MeHg exposure on brain histopathology and courtship behavior in a model songbird species, the zebra finch (Taeniopygia guttata). Egg treatment groups included: a low MeHg dose of 0.2MUg Hg g-1 egg, a high MeHg dose of 3.2MUg Hg g-1 egg, and a vehicle control (water). No adverse effects of in ovo MeHg treatment were detected on courtship song quality or on mating behavior in experimental males at sexually maturity which would suggest that observable neurobehavioral effects of MeHg exposure may depend on the timing of exposure during offspring development. However, neuroanatomical analysis indicated an increase in telencephalon volume with increased MeHg concentrations which may suggest a prolonged inflammatory response in this region of the brain. PMID- 28077287 TI - Iron oxide nanoparticles modulate heat shock proteins and organ specific markers expression in mice male accessory organs. AB - With increased industrial utilization of iron oxide nanoparticles (Fe2O3-NPs), concerns on adverse reproductive health effects following exposure have been immensely raised. In the present study, the effects of Fe2O3-NPs exposure in the seminal vesicle and prostate gland were studied in mice. Mice were exposed to two different doses (25 and 50 mg/kg) of Fe2O3-NPs along with the control and analyzed the expressions of heat shock proteins (HSP60, HSP70 and HSP90) and organ specific markers (Caltrin, PSP94, and SSLP1). Fe2O3-NPs decreased food consumption, water intake, and organo-somatic index in mice with elevated iron levels in serum, urine, fecal matter, seminal vesicle and prostate gland. FTIR spectra revealed alterations in the functional groups of biomolecules on Fe2O3 NPs treatment. These changes are accompanied by increased lactate dehydrogenase levels with decreased total protein and fructose levels. The investigation of oxidative stress biomarkers demonstrated a significant increase in reactive oxygen species, nitric oxide, lipid peroxidation, protein carbonyl content and glutathione peroxidase with a concomitant decrement in the glutathione and ascorbic acid in the male accessory organs which confirmed the induction of oxidative stress. An increase in NADPH-oxidase-4 with a decrease in glutathione-S transferase was observed in the seminal vesicle and prostate gland of the treated groups. An alteration in HSP60, HSP70, HSP90, Caltrin, PSP94, and SSLP1 expression was also observed. Moreover, accumulation of Fe2O3-NPs brought pathological changes in the seminal vesicle and prostate gland of treated mice. These findings provide evidence that Fe2O3-NPs could be an environmental risk factor for reproductive disease. PMID- 28077288 TI - Micro-endoscopic system for functional assessment of neural circuits in deep brain regions: Simultaneous optical and electrical recordings of auditory responses in mouse's inferior colliculus. AB - In vivo Ca2+ imaging is a powerful method for the functional assessment of neural circuits. Although multi-photon excitation fluorescence microscopy has been widely used, observation of circuits in deep brain regions remains challenging. Recently, observing these deep regions has become possible via an endoscope consisting of an optical fiber bundle or gradient-index lens. We have designed a micro-endoscope system that enables simultaneous optical recording of fluorescence and electrical recording of neural activity. Using this system, we recorded auditory responses by simultaneously detecting changes in the fluorescence intensity of a Ca2+ indicator dye, multi-unit activities (MUA), and local field potentials (LFP) in the mouse's inferior colliculus (IC). Such simultaneous optical and electrical recordings enabled detailed comparison of electrically recorded phenomena (MUA and LFP) and optically recorded Ca2+ response. By systematically changing sound frequency and intensity, we determined the frequency tuning of the recording site. The best frequency shifted higher as the probe advanced more deeply, demonstrating that the system is capable of optically measuring the dorso-ventral organization of IC (i.e., tonotopicity). Thus, our new micro-endoscope system will be useful in the neurophysiological studies of a wide range of brain circuits, including those within the auditory system. PMID- 28077290 TI - Hidden symmetries of DNA molecule. AB - Despite the fact that DNA molecule is studied up and down, we know very little about the role of DNA triplets in coding amino acids and stop-codons. The paper aims to fill this gap through attracting spintronic ideas and carrying out QM/MM computations on a full-turn DNA fragment. The computations reveal two hidden symmetries: the spin splitting (the Rashba effect), confined within each triplet, and the quantum "phase" link between the triplet nature (in total, 64 triplets) and the corresponding amino acid and three stop-codons. The hidden symmetries become evident upon binding the magnesium cofactor to DNA triplets in 5'-3' and 3'-5' directions. PMID- 28077289 TI - Vitamin D3 protects against Abeta peptide cytotoxicity in differentiated human neuroblastoma SH- SY5Y cells: A role for S1P1/p38MAPK/ATF4 axis. AB - Besides its classical function of bone metabolism regulation, 1alpha, 25 dihydroxyvitamin D3 (1,25(OH)2D3), acts on a variety of tissues including the nervous system, where the hormone plays an important role as neuroprotective, antiproliferating and differentiating agent. Sphingolipids are bioactive lipids that play critical and complex roles in regulating cell fate. In the present paper we have investigated whether sphingolipids are involved in the protective action of 1,25(OH)2D3. We have found that 1,25(OH)2D3 prevents amyloid-beta peptide (Abeta(1-42)) cytotoxicity both in differentiated SH-SY5Y human neuroblastoma cells and in vivo. In differentiated SH-SY5Y cells, Abeta(1-42) strongly reduces the sphingosine-1-phosphate (S1P)/ceramide (Cer) ratio while 1,25(OH)2D3 partially reverts this effect. 1,25(OH)2D3 reverts also the Abeta(1 42)-induced reduction of sphingosine kinase activity. We have also studied the crosstalk between 1,25(OH)2D3 and S1P signaling pathways downstream to the activation of S1P receptor subtype S1P1. Notably, we found that 1,25(OH)2D3 prevents the reduction of S1P1 expression promoted by Abeta(1-42) and thereby it modulates the downstream signaling leading to ER stress damage (p38MAPK/ATF4). Similar effects were observed by using ZK191784. In addition, chronic treatment with 1,25(OH)2D3 protects from aggregated Abeta(1-42)-induced damage in the CA1 region of the rat hippocampus and promotes cell proliferation in the hippocampal dentate gyrus of adult mice. In conclusion, these results represent the first evidence of the role of 1,25(OH)2D3 and its structural analogue ZK191784 in counteracting the Abeta(1-42) peptide-induced toxicity through the modulation of S1P/S1P1/p38MAPK/ATF4 pathway in differentiated SH-SY5Y cells. PMID- 28077291 TI - In vitro dentin barrier cytotoxicity testing of some dental restorative materials. AB - OBJECTIVES: To investigate the cytotoxicity of four dental restorative materials in three-dimensional (3D) L929 cell cultures using a dentin barrier test. METHODS: The cytotoxicities of light-cured glass ionomer cement (Vitrebond), total-etching adhesive (GLUMA Bond5), and two self-etching adhesives (GLUMA Self Etch and Single Bond Universal) were evaluated. The permeabilities of human dentin disks with thicknesses of 300, 500, and 1000MUm were standardized using a hydraulic device. Test materials and controls were applied to the occlusal side of human dentin disks. The 3D-cell scaffolds were placed beneath the dentin disks. After a 24-h contact with the dentin barrier test device, cell viabilities were measured by performing MTT assays. Statistical analysis was performed using the Mann-Whitney U test. RESULTS: The mean (SD) permeabilities of the 300-MUm, 500-MUm, and 1000-MUm dentin disks were 0.626 (0.214), 0.219 (0.0387) and 0.089 (0.028) MUlmin-1cm-2cm H2O-1. Vitrebond was severely cytotoxic, reducing the cell viability to 10% (300-MUm disk), 17% (500MUm), and 18% (1000MUm). GLUMA Bond5 reduced the cell viability to 40% (300MUm), 83% (500MUm), and 86% (1000MUm), showing moderate cytotoxicity (300-MUm) and non-cytotoxicity (500-MUm and 1000 MUm). Single Bond Universal and GLUMA Self Etch did not significantly reduce cell viability, regardless of the dentin thicknesses, which characterized them as non cytotoxic. CONCLUSIONS: Cytotoxicity varied with the materials tested and the thicknesses of the dentin disks. CLINICAL SIGNIFICANCE: The tested cytotoxicity of materials applied on 300-, 500-, and 1000-MUm dentin disks indicates that the clinical use of the test materials (excepting self-etching adhesives) in deep cavities poses a potential risk of damage to the pulp tissues to an extent, depending on the thickness of the remaining dentin. PMID- 28077292 TI - General and specific factors in the processing of faces. AB - The ability to recognize faces varies considerably between individuals, but does performance co-vary for tests of different aspects of face processing? For 397 participants (of whom the majority were university students) we obtained scores on the Mooney Face Test, Glasgow Face Matching Test (GFMT), Cambridge Face Memory Test (CFMT) and Composite Face Test. Overall performance was significantly correlated for each pair of tests, and we suggest the term f for the factor underlying this pattern of positive correlations. However, there were large variations in the amount of variance shared by individual tests: The GFMT and CFMT are strongly related, whereas the GFMT and the Mooney test tap largely independent abilities. We do not replicate a frequently reported relationship between holistic processing (from the Composite test) and face recognition (from the CFMT)-indeed, holistic processing does not correlate with any of our tests. We report associations of performance with digit ratio and autism-spectrum quotient (AQ), and from our genome-wide association study we include a list of suggestive genetic associations with performance on the four face tests, as well as with f. PMID- 28077293 TI - Autophagosome Maturation and Fusion. AB - Macroautophagy, or simply autophagy, is a degradative pathway that delivers cytoplasmic components, including cytosol and organelles, to the lysosome in double-membrane vesicles called autophagosomes. This process is initiated at the pre-autophagosomal structure or phagophore assembly site and involves a number of highly conserved autophagy-related proteins. These support the generation and conversion of an open membranous cistern known as the phagophore or isolation membrane into a closed autophagosome. Within this review, we will focus on recent insights into the molecular events following the sealing/completion of an autophagosome, which lead to its maturation and subsequent fusion with endosomes/lysosomes. PMID- 28077294 TI - Into the golden anniversary of the yellow journal. PMID- 28077295 TI - Improved mucoadhesive properties of self-nanoemulsifying drug delivery systems (SNEDDS) by introducing acyl chitosan. AB - This study was aimed to improve the mucoadhesive properties of SNEDDS by the incorporation of acyl chitosan including octanoyl chitosan (OC), lauroyl chitosan (LC) and palmitoyl chitosan (PC). SNEDDS and acyl chitosan SNEDDS were characterized regarding droplet size and zeta potential. Their mucoadhesivity on porcine intestinal mucosa was evaluated by falling liquid film technique using Sudan Red G as marker. Degree of substitution of chitosan was determined to be 52.8%, 64.8 and 48.5% for OC, LC and PC, respectively. SNEDDS and acyl chitosan SNEDDS displayed a droplet size less than 50nm and 80-300nm as well as a zeta potential of -0.2 to -1.6 and 0.05 to 0.99mV, respectively. Introducing 2% acyl chitosan into SNEDDS increased the residence time of SNEDDS on intestinal mucosa 2-fold. It is concluded that due to the incorporation of acyl chitosan into SNEDDS, their mucoadhesive properties can be increased. PMID- 28077296 TI - Extracellular vesicle communication pathways as regulatory targets of oncogenic transformation. AB - Pathogenesis of human cancers bridges intracellular oncogenic driver events and their impact on intercellular communication. Among multiple mediators of this 'pathological connectivity' the role of extracellular vesicles (EVs) and their subsets (exosomes, ectosomes, oncosomes) is of particular interest for several reasons. The release of EVs from cancer cells represents a unique mechanism of regulated expulsion of bioactive molecules, a process that also mediates cell-to cell transfer of lipids, proteins, and nucleic acids. Biological effects of these processes have been implicated in several aspects of cancer-related pathology, including tumour growth, invasion, angiogenesis, metastasis, immunity and thrombosis. Notably, the emerging evidence suggests that oncogenic mutations may impact several aspects of EV-mediated cell-cell communication including: (i) EV release rate and protein content; (ii) molecular composition of cancer EVs; (iii) the inclusion of oncogenic and mutant macromolecules in the EV cargo; (iv) EV mediated release of genomic DNA; (v) deregulation of mechanisms responsible for EV biogenesis (vesiculome) and (vi) mechanisms of EV uptake by cancer cells. Intriguingly, EV-mediated intercellular transfer of mutant and oncogenic molecules between subpopulations of cancer cells, their indolent counterparts and stroma may exert profound biological effects that often resemble (but are not tantamount to) oncogenic transformation, including changes in cell growth, clonogenicity and angiogenic phenotype, or cause cell stress and death. However, several biological barriers likely curtail a permanent horizontal transformation of normal cells through EV-mediated mechanisms. The ongoing analysis and targeting of EV-mediated intercellular communication pathways can be viewed as a new therapeutic paradigm in cancer, while the analysis of oncogenic cargo contained in EVs released from cancer cells into biofluids is being developed for clinical use as a biomarker and companion diagnostics. Indeed, studies are underway to further explore the multiple links between molecular causality in cancer and various aspects of cellular vesiculation. PMID- 28077297 TI - Exosomes: Key mediators of metastasis and pre-metastatic niche formation. AB - While tumour cells are classically known to communicate via direct cell-to-cell contact and the secretion of soluble protein-based factors such as cytokines and growth factors, alternative novel mechanisms that promote tumour progression have recently emerged. Now, new critical components of the secretome thought to be involved in tumour progression are exosomes, small vesicles of endocytic origin that carry a variety of bioactive molecules, including proteins, lipids, RNA, as well as DNA molecules. Cancer cell-derived exosomes have been shown to participate in crucial steps of metastatic spread of a primary tumour, ranging from oncogenic reprogramming of malignant cells to formation of pre-metastatic niches. These effects are achieved through the mediation of intercellular cross talk and subsequent modification of both local and distant microenvironments in an autocrine and paracrine fashion. Here, we summarise the recent findings that implicate this non-canonical signalling within the tumour as a critical driver of metastatic disease progression, and discuss how understanding the molecular mechanisms involved in exosome-mediated metastasis is of great value for the development of new therapeutic strategies to prevent cancer progression. PMID- 28077299 TI - Anaplastic lymphoma kinase (ALK) inhibitors in the treatment of ALK-driven lung cancers. AB - Anaplastic lymphoma kinase is expressed in two-thirds of the anaplastic large cell lymphomas as an NPM-ALK fusion protein. Physiological ALK is a receptor protein-tyrosine kinase within the insulin receptor superfamily of proteins that participates in nervous system development. The EML4-ALK fusion protein and four other ALK-fusion proteins play a fundamental role in the development in about 5% of non-small cell lung cancers. The amino-terminal portions of the ALK fusion proteins result in dimerization and subsequent activation of the ALK protein kinase domain that plays a key role in the pathogenesis of various tumors. Downstream signaling from the ALK fusion protein leads to the activation of the Ras/Raf/MEK/ERK1/2 cell proliferation module and the JAK/STAT cell survival pathways. Moreover, nearly two dozen ALK activating mutations are involved in the pathogenesis of childhood neuroblastomas. The occurrence of oncogenic ALK-fusion proteins, particularly in non-small cell lung cancer, has fostered considerable interest in the development of ALK inhibitors. Crizotinib was the first such inhibitor approved by the US Food and Drug Administration for the treatment of ALK-positive non-small cell lung cancer in 2011. The median time for the emergence of crizotinib drug resistance is 10.5 months after the initiation of therapy. Such resistance prompted the development of second-generation drugs including ceritinib and alectinib, which are approved for the treatment of non small cell lung cancer. Unlike the single gatekeeper mutation that occurs in drug resistant epidermal growth factor receptor in lung cancer, nearly a dozen different mutations in the catalytic domain of ALK fusion proteins have been discovered that result in crizotinib resistance. Crizotinib, ceritinib, and alectinib form a complex within the front cleft between the small and large lobes of an inactive ALK protein-kinase domain with a compact activation segment. These drugs are classified as type I1/2 B inhibitors because they bind to an inactive enzyme and they do not extend past the gatekeeper into the back pocket of the drug binding site. PMID- 28077300 TI - Pharmacological strategies to target oncogenic KRAS signaling in pancreatic cancer. AB - The clear importance of mutated KRAS as a therapeutic target has driven the investigation of multiple approaches to inhibit oncogenic KRAS signaling at different molecular levels. However, no KRAS-targeted therapy has reached the clinic to date, which underlies the intrinsic difficulty in developing effective, direct inhibitors of KRAS. Thus, this article provides an overview of the history and recent progress in the development of pharmacological strategies to target oncogenic KRAS with small molecule agents. Mechanistically, these KRAS-targeted agents can be classified into the following four categories. (1) Small-molecule RAS-binding ligands that prevent RAS activation by binding within or outside the nucleotide-binding motif. (2) Inhibitors of KRAS membrane anchorage. (3) Inhibitors that bind to RAS-binding domains of RAS-effector proteins. (4) Inhibitors of KRAS expression. The advantage and limitation of each type of these anti-KRAS agents are discussed. PMID- 28077298 TI - The underestimated N-glycomes of lepidopteran species. AB - BACKGROUND: Insects are significant to the environment, agriculture, health and biotechnology. Many of these aspects display some relationship to glycosylation, e.g., in case of pathogen binding or production of humanised antibodies; for a long time, it has been considered that insect N-glycosylation potentials are rather similar and simple, but as more species are glycomically analysed in depth, it is becoming obvious that there is indeed a large structural diversity and interspecies variability. METHODS: Using an off-line LC-MALDI-TOF MS approach, we have analysed the N-glycomes of two lepidopteran species (the cabbage looper Trichoplusia ni and the gypsy moth Lymantria dispar) as well as of the commonly-used T. ni High Five cell line. RESULTS: We detected not only sulphated, glucuronylated, core difucosylated and Lewis-like antennal fucosylated structures, but also the zwitterion phosphorylcholine on antennal GlcNAc residues, a modification otherwise familiar from nematodes; in L. dispar, N glycans with glycolipid-like antennae containing alpha-linked N acetylgalactosamine were also revealed. CONCLUSION: The lepidopteran glycomes analysed not only display core alpha1,3-fucosylation, which is foreign to mammals, but also up to 5% anionic and/or zwitterionic glycans previously not found in these species. SIGNIFICANCE: The occurrence of anionic and zwitterionic glycans in the Lepidoptera data is not only of glycoanalytical and evolutionary interest, but is of biotechnological relevance as lepidopteran cell lines are potential factories for recombinant glycoprotein production. PMID- 28077301 TI - MiR-124 down-regulation is critical for cancer associated fibroblasts-enhanced tumor growth of oral carcinoma. AB - Cancer associated fibroblasts (CAFs) are known to be involved in initiation, progression and metastasis of various cancers. However, the molecular mechanism of how CAFs affects the biological function of oral cancer (OC) has not been fully-addressed. In this study, we demonstrated that miR-124 was downregulated in oral CAFs and oral cancer cells (OCCs) when compared with matched normal fibroblasts (NFs). Hypermethylation in the promoter region of miR-124 genes was accounted for its downregulation. Interestingly, CAFs but not NFs exerted promotion effect on OCCs cell proliferation, migration and tumor growth in CAFs/NFs-OCCs co-culture. Furthermore, we identified Chemokine (C-C motif) ligand 2 (CCL2) and Interleukin 8 (IL-8) as two direct targets of miR-124. Over expression of miR-124 in CAFs-OCCs co-culture abrogated CAFs-promoted OCCs cell growth and migration, and this inhibitory effect can be rescued by addition of CCL2 and IL-8. Finally, we showed that restoration of miR-124 expression by lentiviral infection or formulated miR-124 injection inhibited oral tumor growth in vivo suggesting miR-124 rescue could be a potential rationale for therapeutic applications in oral cancer in the future. PMID- 28077302 TI - Neutrophil adhesion and crawling dynamics on liver sinusoidal endothelial cells under shear flow. AB - Neutrophil (polymorphonuclear leukocyte, PMN) recruitment in the liver sinusoid takes place in almost all liver diseases and contributes to pathogen clearance or tissue damage. While PMN rolling unlikely appears in liver sinusoids and Mac-1 or CD44 is assumed to play respective roles during in vivo local or systematic inflammatory stimulation, the regulating mechanisms of PMN adhesion and crawling dynamics are still unclear from those in vivo studies. Here we developed a two dimensional in vitro sinusoidal model with primary liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs) to investigate TNF-alpha-induced PMN recruitment under shear flow. Our data demonstrated that LFA-1 dominates the static or shear resistant adhesion of PMNs while Mac-1 decelerates PMN crawling on LSEC monolayer. Any one of LFA-1, Mac-1, and CD44 molecules is not able to work effectively for mediating PMN transmigration across LSEC monolayer. The presence of KCs only affects the randomness of PMN crawling. These findings further the understandings of PMN recruitment under shear flow in liver sinusoids. PMID- 28077303 TI - Analysis and correction of field fluctuations in fMRI data using field monitoring. AB - This work investigates the role of magnetic field fluctuations as a confound in fMRI. In standard fMRI experiments with single-shot EPI acquisition at 3 Tesla the uniform and gradient components of the magnetic field were recorded with NMR field sensors. By principal component analysis it is found that differences of field evolution between the EPI readouts are explainable by few components relating to slow and within-shot field dynamics of hardware and physiological origin. The impact of fluctuating field components is studied by selective data correction and assessment of its influence on image fluctuation and SFNR. Physiological field fluctuations, attributed to breathing, were found to be small relative to those of hardware origin. The dominant confounds were hardware related and attributable to magnet drift and thermal changes. In raw image time series, field fluctuation caused significant SFNR loss, reflected by a 67% gain upon correction. Large part of this correction can be accomplished by traditional image realignment, which addresses slow and spatially uniform field changes. With realignment, explicit field correction increased the SFNR on the order of 6%. In conclusion, field fluctuations are a relevant confound in fMRI and can be addressed effectively by retrospective data correction. Based on the physics involved it is anticipated that the advantage of full field correction increases with field strength, with non-Cartesian readouts, and upon phase-sensitive BOLD analysis. PMID- 28077304 TI - Drosophila dorsal closure: An orchestra of forces to zip shut the embryo. AB - Dorsal closure, a late-embryogenesis process, consists in the sealing of an epidermal gap on the dorsal side of the Drosophila embryo. Because of its similarities with wound healing and neural tube closure in humans, it has been extensively studied in the last twenty years. The process requires the coordination of several force generating mechanisms, that together will zip shut the epidermis. Recent works have provided a precise description of the cellular behavior at the origin of these forces and proposed quantitative models of the process. In this review, we will describe the different forces acting in dorsal closure. We will present our current knowledge on the mechanisms generating and regulating these forces and report on the different quantitative mathematical models proposed so far. PMID- 28077305 TI - In utero exposure to fluoride and cognitive development delay in infants. AB - The objective of this study was to evaluate the association between in utero exposure to fluoride (F) and Mental and Psychomotor Development (MDI and PDI) evaluated through the Bayley Scale of Infant Development II (BSDI-II) in infants. The sample included 65 mother-infant pairs. Environmental exposure to F was quantified in tap and bottled water samples and F in maternal urine was the biological exposure indicator; samples were collected during the 1st, 2nd and 3rd trimester of pregnancy. The mean values of F in tap water for the 1st, 2nd and 3rd trimester were 2.6+/-1.1mg/l, 3.1+/-1.1mg/l and 3.7+/-1.0mg/l respectively; above to 80% of the samples exceeded the reference value of 1.5mg/l (NOM-127-SSA1 1994). Regarding F in maternal urine, mean values were 1.9+/-1.0mg/l, 2.0+/ 1.1mg/l and 2.7+/-1.1mg/l for the 1st, 2nd and 3rd trimester respectively. The infants with MDI and PDI scores less than 85 points were 38.5% and 20.9% respectively. After adjusting for potential confounding factors (gestational age, age of child, marginalization index and type of water for consumption), the MDI showed an inverse association with F levels in maternal urine for the first (beta=-19.05, p=0.04) and second trimester (beta=-19.34, p=0.01). Our data suggests that cognitive alterations in children born from exposed mothers to F could start in early prenatal stages of life. PMID- 28077306 TI - The interaction of dietary isoflavones and estradiol replacement on behavior and brain-derived neurotrophic factor in the ovariectomized rat. AB - Phytoestrogens are plant derived, non-steroidal compounds naturally found in rodent chows that potentially have endocrine-disrupting effects. Isoflavones, the most common phytoestrogens, have a similar structure and molecular weight to 17beta-estradiol (E2) and have the ability to bind and activate both isoforms of the estrogen receptor (ER). Most isoflavones have a higher affinity for ERbeta, which is involved in sexually dimorphic behavioral regulation. The goal of this study was to examine the interaction of isoflavones and E2 presence in the OVX rat on anxiety- and depressive- like behavior and the related BDNF pathophysiology. E2 administration resulted in anxiogenic behaviors when isoflavones were present in the diet (p<0.05), but anxiolytic behaviors when isoflavones were not present (p<0.05). E2 resulted in antidepressive-like behaviors in animals fed an isoflavone-rich diet (p<0.05), with no effect when isoflavones were removed. Increased hippocampal BDNF expression was observed in animals fed an isoflavone-rich diet after E2 administration (p<0.05). BDNF expression in the amygdala and hypothalamus was increased after E2 treatment in animals fed an isoflavone-rich diet. Overall, these results demonstrate that the presence of dietary isoflavones can differentially regulate the effect of E2 replacement on behavior and BDNF expression. PMID- 28077307 TI - Impulsivity and test meal intake among women with bulimia nervosa. AB - Many patients with bulimia nervosa (BN) also meet criteria for a lifetime alcohol use disorder (AUD). In order to understand possible mechanisms contributing to the co-occurrence and perpetuation of these disorders, this study investigated the importance of impulsivity and test meal intake among patients with BN by comparing women with BN only (n = 18), BN and current/past AUDs (n = 13), and healthy controls (n = 12). All participants completed assessments of eating disorder symptoms, frequency of alcohol use, binge eating, and purging via questionnaires and semi-structured interviews over two sessions. Measures of impulsivity consisted of computerized and self-report measures, and laboratory test meals. Significant differences between individuals with BN with/without comorbid AUDs were not found for test meal intake, impulsivity measures, or self reported psychological symptoms. As hypothesized, compared to healthy controls, individuals with BN had significantly higher scores on two subscales and the total score of the Barratt Impulsiveness Scale, a trait measure of impulsivity, and consumed significantly more calories in the binge instruction meal. Total Barratt Impulsiveness Scale scores were also significantly related to kcal consumed during the laboratory test meal when individuals were instructed to binge eat (BN groups). Data from this study add to the existing literature implicating impulsivity in the psychopathology of disorders of binge eating, including BN, and also support the use of laboratory meals as a symptom-specific measure of this trait in eating disorder populations. PMID- 28077308 TI - Cookie or fruit? Relative reinforcing value of snack foods among preschoolers with overweight/obesity compared to healthy weight. AB - The reinforcing value of food is an important determinant of food intake. Research has yet to examine the relative reinforcing value (RRV) of snack foods in young children with overweight and obesity (OW/OB). The current study compared the RRV of high-energy dense foods (cookies) to low-energy dense foods (fruits) between preschoolers with OW/OB and healthy weight (HW). RRV of cookies and fruits in preschoolers with OW/OB (n = 30; Mage = 4.4 +/- 0.84; 60% male) and HW (n = 30; Mage = 4.5 +/- 0.85; 70% male) was assessed with a developmentally tailored computer program which used a progressive fixed ratio reward schedule. The results showed that the RRV of cookies was significantly higher for preschoolers with OW/OB compared to HW while the RRV of fruits was significantly higher for preschoolers with HW compared to OW/OB. These results suggest that cookies are more reinforcing for preschoolers with OW/OB and less reinforcing for preschoolers with HW. Finding ways to reduce the reinforcing value of high-energy dense snack foods and identify alternatives that are as reinforcing for preschoolers is a challenge for weight control treatments. PMID- 28077309 TI - Physical and biological characteristics of multi drug resistance (MDR): An integral approach considering pH and drug resistance in cancer. AB - The role of the Warburg effect in cancer remains to be elucidated with a resurgence in research efforts over the past decade. Why a cancer cell would prefer to use energy inefficient glycolysis, leading to an alteration of pH both inside and outside of the cell, remains to be uncovered. The development of MDR represents a major challenge in the treatment of cancer and it is explained, so far, by the over expression of drug transporters such as the well-known and archetypal P-glycoprotein (Pgp). However, controversies exist regarding the function of Pgp in multi-drug resistance. We suggest here that Pgp-mediated MDR relies fundamentally on pH alterations mediated by the Warburg effect. Furthermore, we propose that the use of proton pump and/or transporters inhibitors (PPIs/PTIs) in cancer are key to controlling both MDR, i.e. sensitize tumors to antineoplastic agents, and drug-related adverse effects. PMID- 28077310 TI - Zebrafish let-7b acts downstream of hypoxia-inducible factor-1alpha to assist in hypoxia-mediated cell proliferation and cell cycle regulation. AB - AIMS: Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcriptional regulator of cellular responses to hypoxic stress. MicroRNAs (miRNAs) play an essential role in hypoxia-mediated cellular responses. Previous studies have identified some let-7 family members as hypoxia-regulated miRNAs (HRMs). In the present study, we aimed to investigate whether zebrafish let-7b/7f contribute cellular hypoxic response in a Hif-1alpha-dependent manner. MAIN METHODS: Stable suppression of zebrafish hif-1alpha was achieved by microinjection of an optimized short-hairpin RNA (shRNA) expression vector. Next-generation sequencing was conducted to characterize miRNA and mRNA expression profiles. MiRNA promoter analysis and target detection was performed by dual-luciferase assay. Quantitative real-time PCR (qRT-PCR) and western blot were used to determine the expression of let-7b/7f, Hif-1alpha and Foxh1. Proliferation of ZF4 cells was examined using Cell Counting Kit-8 (CCK-8) and cell cycle progression was analyzed by flow cytometry assay. KEY FINDINGS: Correlation between 7 miRNAs and 76 putative targets was identified based on integrated analysis of miRNA-mRNA profiles. Let-7b and let-7f were further considered as potential HRMs, with let 7b further validated as Hif-1alpha up-regulated. In addition, Forkhead-box H1 (Foxh1) was confirmed as a bona fide downstream target of let-7b. Furthermore, overexpression of both let-7b and let-7f repressed cell proliferation through blocking cell cycle progression of the G1-S transition. SIGNIFICANCE: Our findings for the first time suggest zebrafish let-7b acts downstream of Hif 1alpha to assist in hypoxia-mediated cell proliferation and cell cycle regulation at least in part through the downregulation of foxh1. We also identified 4 novel potential HIF-1alpha-regulated miRNAs in zebrafish. PMID- 28077311 TI - Cortical thickness increases after simultaneous interpretation training. AB - Simultaneous interpretation is a complex cognitive task that not only demands multilingual language processing, but also requires application of extreme levels of domain-general cognitive control. We used MRI to longitudinally measure cortical thickness in simultaneous interpretation trainees before and after a Master's program in conference interpreting. We compared them to multilingual control participants scanned at the same interval of time. Increases in cortical thickness were specific to trainee interpreters. Increases were observed in regions involved in lower-level, phonetic processing (left posterior superior temporal gyrus, anterior supramarginal gyrus and planum temporale), in the higher level formulation of propositional speech (right angular gyrus) and in the conversion of items from working memory into a sequence (right dorsal premotor cortex), and finally, in domain-general executive control and attention (right parietal lobule). Findings are consistent with the linguistic requirements of simultaneous interpretation and also with the more general cognitive demands on attentional control for expert performance in simultaneous interpreting. Our findings may also reflect beneficial, potentially protective effects of simultaneous interpretation training, which has previously been shown to confer enhanced skills in certain executive and attentional domains over and above those conferred by bilingualism. PMID- 28077312 TI - The effect of calf neuromuscular electrical stimulation and intermittent pneumatic compression on thigh microcirculation. AB - OBJECTIVE: This study compares the effectiveness of a neuromuscular electrical stimulation (NMES) device and an intermittent pneumatic compression (IPC) device on enhancing microcirculatory blood flow in the thigh of healthy individuals, when stimulation is carried out peripherally at the calf. MATERIALS AND METHODS: Blood microcirculation of ten healthy individuals was recorded using laser speckle contrast imaging (LSCI) technique. A region of interest (ROI) was marked on each participant thigh. The mean flux within the ROI was calculated at four states: rest, NMES device with visible muscle actuation (VMA), NMES device with no visible muscle actuation (NVMA) and IPC device. RESULTS: Both NMES and IPC devices increased blood flow in the thigh when stimulation was carried out peripherally at the calf. The NMES device increased mean blood perfusion from baseline by 399.8% at the VMA state and 150.6% at the NVMA state, IPC device increased the mean blood perfusion by 117.3% from baseline. CONCLUSION: The NMES device at VMA state increased microcirculation by more than a factor of 3 in contrast to the IPC device. Even at the NVMA state, the NMES device increased blood flow by 23% more than the IPC device. Given the association between increased microcirculation and reduced oedema, NMES may be a more effective modality than IPC at reducing oedema, therefore further research is needed to explore this. PMID- 28077313 TI - A kind of rd1 mouse in C57BL/6J mice from crossing with a mutated Kunming mouse. AB - We occasionally discovered a mouse with spontaneous retinitis pigmentosa (RP) from Kunming (KM) mouse breeding colony, with no obvious waveforms in ERG recordings. The aim of this study is to cross the spontaneously hereditary retinal degeneration mice (temporarily designated as KM/rd mice) derived from KM mice with C57BL/6J mice to establish a congenic inbred strain (temporarily designated as the B6/rd mice), and study the ocular phenotype and genotype of the mice. Fundus photography, tissue morphology, electroretinography (ERG), qRT-PCR, western blot and DNA sequence analysis were performed to observe the ocular phenotype and genotype of KM/rd and B6/rd mice. The fundus photography showed progressive retinal vascular degeneration and depigmentation in KM/rd and B6/rd mice. Compared to wild-type mice, the histological analysis revealed that the outer nuclear layer of the mutated mice was significantly reduced at 14days post born (P14), and almost disappeared by P21. No obvious waveforms were detected at P14 and P21 in the ERG from KM/rd and B6/rd mice. qRT-PCR results showed that the expression quantities of mRNA of pde6b gene in KM/rd and B6/rd mice were significantly lower compared with those of wild-type controls at P21. Western blot results confirmed an abnormal protein expression of pde6b gene in KM/rd and B6/rd mice with no protein products, while there was an obvious protein expression in wild-type mice. The nonsense mutation in exon 7 (a mutation that changes the codon 347 from TAC to TAA) in the pde6b gene of KM/rd and B6/rd mice was identified by genomic DNA sequence analysis. All these findings revealed that the ocular phenotype and genotype of KM/rd and B6/rd mice were similar to those of rd1 mice, which indicates that KM/rd and B6/rd mice can be used as an RP mouse model. PMID- 28077314 TI - Biological or pharmacological activation of protein kinase C alpha constrains hepatitis E virus replication. AB - Although hepatitis E has emerged as a global health issue, there is limited knowledge of its infection biology and no FDA-approved medication is available. Aiming to investigate the role of protein kinases in hepatitis E virus (HEV) infection and to identify potential antiviral targets, we screened a library of pharmacological kinase inhibitors in a cell culture model, a subgenomic HEV replicon containing luciferase reporter. We identified protein kinase C alpha (PKCalpha) as an essential cell host factor restricting HEV replication. Both specific inhibitor and shRNA-mediated knockdown of PKCalpha enhanced HEV replication. Conversely, over-expression of the activated form of PKCalpha or treatment with its pharmacological activator strongly inhibited HEV replication. Interestingly, upon the stimulation by its activator, PKCalpha efficiently activates its downstream Activator Protein 1 (AP-1) pathway, leading to the induction of antiviral interferon-stimulated genes (ISGs). This process is independent of the JAK-STAT machinery and interferon production. However, PKCalpha induced HEV inhibition appears independent of the AP1 cascade. The discovery that activated PKCalpha restricts HEV replication reveals new insight of HEV-host interactions and provides new target for antiviral drug development. PMID- 28077315 TI - Inhibition of iNOS alleviates cognitive deficits and depression in diabetic mice through downregulating the NO/sGC/cGMP/PKG signal pathway. AB - Diabetes mellitus often results in a number of complications involving impaired brain function, including cognitive deficits and depression. However, the potential mechanisms for diabetes-related cognitive deficits and depression are not fully understood. Neurons in the hippocampal, cortical and amygdala functional regions are more susceptible to damage during hyperglycemia. Neuroprotection in the brain can rescue cognitive deficits and depression induced by hyperglycemia. This study investigated the potential mechanisms underlying diabetes-related congnitive deficits and depression, determined whether the inflammatory factor inducible nitric oxide synthase (iNOS) and the nitric oxide (NO)/soluble guanylyl cyclases (sGC)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) pathway, play key roles in cognitive deficits and depression associated. In the present study, diabetic animal models were induced by streptozotocin (STZ, 150mg/kg) in mice, and aminoguanidine (AG), a selective inhibitor of iNOS, was given by intraperitoneal injection for 10 weeks. Blood glucose, activities of NOS and the levels of NO in serum and brain regions were measured. The spatial memory was detected using the Morris water maze test, depressive behavior was evaluated by the tail suspension test (TST), forced swimming test (FST), closed field test (CFT) and open field test (OFT). We also detected neuronal survival and cleaved caspase-3 positive ratios in three brain regions and the levels of iNOS, sGC, cGMP and PKG in hippocampus and frontal cortex. Data indicated that diabetic mice exerted impairments in spatial memory, decreased locomotor activity and increased immobile time in diabetic mice. In addition, diabetic mice had significantly decreased surviving neuronal density and showed signs of obvious neuronal injury in the hippocampus, frontal cortex and amygdala. iNOS overexpression and its associated signaling pathway NO/sGC/cGMP/PKG in the hippocampus and frontal cortex were implicated during hyperglycemia. However, AG improved the behavior disorders, reduced the activity of iNOS, protected nerve cells and inhibited the level of iNOS, sGC, PKG and cleaved caspase-3 in the hippocampus and cortex. These results suggested that iNOS/NO/sGC/cGMP/PKG signal pathway is a key feature of cognitive deficits and depression associated with diabetes. AG ameliorated cognitive deficits and depression in diabetic mice by exerting anti-inflammatory and neuroprotective effects by suppressing iNOS-associated signaling pathways. PMID- 28077318 TI - Alcohol, microbiome, life style influence alcohol and non-alcoholic organ damage. AB - This paper is based upon the "8th Charles Lieber's Satellite Symposium" organized by Manuela G. Neuman at the Research Society on Alcoholism Annual Meeting, on June 25, 2016 at New Orleans, Louisiana, USA. The integrative symposium investigated different aspects of alcohol-induced liver disease (ALD) as well as non-alcohol-induced liver disease (NAFLD) and possible repair. We revealed the basic aspects of alcohol metabolism that may be responsible for the development of liver disease as well as the factors that determine the amount, frequency and which type of alcohol misuse leads to liver and gastrointestinal diseases. We aimed to (1) describe the immuno-pathology of ALD, (2) examine the role of genetics in the development of alcoholic hepatitis (ASH) and NAFLD, (3) propose diagnostic markers of ASH and non-alcoholic steatohepatitis (NASH), (4) examine age and ethnic differences as well as analyze the validity of some models, (5) develop common research tools and biomarkers to study alcohol-induced effects, 6) examine the role of alcohol in oral health and colon and gastrointestinal cancer and (7) focus on factors that aggravate the severity of organ-damage. The present review includes pre-clinical, translational and clinical research that characterizes ALD and NAFLD. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD with simple fatty infiltrations and chronic alcoholic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes and cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human deficiency virus were discussed. Dysregulation of metabolism, as a result of ethanol exposure, in the intestine leads to colon carcinogenesis. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota have been suggested. The clinical aspects of NASH, as part of the metabolic syndrome in the aging population, have been presented. The symposium addressed mechanisms and biomarkers of alcohol induced damage to different organs, as well as the role of the microbiome in this dialog. The microbiota regulates and acts as a key element in harmonizing immune responses at intestinal mucosal surfaces. It is known that microbiota is an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. The signals at the sites of inflammation mediate recruitment and differentiation in order to remove inflammatory inducers and promote tissue homeostasis restoration. The change in the intestinal microbiota also influences the change in obesity and regresses the liver steatosis. Evidence on the positive role of moderate alcohol consumption on heart and metabolic diseases as well on reducing steatosis have been looked up. Moreover nutrition as a therapeutic intervention in alcoholic liver disease has been discussed. In addition to the original data, we searched the literature (2008-2016) for the latest publication on the described subjects. In order to obtain the updated data we used the usual engines (Pub Med and Google Scholar). The intention of the eighth symposia was to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism. PMID- 28077316 TI - Chromatin dynamics regulate mesenchymal stem cell lineage specification and differentiation to osteogenesis. AB - Multipotent mesenchymal stromal cells (MSCs) are critical for regeneration of multiple tissues. Epigenetic mechanisms are fundamental regulators of lineage specification and cell fate, and as such, we addressed the question of which epigenetic modifications characterize the transition of nascent MSCs to a tissue specific MSC-derived phenotype. By profiling the temporal changes of seven histone marks correlated to gene expression during proliferation, early commitment, matrix deposition, and mineralization stages, we identified distinct epigenetic mechanisms that regulate transcriptional programs necessary for tissue specific phenotype development. Patterns of stage-specific enrichment of histone modifications revealed distinct modes of repression and activation of gene expression that would not be detected using single endpoint analysis. We discovered that at commitment, H3K27me3 is removed from genes that are upregulated and is not acquired on downregulated genes. Additionally, we found that the absence of H3K4me3 modification at promoters defined a subset of osteoblast-specific upregulated genes, indicating that acquisition of acetyl modifications drive activation of these genes. Significantly, loss or gain of H3K36me3 was the primary predictor of dynamic changes in temporal gene expression. Using unsupervised pattern discovery analysis the signature of osteogenic-related histone modifications identified novel functional cis regulatory modules associated with enhancer regions that control tissue-specific genes. Our work provides a cornerstone to understand the epigenetic regulation of transcriptional programs that are important for MSC lineage commitment and lineage, as well as insights to facilitate MSC-based therapeutic interventions. PMID- 28077317 TI - Zoonotic pathogens in Atlantic Forest wild rodents in Brazil: Bartonella and Coxiella infections. AB - Zoonotic pathogens comprise a significant and increasing fraction of all emerging and re-emerging infectious diseases that plague humans. Identifying host species is one of the keys to controlling emerging infectious diseases. From March 2007 until April 2012, we collected a total of 131 wild rodents in eight municipalities of Rio de Janeiro, Brazil. We investigated these rodents for infection with Coxiella burnetii, Bartonella spp. and Rickettsia spp. In total, 22.1% (29/131) of the rodents were infected by at least one pathogen; co infection was detected in 1.5% (2/131) of rodents. Coxiella burnetii was detected in 4.6% (6/131) of the wild animals, 17.6% of the rodents harbored Bartonella spp. No cases of Rickettsia were identified. Bartonella doshiae and Bartonella vinsonii were the species found on the wild mammals. This report is the first to note C. burnetii, B. doshiae and B. vinsonii natural infections in Atlantic Forest wild rodents in Brazil. Our work highlights the potential risk of transmission to humans, since most of the infected specimens belong to generalist species that live near human dwellings. PMID- 28077319 TI - Role of insulin like growth factor axis in the bleomycin induced lung injury in rats. AB - BACKGROUND: Alveolar epithelial cell injury has been proposed as a causative factor for the onset and progression of pulmonary fibrosis. However, the role of type II alveolar epithelial cells (AECs) in the epithelial mesenchymal transition (EMT) is controversial. AIMS: The present study performed in rats instilled with bleomycin investigated a) the expressions of the insulin growth factor (IGF-1) and insulin growth factor binding protein 5 (IGFBP-5) and transforming growth factor (TGF-beta1) in the type II AECs, b) the role of type II AECs in EMT and extracellular matrix (ECM) formation and, c) the effect of pioglitazone on all the above parameters. METHODS: Male Wistar rats were divided into three Groups: Group I (saline control), Group II (Bleomycin, given as a single intratracheal instillation, 7U/kg) and Group III (Bleomycin+Pioglitazone (40mg/kg/day orally, starting 7days post bleomycin instilled as in Group II). From lung tissues, the protein expressions of IGF-1, IGFBP-5, TGF-beta1, surfactant protein C (SP-C, as a marker for type II AECs) and alpha-smooth muscle actin (alpha-SMA, as a marker for EMT), were determined on day 7 in Groups I and II and on days 14, 21 and 35 in all the three groups. RESULTS: IGFBP-5 and IGF-1 expressions were reduced significantly and TGF-beta1 expression increased significantly in type II AECs in Group II from day 7 till day 35 as compared to Group I. An increase in SP-C and alpha-SMA expression and their co-localization were seen in the type II AECs undergoing EMT from day 7 till day 35. A concomitant remodeling and laying down of ECM was observed also. In Group III, with pioglitazone, there was a reversal with significant up-regulation in IGFBP-5 and IGF-1 expressions and down regulation of TGF-beta1 in the type II AECs along with a significant decrease in the solid area fraction, EMT and ECM in the lung tissue. CONCLUSIONS: IGFBP-5, IGF-1 and TGF-beta1 in the type II AECs play a key role in lung injury caused by bleomycin and pioglitazone attenuates the lung injury/fibrosis by restoring IGFBP 5 and IGF-1 and decreasing TGF-beta1 expressions in the type II AECs. PMID- 28077320 TI - Serine/Threonine Phosphatases in Atrial Fibrillation. AB - Serine/threonine protein phosphatases control dephosphorylation of numerous cardiac proteins, including a variety of ion channels and calcium-handling proteins, thereby providing precise post-translational regulation of cardiac electrophysiology and function. Accordingly, dysfunction of this regulation can contribute to the initiation, maintenance and progression of cardiac arrhythmias. Atrial fibrillation (AF) is the most common heart rhythm disorder and is characterized by electrical, autonomic, calcium-handling, contractile, and structural remodeling, which include, among other things, changes in the phosphorylation status of a wide range of proteins. Here, we review AF-associated alterations in the phosphorylation of atrial ion channels, calcium-handling and contractile proteins, and their role in AF-pathophysiology. We highlight the mechanisms controlling the phosphorylation of these proteins and focus on the role of altered dephosphorylation via local type-1, type-2A and type-2B phosphatases (PP1, PP2A, and PP2B, also known as calcineurin, respectively). Finally, we discuss the challenges for phosphatase research, potential therapeutic significance of altered phosphatase-mediated protein dephosphorylation in AF, as well as future directions. PMID- 28077321 TI - CaMKIIdelta subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-kappaB and TNF-alpha. AB - Deletion of Ca2+/calmodulin-dependent protein kinase II delta (CaMKIIdelta) has been shown to protect against in vivo ischemia/reperfusion (I/R) injury. It remains unclear which CaMKIIdelta isoforms and downstream mechanisms are responsible for the salutary effects of CaMKIIdelta gene deletion. In this study we sought to compare the roles of the CaMKIIdeltaB and CaMKIIdeltaC subtypes and the mechanisms by which they contribute to ex vivo I/R damage. WT, CaMKIIdeltaKO, and mice expressing only CaMKIIdeltaB or deltaC were subjected to ex vivo global ischemia for 25min followed by reperfusion. Infarct formation was assessed at 60min reperfusion by triphenyl tetrazolium chloride (TTC) staining. Deletion of CaMKIIdelta conferred significant protection from ex vivo I/R. Re-expression of CaMKIIdeltaC in the CaMKIIdeltaKO background reversed this effect and exacerbated myocardial damage and dysfunction following I/R, while re-expression of CaMKIIdeltaB was protective. Selective activation of CaMKIIdeltaC in response to I/R was evident in a subcellular fraction enriched for cytosolic/membrane proteins. Further studies demonstrated differential regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signaling and tumor necrosis factor alpha (TNF-alpha) expression by CaMKIIdeltaB and CaMKIIdeltaC. Selective activation of CaMKIIdeltaC was also observed and associated with NF kappaB activation in neonatal rat ventricular myocytes (NRVMs) subjected to oxidative stress. Pharmacological inhibition of NF-kappaB or TNF-alpha significantly ameliorated infarct formation in WT mice and those that re-express CaMKIIdeltaC, demonstrating distinct roles for CaMKIIdelta subtypes in I/R and implicating acute activation of CaMKIIdeltaC and NF-kappaB in the pathogenesis of reperfusion injury. PMID- 28077322 TI - A protein kinase A-ezrin complex regulates connexin 43 gap junction communication in liver epithelial cells. AB - Communication between adjacent cells can occur via gap junctions (GJ) composed of connexin (Cx) hexamers that allow passage of small molecules. One of the most widely and highly expressed Cxs in human tissues is Cx43, shown to be regulated through phosphorylation by several kinases including PKA. Ezrin is a membrane associated protein that can serve as an A-kinase anchoring protein (AKAP) and hold an anchored pool of PKA. Here, we used the liver epithelial cell line IAR20, which expresses Cx43 as the predominant GJ protein, to test the hypothesis that Ezrin may associate with Cx43 in cell types that form stable GJs and serve as an AKAP. Our biochemical and proteomics data indicate that Ezrin associates with Cx43 in epithelial cells. Analyses by confocal immunofluorescence microscopy and proximity ligation assays demonstrate that Ezrin and Cx43 co-localize, together with zonula occludens-1 (ZO-1) and PKA RIalpha and RIIalpha, at the cell membrane. Quantitative gap-FRAP experiments show increased GJ intercellular communication after cAMP stimulation. Moreover, loading of cells with the Ht31 peptide that displaces both PKA RIalpha and RIIalpha from the AKAP or a peptide that disrupts the Cx43-Ezrin interaction reverts the effect and reduces the level of communication, supporting the hypothesis that in IAR20 cells Ezrin associates with Cx43 (in complex with ZO-1) which places PKA in proximity to Cx43, enabling its phosphorylation and GJ opening. PMID- 28077323 TI - High glucose down-regulates microRNA-181a-5p to increase pro-fibrotic gene expression by targeting early growth response factor 1 in HK-2 cells. AB - Tubulointerstitial fibrosis (TIF) plays an important role in the progression of renal fibrosis in diabetic nephropathy (DN). Accumulating evidence supports a crucial effect of early growth response factor 1 (Egr1) on renal fibrosis in DN, but the underlying mechanisms are not entirely clear. Here, we explored the aggravating role of Egr1 and identified microRNA-181a-5p (miR-181a-5p) as an upstream regulator of Egr1 in TIF of DN. We demonstrated that overexpression of Egr1 enhanced, whereas small interfering RNA targeting Egr1 decreased the expressions of transforming growth factor beta1 (TGF-beta1) and fibrosis-related genes including fibronectin and collagen I in human proximal tubule cell line (HK 2) cells. We then found that miR-181a-5p expression was down-regulated, accompanied by the corresponding up-regulation of Egr1, TGF-beta1, fibronectin and collagen I in renal tissues of type 2 diabetic Otsuka-Long-Evans-Tokushima Fatty rats with DN, and that the expression of miR-181a-5p was negatively correlated with the level of Egr1 in HK-2 cells treated with high glucose. Furthermore, we identified that miR-181a-5p directly suppressed Egr1 to decrease the expressions of TGF-beta1, fibronectin and collagen I in HK-2 cells through targeting the 3' untranslated region of Egr1. The functional relevance of miR 181a-5p-induced Egr1 decrease was supported by inhibition and overexpression of miR-181a-5p in HK-2 cells. Thus, we concluded that aberrant Egr1 expression, which can be suppressed by miR-181a-5p directly, plays a crucial role in the progression of renal TIF in DN. This study indicates that targeting miR-181a-5p may be a novel therapeutic approach of DN. PMID- 28077325 TI - Role of 14-3-3 sigma in over-expression of P-gp by rifampin and paclitaxel stimulation through interaction with PXR. AB - In this study, we presented the role of 14-3-3sigma to activate CK2-Hsp90beta-PXR MDR1 pathway on rifampin and paclitaxel treated LS174T cells and in vivo LS174T cell-xenografted nude mouse model. Following several in vitro and in vivo experiments, rifampin and paclitaxel were found to be stimulated the CK2 Hsp90beta-PXR-MDR1 pathway. Of the proteins in this pathway, Pregnane X receptor (PXR) is a representative transcription factor of multidrug resistance protein 1 (MDR1). We constructed FLAG-PXR-LS174T stable cell lines and discovered 22 proteins that interacted with PXR on rifampin treatment. Among them, Hsp90beta and 14-3-3sigma were isolated for further study. Both the proteins were found to be localized in cytoplasm on rifampin treatment by using confocal microscopy. On the other hand, PXR was found to be localized in nucleus after rifampin and paclitaxel treatment by using cell fractionation assay. In Western blot analysis, rifampin did not influence the expression of 14-3-3sigma protein. Transient transfection of 14-3-3sigma into LS174T cells induced overexpression of PXR; however, P-glycoprotein (P-gp) was not changed significantly. P-gp overexpression was induced only when 14-3-3sigma transfected LS174T cells were treated with rifampin and paclitaxel, whereas 14-3-3sigma inhibition by nonpeptidic inhibitor, BV02 and 14-3-3sigma siRNA reduced rifampin induced PXR and P-gp expression. Cell survival rates were much higher at 14-3-3sigma-LS174T stable cell lines than LS174T cells following paclitaxel and vincristine treatment. This data indicates that 14-3-3sigma contributes to P-gp overexpression through interaction with PXR with rifampin and paclitaxel treatment. PMID- 28077324 TI - GRK2 as negative modulator of NO bioavailability: Implications for cardiovascular disease. AB - Nitric oxide (NO), initially identified as endothelium-derived relaxing factor (EDRF), is a gaso-transmitter with important regulatory roles in the cardiovascular, nervous and immune systems. In the former, this diatomic molecule and free radical gas controls vascular tone and cardiac mechanics, among others. In the cardiovascular system, it is now understood that beta-adrenergic receptor (betaAR) activation is a key modulator of NO generation. Therefore, it is not surprising that the up-regulation of G protein-coupled receptor kinases (GRKs), in particular GRK2, that restrains betaAR activity contributes to impaired cardiovascular functions via alteration of NO bioavailability. This review, will explore the specific interrelation between betaARs, GRK2 and NO in the cardiovascular system and their inter-relationship for the pathogenesis of the onset of disease. Last, we will update the readers on the current status of GRK2 inhibitors as a potential therapeutic strategy for heart failure with an emphasis on their ability of rescuing NO bioavailability. PMID- 28077326 TI - Longevity in Calumma parsonii, the World's largest chameleon. AB - Large body size of ectothermic species can be correlated with high life expectancy. We assessed the longevity of the World's largest chameleon, the Parson's chameleon Calumma parsonii from Madagascar by using skeletochronology of phalanges taken from preserved specimens held in European natural history museums. Due to the high bone resorption we can provide only the minimum age of each specimen. The highest minimum age detected was nine years for a male and eight years for a female, confirming that this species is considerably long living among chameleons. Our data also show a strong correlation between snout vent length and estimated age. PMID- 28077327 TI - Eliminating stroop effects with post-hypnotic instructions: Brain mechanisms inferred from EEG. AB - The classic Stroop task demonstrates the persistent and automatic effects of the meaning of color words that are very hard to inhibit when the task is to name the word color. Post-hypnotic instructions may enable highly-hypnotizable participants to inhibit the automatic access to word meaning. Here we compared the consequences of hypnosis alone and hypnosis with post-hypnotic instructions on the Stroop effect and its facilitation and inhibition components. Importantly, we studied the mechanisms of the hypnosis effects at the neural level by analyzing EEG frequencies. Highly hypnotizable participants performed the Stroop task in a counterbalanced design following (1) post-hypnotic suggestions that words had lost their meaning, (2) after hypnosis alone, and (3) in a control condition without hypnosis. The overall Stroop effect and both its facilitation and interference components, were not significant after the post-hypnotic suggestion but in both other conditions. Hypnosis alone neither affected the Stroop effect nor - in contrast to some previous reports and claims - overall performance. EEG recorded during the Stroop task showed a significant increase in both frontal theta and frontal beta power when participants were under the impact of post-hypnotic suggestions, in comparison to the two other sessions. Together, these findings indicate that post-hypnotic suggestions - but not hypnosis alone - are powerful tools for eliciting top down processes. Our EEG findings could be interpreted as clue that this is due to the investment of additional cognitive control. PMID- 28077329 TI - Body schema plasticity after stroke: Subjective and neurophysiological correlates of the rubber hand illusion. AB - Stroke can lead to motor impairments that can affect the body structure and restraint mobility. We hypothesize that brain lesions and their motor sequelae can distort the body schema, a sensorimotor map of body parts and elements in the peripersonal space through which human beings embody the reachable space and ready the body for forthcoming movements. Two main constructs have been identified in the embodiment mechanism: body-ownership, the sense that the body that one inhabits is his/her own, and agency, the sense that one can move and control his/her body. To test this, the present study simultaneously investigated different embodiment subcomponents (body-ownership, localization, and agency) and different neurophysiological measures (galvanic skin response, skin temperature, and surface electromyographic activity), and the interaction between them, in clinically-controlled hemiparetic individuals with stroke and in healthy subjects after the rubber hand illusion. Individuals with stroke reported significantly stronger body-ownership and agency and reduced increase of galvanic skin response, skin temperature, and muscular activity in the stimulated hand. We suggest that differences in embodiment could have been motivated by increased plasticity of the body schema and pathological predominance of the visual input over proprioception. We also suggest that differences in neurophysiological responses could have been promoted by a suppression of the reflex activity of the sympathetic nervous system and by the involvement of the premotor cortex in the reconfiguration of the body schema. These results could evidence a body schema plasticity promoted by the brain lesion and a main role of the premotor cortex in this mechanism. PMID- 28077328 TI - Dissociation between working memory performance and proactive interference control in post-traumatic stress disorder. AB - Deficits in working memory (WM) and cognitive control processes have been reported in post-traumatic stress disorder (PTSD), in addition to clinical symptoms such as hypervigilance, re-experiencing, and avoidance of trauma reminders. Given the uncontrollable nature of intrusive memories, an important question is whether PTSD is associated with altered control of interference in WM. Some studies also suggest that episodic memory shows a material-specific dissociation in PTSD, with greater impairments in verbal memory and relative sparing of nonverbal memory. It is unclear whether this dissociation applies to WM, as no studies have used identical task parameters across material. Here we tested 29 combat Veterans with PTSD and 29 age-matched control Veterans on a recent probes WM task with words and visual patterns in separate blocks. Participants studied four-item sets, followed by a probe stimulus that had been presented in the previous set (recent probe) or not (nonrecent probe). Participants with PTSD made more errors than controls, and this decrement was similar for verbal and visual stimuli. Proactive interference from items recently presented, but no longer relevant, was not significantly different in the PTSD group and showed no relationship to re-experiencing symptom severity. These results demonstrate that PTSD is not reliably associated with increased intrusions of irrelevant representations into WM when non-emotional stimuli are used. Future studies that use trauma-related material may provide insight into the flashbacks and intrusive thoughts that plague those with PTSD. PMID- 28077330 TI - Dehydropachymic acid decreases bafilomycin A1 induced beta-Amyloid accumulation in PC12 cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Fuling, the sclerotium of Poria cocos, was frequently used in traditional Chinese medicine (TCM) formulae for Alzheimer's disease (AD) intervention over the past 10 centuries. And its extracts exhibited significant effects in both cellular and animal models of AD in previous studies. However, its mechanisms on prevention and treatment of AD have not been well elucidated yet. AIM OF THE STUDY: To investigate the effect and corresponding mechanisms of dehydropachymic acid, which is one of the major triterpenes in P. cocos, on the clearance of beta-amyloid accumulation in bafilomycin A1 induced PC12 cells. MATERIALS AND METHODS: MTT assay was used to examine the DPA effect on the viability of PC12 cells stable transfected with pCB6-APP (PC12-APP). PC12 APP cells were treated with DPA at the concentration of 6.25, 12.5, 25MUg/mL for 4h, and then co-treated with 50nmol/L bafilomycin A1 for 48h except the controls. The Abeta1-42 content in culture medium was determined by ELISA. The intracellular amount of APP, Abeta1-42, LC3, cathepsin D was measured by Western blotting and normalized to GAPDH loading control. The PC12 cells stable transfected with pSelect-LC3-GFP (PC12-LC3-GFP) was used in the fluorescence microscopy estimation of autophagosomes accumulation. The internal pH in lysosome was detected by LysoTracker Red staining. RESULTS: DPA had no significant effect on the cell viability but could significantly decrease Abeta1-42 content in culture medium and eliminate the intracellular accumulation of APP and Abeta1-42 in bafilomycin A1 induced PC12-APP cells. Furthermore, DPA lowered the LC3-II/LC3 I ratio and reduced the GFP-labeled LC3 puncta which were elevated by bafilomycin A1. And the increase in internal pH of lysosome and decrease in mCatD amount in Bafilomycin A1 induced PC12-APP cells were restored by DPA treatment. These results indicated that DPA could restore the lysosomal acidification and recover the autophgic flux which is impaired by bafilomycin A1. CONCLUSIONS: DPA could effectively clear the accumulation of Abeta1-42 in bafilomycin A1 impaired PC12 cells through restoring the lysosomal acidification and recovering the autophgic flux. And these results highlight its therapeutic potential for AD treatment. PMID- 28077331 TI - Behavioral effects induced by antitumor cleronade diterpenes from Casearia sylvestris and in silico interactions with neuron receptors. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Casearia sylvestris is a medicinal plant traditionally used to treat snakebites, wounds, inflammation and gastric ulcers and scientific supports for have demonstrated its antitumor, antihyperlipidemic and antiparasitic properties. AIM OF THE STUDY: To assess the effects of a fraction with casearins (FC) on adult mice using classical experimental models of animal behavior and theoretical calculations to verify the interaction of Casearin X (Cas X) with neuron receptors. MATERIALS AND METHODS: Animals divided in 6 groups (n=9/group) were intraperitoneally treated with vehicle (DMSO 4%), FC (2.5, 5, 10 and 25mg/kg/day) and diazepam (2mg/kg) for 7 days. Thirty minutes after the last dose of treatment, acute toxicity and behavioral experiments were performed. RESULTS: The highest dose of FC (25mg/kg/day) caused diarrhea, weight loss and death of one animal. Elevated plus maze test showed that lower doses [2.5mg/kg/day (36.4+/-5.1s) and 5mg/kg/day (43.9+/-6.2s)] increased the time spent in open arms (TSOA). Open field test revealed reduction in the number of crossings (54.9%, 51.1%, 48% and 67.7% for 2.5, 5, 10 and 25mg/kg/day, respectively) in all doses of FC studied and decrease of rearings at 25mg/kg/day (p<0.05). Computational calculations showed that the inhibition constant (Ki) for the Cas X-D1 complex is up to 1000-fold more favourable than the Cas X-GABAA complex. All ?G degrees values obtained for Cas X-D1 complexes were more negative than those seen with Cas X-GABAA complexes. CONCLUSIONS: Findings indicate a probable anxiolytic action of the FC since it reduces the number of crossings and rearings and prolonged the time spent in open arms, without sedative and myorelaxant effects, probably due to the interaction of Cas X with dopaminergic system. PMID- 28077332 TI - Molecular identification of StAR and 3betaHSD1 and characterization in response to GnIH stimulation in protogynous hermaphroditic grouper (Epinephelus coioides). AB - Gonadal steroids are critical factors in reproduction and sex reverse process. StAR (steroidogenic acute regulatory protein), transferring the cholesterol from the outer mitochondrial membrane to the inner membrane, is the rate-limiting factor of steroidogenesis. 3betaHSD (3beta-hydroxysteroid dehydrogenase/Delta5 Delta4 isomerase), converting Delta5-steroids into Delta4-steroids, is an important oxidoreductase in steroidogenesis. In the present study, StAR and 3betaHSD1 were cloned and characterized from protogynous orange-spotted grouper. StAR cDNA contains an 861bp open reading frame (ORF), encoding a predicted protein of 286 amino acids, and the ORF of 3betaHSD1 was 1125bp, encoding a predicted protein of 374 amino acids. The transcript of StAR was mainly expressed in gonad, while 3betaHSD1 mRNA was predominantly detected in brain and gonad. In the previous study, we found the expression of GnIH mRNA level in male, as well as in 17 alpha-methyltestosterone (MT)-induced male fish was significantly higher than in female fish, this indicating that GnIH/GnIHR signaling might be involved in the regulation of sex reversal and male maintenance. In order to figure out the function of GnIH in steroidogenesis, the expression of StAR and 3betaHSD1 regulated by GnIH was examined. In vitro study showed that treatment of cultured ovary fragments with gGnIH peptides significantly stimulated the expression of StAR and 3betaHSD1. In addition, the mRNA levels of StAR and 3betaHSD1 were significantly increased after intraperitoneal injection (i.p.) with gGnIH peptides. Moreover, during MT-induced sex change from female to male, the levels of StAR mRNA significantly increased by 5.2, 24.8 and 353.5 folds, and that of 3betaHSD1 mRNA by 3.5, 32.5 and 55.4 folds at the 2nd, 4th and 6th week after MT implantation, respectively. Collectively, our results indicate that GnIH may be involved in the regulation of sex reversal or male maintenance by stimulating the expression of StAR and 3betaHSD1 in protogynous grouper. PMID- 28077333 TI - Molecular cloning, characterization and expression analysis of two juvenile hormone esterase-like carboxylesterase cDNAs in Chinese mitten crab, Eriocheir sinensis. AB - Precise regulation of methyl farnesoate (MF) titer is of prime importance throughout the crustacean life-cycle. Although the synthetic pathway of MF is well-documented, little is known about its degradation and recycling in crustaceans. Juvenile hormone esterase-like (JHE-like) carboxylesterase (CXE) is a key enzyme in MF degradation, thus playing a significant role in regulating the MF titer. We identified and characterized two cDNAs, Es-CXE1 and Es-CXE2, encoding JHE-like CXEs in Chinese mitten crab. Full-length cDNAs of Es-CXE1 and Es-CXE2 encode proteins composed of 584 and 597 amino acids, respectively, both of which contain a typical carboxylesterase domain. Alignment and phylogenetic analyses revealed that the Es-CXEs are highly similar to those of other crustaceans. To further validate their functions, we evaluated the mRNA expression patterns of the Es-CXEs in various tissues and in different physiological conditions. Tissue-specific expression analysis showed that the two Es-CXEs were predominantly expressed in the hepatopancreas and ovaries, which are the major tissues for MF metabolism. Es-CXE2 expression levels in the hepatopancreas and ovaries were about 100 and 25-fold higher, than the respective Es-CXE1 expressions. During ovarian rapid development stage, the global expressions of Es-CXEs were up-regulated in the hepatopancreas and down-regulated in the ovaries. After eyestalk ablation (ESA), the mRNA expressions of the two Es CXEs were up-regulated in the hepatopancreas, further indicating their potential in degrading MF. Taken together, our results suggest that Es-CXEs, the key component of the juvenile hormone degradation pathway, may play vital roles in the development and reproduction of the Chinese mitten crab. PMID- 28077334 TI - The neuroprotective compound P7C3-A20 promotes neurogenesis and improves cognitive function after ischemic stroke. AB - Ischemic stroke is a devastating condition with few therapeutic interventions available. The neuroprotective compound P7C3-A20 inhibits mature neuronal cell death while also increasing the net magnitude of postnatal neurogenesis in models of neurodegeneration and acute injury. P7C3 compounds enhance flux of nicotinamide adenine dinucleotide (NAD) in mammalian cells, a proposed therapeutic approach to treating cerebral ischemia. The effectiveness of P7C3-A20 treatment on chronic histopathological and behavioral outcomes and neurogenesis after ischemic stroke has not previously been established. Here, a transient middle cerebral artery occlusion in rats was followed by twice daily injection of P7C3-A20 or vehicle for 7days. P7C3-A20-treated rats performed significantly better than vehicle-treated controls in sensorimotor cylinder and grid-walk tasks, and in a chronic test of spatial learning and memory. These behavioral improvements with P7C3-A20 treatment were correlated with significantly decreased cortical and hippocampal atrophy, and associated with increased neurogenesis in the subventricular zone and hippocampal dentate gyrus subgranular zone. Furthermore, cerebral ischemia significantly reduced NAD in the cortex but P7C3 A20 treatment restored NAD to sham levels. Thus, P7C3-A20 treatment mitigates neurodegeneration and augments repair in the brain after focal ischemia, which translates into chronic behavioral improvement. This suggests a new therapeutic approach of using P7C3 compounds to safely augment NAD and thereby promote two independent processes critical to protecting the brain from ischemic stroke: mature neuron survival and postnatal neurogenesis throughout the post-ischemic brain. PMID- 28077335 TI - Omega-3 fatty acids regulate NLRP3 inflammasome activation and prevent behavior deficits after traumatic brain injury. AB - Omega-3 fatty acids (omega-3 FAs) attenuate inflammation and improve neurological outcome in response to traumatic brain injury (TBI), but the specific anti inflammatory mechanisms remain to be elucidated. Here we found that NLRP3 inflammasome and subsequent pro-inflammatory cytokines were activated in human brains after TBI. Rats treated with omega-3 FAs had significantly less TBI induced caspase-1 cleavage and IL-1beta secretion than those with vehicle. G protein-coupled receptor 40 (GPR40) was observed to be involved in this anti inflammation. GW1100, a GPR40 inhibitor, eliminated the anti-inflammatory effect of omega-3 FAs after TBI. beta-Arrestin-2 (ARRB2), a downstream scaffold protein of GPR40, was activated to inhibit inflammation via directly binding with NLRP3 in the omega-3 FAs treatment group. Interestingly, we also observed that omega-3 FAs prevented NLRP3 mitochondrial localization, which was reversed by GW1100. Furthermore, omega-3 FAs markedly ameliorated neuronal death and behavioral deficits after TBI, while GW1100 significantly suppressed this effect. Collectively, these data indicate that the GPR40-mediated pathway is involved in the inhibitory effects of omega-3 FAs on TBI-induced inflammation and ARRB2 is activated to interact with NLRP3. PMID- 28077336 TI - Predicting protein submitochondrial locations by incorporating the positional specific physicochemical properties into Chou's general pseudo-amino acid compositions. AB - Predicting protein submitochondrial locations has been studied for about ten years. A dozen of methods were developed in this regard. Although a mitochondrion has four submitochondrial compartments, all existing studies considered only three of them. The mitochondrial intermembrane space proteins were always excluded in these studies. However, there are over 50 mitochondrial intermembrane space proteins in the recent release of UniProt database. We think it is time to incorporate these proteins in predicting protein submitochondrial locations. We proposed the functional domain enrichment score, which can be used as an enhancement to our positional-specific physicochemical properties method. We constructed a high-quality working dataset from the UniProt database. This dataset contains proteins from all four submitochondrial locations. Proteins with multiple submitochondrial locations are also included. Our method achieved over 70% prediction accuracy for proteins with single location on this dataset. On the M3-317 benchmarking dataset, our method achieved comparable prediction performance to other state-of-the-art methods. Our results indicate that the intermembrane space proteins can be incorporated in predicting protein submitochondrial locations. By evaluating our method with the proteins that have multiple submitochondrial locations, we conclude that our method is capable of predicting multiple submitochondrial locations. This is the first report of ab initio methods that can identify intermembrane space proteins. This is also the first attempt to incorporate proteins with multiple submitochondrial locations. The benchmarking dataset can be obtained by emails to the corresponding author. PMID- 28077337 TI - Stress hormone epinephrine (adrenaline) and norepinephrine (noradrenaline) effects on the anaerobic bacteria. AB - Microbial endocrinology is a relatively new research area that already encompasses the anaerobes. Stress hormones, epinephrine and norepinephrine, can affect the growth of anaerobic bacteria such as Fusobacterium nucleatum, Prevotella spp., Porhyromonas spp., Tanerella forsythia and Propionibacterium acnes and can increase virulence gene expression, iron acquisition and many virulence factors of some anaerobic species such as Clostridium perfringens, Porphyromonas gingivalis and Brachyspira pilosicoli. Epinephrine and norepinephrine effects can lead to a growth increase or decrease, or no effect on the growth of the anaerobes. The effects are species-specific and perhaps strain specific. Discrepancies in the results of some studies can be due to the different methods and media used, catecholamine concentrations, measurement techniques and the low number of strains tested. Biological effects of the stress hormones on the anaerobes may range from halitosis and a worsening of periodontal diseases to tissue damages and atherosclerotic plaque ruptures. Optimizations of the research methods and a detailed assessment of the catecholamine effects in conditions mimicking those in affected organs and tissues, as well as the effects on the quorum sensing and virulence of the anaerobes and the full spectrum of biological consequences of the effects are interesting topics for further evaluation. PMID- 28077338 TI - Ten-day bismuth-containing quadruple therapy is effective as first-line therapy for Helicobacter pylori-related chronic gastritis: a prospective randomized study in China. AB - OBJECTIVES: To investigate the effectiveness of 10-day bismuth-containing quadruple (B-quadruple) treatment as first-line therapy in patients with Helicobacter pylori-related chronic gastritis. METHODS: A randomized controlled trial was conducted from October 2011 to December 2013 in Zhejiang, China, including patients with H. pylori-related chronic gastritis who were randomly provided either 10-day omeprazole-based triple therapy (OM-triple; omeprazole 20 mg twice daily, clarithromycin 500 mg twice daily and amoxicillin 1 g twice daily) or 10-day B-quadruple therapy (OM-triple + bismuth subcitrate 120 mg four times daily). H. pylori status, pathologic findings and dyspeptic symptoms were assessed at baseline and after 3 months. The primary outcome was H. pylori eradication rates by intention-to-treat (ITT) and per-protocol (PP) analyses. The secondary outcomes were the histologic and symptomatic benefits from H. pylori eradication. RESULTS: A total of 351 patients with H. pylori-related chronic gastritis were recruited. The eradication rates of the OM-triple and B-quadruple groups were 58.4% (108/185) and 86.1% (143/166) respectively according to ITT analysis (p <0.01). PP rates of H. pylori eradication were 63.2% (108/171) and 92.3% (143/155) respectively (p <0.01). According to the PP analysis, active and chronic inflammation in gastric mucosa was substantially improved in all treated patients (n=326). However, pathologic atrophic gastritis and intestinal metaplasia did not regress in both groups (n=326). The reduction of dyspeptic symptoms score was significantly higher in the B-quadruple group than in the OM triple group (0.59+/-0.057 vs. 0.39+/-0.046) (p <0.01). CONCLUSIONS: Ten-day B quadruple therapy is more effective than OM-triple therapy as first-line therapy for patients with H. pylori-induced chronic gastritis in China. PMID- 28077339 TI - St20, a new venomous animal derived natural peptide with immunosuppressive and anti-inflammatory activities. AB - Peptide toxins from venomous animals are natural resources with diverse biological functions and therapeutic potential towards human diseases. For venomous scorpions, many valuable peptide toxins have been discovered from Buthidae scorpions, but few works were done about non-buthidae scorpions. Here, we cloned and characterized the first disulfide-bridged toxin peptide St20 from the non-buthidae scorpion Scorpiops tibetanus. St20 has a putative 23-residue signal peptide, followed by a presumed 34-residue mature peptide including 8 cysteines. Sequence alignments and structural analysis suggested that St20 is a new member of alpha-KTx23 scorpion toxin subfamily with a conserved CSalpha/beta structural fold. Functional studies showed that St20 inhibited human T lymphocyte surface marker CD69 expression and cytokine IL-2 secretion. Beside this, St20 inhibited two important pro-inflammatory factors TNF-alpha and IFN-gamma secretion in the activated human T lymphocyte. Animal experiments showed that the delayed-type hypersensitivity response in rat autoimmune disease model was ameliorated in the present of peptide toxin St20. Together, our results showed that St20 is the first disulfide-bridged toxin peptide from the non-buthidae scorpion Scorpiops tibetanus with immunosuppressive and anti-inflammatory activities, suggesting that toxins from non-buthidae scorpions might be a new source of peptide drug discovery towards human diseases. PMID- 28077340 TI - Clinicopathological Characteristics of Papillary Thyroid Cancer in Children with Emphasis on Pubertal Status and Association with BRAFV600E Mutation. AB - OBJECTIVE: Papillary thyroid cancer (PTC) may behave differently in prepubertal children as compared to pubertal children and adults. BRAF gene activating mutations may associate with PTC by creating aberrant activation. We aimed to evaluate the clinicopathological characteristics of PTC patients with emphasis on the pubertal status and also to investigate the association of BRAFV600E mutation with disease characteristics. METHODS: The medical records of 75 patients with PTC were reviewed retrospectively. BRAFV600E mutation status was available only in the medical records of 56 patients. RESULTS: Mean age at diagnosis was 12.4+/ 3.8 years. There was no difference in sex, initial signs, tumor histopathology, and pathological evidence of tumor aggressiveness between prepubertal and pubertal children. Although not statistically significant, lateral neck nodal metastasis and lung metastasis at diagnosis were more prevalent in prepubertal children. After excluding patients with microcarcinoma, prepubertal children were found to require lateral neck dissection and further doses of radioactive iodine more frequently than pubertal patients. Recurrence was also more frequent in prepubertal children (p=0.016). Frequency of BRAFV600E mutation was similar in prepubertal and pubertal patients. BRAFV600E mutation was found in 14/56 (25%) patients and was high in the classic variant PTC (p=0.004). Multicentricity was high in BRAFV600E mutation (p=0.01). There was no relation between BRAFV600E mutation and lymph node and pulmonary metastasis at diagnosis, or between BRAFV600E mutation and pathological evidence of tumor aggressiveness. CONCLUSION: PTC is more disseminated in prepubertal children. BRAFV600E mutation does not correlate with a more extensive or aggressive disease. BRAFV600E mutation is not the cause of the differences in the biological behavior of PTC in prepubertal and pubertal children. PMID- 28077341 TI - Serum Irisin and Oxytocin Levels as Predictors of Metabolic Parameters in Obese Children. AB - OBJECTIVE: Irisin and oxytocin can affect energy homeostasis and it has been suggested that they may play an important role in reducing obesity and diabetes. In this study, we aimed to determine the relationship between metabolic parameters (including irisin and oxytocin levels) and anthropometric parameters in obese children. METHODS: Ninety obese children (mean age, 13.85+/-1.63 years) and 30 healthy controls (mean age, 14.32+/-1.58 years) were enrolled in this study. Anthropometric and laboratory parameters (glucose, insulin, lipid, oxytocin, and irisin levels) were analyzed. The serum irisin and oxytocin levels were measured by enzyme-linked immunosorbent assay. Bioelectrical impedance was used to determine body composition. RESULTS: Irisin level was higher in the patients than in the controls (p=0.018), and this higher irisin level was correlated with increased systolic blood pressure, body mass index, waist/hip ratio, fat percentage, fat mass, glucose level, insulin level, and homeostasis model assessment of insulin resistance. Serum oxytocin level was significantly decreased in obese children compared to the controls (p=0.049). Also, among the 60 obese patients, oxytocin level was significantly lower in patients with than in those without metabolic syndrome (8.65+/-2.69 vs. 10.87+/-5.93 ng/L, respectively), while irisin levels were comparable (p=0.049 and p=0.104, respectively). There were no statistically significant relationships between oxytocin or irisin levels and lipid levels (p>0.05). CONCLUSION: Obese children had significantly higher irisin levels than the healthy controls. Additionally, this study shows for the first time that oxytocin level is significantly lower in obese compared with non-obese children and also lower in obese children with metabolic syndrome compared to those without. PMID- 28077342 TI - Can Stoss Therapy Be Used in Children with Vitamin D Deficiency or Insufficiency without Rickets? AB - OBJECTIVE: Stoss vitamin D treatment has been recommended for its non-skeletal benefits in adults, but there is a lack of data on the optimal dose of vitamin D stoss therapy in children with vitamin D deficiency/insufficiency without rickets. This study aimed to compare efficiency/side effects of two different stoss therapy regimens (10 000 IU/kg and 300 000 IU vitamin D3) administered in children with vitamin D deficiency/insufficiency without rickets. METHODS: Sixty four children who had vitamin D deficiency/insufficiency were studied. A serum 25 hydroxyvitamin-D (25-OH-D) level of 15-20 ng/mL was considered as vitamin D insufficient and <15 ng/mL was considered as vitamin D deficient. The patients were divided into two groups according to the stoss therapy doses they received. Serum calcium, phosphate, alkaline phosphatase, 25-OH-D, parathyroid hormone levels, and spot urine calcium/creatinine ratios before/after treatment were recorded. Wrist radiography and renal ultrasonography were performed. RESULTS: The mean age of the subjects was 10.6+/-4.4 years. Thirty-two children were treated with a single vitamin D3 dose of 10 000 IU/kg and 32 patients received 300 000 IU. No difference was found in 25-OH-D levels between the two groups at presentation. The mean level of 25-OH-D was higher in the 10 000 IU/kg group at the second week of therapy. There was no difference between the groups at post treatment weeks 4 and 12. The 25-OH-D was found to be below optimal levels (>=30 ng/mL) in 66.5% and <20 ng/mL in 21.8% of patients at the third month in both groups. None developed hypercalcemia and/or hypercalciuria. Nephrolithiasis was not detected in any patient. CONCLUSION: This study showed that both doses of stoss therapy used in the treatment of vitamin D insufficiency/deficiency are effective and safe. However, an optimal level of 25-OH-D cannot be maintained for more than three months. PMID- 28077343 TI - Disappearance of Acquired Hemophilia A after Complete Remission in a Multiple Myeloma Patient. PMID- 28077344 TI - Heart-Type Fatty Acid Binding Protein Level as a Tool in Identification of Early Cardiac Effects of Diabetic Ketoacidosis. AB - OBJECTIVE: This study aimed to measure the serum levels of heart-type fatty acid binding protein (H-FABP) in patients presenting with diabetic ketoacidosis (DKA) and diabetic ketosis (DK) and to determine its role in identifying early-period cardiac ischemia. METHODS: This prospective study included 35 patients diagnosed with DKA, 20 patients diagnosed with DK, and 20 control subjects. H-FABP, creatine kinase-MB (CK-MB), and troponin I levels were investigated at presentation in patients with DKA and DK and in the control group. H-FABP values were measured again after acidosis correction in the DKA patients. RESULTS: No statistically significant differences were found with respect to troponin I and CK-MB within the groups. The H-FABP values of DKA patients at presentation were found to be significantly higher than those of DK patients and the control group (p=0.015). The H-FABP value of the DKA group was also found to be significantly higher than the value at hour 36 after acidosis correction (p=0.0001). CONCLUSION: We would like to propose H-FABP as a potential marker for indicating myocardial ischemia. PMID- 28077345 TI - Tips and Traps: Lessons From Codesigning a Clinician E-Monitoring Tool for Computerized Cognitive Behavioral Therapy. AB - BACKGROUND: Computerized cognitive behavioral therapy (cCBT) is an acceptable and promising treatment modality for adolescents with mild-to-moderate depression. Many cCBT programs are standalone packages with no way for clinicians to monitor progress or outcomes. We sought to develop an electronic monitoring (e monitoring) tool in consultation with clinicians and adolescents to allow clinicians to monitor mood, risk, and treatment adherence of adolescents completing a cCBT program called SPARX (Smart, Positive, Active, Realistic, X factor thoughts). OBJECTIVE: The objectives of our study were as follows: (1) assess clinicians' and adolescents' views on using an e-monitoring tool and to use this information to help shape the development of the tool and (2) assess clinician experiences with a fully developed version of the tool that was implemented in their clinical service. METHODS: A descriptive qualitative study using semistructured focus groups was conducted in New Zealand. In total, 7 focus groups included clinicians (n=50) who worked in primary care, and 3 separate groups included adolescents (n=29). Clinicians were general practitioners (GPs), school guidance counselors, clinical psychologists, youth workers, and nurses. Adolescents were recruited from health services and a high school. Focus groups were run to enable feedback at 3 phases that corresponded to the consultation, development, and postimplementation stages. Thematic analysis was applied to transcribed responses. RESULTS: Focus groups during the consultation and development phases revealed the need for a simple e-monitoring registration process with guides for end users. Common concerns were raised in relation to clinical burden, monitoring risk (and effects on the therapeutic relationship), alongside confidentiality or privacy and technical considerations. Adolescents did not want to use their social media login credentials for e-monitoring, as they valued their privacy. However, adolescents did want information on seeking help and personalized monitoring and communication arrangements. Postimplementation, clinicians who had used the tool in practice revealed no adverse impact on the therapeutic relationship, and adolescents were not concerned about being e-monitored. Clinicians did need additional time to monitor adolescents, and the e-monitoring tool was used in a different way than was originally anticipated. Also, it was suggested that the registration process could be further streamlined and integrated with existing clinical data management systems, and the use of clinician alerts could be expanded beyond the scope of simply flagging adolescents of concern. CONCLUSIONS: An e-monitoring tool was developed in consultation with clinicians and adolescents. However, the study revealed the complexity of implementing the tool in clinical practice. Of salience were privacy, parallel monitoring systems, integration with existing electronic medical record systems, customization of the e-monitor, and preagreed monitoring arrangements between clinicians and adolescents. PMID- 28077346 TI - The Use of Motion-Based Technology for People Living With Dementia or Mild Cognitive Impairment: A Literature Review. AB - BACKGROUND: The number of people living with dementia and mild cognitive impairment (MCI) is increasing substantially. Although there are many research efforts directed toward the prevention and treatment of dementia and MCI, it is also important to learn more about supporting people to live well with dementia or MCI through cognitive, physical, and leisure means. While past research suggests that technology can be used to support positive aging for people with dementia or MCI, the use of motion-based technology has not been thoroughly explored with this population. OBJECTIVE: The aim of this study was to identify and synthesize the current literature involving the use of motion-based technology for people living with dementia or MCI by identifying themes while noting areas requiring further research. METHODS: A systematic review of studies involving the use of motion-based technology for human participants living with dementia or MCI was conducted. RESULTS: A total of 31 articles met the inclusion criteria. Five questions are addressed concerning (1) context of use; (2) population included (ie, dementia, MCI, or both); (3) hardware and software selection; (4) use of motion-based technology in a group or individual setting; and (5) details about the introduction, teaching, and support methods applied when using the motion-based technology with people living with dementia or MCI. CONCLUSIONS: The findings of this review confirm the potential of motion-based technology to improve the lives of people living with dementia or MCI. The use of this technology also spans across several contexts including cognitive, physical, and leisure; all of which support multidimensional well-being. The literature provides evidence that people living with dementia or MCI can learn how to use this technology and that they enjoy doing so. However, there is a lack of information provided in the literature regarding the introduction, training, and support methods applied when using this form of technology with this population. Future research should address the appropriate introduction, teaching, and support required for people living with dementia or MCI to use the motion-based technology. In addition, it is recommended that the diverse needs of these specific end-users be considered in the design and development of this technology. PMID- 28077347 TI - Translating E-Mental Health Into Practice: What Are the Barriers and Enablers to E-Mental Health Implementation by Aboriginal and Torres Strait Islander Health Professionals? AB - BACKGROUND: With increasing evidence for the effectiveness of e-mental health interventions for enhancing mental health and well-being, a growing challenge is how to translate promising research findings into service delivery contexts. A 2012 e-mental health initiative by the Australian Federal Government (eMHPrac) has sought to address the issue through several strategies, one of which has been to train different health professional workforces in e-mental health (e-MH). OBJECTIVE: The aim of the study was to report on the barriers and enablers of e MH uptake in a cohort of predominantly Aboriginal and Torres Strait Islander health professionals (21 Indigenous, 5 non-Indigenous) who occupied mainly support or case management roles within their organizations. METHODS: A 3- or 2 day e-MH training program was followed by up to 5 consultation sessions (mean 2.4 sessions) provided by the 2 trainers. The trainer-consultants provided written reports on each of the 30 consultation sessions for 7 consultation groups. They were also interviewed as part of the study. The written reports and interview data were thematically analyzed by 2 members of the research team. RESULTS: Uptake of e-MH among the consultation group was moderate (22%-30% of participants). There were significant organizational barriers to uptake resulting from procedural and administrative problems, demanding workloads, prohibitive policies, and a lack of fit between the organizational culture and the introduction of new technologies. Personal barriers included participant beliefs about the applicability of e-MH to certain populations, and workers' lack of confidence and skills. However, enthusiastic managers and tech-savvy champions could provide a counter-balance as organizational enablers of e-MH; and the consultation sessions themselves appear to have enhanced skills and confidence, shifted attitudes to new technologies, and seeded a perception that e-MH could be a valuable health education resource. CONCLUSIONS: A conclusion from the program was that it was important to match e-MH training and resources to work roles. In the latter stages of the consultation sessions, the Aboriginal and Torres Strait Islander health professionals responded very positively to YouTube video clips and apps with a health education dimension. Therapy-oriented apps and programs may fit less well within the scope of practice of some workforces, including this one. We suggest that researchers broaden their focus and definitions of e-MH and give rather more weight to e-MH's health education possibilities. Developing criteria for evaluating apps and YouTube videos may empower a rather greater section of health workforce to use e-MH with their clients. PMID- 28077349 TI - Lack of healthcare funding in Greece is putting patients' lives at risk. PMID- 28077348 TI - User-Centered Design of Serious Games for Older Adults Following 3 Years of Experience With Exergames for Seniors: A Study Design. AB - BACKGROUND: Seniors need sufficient balance and strength to manage in daily life, and sufficient physical activity is required to achieve and maintain these abilities. This can be a challenge, but fun and motivational exergames can be of help. However, most commercial games are not suited for this age group for several reasons. Many usability studies and user-centered design (UCD) protocols have been developed and applied, but to the best of our knowledge none of them are focusing on seniors' use of games for physical activity. In GameUp, a European cofunded project, some prototype Kinect exergames to enhance the mobility of seniors were developed in a user-centered approach. OBJECTIVE: In this paper we aim to record lessons learned in 3 years of experience with exergames for seniors, considering both the needs of older adults regarding user centered development of exergames and participation in UCD. We also provide a UCD protocol for exergames tailored to senior needs. METHODS: An initial UCD protocol was formed based on literature of previous research outcomes. Senior users participated in UCD following the initial protocol. The users formed a steady group that met every second week for 3 years to play exergames and participate in the UCD during the 4 phases of the protocol. Several methods were applied in the 4 different phases of the UCD protocol; the most important methods were structured and semistructured interviews, observations, and group discussions. RESULTS: A total of 16 seniors with an average age above 80 years participated for 3 years in UCD in order to develop the GameUp exergames. As a result of the lessons learned by applying the different methodologies of the UCD protocol, we propose an adjusted UCD protocol providing explanations on how it should be applied for seniors as users. Questionnaires should be turned into semistructured and structured interviews while user consultation sessions should be repeated with the same theme to ensure that the UCD methods produce a valid outcome. By first following the initial and gradually the adjusted UCD protocol, the project resulted in exergame functionalities and interface features for seniors. CONCLUSIONS: The main lessons learned during 3 years of experience with exergames for seniors applying UCD are that devoting time to seniors is a key element of success so that trust can be gained, communication can be established, and users' opinions can be recorded. All different game elements should be taken into consideration during the design of exergames for seniors even if they seem obvious. Despite the limitations of this study, one might argue that it provides a best practice guide to the development of serious games for physical activity targeting seniors. PMID- 28077350 TI - Commentary: We're under financial strain without prescriptions for gluten-free food. PMID- 28077352 TI - Seven day GP access may not be cost effective, auditors warn. PMID- 28077353 TI - Robert Wood. PMID- 28077354 TI - Gut microbiota: implications for sports and exercise medicine. PMID- 28077355 TI - No evidence for the use of stem cell therapy for tendon disorders: a systematic review. AB - INTRODUCTION: Stem cells have emerged as a new treatment option for tendon disorders. We systematically reviewed the current evidence for stem cell therapy in tendon disorders. METHODS: Randomised and non-randomised controlled trials, cohort studies and case series with a minimum of 5 cases were searched in MEDLINE, CENTRAL, EMBASE, CINAHL, PEDro and SPORTDiscus. In addition, we searched grey literature databases and trial registers. Only human studies were included and no time or language restrictions were applied to our search. All references of included trials were checked for possibly eligible trials. Risk of bias assessment was performed using the Cochrane risk of bias tool for controlled trials and the Newcastle-Ottawa scale for case series. Levels of evidence were assigned according to the Oxford levels of evidence. RESULTS: 4 published and three unpublished/pending trials were found with a total of 79 patients. No unpublished data were available. Two trials evaluated bone marrow-derived stem cells in rotator cuff repair surgery and found lower retear rates compared with historical controls or the literature. One trial used allogenic adipose-derived stem cells to treat lateral epicondylar tendinopathy. Improved Mayo Elbow Performance Index, Visual Analogue Pain scale and ultrasound findings after 1 year follow-up compared with baseline were found. Bone marrow-derived stem cell treated patellar tendinopathy showed improved International Knee Documentation Committee, Knee injury and Osteoarthritis Outcome Score subscales and Tegner scores after 5-year follow-up. One trial reported adverse events and found them to be mild (eg, swelling, effusion). All trials were at high risk of bias and only level 4 evidence was available. CONCLUSIONS: No evidence (level 4) was found for the therapeutic use of stem cells for tendon disorders. The use of stem cell therapy for tendon disorders in clinical practice is currently not advised. PMID- 28077356 TI - It is time to stop meniscectomy. PMID- 28077358 TI - Biological signaling by carbon monoxide and carbon monoxide-releasing molecules. AB - Carbon monoxide (CO) is continuously produced in mammalian cells during the degradation of heme. It is a stable gaseous molecule that reacts selectively with transition metals in a specific redox state, and these characteristics restrict the interaction of CO with defined biological targets that transduce its signaling activity. Because of the high affinity of CO for ferrous heme, these targets can be grouped into heme-containing proteins, representing a large variety of sensors and enzymes with a series of diverse function in the cell and the organism. Despite this notion, progress in identifying which of these targets are selective for CO has been slow and even the significance of elevated carbonmonoxy hemoglobin, a classical marker used to diagnose CO poisoning, is not well understood. This is also due to the lack of technologies capable of assessing in a comprehensive fashion the distribution and local levels of CO between the blood circulation, the tissue, and the mitochondria, one of the cellular compartments where CO exerts its signaling or detrimental effects. Nevertheless, the use of CO gas and CO-releasing molecules as pharmacological approaches in models of disease has provided new important information about the signaling properties of CO. In this review we will analyze the most salient effects of CO in biology and discuss how the binding of CO with key ferrous hemoproteins serves as a posttranslational modification that regulates important processes as diverse as aerobic metabolism, oxidative stress, and mitochondrial bioenergetics. PMID- 28077357 TI - Triglyceride-rich lipoprotein lipolysis products increase blood-brain barrier transfer coefficient and induce astrocyte lipid droplets and cell stress. AB - Elevation of blood triglycerides, primarily as triglyceride-rich lipoproteins (TGRL), has been linked to cerebrovascular inflammation, vascular dementia, and Alzheimer's disease (AD). Brain microvascular endothelial cells and astrocytes, two cell components of the neurovascular unit, participate in controlling blood brain barrier (BBB) permeability and regulating neurovascular unit homeostasis. Our studies showed that infusion of high physiological concentrations of TGRL lipolysis products (TGRL + lipoprotein lipase) activate and injure brain endothelial cells and transiently increase the BBB transfer coefficient (Ki = permeability * surface area/volume) in vivo. However, little is known about how blood lipids affect astrocyte lipid accumulation and inflammation. To address this, we first demonstrated TGRL lipolysis products increased lipid droplet formation in cultured normal human astrocytes. We then evaluated the transcriptional pathways activated in astrocytes by TGRL lipolysis products and found upregulated stress and inflammatory-related genes including activating transcription factor 3 (ATF3), macrophage inflammatory protein-3alpha (MIP 3alpha), growth differentiation factor-15 (GDF15), and prostaglandin-endoperoxide synthase 2 (COX2). TGRL lipolysis products also activated the JNK/cJUN/ATF3 pathway, induced endoplasmic reticulum stress protein C/EBP homologous protein (CHOP), and the NF-kappaB pathway, while increasing secretion of MIP-3alpha, GDF15, and IL-8. Thus our results demonstrate TGRL lipolysis products increase the BBB transfer coefficient (Ki), induce astrocyte lipid droplet formation, activate cell stress pathways, and induce secretion of inflammatory cytokines. Our observations are consistent with evidence for lipid-induced neurovascular injury and inflammation, and we, therefore, speculate that lipid-induced astrocyte injury could play a role in cognitive decline. PMID- 28077359 TI - Indoor Tanning and Melanoma Risk: Long-Term Evidence From a Prospective Population-Based Cohort Study. AB - Indoor tanning is associated with increased risk of melanoma, but most evidence comes from case-control studies. Using data from the Norwegian Women and Cancer Study, a large prospective cohort study, we investigated the associations of age at initiation of indoor tanning, duration of tanning-device use, and dose response with melanoma risk and examined the role of indoor tanning in age at melanoma diagnosis. We used Poisson regression to estimate relative risks and 95% confidence intervals for the relationship of indoor tanning to melanoma risk and linear regression to examine age of indoor tanning initiation in relation to age at diagnosis. During follow-up of 141,045 women (1991-2012; mean duration follow up = 13.7 years), 861 women were diagnosed with melanoma. Melanoma risk increased with increasing cumulative number of tanning sessions (for highest tertile of use vs. never use, adjusted relative risk = 1.32, 95% confidence interval (CI): 1.08, 1.63); P-trend = 0.006. Age at initiation <30 years was associated with a higher risk in comparison with never use (adjusted relative risk = 1.31, 95% CI: 1.07, 1.59). Moreover, women who started indoor tanning prior to 30 years of age were 2.2 years (95% CI: 0.9, 3.4) younger at diagnosis, on average, than never users. This cohort study provides strong evidence of a dose-response association between indoor tanning and risk of melanoma and supports the hypothesis that vulnerability to the harmful effects of indoor tanning is greater at a younger age. PMID- 28077360 TI - Invited Commentary: Indoor Tanning-A Melanoma Accelerator? AB - In this issue of the Journal, Ghiasvand et al. (Am J Epidemiol. 2017;185(3):147 156) present results from a longitudinal study of the association between indoor tanning and melanoma in a large cohort of Norwegian women. These new data further support previous findings on the damaging effects of tanning bed exposure on women, particularly young women. The authors present compelling evidence that early exposure to tanning beds advances the date of diagnosis of melanoma by at least 2 years. With a strong design and a large cohort followed for a mean of 13.7 years, this study lends additional support to previous evidence of the negative effects of tanning beds and provides further justification for stronger policy initiatives designed to reduce tanning bed use among young women. PMID- 28077361 TI - Ghiasvand et al. Respond to "Indoor Tanning-A Melanoma Accelerator?" PMID- 28077362 TI - Time to revisit 'Megace' for hot flushes in patients with breast cancer? PMID- 28077363 TI - Tobacco control benefits poor people, says WHO. PMID- 28077364 TI - Socioeconomic disadvantage is linked to obesity across generations, UK study finds. PMID- 28077365 TI - Breast screening benefits have been overstated, Danish study finds. PMID- 28077366 TI - Effectiveness of acupuncture in women with polycystic ovarian syndrome undergoing in vitro fertilisation or intracytoplasmic sperm injection: a systematic review and meta-analysis. AB - OBJECTIVES: The aim of this systematic review was to assess the evidence from randomised controlled trials (RCTs) on the efficacy, effectiveness and safety of acupuncture in women with polycystic ovarian syndrome (PCOS) undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). METHODS: We searched a total of 15 databases through October 2015. The participants were women with PCOS (diagnosed using the Rotterdam criteria) undergoing IVF or ICSI. Eligible trials were those with intervention groups receiving manual acupuncture (MA) or electroacupuncture (EA), and control groups receiving sham acupuncture, no treatment or other treatments. Outcomes included the clinical pregnancy rate (CPR), live birth rate (LBR), ongoing pregnancy rate (OPR) and incidence of ovarian hyperstimulation syndrome (OHSS) and adverse events (AEs). For statistical pooling, the risk ratio (RR) and its 95% (confidence interval) CI was calculated using a random effects model. RESULTS: Four RCTs including 430 participants were selected. All trials compared acupuncture (MA/EA) against no treatment. Acupuncture significantly increased the CPR (RR 1.33, 95% CI 1.03 to 1.71) and OPR (RR 2.03, 95% CI 1.08 to 3.81) and decreased the risk of OHSS (RR 0.63, 95% CI 0.42 to 0.94); however, there was no significant difference in the LBR (RR 1.61, 95% CI 0.73 to 3.58). None of the RCTs reported on AEs. CONCLUSIONS: Acupuncture may increase the CPR and OPR and decrease the risk of OHSS in women with PCOS undergoing IVF or ICSI. Further studies are needed to confirm the efficacy and safety of acupuncture as an adjunct to assisted reproductive technology in this particular population. PMID- 28077367 TI - Electroacupuncture alleviates the inflammatory response via effects on M1 and M2 macrophages after spinal cord injury. AB - BACKGROUND: Macrophages/microglia are important effector cells at the site of spinal cord injury (SCI). M1-type macrophages facilitate innate immunity to remove foreign microbes and wound debris from the injury site. M2-type macrophages exhibit tissue repair properties and attenuate production of pro inflammatory cytokines. Regulation of the polarisation of M1/M2 macrophages may affect the inflammatory response in SCI and may be related to neurotrophin-3 (NT 3). Electroacupuncture (EA) at GV acupuncture points can be used as an adjuvant therapy for SCI. AIM: To investigate the effects of EA on Basso, Beattie and Bresnahan (BBB) functional evaluation and inflammatory cytokines (tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and IL-10), and on the proportions of M1/M2 macrophages, and to provide a greater understanding of the mechanisms underlying the potential clinical treatment of SCI. METHODS: A rat SCI model was induced by spinal segment transection at T10 in 16 Sprague-Dawley rats. A further eight rats were included as a Control group. Ten surviving SCI model rats were divided into two groups (n=5 each): an SCI group that remained untreated; and an SCI+EA group that received EA at GV6 and GV9. RESULTS: EA improved BBB scores, inhibited the proportion of M1 macrophages and TNF-alpha, IL 1beta and IL-6 levels, and downregulated the M1 marker CD86. By contrast, EA enhanced IL-10, the proportion of M2 macrophages and upregulated the M2 marker CD206 and NT-3 expression. CONCLUSIONS: EA had a positive impact on SCI model rats. This may be related to the neuroprotective effect of NT-3, which may increase the polarisation of M2 microglia/macrophages. PMID- 28077368 TI - Team meetings do not devote enough time to complex cancer cases, report warns. PMID- 28077369 TI - The relationship between central visual field sensitivity and macular ganglion cell/inner plexiform layer thickness in glaucoma. AB - AIMS: To explore the correlation of local macular ganglion cell/inner plexiform layer (GC/IPL) thickness measurements with sensitivity at individual test locations on the central 10-2 visual fields (VFs) in patients with glaucoma. METHODS: One hundred thirty-seven eyes of 125 patients with spectral domain optical coherence tomography (OCT) and 10-2 VFs were included. The exported thickness matrices (200*200) of GC/IPL measurements were centred on the fovea. Total deviation values at each test location were correlated with the 20 000 GC/IPL thickness measurements in the corresponding inferior or superior hemiretina, and areas of highest correlation were plotted. Macular structure function relationships were also examined between six wedge-shaped GC/IPL sectors and the corresponding VF clusters. A multivariate model was built to identify the 10-2 VF test locations associated with each GC/IPL sector thickness. RESULTS: Average mean deviation on 10-2 VFs was -9.2+/-6.1 dB. The 10-2 VF test points demonstrated correlations with GC/IPL thickness in localised arcuate patterns mostly limited within the central 4.8*4.0 mm measurement ellipse (rho=0.43-0.74, p<0.05 for all). Twenty-one test points of the 10-2 VF were the best predictors of sectoral GC/IPL thickness. Sectoral VF-OCT correlations were high (rho=0.53 0.66, p<0.001) and did not significantly change after adjusting for retinal GC displacement (p>0.05). CONCLUSIONS: Macular OCT/VF relationships have localised arcuate characteristics in the central region of the macula. Given the overlapping nature of structure-function relationships, a smaller number of VF test locations may be used to summarise macular functional damage. TRIAL REGISTRATION NUMBER: NCT01742819. PMID- 28077370 TI - Preoperative aqueous humour flare values do not predict proliferative vitreoretinopathy in patients with rhegmatogenous retinal detachment. AB - BACKGROUND/AIMS: Patients with rhegmatogenous retinal detachment (RRD) who develop postoperative proliferative vitreoretinopathy (PVR) have been found to have higher preoperative laser flare values than patients with RRD who do not develop this complication. Measurement of laser flare has therefore been proposed as an objective, rapid and non-invasive method for identifying high-risk patients. The purpose of our study was to validate the use of preoperative flare values as a predictor of PVR risk in two additional patient cohorts, and to confirm the sensitivity and specificity of this method for identifying high-risk patients. METHODS: We combined data from two independent prospective studies: centre 1 (120 patients) and centre 2 (194 patients). Preoperative aqueous humour flare was measured with a Kowa FM-500 Laser Flare Meter. PVR was defined as redetachment due to the formation of traction membranes that required reoperation within 6 months of initial surgery. Logistic regression and receiver operating characteristic analysis determined whether higher preoperative flare values were associated with an increased risk of postoperative PVR. RESULTS: PVR redetachment developed in 21/314 patients (6.7%). Median flare values differed significantly between centres, therefore analyses were done separately. Logistic regression showed a small but statistically significant increase in odds with increasing flare only for centre 2 (OR 1.014; p=0.005). Areas under the receiver operating characteristic showed low sensitivity and specificity: centre 1, 0.634 (95% CI 0.440 to 0.829) and centre 2, 0.731 (95% CI 0.598 to 0.865). CONCLUSIONS: Preoperative laser flare measurements are inaccurate in discriminating between those patients with RRD at high and low risk of developing PVR. PMID- 28077371 TI - Markers of endothelial damage in patients with chronic kidney disease on hemodialysis. AB - Patients with Stage 5 chronic kidney disease who are on hemodialysis (HD) remain in a chronic inflammatory state, characterized by the accumulation of uremic toxins that induce endothelial damage and cardiovascular disease (CVD). Our aim was to examine microvesicles (MVs), monocyte subpopulations, and angiopoietins (Ang) to identify prognostic markers in HD patients with or without diabetes mellitus (DM). A total of 160 prevalent HD patients from 10 centers across Spain were obtained from the Biobank of the Nephrology Renal Network (Madrid, Spain): 80 patients with DM and 80 patients without DM who were matched for clinical and demographic criteria. MVs from plasma and several monocyte subpopulations (CD142+/CD16+, CD14+/CD162+) were analyzed by flow cytometry, and the plasma concentrations of Ang1 and Ang2 were quantified by ELISA. Data on CVD were gathered over the 5.5 yr after these samples were obtained. MV level, monocyte subpopulations (CD14+/CD162+ and CD142+/CD16+), and Ang2-to-Ang1 ratios increased in HD patients with DM compared with non-DM patients. Moreover, MV level above the median (264 MVs/ul) was associated independently with greater mortality. MVs, monocyte subpopulations, and Ang2-to-Ang1 ratio can be used as predictors for CVD. In addition, MV level has a potential predictive value in the prevention of CVD in HD patients. These parameters undergo more extensive changes in patients with DM. PMID- 28077372 TI - Extracellular microRNA signature in chronic kidney disease. AB - MicroRNAs (miRNAs) are noncoding RNAs that regulate posttranscriptional gene expression. In this study we characterized the circulating and urinary miRNA pattern associated with reduced glomerular filtration rate, using Affymetrix GeneChip miR 4.0 in 28 patients with chronic kidney disease (CKD). Top miRNA discoveries from the human studies were validated in an Alb/TGFbeta mouse model of CKD, and in rat renal proximal tubular cells (NRK52E) exposed to TGFbeta1. Plasma and urinary levels of procollagen III N-terminal propeptide and collagen IV were elevated in patients with decreased estimated glomerular filtration rate (eGFR). Expression of 384 urinary and 266 circulatory miRNAs were significantly different between CKD patients with eGFR >=30 vs. <30 ml.min-1.1.73 m-2 Pathway analysis mapped multiple miRNAs to TGFbeta signaling-related mRNA targets. Specifically, Let-7a was significantly downregulated, and miR-130a was significantly upregulated, in urine of patients with eGFR <30; miR-1825 and miR 1281 were upregulated in both urine and plasma of patients with decreased eGFR; and miR-423 was significantly downregulated in plasma of patients with decreased eGFR. miRNA expression in urine and plasma of Alb/TGFbeta mice generally resembled and confirmed most, although not all, of the observations from the human studies. In response to TGFbeta1 exposure, rat renal proximal tubular cells overexpressed miR-1825 and downregulated miR-423. Thus, miRNA are associated with kidney fibrosis, and specific urinary and plasma miRNA profile may have diagnostic and prognostic utility in CKD. PMID- 28077373 TI - Determination of renal function and injury using near-infrared fluorimetry in experimental cardiorenal syndrome. AB - Cardiorenal syndrome type 1 causes acute kidney injury but is poorly understood; animal models and diagnostic aids are lacking. Robust noninvasive measurements of glomerular filtration rate are required for injury models and clinical use. Several have been described but are untested in translational models and suffer from biologic interference. We developed a mouse model of cardiorenal syndrome and tested the novel near-infrared fluorophore ZW800-1 to assess renal and cardiac function. We performed murine cardiac arrest and cardiopulmonary resuscitation followed by transthoracic echocardiography, 2 and 24 h later. Transcutaneous fluorescence of ZW800-1 bolus dispersion and clearance was assessed with whole animal imaging and compared with glomerular filtration rate (GFR; inulin clearance), tubular cell death (using unbiased stereology), and serum creatinine. Correlation, Bland-Altman, and polar analyses were used to compare GFR with ZW800-1 clearance. Cardiac arrest and cardiopulmonary resuscitation caused reversible cardiac failure, halving fractional shortening of the left ventricle (n = 12, P = 0.03). Acute kidney injury resulted with near zero GFR and sixfold increase in serum creatinine 24 h later (n = 16, P < 0.01). ZW800-1 biodistribution and clearance were exclusively renal. ZW800-1 t1/2 and clearance correlated with GFR (r = 0.92, n = 31, P < 0.0001). ZW800-1 fluorescence was reduced in cardiac arrest, and cardiopulmonary resuscitation treated mice compared with sham animals 810 s after injection (P < 0.01) and bolus time-dispersion curves demonstrated that ZW800-1 fluorescence dispersion correlated with left ventricular function (r = 0.74, P < 0.01). Cardiac arrest and cardiopulmonary resuscitation lead to experimental cardiorenal syndrome type 1. ZW800-1, a small near-infrared fluorophore being developed for clinical intraoperative imaging, is favorable for evaluating cardiac and renal function noninvasively. PMID- 28077374 TI - Parallel microarray profiling identifies ErbB4 as a determinant of cyst growth in ADPKD and a prognostic biomarker for disease progression. AB - Autosomal dominant polycystic kidney disease (ADPKD) is the fourth most common cause of end-stage renal disease. The disease course can be highly variable and treatment options are limited. To identify new therapeutic targets and prognostic biomarkers of disease, we conducted parallel discovery microarray profiling in normal and diseased human PKD1 cystic kidney cells. A total of 1,515 genes and 5 miRNA were differentially expressed by more than twofold in PKD1 cells. Functional enrichment analysis identified 30 dysregulated signaling pathways including the epidermal growth factor (EGF) receptor pathway. In this paper, we report that the EGF/ErbB family receptor ErbB4 is a major factor driving cyst growth in ADPKD. Expression of ErbB4 in vivo was increased in human ADPKD and Pkd1 cystic kidneys, both transcriptionally and posttranscriptionally by mir-193b 3p. Ligand-induced activation of ErbB4 drives cystic proliferation and expansion suggesting a pathogenic role in cystogenesis. Our results implicate ErbB4 activation as functionally relevant in ADPKD, both as a marker of disease activity and as a new therapeutic target in this major kidney disease. PMID- 28077375 TI - Body composition, diet, and physical activity: a longitudinal cohort study in preschoolers with cerebral palsy. AB - BACKGROUND: Altered body composition in children with cerebral palsy (CP) could be due to differences in energy intake, habitual physical activity (HPA), and sedentary time. OBJECTIVE: We investigated the longitudinal relation between the weight-for-age z score (WZ), fat-free mass (FFM), percentage of body fat (%BF), and modifiable lifestyle factors for all Gross Motor Function Classification System (GMFCS) levels (I-V). DESIGN: The study was a longitudinal population based cohort study of children with CP who were aged 18-60 mo (364 assessments in 161 children; boys: 61%; mean +/- SD recruitment age: 2.8 +/- 0.9 y; GMFCS: I, 48%; II, 11%; III, 15%; IV, 11%; and V, 15%). A deuterium dilution technique or bioelectrical impedance analysis was used to estimate FFM, and the %BF was calculated. Energy intake, HPA, and sedentary time were measured with the use of a 3-d weighed food diary and accelerometer wear. Data were analyzed with the use of a mixed-model analysis. RESULTS: Children in GMFCS group I did not differ from age- and sex-specific reference children with typical development for weight. Children in GMFCS group IV were lighter-for-age, and children in GMFCS group V had a lower FFM-for-height than those in GMFCS group I. Children in GMFCS groups II-V had a higher %BF than that of children in GMFCS group I, with the exception of orally fed children in GMFCS group V. The mean %BF of children with CP classified them as overfat or obese. There was a positive association between energy intake and FFM and also between HPA level and FFM for children in GMFCS group I. CONCLUSIONS: Altered body composition was evident in preschool-age children with CP across functional capacities. Gross motor function, feeding method, energy intake, and HPA level in GMFCS I individuals are the strongest predictors of body composition in children with CP between the ages of 18 and 60 mo. PMID- 28077376 TI - Dietary intake and peripheral arterial disease incidence in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study. AB - Background: Peripheral arterial disease (PAD) is a costly source of morbidity and mortality among older persons in the United States. Dietary intake plays a role in the development of atherosclerotic cardiovascular disease; however, few studies have examined the relation of food intake or dietary patterns with PAD.Objective: We examined the relation between habitual dietary intake at midlife and incident PAD over ~20 y of follow-up.Design: Among 14,082 participants enrolled in the ARIC (Atherosclerosis Risk in Communities) Study initially free of PAD, dietary intake was assessed at baseline in 1987-1989 by using a modified Harvard food-frequency questionnaire. Food groups were created, and principal components analysis was used to develop "healthy" and "Western" dietary patterns; both were categorized into quintiles or quartiles. Incident PAD was determined by an ankle-brachial index <0.9 assessed at 2 subsequent examinations and hospital discharge codes through 2012. Multivariate-adjusted Cox proportional hazards regression was used.Results: During a mean follow-up of 19.9 y, 1569 participants developed incident PAD. In models adjusted for demographic characteristics, behaviors, and food groups, the HRs (95% CIs) for incident PAD increased across quintiles of meat consumption [quintile 1: reference, quintile 2: 1.38 (1.16, 1.65), quintile 3: 1.38 (1.16, 1.65), quintile 4: 1.45 (1.20, 1.74), quintile 5: 1.66 (1.36, 2.03); P-trend <0.001]. Compared with those who drank no alcohol, those who had 1-6 drinks/wk had a lower risk of incident PAD [0.78 (0.68, 0.89)]. For coffee, >=4 cups/d compared with none was inversely associated with incident PAD [quintile 5 compared with quintile 1: 0.84 (0.75, 1.00); P-trend = 0.014]. There was no association between other food groups or patterns and incident PAD.Conclusions: In this prospective cohort study, greater meat consumption was associated with a higher risk, and moderate alcohol consumption was associated with a lower risk of incident PAD. Whether these associations are causal remains to be seen. This trial was registered at clinicaltrials.gov as NCT00005131. PMID- 28077377 TI - A new universal dynamic model to describe eating rate and cumulative intake curves. AB - BACKGROUND: Attempts to model cumulative intake curves with quadratic functions have not simultaneously taken gustatory stimulation, satiation, and maximal food intake into account. OBJECTIVE: Our aim was to develop a dynamic model for cumulative intake curves that captures gustatory stimulation, satiation, and maximal food intake. DESIGN: We developed a first-principles model describing cumulative intake that universally describes gustatory stimulation, satiation, and maximal food intake using 3 key parameters: 1) the initial eating rate, 2) the effective duration of eating, and 3) the maximal food intake. These model parameters were estimated in a study (n = 49) where eating rates were deliberately changed. Baseline data was used to determine the quality of model's fit to data compared with the quadratic model. The 3 parameters were also calculated in a second study consisting of restrained and unrestrained eaters. Finally, we calculated when the gustatory stimulation phase is short or absent. RESULTS: The mean sum squared error for the first-principles model was 337.1 +/- 240.4 compared with 581.6 +/- 563.5 for the quadratic model, or a 43% improvement in fit. Individual comparison demonstrated lower errors for 94% of the subjects. Both sex (P = 0.002) and eating duration (P = 0.002) were associated with the initial eating rate (adjusted R2 = 0.23). Sex was also associated (P = 0.03 and P = 0.012) with the effective eating duration and maximum food intake (adjusted R2 = 0.06 and 0.11). In participants directed to eat as much as they could compared with as much as they felt comfortable with, the maximal intake parameter was approximately double the amount. The model found that certain parameter regions resulted in both stimulation and satiation phases, whereas others only produced a satiation phase. CONCLUSIONS: The first-principles model better quantifies interindividual differences in food intake, shows how aspects of food intake differ across subpopulations, and can be applied to determine how eating behavior factors influence total food intake. PMID- 28077378 TI - Peripheral skeleton bone strength is positively correlated with total and dairy protein intakes in healthy postmenopausal women. AB - BACKGROUND: Bone mineral content (BMC) and bone mineral density (BMD) are positively correlated with dietary protein intakes, which account for 1-8% of BMC and BMD variances. However, the relation between bone strength and microstructure, which are variables that are not captured by areal bone mineral density (aBMD), and dietary protein intakes, particularly from specific dietary sources, has not been clearly established. OBJECTIVE: We investigated the association between the peripheral skeleton-predicted failure load and stiffness, bone microstructure, and dietary protein intakes from various origins (animal, divided into dairy and nondairy, and vegetable origins) in healthy postmenopausal women. DESIGN: In a cross-sectional study in 746 Caucasian women aged 65.0 +/- 1.4 y, we measured the aBMD with the use of dual-energy X-ray absorptiometry, the distal radius and tibia bone microstructures with the use of high-resolution peripheral quantitative computerized tomography, and bone strength with the use of a finite element analysis, and we evaluated dietary protein and calcium with the use of a validated food-frequency questionnaire. RESULTS: Mean dietary calcium and protein intakes were greater than recommended amounts for this class of age. The predicted failure load and stiffness at the distal radius and tibia were positively associated with total, animal, and dairy protein intakes but not with vegetable protein intake. Failure load differences were accompanied by modifications of the aBMD and of cortical and trabecular bone microstructures. The associations remained statistically significant after adjustment for weight, height, physical activity, menopause duration, calcium intake, and the interaction between calcium and protein intake. A principal component analysis of the volumetric BMD and bone microstructure indicated that trabecular bone mainly contributed to the positive association between protein intakes and bone strength. CONCLUSIONS: These results, which were recorded in a very homogeneous population of healthy postmenopausal women, indicate that there is a beneficial effect of animal and dairy protein intakes on bone strength and microstructure. Specifically, there is a positive association between the bone failure load and stiffness of the peripheral skeleton and dietary protein intake, which is mainly related to changes in the trabecular microstructure. This trial was registered at www.controlled-trials.com as ISRCTN11865958. PMID- 28077379 TI - Effects of supplementation with nondigestible carbohydrates on fecal calprotectin and on epigenetic regulation of SFRP1 expression in the large-bowel mucosa of healthy individuals. AB - BACKGROUND: Hyperactive Wnt signaling is frequently observed in colorectal cancer. Higher intakes of dietary fiber [nondigestible carbohydrates (NDCs)] and the fermentation product butyrate are protective against colorectal cancer and may exert their preventative effects via modulation of the Wnt pathway. OBJECTIVES: We investigated the effects of supplementing healthy individuals with 2 NDCs [resistant starch (RS) and polydextrose] on fecal calprotectin concentrations and Wnt pathway-related gene expression. In addition, we determined whether effects on secreted frizzled-related protein 1 (SFRP1) expression are mediated via the epigenetic mechanisms DNA methylation and microRNA expression. DESIGN: In a randomized, double-blind, placebo-controlled trial (the Dietary Intervention, Stem cells and Colorectal Cancer (DISC) Study), 75 healthy participants were supplemented with RS and/or polydextrose or placebo for 50 d in a 2 * 2 factorial design. Pre- and postintervention stool samples and rectal mucosal biopsies were collected and used to quantify calprotectin and expression of 12 Wnt-related genes, respectively. The expression of 10 microRNAs predicted to target SFRP1 was also quantified by quantitative reverse transcriptase-polymerase chain reaction, and DNA methylation was quantified at 7 CpG sites within the SFRP1 promoter region by pyrosequencing. RESULTS: NDC supplementation did not affect fecal calprotectin concentration. SFRP1 mRNA expression was reduced by both RS (P = 0.005) and polydextrose (P = 0.053). RS and polydextrose did not affect SFRP1 methylation or alter the expression of 10 microRNAs predicted to target SFRP1. There were no significant interactions between RS and polydextrose. CONCLUSIONS: RS and polydextrose supplementation did not affect fecal calprotectin concentrations. Downregulation of SFRP1 with RS and polydextrose could result in increased Wnt pathway activity. However, effects on Wnt pathway activity and downstream functional effects in the healthy large-bowel mucosa remain to be investigated. The DISC Study was registered at clinicaltrials.gov as NCT01214681. PMID- 28077380 TI - Metabolomic profiles as reliable biomarkers of dietary composition. AB - Background: Clinical nutrition research often lacks robust markers of compliance, complicating the interpretation of clinical trials and observational studies of free-living subjects.Objective: We aimed to examine metabolomics profiles in response to 3 diets that differed widely in macronutrient composition during a controlled feeding protocol.Design: Twenty-one adults with a high body mass index (in kg/m2; mean +/- SD: 34.4 +/- 4.9) were given hypocaloric diets to promote weight loss corresponding to 10-15% of initial body weight. They were then studied during weight stability while consuming 3 test diets, each for a 4-wk period according to a crossover design: low fat (60% carbohydrate, 20% fat, 20% protein), low glycemic index (40% carbohydrate, 40% fat, 20% protein), or very low carbohydrate (10% carbohydrate, 60% fat, 30% protein). Plasma samples were obtained at baseline and at the end of each 4-wk period in the fasting state for metabolomics analysis by using liquid chromatography-tandem mass spectrometry. Statistical analyses included adjustment for multiple comparisons.Results: Of 333 metabolites, we identified 152 whose concentrations differed for >=1 diet compared with the others, including diacylglycerols and triacylglycerols, branched-chain amino acids, and markers reflecting metabolic status. Analysis of groups of related metabolites, with the use of either principal components or pathways, revealed coordinated metabolic changes affected by dietary composition, including pathways related to amino acid metabolism. We constructed a classifier using the metabolites that differed between diets and were able to correctly identify the test diet from metabolite profiles in 60 of 63 cases (>95% accuracy). Analyses also suggest differential effects by diet on numerous cardiometabolic disease risk factors.Conclusions: Metabolomic profiling may be used to assess compliance during clinical nutrition trials and the validity of dietary assessment in observational studies. In addition, this methodology may help elucidate mechanistic pathways linking diet to chronic disease risk. This trial was registered at clinicaltrials.gov as NCT00315354. PMID- 28077382 TI - Bimodal Pattern of Coronary Microvascular Involvement in Diabetes Mellitus. PMID- 28077383 TI - Neurological Injury in Intermediate-Risk Transcatheter Aortic Valve Implantation. PMID- 28077381 TI - Metabolic syndrome increases dietary alpha-tocopherol requirements as assessed using urinary and plasma vitamin E catabolites: a double-blind, crossover clinical trial. AB - Background: Vitamin E supplementation improves liver histology in patients with nonalcoholic steatohepatitis, which is a manifestation of the metabolic syndrome (MetS). We reported previously that alpha-tocopherol bioavailability in healthy adults is higher than in those with MetS, thereby suggesting that the latter group has increased requirements.Objective: We hypothesized that alpha-tocopherol catabolites alpha-carboxyethyl hydroxychromanol (alpha-CEHC) and alpha carboxymethylbutyl hydroxychromanol (alpha-CMBHC) are useful biomarkers of alpha tocopherol status.Design: Adults (healthy or with MetS; n = 10/group) completed a double-blind, crossover clinical trial with four 72-h interventions during which they co-ingested 15 mg hexadeuterium-labeled RRR-alpha-tocopherol (d6-alpha-T) with nonfat, reduced-fat, whole, or soy milk. During each intervention, we measured alpha-CEHC and alpha-CMBHC excretions in three 8-h urine collections (0 24 h) and plasma alpha-tocopherol, alpha-CEHC, and alpha-CMBHC concentrations at various times <=72 h.Results: During the first 24 h, participants with MetS compared with healthy adults excreted 41% less alpha-CEHC (all values are least squares means +/- SEMs: 0.6 +/- 0.1 compared with 1.0 +/- 0.1 MUmol/g creatinine, respectively; P = 0.002), 63% less hexadeuterium-labeled (d6)-alpha-CEHC (0.04 +/ 0.02 compared with 0.13 +/- 0.02 MUmol/g creatinine, respectively; P = 0.002), and 58% less d6-alpha-CMBHC (0.017 +/- 0.004 compared with 0.041 +/- 0.004 MUmol/g creatinine, respectively; P = 0.0009) and had 52% lower plasma d6-alpha CEHC areas under the concentration curves [area under the curve from 0 to 24 h (AUC0-24h): 27.7 +/- 7.9 compared with 58.4 +/- 7.9 nmol/L * h, respectively; P = 0.01]. d6-alpha-CEHC peaked before d6-alpha-T in 77 of 80 paired plasma concentration curves. Urinary d6-alpha-CEHC 24-h concentrations were associated with the plasma AUC0-24 h of d6-alpha-T (r = 0.53, P = 0.02) and d6-alpha-CEHC (r = 0.72, P = 0.0003), and with urinary d6-alpha-CMBHC (r = 0.88, P < 0.0001), and inversely with the plasma inflammation biomarkers C-reactive protein (r = -0.70, P = 0.0006), interleukin-10 (r = -0.59, P = 0.007), and interleukin-6 (r = -0.54, P = 0.01).Conclusion: Urinary alpha-CEHC and alpha-CMBHC are useful biomarkers to noninvasively assess alpha-tocopherol adequacy, especially in populations with MetS-associated hepatic dysfunction that likely impairs alpha-tocopherol trafficking. This trial was registered at clinicaltrials.gov as NCT01787591. PMID- 28077384 TI - Predictors of Nonuse of a High-Potency Statin After an Acute Coronary Syndrome: Insights From the Stabilization of Plaques Using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) Trial. AB - BACKGROUND: High-potency statins reduce cardiovascular events after acute coronary syndromes but remain underused in clinical practice. We examined predictors of nonuse of high-potency statins after acute coronary syndromes. METHODS AND RESULTS: The Stabilization of pLaques usIng Darapladib-Thrombolysis in Myocardial Infarction (SOLID-TIMI 52) trial enrolled patients after an acute coronary syndrome in 36 countries between 2009 and 2011. Statin use was strongly encouraged throughout the trial, and statin potency was at the discretion of the treating physician. A high-potency statin was defined as >=40 mg atorvastatin, >=20 mg rosuvastatin, or 80 mg simvastatin daily. Predictors of nonuse of high potency statins were examined using logistic regression. Of the patients included (n=12 446), 11 850 (95.2%) were treated with a statin at baseline after acute coronary syndrome (median 14 days), but only 5212 (41.9%) were on a high-potency statin. Selected patient factors associated with nonuse of high-potency statins included age >=75 years (odds ratio 1.39, 95% CI 1.24-1.56), female sex (odds ratio 1.11, 95% CI 1.02-1.22), renal dysfunction (odds ratio 1.17, 95% CI 1.03 1.32), and heart failure during hospital admission (odds ratio 1.43, 95% CI 1.27 1.62). At 3 months after baseline, only 49% of patients had low-density lipoprotein cholesterol <70 mg/dL. Among the 5490 patients (59%) who were not on a high-potency statin at 3 months, lower low-density lipoprotein cholesterol was a predictor of nonuse of a high-potency statin after a median of 2.3 years (odds ratio 1.15 for 10 mg/dL decrease, 95% CI 1.11-1.19). CONCLUSION: Despite the widespread use of statins after acute coronary syndromes, most patients are not treated with high-potency statins early and late after the event, including patients at the highest risk of recurrent cardiovascular events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01000727. PMID- 28077385 TI - Impact of Sex and Contact-to-Device Time on Clinical Outcomes in Acute ST-Segment Elevation Myocardial Infarction-Findings From the National Cardiovascular Data Registry. AB - BACKGROUND: Emergent myocardial reperfusion via primary percutaneous coronary intervention is optimal care for patients presenting with ST-segment elevation myocardial infarction (STEMI). Delays in such interventions are associated with increases in mortality. With the shift in focus to contact-to-device (C2D) time as a new perfusion metric, this study was designed to examine how sex affects C2D time and mortality in STEMI patients. METHODS AND RESULTS: Clinical data on male and female STEMI patients were extracted and analyzed from the National Cardiovascular Data Registry from July 1, 2008 to December 31, 2014. A total of 102 515 patients were included in the final analytic cohort. The median C2D time in female patients with STEMI was delayed when compared to male patients (80 [65 97] versus 75 [61-90] minutes; P<0.001). The unadjusted mortality was higher in female patients when compared to male patients with STEMI (4.1% versus 2.0%; P<0.001). For every 5-minute increase in C2D time, the adjusted odds ratio for mortality was 1.04 (95% CI, 1.03-1.06) for female patients with STEMI and 1.07 (95% CI, 1.06-1.09) for male patients (P for sex by C2D interaction=0.003). CONCLUSIONS: To date, this is the largest analysis of STEMI patients that measures the impact of the new recommended C2D reperfusion metric on in-hospital mortality. Female STEMI patients have longer C2D times and increased mortality. The disparity can be improved and survival can increase in this high-risk patient cohort by decreasing systems issues that cause increased reperfusion times in female STEMI patients. PMID- 28077387 TI - Molecular physiological exploration beyond the transcriptome. Focus on "Molecular mechanisms underlying active desalination and low water permeability in the esophagus of eels acclimated to seawater". PMID- 28077386 TI - Hypertension Severity Is Associated With Impaired Cognitive Performance. AB - BACKGROUND: Most evidence of target-organ damage in hypertension (HTN) is related to the kidneys and heart. Cerebrovascular and cognitive impairment are less well studied. Therefore, this study analyzed changes in cognitive function in patients with different stages of hypertension compared to nonhypertensive controls. METHODS AND RESULTS: In a cross-sectional study, 221 (71 normotensive and 150 hypertensive) patients were compared. Patients with hypertension were divided into 2 stages according to blood pressure (BP) levels or medication use (HTN-1: BP, 140-159/90-99 or use of 1 or 2 antihypertensive drugs; HTN-2: BP, >=160/100 or use of >=3 drugs). Three groups were comparatively analyzed: normotension, HTN stage 1, and HTN stage 2. The Mini-Mental State Examination, Montreal Cognitive Assessment, and a validated comprehensive battery of neuropsychological tests that assessed 6 main cognitive domains were used to determine cognitive function. Compared to the normotension and HTN stage-1, the severe HTN group had worse cognitive performance based on Mini-Mental State Examination (26.8+/-2.1 vs 27.4+/-2.1 vs 28.0+/-2.0; P=0.004) or Montreal Cognitive Assessment (23.4+/-3.7 vs 24.9+/-2.8 vs 25.5+/-3.2; P<0.001). On the neuropsychological tests, patients with hypertension had worse performance in language, processing speed, visuospatial abilities, and memory. Age, hypertension stage, and educational level were the best predictors of cognitive impairment in patients with hypertension in different cognitive domains. CONCLUSIONS: Cognitive impairment was more frequent in patients with hypertension, and this was related to hypertension severity. PMID- 28077388 TI - Na+-taurocholate cotransporting polypeptide (NTCP/SLC10A1) ortholog in the marine skate Leucoraja erinacea is not a physiological bile salt transporter. AB - The Na+-dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1) is a hepatocyte-specific solute carrier, which plays an important role in maintaining bile salt homeostasis in mammals. The absence of a hepatic Na+-dependent bile salt transport system in marine skate and rainbow trout raises a question regarding the function of the Slc10a1 gene in these species. Here, we have characterized the Slc10a1 gene in the marine skate, Leucoraja erinacea The transcript of skate Slc10a1 (skSlc10a1) encodes 319 amino acids and shares 46% identity to human NTCP (hNTCP) with similar topology to mammalian NTCP. SkSlc10a1 mRNA was mostly confined to the brain and testes with minimal expression in the liver. An FXR-bile salt reporter assay indicated that skSlc10a1 transported taurocholic acid (TCA) and scymnol sulfate, but not as effectively as hNTCP. An [3H]TCA uptake assay revealed that skSlc10a1 functioned as a Na+-dependent transporter, but with low affinity for TCA (Km = 92.4 uM) and scymnol sulfate (Ki = 31 uM), compared with hNTCP (TCA, Km = 5.4 uM; Scymnol sulfate, Ki = 3.5 uM). In contrast, the bile salt concentration in skate plasma was 2 uM, similar to levels seen in mammals. Interestingly, skSlc10a1 demonstrated transport activity for the neurosteroids dehydroepiandrosterone sulfate and estrone-3-sulfate at physiological concentration, similar to hNTCP. Together, our findings indicate that skSlc10a1 is not a physiological bile salt transporter, providing a molecular explanation for the absence of a hepatic Na+-dependent bile salt uptake system in skate. We speculate that Slc10a1 is a neurosteroid transporter in skate that gained its substrate specificity for bile salts later in vertebrate evolution. PMID- 28077390 TI - Reversible temperature-dependent differences in brown adipose tissue respiration during torpor in a mammalian hibernator. AB - Although seasonal modifications of brown adipose tissue (BAT) in hibernators are well documented, we know little about functional regulation of BAT in different phases of hibernation. In the 13-lined ground squirrel, liver mitochondrial respiration is suppressed by up to 70% during torpor. This suppression is reversed during arousal and interbout euthermia (IBE), and corresponds with patterns of maximal activities of electron transport system (ETS) enzymes. Uncoupling of BAT mitochondria is controlled by free fatty acid release stimulated by sympathetic activation of adipocytes, so we hypothesized that further regulation at the level of the ETS would be of little advantage. As predicted, maximal ETS enzyme activities of isolated BAT mitochondria did not differ between torpor and IBE. In contrast to this pattern, respiration rates of mitochondria isolated from torpid individuals were suppressed by ~60% compared with rates from IBE individuals when measured at 37 degrees C. At 10 degrees C, however, mitochondrial respiration rates tended to be greater in torpor than IBE. As a result, the temperature sensitivity (Q10) of mitochondrial respiration was significantly lower in torpor (~1.4) than IBE (~2.4), perhaps facilitating energy savings during entrance into torpor and thermogenesis at low body temperatures. Despite the observed differences in isolated mitochondria, norepinephrine stimulated respiration rates of isolated BAT adipocytes did not differ between torpor and IBE, perhaps because the adipocyte isolation requires lengthy incubation at 37 degrees C, potentially reversing any changes that occur in torpor. Such changes may include remodeling of BAT mitochondrial membrane phospholipids, which could change in situ enzyme activities and temperature sensitivities. PMID- 28077389 TI - Enhanced oxidative capacity of ground squirrel brain mitochondria during hibernation. AB - During hibernation, thirteen-lined ground squirrels (Ictidomys tridecemlineatus) regularly cycle between bouts of torpor and interbout arousal (IBA). Most of the brain is electrically quiescent during torpor but regains activity quickly upon arousal to IBA, resulting in extreme oscillations in energy demand during hibernation. We predicted increased functional capacity of brain mitochondria during hibernation compared with spring to accommodate the variable energy demands of hibernation. To address this hypothesis, we examined mitochondrial bioenergetics in the ground squirrel brain across three time points: spring (SP), torpor (TOR), and IBA. Respiration rates of isolated brain mitochondria through complex I of the electron transport chain were more than twofold higher in TOR and IBA than in SP (P < 0.05). We also found a 10% increase in membrane potential between hibernation and spring (P < 0.05), and that proton leak was lower in TOR and IBA than in SP. Finally, there was a 30% increase in calcium loading in SP brain mitochondria compared with TOR and IBA (P < 0.01). To analyze brain mitochondrial abundance between spring and hibernation, we measured the ratio of copy number in a mitochondrial gene (ND1) vs. a nuclear gene (B2M) in frozen cerebral cortex samples. No significant differences were observed in DNA copies between SP and IBA. These data show that brain mitochondrial bioenergetics are not static across the year and suggest that brain mitochondria function more effectively during the hibernation season, allowing for rapid production of energy to meet demand when extreme physiological changes are occurring. PMID- 28077391 TI - Acclimation to hypoxia increases carbohydrate use during exercise in high altitude deer mice. AB - The low O2 experienced at high altitude is a significant challenge to effective aerobic locomotion, as it requires sustained tissue O2 delivery in addition to the appropriate allocation of metabolic substrates. Here, we tested whether high- and low-altitude deer mice (Peromyscus maniculatus) have evolved different acclimation responses to hypoxia with respect to muscle metabolism and fuel use during submaximal exercise. Using F1 generation high- and low-altitude deer mice that were born and raised in common conditions, we assessed 1) fuel use during exercise, 2) metabolic enzyme activities, and 3) gene expression for key transporters and enzymes in the gastrocnemius. After hypoxia acclimation, highland mice showed a significant increase in carbohydrate oxidation and higher relative reliance on this fuel during exercise at 75% maximal O2 consumption. Compared with lowland mice, highland mice had consistently higher activities of oxidative and fatty acid oxidation enzymes in the gastrocnemius. In contrast, only after hypoxia acclimation did activities of hexokinase increase significantly in the muscle of highland mice to levels greater than lowland mice. Highland mice also responded to acclimation with increases in muscle gene expression for hexokinase 1 and 2 genes, whereas both populations increased mRNA expression for glucose transporters. Changes in skeletal muscle with acclimation suggest that highland mice had an increased capacity for the uptake and oxidation of circulatory glucose. Our results demonstrate that highland mice have evolved a distinct mode of hypoxia acclimation that involves an increase in carbohydrate use during exercise. PMID- 28077393 TI - Amanda Howe: Champion the GP. PMID- 28077392 TI - Bidirectional crosstalk between the sensory and sympathetic motor systems innervating brown and white adipose tissue in male Siberian hamsters. AB - The brain networks connected to the sympathetic motor and sensory innervations of brown (BAT) and white (WAT) adipose tissues were originally described using two transneuronally transported viruses: the retrogradely transported pseudorabies virus (PRV), and the anterogradely transported H129 strain of herpes simplex virus-1 (HSV-1 H129). Further complexity was added to this network organization when combined injections of PRV and HSV-1 H129 into either BAT or WAT of the same animal generated sets of coinfected neurons in the brain, spinal cord, and sympathetic and dorsal root ganglia. These neurons are well positioned to act as sensorimotor links in the feedback circuits that control each fat pad. We have now determined the extent of sensorimotor crosstalk between interscapular BAT (IBAT) and inguinal WAT (IWAT). PRV152 and HSV-1 H129 were each injected into IBAT or IWAT of the same animal: H129 into IBAT and PRV152 into IWAT. The reverse configuration was applied in a different set of animals. We found single-labeled neurons together with H129+PRV152 coinfected neurons in multiple brain sites, with lesser numbers in the sympathetic and dorsal root ganglia that innervate IBAT and IWAT. We propose that these coinfected neurons mediate sensory sympathetic motor crosstalk between IBAT and IWAT. Comparing the relative numbers of coinfected neurons between the two injection configurations showed a bias toward IBAT-sensory and IWAT-sympathetic motor feedback loops. These coinfected neurons provide a neuroanatomical framework for functional interactions between IBAT thermogenesis and IWAT lipolysis that occurs with cold exposure, food restriction/deprivation, exercise, and more generally with alterations in adiposity. PMID- 28077394 TI - Metal-backed versus all-polyethylene unicompartmental knee arthroplasty: Proximal tibial strain in an experimentally validated finite element model. AB - OBJECTIVES: Up to 40% of unicompartmental knee arthroplasty (UKA) revisions are performed for unexplained pain which may be caused by elevated proximal tibial bone strain. This study investigates the effect of tibial component metal backing and polyethylene thickness on bone strain in a cemented fixed-bearing medial UKA using a finite element model (FEM) validated experimentally by digital image correlation (DIC) and acoustic emission (AE). MATERIALS AND METHODS: A total of ten composite tibias implanted with all-polyethylene (AP) and metal-backed (MB) tibial components were loaded to 2500 N. Cortical strain was measured using DIC and cancellous microdamage using AE. FEMs were created and validated and polyethylene thickness varied from 6 mm to 10 mm. The volume of cancellous bone exposed to < -3000 uepsilon (pathological loading) and < -7000 uepsilon (yield point) minimum principal (compressive) microstrain and > 3000 uepsilon and > 7000 uepsilon maximum principal (tensile) microstrain was computed. RESULTS: Experimental AE data and the FEM volume of cancellous bone with compressive strain < -3000 uepsilon correlated strongly: R = 0.947, R2 = 0.847, percentage error 12.5% (p < 0.001). DIC and FEM data correlated: R = 0.838, R2 = 0.702, percentage error 4.5% (p < 0.001). FEM strain patterns included MB lateral edge concentrations; AP concentrations at keel, peg and at the region of load application. Cancellous strains were higher in AP implants at all loads: 2.2- (10 mm) to 3.2-times (6 mm) the volume of cancellous bone compressively strained < 7000 uepsilon. CONCLUSION: AP tibial components display greater volumes of pathologically overstrained cancellous bone than MB implants of the same geometry. Increasing AP thickness does not overcome these pathological forces and comes at the cost of greater bone resection.Cite this article: C. E. H. Scott, M. J. Eaton, R. W. Nutton, F. A. Wade, S. L. Evans, P. Pankaj. Metal-backed versus all-polyethylene unicompartmental knee arthroplasty: Proximal tibial strain in an experimentally validated finite element model. Bone Joint Res 2017;6:22-30. DOI:10.1302/2046-3758.61.BJR-2016-0142.R1. PMID- 28077395 TI - The effects of posterior cruciate ligament deficiency on posterolateral corner structures under gait- and squat-loading conditions: A computational knee model. AB - OBJECTIVES: The aim of the current study was to analyse the effects of posterior cruciate ligament (PCL) deficiency on forces of the posterolateral corner structure and on tibiofemoral (TF) and patellofemoral (PF) contact force under dynamic-loading conditions. METHODS: A subject-specific knee model was validated using a passive flexion experiment, electromyography data, muscle activation, and previous experimental studies. The simulation was performed on the musculoskeletal models with and without PCL deficiency using a novel force dependent kinematics method under gait- and squat-loading conditions, followed by probabilistic analysis for material uncertain to be considered. RESULTS: Comparison of predicted passive flexion, posterior drawer kinematics and muscle activation with experimental measurements showed good agreement. Forces of the posterolateral corner structure, and TF and PF contact forces increased with PCL deficiency under gait- and squat-loading conditions. The rate of increase in PF contact force was the greatest during the squat-loading condition. The TF contact forces increased on both medial and lateral compartments during gait-loading conditions. However, during the squat-loading condition, the medial TF contact force tended to increase, while the lateral TF contact forces decreased. The posterolateral corner structure, which showed the greatest increase in force with deficiency of PCL under both gait- and squat-loading conditions, was the popliteus tendon (PT). CONCLUSION: PCL deficiency is a factor affecting the variability of force on the PT in dynamic-loading conditions, and it could lead to degeneration of the PF joint.Cite this article: K-T. Kang, Y-G. Koh, M. Jung, J-H. Nam, J. Son, Y.H. Lee, S-J. Kim, S-H. Kim. The effects of posterior cruciate ligament deficiency on posterolateral corner structures under gait- and squat loading conditions: A computational knee model. Bone Joint Res 2017;6:31-42. DOI: 10.1302/2046-3758.61.BJR-2016-0184.R1. PMID- 28077396 TI - The effects of kinematically aligned total knee arthroplasty on stress at the medial tibia: A case study for varus knee. AB - OBJECTIVES: Little biomechanical information is available about kinematically aligned (KA) total knee arthroplasty (TKA). The purpose of this study was to simulate the kinematics and kinetics after KA TKA and mechanically aligned (MA) TKA with four different limb alignments. MATERIALS AND METHODS: Bone models were constructed from one volunteer (normal) and three patients with three different knee deformities (slight, moderate and severe varus). A dynamic musculoskeletal modelling system was used to analyse the kinematics and the tibiofemoral contact force. The contact stress on the tibial insert, and the stress to the resection surface and medial tibial cortex were examined by using finite element analysis. RESULTS: In all bone models, posterior translation on the lateral side and external rotation in the KA TKA models were greater than in the MA TKA models. The tibiofemoral force at the medial side was increased in the moderate and severe varus models with KA TKA. In the severe varus model with KA TKA, the contact stress on the tibial insert and the stress to the resection surface and to the medial tibial cortex were increased by 41.5%, 32.2% and 53.7%, respectively, compared with MA TKA, and the bone strain at the medial side was highest among all models. CONCLUSION: Near normal kinematics was observed in KA TKA. However, KA TKA increased the contact force, stress and bone strain at the medial side for moderate and severe varus knee models. The application of KA TKA for severe varus knees may be inadequate.Cite this article: S. Nakamura, Y. Tian, Y. Tanaka, S. Kuriyama, H. Ito, M. Furu, S. Matsuda. The effects of kinematically aligned total knee arthroplasty on stress at the medial tibia: A case study for varus knee. Bone Joint Res 2017;6:43-51. DOI: 10.1302/2046-3758.61.BJR-2016 0090.R1. PMID- 28077397 TI - Relationships between flortaucipir PET tau binding and amyloid burden, clinical diagnosis, age and cognition. AB - The advent of tau-targeted positron emission tomography tracers such as flortaucipir (18F-AV-1451, also known as 18F-T807) have made it possible to investigate the sequence of development of tau and amyloid-beta in relationship to age, and to the development of cognitive impairment due to Alzheimer's disease. In this study, flortaucipir tau and florbetapir amyloid positron emission tomography were obtained for 217 subjects including 16 young and 58 older cognitively normal subjects, 95 subjects with mild cognitive impairment (Mini-Mental State Examination 24-30) and 48 subjects with clinically-defined possible or probable Alzheimer's disease (Mini-Mental State Examination >10). Images were evaluated visually and quantitatively by regional and voxel-based cortical to cerebellar standard uptake value ratios. For amyloid positron emission tomography positive (Abeta+) subjects, flortaucipir neocortical standard uptake value ratio was significantly higher with more advanced clinical stage (Alzheimer's disease > mild cognitive impairment > older cognitively normal) and was significantly elevated for Abeta+ mild cognitive impairment and Alzheimer's disease subjects relative to the respective Abeta- subjects. In contrast, florbetapir Abeta- older cognitively normal subjects showed an increase in flortaucipir standard uptake value ratios in mesial temporal lobe regions (amygdala, hippocampus/choroid plexus region of interest) compared to younger cognitively normal subjects, but no increased standard uptake value ratios in neocortical regions. Analysis of covariance with planned contrasts showed no differences in regional or composite posterior neocortical flortaucipir standard uptake value ratio as a function of diagnostic group among Abeta- older cognitively normal or clinically diagnosed Alzheimer's disease or mild cognitive impairment subjects. The pattern of flortaucipir distribution among Abeta+ subjects was reminiscent of the cross-sectional distribution of tau reported in post-mortem pathology studies, in that the most commonly affected regions were the inferior and lateral temporal lobes, the same regions where the first signs of increased retention appeared in Abeta+ cognitively normal subjects. However, there was large variability in extent/density of flortaucipir tau binding among Abeta+ subjects. Although high neocortical flortaucipir retention was consistently associated with an Abeta+ florbetapir positron emission tomography scan, not all Abeta+ subjects had elevated flortaucipir standard uptake value ratios. Finally, within the Abeta+ group, increasing levels of flortaucipir tau binding were associated with increased cognitive impairment, as assessed by Mini Mental State Examination and Alzheimer's Disease Assessment Scale. These results suggest development of tau beyond the mesial temporal lobe is associated with, and may be dependent on, amyloid accumulation. Further, the results are consistent with the hypothesis that cortical tau is associated with cognitive impairment. PMID- 28077398 TI - Mild traumatic brain injury is associated with reduced cortical thickness in those at risk for Alzheimer's disease. AB - Moderate-to-severe traumatic brain injury is one of the strongest environmental risk factors for the development of neurodegenerative diseases such as late-onset Alzheimer's disease, although it is unclear whether mild traumatic brain injury, or concussion, also confers risk. This study examined mild traumatic brain injury and genetic risk as predictors of reduced cortical thickness in brain regions previously associated with early Alzheimer's disease, and their relationship with episodic memory. Participants were 160 Iraq and Afghanistan War veterans between the ages of 19 and 58, many of whom carried mild traumatic brain injury and post traumatic stress disorder diagnoses. Whole-genome polygenic risk scores for the development of Alzheimer's disease were calculated using summary statistics from the largest Alzheimer's disease genome-wide association study to date. Results showed that mild traumatic brain injury moderated the relationship between genetic risk for Alzheimer's disease and cortical thickness, such that individuals with mild traumatic brain injury and high genetic risk showed reduced cortical thickness in Alzheimer's disease-vulnerable regions. Among males with mild traumatic brain injury, high genetic risk for Alzheimer's disease was associated with cortical thinning as a function of time since injury. A moderated mediation analysis showed that mild traumatic brain injury and high genetic risk indirectly influenced episodic memory performance through cortical thickness, suggesting that cortical thinning in Alzheimer's disease-vulnerable brain regions is a mechanism for reduced memory performance. Finally, analyses that examined the apolipoprotein E4 allele, post-traumatic stress disorder, and genetic risk for schizophrenia and depression confirmed the specificity of the Alzheimer's disease polygenic risk finding. These results provide evidence that mild traumatic brain injury is associated with greater neurodegeneration and reduced memory performance in individuals at genetic risk for Alzheimer's disease, with the caveat that the order of causal effects cannot be inferred from cross sectional studies. These results underscore the importance of documenting head injuries even within the mild range as they may interact with genetic risk to produce negative long-term health consequences such as neurodegenerative disease. PMID- 28077400 TI - Differential Expression of Hedgehog and Snail in Cutaneous Fibrosing Disorders: Implications for Targeted Inhibition. AB - OBJECTIVES: To examine Hedgehog signaling in cutaneous fibrosing disorders for which effective approved therapies are lacking, expand our knowledge of pathophysiology, and explore the rationale for targeted inhibition. METHODS: Stain intensity and percentage of cells staining for Sonic hedgehog (Shh), Indian hedgehog (Ihh), Patched (Ptch), glycogen synthase kinase 3 beta (GSK3-beta), beta catenin, and Snail were evaluated in human skin biopsy specimens of keloid, hypertrophic scar (Hscar), scleroderma, nephrogenic systemic fibrosis (NSF), scar, and normal skin using a tissue microarray. RESULTS: Ihh, but not Shh, was detected in a significantly larger proportion of cells for all case types. Ptch, GSK3-beta, and beta-catenin showed a gradient of expression: highest in NSF and keloid; moderate in normal skin, scar, and Hscar; and lowest in scleroderma. Snail expression was binary: low in normal skin but high in all fibrosing conditions studied. CONCLUSIONS: Differential overexpression of Hedgehog and Snail in cutaneous fibrosing disorders demonstrates a role for targeted inhibition. Ptch, GSK3-beta, and beta-catenin can help differentiate scleroderma from NSF in histologically subtle cases. Differences in expression between keloid and hypertrophic scar support the concept that they are pathophysiologically distinct disorders. Our findings implicate Snail as a target for the prevention of fibrogenesis or fibrosis progression and may offer a means to assess response to therapy. PMID- 28077402 TI - Elemental metabolomics. AB - Elemental metabolomics is quantification and characterization of total concentration of chemical elements in biological samples and monitoring of their changes. Recent advances in inductively coupled plasma mass spectrometry have enabled simultaneous measurement of concentrations of > 70 elements in biological samples. In living organisms, elements interact and compete with each other for absorption and molecular interactions. They also interact with proteins and nucleotide sequences. These interactions modulate enzymatic activities and are critical for many molecular and cellular functions. Testing for concentration of > 40 elements in blood, other bodily fluids and tissues is now in routine use in advanced medical laboratories. In this article, we define the basic concepts of elemental metabolomics, summarize standards and workflows, and propose minimum information for reporting the results of an elemental metabolomics experiment. Major statistical and informatics tools for elemental metabolomics are reviewed, and examples of applications are discussed. Elemental metabolomics is emerging as an important new technology with applications in medical diagnostics, nutrition, agriculture, food science, environmental science and multiplicity of other areas. PMID- 28077399 TI - HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. AB - CONTEXT: ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. OBJECTIVES: To establish an evidence-based guideline for HER2 testing in patients with GEA, to formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. DESIGN: The College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology convened an expert panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. RESULTS: The panel is proposing 11 recommendations with strong agreement from the open-comment participants. RECOMMENDATIONS: The panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and a HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. CONCLUSIONS: This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results. PMID- 28077405 TI - VRprofile: gene-cluster-detection-based profiling of virulence and antibiotic resistance traits encoded within genome sequences of pathogenic bacteria. AB - VRprofile is a Web server that facilitates rapid investigation of virulence and antibiotic resistance genes, as well as extends these trait transfer-related genetic contexts, in newly sequenced pathogenic bacterial genomes. The used backend database MobilomeDB was firstly built on sets of known gene cluster loci of bacterial type III/IV/VI/VII secretion systems and mobile genetic elements, including integrative and conjugative elements, prophages, class I integrons, IS elements and pathogenicity/antibiotic resistance islands. VRprofile is thus able to co-localize the homologs of these conserved gene clusters using HMMer or BLASTp searches. With the integration of the homologous gene cluster search module with a sequence composition module, VRprofile has exhibited better performance for island-like region predictions than the other widely used methods. In addition, VRprofile also provides an integrated Web interface for aligning and visualizing identified gene clusters with MobilomeDB-archived gene clusters, or a variety set of bacterial genomes. VRprofile might contribute to meet the increasing demands of re-annotations of bacterial variable regions, and aid in the real-time definitions of disease-relevant gene clusters in pathogenic bacteria of interest. VRprofile is freely available at http://bioinfo mml.sjtu.edu.cn/VRprofile. PMID- 28077407 TI - Celebrating 35 Years of the AJNR: January 1982 edition. PMID- 28077403 TI - Gene co-expression analysis for functional classification and gene-disease predictions. AB - Gene co-expression networks can be used to associate genes of unknown function with biological processes, to prioritize candidate disease genes or to discern transcriptional regulatory programmes. With recent advances in transcriptomics and next-generation sequencing, co-expression networks constructed from RNA sequencing data also enable the inference of functions and disease associations for non-coding genes and splice variants. Although gene co-expression networks typically do not provide information about causality, emerging methods for differential co-expression analysis are enabling the identification of regulatory genes underlying various phenotypes. Here, we introduce and guide researchers through a (differential) co-expression analysis. We provide an overview of methods and tools used to create and analyse co-expression networks constructed from gene expression data, and we explain how these can be used to identify genes with a regulatory role in disease. Furthermore, we discuss the integration of other data types with co-expression networks and offer future perspectives of co expression analysis. PMID- 28077404 TI - High-throughput sequencing of the T-cell receptor repertoire: pitfalls and opportunities. AB - T-cell specificity is determined by the T-cell receptor, a heterodimeric protein coded for by an extremely diverse set of genes produced by imprecise somatic gene recombination. Massively parallel high-throughput sequencing allows millions of different T-cell receptor genes to be characterized from a single sample of blood or tissue. However, the extraordinary heterogeneity of the immune repertoire poses significant challenges for subsequent analysis of the data. We outline the major steps in processing of repertoire data, considering low-level processing of raw sequence files and high-level algorithms, which seek to extract biological or pathological information. The latest generation of bioinformatics tools allows millions of DNA sequences to be accurately and rapidly assigned to their respective variable V and J gene segments, and to reconstruct an almost error free representation of the non-templated additions and deletions that occur. High level processing can measure the diversity of the repertoire in different samples, quantify V and J usage and identify private and public T-cell receptors. Finally, we discuss the major challenge of linking T-cell receptor sequence to function, and specifically to antigen recognition. Sophisticated machine learning algorithms are being developed that can combine the paradoxical degeneracy and cross-reactivity of individual T-cell receptors with the specificity of the overall T-cell immune response. Computational analysis will provide the key to unlock the potential of the T-cell receptor repertoire to give insight into the fundamental biology of the adaptive immune system and to provide powerful biomarkers of disease. PMID- 28077408 TI - Predicting patient 'cost blooms' in Denmark: a longitudinal population-based study. AB - OBJECTIVES: To compare the ability of standard versus enhanced models to predict future high-cost patients, especially those who move from a lower to the upper decile of per capita healthcare expenditures within 1 year-that is, 'cost bloomers'. DESIGN: We developed alternative models to predict being in the upper decile of healthcare expenditures in year 2 of a sample, based on data from year 1. Our 6 alternative models ranged from a standard cost-prediction model with 4 variables (ie, traditional model features), to our largest enhanced model with 1053 non-traditional model features. To quantify any increases in predictive power that enhanced models achieved over standard tools, we compared the prospective predictive performance of each model. PARTICIPANTS AND SETTING: We used the population of Western Denmark between 2004 and 2011 (2 146 801 individuals) to predict future high-cost patients and characterise high-cost patient subgroups. Using the most recent 2-year period (2010-2011) for model evaluation, our whole-population model used a cohort of 1 557 950 individuals with a full year of active residency in year 1 (2010). Our cost-bloom model excluded the 155 795 individuals who were already high cost at the population level in year 1, resulting in 1 402 155 individuals for prediction of cost bloomers in year 2 (2011). PRIMARY OUTCOME MEASURES: Using unseen data from a future year, we evaluated each model's prospective predictive performance by calculating the ratio of predicted high-cost patient expenditures to the actual high-cost patient expenditures in Year 2-that is, cost capture. RESULTS: Our best enhanced model achieved a 21% and 30% improvement in cost capture over a standard diagnosis-based model for predicting population-level high-cost patients and cost bloomers, respectively. CONCLUSIONS: In combination with modern statistical learning methods for analysing large data sets, models enhanced with a large and diverse set of features led to better performance-especially for predicting future cost bloomers. PMID- 28077409 TI - Have health inequalities changed during childhood in the New Labour generation? Findings from the UK Millennium Cohort Study. AB - OBJECTIVES: To examine how population-level socioeconomic health inequalities developed during childhood, for children born at the turn of the 21st century and who grew up with major initiatives to tackle health inequalities (under the New Labour Government). SETTING: The UK. PARTICIPANTS: Singleton children in the Millennium Cohort Study at ages 3 (n=15 381), 5 (n=15 041), 7 (n=13 681) and 11 (n=13 112) years. PRIMARY OUTCOMES: Relative (prevalence ratios (PR)) and absolute health inequalities (prevalence differences (PD)) were estimated in longitudinal models by socioeconomic circumstances (SEC; using highest maternal academic attainment, ranging from 'no academic qualifications' to 'degree' (baseline)). Three health outcomes were examined: overweight (including obesity), limiting long-standing illness (LLSI), and socio-emotional difficulties (SED). RESULTS: Relative and absolute inequalities in overweight, across the social gradient, emerged by age 5 and increased with age. By age 11, children with mothers who had no academic qualifications were considerably more likely to be overweight as compared with those with degree-educated mothers (PR=1.6 (95% CI 1.4 to 1.8), PD=12.9% (9.1% to 16.8%)). For LLSI, inequalities emerged by age 7 and remained at 11, but only for children whose mothers had no academic qualifications (PR=1.7 (1.3 to 2.3), PD=4.8% (2% to 7.5%)). Inequalities in SED (observed across the social gradient and at all ages) declined between 3 and 11, although remained large at 11 (eg, PR=2.4 (1.9 to 2.9), PD=13.4% (10.2% to 16.7%) comparing children whose mothers had no academic qualifications with those of degree-educated mothers). CONCLUSIONS: Although health inequalities have been well documented in cross-sectional and trend data in the UK, it is less clear how they develop during childhood. We found that relative and absolute health inequalities persisted, and in some cases widened, for a cohort of children born at the turn of the century. Further research examining and comparing the pathways through which SECs influence health may further our understanding of how inequalities could be prevented in future generations of children. PMID- 28077410 TI - Health policies on dialysis modality selection: a nationwide population cohort study. AB - OBJECTIVES: In Taiwan, peritoneal dialysis (PD) and haemodialysis are fully accessible to patients with end-stage renal disease. However, the usage of PD is considered low in Taiwan. Since 2005, 4 major policies have been implemented by Taiwan's Ministry of Health and Welfare, namely a multidisciplinary predialysis care programme and usage increasing the PD incidence as a key performance indicator (KPI) for hospital accreditation, both of which were implemented in 2006; reimbursement of the glucose-free dialysate, icodextrin that was implemented in 2007; and insurance reimbursement for renting automated PD machines that was implemented in 2008. The aim of this study was to analyse the associations between the PD promotional policies and the actual PD selection rates. SETTING: We analysed data within the Taiwan Renal Registry Data System from 2006 to 2013, focusing on the PD incidence in relation to the timings of the 4 PD promotional policies; then we stratified the results according to age, sex and the presence of diabetes mellitus. PARTICIPANTS: From 2006 to 2013, 115 565 patients were enrolled in this study. The mean (SD) age of patients on PD was 54.6 (15.7) years. RESULTS: During the time frame in which the 4 PD promotional policies were implemented, the PD incidence increased from 12.8% in 2006 to 15.1% in 2009. The PD incidence started to decline in 2010 (13.8%) when the hospital accreditation policy was repealed. The 3 remaining policies were weakly associated with the PD incidence. The observational analysis determined that the patients' ages, sexes and diabetes mellitus incidence rates were relatively stable from 2006 to 2013. CONCLUSIONS: Of the 4 health policies intended to promote PD usage, using increasing the PD incidence as a KPI for hospital accreditation had the strongest association with the PD incidence. PMID- 28077411 TI - Incidence of surgical site infection following caesarean section: a systematic review and meta-analysis protocol. AB - INTRODUCTION: Caesarean section (CS) rates have increased globally during the past three decades. Surgical site infection (SSI) following CS is a common cause of morbidity with reported rates of 3-15%. SSI represents a substantial burden to the health system including increased length of hospitalisation and costs of postdischarge care. The definition of SSI varies with the postoperative follow-up period among different health systems, resulting in differences in the reporting of SSI incidence. We propose to conduct the first systematic review and meta analysis to determine the pooled estimate for the overall incidence of SSI following CS. METHODS AND ANALYSIS: We will perform a comprehensive search to identify all potentially relevant published studies on the incidence of SSI following CS reported from 1992 in the English language. Electronic databases including PubMed, CINAHL, EMBASE and Scopus will be searched using a detailed search strategy. Following study selection, full-text paper retrieval, data extraction and synthesis, we will appraise study quality and risk of bias and assess heterogeneity. Incidence data will be combined where feasible in a meta analysis using Stata software and fixed-effects or random-effects models as appropriate. This systematic review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. ETHICS AND DISSEMINATION: Ethical approval is not required as this review will use published data. The review will evaluate the overall incidence of SSI following CS and will provide the first quantitative estimate of the magnitude of SSI. It will serve as a benchmark for future studies, identify research gaps and remaining challenges, and emphasise the need for appropriate prevention and control measures for SSI post-CS. A manuscript reporting the results of the systematic review and meta-analysis will be submitted to a peer-reviewed journal and presented at scientific conferences. TRIAL REGISTRATION NUMBER: CRD42015024426. PMID- 28077412 TI - Microvascular Outcomes after Metabolic Surgery (MOMS) in patients with type 2 diabetes mellitus and class I obesity: rationale and design for a randomised controlled trial. AB - INTRODUCTION: There are several randomised controlled trials (RCTs) that have already shown that metabolic/bariatric surgery achieves short-term and long-term glycaemic control while there are no level 1A of evidence data regarding the effects of surgery on the microvascular complications of type 2 diabetes mellitus (T2DM). PURPOSE: The aim of this trial is to investigate the long-term efficacy and safety of the Roux-en-Y gastric bypass (RYGB) plus the best medical treatment (BMT) versus the BMT alone to improve microvascular outcomes in patients with T2DM with a body mass index (BMI) of 30-34.9 kg/m2. METHODS AND ANALYSIS: This study design includes a unicentric randomised unblinded controlled trial. 100 patients (BMI from 30 to 34.9 kg/m2) will be randomly allocated to receive either RYGB plus BMT or BMT alone. The primary outcome is the change in the urine albumin-to-creatinine ratio (uACR) captured as the proportion of patients who achieved nephropathy remission (uACR<30 mg/g of albumin/mg of creatinine) in an isolated urine sample over 12, 24 and 60 months. ETHICS AND DISSEMINATION: The study was approved by the local Institutional Review Board. This study represents the first RCT comparing RYGB plus BMT versus BMT alone for patients with T2DM with a BMI below 35 kg/m2. TRIAL REGISTRATION NUMBER: NCT01821508; Pre-results. PMID- 28077413 TI - Cancer-related hospitalisations and 'unknown' stage prostate cancer: a population based record linkage study. AB - OBJECTIVES: To identify reasons for prostate cancer stage being recorded as 'unknown' in Australia's largest population-based cancer registry. DESIGN: Prospective population-based cohort. SETTING: New South Wales (NSW) is the most populous state in Australia, with almost one third of the total national population. PARTICIPANTS: NSW Cancer Registry (NSWCR) records for prostate cancer cases diagnosed in 2001-2009 were linked to the NSW Admitted Patient Data Collection (APDC) for 2000-2010. All patients in this study had a minimum of 12 months follow-up in the hospital episode records after their date of diagnosis as recorded by the NSWCR. MAIN OUTCOME MEASURES: Incidence of 'unknown' stage prostate cancer and cancer-specific survival. RESULTS: Of 50 597 prostate cancer cases, 39.9% were recorded as having 'unknown' stage. Up to 4 months after diagnosis, 77.2% of cases without a hospital-reported cancer diagnosis were recorded as having 'unknown' stage. Among those patients with a hospital-reported cancer diagnosis, stage was 'unknown' for 7.6% of cases who received a radical prostatectomy (RP) and for 34.0% of cases who had procedures other than RP. In the latter group, the factors that were related to having 'unknown' stage were living in disadvantaged areas (adjusted OR (aOR) range: 1.13 to 1.20), attending a private hospital (aOR range: 1.25 to 2.13), having day-only admission for care (aOR=1.23, 95% CI 1.11 to 1.36), or having procedures other than multiple procedures with imaging (eg, biopsy only, aOR range: 1.11 to 1.45). CONCLUSIONS: Over half of 'unknown' stage prostate cancer cases did not have a hospital reported prostate cancer diagnosis within the 4 months after initial diagnosis. We identified differences in the likelihood of cases being recorded as 'unknown' stage based on socioeconomic status and facility type, which suggests that further investigation of reporting practices in relation to diagnostic and treatment pathways is required. PMID- 28077414 TI - Implementation of a consumer-focused eHealth intervention for people with moderate-to-high cardiovascular disease risk: protocol for a mixed-methods process evaluation. AB - INTRODUCTION: Technology-mediated strategies have potential to engage patients in modifying unhealthy behaviour and improving medication adherence to reduce morbidity and mortality from cardiovascular disease (CVD). Furthermore, electronic tools offer a medium by which consumers can more actively navigate personal healthcare information. Understanding how, why and among whom such strategies have an effect can help determine the requirements for implementing them at a scale. This paper aims to detail a process evaluation that will (1) assess implementation fidelity of a multicomponent eHealth intervention; (2) determine its effective features; (3) explore contextual factors influencing and maintaining user engagement; and (4) describe barriers, facilitators, preferences and acceptability of such interventions. METHODS AND ANALYSIS: Mixed-methods sequential design to derive, examine, triangulate and report data from multiple sources. Quantitative data from 3 sources will help to inform both sampling and content framework for the qualitative data collection: (1) surveys of patients and general practitioners (GPs); (2) software analytics; (3) programme delivery records. Qualitative data from interviews with patients and GPs, focus groups with patients and field notes taken by intervention delivery staff will be thematically analysed. Concurrent interview data collection and analysis will enable a thematic framework to evolve inductively and inform theory building, consistent with a realistic evaluation perspective. Eligible patients are those at moderate-to-high CVD risk who were randomised to the intervention arm of a randomised controlled trial of an eHealth intervention and are contactable at completion of the follow-up period; eligible GPs are the primary healthcare providers of these patients. ETHICS AND DISSEMINATION: Ethics approval has been received from the University of Sydney Human Research Ethics Committee and the Aboriginal Health and Medical Research Council (AH&MRC) of New South Wales. Results will be disseminated via scientific forums including peer-reviewed publications and national and international conferences. TRIAL REGISTRATION NUMBER: ANZCTR 12613000715774. PMID- 28077415 TI - International multiphase mixed methods study protocol to develop a cross-cultural patient-reported outcome instrument for children and young adults with cleft lip and/or palate (CLEFT-Q). AB - INTRODUCTION: Patient-reported outcome (PRO) instruments should be developed according to rigorous guidelines in order to provide clinically meaningful, scientifically sound measurement. Understanding the methodology behind instrument development informs the selection of the most appropriate tool. This mixed methods protocol describes the development of an internationally applicable PRO instrument, the CLEFT-Q, for evaluating outcomes of treatment for cleft lip and/or palate (CL/P). METHODS AND ANALYSIS: The study includes three main phases that occur iteratively and interactively. In phase I, we determine what concepts are important to patients regarding their outcome. A conceptual framework for the CLEFT-Q is formed through a systematic review and an extensive international qualitative study. The systematic review ascertains what concepts have previously been measured in patients with CL/P. The qualitative study employs interpretive description and involves in-depth interviews with patients in high-income and lower-middle income countries. Preliminary items are generated from the qualitative data. Preliminary scales are then created for each theme in the framework. Cognitive debriefing interviews and expert clinician input are used to refine the scales in an iterative process. In phase II, the preliminary scales are administered to a large international group of patients with CL/P. The modern psychometric method of Rasch Measurement Theory analysis is employed to define the measurement characteristics. The preliminary scales are shortened based on these results. In phase III, further tests assess reliability, validity and responsiveness of the instrument. ETHICS AND DISSEMINATION: The study is approved by Research Ethics Boards for each participating site. Findings from this study will be published in open access peer-reviewed journals and presented at national and international conferences. Integrated knowledge translation is employed to engage stakeholders from the outset of the study. Successful execution of the CLEFT-Q will result in an internationally applicable PRO instrument for children and young adults with CL/P. PMID- 28077416 TI - Platelet secretion is crucial to prevent bleeding in the ischemic brain but not in the inflamed skin or lung in mice. AB - Platelets maintain hemostasis after injury, but also during inflammation. Recent studies have shown that platelets prevent inflammatory bleeding through (hem) immunoreceptor tyrosine-based activation motif-dependent mechanisms irrespective of aggregation during skin and lung inflammation. Although the exact mechanisms underlying this process remain unknown, it was speculated that mediators released from platelet granules might be involved. Maintaining cerebral hemostasis during stroke treatment is of high clinical relevance because hemorrhage may aggravate the disease state and increase mortality. Although it was shown that platelets help maintain hemostasis in the ischemic brain, their exact contribution remains ill defined. Here we show that Unc13d-/- /Nbeal2-/- mice, which lack platelet alpha- and dense-granule secretion, show no signs of hemorrhage in models of skin or lung inflammation. In stark contrast, lack of platelet granule release resulted in impaired hemostasis in the ischemic brain after transient middle cerebral artery occlusion leading to increased intracranial hemorrhage and mortality. Our results reveal for the first time that platelet granule constituents are essential for maintenance of hemostasis during thrombo inflammatory brain infarction but not experimental inflammation of the skin or lung, thereby uncovering vascular bed-specific differences in the prevention of inflammatory bleeding. PMID- 28077417 TI - Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells. AB - Recent studies have reported that activation-induced cytidine deaminase (AID) and ten-eleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations of TET2 occur in myeloid malignancies, and hematopoietic specific loss of Tet2 induces aberrant hematopoietic stem cell (HSC) self renewal/differentiation, implicating TET2 as a master regulator of normal and malignant hematopoiesis. Despite the functional link between AID and TET in epigenetic gene regulation, the role of AID loss in hematopoiesis and myeloid transformation remains to be investigated. Here, we show that Aid loss in mice leads to expansion of myeloid cells and reduced erythroid progenitors resulting in anemia, with dysregulated expression of Cebpa and Gata1, myeloid/erythroid lineage-specific transcription factors. Consistent with data in the murine context, silencing of AID in human bone marrow cells skews differentiation toward myelomonocytic lineage. However, in contrast to Tet2 loss, Aid loss does not contribute to enhanced HSC self-renewal or cooperate with Flt3-ITD to induce myeloid transformation. Genome-wide transcription and differential methylation analysis uncover the critical role of Aid as a key epigenetic regulator. These results indicate that AID and TET2 share common effects on myeloid and erythroid lineage differentiation, however, their role is nonredundant in regulating HSC self-renewal and in myeloid transformation. PMID- 28077419 TI - Effect of Vitamin D on Endothelial Function: A Randomized, Double-Blind, Placebo Controlled Trial. AB - BACKGROUND: In nonhypertensive individuals, lower levels of 25-hydroxyvitamin D (25[OH]D) have been associated with an increased risk of hypertension, and vitamin D deficiency has been associated with endothelial dysfunction in such individuals. However, the effect of vitamin D supplementation on endothelial dysfunction in nonhypertensive individuals has not been examined in a rigorous fashion. METHODS: In this randomized, double-blind, placebo-controlled trial of nonhypertensive, nondiabetic overweight, or obese individuals with vitamin D deficiency (body mass index >=25 and 25[OH]D <= 20 ng/ml), we assigned subjects to receive either ergocalciferol (50,000 units) or matching placebo, once a week for 8 weeks. Our primary outcome was endothelial-dependent vasodilation (EDV) measured by brachial artery ultrasound at baseline and 8 weeks postrandomization. RESULTS: By the end of the trial, 46 and 47 participants were allocated to receive ergocalciferol and placebo, respectively. Mean 25(OH)D levels increased from 14.9 to 30.3 in the vitamin D group and 14.4 to 17.4 in the placebo. EDV did not change significantly with either vitamin D repletion (from 6.3 +/- 3.6% at baseline to 6.1 +/- 4.6% at 8 weeks; P value = 0.78) or placebo (7.9 +/- 4.7% to 6.8 +/- 4.7%; P = 0.17). The treatment effect P value (comparing the 8-week change with ergocalciferol to the change with placebo) was 0.35. CONCLUSIONS: In this randomized, double-blind, placebo-controlled trial, there was no improvement in endothelial function (measured as EDV) after repletion of vitamin D in overweight/obese nonhypertensive individuals. PMID- 28077418 TI - A novel humanized mouse model with significant improvement of class-switched, antigen-specific antibody production. AB - Humanized mice are a powerful tool for the study of human hematopoiesis and immune function in vivo. However, the existing models cannot support robust adaptive immune responses, especially the generation of class-switched, antigen specific antibody responses. Here we describe a new mouse strain, in which human interleukin 6 (IL-6) gene encoding the cytokine that is important for B- and T cell differentiation was knocked into its respective mouse locus. The provision of human IL-6 not only enhanced thymopoiesis and periphery T-cell engraftment, but also significantly increased class switched memory B cells and serum immunoglobulin G (IgG). In addition, immunization with ovalbumin (OVA) induced OVA-specific B cells only in human IL-6 knock-in mice. These OVA-specific antibodies displayed the highest frequency of somatic mutation, further suggesting that human IL-6 is important for efficient B-cell activation and selection. We conclude that human IL-6 knock-in mice represent a novel and improved model for human adaptive immunity without relying on complex surgery to transplant human fetal thymus and liver. These mice can therefore be used to exploit or evaluate immunization regimes that would be unethical or untenable in humans. PMID- 28077420 TI - Polymorphisms of Leptin (G2548A) and Leptin Receptor (Q223R and K109R) Genes and Blood Pressure During Pregnancy and the Postpartum Period: A Cohort. AB - BACKGROUND: The genetic component related to blood pressure (BP) changes during pregnancy is still not elucidated. Thus, the aim of the study was to evaluate the association between leptin and leptin receptor polymorphisms and systolic (SBP) and diastolic BP (DBP) variation during pregnancy and the postpartum period. METHODS: Prospective cohort of 146 women followed at a Public Health Center in Rio de Janeiro, Brazil, during pregnancy and the postpartum. SBP and DBP (mm Hg) were measured using an automatic sphygmomanometer. DNA was extracted by phenol chloroform protocol and leptin (G2548A) and leptin receptor genes (Q223R and K109R) polymorphisms were genotyped using real-time PCR method. Statistical analyses included longitudinal linear mixed-effect models. RESULTS: Adjusted longitudinal models showed that women carrying the G-allele of leptin gene's polymorphism began pregnancy with higher BP levels compared to the AA genotype and their levels remained higher throughout pregnancy and the postpartum period (beta SBP = 4.5; 95% confidence interval (CI) = 1.0-8.0; P = 0.012; beta DBP = 2.9; 95% CI = 0.1-5.8; P = 0.040). There was a significant interaction between leptin gene polymorphism and body mass index (BMI), in which the effect of BMI on increasing BP was steeper in women homozygous for the A-allele, compared with those who had at least one G-allele (beta G-allele#BMI = -0.8; 95% CI = -1.5 to 0.1; P = 0.022). We did not find significant associations between leptin receptor polymorphisms and BP changes. CONCLUSIONS: The G-allele of leptin gene polymorphism (G2548A) was associated with increased BP levels during pregnancy and the postpartum. Furthermore, leptin polymorphism genotypes seem to modify the well-known effect of BMI on BP. PMID- 28077421 TI - Aortic Wave Reflection During Orthostatic Challenges: Influence of Body Position and Venous Pooling. AB - BACKGROUND: Aortic wave reflection (augmentation index; AIx) decreases during orthostatic challenges despite increased peripheral resistance, which is thought to be due to venous pooling. The purpose of this study was to examine if the decrease in AIx during an orthostatic challenge is due to venous pooling alone or body position manipulation. METHODS: Twenty-three young, healthy adults (11F/12M) participated in 3 separate orthostatic challenges (5 minutes each); 60 degrees head-up tilt (HUT), 60 degrees HUT with bilateral rhythmic blood pressure (BP) cuff inflation on calves (75 mm Hg) to minimize venous pooling, and lower body negative pressure (LBNP; -30 mm Hg) for venous pooling independent of body position. High-fidelity radial artery pressure waveforms using applanation tonometry were recorded at minutes 2:30 and 5:00 during each condition. Aortic BP and wave reflection were analyzed from a synthesized aortic BP waveform. RESULTS: Compared to resting (baseline) measurements, AIx did not significantly decrease at minutes 2:30 or 5:00 of HUT conditions (HUT 0 +/- 2% vs. -3 +/- 3%, 0 +/- 2%; HUT w/cuffs 0 +/- 2% vs. -4 +/- 2%, 0 +/- 2%). Conversely, LBNP substantially reduced AIx at minutes 2:30 and 5:00 (1 +/- 2% vs. -15 +/- 2% and -12 +/- 2%; P < 0.01). When standardized to heart rate (AIx@75), AIx@75 increased relative to baseline during HUT conditions (P < 0.05). CONCLUSIONS: In contrast to previous studies, AIx did not decrease during passive HUT, yet decreased substantially during LBNP. Despite being well matched for peripheral hemodynamics, it appears that LBNP elicits a greater effect on central hemodynamics, relative to passive HUT. Collectively, changes in body position alone do not explain differences in AIx during orthostatic conditions. PMID- 28077422 TI - ANTXR2 Knock-Out Does Not Result in the Development of Hypertension in Rats. AB - BACKGROUND: Our recent genetic study as well as robust evidences reported by previous genome-wide association studies (GWASs) have indicated that the single nucleotide polymorphism rs16998073, located near gene anthrax toxin receptor 2 (ANTXR2), was significantly associated with hypertension in Asians and Europeans. The aim of the present study was to determine whether ANTXR2 is the causal gene of hypertension at the 4q21 locus using an ANTXR2 knock-out model. METHODS: Relative expression of ANTXR2 in Wistar-Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) were determined by real-time quantitative polymerase chain reaction and western blot analysis. ANTXR2 knock-out rats were created using CRISPR/Cas9-mediated genome editing and blood pressure values were measured in ANTXR2-/- and wild type (WT) rats by tail-cuff method and carotid arterial catheterization method. RESULTS: Neither the mRNA nor protein levels of ANTXR2 were significantly different between tissues from SHRs and WKYs. To create ANTXR2 /- rats, 67 base pairs were deleted in exon 1 of ANTXR2 using CRISPR/Cas9 mediated genome editing. ANTXR2 protein decreased significantly in aortas of ANTXR2-/- rats, suggesting sufficient efficiency of ANTXR2 knock-out in this model. However, ANTXR2-/- rats exhibited nearly the same blood pressure as WT rats at baseline conditions as well as during Angiotensin II (400ng/kg/min) infusion or high-salt diet treatment. CONCLUSIONS: These findings suggest that ANTXR2 might not be associated with hypertension and thus further functional analysis is warranted to identify the causal gene at this locus. PMID- 28077425 TI - Metastasis suppressor NM23 limits oxidative stress in mammals by preventing activation of stress-activated protein kinases/JNKs through its nucleoside diphosphate kinase activity. AB - NME1 (nonmetastatic expressed 1) gene, which encodes nucleoside diphosphate kinase (NDPK) A [also known as nonmetastatic clone 23 (NM23)-H1 in humans and NM23-M1 in mice], is a suppressor of metastasis, but several lines of evidence mostly from plants-also implicate it in the regulation of the oxidative stress response. Here, our aim was to investigate the physiologic relevance of NDPK A with respect to the oxidative stress response in mammals and to study its molecular basis. NME1-knockout mice died sooner, suffered greater hepatocyte injury, and had lower superoxide dismutase activity than did wild-type (WT) mice in response to paraquat-induced acute oxidative stress. Deletion of NME1 reduced total NDPK activity and exacerbated activation of the stress-related MAPK, JNK, in the liver in response to paraquat. In a mouse transformed hepatocyte cell line and in primary cultures of normal human keratinocytes, MAPK activation in response to H2O2 and UVB, respectively, was dampened by expression of NM23 M1/NM23-H1, dependent on its NDPK catalytic activity. Furthermore, excess or depletion of NM23-M1/NM23-H1 NDPK activity did not affect the intracellular bulk concentration of nucleoside di- and triphosphates. NME1-deficient mouse embryo fibroblasts grew poorly in culture, were more sensitive to stress than WT fibroblasts, and did not immortalize, which suggested that they senesce earlier than do WT fibroblasts. Collectively, these results indicate that the NDPK activity of NM23-M1/NM23-H1 protects cells from acute oxidative stress by inhibiting activation of JNK in mammal models.-Peuchant, E., Bats, M.-L., Moranvillier, I., Lepoivre, M., Guitton, J., Wendum, D., Lacombe, M.-L., Moreau Gaudry, F., Boissan, M., Dabernat, S. Metastasis suppressor NM23 limits oxidative stress in mammals by preventing activation of stress-activated protein kinases/JNKs through its nucleoside diphosphate kinase activity. PMID- 28077426 TI - Nut Consumption and Lung Cancer Risk: Results from Two Large Observational Studies. AB - Background: Epidemiologic evidence on the association between nut consumption and lung cancer risk is limited.Methods: We investigated this relationship in the Environment and Genetics in Lung Cancer Etiology (EAGLE) study, a population based case-control study, and the National Institutes of Health (NIH) American Association of Retired Persons (AARP) Diet and Health Study, a prospective cohort. We identified 2,098 lung cases for EAGLE and 18,533 incident cases in AARP. Diet was assessed by food frequency questionnaire for both studies. Multivariable ORs and HRs and respective 95% confidence intervals (CI) were calculated using unconditional logistic regression and Cox proportional hazards regression for EAGLE and AARP, respectively.Results: Higher frequency of intake of nut consumption was inversely associated with overall lung cancer risk (highest vs. lowest quintile, OREAGLE = 0.74; 95% CI, 0.57-0.95; HRAARP = 0.86; 95% CI, 0.81-0.91), regardless of smoking status. Results from the prospective cohort showed similar associations across histologic subtypes and a more pronounced benefits from nut consumption for those who smoked 1 to 20 cigarettes/day (OREAGLE = 0.61; 95% CI, 0.39-0.95; HRAARP = 0.83; 95% CI, 0.74 0.94).Conclusions: Nut consumption was inversely associated with lung cancer in two large population-based studies, and associations were independent of cigarette smoking and other known risk factors.Impact: To our knowledge, this is the first study that examined the association between nut consumption and lung cancer risk by histologic subtypes and smoking intensity. Cancer Epidemiol Biomarkers Prev; 26(6); 826-36. (c)2017 AACR. PMID- 28077427 TI - Serum Trimethylamine N-oxide, Carnitine, Choline, and Betaine in Relation to Colorectal Cancer Risk in the Alpha Tocopherol, Beta Carotene Cancer Prevention Study. AB - Background: Trimethylamine N-oxide (TMAO), a choline-derived metabolite produced by gut microbiota, and its biomarker precursors have not been adequately evaluated in relation to colorectal cancer risk.Methods: We investigated the relationship between serum concentrations of TMAO and its biomarker precursors (choline, carnitine, and betaine) and incident colorectal cancer risk in a nested case-control study of male smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We measured biomarker concentrations in baseline fasting serum samples from 644 incident colorectal cancer cases and 644 controls using LC/MS-MS. Logistic regression models estimated the ORs and 95% confidence interval (CI) for colorectal cancer by quartile (Q) of serum TMAO, choline, carnitine, and betaine concentrations.Results: Men with higher serum choline at ATBC baseline had approximately 3-fold greater risk of developing colorectal cancer over the ensuing (median +/- IQR) 14 +/- 10 years (in fully adjusted models, Q4 vs. Q1, OR, 3.22; 95% CI, 2.24-4.61; Ptrend < 0.0001). The prognostic value of serum choline for prediction of incident colorectal cancer was similarly robust for proximal, distal, and rectal colon cancers (all P < 0.0001). The association between serum TMAO, carnitine, or betaine and colorectal cancer risk was not statistically significant (P = 0.25, 0.71, and 0.61, respectively).Conclusions: Higher serum choline concentration (but not TMAO, carnitine, or betaine) was associated with increased risk of colorectal cancer.Impact: Serum choline levels showed strong prognostic value for prediction of incident colorectal cancer risk across all anatomical subsites, suggesting a role of altered choline metabolism in colorectal cancer pathogenesis. Cancer Epidemiol Biomarkers Prev; 26(6); 945-52. (c)2017 AACR. PMID- 28077428 TI - Reproductive experiences of women who cryopreserved oocytes for non-medical reasons. AB - STUDY QUESTION: What are the reproductive experiences of women who cryopreserve oocytes for non-medical reasons? SUMMARY ANSWER: One in three women had been pregnant at some stage in their lives and while most still wanted to have a child or another child, very few had used their stored oocytes, predominantly because they did not want to be single parents. WHAT IS KNOWN ALREADY: The number of healthy women who freeze oocytes to avoid age-related infertility is increasing. Evidence about reproductive outcomes after oocyte cryopreservation for non medical reasons is needed to help women make informed decisions. STUDY DESIGN SIZE, DURATION: A cross-sectional survey was carried out. Study packs which included a self-administered questionnaire were mailed by clinic staff to 193 eligible women. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who had stored oocytes for non-medical reasons at Melbourne IVF, a private ART clinic, between 1999 and 2014 were identified from medical records and invited to complete an anonymous questionnaire about their reproductive histories and experience of oocyte cryopreservation. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 10 survey packs were returned to the clinic marked 'address unknown'. Of the 183 potential respondents, 96 (53%) returned the questionnaire. One respondent provided only free-text comments, thus data from 95 respondents were compiled. The mean age at the time of freezing oocytes was 37.1 years (SD +/- 2.6, range: 27-42) and the average number of oocytes stored was 14.2 (SD +/- 7.9, range: 0 42); 2% had attempted to store oocytes but had none suitable for freezing, 24% had stored <8 oocytes, 35% had 8-15, 25% had 16-23 and 14% had stored >23 oocytes. About one-third of respondents (34%) had been pregnant at some point in their lives. Six women (6%) had used their stored oocytes and three of them had given birth as a result. The main reason for not using stored oocytes was not wanting to be a single parent. Of the 87 (91%) women who still had oocytes stored, 21% intended to use them while 69% indicated that their circumstances would determine usage. The mean number of children respondents would ideally have liked to have was significantly higher than the number of children they expected to have (2.11 versus 1.38, P < 0.001). LIMITATIONS, REASONS FOR CAUTION: The limitations are inherent to any anonymously completed questionnaire: participation bias, missing data and the possibility that some questions or response alternatives may have been ambiguous. WIDER IMPLICATIONS OF THE FINDINGS: The findings add to the very limited evidence about the reproductive outcomes experienced by women who freeze oocytes for non-medical reasons and can be used to help women make informed decisions about whether to store oocytes. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by Melbourne IVF. K.H. has received honoraria from Merck-Serono, J.M. is a clinician at Melbourne IVF, F.A. is a Melbourne IVF employee, J.F. is supported by a Monash Professorial Fellowship and the Jean Hailes Professorial Fellowship which receives funding from the L and H Hecht Trust, managed by Perpetual Trustees Pty Ltd. M.K., N.P., M.H., M.P. and C.B. have no competing interests. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 28077429 TI - Composite End Points in Clinical Trials of Heart Failure Therapy: How Do We Measure the Effect Size? AB - Composite end points are popular outcomes in clinical trials of heart failure therapies. For example, a global rank composite is typically analyzed using a Mann-Whitney U test, and the results are summarized by the mean of ranks and a corresponding P value. The mean of ranks is uninformative, and a clinically meaningful estimate of the treatment effect is needed to communicate study results and facilitate an assessment of heterogeneity (the consistency of the effect across outcomes). The probability index is intuitive for clinicians, easy to calculate, and may be applied to various composites. We suggest a simple and familiar plot to assess heterogeneity across outcomes, which should be routine when analyzing composites. We think that the probability index provides an immediate and simple solution to an overt problem. PMID- 28077431 TI - Enantiomers Recognition of Propranolol Based on Organic-Inorganic Hybrid Open Tubular MIPs-CEC Column Using 3-(Trimethoxysilyl)Propyl Methacrylate as a Cross Linking Monomer. AB - In this study, 3-(trimethoxysilyl)propyl methacrylate (gamma-MPS), a bifunctional group compound, was used as a single cross-linking agent to prepare molecular imprinted inorganic-organic hybrid polymers by in situ polymerization for open tubular capillary electro chromatography (CEC) column. The optimal preparation conditions were: the ratio between template molecule and functional monomer was 1:4; the volume proportion of porogen toluene and methanol was 1:1 and the volume of cross-linking agent gamma-MPS was 69 MUL. The optimal separation conditions were separation voltage of 15 kV; detection wavelength at 215 nm and background electrolyte composed of 70% acetonitrile/20 mmol/L boric acid salt (pH 6.9). Under the optimized conditions, the propranolol enantiomers can be separated well by CEC. The method is simple and fast, it can be a potentially useful approach for propranolol enantiomers separation. PMID- 28077430 TI - Successful Aging as the Intersection of Individual Resources, Age, Environment, and Experiences of Well-being in Daily Activities. AB - Objective: We conceptualize successful aging as a cumulative index of individual resources (the absence of disease and disability, high cognitive and physical functioning, social embeddedness) in the service of successful aging outcomes (global well-being, experienced well-being, and vital status), and conditioned by age, social structure, and environment. Method: The study used baseline and follow-up data from the 2008-2014 waves of the Health and Retirement Study (N = 17,230; age = 51-101). Linear, multilevel, and logistic models compared individual resources at baseline as independent, cumulative, and binary predictors of outcomes 4 years later. Results: Individual resources were unequally distributed across age group and social structures (education, wealth, race, gender) and had a cumulative effect on all successful aging outcomes. For experienced well-being, individual resources were most important at midlife and for groups with lower education. Person-environment congruence (social cohesion, city satisfaction) was associated with all successful aging outcomes and conditioned the effect of individual resources on experienced well-being. Discussion: A cumulative index allows for gradations in resources that can be compensated for by external factors such as person-environment congruence. This index could guide policy and interventions to enhance resources in vulnerable subgroups and diminish inequalities in successful aging outcomes. PMID- 28077432 TI - Determination of tetracyclines in bovine milk using laccaic acid-loaded magnetite nanocomposite for magnetic solid-phase extraction. AB - An efficient magnetic sorbent of laccaic acid-loaded magnetite nanocomposite was successfully synthesized for extraction and preconcentration of tetracyclines (TCs) from bovine milk sample. The synthesized nanocomposite was characterized by scanning electron microscopy and Fourier transform-infrared spectroscopy. Determination of the extracted TCs was performed by high performance liquid chromatography. Parameters affecting the efficiency of magnetic solid-phase extraction were studied and optimized. The best adsorption conditions were 80 mg of sorbent, 50 mL of sample volume, pH 7, 45 degrees C and 20 min; the elution conditions were 0.5 mL of acetonitrile, pH 5.5, 75 degrees C and 5 min. Under optimized conditions, the preconcentration factor of TCs was 100. The calibration curves were linear at a concentration range of 10-300 MUg/kg for oxytetracycline and TC, and 5-300 MUg/kg for chlortetracycline and doxycycline. The limit of detection was from 3.2 to 7.1 MUg/kg, the limit of quantification was from 10.7 to 23.7 MUg/kg, the relative standard deviation was between 2.8 and 5.3 and the recoveries were between 95.2% and 106.2%. In terms of the proposed procedure, the developed method was successfully applied for TCs detection in bovine milk samples. PMID- 28077433 TI - Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin alphavbeta3/FAK/AKT Pathway Suppression. AB - BACKGROUND: Pulmonary arterial remodeling characterized by increased vascular smooth muscle proliferation is commonly seen in life-threatening disease, pulmonary arterial hypertension (PAH). Clinical studies have suggested a correlation between osteoprotegerin serum levels and PAH severity. Here, we aimed to invhestigate vascular osteoprotegerin expression and its effects on pulmonary arterial smooth muscle cell proliferation in vitro and in vivo, as well as examine the signal transduction pathways mediating its activity. METHODS AND RESULTS: Serum osteoprotegerin levels were significantly elevated in patients with PAH and correlated with disease severity as determined by the World Health Organization (WHO) functional classifications and 6-minute walking distance tests. Similarly, increased osteoprotegerin expression was observed in the pulmonary arteries of hypoxia plus SU5416- and monocrotaline-induced PAH animal models. Moreover, osteoprotegerin disruption attenuated hypoxia plus SU5416 induced PAH progression by reducing pulmonary vascular remodeling, whereas lentiviral osteoprotegerin reconstitution exacerbated PAH by increasing pulmonary arterial smooth muscle cell proliferation. Furthermore, pathway analysis revealed that osteoprotegerin induced pulmonary arterial smooth muscle cell proliferation by interacting with integrin alphavbeta3 to elicit downstream focal adhesion kinase and AKT pathway activation. CONCLUSIONS: Osteoprotegerin facilitates PAH pathogenesis by regulating pulmonary arterial smooth muscle cell proliferation, suggesting that it may be a potential biomarker and therapeutic target in this disease. PMID- 28077435 TI - BLU-285, DCC-2618 Show Activity against GIST. AB - Tyrosine kinase inhibitors may initially control gastrointestinal stromal tumors, but most patients eventually experience disease progression due to activation loop mutations, which are resistant to approved drugs. However, phase I trials suggest that the cancer is sensitive to two new agents: BLU-285 and DCC-2618. In addition, liquid biopsies, which were used to follow patients during the trials, may be valuable tools in tracking disease progression and assessing tumor heterogeneity. PMID- 28077436 TI - Project GENIE Goes Public. AB - The American Association for Cancer Research's Project Genomics Evidence Neoplasia Information Exchange released almost 19,000 deidentified genomic records collected from patients with cancer who were treated at one of eight renowned medical centers. One of the largest pools of genomic information ever made publicly accessible, it includes data on 59 types of cancer. PMID- 28077434 TI - Transfer of Allogeneic CD4+ T Cells Rescues CD8+ T Cells in Anti-PD-L1-Resistant Tumors Leading to Tumor Eradication. AB - Adoptively transferred CD8+ T cells can stabilize the size of solid tumors over long periods of time by exclusively recognizing antigen cross-presented on tumor stroma. However, these tumors eventually escape T-cell-mediated growth control. The aim of this study was to eradicate such persistent cancers. In our model, the SIYRYYGL antigen is expressed by cancer cells that lack the MHC-I molecule Kb needed for direct presentation, but the antigen is picked up and cross-presented by tumor stroma. A single injection of antigen-specific 2C CD8+ T cells caused long-term inhibition of tumor growth, but without further intervention, tumors started to progress after approximately 3 months. Escape was associated with reduced numbers of circulating 2C cells. Tumor-infiltrating 2C cells produced significantly less TNFalpha and expressed more of the "exhaustion" markers PD-1 and Tim-3 than T cells from lymphoid organs. High-dose local ionizing radiation, depletion of myeloid-derived suppressor cells, infusions of additional 2C cells, and antibodies blocking PD-L1 did not prevent tumor escape. In contrast, adoptive transfer of allogeneic CD4+ T cells restored the numbers of circulating Ag specific CD8+ T cells and their intratumoral function, resulting in tumor eradication. These CD4+ T cells had no antitumor effects in the absence of CD8+ T cells and recognized the alloantigen cross-presented on tumor stroma. CD4+ T cells might also be effective in cancer patients when PD-1/PD-L1 blockade does not rescue intratumoral CD8+ T-cell function and tumors persist. Cancer Immunol Res; 5(2); 127-36. (c)2017 AACR. PMID- 28077437 TI - Sensitized signalling between L-type Ca2+ channels and ryanodine receptors in the absence or inhibition of FKBP12.6 in cardiomyocytes. AB - Aims: The heart contraction is controlled by the Ca2+-induced Ca2+ release (CICR) between L-type Ca2+ channels and ryanodine receptors (RyRs). The FK506-binding protein FKBP12.6 binds to RyR subunits, but its role in stabilizing RyR function has been debated for long. Recent reports of high-resolution RyR structure show that the HD2 domain that binds to the SPRY2 domain of neighbouring subunit in FKBP-bound RyR1 is detached and invisible in FKBP-null RyR2. The present study was to test the consequence of FKBP12.6 absence on the in situ activation of RyR2. Methods and results: Using whole-cell patch-clamp combined with confocal imaging, we applied a near threshold depolarization to activate a very small fraction of LCCs, which in turn activated RyR Ca2+ sparks stochastically. FKBP12.6-knockout and FK506/rapamycin treatments increased spark frequency and LCC-RyR coupling fidelity without altering LCC open probability. Neither FK506 nor rapamycin further altered LCC-RyR coupling fidelity in FKBP12.6-knockout cells. In loose-seal patch-clamp experiments, the LCC-RyR signalling kinetics, indexed by the delay for a LCC sparklet to trigger a RyR spark, was accelerated after FKBP12.6 knockout and FK506/rapamycin treatments. These results demonstrated that RyRs became more sensitive to Ca2+ triggers without FKBP12.6. Isoproterenol (1 MUM) further accelerated the LCC-RyR signalling in FKBP12.6 knockout cells. The synergistic sensitization of RyRs by catecholaminergic signalling and FKBP12.6 dysfunction destabilized the CICR system, leading to chaotic Ca2+ waves and ventricular arrhythmias. Conclusion: FKBP12.6 keeps the RyRs from over-sensitization, stabilizes the potentially regenerative CICR system, and thus may suppress the life-threatening arrhythmogenesis. PMID- 28077439 TI - The functional expression of transient receptor potential channels in the mouse endometrium. AB - STUDY QUESTION: Does mouse endometrial epithelial cells and stromal cells have a similar transient receptor potential (TRP)-channel expression profile and to that found in the human endometrium? SUMMARY ANSWER: Mouse endometrial epithelial and stromal cells have a distinct TRP channel expression profile analogous to what has been found in human endometrium, and hence suggests the mouse a good model to investigate the role of TRP channels in reproduction. WHAT IS KNOWN ALREADY: An optimal intercellular communication between epithelial and stromal endometrial cells is crucial for successful reproduction. Members of the TRP family were recently described in the human endometrial stroma; however their functional expression in murine endometrium remains unspecified. Furthermore, epithelial and stromal cells have distinct functions in the reproductive process, implying the possibility for a different expression profile. However, knowledge about the functional expression pattern of TRP channels in either epithelial or stromal cells is not available. STUDY DESIGN, SIZE, DURATION: In this study, the expression pattern of TRP channels in the murine (C57BL/6 J strain) endometrium was investigated and compared to the human expression pattern. Therefore, expression was examined in uterine tissue isolated during the natural estrous cycle (n = 16) or during an induced menstrual cycle using the menstruating mouse model (n = 28). Next, the functional expression of TRP channels was assessed separately in endometrial epithelial and stromal cell populations. PARTICIPANTS/MATERIALS, SETTING, METHODS: Quantitative RT-PCR was used to evaluate the relative mRNA expression of TRP channels in murine uterine tissue and cells. To further assess the functional expression in epithelial or stromal cells, primary endometrial cell cultures and Fura2-based calcium-microfluorimetry experiments were performed. MAIN RESULTS AND THE ROLE OF CHANCE: The expression pattern of TRP channels during the natural estrous cycle or the induced menstrual cycle is analog to what has been shown in human samples. Furthermore, a very distinct expression pattern was observed in epithelial cells compared to stromal cells. Expression of TRPV4, TRPV6 and TRPM6 was significantly higher in epithelial cells whereas TRPV2, TRPC1/4 and TRPC6 were almost exclusively expressed in stromal cells. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Although relevant mRNA levels are detected for TRPV6 and TRPM6, and TRPM4, lack of selective, available pharmacology restricted functional analysis of these ion channels. WIDER IMPLICATIONS OF THE FINDINGS: Successful reproduction, and more specifically embryo implantation, is a dynamic developmental process that integrates many signaling molecules into a precisely orchestrated program. Here, we describe the expression pattern of TRP channels in mouse endometrium that is similar to human tissue and their restricted functionality in either stromal cells or epithelial cells, suggesting a role in the epithelial-stromal crosstalk. These results will be very helpful to identify key players involved in the signaling cascades required for successful embryo implantation. In addition, these results illustrate that mouse endometrium is a valid representative for human endometrium to investigate TRP channels in the field of reproduction. STUDY FUNDING/COMPETING INTEREST(S): The Research Foundation-Flanders (G.0856.13 N to J.V.); the Research Council of the Katholieke Universiteit Leuven (OT/13/113 to J.V. and PF-TRPLe to T.V.); the Planckaert-De Waele fund (to J.V.); Fonds Wetenschappelijk Onderzoek Belgium (to K.D.C. and A.H.). None of the authors have a conflict of interest. PMID- 28077438 TI - Fibroblast drug scavenging increases intratumoural gemcitabine accumulation in murine pancreas cancer. AB - OBJECTIVE: Desmoplasia and hypovascularity are thought to impede drug delivery in pancreatic ductal adenocarcinoma (PDAC). However, stromal depletion approaches have failed to show clinical responses in patients. Here, we aimed to revisit the role of the tumour microenvironment as a physical barrier for gemcitabine delivery. DESIGN: Gemcitabine metabolites were analysed in LSL-KrasG12D/+ ; LSL Trp53R172H/+ ; Pdx-1-Cre (KPC) murine tumours and matched liver metastases, primary tumour cell lines, cancer-associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs) by liquid chromatography-mass spectrometry/mass spectrometry. Functional and preclinical experiments, as well as expression analysis of stromal markers and gemcitabine metabolism pathways were performed in murine and human specimen to investigate the preclinical implications and the mechanism of gemcitabine accumulation. RESULTS: Gemcitabine accumulation was significantly enhanced in fibroblast-rich tumours compared with liver metastases and normal liver. In vitro, significantly increased concentrations of activated 2',2'-difluorodeoxycytidine-5'-triphosphate (dFdCTP) and greatly reduced amounts of the inactive gemcitabine metabolite 2',2'-difluorodeoxyuridine were detected in PSCs and CAFs. Mechanistically, key metabolic enzymes involved in gemcitabine inactivation such as hydrolytic cytosolic 5'-nucleotidases (Nt5c1A, Nt5c3) were expressed at low levels in CAFs in vitro and in vivo, and recombinant expression of Nt5c1A resulted in decreased intracellular dFdCTP concentrations in vitro. Moreover, gemcitabine treatment in KPC mice reduced the number of liver metastases by >50%. CONCLUSIONS: Our findings suggest that fibroblast drug scavenging may contribute to the clinical failure of gemcitabine in desmoplastic PDAC. Metabolic targeting of CAFs may thus be a promising strategy to enhance the antiproliferative effects of gemcitabine. PMID- 28077440 TI - Monophosphoryl Lipid A Enhances Efficacy of a Francisella tularensis LVS Catanionic Nanoparticle Subunit Vaccine against F. tularensis Schu S4 Challenge by Augmenting both Humoral and Cellular Immunity. AB - Francisella tularensis, a bacterial biothreat agent, has no approved vaccine in the United States. Previously, we showed that incorporating lysates from partially attenuated F. tularensis LVS or fully virulent F. tularensis Schu S4 strains into catanionic surfactant vesicle (V) nanoparticles (LVS-V and Schu S4 V, respectively) protected fully against F. tularensis LVS intraperitoneal (i.p.) challenge in mice. However, we achieved only partial protection against F. tularensis Schu S4 intranasal (i.n.) challenge, even when employing heterologous prime-boost immunization strategies. We now extend these findings to show that both LVS-V and Schu S4-V immunization (i.p./i.p.) elicited similarly high titers of anti-F. tularensis IgG and that the titers could be further increased by adding monophosphoryl lipid A (MPL), a nontoxic Toll-like receptor 4 (TLR4) adjuvant that is included in several U.S. FDA-approved vaccines. LVS-V+MPL immune sera also detected more F. tularensis antigens than LVS-V immune sera and, after passive transfer to naive mice, significantly delayed the time to death against F. tularensis Schu S4 subcutaneous (s.c.) but not i.n. challenge. Active immunization with LVS-V+MPL (i.p./i.p.) also increased the frequency of gamma interferon (IFN-gamma)-secreting activated helper T cells, IFN-gamma production, and the ability of splenocytes to control intramacrophage F. tularensis LVS replication ex vivo Active LVS-V+MPL immunization via heterologous routes (i.p./i.n.) significantly elevated IgA and IgG levels in bronchoalveolar lavage fluid and significantly enhanced protection against i.n. F. tularensis Schu S4 challenge (to ~60%). These data represent a significant step in the development of a subunit vaccine against the highly virulent type A strains. PMID- 28077442 TI - Miniaturized Nanopore DNA Sequencing: Accelerating the Path to Precision Medicine. PMID- 28077441 TI - Using Data from Macaques To Predict Gamma Interferon Responses after Mycobacterium bovis BCG Vaccination in Humans: a Proof-of-Concept Study of Immunostimulation/Immunodynamic Modeling Methods. AB - Macaques play a central role in the development of human tuberculosis (TB) vaccines. Immune and challenge responses differ across macaque and human subpopulations. We used novel immunostimulation/immunodynamic modeling methods in a proof-of-concept study to determine which macaque subpopulations best predicted immune responses in different human subpopulations. Data on gamma interferon (IFN gamma)-secreting CD4+ T cells over time after recent Mycobacterium bovis BCG vaccination were available for 55 humans and 81 macaques. Human population covariates were baseline BCG vaccination status, time since BCG vaccination, gender, and the monocyte/lymphocyte cell count ratio. The macaque population covariate was the colony of origin. A two-compartment mathematical model describing the dynamics of the IFN-gamma T cell response after BCG vaccination was calibrated to these data using nonlinear mixed-effects methods. The model was calibrated to macaque and human data separately. The association between subpopulations and the BCG immune response in each species was assessed. The macaque subpopulations that best predicted immune responses in different human subpopulations were identified using Bayesian information criteria. We found that the macaque colony and the human baseline BCG status were significantly (P < 0.05) associated with the BCG-induced immune response. For humans who were BCG naive at baseline, Indonesian cynomolgus macaques and Indian rhesus macaques best predicted the immune response. For humans who had already been BCG vaccinated at baseline, Mauritian cynomolgus macaques best predicted the immune response. This work suggests that the immune responses of different human populations may be best modeled by different macaque colonies, and it demonstrates the potential utility of immunostimulation/immunodynamic modeling to accelerate TB vaccine development. PMID- 28077443 TI - Single-Dose Intracardiac Injection of Pro-Regenerative MicroRNAs Improves Cardiac Function After Myocardial Infarction. AB - RATIONALE: Recent evidence indicates that a few human microRNAs (miRNAs), in particular hsa-miR-199a-3p and hsa-miR-590-3p, stimulate proliferation of cardiomyocytes and, once expressed in the mouse heart using viral vectors, induce cardiac regeneration after myocardial infarction. Viral vectors, however, are not devoid of safety issues and, more notably, drive expression of the encoded miRNAs for indefinite periods of time, which might not be desirable in light of human therapeutic application. OBJECTIVE: As an alternative to the use of viral vectors, we wanted to assess the efficacy of synthetic miRNA mimics in inducing myocardial repair after single intracardiac injection using synthetic lipid formulations. METHODS AND RESULTS: We comparatively analyzed the efficacy of different lipid formulations in delivering hsa-miR-199a-3p and hsa-miR-590-3p both in primary neonatal mouse cardiomyocytes and in vivo. We established a transfection protocol allowing persistence of these 2 mimics for at least 12 days after a single intracardiac injection, with minimal dispersion to other organs and long-term preservation of miRNA functional activity, as assessed by monitoring the expression of 2 mRNA targets. Administration of this synthetic formulation immediately after myocardial infarction in mice resulted in marked reduction of infarct size and persistent recovery of cardiac function. CONCLUSIONS: A single administration of synthetic miRNA-lipid formulations is sufficient to stimulate cardiac repair and restoration of cardiac function. PMID- 28077445 TI - Human Antiviral Protein IFIX Suppresses Viral Gene Expression during Herpes Simplex Virus 1 (HSV-1) Infection and Is Counteracted by Virus-induced Proteasomal Degradation. AB - The interferon-inducible protein X (IFIX), a member of the PYHIN family, was recently recognized as an antiviral factor against infection with herpes simplex virus 1 (HSV-1). IFIX binds viral DNA upon infection and promotes expression of antiviral cytokines. How IFIX exerts its host defense functions and whether it is inhibited by the virus remain unknown. Here, we integrated live cell microscopy, proteomics, IFIX domain characterization, and molecular virology to investigate IFIX regulation and antiviral functions during HSV-1 infection. We find that IFIX has a dynamic localization during infection that changes from diffuse nuclear and nucleoli distribution in uninfected cells to discrete nuclear puncta early in infection. This is rapidly followed by a reduction in IFIX protein levels. Indeed, using immunoaffinity purification and mass spectrometry, we define IFIX interactions during HSV-1 infection, finding an association with a proteasome subunit and proteins involved in ubiquitin-proteasome processes. Using synchronized HSV-1 infection, microscopy, and proteasome-inhibition experiments, we demonstrate that IFIX co-localizes with nuclear proteasome puncta shortly after 3 h of infection and that its pyrin domain is rapidly degraded in a proteasome-dependent manner. We further demonstrate that, in contrast to several other host defense factors, IFIX degradation is not dependent on the E3 ubiquitin ligase activity of the viral protein ICP0. However, we show IFIX degradation requires immediate-early viral gene expression, suggesting a viral host suppression mechanism. The IFIX interactome also demonstrated its association with transcriptional regulatory proteins, including the 5FMC complex. We validate this interaction using microscopy and reciprocal isolations and determine it is mediated by the IFIX HIN domain. Finally, we show IFIX suppresses immediate-early and early viral gene expression during infection. Altogether, our study demonstrates that IFIX antiviral functions work in part via viral transcriptional suppression and that HSV-1 has acquired mechanisms to block its functions via proteasome-dependent degradation. PMID- 28077444 TI - Protein Interactions during the Flavivirus and Hepacivirus Life Cycle. AB - Protein-protein interactions govern biological functions in cells, in the extracellular milieu, and at the border between cells and extracellular space. Viruses are small intracellular parasites and thus rely on protein interactions to produce progeny inside host cells and to spread from cell to cell. Usage of host proteins by viruses can have severe consequences e.g. apoptosis, metabolic disequilibria, or altered cell proliferation and mobility. Understanding protein interactions during virus infection can thus educate us on viral infection and pathogenesis mechanisms. Moreover, it has led to important clinical translations, including the development of new therapeutic and vaccination strategies. Here, we will discuss protein interactions of members of the Flaviviridae family, which are small enveloped RNA viruses. Dengue virus, Zika virus and hepatitis C virus belong to the most prominent human pathogenic Flaviviridae With a genome of roughly ten kilobases encoding only ten viral proteins, Flaviviridae display intricate mechanisms to engage the host cell machinery for their purpose. In this review, we will highlight how dengue virus, hepatitis C virus, Japanese encephalitis virus, tick-borne encephalitis virus, West Nile virus, yellow fever virus, and Zika virus proteins engage host proteins and how this knowledge helps elucidate Flaviviridae infection. We will specifically address the protein composition of the virus particle as well as the protein interactions during virus entry, replication, particle assembly, and release from the host cell. Finally, we will give a perspective on future challenges in Flaviviridae interaction proteomics and why we believe these challenges should be met. PMID- 28077447 TI - Role of vacuoles in phosphorus storage and remobilization. AB - Vacuoles play a fundamental role in storage and remobilization of various nutrients, including phosphorus (P), an essential element for cell growth and development. Cells acquire P primarily in the form of inorganic orthophosphate (Pi). However, the form of P stored in vacuoles varies by organism and tissue. Algae and yeast store polyphosphates (polyPs), whereas plants store Pi and inositol phosphates (InsPs) in vegetative tissues and seeds, respectively. In this review, we summarize how vacuolar P molecules are stored and reallocated and how these processes are regulated and co-ordinated. The roles of SYG1/PHO81/XPR1 (SPX)-domain-containing membrane proteins in allocating vacuolar P are outlined. We also highlight the importance of vacuolar P in buffering the cytoplasmic Pi concentration to maintain cellular homeostasis when the external P supply fluctuates, and present additional roles for vacuolar polyP and InsP besides being a P reserve. Furthermore, we discuss the possibility of alternative pathways to recycle Pi from other P metabolites in vacuoles. Finally, future perspectives for researching this topic and its potential application in agriculture are proposed. PMID- 28077448 TI - Computation Error. PMID- 28077446 TI - Regulating chromosomal movement by the cochaperone FKB-6 ensures timely pairing and synapsis. AB - In meiotic prophase I, homologous chromosome pairing is promoted through chromosome movement mediated by nuclear envelope proteins, microtubules, and dynein. After proper homologue pairing has been established, the synaptonemal complex (SC) assembles along the paired homologues, stabilizing their interaction and allowing for crossing over to occur. Previous studies have shown that perturbing chromosome movement leads to pairing defects and SC polycomplex formation. We show that FKB-6 plays a role in SC assembly and is required for timely pairing and proper double-strand break repair kinetics. FKB-6 localizes outside the nucleus, and in its absence, the microtubule network is altered. FKB 6 is required for proper movement of dynein, increasing resting time between movements. Attenuating chromosomal movement in fkb-6 mutants partially restores the defects in synapsis, in agreement with FKB-6 acting by decreasing chromosomal movement. Therefore, we suggest that FKB-6 plays a role in regulating dynein movement by preventing excess chromosome movement, which is essential for proper SC assembly and homologous chromosome pairing. PMID- 28077449 TI - Waterpipe Promotion and Use on Instagram: #Hookah. AB - Introduction: Waterpipe (hookah) use is becoming more prevalent in the United States and abroad with potential implications for public health. As waterpipe use rapidly grows in popularity, novel data streams are needed that can help capture and document the social and environmental context in which individuals use, and are marketed, this emerging tobacco product. This study characterized waterpipe related posts on Instagram in order to inform regulatory and policy activities in the United States. Methods: Data were collected from Instagram, an image-based social media site. Inclusion criteria for this study comprised an Instagram post with the hashtag "#hookah" that was accompanied by geo-location metadata demonstrating that the post was inside the contiguous United States. Rules were established for coding themes of images (n = 1705). Results: Seven percent of images depicted a single person using a waterpipe and/or blowing smoke, 25% depicted two or more persons lounging and/or using a waterpipe, 6% depicted waterpipes, coals or flavored tobacco without people, 18% of images were promotional material for hookah lounges and restaurant/bars/nightclubs referencing hookah in the text or depicting a waterpipe, 25% were non-waterpipe related promotional material, 1% were sexually explicit material, and 18% other. 31% of all images depicted or referenced alcohol. 30% of posts provided geo location from a hookah lounge, 56% from a restaurant/bar/nightclub, and 14% from other types of locations. Conclusions: The cross promotion of waterpipe and alcohol use by hookah lounges, and restaurants/bars/nightclubs suggests that poly substance use is regularly depicted, and promoted, in nightlife entertainment as well as normalized on Instagram in the United States. Implications: In the US Instagram posts with the hashtag #hookah regularly depicted waterpipe use in conjunction with alcohol use. Instagram's focus on images facilitates picture based advertising where hookah lounges promote drink specials at the same time nightclubs promote waterpipe specials. Instagram users often document the variety of shapes, sizes, and styles, of waterpipes, suggesting users take pride in their purchases and like to show their customized, and often times elaborate, waterpipes to their followers. Instagram has been underutilized in understanding tobacco related-behaviors and identifying tobacco-related promotional material. PMID- 28077450 TI - Aging in Myanmar. AB - This spotlight provides an overview of the situation of older persons in Myanmar, an understudied country of over-50-million population. Myanmar is of particular interest to researchers and policy makers, given its overall level of poverty and modestly rapid population aging. Research on older persons, while increasing in recent years, remains sparse. Empirical evidence indicates that Myanmar older persons are in relatively poorer health compared to those in neighboring countries. Many live in abject poverty and depend on their families for material support. Coresidence is very common and facilitates reciprocal exchanges across generations. Looking ahead, Myanmar confronts important challenges including demographic shifts that reduce availability of family support for older persons and increasing burden from chronic illnesses. Currently, government measures are essentially absent, although a law on aging was drafted and is in the process to become legislation. PMID- 28077451 TI - The Increasing Use of Cannabis Among Older Americans: A Public Health Crisis or Viable Policy Alternative? AB - Cannabis use among older Americans is increasing. Although much of this growth has been attributed to the entry of a more tolerant baby boom cohort into older age, recent evidence suggests the pathways to cannabis are more complex. Some older persons have responded to changing social and legal environments and are increasingly likely to take cannabis recreationally. Other older persons are experiencing age-related health care needs, and some take cannabis for symptom management, as recommended by a medical doctor. Whether these pathways to recreational and medical cannabis are separate or somewhat tangled remains largely unknown. There have been few studies examining cannabis use among the growing population of Americans aged 65 and older. In this essay, we illuminate what is known about the intersection between cannabis and the aging American population. We review trends concerning cannabis use and apply the age-period cohort paradigm to explicate varied pathways and outcomes. Then, after considering the public health problems posed by those who misuse or abuse cannabis, we turn our attention to how cannabis may be a viable policy alternative in terms of supporting the health and well-being of a substantial number of aging Americans. On the one hand, cannabis may be an effective substitute for prescription opioids and other misused medications; on the other hand, cannabis has emerged as an alternative for the undertreatment of pain at the end of life. As intriguing as these alternatives may be, policy makers must first address the need for empirically driven, representative research to advance the discourse. PMID- 28077452 TI - Does it Matter if We Disagree? The Impact of Incongruent Care Preferences on Persons with Dementia and Their Care Partners. AB - Purpose: To gain a better understanding of how actual and perceived incongruence of care preferences affects the psychosocial well-being of persons with dementia and their family caregiver. Design and Methods: In-depth interviews were conducted with 128 dyads each consisting of a person with dementia and a family caregiver. Baseline data from an intervention study were used to examine the relationship between the caregiver's care-related preferences, the person with dementia's care-related preferences, and the caregiver's perception of the person with dementia's preferences. Preferences for three care-related domains were recorded: personal activities of daily living (PADLs), instrumental activities of daily living (IADLs), and socioemotional issues. Primary outcomes included dyadic relationship strain, quality of life, and mood for both the caregiver and person with dementia. Results: Perceived incongruence of care preferences was a better predictor of negative psychosocial outcomes than actual incongruence. Actual incongruence for socioemotional care preferences was a predictor of greater relationship strain and worse mood for the person with dementia, whereas perceived incongruence for socioemotional care preferences was related to lower quality of life and worse mood for the caregiver. Interestingly, perceived incongruence for PADLs predicted higher quality of life and better mood for the caregiver. Implications: Findings have implications for communication between care partners, especially regarding socioemotional care preferences. Socioemotional preferences, which might be overlooked in the creation of a care plan, may influence the person with dementia's well-being. PMID- 28077453 TI - State Regulatory Approaches for Dementia Care in Residential Care and Assisted Living. AB - Purpose: This policy study analyzed states' residential care and assisted living (RC/AL) regulations for dementia care requirements. Estimates suggest that at least half of RC/AL residents have dementia, and 22% of settings provide or specialize in dementia care. Residents with dementia might benefit from regulations that account for specific behaviors and needs associated with dementia, making states' RC/AL regulations address dementia care an important policy topic. Design and Methods: This study examined RC/AL regulations in all 50 states and the District of Columbia for regulatory requirements on five topics important to the quality of life of RC/AL residents with dementia: pre-admission assessment, consumer disclosure, staffing types and levels, administrator training, and physical environment. Results: Sixteen states license or certify dementia care units within RC/AL settings. All states had at least one dementia care requirement, though only four states had requirements for all five of the topics reviewed. Most states addressed administrator training, consumer disclosure, and physical environment, 17 addressed staffing types and levels, and 14 addressed pre-admission assessment for dementia. Thus, most states rely on general RC/AL regulations to cover dementia care policies and practices. Implications: This policy study provides a resource for researchers who do cross state studies of dementia care in RC/AL settings and state policymakers who are updating RC/AL regulations, including those responding to a 2014 Centers for Medicare and Medicaid Services rule change. PMID- 28077454 TI - Using the National Institutes of Health Stroke Scale: A Cautionary Tale. PMID- 28077455 TI - Symptomatic Carotid Occlusion Is Frequently Associated With Microembolization. AB - BACKGROUND AND PURPOSE: Symptomatic carotid artery disease is associated with significant morbidity and mortality. The pathophysiologic mechanisms of cerebral ischemia among patients with carotid occlusion remain underexplored. METHODS: We conducted a prospective observational cohort study of patients hospitalized within 7 days of ischemic stroke or transient ischemic attack because of >=50% carotid artery stenosis or occlusion. Transcranial Doppler emboli detection was performed in the middle cerebral artery ipsilateral to the symptomatic carotid. We describe the prevalence of microembolic signals (MES), characterize infarct topography, and report clinical outcomes at 90 days. RESULTS: Forty-seven patients, 19 with carotid occlusion and 28 with carotid stenosis, had complete transcranial Doppler recordings and were included in the final analysis. MES were present in 38%. There was no difference in MES between those with carotid occlusion (7/19, 37%) compared with stenosis (11/28, 39%; P=0.87). In patients with radiographic evidence of infarction (n=39), 38% had a watershed pattern of infarction, 41% had a nonwatershed pattern, and 21% had a combination. MES were present in 40% of patients with a watershed pattern of infarction. Recurrent cerebral ischemia occurred in 9 patients (19%; 6 with transient ischemic attack, 3 with ischemic stroke). There was no difference in the rate of recurrence in those with compared to those without MES. CONCLUSIONS: Cerebral embolization plays an important role in the pathophysiology of ischemia in both carotid occlusion and stenosis, even among patients with watershed infarcts. The role of aggressive antithrombotic and antiplatelet therapy for symptomatic carotid occlusions may warrant further investigation given our findings. PMID- 28077456 TI - Revealing nonclassicality beyond Gaussian states via a single marginal distribution. AB - A standard method to obtain information on a quantum state is to measure marginal distributions along many different axes in phase space, which forms a basis of quantum-state tomography. We theoretically propose and experimentally demonstrate a general framework to manifest nonclassicality by observing a single marginal distribution only, which provides a unique insight into nonclassicality and a practical applicability to various quantum systems. Our approach maps the 1D marginal distribution into a factorized 2D distribution by multiplying the measured distribution or the vacuum-state distribution along an orthogonal axis. The resulting fictitious Wigner function becomes unphysical only for a nonclassical state; thus the negativity of the corresponding density operator provides evidence of nonclassicality. Furthermore, the negativity measured this way yields a lower bound for entanglement potential-a measure of entanglement generated using a nonclassical state with a beam-splitter setting that is a prototypical model to produce continuous-variable (CV) entangled states. Our approach detects both Gaussian and non-Gaussian nonclassical states in a reliable and efficient manner. Remarkably, it works regardless of measurement axis for all non-Gaussian states in finite-dimensional Fock space of any size, also extending to infinite-dimensional states of experimental relevance for CV quantum informatics. We experimentally illustrate the power of our criterion for motional states of a trapped ion, confirming their nonclassicality in a measurement-axis independent manner. We also address an extension of our approach combined with phase-shift operations, which leads to a stronger test of nonclassicality, that is, detection of genuine non-Gaussianity under a CV measurement. PMID- 28077457 TI - Systems Biology-Derived Biomarkers to Predict Progression of Renal Function Decline in Type 2 Diabetes. AB - OBJECTIVE: Chronic kidney disease (CKD) in diabetes has a complex molecular and likely multifaceted pathophysiology. We aimed to validate a panel of biomarkers identified using a systems biology approach to predict the individual decline of estimated glomerular filtration rate (eGFR) in a large group of patients with type 2 diabetes and CKD at various stages. RESEARCH DESIGN AND METHODS: We used publicly available "omics" data to develop a molecular process model of CKD in diabetes and identified a representative parsimonious set of nine molecular biomarkers: chitinase 3-like protein 1, growth hormone 1, hepatocyte growth factor, matrix metalloproteinase (MMP) 2, MMP7, MMP8, MMP13, tyrosine kinase, and tumor necrosis factor receptor-1. These biomarkers were measured in baseline serum samples from 1,765 patients recruited into two large clinical trials. eGFR decline was predicted based on molecular markers, clinical risk factors (including baseline eGFR and albuminuria), and both combined, and these predictions were evaluated using mixed linear regression models for longitudinal data. RESULTS: The variability of annual eGFR loss explained by the biomarkers, indicated by the adjusted R2 value, was 15% and 34% for patients with eGFR >=60 and <60 mL/min/1.73 m2, respectively; variability explained by clinical predictors was 20% and 31%, respectively. A combination of molecular and clinical predictors increased the adjusted R2 to 35% and 64%, respectively. Calibration analysis of marker models showed significant (all P < 0.0001) but largely irrelevant deviations from optimal calibration (calibration-in-the-large: -1.125 and 0.95; calibration slopes: 1.07 and 1.13 in the two groups, respectively). CONCLUSIONS: A small set of serum protein biomarkers identified using a systems biology approach, combined with clinical variables, enhances the prediction of renal function loss over a wide range of baseline eGFR values in patients with type 2 diabetes and CKD. PMID- 28077458 TI - Type 2 Diabetes and Comorbid Symptoms of Depression and Anxiety: Longitudinal Associations With Mortality Risk. AB - OBJECTIVE: Depression is strongly linked to increased mortality in individuals with type 2 diabetes. Despite high rates of co-occurring anxiety and depression, the risk of death associated with comorbid anxiety in individuals with type 2 diabetes is poorly understood. This study documented the excess mortality risk associated with symptoms of depression and/or anxiety comorbid with type 2 diabetes. RESEARCH DESIGN AND METHODS: Using data for 64,177 Norwegian adults from the second wave of the Nord-Trondelag Health Study (HUNT2), with linkage to the Norwegian Causes of Death Registry, we assessed all-cause mortality from survey participation in 1995 through to 2013. We used Cox proportional hazards models to examine mortality risk over 18 years associated with type 2 diabetes status and the presence of comorbid affective symptoms at baseline. RESULTS: Three clear patterns emerged from our findings. First, mortality risk in individuals with diabetes increased in the presence of depression or anxiety, or both. Second, mortality risk was lowest for symptoms of anxiety, higher for comorbid depression-anxiety, and highest for depression. Lastly, excess mortality risk associated with depression and anxiety was observed in men with diabetes but not in women. The highest risk of death was observed in men with diabetes and symptoms of depression only (hazard ratio 3.47, 95% CI 1.96, 6.14). CONCLUSIONS: This study provides evidence that symptoms of anxiety affect mortality risk in individuals with type 2 diabetes independently of symptoms of depression, in addition to attenuating the relationship between depressive symptoms and mortality in these individuals. PMID- 28077459 TI - The Virtual Office Visit for Women With Gestational Diabetes Mellitus. PMID- 28077460 TI - Glyburide Versus Metformin and Their Combination for the Treatment of Gestational Diabetes Mellitus: A Randomized Controlled Study. AB - OBJECTIVE: To compare the efficacy and safety of glyburide versus metformin and their combination for the treatment of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: In this prospective randomized controlled study, we randomly assigned patients with GDM at 13-33 weeks gestation and whose blood glucose was poorly controlled by diet to receive either glyburide or metformin. If optimal glycemic control was not achieved, the other drug was added. If adverse effects occurred, the drug was replaced. If both failed, insulin was given. The primary outcomes were the rate of treatment failure and glycemic control after the first-line medication according to mean daily glucose charts. RESULTS: Glyburide was started in 53 patients and metformin in 51. In the glyburide group, the drug failed in 18 (34%) patients due to adverse effects (hypoglycemia) in 6 (11%) and lack of glycemic control in 12 (23%). In the metformin group, the drug failed in 15 (29%) patients, due to adverse effects (gastrointestinal) in 1 (2%) and lack of glycemic control in 14 (28%). Treatment success after second-line therapy was higher in the metformin group than in the glyburide group (13 of 15 [87%] vs. 9 of 18 [50%], respectively; P = 0.03). In the glyburide group, nine (17%) patients were eventually treated with insulin compared with two (4%) in the metformin group (P = 0.03). The combination of the drugs reduced the need for insulin from 33 (32%) to 11 (11%) patients (P = 0.0002). Mean daily blood glucose and other obstetrical and neonatal outcomes were comparable between groups, including macrosomia, neonatal hypoglycemia, and electrolyte imbalance. CONCLUSIONS: Glyburide and metformin are comparable oral treatments for GDM regarding glucose control and adverse effects. Their combination demonstrates a high efficacy rate with a significantly reduced need for insulin, with a possible advantage for metformin over glyburide as first-line therapy. PMID- 28077461 TI - Human RIF1 and protein phosphatase 1 stimulate DNA replication origin licensing but suppress origin activation. AB - The human RIF1 protein controls DNA replication, but the molecular mechanism is largely unknown. Here, we demonstrate that human RIF1 negatively regulates DNA replication by forming a complex with protein phosphatase 1 (PP1) that limits phosphorylation-mediated activation of the MCM replicative helicase. We identify specific residues on four MCM helicase subunits that show hyperphosphorylation upon RIF1 depletion, with the regulatory N-terminal domain of MCM4 being particularly strongly affected. In addition to this role in limiting origin activation, we discover an unexpected new role for human RIF1-PP1 in mediating efficient origin licensing. Specifically, during the G1 phase of the cell cycle, RIF1-PP1 protects the origin-binding ORC1 protein from untimely phosphorylation and consequent degradation by the proteasome. Depletion of RIF1 or inhibition of PP1 destabilizes ORC1, thereby reducing origin licensing. Consistent with reduced origin licensing, RIF1-depleted cells exhibit increased spacing between active origins. Human RIF1 therefore acts as a PP1-targeting subunit that regulates DNA replication positively by stimulating the origin licensing step, and then negatively by counteracting replication origin activation. PMID- 28077463 TI - Novel method for detection of glycogen in cells. AB - y: Glycogen, a branched polymer of glucose, functions as an energy reserve in many living organisms. Abnormalities in glycogen metabolism, usually excessive accumulation, can be caused genetically, most often through mutation of the enzymes directly involved in synthesis and degradation of the polymer leading to a variety of glycogen storage diseases (GSDs). Microscopic visualization of glycogen deposits in cells and tissues is important for the study of normal glycogen metabolism as well as diagnosis of GSDs. Here, we describe a method for the detection of glycogen using a renewable, recombinant protein which contains the carbohydrate-binding module (CBM) from starch-binding domain containing protein 1 (Stbd1). We generated a fusion protein containing g lutathione S transferase, a cM c eptitope and the tbd1 BM (GYSC) for use as a glycogen-binding probe, which can be detected with secondary antibodies against glutathione S transferase or cMyc. By enzyme-linked immunosorbent assay, we demonstrate that GYSC binds glycogen and two other polymers of glucose, amylopectin and amylose. Immunofluorescence staining of cultured cells indicate a GYSC-specific signal that is co-localized with signals obtained with anti-glycogen or anti-glycogen synthase antibodies. GYSC-positive staining inside of lysosomes is observed in individual muscle fibers isolated from mice deficient in lysosomal enzyme acid alpha-glucosidase, a well-characterized model of GSD II (Pompe disease). Co localized GYSC and glycogen signals are also found in muscle fibers isolated from mice deficient in malin, a model for Lafora disease. These data indicate that GYSC is a novel probe that can be used to study glycogen metabolism under normal and pathological conditions. PMID- 28077464 TI - Integrated care of patients with atrial fibrillation: the 2016 ESC atrial fibrillation guidelines. PMID- 28077462 TI - Bromodomains in Protozoan Parasites: Evolution, Function, and Opportunities for Drug Development. AB - Parasitic infections remain one of the most pressing global health concerns of our day, affecting billions of people and producing unsustainable economic burdens. The rise of drug-resistant parasites has created an urgent need to study their biology in hopes of uncovering new potential drug targets. It has been established that disrupting gene expression by interfering with lysine acetylation is detrimental to survival of apicomplexan (Toxoplasma gondii and Plasmodium spp.) and kinetoplastid (Leishmania spp. and Trypanosoma spp.) parasites. As "readers" of lysine acetylation, bromodomain proteins have emerged as key gene expression regulators and a promising new class of drug target. Here we review recent studies that demonstrate the essential roles played by bromodomain-containing proteins in parasite viability, invasion, and stage switching and present work showing the efficacy of bromodomain inhibitors as novel antiparasitic agents. In addition, we performed a phylogenetic analysis of bromodomain proteins in representative pathogens, some of which possess unique features that may be specific to parasite processes and useful in future drug development. PMID- 28077465 TI - Cost-effectiveness of the polypill versus risk assessment for prevention of cardiovascular disease. AB - OBJECTIVE: There is an international trend towards recommending medication to prevent cardiovascular disease (CVD) in individuals at increasingly lower cardiovascular risk. We assessed the cost-effectiveness of a population approach with a polypill including a statin (simvastatin 20 mg) and three antihypertensive agents (amlodipine 2.5 mg, losartan 25 mg and hydrochlorothiazide 12.5 mg) and periodic risk assessment with different risk thresholds. METHODS: We developed a microsimulation model for lifetime predictions of CVD events, diabetes, and death in 259 146 asymptomatic UK Biobank participants aged 40-69 years. We assessed incremental costs and quality-adjusted life-years (QALYs) for polypill scenarios with the same combination of agents and doses but differing for starting age, and periodic risk assessment with 10-year CVD risk thresholds of 10% and 20%. RESULTS: Restrictive risk assessment, in which statins and antihypertensives were prescribed when risk exceeded 20%, was the optimal strategy gaining 123 QALYs (95% credible interval (CI) -173 to 387) per 10 000 individuals at an extra cost of L1.45 million (95% CI 0.89 to 1.94) as compared with current practice. Although less restrictive risk assessment and polypill scenarios prevented more CVD events and attained larger survival gains, these benefits were offset by the additional costs and disutility of daily medication use. Lowering the risk threshold for prescription of statins to 10% was economically unattractive, costing L40 000 per QALY gained. Starting the polypill from age 60 onwards became the most cost-effective scenario when annual drug prices were reduced below L240. All polypill scenarios would save costs at prices below L50. CONCLUSIONS: Periodic risk assessment using lower risk thresholds is unlikely to be cost effective. The polypill would become cost-effective if drug prices were reduced. PMID- 28077466 TI - Tea consumption and risk of ischaemic heart disease. AB - OBJECTIVE: To prospectively examine the association between tea consumption and the risk of ischaemic heart disease (IHD). METHODS: Prospective study using the China Kadoorie Biobank; participants from 10 areas across China were enrolled during 2004-2008 and followed up until 31 December 2013. After excluding participants with cancer, heart disease and stroke at baseline, the present study included 199 293 men and 288 082 women aged 30-79 years at baseline. Information on IHD incidence was collected through disease registries and the new national health insurance databases. RESULTS: During a median follow-up of 7.2 years, we documented 24 665 (7.19 cases/1000 person-years) incident IHD cases and 3959 (1.13 cases/1000 person-years) major coronary events (MCEs). Tea consumption was associated with reduced risk of IHD and MCE. In the whole cohort, compared with participants who never consumed tea during the past 12 months, the multivariable adjusted HRs and 95% CIs for less than daily and daily tea consumers were 0.97 (0.94 to 1.00) and 0.92 (0.88 to 0.95) for IHD, 0.92 (0.85 to 1.00) and 0.90 (0.82 to 0.99) for MCE. No linear trends in the HRs across the amount of tea were observed in daily consumers for IHD and MCE (PLinear >0.05). The inverse association between tea consumption and IHD was stronger in rural (PInteraction 0.006 for IHD, <0.001 for MCE), non-obese (PInteraction 0.012 for MCE) and non diabetes participants (PInteraction 0.004 for IHD). CONCLUSIONS: In this large prospective study, daily tea consumption was associated with a reduced risk of IHD. PMID- 28077467 TI - Gut microbiota-dependent trimethylamine N-oxide in acute coronary syndromes: a prognostic marker for incident cardiovascular events beyond traditional risk factors. AB - Aims: Systemic levels of trimethylamine N-oxide (TMAO), a pro-atherogenic and pro thrombotic metabolite produced from gut microbiota metabolism of dietary trimethylamine (TMA)-containing nutrients such as choline or carnitine, predict incident cardiovascular event risks in stable primary and secondary prevention subjects. However, the prognostic value of TMAO in the setting of acute coronary syndromes (ACS) remains unknown. Methods and results: We investigated the relationship of TMAO levels with incident cardiovascular risks among sequential patients presenting with ACS in two independent cohorts. In the Cleveland Cohort, comprised of sequential subjects (n = 530) presenting to the Emergency Department (ED) with chest pain of suspected cardiac origin, an elevated plasma TMAO level at presentation was independently associated with risk of major adverse cardiac events (MACE, including myocardial infarction, stroke, need for revascularization, or death) over the ensuing 30-day (4th quartile (Q4) adjusted odds ratio (OR) 6.30, 95% confidence interval (CI), 1.89-21.0, P < 0.01) and 6 month (Q4 adjusted OR 5.65, 95%CI, 1.91-16.7; P < 0.01) intervals. TMAO levels were also a significant predictor of the long term (7-year) mortality (Q4 adjusted HR 1.81, 95%CI, 1.04-3.15; P < 0.05). Interestingly, TMAO level at initial presentation predicted risk of incident MACE over the near-term (30 days and 6 months) even among subjects who were initially negative for troponin T (< 0.1 ng/mL) (30 days, Q4 adjusted OR 5.83, 95%CI, 1.79-19.03; P < 0.01). The prognostic value of TMAO was also assessed in an independent multicentre Swiss Cohort of ACS patients (n = 1683) who underwent coronary angiography. Trimethylamine N-oxide again predicted enhanced MACE risk (1-year) (adjusted Q4 hazard ratios: 1.57, 95% CI, 1.03-2.41; P <0.05). Conclusion: Plasma TMAO levels among patients presenting with chest pain predict both near- and long-term risks of incident cardiovascular events, and may thus provide clinical utility in risk stratification among subjects presenting with suspected ACS. PMID- 28077468 TI - Integrated imaging of echocardiography and computed tomography to grade mitral regurgitation severity in patients undergoing transcatheter aortic valve implantation. AB - Aims: Quantitative mitral regurgitation (MR) grading remains challenging. This study evaluated the concept of integrating echocardiography and computed tomography for grading MR severity. Specifically, an integrated parameter was developed that combines the true cross-sectional mitral regurgitant orifice area (ROA) assessed with multi-detector row computed tomography (MDCT) with flow data from echocardiography. Methods and results: Systolic MDCT data of 73 patients, referred for transcatheter aortic valve implantation (TAVI) who also had MR, were evaluated. The MDCT systolic phase with the smaller left ventricular volume and the largest mitral regurgitant orifice was selected. Using planimetry, the mitral ROA was measured. The mitral ROA was multiplied with the velocity time integral of the MR jet on echocardiography for the calculation of the integrated regurgitant volume (RVol). MDCT analysis showed a mean mitral ROA of 11.3 +/- 7.4 mm2 and a mean integrated RVol of 21.4 +/- 14.7 mL/beat, whereas echocardiography showed a mean effective ROA and RVol of MR of 13.3 +/- 8.2 mm2 and 23.9 +/- 13.6 mL/beat, respectively. Compared with echocardiography, grading based on integrated mitral RVol resulted in reclassification of 10% of the patients from severe to non-severe MR and 14% of the patients from non-severe to severe MR. Conclusions: Integrated mitral RVol is a quantitative parameter of MR severity by combining the true cross-sectional mitral ROA assessed with MDCT and Doppler mitral haemodynamics which resulted in a significant reclassification of MR grade in patients with severe aortic stenosis undergoing TAVR. PMID- 28077469 TI - Risk factors for excess mortality in adults with congenital heart diseases. AB - Aims: To examine factors related to excess mortality in a cohort of adults with congenital heart disease (CHD). Methods and results: We conducted a survival analysis using prospective data of 3311 adults with CHD [50.5% males, median age at entry 22.5 years (IQR 18-39), median follow-up time 10.5 years (IQR: 4.4-18)]. Survival status of each patient was further verified by cross checking with the Spanish National Death Index. During a total follow-up of 37608 person-years, 336 (10%) patients died. Annual death rate was 0.89% and standardized mortality ratio (SMR) 2.64 [95% confidence interval (CI) 2.3-3.0; P < 0.001]. Median age at death estimated by left-truncated Kaplan-Meier method was 75.1 years (95% CI 73-77). Survival was reduced compared with the general population whatever their level of complexity, repair status, or underlying CHD. Independent risk factors for excess mortality, including cyanosis, univentricular physiology, genetic disorders, ventricular dysfunction, residual haemodynamic lesions and acquired late complications, among others, were identified by left-truncated Cox regression model. SMR was 5.22 (95% CI 4.5-6.0; P < 0.001) and median age at death 55.6 years (95% CI 50-61) for 996 patients (30%) with at least one risk factor. In contrast, SMR was 1.14 (95% CI 0.9-1.5; P = 0.19) and median age at death 83.7 years (95% CI 82-87) in 2315 patients (70%) with no risk factors. Conclusions: Clinical parameters, such as anatomical features, haemodynamic sequelae, or acquired complications, were independent predictors of excess mortality in adults with CHD. Survival of individuals with no risk factors did not differ from the reference population. PMID- 28077470 TI - Comprehensive efforts to increase adherence to statin therapy. PMID- 28077471 TI - Individual risk stratification in adult congenital heart disease: the way to go? PMID- 28077474 TI - Does newborn screening influence the young cystic fibrosis cohort included in national registries? PMID- 28077475 TI - Equatorial Guinea, a multidrug-resistant tuberculosis hotspot in Central Africa. PMID- 28077476 TI - Acute pulmonary embolism: mortality prediction by the 2014 European Society of Cardiology risk stratification model. PMID- 28077478 TI - Acute pulmonary embolism: mortality prediction by the 2014 European Society of Cardiology risk stratification model. PMID- 28077473 TI - A joint ERS/ATS policy statement: what constitutes an adverse health effect of air pollution? An analytical framework. AB - The American Thoracic Society has previously published statements on what constitutes an adverse effect on health of air pollution in 1985 and 2000. We set out to update and broaden these past statements that focused primarily on effects on the respiratory system. Since then, many studies have documented effects of air pollution on other organ systems, such as on the cardiovascular and central nervous systems. In addition, many new biomarkers of effects have been developed and applied in air pollution studies.This current report seeks to integrate the latest science into a general framework for interpreting the adversity of the human health effects of air pollution. Rather than trying to provide a catalogue of what is and what is not an adverse effect of air pollution, we propose a set of considerations that can be applied in forming judgments of the adversity of not only currently documented, but also emerging and future effects of air pollution on human health. These considerations are illustrated by the inclusion of examples for different types of health effects of air pollution. PMID- 28077477 TI - The Global Asthma Network rationale and methods for Phase I global surveillance: prevalence, severity, management and risk factors. AB - The Global Asthma Network (GAN), established in 2012, followed the International Study of Asthma and Allergies in Childhood (ISAAC). ISAAC Phase One involved over 700 000 adolescents and children from 156 centres in 56 countries; it found marked worldwide variation in symptom prevalence of asthma, rhinitis and eczema that was not explained by the current understanding of these diseases; ISAAC Phase Three involved over 1 187 496 adolescents and children (237 centres in 98 countries). It found that asthma symptom prevalence was increasing in many locations especially in low- and middle-income countries where severity was also high, and identified several environmental factors that required further investigation.GAN Phase I, described in this article, builds on the ISAAC findings by collecting further information on asthma, rhinitis and eczema prevalence, severity, diagnoses, asthma emergency room visits, hospital admissions, management and use of asthma essential medicines. The subjects will be the same age groups as ISAAC, and their parents. In this first global monitoring of asthma in children and adults since 2003, further evidence will be obtained to understand asthma, management practices and risk factors, leading to further recognition that asthma is an important non-communicable disease and to reduce its global burden. PMID- 28077479 TI - Obstructive sleep apnoea as a cause of nocturnal nondipping blood pressure: recent evidence regarding clinical importance and underlying mechanisms. PMID- 28077480 TI - Tiotropium in paediatric asthma. PMID- 28077481 TI - Splenomegaly in the returning traveller: a diagnostic workup. AB - Isolated splenomegaly is an unusual condition encompassing a broad range of diagnoses. We report a case of a 38-year-old Asian man who presented with insidious abdominal discomfort and night sweats following recent travel to India. Massive splenomegaly was the only prominent feature on clinical examination and on subsequent imaging. Extensive investigations were performed, ultimately resulting in transfer to a tertiary centre for definitive diagnosis via a splenic biopsy. A fine-needle aspiration was performed, and revealed diffuse large B-cell lymphoma (DLBCL). Consequently, he was successfully treated with a course of chemotherapy. PMID- 28077482 TI - Rare case of haemoptysis. AB - We report a case of a 39-year-old man who presented with coughing up blood for 5 days. On the day of admission, he coughed up about 300 mL of fresh blood. He mentioned that he has had cough for the past 10 years. On clinical examination, he was afebrile, tachypneic, tahycardic and normotensive. Rest of the physical examination was normal. His oxygen saturation breathing room air was 96%. His full blood count showed haemoglobin 9.3 g/dL. His chest radiograph was reported as normal. CT chest showed a vascular right paracardiac soft tissue density. On the basis of this, a diagnosis of pulmonary sequestration was considered. CT angiography of the soft tissue density identified multiple sources of systemic arterial blood. Two arteries were arising from the descending aorta and a third artery was coming from the right renal artery. Surgical removal of the sequestrated lobe was performed. The patient has an uneventful postoperative recovery and remained well at follow-up 2 months after surgery. PMID- 28077483 TI - Primary sarcomatoid carcinoma of the small intestine: very rare and aggressive tumour. AB - Sarcomatoid carcinoma of the small intestine is a very rare and aggressive variant of small intestinal cancers with poor prognosis. The tumour primarily affects middle-aged and older patients with a mean age of 57 years at the time of presentation. We report a woman aged 58 years without any relevant medical history who presented with small intestinal obstruction. She underwent radiologic and endoscopy investigation with persistent features of small bowel obstruction. The patient was found to have a small bowel tumour causing the obstruction and underwent surgical excision of the tumour. Pathology revealed malignant neoplasm with sarcomatoid and epithelioid features involving the terminal ileum. The use of immunohistochemical markers helps in wide range of differential diagnoses. Surgical resection is still considered the best and first-line therapy with poor response to chemotherapy and radiotherapy. PMID- 28077484 TI - 'Bizarre' rash: adult-onset cutaneous Langerhans cell histiocytosis. PMID- 28077485 TI - Persistent anterior interosseous nerve palsy following forearm crutch use. AB - A 43-year-old man presented with weakness of the interphalageal joint of his right thumb following the use of forearm crutches. On examination he was unable to oppose his thumb and index finger to form the 'ok' sign. Nerve conduction showed anterior interosseous nerve (AIN) damage along its path to the flexor pollicis longus. The patient was managed conservatively with little clinical improvement seen at 4 months. AIN palsies are very rare and account for <1% of all upper limb lesions. Although AIN palsies resulting from other causes such as surgery and blunt trauma are more common, we report the second case of AIN palsy following crutch use, and the first case in which clinical identification was confirmed using electrodiagnosis. Usual clinical practice recommends a prolonged period of conservative management with surgical management withheld for a minimum of 12 months. Correct crutch fitting and early identification of signs of associated injuries are of paramount importance. PMID- 28077486 TI - Severe pulmonary arterial hypertension in a patient with small ventricular septal defect. PMID- 28077487 TI - Calcium-permeable AMPA receptors and silent synapses in cocaine-conditioned place preference. AB - Exposure to cocaine generates silent synapses in the nucleus accumbens (NAc), whose eventual unsilencing/maturation by recruitment of calcium-permeable AMPA type glutamate receptors (CP-AMPARs) after drug withdrawal results in profound remodeling of NAc neuro-circuits. Silent synapse-based NAc remodeling was shown to be critical for several drug-induced behaviors, but its role in acquisition and retention of the association between drug rewarding effects and drug associated contexts has remained unclear. Here, we find that the postsynaptic proteins PSD-93, PSD-95, and SAP102 differentially regulate excitatory synapse properties in the NAc. Mice deficient for either of these scaffold proteins exhibit distinct maturation patterns of silent synapses and thus provided instructive animal models to examine the role of NAc silent synapse maturation in cocaine-conditioned place preference (CPP). Wild-type and knockout mice alike all acquired cocaine-CPP and exhibited increased levels of silent synapses after drug context conditioning. However, the mice differed in CPP retention and CP-AMPAR incorporation. Collectively, our results indicate that CP-AMPAR-mediated maturation of silent synapses in the NAc is a signature of drug-context association, but this maturation is not required for establishing or retaining cocaine-CPP. PMID- 28077488 TI - Id2 controls specification of Lgr5+ intestinal stem cell progenitors during gut development. AB - The adult intestinal stem cells (ISCs), their hierarchies, mechanisms of maintenance and differentiation have been extensively studied. However, when and how ISCs are established during embryogenesis remains unknown. We show here that the transcription regulator Id2 controls the specification of embryonic Lgr5+ progenitors in the developing murine small intestine. Cell fate mapping analysis revealed that Lgr5+ progenitors emerge at E13.5 in wild-type embryos and differ from the rest on the intestinal epithelium by a characteristic ISC signature. In the absence of Id2, the intestinal epithelium differentiates into Lgr5+ cells already at E9.5. Furthermore, the size of the Lgr5+ cell pool is significantly increased. We show that Id2 restricts the activity of the Wnt signalling pathway at early stages and prevents precocious differentiation of the embryonic intestinal epithelium. Id2-deficient embryonic epithelial cells cultured ex vivo strongly activate Wnt target genes as well as markers of neoplastic transformation and form fast growing undifferentiated spheroids. Furthermore, adult ISCs from Id2-deficient mice display a distinct transcriptional signature, supporting an essential role for Id2 in the correct specification of ISCs. PMID- 28077489 TI - Rescue of severe brain and cervical cord IRIS by restarting natalizumab in a pregnant MS patient. PMID- 28077490 TI - Improving uniformity in brain death determination policies over time. AB - OBJECTIVE: To demonstrate that progress has been made in unifying brain death determination guidelines in the last decade by directly comparing the policies of the US News and World Report's top 50 ranked neurologic institutions from 2006 and 2015. METHODS: We solicited official hospital guidelines in 2015 from these top 50 institutions, generated summary statistics of their criteria as benchmarked against the American Academy of Neurology Practice Parameters (AANPP) and the comparison 2006 cohort in 5 key categories, and statistically compared the 2 cohorts' compliance with the AANPP. RESULTS: From 2008 to 2015, hospital policies exhibited significant improvement (p = 0.005) in compliance with official guidelines, particularly with respect to criteria related to apnea testing (p = 0.009) and appropriate ancillary testing (p = 0.0006). However, variability remains in other portions of the policies, both those with specific recommendation from the AANPP (e.g., specifics for ancillary tests) and those without firm guidance (e.g., the level of involvement of neurologists, neurosurgeons, or physicians with education/training specific to brain death in the determination process). CONCLUSIONS: While the 2010 AANPP update seems to be concordant with progress in achieving greater uniformity in guidelines at the top 50 neurologic institutions, more needs to be done. Whether further interventions come as grassroots initiatives that leverage technological advances in promoting adoption of new guidelines or as top-down regulatory rulings to mandate speedier approval processes, this study shows that solely relying on voluntary updates to professional society guidelines is not enough. PMID- 28077491 TI - Sphingosine 1-phosphate lyase deficiency causes Charcot-Marie-Tooth neuropathy. AB - OBJECTIVE: To identify the unknown genetic cause in a nuclear family with an axonal form of peripheral neuropathy and atypical disease course. METHODS: Detailed neurologic, electrophysiologic, and neuropathologic examinations of the patients were performed. Whole exome sequencing of both affected individuals was done. The effect of the identified sequence variations was investigated at cDNA and protein level in patient-derived lymphoblasts. The plasma sphingoid base profile was analyzed. Functional consequences of neuron-specific downregulation of the gene were studied in Drosophila. RESULTS: Both patients present an atypical form of axonal peripheral neuropathy, characterized by acute or subacute onset and episodes of recurrent mononeuropathy. We identified compound heterozygous mutations cosegregating with disease and absent in controls in the SGPL1 gene, encoding sphingosine 1-phosphate lyase (SPL). The p.Ser361* mutation triggers nonsense-mediated mRNA decay. The missense p.Ile184Thr mutation causes partial protein degradation. The plasma levels of sphingosine 1-phosphate and sphingosine/sphinganine ratio were increased in the patients. Neuron-specific downregulation of the Drosophila orthologue impaired the morphology of the neuromuscular junction and caused progressive degeneration of the chemosensory neurons innervating the wing margin bristles. CONCLUSIONS: We suggest SPL deficiency as a cause of a distinct form of Charcot-Marie-Tooth disease in humans, thus extending the currently recognized clinical and genetic spectrum of inherited peripheral neuropathies. Our data emphasize the importance of sphingolipid metabolism for neuronal function. PMID- 28077492 TI - Dystonia treatment: Patterns of medication use in an international cohort. AB - OBJECTIVE: To determine the frequency of medication use in patients with dystonia enrolled in an international biorepository study. METHODS: In a cross-sectional analysis, we included 2,026 participants enrolled at 37 sites in the United States, Canada, Europe, and Australia through Project 1 of the Dystonia Coalition, an international biorepository study. The primary aim was to assess the frequency of medication classes recommended for treating patients with dystonia, and the secondary aim was to compare characteristics (disease type, age, sex, duration of disease, comorbid conditions, severity). RESULTS: Querying the database for the presence of any medication for dystonia used (includes both injectable and oral therapy), we found 73% using medications (n = 1,488) and 27% using no dystonia medications (n = 538). Furthermore, 61% of the total sample used botulinum toxin (BoNT) therapy alone or in combination. Differences were found in medication use patterns by dystonia type, with the lowest oral medication use in focal dystonia and highest use in generalized dystonia; by region, with highest BoNT therapy rate reported in Italy and the lowest in the Northeast region of the United States; and by focal dystonia subtype, with highest BoNT therapy alone in blepharospasm and spasmodic dysphonia (49%) and lowest in other cranial dystonia (32%). CONCLUSIONS: The majority of patients with dystonia enrolled in the Dystonia Coalition Project 1 were using medications to treat their dystonia. Overall, a complex picture of medication use patterns emerged, with factors such as region, disease duration, type of dystonia, disease severity, and psychiatric comorbidities all playing a significant role. PMID- 28077493 TI - Disease-modifying therapies modulate retinal atrophy in multiple sclerosis: A retrospective study. AB - OBJECTIVE: To retrospectively investigate whether disease-modifying therapies (DMTs) exert differential effects on rates of retinal atrophy in relapsing remitting multiple sclerosis (RRMS), as assessed using optical coherence tomography (OCT). METHODS: A total of 402 patients with RRMS followed at the Johns Hopkins MS Center who underwent Cirrus-HD OCT were assessed for eligibility. Inclusion criteria included at least 1 year of OCT follow-up and adherence to a single DMT during the period of follow-up. Combined thickness of the ganglion cell + inner plexiform (GCIP) and other retinal layers was computed utilizing automated macular segmentation. Retinal thickness changes were analyzed using mixed-effects linear regression. RESULTS: The effects of glatiramer acetate (GA; n = 48), natalizumab (NAT; n = 46), and interferon-beta-1a subcutaneously (IFNSC; n = 35) and intramuscularly (IFNIM; n = 28) were assessed. Baseline analyses revealed no significant differences between groups in terms of age, sex, optic neuritis history, or follow-up duration. During follow-up, relative to NAT treated patients, IFNSC- and GA-treated patients exhibited 0.37 MUm/y (p < 0.001) and 0.14 MUm/y (p = 0.035) faster rates of GCIP thinning, respectively, adjusting for the interval between initiation of DMT and OCT monitoring (gap time), age, sex, relapses, and disease duration. In the IFNSC group, GCIP thinning was 1.53 MUm/y faster during the first year of therapy vs during the time interval afterwards (p < 0.001). CONCLUSIONS: Rates of GCIP atrophy in patients with RRMS vary according to DMT utilization. Our findings support OCT for monitoring neurodegenerative treatment effects in the retina, an easily accessible tissue, and as a practical outcome measure in RRMS clinical trials. PMID- 28077494 TI - Practice guideline summary: Use of fMRI in the presurgical evaluation of patients with epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. AB - OBJECTIVE: To assess the diagnostic accuracy and prognostic value of functional MRI (fMRI) in determining lateralization and predicting postsurgical language and memory outcomes. METHODS: An 11-member panel evaluated and rated available evidence according to the 2004 American Academy of Neurology process. At least 2 panelists reviewed the full text of 172 articles and selected 37 for data extraction. Case reports, reports with <15 cases, meta-analyses, and editorials were excluded. RESULTS AND RECOMMENDATIONS: The use of fMRI may be considered an option for lateralizing language functions in place of intracarotid amobarbital procedure (IAP) in patients with medial temporal lobe epilepsy (MTLE; Level C), temporal epilepsy in general (Level C), or extratemporal epilepsy (Level C). For patients with temporal neocortical epilepsy or temporal tumors, the evidence is insufficient (Level U). fMRI may be considered to predict postsurgical language deficits after anterior temporal lobe resection (Level C). The use of fMRI may be considered for lateralizing memory functions in place of IAP in patients with MTLE (Level C) but is of unclear utility in other epilepsy types (Level U). fMRI of verbal memory or language encoding should be considered for predicting verbal memory outcome (Level B). fMRI using nonverbal memory encoding may be considered for predicting visuospatial memory outcomes (Level C). Presurgical fMRI could be an adequate alternative to IAP memory testing for predicting verbal memory outcome (Level C). Clinicians should carefully advise patients of the risks and benefits of fMRI vs IAP during discussions concerning choice of specific modality in each case. PMID- 28077495 TI - Left ventricular wall motion abnormalities are associated with stroke recurrence. AB - OBJECTIVE: To investigate the role of left ventricular wall motion abnormalities (LVWMA), unrelated to high-risk cardioembolic conditions, in stroke recurrence. METHODS: This study included consecutive acute ischemic stroke patients. Transthoracic echocardiography was performed as a routine evaluation for stroke patients. The outcomes were the time to recurrent any stroke and ischemic stroke. RESULTS: Among 4,316 acute ischemic stroke patients, 430 had LVWMA without high risk cardioembolic sources. The median observation periods of patients at risk of any stroke and ischemic stroke were 24.5 and 24.7 months. During the follow-up, any stroke and ischemic stroke recurrence were observed in 310 (7.2%) and 250 (5.8%) patients. LVWMA were associated with outcomes after adjustment for traditional cardiovascular risk factors, laboratory and imaging variables, and therapeutic interventions (hazard ratio [HR] 1.707, 95% confidence interval [CI] 1.262-2.310 for any stroke; HR 1.709, 95% CI 1.222-2.390 for ischemic stroke). Moreover, LVWMA could still be considered as independent risk factors after correction for covariates that were significantly associated with outcomes in univariable regression (HR 1.747, 95% CI 1.292-2.364 for any stroke; HR 1.704, 95% CI 1.219-2.382 for ischemic stroke). There were no significant interactions between LVWMA and outcomes between the subgroups except for the statin treatment subgroup. CONCLUSIONS: This study suggests that LVWMA, even when unassociated with high-risk cardioembolic sources, could be an independent predictor for stroke recurrence in patients with ischemic stroke. PMID- 28077496 TI - Left ventricular wall motion abnormalities: What can they tell us about stroke recurrence? PMID- 28077497 TI - Bone material strength index as measured by impact microindentation is altered in patients with acromegaly. AB - OBJECTIVE: Acromegaly is a rare disease caused by excess growth hormone (GH) production by the pituitary adenoma. The skeletal complications of GH and IGF-1 excess include increased bone turnover, increased cortical bone mass and deteriorated microarchitecture of trabecular bone, associated with a high risk of vertebral fractures in the presence of relatively normal bone mineral density (BMD). We aimed to evaluate tissue-level properties of bone using impact microindentation (IMI) in well-controlled patients with acromegaly aged >=18 years compared to 44 controls from the outpatient clinic of the Centre for Bone Quality. DESIGN AND METHODS: In this cross-sectional study, bone material strength index (BMSi) was measured in 48 acromegaly patients and 44 controls with impact microindentation using the osteoprobe. RESULTS: Mean age of acromegaly patients (54% male) was 60.2 years (range 37.9-76.5), and 60.5 years (range 39.8 78.6) in controls (50% male). Patients with acromegaly and control patients had comparable BMI (28.2 kg/m2 +/- 4.7 vs 26.6 kg/m2 +/- 4.3, P = 0.087) and comparable BMD at the lumbar spine (1.04 g/cm2 +/- 0.21 vs 1.03 g/cm2 +/- 0.13, P = 0.850) and at the femoral neck (0.84 g/cm2 +/- 0.16 vs 0.80 g/cm2 +/- 0.09, P = 0.246). BMSi was significantly lower in acromegaly patients than that in controls (79.4 +/- 0.7 vs 83.2 +/- 0.7; P < 0.001). CONCLUSION: Our data indicates that tissue-level properties of cortical bone are significantly altered in patients with controlled acromegaly after reversal of long-term exposure to pathologically high GH and IGF-1 levels. Our findings also suggest that methods other than DXA should be considered to evaluate bone fragility in patients with acromegaly. PMID- 28077499 TI - Dynamic GnRH and hCG testing: establishment of new diagnostic reference levels. AB - OBJECTIVE: Gonadotropin-releasing hormone (GnRH) and human chorionic gonadotropin (hCG) stimulation tests may be used to evaluate the pituitary and testicular capacity. Our aim was to evaluate changes in follicular-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone after GnRH and hCG stimulation in healthy men and assess the impact of six single nucleotide polymorphisms on the responses. DESIGN: GnRH and hCG stimulation tests were performed on 77 healthy men, 18-40 years (reference group) at a specialized andrology referral center at a university hospital. The potential influence of the tests was illustrated by results from 45 patients suspected of disordered hypothalamic pituitary-gonadal axis. METHODS: Baseline, stimulated, relative and absolute changes in serum FSH and LH were determined by ultrasensitive TRIFMA, and testosterone was determined by LC-MS/MS. RESULTS: For the reference group, LH and FSH increased almost 400% and 40% during GnRH testing, stimulated levels varied from 4.4 to 58.8 U/L and 0.2 to 11.8 U/L and FSH decreased in nine men. Testosterone increased approximately 110% (range: 18.7-67.6 nmol/L) during hCG testing. None of the polymorphisms had any major impact on the test results. Results from GnRH and hCG tests in patients compared with the reference group showed that the stimulated level and absolute increase in LH showed superior identification of patients compared with the relative increase, and the absolute change in testosterone was superior in identifying men with Leydig cell insufficiency, compared with the relative increase. CONCLUSIONS: We provide novel reference ranges for GnRH and hCG test in healthy men, which allows future diagnostic evaluation of hypothalamic-pituitary-gonadal disorders in men. PMID- 28077498 TI - Modulation of SHBG binding to testosterone and estradiol by sex and morbid obesity. AB - OBJECTIVE: Sex hormone-binding globulin (SHBG) binds and transports testosterone and estradiol in plasma. The possibility that SHBG is a mixture of transporting proteins has been postulated. We analyzed in parallel the effects of obesity status on the levels and binding capacity of circulating SHBG and their relationship with testosterone and estradiol. DESIGN: Anthropometric measures and plasma were obtained from apparently healthy young (i.e. 35 +/- 7 years) premenopausal women (n = 32) and men (n = 30), with normal weight and obesity (BMI >30 kg/m2). METHODS: SHBG protein (Western blot), as well as the plasma levels of testosterone, estradiol, cortisol and insulin (ELISA) were measured. Specific binding of estradiol and testosterone to plasma SHBG was analyzed using tritium-labeled hormones. RESULTS: Significant differences in SHBG were observed within the obesity status and gender, with discordant patterns of change in testosterone and estradiol. In men, testosterone occupied most of the binding sites. Estrogen binding was much lower in all subjects. Lower SHBG of morbidly obese (BMI >40 kg/m2) subjects affected testosterone but not estradiol. The ratio of binding sites to SHBG protein levels was constant for testosterone, but not for estradiol. The influence of gender was maximal in morbid obesity, with men showing the highest binding/SHBG ratios. CONCLUSIONS: The results reported here are compatible with SHBG being a mixture of at least two functionally different hormone-binding globulins, being affected by obesity and gender and showing different structure, affinities for testosterone and estradiol and also different immunoreactivity. PMID- 28077500 TI - Distinct inflammatory gene expression in extraocular muscle and fat from patients with Graves' orbitopathy. AB - OBJECTIVE: This study sought to compare patients with thyroid eye disease (TED) and normal controls with respect to the expression of the NR3C1, CHUK, IKBKB, FOS, NFKB and HSD11B1 genes in orbital fat (OF) and extraocular muscle (EOM). DESIGN AND METHODS: A prospective study design was used to evaluate 34 TED patients and 38 healthy controls. OF was harvested from 33 TED patients and 27 controls. EOM biopsies were obtained from 32 TED patients and 18 controls. Samples were examined by real-time PCR and evaluated using appropriate statistical analyses with a significance cut-off of P < 0.05. RESULTS: NR3C1 mRNA levels were higher in TED EOM (median 213 (96-376)) than those in control EOM (78 (34-138)) (P < 0.001), and NFKB expression was elevated in TED muscle (223 (31 520)) relative to that in control muscle (8 (6-31)) (P < 0.001). HSD11B1 expression was higher in TED EOM (0.78 (0.47-2.01)) than that in control EOM (0.22 (0.09-0.51)) (P < 0.001). Levels of CHUK, IKBKB, and FOS were higher in TED EOM (115 (20-223), 111 (54-299) and 0.11 (0.03-0.19), respectively) than those in control EOM (5.8 (2-13), 21 (5-52) and 0.05 (0.001-0.03) respectively) (P < 0.001). CONCLUSION: Tissues involved in GO exhibited different mRNA levels of NR3C1, CHUK, IKBKB, FOS, NFKB and HSD11B1. Gene expression in OF was similar for TED patients and controls. CHUK, IKBKB, FOS, NFKB, and HSD11B1 mRNA levels were higher in TED EOM than those in control EOM. NFKB was disproportionally elevated compared with NR3C1; this finding was indicative of a local proinflammatory profile. PMID- 28077501 TI - Guidelines for transposition surgery and why we need them. PMID- 28077502 TI - Cannulation of an arch artery for hostile aorta. PMID- 28077503 TI - European Association for Cardio-Thoracic Surgery expert consensus statement on the prevention and management of mediastinitis. AB - Mediastinitis continues to be an important and life-threatening complication after median sternotomy despite advances in prevention and treatment strategies, with an incidence of 0.25-5%. It can also occur as extension of infection from adjacent structures such as the oesophagus, airways and lungs, or as descending necrotizing infection from the head and neck. In addition, there is a chronic form of 'chronic fibrosing mediastinitis' usually caused by granulomatous infections. In this expert consensus, the evidence for strategies for treatment and prevention of mediatinitis is reviewed in detail aiming at reducing the incidence and optimizing the management of this serious condition. PMID- 28077504 TI - Influence of history of cannabis smoking in selected donors on the outcomes of lung transplantation. AB - OBJECTIVES: Cannabis is the most commonly abused illicit drug and the smokers are at the risk of lung infections, bullous emphysema and lung cancer. However, no evidence about the outcomes of lung transplantation (LTx) utilizing the lungs from such donors is available in the literature. METHODS: We retrospectively analysed lung 'organ offers' and LTx at our centre between January 2007 and November 2013. The outcomes of LTx utilizing lungs from donors with a history of cannabis smoking were compared with the outcomes of those with no such history using unadjusted model as well as propensity score matching. RESULTS: A total of 302 LTxs were performed during this period and were grouped depending on the history of cannabis smoking in donors-'cannabis' (n = 19) and control group (n = 283). All the donors in 'cannabis' group were tobacco smokers compared with 43% in the control group. Preoperative characteristics in recipients in both groups were comparable. Intraoperative and post-LTx variables including 1- and 3-year survivals were comparable in both groups. CONCLUSIONS: The history of donor cannabis smoking does not appear to affect early and mid-term outcomes after LTx and potentially improve the donor pool. As it does not seem to negatively affect the outcomes after LTx, it should not be per se considered a contraindication for lung donation. PMID- 28077505 TI - Spotlight on recently published ICVTS articles. PMID- 28077506 TI - Clinical guidelines for the management of patients with transposition of the great arteries with intact ventricular septum. PMID- 28077507 TI - Stroke and Mortality Risk in Patients With Various Patterns of Atrial Fibrillation: Results From the ENGAGE AF-TIMI 48 Trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48). AB - BACKGROUND: Whether the pattern of atrial fibrillation (AF) modifies the risk/benefit of anticoagulation is controversial. In ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation Thrombolysis in Myocardial Infarction 48), the factor Xa inhibitor edoxaban was noninferior to warfarin in preventing stroke or systemic embolic events and significantly reduced bleeding and cardiovascular mortality. However, detailed analyses by AF pattern have not been reported. METHODS AND RESULTS: The 21 105 patients were categorized as having paroxysmal (<7 days duration), persistent (>=7 days but <1 year), or permanent (>=1 year or failed cardioversion) AF patterns at randomization. Efficacy and safety outcomes were evaluated during the 2.8 years median follow-up and compared by AF pattern. The primary end point of stroke/systemic embolic event was lower in those patients with paroxysmal AF (1.49%/year), compared with persistent (1.83%/year; P-adj =0.015) and permanent AF (1.95%/year; P-adj =0.004). Overall, all-cause mortality also was lower with paroxysmal (3.0%/year) compared with persistent (4.4%/year; P-adj <0.001) and permanent AF (4.4%/year; P-adj <0.001). Annualized major bleeding rates were similar across AF patterns (2.86% versus 2.65% versus 2.73%). There was no effect modification by treatment assignment. CONCLUSIONS: In ENGAGE AF-TIMI 48 trial, patients with paroxysmal AF suffered fewer thromboembolic events and deaths compared with those with persistent and permanent AF. The efficacy and safety profile of edoxaban as compared with warfarin was consistent across the 3 patterns of AF. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391. PMID- 28077508 TI - Not All Types of Atrial Fibrillation Carry the Same Stroke Risk, but Most Benefit From Oral Anticoagulation. PMID- 28077509 TI - The "basic" approach: a single-centre experience with a cost-reducing model for paediatric cardiac extracorporeal membrane oxygenation. AB - Objectives: Extracorporeal membrane oxygenation (ECMO) is a lifesaving but expensive therapy in terms of financial, technical and human resources. We report our experience with a 'basic' ECMO support model, consisting of ECMO initiated and managed without the constant presence of a bedside specialist, to assess safety, clinical outcomes and financial impact on our health system. Methods: We did a retrospective single-centre study of paediatric cardiac ECMO between January 2001 and March 2014. Outcomes included postimplant complications and survival at weaning and at discharge. We used activity based costing to compare the costs of current basic ECMO with those of a 'full optional' dedicated ECMO team (hypothesis 1); ECMO with a bedside nurse and perfusionist (hypothesis 2), and ECMO with a bedside perfusionist (hypothesis 3). Results: Basic cardiac ECMO was required for 121 patients (median age 75 days, median weight 4.4 kg). A total of 107 patients (88%) had congenital heart disease; 37 had univentricular physiology. The median duration of ECMO was 7 days (interquartile range [IQR], 4 15 days). Overall survival at weaning and at 30 days in the neonatal and paediatric age groups was 58.6% and 30.6%, respectively; these results were not significantly different from Extracorporeal Life Support Organization data. Cost analysis revealed a saving of ?30 366, ?22 144 and ?13 837 for each patient on basic ECMO for hypotheses 1, 2 and 3, respectively. Conclusions: Despite reduced human, technical and economical resources, a basic ECMO model without a bedside specialist was associated with satisfactory survival and lower costs. PMID- 28077510 TI - Mitral implant of the Inovare transcatheter heart valve in failed surgical bioprostheses: a novel alternative for valve-in-valve procedures. AB - Objectives: Reoperative procedure for the treatment of a failed mitral bioprosthesis is associated with considerable risk. In some cases, mortality is high and might contraindicate the benefit of the procedure. The minimally invasive valve-in-valve (ViV) transcatheter mitral valve implant offers an alternative less-invasive approach, reducing morbidity and mortality. The objective of this paper was to evaluate the mitral ViV approach using the Braile Inovare prosthesis. Methods: The transcatheter balloon-expandable Braile Inovare prosthesis was used in 12 cases. Procedures were performed in a hybrid operating room, under fluoroscopic and echocardiographic control. Through left minithoracotomy, the prostheses were implanted through the cardiac apex. Serial echocardiographic and clinical examinations were performed. Follow-up varied from 1 to 30 months. Results: A total of 12 transapical mitral ViV procedures were performed. Patients had a mean age of 61.6 +/- 9.9 years and 92% were women. Mean logistic EuroSCORE was 20.1%. Successful valve implantation was possible in all cases. In one case, a right lateral thoracotomy was performed for the removal of an embolized prosthesis. There was no operative mortality. Thirty-day mortality was 8.3%. Ejection fraction was preserved after the implant (66.7%; 64.8%; P = 0.3). The mitral gradient showed a significant reduction (11 mmHg; 6 mmHg; P < 0.001). Residual mitral regurgitation was not present. There was no left ventricular outflow tract obstruction. Conclusions: The mitral ViV implant in a failed bioprosthesis is an effective procedure. This possibility might alter prosthesis selection in the future initial surgical prosthesis selection, favouring bioprostheses. Further large trials should explore its safety. PMID- 28077511 TI - Altered Connectivity and Synapse Maturation of the Hippocampal Mossy Fiber Pathway in a Mouse Model of the Fragile X Syndrome. AB - The Fragile X syndrome (FXS) as the most common monogenetic cause of cognitive impairment and autism indicates how tightly the dysregulation of synapse development is linked to cognitive deficits. Symptoms of FXS include excessive adherence to patterns that point to compromised hippocampal network formation. Surprisingly, one of the most complex hippocampal synapses connecting the dentate gyrus (DG) to CA3 pyramidal neurons has not been analyzed in FXS yet. Intriguingly, we found altered synaptic function between DG and CA3 in a mouse model of FXS (fmr1 knockout [KO]) demonstrated by increased mossy fiber-dependent miniature excitatory postsynaptic current (mEPSC) frequency at CA3 pyramidal neurons together with increased connectivity between granule cells and CA3 neurons. This phenotype is accompanied by increased activity of fmr1 KO animals in the marble burying task, detecting repetitive and obsessive compulsive behavior. Spine apparatus development and insertion of AMPA receptors is enhanced at postsynaptic thorny excrescences (TEs) in fmr1 KO mice. We report age dependent alterations in TE morphology and in the underlying actin dynamics possibly linked to a dysregulation in profilin1 expression. TEs form detonator synapses guiding CA3 network activity. Thus, alterations described here are likely to contribute substantially to the impairment in hippocampal function and therefore to the pathogenesis of FXS. PMID- 28077512 TI - Differential Contribution of Low- and High-level Image Content to Eye Movements in Monkeys and Humans. AB - Oculomotor selection exerts a fundamental impact on our experience of the environment. To better understand the underlying principles, researchers typically rely on behavioral data from humans, and electrophysiological recordings in macaque monkeys. This approach rests on the assumption that the same selection processes are at play in both species. To test this assumption, we compared the viewing behavior of 106 humans and 11 macaques in an unconstrained free-viewing task. Our data-driven clustering analyses revealed distinct human and macaque clusters, indicating species-specific selection strategies. Yet, cross-species predictions were found to be above chance, indicating some level of shared behavior. Analyses relying on computational models of visual saliency indicate that such cross-species commonalities in free viewing are largely due to similar low-level selection mechanisms, with only a small contribution by shared higher level selection mechanisms and with consistent viewing behavior of monkeys being a subset of the consistent viewing behavior of humans. PMID- 28077513 TI - Cognitive Control Structures in the Imitation Learning of Spatial Sequences and Rhythms-An fMRI Study. AB - Imitation learning involves the acquisition of novel motor patterns based on action observation (AO). We used event-related functional magnetic resonance imaging to study the imitation learning of spatial sequences and rhythms during AO, motor imagery (MI), and imitative execution in nonmusicians and musicians. While both tasks engaged the fronto-parietal mirror circuit, the spatial sequence task recruited posterior parietal and dorsal premotor regions more strongly. The rhythm task involved an additional network for auditory working memory. This partial dissociation supports the concept of task-specific mirror mechanisms. Two regions of cognitive control were identified: 1) dorsolateral prefrontal cortex (DLPFC) was found to be more strongly activated during MI of novel spatial sequences, which allowed us to extend the 2-level model of imitation learning by Buccino et al. (2004) to spatial sequences. 2) During imitative execution of both tasks, the posterior medial frontal cortex was robustly activated, along with the DLPFC, which suggests that both regions are involved in the cognitive control of imitation learning. The musicians' selective behavioral advantage for rhythm imitation was reflected cortically in enhanced sensory-motor processing during AO and by the absence of practice-related activation differences in DLPFC during rhythm execution. PMID- 28077515 TI - Medial Prefrontal Cortex-Pontine Nuclei Projections Modulate Suboptimal Cue Induced Associative Motor Learning. AB - Diverse and powerful mechanisms have evolved to enable organisms to modulate learning and memory under a variety of survival conditions. Cumulative evidence has shown that the prefrontal cortex (PFC) is closely involved in many higher order cognitive functions. However, when and how the medial PFC (mPFC) modulates associative motor learning remains largely unknown. Here, we show that delay eyeblink conditioning (DEC) with the weak conditioned stimulus (wCS) but not the strong CS (sCS) elicited a significant increase in the levels of c-Fos expression in caudal mPFC. Both optogenetic inhibition and activation of the bilateral caudal mPFC, or its axon terminals at the pontine nucleus (PN) contralateral to the training eye, significantly impaired the acquisition, recent and remote retrieval of DEC with the wCS but not the sCS. However, direct optogenetic activation of the contralateral PN had no significant effect on the acquisition, recent and remote retrieval of DEC. These results are of great importance in understanding the elusive role of the mPFC and its projection to PN in subserving the associative motor learning under suboptimal learning cue. PMID- 28077514 TI - Representational Similarity Mapping of Distributional Semantics in Left Inferior Frontal, Middle Temporal, and Motor Cortex. AB - Language comprehension engages a distributed network of frontotemporal, parietal, and sensorimotor regions, but it is still unclear how meaning of words and their semantic relationships are represented and processed within these regions and to which degrees lexico-semantic representations differ between regions and semantic types. We used fMRI and representational similarity analysis to relate word elicited multivoxel patterns to semantic similarity between action and object words. In left inferior frontal (BA 44-45-47), left posterior middle temporal and left precentral cortex, the similarity of brain response patterns reflected semantic similarity among action-related verbs, as well as across lexical classes between action verbs and tool-related nouns and, to a degree, between action verbs and food nouns, but not between action verbs and animal nouns. Instead, posterior inferior temporal cortex exhibited a reverse response pattern, which reflected the semantic similarity among object-related nouns, but not action related words. These results show that semantic similarity is encoded by a range of cortical areas, including multimodal association (e.g., anterior inferior frontal, posterior middle temporal) and modality-preferential (premotor) cortex and that the representational geometries in these regions are partly dependent on semantic type, with semantic similarity among action-related words crossing lexical-semantic category boundaries. PMID- 28077516 TI - Early-Onset Invasive Candidiasis in Extremely Low Birth Weight Infants: Perinatal Acquisition Predicts Poor Outcome. AB - Background: Neonatal invasive candidiasis (IC) presenting in the first week of life is less common and less well described than later-onset IC. Risk factors, clinical features, and disease outcomes have not been studied in early-onset disease (EOD, <=7 days) or compared to late-onset disease (LOD, >7 days). Methods: All extremely low birth weight (ELBW, <1000 g) cases with IC and controls from a multicenter study of neonatal candidiasis enrolled from 2001 to 2003 were included in this study. Factors associated with occurrence and outcome of EOD in ELBW infants were determined. Results: Forty-five ELBW infants and their 84 matched controls were included. Fourteen (31%) ELBW infants had EOD. Birth weight <750 g, gestation <25 weeks, chorioamnionitis, and vaginal delivery were all strongly associated with EOD. Infection with Candida albicans, disseminated disease, pneumonia, and cardiovascular disease were significantly more common in EOD than in LOD. The EOD case fatality rate (71%) was higher than in LOD (32%) or controls (15%) (P = .0001). The rate of neurodevelopmental impairment and mortality combined was similar in EOD (86%) and LOD (72%), but higher than in controls (32%; P = .007). Conclusions: ELBW infants with EOD have a very poor prognosis compared to those with LOD. The role of perinatal transmission in EOD is supported by its association with chorioamnionitis, vaginal delivery, and pneumonia. Dissemination and cardiovascular involvement are common, and affected infants often die. Empiric treatment should be considered for ELBW infants delivered vaginally who have pneumonia and whose mothers have chorioamnionitis or an intrauterine foreign body. PMID- 28077519 TI - HIV/AIDS in Iran. PMID- 28077517 TI - Two-Phase Hospital-Associated Outbreak of Mycobacterium abscessus: Investigation and Mitigation. AB - Background: Nontuberculous mycobacteria (NTM) commonly colonize municipal water supplies and cause healthcare-associated outbreaks. We investigated a biphasic outbreak of Mycobacterium abscessus at a tertiary care hospital. Methods: Case patients had recent hospital exposure and laboratory-confirmed colonization or infection with M. abscessus from January 2013 through December 2015. We conducted a multidisciplinary epidemiologic, field, and laboratory investigation. Results: The incidence rate of M. abscessus increased from 0.7 cases per 10000 patient days during the baseline period (January 2013-July 2013) to 3.0 cases per 10000 patient-days during phase 1 of the outbreak (August 2013-May 2014) (incidence rate ratio, 4.6 [95% confidence interval, 2.3-8.8]; P < .001). Thirty-six of 71 (51%) phase 1 cases were lung transplant patients with positive respiratory cultures. We eliminated tap water exposure to the aerodigestive tract among high risk patients, and the incidence rate decreased to baseline. Twelve of 24 (50%) phase 2 (December 2014-June 2015) cases occurred in cardiac surgery patients with invasive infections. Phase 2 resolved after we implemented an intensified disinfection protocol and used sterile water for heater-cooler units of cardiopulmonary bypass machines. Molecular fingerprinting of clinical isolates identified 2 clonal strains of M. abscessus; 1 clone was isolated from water sources at a new hospital addition. We made several water engineering interventions to improve water flow and increase disinfectant levels. Conclusions: We investigated and mitigated a 2-phase clonal outbreak of M. abscessus linked to hospital tap water. Healthcare facilities with endemic NTM should consider similar tap water avoidance and engineering strategies to decrease risk of NTM infection. PMID- 28077518 TI - T-Helper 17 Cell Cytokine Responses in Lyme Disease Correlate With Borrelia burgdorferi Antibodies During Early Infection and With Autoantibodies Late in the Illness in Patients With Antibiotic-Refractory Lyme Arthritis. AB - Background: Control of Lyme disease is attributed predominantly to innate and adaptive T-helper 1 cell (TH1) immune responses, whereas the role of T-helper 17 cell (TH17) responses is less clear. Here we characterized these inflammatory responses in patients with erythema migrans (EM) or Lyme arthritis (LA) to elucidate their role early and late in the infection. Methods: Levels of 21 cytokines and chemokines, representative of innate, TH1, and TH17 immune responses, were assessed by Luminex in acute and convalescent sera from 91 EM patients, in serum and synovial fluid from 141 LA patients, and in serum from 57 healthy subjects. Antibodies to Borrelia burgdorferi or autoantigens were measured by enzyme-linked immunosorbent assay. Results: Compared with healthy subjects, EM patients had significantly higher levels of innate, TH1, and TH17 associated mediators (P <= .05) in serum. In these patients, the levels of inflammatory mediators, particularly TH17-associated cytokines, correlated directly with B. burgdorferi immunoglobulin G antibodies (P <= .02), suggesting a beneficial role for these responses in control of early infection. Late in the disease, in patients with LA, innate and TH1-associated mediators were often >10 fold higher in synovial fluid than serum. In contrast, the levels of TH17 associated mediators were more variable, but correlated strongly with autoantibodies to endothelial cell growth factor, matrix metalloproteinase 10, and apolipoprotein B-100 in joints of patients with antibiotic-refractory LA, implying a shift in TH17 responses toward an autoimmune phenotype. Conclusions: Patients with Lyme disease often develop pronounced TH17 immune responses that may help control early infection. However, late in the disease, excessive TH17 responses may be disadvantageous by contributing to autoimmune responses associated with antibiotic-refractory LA. PMID- 28077520 TI - Hepatitis E Virus (HEV) Infection in Anti-HEV Immunoglobulin G-Carrying Patients After Successful Hepatitis C Virus Treatment: Reactivation or Reinfection? AB - Although hepatitis E virus (HEV) is regarded as a self-limiting infection and anti-HEV antibodies seem to protect against reinfection, its pathogenesis is not well established. We describe 2 cases of acute symptomatic HEV infection after hepatitis C therapy in patients carrying anti-HEV immunoglobulin G antibodies, raising 2 major questions: reactivation or reinfection? PMID- 28077521 TI - Reply to El-Mallawany et al. PMID- 28077522 TI - Increasing Numbers of New Kaposi Sarcoma Diagnoses in HIV-Infected Children and Adolescents Despite the Wide Availability of Antiretroviral Therapy in Malawi. PMID- 28077524 TI - When more is less efficacious: fibrinogen concentrate in complex cardiac surgery. PMID- 28077525 TI - Oxygen supplementation during prolonged tracheal intubation should be the standard of care. PMID- 28077523 TI - Autologous adipose-derived mesenchymal stem cells improve healing of coiled experimental saccular aneurysms: an angiographic and histopathological study. AB - PURPOSE: Long-term occlusion of coiled aneurysms frequently fails, probably because of poor intrasaccular healing and inadequate endothelialization across the aneurysm neck. The purpose of this study was to determine if attachment of autologous mesenchymal stem cells (MSCs) to platinum coils would improve the healing response in an elastase-induced aneurysm model in rabbits. MATERIALS AND METHODS: With approval from the institutional animal care and use committee, aneurysms were created in rabbits and embolized with control platinum coils (Axium; Medtronic) (n=6) or coils seeded ex vivo with autologous adipose-tissue MSCs (n=7). Aneurysmal occlusion after embolization was evaluated at 1 month with angiography. Histological samples were analyzed by gross imaging and graded on the basis of neck and dome healing on H&E staining. Fibrosis was evaluated using a ratio of the total area presenting collagen. Endothelialization of the neck was quantitatively analyzed using CD31 immunohistochemistry. chi2 and Student's t test were used to compare groups. RESULTS: Healing score (11.5 vs 8.0, p=0.019), fibrosis ratio (10.3 vs 0.13, p=0.006) and endothelialization (902 262 MUm2 vs 31 810 MUm2, p=0.041) were significantly greater in the MSC group. The MSC group showed marked cellular proliferation and thrombus organization, with a continuous membrane bridging the neck of the aneurysm. Angiographic stable or progressive occlusion rate was significantly lower in the MSC group (0.00, 95% CI 0.00 to 0.41) compared with controls (0.67, 95% CI 0.22 to 0.96) (p=0.02). CONCLUSIONS: Autologous MSCs attached to platinum coils significantly improve histological healing, as they result in improved neck endothelialization and collagen matrix formation within the aneurysm sac. PMID- 28077526 TI - Patient safety and the risk of i.v. fluid therapy in perioperative medicine: importance of host susceptibility and exposure dose. PMID- 28077527 TI - Cataract surgery in dementia patients-time to reconsider anaesthetic options. PMID- 28077528 TI - What makes a good systematic review and meta-analysis? PMID- 28077529 TI - Poor agreement in significant findings between meta-analyses and subsequent large randomized trials in perioperative medicine. AB - BACKGROUND: The reliability of meta-analysis (MA) in predicting the findings of subsequent large randomized controlled trials (RCTs) has not been assessed in perioperative medicine and anaesthesia. METHODS: Using Medline and PubMed, large RCTs (n>=1000) published since 2000 in the anaesthesia and perioperative medicine/critical care literature were identified. All previous MAs of RCTs investigating the same intervention and population were sourced. For all reported major morbid endpoints common to each, results (significant/non-significant P<0.05) were compared. RESULTS: 18 large RCTs and 44 prior MAs investigating the effects of 16 interventions were identified. Where endpoint results in the large RCTs were each compared with the single largest recent preceding MA, 35 of a total of 57 outcomes were predicted correctly by the MAs (61.4%). The odds ratio for a significant result from MA compared with the subsequent large RCT was 3.6, P=0.033 Bonferroni corrected. The positive predictive value of MAs was 22.7%; the negative predictive value was 85.7%, Kappa was 0.094 indicating slight agreement. The estimated power for each endpoint for large RCTs and MAs were similar, but the median study size for large RCTs was larger than that of the MAs, n=4,482 vs 1,389, P<0.0001. CONCLUSIONS: There was a strong tendency towards positive findings in MA not substantiated by subsequent large RCTs, which was not attributable to differences in study power. This finding suggests caution in clinical decision-making in anaesthesia and perioperative medicine based on findings of meta-analysis. PMID- 28077530 TI - Impact of balanced tetrastarch raw material on perioperative blood loss: a randomized double blind controlled trial. AB - BACKGROUND: As 6% hydroxyethyl starch (HES) 130/0.40 or 130/0.42 can originate from different vegetable sources, they might have different clinical effects. The purpose of this prospective, randomized, double-blind controlled trial was to compare two balanced tetrastarch solutions, one maize-derived and one potato derived, on perioperative blood loss in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). METHODS: We randomly assigned 118 patients undergoing elective cardiac surgery into two groups, to receive either a maize- or a potato-derived HES solution. Study fluids were administered perioperatively (including priming of CPB) until the second postoperative day (POD#2) using a goal directed algorithm. The primary outcome was calculated postoperative blood loss up to POD#2. Secondary outcomes included short-term incidence of acute kidney injury (AKI), and long-term effect (up to one yr) on renal function. RESULTS: Preoperative and intraoperative characteristics of the subjects were similar between groups. Similar volumes of HES were administered (1950 ml [1250 2325] for maize-HES and 2000 ml [1500-2700] for potato-HES; P=0.204). Calculated blood loss (504 ml [413-672] for maize-HES vs 530 ml [468-705] for potato-HES; P=0.107) and the need for blood components were not different between groups. The incidence of AKI was similar in both groups (P=0.111). Plasma creatinine concentration and glomerular filtration rates did vary over time, although changes were minimal. CONCLUSIONS: Under our study conditions, HES 130/0.4 or 130/0.42 raw material did not have a significant influence on perioperative blood loss. Moreover, we did not find any effect of tetrastarch raw material composition on short and long-term renal function. CLINICAL TRIAL REGISTRATION: EudraCT number: 2011-005920-16. PMID- 28077531 TI - Sodium bicarbonate does not prevent postoperative acute kidney injury after off pump coronary revascularization: a double-blinded randomized controlled trial. AB - BACKGROUND: Acute kidney injury (AKI) is a common morbidity after off-pump coronary revascularization. We investigated whether perioperative administration of sodium bicarbonate, which might reduce renal injury by alleviating oxidative stress in renal tubules, prevents postoperative AKI in off-pump coronary revascularization patients having renal risk factors. METHODS: Patients (n=162) having at least one of the following AKI risk factors were enrolled: (i) age >70 yr; (ii) diabetes mellitus; (iii) chronic renal disease; (iv) congestive heart failure or left ventricular ejection fraction <35%; and (v) reoperation or emergency. Patients were evenly randomized to receive either sodium bicarbonate (0.5 mmol kg-1 for 1 h upon induction of anaesthesia followed by 0.15 mmol kg-1 h 1 for 23 h) or 0.9% saline. Acute kidney injury within 48 h after surgery was assessed using the Acute Kidney Injury Network criteria. RESULTS: The incidences of AKI were 21 and 26% in the bicarbonate and control groups, respectively (P=0.458). Serially measured serum creatinine concentrations and perioperative fluid balance were also comparable between the groups. The length of postoperative hospitalization and incidence of morbidity end points were similar between the groups, whereas significantly more patients in the bicarbonate group required prolonged mechanical ventilation (>24 h) relative to the control group (20 vs 6, P=0.003). CONCLUSIONS: Perioperative sodium bicarbonate administration did not decrease the incidence of AKI after off-pump coronary revascularization in high-risk patients and might even be associated with a need for prolonged ventilatory care. CLINICAL TRIAL REGISTRATION: NCT01840241. PMID- 28077532 TI - Modern hydroxyethyl starch and acute kidney injury after cardiac surgery: a prospective multicentre cohort. AB - BACKGROUND: Recent trials have shown hydroxyethyl starch (HES) solutions increase the risk of acute kidney injury (AKI) in critically ill patients. It is uncertain whether these adverse effects also affect surgical patients. We sought to determine the renal safety of modern tetrastarch (6% HES 130/0.4) use in cardiac surgical patients. METHODS: In this multicentre prospective cohort study, 1058 consecutive patients who underwent cardiac surgery from 15th September 2012 to 15th December 2012 were recruited in 23 Spanish hospitals. RESULTS: We identified 350 patients (33%) administered 6% HES 130/0.4 intraoperatively and postoperatively, and 377 (36%) experienced postoperative AKI (AKI Network criteria). In-hospital death occurred in 45 (4.2%) patients. Patients in the non HES group had higher Euroscore and more comorbidities including unstable angina, preoperative cardiogenic shock, preoperative intra-aortic balloon pump use, peripheral arterial disease, and pulmonary hypertension. The non-HES group received more intraoperative vasopressors and had longer cardiopulmonary bypass times. After multivariable risk-adjustment, 6% HES 130/0.4 use was not associated with significantly increased risks of AKI (adjusted odds ratio 1.01, 95% CI 0.71 1.46, P=0.91). These results were confirmed by propensity score-matched pairs analyses. CONCLUSIONS: The intraoperative and postoperative use of modern hydroxyethyl starch 6% HES 130/0.4 was not associated with increased risks of AKI and dialysis after cardiac surgery in our multicentre cohort. PMID- 28077533 TI - Cefalotin as antimicrobial prophylaxis in patients with known intraoperative anaphylaxis to cefazolin. AB - BACKGROUND: The most common trigger for intraoperative anaphylaxis in Western Australia for the period 2014-5 was an antibiotic used for surgical prophylaxis, cefazolin. In these patients who subsequently present for surgery, alternative cephalosporins are forbidden by current guidelines because of concerns regarding an increased risk of anaphylaxis. However, consideration of the structure activity relationships relevant to anaphylaxis suggests that cefalotin is a safe alternative because of structural dissimilarities, although there are no pubished clinical data relevant to the perioperative setting. METHODS: Patients diagnosed with intraoperative anaphylaxis to cefazolin at the Western Australian Anaesthetic Allergy Clinic were tested with intradermal cefalotin and, if negative, subsequently challenged i.v. If tolerated, cefalotin was recommended for subsequent surgery, and subjects were followed up to determine the safety of subsequent intraoperative doses. RESULTS: Twenty-one subjects diagnosed with immediate hypersensitivity to cephazolin, including 19 subjects with confirmed anaphylaxis, participated. None tested positive to intradermal cefalotin, and all received a graded i.v. challenge to cefalotin without developing signs or symptoms of anaphylaxis. Three subjects subsequently received intraoperative cefalotin 12-139 days later without adverse events. CONCLUSIONS: A negative intradermal cefalotin skin test has a good negative predictive value in patients who have previously suffered anaphylaxis to cefazolin, allowing the rational and desirable use of this alternative cephalosporin for future surgery and the avoidance of less desirable antimicrobial agents. PMID- 28077534 TI - Reduced mortality by meeting guideline criteria before using recombinant activated factor VII in severe trauma patients with massive bleeding. AB - BACKGROUND: Management of trauma patients with severe bleeding has led to criteria before considering use of recombinant activated factor VII (rFVIIa), including haemoglobin >8 g dl-1, serum fibrinogen >=1.0 g l-1, platelets >50,000 x 109 l-1, arterial pH >= 7.20, and body temperature >=34 degrees C. We hypothesized that meeting these criteria is associated with improved outcomes. METHODS: In this prospective cohort study of 26 French trauma centres, subjects were included if they received rFVIIa for persistent massive bleeding despite appropriate care after severe blunt and/or penetrating trauma. RESULTS: After surgery and/or embolization as haemostatic interventions, 112 subjects received a first dose of 103 MUg kg-1 rFVIIa (82-200) (median, 25th-75th percentile) at 420 min (285-647) post-trauma. Of these, 71 (63%) "responders" were still alive at 24h post-trauma and had their transfusion requirements reduced by > 2 packed red blood cell units after rFVIIa treatment. Mortality was 54% on day 30 post-trauma. There were 21%, 44% and 35% subjects who fulfilled 0-1, 2-3 or 4-5, respectively, of the guidelines before receiving rFVIIa. Survival at day 30 was 13%, 49% and 64% and the proportion of responders was 39%, 64% and 82%, when subjects fulfilled 0-1, 2-3 or 4-5 conditions, respectively (both P <0.01). CONCLUSIONS: In actively bleeding trauma patients, meeting guideline criteria before considering rFVIIa was associated with lower mortality and a higher proportion of responders to the rFVIIa. PMID- 28077535 TI - The impact of a perceptual and adaptive learning module on transoesophageal echocardiography interpretation by anaesthesiology residents. AB - BACKGROUND: The role of transoesophageal echocardiography (TOE) in anaesthetic practice is expanding. We evaluated the effect of a TOE perceptual and adaptive learning module (PALM) on first-yr anaesthesiology residents' performance, in diagnosing cardiac pathology by TOE. METHODS: First-yr residents were assigned to a group (n = 12) that used a TOE PALM or a control group that did not (n = 12). Both groups received a TOE pretest that measured their accuracy and response times. The PALM group completed the PALM and a posttest within 30 min and a delayed test six months later. The control group received a delayed test six months after their pretest. Accuracy and fluency (accurate responses within 10 s) were measured. RESULTS: The PALM group had statistically significant improvements for both accuracy and fluency (P < 0.0001) in diagnosing cardiac pathology by TOE. After six months, the PALM group's performance remained significantly higher than their pretest values for accuracy (P = 0.0002, d = 2.7) and fluency (P < 0.0001, d = 2.3). CONCLUSIONS: In this pilot study, exposure to a PALM significantly improved accuracy and fluency in diagnosing TOE cardiac pathology, in a group of first-year anaesthesiology residents. PALMs can significantly improve learning and pattern recognition in medical education. PMID- 28077536 TI - Cerebral oxygen saturation and cardiac output during anaesthesia in sitting position for neurosurgical procedures: a prospective observational study. AB - BACKGROUND: Neurosurgical operations in the dorsal cranium often require the patient to be positioned in a sitting position. This can be associated with decreased cardiac output and cerebral hypoperfusion, and possibly, inadequate cerebral oxygenation. In the present study, cerebral oxygen saturation was measured during neurosurgery in the sitting position and correlated with cardiac output. METHODS: Perioperative cerebral oxygen saturation was measured continuously with two different monitors, INVOS(r) and FORE-SIGHT(r). Cardiac output was measured at eight predefined time points using transoesophageal echocardiography. RESULTS: Forty patients were enrolled, but only 35 (20 female) were eventually operated on in the sitting position. At the first time point, the regional cerebral oxygen saturation measured with INVOS(r) was 70 (sd 9)%; thereafter, it increased by 0.0187% min-1 (P<0.01). The cerebral tissue oxygen saturation measured with FORE-SIGHT(r) started at 68 (sd 13)% and increased by 0.0142% min-1 (P<0.01). The mean arterial blood pressure did not change. Cardiac output was between 6.3 (sd 1.3) and 7.2 (1.8) litre min-1 at the predefined time points. Cardiac output, but not mean arterial blood pressure, showed a positive and significant correlation with cerebral oxygen saturation. CONCLUSIONS: During neurosurgery in the sitting position, the cerebral oxygen saturation slowly increases and, therefore, this position seems to be safe with regard to cerebral oxygen saturation. Cerebral oxygen saturation is stable because of constant CO and MAP, while the influence of CO on cerebral oxygen saturation seems to be more relevant. CLINICAL TRIAL REGISTRATION: NCT01275898. PMID- 28077537 TI - Chronic postsurgical pain in children: prevalence and risk factors. A prospective observational study. AB - BACKGROUND: Chronic postsurgical pain (CPSP) is well known in adults, with prevalence rates ranging from 10 to 50%. Little is known about the epidemiology of CPSP in children. The aim of this prospective observational study was to evaluate the prevalence of CPSP after surgery in children. METHODS: After informed consent, children aged six to18 yr were included. Characteristics and risk factors for CPSP were recorded. Exclusion criteria included ambulatory surgery, refusal, inability to understand and change of address. All eligible children completed a preoperative questionnaire the day before surgery about pain, anxiety and their medical history. All data concerning anaesthetic and surgical procedures, such as acute pain scores (VAS) during the first 24 h were recorded. Three months after surgery all included children were sent a postoperative questionnaire about pain at the surgical site. RESULTS: Altogether, 291 children were enrolled; the mean age was 12 yr, most subjects were male (60%). The most common type of surgery was orthopaedic (63%). In the 258 patients who completed the study, the prevalence of CPSP was 10.9%, most often with a neuropathic origin (64.3%). The two main risk factors were the existence of recent pain before surgery (<1 month) and the severity of acute postoperative pain (VAS >30 mm) in the first 24 h after orthopaedic and thoracic surgeries. Six months after surgery, only five children needed a visit with a chronic pain practitioner. CONCLUSIONS: These results highlight the necessity of evaluating and treating perioperative pain in order to prevent CPSP in children. PMID- 28077538 TI - Magnesium sulphate attenuates acute postoperative pain and increased pain intensity after surgical injury in staged bilateral total knee arthroplasty: a randomized, double-blinded, placebo-controlled trial. AB - BACKGROUND: We evaluated the effect of magnesium sulphate on increased pain in 44 patients undergoing staged bilateral total knee arthroplasty (TKA). METHODS: The magnesium group (n=22) and the control group (n=22) received magnesium sulphate and isotonic saline, respectively, throughout the surgery. Postoperative pain (visual analogue scale, VAS) at rest and the amounts of patient-controlled analgesia (PCA, fentanyl) and rescue analgesia (ketoprofen) administered during the first 48 h were compared between the two groups and within each group between the first and second TKA. RESULTS: The VAS scores were significantly higher in the control group than in the magnesium group not only after the first TKA [29 (11) vs 19 (9) at 24 h and 33 (8) vs 24 (10) at 48 h; P=0.001] but also after the second TKA [44 (17) vs 20 (10) at 24 h and 43 (14) vs 25 (10) at 48 h; P<0.001]. In the control group, VAS scores were significantly higher for the second than for the first operated knee [44 (17) vs 29 (11) at 24 h and 43 (14) vs 33 (8) at 48 h; P<0.001 and P=0.006, respectively]. In the magnesium group, there were no significant differences in VAS scores between the first and second TKA. Magnesium significantly reduced the amounts of rescue analgesics and fentanyl administered over the first 48 h postoperatively. CONCLUSIONS: Magnesium sulphate administration significantly reduced postoperative pain and minimized the difference in pain intensity between the first and second operations. CLINICAL TRIAL REGISTRATION: KCT0001361. PMID- 28077539 TI - Preoperative butorphanol and flurbiprofen axetil therapy attenuates remifentanil induced hyperalgesia after laparoscopic gynaecological surgery: a randomized double-blind controlled trial. AB - BACKGROUND: Several studies indicate that remifentanil exposure may engender opioid-induced hyperalgesia. Butorphanol and flurbiprofen axetil are proposed as adjunctive analgesics for postoperative pain control. This randomized double blind controlled study was designed to investigate the antihyperalgesic effects of butorphanol combined with flurbiprofen axetil on opioid-induced hyperalgesia. METHODS: One hundred and twenty patients undergoing elective laparoscopic gynaecological surgery with sevoflurane anaesthesia were randomized to one of four groups, as follows: intraoperative sufentanil 0.30 ug kg-1 (Group S); remifentanil 0.30 ug kg-1 min-1 (Group R); intraoperative remifentanil and pre anaesthesia butorphanol 20 ug kg-1 (Group B); or intraoperative remifentanil and pre-anaesthesia butorphanol 10 ug kg-1 combined with flurbiprofen axetil 0.5 mg kg-1 (Group BF). Sufentanil was used to control postoperative pain. The threshold and area of postoperative mechanical hyperalgesia were measured with Von Frey filaments. Pain intensity, sufentanil consumption, and side-effects were recorded for 24 h after surgery. RESULTS: Compared with Group S, remifentanil anaesthesia increased the pain score, postoperative sufentanil consumption, and area of hyperalgesia [mean 49.9 (sd 8.6) vs 60.5 (10.0) cm2, P<0.001] and reduced the hyperalgesia threshold on the dominant inner forearm [mean 89.5 (sd 23.4) vs 60.6 (22.6) g, P=0.004]. Compared with Group R, the pain score, sufentanil consumption, and area of hyperalgesia were reduced and hyperalgesia threshold was elevated likewise in Groups B and BF. However, the efficacy in Group BF was higher than in Group B (P=0.021). CONCLUSIONS: The preoperative combination of butorphanol and flurbiprofen axetil effectively ameliorated opioid-induced hyperalgesia in patients undergoing laparoscopic gynaecological surgery under sevoflurane-remifentanil anaesthesia. CLINICAL TRIAL REGISTRATION: NCT02043366. PMID- 28077540 TI - Leukemia inhibitory factor (LIF) potentiates antinociception activity and inhibits tolerance induction of opioids. AB - BACKGROUND: The efficacy of opioids typically decreases after long-term use owing to the development of tolerance. Glial activation and the upregulation of proinflammatory cytokines are related to the induction of tolerance. We investigated the effect of leukemia inhibitory factor (LIF) on morphine analgesia and tolerance. METHODS: LIF concentrations in rat spinal cords were measured by polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) after morphine administration. LIF distribution was examined using confocal microscopy. To evaluate the effects of LIF on morphine analgesia and tolerance, LIF was intrathecally administered 30 min before morphine injection. The analgesic effect of morphine was evaluated by measuring tail-flick latency. Human LIF concentrations from the cerebrospinal fluid (CSF) of opioid tolerant patients were also determined by specific ELISA. RESULTS: Chronic morphine administration upregulated LIF concentrations in rat spinal cords. Intrathecal injection of LIF potentiated the analgesic action of morphine. Patch clamp recording of spinal cord slices showed that LIF enhanced DAMGO ([D-Ala2, N-MePhe4, Gly-ol] enkephalin)-induced outward potassium current. The development of tolerance was markedly suppressed by exogenous LIF, whereas neutralizing the endogenously released LIF with anti-LIF antibodies accelerated the tolerance induction. Moreover, LIF concentrations in the CSF of opioid-tolerant patients were higher than those in the opioid-naive controls. CONCLUSIONS: Intrathecal administration of LIF potentiated morphine antinociceptive activity and attenuated the development of morphine tolerance. Upregulation of endogenously released LIF by long-term use of opioids might counterbalance the tolerance induction effects of other proinflammatory cytokines. LIF might be a novel drug candidate for inhibiting opioid tolerance induction. PMID- 28077542 TI - Difficult airway society 2015 guidelines for management of unanticipated difficult intubation in adults: Need to be revisited? PMID- 28077541 TI - The role of bicarbonate precursors in balanced fluids during haemorrhagic shock with and without compromised liver function. AB - BACKGROUND: Lactate, acetate, and gluconate are anions used in balanced resuscitation fluids, of which lactate and acetate are considered bicarbonate precursors. This study investigated the role of the liver in the ability of balanced and unbalanced solutions to correct acid-base alterations and renal haemodynamics and microvascular oxygenation in a rat model of resuscitated haemorrhagic shock. METHODS: Ringer's lactate, Ringer's acetate, PlasmaLyte, or normal saline were administered following haemorrhagic shock in the presence or absence of a 70% partial liver resection. Renal haemodynamics and microvascular oxygenation (by oxygen-dependent quenching of phosphorescence) were measured as well as concentrations of lactate, gluconate, and acetate in plasma and urine. Kidney wet and dry weight was also assessed. RESULTS: Partial liver resection resulted in increased liver enzymes compared with control and shock groups (P < 0.01). Haemorrhagic shock decreased systemic and renal perfusion and reduced microvascular kidney oxygenation with lactic acidosis (P < 0.01). Resuscitation with balanced fluids did not fully restore renal oxygenation (P < 0.01). Ringer's acetate and PlasmaLyte increased bicarbonate content and restored pH better than Ringer's lactate or saline after partial liver resection (P < 0.01). Liver resection caused an increase in plasma gluconate after PlasmaLyte resuscitation (P < 0.05). CONCLUSIONS: Acetate-buffered balanced fluids show superior buffering effects compared with Ringer's lactate or saline. Gluconate is partially metabolized by the liver, although it does not contribute to acid-base control because of its excretion in urine. Acetate is metabolized regardless of liver function and may be the most efficient bicarbonate precursor. Lactate infusion tends to overwhelm the metabolism capacity of the residual liver. PMID- 28077543 TI - Reply. PMID- 28077544 TI - DAS guidelines: the end for pre-paralysis mask ventilation check? PMID- 28077546 TI - Atracurium - check, ventilation - check. PMID- 28077545 TI - Reply. PMID- 28077547 TI - DAS 2015 guidelines for management of CICO. PMID- 28077548 TI - Plan D: cannula first, or scalpel only? PMID- 28077549 TI - Reply. PMID- 28077550 TI - Dilutional effect of nasal oxygenation. PMID- 28077551 TI - Reply. PMID- 28077552 TI - Evidence no longer supports use of cricoid pressure. PMID- 28077554 TI - Cricoid pressure - already in decline? PMID- 28077553 TI - Reply. PMID- 28077555 TI - 'Bougie-assisted' cricothyroidotomy technique. PMID- 28077556 TI - Reply. PMID- 28077559 TI - In the October BJA.... PMID- 28077557 TI - Selective primary outcome reporting in high-impact journals of anaesthesia and pain. PMID- 28077560 TI - Mechanistic insights into type I toxin antitoxin systems in Helicobacter pylori: the importance of mRNA folding in controlling toxin expression. AB - Type I toxin-antitoxin (TA) systems have been identified in a wide range of bacterial genomes. Here, we report the characterization of a new type I TA system present on the chromosome of the major human gastric pathogen, Helicobacter pylori. We show that the aapA1 gene encodes a 30 amino acid peptide whose artificial expression in H. pylori induces cell death. The synthesis of this toxin is prevented by the transcription of an antitoxin RNA, named IsoA1, expressed on the opposite strand of the toxin gene. We further reveal additional layers of post-transcriptional regulation that control toxin expression: (i) transcription of the aapA1 gene generates a full-length transcript whose folding impedes translation (ii) a 3? end processing of this message generates a shorter transcript that, after a structural rearrangement, becomes translatable (iii) but this rearrangement also leads to the formation of two stem-loop structures allowing formation of an extended duplex with IsoA1 via kissing-loop interactions. This interaction ensures both the translation inhibition of the AapA1 active message and its rapid degradation by RNase III, thus preventing toxin synthesis under normal growth conditions. Finally, a search for homologous mRNA structures identifies similar TA systems in a large number of Helicobacter and Campylobacter genomes. PMID- 28077561 TI - microRNAs stimulate translation initiation mediated by HCV-like IRESes. AB - MicroRNAs (miRNAs) are small non-coding RNAs that control gene expression by recognizing and hybridizing to a specific sequence generally located in the 3? untranslated region (UTR) of targeted mRNAs. miRNA-induced inhibition of translation occurs during the initiation step, most probably at the level of ribosome scanning. In this process, the RNA-induced silencing complex interacts both with PABP and the 43S pre-initiation complex to disrupt scanning of the 40S ribosome. However, in some specific cases, miRNAs can stimulate translation. Although the mechanism of miRNA-mediated upregulation is unknown, it appears that the poly(A) tail and the lack of availability of the TNRC6 proteins are amongst major determinants. The genomic RNA of the Hepatitis C Virus is uncapped, non polyadenylated and harbors a peculiar internal ribosome entry site (IRES) that binds the ribosome directly to the AUG codon. Thus, we have exploited the unique properties of the HCV IRES and other related IRESes (HCV-like) to study how translation initiation can be modulated by miRNAs on these elements. Here, we report that miRNA binding to the 3? UTR can stimulate translation of a reporter gene given that its expression is driven by an HCV-like IRES and that it lacks a poly(A) tail at its 3? extremity. PMID- 28077562 TI - Sensitive and inexpensive digital DNA analysis by microfluidic enrichment of rolling circle amplified single-molecules. AB - Single molecule quantification assays provide the ultimate sensitivity and precision for molecular analysis. However, most digital analysis techniques, i.e. droplet PCR, require sophisticated and expensive instrumentation for molecule compartmentalization, amplification and analysis. Rolling circle amplification (RCA) provides a simpler means for digital analysis. Nevertheless, the sensitivity of RCA assays has until now been limited by inefficient detection methods. We have developed a simple microfluidic strategy for enrichment of RCA products into a single field of view of a low magnification fluorescent sensor, enabling ultra-sensitive digital quantification of nucleic acids over a dynamic range from 1.2 aM to 190 fM. We prove the broad applicability of our analysis platform by demonstrating 5-plex detection of as little as ~1 pg (~300 genome copies) of pathogenic DNA with simultaneous antibiotic resistance marker detection, and the analysis of rare oncogene mutations. Our method is simpler, more cost-effective and faster than other digital analysis techniques and provides the means to implement digital analysis in any laboratory equipped with a standard fluorescent microscope. PMID- 28077563 TI - The BioC-BioGRID corpus: full text articles annotated for curation of protein protein and genetic interactions. AB - A great deal of information on the molecular genetics and biochemistry of model organisms has been reported in the scientific literature. However, this data is typically described in free text form and is not readily amenable to computational analyses. To this end, the BioGRID database systematically curates the biomedical literature for genetic and protein interaction data. This data is provided in a standardized computationally tractable format and includes structured annotation of experimental evidence. BioGRID curation necessarily involves substantial human effort by expert curators who must read each publication to extract the relevant information. Computational text-mining methods offer the potential to augment and accelerate manual curation. To facilitate the development of practical text-mining strategies, a new challenge was organized in BioCreative V for the BioC task, the collaborative Biocurator Assistant Task. This was a non-competitive, cooperative task in which the participants worked together to build BioC-compatible modules into an integrated pipeline to assist BioGRID curators. As an integral part of this task, a test collection of full text articles was developed that contained both biological entity annotations (gene/protein and organism/species) and molecular interaction annotations (protein-protein and genetic interactions (PPIs and GIs)). This collection, which we call the BioC-BioGRID corpus, was annotated by four BioGRID curators over three rounds of annotation and contains 120 full text articles curated in a dataset representing two major model organisms, namely budding yeast and human. The BioC-BioGRID corpus contains annotations for 6409 mentions of genes and their Entrez Gene IDs, 186 mentions of organism names and their NCBI Taxonomy IDs, 1867 mentions of PPIs and 701 annotations of PPI experimental evidence statements, 856 mentions of GIs and 399 annotations of GI evidence statements. The purpose, characteristics and possible future uses of the BioC BioGRID corpus are detailed in this report.Database URL: http://bioc.sourceforge.net/BioC-BioGRID.html. PMID- 28077564 TI - blend4php: a PHP API for galaxy. AB - Galaxy is a popular framework for execution of complex analytical pipelines typically for large data sets, and is a commonly used for (but not limited to) genomic, genetic and related biological analysis. It provides a web front-end and integrates with high performance computing resources. Here we report the development of the blend4php library that wraps Galaxy's RESTful API into a PHP based library. PHP-based web applications can use blend4php to automate execution, monitoring and management of a remote Galaxy server, including its users, workflows, jobs and more. The blend4php library was specifically developed for the integration of Galaxy with Tripal, the open-source toolkit for the creation of online genomic and genetic web sites. However, it was designed as an independent library for use by any application, and is freely available under version 3 of the GNU Lesser General Public License (LPGL v3.0) at https://github.com/galaxyproject/blend4phpDatabase URL: https://github.com/galaxyproject/blend4php. PMID- 28077565 TI - MAHMI database: a comprehensive MetaHit-based resource for the study of the mechanism of action of the human microbiota. AB - The Mechanism of Action of the Human Microbiome (MAHMI) database is a unique resource that provides comprehensive information about the sequence of potential immunomodulatory and antiproliferative peptides encrypted in the proteins produced by the human gut microbiota. Currently, MAHMI database contains over 300 hundred million peptide entries, with detailed information about peptide sequence, sources and potential bioactivity. The reference peptide data section is curated manually by domain experts. The in silico peptide data section is populated automatically through the systematic processing of publicly available exoproteomes of the human microbiome. Bioactivity prediction is based on the global alignment of the automatically processed peptides with experimentally validated immunomodulatory and antiproliferative peptides, in the reference section. MAHMI provides researchers with a comparative tool for inspecting the potential immunomodulatory or antiproliferative bioactivity of new amino acidic sequences and identifying promising peptides to be further investigated. Moreover, researchers are welcome to submit new experimental evidence on peptide bioactivity, namely, empiric and structural data, as a proactive, expert means to keep the database updated and improve the implemented bioactivity prediction method. Bioactive peptides identified by MAHMI have a huge biotechnological potential, including the manipulation of aberrant immune responses and the design of new functional ingredients/foods based on the genetic sequences of the human microbiome. Hopefully, the resources provided by MAHMI will be useful to those researching gastrointestinal disorders of autoimmune and inflammatory nature, such as Inflammatory Bowel Diseases. MAHMI database is routinely updated and is available free of charge. Database URL: http://mahmi.org/. PMID- 28077566 TI - Duplicates, redundancies and inconsistencies in the primary nucleotide databases: a descriptive study. AB - GenBank, the EMBL European Nucleotide Archive and the DNA DataBank of Japan, known collectively as the International Nucleotide Sequence Database Collaboration or INSDC, are the three most significant nucleotide sequence databases. Their records are derived from laboratory work undertaken by different individuals, by different teams, with a range of technologies and assumptions and over a period of decades. As a consequence, they contain a great many duplicates, redundancies and inconsistencies, but neither the prevalence nor the characteristics of various types of duplicates have been rigorously assessed. Existing duplicate detection methods in bioinformatics only address specific duplicate types, with inconsistent assumptions; and the impact of duplicates in bioinformatics databases has not been carefully assessed, making it difficult to judge the value of such methods. Our goal is to assess the scale, kinds and impact of duplicates in bioinformatics databases, through a retrospective analysis of merged groups in INSDC databases. Our outcomes are threefold: (1) We analyse a benchmark dataset consisting of duplicates manually identified in INSDC a dataset of 67 888 merged groups with 111 823 duplicate pairs across 21 organisms from INSDC databases - in terms of the prevalence, types and impacts of duplicates. (2) We categorize duplicates at both sequence and annotation level, with supporting quantitative statistics, showing that different organisms have different prevalence of distinct kinds of duplicate. (3) We show that the presence of duplicates has practical impact via a simple case study on duplicates, in terms of GC content and melting temperature. We demonstrate that duplicates not only introduce redundancy, but can lead to inconsistent results for certain tasks. Our findings lead to a better understanding of the problem of duplication in biological databases.Database URL: the merged records are available at https://cloudstor.aarnet.edu.au/plus/index.php/s/Xef2fvsebBEAv9w. PMID- 28077568 TI - Automatic query generation using word embeddings for retrieving passages describing experimental methods. AB - Information regarding the physical interactions among proteins is crucial, since protein-protein interactions (PPIs) are central for many biological processes. The experimental techniques used to verify PPIs are vital for characterizing and assessing the reliability of the identified PPIs. A lot of information about PPIs and the experimental methods are only available in the text of the scientific publications that report them. In this study, we approach the problem of identifying passages with experimental methods for physical interactions between proteins as an information retrieval search task. The baseline system is based on query matching, where the queries are generated by utilizing the names (including synonyms) of the experimental methods in the Proteomics Standard Initiative Molecular Interactions (PSI-MI) ontology. We propose two methods, where the baseline queries are expanded by including additional relevant terms. The first method is a supervised approach, where the most salient terms for each experimental method are obtained by using the term frequency-relevance frequency (tf.rf) metric over 13 articles from our manually annotated data set of 30 full text articles, which is made publicly available. On the other hand, the second method is an unsupervised approach, where the queries for each experimental method are expanded by using the word embeddings of the names of the experimental methods in the PSI-MI ontology. The word embeddings are obtained by utilizing a large unlabeled full text corpus. The proposed methods are evaluated on the test set consisting of 17 articles. Both methods obtain higher recall scores compared with the baseline, with a loss in precision. Besides higher recall, the word embeddings based approach achieves higher F-measure than the baseline and the tf.rf based methods. We also show that incorporating gene name and interaction keyword identification leads to improved precision and F-measure scores for all three evaluated methods. The tf.rf based approach was developed as part of our participation in the Collaborative Biocurator Assistant Task of the BioCreative V challenge assessment, whereas the word embeddings based approach is a novel contribution of this article.Database URL: https://github.com/ferhtaydn/biocemid/. PMID- 28077567 TI - FARME DB: a functional antibiotic resistance element database. AB - Antibiotic resistance (AR) is a major global public health threat but few resources exist that catalog AR genes outside of a clinical context. Current AR sequence databases are assembled almost exclusively from genomic sequences derived from clinical bacterial isolates and thus do not include many microbial sequences derived from environmental samples that confer resistance in functional metagenomic studies. These environmental metagenomic sequences often show little or no similarity to AR sequences from clinical isolates using standard classification criteria. In addition, existing AR databases provide no information about flanking sequences containing regulatory or mobile genetic elements. To help address this issue, we created an annotated database of DNA and protein sequences derived exclusively from environmental metagenomic sequences showing AR in laboratory experiments. Our Functional Antibiotic Resistant Metagenomic Element (FARME) database is a compilation of publically available DNA sequences and predicted protein sequences conferring AR as well as regulatory elements, mobile genetic elements and predicted proteins flanking antibiotic resistant genes. FARME is the first database to focus on functional metagenomic AR gene elements and provides a resource to better understand AR in the 99% of bacteria which cannot be cultured and the relationship between environmental AR sequences and antibiotic resistant genes derived from cultured isolates.Database URL: http://staff.washington.edu/jwallace/farme. PMID- 28077570 TI - KTCNlncDB-a first platform to investigate lncRNAs expressed in human keratoconus and non-keratoconus corneas. AB - Keratoconus (KTCN, OMIM 148300) is a degenerative eye disorder characterized by progressive stromal thinning that leads to a conical shape of the cornea, resulting in optical aberrations and even loss of visual function. The biochemical background of the disease is poorly understood, which motivated us to perform RNA-Seq experiment, aimed at better characterizing the KTCN transcriptome and identification of long non-coding RNAs (lncRNAs) that might be involved in KTCN etiology. The in silico functional studies based on predicted lncRNA:RNA base-pairings led us to recognition of a number of lncRNAs possibly regulating genes with known or plausible links to KTCN. The lncRNA sequences and data regarding their predicted functions in controlling the RNA processing and stability are available for browse, search and download in KTCNlncDB (http://rhesus.amu.edu.pl/KTCNlncDB/), the first online platform devoted to KTCN transcriptome.Database URL: http://rhesus.amu.edu.pl/KTCNlncDB/. PMID- 28077569 TI - RAIN: RNA-protein Association and Interaction Networks. AB - Protein association networks can be inferred from a range of resources including experimental data, literature mining and computational predictions. These types of evidence are emerging for non-coding RNAs (ncRNAs) as well. However, integration of ncRNAs into protein association networks is challenging due to data heterogeneity. Here, we present a database of ncRNA-RNA and ncRNA-protein interactions and its integration with the STRING database of protein-protein interactions. These ncRNA associations cover four organisms and have been established from curated examples, experimental data, interaction predictions and automatic literature mining. RAIN uses an integrative scoring scheme to assign a confidence score to each interaction. We demonstrate that RAIN outperforms the underlying microRNA-target predictions in inferring ncRNA interactions. RAIN can be operated through an easily accessible web interface and all interaction data can be downloaded.Database URL: http://rth.dk/resources/rain. PMID- 28077572 TI - Impact of a High-fat Diet on Tissue Acyl-CoA and Histone Acetylation Levels. AB - Cellular metabolism dynamically regulates the epigenome via availability of the metabolite substrates of chromatin-modifying enzymes. The impact of diet on the metabolism-epigenome axis is poorly understood but could alter gene expression and influence metabolic health. ATP citrate-lyase produces acetyl-CoA in the nucleus and cytosol and regulates histone acetylation levels in many cell types. Consumption of a high-fat diet (HFD) results in suppression of ATP citrate-lyase levels in tissues such as adipose and liver, but the impact of diet on acetyl-CoA and histone acetylation in these tissues remains unknown. Here we examined the effects of HFD on levels of acyl-CoAs and histone acetylation in mouse white adipose tissue (WAT), liver, and pancreas. We report that mice consuming a HFD have reduced levels of acetyl-CoA and/or acetyl-CoA:CoA ratio in these tissues. In WAT and the pancreas, HFD also impacted the levels of histone acetylation; in particular, histone H3 lysine 23 acetylation was lower in HFD-fed mice. Genetic deletion of Acly in cultured adipocytes also suppressed acetyl-CoA and histone acetylation levels. In the liver, no significant effects on histone acetylation were observed with a HFD despite lower acetyl-CoA levels. Intriguingly, acetylation of several histone lysines correlated with the acetyl-CoA: (iso)butyryl-CoA ratio in liver. Butyryl-CoA and isobutyryl-CoA interacted with the acetyltransferase P300/CBP-associated factor (PCAF) in liver lysates and inhibited its activity in vitro This study thus provides evidence that diet can impact tissue acyl-CoA and histone acetylation levels and that acetyl-CoA abundance correlates with acetylation of specific histone lysines in WAT but not in the liver. PMID- 28077573 TI - A Cdc48 "Retrochaperone" Function Is Required for the Solubility of Retrotranslocated, Integral Membrane Endoplasmic Reticulum-associated Degradation (ERAD-M) Substrates. AB - A surprising feature of endoplasmic reticulum (ER)-associated degradation (ERAD) is the movement, or retrotranslocation, of ubiquitinated substrates from the ER lumen or membrane to the cytosol where they are degraded by the 26S proteasome. Multispanning ER membrane proteins, called ERAD-M substrates, are retrotranslocated to the cytosol as full-length intermediates during ERAD, and we have investigated how they maintain substrate solubility. Using an in vivo assay, we show that retrotranslocated ERAD-M substrates are moved to the cytoplasm as part of the normal ERAD pathway, where they are part of a solely proteinaceous complex. Using proteomics and direct biochemical confirmation, we found that Cdc48 serves as a critical "retrochaperone" for these ERAD-M substrates. Cdc48 binding to retrotranslocated, ubiquitinated ERAD-M substrates is required for their solubility; removal of the polyubiquitin chains or competition for binding by addition of free polyubiquitin liberated Cdc48 from retrotranslocated proteins and rendered them insoluble. All components of the canonical Cdc48 complex Cdc48 Npl4-Ufd1 were present in solubilized ERAD-M substrates. This function of the complex was observed for both HRD and DOA pathway substrates. Thus, in addition to the long known ATP-dependent extraction of ERAD substrates during retrotranslocation, the Cdc48 complex is generally and critically needed for the solubility of retrotranslocated ERAD-M intermediates. PMID- 28077574 TI - Platelet-activating Factor Mediates Endotoxin Tolerance by Regulating Indoleamine 2,3-Dioxygenase-dependent Expression of the Suppressor of Cytokine Signaling 3. AB - Indoleamine 2,3-dioxygenase (IDO) mediates immune tolerance, and suppressor of cytokine signaling 3 (SOCS3) negatively regulates the JAK/STAT signal transduction pathway. We determined previously that platelet-activating factor (PAF) protects mice against LPS-induced endotoxic shock, but its detailed mechanism of action was unknown. We performed survival experiments in IDO+/+ and IDO-/- mice using an LPS-induced endotoxemia model and rated organ injury (neutrophil infiltration and liver function). Using ELISA and Western blotting, we also investigated the mechanism of PAF-mediated endotoxin tolerance during endotoxemia. PAF-mediated endotoxin tolerance was dependent on IDO in vivo and in vitro and was not observed in IDO-/- mice. JAK/STAT signaling, crucial for SOCS3 expression, was also impaired in the absence of IDO. In an IDO- and STAT dependent manner, PAF mediated a decrease in IL-12 and a dramatic increase in IL 10 and reduced mouse mortality. In addition, PAF attenuated LPS-mediated neutrophil infiltration into the lungs and interactions between neutrophil-like (THP-1) and endothelial cells (human umbilical vein endothelial cells). These results indicate that PAF-mediated endotoxin tolerance is initiated via IDO- and JAK/STAT-dependent expression of SOCS3. Our study has revealed a novel tolerogenic mechanism of IDO action and an important association between IDO and SOCS3 with respect to endotoxin tolerance. PMID- 28077575 TI - Effector-attenuating Substitutions That Maintain Antibody Stability and Reduce Toxicity in Mice. AB - The antibody Fc region regulates antibody cytotoxic activities and serum half life. In a therapeutic context, however, the cytotoxic effector function of an antibody is often not desirable and can create safety liabilities by activating native host immune defenses against cells expressing the receptor antigens. Several amino acid changes in the Fc region have been reported to silence or reduce the effector function of antibodies. These earlier studies focused primarily on the interaction of human antibodies with human Fc-gamma receptors, and it remains largely unknown how such changes to Fc might translate to the context of a murine antibody. We demonstrate that the commonly used N297G (NG) and D265A, N297G (DANG) variants that are efficacious in attenuating effector function in primates retain potent complement activation capacity in mice, leading to safety liabilities in murine studies. In contrast, we found an L234A, L235A, P329G (LALA-PG) variant that eliminates complement binding and fixation as well as Fc-gamma-dependent, antibody-dependent, cell-mediated cytotoxity in both murine IgG2a and human IgG1. These LALA-PG substitutions allow a more accurate translation of results generated with an "effectorless" antibody between mice and primates. Further, we show that both human and murine antibodies containing the LALA-PG variant have typical pharmacokinetics in rodents and retain thermostability, enabling efficient knobs-into-holes bispecific antibody production and a robust path to generating highly effector-attenuated bispecific antibodies for preclinical studies. PMID- 28077576 TI - Specific Inhibition of Acyl-CoA Oxidase-1 by an Acetylenic Acid Improves Hepatic Lipid and Reactive Oxygen Species (ROS) Metabolism in Rats Fed a High Fat Diet. AB - A chronic high fat diet results in hepatic mitochondrial dysfunction and induction of peroxisomal fatty acid oxidation (FAO); whether specific inhibition of peroxisomal FAO benefits mitochondrial FAO and reactive oxygen species (ROS) metabolism remains unclear. In this study a specific inhibitor for the rate limiting enzyme involved in peroxisomal FAO, acyl-CoA oxidase-1 (ACOX1) was developed and used for the investigation of peroxisomal FAO inhibition upon mitochondrial FAO and ROS metabolism. Specific inhibition of ACOX1 by 10,12 tricosadiynoic acid increased hepatic mitochondrial FAO via activation of the SIRT1-AMPK (adenosine 5'-monophosphate-activated protein kinase) pathway and proliferator activator receptor alpha and reduced hydrogen peroxide accumulation in high fat diet-fed rats, which significantly decreased hepatic lipid and ROS contents, reduced body weight gain, and decreased serum triglyceride and insulin levels. Inhibition of ACOX1 is a novel and effective approach for the treatment of high fat diet- or obesity-induced metabolic diseases by improving mitochondrial lipid and ROS metabolism. PMID- 28077577 TI - Extracellular MicroRNA Signature of Human Helper T Cell Subsets in Health and Autoimmunity. AB - Upon T cell receptor stimulation, CD4+ T helper (Th) lymphocytes release extracellular vesicles (EVs) containing microRNAs. However, no data are available on whether human CD4+ T cell subsets release EVs containing different pattern of microRNAs. The present work aimed at filling this gap by assessing the microRNA content in EVs released upon in vitro T cell receptor stimulation of Th1, Th17, and T regulatory (Treg) cells. Our results indicate that EVs released by Treg cells are significantly different compared with those released by the other subsets. In particular, miR-146a-5p, miR-150-5p, and miR-21-5p are enriched, whereas miR-106a-5p, miR-155-5p, and miR-19a-3p are depleted in Treg-derived EVs. The in vitro identified EV-associated microRNA signature was increased in serum of autoimmune patients with psoriasis and returned to healthy levels upon effective treatment with etanercept, a biological drug targeting the TNF pathway and suppressing inflammation. Moreover, Gene Set Enrichment Analysis showed an over-representation of genes relevant for T cell activation, such as CD40L, IRAK1, IRAK2, STAT1, and c-Myb in the list of validated targets of Treg-derived EV miRNAs. At functional level, Treg-derived (but not Th1/Th17-derived) EVs inhibited CD4+ T cell proliferation and suppressed two relevant targets of miR 146a-5p: STAT1 and IRAK2. In conclusion, our work identified the miRNAs specifically released by different human CD4+ T cell subsets and started to unveil the potential use of their quantity in human serum to mark the pathological elicitation of these cells in vivo and their biological effect in cell to cell communication during the adaptive immune response. PMID- 28077578 TI - Novel Serine 176 Phosphorylation of YBX1 Activates NF-kappaB in Colon Cancer. AB - Y box protein 1 (YBX1) is a well known oncoprotein that has tumor-promoting functions. YBX1 is widely considered to be an attractive therapeutic target in cancer. To develop novel therapeutics to target YBX1, it is of great importance to understand how YBX1 is finely regulated in cancer. Previously, we have shown that YBX1 could function as a tumor promoter through phosphorylation of its Ser 165 residue, leading to the activation of the NF-kappaB signaling pathway (1). In this study, using mass spectrometry analysis, we discovered a distinct phosphorylation site, Ser-176, on YBX1. Overexpression of the YBX1-S176A (serine to-alanine) mutant in either HEK293 cells or colon cancer HT29 cells showed dramatically reduced NF-kappaB-activating ability compared with that of WT-YBX1, confirming that Ser-176 phosphorylation is critical for the activation of NF kappaB by YBX1. Importantly, the mutant of Ser-176 and the previously reported Ser-165 sites regulate distinct groups of NF-kappaB target genes, suggesting the unique and irreplaceable function of each of these two phosphorylated serine residues. Our important findings could provide a novel cancer therapy strategy by blocking either Ser-176 or Ser-165 phosphorylation or both of YBX1 in colon cancer. PMID- 28077579 TI - Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival. AB - Pancreatic beta cell failure is the central event leading to diabetes. Beta cells share many phenotypic traits with neurons, and proper beta cell function relies on the activation of several neuron-like transcription programs. Regulation of gene expression by alternative splicing plays a pivotal role in brain, where it affects neuronal development, function, and disease. The role of alternative splicing in beta cells remains unclear, but recent data indicate that splicing alterations modulated by both inflammation and susceptibility genes for diabetes contribute to beta cell dysfunction and death. Here we used RNA sequencing to compare the expression of splicing-regulatory RNA-binding proteins in human islets, brain, and other human tissues, and we identified a cluster of splicing regulators that are expressed in both beta cells and brain. Four of them, namely Elavl4, Nova2, Rbox1, and Rbfox2, were selected for subsequent functional studies in insulin-producing rat INS-1E, human EndoC-betaH1 cells, and in primary rat beta cells. Silencing of Elavl4 and Nova2 increased beta cell apoptosis, whereas silencing of Rbfox1 and Rbfox2 increased insulin content and secretion. Interestingly, Rbfox1 silencing modulates the splicing of the actin-remodeling protein gelsolin, increasing gelsolin expression and leading to faster glucose induced actin depolymerization and increased insulin release. Taken together, these findings indicate that beta cells share common splicing regulators and programs with neurons. These splicing regulators play key roles in insulin release and beta cell survival, and their dysfunction may contribute to the loss of functional beta cell mass in diabetes. PMID- 28077582 TI - Severity of Plasma Leakage Is Associated With High Levels of Interferon gamma Inducible Protein 10, Hepatocyte Growth Factor, Matrix Metalloproteinase 2 (MMP 2), and MMP-9 During Dengue Virus Infection. AB - BACKGROUND: Dengue virus infection typically causes mild dengue fever, but, in severe cases, life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) occur. The pathophysiological hallmark of DHF and DSS is plasma leakage that leads to enhanced vascular permeability, likely due to a cytokine storm. METHODS: Ninety patients with dengue during 2010-2012 in Singapore were prospectively recruited and stratified according to their disease phase, primary and secondary infection status, and disease severity, measured by plasma leakage. Clinical parameters were recorded throughout the disease progression. The levels of various immune mediators were quantified using comprehensive multiplex microbead-based immunoassays for 46 immune mediators. RESULTS: Associations between clinical parameters and immune mediators were analyzed using various statistical methods. Potential immune markers, including interleukin 1 receptor antagonist, interferon gamma-inducible protein 10, hepatocyte growth factor, soluble p75 tumor necrosis factor alpha receptor, vascular cell adhesion molecule 1, and matrix metalloproteinase 2, were significantly associated with significant plasma leakage. Secondary dengue virus infections were also shown to influence disease outcome in terms of disease severity. CONCLUSIONS: This study identified several key markers for exacerbated dengue pathogenesis, notably plasma leakage. This will allow a better understanding of the molecular mechanisms of DHF and DSS in patients with dengue. PMID- 28077581 TI - Redeploying beta-Lactams Against Staphylococcus aureus: Repurposing With a Purpose. PMID- 28077580 TI - Peptide from Sea Anemone Metridium senile Affects Transient Receptor Potential Ankyrin-repeat 1 (TRPA1) Function and Produces Analgesic Effect. AB - The transient receptor potential ankyrin-repeat 1 (TRPA1) is an important player in pain and inflammatory pathways. It is a promising target for novel drug development for the treatment of a number of pathological states. A novel peptide producing a significant potentiating effect on allyl isothiocyanate- and diclofenac-induced currents of TRPA1 was isolated from the venom of sea anemone Metridium senile. It is a 35-amino acid peptide cross-linked by two disulfide bridges named tau-AnmTX Ms 9a-1 (short name Ms 9a-1) according to a structure similar to other sea anemone peptides belonging to structural group 9a. The structures of the two genes encoding the different precursor proteins of Ms 9a-1 were determined. Peptide Ms 9a-1 acted as a positive modulator of TRPA1 in vitro but did not cause pain or thermal hyperalgesia when injected into the hind paw of mice. Intravenous injection of Ms 9a-1 (0.3 mg/kg) produced a significant decrease in the nociceptive and inflammatory response to allyl isothiocyanate (the agonist of TRPA1) and reversed CFA (Complete Freund's Adjuvant)-induced inflammation and thermal hyperalgesia. Taken together these data support the hypothesis that Ms 9a-1 potentiates the response of TRPA1 to endogenous agonists followed by persistent functional loss of TRPA1-expressing neurons. We can conclude that TRPA1 potentiating may be useful as a therapeutic approach as Ms 9a 1 produces significant analgesic and anti-inflammatory effects in mice models of pain. PMID- 28077583 TI - A Live Attenuated Chimeric West Nile Virus Vaccine, rWN/DEN4Delta30, Is Well Tolerated and Immunogenic in Flavivirus-Naive Older Adult Volunteers. AB - West Nile virus (WNV) is a major cause of mosquito-borne illness in the United States. Human disease ranges from mild febrile illness to severe fatal neurologic infection. Adults aged >60 years are more susceptible to neuroinvasive disease accompanied by a high mortality rate or long-lasting neurologic sequelae. A chimeric live attenuated West Nile virus vaccine, rWN/DEN4Delta30, was shown to be safe and immunogenic in healthy adults aged 18-50 years. This study evaluated rWN/DEN4Delta30 in flavivirus-naive adults aged 50-65 years and found it to be safe and immunogenic. Outbreaks of WNV infection tend to be unpredictable, and a safe and effective vaccine will be an important public health tool. PMID- 28077584 TI - 2-Year Efficacy, Immunogenicity, and Safety of Vigoo Enterovirus 71 Vaccine in Healthy Chinese Children: A Randomized Open-Label Study. AB - BACKGROUND: This study evaluated the 2-year efficacy, immunogenicity, and safety of the Vigoo enterovirus 71 (EV71) vaccine. METHOD: In an initial phase 3 study, we randomly assigned healthy infants and children aged 6-35 months (ratio, 1:1) to receive 2 doses of either EV71 vaccine (5120 participants) or placebo (5125 participants) at days 0 and 28, and followed them for 12 months after vaccination. In this extended follow-up study, we continued to evaluate the efficacy, immunogenicity, and safety of the EV71 vaccine for up to 2 years. RESULTS: Overall efficacy was 94.84% (95% confidence interval [CI], 83.53% 98.38%) during the 2-year follow-up period (P < .0001), and the vaccine efficacy during the second year was 100.00% (95% CI, 84.15%-100.00%) against EV71 associated hand-foot-and-mouth disease (HFMD; P < .0001). Geometric mean titers of neutralizing antibody in participants remained high during the 2-year follow up period, and no vaccine-related serious adverse events were recorded. CONCLUSIONS: Two doses of Vigoo EV71 vaccine could provide sustained protection against EV71-associated HFMD in healthy Chinese children. CLINICAL TRIALS REGISTRATION: NCT01508247. PMID- 28077585 TI - Humanized Mice Reproduce Acute and Persistent Human Adenovirus Infection. AB - Severe human adenovirus (HAdV) infections are an increasing threat for immunosuppressed individuals, particularly those who have received stem cell transplants. It has been previously hypothesized that severe infections might be due to reactivation of a persistent infection, but this hypothesis has been difficult to test owing to the lack of a permissive in vivo model of HAdV infection. Here we established a humanized mouse model that reproduces features of acute and persistent HAdV infection. In this model, acute infection correlated with high mortality, weight loss, liver pathology, and expression of viral proteins in several organs. In contrast, persistent infection was asymptomatic and led to establishment of HAdV-specific adaptive immunity and expression of early viral genes exclusively in the bone marrow. These findings validate the use of humanized mice to study acute and persistent HAdV infection and strongly suggest the presence of cellular reservoirs in the bone marrow. PMID- 28077586 TI - Redeploying beta-Lactam Antibiotics as a Novel Antivirulence Strategy for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections. AB - Innovative approaches to the use of existing antibiotics is an important strategy in efforts to address the escalating antimicrobial resistance crisis. We report a new approach to the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections by demonstrating that oxacillin can be used to significantly attenuate the virulence of MRSA despite the pathogen being resistant to this drug. Using mechanistic in vitro assays and in vivo models of invasive pneumonia and sepsis, we show that oxacillin-treated MRSA strains are significantly attenuated in virulence. This effect is based primarily on the oxacillin dependent repression of the accessory gene regulator quorum-sensing system and altered cell wall architecture, which in turn lead to increased susceptibility to host killing of MRSA. Our data indicate that beta-lactam antibiotics should be included in the treatment regimen as an adjunct antivirulence therapy for patients with MRSA infections. This would represent an important change to current clinical practice for treatment of MRSA infection, with the potential to significantly improve patient outcomes in a safe, cost-effective manner. PMID- 28077587 TI - Malaria Parasitemia and Parasite Density in Antiretroviral-Treated HIV-Infected Adults Following Discontinuation of Cotrimoxazole Prophylaxis. AB - BACKGROUND: Cotrimoxazole (CTX) discontinuation increases malaria incidence in human immunodeficiency virus (HIV)-infected individuals. Rates, quantity, and timing of parasitemia rebound following CTX remain undefined. METHODS: Serial specimens from a trial of HIV-infected individuals receiving antiretroviral treatment (ART) randomized to continue (the CTX arm) or discontinue (the STOP-CTX arm) were examined for malaria parasites by quantitative reverse transcription polymerase chain reaction (PCR). Specimens obtained at enrollment and then quarterly for 12 months and at sick visits were assessed; multiplicity of infection was evaluated by PCR that targeted the polymorphic msp-1/msp-2 alleles. RESULTS: Among 500 HIV-infected adults receiving ART (median ART duration, 4.5 years), 5% had detectable parasitemia at baseline. After randomization, parasite prevalence increased over time in the STOP-CTX arm, compared with the CTX arm, with values of 4% and <1%, respectively, at month 3, 8% and 2% at month 6, 14% and 2% at month 9, and 22% and 4% at month 12 (P = .0034). The combined mean parasite density at the various time points was higher in the STOP-CTX arm (4.42 vs 3.13 log10 parasites/mL; P < .001). The parasitemia incidence was 42.0 cases per 100 person-years in the STOP-CTX arm and 9.9 cases per 100 person-years in the CTX arm, with an incidence rate ratio of 4.3 (95% confidence interval, 2.7 7.1; P < .001). After enrollment, mixed infections (multiplicity of infection, >1) were only present in the STOP-CTX arm. CONCLUSION: Discontinuation of CTX by HIV-infected adults receiving ART resulted in progressive increases in malaria parasitemia prevalence and burden. CLINICAL TRIALS REGISTRATION: NCT01425073. PMID- 28077589 TI - Trimethoprim-Sulfamethoxazole Prophylaxis During Live Malaria Sporozoite Immunization Induces Long-Lived, Homologous, and Heterologous Protective Immunity Against Sporozoite Challenge. AB - Trimethoprim-sulfamethoxazole (TMP-SMX) is widely used in malaria-endemic areas in human immunodeficiency virus (HIV)-infected children and HIV-uninfected, HIV exposed children as opportunistic infection prophylaxis. Despite the known effects that TMP-SMX has in reducing clinical malaria, its impact on development of malaria-specific immunity in these children remains poorly understood. Using rodent malaria models, we previously showed that TMP-SMX, at prophylactic doses, can arrest liver stage development of malaria parasites and speculated that TMP SMX prophylaxis during repeated malaria exposures would induce protective long lived sterile immunity targeting pre-erythrocytic stage parasites in mice. Using the same models, we now demonstrate that repeated exposures to malaria parasites during TMP-SMX administration induces stage-specific and long-lived pre erythrocytic protective anti-malarial immunity, mediated primarily by CD8+ T cells. Given the HIV infection and malaria coepidemic in sub-Saharan Africa, clinical studies aimed at determining the optimum duration of TMP-SMX prophylaxis in HIV-infected or HIV-exposed children must account for the potential anti infection immunity effect of TMP-SMX prophylaxis. PMID- 28077590 TI - Molecular Epidemiology of Ascaris Infection Among Pigs in Iowa. AB - Ascaris is a large roundworm parasite that infects humans and pigs throughout the world. Molecular markers have been used to study parasite transmission in Ascaris endemic and -nonendemic regions of the world. In the United States, ascariasis still persists in commercial swine and has been designated a neglected disease of poverty in humans. However, relatively few data are available for evaluation of zoonotic transmission. In the present study, we obtained adult worms from abattoirs and characterized each worm on the basis of the gene encoding nuclear internal transcribed sequence (ITS) and mitochondrial cox1 Restriction fragment length polymorphism analysis of ITS revealed swine, human, and hybrid genotypes. cox1 sequences were compared to all complete sequences available in GenBank, and haplotype analysis demonstrated 92 haplotypes worldwide. Sequences from the parasites in this study represented 10 haplotypes, including 6 new haplotypes that have not been previously described. Our results indicate that anthropozoonotic transmission has occurred in the past, resulting in the presence of human genotypes in pigs and supporting further investigation of zoonotic Ascaris transmission in the United States. PMID- 28077588 TI - First-in-Human Evaluation of the Safety and Immunogenicity of an Intranasally Administered Replication-Competent Sendai Virus-Vectored HIV Type 1 Gag Vaccine: Induction of Potent T-Cell or Antibody Responses in Prime-Boost Regimens. AB - BACKGROUND: We report the first-in-human safety and immunogenicity assessment of a prototype intranasally administered, replication-competent Sendai virus (SeV) vectored, human immunodeficiency virus type 1 (HIV-1) vaccine. METHODS: Sixty five HIV-1-uninfected adults in Kenya, Rwanda, and the United Kingdom were assigned to receive 1 of 4 prime-boost regimens (administered at 0 and 4 months, respectively; ratio of vaccine to placebo recipients, 12:4): priming with a lower dose SeV-Gag given intranasally, followed by boosting with an adenovirus 35 vectored vaccine encoding HIV-1 Gag, reverse transcriptase, integrase, and Nef (Ad35-GRIN) given intramuscularly (SLA); priming with a higher-dose SeV-Gag given intranasally, followed by boosting with Ad35-GRIN given intramuscularly (SHA); priming with Ad35-GRIN given intramuscularly, followed by boosting with a higher dose SeV-Gag given intranasally (ASH); and priming and boosting with a higher dose SeV-Gag given intranasally (SHSH). RESULTS: All vaccine regimens were well tolerated. Gag-specific IFN-gamma enzyme-linked immunospot-determined response rates and geometric mean responses were higher (96% and 248 spot-forming units, respectively) in groups primed with SeV-Gag and boosted with Ad35-GRIN (SLA and SHA) than those after a single dose of Ad35-GRIN (56% and 54 spot-forming units, respectively) or SeV-Gag (55% and 59 spot-forming units, respectively); responses persisted for >=8 months after completion of the prime-boost regimen. Functional CD8+ T-cell responses with greater breadth, magnitude, and frequency in a viral inhibition assay were also seen in the SLA and SHA groups after Ad35-GRIN boost, compared with those who received either vaccine alone. SeV-Gag did not boost T cell counts in the ASH group. In contrast, the highest Gag-specific antibody titers were seen in the ASH group. Mucosal antibody responses were sporadic. CONCLUSIONS: SeV-Gag primed functional, durable HIV-specific T-cell responses and boosted antibody responses. The prime-boost sequence appears to determine which arm of the immune response is stimulated. CLINICAL TRIALS REGISTRATION: NCT01705990. PMID- 28077591 TI - Critical Microbiological View of SER-109. PMID- 28077592 TI - Reply to Lagier et al. PMID- 28077593 TI - Wu et al (J Infect Dis 2016; 214[suppl 3]:S326-32). PMID- 28077594 TI - The N-linking glycosylation system from Actinobacillus pleuropneumoniae is required for adhesion and has potential use in glycoengineering. AB - Actinobacillus pleuropneumoniae is a mucosal respiratory pathogen causing contagious porcine pleuropneumonia. Pathogenesis studies have demonstrated a major role for the capsule, exotoxins and outer membrane proteins. Actinobacillus pleuropneumoniae can also glycosylate proteins, using a cytoplasmic N-linked glycosylating enzyme designated NGT, but its transcriptional arrangement and role in virulence remains unknown. We investigated the NGT locus and demonstrated that the putative transcriptional unit consists of rimO, ngt and a glycosyltransferase termed agt. From this information we used the A. pleuropneumoniae glycosylation locus to decorate an acceptor protein, within Escherichia coli, with a hexose polymer that reacted with an anti-dextran antibody. Mass spectrometry analysis of a truncated protein revealed that this operon could add up to 29 repeat units to the appropriate sequon. We demonstrated the importance of NGT in virulence, by creating deletion mutants and testing them in a novel respiratory cell line adhesion model. This study demonstrates the importance of the NGT glycosylation system for pathogenesis and its potential biotechnological application for glycoengineering. PMID- 28077596 TI - The neuroendocrine immunomodulatory axis-like pathway mediated by circulating haemocytes in pacific oyster Crassostrea gigas. AB - The neuroendocrine-immune (NEI) regulatory network is a complex system, which plays an indispensable role in the immunity of host. In this study, a neuroendocrine immunomodulatory axis (NIA)-like pathway mediated by the nervous system and haemocytes was characterized in the oyster Crassostrea gigas Once invaded pathogen was recognized by the host, the nervous system would temporally release neurotransmitters to modulate the immune response. Instead of acting passively, oyster haemocytes were able to mediate neuronal immunomodulation promptly by controlling the expression of specific neurotransmitter receptors on cell surface and modulating their binding sensitivities, thus regulating intracellular concentration of Ca2+ This neural immunomodulation mediated by the nervous system and haemocytes could influence cellular immunity in oyster by affecting mRNA expression level of TNF genes, and humoral immunity by affecting the activities of key immune-related enzymes. In summary, though simple in structure, the 'nervous-haemocyte' NIA-like pathway regulates both cellular and humoral immunity in oyster, meaning a world to the effective immune regulation of the NEI network. PMID- 28077595 TI - Long non-coding RNA LINC00152 promotes gallbladder cancer metastasis and epithelial-mesenchymal transition by regulating HIF-1alpha via miR-138. AB - Long non-coding RNA LINC00152 had been reported as an oncogene in gastric and hepatocellular cancer. In this study, we show that LINC00152 is overexpressed in gallbladder cancer (GBC) tissue samples and cell lines. The high LINC00152 levels correlated negatively with the overall survival time in GBC patients. Functionally, LINC00152 dramatically promoted cell migration, invasion and epithelial-mesenchymal transition (EMT) progression in vitro. In vivo, LINC00152 overexpression significantly promoted tumour peritoneal spreading and metastasis. Mechanistic analyses indicated that LINC00152 functions as a molecular sponge for miR-138, which directly suppresses the expression of hypoxia inducible factor 1alpha (HIF-1alpha). We revealed that miR-138 is a suppressor of GBC cell metastasis and EMT progression, and a similar phenomenon was observed in HIF 1alpha knockdown NOZ cells. Through binding to miR-138, LINC00152 has an oncogenic effect on GBC. Overall, our study suggested that the LINC00152/miR 138/HIF-1alpha pathway potentiates the progression of GBC, and LINC00152 may be a novel therapeutic target. PMID- 28077597 TI - Muscle developmental defects in heterogeneous nuclear Ribonucleoprotein A1 knockout mice. AB - Heterogeneous ribonucleoprotein A1 (hnRNP A1) is crucial for regulating alternative splicing. Its integrated function within an organism has not, however, been identified. We generated hnRNP A1 knockout mice to study the role of hnRNP A1 in vivo The knockout mice, hnRNP A1-/-, showed embryonic lethality because of muscle developmental defects. The blood pressure and heart rate of the heterozygous mice were higher than those of the wild-type mice, indicating heart function defects. We performed mouse exon arrays to study the muscle development mechanism. The processes regulated by hnRNP A1 included cell adhesion and muscle contraction. The expression levels of muscle development-related genes in hnRNP A1+/- mice were significantly different from those in wild-type mice, as detected using qRT-PCR. We further confirmed the alternative splicing patterns of muscle development-related genes including mef2c, lrrfip1, usp28 and abcc9 Alternative mRNA isoforms of these genes were increased in hnRNP A1+/- mice compared with wild-type mice. Furthermore, we revealed that the functionally similar hnRNP A2/B1 did not compensate for the expression of hnRNP A1 in organisms. In summary, our study demonstrated that hnRNP A1 plays a critical and irreplaceable role in embryonic muscle development by regulating the expression and alternative splicing of muscle-related genes. PMID- 28077599 TI - BLT1 Mediates Bleomycin-Induced Lung Fibrosis Independently of Neutrophils and CD4+ T Cells. AB - Leukotriene B4 (LTB4) and its functional receptor BLT1 are closely involved in tissue inflammation by primarily mediating leukocyte recruitment and activation. Elevated LTB4 was reported in patients with lung fibrosis; however, the role of the LTB4/BLT1 axis in lung fibrosis remains unknown. In this study, we demonstrated that BLT1-/- mice exhibited significantly attenuated bleomycin (BLM) induced lung fibrosis. Interestingly, BLT1 blockade with its specific antagonist U75302 in the acute injury phase (days 0-10 after BLM treatment) significantly attenuated lung fibrosis, which was accompanied by significant decreases in early infiltrating neutrophils and later infiltrating CD4+ T cells and the production of TGF-beta, IL-13, and IL-17A. In contrast, BLT1 blockade in the fibrotic phase (days 10-21 after BLM treatment) had no effect on lung fibrosis and TGF-beta production, although it significantly decreased CD4+ T cell infiltration. Furthermore, depletion of neutrophils or CD4+ T cells had no effect on BLM induced lung fibrosis, suggesting the independence of profibrotic activity of the LTB4/BLT1 axis on BLT1-dependent lung recruitment of these two leukocytes. Finally, although BLT1 blockade had no effect on the recruitment and phenotype of macrophages in BLM-induced lung fibrosis, the LTB4/BLT1 axis could promote TGF beta production by macrophages stimulated with BLM or supernatants from BLM exposed airway epithelial cells in an autocrine manner, which further induced collagen secretion by lung fibroblasts. Collectively, our study demonstrates that the LTB4/BLT1 axis plays a critical role in acute injury phase to promote BLM induced lung fibrosis, and it suggests that early interruption of the LTB4/BLT1 axis in some inflammatory diseases could prevent the later development of tissue fibrosis. PMID- 28077598 TI - Notch Ligand Delta-like 4 Promotes Regulatory T Cell Identity in Pulmonary Viral Infection. AB - Regulatory T (Treg) cells establish tolerance, prevent inflammation at mucosal surfaces, and regulate immunopathology during infectious responses. Recent studies have shown that Delta-like ligand 4 (Dll4) was upregulated on APC after respiratory syncytial virus (RSV) infection, and its inhibition leads to exaggerated immunopathology. In the present study, we outline the role of Dll4 in Treg cell differentiation, stability, and function in RSV infection. We found that Dll4 was expressed on CD11b+ pulmonary dendritic cells in the lung and draining lymph nodes in wild-type BALB/c mice after RSV infection. Dll4 neutralization exacerbated RSV-induced disease pathology, mucus production, group 2 innate lymphoid cell infiltration, IL-5 and IL-13 production, as well as IL 17A+ CD4 T cells. Dll4 inhibition decreased the abundance of CD62LhiCD44loFoxp3+ central Treg cells in draining lymph nodes. The RSV-induced disease was accompanied by an increase in Th17-like effector phenotype in Foxp3+ Treg cells and a decrease in granzyme B expression after Dll4 blockade. Finally, Dll4 exposed induced Treg cells maintained the CD62LhiCD44lo central Treg cell phenotype, had increased Foxp3 expression, became more suppressive, and were resistant to Th17 skewing in vitro. These results suggest that Dll4 activation during differentiation sustained Treg cell phenotype and function to control RSV infection. PMID- 28077600 TI - Ibrutinib Therapy Increases T Cell Repertoire Diversity in Patients with Chronic Lymphocytic Leukemia. AB - The Bruton's tyrosine kinase inhibitor ibrutinib is a highly effective, new targeted therapy for chronic lymphocytic leukemia (CLL) that thwarts leukemia cell survival, growth, and tissue homing. The effects of ibrutinib treatment on the T cell compartment, which is clonally expanded and thought to support the growth of malignant B cells in CLL, are not fully characterized. Using next generation sequencing technology, we characterized the diversity of TCRbeta chains in peripheral blood T cells from 15 CLL patients before and after 1 y of ibrutinib therapy. We noted elevated CD4+ and CD8+ T cell numbers and a restricted TCRbeta repertoire in all pretreatment samples. After 1 y of ibrutinib therapy, elevated peripheral blood T cell numbers and T cell-related cytokine levels had normalized, and T cell repertoire diversity increased significantly. Dominant TCRbeta clones in pretreatment samples declined or became undetectable, and the number of productive unique clones increased significantly during ibrutinib therapy, with the emergence of large numbers of low-frequency TCRbeta clones. Importantly, broader TCR repertoire diversity was associated with clinical efficacy and lower rates of infections during ibrutinib therapy. These data demonstrate that ibrutinib therapy increases diversification of the T cell compartment in CLL patients, which contributes to cellular immune reconstitution. PMID- 28077601 TI - A New RNA-Based Adjuvant Enhances Virus-Specific Vaccine Responses by Locally Triggering TLR- and RLH-Dependent Effects. AB - Among innovative adjuvants conferring a Th1-shift, RNAdjuvant is a promising candidate. This adjuvant consists of a 547-nt uncapped noncoding ssRNA containing polyU repeats that is stabilized by a cationic carrier peptide. Whereas vaccination of mice with an influenza subunit vaccine induced moderate virus specific IgG1, vaccination together with RNAdjuvant significantly enhanced this IgG1 and additionally promoted the formation of IgG2b/c, which is indicative of Th1 responses. Furthermore, such sera neutralized influenza virus, whereas this effect was not detected upon vaccination with the subunit vaccine alone. Similarly, upon vaccination with virus-like particles displaying vesicular stomatitis virus G protein, RNAdjuvant promoted the formation of virus-specific IgG2b/c and enhanced neutralizing IgG responses to an extent that mice were protected against lethal virus infection. RNAdjuvant induced dendritic cells to upregulate activation markers and produce IFN-I. Although these effects were strictly TLR7 dependent, RNAdjuvant-mediated augmentation of vaccine responses needed concurrent TLR and RIG-I-like helicase signaling. This was indicated by the absence of the adjuvant effect in vaccinated MyD88-/-Cardif-/- mice, which are devoid of TLR (with the exception of TLR3) and RIG-I-like helicase signaling, whereas in vaccinated MyD88-/- mice the adjuvant effect was reduced. Notably, i.m. RNAdjuvant injection induced local IFN-I responses and did not induce systemic effects, implying good tolerability and a favorable safety profile for RNAdjuvant. PMID- 28077602 TI - Diagnoses of sexual abuse and their common registered comorbidities in the total population of Stockholm. AB - BACKGROUND: Prior research based on self-reports has proven sexual abuse to be a risk factor for pain and psychiatric disorders. However, less is known about how this is reflected within the healthcare system. The aim of this study was to study the 2-year prevalence of diagnosis of sexual abuse and concomitant conditions. METHODS: Using data from VAL, the study population included all living persons in Stockholm County, Sweden, between 1 January 2008 and 31 December 2014 (N=2 549 496). Diagnoses of sexual abuse were identified during 2013-2014, with information on the concomitant conditions somatic pain, depression, anxiety, psychotic disorders and bipolar disorders, stress disorders and alcohol and substance abuse. All diagnoses were prospectively registered. Age and neighbourhood socioeconomic status-adjusted ORs with 95% CIs for individuals with a diagnosis of sexual abuse, using individuals without sexual abuse as referents, were calculated. RESULTS: Girls at the ages 13-17 years had the highest 2-year prevalence (0.69%) of sexual abuse followed by girls 5-12 years (0.11%), and girls 0-4 years (0.04%). For women 45 years and older the 2-year prevalence rates were substantially lower (0.008-0.004%). The highest 2-year prevalence of sexual abuse in men was seen in boys 5-12 (0.03%) years. The total 2-year prevalence of diagnoses of sexual abuse among the population in the material was 0.04%. The highest ORs of comorbidities for girls (ages 0-17 years) with sexual abuse versus those without sexual abuse were: Stress disorder; 15.7 (13.1 to 18.9), drug abuse; 10.0 (7.7 to 13.0), and alcohol abuse; 9.7(7.8 to 12.0). For boys (ages 0-17 years), the highest ORs of comorbidities were: Stress disorder 12.4 (6.0 to 25.7), anxiety disorders; 5.5 (2.6 to 11.5), and alcohol abuse; 3.9 (1.4 to 11.3). The highest ORs of comorbidities for women (18-) with sexual abuse versus those without sexual abuse were: alcohol abuse; 19.3 (12.6 to 29.6), drug abuse; 16.7 (10.7 to 26.1) and psychotic disorders; 15.3 (8.0 to 29.4). For men (18-) the highest ORs of comorbidities were: alcohol abuse; 25.8 (15.2 to 43.9), anxiety disorders; 14.3 (8.5 to 24.2) stress disorder; 12.9 (7.5 to 22.1) and drug abuse; 12.9 (6.9 to 24.1). CONCLUSIONS: Diagnoses of drug and alcohol abuse, psychotic, bipolar, stress anxiety disorders, depression and somatic pain are more common among individuals with a diagnosis of sexual abuse than among individuals without a diagnosis of sexual abuse. PMID- 28077603 TI - Influence of focus of attention, reinvestment and fall history on elderly gait stability. AB - Falls represent a substantial risk in the elderly. Previous studies have found that a focus on the outcome or effect of the movement (external focus of attention) leads to improved balance performance, whereas a focus on the movement execution itself (internal focus of attention) impairs balance performance in elderly. A shift toward more conscious, explicit forms of motor control occurs when existing declarative knowledge is recruited in motor control, a phenomenon called reinvestment. We investigated the effects of attentional focus and reinvestment on gait stability in elderly fallers and nonfallers. Full body kinematics was collected from twenty-eight healthy older adults walking on a treadmill, while focus of attention was manipulated through instruction. Participants also filled out the Movement Specific Reinvestment Scale (MSRS) and the Falls Efficacy Scale International (FES-I), and provided details about their fall history. Coefficients of Variation (CV) of spatiotemporal gait parameters and Local Divergence Exponents (LDE) were calculated as measures of gait variability and gait stability, respectively. Larger stance time CV and LDE (decreased gait stability) were found for fallers compared to nonfallers. No significant effect of attentional focus was found for the gait parameters, and no significant relation between MSRS score (reinvestment) and fall history was found. We conclude that external attention to the walking surface does not lead to improved gait stability in elderly. Potential benefits of an external focus of attention might not apply to gait, because walking movements are not geared toward achieving a distinct environmental effect. PMID- 28077606 TI - Correction to: Inorganic Nitrate Supplementation Lowers Blood Pressure in Humans: Role for Nitrite-Derived NO. PMID- 28077607 TI - Anatomy of Mdm2 and Mdm4 in evolution. AB - Mouse double minute (Mdm) genes span an evolutionary timeframe from the ancient eukaryotic placozoa Trichoplax adhaerens to Homo sapiens, implying a significant and possibly conserved cellular role throughout history. Maintenance of DNA integrity and response to DNA damage involve many key regulatory pathways, including precise control over the tumour suppressor protein p53. In most vertebrates, degradation of p53 through proteasomal targeting is primarily mediated by heterodimers of Mdm2 and the Mdm2-related protein Mdm4 (also known as MdmX). Both Mdm2 and Mdm4 have p53-binding regions, acidic domains, zinc fingers, and C-terminal RING domains that are conserved throughout evolution. Vertebrates typically have both Mdm2 and Mdm4 genes, while analyses of sequenced genomes of invertebrate species have identified single Mdm genes, suggesting that a duplication event occurred prior to emergence of jawless vertebrates about 550 440 million years ago. The functional relationship between Mdm and p53 in T. adhaerens, an organism that has existed for 1 billion years, implies that these two proteins have evolved together to maintain a conserved and regulated function. PMID- 28077604 TI - The mitochondrial DNA content of cumulus granulosa cells is linked to embryo quality. AB - STUDY QUESTION: Could the mitochondrial DNA (mtDNA) content of cumulus granulosa cells (CGCs) be related to oocyte competence? SUMMARY ANSWER: The quality of embryos obtained during IVF procedures appears to be linked to mtDNA copy numbers in the CGCs. WHAT IS KNOWN ALREADY: Oocyte quality is linked to oocyte mtDNA content in the human and other species, and the mtDNA copy number of the oocyte is related to that of the corresponding CGCs. Moreover, the quantification of CGC mtDNA has recently been proposed as a biomarker of embryo viability. STUDY DESIGN SIZE, DURATION: An observational study was performed on 452 oocyte-cumulus complexes retrieved from 62 patients undergoing ICSI at the ART Center of the University Hospital of Angers, France, from January to May 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: The average mtDNA content of CGCs was assessed by using a quantitative real-time PCR technique. The relationship between CGC mtDNA content and oocyte maturity and fertilizability, on one hand, and embryo quality, on the other, was investigated using univariate and multivariate generalized models with fixed and mixed effects. MAIN RESULTS AND THE ROLE OF CHANCE: No relationship was found between CGC mtDNA content and oocyte maturity or fertilizability. In contrast, there was a significant link between the content of mtDNA in CGCs surrounding an oocyte and the embryo quality, with significantly higher mtDNA copy numbers being associated with good quality embryos compared with fair or poor quality embryos [interquartile range, respectively, 738 (250-1228) and 342 (159-818); P = 0.006]. However, the indication provided by the quantification of CGC mtDNA concerning the eventuality of good embryo quality was seriously subject to patient effect (AUC = 0.806, 95%CI = 0.719-0.869). The quantity of CGC mtDNA was influenced by BMI and smoking. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: The quantification of CGC mtDNA may indicate embryo quality. However, since it is affected by patient specificity, it should be used with caution. It remains to be seen whether this marker could directly predict the implantation capacity of the embryo, which is the main objective in IVF practice. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests that the quantification of CGC mtDNA may be a novel biomarker of embryo viability. However, patient specificity makes it impossible to establish a general threshold value, valid for all patients. Nevertheless, further studies are needed to determine whether the quantification of CGC mtDNA may, in combination with the morpho-kinetic method, offer an additional criterion for selecting the best embryo for transfer from a given cohort. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the University Hospital of Angers, the University of Angers, France, and the French national research centres INSERM and the CNRS. There were no competing interests. PMID- 28077608 TI - 'Holiday sickness'-reported exploratory outcome of over 500 United Kingdom holidaymakers with travellers' diarrhoea. AB - AIMS: To ascertain any predictors of potential food poisoning pathogens and development of post-infective irritable bowel syndrome (IBS) in UK travellers. An analysis was undertaken on prospectively collected data on 527 patients reporting symptoms of suspected food poisoning between June 2012 and June 2015. MAIN OUTCOME MEASURES: Positive stool sample indicative of food poisoning pathogens and diagnosis of post-infective IBS. RESULTS: Data on 527 patients were examined. The large majority of patients did not provide a stool sample on return from holiday (n = 430, 81.6%) as few visited a Doctor locally or in the UK. Only 18 patients (18.6%, 95% confidence interval [CI] 11.4-27.7) who provided a stool sample were positive for microbiological food poisoning pathogens. Univariate analysis indicated a significant relationship between a positive stool sample and whether the individual sought any medical assistance at the resort (odds ratio [OR] 0.24, 95% CI 0.08-0.70) and whether they took any treatment (including self medicated), (OR 0.21, 95% CI 0.06-0.67). Of the 527 patients only 30 (5.7%, 95% CI 3.9-8.1) experienced post-infective IBS. Univariate regression indicated a significant relationship between experiencing Per Rectal (PR) bleeding and a diagnosis of post-infective IBS (OR 3.64, 95% CI 1.00-10.49). Univariate regression also indicated an increase in the risk of developing post-infective IBS with increasing duration of symptoms (OR 1.04, 95% CI 1.02-1.05). No significant relationship was found between a positive stool sample and developing post-infective IBS (P = 0.307). CONCLUSIONS: Very few patients provide a stool sample after experiencing holiday sickness abroad. Of those that do, only a small proportion have a positive stool sample indicative of a food poisoning microorganism. Around 6% of individuals were diagnosed with post-infective IBS. Those individuals with PR bleeding and symptoms persisting for longer durations were significantly more at risk of developing post-infective IBS, whilst medical aid and treatment abroad was found to reduce the odds of a positive stool sample. PMID- 28077610 TI - Seroprevalence of Toxocariasis in Children with Urticaria: A Population-based Study. AB - Objective: This study described the prevalence of IgG class antibodies against Toxocara spp. and their association with urticaria in 2- to 12-year-old children. Methods: This population-based cross-sectional study was conducted between May 2012 and September 2014. The study sample comprised 168 children. Blood samples were collected to verify the presence of toxocariasis by using ELISA to detect IgG antibodies. The guardians of the children were interviewed to characterize the presence or absence of other diseases, such as urticaria. Results: The presence of urticaria was observed in 38% of participants. The seroprevalence of toxocariasis in this population was 16%. This study confirmed a positive association between urticaria and positive serology for Toxocara and a negative independent association with canine contact and the number of household residents. Conclusions: There are no previous reports in the literature of a population-based study that correlates the presence of urticaria with serology for toxocariasis. PMID- 28077611 TI - Umbilical Venous Catheter Versus Peripherally Inserted Central Catheter in Neonates: A Randomized Controlled Trial. AB - : Peripherally inserted central catheter (PICC) and umbilical venous catheter (UVC) in terms of success rate, complications, cost and time of insertion in neonatal intensive care were compared. Neonates requiring vascular access for minimum 7 days were included. Sample size of 72 per group was determined. Trial was registered at Clinical Trials Registry of India (CTRI/2015/02/005529). Success rates of the UVC and PICC were 68.1% and 65.3%, respectively (p = 0.724). Mean (SD) time needed for PICC and UVC insertion was 34.13 (34.69) and 28.31 (17.19) min, respectively (p = 0.205). Mean (SD) cost of PICC insertion vs. UVC insertion was 60.9 (8.6) vs. 11.9 (8.7) US dollars (p < 0.0001). Commonest cause for failure of UVC was displacement [6 (8.3%)] and that for PICC was blockage [9 (12.5%)]. CONCLUSIONS: UVC is a cheaper alternative to PICC, with similar success rate, short-term complications and time needed for insertion. PMID- 28077609 TI - Travellers and influenza: risks and prevention. AB - BACKGROUND: Influenza viruses are among the major causes of serious human respiratory tract infection worldwide. In line with the high disease burden attributable to influenza, these viruses play an important, but often neglected, role in travel medicine. Guidelines and recommendations regarding prevention and management of influenza in travellers are scarce. Of special interest for travel medicine are risk populations and also circumstances that facilitate influenza virus transmission and spread, like travel by airplane or cruise ship and mass gatherings. METHODS: We conducted a PUBMED/MEDLINE search for a combination of the MeSH terms Influenza virus, travel, mass gathering, large scale events and cruise ship. In addition we gathered guidelines and recommendations from selected countries and regarding influenza prevention and management in travellers. By reviewing these search results in the light of published knowledge in the fields of influenza prevention and management, we present best practice advice for the prevention and management of influenza in travel medicine. RESULTS: Seasonal influenza is among the most prevalent infectious diseases in travellers. Known host-associated risk factors include extremes of age and being immune compromised, while the most relevant environmental factors are associated with holiday cruises and mass gatherings. CONCLUSIONS: Pre-travel advice should address influenza and its prevention for travellers, whenever appropriate on the basis of the epidemiological situation concerned. Preventative measures should be strongly recommended for travellers at high-risk for developing complications. In addition, seasonal influenza vaccination should be considered for any traveller wishing to reduce the risk of incapacitation, particularly cruise ship crew and passengers, as well as those participating in mass gatherings. Besides advice concerning preventive measures and vaccination, advice on the use of antivirals may be considered for some travellers. PMID- 28077612 TI - Professor Neil Pride. PMID- 28077614 TI - Occupational exposure to pesticides: time to nip it in the bud? PMID- 28077615 TI - Treatment decisions for MRSA in patients with cystic fibrosis (CF): when is enough, enough? PMID- 28077613 TI - Socioeconomic deprivation and the outcome of pulmonary rehabilitation in England and Wales. AB - BACKGROUND: Pulmonary rehabilitation (PR) improves exercise capacity and health status in patients with COPD, but many patients assessed for PR do not complete therapy. It is unknown whether socioeconomic deprivation associates with rates of completion of PR or the magnitude of clinical benefits bequeathed by PR. METHODS: PR services across England and Wales enrolled patients to the National PR audit in 2015. Deprivation was assessed using Index of Multiple Deprivation (IMD) derived from postcodes. Study outcomes were completion of therapy and change in measures of exercise performance and health status. Univariate and multivariate analyses investigated associations between IMD and these outcomes. RESULTS: 210 PR programmes enrolled 7413 patients. Compared with the general population, the PR sample lived in relatively deprived neighbourhoods. There was a statistically significant association between rates of completion of PR and quintile of deprivation (70% in the least and 50% in the most deprived quintiles). After baseline adjustments, the risk ratio (95% CI) for patients in the most deprived relative to the least deprived quintile was 0.79 (0.73 to 0.85), p<0.001. After baseline adjustments, IMD was not significantly associated with improvements in exercise performance and health status. CONCLUSIONS: In a large national dataset, we have shown that patients living in more deprived areas are less likely to complete PR. However, deprivation was not associated with clinical outcomes in patients who complete therapy. Interventions targeted at enhancing referral, uptake and completion of PR among patients living in deprived areas could reduce morbidity and healthcare costs in such hard-to-reach populations. PMID- 28077616 TI - Different modes of enhancer-specific regulation by Runt and Even-skipped during Drosophila segmentation. AB - The initial metameric expression of the Drosophila sloppy paired 1 (slp1) gene is controlled by two distinct cis-regulatory DNA elements that interact in a nonadditive manner to integrate inputs from transcription factors encoded by the pair-rule segmentation genes. We performed chromatin immunoprecipitation on reporter genes containing these elements in different embryonic genotypes to investigate the mechanism of their regulation. The distal early stripe element (DESE) mediates both activation and repression by Runt. We find that the differential response of DESE to Runt is due to an inhibitory effect of Fushi tarazu (Ftz) on P-TEFb recruitment and the regulation of RNA polymerase II (Pol II) pausing. The proximal early stripe element (PESE) is also repressed by Runt, but in this case, Runt prevents PESE-dependent Pol II recruitment and preinitiation complex (PIC) assembly. PESE is also repressed by Even-skipped (Eve), but, of interest, this repression involves regulation of P-TEFb recruitment and promoter-proximal Pol II pausing. These results demonstrate that the mode of slp1 repression by Runt is enhancer specific, whereas the mode of repression of the slp1 PESE enhancer is transcription factor specific. We propose a model based on these differential regulatory interactions that accounts for the nonadditive interactions between the PESE and DESE enhancers during Drosophila segmentation. PMID- 28077617 TI - Calcineurin, the Ca2+-dependent phosphatase, regulates Rga2, a Cdc42 GTPase activating protein, to modulate pheromone signaling. AB - Calcineurin, the conserved Ca2+/calmodulin-activated phosphatase, is required for viability during prolonged exposure to pheromone and acts through multiple substrates to down-regulate yeast pheromone signaling. Calcineurin regulates Dig2 and Rod1/Art4 to inhibit mating-induced gene expression and activate receptor internalization, respectively. Recent systematic approaches identified Rga2, a GTPase-activating protein (GAP) for the Cdc42 Rho-type GTPase, as a calcineurin substrate. Here we establish a physiological context for this regulation and show that calcineurin dephosphorylates and positively regulates Rga2 during pheromone signaling. Mating factor activates the Fus3/MAPK kinase, whose substrates induce gene expression, cell cycle arrest, and formation of the mating projection. Our studies demonstrate that Fus3 also phosphorylates Rga2 at inhibitory S/TP sites, which are targeted by Cdks during the cell cycle, and that calcineurin opposes Fus3 to activate Rga2 and decrease Cdc42 signaling. Yeast expressing an Rga2 mutant that is defective for regulation by calcineurin display increased gene expression in response to pheromone. This work is the first to identify cross talk between Ca2+/calcineurin and Cdc42 signaling and to demonstrate modulation of Cdc42 activity through a GAP during mating. PMID- 28077618 TI - Mechanism of nuclear movements in a multinucleated cell. AB - Multinucleated cells are important in many organisms, but the mechanisms governing the movements of nuclei sharing a common cytoplasm are not understood. In the hyphae of the plant pathogenic fungus Ashbya gossypii, nuclei move back and forth, occasionally bypassing each other, preventing the formation of nuclear clusters. This is essential for genetic stability. These movements depend on cytoplasmic microtubules emanating from the nuclei that are pulled by dynein motors anchored at the cortex. Using three-dimensional stochastic simulations with parameters constrained by the literature, we predict the cortical anchor density from the characteristics of nuclear movements. The model accounts for the complex nuclear movements seen in vivo, using a minimal set of experimentally determined ingredients. Of interest, these ingredients power the oscillations of the anaphase spindle in budding yeast, but in A. gossypii, this system is not restricted to a specific nuclear cycle stage, possibly as a result of adaptation to hyphal growth and multinuclearity. PMID- 28077619 TI - Relative importance of betacyto- and gammacyto-actin in primary mouse embryonic fibroblasts. AB - The highly homologous beta (betacyto) and gamma (gammacyto) cytoplasmic actins are hypothesized to carry out both redundant and unique essential functions, but studies using targeted gene knockout and siRNA-mediated transcript knockdown to examine betacyto- and gammacyto-isoform--specific functions in various cell types have yielded conflicting data. Here we quantitatively characterized actin transcript and protein levels, as well as cellular phenotypes, in both gene- and transcript-targeted primary mouse embryonic fibroblasts. We found that the smooth muscle alphasm-actin isoform was the dominantly expressed actin isoform in WT primary fibroblasts and was also the most dramatically up-regulated in primary betacyto- or beta/gammacyto-actin double-knockout fibroblasts. Gene targeting of betacyto-actin, but not gammacyto-actin, led to greatly decreased cell proliferation, decreased levels of cellular ATP, and increased serum response factor signaling in primary fibroblasts, whereas immortalization induced by SV40 large T antigen supported fibroblast proliferation in the absence of betacyto actin. Consistent with in vivo gene-targeting studies in mice, both gene- and transcript-targeting approaches demonstrate that the loss of betacyto-actin protein is more disruptive to primary fibroblast function than is the loss of gammacyto-actin. PMID- 28077620 TI - Mitogen-induced distinct epialleles are phosphorylated at either H3S10 or H3S28, depending on H3K27 acetylation. AB - Stimulation of the MAPK pathway results in mitogen- and stress-activated protein kinase 1/2 (MSK1/2)-catalyzed phosphorylation of histone H3 at serine 10 or 28 and expression of immediate-early (IE) genes. In 10T1/2 mouse fibroblasts, phosphorylation of H3S10 and H3S28 occurs on different H3 molecules and in different nuclear regions. Similarly, we show that mitogen-induced H3S10 and H3S28 phosphorylation occurs in separate pools in human primary fibroblasts. High resolution imaging studies on both cell types reveal that H3S10 and H3S28 phosphorylation events can be induced in a single cell but on different alleles, giving rise to H3S10ph and H3S28ph epialleles. Coimmunoprecipitation and inhibition studies demonstrate that CBP/p300-mediated H3K27 acetylation is required for MSK1/2 to phosphorylate S28. Although the K9ac and S10ph marks coexist on H3, S10 phosphorylation is not dependent on K9 acetylation by PCAF. We propose that random targeting of H3S10 or H3S28 results from the stochastic acetylation of H3 by CBP/p300 or PCAF, a process comparable to transcriptional bursting causing temporary allelic imbalance. In 10T1/2 cells expressing Jun, at least two of three alleles per cell were induced, a sign of high expression level. The redundant roles of H3S10ph and H3S28ph might enable rapid and efficient IE gene induction. PMID- 28077621 TI - Functional redundancy and nonredundancy between two Troponin C isoforms in Drosophila adult muscles. AB - We investigated the functional overlap of two muscle Troponin C (TpnC) genes that are expressed in the adult fruit fly, Drosophila melanogaster: TpnC4 is predominantly expressed in the indirect flight muscles (IFMs), whereas TpnC41C is the main isoform in the tergal depressor of the trochanter muscle (TDT; jump muscle). Using CRISPR/Cas9, we created a transgenic line with a homozygous deletion of TpnC41C and compared its phenotype to a line lacking functional TpnC4 We found that the removal of either of these genes leads to expression of the other isoform in both muscle types. The switching between isoforms occurs at the transcriptional level and involves minimal enhancers located upstream of the transcription start points of each gene. Functionally, the two TpnC isoforms were not equal. Although ectopic TpnC4 in TDT muscles was able to maintain jumping ability, TpnC41C in IFMs could not effectively support flying. Simultaneous functional disruption of both TpnC genes resulted in jump-defective and flightless phenotypes of the survivors, as well as abnormal sarcomere organization. These results indicated that TpnC is required for myofibril assembly, and that there is functional specialization among TpnC isoforms in Drosophila. PMID- 28077622 TI - Ciliary entry of KIF17 is dependent on its binding to the IFT-B complex via IFT46 IFT56 as well as on its nuclear localization signal. AB - Cilia function as cellular antennae to sense and transduce extracellular signals. A number of proteins are specifically localized in cilia. Anterograde and retrograde ciliary protein trafficking are mediated by the IFT-B and IFT-A complexes in concert with kinesin-2 and dynein-2 motors, respectively. However, the role of KIF17, a homodimeric kinesin-2 protein, in protein trafficking has not been fully understood in vertebrate cilia. In this study, we demonstrated, by using the visible immunoprecipitation assay, that KIF17 interacts with the IFT46 IFT56 dimer in the IFT-B complex through its C-terminal sequence located immediately upstream of the nuclear localization signal (NLS). We then showed that KIF17 reaches the ciliary tip independently of its motor domain and requires IFT-B binding for its entry into cilia rather than for its intraciliary trafficking. We further showed that KIF17 ciliary entry depends not only on its binding to IFT-B but also on its NLS, to which importin alpha proteins bind. Taking the results together, we conclude that in mammalian cells, KIF17 is dispensable for ciliogenesis and IFT-B trafficking but requires IFT-B, as well as its NLS, for its ciliary entry across the permeability barrier located at the ciliary base. PMID- 28077623 TI - A Quality Improvement Project to Decrease Human Milk Errors in the NICU. AB - BACKGROUD AND OBJECTIVE: Ensuring safe human milk in the NICU is a complex process with many potential points for error, of which one of the most serious is administration of the wrong milk to the wrong infant. Our objective was to describe a quality improvement initiative that was associated with a reduction in human milk administration errors identified over a 6-year period in a typical, large NICU setting. METHODS: We employed a quasi-experimental time series quality improvement initiative by using tools from the model for improvement, Six Sigma methodology, and evidence-based interventions. Scanned errors were identified from the human milk barcode medication administration system. Scanned errors of interest were wrong-milk-to-wrong-infant, expired-milk, or preparation errors. The scanned error rate and the impact of additional improvement interventions from 2009 to 2015 were monitored by using statistical process control charts. RESULTS: From 2009 to 2015, the total number of errors scanned declined from 97.1 per 1000 bottles to 10.8. Specifically, the number of expired milk error scans declined from 84.0 per 1000 bottles to 8.9. The number of preparation errors (4.8 per 1000 bottles to 2.2) and wrong-milk-to-wrong-infant errors scanned (8.3 per 1000 bottles to 2.0) also declined. CONCLUSIONS: By reducing the number of errors scanned, the number of opportunities for errors also decreased. Interventions that likely had the greatest impact on reducing the number of scanned errors included installation of bedside (versus centralized) scanners and dedicated staff to handle milk. PMID- 28077624 TI - The Continuing Rise of Gun Violence in PG-13 Movies, 1985 to 2015. PMID- 28077625 TI - Radiotherapy for localized gastric mucosa-associated lymphoid tissue lymphoma: long-term outcomes over 10 years. AB - This study aimed to assess the long-term outcomes of radiotherapy in patients with localized gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Twenty seven patients with Stage I gastric MALT lymphoma were treated with radiotherapy from 1999 to 2010. The median age was 65 years (range: 31-84). Fifteen patients were Helicobacter pylori-negative. Thirteen patients were treated with definitive radiotherapy alone. The other 14 patients who had refractory or residual disease following a prior treatment received salvage radiotherapy. The median dose of the radiotherapy was 30 Gy in 20 fractions (range: 30-39.5 Gy). The median follow-up period was 121 months (range: 8-176 months). The 5- and 10-year overall survival rates for all patients were 92% and 87%, respectively. No patients died from MALT lymphoma. Three patients died of other diseases at 8, 33 and 74 months after radiotherapy (myocardial infarction, pneumonia and hepatocellular carcinoma, respectively). No cases of local recurrence were observed during the follow-up period. There were no serious late gastric, liver or kidney complications during a median follow-up period of over 10 years. Two patients remain alive with distant metastases: a lung metastasis and an abdominal lymph node metastasis at 104 months and 21 months after radiotherapy, respectively. Excellent long-term local control was observed in patients with localized gastric MALT lymphoma after radiotherapy. However, lifelong follow-up should be conducted to detect cases of late recurrence, especially distant metastases. PMID- 28077627 TI - A feasibility study on the use of phantoms with statistical lung masses for determining the uncertainty in the dose absorbed by the lung from broad beams of incident photons and neutrons. AB - Computational models of the human body have gradually become crucial in the evaluation of doses absorbed by organs. However, individuals may differ considerably in terms of organ size and shape. In this study, the authors sought to determine the energy-dependent standard deviations due to lung size of the dose absorbed by the lung during external photon and neutron beam exposures. One hundred lungs with different masses were prepared and located in an adult male International Commission on Radiological Protection (ICRP) reference phantom. Calculations were performed using the Monte Carlo N-particle code version 5 (MCNP5). Variation in the lung mass caused great uncertainty: ~90% for low-energy broad parallel photon beams. However, for high-energy photons, the lung-absorbed dose dependency on the anatomical variation was reduced to <1%. In addition, the results obtained indicated that the discrepancy in the lung-absorbed dose varied from 0.6% to 8% for neutron beam exposure. Consequently, the relationship between absorbed dose and organ volume was found to be significant for low-energy photon sources, whereas for higher energy photon sources the organ-absorbed dose was independent of the organ volume. In the case of neutron beam exposure, the maximum discrepancy (of 8%) occurred in the energy range between 0.1 and 5 MeV. PMID- 28077626 TI - Low-dose or low-dose-rate ionizing radiation-induced bioeffects in animal models. AB - Animal experimental studies indicate that acute or chronic low-dose ionizing radiation (LDIR) (<=100 mSv) or low-dose-rate ionizing radiation (LDRIR) (<6 mSv/h) exposures may be harmful. It induces genetic and epigenetic changes and is associated with a range of physiological disturbances that includes altered immune system, abnormal brain development with resultant cognitive impairment, cataractogenesis, abnormal embryonic development, circulatory diseases, weight gain, premature menopause in female animals, tumorigenesis and shortened lifespan. Paternal or prenatal LDIR/LDRIR exposure is associated with reduced fertility and number of live fetuses, and transgenerational genomic aberrations. On the other hand, in some experimental studies, LDIR/LDRIR exposure has also been reported to bring about beneficial effects such as reduction in tumorigenesis, prolonged lifespan and enhanced fertility. The differences in reported effects of LDIR/LDRIR exposure are dependent on animal genetic background (susceptibility), age (prenatal or postnatal days), sex, nature of radiation exposure (i.e. acute, fractionated or chronic radiation exposure), type of radiation, combination of radiation with other toxic agents (such as smoking, pesticides or other chemical toxins) or animal experimental designs. In this review paper, we aimed to update radiation researchers and radiologists on the current progress achieved in understanding the LDIR/LDRIR-induced bionegative and biopositive effects reported in the various animal models. The roles played by a variety of molecules that are implicated in LDIR/LDRIR-induced health effects will be elaborated. The review will help in future investigations of LDIR/LDRIR induced health effects by providing clues for designing improved animal research models in order to clarify the current controversial/contradictory findings from existing studies. PMID- 28077628 TI - The Creatininase Homolog MftE from Mycobacterium smegmatis Catalyzes a Peptide Cleavage Reaction in the Biosynthesis of a Novel Ribosomally Synthesized Post translationally Modified Peptide (RiPP). AB - Most ribosomally synthesized and post-translationally modified peptide (RiPP) natural products are processed by tailoring enzymes to create complex natural products that are still recognizably peptide-based. However, some tailoring enzymes dismantle the peptide en route to synthesis of small molecules. A small molecule natural product of as yet unknown structure, mycofactocin, is thought to be synthesized in this way via the mft gene cluster found in many strains of mycobacteria. This cluster harbors at least six genes, which appear to be conserved across species. We have previously shown that one enzyme from this cluster, MftC, catalyzes the oxidative decarboxylation of the C-terminal Tyr of the substrate peptide MftA in a reaction that requires the MftB protein. Herein we show that mftE encodes a creatininase homolog that catalyzes cleavage of the oxidatively decarboxylated MftA peptide to liberate its final two residues, including the C-terminal decarboxylated Tyr (VY*). Unlike MftC, which requires MftB for function, MftE catalyzes the cleavage reaction in the absence of MftB. The identification of this novel metabolite, VY*, supports the notion that the mft cluster is involved in generating a small molecule from the MftA peptide. The ability to produce VY* from MftA by in vitro reconstitution of the activities of MftB, MftC, and MftE sets the stage for identification of the novel metabolite that results from the proteins encoded by the mft cluster. PMID- 28077629 TI - SUN2 Silencing Impairs CD4 T Cell Proliferation and Alters Sensitivity to HIV-1 Infection Independently of Cyclophilin A. AB - Linker of nucleoskeleton and cytoskeleton (LINC) complexes connect the nucleus to the cytoskeleton in eukaryotic cells. We previously reported that the overexpression of SUN2, an inner nuclear membrane protein and LINC complex component, inhibits HIV infection between the steps of reverse transcription and nuclear import in a capsid-specific manner. We also reported that SUN2 silencing does not modulate HIV infection in several cell lines. Silencing of SUN2 was recently reported to decrease HIV infection of CD4 T cells, an effect which was suggested to result from modulation of cyclophilin A (CypA)-dependent steps of HIV infection. We confirm here that HIV infection of primary CD4 T cells is compromised in the absence of endogenous SUN2, and we extend these findings to additional viral strains. However, we find that CypA is not required for the decreased infection observed in SUN2-silenced cells and, conversely, that endogenous SUN2 is not required for the well-documented positive modulation of HIV infection by CypA. In contrast, CD4 T cells lacking SUN2 exhibit a considerable defect in proliferative capacity and display reduced levels of activation markers and decreased viability. Additionally, SUN2-silenced CD4 T cells that become infected support reduced levels of viral protein expression. Our results demonstrate that SUN2 is required for the optimal activation and proliferation of primary CD4 T cells and suggest that the disruption of these processes explains the contribution of endogenous SUN2 to HIV infection in primary lymphocytes.IMPORTANCE Linker of nucleoskeleton and cytoskeleton (LINC) complexes connect the nucleus to the cytoskeleton. We previously reported that the overexpression of the LINC complex protein SUN2 inhibits HIV infection by targeting the viral capsid and blocking infection before the virus enters the nucleus. A recent report showed that the depletion of endogenous SUN2 in primary CD4 T cells results in decreased HIV infection and that this involves cyclophilin A (CypA), a host protein that interacts with the capsid of HIV to promote infection. We confirm that HIV infection is reduced in CD4 T cells lacking SUN2, but we find no role for CypA. Instead, SUN2 silencing results in CD4 T cells with decreased viability and much lower proliferation rates. Our results show that SUN2 is required for optimal CD4 T cell activation and proliferation and explain the reduced level of HIV infection in the absence of SUN2. PMID- 28077630 TI - MAVS Is Essential for Primary CD4+ T Cell Immunity but Not for Recall T Cell Responses following an Attenuated West Nile Virus Infection. AB - The use of pathogen recognition receptor (PRR) agonists and the molecular mechanisms involved have been the major focus of research in individual vaccine development. West Nile virus (WNV) nonstructural (NS) 4B-P38G mutant has several features for an ideal vaccine candidate, including significantly reduced neuroinvasiveness, induction of strong adaptive immunity, and protection of mice from wild-type (WT) WNV infection. Here, we determined the role of mitochondrial antiviral signaling protein (MAVS), the adaptor protein for RIG-I-like receptor in regulating host immunity against the NS4B-P38G vaccine. We found that Mavs-/- mice were more susceptible to NS4B-P38G priming than WT mice. Mavs-/- mice had a transiently reduced production of antiviral cytokines and an impaired CD4+ T cell response in peripheral organs. However, antibody and CD8+ T cell responses were minimally affected. NS4B-P38G induced lower type I interferon (IFN), IFN stimulating gene, and proinflammatory cytokine responses in Mavs-/- dendritic cells and subsequently compromised the antigen-presenting capacity for CD4+ T cells. Interestingly, Mavs-/- mice surviving NS4B-P38G priming were all protected from a lethal WT WNV challenge. NS4B-P38G-primed Mavs-/- mice exhibited equivalent levels of protective CD4+ T cell recall response, a modestly reduced WNV-specific IgM production, but more robust CD8+ T cell recall response. Taken together, our results suggest that MAVS is essential for boosting optimal primary CD4+ T cell responses upon NS4B-P38G vaccination and yet is dispensable for host protection and recall T cell responses during secondary WT WNV infection.IMPORTANCE The production of innate cytokines induced by the recognition of pathogen recognition receptors (PRRs) via their cognate ligands are critical for enhancing antigen-presenting cell functions and influencing T cell responses during microbial infection. The use of PRR agonists and the underlying molecular mechanisms have been the major focus in individual vaccine development. Here, we determined the role of mitochondrial antiviral-signaling protein (MAVS), the adaptor protein for RIG-I like receptor in regulating host immunity against the live attenuated West Nile virus (WNV) vaccine strain, the nonstructural (NS) 4B-P38G mutant. We found that MAVS is important for boosting optimal primary CD4+ T cell response during NS4B-P38G vaccination. However, MAVS is dispensable for memory T cell development and host protection during secondary wild-type WNV infection. Overall, these results may be utilized as a paradigm to aid in the rational development of other efficacious live attenuated flavivirus vaccines. PMID- 28077631 TI - Vaccine Efficacy of Inactivated, Chimeric Hemagglutinin H9/H5N2 Avian Influenza Virus and Its Suitability for the Marker Vaccine Strategy. AB - In order to produce a dually effective vaccine against H9 and H5 avian influenza viruses that aligns with the DIVA (differentiating infected from vaccinated animals) strategy, we generated a chimeric H9/H5N2 recombinant vaccine that expressed the whole HA1 region of A/CK/Korea/04163/04 (H9N2) and the HA2 region of recent highly pathogenic avian influenza (HPAI) A/MD/Korea/W452/14 (H5N8) viruses. The chimeric H9/H5N2 virus showed in vitro and in vivo growth properties and virulence that were similar to those of the low-pathogenic avian influenza (LPAI) H9 virus. An inactivated vaccine based on this chimeric virus induced serum neutralizing (SN) antibodies against both H9 and H5 viruses but induced cross-reactive hemagglutination inhibition (HI) antibody only against H9 viruses. Thus, this suggests its compatibility for use in the DIVA strategy against H5 strains. Furthermore, the chimeric H9/H5N2 recombinant vaccine protected immunized chickens against lethal challenge by HPAI H5N8 viruses and significantly attenuated virus shedding after infection by both H9N2 and HPAI H5N8 viruses. In mice, serological analyses confirmed that HA1- and HA2 stalk specific antibody responses were induced by vaccination and that the DIVA principle could be employed through the use of an HI assay against H5 viruses. Furthermore, each HA1- and HA2 stalk-specific antibody response was sufficient to inhibit viral replication and protect the chimeric virus-immunized mice from lethal challenge with both mouse-adapted H9N2 and wild-type HPAI H5N1 viruses, although differences in vaccine efficacy against a homologous H9 virus (HA1 head domain immune-mediated protection) and a heterosubtypic H5 virus (HA2 stalk domain immune-mediated protection) were observed. Taken together, these results demonstrate that the novel chimeric H9/H5N2 recombinant virus is a low-pathogenic virus, and this chimeric vaccine is suitable for a DIVA vaccine with broad spectrum neutralizing antibody against H5 avian influenza viruses.IMPORTANCE Current influenza virus killed vaccines predominantly induce antihemagglutinin (anti-HA) antibodies that are commonly strain specific in that the antibodies have potent neutralizing activity against homologous strains but do not cross react with HAs of other influenza virus subtypes. In contrast, the HA2 stalk domain is relatively well conserved among subtypes, and recently, broadly neutralizing antibodies against this domain have been isolated. Therefore, in light of the need for a vaccine strain that applies the DIVA strategy utilizing an HI assay and induces broad cross-protection against H5N1 and H9N2 viruses, we generated a novel chimeric H9/H5N1 virus that expresses the entire HA1 portion from the H9N2 virus and the HA2 region of the heterosubtypic H5N8 virus. The chimeric H9/H5N2 recombinant vaccine protected immunized hosts against lethal challenge with H9N2 and HPAI H5N1 viruses with significantly attenuated virus shedding in immunized hosts. Therefore, this chimeric vaccine is suitable as a DIVA vaccine against H5 avian influenza viruses. PMID- 28077632 TI - Phyloepidemiological Analysis Reveals that Viral Divergence Led to the Paucity of Simian Immunodeficiency Virus SIVmus/gsn/mon Infections in Wild Populations. AB - Human immunodeficiency virus type 1 (HIV-1) is the result of cross-species transmission of simian immunodeficiency virus from chimpanzees (SIVcpz). SIVcpz is a chimeric virus which shares common ancestors with viruses infecting red capped mangabeys and a subset of guenon species. The epidemiology of SIV infection in hominoids is characterized by low prevalences and an uneven geographic distribution. Surveys in Cameroon indicated that two closely related members of the guenon species subset, mustached guenons and greater spot-nosed guenons, infected with SIVmus and SIVgsn, respectively, also have low rates of SIV infections in their populations. Compared to that for other monkeys, including red-capped mangabeys and closely related guenon species, such an epidemiology is unusual. By intensifying sampling of geographically distinct populations of mustached and greater spot-nosed guenons in Gabon and including large sample sets of mona guenons from Cameroon, we add strong support to the hypothesis that the paucity of SIV infections in wild populations is a general feature of this monophyletic group of viruses. Furthermore, comparative phylogenetic analysis reveals that this phenotype is a feature of this group of viruses infecting phylogenetically disparate hosts, suggesting that this epidemiological phenotype results from infection with these HIV-1-related viruses rather than from a common host factor. Thus, these HIV-1-related viruses, i.e., SIVcpz and the guenon viruses which share an ancestor with part of the SIVcpz genome, have an epidemiology distinct from that found for SIVs in other African primate species.IMPORTANCE Stable virus-host relationships are established over multiple generations. The prevalence of viral infections in any given host is determined by various factors. Stable virus-host relationships of viruses that are able to cause persistent infections and exist with high incidences of infection are generally characterized by a lack of morbidity prior to host reproduction. Such is the case for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections of humans. SIV infections of most African primate species also satisfy these criteria, with these infections found at a high prevalence and with rare cases of clinical disease. In contrast, SIVcpz, the ancestor of HIV-1, has a different epidemiology, and it has been reported that infected animals suffer from an AIDS-like disease in the wild. Here we conclusively demonstrate that viruses which are closely related to SIVcpz and infect a subset of guenon monkeys show an epidemiology resembling that of SIVcpz. PMID- 28077633 TI - Surveillance of Bat Coronaviruses in Kenya Identifies Relatives of Human Coronaviruses NL63 and 229E and Their Recombination History. AB - Bats harbor a large diversity of coronaviruses (CoVs), several of which are related to zoonotic pathogens that cause severe disease in humans. Our screening of bat samples collected in Kenya from 2007 to 2010 not only detected RNA from several novel CoVs but, more significantly, identified sequences that were closely related to human CoVs NL63 and 229E, suggesting that these two human viruses originate from bats. We also demonstrated that human CoV NL63 is a recombinant between NL63-like viruses circulating in Triaenops bats and 229E-like viruses circulating in Hipposideros bats, with the breakpoint located near 5' and 3' ends of the spike (S) protein gene. In addition, two further interspecies recombination events involving the S gene were identified, suggesting that this region may represent a recombination "hot spot" in CoV genomes. Finally, using a combination of phylogenetic and distance-based approaches, we showed that the genetic diversity of bat CoVs is primarily structured by host species and subsequently by geographic distances.IMPORTANCE Understanding the driving forces of cross-species virus transmission is central to understanding the nature of disease emergence. Previous studies have demonstrated that bats are the ultimate reservoir hosts for a number of coronaviruses (CoVs), including ancestors of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and human CoV 229E (HCoV-229E). However, the evolutionary pathways of bat CoVs remain elusive. We provide evidence for natural recombination between distantly related African bat coronaviruses associated with Triaenops afer and Hipposideros sp. bats that resulted in a NL63-like virus, an ancestor of the human pathogen HCoV-NL63. These results suggest that interspecies recombination may play an important role in CoV evolution and the emergence of novel CoVs with zoonotic potential. PMID- 28077634 TI - Characterization of Hepatitis C Virus (HCV) Envelope Diversification from Acute to Chronic Infection within a Sexually Transmitted HCV Cluster by Using Single Molecule, Real-Time Sequencing. AB - In contrast to other available next-generation sequencing platforms, PacBio single-molecule, real-time (SMRT) sequencing has the advantage of generating long reads albeit with a relatively higher error rate in unprocessed data. Using this platform, we longitudinally sampled and sequenced the hepatitis C virus (HCV) envelope genome region (1,680 nucleotides [nt]) from individuals belonging to a cluster of sexually transmitted cases. All five subjects were coinfected with HIV 1 and a closely related strain of HCV genotype 4d. In total, 50 samples were analyzed by using SMRT sequencing. By using 7 passes of circular consensus sequencing, the error rate was reduced to 0.37%, and the median number of sequences was 612 per sample. A further reduction of insertions was achieved by alignment against a sample-specific reference sequence. However, in vitro recombination during PCR amplification could not be excluded. Phylogenetic analysis supported close relationships among HCV sequences from the four male subjects and subsequent transmission from one subject to his female partner. Transmission was characterized by a strong genetic bottleneck. Viral genetic diversity was low during acute infection and increased upon progression to chronicity but subsequently fluctuated during chronic infection, caused by the alternate detection of distinct coexisting lineages. SMRT sequencing combines long reads with sufficient depth for many phylogenetic analyses and can therefore provide insights into within-host HCV evolutionary dynamics without the need for haplotype reconstruction using statistical algorithms.IMPORTANCE Next-generation sequencing has revolutionized the study of genetically variable RNA virus populations, but for phylogenetic and evolutionary analyses, longer sequences than those generated by most available platforms, while minimizing the intrinsic error rate, are desired. Here, we demonstrate for the first time that PacBio SMRT sequencing technology can be used to generate full-length HCV envelope sequences at the single-molecule level, providing a data set with large sequencing depth for the characterization of intrahost viral dynamics. The selection of consensus reads derived from at least 7 full circular consensus sequencing rounds significantly reduced the intrinsic high error rate of this method. We used this method to genetically characterize a unique transmission cluster of sexually transmitted HCV infections, providing insight into the distinct evolutionary pathways in each patient over time and identifying the transmission-associated genetic bottleneck as well as fluctuations in viral genetic diversity over time, accompanied by dynamic shifts in viral subpopulations. PMID- 28077635 TI - Virion Structure of Black Queen Cell Virus, a Common Honeybee Pathogen. AB - Viral diseases are a major threat to honeybee (Apis mellifera) populations worldwide and therefore an important factor in reliable crop pollination and food security. Black queen cell virus (BQCV) is the etiological agent of a fatal disease of honeybee queen larvae and pupae. The virus belongs to the genus Triatovirus from the family Dicistroviridae, which is part of the order Picornavirales Here we present a crystal structure of BQCV determined to a resolution of 3.4 A. The virion is formed by 60 copies of each of the major capsid proteins VP1, VP2, and VP3; however, there is no density corresponding to a 75-residue-long minor capsid protein VP4 encoded by the BQCV genome. We show that the VP4 subunits are present in the crystallized virions that are infectious. This aspect of the BQCV virion is similar to that of the previously characterized triatoma virus and supports the recent establishment of the separate genus Triatovirus within the family Dicistroviridae The C terminus of VP1 and CD loops of capsid proteins VP1 and VP3 of BQCV form 34-A-tall finger like protrusions at the virion surface. The protrusions are larger than those of related dicistroviruses.IMPORTANCE The western honeybee is the most important pollinator of all, and it is required to sustain the agricultural production and biodiversity of wild flowering plants. However, honeybee populations worldwide are suffering from virus infections that cause colony losses. One of the most common, and least known, honeybee pathogens is black queen cell virus (BQCV), which at high titers causes queen larvae and pupae to turn black and die. Here we present the three-dimensional virion structure of BQCV, determined by X-ray crystallography. The structure of BQCV reveals large protrusions on the virion surface. Capsid protein VP1 of BQCV does not contain a hydrophobic pocket. Therefore, the BQCV virion structure provides evidence that capsid-binding antiviral compounds that can prevent the replication of vertebrate picornaviruses may be ineffective against honeybee virus infections. PMID- 28077636 TI - Klebsiella Phage PhiK64-1 Encodes Multiple Depolymerases for Multiple Host Capsular Types. AB - The genome of the multihost bacteriophage PhiK64-1, capable of infecting Klebsiella capsular types K1, K11, K21, K25, K30, K35, K64, and K69, as well as new capsular types KN4 and KN5, was analyzed and revealed that 11 genes (S1-1, S1 2, S1-3, S2-1, S2-2, S2-3, S2-4, S2-5, S2-6, S2-7, and S2-8) encode proteins with amino acid sequence similarity to tail fibers/spikes or lyases. S2-5 previously was shown to encode a K64 capsule depolymerase (K64dep). Specific capsule degrading activities of an additional eight putative capsule depolymerases (S2-4 against K1, S1-1 against K11, S1-3 against K21, S2-2 against K25, S2-6 against K30/K69, S2-3 against K35, S1-2 against KN4, and S2-1 against KN5) was demonstrated by expression and purification of the recombinant proteins. Consistent with the capsular type-specific depolymerization activity of these gene products, phage mutants of S1-2, S2-2, S2-3, or S2-6 lost infectivity for KN4, K25, K35, or K30/K69, respectively, indicating that capsule depolymerase is crucial for infecting specific hosts. In conclusion, we identified nine functional capsule depolymerase-encoding genes in a bacteriophage and correlated activities of the gene products to all ten hosts of this phage, providing an example of type-specific host infection mechanisms in a multihost bacteriophage.IMPORTANCE We currently identified eight novel capsule depolymerases in a multihost Klebsiella bacteriophage and correlated the activities of the gene products to all hosts of this phage, providing an example of carriage of multiple depolymerases in a phage with a wide capsular type host spectrum. Moreover, we also established a recombineering system for modification of Klebsiella bacteriophage genomes and demonstrated the importance of capsule depolymerase for infecting specific hosts. Based on the powerful tool for modification of phage genome, further studies can be conducted to improve the understanding of mechanistic details of Klebsiella phage infection. Furthermore, the newly identified capsule depolymerases will be of great value for applications in capsular typing. PMID- 28077637 TI - Role of Litopenaeus vannamei Yin Yang 1 in the Regulation of the White Spot Syndrome Virus Immediate Early Gene ie1. AB - Yin Yang 1 (YY1) is a multifunctional zinc finger transcription factor that regulates many key cellular processes. In this study, we report the cloning of YY1 from Litopenaeus vannamei shrimp (LvYY1). This study shows that LvYY1 is ubiquitously expressed in shrimp tissues, and knockdown of LvYY1 expression by double-stranded RNA (dsRNA) injection in white spot syndrome virus (WSSV) infected shrimp reduced both mRNA levels of the WSSV immediate early gene ie1 as well as overall copy numbers of the WSSV genome. The cumulative mortality rate of infected shrimp also declined with LvYY1 dsRNA injection. Using an insect cell model, we observed that LvYY1 activates ie1 expression, and a mutation introduced into the ie1 promoter subsequently repressed this capability. Moreover, reporter assay results suggested that LvYY1 is involved in basal transcriptional regulation via an interaction with L. vannamei TATA-binding protein (LvTBP). Electrophoretic mobility shift assay (EMSA) results further indicated that LvYY1 binds to a YY1-binding site in the region between positions -119 and -126 in the ie1 promoter. Chromatin immunoprecipitation analysis also confirmed that LvYY1 binds to the ie1 promoter in WSSV-infected shrimp. Taken together, these results indicate that WSSV uses host LvYY1 to enhance ie1 expression via a YY1-binding site and the TATA box in the ie1 promoter, thereby facilitating lytic activation and viral replication.IMPORTANCE WSSV has long been a scourge of the shrimp industry and remains a serious global threat. Thus, there is a pressing need to understand how the interactions between WSSV and its host drive infection, lytic development, pathogenesis, and mortality. Our successful cloning of L. vannamei YY1 (LvYY1) led to the elucidation of a critical virus-host interaction between LvYY1 and the WSSV immediate early gene ie1 We observed that LvYY1 regulates ie1 expression via a consensus YY1-binding site and TATA box. LvYY1 was also found to interact with L. vannamei TATA-binding protein (LvTBP), which may have an effect on basal transcription. Knockdown of LvYY1 expression inhibited ie1 transcription and subsequently reduced viral DNA replication and decreased cumulative mortality rates of WSSV-infected shrimp. These findings are expected to contribute to future studies involving WSSV-host interactions. PMID- 28077638 TI - A Conserved Glycine Residue Is Required for Proper Functioning of a Baculovirus VP39 Protein. AB - The baculovirus VP39 protein is a major nucleocapsid protein essential for viral propagation. However, the critical domains or residues of the VP39 protein have not yet been identified. Here, we performed mutagenesis experiments with Bombyx mori nucleopolyhedrovirus (BmNPV) using 5-bromo-2'-deoxyuridine and isolated a BmNPV mutant that produced fewer occlusion bodies than the wild-type virus. This mutant also produced fewer infectious budded viruses (BVs) than the wild-type virus in both cultured cells and B. mori larvae. Marker rescue experiments using genomic libraries identified a single nucleotide mutation in the vp39 gene. This mutation resulted in an amino acid substitution at glycine 276 (Gly-276) to serine, which was required for all the defective phenotypes observed in the mutant. Sequence comparison revealed that this residue is completely conserved among the VP39 proteins of the sequenced alphabaculoviruses, betabaculoviruses, and gammabaculoviruses. Although early viral gene expression was not significantly affected, the level of expression of a late gene, vcath, was reduced. In addition, two of the very late genes were markedly downregulated in cells infected with this mutant. Western blot and quantitative PCR analyses revealed that the BVs produced from cells infected with this mutant contained smaller amounts of the VP39 protein and viral genomic DNA than those produced from wild-type virus-infected cells. Combined with the results of transmission electron microscopy, VP39 Gly-276 can be concluded to be essential for correct nucleocapsid assembly, viral DNA packaging, and viral gene expression, especially of very late genes.IMPORTANCE The major nucleocapsid protein gene vp39 is one of the most well-known baculovirus genes. Although several viral and host proteins that interact with the VP39 protein have been identified, the functionally important domains or residues of this protein remain unknown. The present study revealed that the glycine residue at residue 276, which is completely conserved among sequenced alphabaculoviruses, betabaculoviruses, and gammabaculoviruses, is important for the VP39 function, i.e., structural assembly of nucleocapsids and viral DNA packaging. Moreover, our results provide evidence for the link between nucleocapsid formation and the transcription of viral very late genes. PMID- 28077639 TI - Identification of a Continuous Neutralizing Epitope within UL128 of Human Cytomegalovirus. AB - As human cytomegalovirus (HCMV) is the most common infectious cause of fetal anomalies during pregnancy, development of a vaccine that prevents HCMV infection is considered a global health priority. Although HCMV immune correlates of protection are only poorly defined, neutralizing antibodies (NAb) targeting the envelope pentamer complex (PC) composed of the subunits gH, gL, UL128, UL130, and UL131A are thought to contribute to the prevention of HCMV infection. Here, we describe a continuous target sequence within UL128 that is recognized by a previously isolated potent PC-specific NAb termed 13B5. By using peptide-based scanning procedures, we identified a 13-amino-acid-long target sequence at the UL128 C terminus that binds the 13B5 antibody with an affinity similar to that of the purified PC. In addition, the 13B5 binding site is universally conserved in HCMV, contains a previously described UL128/gL interaction site, and interferes with the 13B5 neutralizing function, indicating that the 13B5 epitope sequence is located within the PC at a site of critical importance for HCMV neutralization. Vaccination of mice with peptides containing the 13B5 target sequence resulted in the robust stimulation of binding antibodies and, in a subset of immunized animals, in the induction of detectable NAb, supporting that the identified 13B5 target sequence constitutes a PC-specific neutralizing epitope. These findings provide evidence for the discovery of a continuous neutralizing epitope within the UL128 subunit of the PC that could be an important target of humoral immune responses that are involved in protection against congenital HCMV infection.IMPORTANCE Neutralizing antibodies (NAb) targeting the human cytomegalovirus (HCMV) envelope pentamer complex (PC) are thought to be important for preventing HCMV transmission from the mother to the fetus, thereby mitigating severe developmental disabilities in newborns. However, the epitope sequences within the PC that are recognized by these potentially protective antibody responses are only poorly defined. Here, we provide evidence for the existence of a highly conserved, continuous, PC-specific epitope sequence that appears to be located within the PC at a subunit interaction site of critical importance for HCMV neutralization. These discoveries provide insights into a continuous PC specific neutralizing epitope, which could be an important target for a vaccine formulation to interfere with congenital HCMV infection. PMID- 28077641 TI - Chikungunya, Influenza, Nipah, and Semliki Forest Chimeric Viruses with Vesicular Stomatitis Virus: Actions in the Brain. AB - Recombinant vesicular stomatitis virus (VSV)-based chimeric viruses that include genes from other viruses show promise as vaccines and oncolytic viruses. However, the critical safety concern is the neurotropic nature conveyed by the VSV glycoprotein. VSVs that include the VSV glycoprotein (G) gene, even in most recombinant attenuated strains, can still show substantial adverse or lethal actions in the brain. Here, we test 4 chimeric viruses in the brain, including those in which glycoprotein genes from Nipah, chikungunya (CHIKV), and influenza H5N1 viruses were substituted for the VSV glycoprotein gene. We also test a virus like vesicle (VLV) in which the VSV glycoprotein gene is expressed from a replicon encoding the nonstructural proteins of Semliki Forest virus. VSVDeltaG CHIKV, VSVDeltaG-H5N1, and VLV were all safe in the adult mouse brain, as were VSVDeltaG viruses expressing either the Nipah F or G glycoprotein. In contrast, a complementing pair of VSVDeltaG viruses expressing Nipah G and F glycoproteins were lethal within the brain within a surprisingly short time frame of 2 days. Intranasal inoculation in postnatal day 14 mice with VSVDeltaG-CHIKV or VLV evoked no adverse response, whereas VSVDeltaG-H5N1 by this route was lethal in most mice. A key immune mechanism underlying the safety of VSVDeltaG-CHIKV, VSVDeltaG-H5N1, and VLV in the adult brain was the type I interferon response; all three viruses were lethal in the brains of adult mice lacking the interferon receptor, suggesting that the viruses can infect and replicate and spread in brain cells if not blocked by interferon-stimulated genes within the brain.IMPORTANCE Vesicular stomatitis virus (VSV) shows considerable promise both as a vaccine vector and as an oncolytic virus. The greatest limitation of VSV is that it is highly neurotropic and can be lethal within the brain. The neurotropism can be mostly attributed to the VSV G glycoprotein. Here, we test 4 chimeric viruses of VSV with glycoprotein genes from Nipah, chikungunya, and influenza viruses and nonstructural genes from Semliki Forest virus. Two of the four, VSVDeltaG-CHIKV and VLV, show substantially attenuated neurotropism and were safe in the healthy adult mouse brain. VSVDeltaG-H5N1 was safe in the adult brain but lethal in the younger brain. VSVDeltaG Nipah F+G was even more neurotropic than wild-type VSV, evoking a rapid lethal response in the adult brain. These results suggest that while chimeric VSVs show promise, each must be tested with both intranasal and intracranial administration to ensure the absence of lethal neurotropism. PMID- 28077640 TI - Viral RNA at Two Stages of Reovirus Infection Is Required for the Induction of Necroptosis. AB - Necroptosis, a regulated form of necrotic cell death, requires the activation of the RIP3 kinase. Here, we identify that infection of host cells with reovirus can result in necroptosis. We find that necroptosis requires sensing of the genomic RNA within incoming virus particles via cytoplasmic RNA sensors to produce type I interferon (IFN). While these events that occur prior to the de novo synthesis of viral RNA are required for the induction of necroptosis, they are not sufficient. The induction of necroptosis also requires late stages of reovirus infection. Specifically, efficient synthesis of double-stranded RNA (dsRNA) within infected cells is required for necroptosis. These data indicate that viral RNA interfaces with host components at two different stages of infection to induce necroptosis. This work provides new molecular details about events in the viral replication cycle that contribute to the induction of necroptosis following infection with an RNA virus.IMPORTANCE An appreciation of how cell death pathways are regulated following viral infection may reveal strategies to limit tissue destruction and prevent the onset of disease. Cell death following virus infection can occur by apoptosis or a regulated form of necrosis known as necroptosis. Apoptotic cells are typically disposed of without activating the immune system. In contrast, necroptotic cells alert the immune system, resulting in inflammation and tissue damage. While apoptosis following virus infection has been extensively investigated, how necroptosis is unleashed following virus infection is understood for only a small group of viruses. Here, using mammalian reovirus, we highlight the molecular mechanism by which infection with a dsRNA virus results in necroptosis. PMID- 28077642 TI - Studies on the Interaction of Tumor-Derived HD5 Alpha Defensins with Adenoviruses and Implications for Oncolytic Adenovirus Therapy. AB - Defensins are small antimicrobial peptides capable of neutralizing human adenovirus (HAdV) in vitro by binding capsid proteins and blocking endosomal escape of virus. In humans, the alpha defensin HD5 is produced by specialized epithelial cells of the gastrointestinal and genito-urinary tracts. Here, we demonstrate, using patient biopsy specimens, that HD5 is also expressed as an active, secreted peptide by epithelial ovarian and lung cancer cells in situ This finding prompted us to study the role of HD5 in infection and spread of replication-competent, oncolytic HAdV type 3 (HAdV3). HAdV3 produces large amounts of penton-dodecahedra (PtDd), virus-like particles, during replication. We have previously shown that PtDd are involved in opening epithelial junctions, thus facilitating lateral spread of de novo-produced virions. Here, we describe a second function of PtDd, namely, the blocking of HD5. A central tool to prove that viral PtDd neutralize HD5 and support spread of progeny virus was an HAdV3 mutant virus in which formation of PtDd was disabled (mut-Ad3GFP, where GFP is green fluorescent protein). We demonstrated that viral spread of mut-Ad3GFP was blocked by synthetic HD5 whereas that of the wild-type (wt) form (wt-Ad3GFP) was only minimally impacted. In human colon cancer Caco-2 cells, induction of cellular HD5 expression by fibroblast growth factor 9 (FGF9) significantly inhibited viral spread and progeny virus production of mut-Ad3GFP but not of wt Ad3GFP. Finally, the ectopic expression of HD5 in tumor cells diminished the in vivo oncolytic activity of mut-Ad3GFP but not of wt-Ad3GFP. These data suggest a new mechanism of HAdV3 to overcome innate antiviral host responses. Our study has implications for oncolytic adenovirus therapy.IMPORTANCE Previously, it has been reported that human defensin HD5 inactivates specific human adenoviruses by binding to capsid proteins and blocking endosomal escape of virus. The central new findings described in our manuscript are the following: (i) the discovery of a new mechanism used by human adenovirus serotype 3 to overcome innate antiviral host responses that is based on the capacity of HAdV3 to produce subviral penton dodecahedral particles that act as decoys for HD5, thus preventing the inactivation of virus progeny produced upon replication; (ii) the demonstration that ectopic HD5 expression in cancer cells decreases the oncolytic efficacy of a serotype 5-based adenovirus vector; and (iii) the demonstration that epithelial ovarian and lung cancers express HD5. The study improves our understanding of how adenoviruses establish infection in epithelial tissues and has implications for cancer therapy with oncolytic adenoviruses. PMID- 28077643 TI - Efficient Vpu-Mediated Tetherin Antagonism by an HIV-1 Group O Strain. AB - Simian immunodeficiency viruses (SIVs) use their Nef proteins to counteract the restriction factor tetherin. However, a deletion in human tetherin prevents antagonism by the Nef proteins of SIVcpz and SIVgor, which represent the ape precursors of human immunodeficiency virus type 1 (HIV-1). To promote virus release from infected cells, pandemic HIV-1 group M strains evolved Vpu as a tetherin antagonist, while the Nef protein of less widespread HIV-1 group O strains acquired the ability to target a region adjacent to this deletion. In this study, we identified an unusual HIV-1 group O strain (RBF206) that evolved Vpu as an effective antagonist of human tetherin. While both RBF206 Vpu and Nef exert anti-tetherin activity in transient-transfection assays, mainly Vpu promotes RBF206 release in infected CD4+ T cells. Although mutations distinct from the adaptive changes observed in group M Vpus (M-Vpus) were critical for the acquisition of its anti-tetherin activity, RBF206 O-Vpu potently suppresses NF kappaB activation and reduces CD4 cell surface expression. Interestingly, RBF206 Vpu counteracts tetherin in a largely species-independent manner, degrading both the long and short isoforms of human tetherin. Downmodulation of CD4, but not counteraction of tetherin, by RBF206 Vpu was dependent on the cellular ubiquitin ligase machinery. Our data present the first example of an HIV-1 group O Vpu that efficiently antagonizes human tetherin and suggest that counteraction by O-Nefs may be suboptimal.IMPORTANCE Previous studies showed that HIV-1 groups M and O evolved two alternative strategies to counteract the human ortholog of the restriction factor tetherin. While HIV-1 group M switched from Nef to Vpu due to a deletion in the cytoplasmic domain of human tetherin, HIV-1 group O, which lacks Vpu-mediated anti-tetherin activity, acquired a Nef protein that is able to target a region adjacent to the deletion. Here we report an unusual exception, identifying a strain of HIV-1 group O (RBF206) whose Vpu protein evolved an effective antagonism of human tetherin. Interestingly, the adaptive changes in RBF206 Vpu are distinct from those found in M-Vpus and mediate efficient counteraction of both the long and short isoforms of this restriction factor. Our results further illustrate the enormous flexibility of HIV-1 in counteracting human defense mechanisms. PMID- 28077644 TI - Ultrasensitive HIV-1 p24 Assay Detects Single Infected Cells and Differences in Reservoir Induction by Latency Reversal Agents. AB - The existence of HIV reservoirs in infected individuals under combined antiretroviral therapy (cART) represents a major obstacle toward cure. Viral reservoirs are assessed by quantification of HIV nucleic acids, a method which does not discriminate between infectious and defective viruses, or by viral outgrowth assays, which require large numbers of cells and long-term cultures. Here, we used an ultrasensitive p24 digital assay, which we report to be 1,000 fold more sensitive than classical enzyme-linked immunosorbent assays (ELISAs) in the quantification of HIV-1 Gag p24 production in samples from HIV-infected individuals. Results from ultrasensitive p24 assays were compared to those from conventional viral RNA reverse transcription-quantitative PCR (RT-qPCR)-based assays and from outgrowth assay readout by flow cytometry. Using serial dilutions and flow-based single-cell sorting, we show that viral proteins produced by a single infected cell can be detected by the ultrasensitive p24 assay. This unique sensitivity allowed the early (as soon as day 1 in 43% of cases) and more efficient detection and quantification of p24 in phytohemagglutinin-L (PHA) stimulated CD4+ T cells from individuals under effective cART. When seven different classes of latency reversal agents (LRA) in resting CD4+ T cells from HIV-infected individuals were tested, the ultrasensitive p24 assay revealed differences in the extent of HIV reactivation. Of note, HIV RNA production was infrequently accompanied by p24 protein production (19%). Among the drugs tested, prostratin showed a superior capacity in inducing viral protein production. In summary, the ultrasensitive p24 assay allows the detection and quantification of p24 produced by single infected CD4+ T cells and provides a unique tool to assess early reactivation of infectious virus from reservoirs in HIV-infected individuals.IMPORTANCE The persistence of HIV reservoirs in infected individuals under effective antiretroviral treatment represents a major obstacle toward cure. Different methods to estimate HIV reservoirs exist, but there is currently no optimal assay to measure HIV reservoirs in HIV eradication interventions. In the present study, we report an ultrasensitive digital ELISA platform for quantification of the HIV-1 protein p24. This method was employed to assess the early reactivation of infectious virus from reservoirs in HIV-1-infected individuals. We found that viral proteins produced by a single infected cell can be detected by an ultrasensitive p24 assay. This unprecedented resolution showed major advantages in comparison to other techniques currently used to assess viral replication in reactivation studies. In addition, such a highly sensitive assay allows discrimination of drug-induced reactivation of productive HIV based on protein expression. The present study heralds new opportunities to evaluate the HIV reservoir and the efficacy of drugs used to target it. PMID- 28077645 TI - Herpes Simplex Virus 1 Abrogates the cGAS/STING-Mediated Cytosolic DNA-Sensing Pathway via Its Virion Host Shutoff Protein, UL41. AB - Cyclic GMP-AMP synthase (cGAS) is a key DNA sensor capable of detecting microbial DNA and activating the adaptor protein stimulator of interferon genes (STING), leading to interferon (IFN) production and host antiviral responses. Cells exhibited reduced type I IFN production in response to cytosolic DNA in the absence of cGAS. Although the cGAS/STING-mediated DNA-sensing signal is crucial for host defense against many viruses, especially for DNA viruses, few viral components have been identified to specifically target this signaling pathway. Herpes simplex virus 1 (HSV-1) is a DNA virus that has evolved multiple strategies to evade host immune responses. In the present study, we found that HSV-1 tegument protein UL41 was involved in counteracting the cGAS/STING-mediated DNA-sensing pathway. Our results showed that wild-type (WT) HSV-1 infection could inhibit immunostimulatory DNA-induced activation of the IFN signaling pathway compared with the UL41-null mutant virus (R2621), and ectopic expression of UL41 decreased cGAS/STING-mediated IFN-beta promoter activation and IFN-beta production. Further study indicated that UL41 reduced the accumulation of cGAS to abrogate host recognition of viral DNA. In addition, stable knockdown of cGAS facilitated the replication of R2621 but not WT HSV-1. For the first time, HSV-1 UL41 was demonstrated to evade the cGAS/STING-mediated DNA-sensing pathway by degrading cGAS via its RNase activity.IMPORTANCE HSV-1 is well known for its ability to evade host antiviral responses and establish a lifelong latent infection while triggering reactivation and lytic infection under stress. Currently, whether HSV-1 evades the cytosolic DNA sensing and signaling is still poorly understood. In the present study, we found that tegument protein UL41 targeted the cGAS/STING-mediated cellular DNA-sensing pathway by selectively degrading cGAS mRNA. Knockdown of endogenous cGAS could facilitate the replication of R2621 but not WT HSV-1. Furthermore, UL41 was shown for the first time to act directly on cGAS. Findings in this study could provide new insights into the host-virus interaction and help develop new approaches against HSV-1. PMID- 28077646 TI - Adenovirus Modulates Toll-Like Receptor 4 Signaling by Reprogramming ORP1L-VAP Protein Contacts for Cholesterol Transport from Endosomes to the Endoplasmic Reticulum. AB - Human adenoviruses (Ads) generally cause mild self-limiting infections but can lead to serious disease and even be fatal in high-risk individuals, underscoring the importance of understanding how the virus counteracts host defense mechanisms. This study had two goals. First, we wished to determine the molecular basis of cholesterol homeostatic responses induced by the early region 3 membrane protein RIDalpha via its direct interaction with the sterol-binding protein ORP1L, a member of the evolutionarily conserved family of oxysterol-binding protein (OSBP)-related proteins (ORPs). Second, we wished to determine how this interaction regulates innate immunity to adenovirus. ORP1L is known to form highly dynamic contacts with endoplasmic reticulum-resident VAP proteins that regulate late endosome function under regulation of Rab7-GTP. Our studies have demonstrated that ORP1L-VAP complexes also support transport of LDL-derived cholesterol from endosomes to the endoplasmic reticulum, where it was converted to cholesteryl esters stored in lipid droplets when ORP1L was bound to RIDalpha. The virally induced mechanism counteracted defects in the predominant cholesterol transport pathway regulated by the late endosomal membrane protein Niemann-Pick disease type C protein 1 (NPC1) arising during early stages of viral infection. However, unlike NPC1, RIDalpha did not reconstitute transport to endoplasmic reticulum pools that regulate SREBP transcription factors. RIDalpha-induced lipid trafficking also attenuated proinflammatory signaling by Toll-like receptor 4, which has a central role in Ad pathogenesis and is known to be tightly regulated by cholesterol-rich "lipid rafts." Collectively, these data show that RIDalpha utilizes ORP1L in a way that is distinct from its normal function in uninfected cells to fine-tune lipid raft cholesterol that regulates innate immunity to adenovirus in endosomes.IMPORTANCE Early region 3 proteins encoded by human adenoviruses that attenuate immune-mediated pathology have been a particularly rich source of information regarding intracellular protein trafficking. Our studies with the early region 3-encoded RIDalpha protein also provided fundamental new information regarding mechanisms of nonvesicular lipid transport and the flow of molecular information at membrane contacts between different organelles. We describe a new pathway that delivers cholesterol from endosomes to the endoplasmic reticulum, where it is esterified and stored in lipid droplets. Although lipid droplets are attracting renewed interest from the standpoint of normal physiology and human diseases, including those resulting from viral infections, experimental model systems for evaluating how and why they accumulate are still limited. Our studies also revealed an intriguing relationship between lipid droplets and innate immunity that may represent a new paradigm for viruses utilizing these organelles. PMID- 28077647 TI - Sensitive Next-Generation Sequencing Method Reveals Deep Genetic Diversity of HIV 1 in the Democratic Republic of the Congo. AB - As the epidemiological epicenter of the human immunodeficiency virus (HIV) pandemic, the Democratic Republic of the Congo (DRC) is a reservoir of circulating HIV strains exhibiting high levels of diversity and recombination. In this study, we characterized HIV specimens collected in two rural areas of the DRC between 2001 and 2003 to identify rare strains of HIV. The env gp41 region was sequenced and characterized for 172 HIV-positive specimens. The env sequences were predominantly subtype A (43.02%), but 7 other subtypes (33.14%), 20 circulating recombinant forms (CRFs; 11.63%), and 20 unclassified (11.63%) sequences were also found. Of the rare and unclassified subtypes, 18 specimens were selected for next-generation sequencing (NGS) by a modified HIV-switching mechanism at the 5' end of the RNA template (SMART) method to obtain full-genome sequences. NGS produced 14 new complete genomes, which included pure subtype C (n = 2), D (n = 1), F1 (n = 1), H (n = 3), and J (n = 1) genomes. The two subtype C genomes and one of the subtype H genomes branched basal to their respective subtype branches but had no evidence of recombination. The remaining 6 genomes were complex recombinants of 2 or more subtypes, including subtypes A1, F, G, H, J, and K and unclassified fragments, including one subtype CRF25 isolate, which branched basal to all CRF25 references. Notably, all recombinant subtype H fragments branched basal to the H clade. Spatial-geographical analysis indicated that the diverse sequences identified here did not expand globally. The full genome and subgenomic sequences identified in our study population significantly increase the documented diversity of the strains involved in the continually evolving HIV-1 pandemic.IMPORTANCE Very little is known about the ancestral HIV-1 strains that founded the global pandemic, and very few complete genome sequences are available from patients in the Congo Basin, where HIV-1 expanded early in the global pandemic. By sequencing a subgenomic fragment of the HIV-1 envelope from study participants in the DRC, we identified rare variants for complete genome sequencing. The basal branching of some of the complete genome sequences that we recovered suggests that these strains are more closely related to ancestral HIV-1 strains than to previously reported strains and is evidence that the local diversification of HIV in the DRC continues to outpace the diversity of global strains decades after the emergence of the pandemic. PMID- 28077648 TI - Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor. AB - The cytidine deaminase APOBEC3B (A3B) underlies the genetic heterogeneity of several human cancers, including cervical cancer, which is caused by human papillomavirus (HPV) infection. We previously identified a region within the A3B promoter that is activated by the viral protein HPV16 E6 in human keratinocytes. Here, we discovered three sites recognized by the TEAD family of transcription factors within this region of the A3B promoter. Reporter assays in HEK293 cells showed that exogenously expressed TEAD4 induced A3B promoter activation through binding to these sites. Normal immortalized human keratinocytes expressing E6 (NIKS-E6) displayed increased levels of TEAD1/4 protein compared to parental NIKS. A series of E6 mutants revealed that E6-mediated degradation of p53 was important for increasing TEAD4 levels. Knockdown of TEADs in NIKS-E6 significantly reduced A3B mRNA levels, whereas ectopic expression of TEAD4 in NIKS increased A3B mRNA levels. Finally, chromatin immunoprecipitation assays demonstrated increased levels of TEAD4 binding to the A3B promoter in NIKS-E6 compared to NIKS. Collectively, these results indicate that E6 induces upregulation of A3B through increased levels of TEADs, highlighting the importance of the TEAD-A3B axis in carcinogenesis.IMPORTANCE The expression of APOBEC3B (A3B), a cellular DNA cytidine deaminase, is upregulated in various human cancers and leaves characteristic, signature mutations in cancer genomes, suggesting that it plays a prominent role in carcinogenesis. Viral oncoproteins encoded by human papillomavirus (HPV) and polyomavirus have been reported to induce A3B expression, implying the involvement of A3B upregulation in virus associated carcinogenesis. However, the molecular mechanisms causing A3B upregulation remain unclear. Here, we demonstrate that exogenous expression of the cellular transcription factor TEAD activates the A3B promoter. Further, the HPV oncoprotein E6 increases the levels of endogenous TEAD1/4 protein, thereby leading to A3B upregulation. Since increased levels of TEAD4 are frequently observed in many cancers, an understanding of the direct link between TEAD and A3B upregulation is of broad oncological interest. PMID- 28077649 TI - T-Cell Receptor (TCR) Clonotype-Specific Differences in Inhibitory Activity of HIV-1 Cytotoxic T-Cell Clones Is Not Mediated by TCR Alone. AB - Functional analysis of T-cell responses in HIV-infected individuals has indicated that virus-specific CD8+ T cells with superior antiviral efficacy are well represented in HIV-1 controllers but are rare or absent in HIV-1 progressors. To define the role of individual T-cell receptor (TCR) clonotypes in differential antiviral CD8+ T-cell function, we performed detailed functional and mass cytometric cluster analysis of multiple CD8+ T-cell clones recognizing the identical HLA-B*2705-restricted HIV-1 epitope KK10 (KRWIILGLNK). Effective and ineffective CD8+ T-cell clones segregated based on responses to HIV-1-infected and peptide-loaded target cells. Following cognate peptide stimulation, effective HIV-specific clones displayed significantly more rapid TCR signal propagation, more efficient initial lytic granule release, and more sustained nonlytic cytokine and chemokine secretion than ineffective clones. To evaluate the TCR clonotype contribution to CD8+ T-cell function, we cloned the TCR alpha and beta chain genes from one effective and two ineffective CD8+ T-cell clones from an elite controller into TCR-expressing lentivectors. We show that Jurkat/MA cells and primary CD8+ T cells transduced with lentivirus expressing TCR from one of the ineffective clones exhibited a level of activation by cognate peptide and inhibition of in vitro HIV-1 infection, respectively, that were comparable to those of the effective clonotype. Taken together, these data suggest that the potent antiviral capacity of some HIV-specific CD8+ T cells is a consequence of factors in addition to TCR sequence that modulate functionality and contribute to the increased antiviral capacity of HIV-specific CD8+ T cells in elite controllers to inhibit HIV infection.IMPORTANCE The greater ex vivo antiviral inhibitory activity of CD8+ T cells from elite controllers than from HIV-1 progressors supports the crucial role of effective HIV-specific CD8+ T cells in controlling HIV-1 replication. The contribution of TCR clonotype to inhibitory potency was investigated by delineating the responsiveness of effective and ineffective CD8+ T-cell clones recognizing the identical HLA-B*2705-restricted HIV-1 Gag-derived peptide, KK10 (KRWIILGLNK). KK10-stimulated "effective" CD8+ T cell clones displayed significantly more rapid TCR signal propagation, more efficient initial lytic granule release, and more sustained cytokine and chemokine secretion than "ineffective" CD8+ T-cell clones. However, TCRs cloned from an effective and one of two ineffective clones conferred upon primary CD8+ T cells the equivalent potent capacity to inhibit HIV-1 infection. Taken together, these data suggest that other factors aside from intrinsic TCR-peptide-major histocompatibility complex (TCR-peptide-MHC) reactivity can contribute to the potent antiviral capacity of some HIV-specific CD8+ T-cell clones. PMID- 28077650 TI - Melanin or a Melanin-Like Substance Interacts with the N-Terminal Portion of Prion Protein and Inhibits Abnormal Prion Protein Formation in Prion-Infected Cells. AB - Prion diseases are progressive fatal neurodegenerative illnesses caused by the accumulation of transmissible abnormal prion protein (PrP). To find treatments for prion diseases, we searched for substances from natural resources that inhibit abnormal PrP formation in prion-infected cells. We found that high molecular-weight components from insect cuticle extracts reduced abnormal PrP levels. The chemical nature of these components was consistent with that of melanin. In fact, synthetic melanin produced from tyrosine or 3-hydroxy-l tyrosine inhibited abnormal PrP formation. Melanin did not modify cellular or cell surface PrP levels, nor did it modify lipid raft or cellular cholesterol levels. Neither did it enhance autophagy or lysosomal function. Melanin was capable of interacting with PrP at two N-terminal domains. Specifically, it strongly interacted with the PrP region of amino acids 23 to 50 including a positively charged amino acid cluster and weakly interacted with the PrP octarepeat peptide region of residues 51 to 90. However, the in vitro and in vivo data were inconsistent with those of prion-infected cells. Abnormal PrP formation in protein misfolding cyclic amplification was not inhibited by melanin. Survival after prion infection was not significantly altered in albino mice or exogenously melanin-injected mice compared with that of control mice. These data suggest that melanin, a main determinant of skin color, is not likely to modify prion disease pathogenesis, even though racial differences in the incidence of human prion diseases have been reported. Thus, the findings identify an interaction between melanin and the N terminus of PrP, but the pathophysiological roles of the PrP melanin interaction remain unclear.IMPORTANCE The N-terminal region of PrP is reportedly important for neuroprotection, neurotoxicity, and abnormal PrP formation, as this region is bound by many factors, such as metal ions, lipids, nucleic acids, antiprion compounds, and several proteins, including abnormal PrP in prion disease and the Abeta oligomer in Alzheimer's disease. In the present study, melanin, a main determinant of skin color, was newly found to interact with this N-terminal region and inhibits abnormal PrP formation in prion-infected cells. However, the data for prion infection in mice lacking melanin production suggest that melanin is not associated with the prion disease mechanism, although the incidence of prion disease is reportedly much higher in white people than in black people. Thus, the roles of the PrP-melanin interaction remain to be further elucidated, but melanin might be a useful competitive tool for evaluating the functions of other ligands at the N-terminal region. PMID- 28077651 TI - BRD4 Couples NF-kappaB/RelA with Airway Inflammation and the IRF-RIG-I Amplification Loop in Respiratory Syncytial Virus Infection. AB - The airway mucosa expresses protective interferon (IFN) and inflammatory cytokines in response to respiratory syncytial virus (RSV) infection. In this study, we examine the role of bromodomain containing 4 (BRD4) in mediating this innate immune response in human small airway epithelial cells. We observe that RSV induces BRD4 to complex with NF-kappaB/RelA. BRD4 is functionally required for expression of the NF-kappaB-dependent inflammatory gene regulatory network (GRN), including the IFN response factor 1 (IRF1) and IRF7, which mediate a cross talk pathway for RIG-I upregulation. Mechanistically, BRD4 is required for cyclin dependent kinase 9 (CDK9) recruitment and phospho-Ser 2 carboxy-terminal domain (CTD) RNA polymerase (Pol) II formation on the promoters of IRF1, IRF7, and RIG I, producing their enhanced expression by transcriptional elongation. We also find that BRD4 independently regulates CDK9/phospho-Ser 2 CTD RNA Pol II recruitment to the IRF3-dependent IFN-stimulated genes (ISGs). In vivo, poly(I.C) induced neutrophilia and mucosal chemokine production are blocked by a small molecule BRD4 bromodomain inhibitor. Similarly, BRD4 inhibition reduces RSV induced neutrophilia, mucosal CXC chemokine expression, activation of the IRF7 RIG-I autoamplification loop, mucosal IFN expression, and airway obstruction. RSV infection activates BRD4 acetyltransferase activity on histone H3 Lys (K) 122, demonstrating that RSV infection activates BRD4 in vivo These data validate BRD4 as a major effector of RSV-induced inflammation and disease. BRD4 is required for coupling NF-kappaB to expression of inflammatory genes and the IRF-RIG-I autoamplification pathway and independently facilitates antiviral ISG expression. BRD4 inhibition may be a strategy to reduce exuberant virus-induced mucosal airway inflammation.IMPORTANCE In the United States, 2.1 million children annually require medical attention for RSV infections. A first line of defense is the expression of the innate gene network by infected epithelial cells. Expression of the innate response requires the recruitment of transcriptional elongation factors to rapidly induce innate response genes through an unknown mechanism. We discovered that RSV infection induces a complex of bromodomain containing 4 (BRD4) with NF-kappaB and cyclin-dependent kinase 9 (CDK9). BRD4 is required for stable CDK9 binding, phospho-Ser 2 RNA Pol II formation, and histone acetyltransferase activity. Inhibition of BRD4 blocks Toll-like receptor 3 (TLR3) dependent neutrophilia and RSV-induced inflammation, demonstrating its importance in the mucosal innate response in vivo Our study shows that BRD4 plays a central role in inflammation and activation of the IRF7-RIG-I amplification loop vital for mucosal interferon expression. BRD4 inhibition may be a strategy for modulating exuberant mucosal airway inflammation. PMID- 28077652 TI - Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells. AB - Fibrogenic pathways in the liver are principally regulated by activation of hepatic stellate cells (HSC). Fibrosis is associated with chronic hepatitis C virus (HCV) infection, although the mechanism is poorly understood. HSC comprise the major population of nonparenchymal cells in the liver. Since HCV does not replicate in HSC, we hypothesized that exosomes secreted from HCV-infected hepatocytes activate HSC. Primary or immortalized human hepatic stellate (LX2) cells were exposed to exosomes derived from HCV-infected hepatocytes (HCV-exo), and the expression of fibrosis-related genes was examined. Our results demonstrated that HCV-exo internalized to HSC and increased the expression of profibrotic markers. Further analysis suggested that HCV-exo carry miR-19a and target SOCS3 in HSC, which in turn activates the STAT3-mediated transforming growth factor beta (TGF-beta) signaling pathway and enhances fibrosis marker genes. The higher expression of miR-19a in exosomes was also observed from HCV infected hepatocytes and in sera of chronic HCV patients with fibrosis compared to healthy volunteers and non-HCV-related liver disease patients with fibrosis. Together, our results demonstrated that miR-19a carried through the exosomes from HCV-infected hepatocytes activates HSC by modulating the SOCS-STAT3 axis. Our results implicated a novel mechanism of exosome-mediated intercellular communication in the activation of HSC for liver fibrosis in HCV infection.IMPORTANCE HCV-associated liver fibrosis is a critical step for end stage liver disease progression. However, the molecular mechanisms for hepatic stellate-cell activation by HCV-infected hepatocytes are underexplored. Here, we provide a role for miR-19a carried through the exosomes in intercellular communication between HCV-infected hepatocytes and HSC in fibrogenic activation. Furthermore, we demonstrate the role of exosomal miR-19a in activation of the STAT3-TGF-beta pathway in HSC. This study contributes to the understanding of intercellular communication in the pathogenesis of liver disease during HCV infection. PMID- 28077653 TI - Characterizing HIV-1 Splicing by Using Next-Generation Sequencing. AB - Full-length human immunodeficiency virus type 1 (HIV-1) RNA serves as the genome or as an mRNA, or this RNA undergoes splicing using four donors and 10 acceptors to create over 50 physiologically relevant transcripts in two size classes (1.8 kb and 4 kb). We developed an assay using Primer ID-tagged deep sequencing to quantify HIV-1 splicing. Using the lab strain NL4-3, we found that A5 (env/nef) is the most commonly used acceptor (about 50%) and A3 (tat) the least used (about 3%). Two small exons are made when a splice to acceptor A1 or A2 is followed by activation of donor D2 or D3, and the high-level use of D2 and D3 dramatically reduces the amount of vif and vpr transcripts. We observed distinct patterns of temperature sensitivity of splicing to acceptors A1 and A2. In addition, disruption of a conserved structure proximal to A1 caused a 10-fold reduction in all transcripts that utilized A1. Analysis of a panel of subtype B transmitted/founder viruses showed that splicing patterns are conserved, but with surprising variability of usage. A subtype C isolate was similar, while a simian immunodeficiency virus (SIV) isolate showed significant differences. We also observed transsplicing from a downstream donor on one transcript to an upstream acceptor on a different transcript, which we detected in 0.3% of 1.8-kb RNA reads. There were several examples of splicing suppression when the env intron was retained in the 4-kb size class. These results demonstrate the utility of this assay and identify new examples of HIV-1 splicing regulation. IMPORTANCE During HIV-1 replication, over 50 conserved spliced RNA variants are generated. The splicing assay described here uses new developments in deep-sequencing technology combined with Primer ID-tagged cDNA primers to efficiently quantify HIV-1 splicing at a depth that allows even low-frequency splice variants to be monitored. We have used this assay to examine several features of HIV-1 splicing and to identify new examples of different mechanisms of regulation of these splicing patterns. This splicing assay can be used to explore in detail how HIV-1 splicing is regulated and, with moderate throughput, could be used to screen for structural elements, small molecules, and host factors that alter these relatively conserved splicing patterns. PMID- 28077654 TI - Neutralization of Diverse Human Cytomegalovirus Strains Conferred by Antibodies Targeting Viral gH/gL/pUL128-131 Pentameric Complex. AB - Human cytomegalovirus (HCMV) is the leading cause of congenital viral infection, and developing a prophylactic vaccine is of high priority to public health. We recently reported a replication-defective human cytomegalovirus with restored pentameric complex glycoprotein H (gH)/gL/pUL128-131 for prevention of congenital HCMV infection. While the quantity of vaccine-induced antibody responses can be measured in a viral neutralization assay, assessing the quality of such responses, including the ability of vaccine-induced antibodies to cross neutralize the field strains of HCMV, remains a challenge. In this study, with a panel of neutralizing antibodies from three healthy human donors with natural HCMV infection or a vaccinated animal, we mapped eight sites on the dominant virus-neutralizing antigen-the pentameric complex of glycoprotein H (gH), gL, and pUL128, pUL130, and pUL131. By evaluating the site-specific antibodies in vaccine immune sera, we demonstrated that vaccination elicited functional antiviral antibodies to multiple neutralizing sites in rhesus macaques, with quality attributes comparable to those of CMV hyperimmune globulin. Furthermore, these immune sera showed antiviral activities against a panel of genetically distinct HCMV clinical isolates. These results highlighted the importance of understanding the quality of vaccine-induced antibody responses, which includes not only the neutralizing potency in key cell types but also the ability to protect against the genetically diverse field strains.IMPORTANCE HCMV is the leading cause of congenital viral infection, and development of a preventive vaccine is a high public health priority. To understand the strain coverage of vaccine-induced immune responses in comparison with natural immunity, we used a panel of broadly neutralizing antibodies to identify the immunogenic sites of a dominant viral antigen-the pentameric complex. We further demonstrated that following vaccination of a replication-defective virus with the restored pentameric complex, rhesus macaques can develop broadly neutralizing antibodies targeting multiple immunogenic sites of the pentameric complex. Such analyses of site specific antibody responses are imperative to our assessment of the quality of vaccine-induced immunity in clinical studies. PMID- 28077655 TI - Expression of Ifnlr1 on Intestinal Epithelial Cells Is Critical to the Antiviral Effects of Interferon Lambda against Norovirus and Reovirus. AB - Lambda interferon (IFN-lambda) has potent antiviral effects against multiple enteric viral pathogens, including norovirus and rotavirus, in both preventing and curing infection. Because the intestine includes a diverse array of cell types, however, the cell(s) upon which IFN-lambda acts to exert its antiviral effects is unclear. Here, we sought to identify IFN-lambda-responsive cells by generation of mice with lineage-specific deletion of the receptor for IFN-lambda, Ifnlr1 We found that expression of IFNLR1 on intestinal epithelial cells (IECs) in the small intestine and colon is required for enteric IFN-lambda antiviral activity. IEC Ifnlr1 expression also determines the efficacy of IFN-lambda in resolving persistent murine norovirus (MNoV) infection and regulates fecal shedding and viral titers in tissue. Thus, the expression of Ifnlr1 by IECs is necessary for the response to both endogenous and exogenous IFN-lambda. We further demonstrate that IEC Ifnlr1 expression is required for the sterilizing innate immune effects of IFN-lambda by extending these findings in Rag1-deficient mice. Finally, we assessed whether our findings pertained to multiple viral pathogens by infecting mice specifically lacking IEC Ifnlr1 expression with reovirus. These mice phenocopied Ifnlr1-null animals, exhibiting increased intestinal tissue titers and enhanced reovirus fecal shedding. Thus, IECs are the critical cell type responding to IFN-lambda to control multiple enteric viruses. This is the first genetic evidence that supports an essential role for IECs in IFN-lambda-mediated control of enteric viral infection, and these findings provide insight into the mechanism of IFN-lambda-mediated antiviral activity.IMPORTANCE Human noroviruses (HNoVs) are the leading cause of epidemic gastroenteritis worldwide. Type III interferons (IFN-lambda) control enteric viral infections in the gut and have been shown to cure mouse norovirus, a small animal model for HNoVs. Using a genetic approach with conditional knockout mice, we identified IECs as the dominant IFN-lambda-responsive cells in control of enteric virus infection in vivo Upon murine norovirus or reovirus infection, Ifnlr1 depletion in IECs largely recapitulated the phenotype seen in Ifnlr1-/- mice of higher intestinal tissue viral titers and increased viral shedding in the stool. Moreover, IFN-lambda-mediated sterilizing immunity against murine norovirus requires the capacity of IECs to respond to IFN-lambda. These findings clarify the mechanism of action of this cytokine and emphasize the therapeutic potential of IFN-lambda for treating mucosal viral infections. PMID- 28077656 TI - Hierarchical and Redundant Roles of Activating FcgammaRs in Protection against Influenza Disease by M2e-Specific IgG1 and IgG2a Antibodies. AB - The ectodomain of matrix protein 2 is a universal influenza A virus vaccine candidate that provides protection through antibody-dependent effector mechanisms. Here we compared the functional engagement of Fcgamma receptor (FcgammaR) family members by two M2e-specific monoclonal antibodies (MAbs), MAb 37 (IgG1) and MAb 65 (IgG2a), which recognize a similar epitope in M2e with similar affinities. The binding of MAb 65 to influenza A virus-infected cells triggered all three activating mouse Fcgamma receptors in vitro, whereas MAb 37 activated only FcgammaRIII. The passive transfer of MAb 37 or MAb 65 in wild type, Fcer1g-/-, Fcgr3-/-, and Fcgr1-/-Fcgr3-/- BALB/c mice revealed the importance of these receptors for protection against influenza A virus challenge, with a clear requirement of FcgammaRIII for IgG1 MAb 37 being found. We also report that FcgammaRIV contributes to protection by M2e-specific IgG2a antibodies.IMPORTANCE There is increased awareness that protection by antibodies directed against viral antigens is also mediated by the Fc domain of these antibodies. These Fc-mediated effector functions are often missed in clinical assays, which are used, for example, to define correlates of protection induced by vaccines. The use of antibodies to prevent and treat infectious diseases is on the rise and has proven to be a promising approach in our battle against newly emerging viral infections. It is now also realized that Fcgamma receptors significantly enhance the in vivo protective effect of broadly neutralizing antibodies directed against the conserved parts of the influenza virus hemagglutinin. We show here that two M2e-specific monoclonal antibodies with close to identical antigen-binding specificities and affinities have a very different in vivo protective potential that is controlled by their capacity to interact with activating Fcgamma receptors. PMID- 28077657 TI - Latent Membrane Protein 1 (LMP1) and LMP2A Collaborate To Promote Epstein-Barr Virus-Induced B Cell Lymphomas in a Cord Blood-Humanized Mouse Model but Are Not Essential. AB - Epstein-Barr virus (EBV) infection is associated with B cell lymphomas in humans. The ability of EBV to convert human B cells into long-lived lymphoblastoid cell lines (LCLs) in vitro requires the collaborative effects of EBNA2 (which hijacks Notch signaling), latent membrane protein 1 (LMP1) (which mimics CD40 signaling), and EBV-encoded nuclear antigen 3A (EBNA3A) and EBNA3C (which inhibit oncogene induced senescence and apoptosis). However, we recently showed that an LMP1 deleted EBV mutant induces B cell lymphomas in a newly developed cord blood humanized mouse model that allows EBV-infected B cells to interact with CD4 T cells (the major source of CD40 ligand). Here we examined whether the EBV LMP2A protein, which mimics constitutively active B cell receptor signaling, is required for EBV-induced lymphomas in this model. We find that the deletion of LMP2A delays the onset of EBV-induced lymphomas but does not affect the tumor phenotype or the number of tumors. The simultaneous deletion of both LMP1 and LMP2A results in fewer tumors and a further delay in tumor onset. Nevertheless, the LMP1/LMP2A double mutant induces lymphomas in approximately half of the infected animals. These results indicate that neither LMP1 nor LMP2A is absolutely essential for the ability of EBV to induce B cell lymphomas in the cord blood-humanized mouse model, although the simultaneous loss of both LMP1 and LMP2A decreases the proportion of animals developing tumors and increases the time to tumor onset. Thus, the expression of either LMP1 or LMP2A may be sufficient to promote early-onset EBV-induced tumors in this model.IMPORTANCE EBV causes human lymphomas, but few models are available for dissecting how EBV causes lymphomas in vivo in the context of a host immune response. We recently used a newly developed cord blood-humanized mouse model to show that EBV can cooperate with human CD4 T cells to cause B cell lymphomas even when a major viral transforming protein, LMP1, is deleted. Here we examined whether the EBV protein LMP2A, which mimics B cell receptor signaling, is required for EBV induced lymphomas in this model. We find that the deletion of LMP2A alone has little effect on the ability of EBV to cause lymphomas but delays tumor onset. The deletion of both LMP1 and LMP2A results in a smaller number of lymphomas in infected animals, with an even more delayed time to tumor onset. These results suggest that LMP1 and LMP2A collaborate to promote early-onset lymphomas in this model, but neither protein is absolutely essential. PMID- 28077658 TI - A Cytoplasmic RNA Virus Alters the Function of the Cell Splicing Protein SRSF2. AB - To replicate efficiently, viruses must create favorable cell conditions and overcome cell antiviral responses. We previously reported that the reovirus protein MU2 from strain T1L, but not strain T3D, represses one antiviral response: alpha/beta interferon signaling. We report here that T1L, but not T3D, MU2 localizes to nuclear speckles, where it forms a complex with the mRNA splicing factor SRSF2 and alters its subnuclear localization. Reovirus replicates in cytoplasmic viral factories, and there is no evidence that reovirus genomic or messenger RNAs are spliced, suggesting that T1L MU2 might target splicing of cell RNAs. Indeed, RNA sequencing revealed that reovirus T1L, but not T3D, infection alters the splicing of transcripts for host genes involved in mRNA posttranscriptional modifications. Moreover, depletion of SRSF2 enhanced reovirus replication and cytopathic effect, suggesting that T1L MU2 modulation of splicing benefits the virus. This provides the first report of viral antagonism of the splicing factor SRSF2 and identifies the viral protein that determines strain specific differences in cell RNA splicing.IMPORTANCE Efficient viral replication requires that the virus create favorable cell conditions. Many viruses accomplish this by repressing specific antiviral responses. We demonstrate here that some mammalian reoviruses, RNA viruses that replicate strictly in the cytoplasm, express a protein variant that localizes to nuclear speckles, where it targets a cell mRNA splicing factor. Infection with a reovirus strain that targets this splicing factor alters splicing of cell mRNAs involved in the maturation of many other cell mRNAs. Depletion of this cell splicing factor enhances reovirus replication and cytopathic effect. Our results provide the first evidence of viral antagonism of this splicing factor and suggest that downstream consequences to the cell are global and benefit the virus. PMID- 28077659 TI - HIV Controllers Exhibit Enhanced Frequencies of Major Histocompatibility Complex Class II Tetramer+ Gag-Specific CD4+ T Cells in Chronic Clade C HIV-1 Infection. AB - Immune control of viral infections is heavily dependent on helper CD4+ T cell function. However, the understanding of the contribution of HIV-specific CD4+ T cell responses to immune protection against HIV-1, particularly in clade C infection, remains incomplete. Recently, major histocompatibility complex (MHC) class II tetramers have emerged as a powerful tool for interrogating antigen specific CD4+ T cells without relying on effector functions. Here, we defined the MHC class II alleles for immunodominant Gag CD4+ T cell epitopes in clade C virus infection, constructed MHC class II tetramers, and then used these to define the magnitude, function, and relation to the viral load of HIV-specific CD4+ T cell responses in a cohort of untreated HIV clade C-infected persons. We observed significantly higher frequencies of MHC class II tetramer-positive CD4+ T cells in HIV controllers than progressors (P = 0.0001), and these expanded Gag-specific CD4+ T cells in HIV controllers showed higher levels of expression of the cytolytic proteins granzymes A and B. Importantly, targeting of the immunodominant Gag41 peptide in the context of HLA class II DRB1*1101 was associated with HIV control (r = -0.5, P = 0.02). These data identify an association between HIV-specific CD4+ T cell targeting of immunodominant Gag epitopes and immune control, particularly the contribution of a single class II MHC-peptide complex to the immune response against HIV-1 infection. Furthermore, these results highlight the advantage of the use of class II tetramers in evaluating HIV-specific CD4+ T cell responses in natural infections.IMPORTANCE Increasing evidence suggests that virus-specific CD4+ T cells contribute to the immune-mediated control of clade B HIV-1 infection, yet there remains a relative paucity of data regarding the role of HIV-specific CD4+ T cells in shaping adaptive immune responses in individuals infected with clade C, which is responsible for the majority of HIV infections worldwide. Understanding the contribution of HIV-specific CD4+ T cell responses in clade C infection is particularly important for developing vaccines that would be efficacious in sub Saharan Africa, where clade C infection is dominant. Here, we employed MHC class II tetramers designed to immunodominant Gag epitopes and used them to characterize CD4+ T cell responses in HIV-1 clade C infection. Our results demonstrate an association between the frequency of HIV-specific CD4+ T cell responses targeting an immunodominant DRB1*11-Gag41 complex and HIV control, highlighting the important contribution of a single class II MHC-peptide complex to the immune response against HIV-1 infections. PMID- 28077660 TI - Muscle spindles in human tibialis anterior encode muscle fascicle length changes. AB - Muscle spindles provide exquisitely sensitive proprioceptive information regarding joint position and movement. Through passively driven length changes in the muscle-tendon unit (MTU), muscle spindles detect joint rotations because of their in-parallel mechanical linkage to muscle fascicles. In human microneurography studies, muscle fascicles are assumed to follow the MTU and, as such, fascicle length is not measured in such studies. However, under certain mechanical conditions, compliant structures can act to decouple the fascicles, and, therefore, the spindles, from the MTU. Such decoupling may reduce the fidelity by which muscle spindles encode joint position and movement. The aim of the present study was to measure, for the first time, both the changes in firing of single muscle spindle afferents and changes in muscle fascicle length in vivo from the tibialis anterior muscle (TA) during passive rotations about the ankle. Unitary recordings were made from 15 muscle spindle afferents supplying TA via a microelectrode inserted into the common peroneal nerve. Ultrasonography was used to measure the length of an individual fascicle of TA. We saw a strong correlation between fascicle length and firing rate during passive ankle rotations of varying rates (0.1-0.5 Hz) and amplitudes (1-9 degrees ). In particular, we saw responses observed at relatively small changes in muscle length that highlight the sensitivity of the TA muscle to small length changes. This study is the first to measure spindle firing and fascicle dynamics in vivo and provides an experimental basis for further understanding the link between fascicle length, MTU length, and spindle firing patterns.NEW & NOTEWORTHY Muscle spindles are exquisitely sensitive to changes in muscle length, but recordings from human muscle spindle afferents are usually correlated with joint angle rather than muscle fascicle length. In this study, we monitored both muscle fascicle length and spindle firing from the human tibialis anterior muscle in vivo. Our findings are the first to measure these signals in vivo and provide an experimental basis for exploring this link further. PMID- 28077661 TI - Characterizing differential poststroke corticomotor drive to the dorsi- and plantarflexor muscles during resting and volitional muscle activation. AB - Imbalance of corticomotor excitability between the paretic and nonparetic limbs has been associated with the extent of upper extremity motor recovery poststroke, is greatly influenced by specific testing conditions such as the presence or absence of volitional muscle activation, and may vary across muscle groups. However, despite its clinical importance, poststroke corticomotor drive to lower extremity muscles has not been thoroughly investigated. Additionally, whereas conventional gait rehabilitation strategies for stroke survivors focus on paretic limb foot drop and dorsiflexion impairments, most contemporary literature has indicated that paretic limb propulsion and plantarflexion impairments are the most significant limiters to poststroke walking function. The purpose of this study was to compare corticomotor excitability of the dorsi- and plantarflexor muscles during resting and active conditions in individuals with good and poor poststroke walking recovery and in neurologically intact controls. We found that plantarflexor muscles showed reduced corticomotor symmetry between paretic and nonparetic limbs compared with dorsiflexor muscles in individuals with poor poststroke walking recovery during active muscle contraction but not during rest. Reduced plantarflexor corticomotor symmetry during active muscle contraction was a result of reduced corticomotor drive to the paretic muscles and enhanced corticomotor drive to the nonparetic muscles compared with the neurologically intact controls. These results demonstrate that atypical corticomotor drive exists in both the paretic and nonparetic lower limbs and implicate greater severity of corticomotor impairments to plantarflexor vs. dorsiflexor muscles during muscle activation in stroke survivors with poor walking recovery.NEW & NOTEWORTHY The present study observed that lower-limb corticomotor asymmetry resulted from both reduced paretic and enhanced nonparetic limb corticomotor excitability compared with neurologically intact controls. The most asymmetrical corticomotor drive was observed in the plantarflexor muscles of individuals with poor poststroke walking recovery. This suggests that neural function of dorsi- and plantarflexor muscles in both paretic and nonparetic limbs may play a role in poststroke walking function, which may have important implications when developing targeted poststroke rehabilitation programs to improve walking ability. PMID- 28077662 TI - Stability and plasticity in neural encoding of linguistically relevant pitch patterns. AB - While lifelong language experience modulates subcortical encoding of pitch patterns, there is emerging evidence that short-term training introduced in adulthood also shapes subcortical pitch encoding. Here we use a cross-language design to examine the stability of language experience-dependent subcortical plasticity over multiple days. We then examine the extent to which behavioral relevance induced by sound-to-category training leads to plastic changes in subcortical pitch encoding in adulthood relative to adolescence, a period of ongoing maturation of subcortical and cortical auditory processing. Frequency following responses (FFRs), which reflect phase-locked activity from subcortical neural ensembles, were elicited while participants passively listened to pitch patterns reflective of Mandarin tones. In experiment 1, FFRs were recorded across three consecutive days from native Chinese-speaking (n = 10) and English-speaking (n = 10) adults. In experiment 2, FFRs were recorded from native English-speaking adolescents (n = 20) and adults (n = 15) before, during, and immediately after a session of sound-to-category training, as well as a day after training ceased. Experiment 1 demonstrated the stability of language experience-dependent subcortical plasticity in pitch encoding across multiple days of passive exposure to linguistic pitch patterns. In contrast, experiment 2 revealed an enhancement in subcortical pitch encoding that emerged a day after the sound-to-category training, with some developmental differences observed. Taken together, these findings suggest that behavioral relevance is a critical component for the observation of plasticity in the subcortical encoding of pitch.NEW & NOTEWORTHY We examine the timescale of experience-dependent auditory plasticity to linguistically relevant pitch patterns. We find extreme stability in lifelong experience-dependent plasticity. We further demonstrate that subcortical function in adolescents and adults is modulated by a single session of sound-to-category training. Our results suggest that behavioral relevance is a necessary ingredient for neural changes in pitch encoding to be observed throughout human development. These findings contribute to the neurophysiological understanding of long- and short-term experience-dependent modulation of pitch. PMID- 28077663 TI - Temporally precise control of single-neuron spiking by juxtacellular nanostimulation. AB - Temporal patterns of action potentials influence a variety of activity-dependent intra- and intercellular processes and play an important role in theories of neural coding. Elucidating the mechanisms underlying these phenomena requires imposing spike trains with precisely defined patterns, but this has been challenging due to the limitations of existing stimulation techniques. Here we present a new nanostimulation method providing control over the action potential output of individual cortical neurons. Spikes are elicited through the juxtacellular application of short-duration fluctuating currents ("kurzpulses"), allowing for the sub-millisecond precise and reproducible induction of arbitrary patterns of action potentials at all physiologically relevant firing frequencies (<120 Hz), including minute-long spike trains recorded in freely moving animals. We systematically compared our method to whole cell current injection, as well as optogenetic stimulation, and show that nanostimulation performance compares favorably with these techniques. This new nanostimulation approach is easily applied, can be readily performed in awake behaving animals, and thus promises to be a powerful tool for systematic investigations into the temporal elements of neural codes, as well as the mechanisms underlying a wide variety of activity dependent cellular processes.NEW & NOTEWORTHY Assessing the impact of temporal features of neuronal spike trains requires imposing arbitrary patterns of spiking on individual neurons during behavior, but this has been difficult to achieve due to limitations of existing stimulation methods. We present a technique that overcomes these limitations by using carefully designed short-duration fluctuating juxtacellular current injections, which allow for the precise and reliable evocation of arbitrary patterns of neuronal spikes in single neurons in vivo. PMID- 28077664 TI - In monkeys making value-based decisions, amygdala neurons are sensitive to cue value as distinct from cue salience. AB - Neurons in the lateral intraparietal (LIP) area of macaque monkey parietal cortex respond to cues predicting rewards and penalties of variable size in a manner that depends on the motivational salience of the predicted outcome (strong for both large reward and large penalty) rather than on its value (positive for large reward and negative for large penalty). This finding suggests that LIP mediates the capture of attention by salient events and does not encode value in the service of value-based decision making. It leaves open the question whether neurons elsewhere in the brain encode value in the identical task. To resolve this issue, we recorded neuronal activity in the amygdala in the context of the task employed in the LIP study. We found that responses to reward-predicting cues were similar between areas, with the majority of reward-sensitive neurons responding more strongly to cues that predicted large reward than to those that predicted small reward. Responses to penalty-predicting cues were, however, markedly different. In the amygdala, unlike LIP, few neurons were sensitive to penalty size, few penalty-sensitive neurons favored large over small penalty, and the dependence of firing rate on penalty size was negatively correlated with its dependence on reward size. These results indicate that amygdala neurons encoded cue value under circumstances in which LIP neurons exhibited sensitivity to motivational salience. However, the representation of negative value, as reflected in sensitivity to penalty size, was weaker than the representation of positive value, as reflected in sensitivity to reward size.NEW & NOTEWORTHY This is the first study to characterize amygdala neuronal responses to cues predicting rewards and penalties of variable size in monkeys making value-based choices. Manipulating reward and penalty size allowed distinguishing activity dependent on motivational salience from activity dependent on value. This approach revealed in a previous study that neurons of the lateral intraparietal (LIP) area encode motivational salience. Here, it reveals that amygdala neurons encode value. The results establish a sharp functional distinction between the two areas. PMID- 28077665 TI - Spatial cognition in a virtual reality home-cage extension for freely moving rodents. AB - Virtual reality (VR) environments are a powerful tool to investigate brain mechanisms involved in the behavior of animals. With this technique, animals are usually head fixed or secured in a harness, and training for cognitively more complex VR paradigms is time consuming. A VR apparatus allowing free animal movement and the constant operator-independent training of tasks would enable many new applications. Key prospective usages include brain imaging of animal behavior when carrying a miniaturized mobile device such as a fluorescence microscope or an optetrode. Here, we introduce the Servoball, a spherical VR treadmill based on the closed-loop tracking of a freely moving animal and feedback counterrotation of the ball. Furthermore, we present the complete integration of this experimental system with the animals' group home cage, from which single individuals can voluntarily enter through a tunnel with radio frequency identification (RFID)-automated access control and commence experiments. This automated animal sorter functions as a mechanical replacement of the experimenter. We automatically trained rats using visual or acoustic cues to solve spatial cognitive tasks and recorded spatially modulated entorhinal cells. When electrophysiological extracellular recordings from awake behaving rats were performed, head fixation can dramatically alter results, so that any complex behavior that requires head movement is impossible to achieve. We circumvented this problem with the use of the Servoball in open-field scenarios, as it allows the combination of open-field behavior with the recording of nerve cells, along with all the flexibility that a virtual environment brings. This integrated home cage with a VR arena experimental system permits highly efficient experimentation for complex cognitive experiments.NEW & NOTEWORTHY Virtual reality (VR) environments are a powerful tool for the investigation of brain mechanisms. We introduce the Servoball, a VR treadmill for freely moving rodents. The Servoball is integrated with the animals' group home cage. Single individuals voluntarily enter using automated access control. Training is highly time efficient, even for cognitively complex VR paradigms. PMID- 28077666 TI - Motor plan differs for young and older adults during similar movements. AB - Older adults exhibit altered activation of the agonist and antagonist muscles during goal-directed movements compared with young adults. However, it remains unclear whether the differential activation of the antagonistic muscles in older adults results from an impaired motor plan or an altered ability of the muscle to contract. The purpose of this study, therefore, was to determine whether the motor plan differs for young and older adults. Ten young (26.1 +/- 4.3 yr, 4 women) and 16 older adults (71.9 +/- 6.9 yr, 9 women) participated in the study. Participants performed 100 trials of fast goal directed movements with ankle dorsiflexion while we recorded the electromyographic activity of the primary agonist (tibialis anterior; TA) and antagonist (soleus; SOL) muscles. From those 100 trials we selected 5 trials in each of 3 movement end-point categories (fast, accurate, and slow). We investigated age-associated differences in the motor plan by quantifying the individual activity and coordination of the agonist and antagonist muscles. During similar movement end points, older adults exhibited similar activation of the agonist (TA) and antagonist (SOL) muscles compared with young adults. In addition, the coordination of the agonist and antagonist muscles (TA and SOL) was different between the two age groups. Specifically, older adults exhibited lower TA-SOL overlap (F1,23 = 41.2, P < 0.001) and greater TA-SOL peak EMG delay (F1,25 = 35.5, P < 0.001). This finding suggests that although subjects in both age groups displayed similar movement end points, they exhibited a different motor plan, as demonstrated by altered coordination between the agonist and antagonist muscles.NEW & NOTEWORTHY We aimed to determine whether the altered activation of muscles in older adults compared with young adults during fast goal directed movements is related to an altered motor plan. For matched movements, there were differences in the coordination of antagonistic muscles but no differences in the individual activation of muscles. We provide novel evidence that the differential activation of muscles in older adults is related to an altered motor plan. PMID- 28077667 TI - Role of the cerebellum in high stages of motor planning hierarchy. AB - Motor planning is not a monolithic process, and distinct stages of motor planning are responsible for encoding different levels of abstractness. However, how these distinct components are mapped into different neural substrates remains an open question. We studied one of these high-level motor planning components, defined as second-order motor planning, in a patient (R.G.) with an extremely rare case of cerebellar agenesis but without any other cortical malformations. Second-order motor planning dictates that when two acts must be performed sequentially, planning of the second act can influence execution of the first. We used an optoelectronic system for kinematic analysis to compare R.G.'s performance with age-matched controls in a second-order motor planning task. The first act was to reach for an object, and the second was to place it into a small or large container. Our results showed that despite the expected difficulties in fine motor skills, second-order motor planning (i.e., the ability to modulate the first act as a function of the nature of the second act) was preserved even in the patient with congenital absence of the cerebellum. These results open new intriguing speculations about the role of the cerebellum in motor planning abilities. Although prudence is imperative when suggesting conclusions made on the basis of single-case findings, this evidence suggests fascinating hypotheses about the neural circuits that support distinct stages of the motor planning hierarchy, and regarding the functional role of second-order motor planning in motor cognition and its potential dysfunction in autism.NEW & NOTEWORTHY Traditionally, the cerebellum was considered essential for motor planning. By studying an extremely rare patient with cerebellar agenesis and a group of neurotypical controls, we found that high stages of the motor planning hierarchy can be preserved even in this patient with congenital absence of the cerebellum. Our results provide interesting insights that shed light on the neural circuits supporting distinct levels of motor planning. Furthermore, the results are intriguing because of their potential clinical implications in autism. PMID- 28077668 TI - Auditory adaptation improves tactile frequency perception. AB - Our ability to process temporal frequency information by touch underlies our capacity to perceive and discriminate surface textures. Auditory signals, which also provide extensive temporal frequency information, can systematically alter the perception of vibrations on the hand. How auditory signals shape tactile processing is unclear; perceptual interactions between contemporaneous sounds and vibrations are consistent with multiple neural mechanisms. Here we used a crossmodal adaptation paradigm, which separated auditory and tactile stimulation in time, to test the hypothesis that tactile frequency perception depends on neural circuits that also process auditory frequency. We reasoned that auditory adaptation effects would transfer to touch only if signals from both senses converge on common representations. We found that auditory adaptation can improve tactile frequency discrimination thresholds. This occurred only when adaptor and test frequencies overlapped. In contrast, auditory adaptation did not influence tactile intensity judgments. Thus auditory adaptation enhances touch in a frequency- and feature-specific manner. A simple network model in which tactile frequency information is decoded from sensory neurons that are susceptible to auditory adaptation recapitulates these behavioral results. Our results imply that the neural circuits supporting tactile frequency perception also process auditory signals. This finding is consistent with the notion of supramodal operators performing canonical operations, like temporal frequency processing, regardless of input modality.NEW & NOTEWORTHY Auditory signals can influence the tactile perception of temporal frequency. Multiple neural mechanisms could account for the perceptual interactions between contemporaneous auditory and tactile signals. Using a crossmodal adaptation paradigm, we found that auditory adaptation causes frequency- and feature-specific improvements in tactile perception. This crossmodal transfer of aftereffects between audition and touch implies that tactile frequency perception relies on neural circuits that also process auditory frequency. PMID- 28077669 TI - Preparatory alpha-band oscillations reflect spatial gating independently of predictions regarding target identity. AB - Preparatory modulations of cortical alpha-band oscillations are a reliable index of the voluntary allocation of covert spatial attention. It is currently unclear whether attentional cues containing information about a target's identity (such as its visual orientation), in addition to its location, might additionally shape preparatory alpha modulations. Here, we explore this question by directly comparing spatial and feature-based attention in the same visual detection task while recording brain activity using magnetoencephalography (MEG). At the behavioral level, preparatory feature-based and spatial attention cues both improved performance and did so independently of each other. Using MEG, we replicated robust alpha lateralization following spatial cues: in preparation for a visual target, alpha power decreased contralaterally and increased ipsilaterally to the attended location. Critically, however, preparatory alpha lateralization was not significantly modulated by predictions regarding target identity, as carried via the behaviorally effective feature-based attention cues. Furthermore, nonlateralized alpha power during the cue-target interval did not differentiate between uninformative cues and cues carrying feature-based predictions either. Based on these results we propose that preparatory alpha modulations play a role in the gating of information between spatially segregated cortical regions and are therefore particularly well suited for spatial gating of information.NEW & NOTEWORTHY The present work clarifies if and how human brain oscillations in the alpha-band support multiple types of anticipatory attention. Using magnetoencephalography, we show that posterior alpha-band oscillations are modulated by predictions regarding the spatial location of an upcoming visual target, but not by feature-based predictions regarding its identity, despite robust behavioral benefits. This provides novel insights into the functional role of preparatory alpha mechanisms and suggests a limited specificity with which they may operate. PMID- 28077670 TI - The mammalian efferent vestibular system plays a crucial role in vestibulo-ocular reflex compensation after unilateral labyrinthectomy. AB - The alpha9-nicotinic acetylcholine receptor (alpha9-nAChR) subunit is expressed in the vestibular and auditory periphery, and its loss of function could compromise peripheral input from the predominantly cholinergic efferent vestibular system (EVS). A recent study has shown that alpha9-nAChRs play an important role in short-term vestibulo-ocular reflex (VOR) adaptation. We hypothesize that alpha9-nAChRs could also be important for other forms of vestibular plasticity, such as that needed for VOR recovery after vestibular organ injury. We measured the efficacy of VOR compensation in alpha9 knockout mice. These mice have deletion of most of the gene (chrna9) encoding the nAChR and thereby lack alpha9-nAChRs. We measured the VOR gain (eye velocity/head velocity) in 20 alpha9 knockout mice and 16 cba129 controls. We measured the sinusoidal (0.2-10 Hz, 20-100 degrees /s) and transient (1,500-6,000 degrees /s2) VOR in complete darkness before (baseline) unilateral labyrinthectomy (UL) and then 1, 5, and 28 days after UL. On day 1 after UL, cba129 mice retained ~50% of their initial function for contralesional rotations, whereas alpha9 knockout mice only retained ~20%. After 28 days, alpha9 knockout mice had ~50% lower gain for both ipsilesional and contralesional rotations compared with cba129 mice. Cba129 mice regained ~75% of their baseline function for ipsilesional and ~90% for contralesional rotations. In contrast, alpha9 knockout mice only regained ~30% and ~50% function, respectively, leaving the VOR severely impaired for rotations in both directions. Our results show that loss of alpha9-nAChRs severely affects VOR compensation, suggesting that complimentary central and peripheral EVS mediated adaptive mechanisms might be affected by this loss.NEW & NOTEWORTHY Loss of the alpha9-nicotinic acetylcholine receptor (alpha9-nAChR) subunit utilized by the efferent vestibular system (EVS) has been shown to significantly affect vestibulo-ocular reflex (VOR) adaptation. In our present study we have shown that loss of alpha9-nAChRs also affects VOR compensation, suggesting that the mammalian EVS plays an important role in vestibular plasticity, in general, and that VOR compensation is a more distributed process than previously thought, relying on both central and peripheral changes. PMID- 28077671 TI - Impact of long-term care facility residence on the antibiotic resistance of urinary tract Escherichia coli and Klebsiella. AB - Background: Long-term care facilities (LTCFs) are thought to be important reservoirs of antimicrobial-resistant (AMR) bacteria; however, there is no routine surveillance of resistance in LTCF residents, or large population-based studies comparing AMR in LTCFs with the community, so the relative burden of AMR in LTCFs remains unknown. Objectives: To compare the frequency of antibiotic resistance of urinary tract bacteria from residents of LTCFs for the elderly and adults aged 70 years or older living in the community. Methods: Positive urine specimens reported to any diagnostic microbiology laboratory in the West Midlands region (England) from 1 April 2010 to 31 March 2014 collected from individuals aged 70 years or older were analysed. The resistance of Escherichia coli and Klebsiella to trimethoprim, nitrofurantoin, third-generation cephalosporins and ciprofloxacin and the rate of laboratory-confirmed E. coli and Klebsiella urinary tract infection (UTI) were assessed in LTCF residents and in the community. Results: LTCF residents had a laboratory-confirmed E. coli and Klebsiella UTI rate of 21 per 100 person years compared with 8 per 100 person years in the elderly living in the community [rate ratio (RR)=2.66, 95% CI = 2.58-2.73] and a higher rate of developing E. coli and Klebsiella UTIs caused by bacteria resistant to trimethoprim (RR = 4.41, 95% CI = 4.25-4.57), nitrofurantoin (RR = 4.38, 95% CI = 3.98-4.83), ciprofloxacin (RR = 5.18, 95% CI = 4.82-5.57) and third-generation cephalosporins (RR = 4.49, 95% CI = 4.08-4.94). Conclusions: Residents of LTCFs for the elderly had more than double the rate of E. coli and Klebsiella UTI and more than four times the rate of E. coli and Klebsiella UTI caused by antibiotic-resistant bacteria compared with those living in the community. PMID- 28077672 TI - Potentiation of ceftazidime by avibactam against beta-lactam-resistant Pseudomonas aeruginosa in an in vitro infection model. AB - Objectives: This study evaluated the in vitro pharmacodynamics of combinations of ceftazidime and the non-beta-lactam beta-lactamase inhibitor, avibactam, against ceftazidime-, piperacillin/tazobactam- and meropenem-multiresistant Pseudomonas aeruginosa by a quantitative time-kill method. Methods: MICs of ceftazidime plus 0-16 mg/L avibactam were determined against eight isolates of P. aeruginosa . Single-compartment, 24 h time-kill kinetics were investigated for three isolates at 0-16 mg/L avibactam with ceftazidime at 0.25-4-fold the MIC as measured at the respective avibactam concentration. Ceftazidime and avibactam concentrations were measured by LC-MS/MS during the time-kill kinetic studies to evaluate drug degradation. Results: Avibactam alone displayed no antimicrobial activity. MICs of ceftazidime decreased by 8-16-fold in the presence of avibactam at 4 mg/L. The changes in log 10 cfu/mL at both the 10 h and 24 h timepoints (versus 0 h) revealed bacterial killing at >=1-fold MIC. Significantly higher concentrations of ceftazidime alone, as compared with those of ceftazidime in combination, were required to produce any given kill. Without avibactam, ceftazidime degradation was significant (defined as degradation t 1/2 < 24 h), with as little as 19% +/- 18% of the original concentration remaining at 8 h for the most resistant strain. In combination with avibactam, ceftazidime degradation at >= 1-fold MIC was negligible. Conclusion: The addition of avibactam protected ceftazidime from degradation in a dose-dependent manner and restored its cidal and static activity at concentrations in combination well below the MIC of ceftazidime alone. PMID- 28077673 TI - Outpatient parenteral antibiotic therapy (OPAT) in Asia: missing an opportunity. AB - Objectives: Healthcare facilities internationally have grown outpatient parenteral antibiotic administration services for the last few decades. The literature contains publications from dozens of countries describing systematized processes with specialist oversight and their levels of service provision and outcomes. Such descriptions are absent in the majority of Asian countries. We sought to elucidate the extent and nature of outpatient parenteral antibiotic therapy (OPAT) in Asia and to consider the ramifications and opportunities for improvement. Methods: Utilizing colleagues and their personal networks, we surveyed healthcare facilities across 17 countries in Asia to ascertain the current means (if any) of providing OPAT. In that survey we also sought to explore the capacity and interest of these facilities in developing systematized OPAT services. Results: Responses were received from 171 different healthcare facilities from 17 countries. Most (97/171, 57%) stated that they administer outpatient parenteral antibiotics, but only 5 of 162 facilities (3%) outside of Singapore described comprehensive services with specialist oversight. Conclusions: There is very likely a large unrecognized problem of unchecked outpatient parenteral antibiotic administration in Asia. Developing comprehensive and systematized OPAT in Asia is needed as a priority in an environment in which the infectious diseases community is demanding broad stewardship approaches. There are nonetheless challenges in establishing and sustaining OPAT programmes. Local champions and leverage off identified local incentives and needs are key to regional advancement. PMID- 28077674 TI - Population structure of Japanese extraintestinal pathogenic Escherichia coli and its relationship with antimicrobial resistance. AB - Objectives: To define the population structure of extraintestinal pathogenic Escherichia coli (ExPEC) in Japan and its relationship with antimicrobial resistance and the major resistance mechanisms for fluoroquinolones and beta lactams, we designed a multicentre prospective study. Methods: A total of 329 ExPEC isolates were collected at 10 Japanese acute-care hospitals during December 2014. We defined the clonal groups of ExPEC by fumC and fimH sequencing (CH typing). Antimicrobial susceptibility testing of 18 agents and the detection of mutations in quinolone resistance-determining regions (QRDRs) and beta-lactamases were performed. Results: Among the study isolates, 103 CH types were found, and CH40-30 (25%) and another 10 CH types (35% in total) constituted the major ExPEC population. Ciprofloxacin non-susceptibility, ESBLs and MDR phenotypes were found in 34%, 22% and 33%, respectively. CH40-30, corresponding to the C/H30 clade of the global pandemic ST131 clone, was associated with four QRDR mutations (100%) and bla CTX-M (60%) and was the most frequent type in 15 antimicrobial-non susceptible populations (dominating 39%-75% of each population, the highest prevalence for ciprofloxacin), the ESBL producers (70%) and the MDR isolates (59%). Isolates that were non-susceptible to nalidixic acid and low-level resistant to ciprofloxacin with one or two QRDR mutations represented 16% of the study isolates and were distributed among the eight major and non-major CH types. Conclusions: More than half of the ExPEC population in Japan consisted of 11 major clones. Of these clones, the CH40-30-ST131-C/H30 clone was the predominant antimicrobial-resistant population. The presence of major clones with low-level ciprofloxacin resistance supports the potential future success of a non-ST131 fluoroquinolone-resistant clone. PMID- 28077675 TI - Post hoc assessment of the immunogenicity of bioengineered factor VIIa demonstrates the use of preclinical tools. AB - Immunogenicity is an important consideration in the licensure of a therapeutic protein because the development of neutralizing anti-drug antibodies (ADAs) can affect both safety and efficacy. Neoantigens introduced by bioengineering of a protein drug are a particular cause for concern. The development of a bioengineered recombinant factor VIIa (rFVIIa) analog was discontinued after phase 3 trials because of the development of ADAs. The unmodified parent molecule (rFVIIa), on the other hand, has been successfully used as a drug for more than two decades with no reports of immunogenicity in congenital hemophilia patients with inhibitors. We used computational and experimental methods to demonstrate that the observed ADAs could have been elicited by neoepitopes in the engineered protein. The human leukocyte antigen type of the patients who developed ADAs is consistent with this hypothesis of a neoepitope-driven immune response, a finding that might have implications for the preclinical screening of therapeutic protein analogs. PMID- 28077676 TI - A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions. AB - Disease relapse after treatment is common in triple-negative breast cancer (TNBC), ovarian cancer (OVCA), and non-small cell lung cancer (NSCLC). Therapies that target tumor-initiating cells (TICs) should improve patient survival by eliminating the cells that can drive tumor recurrence and metastasis. We demonstrate that protein tyrosine kinase 7 (PTK7), a highly conserved but catalytically inactive receptor tyrosine kinase in the Wnt signaling pathway, is enriched on TICs in low-passage TNBC, OVCA, and NSCLC patient-derived xenografts (PDXs). To deliver a potent anticancer drug to PTK7-expressing TICs, we generated a targeted antibody-drug conjugate (ADC) composed of a humanized anti-PTK7 monoclonal antibody, a cleavable valine-citrulline-based linker, and Aur0101, an auristatin microtubule inhibitor. The PTK7-targeted ADC induced sustained tumor regressions and outperformed standard-of-care chemotherapy. Moreover, the ADC specifically reduced the frequency of TICs, as determined by serial transplantation experiments. In addition to reducing the TIC frequency, the PTK7 targeted ADC may have additional antitumor mechanisms of action, including the inhibition of angiogenesis and the stimulation of immune cells. Together, these preclinical data demonstrate the potential for the PTK7-targeted ADC to improve the long-term survival of cancer patients. PMID- 28077678 TI - Disruptive reproductive technologies. AB - In vitro gametogenesis raises new possibilities for reproductive and regenerative medicine as well as vexing policy challenges. PMID- 28077677 TI - Pharmacological rescue of diabetic skeletal stem cell niches. AB - Diabetes mellitus (DM) is a metabolic disease frequently associated with impaired bone healing. Despite its increasing prevalence worldwide, the molecular etiology of DM-linked skeletal complications remains poorly defined. Using advanced stem cell characterization techniques, we analyzed intrinsic and extrinsic determinants of mouse skeletal stem cell (mSSC) function to identify specific mSSC niche-related abnormalities that could impair skeletal repair in diabetic (Db) mice. We discovered that high serum concentrations of tumor necrosis factor alpha directly repressed the expression of Indian hedgehog (Ihh) in mSSCs and in their downstream skeletogenic progenitors in Db mice. When hedgehog signaling was inhibited during fracture repair, injury-induced mSSC expansion was suppressed, resulting in impaired healing. We reversed this deficiency by precise delivery of purified Ihh to the fracture site via a specially formulated, slow-release hydrogel. In the presence of exogenous Ihh, the injury-induced expansion and osteogenic potential of mSSCs were restored, culminating in the rescue of Db bone healing. Our results present a feasible strategy for precise treatment of molecular aberrations in stem and progenitor cell populations to correct skeletal manifestations of systemic disease. PMID- 28077680 TI - Endomicroscope sheds light on cervical tissue. AB - A pilot study of a handheld fluorescence endomicroscope demonstrates both in vivo imaging and differentiation of normal from precancerous cervical tissue. PMID- 28077679 TI - CRISPR-Cas9 gene repair of hematopoietic stem cells from patients with X-linked chronic granulomatous disease. AB - Gene repair of CD34+ hematopoietic stem and progenitor cells (HSPCs) may avoid problems associated with gene therapy, such as vector-related mutagenesis and dysregulated transgene expression. We used CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9 (CRISPR-associated 9) to repair a mutation in the CYBB gene of CD34+ HSPCs from patients with the immunodeficiency disorder X-linked chronic granulomatous disease (X-CGD). Sequence-confirmed repair of >20% of HSPCs from X-CGD patients restored the function of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase and superoxide radical production in myeloid cells differentiated from these progenitor cells in vitro. Transplant of gene-repaired X-CGD HSPCs into NOD (nonobese diabetic) SCID (severe combined immunodeficient) gammac-/- mice resulted in efficient engraftment and production of functional mature human myeloid and lymphoid cells for up to 5 months. Whole-exome sequencing detected no indels outside of the CYBB gene after gene correction. CRISPR-mediated gene editing of HSPCs may be applicable to other CGD mutations and other monogenic disorders of the hematopoietic system. PMID- 28077681 TI - Tune into the rhythm of your bugs. AB - Diurnal changes in gut microbiota localization and function alter host physiology through circadian epigenetic and transcriptional changes. PMID- 28077682 TI - A weighty problem. AB - Altered dopamine signaling in obesity might decrease physical activity without contributing to weight gain. PMID- 28077683 TI - DAMPening the effects of trauma-induced inflammation. AB - Amine-containing polymers immobilized on mesh and placed at trauma sites scavenge biomolecules that initiate a damaging immune response. PMID- 28077684 TI - Targeting Aurora kinase A and JAK2 prevents GVHD while maintaining Treg and antitumor CTL function. AB - Graft-versus-host disease (GVHD) is a leading cause of nonrelapse mortality after allogeneic hematopoietic cell transplantation. T cell costimulation by CD28 contributes to GVHD, but prevention is incomplete when targeting CD28, downstream mammalian target of rapamycin (mTOR), or Aurora A. Likewise, interleukin-6 (IL-6) mediated Janus kinase 2 (JAK2) signaling promotes alloreactivity, yet JAK2 inhibition does not eliminate GVHD. We provide evidence that blocking Aurora A and JAK2 in human T cells is synergistic in vitro, prevents xenogeneic GVHD, and maintains antitumor responses by cytotoxic T lymphocytes (CTLs). Aurora A/JAK2 inhibition is immunosuppressive but permits the differentiation of inducible regulatory T cells (iTregs) that are hyperfunctional and CD39 bright and efficiently scavenge adenosine triphosphate (ATP). Increased iTreg potency is primarily a function of Aurora A blockade, whereas JAK2 inhibition suppresses T helper 17 (TH17) differentiation. Inhibiting either Aurora A or JAK2 significantly suppresses TH1 T cells. However, CTL generated in vivo retains tumor-specific killing despite Aurora A/JAK2 blockade. Thus, inhibiting CD28 and IL-6 signal transduction pathways in donor T cells can increase the Treg/Tconv ratio, prevent GVHD, and preserve antitumor CTL. PMID- 28077685 TI - Working with what you've got: unattractive males show greater mate-guarding effort in a duetting songbird. AB - When mates are limited, individuals should allocate resources to mating tactics that maximize fitness. In species with extra-pair paternity (EPP), males can invest in mate guarding, or, alternatively, in seeking EPP. Males should optimize fitness by adjusting investment according to their attractiveness to females, such that attractive males seek EPP, and unattractive males guard mates. This theory has received little empirical testing, leaving our understanding of the evolution of mating tactics incomplete; it is unclear how a male's relative attractiveness influences his tactics. We conducted observations and experiments on red-backed fairy-wrens (Malurus melanocephalus) to address this question. We found that older, more attractive (red-black) males sought EPP, whereas unattractive (brown) males invested in alternative tactics-physical and acoustic mate guarding. Younger red-black males used intermediate tactics. This suggests that males adopt mating tactics appropriate to their attributes. Males obtained similar reproductive success, suggesting these alternative tactics may maximize each male's paternity gain. Though it is likely that female choice also determines paternity, rather than just male tactics, we establish that the many interconnected components of a male's sexual phenotype influence the evolution of his decision-making rules, deepening our understanding of how mating tactics evolve under sexual selection. PMID- 28077686 TI - Evolution of iris colour in relation to cavity nesting and parental care in passerine birds. AB - Strong selection pressures are known to act on animal coloration. Although many animals vary in eye colour, virtually no research has investigated the functional significance of these colour traits. Passeriformes have a range of iris colours, making them an ideal system to investigate how and why iris colour has evolved. Using phylogenetic comparative methods, we tested the hypothesis that conspicuous iris colour in passerine birds evolved in response to (a) coordination of offspring care and (b) cavity nesting, two traits thought to be involved in intra specific gaze sensitivity. We found that iris colour and cooperative offspring care by two or more individuals evolved independently, suggesting that bright eyes are not important for coordinating parental care through eye gaze. Furthermore, we found that evolution between iris colour and nesting behaviour did occur in a dependent manner, but contrary to predictions, transitions to coloured eyes were not more frequent in cavity nesters than non-cavity nesters. Instead, our results indicate that selection away from having bright eyes was much stronger in non-cavity nesters than cavity nesters, perhaps because conspicuous eye coloration in species not concealed within a cavity would be more visible to predators. PMID- 28077687 TI - Stronger seasonal adjustment in leaf turgor loss point in lianas than trees in an Amazonian forest. AB - Pan-tropically, liana density increases with decreasing rainfall and increasing seasonality. This pattern has led to the hypothesis that lianas display a growth advantage over trees under dry conditions. However, the physiological mechanisms underpinning this hypothesis remain elusive. A key trait influencing leaf and plant drought tolerance is the leaf water potential at turgor loss point (pitlp). pitlp adjusts under drier conditions and this contributes to improved leaf drought tolerance. For co-occurring Amazonian tree (n = 247) and liana (n = 57) individuals measured during the dry and the wet seasons, lianas showed a stronger osmotic adjustment than trees. Liana leaves were less drought-tolerant than trees in the wet season, but reached similar drought tolerances during the dry season. Stronger osmotic adjustment in lianas would contribute to turgor maintenance, a critical prerequisite for carbon uptake and growth, and to the success of lianas relative to trees in growth under drier conditions. PMID- 28077688 TI - Pattern, process, inference and prediction in extinction biology. AB - Extinction is a key feature of the evolutionary history of life, and assessments of extinction risk are essential for the effective protection of biodiversity. The goal in assembling this special issue of Biology Letters was to highlight problems and questions at the research frontier of extinction biology, with an emphasis on recent developments in the methodology of inferring the patterns and processes of extinction from a background of often noisy and sparse data. In selecting topics, we sought to illustrate how extinction is not simply a self evident phenomenon, but the subject of a dynamic and quantitatively rigorous field of natural science, with practical applications to conservation. PMID- 28077689 TI - Giant cell arteritis and vascular disease-risk factors and outcomes: a cohort study using UK Clinical Practice Research Datalink. AB - Objective: To evaluate the associations between GCA and vascular diseases and other comorbidities in patients with GCA compared with non-vasculitis patients. Methods: Using the UK-based Clinical Practice Research Datalink we identified 9778 newly diagnosed GCA patients in 1990-2014, and up to 10 non-vasculitis patients randomly matched to each case on age, sex, practice and years of history before cohort entry. We compared the distributions of 9 different pre-existing vascular diseases and 11 other comorbidities, and risks of incident vascular diseases and other comorbidities after cohort entry between GCA and non vasculitis patients. Results: Patients with GCA were more likely to have a history of vascular diseases and other comorbidities except myocardial infarction, type 2 diabetes, obesity and cancer, compared with non-vasculitis patients. Patients with GCA had increased risks for all types of incident vascular disease compared with non-vasculitis patients: adjusted hazard ratios were 1.57 (95% CI: 1.36, 1.82) for myocardial infarction, 1.41 (95% CI: 1.29, 1.55) for stroke, 1.75 (95% CI: 1.49, 2.06) for peripheral vascular disease, 1.98 (95% CI: 1.50, 2.62) for aortic aneurysm and 2.03 (95% CI: 1.77, 2.33) for venous thromboembolism. Patients with GCA also had increased risks for other incident comorbidities (type 2 diabetes, depression, etc.), but not for cancer. Conclusion: Patients with GCA had more prior vascular diseases and other comorbidities before the diagnosis and they also had increased risks for incident vascular diseases and many other incident comorbidities after the diagnosis compared with non-vasculitis population. PMID- 28077690 TI - Educating people with rare rheumatological conditions. PMID- 28077691 TI - Establishment and baseline characteristics of a nationwide Danish cohort of patients with Ehlers-Danlos syndrome. AB - Objectives: The aim of this study was to investigate national prevalence, general demographic characteristics and survival of Danish patients with Ehlers-Danlos syndrome (EDS). Method: A population-based cohort study was conducted using a database consisting of the entire Danish population alive at any given time between 1 January 2000 and 31 December 2012, based upon longitudinal Danish national registers. All patients with EDS were identified, and the cohort was described by disease prevalence, basic demographic characteristics, mean age at death and mortality for the observational period of 13 years. Results: The cohort held 1427 unique persons with EDS, giving a national prevalence of 0.02%. The EDS population had a mean ( s . d .) age of 34.9 (18.6) years and comprised 73.9% females and 26.1% males. Of the cohort, 95.9% originated from Denmark and 57% were unmarried. We found that 31.6% of the cohort received state-granted subsidies, of which 77% were in the form of early retirement pension. Regarding educational status, 28.1% of the EDS cohort had completed primary education (?10th grade) as their highest educational level, while 71.9% had completed a higher level. During the observation period, 42 patients died, with a mean ( s . d .) age at death of 53.6 (21.7) years. Conclusion: This study confirmed a small national prevalence of patients diagnosed with EDS and showed that the majority of patients diagnosed are female. The EDS cohort had a lower educational level, mean age and life expectancy compared with the background population and showed a predisposition for receiving state-granted subsidies. PMID- 28077692 TI - Reference curves for the Australian/Canadian Hand Osteoarthritis Index in the middle-aged Dutch population. AB - Objective: The aim was to establish reference curves of the Australian/Canadian Hand Osteoarthritis Index (AUSCAN), a widely used questionnaire assessing hand complaints. Methods: Analyses were performed in a population-based sample, The Netherlands Epidemiology of Obesity study (n = 6671, aged 45-65 years). Factors associated with AUSCAN scores were analysed with ordered logistic regression, because AUSCAN data were zero inflated, dividing AUSCAN into three categories (0 vs 1-5 vs >5). Age- and sex-specific reference curves for the AUSCAN (range 0-60; higher is worse) were developed using quantile regression in conjunction with fractional polynomials. Observed scores in relevant subgroups were compared with the reference curves. Results: The median age was 56 [interquartile range (IQR): 50-61] years; 56% were women and 12% had hand OA according to ACR criteria. AUSCAN scores were low (median 1; IQR: 0-4). Reference curves where higher for women, and increased moderately with age: 95% percentiles for AUSCAN in men and women were, respectively, 5.0 and 12.3 points for a 45-year-old, and 15.2 and 33.6 points for a 65-year-old individual. Additional associated factors included hand OA, inflammatory rheumatic diseases, FM, socio-economic status and BMI. Median AUSCAN pain subscale scores of women with hand OA lay between the 75th and 90th centiles of the general population. Conclusion: AUSCAN scores in the middle aged Dutch population were low overall, and higher in women than in men. AUSCAN reference curves could serve as a benchmark in research and clinical practice settings. However, the AUSCAN does not measure hand complaints specific for hand OA. PMID- 28077693 TI - New GRAPPA and EULAR recommendations for the management of psoriatic arthritis. PMID- 28077694 TI - Laboratory Testing of Donors and Stool Samples for Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection. AB - Fecal microbiota transplantation is an efficacious and inexpensive therapy for recurrent Clostridium difficile infection, yet its safety is thought to depend on appropriate fecal donor screening. FDA guidance for regulation of this procedure is in flux, but screening and manufacture of fecal material from asymptomatic donors present many challenges to clinical laboratories. This minireview summarizes FDA regulatory changes, principles of donor selection, and recommended laboratory screening practices for fecal microbiota transplantation. PMID- 28077695 TI - Stability Studies on Dry Swabs and Wet Mailed Swabs for Detection of Chlamydia trachomatis and Neisseria gonorrhoeae in Aptima Assays. AB - The Aptima Combo 2 (AC2) and Aptima CT (ACT) (Hologic Inc., San Diego, CA) are nucleic acid amplification tests (NAATs) that detect Chlamydia trachomatis AC2 also detects Neisseria gonorrhoeae Storage and temperature conditions may impact the utility of NAATs in some settings and screening programs. We evaluated specimen stability for use beyond the Aptima package insert specifications for temperature and duration of storage (between 2 degrees C and 30 degrees C and 60 days, respectively) in two studies: (i) dry C. trachomatis-seeded swabs were used with ACT after storage at 4 degrees C, 23 degrees C, or 36 degrees C for up to 84 days and (ii) swabs seeded with C. trachomatis and N. gonorrhoeae and then placed in transport medium were tested with AC2, after being mailed via the U.S. Postal Service to three different sites. Prolonged storage of samples had no effect, and samples stored at 4 degrees C, 23 degrees C, and 36 degrees C for up to 84 days yielded comparable ACT positivities, although there was a drop in signal intensity for virtually all specimens under all storage/shipping conditions after day 21. In the mailing study, 80%, 52% and 29% of seeded swabs were exposed to temperatures of >30 degrees C during three rounds in transit, and 2% reached temperatures of >40 degrees C. No evidence of signal degradation in the AC2 assay for detection of C. trachomatis or N. gonorrhoeae was observed, although some mailed swabs took more than 5 weeks to reach the laboratory site. These two studies support the potential use of swabs at temperatures above 36 degrees C and storage beyond 60 days and provide confidence regarding this commercially available NAAT for testing of specimens after mailing. PMID- 28077696 TI - A New Development in Trypanosoma cruzi Detection. AB - Chagas disease is caused by the parasite Trypanosoma cruzi and is an important cause of morbidity and mortality in areas of Latin America where Chagas disease is endemic and among infected individuals who have migrated to nonendemic areas of North America and Europe. There are many diagnostic tests that are employed in the serological diagnosis of this infection. In this issue of the Journal of Clinical Microbiology, Bautista-Lopez et al. provide characterization of excretory vesicles (EVs) from Vero cells infected with T. cruzi and provide data on the EVs produced by trypomastigotes and amastigotes (N. L. Bautista-Lopez et al., J Clin Microbiol 55:744-758, 2017, https://doi.org/10.1128/JCM.01649-16). Their proteomic study defines potential targets to evaluate for improved diagnostic tests, effects on host cell biology that contribute to the pathogenesis of infection, and vaccine candidates. If any of the EV-associated proteins identified were to be correlated to cure of infection, this would be a major advance. PMID- 28077697 TI - Point-Counterpoint: What Is the Optimal Approach for Detection of Clostridium difficile Infection? AB - INTRODUCTIONIn 2010, we published an initial Point-Counterpoint on the laboratory diagnosis of Clostridium difficile infection (CDI). At that time, nucleic acid amplification tests (NAATs) were just becoming commercially available, and the idea of algorithmic approaches to CDI was being explored. Now, there are numerous NAATs in the marketplace, and based on recent proficiency test surveys, they have become the predominant method used for CDI diagnosis in the United States. At the same time, there is a body of literature that suggests that NAATs lack clinical specificity and thus inflate CDI rates. Hospital administrators are taking note of institutional CDI rates because they are publicly reported. They have become an important metric impacting hospital safety ratings and value-based purchasing; hospitals may have millions of dollars of reimbursement at risk. In this Point Counterpoint using a frequently asked question approach, Ferric Fang of the University of Washington, who has been a consistent advocate for a NAAT-only approach for CDI diagnosis, will discuss the value of a NAAT-only approach, while Christopher Polage of the University of California Davis and Mark Wilcox of Leeds University, Leeds, United Kingdom, each of whom has recently written important articles on the value of toxin detection in the diagnosis, will discuss the impact of toxin detection in CDI diagnosis. PMID- 28077698 TI - Detection of Antigenic Variants of Subtype H3 Swine Influenza A Viruses from Clinical Samples. AB - A large population of genetically and antigenically diverse influenza A viruses (IAVs) are circulating among the swine population, playing an important role in influenza ecology. Swine IAVs not only cause outbreaks among swine but also can be transmitted to humans, causing sporadic infections and even pandemic outbreaks. Antigenic characterizations of swine IAVs are key to understanding the natural history of these viruses in swine and to selecting strains for effective vaccines. However, influenza outbreaks generally spread rapidly among swine, and the conventional methods for antigenic characterization require virus propagation, a time-consuming process that can significantly reduce the effectiveness of vaccination programs. We developed and validated a rapid, sensitive, and robust method, the polyclonal serum-based proximity ligation assay (polyPLA), to identify antigenic variants of subtype H3N2 swine IAVs. This method utilizes oligonucleotide-conjugated polyclonal antibodies and quantifies antibody antigen binding affinities by quantitative reverse transcription-PCR (RT-PCR). Results showed the assay can rapidly detect H3N2 IAVs directly from nasal wash or nasal swab samples collected from laboratory-challenged animals or during influenza surveillance at county fairs. In addition, polyPLA can accurately separate the viruses at two contemporary swine IAV antigenic clusters (H3N2 swine IAV-alpha and H3N2 swine IAV-beta) with a sensitivity of 84.9% and a specificity of 100.0%. The polyPLA can be routinely used in surveillance programs to detect antigenic variants of influenza viruses and to select vaccine strains for use in controlling and preventing disease in swine. PMID- 28077699 TI - Antimicrobial Susceptibility Patterns among a Large, Nationwide Cohort of Abiotrophia and Granulicatella Clinical Isolates. AB - Antimicrobial susceptibility patterns from 599 A. defectiva, G. adiacens, and G. elegans clinical isolates were determined by broth microdilution. We observed significant differences in susceptibility across species, particularly to penicillin and ceftriaxone, and across geographical regions. A. defectiva was the least susceptible species overall to penicillin. All isolates were susceptible to vancomycin and >90% were susceptible to levofloxacin. PMID- 28077700 TI - Evaluation of Alere i RSV for Rapid Detection of Respiratory Syncytial Virus in Children Hospitalized with Acute Respiratory Tract Infection. AB - Alere i RSV is a novel rapid test which applies a nicking enzyme amplification reaction to detect respiratory syncytial virus in point-of-care settings. In this study, we evaluated the Alere i RSV assay by using frozen nasopharyngeal swab samples that were collected in viral transport medium from children hospitalized with acute respiratory tract infection during the 2015-2016 winter season. Alere i RSV assay results were compared to those for Altona RealStar RSV real-time reverse transcription-PCR (RT-PCR). We found that the overall sensitivity and specificity of the Alere i RSV test was 100% (95% confidence intervals [CI], 93% to 100%) and 97% (95% CI, 89% to 100%), respectively. Positive samples were identified within 5 to 7 min from sample collection. Overall, the Alere i RSV test performed well compared to the RT-PCR assay and has the potential to facilitate the detection of RSV in point-of-care settings. PMID- 28077701 TI - Comparison of 11 Phenotypic Assays for Accurate Detection of Carbapenemase Producing Enterobacteriaceae. AB - Early identification of carbapenemase-producing Enterobacteriaceae (CPE) is essential to prevent their dissemination within health care settings. Our objective was to evaluate the accuracy of 11 phenotypic assays for the detection of CPE. Two collections of carbapenem-resistant Enterobacteriaceae (CRE) isolates were evaluated, including 191 retrospective isolates (122 CP-CRE and 69 non-CP isolates) as well as 45 prospective clinical isolates (15 CP-CRE and 30 non-CP CRE) obtained over a 3-month period. The sensitivity and specificity of each test was determined, with molecular genotype serving as the gold standard. Among the retrospective cohort, sensitivities ranged from 72% for the boronic acid synergy test for the detection of KPC producers to >=98% for the modified Carba NP, the Rapidec Carba NP, the manual Blue Carba, and the modified carbapenem inactivation method for the detection of any CPE. Sensitivity differed among tests across enzyme classes. All assays had excellent specificity exceeding 95%, with the exception of the boronic acid synergy test (88%) and modified Hodge test (91%). Prospectively, 45 CRE isolates were encountered over a 3-month period, including 15 CPE (33%) and 30 non-CP-CRE (67%). Results from the prospective cohort were similar. However, a decrease in specificity was observed across most tests, likely due to restricted inclusion of non-CP-CRE to assess the specificity of the assays. Overall, accuracy of CPE detection varied across phenotypic tests. Local epidemiology of CP genotypes, turnaround time, and ease of incorporation into the laboratory workflow should be considered when selecting a phenotypic assay for clinical use. PMID- 28077702 TI - Direct Submissions from bioRxiv. PMID- 28077703 TI - APP Modulates Abeta-Induced Activation of Microglia in Mouse Model of Alzheimer's Disease. PMID- 28077704 TI - Emerging Evidence for a Direct Link between EAAT-Associated Anion Channels and Neurological Disorders. PMID- 28077705 TI - Processing of Intraoral Olfactory and Gustatory Signals in the Gustatory Cortex of Awake Rats. AB - : The integration of gustatory and olfactory information is essential to the perception of flavor. Human neuroimaging experiments have pointed to the gustatory cortex (GC) as one of the areas involved in mediating flavor perception. Although GC's involvement in encoding the chemical identity and hedonic value of taste stimuli is well studied, it is unknown how single GC neurons process olfactory stimuli emanating from the mouth. In this study, we relied on multielectrode recordings to investigate how single GC neurons respond to intraorally delivered tastants and tasteless odorants dissolved in water and whether/how these two modalities converge in the same neurons. We found that GC neurons could either be unimodal, responding exclusively to taste (taste-only) or odor (odor-only), or bimodal, responding to both gustatory and olfactory stimuli. Odor responses were confirmed to result from retronasal olfaction: monitoring respiration revealed that exhalation preceded odor-evoked activity and reversible inactivation of olfactory receptors in the nasal epithelium significantly reduced responses to intraoral odorants but not to tastants. Analysis of bimodal neurons revealed that they encode palatability significantly better than the unimodal taste-only group. Bimodal neurons exhibited similar responses to palatable tastants and odorants dissolved in water. This result suggested that odorized water could be palatable. This interpretation was further supported with a brief access task, where rats avoided consuming aversive taste stimuli and consumed the palatable tastants and dissolved odorants. These results demonstrate the convergence of the chemosensory components of flavor onto single GC neurons and provide evidence for the integration of flavor with palatability coding. SIGNIFICANCE STATEMENT: Food perception and choice depend upon the concurrent processing of olfactory and gustatory signals from the mouth. The primary gustatory cortex has been proposed to integrate chemosensory stimuli; however, no study has examined the single-unit responses to intraoral odorant presentation. Here we found that neurons in gustatory cortex can respond either exclusively to tastants, exclusively to odorants, or to both (bimodal). Several differences exist between these groups' responses; notably, bimodal neurons code palatability significantly better than unimodal neurons. This group of neurons might represent a substrate for how odorants gain the quality of tastants. PMID- 28077707 TI - Organization of the Claustrum-to-Entorhinal Cortical Connection in Mice. AB - : The claustrum, a subcortical structure situated between the insular cortex and striatum, is reciprocally connected with almost all neocortical regions. Based on this connectivity, the claustrum has been postulated to integrate multisensory information and, in turn, coordinate widespread cortical activity. Although studies have identified how sensory information is mapped onto the claustrum, the function of individual topographically arranged claustro-cortical pathways has been little explored. Here, we investigated the organization and function of identified claustro-cortical pathways in mice using multiple anatomical and optogenetic techniques. Retrograde and anterograde tracing demonstrated that the density of anterior claustrum-to-cortical projection differs substantially depending on the target cortical areas. One of the major targets was the medial entorhinal cortex (MEC) and the MEC-projecting claustral neurons were largely segregated from the neurons projecting to primary cortices M1, S1, or V1. Exposure to a novel environment induced c-Fos expression in a substantial number of MEC-projecting claustral neurons and some M1/S1/V1-projecting claustral neurons. Optogenetic silencing of the MEC-projecting claustral neurons during contextual fear conditioning impaired later memory retrieval without affecting basal locomotor activity or anxiety-related behavior. These results suggest that the dense, anterior claustro-MEC pathway that is largely separated from other claustro-cortical pathways is activated by novel context and modulates the MEC function in contextual memory. SIGNIFICANCE STATEMENT: The claustrum is a poorly understood subcortical structure reciprocally connected with widespread neocortical regions. We investigated the organization and function of identified claustro-cortical projections in mice using pathway-specific approaches. Anatomical tracing showed that the density of anterior claustrum-to-cortical projection is dependent on the target cortical areas and that the medial entorhinal cortex (MEC) is one of the major projection targets. Novel context exposure activated multiple claustro-cortical pathways and a large fraction of the activated neurons projected to the MEC. Optogenetic silencing of the claustro MEC pathway during contextual fear learning suppressed subsequent memory retrieval. These results suggest that the dense claustro-MEC pathway is activated by novel context and modulates MEC function in contextual memory. PMID- 28077708 TI - Dynamic Shifts in Large-Scale Brain Network Balance As a Function of Arousal. AB - : The ability to temporarily prioritize rapid and vigilant reactions over slower higher-order cognitive functions is essential for adaptive responding to threat. This reprioritization is believed to reflect shifts in resource allocation between large-scale brain networks that support these cognitive functions, including the salience and executive control networks. However, how changes in communication within and between such networks dynamically unfold as a function of threat-related arousal remains unknown. To address this issue, we collected functional MRI data and continuously assessed the heart rate from 120 healthy human adults as they viewed emotionally arousing and ecologically valid cinematographic material. We then developed an analysis method that tracks dynamic changes in large-scale network cohesion by quantifying the level of within-network and between-network interaction. We found a monotonically increasing relationship between heart rate, a physiological index of arousal, and within-network cohesion in the salience network, indicating that coordination of activity within the salience network dynamically tracks arousal. Strikingly, salience-executive control between-network cohesion peaked at moderate arousal. These findings indicate that at moderate arousal, which has been associated with optimal noradrenergic signaling, the salience network is optimally able to engage the executive control network to coordinate cognitive activity, but is unable to do so at tonically elevated noradrenergic levels associated with acute stress. Our findings extend neurophysiological models of the effects of stress-related neuromodulatory signaling at the cellular level to large-scale neural systems, and thereby explain shifts in cognitive functioning during acute stress, which may play an important role in the development and maintenance of stress-related mental disorders. SIGNIFICANCE STATEMENT: How does brain functioning change in arousing or stressful situations? Extant literature suggests that through global projections, arousal-related neuromodulatory changes can rapidly alter coordination of neural activity across brain-wide neural systems or large-scale networks. Since it is unknown how such processes unfold, we developed a method to dynamically track levels of within-network and between-network interaction. We applied this technique to human neuroimaging data acquired while participants watched realistic and emotionally arousing cinematographic material. Results demonstrate that cohesion within the salience network monotonically increases with arousal, while cohesion of this network with the executive control network peaks at moderate arousal. Our findings explain how cognitive performance shifts as a function of arousal, and provide new insights into vulnerability for stress related psychopathology. PMID- 28077706 TI - Connexin-Mediated Signaling in Nonsensory Cells Is Crucial for the Development of Sensory Inner Hair Cells in the Mouse Cochlea. AB - : Mutations in the genes encoding for gap junction proteins connexin 26 (Cx26) and connexin 30 (Cx30) have been linked to syndromic and nonsyndromic hearing loss in mice and humans. The release of ATP from connexin hemichannels in cochlear nonsensory cells has been proposed to be the main trigger for action potential activity in immature sensory inner hair cells (IHCs), which is crucial for the refinement of the developing auditory circuitry. Using connexin knock-out mice, we show that IHCs fire spontaneous action potentials even in the absence of ATP-dependent intercellular Ca2+ signaling in the nonsensory cells. However, this signaling from nonsensory cells was able to increase the intrinsic IHC firing frequency. We also found that connexin expression is key to IHC functional maturation. In Cx26 conditional knock-out mice (Cx26Sox10-Cre), the maturation of IHCs, which normally occurs at approximately postnatal day 12, was partially prevented. Although Cx30 has been shown not to be required for hearing in young adult mice, IHCs from Cx30 knock-out mice exhibited a comprehensive brake in their development, such that their basolateral membrane currents and synaptic machinery retain a prehearing phenotype. We propose that IHC functional differentiation into mature sensory receptors is initiated in the prehearing cochlea provided that the expression of either connexin reaches a threshold level. As such, connexins regulate one of the most crucial functional refinements in the mammalian cochlea, the disruption of which contributes to the deafness phenotype observed in mice and DFNB1 patients. SIGNIFICANCE STATEMENT: The correct development and function of the mammalian cochlea relies not only on the sensory hair cells, but also on the surrounding nonsensory cells. Although the nonsensory cells have been largely implicated in the general homeostasis in the mature cochlea, their involvement in the initial functional differentiation of the sensory inner hair cells is less clear. Using mutant mouse models for the most common form of congenital deafness in humans, which are knock-outs for the gap-junction channels connexin 26 and connexin 30 genes, we show that defects in nonsensory cells prevented the functional maturation of inner hair cells. In connexin knock-outs, inner hair cells remained stuck at a prehearing stage of development and, as such, are unable to process sound information. PMID- 28077709 TI - Semantic Congruence Accelerates the Onset of the Neural Signals of Successful Memory Encoding. AB - : As the stream of experience unfolds, our memory system rapidly transforms current inputs into long-lasting meaningful memories. A putative neural mechanism that strongly influences how input elements are transformed into meaningful memory codes relies on the ability to integrate them with existing structures of knowledge or schemas. However, it is not yet clear whether schema-related integration neural mechanisms occur during online encoding. In the current investigation, we examined the encoding-dependent nature of this phenomenon in humans. We showed that actively integrating words with congruent semantic information provided by a category cue enhances memory for words and increases false recall. The memory effect of such active integration with congruent information was robust, even with an interference task occurring right after each encoding word list. In addition, via electroencephalography, we show in 2 separate studies that the onset of the neural signals of successful encoding appeared early (~400 ms) during the encoding of congruent words. That the neural signals of successful encoding of congruent and incongruent information followed similarly ~200 ms later suggests that this earlier neural response contributed to memory formation. We propose that the encoding of events that are congruent with readily available contextual semantics can trigger an accelerated onset of the neural mechanisms, supporting the integration of semantic information with the event input. This faster onset would result in a long-lasting and meaningful memory trace for the event but, at the same time, make it difficult to distinguish it from plausible but never encoded events (i.e., related false memories). SIGNIFICANCE STATEMENT: Conceptual or schema congruence has a strong influence on long-term memory. However, the question of whether schema-related integration neural mechanisms occur during online encoding has yet to be clarified. We investigated the neural mechanisms reflecting how the active integration of words with congruent semantic categories enhances memory for words and increases false recall of semantically related words. We analyzed event related potentials during encoding and showed that the onset of the neural signals of successful encoding appeared early (~400 ms) during the encoding of congruent words. Our findings indicate that congruent events can trigger an accelerated onset of neural encoding mechanisms supporting the integration of semantic information with the event input. PMID- 28077710 TI - Sensory Flow as a Basis for a Novel Distance Cue in Freely Behaving Electric Fish. AB - : The sensory input that an animal receives is directly linked to its motor activity. Behavior thus enables animals to influence their sensory input, a concept referred to as active sensing. How such behavior can serve as a scaffold for generating sensory information is of general scientific interest. In this article, we investigate how behavior can shape sensory information by using some unique features of the sensorimotor system of the weakly electric fish. Based on quantitative behavioral characterizations and computational reconstruction of sensory input, we show how electrosensory flow is actively created during highly patterned, spontaneous behavior in Gnathonemus petersii. The spatiotemporal structure of the sensory input provides information for the computation of a novel distance cue, which allows for a continuous estimation of distance. This has significant advantages over previously known nondynamic distance estimators as determined from electric image blur. Our investigation of the sensorimotor interactions in pulsatile electrolocation shows, for the first time, that the electrosensory flow contains behaviorally relevant information accessible only through active behavior. As patterned sensory behaviors are a shared feature of (active) sensory systems, our results have general implications for the understanding of (active) sensing, with the proposed sensory flow-based measure being potentially pertinent to a broad range of sensory modalities. SIGNIFICANCE STATEMENT: Acquisition of sensory information depends on motion, as either an animal or its sensors move. Behavior can thus actively influence the sensory flow; and in this way, behavior can be seen as a manifestation of the brain's integrative functions. The properties of the active pulsatile electrolocation system in Gnathonemus petersii allow for the sensory input to be computationally reconstructed, enabling us to link the informational content of spatiotemporal sensory dynamics to behavior. Our study reveals a novel sensory cue for estimating depth that is actively generated by the fishes' behavior. The physical and behavioral similarities between electrolocation and other active sensory systems suggest that this may be a mechanism shared by (active) sensory systems. PMID- 28077711 TI - Phase-Amplitude Coupling and Long-Range Phase Synchronization Reveal Frontotemporal Interactions during Visual Working Memory. AB - : It has been suggested that cross-frequency phase-amplitude coupling (PAC), particularly in temporal brain structures, serves as a neural mechanism for coordinated working memory storage. In this magnetoencephalography study, we show that during visual working memory maintenance, temporal cortex regions, which exhibit enhanced PAC, interact with prefrontal cortex via enhanced low-frequency phase synchronization. Healthy human participants were engaged in a visual delayed match-to-sample task with pictures of natural objects. During the delay period, we observed increased spectral power of beta (20-28 Hz) and gamma (40-94 Hz) bands as well as decreased power of theta/alpha band (7-9 Hz) oscillations in visual sensory areas. Enhanced PAC between the phases of theta/alpha and the amplitudes of beta oscillations was found in the left inferior temporal cortex (IT), an area known to be involved in visual object memory. Furthermore, the IT was functionally connected to the prefrontal cortex by increased low-frequency phase synchronization within the theta/alpha band. Together, these results point to a mechanism in which the combination of PAC and long-range phase synchronization subserves enhanced large-scale brain communication. They suggest that distant brain regions might coordinate their activity in the low-frequency range to engage local stimulus-related processing in higher frequencies via the combination of long-range, within-frequency phase synchronization and local cross frequency PAC. SIGNIFICANCE STATEMENT: Working memory maintenance, like other cognitive functions, requires the coordinated engagement of brain areas in local and large-scale networks. However, the mechanisms by which spatially distributed brain regions share and combine information remain primarily unknown. We show that the combination of long-range, low-frequency phase synchronization and local cross-frequency phase-amplitude coupling might serve as a mechanism to coordinate memory processes across distant brain areas. In this study, low-frequency phase synchronization between prefrontal and temporal cortex co-occurred with local cross-frequency phase-amplitude coupling to higher frequencies in the latter. By such means, ongoing working memory storage taking place in higher frequencies in temporal regions might be effectively coordinated by distant frontal brain regions through synchronized activity in the low-frequency range. PMID- 28077712 TI - Changes in Properties of Auditory Nerve Synapses following Conductive Hearing Loss. AB - : Auditory activity plays an important role in the development of the auditory system. Decreased activity can result from conductive hearing loss (CHL) associated with otitis media, which may lead to long-term perceptual deficits. The effects of CHL have been mainly studied at later stages of the auditory pathway, but early stages remain less examined. However, changes in early stages could be important because they would affect how information about sounds is conveyed to higher-order areas for further processing and localization. We examined the effects of CHL at auditory nerve synapses onto bushy cells in the mouse anteroventral cochlear nucleus following occlusion of the ear canal. These synapses, called endbulbs of Held, normally show strong depression in voltage clamp recordings in brain slices. After 1 week of CHL, endbulbs showed even greater depression, reflecting higher release probability. We observed no differences in quantal size between control and occluded mice. We confirmed these observations using mean-variance analysis and the integration method, which also revealed that the number of release sites decreased after occlusion. Consistent with this, synaptic puncta immunopositive for VGLUT1 decreased in area after occlusion. The level of depression and number of release sites both showed recovery after returning to normal conditions. Finally, bushy cells fired fewer action potentials in response to evoked synaptic activity after occlusion, likely because of increased depression and decreased input resistance. These effects appear to reflect a homeostatic, adaptive response of auditory nerve synapses to reduced activity. These effects may have important implications for perceptual changes following CHL. SIGNIFICANCE STATEMENT: Normal hearing is important to everyday life, but abnormal auditory experience during development can lead to processing disorders. For example, otitis media reduces sound to the ear, which can cause long-lasting deficits in language skills and verbal production, but the location of the problem is unknown. Here, we show that occluding the ear causes synapses at the very first stage of the auditory pathway to modify their properties, by decreasing in size and increasing the likelihood of releasing neurotransmitter. This causes synapses to deplete faster, which reduces fidelity at central targets of the auditory nerve, which could affect perception. Temporary hearing loss could cause similar changes at later stages of the auditory pathway, which could contribute to disorders in behavior. PMID- 28077714 TI - Formation of Long-Term Locomotor Memories Is Associated with Functional Connectivity Changes in the Cerebellar-Thalamic-Cortical Network. AB - : Although motor adaptation is typically rapid, accumulating evidence shows that it is also associated with long-lasting behavioral and neuronal changes. Two processes were suggested to explain the formation of long-term motor memories: recall, reflecting a retrieval of previous motor actions, and faster relearning, reflecting an increased sensitivity to errors. Although these manifestations of motor memories were initially demonstrated in the context of adaptation experiments in reaching, indications of long-term motor memories were also demonstrated recently in other kinds of adaptation such as in locomotor adaptation. Little is known about the neural processes that underlie these distinct aspects of memory. We hypothesize that recall and faster relearning reflect different learning processes that operate at the same time and depend on different neuronal networks. Seventeen subjects performed a multisession locomotor adaptation experiment in the laboratory, together with resting-state and localizer fMRI scans, after the baseline and the locomotor adaptation sessions. We report a modulation of the cerebellar-thalamic-cortical and cerebellar-basal ganglia networks after locomotor adaptation. Interestingly, whereas thalamic-cortical baseline connectivity was correlated with recall, cerebellar-thalamic baseline connectivity was correlated with faster relearning. Our results suggest that separate neuronal networks underlie error sensitivity and retrieval components. Individual differences in baseline resting-state connectivity can predict idiosyncratic combination of these components. SIGNIFICANCE STATEMENT: The ability to shape our motor behavior rapidly in everyday activity, such as when walking on sand, suggests the existence of long term motor memories. It was suggested recently that this ability is achieved by the retrieval of previous motor actions and by enhanced relearning capacity. Little is known about the neural mechanisms that underlie these memory processes. We studied the modularity in long-term motor memories in the context of locomotor adaptation using resting-state fMRI. We show that retrieval and relearning effects are associated with separate locomotor control networks and that intersubject variability in learning and in the generation of motor memories could be predicted from baseline resting-state connectivity in locomotor-related networks. PMID- 28077713 TI - Reversible Disruption of Neuronal Mitochondria by Ischemic and Traumatic Injury Revealed by Quantitative Two-Photon Imaging in the Neocortex of Anesthetized Mice. AB - : Mitochondria play a variety of functional roles in cortical neurons, from metabolic support and neuroprotection to the release of cytokines that trigger apoptosis. In dendrites, mitochondrial structure is closely linked to their function, and fragmentation (fission) of the normally elongated mitochondria indicates loss of their function under pathological conditions, such as stroke and brain trauma. Using in vivo two-photon microscopy in mouse brain, we quantified mitochondrial fragmentation in a full spectrum of cortical injuries, ranging from severe to mild. Severe global ischemic injury was induced by bilateral common carotid artery occlusion, whereas severe focal stroke injury was induced by Rose Bengal photosensitization. The moderate and mild traumatic injury was inflicted by focal laser lesion and by mild photo-damage, respectively. Dendritic and mitochondrial structural changes were tracked longitudinally using transgenic mice expressing fluorescent proteins localized either in cytosol or in mitochondrial matrix. In response to severe injury, mitochondrial fragmentation developed in parallel with dendritic damage signified by dendritic beading. Reconstruction from serial section electron microscopy confirmed mitochondrial fragmentation. Unlike dendritic beading, fragmentation spread beyond the injury core in focal stroke and focal laser lesion models. In moderate and mild injury, mitochondrial fragmentation was reversible with full recovery of structural integrity after 1-2 weeks. The transient fragmentation observed in the mild photo damage model was associated with changes in dendritic spine density without any signs of dendritic damage. Our findings indicate that alterations in neuronal mitochondria structure are very sensitive to the tissue damage and can be reversible in ischemic and traumatic injuries. SIGNIFICANCE STATEMENT: During ischemic stroke or brain trauma, mitochondria can either protect neurons by supplying ATP and adsorbing excessive Ca2+, or kill neurons by releasing proapoptotic factors. Mitochondrial function is tightly linked to their morphology: healthy mitochondria are thin and long; dysfunctional mitochondria are thick (swollen) and short (fragmented). To date, fragmentation of mitochondria was studied either in dissociated cultured neurons or in brain slices, but not in the intact living brain. Using real-time in vivo two-photon microscopy, we quantified mitochondrial fragmentation during acute pathological conditions that mimic severe, moderate, and mild brain injury. We demonstrated that alterations in neuronal mitochondria structural integrity can be reversible in traumatic and ischemic injuries, highlighting mitochondria as a potential target for therapeutic interventions. PMID- 28077715 TI - Excitatory Hindbrain-Forebrain Communication Is Required for Cisplatin-Induced Anorexia and Weight Loss. AB - : Cisplatin chemotherapy is commonly used to treat cancer despite severe energy balance side effects. In rats, cisplatin activates nucleus tractus solitarius (NTS) projections to the lateral parabrachial nucleus (lPBN) and calcitonin-gene related peptide (CGRP) projections from the lPBN to the central nucleus of the amygdala (CeA). We demonstrated previously that CeA glutamate receptor signaling mediates cisplatin-induced anorexia and body weight loss. Here, we used neuroanatomical tracing, immunofluorescence, and confocal imaging to demonstrate that virtually all NTS->lPBN and lPBN->CeA CGRP projections coexpress vesicular glutamate transporter 2 (VGLUT2), providing evidence that excitatory projections mediate cisplatin-induced energy balance dysregulation. To test whether lPBN->CeA projection neurons are required for cisplatin-induced anorexia and weight loss, we inhibited these neurons chemogenetically using a retrograde Cre-recombinase expressing canine adenovirus-2 in combination with Cre-dependent inhibitory Designer Receptors Exclusive Activated by Designer Drugs (DREADDs) before cisplatin treatment. Inhibition of lPBN->CeA neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Using a similar approach, we additionally demonstrated that inhibition of NTS->lPBN neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Together, our data support the view that excitatory hindbrain-forebrain projections are necessary for cisplatin's untoward effects on energy intake, elucidating a key neuroanatomical circuit driving pathological anorexia and weight loss that accompanies chemotherapy treatment. SIGNIFICANCE STATEMENT: Chemotherapy treatments are commonly used to treat cancers despite accompanying anorexia and weight loss that may limit treatment adherence and reduce patient quality of life. Strikingly, we lack a neural understanding of, and effective treatments for, chemotherapy-induced anorexia and weight loss. The current data characterize the excitatory nature of neural projections activated by cisplatin in rats and reveal the necessity of specific hindbrain-forebrain projections for cisplatin induced anorexia and weight loss. Together, these findings help to characterize the neural mechanisms mediating cisplatin-induced anorexia, advancing opportunities to develop better-tolerated chemotherapies and adjuvant therapies to prevent anorexia and concurrent nutritional deficiencies during cancer treatment. PMID- 28077716 TI - The Attraction Effect Modulates Reward Prediction Errors and Intertemporal Choices. AB - : Classical economic theory contends that the utility of a choice option should be independent of other options. This view is challenged by the attraction effect, in which the relative preference between two options is altered by the addition of a third, asymmetrically dominated option. Here, we leveraged the attraction effect in the context of intertemporal choices to test whether both decisions and reward prediction errors (RPE) in the absence of choice violate the independence of irrelevant alternatives principle. We first demonstrate that intertemporal decision making is prone to the attraction effect in humans. In an independent group of participants, we then investigated how this affects the neural and behavioral valuation of outcomes using a novel intertemporal lottery task and fMRI. Participants' behavioral responses (i.e., satisfaction ratings) were modulated systematically by the attraction effect and this modulation was correlated across participants with the respective change of the RPE signal in the nucleus accumbens. Furthermore, we show that, because exponential and hyperbolic discounting models are unable to account for the attraction effect, recently proposed sequential sampling models might be more appropriate to describe intertemporal choices. Our findings demonstrate for the first time that the attraction effect modulates subjective valuation even in the absence of choice. The findings also challenge the prospect of using neuroscientific methods to measure utility in a context-free manner and have important implications for theories of reinforcement learning and delay discounting. SIGNIFICANCE STATEMENT: Many theories of value-based decision making assume that people first assess the attractiveness of each option independently of each other and then pick the option with the highest subjective value. The attraction effect, however, shows that adding a new option to a choice set can change the relative value of the existing options, which is a violation of the independence principle. Using an intertemporal choice framework, we tested whether such violations also occur when the brain encodes the difference between expected and received rewards (i.e., the reward prediction error). Our results suggest that neither intertemporal choice nor valuation without choice adhere to the independence principle. PMID- 28077718 TI - Integrin-Linked Kinase (ILK) Deletion Disrupts Oligodendrocyte Development by Altering Cell Cycle. AB - : During development, oligodendrocytes are initially specified, after which oligodendrocyte precursor cells (OPCs) migrate and proliferate before differentiating into myelinating cells. Lineage-specific programming of oligodendrocytes results from sensing environmental cues through membrane-bound receptors and related intracellular signaling molecules. Integrin-linked kinase (ILK) is an important protein that is expressed at the inner margins of the plasma membrane and can mediate some of these signals. The current studies demonstrate that ILK deletion reduces the proliferation and differentiation of OPCs in the developing CNS. There was a significant decrease in the number of OPCs and mature oligodendrocytes throughout postnatal development in Olig1Cre+/- * ILKfl/fl mice. These changes were accompanied by reduced numbers of myelinated axons. Key proteins involved in cell cycle regulation were dysregulated. Cyclin D1/D3 and cyclin-dependent kinase 2/4 (cdc2/cdc4) were downregulated and the cell cycle inhibitor protein p27 Kip1 was upregulated. Therefore, ILK deletion impaired the developmental profile, proliferation, and differentiation of OPCs by altering the expression of regulatory cytoplasmic and nuclear factors. SIGNIFICANCE STATEMENT: Integrin-linked kinase (ILK) is a scaffolding protein involved in integrating signals from the extracellular environment and communicating those signals to downstream effectors within cells. It has been proposed to regulate aspects of oligodendrocyte process extension and thereby myelination. However, the current studies demonstrate that it has an earlier impact on cells in this lineage. Knocking down ILK in Olig1-Cre-expressing cells reduces the pool of oligodendrocyte progenitor cells (OPCs). This smaller pool of OPCs results from altered cell cycle and reduced cell proliferation. These cells myelinate fewer axons than in wild-type mice and, in corpus callosum, the myelin is thinner than in controls. Interestingly, the smaller pool of spinal cord oligodendrocytes generates myelin that is of normal thickness. PMID- 28077717 TI - Complexin Mutants Reveal Partial Segregation between Recycling Pathways That Drive Evoked and Spontaneous Neurotransmission. AB - : Synaptic vesicles fuse at morphological specializations in the presynaptic terminal termed active zones (AZs). Vesicle fusion can occur spontaneously or in response to an action potential. Following fusion, vesicles are retrieved and recycled within nerve terminals. It is still unclear whether vesicles that fuse spontaneously or following evoked release share similar recycling mechanisms. Genetic deletion of the SNARE-binding protein complexin dramatically increases spontaneous fusion, with the protein serving as the synaptic vesicle fusion clamp at Drosophila synapses. We examined synaptic vesicle recycling pathways at complexin null neuromuscular junctions, where spontaneous release is dramatically enhanced. We combined loading of the lipophilic dye FM1-43 with photoconversion, electron microscopy, and electrophysiology to monitor evoked and spontaneous recycling vesicle pools. We found that the total number of recycling vesicles was equal to those retrieved through spontaneous and evoked pools, suggesting that retrieval following fusion is partially segregated for spontaneous and evoked release. In addition, the kinetics of FM1-43 destaining and synaptic depression measured in the presence of the vesicle-refilling blocker bafilomycin indicated that spontaneous and evoked recycling pools partially intermix during the release process. Finally, FM1-43 photoconversion combined with electron microscopy analysis indicated that spontaneous recycling preferentially involves synaptic vesicles in the vicinity of AZs, whereas vesicles recycled following evoked release involve a larger intraterminal pool. Together, these results suggest that spontaneous and evoked vesicles use separable recycling pathways and then partially intermix during subsequent rounds of fusion. SIGNIFICANCE STATEMENT: Neurotransmitter release involves fusion of synaptic vesicles with the plasma membrane in response to an action potential, or spontaneously in the absence of stimulation. Upon fusion, vesicles are retrieved and recycled, and it is unclear whether recycling pathways for evoked and spontaneous vesicles are segregated after fusion. We addressed this question by taking advantage of preparations lacking the synaptic protein complexin, which have elevated spontaneous release that enables reliable tracking of the spontaneous recycling pool. Our results suggest that spontaneous and evoked recycling pathways are segregated during the retrieval process but can partially intermix during stimulation. PMID- 28077720 TI - Local Circuits of V1 Layer 4B Neurons Projecting to V2 Thick Stripes Define Distinct Cell Classes and Avoid Cytochrome Oxidase Blobs. AB - : Decades of anatomical studies on the primate primary visual cortex (V1) have led to a detailed diagram of V1 intrinsic circuitry, but this diagram lacks information about the output targets of V1 cells. Understanding how V1 local processing relates to downstream processing requires identification of neuronal populations defined by their output targets. In primates, V1 layers (L)2/3 and 4B send segregated projections to distinct cytochrome oxidase (CO) stripes in area V2: neurons in CO blob columns project to thin stripes while neurons outside blob columns project to thick and pale stripes, suggesting functional specialization of V1-to-V2 CO streams. However, the conventional diagram of V1 shows all L4B neurons, regardless of their soma location in blob or interblob columns, as projecting selectively to CO blobs in L2/3, suggesting convergence of blob/interblob information in L2/3 blobs and, possibly, some V2 stripes. However, it is unclear whether all L4B projection neurons show similar local circuitries. Using viral-mediated circuit tracing, we have identified the local circuits of L4B neurons projecting to V2 thick stripes in macaque. Consistent with previous studies, we found the somata of this L4B subpopulation to reside predominantly outside blob columns; however, unlike previous descriptions of local L4B circuits, these cells consistently projected outside CO blob columns in all layers. Thus, the local circuits of these L4B output neurons, just like their extrinsic projections to V2, preserve CO streams. Moreover, the intra-V1 laminar patterns of axonal projections identify two distinct neuron classes within this L4B subpopulation, including a rare novel neuron type, suggestive of two functionally specialized output channels. SIGNIFICANCE STATEMENT: Conventional diagrams of primate primary visual cortex (V1) depict neuronal connections within and between different V1 layers, but lack information about the cells' downstream targets. This information is critical to understanding how local processing in V1 relates to downstream processing. We have identified the local circuits of a population of cells in V1 layer (L)4B that project to area V2. These cells' local circuits differ from classical descriptions of L4B circuits in both the laminar and functional compartments targeted by their axons, and identify two neuron classes. Our results demonstrate that both local intra-V1 and extrinsic V1-to-V2 connections of L4B neurons preserve CO-stream segregation, suggesting that across stream integration occurs downstream of V1, and that output targets dictate local V1 circuitry. PMID- 28077719 TI - Suppressing N-Acetyl-l-Aspartate Synthesis Prevents Loss of Neurons in a Murine Model of Canavan Leukodystrophy. AB - : Canavan disease is a leukodystrophy caused by aspartoacylase (ASPA) deficiency. The lack of functional ASPA, an enzyme enriched in oligodendroglia that cleaves N acetyl-l-aspartate (NAA) to acetate and l-aspartic acid, elevates brain NAA and causes "spongiform" vacuolation of superficial brain white matter and neighboring gray matter. In children with Canavan disease, neuroimaging shows early-onset dysmyelination and progressive brain atrophy. Neuron loss has been documented at autopsy in some cases. Prior studies have shown that mice homozygous for the Aspa nonsense mutation Nur7 also develop brain vacuolation. We now report that numbers of cerebral cortical and cerebellar neurons are decreased and that cerebral cortex progressively thins in AspaNur7/Nur7 mice. This neuronal pathology is prevented by constitutive disruption of Nat8l, which encodes the neuronal NAA synthetic enzyme N-acetyltransferase-8-like. SIGNIFICANCE STATEMENT: This is the first demonstration of cortical and cerebellar neuron depletion and progressive cerebral cortical thinning in an animal model of Canavan disease. Genetic suppression of N-acetyl-l-aspartate (NAA) synthesis, previously shown to block brain vacuolation in aspartoacylase-deficient mice, also prevents neuron loss and cerebral cortical atrophy in these mice. These results suggest that lowering the concentration of NAA in the brains of children with Canavan disease would prevent or slow progression of neurological deficits. PMID- 28077721 TI - Temporal Expectations Guide Dynamic Prioritization in Visual Working Memory through Attenuated alpha Oscillations. AB - : Although working memory is generally considered a highly dynamic mnemonic store, popular laboratory tasks used to understand its psychological and neural mechanisms (such as change detection and continuous reproduction) often remain relatively "static," involving the retention of a set number of items throughout a shared delay interval. In the current study, we investigated visual working memory in a more dynamic setting, and assessed the following: (1) whether internally guided temporal expectations can dynamically and reversibly prioritize individual mnemonic items at specific times at which they are deemed most relevant; and (2) the neural substrates that support such dynamic prioritization. Participants encoded two differently colored oriented bars into visual working memory to retrieve the orientation of one bar with a precision judgment when subsequently probed. To test for the flexible temporal control to access and retrieve remembered items, we manipulated the probability for each of the two bars to be probed over time, and recorded EEG in healthy human volunteers. Temporal expectations had a profound influence on working memory performance, leading to faster access times as well as more accurate orientation reproductions for items that were probed at expected times. Furthermore, this dynamic prioritization was associated with the temporally specific attenuation of contralateral alpha (8-14 Hz) oscillations that, moreover, predicted working memory access times on a trial-by-trial basis. We conclude that attentional prioritization in working memory can be dynamically steered by internally guided temporal expectations, and is supported by the attenuation of alpha oscillations in task-relevant sensory brain areas. SIGNIFICANCE STATEMENT: In dynamic, everyday-like, environments, flexible goal-directed behavior requires that mental representations that are kept in an active (working memory) store are dynamic, too. We investigated working memory in a more dynamic setting than is conventional, and demonstrate that expectations about when mnemonic items are most relevant can dynamically and reversibly prioritize these items in time. Moreover, we uncover a neural substrate of such dynamic prioritization in contralateral visual brain areas and show that this substrate predicts working memory retrieval times on a trial-by-trial basis. This places the experimental study of working memory, and its neuronal underpinnings, in a more dynamic and ecologically valid context, and provides new insights into the neural implementation of attentional prioritization within working memory. PMID- 28077722 TI - Higher Heart-Rate Variability Is Associated with Ventromedial Prefrontal Cortex Activity and Increased Resistance to Temptation in Dietary Self-Control Challenges. AB - : Higher levels of self-control in decision making have been linked to better psychosocial and physical health. A similar link to health outcomes has been reported for heart-rate variability (HRV), a marker of physiological flexibility. Here, we sought to link these two, largely separate, research domains by testing the hypothesis that greater HRV would be associated with better dietary self control in humans. Specifically, we examined whether total HRV at sedentary rest (measured as the SD of normal-to-normal intervals) can serve as a biomarker for the neurophysiological adaptability that putatively underlies self-controlled behavior. We found that HRV explained a significant portion of the individual variability in dietary self-control, with individuals having higher HRV being better able to downregulate their cravings in the face of taste temptations. Furthermore, HRV was associated with activity patterns in the ventromedial prefrontal cortex (vmPFC), a key node in the brain's valuation and decision circuitry. Specifically, individuals with higher HRV showed both higher overall vmPFC blood-oxygen-level-dependent activity and attenuated taste representations when presented with a dietary self-control challenge. Last, the behavioral and neural associations with HRV were consistent across both our stress induction and control experimental conditions. The stability of this association across experimental conditions suggests that HRV may serve as both a readily obtainable and robust biomarker for self-control ability across environmental contexts. SIGNIFICANCE STATEMENT: Self-control is associated with better health, but behavioral and psychometric self-control measures allow only indirect associations with health outcomes and may be distorted by reporting bias. We tested whether resting heart-rate variability (HRV), a physiological indicator of psychological and physical health, can predict individual differences in dietary self-control in humans. We found that higher HRV was associated with better self control and improved predictions of choice behavior. Specifically, higher HRV was associated with more effective downregulation of taste temptations, and with a diminished neural representation of taste temptations during self-control challenges. Our results suggest that HRV may serve as an easily acquired, noninvasive, and low-cost biomarker for self-control ability. PMID- 28077724 TI - TREM2 Promotes Microglial Survival by Activating Wnt/beta-Catenin Pathway. AB - Triggering Receptor Expressed on Myeloid cells 2 (TREM2), which is expressed on myeloid cells including microglia in the CNS, has recently been identified as a risk factor for Alzheimer's disease (AD). TREM2 transmits intracellular signals through its transmembrane binding partner DNAX-activating protein 12 (DAP12). Homozygous mutations inactivating TREM2 or DAP12 lead to Nasu-Hakola disease; however, how AD risk-conferring variants increase AD risk is not clear. To elucidate the signaling pathways underlying reduced TREM2 expression or loss of function in microglia, we respectively knocked down and knocked out the expression of TREM2 in in vitro and in vivo models. We found that TREM2 deficiency reduced the viability and proliferation of primary microglia, reduced microgliosis in Trem2-/- mouse brains, induced cell cycle arrest at the G1/S checkpoint, and decreased the stability of beta-catenin, a key component of the canonical Wnt signaling pathway responsible for maintaining many biological processes, including cell survival. TREM2 stabilized beta-catenin by inhibiting its degradation via the Akt/GSK3beta signaling pathway. More importantly, treatment with Wnt3a, LiCl, or TDZD-8, which activates the beta-catenin-mediated Wnt signaling pathway, rescued microglia survival and microgliosis in Trem2-/- microglia and/or in Trem2-/- mouse brain. Together, our studies demonstrate a critical role of TREM2-mediated Wnt/beta-catenin pathway in microglial viability and suggest that modulating this pathway therapeutically may help to combat the impaired microglial survival and microgliosis associated with AD.SIGNIFICANCE STATEMENT Mutations in the TREM2 (Triggering Receptor Expressed on Myeloid cells 2) gene are associated with increased risk for Alzheimer's disease (AD) with effective sizes comparable to that of the apolipoprotein E (APOE) epsilon4 allele, making it imperative to understand the molecular pathway(s) underlying TREM2 function in microglia. Our findings shed new light on the relationship between TREM2/DNAX-activating protein 12 (DAP12) signaling and Wnt/beta-catenin signaling and provide clues as to how reduced TREM2 function might impair microglial survival in AD pathogenesis. We demonstrate that TREM2 promotes microglial survival by activating the Wnt/beta-catenin signaling pathway and that it is possible to restore Wnt/beta-catenin signaling when TREM2 activity is disrupted or reduced. Therefore, we demonstrate the potential for manipulating the TREM2/beta-catenin signaling pathway for the treatment of AD. PMID- 28077725 TI - Encoding of Both Reaching and Grasping Kinematics in Dorsal and Ventral Premotor Cortices. AB - Classically, it has been hypothesized that reach-to-grasp movements arise from two discrete parietofrontal cortical networks. As part of these networks, the dorsal premotor cortex (PMd) has been implicated in the control of reaching movements of the arm, whereas the ventral premotor cortex (PMv) has been associated with the control of grasping movements of the hand. Recent studies have shown that such a strict delineation of function along anatomical boundaries is unlikely, partly because reaching to different locations can alter distal hand kinematics and grasping different objects can affect kinematics of the proximal arm. Here, we used chronically implanted multielectrode arrays to record unit spiking activity in both PMd and PMv simultaneously while rhesus macaques engaged in a reach-to-grasp task. Generalized linear models were used to predict the spiking activity of cells in both areas as a function of different kinematic parameters, as well as spike history. To account for the influence of reaching on hand kinematics and vice versa, we applied demixed principal components analysis to define kinematics synergies that maximized variance across either different object locations or grip types. We found that single cells in both PMd and PMv encode the kinematics of both reaching and grasping synergies, suggesting that this classical division of reach and grasp in PMd and PMv, respectively, does not accurately reflect the encoding preferences of cells in those areas.SIGNIFICANCE STATEMENT For reach-to-grasp movements, the dorsal premotor cortex (PMd) has been implicated in the control of reaching movements of the arm, whereas the ventral premotor cortex (PMv) has been associated with the control of grasping movements of the hand. We recorded unit-spiking activity in PMd and PMv simultaneously while macaques performed a reach-to-grasp task. We modeled the spiking activity of neurons as a function of kinematic parameters and spike history. We applied demixed principal components analysis to define kinematics synergies. We found that single units in both PMd and PMv encode the kinematics of both reaching and grasping synergies, suggesting that the division of reach and grasp in PMd and PMv, respectively, cannot be made based on their encoding properties. PMID- 28077726 TI - Climbing Fibers Control Purkinje Cell Representations of Behavior. AB - A crucial issue in understanding cerebellar function is the interaction between simple spike (SS) and complex spike (CS) discharge, the two fundamentally different activity modalities of Purkinje cells. Although several hypotheses have provided insights into the interaction, none fully explains or is completely consistent with the spectrum of experimental observations. Here, we show that during a pseudo-random manual tracking task in the monkey (Macaca mulatta), climbing fiber discharge dynamically controls the information present in the SS firing, triggering robust and rapid changes in the SS encoding of motor signals in 67% of Purkinje cells. The changes in encoding, tightly coupled to CS occurrences, consist of either increases or decreases in the SS sensitivity to kinematics or position errors and are not due to differences in SS firing rates or variability. Nor are the changes in sensitivity due to CS rhythmicity. In addition, the CS-coupled changes in encoding are not evoked by changes in kinematics or position errors. Instead, CS discharge most often leads alterations in behavior. Increases in SS encoding of a kinematic parameter are associated with larger changes in that parameter than are decreases in SS encoding. Increases in SS encoding of position error are followed by and scale with decreases in error. The results suggest a novel function of CSs, in which climbing fiber input dynamically controls the state of Purkinje cell SS encoding in advance of changes in behavior.SIGNIFICANCE STATEMENT Purkinje cells, the sole output of the cerebellar cortex, manifest two fundamentally different activity modalities, complex spike (CS) discharge and simple spike (SS) firing. Elucidating cerebellar function will require an understanding of the interactions, both short- and long-term, between CS and SS firing. This study shows that CSs dynamically control the information encoded in a Purkinje cell's SS activity by rapidly increasing or decreasing the SS sensitivity to kinematics and/or performance errors independent of firing rate. In many cases, the CS coupled shift in SS encoding leads a change in behavior. These novel findings on the interaction between CS and SS firing provide for a new hypothesis in which climbing fiber input adjusts the encoding of SS information in advance of a change in behavior. PMID- 28077727 TI - Asymmetries of Dark and Bright Negative Afterimages Are Paralleled by Subcortical ON and OFF Poststimulus Responses. AB - Humans are more sensitive to luminance decrements than increments, as evidenced by lower thresholds and shorter latencies for dark stimuli. This asymmetry is consistent with results of neurophysiological recordings in dorsal lateral geniculate nucleus (dLGN) and primary visual cortex (V1) of cat and monkey. Specifically, V1 population responses demonstrate that darks elicit higher levels of activation than brights, and the latency of OFF responses in dLGN and V1 is shorter than that of ON responses. The removal of a dark or bright disc often generates the perception of a negative afterimage, and here we ask whether there also exist asymmetries for negative afterimages elicited by dark and bright discs. If so, do the poststimulus responses of subcortical ON and OFF cells parallel such afterimage asymmetries? To test these hypotheses, we performed psychophysical experiments in humans and single-cell/S-potential recordings in cat dLGN. Psychophysically, we found that bright afterimages elicited by luminance decrements are stronger and last longer than dark afterimages elicited by luminance increments of equal sizes. Neurophysiologically, we found that ON cells responded to the removal of a dark disc with higher firing rates that were maintained for longer than OFF cells to the removal of a bright disc. The ON and OFF cell asymmetry was most pronounced at long stimulus durations in the dLGN. We conclude that subcortical response strength differences between ON and OFF channels parallel the asymmetries between bright and dark negative afterimages, further supporting a subcortical origin of bright and dark afterimage perception.SIGNIFICANCE STATEMENT Afterimages are physiological aftereffects following stimulation of the eye, the study of which helps us to understand how our visual brain generates visual perception in the absence of physical stimuli. We report, for the first time to our knowledge, asymmetries between bright and dark negative afterimages elicited by luminance decrements and increments, respectively. Bright afterimages are stronger and last longer than dark afterimages. Subcortical neuronal recordings of poststimulus responses of ON and OFF cells reveal similar asymmetries with respect to response strength and duration. Our results suggest that subcortical differences between ON and OFF channels help explain intensity and duration asymmetries between bright and dark afterimages, supporting the notion of a subcortical origin of bright and dark afterimages. PMID- 28077728 TI - Looking the part (to me): effects of racial prototypicality on race perception vary by prejudice. AB - Less racially prototypic faces elicit more category competition during race categorization. Top-down factors (e.g. stereotypes), however, affect categorizations, suggesting racial prototypicality may enhance category competition in certain perceivers. Here, we examined how prejudice affects race category competition and stabilization when perceiving faces varying in racial prototypicality. Prototypically low vs high Black relative to White faces elicited more category competition and slower response latencies during categorization (Experiment 1), suggesting a pronounced racial prototypicality effect on minority race categorization. However, prejudice predicted the extent of category competition between prototypically low vs high Black faces. Suggesting more response conflict toward less prototypic Black vs White faces, anterior cingulate cortex activity increased toward Black vs White faces as they decreased in racial prototypicality, with prejudice positively predicting this difference (Experiment 2). These findings extend the literature on racial prototypicality and categorization by showing that relative prejudice tempers the extent of category competition and response conflict engaged when initially perceiving faces. PMID- 28077730 TI - Effect of an Early Dose of Measles Vaccine on Morbidity Between 18 Weeks and 9 Months of Age: A Randomized, Controlled Trial in Guinea-Bissau. AB - Background: Children in Guinea-Bissau receive measles vaccine (MV) at 9 months of age, but studies have shown that an additional dose before 9 months of age might have beneficial nonspecific effects. Within a randomized trial designed to examine nonspecific effects of early MV receipt on mortality, we conducted a substudy to investigate the effect of early MV receipt on morbidity. Methods: Children were randomly assigned at a ratio of 2:1 to receive 2 doses of MV at 18 weeks and age 9 months (intervention group) or 1 dose of MV at age 9 months, in accordance with current practice (control group). Children were visited weekly from enrollment to age 9 months; the mother reported morbidity, and the field assistants examined the children. Using Cox and binomial regression models, we compared the 2 randomization groups. Results: Among the 1592 children, early measles vaccination was not associated with a higher risk of the well-known adverse events of fever, rash, and convulsions within the first 14 days. From 15 days after randomization to age 9 months, early measles vaccination was associated with reductions in maternally reported diarrhea (hazard ratio [HR], 0.89; 95% confidence interval [CI], .82-.97), vomiting (HR, 0.86; 95% CI, .75 .98), and fever (HR, 0.93; 95% CI, .87-1.00). Conclusion: Early MV receipt was associated with reduced general morbidity in the following months, supporting that early MV receipt may improve the general health of children. PMID- 28077731 TI - omega-3 Fatty Acid Supplementation Does Not Affect Autism Spectrum Disorder in Children: A Systematic Review and Meta-Analysis. AB - Background: Effective treatments for the core symptoms of autism spectrum disorder (ASD) are still lacking.Objective: We aimed to update the data on the effectiveness of omega-3 (n-3) fatty acid (FA) supplementation as a treatment for ASD.Methods: The Cochrane Library, MEDLINE, and EMBASE databases were systematically searched up until August 2016 with no language restrictions for randomized controlled trials (RCTs) comparing omega-3 FA supplementation with placebo or with no supplementation. Participants were children diagnosed with ASD. All functional outcome measures reported were considered. For dichotomous outcomes, the results for individual studies and pooled statistics were reported as RRs. Mean differences (MDs) were calculated for continuous outcomes.Results: Five RCTs (183 participants) were included. With 4 exceptions, there were no statistically significant differences in ASD symptoms between groups measured by validated scales. Among studies that used the Aberrant Behavior Checklist, parents' ratings indicated significant improvement in lethargy symptoms in the omega-3 FA group compared with the placebo group (2 RCTs) (pooled MD: 1.98; 95% CI: 0.32, 3.63). Among studies that used the Behavioral Assessment System for Children, parents' ratings indicated significant worsening of both externalizing behavior (2 RCTs) (pooled MD: -6.22; 95% CI: -10.9, -1.59) and social skills (1 RCT) (MD: -7; 95% CI: -13.62, -0.38) in the omega-3 FA group compared with the placebo group. One RCT reported a significant improvement in the omega-3 FA group for the daily-living component of the Vineland Adaptive Behavior Scale (MD: 6.2; 95% CI: 0.37, 12.03). Adverse effects were similar in both groups.Conclusions: Because of the limited number of included studies and small sample sizes, no firm conclusions can be drawn. However, the limited data currently available suggest that omega-3 FA supplementation does not enhance the performance of children with ASD. PMID- 28077732 TI - High-Protein and High-Dietary Fiber Breakfasts Result in Equal Feelings of Fullness and Better Diet Quality in Low-Income Preschoolers Compared with Their Usual Breakfast. AB - Background: In the United States, 17% of children are currently obese. Increasing feelings of fullness may prevent excessive energy intake, lead to better diet quality, and promote long-term maintenance of healthy weight.Objective: The purpose of this study was to develop a fullness-rating tool (aim 1) and to determine whether a high-protein (HP), high-fiber (HF), and combined HP and HF (HPHF) breakfast increases preschoolers' feelings of fullness before (pre) and after (post) breakfast and pre-lunch, as well as their diet quality, as measured by using a composite diet quality assessment tool, the Revised Children's Diet Quality Index (aim 2).Methods: Children aged 4 and 5 y (n = 41; 22 girls and 19 boys) from local Head Start centers participated in this randomized intervention trial. Sixteen percent of boys and 32% of girls were overweight or obese. After the baseline week, children rotated through four 1-wk periods of consuming ad libitum HP (19-20 g protein), HF (10-11 g fiber), HPHF (19-21 g protein, 10-12 g fiber), or usual (control) breakfasts. Food intake at breakfast was estimated daily, and for breakfast, lunch, and snack on day 3 of each study week Student's t tests and ANOVA were used to determine statistical differences.Results: Children's post-breakfast and pre-lunch fullness ratings were >=1 point higher than those of pre-breakfast (aim 1). Although children consumed, on average, 65 kcal less energy during the intervention breakfasts (P < 0.007) than during the control breakfast, fullness ratings did not differ (P = 0.76). Relative to the control breakfast, improved diet quality (12%) was calculated for the HP and HF breakfasts (P < 0.027) but not for the HPHF breakfast (aim 2).Conclusions: Post breakfast fullness ratings were not affected by the intervention breakfasts relative to the control breakfast. HP and HF breakfasts resulted in higher diet quality. Serving HP or HF breakfasts may be valuable in improving diet quality without lowering feelings of satiation or satiety. This trial was registered at clinicaltrials.gov as NCT02122224. PMID- 28077733 TI - Identification of Potential Plasma Biomarkers for Nonalcoholic Fatty Liver Disease by Integrating Transcriptomics and Proteomics in Laying Hens. AB - Background: Prevalent worldwide obesity is associated with increased incidence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome. The identification of noninvasive biomarkers for NAFLD is of recent interest. Because primary de novo lipogenesis occurs in chicken liver as in human liver, adult chickens with age-associated steatosis resembling human NAFLD is an appealing animal model.Objective: The objective of this study was to screen potential biomarkers in the chicken model for NAFLD by transcriptomic and proteomic analysis.Methods: Hy-Line W-36 laying hens were fed standard feed from 25 to 45 wk of age to induce fatty liver. They were killed every 4 wk, and liver and plasma were collected at each time point to assess fatty liver development and for transcriptomic and proteomic analysis. Next, selected biomarkers were confirmed in additional experiments by providing supplements of the hepatoprotective nutrients betaine [300, 600, or 900 parts per million (ppm) in vivo; 2 mM in vitro] or docosahexaenoic acid (DHA; 1% in vivo; 100 MUM in vitro) to 30-wk-old Hy-Line W-36 laying hens for 4 mo and to Hy-Line W-36 chicken primary hepatocytes with oleic acid-induced steatosis. Liver or hepatocyte lipid contents and the expression of biomarkers were then examined.Results: Plasma acetoacetyl-CoA synthetase (AACS), dipeptidyl-peptidase 4 (DPP4), glutamine synthetase (GLUL), and glutathione S-transferase (GST) concentrations are well established biomarkers for NAFLD. Selected biomarkers had significant positive associations with hepatic lipid deposition (P < 0.001). Betaine (900 ppm in vivo; 2 mM in vitro) and DHA (1% in vivo; 100 MUM in vitro) supplementation both resulted in lower steatosis accompanied by the reduced expression of selected biomarkers in vivo and in vitro (P < 0.05).Conclusion: This study used adult laying hens to identify biomarkers for NAFLD and indicated that AACS, DPP4, GLUL, and GST could be considered to be potential diagnostic indicators for NAFLD in the future. PMID- 28077734 TI - Intake of up to 3 Eggs per Day Is Associated with Changes in HDL Function and Increased Plasma Antioxidants in Healthy, Young Adults. AB - Background: HDL function may be more important than HDL concentration in determining risk for cardiovascular disease. In addition, HDL is a carrier of carotenoids and antioxidant enzymes, which protect HDL and LDL particles against oxidation.Objective: The goal of this study was to determine the impact of consuming 0-3 eggs/d on LDL and HDL particle size, HDL function, and plasma antioxidants in a young, healthy population.Methods: Thirty-eight healthy men and women [age 18-30 y, body mass index (in kg/m2) 18.5-29.9] participated in this 14 wk crossover intervention. Subjects underwent a 2-wk washout (0 eggs/d) followed by sequentially increasing intake of 1, 2, and 3 eggs/d for 4 wk each. After each period, fasting blood was collected for analysis of lipoprotein subfractions, plasma apolipoprotein (apo) concentration, lutein and zeaxanthin concentration, and activities of lecithin-cholesterol acyltransferase, cholesteryl ester transfer protein, and paraoxonase-1.Results: Compared with intake of 0 eggs/d, consuming 1-3 eggs/d resulted in increased large-LDL (21-37%) and large-HDL (6 13%) particle concentrations, plasma apoAI (9-15%), and lecithin-cholesterol acyltransferase activity (5-15%) (P < 0.05 for all biomarkers). Intake of 2-3 eggs/d also promoted an 11% increase in apoAII (P < 0.05) and a 20-31% increase in plasma lutein and zeaxanthin (P < 0.05), whereas intake of 3 eggs/d resulted in a 9-16% increase in serum paraoxonase-1 activity compared with intake of 1-2 eggs/d (P < 0.05). Egg intake did not affect cholesteryl ester transfer protein activity.Conclusions: Intake of 1 egg/d was sufficient to increase HDL function and large-LDL particle concentration; however, intake of 2-3 eggs/d supported greater improvements in HDL function as well as increased plasma carotenoids. Overall, intake of <=3 eggs/d favored a less atherogenic LDL particle profile, improved HDL function, and increased plasma antioxidants in young, healthy adults. This trial was registered at clinicaltrials.gov as NCT02531958. PMID- 28077735 TI - Tuberculosis mimicking metastases by malignancy in FDG PET/CT. PMID- 28077736 TI - Atypical Presentation of Majocchi's Granuloma in an Immunocompetent Host. PMID- 28077737 TI - New Diagnostics for Yaws. PMID- 28077738 TI - Evidence-Based Policies on Migration and Global Health are Essential to Maintain the Health of Those Inside and Outside the United States. PMID- 28077739 TI - The Emergence of Undergraduate Majors in Global Health: Systematic Review of Programs and Recommendations for Future Directions. AB - Global health education has been expanding rapidly and several universities have created an undergraduate major degree (bachelor's degree) in global heath or global health studies. Because there are currently no national guidelines for undergraduate degrees in global health, each of these programs was developed along individual lines. To guide the development of future global health majors, we conducted a systematic review of undergraduate majors in global health. We identified eight programs and invited program directors or representatives to a symposium at the Consortium of Universities for Global Health 2016 conference to review their existing undergraduate major in global health and to discuss lessons learned and recommendations for other colleges and universities seeking to develop undergraduate degrees in global health. We noted significant diversity among the existing programs in terms of required courses, international field experiences, and thesis research projects. In this review, we describe these global health programs, their student characteristics, as well as the key educational competencies, program requirements, and core global health courses. Based on program reviews and discussions, we identify seven recommendations for the development and expansion of an undergraduate major in global health and discuss issues that have arisen in the curricular development of these programs that warrant further exploration. As the field of global health education continues to expand, following these students after graduation will be essential to ensure that the degree programs in global health both meet student needs and launch students on viable career pathways. PMID- 28077740 TI - The Jarisch-Herxheimer Reaction After Antibiotic Treatment of Spirochetal Infections: A Review of Recent Cases and Our Understanding of Pathogenesis. AB - Within 24 hours after antibiotic treatment of the spirochetal infections syphilis, Lyme disease, leptospirosis, and relapsing fever (RF), patients experience shaking chills, a rise in temperature, and intensification of skin rashes known as the Jarisch-Herxheimer reaction (JHR) with symptoms resolving a few hours later. Case reports indicate that the JHR can also include uterine contractions in pregnancy, worsening liver and renal function, acute respiratory distress syndrome, myocardial injury, hypotension, meningitis, alterations in consciousness, seizures, and strokes. Experimental evidence indicates it is caused by nonendotoxin pyrogen and spirochetal lipoproteins. Mediation of the JHR in RF by the pro-inflammatory cytokines tumor necrosis factor (TNF), interleukin (IL)-6, and IL-8 has been proposed, consistent with measurements in patients' blood and inhibition by anti-TNF antibodies. Accelerated phagocytosis of spirochetes by polymorphonuclear (PMN) leukocytes before rise in cytokines is responsible for removal of organisms from the blood, suggesting an early inflammatory signal from PMNs. Rarely fatal, except in neonates and in pregnancy for African women whose babies showed high perinatal mortality because of low birth weight, the JHR can be regarded as an adverse effect of antibiotics, necessary for achieving a cure of spirochetal infections. PMID- 28077741 TI - Is Using a Latrine "A Strange Thing To Do"? A Mixed-Methods Study of Sanitation Preference and Behaviors in Rural Ethiopia. AB - Latrines are the most basic form of improved sanitation and are a common public health intervention. Understanding motivations for building and using latrines can help develop effective, sustainable latrine promotion programs. We conducted a mixed-methods study of latrine use in the Amhara region of Ethiopia. We held 15 focus group discussions and surveyed 278 households in five communities. We used the Integrated Behavioral Model for Water, Sanitation, and Hygiene interventions to guide our qualitative analysis. Seventy-one percent of households had a latrine, but coverage varied greatly across communities. Higher household income was not associated with latrine use (odds ratio [OR] = 1.9; 95% confidence interval [CI] = 0.5, 7.7); similarly, cost and availability of materials were not discussed as barriers to latrine use in the focus groups. Male-headed households were more likely to use latrines than households with female heads (OR = 3.5; 95% CI = 1.6, 7.7), and households with children in school were more likely to use latrines than households without children in school (OR = 2.3; 95% CI = 1.6, 3.3). These quantitative findings were confirmed in focus groups, where participants discussed how children relay health messages from school. Participants discussed how women prefer not to use latrines, often finding them strange or even scary. These findings are useful for public health implementation; they imply that community-level drivers are important predictors of household latrine use and that cost is not a significant barrier. These findings confirm that school-aged children may be effective conduits of health messages and suggest that latrines can be better marketed and designed for women. PMID- 28077742 TI - Colonization Factors in Enterotoxigenic Escherichia coli Strains in Travelers to Mexico, Guatemala, and India Compared with Children in Houston, Texas. AB - Enterotoxigenic Escherichia coli (ETEC) can be attributed to around 200 million diarrheal episodes and 380,000 deaths in the developing regions. Travelers' diarrhea occurs in 15-40% of travelers to developing regions with ETEC being the most important etiologic agent. This study aims to describe the distribution of enterotoxins and colonization factor (CF) profiles of ETEC isolates from stool samples of adult travelers acquiring diarrhea in Mexico, Guatemala, and India and a group of children with acute diarrhea in Houston, TX, between 2007 and 2012. The heat-labile/heat-stable (LT/ST) enterotoxins and CFs from 252 patients were determined using polymerase chain reaction assay. Among the 252 ETEC isolates, 15% were LT-only, 58% were ST-only, and 28% produced both LT and ST. The distribution of LT-only (12-15%) and ST-only (55-56%) isolates was similar between Latin American and Indian sites. The most prevalent CF was CS21, expressed in 65% of the isolates followed by CS6 (25%) and CS3 (17%). Among the international travelers, 64% of the ETEC isolates expressed CS21. CS21 was expressed in 46% of isolates from Latin America compared with 96% of isolates from India (P < 0.0001). CS21 was expressed in 85% isolates from Houston children. CS21 was increasingly found in ST-only (P = 0.003) and ST/LT (P = 0.026) ETEC compared with LT-only ETEC. High frequency of finding CS21 among recent isolates of ETEC over a wide geographic distribution warrants additional studies on this CF. Highly conserved CS21 is an important target for potential multivalent ETEC vaccines. PMID- 28077743 TI - Seroepidemiology of Human Brucellosis Among Blood Donors in Southern Ethiopia: Calling Attention to a Neglected Zoonotic Disease. AB - Human brucellosis is neglected in southern Ethiopia. Although traditional food processing practices and animal husbandry which increase the risk of brucellosis are common, it has not been properly studied yet. This study was conducted to determine the seroepidemiology of brucellosis among apparently healthy individuals in southern Ethiopia. In the study, blood samples were collected to screen for serum agglutinins reactive to stained antigen of Brucella abortus Standard tube titration was performed for reactive serum to determine the titer of the agglutinin. A structured questionnaire was used to collect data on possible risk factors for brucellosis. The seroprevalence of human brucellosis in this study was found to be 10.6% (95% confidence interval = 7.0, 14.0). Possession of domestic ruminant animals, contact with ruminant animals, and husbandry practices at home were associated with seropositivity. The higher seroprevalence of human brucellosis in the study area needs attention and additional confirmatory investigation. PMID- 28077744 TI - Neuropsychiatric Outcomes After Mefloquine Exposure Among U.S. Military Service Members. AB - Mefloquine was widely prescribed to U.S. military service members until 2009 when use was limited to personnel with contraindications to doxycycline and no contraindications to mefloquine. The need to estimate the occurrence of neuropsychiatric outcomes (NPOs) in service members prescribed mefloquine warranted a comprehensive evaluation of this issue. Active component service members filling a prescription for mefloquine, doxycycline, or atovaquone/proguanil (A/P) between January 1, 2008 and June 30, 2013, were included in the analysis. The risk of developing incident NPOs and the risk of subsequent NPOs among subjects with a history of the condition were assessed. A total of 367,840 individuals were evaluated (36,538 received mefloquine, 318,421 received doxycycline, and 12,881 received A/P). Among deployed individuals prescribed mefloquine, an increased risk of incident anxiety was seen when compared with doxycycline recipients (incidence rate ratio [IRR] = 1.12 [1.01 1.24]). Among nondeployed mefloquine recipients, an increased risk of posttraumatic stress disorder (PTSD) was seen when compared with A/P recipients (IRR = 1.83 [1.07-3.14]). An increased risk of tinnitus was seen for both deployed and nondeployed mefloquine recipients compared with A/P recipients (IRR = 1.81 [1.18-2.79]), 1.51 (1.13-2.03), respectively). Six percent of the mefloquine cohort had an NPO in the year before receiving mefloquine. When comparing individuals with a prior neuropsychiatric history to those without, the ratio of relative risks for adjustment disorder, anxiety, insomnia, and PTSD were higher (not statistically significant) for mefloquine compared with doxycycline. These findings emphasize the continued need for physicians prescribing mefloquine to conduct contraindication screening. PMID- 28077745 TI - Congenital Plasmodium falciparum Malaria in Washington, DC. AB - Congenital malaria is rare in the United States, but is an important diagnosis to consider when evaluating febrile infants. Herein, we describe a case of congenital Plasmodium falciparum malaria in a 2-week-old infant born in the United States to a mother who had emigrated from Nigeria 3 months before delivery. PMID- 28077746 TI - Vector Competence of Lutzomyia cruzi Naturally Demonstrated for Leishmania infantum and Suspected for Leishmania amazonensis. AB - Corumba city is one of the oldest visceral leishmaniasis-endemic foci in the state of Mato Grosso do Sul, Brazil, where the transmission of Leishmania infantum has been attributed to Lutzomyia cruzi Aiming at investigating the parameters of the vectorial capacity of Lu. cruzi for L. infantum, a project was undertaken in this city. Among these parameters, vector competence was investigated and the results obtained are reported herein. Of the 12 hamsters exposed to feed wild-caught female sandflies, two developed infection with L. infantum and surprisingly, one with Leishmania amazonensis In addition, hamsters with L. infantum infection were bitten only by females of Lu. cruzi, whereas the hamster infected with L. amazonensis was bitten by 124 Lu. cruzi females and one of Evandromyia corumbaensis Although there is a strong suspicion regarding the competence of Lu. cruzi in transmitting L. amazonensis naturally, it was not demonstrated. PMID- 28077747 TI - First Molecular Identifications of Necator americanus and Ancylostoma ceylanicum Infecting Rural Communities in Lower Myanmar. AB - Hookworms are enteric parasitic roundworms infecting an estimated 400 million persons worldwide. Herein, we provide the first molecular identifications of human hookworms from certain parts of rural Lower Myanmar. DNA was extracted from hookworm-positive stool samples, as determined by microscopy. DNA sequences of the partial internal transcribed spacer 1, full length 5.8S gene, and partial internal transcribed spacer 2 were determined and compared with available hookworm sequences from public databases. Of the 11 polymerase chain reaction positive samples, eight (Bago Region, N = 4; Mon State, N = 4) yielded sequences with high similarity to those of Necator americanus A further three sequences (Mon State, N = 2; Bago Region, N = 1) showed high similarity with those of Ancylostoma ceylanicum The latter is primarily a parasite of dogs and represents a zoonosis. Given that different species of hookworms exhibit different epidemiological and biological characteristics, accurate identification is essential for the planning and execution of effective control programs for hookworm infections. PMID- 28077748 TI - Poor Validity of Noninvasive Hemoglobin Measurements by Pulse Oximetry Compared with Conventional Absorptiometry in Children in Cote d'Ivoire. AB - Anemia remains a major public health issue in many African communities. We compared a novel, commercially available noninvasive hemoglobin (Hb)-measuring device to direct Hb measurements by finger-prick samples in a pediatric cohort in rural Cote d'Ivoire. Noninvasive Hb measurements were attempted in 191 children 2 15 years of age and obtained in 102 (53.5%) children. The median Hb for the 102 children was 12.0 g/dL (interquartile range [IQR] = 11.3-12.7 g/dL) for conventional absorptiometry and 13.3 g/dL (IQR = 12.1-14.2 g/dL) for noninvasive measurements. A Bland-Altman analysis demonstrated a median bias of +1.1 g/dL (IQR = 0.4-2.0 g/dL), with greater overestimation of Hb by noninvasive testing occurring at low Hb values. This overestimation of the noninvasive Hb-measuring device to direct Hb measurements persisted across preschool- and school-aged children, and both sexes. The Pearson correlation coefficient was 0.50 for children 4-9 years of age, and 0.33 for children 10-15 years of age. Further study and development of noninvasive Hb devices is necessary prior to implementation in African pediatric populations. PMID- 28077749 TI - Survey of Obstetrician-Gynecologists in the United States About Taeniasis and Cysticercosis. AB - An estimated 50 million persons worldwide are infected with cysticerci, the larval forms of the Taenia solium tapeworm. Neurocysticercosis can cause seizures, epilepsy, and hydrocephalus, and fatal cases have been reported in the United States in immigrants and in travelers returning from endemic countries. Pregnant women with symptomatic neurocysticercosis present treatment challenges, whereas those with the adult tapeworm infection (i.e., taeniasis) can put their infants and other family members, as well as obstetrician-gynecologists and their staff, at risk for cysticercosis. A questionnaire developed by the American College of Obstetricians and Gynecologists was sent to a representative sample of 1,000 physicians to assess their awareness of T. solium infection and the potential for it to be encountered in an obstetrics and gynecology setting. In total, 31.4% of respondents correctly answered that taeniasis is caused by eating undercooked pork containing T. solium cysts (95% confidence interval [CI] = 26.6 36.5). While only 14.5% (95% CI = 11.0-18.6) of respondents correctly answered that cysticercosis is acquired by ingesting tapeworm eggs shed in human stools, twice that number (30.3%; 95% CI = 25.5-35.3) correctly answered that a mother with taeniasis can cause cysticercosis in her infant. Practicing in a state in which cysticercosis was reportable at the time of the survey was not significantly associated with answering any of the 12 knowledge questions correctly. Overall, knowledge of T. solium infection among U.S. obstetricians gynecologists is limited. This may result in missed opportunities to diagnose and treat pregnant women with taeniasis, which may put family members and obstetrics clinical staff at risk for cysticercosis. PMID- 28077750 TI - The Association Between Neurocysticercosis and Hippocampal Atrophy is Related to Age. AB - Neurocysticercosis (NCC) has been associated with hippocampal atrophy, but the prevalence and pathogenic mechanisms implicated in this relationship are unknown. Using a population-based, case-control study design, residents in a rural village (Atahualpa) aged >= 40 years with calcified NCC were identified as cases and paired to NCC-free individuals (control subjects) matched by age, sex, and level of education. Cases and control subjects underwent magnetic resonance imaging for hippocampal rating according to the Scheltens' scale for medial temporal atrophy and were interviewed to identify those with a clinical seizure disorder. The prevalence of hippocampal atrophy was compared between cases and control subjects by the use of the McNemar's test for correlated proportions. Seventy-five individuals with calcified NCC and their matched control subjects were included in the analysis. Hippocampal atrophy was noted in 26 (34.7%) cases and nine (12%) control subjects (odds ratio: 4.4; 95% confidence interval: 1.6-14.9, P < 0.0021). Stratification of pairs according to tertiles of age revealed an age related trend in this association, which became significant only in those aged >= 68 years (P = 0.027). Only five cases and one control had recurrent seizures (P = 0.221); three of these five cases had hippocampal atrophy, and the single control subject had normal hippocampi. This study confirms an association between NCC and hippocampal atrophy, and shows that this association is stronger in older age groups. This suggests that NCC-related hippocampal atrophy takes a long time to develop. PMID- 28077752 TI - "Padon pa geri maleng" ("Sorry doesn't heal the scars"). PMID- 28077751 TI - Performance of Health Workers Using an Electronic Algorithm for the Management of Childhood Illness in Tanzania: A Pilot Implementation Study. AB - In low-resource settings, where qualified health workers (HWs) are scarce and childhood mortality high, rational antimicrobial prescription for childhood illnesses is a challenge. To assess whether smartphones running guidelines, as compared with paper support, improve consultation process and rational use of medicines for children, a pilot cluster-randomized controlled study was conducted in Tanzania. Nine primary health-care facilities (HFs) were randomized into three arms: 1) paper algorithm, 2) electronic algorithm on a smartphone, and 3) control. All HWs attending children aged 2-59 months for acute illness in intervention HFs were trained on a new clinical algorithm for management of childhood illness (ALMANACH) either on 1) paper or 2) electronic support; 4 months after training, consultations were observed. An expert consultation was the reference for classification and treatment. Main outcomes were proportion of children checked for danger signs, and antibiotics prescription rate. A total of 504 consultations (166, 171, and 167 in control, paper, and phone arms, respectively) were observed. The use of smartphones versus paper was associated with a significant increase in children checked for danger signs (41% versus 74%, P = 0.04). Antibiotic prescriptions rate dropped from 70% in the control to 26%, and 25% in paper and electronic arms. The HWs-expert agreement on pneumonia classification remained low (expert's pneumonia identified by HWs in 26%, 30%, and 39% of patients, respectively).Mobile technology in low-income countries is implementable and has a potential to improve HWs' performance. Additional point of-care diagnostic tests are needed to ensure appropriate management. Improving the rational use of antimicrobial is a challenge that ALMANACH can help to take up. PMID- 28077753 TI - Prevalence, location and concurrent diseases of ultrasonographic cyst-like lesions of abdominal lymph nodes in dogs. AB - Lymph nodal cyst-like lesions are occasionally identified during abdominal ultrasound in dogs. However, a study evaluating their prevalence and clinical significance is lacking. The aim of this observational cross-sectional study was to evaluate prevalence, most common location and concurrent diseases of cyst-like lymph nodes detected during abdominal ultrasound. Affected lymph nodes, patient signalment and concurrent diseases of dogs with cyst-like lymph nodal lesions having undergone abdominal ultrasound over a one-year period were recorded. Twenty-three affected lymph nodes were observed in 17/553 dogs (prevalence=3 per cent). The most commonly affected was the lumbar lymphocenter (7/23), followed by the coeliac (6/23), the cranial mesenteric (5/23) and the iliosacral (5/23). Twenty-three concurrent diseases were diagnosed in 17 dogs, among which 16/23 were non-neoplastic (70 per cent). The most common concurrent disease was renal insufficiency (8/23), followed by neoplasia (7/23), gastroenteropathy (3/23), benign prostatic disease (2/23), pancreatitis (1/23), peritonitis (1/23) and neurological disease (1/23). No statistical correlation existed between cyst-like lymph nodal lesion and a specific neoplastic or non-neoplastic disease. In conclusion, in the present study, cyst-like lymph nodal lesions have a low prevalence, involve different lymphocenters and were found in dogs affected by different diseases, including both non-neoplastic and neoplastic aetiologies. PMID- 28077754 TI - Double-blinded randomised placebo-controlled clinical trial of individualised homeopathic treatment of hyperthyroid cats. AB - Feline hyperthyroidism is a common endocrine disorder in older cats for which homeopathic treatment has been advocated. A double-blinded, placebo-controlled randomised trial was performed to look for evidence of efficacy for the use of individualised homeopathy in the treatment of this disease. Using a case definition of a concentration of the thyroid hormone T4 >66 nmol/l, cats were randomised into two treatment arms. Either a placebo or a homeopathic treatment was given to each cat blindly. After 21 days, the T4 levels, weight (Wt) and heart rate (HR) were compared with pretreatment values. There were no statistically significant differences in the changes seen between the two treatment arms following placebo or homeopathic treatment (T4 P=0.96, Wt P=0.16, HR P=0.36) or between the means of each parameter for either treatment arm before and after placebo or homeopathic treatment (all P values >0.13). In a second phase of the study, patients in both treatment arms were given methimazole treatment for 21 days and T4, Wt and HR determined again. Again there were no statistically significant differences between the groups, but there were statistically significant reductions in T4 (P<0.0001) and HR (P=0.02), and a statistically significant increase in Wt (P=0.004) in both groups compared with their pre-methimazole treatment levels. The results of this study failed to provide any evidence of the efficacy of homeopathic treatment of feline hyperthyroidism. PMID- 28077755 TI - Risk factors for road traffic accidents in cats up to age 12 months that were registered between 2010 and 2013 with the UK pet cat cohort ('Bristol Cats'). AB - Road traffic accidents (RTAs) are a common cause of death and injury in domestic cats, and a concern to many owners. This study assessed potential risk factors for RTAs in cats up to 12 months of age within a UK cat cohort known as 'The Bristol Cats study'. Data were obtained from three questionnaires, completed by cat owners when their cats were approximately 8-16 weeks old, 6 months old and 12 months old. Information was gathered regarding environmental conditions, cat characteristics and owner management factors. Univariable and multivariable logistic regression models were used to assess associations between these factors and RTAs. Of 1264 eligible study cats, 49 (3.9 per cent) had been involved in an RTA, of which 71.4 per cent (35/49) were known to result in fatal injuries. Rural locations were associated with a higher odds of RTAs than towns, cities or suburban locations. An increased odds of an RTA was also associated with cats that were reported by their owners to hunt at the roadside, as well as cats whose owners classified the road by their house as being a 'long straight section of road'. No significant associations were found between coat colour, breed, sex or neuter status and the odds of an RTA. PMID- 28077756 TI - Developing a risk-based trading scheme for cattle in England: farmer perspectives on managing trading risk for bovine tuberculosis. AB - This paper examines farmer attitudes towards the development of a voluntary risk based trading scheme for cattle in England as a risk mitigation measure for bovine tuberculosis (bTB). The research reported here was commissioned to gather evidence on the type of scheme that would have a good chance of success in improving the information farmers receive about the bTB risk of cattle they buy. Telephone interviews were conducted with a stratified random sample of 203 cattle farmers in England, splitting the interviews equally between respondents in the high-risk area and low-risk area for bTB. Supplementary interviews and focus groups with farmers were also carried out across the risk areas. Results suggest a greater enthusiasm for a risk-based trading scheme in low-risk areas compared with high-risk areas and among members of breed societies and cattle health schemes. Third-party certification of herds by private vets or the Animal and Plant Health Agency were regarded as the most credible source, with farmer self certification being favoured by sellers, but being regarded as least credible by buyers. Understanding farmers' attitudes towards voluntary risk-based trading is important to gauge likely uptake, understand preferences for information provision and to assist in monitoring, evaluating and refining the scheme once established. PMID- 28077757 TI - Biotypes and ScM types of isolates of Streptococcus canis from diseased and healthy cats. AB - Lancefield group G Streptococcus canis is a component of the normal urogenital and pharyngeal flora of the cat. It is also frequently implicated in epizootics of severe disease in closed cat colonies and animal shelters. Given the importance of S canis as a feline pathogen and relative lack of published information on characteristics potentially associated with virulence, the authors have compared isolates from healthy and diseased cats in New York and California using fermentation profiles (biotype) and ScM sequences. With few exceptions, isolates associated with disease were biotype 1. Four alleles of scm were identified of which type 1 dominated in diseased cats. Type 4 allelic variants were found only in healthy cats and all but one were biotype 2. Type 2 and 3 alleles showed extensive N-terminal variation suggesting a plasminogen-binding site as found on the type 1 allele was absent. Cat antisera to ScM were opsonobactericidal, and these potentially protective antibodies increased during convalescence. PMID- 28077758 TI - Inter-rater agreement in radiographic canine hip dysplasia evaluation. AB - The objective was to determine the agreement between scrutineers assessing canine hip dysplasia (CHD) within and between the Federation Cynologique Internationale (FCI) and the Swiss (CH) grading schemes, and between first-opinion and second opinion scrutineers using the CH scheme. 62 scrutineers, participating in a quality assessment programme, were asked to evaluate 12 sets of hip radiographs. All radiographs had been previously evaluated by a first-opinion and 7 by both a first-opinion and second-opinion scrutineers using the CH scheme. Inter-rater agreement (kappa) and intraclass correlation (ICC) were evaluated for the Norberg angle and dysplasia grades, and ICC for the numerical CH scores. The kappa and ICC were 0.290 and 0.471 for Norberg angles, 0.372 and 0.577 for FCI grades, and 0.417 and 0.567 for CH grades, respectively. The ICC for CH scores was 0.614. Total agreement for grades was found in a single case. For radiographs evaluated using both schemes, raters gave the same grade in 441 cases, a lower FCI than CH grade in 78 cases and a lower CH than FCI grade in 32 cases. Intrarater agreement between grades of the two schemes was 0.786. Agreement between the first-opinion and second-opinion scrutineers was 0.250 for Norberg angles and -0.286 for CH grades. Although agreement between the two schemes was good, agreement between scrutineers using either scheme was only fair to moderate, and no agreement was found between first-opinion and second-opinion scrutineers. Application of the FCI and CH schemes may impact the incidence of hip dysplasia in populations with both severe and moderate dysplasia, but is unlikely to impact populations with only mild dysplasia. The CH system of first-opinion and second-opinion examinations should be re-evaluated. PMID- 28077760 TI - Effective delivery of volatile biocides employing mesoporous silicates for treating biofilms. AB - Nanoparticulate delivery of biocides has the potential to decrease levels of exposure to non-target organisms, and miminize long-term exposure that can promote the development of resistance. Silica nanoparticles are an ideal vehicle since they are inert, biocompatible, biodegradable, and thermally and chemically stable. Encapsulation of biocides within nanoparticulates can improve their stability and longevity and maximize the biocidal potential of hydrophobic volatile compounds. Herein, we have shown that the plant secondary metabolites allyl isothiocyanate and cinnamaldehyde demonstrated increased antimicrobial activity against Escherichia coli in planktonic form, when packaged into mesoporous silica nanoparticles. Furthermore, the biocide-loaded nanoparticles showed activity against Pseudomonas aeruginosa biofilms that have inherent resistance to antimicrobial agents. The delivery platform can also be expanded to traditional biocides and other non-conventional antimicrobial agents. PMID- 28077759 TI - Complex responses to movement-based disease control: when livestock trading helps. AB - Livestock disease controls are often linked to movements between farms, for example, via quarantine and pre- or post-movement testing. Designing effective controls, therefore, benefits from accurate assessment of herd-to-herd transmission. Household models of human infections make use of R*, the number of groups infected by an initial infected group, which is a metapopulation level analogue of the basic reproduction number R0 that provides a better characterization of disease spread in a metapopulation. However, existing approaches to calculate R* do not account for individual movements between locations which means we lack suitable tools for livestock systems. We address this gap using next-generation matrix approaches to capture movements explicitly and introduce novel tools to calculate R* in any populations coupled by individual movements. We show that depletion of infectives in the source group, which hastens its recovery, is a phenomenon with important implications for design and efficacy of movement-based controls. Underpinning our results is the observation that R* peaks at intermediate livestock movement rates. Consequently, under movement-based controls, infection could be controlled at high movement rates but persist at intermediate rates. Thus, once control schemes are present in a livestock system, a reduction in movements can counterintuitively lead to increased disease prevalence. We illustrate our results using four important livestock diseases (bovine viral diarrhoea, bovine herpes virus, Johne's disease and Escherichia coli O157) that each persist across different movement rate ranges with the consequence that a change in livestock movements could help control one disease, but exacerbate another. PMID- 28077761 TI - On the autorotation of animal wings. AB - Botanical samaras spin about their centre of mass and create vertical aerodynamic forces which slow their rate of descent. Descending autorotation of animal wings, however, has never been documented. We report here that isolated wings from Anna's hummingbirds, and also from 10 species of insects, can stably autorotate and achieve descent speeds and aerodynamic performance comparable to those of samaras. A hummingbird wing loaded at its base with the equivalent of 50% of the bird's body mass descended only twice as fast as an unloaded wing, and rotated at frequencies similar to those of the wings in flapping flight. We found that even entire dead insects could stably autorotate depending on their wing postures. Feather removal trials showed no effect on descent velocity when the secondary feathers were removed from hummingbird wings. By contrast, partial removal of wing primaries substantially improved performance, except when only the outer primary was present. A scaling law for the aerodynamic performance of autorotating wings is well supported if the wing aspect ratio and the relative position of the spinning axis from the wing base are included. Autorotation is a useful and practical method that can be used to explore the aerodynamics of wing design. PMID- 28077762 TI - Inverse problems in reduced order models of cardiovascular haemodynamics: aspects of data assimilation and heart rate variability. AB - Inverse problems in cardiovascular modelling have become increasingly important to assess each patient individually. These problems entail estimation of patient specific model parameters from uncertain measurements acquired in the clinic. In recent years, the method of data assimilation, especially the unscented Kalman filter, has gained popularity to address computational efficiency and uncertainty consideration in such problems. This work highlights and presents solutions to several challenges of this method pertinent to models of cardiovascular haemodynamics. These include methods to (i) avoid ill-conditioning of the covariance matrix, (ii) handle a variety of measurement types, (iii) include a variety of prior knowledge in the method, and (iv) incorporate measurements acquired at different heart rates, a common situation in the clinic where the patient state differs according to the clinical situation. Results are presented for two patient-specific cases of congenital heart disease. To illustrate and validate data assimilation with measurements at different heart rates, the results are presented on a synthetic dataset and on a patient-specific case with heart valve regurgitation. It is shown that the new method significantly improves the agreement between model predictions and measurements. The developed methods can be readily applied to other pathophysiologies and extended to dynamical systems which exhibit different responses under different sets of known parameters or different sets of inputs (such as forcing/excitation frequencies). PMID- 28077763 TI - A simplified mathematical model of directional DNA site-specific recombination by serine integrases. AB - Serine integrases catalyse site-specific recombination to integrate and excise bacteriophage genomes into and out of their host's genome. These enzymes exhibit remarkable directionality; in the presence of the integrase alone, recombination between attP and attB DNA sites is efficient and irreversible, giving attL and attR products which do not recombine further. However, in the presence of the bacteriophage-encoded recombination directionality factor (RDF), integrase efficiently promotes recombination between attL and attR to re-form attP and attB The DNA substrates and products of both reactions are approximately isoenergetic, and no cofactors (such as adenosine triphosphate) are required for recombination. The thermodynamic driving force for directionality of these reactions is thus enigmatic. Here, we present a minimal mathematical model which can explain the directionality and regulation of both 'forward' and 'reverse' reactions. In this model, the substrates of the 'forbidden' reactions (between attL and attR in the absence of RDF, attP and attB in the presence of RDF) are trapped as inactive protein-DNA complexes, ensuring that these 'forbidden' reactions are extremely slow. The model is in good agreement with the observed in vitro kinetics of recombination by phiC31 integrase, and defines core features of the system necessary and sufficient for directionality. PMID- 28077764 TI - Antimicrobial peptide coatings for hydroxyapatite: electrostatic and covalent attachment of antimicrobial peptides to surfaces. AB - The interface between implanted devices and their host tissue is complex and is often optimized for maximal integration and cell adhesion. However, this also gives a surface suitable for bacterial colonization. We have developed a novel method of modifying the surface at the material-tissue interface with an antimicrobial peptide (AMP) coating to allow cell attachment while inhibiting bacterial colonization. The technology reported here is a dual AMP coating. The dual coating consists of AMPs covalently bonded to the hydroxyapatite surface, followed by deposition of electrostatically bound AMPs. The dual approach gives an efficacious coating which is stable for over 12 months and can prevent colonization of the surface by both Gram-positive and Gram-negative bacteria. PMID- 28077766 TI - Historical citizen science to understand and predict climate-driven trout decline. AB - Historical species records offer an excellent opportunity to test the predictive ability of range forecasts under climate change, but researchers often consider that historical records are scarce and unreliable, besides the datasets collected by renowned naturalists. Here, we demonstrate the relevance of biodiversity records developed through citizen-science initiatives generated outside the natural sciences academia. We used a Spanish geographical dictionary from the mid nineteenth century to compile over 10 000 freshwater fish records, including almost 4 000 brown trout (Salmo trutta) citations, and constructed a historical presence-absence dataset covering over 2 000 10 * 10 km cells, which is comparable to present-day data. There has been a clear reduction in trout range in the past 150 years, coinciding with a generalized warming. We show that current trout distribution can be accurately predicted based on historical records and past and present values of three air temperature variables. The models indicate a consistent decline of average suitability of around 25% between 1850s and 2000s, which is expected to surpass 40% by the 2050s. We stress the largely unexplored potential of historical species records from non-academic sources to open new pathways for long-term global change science. PMID- 28077765 TI - Acute embryonic anoxia exposure favours the development of a dominant and aggressive phenotype in adult zebrafish. AB - Eutrophication and climate change are increasing the incidence of severe hypoxia in fish nursery habitats, yet the programming effects of hypoxia on stress responsiveness in later life are poorly understood. In this study, to investigate whether early hypoxia alters the developmental trajectory of the stress response, zebrafish embryos were exposed to 4 h of anoxia at 36 h post-fertilization and reared to adults when the responses to secondary stressors were assessed. While embryonic anoxia did not affect basal cortisol levels or the cortisol response to hypoxia in later life, it had a marked effect on the responses to a social stressor. In dyadic social interactions, adults derived from embryonic anoxia initiated more chases, bit more often, entered fewer freezes and had lower cortisol levels. Adults derived from embryonic anoxia also performed more bites towards their mirror image, had lower gonadal aromatase gene expression and had higher testosterone levels. We conclude that acute embryonic anoxia has long lasting consequences for the hormonal and behavioural responses to social interactions in zebrafish. Specifically, we demonstrate that acute embryonic anoxia favours the development of a dominant and aggressive phenotype, and that a disruption in sex steroid production may contribute to the programming effects of environmental hypoxia. PMID- 28077767 TI - What North America's skeleton crew of megafauna tells us about community disassembly. AB - Functional trait diversity is increasingly used to model future changes in community structure despite a poor understanding of community disassembly's effects on functional diversity. By tracking the functional diversity of the North American large mammal fauna through the End-Pleistocene megafaunal extinction and up to the present, I show that contrary to expectations, functionally unique species are no more likely to go extinct than functionally redundant species. This makes total functional richness loss no worse than expected given similar taxonomic richness declines. However, where current species sit in functional space relative to pre-anthropogenic baselines is not random and likely explains ecosystem functional changes better than total functional richness declines. Prehistoric extinctions have left many extant species functionally isolated and future extinctions will cause even more rapid drops in functional richness. PMID- 28077768 TI - Corticosterone and timing of migratory departure in a songbird. AB - Bird migration entails replenishing fuel stores at stopover sites. There, individuals make daily decisions whether to resume migration, and must also decide their time of departure. Variation in departure timing affects the total time required to complete a migratory journey, which in turn affects fitness through arrival time at the breeding and wintering grounds. It is well established that stopover departure decisions are based on cues from innate rhythms, intrinsic factors and extrinsic factors. Yet, virtually nothing is known about the physiological mechanism(s) linking these cues to departure decisions. Here, we show for a nocturnal migratory songbird, the northern wheatear (Oenanthe oenanthe), that baseline corticosterone levels of birds at stopover increased both over the migratory season and with wind assistance towards the migratory destination. Corticosterone in turn predicted departure probability; individuals with high baseline corticosterone levels were more likely to resume migration on a given night. Corticosterone further predicted the departure time within the night, with high baseline levels being associated with early departures. These novel findings indicate that corticosterone may be mediating between departure cues and the timing of departure from a stopover site, which is a major step towards understanding the hormonal control of animal migration. PMID- 28077769 TI - Dog-directed speech: why do we use it and do dogs pay attention to it? AB - Pet-directed speech is strikingly similar to infant-directed speech, a peculiar speaking pattern with higher pitch and slower tempo known to engage infants' attention and promote language learning. Here, we report the first investigation of potential factors modulating the use of dog-directed speech, as well as its immediate impact on dogs' behaviour. We recorded adult participants speaking in front of pictures of puppies, adult and old dogs, and analysed the quality of their speech. We then performed playback experiments to assess dogs' reaction to dog-directed speech compared with normal speech. We found that human speakers used dog-directed speech with dogs of all ages and that the acoustic structure of dog-directed speech was mostly independent of dog age, except for sound pitch which was relatively higher when communicating with puppies. Playback demonstrated that, in the absence of other non-auditory cues, puppies were highly reactive to dog-directed speech, and that the pitch was a key factor modulating their behaviour, suggesting that this specific speech register has a functional value in young dogs. Conversely, older dogs did not react differentially to dog directed speech compared with normal speech. The fact that speakers continue to use dog-directed with older dogs therefore suggests that this speech pattern may mainly be a spontaneous attempt to facilitate interactions with non-verbal listeners. PMID- 28077770 TI - Correction to 'Life-history characteristics influence physiological strategies to cope with hypoxia in Himalayan birds'. PMID- 28077771 TI - The correlated evolution of antipredator defences and brain size in mammals. AB - Mammals that possess elaborate antipredator defences such as body armour, spines and quills are usually well protected, intermediate in size, primarily insectivorous and live in simple open environments. The benefits of such defences seem clear and may relax selection on maintaining cognitive abilities that aid in vigilance and predator recognition, and their bearers may accrue extensive production and maintenance costs. Here, in this comparative phylogenetic analysis of measurements of encephalization quotient and morphological defence scores of 647 mammal species representing nearly every order, we found that as lineages evolve stronger defences, they suffer a correlated reduction in encephalization. The only exceptions were those that live in trees-a complex three-dimensional world probably requiring greater cognitive abilities. At the proximate level, because brain tissue is extremely energetically expensive to build, mammals may be trading off spending more on elaborate defences and saving by building less powerful brains. At the ultimate level, having greater defences may also reduce the need for advanced cognitive abilities for constant assessment of environmental predation risk, especially in simple open environments. PMID- 28077772 TI - Phylogenomics provides new insight into evolutionary relationships and genealogical discordance in the reef-building coral genus Acropora. AB - Understanding the genetic basis of reproductive isolation is a long-standing goal of speciation research. In recently diverged populations, genealogical discordance may reveal genes and genomic regions that contribute to the speciation process. Previous work has shown that conspecific colonies of Acropora that spawn in different seasons (spring and autumn) are associated with highly diverged lineages of the phylogenetic marker PaxC Here, we used 10 034 single nucleotide polymorphisms to generate a genome-wide phylogeny and compared it with gene genealogies from the PaxC intron and the mtDNA Control Region in 20 species of Acropora, including three species with spring- and autumn-spawning cohorts. The PaxC phylogeny separated conspecific autumn and spring spawners into different genetic clusters in all three species; however, this pattern was not supported in two of the three species at the genome level, suggesting a selective connection between PaxC and reproductive timing in Acropora corals. This genome wide phylogeny provides an improved foundation for resolving phylogenetic relationships in Acropora and, combined with PaxC, provides a fascinating platform for future research into regions of the genome that influence reproductive isolation and speciation in corals. PMID- 28077773 TI - Low functional diversity promotes niche changes in natural island pollinator communities. AB - Functional diversity loss among pollinators has rapidly progressed across the globe and is expected to influence plant-pollinator interactions in natural communities. Although recent findings suggest that the disappearance of a certain pollinator functional group may cause niche expansions and/or shifts in other groups, no study has examined this prediction in natural communities with high plant and pollinator diversities. By comparing coastal pollination networks on continental and oceanic islands, we examined how community-level flower visit patterns are influenced by the relative biomass of long-tongued pollinators (RBLP). We found that RBLP significantly correlated with pollinator functional diversity and was lower in oceanic than in continental islands. Pollinator niches shifted with decreasing RBLP, such that diverse species with various proboscis lengths, especially short-tongued species, increasingly visited long-tubed flowers. However, we found no conspicuous negative impacts of low RBLP and the consequent niche shifts on pollinator visit frequencies to flowers in oceanic island communities. Notably, fruit set significantly decreased as RBLP decreased in a study plant species. These results suggest that niche shifts by other functional groups can generally compensate for a decline in long-tongued pollinators in natural communities, but there may be negative impacts on plant reproduction. PMID- 28077774 TI - Tropical ancient DNA reveals relationships of the extinct Bahamian giant tortoise Chelonoidis alburyorum. AB - Ancient DNA of extinct species from the Pleistocene and Holocene has provided valuable evolutionary insights. However, these are largely restricted to mammals and high latitudes because DNA preservation in warm climates is typically poor. In the tropics and subtropics, non-avian reptiles constitute a significant part of the fauna and little is known about the genetics of the many extinct reptiles from tropical islands. We have reconstructed the near-complete mitochondrial genome of an extinct giant tortoise from the Bahamas (Chelonoidis alburyorum) using an approximately 1 000-year-old humerus from a water-filled sinkhole (blue hole) on Great Abaco Island. Phylogenetic and molecular clock analyses place this extinct species as closely related to Galapagos (C. niger complex) and Chaco tortoises (C. chilensis), and provide evidence for repeated overseas dispersal in this tortoise group. The ancestors of extant Chelonoidis species arrived in South America from Africa only after the opening of the Atlantic Ocean and dispersed from there to the Caribbean and the Galapagos Islands. Our results also suggest that the anoxic, thermally buffered environment of blue holes may enhance DNA preservation, and thus are opening a window for better understanding evolution and population history of extinct tropical species, which would likely still exist without human impact. PMID- 28077775 TI - Dung odours signal sex, age, territorial and oestrous state in white rhinos. AB - Mammals commonly communicate olfactorily via urine. However, the extent to which they communicate via dung, another waste product, is unknown. Behavioural studies suggest that mammals can obtain information from dung odours but are unclear about the information transmitted. Moreover, an understanding of the volatile organic compounds (VOCs) released from dung is limited. To address this, we analysed the odours emitted from the dung of free-ranging white rhinos, and found that 2,3-dimethylundecane signalled an individual's sex, heptanal discriminated age class, nonane defined male territorial status and 2,6-dimethylundecane indicated female oestrous state. To validate these findings, we artificially reproduced key elements of the territorial and oestrous odour profiles (i.e. profiles likely to elicit behavioural responses from receivers). We then exposed free-ranging territorial males to these odours. In response, males elicited behaviours associated with the specific odours (e.g. territorial male (potential threat): reduced latency in assuming vigilance; oestrous female (potential mate): increased investigation). These results indicate that the VOCs identified from the dung of free-ranging individuals do transmit key information. Moreover, as white rhinos of all ages and sexes defecate communally, middens probably act as information centres. Furthermore, as many other mammals defecate communally, olfactory communication via dung odours is likely a widespread phenomenon. PMID- 28077776 TI - Odour-based discrimination of similarity at the major histocompatibility complex in birds. AB - Many animals are known to preferentially mate with partners that are dissimilar at the major histocompatibility complex (MHC) in order to maximize the antigen binding repertoire (or disease resistance) in their offspring. Although several mammals, fish or lizards use odour cues to assess MHC similarity with potential partners, the ability of birds to assess MHC similarity using olfactory cues has not yet been explored. Here we used a behavioural binary choice test and high throughput-sequencing of MHC class IIB to determine whether blue petrels can discriminate MHC similarity based on odour cues alone. Blue petrels are seabirds with particularly good sense of smell, they have a reciprocal mate choice and are known to preferentially mate with MHC-dissimilar partners. Incubating males preferentially approached the odour of the more MHC-dissimilar female, whereas incubating females showed opposite preferences. Given their mating pattern, females were, however, expected to show preference for the odour of the more MHC dissimilar male. Further studies are needed to determine whether, as in women and female mice, the preference varies with the reproductive cycle in blue petrel females. Our results provide the first evidence that birds can use odour cues only to assess MHC dissimilarity. PMID- 28077777 TI - No evidence for thermal transgenerational plasticity in metabolism when minimizing the potential for confounding effects. AB - Environmental change may cause phenotypic changes that are inherited across generations through transgenerational plasticity (TGP). If TGP is adaptive, offspring fitness increases with an increasing match between parent and offspring environment. Here we test for adaptive TGP in somatic growth and metabolic rate in response to temperature in the clonal zooplankton Daphnia pulex Animals of the first focal generation experienced thermal transgenerational 'mismatch' (parental and offspring temperatures differed), whereas conditions of the next two generations matched the (grand)maternal thermal conditions. Adjustments of metabolic rate occurred during the lifetime of the first generation (i.e. within generation plasticity). However, no further change was observed during the subsequent two generations, as would be expected under TGP. Furthermore, we observed no tendency for increased juvenile somatic growth (a trait highly correlated with fitness in Daphnia) over the three generations when reared at new temperatures. These results are inconsistent with existing studies of thermal TGP, and we describe how previous experimental designs may have confounded TGP with within-generation plasticity and selective mortality. We suggest that the current evidence for thermal TGP is weak. To increase our understanding of the ecological and evolutionary role of TGP, future studies should more carefully identify possible confounding factors. PMID- 28077778 TI - Uncertain-tree: discriminating among competing approaches to the phylogenetic analysis of phenotype data. AB - Morphological data provide the only means of classifying the majority of life's history, but the choice between competing phylogenetic methods for the analysis of morphology is unclear. Traditionally, parsimony methods have been favoured but recent studies have shown that these approaches are less accurate than the Bayesian implementation of the Mk model. Here we expand on these findings in several ways: we assess the impact of tree shape and maximum-likelihood estimation using the Mk model, as well as analysing data composed of both binary and multistate characters. We find that all methods struggle to correctly resolve deep clades within asymmetric trees, and when analysing small character matrices. The Bayesian Mk model is the most accurate method for estimating topology, but with lower resolution than other methods. Equal weights parsimony is more accurate than implied weights parsimony, and maximum-likelihood estimation using the Mk model is the least accurate method. We conclude that the Bayesian implementation of the Mk model should be the default method for phylogenetic estimation from phenotype datasets, and we explore the implications of our simulations in reanalysing several empirical morphological character matrices. A consequence of our finding is that high levels of resolution or the ability to classify species or groups with much confidence should not be expected when using small datasets. It is now necessary to depart from the traditional parsimony paradigms of constructing character matrices, towards datasets constructed explicitly for Bayesian methods. PMID- 28077779 TI - From the Cover: Embryonic Exposure to TCDD Impacts Osteogenesis of the Axial Skeleton in Japanese medaka, Oryzias latipes. AB - Recent studies from mammalian, fish, and in vitro models have identified bone and cartilage development as sensitive targets for dioxins and other aryl hydrocarbon receptor ligands. In this study, we assess how embryonic 2,3,7,8 tetrachlorochlorodibenzo-p-dioxin (TCDD) exposure impacts axial osteogenesis in Japanese medaka (Oryzias latipes), a vertebrate model of human bone development. Embryos from inbred wild-type Orange-red Hd-dR and 3 transgenic medaka lines (twist:EGFP, osx/sp7:mCherry, col10a1:nlGFP) were exposed to 0.15 nM and 0.3 nM TCDD and reared until 20 dpf. Individuals were stained for mineralized bone and imaged using confocal microscopy to assess skeletal alterations in medial vertebrae in combination with a qualitative spatial analysis of osteoblast and osteoblast progenitor cell populations. Exposure to TCDD resulted in an overall attenuation of vertebral ossification characterized by truncated centra, and reduced neural and hemal arch lengths. Effects on mineralization were consistent with modifications in cell number and cell localization of transgene-labeled osteoblast and osteoblast progenitor cells. Endogenous expression of osteogenic regulators runt-related transcription factor 2 (runx2) and osterix (osx/sp7), and extracellular matrix genes osteopontin (spp1), collagen type I alpha I (col1), collagen type X alpha I (col10a1), and osteocalcin (bglap/osc) was significantly diminished at 20 dpf following TCDD exposure as compared with controls. Through global transcriptomic analysis more than 590 differentially expressed genes were identified and mapped to select pathological states including inflammatory disease, connective tissue disorders, and skeletal and muscular disorders. Taken together, results from this study suggest that TCDD exposure inhibits axial bone formation through dysregulation of osteoblast differentiation. This approach highlights the advantages and sensitivity of using small fish models to investigate how xenobiotic exposure may impact skeletal development. PMID- 28077780 TI - Editor's Highlight: Exposure to CrVI during Early Pregnancy Increases Oxidative Stress and Disrupts the Expression of Antioxidant Proteins in Placental Compartments. AB - Epidemiologic studies document relationships between chromium VI (CrVI) exposure and increased risk of spontaneous abortion, stillbirth, preterm birth, and neonatal death in pregnant women. Environmental contamination with CrVI is a growing problem both in the United States and developing countries. CrVI is widely used in numerous industries. This study was designed to understand the mechanism of CrVI toxicity on placental oxidative stress and antioxidant (AOX) machinery. Pregnant mother rats were treated with or without CrVI (50 ppm K2Cr2O7) through drinking water from gestational day (GD) 9.5-14.5, and placentas were analyzed on GD 18.5. Results indicated that CrVI reduced the trophoblast cell population. CrVI increased reactive oxygen species (ROS) and decreased the expression of AOX proteins. CrVI disrupts the trophoblast proliferation of the placenta. This study provides insight into the critical role of AOXs in placental function. PMID- 28077781 TI - Effects of an unusual poison identify a lifespan role for Topoisomerase 2 in Saccharomyces cerevisiae. AB - A progressive loss of genome maintenance has been implicated as both a cause and consequence of aging. Here we present evidence supporting the hypothesis that an age-associated decay in genome maintenance promotes aging in Saccharomyces cerevisiae (yeast) due to an inability to sense or repair DNA damage by topoisomerase 2 (yTop2). We describe the characterization of LS1, identified in a high throughput screen for small molecules that shorten the replicative lifespan of yeast. LS1 accelerates aging without affecting proliferative growth or viability. Genetic and biochemical criteria reveal LS1 to be a weak Top2 poison. Top2 poisons induce the accumulation of covalent Top2-linked DNA double strand breaks that, if left unrepaired, lead to genome instability and death. LS1 is toxic to cells deficient in homologous recombination, suggesting that the damage it induces is normally mitigated by genome maintenance systems. The essential roles of yTop2 in proliferating cells may come with a fitness trade-off in older cells that are less able to sense or repair yTop2-mediated DNA damage. Consistent with this idea, cells live longer when yTop2 expression levels are reduced. These results identify intrinsic yTop2-mediated DNA damage as potentially manageable cause of aging. PMID- 28077783 TI - Association between metformin use and mortality in patients with type 2 diabetes mellitus and localized resectable pancreatic cancer: a nationwide population based study in korea. AB - BACKGROUND: Preclinical studies support an antitumor effect of metformin. However, clinical studies have conflicting results and metformin's effect remains controversial. The aim of this study was to evaluate metformin's effect on clinical outcomes in diabetic patients with pancreatic cancer treated with curative resection. RESULTS: A total of 764 patients underwent curative resection, met none of the exclusion criteria, and were prescribed oral hypoglycemic agents. The cancer-specific survival (5-year, 31.9% vs. 22.2%, p < 0.001) was significantly higher in the 530 metformin users than in the 234 diabetic metformin non-users. After multivariable adjustments, metformin users had significantly lower cancer-specific mortality as compared with metformin non users (hazard ratio, 0.727; 95% confidence interval, 0.611-0.868). Cubic spline regression analysis demonstrated significantly decreased cancer-specific mortality with increasing dose of metformin (p = 0.0047). MATERIALS AND METHODS: Data were provided from the Korea Central Cancer Registry and the National Health Insurance Service in the Republic of Korea. The study cohort consisted of 28,862 patients newly diagnosed with pancreatic cancer between 2005 and 2011. Metformin exposure was determined from prescription information from 6 months before the first diagnosis of pancreatic cancer to last follow-up. The main outcome was cancer-specific survival. CONCLUSIONS: This large study indicates that metformin might decrease cancer-specific mortality rates in localized resectable pancreatic cancer patients with pre-existing diabetes, independently of other factors, with a dose-response relationship. PMID- 28077784 TI - Identification and characterization of HPV-independent cervical cancers. AB - BACKGROUND: Human papillomavirus (HPV) initiates cervical cancer, and continuous expression of HPV oncogenes E6 and E7 is thought to be necessary to maintain malignant growth. Current therapies target proliferating cells, rather than specific pathways, and most experimental therapies specifically target E6/E7. We investigated the presence and expression of HPV in cervical cancer, to correlate HPV oncogene expression with clinical and molecular features of these tumors that may be relevant to new targeted therapies. RESULTS: While virtually all cervical cancers contained HPV DNA, and most expressed E6/E7 (HPV-active), a subset (8%) of HPV DNA-positive cervical cancers did not express HPV transcripts (HPV inactive). HPV-inactive tumors occurred in older women (median 54 vs. 45 years, p = 0.02) and were associated with poorer survival (median 715 vs 3046 days, p = 0.0003). Gene expression profiles of HPV-active and -inactive tumors were distinct. HPV-active tumors expressed E2F target genes and increased AKT/MTOR signaling. HPV-inactive tumors had increased WNT/beta-catenin and Sonic Hedgehog signaling. Substantial genome-wide differences in DNA methylation were observed. HPV-inactive tumors had a global decrease in DNA methylation; however, many promoter-associated CpGs were hypermethylated. Many inflammatory response genes showed promoter methylation and decreased expression. The somatic mutation landscapes were significantly different. HPV-active tumors carried few somatic mutations in driver genes, whereas HPV-inactive tumors were enriched for non synonymous somatic mutations (p-value < 0.0000001) specifically targeting TP53, ARID, WNT, and PI3K pathways. MATERIALS AND METHODS: The Cancer Genome Atlas (TCGA) cervical cancer data were analyzed. CONCLUSIONS: Many of the gene expression changes and somatic mutations found in HPV-inactive tumors alter pathways for which targeted therapeutics are available. Treatment strategies focused on WNT, PI3K, or TP53 mutations may be effective against HPV-inactive tumors and could improve survival for these cervical cancer patients. PMID- 28077785 TI - The diagnostic performance of shear wave speed (SWS) imaging for thyroid nodules with elasticity modulus and SWS measurement. AB - To evaluate the diagnostic performance of a new technique of shear wave speed (SWS) imaging for the diagnosis of thyroid nodule with elasticity modulus and SWS measurement. 322 thyroid nodules in 322 patients (216 benign nodules, 106 malignant nodules) were included in this study. All the nodules received conventional ultrasound (US) and SWS imaging (Aplio500, Toshiba Medical Systems, Japan) before fine-needle aspiration (FNA) and/or surgery. The values of E-max and E-mean with elastic modulus (61.27 +/- 36.31 kPa and 31.89 +/- 19.11 kPa) or SWS (4.45 +/- 1.49 m/s and 3.26 +/- 2.71 m/s) in malignant nodules were significantly higher than those in benign lesions (29.18 +/- 18.62 kPa and 15.85 +/- 6.96 kPa, or 2.98 +/- 0.85 m/s and 2.19 +/- 0.42 m/s, all P < 0.001). No significant differences in area under the curve (AUC) between the SWS imaging parameters were found (all P > 0.05). In multivariate logistic regression analysis, E-max (m/s) with SWS was identified to be the strongest independent predictor for malignant nodules (odds ratio [OR] = 16.760), followed by poorly defined margin (OR = 7.792), taller-than-wide shape (OR = 3.160), micro calcification (OR = 2.422), and E-max (kPa) with elastic modulus (OR = 0.914). The AUC was 0.813 for E-max with SWS (m/s) and 0.796 for E-max with elastic modulus (kPa). With cut-off SWS value of 3.52 m/s in E-max, sensitivity of 69.8%, specificity of 81.5%, and accuracy of 77.6% were achieved. SWS imaging is a valuable tool in predicting thyroid malignancy. E-max with SWS measurement is the strongest independent predictor for thyroid malignancy. PMID- 28077786 TI - Nomogram analysis and external validation to predict the risk of lymph node metastasis in gastric cancer. AB - AIM: To identify risk factors for lymph node metastasis using a nomogram for gastric cancer patients to predict lymph node metastasis. RESULTS: The Chi-square test and the logistic regression showed that the Boarrmann type, preoperative CA199 level, T stage and N stage by CT scan were independent risk factors. The concordance index (C-index) was 0.786 in the internal validation of the Nomogram model. In the external validation, the C-index was 0.809, and the AUC was 0.894. The total accuracy of the prediction was 82.2%, and the false-negative rate was 5.4% with a cut-off value set at 0.109. MATERIALS AND METHODS: The study consisted of 451 patients with a histological diagnosis of gastric cancer with 0 or 1 lymph node metastasis from the Sun Yat-sen University Cancer Center as the development set, and the validation set consisted of 186 gastric cancer patients from the Sixth Affiliated Hospital of Sun Yat-Sen University. A Chi-square test and a logistic regression analysis were used to compare the clinicopathological variables and lymph node metastasis. The C-index and ROC curve were computed for comparisons of the nomogram's predictive ability. CONCLUSIONS: We developed and validated a nomogram to predict lymph node metastasis in gastric cancer before surgery. This nomogram can be broadly applied, even in general hospitals, and is useful for decisions regarding treatment programs for patients. PMID- 28077782 TI - Serum and tissue markers in hepatocellular carcinoma and cholangiocarcinoma: clinical and prognostic implications. AB - HCC represents the sixth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence, treatment options for advanced HCC remain limited and unsuccessful, resulting in a poor prognosis. Despite the major advances achieved in the diagnostic management of HCC, only one third of the newly diagnosed patients are presently eligible for curative treatments. Advances in technology and an increased understanding of HCC biology have led to the discovery of novel biomarkers. Improving our knowledge about serum and tissutal markers could ultimately lead to an early diagnosis and better and early treatment strategies for this deadly disease. Serum biomarkers are striking potential tools for surveillance and early diagnosis of HCC thanks to the non-invasive, objective, and reproducible assessments they potentially enable. To date, many biomarkers have been proposed in the diagnosis of HCC. Cholangiocarcinoma (CCA) is an aggressive malignancy, characterized by early lymph node involvement and distant metastasis, with 5-year survival rates of 5% 10%. The identification of new biomarkers with diagnostic, prognostic or predictive value is especially important as resection (by surgery or combined with a liver transplant) has shown promising results and novel therapies are emerging. However, the relatively low incidence of CCA, high frequency of co existing cholestasis or cholangitis (primary sclerosing cholangitis -PSC- above all), and difficulties with obtaining adequate samples, despite advances in sampling techniques and in endoscopic visualization of the bile ducts, have complicated the search for accurate biomarkers. In this review, we attempt to analyze the existing literature on this argument. PMID- 28077787 TI - Androgen suppresses protein kinase D1 expression through fibroblast growth factor receptor substrate 2 in prostate cancer cells. AB - In prostate cancer, androgen/androgen receptor (AR) and their downstream targets play key roles in all stages of disease progression. The protein kinase D (PKD) family, particularly PKD1, has been implicated in prostate cancer biology. Here, we examined the cross-regulation of PKD1 by androgen signaling in prostate cancer cells. Our data showed that the transcription of PKD1 was repressed by androgen in androgen-sensitive prostate cancer cells. Steroid depletion caused up regulation of PKD1 transcript and protein, an effect that was reversed by the AR agonist R1881 in a time- and concentration-dependent manner, thus identifying PKD1 as a novel androgen-repressed gene. Kinetic analysis indicated that the repression of PKD1 by androgen required the induction of a repressor protein. Furthermore, inhibition or knockdown of AR reversed AR agonist-induced PKD1 repression, indicating that AR was required for the suppression of PKD1 expression by androgen. Downstream of AR, we identified fibroblast growth factor receptor substrate 2 (FRS2) and its downstream MEK/ERK pathway as mediators of androgen-induced PKD1 repression. In summary, PKD1 was identified as a novel androgen-suppressed gene and could be downregulated by androgen through a novel AR/FRS2/MEK/ERK pathway. The upregulation of prosurvival PKD1 by anti-androgens may contribute to therapeutic resistance in prostate cancer treatment. PMID- 28077788 TI - Androgen receptor splice variants and prostate cancer: From bench to bedside. AB - Therapeutic interventions for advanced prostate cancer (PCa) center on inhibiting androgen receptor (AR) and downstream signaling pathways. Resistance to androgen deprivation therapy and/or AR antagonists is inevitable and molecular mechanisms driving castration-resistant PCa (CR-PCa) primarily involve alterations in AR expression and activity. Detailed molecular biology work over the past decade, discussed at length in this review article, has revealed several AR transcripts that result from alternative splicing. These AR splice variants are increased in cell and mouse models of CR-PCa and in CR-PCa tumors. Several AR variants lack the ligand binding domain, but retain their ability to bind DNA and activate transcription-linking constitutive AR function and therapeutic failure. ARV7 is the only variant endogenously detected at the protein level and thus has undergone more thorough molecular characterization. Clinical trials in PCa are currently investigating ARV7 utility as a biomarker and new therapeutics that inhibit ARV7 . Overall, this review will illustrate the historical perspectives of AR splice variant discovery using fundamental molecular biology techniques and how it changed the clinical approach to both therapeutic decisions and strategy. The body of work investigating AR splice variants in PCa represents a true example of translational research from bench to bedside. PMID- 28077789 TI - Biological functions of CDK5 and potential CDK5 targeted clinical treatments. AB - Cyclin dependent kinases are proline-directed serine/threonine protein kinases that are traditionally activated upon association with a regulatory subunit. For most CDKs, activation by a cyclin occurs through association and phosphorylation of the CDK's T-loop. CDK5 is unusual because it is not typically activated upon binding with a cyclin and does not require T-loop phosphorylation for activation, even though it has high amino acid sequence homology with other CDKs. While it was previously thought that CDK5 only interacted with p35 or p39 and their cleaved counterparts, Recent evidence suggests that CDK5 can interact with certain cylins, amongst other proteins, which modulate CDK5 activity levels. This review discusses recent findings of molecular interactions that regulate CDK5 activity and CDK5 associated pathways that are implicated in various diseases. Also covered herein is the growing body of evidence for CDK5 in contributing to the onset and progression of tumorigenesis. PMID- 28077790 TI - FLT3 activating mutations display differential sensitivity to multiple tyrosine kinase inhibitors. AB - Fms-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase that normally functions in hematopoietic cell survival, proliferation and differentiation. Constitutively activating mutations of FLT3 map predominately to the juxtamembrane domain (internal tandem duplications; ITD) or the activation loop (AL) of the kinase domain and are detected in about 1/3 of de novo acute myeloid leukemia (AML) patients. Small molecule tyrosine kinase inhibitors (TKI) effectively target FLT3/ITD mutations, but some activating mutations, particularly those on the AL, are relatively resistant to many FLT3 TKI. We reproduced many of the AL or other non-ITD activating mutations and tested 13 FLT3 TKI for their activity against these and wild-type FLT3. All 13 TKI tested inhibited BaF3/ITD cell proliferation in a concentration-dependent manner as reported, but most TKI exhibited a wide range of differential activity against AL and other point mutants. Western blotting results examining inhibition of FLT3 autophosphorylation and signaling pathways indicate that many AL mutations reduce TKI binding. Most FLT3 TKI effectively target wild-type FLT3 signaling. As a demonstration of this differential activity, treatment of BaF3 D835Y cells transplanted in BALB/c mice with sorafenib showed no effect in vivo against this mutant whereas lestaurtinib proved effective at reducing disease burden. Thus, while FLT3 TKI have been selected based on their ability to inhibit FLT3/ITD, the selection of appropriate TKI for AML patients with FLT3 AL and other activating point mutations requires personalized consideration. PMID- 28077791 TI - Carcinoma-risk variant of EBNA1 deregulates Epstein-Barr Virus episomal latency. AB - Epstein-Barr Virus (EBV) latent infection is a causative co-factor for endemic Nasopharyngeal Carcinoma (NPC). NPC-associated variants have been identified in EBV-encoded nuclear antigen EBNA1. Here, we solve the X-ray crystal structure of an NPC-derived EBNA1 DNA binding domain (DBD) and show that variant amino acids are found on the surface away from the DNA binding interface. We show that NPC derived EBNA1 is compromised for DNA replication and episome maintenance functions. Recombinant virus containing the NPC EBNA1 DBD are impaired in their ability to immortalize primary B-lymphocytes and suppress lytic transcription during early stages of B-cell infection. We identify Survivin as a host protein deficiently bound by the NPC variant of EBNA1 and show that Survivin depletion compromises EBV episome maintenance in multiple cell types. We propose that endemic variants of EBNA1 play a significant role in EBV-driven carcinogenesis by altering key regulatory interactions that destabilize latent infection. PMID- 28077794 TI - Large-scale genomic deletions mediated by CRISPR/Cas9 system. PMID- 28077795 TI - PRAK mediates Abeta-RAGE driven autophagy pathway. PMID- 28077793 TI - Integrated proteomic and N-glycoproteomic analyses of doxorubicin sensitive and resistant ovarian cancer cells reveal glycoprotein alteration in protein abundance and glycosylation. AB - Ovarian cancer is one of the most common cancer among women in the world, and chemotherapy remains the principal treatment for patients. However, drug resistance is a major obstacle to the effective treatment of ovarian cancers and the underlying mechanism is not clear. An increased understanding of the mechanisms that underline the pathogenesis of drug resistance is therefore needed to develop novel therapeutics and diagnostic. Herein, we report the comparative analysis of the doxorubicin sensitive OVCAR8 cells and its doxorubicin-resistant variant NCI/ADR-RES cells using integrated global proteomics and N glycoproteomics. A total of 1525 unique N-glycosite-containing peptides from 740 N-glycoproteins were identified and quantified, of which 253 N-glycosite containing peptides showed significant change in the NCI/ADR-RES cells. Meanwhile, stable isotope labeling by amino acids in cell culture (SILAC) based comparative proteomic analysis of the two ovarian cancer cells led to the quantification of 5509 proteins. As about 50% of the identified N-glycoproteins are low-abundance membrane proteins, only 44% of quantified unique N-glycosite containing peptides had corresponding protein expression ratios. The comparison and calibration of the N-glycoproteome versus the proteome classified 14 change patterns of N-glycosite-containing peptides, including 8 up-regulated N-glycosite containing peptides with the increased glycosylation sites occupancy, 35 up regulated N-glycosite-containing peptides with the unchanged glycosylation sites occupancy, 2 down-regulated N-glycosite-containing peptides with the decreased glycosylation sites occupancy, 46 down-regulated N-glycosite-containing peptides with the unchanged glycosylation sites occupancy. Integrated proteomic and N glycoproteomic analyses provide new insights, which can help to unravel the relationship of N-glycosylation and multidrug resistance (MDR), understand the mechanism of MDR, and discover the new diagnostic and therapeutic targets. PMID- 28077792 TI - Prognostic value of the pretreatment neutrophil-to-lymphocyte ratio in cervical cancer: a meta-analysis and systematic review. AB - The prognostic value of pretreatment neutrophil-to-lymphocyte ratio (NLR) in cervical cancer remains controversial. We conducted a meta-analysis based on the data from 13 studies with 3729 patients to evaluate the association between the pretreatment NLR and the clinical outcomes of overall survival and progression free survival in patients with cervical cancer. The relationship between NLR and clinicopathological parameters was also assessed. Hazard ratio (HR) or odds ratio (OR) with its 95% confidence interval (CI) was used as the effect size estimate. Our analysis indicated that elevated pretreatment NLR was a poor prognostic marker for patients with cervical cancer because it predicted unfavorable overall survival (HR = 1.375, 95% CI: 1.200-1.576) and progression-free survival (HR = 1.646, 95% CI: 1.313-2.065). Increased NLR is also significantly associated with the larger tumor size (OR = 1.780, 95% CI: 1.090-2.908), advanced clinical stage (OR = 2.443, 95% CI: 1.730-3.451), and positive lymph node metastasis (OR = 2.380, 95% CI: 1.775-3.190). By these results, high pretreatment NLR predicted a shorter survival period for patients with cervical cancer, and it could be served as a novel index of prognostic evaluation in patients with cervical cancer. PMID- 28077796 TI - Tumor cell migration is inhibited by a novel therapeutic strategy antagonizing the alpha-7 receptor. AB - A 14mer peptide (T14) derived from the C-terminus of acetylcholinesterase (AChE) selectively activates metastatic breast cancer cells via the alpha-7 nicotinic receptor (alpha7 nAChR). This naturally occurring peptide is also present in brain, is elevated in Alzheimer's disease, and is antagonised by a cyclized variant (NBP-14). Here we investigated the effects of NBP-14 in six different cancer cell lines, primary leukemia B-cells and normal B-cells. All cells tested expressed alpha7 nAChR, intracellular and extracellular T14. However, NBP-14 showed low toxicity and weak anti-proliferative effects in the majority of the cell lines and was even less toxic in normal B-cells when compared to primary chronic lymphocytic leukemia cells (P < 0.001). Given the potential role of T14 peptide in metastasis, we next investigated the effects of NBP-14 on tumor cell migration, where it caused a dose-dependent reduction. The extent of NBP-14 inhibition positively correlated with the migration of the cells (r2 = 0.45; P = 0.06). Furthermore, NBP-14 preferentially inhibited the migration of primary leukemia cells when compared with normal B-cells (P = 0.0002); when the normal B cell data was excluded, this correlation was strengthened (r2 = 0.80; P = 0.006). Importantly, the constitutive alpha7 nAChR expression positively correlated with intracellular T14 levels (r2 = 0.91; P = 0.0003) and inversely correlated with extracellular T14 levels in the cell culture supernatants (r2 = -0.79; P = 0.034). However, in the presence of NBP-14, alpha7 nAChR expression was reduced (P = 0.04) and the most migratory cells showed the largest reduction in expression. In conclusion, NBP-14-mediated antagonism of the alpha7 nAChR offers a novel therapeutic strategy with the potential to inhibit tumor cell migration. PMID- 28077798 TI - Uniquely conserved immunosuppressive viral exoribonucleases. PMID- 28077797 TI - Repression of Fyn-related kinase in breast cancer cells is associated with promoter site-specific CpG methylation. AB - The triple-negative breast cancer subtype is highly aggressive and has no defined therapeutic target. Fyn-related kinase (FRK) is a non-receptor tyrosine kinase, reported to be downregulated in breast cancer and gliomas, where it is suggested to have tumor suppressor activity. We examined the expression profile of FRK in a panel of 40 breast cancer cells representing all the major subtypes, as well as in 4 non-malignant mammary epithelial cell lines. We found that FRK expression was significantly repressed in a proportion of basal B breast cancer cell lines. We then determined the mechanism of suppression of FRK in FRK-low or negative cell lines. In silico analyses of the FRK promoter region led to the identification of at least 17 CpG sites. Bisulphite sequencing of the promoter region revealed that two of these sites were consistently methylated in FRK low/negative cell lines and especially in the basal B breast cancer subtype. We further show that treatment of these cells with histone deacetylase inhibitors, Entinostat and Mocetinostat' promoted re-expression of FRK mRNA and protein. Further, using luciferase reporter assays, we show that both GATA3-binding protein FOG1 and constitutively active STAT5A increased the activity of FRK promoter. Together, our results present the first evidence that site-specific promoter methylation contributes to the repression of FRK more so in basal B breast cancers. Our study also highlights the potential clinical significance of targeting FRK using epigenetic drugs specifically in basal B breast cancers which are usually triple negative and very aggressive. PMID- 28077799 TI - KRAS and TP53 mutations in inflammatory bowel disease-associated colorectal cancer: a meta-analysis. AB - Although KRAS and TP53 mutations are common in both inflammatory bowel disease associated colorectal cancer (IBD-CRC) and sporadic colorectal cancer (S-CRC), molecular events leading to carcinogenesis may be different. Previous studies comparing the frequency of KRAS and TP53 mutations in IBD-CRC and S-CRC were inconsistent. We performed a meta-analysis to compare the presence of KRAS and TP53 mutations among patients with IBD-CRC, S-CRC, and IBD without dysplasia. A total of 19 publications (482 patients with IBD-CRC, 4,222 with S-CRC, 281 with IBD without dysplasia) met the study inclusion criteria. KRAS mutation was less frequent (RR=0.71, 95%CI 0.56-0.90; P=0.004) while TP53 mutation was more common (RR=1.24, 95%CI 1.10-1.39; P<0.001) in patients with IBD-CRC compared to S-CRC. Both KRAS (RR=3.09, 95%CI 1.47-6.51; P=0.003) and TP53 (RR=2.15, 95%CI 1.07-4.31 P=0.03) mutations were more prevalent in patients with IBD-CRC compared to IBD without dysplasia. In conclusion, IBD-CRC and S-CRC appear to have biologically different molecular pathways. TP53 appears to be more important than KRAS in IBD CRC compared to S-CRC. Our findings suggest possible roles of TP53 and KRAS as biomarkers for cancer and dysplasia screening among patients with IBD and may also provide targeted therapy in patients with IBD-CRC. PMID- 28077800 TI - Oxidative stress induced by Se-deficient high-energy diet implicates neutrophil dysfunction via Nrf2 pathway suppression in swine. AB - The mechanism of the interaction between Se deficiency and high energy remains limited. The aim of the current study was to identify whether Se-deficient, high energy diet can induce oxidative stress, and downregulate the Nrf2 pathway and phagocytic dysfunction of neutrophils. We detected the phagocytic activity, ROS production, protein levels of Nrf2 and Nrf2 downstream target genes, and the mRNA levels of 25 selenoproteins, heat shock proteins, and cytokines in neutrophils. Cytokine ELISA kits were used to measure the serum cytokines. The concentration of ROS was elevated (P < 0.05) in obese swine fed on a low Se diet (less than 0.03 mg/kg Se) compared to control swine. The protein levels of Nrf2 and its downstream target genes were depressed during Se deficiency and high-energy intake. The mRNA levels of 16 selenoproteins were significantly decreased (P < 0.05) in the Se-deficient group and Se-deficient, high-energy group compared to the control group. However, the mRNA levels of 13 selenoproteins in peripheral blood neutrophils were upregulated in high energy group, except TrxR1, SelI and SepW. In summary, these data indicated that a Se-deficient, high-energy diet inhibits the Nrf2 pathway and its regulation of oxidative stress, and prompted a pleiotropic mechanism that suppresses phagocytosis. PMID- 28077801 TI - Human papillomavirus type 16 E6 suppresses microRNA-23b expression in human cervical cancer cells through DNA methylation of the host gene C9orf3. AB - Oncogenic protein E6 of human papillomavirus type 16 (HPV-16) is believed to involve in the aberrant methylation in cervical cancer as it upregulates DNA methyltransferase 1 (DNMT1) through tumor suppressor p53. In addition, DNA demethylating agent induces the expression of one of the HPV-16 E6 regulated microRNAs (miRs), miR-23b, in human cervical carcinoma SiHa cells. Thus, the importance of DNA methylation and miR-23b in HPV-16 E6 associated cervical cancer development is investigated. In the present study, however, it is found that miR 23b is not embedded in any typical CpG island. Nevertheless, a functional CpG island is predicted in the promoter region of C9orf3, the host gene of miR-23b, and is validated by methylation-specific PCR and bisulfite genomic sequencing analyses. Besides, c-MET is confirmed to be a target gene of miR-23b. Silencing of HPV-16 E6 is found to increase the expression of miR-23b, decrease the expression of c-MET and thus induce the apoptosis of SiHa cells through the c-MET downstream signaling pathway. Taken together, the tumor suppressive miR-23b is epigenetically inactivated through its host gene C9orf3 and this is probably a critical pathway during HPV-16 E6 associated cervical cancer development. PMID- 28077802 TI - NMI promotes hepatocellular carcinoma progression via BDKRB2 and MAPK/ERK pathway. AB - Hepatocellular carcinoma (HCC) is one of the most prevalent and aggressive malignant tumors. The involvement of N-myc (and STAT) interactor (NMI) and its possible functional mechanisms in HCC progression still remain to be elucidated. In this study, we found that NMI was overexpressed in metastatic HCC cell lines compared with non-metastatic ones; and the expression levels of NMI in the HCC samples with metastasis were higher than that in the non-metastatic specimens. Furthermore, NMI depletion significantly decreased HCC cell proliferation and invasiveness in vitro, and also inhibited tumor growth and lung metastasis in vivo in nude mice models bearing human HCC. By contrast, NMI stable overexpression can enhance the malignant behaviors obviously. Moreover, we further verified that NMI promotes the expression of BDKRB2 and mediates the activation of MAPK/ERK signaling pathway according to the bidirectional perturbations of NMI expression in vivo or in vitro of HCC. Taken together, NMI is a pro-metastatic molecule and partially responsible for HCC tumor growth and motility. NMI could improve its downstream target BDKRB2 expression to induce ERK1/2 activation, and thereby further evoke malignant progression of HCC. PMID- 28077803 TI - Gerosuppression by pan-mTOR inhibitors. AB - Rapamycin slows organismal aging and delays age-related diseases, extending lifespan in numerous species. In cells, rapamycin and other rapalogs such as everolimus suppress geroconversion from quiescence to senescence. Rapamycin inhibits some, but not all, activities of mTOR. Recently we and others demonstrated that pan-mTOR inhibitors, known also as dual mTORC1/C2 inhibitors, suppress senescent phenotype. As a continuation of these studies, here we investigated in detail a panel of pan-mTOR inhibitors, to determine their optimal gerosuppressive concentrations. During geroconversion, cells become hypertrophic and flat, accumulate lysosomes (SA-beta-Gal staining) and lipids (Oil Red staining) and lose their re-proliferative potential (RPP). We determined optimal gerosuppressive concentrations: Torin1 (30 nM), Torin 2 (30 nM), AZD8055 (100 nM), PP242 (300 nM), both KU-006379 and GSK1059615 (1000 nM). These agents decreased senescence-associated hypertrophy with IC50s: 20, 18, 15, 200 and 400 nM, respectively. Preservation of RPP by pan-mTOR inhibitors was associated with inhibition of the pS6K/pS6 axis. Inhibition of rapamycin-insensitive functions of mTOR further contributed to anti-hypertrophic and cytostatic effects. Torin 1 and PP242 were more "rapamycin-like" than Torin 2 and AZD8055. Pan-mTOR inhibitors were superior to rapamycin in suppressing hypertrophy, senescent morphology, Oil Red O staining and in increasing so-called "chronological life span (CLS)". We suggest that, at doses lower than anti-cancer concentrations, pan-mTOR inhibitors can be developed as anti-aging drugs. PMID- 28077805 TI - Spin-exciton interaction and related micro-photoluminescence spectra of ZnSe:Mn DMS nanoribbon. AB - For their spintronic applications the magnetic and optical properties of diluted magnetic semiconductors (DMS) have been studied widely. However, the exact relationships between the magnetic interactions and optical emission behaviors in DMS are not well understood yet due to their complicated microstructural and compositional characters from different growth and preparation techniques. Manganese (Mn) doped ZnSe nanoribbons with high quality were obtained by using the chemical vapor deposition (CVD) method. Successful Mn ion doping in a single ZnSe nanoribbon was identified by elemental energy-dispersive x-ray spectroscopy mapping and micro-photoluminescence (PL) mapping of intrinsic d-d optical transition at 580 nm, i.e. the transition of 4 T 1(4 G) -> 6 A 1(6 s),. Besides the d-d transition PL peak at 580 nm, two other PL peaks related to Mn ion aggregates in the ZnSe lattice were detected at 664 nm and 530 nm, which were assigned to the d-d transitions from the Mn2+-Mn2+ pairs with ferromagnetic (FM) coupling and antiferromagnetic (AFM) coupling, respectively. Moreover, AFM pair formation goes along with strong coupling with acoustic phonon or structural defects. These arguments were supported by temperature-dependent PL spectra, power-dependent PL lifetimes, and first-principle calculations. Due to the ferromagnetic pair existence, an exciton magnetic polaron (EMP) is formed and emits at 460 nm. Defect existence favors the AFM pair, which also can account for its giant enhancement of spin-orbital coupling and the spin Hall effect observed in PRL 97, 126603(2006) and PRL 96, 196404(2006). These emission results of DMS reflect their relation to local sp-d hybridization, spin-spin magnetic coupling, exciton-spin or phonon interactions covering structural relaxations. This kind of material can be used to study the exciton-spin interaction and may find applications in spin-related photonic devices besides spintronics. PMID- 28077806 TI - Low-protein diet for the prevention of renal failure. AB - The prevalence of chronic kidney disease (CKD) is estimated to be 8-16% worldwide, and it is increasing. CKD is a risk factor for heart attack and stroke, and it can progress to kidney failure requiring dialysis or transplantation. Recently, diabetic nephropathy has become the most common cause of CKD. In Japan, the cumulative probability of requiring hemodialysis by the age 80 years is 1/50 in males and 1/100 in females. The number of patients under hemodialysis in Japan exceeded 320,000 in 2014, among which 38,000 were newcomers and 27,000 died.The annual medical costs of hemodialysis are 1.25 trillion yen in Japan, representing 4% of the total national medical expenditures in 2014. A low protein diet (less than 0.5 g/kg b.wt.) is a very effective intervention. Low protein rice (1/10 to 1/25 of the normal protein contents) is helpful to control the consumption of proteins, decreasing at the same time the intake of potassium and phosphate.Protein restriction is indicated as soon as the eGFR becomes lower than 60 ml/min/1.73 m2 body surface, in order, to slow disease progression. The newly developed low-protein Indica rice is expected to help many CKD patients in China and Southeast Asia. PMID- 28077808 TI - Rupture, waves and earthquakes. AB - Normally, an earthquake is considered as a phenomenon of wave energy radiation by rupture (fracture) of solid Earth. However, the physics of dynamic process around seismic sources, which may play a crucial role in the occurrence of earthquakes and generation of strong waves, has not been fully understood yet. Instead, much of former investigation in seismology evaluated earthquake characteristics in terms of kinematics that does not directly treat such dynamic aspects and usually excludes the influence of high-frequency wave components over 1 Hz. There are countless valuable research outcomes obtained through this kinematics-based approach, but "extraordinary" phenomena that are difficult to be explained by this conventional description have been found, for instance, on the occasion of the 1995 Hyogo-ken Nanbu, Japan, earthquake, and more detailed study on rupture and wave dynamics, namely, possible mechanical characteristics of (1) rupture development around seismic sources, (2) earthquake-induced structural failures and (3) wave interaction that connects rupture (1) and failures (2), would be indispensable. PMID- 28077807 TI - Folding of apomyoglobin: Analysis of transient intermediate structure during refolding using quick hydrogen deuterium exchange and NMR. AB - The structures of apomyoglobin folding intermediates have been widely analyzed using physical chemistry methods including fluorescence, circular dichroism, small angle X-ray scattering, NMR, mass spectrometry, and rapid mixing. So far, at least two intermediates (on sub-millisecond- and millisecond-scales) have been demonstrated for apomyoglobin folding. The combination of pH-pulse labeling and NMR is a useful tool for analyzing the kinetic intermediates at the atomic level. Its use has revealed that the latter-phase kinetic intermediate of apomyoglobin (6 ms) was composed of helices A, B, G and H, whereas the equilibrium intermediate, called the pH 4 molten-globule intermediate, was composed mainly of helices A, G and H. The improved strategy for the analysis of the kinetic intermediate was developed to include (1) the dimethyl sulfoxide method, (2) data processing with the various labeling times, and (3) a new in-house mixer. Particularly, the rapid mixing revealed that helices A and G were significantly more protected at the earlier stage (400 us) of the intermediate (former-phase intermediate) than the other helices. Mutation studies, where each hydrophobic residue was replaced with an alanine in helices A, B, E, F, G and H, indicated that both non-native and native-like structures exist in the latter-phase folding intermediate. The N-terminal part of helix B is a weak point in the intermediate, and the docking of helix E residues to the core of the A, B, G and H helices was interrupted by a premature helix B, resulting in the accumulation of the intermediate composed of helices A, B, G and H. The prediction-based protein engineering produced important mutants: Helix F in a P88K/A90L/S92K/A94L mutant folded in the latter-phase intermediate, although helix F in the wild type does not fold even at the native state. Furthermore, in the L11G/W14G/A70L/G73W mutant, helix A did not fold but helix E did, which is similar to what was observed in the kinetic intermediate of apoleghemoglobin. Thus, this protein engineering resulted in a changed structure for the apomyoglobin folding intermediate. PMID- 28077810 TI - Increased Expression of Long Non-Coding RNA BCAR4 Is Predictive of Poor Prognosis in Patients with Non-Small Cell Lung Cancer. AB - Lung cancer is the most common human cancer, and the majority of lung cancer cases are categorized as non-small cell lung cancer (NSCLC). Long non-coding RNAs (lncRNAs) play key roles in the development and progression of human cancers. LncRNA breast cancer anti-estrogen resistance 4 (BCAR4) has been identified as an oncogenic lncRNA involved in the progression of breast cancer and osteosarcoma. However, the clinical significance of the lncRNA BCAR4 in NSCLC remains largely unclear. In the present study, real-time quantitative reverse transcriptase polymerase chain reaction was used to examine the relative level of lncRNA BCAR4 in 68 cases of NSCLC tissues and their adjacent non-tumor tissues. Our data showed that the expression level of lncRNA BCAR4 was significantly higher in NSCLC tissues compared to their matched non-tumor tissues. Moreover, BCAR4 expression was significantly upregulated in NSCLC cell lines, when compared to the normal human bronchial epithelial cell line BEAS-2B. In addition, the BCAR4 expression was associated with the lymph node metastasis, distant metastasis and clinical stage, but not with the age, sex, tumor size, histological grade, and histological type. The increased expression of BCAR4 was significantly associated with poorer 5-year overall survival rate of NSCLC patients. Multivariate survival analysis indicated that BCAR4 was an independent prognostic factor for NSCLC patients. Taken together, our study suggests that the upregulation of lncRNA BCAR4 expression plays a promoting role in the malignant progression of NSCLC. Thus, BCAR4 is a potential biomarker for NSCLC progress and a therapeutic target for NSCLC. PMID- 28077809 TI - Cytotoxic Steroids from the Vietnamese Soft Coral Sinularia conferta. AB - Twelve steroids, including five new compounds 1-5, were isolated and structurally elucidated from a methanol extract of the Vietnamese soft coral Sinularia conferta. Their cytotoxic effects against three human cancer cell lines, lung carcinoma (A-549), cervical adenocarcinoma (HeLa), and pancreatic epithelioid carcinoma (PANC-1), were evaluated using 3-(4,5-dimethylthiazolyl-2)-2,5 diphenyltetrazolium bromide (MTT) assays. Among isolated compounds, 10 exhibited potent cytotoxic effects on all three tested cell lines with IC50 values of 3.64+/-0.18, 19.34+/-0.42, and 1.78+/-0.69 uM, respectively. PMID- 28077804 TI - The complex genetics of gait speed: genome-wide meta-analysis approach. AB - Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging. PMID- 28077811 TI - Nutrition Status Predicts Severity of Vascular Calcification in Non-Dialyzed Chronic Kidney Disease. AB - BACKGROUND: Vascular calcification is a major complication in chronic kidney disease (CKD) that increases the risk of adverse clinical outcomes. Geriatric nutritional risk index (GNRI) is a simple nutritional assessment tool that predicts poor prognosis in elderly subjects. The purpose of the present study was to evaluate the correlation between GNRI and severity of vascular calcification in non-dialyzed CKD patients.Methods and Results:We enrolled 323 asymptomatic CKD patients. To evaluate abdominal aortic calcification (AAC), we used aortic calcification index (ACI) determined on non-contrast computed tomography. The patients were divided into three groups according to GNRI tertile. Median ACI significantly decreased with increasing GNRI tertile (15.5%, 13.6%, and 7.9%, respectively; P=0.001). On multivariate regression analysis GNRI was significantly correlated with ACI (beta=-0.15, P=0.009). We also investigated the combination of GNRI and C-reactive-protein (CRP) for predicting the severity of AAC. Low GNRI and high CRP were significantly associated with severe AAC, compared with high GNRI and low CRP (OR, 4.07; P=0.004). CONCLUSIONS: GNRI was significantly associated with AAC in non-dialyzed CKD patients. PMID- 28077813 TI - Nocardia Identification at the Genus Level - Reply. PMID- 28077812 TI - Nocardia Identification at the Genus Level. PMID- 28077814 TI - Life-Threatening Ventricular Arrhythmia and Brugada-Type ST-Segment Elevation Associated With Acute Ischemia of the Right Ventricular Outflow Tract. AB - BACKGROUND: Brugada-type ECG (Br-ECG) is occasionally observed during acute myocardial ischemia of the right ventricular outflow tract (RVOT). No studies have explored, however, the association of ventricular tachyarrhythmia and development of Br-ECG due to acute ischemia of the RVOT.Methods and Results:The study included 13 consecutive patients with acute ischemia of the RVOT during coronary catheterization. Patients were divided into 2 groups: those with Br-ECG (group B) and those without (group N). The proportion of male patients was higher in group B than in group N (100% vs. 25%, P<0.01), and VT/VF developed in only patients with Br-ECG (group B). In group B, VT/VF was observed in patients without pre-existing organic change in the conus/right ventricular (RV) branch of the right coronary artery and no VT/VF was seen in patients with organic coronary stenosis despite Br-ECG. CONCLUSIONS: Acute myocardial ischemia of the RVOT caused Br-ECG predominantly in male patients and subsequent development of VT/VF in some patients. VT/VF was seen in patients without any obstructive lesion but arrhythmic events were not observed in RVOT ischemia in the case of pre-existing coronary occlusion or stenosis of the conus or RV branch, suggesting the effects of precondition. PMID- 28077815 TI - The J-wave as a Predictor of Life-Threatening Arrhythmia in ICD Patients. AB - The J-wave has been reported to be associated with life-threatening ventricular arrhythmia. However, the clinical implication of the J-wave is still unclear in patients with an implantable cardioverter defibrillator (ICD).The study population consisted of 170 ICD patients (age, 56 +/- 16 years, 79.4% male) treated at Kitasato University Hospital between 2003 and 2014. Ventricular fibrillation (VF) and ventricular tachycardia (VT) events were documented via ICD interrogation, and the patients were divided into 3 groups: 1) VF event group, 2) VT event group, and 3) No-event group. To predict VT or VF events, univariate and multivariate analysis of clinical data including ECG findings were performed. A J wave was defined as the presence of notching or slurring of the QRS complex (>= 0.1 mV) in inferior/lateral leads. Among the 170 patients examined, 23 experienced VF and 38 experienced VT during 54 +/- 39 months follow-up. In the multivariate Cox proportional hazards model, the J-wave was identified as an independent predictor for a VF event (HR: 3.886, 95% CI: 1.313-10.568, P = 0.012). In contrast, BNP (HR: 1.002, 95% CI: 1.000-1.003, P = 0.043) and left ventricular diastolic diameter (HR: 1.039, 95% CI: 1.002-1.081, P = 0.049) were independent predictors for a VT event.The results suggest J-waves in the stable phase in an ECG may be a useful predictor for a VF event in ICD patients. PMID- 28077816 TI - Incidence of Atrial Tachyarrhythmias in Patients With Early Repolarization Syndrome. AB - Atrial tachyarrhythmias (ATAs) occur in a significant proportion of Brugada syndrome (BrS) patients and are often an important cause of inappropriate shocks. The aim of this retrospective study was to evaluate the incidence of ATAs and ATA induced inappropriate shocks in early repolarization syndrome (ERS) patients as compared to BrS patients.We analyzed data from 20 consecutive patients who were diagnosed with ERS and compared them with patients diagnosed with BrS (n = 31). Clinical and ICD interrogation data were collected and analyzed for all events with ICD shocks.Three patients had a history of atrial fibrillation (AF) prior to ICD implantation. One patient had AV reentrant tachycardia and was successfully ablated before ICD implantation. ATAs were newly diagnosed in 4 patients with no prior history of AF. There were no significant differences in gender, age, or left atrial diameter between ATA development. Four (20%) of 20 consecutive patients received inappropriate ICD shocks for ATAs. One suffered from repeat inappropriate shocks triggered by paroxysmal AF and received catheter ablation for AF.ATAs were not infrequent in patients with ERS and seemed to be related to inappropriate ICD therapy. Careful ICD programming is required to reduce ATA related inappropriate ICD shock in patients with ERS. PMID- 28077817 TI - Prognostic Significance of Non-Dilated Left Ventricular Size and Mitral Regurgitation in Patients With Dilated Phase of Hypertrophic Cardiomyopathy. AB - Although a subtype of hypertrophic cardiomyopathy (HCM), dilated phase of HCM (D HCM) characterized by left ventricular (LV) systolic dysfunction, has been reported to have a poor prognosis, some patients with D-HCM survive for a relatively long period. The degree of LV dilatation and functional mitral regurgitation (MR) are generally thought to be important predictors of poor prognosis in patients with LV systolic dysfunction. However, there is little information available on the relations among LV size, presence of significant MR, and prognosis in D-HCM patients.We retrospectively studied 31 patients with D-HCM to determine whether echocardiographic assessment of LV size and MR provides incremental prognostic information.During a follow-up period of 5.6 +/- 4.2 years, there were 13 cardiovascular deaths. When the patients were divided into two groups by LV size at diagnosis of D-HCM, a non-dilated LV group (LV end diastolic diameter (LVEDD) < 50 mm, n = 9) and a dilated LV group (LVEDD >= 50 mm, n = 22), the clinical course in the non-dilated LV group was significantly worse. As for the clinical impact of MR, no patient in the non-dilated LV group showed significant MR and 7 of the patients with dilated LV size showed significant MR during follow-up. Once significant MR was reached, cardiovascular deaths were significantly more frequent in patients with MR.Patients with D-HCM, particularly those with less LV dilatation at diagnosis of dilated phase and with significant MR during follow-up, have a poor prognosis. PMID- 28077818 TI - Enlargement of the Excluded Left Atrial Appendage With Thrombus. AB - We report progressive enlargement of the excluded left atrial appendage (LAA) with a thrombus in a patient who had undergone valve surgery and endocardial suture closure of the LAA previously. Echocardiography and CT detected no communication between the LAA and the left atrium. Magnetic resonance imaging showed the LAA was filled with fresh and old thrombi. Coronary arteriography demonstrated small left coronary artery-LAA fistulae. At surgery, successful exclusion of the LAA was confirmed after removal of the thrombi. Persistent inflow of blood through the coronary artery fistulae to the excluded LAA may be the primary mechanism of this pathology. PMID- 28077819 TI - Association Between Blood Transfusions and 12-Month Mortality After Transcatheter Aortic Valve Implantation. AB - Blood transfusions are considered as an important predictor of adverse outcome in patients with severe aortic (AS) undergoing transcatheter aortic valve implantation (TAVI). We sought to investigate the association between blood transfusions and mortality after TAVI. We enrolled 101 consecutive patients with severe AS undergoing TAVI. Patients who required transfusion were defined as patients in whom at least one unit of packed red blood cells (PRBCs) was transfused in the perioperative period. Twelve-month outcomes were assessed based on Valve Academic Research Consortium definitions. A total of 28 (27.7%) patients required blood transfusion after TAVI. Baseline characteristics of the patients with and without a transfusion were similar. Median amount of PRBCs was 2 (interquartile range, 2-4). Twelvemonth all-cause mortality was higher in patients with than without a blood transfusion (39.3% versus 9.6%; P = 0.001). Importantly, the need for a blood transfusion after TAVI was an independent predictor of higher mortality rates after 12 months (hazard ratio (HR) 2.84 95%CI (1.06-7.63); P = 0.039; (HR for incomplete coronary revascularization 10.86, 95%CI 3.72-31.73; P < 0.001; HR for a history of stroke/TIA 3.93, 95%CI 1.39 11.07; P < 0.001). The duration of inhospital stay was longer in patients requiring transfusion (16.0 (14.0-22.0) versus 7.0 (7.0-11.5) days; P = 0.014). In conclusion, blood transfusions after TAVI were associated with higher mortality rates after 12 months, longer in-hospital stay, and were identified as an independent predictor of impaired clinical outcome. PMID- 28077820 TI - Acute Coronary Syndrome Demonstrating Plaque Rupture in Calcified Lesions Visualized by Optical Frequency Domain Imaging. AB - A 68-year-old female with acute coronary syndrome was transferred to our hospital. Emergency coronary angiography showed 90% stenosis with severe calcification in the proximal right coronary artery (RCA). Intravascular ultrasound (IVUS) images were obtained and showed circumferential heavy calcification without any evidence of plaque rupture. Optical frequency domain imaging (OFDI) images were obtained in the RCA lesion 3 days after the initial coronary angiography. A cavity of plaque rupture in the calcified plaque by using OFDI was observed in the lesion, which could not be recognized by IVUS. Necrotic tissue was observed frequently in heavy calcified lesions and was usually hidden behind calcification. Judging from the OFDI images in this case, the thin fibrous cap over the necrotic tissue even if surrounded by calcification was disrupted and might have caused the acute coronary syndrome. However, necrotic tissue surrounded by calcification is generally recognized as calcified plaque in OFDI images because discrimination between necrotic tissue and calcification is based on the border characteristics (low intensity with diffuse border: necrotic tissue, low intensity with sharp border: calcification). Superficial residual necrotic tissue not yet replaced completely by calcification might cause plaque rupture and thus, result in acute coronary syndrome. In fact, there is a variety of OFDI and optical coherence tomography (OCT) characteristics in calcified plaque, such as relatively high intensity without attenuation or very low intensity with attenuation. Residual necrotic tissue within calcification could pose a problem in OCT/OFDI plaque evaluation. PMID- 28077821 TI - Ascending Aortic Constriction Promotes Cardiomyocyte Proliferation in Neonatal Rats. AB - Adult heart suffering from increased workload will undergo myocardial hypertrophy, subsequent cardiomyocyte (CM) death, and eventually heart failure. However, the effect of increasing afterload on the neonatal heart remains unknown. We performed ascending aortic constriction (AAC) in neonatal rats 8-12 hours after birth (P0, P indicates postpartum). Seven days after surgery, in vivo heart function was evaluated using cardiac ultrasonography. Haematoxylineosin and Masson staining were used to assess CM diameter and collagen deposition. Moreover, expression of both EdU and Ki67 were evaluated to determine DNA synthesis levels, and pH3 and aurora B as markers for mitosis in CMs. CM isolation was performed by heart perfusion at P0, P3, P5, and P7, respectively. CM number on P0 was 1.01 +/- 0.29 * 106. We found that CM cell cycle activation was significantly increased among constricted hearts, as demonstrated by increased Ki67, EdU, pH3, and aurora B positive cells/1000 CMs. At day 7 (P7), constriction group hearts manifested increased wall thickness (0.55 +/- 0.05 mm versus 0.85 +/- 0.10 mm, P < 0.01, n = 6), and improved hemodynamics as well as left ventricular ejection fraction (65.5 +/- 3.7% versus 77.7 +/- 4.8%, P < 0.01, n = 6). Of note, the population of CMs was also markedly increased in the constriction group (2.92 +/- 0.27 * 106 versus 3.41 +/- 0.40 * 106, P < 0.05, n = 6). In summary, we found that during the first week after birth significant numbers of neonatal CMs can reenter the cell cycle. Ascending aortic constriction promotes neonatal rat CM proliferation resulting in 16.7% more CMs in the heart. PMID- 28077822 TI - Factors associated with work ability index (WAI) among intensive care units' (ICUs') nurses. AB - OBJECTIVES: Work ability is a crucial occupational health issue in health care settings where a high physical and psychosocial work capacity is required and a high risk of disabling injuries and illnesses is predictable. This study aims to examine the association between the work ability index (WAI) and individual characterizations, workload, fatigue, and diseases among intensive care units' (ICUs') nurses. METHODS: The study sample included 214 nurses selected by a random sampling method from a target population consisting of 321 registered nurses working in eight ICUs. Multiple linear regression analysis was used to test the association between WAI scores and each of the independent variables. RESULTS: Results of multivariate analysis revealed a strong and negative association between WAI scores and diseases (B=-5.82, 95% CI=-7.16, -4.48, P<0.001). Among the studied individual characterizations, body mass index (BMI) was significantly and inversely associated with WAI scores. A significant and negative association was also found between WAI scores and dimensions of MFI-20, such as general fatigue (B=-0.31, 95% CI=-0.53, -0.09, P=0.005) and physical fatigue (B=-0.44, 95% CI=-0.65, -0.23, P<0.001). From dimensions of workload, frustration (B=-0.04, 95% CI=-0.07, -0.02, P<0.001) and temporary demand (B= 0.04, 95% CI=-0.08, -0.0001, P=0.04) showed a negative and significant association with WAI scores, while performance showed a positive and significant association (B=0.04, 95% CI=0.01, 0.07, P=0.005). CONCLUSIONS: Based on the study findings, development of health care programs with the aim of setting up a healthy work environment characterized by a well-structured preventive attitude toward controlling diseases, and a well-designed organizational framework toward increasing the level of performance and motivation, reducing the level of fatigue, as well as reducing the workload, is necessary to promote work ability among ICUs' nurses. PMID- 28077823 TI - Association of health symptoms with low-level exposure to organophosphates, DNA damage, AChE activity, and occupational knowledge and practice among rice, corn, and double-crop farmers. AB - OBJECTIVES: This study aims to determine (1) total dialkylphosphate (SigmaDAP) levels, occupational knowledge and practice, DNA damage, AChE activity, and health symptoms in rice, corn, and double-crop farmers; (2) the association of health symptoms with SigmaDAP levels, occupational knowledge and practice, DNA damage, and AChE activity in farmers; and (3) the prevalence of health symptoms between farmers and non-farmers. METHODS: A cross-sectional study was conducted by interviewing as well as analyzing urine and blood samples during July to August 2014. RESULTS: There were no differences in SigmaDAP levels, AChE activity, and occupational knowledge and practice scores among all farmer groups. In terms of health symptoms related to SigmaDAP, AChE activity, DNA damage, and occupational knowledge and practice, pesticide-related symptoms were determined, including breathlessness, chest pain, dry throat, numbness, muscle weakness, cramp, headache, dizziness, eye irritation, white/red rash, and white/red pimple, which were classified as respiratory, muscle, nervous, and epithelial symptoms. A remarkable finding was that farmers had a significantly higher prevalence of muscle weakness (odds ratio (OR)=3.79) and numbness (OR=3.45) as compared with non-farmers. CONCLUSION: Our findings, therefore, suggest that a long-term low level exposure to organophosphates (OPs) may be associated with an increasing prevalence of muscle symptoms. However, a further cohort study incorporating sensitive health outcomes and measurement of multiple pesticides monitoring on a larger scale is warranted. PMID- 28077824 TI - Burnout among public servants after the Great East Japan Earthquake: decomposing the construct aftermath of disaster. AB - OBJECTIVES: To examine whether disaster-related variables, in addition to known work-related risk factors, influence burnout and its subscales (exhaustion, cynicism, and lack of professional efficacy) among public servants who experienced a major disaster. METHODS: Cross-sectional studies were conducted among public servants of Miyagi prefecture at 2 and 16 months after the Great East Japan Earthquake (n=3,533, response rate 66.8%); burnout was assessed at 16 months using the Japanese version of the Maslach Burnout Inventory-General Survey. We examined the relationships between burnout and its subscales with disaster-related variables at 2 months after the disaster, while controlling for age, gender, and work-related variables at 16 months after the disaster. RESULTS: After controlling for age, gender, and work-related variables, a significant risk factor of burnout was having severe house damage. For the each subscale of burnout, living someplace other than their own house increased the risk of both exhaustion and cynicism, while handling residents' complaints did so only for exhaustion. Notably, workers from health and welfare departments showed an increased risk of burnout, exhaustion, and cynicism, but not lack of professional efficacy. CONCLUSIONS: The findings suggest that special attention is needed for workers with severe house damage to prevent burnout, as well as those who lived someplace other than their own house to prevent exhaustion and cynicism after a major disaster. Interventions directed at workers of the health and welfare department should focus more on limiting exhaustion and cynicism, rather than promoting professional efficacy. PMID- 28077825 TI - [Inhalation Effects of Aroma Essential Oil on Quality of Sleep for Shift Nurses after Night Work]. AB - PURPOSE: This study was an experimental study to compare the inhalation effects of aroma essential oil on the quality of sleep (QOS) for shift nurses after working nights. METHODS: The participants were 60 healthy adults who didn't have any disease. As an experimental treatment, the participants in the experimental group were asked to inhale essential oil for 3 minutes at a distance of approximately 10 cm fromt heir nose and then they were asked to sleep with the aroma stone beside their head (within a 30 cm distance). QOS were measured four times on Pretest, Day 1, Day 2, and Day 3 after they slept. To measure QOS, Perceived QOS (Numeric Rating Scale), the Verran & Synder-Halpern (VSH) Sleep Scale were used, and number of awakenings (NoA) was measured by Actigraph. RESULTS: There were no significant differences in the homogeneity tests for general characteristics and dependent variables prior to the experiments, except for VSH of subjective sleep quality. Also, there was no significant interaction between group and time. The VSH of the experimental group was higher than the control group (F=6.39, p=.002). The NoA between the experimental group and the control group was significantly different after experimental treatment 3rd day (F=13.35, p=.001). CONCLUSION: The findings show that the inhalation of aroma essential oil had effects to increase the quality of sleep. Therefore, the inhalation of aroma essential oil could be applied to general nursing interventions to improve the quality of sleep. PMID- 28077826 TI - [Effects of a Customized Birth Control Program for Married Immigrant Postpartum Mothers]. AB - PURPOSE: This study was conducted to develop a customized birth control program and identify its effects on attitude, subjective norm, behavioral control, intention, and behavior of contraception among immigrant postpartum mothers. METHODS: In this experimental study, Vietnamese, Filipino or Cambodian married immigrant postpartum mothers were recruited. They were assigned to the experiment group (n=21) or control group (n=21). The customized birth control program was provided to the experimental group for 4 weeks. RESULTS: The experimental group showed a significant increase in the score of attitude, subjective norm, behavioral control, intention, and behavior of contraception. CONCLUSION: Findings in this study indicate that the customized postpartum birth control program, a systematic and integrative intervention program composed of customized health education, counseling and telephone monitoring, is able to provide effective planning for postpartum health promotion and birth control behavior practice in married immigrant women. PMID- 28077827 TI - [Development of the Developmental Support Competency Scale for Nurses Caring for Preterm Infants]. AB - PURPOSE: Developmental care has been recognized as a very important component for the development and health promotion of preterm infants. However, research on how to assess developmental nursing competency has not been studied as expected. This study was done to develop and evaluate a new scale to measure nursing competency for developmental support of preterm infants. METHODS: Concept analysis was done with using the Hybrid model of Schwartz-Barcott and Kim (2000), from which a preliminary new scale (30 items) was developed. To test the validity and reliability of the new scale being developed, data were collected from 122 NICU nurses at 4 hospitals in 3 cities in the Republic of Korea, from December, 2014 to March, 2015. RESULTS: The final version of the Developmental Support Competency Scale for Nurses (DSCS-N) caring for premature infants was a 4-point Likert type scale, consisting of 19 items, and categorized as 6 factors, explaining 62.5% of the total variance. Each of the factors were named as follows; 'environmental support' (4 items), 'parental support' (3 items), 'interaction' (3 items), 'critical thinking' (3 items), 'professional development' (3 items), and 'partnership' (3 items). The Cronbach's alpha coefficient for the scale was .83 and the reliability of the subscales ranged from .60~.76. CONCLUSION: The psychometric evaluation of the new scale demonstrated an acceptable validity and reliability. Findings indicate that the DSCS-N can be used as the tool to test the effect of educational programs for nurses and contribute to advance developmental care for preterm infants. PMID- 28077828 TI - [Hospital Arrival Rate within Golden Time and Factors Influencing Prehospital Delays among Patients with Acute Myocardial Infarction]. AB - PURPOSE: This research was done to identify the hospital arrival rate and factors related to prehospital delay in arriving at an emergency medical center within the golden time after symptom onset in patients with acute myocardial infarction (AMI). METHODS: Data used in the research was from the National Emergency Department Information System of the National Emergency Medical Center which reported that in 2014, 9,611 patients went to emergency medical centers for acute myocardial infarction. Prehospital time is the time from onset to arrival at an emergency medical center and is analyzed by subdividing arrival and delay based on golden time of 2 hour. RESULTS: After onset of acute myocardial infarction, arrival rate to emergency medical centers within the golden time was 44.0%(4,233), and factors related to prehospital delay were gender, age, region of residence, symptoms, path to hospital visit, and method of transportation. CONCLUSION: Results of this study show that in 2014 more than half of AMI patients arrive at emergency medical centers after the golden time for proper treatment of AMI. In order to reduce prehospital delay, new policy that reflects factors influencing prehospital delay should be developed. Especially, public campaigns and education to provide information on AMI initial symptoms and to enhance utilizing EMS to get to the emergency medical center driectly should be implemented for patients and/or caregivers. PMID- 28077829 TI - [Development of a Psychological Insulin Resistance Scale for Korean Patients with Diabetes]. AB - PURPOSE: This study was done to develop and validate a measure to evaluate the Korean version of psychological insulin resistance (K-PIR) in patients with diabetes in Korea. METHODS: Items were initially generated from literature reviews and interviews with 19 patients with diabetes. The content validity of the items was evaluated by experts. Participants were 424 patients with diabetes recruited through convenience sampling. A cross-sectional survey was designed for item-analysis, exploratory factor analysis with principal axis factoring, and confirmatory factor analysis. Cronbach's alpha was calculated to measure the internal consistency. RESULTS: For the 24 items of the Korean version of psychological insulin resistance, six items were eliminated because of low correlation with the other items. Exploratory factor analysis with 18-item showed that two factors (psycho-cognitive factor and supportive factor) explained 41.8% of the variance, and the factor structure of K-PIR model had a good fit. Internal consistency of K-PIR with 18 items revealed good reliability. CONCLUSION: The findings show that the K-PIR is reliable for measuring the psychological resistance to insulin therapy for Korean patients with diabetes. However, further study is needed to evaluate the validation because the proportion of variation of K-PIR was low in this study. PMID- 28077831 TI - [Effects of Home Care Services Use by Older Adults on Family Caregiver Distress]. AB - PURPOSE: The purpose of this study was to examine the association between utilization of home care services under the national long-term care insurance system and family caregiver distress. METHODS: A secondary data analysis was conducted in this study using data collected in 2011 and 2012 from the Korean version of International Resident Assessment Instrument (interRAI) Home Care assessment system. The study sample included 228 clients receiving community based home care and their family caregivers in Korea. Descriptive statistics, chi2 test, t-test, and Heckman selection model analysis were conducted using SAS 9.3. RESULTS: Presence of family caregiver distress was significantly associated with days of nurse visits (beta=-.89, p=<.001) and home helper visits (beta=-.53, p=.014). Level of caregiver distress was also significantly associated with days of nurse visits (beta=-.66, p=.028). Other factors which were significantly associated with caregiver distress were depression, cognitive function, inadequate pain control, social support for older adult, and caregiver relationship to the older adult. CONCLUSION: The results of this study show that visiting nurse service and appropriate support programs for Older Adults and family caregivers experiencing caregiver distress should be developed and provided to families based on the health care needs of older adults and their family caregivers for effective and sustainable home care. PMID- 28077830 TI - [Path analysis of the Influence of Hospital Ethical Climate Perceived by Nurses on Supervisor Trust and Organizational Effectiveness]. AB - PURPOSE: The purpose of this study was to analyze the paths of influence that a hospital's ethical climate exerts on nurses' organizational commitment and organizational citizenship behavior, with supervisor trust as the mediating factor, and verify compatibility of the models in hospital nurses. METHODS: The sample consisted of 374 nurses recruited from four hospitals in 3 cities in Korea. The measurements included the Ethical Climate Questionnaire, Supervisor Trust Questionnaire, Organizational Commitment Questionnaire and Organizational Citizenship Behavior Questionnaire. Ethical Climate Questionnaire consisted of 6 factors; benevolence, personal morality, company rules and procedures, laws and professional codes, self-interest and efficiency. Data were analysed using SPSS version 18.0 and AMOS version 18.0. RESULTS: Supervisor trust was explained by benevolence and self-interest (29.8%). Organizational commitment was explained by benevolence, supervisor trust, personal morality, and rules and procedures (40.4%). Organizational citizenship behavior was explained by supervisor trust, laws and codes, and benevolence (21.8%). CONCLUSION: Findings indicate that managers need to develop a positive hospital ethical climate in order to improve nurses' trust in supervisors, organizational commitment and organizational citizenship behavior. PMID- 28077832 TI - [Frailty and its related Factors in Vulnerable Elderly Population by Age Groups]. AB - PURPOSE: This study aimed to investigate factors affecting frailty by age groups among vulnerable elders in Korea. METHODS: In this secondary analysis, data were collected from records for 22,868 eldesr registered in the Visiting Health Management program of Publci Health Centers in 2012. Health behaviors, clinically diagnosed disease, frailty, depression and cognitive condition were assessed. Data were analyzed using stepwise regression to determine the associated factors of frailty by age group. RESULTS: Alcohol consumption, physical activity, number of diseases, DM, CVA, arthritis, urinary incontinence, depression and cognitive condition were found to be factors significantly associated with frailty among the elders aged 65~74 (F=135.66, p<.001). Alcohol consumption, physical activity, CVA, arthritis, urinary incontinence, depression and cognitive condition were found to be factors associated with frailty in the elders aged 75~84 (F=245.40, p<.001). Physical activity, CVA, arthritis, depression and cognitive condition were factors associated with frailty in the elders over 85 years of age (F=96.48, p<.001). CONCLUSION: The findings show that frailty of elders and associated factors were different by age group, and common factors affecting frailty were physical activity, CVA, arthritis, depression and cognitive condition. Thus, these factors should be considered in the development of intervention program for care and prevention of frailty and program should be modified according to age group. PMID- 28077833 TI - [Adaptation Process to Group Home Living by Older Adults]. AB - PURPOSE: The purpose of the study was to explore and describe the adaptation process of older people to group homes. METHODS: Participants were twenty older adults aged 65 or older who were living in group homes. Data were collected from January to April, 2015. In-depth unstructured interviews were conducted with individual participants. Data were analyzed using Strauss and Corbin's grounded theory method. RESULTS: From open coding, 100 concepts, 38 sub-categories, and 14 categories were identified. Analysis showed that the central phenomenon of the adaptation process of older people to group homes was 'gradually giving up'. Causal conditions were 'good-for-nothing body', contextual conditions were 'pushed', 'beleaguered'. Intervening conditions were 'reliable pillar: children', 'having affection more than having it from family: facility workers', 'comfort - like feeling at home', 'relieved: system'. Action/interaction strategies were 'facing the unfamiliar reality', 'building relationships with other people', 'accepting reality'. Consequences were 'a good place, more than expected', 'hope for the remaining days', 'waiting for a peaceful death'. CONCLUSION: The results of this study provide an in-depth understanding of the experience of the adaptation process of older people to group homes. The findings from this study can be used as basic data to establish policies to increase the number of small scale facilities which can help older adults adapt easily to the facilities. PMID- 28077834 TI - [Validity and Reliability of Korean Version of the Spiritual Care Competence Scale]. AB - PURPOSE: The aim of this study was to examine the validity and reliability of the Korean Version of the Spiritual Care Competence Scale (K-SCCS). METHODS: A cross sectional study design was used. The K-SCCS consisted of 26 questions to measure spiritual care competence of nurses. Participants, 228 nurses who had more than 3 years'experience as a nurse, completed the survey. Confirmatory factor analysis was used to examine the construct validity and correlations of K-SCCS and spiritual well-being (SWB) were used to examine the criterion validity of K-SCCS. Cronbach's alpha was used to test internal consistency. RESULTS: The construct and the criterion-related validity of K-SCCS were supported as measures of spiritual care competence. Cronbach's alpha was .95. Factor loadings of the 26 questions ranged from .60 to .96. Construct validity of K-SCCS was verified by confirmatory factor analysis (RMSEA=.08, CFI=.90, NFI=.85). Criterion validity compared to the SWB showed significant correlation (r=.44, p<.001). CONCLUSION: The findings suggest that K-SCCS serves as an appropriate measure of spiritual care competence with validity and reliability. However, further study is needed to retest the verification of the factor analysis related to factor 2 (professionalisation and improving the quality of spiritual care) and factor 3 (personal support and patient counseling). Therefore, we recommend using the total score without distinguishing subscales. PMID- 28077835 TI - [Development and Effects of a Heart Health Diary for Self-Care Enhancement of Patients with Heart Failure]. AB - PURPOSE: The purpose of this study was to develop a heart health diary to promote self-care ability among patients with heart failure (HF), and to identify the diary's effect on self-care adherence, self-efficacy, and physical activity. METHODS: A randomized control-group pretestposttest design was adopted using block randomization. A calender-typed health diary was developed and it included a self-care checklist and education information on HF management. The experimental group were given guided counseling and education for 8 weeks and wrote a daily health diary during that period. Data were collected from the outpatient department of a tertiary medical center from February to April 2016. To verify the hypotheses, data for the experimental group (n=28) and control group (n=33) were analysed using the independent t-test with SPSS/WIN 21.0. RESULTS: At the end of 8 weeks the experimental group had significantly higher scores for self-care adherence (t=-2.48, p=.016) and exercise related self efficacy (t=-3.44, p=.001) compared to the control group. CONCLUSION: The findings show that the application of a patient-directed heart health diary is an effective nursing intervention for improving HF patients' self-care adherence and exercise self-efficacy. Strategies to promote dietary self-efficacy are necessary along with further studies including repeated research with an increasing intervention period. Healthcare providers need to encourage the utilization of a health diary for HF patients as a tool for evaluation and for implementation that leads to self-care. PMID- 28077836 TI - [Decision Making Experience on Breast Reconstruction for Women with Breast Cancer]. AB - PURPOSE: The purpose of this study was to explore decision making experiences of Korean women with breast cancer who underwent breast reconstruction with/after a mastectomy. METHODS: Data were collected during 2015-2016 through individual in depth interviews with 10 women who had both mastectomy and breast reconstruction, and analyzed using phenomenological method to identify essential themes on experiences of making a decision to have breast reconstruction. RESULTS: Five theme clusters emerged. First, "expected loss of sexuality and discovery of autonomy" illustrates various aims of breast reconstruction. Second, "holding tight to the reputation of doctors amid uncertainty" specifies the importance of a trust relationship with their physician despite a lack of information. Third, "family members to step back in position" describes support or opposition from family members in the decision making process. Fourth, "bewilderment due to the paradox of appearance-oriented views" illustrates paradoxical environment, resulting in confusion and anger. Lastly, "decision to be made quickly with limited time to oneself" describes the crazy whirling process of decision making. CONCLUSION: Findings highlight aims, worries, barriers, and facilitators that women with breast cancer experience when making a decision about breast reconstruction. Deciding on breast reconstruction was not only a burden for women in a state of shock with a diagnosis of breast cancer, but also an opportunity to decide to integrate their body, femininity, and self which might be wounded from a mastectomy. These findings will help oncology professionals provide effective educational counselling before the operation to promote higher satisfaction after the operation. PMID- 28077837 TI - Curcumin Inhibits Gastric Carcinoma Cell Growth and Induces Apoptosis by Suppressing the Wnt/beta-Catenin Signaling Pathway. AB - BACKGROUND Curcumin has well-known, explicit biological anti-tumor properties. The Wnt/beta-catenin signaling pathway plays a central role in tumor cell proliferation and curcumin can regulate the Wnt/b-catenin signaling pathway of several carcinomas. The aim of this study was to investigate the impact of curcumin on the Wnt/beta-catenin signaling pathway in human gastric cancer cells. MATERIAL AND METHODS We used 3 gastric cancer cell lines: SNU-1, SNU-5, and AGS. Research methods used were MTT assay, flow cytometry, clonogenic assay, annexin V/PI method, Western blotting analysis, tumor formation assay, and in vivo in the TUNEL assay. RESULTS Curcumin markedly impaired tumor cell viability and induced apoptosis in vitro. Curcumin significantly suppressed the levels of Wnt3a, LRP6, phospho-LRP6, beta-catenin, phospho-beta-catenin, C-myc, and survivin. Xenograft growth in vivo was inhibited and the target genes of Wnt/beta-catenin signaling were also reduced by curcumin treatment. CONCLUSIONS Curcumin exerts anti proliferative and pro-apoptotic effect in gastric cancer cells and in a xenograft model. Inhibition of the Wnt/beta-catenin signaling pathway and the subsequently reduced expression of Wnt target genes show potential as a newly-identified molecular mechanism of curcumin treatment. PMID- 28077838 TI - Low-Grade Metabolically-Induced Inflammation Mediators Interleukin-6, Adiponectin, and TNF-alpha Serum Levels in Obese Pregnant Patients in the Perinatal Period. AB - BACKGROUND Obesity is a major clinical problem. The number of obese pregnant women is rising rapidly. The consequences of obesity are significant and affect every aspect of perinatal care for both the mother and the developing fetus. Adipose tissue may be responsible for chronic subclinical inflammation in obesity, being a source of inflammatory mediators. The study was designed to evaluate the analysis of the serum concentration of inflammatory mediators, including interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and adiponectin, in obese pregnant women at full-term pregnancies. MATERIAL AND METHODS The study included 40 women with body mass index (BMI) less than 30 and 24 pregnant women with BMI equal to or greater than 30, admitted to the Perinatology and Obstetrics Department of the University Hospital in Cracow in the first stage of labor. Blood samples were taken from patients to detect the serum concentration of cytokines. Ultrasound was used to evaluate the development of the fetus, including estimated fetal weight, Doppler flows, and the amount of amniotic fluid. We also included the history of chronic diseases and other complications of the pregnancy. A p-value <0.05 was considered significant. RESULTS The level of adiponectin in obese patients as compared to controls was significantly lower. There was no statistically significant difference in either group when TNF-alpha and IL-6 were measured. The results of the survey are consistent with previous reports. CONCLUSIONS The exact role of inflammation in pregnancy is not well understood. Determining the exact functions of the different cytokines in physiological pregnancy and pregnancy complicated by obesity requires further study. PMID- 28077839 TI - Atypical Trigeminal Neuralgia: A Rare Neurological Manifestation of Systemic Lupus Erythematosus. AB - BACKGROUND Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder of unknown etiology which can present at any age with symptoms of mucocutaneous, musculoskeletal, renal, central nervous system, and nonspecific clinical pictures making the disease a "master of mimicry". CASE REPORT A 53-year old female, who was recently diagnosed with SLE, presented with right-sided sharp and electric shock-like facial pain starting at the side of her right nostril and traveling down the naso-labial fold and then back to the angle of the jaw, mostly in the region of V2-V3 distribution with no radiation beyond trigeminal distribution. Her pain had been going for the last 2 years and was regarded as "pretrigeminal neuralgia"; however, it progressed in frequency over the last 2 weeks, with no clear identifying triggering factors. Her laboratory test results showed positive anti-nuclear antibodies (ANA) with raised titer, anti-double stranded DNA, anti-ribonucleoprotein, anti-Sjogren's syndrome-related antigen A, anti-Sjogren's syndrome-related antigen B, and anti-smooth muscle antibodies. Other possibilities of migraine, postherpetic neuralgia, Bell's palsy, and brain tumor were ruled out. A diagnosis of SLE with trigeminal neuralgia (TN) was made and carbamazepine 100 mg 2 times a day was prescribed. CONCLUSIONS TN is seldom mentioned as a neurological manifestation of SLE; hence, we recommend further studies to investigate the SLE-mediated injury to trigeminal fibers to make a timely diagnosis of TN and to prevent progressive autoimmune process-related vasculitic and demyelinating changes. PMID- 28077840 TI - Novel GATAD2B loss-of-function mutations cause intellectual disability in two unrelated cases. AB - GATA zinc finger domain-containing 2B (GATAD2B) is a subunit of the methyl-CpG binding protein-1 complex (MECP1), which deacetylates methylated nucleosomes and regresses transcriptional activity. Recently, GATAD2B has been elucidated as a candidate gene in patients with intellectual disability (ID). In this study, we identified two novel heterozygous frameshift mutations of GATAD2B in two unrelated ID cases through next-generation sequencing (NGS). Both of the mutations c.80_81insGATGT and c.552_555delGAAA cause truncated proteins that might be detrimental to neurodevelopment. We performed western blotting and observed a reduction in the target protein compared with normal controls. This is the first report of GATAD2B in Chinese ID patients. Our findings will broaden the spectrum of GATAD2B mutations and facilitate genetic diagnosis and counseling. PMID- 28077842 TI - Psychoanalysis and the Emigration of Central and Eastern European Intellectuals. AB - One of the most important phenomena in the intellectual history of the 20th century was the exodus of the European mind, the emigration of persons, ideas, techniques, and institutions in the vast areas of social, human, and natural sciences, as well as in literature and the visual arts. Among these exiled intellectuals, psychoanalysts formed a special group. This paper examines the major lines of the emigration of psychoanalysts from the countries of issue to the countries of reception. It focuses, in particular on Hungarian analysts and analytic candidates who left their country of birth in two waves, first after the failure of revolutions in 1918/19 for Berlin, and then after 1938, to escape the Nazis. The paper comments on the existential situation of emigre psychoanalysts in light of Hannah Arendt's writings on refugees. PMID- 28077841 TI - PARS2 and NARS2 mutations in infantile-onset neurodegenerative disorder. AB - Here we present four unrelated families with six individuals that have infantile onset developmental delay/regression and epilepsy. Whole-exome sequencing revealed compound heterozygous mutations, c.[283G>A];[607G>A] in a gene encoding prolyl-tRNA synthetase (PARS2) in one family. Two pairs of compound heterozygous mutations, c.[151C>T];[1184T>G] and c.[707T>G];[594+1G>A], and a homozygous mutation, c.[500A>G];[500A>G], in a gene encoding asparaginyl-tRNA synthetase (NARS2) were also identified in the other three families. Mutations in genes encoding aminoacyl-tRNA synthetases cause gene-specific mitochondrial disorders. Biallelic PARS2 or NARS2 mutations are reported to cause Alpers' syndrome, which is an autosomal recessive neurodegenerative disorder characterized by psychomotor regression and epilepsy with variable degree of liver involvement. Moreover, it is known that NARS2 mutations cause various clinical phenotypes, including non syndromic hearing loss, Leigh syndrome, intellectual disability with epilepsy and severe myopathy. The individuals with PARS2 and NARS2 mutations, we have reported here demonstrate similar neurological features as those previously reported, with diversity in clinical presentation such as hearing loss and seizure type. Our data broaden the clinical and mutational spectrum of PARS2- and NARS2-related disorders. PMID- 28077843 TI - ORPHA, ORPHIC FUNCTIONS, AND THE ORPHIC ANALYST: WINNICOTT'S "REGRESSION TO DEPENDENCE" IN THE LANGUAGE OF FERENCZI. AB - Early developmental trauma is imprinted in the psyche by survival fragmentation and dissociation. Traumatized patients need the analyst to be actively involved and allow for regression to dependence in order to strengthen, create and construct their psychic functioning and structure so that environmental failures will be contained and not rupture continuity of being. I suggest that Ferenczi's and Winnicott's ideas about regression to dependence in analysis are fundamental contributions to these quests, and that Ferenczi set the foundation, which Winnicott further explored and developed. I would like to focus on their clinical theory of treating early developmental trauma of the psyche, describing it in the less known language of Ferenczi, reviving his concept of Orpha and its functions. The complementarities of the two approaches can enrich and broaden our understanding of the clinical complications that arise in the analysis of such states. PMID- 28077844 TI - Introduction. PMID- 28077845 TI - When Words were Wanted, But Woefully Wanting, We Waged War With Chess. AB - What do you say to a child who rarely speaks? How do you work with such a youngster? What are the sine qua nons or guiding principles upon which analysts can draw? And, how do we know if we are being helpful? Sam was 9-years when I began treating him. He was extremely withdrawn and rarely spoke more than a few words. Instead, he mainly played chess. I did not know at first whether Sam's taciturn demeanor was due to shyness, limited verbal abilities, or the stultifying effects of trauma. Fortuitously, during one of many seemingly "innocent" games of chess, Sam happened to make a bold move, to which I admiringly remarked, "What a move, you're killing me." His surprising reaction permanently altered the trajectory of treatment. Curiously, upon returning from summer vacation, not only did Sam no longer need to play chess, but he also found his voice. It was then that he began to discuss things for the first time. Initially, what he said was cloaked in symbolic and indirect referents, suggesting that there were things about which he still could not speak. I proceeded with patience and eventually Sam was able to disclose what he had been harboring inside. In this article, I will discuss the role and psychoanalytic meaning of chess in Sam's play therapy and how it served as a means of symbolically expressing an unspoken, yet ongoing trauma; how it non-verbally, and thus safely communicated Sam's desperate need for understanding and his urgent (but silent) disguised plea for help. PMID- 28077846 TI - Relaxation in Technique Leading to New Beginnings. AB - This paper explores how standard analytic technique may result in a repetition of past traumatic experiences in the transference and countertransference analytic situation. Relaxation and elasticity of technique can lead to re-integration of previously fragmented ego functions, and in remembering and re-experiencing of previously repressed symbolic representations of fragmenting past traumatic experiences, resulting in neocatharsis and working through, thus healing wounds and scars sustained in self development. This healing process will be described through a detailed depiction of an analytic process introducing relaxation of technique, in a response by the analyst, to the patient's Orpha (self-protective) function. Responsiveness to the patient's implicitly or explicitly expressed needs, in the analytic space, may require a departure from standard technique for a deeper level of dynamic work where symbolization of unrepresented emotional experiences becomes possible. PMID- 28077847 TI - Introjective identification: the analytic work of evocation. AB - This paper focuses on a particular counter-transference process-introjective identification and the evocation it enables. Introjective identification enables evocation because it engages the analyst's radical openness to the experience of the patient at the most primordial level. The accumulated wisdom of Ferenczi and those who followed him is used to discuss the role of introjective identification in the treatment of patients with non-neurotic structures. PMID- 28077848 TI - The Economy of the Totalitarian Mind: the Case of the Immigrant Child. AB - Immigration in early childhood can be considered as a traumatic situation. It often goes unrecognized since children adapt to most conditions and conform to their environment with astonishing agility. Inspired by the sensitive work of Sandor Ferenczi, and Donald Winnicott, regarding the psychic economy of maturational processes, the author explores the concept of totalitarian functioning and its obstruction of the growing psyche. Before birth we are all totalitarian, one with the mother; this symbiotic, invincible state of survival mode is prolonged as the immature newborn child ignores the requirements of reality and enjoys omnipotent pleasure through hallucination. The loss of place in immigration often becomes the loss of identity-the question of "where am I?" becomes confused with "who am I?". Clinical practice exposes this fragility in adults torn from their home environment at an early age, forced into precocious maturity, never to grow up in reality. Through clinical examples, the author illustrates how totalitarian mental functioning of "all or nothing, right or wrong, black or white" is exposed in the transference and can be worked through within the psychoanalytical space. PMID- 28077849 TI - Emigration from Within. AB - Listening to the stories of people belonging to different generations in motion both in our consulting rooms and our personal lives-served as introductory lectures into the fundamental aspects of changing context. Through these rich and diverse stories, one enters a territory which is not only multilingual but multidimensional: defined and shaped by historical, political, economic and socio cultural transformations. Giving voice to these silent stories proved helpful for us when going behind walls that traditional analysis could not always penetrate, partly because, in many cases, analysts and analysands have been struggling with the same untouchable issues. It is our professional task to find creative ways to make sense of past and recent experiences of emigration, new prejudices, discriminative forms and attitudes-in order to achieve a better psychoanalytical understanding of the external and internal confusion that has been brought about by the immense changes during the past centuries and the present one. PMID- 28077854 TI - Current updates in tuberculosis. PMID- 28077855 TI - The NOX2-derived reactive oxygen species damaged endothelial nitric oxide system via suppressed BKCa/SKCa in preeclampsia. AB - The endothelial nitric oxide (NO) system may be damaged in preeclampsia; however, the involved mechanisms are unclear. In this study, we used primary human umbilical vein endothelial cells (HUVECs) to evaluate the endothelial NO system in preeclampsia and to determine the underlying mechanisms that are involved. We isolated and cultured HUVECs from normal and preeclamptic pregnancies and evaluated endothelial NO synthase enzyme (eNOS) expression and NO production. Whole-cell K+ currents and oxidative stress were also determined in normal and preeclamptic HUVECs. Compared with normal HUVECs, eNOS expression, NO production and whole-cell K+ currents in preeclamptic HUVECs were markedly decreased, whereas oxidative stress was significantly increased. The decreased K+ currents were associated with damaged Ca2+-activated K+ (KCa) channels, especially the large (BKCa) and small (SKCa) conductance KCa channels, and were involved in the downregulated eNOS expression in preeclamptic HUVECs. Moreover, the increased oxidative stress detected in preeclamptic HUVECs was mediated by NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 2 (NOX2)-dependent reactive oxygen species overproduction that could downregulate whole-cell K+ currents, eNOS expression and NO production. Taken together, our study indicated that the increased oxidative stress in preeclamptic HUVECs could downregulate the NO system by suppressing BKCa and SKCa channels. Because the damaged NO system was closely related to endothelial dysfunction, this study provides important information to further understand the pathological process of endothelial cell dysfunction in preeclampsia. PMID- 28077856 TI - Relationship between cardiorespiratory fitness and blood pressure in young adults: a mediation analysis of body composition. AB - High blood pressure levels are among the most important cardiovascular disease risk factors and are influenced by physical fitness and body composition. However, the degree to which obesity may attenuate or modify the beneficial effects of physical fitness on blood pressure levels in young adults is uncertain. Thus, the aim of this study was to analyze whether body composition is a mediator between cardiorespiratory fitness (CRF) and blood pressure levels in young adults. This work was a cross-sectional study involving first-year college students (n=386) at the University Campus of Cuenca (Spain). We measured weight, height, waist circumference, fat mass percentage (by densitometry), systolic and diastolic blood pressure and CRF levels (by a 20 m shuttle run test). Partial correlation coefficients were estimated to examine the relationships among adiposity variables, CRF and blood pressure variables, controlling for age and sex. ANCOVA models were conducted to explore differences in blood pressure levels across adiposity and CRF categories. Hayes's PROCESS macro was used for the simple mediation analysis. The indirect effect and Sobel test were significant (P<0.001), confirming that all body composition variables mediate between CRF and all of the included blood pressure variables. All body composition variables acted as mediators between CRF and blood pressure. These results highlight the importance of maintaining a healthy body composition to prevent hypertension in young adults. PMID- 28077857 TI - Definition of pediatric hypertension: are blood pressure measurements on three separate occasions necessary? AB - The US Fourth Report (2004) recommended that elevated blood pressure (BP) on at least three occasions should be used to define hypertension in children and adolescents. However, there is no sufficient evidence to support this decision. This study aimed to assess the change in the prevalence of elevated BP obtained on three separate visits in children and adolescents worldwide using a meta analysis. The PubMed database was searched for eligible studies published in English until 20 April 2016. Included studies were population based and reported on the prevalence of elevated BP measured on two or three separate occasions in pediatric populations. A meta-analysis was performed to calculate a summary prevalence of elevated BP over three different visits. A total of 21 studies with 179 561 participants aged 3-20 years were included in the present meta-analysis. The summary prevalence of elevated BP decreased across visits, from 12.1% (95% confidence interval (CI)=10.1-14.0%) during the first visit to 5.6% (95% CI=4.3 7.0%) during the second visit and to 2.7% (95% CI=2.1-3.3%) during the third visit. These findings were independent of sex, age group, ethnicity/race and the definition of elevated BP. When compared with visit 1, the prevalence of elevated BP decreased by 53.7% during visit 2 and by 77.7% during visit 3. Our study suggested that the prevalence of elevated BP decreased substantially from the first visit to the subsequent visits. Worldwide, the true prevalence of hypertension in children and adolescents is ~3% over three different visits. PMID- 28077858 TI - Left ventricular hypertrophy by electrocardiogram as a predictor of success in home blood pressure control: HOMED-BP study. AB - Few studies have focused on the effect of organ damage on achievement of long term home blood pressure (BP) control. Based on the nationwide home BP-based trial data, we aimed to investigate the factors associated with home BP control, in particular, left ventricular hypertrophy (LVH) using the electrocardiogram in patients who started antihypertensive drug treatment. According to the trial protocol, we defined BP as controlled when systolic home BP reached specified targets (125-134 mm Hg in usual control (UC), n=1261; <125 mm Hg in tight control (TC), n=1288). At baseline, before drug treatment started, the mean Sokolow-Lyon voltage was 2.57+/-0.87 mV, and the mean Cornell product was 1573+/-705 mm.ms. The numbers of patients who achieved the target BP level in the UC and TC groups were 892 (70.7%) and 576 (44.7%), respectively. In both the UC and TC groups, systolic home BP at baseline was significantly lower in patients who achieved target levels than in those who did not achieve target levels (P<0.0001). Sokolow Lyon voltage was significantly lower in patients who achieved target levels than in those who did not (P?0.0055). The Cornell product levels in each group were similar (P?0.12), although significantly different between patients who did or did not achieve the target level when the UC and TC groups were combined for analysis (P=0.031). Sokolow-Lyon voltage was significantly associated with achievement of home BP control in the multivariable-adjusted model (odds ratio, 1.13; 95% confidence intervals, 1.02-1.26; P=0.015), but Cornell product was not (P=0.13). These results indicate the difficulty of sufficient antihypertensive treatment when untreated patients had target organ damage, that is, LVH diagnosed by Sokolow-Lyon voltage. PMID- 28077859 TI - Benefits of whole-body vibration training on arterial function and muscle strength in young overweight/obese women. AB - The early arterial dysfunction linked with obesity and a sedentary lifestyle heightens the likelihood of suffering from future cardiovascular events. Whole body vibration training (WBVT) may improve systemic arterial stiffness (brachial ankle pulse wave velocity (baPWV)) and muscle strength in pre- and post menopausal women. However, the effectiveness of WBVT to impact the arterial segments included in baPWV is unknown. The aim of this study was to investigate the effects of WBVT on aortic and leg arterial stiffness in young sedentary overweight/obese women. Thirty-eight young (21 years) overweight/obese women were randomized to WBVT (n=25) or a nonexercising control (CON, n=13) groups for 6 weeks. PWV, brachial and aortic blood pressures (BP), wave reflection (augmentation index (AIx)) and leg muscle strength measurements were acquired before and after 6 weeks. WBVT significantly reduced carotid-femoral PWV (aortic stiffness, P<0.05), femoral-ankle (leg arterial stiffness, P<0.01) and baPWV (systemic arterial stiffness, P<0.01) compared with CON. The reduction in brachial systolic BP (SBP), heart rate, aortic SBP, aortic diastolic BP, AIx normalized to a heart rate of 75 beats per min (AIx@75; P<0.01) and AIx (P<0.05) following WBVT was significant compared with CON (P<0.05). WBVT increased leg muscle strength compared with CON (P<0.001). There was a significant negative correlation between changes in relative muscle strength and aortic stiffness (r= 0.41, P<0.05). WBVT led to reductions in arterial stiffness, central BP and wave reflection in young obese women. WBVT may be an effective intervention toward vascular health promotion and prevention in young overweight/obese women (ClinicalTrials.gov identifier: NCT02679898). PMID- 28077860 TI - Impact of cuff positioning on blood pressure measurement accuracy: may a specially designed cuff make a difference? AB - During blood pressure (BP) measurement, the recommended positioning of the cuff bladder center is directly above the brachial artery. We investigated the relevance of incorrect cuff positioning during (1) auscultatory measurement with an appropriate or improperly small cuff and (2) oscillometric measurement with a wide-range cuff designed to guarantee accurate measurements regardless of position. In subjects with wide BP and arm circumference ranges, (1) auscultatory BP was repeatedly measured with a properly positioned cuff (reference) and, simultaneously, with an identical cuff placed on the other arm in either a correct or an incorrect position (test). The measurements were performed with a properly sized (N=57) or an improperly small cuff (N=33). (2) Auscultatory measurements obtained with a properly positioned and sized cuff were compared with oscillometric measurements obtained with a specially designed wide-range cuff (Omron IntelliWrap) placed on the contralateral arm either in a correct or an incorrect position. Auscultatory BP measures were unaffected by incorrect positioning of a properly sized cuff, whereas with undercuffing, BP was overestimated with the cuff displaced by 90 degrees laterally (systolic/diastolic BP differences: 4.9+/-4.6/4.0+/-4.6 mm Hg, P<0.01) or by 180 degrees (3.9+/-5.4/4.2+/-5.1 mm Hg, P<0.01) in relation to the correct position. Incorrect placement of the oscillometric cuff had no significant effect on the accuracy of the measurements (difference with correct position <1.5 mm Hg). Incorrect cuff positioning introduces a systematic overestimation of auscultatory BP when the cuff is too small in relation to arm circumference but not when it is correctly sized. No systematic error was observed with oscillometric measurements obtained with a specially designed wide-range cuff. PMID- 28077861 TI - Economics and obesity policy. AB - This paper elucidates the challenges surrounding the economics of some popular obesity-related policy proposals. Solid economic justifications for anti-obesity policies are often lacking, and evidence suggests policies like fat and soda taxes or restrictions on food stamp spending are unlikely to substantively affect obesity prevalence. In short, many of the same factors that make obesity such a complicated and multifaceted issue extend to the economic analysis of public health policies. PMID- 28077862 TI - What are the challenges in developing effective health policies for obesity? AB - Identifying and implementing thoughtful, evidence-based (or at least evidence informed) public health approaches to influencing obesity is a complex issue fraught with multiple challenges. These challenges begin with determining whether obesity policy approaches should be implemented. This is considered within the broader context of how common public health policy approaches may be relevant and applied to obesity. Additional challenges discussed include inconsistencies in clearly identifying obesity policy targets (for example, prevention versus treatment), selection of appropriate intervention targets and the identification and measurement of meaningful outcomes. Current policy initiatives are drawn upon to illustrate these challenges in the context of promoting solution-focused dialog aimed toward improving current initiatives and informing the development of new programs. PMID- 28077864 TI - Knowledge and perceptions of polio and polio immunization in polio high-risk areas of Pakistan. AB - Pakistan and Afghanistan remain the only countries where polio is endemic, and Pakistan reports the most cases in the world. Although the rate is lower than in previous years, the situation remains alarming. We conducted a mixed methods study in high-risk areas of Pakistan to identify knowledge, attitudes, and practices of target populations about polio vaccine and its eradication, and to estimate coverage of routine immunization and oral polio vaccine. We surveyed 10,685 households in Karachi, 2522 in Pishin, and 2005 in Bajaur. Some knowledge of polio is universal, but important misconceptions persist. The findings of this study carry strategic importance for program direction and implementation. PMID- 28077863 TI - What have human experimental overfeeding studies taught us about adipose tissue expansion and susceptibility to obesity and metabolic complications? AB - Overfeeding experiments, in which we impose short-term positive energy balance, help unravel the cellular, physiological and behavioural adaptations to nutrient excess. These studies mimic longer-term mismatched energy expenditure and intake. There is considerable inter-individual heterogeneity in the magnitude of weight gain when exposed to similar relative caloric excess reflecting variable activation of compensatory adaptive mechanisms. Significantly, given similar relative weight gain, individuals may be protected from/predisposed to metabolic complications (insulin resistance, dyslipidaemia, hypertension), non-alcoholic fatty liver disease and cardiovascular disease. Similar mechanistic considerations underpinning the heterogeneity of overfeeding responses are pertinent in understanding emerging metabolic phenotypes, for example, metabolically unhealthy normal weight and metabolically healthy obesity. Intrinsic and extrinsic factors modulate individuals' overfeeding response: intrinsic factors include gender/hormonal status, genetic/ethnic background, baseline metabolic health and cardiorespiratory fitness; extrinsic factors include macronutrient (fat vs carbohydrate) content, fat/carbohydrate composition and overfeeding pattern. Subcutaneous adipose tissue (SAT) analysis, coupled with metabolic assessment, with overfeeding have revealed how SAT remodels to accommodate excess nutrients. SAT remodelling occurs either by hyperplasia (increased adipocyte number) or by hypertrophy (increased adipocyte size). Biological responses of SAT also govern the extent of ectopic (visceral/liver) triglyceride deposition. Body composition analysis by DEXA/MRI (dual energy X-ray absorptiometry/magnetic resonance imaging) have determined the relative expansion of SAT (including abdominal/gluteofemoral SAT) vs ectopic fat with overfeeding. Such studies have contributed to the adipose expandability hypothesis whereby SAT has a finite capacity to expand (governed by intrinsic biological characteristics), and once capacity is exceeded ectopic triglyceride deposition occurs. The potential for SAT expandability confers protection from/predisposes to the adverse metabolic responses to overfeeding. The concept of a personal fat threshold suggests a large inter-individual variation in SAT capacity with ectopic depot expansion/metabolic decompensation once one's own threshold is exceeded. This review summarises insight gained from overfeeding studies regarding susceptibility to obesity and related complications with nutrient excess. PMID- 28077865 TI - Systemic sclerosis in 2016: Dermal white adipose tissue implicated in SSc pathogenesis. PMID- 28077866 TI - Paediatric rheumatic disease: Systemic JIA genetically distinct. PMID- 28077867 TI - Microbiome in 2016: T follicular helper cells and the gut microbiome in arthritis. PMID- 28077868 TI - Rheumatoid arthritis: TAK-ing the road to suppress inflammation in synovial fibroblasts. PMID- 28077869 TI - Age, extent and carbon storage of the central Congo Basin peatland complex. AB - Peatlands are carbon-rich ecosystems that cover just three per cent of Earth's land surface, but store one-third of soil carbon. Peat soils are formed by the build-up of partially decomposed organic matter under waterlogged anoxic conditions. Most peat is found in cool climatic regions where unimpeded decomposition is slower, but deposits are also found under some tropical swamp forests. Here we present field measurements from one of the world's most extensive regions of swamp forest, the Cuvette Centrale depression in the central Congo Basin. We find extensive peat deposits beneath the swamp forest vegetation (peat defined as material with an organic matter content of at least 65 per cent to a depth of at least 0.3 metres). Radiocarbon dates indicate that peat began accumulating from about 10,600 years ago, coincident with the onset of more humid conditions in central Africa at the beginning of the Holocene. The peatlands occupy large interfluvial basins, and seem to be largely rain-fed and ombrotrophic-like (of low nutrient status) systems. Although the peat layer is relatively shallow (with a maximum depth of 5.9 metres and a median depth of 2.0 metres), by combining in situ and remotely sensed data, we estimate the area of peat to be approximately 145,500 square kilometres (95 per cent confidence interval of 131,900-156,400 square kilometres), making the Cuvette Centrale the most extensive peatland complex in the tropics. This area is more than five times the maximum possible area reported for the Congo Basin in a recent synthesis of pantropical peat extent. We estimate that the peatlands store approximately 30.6 petagrams (30.6 * 1015 grams) of carbon belowground (95 per cent confidence interval of 6.3-46.8 petagrams of carbon)-a quantity that is similar to the above ground carbon stocks of the tropical forests of the entire Congo Basin. Our result for the Cuvette Centrale increases the best estimate of global tropical peatland carbon stocks by 36 per cent, to 104.7 petagrams of carbon (minimum estimate of 69.6 petagrams of carbon; maximum estimate of 129.8 petagrams of carbon). This stored carbon is vulnerable to land-use change and any future reduction in precipitation. PMID- 28077871 TI - Hyoliths are Palaeozoic lophophorates. AB - Hyoliths are abundant and globally distributed 'shelly' fossils that appear early in the Cambrian period and can be found throughout the 280 million year span of Palaeozoic strata. The ecological and evolutionary importance of this group has remained unresolved, largely because of their poorly constrained soft anatomy and idiosyncratic scleritome, which comprises an operculum, a conical shell and, in some taxa, a pair of lateral spines (helens). Since their first description over 175 years ago, hyoliths have most often been regarded as incertae sedis, related to molluscs or assigned to their own phylum. Here we examine over 1,500 specimens of the mid-Cambrian hyolith Haplophrentis from the Burgess Shale and Spence Shale Lagerstatten. We reconstruct Haplophrentis as a semi-sessile, epibenthic suspension feeder that could use its helens to elevate its tubular body above the sea floor. Exceptionally preserved soft tissues include an extendable, gullwing shaped, tentacle-bearing organ surrounding a central mouth, which we interpret as a lophophore, and a U-shaped digestive tract ending in a dorsolateral anus. Together with opposing bilateral sclerites and a deep ventral visceral cavity, these features indicate an affinity with the lophophorates (brachiopods, phoronids and tommotiids), substantially increasing the morphological disparity of this prominent group. PMID- 28077870 TI - The role of interfacial lipids in stabilizing membrane protein oligomers. AB - Oligomerization of membrane proteins in response to lipid binding has a critical role in many cell-signalling pathways but is often difficult to define or predict. Here we report the development of a mass spectrometry platform to determine simultaneously the presence of interfacial lipids and oligomeric stability and to uncover how lipids act as key regulators of membrane-protein association. Evaluation of oligomeric strength for a dataset of 125 alpha-helical oligomeric membrane proteins reveals an absence of interfacial lipids in the mass spectra of 12 membrane proteins with high oligomeric stability. For the bacterial homologue of the eukaryotic biogenic transporters (LeuT, one of the proteins with the lowest oligomeric stability), we found a precise cohort of lipids within the dimer interface. Delipidation, mutation of lipid-binding sites or expression in cardiolipin-deficient Escherichia coli abrogated dimer formation. Molecular dynamics simulation revealed that cardiolipin acts as a bidentate ligand, bridging across subunits. Subsequently, we show that for the Vibrio splendidus sugar transporter SemiSWEET, another protein with low oligomeric stability, cardiolipin shifts the equilibrium from monomer to functional dimer. We hypothesized that lipids are essential for dimerization of the Na+/H+ antiporter NhaA from E. coli, which has the lowest oligomeric strength, but not for the substantially more stable homologous Thermus thermophilus protein NapA. We found that lipid binding is obligatory for dimerization of NhaA, whereas NapA has adapted to form an interface that is stable without lipids. Overall, by correlating interfacial strength with the presence of interfacial lipids, we provide a rationale for understanding the role of lipids in both transient and stable interactions within a range of alpha-helical membrane proteins, including G-protein-coupled receptors. PMID- 28077872 TI - Structural basis for nutrient acquisition by dominant members of the human gut microbiota. AB - The human large intestine is populated by a high density of microorganisms, collectively termed the colonic microbiota, which has an important role in human health and nutrition. The survival of microbiota members from the dominant Gram negative phylum Bacteroidetes depends on their ability to degrade dietary glycans that cannot be metabolized by the host. The genes encoding proteins involved in the degradation of specific glycans are organized into co-regulated polysaccharide utilization loci, with the archetypal locus sus (for starch utilisation system) encoding seven proteins, SusA-SusG. Glycan degradation mainly occurs intracellularly and depends on the import of oligosaccharides by an outer membrane protein complex composed of an extracellular SusD-like lipoprotein and an integral membrane SusC-like TonB-dependent transporter. The presence of the partner SusD-like lipoprotein is the major feature that distinguishes SusC-like proteins from previously characterized TonB-dependent transporters. Many sequenced gut Bacteroides spp. encode over 100 SusCD pairs, of which the majority have unknown functions and substrate specificities. The mechanism by which extracellular substrate binding by SusD proteins is coupled to outer membrane passage through their cognate SusC transporter is unknown. Here we present X-ray crystal structures of two functionally distinct SusCD complexes purified from Bacteroides thetaiotaomicron and derive a general model for substrate translocation. The SusC transporters form homodimers, with each beta-barrel protomer tightly capped by SusD. Ligands are bound at the SusC-SusD interface in a large solvent-excluded cavity. Molecular dynamics simulations and single channel electrophysiology reveal a 'pedal bin' mechanism, in which SusD moves away from SusC in a hinge-like fashion in the absence of ligand to expose the substrate-binding site to the extracellular milieu. These data provide mechanistic insights into outer membrane nutrient import by members of the microbiota, an area of major importance for understanding human-microbiota symbiosis. PMID- 28077873 TI - Translation from unconventional 5' start sites drives tumour initiation. AB - We are just beginning to understand how translational control affects tumour initiation and malignancy. Here we use an epidermis-specific, in vivo ribosome profiling strategy to investigate the translational landscape during the transition from normal homeostasis to malignancy. Using a mouse model of inducible SOX2, which is broadly expressed in oncogenic RAS-associated cancers, we show that despite widespread reductions in translation and protein synthesis, certain oncogenic mRNAs are spared. During tumour initiation, the translational apparatus is redirected towards unconventional upstream initiation sites, enhancing the translational efficiency of oncogenic mRNAs. An in vivo RNA interference screen of translational regulators revealed that depletion of conventional eIF2 complexes has adverse effects on normal but not oncogenic growth. Conversely, the alternative initiation factor eIF2A is essential for cancer progression, during which it mediates initiation at these upstream sites, differentially skewing translation and protein expression. Our findings unveil a role for the translation of 5' untranslated regions in cancer, and expose new targets for therapeutic intervention. PMID- 28077874 TI - Asgard archaea illuminate the origin of eukaryotic cellular complexity. AB - The origin and cellular complexity of eukaryotes represent a major enigma in biology. Current data support scenarios in which an archaeal host cell and an alphaproteobacterial (mitochondrial) endosymbiont merged together, resulting in the first eukaryotic cell. The host cell is related to Lokiarchaeota, an archaeal phylum with many eukaryotic features. The emergence of the structural complexity that characterizes eukaryotic cells remains unclear. Here we describe the 'Asgard' superphylum, a group of uncultivated archaea that, as well as Lokiarchaeota, includes Thor-, Odin- and Heimdallarchaeota. Asgard archaea affiliate with eukaryotes in phylogenomic analyses, and their genomes are enriched for proteins formerly considered specific to eukaryotes. Notably, thorarchaeal genomes encode several homologues of eukaryotic membrane-trafficking machinery components, including Sec23/24 and TRAPP domains. Furthermore, we identify thorarchaeal proteins with similar features to eukaryotic coat proteins involved in vesicle biogenesis. Our results expand the known repertoire of 'eukaryote-specific' proteins in Archaea, indicating that the archaeal host cell already contained many key components that govern eukaryotic cellular complexity. PMID- 28077875 TI - Structural basis of co-translational quality control by ArfA and RF2 bound to ribosome. AB - Quality control mechanisms intervene appropriately when defective translation events occur, in order to preserve the integrity of protein synthesis. Rescue of ribosomes translating on messenger RNAs that lack stop codons is one of the co translational quality control pathways. In many bacteria, ArfA recognizes stalled ribosomes and recruits the release factor RF2, which catalyses the termination of protein synthesis. Although an induced-fit mechanism of nonstop mRNA surveillance mediated by ArfA and RF2 has been reported, the molecular interaction between ArfA and RF2 in the ribosome that is responsible for the mechanism is unknown. Here we report an electron cryo-microscopy structure of ArfA and RF2 in complex with the 70S ribosome bound to a nonstop mRNA. The structure, which is consistent with our kinetic and biochemical data, reveals the molecular interactions that enable ArfA to specifically recruit RF2, not RF1, into the ribosome and to enable RF2 to release the truncated protein product in this co-translational quality control pathway. The positively charged C-terminal domain of ArfA anchors in the mRNA entry channel of the ribosome. Furthermore, binding of ArfA and RF2 induces conformational changes in the ribosomal decoding centre that are similar to those seen in other protein-involved decoding processes. Specific interactions between residues in the N-terminal domain of ArfA and RF2 help RF2 to adopt a catalytically competent conformation for peptide release. Our findings provide a framework for understanding recognition of the translational state of the ribosome by new proteins, and expand our knowledge of the decoding potential of the ribosome. PMID- 28077876 TI - Microenvironmental autophagy promotes tumour growth. AB - As malignant tumours develop, they interact intimately with their microenvironment and can activate autophagy, a catabolic process which provides nutrients during starvation. How tumours regulate autophagy in vivo and whether autophagy affects tumour growth is controversial. Here we demonstrate, using a well characterized Drosophila melanogaster malignant tumour model, that non-cell autonomous autophagy is induced both in the tumour microenvironment and systemically in distant tissues. Tumour growth can be pharmacologically restrained using autophagy inhibitors, and early-stage tumour growth and invasion are genetically dependent on autophagy within the local tumour microenvironment. Induction of autophagy is mediated by Drosophila tumour necrosis factor and interleukin-6-like signalling from metabolically stressed tumour cells, whereas tumour growth depends on active amino acid transport. We show that dormant growth impaired tumours from autophagy-deficient animals reactivate tumorous growth when transplanted into autophagy-proficient hosts. We conclude that transformed cells engage surrounding normal cells as active and essential microenvironmental contributors to early tumour growth through nutrient-generating autophagy. PMID- 28077877 TI - Integration of temporal and spatial patterning generates neural diversity. AB - In the Drosophila optic lobes, 800 retinotopically organized columns in the medulla act as functional units for processing visual information. The medulla contains over 80 types of neuron, which belong to two classes: uni-columnar neurons have a stoichiometry of one per column, while multi-columnar neurons contact multiple columns. Here we show that combinatorial inputs from temporal and spatial axes generate this neuronal diversity: all neuroblasts switch fates over time to produce different neurons; the neuroepithelium that generates neuroblasts is also subdivided into six compartments by the expression of specific factors. Uni-columnar neurons are produced in all spatial compartments independently of spatial input; they innervate the neuropil where they are generated. Multi-columnar neurons are generated in smaller numbers in restricted compartments and require spatial input; the majority of their cell bodies subsequently move to cover the entire medulla. The selective integration of spatial inputs by a fixed temporal neuroblast cascade thus acts as a powerful mechanism for generating neural diversity, regulating stoichiometry and the formation of retinotopy. PMID- 28077879 TI - Determinants of visual acuity outcomes in eyes with neovascular AMD treated with anti-VEGF agents: an instrumental variable analysis of the AURA study. PMID- 28077878 TI - PLA2G16 represents a switch between entry and clearance of Picornaviridae. AB - Picornaviruses are a leading cause of human and veterinary infections that result in various diseases, including polio and the common cold. As archetypical non enveloped viruses, their biology has been extensively studied. Although a range of different cell-surface receptors are bound by different picornaviruses, it is unclear whether common host factors are needed for them to reach the cytoplasm. Using genome-wide haploid genetic screens, here we identify the lipid-modifying enzyme PLA2G16 (refs 8, 9, 10, 11) as a picornavirus host factor that is required for a previously unknown event in the viral life cycle. We find that PLA2G16 functions early during infection, enabling virion-mediated genome delivery into the cytoplasm, but not in any virion-assigned step, such as cell binding, endosomal trafficking or pore formation. To resolve this paradox, we screened for suppressors of the DeltaPLA2G16 phenotype and identified a mechanism previously implicated in the clearance of intracellular bacteria. The sensor of this mechanism, galectin-8 (encoded by LGALS8), detects permeated endosomes and marks them for autophagic degradation, whereas PLA2G16 facilitates viral genome translocation and prevents clearance. This study uncovers two competing processes triggered by virus entry: activation of a pore-activated clearance pathway and recruitment of a phospholipase to enable genome release. PMID- 28077880 TI - Interleukin-2 receptor-alpha proximal promoter hypomethylation is associated with multiple sclerosis. AB - Genetic studies have demonstrated association between single-nucleotide polymorphisms within the IL2RA (interleukin-2 receptor alpha-subunit) gene and risk of developing multiple sclerosis (MS); however, these variants do not have obvious functional consequences. DNA methylation is a source of genetic variation that could impact on autoimmune disease risk. We investigated DNA methylation of the IL2RA promoter in genomic DNA obtained from peripheral blood mononuclear cells and neural tissue using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. A differential methylation profile of IL2RA was identified, suggesting that IL2RA expression was regulated by DNA methylation. We extended our analysis of DNA methylation to peripheral blood mononuclear cell (PBMC) of MS cases and controls using MALDI-TOF and Illumina HumanMethylation450 arrays. Analyses of CpG sites within the proximal promoter of IL2RA in PBMC showed no differences between MS cases and controls despite an increase in IL2RA expression. In contrast, we inferred significant DNA methylation differences specific to particular leukocyte subtypes in MS cases compared with controls by deconvolution of the array data. The decrease in methylation in patients correlated with an increase in IL2RA expression in T cells from MS cases in comparison with controls. Our data suggest that differential methylation of the IL2RA promoter in T cells could be an important pathogenic mechanism in MS. PMID- 28077881 TI - A pilot study of penile hemodynamics in men with penile curvatures. AB - Penile curvature (PC) is bothersome to the patient. PC is either congenital or acquired. In most of the circulatory system, blood flows in a laminar profile with minimal energy expenditure. When a fluid passes in a curved tube, the laminar profile is disturbed and changed into a turbulent flow. It increases the energy expenditure and reduces the flow. Turbulent flow may have a role in the development of an atherosclerotic plaque and in localizing its site. The aim of this research was to study penile hemodynamics before and after correction of PC. This prospective study included 20 participants, with PC more than 30 degrees . For each participant, preoperative color duplex doppler ultrasonography (CDDU), correction of the curvature using 16 dot plication technique and post-operative CDDU were done. Furhtermore, arterial systolic velocity was estimated distal to the site of curvature/correction every 5 min for 25 min. The degree of curvature ranged from 30 degrees to 90 degrees with a mean of 55+/-18.98. Comparative study between the preoperative and post-operative data proved a significantly higher postoperative peak systolic velocity distal to the site of correction, whereas CDDU data had insignificant differences. We concluded that correction of PC is associated with improvement of penile arterial blood flow distal to the site of correction. PMID- 28077882 TI - Nucleophilic Chiral Phosphines: Powerful and Versatile Catalysts for Asymmetric Annulations. AB - Recent advances in chiral-phosphine-catalyzed asymmetric annulation reactions; including annulations of allenes, alkynes, Morita-Baylis-Hillman (MBH) carbonates, and ketenes; and their applications in the synthesis of bioactive molecules and natural products are reviewed. PMID- 28077884 TI - Chemical vs. Physical Acceleration of Cement Hydration. AB - Cold weather concreting often requires the use of chemical accelerators to speed up the hydration reactions of the cement, so that setting and early-age strength development will occur in a timely manner. While calcium chloride (dihydrate - CaCl2.2H2O) is the most commonly used chemical accelerator, recent research using fine limestone powders has indicated their high proficiency for physically accelerating early-age hydration and reducing setting times. This paper presents a comparative study of the efficiency of these two approaches in accelerating hydration (as assessed via isothermal calorimetry), reducing setting times (Vicat needle), and increasing early-age mortar cube strength (1 d and 7 d). Both the CaCl2 and the fine limestone powder are used to replace a portion of the finest sand in the mortar mixtures, while keeping both the water-to-cement ratio and volume fractions of water and cement constant. Studies are conducted at 73.4 degrees F (23 degrees C) and 50 degrees F (10 degrees C), so that activation energies can be estimated for the hydration and setting processes. Because the mechanisms of acceleration of the CaCl2 and limestone powder are different, a hybrid mixture with 1 % CaCl2 and 20 % limestone powder (by mass of cement) is also investigated. Both technologies are found to be viable options for reducing setting times and increasing early-age strengths, and it is hoped that concrete producers and contractors will consider the addition of fine limestone powder to their toolbox of techniques for assuring performance in cold weather and other concreting conditions where acceleration may be needed. PMID- 28077883 TI - Performance Pressure Enhances Speech Learning. AB - Real-world speech learning often occurs in high pressure situations such as trying to communicate in a foreign country. However, the impact of pressure on speech learning success is largely unexplored. In this study, adult, native speakers of English learned non-native speech categories under pressure or no pressure conditions. In the pressure conditions, participants were informed that they were paired with a (fictitious) partner, and that each had to independently exceed a performance criterion for both to receive a monetary bonus. They were then informed that their partner had exceeded the bonus and the fate of both bonuses depended upon the participant's performance. Our results demonstrate that pressure significantly enhanced speech learning success. In addition, neurobiologically-inspired computational modeling revealed that the performance advantage was due to faster and more frequent use of procedural learning strategies. These results integrate two well-studied research domains and suggest a facilitatory role of motivational factors in speech learning performance that may not be captured in traditional training paradigms. PMID- 28077885 TI - Designing and Implementation of Retina Image Drawing System and Automatic Report Generation from Retina Examinations. AB - INTRODUCTION: Electronic medical records as one of major parts of electronic health records is an important application of Medical Informatics. EMR includes different types of data, Graphical items being one of these data types. To this end, a standard structure for storing and recovering and finally exchanging this data type is required. In order to standardize information items in this research, UMLS standard is used. In this research, graphical information from fondues designing in retina surgery forms is used for the task of implementation. IMPLEMENTATION: Three-layer software architecture is used for implementation of this system, which includes user interface, data base access and business logic. XML database is used for storing and exchanging of data. User interface is designed by the means of Adobe Flash. Also in the user interface for eye examinations, appropriate icons compatible with current pathologies in retina examinations are considered and UMLS codes are used for standardizations purposes. RESULTS: As this project is independently implemented in Adobe Flash, it can be run in most of electronic patient records software. For evaluation purposes of this research, an EMR system for eye clinics is used. Tree structure is used for data entry and finally a text report based on the entered data will be generated. By storing graphical items in this software editing and searching in medical concepts and also comparing features will be available. CONCLUSION: One of the data items that we encounter in various medical records is graphical data. In order to cover the patient's complete electronic medical records, the Electronic Implementation of this information is important. For this purpose, graphical items in retina surgery forms were used and finally a software application for drawing retina picture was developed. Also, XML files were used for the purpose of storing valuable medical data from the pictures, and also UMLS were applied for the standardization purpose. The developed software is currently being used in some of eye clinics in Iran. PMID- 28077886 TI - Effect of Dental Chair Light on Enamel Bonding of Orthodontic Brackets Using Light Cure Based Adhesive System: An In-Vitro Study. AB - AIM: The aim of this in vitro study was to evaluate the influence of the Dental chair light on the bond strength of light cured composite resin. MATERIALS AND METHODS: Sixty therapeutically extracted human premolar teeth were randomly allocated to two groups of 30 specimens each. In both groups light cured composite resin (Transbond XT) and MBT premolar metal brackets (3M Unitek) was used to bond brackets. In group I and II light curing was done using Light emitting diode light curing units without and with the dental chair light respectively. After bonding, all samples were stored in distilled water at room temperature for 24 hours and subsequently tested for shear bond strength and Adhesive Remnant Index (ARI) scores. Data was subjected to Mann Whitney U statistical test. RESULTS: Results indicated that there was significantly higher shear bond strength (7.71 +/- 1.90) for the Group II (composite cured with LED and dental chair light) compared with Group I (composite cured with LED LCU only) (5.74 +/- 1.13).the obtained difference was statistically significant. There was no statistical significant difference between ARI scores in between the groups. CONCLUSIONS: light cure bonding with dental chair light switched on will produce greater bond strength than the conventional bonding. However, the ARI score were similar to both the groups. It is advised that the inexperienced orthodontist should always switch off the dental chair light while bonding for enough working time during the bracket placement. PMID- 28077887 TI - Examination of The Predictive Power of Electromyography and Urodynamic Study in Patients with Cauda Equina Syndrome (Horse Tail Syndrome). AB - BACKGROUND: Cauda equina syndrome is a rare disorder that causes loss of Lumbar plexus function (nerve roots) lower than conus medullaris. No risk factor has been defined for this disease yet. Due to the high morbidity of Cauda equina syndrome and lack of sufficient information about the connection between the disease and urodynamic findings and EMG (Electromyography) findings, the need for this comprehensive study is felt. OBJECTIVE: The aim is to determine the predictive power of findings resulted from urodynamics and electromyography of perineal region and around sphincter in the clinical cure rate of urination in patients with urinary retention followed by Cauda equina syndrome. METHOD: Patients referred to Shohadaye Tajrish Hospital during the years 2009 to 2013, in case of having Cauda equina syndrome symptoms (confirmed with Lumbar MRI), were undergone urodynamic examination and perineal electromyography after surgical decompression action. These both assessments (urodynamic study and electromyography) were repeated during the follow-up of 15 patients in the first and sixth months after surgery and findings were compared with each other. RESULTS: Among the Urodynamic findings, Qmax (maximum urine flow) during three studies had a significant relationship with long-term recovery rate of patients (P <0.05). The relationship had been more valuable in follow-ups after one month (P = 0.0001). Also, BCI (Bladder Contractility Index) in all three studies had a significant relationship with clinical improvement in the ability to urinate (P <0.001). The residual urine (PVR) compared to two previous urodynamic findings showed a less significant relationship with clinical cure rate (P = 0.04). Among the findings of muscle-nerve (MUAP Fibrillation, Positive sharp way) none of them had a significant relationship with cure rate. CONCLUSION: Urodynamic finding, especially Qmax and bladder contractility index, can be considered as predictive indicators for patients' recovery after surgery. PMID- 28077888 TI - Molecular Dynamic Screening Sesquiterpenoid Pogostemon Herba as Suggested Cyclooxygenase Inhibitor. AB - OBJECTIVE: Virtual molecular dynamic sesquiterpenoid Pogostemon Herba (CID56928117, CID94275, CID107152, and CID519743) have screening as cyclooxygenase (COX-1/COX-2) selective inhibitor. METHODS: Molecular interaction studies sesquiterpenoid compounds with COX-1 and COX-2 were using the molecular docking tools by Hex 8.0 and interactions were further visualized using by Discovery Studio Client 3.5 software tool and Virtual Molecular Dynamic 1.9.1 software. The binding energy calculation of molecular dynamic interaction was calculated by AMBER12 software. RESULT: The analysis of the sesquiterpenoid compounds showed that CID56928117, CID94275, CID107152, and CID519743 have suggested as inhibitor of COX-1 and COX-2. CONCLUSION: Collectively, the scoring binding energy calculation (with PBSA Model Solvent) sesquiterpenoid compounds: CID519743 had suggested as candidate for non-selective inhibitor; CID56928117 and CID94275 had suggested as candidate for a selective COX-1 inhibitor; and CID107152 had suggested as candidate for a selective COX-2 inhibitor. PMID- 28077889 TI - Differential Diagnosis of Erythmato-Squamous Diseases Using Classification and Regression Tree. AB - INTRODUCTION: Differential diagnosis of Erythmato-Squamous Diseases (ESD) is a major challenge in the field of dermatology. The ESD diseases are placed into six different classes. Data mining is the process for detection of hidden patterns. In the case of ESD, data mining help us to predict the diseases. Different algorithms were developed for this purpose. OBJECTIVE: we aimed to use the Classification and Regression Tree (CART) to predict differential diagnosis of ESD. METHODS: we used the Cross Industry Standard Process for Data Mining (CRISP DM) methodology. For this purpose, the dermatology data set from machine learning repository, UCI was obtained. The Clementine 12.0 software from IBM Company was used for modelling. In order to evaluation of the model we calculate the accuracy, sensitivity and specificity of the model. RESULTS: The proposed model had an accuracy of 94.84% (. STANDARD DEVIATION: 24.42) in order to correct prediction of the ESD disease. CONCLUSIONS: Results indicated that using of this classifier could be useful. But, it would be strongly recommended that the combination of machine learning methods could be more useful in terms of prediction of ESD. PMID- 28077890 TI - Effect of Lead Nanoparticles Inhalation on Bone Calcium Sensing Receptor, Hydroxyapatite Crystal and Receptor Activator of Nuclear Factor-Kappa B in Rats. AB - This study aimed to investigate whether Pb nanoparticle exposure affects the bone calcium sensing receptor (CaSR), hydroxyapatite crystal, and receptor activator of nuclear factor-kappa B (RANK) in rats exposed to subchronic and chronic inhalation. Thirty two rats were randomly divided into eight groups. One group is a non-exposed group. While three groups were exposed to nanoparticles Pb at the following doses 6.25; 12.5; or 25 mg/m3 an hour daily for 28 days. Another three groups were exposed to nanoparticles Pb at following doses 6.25; 12.5; and 25 mg/m3 one hour daily for 6 months. The expression of trabecular CaSR was significantly decreased at the all doses subchronic exposure compared to the control group (P < 0.05). The CaSR expression significantly decreased in second and third doses subchronic exposure groups compared to the control groups (P < 0.05). With subchronic exposure, the crystal size was increased in second dose group and decreased in lowest and highest doses compared to the control (untreated) group. The crystal size and c-axis were decreased in all dose chronic exposures compared to the control (untreated) group. The expression of cortical RANK was significantly lower at the two lowest dose chronic exposures compared to the control group (P < 0.05). In conclusion, Pb nanoparticle inhibit hydroxyapatite crystal growth at least a part via down regulation of CaSR and RANK. PMID- 28077891 TI - Evaluation the Relationship Between Thyroid Nodule Size with Malignancy and Accuracy of Fine Needle Aspiration Biopsy (FNAB). AB - INTRODUCTION: Some studies have shown largest thyroid nodule size, especially >=4cm that can predict malignancy and reduce fine needle aspiration biopsy (FNAB) accuracy. Therefore, this study is designed to evaluate relationship between thyroid nodule sizes with malignancy and its effect on FNBA accuracy. MATERIALS AND METHODS: a retrospective analytical study design aims to investigate all patients with thyroid nodules who referred to surgery department of Imam-Khomeini Hospital of Mazandaran University of Medical Sciences in Sari from 20 March 2008 to 22 March 2014. We collected patient's demographic data, nodules size, FNAB reports and final pathology (after surgery) reports from their medical records. All data were analyses performed by SPSS18. RESULTS: 167 patients (153 women) with mean age of 41.56+/-13.24 years old were enrolled for this study. In final pathology; 38 patients (22.8%) had malignant nodules. The mean age of patients with or without malignant nodules were 34.93+/-11.86 and 42.37+/-12.26 years old, respectively (P=0.002). The mean size of benign and malignant nodules were 2.91+/ 1.29 cm and 3.38+/-1.86 cm, respectively (P=0.15). 25.2% of <4 cm nodules and 17.9% of >=4 cm nodules were diagnosed as a malignant (P=0.29). FNAB was done on 95 patients that reported benign in 60 patients (63.2%), malignant in 18 patients (18.9%) and suspicious in 17 patients (17.9%). Positive and negative results of FNAB in all nodules were 3.5% and 6.3%, in <4cm nodules were 5.8% and 6.2% and in >=4cm nodules were zero and 6.7%, respectively. The sensitivity, specificity, Positive predict value (PPV), negative predict value (NPV) and overall accuracy (OA) of FNAB in all nodules were 76.19%, 96.49%, 88.88%, 91.66% and 91.02%, and in <4cm nodules were 78.57%, 94.11%, 84.61%, 91.42% and 89.58%, and in >=4cm nodules were 71.4%, 100%, 100%, 92% and 93.33%, respectively. CONCLUSION: the results of this study revealed that the size of the thyroid nodules is not reliable at predicting malignancy and should not be applied in medical decision making. FNAB showed good specificity but the sensitivity was low in our study. In >=4cm nodules; FNAB sensitivity was decreased and accompanied by higher false negative results. Furthermore, FNABs with suspicious results were associated with high probability of malignancy. PMID- 28077892 TI - Accuracy of Conventional Diagnostic Methods for Identifying Structural Changes in Patients with Focal Epilepsy. AB - BACKGROUND: Epilepsy is a neurological disorder characterized by abnormal firing of nerve impulses in the brain. AIM: This study aims to investigate the frequency of appearance of pathological changes in conventional examination methods (electroencephalography-EEG, brain computerized tomography -CT or brain magnetic resonance imaging - MRI) in patients with epilepsy, and relationship between clinical manifestations and localization of changes in CT or MRI. METHODS: In this study we have included 110 patients with focal epilepsy who fulfilled the inclusion criteria out of 557 initially diagnosed patients. Detailed clinical examination together with brain imaging (CT and MRI) and electroencephalography examination was performed. We have evaluated the accuracy of each diagnostic method to localize the epileptic focus. Diagnosis of epilepsy was determined by the ILAE (International League Against Epilepsy) criteria of the year 1989, and classification of epileptic seizures was made according to the ILAE classification 2010. RESULTS: Electroencephalography presented changes in 60.9% of patients; brain CT in 42.1%, and MRI in 78% of the patients. The results of our study showed that clinical manifestations were not always conveyed with pathological changes in conventional examining methods performed. Of the total of 79 patients with changes in imaging (8 with changes in CT and 71 in MRI), 79.7% presented a clinical picture compatible with the region in which morphological changes were found, while in 20.3% of patients the presented morphological changes were not aligned with the clinical picture. CONCLUSION: In patients with epilepsy, conventional examination methods do not always find pathological changes, while clinical manifestations of epilepsy did not always coincide with the location of changes in imaging. Further studies are needed to see if there is clear border between focal and generalized epilepsy. PMID- 28077893 TI - The Prediction of the Risk Level of Pulmonary Embolism and Deep Vein Thrombosis through Artificial Neural Network. AB - BACKGROUND: Venous thromboembolism is a common cause of mortality among hospitalized patients and yet it is preventable through detecting the precipitating factors and a prompt diagnosis by specialists. The present study has been carried out in order to assist specialists in the diagnosis and prediction of the risk level of pulmonary embolism in patients, by means of artificial neural network. METHOD: A number of 31 risk factors have been used in this study in order to evaluate the conditions of 294 patients hospitalized in 3 educational hospitals affiliated with Kerman University of Medical Sciences. Two types of artificial neural networks, namely Feed-Forward Back Propagation and Elman Back Propagation, were compared in this study. RESULTS: Through an optimized artificial neural network model, an accuracy and risk level index of 93.23 percent was achieved and, subsequently, the results have been compared with those obtained from the perfusion scan of the patients. 86.61 percent of high risk patients diagnosed through perfusion scan diagnostic method were also diagnosed correctly through the method proposed in the present study. CONCLUSIONS: The results of this study can be a good resource for physicians, medical assistants, and healthcare staff to diagnose high risk patients more precisely and prevent the mortalities. Additionally, expenses and other unnecessary diagnostic methods such as perfusion scans can be efficiently reduced. PMID- 28077894 TI - Information Expensiveness Perceived by Vietnamese Patients with Respect to Healthcare Provider's Choice. AB - BACKGROUND: Patients have to acquire information to support their decision on choosing a suitable healthcare provider. But in developing countries like Vietnam, accessibility issues remain an obstacle, thus adversely affect both quality and costliness of healthcare information. Vietnamese use both sources from health professionals and friends/relatives, especially when quality of the Internet-based cheaper sources appear to be still questionable. The search of information from both professionals and friends/relatives incurs some cost, which can be viewed as low or high depending low or high accessibility to the sources. These views potentially affect their choices. AIM AND OBJECTIVES: To investigate the effects that medical/health services information on perceived expensiveness of patients' labor costs. Two related objectives are a) establishing empirical relations between accessibility to sources and expensiveness; and, b) probabilistic trends of probabilities for perceived expensiveness. RESULTS: There is evidence for established relations among the variables "Convexp" and "Convrel" (all p's < 0.01), indicating that both information sources (experts and friends/relatives) have influence on patients perception of information expensiveness. The use of experts source tends to increase the probability of perceived expensiveness. CONCLUSION: a) Probabilistic trends show Vietnamese patients have propensity to value healthcare information highly and do not see it as "expensive"; b) The majority of Vietnamese households still take non professional advices at their own risks; c) There is more for the public healthcare information system to do to reduce costliness and risk of information. The Internet-based health service users communities cannot replace this system. PMID- 28077895 TI - Applying Naive Bayesian Networks to Disease Prediction: a Systematic Review. AB - INTRODUCTION: Naive Bayesian networks (NBNs) are one of the most effective and simplest Bayesian networks for prediction. OBJECTIVE: This paper aims to review published evidence about the application of NBNs in predicting disease and it tries to show NBNs as the fundamental algorithm for the best performance in comparison with other algorithms. METHODS: PubMed was electronically checked for articles published between 2005 and 2015. For characterizing eligible articles, a comprehensive electronic searching method was conducted. Inclusion criteria were determined based on NBN and its effects on disease prediction. A total of 99 articles were found. After excluding the duplicates (n= 5), the titles and abstracts of 94 articles were skimmed according to the inclusion criteria. Finally, 38 articles remained. They were reviewed in full text and 15 articles were excluded. Eventually, 23 articles were selected which met our eligibility criteria and were included in this study. RESULT: In this article, the use of NBN in predicting diseases was described. Finally, the results were reported in terms of Accuracy, Sensitivity, Specificity and Area under ROC curve (AUC). The last column in Table 2 shows the differences between NBNs and other algorithms. DISCUSSION: This systematic review (23 studies, 53,725 patients) indicates that predicting diseases based on a NBN had the best performance in most diseases in comparison with the other algorithms. Finally in most cases NBN works better than other algorithms based on the reported accuracy. CONCLUSION: The method, termed NBNs is proposed and can efficiently construct a prediction model for disease. PMID- 28077896 TI - Study of Scientific Production of Community Medicines' Department Indexed in ISI Citation Databases. AB - BACKGROUND: In the scientometric, the main criterion in determining the scientific position and ranking of the scientific centers, particularly the universities, is the rate of scientific production and innovation, and in all participations in the global scientific development. One of the subjects more involved in repeatedly dealt with science and technology and effective on the improvement of health is medical science fields. In this research using scientometric and citation analysis, we studied the rate of scientific productions in the field of community medicine, which is the numbers of articles published and indexed in ISI database from 2000 to 2010. METHODS: This study is scientometric using the survey and analytical citation. The study samples included all of the articles in the ISI database from 2000 to 2010. For the data collection, the advance method of searching was used at the ISI database. The ISI analyses software and descriptive statistics were used for data analysis. RESULTS: Results showed that among the five top universities in producing documents, Tehran University of Medical Sciences with 88 (22.22%) documents are allocated to the first rank of scientific products. M. Askarian with 36 (90/9%) published documents; most of the scientific outputs in Community medicine, in the international arena is the most active author in this field. In collaboration with other writers, Iranian departments of Community Medicine with 27 published articles have the greatest participation with scholars of English authors. In the process of scientific outputs, the results showed that the scientific process was in its lowest in the years 2000 to 2004, and while the department of Community medicine in 2009 allocated most of the production process to itself. Iranian Journal of Public Health and Saudi Medical Journal each of them had 16 articles which had most participation rate in the publishing of community medicine's department. On the type of carrier, community medicine's department by presentation of 340(85.86%) articles had presented most of their scientific productions in the format of article, also in the field of community medicine outputs, article entitled: "Iron loading and erythrophagocytosis increase ferroportin 1 (FPN1) expression in J774 macrophages"(1) with 81 citations ranked first in cited articles. Subject areas of occupational health with 70 articles and subject areas of general medicine with 69 articles ranked the most active research areas in the Production of community medicine's department. CONCLUSION: the obtained data showed the much growth of scientific production. The Tehran University of medical Sciences ranked the first in publishing articles in community medicine's department and with most collaboration with community medicine department of England writers in this field and most writers will present their works in paper format. PMID- 28077897 TI - The Most Influential Scientist in the Development of Medical informatics (14): Branko Cesnik. PMID- 28077898 TI - Quality Improvement of Liver Ultrasound Images Using Fuzzy Techniques. AB - BACKGROUND: Liver ultrasound images are so common and are applied so often to diagnose diffuse liver diseases like fatty liver. However, the low quality of such images makes it difficult to analyze them and diagnose diseases. The purpose of this study, therefore, is to improve the contrast and quality of liver ultrasound images. METHODS: In this study, a number of image contrast enhancement algorithms which are based on fuzzy logic were applied to liver ultrasound images - in which the view of kidney is observable - using Matlab2013b to improve the image contrast and quality which has a fuzzy definition; just like image contrast improvement algorithms using a fuzzy intensification operator, contrast improvement algorithms applying fuzzy image histogram hyperbolization, and contrast improvement algorithms by fuzzy IF-THEN rules. RESULTS: With the measurement of Mean Squared Error and Peak Signal to Noise Ratio obtained from different images, fuzzy methods provided better results, and their implementation - compared with histogram equalization method - led both to the improvement of contrast and visual quality of images and to the improvement of liver segmentation algorithms results in images. CONCLUSION: Comparison of the four algorithms revealed the power of fuzzy logic in improving image contrast compared with traditional image processing algorithms. Moreover, contrast improvement algorithm based on a fuzzy intensification operator was selected as the strongest algorithm considering the measured indicators. This method can also be used in future studies on other ultrasound images for quality improvement and other image processing and analysis applications. PMID- 28077899 TI - A Double-Blind Randomized Clinical Trial Comparing the Effect of Neostigmine and Metoclopramide on Gastric Residual Volume of Mechanically Ventilated ICU Patients. AB - BACKGROUND: In critically ill patients, enteral feeding through the nasogastric tube is the method of choice for nutritional support. Gastrointestinal feeding intolerance and disturbed gastric emptying are common challenges in these patients. The aim of this study was to compare the effect of Neostigmine and Metoclopramide on gastric residual volume (GRV) in mechanically ventilated ICU patients. METHODS: In a double blind, randomized clinical trial, a total of 60 mechanically ventilated ICU patients with GRV >120 mL (3 hours after the last gavage), were randomly assigned into two groups A and B. At baseline and 6 hours later, patients in group A and B received intravenous infusion of neostigmine in a dose of 2.5 mg and metoclopramide in a dose of 10 mg in 100 ml of normal saline, within 30 minutes. Patients' gastric residual volumes were evaluated before the beginning of the intervention, and 3, 6, 9 and 12 hours after the intervention. RESULTS: After adjusting of other variables (Sex, BMI and ICU stay period) generalized estimating equation (GEE) model revealed that neostigmine treatment increased odds of GRV improvement compare to metoclopramide group (Estimate 1.291, OR= 0.3.64, 95% CI 1.07-12.34). However there is a statistically significant time trend (within-subject differences or time effect) regardless of treatment groups (P<0.001). The median time from intervention to GRV improvement was 6 hours (95% CI 3.75-8.25) and 9 hours (95% CI 7.38-10.17) in neostigmine and metoclopramide groups, respectively. This difference was statistically significant (P<0.05). CONCLUSION: It seems that neostigmine is more effective than metoclopramide in reducing GRV and improving gastric emptying in mechanically ventilated ICU patients without significant complication and this protocol may be effective on the tolerance of enteral feeding in ICU patients. Further well-designed randomized clinical trials are needed. PMID- 28077900 TI - Prevalence of Oral Lichen Planus in Diabetes Mellitus: a Meta-Analysis Study. AB - BACKGROUND: Oral lichen planus (OLP) is associated with various other systemic conditions such as hypertension, diabetes mellitus (DM). This study evaluated the prevalence of OLP in DM patients compared with non-diabetic control subjects in a meta-analysis study. METHODS: In this study from January 1973 to August 2016, we searched the studies in Web of Science, Medline/PubMed, Scopus, Science direct, SID (Scientific Information Database), Cochrane and Embase databases. Strategy search was the Medical Subject Heading (MeSH) term oral lichen planus or oral mucosa combined with diabetes in PubMed and this search in other databases. Heterogeneity between estimates was evaluated by the Q and I2 statistic. Also, publication bias was assessed through funnel plot analysis with the Kendall's and Egger's tests. RESULTS: From 831 studies were identified with different search strategies, 11 studies met the criteria to be included in meta-analysis (11 case control studies). The overall prevalence of OLP in 11 studies with 4937 DM patients and 3698 control subjectswas 1.5% and 0.75%, respectively. In this meta analysis, the OR in prevalence of OLP in DM patients compared with control subjects was 1.584 (95%CI1.013-2.477; P=0.044) with a low level of heterogeneity (I2 = 0%) that the result showed the prevalence of OLP in DM patients is significantly more than control subjects. CONCLUSIONS: This meta-analysis study showed an association between OLP with DM, whereas this association was no significant in previous studies, it was probably because different selecting of age, sex, type of DM, medications and criteria. Totally, the meta-analysis showed the risk of OLP in DM was higher compared with control subjects. PMID- 28077901 TI - Feasibility and Value of Radiographic Union Score Hip Fracture after Treatment with Intramedullary Nail of Stable Hip Fractures. AB - INTRODUCTION: Given the importance of fracture healing on patient outcome in clinical practice, it is critical to assess fracture healing. AIM: The aim of this study was to evaluate the feasibility of the Radiographic Union Score Hip fracture after treatment with intramedullary nail of stable hip fractures. PATIENTS AND METHODS: We retrospectively collected the data from the clinical records of our institution of the 47 patientswho had undergone intertrochanteric hip fracture treatment using an intramedullary nail. Pain visual analogic score (VAS) was collected the same day that X-rays were taken. Plain hip X-rays were performed, in two radiographic views, at 40 and 90 days after the surgical procedure. The correlation between the RUSH and VAS score was evaluated. RESULTS: Mean RUSH and VAS scores showed a strong statistical improvement between the 40 and 90 day follow-ups. RUSH value at 40 days fitted an inverse linear regression with VAS, p-value of 0.0063 and r2 of 0.15. At 90 days the regression between RUSH and VAS scores was not significant. CONCLUSION: RUSH could be proposed as an objective system to evaluate union in hip fractures treated with intramedullary nail. PMID- 28077902 TI - The Length of the Greater Palatine Canal in a Lebanese Population: a Radio anatomical Study. AB - OBJECTIVE: The aim of this study was to evaluate the length of the greater palatine canal in a Lebanese population using cone-beam computed tomography (CBCT) technology. MATERIAL AND METHODS: In this study, we measured the length of 148 greater palatine canals in 74 CBCT images of Lebanese adult patients (38 females and 36 males). The data obtained was analyzed statistically to determine 1) if age is related to the length of the canal, 2) if the length of the left side tends to be systematically larger or smaller than the length of the right side, and 3) if the mean length of the canals in females is different than the one in males. RESULTS: In a sagittal plane, the average length of the greater palatine canal was 30.62 (30.64 mm on the right and 30.60 mm on the left). CONCLUSION: Within the limits of this study, we concluded that in our sample in a Lebanese population, the length of the greater palatine canal does not significantly vary according to age, gender, and side. PMID- 28077903 TI - Self-citation of Medical and Non-medical Universities in Northern Iran. AB - BACKGROUND: Self-citation is one of the main challenges in the evaluation of researchers' scientific output. This study aimed at comparing the institutional self-citation among the universities located in Northern Iran. METHODS: This study was conducted as a scientometric study. Research population included all scientific productions of 16 Northern Iran Universities with at least 100 indexed documents indexed in the Web of Science (WoS) by 2 June 2015. The citation analysis section of WoS was used for data collection. SPSS was applied for data analysis. Study hypotheses were tested with two independent sample t-test and paired sample t-test. RESULTS: Producing 16,399 papers, northern Iran universities had 5.33% of contribution in Iran's scientific production. They received 84,058 citations with 17% and 12% of self-citations belonged to the non medical and medical universities, respectively. Testing hypotheses revealed that increase in received citations significantly increases the rate of self-citation and increase in scientific production does not necessarily increase the rate of self-citation. CONCLUSION: The rate of self-citation in the studied universities was not relatively high. However, investigating into the factors affecting the rate of and motives for self-citation needs further research. PMID- 28077904 TI - Regadenoson in Myocardial Perfusion Study - First Institutional Experiences in Bosnia and Herzegovina. AB - INTRODUCTION: Myocardial perfusion imaging (MPI) is widely used in the evaluation of known and suspected coronary artery disease (CAD). Imaging of heart in stress and rest enables the comparison of myocardial uptake of radiotracer in proportion to the needs and coronary flow, which is used for detection of perfusion defects. Exercise stress and pharmacologic agents are used for the stressing purpose. Novel pharmacologic stressor regadenoson is A2A selective adenosine agonist, which selectively binds to the adenosine receptors in coronary arteries causing coronary dilatation. MATERIALS AND METHODS: We analyzed 50 myocardial perfusion studies performed with regadenoson as a pharmacologic agent that was injected before Tc99m-sestamibi in stress imaging. Stress and rest sets of images were evaluated for relative uptake of Tc99m-sestamibi in order to detect and characterize perfusion defects. After the injection of regadenoson, hemodynamic parameters and potential side-effects were closely monitored. Side-effects were stratified per severity as mild, moderate and severe. Studies were read by nuclear medicine physicians using quantitative perfusion SPECT software. Additional diagnostic information such as wall motion and wall thickening were provided by gating. RESULTS: Thirty-three patients (66%) experienced one or more side-effects upon the administration of regadenoson, most commonly warmth and chest discomfort. In all patients but one (98%), the symptoms were mild, of short duration and self-limiting. Out of all side-effects registered, 44 (96%) were mild, and 2 (4%) were moderate. Two moderate side-effects developed in one patient with a prior history of asthma, and included shortness of breath and cough. Heart rate changed by 16 +- 31 bpm. Highest increase in blood pressure was 30 mm Hg for systolic, and 10 mm Hg for diastolic. One case of significant decrease in blood pressure was noted from the hypertensive basal values, 50 mm for systolic, and 30 mm Hg for diastolic. ST segment depression of up to 1 mm occurred in 4 cases (8%), and T-wave changes in 3 cases (6%). No conduction abnormalities, significant hypotension, symptomatic bradycardia or cardiac arrest ocurred. CONCLUSION: Our first institutional experiences proved regadenoson as A2A selective adenosine agonist as a pharmacologic stressor to be safe, tolerable and easily used. Its safety profile enabled the study to be performed in patients with respiratory disease also. PMID- 28077905 TI - Biomedical Scientific and Professional Social Networks in the Service of the Development of Modern Scientific Publishing. AB - Information technologies have found their application in virtually every branch of health care. In recent years they have demonstrated their potential in the development of online library, where scientists and researchers can share their latest findings. Academia.edu, ResearchGate, Mendeley, Kudos, with the support of platform GoogleScholar, have indeed increased the visibility of scientific work of one author, and enable a much greater availability of the scientific work to the broader audience. Online libraries have allowed free access to the scientific content to the countries that could not follow the economic costs of getting access to certain scientific bases. Especially great benefit occurred in countries in transition and developing countries. Online libraries have great potential in terms of expanding knowledge, but they also present a major problem for many publishers, because their rights can be violated, which are signed by the author when publishing the paper. In the future it will lead to a major conflict of the author, the editorial board and online database, about the right to scientific content This question certainly represents one of the most pressing issues of publishing, whose future in printed form is already in the past, and the future of the online editions will be a problem of large-scale. PMID- 28077906 TI - How to Improve Visibility of Scientific Biomedical Sources. AB - With the rapid development of information and communications technologies, industrial nations are transforming into societies in which knowledge is the most contested and valuable good. The increased speed at which we have to acquire new knowledge, insights, and abilities is forcing us to divide up learning into novel, shorter phases. The traditional choreography of learning with its long, rigid defined school, job, and university educational periods is already obsolete today. Self-organized, lifelong learning is becoming a must. Everyone knows that without the uncertainty of the new nothing new is possible. To try to prevent this in one way or another would be fatal for science, as well as for our society as a whole. Research means thinking ahead. Research means recognizing challenges and taking responsibility for the new. The freedom needed for this is now the international standard, to which we have to adapt. The question of the development of such standards for research can therefore not be posed frequently and persistently enough. We all know that creativity is biological privilege of young age and the best test for their scientific creativity is publication in respectable journals with a solid impact factor. Conferences like this one in Sarajevo in 2016 should be very stimulated for younger as well as more senior research workers. PMID- 28077907 TI - How to Compose, Write and Publish a Scientific or Professional Communication. AB - There is an ample number of recommendations, guides and monographs addressing the art of composing and publishing written, oral or visual communications in science and various professions. In order to write an article, autors have to follow certain rules. Presentation of the article (oral or poster presentation) also requires skill, meaning that you have to fulfill certain guidelines and regulations. PMID- 28077908 TI - Magnetic Resonance Imaging of a Case of Central Neurocytoma. AB - BACKGROUND: The purpose of this study is to investigate the MRI features of central neurocytoma. CASE REPORT: A 45 year old man with 3 months of worsening daily headaches. These headaches were diffuse, lasted for several hours, and mostly occurred in the morning. She was initially diagnosed and treated for migraines but later he had epileptic attack and diplopia and neurolog recomaded MRI. METHODS: precontrast MRI; TSE/T2Wsequence in axial/coronal planes; 3D-Hi resolution T1W sagittal; FLAIR/T2W axial; FLAIR/T2W and Flash/T2W oblique coronal plane (perpendicular to temporal lobes) GRE/T2W axial plane for detection of heme products. Post-contrast TSE/T1W sequence in axial, coronal and sagittal planes. Diffusion weighted and ADC mapping MRI images for EPI sequence in axial plane. RESULTS: A 23x12mm heterogeneous mass within aqueductus cerebri, with calcified and hemorrhagic foci and extending downwards till fourth ventricle. It's originating from the right paramedian posterior aqueductal wall (tectum), and also extending to and involving the tegmentum of mesencephalon at its right paramedian aspect. CSF flow obstruction secondary to described aqueductal mass, with resultant triventricular hydrocephalus). Marked transependymal CSF leak can be noted at periventricular white matter, secondary to severe hydrocephalus. After IV injection of contrast media, this mass shows mild-to-moderate heterogenous speckled enhancement. CONCLUSION: MRI is helpful in defining tumor extension, which is important in preoperative planning. Although IN is a relatively rare lesion, it should be considered in the differential diagnosis of intraventricular lesions in the presence of such typical MR findings. However, a definitive diagnosis requires immunochemical study and electron microscopy. PMID- 28077909 TI - The Most Influential Scientists in the Development of Medical Informatics (15). PMID- 28077910 TI - The First Mediterranean Seminar on Science Writing, Editing and Publishing, Sarajevo, December 2-3, 2016. AB - The First Mediterranean Seminar on Science Writing, Editing & Publishing (SWEP 2016) was held in Sarajevo, Bosnia & Herzegovina from 2nd to 3rd December 2016. It was organized by Academy of Medical Sciences of Bosnia and Herzegovina, running concurrent sessions as part of its Annual Meeting titled " "Days of AMNuBiH - Theory and Practice in Science Communication and Scientometrics". Hotel Bosnia in the city centre was the chosen venue. On the first day, nineteen presentations on various issues of science writing and publication ethics were delivered by speakers from Croatia, Serbia, Macedonia, Albania, Bosnia & Herzegovina and the UK (Asim Kurjak, Milivoj Boranic, Doncho Donev, Osman Sinanovic, Miro Jakovljevic, Enver Zerem, Dejan Milosevic, Silva Dobric, Srecko Gajovic, Izet Masic, Armen Yuri Gasparyan, Sekib Sokolovic, Nermin Salkic, Selma Uzunovic, Admir Kurtcehajic, Edin Begic and Floreta Kurti). Each presentation had a take-home message for novice and seasoned authors, encountering numerous problems in non-Anglophone research environment. Lecturers, who were internationally recognized editors of regional journals, generously shared their experience of adhering to the best ethical guidance. Elegant presentations by Srecko Gajovic (Editor-in-Chief of the Croatian Medical Journal) and Armen Yuri Gasparyan (past Chief Editor of the European Science Editing) showcased their accomplishments that strengthened ties between authors from all over the world. Gasparyan reflected on educational resources of editorial associations, such as the International Committee of Medical Journal Editors (ICMJE) and the Committee on Publication Ethics (COPE), and called not just to declare the adherence to, but also to enforce their ethical guidance in daily practice. Editors of Medical Archives, Croatian Medica Journal, Vojnosanitetski Pregled, Psychiatria Danubina, Acta Informatica Medica, Materia Socio-Medica, The Donald School Journal of Ultrasound in Obstretics and Gynecology, Acta Medica Saliniana and Medicinski Glasnik presented their editorial strategies aimed at attracting best authors and resolving problems with authorship, conflicts of interest, and plagiarism. Topical education on science writing and editing was considered as an inseparable part of continuing professional development in biomedicine. Armen Yuri Gasparyan (UK) was offered an opportunity to interact with more than 70 participants, attending the SWEP 2016 on the second day. The lecturer talked about author contributions, disclosures of conflicts of interests, plagiarism of ideas and words, research performance and impact indicators, and targeting ethical journals. Topics were presented in a way to help non-Anglophone authors, reviewers and editors avoid common ethical problems. Dr Gasparyan stressed the importance of regularly arranging such meetings across Balkan and Mediterranean countries to eradicate plagiarism and other forms research misconduct. The organizers of the SWEP 2016 awarded selected keynote speakers with certificates of lifetime achievement in journal editing, and decided to run the Seminar annually with support of Balkan and Mediterranean editors and publishers. The SWEP 2016 marked a turning point in the process of regional developments since all attending editors opted for nurturing enthusiasm of the organizers and launching the Mediterranean Association of Science Editors and Publishers (MASEP). The Seminar was a great success with its impressive scientific and social activities. It attracted more than 100 students, researchers, editors, and publishers from Bosnia & Herzegovina and neighbouring countries. Proceedings, in the form of short reports, were published in Acta Informatica Medica and archived in PubMed Central. New friendships were forged between regional experts in editing and young specialists during those unforgettable two days of intensive discussions and informal interactions (a-y). PMID- 28077911 TI - A Decade of Data Protection for Innovative Drugs in Canada: Issues, Limitations, and Time for a Reassessment. AB - Drug regulators in Canada and in other nations require innovative pharmaceutical companies to submit undisclosed clinical or other data as a condition of approving the marketing of new pharmaceutical products-the origination of which involves considerable effort and investment. Data protection regulations were enacted in Canada in 2006, which-to some extent-closed a loophole in intellectual property law that had previously left innovative companies with no effective data protection for their clinical data. Although the regulations were intended to clarify and effectively implement Canada's international treaty obligations in the spirit of innovation, a review of Canada's first decade of effective data protection shows that Health Canada and Canadian courts have interpreted the scope of data protection for innovative drugs in a narrow manner that undermines and is inconsistent with the intent of the regulations. As the 10-year anniversary of data protection in Canada is this year (2016), this article demonstrates the need to advance Canada's data protection regime into one that consistently contributes to the promotion of investment in pharmaceutical research and development, to the mutual advantage of innovators and patients, in a manner conducive to the social and economic welfare of Canadians. PMID- 28077912 TI - EmptyHeaded: A Relational Engine for Graph Processing. AB - There are two types of high-performance graph processing engines: low- and high level engines. Low-level engines (Galois, PowerGraph, Snap) provide optimized data structures and computation models but require users to write low-level imperative code, hence ensuring that efficiency is the burden of the user. In high-level engines, users write in query languages like datalog (SociaLite) or SQL (Grail). High-level engines are easier to use but are orders of magnitude slower than the low-level graph engines. We present EmptyHeaded, a high-level engine that supports a rich datalog-like query language and achieves performance comparable to that of low-level engines. At the core of EmptyHeaded's design is a new class of join algorithms that satisfy strong theoretical guarantees but have thus far not achieved performance comparable to that of specialized graph processing engines. To achieve high performance, EmptyHeaded introduces a new join engine architecture, including a novel query optimizer and data layouts that leverage single-instruction multiple data (SIMD) parallelism. With this architecture, EmptyHeaded outperforms high-level approaches by up to three orders of magnitude on graph pattern queries, PageRank, and Single-Source Shortest Paths (SSSP) and is an order of magnitude faster than many low-level baselines. We validate that EmptyHeaded competes with the best-of-breed low-level engine (Galois), achieving comparable performance on PageRank and at most 3* worse performance on SSSP. PMID- 28077913 TI - Understanding changes in the hydrological behaviour within a karst aquifer (Lurbach system, Austria). AB - A thorough data analysis combined with groundwater modelling was conducted in an Austrian binary karst aquifer to better understand changes in the hydrological behaviour observed at a karst spring. During a period of 4 years after a major flood event the spring hydrograph appears to be more damped with lower peak flow and higher baseflow than in the years before. The analysis of the hydrograph recession suggests that the observed hydrological change is caused by changes within the karst system rather than by varying hydro-meteorological conditions. The functioning of the aquifer and potential causes of the observed changes are further examined using the groundwater flow model MODFLOW. The simulation results suggest that a modification of hydraulic conductivity and storage within the conduit network, e.g. due to the plugging of the drainage conduits with sediments, may be the cause of the different behaviour. MODFLOW was able to reproduce the observed dynamics of spring flow, although it does not account for turbulent flow within karst conduits. Using a simplified model scenario it is demonstrated that the damping of the hydrograph is much stronger if turbulent conduit flow is taken into account. Thus, a turbulent flow model is needed to assess potential changes in the storage properties quantitatively. PMID- 28077914 TI - Modelling expertise at different levels of granularity using semantic similarity measures in the context of collaborative knowledge-curation platforms. AB - Collaboration platforms provide a dynamic environment where the content is subject to ongoing evolution through expert contributions. The knowledge embedded in such platforms is not static as it evolves through incremental refinements - or micro-contributions. Such refinements provide vast resources of tacit knowledge and experience. In our previous work, we proposed and evaluated a Semantic and Time-dependent Expertise Profiling (STEP) approach for capturing expertise from micro-contributions. In this paper we extend our investigation to structured micro-contributions that emerge from an ontology engineering environment, such as the one built for developing the International Classification of Diseases (ICD) revision 11. We take advantage of the semantically related nature of these structured micro-contributions to showcase two major aspects: (i) a novel semantic similarity metric, in addition to an approach for creating bottom-up baseline expertise profiles using expertise centroids; and (ii) the application of STEP in this new environment combined with the use of the same semantic similarity measure to both compare STEP against baseline profiles, as well as to investigate the coverage of these baseline profiles by STEP. PMID- 28077915 TI - A Single Bout of Fasting (24 h) Reduces Basal Cytokine Expression and Minimally Impacts the Sterile Inflammatory Response in the White Adipose Tissue of Normal Weight F344 Rats. AB - Sterile inflammation occurs when inflammatory proteins are increased in blood and tissues by nonpathogenic states and is a double-edged sword depending on its cause (stress, injury, or disease), duration (transient versus chronic), and inflammatory milieu. Short-term fasting can exert a host of health benefits through unknown mechanisms. The following experiment tested if a 24 h fast would modulate basal and stress-evoked sterile inflammation in plasma and adipose. Adult male F344 rats were either randomized to ad libitum access to food or fasted for 24 h prior to 0 (control), 10, or 100, 1.5 mA-5 s intermittent, inescapable tail shocks (IS). Glucose, nonesterified free fatty acids (NEFAs), insulin, leptin, and corticosterone were measured in plasma and tumor necrosis factor- (TNF-) alpha, interleukin- (IL-) 1beta, IL-6, and IL-10 in plasma, and subcutaneous, intraperitoneal, and visceral compartments of white adipose tissue (WAT). In control rats, a 24 h fast reduced all measured basal cytokines in plasma and visceral WAT, IL-1beta and IL-6 in subcutaneous WAT, and IL-6 in intraperitoneal WAT. In stressed rats (IS), fasting reduced visceral WAT TNF alpha, subcutaneous WAT IL-1beta, and plasma insulin and leptin. Short-term fasting may thus prove to be a useful dietary strategy for reducing peripheral inflammatory states associated with visceral obesity and chronic stress. PMID- 28077916 TI - Expression of Interferon Effector Gene SART1 Correlates with Interferon Treatment Response against Hepatitis B Infection. AB - Interferon-alpha (IFN-alpha) has limited response rate in the treatment of chronic hepatitis B (CHB). The underlying mechanism of differential responsiveness to IFN remains elusive. It has been recently reported that SART1 mediates antiviral effects of IFN-alpha in the hepatitis C virus (HCV) cell culture model. In this study, we investigated the role of SART1 in antiviral activity of IFN-alpha against hepatitis B virus (HBV) using blood and liver biopsy samples from chronic hepatitis B patients treated with pegylated IFN-alpha and HepG2 cells transfected with cloned HBV DNA. We observed that the basal SART1 expression in liver and PBMCs before IFN treatment was significantly higher in responders than in nonresponders. Furthermore, baseline SART1 expression level positively correlated with the degree of HBV DNA and HBeAg decline after IFN treatment. Mechanistically, silencing SART1 abrogated the antiviral activity of IFN-alpha, reduced the expression of IFN-stimulated genes (ISGs) Mx, OAS, and PKR, and attenuated JAK-STAT signaling in HepG2 cells, suggesting that SART1 regulates IFN-mediated antiviral activity through JAK-STAT signaling and ISG expression. Our study elucidates the important role of SART1 in IFN-mediated anti HBV response and provides new insights into understanding variation of IFN treatment response in CHB patients. PMID- 28077917 TI - Disturbed Expression of EphB4, but Not EphrinB2, Inhibited Bone Regeneration in an In Vivo Inflammatory Microenvironment. AB - The important role of ephrinB2-EphB4 signaling pathway in bone remodeling has been well established. However, it is still unclear whether this bidirectional signaling also has effects on the regenerative processes of bone defects created in an inflammatory microenvironment. In this study, an experimental animal model of bone defects treated with lentiviruses was prepared and an inflammatory microenvironment was established. Expression levels of bone marker genes were monitored in the newly formed bone tissue using quantitative reverse transcriptase polymerase chain reaction and western blot. Immunohistochemical (IHC) staining and histomorphometric analysis were also performed to evaluate bone healing processes. Compared with the pLenti6.3-ctrl group, the pLenti6.3 ephb4siRNA group exhibited lower expression levels of bone formation marker genes and a higher level of NFATc1 in the new bone tissue. In addition, the newly formed bone was thinner and the number of giant osteoclasts was higher in the pLenti6.3-ephb4siRNA group than that in the pLenti6.3-ctrl group. In contrast, there was no significant difference between the pLenti6.3-efnb2siRNA group and the pLenti6.3-ctrl group. In conclusion, EphB4 plays an irreplaceable role in bone regeneration in an inflammatory microenvironment, whereas the functional loss of ephrinB2 can be effectively compensated, most possibly by other ephrins with similar chemical structures. PMID- 28077920 TI - A new S-type eigenvalue inclusion set for tensors and its applications. AB - In this paper, a new S-type eigenvalue localization set for a tensor is derived by dividing [Formula: see text] into disjoint subsets S and its complement. It is proved that this new set is sharper than those presented by Qi (J. Symb. Comput. 40:1302-1324, 2005), Li et al. (Numer. Linear Algebra Appl. 21:39-50, 2014) and Li et al. (Linear Algebra Appl. 481:36-53, 2015). As applications of the results, new bounds for the spectral radius of nonnegative tensors and the minimum H eigenvalue of strong M-tensors are established, and we prove that these bounds are tighter than those obtained by Li et al. (Numer. Linear Algebra Appl. 21:39 50, 2014) and He and Huang (J. Inequal. Appl. 2014:114, 2014). PMID- 28077919 TI - Noncanonical IFN Signaling: Mechanistic Linkage of Genetic and Epigenetic Events. AB - The canonical model of cytokine signaling via the JAK/STAT pathway dominates our view of signal transduction but provides no insight into the significance of the simultaneous presence of activated JAKs and STATs in the nucleus of cells treated with cytokines. Such a mechanistic shortcoming challenges the usefulness of the model in its present form. Focusing on the interferon (IFN) cytokines, we have developed a noncanonical model of IFN signaling that naturally connects activated JAKs and STATs at or near response elements of genes that are activated by the IFNs. Specifically, cells treated with IFNgamma showed association of activated STAT1alpha and JAK2 at the GAS element of genes activated by IFNgamma. For IFNalpha treated cells, the association involved activated STAT1alpha and TYK2 JAK kinase at the ISRE promoter. The power of the noncanonical model is that it provides mechanistic insight into specific gene activation at the level of the associated epigenetics, akin to that of steroid/steroid receptor signaling. PMID- 28077918 TI - Lactate, a Neglected Factor for Diabetes and Cancer Interaction. AB - Increasing body of evidence suggests that there exists a connection between diabetes and cancer. Nevertheless, to date, the potential reasons for this association are still poorly understood and currently there is no clinical evidence available to direct the proper management of patients presenting with these two diseases concomitantly. Both cancer and diabetes have been associated with abnormal lactate metabolism and high level of lactate production is the key biological property of these diseases. Conversely, high lactate contribute to a higher insulin resistant status and a more malignant phenotype of cancer cells, promoting diabetes and cancer development and progression. In view of associations between diabetes and cancers, the role of high lactate production in diabetes and cancer interaction should not be neglected. Here, we review the available evidence of lactate's role in different biological characteristics of diabetes and cancer and interactive relationship between them. Understanding the molecular mechanisms behind metabolic remodeling of diabetes- and cancer-related signaling would endow novel preventive and therapeutic approaches for diabetes and cancer treatment. PMID- 28077921 TI - Iterative methods of strong convergence theorems for the split feasibility problem in Hilbert spaces. AB - In this paper, we propose several new iterative algorithms to solve the split feasibility problem in the Hilbert spaces. By virtue of new analytical techniques, we prove that the iterative sequence generated by these iterative procedures converges to the solution of the split feasibility problem which is the best close to a given point. In particular, the minimum-norm solution can be found via our iteration method. PMID- 28077922 TI - Evaluating Youth Development Programs: Progress and Promise. AB - Advances in theories of adolescent development and positive youth development have greatly increased our understanding of how programs and practices with adolescents can impede or enhance their development. In this paper the authors reflect on the progress in research on youth development programs in the last two decades, since possibly the first review of empirical evaluations by Roth, Brooks Gunn, Murray, and Foster (1998). The authors use the terms Version 1.0, 2.0 and 3.0 to refer to changes in youth development research and programs over time. They argue that advances in theory and descriptive accounts of youth development programs (Version 2.0) need to be coupled with progress in definitions of youth development programs, measurement of inputs and outputs that incorporate an understanding of programs as contexts for development, and stronger design and evaluation of programs (Version 3.0). The authors also advocate for an integration of prevention and promotion research, and for use of the term youth development rather than positive youth development. PMID- 28077924 TI - Temperature during pregnancy influences the fetal growth and birth size. AB - BACKGROUND: Birth weight and length have seasonal fluctuations. However, it is uncertain which meteorological element has an effect on birth outcomes and which timing of pregnancy would explain such effect. Therefore, the purpose of this study was to examine temperature effects during pregnancy and which timing of pregnancy has effects on size at birth. METHODS: A large, randomized, controlled trial of food and micronutrient supplementation for pregnant women was conducted in Matlab, Bangladesh (MINIMat Study), where women were enrolled from November 2001 to October 2003. The fetal growth data which included the size at birth and information of their mothers were obtained (n = 3267). Meteorological data such as temperature, precipitation, relative humidity, and daily sunshine hours during pregnancy were observed at the nearest observatory site of Bangladesh Meteorological Department. RESULTS: Infants born in colder months (November January) were shorter than those born in hot and dry, and monsoon months (mean (SD) of birth length was 47.5 cm (2.2) vs. 47.8 cm (2.1) vs. 47.9 cm (2.1) respectively; P < 0.001). Increased temperature during the last month of pregnancy was significantly related with increased birth length with adjustment for gestational weeks and the season at birth, and remained significant with further adjustments for precipitation, sex of infants, maternal early-pregnancy BMI, parity, and education status of the mother (P < 0.01). On the other hand, increased temperature at mid-gestation was associated with increased birth weight (P < 0.05). CONCLUSIONS: These findings suggest that temperature affects both birth weight and length. The more temperature increased at the last month of pregnancy, birth length became longer. For birth weight, the temperature at mid pregnancy affected in a positive way. PMID- 28077923 TI - How Safe Are Common Analgesics for the Treatment of Acute Pain for Children? A Systematic Review. AB - Background. Fear of adverse events and occurrence of side effects are commonly cited by families and physicians as obstructive to appropriate use of pain medication in children. We examined evidence comparing the safety profiles of three groups of oral medications, acetaminophen, nonsteroidal anti-inflammatory drugs, and opioids, to manage acute nonsurgical pain in children (<18 years) treated in ambulatory settings. Methods. A comprehensive search was performed to July 2015, including review of national data registries. Two reviewers screened articles for inclusion, assessed methodological quality, and extracted data. Risks (incidence rates) were pooled using a random effects model. Results. Forty four studies were included; 23 reported on adverse events. Based on limited current evidence, acetaminophen, ibuprofen, and opioids have similar nausea and vomiting profiles. Opioids have the greatest risk of central nervous system adverse events. Dual therapy with a nonopioid/opioid combination resulted in a lower risk of adverse events than opioids alone. Conclusions. Ibuprofen and acetaminophen have similar reported adverse effects and notably less adverse events than opioids. Dual therapy with a nonopioid/opioid combination confers a protective effect for adverse events over opioids alone. This research highlights challenges in assessing medication safety, including lack of more detailed information in registry data, and inconsistent reporting in trials. PMID- 28077926 TI - Migrant children and migrants' children: Nativity differences in school enrollment in Mexico and the United States. AB - BACKGROUND: The growing prevalence of migrant children in diverse contexts requires a reconsideration of the intergenerational consequences of migration. To understand how migration and duration of residence are associated with children's schooling, we need more comparative work that can point to the similarities and differences in outcomes for children across contexts. OBJECTIVE: This paper addresses the importance of nativity and duration of residence for children's school enrollment on both sides of a binational migration system: The United States and Mexico. The analyses are designed to determine whether duration of residence has a similar association with school enrollment across these different settings. METHODS: The analyses are based on nationally representative household data from the 2010 Mexican Census and the 2006-2010 American Community Survey. Logistic regression models compare school enrollment patterns of Mexican and U.S. born children of Mexican origin in the United States and those of Mexican and U.S.-born children in Mexico. Interactions for nativity/duration of residence and age are also included. RESULTS: The results demonstrate that, adjusting for household resources and household-level migration experience, Mexican-born children in the United States and U.S.-born children in Mexico, particularly those who arrived recently, lag behind in school enrollment. These differences are most pronounced at older ages. CONCLUSIONS: The comparisons across migration contexts point to greater school attrition and non-enrollment among older, recent migrant youth, regardless of the context. The interactions suggest that recent migration is associated with lower schooling for youth who engage in migration at older ages in both the United States and Mexico. PMID- 28077925 TI - Artificial cells: from basic science to applications. AB - Artificial cells have attracted much attention as substitutes for natural cells. There are many different forms of artificial cells with many different definitions. They can be integral biological cell imitators with cell-like structures and exhibit some of the key characteristics of living cells. Alternatively, they can be engineered materials that only mimic some of the properties of cells, such as surface characteristics, shapes, morphology, or a few specific functions. These artificial cells can have applications in many fields from medicine to environment, and may be useful in constructing the theory of the origin of life. However, even the simplest unicellular organisms are extremely complex and synthesis of living artificial cells from inanimate components seems very daunting. Nevertheless, recent progress in the formulation of artificial cells ranging from simple protocells and synthetic cells to cell mimic particles, suggests that the construction of living life is now not an unrealistic goal. This review aims to provide a comprehensive summary of the latest developments in the construction and application of artificial cells, as well as highlight the current problems, limitations, challenges and opportunities in this field. PMID- 28077927 TI - Utility of self-competency ratings during residency training in family medicine education-emerging countries: findings from Japan. AB - BACKGROUND: Family medicine education-emerging countries face challenges in demonstrating a new program's ability to train residents in womb-to-tomb care and resident ability to provide such care competently. We illustrate the experience of a new Japanese family medicine program with resident self-competency assessments. METHODS: In this longitudinal cross-sectional study, residents completed self-competency assessment surveys online during 2011-2015. Each year of training, residents self-ranked their competence using a 100-point visual analog scale for 142 conditions: acute (30 conditions), chronic (28 conditions) women's health (eight conditions), and geriatrics/home (12 conditions) care; procedures (38 types); health promotion (21 conditions). RESULTS: Twenty residents (11 women, 9 men) participated. Scores improved annually by training year from baseline to graduation; the mean composite score advanced from 31 to 65%. All subcategories showed improvement. Scores for care involving acute conditions rose from 49 to 75% (26% increase); emergency procedures, 46-65% (19% increase); chronic care, 33-73% (40% increase); women's health, 16-59% (43% increase); procedural care, 26-56% (30% increase); geriatrics care-procedures, 8 65% (57% increase); health promotion, 21-63% (42% increase). Acute care, chronic care, and health promotion achieved the highest levels. Women's health care, screenings, and geriatrics experienced the greatest increase. Health promotion gains occurred most dramatically in the final residency year. CONCLUSIONS: A resident self-competency assessment provides a simple and practical way to conduct an assessment of skills, to monitor skills over time, to use the data to inform residency program improvement, and to demonstrate the breadth of family medicine training to policymakers, and other stakeholders. PMID- 28077928 TI - Phytoplankton composition and microcystin concentrations in open and closed bays of Lake Victoria, Tanzania. AB - This study was carried out in order to investigate the spatial variation of algal toxin (microcystin) concentrations along the shoreline of Lake Victoria. A total of 16 nearshore stations differing in connectivity to the main lake basin were categorized as either closed bays (ratio of bay area to bay opening < 1) or open bays (ratio >= 1) and sampled during November and December 2009. Water samples were analyzed for total phosphorus (TP), chlorophyll a, phytoplankton community composition and concentrations of microcystin (MC). Open and closed bays were significantly different for phytoplankton abundance and composition: Average phytoplankton biovolume was higher for closed bays (45 mm3 L-1 +/- 11 SE) than open bays (5 +/- 2 mm3 L-1). Cyanobacterial biovolume (mainly Microcystis spp., Anabaena spp. and Planktolyngbya spp.) also was significantly higher in closed bays (82 +/- 9% of total biovolume) than in open bays (44 +/- 5%). In contrast, diatom biovolume was lower in closed bays (7 +/- 1%) than in open bays (36 +/- 6%). MCs were found only among sites from closed bays and concentrations ranged from 0.4 to 13 MUg L-1 MC-LR equiv. and coincided with high abundance of Microcystis spp. It is concluded that the level of water exchange from individual bays to the main basin is an important factor influencing eutrophication and microcystin production in nearshore habitats of Lake Victoria. PMID- 28077929 TI - HNRNPA2B1 regulates the epithelial-mesenchymal transition in pancreatic cancer cells through the ERK/snail signalling pathway. AB - BACKGROUND: Heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) is closely related to tumour occurrence and development, oncogene expression, apoptosis inhibition and invasion and metastasis capacities. However, its function in the epithelial-mesenchymal transition (EMT) of pancreatic cancer is not fully understood. METHODS: By comparing various wild-type pancreatic cancer cell lines, we determined which have a higher expression level of HNRNPA2B1 accompanied by the higher expression of N-cadherin and vimentin and lower expression of E cadherin. Therefore, to elucidate the role of HNRNPA2B1 in EMT, we generated models of HNRNPA2B1 knockdown and overexpression in different types of pancreatic cancer cell lines (MIA Paca-2, PANC-1 and Patu-8988) and examined changes in expression of EMT-related factors, including CDH1, CDH2, vimentin and snail. RESULTS: The results show that HNRNPA2B1 promotes EMT development by down regulating E-cadherin and up-regulating N-cadherin and vimentin, and also stimulates the invasion capacity and inhibits viability in human pancreatic cancer cell lines, the similar results in vivo experiments. Moreover, we found that HNRNPA2B1 likely regulates EMT progression in pancreatic carcinoma via the ERK/snail signalling pathway. CONCLUSIONS: The results of this work suggest that HNRNPA2B1 inhibition has potential antitumour effects, which warrants in-depth investigation. PMID- 28077930 TI - Before the freeze: otoliths from the Eocene of Seymour Island, Antarctica, reveal dominance of gadiform fishes (Teleostei). AB - The first record of fossil teleostean otoliths from Antarctica is reported. The fossils were obtained from late Early Eocene shell beds of the La Meseta Formation, Seymour Island that represent the last temperate marine climate phase in Antarctica prior to the onset of cooling and subsequent glaciation during the late Eocene. A total of 17 otolith-based teleost taxa are recognized, with 10 being identifiable to species level containing nine new species and one new genus: Argentina antarctica sp. nov., Diaphus? marambionis sp. nov., Macruronus eastmani sp. nov., Coelorinchus balushkini sp. nov., Coelorinchus nordenskjoeldi sp. nov., Palimphemus seymourensis sp. nov., Hoplobrotula? antipoda sp. nov., Notoberyx cionei gen. et sp. nov. and Cepola anderssoni sp. nov. Macruronus eastmani sp. nov. is also known from the late Eocene of Southern Australia, and Tripterophycis immutatus Schwarzhans, widespread in the southern oceans during the Eocene, has been recorded from New Zealand, southern Australia, and now Antarctica. The otolith assemblage shows a typical composition of temperate fishes dominated by gadiforms, very similar at genus and family levels to associations known from middle Eocene strata of New Zealand and the late Eocene of southern Australia, but also to the temperate Northern Hemisphere associations from the Paleocene of Denmark. The Seymour Island fauna bridges a gap in the record of global temperate marine teleost faunas during the early Eocene climate maximum. The dominant gadiforms are interpreted as the main temperate faunal component, as in the Paleocene of Denmark. Here they are represented by the families Moridae, Merlucciidae (Macruroninae), Macrouridae and Gadidae. Nowadays Gadidae are a chiefly Northern Hemisphere temperate family. Moridae, Macruroninae and Macrouridae live today on the lower shelf to deep-water or mesopelagically with Macruroninae being restricted to the Southern Ocean. The extant endemic Antarctic gadiform family Muraenolepididae is missing, as are the dominant modern Antarctic fishes of the perciform suborder Notothenioidei. Recently, there has been much debate on isolated jaw bones of teleost fishes found in the La Meseta Formation and whether they would represent gadiforms (Merlucciidae in this case) or some early, primitive notothenioid. Otoliths are known to often complement rather than duplicate skeletal finds. With this in mind, we conclude that our otolith data support the presence of gadiforms in the early Eocene of Antarctica while it does not rule out the presence of notothenioids at the same time. http://zoobank.org/urn:lsid:zoobank.org:pub:A30E5364-0003-4467-B902-43A41AD456CC. PMID- 28077931 TI - Proteome changes in the small intestinal mucosa of growing pigs with dietary supplementation of non-starch polysaccharide enzymes. AB - BACKGROUND: Non-starch polysaccharide enzymes (NSPEs) have long been used in monogastric animal feed production to degrade non-starch polysaccharides (NSPs) to oligosaccharides in order to promote growth performance and gastrointestinal (GI) tract health. However, the precise molecular mechanism of NSPEs in the improvement of the mammalian small intestine remains unknown. METHODS: In this study, isobaric tags were applied to investigate alterations of the small intestinal mucosa proteome of growing pigs after 50 days of supplementation with 0.6% NSPEs (mixture of xylanase, beta-glucanase and cellulose) in the diet. Bioinformatics analysis including gene ontology annotation was performed to determine the differentially expressed proteins. A protein fold-change of >= 1.2 and a P-value of < 0.05 were selected as thresholds. RESULTS: Dietary supplementation of NSPEs improved the growth performance of growing pigs. Most importantly, a total of 90 proteins were found to be differentially abundant in the small intestinal mucosa between a control group and the NSPE group. Up regulated proteins were related to nutrient metabolism (energy, lipids, protein and mineral), immunity, redox homeostasis, detoxification and the cell cytoskeleton. Down-regulated proteins were primarily related to transcriptional and translational regulation. Our results indicate that the effect of NSPEs on the increase of nutrient availability in the intestinal lumen facilitates the efficiency of nutrient absorption and utilization, and the supplementation of NSPEs in growing pigs also modulates redox homeostasis and enhances immune response during simulating energy metabolism due to a higher uptake of nutrients in the small intestine. CONCLUSIONS: These findings have important implications for understanding the mechanisms of NSPEs on the small intestine of pigs, which provides new information for the better utilization of this feed additive in the future. PMID- 28077932 TI - A world without parasites: exploring the hidden ecology of infection. AB - Parasites have historically been considered a scourge, deserving of annihilation. Although parasite eradications rank among humanity's greatest achievements, new research is shedding light on the collateral effects of parasite loss. Here, we explore a "world without parasites": a thought experiment for illuminating the ecological roles that parasites play in ecosystems. While there is robust evidence for the effects of parasites on host individuals (eg affecting host vital rates), this exercise highlights how little we know about the influence of parasites on communities and ecosystems (eg altering energy flow through food webs). We present hypotheses for novel, interesting, and general effects of parasites. These hypotheses are largely untested, and should be considered a springboard for future research. While many uncertainties exist, the available evidence suggests that a world without parasites would be very different from the world we know, with effects extending from host individuals to populations, communities, and even ecosystems. PMID- 28077933 TI - bayesPop: Probabilistic Population Projections. AB - We describe bayesPop, an R package for producing probabilistic population projections for all countries. This uses probabilistic projections of total fertility and life expectancy generated by Bayesian hierarchical models. It produces a sample from the joint posterior predictive distribution of future age- and sex-specific population counts, fertility rates and mortality rates, as well as future numbers of births and deaths. It provides graphical ways of summarizing this information, including trajectory plots and various kinds of probabilistic population pyramids. An expression language is introduced which allows the user to produce the predictive distribution of a wide variety of derived population quantities, such as the median age or the old age dependency ratio. The package produces aggregated projections for sets of countries, such as UN regions or trading blocs. The methodology has been used by the United Nations to produce their most recent official population projections for all countries, published in the World Population Prospects. PMID- 28077935 TI - Development of a microarray-based method for allergen-specific IgE and IgG4 detection. AB - BACKGROUND: sIgE and sIgG4 detection is necessary for more accurate and effective type I hypersensitivity diagnostics and the estimation of disease development. Typically, the analyses of these antibodies are performed separately with the help of various specialized systems. The aim of this study was to develop a microarray-based method for the simultaneous quantitative detection of sIgE and sIgG4 to the most common allergens in a single sample. METHODS: A quantitative method for the simultaneous detection of sIgE and sIgG4 was developed based on the technology of hydrogel microchips previously designed at Engelhardt Institute of Molecular Biology, Russian Academy of Sciences (EIMB RAS). The microarray contained gel pads with immobilized allergens and gel pads that allow for the obtaining of sIgE and sIgG4 internal calibration curves for each allergen during the assay. The possibility of the simultaneous detection of sIgE and sIgG4 was developed using the corresponding Cy5 and Cy3 fluorescent dyes. RESULTS: The multiplex immunoassay method using hydrogel microarrays developed in this study allowed the quantitative detection of sIgE and sIgG4 to 31 allergens from different groups in a single assay. A comparison of the microarray with the existing plate-based analogues (i.e., ALLERG-O-LIQ and sIgG4 ELISA) was performed by analysing 152 blood serum samples and by evaluating Pearson correlation coefficients, ROC analysis, and Passing-Bablok linear regression results. CONCLUSION: The implementation of this method in allergy diagnostics will provide the possibility of simultaneously performing primary patient screening and obtaining additional information concerning the severity of the allergies and the choice of an appropriate therapy. PMID- 28077934 TI - Serum reference value of two potential doping candidates-myostatin and insulin like growth factor-I in the healthy young male. AB - BACKGROUND: Myostatin negatively regulates muscle growth, and its inhibition by suitable proteins can increase muscle bulk and exercise performance. However, the reference values of serum myostatin in athletes performing strength training are still lacking. METHODS: A cross-sectional study recruiting28 male collegiate athletes performing strength training and 29 age-matched normal controls was conducted. The serum concentration of myostatin and insulin-like growth factor 1 (IGF-1), grip strength, and body composition were the main outcome measures. We used regression models to analyze the correlation between serum markers and the physiological parameters. The athlete group had greater height, weight, body mass index (BMI), fat mass percentage, fat-free mass, muscle mass, waist girth, grip strength, and estimated daily energy expenditure. RESULTS: The IGF-1 concentration was higher in the athlete group (324 +/- 80 vs. 263 +/- 134 ng/ml), but the myostatin levels did not differ (12.1 +/- 3.7 vs. 12.4 +/- 3.5 ng/ml). The reference value for IGF-1 among the healthy young males was 293 +/- 114 ng/ml, correlated with age and height; the value for myostatin was 12.3 +/- 3.6 ng/ml, correlated negatively with BMI, fat mass percentage, and waist girth after adjustment for age. CONCLUSION: Myostatin level is negatively related to fat percentage, and serum IGF-1 is positively related to height. The reference values could provide a basis for future doping-related study. PMID- 28077936 TI - Redox proteomic identification of carbonylated proteins in autism plasma: insight into oxidative stress and its related biomarkers in autism. AB - BACKGROUND: Autism is a severe childhood neurological disorder with poorly understood etiology and pathology. Currently, there is no authentic laboratory test to confirm the diagnosis of autism. Oxidative damage may play a central role in the pathogenesis of autism. Present study is an effort to search for possible biomarkers of autism and further clarify the molecular changes associated with oxidative stress that occurs in the plasma of autistic children. METHODS: We performed redox proteomics analysis to compare carbonylated proteins in the plasma of autistic subjects and healthy controls. Immunoprecipitation and Western blot analysis were used to validate carbonylated proteins identified by the redox proteomics. RESULTS: Protein carbonylation levels in two proteins, complement component C8 alpha chain and Ig kappa chain C were found to be significantly increased in autistic patients compared with controls. These two proteins were successfully validated via immunoprecipitation and Western blot analysis. CONCLUSIONS: The results further highlight the role of oxidative stress in the pathogenesis of autism and provide some information for the diagnosis and/or monitoring of autism. PMID- 28077937 TI - Heart rate variability biofeedback: Theoretical basis, delivery, and its potential for the treatment of substance use disorders. AB - Heart rate variability biofeedback (HRV BFB) is a biobehavioural clinical intervention that is gaining growing empirical support for the treatment of a number of psychological disorders, several of which are highly comorbid with substance use disorders (SUDs). The present article reviews the autonomic nervous system bases of two key processes implicated in the formation and maintenance of addictive pathology-affect dysregulation and craving-and asks if HRV BFB may be an effective intervention to ameliorate autonomic nervous system dysregulation in these processes, and as such, prove to be an effective intervention for SUDs. A detailed description of HRV BFB and its delivery is provided. Preliminary evidence suggests HRV BFB may be an effective addendum to current first-line SUD treatments, though no firm conclusions can be drawn at this time; more research is needed. PMID- 28077939 TI - CONSTRUCTION OF SCALAR AND VECTOR FINITE ELEMENT FAMILIES ON POLYGONAL AND POLYHEDRAL MESHES. AB - We combine theoretical results from polytope domain meshing, generalized barycentric coordinates, and finite element exterior calculus to construct scalar and vector-valued basis functions for conforming finite element methods on generic convex polytope meshes in dimensions 2 and 3. Our construction recovers well-known bases for the lowest order Nedelec, Raviart-Thomas, and Brezzi-Douglas Marini elements on simplicial meshes and generalizes the notion of Whitney forms to non-simplicial convex polygons and polyhedra. We show that our basis functions lie in the correct function space with regards to global continuity and that they reproduce the requisite polynomial differential forms described by finite element exterior calculus. We present a method to count the number of basis functions required to ensure these two key properties. PMID- 28077938 TI - Syndemic factors associated with drinking patterns among Latino men and Latina transgender women who have sex with men in New York City. AB - Alcohol consumption is a significant public health concern among Latino men and Latina transgender women who have sex with men. However, characteristics and behaviors associated with alcohol consumption in this population, particularly in regard to the complex influence of syndemic factors, remain understudied. The purpose of this study was to examine predictors of high-risk alcohol consumption (i.e. binge or heavy drinking). Between January and March of 2014, 176 Latino men and Latina transgender women in New York City completed an interviewer administered questionnaire. We developed a syndemics scale to reflect the total number of syndemic factors - clinically significant depression, childhood sexual abuse, intimate partner violence, and discrimination - reported by each participant. We also carried out a multinomial logistic regression model predicting binge and heavy drinking. Forty-seven percent of participants reported high-risk alcohol consumption in the past 30 days (21% binge and 26% heavy). Approximately 16% of participants reported no syndemic factors, 27% reported one factor, 39% reported two factors, and 18% reported three or four. In the multinomial logistic regression model, our syndemic factors scale was not significantly associated with binge drinking. However, participants who reported three or four factors were significantly more likely to report heavy drinking. In addition, having multiple sexual partners was associated with an increased risk of binge and heavy drinking; involvement in a same-sex relationship was associated with binge drinking. Further work is needed to develop effective prevention intervention approaches for high-risk alcohol consumption within this population. PMID- 28077940 TI - Physician tobacco screening and advice to quit among U.S. adolescents - National Survey on Drug Use and Health, 2013. AB - BACKGROUND: Initiating tobacco use in adolescence increases the risk of nicotine dependence and continued smoking. Physician screening for tobacco use increases the odds of physicians intervening with patients who smoke; However, without appropriate follow-through by the physician, screening for tobacco use is not enough to significantly increase cessation rates. Given the critical phase of development adolescence poses in tobacco use and evidence that physician intervention improves adult cessation efforts, we sought to examine physician tobacco use screening and advice to quit among adolescents (12-17 years). METHODS: Using data from the 2013 National Survey on Drug Use and Health (NSDUH), we examined the prevalence and correlates of tobacco use screening in adolescent respondents who reported visiting their physician within the past year (N = 12,798). Multivariable logistic regression analyses explored the relationship between tobacco use screening and physician advice to quit in a sub-set of the sample who reported on physician advice to quit (n = 1,868), controlling for sociodemographics, cigarette use, and substance use and screening. RESULTS: Only 49% of adolescents who visited a physician within the past year reported being screened for tobacco use. Adolescents who were screened by their physician were predominantly female (56.6%), White (60.1%), in late adolescence (83.0%), and covered by private health insurance (63.8%). Screening for tobacco use was highly correlated with physician advice to quit smoking, controlling for sociodemographic characteristics and cigarette use; this relationship was attenuated, but remained significant, after screening for alcohol and marijuana were added to the model. Hispanic adolescents were significantly less likely to receive physician advice to quit in all multivariable models. CONCLUSIONS: Our findings suggest missed opportunities for youth tobacco use prevention and cessation efforts in the clinical setting. Further research is needed to better facilitate an open dialogue on tobacco use between physicians and their adolescent patients. PMID- 28077941 TI - Corrigendum: Optimization of Agroinfiltration in Pisum sativum Provides a New Tool for Studying the Salivary Protein Functions in the Pea Aphid Complex. AB - [This corrects the article on p. 1171 in vol. 7, PMID: 27555856.]. PMID- 28077943 TI - Natalizumab Treatment Modulates Peroxisome Proliferator-Activated Receptors Expression in Women with Multiple Sclerosis. AB - Peroxisome Proliferator-Activated Receptors (PPAR) are transcription factors suggested to be involved in inflammatory lesions of autoimmune encephalomyelitis and multiple sclerosis (MS). Our objective was to assess whether Natalizumab (NTZ) therapy is associated with alterations of PPAR expression in MS patients. We analyzed gene expression of PPAR in peripheral blood mononuclear cells (PBMC) as well as blood inflammatory markers in women with MS previously medicated with first-line immunomodulators (baseline) and after NTZ therapy. No differences in PPARalpha, PPARbeta/delta, PPARgamma, and CD36 mRNA expression were found in PBMC between patients under baseline and healthy controls. At three months, NTZ increased PPARbeta/delta mRNA (p = 0.009) in comparison to baseline, while mRNA expression of PPARgamma and CD36 (a well-known PPAR target gene) was lower in comparison to healthy controls (p = 0.026 and p = 0.028, resp.). Although these trends of alterations remain after six months of therapy, the results were not statistically significant. Osteopontin levels were elevated in patients (p = 0.002) and did not change during the follow-up period of NTZ treatment. These results suggest that PPAR-mediated processes may contribute to the mechanisms of action of NTZ therapy. PMID- 28077942 TI - PPARdelta as a Metabolic Initiator of Mammary Neoplasia and Immune Tolerance. AB - PPARdelta is a ligand-activated nuclear receptor that regulates the transcription of genes associated with proliferation, metabolism, inflammation, and immunity. Within this transcription factor family, PPARdelta is unique in that it initiates oncogenesis in a metabolic and tissue-specific context, especially in mammary epithelium, and can regulate autoimmunity in some tissues. This review discusses its role in these processes and how it ultimately impacts breast cancer. PMID- 28077944 TI - Procedure Time for Gastric Endoscopic Submucosal Dissection according to Location, considering Both Mucosal Circumferential Incision and Submucosal Dissection. AB - Background. Previous assessments of technical difficulty and procedure time for endoscopic submucosal dissection (ESD) of gastric neoplasms did not take into account several critical determinants of these parameters. However, two key phases of ESD determine the total procedure time: the mucosal circumference incision speed (CIS) and submucosal dissection speed (SDS). Methods. We included 302 cases of en bloc and R0 resection of gastric neoplasms performed by 10 operators who had completed the training program at our hospital. Twelve locations were classified based on multiple criteria, such as condition of surrounding mucosa, lesion vascularity, presence of submucosal fat, ulcers, scars, fibrosis, and scope and device maneuverability. Lesions in different locations were classified into three groups based on the length of the procedure: fast, moderate, or late. Results. A significant difference was found in CIS and SDS for each location (p < 0.01), which demonstrates the validity of this classification system. In several locations, CIS and SDS were not consistent with each other. Conclusion. CIS and SDS did not correspond to each other even for lesions in the same location. Consideration of ESD procedure time for gastric neoplasms requires a more elaborate classification system than that previously reported. PMID- 28077945 TI - ANA-Negative Presentation of SLE in Man with Severe Autoimmune Neutropenia. AB - Background. Systemic lupus erythematosus (SLE) is a chronic, inflammatory, connective tissue disease that commonly affects the joints and a variety of organs due to an overactivation of the body's immune system. There is wide heterogeneity in presentation of SLE patients, including lung, central nervous system, skin, kidney, and hematologic manifestations. Case Presentation. We report a case of atypical manifestation of SLE in a 53-year-old man who presented with neutropenic fever. Physical findings of interest included oral ulcers on the lower lip, a malar-like rash across the bridge of the nose, and a discoid-like rash on extensor surfaces of the elbows and knees. Labs include ANC <100, weakly positive anti-dsDNA, negative ANA, ferritin 1237 ng/mL, low C3/C4, and positive direct Coombs' test. A thorough workup for infection and hematologic malignancy was negative. Two days after initiation of therapy with 25 mg IV solumedrol twice a day, the patient's daily fevers resolved. ANC drastically improved to 2000 after two weeks of steroid treatment. He was later found to have a high titer of anti-neutrophil antibodies. Discussion. Autoimmune leukopenia is a common presentation in SLE, occurring in 50-60% of patients. Severe autoimmune neutropenia is uncommon and may correlate with high anti-neutrophil antibody activity despite a negative ANA. As neutropenia is usually mild, there are currently no guidelines for therapy. For our patient, we started him on low dose IV solumedrol and found that he responded drastically to treatment. Given strongly positive nonspecific anti-neutrophil antibodies in the setting of a negative ANA noted in our patient, it is likely that there are other currently unknown antibodies associated with SLE which may correlate strongly with autoimmune neutropenia. PMID- 28077946 TI - Epileptic Seizures Induced by a Spontaneous Carotid Cavernous Fistula. AB - A 79-year-old woman was admitted to our emergency department with complaints of fainting and loss of consciousness three times during the past month. She was diagnosed with epilepsy and started to be treated with antiepileptic drug. Physical examination showed, in the left eye, chemosis, limited eye movements in all directions, and minimal exophthalmos as unexisting symptoms on admission developed on the sixth day. Orbital magnetic resonance imaging (MRI) and digital subtraction angiography (DSA) imaging revealed a carotid cavernous fistula (CCF). Epileptic attacks and ophthalmic findings previously present but diagnosed during our examinations were determined to ameliorate completely after performing the coil embolization. Based on literature, we present the first case with nontraumatic CCF manifesting with epileptic seizures and intermittent eye symptoms in the present report. PMID- 28077948 TI - Exploratory Factor Analysis for Validating Traditional Chinese Syndrome Patterns of Chronic Atrophic Gastritis. AB - Background. Traditional Chinese medicine (TCM) has long been used to treat chronic atrophic gastritis (CAG). The aim of the present study was to evaluate the TCM syndrome characteristics of CAG and its core pathogenesis so as to promote optimization of treatment strategies. Methods. This study was based on a participant survey conducted in 4 hospitals in China. Patients diagnosed with CAG were recruited by simple random sampling. Exploratory factor analysis (EFA) was conducted on syndrome extraction. Results. Common factors extracted were assigned to six syndrome patterns: qi deficiency, qi stagnation, blood stasis, phlegm turbidity, heat, and yang deficiency. Distribution frequency of all syndrome patterns showed that qi deficiency, qi stagnation, blood stasis, phlegm turbidity, and heat excess were higher (76.7%-84.2%) compared with yang deficiency (42.5%). Distribution of main syndrome patterns showed that frequencies of qi deficiency, qi stagnation, phlegm turbidity, heat, and yang deficiency were higher (15.8%-20.8%) compared with blood stasis (8.3%). Conclusions. The core pathogenesis of CAG is combination of qi deficiency, qi stagnation, blood stasis, phlegm turbidity, heat, and yang deficiency. Therefore, treatment strategy of herbal prescriptions for CAG should include herbs that regulate qi, activate blood, resolve turbidity, clear heat, remove toxin, and warm yang. PMID- 28077947 TI - Asthma and the microbiome: defining the critical window in early life. AB - Asthma is a chronic inflammatory immune disorder of the airways affecting one in ten children in westernized countries. The geographical disparity combined with a generational rise in prevalence, emphasizes that changing environmental exposures play a significant role in the etiology of this disease. The microflora hypothesis suggests that early life exposures are disrupting the composition of the microbiota and consequently, promoting immune dysregulation in the form of hypersensitivity disorders. Animal model research supports a role of the microbiota in asthma and atopic disease development. Further, these model systems have identified an early life critical window, during which gut microbial dysbiosis is most influential in promoting hypersensitivity disorders. Until recently this critical window had not been characterized in humans, but now studies suggest that the ideal time to use microbes as preventative treatments or diagnostics for asthma in humans is within the first 100 days of life. This review outlines the major mouse-model and human studies leading to characterization of the early life critical window, emphasizing studies analyzing the intestinal and airway microbiotas in asthma and atopic disease. This research has promising future implications regarding childhood immune health, as ultimately it may be possible to therapeutically administer specific microbes in early life to prevent the development of asthma in children. PMID- 28077949 TI - The Role of Liuwei Dihuang Pills and Ginkgo Leaf Tablets in Treating Diabetic Complications. AB - Objective. To observe the clinical prophylactic and therapeutic efficacy of Liuwei Dihuang Pills and Ginkgo Leaf Tablets for type 2 diabetic vascular complications. Methods. It was a randomized, double-blind and placebo-controlled clinical trial. 140 outpatients with type 2 diabetes were recruited and randomly divided into the treatment group and control group. The two groups were given basic therapy (management of blood sugar, blood pressure, etc.). Additionally, the treatment group was given Liuwei Dihuang Pills and Ginkgo Leaf Tablets, while the control group was given Liuwei Dihuang Pills and Ginkgo Leaf Tablets placebos. All subjects were followed up for consecutive 36 months and observed monthly. The clinical data as urinary microalbumin to urinary creatinine ratio (Umalb/cr), carotid intima-media thickness (IMT), diabetic nephropathy (DN) and diabetic retinopathy (DR) prevalence, cardiovascular and cerebrovascular events, blood glucose, and blood pressure were collected and analyzed statistically. Results. After 36-month treatment, the Umalb/cr level and DN and DR prevalence in treatment group were all significantly lower than control group (P < 0.05). However, the IMT level and the incidence of cardiovascular and cerebrovascular events were not significantly different between the two groups (P > 0.05). Conclusions. Liuwei Dihuang Pills and Ginkgo Leaf Tablets are beneficial to diabetic microvascular complications, while the efficacy to diabetic macrovascular complications needs more observations. PMID- 28077950 TI - Yoga Therapy in Children with Cystic Fibrosis Decreases Immediate Anxiety and Joint Pain. AB - This study was designed to determine whether yoga might alleviate symptoms of pain, sleep disturbance, anxiety, and depression in children with cystic fibrosis (CF). CF is the most common genetic, life-limiting chronic disease among Caucasian populations. It primarily affects the lungs but also many other secretory organs and consequently leads to significant morbidities. Research has shown that children with CF have significantly increased depression, anxiety, and pain compared to their healthy counterparts. Subjects participated in six one-on one sessions over a 10-week period with a certified instructor who designed each yoga practice based on a preestablished list of 30 yoga asanas. Questionnaires evaluating pain, sleep disturbance, sustained anxiety, immediate anxiety, and depression were administered. Differences between premeasures and postmeasures were evaluated using a two-sided test. Twenty subjects were assessed (12 females/8 males), median age of 11 (7-20) years. Mean immediate anxiety scores decreased (before session to after session 29 to 23.6, respectively, p < 0.001). Joint pain improved (3.25 to 3.65, p = 0.028). CFQ-R emotion subscale improved from 79.2 to 85 (p = 0.073), and the respiratory subscale improved from 66.7 to 79.2 (p = 0.076). Other results were less notable. We conclude that yoga may reduce immediate anxiety and joint pain in patients with CF. PMID- 28077951 TI - Spatially-localized bench-top X-ray scattering reveals tissue-specific microfibril orientation in Moso bamboo. AB - BACKGROUND: Biological materials have a complex, hierarchical structure, with vital structural features present at all size scales, from the nanoscale to the macroscale. A method that can connect information at multiple length scales has great potential to reveal novel information. This article presents one such method with an application to the bamboo culm wall. Moso (Phyllostachys edulis) bamboo is a commercially important bamboo species. At the cellular level, bamboo culm wall consists of vascular bundles embedded in a parenchyma cell tissue matrix. The microfibril angle (MFA) in the bamboo cell wall is related to its macroscopic longitudinal stiffness and strength and can be determined at the nanoscale with wide-angle X-ray scattering (WAXS). Combining WAXS with X-ray microtomography (XMT) allows tissue-specific study of the bamboo culm without invasive chemical treatment. RESULTS: The scattering contribution of the fiber and parenchyma cells were separated with spatially-localized WAXS. The fiber component was dominated by a high degree of orientation corresponding to small MFAs (mean MFA 11 degrees ). The parenchyma component showed significantly lower degree of orientation with a maximum at larger angles (mean MFA 65 degrees ). The fiber ratio, the volume of cell wall in the fibers relative to the overall volume of cell wall, was determined by fitting the scattering intensities with these two components. The fiber ratio was also determined from the XMT data and similar fiber ratios were obtained from the two methods, one connected to the cellular level and one to the nanoscale. X-ray diffraction tomography was also done to study the differences in microfibril orientation between fibers and the parenchyma and further connect the microscale to the nanoscale. CONCLUSIONS: The spatially-localized WAXS yields biologically relevant, tissue-specific information. With the custom-made bench-top set-up presented, diffraction contrast information can be obtained from plant tissue (1) from regions-of interest, (2) as a function of distance (line scan), or (3) with two-dimensional or three-dimensional tomography. This nanoscale information is connected to the cellular level features. PMID- 28077952 TI - The Irr1/Scc3 protein implicated in chromosome segregation in Saccharomyces cerevisiae has a dual nuclear-cytoplasmic localization. AB - BACKGROUND: Correct chromosome segregation depends on the sister chromatid cohesion complex. The essential, evolutionarily conserved regulatory protein Irr1/Scc3, is responsible for the complex loading onto DNA and for its removal. We found that, unexpectedly, Irr1 is present not only in the nucleus but also in the cytoplasm. RESULTS: We show that Irr1 protein is enriched in the cytoplasm upon arrest of yeast cells in G1 phase following nitrogen starvation, diauxic shift or alpha-factor action, and also during normal cell cycle. Despite the presence of numerous Crm1-dependent export signals, the cytoplasmic pool of Irr1 is not derived through export from the nucleus but instead is simply retained in the cytoplasm. Cytoplasmic Irr1 interacts with the Imi1 protein implicated in glutathione homeostasis and mitochondrial integrity. CONCLUSIONS: Besides regulation of the sister chromatid cohesion complex in the nucleus Irr1 appears to have an additional role in the cytoplasm, possibly through interaction with the cytoplasmic protein Imi1. PMID- 28077953 TI - Systematic epistatic mapping of cellular processes. AB - Genetic screens have identified many novel components of various biological processes, such as components required for cell cycle and cell division. While forward genetic screens typically generate unstructured 'hit' lists, genetic interaction mapping approaches can identify functional relations in a systematic fashion. Here, we discuss a recent study by our group demonstrating a two-step approach to first screen for regulators of the mitotic cell cycle, and subsequently guide hypothesis generation by using genetic interaction analysis. The screen used a high-content microscopy assay and automated image analysis to capture defects during mitotic progression and cytokinesis. Genetic interaction networks derived from process-specific features generate a snapshot of functional gene relations in those processes, which follow a temporal order during the cell cycle. This complements a recently published approach, which inferred directional genetic interactions reconstructing hierarchical relationships between genes across different phases during mitotic progression. In conclusion, this strategy leverages unbiased, genome-wide, yet highly sensitive and process-focused functional screening in cells. PMID- 28077954 TI - Upper Limb Multifactorial Movement Analysis in Brachial Plexus Birth Injury. AB - : Multifactorial motion analysis was first established for gait and then developed in the upper extremity. Recordings of infrared light reflecting sensitive passive markers in space, combined with surface eletromyographic recordings and/or transmitted forces, allow eclectic study of muscular coordination in the upper limb. Brachial plexus birth injury is responsible for various patterns of muscle weakness, imbalance, and/or simultaneous activation, soft tissue contractures, and bone-joint deformities, leading to individual motion patterns and adaptations, which we studied by means of motion analysis tools. We describe the technical development and examination setup to evaluate motion impairment and present first clinical results. Motion analysis is a reliable objective assessment tool allowing precise pre- and postoperative multimodal evaluation of upper limb function. LEVEL OF EVIDENCE: II. PMID- 28077955 TI - The Surgical Strategy to Correct the Rotational Imbalance of the Glenohumeral Joint after Brachial Plexus Birth Injury. AB - In upper brachial plexus birth injury, rotational balance of the glenohumeral joint is frequently affected and contracture in medial rotation of the arm develops, due to a severe palsy or insufficient recovery of the lateral rotators. Some of these children present with a severe glenohumeral joint contracture in the first months, although regular physiotherapy has been provided, a condition associated with a posteriorly subdislocated or dislocated humeral head. These conditions should be screened early by a pediatrician or specialized physiotherapist. Both aspects of muscular weakness affecting the lateral rotators and the initial or progressive glenohumeral deformity and/or subdislocation must be identified and treated accordingly, focusing on the reestablishment of joint congruence and strengthening of the lateral rotators to improve rotational balance, thus working against joint dysplasia and loss of motor function of the shoulder in a growing child. Our treatment strategy adapted over the last 20 years to results from retrospective studies, including biomechanical aspects on muscular imbalance and tendon transfers. With this review, we confront our actual concept to recent literature. PMID- 28077956 TI - Thiel Cadaveric Nerve Tissue: A Model for Microsurgical Simulation. PMID- 28077957 TI - Dorsal Scapular Artery Variations and Relationship to the Brachial Plexus, and a Related Thoracic Outlet Syndrome Case. AB - Rationale Knowledge of the relationship of the dorsal scapular artery (DSA) with the brachial plexus is limited. Objective We report a case of a variant DSA path, and revisit DSA origins and under-investigated relationship with the plexus in cadavers. Methods The DSA was examined in a male patient and 106 cadavers. Results In the case, we observed an unusual DSA compressing the lower plexus trunk, that resulted in intermittent radiating pain and paresthesia. In the cadavers, the DSA originated most commonly from the subclavian artery (71%), with 35% from the thyrocervical trunk. Nine sides of eight cadavers (seven females) had two DSA branches per side, with one branch from each origin. The most typical DSA path was a subclavian artery origin before passing between upper and middle brachial plexus trunks (40% of DSAs), versus between middle and lower trunks (23%), or inferior (4%) or superior to the plexus (1%). Following a thyrocervical trunk origin, the DSA passed most frequently superior to the plexus (23%), versus between middle and lower trunks (6%) or upper and middle trunks (4%). Bilateral symmetry in origin and path through the brachial plexus was observed in 13 of 35 females (37%) and 6 of 17 males (35%), with the most common bilateral finding of a subclavian artery origin and a path between upper and middle trunks (17%). Conclusion Variability in the relationship between DSA and trunks of the brachial plexus has surgical and clinical implications, such as diagnosis of thoracic outlet syndrome. PMID- 28077958 TI - The Influence of Glutamate on Axonal Compound Action Potential In Vitro. AB - Background Our previous experiments demonstrated modulation of the amplitude of the axonal compound action potential (CAP) by electrical stimulation. To verify assumption that glutamate released from axons could be involved in this phenomenon, the modification of the axonal CAP induced by glutamate was investigated. Objectives The major objective of this research is to verify the hypothesis that axonal activity would trigger the release of glutamate, which in turn would interact with specific axonal receptors modifying the amplitude of the action potential. Methods Segments of the sciatic nerve were exposed to exogenous glutamate in vitro, and CAP was recorded before and after glutamate application. In some experiments, the release of radioactive glutamate analog from the sciatic nerve exposed to exogenous glutamate was also evaluated. Results The glutamate induced increase in CAP was blocked by different glutamate receptor antagonists. The effect of glutamate was not observed in Ca-free medium, and was blocked by antagonists of calcium channels. Exogenous glutamate, applied to the segments of sciatic nerve, induced the release of radioactive glutamate analog, demonstrating glutamate-induced glutamate release. Immunohistochemical examination revealed that axolemma contains components necessary for glutamatergic neurotransmission. Conclusion The proteins of the axonal membrane can under the influence of electrical stimulation or exogenous glutamate change membrane permeability and ionic conductance, leading to a change in the amplitude of CAP. We suggest that increased axonal activity leads to the release of glutamate that results in changes in the amplitude of CAPs. PMID- 28077959 TI - A Vascular Malformation Presenting as a Peripheral Nerve Sheath Tumor. AB - We present the case of a venous malformation (VM) masquerading as a schwannoma. VMs are thin-walled vascular dilations of various sizes that typically present as soft, compressible, blue masses that are associated with pain or dysesthesia. VMs are commonly found in the head and neck as well as the distal extremities. Notably, slow-flow VMs are hypointense on T1-weighted imaging, hyperintense on T2 weighted imaging, and enhance markedly with contrast. However, VMs tend to be poorly circumscribed and fraught with venous lakes and phleboliths. Conservative therapy and sclerotherapy are the primary treatment options. In this case report, we present a VM presenting near the neurovascular bundle of the upper extremity axilla. Our case is unique in that the patient presented with symptoms and imaging qualities characteristic for a peripheral nerve schwannoma. PMID- 28077960 TI - Evaluation of Self-Concept and Emotional-Behavioral Functioning of Children with Brachial Plexus Birth Injury. AB - Background The reported incidence of brachial plexus birth injury (BPBI) is 0.87 to 2.2 per 1,000 live births. The psychological functioning, including self concept and emotional-behavioral functioning, of children with BPBI has only been examined to a limited extent. Objective The purpose of this study was to describe the self-concept and emotional-behavioral functioning in children with BPBI from both the child's and parent's perspective. Methods Thirty-one children with BPBI, mean age 11 years 1 month, completed the Draw A Person: Screening Procedure for Emotional Disturbance (DAP:SPED) and Piers Harris Children's Self-Concept Scale (PHCSCS). The parents answered questions from the Behavior Assessment System for Children, Parent Rating Scales (BASC-2 PRS). Results The scores from the DAP:SPED drawings showed further evaluation was not strongly indicated in the majority of the children. The PHCSCS Total score demonstrated that the children had a strongly positive self-concept. The parental responses to the BASC-2 PRS indicated that few children were at risk or in the clinically significant range for the four composite scores and all of the component clinical or adaptive scales. Gender comparison revealed females exhibited greater anxiety than males. Conclusion Both children and parents reported a positive psychological well-being for the majority of the children. Parents had greater concerns about their child's social-emotional functioning, particularly anxiety. An interdisciplinary approach (occupational therapy evaluation, clinical observation, and parental interview) is necessary to determine the need for mental health referral. PMID- 28077961 TI - Large Cervical Vagus Nerve Tumor in a Patient with Neurofibromatosis Type 1 Treated with Gross Total Resection: Case Report and Review of the Literature. AB - Neurofibromas are benign peripheral nerve sheath tumors that occur commonly in individuals with neurocutaneous disorders such as neurofibromatosis type 1. Vagal nerve neurofibromas, however, are a relatively rare occurrence. We present the case of a 22-year-old man with neurofibromatosis type 1 with a neurofibroma of the left cervical vagal nerve. The mass was resected through an anterior approach without major event. In the postoperative course, the patient developed left vocal cord paralysis treated with medialization with injectable gel. We then present a comprehensive review of the literature for surgical resection of vagal nerve neurofibromas. PMID- 28077962 TI - The influence of duodenally-delivered Shakuyakukanzoto (Shao Yao Gan Cao Tang) on duodenal peristalsis during endoscopic retrograde cholangiopancreatography: a randomised controlled trial. AB - BACKGROUND: Anti-cholinergic agents may be used to inhibit duodenal peristalsis, but they may have adverse effects. Shakuyakukanzoto (Shao Yao Gan Cao Tang) has an anti-spasmodic effect and has been used before for oesophagogastroduodenoscopy and colonoscopy. This randomised clinical trial aimed to evaluate the inhibitory effect of Shakuyakukanzoto on duodenal peristalsis, and its usefulness when administered into the duodenum just before endoscopic retrograde cholangiopancreatography (ERCP). METHODS: Participants were recruited between June 2008 and December 2010. All were aged >=18 years and provided written informed consent. Exclusion criteria were: acute pancreatitis, a history of ischemic heart disease, prostatic hypertrophy or glaucoma, and altered/postsurgical upper gastrointestinal anatomy. The recruited participants were randomly assigned to the Shakuyakukanzoto group and control group. Shakuyakukanzoto 100 mg/mL solution or placebo (warm water) was administered directly as a spray into the duodenum during endoscopy. Efficacy was evaluated by observing the extent of duodenal peristalsis and assessing the difficulty of cannulating the common bile duct, the required time (RT) from administration to inhibition of duodenal peristalsis and the stop duration time (DT, the duration for which peristalsis was inhibited). Side effects were evaluated by measuring serum potassium concentration after ERCP. RESULTS: Of 28 participants, 15 were assigned to the Shakuyakukanzoto group and 13 to the control group. Duodenal peristalsis was inhibited in eight of the 10 eligible participants (80.0%) in the Shakuyakukanzoto group and none (0%) of the nine eligible participants in the control group (P = 0.026). In the Shakuyakukanzoto group, mean RT (+/-standard deviation) was 76.0 +/- 23.9 s and DT was 11.3 +/- 4.2 min. No adverse effects were observed in the Shakuyakukanzoto group during or after ERCP. CONCLUSION: Duodenal peristalsis can be inhibited by spraying Shakuyakukanzoto solution directly into the duodenum. Trial registration UMIN Clinical Trials Registry (UMIN-CTR) UMIN000011469. PMID- 28077963 TI - Quality control of Lycium chinense and Lycium barbarum cortex (Digupi) by HPLC using kukoamines as markers. AB - BACKGROUND: Lycii Cortex (LyC), composed of Lycium chinense and Lycium barbarum cortex and having the Chinese name Digupi, is used to treat chronic diseases like cough, hypertension, and diabetes in Eastern Asia. However, chromatographic methods, such as TLC and HPLC, to determine the phytochemical composition of LyC have not been included in any official compendiums. This study aims to establish a validated HPLC method for quality control of LyC. METHODS: Kukoamines A and B (KA and KB, respectively) were selected as markers for the HPLC method. An acetic acid solution was adopted for sample extraction because it facilitated the release of kukoamines and effectively prevented their degradation. Optimal separation of the kukoamine isomers was achieved on hydrophilic ligand-coated C18 columns with a gradient elution of acetonitrile and 0.1% (v/v) trifluoroacetic acid. The average contents and proposed contents for LyC were calculated with a t test and an uncertainty test based on 16 batches of authentic samples. RESULTS: The method was validated with linearity (r2 = 0.9999 for both KA and KB), precision (RSD = 1.29% for KA and 0.57% for KB), repeatability (RSD = 1.81% for KA and 0.92% for KB), and accuracy (recovery of 90.03-102.30% for KA, and 98.49 101.67% for KB), indicating that the method could offer reliable results for quality control analysis of LyC. At the 95% confidence level, the calculated content limits were 1.45 mg/g for KA and 4.72 mg/g for KB. CONCLUSION: Compared with conventional morphological identification, the HPLC method involving KA and KB contents offers precise, objective, and quantitative results for quality control of LyC. PMID- 28077964 TI - Erratum to: A bedr way of genomic interval processing. AB - [This corrects the article DOI: 10.1186/s13029-016-0059-5.]. PMID- 28077965 TI - Distinct profiles of reactive and proactive aggression in adolescents: associations with cognitive and affective empathy. AB - BACKGROUND: Aggression comprises a heterogeneous set of behavioral patterns that aim to harm and hurt others. Empathy represents a potential mechanism that inhibits aggressive conduct and enhances prosocial behavior. Nevertheless, research results on the relationship between empathy and aggression are mixed. Subtypes of aggressive behavior, such as reactive and proactive aggression might be differently related to empathy. The aim of the present study was to investigate the interrelations of cognitive and affective empathy with reactive and proactive aggression. METHODS: We recruited a sample of 177 (33% female, M age 15.6) adolescents from socio-educational and juvenile justice institutions and a community sample of 77 (36% female, M age 13.1) adolescents from secondary schools. Using bivariate correlation analysis and hierarchical multiple regression analysis, we firstly investigated associations between cognitive and affective empathy and reactive and proactive aggression. Subsequently, we performed cluster analysis to identify clusters of adolescents with meaningful profiles of aggressive behavior and compared derived clusters on measures of empathy. We applied the Basic Empathy Scale and the Reactive-Proactive Aggression Questionnaire. RESULTS: Bivariate analysis and hierarchical regression analysis showed that cognitive and affective empathy were negatively associated with proactive aggression, but not with reactive aggression. Cluster-analysis revealed three clusters of adolescents with distinct aggression profiles: a cluster with elevated scores on reactive and proactive aggression, a clusters with high scores on reactive aggression only, and a low aggression cluster. Cluster comparisons revealed that the reactive-proactive aggression cluster showed significantly lower scores on cognitive and affective empathy than both other clusters. Results further indicated that within the reactive-proactive aggression cluster, girls did not differ significantly from boys in empathy. CONCLUSIONS: The present study extends previously published findings, and possibly explains conflicting results in prior research. Our results indicated that cognitive and affective empathy are reduced in adolescents with high levels of reactive and proactive aggression. Our study may contribute to the development of tailored clinical interventions for different aggression clusters. PMID- 28077966 TI - Marital relationship, parenting practices, and social skills development in preschool children. AB - BACKGROUND: This study examined the pathways by which destructive and constructive marital conflict leading to social skills development in preschool children, are mediated through negative and positive parenting practices. METHODS: Mothers of 2931 Japanese children, aged 5-6 years, completed self-report questionnaires regarding their marital relationship (the Quality of co-parental communication scale) and parental practices (the Alabama parenting questionnaire). The children's teachers evaluated their social skills using the Social skills scale. RESULTS: Path analyses revealed significant direct paths from destructive marital conflict to negative parenting practices and lower scores on the self-control component of social skills. In addition, negative parenting practices mediated the relationship between destructive marital conflict and lower scores on cooperation, self-control, and assertion. Our analyses also revealed significant direct paths from constructive marital conflict to positive parenting practices, and higher scores on cooperation and assertion. Positive parenting practices mediated the relationship between constructive marital conflict and higher scores on self-control and assertion. CONCLUSIONS: These findings suggest that destructive and constructive marital conflict may directly and indirectly influence children's social skills development through the mediation of parenting practices. PMID- 28077968 TI - Lipoma of the Palate: An Uncommon Finding. AB - BACKGROUND: Lipoma is a benign neoplasm originated from adipose cells circumscribed by connective tissue. This neoplasm represents about 1% to 4.4% of all oral benign tumors and it is rarely located in the palate area. OBJECTIVE: This case reports the occurrence of an oral lipoma in the hard palate of a 57 year-old woman and discusses its etiology and treatment. CASE REPORT: The treatment consisted in the total resection of the lesion and laser therapy. The patient is being followed up for forty three months with no signs of recurrence. CONCLUSION: Lipoma in hard palate is a rare entity that may be associated with endocrine factors and local inflammation. PMID- 28077967 TI - Integrated omics analyses reveal the details of metabolic adaptation of Clostridium thermocellum to lignocellulose-derived growth inhibitors released during the deconstruction of switchgrass. AB - BACKGROUND: Clostridium thermocellum is capable of solubilizing and converting lignocellulosic biomass into ethanol. Although much of the work-to-date has centered on characterizing this microbe's growth on model cellulosic substrates, such as cellobiose, Avicel, or filter paper, it is vitally important to understand its metabolism on more complex, lignocellulosic substrates to identify relevant industrial bottlenecks that could undermine efficient biofuel production. To this end, we have examined a time course progression of C. thermocellum grown on switchgrass to assess the metabolic and protein changes that occur during the conversion of plant biomass to ethanol. RESULTS: The most striking feature of the metabolome was the observed accumulation of long-chain, branched fatty acids over time, implying an adaptive restructuring of C. thermocellum's cellular membrane as the culture progresses. This is undoubtedly a response to the gradual accumulation of lignocellulose-derived inhibitory compounds as the organism deconstructs the switchgrass to access the embedded cellulose. Corroborating the metabolomics data, proteomic analysis revealed a corresponding time-dependent increase in various enzymes, including those involved in the interconversion of branched amino acids valine, leucine, and isoleucine to iso- and anteiso-fatty acid precursors. Additionally, the metabolic accumulation of hemicellulose-derived sugars and sugar alcohols concomitant with increased abundance of enzymes involved in C5 sugar metabolism/pentose phosphate pathway indicates that C. thermocellum shifts glycolytic intermediates to alternate pathways to modulate overall carbon flux in response to C5 sugar metabolites that increase during lignocellulose deconstruction. CONCLUSIONS: Integrated omic platforms provided complementary systems biological information that highlight C. thermocellum's specific response to cytotoxic inhibitors released during the deconstruction and utilization of switchgrass. These additional viewpoints allowed us to fully realize the level to which the organism adapts to an increasingly challenging culture environment-information that will prove critical to C. thermocellum's industrial efficacy. PMID- 28077970 TI - Patient's Satisfaction with Removable Partial Dentures: A Retrospective Case Series. AB - : This retrospective clinical study aimed to assess patient's satisfaction with removable partial dentures (RPDs), as retention, chewing ability, aesthetics during the observation period. MATERIAL AND METHODS: A total of 63 patients with RPDs, participated in this study. The following data was collected: Kennedy classification, denture design, denture support, satisfaction and success of RPD. RESULT: The results showed that 73.6% of patients were wearing RPD for the first time and were finally satisfied. According to the denture support of RPDs, clasp retained quadrangular RPDs were 100% effective, followed by triangular dental support 81% and linear dental support 47.7%. Comparison of RPDs with attachment with RPDs with claps assessed through Fisher exact test, confirmed statistically significant difference (P=0.008), despite retention; however, chewing ability and aesthetics showed no statistically significant difference with X 2 test on patient's satisfaction with RPD with or without attachment. CONCLUSION: Patients often would prefer not showing the anterior buccal clasps of RPD, therefore are generally satisfied more with RPD with attachment based on level of retention, chewing ability and aesthetics. PMID- 28077969 TI - Odontogenic Sinusitis Caused by an Inflammation of a Dentigerous Cyst and Subsequent Finding of a Fibrous Dysplasia. A Case Report. AB - We report the case of a 38-year old male patient with sinusitis caused by an infected follicular cyst due to an ectopic impacted third molar in the right maxillary sinus. A 10-day antibiotherapy regimen was administered; subsequently, the cyst and the third molar were removed achieving complete recovery. Fibrous dysplasia was diagnosed at follow-up examination (occupation of the maxillary sinus by bone tissue was observed in a radiographic examination) and confirmed by biopsy. In cases of odontogenic sinusitis, thorough examination is crucial, as evidenced by the case reported in this study. A Literature review was performed in order to identify the diagnostic methods currently available and the clinical features, complications and treatment for both, odontogenic maxillary sinusitis and fibrous dysplasia. PMID- 28077971 TI - The Effect of Chin-cup Therapy in Class III Malocclusion: A Systematic Review. AB - BACKGROUND: The treatment of Class III malocclusion has been challenging for orthodontists. Among a plethora of treatment modalities, the chin-cup is considered a traditional appliance for early orthopedic intervention. OBJECTIVE: The present study aims to investigate the current scientific evidence regarding the effectiveness of chin-cup therapy in Class III malocclusion of prognathic growing patients. METHOD: A systematic review of the literature was conducted using PubMed/Medline and the Cochrane Central Register of Controlled Trials from January 1954 to October 2015. Articles were selected based on established inclusion/ exclusion criteria. RESULTS: The search strategy resulted in 3285 articles.14 studies were selected for the final analysis. They were all CCTs, 13 of retrospective and 1 of prospective design. Methodological quality was evaluated by a risk of bias assessment, as suggested by the Cochrane Risk of Bias Assessment Tool for Non-Randomized Studies on Interventions. The reported evidence presented favorable short-term outcomes both in hard and soft tissues improving the Class III profile, as well as desirable dento-alveolar changes, positively affecting the Class III malocclusion. CONCLUSION: There is considerable agreement between studies that chin-cup therapy can be considered for the short-term treatment of growing patients with Class III malocclusion, as indicated by favorable changes both in the hard and soft tissues. The existence of considerable risk of bias in all selected studies and the unclear long-term effectiveness of chin-cup therapy highlight the need for further investigation to draw reliable conclusions. PMID- 28077972 TI - A One-year Follow-up Study of a Tapered Hydrophilic Implant Design Using Various Placement Protocols in the Maxilla. AB - PURPOSE: To study the clinical/radiographic outcomes and stability of a tapered implant design with a hydrophilic surface when placed in the maxilla using various protocols and followed for one year. METHODS: Ninety-seven consecutive patients treated as part of daily routine in two clinics with 163 tapered implants in healed sites, in extraction sockets and together with bone augmentation procedures in the maxilla were evaluated after one year in function. Individual healing periods varying from 0 to 6 months had been used. Insertion torque (IT) and resonance frequency analysis (RFA) measurements were made at baseline. Follow-up RFA registrations were made after 6 and 12 months of loading. The marginal bone levels were measured in intraoral radiographs from baseline and after 12 months. A reference group consisting of 163 consecutive straight maxillary implants was used for the comparison of baseline IT and RFA measurements. RESULTS: Five implants failed before loading, giving an implant survival rate of 96.9% and a prosthesis survival rate of 99.4% after one year. The mean marginal bone loss after one year was 0.5 mm (SD 0.4). The mean IT was statistically significantly higher for tapered than for straight reference implants (41.3 +/- 12.0 Ncm vs 33.6 +/- 12.5 Ncm, p < 0.001). The tapered implants showed a statistically insignificantly higher mean ISQ value than the straight references implants (73.7 +/- 6.4 ISQ vs 72.2 +/- 8.0 ISQ, p=0.119). There was no correlation between IT and marginal bone loss. There was a correlation between IT and RFA measurements (p < 0.001). CONCLUSION: The tapered implant showed a high survival rate and minimal marginal bone loss after one year in function when using various protocols for placement. The tapered implant showed significantly higher insertion torque values than straight reference implants. PMID- 28077973 TI - Respiratory Tularemia: Francisella Tularensis and Microarray Probe Designing. AB - BACKGROUND: Francisella tularensis (F. tularensis) is the etiological microorganism for tularemia. There are different forms of tularemia such as respiratory tularemia. Respiratory tularemia is the most severe form of tularemia with a high rate of mortality; if not treated. Therefore, traditional microbiological tools and Polymerase Chain Reaction (PCR) are not useful for a rapid, reliable, accurate, sensitive and specific diagnosis. But, DNA microarray technology does. DNA microarray technology needs to appropriate microarray probe designing. OBJECTIVE: The main goal of this original article was to design suitable long oligo microarray probes for detection and identification of F. tularensis. METHOD: For performing this research, the complete genomes of F. tularensis subsp. tularensis FSC198, F. tularensis subsp. holarctica LVS, F. tularensis subsp. mediasiatica, F. tularensis subsp. novicida (F. novicida U112), and F. philomiragia subsp. philomiragia ATCC 25017 were studied via NCBI BLAST tool, GView and PanSeq Servers and finally the microarray probes were produced and processed via AlleleID 7.7 software and Oligoanalyzer tool, respectively. RESULTS: In this in silico investigation, a number of long oligo microarray probes were designed for detecting and identifying F. tularensis. Among these probes, 15 probes were recognized as the best candidates for microarray chip designing. CONCLUSION: Calibrated microarray probes reduce the biasis of DNA microarray technology as an advanced, rapid, accurate and cost-effective molecular diagnostic tool with high specificity and sensitivity. Professional microarray probe designing provides us with much more facility and flexibility regarding preparation of a microarray diagnostic chip. PMID- 28077974 TI - Cardiobacterium hominis and Cardiobacterium valvarum: Two Case Stories with Infective Episodes in Pacemaker Treated Patients. AB - INTRODUCTION: Cardiobacterium hominis and Cardiobacterium valvarum are well known, though rare, etiologic agents of infective endocarditis. Cardiac devices are increasingly implanted. CASE REPORTS: Two cases of infective episodes in pacemaker (PM) treated patients with respectively C. hominis and C. valvarum are presented. In one case blood-culture bottles yielded growth of C. hominis at two episodes with two years apart. At the second episode a vegetation was recognized at the PM lead and the PM device and lead was removed. In the C. valvarum case, echocardiography revealed a bicuspid aortic valve with severe regurgitation and a more than 1 cm sized vegetation. CONCLUSION: The cases illustrate the diversity in disease severity by Cardiobacterium species. Careful follow up has to be performed in order not to overlook a relatively silent relapsing infection. PMID- 28077975 TI - Evaluate the Relationship Between Class 1 Integrons and Drug Resistance Genes in Clinical Isolates of Pseudomonas aeruginosa. AB - BACKGROUND: The prevalence of resistant Pseudomonas aeruginosa isolates is increasing and it is considered as one of the major public health concerns in the world. The association between integrons and drug resistance has been proven and evidences suggest that integrons are coding and responsible for dissemination of antibiotic resistance among P. aeruginosa isolates. OBJECTIVE: This study is aimed to evaluate the relationship between class 1 integrons and drug resistance genes in clinical isolates of P. aeruginosa from burn patients. METHODS: 100 isolates of P. aeruginosa were collected from burn patients hospitalized in the skin ward of Shahid Motahari hospital and susceptibility testing was performed by disk diffusion method (Kirby-Bauer). Then DNA was extracted and PCR technique was performed for the detection of class 1 integrons and drug resistance genes. Then data was analyzed using SPSS software. RESULTS: The most effective antibiotic was polymyxin B with sensitivity 100%, and the most resistance was observed to the ciprofloxacin (93%) and amikacin (67%), respectively. The maximum and lowest frequencies of drug resistance genes belonged to the aac (6 ') - 1, VEB-1 with prevalence rate 93% and 10%, respectively. The statistical Chi-square test did not find any significant correlation between class 1 integrons and drug resistance genes (p? 0.05). CONCLUSION: Although no significant correlation between class 1 integrons and drug resistance was observed, but the resistance rate to antibiotics tested among P. aeruginosa isolates was high. So, surveillance, optimization and strict consideration of antimicrobial use and control of infection are necessary. PMID- 28077976 TI - Antifungal Activity and Aflatoxin Degradation of Bifidobacterium Bifidum and Lactobacillus Fermentum Against Toxigenic Aspergillus Parasiticus. AB - Food and feedstuff contamination with aflatoxins (AFTs) is a serious health problem for humans and animals, especially in developing countries. The present study evaluated antifungal activities of two lactic acid bacteria (LAB) against growth and aflatoxin production of toxigenic Aspergillus parasiticus. The mycelial growth inhibition rate of A. parasiticus PTCC 5286 was investigated in the presence of Bifidobacterium bifidum PTCC 1644 and Lactobacillus fermentum PTCC 1744 by the pour plate method. After seven days incubation in yeast extract sucrose broth at 30 degrees C, the mycelial mass was weighed after drying. The inhibitory activity of LAB metabolites against aflatoxin production by A. parasiticus was evaluated using HPLC method. B. bifidum and L. fermentum significantly reduced aflatoxin production and growth rate of A. parasiticus in comparison with the controls (p<=0.05). LAB reduced total aflatoxins and B1, B2, G1 and G2 fractions by more than 99%. Moreover, LAB metabolites reduced the level of standard AFB1, B2, G1 and G2 from 88.8% to 99.8% (p<=0.05). Based on these findings, B. bifidum and L. fermentum are recommended as suitable biocontrol agents against the growth and aflatoxin production by aflatoxigenic Aspergillus species. PMID- 28077977 TI - Two Subsets of Large Vessel Vasculitis Characterized by the Absence or Presence of Spondyloarthritis or its Associated Diseases. AB - BACKGROUND: Whilst large vessel vasculitis (LVV) predominantly occurs in isolation, associations with other infectious and non-infectious diseases have been reported. Limited data describing associations with various autoimmune diseases (AI), including spondyloarthritis exists. The aim of this study was to characterize the association of LVV and spondyloarthritis or its associated diseases (SpAD). METHODS: A single centre, retrospective study of patients >=50yrs with first presentation LVV between 01.06.2008-01.06.2015 was performed. Patients were categorized according to SpA or associated disease, other AI or idiopathic LVV (iLVV). Clinical, laboratory and imaging findings were compared. Kaplan-Meyer survival analysis, with relapse taken as the primary end-point, was performed. RESULTS: LVV was confirmed in 62 pts, of who 16/62 (26%) had SpA or associated disease. In these patients, LVV presented earlier (59.2 SpAD vs. 68.1 AI and 70.3yrs iLVV; p=0.01) and occurred predominantly in spring compared to autumn and winter in non-SpA patients, was associated with more centralised pattern of distribution (p=0.05) and was more likely to exhibit a refractory course (p=0.05). Overall relapse rates were similar across groups. Smoking-status influenced age of onset in all groups, being associated with earlier onset. CONCLUSION: A clear association between LVV and SpAD exists. LVV associated with SpAD has a particular phenotype characterised by earlier onset, thorax-limited disease and increased risk of a refractory course. Given on-going LVV treatment trials further genetic and pathophysiological characterization appears warranted, to evaluate potential variation in treatment response and optimize future care. PMID- 28077978 TI - Fibromyalgia Outcomes Over Time: Results from a Prospective Observational Study in the United States. AB - BACKGROUND: Longitudinal research on outcomes of patients with fibromyalgia is limited. OBJECTIVE: To assess clinician and patient-reported outcomes over time among fibromyalgia patients. METHODS: At enrollment (Baseline) and follow-up (approximately 2 years later), consented patients were screened for chronic widespread pain (CWP), attended a physician site visit to determine fibromyalgia status, and completed an online questionnaire assessing pain, sleep, function, health status, productivity, medications, and healthcare resource use. RESULTS: Seventy-six fibromyalgia patients participated at both time points (at Baseline: 86.8% white, 89.5% female, mean age 50.9 years, and mean duration of fibromyalgia 4.1 years). Mean number of tender points at each physician visit was 14.1 and 13.5, respectively; 11 patients no longer screened positive for CWP at follow-up. A majority reported medication use for pain (59.2% at Baseline, 62.0% at Follow up). The most common medication classes were opioids (32.4%), SSRIs (16.9%), and tramadol (14.1%) at Follow-up. Significant mean changes over time were observed for fibromyalgia symptoms (modified American College of Rheumatology 2010 criteria: 18.4 to 16.9; P=0.004), pain interference with function (Brief Pain Inventory-Short Form: 5.9 to 5.3; P=0.013), and sleep (Medical Outcomes Study Sleep Scale: 58.3 to 52.7; P=0.004). Patients achieving >=2 point improvement in pain (14.5%) experienced greater changes in pain interference with function (6.8 to 3.4; P=0.001) and sleep (62.4 to 51.0; P=0.061). CONCLUSION: Fibromyalgia patients reported high levels of burden at both time points, with few significant changes observed over time. Outcomes were variable among patients over time and were better among those with greater pain improvement. PMID- 28077979 TI - Anti-MDA5 Antibody Dermatomyositis Overlap with Systemic Lupus Erythematosus: A Case Report and Review of the Literature. AB - BACKGROUND: Dermatomyositis (DM) is an autoimmune connective tissue disease that primarily targets the muscle, skin, and lungs. Many patients have autoantibodies that correspond to distinct clinical phenotypes. Melanoma differentiation associated gene 5 (anti-MDA5) antibody, a specific antibody that targets the melanoma differentiation-associated gene 5 (MDA5), has been reported in DM cases and is significant for a distinct cutaneous presentation and rapidly progressive interstitial lung disease. OBJECTIVE: Herein, we describe a patient with DM with a positive anti-MDA5 antibody and characteristic clinical phenotype, who subsequently developed coexisting systemic lupus erythematosus (SLE). A diagnosis of SLE was supported by his clinical phenotype, positive serologies, hypocomplementemia, and progression to glomerulonephritis and lupus cerebritis, features of which fulfilled the American College of Rheumatology criteria for SLE. CONCLUSION: DM is known to overlap with other autoimmune diseases, including SLE, and coexistence can lead to a wide variety of clinical presentations. SLE overlapping with anti-MDA5 positive DM may present with distinct clinical features. PMID- 28077980 TI - A Review of Chikungunya Virus-induced Arthralgia: Clinical Manifestations, Therapeutics, and Pathogenesis. AB - BACKGROUND: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that circulates predominantly in tropical and subtropical regions, potentially affecting over 1 billion people. Recently, an outbreak began in the western hemisphere and has resulted in over 1.8 million reported suspected cases. Infection often results in severe fever, rash and debilitating polyarthralgia lasting weeks to months. Additionally, the current literature reports that CHIKV can result in a severe chronic arthralgia and/or arthritis that can last months to years following the initial infection. OBJECTIVE: The purpose of this review is to evaluate the literature and summarize the current state of knowledge regarding CHIKV-associated disease, including clinical presentation, diagnosis, risk factors for development of severe disease, treatment, and pathogenesis in human patients. Additionally, recommendations are presented regarding avenues for clinical research to help further elucidate the pathogenesis of joint disease associated with CHIKV infection. CONCLUSION: While there is an association between initial CHIKV infection and acute disease, a causal relationship with development of chronic arthralgia has not been established at this time. Potential causes of chronic CHIKV-induced arthritis have been postulated, including viral persistence, induction of autoimmune disease, and exacerbation of pre-existing joint disease. While there are numerous reports of chronic CHIKV associated arthralgia and/or arthritis, there is currently no evidence of a definitive link between initial infection and development of chronic disease. Additional, prospective clinical research on CHIKV-associated disease is necessary to further determine the potential role of virus and development of chronic joint disease. PMID- 28077981 TI - DNA polymerase kappa protects human cells against MMC-induced genotoxicity through error-free translesion DNA synthesis. AB - BACKGROUND: Interactions between genes and environment are critical factors for causing cancer in humans. The genotoxicity of environmental chemicals can be enhanced via the modulation of susceptible genes in host human cells. DNA polymerase kappa (Pol kappa) is a specialized DNA polymerase that plays an important role in DNA damage tolerance through translesion DNA synthesis. To better understand the protective roles of Pol kappa, we previously engineered two human cell lines either deficient in expression of Pol kappa (KO) or expressing catalytically dead Pol kappa (CD) in Nalm-6-MSH+ cells and examined cytotoxic sensitivity against various genotoxins. In this study, we set up several genotoxicity assays with cell lines possessing altered Pol kappa activities and investigated the protective roles of Pol kappa in terms of genotoxicity induced by mitomycin C (MMC), a therapeutic agent that induces bulky DNA adducts and crosslinks in DNA. RESULTS: We introduced a frameshift mutation in one allele of the thymidine kinase (TK) gene of the KO, CD, and wild-type Pol kappa cells (WT), thereby establishing cell lines for the TK gene mutation assay, namely TK+/- cells. In addition, we formulated experimental conditions to conduct chromosome aberration (CA) and sister chromatid exchange (SCE) assays with cells. By using the WT TK+/- and KO TK+/- cells, we assayed genotoxicity of MMC. In the TK gene mutation assay, the cytotoxic and mutagenic sensitivities of KO TK+/- cells were higher than those of WT TK+/- cells. MMC induced loss of heterozygosity (LOH), base pair substitutions at CpG sites and tandem mutations at GpG sites in both cell lines. However, the frequencies of LOH and base substitutions at CpG sites were significantly higher in KO TK+/- cells than in WT TK+/- cells. MMC also induced CA and SCE in both cell lines. The KO TK+/- cells displayed higher sensitivity than that displayed by WT TK+/- cells in the SCE assay. CONCLUSIONS: These results suggest that Pol kappa is a modulating factor for the genotoxicity of MMC and also that the established cell lines are useful for evaluating the genotoxicity of chemicals from multiple endpoints in different genetic backgrounds of Pol kappa. PMID- 28077982 TI - Surface-Enhanced Hyper-Raman Spectra of Adenine, Guanine, Cytosine, Thymine, and Uracil. AB - Using picosecond excitation at 1064 nm, surface-enhanced hyper-Raman scattering (SEHRS) spectra of the nucleobases adenine, guanine, cytosine, thymine, and uracil with two different types of silver nanoparticles were obtained. Comparing the SEHRS spectra with SERS data from the identical samples excited at 532 nm and with known infrared spectra, the major bands in the spectra are assigned. Due to the different selection rules for the one- and two-photon excited Raman scattering, we observe strong variation in relative signal strengths of many molecular vibrations obtained in SEHRS and SERS spectra. The two-photon excited spectra of the nucleobases are found to be very sensitive with respect to molecule-nanoparticle interactions. Using both the SEHRS and SERS data, a comprehensive vibrational characterization of the interaction of nucleobases with silver nanostructures can be achieved. PMID- 28077983 TI - Surface-Enhanced Raman and Surface-Enhanced Hyper-Raman Scattering of Thiol Functionalized Carotene. AB - A thiol-modified carotene, 7'-apo-7'-(4-mercaptomethylphenyl)-beta-carotene, was used to obtain nonresonant surface-enhanced Raman scattering (SERS) spectra of carotene at an excitation wavelength of 1064 nm, which were compared with resonant SERS spectra at an excitation wavelength of 532 nm. These spectra and surface-enhanced hyper-Raman scattering (SEHRS) spectra of the functionalized carotene were compared with the spectra of nonmodified beta-carotene. Using SERS, normal Raman, and SEHRS spectra, all obtained for the resonant case, the interaction of the carotene molecules with silver nanoparticles, as well as the influence of the resonance enhancement and the SERS enhancement on the spectra, were investigated. The interaction with the silver surface occurs for both functionalized and nonfunctionalized beta-carotene, but only the stronger functionalization-induced interaction enables the acquisition of nonresonant SERS spectra of beta-carotene at low concentrations. The resonant SEHRS and SERS spectra are very similar. Nevertheless, the SEHRS spectra contain additional bands of infrared-active modes of carotene. Increased contributions from bands that experience low resonance enhancement point to a strong interaction between silver nanoparticles and electronic levels of the molecules, thereby giving rise to a decrease in the resonance enhancement in SERS and SEHRS. PMID- 28077984 TI - Use of Multiple Adjunctive Negative Pressure Wound Therapy Modalities to Manage Diabetic Lower-Extremity Wounds. AB - Objective: Various treatment options exist for wound healing; however, clinical assessment of the patient and the wound environment must be considered before determining an optimal wound treatment plan. Negative pressure wound therapy alone and/or with an instilled topical solution can be effective in adjunctive management of acute and chronic wounds. Hyperbaric oxygen therapy has also been shown to contribute to the wound-healing process. A pilot evaluation using a multistep approach of adjunctive negative pressure wound therapy with instillation and a dwell time, standard negative pressure wound therapy, and hyperbaric oxygen therapy was explored to manage postsurgical, diabetic lower extremity wounds with a significant bioburden. Methods: Three diabetic patients with lower-extremity ulcers were treated after surgical intervention. Multistep wound therapy consisted of (1) negative pressure wound therapy with instillation of normal saline with a 20-minute dwell time, followed by 2 hours of negative pressure at -150 mm Hg for 3 to 4 days; (2) 1 to 3 weeks of continuous negative pressure at -150 mm Hg; and (3) multiple treatments of hyperbaric oxygen therapy. Results: After surgery, wound closure was achieved within 4 weeks postinitiation of multistep wound therapy. All patients regained limb function and recovered with no long-term sequelae. Conclusions: In these 3 cases, a multistep wound therapy approach after surgery resulted in successful outcomes; however, larger prospective studies are needed to demonstrate the potential efficacy of this approach in the postsurgical management of complex, diabetic lower-extremity wounds. PMID- 28077985 TI - Tissue Liquefaction Liposuction for Body Contouring and Autologous Fat Transfer: A Retrospective Review Over 3 Years. AB - Objective: Tissue liquefaction lipoplasty is a novel, low-energy method cleared for use in aesthetic body contouring and autologous fat transfer. This is a retrospective review of the clinical effectiveness and safety of a liquefaction lipoplasty system for liposuction and autologous fat transfer. Methods: A retrospective review was done evaluating all liquefaction lipoplasty procedures with or without autologous fat transfer performed by a single surgeon (March 2013 to June 2016). Patient demographics, operative details, and any complications were tabulated from patient charts. A typical case reported is presented with pre /postoperative photographs. Results: Two hundred fifty-five consecutive liquefaction lipoplasty procedures were performed over 39 months. The average lipoaspirate volume was 1208 +/- 991 mL and the average fat graft volume was 322 +/- 277 mL. The overall complication rate was 9 of 255 (3.52%). There were 2 episodes of seroma (0.78%) that were aspirated and 2 episodes of cellulitis (0.78%) that responded to oral antibiotics. In the autologous fat transfer cohort, there were 5 of 103 (4.85%) cases of mild to moderate fat necrosis, with 1 patient requiring return to the operating room for removal of an oil cyst. No revisions of donor sites were required. Conclusions: Liquefaction lipoplasty appears safe for liposuction and autologous fat transfer, with a complication profile that is comparable with other widely used forms of suction-assisted liposuction. The liquefaction lipoplasty technology also provides potential time savings in the operating room that can minimize surgeon fatigue when harvesting large volumes of high-quality fat. Liquefaction lipoplasty appears to have advantages for both the patient and the surgeon, and further studies are underway. PMID- 28077986 TI - An Interesting Case of a Retrobulbar Cavernous Hemangioma. PMID- 28077987 TI - Revision of a Hypertrophic Tracheostomy Scar. PMID- 28077988 TI - Retracted: Nitroxyl (HNO): A Reduced Form of Nitric Oxide with Distinct Chemical, Pharmacological, and Therapeutic Properties. AB - [This retracts the article DOI: 10.1155/2016/4867124.]. PMID- 28077989 TI - Overview of the Role of Vanillin on Redox Status and Cancer Development. AB - Bioactive natural products play critical roles in modern drug development, especially anticancer agents. It has been widely reported that various pharmacological activities of such compounds are related to their antioxidant properties. Vanillin is a natural substance widely found in many plant species and often used in beverages, foods, cosmetics, and pharmaceutical products. Antioxidant and anticancer potential have been described for this compound. Considering the importance of vanillin in the area of human health and food and pharmaceuticals sectors, in this review, we discuss the role of vanillin on redox status and its potential contribution to the prevention and the treatment of cancer. PMID- 28077990 TI - Experimental in vivo and ex vivo models for the study of human aortic dissection: promises and challenges. AB - Aortic dissection (AD) is a life-threatening aortopathy with high mortality. To mimic spontaneous AD, investigate the pathogenesis of AD and develop novel therapeutic targets and measures, multiple AD experimental models have been generated, including drugs or chemicals induced experimental models, genetically modified experimental models, surgically or invasively induced experimental models, and ex vivo models. However, the perfect model of AD that replicates every aspect of the natural disease has not be generated yet. This review provides an overview of the experimental models used in AD preclinical research. The value and challenges of each in vivo and ex vivo model are discussed. PMID- 28077991 TI - LncRNAs and miRNAs: potential biomarkers and therapeutic targets for prostate cancer. AB - Prostate cancer (PCa) is the second lethal disease for men in western countries. Although androgen receptor (AR) signaling has been widely investigated, noncoding RNAs (ncRNAs), deficient of open reading frame, have also received considerable attention. Growing studies showed that the aberrant ncRNAs expression contributed to cell proliferation, metastasis and drug resistance in PCa. Therefore, therapeutically targeting ncRNAs may synergize androgen deprivation therapy (ADT) to have a better effect to fight against PCa, especially castration-resistant prostate cancer (CRPC). This review would systematically summarize the multicellular events controlled by ncRNAs and give a snapshot of future scientific activities and clinical applications. PMID- 28077992 TI - Effect of early administration of lower dose versus high dose of fresh mitochondria on reducing monocrotaline-induced pulmonary artery hypertension in rat. AB - OBJECTIVE: This study aim to investigate whether early mitochondrial administration would be effective and whether high-dose mitochondria (15000 MUg/rat) would be more effective than low-dose mitochondria (1500 MUg/rat) for attenuating the monocrotaline (MCT/65 mg/kg/rat)-induced pulmonary artery hypertension (PAH) in rat. METHOD AND RESULTS: Male-adult SD rats (n = 32) were randomized categorized into groups 1 (sham-control), 2 (PAH), 3 (PAH + low-dose mitochondria), and 4 (PAH + high-dose mitochondria). Mitochondria were admitted at day 5 and rats were sacrificed at day 35 post-MCT treatment. By day 35, oxygen saturation (saO2) was highest in group 1 and lowest in group 2, and significantly higher in group 3 than in group 4 (P<0.001). Conversely, right ventricular systolic blood pressure showed an opposite pattern compared with saO2 among all groups (P<0.001). Histological integrity of alveolar sacs exhibited a pattern identical to saO2, whereas lung crowding score and number of muscularized artery displayed an opposite pattern (all P<0.001). The protein expression of indices of inflammation (MMP-9, TNF-alpha, NF-kappaB), oxidative stress (oxidized protein, NO-1, NOX-2, NOX-4), apoptosis (Bax, cleaved caspase-3 and PARP), fibrosis (p Smad3, TGF-beta), mitochondrial-damage (cytosolic cytochrome-C), and hypoxia smooth muscle proliferative factors (HIF-alpha, connexin43, TRPCs) showed an opposite pattern compared, whereas anti-fibrosis (p-Smad1/5, BMP-2) and mitochondrial integrity (mitochondrial cytochrome-C) exhibited an identical pattern to saO2 in all groups (all P<0.001). CONCLUSION: Low dose is superior to high dose of mitochondria for protecting against MCT-induced PAH. The paradoxical beneficial effect may imply therapy with 15000 MUg/rat mitochondria is overdose in this situation. PMID- 28077993 TI - Peroxisome proliferator-activated receptor gamma (PPARgamma) mediates the protective effect of quercetin against myocardial ischemia-reperfusion injury via suppressing the NF-kappaB pathway. AB - Quercetin plays an important role in myocardial ischemia and reperfusion injury (IRI). However, the underlying mechanism for the protective effect of quercetin is largely unclear. In this study, we explored the protected effects of quercetin against myocardial IRI and its molecular mechanisms. Quercetin, GW9962 (PPARgamma antagonist) or PPARgamma-siRNA was administered alone or in combination prior to myocardial IRI in mice or to hypoxia and reoxygenation (H/R) treatment in H9C2 cells. Infarct size was evaluated by TTC staining after reperfusion. Myocardial injury was assessed by the serum levels of AST, CK-MB, cardiac troponin T (cTnT) and LDH. Cardiac function was measured by echocardiography. Oxidative stress injury was evaluated by analyses of inducible nitric oxide synthase (iNOS), MDA, SOD and glutathione peroxidase (GSH-PX) levels and by reactive oxygen species (ROS) detection. Myocardium apoptosis was evaluated by TUNEL staining, cleaved caspase-3 and Annexin V/PI detection. Moreover, activation of the NF-kappaB pathway was reflected by phosphorylation of IkappaB (p-IkappaB) and nuclear translocation of NF-kappaB p65. We reported that pretreatment of quercetin significantly improved cardiac function, diminished myocardial injury and reduced the infarct size. Myocardium oxidative damage and apoptosis were remarkably improved by quercetin treatment in vivo and in vitro. Quercetin also suppressed the activation of the NF-kappaB pathway induced by myocardial IRI. GW9662 or PPARgamma knockdown partially attenuated these cardioprotective effects of quercetin during myocardial IRI. In conclusion, our findings suggest that quercetin ameliorated IRI-induced heart damage via PPARgamma activation and the underlying mechanism might involve the inhibition of NF-kappaB pathway by PPARgamma activation. PMID- 28077994 TI - Reverse screening approach to identify potential anti-cancer targets of dipyridamole. AB - Dipyridamole (DIP) inhibits thrombus formation when given chronically, and causes vasodilation over a short time. To date, DIP can increase the anticancer drugs (5 fluorouracil, methotrexate, piperidine, vincristine) concentration in cancer cells and hence enhance the efficacy of treatment cancer. The inhibition of DIP may result in increased 5-fluorouracil efficacy and diminish the drug side effects. But the actual molecular targets remain unknown. In this study, reverse protein-ligands docking, and quantum mechanics were used to search for the potential molecular targets of DIP. The quantum mechanics calculation was performed by using Gaussian 03 program package. Reverse pharmacophore mapping was used to search for potential molecular target candidates for a given small molecule. The docking study was used for exploring the potential anti-cancer targets of dipyridamole. The two predicted binders with the statistically significant prediction are dihydropyrimidine dehydrogenase (DPD) (PDB Id: 1GTE) and human spindle checkpoint kinase Bub1 (PDB Id: 3E7E). Structure analysis suggests that electrostatic interaction and hydrogen bonding play an important role in their binding process. The strong functional linkage of DIP and 5FU supports our prediction. In conclusion, these results generate a tractable set of anticancer proteins. The exploration of polypharmacology will provide us new opportunities in treating systematic diseases, such as the cancers. The results would generate a tractable set of anticancer target proteins for future experimental validations. PMID- 28077995 TI - NADPH oxidase activation played a critical role in the oxidative stress process in stable coronary artery disease. AB - OBJECTIVES: The study was designed to investigate the oxidative stress levels of endothelial progenitor cells (EPCs) in stable coronary artery disease (CAD) and to explore the underlying mechanisms of NADPH oxidase activation and subsequent EPCs dysfunction. METHODS: EPCs were isolated from patients with stable CAD (n=50) and matched healthy volunteers (n=50). NADPH oxidase activation was detected by measuring the expression of each subunit using western blotting and qPCR analyses and the membrane translocation of p47phox using immunofluorescence. The in vivo angiogenesis capacity was evaluated using immunofluorescence by transplanting EPCs into a rat hind limb ischemia model. The PKC inhibitor GO-6983 was used to determine the role of PKC in NADPH oxidase activation. RESULTS: Oxidative stress level was increased and the in vivo angiogenesis capacity was impaired in EPCs obtained from CAD subjects with the activation of NADPH oxidase. P47phox membrane translocation increased in CAD group vs controls. These effects were resolved by NADPH oxidase inhibition. Up-regulation of PKCalpha/beta2 was found in EPCs from CAD subjects, PKC inhibition GO-6983 could reduce the expression and activity of NADPH oxidation. CONCLUSIONS: NADPH oxidase activation via p47phox membrane translocation played a critical role in the initiation and progression of CAD, and the PKCalpha/beta2 signaling pathway might be involved. PMID- 28077996 TI - Effect of pterostilbene on glioma cells and related mechanisms. AB - Neuroglioma is the most common primary malignant tumor in neurosurgery. Due to unfavorable life quality of patients, the treatment of glioma is a major challenge in clinics. The search for effect treatment drugs thus benefits patient prognosis. As one derivative of resveratrol, pterostilbene has a wide spectrum of pharmaceutical functions, especially with the anti-tumor effects. This study thus investigated the effect of pterostilbene on neuroglioma and related mechanisms. U87 glioma cell line was divided into control, normal culture and different dosages of pterostilbene groups, which received 5 mM or 10 mM pterostilbene for 48 h. MTT assay was used to detect U87 cell proliferation, while invasion assay was employed to test the effect of pterostilbene on cell invasion, followed by flow cytometry assay for analyzing U87 cell apoptosis. Real-time PCR was used to test mRNA expression of Bcl-2 and Bax in glioma cells under the effect of pterostilbene, while Western blotting was used to detect alternation of Bcl-2 and Bax protein levels. Pterostilbene significantly inhibited proliferation and invasion abilities of glioma cells compared to those in control group (P<0.05). It can also enhance cell apoptosis, decrease mRNA and protein of Bcl-2 expression, and increase mRNA and protein expressions of Bax (P<0.05 compared to control group) in a dose-dependent manner. Pterostilbene can facilitate apoptosis of glioma cells, and inhibit their proliferation and invasion via mediating apoptotic/anti-apoptotic homeostasis. PMID- 28077997 TI - Long non-coding RNA LOC283070 mediates the transition of LNCaP cells into androgen-independent cells possibly via CAMK1D. AB - AIMS: The present study is to investigate the role of long non-coding RNAs (lncRNAs) in the development of androgen independence in prostate cancer and its underlying mechanism. METHODS: We established an androgen-independent prostate carcinoma (AIPC) cell line LNCaP-AI from androgen-dependent prostate carcinoma (ADPC) cell line LNCaP. Different expression profiles of lncRNAs and mRNAs between LNCaP and LNCaP-AI cells were investigated using microarray analysis. The expression of RNAs was determined using quantitative real-time polymerase chain reaction. Protein levels were measured using Western blotting. MTT assay was used to test cell viability. Tumor formation assay was performed in nude mice to detect tumor growth in vivo. Flow cytometry was performed to detect cell cycles. Transwell assay was employed to test cell migration and invasion. RESULTS: According to bioinformatics prediction, lncRNA LOC283070 could possibly play an important role in the transition of LNCaP cells into LNCaP-AI cells. LOC283070 was up-regulated in LNCaP-AI cells and frequently up-regulated in AIPC cell lines. Overexpression of LOC283070 in LNCaP cells accelerated cell proliferation and migration, even under androgen-independent circumstances. Knockdown of LOC283070 inhibited LNCaP-AI cell proliferation and migration. Moreover, overexpression of LOC283070 promoted tumor growth in vivo in both normal mice and castrated mice. CAMK1D overexpression had similar effect with LOC283070, and CAMK1D knockdown fully abrogated the effect of LOC283070 overexpression on the transition of LNCaP cells into androgen-independent cells. CONCLUSIONS: The present study shows that overexpression of LOC283070 mediates the transition of LNCaP cells into androgen-independent LNCaP-AI cells possibly via CAMK1D. PMID- 28077998 TI - Transplantation of human umbilical cord mesenchymal stem cells in cochlea to repair sensorineural hearing. AB - To examine if transplantation of human umbilical cord mesenchymal stem cells (UMSC) into cochlea can be used to repair sensorineural hearing. Here we transplanted the fifth and sixth generations of UMSCs through the subarachnoid cavity of congenital deaf albino pigs. Auditory brainstem responses (ABR) were measured before and after UMSC transplantation. Cochlear samples were collected at 2 hrs, 3 days, 1, 2, 3, 4 and 8 weeks after transplantation. Immunohistochemistry was used to detect the proliferated cell nuclear antigen (PCNA). The UMSCs were found in different regions of the cochlea, including the stria vascularis, the basal membrane and the spiral ganglions, 3 days to 4 weeks after the transplantation. UMSCs and their DNA were found also in the areas of the brain, the heart, the liver, the kidney and the lung. ABR tests displayed a new waveform in the congenital deaf albino pigs after the UMSCs transplantation. We conclude that human UMSCs injected into the subarachnoid space can migrate into the inner ear, the central nervous system and the periphery organs. The presence of UMSCs in the cochlea maybe associated with changes of ABR waveforms in the congenital deaf albino pigs. PMID- 28077999 TI - Menadione induces G2/M arrest in gastric cancer cells by down-regulation of CDC25C and proteasome mediated degradation of CDK1 and cyclin B1. AB - Menadione (vitamin K3) has been reported to induce apoptotic cell death and growth inhibition in various types of cancer cells. However, involvement of menadione in cell cycle control has not been considered in gastric cancer cells yet. In the current study, we have investigated whether menadione is involved in the cell cycle regulation and suppression of growth in gastric cancer cells. In the cell cycle analysis, we found that menadione induced G2/M cell cycle arrest in AGS cells. To elucidate the underlying mechanism, we investigated the cell cycle regulatory molecules involved in the G2/M cell cycle transition. After 24 h of menadione treatment, the protein level of CDK1, CDC25C and cyclin B1 in AGS cells was decreased in a menadione dose-dependent manner. In the time course experiment, the protein level of CDC25C decreased in 6 h, and CDK1and cyclin B1 protein levels began to decrease after 18 h of menadione treatment. We found that mRNA level of CDC25C decreased by menadione treatment in 6 h. Menadione did not have an influence on mRNA level of CDK1 and cyclin B1 though the protein levels were decreased. However, the decreased protein levels of CDK1 and cyclin B1 were recovered by inhibition of proteasome. Collectively, these results suggest that menadione inhibits growth of gastric cancer cells by reducing expression of CDC25C and promoting proteasome mediated degradation of CDK1 and cyclin B1 thereby blocking transition of the cell cycle from G2 phase to M phase. PMID- 28078000 TI - Probiotics enhance the effect of allergy immunotherapy on regulating antigen specific B cell activity in asthma patients. AB - Immune regulatory system dysfunction plays a role in the pathogenesis of asthma. The therapeutic effect of allergic asthma is to be improved. The immune regulatory function of probiotics has been recognized. This study tests a hypothesis that Clostridium butyricum (CB) enhances the effect of allergen specific immunotherapy (AIT) on asthma. In this study patients with allergic asthma were treated with AIT or/and CB for six months. The therapeutic effect and IgE production of the patients were observed. The results showed that administration with AIT alone alleviated the asthma symptoms; but the serum levels of interleukin (IL)-4, IL-5, IL-13 and specific IgE were not altered, which was markedly improved by the administration with CB plus AIT. Such effects were maintained only for two months in the patients treated with AIT alone; but maintained more than 12 months in those patients treated with both AIT and CB. CB facilitated AIT to induce IL-10+ B cells (B10 cells) in asthma patients. AIT/CB therapy converted antigen specific B cells to antigen specific regulatory B cells. Butyrate modulated the gene transcription of IgE and IL-10 in the allergen specific B cells. In conclusion, administration of CB can enhance the therapeutic effect of AIT in the treatment of allergic asthma via facilitating generation of B10 cells. PMID- 28078001 TI - Endogenous nitric oxide regulates blood vessel growth factors, capillaries in the cortex, and memory retention in Sprague-Dawley rats. AB - The effects of nitric oxide (NO) on cerebral capillary angiogenesis and the regulation of pro- and anti-angiogenic factors that affect cerebral capillary angiogenesis, spatial learning, and memory ability are unclear. We assessed the effects of the NO precursor L-arginine (L-ARG) and the NO synthesis inhibitor Nomega-nitro-L-arginine methylester (L-NAME) on cortical capillaries and spatial learning and memory abilities. We administered intracerebroventricular injections of L-ARG or L-NAME to rats before they were evaluated in the Morris water maze. We measured the levels of NO synthase activity, pro-angiogenic factors, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2), and the expression of the anti-angiogenic factors angiostatin and endostatin. We also quantitatively investigated parameters of the cortical capillaries using immunohistochemistry and stereological methods. The L-ARG treatment significantly improved rats' spatial learning abilities and increased NOS activity in the cortex. L-NAME disrupted spatial learning. Following the L-ARG treatment, the expression of the pro-angiogenic factors (VEGF and FGF-2) was higher and the expression of anti-angiogenic factors (endostatin) was lower than the vehicle treated animals. In contrast, the L-NAME treatment reduced the expression of VEGF and increased the expression of endostatin. Based on these results, modulation of the NO content in the brain regulates VEGF, FGF-2, and endostatin expression, as well as capillary parameters in the cortex, which in turn influence spatial learning and memory performance. PMID- 28078002 TI - LncRNA-LINC00152 down-regulated by miR-376c-3p restricts viability and promotes apoptosis of colorectal cancer cells. AB - Recent studies have demonstrated that the crucial regulatory roles of long noncoding RNAs (lncRNAs) in tumorigenesis. Expression levels of several lncRNAs are abnormally up-regulated or down-regulated and play a primary role in colorectal cancer (CRC) cell tumorigenesis. However, the potential role and regulatory mechanisms of the novel human lncRNA, LINC00152, in CRC cells are poorly understood. Here, we found that LINC00152 expression was significantly decreased in CRC tissues and CRC cell lines, and this change was more frequent in patients with advanced stage (tumor-node-metastasisi (TNM) III and IV). Overexpression of LINC00152 (LINC000152over) resulted in decreased cell viability and increased apoptosis in CSC cell lines (HT-29 and SW480). Furthermore, decreased Ki-67 and B-cell lymphoma-2 (Bcl-2), and increased Fas, were observed in CSC cells. However, a change in Bax expression was undetected. Interestingly, microRNA (miR)-376c-3p down-regulated the expression of LINC00152 in CSC cells. Overexpression of miR-376c-3p (miR-376c-3pover) enhanced viability and limited apoptosis of CSC cells. In addition, miR-376c-3pover suppressed the effect of LINC00152over on the viability and apoptosis of CSC cells. Taken together, these data indicate that LINC00152 in CSC cells negatively regulated by miR-376c-3p, restricts cell viability and stimulates cell apoptosis, possibly by modulating the expression of Ki-67, Bcl-2, and Fas. MiR-376c-3p/LINC00152 plays an important role in the pathogenesis of CRC and may serve as a potential target for its diagnosis and treatment. PMID- 28078003 TI - Methylation of the FOXP3 upstream enhancer as a clinical indicator of defective regulatory T cells in patients with acute coronary syndrome. AB - Atherosclerosis is an immune-mediated inflammatory process, which acts as the main cause of acute coronary syndrome (ACS). Regulatory CD4+CD25+FOXP3+T cells (Tregs) are thought to play a major role in inhibiting the formation and progression of atherosclerosis. However, the exact role played by Tregs in the pathogenesis of ACS is yet remained unclear. FOXP3 is a key regulator of Treg formation and function. Demethylation at the CpG-rich island of FOXP3 upstream enhancers can alter FOXP3 expression, and may affect Treg function during the development of ACS. This study investigated the immunosuppressive function and methylation status of a FOXP3 upstream enhancer in Tregs in ACS patients. Notably, Tregs from ACS patients exhibited a significantly lower immunosuppressive effect on Teffs. Furthermore, the methylation status of the FOXP3 upstream enhancer was significantly increased in ACS patients. Consistent with these observations, Tregs originated from ACS patients manifested significantly lower levels of FOXP3 mRNA. The immunosuppressive effect of Tregs on Teffs was compromised in ACS patients. Together, our data suggest that examination of the methylation status of the FOXP3 upstream enhancer might be a novel approach to diagnose ACS and to differentiate ACS subtypes. PMID- 28078004 TI - Adipose-specific ablation of Nrf2 transiently delayed high-fat diet-induced obesity by altering glucose, lipid and energy metabolism of male mice. AB - Nuclear factor E2-related factor 2 (NRF2) is a well-known master controller of the cellular adaptive antioxidant and detoxification response. Recent studies demonstrated altered glucose, lipid and energy metabolism in mice with a global Nrf2 knockout. In the present study, we aim to determine the effects of an adipose-specific ablation of Nrf2 (ASAN) on diet-induced obesity (DIO) in male mice. The 6-week-old adipose-specific Nrf2 knockout (NK) and its Nrf2 control (NC) mice were fed with either control diet (CD) or high-fat diet (HFD) for 14 weeks. NK mice exhibited transiently delayed body weight (BW) growth from week 5 to week 11 of HFD feeding, higher daily physical activity levels and preferential use of fat over carbohydrates as a source of energy at week 8 of the CD-feeding period. After 14 weeks of feeding, NK mice showed comparable results with NC mice with respect to the overall BW and body fat content, but exhibited reduced blood glucose, reduced number but increased size of adipocytes, accompanied with elevated expression of many genes and proteins in the visceral fat related to glucose, lipid and energy metabolism (e.g. Fgf21, Pgc1a). These results indicated that NRF2 is an important mediator for glucose, lipid and energy metabolism in adipose tissue, and ASAN could have beneficial effect for prevention of DIO during the early development of mice. PMID- 28078005 TI - Thiol peroxiredoxin, a novel allergen from Bombyx mori, modulates functions of macrophages and dendritic cells. AB - Bombyx mori (B.mori, also known as silkworm) plays a role in the pathogenesis of allergic diseases. However, its allergens are to be characterized. The aim of this paper is to identify new silkworm allergens. Two-dimensional gel electrophoresis (2-DE) and mass spectrometry were employed to separate and identify potential allergens from silkworm pupa. Six potential allergens were identified in this study. Thiol peroxiredoxin (TP), one of the 6 allergens, reacted to serum IgE from patients sensitized to silkworm. By sensitizing with TP allergic asthma like symptoms were induced in mice, including elevation of the levels of serum IgE, IL-4 from bronchoalveolar lavage fluid and culture supernatant of spleen cells. In vitro experiments showed that TP significantly induced RAW264.7 cells (a macrophage cell line) apoptosis via modulating the BCL2 and Caspase9 pathways. The levels of CD80, CD40, CD83 and TNF-alpha in DC2.4 cells (a dendritic cell line) were increased in the culture after exposure to TP. In summary, TP is an allergic component of silkworm. It induces allergic asthma, and modulates the functions of macrophages and dendritic cells. PMID- 28078006 TI - Effects of long non-coding RNA SPRY4-IT1 on osteosarcoma cell biological behavior. AB - Recent findings indicate that long noncoding RNAs (lncRNAs) were dysregulated in many kinds of tumors including osteosarcoma (OS). SPRY4-IT1 has been recently revealed as oncogenic regulator in various cancers, while its clinical value and potential function in OS are still unknown. To investigate the role of SPRY4-IT1 in OS, we evaluated the expression SPRY4-IT1 in OS tissues and cell lines, and investigated the effect of SPRY4-IT1 siRNA on cell proliferation, migration and invasion of OS in vitro. Our result showed that SPRY4-IT1 was upregulated in OS tissues. Further experiments revealed that SPRY4-IT1 knockdown significantly inhibited OS cells proliferation by causing G1 arrest and promoting apoptosis. Furthermore, inhibitory effects of SPRY4-IT1 on cell migration and invasion were partly associated with EMT process. In conclusion, these data suggest that SPRY4 IT1 could be an oncogene for OS, and may be served as a candidate target for new therapies in human OS. PMID- 28078007 TI - Eotaxin-2 increased toll-like receptor 4 expression in endothelial cells in vitro and exacerbates high-cholesterol diet-induced atherogenesis in vivo. AB - Eotaxin-2 is a potent chemoattractant. High concentration of eotaxin-2 triggers the inflammation and tumor metastasis. Inhibition of eotaxin-2 may protect experimental atherogenesis although the mechanism is still unclear. Toll-like receptor 4 (TLR4) plays a major role mediating vascular inflammation, which is related to atherogenesis. In the results, we demonstrated that eotaxin-2 potentially impairs the tube formation capacity of human coronary artery endothelial cells (HCAECs). Eotaxin-2 augments the monocytic adhesion in lipopolysaccharides (LPS)-induced HCAECs, and which were reversed by TLR4 siRNA. Thus this study was conducted to investigate whether eotaxin-2 increases TLR4 expression, and then enhances the sensitivity of cells to antigen stimulation in HCAECs, which mediates the increasing of the development of serious atherosclerosis. In fact, we showed that JNK/SAPK, p38 MAPK, and ERK1/2 activation contribute to the transcriptional signaling pathway, JNK/SAPK and p38 MAPK regulate post-transcriptional modification, as well as protein-trafficking pathway in eotaxin-2-treated HCAECs TLR4 expression. RNA binding proteins, such as human antigen R (HuR) and tristetraprolin (TTP) mediate stability of TLR4 mRNA and chaperone, such as PRAT4A (a protein associated with TLR4) regulate trafficking of TLR4 protein might confer eotaxin-2 responsiveness. Eotaxin-2 administration led to a significant elevation of high cholesterol diet-induced atherosclerosis, and of TLR4 expression in B6.129S7-Ldlrtm1Her /J but not Ldlr-/- /-/Tlr4-/- mice. Our results revealed that eotaxin-2 induced overexpression TLR4 via mitogen-activated protein kinases (MAPK) signaling pathways, RNA binding proteins-mediated mRNA stabilization, and PRAT4A-regulated trafficking in HCAECs. These effects may lead to amplification of inflammatory responses contribute to the pathogenesis of cardiovascular disorders. PMID- 28078008 TI - Dicer-dependent pathway contribute to the osteogenesis mediated by regulation of Runx2. AB - Osteogenesis is mediated by sophisticated interactions of various molecular functions and biological processes, including post-transcriptional regulation. A range of miRNAs have been reported to regulate bone homeostasis and osteoblasts differentiation either positively or negatively through multiple signaling pathways. RNase III endonuclease Dicer is the key enzyme required for the biogenesis of miRNAs and small interfering RNAs. To determine the global influence of miRNAs on regulation of osteogenesis of pre-osteoblast cells, the transcriptional regulation of Dicer and the function of Dicer during osteoblast differentiation and mineralization were investigated. Runx2 binding directly to the Dicer promoter region was characterized in MC3T3-E1 cells by chromatin immunoprecipitation (ChIP) and luciferase promoter reporter assays. Overexpression or knockdown of Runx2 resulted in increase or decrease of Dicer expression, respectively. Furthermore, abatement of Dicer in MC3T3-E1 cells down regulated the expression of osteogenic marker genes and mineralization ability, at least partly involving Dicer-dependent processing of the miR-21a-5p targeting PTEN via pAKT/pGSK3beta/beta-catenin signaling pathways. Taken together, the study demonstrates the role of Dicer in osteogenesis and suggests that Dicer is required, in part, for Runx2 regulation of osteoblast differentiation. PMID- 28078009 TI - The iron chelator Dp44mT suppresses osteosarcoma's proliferation, invasion and migration: in vitro and in vivo. AB - Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), the novel iron chelator, has been reported to inhibit the tumorigenesis and progression of various cancer cells, including neuroblastoma, neuroepithelioma and prostate cancer. However, whether Dp44mT has anticancer effects in osteosarcoma is still unknown. Here, we investigated the antitumor action of Dp44mT in osteosarcoma and its underlying mechanisms. A human osteosarcoma 143B cell line in vitro and 143B xenograft in nude mice in vivo were utilized, the anticancer effects of Dp44mT were examined through methods of MTT assay, transwell, wound healing assay, flow cytometry, western blot, immunohistochemistry and H&E staining. We showed that Dp44mT inhibits cell proliferation, invasion and migration in vitro. In addition, flow cytometry further illustrated that Dp44mT suppression of 143B cell proliferation, invasion and migration were partially due to induction of cell apoptosis, cell cycle arrest in S phase and ROS production. Also in vitro and in vivo, the expression levels of Bcl2, Bax, Caspase3, Caspase9, LC3-II, beta catenin and its downstream targets such as C-myc and Cyclin D1 demonstrated that cell apoptosis and autophagy, as well as Wnt/beta-catenin pathway were involved in Dp44mT induced osteosarcoma suppression. The Dp44mT inhibition of osteosarcoma was further verified via animal models. The findings indicated that in vivo Dp44mT showed a significant reduction in the 143B xenograft tumor growth and metastasis. In conclusion, our data demonstrated that Dp44mT has effective anticancer capability in osteosarcoma and that may represent a promising treatment strategy for osteosarcoma. PMID- 28078011 TI - URI prevents potassium dichromate-induced oxidative stress and cell death in gastric cancer cells. AB - Chromium VI can provoke oxidative stress, DNA damage, cytotoxicity, mutagenesis and carcinogenesis. Aberrantly high level of reactive oxygen species (ROS) has been associated with oxidative stress and subsequent DNA damage. Notably, multiple previous studies have shown the increased level of ROS in chromium (VI) induced oxidative stress, but its effect on cell death and the underlying mechanism remain to be determined. In this study, we aimed to investigate the role of URI, an unconventional prefoldin RBP5 interactor, in potassium dichromate induced oxidative stress and cell death through in vitro loss-of-function studies. We have shown that knockdown of URI in human gastric cancer SGC-7901 cells by URI siRNA enhanced potassium dichromate-induced production of ROS. The level of rH2AX, a marker of DNA damage, was significantly increased, along with a reduced cell viability in URI siRNA treated cells that were also exposed to potassium dichromate. Comet assay showed that URI knockdown increased the tail moment in potassium dichromate-treated SGC-7901 cells. Accordingly, the cell rates of apoptosis and necrosis were also increased in URI knockdown cells treated with potassium dichromate at different concentrations. Together, these results suggest that URI is preventive for the oxidative stress and cell death induced by potassium dichromate, which potentially leads to cancer cell survival and therapeutic resistance. PMID- 28078012 TI - GSK3beta inhibition accelerates axon debris clearance and new axon remyelination. AB - Glycogen synthase kinase 3beta (GSK3beta) inhibitors, especially the mood stabilizer lithium chloride, are also used as neuroprotective or anti inflammatory agents. We studied the influence of LiCl on inducing early myelin clearance and on regulating the remyelination following peripheral nerves injury. We showed that the oral administration of adult mice with LiCl after sciatic nerve crush injury accelerated in vivo myelin debris clearance stimulated the expression of myelin proteins, restored the myelin structure, and accelerated the recovery of sciatic functions. LiCl treatment also promoted remyelination of the sciatic nerve after crush. Furthermore, we also demonstrated that LiCl exerts its action in Schwann cells by increasing the amount of beta-catenin and provoking its nuclear localization in vivo. We showed by ChIP experiments that LiCl treatment drives beta-catenin to bind to T-cell factor/lymphoid-enhancer factor response elements identified in myelin-related genes. Taken together, our results provide the first evidence that the GSK3beta could be considered as an important drug in inducing early myelin debris clearance and regulating the expression of myelin genes, which open new approaches in the clinical treatment of nerve injuries by utilizing GSK3beta inhibitors such as lithium. PMID- 28078010 TI - Fn14 is regulated via the RhoA pathway and mediates nuclear factor-kappaB activation by Angiotensin II. AB - Angiotesin II (Ang II) plays an important role in cardiac remodeling. Fibroblast growth factor inducible-14 (Fn14) is the smallest member of the tumor necrosis factor superfamily of receptors. Currently, little is known about the functional role of Fn14 in the heart. Chiefly, we observe the up-regulation of extracellular matrix in in vivo model. We therefore assess the expression and regulation of Fn14 in cardiomyocytes and in vivo models induced by Ang II. In order to study the regulation of Fn14, cardiac remodeling was established in rats and neonatal cardiomyocytes were used in in vitro model. As well, Ang II is able to strongly induce Fn14 expression in in vivo and in vitro models. Fn14 is mediated via RhoA pathways, since siRNA against RhoA prevented the expression of Fn14 in cardiomyocytes. Pretreatment of cardiomyoctes with siRNA against NF-kappaB and IkappaBalpha also decreased Fn14 expression induced by Ang II. We here describe for the first time Ang II regulation of Fn14 in in vivo and in vitro models via RhoA, NF-kappaB and NF-kappaB driven gene signaling pathway. In conclusion, Fn14 may be important in regulating the process of cardiac remodeling induced by Ang II. PMID- 28078013 TI - Overexpression and biological function of IQGAP3 in human pancreatic cancer. AB - IQGAP3 (IQ motif containing GTPase activating protein3) belongs to IQGAP family. Recent studies have investigated that IQGAP3 was overexpressed in several tumor tissues. This study was designed to explore the expression and role of IQGAP3 in pancreatic cancer, a highly lethal disease. IQGAP3 mRNA expression was significantly increased in pancreatic cancer tissues, compared with non-cancerous tissues. Moreover, its expression was strongly associated with tumor size, differentiation, lymph node metastasis and patients' overall survival. Gene set enrichment analysis (GSEA) on The Cancer Genome Atlas (TCGA) dataset showed that cell apoptosis, metastasis and Cdc42 pathways were strongly associated with IQGAP3 expression in pancreatic cancer patients. Knocking down of IQGAP3 in two pancreatic cancer cell lines with high level of IQGAP3 (BXPC-3 and SW1990) significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis. Moreover, silencing of IQGAP3 also affected the expression of cell apoptosis-, metastasis- and Cdc42 pathway-related proteins. Cdc42 knockdown had similar inhibitory effects on the cellular behavior of BXPC-3 cells. In conclusion, IQGAP3 may act as an oncogene in pancreatic cancer through regulating Cdc42 expression. Our data suggest IQGAP3 might be a novel diagnostic marker and therapeutic target for this cancer. PMID- 28078014 TI - MiRNA-34a overexpression inhibits multiple myeloma cancer stem cell growth in mice by suppressing TGIF2. AB - Hematological malignancy originated from B-cell line, multiple myeloma (MM), is a kind of plasma cells in bone marrow hyperplasia and cause of osteoclast-mediated skeletal destruction disease. MiR-34a plays an important epigenetic regulating role in malignant tumors and presents a therapeutic potential. In this study, we investigated the effects of overexpression of miR-34a in MM cancer stem cells (CSCs) on tumor growth and bone lesions. Here we showed that miR-34a overexpression inhibited cell proliferation, colony formation, and increased CSC apoptosis in vitro. The apparent epigenetic modulation induced by miR-34a overexpression was found no only in MM RPMI8226 cells but also in CSC xenograft MM. Both bioinformatics prediction and dual-luciferase reporter assay showed that transforming growth interaction factor 2 (TGIF2) was sufficient to confer miR-34a regulation. The results of qRT-PCR and Western blot assays demonstrated that the expression of TGIF2 was significant decreased in tumor tissues from NOD/SCID mice injected with miR-34a-MM CSCs. We conclude that miR-34a overexpression in MM CSCs significantly suppressed the tumorigenicity and lytic bone lesions in mouse model by inducing apoptosis and inhibiting TGIF2 expression. PMID- 28078015 TI - Long non-coding RNA CCAT1 that can be activated by c-Myc promotes pancreatic cancer cell proliferation and migration. AB - This study aimed to investigate the potential role of lncRNA CCAT1 in the progression of pancreatic cancer (PC) and to reveal its possible molecular mechanism. The expression of CCAT1 was analyzed in PC tissues and their adjacent normal tissues from patients diagnosed with PC and in two pancreas cancer cell lines, namely PANC-1 and Aspc-1 using real-time polymerase chain reaction (qRT PCR) and western blot, respectively. The effects of CCAT1 expression on cell proliferation, cell cycle, and migration were analyzed using MTT assay, flow cytometry, and transwell assay, respectively. The effects of c-Myc expression on the expression of CCAT1 and E-box were also analyzed using RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) assays, respectively. The results showed that CCAT1 was highly expressed in PC tissues compared to the adjacent tissues (P<0.01) and was also overexpressed in PANC-1 and Aspc-1 cells (P<0.05). The silencing of CCAT1 significantly inhibited cell proliferation and migration (P<0.05), arrested cell cycle at G0/G1 stage, and decreased cyclin D1 expression (P<0.05). An increased expression of c-Myc was observed in the PC tissues compared to the adjacent tissues. We found that suppression of c-Myc altered CCAT1 expression by targeting its promoter at E-box. This study demonstrated that c-Myc-activated CCAT1 may contribute to tumorigenesis and metastasis of PC, which may serve as a potential target for the therapy of PC. PMID- 28078016 TI - Trichosanatine alleviates oxidized low-density lipoprotein induced endothelial cells injury via inhibiting the LOX-1/p38 MAPK pathway. AB - The LOX-1/p38 mitogen-activated protein kinase (MAPK) pathway has been proved to participate in the endothelial dysfunction in atherosclerosis. Trichosanatineis is an active compound isolated from the peel of Trichosanthes kirilowii. This study aims to determine whether trichosanatine prevents the oxidized low-density lipoprotein (ox-LDL)-induced insult through inhibition of the LOX-1/p38 MAPK pathway in HUVECs. HUVECs were treated with 150 mg/ml ox-LDL for 24 h to establish an ox-LDL-induced endothelial injury model. Cell viability, mitochondrial membrane potential (MMP), apoptosis, reactive oxygen species (ROS) level, LOX-1 and p38 MAPK expression level were measured. The results indicated that HUVECs were pretreated with either 100 mM trichosanatine or LOX-1 shRNA prior to exposure to ox-LDL for 24 h. Exposure of HUVECs to 150 mg/ml ox-LDL for 24 h significantly up-regulated the expression levels of LOX-1. The increased expression levels of LOX-1 were markedly attenuated by pretreatment with 100 mM trichosanatine. In addition, the ox-LDL-induced increase in phosphorylated (p) p38 MAPK expression was ameliorated by pretreatment with LOX-1 shRNA. Pretreatment of HUVECs with either trichosanatine or LOX-1 shRNA before exposure to ox-LDL significantly inhibited the ox-LDL-induced injuries, as evidenced by an increase in cell viability, a decrease in apoptotic cells, a ROS generation and a loss of MMP. In conclusion, we have demonstrated for the first time that the LOX 1/p38 MAPK pathway contributes to the ox-LDL-induced injury in HUVECs. Meanwhile, the trichosanatine protects the HUVECs against ox-LDL-induced injury at least in part by inhibiting the activated of LOX-1/p38 MAPK pathway. PMID- 28078017 TI - Runx2-interacting genes identified by yeast two-hybrid screening of libraries generated from hypertrophic chondrocytes. AB - Runx2, a member of the Runt domain family, is a well-known master transcription factor for osteoblast differentiation. Runx2 has also been shown to play essential roles during chondrocyte hypertrophy, an important late stage of endochondral ossification linking both bone and cartilage development. To identify the co-factors that may interact with Runx2 together to regulate this critical process, we have performed yeast two-hybrid (Y2H) screening using Runx2 as a bait to screen a cDNA library of hypertrophic chondrocytes. The bait expressing cassette was constructed by fusing Runx2 with the pGBKT7 vector containing the Gal4 DNA binding domain (BD). The Mate & Plate libraries were constructed using pGADT7-Rec and cDNAs derived from hypertrophic chondrocytes enriched limb tissues or hypertrophic MCT cells. After co-transformation of pGBKT7-Runx2 and the cDNA libraries, colonies that grew in nutrition deficient medium were selected and subjected to PCR and sequencing analysis. We successfully identified more than 30 candidate genes, including Lectin-1 (Lgals1), Col1a2, Edf1 and Timp-2. We have performed literature review and bioinformatics analysis of these genes using GenePaint. Most of them show ubiquitous expression with Lgals1 show enhanced expression in hypertrophic chondrocytes. We further performed preliminary expression analysis by quantitative PCR and detected differential expression of these candidate genes in proliferative and hypertrophic MCT cells, with Timp-2 significantly (around 3 fold) and Lgals1 moderately (around 1.5 fold) upregulated in hypertrophic MCT cells. Our results suggest that, candidate gene Timp-2 is very likely to interact with Runx2 and together to play essential function during cartilage development, and possibly its homeostasis. PMID- 28078018 TI - MicroRNA-613 targets FMNL2 and suppresses progression of colorectal cancer. AB - Increasing evidence indicates that dysregulation of miRNAs is involved in the initiation and progression of colorectal cancer (CRC). MicroRNA (miR)-613 has been reported to function as a tumor suppressor in many cancers. However, the precise role of miR-613 in CRC progression is unclear. This study aimed to investigate the role and underlying mechanism of miR-613 in growth and metastasis of CRC. Real-time quantitative PCR (qPCR) and western blot techniques were used to assess expression of miR-613 and formin-like 2 (FMNL2) in CRC cell lines and tissues. Luciferase reporter assays were conducted to investigate the association between miR-613 and FMNL2. Proliferation, wound healing, and transwell invasion assays, as well as flow cytometric analysis, were performed to evaluate the effect of miR-613 on proliferation, migration, invasion, and cell-cycle status, respectively, of CRC cells. We found that miR-613 was significantly downregulated in CRC cell lines and tissue samples, and correlated closely with TNM stage. miR 613 suppressed CRC cell proliferation, migration, and invasion, and induced cell cycle arrest at G1 phase. FMNL2 was identified as a direct target of miR-613 in CRC cells. Importantly, FMNL2 overexpression rescued miR-613-induced suppression of proliferation, migration, and invasion of CRC cells. These results suggest that miR-613 functions as a tumor suppressor in the progression of CRC by regulating FMNL2. PMID- 28078019 TI - Intramuscular nerve distribution patterns of anterior forearm muscles in children: a guide for botulinum toxin injection. AB - Botulinum toxin (BoNT) can relieve muscle spasticity by blocking axon terminals acetylcholine release at the motor endplate (MEP) and is the safest and most effective agent for the treatment of muscle spasticity in children with cerebral palsy. In order to achieve maximum effect with minimum effective dose of BoNT, one needs to choose an injection site as near to the MEP zone as possible. This requires a detailed understanding about the nerve terminal distributions within the muscles targeted for BoNT injection. This study focuses on BoNT treatment in children with muscle spasms caused by cerebral palsy. Considering the differences between children and adults in anatomy, we used child cadavers and measured both the nerve entry points and nerve terminal sense zones in three deep muscles of the anterior forearm: flexor digitorum profundus (FDP), flexor pollicis longus (FPL), and pronator quadratus (PQ). We measured the nerve entry points by using the forearm midline as a reference and demonstrated intramuscular nerve terminal dense zones by using a modified Sihler's nerve staining technique. The locations of the nerve entry points and that of the nerve terminal dense zones in the muscles were compared. We found that all nerve entry points are away from the corresponding intramuscular nerve terminal dense zones. Simply selecting nerve entry points as the sites for BoNT injection may not be an optimal choice for best effects in blocking muscle spasm. We propose that the location of the nerve terminal dense zones in each individual muscle should be used as the optimal target sites for BoNT injection when treating muscle spasms in children with cerebral palsy. PMID- 28078020 TI - Miniature pigs: a large animal model of cochlear implantation. AB - The objective of this paper was to investigate the suitability of the miniature pig as a large animal model of cochlear implantation (CI). Micro-CT scanning and three-dimensional reconstructions of the inner ear were completed in six animals. Photographs of the procedures and measurements of the inner ear were made. The CI procedure was simulated in 10 animals. Electrically evoked auditory brain stem responses (EABRs) and radiographic images were evaluated during or after the CI procedure. Morphological examination and measurements of inner ears of the miniature pigs were completed by micro-CT scanning. The height of the scala tympani was 873.12 um in the 1st turn, 641.46 um in the 2nd turn, 445.13 um in the third turn and 339.19 um in the fourth turn. The length of the cochlea was 38.6 mm, larger than other animal models (7.2 mm in rats and 22 mm in macaque, for example) and similar to that in the human (36 mm). Commercial electrodes used in humans (870 um at the end and 630 um at the tip in diameter) were implanted in the pig's cochlea, through which normal eABRs were obtained. Radiographic images after the CI procedure revealed electrodes located in the scala tympani of the first and second turns. Compared with traditional animal models, greater similarities of the inner ear between miniature pigs and humans make this animal a potentially useful model for CI studies. PMID- 28078021 TI - Micro RNA-19a suppresses thrombospondin-1 in CD35+ B cells in the intestine of mice with food allergy. AB - Disruption of immune tolerance is associated in the pathogenesis of allergy. Thrombospondin-1 (TSP1) plays a role in the maintenance of immune tolerance, which is compromised in allergic disorders. Micro RNA (miR) is involved in the regulation of immune responses. This study tests a hypothesis that miR-17-92 cluster is involved in the regulation of TSP1 in the intestinal CD35+ B cells. In this study, a food allergy mouse model was developed. The intestinal B cells were isolated to be analyzed for the expression of a miR-17-92 cluster and TSP1. The role of miR-19a in the suppression of TSP1 in B cells was tested in a cell culture model. We observed that the levels of TSP1 were significantly decreased; the levels of miR-19a were significantly increased in intestinal CD35+ B cells of mice sensitized to ovalbumin (OVA) as compared with naive controls. Exposure to interleukin (IL)-4 suppressed the expression of TSP1 in B cells, which was abolished by inhibition of miR-19a. miR-19a mediated the effects of IL-4 on repressing TSP1 expression in B cells. We conclude that IL-4 suppresses the expression of TSP1 in the intestinal CD35+ B cells via up regulating miR-19a. The miR-19a may be a target to regulate the immune tolerant status in the body. PMID- 28078022 TI - MiR-19 suppresses fibroblast-like synoviocytes cytokine release by targeting toll like receptor 2 in rheumatoid arthritis. AB - Fibroblast-like synoviocytes (FLS) play an important role in the pathogenesis of rheumatoid arthritis (RA) through participating in joint tissue inflammation and joint damage. MicroRNAs are a kind of small non-coding RNAs that can regulate gene expression in the transcription level to affect cell behaviors. This study intended to investigate the expression of miR-19 in FLS from RA patients and related mechanism. A total of 126 RA patients were selected in this study. MiR-19 expression in FLS was detected by qRT-PCR. Toll like receptor 2 (TLR2) protein expression was tested by Western blot. MiR-19 target genes were confirmed by bioinformatics analysis and luciferase reporter assay. The impact of miR-19 on the expression of TLR2, interleukin 6 (IL-6), and matrix metalloproteinase 3 (MMP 3) in FLS were analyzed by cell transfection and Western blot. MiR-19 expression in FLS from RA patients was significantly downregulated compared with control (P < 0.05), while TLR2 level was increased (P < 0.05). Bioinformatics analysis and luciferase reporter assay confirmed that TLR2 was the target gene of miR-19. Transfection of miR-19 mimic or miR-19 inhibitor obviously suppressed or increased TLR2 expression, and reduced or promoted release of cytokines IL-6 and MMP-3 in FLS, respectively. In conclusion, MiR-19 expression was downregulated in FLS from RA patients, leading to increased TLR2 expression and enhanced cytokines release. PMID- 28078023 TI - Picroside II protects against sepsis via suppressing inflammation in mice. AB - Picroside II, an iridoid compound extracted from Picrorhiza, exhibits anti inflammatory and anti-apoptotic activities. We explored the protective effects and mechanisms of picroside II in a mouse model of sepsis induced by cecal ligation and puncture (CLP), using three groups of mice: Group A (sham), Group B (CLP+NS) and Group C (CLP+20 mg/kg picroside II). The mortality in mice with sepsis was decreased by the administration of picroside II, and lung injury was alleviated simultaneously. Picroside II treatment enhanced bacterial clearance in septic mice. Further, picroside II treatment alleviated the inflammatory response in sepsis and enhanced immune function by inhibiting the activation of NLRP3 inflammasome and NF-kappaB pathways. Picroside II may represent an anti inflammatory drug candidate, providing novel insight into the treatment of sepsis. PMID- 28078024 TI - Neuroprotective effect of picroside II in brain injury in mice. AB - Various types of brain injury which led to the damage of brain tissue structure and neurological dysfunction continues to be the major causes of disability and mortality. Picroside II (PII) possesses a wide range of pharmacological effects and has been proved to ameliorate ischemia and reperfusion injury of kidney and brain. However, critical questions remain about other brain injuries. We investigated the protective effect of PII in four well-characterized murine models of brain injury. Models showed a subsequent regional inflammatory response and oxidative stress in common, which might be improved by the administration of PII (20 mg/kg). Meanwhile, a series of morphological and histological analyses for reinforcement was performed. In traumatic, ischemic and infectious induced injuries, it was observed that the survival rate, apoptosis related proteins, Caspase-3, and the expression of acute inflammatory cytokines (IL-1beta, IL-6 and TNF-alpha) were significantly alleviated after PII injection, but PII treatment alone showed no effect on them as well. The western blot results indicated that TLR4 and NF-kappaB were clearly downregulated with PII administration. In conclusion, our results suggested that PII with a recommended concentration of 20 mg/kg could provide neuroprotective effects against multi-cerebral injuries in mice by suppressing the over-reactive inflammatory responses and oxidative stress and attenuating the damage of brain tissue for further neurological recovery. PMID- 28078025 TI - Potential herb-drug interaction of shexiang baoxin pill in vitro based on drug metabolism/transporter. AB - Many researches have proved functions of anti-oxidation, endothelial protection and pro-angiogenesis efficiency of Shexiang Baoxin Pill (SBP). This study aims to investigate potential for metabolism-based interaction on CYP450s and transporter based interaction on OATP1B1, BRCP and MDR1. Human primary hepatocytes were used in this study. Probe substrates of cytochrome P450 enzymes were incubated in human liver microsomes (HLMs) with or without SBP and IC50 values were estimated. Inhibitive potential of SBP on activities of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4 was evaluated. Inducible potential of SBP on activities of CYP1A2, 2B6 and 3A4 was accessed. Inhibitive potential of SBP on human OATP1B1 was evaluated using cell-based assay. Inhibitive potential of SBP on human MDR1 and BCRP was also evaluated using vesicles assay. MDR1 and BCRP vesicle kit were used to determine ATP dependent uptake activity when incubated with SBP. SBP was a competitive inhibitor of CYP2B6, 2C19, while neither inhibitory nor inductive potentials toward other CYP450s were detected. No significant MDR1 inhibitory potential was estimated, while only high concentration of SBP (500 MUg/ml) could inhibit activity of BCRP. Probe substrates Estradiol-17 beta-glucuronide was incubated in HEK293-OATP1B1 and HEK293-MOCK cell system with different concentration of SBP and estimated IC50 was 179 MUg/mL, which demonstrated a moderate inhibition potential against OATP1B1. In conclusion, outcome of this study suggests that SBP plays an important role in inhibition of CYP450 isozymes (including CYP2B6 and 2C9) and transporter OATP1B1. Therefore, precautions should be taken when using SBP for CYP and OATP-related herb-drug interactions. PMID- 28078026 TI - Lugrandoside attenuates LPS-induced acute respiratory distress syndrome by anti inflammation and anti-apoptosis in mice. AB - This study aimed to investigate the protective effects and specific mechanisms of lugrandoside (LG) on lipopolysaccharides (LPS)-induced acute respiratory distress syndrome (ARDS). LG is a novel phenylpropanoid glycoside with many biological properties, isolated from the culinary leaves of Digitalis lutea L. and Digitalis grandiflora Miller. The primary indicators to assess the lung injury were infiltration of inflammatory cells; pulmonary edema; expression of proinflammatory cytokines, cyclo-oxygenase 2, and intracellular adhesion molecule 1; activation of nuclear factor-kappaB pathways; and cellular apoptosis. The results showed that LG evidently alleviated the inflammatory response, decreased the apoptosis of alveolar macrophages, and improved the lung injury in mice with LPS-induced ARDS. In conclusion, LG improved LPS-induced ARDS by anti inflammation and anti-apoptosis and might be a promising pharmacological therapy for ARDS. PMID- 28078027 TI - Advanced glycosylation end product promotes forkhead box O1 and inhibits Wnt pathway to suppress capacities of epidermal stem cells. AB - Diabetes mellitus is frequently accompanied by chronic complications like delayed wound healing, which is consider to be attributed to the accumulation of advanced glycosylation end product (AGE). However, the impacts of AGE on epidermal stem cells (ESCs) are largely unknown. This study aims to address the influence and mechanism of AGE on ESCs. ESCs isolated from rats were cultured in AGE-modified bovine serum albumin and transfected with small interfering RNA to knock down AGE specific receptor (AGER). Expression of stem cell markers integrin beta1 (ITGB1) and keratin 19 (KRT19), cell viability, apoptosis and reactive oxygen species (ROS) were examined. Wnt pathway-related factors Wnt family member 1 (WNT1), WNT3A, beta-catenin, v-myc avian myelocytomatosis viral oncogene homolog (MYC), cyclin D1 (CCND1) and matrix metallopeptidase 7 (MMP7) were quantified. The interaction between forkhead box O1 (FOXO1) and beta-catenin was assessed by co immunoprecipitation. Results indicated that AGE down-regulated ITGB1 and KRT19 expression, suppressed ESC viability and promoted apoptosis, and ROS level (P < 0.01), implying decreased capacities of ESCs. AGE also promoted AGER and FOXO1, while AGER knockdown had the opposite effects. Moreover, AGER knockdown elevated the level of WNT1, WNT3A, MYC, CCND1 and MMP7 that were suppressed by AGE (P < 0.01). Immunoprecipitation analysis showed that FOXO1 could compete with lymphoid enhancer binding factor 1 to interact with beta-catenin, which might help to elucidate the mechanism of AGE repressing ESCs. This study helps to understand the mechanism of accumulated AGE in affecting ESC capacities, and provides potential therapeutic targets to meliorate diabetic wound healing. PMID- 28078028 TI - Activation of 5-HT and NR2B contributes to visceral hypersensitivity in irritable bowel syndrome in rats. AB - The roles of 5-hydroxytryptamine (5-HT) and spinal N-methyl-D-aspartic acid receptor 2B (NR2B) in visceral hypersensitivity were investigated. A rat model with irritable bowel syndrome (IBS) was established by intracolonic injections of acetic acid onpost-natal days 8-21. Rats were randomly divided into five groups: normal intact (control) group, IBS model group, Ro25-6981-treated IBS rats (Ro25 6981, a NR2B antagonist) group, amitriptyline-treated IBS rats (amitriptyline, a 5-HT antagonist) and Ro25-6981 plus amitriptyline-treated IBS rats (Ro25 6981+amitriptyline) group. The expressions of 5-HT, NR2B, 5-HT2AR, 5-HT7R, SERT, TNF-alpha and IL-1beta in colon, dorsal root ganglion (DRG) and hypothalamus, respectively, were measured by Immunohistochemical staining, Real-Time Reverse Transcription-PCR and Western blotting. Our results showed increased DRG and hypothalamus expression of 5-HT, NR2B, 5-HT2AR, 5-HT7R in IBS model group and decreased expression of those in Ro25-6981 and amitriptyline alone or both treatment groups. Moreover, SERT expression was decreased in colorectal, DRG and hypothalamus of ISB model rats, but increased by Ro25-6981 and amitriptyline alone or both treatments. Ro25-6981 and amitriptyline treatment also decreased colorectal expression of TNF-alpha and IL-1beta induced by IBS model. In conclusion, activation of 5-HT and NR2B may play a crucial role in visceral hypersensitivity in irritable bowel syndrome in rats. PMID- 28078029 TI - Intrinsically 89Zr-labeled Gd2O2S:Eu nanophosphors with high in vivo stability for dual-modality imaging. AB - Radioluminescence imaging (RLI) employs high energy particles from radioisotope decay for in situ excitation of selected nanophosphors. Co-injection of radiopharmaceuticals and nanophosphors suffers from suboptimal RL efficiency owing to the large separation between the source and the emitter. In addition, vastly different pharmacokinetic profiles of the two further impede the practical applications of this approach. To overcome the above challenges, chelator-free radiolabeled nanophosphors with excellent RL efficiency and dual-modality imaging capabilities have been proposed. Abundant O2- donors on Gd2O2S:Eu could intrinsically chelate oxophilic radionuclide 89Zr with ~80 % labeling yield. Positron emission tomography demonstrated superb long-term radiostability of [89Zr]Gd2O2S:Eu@PEG nanoparticles in vivo, and a conventional optical imaging system was used to study radiouminescence properties of [89Zr]Gd2O2S:Eu@PEG nanoparticles in vitro and in vivo. PMID- 28078031 TI - Calmodulin regulates KCNQ2 function in epilepsy. AB - Epilepsy is linked to mutations in KCNQ channels. KCNQ channels including KCNQ2 and KCNQ3 are enriched in neurons, regulating action potential generation and modulation. Here, we showed that properties of KCNQ2 channel in rat hippocampal cultured neurons are regulated by ubiquitous calcium sensor calmodulin. We analyzed calmodulin function on the KCNQ2 channel in both HEK293 cells and neurons. We used shRNAs to suppress expression of calmodulin protein. On the other hand, we used cDNA to over-express calmodulin in HEK293 and neuron cells. In wild type and mis-sense mutations of KCNQ2 proteins, calmodulin over expression enhanced outward K+ current and decreased neuronal activity. Meanwhile, calmodulin knockdown reduced KCNQ2 current and increased neuronal activity, showing that hippocampal neuronal excitability is regulated by expression level of calmodulin protein. Our data suggest that calmodulin performs a major function in regulating KCNQ2 properties via direct binding to KCNQ2 protein, indicating that calmodulin could be a target of as gene therapy in epilepsy. PMID- 28078030 TI - Lymph node metastasis in patients with gastric cancer: a multi-modality, morphologic and functional imaging study. AB - The aim of the study was to investigate the value of computed tomography (CT), magnetic resonance imaging (MRI) and diffusion weighted imaging (DWI) for diagnosing lymph nodes metastasis before treatment in gastric cancer. Eighty-two patients with proven gastric cancer underwent CT, morphological MRI (T2WI) and DWI examinations. Two radiologists independently assessed these images for the presence of lymph nodes involvement. Pathologic findings were considered as "gold standard". Independent samples t-test was used for the comparisons of short diameters and ADC values between the positive lymph nodes and the negative lymph nodes. Diagnostic accuracy of these three imaging modalities was evaluated by area under the receiver operating characteristics (ROC) curve (AUC). The ADC value of the positive lymph nodes was (1.15 +/- 0.01) * 10-3 mm2/s, which was significantly lower than that of the negative lymph nodes (1.48 +/- 0.01) * 10-3 mm2/s (t = 18.70, P < 0.0001). The short diameter of the positive lymph nodes (1.54 +/- 0.38 cm) was significantly greater than that of the negative lymph nodes (0.95 +/- 0.12 mm) (t = 19.03, P < 0.001). The AUC for all imaging modalities combined (0.893) was significantly larger than that for each imaging modality alone (P < 0.05), and the AUC of DWI (0.797) was significantly larger than (P < 0.05) that of morphological MRI (0.733). There was no statistically significant difference between the AUCs of CT and morphological MRI (P = 0.462). In conclusion, CT, MRI and DWI combined present significantly higher accuracy than each imaging modality alone in the detection of lymph nodes involvement. PMID- 28078032 TI - Extracellular matrix metalloproteinase inducer enhances host resistance against pseudomonas aeruginosa infection through MAPK signaling pathway. AB - This study aims to explore the role of extra-cellular matrix metalloproteinase inducer (EMMPRIN) in the drug resistance of the pseudomonas aeruginosa (PA). The BALB/c mice were transfected with PA, then the mice were infected with the siRNA of EMMPRIN to silence the EMMPRIN gene. The EMMPRIN mRNA and protein were detected by using RT-PCR and western blot, respectively. In order to examine the function of EMMPRIN in drug resistance of PA, the BALB/c and C57BL/6 mice were treated with EMMPRIN siRNA. The cytokines, EMMPRIN and MMP9 were examined by the RP-PCR and ELISA, respectively, undergoing the silence of EMMPRIN siRNA. Moreover, the western blot assay was also used to test the phosphorylated MAPK in the murine macrophages after silenced by the EMMPRIN siRNA. The EMMPRIN was activated, with lipopolysaccharide stimulation and treated with the MAPK inhibitor, to evaluate whether the MAPK participates in the EMMPRIN-triggered drug resistance. The results indicated that the EMMPRIN expression was elevated in the infected BALB/c at 3 or 5 days post-infection. Silence of EMMPRIN Enhanced the Production of pro-inflammatory cytokines in PA keratitis. Silence of EMMPRIN significantly up-regulated Th1-type cytokines IFN-gamma, IL-12, and IL-18, but down-regulated Th2-type cytokines IL-4, IL-5, and IL-10. MMP9 was increased in the cells with rEMMPRIN treatment. EMMPRIN inhibits pro-inflammatory cytokine production via a MAPK signaling pathway. In conclusion, EMMPRIN promotes host resistance against pseudomonas aeruginosa infection via MAPK signaling pathway. PMID- 28078033 TI - Bone marrow-derived mesenchymal stem cells reduce immune reaction in a mouse model of allergic rhinitis. AB - OBJECT: To determine the potential of bone marrow-derived mesenchymal stem cells (BMSCs) for immunomodulatory mechanism in mice model of allergic rhinitis (AR). METHODS: BMSCs were isolated and the surface markers and stemness were analyzed. The effect of BMSCs was evaluated in BALB/c mice that were randomly divided into three groups (control group, ovalbumin (OVA) group, OVA+BMSCs group). BMSCs were administered intravenously to OVA sensitized mice on days 1, 7, 14 and 21, and subsequent OVA challenge was conducted daily from days 22 to 35. Several parameters of allergic inflammation were assessed. RESULTS: Mesenchymal stem cells can be successfully isolated from bone marrow of mice. Intravenous injection of BMSCs significantly reduced allergic symptoms, eosinophil infiltration, OVA-specific immunoglobulin E (IgE), T-helper 2 (Th2) cytokine profile (interleukin (IL)-4, IL-5 and IL-13) and regulatory cytokines (IL-10). In addition, level of Th1 (IFN-gamma) was significantly increased. CONCLUSION: Administration of BMSCs effectively reduced allergic symptoms and inflammatory parameters in the mice model of AR. BMSCs treatment is potentially an alternative therapeutic modality in AR. PMID- 28078034 TI - Reactivated astrocytes as a possible source of oligodendrocyte precursors for remyelination in remitting phase of experimental autoimmune encephalomyelitis rats. AB - Multiple sclerosis (MS) is ademyelinating disease in the central nervous system (CNS). Majority of the MS patients show relapsing-remitting disease course. Evidences show that oligodendrocyte precursor cells (OPCs), which remain relatively quiescent in normal adult CNS, play a key role in the remitting phase by proliferation and remyelination. In the present study, we found that spinal cord astrocytesco-expressed progenitor cell marker and oligodendroglial lineage markers in the remittance phase in adult rat experimental autoimmune encephalomyelitis (EAE) model. We suggest that activated astrocyte could de differentiate into OPCs and re-differentiate into mature oligodendrocytes, raising the possibility that astrocytes can be a potential source of OPCs in the adult demyelinated spinal cord. PMID- 28078035 TI - Impact of perinatal exposure to acetaminophen on hepatocellular metabolic function in offspring. AB - Acetaminophen (APAP), an over the counter (OTC) medication, is widely used in antipyretic treatment. Although the risk of dose-dependent cytotoxicity has been known, the potential effect of perinatal exposure to acetaminophen on metabolic function in offspring remains uninvestigated. Therefore, we established a prenatally APAP-exposed pregnancy mouse model to assess the possible adverse effect on liver metabolic function in offspring. Biochemical assays were applied in analysis of basic metabolic parameters in postnatal mice. Further, immunoblotting assay was used to assess the expressions of insulin receptor beta (IRbeta), insulin receptor substrate 1 (IRS1), phospho-Akt and phospho-GSK-3beta proteins in liver cells. In addition, hepatic glucose transporter 2 (GLUT2) immunoactivity was determined by using immunohistochemistry staining. Compared with untreated postnatal mice, APAP-exposed offspring induced impaired glucose metabolism, increased plasma insulin level, and reduced liver glycogen content. In addition, APAP exposure decreased the expressions of IRS1 and phospho-GSK 3beta, phospho-AKT proteins and down-regulated the level of glucose-import regulator GLUT2 in the liver. Taken together, our preliminary findings indicate that perinatal APAP exposure-impaired hepatic glucose metabolism in offspring may be associated with disturbance of insulin-dependent AKT signaling in the liver. PMID- 28078036 TI - Combined thermosensitive in situ gel with AMD3100 in sutureless technique improves the survival and function of kidney transplants in mice. AB - The mouse is an optimal animal model for kidney transplantation. Recent reports suggest that application of poloxamer 407, a thermosensitive in situ gel, during the sutureless technique significantly increases animal survival, compared to traditional methods. However, further improvement of this technology is greatly needed but remains unexplored. Here, we detected significant inflammation at the region of ureter anastomosis, after kidney transplantation using poloxamer 407. Since chemokines play a pivotal role during inflammation, we implanted an Alzet osmotic pump that gradually releases AMD3100 (a specific inhibitor of the binding of stromal cell-derived factor 1 (SDF-1) to its receptor, CXCR4) at the site of ureter anastomosis in mice that had undergone kidney transplantation. We found that AMD3100 significantly reduced local inflammation, significantly improved animal survival after kidney transplantation, and significantly improved kidney function. Together, these data suggest that inhibition of chemokine signaling at the site of ureter anastomosis may substantially improve animal survival after kidney transplantation through suppression of suturing-related inflammation. PMID- 28078037 TI - Identification of chaperones in a MPP+-induced and ATRA/TPA-differentiated SH SY5Y cell PD model. AB - Parkinson's disease (PD) is characterized by the pathological accumulation of misfolded proteins. Molecular chaperones assist in the proper folding of proteins and removal of irreversibly misfolded proteins. This study aims to identify potential chaperones associated with protein misfolding and accumulation in PD. ATRA/TPA-differentiated SH-SY5Y cells were treated with 1 mM of MPP+ for 48 hours. Proteins were analyzed by 2D-DIGE followed by MALDI-ToF MS. The treatment of differentiated SH-SY5Y cells by MPP+ led to the unambiguous identification of 10 protein spots, which corresponds to six proteins. Among these six proteins, four were chaperone proteins including nucleophosmin (NPM1), chaperonin containing TCP-1 subunit 2 (CCT2 or CCTbeta), heat shock 90 kDa protein 1 beta (HSP90AB1 or HSP90-beta), and tyrosin3/tryptopha5-monoxygenase activation protein, zeta polypeptide (14-3-3zeta, gene symbol: Ywhaz). To our knowledge, this is the first report that linked the upregulation of chaperones after MPP+ treatment with SH-SY5Y cells. However, the NPM1 protein was identified for the first time in the PD model. The upregulation of four chaperone proteins provided evidence that these chaperones have a complementary effect on protein misfolding in the pathogenesis of PD, and hold promise as a good therapeutic target for PD treatment. PMID- 28078038 TI - Insulin resistance is associated with specific gut microbiota in appendix samples from morbidly obese patients. AB - Alterations in intestinal microbiota composition could promote a proinflammatory state in adipose tissue that is associated with obesity and insulin resistance. Our aim was to identify the gut microbiota associated with insulin resistance in appendix samples from morbidly obese patients classified in 2 groups, high (IR MO) and low insulin-resistant (NIR-MO), and to determine the possible association between these gut microbiota and variables associated with insulin resistance and the expression of genes related to inflammation and macrophage infiltration in adipose tissue. Appendix samples were obtained during gastric bypass surgery and the microbiome composition was determined by 16S rRNA pyrosequencing and bioinformatics analysis by QIIME. The Chao and Shannon indices for each study group suggested similar bacterial richness and diversity in the appendix samples between both study groups. 16S rRNA pyrosequencing showed that the IR-MO group had a significant increase in the abundance of Firmicutes, Fusobacteria, Pseudomonaceae, Prevotellaceae, Fusobacteriaceae, Pseudomonas, Catenibacterium, Prevotella, Veillonella and Fusobacterium compared to the NIR-MO group. Moreover, in the IR-MO group we found a significant positive correlation between the abundance of Prevotella, Succinovibrio, Firmicutes and Veillonella and the visceral adipose tissue expression level of IL6, TNF alpha, ILB1 and CD11b respectively, and significant negative correlations between the abundance of Butyricimonas and Bifidobacterium, and plasma glucose and insulin levels, respectively. In conclusion, an appendix dysbiosis occurs in IR-MO patients, with a loss of butyrate-producing bacteria, essential to maintenance of gut integrity, together with an increase in mucin-degrading bacteria and opportunistic pathogens. The microbiota present in the IR-MO group were related to low grade inflammation in adipose tissue and could be useful for developing strategies to control the development of insulin resistance. PMID- 28078039 TI - Inhibition of hepatic cells pyroptosis attenuates CLP-induced acute liver injury. AB - Pyroptosis is a programmed cell death associated with caspase-1 and accompanied by the secretion of a large number of pro-inflammatory cytokines. In the acute stage of sepsis, the release of several pro-inflammatory cytokines aggravates hepatic cell death, and acute liver injury is aggravated with the progress of the disease, resulting in acute liver failure with a very high mortality rate. The present study investigated the effect of inhibiting hepatic cell pyroptosis on the septic acute liver injury. Septic acute liver injury mice model was established by cecal ligation and puncture (CLP model). The liver tissues were assessed for inflammatory infiltration by HE, serum concentrations of ALT, AST, IL-1beta, and IL-18 were examined by ELISA, hepatic cell pyroptosis was determined by flow cytometry, and expressions of caspase-1 and NLRP3 were assessed by Western blot. CLP-induced acute liver injury was distinct at 24 h post-operation, with the highest hepatic cell pyroptosis rate. The pyroptosis rate and liver injury indexes were positively correlated. Western blot showed that the expressions of pyroptosis-related proteins, caspase-1, and NLRP3, were increased. Normal mouse hepatic cells were cultured in vitro and LPS+ATP introduced to establish the cell model of septic acute liver injury. The expressions of caspase-1, NLRP3, IL-1beta, and IL-18 in LPS+ATP group were significantly higher than the control group by Western blot and ELISA. The inhibitors of NLRP3 (Glyburide) and caspase-1 (AC-YVAD-CMK) alone or in combination were used to pre-treat the hepatic cells, which revealed that the pyroptosis rate was decreased and the cell damage alleviated. The in vivo assay in rats showed that post inhibitor treatment, the 10-days survival was significantly improved and the liver damage reduced. Therefore, inhibiting the hepatic cell pyroptosis could alleviate CLP-induced acute liver injury, providing a novel treatment target for septic acute liver injury. PMID- 28078040 TI - TLR4-dependent internalization of CX3CR1 aggravates sepsis-induced immunoparalysis. AB - Sepsis, the most severe manifestation of infection, poses a major challenge to health-care systems around the world. Limited ability to clean and remove the pathogen renders difficulty in septic patients to recover from the phase of immunoparalysis. The present study found the vital role of CX3CR1 internalization on sepsis-induced immunoparalysis. A mouse model with cecal ligation and puncture (CLP) and cell model with lipopolysaccharides (LPS) were employed to explore the relationship between CX3CR1 internalization and septic immunoparalysis. Immunoparalysis model in mice was established 4 days after CLP with significantly decreased proinflammatory cytokines. Flow cytometry analysis found a decreased surface expression of CX3CR1 during immunoparalysis, which was associated with reduced mRNA level and increased internalization of CX3CR1. G-protein coupled receptor kinase 2 (GRK2) and beta-arrestin2 were significantly increased during septic immunoparalysis and involved in the internalization of CX3CR1. TLR4-/- or TLR4 inhibitor-treated macrophages exhibited an inhibited expression of GRK2 and beta-arrestin2, along with reduced internalization of CX3CR1. Moreover, the knockdown of GRK2 and beta-arrestin2 inhibited the internalization of CX3CR1 and led to a higher response on the second hit, which was associated with an increased activation of NF-kappaB. The critical association between internalization of CX3CR1 and immunosuppression in sepsis may provide a novel reference for clinical therapeutics. PMID- 28078041 TI - Treatment of de-peritonealized intestine with 4DryField(r) PH prevents adhesions between non-resorbable intra-peritoneal hernia mesh and bowel. AB - BACKGROUND: Intraperitoneal onlay meshes (IPOM) can be associated with intestine to-mesh adhesion formation, implementing risks like pain, enterocutaneous fistula, infection, and female infertility. This study investigates, whether a treatment of impaired intestinum with the anti-adhesive and hemostyptic agent 4DryField(r) PH prevents adhesion formation. METHODS: In 20 male LEWIS rats uncoated polypropylene meshes were sewn to the inner abdominal wall and the cecum of the respective animal was de-peritonealized by peritoneal abrasion by a gauze swap, and meso-sutures ensured a constant contact of injured areas. Rats were treated with 4DryField(r) PH gel either premixed or applied as a powder with in situ transformation (100 mg powder plus 0.4 ml 0.9% saline solution). One week postoperatively, the extent of intestine-to-mesh adhesions and the quality of mesh ingrowth were evaluated macroscopically by two independent investigators using two scoring systems. Furthermore, specimens were analysed microscopically. All data were compared with control animals without 4DryField(r) PH treatment and analysed statistically using student's t-test. RESULTS: Treatment of de peritonealised cecum with 4DryField(r) PH significantly reduced intestine-to-mesh adhesions in both treatment groups as compared to controls without 4DryField(r) PH treatment (68% reduction with premixed gel, P<0.0001; 80% reduction with in situ gel, P<0.0001). There was no impact on the quality of mesh ingrowth, confirmed histologically by a single-layer mesothelial coverage. CONCLUSION: These experiments mimick clinical IPOM implantation scenarios with adjacent bowel depleted from peritoneum. 4DryField(r) PH gel treatment resulted in intestinal mesothelial surface recovering without development of bowel-to-mesh adhesions. Concurrently, integration of mesh into the abdominal wall is undisturbed by 4DryField(r) PH treatment. PMID- 28078042 TI - Immunoglobulin E induces colon cancer cell apoptosis via enhancing cyp27b1 expression. AB - The pathogenesis of colon cancer (Cca) is to be further investigated. Vitamin D deficiency is associated with cancer growth; the underlying mechanism is unclear. Published data indicate that Cca cells express CD23. This study tests a hypothesis that exposure to IgE induces Cca cell apoptosis. In this study, the effect of ligation of CD23 by IgE on the expression of cyp27b1 was performed with Cca cells. The induction of apoptosis of Cca cells by IgE was assessed in a cell culture model. We observed that Cca cells express CD23; ligation of CD23 with IgE on Cca cells increased the expression of cyp27b1 in Cca, which promoted the conversion of VD3 to calcitriol, the latter increased the expression of FasL by Cca cells, and induced apoptosis of Cca cells. In conclusion, IgE is capable of inducing the cancer cell apoptosis via ligating CD23 and converting VD3 to calcitriol. The results suggest that IgE may have therapeutic potential in the treatment of Cca. PMID- 28078043 TI - Inhibitory effect of miR-145 on RPE cell proliferation. AB - OBJECTIVE: This study aims to explore the impact of micro RNA miR-145 on retinal pigment epithelial cell proliferation and apoptosis. METHODS: A stable culture and passage system of hPNE cells was first established, and its migration ability was determined. Then, miR-145 lentiviral vectors were constructed to transfect hPRE cells. Thereafter, hRPE cell proliferation was detected by MTT assay after they were transfected by lentivirus, cell cycle was analyzed by flow cytometry, and apoptosis was detected by Annexin V/PI double staining immunofluorescence. RESULTS: Cultured hPRE cells had good migrating and metastatic ability, in which subsequent lentivirus infection experiments can be carried out. After transfection by miR-145 lentiviral vectors, hPRE cell proliferation slowed down and RPE cells in the G1 phase was inhibited; thus, apoptosis rate increased. CONCLUSION: MiR-145 can slow down retinal pigment epithelial cell proliferation and increase their apoptosis rate. This has a certain therapeutic potential for diseases caused by RPE cell proliferation such as PVR. PMID- 28078044 TI - Tumor profiling of co-regulated receptor tyrosine kinase and chemoresistant genes reveal different targeting options for lung and gastroesophageal cancers. AB - The expression of a number of genes can influence the response rates to chemotherapy while genes encoding receptor tyrosine kinases (RTKs) determine the response to most targeted cancer therapies currently used in clinics. In this study, we evaluated seven genes known to influence chemotherapeutic response (ERCC1, BRCA1, RRM1, TUBB3, STMN1, TYMS, and TOP2A) and five RTKs (EGFR, ERBB2, PDGFRB, VEGFR1 and VEGFR2) in non-small cell lung cancer (NSCLC) and esophagus cancer (EC) and the data are compared to gastric cancer (GC) data reported previously. We demonstrate significant differences in the expression profiles between different cancer types as well as heterogeneity among patients within the same cancer type. In all three cancer types, five chemoresistant genes (TOP2A, STMN1, TYMS, BRCA1 and RRM1) are coordinately up-regulated in almost all EC, approximately 90% of NSCLC and one third of GC patients. Most EC and nearly half of GC patients have increased expression of the three RTKs critical to angiogenesis (PDGFR, VEGFR1 and VEGFR2), while almost none of the NSCLC patients have elevated expression of angiogenic RTKs. A variable percentage of patients in the three cancer types show upregulation of the EGFR family RTKs, EGFR and/or ERBB2. It is of interest to note that approximately 10% of the NSCLC and GC patients are triple-negative for the chemosensitivity genes, angiogenic and EGFR RTK genes. The results suggest significant gene expression differences between different cancer types as well as heterogeneity within each cancer type and therefore different molecules should be targeted for future drug development and clinical trials. PMID- 28078045 TI - The correlation and clinical implication of VEGF-C expression in microvascular density and lymph node metastasis of gastric carcinoma. AB - As the most common malignant tumor, gastric cancer had persistently high occurrence and mortality rate worldwide. Unfavorable treating outcome occur due to distal metastasis, making the inhibition of angiogenesis and managing tumor metastasis being crucial factors for affecting prognosis. Vascular endothelial growth factor-C (VEGF-C) is one important angiogenesis factor and mainly facilitates proliferation and differentiation of vascular endothelial cells in angiogenesis. It has been indicated in development and occurrence in gastric cancer, while its expression and correlation with microvascular density (MVD)/lymph node metastasis are still unclear. A total of 52 gastric tumor and 25 normal tissue samples were recruited for quantifying mRNA and protein expression of VEGF-C by real-time PCR and Western blotting. MVD and lymph tube density were quantified for further analysis of the correlation between VEGF-C and pathological parameters including clinical stage and lymph node metastasis. Both mRNA and protein levels of VEGF-C were significantly elevated in gastric tissues (p<0.05). In lymph node metastasis cases, VEGF-C was further potentiated compared to non-metastatic group (p<0.05). VEGF-C expression was positively correlated with MVD, lymph tube density and clinical stage (p<0.05) but not with age, sex or differentiation grade. VEGF-C expression is closely correlated with lymph node metastasis of gastric cancer. It may participate in the progression of gastric cancer via facilitating angiogenesis and lymph node metastasis, thus can be used in predicting prognosis of patients with gastric carcinoma. PMID- 28078046 TI - Effects of etomidate and propofol on immune function in patients with lung adenocarcinoma. AB - OBJECTIVE: To investigate the effects of etomidate and propofol on immune function in patients with lung adenocarcinoma. METHODS: Sixty patients who were scheduled for lung cancer surgery under general anesthesia were studied. The patients were randomly divided into an etomidate total intravenous anesthesia group (group E) and a propofol total intravenous anesthesia group (group P), with 30 cases in each group. RESULTS: Within group comparison: The percentage of CD4+ in the two groups was significantly reduced at 24 hours post-operation (T2) compared with the percentage before surgery, whereas the percentage of CD8+ was higher at T2. Between group comparison: The CD4+ percentage of group E was higher than that of group P (P < 0.05) at T2, whereas the CD8+ percentage was lower than that of group P (P < 0.05) at T1. CONCLUSION: Using etomidate for anesthesia has less of an effect on immune function in patients with lung adenocarcinoma. PMID- 28078047 TI - Inhibition of NF-kappaB with Dehydroxymethylepoxyquinomicin modifies the function of human peritoneal mesothelial cells. AB - Peritoneal mesothelial cells exposed to bioincompatible dialysis fluids contribute to damage of the peritoneum during chronic dialysis. Inflammatory response triggered in the mesothelium leading to neovascularization and fibrosis plays an important role in that process. We studied the effects of Dehydroxymethyepoxyquinmicin (DHMEQ)-an NF-kappaB inhibitor on function of human peritoneal mesothelial cells (HPMC) in in vitro culture. DHMEQ studied in concentrations of 1-10 ug/ml was not toxic to HPMC. Synthesis of IL-6, MCP-1 and hyaluronan in unstimulated and stimulated with interleukin-1 (100 pg/ml) HPMC was inhibited in the presence of DHMEQ and the effect was proportional to the dose of the drug. DHMEQ (10 ug/ml) reduced in unstimulated HPMC synthesis of IL-6 (-55%), MCP-1 (-58%) and hyaluronan (-41%). Respective values for stimulated HMPC were: 63% for IL-6, -57% for MCP-1 and -67% for hyaluronan. The observed effects were due to the suppression of the expression of genes responsible for the synthesis of these molecules. DHMEQ modified the effects of the effluent dialysates from CAPD patients on the function of HMPC. Dialysate induced accelerated growth of these cells, and synthesis of collagen was inhibited in the presence of DHMEQ 10 ug/ml, by 69% and 40%, respectively. The results of our study show that DHMEQ effectively reduces inflammatory response in HMPC and prevents excessive dialysate induced proliferation and collagen synthesis in these cells. All of these effects may be beneficial during chronic peritoneal dialysis and prevents progressive dialysis-induced damage to the peritoneum. PMID- 28078048 TI - Post-transcriptional regulation of interleukin-10 in peripheral B cells of airway allergy patients. AB - The dysfunction of peripheral immune tolerance plays an important role in the pathogenesis of allergic diseases. Recent reports indicate that micro RNA (miR) 98 is associated with the process of aberrant immune responses. This study aims to test a hypothesis that miR-98 is associated with the pathogenesis of airway allergy via interfering with the development of regulatory B cells (Breg). In this study, patients with airway allergy were recruited into this study. The frequency of Bregs was assessed by flow cytometry. The levels of miR-98 in peripheral B cells were determined by RT-qPCR. A cell-culture model of B cells was developed to test the role of miR-98 in the repressing of interleukin (IL)-10 in B cells. The results showed that the levels of IL-10 in peripheral B cells were significantly lower in patients with airway allergy as compared with healthy subjects. High levels of miR-98 (one of the miR-98 members) were detected in peripheral B cells of patients with airway allergy, which was mimicked by stimulating B cells with IL-4. Histone acetyltransferase p300 was involved in the IL-4-induced miR-98 expression. miR-98 mediated the IL-4-inhibited IL-10 expression in B cells. In conclusion, miR-98 affects the expression of IL-10 in B cells and may be a novel therapeutic target for the treatment of allergic diseases. PMID- 28078049 TI - M1 macrophages promote aortic valve calcification mediated by microRNA-214/TWIST1 pathway in valvular interstitial cells. AB - OBJECTIVE: The identification of the biological function of M1 macrophages and the mechanism underlying their role in valvular interstitial cell (VIC) calcification may provide therapeutic targets for the prevention of aortic valve calcification (AVC). This study investigated the mechanism by which M1 macrophages and macrophage-derived microvesicles (MVs) affected the calcification of VICs. An additional aim was to investigate the involvement of the miR-214 pathway in this process. METHODS: The M1 or M2 macrophage phenotype in human calcific aortic valve was confirmed by gene expression analysis of M1 or M2 macrophage markers. Two macrophage cell lines (BMDMs and RAW 264.7 macrophages) were transformed into M1 macrophages by lipopolysaccharide (LPS) stimulation. To investigate the mechanism by which M1 macrophages promoted VIC calcification, the generated M1 macrophages and macrophage-derived MVs were co-cultured with VICs and VICs were then used for calcification or signals analysis. In addition, a hypercholesterolemic apoE-/- AVC murine model was used to evaluate the therapeutic efficacy of miR-214 specific-siRNA (miR-214 inhibitor). RESULTS: Macrophages in calcific aortic valves showed M1-directed polarization. In the VICs co-cultured with LPS-stimulated M1 macrophages and macrophage-derived MVs, VIC calcification was enhanced, and the expression of TWIST1, a direct target of miR-214, was downregulated. We showed that knockdown of TWIST1 serves as a responding molecule for miR-214 and reversed the anti-calcification action of miR 214 inhibitor, mediating signal delivery by the M1 macrophage-derived MVs to VICs and promoting VIC calcification. When M1 macrophages co-cultured with VICs, TWIST1 overexpression in M1 macrophages had no effect on the expression of TWIST1 in VICs. As shown by intravenous therapy, knockdown of miR-214 in mice seemed to improve AVC in apoE-/- mice with high-cholesterol (HC)-diet induced AVC. CONCLUSIONS: These findings suggested that M1 macrophages promoted AVC by the delivery of miR-214 to valvular interstitial cells via macrophage-derived MVs and subsequent downregulation of TWIST1 of valvular interstitial cells. PMID- 28078051 TI - Complete genome sequence of Pseudomonas brassicacearum strain L13-6-12, a biological control agent from the rhizosphere of potato. AB - Pseudomonas brassicacearum strain L13-6-12 is a rhizosphere colonizer of potato, lettuce and sugar beet. Previous studies have shown that this motile, Gram negative, non-sporulating bacterium is an effective biocontrol agent against different phytopathogens. Here, we announce and describe the complete genome sequence of P. brassicacearum L13-6-12 consisting of a single 6.7 Mb circular chromosome that consists of 5773 protein coding genes and 85 RNA-only encoding genes. Genome analysis revealed genes encoding specialized functions for pathogen suppression, thriving in the rhizosphere and interacting with eukaryotic organisms. PMID- 28078050 TI - Complete genome sequence of Lutibacter profundi LP1T isolated from an Arctic deep sea hydrothermal vent system. AB - Lutibacter profundi LP1T within the family Flavobacteriaceae was isolated from a biofilm growing on the surface of a black smoker chimney at the Loki's Castle vent field, located on the Arctic Mid-Ocean Ridge. The complete genome of L. profundi LP1T is the first genome to be published within the genus Lutibacter. L. profundi LP1T consists of a single 2,966,978 bp circular chromosome with a GC content of 29.8%. The genome comprises 2,537 protein-coding genes, 40 tRNA species and 2 rRNA operons. The microaerophilic, organotrophic isolate contains genes for all central carbohydrate metabolic pathways. However, genes for the oxidative branch of the pentose-phosphate-pathway, the glyoxylate shunt of the tricarboxylic acid cycle and the ATP citrate lyase for reverse TCA are not present. L. profundi LP1T utilizes starch, sucrose and diverse proteinous carbon sources. In accordance, the genome harbours 130 proteases and 104 carbohydrate active enzymes, indicating a specialization in degrading organic matter. Among a small arsenal of 24 glycosyl hydrolases, which offer the possibility to hydrolyse diverse poly- and oligosaccharides, a starch utilization cluster was identified. Furthermore, a variety of enzymes may be secreted via T9SS and contribute to the hydrolytic variety of the microorganism. Genes for gliding motility are present, which may enable the bacteria to move within the biofilm. A substantial number of genes encoding for extracellular polysaccharide synthesis pathways, curli fibres and attachment to surfaces could mediate adhesion in the biofilm and may contribute to the biofilm formation. In addition to aerobic respiration, the complete denitrification pathway and genes for sulphide oxidation e.g. sulphide:quinone reductase are present in the genome. sulphide:quinone reductase and denitrification may serve as detoxification systems allowing L. profundi LP1T to thrive in a sulphide and nitrate enriched environment. The information gained from the genome gives a greater insight in the functional role of L. profundi LP1T in the biofilm and its adaption strategy in an extreme environment. PMID- 28078052 TI - Dose-rate plays a significant role in synchrotron radiation X-ray-induced damage of rodent testes. AB - Synchrotron radiation (SR) X-ray has significant potential for applications in medical imaging and cancer treatment. However, the mechanisms underlying SR X-ray induced tissue damage remain unclear. Previous studies on regular X-ray-induced tissue damage have suggested that dose-rate could affect radiation damage. Because SR X-ray has exceedingly high dose-rate compared to regular X-ray, it remains to be determined if dose-rate may affect SR X-ray-induced tissue damage. We used rodent testes as a model to investigate the role of dose-rate in SR X-ray induced tissue damage. One day after SR X-ray irradiation, we determined the effects of the irradiation of the same dosage at two different dose-rates, 0.11 Gy/s and 1.1 Gy/s, on TUNEL signals, caspase-3 activation and DNA double-strand breaks (DSBs) of the testes. Compared to those produced by the irradiation at 0.11 Gy/s, irradiation at 1.1 Gy/s produced higher levels of DSBs, TUNEL signals, and caspase-3 activation in the testes. Our study has provided the first evidence suggesting that dose-rate could be a significant factor in SR X-ray-induced tissue damage, which may establish a valuable base for utilizing this factor to manipulate the tissue damage in SR X-ray-based medical applications. PMID- 28078053 TI - Amyloid beta peptide 22-35 induces a negative inotropic effect on isolated rat hearts. AB - Evidences indicate that deposition of amyloid beta peptides (Abetas) plays an important role in the pathogenesis of Alzheimer disease. Abetas may influence cardiovascular system and ileum contractions. But the effect of amyloid beta peptide 22-35 (Abeta22-35) on cardiovascular functions and contractions of ileum has not been studied. Therefore, the present study aimed to investigate the possible effects of this peptide on isolated rat heart and ileum smooth muscle. Langendorff-perfused rat heart preparations were established. The hearts were perfused under constant pressure (60 mmHg) with modified Krebs-Henseleit solution. Abeta22-35 at doses of 1, 10 and 100 nM significantly decreased left ventricular developed pressure (LVDP; an index of cardiac contractility) and maximal rate of pressure development of left ventricle (+dP/dtmax; another index of cardiac contractility). This peptide at doses studied had no significant effect on heart rate, coronary flow, monophasic action potential amplitude (MAPamp), MAP duration at 90% repolarization (MAP90) and ileum contractions. We suggest that Abeta22-35 exerts a negative inotropism on isolated rat hearts with unchanged heart rate, coronary flow, MAPamp, MAP90 and smooth muscle contractility of ileum. PMID- 28078054 TI - The effect of thymoquinone on the renal functions following ischemia-reperfusion injury in the rat. AB - INTRODUCTION: The aim of this study was to investigate the effect of thymoquinone, an antioxidant phytochemical compound found in the plant Nigella sativa, on the alterations in renal functional parameters following warm renal ischemia-reperfusion injury (IRI) in the rat. METHODS: Wistar rats underwent left renal ischemia for 35 minutes. Group-TQ (n=15) received thymoquinone 10 mg/kg/day (dissolved in a vehicle (corn oil) orally by gavage starting 4 days prior to IRI and continued 6 days thereafter when the hemodynamic and tubular renal functions of the right and left kidneys were measured using clearance techniques. Group-Vx (n=15) underwent similar protocol but received only the vehicle. RESULTS: IRI affected all hemodynamic and tubular parameters in the affected kidney. Thymoquinone attenuated the IRI-related alteration in renal functions so when the left ischemic kidney in Group-TQ and Group-Vx were compared, the left RBF and GFR were significantly higher in Group-TQ (2.02+/-0.39 vs. 1.27+/-0.21, P=0.04 and 0.33+/-0.08 vs. 0.18+/-0.03, P=0.03, respectively). Thymoquinone also improved left renal FENa (1.59+/-0.28 vs. 2.40+/-0.35, P=0.04). In addition, it decreased the gene expressions of KIM-1, NGAL, TNF-alpha, TGF-beta1 and PAI-1 (143+/-20 vs. 358+/-49, 16+/-3 vs. 34+/-6, (1.1+/-0.2 vs. 2.8+/-0.4, 1.6+/-0.1 vs. 2.8+/-0.1, and 2.4+/-0.3 vs. 5.8+/-1.0, P<0.05 for all). CONCLUSION: Thymoquinone ameliorated the IRI effect on the hemodynamic and tubular renal functional parameters as well as the expression of some kidney injury markers and pro inflammatory and pro-fibrotic cytokines indicating a renoprotective effect of this agent on the IRI-induced renal dysfunction with potential clinical implications. PMID- 28078055 TI - Comparative changes in antioxidant enzymes and oxidative stress in cardiac, fast twitch and slow twitch skeletal muscles following endurance exercise training. AB - The aim of this study was to evaluate exercise-induced transcriptional and protein responses of heart, soleus (slow oxidative), and plantaris (fast glycolytic) muscle in response to ten days of endurance exercise training. Four month old female Sprague-Dawley rats were assigned to either a sedentary (SED) or endurance exercise-training (EXE) group (n=8 per group). The heart, plantaris, and soleus were excised and used for biochemical analyses. Our results show that heart and plantaris from EXE animals had higher protein levels of superoxide dismutase 2 (SOD2) compared to SED animals (P<0.05). Also, the protein levels of catalase were higher in plantaris of EXE animals compared to SED animals (P<0.05). No significant differences existed for 4 hydroxynonenal (4HNE) conjugated proteins (index of oxidative damage) in the three tissues between SED and EXE animals. mRNA levels of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1alpha) were higher in plantaris of EXE animals compared to SED animals (P<0.05), and mRNA levels of estrogen-related receptor alpha (ERRalpha) were lower in the heart of EXE animals compared to SED animals. In conclusion, heart and plantaris are responsive to ten days of treadmill training, while greater exercise intensities or durations may be needed to elicit alterations in soleus. PMID- 28078056 TI - Proton pump inhibitor-induced hypomagnesaemia and hypocalcaemia: case review. AB - Proton pump inhibitor (PPI)-induced hypomagnesaemia is a rare but serious adverse effect of a widely prescribed medication. It has become an increasingly recognised complication since 2006, with the U.S. Food and Drug Administration issuing a warning for this risk with regards to long-term PPI use. We present the case of PPI-associated hypomagnesaemia and hypocalcaemia. A 91 year old male presented with tetany from severe hypomagnesaemia and hypocalcaemia. This condition occurred in the context of 18 months of PPI use, and resolved following cessation of PPI therapy and the replenishment of magnesium and calcium stores. Monitoring of magnesium, calcium and potassium levels is crucial in patients prescribed PPIs long-term; especially the elderly patient. PMID- 28078057 TI - The advancements of heparanase in fibrosis. AB - Fibrosis is the endpoint in many chronic inflammatory diseases and is defined as an abnormal accumulation of extracellular matrix components. Fibrosis can affect almost any tissue, especially heart, lung, liver, and kidney, and numerous studies have been conducted to find satisfactory treatments. Since heparanase is a kind of endo-beta-D-glucuronidase that is capable of cleaving heparan sulfate side chains of heparan sulfate proteoglycans on cell surfaces and the extracellular matrix, which further regulate the bioavailability of growth factors (FGF-2, TGF-beta). Meanwhile, FGF-2 and TGF-beta play a major role in the fibrosis process. Recent studies including ours have consistently demonstrated that heparanase could promote fibrosis process in different organs. Thus in this mini-review, we updated the advancement of heparanase in the regulation of fibrosis generation, and discussed its impact on several critical signaling pathways relevant to fibrosis. PMID- 28078058 TI - Colonization Rate and Risk Factors of Vancomycin-Resistant Enterococci among Patients Received Hematopoietic Stem Cell Transplantation in Shiraz, Southern Iran. AB - BACKGROUND: Infections caused by antimicrobial-resistant bacteria are associated with increased mortality and health care costs. Enterococci have been recognized as a clinically important pathogen in hospitalized patients. Vancomycin-resistant enterococci (VRE) infections cause significant morbidity and mortality among patients undergoing transplantation. OBJECTIVE: To identify epidemiology of VRE colonization and related risk factors among patients with hematological malignancies after hematopoietic stem cell transplantation (HSCT). METHODS: This cross-sectional study was performed on 42 patients who underwent bone-marrow transplantation between July 2013 and March 2014. A stool sample was taken from each patient 3-5 days after transplantation and cultured on appropriate media. Suspected colonies of enterococci were detected to species level by their culture characteristics, biochemical reactions and molecular features. VRE were confirmed via phenotypic and genotypic methods. RESULTS: VRE were detected in 14 (33%) of studied samples. 10 (71%) of the detected VRE isolates were identified as high level vancomycin-resistant E. faecium with minimum inhibitory concentration (MIC) of >=256 MUg/mL of vancomycin; 3 isolates were E. galinarum and 1 was E. casseliflavus with an MIC of 8-16 MUg/mL. VanA was dominant phenotype and all VRE isolates with high-level of vancomycin resistance had vanA gene. VRE isolation was mostly observed in patients with acute lymphoblastic leukemia (ALL) than other diseases. Moreover, antibiotic prophylaxis and hospitalization were independent risk factors for acquisition of VRE after transplantation. CONCLUSION: We found high level of vancomycin-resistance in E. faecium isolates obtained from HSCT patients. The vancomycin-resistant isolates of E.faecium had vanA and/or simultaneously vanB genes. PMID- 28078059 TI - Identification of Candida Species Isolated from Renal Transplant Recipients with Candiduria. AB - BACKGROUND: Renal transplantation has long been considered the gold standard medical care for patients with end-stage renal disease. Candiduria continue to be a significant complication for renal transplant recipients. The risk of infections depends on the amount of immunosuppression and exposure to the potential pathogens. OBJECTIVE: Molecular identification of Candida species isolated from renal transplant recipients with candiduria. METHODS: Between 2009 and 2014, 62 Candida isolates were collected from 485 renal transplant recipients. All isolates were identified by PCR-RFLP profiles after digestion with the restriction enzyme MspI. RESULTS: C. albicans (44%) and C. parapsilosis complex (5%) had the most and the least prevalence, respectively. Male to female ratio was 26/36, ranging in age from 19 to 62 years. CONCLUSION: Due to the fact that candiduria is connected with increased mortality in renal transplant recipients, precise identification of Candida species by molecular techniques can lead to an appropriate therapy among high risk patients. C. albicans remains the most prevalent species isolated from renal transplant recipients, Nevertheless, the number of non-C. albicans Candida species looks to be emerging. PMID- 28078060 TI - Natural Killer Cell Subsets and IL-2, IL-15, and IL-18 Genes Expressions in Chronic Kidney Allograft Dysfunction and Graft Function in Kidney Allograft Recipients. AB - BACKGROUND: While acute rejection and early graft loss rates have decreased substantially over the past four decades, progressive chronic allograft dysfunction (CAD) still remains a common cause of late graft loss in kidney transplant recipients. OBJECTIVE: This study was conducted to investigate the percentage of natural killer (NK) cell subsets and IL-2, 15 and 18 genes expression in two groups of CAD and well-function graft (WFG) recipients. METHODS: 30 renal allograft recipients with biopsy-proven interstitial fibrosis/tubular atrophy (IF/TA) and impaired renal function, and 30 sex- and age matched WFG patients were enrolled in this study. The percentage of NK cell subsets including NK CD56bright and NK CD56dim cells were determined by flowcytometry; IL-2, IL-15, and IL-18 genes expressions were assessed by real time PCR. RESULTS: Compared to WFG patients, there was a significant (p<0.05) increase in the percentage of NK CD56bright cells in CAD patients. However, the difference in percentage of NK CD56dim cells or CD56dim/CD56bright ratio between the studied groups was not significant. In addition, IL-2, 15 and 18 genes expressions were almost similar in CAD and WFG patients. CONCLUSION: We found higher percentages of NK CD56bright subset in kidney transplant recipients with CAD without considerable changes in related cytokines' gene expression, suggesting a possible defect of NK cells maturation in these patients. PMID- 28078061 TI - The First Experience of Ex-Vivo Lung Perfusion (EVLP) in Iran: An Effective Method to Increase Suitable Lung for Transplantation. AB - BACKGROUND: Although lung transplantation is a well-accepted treatment for end stage lung diseases patients, only 15%-20% of the brain-dead donors' lungs are usable for transplantation. This results in high mortality of candidates on waiting lists. Ex-vivo lung perfusion (EVLP) is a novel method for better evaluation of a potential lung for transplantation. OBJECTIVE: To report the first experience of EVLP in Iran. METHODS: The study included a pig in Vienna Medical University, Vienna, Austria, and 4 humans in Masih Daneshvari Hospital, Tehran, Iran. All brain-dead donors from 2013 to 2015 in Tehran were evaluated for EVLP. Donors without signs of severe chest trauma or pneumonia, with poor oxygenation were included. RESULTS: An increasing trend in difference between the pulmonary arterial pO2 and left atrial pO2, an increasing pattern in dynamic lung compliance, and a decreasing trend in the pulmonary vascular resistance, were observed. CONCLUSION: The initial experience of EVLP in Iran was successful in terms of important/critical parameters. The results emphasize on some important considerations such as precisely following standard lung harvesting and monitoring temperature and pressure. EVLP technique may not be a cost-effective option for low-income countries at first glance. However, because this is the only therapeutic treatment for end-stage lung disease, it is advisable to continue working on this method to find alternatives with lesser costs. PMID- 28078062 TI - Left-Sided Inferior Vena Cava Encountered During Organ Retrieval Surgery: Report of Two Cases. AB - Left-sided inferior vena cava (IVC) is the second most common anatomical anomaly of the IVC after duplication. Herein, we present two cases of left-sided IVC, diagnosed during organ retrieval procedure. In a young brain-dead man, a single left-sided IVC was observed; it originated from iliac confluence in the left side of the aorta and extended throughout the abdomen. There was no retrohepatic IVC in the patient; hepatic veins drained directly into the right atrium. The second case was a brain-dead young woman with a left-sided IVC originated from iliac confluence to the kidney level; then, the IVC crossed anterior to the abdominal aorta to join a normally positioned retrohepatic IVC. In cases of retroperitoneal surgeries, IVC anomalies should be considered during preoperative imaging studies, because they may be misdiagnosed as para-aortic lymphadenopathy, tumor or dilated gonadal vein that may result in iatrogenic damage during surgery. PMID- 28078063 TI - Anesthetic Management of a Patient with DRESS Syndrome for Renal Transplantation. AB - Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but potentially life-threatening hypersensitivity reaction characterized by widespread erythematous skin eruptions with fever, lymphadenopathy and visceral involvement-hepatitis, nephritis, pericarditis, and pneumonitis. There are numerous reports describing the management of such patients in intensive care units but hardly any describing the intraoperative anesthetic management of such patients. Herein, we report on a patient with DRESS syndrome who was scheduled for renal transplantation. The main goal in this case was to prevent a hypersensitive drug reaction intraoperatively and develop a safe alternative anesthesia plan for the patient. After pre-operative skin and intradermal tests, we chose the drugs that could be safely used for anesthesia. Usually general anesthesia is preferred for renal transplantation but in this patient we opted for combined spinal epidural anesthesia. Precautions that are to taken in such a case and the anesthetic management are discussed in detail herewith. PMID- 28078064 TI - BK Virus and Nephropathy in Kidney Transplant Recipients. PMID- 28078065 TI - Clinical Features of Neuromuscular Disorders in Patients with N-Type Voltage Gated Calcium Channel Antibodies. AB - Neuromuscular junction disorders affect the pre- or postsynaptic nerve to muscle transmission due to autoimmune antibodies. Members of the group like myasthenia gravis and Lambert-Eaton syndrome have pathophysiologically distinct characteristics. However, in practice, distinction may be difficult. We present a series of three patients with a myasthenic syndrome, dropped-head syndrome, bulbar and respiratory muscle weakness and positive testing for anti-N-type voltage-gated calcium channel antibodies. In two cases anti-acetylcholin receptor antibodies were elevated, anti-P/Q-type voltage-gated calcium channel antibodies were negative. All patients initially responded to pyridostigmine with a non response in the course of the disease. While one patient recovered well after treatment with intravenous immunoglobulins, 3,4-diaminopyridine, steroids and later on immunosuppression with mycophenolate mofetil, a second died after restriction of treatment due to unfavorable cancer diagnosis, the third patient declined treatment. Although new antibodies causing neuromuscular disorders were discovered, clinical distinction has not yet been made. Our patients showed features of pre- and postsynaptic myasthenic syndrome as well as severe dropped head syndrome and bulbar and axial muscle weakness, but only anti-N-type voltage gated calcium channel antibodies were positive. When administered, one patient benefited from 3,4-diaminopyridine. We suggest that this overlap-syndrome should be considered especially in patients with assumed seronegative myasthenia gravis and lack of improvement under standard therapy. PMID- 28078067 TI - alpha-Linolenic Acid Reduces TNF-Induced Apoptosis in C2C12 Myoblasts by Regulating Expression of Apoptotic Proteins. AB - Impaired regeneration and consequent muscle wasting is a major feature of muscle degenerative diseases. Nutritional interventions such as adjuvant strategy for preventing these conditions are recently gaining increasing attention. Ingestion of n3-polyunsaturated fatty acids has been suggested as having a positive impact on muscle diseases. We recently demonstrated that a diet enriched with plant derived n3-fatty acid, alpha-linolenic acid (ALA), exerts potent beneficial effects in preserving skeletal muscle regeneration in models of muscle dystrophy. To better elucidate the underlying mechanism we here investigate on the expression level of the anti- and pro-apoptotic proteins, as well as caspase-3 activity, in C2C12 myoblasts challenged with pathological levels of tumor necrosis factor-alpha (TNF). The results demonstrated that ALA protective effect on C2C12 myoblasts was associated with a decrease in caspase-3 activity and an increase of the Bcl-2/Bax ratio. Indeed, the effect of ALA was directed to rescuing Bcl-2 expression and to revert Bax translocation to mitochondria both affected in an opposite way by TNF, a major pro-inflammatory cytokine expressed in damaged skeletal muscle. Therefore, ALA counteracts inflammatory signals in the muscle microenvironment and may represent a valuable strategy for ameliorating skeletal muscle pathologies. PMID- 28078066 TI - Use it or Lose It: Tonic Activity of Slow Motoneurons Promotes Their Survival and Preferentially Increases Slow Fiber-Type Groupings in Muscles of Old Lifelong Recreational Sportsmen. AB - : Histochemistry, immuno-histochemistry, gel electrophoresis of single muscle fibers and electromyography of aging muscles and nerves suggest that: i) denervation contributes to muscle atrophy, ii) impaired mobility accelerates the process, and iii) lifelong running protects against loss of motor units. Recent corroborating results on the muscle effects of Functional Electrical Stimulation (FES) of aged muscles will be also mentioned, but we will in particular discuss how and why a lifelong increased physical activity sustains reinnervation of muscle fibers. By analyzing distribution and density of muscle fibers co expressing fast and slow Myosin Heavy Chains (MHC) we are able to distinguish the transforming muscle fibers due to activity related plasticity, to those that adapt muscle fiber properties to denervation and reinnervation. In muscle biopsies from septuagenarians with a history of lifelong high-level recreational activity we recently observed in comparison to sedentary seniors: 1. decreased proportion of small-size angular myofibers (denervated muscle fibers); 2. considerable increase of fiber-type groupings of the slow type (reinnervated muscle fibers); 3. sparse presence of muscle fibers co-expressing fast and slow MHC. Immuno-histochemical characteristics fluctuate from those with scarce fiber type modulation and groupings to almost complete transformed muscles, going through a process in which isolated fibers co-expressing fast and slow MHC fill the gaps among fiber groupings. Data suggest that lifelong high-level exercise allows the body to adapt to the consequences of the age-related denervation and that it preserves muscle structure and function by saving otherwise lost muscle fibers through recruitment to different slow motor units. This is an opposite behavior of that described in long term denervated or resting muscles. These effects of lifelong high level activity seems to act primarily on motor neurons, in particular on those always more active, i.e., on the slow motoneurons. The preferential reinnervation that follows along decades of increased activity maintains neuron and myofibers. All together the results open interesting perspectives for applications of FES and electroceuticals for rejuvenation of aged muscles to delay functional decline and loss of independence that are unavoidable burdens of advanced aging. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01679977. PMID- 28078068 TI - Efficacy of EMG/Bioimpedance-Triggered Functional Electrical Stimulation on Swallowing Performance. AB - In order to support swallowing, the efficacy of functional electrical stimulation for different stimulation settings of the submental musculature has been investigated. The stimulation was administrated at rest and synchronously to voluntary initiated swallows. The onset of a swallow was detected in real-time by a combined electromyography/ bioimpedance measurement at the neck in order to trigger the stimulation. The amplitude and speed of larynx elevation caused by the FES has been assessed by the observed change in bioimpedance whereas a reduction of bioimpedance corresponds to an increase in larynx elevation. Study results from 40 healthy subjects revealed that 73% of the subjects achieved a larger and faster larynx elevation during swallowing with triggered FES and therefor a better protection of their airways. However, we also observed a decrease in larynx elevation compared to normal swallowing in 11 out of the 40 subjects what might not benefit from such a treatment. The largest improvement of larynx elevation and speed during swallowing could be achieved with three stimulation channels formed by four electrodes in the submental region. PMID- 28078069 TI - Skeletal Muscle Microalterations in Patients Carrying Malignant Hyperthermia Related Mutations of the e-c Coupling Machinery. AB - We have compared the ultrastructure of skeletal muscle biopsies from patients that have survived a [Malignant Hyperthermia, MH] episode and siblings that test positive for MH susceptibility with those from siblings that tested negatives. The aim is to establish whether life long exposure to the MH-related mutation effects may result in subtle abnormalities even in the absence of active episodes and/or clinically detectable deficiencies. Although a specific ultrastructural signature for MH mutants cannot be demonstrated, an MH related pattern of minor alterations does exist. These include the tendency for micro damage to the contractile apparatus and a higher than normal level of mitochondrial abnormalities. PMID- 28078070 TI - Stem Cells and Tissue Niche: Two Faces of the Same Coin of Muscle Regeneration. AB - Capacity of adult muscle to regenerate in response to injury stimuli represents an important homeostatic process. Regeneration is a highly coordinated program that partially recapitulates the embryonic developmental program. However, muscle regeneration is severely compromised in several pathological conditions. It is likely that the restricted tissue repair program under pathological conditions is due to either progressive loss of stem cell populations or to missing signals that limit the damaged tissues to efficiently activate a regenerative program. It is therefore plausible that loss of control over these cell fates might lead to a pathological cell transdifferentiation, limiting the ability of a pathological muscle to sustain an efficient regenerative process. The critical role of microenvironment on stem cells activity and muscle regeneration is discussed. PMID- 28078071 TI - Electrical Stimulation to Reduce the Overload in Upper Limbs During Sitting Pivot Transfer in Paraplegic: A Preliminary Study. AB - Transfer is a key ability and allows greater interact with the environment and social participation. Conversely, paraplegics have great risk of pain and injury in the upper limbs due to joint overloads during activities of daily living, like transfer. The main goal of this study is to verify if the use of functional electrical stimulation (FES) in the lower limbs of paraplegic individuals can assist the sitting pivot transfer (SPT). The secondary objective is to verify if there is a greater participation of the lower limbs during lift pivot phase. A preliminary study was done with one complete paraplegic individual. Temporal parameters were calculated and a kinetic assessment was done during the SPT. The preliminary results showed the feasibility of FES for assisting the SPT. PMID- 28078072 TI - Multisensor Classification System for Triggering FES in Order to Support Voluntary Swallowing. AB - In dysphagia the ability of elevating the larynx and hyoid is usually impaired. Electromyography (EMG) and Bioimpedance (BI) measurements at the neck can be used to trigger functional electrical stimulation (FES) of swallowing related muscles. Nahrstaedt et al.1 introduced an algorithm to trigger the stimulation in phase with the voluntary swallowing to improve the airway closure and elevation speed of the larynx and hyoid. However, due to non-swallow related movements like speaking, chewing or head turning, stimulations might be unintentionally triggered. So far a switch was used to enable the BI/EMG-triggering of FES when the subject was ready to swallow, which is inconvenient for practical use. In this contribution, a range image camera system is introduced to obtain data of head, mouth, and jaw movements. This data is used to apply a second classification step to reduce the number of false stimulations. In experiments with healthy subjects, the amount of potential false stimulations could be reduced by 47% while 83% of swallowing intentions would have been correctely supported by FES. PMID- 28078073 TI - Soft Encapsulation of Flexible Electrical Stimulation Implant: Challenges and Innovations. AB - In this document we discuss the main challenges encountered when producing flexible electrical stimulation implants, and present our approach to solving them for prototype production. We include a study of the optimization of the flexible PCB design, the selection of additive manufacturing materials for the mold, and the chemical compatibility of the different materials. Our approach was tested on a flexible gastro-stimulator as part of the ENDOGES research program. PMID- 28078074 TI - FES in Europe and Beyond: Current Translational Research. AB - Capacity of adult neural and muscle tissues to respond to external Electrical Stimulation (ES) is the biological basis for the development and implementation of mobility impairment physiotherapy protocols and of related assistive technologies, e.g, Functional Electrical Stimulation (FES). All body tissues, however, respond to electrical stimulation and, indeed, the most successful application of FES is electrical stimulation of the heart to revert or limit effects of arrhythmias (Pace-makers and Defibrillators). Here, we list and discuss results of FES current research activities, in particular those presented at 2016 Meetings: the PaduaMuscleDays, the Italian Institute of Myology Meeting, the 20th International Functional Electrical Stimulation Society (IFESS) conference held in Montpellier and the Vienna Workshop on FES. Several papers were recently e-published in the European Journal of Translational Myology as reports of meeting presentations. All the events and publications clearly show that FES research in Europe and beyond is alive and promisses translation of results into clinical management of a very large population of persons with deficiencies. PMID- 28078075 TI - A Design Method for FES Bone Health Therapy in SCI. AB - FES assisted activities such as standing, walking, cycling and rowing induce forces within the leg bones and have been proposed to reduce osteoporosis in spinal cord injury (SCI). However, details of the applied mechanical stimulus for osteogenesis is often not reported. Typically, comparisons of bone density results are made after costly and time consuming clinical trials. These studies have produced inconsistent results and are subject to sample size variations. Here we propose a design process that may be used to predict the clinical outcome based on biomechanical simulation and mechano-biology. This method may allow candidate therapies to be optimized and quantitatively compared. To illustrate the approach we have used data obtained from a rower with complete paraplegia using the RowStim (III) system. PMID- 28078076 TI - Sex-dependent alteration of cardiac cytochrome P450 gene expression by doxorubicin in C57Bl/6 mice. AB - BACKGROUND: There is inconclusive evidence about the role of sex as a risk factor for doxorubicin (DOX)-induced cardiotoxicity. Recent experimental studies have shown that adult female rats are protected against DOX-induced cardiotoxicity. However, the mechanisms of this sexual dimorphism are not fully elucidated. We have previously demonstrated that DOX alters the expression of several cytochrome P450 (CYP) enzymes in the hearts of male rats. Nevertheless, the sex-dependent effect of DOX on the expression of CYP enzymes is still not known. Therefore, in the present study, we determined the effect of acute DOX exposure on the expression of CYP genes in the hearts of both male and female C57Bl/6 mice. METHODS: Acute DOX cardiotoxicity was induced by a single intraperitoneal injection of 20 mg/kg DOX in male and female adult C57Bl/6 mice. Cardiac function was assessed 5 days after DOX exposure by trans-thoracic echocardiography. Mice were euthanized 1 day or 6 days after DOX or saline injection. Thereafter, the hearts were harvested and weighed. Heart sections were evaluated for pathological lesions. Total RNA was extracted and expression of natriuretic peptides, inflammatory and apoptotic markers, and CYP genes was measured by real-time PCR. RESULTS: Adult female C57Bl/6 mice were protected from acute DOX-induced cardiotoxicity as they show milder pathological lesions, less inflammation, and faster recovery from DOX-induced apoptosis and DOX-mediated inhibition of beta type natriuretic peptide. Acute DOX exposure altered the gene expression of multiple CYP genes in a sex-dependent manner. In 24 h, DOX exposure caused male specific induction of Cyp1b1 and female-specific induction of Cyp2c29 and Cyp2e1. CONCLUSIONS: Acute DOX exposure causes sex-dependent alteration of cardiac CYP gene expression. Since cardiac CYP enzymes metabolize several endogenous compounds to biologically active metabolites, sex-dependent alteration of CYP genes may play a role in the sexual dimorphism of acute DOX-induced cardiotoxicity. PMID- 28078078 TI - Radiotherapy in the management of gist: state of the art and new potential scenarios. AB - BACKGROUND: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. The main treatment for localized gastrointestinal stromal tumors is surgical resection. Unresectable or advanced GIST are poorly responsive to conventional cytotoxic chemotherapy but the introduction of tyrosine kinase inhibitors (TKIs) marked a revolutionary step in the treatment of these patients, radically improving prognosis and clinical benefit. Historically GIST has been considered radiation-resistant, and the role of radiotherapy in the management of patients with GIST is currently restricted to symptomatic palliation in current treatment guidelines. CASE PRESENTATION: Here we report two patients affected by metastatic GIST, treated with radiotherapy and radiosurgery in combination with TKIs, achieving an unexpected objective response in the first case and a significant clinical benefit associated with a local tumor control of several months in the second case. CONCLUSIONS: These and other successful experiences that are progressively accumulating, open up new scenarios of use of radiation therapy in various settings of treatment. GIST is not universally radioresistant and radiotherapy, especially if combined with molecularly targeted therapy, can improve the outcomes for patients diagnosed with GIST. PMID- 28078079 TI - Looking forward to new targeted treatments for chronic spontaneous urticaria. AB - The introduction of omalizumab to the management of chronic spontaneous urticaria (CSU) has markedly improved the therapeutic possibilities for both, patients and physicians dealing with this disabling disease. But there is still a hard core of patients who do not tolerate or benefit from existing therapies and who require effective treatment. Novel approaches include the use of currently available drugs off-licence, investigational drugs currently undergoing clinical trials and exploring the potential for therapies directed at pathophysiological targets in CSU. Off-licence uses of currently available drugs include rituximab and tumour necrosis factor inhibitors. Ligelizumab (anti-IgE), canakinumab (anti-IL-1), AZD1981 (a PGD2 receptor antagonist) and GSK 2646264 (a selective Syk inhibitor) are currently in clinical trials for CSU. Examples of drugs that could target potential pathophysiological targets in CSU include substance P antagonists, designed ankyrin repeat proteins, C5a/C5a receptor inhibitors, anti-IL-4, anti-IL 5 and anti-IL-13 and drugs that target inhibitory mast cell receptors. Other mediators and receptors of likely pathogenic relevance should be explored in skin profiling and functional proof of concept studies. The exploration of novel therapeutic targets for their role and relevance in CSU should help to achieve a better understanding of its etiopathogenesis. PMID- 28078080 TI - Three cases of anaphylaxis following injection of a depot corticosteroid with evidence of IgE sensitization to macrogols rather than the active steroid. AB - We present three cases with anaphylaxis after injection of a depot corticosteroid. First, the steroid was suspected as the elicitor, but after evaluation the excipient macrogol was found to be the elicitor. One of the patients had reactions to several unrelated drugs. Increased awareness of anaphylaxis to excipients such as macrogols is needed, especially when allergy tests for the active drug is negative and in patients with a history of repeated anaphylaxis to seemingly unrelated drugs. To establish the correct diagnosis it is important to test with the exact formulation of the culprit drug, as well as all the ingredients including excipients. PMID- 28078081 TI - Occurrence of Pasteurella multocida among pigs with respiratory disease in China between 2011 and 2015. AB - BACKGROUND: Prior to the 1990s, P. multocida capsular serogroup A was the most prevalent in China, followed by serogroups B and D. Thirty years later, serogroup D became the most prevalent, followed by serogroups A and B. However, the P. multocida capsular serogroups currently circulating in China remain unclear. Therefore, the aim of the present study was to provide an update on P. multocida serogroups isolated from diagnostic samples collected from clinically diseased pigs in Central and Eastern China from 2011 to 2015. RESULTS: Between February 2011 and October 2015, 296 isolates of Pasteurella multocida were collected from 3212 pigs with clinical respiratory disease in 12 provinces of China (isolation rate of 9.2%). Of the 296 collected isolates, 146 (49.3%) were P. multocida capsular type A, 141 (47.6%) were capsular type D, and one was capsular type B. Streptococcus suis (94/193; 48.7%), Haemophilus parasuis (76/193; 39.3%), Escherichia coli (53/193; 27.5%), and Bordetella bronchiseptica (26/193; 13.5%) were frequently isolated together with P. multocida. A total of 14 toxigenic P. multocida strains co-isolated with other pathogens from 32 cases of atrophic rhinitis were classified into serogroup D. The virulence of P. multocida capsular type A isolates was higher than that of capsular type D isolates based on LD50 studies in mice. CONCLUSIONS: Over the past 5 years, P. multocida capsular type A was the most frequently isolated from diagnostic submissions in Central and Eastern China, followed by serogroups D and B. PMID- 28078083 TI - Over-expression of Toll-like receptor 2 up-regulates heme oxygenase-1 expression and decreases oxidative injury in dairy goats. AB - BACKGROUND: Mastitis, an infection caused by Gram-positive bacteria, produces udder inflammation and oxidative injury in milk-producing mammals. Toll-like receptor 2 (TLR2) is important for host recognition of invading Gram-positive microbes. Over-expression of TLR2 in transgenic dairy goats is a useful model for studying various aspects of infection with Gram-positive bacteria, in vivo. METHODS: We over-expressed TLR2 in transgenic dairy goats. Pam3CSK4, a component of Gram-positive bacteria, triggered the TLR2 signal pathway by stimulating the monocytes-macrophages from the TLR2-positive transgenic goats, and induced over expression of activator protein-1 (AP-1), phosphatidylinositol 3-kinase (PI3K) and transcription factor nuclear factor kappa B (NF-kappaB) and inflammation factors downstream of the signal pathway. RESULTS: Compared with wild-type controls, measurements of various oxidative stress-related molecules showed that TLR2, when over-expressed in transgenic goat monocytes-macrophages, resulted in weak lipid damage, high level expression of anti-oxidative stress proteins, and significantly increased mRNA levels of transcription factor NF-E2-related factor 2 (Nrf2) and the downstream gene, heme oxygenase-1 (HO-1). When Pam3CSK4 was used to stimulate ear tissue in vivo the HO-1 protein of the transgenic goats had a relatively high expression level. CONCLUSIONS: The results indicate that the oxidative injury in goats over-expressing TLR2 was reduced following Pam3CSK4 stimulation. The underlying mechanism for this reduction was increased expression of the anti-oxidation gene HO-1 by activation of the Nrf2 signal pathway. PMID- 28078084 TI - Promoting workplace stair climbing: sometimes, not interfering is the best. AB - BACKGROUND: Stair climbing is a vigorous activity and can lead to several health benefits. Studies seeking to increase stair climbing in various public locations have shown positive effects, while results from similar studies conducted in the workplace are inconclusive. This study examined stair climbing in the workplace, and monitored effects from a single- and a combined intervention. Interventions were inspired by nudging, the libertarian method of influencing behavior. METHODS: By quasi-experimental design, stair- and elevator traffic in two office buildings was monitored preceding-, during- and following interventions with stair leading footprints alone, and combined with stair-riser banners. Chi square tests were applied to determine differences between baseline and the subsequent periods. Web-based questionnaires were distributed after follow-up period. RESULTS: Elevators and stairs were used 45 237 times, of which 89.6% was stair use. Intervention site stair climbing at baseline (79.0%) was significantly reduced with footprints (-5.1%, p < 0.001), and footprints with stair-riser banners (-5.7%, p < 0.001) while baseline stair climbing at the control site (94.2%) remained stable (p > 0.027). CONCLUSIONS: Stair climbing was significantly reduced during the intervention periods. Use of stair leading footprints alone, or combined with stair-riser banners in an attempt to influence stair climbing may be ineffective, or cause a negative reaction, when applied in a workplace with a pre-existing high amount of stair climbing. PMID- 28078082 TI - Core components for effective infection prevention and control programmes: new WHO evidence-based recommendations. AB - Health care-associated infections (HAI) are a major public health problem with a significant impact on morbidity, mortality and quality of life. They represent also an important economic burden to health systems worldwide. However, a large proportion of HAI are preventable through effective infection prevention and control (IPC) measures. Improvements in IPC at the national and facility level are critical for the successful containment of antimicrobial resistance and the prevention of HAI, including outbreaks of highly transmissible diseases through high quality care within the context of universal health coverage. Given the limited availability of IPC evidence-based guidance and standards, the World Health Organization (WHO) decided to prioritize the development of global recommendations on the core components of effective IPC programmes both at the national and acute health care facility level, based on systematic literature reviews and expert consensus. The aim of the guideline development process was to identify the evidence and evaluate its quality, consider patient values and preferences, resource implications, and the feasibility and acceptability of the recommendations. As a result, 11 recommendations and three good practice statements are presented here, including a summary of the supporting evidence, and form the substance of a new WHO IPC guideline. PMID- 28078085 TI - Comparing effects: a reanalysis of two studies on season of birth bias in anorexia nervosa. AB - BACKGROUND: Outcomes from studies on season of birth bias in eating disorders have been inconsistent. This inconsistency has been explained by differences in methodologies resulting in different types of effect sizes. The aim of the current study was to facilitate comparison by using the same methodology on samples from two studies with differing conclusions. METHODS: The statistical analyses used in each study were applied to the samples from the other study and the resulting effect sizes, Cramer's V and odds ratio (OR), were compared and discussed. RESULTS: For both studies, the Cramer's Vs ranged between 0.03 and 0.08 and the OR ranged between 0.85 and 1.31. According to common conventions, Cramer's Vs below 0.10 and ORs below 1.44 are considered small. CONCLUSION: As a marker of one or more potential risk factors, the observed effects are considered to be small. When reanalysed allowing for direct comparisons, studies with contrasting conclusions converge towards an absence of support for a season of birth bias for patients with AN. PMID- 28078087 TI - Clostridium difficile infection in cystic fibrosis: an uncommon but life threatening complication. AB - Adults with cystic fibrosis (CF) have significant rates of asymptomatic Clostridium difficile carriage and are frequently exposed to risk factors for C. difficile infection (CDI). Despite this, the rate of reported CDI in CF is low. We describe three cases of near fatal CDI in adults with CF and review the literature regarding presentation, management, and recurrence prevention. Early recognition is important as the clinical presentation may be atypical and the illness can be severe and even life-threatening. Management can be complicated by respiratory and nutritional failure. CF-related gastrointestinal dysfunction may alter the typical host-pathogen interaction between patient and C. difficile, potentially explaining the low rates of CDI and atypical presentation. PMID- 28078086 TI - Unusual aerobic performance at high temperatures in juvenile Chinook salmon, Oncorhynchus tshawytscha. AB - Understanding how the current warming trends affect fish populations is crucial for effective conservation and management. To help define suitable thermal habitat for juvenile Chinook salmon, the thermal performance of juvenile Chinook salmon acclimated to either 15 or 19 degrees C was tested across a range of environmentally relevant acute temperature changes (from 12 to 26 degrees C). Swim tunnel respirometers were used to measure routine oxygen uptake as a measure of routine metabolic rate (RMR) and oxygen uptake when swimming maximally as a measure of maximal metabolic rate (MMR) at each test temperature. We estimated absolute aerobic scope (AAS = MMR - RMR), the capacity to supply oxygen beyond routine needs, as well as factorial aerobic scope (FAS = MMR/RMR). All fish swam at a test temperature of 23 degrees C regardless of acclimation temperature, but some mortality occurred at 25 degrees C during MMR measurements. Overall, RMR and MMR increased with acute warming, but aerobic capacity was unaffected by test temperatures up to 23 degrees C in both acclimation groups. The mean AAS for fish acclimated and tested at 15 degrees C (7.06 +/- 1.76 mg O2 kg-1 h-1) was similar to that measured for fish acclimated and tested at 19 degrees C (8.80 +/- 1.42 mg O2 kg-1 h-1). Over the entire acute test temperature range, while MMR and AAS were similar for the two acclimation groups, RMR was significantly lower and FAS consequently higher at the lower test temperatures for the fish acclimated at 19 degrees C. Thus, this stock of juvenile Chinook salmon shows an impressive aerobic capacity when acutely warmed to temperatures close to their upper thermal tolerance limit, regardless of the acclimation temperature. These results are compared with those for other salmonids, and the implications of our findings for informing management actions are discussed. PMID- 28078088 TI - Immunoglobulin G4-related disease presenting as a pulmonary nodule with an irregular margin. AB - We report a case of immunoglobulin G4 (IgG4)-related lung disease presenting as a solitary pulmonary nodule with an irregular margin on computed tomography. The nodule showed a high standardized uptake value on positron emission tomography. A malignant pulmonary tumour could not be excluded. Middle lobectomy was performed. Histological analysis revealed marked lymphoplasmacytic infiltration and storiform fibrosis. Immunostaining indicated the presence of IgG4-positive plasma cells. A definitive diagnosis of IgG4-related disease was confirmed. PMID- 28078089 TI - The specificity of emotion dysregulation in adolescents with borderline personality disorder: comparison with psychiatric and healthy controls. AB - BACKGROUND: Research has supported the notion that emotion dysregulation is a core feature of BPD. However, given that this feature is typical of healthy adolescents as well as adolescents with other psychiatric disorders, the specificity of emotion dysregulation to BPD in this age group has not yet been determined. The overall aim of this study was to examine emotion dysregulation in adolescent inpatients with BPD compared with non-BPD inpatient adolescents and healthy non-clinical adolescents, taking into account both global emotion dysregulation deficits and more specific impairments. METHOD: The sample included 185 adolescent inpatients with BPD (M = 15.23, SD = 1.52), 367 non-BPD psychiatric inpatient adolescents (M = 15.37, SD = 1.40), and 146 healthy adolescents (M = 15.23, SD = 1.22), all of whom were between the ages of 12 and 17. Borderline personality features were assessed, along with emotion dysregulation and psychiatric severity. RESULTS: After controlling for age, gender, and psychiatric severity, results revealed that adolescents with BPD had higher overall emotional dysregulation compared with non-BPD psychiatric controls and healthy controls. These differences were apparent in only two domains of emotion dysregulation including limited access to emotion regulation strategies perceived as effective and impulse control difficulties when experiencing negative emotions. CONCLUSIONS: Findings suggest BPD-specific elevations on emotion dysregulation generally, and subscales related to behavioral regulation specifically. PMID- 28078090 TI - The effect of ongoing feedback on physical activity levels following an exercise intervention in older adults: a randomised controlled trial protocol. AB - BACKGROUND: Physical inactivity ranks as a major contributing factor in the development and progression of chronic disease. Lifestyle interventions reduce the progression of chronic disease, however, compliance decreases over time and health effects only persist as long as the new lifestyle is maintained. Telephone counselling (TC) is an effective way to provide individuals with ongoing support to maintain lifestyle changes. Remote physical activity monitoring and feedback (RAMF) via interactive technologies such as activity trackers and smartphones may be a cost-effective alternative to TC, however, this comparison has not been made. This study, therefore, aims to determine the effect of ongoing feedback (TC vs. RAMF) on the maintenance of physical activity following a 12-week individualised lifestyle program, and the effect of this on health risk factors and health services usage. METHODS AND DESIGN: A randomised controlled trial with a parallel groups design. A total of 150 adults (>=60 years) who participate in a 12-week face-to-face individualised lifestyle program will be randomised to twelve months of RAMF (n = 50), TC (n = 50), or usual care (n = 50). Participants randomised to RAMF will use a smartphone activity tracker app, synced to a wrist worn activity tracker, to provide them with automated feedback regarding compliance to prescribed activity targets. Telephone counselling involves a follow-up phone call every fortnight for the first three months and a monthly call for the remaining nine months of the follow-up period. The primary outcome measures are physical activity compliance (accelerometry and Active Australia survey). Secondary outcome measures include cardiorespiratory fitness, muscle strength, dynamic balance, quality of life, blood pressure, body composition, and health services usage. Measures will be made before and after the individualised lifestyle program, and at three, six and twelve months during the intervention. DISCUSSION: The results of this study will help to determine the efficacy of RAMF devices on compliance to prescribed physical activity compared to the current gold standard of TC. If the remote monitoring proves effective, it may provide a cost efficient alternative method of assisting maintenance of behaviour change from lifestyle interventions. TRIAL REGISTRATION: ACTRN12615001104549. Retrospectively Registered 20/10/2015. PMID- 28078092 TI - Severe obesity, emotions and eating habits: a case-control study. AB - BACKGROUND: Obesity has a multifaceted etiology that involves genetic, biological and behavioral factors, body growth, eating habits, energy expenditure and the function of adipose tissue. The present study aimed to expand upon knowledge about the relationships among obesity, emotions and eating habits in severely obese individuals using a case-control method. METHODS: The subject group consisted of 112 individuals (81 females and 31 males) receiving a permanent disability pension primarily for obesity. The control subjects were randomly selected from the same area and were receiving a disability pension for a different primary illness. The controls were matched with the subjects by the place of residence, sex, age, the time since the pension was granted and occupation. Psychiatric interviews were conducted on all participants. The results were analyzed using the chi-squared test (chi2-test) and the percent distribution. The subject and control groups were compared using the t-test for paired variables. Conditional logistic regression analysis was also conducted. RESULTS: The emotional state of eating was significantly associated with quarrels and feelings of loneliness. The subjects suffered from night eating syndrome, which was associated with an increased risk of early retirement. Binge eating syndrome was observed more frequently in the study group. The subjects reported feeling increased hunger compared with the controls. A significant percentage of the subjects had a body mass index of >= 40. No differences in eating habits were observed between the groups. CONCLUSION: This study provides information on the relationship between emotions and eating habits in obesity, which is a rarely studied topic. We believe that our study provides a novel and necessary overview of the associations among severe obesity, emotions and eating habits. PMID- 28078091 TI - Body mass index-measured adiposity and population attributability of associated factors: a population-based study from Buea, Cameroon. AB - BACKGROUND: Obesity is currently a global health challenge driven by a mix of behavioural, environmental and genetic factors. Up to date population-based disease burden estimates are needed to guide successful prevention and control efforts in African countries. We investigated the prevalence and population attributable fractions of overweight and obesity in Buea, the Southwest region of Cameroon. METHODS: Data are from a community-based cross-sectional study involving randomly selected adults conducted in 2016. Body mass index (BMI) was categorized according to the WHO classification. Multivariable logistic regressions were used to investigate factors independently associated with obesity. Corresponding population attributable fractions were estimated. RESULTS: Among the 1,139 participants, age-standardized prevalence (95% CI) of overweight and obesity were; 36.5 (33.7-39.3) and 11.1 (9.3-12.9) percent respectively. Mean BMI was 25.3 +/- 4.3 kg/m2; women were heavier than men (25.8 vs. 24.4 kg/m2; p <0.0001). Factors associated with obesity were; female gender [odds ratio 3.20 (95% CI: 1.93-5.59)], age > 31 years [3.21 (1.86-5.28)] and being married [2.10 (1.60-3.51)]. At the population level; older age, being married, low level of education, high monthly income and physical inactivity accounted respectively for 11.9%, 21.8%, 11.6%, 6.4% and 8.7% of overweight and obesity among the women, while older age and being married explained 9.2% and 28.3% of overweight and obesity in men. CONCLUSION: The prevalence of overweight and obesity in this semi urban Cameroonian population is high, affecting over a third of individuals. Community-based interventions to control weight would need to take into account gender specificities and socio-economic status. PMID- 28078093 TI - Health communication implications of the perceived meanings of terms used to denote unhealthy foods. AB - BACKGROUND: Using appropriate terminology in nutrition education programs and behaviour change campaigns is important to optimise the effectiveness of these efforts. To inform future communications on the topic of healthy eating, this study explored adults' perceptions of the meaning of four terms used to describe unhealthy foods: junk food, snack food, party food, and discretionary food. METHODS: Australian adults were recruited to participate in an online survey that included demographic items and open-ended questions relating to perceptions of the four terms. In total, 409 respondents aged 25-64 years completed the survey. RESULTS: 'Junk food' was the term most clearly aligned with unhealthiness, and is therefore likely to represent wording that will have salience and relevance to many target audience members. Snack foods were considered to include both healthy and unhealthy food products, and both snack foods and party foods were often described as being consumed in small portions. Despite being used in dietary guidelines, the term 'discretionary food' was unfamiliar to many respondents. CONCLUSIONS: These results demonstrate that different terms for unhealthy foods can have substantially different meanings for audience members. A detailed understanding of these meanings is needed to ensure that nutrition guidance and health promotion campaigns use appropriate terminology. PMID- 28078094 TI - What is the elevator pitch for open access? PMID- 28078095 TI - What factors influence ward nurses' recognition of and response to patient deterioration? An integrative review of the literature. AB - AIM: In this integrative review, we aimed to: first, identify and summarize published studies relating to ward nurses' recognition of and response to patient deterioration; second, to critically evaluate studies that described or appraised the practice of ward nurses in recognizing and responding to patient deterioration; and third, identify gaps in the literature for further research. DESIGN: An integrative review. METHODS: The Cumulative Index to Nursing and Allied Health Literature (CINAHL) Ovid Medline, Informit and Google Scholar databases were accessed for the years 1990-2014. Data were extracted and summarized in tables and then appraised using the Mixed Method Appraisal Tool. Data were grouped into two domains; recognizing and responding to deterioration and then thematic analysis was used to identify the emerging themes. RESULTS: Seventeen studies were reviewed and appraised. Recognizing patient deterioration was encapsulated in four themes: (1) assessing the patient; (2) knowing the patient; (3) education and (4) environmental factors. Responding to patient deterioration was encapsulated in three themes; (1) non-technical skills; (2) access to support and (3) negative emotional responses. CONCLUSION: Issues involved in timely recognition of and response to clinical deterioration remain complex, yet patient safety relies on nurses' timely assessments and actions. PMID- 28078096 TI - Preceptor characteristics and the socialization outcomes of new graduate nurses during a preceptorship programme. AB - AIM: The purpose of this study was to explore the relationships between preceptor characteristics (emotional intelligence, personality and cognitive intelligence) and new graduate nurse socialization outcomes regarding turnover intent, job satisfaction, role conflict and ambiguity during a preceptorship programme. To date, no studies have explored these relationships. DESIGN: A cross-sectional and multi-site design with purposeful sampling. METHODS: Dyads of preceptors and new nurses were recruited at the end of their preceptorship programme. Pearson's correlational analysis was used to examine the relationships. RESULTS: A sample of 41 preceptors and 44 new graduate nurses participated in this study, making 38 dyads with complete data. The preceptor personality traits of openness, conscientiousness and emotional stability were significantly related to new graduate nurses who reported greater turnover intent, job dissatisfaction, role conflict and ambiguity. No significant relationships were noted between preceptor EI and IQ and the outcome of new graduate nurses. PMID- 28078097 TI - Rasch analysis of Stamps's Index of Work Satisfaction in nursing population. AB - AIM: One of the most commonly used tools for measuring job satisfaction in nursing is the Stamps Index of Work Satisfaction. Several studies have reported on the reliability of the Stamps' tool based on traditional statistical model. The aim of this study was to apply the Rasch model to examine the adequacy of Stamps's Index of Work Satisfaction for measuring nurses' job satisfaction cross culturally and to determine the validity and reliability of the instrument using the Rasch criteria. DESIGN: A secondary data analysis was conducted on a sample of 556 registered nurses from two countries. METHODS: The RUMM 2030 software was used to analyse the psychometric properties of the Index of Work Satisfaction. RESULTS: The persons mean location of -0.018 approximated the items mean of 0.00, suggesting a good alignment of the measure and the traits being measured. However, at the items level, some items were misfiting to the Rasch model. PMID- 28078098 TI - Transfer of nursing home residents to emergency departments: organizational differences between nursing homes with high vs. low transfer rates. AB - AIM: To explore possible factors in the organization of nursing homes that could be related to differences in the rate of transfer of residents from nursing homes to emergency department. DESIGN: Explorative. METHOD: In a single municipality, qualitative and quantitative data were collected from documents and through semi structured interviews with 11 RNs from five nursing homes identified as having the highest vs. six identified as having the lowest transfer rates to emergency department. Data were analysed by non-parametric tests and basic content analysis. RESULTS: All nursing homes in the highest transfer rate group and one in the lowest transfer rate group were run by private for-profit providers. Compared with the low group, the high group had fewer updated advance care plans and the RNs interviewed had less work experience in care of older people and less training in care of persons with dementia. There was no difference in nursing home size or staff/resident ratio. The RNs described similar possibilities to provide palliative care, medical equipment and perceived medical support from GPs. PMID- 28078099 TI - Aligning the planets: The role of nurses in the care of patients with non-ST elevation myocardial infarction. AB - BACKGROUND: Studies have shown variation in care for patients with non-ST elevation myocardial infarction (NSTEMI), including in the roles of specialist and advanced practice nurses in diagnosis, treatment and coordination of care. AIM: The aim of this study was to describe the roles and responsibilities of specialist and advanced practice nurses in providing care for patients with NSTEMI. METHODS: Secondary analysis of observational field notes and interviews from an ethnographic study of variation in care for NSTEMI patients in 10 UK hospitals conducted 2011-2012. Data were thematically analysed to identify key concepts and themes related to the roles of specialist nurses. RESULTS: Seven of 10 hospitals had roles for specialist nurses in NSTEMI care. The major theme related to high demand and the complexity of patients and organizations ('Aligning the planets'). In this theme, nurses contributed to improving services or compensating for deficiencies ('Making the system work versus making up for the system'). Data collection for audit could take precedence over time with patients ('Paying worship to the paper'). Nurses expressed a sense of ownership of cardiovascular patients that drove their desire to provide quality of care ('They are our patients'). PMID- 28078101 TI - Intrauterine diabetic milieu instigates dysregulated adipocytokines production in F1 offspring. AB - BACKGROUND: Intrauterine environment plays a pivotal role in the origin of fatal diseases such as the metabolic syndrome. Diabetes is associated with low-grade inflammatory state and dysregulated adipokines production. The aim of this study is to investigate the effect of maternal diabetes on adipocytokines (adiponectin, leptin and TNF-alpha) production in F1 offspring in rats. METHODS: The offspring groups were as follows: F1 offspring of control mothers under control diet (CD) (CF1-CD), F1 offspring of control mothers under high caloric diet (HCD) (CF1 HCD), F1 offspring of diabetic mothers under CD (DF1-CD), and F1 offspring of diabetic mothers under HCD (DF1-HCD). Every 5 weeks post-natal, 10 pups of each subgroup were culled to obtain blood samples for biochemical analysis. RESULTS: The results indicate that DF1-CD and DF1-HCD groups exhibited hyperinsulinemia, dyslipidemia, insulin resistance and impaired glucose homeostasis compared to CF1 CD (p > 0.05). DF1-CD and DF1-HCD groups had high hepatic and muscular depositions of TGs. The significant elevated NEFA level only appeared in offspring of diabetic mothers that was fed HCD. DF1-CD and DF1-HCD groups demonstrated low serum levels of adiponectin, high levels of leptin, and elevated levels of TNF-alpha compared to CF1-CD (p > 0.05). These results reveal the disturbed metabolic lipid profile of offspring of diabetic mothers and could guide further characterization of the mechanisms involved. CONCLUSION: Dysregulated adipocytokines production could be a possible mechanism for the transgenerational transmittance of diabetes, especially following a postnatal diabetogenic environment. Moreover, the exacerbating effects of postnatal HCD on NEFA in rats might be prone to adipcytokine dysregulation. Furthermore, dysregulation of serum adipokines is a prevalent consequence of maternal diabetes and could guide further investigations to predict the development of metabolic disturbances. PMID- 28078100 TI - Asthma costs and social impact. AB - In recent decades, both asthma prevalence and incidence have been increasing worldwide, not only due to the genetic background, but mainly because of the effect of a wide number of environmental and lifestyle risk factors. In many countries noncommunicable diseases, like asthma, are not yet considered a healthcare priority. This review will analyze and discuss disparities in asthma management in several countries and regions, such as access to healthcare human resources and medications, due to limited financial capacity to develop strategies to control and prevent this chronic disease. This review tries to explore the social and economic burden of asthma impact on society. Although asthma is generally accepted as a costly illness, the total costs to society (direct, indirect and intangible asthma costs) are difficult to estimate, mainly due to different disease definitions and characterizations but also to the use of different methodologies to assess the asthma socio-economic impact in different societies. The asthma costs are very variables from country to country, however we can estimate that a mean cost per patient per year, including all asthmatics (intermittent, mild, moderate and severe asthma) in Europe is $USD 1,900, which seems lower than USA, estimated mean $USD 3,100. PMID- 28078102 TI - Repeated mild traumatic brain injury causes focal response in lateral septum and hippocampus. AB - AIM: To advance our understanding of regional and temporal cellular responses to repeated mild traumatic brain injury (rmTBI), we used a mouse model of rmTBI that incorporated acceleration, deceleration and rotational forces. MATERIALS & METHODS: A modified weight-drop method was used to compare two inter-injury intervals, rmTBI-short (five hits delivered over 3 days) and rmTBI-long (five hits delivered over 15 days). Regional investigations of forebrain and midbrain histological alterations were performed at three post-injury time points (immediate, 2 weeks and 6 weeks). RESULTS: The rmTBI-short protocol generated an immediate, localized microglial and astroglial response in the dorsolateral septum and hippocampus, with the astroglial response persisting in the dorsolateral septum. The rmTBI-long protocol showed only a transitory astroglial response in the dorsolateral septum. CONCLUSION: Our results indicate that the lateral septum and hippocampus are particularly vulnerable regions in rmTBI, possibly contributing to memory and emotional impairments associated with repeated concussions. PMID- 28078103 TI - The potential of spectral domain optical coherence tomography imaging based retinal biomarkers. AB - BACKGROUND: Biomarker", a merged word of "biological marker", refers to a broad subcategory of medical signs that objectively indicate the state of health, and well-being of an individual. Biomarkers hold great promise for personalized medicine as information gained from diagnostic or progression markers can be used to tailor treatment to the individual for highly effective intervention in the disease process. Optical coherence tomography (OCT) has proved useful in identifying various biomarkers in ocular and systemic diseases. MAIN BODY: Spectral domain optical coherence tomography imaging-based biomarkers provide a valuable tool for detecting the earlier stages of the disease, tracking progression, and monitoring treatment response. The aim of this review article is to analyze various OCT based imaging biomarkers and their potential to be considered as surrogate endpoints for diabetic retinopathy, age related macular degeneration, retinitis pigmentosa and vitreomacular interface disorder. These OCT based surrogate markers have been classified as retinal structural alterations (macular central subfield thickness and cube average thickness); retinal ultrastructural alterations (disruption of external limiting membrane and ellipsoid zone, thinning of retinal nerve fiber layer and ganglion cell layer); intraretinal microangiopathic changes; choroidal surrogate endpoints; and vitreoretinal interface endpoints. CONCLUSION: OCT technology is changing very quickly and throughout this review there are some of the multiple possibilities that OCT based imaging biomarkers will be more useful in the near future for diagnosis, prognosticating disease progression and as endpoint in clinical trials. PMID- 28078104 TI - Discovery of flavivirus-derived endogenous viral elements in Anopheles mosquito genomes supports the existence of Anopheles-associated insect-specific flaviviruses. AB - The Flavivirus genus encompasses several arboviruses of public health significance such as dengue, yellow fever, and Zika viruses. It also includes insect-specific flaviviruses (ISFs) that are only capable of infecting insect hosts. The vast majority of mosquito-infecting flaviviruses have been associated with mosquito species of the Aedes and Culex genera in the Culicinae subfamily, which also includes most arbovirus vectors. Mosquitoes of the Anophelinae subfamily are not considered significant arbovirus vectors; however, flaviviruses have occasionally been detected in field-caught Anopheles specimens. Whether such observations reflect occasional spillover or laboratory contamination or whether Anopheles mosquitoes are natural hosts of flaviviruses is unknown. Here, we provide in silico and in vivo evidence of transcriptionally active, flavivirus derived endogenous viral elements (EVEs) in the genome of Anopheles minimus and Anopheles sinensis. Such non-retroviral endogenization of RNA viruses is consistent with a shared evolutionary history between flaviviruses and Anopheles mosquitoes. Phylogenetic analyses of the two newly described EVEs support the existence of a distinct clade of Anopheles-associated ISFs. PMID- 28078105 TI - Asymmetric Facial Bone Fragmentation Mirrors Asymmetric Distribution of Cranial Neuromasts in Blind Mexican Cavefish. AB - Craniofacial asymmetry is a convergent trait widely distributed across animals that colonize the extreme cave environment. Although craniofacial asymmetry can be discerned easily, other complex phenotypes (such as sensory organ position and numerical variation) are challenging to score and compare. Certain bones of the craniofacial complex demonstrate substantial asymmetry, and co-localize to regions harboring dramatically expanded numbers of mechanosensory neuromasts. To determine if a relationship exists between this expansion and bone fragmentation in cavefish, we developed a quantitative measure of positional symmetry across the left-right axis. We found that three different cave-dwelling populations were significantly more asymmetric compared to surface-dwelling fish. Moreover, cave populations did not differ in the degree of neuromast asymmetry. This work establishes a method for quantifying symmetry of a complex phenotype, and demonstrates that facial bone fragmentation mirrors the asymmetric distribution of neuromasts in different cavefish populations. Further developmental studies will provide a clearer picture of the developmental and cellular changes that accompany this extreme phenotype, and help illuminate the genetic basis for facial asymmetry in vertebrates. PMID- 28078106 TI - Advances in cholangiocarcinoma research: report from the third Cholangiocarcinoma Foundation Annual Conference. PMID- 28078107 TI - Phase II study of bevacizumab and preoperative chemoradiation for esophageal adenocarcinoma. AB - BACKGROUND: A standard-of-care for locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma is pre-operative chemoradiation. Elevated levels of vascular endothelial growth factor (VEGF) have been associated with worse outcomes following chemoradiation and anti-VEGF therapies can potentiate radiation efficacy. METHODS: In this single-arm phase II study, we added bevacizumab to induction chemotherapy and concurrent chemoradiation with cisplatin/irinotecan for locally advanced esophageal and GEJ adenocarcinomas. RESULTS: Thirty-three patients were enrolled, with all evaluable. All tumors involved the GEJ and 67% were node-positive by endoscopic ultrasound (EUS) and imaging. Twenty-eight patients completed chemoradiation and 26 patients underwent surgery (25 R0 resections). Toxicities were not clearly increased. The pathologic complete response (pCR) rate was 15%. Median progression-free survival (PFS) and overall survival (OS) were 15.1 and 30.5 months respectively. Higher baseline VEGF-A levels were associated with a trend toward improved OS (not reached vs. 21.0 months, P=0.11). Response on positron emission tomography (PET) scan after induction chemotherapy was predictive of PFS and showed trends toward improved OS and pCR rate. CONCLUSIONS: The addition of bevacizumab to chemoradiation was not associated with clear worsening of toxicities but also led to no improvement in outcomes, when compared to a prior phase II study of 55 patients. Higher baseline VEGF-A levels correlated with a trend toward improved survival and might be used to stratify or select patients for future studies incorporating this or similar agents. PET scan to assess response following induction chemotherapy and change chemotherapy in non-responders during chemoradiation is the subject of a fully accrued national trial (NCT01333033). PMID- 28078108 TI - EGFR family and cMet expression profiles and prognostic significance in esophagogastric adenocarcinoma. AB - BACKGROUND: Targeted therapy with anti-human epidermal growth factor receptor-2 (HER2) monoclonal antibody in patients with HER2 overexpressed esophagogastric adenocarcinoma (EGA) improves survival; however, the effect is transient due to the development of resistance. Some studies suggest that cMet overexpression provides cross talk for epidermal growth factor receptor (EGFR) and HER2 inhibition. We sought to characterize the expression profile of the EGFR family and cMet receptors in untreated, resected EGA. METHODS: This retrospective analysis included all sequential patients with esophageal or gastroesophageal junction (GEJ) adenocarcinoma who underwent primary resection, without neoadjuvant therapy or HER2 inhibition, with adequate tissue, at the University of Florida from 2001 to 2011. Central blinded immunohistochemistry (IHC) was performed on tumor specimens with EGFR, HER2, HER3, HER4 and cMet expression scored as low (0, 1+) or high (2+, 3+). Demographic and tumor characteristics were compared using Fisher exact test. Kaplan-Meier curves and univariate analysis compared survival among different receptors. RESULTS: Total 52 patients were included in the study with median age 66 years. High expression of EGFR (73%), HER2 (40%), HER3 (75%), HER4 (35%) and cMet (69%) was detected among the study group. HER3 and HER4 co-expression was found in 18 (35%) cases. Pan expression of all four EGFR family members with cMet was noted in only 17% of cases. On univariate analysis, tumor stage and depth correlated with survival, while cMet + HER3 +/- EGFR receptor co-expression trended towards a worse survival. CONCLUSIONS: EGFR family and cMet are frequently co-expressed in treatment naive resected EGA or GEJ tumors. Although our data do not significantly show receptor status as a prognostic factor, the co-expression profiles support for further investigation to improve targeting of this signal transduction axis. PMID- 28078109 TI - Prognostic impact of tumour-associated B cells and plasma cells in oesophageal and gastric adenocarcinoma. AB - BACKGROUND: While it is well established that the cell-mediated immune response plays an important role in cancer progression and spread, the role of the humoral immune response in this regard has been less studied. According to the existing literature, dense infiltration of B cells or plasma cells appears to correlate mainly with an improved prognosis in several types of cancer, but their prognostic impact in oesophageal and gastric cancer has not yet been described. METHODS: Immunohistochemistry was applied on tissue microarrays (TMA) to assess the stromal density of B cells (CD20+) and plasma cells [CD138+ or immunoglobulin kappa C (IGKC+)] in chemo-/radiotherapy-naive tumours from a consecutive cohort of 174 patients with resected oesophageal or gastric adenocarcinoma. Cox proportional hazard's modelling was applied to examine the impact of the investigated markers on overall survival (OS) and time to recurrence (TTR). RESULTS: In curatively treated patients with oesophageal adenocarcinoma, high expression of IGKC was an independent predictor of a prolonged OS [hazard ratio (HR) 0.10; 95% confidence interval (CI), 0.02-0.57], and TTR (HR 0.15; 95% CI, 0.03-0.71). In curatively treated patients with gastric adenocarcinoma, high expression of IGKC independently predicted a prolonged OS (HR 0.46; 95% CI, 0.24 0.87) and TTR (HR 0.46; 95% CI, 0.21-0.98). Expression of CD20 was not prognostic, and CD138 expression was only prognostic in unadjusted analysis of TTR in gastric cancer. CONCLUSIONS: These results demonstrate, for the first time, that abundant infiltration of IGKC+ plasma cells independently predicts a prolonged survival in both oesophageal and gastric cancer. PMID- 28078110 TI - Radioembolization with 90Y glass microspheres for the treatment of unresectable metastatic liver disease from chemotherapy-refractory gastrointestinal cancers: final report of a prospective pilot study. AB - BACKGROUND: This prospective pilot single-institution study was undertaken to document the feasibility, safety, and efficacy of radioembolization of liver dominant metastatic gastrointestinal cancer using 90Y glass microspheres. METHODS: Between June 2010 and October 2013, 42 adult patients (26 men, 16 women; median age 60 years) with metastatic chemotherapy-refractory unresectable colorectal (n=21), neuroendocrine (n=11), intrahepatic bile duct (n=7), pancreas (n=2), and esophageal (n=1) carcinomas underwent 60 lobar or segmental administrations of 90Y glass microspheres. Data regarding clinical and laboratory adverse events (AE) were collected prospectively for up to 5.5 years after radioembolization. Radiographic responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Time to maximum response, response duration, progression-free survival (PFS) (hepatic and extrahepatic), and overall survival (OS) were measured. RESULTS: Median target dose and activity were 109.4 Gy and 2.6 GBq per treatment session, respectively. Majority of clinical AE were grade 1 or 2 in severity. Patients with colorectal cancer had hepatic objective response rate (ORR) of 25% and a hepatic disease control rate (DCR) of 80%. Median PFS and OS were 1.0 and 4.4 months, respectively. Patients with neuroendocrine tumors (NET) had hepatic ORR and DCR of 73% and 100%, respectively. Median PFS was 8.9 months for this cohort. DCR and median PFS and OS for patients with cholangiocarcinoma were 86%, 1.1 months, and 6.7 months, respectively. CONCLUSIONS: 90Y glass microspheres device has a favorable safety profile, and achieved prolonged disease control of hepatic tumor burden in a subset of patients, including all patients enrolled in the neuroendocrine cohort. PMID- 28078111 TI - Percutaneous biliary drainage catheter insertion in patients with extensive hepatic metastatic tumor burden. AB - BACKGROUND: Patients with metastatic disease of the liver can have hyperbilirubinemia due to a number of reasons, including biliary obstruction. The purpose of this study was to analyze patient outcomes after percutaneous biliary drainage (PBD) catheter insertion in patients with extensive hepatic metastatic tumor burden. METHODS: Out of 746 PBD insertions, 44 patients (24 males, 20 females, mean age 57.4 years, range, 34-80 years) had metastatic malignancy with a hepatic tumor burden of greater than 20% parenchymal volume based on pre procedure computed tomography (CT) or magnetic resonance imaging (MRI). Laboratory data before and after PBD insertion were compared. Survival and outcomes analysis performed. A subanalysis was performed on patients with CT demonstrated catheter traversal of tumoral tissue. RESULTS: A PBD catheter was successfully inserted in all patients. The mean serum bilirubin level decreased significantly from 10.9+/-6.4 mg/dL immediately prior to PBD insertion to 7.1+/ 5.6 mg/dL (P<0.001) within one month post PBD insertion. Four patients (11%) demonstrated normalization of bilirubin levels to less than 1.6 mg/dL. Of the 14 patients with a post-procedure CT or MRI, the PBD catheter traversed a tumor in 11 (79%). One of these patients required a transfusion after the procedure and one had recurrent catheter exchanges due to pericatheter leakage. The 30-day overall survival was 41% with a median survival of 19 days. The percentage decrease in serum bilirubin after PBD insertion and pre-procedure international normalized ratio (INR) were correlated with improved survival (OR =3.7, P=0.010 and OR =4.9, P=0.028 respectively). The PBD-associated major complication rate was 16%. CONCLUSIONS: In patients with hyperbilirubinemia and extensive hepatic metastatic disease burden, survival was dismal after PBD catheter insertion. Serum bilirubin level normalization occurred rarely. PMID- 28078113 TI - Results of intraoperative electron beam radiotherapy containing multimodality treatment for locally unresectable T4 rectal cancer: a pooled analysis of the Mayo Clinic Rochester and Catharina Hospital Eindhoven. AB - BACKGROUND: The aim of this study is to analyse the pooled results of intraoperative electron beam radiotherapy (IOERT) containing multimodality treatment of locally advanced T4 rectal cancer, initially unresectable for cure, from the Mayo Clinic, Rochester, USA (MCR) and Catharina Hospital, Eindhoven, The Netherlands (CHE), both major referral centers for locally advanced rectal cancer. A rectal tumor is called locally unresectable for cure if after full clinical work-up infiltration into the surrounding structures or organs has been demonstrated, which would result in positive surgical margins if resection was the initial component of treatment. This was the reason to refer these patients to the IOERT program of one of the centers. METHODS: In the period from 1981 to 2010, 417 patients with locally unresectable T4 rectal carcinomas at initial presentation were treated with multimodality treatment including IOERT at either one of the two centres. The preferred treatment approach was preoperative (chemo) radiation and intended radical surgery combined with IOERT. Risk factors for local recurrence (LR), cancer specific survival, disease free survival and distant metastases (DM) were assessed. RESULTS: A total of 306 patients (73%) underwent a R0 resection. LRs and metastases occurred more frequently after an R1 2 resection (P<0.001 and P<0.001 respectively). Preoperative chemoradiation (preop CRT) was associated with a higher probability of having a R0 resection. Waiting time after preoperative treatment was inversely related with the chance of developing a LR, especially after R+ resection. In 16% of all cases a LR developed. Five-year disease free survival and overall survival (OS) were 55% and 56% respectively. CONCLUSIONS: An acceptable survival can be achieved in treatment of patients with initially unresectable T4 rectal cancer with combined modality therapy that includes preop CRT and IOERT. Completeness of the resection is the most important predictive and prognostic factor in the treatment of T4 rectal cancer for all outcome parameters. IOERT can reduce the LR rate effectively, especially in R+ resected patients. PMID- 28078112 TI - Molecular spectrum of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC somatic gene mutations in Arab patients with colorectal cancer: determination of frequency and distribution pattern. AB - BACKGROUND: The frequency rates of mutations such as KRAS, NRAS, BRAF, and PIK3CA in colorectal cancer (CRC) differ among populations. The aim of this study was to assess mutation frequencies in the Arab population and determine their correlations with certain clinicopathological features. METHODS: Arab patients from the Arab Gulf region and a population of age- and sex-matched Western patients with CRC whose tumors were evaluated with next-generation sequencing (NGS) were identified and retrospectively reviewed. The mutation rates of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC were recorded, along with clinicopathological features. Other somatic mutation and their rates were also identified. Fisher's exact test was used to determine the association between mutation status and clinical features. RESULTS: A total of 198 cases were identified; 99 Arab patients and 99 Western patients. Fifty-two point seven percent of Arab patients had stage IV disease at initial presentation, 74.2% had left-sided tumors. Eighty nine point two percent had tubular adenocarcinoma and 10.8% had mucinous adenocarcinoma. The prevalence rates of KRAS, NRAS, BRAF, PIK3CA, TP53, APC, SMAD, FBXW7 mutations in Arab population were 44.4%, 4%, 4%, 13.1%, 52.5%, 27.3%, 2% and 3% respectively. Compared to 48.4%, 4%, 4%, 12.1%, 47.5%, 24.2%, 11.1% and 0% respectively in matched Western population. Associations between these mutations and patient clinicopathological features were not statistically significant. CONCLUSIONS: This is the first study to report comprehensive hotspot mutations using NGS in Arab patients with CRC. The frequency of KRAS, NRAS, BRAF, TP53, APC and PIK3CA mutations were similar to reported frequencies in Western population except SMAD4 that had a lower frequency and higher frequency of FBXW7 mutation. PMID- 28078114 TI - Colorectal cancer anatomic distribution patterns remain the same after sessile serrated adenoma/polyp considered cancer precursor: a 9-year comparison study from community-based endoscopy centers. AB - BACKGROUND: The overall incidence of colorectal cancer (CRC) in the United States has steadily decreased. However, the incidence of right-sided CRC remains unchanged for the past two decades. The serrated neoplastic pathway (sessile serrated adenoma/polyp, SSA/P) has been considered an important pathway of colorectal carcinogenesis, especially in the right-sided CRC. The aim of this study was to compare CRC anatomic distribution patterns in a 9-year interval in the general population before and after SSA/P was recognized and treated as a CRC precursor. METHODS: The Miraca Life Sciences (MLS) pathology database was queried for all primary CRCs diagnosed between 8/3/2000 to 12/31/2005 (control group) and 1/1/2014 to 12/31/2014 (current group). Patients' demographics, clinical information, and pathology reports were collected and analyzed. RESULTS: A total of 5,602 patients with 5,685 CRCs were identified, of which 2,728 patients with 2,765 CRCs in current group and 2,874 patients with 2,920 CRCs in control group. Overall, there were no statistical differences in the current group in regards to the anatomical distribution patterns of CRCs in the proximal, right-sided, distal, and left-sided colon or genders compared with the control group (all P>0.05). Among the current group, there were 33 (1.2%) patients with 38 (1.4%) CRCs arising in SSA/Ps [serrated carcinomas (SCAs)], of which 33 (86.8%) were in the right-sided colon and 5 (13.2%) in the left-sided colon. Twenty-three (69.7%) SCA patients were female with significant advanced age than male (76.4 vs. 69.6, P=0.023). CONCLUSIONS: The overall current CRC anatomic distribution patterns after SSA/Ps managed as CRC precursor remain the same in the patients' population from the community-based endoscopy centers in the U.S. It is suggested that the current SSA/P management might need to be further modified. PMID- 28078115 TI - Usefulness and feasibility of endoscopic submucosal dissection for colorectal tumor: a nationwide multicenter retrospective study in Korea. AB - BACKGROUND: Detection rate of precursor lesion of colorectal cancer and early colon cancer have recently been rising because of increased screening endoscopy and increased incidence of colorectal cancer. Endoscopic submucosal dissection (ESD) technique has been reported to be useful in the treatment of such superficial lesions in colon. However, nationwide multicenter study for usefulness and feasibility of colorectal ESD is still limited. METHODS: From January 2009 to February 2014, colorectal ESD data performed at nationwide university hospitals were enrolled in retrospective design. Demographic, clinical, technical data, and data of complications were reviewed. RESULTS: A total of 189 patients were included with 191 lesions resected by colorectal ESD. The indications were epithelial lesions (n=120), neuroendocrine tumor (n=25), cancer (n=46). The lesion locations were right colon (n=45), transverse colon (n=17), descending colon (n=8), sigmoid colon (n=33), rectum (n=88). The median size of the lesions was 21.1 mm. En bloc resection rate of the lesion was 83.3%, with complete R0 resection in 73.3%. The median duration of ESD was 53.7 minutes. Factor related to En bloc resection was tumor location (right colon/transverse colon 72.6% vs. other location 89.2%, P=0.004). Factors related complication were tumor location (right colon/transverse colon 12.9% vs. Other location 10.13%, P=0.044) and tumor size (without complication 20.5+/-10.2 mm vs. with complication 25.9+/-11.7 mm, P=0.027). The short term morbidity rate was 11.0% including 5 hemorrhages (2.6%) and 16 perforations (8.4%). CONCLUSIONS: In this study, ESD shows promise as a useful, potentially feasible procedure in colorectal superficial tumor because of high en bloc resection rate and low morbidity rate, especially in small lesions located from descending colon to rectum. PMID- 28078116 TI - Pretreatment tumor volume as a prognostic factor in metastatic colorectal cancer treated with selective internal radiation to the liver using yttrium-90 resin microspheres. AB - BACKGROUND: Yttrium-90 (90Y)-resin microspheres can prolong intrahepatic disease control and improve overall survival (OS) in patients with metastatic colorectal cancer (CRC). Prognostic factors for improved outcomes in patients undergoing selective internal radiation therapy (SIRT) have been studied, but the relationship between pre-SIRT liver tumor volume and outcomes has not well described. METHODS: We retrospectively reviewed the records of patients with metastatic CRC who were treated at our institution with 90Y-resin microspheres. Each patient underwent either MR or CT imaging of the liver with intravenous (IV) contrast before and within ~2-3 months after SIRT. Imaging data were transferred into our treatment planning system. Each metastatic liver lesion was contoured, and the volume of each lesion was summed to determine the total liver tumor volume at a given time point. We evaluated whether pretreatment liver tumor volume was related to OS. We also evaluated the relationship between pre-SIRT tumor volume and radiographic treatment response by either unidimensional Response Evaluation Criteria in Solid Tumors (RECIST) or three-dimensional volumetric criteria. RESULTS: We included 60 patients with a median age of 59 years (range, 38-97 years); 60% of patients received sequential lobar treatment. The median number of chemotherapy cycles received prior to SIRT was 2. Median follow-up from first SIRT was 8.9 months. Pre- and post-SIRT tumor volumes were primarily calculated on CT (87%). The median pre-SIRT tumor volume was 77 cc (range, 4.5-2,170.4 cc). The median intervals between the first SIRT and the first, second, and third follow-up scans were 2.2, 4.4, and 7.7 months, respectively. No patient experienced a radiographic complete response. Pretreatment volume was a significant predictor for estimating the odds of a patient having stable disease or partial response using volumetric response criteria at first (P=0.016), second (P=0.023), and third (P=0.015) follow-ups. For each unit increase in log volume, a patient's odds of having a stable or partial response were 0.57, 0.63, and 0.61 times as likely at first, second, and third follow-up, respectively. OS was not significantly associated with pretreatment tumor volume. CONCLUSIONS: Patients with metastatic CRC with larger overall pretreatment liver tumor volumes, regardless of number of individual liver lesions, are less likely to have radiographic evidence of stable disease or partial response following SIRT using volumetric response criteria. However, pretreatment volume was not significantly associated with OS, and thus SIRT should be considered for patients with larger pretreatment volumetric tumor burden. PMID- 28078117 TI - Effect of gender on psychosocial adjustment of colorectal cancer survivors with ostomy. AB - BACKGROUND: Stoma can pose extensive challenges for colorectal cancer survivors. Identifying the psychological and social adjustment among them and how it differs by gender will aid in identifying those particularly at risk of having poor adjustment and in planning programs to improve their adjustment. The purpose of this study was to determine the effect of gender on psychosocial adjustment of colorectal cancer survivors with ostomy. METHODS: A descriptive cross sectional study was carried out in the stoma clinic of B.P. Koirala Memorial Cancer Hospital, Bharatpur, Nepal. A purposive sample of 122 patients with ostomy was taken from the above mentioned setting. Selection criteria included colorectal cancer survivors having ostomy for at least 6 months. Data on socio-demographic and clinical variables were collected. Psychosocial adjustment was measured using Ostomy Adjustment Inventory-23 (OAI-23). RESULTS: A total of 122 patients were included in the study. Mean time since ostomy surgery was 2.53 and 1.98 years for men and women respectively. Both men and women had significant impairment in the psychosocial adjustment, however, men had significantly lower psychosocial adjustment score (37.68+/-12.96 vs. 43.45+/-12.81, t=-2.47, P=0.015) at 95% CI as compared to women and they reported more negative emotions. Furthermore, men significantly predicted low acceptance {beta=-3.078, P=0.023, DeltaR2=0.036, F [4,117] =7.90, P<0.001} and social engagement score {beta=-2.501, P<0.001, DeltaR2=0.098, F [4,117] =6.03, P<0.001}. CONCLUSIONS: Colorectal cancer survivors with ostomy should be monitored for psychosocial concerns in regular basis and health care providers should tailor care based on their need. Approaches of survivorship care and psychosocial interventions in colorectal cancer survivors with ostomy should take into account gender specific concerns and requirements to aid adjustment. PMID- 28078118 TI - Less than 12 lymph nodes in the surgical specimen after neoadjuvant chemo radiotherapy: an indicator of tumor regression in locally advanced rectal cancer? AB - BACKGROUND: The number of lymph node retrieved in the surgical specimen is important for tumor staging and has paramount impact on prognosis in colorectal cancer and imitates the adequacy of lymph node surgical clearance. The paucity of lymph node yields in patients undergoing resection after preoperative chemo radiotherapy (CRT) in rectal cancer has seen. Lower total number of lymph nodes in the total mesoractal excision (TME) specimen after CRT, could a marker of better tumor response. METHODS: We retrospectively reviewed the prospectively managed data of patients underwent excision for rectal cancer, who treated by neoadjuvant radiotherapy with or without chemotherapy in locally advanced rectal cancer. From 2010 to 2014, 364 patients underwent rectal cancer surgery, of which ninety-one treated with neoadjuvant treatment. Standard surgical and pathological protocols were followed. Patients were categorized into two groups based on the number of total harvested lymph nodes with group 1, having 12 or more nodes harvested, and group 2 including patients who had <12 lymph nodes harvested. The total number of lymph nodes retrieved from the surgical specimen was correlated with grade of tumor regression with neoadjuvant treatment. RESULTS: Out of 91 patients, 38 patients (42%) had less than 12 lymph nodes examined in specimen. The difference in median number of lymph nodes was observed significantly as 9 (range, 2-11) versus 16 (range, 12-32), in group 2 and 1, respectively (P<0.01). Patients with fewer lymph node group were comparable with respect to age, BMI, pre-operative staging, neoadjuvant treatment. Pathological complete response in tumor pCR was seen with significantly higher rate (40% vs. 26%, P<0.05) in group 2. As per Mandard criteria, there was significant difference in tumor regression grade (TRG) between both the groups (P<0.05). Among patients with metastatic lymph nodes, median LNR was lower in <12 lymph nodes group at 0.167 (range, 0.09 0.45) versus 0.187 (range, 0.05-0.54), difference was not statistically significant (P=0.81). CONCLUSIONS: Retrieval of fewer than 12 lymph nodes in surgical specimen of rectal cancer who had received neo-adjuvant radiotherapy with or without chemotherapy should be considered as a good indicator of tumor response with better local disease control, and a good prognostic factor, rather than as a pointer of poor diligence of the surgical and pathological assessment. PMID- 28078120 TI - Disparities in receipt of radiotherapy and survival by age, sex, and race among patients with non-metastatic squamous cell carcinoma of the anus. AB - BACKGROUND: Combination chemoradiotherapy is the standard of care for treatment of non-metastatic squamous cell carcinoma of the anus (SCCA). This population based study evaluated disparities in receipt of radiotherapy (RT) as well as comparative survival rates for SCCA patients in the United States. METHODS: The Surveillance, Epidemiology, and End Results (SEER) 18 database was used to identify patients with non-metastatic SCCA diagnosed between 1998 and 2008. Multivariate logistic regression was used to model the relationships between age, sex, and race and the receipt of RT, adjusting for marital status and stage of disease. Relative survival (RS) rates were compared by each factor, with added adjustment for RT status, using Cox proportional hazards model. RESULTS: A total of 3,885 patients with localized or regional SCCA as the only primary malignancy were included in the study, of which, 3,192 (82%) received RT. In our multivariate analysis, lower rates of RT were found for those 65+ years old [adjusted odds ratio (OR) 0.71; P<0.001], males (adjusted OR 0.65; P<0.001), and blacks (adjusted OR 0.78; P=0.049). Multivariate survival analysis showed worse survival among those 65+ years old (adjusted HR 1.65; P<0.001), males (adjusted HR 1.53; P<0.001), and blacks (adjusted HR 1.35; P=0.001). CONCLUSIONS: This population based study identified older patients, males, and blacks as less likely to receive RT. Worse survival was also found in these groups. PMID- 28078119 TI - Surgical outcomes of post chemoradiotherapy unresectable locally advanced rectal cancers improve with interim chemotherapy, is FOLFIRINOX better than CAPOX? AB - BACKGROUND: Role of chemotherapy in patients who continue to have unresectable disease after pre-operative chemo-radiotherapy (CRT) remains largely unaddressed. METHODS: Patients with LA rectal cancer from January 2013 to June 2015 were evaluated. Post-CRT, patients, who were deemed unresectable, were considered for further interim chemotherapy (i-CT). RESULTS: Seventy six patients (15%) with median age of 38.5 years received i-CT after CRT. About 61.8% patients receiving i-CT managed to undergo a definitive surgery and the extent of surgery was reduced in 48.7% patients. With the median follow up of 19 months, the estimated 2-year event free survival (EFS) of 48% and OS was 56%. The estimated 2-year OS was 81% in mucinous tumors whereas it was 44.4% in signet ring pathology (P=0.045). The 2-year OS of 86% for whom surgery was done vs. 38% (2-year OS) in whom surgery was not done (P=0.011). Survival was better in conservative surgery group vs. total pelvic exenteration (TPE) vs. no surgery (2-year OS: 84% vs. 59.1% vs. 38%; P=0.033). In the CAPE-OX group, 71.4% (14/23) underwent surgery whereas 75.9% (29/47) in the 5-FU plus irinotecan plus oxaliplatin (FOLFIRINOX) group with EFS (P=0.570) and OS (P=0.120). In conservative surgery group, OS was better in FOLFIRINOX (2-year OS: 95.7%) vs. capecitabine plus oxaliplatin (CAPOX) (2-year OS: 70%) (P=0.012). CONCLUSIONS: i-CT can lead to improved resection rates, improved survivals and downstaging with acceptable toxicity. FOLFIRINOX appears to better over CAPOX, specifically in whom conservative surgery is feasible. PMID- 28078121 TI - Clinical, morphologic, and immunophenotypic characteristics of ampullary carcinomas with an emphasis on SMAD4 expression. AB - BACKGROUND: The purpose of our study was to examine the relationship between clinicopathologic variables and morphologic subtypes in ampullary carcinoma, with an emphasis on the expression of SMAD4 tumor suppressor gene. METHODS: Sixty three cases of ampullary carcinomas resected between 2000-2011 were included in this study. Clinical characteristics and outcome data were recorded. Tumors were classified as pancreatobiliary or intestinal type based on morphology, and immunohistochemical (IHC) studies for cytokeratin 7 (CK7), cytokeratin 20 (CK20), cytokeratin 17 (CK17), and SMAD4 were performed. RESULTS: Forty-nine percent of the ampullary tumors were pancreatobiliary, 29% were intestinal, and 22% were other variants. Tumors with pancreatobiliary morphology showed worse overall survival than those with intestinal morphology or other variants (P=0.03). A trend for higher stage, recurrence and less survival was seen in cases with negative SMAD4 expression. In multivariate analysis, age group (<=60 vs. >60 years) and expression of CK17 were the most prognostic of survival. CONCLUSIONS: Ampullary tumors with pancreatobiliary morphology have a worse overall survival, while negative SMAD4 expression is associated with a trend of less survival. PMID- 28078122 TI - Performance status and neutrophil-lymphocyte ratio are important prognostic factors in elderly patients with unresectable pancreatic cancer. AB - BACKGROUND: The usefulness of various prognostic factors for pancreatic cancer (PC) has been reported, but the number of elderly patients in these studies is disproportionately fewer compared with those in everyday practice. The purpose of this study was to investigate the prognostic factors for unresectable PC in elderly patients. METHODS: We retrospectively analyzed 67 elderly (age >=75 years) patients with unresectable PC who underwent chemotherapy between January 2006 and December 2014 at our hospital. Univariate and multivariate Cox regression models were applied to investigate independent prognostic factors. RESULTS: Multivariate analysis revealed that an increased neutrophil-lymphocyte ratio (NLR) [hazard ratio (HR) 1.91, P=0.03] and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 (HR 2.74, P=0.01) were independent negative prognostic factors. CONCLUSIONS: The two prognostic factors identified herein are useful in the identification of patients with a poor prognosis and subsequent administration of supportive care alone, which may help avoid the unnecessary adverse effects and complications of systemic chemotherapy. PMID- 28078123 TI - Diminished expression of MGMT & RASSF1A genes in gastric cancer in ethnic population of Kashmir. AB - BACKGROUND: Cancer initiation and progression are accompanied by profound changes in DNA. DNA methylation that was the first epigenetic alterations identified in cancer. DNA hypermethylation at promoter sites is closely associated with down regulation of protein and as major participant in the development and progression of series of human tumors. Therefore we hypothesized that promoter hypermethylation of RASSF1A & MGMT gene could influence susceptibility to gastric cancer (GC) as well, and we conducted this study to test the hypothesis in Kashmiri population. METHODS: A hospital based case-control study; including 200 GC cases and 200 matched controls from patients who went surgical resection. Promoter hypermethylation was determined by Methylation Specific Polymerase chain reaction. The expression of MGMT & RASSF1A protein was examined by Western blotting technique. RESULTS: Frequency of promoter region hypermethylation of MGMT gene were 46.5% in cases and 5.5% in controls (P<0.05) while as in case of RASSF1A frequency was 44% in cases and 4.5% in controls (P<0.05). Further, frequency of hypermethylation of both genes was found predominant in males, aged and advanced pathological stage subjects. Loss of MGMT expression was found in 46.5% cases (P<0.05) while as loss of RASSF1A expression was found in 40.5% cases (P<0.05). In both genes a positive correlation was observed between promoter CpG island hypermethylation and down regulation of respective proteins. CONCLUSIONS: These findings indicate that promoter hypermethylation at CpG island may be responsible for reduction of expression at protein level which may be an initial event in carcinogenesis and the progression of GC. PMID- 28078125 TI - Changing paradigm in pancreatic cancer: from adjuvant to neoadjuvant chemoradiation. AB - BACKGROUND: Historically, management of pancreatic cancer has been determined based on whether the tumor was amenable to resection and all patients deemed resectable received curative intent surgery followed by adjuvant therapy with chemotherapy (CT) +/- RT. However, patients who undergo resection with microscopic (R1) positive margins have inferior rates of survival. The purpose of this study is to identify patients who have undergone pancreatectomy for pancreatic cancer, determine the surgical margins, types of adjuvant therapies given and patterns of failure. Our hypothesis was that in patients who have surgery without pre-operative therapy, there is a high rate of R1 resections and subsequent local recurrence, despite adjuvant therapy. METHODS: Seventy-one patients with curative resections for pancreatic cancer between 2003 and 2015 were reviewed. Tumor stage, margin status, distance to closest margin, receipt of adjuvant therapy and length of survival were collected. Patients were divided into two groups based on whether they received adjuvant CT + RT (n=37) or CT alone (n=37). Patients were further divided based on whether resection was R1 (n=29) or R0 (n=42). Wilcoxon survival tests and Cox proportional hazards regression models were performed to determine the effects of CT + RT vs. CT alone, stratified by surgical margin status. RESULTS: Of the 29 patients (39%) who had R1, 15 received CT + RT and 14 received only CT. Patients who received CT + RT experienced a significantly longer period of PFS (13 vs. 7.5 mos, P=0.03) than patients who received CT alone. However, there was no significant difference found in time to death post cancer resection between CT + RT vs. CT alone (P=0.73). Of the 42 patients with R0, 21 received CT + RT and 21 received CT. There was a trend towards increase in PFS in patients treated with CT + RT (25 vs. 17 months, P=0.05), but there was no significant increase in time to death compared to patients treated with CT alone (P=0.53. Of the 36 patients with CT + RT, 21 had R0 and 15 had R1. Patients with R0 were more likely to have longer PFS (25 vs. 13 months, P=0.06), but there was no significant difference in time to death compared to patients with CT alone (P=0.68). CONCLUSIONS: After curative resection, the addition of RT to CT improves PFS in both R0 and R1 settings. However, patients with R1 have significantly worse PFS and OS compared to patients with R0 and even aggressive adjuvant therapy does not make up for the difference. The paradigm has shifted and now for patients with resectable pancreatic cancers we recommend neoadjuvant CT + RT to improve RT targeting and treatment response assessment and most importantly, improve chances of obtaining R0. PMID- 28078124 TI - Advanced biliary tract cancer: clinical outcomes with ABC-02 regimen and analysis of prognostic factors in a tertiary care center in the United States. AB - BACKGROUND: Gemcitabine plus cisplatin (GC) is currently the standard regimen for advanced biliary tract cancers (BTC) based on the outcomes in ABC-02 trial. Multiple factors can affect outcomes in these patients. This retrospective review evaluates the University of Cincinnati experience with GC in advanced intrahepatic (IHC)/extrahepatic cholangiocarcinoma (EHC) and gall bladder carcinoma (GBC). METHODS: In this study approved by University of Cincinnati IRB, retrospective analysis of advanced BTC patients seen between 01/2008 and 01/2015 was done. Kaplan Meyer method was used to calculate progression free survival (PFS), and overall survival (OS). Cox model was used to test the association between baseline variables and OS/PFS, adjusting for gender and age at diagnosis. Patients were identified using ICD code for BT tumors, 26 patients met inclusion criteria: histologically proven advanced BTC that received GC as their initial chemotherapy. GC was given as per ABC-02 protocol with appropriate modifications until disease progression or unacceptable toxicities. RESULTS: Median age at diagnosis was 62 years (range, 31-81 years). Eighteen (69%) were IHC, 5 EHC, 3 GBC, 61% male, 73% whites. Performance status (PS): 0-1: 69%, PS 2: 31%. Baseline CA19-9 data was available for 21 patients, (range 1 to 69,543), and abnormal CA19 9 was seen in 14 patients (54%). PFS was 4.5 months (95% CI: 3.1-8.9 months) and OS was 10.5 months (95% CI: 7.9-18.8 months). OS at 6 and 12 months was 69% (18/26) and 42% (11/26). Thirty-eight percent (10/26) received 2nd line chemotherapy, of these 9/10 received 5FU based chemotherapy. Eleven percent (3/26) received 3rd line chemotherapy. Increase in baseline carcinoembryonic antigen (CEA), alanine aminotransferase, alkaline phosphatase (ALP) and total bilirubin was associated with increased risk of death while increase in baseline CEA and ALP was associated with increased risk of progression (P valve <0.05). In the group of patients who had all three major risk factors (PS >=2, CEA >3, and stage IVb), the median survival was 2.9 months (95% CI: 2.6-9.3 months), which was significantly worse compared to rest of the population [median 18 months (95% CI: 5.4-19.5 months), P<0.01]. CONCLUSIONS: Our data supports the use of GC as a first line regimen for advance BTC in a non-clinical trial setting. Results are comparable to those reported in ABC-02 trial, despite inclusion of PS 2 patients whom constituted 31% of our population. In the patient population studied, baseline CEA and liver function test appeared able to predict response to GC in advanced BTC. Patients with all three high risk factors (PS >=2, CEA >3, and stage IVb) did poorly and may need careful selection prior to initiating chemotherapy. PMID- 28078126 TI - Gastrointestinal lymphoma in Western Algeria: pattern of distribution and histological subtypes (retrospective study). AB - BACKGROUND: Primary gastrointestinal (GI) lymphomas (GIL) are uncommon diseases that can involve the whole GI tract. Considerable variation exists in the literature with respect to incidence of the various histological subtypes and sites of involvement. This study was undertaken to establish the anatomic distribution, histological subtypes and sites of GI lymphomas of patients from Western Algeria. METHODS: The case records of 58 consecutive patients with GIL diagnosed at the Pathologies Departments of Algerian west region (the Military Hospital of Oran city and the Central University Hospital of Sidi Bel Abbes city) from January 2006 to December 2013 were retrospectively evaluated for epidemiology and histopathology report. All lymphomas were reclassified according to the WHO 2008 classification. RESULTS: A total of 58 patients (39 male, 19 female) with mean age of 61 years and a range of 20-89 years were included in this study. Stomach was the most common site involved (70.7%). The commonest histological subtype was mucosa-associated lymphoid tissue (MALT) B cell lymphoma (46.6%), followed by diffuse large B-cell lymphomas (DLBCL) (43.1%).The frequency of Helicobacter pylori (HP) positivity differ between gastric and intestinal location P=0.003 and correlates with the histological type P=0.01. CONCLUSIONS: This retrospective study of patients with GI lymphoma from Western Algeria illustrates the pattern of distribution of various common and rare histological subtypes. More studies are necessary to find a potential cause, risk factor or genetic mutation that can explain these specific characteristics of GIL. PMID- 28078127 TI - Prophylactic hyperthermic intraperitoneal chemotherapy can be considered in the management of advanced gastric cancer. PMID- 28078128 TI - Endoscopic ultrasound in pancreatic cancer: innovative applications beyond the basics. AB - Endoscopic ultrasound (EUS) has become a mainstay in assisting in the diagnosis and staging of pancreatic cancer. In addition, EUS provides a modality to treat chronic pain through celiac plexus neurolysis. Currently, there is growing data and utilization of EUS in more diverse and innovative applications aimed at providing more sophisticated diagnostic, prognostic and therapeutic options for patients with pancreatic cancer. EUS delivery of chemotherapy, viral and biological vectors and fiducial markers may eventually revolutionize the way clinicians approach the care of a patient with pancreatic cancer. PMID- 28078129 TI - Osteonecrosis of the jaw associated with ziv-aflibercept. AB - Medication-related osteonecrosis of the jaw (MRONJ) has been associated with medications that include bisphosphonates (BPs), denosumab, bevacizumab and sunitinib. Ziv-aflibercept is a recombinant human vascular endothelial growth factor (VEGF) receptor which has been used to treat patients with various advanced solid tumors. We report three patients without a history of the use of medications known to cause MRONJ presenting with jaw osteonecrosis typical for MRONJ following therapy with ziv-aflibercept. All patients had metastatic gastrointestinal cancer treated with ziv-aflibercept and were evaluated for MRONJ because of exposed bone in the oral cavity. None of the patients had received antiresorptive therapies or any other medication known to cause MRONJ, and none had received radiation therapy to the jaws. Patients were aged 43, 51, 63 and all were males. Patients received 7, 16 and 23 cycles of ziv-aflibercept treatment and developed necrotic bone. All three patients presented with mandibular involvement, with two reporting pain. Patients were managed with anti-microbial mouth rinse, antibiotics and non-surgical sequestrectomy and followed up for 1.5, 2, and 2 months; two patients became asymptomatic while one patient continued to have pain. These three reported patients with a history of ziv-aflibercept therapy and no reported use of other medications known to cause MRONJ developed exposed necrotic bone of the jaw. We believe that ziv-aflibercept is another medication that can potentially cause MRONJ probably through its anti-VEGF activity, similar to bevacizumab and sunitinib. PMID- 28078130 TI - Radiographic and endoscopic regression of metastatic gastric cancer to the colon in the setting of 5-aminosalicylic acid use. AB - Colonic metastases from gastric cancer are a rare phenomenon and sparsely reported in the literature. We report a case of a 59-year-old woman who presented with vague abdominal symptoms and initial computer tomography (CT) imaging suggestive of a colonic apple-core lesion with serial colonoscopic biopsies diagnostic of metastatic signet ring cell gastric adenocarcinoma. This case is unique given the evolving CT and endoscopic findings that suggested a regression in colonic wall thickening in the setting of 5-aminosalicylic acid (5-ASA) use prior to histologic diagnosis. PMID- 28078131 TI - A novel management of post-oesophagectomy gastro-pleural fistula. AB - Oesophageal anastomotic leak and fistula are major and life-threatening complications of oesophagectomy with resultant increased mortality. Non-operative approach of such cases should be the initial strategy. Re-operative surgery and/or stent insertion are considered if conservative measures failed. Although oesophageal stenting is a safe option for the leaks, stent migration and failure to completely cover large anastomotic leaks are the main complications and pitfalls of the procedure. These can be overcome by using multiple or larger stents. We describe a case of a 73-year-old man who underwent a laparoscopic oesophagectomy for an oesophageal adenocarcinoma. The procedure was complicated by a large gastro-pleural fistula and anastomotic leak, resulting into a chronic empyema. The initial conservative treatment and a conventional oesophageal stent insertion failed to heal the fistula and to resolve the empyema. Re-operative surgery was ruled out because of the patient's poor general health and high surgical risk. Due to the changed oesophago-gastric anatomy and a potential risk of migration of the additional conventional stent, a mega stent was deployed with successful closure of the oesophageal leak. Post-stenting contrast studies and an out-patient follow up review of the case confirmed no further anastomotic leakage. PMID- 28078132 TI - Impressive response to dual BRAF and MEK inhibition in patients with BRAF mutant intrahepatic cholangiocarcinoma-2 case reports and a brief review. AB - Intrahepatic cholangiocarcinoma (ICC) typically presents at an advanced stage and is associated with a poor oncological outcome. The median survival for metastatic ICC is less than 1 year with standard chemotherapy. ICC is associated with distinct oncogenic drivers including IDH (isocitrate dehydrogenase), HER-2 (human epidermal growth factor 2), and BRAF (v-Raf murine sarcoma viral oncogene homolog B), which may benefit from matching targeted therapies. Hereby we report 2 cases of BRAF V600E refractory ICC treated with dual BRAF and MEK inhibitors (dabrafenib and trametinib) with excellent clinical and radiological response to therapy and with protracted duration of disease control. Our first patient achieved CR (complete remission) at 6 months of treatment with ultimate disease progression at 9 months. The second patient achieved a PR (partial response) at 2 months from starting treatment and remains progression free at 5 months. Our results confirm the activity of dual BRAF and MEK targeting in BRAF mutated ICC, adding further support to 3 additional case-reports in the literature. Dual targeting appears superior to other case reports with BRAF inhibition alone and appear favorable to historic data with cytotoxic chemotherapy. Given the poor outlook and refractoriness of BRAF mutant ICC, future studies should focus on early integration of BRAF/MEK inhibition. PMID- 28078133 TI - Successful hepatectomy for metastatic squamous cell carcinoma of the anal canal-a case report. AB - Despite rare, metastatic anal carcinoma confers a poor prognosis. Systemic chemotherapy is the mainstay of treatment for advanced disease while the role of biologics and/or surgical resection of metastatic disease are anecdotal. Compared to isolated liver colorectal or neuroendocrine cancer liver metastases, there is far less experience with resection or nonsurgical local ablative procedures for patients with metastatic anal carcinoma to the liver. We report the case of a 67 year-old woman with metastatic anal carcinoma to the liver who was successfully treated with liver resection and remains free of relapse more than one year later. PMID- 28078134 TI - Malignant transformation of biliary adenofibroma: a rare biliary cystic tumor. AB - Biliary adenofibromas (BAFs) are rare, benign biliary cystic tumors with potential for malignant transformation. Of the eleven prior cases of BAF reported in the literature, six showed evidence of malignant transformation. We describe the clinical, imaging and pathology features of two cases of malignant BAF and review the existing literature to raise awareness of this entity and provide additional tools for diagnosing this rare tumor Additionally, we identified a loss of function mutation in the cyclin-dependent kinase inhibitor 2A (CDKN2A) tumor suppressor gene in a malignant caudate lobe BAF, thereby providing potential insight into the molecular pathogenesis of BAF malignant transformation. Although additional cases and longer-term follow-up are needed, our cases suggest that recurrence or metastasis of malignant BAF is not common and that complete surgical resection can be curative. PMID- 28078135 TI - Investigating the prognostic value of KOC (K homology domain containing protein overexpressed in cancer) overexpression after curative intent resection of pancreatic ductal adenocarcinoma. AB - BACKGROUND: Pancreatic adenocarcinoma (PDAC) is now the third leading cause of cancer mortality in the United States. More than 80% of patients present with distant metastasis precluding surgical eligibility. Even among patients with localized disease deemed eligible for surgical resection, the median survival is only 22.8 months due to high recurrence rates. Identification of a biomarker correlated with patient specific prognosis upon initial diagnosis can serve as a way to individualize treatment options. METHODS: We performed a retrospective cohort study analyzing pathology of patients who underwent curative intent surgery for PDAC at Geisinger Medical Center from 1998-2011 to identify whether the expression of KOC can be predictive of patient specific prognosis. Tissue microarrays of specimens were assessed by immunohistochemistry. RESULTS: A total of 62 patients are included. Comparisons between groups on overall survival (OS) and progression free survival (PFS) are estimated using the Kaplan-Meier method and the log-rank test. Each biomarker was represented as low and high expression by categorizing the expression score at <4+ or >4+, based on intensity and extent of cells stained. 40 deaths occurred in the sample. Distant metastasis and differentiation (well/moderate vs. poor) were related to OS (P=0.0120, P=0.0086). Twenty-nine patients progressed in their disease. High/low KOC expression were significantly related to PFS (P=0.0556). Patients with a high KOC expression were more than 2 times more likely to progress compared to those with a low KOC expression (HR =2.04; 95% CI: 0.97, 4.29). CONCLUSIONS: Our data is suggestive of KOC being a useful prognostic biomarker for identifying those patients with PDAC who have a high risk for early progression and distant metastasis. Larger studies are needed to determine whether KOC can be a therapeutic target in the treatment of pancreatic cancer. Furthermore, considering high KOC expressers had a worse PFS than their counterparts, investigation regarding the use of KOC expression as a biomarker to preselect patients who may benefit most from neoadjuvant chemotherapy is warranted. PMID- 28078136 TI - Effects of a New Eyelid Shampoo on Lid Hygiene and Eyelash Length in Patients with Meibomian Gland Dysfunction: A Comparative Open Study. AB - Purpose. Meibomian gland dysfunction (MGD) can lead to abnormalities in the composition and function of tear film, resulting in dry eye. Eyelid hygiene is a key to management of MGD. We tested a novel eyelid shampoo (Eye Shampoo Long, ESL) for its ability to maintain lid hygiene. This shampoo is nonirritating and can potentially lengthen eyelashes. This study was aimed to evaluate the efficacy of ESL in the treatment of MGD and its effects on eyelash length. Methods. Ten patients with MGD and 10 healthy subjects without MGD applied ESL twice daily for 8 weeks. Patients were examined for lid margin and dry eye before and after the trial. Subjective symptoms were evaluated. Eyelash length was measured at baseline and at the end of the trial. Results. In the MGD group, significant improvements were observed in subjective symptoms obstruction of the meibomian orifice, secretion of meibum, eyelashes contamination, eyelid margin foam, and SPK. Eyelash length became significantly longer. Conclusions. Maintaining eyelid hygiene using ESL improved the eyelid margins and symptoms of dry eye in MGD patients and increased eyelash length. These findings are promising and warrant confirmation in a larger randomized controlled study. PMID- 28078137 TI - Comment on "Invisible Victims: Delayed Onset Depression among Adults with Same Sex Parents". PMID- 28078138 TI - Use of Action Research in Nursing Education. AB - Purpose. The purpose of this article is to describe action research in nursing education and to propose a definition of action research for providing guidelines for research proposals and criteria for assessing potential publications for nursing higher education. Methods. The first part of this project involved a search of the literature on action research in nursing higher education from 1994 to 2013. Searches were conducted in the CINAHL and MEDLINE databases. Applying the criteria identified, 80 publications were reviewed. The second part of the project involved a literature review of action research methodology from several disciplines to assist in assessing articles in this review. Results. This article summarizes the nursing higher education literature reviewed and provides processes and content related to four topic areas in nursing higher education. The descriptions assist researchers in learning more about the complexity of both the action research process and the varied outcomes. The literature review of action research in many disciplines along with the review of action research in higher education provided a framework for developing a nursing-education-centric definition of action research. Conclusions. Although guidelines for developing action research and criteria for publication are suggested, continued development of methods for synthesizing action research is recommended. PMID- 28078139 TI - TULAA: A Minimally Invasive Appendicectomy Technique for the Paediatric Patient. AB - TULAA or Transumbilical Laparoscopic Assisted Appendicectomy is a minimally invasive technique described by Pelosi in 1992 for the removal of the inflamed appendix. Its main advantage is the possibility of exploring the peritoneal cavity and performing a simple and safe extracorporeal appendicectomy. Since its first description, different authors reported their experience with such technique. The aim of this review is to summarise the surgical outcomes currently reported in the literature for this minimally invasive surgical approach and compare it with standard open and laparoscopic appendicectomy. PMID- 28078140 TI - Pregnancy and the Use of Disease-Modifying Therapies in Patients with Multiple Sclerosis: Benefits versus Risks. AB - The burden of multiple sclerosis (MS) in women of childbearing potential is increasing, with peak incidence around the age of 30 years, increasing incidence and prevalence, and growing female : male ratio. Guidelines recommend early use of disease-modifying therapies (DMTs), which are contraindicated or recommended with considerable caution, during pregnancy/breastfeeding. Many physicians are reluctant to prescribe them for a woman who is/is planning to be pregnant. Interferons are not absolutely contraindicated during pregnancy, since interferon beta appears to lack serious adverse effects in pregnancy, despite a warning in its labelling concerning risk of spontaneous abortion. Glatiramer acetate, natalizumab, and alemtuzumab also may not induce adverse pregnancy outcomes, although natalizumab may induce haematologic abnormalities in newborns. An accelerated elimination procedure is needed for teriflunomide if pregnancy occurs on treatment or if pregnancy is planned. Current evidence supports the contraindication for fingolimod during pregnancy; data on other DMTs remains limited. Increased relapse rates following withdrawal of some DMTs in pregnancy are concerning and require further research. The postpartum period brings increased risk of disease reactivation that needs to be carefully addressed through effective communication between treating physicians and mothers intending to breastfeed. We address the potential for use of the first- and second-line DMTs in pregnancy and lactation. PMID- 28078141 TI - Experiences of Habitual Physical Activity in Maintaining Roles and Functioning among Older Adults: A Qualitative Study. AB - Physically active older adults have reduced risk of functional restrictions and role limitations. Several aspects may interrelate and influence habitual physical activity (PA). However, older adults' own perspectives towards their PA need to be addressed. The aim of this study was to explore the experiences of habitual physical activity in maintaining roles and functioning among older adult Palestinians >=60 years. Data were collected through in-depth interviews based on a narrative approach. Seventeen participants were recruited (aged 64-84 years). Data were analyzed using a narrative interpretative method. Findings. Three central narratives were identified, "keep moving, stay healthy," "social connectedness, a motive to stay active," and "adapting strategies to age-related changes." Conclusion. Habitual physical activity was perceived as an important factor to maintain functioning and to preserve active roles in older adults. Walking was the most prominent pattern of physical activity and it was viewed as a vital tool to maintain functioning among the older adults. Social connectedness was considered as a contributing factor to the status of staying active. To adapt the process of age-related changes in a context to stay active, the participants have used different adapting strategies, including protective strategy, awareness of own capabilities, and modifying or adopting new roles. PMID- 28078142 TI - Normal Non-HDL Cholesterol, Low Total Cholesterol, and HDL Cholesterol Levels in Sickle Cell Disease Patients in the Steady State: A Case-Control Study of Tema Metropolis. AB - Background. Abnormal lipid homeostasis in sickle cell disease (SCD) is characterized by defects in plasma and erythrocyte lipids and may increase the risk of cardiovascular disease. This study assessed the lipid profile and non-HDL cholesterol level of SCD patients. Methods. A hospital-based cross-sectional study was conducted in 50 SCD patients, in the steady state, aged 8-28 years, attending the SCD clinic, and 50 healthy volunteers between the ages of 8-38 years. Serum lipids were determined by enzymatic methods and non-HDL cholesterol calculated by this formula: non-HDL-C = TC-HDL-C. Results. Total cholesterol (TC) (p = 0.001) and high-density lipoprotein cholesterol (HDL-C) (p < 0.0001) were significantly decreased in cases compared to controls. The levels of non-HDL-C, low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were similar among the participants. The levels of decrease in TC and HDL were associated with whether a patient was SCD-SS or SCD-SC. Systolic blood pressure and diastolic blood pressure were each significantly associated with increased VLDL [SBP, p = 0.01, OR: 0.74 (CI: 0.6-0.93); DBP, p = 0.023, OR: 1.45 (CI: 1.05-2.0)]. Conclusion. Dyslipidemia is common among participants in this study. It was more pronounced in the SCD-SS than in SCD-SC. This dyslipidemia was associated with high VLDL as well as increased SBP and DBP. PMID- 28078143 TI - Breast Cancer Profile among Patients with a History of Chemoprevention. AB - Purpose. This study identifies women with breast cancer who utilized chemoprevention agents prior to diagnosis and describes their patterns of disease. Methods. Our database was queried retrospectively for patients with breast cancer who reported prior use of chemoprevention. Patients were divided into primary (no history of breast cancer) and secondary (previous history of breast cancer) groups and compared to patients who never took chemoprevention. Results. 135 (6%) of 2430 women used chemoprevention. In the primary chemoprevention group (n = 18, 1%), 39% had completed >5 years of treatment, and fully 50% were on treatment at time of diagnosis. These patients were overwhelmingly diagnosed with ER/PR positive cancers (88%/65%) and were diagnosed with equal percentages (44%) of IDC and DCIS. 117 (87%) used secondary chemoprevention. Patients in this group were diagnosed with earlier stage disease and had lower rates of ER/PR-positivity (73%/65%) than the nonchemoprevention group (84%/72%). In the secondary group, 24% were on chemoprevention at time of diagnosis; 73% had completed >5 years of treatment. Conclusions. The majority of patients who used primary chemoprevention had not completed treatment prior to diagnosis, suggesting that the timing of initiation and compliance to prevention strategies are important in defining the pattern of disease in these patients. PMID- 28078144 TI - Progress of Research on Diffuse Axonal Injury after Traumatic Brain Injury. AB - The current work reviews the concept, pathological mechanism, and process of diagnosing of DAI. The pathological mechanism underlying DAI is complicated, including axonal breakage caused by axonal retraction balls, discontinued protein transport along the axonal axis, calcium influx, and calpain-mediated hydrolysis of structural protein, degradation of axonal cytoskeleton network, the changes of transport proteins such as amyloid precursor protein, and changes of glia cells. Based on the above pathological mechanism, the diagnosis of DAI is usually made using methods such as CT, traditional and new MRI, biochemical markers, and neuropsychological assessment. This review provides a basis in literature for further investigation and discusses the pathological mechanism. It may also facilitate improvement of the accuracy of diagnosis for DAI, which may come to play a critical role in breaking through the bottleneck of the clinical treatment of DAI and improving the survival and quality of life of patients through clear understanding of pathological mechanisms and accurate diagnosis. PMID- 28078145 TI - Thirty Years Later: Evolution of Treatment for Acute Left Main Coronary Artery Occlusion. AB - Acute occlusion of left main coronary artery is a catastrophic event. We describe two patients with acute occlusion of the left main coronary artery treated thirty years apart. The first patient was treated in 1982 and survived the event without revascularization but developed severe heart failure. His survival was so unusual that it merited a case report at that time. The second patient was treated at the end of 2015. Early revascularization resulted in myocardial reperfusion and near normal left ventricular function. These patients exemplify the progress in therapeutic cardiology over the last 30 years. PMID- 28078146 TI - Solitary Plasmacytoma in the Mandible Resembling an Odontogenic Cyst/Tumor. AB - A 46-year-old male patient referred to Department of Oral Medicine, with the primary chief complaint of a painless swelling in the right side of mandibular. A panoramic radiograph revealed a well-defined, multilocular radiolucent bony lesion with thin and straight septa in the right side of mandible extending from distal of canine to mesial of third molar. Histological examination showed a solid proliferation of atypical plasmacytoid cells, which was indicative of plasmacytoma. A systemic workup for the final diagnosis was performed to rule out multiple myeloma. PMID- 28078147 TI - Reestablishing the Function and Esthetics in Traumatized Permanent Teeth with Large Apical Lesion. AB - Dental trauma is a challenge for dental integrity and can lead to pulp necrosis. The clinical case reports the diagnosis of a maxillary right central incisor traumatized and its multidisciplinary treatment. Calcium hydroxide material was used to perform the processing apexification. An apical surgery was carried out to remove the apical periodontitis and to return the aesthetics to the patient; internal and external tooth whitening in maxillary right central incisor was performed. We conclude that surgery associated with the root filling in the central incisor led to a successful completion. Moreover, it is of utmost importance to demonstrate the interaction between the various areas of dentistry. PMID- 28078148 TI - Colonoscopic Splenic Injury: A Simplified Radiologic Approach. AB - Colonoscopy is a commonly performed procedure for diagnosis and treatment of large bowel diseases. Recognized complications include bleeding and perforation. Splenic injury during colonoscopy is a rare complication. We report a case of a 73-year-old woman who presented with left-sided abdominal pain after colonoscopy with finding of splenic injury on CT scan. She was managed conservatively. We discuss the diagnostic and therapeutic approach to colonoscopic splenic injury. PMID- 28078149 TI - Rapid Fatal Outcome of Cryptococcal Meningoencephalitis in a Non-HIV Immunocompromised Patient with a Low Fluconazole Susceptibility Isolate: A Case Report from Madagascar. AB - Cryptococcal meningoencephalitis is considered rare in HIV-negative individuals. In Madagascar, the epidemiology of cryptococcosis has not yet been well described, neither in immunocompetent nor in immunocompromised patients. We report here the first Malagasy detailed case of cryptococcal meningoencephalitis in a non-HIV immunocompromised adult patient carrying a low fluconazole susceptibility isolate. We emphasize the importance of early and accurate diagnosis to meet the challenges of managing cryptococcosis in developing countries. PMID- 28078150 TI - Dengue Fever-Associated Maculopathy and Panuveitis in Australia. AB - Purpose. To describe a case of dengue fever-associated maculopathy and panuveitis to raise awareness of these ophthalmic complications of dengue in Australia in the light of recent increasing numbers of outbreaks from equatorial through to tropical Australia. Case Report. A 37-year-old Caucasian Australian male returning from Cambodia presented with a bilateral dengue fever-associated maculopathy with left panuveitis diagnosed clinically and haematologically. Automated perimetry revealed bilateral paracentral scotomas while optical coherence tomography demonstrated the maculopathies to be of the diffuse retinal thickening type in the right eye and acute macular neuroretinopathy (AMN) type in the left eye. He was treated conservatively with only topical steroids and cycloplegia and made a full clinical visual recovery. Conclusion. Our case study underscores the importance of the awareness of the ophthalmic complications of dengue fever as despite their rarity they can be potentially sight threatening. The incidence of these complications is likely to rise in Australia with increased global warming and the distribution of Aedes aegypti into subtropical Australia. PMID- 28078151 TI - Atypical Presentation of Idiopathic Bilateral Optic Perineuritis in a Young Patient. AB - A previously healthy 27-year-old Malay male presented with acute onset of painless, severe blurring of vision in his right eye. It was associated with headache and vomiting for the past week. Relative afferent pupillary defect was present in the right eye, with reduced optic nerve function. Patient also had bilateral generalised optic disc swelling, splinter haemorrhages, and tortuous vessels. Initial examination was suggestive of either optic neuritis or raised intracranial pressure. Typical features of bilateral optic perineuritis (OPN) such as tram track and doughnut sign were observed on magnetic resonance imaging. Connective tissue and infective screening were negative. He was diagnosed with bilateral optic perineuritis and treated with high dose intravenous corticosteroids followed by a three-month course of oral steroids. His vision and optic nerve function recovered to baseline levels. PMID- 28078152 TI - An Unusual Traumatic Presentation: Luxatio Erecta Humeri and Concomitant Hip Dislocation. AB - Introduction. Inferior dislocation of the glenohumeral joint, known as luxatio erecta humeri, and posterior hip dislocation are both rare presentations in the emergency department. The most common aetiology is falling for luxatio erecta humeri. The aim of this manuscript was to present a unique case in terms of luxatio erecta humeri, which has a different aetiology, treatment method, and concomitant injury. Presentation of Case. We report a construction worker who was rescued from a collapsed building who presented with both luxatio erecta humeri and complex posterior hip dislocation. An orthopaedic surgeon reducted luxatio erecta humeri with a one-step reduction technique under procedural anaesthesia as soon as the patient's vital signs were stable. Discussion. Different concomitant injuries and various injury mechanisms have been described in regard to inferior shoulder dislocation in the literature. However, posterior dislocation of the hip as a concomitant distant region injury and trapping as an injury mechanism for luxatio erecta humeri are being described for the first time in this case report. Two reduction manoeuvers, one-step and two-step, have been used for this dislocation. Some authors suggested that a two-step manoeuver can be more easy to apply. In our specific case, luxatio erecta was easily reducted by a single operator in a single attempt. Conclusion. Luxatio erecta humeri may occur from trapping and complex injuries can accompany luxatio erecta humeri in patients with multiple trauma. A one-step closed reduction can be easily applied by a single operator under procedural anaesthesia. PMID- 28078153 TI - A Delayed Postoperative C5 Palsy due to Spinal Cord Lesion: A Typical Clinical Presentation but Unusual Imaging Findings. AB - Postoperative C5 palsy (C5 palsy) is a troublesome complication after cervical spine surgery and its etiology is still unclear. We experienced a case of C5 palsy after anterior decompression with fusion for cervical ossification of posterior longitudinal ligament with the typical clinical presentation of left deltoid and bicep weakness and left-arm pain without deterioration of myelopathy symptoms, albeit with the unusual imaging findings not shown preoperatively of a swelling in the spinal cord, and intramedullary high intensity change on T2 weighed MRI. The additional posterior surgery was carried out to decompress the swollen spinal cord. The abnormal findings disappear on MRI taken three weeks following the second surgery and the weakness improved fully within three months after the second surgery. This case report highlights the possibility of spinal cord lesion due to circulatory impairment as a cause of C5 palsy. PMID- 28078154 TI - A Rare Case of Pheohyphomycotic Lumbar Spondylodiscitis Mistreated as Koch's Spine. AB - Pheohyphomycosis is an uncommon infection and its association in spondylodiscitis has not yet been reported. The purpose of this case report is to describe a rare case of Pheohyphomycotic spondylodiscitis and methods to diagnose and manage the patient with less invasive techniques. A 29-year-old male patient presented to the outpatient department with complaints of gradually increasing low back pain with bilateral lower limbs radicular pain since one and a half years. He had associated fever, weight loss, voice changes, and dry, scaly, erythematous skin with elevated ESR. The patient had been taking anti-Koch's therapy since 1 year with little relief in pain and no radiological improvement. Percutaneous pedicle biopsy of L4 vertebra was taken under local anaesthesia and confirmed Pheohyphomycosis which was treated with antifungal medications. The patient showed sequential improvement with long term antifungal treatment. He was eventually able to walk independently without support. PMID- 28078156 TI - Undifferentiated Malignant Neoplasm Involving Parotid and Thyroid: Sampling and PAX8 Cross-Reactivity Can Obscure the Diagnosis of Lymphoma. AB - Poorly differentiated malignant neoplasia arising within the head and neck region may originate from diverse sources. We report a case of a cytologically undifferentiated malignant neoplasm clinically presenting as masses involving thyroid and parotid. Although PAX8 was immunoreactive and thus worrisome for anaplastic thyroid carcinoma, the tumor was eventually proven to represent PAX5 positive diffuse large B-cell lymphoma expressing cross-reactivity with polyclonal PAX8 antibody. Cross-reactivity between commercially available polyclonal PAX8 and PAX5 immunostains has been described in the literature but is not widely known, and it is a potential pitfall for making a misdiagnosis. This distinction can have importance in selection of subsequent clinical therapy and should be considered in choice of immunohistochemical stains for diagnostic purposes. PMID- 28078155 TI - Lipomatous Hypertrophy of the Atrial Septum in a Patient Undergoing Coronary Artery Bypass Surgery. AB - Background. Lipomatous hypertrophy of the atrial septum (LHAS) is a rare entity characterized by mass-forming deposition of fatty tissue within the atrial septum. To date, <300 cases have been reported; many of them were autopsy findings. The clinical presentation of LHAS varies from incidental asymptomatic mass (most frequent form) to severe life-threatening cardiovascular complications necessitating emergency cardiac surgery. Case Presentation. Here, we present the successful surgical resection of such a massive LHAS which was found incidentally on preoperative investigation of a 71-year-old patient with progressive coronary heart disease. Histology confirmed the diagnosis of lipomatous hypertrophy of the atrial septum. Conclusions. The described case report illustrates an unusual example of LHAS in a patient undergoing a planned coronary artery bypass surgery. In this case, surgical intervention was justified to avoid later outflow obstructions. PMID- 28078157 TI - Dendritic Fibromyxolipoma of the Pyriform Sinus: A Case Report and Review of the Literature. AB - Dendritic fibromyxolipoma is a rare and distinctive soft tissue neoplasm that is considered by many authors as a variant of spindle cell lipoma and characterized by the presence of dendritic cytoplasmic processes, plexiform vascular pattern, and keloidal collagen. It has never been reported in the larynx and hypopharynx. Its rarity and the potential to mistake it as a more clinically aggressive myxoid soft tissue neoplasm highlight the importance of its recognition. Here, a case of a dendritic fibromyxolipoma of the pyriform sinus in a 38-year-old male who presented with dysphagia, change of voice, and stridor is reported. A review of the literature, including histopathologic features and differential diagnosis, is also included. PMID- 28078158 TI - Unusual Presentation of Primary Squamous Cell Carcinoma of Mandible. AB - Carcinoma arising primarily from the jaw is a locally aggressive lesion with poor prognosis. Primary intraosseous carcinoma (PIOC) lesion develops either de novo remnants of odontogenic epithelium, odontogenic cyst/tumor, epithelium remnants, or/and salivary gland residues. We describe very interesting case of primary intraosseous carcinoma of mandible. This extensive lesion was sent for oncological opinion and further management. Due to the uncertainty of diagnostic criteria of PIOC, only few cases of this lesion with a typical presentation have been reported. This article presents a case of primary intraosseous carcinoma with a unique appearance and detailed review stating its clinicopathological correlation. PMID- 28078159 TI - Schwannoma Localized Retroperitoneally in a 14-Year-Old Boy. AB - Schwannomas usually occur in adults being between the second and fifth decades, and such neoplasms are extremely rare in a pediatric population. In addition, they are not normally found in the retroperitoneal region. Here, we present a pediatric case of a retroperitoneal schwannoma in an adrenal location where the tumor was not able to be preoperatively differentiated from other benign or malign adrenal gland tumors. In our opinion, this tumor can be included in the differential diagnosis of a nonfunctioning retroperitoneal adrenal mass in children. PMID- 28078160 TI - Primary Mucinous Adenocarcinoma of the Urinary Bladder with Signet-Ring Cells: Description of an Uncommon Case and Critical Points in Its Management. AB - We present an uncommon case of mucinous adenocarcinoma of the bladder (MAB) with signet-ring cells extensively infiltrating prostate gland and pelvic/retroperitoneal lymph node stations and not responsive to usual systemic chemotherapy regimens. This case highlights the important features of MAB including the pattern of tumor spread, the tendency for initial misdiagnosis, and the importance of immunohistochemical study in order to define its primary origin from the bladder and choose the most appropriate treatment since the beginning. PMID- 28078161 TI - A Case-Control Association Study of RANTES (-28C>G) Polymorphism as a Risk Factor for Parkinson's Disease in Isparta, Turkey. AB - Background. Recent studies have revealed that inflammatory processes are involved in the pathogenesis of Parkinson's disease (PD). Multiple lines of evidence have suggested that chemokines and their receptors are involved in several neurodegenerative disorders. We have examined whether genetic polymorphisms at the genes encoding chemokines IL-8 (-251A>T), MCP-1 (-2518A/G), and RANTES ( 28C>G) and chemokine receptors CCR2 (V64I) and CCR5 (-Delta32) were associated with sporadic PD risk in Isparta, Turkey. Method. The pilot case-control association study included 30 PD patients and 60 control subjects, who were all genotyped with PCR-RFLP for the five polymorphisms. Their genotype and haplotype frequencies were compared statistically. Results. One SNP (-28C>G) in RANTES revealed a significant association with PD (P (allele) < 0.0001, p-trend = 0.0007). The risk allele (G) in the homozygous and dominant models (OR = 17.29 and 32.10, 95% CI = 0.86-347.24 and 1.74-591.937, resp.) suggests additional PD risk. The haplotype TGCAN from the IL-8 (-251A>T), MCP-1 (-2518A>G), RANTES ( 28C>G), CCR-2 (V64I), and CCR-5 (-Delta32) has protective effect (OR = 0.08 [CI = 0.01-0.63], p = 0.019). Conclusions. Our data are the first indication of the role of RANTES (-28C>G) in PD risk. PMID- 28078162 TI - Ophthalmologic Baseline Characteristics and 2-Year Ophthalmologic Safety Profile of Pramipexole IR Compared with Ropinirole IR in Patients with Early Parkinson's Disease. AB - Background. Parkinson's disease (PD) progressively affects dopaminergic neurotransmission and may affect retinal dopaminergic functions and structures. Objective. This 2-year randomized, open-label, parallel-group, flexible-dose study, NCT00144300, evaluated ophthalmologic safety profiles of immediate-release (IR) pramipexole and ropinirole in patients with early idiopathic PD with <=6 months' prior dopamine agonist exposure and without preexisting major eye disorders. Methods. Patients received labeled IR regimens of pramipexole (n = 121) or ropinirole (n = 125) for 2 years. Comprehensive ophthalmologic assessments (COA) included corrected acuity, Roth 28-color test, slit-lamp biomicroscopy, intraocular pressure, computerized visual field test, fundus photography, and electroretinography. Results. At baseline, we observed retinal pigmentary epithelium (RPE) hypopigmentation not previously reported in PD patients. The estimated relative risk of 2-year COA worsening with pramipexole versus ropinirole was 1.07 (95% CI: 0.71-1.60). Mean changes from baseline in Unified Parkinson's Disease Rating System parts II+III total scores (pramipexole: 1 year, -4.1 +/- 8.9, and 2 years, -0.7 +/- 10.1, and ropinirole: 1 year, -3.7 +/ 8.2, and 2 years, -1.7 +/- 10.5) and Hoehn-Yahr stage distribution showed therapeutic effects on PD symptoms. Safety profiles were consistent with labeling. Conclusions. The risk of retinal deterioration did not differ in early idiopathic PD patients receiving pramipexole versus ropinirole. RPE hypopigmentation at baseline was not previously reported in this population. This trial is registered with NCT00144300. PMID- 28078163 TI - Catalase-Based Modified Graphite Electrode for Hydrogen Peroxide Detection in Different Beverages. AB - A catalase-based (NAF/MWCNTs) nanocomposite film modified glassy carbon electrode for hydrogen peroxide (H2O2) detection was developed. The developed biosensor was characterized in terms of its bioelectrochemical properties. Cyclic voltammetry (CV) technique was employed to study the redox features of the enzyme in the absence and in the presence of nanomaterials dispersed in Nafion(r) polymeric solution. The electron transfer coefficient, alpha, and the electron transfer rate constant, ks , were found to be 0.42 and 1.71 s-1, at pH 7.0, respectively. Subsequently, the same modification steps were applied to mesoporous graphite screen-printed electrodes. Also, these electrodes were characterized in terms of their main electrochemical and kinetic parameters. The biosensor performances improved considerably after modification with nanomaterials. Moreover, the association of Nafion with carbon nanotubes retained the biological activity of the redox protein. The enzyme electrode response was linear in the range 2.5-1150 MUmol L-1, with LOD of 0.83 MUmol L-1. From the experimental data, we can assess the possibility of using the modified biosensor as a useful tool for H2O2 determination in packaged beverages. PMID- 28078164 TI - Effectiveness of Laser Therapy in the Management of Recurrent Aphthous Stomatitis: A Systematic Review. AB - Objectives. Laser therapy is a promising new treatment for patients with recurrent aphthous stomatitis (RAS). However, the clinical effect and security issue of laser therapy remain controversial. This systematic review was conducted to evaluate the clinical effectiveness and security of laser treatment in RAS patients. Methods. Five electronic databases were searched (MEDLINE (PubMed), EMBASE, ScienceDirect, the Cochrane Library, and Web of Science) to identify all studies that were about randomized controlled clinical trials, involving the effect of laser therapy in RAS patients. Conclusion. Twenty-three studies were retained for full-text analysis after screening the titles and abstracts of potential articles, but only 10 studies satisfied the inclusion criteria after the full texts were reviewed. The included studies reported a comparison of the effectiveness between the laser treatment and placebo laser therapy (or conventional drug therapy) when managing the RAS patients. It can be concluded that laser therapy has the superiority in relieving ulcer pain and shortening healing time when compared with placebo group or medical treatment group. Although laser therapy is a promising effective treatment for RAS, high-quality clinical studies with large sample size must be further performed to confirm the effectiveness of this therapy. PMID- 28078165 TI - The globalization of messenger RNA regulation. PMID- 28078166 TI - Selective Cobalt-Catalyzed Reduction of Terminal Alkenes and Alkynes Using (EtO)2Si(Me)H as a Stoichiometric Reductant. AB - While attempting to effect Co-catalyzed hydrosilylation of beta-vinyl trimethylsilyl enol ethers we discovered that depending on the silane, solvent and the method of generation of the reduced cobalt catalyst, a highly efficient and selective reduction or hydrosilylation of an alkene can be achieved. This paper deals with this reduction reaction, which has not been reported before in spite of the huge research activity in this area. The reaction, which uses an air stable [2,6-di(aryliminoyl)pyridine)]CoCl2 activated by 2 equivalents of NaEt3BH as a catalyst (0.001-0.05 equiv) and (EtO)2SiMeH as the hydrogen source, is best run at ambient temperature in toluene and is highly selective for the reduction of simple unsubstituted 1-alkenes and the terminal double bonds in 1,3- and 1,4 dienes, beta-vinyl ketones and silyloxy dienes. The reaction is tolerant of various functional groups such as a bromide, alcohol, amine, carbonyl, and di or trisubstituted double bonds, and water. Highly selective reduction of a terminal alkyne to either an alkene or alkane can be accomplished by using stoichiometric amounts of the silane. Preliminary mechanistic studies indicate that the reaction is stoichiometric in the silane and both hydrogens in the product come from the silane. PMID- 28078167 TI - A Novel Strategy for Attenuating Opioid Withdrawal in Neonates. AB - The rate of Neonatal Abstinence Syndrome (NAS) has drastically increased over the past decade. The average hospital expense per NAS patient has tripled, while the number of babies born to opioid-dependent mothers has increased to 5 in 1000 births. Current treatment options are limited to opioid replacement and tapering. Consequently, we examined the efficacy of prenatal, low-dose and short-term vigabatrin (gamma-vinyl GABA, GVG) exposure for attenuating these symptoms as well as the metabolic changes observed in the brains of these animals upon reaching adolescence. Pregnant Sprague-Dawley rats were treated in one of four ways: 1) saline; 2) morphine alone; 3) morphine+GVG at 25 mg/kg; 4) morphine+GVG at 50 mg/kg. Morphine was administered throughout gestation, while GVG administration occurred only during the last 5 days of gestation. On post-natal day 1, naloxone-induced withdrawal behaviours were recorded in order to obtain a gross behaviour score. Approximately 28 days following birth, 18FDG microPET scans were obtained on these same animals (Groups 1, 2, and 4). Morphine-treated neonates demonstrated significantly higher withdrawal scores than saline controls. However, GVG at 50 but not 25 mg/kg/day significantly attenuated them. Upon reaching adolescence, morphine treated animals showed regionally specific changes in 18FDG uptake. Again, prenatal GVG exposure blocked them. These data demonstrate that low-dose, short-term prenatal GVG administration blocks naloxone induced withdrawal in neonates. Taken together, these preliminary findings suggest that GVG may provide an alternative and long-lasting pharmacologic approach for the management of neonatal and adolescent symptoms associated with NAS. PMID- 28078168 TI - Concurrent Validity of Caffeine Problems and Diagnostic Criteria for Substance Use Disorders. AB - Background: The DSM-5 proposes caffeine use disorder (CUD) as a condition for further study. The objective of this study was to report on the prevalence of CUD and rates of endorsement for each substance use disorder (SUD) criterion in relation to caffeine compared to alcohol and marijuana in a sample of adolescents presenting for medical care in the primary, adolescent, and substance use clinics at an academic medical center. Methods: A convenience sample of patients (N = 213; 66.7% female) aged 12-17 presenting for medical care completed the Composite Diagnostic Interview-Substance Abuse Module questionnaire, with questions regarding use of caffeine, alcohol, and marijuana. Descriptive analyses were used to determine prevalence of CUD and frequency of each endorsed SUD criterion as applied to caffeine versus alcohol or marijuana. Comparative Fit Index (CFI) and Tucker-Lewis Index (TLI) were used to determine psychometric properties for CUD. Results: The majority of subjects (N = 153) reported past 30-day caffeine use and of these, six (4%) met criteria for CUD. All six also met criteria for either alcohol and/or marijuana use disorders. Of the three essential CUD criteria (failure to quit, use despite harm, and withdrawal), both harm and withdrawal were endorsed significantly more often in relation to caffeine versus alcohol. Descriptive fit indices for the CUD model were excellent (CFI = 0.994, TLI = 0.991). Conclusions: In our sample, the proportion of adolescents that met proposed CUD criteria was low, suggesting that the proposed criteria would not lead to overdiagnosis of CUD. CUD was highly correlated with other SUDs. PMID- 28078169 TI - A Survey of Energy Drink Consumption Patterns Among College Students at a Mostly Hispanic University. AB - Background: The purpose of this study was to determine energy drink (ED) consumption patterns among Hispanic college students. We measured the prevalence and frequency of ED consumption according to gender, degree programs, and specific university-related and social situations. In addition, we assessed the frequency of consumption of EDs mixed with alcoholic beverages. Methods: A total of 508 college students from the University of Puerto Rico, the largest Hispanic institution of higher education statewide, completed an online questionnaire. Results: Twenty-one percent of participants reported consuming EDs with the majority consuming EDs either occasionally (every 2-3 months) or at least once or twice a month. Men were found to be more likely to consume EDs than women. Undergraduate students were found less likely to consume EDs than graduate students. Most students consumed EDs while studying and during social activities. More than one-third of participants that consume EDs admitted mixing them with an alcoholic beverage. Graduate students were found to consume EDs mixed with alcohol more often. Conclusions: The majority of students consumed EDs occasionally and while studying. Most side effects reported after consuming EDs were similar to previous findings. The higher consumption of EDs and of EDs mixed with alcohol by students in graduate programs could be explained by a higher and more complex study load requiring longer periods of wakefulness and concentration. Future studies looking at the consumption patterns of EDs in more competitive graduate programs such as medical and/or dentistry school should be considered. PMID- 28078170 TI - Computational fluid dynamics assisted characterization of parafoveal hemodynamics in normal and diabetic eyes using adaptive optics scanning laser ophthalmoscopy. AB - Diabetic retinopathy (DR) is the leading cause of visual loss in working-age adults worldwide. Previous studies have found hemodynamic changes in the diabetic eyes, which precede clinically evident pathological alterations of the retinal microvasculature. There is a pressing need for new methods to allow greater understanding of these early hemodynamic changes that occur in DR. In this study, we propose a noninvasive method for the assessment of hemodynamics around the fovea (a region of the eye of paramount importance for vision). The proposed methodology combines adaptive optics scanning laser ophthalmoscopy and computational fluid dynamics modeling. We compare results obtained with this technique with in vivo measurements of blood flow based on blood cell aggregation tracking. Our results suggest that parafoveal hemodynamics, such as capillary velocity, wall shear stress, and capillary perfusion pressure can be noninvasively and reliably characterized with this method in both healthy and diabetic retinopathy patients. PMID- 28078171 TI - Could Revision of the Embryology Influence Our Cesarean Delivery Technique: Towards an Optimized Cesarean Delivery for Universal Use. AB - Until today, there is no standardized Cesarean Section method and many variations exist. The main variations concern the type of abdominal incision, usage of abdominal packs, suturing the uterus in one or two layers, and suturing the peritoneal layers or leaving them open. One of the questions is the optimal location of opening the uterus. Recently, omission of the bladder flap was recommended. The anatomy and histology as results from the embryological knowledge might help to solve this question. The working thesis is that the higher the incision is done, the more damage to muscle tissue can take place contrary to incision in the lower segment, where fibrous tissue prevails. In this perspective, a call for participation in a two-armed prospective study is included, which could result in an optimal, evidence-based Cesarean Section for universal use. PMID- 28078172 TI - Gastric Rupture in Pregnancy: Case Series from a Tertiary Institution in Rwanda and Review of the Literature. AB - Background Gastric rupture is a rare, life-threatening condition during pregnancy. Case study We present three cases of gastric perforation during pregnancy and the puerperium. The first patient presented with gastric perforation 4 days following an uncomplicated cesarean delivery for obstetric indications. She initially complained of epigastric pain; however, those symptoms resolved. She later demonstrated worsening abdominal distension, intra-abdominal free fluid, and signs of peritonitis. At laparotomy, an ascariasis-associated gastric rupture was diagnosed. She died from sepsis 4 days following the laparotomy. The second patient presented 19 days following a normal vaginal delivery. She presented with hemodynamic instability and underwent emergent laparotomy due to suspected septic shock peritonitis. Gastric rupture was diagnosed intraoperatively. She improved clinically and was discharged home. The third patient underwent emergency cesarean delivery due to non-reassuring fetal status in the setting of preeclampsia. She was initially diagnosed with ascites and pulmonary edema as a result of preeclampsia. Later in her course, she developed features in favor of acute abdomen and signs of sepsis. At the time of emergent laparotomy, a gastric rupture was identified and repaired. She died 2 days later from sepsis. Conclusion We report the management and outcome of three cases of pregnancy-related gastric rupture. To our knowledge, these three cases represent the largest series of pregnancy-related gastric ruptures from a single institution. PMID- 28078173 TI - Screening of SMAD7 in Malay patients with ventricular septal defect. AB - Ventricular septal defect (VSD) is the most common form of cardiac malformations accounting approximately 20% of all congenital heart defects. SMAD7 is an inhibitory protein that antagonizes the signalling of TGF-beta family member and has been found in the development and function of mouse heart models. This study aims to screen and identify the polymorphisms of SMAD7 exonic regions in Malay population with VSD. Peripheral blood samples were collected and extracted from 30 clinically diagnosed VSD patients. PCR amplification was performed using 12 sets of designed primers encompassing seven exons of SMAD7. Re-sequencing was conducted to characterize the polymorphisms of SMAD7. Observed polymorphisms were then genotyped in 30 healthy individuals using both re-sequencing and allele specific PCR techniques. A total of 10 variants were identified in the patient population located in the upstream (rs7236774), exonic (rs368427729, rs145686330, rs3764482, rs3809922, rs780863704 and rs3809923), intronic (rs3736242) and 3'UTR regions (rs375444823 and rs16950113). No significant difference of genotype and allele frequency was observed among these SNPs. Two synonymous variants (rs3809922 and rs3809923) were found in complete linkage disequilibrium (r2=1.0) with each other indicate a strong correlation of these SNPs. The identification of these SNPs provides a new perspective of the VSD causation. PMID- 28078174 TI - Influence of different doses of coffee on post-exercise blood pressure response. AB - The reduction in blood pressure after the physical exercise practice is called postexercise hypotension (PEH). Previous studies have demonstrated that the ingestion of caffeine at levels corresponding to three doses of coffee eliminates this phenomenon. Thus, we evaluated the influence of different doses of coffee in the PEH in twelve hypertensives, who performed four experimental sessions of aerobic exercise on a cycle ergometer (lasting 40 minutes, with intensity between 60% and 80% of maximum heart rate), followed by the ingestion of one (CAF-1), two (CAF-2), or three (CAF-3) doses of caffeinated coffee, or three doses of decaffeinated coffee (DESC). The blood pressure was measured at rest and at 10 minute intervals during 120 minutes of recovery post exercise. DESC resulted in systolic PEH at all moments of measurement, with averages of -4.1+/-1.2 mmHg and 1.8+/-1.3 mmHg on the 1st and 2nd hours post exercise, respectively. In CAF-1, both systolic hypotensive and hypertensive responses to the exercise were identified, with averages of -1.2+/-1.7 and 0.5+/-0.4 mmHg after one and two hours of recovery. Conversely, hypertensive systolic response occurred in all measurements compared rest blood pressure. The 1st and 2nd hours post exercise was 4.5+/-1.1 and 6.5+1.1 mmHg in CAF-2 and 5.1+0.9 and 6.5+1.0 mmHg to CAF-3. Diastolic PEH was not found in any of the experimental sessions. Therefore, the ingestion of two and three doses of caffeinated coffee completely blunts the PEH, while one dose results in partial elimination of the PEH. PMID- 28078175 TI - Effects of sitagliptin on coronary atherosclerosis in patients with type 2 diabetes-A serial integrated backscatter-intravascular ultrasound study. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors have demonstrated anti-inflammatory and anti-atherogenic effects in an animal model. However, the clinical usefulness of DPP-4 inhibitors, particularly its effects on coronary atherosclerosis, has not been evaluated thus far. Therefore, in this study, we evaluated the effects of sitagliptin, a DPP-4 inhibitor, on coronary atherosclerosis using integrated backscatter (IB)-intravascular ultrasound (IVUS) in patients with type 2 diabetes. This trial was a prospective, open-labeled, randomized, multicenter study. Twenty-eight patients with type 2 diabetes who underwent elective percutaneous coronary intervention (PCI) were randomly assigned to either the sitagliptin group (group S) or the control group (group C). Non-PCI lesions were evaluated using IB-IVUS at the time of PCI and at the 48-week follow-up. The primary endpoint was the percentage change in plaque volume measured using grayscale IVUS, and the secondary endpoint was changes in plaque composition evaluated using IB-IVUS. Grayscale IVUS analysis demonstrated that plaque volume tended to decrease in both groups (group S: -1.7+/-8.5%; group C: -3.2+/-12.2%), but a between-group difference was not observed. A decrease in the lipid plaque volume (group S: from 200.1+/-116.2 to 179.8+/-121.0 mm3, P = 0.02; group C: from 298.3+/-363.0 to 256.6+/-386.1 mm3, P = 0.1) and an increase in the calcified plaque volume (group S: from 2.1+/-0.9 to 3.2+/-1.8 mm3, P = 0.06; group C: from 2.3+/-1.7 to 4.8+/-3.5 mm3, P = 0.04) was observed on IB-IVUS analysis. Univariate and multivariate regression analyses showed that the percentage change in serum non-high-density lipoprotein (HDL) cholesterol level was an independent and significant predictor of a reduction in lipid plaque volume (beta = 0.445, P = 0.04). In conclusions, sitagliptin did not significantly reduce coronary plaque volume in patients with type 2 diabetes. However, a decrease in the lipid plaque volume was observed in the sitagliptin group. A decrease in non-HDL cholesterol level was associated with a reduction in the lipid volume of coronary artery plaques. PMID- 28078176 TI - The function of cathepsins B, D, and X in atherosclerosis. AB - Cathepsins are proteolytic enzymes typically located within the lysosomes of macrophages. Once released, they can enhance the inflammatory process in atherosclerosis. Cathepsin X aids in the migration of T-lymphocytes and the release of cytokines. Cathepsin D modifies low-density lipoprotein to promote its uptake by macrophages and its subsequent foam cell formation. Furthermore, cathepsin D regulates apoptosis. Cathepsin B degrades the extracellular matrix within the arterial intima. Together, they increase plaque vulnerability. This evidence suggests that cathepsins play an important role in the pathogenesis of atherosclerosis. PMID- 28078177 TI - Generation of a giant coronary artery aneurysm from an intra-plaque cavity with a ruptured fibrous cap: an observation over time through coronary angiography. AB - A 74-year-old man underwent coronary artery bypass graft surgery. Thirteen years later, he presented with complaints of exertional anterior chest oppression again. Computed tomography coronary angiography revealed the significant stenosis at the mid right coronary artery (RCA). In addition, a giant proximal left anterior descending (LAD) coronary artery aneurysm (CAA) was found. We did not observe this aneurysm on his previous coronary angiogram, performed 12 years previously (i.e., 1 year after his surgery). Diagnostic coronary angiography confirmed the computed tomography findings. We found the significant stenosis at the mid RCA site and a giant proximal LAD coronary artery aneurysm. First, we performed the percutaneous coronary intervention (PCI) at the mid RCA significant stenosis. We implanted the drug eluting stent. After that, we performed PCI to treat the giant proximal LAD coronary artery aneurysm with a covered stent (a 2.8/26-mm polytetrafluoroethylene covered stent), and complete exclusion of the aneurysm was obtained. The etiology of this patient's aneurysm was unclear, but we speculate that the mechanism responsible for the appearance of this aneurysm was the expansion of the intra-plaque cavity with the ruptured fibrous cap. This observation over time through coronary angiography suggests that giant CAAs might be generated asymptomatically under certain conditions. In this case, the possible conditions might have been the chronic total occlusion of the mid-LAD and the significant stenosis just distal to this aneurysm, so increasing flow and pressure against this diseased cavity might have caused this giant CAA to form. In addition, another speculation might have been the local inflammation or macrophage-based degradation after coronary artery bypass graft surgery. PMID- 28078178 TI - Relationship between R-R interval and left ventricular systolic synchrony in subjects with coronary artery disease determined using angiography. AB - The aim of this study was to assess the relationship between R-R interval and left ventricular systolic synchrony in subjects with coronary artery disease determined using angiography. A total of 277 subjects who underwent coronary angiography for suspected CAD were recruited in this study. For all subjects, the R-R interval was quantified using simultaneous ECG, and the times to peak systolic longitudinal strain (Tssl) on 17 LV segments were quantified using four dimensional (4D) speckle tracking echocardiography (STE) and manually measured. The independent predictors of R-R interval using multiple linear regression analyses were the time to peak systolic longitudinal strain in the apical-septal segment (Tssl-Apical-S) (beta=0.325, P=0.000), smoking status (beta=0.141, P=0.013), and the time to peak systolic longitudinal strain in the basal anterolateral segment (Tssl-Basal-AL) (beta=0.151, P=0.014), which were significantly independently associated with the R-R interval. In multiple regression analyses, smoking status (OR, 1.943; 95% CI, 1.119-3.375, P=0.018), Tssl-Basal-AL (OR, 1.002; 95% CI, 1.000-1.004, P=0.043), the time to peak systolic longitudinal strain in the mid-inferoseptal segment (Tssl-Mid-IS) (OR, 1.008; 95% CI, 1.003-1.013, P=0.004), and Tssl-Apical-S (OR, 1.010; 95% CI, 1.004 1.016, P=0.002) remained independently associated with the risk of a longer R-R interval (the median 849.49 ms was set as the cutoff value) in the population. Our findings may provide the basis for future investigations of LV systolic synchrony and cardiac resynchronization therapy. PMID- 28078179 TI - Tsutsugamushi disease presenting with aortic valve endocarditis: a case report and literature review. AB - Tsutsugamushi disease is a zoonotic disease caused by Orientia tsutsugamushi in which humans are accidental hosts. Infective endocarditis associated with Tsutsugamushi disease has not been previously reported. We are describing a case of Tsutsugamushi disease presenting with aortic valve endocarditis. The clinical data of a 67-year-old female with O. tsutsugamushi-induced aortic valve endocarditis was summarized retrospectively and analyzed with a literature review. Treatment of O. tsutsugamushi-induced aortic valve endocarditis with chloramphenicol is recommended. PMID- 28078180 TI - Effects of the nephrilin peptide on post-burn glycemic control, renal function, fat and lean body mass, and wound healing. AB - The mechanisms underlying the effects of severe burn trauma are not well understood. We previously demonstrated the ability of nephrilin peptide (an iron binding peptide believed to enter cells through iron-uptake pathways) to suppress aspects of the neuroinflammatory response in a rat scald model, as well as sepsis mortality in a mouse model. This study explores the effect of nephrilin on other clinically relevant outcomes in the rat scald model. In a rat scald model, animals were treated with nephrilin either in week 1 or week 2 post-burn. Measurements were made of serum glucose and creatinine as well as wound area by planimetry and body composition by DEXA. Given the potential role of iron, results were analyzed both for the entire cohort of animals and for the normoferremic (>100 ug/dL serum iron) subset of animals. Nephrilin improved body composition, wound healing, kidney function, and glycemic control. The first two effects were significant in normoferremic but not in hypoferremic animals suggesting an effect of iron status on burn injury outcomes. Nephrilin treatment modulates a number of relevant variables in the rat scald model. PMID- 28078181 TI - Use of nano-sized clay crystallites to restore adhesion among tumor and aging stem cells - a molecular simulations approach. AB - Adhesion of cells to the ECM is key to the regulation of cellular morphology, migration, proliferation, survival, and differentiation. The decrease in or loss of the cell's ability of mutual adhesiveness has been considered as one of the specific abnormalities in the surface properties of malignant cells. A change in the association of plasma membrane with cytoskeletal structures also seems to have a close relation with these abnormalities. Similar to the role of adhesions in tumor cells, stem cells' self-renewal is also tightly controlled by the concerted action of stem cell-intrinsic factors and signals within the niche. This study has demonstrated through molecular simulations the potential use of smectite (Na-montmorillonite) clay crystallites to create adhesions among tumor and stem cells. High electrostatic energies and cohesive energy densities measured in the simulations after the sorption of clay crystallites on cell-cell and cell-ECM complexes validate the concept of using these crystallites for the purposes. As results of this study are quite promising and clay crystallites could be considered as an option to restore adhesions in tumor and stem cells, other confirmatory tests and live cell culture studies are in process for the final validation. PMID- 28078182 TI - Utility of 11C-methionine and 11C-donepezil for imaging of Staphylococcus aureus induced osteomyelitis in a juvenile porcine model: comparison to autologous 111In labelled leukocytes, 99m Tc-DPD, and 18F-FDG. AB - The aim of this study was to compare 11C-methionine and 11C-donepezil positron emission tomography (PET) with 111In-labeled leukocyte and 99m Tc-DPD (Tc-99m 3,3 diphosphono-1,2-propanedicarboxylic acid) single-photon emission computed tomography (SPECT), and 18F-fluorodeoxyglucose (18F-FDG) PET to improve detection of osteomyelitis. The tracers' diagnostic utility where tested in a juvenile porcine hematogenously induced osteomyelitis model comparable to osteomyelitis in children. Five 8-9 weeks old female domestic pigs were scanned seven days after intra-arterial inoculation in the right femoral artery with a porcine strain of Staphylococcus aureus. The sequential scan protocol included Computed Tomography, 11C-methionine and 11C-donepezil PET, 99m Tc-DPD and 111In-labelled leukocytes scintigraphy, and 18F-FDG PET. This was followed by necropsy of the pigs and gross pathology, histopathology, and microbial examination. The pigs developed a total of 24 osteomyelitic lesions, 4 lesions characterized as contiguous abscesses and pulmonary abscesses (in two pigs). By comparing the 24 osteomyelitic lesions, 18F-FDG accumulated in 100%, 111In-leukocytes in 79%, 11C methionine in 79%, 11C-donepezil in 58%, and 99m Tc-DPD in none. Overall, 18F-FDG PET was superior to 111In-leukocyte SPECT and 11C-methionine in marking infectious lesions. PMID- 28078183 TI - Absorbed radiation dosimetry of the D3-specific PET radioligand [18F]FluorTriopride estimated using rodent and nonhuman primate. AB - [18F]FluorTriopride ([18F]FTP) is a dopamine D3-receptor preferring radioligand with potential for investigation of neuropsychiatric disorders including Parkinson disease, dystonia and schizophrenia. Here we estimate human radiation dosimetry for [18F]FTP based on the ex-vivo biodistribution in rodents and in vivo distribution in nonhuman primates. Biodistribution data were generated using male and female Sprague-Dawley rats injected with ~370 KBq of [18F]FTP and euthanized at 5, 30, 60, 120, and 240 min. Organs of interest were dissected, weighed and assayed for radioactivity content. PET imaging studies were performed in two male and one female macaque fascicularis administered 143-190 MBq of [18F]FTP and scanned whole-body in sequential sections. Organ residence times were calculated based on organ time activity curves (TAC) created from regions of Interest. OLINDA/EXM 1.1 was used to estimate human radiation dosimetry based on scaled organ residence times. In the rodent, the highest absorbed radiation dose was the upper large intestines (0.32-0.49 mGy/MBq), with an effective dose of 0.07 mSv/MBq in males and 0.1 mSv/MBq in females. For the nonhuman primate, however, the gallbladder wall was the critical organ (1.81 mGy/MBq), and the effective dose was 0.02 mSv/MBq. The species discrepancy in dosimetry estimates for [18F]FTP based on rat and primate data can be attributed to the slower transit of tracer through the hepatobiliary track of the primate compared to the rat, which lacks a gallbladder. Out findings demonstrate that the nonhuman primate model is more appropriate model for estimating human absorbed radiation dosimetry when hepatobiliary excretion plays a major role in radiotracer elimination. PMID- 28078185 TI - CXCL11 Expression by Keratinocytes Occurs Transiently Between Reaching Confluence and Cellular Compaction. AB - Objective: To investigate whether differentiation or cellular confluence is responsible for CXCL11 expression patterns in re-epithelialization. Approach:In vitro model systems of re-epithelialization using the HaCaT keratinocyte cell line were utilized in monitoring expression of differentiation markers, including desmoplakin and various cytokeratins while evaluating for an association with chemokine CXCL11 expression. Results: CXCL11 expression was elevated in sparse culture with peak expression near the time of confluence. This somewhat followed the accumulation of desmoplakin in detergent-insoluble pool of proteins. However, in postconfluent, despite continued accumulation of desmoplakin within cells, CXCL11 expression decreased to baseline levels. This biphasic pattern was also seen in low calcium culture, an environment that inhibits keratinocyte differentiation and accumulation of desmosomal proteins. Highest CXCL11 expressing areas best correlated with newly confluent areas within culture expressing basal keratin 14, but also activated keratin 6. Innovation: Achievement of a threshold cellular density induces cell signaling cascade through CXCR3 that, in addition to other undiscovered pathways, can progress cutaneous wounds from the proliferative into the remodeling phases of cutaneous wound healing. Conclusion: These results suggest that the achievement of confluence with increased cellular density by migrating keratinocytes at the wound edge triggers expression of CXCL11. Since CXCR3 stimulation in endothelial cells results in apoptosis and causes neovascular pruning, whereas stimulation of CXCR3 in fibroblasts results decreased motility and cellular contraction, we speculate that CXCL11 expression by epidermal cells upon achieving cellular confluence could be the source of CXCR3 stimulation in the dermis ushering a transition from proliferative to remodeling phases of wound healing. PMID- 28078186 TI - Soluble Receptor for Advanced Glycation End Products Improves Stromal Cell Derived Factor-1 Activity in Model Diabetic Environments. AB - Objective: In diabetes, hyperglycemia causes the accumulation of advanced glycation end products (AGEs) that trigger reactive oxygen species (ROS) generation through binding the receptor for AGEs (RAGE). Because exogenous growth factors have had little success in enhancing chronic wound healing, we investigated whether hyperglycemia-induced AGEs interfere with cellular responses to extracellular signals. We used stromal cell-derived factor-1 (SDF-1), an angiogenic chemokine also known to promote stem cell recruitment in skin wounds. Approach: Human leukemia-60 (HL-60) cells and mouse peripheral blood mononuclear cells (PBMCs), which express the SDF-1 receptor CXCR-4, were incubated for 24 h in medium supplemented with 25 mM d-glucose. Soluble RAGE (sRAGE) was used to block RAGE activation. Response to SDF-1 was measured in cellular migration and ROS assays. A diabetic murine excisional wound model measured SDF-1 liposome and sRAGE activity in vivo. Results: Hyperglycemia led to significant accumulation of AGEs, decreased SDF-1-directed migration, and elevated baseline ROS levels; it suppressed the ROS spike normally triggered by SDF-1. sRAGE decreased the ROS baseline and restored both the SDF-1-mediated spike and cell migration. Topically applied sRAGE alone promoted healing and enhanced the effect of exogenous SDF-1 on diabetic murine wounds. Innovation: While there is interest in using growth factors to improve wound healing, this strategy is largely ineffective in diabetic wounds. We show that sRAGE may restore signaling, thus potentiating the effect of exogenously applied growth factors. Conclusion: Blocking RAGE with sRAGE restores SDF-1-mediated cellular responses in hyperglycemic environments and may potentiate the effectiveness of SDF-1 applied in vivo. PMID- 28078184 TI - Precision medicine and molecular imaging: new targeted approaches toward cancer therapeutic and diagnosis. AB - This paper presents a review of the importance and role of precision medicine and molecular imaging technologies in cancer diagnosis with therapeutics and diagnostics purposes. Precision medicine is progressively becoming a hot topic in all disciplines related to biomedical investigation and has the capacity to become the paradigm for clinical practice. The future of medicine lies in early diagnosis and individually appropriate treatments, a concept that has been named precision medicine, i.e. delivering the right treatment to the right patient at the right time. Molecular imaging is quickly being recognized as a tool with the potential to ameliorate every aspect of cancer treatment. On the other hand, emerging high-throughput technologies such as omics techniques and systems approaches have generated a paradigm shift for biological systems in advanced life science research. In this review, we describe the precision medicine, difference between precision medicine and personalized medicine, precision medicine initiative, systems biology/medicine approaches (such as genomics, radiogenomics, transcriptomics, proteomics, and metabolomics), P4 medicine, relationship between systems biology/medicine approaches and precision medicine, and molecular imaging modalities and their utility in cancer treatment and diagnosis. Accordingly, the precision medicine and molecular imaging will enable us to accelerate and improve cancer management in future medicine. PMID- 28078187 TI - Bioelectric Field Enhancement: The Influence on Membrane Potential and Cell Migration In Vitro. AB - Objective: The extracellular matrix consists of critical components that affect fibroblast polarization and migration. The existence of both intrinsic and extrinsic electrical signals that play essential roles in the development, physiology, regeneration, and pathology of cells was discovered over a century ago. In this study, we study how the Bioelectric Field Enhancement (BEFE) device and its generated electromagnetic field (EMF) by continuous direct current (DC) significantly affect the membrane potential and cell migration of fibroblasts in vitro. Approach: This is an experimental analysis of membrane potential and cell migration of murine fibroblasts when grown in treated media that has been reconstituted with an aqueous solution that has been exposed to an EMF, which is generated by this device versus fibroblasts grown in identically prepared control media that has not been exposed to the EMF. Results: The growth of fibroblasts in the treated media shows a strong percent change in polarization of the plasma membrane and significant increase in cell migration compared to control groups. Innovation: These experiments show the potential for an adjunct wound care therapy using a continuous DC EMF application through a medium of water. Conclusion: Growth media that was reconstituted with an aqueous solution that had been exposed to this DC derived EMF shows significant changes in cell polarity and cell migration of fibroblasts in vitro. The BEFE device has shown enhanced chronic wound healing in anecdotal reports from patients globally for decades when used as a footbath/bath and could lead to a novel EMF application in wound healing. PMID- 28078188 TI - New Innovations for Deep Partial-Thickness Burn Treatment with ACell MatriStem Matrix. AB - Objective: Burn injuries remain a large financial burden on the healthcare system. According to CDC statistics (2010), nonfatal and hospitalized burns in the U.S. cost $1.8 billion for an annual incidence of ~486,000 cases. To date, no technique proves to be the ideal therapy of deep partial-thickness burns. In this study, we review a trial usage of ACell (ACell, Inc.) wound matrix on deep partial-thickness burns. Approach: Burn patients were admitted through the Vanderbilt Emergency Department. Three were consented to receive ACell therapy. Each patient suffered extremity burns, to which ACell MatriStem matrix was applied. Time to epithelialization and healing was monitored up to 1 month postintervention. Results: ACell MatriStem matrix use in deep partial-thickness burns enabled healing by 29 days on average without requiring autografts. The average total body surface area (TBSA) of injury was 7.2% with average TBSA treated with ACell equal to 2.5%. All burn sites underwent re-epithelialization after 5.6 days on average (range 4-7 days). Average length of stay after ACell placement totaled 2 days. All patients fully healed without the need for subsequent grafting or contracture development. No postoperative complications were noted. Innovation: To the extent of our knowledge, this is one of the first reported series to utilize ACell MatriStem product in deep partial-thickness extremity burns. Conclusion: Despite numerous products currently available for burn reconstruction, no one product embodies all the characteristics of an ideal graft. ACell biological extracellular matrix scaffolding appears promising, allowing for healing without use of an autograft. PMID- 28078189 TI - Dabrafenib and trametinib activity in a patient with BRAF V600E mutated and microsatellite instability high (MSI-H) metastatic endometrial cancer. AB - BACKGROUND: Targeting BRAF V600E mutation has been proven effective in the treatment of several types of cancer. In endometrial adenocarcinoma, the BRAF V600E mutation has been rarely reported. Whether targeting BRAF oncogene may represent a plausible therapeutic strategy for the rare patients with BRAF mutated endometrial cancer remains to be ascertained in prospective studies. CASE PRESENTATION: We report herein the case of a heavily pre-treated patient with recurrent microsatellite instability high (MSI-H) BRAF V600E mutated endometrial adenocarcinoma, which was successfully treated with the V600E targeting agent dabrafenib. After developing resistance to this agent, the MEK targeting agent trametinib was added to dabrafenib achieving again a therapeutic response. CONCLUSIONS: This case shows that dabrafenib both as monotherapy and when combined with trametinib may exert significant therapeutic activity in heavily pretreated BRAF V600E mutated endometrial adenocarcinoma, and highlight potential benefits of personalized treatment in this disease. PMID- 28078190 TI - Loss of quiescence and self-renewal capacity of hematopoietic stem cell in an in vitro leukemic niche. AB - BACKGROUND: Leukemic and mesenchymal stem cells interact in the leukemic microenvironment and affect each other differently. This interplay has also important implications for the hematopoietic stem cell (HSC) biology and function. This study evaluated human HSC self-renewal potential and quiescence in an in vitro leukemic niche without leukemic cells. METHODS: A leukemic niche was established by co-culturing mesenchymal stem cells with a fresh conditioned medium obtained from a leukemic (REH) cell line. After 3 days, the REH conditioned medium was removed and freshly isolated CD34+ at a density of up to 100,000 cells/ml were added to the leukemic niche. CD34+ cell evaluations (cell cycle, self-renewal gene expression and migration capacity) were performed after 3 further days of co-culture. Additionally, we preliminary investigated the soluble factors present in the leukemic niche and their effect on the mesenchymal stem cells. Statistical significance was assessed by Student's t test or the nonparametric test Kolmogorov-Smirnov. RESULTS: By co-culturing normal mesenchymal stem cells with the REH-conditioned medium we showed that hematopoietic stem cells, normally in a quiescent state, enter cell cycle and proliferate. This loss of quiescence was accompanied by an increased expression of Ki-67 and c-Myc, two well-known cell proliferation-associated markers. Two central regulators of quiescence GATA2 and p53 were also down regulated. Importantly, two genes involved in HSC self-renewal, Klf4 and the histone-lysine N-methyltransferase enzyme Ezh2, were severely affected. On the contrary, c-Kit expression, the stem cell factor receptor, was upregulated in hematopoietic stem cells when compared to the normal niche. Interestingly, mesenchymal stem cells incubated with the REH-conditioned medium stopped growing, showed a flattened morphology with the appearance of small vacuoles, and importantly, became positive for the senescence-associated beta-galactosidase activity. Evaluation of the leukemic-conditioned medium showed increased IL-6 and IL-8, suggesting that these cytokines could be responsible for the observed changes. CONCLUSIONS: Our results showed that quiescence and self-renewal are severely affected in this leukemic niche. This in vitro leukemic niche, established without leukemic cells, will facilitate HSC gene expression evaluation and the development of therapeutic agents aimed to neutralize soluble factors and the cell signaling pathways involved in HSC alterations. PMID- 28078191 TI - Comparison of single nucleotide polymorphisms [SNP] at TNF-alpha promoter region with TNF receptor 2 (TNFR2) in susceptibility to pulmonary tuberculosis; using PCR-RFLP technique. AB - Since apoptosis and survival of the immune cells are crucially important in prevention or predisposition of individual from/to infections, especially in intracellular ones, the current study was performed to assess the correlation of host genetic polymorphisms with susceptibility to TB. For this reason, we investigated the difference of the single nucleotide polymorphisms [SNPs] in tumor necrosis factors [TNF-alpha] genes at (-238, -308, -857 and -863 position) and tumor necrosis factors receptors two [TNFR2] at (T 587 G position) between patients [n=151] and control [n=83]. The genotyping was studied by using PCR-RFLP which had high sensitivity in detecting compared with other techniques. The results showed a strong correlation between two polymorphisms in different loci of TNF-alpha gene including TNF-alpha T-857 C and A 238 G. But no association were found in TNFR2 genes with susceptibility to TB. And we found no correlation between TNFR2 and TNF-alpha gene polymorphisms. Therefore, the TNF-alpha T 857 C and A 238 G SNPs could be promising marker for identifying risk populations. PMID- 28078192 TI - Etanercept in the treatment of refractory SAPHO syndrome. AB - OBJECTIVE: To explore the application and efficacy of TNF-alpha inhibitors in the treatment of SAPHO syndrome. METHODS: Two cases of refractory SAPHO syndrome were successfully treated with etanercept. And pain scores, laboratory parameters and functional index were used to judge the efficacies. Literature was also systemically reviewed. RESULTS: Both patients achieved marked clinical remission. There was no obvious toxic or adverse response. CONCLUSION: Etanercept has rapid and definite efficacies in the treatment of patients with refractory SAPHO syndrome. PMID- 28078193 TI - Metabolic, inflammatory, and microvascular determinants of white matter disease and cognitive decline. AB - White Matter Disease is increasingly being recognized as an important cause of cognitive decline and dementia. Various investigations have linked chronic diet related conditions to the development of white matter lesions, which appear as white matter hyperintensities on T2-weighted magnetic resonance imaging (MRI) scans of the brain. Thus, it can be postulated that the metabolic, inflammatory, and microvascular changes accompanying a western diet, hyperlipidemia, hypertension, and diabetes mellitus type II (DMII) are potential mediators in the development and progression of white matter disease, which in turn contributes to the development and progression of cognitive decline. This review will examine evidence for potential metabolic, inflammatory, and microvascular determinants of white matter disease and cognitive decline. Specifically, we will focus on the effects of altered insulin signaling in diabetes, obesity-induced oxidative stress, neuroinflammation, arterial stiffness due to hypertension, ischemia secondary to cerebral small vessel disease, and blood brain barrier disturbances. PMID- 28078194 TI - Trauma-Exposed Latina Immigrants' Networks: A Social Network Analysis Approach. AB - OBJECTIVE: Trauma exposure among Latina immigrants is common. Social support networks can buffer the impact of trauma on mental health. This study characterizes the social networks of trauma-exposed Latina immigrants using a social network analysis perspective. METHODS: In 2011-2012 a convenience sample (n=28) of Latina immigrants with trauma exposure and presumptive depression or posttraumatic stress disorder was recruited from a community clinic in Washington DC. Participants completed a social network assessment and listed up to ten persons in their network (alters). E-Net was used to describe the aggregate structural, interactional, and functional characteristics of networks and Node-XL was used in a case study to diagram one network. RESULTS: Most participants listed children (93%), siblings (82%), and friends (71%) as alters, and most alters lived in the US (69%). Perceived emotional support and positive social interaction were higher compared to tangible, language, information, and financial support. A case study illustrates the use of network visualizations to assess the strengths and weaknesses of social networks. CONCLUSIONS: Targeted social network interventions to enhance supportive networks among trauma-exposed Latina immigrants are warranted. PMID- 28078195 TI - Using Voice Coils to Actuate Modular Soft Robots: Wormbot, an Example. AB - In this study, we present a modular worm-like robot, which utilizes voice coils as a new paradigm in soft robot actuation. Drive electronics are incorporated into the actuators, providing a significant improvement in self-sufficiency when compared with existing soft robot actuation modes such as pneumatics or hydraulics. The body plan of this robot is inspired by the phylum Annelida and consists of three-dimensional printed voice coil actuators, which are connected by flexible silicone membranes. Each electromagnetic actuator engages with its neighbor to compress or extend the membrane of each segment, and the sequence in which they are actuated results in an earthworm-inspired peristaltic motion. We find that a minimum of three segments is required for locomotion, but due to our modular design, robots of any length can be quickly and easily assembled. In addition to actuation, voice coils provide audio input and output capabilities. We demonstrate transmission of data between segments by high-frequency carrier waves and, using a similar mechanism, we note that the passing of power between coupled coils in neighboring modules-or from an external power source-is also possible. Voice coils are a convenient multifunctional alternative to existing soft robot actuators. Their self-contained nature and ability to communicate with each other are ideal for modular robotics, and the additional functionality of sound input/output and power transfer will become increasingly useful as soft robots begin the transition from early proof-of-concept systems toward fully functional and highly integrated robotic systems. PMID- 28078196 TI - Prosthetic Jamming Terminal Device: A Case Study of Untethered Soft Robotics. AB - This article illuminates the major and often overlooked challenge of untethering soft robotic systems through the context of recent work, in which soft robotic gripper technology enabled by jamming of granular media was applied to a prosthetic jamming terminal device (PJTD). The PJTD's technical and market feasibility was evaluated in a pilot study with two upper-limb amputees. A PJTD prototype was tested against a commercial device (Motion Control electric terminal service with a one degree-of-freedom pinching mechanism) using two existing hand function tests: the first quantified the device's speed in picking and placing small blocks and the second evaluated a person's ability to perform activities of daily living (ADLs). The PJTD prototype performed slightly slower than its commercial counterpart in the first test. While both participants successfully completed all the ADLs with both devices in the second test, the commercial device scored marginally higher. Results suggested that PJTD can have potential benefits over existing terminal devices, such as providing the capability to firmly grasp tools due to the ability of PJTD to conform to arbitrary surfaces and reducing compensatory shoulder movements due to its axisymmetric design. Some downsides were that users reported fatigue while operating the PJTD, as most operations require pushing the PJTD against target objects to adequately conform to them. The greatest drawback for the PJTD is also a major roadblock preventing a number of soft robotic research projects from making an impact in real-world applications: pneumatic technology required for operating the PJTD is currently too large and heavy to enable compact untethered operation. PMID- 28078197 TI - Soft Robotics Commercialization: Jamming Grippers from Research to Product. AB - Recent work in the growing field of soft robotics has demonstrated a number of very promising technologies. However, to make a significant impact in real-world applications, these new technologies must first transition out of the laboratory through successful commercialization. Commercialization is perhaps the most critical future milestone facing the field of soft robotics today, and this process will reveal whether the apparent impact we now perceive has been appropriately estimated. Since 2012, Empire Robotics has been one of the first companies to attempt to reach this milestone through our efforts to commercialize jamming-based robotic gripper technology in a product called VERSABALL(r). However, in spring 2016 we are closing our doors, having not been able to develop a sustainable business around this technology. This article presents some of the key takeaways from the technical side of the commercialization process and lessons learned that may be valuable to others. We hope that sharing this information will provide a frame of reference for technology commercialization that can help others motivate research directions and maximize research impact. PMID- 28078198 TI - Multidisciplinary Approach to Management of Temporal Bone Giant Cell Tumor. AB - Background Giant cell tumors (GCTs) are rare osseous tumors that rarely appear in the skull. Methods We review the clinical course of a 28-year-old previously healthy woman with a complicated GCT. Results The reviewed patient presented with a middle cranial fossa tumor acutely complicated by reactive mastoiditis. Left tympanomastoidectomy was performed for drainage of the mastoiditis and for biopsies of the tumor. Due to the challenging tumor location, the patient was treated with denosumab, a fully humanized monoclonal antibody against receptor activator of nuclear factor kappa-B ligand, for 7 months, which resulted in significant preoperative tumor shrinkage. Extensive temporal craniotomy and resection of the tumor followed utilizing a temporomandibular joint total endoprosthesis for reconstruction. A recurrence of the tumor was detected on computed tomography at 19 months after surgery and treated with transtemporal tumor resection, parotidectomy, and mandible re-reconstruction. Conclusion A multidisciplinary approach resulted in a good functional result and, finally, an eradication of the challengingly located middle cranial fossa tumor. PMID- 28078199 TI - Heart-Failing Jehovah's Witness Patient Successfully Treated by Minimally Invasive LVAD Implantation without Any Blood Transfusions. AB - Left ventricular assist device (LVAD) implantation without the use of any blood products is considered as a challenge. We present a 48-year-old patient (175 cm, 75 kg, body mass index 24.5 kg/m2) who was admitted to our clinic due to end stage heart failure. The patient is a Jehovah's witness. He declined full blood transfusion as well as use of coagulation factors. Therefore, we interdisciplinary decided to implant an LVAD via minimally invasive technique. The patient experienced an uneventful intrahospital stay and was successfully discharged home on his 17th postoperative day, proving that LVAD implantation without blood transfusions is possible by using a minimally invasive technique. This benefits not only Jehovah's witness patients, but also all patients in need of an LVAD. PMID- 28078200 TI - Correlation of Serum Cystatin C with Glomerular Filtration Rate in Patients Receiving Platinum-Based Chemotherapy. AB - Objectives. Serum cystatin C seems to be an accurate marker of glomerular filtration rate (GFR) compared to serum creatinine. The aim of this work was to explore the possibility of using serum cystatin C instead of serum creatinine to early predict renal failure in cancer patients who received platinum based chemotherapy. Design and Methods. Serum creatinine, serum cystatin C concentrations, and GFR were determined simultaneously in 52 cancer patients received carboplatin-based or cisplatin-based chemotherapy. Serum creatinine was assayed on Cobas C6000-Roche, serum cystatin C assay was performed on AIA 360 Tosoh, and GFR was determined in all patients, before the first cycle of chemotherapy and before the subsequent administrations. Results. In the overall series, for the prediction of a fall of GFR < 80 mL/min/1.73 m2, the AUC of the ROC curve for cystatin C was 0,667 and the best threshold was 1.135 mg/L (sensitivity 90.5%, specificity 61.1%). For a GFR fall < 60 mL/min/1.73 m2, the AUC of ROC curve for cystatin C was 74.3% and the best threshold was 1.415 mg/L (sensitivity 66.7%, specificity 73.2%). Conclusions. Baseline cystatin C values were not able to predict renal failure during subsequent treatment. In conclusion, serum cystatin C is not a reliable early marker to efficiently predict renal failure in patients receiving chemotherapy. PMID- 28078201 TI - The economic side of social remittances: how money and ideas circulate between Paris, Dakar, and New York. AB - This paper shows how economic remittances undergird the circulation of social remittances between New York, Paris, and Dakar. It compares the transnational practices of Senegalese-born migrants living in France and in the United States during the 2012 Senegalese presidential campaign to demonstrate how economic and political transnational practices mutually reinforce each other. This paper contributes to scholarship in three key ways: it confirms the benefits of combining qualitative and quantitative transnational data, collected from origin and destination countries. It offers a welcome geographic extension to a literature on social remittances from which Africa remains absent. It makes a significant theoretical contribution by connecting economic sociology and migration studies to illuminate the impact of migrants' transnational practices. PMID- 28078203 TI - Catatonia: Our current understanding of its diagnosis, treatment and pathophysiology. AB - Catatonia is a psychomotor syndrome that has been reported to occur in more than 10% of patients with acute psychiatric illnesses. Two subtypes of the syndrome have been identified. Catatonia of the retarded type is characterized by immobility, mutism, staring, rigidity, and a host of other clinical signs. Excited catatonia is a less common presentation in which patients develop prolonged periods of psychomotor agitation. Once thought to be a subtype of schizophrenia, catatonia is now recognized to occur with a broad spectrum of medical and psychiatric illnesses, particularly affective disorders. In many cases, the catatonia must be treated before any underlying conditions can be accurately diagnosed. Most patients with the syndrome respond rapidly to low-dose benzodiazepines, but electroconvulsive therapy is occasionally required. Patients with longstanding catatonia or a diagnosis of schizophrenia may be less likely to respond. The pathobiology of catatonia is poorly understood, although abnormalities in gamma-aminobutyric acid and glutamate signaling have been suggested as causative factors. Because catatonia is common, highly treatable, and associated with significant morbidity and mortality if left untreated, physicians should maintain a high level of suspicion for this complex clinical syndrome. Since 1989, we have systematically assessed patients presenting to our psychiatry service with signs of retarded catatonia. In this paper, we present a review of the current literature on catatonia along with findings from the 220 cases we have assessed and treated. PMID- 28078202 TI - Mechanical transduction by ion channels: A cautionary tale. AB - Mechanical transduction by ion channels occurs in all cells. The physiological functions of these channels have just begun to be elaborated, but if we focus on the upper animal kingdom, these channels serve the common sensory services such as hearing and touch, provide the central nervous system with information on the force and position of muscles and joints, and they provide the autonomic system with information about the filling of hollow organs such as blood vessels. However, all cells of the body have mechanosensitive channels (MSCs), including red cells. Most of these channels are cation selective and are activated by bilayer tension. There are also K+ selective MSCs found commonly in neurons where they may be responsible for both general anesthesia and knockout punches in the boxing ring by hyperpolarizing neurons to reduce excitability. The cationic MSCs are typically inactive under normal mechanical stress, but open under pathologic stress. The channels are normally inactive because they are shielded from stress by the cytoskeleton. The cationic MSCs are specifically blocked by the externally applied peptide GsMtx4 (aka, AT-300). This is the first drug of its class and provides a new approach to many pathologies since it is nontoxic, non immunogenic, stable in a biological environment and has a long pharmacokinetic lifetime. Pathologies involving excessive stress are common. They produce cardiac arrhythmias, contraction in stretched dystrophic muscle, xerocytotic and sickled red cells, etc. The channels seem to function primarily as "fire alarms", providing feedback to the cytoskeleton that a region of the bilayer is under excessive tension and needs reinforcing. The eukaryotic forms of MSCs have only been cloned in recent years and few people have experience working with them. "Newbies" need to become aware of the technology, potential artifacts, and the fundamentals of mechanics. The most difficult problem in studying MSCs is that the actual stimulus, the force applied to the channel, is not known. We don't have direct access to the channels themselves but only to larger regions of the membrane as seen in patches. Cortical forces are shared by the bilayer, the cytoskeleton and the extracellular matrix. How much of an applied stimulus reaches the channel is unknown. Furthermore, many of these channels exist in spatial domains where the forces within a domain are different from forces outside the domain, although we often hope they are proportional. This review is intended to be a guide for new investigators who want to study mechanosensitive ion channels. PMID- 28078205 TI - Reasoning and Rehabilitation cognitive skills programme for mentally disordered offenders: Predictors of outcome. AB - AIM: To investigate factors predicting treatment completion and treatment outcome of the Reasoning and Rehabilitation Mental Health Programme (R&R2MHP) cognitive skills programme for mentally disordered offenders. METHODS: Secondary analysis of data previously obtained from 97 male patients who were sectioned and detained under the United Kingdom Mental Health Act in low, medium and high security hospitals and who had completed R&R2MHP. Predictors of treatment completion included background variables and five outcome measures: Four self-reported measures of violent attitudes, social problem-solving skills, reactive anger and locus of control and an objective measure of behaviour on the ward that was completed by staff. Completion of the 16 session programme, which was delivered on a weekly basis, was classified as >= 12 sessions. RESULTS: It was found that the R&R2MHP is appropriate for delivery to participants of different ages, ethnic background, and at different levels of security without the completion rate or treatment effectiveness being compromised. Participants taking oral typical psychotropic medication were over seven times more likely to complete the programme than other participants. Behavioural disturbance on the ward prior to commencing the programme predicted non-completion (medium effect size). As far as treatment completion was concerned, none of the background factors predicted treatment effectiveness (age, ethnic background, level of security, number of previous convictions and number of previous hospital admissions). The best predictor of treatment effectiveness was attitude towards violence suggesting that this should be the primary outcome measure in future research evaluating outcomes of the R&R2MHP cognitive skills program. CONCLUSION: The findings suggest that a stable mental state is a key factor that predicts treatment completion. PMID- 28078204 TI - Treatment-adherence in bipolar disorder: A patient-centred approach. AB - About half of the patients diagnosed with bipolar disorder (BD) become non adherent during long-term treatment, a rate largely similar to other chronic illnesses and one that has remained unchanged over the years. Non-adherence in BD is a complex phenomenon determined by a multitude of influences. However, there is considerable uncertainty about the key determinants of non-adherence in BD. Initial research on non-adherence in BD mostly limited itself to examining demographic, clinical and medication-related factors impacting adherence. However, because of inconsistent results and failure of these studies to address the complexities of adherence behaviour, demographic and illness-related factors were alone unable to explain or predict non-adherence in BD. This prompted a shift to a more patient-centred approach of viewing non-adherence. The central element of this approach includes an emphasis on patients' decisions regarding their own treatment based on their personal beliefs, life circumstances and their perceptions of benefits and disadvantages of treatment. Patients' decision-making processes are influenced by the nature of their relationship with clinicians and the health-care system and by people in their immediate environment. The primacy of the patient's perspective on non-adherence is in keeping with the current theoretical models and concordance-based approaches to adherence behaviour in BD. Research over the past two decades has further endorsed the critical role of patients' attitudes and beliefs regarding medications, the importance of a collaborative treatment-alliance, the influence of the family, and the significance of other patient-related factors such as knowledge, stigma, patient satisfaction and access to treatment in determining non-adherence in BD. Though simply moving from an illness-centred to a patient-centred approach is unlikely to solve the problem of non-adherence in BD, such an approach is more likely to lead to a better understanding of non-adherence and more likely to yield effective solutions to tackle this common and distressing problem afflicting patients with BD. PMID- 28078207 TI - Health-care needs of remitted patients with bipolar disorder: A comparison with schizophrenia. AB - AIM: To investigate health-care needs and their correlates among patients with remitted bipolar disorder (BD) compared to patients with remitted schizophrenia. METHODS: Outpatients with BD (n = 150) and schizophrenia (n = 75) meeting clearly defined remission criteria were included in the study along with their relatives. Diagnostic ascertainment was carried out using the Mini International Neuropsychiatric Interview. Demographic and clinical details were recorded using structured formats. Residual symptoms were assessed using standardized scales. Health-care needs were assessed on two separate scales. The principal instrument employed to assess health-care needs was the Camberwell Assessment of Need Research version (CAN-R). To further evaluate health-care needs we felt that an additional instrument, which was more relevant for Indian patients and treatment settings and designed to cover those areas of needs not specifically covered by the CAN-R was required. This instrument with a structure and scoring pattern similar to the CAN-R was used for additional evaluation of needs. Patients' level of functioning was assessed using the Global Assessment of Functioning Scale and their quality of life (QOL) using the World Health Organization Quality Of Life BREF version in Hindi. RESULTS: An average of 6-7 needs was reported by patients with BD as well as their relatives. Commonly reported needs were in the areas of economic and welfare needs, informational needs, social needs and the need for treatment. According to the CAN-R, both patients and relatives reported that more than 60% of the total needs were being met. However, over 90% of the needs covered by the additional evaluation were unmet according to patients and relatives. Needs in the areas of economic and welfare-benefits, information, company, daytime activities and physical health-care were largely unmet according to patients and relatives. Total, met and unmet needs were significantly higher for schizophrenia, but the most common types of needs were quite similar to BD. Relatives reported more needs than patients with certain differences in the types of needs reported. Level of patients' functioning was the principal correlate of greater total and unmet needs in both groups. Significant associations were also obtained with residual symptoms and QOL. CONCLUSION: The presence of unmet needs in remitted patients with BD was an additional marker of the enduring psychosocial impairment characteristic of the remitted phase of BD. PMID- 28078208 TI - Influence of different second generation antipsychotics on the QTc interval: A pragmatic study. AB - AIM: To investigate whether differential influence on the QTc interval exists among four second generation antipsychotics (SGAs) in psychosis. METHODS: Data were drawn from a pragmatic, randomized head-to-head trial of the SGAs risperidone, olanzapine, quetiapine, and ziprasidone in acute admissions patients with psychosis, and with follow-up visits at discharge or maximally 6-9 wk, 3, 6, 12 and 24 mo. Electrocardiograms were recorded on all visits. To mimic clinical shared decision-making, the patients were randomized not to a single drug, but to a sequence of the SGAs under investigation. The first drug in the sequence defined the randomization group, but the patient and/or clinician could choose an SGA later in the sequence if prior negative experiences with the first one(s) in the sequence had occurred. The study focuses on the time of, and actual use of the SGAs under investigation, that is until treatment discontinuation or change, in order to capture the direct medication effects on the QTc interval. Secondary intention-to-treat (ITT) analyses were also performed. RESULTS: A total of 173 patients, with even distribution among the treatment groups, underwent ECG assessments. About 70% were males and 43% had never used antipsychotic drugs before the study. The mean antipsychotic doses in milligrams per day with standard deviations (SD) were 3.4 (1.2) for risperidone, 13.9 (4.6) for olanzapine, 325.9 (185.8) for quetiapine, and 97.2 (42.8) for ziprasidone treated groups. The time until discontinuation of the antipsychotic drug used did not differ in a statistically significant way among the groups (Log-Rank test: P = 0.171). The maximum QTc interval recorded during follow-up was 462 ms. Based on linear mixed effects analyses, the QTc interval change per day with standard error was -0.0030 (0.0280) for risperidone; -0.0099 (0.0108) for olanzapine; 0.0027 (0.0170) for quetiapine, and -0.0081 (0.0229) for ziprasidone. There were no statistically significant differences among the groups in this regard. LME analyses based on ITT groups (the randomization groups), revealed almost identical slopes with -0.0063 (0.0160) for risperidone, -0.0130 (0.0126) for olanzapine, -0.0034 (0.0168) for quetiapine, and -0.0045 (0.0225) for ziprasidone. CONCLUSION: None of the SGAs under investigation led to statistically significant QTc prolongation. No statistically significant differences among the SGAs were found. PMID- 28078206 TI - Infectious, atopic and inflammatory diseases, childhood adversities and familial aggregation are independently associated with the risk for mental disorders: Results from a large Swiss epidemiological study. AB - AIM: To examine the associations between mental disorders and infectious, atopic, inflammatory diseases while adjusting for other risk factors. METHODS: We used data from PsyCoLaus, a large Swiss Population Cohort Study (n = 3720; age range 35-66). Lifetime diagnoses of mental disorders were grouped into the following categories: Neurodevelopmental, anxiety (early and late onset), mood and substance disorders. They were regressed on infectious, atopic and other inflammatory diseases adjusting for sex, educational level, familial aggregation, childhood adversities and traumatic experiences in childhood. A multivariate logistic regression was applied to each group of disorders. In a complementary analysis interactions with sex were introduced via nested effects. RESULTS: Associations with infectious, atopic and other chronic inflammatory diseases were observable together with consistent effects of childhood adversities and familial aggregation, and less consistent effects of trauma in each group of mental disorders. Streptococcal infections were associated with neurodevelopmental disorders (men), and measles/mumps/rubella-infections with early and late anxiety disorders (women). Gastric inflammatory diseases took effect in mood disorders (both sexes) and in early disorders (men). Similarly, irritable bowel syndrome was prominent in a sex-specific way in mood disorders in women, and, moreover, was associated with early and late anxiety disorders. Atopic diseases were associated with late anxiety disorders. Acne (associations with mood disorders in men) and psoriasis (associations with early anxiety disorders in men and mood disorders in women) contributed sex-specific results. Urinary tract infections were associated with mood disorders and, in addition, in a sex-specific way with late anxiety disorders (men), and neurodevelopmental and early anxiety disorders (women). CONCLUSION: Infectious, atopic and inflammatory diseases are important risk factors for all groups of mental disorders. The sexual dimorphism of the associations is pronounced. PMID- 28078209 TI - Cognitive-behavioural therapy for obsessive-compulsive disorder co-occurring with psychosis: Systematic review of evidence. AB - AIM: To review available evidence on the use of cognitive behavioural therapy (CBT) for treating obsessive compulsive disorder co-occurring with psychosis. METHODS: In this paper we present a detailed and comprehensive review of the current literature focusing on CBT treatment of obsessive compulsive disorder (OCD) co-occurring with schizophrenia or schizoaffective disorder. We identified relevant literature published between 2001 and May 2016 through MEDLINE/PubMed search using as search string ("obsessive compulsive disorders" or "obsessive compulsive symptoms") and ("schizophrenia" or "schizoaffective disorder" or "psychosis") and ("cognitive behavioural therapy"). Other citations of interest were further identified from references reported in the accessed articles. The search was limited to studies written in English and carried out in adult patients. A total of 9 studies, 8 case reports and 1 case series, were found. RESULTS: The reviewed evidence indicates that CBT is: (1) safe, i.e., does not worsen psychotic symptoms; (2) well accepted, with a discontinuation rate quite similar to that reported for patients with OCD without psychosis comorbidity; (3) effective, with a symptom reduction quite similar to that reported for patients with OCD without psychosis and for SRIs treatment of OCD co-occurring with psychosis; and (4) effective in patients with OCD induced by second-generation antipsychotic as well as in patients with OCD not induced by second-generation antipsychotic. Alcohol/substance use disorder comorbidity and OCD onset preceding that of SCH/SA was predictors of poor outcome. These results are derived only by additional studies with adequate sample size. CONCLUSION: Our results support the use of CBT for OCD in patients with psychosis. PMID- 28078210 TI - Testosterone replacement therapy. PMID- 28078211 TI - A case series of the safety and efficacy of testosterone replacement therapy in renal failure and kidney transplant patients. AB - BACKGROUND: Hypogonadism is common in patients with renal dysfunction and does not always correct following transplantation. Recent studies show increased mortality for dialysis and transplant patients with low testosterone (T). These patients are often not treated due to concerns over efficacy and complications (both real and imagined). There is surprisingly scant literature supporting the use of T therapy in these patients. We wished to examine the results of T therapy in our patients with renal failure or following transplant. METHODS: We identified 15 men in our Men's Health Registry treated with T who either were on dialysis or had a functioning transplant at time of therapy. Demographic, laboratory and clinical outcome data were collected from the electronic medical record. RESULTS: There were 3 men on dialysis and 12 with a functioning transplant. Mean age was 53.7 years (range, 39-71 years) and mean total serum T was 207.9 ng/mL (range, 45-330 ng/mL). All had bothersome symptoms including fatigue (15/15) and erectile dysfunction (ED) (14/15). Mean hematocrit was 35.8% and 9/15 were anemic. Therapy included patches in 1, topical gels in 6 and testopel pellets in 8. With a mean follow-up of 22.7 months (range, 11-58 months), mean T post therapy was 528 (range, 226-869). Mean hematocrit improved to 42.6% and 7/9 anemic patients improved out of the anemic range. There were no cardiovascular or infectious complications. CONCLUSIONS: Symptomatic hypogonadism is common in dialysis and transplant patients and T replacement therapy can be safely given with improvement in T values and symptoms in most patients. Anemia is usually improved. Testopel pellets can be used in immunosuppressed transplant recipients without infectious complications. PMID- 28078212 TI - Improvement of endothelial function following initiation of testosterone replacement therapy. AB - BACKGROUND: Isolated recent studies have suggested an increased risk of heart attack as early as 3 months following testosterone replacement therapy (TRT). Such a rapid risk increase would likely require rapid deterioration of arterial endothelial function. Our goal was to assess arterial endothelial function in hypogonadal men prior to and at least 3 months after initiation of TRT. METHODS: Adult men were consented if they had symptoms of hypogonadism, a total testosterone <350 ng/dL, and planned to begin TRT. Endothelial function was non invasively assessed using the EndoPAT-2000 machine. We measured the augmentation index (AI) (normal <3%), a measure of arterial stiffness and reactive hyperemia index (RHI), a measure of endothelial vasodilation (normal >1.69). Prior studies suggest that a 10% level of day-to-day test variability is expected. Endothelial function was reassessed at the next clinic visit, between 3 and 6 months if the patients were compliant with therapy. Changes in continuous variables were assessed with the paired t test. RESULTS: Twenty-three patients were consented with a mean age of 52.7 years (range, 34-68 years) and starting testosterone 196.9 ng/dL (range, 35-339 ng/dL). There was a history of diabetes in four, hypertension in ten and coronary artery disease in five. Mean RHI was 1.67+/-0.37 (70% were abnormal) and mean AI was 2.57%+/-14.0% (39% were abnormal). There were no cardiac events. At follow-up 20 patients were compliant with therapy and retested. Mean testosterone increased from 203 to 511 (P<0.0001). Mean RHI improved from 1.70 to 2.14 (P=0.01). Mean AI improved from 2.9% to -1.75% (P=0.01). In four men RHI worsened but in each case less than the 10% error of the test. No man had worsened AI. CONCLUSIONS: Men with symptomatic hypogonadism often have abnormal arterial endothelial function. Following TRT, endothelial function either remains unchanged or improves. PMID- 28078213 TI - Adult-onset hypogonadism: evaluation and role of testosterone replacement therapy. AB - Testosterone deficiency (TD) has become a growing concern in the field of men's sexual health, with an increasing number of men presenting for evaluation of this condition. Given the increasing demand for testosterone replacement therapy (TRT), a panel of experts met in August of 2015 to discuss the treatment of men who present for evaluation in the setting of low or normal gonadotropin levels and the associated signs and symptoms of hypogonadism. This constellation of factors can be associated with elements of both primary and secondary hypogonadism. Because this syndrome commonly occurs in men who are middle-aged and older, it was termed adult-onset hypogonadism (AOH). AOH can be defined by the following elements: low levels of testosterone, associated signs and symptoms of hypogonadism, and low or normal gonadotropin levels. Although there are significant benefits of TRT for patients with AOH, candidates also need to understand the potential risks. Patients undergoing TRT will need to be monitored regularly because there are potential complications that can develop with long term use. This review is aimed at providing a deeper understanding of AOH, discussing the benefits and risks of TRT, and outlining each modality of TRT in use for AOH. PMID- 28078214 TI - Pharmacology of testosterone replacement therapy preparations. AB - The goal of testosterone replacement therapy (TRT) is to return serum testosterone levels to within physiologic range and improve symptoms in hypogonadal men. Some of the symptoms aimed to improve upon include decreased libido, erectile dysfunction, infertility, hot flashes, depressed mood, and loss of muscle mass or hair. Clinical use of testosterone for replacement therapy began approximately 70 years ago. Over the decades, numerous preparations and formulations have been developed primarily focusing on different routes of delivery and thus pharmacokinetics (PKs). Currently the routes of delivery approved for use by the United States Food and Drug Administration encompasses buccal, nasal, subdermal, transdermal, and intramuscular (IM). Many factors must be considered when a clinician is choosing the most correct formulation for a patient. As this decision depends highly on the patient, active patient participation is important for effective selection. The aim of this review is to describe and compare all testosterone preparations currently available and approved by the United States Food and Drug Administration. Areas of focus will include pharmacology, PKs, adverse effects, and specifics related to individual delivery routes. PMID- 28078215 TI - Off label therapies for testosterone replacement. AB - The incidence of hypogonadism has been steadily increasing over the last few years. Exogenous testosterone has been the standard treatment for hypogonadal men, but is associated with suppression of spermatogenesis as well as other possible adverse effects. There are other medications, currently considered "off label" for androgen replenishment, that exert their effect through modulation of the hypothalamic-gonadal axis. These medications increase endogenous testosterone levels and offer a different therapeutic approach. This review will focus on these alternative (off-label) therapies for androgen replacement in men. PMID- 28078216 TI - Testosterone replacement therapy: role of pituitary and thyroid in diagnosis and treatment. AB - Crosstalk among hormones characterizes endocrine function, and assessment of the hypogonadal man should take that into consideration. In men for whom testosterone deficiency is a concern, initial evaluation should include a thorough history and physical exam in which other endocrinopathies are being considered. Hypogonadism can be associated with both pituitary and thyroid dysfunction, for which appropriate biochemical evaluation should be undertaken in certain clinical scenarios. If low serum testosterone is confirmed measurement of luteinizing and follicle stimulating hormones (LH and FSH respectively) is essential to establish whether the hypogonadism is primary or secondary. In secondary hypogonadism measurement of prolactin is always necessary, and measurement of other pituitary hormones, along with pituitary imaging, may be indicated. Checking thyroid function may also be enlightening, and can raise additional therapeutic considerations. Correction of other pituitary axes may attenuate the need for testosterone replacement therapy in some cases. PMID- 28078217 TI - Testosterone replacement in the infertile man. AB - Hypogonadism is a common clinical condition affecting men of different age groups. In addition to its sexual consequences, it has several implications posing significant concerns for a man's health and well-being. Recent advances in testosterone (T) supplementation have facilitated hypogonadism treatment. Despite that, patients complaining of infertility or seeking conception are still hindered by the unfavorable effects supplemental T has on testicular function. Consequently, alternative approaches that can stimulate endogenous T production are favored. Selective estrogen receptor modulators, gonadotropins and aromatase inhibitors (AIs) can be successful in restoring serum T levels, preserving fertility, and providing symptomatic relief. PMID- 28078219 TI - Hormone therapy for transgender patients. AB - Many transgender men and women seek hormone therapy as part of the transition process. Exogenous testosterone is used in transgender men to induce virilization and suppress feminizing characteristics. In transgender women, exogenous estrogen is used to help feminize patients, and anti-androgens are used as adjuncts to help suppress masculinizing features. Guidelines exist to help providers choose appropriate candidates for hormone therapy, and act as a framework for choosing treatment regimens and managing surveillance in these patients. Cross-sex hormone therapy has been shown to have positive physical and psychological effects on the transitioning individual and is considered a mainstay treatment for many patients. Bone and cardiovascular health are important considerations in transgender patients on long-term hormones, and care should be taken to monitor certain metabolic indices while patients are on cross-sex hormone therapy. PMID- 28078218 TI - Effects of varicocelectomy on serum testosterone. AB - Varicocele is most often surgically repaired due to male infertility, however, has recently been linked to low serum testosterone. This paper serves to review the current literature regarding varicocele and its subsequent repair on serum testosterone. Twenty-eight human studies were identified with fifteen showing improved serum testosterone after repair. The majority of the studies that demonstrated improvement had preoperative testosterone levels that were low or below normal. Additionally, multiple well-designed studies with control groups not undergoing surgical repair demonstrated significant difference between groups. This improvement was less observed in studies with normal preoperative serum testosterone. A majority of these patients studied were presenting for infertility. It remains to be determined if these findings can be reproduced in men without infertility. The findings suggest that microsurgical varicocele repair can improve serum testosterone in men with low levels preoperatively in appropriately counseled men. It remains to be seen whether varicocele repair can help prevent the development of low testosterone in the future or which patients are at risk of developing low testosterone due to varicocele. PMID- 28078220 TI - Hypogonadism and testosterone replacement therapy in end-stage renal disease (ESRD) and transplant patients. AB - Hypogonadism is a common problem in the end-stage renal disease (ESRD) and renal transplant population. It has widespread systemic effects and has been linked with mortality in dialysis patients and at the time of renal transplant. The etiology is likely multifactorial and most patients are afflicted by various comorbidities that can contribute to hypogonadism. Clinical manifestations are mostly nonspecific. We review the approach to the diagnosis of hypogonadism, focusing on both laboratory values and clinical signs and symptoms. We review treatment with testosterone replacement in this population and highlight various studies that tend to have small sample sizes. Though these studies provide insight into testosterone replacement, the need for larger studies is emphasized to better understand the effects and safety of therapy. PMID- 28078221 TI - Testosterone replacement therapy and voiding dysfunction. AB - Testosterone replacement therapy (TRT) represents an increasing popular treatment option for men with late-onset hypogonadism (LOH). Because of unsubstantiated beliefs of testosterone's effect on the prostate, the FDA has recently placed a warning on testosterone products, stating that TRT may worsen benign prostatic hyperplasia (BPH). Within this review article we have demonstrated the current understanding of the physiology of testosterone and its relationship with prostatic and lower urinary tract physiology. The current evidence suggests that not only does TRT not worsen lower urinary tract symptoms (LUTS), but that hypogonadism itself is an important risk factor for LUTS/BPH. PMID- 28078222 TI - Testosterone replacement therapy and the heart: friend, foe or bystander? AB - The role of testosterone therapy (TTh) in cardiovascular disease (CVD) outcomes is still controversial, and it seems will remain inconclusive for the moment. An extensive body of literature has investigated the association of endogenous testosterone and use of TTh with CVD events including several meta-analyses. In some instances, a number of studies reported beneficial effects of TTh on CVD events and in other instances the body of literature reported detrimental effects or no effects at all. Yet, no review article has scrutinized this body of literature using the magnitude of associations and statistical significance reported from this relationship. We critically reviewed the previous and emerging body of literature that investigated the association of endogenous testosterone and use of TTh with CVD events (only fatal and nonfatal). These studies were divided into three groups, "beneficial (friendly use)", "detrimental (foe)" and "no effects at all (bystander)", based on their magnitude of associations and statistical significance from original research studies and meta-analyses of epidemiological studies and of randomized controlled trials (RCT's). In this review article, the studies reporting a significant association of high levels of testosterone with a reduced risk of CVD events in original prospective studies and meta-analyses of cross-sectional and prospective studies seems to be more consistent. However, the number of meta-analyses of RCT's does not provide a clear picture after we divided it into the beneficial, detrimental or no effects all groups using their magnitudes of association and statistical significance. From this review, we suggest that we need a study or number of studies that have the adequate power, epidemiological, and clinical data to provide a definitive conclusion on whether the effect of TTh on the natural history of CVD is real or not. PMID- 28078224 TI - Impact of recent FDA ruling on testosterone replacement therapy (TRT). PMID- 28078223 TI - Testosterone therapy and prostate cancer. AB - The use of exogenous testosterone to treat hypogonadism in the men with a history of prostate cancer (CaP) remains controversial due to fears of cancer recurrence or progression. Due to the detrimental impact of hypogonadism on patient quality of life, recent work has examined the safety of testosterone therapy (TTh) in men with a history of CaP. In this review, we evaluate the literature with regards to the safety of TTh in men with a history of CaP. TTh results in improvements in quality of life with little evidence of biochemical recurrence or progression in men with a history of CaP, or de novo cancer in unaffected men. An insufficient amount of evidence is currently available to truly demonstrate the safe use of TTh in men with low risk CaP. In men with high-risk cancer, more limited data suggest that TTh may be safe, but these findings remain inconclusive. Despite the historic avoidance of TTh in men with a history of CaP, the existing body of evidence largely supports the safe and effective use of testosterone in these men, although additional study is needed before unequivocal safety can be demonstrated. PMID- 28078225 TI - Testicular compartment syndrome: an overview of pathophysiology, etiology, evaluation, and management. AB - Testicular compartment syndrome (TCS) refers to the impairment of microcirculation in the testicle due to either increased venous resistance or extraluminal compression, which leads to hypoxia. TCS releases oxidants through hypoxia and ischemia/reperfusion injury (IRI). The pathophysiology, etiology, evaluation, and management of TCS are reviewed. Based on the properties of TCS, specific causes, e.g., varicocele, hydrocele, orchitis, cryptorchidism, and scrotal hernia, are suggested and categorized. The oxidant-induced stress from TCS may explain the correlations between these causes and infertility. A chief shortcoming of current imaging modalities is that they detect TCS late after it has progressed to impair the macrocirculation of the testicle. We propose frequent sequential periodic power Doppler ultrasonography to monitoring for earlier detection. Intraoperatively, TCS can be diagnosed by the dull purple appearance of a hypoxic testicle and by tissue pressures above 30 mmHg. When compartment pressure is low, the underlying etiology must be promptly treated. During acute presentation, an incision of the resilient tunica albuginea may be necessary. A great challenge of treating TCS is restoring microcirculation while minimizing IRI; concomitant antioxidant therapy secondary to treatment may be effective and harmless at the least. Because testicular oxidant stress is common in infertility and since TCS can cause such a stress, TCS may be a larger factor in infertility than currently suspected. PMID- 28078227 TI - Intralesional collagenase clostridium histolyticum study provides real-world analysis. PMID- 28078226 TI - Clinical utility of sperm DNA fragmentation testing: practice recommendations based on clinical scenarios. AB - Sperm DNA fragmentation (SDF) has been generally acknowledged as a valuable tool for male fertility evaluation. While its detrimental implications on sperm function were extensively investigated, little is known about the actual indications for performing SDF analysis. This review delivers practice based recommendations on commonly encountered scenarios in the clinic. An illustrative description of the different SDF measurement techniques is presented. SDF testing is recommended in patients with clinical varicocele and borderline to normal semen parameters as it can better select varicocelectomy candidates. High SDF is also linked with recurrent spontaneous abortion (RSA) and can influence outcomes of different assisted reproductive techniques. Several studies have shown some benefit in using testicular sperm rather than ejaculated sperm in men with high SDF, oligozoospermia or recurrent in vitro fertilization (IVF) failure. Infertile men with evidence of exposure to pollutants can benefit from sperm DNA testing as it can help reinforce the importance of lifestyle modification (e.g., cessation of cigarette smoking, antioxidant therapy), predict fertility and monitor the patient's response to intervention. PMID- 28078228 TI - Belatacept in renal transplantation-quo vadis? PMID- 28078229 TI - Commentary to low-energy shock wave therapy ameliorates erectile dysfunction in a pelvic neurovascular injuries rat model, published in J Sex Med 2016;13:22-32 by Li H, Matheu P, Sun F, et al. PMID- 28078230 TI - Invited commentary on GETUG-AFU 16. PMID- 28078231 TI - Friend or foe: role of E-cadherin in prostate cancer metastasis. PMID- 28078232 TI - The luminal-basal paradigm in the urothelial cancer: hope for individualized approach. PMID- 28078233 TI - Prostate cancer and hypofractionation: really a new standard of care? PMID- 28078234 TI - Radium-223 and concomitant therapies: prospects and prudence. PMID- 28078235 TI - A randomised control trial of salvage radiotherapy and androgen deprivation therapy following prostatectomy: commentary on five year follow-up findings. PMID- 28078236 TI - Cabozantinib in advanced renal cell carcinoma: a METEOR impact on clinical practice. PMID- 28078237 TI - Low-energy shock wave therapy ameliorates erectile dysfunction in a pelvic neurovascular injuries rat model. PMID- 28078238 TI - Liquid biopsies in bladder cancer-did we find the Holy Grail for biomarker analyses? PMID- 28078239 TI - The panoramic view of clear cell renal cell carcinoma metabolism: values of integrated global cancer metabolomics. PMID- 28078240 TI - Effect of methanol leaf extract of Dalbergia saxatilis Hook.f (fabaceae) on renal function. AB - OBJECTIVE: Dalbegia saxatilis (D.saxatilis) is used as a decoction in traditional medicine for ailments such as cough, small pox, skin lesions, bronchial ailments and toothache. This study is aimed at evaluating the toxic effect of methanol leaf extract of D.saxatilis on renal function. MATERIALS AND METHODS: Wistar rats of both sexes were divided into four groups of five: control animals (group 1) received distilled water 1 ml/kg while groups 2, 3 and 4 were given graded doses of the extract (250, 500 and 1000 mg/kg body weight, respectively) daily for 28 days. Body weight changes were estimated by weighing the rats twice weekly using digital weighing balance. After 28 days, blood samples were obtained for evaluation of renal indices and the kidney was used for histopathology. Data were analysed using one-way and repeated measures ANOVA using SPSS version 20. RESULTS: Significant weight increase in all groups were observed (p<0.05). Significant reduction in electrolytes concentration was observed following treatment with extract (250 and 500 mg/kg) (p<0.05). Histopathological findings of the kidney revealed massive necrosis of the glomerulus with tubular distortion and lymphocyte hyperplasia at 250 and 500 mg/kg while intense glomerular and tubular necrosis was observed at 1000 mg/kg of the extract. CONCLUSION: Since different doses of the extract caused reduction in electrolyte concentration and damage to the kidney it is suggested that prolonged administration of the extract is associated with increased risk of kidney toxicity. PMID- 28078241 TI - The effect of Zataria multiflora Boiss hydroalcoholic extract and fractions in pentylenetetrazole-induced kindling in mice. AB - OBJECTIVE: At present, there are many antiepileptic drugs with a wide range of side effects on the human body. It was assumed that Zataria multiflora Boiss (Z. multiflora) with sedative, anti-spasmodic and anti-inflammatory activity may be effective in the treatment of epilepsy. The aim of the present study was to elucidate the effect of Z. multiflora hydroalcoholic extract and its fraction extracts on pentylenetetrazole (PTZ)-induced chemical kindling. MATERIALS AND METHODS: In this experimental study, eight separate groups of male albino mice were used. All groups received 11 separate intraperitoneal injections of PTZ (35 mg/kg) with two-day intervals. 30 min before the injection of PTZ, mice received vehicle, Z. multiflora hydroalcoholic extract (300 and 600 mg/kg), n-hexane, acetone, methanol fraction extracts (150 mg/kg), or diazepam (10 mg/kg). RESULTS: The kindled mice that were pretreated with vehicle showed a gradual increase in their seizure scores up to the end of the study. The hydroalcoholic extract of Z. multiflora (300 and 600 mg/kg) reduced seizure scores significantly. However, n hexane, acetone and methanol extracts did not affect seizure scores significantly. CONCLUSION: The present findings demonstrate that the hydroalcoholic extract of Z. multiflora did reduce the severity of seizure attacks in PTZ-induced chemical kindling in mice. PMID- 28078242 TI - Saffron'omics': The challenges of integrating omic technologies. AB - Saffron is one of the highly exotic spices known for traditional values and antiquity. It is used for home decor besides serving as a colorant flavor and is widely known for medicinal value. Over the last few years, saffron has garnered a lot of interest due to its anti-cancer, anti-mutagenic, anti-oxidant and immunomodulatory properties. Integration of systems biology approaches with wide applications of saffron remains a growing challenge as new techniques and methods advance. Keeping in view of the dearth of a review summarizing the omics and systems biology of saffron, we bring an outline on advancements in integrating omic technologies, the medicinal plant has seen in recent times. PMID- 28078243 TI - Ethnobotanical knowledge of Apiaceae family in Iran: A review. AB - OBJECTIVE: Apiaceae (Umbelliferae) family is one of the biggest plant families on the earth. Iran has a huge diversity of Apiaceae members. This family possesses a range of compounds that have many biological activities. The members of this family are well known as vegetables, culinary and medicinal plants. Here, we present a review of ethnobotanical uses of Apiaceae plants by the Iranian people in order to provide a comprehensive documentation for future investigations. MATERIALS AND METHODS: We checked scientific studies published in books and journals in various electronic databases (Medline, PubMed, Science Direct, Scopus and Google Scholar websites) from 1937 to 2015 and reviewed a total of 52 publications that provided information about different applications of these plant species in human and livestock. RESULTS: As a result of this review, several ethnobotanical usages of 70 taxa, 17 of which were endemic, have been determined. These plants were used for medicinal and non-medicinal purposes. The most commonly used parts were fruits, leaves, aerial parts and gums. The most common methods of preparation were decoction, infusion and poultice. CONCLUSION: To our knowledge, this paper represents a comprehensive literature search of ethnobotanical uses of Apiaceae reported from Iran. This study highlights the rich traditional knowledge of this family that has remained in Iran. However, most of this knowledge survive only as memories from the past in the minds of the elderly, and will probably vanish in a few decades. Thus, we compiled these scattered data together in a single document for the next scientific works with ethnobotanical interests. PMID- 28078244 TI - Carvacrol attenuates serum levels of total protein, phospholipase A2 and histamine in asthmatic guinea pig. AB - OBJECTIVE: Pharmacological effects of carvacrol such as its anti-inflammatory activities have been shows. In this study the effects of carvacrol on serum levels of total protein (TP), phospholipase A2 (PLA2) and histamine in sensitized guinea pigs was evaluated. MATERIALS AND METHODS: Sensitized guinea pigs were given drinking water alone (group S), drinking water containing three concentrations of carvacrol (40, 80 and 160 ug/ml) or dexamethasone. Serum levels of TP, PLA2 and histamine were examined I all sensitized groups as well as a non sensitized control group (n=6 for each group). RESULTS: In sensitized animals, serum levels of TP, PLA2 and histamine were significantly increased compared to control animals (p<0.05 to p<0.001). Significant reduction in TP, PLA2 and histamine levels were observed in treated groups with the two higher concentrations of carvacrol but dexamethasone treatment only decreased serum level of PLA2 (p<0.05 to p<0.001). Although the effect of the lowest concentration of the extract was less than that of dexamethasone (p<0.05 for TP and p<0.001 for PLA2), the effects of the two higher concentrations on PLA2 were similar to dexamethasone and on TP (p<0.01) and histamine (p<0.001) were higher than those of dexamethasone. CONCLUSION: These results showed that carvacrol reduced serum levels of TP, PLA2 and histamine in sensitized guinea pigs which may indicate an anti-inflammatory effect of this agent in inflammatory disorders such as asthma. PMID- 28078245 TI - The effects of cinnamaldehyde and eugenol on human adipose-derived mesenchymal stem cells viability, growth and differentiation: a cheminformatics and in vitro study. AB - OBJECTIVE: The aim of this study was to estimate the cheminformatics and qualitative structure-activity relationship (QSAR) of cinnamaldehyde and eugenol. The effects of cinnamaldehyde and eugenol on the viability, doubling time and adipogenic or osteogenic differentiations of human adipose-derived mesenchymal stem cells (hASCs) were also investigated. MATERIALS AND METHODS: QSAR and toxicity indices of cinnamaldehyde and eugenol were evaluated using cheminformatics tools including Toxtree and Toxicity Estimation Software Tool (T.E.S.T) and molinspiration server. Besides, their effects on the hASCs viability, doubling time and differentiation to adipogenic or osteogenic lineages were evaluated. RESULTS: Cinnamaldehyde is predicted to be more lipophilic and less toxic than eugenol. Both phytochemicals may be developmental toxicants. They probably undergo hydroxylation and epoxidation reactions by cytochrome-P450. The 2.5 uM/ml cinnamaldehyde and 0.1 ug/ml eugenol did not influence hASCs viability following 72 hr of treatment. But higher concentrations of these phytochemicals insignificantly increased hASCs doubling time till 96 hr, except 1 ug/ml eugenol for which the increase was significant. Only low concentrations of both phytochemicals were tested for their effects on the hASCs differentiation. The 2.5 uM/ml cinnamaldehyde and 0.1 ug/ml eugenol enhanced the osteogenesis and decreased the adipogenesis of hASCs meaningfully. CONCLUSION: According to the cheminformatics analysis and in vitro study, cinnamaldehyde and eugenol are biocompatible and low toxic for hASCs. Both phytochemicals may be suitable for regenerative medicine and tissue engineering when used at low concentrations, but maybe useful for neoplastic growth inhibition when used at high concentrations. PMID- 28078247 TI - Effects of Biebersteinia multifida hydro-ethanol extract on proliferation and apoptosis of human prostate cancer and human embryonic kidney cells. AB - OBJECTIVE: Biebersteinia (Geraniaceae) has a history of use in traditional medicine in some countries including Iran. In the present study, cytotoxic and apoptogenic properties of hydro-ethanol extract of B. multifidi was investigated on human prostate cancer cell lines (PC3 and DU 145) and human embryonic kidney 293 (HEK293) cells. MATERIALS AND METHODS: Cells were cultured in RPMI-1640 medium supplemented with 10% FBS at 37oC in a humidified atmosphere of 95% air and 5% CO2. The root of the plant was macerated with EtOH 70%. Cytotoxic activity of ethanol extract of B. multifida was assessed using alamarBlue(r) assay after 48 hr of treatment. Apoptotic cells were stained with propidium iodide (PI) and detected by flow cytometry (sub-G1 peak). RESULTS: B.multifidi had cytotoxic effect on malignant cells and normal HEK293 cells in a dose-dependent manner and significantly decreased the cell viability (IC50 values were between 199.2 and 302.9 ug/ml). B. multifida increased the sub-G1 peak in flow cytometry histogram of treated PC3 cells compared to control showing the induction of apoptosis and DNA fragmentation. CONCLUSION: Due to cytotoxic and apoptotic activity of B. multifida, the plant is suggested for further phytochemical analysis and mechanistic evaluation. PMID- 28078246 TI - The effects of crocin, insulin and their co-administration on the heart function and pathology in streptozotocin-induced diabetic rats. AB - OBJECTIVE: Crocin is a saffron constituent with a potent anti-oxidant activity. The present study investigated the effects of crocin and insulin treatments (alone or in combination) on cardiac function and pathology in diabetic rats. MATERIALS AND METHODS: Diabetes was induced by intraperitoneal (i.p.) injection of streptozotocin (STZ, 50 mg/kg). Thereafter, crocin (5, 10 and 20 mg/kg, i.p.), subcutaneous (s.c.) injection of insulin (4 IU/kg) and their combination were administered for eight weeks. Blood glucose level and whole heart and body weights were measured. Electrocardiography (ECG) was carried out using the lead II. Serum concentrations of lactate dehydrogenase (LDH), creatine kinase-MB isoenzyme (CK-MB), and the heart tissue malodialdehyde (MDA) and superoxide dismutase (SOD) contents were determined. The heart lesions were evaluated by light microscopy. RESULTS: STZ decreased body weight and increased whole heart weight/body weight ratio. It also decreased heart rate, and increased RR and QT intervals and T wave amplitude. STZ increased blood glucose, serum LDH and CK-MB levels, augmented heart tissue MDA content, decreased SOD content of heart tissue, and produced hemorrhages, degeneration, interstitial edema, and fibroblastic proliferation in the heart tissue. Crocin (10 and 20 mg/kg, i.p.), insulin (4 IU/kg, s.c.) and their combination (5 mg/kg of crocin with 4 IU/kg of insulin) treatments recovered the ECG, biochemical and histopathological changes induced by STZ. CONCLUSION: The results showed cardioprotective effects of crocin and insulin in STZ-induced diabetic rats. The antioxidant and anti-hyperglycemic properties of crocin and insulin may be involved in their cardioprotective actions. PMID- 28078248 TI - Origanum vulgare leaf extract protects mice bone marrow cells against ionizing radiation. AB - OBJECTIVE: Ionizing radiation produces free radicals which induce DNA damage and cell death. Origanum vulgare leaf extract (OVLE) is a natural compound and its capability of scavenging free radicals and its antioxidant activity have been demonstrated by many researchers. In this study, using micronucleus assay, radioprotective effect of OVLE against clastogenic and cytotoxic effect of gamma irradiation has been investigated in mice bone marrow cells. MATERIALS AND METHODS: OVLE was injected intraperitoneally to the BALB/c mice 1hr prior to gamma irradiation (3Gy) at the doses of 100 and 200 mg/kg. Twenty four hours after irradiation or treatment, animals were killed and smears were prepared from the bone marrow cells. The slides were stained with May Grunwald-Giemsa method and analyzed microscopically. The frequency of micronucleated polychromatic erythrocytes (MnPCEs), micronucleated normochromatic erythrocyte (MnNCEs) and cell proliferation ratio PCE/PCE+NCE (polychromatic erythrocyte/polychromatic erythrocyte + normochromatic erythrocyte) were calculated. RESULTS: The results showed that gamma irradiation (3Gy) increased the frequency of MnPCEs, MnNCEs and reduced the PCE/PCE+NCE ratio in mice bone marrow compared to the non-irradiated control group (p<0.0001). Injection of OVLE significantly reduced the frequency of MnPCEs (p<0.0001) and MnNCEs (p<0.05) and increased the PCE/PCE+NCE ratio as compared to the irradiated control group (p<0.05). CONCLUSION: It seems that OVLE with its antioxidant properties and its capability of scavenging free radicals and reactive oxygen species can reduce the cytotoxic effects of gamma irradiation in mice bone marrow cells. PMID- 28078249 TI - Effects of Urtica dioica supplementation on blood lipids, hepatic enzymes and nitric oxide levels in type 2 diabetic patients: A double blind, randomized clinical trial. AB - OBJECTIVE: Oxidative stress plays an important role in the development of diabetic complications including metabolic abnormality-induced diabetic micro vascular and macro-vascular complications. Urtica dioica L. (U. dioica) has been traditionally used in Iranian medicine as an herbal remedy for hypoglycemic or due to its anti-inflammatory properties. The aim of the present study was to evaluate the effects of hydro-alcoholic extract of U. dioica on blood lipids, hepatic enzymes and nitric oxide levels in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: 50 women with type 2 diabetes participated in this study and were randomly divided into two groups namely, control and intervention groups. Control group received placebo and intervention group received hydro-alcoholic extract of U. dioica. Before and after 8 weeks of continuous treatment, some biochemical serum levels including FPG, TG, SGPT, SGOT, HDL, LDL, SOD and NO were measured. RESULTS: The results indicated that after 8 weeks, in the intervention group, FPG, TG, and SGPT levels significantly decreased and HDL, NO and SOD levels significantly increased as compared to the control group. CONCLUSION: Our results encourage the use of hydro-alcoholic extract of U. dioica as an antioxidant agent for additional therapy of diabetes as hydro-alcoholic extract of U. dioica may decrease risk factors of cardiovascular incidence and other complications in patients with diabetes mellitus. PMID- 28078250 TI - Effects of Mimosa pudica L. leaves extract on anxiety, depression and memory. AB - OBJECTIVE: The present study was carried out to investigate the neuropharmacological activities of ethyl acetate extract of Mimosa pudica (EAMP) leaves on anxiety, depression and memory in a mouse model. MATERIALS AND METHODS: Anti-anxiety potential of EAMP was evaluated by elevated plus maze (EPM), light dark box (LDB) and social interaction (SI) tests in mice.Anti-depressant potential of EAMP was evaluated by forced swimming (FST), tail suspension (TST), and open field tests (OFT). The behavioral findings were further corroborated with estimation of neurotransmitters and their metabolites from mouse brain homogenate. Effect on learning and memory was evaluated by EPM, passive avoidance (PA) tests. Further, it was confirmed with assessment of acetylcholinesterase and caspase-3 activity in brain homogenate. RESULTS: EAMP showed significant anti anxiety activity by increasing the time spent in open arm of EPM, light box of LDB. Social interaction time was increased significantly (p<0.01) as compared to vehicle control. There was also significant reduction of immobility time in both FST and TST without any changes in locomotor activity in the OFT. Monoamine neurotransmitters (dopamine and norepinephrine) concentrations were increased significantly (p<0.01) after 4 weeks of treatment as compared to stress control and substantiated the anti-depressant activity. Step down latency was increased (p<0.01) in PA test and transfer latency was decreased (p<0.01) in EPM test of EAMP-treated mice. Acetylcholinesterase and caspase-3 activity was significantly (p<0.05) changed in mice treated with EAMP (200 and 400 mg/kg). CONCLUSION: The results revealed that EAMP has anti-anxiety, anti-depressant and memory enhancing activities that are mediated through multiple mechanisms. PMID- 28078252 TI - The Evaluation of the Effect of Herbal Extract on Osteoarthritis: In Vitro and In Vivo Study. AB - In this study, the anti-osteoarthritis effects of Cynanchum wilfordii, Phlomis umbrosa, and Angelica gigas extract (CPAE), observed and confirmed in previously clinical studies were further investigated by in vitro and in vivo studies. Anabolic biomarkers related to healthy cartilage maintenance, such as aggrecan, type II collagen alpha-1 (Col2a1), sex determining region Y-box-9 (Sox-9), and catabolic biomarkers related to osteoarthritis, such as cyclooxygenase-2 (Cox-2), matrix metalloproteinase-13 (Mmp13), and nuclear factor kappa-light-chain enhancer of activated B cells (Nfkappab), were evaluated by quantitative reverse transcriptase polymerase chain reaction and reporter gene assay. In vitro study results showed significant changes in both anabolic and catabolic biomarkers. For anabolic factors, significant changes in the level of aggrecan (P<0.05), Col2a1 (P<0.05), and Sox-9 (P<0.01) activation were shown after treatment of cartilage cells with CPAE (50 ng/mL) with similar efficacy compared to insulin growth factor, the positive control (100 ng/mL). For catabolic factors, significant changes in the inhibition activity of Cox-2 (P<0.05), Mmp13 (P<0.01), and Nfkappab (P<0.05) were shown for CPAE (50 ng/mL) with similar efficacy compared to Celecoxib, the positive control (10 MUM). In the in vivo carrageenan-induced paw edema model study results showed that CPAE-treated groups (100 mg/kg) and Celecoxib-treated groups (60 mg/kg) showed comparably significant efficacy of inhibition by 37.1% and 52.1%, respectively. Furthermore, CPAE (200 mg/kg) showed similar effect to Celecoxib (60 mg/kg) with an inhibition rate of 54.3%. This result confirms that CPAE effectively inhibited the inflammation-induced osteoarthritis symptoms. PMID- 28078251 TI - A Review of Fermented Foods with Beneficial Effects on Brain and Cognitive Function. AB - Around the world, fermentation of foods has been adopted over many generations, primarily due to their commercial significance with enriched flavors and high profile nutrients. The increasing application of fermented foods is further promoted by recent evidence on their health benefits, beyond the traditionally recognized effects on the digestive system. With recent advances in the understanding of gut-brain interactions, there have also been reports suggesting the fermented food's efficacy, particularly for cognitive function improvements. These results are strengthened by the proposed biological effects of fermented foods, including neuroprotection against neurotoxicity and reactive oxygen species. This paper reviews the beneficial health effects of fermented foods with particular emphasis on cognitive enhancement and neuroprotective effects. With an extensive review of fermented foods and their potential cognitive benefits, this paper may promote commercially feasible applications of fermented foods as natural remedies to cognitive problems. PMID- 28078253 TI - Effects of Eicosapentaenoic Acid and Docosahexaenoic Acid on Mitochondrial DNA Replication and PGC-1alpha Gene Expression in C2C12 Muscle Cells. AB - Mitochondrial biogenesis is a complex process requiring coordinated expression of nuclear and mitochondrial genomes. The peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1alpha) is a key regulator of mitochondrial biogenesis, and it controls mitochondrial DNA (mtDNA) replication within diverse tissues, including muscle tissue. The aim of this study was to investigate the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on mtDNA copy number and PGC-1alpha promoter activity in C2C12 muscle cells. mtDNA copy number and mRNA levels of genes related to mitochondrial biogenesis such as PGC 1alpha, nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (Tfam) were assayed by quantitative real-time PCR. The PGC-1alpha promoter from -970 to +412 bp was subcloned into the pGL3-basic vector, which includes a luciferase reporter gene. Both EPA and DHA significantly increased mtDNA copy number, dose and time dependently, and up-regulated mRNA levels of PGC 1alpha, NRF1, and Tfam. Furthermore, EPA and DHA stimulated PGC-1alpha promoter activity in a dose-dependent manner. These results suggest that EPA and DHA may modulate mitochondrial biogenesis, which was partially associated with increased mtDNA replication and PGC-1alpha gene expression in C2C12 muscle cells. PMID- 28078254 TI - Achyranthes japonica Nakai Water Extract Suppresses Binding of IgE Antibody to Cell Surface FcERI. AB - Achyranthes japonica Nakai (AJN) water extract has a variety of physiological properties, including anti-diabetic, anti-cancer, anti-inflammatory, anti microbial, and anti-oxidative activities. In the present study, the inhibitory effects of AJN extract were investigated in high affinity immunoglobulin E receptor (FcERI)-mediated KU812F cells activation. AJN extract showed suppressive effects on histamine release and intracellular calcium [Ca2+]i elevation from anti-FcERI antibody (CRA-1)-stimulated cells in a dose-dependent manner. Flow cytometric analysis showed that AJN extract treatment caused a dose-dependent decrease in the cell surface FcERI expression and the binding between the cell surface FcERI and the IgE antibody. Moreover, reverse transcription-polymerase chain reaction analysis showed that levels of the mRNA for the FcERI alpha chain was decreased by treatment with AJN extract. These results indicate that AJN extract may exert anti-allergic effects via the inhibition of calcium influx and histamine release, which occurs as a result from the down-regulation of the binding of IgE antibody to cell surface FcERI. This mechanism may occur through FcERI expression inhibition. PMID- 28078255 TI - Quality Characteristics and Antioxidant Activity of Yogurt Supplemented with Aronia (Aronia melanocarpa) Juice. AB - We investigated the quality characteristics and antioxidant activities of yogurt supplemented with 1%, 2%, and 3% aronia juice and fermented for 24 h at 37 degrees C. The total acidity increased with increasing levels of aronia juice and incubation time. Lightness and yellowness of the yogurt decreased, but redness increased, with increasing aronia juice content and incubation time. The number of lactic acid bacteria (LAB) increased with increased incubation time, and yogurt containing 2% and 3% aronia juice showed higher LAB counts than 1% aroinia juice-supplemented yogurt. The total polyphenol and flavonoid contents increased proportionally with increasing levels of aronia juice. Antioxidant activity of aronia-containing yogurt was significantly higher than that of the control and increased proportionally with aronia juice concentration. Yogurt with 2% aronia juice had the best taste (P<0.05). Aronia juice may be a useful additive for improving the taste and antioxidant potential of yogurt. PMID- 28078256 TI - Volatile Compound, Physicochemical, and Antioxidant Properties of Beany Flavor Removed Soy Protein Isolate Hydrolyzates Obtained from Combined High Temperature Pre-Treatment and Enzymatic Hydrolysis. AB - The present study investigated the volatile compound, physicochemical, and antioxidant properties of beany flavor-removed soy protein isolate (SPI) hydrolyzates produced by combined high temperature pre-treatment and enzymatic hydrolysis. Without remarkable changes in amino acid composition, reductions of residual lipoxygenase activity and beany flavor-causing volatile compounds such as hexanol, hexanal, and pentanol in SPI were observed after combined heating and enzymatic treatments. The degree of hydrolysis, emulsion capacity and stability, 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity, and superoxide radical scavenging activity of SPI were significantly increased, but the magnitudes of apparent viscosity, consistency index, and dynamic moduli (G', G") of SPI were significantly decreased after the combined heating and enzymatic treatments. Based on these results, it was suggested that the enzymatic hydrolysis in combination with high temperature pre-treatment may allow for the production of beany flavor-removed SPI hydrolyzates with superior emulsifying and antioxidant functionalities. PMID- 28078257 TI - Physicochemical Characteristics of Black Garlic after Different Thermal Processing Steps. AB - This study investigated the physicochemical characteristics of black garlic (BG) after different thermal processing steps. Compared with fresh garlic (FG), the moisture content and pH in BG decreased significantly, while the ash content and browning intensity increased during thermal processing. The total mineral and the free sugar contents were significantly higher than that of the BG2 and BG4 samples, respectively. The free sugar content increased by 16-fold in the BG cloves compared with that of FG, while the amino acid content increased during the first stage of thermal processing, and subsequently decreased. The thiosulfinate content in all samples decreased to during thermal processing. The pyruvic acid content initially increased and then decreased during thermal processing. These results contribute to our understanding of the role of thermal processing in the quality formation of BG. PMID- 28078258 TI - Multiresponse Optimization and Prediction of Antioxidant Properties of Aqueous Ginger Extract. AB - The influence of extraction temperature, powder concentration, and extraction time on the antioxidant properties of aqueous ginger extract was investigated. The possibility of estimating the antioxidant properties of the extract from its absorbance and colour properties was also investigated. Results indicated that powder concentration was the most significant factor to consider in optimizing antioxidant extraction. However, temperature and time still influenced the 2,2' azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activity while extraction temperature influenced the 2,2-diphenyl-1 picrylhydrazyl (DPPH) radical scavenging activity of the extract. Using the total phenol content, total flavonoid content, ABTS radical scavenging activity, and DPPH radical scavenging activity of the extract, the multiresponse optimization condition for extraction of antioxidant based on the experimental range studied is 96 degrees C, 2.10 g/100 mL, and 90 min. The absorbance of the ginger extract at 610 nm could be exploited for rapid estimation of its total flavonoid and polyphenol with a R2 of 0.713 and 0.753, respectively. PMID- 28078259 TI - Effects of Blends of Low-Protein Winter Wheat Flour and Barley Byproducts on Quality Changes in Noodles. AB - The physicochemical characteristics of fresh noodles made with blends of low protein wheat flour and barley byproduct (BBP, 250 MUm) were investigated. The crude protein contents (PC) of flour from Goso and Backjoong cultivars were 7.91% and 7.67%, respectively. PC and beta-glucan contents from the BBP were 14.10% and 3.11%, respectively, which were higher than those in wheat flour. The water holding capacity (WHC) of various blends was increased as a function of BBP but not gluten contents. Goso flour had the highest starch content (78.68%), with peak and final viscosities of 3,099 and 3,563 cp, respectively. Peak and final viscosities, trough, breakdown, and setback of the blends were decreased with the addition of BBP. Noodles made with Backjoong had the highest thickness score, while the hardness of noodles made with blends of Goso or Backjoong and 20% BBP were similar to those made from wheat flour only. The WHC of the samples was strongly correlated with PC, crude fiber, and beta-glucan. The PC was not correlated with final viscosity, setback, thickness, hardness, gumminess, or chewiness. PMID- 28078260 TI - Rheological and Pasting Properties of Naked Barley Flour as Modified by Guar, Xanthan, and Locust Bean Gums. AB - To understand the effects of adding different gums (guar, xanthan, and locust bean gums) on naked barley flour (NBF), the rheological and pasting properties of NBF-gum mixtures were measured at different gum concentrations (0, 0.3, and 0.6% w/w). Steady shear rheological properties were determined by rheological parameters for power law and Casson models. All samples showed a clear trend of shear-thinning behavior (n=0.16~0.48) and had a non-Newtonian nature with yield stress. Consistency index, apparent viscosity, and yield stress values increased with an increase in gum concentration. Storage modulus values were more predominant than loss modulus values with all concentrations of gums. There is a more pronounced synergistic effect of elastic properties of NBF in the presence of xanthan gum. Rapid visco analyser pasting properties showed that the addition of gums resulted in a significant increase in the peak, breakdown, setback, and final viscosities, whereas the pasting temperature decreased. PMID- 28078261 TI - Effects of Aqueous Extracts of Cynanchum wilfordii in Rat Models for Postmenopausal Hot Flush. AB - Menopausal hot flushes (HFs), which manifest as a transient increase in skin temperature, occur most frequently in postmenopausal women, and sometimes negatively influence daily life. We investigated the effect of an aqueous extract of Cynanchum wilfordii (CWW) in a rat model of menopausal HFs, where tail skin temperature (TST) is increased after the rapid estrogen decline induced by ovariectomy. Ten-week-old female rats were ovariectomized and treated with CWW for 1 week. We measured TST and rectal temperatures (RT) and investigated serum estradiol. The TST in ovariectomized (OVX) rats was significantly elevated after ovariectomy compared with control rats, whereas the RT in OVX rats was not elevated. Administration of CWW (200 mg/kg/d for 7 days, p.o.) significantly improved the skin temperature increase in OVX rats. The lower level of serum estradiol in OVX rats was significantly increased by supplying E2, but it was not affected by CWW. The present study indicates a need for future research involving treatment with high concentrations of C. wilfordii and measurement over 24 h. PMID- 28078262 TI - The Leaf of Diospyros kaki Thumb Ameliorates Renal Oxidative Damage in Mice with Type 2 Diabetes. AB - Diabetic kidney disease is the most common and severe chronic complication of diabetes. The leaf of Diospyros kaki Thumb (persimmon) has been commonly used for herbal tea and medicinal purposes to treat a variety of conditions, including hypertension and atherosclerosis. However, the effect of persimmon leaf on kidney failure has not been investigated. This study aimed to examine the role of persimmon leaf in protecting the diabetes-associated kidney damage in a mouse model of type 2 diabetes. Mice were fed either a normal chow diet with or without powered persimmon leaf (5%, w/w) for 5 weeks. In addition to kidney morphology and blood markers of kidney function, we assessed levels of oxidative stress markers as well as antioxidant enzymes activities and mRNA expression in the kidney. Supplementation of the diet with powered persimmon leaf not only decreased the concentration of blood urea nitrogen in the plasma but also improved glomerular hypertrophy. Furthermore, the persimmon leaf significantly decreased the levels of hydrogen peroxide and lipid peroxide in the kidney. The activities of superoxide dismutase, catalase, and glutathione peroxidase and the mRNA expression of their respective genes were also increased in the kidney of persimmon leaf-supplemented db/db mice. Taken together, these results suggest that supplementation with the persimmon leaf may have protective effects against type 2 diabetes-induced kidney dysfunction and oxidative stress. PMID- 28078263 TI - Cytotoxic Effects of Strawberry, Korean Raspberry, and Mulberry Extracts on Human Ovarian Cancer A2780 Cells. AB - Reactive oxygen species are tumorigenic by their ability to increase cell proliferation, survival, and cellular migration. The purpose of the present study was to compare the antioxidant activity and cytotoxic effects of 3 berry extracts (strawberry, Korean raspberry, and mulberry) in A2780 human ovarian carcinoma cells. Except for raspberry, the ethyl acetate or methylene chloride fractions of berries containing phenolic compounds exerted dose dependent free radical scavenging activities. In the raspberry fractions, the hexane fraction also exhibited potent antioxidant activity. The cytotoxic effects of berries extracts in A2780 human ovarian carcinoma cells were measured using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Surprisingly, co treatment with n-butanol (BuOH) fractions of berries showed stronger cytotoxic effects compared to the other fractions. These findings suggest that potent anticancer molecules are found in the BuOH fractions of berries that have stronger cytotoxic activity than antioxidants. PMID- 28078264 TI - Comparison of Ginsenoside Contents in Different Parts of Korean Ginseng (Panax ginseng C.A. Meyer). AB - The present study was conducted to investigate the ginsenoside profiles of the main root, root hair, and leaf of ginseng in order to demonstrate their possible application in medicine. The total ginsenoside content of the leaf was up to 12 times than that in the main root, and the content of protopanaxadiol groups was higher than that of protopanaxatriol groups in all the samples. The leaf was shown to contain high amounts of ginsenosides Rb3 and Rh1, whereas the main root contained large amounts of ginsenosides Rb1 and Rc. Moreover, Rb2, Rb3, and Rg1 were only detected in the root hair, leaf, and main root, respectively. The ginsenoside Re content of Panax ginseng leaf and root hair was 2.6~4 times higher than that of the main root. Therefore, the results indicate that the ginsenoside content of Panax ginseng is higher in the leaf and root hair, and lower in the main root. PMID- 28078265 TI - Classification of 31 Korean Wheat (Triticum aestivum L.) Cultivars Based on the Chemical Compositions. AB - Whole grain wheat flour (WGWF) is the entire grain (bran, endosperm, and germ) milled to make flour. The WGWF of 31 Korean wheat (Triticum aestivum L.) cultivars were analyzed for the chemical compositions, and classified into groups by hierarchical cluster analysis (HCL). The average composition values showed a substantial variation among wheat varieties due to different wheat varieties. Wheat cv. Shinmichal1 (waxy wheat) had the highest ash, lipid, and total dietary fiber contents of 1.76, 3.14, and 15.49 g/100 g, respectively. Using HCL efficiently classified wheat cultivars into 7 clusters. Namhae, Sukang, Gobun, and Joeun contained higher protein values (12.88%) and dietary fiber (13.74 %). Regarding multi-trait crop breeding, the variation in chemical compositions found between the clusters might be attributed to wheat genotypes, which was an important factor in accumulating those chemicals in wheat grains. Thus, once wheat cultivars with agronomic characteristics were identified, those properties might be included in the breeding process to develop a new variety of wheat with the trait. PMID- 28078267 TI - Correction of Table. AB - [This corrects the article on p. 165 in vol. 21, PMID: 27752491.]. PMID- 28078266 TI - Evaluation of Melanoidins Formed from Black Garlic after Different Thermal Processing Steps. AB - The objective of this study was to evaluate the characteristics of melanoidins formed from black garlic (BG) after different thermal processing steps. The melanoidins formed from BG during thermal processing were produced in large amounts, and the initial (280 nm), intermediate (360 nm), and final stage product (420 nm) had similar tendencies. Compounds like degraded proteins, peptides, and phenolic acids were present in the melanoidins during thermal processing. All the melanoidin samples showed different absorptions in the UV-visible spectra, although these had similar shapes. Moreover, the carbon, hydrogen, and oxygen content of melanoidins formed from BG during thermal processing decreased initially, and then increased. However, the nitrogen content increased during thermal processing. As thermal processing progressed, the molecular weight of all the melanoidin samples showed increasing intensities, whereas the major peaks of each melanoidin sample had different retention times. Furthermore, the melanoidins formed from BG after different thermal processing steps contained OH, -CH, amide I, and III groups. The crystallinity of the melanoidins was majorly formed at 31.58 degrees and 43.62 degrees (2theta). PMID- 28078268 TI - Blocking TGF-beta and BMP SMAD-dependent cell differentiation is a master key to expand all kinds of epithelial stem cells. PMID- 28078269 TI - Comment on: Expandable cardiovascular progenitor cells reprogrammed from fibroblasts. PMID- 28078270 TI - Wilms tumor 1 peptide vaccination after hematopoietic stem cell transplant in leukemia patients. AB - Although the prognosis of leukemia patients after allogeneic hematopoietic stem cell transplantation (HSCT) has greatly improved, relapse is still a major cause of death after HSCT. Cancer vaccines may have the potential to enhance the graft versus-leukemia (GVL) effect. The post-allogeneic HSCT period provides a unique platform for vaccination, because (I) tumor burden is minimal, (II) lymphopenia allows for rapid expansion of cytotoxic T cells (CTLs), (III) donor-derived CTLs are not exhausted, (IV) inflammation is caused by alloreactions, and (V) the abundance of regulatory T cells is low due to their late recovery. Tumor cell lysates, dendritic cells (DCs), and peptides derived from leukemia-associated antigens (LAAs) have been used as vaccines. Clinical trials with several types of vaccines for post-HSCT patients revealed that the vaccination induced an immunological response and might benefit patients with minimal residual disease; however, the efficacy of this approach must be examined in randomized studies. In addition, it is important to consider the combination of cancer vaccine with checkpoint antibodies, recently shown to be useful in treating leukemia relapse after HSCT. PMID- 28078271 TI - Cell sources for regenerative medicine of the liver and endoderm organs: strategies and perspectives. PMID- 28078272 TI - Novel methods for the treatment of liver fibrosis using in vivo direct reprogramming technology. PMID- 28078273 TI - Combining retinoic acid and oral arsenic may be potentially the first-line therapy for non-high-risk acute promyelocytic leukemia. PMID- 28078274 TI - Outside the brain: an inside view on transgenic animal and stem cell-based models to examine neuronal serotonin-dependent regulation of HPA axis-controlled events during development and adult stages. AB - Recently, Trista North and colleagues showed that neuronal synthesis of serotonin is an essential key process for embryonic hematopoietic stem (HPS) cell production in zebrafish. Using their experimental design, they were able to show that neuronal serotonin activates the stress-responsive hypothalamic-pituitary adrenal (HPA) axis and glucocorticoid receptor activity which in turn induces HPS cell formation. In our perspective, we give a short overview on established experimental approaches for serotonergic neurotransmission in vivo and in vitro and their potential to address putative contributions of serotonergic neurotransmission to physiological processes beyond the central nervous systems (CNS). We briefly introduce common features of brain serotonin-depleted, tryptophan hydroxylase-2 knockout mice, which can be applied to investigate the contribution of brain-derived serotonin to developmental and adult physiological processes outside the CNS. These models allow to analyzing gender-specific, HPA axis-dependent processes in female and male knockout mice during developmental and adult stages. We also highlight the application of human and mouse stem cell derived serotonergic neurons as an independent research model as well as complementary experimental approach to transgenic animal models. In case of human serotonergic neurotransmission, human in vitro-generated neurons present a very promising and highly valuable experimental approach to address characteristics of human neuronal serotonin signaling on a molecular and cellular level. The combination of transgenic animal models and newly established stem cell technologies will provide powerful research platforms, which will help to answer yet unsolved mysteries of serotonergic neurotransmission. PMID- 28078275 TI - Peptide vaccination against multiple myeloma using peptides derived from anti apoptotic proteins: a phase I trial. AB - The B-cell lymphoma-2 (Bcl-2) family of proteins play a crucial role in multiple myeloma (MM), contributing to lacking apoptosis which is a hallmark of the disease. This makes the Bcl-2 proteins interesting targets for therapeutic peptide vaccination. We report a phase I trial of therapeutic vaccination with peptides from the proteins Bcl-2, Bcl-XL and Mcl-1 in patients with relapsed MM. Vaccines were given concomitant with bortezomib. Out of 7 enrolled patients, 4 received the full course of 8 vaccinations. The remaining 3 patients received fewer vaccinations due to progression, clinical decision of lacking effect and development of hypercalcemia, respectively. There were no signs of toxicity other than what was to be expected from bortezomib. Immune responses to the peptides were seen in all 6 patients receiving more than 2 vaccinations. Three patients had increased immune responses after vaccination. Vaccination against Bcl-2 was well tolerated and was able to induce immune responses in patients with relapsed MM. PMID- 28078276 TI - Increased vulnerability of photoreceptors to aberrant splicing highlight the utility of AON-based therapy for CEP290-LCA. PMID- 28078277 TI - Influence of Processing Methods on Proximate Composition and Dieting of Two Amaranthus Species from West Cameroon. AB - The effects of various processing methods on the proximate composition and dieting of Amaranthus hybridus and Amaranthus cruentus from West Cameroon were investigated in this study. Both amaranths leaves were subjected to same treatments (sun-dried and unsliced, sliced and cooked), milled, and analysed for their mineral and proximate composition. Thirty-Six Wistar albino rats of 21 to 24 days old were distributed in six groups and fed for 14 days with 10% protein based diets named D0 (protein-free diet), DI (egg white as reference protein), DII (sun-dried and unsliced A. hybridus), DIII (cooked and sliced A. hybridus), DIV (sun-dried and unsliced A. cruentus), and DV (cooked and sliced A. cruentus). The protein bioavailability and haematological and biochemical parameters were assessed in rats. The results showed that K, P, Mg, Zn, and Fe had the higher content in both samples regardless of processing method. The sun-dried and unsliced A. cruentus contained the highest value of crude protein 32.22 g/100 g DM (dry matter) while the highest crude lipid, 3.80 and 2.58%, was observed, respectively, in sun-dried and unsliced A. hybridus and cooked and sliced A. cruentus. Cooked and sliced A. hybridus and A. cruentus contained high crude fiber of 14 and 12.18%, respectively. Rats fed with diet DIII revealed the best protein bioavailability and haematological parameters whereas 100% mortality rate was recorded with group fed with diet DIV. From this study, it is evident that cooked and sliced A. hybridus and A. cruentus could play a role in weight reduction regimes. PMID- 28078278 TI - Interactions between CYP11B2 Promoter Methylation and Smoking Increase Risk of Essential Hypertension. AB - Aldosterone synthase (CYP11B2) is closely linked to essential hypertension (EH). However, it remains unclear whether the methylation of the CYP11B2 promoter is involved in the development of EH in humans. Our study is aimed at evaluating the contribution of CYP11B2 promoter methylation to the risk of EH. Methylation levels were measured using pyrosequencing technology in 192 participants in a hospital-based case-control study. Logistic regression and multiple linear regression analyses were utilized to adjust for confounding factors and the GMDR method was applied to investigate high-order gene-environment interactions. Although no significant result was observed linking the four analyzed CpG sites to EH, GMDR detected significant interactions among CpG1, CpG3, CpG4, and smoking correlated with an increased risk of EH (OR = 4.62, adjusted P = 0.011). In addition, CpG2 (adjusted P = 0.013) and CpG3 (adjusted P = 0.039) methylation was significantly lower in healthy males than in healthy females. Likewise, after adjusting for confounding factors, CpG2 methylation (adjusted P = 0.007) still showed significant gender-specific differences among the participants of the study. CpG1 (P = 0.009) site was significantly positively correlated with age, and CpG3 (P = 0.007) and CpG4 (P = 0.006) were both inversely linked to smoking. Our findings suggest that gene-environment interactions are associated with the pathogenesis and progression of EH. PMID- 28078279 TI - Anatomical Location of the Common Iliac Veins at the Level of the Sacrum: Relationship between Perforation Risk and the Trajectory Angle of the Screw. AB - Purpose. To determine the safety of transarticular surface screw (TASS) insertion and the anatomical location of the common iliac veins (CIVs) at the level of the promontorium. Materials and Methods. The locations of the CIVs on 1 mm computed tomography-myelography slices of 50 patients at the level of the promontorium and 20 human cadavers were investigated. Results. Among the patients, the left CIV was closer to the S1 anterior wall than the right CIV (mean distance: 5.0 +/- 3.0 and 7.0 +/- 4.2 mm, resp.). The level of the inferior vena cava (IVC) formation varied among the cadavers. The mean distance between the IVC formation and promontorium tip was 30.2 +/- 12.8 mm. The height of the IVC formation and distance between the right and the left CIVs at the level of the promontorium were significantly correlated (P < 0.001). Conclusion. The TASS trajectory is safe as long as the screw does not penetrate the anterior cortex of S1. The level of the IVC formation can help to predict the distance between the right and the left CIVs at the level of the promontorium. The CIVs do not have a uniform anatomical location; therefore, preoperative computed tomography is necessary to confirm their location. PMID- 28078280 TI - Protective Effects of Emodin-Induced Neutrophil Apoptosis via the Ca2+-Caspase 12 Pathway against SIRS in Rats with Severe Acute Pancreatitis. AB - Severe acute pancreatitis (SAP) results in high mortality. This is partly because of early multiple organ dysfunction syndromes that are usually caused by systemic inflammatory response syndrome (SIRS). Many studies have reported the beneficial effects of emodin against SAP with SIRS. However, the exact mechanism underlying the effect of emodin remains unclear. This study was designed to explore the protective effects and underlying mechanisms of emodin against SIRS in rats with SAP. In the present study, cytosolic Ca2+ levels, calpain 1 activity, and the expression levels of the active fragments of caspases 12 and 3 decreased in neutrophils from rats with SAP and increased after treatment with emodin. Delayed neutrophil apoptosis occurred in rats with SAP and emodin was able to reverse this delayed apoptosis and inhibit SIRS. The effect of emodin on calpain 1 activity, the expression levels of the active fragments of caspases 12 and 3, neutrophil apoptosis, and SIRS scores were attenuated by PD150606 (an inhibitor of calpain). These results suggest that emodin inhibits SIRS in rats with SAP by inducing circulating neutrophil apoptosis via the Ca2+-calpain 1-caspase 12 caspase 3 signaling pathway. PMID- 28078281 TI - The Role of BRCA2 Mutation Status as Diagnostic, Predictive, and Prognosis Biomarker for Pancreatic Cancer. AB - Pancreatic cancer is one of the deadliest cancers worldwide, and life expectancy after diagnosis is often short. Most pancreatic tumours appear sporadically and have been highly related to habits such as cigarette smoking, high alcohol intake, high carbohydrate, and sugar consumption. Other observational studies have suggested the association between pancreatic cancer and exposure to arsenic, lead, or cadmium. Aside from these factors, chronic pancreatitis and diabetes have also come to be considered as risk factors for these kinds of tumours. Studies have found that 10% of pancreatic cancer cases arise from an inherited syndrome related to some genetic alterations. One of these alterations includes mutation in BRCA2 gene. BRCA2 mutations impair DNA damage response and homologous recombination by direct regulation of RAD51. In light of these findings that link genetic factors to tumour development, DNA damage agents have been proposed as target therapies for pancreatic cancer patients carrying BRCA2 mutations. Some of these drugs include platinum-based agents and PARP inhibitors. However, the acquired resistance to PARP inhibitors has created a need for new chemotherapeutic strategies to target BRCA2. The present systematic review collects and analyses the role of BRCA2 alterations to be used in early diagnosis of an inherited syndrome associated with familiar cancer and as a prognostic and predictive biomarker for the management of pancreatic cancer patients. PMID- 28078282 TI - The Double-Row Suture Technique: A Better Option for the Treatment of Haglund Syndrome. AB - Purpose. The purpose of this study is to investigate whether double-row suture technique is a better option for the treatment of Haglund syndrome than single row suture technique regarding the surgical outcomes. Methods. Thirty-two patients with Haglund syndrome were recruited in this study. Patients were divided into Group 1 (treated with single-row suture technique) and Group 2 (treated with double-row suture technique). There were 16 patients in each group. The AOFAS-ankle-hindfoot scale, VISA-A scores, and Arner-Lindholm standard were used to assess the clinical outcomes. The pre- and postoperative X-rays were used to assess the radiological outcome. Results. Both AOFAS-ankle-hindfoot scale score and VISA-A score had varying degrees of improvement in both groups. In latest follow-up assessment, the Arner-Lindholm standard investigation showed there were 7 excellent, 7 good, and 2 bad outcomes in Group 1 and 12 excellent and 4 good outcomes in Group 2. In Group 2 patients, there were no more posterosuperior bony prominence of the calcaneum in post-op X-rays and there were no recurrent cases. The ankle-related scale score was statistically significantly higher in Group 2 than in Group 1 (P = 0.029). Conclusion. The double-row suture technique seems to be a better option to treat Haglund syndrome than single-row suture technique. PMID- 28078283 TI - Periosteal Distraction Osteogenesis: An Effective Method for Bone Regeneration. AB - The treatment of bone defects is challenging and controversial. As a new technology, periosteal distraction osteogenesis (PDO) uses the osteogenicity of periosteum, which creates an artificial space between the bone surface and periosteum to generate new bone by gradually expanding the periosteum with no need for corticotomy. Using the newly formed bone of PDO to treat bone defects is effective, which can not only avoid the occurrence of immune-related complications, but also solve the problem of insufficient donor. This review elucidates the availability of PDO in the aspects of mechanisms, devices, strategies, and measures. Moreover, we also focus on the future prospects of PDO and hope that PDO will be applied to the clinical treatment of bone defects in the future. PMID- 28078285 TI - Combination of Salivary Gland Ultrasonography and Virtual Touch Quantification for Diagnosis of Sjogren's Syndrome: A Preliminary Study. AB - A total of 136 subjects (51 SS patients, 35 sicca syndrome patients without SS, and 50 healthy volunteers) were enrolled in this study. The mean SWV value for salivary glands of SS patients was statistically higher than that of controls (2.81 +/- 0.66 m/s versus 1.85 +/- 0.28 m/s for parotid glands and 2.29 +/- 0.34 m/s versus 1.82 +/- 0.25 m/s for submandibular glands, resp.). Combining SWV values of parotid and submandibular glands gives a sensitivity of 88.2% (95% CI: 76.1-95.6%) and specificity of 96.0% (95% CI: 86.3-99.5%) at the cutoff point of 2.19 m/s, with an AUROC of 0.954 (95% CI: 0.893-0.986). In addition, combining SGUS score and SWV value yields a sensitivity of 98.0% (95% CI: 89.6-100%), specificity of 90.0% (95% CI: 78.2-96.7%), and AUROC of 0.962 (95% CI: 0.904 0.990). Classification tree considering the sequential use of SGUS score and SWV value achieved 92.1% accuracy for diagnosis of SS. Similarly, the ROC curve of combined SGUS scores and SWV values yields an AUROC of 0.954 (95% CI: 0.885 0.987), sensitivity of 97.1% (95% CI: 85.1-99.9%), and specificity of 92.2% (95% CI: 81.1-97.8%) for separating sicca syndrome patients (without SS) from SS patients. Combining SGUS and VTQ provides a promising tool for diagnosis of SS. PMID- 28078284 TI - Extracellular Vesicles and Autophagy in Osteoarthritis. AB - Osteoarthritis (OA) is a type of chronic joint disease that is characterized by the degeneration and loss of articular cartilage and hyperplasia of the synovium and subchondral bone. There is reasonable knowledge about articular cartilage physiology, biochemistry, and chondrocyte metabolism. However, the etiology and pathogenesis of OA remain unclear and need urgent clarification to guide the early diagnosis and treatment of OA. Extracellular vesicles (EVs) are small membrane-linking particles that are released from cells. In recent decades, several special biological properties have been found in EV, especially in terms of cartilage. Autophagy plays a critical role in the regulation of cellular homeostasis. Likewise, more and more research has gradually focused on the effect of autophagy on chondrocyte proliferation and function in OA. The synthesis and release of EV are closely associated with autophagy. At the same time, both EV and autophagy play a role in OA development. Based on the mechanism of EV and autophagy in OA development, EV may be beneficial in the early diagnosis of OA; on the other hand, the combination of EV and autophagy-related regulatory drugs may provide insight into possible OA therapeutic strategies. PMID- 28078286 TI - Placenta Derived Mesenchymal Stem Cells Hosted on RKKP Glass-Ceramic: A Tissue Engineering Strategy for Bone Regenerative Medicine Applications. AB - In tissue engineering protocols, the survival of transplanted stem cells is a limiting factor that could be overcome using a cell delivery matrix able to support cell proliferation and differentiation. With this aim, we studied the cell-friendly and biocompatible behavior of RKKP glass-ceramic coated Titanium (Ti) surface seeded with human amniotic mesenchymal stromal cells (hAMSCs) from placenta. The sol-gel synthesis procedure was used to prepare the RKKP glass ceramic material, which was then deposited onto the Ti surface by Pulsed Laser Deposition method. The cell metabolic activity and proliferation rate, the cytoskeletal actin organization, and the cell cycle phase distribution in hAMSCs seeded on the RKKP coated Ti surface revealed no significant differences when compared to the cells grown on the treated plastic Petri dish. The health of of hAMSCs was also analysed studying the mRNA expressions of MSC key genes and the osteogenic commitment capability using qRT-PCR analysis which resulted in being unchanged in both substrates. In this study, the combination of the hAMSCs' properties together with the bioactive characteristics of RKKP glass-ceramics was investigated and the results obtained indicate its possible use as a new and interesting cell delivery system for bone tissue engineering and regenerative medicine applications. PMID- 28078287 TI - Paramagnetic Manganese in the Atherosclerotic Plaque of Carotid Arteries. AB - The search for adequate markers of atherosclerotic plaque (AP) instability in the context of assessment of the ischemic stroke risk in patients with atherosclerosis of the carotid arteries as well as for solid physical and chemical factors that are connected with the AP stability is extremely important. We investigate the inner lining of the carotid artery specimens from the male patients with atherosclerosis (27 patients, 42-64 years old) obtained during carotid endarterectomy by using different analytical tools including ultrasound angiography, X-ray analysis, immunological, histochemical analyses, and high field (3.4 T) pulse electron paramagnetic resonance (EPR) at 94 GHz. No correlation between the stable and unstable APs in the sense of the calcification is revealed. In all of the investigated samples, the EPR spectra of manganese, namely, Mn2+ ions, are registered. Spectral and relaxation characteristics of Mn2+ ions are close to those obtained for the synthetic (nano) hydroxyapatite species but differ from each other for stable and unstable APs. This demonstrates that AP stability could be specified by the molecular organization of their hydroxyapatite components. The origin of the obtained differences and the possibility of using EPR of Mn2+ as an AP stability marker are discussed. PMID- 28078288 TI - Knowledge, Perceptions, and Practice of Nurses on Surveillance of Adverse Events following Childhood Immunization in Nairobi, Kenya. AB - Background. Although vaccines currently approved for routine childhood immunization are safe and effective, frequent adverse events following immunization often cause illnesses and sometimes loss of public trust in immunization programs. Nurses are essential in this surveillance system. Objective. To determine nurses' knowledge, perception, and practice towards surveillance of postimmunization adverse events within Nairobi County health centers, Kenya. Methods. This is a cross-sectional survey involving nurses (n = 274). Data were collected using self-administered questionnaires. Data analysis was performed using SPSS version 20. Differences in proportions of categorical variables were compared between groups using chi-square tests. Binary logistic regression model was used to compute independent predictors of outcome. Results. 29.2%, 32.1%, and 45.3% of the respondents had good knowledge, good practices, and good perceptions on AEFI surveillance, respectively. Respondents with diploma or degree nursing training level were 1.8 times and 2.5 times more likely to have good knowledge and good perception in AEFI surveillance, respectively. Nurses with previous AEFI training were 9.7 times and 1.8 times more likely to have good AEFI knowledge and practices, respectively. Conclusion. There is a need to train and mentor nurses on AEFI surveillance. Findings of this study will be valuable in informing policy review on childhood immunization programs. PMID- 28078289 TI - Prospective Study to Assess Progression of Renal Markers after Interruption of Tenofovir due to Nephrotoxicity. AB - Background. Prospective studies about the reversibility of tenofovir disoproxil fumarate- (TDF-) related renal impairment remain scarce. Methods. This is an observational prospective study including all patients that presented at our HIV Unit who interrupted TDF owing to nephrotoxicity. We assessed the evolution of renal parameters after discontinuation of this drug. Results. We included 59 patients, who were followed up for 72 weeks. Most were male (41, 69.5%), median (IQR) age was 53 (44; 58) years, and median time receiving TDF-containing regimens was 55.4 (28; 87.7) months. Most patients were receiving PI-based treatments (67%). At the final visit, most of the subjects showed complete recovery (35, 59.3%) or improvement (13 subjects, 22%). Significant improvements were observed in creatinine levels (from 84.9 [73.8; 97.5] to 78 [69.6; 91] MUmol/L, p = 0.013), estimated glomerular filtration rate (eGFR, CKD EPI equation, from 87.7 [67; 99] to 89.9 [73.6; 99.3] mL/min/1.73 m2, p = 0.017), and number of patients with eGFR <60 mL/min/1.73 m2 (from 9 [15.3%] to 1 [1.7%], p = 0.031). A trend toward significance was observed in abnormal urine proteinuria/creatinine ratio (from 22 [37%] to 8 [13.6%], p = 0.057). Conclusions. Our results corroborate the high frequency of complete or partial renal recovery in patients receiving TDF-containing regimens who discontinued therapy owing to nephrotoxicity. PMID- 28078290 TI - Assessment of Serum Nitrogen Species and Inflammatory Parameters in Relapsing Remitting Multiple Sclerosis Patients Treated with Different Therapeutic Approaches. AB - The role of nitric oxide and its reactive derivatives (NO x ) is well known in the pathogenesis of multiple sclerosis, which is an inflammatory disease while NO x seems to be important in coordinating inflammatory response. The purpose of the present study was to assess serum NO x as one of the nitrogen species and inflammatory parameters in relapsing-remitting multiple sclerosis patients and to compare the effectiveness of various types of disease-modifying therapies that reduce nitric oxide and inflammatory biomarkers. Elevated NO x level was observed in patients who received the first-line disease-modifying therapy (interferons beta-1a and beta-1b) in comparison with the subjects treated with the second-line disease-modifying therapy (natalizumab; fingolimod) and healthy controls without significant differences in C-reactive protein and interleukin-1 beta. A negative correlation was observed between serum NO x level and the duration of multiple sclerosis confirmed in the whole study population and in subjects treated with the first-line agents. Only serum NO x , concentration could reveal a potential efficacy of disease-modifying therapy with a better reduction in NO x level due to the second-line agents of disease-modifying therapy. PMID- 28078292 TI - The Regulation of Innate Immunity by Nutritional Factors. PMID- 28078291 TI - Methicillin-Resistant Staphylococcus aureus Biofilms and Their Influence on Bacterial Adhesion and Cohesion. AB - Twenty-five methicillin-resistant Staphylococcus aureus (MRSA) isolates were characterized by staphylococcal protein A gene typing and the ability to form biofilms. The presence of exopolysaccharides, proteins, and extracellular DNA and RNA in biofilms was assessed by a dispersal assay. In addition, cell adhesion to surfaces and cell cohesion were evaluated using the packed-bead method and mechanical disruption, respectively. The predominant genotype was spa type t127 (22 out of 25 isolates); the majority of isolates were categorized as moderate biofilm producers. Twelve isolates displayed PIA-independent biofilm formation, while the remaining 13 isolates were PIA-dependent. Both groups showed strong dispersal in response to RNase and DNase digestion followed by proteinase K treatment. PIA-dependent biofilms showed variable dispersal after sodium metaperiodate treatment, whereas PIA-independent biofilms showed enhanced biofilm formation. There was no correlation between the extent of biofilm formation or biofilm components and the adhesion or cohesion abilities of the bacteria, but the efficiency of adherence to glass beads increased after biofilm depletion. In conclusion, nucleic acids and proteins formed the main components of the MRSA clone t127 biofilm matrix, and there seems to be an association between adhesion and cohesion in the biofilms tested. PMID- 28078293 TI - Biodegradation of Dimethyl Phthalate by Freshwater Unicellular Cyanobacteria. AB - The biodegradation characteristics of dimethyl phthalate (DMP) by three freshwater unicellular organisms were investigated in this study. The findings revealed that all the organisms were capable of metabolizing DMP; among them, Cyanothece sp. PCC7822 achieved the highest degradation efficiency. Lower concentration of DMP supported the growth of the Cyanobacteria; however, with the increase of DMP concentration growth of Cyanobacteria was inhibited remarkably. Phthalic acid (PA) was detected to be an intermediate degradation product of DMP and accumulated in the culture solution. The optimal initial pH value for the degradation was detected to be 9.0, which mitigated the decrease of pH resulting from the production of PA. The optimum temperature for DMP degradation of the three species of organisms is 30 degrees C. After 72 hours' incubation, no more than 11.8% of the residual of DMP aggregated in Cyanobacteria cells while majority of DMP remained in the medium. Moreover, esterase was induced by DMP and the activity kept increasing during the degradation process. This suggested that esterase could assist in the degradation of DMP. PMID- 28078294 TI - Factors Associated with Missed Detection of Mycobacterium tuberculosis by Automated BACTEC MGIT 960 System. AB - Despite the demonstration of excellent performance, mycobacterial growth in BACTEC MGIT 960 can go undetected. The aim of this study was to investigate the prevalence of "false-negative" culture sample in Beijing and the potential factors associated with the detection failures by MGIT 960. Of the 577 sputum samples tested, 141 (24.4%) were culture-positive for mycobacteria, of which 133 (94.3%) were automatically determined by MGIT 960 system and 8 (5.7%) were positive for visual growth (false negative by MGIT). Statistical analysis showed that positive grade of specimen had no influence on the false-negative rate by MGIT 960 system (chi2 = 2.207, P = 0.820). In addition, the mean time to detection (TTD) was 241.4 (range: 224-261) hours for false-negative group and 186.8 (range: 173-199) hours for positive group. The difference in TTD between false-negative and positive groups was statistically significant (P < 0.01). In conclusion, our data demonstrate that the automatic MGIT missed a small portion of bacteriological mycobacterial patients. In addition, the poor growth rate rather than the low grade of AFB smear is associated with the detection failure by MGIT. Our findings highlight the notion that manual inspection for all instrument-negative MGIT tubes will bring about considerable benefit to patients and clinicians. PMID- 28078295 TI - Application of Computed Tomography Processed by Picture Archiving and Communication Systems in the Diagnosis of Acute Achilles Tendon Rupture. AB - The applications of CT examination in the diagnosis of the acute Achilles tendon rupture (AATR) were investigated. A total of 36 patients with suspected acute Achilles tendon rupture were tested using physical examination, ultrasound, and 3DCT scanning, respectively. Then, surgery was performed for the patients who showed positive result in at least two of the three tests for AATR. 3DVR, MPR, and the other CT scan image processing and diagnosis were conducted in PACS (picture archiving and communication system). PACS was also used to measure the length of distal broken ends of the Achilles tendon (AT) to tendon calcaneal insertion. Our study indicated that CT has the highest accuracy in diagnosis of acute Achilles tendon complete rupture. The length measurement is matched between PACS and those actually measured in operation. CT not only demonstrates more details directly in three dimensions especially with the rupture involved calcaneal insertion flap but also locates the rupture region for percutaneous suture by measuring the length of distal stump in PACS without the effect of the position of ankle. The accuracy of CT diagnosis for Achilles tendon partial rupture is yet to be studied. PMID- 28078296 TI - The Value of the Model and Quantitative Parameters of Contrast-Enhanced Ultrasound in Judging the Severity of SHPT. AB - Using the model and quantitative parameters of contrast-enhanced ultrasound (CEUS) to assess the severity of secondary hyperparathyroidism (SHPT) was proposed. 42 SHPT patients who underwent CEUS examination were divided into three groups, light, moderate, and heavy as per parathyroid hormone (PTH). The process of CEUS was divided into two phases, wash-in phase and wash-out phase. The three groups were analyzed with their enhancing model in the two phases. The quantitative parameters of CEUS such as Arrival Time (AT), Time to Peak (TTP), Mean Transit Time (MTT), and Maximum Intensity (IMAX) were measured by time intensity curve (TIC) and compared among the three groups. The enhancing model of light SHPT, moderate SHPT, and heavy SHPT showed statistical significance in wash in phase and wash-out phase (P < 0.05). No difference was observed in AT and TTP among the three groups (P > 0.05) while MTT and IMAX showed statistical significance (P < 0.05). The CEUS of light SHPT was characterized by "slow-in, fast-out, and lower-enhancement" with short enhancement time; the CEUS of moderate SHPT was characterized by "fast-in, fast-out, and higher-enhancement" with slightly long enhancement time; the CEUS of heavy SHPT was characterized by "fast-in, slow-out, and higher-enhancement" with long enhancement time. Therefore, the model and quantitative parameters of CEUS can be benefit for the assessment of the severity of SHPT. PMID- 28078297 TI - Comparative Genomics of H. pylori and Non-Pylori Helicobacter Species to Identify New Regions Associated with Its Pathogenicity and Adaptability. AB - The genus Helicobacter is a group of Gram-negative, helical-shaped pathogens consisting of at least 36 bacterial species. Helicobacter pylori (H. pylori), infecting more than 50% of the human population, is considered as the major cause of gastritis, peptic ulcer, and gastric cancer. However, the genetic underpinnings of H. pylori that are responsible for its large scale epidemic and gastrointestinal environment adaption within human beings remain unclear. Core pan genome analysis was performed among 75 representative H. pylori and 24 non pylori Helicobacter genomes. There were 1173 conserved protein families of H. pylori and 673 of all 99 Helicobacter genus strains. We found 79 genome unique regions, a total of 202,359bp, shared by at least 80% of the H. pylori but lacked in non-pylori Helicobacter species. The operons, genes, and sRNAs within the H. pylori unique regions were considered as potential ones associated with its pathogenicity and adaptability, and the relativity among them has been partially confirmed by functional annotation analysis. However, functions of at least 54 genes and 10 sRNAs were still unclear. Our analysis of protein-protein interaction showed that 30 genes within them may have the cooperation relationship. PMID- 28078298 TI - Distribution of Suicin Gene Clusters in Streptococcus suis Serotype 2 Belonging to Sequence Types 25 and 28. AB - Recently, we reported the purification and characterization of three distinct lantibiotics (named suicin 90-1330, suicin 3908, and suicin 65) produced by Streptococcus suis. In this study, we investigated the distribution of the three suicin lantibiotic gene clusters among serotype 2 S. suis strains belonging to sequence type (ST) 25 and ST28, the two dominant STs identified in North America. The genomes of 102 strains were interrogated for the presence of suicin gene clusters encoding suicins 90-1330, 3908, and 65. The gene cluster encoding suicin 65 was the most prevalent and mainly found among ST25 strains. In contrast, none of the genes related to suicin 90-1330 production were identified in 51 ST25 strains nor in 35/51 ST28 strains. However, the complete suicin 90-1330 gene cluster was found in ten ST28 strains, although some genes in the cluster were truncated in three of these isolates. The vast majority (101/102) of S. suis strains did not possess any of the genes encoding suicin 3908. In conclusion, this study indicates heterogeneous distribution of suicin genes in S. suis. PMID- 28078299 TI - Research Advances on Hepatotoxicity of Herbal Medicines in China. AB - In general, herbal medicines have been considered as safe by the general public, since they are naturally occurring and have been applied in treatment for over thousands of years. As the use of herbal medicine is rapidly increasing globally, the potential toxicity of herbal drugs, in particular drug-induced liver injury (DILI), has now become a serious medical issue. According to the literature, the authors analyzed and discussed the hepatotoxicity problem of Chinese herbal medicines (CHM), including global overview on herbal-induced liver injury (HILI), current research progress on toxic CHM, diagnosis and treatment of HILI, and modern approaches and technologies of study of hepatotoxicity. As to promote the recognition of HILI and tackle the issue, a guideline for the diagnosis and treatment of HILI has recently been drafted by Chinese scientists. As suggested by the guideline, the hepatotoxicity issue of CHM, as a matter of fact, is overestimated. Up to date, the investigation of hepatotoxicity of CHM is now booming with worldwide application of CHM. This review therefore provides useful information for investigating hepatotoxicity of herbal medicine and characterizing DILI caused by CHM. In addition, authors describe in which way further efforts should be made to study the rationale of CHM and liver injury. PMID- 28078300 TI - Agreement among Four Prevalence Metrics for Urogenital Schistosomiasis in the Eastern Region of Ghana. AB - Few studies assess agreement among Schistosoma haematobium eggs, measured hematuria, and self-reported metrics. We assessed agreement among four metrics at a single time point and analyzed the stability of infection across two time points with a single metric. We used data from the Eastern Region of Ghana and constructed logistic regression models. Girls reporting macrohematuria were 4.1 times more likely to have measured hematuria than girls not reporting macrohematuria (CI95%: 2.1-7.9); girls who swim were 3.6 times more likely to have measured hematuria than nonswimmers (CI95%: 1.6-7.9). For boys, neither self reported metric was predictive. Girls with measured hematuria in 2010 were 3.3 times more likely to be positive in 2012 (CI95%: 1.01-10.5), but boys showed no association. Boys with measured hematuria in 2008 were 6.0 times more likely to have measured hematuria in 2009 (CI95%: 1.5-23.9) and those with eggs in urine in 2008 were 4.8 times more likely to have eggs in urine in 2009 (CI95%: 1.2-18.8). For girls, measured hematuria in 2008 predicted a positive test in 2009 (OR = 2.8; CI95%: 1.1-6.8), but egg status did not. Agreement between dipstick results and eggs suggests continued dipstick used is appropriate. Self-reported swimming should be further examined. For effective disease monitoring, we recommend annual dipstick testing. PMID- 28078301 TI - 125I Seeds Radiation Induces Paraptosis-Like Cell Death via PI3K/AKT Signaling Pathway in HCT116 Cells. AB - 125I seeds brachytherapy implantation has been extensively performed in unresectable and rerecurrent rectal carcinoma. Many studies on the cancer-killing activity of 125I seeds radiation mainly focused on its ability to trigger apoptosis, which is the most well-known and dominant type of cell death induced by radiation. However our results showed some unique morphological features such as cell swelling, cytoplasmic vacuolation, and plasma membrane integrity, which is obviously different to apoptosis. In this study, clonogenic proliferation was carried out to assay survival fraction. Transmission electron microscopy was used to analyze ultrastructural and evaluate morphologic feature of HCT116 cells after exposure to 125I seeds radiation. Immunofluorescence analysis was used to detect the origin of cytoplasmic vacuoles. Flow cytometry analysis was employed to detect the size and granularity of HCT116 cells. Western blot was performed to measure the protein level of AIP1, caspase-3, AKT, p-Akt (Thr308), p-Akt (Ser473), and beta-actin. We found that 125I seeds radiation activated PI3K/AKT signaling pathway and could trigger paraptosis-like cell death. Moreover, inhibitor of PI3K/AKT signaling pathway could inhibit paraptosis-like cell death induced by 125I seeds radiation. Our data suggest that 125I seeds radiation can induce paraptosis-like cell death via PI3K/AKT signaling pathway. PMID- 28078302 TI - The Evolution of Human Basophil Biology from Neglect towards Understanding of Their Immune Functions. AB - Being discovered long ago basophils have been neglected for more than a century. During the past decade evidence emerged that basophils share features of innate and adaptive immunity. Nowadays, basophils are best known for their striking effector role in the allergic reaction. They hence have been used for establishing new diagnostic tests and therapeutic approaches and for characterizing natural and recombinant allergens as well as hypoallergens, which display lower or diminished IgE-binding activity. However, it was a long way from discovery in 1879 until identification of their function in hypersensitivity reactions, including adverse drug reactions. Starting with a historical background, this review highlights the modern view on basophil biology. PMID- 28078304 TI - Prenatal Dexamethasone Exposure Increases the Susceptibility to Autoimmunity in Offspring Rats by Epigenetic Programing of Glucocorticoid Receptor. AB - Objective. Prenatal glucocorticoids (GC) can induce long term effects on offspring health. However, reports and related studies regarding the prolonged effects of prenatal GC on the development of autoimmunity are limited. Here, we aimed to explore the immunological effects of dexamethasone (DEX) exposure on young adults and whether glucocorticoid receptor (GR) is involved in this process. Methods. Wistar rats were given DEX during pregnancy. Susceptibility to autoimmunity in offspring was assessed using experimental autoimmune encephalomyelitis (EAE) and adjuvant-induced arthritis (AIA) animal models. To reveal the possible mechanism, glucocorticoid response, GR expression, and methylation status were measured in peripheral blood mononuclear cells (PBMCs). Results. Our results showed that the DEX-treated rats had greater susceptibility to EAE (100% versus 62.5%, P < 0.05) and AIA (63.6% versus 0%, P < 0.05) than saline control group. Glucocorticoid response and GR expression were decreased in DEX rats. Significant difference was also found in the methylation levels of GR exon 1-10 to exon 1-11 region. Conclusions. Prenatal DEX administration increases the susceptibility to autoimmune diseases, which is potentially mediated by programming GR methylation status and glucocorticoid sensitivity. PMID- 28078303 TI - Functions of the Tumor Suppressors p53 and Rb in Actin Cytoskeleton Remodeling. AB - Mechanical microenvironments, such as extracellular matrix stiffness and strain, have crucial roles in cancer progression. Cells sense their microenvironments with mechanosensing biomolecules, which is accompanied by the modulation of actin cytoskeleton structures, and the signals are subsequently transduced downstream as biochemical signals. The tumor suppressors p53 and retinoblastoma protein (Rb) are known to prevent cancer progression. The p53 and Rb signaling pathways are disrupted in many types of cancers. Here, we review recent findings about the roles of these tumor suppressors in the regulation of mechanosensing biomolecules and the actin cytoskeleton. We further discuss how dysfunction in the p53- and/or Rb-mediated mechanosignaling pathways is potentially involved in cancer progression. These pathways might provide good targets for developing anticancer therapies. PMID- 28078305 TI - miR-375 and miR-205 Regulate the Invasion and Migration of Laryngeal Squamous Cell Carcinoma Synergistically via AKT-Mediated EMT. AB - Previous studies have found that miR-375 and miR-205 were significantly dysregulated in laryngeal squamous cell carcinoma, which contributed to the invasion and migration of LSCC. However, the mechanisms of miR-375 and miR-205 regulating the invasion and migration of LSCC remain unknown. qRT-PCR was performed in 40 pairs of tissue samples to investigate the expression of miR-375 and miR-205 in LSCC and paracarcinoma tissues. To investigate whether or not miR 375 and miR-205 regulated the invasion and migration of LSCC synergistically via AKT-mediated epithelial-mesenchymal transition, miR-375 mimic and miR-205 inhibitor were transfected into SNU899 cells and miR-375 inhibitor and miR-205 mimic were transfected into SNU899 cells, respectively, with or without AKT inhibitor. Then the expressions of miR-375 and miR-205 were validated by qRT-PCR, cell migration and invasion were determined by wound healing assay and transwell invasive assay, and western blot analysis was performed to detect the expression of related proteins. Our results showed that miR-375 and miR-205 regulated the invasion and migration of LSCC via AKT-mediated EMT synergistically. In conclusion, our findings provided not only new information about the molecular mechanism of miRNAs regulating invasion and migration of LSCC, but also a theoretical principle for potential targeting therapy of laryngeal squamous carcinoma. PMID- 28078306 TI - Diabetic Retinopathy Screening Using Telemedicine Tools: Pilot Study in Hungary. AB - Introduction. Diabetic retinopathy (DR) is a sight-threatening complication of diabetes. Telemedicine tools can prevent blindness. We aimed to investigate the patients' satisfaction when using such tools (fundus camera examination) and the effect of demographic and socioeconomic factors on participation in screening. Methods. Pilot study involving fundus camera screening and self-administered questionnaire on participants' experience during fundus examination (comfort, reliability, and future interest in participation), as well as demographic and socioeconomic factors was performed on 89 patients with known diabetes in Csongrad County, a southeastern region of Hungary. Results. Thirty percent of the patients had never participated in any ophthalmological screening, while 25.7% had DR of some grade based upon a standard fundus camera examination and UK-based DR grading protocol (SpectraTM software). Large majority of the patients were satisfied with the screening and found it reliable and acceptable to undertake examination under pupil dilation; 67.3% were willing to undergo nonmydriatic fundus camera examination again. There was a statistically significant relationship between economic activity, education and marital status, and future interest in participation. Discussion. Participants found digital retinal screening to be reliable and satisfactory. Telemedicine can be a strong tool, supporting eye care professionals and allowing for faster and more comfortable DR screening. PMID- 28078307 TI - The Memories of NK Cells: Innate-Adaptive Immune Intrinsic Crosstalk. AB - Although NK cells are considered part of the innate immune system, a series of evidences has demonstrated that they possess characteristics typical of the adaptive immune system. These NK adaptive features, in particular their memory like functions, are discussed from an ontogenetic and evolutionary point of view. PMID- 28078308 TI - Cloning, Expression, and Characterization of Prophenoloxidases from Asian Corn Borer, Ostrinia furnacalis (Gunee). AB - Insect phenoloxidase (PO) belongs to the type 3 copper protein family and possesses oxidoreductase activities. PO is typically synthesized as a zymogen called prophenoloxidase (PPO) and requires the proteolytic activation to function. We here cloned full-length cDNA for 3 previously unidentified PPOs, which we named OfPPO1a, OfPPO1b, and OfPPO3, from Asian corn borer, Ostrinia furnacalis (Gunee), in addition to the previously known OfPPO2. These conceptual PPOs and OfPPO2 all contain two common copper-binding regions, two potential proteolytic activation sites, a plausible thiol-ester site, and a conserved C terminal region but lack a secretion signal peptide sequence at the N-terminus. O. furnacalis PPOs were highly similar to other insect PPOs (42% to 79% identity) and clustered well with other lepidopteran PPOs. RT-PCR assay showed the transcripts of the 4 OfPPOs were all detected at the highest level in hemocytes and at the increased amounts after exposure to infection by bacteria and fungi. Additionally, we established an Escherichia coli (E. coli) expression system to produce recombinant O. furnacalis PPO proteins for future use in investigating their functions. These insights could provide valuable information for better understanding the activation and functioning mechanisms of O. furnacalis PPOs. PMID- 28078310 TI - POLG2 deficiency causes adult-onset syndromic sensory neuropathy, ataxia and parkinsonism. AB - OBJECTIVE: Mitochondrial dysfunction plays a key role in the pathophysiology of neurodegenerative disorders such as ataxia and Parkinson's disease. We describe an extended Belgian pedigree where seven individuals presented with adult-onset cerebellar ataxia, axonal peripheral ataxic neuropathy, and tremor, in variable combination with parkinsonism, seizures, cognitive decline, and ophthalmoplegia. We sought to identify the underlying molecular etiology and characterize the mitochondrial pathophysiology of this neurological syndrome. METHODS: Clinical, neurophysiological, and neuroradiological evaluations were conducted. Patient muscle and cultured fibroblasts underwent extensive analyses to assess mitochondrial function. Genetic studies including genome-wide sequencing were conducted. RESULTS: Hallmarks of mitochondrial dysfunction were present in patients' tissues including ultrastructural anomalies of mitochondria, mosaic cytochrome c oxidase deficiency, and multiple mtDNA deletions. We identified a splice acceptor variant in POLG2, c.970-1G>C, segregating with disease in this family and associated with a concomitant decrease in levels of POLG2 protein in patient cells. INTERPRETATION: This work extends the clinical spectrum of POLG2 deficiency to include an overwhelming, adult-onset neurological syndrome that includes cerebellar syndrome, peripheral neuropathy, tremor, and parkinsonism. We therefore suggest to include POLG2 sequencing in the evaluation of ataxia and sensory neuropathy in adults, especially when it is accompanied by tremor or parkinsonism with white matter disease. The demonstration that deletions of mtDNA resulting from autosomal-dominant POLG2 variant lead to a monogenic neurodegenerative multicomponent syndrome provides further evidence for a major role of mitochondrial dysfunction in the pathomechanism of nonsyndromic forms of the component neurodegenerative disorders. PMID- 28078309 TI - Yeast Surface-Displayed H5N1 Avian Influenza Vaccines. AB - Highly pathogenic H5N1 avian influenza viruses pose a pandemic threat to human health. A rapid vaccine production against fast outbreak is desired. We report, herein, a paradigm-shift influenza vaccine technology by presenting H5N1 hemagglutinin (HA) to the surface of yeast. We demonstrated, for the first time, that the HA surface-presented yeast can be used as influenza vaccines to elicit both humoral and cell-mediated immunity in mice. The HI titer of antisera reached up to 128 in vaccinated mice. A high level of H5N1 HA-specific IgG1 and IgG2a antibody production was detected after boost immunization. Furthermore, we demonstrated that the yeast surface-displayed HA preserves its antigenic sites. It preferentially binds to both avian- and human-type receptors. In addition, the vaccine exhibited high cross-reactivity to both homologous and heterologous H5N1 viruses. A high level production of anti-HA antibodies was detected in the mice five months after vaccination. Finally, our animal experimental results indicated that the yeast vaccine offered complete protection of mice from lethal H5N1 virus challenge. No severe side effect of yeast vaccines was noted in animal studies. This new technology allows for rapid and large-scale production of influenza vaccines for prepandemic preparation. PMID- 28078311 TI - Common variant rs356182 near SNCA defines a Parkinson's disease endophenotype. AB - OBJECTIVE: Parkinson's disease (PD) presents clinically with several motor subtypes that exhibit variable treatment response and prognosis. Here, we investigated genetic variants for their potential association with PD motor phenotype and progression. METHODS: We screened 10 SNPs, previously associated with PD risk, for association with tremor-dominant (TD) versus postural instability gait disorder (PIGD) motor subtypes. SNPs that correlated with the TD/PIGD ratio in a discovery cohort of 251 PD patients were then evaluated in a multi-site replication cohort of 559 PD patients. SNPs associated with motor phenotype in both cross-sectional cohorts were next evaluated for association with (1) rates of motor progression in a longitudinal subgroup of 230 PD patients and (2) brain alpha-synuclein (SNCA) expression in the GTEx (Genotype-Tissue Expression project) consortium database. RESULTS: Genotype at rs356182, near SNCA, correlated with the TD/PIGD ratio in both the discovery (Bonferroni corrected P = 0.04) and replication cohorts (P = 0.02). The rs356182 GG genotype was associated with a more tremor-predominant phenotype and predicted a slower rate of motor progression (1-point difference in annual rate of UPDRS-III motor score change, P = 0.01). The rs356182 genotype was associated with SNCA expression in the cerebellum (P = 0.005). INTERPRETATION: Our study demonstrates that the GG genotype at rs356182 provides molecular definition for a clinically important endophenotype associated with (1) more tremor-predominant motor phenomenology, (2) slower rates of motor progression, and (3) decreased brain expression of SNCA. Such molecularly defined endophenotyping in PD may benefit both clinical trial design and tailoring of clinical care as we enter the era of precision medicine. PMID- 28078312 TI - Biallelic SCN10A mutations in neuromuscular disease and epileptic encephalopathy. AB - OBJECTIVES: Two consanguineous families, one of Sudanese ethnicity presenting progressive neuromuscular disease, severe cognitive impairment, muscle weakness, upper motor neuron lesion, anhydrosis, facial dysmorphism, and recurrent seizures and the other of Egyptian ethnicity presenting with neonatal hypotonia, bradycardia, and recurrent seizures, were evaluated for the causative gene mutation. METHODS AND RESULTS: Homozygosity mapping and whole exome sequencing (WES) identified damaging homozygous variants in SCN10A, namely c.4514C>T; p.Thr1505Met in the first family and c.4735C>T; p.Arg1579* in the second family. A third family, of Western European descent, included a child with febrile infection-related epilepsy syndrome (FIRES) who also had compound heterozygous missense mutations in SCN10A, namely, c.3482T>C; p.Met1161Thr and c.4709C>A; p.Thr1570Lys. A search for SCN10A variants in three consortia datasets (EuroEPINOMICS, Epi4K/EPGP, Autism/dbGaP) identified an additional five individuals with compound heterozygous variants. A Hispanic male with infantile spasms [c.2842G>C; p.Val948Leu and c.1453C>T; p.Arg485Cys], and a Caucasian female with Lennox-Gastaut syndrome [c.1529C>T; p.Pro510Leu and c.4984G>A; p.Gly1662Ser] in the epilepsy databases and three in the autism databases with [c.4009T>A; p.Ser1337Thr and c.1141A>G; p.Ile381Val], [c.2972C>T; p.Pro991Leu and c.2470C>T; p.His824Tyr], and [c.4009T>A; p.Ser1337Thr and c.2052G>A; p.Met684Ile]. INTERPRETATION: SCN10A is a member of the voltage-gated sodium channel (VGSC) gene family. Sodium channels are responsible for the instigation and proliferation of action potentials in central and peripheral nervous systems. Heterozygous mutations in VGSC genes cause a wide range of epileptic and peripheral nervous system disorders. This report presents autosomal recessive mutations in SCN10A that may be linked to epilepsy-related phenotypes, Lennox Gastaut syndrome, infantile spasms, and Autism Spectrum Disorder. PMID- 28078313 TI - Unilobar surgery for symptomatic epileptic spasms. AB - OBJECTIVE: To assess factors associated with favorable seizure outcome after surgery for symptomatic epileptic spasms and improve knowledge on pathophysiology of this seizure type. METHODS: Inclusion criteria were: (1) age between 6 months and 15 years at surgery; (2) active epileptic spasms; (3) follow-up after surgery >1 year. RESULTS: We retrospectively studied 80 children (aged 1.3 +/- 2 years at seizure onset; 5.8 +/- 4 years at surgery, 11.7 +/- 5.7 years at last follow up). Magnetic resonance imaging (MRI) revealed structural abnormalities in 77/80 patients (96.3%; unilateral in 69: 89.6%). We performed invasive recordings in 24 patients (30%). In 21 patients in whom MRI or histopathology detected a lesion, electrodes exploring it constantly captured initial ictal activity at spasm onset. Fifty-eight patients (72.5%) underwent unilobar and 22 (27.5%) multilobar or hemispheric procedures. At last follow-up, 49 patients (61.3%) were in Engel class I. Multivariate logistic models showed completeness of resection of the seizure onset zone (OR = 0.016, 95%CI: 0.002, 0.122) and of the MRI visible lesion (OR = 0.179, 95% CI: 0.032, 0.999) to be significantly associated with Engel class IA outcome. Unfavorable outcome was associated with an older age at surgery, when it reflected a longer duration of epilepsy (OR = 1.383, 95% CI: 0.994,1.926). INTERPRETATION: Data emerging from invasive recordings and the good seizure outcome following removal of discrete epileptogenic lesions support a focal cortical origin of spasms. In patients with discrete epileptogenic lesions, the pragmatic approach to surgery should follow the same principles applied to focal epilepsy favoring, whenever possible, unilobar, one-stage resections. PMID- 28078314 TI - Onset of secondary progressive MS after long-term rituximab therapy - a case report. AB - A patient with relapsing multiple sclerosis (RMS) was treated with a standard immunomodulatory therapy, but due to ongoing disease activity was switched to rituximab. Relapses ceased, but secondary progressive MS (SPMS) eventually appeared, associated with new focal spinal cord white matter lesions. Cerebrospinal fluid (CSF) showed persistent oligoclonal bands (OCB) and clonally related B cells in CSF and peripheral blood. The treatment escalation approach failed to prevent evolution to SPMS, raising the question of whether initiation of B-cell depleting therapy at the time of RMS diagnosis should be tested to more effectively address the immune pathology leading to SPMS. PMID- 28078315 TI - Degenerative Ataxias: challenges in clinical research. AB - The degenerative ataxias are a very heterogeneous group of disorders that include numerous genetic diseases as well as apparently "sporadic" entities. There has been an explosion of discoveries related to genetic defects and related pathomechanisms that has brought us to the threshold of meaningful therapies in some but not all of these diseases. There also continues to be lack of knowledge of the causation of disease in a sizeable proportion of these patients. The overall rarity of ataxias as a whole and certainly of the individual genetic entities together with slow and variable progression and variable prognosis in juxtaposition with a rapid development of possible therapies in the horizon such as gene replacement and gene knock-down strategies places the ataxias in a unique position distinct from other similar neurodegenerative diseases. The pace of laboratory research seems not matched by the pace of clinical research and clinical trial readiness. This review summarizes the author's views on the various challenges in translational research in ataxias and hopes to stimulate further thought and discussions on how to bring real help to these patients. PMID- 28078317 TI - Corrigendum. AB - [This corrects the article DOI: 10.1002/acn3.307.]. PMID- 28078316 TI - Covert narrative capacity: Mental life in patients thought to lack consciousness. AB - Despite the apparent absence of external signs of consciousness, a significant proportion of behaviorally nonresponsive patients can respond to commands by willfully modulating their brain activity. However, little is known about the mental life of these patients. We discuss a recent innovative approach, which sheds light on the preserved cognitive capacities of these patients, including executive function, theory of mind, and the experience of affective states. This research represents a fundamental shift in our understanding of these patients, and has important implications for both their continued treatment and care. Moreover, this research marks out avenues for future inquiry into the residual cognitive capacities of these patients. PMID- 28078318 TI - Geographical Clusters of Rape in the United States: 2000-2012. AB - BACKGROUND: While rape is a very serious crime and public health problem, no spatial mapping has been attempted for rape on the national scale. This paper addresses the three research questions: (1) Are reported rape cases randomly distributed across the USA, after being adjusted for population density and age, or are there geographical clusters of reported rape cases? (2) Are the geographical clusters of reported rapes still present after adjusting for differences in poverty levels? (3) Are there geographical clusters where the proportion of reported rape cases that lead to an arrest is exceptionally low or exceptionally high? METHODS: We studied the geographical variation of reported rape events (2003-2012) and rape arrests (2000-2012) in the 48 contiguous states of the USA. The disease Surveillance software SaTScanTM with its spatial scan statistic is used to evaluate the spatial variation in rapes. The spatial scan statistic has been widely used as a geographical surveillance tool for diseases, and we used it to identify geographical areas with clusters of reported rape and clusters of arrest rates for rape. RESULTS: The spatial scan statistic was used to identify geographical areas with exceptionally high rates of reported rape. The analyses were adjusted for age, and in secondary analyses, for both age and poverty level. We also identified geographical areas with either a low or a high proportion of reported rapes leading to an arrest. CONCLUSIONS: We have identified geographical areas with exceptionally high (low) rates of reported rape. The geographical problem areas identified are prime candidates for more intensive preventive counseling and criminal prosecution efforts by public health, social service, and law enforcement agencies Geographical clusters of high rates of reported rape are prime areas in need of expanded implementation of preventive measures, such as changing attitudes in our society toward rape crimes, in addition to having the criminal justice system play an even larger role in preventing rape. PMID- 28078319 TI - Gut microbiota, inflammation and colorectal cancer. AB - Although genes contribute to colorectal cancer, the gut microbiota are an important player. Accumulating evidence suggests that chronic infection and the ensuing inflammation contributes to tumor initiation and tumor progression. A variety of bacterial species and tumor-promoting virulence mechanisms have been investigated. Significant advances have been made in understanding the composition and functional capabilities of the gut microbiota and its roles in cancer. In the current review, we discuss the novel roles of microbiota in the progression of colon cancer. Although microbiota technically include organisms other than bacteria e.g., viruses and fungi, this review will primarily focus on bacteria. We summarize epidemiological studies of human microbiome and colon cancer. We discuss the progress in the scientific understanding of the interplay between the gut microbiota, barrier function, and host responses in experimental models. Further, we discuss the potential application in prevention, diagnosis, and therapy of colon cancer by targeting microbiota. We discuss the challenges lie ahead and the future direction in studying gut microbiome in colon cancer to close the gap between the basic sciences and clinical application. PMID- 28078321 TI - Efficiency of an Active Rehabilitation Intervention in a Slow-to-Recover Paediatric Population following Mild Traumatic Brain Injury: A Pilot Study. AB - Objective. The aim of this study was to identify whether the addition of an individualised Active Rehabilitation Intervention to standard care influences recovery of young patients who are slow-to-recover following a mTBI. Methods. Fifteen participants aged 15 +/- 2 years received standard care and an individualised Active Rehabilitation Intervention which included (1) low- to high intensity aerobic training; (2) sport-specific coordination exercises; and (3) therapeutic balance exercises. The following criteria were used to measure the resolution of signs and symptoms of mTBI: (1) absence of postconcussion symptoms for more than 7 consecutive days; (2) cognitive function corresponding to normative data; and (3) absence of deficits in coordination and balance. Results. The Active Rehabilitation Intervention lasted 49 +/- 17 days. The duration of the intervention was correlated with self-reported participation ([Formula: see text]%, r = -0.792, p < 0.001). The average postconcussion symptom inventory (PCSI) score went from a total of 36.85 +/- 23.21 points to 4.31 +/- 5.04 points after the intervention (Z = -3.18, p = 0.001). Conclusion. A progressive submaximal Active Rehabilitation Intervention may represent an important asset in the recovery of young patients who are slow-to-recover following a mTBI. PMID- 28078322 TI - Diagnostic Dilemma in Discordant Thyroid Function Tests Due to Thyroid Hormone Autoantibodies. AB - OBJECTIVE: Assay interference could be the cause of abnormal thyroid function tests. Early recognition prevents inappropriate patient management. The objective of this report is to present a case with discordant thyroid function tests in different thyroid assay platforms due to thyroid autoantibodies. METHODS: We present a case her family, laboratory data and methods that investigate immunoassay interference. RESULTS: A 21-year-old woman with autoimmune thyroid disease was treated for hypothyroidism with levothyroxine and noted to have elevated total and free thyroxine, free triiodothyronine but normal thyroid stimulating hormone. Repeat thyroid function tests using different platforms revealed discrepant results. Further investigation showed that the patient had positive thyroid hormone autoantibodies (THAAbs). CONCLUSION: We demonstrates abnormal thyroid function tests caused by THAAbs. The latter were the cause of interference with assays resulting in discrepant test results inconsistent with the clinical presentation. Early recognition would prevent inappropriate patient management. PMID- 28078320 TI - LGR4 and LGR5 Function Redundantly During Human Endoderm Differentiation. AB - BACKGROUND & AIMS: The Lgr family of transmembrane proteins (Lgr4, 5, 6) act as functional receptors for R-spondin proteins (Rspo 1, 2, 3, 4), and potentiate Wnt signaling in different contexts. Lgr5 is arguably the best characterized of the Lgr family members in a number of adult and embryonic contexts in mice. However, the function of LGR family members in early embryonic development is unclear, and has not been explored during human development or tissue differentiation in detail. METHODS: We interrogated the function and expression of LGR family members using human pluripotent stem cell-derived tissues including definitive endoderm, mid/hindgut, and intestinal organoids. We performed embryonic lineage tracing in Lgr5-GFP-IRES-CreERT2 mice. RESULTS: We show that LGR5 is part of the human definitive endoderm (DE) gene signature, and LGR5 transcripts are induced robustly when human pluripotent stem cells are differentiated into DE. Our results show that LGR4 and 5 are functionally required for efficient human endoderm induction. Consistent with data in human DE, we observe Lgr5 reporter (eGFP) activity in the embryonic day 8.5 mouse endoderm, and show the ability to lineage trace these cells into the adult intestine. However, gene expression data also suggest that there are human-mouse species-specific differences at later time points of embryonic development. CONCLUSIONS: Our results show that LGR5 is induced during DE differentiation, LGR receptors are functionally required for DE induction, and that they function to potentiate WNT signaling during this process. PMID- 28078323 TI - Genetic architecture of age-related cognitive decline in African Americans. AB - OBJECTIVE: To identify genetic risk factors associated with susceptibility to age related cognitive decline in African Americans (AAs). METHODS: We performed a genome-wide association study (GWAS) and an admixture-mapping scan in 3,964 older AAs from 5 longitudinal cohorts; for each participant, we calculated a slope of an individual's global cognitive change from neuropsychological evaluations. We also performed a pathway-based analysis of the age-related cognitive decline GWAS. RESULTS: We found no evidence to support the existence of a genomic region which has a strongly different contribution to age-related cognitive decline in African and European genomes. Known Alzheimer disease (AD) susceptibility variants in the ABCA7 and MS4A loci do influence this trait in AAs. Of interest, our pathway-based analyses returned statistically significant results highlighting a shared risk from lipid/metabolism and protein tyrosine signaling pathways between cognitive decline and AD, but the role of inflammatory pathways is polarized, being limited to AD susceptibility. CONCLUSIONS: The genetic architecture of aging-related cognitive in AA individuals is largely similar to that of individuals of European descent. In both populations, we note a surprising lack of enrichment for immune pathways in the genetic risk for cognitive decline, despite strong enrichment of these pathways among genetic risk factors for AD. PMID- 28078324 TI - Paraganglioma of the Seminal Vesicle Case Report and Review of the Literature. AB - Background: The present case report describes an extremely rare case of a norepinephrine secreting extraadrenal paraganglioma (PGL) located in the seminal vesicle. Case Presentation: A 36-year-old patient had signs of intermittent hypertensive derailments, bradycardia, increased norepinephrine excretion in 24 hour urine, an increased metanephrine plasma concentration, and a positive clonidine suppression test. A suspicious mass was detected in an (18)F-DOPA PET/CT-scan in the left seminal vesicle. Following adrenergic blockade, a robotically assisted laparoscopic left vesiculectomy with negative soft tissue surgical margins was performed. The patient sustained a couple of few months of voiding difficulties of the lower urinary tract and obstruction of the left upper urinary tract after the surgery, which resolved spontaneously with home medical treatment. Two years after the initial treatment, the patient relapsed, which was confirmed by endocrinologic follow-up tests with increased urine catecholamine, a positive clonidine suppression test, as well as an elevated blood pressure. Staging with (18)F-DOPA-PET/CT-scan confirmed the diagnosis of a recurrent PGL. This was followed by subsequent open surgical removal of the suspicious lesion in the seminal fossa. The patient is still recurrence free 15 months after the second surgery. Complications after the second surgery included an intermittent paresthesia of the left leg lasting 3 to 4 months. No other urologic symptoms such as voiding or erectile dysfunction occurred. Conclusion: DaVinci-assisted laparoscopic vesiculectomy is a viable procedure to treat such cases providing satisfactory results. Relevant for clinical practice are the regular and lifelong follow-up examinations to detect recurrences. PMID- 28078325 TI - Laparoscopic Unilateral Total and Contralateral Subtotal Adrenalectomy for Bilateral Adrenocorticotropic Hormone-Secreting Pheochromocytoma: Report of a Rare Case. AB - Background: Bilateral adrenal tumors are not common in clinical practice, but are an important source of ectopic adrenocorticotropic hormone (ACTH) secretion. Standard operative management for bilateral pheochromocytomas might dictate the removal of the involved adrenal gland and the removal of the contralateral adrenal gland. We present a case of bilateral ACTH-secreting pheochromocytoma treated with staged laparoscopic unilateral total and contralateral subtotal adrenalectomy. Case Presentation: A 58-year-old male with elevated hyperglycemia and general fatigue was hospitalized for pneumonia. CT incidentally revealed bilateral adrenal tumor. Biochemical examination was significant for elevated urinary metanephrine and normetanephrines, and plasma catecholamine level. CT scan of the head, neck, thorax, and pelvis was normal. Under the clinical diagnosis of ACTH-dependent pheochromocytoma, laparoscopic right total adrenalectomy was performed. As endocrinologic examination showed residual ACTH dependent pheochromocytoma after surgery, laparoscopic left subtotal adrenalectomy was performed. Pathology analysis revealed pheochromocytoma with stained ACTH lesions in both adrenal tumors. Conclusion: This is a rare case of ACTH-secreting bilateral pheochromocytoma effectively treated with staged laparoscopic unilateral total and contralateral subtotal adrenalectomy, in which the production of ACTH was confirmed by immunohistochemical staining. PMID- 28078326 TI - Upper Tract Urothelial Carcinoma in the Genetically Predisposed Patient: Role of Urinary Markers in Predicting Recurrence. AB - Background: Upper tract urothelial carcinoma (UTUC) is an uncommon disease that is diagnosed clinically by the selective use of urine cytology, urine biomarkers, and imaging of the upper tract. We present a case of a patient with Lynch syndrome and high-grade UTUC that was diagnosed by an abnormal Cxbladder assay, prompting further endoscopic examination. Case Presentation: A 59-year-old Caucasian female with a history of endometrial cancer and bladder cancer with Lynch syndrome presented for evaluation of recurrent urothelial carcinoma. Her previous bladder tumors have been T1 high grade and Ta high grade and have been treated with resection and multiple cycles of intravesical Bacillus Calmette Guerin (BCG) therapy. She had also undergone a robotic left distal ureterectomy and psoas hitch for a high-grade distal ureteral tumor. Surveillance cystoscopy 7 months after revealed a biopsy-confirmed bladder tumor, which was resected, and she was started on maintenance BCG therapy. At presentation, follow-up urine cytology and UroVysion studies were negative. Cxbladder test was also initially negative. However, during close clinical monitoring, the Cxbladder test became positive. Cystoscopy was once more performed, which was unremarkable. Bilateral ureteroscopy was performed, revealing high-grade upper tract renal papillary carcinoma (UTUC) in the left renal pelvis. The patient declined a nephroureterectomy. She was treated with two sessions of holmium laser ablation of the left renal pelvis tumor and underwent 6 weekly courses of BCG + interferon instilled into her left renal pelvis using a 5F open-ended catheter. Repeat urine cytology, UroVysion, and Cxbladder tests were negative after completion of upper tract BCG therapy. Conclusion: Cxbladder test may be useful and an adjunct to urine cytology and the UroVysion FISH assay to evaluate patients at high risk for recurrent UTUC. PMID- 28078327 TI - Surgical Clips Migration up to Renal Collecting System from Ileal Conduit Postcystectomy. AB - This is a 49-year-old female known to have had cystectomy and ileal conduit 4 years ago presented to our hospital complaining of left flank pain with recurrent urinary tract infection. Radiologic investigations showed left lower pole renal stone. She underwent left laser flexible ureterorenoscopy. Renal collection system was fully explored that showed stone occupying the lower calix, laser disintegration of the stone revealed what we assumed are surgical clips. PMID- 28078328 TI - Conservative Management of Ureteral Injury Caused by a Lumbar Osteophyte. AB - Background: Osteophytes are bony outgrowths commonly found on lumbar vertebrae. They rarely produce complications with the most common complication being nerve entrapment, but rarer complications including aorta or inferior vena cava rupture, superior mesenteric artery syndrome, compression of the iliopsoas muscle, and cerebrospinal fluid leaks have been described. Rare cases affecting the ureter resulting in ureteral colic or extravasation of urine have been described. Case Presentation: We describe a case in which a lumbar osteophyte bridging the L4 and L5 disks was encircling the ureter and minor trauma caused a ureteral injury, resulting in urine extravasation into the L4 and L5 disks space and the retroperitoneum. Owing to the comorbidities of this patient, this case was treated conservatively with stenting and the patient has suffered no further complications. Conclusion: This is a rare complication of a lumbar osteophyte but should be considered as a potential cause of ureter injury. Treatment should be individualized by patient preference and comorbidities, as some patients would elect to pursue more aggressive therapy whereas others would incline for conservative measures. PMID- 28078329 TI - Hypovolemic Shock Caused by Massive Renal Hematoma After a Third Consecutive Extracorporeal Shockwave Lithotripsy Session: A Case Report. AB - Extracorporeal shockwave lithotripsy (SWL) is a commonly used technique for treating urinary calculi. Although noninvasive, highly effective, and widely accepted, SWL is not without complications. Next to fragmenting the calculi, the surrounding tissue is damaged, which can result in renal hematoma, a well described complication. In most cases, the collateral tissue damage is mild and resolves with conservative treatment. However, rarely, severe complications may arise. Here we present a case of a 46-year-old male who developed a massive hematoma, both subcapsular and retroperitoneal, after a third consecutive SWL session, resulting in hypovolemic shock. Different probable causes are proposed, of which one cause, the length of the interval between SWL sessions, is not yet studied properly. Probably, short intervals keep the damaged tissue from healing sufficiently, as proposed in our case. Possibly, life-threatening situations can be avoided if more evidence-based guidelines are available. PMID- 28078331 TI - Pathways for Learning from 3D Technology. AB - The purpose of this study was to find out if 3D stereoscopic presentation of information in a movie format changes a viewer's experience of the movie content. Four possible pathways from 3D presentation to memory and learning were considered: a direct connection based on cognitive neuroscience research; a connection through "immersion" in that 3D presentations could provide additional sensorial cues (e.g., depth cues) that lead to a higher sense of being surrounded by the stimulus; a connection through general interest such that 3D presentation increases a viewer's interest that leads to greater attention paid to the stimulus (e.g., "involvement"); and a connection through discomfort, with the 3D goggles causing discomfort that interferes with involvement and thus with memory. The memories of 396 participants who viewed two-dimensional (2D) or 3D movies at movie theaters in Southern California were tested. Within three days of viewing a movie, participants filled out an online anonymous questionnaire that queried them about their movie content memories, subjective movie-going experiences (including emotional reactions and "presence") and demographic backgrounds. The responses to the questionnaire were subjected to path analyses in which several different links between 3D presentation to memory (and other variables) were explored. The results showed there were no effects of 3D presentation, either directly or indirectly, upon memory. However, the largest effects of 3D presentation were on emotions and immersion, with 3D presentation leading to reduced positive emotions, increased negative emotions and lowered immersion, compared to 2D presentations. PMID- 28078330 TI - Pheochromocytoma in Urologic Practice. AB - CONTEXT: Pheochromocytoma is regularly encountered in urological practice and requires a thoughtful and careful clinical approach. OBJECTIVE: To review clinical aspects of management of pheochromocytoma in urologic practice. EVIDENCE ACQUISITION: A systematic review of English-language literature was performed through year 2015 using the Medline database. Manuscripts were selected with consensus of the coauthors and evaluated using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria. EVIDENCE SYNTHESIS: Findings and recommendations of the evaluated manuscripts are discussed with an emphasis on the description of presentation, diagnosis, evaluation, and perioperative care. CONCLUSION: In addition to surgical expertise, appropriate management of pheochromocytoma in urologic practice requires nuanced understanding of pathophysiology, genetics, and endocrinological principles. When skillfully managed, the vast majority of patients with pheochromocytoma should expect an excellent prognosis. PATIENT SUMMARY: In this article we review the clinical approach to patients with pheochromocytoma, a tumor that stems from the innermost part of the adrenal gland and that often secretes excessive amounts of powerful hormones such as noradrenaline and adrenaline. Significant expertise is required to appropriately manage patients with these tumors. TAKE HOME MESSAGE: In addition to surgical expertise, appropriate management of pheochromocytoma in urologic practice requires nuanced understanding of pathophysiology, genetics, and endocrinological principles. When skillfully managed, vast majority of patients with pheochromocytoma should expect an excellent prognosis. PMID- 28078332 TI - Surface tension and a self-consistent theory of soft composite solids with elastic inclusions. AB - The importance of surface tension effects is being recognized in the context of soft composite solids, where they are found to significantly affect the mechanical properties, such as the elastic response to an external stress. It has recently been discovered that Eshelby's inclusion theory breaks down when the inclusion size approaches the elastocapillary length L=gamma/E, where gamma is the inclusion/host surface tension and E is the host Young's modulus. Extending our recent results for liquid inclusions, here we model the elastic behavior of a non-dilute distribution of isotropic elastic spherical inclusions in a soft isotropic elastic matrix, subject to a prescribed infinitesimal far-field loading. Within our framework, the composite stiffness is uniquely determined by the elastocapillary length L, the spherical inclusion radius R, and the stiffness contrast parameter C, which is the ratio of the inclusion to the matrix stiffness. We compare the results with those from the case of liquid inclusions, and we derive an analytical expression for elastic cloaking of the composite by the inclusions. Remarkably, we find that the composite stiffness is influenced significantly by surface tension even for inclusions two orders of magnitude more stiff than the host matrix. Finally, we show how to simultaneously determine the surface tension and the inclusion stiffness using two independent constraints provided by global and local measurements. PMID- 28078333 TI - Topography-guided buckling of swollen polymer bilayer films into three dimensional structures. AB - Thin films that exhibit spatially heterogeneous swelling often buckle into the third dimension to minimize stress. These effects, in turn, offer a promising strategy to fabricate complex three-dimensional structures from two-dimensional sheets. Here we employ surface topography as a new means to guide buckling of swollen polymer bilayer films and thereby control the morphology of resulting three-dimensional objects. Topographic patterns are created on poly(dimethylsiloxane) (PDMS) films selectively coated with a thin layer of non swelling parylene on different sides of the patterned films. After swelling in an organic solvent, various structures are formed, including half-pipes, helical tubules, and ribbons. We demonstrate these effects and introduce a simple geometric model that qualitatively captures the relationship between surface topography and the resulting swollen film morphologies. The model's limitations are also examined. PMID- 28078334 TI - Confinement-induced alterations in the evaporation dynamics of sessile droplets. AB - Evaporation of sessile droplets has been a topic of extensive research. However, the effect of confinement on the underlying dynamics has not been well explored. Here, we report the evaporation dynamics of a sessile droplet in a confined fluidic environment. Our findings reveal that an increase in the channel length delays the completion of the evaporation process and leads to unique spatio temporal evaporation flux and internal flow. The evaporation modes (constant contact angle and constant contact radius) during the droplet lifetime however exhibit global similarity when normalized by appropriate length and timescales. These results are explained in light of an increase in vapor concentration inside the channel due to greater accumulation of water vapor on account of increased channel length. We have formulated a theoretical framework which introduces two key parameters namely an enhanced concentration of the vapor field in the vicinity of the confined droplet and a corresponding accumulation lengthscale over which the accumulated vapor relaxes to the ambient concentration. Using these two parameters and modified diffusion based evaporation we are able to show that confined droplets exhibit a universal behavior in terms of the temporal evolution of each evaporation mode irrespective of the channel length. These results may turn out to be of profound importance in a wide variety of applications, ranging from surface patterning to microfluidic technology. PMID- 28078335 TI - Dynamics of active Rouse chains. AB - We consider how active forces modeled as non-thermal random noise affect the average dynamical properties of a Rouse polymer. As the power spectrum of the noise is not known we keep the analytical treatment as generic as possible and then present results for a few examples of active noise. We discuss the connection between our results and recent experimental studies of dynamics of labeled DNA telomeres in living cells, and propose new chromatin tracking experiments that will allow one to determine the statistical properties of the active forces associated with chromatin remodeling processes. PMID- 28078336 TI - Design of latex-layered double hydroxide composites by tuning the aggregation in suspensions. AB - Colloidal stability of polymeric latex particles was studied in the presence of oppositely charged layered double hydroxide (LDH) platelets of different interlayer anions. Adsorption of the LDH particles led to charge neutralization and to overcharging of the latex at appropriate concentrations. Mixing stable colloidal suspensions of individual particles results in rapid aggregation once the LDH adsorption neutralizes the negative charges of the polymer spheres, while stable suspensions were observed at high and low LDH doses. The governing interparticle interactions included repulsive electrical double layer forces as well as van der Waals and patch-charge attractions, whose strength depended on the amount of LDH particles adsorbed on the latex surface. The type of the LDH interlayer anions did not affect the colloidal stability of the samples. Structural investigation of the obtained latex-LDH composites revealed that the polymer spheres were completely coated with the inorganic platelets once their concentration was sufficiently high. These results are especially important for designing synthetic routes for hybrid systems in suspensions, where stable colloids are required for uniform film-formation and for the homogeneous distribution of the inorganic filler within the composite materials. PMID- 28078337 TI - A solvable model of axisymmetric and non-axisymmetric droplet bouncing. AB - We introduce a solvable Lagrangian model for droplet bouncing. The model predicts that, for an axisymmetric drop, the contact time decreases to a constant value with increasing Weber number, in qualitative agreement with experiments, because the system is well approximated as a simple harmonic oscillator. We introduce asymmetries in the velocity, initial droplet shape, and contact line drag acting on the droplet and show that asymmetry can often lead to a reduced contact time and lift-off in an elongated shape. The model allows us to explain the mechanisms behind non-axisymmetric bouncing in terms of surface tension forces. Once the drop has an elliptical footprint the surface tension force acting on the longer sides is greater. Therefore the shorter axis retracts faster and, due to the incompressibility constraints, pumps fluid along the more extended droplet axis. This leads to a positive feedback, allowing the drop to jump in an elongated configuration, and more quickly. PMID- 28078338 TI - Dual physically crosslinked double network hydrogels with high toughness and self healing properties. AB - Toughness and self-healing properties are desirable characteristics in engineered hydrogels used for many practical applications. However, it is still challenging to develop hydrogels exhibiting both of these attractive properties in a single material. In this work, we present the fabrication of fully physically-linked Agar/PAAc-Fe3+ DN gels. These hydrogels exhibited dual physical crosslinking through a hydrogen bonded crosslinked agar network firstly, and a physically linked PAAc-Fe3+ network via Fe3+ coordination interactions secondly. Due to this dual physical crosslinking, the fabricated Agar/PAAc-Fe3+ DN gels exhibited very favorable mechanical properties (tensile strength 320.7 kPa, work of extension 1520.2 kJ m-3, elongation at break 1130%), fast self-recovery properties in Fe3+ solution (100% recovery within 30 min), in 50 degrees C conditions (100% recovery within 15 min), and under ambient conditions (100% recovery of the initial properties within 60 min), as well as impressive self-healing properties under ambient conditions. All of the data indicate that both the hydrogen bonds in the first network and the ionic coordination interactions in the second network act as reversible sacrificial bonds to dissipate energy, thus conferring high mechanical and recovery properties to the prepared Agar/PAAc-Fe3+ DN gels. PMID- 28078339 TI - Simultaneous topographical, electrical and optical microscopy of optoelectronic devices at the nanoscale. AB - Novel optoelectronic devices rely on complex nanomaterial systems where the nanoscale morphology and local chemical composition are critical to performance. However, the lack of analytical techniques that can directly probe these structure-property relationships at the nanoscale presents a major obstacle to device development. In this work, we present a novel method for non-destructive, simultaneous mapping of the morphology, chemical composition and photoelectrical properties with <20 nm spatial resolution by combining plasmonic optical signal enhancement with electrical-mode scanning probe microscopy. We demonstrate that this combined approach offers subsurface sensitivity that can be exploited to provide molecular information with a nanoscale resolution in all three spatial dimensions. By applying the technique to an organic solar cell device, we show that the inferred surface and subsurface composition distribution correlates strongly with the local photocurrent generation and explains macroscopic device performance. For instance, the direct measurement of fullerene phase purity can distinguish between high purity aggregates that lead to poor performance and lower purity aggregates (fullerene intercalated with polymer) that result in strong photocurrent generation and collection. We show that the reliable determination of the structure-property relationship at the nanoscale can remove ambiguity from macroscopic device data and support the identification of the best routes for device optimisation. The multi-parameter measurement approach demonstrated herein is expected to play a significant role in guiding the rational design of nanomaterial-based optoelectronic devices, by opening a new realm of possibilities for advanced investigation via the combination of nanoscale optical spectroscopy with a whole range of scanning probe microscopy modes. PMID- 28078340 TI - Biocompatible CuS-based nanoplatforms for efficient photothermal therapy and chemotherapy in vivo. AB - Near-infrared (NIR) photothermal therapy (PTT) is a new approach to ablate cancer without affecting normal tissues. A pivotal concern of PPT is to develop photo responsive agents with high biocompatibility as well as effective photothermal conversion efficiency. Copper sulfide (CuS) nanoparticles prepared are characterized by their low synthesis cost, wide NIR absorption range, good biocompatibility and favorable NIR photothermal conversion efficiency. CuS nanoparticles were then coated with mesoporous silicon dioxide (SiO2) by the Stober method, and further loaded with anticancer drug doxorubicin (DOX). The nanocomposites obtained were named CuS@MSN-DOX. The infrared thermal imaging of CuS@MSN-DOX demonstrated its favorable photothermal efficacy. The potential of CuS@MSN-DOX utilized as a multifunctional platform for combined PPT and chemotherapy was exploited both at the cell level and in a mice model. The result demonstrated that CuS@MSN-DOX was endowed with the synergistic effect of chemo photothermal therapy, which confirmed that it is a promising candidate for combined therapy of cancer. PMID- 28078341 TI - The role of UV radiation and vitamin D in the seasonality and outcomes of infectious disease. AB - The seasonality of infectious disease outbreaks suggests that environmental conditions have a significant effect on disease risk. One of the major environmental factors that can affect this is solar radiation, primarily acting through ultraviolet radiation (UVR), and its subsequent control of vitamin D production. Here we show how UVR and vitamin D, which are modified by latitude and season, can affect host and pathogen fitness and relate them to the outcomes of bacterial, viral and vector-borne infections. We conducted a thorough comparison of the molecular and cellular mechanisms of action of UVR and vitamin D on pathogen fitness and host immunity and related these to the effects observed in animal models and clinical trials to understand their independent and complementary effects on infectious disease outcome. UVR and vitamin D share common pathways of innate immune activation primarily via antimicrobial peptide production, and adaptive immune suppression. Whilst UVR can induce vitamin D independent effects in the skin, such as the generation of photoproducts activating interferon signaling, vitamin D has a larger systemic effect due to its autocrine and paracrine modulation of cellular responses in a range of tissues. However, the seasonal patterns in infectious disease prevalence are not solely driven by variation in UVR and vitamin D levels across latitudes. Vector borne pathogens show a strong seasonality of infection correlated to climatic conditions favoring their replication. Conversely, pathogens, such as influenza A virus, Mycobacterium tuberculosis and human immunodeficiency virus type 1, have strong evidence to support their interaction with vitamin D. Thus, UVR has both vitamin D-dependent and independent effects on infectious diseases; these effects vary depending on the pathogen of interest and the effects can be complementary or antagonistic. PMID- 28078342 TI - Modular construction of single-component polymer nanocapsules through a one-step surfactant-free microemulsion templated synthesis. AB - Formation of O/W surfactant-free microemulsions from water/oil/acetone ternary systems is exploited to construct precisely-defined shell-functionalized core loaded nanocapsules with tunable diameters (ranging from 50 to 190 nm) in one step. PMID- 28078343 TI - Differential effects of silver and iron oxide nanoparticles on IAPP amyloid aggregation. AB - Recent studies have shown promise on the use of small molecules and nanoparticles (NPs) for the inhibition of protein aggregation, a hallmark of neurodegenerative diseases and type 2 diabetes (T2D). Towards this end here we show the differential effects of silver and iron oxide nanoparticles (AgNPs and IONPs) on the mesoscopic properties of human islet amyloid polypeptide (IAPP) aggregation associated with T2D. Both citrate- and branched polyethyleneimine-coated AgNPs (c AgNPs, bPEI-AgNPs) inhibited IAPP aggregation at 500 MUg mL-1, likely through electrostatic attraction and sequestering of IAPP monomers from fibrillation. In comparison, bare, brushed polyethylene glycol- and phosphorylcholine-grafted IONPs (bPEG-IONPs, bPC-IONPs) at 500 MUg mL-1 elicited no major effect on IAPP fibril contour length, while bPC-IONPs induced significant fibril softening and looping likely mediated by dipolar interactions. While monovalent Ag+ up to 50 MUg mL-1 showed no effect on the contour length or stiffness of IAPP fibrils, multivalent Fe3+ at 5 MUg mL-1 halted IAPP fibrillation likely through ion peptide crosslinking. Except bPEI-AgNPs, all three types of IONPs and c-AgNPs at 100 MUg mL-1 alleviated IAPP toxicity in HEK293 cells indicating no clear correlation between protein aggregation and their induced cytotoxicity. This study demonstrates the complexity of protein aggregation intervened by NPs of different physicochemical properties and - together with existing literature - facilitates nanotechnological applications for mitigating amyloid-mediated pathologies. PMID- 28078344 TI - Kinetic analysis of copper transfer from a chaperone to its target protein mediated by complex formation. AB - Chaperone proteins that traffic copper around the cell minimise its toxicity by maintaining it in a tightly bound form. The transfer of copper from chaperones to target proteins is promoted by complex formation, but the kinetic characteristics of transfer have yet to be demonstrated for any chaperone-target protein pair. Here we report studies of copper transfer between the Atx1-type chaperone CopZ from Bacillus subtilis and the soluble domains of its cognate P-type ATPase transporter, CopAab. Transfer of copper from CopZ to CopAab was found to occur rapidly, with a rate constant at 25 degrees C of ~267 s-1, many orders of magnitude higher than that for Cu(i) dissociation from CopZ in the absence of CopAab. The data demonstrate that complex formation between CopZ and CopAab, evidence for which is provided by NMR and electrospray ionisation mass spectrometry, dramatically enhances the rate of Cu(i) dissociation from CopZ. PMID- 28078345 TI - Comparison between the optical properties of aerosols in the fine and coarse fractions over Valladolid, Spain. AB - Continuous measurements of the optical properties of aerosol particles have been made at Valladolid, Spain, covering the period from June 2011 to July 2012. The measurements were made at two size cuts: sub-10 MUm and sub-1 MUm (PM10 and PM1). The data measured were the scattering and backscattering coefficients, sigmas and sigmabs, obtained from an integrating nephelometer, and the absorption coefficient, sigmaa, obtained from a particle soot absorption photometer. Spectrally resolved data were obtained from both instruments at 3 wavelengths (blue/green/red) at low relative humidity (RH < 40%). The statistical data for the instruments were calculated based on the hourly averages. For the PM10 fraction, the hourly mean values of sigmas and sigmaa at 550 nm were 33 Mm-1 (StD = 30 Mm-1) and 4 Mm-1 (StD = 3 Mm-1), respectively. For the PM1 fraction, sigmas and sigmaa mean values were 16 Mm-1 (StD = 14 Mm-1) and 4 Mm-1 (StD = 3 Mm-1), also at 550 nm. The derived parameters analyzed were the single scattering albedo, omega0, the backscatter fraction, sigmabs/sigmas, and the Angstrom exponents of scattering, absorption and single scattering albedo, alphas, alphaa and alphaomega0. The contribution of the PM10 and the PM1 fractions for all these parameters plays a central role throughout the paper, allowing an improved classification of aerosol types. Our data are dominated by elemental carbon (EC) and elemental carbon/organic carbon mixed (EC/OC). For the PM10 data, dust dominated aerosol is also observed. Although we found that fine particles contribute more than coarse particles for decreasing the omega0 values, results suggest that it is also necessary to quantify the effect of coarse particles. Fine particles were found to produce omega0 spectra that decrease with the wavelength, alphaomega0 > 0, while PM10 fractions were found to produce spectra that can decrease or increase with the wavelength, 0 < alphaomega0 < 0. Both daily cycle and monthly variations are analyzed and related to local features as well as the transport of particles from elsewhere. A diurnal pattern characteristic of urban areas is observed, but it is less evident on weekends. The main long range transport influences are Atlantic advection, anthropogenic events from Central Europe and dust events. PMID- 28078346 TI - An antimicrobial peptide with an aggregation-induced emission (AIE) luminogen for studying bacterial membrane interactions and antibacterial actions. AB - A fluorescence technique to investigate the interactions between bacterial membranes and an aggregation-induced emission (AIE) luminogen-decorated AMP (TPE AMP) was reported. Our simple and fast method consists of mixing TPE-AMP and bacterial suspensions and recording the fluorescence signals by flow cytometry and confocal microscopy in a "non-washing" manner. PMID- 28078347 TI - Alterations of the platelet proteome in type I Glanzmann thrombasthenia caused by different homozygous delG frameshift mutations in ITGA2B. AB - Glanzmann thrombasthenia (GT) is one of the best characterised inherited platelet function disorders but global platelet proteome has not been determined in these patients. We investigated the proteome and function of platelets from two patients with type I GT, caused by different homozygous ITGA2b mutations, from family members and unrelated controls. The global proteome of highly purified washed platelets was quantified by liquid chromatography-mass spectrometry (LC MS) and targeted MS-methods. Platelet function was analysed by flow cytometry, light transmission aggregometry and flow-based assays. Platelets from GT patients showed less than 5 % relative levels of the integrin subunit alphaIIb and 5-9 % fibrinogen compared to controls. These patients demonstrated loss of alphaIIbbeta3-dependent platelet function, but normal platelet granule secretion induced by physiological agonists. Platelets from heterozygous family members of a patient expressed 50-60 % of control alphaIIb levels which were sufficient for normal alphaIIbbeta3-dependent platelet function. Studying type I GT as model disease we established quantitative LC-MS to detect and clearly distinguish normal platelets, platelets from GT heterozygotes and platelets from GT patients. Diminished levels of factor XIIIB chain, plasminogen and carboxypeptidase 2B were identified in thrombasthenic platelets. Additionally, GT platelets showed up to 2.5-fold increased levels of FcgammaRIIA and laminin-alpha4 chain. Elevated levels of platelet FcgammaRIIA was associated with increased CD63-surface expression after FcgammaRIIA-crosslinking in one GT-patient which might present a compensatory mechanism of platelet activation in GT. We demonstrate that quantitative LC-MS based proteomics is suitable to validate known but also to identify previously unknown protein level changes of dysfunctional platelets. PMID- 28078348 TI - The fifth epidermal growth factor like region of thrombomodulin alleviates LPS induced sepsis through interacting with GPR15. AB - Thrombomodulin (TM) exerts cytoprotection via the fifth region of epidermal growth factor (EGF)-like domain of TM (TME5) by interacting with G-protein coupled receptor 15 (GPR15) expressed on cell surface of vascular endothelial cells. TM is also implied to mediate anti-inflammatory functions by unknown mechanism. By applying a lipopolysaccharide (LPS)-induced murine sepsis model, we assessed the role of TME5 in septic inflammation and coagulation. We found that TME5 treatment protected mice in association with ameliorating inflammation and coagulopathy in LPS-induced sepsis. Further study confirmed that TME5 bound GPR15 in vitro. Knock out of GPR15 abolished protective role of TME5 in sepsis model. GPR15 mediated anti-inflammatory function of TME5 through suppression of phosphorylation of IkappaBalpha, nuclear translocation of NF-kappaB and release of pro-inflammatory cytokines in macrophages (Macs). Knock out of GPR15 resulted in dysregulated immune response of Macs, characterised by excessive expression of pro-inflammatory genes and failing to limit immune response. This study indicates that TME5 exerts anti-inflammatory function through inhibition of NF-kappaB in a GPR15-dependent manner. The use of TME5 may be a potential therapeutic option for treatment of sepsis. PMID- 28078349 TI - Control of anticoagulation with VKAs: overestimation of median TTR when assessed by linear extrapolation: A comment. PMID- 28078350 TI - Efficacy and safety of extended thromboprophylaxis for medically ill patients. A meta-analysis of randomised controlled trials. AB - Compelling evidence suggests that the risk of pulmonary embolism (PE) and deep vein thrombosis (DVT) persists after hospital discharge in acutely-ill medical patients. However, no studies consistently supported the routine use of extended duration thromboprophylaxis (ET) in this setting. We performed a meta-analysis to assess efficacy and safety of ET in acutely-ill medical patients. Efficacy outcome was defined by the prevention of symptomatic DVT, PE, venous thromboembolism (VTE) and VTE-related mortality. Safety outcome was the occurrence of major bleeding (MB) and fatal bleeding (FB). Pooled odds ratios (ORs) and 95 % confidence intervals (95 %CI) were calculated for each outcome using a random effects model. Four RCTs for a total of 28,105 acutely-ill medical patients were included. ET was associated with a significantly lower risk of DVT (0.3 % vs 0.6 %, OR 0.504, 95 %CI: 0.287-0.885) and VTE (0.5 % vs 1.0 %, OR: 0.544, 95 %CI: 0.297-0.997); a non-significantly lower risk of PE (0.3 % vs 0.4 %, OR 0.633, 95 %CI: 0.388-1.034) and of VTE-related mortality (0.2 % vs 0.3 %, OR 0.687, 95 %CI: 0.445-1.059) and with a significantly higher risk of MB (0.8 % vs 0.4 %, OR 2.095, 95 %CI: 1.333-3.295). No difference in FB was found (0.06 % vs 0.03 %, OR 1.79, 95 %CI: 0.384-8.325). The risk benefit analysis showed that the NNT for DVT was 339, for VTE was 239, and the NNH for MB was 247. Results of our meta-analyses focused on clinical important outcomes did not support a general use of antithrombotic prophylaxis beyond the period of hospitalization in acutely-ill medical patients. PMID- 28078351 TI - Outcomes of low-molecular-weight heparin treatment for venous thromboembolism in patients with primary and metastatic brain tumours. AB - Venous thromboembolism (VTE) is one of the most common complications in patients with brain tumours. There is limited data available in the literature on VTE treatment in these patients. We conducted a matched retrospective cohort study of patients with primary or metastatic brain cancer who were diagnosed with cancer associated VTE. Patients were selected after a retrospective chart review of consecutive patients who were diagnosed with cancer-associated VTE between January 2010 and January 2014 at the Juravinski Thrombosis Clinic, Hamilton, Canada. Controls were age- and gender-matched patients with cancer-associated VTE from the same cohort, but without known brain tumours. A total of 364 patients with cancer-associated VTE were included (182 with primary or metastatic brain tumours and 182 controls). The median follow-up duration was 6.7 (interquartile range 2.5-15.8) months. The incidence rate of recurrent VTE was 11.0 per 100 patient-years (95 % CI; 6.7-17.9) in patients with brain tumours and 13.5 per 100 patient-years (95 % CI; 9.3-19.7) in non-brain tumour group. The incidence of major bleeding was 8.6 per 100 (95 % CI; 4.8-14.7) patient-years in patients with brain tumours versus 5.0 per 100 patient-years (95 % CI; 2.8-9.2) in controls. Rate of intracranial bleeding was higher in brain tumour patients (4.4 % vs 0 %, p-value=0.004). In summary, rates of recurrent VTE and major bleeding were not significantly different in patients with cancer-associated VTE in the setting of primary or metastatic brain tumours compared those without known brain tumours. However, greater numbers of intracranial bleeds were observed in patients with brain tumours. PMID- 28078352 TI - Susceptibility to chronic social stress increases plaque progression, vulnerability and platelet activation. PMID- 28078353 TI - Comparison of "Nil by Mouth" Versus Early Oral Intake in Three Different Diet Regimens Following Esophagectomy. AB - BACKGROUND: The literature on oral intake after esophagectomy and its influence on anastomotic leakage and complications is sparse. METHODS: This retrospective study included 359 patients undergoing esophagectomy between January 2011 and August 2015. Three oral intake protocols were evaluated: regimen 1, nil by mouth until postoperative day (POD) 7 followed by a normal diet; regimen 2, oral intake of clear fluids from POD 1 followed by a normal diet; regimen 3, nil by mouth until POD 7 followed by a slow increase to a blended diet. The outcome endpoints were: (1) anastomotic leakage, (2) complications [severity and number described using the Dindo-Clavien Classification and Comprehensive Complication Index (CCI)] and (3) length of stay. A multivariate logistic regression model was obtained for CCI and anastomotic leakage using Wald's stepwise selection. RESULTS: CCI was significantly lower in regimen 3 (16 vs. 22 and 26 in regimen 1 and 2, p = 0.027). Additionally, significantly fewer patients in regimen 3 suffered from severe complications of Dindo-Clavien grade IIIb-IV (p = 0.025). The incidence of anastomotic leakage reached its lowest in regimen 3, 2%, compared to 7-9%. Multivariate analyses revealed that high American Society of Anesthesiologist score was a predicting factor for both CCI and anastomotic leakage. CONCLUSION: The study indicates that nil by mouth until postoperative day 7 followed by a slow increase to a blended diet after esophagectomy results in less severe complications and a tendency of fewer anastomotic leakages. Multiple comorbidities proved to be an important predictive factor of the postoperative course. PMID- 28078354 TI - [Tracheal laceration after dilatational tracheostomy : A case of succesful conservative management]. AB - During bronchoscopically guided percutaneous dilatational tracheostomy, a 71-year old woman suffered a long-stretched tear to the posterior tracheal wall. The injury was suspected to be caused by blunt trauma during dilation or cannula insertion, possibly aggravated by vigorous cuff inflation. Since the defect ended just 0.5 cm proximal to the main carina, placing a cuffed endotracheal tube beyond the injury was not an option. However, we decided for a conservative treatment approach by placing a cuffed endotracheal tube under bronchoscopic visualization in direct proximity to the cranial end of the laceration. The further course of the patient was uneventful and complete healing was documented by bronchoscopic inspection on a regular basis. PMID- 28078355 TI - [Compression therapy of venous leg ulcers in the decongestion phase]. AB - Compression therapy is the basis for successful treatment in most patients with venous leg ulcers. Concerning compression therapy, the initial phase of decongestion and the following phase of maintenance should be differentiated. While in the maintenance phase (ulcer) stocking systems are now frequently recommended, in the decongestion phase compression bandages are mostly still used, which however are often inappropriately applied. In German-speaking countries, compression therapy with short-stretch bandages has a long tradition. However, their correct application requires good training and monitoring, which is often lacking in daily practice. Less error-prone treatment alternatives are multicomponent systems, some of which have an optical marker for the control of the correct subbandage pressure. In another new type of compression system, which is called adaptive or wrap bandages, the compression pressure can be adjusted using a Velcro fastener. Accompanying intermittent pneumatic compression therapy can also be used in the decongestion phase. Thus, there are now several different treatment options that can be used for the decongestion phase in patients with venous leg ulcers. Often bandages with short-stretch materials are very prone to errors and should in most cases be replaced by other compression systems today. The patient's preference, need, and capability should be considered when selecting the appropriate system for the individual patient. PMID- 28078356 TI - [Marketability of food supplements - criteria for the legal assessment]. AB - To be placed on the market legally, food supplements have to meet national and European food law regulations. This is true for all substances used as well as for the labeling on the packaging of and the advertising for food supplements. The food business operator is responsible for its compliance with all regulations. Therefore, in this article, a concise step-by-step assessment is presented, covering all necessary legal requirements to market food supplements. Additionally, all steps are visualized in a flow chart. All vitamins, minerals and other substances used have to meet the legal conditions. Food business operators have to make sure that their products do not contain medicinal ingredients based on their pharmacologic effect. It is prohibited to place medicinal products as food supplements on the market. Furthermore, food business operators have to make sure that their products are not non-authorized novel foods according to the novel food regulation (EC) no. 258/97. Also, food supplements have to meet the requirements of article 14 of Regulation (EC) No. 178/2002 concerning the safety of foodstuff. Food shall not be placed on the market if it is unsafe. For food supplements that fail the German food-related legal standards but are legally manufactured in another EU member state or are legally put into circulation, the importer requires the so-called general disposition, which must be applied for at the BVL according to S 54 of the German Food and Feed Act. Another possibility for food which fails to meet German food law is to apply for a certificate of exemption according to S 68 of the Food and Feed Act. The food business operator has to meet the harmonized regulations concerning maximum and minimum levels of additives, flavors and enzymes. The packaging has to meet the compulsory labeling as well the voluntary labeling, like health claims. The BVL is also the relevant authority for other tasks concerning food supplements. A figure shows all notifications since 2005 of food supplements in Germany at the BVL. Additionally, an overview for notifications in the rapid alert system for food and feed concerning food supplements is given as well as a brief introduction into the survey of food supplements marketed on the internet. PMID- 28078357 TI - Intralesional treatment of metastatic melanoma: a review of therapeutic options. AB - Intralesional therapy of melanoma patients with locally advanced metastatic disease is attracting increasing interest, not least due to its ability to lead to both direct tumor cell killing and the stimulation of both a local and a systemic immune response. An obvious pre-requisite for this type of approach is the presence of accessible metastases that are amenable to direct injection with the therapeutic agent of interest. Patients who present with these characteristics belong to stages IIIB/C or IV of the disease. Surgical resection with intention to cure is the standard of care for patients with limited tumor burden and confined spread of disease (resectable patients). However, this category of patients is at a high risk of further recurrences until the disease becomes inoperable (unresectable) or progresses to a more advanced stage with visceral organ involvement, after which the prognosis is particularly grim. Most of the intralesional treatments tested so far, including the recently approved oncolytic virus talimogene laherparepvec, target the subpopulation of patients with unresectable disease, but the possibility to use the intralesional treatment in a neoadjuvant setting for fully resectable patients is attracting considerable interest. The present article reviews approved products and advanced stage pharmaceutical agents in development for the intralesional treatment of melanoma patients. PMID- 28078359 TI - In touch with mental rotation: interactions between mental and tactile rotations and motor responses. AB - Although several process models have described the cognitive processing stages that are involved in mentally rotating objects, the exact nature of the rotation process itself remains elusive. According to embodied cognition, cognitive functions are deeply grounded in the sensorimotor system. We thus hypothesized that modal rotation perceptions should influence mental rotations. We conducted two studies in which participants had to judge if a rotated letter was visually presented canonically or mirrored. Concurrently, participants had to judge if a tactile rotation on their palm changed direction during the trial. The results show that tactile rotations can systematically influence mental rotation performance in that same rotations are favored. In addition, the results show that mental rotations produce a response compatibility effect: clockwise mental rotations facilitate responses to the right, while counterclockwise mental rotations facilitate responses to the left. We conclude that the execution of mental rotations activates cognitive mechanisms that are also used to perceive rotations in different modalities and that are associated with directional motor control processes. PMID- 28078358 TI - Major histocompatibility complex haplotyping and long-amplicon allele discovery in cynomolgus macaques from Chinese breeding facilities. AB - Very little is currently known about the major histocompatibility complex (MHC) region of cynomolgus macaques (Macaca fascicularis; Mafa) from Chinese breeding centers. We performed comprehensive MHC class I haplotype analysis of 100 cynomolgus macaques from two different centers, with animals from different reported original geographic origins (Vietnamese, Cambodian, and Cambodian/Indonesian mixed-origin). Many of the samples were of known relation to each other (sire, dam, and progeny sets), making it possible to characterize lineage-level haplotypes in these animals. We identified 52 Mafa-A and 74 Mafa-B haplotypes in this cohort, many of which were restricted to specific sample origins. We also characterized full-length MHC class I transcripts using Pacific Biosciences (PacBio) RS II single-molecule real-time (SMRT) sequencing. This technology allows for complete read-through of unfragmented MHC class I transcripts (~1100 bp in length), so no assembly is required to unambiguously resolve novel full-length sequences. Overall, we identified 311 total full-length transcripts in a subset of 72 cynomolgus macaques from these Chinese breeding facilities; 130 of these sequences were novel and an additional 115 extended existing short database sequences to span the complete open reading frame. This significantly expands the number of Mafa-A, Mafa-B, and Mafa-I full-length alleles in the official cynomolgus macaque MHC class I database. The PacBio technique described here represents a general method for full-length allele discovery and genotyping that can be extended to other complex immune loci such as MHC class II, killer immunoglobulin-like receptors, and Fc gamma receptors. PMID- 28078360 TI - Multimodal nerve monitoring during periacetabular osteotomy identifies surgical steps associated with risk of injury. AB - PURPOSE: Sciatic nerve palsy after periacetabular osteotomy (PAO) is a serious complication. The purpose of this study was to determine whether a multimodal sciatic monitoring technique allows for identification of surgical steps that place the sciatic nerve at risk. METHODS: Transcranial electrical motor evoked potentials (TcMEPs), somatosensory evoked potentials (SSEPs), and spontaneous electromyography (EMG) were monitored in a consecutive series of 34 patients (40 hips) who underwent PAO for the treatment of symptomatic hip dysplasia between January 2012 and November 2014. There were 29 females (85%) and five males (15%) with an average age of 19 years (range, 12-36 years) at the time of surgery. RESULTS: We detected eight temporary sciatic nerve monitoring alerts in six patients (incidence of 15%). The events included decrease in amplitude of the TcMEPs related to the position of the hip during incomplete ischium osteotomy and placement of a retractor in the sciatic notch during the posterior column osteotomy (N = 3), generalized bilateral decrease in TcMEPs during fragment manipulation and fixation in association with acute blood loss (N = 2), and a change in SSEPs during a superior pubic osteotomy and supra-acetabular osteotomy (N = 1). At the end of the procedure, TcMEPs and SSEPs were at baseline and there was no abnormal pattern on EMG in all patients. Post-operatively, at two, six, 12 weeks, and six and 12 months, no motor weakness or sensory deficits were noted. CONCLUSION: Multimodal neuromonitoring allowed for identification of intra operative steps and maneuvers that potentially place the sciatic nerve at higher risk of injury. PMID- 28078361 TI - INFIX versus plating for pelvic fractures with disruption of the symphysis pubis. AB - PURPOSE: The purpose of this study is to compare INFIX to plating in the treatment of unstable pelvic ring injuries with disruption of the symphysis. METHODS: Twenty-four patients treated with INFIX were compared to 28 patients fixed by plating. All patients had anterior and posterior fixation. Injuries were classified using the Young and Burgess and AO/OTA classification systems. Reductions of the pelvic ring were assessed using the pelvic deformity index (PDI) and symphyseal widening. Patients were contacted to get functional outcomes using the Majeed scoring system and complications were tabulated . RESULTS: INFIX was inferior to plating at reducing symphyseal widening (INFIX 10.72+/- 5.0 Plates 6.97 +/- 3.39 P = 0.012) but similar in reducing the pelvic deformity index. (INFIX 0.0221+/- .015 Plates 0.0190 +/- .0105 P = 0 .38). Majeed scores were similar 83.95 +/- 15.2 (median 89, range 51-100) for INFIX and 77.67+/- 16.7 (median 79, range 54-100) for plating. Complications included infection (1 (4%) INFIX , 4 (14%) plates), improper hardware placement or failure (2 (8%) INFIX, 3 (11%) plates), and heterotopic ossification (11 (46%) INFIX, 16 (57.1%) plates). Infection in the plated patients was related to urological injury in 3/4 cases. CONCLUSIONS: Plating provides better reduction of the pubic symphysis and requires only one surgery. Outcomes scores were similar. INFIX may be preferable in obese patients, young women of childbearing age or those with urological injury. PMID- 28078362 TI - Use of dual-mobility cup in revision hip arthroplasty reduces the risk for further dislocation: analysis of seven hundred and ninety one first-time revisions performed due to dislocation, reported to the Swedish Hip Arthroplasty Register. AB - PURPOSE: Dislocation after total hip arthroplasty (THA) is a common reason for revision. The last decade fostered a significant increase in the use of dual mobility cups (DMCs). Here we report our study on the short-term survival rate of a cemented DMC reported to the Swedish Hip Arthroplasty Register (SHAR) compared with other cemented designs used in first-time revision due to dislocation. METHODS: During 2005-2015, 984 first-time revisions for dislocation were reported to SHAR. In 436 of these cases a cemented dual articular cup was used. During the same time period, 355 revisions performed with a standard cemented cup (femoral head size 28-36 mm) were reported to the SHAR. Patients receiving a DMC were slightly older (75 years, p = 0.005). Re-revision for all reasons was used as primary endpoint. We also anlaysed risk for re-revision of the acetabular component and re-revision due to dislocation. Kaplan-Meier implant survival and a Cox regression analyses adjusted for age and gender were performed. RESULTS: Implant survival at 4 years for all reasons (91% +/- 3.7% vs 86% +/- 4.1%, p = 0.02), and especially for re-operation because of dislocation, favours the DMC group (96% +/- 3.0% vs 92% +/- 3.3%, p = 0.001). DISCUSSION: Our findings indicate that use of a cemented DMC reduces the short- to mid-term risk of a second revision in first-time revisions compared with classic cup designs. Longer follow-up is needed to establish any long-term clinical advantages when DMCs are used in revisions performed due to dislocation. PMID- 28078363 TI - Short-term outcome after total hip arthroplasty using dual-mobility cup: report from Lithuanian Arthroplasty Register. AB - PURPOSE: The purpose of the study was to investigate how the use of dual-mobility cups (DMCs) affected the risk of revision due to dislocation as well as overall risk of revision compared with a conventional total hip arthroplasty (THA) system in the short term. METHODS: A total of 12,657 primary THAs were registered from the start of 2011 to the end of 2014. 620 THAs were with DMCs. For comparison, we included all registered THAs with Exeter cup and a cemented Exeter stem combined with 28-mm femoral head. Patients were followed up with respect to revision and/or death until 1 January 2016. For survival analysis, we used revision as an endpoint. Cox proportional hazards models were used to analyse the influence of various covariates (age, gender, surgical approach, THA model and pre-operative diagnosis). RESULTS: Of the 620 dual-mobility THAs and 2170 Exeter THAs, 100 had been revised. The overall unadjusted cumulative revision rate (CRR) for any reason of revision at five years after surgery was 3.9% in the dual-mobility group and 5.2% in the Exeter group. Cox regression analysis, adjusting for age, gender, THA type, surgical approach and pre-operative diagnosis, showed that the risk of revision was less in patients operated with DMCs and in patients having their operation for osteoarthritis. CONCLUSION: The DM implant had a lower short term complication rate than a conventional well defined THA. Low dislocation rate suggests that it is a good choice for high risk patients. PMID- 28078364 TI - [Ligament injuries of fingers and thumbs]. AB - Degenerative and traumatic ligament lesions of the carpometacarpal joints frequently occur at the thumb ray, whereas the carpometacarpal amphiarthrosis of other finger rays are rarely affected. The metacarpophalangeal and interphalangeal joints of the thumb and fingers are stabilized by bilaterally running collateral ligaments and palmar plates. At the base of the metacarpophalangeal joints, several ligaments of the extensor hoods guide the extensor tendons and coordinate the fine motoric skills of phalangeal flexing and extending. Several annular and cruciform ligaments hold the flexor tendons close to the finger skeleton. Other than at the wrist, differentiation between dynamic and static instability patterns is possible by physical examination. This review article presents the ligaments of the thumb and the fingers, the traumatic and degenerative lesions as well as the diagnostic capability of x-rays, cinematography, magnetic resonance imaging (MRI) and MR arthrography. PMID- 28078366 TI - Genetic Screening of WNT4 and WNT5B in Two Populations with Deviating Bone Mineral Densities. AB - A role for WNT4 and WNT5B in bone metabolism was indicated by genome-wide association studies (GWAS) and a Wnt4 knockout mouse model. The aim of this study was therefore to replicate and further investigate the causality between genetic variation in WNT4 and WNT5B and deviating bone mineral density (BMD) values. A WNT4 and WNT5B mutation screening was performed in patients with craniotubular hyperostosis using Sanger sequencing. Here, no putative causal mutations were detected. Moreover, a high and low BMD cohort was selected from the Odense Androgen Study population for re-sequencing. In WNT4 we detected four variants (three rare, one common), while in WNT5B we detected five variants (two rare, three common). For the common variants, no significant difference in genotype frequencies between the high and low BMD cohorts was observed. The SNPs associated with the GWAS were genotyped in these cohorts, but again no significant difference in genotype frequencies was observed. Despite the findings of the GWAS, we were not able to replicate or further verify the genetic association of polymorphisms in WNT4 and WNT5B with BMD. In order to do so, the intronic regions of both genes could be investigated more thoroughly in more extended populations (or extremes) with greater power. Future genetic and functional studies toward adjacent genes of WNT4 and WNT5B can also be interesting to figure out whether the signal from GWAS could possibly be attributed to genetic variation in these genes. PMID- 28078367 TI - Topographical relationship between positions of lingual foramina and attachment of mylohyoid muscle in mental region. AB - PURPOSE: Lingual foramina can be observed between the lingual aspects of the mandible in humans. A sublingual artery is thought to exist in sublingual space and a submental artery in submaxillary space, which pierce the mandible through lingual foramina. During surgery for oral implant placement between apices of the mental foramen, it is important to determine the existence and positioning of lingual foramina. The purpose of this study was to investigate the positions of lingual foramina in relation to the mylohyoid muscle and vertical position of the mylohyoid line using cone-beam computed tomography (CBCT) images. METHODS: We examined 20 formalin-perfused cadavers. The mylohyoid muscle was dissected and marked with a silicone tube, then CBCT images were obtained to evaluate the relationship of that muscle with lingual foramina. RESULTS: We observed 37 lingual foramina in the 20 cadavers. As for vertical positioning, 16 lingual foramina were found in sublingual space, while in horizontal positioning, 6 were found in the anterior region of sublingual space. The ratio of vertical distance from the inferior margin to the mylohyoid line and mental spine was lower in the anterior region as compared to the posterior region. CONCLUSION: In this study, lingual foramina were found to commonly exist in sublingual space above the mylohyoid muscle and pierce the mesial side. For evaluation of the vertical position of the mylohyoid line, it is better to use the stable mental spine rather than the alveolar process. PMID- 28078368 TI - Time-Dependent Toxicity Responses in Daphnia magna Exposed to CuO and ZnO Nanoparticles. AB - Aggregation and dissolution of CuO and ZnO nanoparticles (NPs) increased with increasing exposure time (24, 48, and 72 h). Acute toxicity of CuO NPs to Daphnia magna also increased significantly with increasing exposure time (p < 0.05), whereas exposure time did not significantly affect acute toxicity of ZnO NPs. The dissolved Cu concentration of CuO NPs was much lower than the median effective concentration (EC50) value (44 MUg L-1 at 72 h), implying that the increase in acute toxicity was caused by particles rather than by dissolved ions. However, the dissolved Zn concentration of ZnO NPs was higher than the EC50 value (600 MUg L-1 at 72 h), suggesting this acute toxicity may be caused by dissolved ions. Moreover, CuO NPs induced greater lipid peroxidation than Cu ions did at an exposure time of 72 h, whereas converse results were observed for ZnO NPs. PMID- 28078369 TI - Effectiveness of Integrated Best Management Practices on Mitigation of Atrazine and Metolachlor in an Agricultural Lake Watershed. AB - The study examined the influence of land-use (cropping patterns) and integrated agricultural best management practices (BMPs) on spring herbicide levels in an agricultural watershed. Atrazine and metolachlor were applied for weed control during spring of 1998-2002, 2005, and 2007-2013. Watershed-wide mass of applied herbicides ranged from 12.7 to 209.2 g atrazine and 10.9-302.2 g metolachlor with greatest application during 1998, 2009-2010 (atrazine) and 2007-2013 (metolachlor). Spring herbicide concentrations in Beasley Lake water ranged from below detection to 3.54 MUg atrazine/L and 3.01 MUg metolachlor/L. Multiple linear regression analyses with cropping patterns, BMPs, rainfall and time as independent variables, showed atrazine applications were associated with increases in cotton acreage and quail buffer, while metolachlor applications increased over time. Multiple linear regressions showed lake atrazine concentrations were associated with conservation tillage, rainfall, and corn, while lake metolachlor concentrations were associated with the cumulative metolachlor application and sediment retention pond installation. PMID- 28078370 TI - Evaluation of Groundwater Quality in the Eastern District of Abu Dhabi Emirate, UAE. AB - Water samples were collected to evaluate the groundwater quality in the shallow unconfined alluvial aquifer in the eastern part of Abu-Dhabi Emirate, UAE. The chemical monitoring revealed some spatial variability in chemical parameters as influenced by matrix aquifer changes in geological formations. Results show that changes in groundwater chemistry in the aquifer is mainly controlled by evaporation, silicate mineral dissolution, evaporite dissolution, and cation exchange. The concentration increases were accounted for primarily by dissolved sodium, chloride, and sulphate. The high value of total dissolved solids of shallow groundwater is mainly controlled by evaporation. The dominance of sodium ion was evident among the cationic compositions with an average of 2621.1 mg/L, while the chloride ion was the dominant among the anionic constituents with an average of 6249 mg/L. The prevalence of those two elements in most water samples contributes to the existence of saline water occurrence in the study area. PMID- 28078371 TI - Acetabular defect classification in times of 3D imaging and patient-specific treatment protocols. AB - Parallel to the rising number of revision hip procedures, an increasing number of complex periprosthetic osseous defects can be expected. Stable long-term fixation of the revision implant remains the ultimate goal of the surgical protocol. Within this context, an elaborate preoperative planning process including anticipation of the periacetabular defect form and size and analysis of the remaining supporting osseous elements are essential. However, detection and evaluation of periacetabular bone defects using an unsystematic analysis of plain anteroposterior radiographs of the pelvis is in many cases difficult. Therefore, periacetabular bone defect classification schemes such as the Paprosky system have been introduced that use standardized radiographic criteria to better anticipate the intraoperative reality. Recent studies were able to demonstrate that larger defects are often underestimated when using the Paprosky classification and that the intra- and interobserver reliability of the system is low. This makes it hard to compare results in terms of defects being studied. Novel software tools that are based on the analysis of CT data may provide an opportunity to overcome the limitations of native radiographic defect analysis. In the following article we discuss potential benefits of these novel instruments against the background of the obvious limitations of the currently used native radiographic defect analysis. PMID- 28078372 TI - Fragility fractures of the spine. PMID- 28078373 TI - [Aus "Fehler und Gefahren" wird "Patientensicherheit" und aus "Trends und Medizinokonomie" wird "Qualitatsmanagement und Medizinokonomie"]. PMID- 28078374 TI - [Anaesthesia procedures and invasive vascular access in severely injured patients at trauma room admission in Germany : An online survey]. AB - BACKGROUND: The continuous monitoring of vital parameters and subsequent therapy belong to the core duties of anaesthetists during acute trauma resuscitation in the trauma room. Important procedures may include placement of arterial lines and central venous catheters (CVCs). Knowledge of indication, performance and localization of invasive catheterisation of trauma care in Germany is scarce. METHODS: After approval of the German Society of Anaesthesiology and Intensive Care Medicine we conducted an online survey about arterial and central venous catheterisation of severely injured patients with consideration of common practice used by anaesthetists in German trauma rooms. Data are presented in a descriptive manner. RESULTS: Of 843 hospitals invited for the survey, 72 (8.5%) had complete and valid data and were thus included in the analysis. Of these, 47% were supra-regional (level 1) trauma centres, 38% regional trauma centres and 15% local trauma centres. The annual mean injury severity score (ISS) of admitted patients to these hospitals was 21 +/- 10. In the trauma room, the responding hospitals place CVCs (49%) and arterial lines (59%) only in haemodynamically unstable patients, whereas 24% (CVC) and 39% (arterial line) do when pathological laboratory tests were confirmed. Standard operating procedures (SOPs) merely exist for placement of either arterial lines (25%) or CVCs (22%) in multiple trauma resuscitation. The decision to perform CVC or arterial line placement is usually (79%) at the discretion of the attending anaesthetist. The preferred anatomical access site for CVCs is the right internal jugular vein (46%) and for arterial lines the radial artery (without side preference) (57%), respectively. Of the responding hospitals, 49% prefer landmark-guided CVC-puncture (91% of arterial lines) instead of 43% using sonographic guidance (9% of arterial lines). Intravascular electrocardiography monitoring for CVC tip detection is used by 36%. CONCLUSION: In Germany, medical indication and schedule of invasive vascular catheterisation of severely injured patients in the trauma room is rarely regulated by SOPs and often performed at the discretion of the attending trauma team. Sonographic assistance during vascular puncture and electrocardiography for CVC tip detection is not as common as in non-emergency anaesthesia. Further studies are required to explore the real necessity and safety of invasive vascular catheterisation in multiple trauma patients in order to improve trauma care. PMID- 28078376 TI - Ipsilateral Dual-Site, Same-Sitting Percutaneous Lung Biopsy: A Feasibility Study. AB - PURPOSE: Patients with thoracic malignancies often have more than one site of pulmonary, nodal or pleural disease within one hemithorax. In addition, large heterogeneous lesions may comprise distinct, mixed pathological entities. Histological analysis of these lesions can alter tumour staging and treatment options. We investigated the feasibility, safety and benefit of performing image guided percutaneous lung biopsy (PLB) of two lesions in the same hemithorax at a single sitting. MATERIALS AND METHODS: Ten consecutive outpatients with two or more potential disease foci within the same hemithorax were analysed over a 15 month period. The mean age of the patients was 66 years (range 46-81 years). Patients underwent CT-guided coaxial 20G core biopsy of both lesions, with separate coaxial punctures for each lesion. Patients were managed as per established local institution ambulatory lung biopsy protocol using small-calibre Heimlich-valve chest drain (HVCD) to treat significant post-PLB pneumothorax in an outpatient setting. Data regarding lesion characteristics, diagnoses and complications were recorded. RESULTS: All 10 patients (n = 20 biopsies, 100% technical success) received informative histological diagnosis on both lesions. This altered management in all cases. Although a high rate of pneumothorax occurred (60%; 6/10), only two of these patients required treatment with HVCD. No other significant complications occurred in those patients with small asymptomatic pneumothoraces or those that required HVCD placement. CONCLUSIONS: Dual-site lung biopsy, performed as a single procedure, is potentially a safe and effective technique for diagnosing patients with multiple thoracic lesions, and can provide useful staging information to guide patient management. PMID- 28078375 TI - Assessing Intra-arterial Complications of Planning and Treatment Angiograms for Y 90 Radioembolization. AB - PURPOSE: To report hepatic arterial-related complications encountered during planning and treatment angiograms for radioembolization and understand any potential-associated risk factors. MATERIALS AND METHODS: 518 mapping or treatment angiograms for 180 patients with primary or metastatic disease to the liver treated by Yttrium-90 radioembolization between 2/2010 and 12/2015 were retrospectively reviewed. Intra-procedural complications were recorded per SIR guidelines. Patient demographics, indication for treatment, prior exposure to chemotherapeutic agents, operator experience, and disease burden were reviewed. Technical variables including type of radioembolic (glass vs. resin microspheres), indication for angiography (mapping vs. treatment), variant anatomy, and attempts at coil embolization were also assessed. RESULTS: Thirteen (13/518, 2.5%) arterial-related complications occurred in 13 patients. All but two complications resulted during transcatheter coil embolization to prevent non target embolization. Complications included coil migration (n = 6), arterial dissection (n = 2), focal vessel perforation (n = 2), arterial thrombus (n = 2), and vasospasm prohibiting further arterial sub-selection (n = 1). Transarterial coiling was identified as a significant risk factor of complications on both univariate and multivariate regression analysis (odds ratio 7.8, P = 0.004). Usage of resin microspheres was also a significant risk factor (odds ratio 9.5, P = 0.042). No other technical parameters or pre-procedural variables were significant after adjusting for confounding on multivariate analysis (P > 0.05). CONCLUSION: Intra-procedural hepatic arterial complications encountered during radioembolization were infrequent but occurred mainly during coil embolization to prevent non-target delivery to extra-hepatic arteries. PMID- 28078377 TI - Advances in Imaging and Management Trends of Traumatic Aortic Injuries. AB - Acute traumatic aortic injury (ATAI) is a life-threatening injury. CT is the imaging tool of choice, and the knowledge of direct and indirect signs of injury, grading system, and current management protocol helps the emergency radiologist to better identify and classify the injury and provide additional details that can impact management options. Newer dual-source CT technology with ultrafast acquisition speed has also influenced the appropriate protocol for imaging in patients with suspected ATAI. This review highlights the imaging protocol in patients with blunt trauma, CT appearance and grading systems of ATAI, management options, and the role of the multidisciplinary team in the management of these patients. We also briefly review the current literature on the definition, treatment, and follow-up protocol in patients with minimal aortic injury. PMID- 28078378 TI - Post-procedural Care in Interventional Radiology: What Every Interventional Radiologist Should Know-Part I: Standard Post-procedural Instructions and Follow Up Care. AB - Interventional radiology (IR) has evolved into a full-fledged clinical specialty with attendant patient care responsibilities. Success in IR now requires development of a full clinical practice, including consultations, inpatient admitting privileges, and an outpatient clinic. In addition to technical excellence and innovation, maintaining a comprehensive practice is imperative for interventional radiologists to compete successfully for patients and referral bases. A structured approach to periprocedural care, including routine follow-up and early identification and management of complications, facilitates efficient and thorough management with an emphasis on quality and patient safety. PMID- 28078379 TI - Chitosan-Sodium Tetradecyl Sulfate Hydrogel: Characterization and Preclinical Evaluation of a Novel Sclerosing Embolizing Agent for the Treatment of Endoleaks. AB - PURPOSE: To compare the efficacy of an embolization agent with sclerosing properties (made of chitosan and sodium tetradecyl sulfate, CH-STS) with a similar embolization agent but without sclerosing properties (made of chitosan, CH) in treating endoleaks in a canine endovascular aneurysm repair model. METHODS: Two chitosan-based radiopaque hydrogels were prepared, one with STS and one without STS. Their rheological, injectability, and embolizing properties were assessed in vitro; afterwards, their efficacy in occluding endoleaks was compared in a canine bilateral aneurysm model reproducing type I endoleaks (n = 9 each). The primary endpoint was endoleak persistence at 3 or 6 months, assessed on a CT scan and macroscopic examination. Secondary endpoints were the occurrence of stent-graft (SG) thrombosis, the evolution of the aneurysm mean diameter, as well as aneurysm healing and inflammation scores in pathology examinations. RESULTS: In vitro experiments showed that both products gelled rapidly and presented initial storage moduli greater than 800 Pa, which increased with time. Both gels were compatible with microcatheter injection and occlude flow up to physiological pressure in vitro. In a type I endoleak model, the injection of CH-STS sclerosing gel tended to reduce the risk of occurrence of endoleaks, compared to CH non sclerosing agent (2/9 vs. 6/9, p = 0.069). No case of SG thrombosis was observed. Moderate inflammation was found around both gels, with a comparable intensity score in both CH and CH-STS groups (2.6 +/- 0.9 and 2.7 +/- 0.9, respectively; p = 0.789). CONCLUSIONS: Flow occlusion combined with chemical endothelial denudation appears promising for the treatment of endoleaks. LEVEL OF EVIDENCE: N/A. PMID- 28078380 TI - Imaging features of hepatic sarcomatous carcinoma on computed tomography and gadoxetic acid-enhanced magnetic resonance imaging. AB - PURPOSE: To determine the imaging features of hepatic sarcomatous carcinoma including sarcomatous intrahepatic cholangiocarcinoma (S-ICC) and sarcomatous hepatocellular carcinoma (S-HCC) on computed tomography (CT) and gadoxetic acid enhanced magnetic resonance imaging (MRI). MATERIALS AND METHODS: Twenty-four patients with pathologically confirmed S-ICCs (n = 13), S-HCCs (n = 7), sarcomatous carcinoma (n = 2), carcinosarcoma (n = 1), and sarcomatous combined HCC-CC (n = 1) (size range 2.1-23 cm, mean 8.3 cm) underwent gadoxetic acid enhanced MRI (n = 20) and/or dynamic CT (N = 24). Underlying chronic hepatitis or cirrhosis was found in 17 patients. Two reviewers evaluated morphology, signal intensity, and enhancement features of tumors based on a consensus. RESULTS: Lobulated contour was observed in 15 tumors (62.5%); the rest were round or oval masses. During dynamic imaging, S-ICCs showed poor enhancement (n = 10 on CT; n = 7 on MRI) or initial thin-rim enhancement with/without progressive enhancement (n = 3 on CT; n = 6 on MRI). S-HCCs and the other four tumors showed a thin or thick enhancement pattern on both CT and MRI. T2 bright signal intensity similar to fluid was found in 10 tumors. Target appearance on hepatobiliary phase and diffusion-weighted imaging was seen in two S-ICCs and two S-HCCs. Of 18 surgically resected tumors, 17 showed vascular invasion and/or thrombosis in histology and 12 in CT and MRI. Ten tumors were accompanied by intrahepatic metastasis or tumor seeding and 19 patients had recurrence or progression of tumors during follow-up. CONCLUSION: Hepatic sarcomatous carcinoma including S HCC and S-ICC generally presents minimal rim-like arterial enhancement or extreme hypovascularity on CT and gadoxetic acid-enhanced MRI with a high frequency of T2 bright area due to extensive necrosis and vascular invasion. PMID- 28078381 TI - Celiac disease: a clinical review. AB - Celiac disease (CD) is an immune-mediated inflammatory enteropathy triggered by gluten exposure in genetically susceptible individuals. It has a high prevalence approaching 1% of the US population. A high index of suspicion is warranted to diagnose CD as frequently patients present with extraintestinal or atypical manifestations. CD is diagnosed by a combination of serum serologies and duodenal biopsies. The majority of patients will respond to a lifelong gluten-free diet which is the cornerstone of therapy. Complications such as refractory CD, ulcerative jejunoileitis, enteropathy associated T-cell lymphoma and small bowel adenocarcinoma occur in a minority of patients. PMID- 28078382 TI - Timing and Mode of Delivery in Prenatally Diagnosed Congenital Heart Disease- an Analysis of Practices within the University of California Fetal Consortium (UCfC). AB - Prenatal diagnosis of critical congenital heart disease (CHD) is associated with decreased morbidity. It is also associated with lower birth weights and earlier gestational age at delivery. The University of California Fetal Consortium (UCfC) comprises five tertiary medical centers, and was created to define treatment practices. We utilized this consortium to assess delivery patterns and outcomes in subjects with prenatal and postnatal diagnosis of CHD. A retrospective cohort study was conducted on maternal-neonatal pairs diagnosed with complex CHD prenatally (n = 186) and postnatally (n = 110) from 2011 to 2013. Outcomes were assessed between groups after adjusting for disease severity. Prenatally diagnosed subjects were born earlier (38.1 +/- 0.11 vs. 39 +/- 0.14 weeks, p = < 0.001), and had lower birth weights (2853 +/- 49 vs. 3074 +/- 58 g, p = 0.005) as compared to postnatal diagnosis. For every week increase in gestational age and 100 g increase in birth weight, length of stay decreased by 12.3 +/- 2.7% (p < 0.001) and 3.9 +/- 0.9% (p < 0.001). Subjects with prenatal diagnosis were more often born via cesarean both planned (35.6 vs. 26.2%, p = 0.004) and after a trial of labor (13 vs. 7.8%, p = 0.017). Neonates with cesarean delivery trended toward a longer length of stay (2.6 days longer), and were born earlier as compared to other modalities (37.7 +/- 0.22 weeks, p = 0.001). Management after prenatal diagnosis of CHD appears to have modifiable disadvantages for maternal and neonatal outcomes. The UCfC provides a platform to study best practices and standardization of care for future studies. PMID- 28078383 TI - Effects of Triple Cryoenergy Application on Lesion Formation and Coronary Arteries in the Developing Myocardium. AB - To improve long-term outcome after cryoablation of substrates of supraventricular tachycardia, application of two and three consecutive freeze-thaw cycles has been performed. The effect of triple freeze-thaw cycles on lesion formation within developing myocardium and coronary arteries, however, has not been studied yet. In eight piglets (mean age 15 weeks, weight 15-20 kg), 30 cryolesions (three consecutive freeze-thaw cycles) were applied to the atrial aspect of both AV valve annuli (n = 18) as well as to ventricular myocardium below the valves (n = 12). Coronary angiography was performed before and after cryoenergy application. The animals were reevaluated by coronary angiography and intracoronary ultrasound (ICUS) after 48 h. All hearts were removed for histological examination of the lesions subsequently. After staining (hematoxylin-eosin, desmin immunohistochemistry), lesions was measured by planimetry with a digital virtual miscroscope analysis system and volumes of the cryolesions were calculated. Mean atrial lesion volume was 190.68 +/- 167.53 mm3 (n = 18), and mean ventricular lesion volume was 184.34 +/- 107.42 mm3 (n = 12). Compared with previously reported data on lesion volumes after single and double freeze-thaw cycles, lesions were significantly larger. Coronary arteries were unaffected on coronary angiography as well as on ICUS. No affection of coronary arteries was found on histological examination. Application of three consecutive freeze-thaw cycles resulted in increased lesion volume compared with single and double freeze-thaw cycles. No affection of the coronary arteries was evident. To evaluate the clinical benefit and safety of triple cryoenergy application for catheter ablation, prospective randomized trials are required. PMID- 28078384 TI - Echocardiographic Versus Angiographic Assessment of Patent Arterial Duct in Percutaneous Closure: Towards X-ray Free Duct Occlusion? AB - Device selection and procedural guidance for percutaneous ductal closure strongly rely upon angiographic and echocardiographic imaging. Current literature recognises 2D echocardiography as an essential tool for diagnosis and assessment but does not define a consistent methodology to optimise ductal measurement. There is little research comparing echocardiography with gold standard angiography for ductal measurement. Proving 2D echocardiographic ductal measurement to be equivalent to angiography could pave the way for its use as the primary modality in image guidance for percutaneous closure of the ductus. This was a retrospective study of 100 consecutive paediatric patients who underwent percutaneous ductal closure. Echocardiographic images were studied to determine ductal (a) morphology (b) dimensions (length, aortic ampulla, pulmonary end, minimum diameter) (c) size of device that would be appropriate for closure. These data were compared to corresponding measurements generated by angiographic images. Inter and intra-observer ratings were calculated to assess levels of agreement. There were significant differences between the imaging methods in classifying the morphological sub-type and ductal measurements (p < 0.005), except for length which was not found to be significantly different between modalities. Prediction of device selection from angiographic images showed excellent agreement (weighted k = 0.81). Predictions based on echocardiographic images showed a poor level of agreement (weighted k = 0.14). We found poor correlation between echocardiography and angiography for measurement, morphological assessment and device selection. Based on our findings, percutaneous arterial duct occlusion without angiographic guidance in this age group cannot be advocated. PMID- 28078385 TI - Glucose and fatty acids synergistically and reversibly promote beta cell proliferation in rats. AB - AIMS/HYPOTHESIS: The mechanisms underlying pancreatic islet mass expansion have attracted considerable interest as potential therapeutic targets to prevent or delay the onset of type 2 diabetes. While several factors promoting beta cell proliferation have been identified, in the context of nutrient excess the roles of glucose or NEFA in relation to insulin resistance remain unclear. Here we tested the hypothesis that glucose and NEFA synergistically and reversibly promote beta cell proliferation in the context of nutrient-induced insulin resistance. METHODS: Using 72 h infusions of glucose (GLU) or the oleate-enriched lipid emulsion ClinOleic (CLI), singly or in combination, we assessed beta cell proliferation, islet mass and insulin sensitivity in male Lewis rats. The effects of nutrients and endogenous circulating factors were examined in isolated and transplanted islets. Reversibility was studied 3 and 6 days after the end of the infusion. RESULTS: GLU infusions modestly stimulated beta cell proliferation, CLI alone had no effect and GLU+CLI infusions markedly stimulated beta cell proliferation. Insulin sensitivity was equally decreased in GLU and GLU+CLI infusions. GLU+CLI infusions also stimulated beta cell proliferation in islets transplanted under the kidney capsule, albeit to a lesser extent compared with endogenous islets. Ex vivo, the combination of glucose and NEFA enhanced beta cell proliferation in rat and human islets independently from secreted insulin, and serum from GLU+CLI-infused rats potentiated the effect of glucose. Glucose tolerance, beta cell proliferation and islet mass were all restored to normal levels 6 days after termination of the infusion. CONCLUSIONS/INTERPRETATION: Glucose and NEFA synergistically and reversibly promote beta cell proliferation in part via direct action on the beta cell and independently from secreted insulin. PMID- 28078386 TI - Early differences in islets from prediabetic NOD mice: combined microarray and proteomic analysis. AB - AIMS/HYPOTHESIS: Type 1 diabetes is an endocrine disease where a long preclinical phase, characterised by immune cell infiltration in the islets of Langerhans, precedes elevated blood glucose levels and disease onset. Although several studies have investigated the role of the immune system in this process of insulitis, the importance of the beta cells themselves in the initiation of type 1 diabetes is less well understood. The aim of this study was to investigate intrinsic differences present in the islets from diabetes-prone NOD mice before the onset of insulitis. METHODS: The islet transcriptome and proteome of 2-3-week old mice was investigated by microarray and 2-dimensional difference gel electrophoresis (2D-DIGE), respectively. Subsequent analyses using sophisticated pathway analysis and ranking of differentially expressed genes and proteins based on their relevance in type 1 diabetes were performed. RESULTS: In the preinsulitic period, alterations in general pathways related to metabolism and cell communication were already present. Additionally, our analyses pointed to an important role for post-translational modifications (PTMs), especially citrullination by PAD2 and protein misfolding due to low expression levels of protein disulphide isomerases (PDIA3, 4 and 6), as causative mechanisms that induce beta cell stress and potential auto-antigen generation. CONCLUSIONS/INTERPRETATION: We conclude that the pancreatic islets, irrespective of immune differences, may contribute to the initiation of the autoimmune process. DATA AVAILABILITY: All microarray data are available in the ArrayExpress database ( www.ebi.ac.uk/arrayexpress ) under accession number E-MTAB-5264. PMID- 28078387 TI - Landowners' Perspectives on Coordinated, Landscape-Level Invasive Species Control: The Role of Social and Ecological Context. AB - To achieve biodiversity gains, landowner engagement in coordinated invasive species control programs across private lands is needed. Understanding landowners' perspectives toward such coordinated control efforts is crucial to facilitating engagement. We conducted in person and mail surveys of 68 landowners in and adjacent to the area of a proposed invasive predator control program in New Zealand. We find that, similar to previous studies, landowners consider the potential socioeconomic and ecological benefits of invasive species control and express a strong desire to enhance native biodiversity. However, we also find that landowners take into account the complexity of the local social and ecological context in which a program will unfold in three ways: they consider (1) the level of contribution by other landowners and urban residents who are benefiting from collective control efforts; (2) the potential for the program to upset the local "ecological balance", leading to increases in other pests; and (3) the probability that the program will be successful given the likelihood of others participating and control tactics being effective. We suggest that managers of coordinated invasive species control efforts may benefit from devoting time and resources toward addressing beliefs about social and ecological context, rather than solely providing financial subsidies and information about control tactics or the impacts of invasive species. PMID- 28078388 TI - High Stocking Density Controls Phillyrea Angustifolia in Mediterranean Grasslands. AB - Extensive grazing applied in the form of low instantaneous pressure over a long period is a widespread management practice in protected areas. However this kind of stocking method does not always achieve the expected results, in particular because it fails to limit colonization by woody plants.This is the case in the relict xero-halophytic grasslands of the northern Mediterranean coastal region, subjected to widespread colonization by the shrub Phillyrea angustifolia despite the presence of extensive grazing. In this study, we investigated, for an equal annual stocking rate, the respective impact of high stocking density applied over a short period (mob grazing) and low stocking density applied over a long period on both P. angustifolia and herbaceous cover, using an in situ experimental design run for 7 years. Only mob grazing was effective both in controlling the establishment and increasing the mortality of P. angustifolia individuals. We did not find any difference after the 7 years of experimentation between the two stocking methods with regard to the herbaceous community parameters tested: species richness, diversity, evenness, contribution of annual characteristic species. By contrast, the exclusion of domestic grazing led to a strong reduction of these values.The use of mob grazing may be well suited for meeting conservation goals such as maintaining open habitats in these grasslands. PMID- 28078389 TI - Responses of a Federally Endangered Songbird to Understory Thinning in Oak Juniper Woodlands. AB - Wildlife conservation and management on military lands must be accomplished in the context of military readiness, which often includes ground-based training that is perceived to conflict with wildlife needs and environmental regulations. From 2008-2012, we examined territory density, pairing success, and fledging success of the federally endangered golden-cheeked warbler (Setophaga chrysoparia; hereafter warbler) in relation to removal of small-diameter trees from the understory of mature oak-juniper (Quercus-Juniperus) woodland at the 87,890 ha Fort Hood Military Reservation in central Texas. Understory thinning created troop maneuver lanes, but left canopy vegetation intact. Warbler density, pairing success, and fledging success were similar across thinned and control sites. We found that warbler pairing and fledging success were best predicted by Ecological site (hereafter Ecosite), an indicator of hardwood tree species composition. Warbler pairing and fledging success were about 1.5 and 1.6 times higher, respectively, for territories dominated by the Low Stony Hill Ecosite than territories dominated by the Redlands Ecosite. Our results indicate that understory thinning for military training purposes did not have a negative effect on warblers at Fort Hood in the manner tested, and suggest that removal of smaller trees from the understory in a way that replicates historic conditions may elicit neutral responses from this forest-dependent songbird. Quantifying wildlife responses to military activities provides the Department of Defense and US Fish and Wildlife Service with data to guide conservation of threatened and endangered species on Department of Defense facilities while maintaining the military mission, and supports wildlife management efforts on other public and private lands. PMID- 28078390 TI - Group Development and Integration in a Cross-Disciplinary and Intercultural Research Team. AB - Cross-disciplinary research is necessary to solve many complex problems that affect society today, including problems involving linked social and environmental systems. Examples include natural resource management or scarcity problems, problematic effects of climate change, and environmental pollution issues. Intercultural research teams are needed to address many complex environmental matters as they often cross geographic and political boundaries, and involve people of different countries and cultures. It follows that disciplinarily and culturally diverse research teams have been organized to investigate and address environmental issues. This case study investigates a team composed of both monolingual and bilingual Chilean and US university researchers who are geoscientists, engineers and economists. The objective of this research team was to study both the natural and human parts of a hydrologic system in a hyper-arid region in northern Chile. Interviews (n = 8) addressed research questions focusing on the interaction of cross-disciplinary diversity and cultural diversity during group integration and development within the team. The case study revealed that the group struggled more with cross-disciplinary challenges than with intercultural ones. Particularly challenging ones were instances the of disciplinary crosstalk, or hidden misunderstandings, where team members thought they understood their cross-disciplinary colleagues, when in reality they did not. Results showed that translation served as a facilitator to cross-disciplinary integration of the research team. The use of translation in group meetings as a strategy for effective cross-disciplinary integration can be extended to monolingual cross-disciplinary teams as well. PMID- 28078391 TI - Soil Organic Carbon Fractions and Stocks Respond to Restoration Measures in Degraded Lands by Water Erosion. AB - Assessing the degree to which degraded soils can be recovered is essential for evaluating the effects of adopted restoration measures. The objective of this study was to determine the restoration of soil organic carbon under the impact of terracing and reforestation. A small watershed with four typical restored plots (terracing and reforestation (four different local plants)) and two reference plots (slope land with natural forest (carbon-depleted) and abandoned depositional land (carbon-enriched)) in subtropical China was studied. The results showed that soil organic carbon, dissolved organic carbon and microbial biomass carbon concentrations in the surface soil (10 cm) of restored lands were close to that in abandoned depositional land and higher than that in natural forest land. There was no significant difference in soil organic carbon content among different topographic positions of the restored lands. Furthermore, the soil organic carbon stocks in the upper 60 cm soils of restored lands, which were varied between 50.08 and 62.21 Mg C ha-1, were higher than 45.90 Mg C ha-1 in natural forest land. Our results indicated that the terracing and reforestation could greatly increase carbon sequestration and accumulation and decrease carbon loss induced by water erosion. And the combination measures can accelerate the restoration of degraded soils when compared to natural forest only. Forest species almost have no impact on the total amount of soil organic carbon during restoration processes, but can significantly influence the activity and stability of soil organic carbon. Combination measures which can provide suitable topography and continuous soil organic carbon supply could be considered in treating degraded soils caused by water erosion. PMID- 28078392 TI - Carbon footprint assessment of Western Australian Groundwater Recycling Scheme. AB - This research has determined the carbon footprint or the carbon dioxide equivalent (CO2 eq) of potable water production from a groundwater recycling scheme, consisting of the Beenyup wastewater treatment plant, the Beenyup groundwater replenishment trial plant and the Wanneroo groundwater treatment plant in Western Australia, using a life cycle assessment approach. It was found that the scheme produces 1300 tonnes of CO2 eq per gigalitre (GL) of water produced, which is 933 tonnes of CO2 eq higher than the desalination plant at Binningup in Western Australia powered by 100% renewable energy generated electricity. A Monte Carlo Simulation uncertainty analysis calculated a Coefficient of Variation value of 5.4%, thus confirming the accuracy of the simulation. Electricity input accounts for 83% of the carbon dioxide equivalent produced during the production of potable water. The chosen mitigation strategy was to consider the use of renewable energy to generate electricity for carbon intensive groundwater replenishment trial plant. Depending on the local situation, a maximum of 93% and a minimum of 21% greenhouse gas saving from electricity use can be attained at groundwater replenishment trial plant by replacing grid electricity with renewable electricity. In addition, the consideration of vibrational separation (V-Sep) that helps reduce wastes generation and chemical use resulted in a 4.03 tonne of CO2 eq saving per GL of water produced by the plant. PMID- 28078393 TI - Antipsychotic use is a risk factor for hyponatremia in patients with schizophrenia: a 15-year follow-up study. AB - RATIONALE: Hyponatremia affects 10% of patients with chronic schizophrenia and can lead to severe consequences. However, the role of antipsychotics and other risk factors in hyponatremia occurrence has remained inconsistent. OBJECTIVE: This study examined the association between antipsychotic use and hyponatremia occurrence in patients with schizophrenia. METHODS: We utilized the National Health Insurance Research Database to follow 2051 patients with schizophrenia from 1998 to 2013. Among them, 137 (6.7%) developed hyponatremia. Sociodemographic characteristics, physical comorbidities, and psychiatric treatment experiences were compared between those who had hyponatremia and those who did not. A Cox proportional hazards model was used to examine the hazard ratios (HRs) of these characteristics. RESULTS: In patients with hyponatremia, the mean age at first hyponatremia occurrence was 54.7 +/- 13.9 years, an average of 9.5 +/- 4.0 years after schizophrenia diagnosis, and 32.9% of them were off antipsychotics before hyponatremia occurrences. Age at schizophrenia diagnosis (HR = 1.1), low-income household (HR = 2.4), comorbidities (HR = 1.2), and psychiatric admissions (HR = 1.04) were associated with the risks of hyponatremia. Compared with no antipsychotic use, atypical (HR = 2.1) and typical antipsychotics (HR = 3.1) were associated with an elevated risk of hyponatremia, after adjustment for age, sex, and physical comorbidities. Carbamazepine use (HR = 2.9) was also a significant risk factor for hyponatremia (p < 0.05). CONCLUSIONS: Antipsychotic use in patients with schizophrenia with polypharmacy should be monitored for hyponatremia occurrences. Clinicians should pay attention to the impact of poor living conditions on hyponatremia occurrence. PMID- 28078394 TI - Kinematics of a bicruciate-retaining total knee arthroplasty. AB - PURPOSE: The recently reintroduced bicruciate-retaining Total Knee Arthroplasty (BCR TKA) is an interesting approach in the quest for close replication of knee joint biomechanics and kinematics closer to the native knee. Therefore, this study aimed at providing a detailed biomechanical view on the functional resemblance of BCR TKA to the native knee joint. METHODS: Seven fresh-frozen full leg cadaver specimens (76 +/- 10 year) were mounted in a 6 degrees-of-freedom kinematic rig that applied a dynamic squatting motion knee flexion. Two motion patterns were performed pre- and post-implantation of a fixed bearing BCR TKA: passive flexion-extension and squatting while an infrared camera system tracked the location of reflective markers attached to the tibia and femur. Additionally, specimen laxity was assessed using Lachman tests and varus/valgus stress tests in triplicate. RESULTS: Overall, differences in tibiofemoral kinematics between native knee and BCR TKA were small. Some minor differences appeared under the load of a squat: less internal tibial rotation and some minor paradoxical anterior translation of the medial femoral condyle during mid-flexion. BCR TKA may slightly elevate the joint line. Knee laxity as measured by the Lachman and varus/valgus tests was not significantly influenced by BCR TKA implantation. CONCLUSION: As both cruciate ligaments are preserved with BCR TKA the unloaded knee closely resembles native knee kinematics including preserving the rollback mechanism. The loss of the conforming anatomy of menisci and tibial cartilage and replacement via a relatively flat polyethylene inlay may account for the loss of tibial internal rotation and the slight paradoxical AP motion of the medial femoral condyle with BCR TKA. This phenomenon reproduces findings made earlier with fixed bearing unicondylar knee arthroplasty. PMID- 28078395 TI - High production of 2,3-butanediol from glycerol without 1,3-propanediol formation by Raoultella ornithinolytica B6. AB - Conversion of crude glycerol derived from biodiesel processes to value-added chemicals has attracted much attention. Herein, Raoultella ornithinolytica B6 was investigated for the high production of 2,3-butanediol (2,3-BD) from glycerol without 1,3-propanediol (1,3-PD) formation, a by-product hindering 2,3-BD purification. By evaluating the effects of temperature, agitation speed, and pH control strategy, the fermentation conditions favoring 2,3-BD production were found to be 25 degrees C, 400 rpm, and pH control with a lower limit of 5.5, respectively. Notably, significant pH fluctuations which positively affect 2,3-BD production were generated by simply controlling the lower pH limit at 5.5. In fed batch fermentation under those conditions, R. ornithinolytica B6 produced 2,3-BD up to 79.25 g/L, and further enhancement of 2,3-BD production (89.45 g/L) was achieved by overexpressing homologous 2,3-BD synthesis genes (the budABC). When pretreated crude glycerol was used as a sole carbon source, R. ornithinolytica B6 overexpressing budABC produced 78.10 g/L of 2,3-BD with the yield of 0.42 g/g and the productivity of 0.62 g/L/h. The 2,3-BD titer, yield, and productivity values obtained in this study are the highest 2,3-BD production from glycerol among 1,3 PD synthesis-deficient 2,3-BD producers, demonstrating R. ornithinolytica B6 as a promising 2,3-BD producer from glycerol. PMID- 28078396 TI - A genetic method to enhance the accumulation of S-adenosylmethionine in yeast. AB - S-Adenosylmethionine (SAM) is a key component of sulphur amino acid metabolism in living organisms and is synthesised from methionine and adenosine triphosphate by methionine adenosyltransferase. This molecule serves as the main biological methyl donor due to its active methylthio ether group. Notably, SAM has shown beneficial effects in clinical trials for the treatment of alcoholic liver disease, depression and joint pain. Due to the high potential value of SAM, current research efforts are attempting to develop a more rapid, cost-effective and higher yielding SAM production method than the conventional production system. In this mini-review, we describe the previously reported yeast gene that contributes to SAM accumulation by overexpression, mutation or deletion and summarise the genetic approach for the production of SAM in large industrial quantities. PMID- 28078398 TI - Potential coupling effects of ammonia-oxidizing and anaerobic ammonium-oxidizing bacteria on completely autotrophic nitrogen removal over nitrite biofilm formation induced by the second messenger cyclic diguanylate. AB - The objective of this study was to investigate the influence of extracellular polymeric substance (EPS) on the coupling effects between ammonia-oxidizing bacteria (AOB) and anaerobic ammonium-oxidizing (anammox) bacteria for the completely autotrophic nitrogen removal over nitrite (CANON) biofilm formation in a moving bed biofilm reactor (MBBR). Analysis of the quantity of EPS and cyclic diguanylate (c-di-GMP) confirmed that the contents of polysaccharides and c-di GMP were correlated in the AOB sludge, anammox sludge, and CANON biofilm. The anammox sludge secreted more EPS (especially polysaccharides) than AOB with a markedly higher c-di-GMP content, which could be used by the bacteria to regulate the synthesis of exopolysaccharides that are ultimately used as a fixation matrix, for the adhesion of biomass. Indeed, increased intracellular c-di-GMP concentrations in the anammox sludge enhanced the regulation of polysaccharides to promote the adhesion of AOB and formation of the CANON biofilm. Overall, the results of this study provide new comprehensive information regarding the coupling effects of AOB and anammox bacteria for the nitrogen removal process. PMID- 28078397 TI - Optimized synthesis of novel prenyl ferulate performed by feruloyl esterases from Myceliophthora thermophila in microemulsions. AB - Five feruloyl esterases (FAEs; EC 3.1.1.73), FaeA1, FaeA2, FaeB1, and FaeB2 from Myceliophthora thermophila C1 and MtFae1a from M. thermophila ATCC 42464, were tested for their ability to catalyze the transesterification of vinyl ferulate (VFA) with prenol in detergentless microemulsions. Reaction conditions were optimized investigating parameters such as the medium composition, the substrate concentration, the enzyme load, the pH, the temperature, and agitation. FaeB2 offered the highest transesterification yield (71.5 +/- 0.2%) after 24 h of incubation at 30 degrees C using 60 mM VFA, 1 M prenol, and 0.02 mg FAE/mL in a mixture comprising of 53.4:43.4:3.2 v/v/v n-hexane:t-butanol:100 mM MOPS-NaOH, pH 6.0. At these conditions, the competitive side hydrolysis of VFA was 4.7-fold minimized. The ability of prenyl ferulate (PFA) and its corresponding ferulic acid (FA) to scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals was significant and similar (IC50 423.39 MUM for PFA, 329.9 MUM for FA). PFA was not cytotoxic at 0.8-100 MUM (IC50 220.23 MUM) and reduced intracellular reactive oxygen species (ROS) in human skin fibroblasts at concentrations ranging between 4 and 20 MUM as determined with the dichloro-dihydro-fluorescein diacetate (DCFH DA) assay. PMID- 28078399 TI - FIP-sch2, a new fungal immunomodulatory protein from Stachybotrys chlorohalonata, suppresses proliferation and migration in lung cancer cells. AB - Fungal immunomodulatory protein (FIP)-sch2, an immunomodulatory protein identified in the ascomycete Stachybotrys chlorohalonata by a sequence similarity search, is a novel member of the FIP family. FIP-sch2 shares high sequence identity, structure, and evolutionary conservation with previously reported FIPs. It was satisfactorily expressed in Escherichia coli with a glutathione S transferase (GST) tag and purified by GST-affinity magnetic beads. To characterize the direct antitumor effects, human lung adenocarcinoma A549 cells were treated with different concentrations of recombinant FIP (rFIP)-sch2 in vitro, and the results showed that rFIP-sch2 could reduce cell viability dose dependently with a half-maximal inhibitory concentration (IC50) of 9.48 MUg/mL. Furthermore, rFIP-sch2 at 8 MUg/mL could significantly induce apoptosis and interrupt migration in A549 cells. Notably, the antitumor effect of rFIP-sch2 was equivalent to that of rLZ-8 but was obviously increased compared to rFIP-fve. In addition, the exploration of the antitumor mechanism suggested that rFIP-sch2 induced lung cancer cell death by activating apoptosis and inhibiting migration. Our results indicated that rFIP-sch2 was a promising candidate for use in future cancer therapy. PMID- 28078401 TI - [The pregnant surgeon : Scope and limitations of employment prohibition according to the draft of the new Maternity Protection Act ("Mutterschutzgesetz", MuSchG E)]. PMID- 28078400 TI - Characterization of four endophytic fungi as potential consolidated bioprocessing hosts for conversion of lignocellulose into advanced biofuels. AB - Recently, several endophytic fungi have been demonstrated to produce volatile organic compounds (VOCs) with properties similar to fossil fuels, called "mycodiesel," while growing on lignocellulosic plant and agricultural residues. The fact that endophytes are plant symbionts suggests that some may be able to produce lignocellulolytic enzymes, making them capable of both deconstructing lignocellulose and converting it into mycodiesel, two properties that indicate that these strains may be useful consolidated bioprocessing (CBP) hosts for the biofuel production. In this study, four endophytes Hypoxylon sp. CI4A, Hypoxylon sp. EC38, Hypoxylon sp. CO27, and Daldinia eschscholzii EC12 were selected and evaluated for their CBP potential. Analysis of their genomes indicates that these endophytes have a rich reservoir of biomass-deconstructing carbohydrate-active enzymes (CAZys), which includes enzymes active on both polysaccharides and lignin, as well as terpene synthases (TPSs), enzymes that may produce fuel-like molecules, suggesting that they do indeed have CBP potential. GC-MS analyses of their VOCs when grown on four representative lignocellulosic feedstocks revealed that these endophytes produce a wide spectrum of hydrocarbons, the majority of which are monoterpenes and sesquiterpenes, including some known biofuel candidates. Analysis of their cellulase activity when grown under the same conditions revealed that these endophytes actively produce endoglucanases, exoglucanases, and beta-glucosidases. The richness of CAZymes as well as terpene synthases identified in these four endophytic fungi suggests that they are great candidates to pursue for development into platform CBP organisms. PMID- 28078402 TI - [Certificate, certification, certificateitis : Not every certificate delivers all it promises]. PMID- 28078403 TI - [Chief surgeon surgery only with a chief surgeon? : Liability in cases of inadmissible representation]. PMID- 28078404 TI - [Caution in the face of medical invoice recommendations : Violation of competition law by specialist medical professional organizations and societies]. PMID- 28078406 TI - [Temporary hearing threshold shift (TTS) caused by impulse noise]. PMID- 28078405 TI - [Radiosurgery and fractionated stereotactic radiotherapy of vestibular schwannoma]. AB - Management of vestibular schwannoma (VS) should always be interdisciplinary and results better than the natural course. Particularly in small VS, either microsurgical resection or radiosurgery (RS) can be employed. RS is a special method (initially only possible stereotactically) for delivering high-precision radiation from many directions to the target point (the isocenter) in a single high dose. With the development of three different systems-Gamma Knife (Elekta, Stockholm, Sweden), special linear accelerators, and CyberKnife (Accuray, Sunnyvale, CA, USA)-the options were extended to 1-5 fractions for RS and multisession RS (msRS), and to up to 6 weeks of conventional fractionation as stereotactic radiotherapy (SRT). Whereas RS uses high ablative single doses, SRT is based on the well-known radiobiological effects of multiple fractions comprising lower single doses up to a required much higher total dose. Evaluation showed that RS and SRT achieve similarly high rates of tumor control of around 90% and low rates of side effects (1-7%). Therefore, SRT is unnecessary for small but clearly progressing VS, which has made RS a very comfortable, effective treatment option. In addition to SRT, larger VS can be treated comparably effectively with CyberKnife-based msRS. Since modern MRI frequently discovers small VS as "incidental findings", the initial biding strategy (wait and scan) is of particular importance. Only with increasing symptoms and detectable tumor growth is the treatment indication established, at which time the decision for surgery and RS/SRT should be taken interdisciplinary under consideration of the patient's wishes. PMID- 28078408 TI - [Rehabilitation in children and adults : An overview]. AB - BACKGROUND: The rehabilitation of patients with hearing loss includes technical, medical, and therapeutic education interventions. The success of cochlear implant (CI) treatment depends on joint coordination and execution of all measures. During the history of CI, expansion of the spectrum of indication criteria has led to evolution of auditory-verbal therapy, speech therapy, and auditory training. MATERIALS AND METHODS: This paper describes the current status of therapeutic knowledge and experience of hearing and speech therapeutic rehabilitation in children and adults. Current treatments and quality assurance measures are presented. RESULTS: Effective auditory-verbal rehabilitation of children and auditory training in adults depends on individual objectives. In addition to subjective patient reports, the success of CI fitting is regularly monitored using specific tests. Therapeutic approaches that enhance the communication skills of children and adults are described in a structured manner. Established tests and their application in treatment, educational diagnostics, aftercare, and quality assurance complement the description. CONCLUSION: Within an interdisciplinary team, structured auditory-verbal therapeutic interventions and reliable testing are crucial for documenting individual outcomes, discussing these compared to the expected result, and counselling the patient in terms of further therapeutic measures. PMID- 28078407 TI - [Diagnostic accuracy of outpatient polygraphy devices : A comparison with inpatient polysomnography in clinical routine]. AB - BACKGROUND: Cardiorespiratory polysomnography (PSG) is considered the reference method for diagnosis of obstructive sleep apnea (OSA). Due to waiting times and high costs, payers increasingly request outpatient polygraphy (PG) as an alternative to inpatient PSG. The aim of the present study was to evaluate the diagnostic accuracy of different outpatient PG devices compared to stationary PSG in clinical practice. MATERIALS AND METHODS: Externally collected outpatient PG findings of 406 patients were retrospectively compared with the corresponding PSG findings. RESULTS: Among the 406 patients were 343 men (85%) and 63 women (15%), with mean age 50 years. Mean body mass index (BMI) was 30 kg/m2. The rank correlation coefficient for PG- and PSG- derived apnea-hypopnea index (AHI) values was r = 0.574. On average, PG underestimated the AHI by 6.4 (+/-20.5) events/h. OSAS severity was determined correctly by PG in only 43% of cases. Sensitivity (90.7%) and specificity (45.2%) of ambulatory PG was calculated for the threshold value AHI >= 5/h. Based on the results of PG, an indicated therapy would have been omitted in 35 cases (9%) and unnecessary treatment initiated in 17 cases (4%). The PG devices used showed a comparable diagnostic accuracy (r = 0.513-0.657), with a sensitivity of 81.3-96.9% and a specificity of 33.3-50.0%. CONCLUSION: Outpatient PG cannot reliably assess OSA severity in clinical routine. Confirmation by PSG in a sleep lab in symptomatic patients is obligatory. Outpatient PG devices should only be used as an upstream screening method. The automatic evaluation of the PG should always be proofed. PMID- 28078409 TI - Determination of molecular size parameters and quantification of polyacrylic acid by high performance size-exclusion chromatography with triple detection. AB - Synthetic polyelectrolytes are a broad class of vaccine adjuvants. Among them, polyacrylic acid (PAA), a polyanionic polymer, is currently evaluated by Sanofi Pasteur. As chain length is considered to be a critical quality attribute for adjuvant properties of PAA, measurement of precise and accurate molecular size parameters is important for these polymers. In the field of synthetic polymer chemistry, methods for determination of molecular size parameters are well defined. Specifically, high performance size-exclusion chromatography (HPSEC) with multi-detection system is a method of choice. This paper describes the development of HPSEC method to well characterize and precisely quantify PAA in different adjuvant formulations. A first set of characterizations were made, with determination of dn/dc coefficient, which enabled the determination of weight- and number-average molecular weight, viscosimetric radius, and intrinsic viscosity. In-depth characterization was also made with branching study through the use of Mark-Houwink parameter determination. The quantification method was also evaluated according to validation method-like criteria: limit of detection and limit of quantification, repeatability, accuracy, and specificity with recombinant surface glycoprotein gB from human cytomegalovirus (CMV-gB) as model antigen. PMID- 28078410 TI - Effects of direct current electric fields on lung cancer cell electrotaxis in a PMMA-based microfluidic device. AB - Tumor metastasis is the primary cause of cancer death. Numerous studies have demonstrated the electrotactic responses of various cancer cell types, and suggested its potential implications in metastasis. In this study, we used a microfluidic device to emulate endogenous direct current electric field (dcEF) environment, and studied the electrotactic migration of non-small cell lung cancer cell lines (H460, HCC827, H1299, and H1975) and the underlying mechanisms. These cell lines exhibited greatly different response in applied dcEFs (2-6 V/cm). While H460 cells (large cell carcinoma) showed slight migration toward cathode, H1299 cells (large cell carcinoma) showed increased motility and dcEF dependent anodal migration with cell reorientation. H1975 cells (adenocarcinoma) showed dcEF-dependent cathodal migration with increased motility, and HCC827 cells (adenocarcinoma) responded positively in migration speed and reorientation but minimally in migrating directions to dcEF. Activation of MAPK and PI3K signaling pathways was found to be associated with the realignment and directed migration of lung cancer cells. In addition, both Ca2+ influx through activated stretch-activated calcium channels (SACCs) (but not voltage-gated calcium channels, VGCCs) and Ca2+ release from intracellular storage were involved in lung cancer cell electrotactic responses. The results demonstrated that the microfluidic device provided a stable and controllable microenvironment for cell electrotaxis study, and revealed that the electrotactic responses of lung cancer cells were heterogeneous and cell-type dependent, and multiple signals contributed to lung cancer cells electrotaxis. PMID- 28078411 TI - In vitro and in silico assessment of the structure-dependent binding of bisphenol analogues to glucocorticoid receptor. AB - Widespread use of bisphenol A (BPA) and other bisphenol analogues has attracted increasing attention for their potential adverse effects. As environmental endocrine-disrupting compounds (EDCs), bisphenols (BPs) may activate a variety of nuclear receptors, including glucocorticoid receptor (GR). In this work, the binding of 11 BPs to GR was investigated by fluorescence polarization (FP) assay in combination with molecular dynamics simulations. The human glucocorticoid receptor was prepared as a soluble recombinant protein. A fluorescein-labeled dexamethasone derivative (Dex-fl) was employed as tracer. Competitive displacement of Dex-fl from GR by BPs showed that the binding affinities of bisphenol analogues were largely dependent on their characteristic functional groups. In order to further understand the relationship between BPs structures and their GR-mediated activities, molecular docking was utilized to explore the binding modes at the atomic level. The results confirmed that structural variations of bisphenol analogues contributed to different interactions of BPs with GR, potentially causing distinct toxic effects. Comparison of the calculated binding energies vs. experimental binding affinities yielded a good correlation (R 2 = 0.8266), which might be helpful for the design of environmentally benign materials with reduced toxicities. In addition, the established FP assay based on GR exhibited the potential to offer an alternative to traditional methods for the detection of bisphenols. PMID- 28078412 TI - Simultaneous determination of four food allergens using compact disc immunoassaying technology. AB - A multiplex competitive microimmunoassay for the simultaneous determination of gliadin, casein, beta-lactoglobulin, and ovalbumin is presented. The assay in microarray format is performed on a DVD where the allergens are physisorbed on the polycarbonate surface of the disc. The immunointeraction is detected using a mixture of specific gold-labeled antibodies and the signal amplified with the silver enhancement method. The optical density of the precipitate, read by a DVD drive, is related to the concentration of the four allergens in sample. An optimized protocol for the simultaneous extraction of the allergen proteins from food samples is also addressed. The suitability of the method is demonstrated for the simultaneous quantitative extraction and determination of the targeted allergens in spiked baby foods, juices, and beers. The sensitivity (EC50) of the multiplexed assay was 0.04, 0.40, 0.08, and 0.16 mg L-1 for gliadin, casein, beta lactoglobulin, and ovalbumin, respectively, and the recovery results from the analysis of food samples ranged from 72 to 117%. A portable, easy-to-use, array based bioanalytical method is developed for quantification of food allergens with a limit of detection below the accepted levels of the international legislations, which allows promotion of food safety and quality. Graphical abstract GLI Gliadin, CAS Casein, beta-LAC beta-lactoglobulin, OVA Ovalbumin. PMID- 28078413 TI - Establishment of a sandwich enzyme-linked immunosorbent assay for specific detection of Bacillus thuringiensis (Bt) Cry1Ab toxin utilizing a monoclonal antibody produced with a novel hapten designed with molecular model. AB - Cry1Ab toxin is commonly expressed in genetically modified crops in order to control chewing pests. At present, the detection method with enzyme-linked immunosorbent assay (ELISA) based on monoclonal antibody cannot specifically detect Cry1Ab toxin for Cry1Ab's amino acid sequence and spatial structure are highly similar to Cry1Ac toxin. In this study, based on molecular design, a novel hapten polypeptide was synthesized and conjugated to keyhole limpet hemocyanin (KLH). Then, through animal immunization with this antigen, a monoclonal antibody named 2C12, showing high affinity to Cry1Ab and having no cross reaction with Cry1Ac, was produced. The equilibrium dissociation constant (K D) value of Cry1Ab toxin with MAb 2C12 was 1.947 * 10-8 M. Based on this specific monoclonal antibody, a sandwich enzyme-linked immunosorbent assay (DAS-ELISA) was developed for the specific determination of Cry1Ab toxin and the LOD and LOQ values were determined as 0.47 +/- 0.11 and 2.43 +/- 0.19 ng mL-1, respectively. The average recoveries of Cry1Ab from spiked rice leaf and rice flour samples ranged from 75 to 115%, with coefficient of variation (CV) less than 8.6% within the quantitation range (2.5-100 ng mL-1), showing good accuracy for the quantitative detection of Cry1Ab toxin in agricultural samples. In conclusion, this study provides a new approach for the production of high specific antibody and the newly developed DAS-ELISA is a useful method for Cry1Ab monitoring in agriculture products. Graphical Abstract Establishment of a DAS-ELISA for the specific detecting of Bacillus thuringiensis (Bt) Cry1Ab toxin. PMID- 28078414 TI - Application of HS-SPME-GC-MS method for the detection of active moulds on historical parchment. AB - The goal of this work was to analyse the profile of microbial volatile organic compounds (MVOCs) emitted by moulds growing on parchment samples, in search of particular volatiles mentioned in the literature as indicators of active mould growth. First, the growth of various moulds on samples of parchment was assessed. Those species that showed collagenolytic activity were then inoculated on two types of media: samples of parchment placed on media and on media containing amino acids that are elements of the structure of collagen. All samples were prepared inside 20-ml vials (closed system). In the first case, the media did not contain any sources of organic carbon, nitrogen, or sulphur, i.e. parchment was the only nutrient for the moulds. A third type of sample was historical parchment prepared in a Petri dish without a medium and inoculated with a collagenolytically active mould (open system). The MVOCs emitted by moulds were sampled with the headspace-SPME method. Volatiles extracted on DVB/CAR/PDMS fibres were analysed in a gas chromatography-mass spectrometry system. Qualitative and quantitative analyses of chromatograms were carried out in search of indicators of metabolic activity. The results showed that there are three groups of volatiles that can be used for the detection of active forms of moulds on parchment objects. To the best of our knowledge, this is the first work to measure MVOCs emitted by moulds growing on parchment. PMID- 28078415 TI - GC-MS method validation and levels of methyl eugenol in a diverse range of tea tree (Melaleuca alternifolia) oils. AB - Tea tree oil distilled from Melaleuca alternifolia has widespread use in the cosmetic industry as an antimicrobial as well as for other functions in topical products. Concerns were first raised by the European Commission's Scientific Committee on Consumer Products in 2004 about the level of the potentially carcinogenic phenylpropanoid compound methyl eugenol in tea tree oil. Limits on oil content in different types of cosmetic products were set based on a reported upper level of 0.9% methyl eugenol in the oil. A previous publication indicated that these levels were based on oil from a Melaleuca species not used in the commercial production of oil. Even the highest recorded levels in Melaleuca alternifolia, the overwhelmingly most common species used, were ~15 times less than this, meaning that more oil could be safely used in the products. The current study, including details on methodology and reproducibility, extends that work across a suite of 57 plantation-sourced oils from a range of geographical locations and production years, as well as many Australian and international commercial oils. Lower levels of methyl eugenol in oils of known provenance were confirmed, with a recorded range of 160-552 ppm and a mean of 337 ppm. Analysis of variance showed methyl eugenol levels in Australian plantation oils to be correlated to the geographical region but not to the year of production. Average methyl eugenol levels in commercial oils were significantly lower, and these samples were divided into an authentic group and a group that were suspected of being adulterated based on an independent test. Authentic commercial oils had similar levels of methyl eugenol to Australian provenance material, whilst the oils classed as suspect had significantly lower levels. PMID- 28078416 TI - Poly(ethylene glycol) functionalization of monolithic poly(divinyl benzene) for improved miniaturized solid phase extraction of protein-rich samples. AB - Non-specific protein adsorption on hydrophobic solid phase extraction (SPE) adsorbents can reduce the efficacy of purification. To improve sample clean-up, poly(divinyl benzene) (PDVB) monoliths grafted with hydrophilic polyethylene glycol methacrylate (PEGMA) were developed. Residual vinyl groups (RVGs) of the PDVB were employed as anchor points for PEGMA grafting. Two PEGMA monomers, M n 360 and 950, were compared for graft solutions containing 5-20% monomer. Protein binding was qualitatively screened using fluorescently labeled human serum albumin (HSA) to determine optimal PEGMA concentration. The fluorescent signal of PDVB was reduced for PDVB-g-PEGMA360 (10%) and PDVB-g-PEGMA950 (20%). The PEGMA content (w/w%) was quantified by solid state 1H NMR to be 29.9 +/- 1.6% for PDVB g-PEGMA360 and 7.7 +/- 1.2% for PDVB-g-PEGMA950. To assess adsorbent performance breakthrough curves for PDVB, PDVB-g-PEGMA360 and PDVB-g-PEGMA950 were compared. The breakthrough volume (V B) and shape of the curve for PDVB-g-PEGMA950 were maintained relative to PDVB (2.3 and 2.8 mL, respectively). A reduced V B of 0.5 mL and shallow breakthrough curve indicated PDVB-g-PEGMA360 was not suitable for SPE. A high ibuprofen recovery of 92 +/- 0.30 and 78 +/- 0.93% was seen for PDVB and PDVB-g-PEGMA950, respectively. Protein adsorption was reduced from 31 +/- 2.41 to 12 +/- 0.49% for PDVB and PDVB-g-PEGMA950, respectively. SPE of ibuprofen from plasma was compared for PDVB and PDVB-g-PEGMA950 by at-line electrospray ionization mass spectrometry (ESI-MS). PDVB-g-PEGMA950 demonstrated a threefold increase in assay sensitivity indicating a superior analyte purification. PMID- 28078417 TI - Covalent organic framework-coated magnetic graphene as a novel support for trypsin immobilization. AB - Deep and efficient proteolysis is the critical premise in mass spectrometry-based bottom-up proteomics. It is difficult for traditional in-solution digestion to meet the requirement unless prolonged digestion time and enhanced enzyme dosage are employed, which makes the whole workflow time-consuming and costly. The abovementioned problems could be effectively ameliorated by anchoring many proteases on solid supports. In this work, covalent organic framework-coated magnetic graphene (MG@TpPa-1) was designed and prepared as a novel enzyme carrier for the covalent immobilization of trypsin with a high degree of loading (up to 268 MUg mg-1). Profiting from the advantages of magnetic graphene and covalent organic frameworks, the novel trypsin bioreactor was successfully applied for the enzymatic digestion of a model protein with dramatically improved digestion efficiency, stability, and reusability. Complete digestion could be achieved in a time period as short as 2 min. For the digestion of proteins extracted from Amygdalus pedunculata, a total of 2833 protein groups were identified, which was slightly more than those obtained by 12 h of in-solution digestion (2739 protein groups). All of the results demonstrate that MG@TpPa-1-trypsin is an excellent candidate for sample preparation in a high-throughput proteomics analysis. Graphical abstract Covalent organic frameworks-coated magnetic graphene was prepared as novel carrier for highly efficient tryptic immobilization. PMID- 28078418 TI - Absolute quantification of myosin heavy chain isoforms by selected reaction monitoring can underscore skeletal muscle changes in a mouse model of amyotrophic lateral sclerosis. AB - Skeletal muscle fibers contain different isoforms of myosin heavy chain (MyHC) that define distinctive contractile properties. In light of the muscle capacity to adapt MyHC expression to pathophysiological conditions, a rapid and quantitative assessment of MyHC isoforms in small muscle tissue quantities would represent a valuable diagnostic tool for (neuro)muscular diseases. As past protocols did not meet these requirements, in the present study we applied a targeted proteomic approach based on selected reaction monitoring that allowed the absolute quantification of slow and fast MyHC isoforms in different mouse skeletal muscles with high reproducibility. This mass-spectrometry-based method was validated also in a pathological specimen, by comparison of the MyHC expression profiles in different muscles from healthy mice and a genetic mouse model of amyotrophic lateral sclerosis (ALS) expressing the SOD1(G93A) mutant. This analysis showed that terminally ill ALS mice have a fast-to-slow shift in the fiber type composition of the tibialis anterior and gastrocnemius muscles, as previously reported. These results will likely open the way to accurate and rapid diagnoses of human (neuro)muscular diseases by the proposed method. Graphical Abstract Methods for myosin heavy chain (MyHC) quantification: a comparison of classical methods and selected reaction monitoring (SRM)-based mass spectrometry approaches. PMID- 28078419 TI - Nanostructured NiO-based reagentless biosensor for total cholesterol and low density lipoprotein detection. AB - Nanostructured nickel oxide (NiO) thin film has been explored as a matrix to develop a reagentless biosensor for free and total cholesterol as well as low density lipoprotein (LDL) detection. The redox property of the matrix has been exploited to enhance the electron transfer between the enzyme and the electrode as well as to eliminate the toxic mediator in solution. X-ray diffraction, scanning electron microscopy, atomic force microscopy, and Fourier transform infrared spectroscopy were carried out to characterize the NiO thin film. Biosensing response studies were accomplished using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and differential pulse voltammetry (DPV). The developed biosensors exhibited a high sensitivity of 27 and 63 MUA/mM/cm2 over a linear range of 0.12-10.23 and 1-12 mM, respectively, for free and total cholesterol. Reagentless estimation of LDL was also achieved over the wide range 0.018-0.5 MUM with a sensitivity of 0.12 mA/MUM/cm2. The results are extremely promising for the realization of an integrated biosensor for complete detection of cholesterol in the serum samples. Graphical Abstract Reagentless sensing mechanism of (a) free cholesterol and (b) total cholesterol using nanostructured NiO matrix. PMID- 28078420 TI - Comprehensive polyphenol profiling of a strawberry extract (Fragaria * ananassa) by ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry. AB - The aim of metabolic untargeted profiling is to detect and identify unknown compounds in a biological matrix to achieve the most comprehensive metabolic coverage. In phytochemical mixtures, however, the complexity of the sample could present significant difficulties in compound identification. In this case, the optimization of both the chromatographic and the mass-spectrometric conditions is supposed to be crucial for the detection and identification of the largest number of compounds. In this work, a systematic investigation of different chromatographic and mass-spectrometric conditions is presented to achieve a comprehensive untargeted profiling of a strawberry extract (Fragaria * ananassa). To fulfill this aim, an ultra-high-pressure liquid chromatography system coupled via an electrospray source to a hybrid quadrupole-Orbitrap mass spectrometer was used. Spectra were acquired in data-dependent mode, and several parameters were investigated to acquire the largest possible number of both mass spectrometry (MS) features and MS2 mass spectra for unique metabolites. The main classes of polyphenols studied were flavonoids, phenolic acids, dihydrochalcones, ellagitannins, and proanthocyanidins. Method optimization allowed to us identify and tentatively identify 18 and 113 compounds, respectively, among which 74 have never been reported before in strawberries and, to the best of our knowledge, 22 of them have never been reported before. The results show the importance of an extended investigation of the chromatographic and mass-spectrometric method before a complete untargeted profiling of complex phytochemical mixtures. PMID- 28078421 TI - [Editorial]. PMID- 28078422 TI - [PREFERE - the failure of an (almost) perfect study : Does the human factor interfere when answering highly complex questions?] PMID- 28078423 TI - [Sexual medicine in daily practice : Germany-wide questionnaire of urologists]. AB - BACKGROUND: Sexual-related problems are very prevalent. Physicians of different disciplines are frequently contacted by men with those problems. OBJECTIVES: The aim of this study was to investigate the situation of sexual medicine in daily practice and to evaluate German urologists' need for further training in this field with a focus on gender-specific differences. MATERIALS AND METHODS: A five page questionnaire included questions about sexual medicine in daily practice. A focus was set on physicians dealing with sexual medicine in daily practice and their need for further training in this field. In April/Mai 2015, questionnaires were sent per mail to 5955 urologists, urology residents and andrologists throughout Germany. The questionnaire was developed based on previously published studies and a pretest was performed to evaluate comprehensibility. A chi2 test was performed to determine significant gender-specific differences; for this propose response options were dichotomised. P values <=0.05 were considered significant. RESULTS: The response rate was 16.0%, representing 955 questionnaires. A total of 50 questionnaires from non-urologists were excluded, so 905 questionnaires were analysed. The mean age was 47.7 +/- 10.4 years, 78.9% were male, 97.0% had studied in Germany, 86.7% were specialists and 37.7% had further qualification in andrology. CONCLUSION: Our results emphasize the need for further training in sexual medicine, especially for female physicians. This study underlines the demand for advanced qualification in sexual medicine. PMID- 28078424 TI - [Adjuvant chemotherapy for invasive bladder cancer (individual patient data)]. PMID- 28078425 TI - Odorant receptors and antennal lobe morphology offer a new approach to understanding olfaction in the Asian longhorned beetle. AB - The Asian longhorned beetle Anoplophora glabripennis (Motchulsky) is an exotic forest pest that has repeatedly invaded North America and Europe from Asia, and has the potential to kill millions of trees and cause billions of dollars in damage. Traps baited with an attractive mixture of volatile organic compounds from hosts have been of limited success in monitoring invasion sites. We propose that lures might be improved through studying the olfactory system of adult beetles, especially the gene family of odorant receptors (ORs) and the structure of the antennal lobes of the brain. Here, we report identification of 132 ORs in the genome of A. glabripennis (inclusive of one Orco gene and 11 pseudogenes), some of which are orthologous to known pheromone receptors of other cerambycid beetles. We also identified three ORs that are strongly biased toward expression in the female transcriptome, and a single OR strongly biased toward males. Three dimensional reconstruction of the antennal lobes of adults suggested a male specific macroglomerulus and several enlarged glomeruli in females. We predict that functional characterization of ORs and glomeruli will lead to identification of key odorants in the life history of A. glabripennis that may aid in monitoring and controlling future invasions. PMID- 28078426 TI - Calreticulin is required for calcium homeostasis and proper pollen tube tip growth in Petunia. AB - MAIN CONCLUSION: Calreticulin is involved in stabilization of the tip-focused Ca 2+ gradient and the actin cytoskeleton arrangement and function that is required for several key processes driving Petunia pollen tube tip growth. Although the precise mechanism is unclear, stabilization of a tip-focused calcium (Ca2+) gradient seems to be critical for pollen germination and pollen tube growth. We hypothesize that calreticulin (CRT), a Ca2+-binding/buffering chaperone typically residing in the lumen of the endoplasmic reticulum (ER) of eukaryotic cells, is an excellent candidate to fulfill this role. We previously showed that in Petunia pollen tubes growing in vitro, CRT is translated on ER membrane-bound ribosomes that are abundant in the subapical zone of the tube, where CRT's Ca2+-buffering and chaperone activities might be particularly required. Here, we sought to determine the function of CRT using small interfering RNA (siRNA) to, for the first time in pollen tubes growing in vitro, knockdown expression of a gene. We demonstrate that siRNA-mediated post-transcriptional silencing of Petunia hybrida CRT gene (PhCRT) expression strongly impairs pollen tube growth, cytoplasmic zonation, actin cytoskeleton organization, and the tip-focused Ca2+ gradient. Moreover, reduction of CRT alters the localization and disturbs the structure of the ER in abnormally elongating pollen tubes. Finally, cytoplasmic streaming is inhibited, and most of the pollen tubes rupture. Our data clearly show an interplay between CRT, Ca2+ gradient, actin-dependent cytoplasmic streaming, organelle positioning, and vesicle trafficking during pollen tube elongation. Thus, we suggest that CRT functions in Petunia pollen tube growth by stabilizing Ca2+ homeostasis and acting as a chaperone to assure quality control of glycoproteins passing through the ER. PMID- 28078428 TI - Erratum to: Efficacy and safety of fermented garlic extract on hepatic function in adults with elevated serum gamma-glutamyl transpeptidase levels: a double blind, randomized, placebo-controlled trial. PMID- 28078427 TI - Response to the comment on "The biomechanical properties of the cornea of patients with glaucoma treated with anti-glaucoma topical medication". PMID- 28078429 TI - Aims and tasks in parental caregiving for children receiving palliative care at home: a qualitative study. AB - : In paediatric palliative care (PPC), parents are confronted with increasing caregiving demands. More children are cared for at home, and the need for PPC of children is lengthened due to technical and medical improvements. Therefore, a clear understanding of the content of parental caregiving in PPC becomes increasingly important. The objective is to gain insight into parental caregiving based on the lived experience of parents with a child with a life-limiting disease. An interpretative qualitative study using thematic analysis was performed. Single or repeated interviews were undertaken with 42 parents of 24 children with a malignant or non-malignant disease, receiving PPC. Based on their ambition to be a 'good parent', parents caring for a child with a life-limiting disease strived for three aims: controlled symptoms and controlled disease, a life worth living for their ill child and family balance. These aims resulted in four tasks that parents performed: providing basic and complex care, organising good quality care and treatment, making sound decisions while managing risks and organising a good family life. CONCLUSION: Parents need early explanation from professionals about balancing between their aims and the related tasks to get a grip on their situation and to prevent becoming overburdened. What is Known: * In paediatric palliative care, parents are confronted with increasing caregiving demands. * Parenting is often approached from the perspective of stress. What is New: * Parents strive for three aims: controlled symptoms and controlled disease, a life worth living for their child and family balance. * Parents perform four tasks: providing basic and complex care, organising good quality care, making decisions while managing risks and organising a good family life. * Professionals need insight into the parents' aims and tasks from the parental perspective to strengthen parents' resilience. PMID- 28078430 TI - Blood urea nitrogen to serum creatinine ratio is an accurate predictor of outcome in diarrhea-associated hemolytic uremic syndrome, a preliminary study. AB - : Diarrhea-associated hemolytic uremic syndrome (D+HUS) is a common thrombotic microangiopathy during childhood and early identification of parameters predicting poor outcome could enable timely intervention. This study aims to establish the accuracy of BUN-to-serum creatinine ratio at admission, in addition to other parameters in predicting the clinical course and outcome. Records were searched for children between 1 January 2008 and 1 January 2015 admitted with D+HUS. A complicated course was defined as developing one or more of the following: neurological dysfunction, pancreatitis, cardiac or pulmonary involvement, hemodynamic instability, and hematologic complications while poor outcome was defined by death or development of chronic kidney disease. Thirty four children were included from which 11 with a complicated disease course/poor outcome. Risk of a complicated course/poor outcome was strongly associated with oliguria (p = 0.000006) and hypertension (p = 0.00003) at presentation. In addition, higher serum creatinine (p = 0.000006) and sLDH (p = 0.02) with lower BUN-to-serum creatinine ratio (p = 0.000007) were significantly associated with development of complications. A BUN-to-sCreatinine ratio <=40 at admission was a sensitive and highly specific predictor of a complicated disease course/poor outcome. CONCLUSION: A BUN-to-serum Creatinine ratio can accurately identify children with D+HUS at risk for a complicated course and poor outcome. What is Known: * Oliguria is a predictor of poor long-term outcome in D+HUS What is New: * BUN-to-serum Creatinine ratio at admission is an entirely novel and accurate predictor of poor outcome and complicated clinical outcome in D+HUS * Early detection of the high risk group in D+HUS enabling early treatment and adequate monitoring. PMID- 28078431 TI - Degradation of Di(2-Ethylhexyl) Phthalate by a Novel Gordonia alkanivorans Strain YC-RL2. AB - One bacterial strain, YC-RL2, isolated from petroleum-contaminated soil, could utilize environmental hormone Di(2-Ethylhexyl) phthalate (DEHP) as a sole carbon source for growth. Strain YC-RL2 was identified as Gordonia alkanivorans by 16S rRNA gene analysis and Biolog tests. The effects of environmental factors which might affect the degrading process were optimized at 30 degrees C and pH 8.0. Strain YC-RL2 showed superior halotolerance and could tolerate up to 0-5% NaCl in trace element medium supplemented with DEHP, although the DEHP degradation rates slowed as NaCl concentration increased. It also showed an outstanding performance in a wide range of pH (6.0-11.0). Meanwhile, strain YC-RL2 was able to withstand high concentrations of DEHP (from 100 to 800 mg/L), and the degradation rates were all above 94%. The DEHP intermediates were detected by HPLC-MS, and the degradation pathway was deduced tentatively. DEHP was transformed into phthalic acid (PA) via mono (2-ethylhexyl) phthalate (MEHP), and PA was further utilized for growth via benzoic acid (BA). The enzyme expected to catalyze the hydrolysis of MEHP to PA was identified from strain YC-RL2. Further investigation found that the enzyme could catalyze the transformation of a wide range of monoalkyl phthalates to PA. This study is the first report about species G. alkanivorans which could degrade several kinds of phthalic acid esters (PAEs), and indicates its application potential for bioremediation of PAE-polluted sites. PMID- 28078432 TI - [Evidence-based recommendations for diagnostics and treatment of gouty arthritis in the specialist sector : S2e guidelines of the German Society of Rheumatology in cooperation with the AWMF]. AB - Due to the increasing prevalence of gout, particularly in old age, the disease is becoming of increasing importance in Germany. Gout is one of the most common forms of recurrent inflammatory arthritis and is induced by the deposition of monosodium urate crystals in synovial fluid and other tissues. The principal goals of therapy in chronic gout are the symptomatic treatment of the acute joint inflammation and the causal treatment of the underlying metabolic cause, the hyperuricemia. Only a consistent and permanent reduction of the serum uric acid level ultimately results in an efficient avoidance of further gout attacks and therefore the prevention of structural damage. Due to an often inadequate treatment of gout, the target of healing the disease is often not achieved. A correct and timely diagnosis and adequate assessment of comorbidities associated with gout are, however, of substantial importance for patient and physician to achieve remission of the disease. In order to create a solid basis for a timely and effective treatment of affected patients, in 2016 the German Society of Rheumatology (DGRh) initiated the development of S2e guidelines on gouty arthritis for specialists. This article summarizes these S2e guidelines on the management of gouty arthritis in the specialist sector. PMID- 28078433 TI - A meta-analysis of the clinicopathological characteristics and survival outcomes of inflammatory bowel disease associated colorectal cancer. AB - PURPOSE: The current study aims to use meta-analytical techniques to compare the clinicopathological characteristics and survival outcomes of inflammatory bowel disease (IBD) associated and sporadic colorectal carcinoma (CRC). Patients with IBD have an established increased risk of developing CRC. There is no consensus, however, on the clinicopathological characteristics and survival outcomes of IBD associated CRC when compared to sporadic CRC. METHODS: A comprehensive search for published studies comparing IBD associated and sporadic CRC was performed. Random effect methods were used to combine data. This study adhered to the recommendations of the MOOSE guidelines. RESULTS: Data were retrieved from 20 studies describing 571,278 patients. IBD associated CRC had an increased rate of synchronous tumors (OR 4.403, 95% CI 2.320-8.359; p < 0.001), poor differentiation (OR 1.875, 95% CI 1.425-2.466; p < 0.001), and a reduced rate of rectal cancer (OR 0.827, 95% CI 0.735-0.930; p = 0.002). IBD associated CRC however did not affect the frequency of T3/T4 tumors (OR 0.931, 95% CI 0.782 1.108; p = 0.421), lymph node positivity (OR 1.061, 95% CI 0.929-1.213; p = 0.381), metastasis at presentation (OR 0.970, 95% CI 0.776-1.211; p = 0.786), sex distribution (OR 0.978, 95% CI 0.890-1.074; p = 0.640), or 5-year overall survival (OR 1.105, 95% CI 0.414-2.949; p = 0.842). CONCLUSIONS: In this large analysis of available data, IBD associated CRC was characterized by less rectal tumors and more synchronous and poorly differentiated tumors compared with sporadic cancers, but no discernable difference in sex distribution, stage at presentation, or survival could be identified. PMID- 28078434 TI - A retrospective open-label uncontrolled study of Epoetin zeta on the treatment of chemotherapy-induced anemia in solid tumors. AB - PURPOSE: This is a single-center uncontrolled retrospective study to evaluate the efficacy and safety of the biosimilar epoetin zeta after approval in chemotherapy induced anemia (CIA). METHODS: Patients screened were >18 years old suffering from solid malignancies and CIA with Hg <=10 or <11 g/dl if symptomatic anemia. Patients had measurable disease by TNM and Eastern Cooperative Oncology Group (ECOG). Patients were treated for at least 12 weeks and the primary endpoint was to determine the incidence of blood transfusions, and secondarily, the overall safety and efficacy defined as >=1 g/dl rise in Hb concentration or >=40,000 cells/MUl rise in reticulocyte count. Quality of life was assessed with ECOG performance status (PS) and functional assessment of cancer therapy-anemia (FACT An) score. RESULTS: 1287 patients with median Hb 9.3 g/dl (range 8.3-10.6) were enrolled and included in the evaluation. Median age was 63 years (range 33-78). 74% of patients were stage III/IV. Patients received epoetin zeta subcutaneously at fixed 40,000-IU once weekly. Blood transfusions were given in 178 patients (13.8%; 95% CI 11.9-15.6%). Appropriate response was observed in 79% patients by week 4, 87% by week 8, and 91% by week 12. A mean Hb increase of 2.5 g/dl was observed by week 12 which correlated with an improvement in PS and Fact-An score. Thrombotic events occurred in 5.2% (95% CI 3.4-7.1%) of patients. CONCLUSIONS: Epoetin zeta is effective in palliation and treatment of CIA in patients with solid tumors. Overall, it is well tolerated and safe even in patients with increased disease burden. PMID- 28078436 TI - Adhering to the 2014 WHO terminology on borderline ovarian tumors. PMID- 28078437 TI - Senescence in the lesional fibroblasts of non-segmental vitiligo patients. AB - Dermal fibroblasts secrete various growth factors which are important for skin pigmentation. Imbalance in the synchronization of epidermal and dermal cells in the skin can play vital role in the pathogenesis of pigmentary disorder vitiligo. Therefore, our objective was to check the lesional fibroblasts for any abnormality and senescence in non-segmental vitiligo patients (NSV). Skin punch biopsies were taken from NSV patients and healthy controls. Explant culture of fibroblast from lesional dermis, non-lesional dermis, and control was analyzed. The senescence was confirmed by beta-galactosidase staining in the cultured fibroblasts. Senescence was checked at mRNA level in lesional dermis, non lesional dermis of NSV patients by senescence markers p16, p21, and hp1 by quantitative real-time polymerase chain reaction (qRT-PCR) and immunofluorescence study was used for protein analysis. Morphological results showed number of fibroblasts with bigger perinuclear region and vacuoles were more in the lesional fibroblasts. Number of beta-galactosidase positive fibroblasts in the lesional skin of NSV patients was higher as compared to the non-lesional and control fibroblasts. Results showed higher relative gene expression of senescence markers p16, p21, and hp1 in the lesional dermis of NSV patients at mRNA level and protein level as compared with control. Senescence in the dermal fibroblasts can decrease the secretion of growth factors and cytokines secreted by fibroblasts which may lead to the melanocyte death and progression of vitiligo. However, further studies on larger number of patients are needed to confirm the role of fibroblasts in the vitiligo pathogenesis. PMID- 28078435 TI - The effects of therapeutic exercises on pain, muscle strength, functional capacity, balance and hemodynamic parameters in knee osteoarthritis patients: a randomized controlled study of supervised versus home exercises. AB - The aim of the study was to compare the effects of low-intensity exercise programs for lower extremities, either supervised or at home, on pain, muscle strength, balance and the hemodynamic parameters of knee osteoarthritis (OA) patients. This randomized study included 78 patients with knee OA in 2 groups of supervised and home-based exercise program. Exercises were applied to the first group in the clinic as a group exercise program and were demonstrated to the second group to be performed at home. Before and after the 6-week exercise program, assessment was made of pain, quadriceps and hamstring muscle strengths, 6-min walk test (6MWT), and non-invasive hemodynamic parameters. Results of the 78 patients, 56 completed the study. Pain, muscle strength, and 6MWT scores showed significant improvements in both groups. There were also significant differences in the amount of change in pain and muscle strength (pain: p = 0.041, Rqdc: 0.009, Lqdc: 0.013, Rhms: 0.04) which indicated greater improvements in the supervised group. The balance scores of supervised group showed a significant improvement (p = 0.009). No significant change was determined in hemodynamic parameters of either group. Conclusion according to the results of this study showed that low-intensity lower extremity exercises conducted in a clinic under the supervision of a physiotherapist were more effective than home-based exercises in reducing post-activity pain levels and improving quadriceps and right hamstring muscle strength. Both the supervised and home exercise programs were seen to be effective in reducing rest pain and increasing 6 MW distance in knee osteoarthritis patients. PMID- 28078438 TI - Biological monitoring of cobalt in hard metal factory workers. AB - PURPOSE: The main aim of this study was to investigate the cobalt (Co) concentrations in urine along 4 months and their relationship with Co concentrations in blood and haemoglobin (adducts) in 34 workers from a hard metal manufacturing plant where metallic Co and Co oxide were used. Furthermore, the excretion kinetics of Co was investigated and the half-lives of Co in blood, plasma and urine were calculated along 18 days of non-exposure in the same workers. METHODS: Co was analysed, in all biological samples, by ICP/MS. RESULTS: Wide fluctuations in the urinary Co concentration were observed throughout the work shift and during the work week. A highly significant linear correlation was found between Co concentration (geometrical mean) in urine samples provided each Thursday (end shift) during 16 subsequent weeks and levels of Co-haemoglobin adducts or blood Co concentrations at the end of the same period. The Co elimination kinetics in globin calculated along 18 days without Co exposure was slow, being related to the physiological metabolism of haemoglobin, while in blood, plasma and urine Co half-lives were 12.3, 9.1 and 5.3 days, respectively. CONCLUSION: Co concentrations in haemoglobin or blood are highly related to the geometrical mean concentration of urinary Co when samples are collected weekly for several subsequent weeks. The biological monitoring of occupational exposure to Co in hard metal facilities provides reliable results by using the Co concentrations in haemoglobin or in whole blood. The urinary findings, though, do not show the same reliability because of their wide daily and weekly fluctuations. PMID- 28078439 TI - Liquid-based versus conventional cytology of oral brush biopsies: a split-sample pilot study. AB - OBJECTIVE: The aim of this prospective split sample study was to evaluate the applicability of liquid-based cytology (LBC) of oral brush biopsies for detection of oral cancer. METHODS: Two different preparation techniques were investigated: the conventional transfer procedure to glass slides and the LBC preparation method. The obtainments of epithelial cells were performed five times with a nylon brush and transferred onto five glass slides. Additionally, the brushes, which were normally discarded, were stored in a fixative solution. Conventional slides and respective thin layers from a total of 113 cases were reviewed with both techniques. RESULTS: Thin layers showed excellent morphology on a clear background, which allowed an accurate diagnosis. In contrast, the conventional glass slides showed significantly more blood contamination and cell overlapping. The sensitivity of conventional cytological diagnosis was 96.3%, the specificity archived 90.6%, the positive predictive value was 96.3% and the negative predictive value scored 90.6%. The sensitivity of the cytological diagnosis using thin layers archived 97.5%, the specificity was 68.8%, the positive predictive value revealed 88.76% and negative predictive value was 91.7%. CONCLUSION: Our findings indicate that in oral cytology, LBC may replace other types of wet-fixed preparations using the full amount of collected cells, resulting in enhanced specimen quality archiving comparable values of diagnostic accuracy. CLINICAL RELEVANCE: LBC facilitates the cell collection due to simpler handling and less transfer errors by dentists and may improve the overall diagnostic accuracy of oral brush biopsies in future. PMID- 28078441 TI - [Palliative care in nursing homes : Results of a survey about knowledge and self efficacy of nursing staff]. AB - BACKGROUND: Nursing homes are confronted more and more with palliative care patients, which present a challenge for nursing and medical personnel. Deficits in the palliative care of geriatric patients have been repeatedly demonstrated and many nursing home residents, especially those suffering from dementia, are undersupplied regarding pain management. OBJECTIVES: The present study was carried out to measure the knowledge and self-efficacy of nursing staff in the province of Carinthia (Austria) regarding palliative care of nursing home residents. MATERIAL AND METHODS: A total of 330 nursing personnel were surveyed using the Bonn test for knowledge in palliative care (BPW), which measures knowledge and self-efficacy in nursing home personnel. In addition to descriptive analyses, the effects of the professional group (registered nurses vs. nursing assistants) and working experience were tested. RESULTS: On average a little more than half of the knowledge items were answered correctly. Nurses' self-efficacy was high. Registered nurses exhibited more knowledge and higher self-efficacy compared to nursing assistants. Effects of working experience could only be demonstrated regarding self-efficacy. CONCLUSION: The results are to a large extent in line with results from Germany and indicate the necessity of interventions for improving nurses' knowledge as a major basis for adequate palliative care in nursing home residents. PMID- 28078440 TI - Alternative intronic promoters in development and disease. AB - Approximately 20,000 mammalian genes are estimated to encode between 250 thousand and 1 million different proteins. This enormous diversity of the mammalian proteome is caused by the ability of a single-gene locus to encode multiple protein isoforms. Protein isoforms encoded by one gene locus can be functionally distinct, and they can even have antagonistic functions. One of the mechanisms involved in creating this proteome complexity is alternative promoter usage. Alternative intronic promoters are located downstream from their canonical counterparts and drive the expression of alternative RNA isoforms that lack upstream exons. These upstream exons can encode some important functional domains, and proteins encoded by alternative mRNA isoforms can be thus functionally distinct from the full-length protein encoded by canonical mRNA isoforms. Since any misbalance of functionally distinct protein isoforms is likely to have detrimental consequences for the cell and the whole organism, their expression must be precisely regulated. Misregulation of alternative intronic promoters is frequently associated with various developmental defects and diseases including cancer, and it is becoming increasingly clear that this phenomenon deserves more attention. PMID- 28078442 TI - In Reply: Sedation choices and mortality: a well-defined tandem? PMID- 28078443 TI - Double stenting with silicone and metallic stents for malignant airway stenosis. AB - For severe malignant airway stenosis, there are several types of commercially available airway stents, and each has its own advantages and disadvantages. We herein describe the safety and efficacy of combination stenting with silicone and metallic stents for patients with extended malignant airway stenosis. Seven patients with malignant airway stenosis were treated via combination stenting with a silicone stent and a metallic stent for extended airway stenosis from the central to peripheral airways. Five patients were diagnosed with advanced esophageal cancer, two of whom had tracheoesophageal fistulas. One patient had adenoid cystic carcinoma, and another had mediastinal tumor. There were no specific complications related to the double stenting. Combination stenting with silicone and metallic stents proved to be a safe option for patients with severe, extended, and complicated malignant airway stenosis. PMID- 28078444 TI - MPS analysis of the mtDNA hypervariable regions on the MiSeq with improved enrichment. AB - The non-coding displacement (D) loop of the human mitochondrial (mt) genome contains two hypervariable regions known as HVR1 and HVR2 that are most often analyzed by forensic DNA laboratories. The massively parallel sequencing (MPS) protocol from Illumina (Human mtDNA D-Loop Hypervariable Region protocol) utilizes four sets of established PCR primer pairs for the initial amplification (enrichment) step that span the hypervariable regions. Transposase adapted (TA) sequences are attached to the 5'-end of each primer, allowing for effective library preparation prior to analysis on the MiSeq, and AmpliTaq Gold DNA polymerase is the enzyme recommended for amplification. The amplification conditions were modified by replacing AmpliTaq Gold with TaKaRa Ex Taq(r) HS, along with an enhanced PCR buffer system. The resulting method was compared to the recommended protocol and to a conventional non-MPS approach used in an operating forensic DNA laboratory. The modified amplification conditions gave equivalent or improved results, including when amplifying low amounts of DNA template from hair shafts which are a routine evidence type in forensic mtDNA cases. Amplification products were successfully sequenced using an MPS approach, addressing sensitivity of library preparation, evaluation of precision and accuracy through repeatability and reproducibility, and mixture studies. These findings provide forensic laboratories with a robust and improved enrichment method as they begin to implement the D-loop protocol from Illumina. Given that Ex Taq(r) HS is a proofreading enzyme, using this approach should allow for improved analysis of low-level mtDNA heteroplasmy. PMID- 28078445 TI - Energy-dependent expansion of .177 caliber hollow-point air gun projectiles. AB - Amongst hundreds of different projectiles for air guns available on the market, hollow-point air gun pellets are of special interest. These pellets are characterized by a tip or a hollowed-out shape in their tip which, when fired, makes the projectiles expand to an increased diameter upon entering the target medium. This results in an increase in release of energy which, in turn, has the potential to cause more serious injuries than non-hollow-point projectiles. To the best of the authors' knowledge, reliable data on the terminal ballistic features of hollow-point air gun projectiles compared to standard diabolo pellets have not yet been published in the forensic literature. The terminal ballistic performance (energy-dependent expansion and penetration) of four different types of .177 caliber hollow-point pellets discharged at kinetic energy levels from approximately 3 J up to 30 J into water, ordnance gelatin, and ordnance gelatin covered with natural chamois as a skin simulant was the subject of this investigation. Energy-dependent expansion of the tested hollow-point pellets was observed after being shot into all investigated target media. While some hollow point pellets require a minimum kinetic energy of approximately 10 J for sufficient expansion, there are also hollow-point pellets which expand at kinetic energy levels of less than 5 J. The ratio of expansion (RE, calculated by the cross-sectional area (A) after impact divided by the cross-sectional area (A 0) of the undeformed pellet) of hollow-point air gun pellets reached values up of to 2.2. The extent of expansion relates to the kinetic energy of the projectile with a peak for pellet expansion at the 15 to 20 J range. To conclude, this work demonstrates that the hollow-point principle, i.e., the design-related enlargement of the projectiles' frontal area upon impact into a medium, does work in air guns as claimed by the manufacturers. PMID- 28078446 TI - Detection of RAGE expression and its application to diabetic wound age estimation. AB - With the prevalence of diabetes, it is becoming important to analyze the diabetic wound age in forensic practice. The present study investigated the time-dependent expression of receptor for advanced glycation end products (RAGE) during diabetic wound healing in mice and its applicability to wound age determination by immunohistochemistry, double immunofluorescence, and Western blotting. After an incision was created in genetically diabetic db/db mice and control mice, mice were killed at posttraumatic intervals ranging from 6 h to 14 days, followed by the sampling of wound margin. Compared with control mice, diabetic mice showed the delayed wound healing. In control and diabetic wound specimens, RAGE immunoreactivity was observed in a small number of polymorphonuclear cells (PMNs), a number of macrophages, and fibroblasts. Morphometrically, the positive ratios of RAGE in macrophages or fibroblasts considerably increased in diabetic wounds during late repair, which exceeded 60% at 7 and 10 days post-injury. There were no control wound specimens to show a ratio of >60% in macrophages or fibroblasts. By Western blotting analysis, the ratios of RAGE to GAPDH were >1.4 in all diabetic wound samples from 7 to 10 days post-injury, which were >1.8 at 10 days after injury. By comparison, no control wound specimens indicated a ratio of >1.4. In conclusion, the expression of RAGE is upregulated and temporally distributed in macrophages and fibroblasts during diabetic wound healing, which might be closely involved in prolonged inflammation and deficient healing. Moreover, RAGE is promising as a useful marker for diabetic wound age determination. PMID- 28078447 TI - Trends in aortic valve replacement in Germany in 2015: transcatheter versus isolated surgical aortic valve repair. AB - AIMS: We analysed the number of procedures, indications, and in-hospital mortality rates of all patients undergoing isolated surgical aortic valve replacement (sAVR) or transvascular (TV-) and transapical (TA-) transcatheter aortic valve implantation (TAVI) from 2012 to 2015 in Germany. METHODS AND RESULTS: More than 31,000 aortic valve procedures were performed in 2015 in Germany, representing a total increase of 4.5% over 2014. TV-TAVI accounts for 13,108 of these procedures, with an increase of 21%, whereas the numbers of isolated sAVR and TA-TAVI decreased slightly. Age, frailty, high risk, and patients' choice were the main reasons for a catheter-based intervention. In 2015, the in-hospital mortality rate after TV-TAVI decreased to 3.4%, approaching that of sAVR (2.9%), despite a considerably higher baseline risk. A stratified analysis according to the German aortic valve (AKL) score demonstrated a further decrease of the in-hospital mortality for TV-TAVI, showing a lower in-hospital mortality rate than expected in all risk groups. Importantly, this also accounts for the lowest risk group with an AKL score <3% showing an in-hospital mortality rate of 1.7%, which is now comparable to that of sAVR (1.5%). In all other risk groups, the in-hospital mortality in patients undergoing TV-TAVI was lower than in patients undergoing sAVR. CONCLUSIONS: Mortality after TV-TAVI keeps decreasing over the last years and equals that of SAVR in the lowest risk cohort in the meanwhile. All TV-TAVI patients have significantly lower observed than expected mortality, which will further lead to a redefinition of standard of care. PMID- 28078448 TI - Synergic impact of oral anticoagulation control and renal function in determining major adverse events in atrial fibrillation patients undergoing percutaneous coronary intervention: insights from the AFCAS registry. AB - BACKGROUND: In patients with atrial fibrillation (AF), quality of oral anticoagulation control as well as impaired renal function are associated with adverse outcomes. Our objective was to analyze if there was a synergistic impact of these factors in determining adverse outcomes in AF patients undergoing percutaneous coronary intervention and stent (PCI-S). METHODS: Post-hoc analysis from the Atrial Fibrillation Undergoing Coronary Artery Stenting (AFCAS) registry. Poor oral anticoagulation control was defined as time in therapeutic range (TTR) <65%, while impaired renal function as creatinine clearance (CrCl) <60 ml/min. RESULTS: Of the whole cohort, 448 were eligible for this post-hoc analysis. Of these, 27.9% had TTR <65%only (Group I), 19.2% had CrCl <60 ml/min only (Group II), while 13.8% had both conditions (Group III). At follow-up, patients in Group III had a higher rate of major adverse cardiovascular and cerebrovascular events (MACCE) (p = 0.007), while patients in Groups I and III had higher rates of major bleeding. Kaplan-Meier analyses showed that patients in Group III had higher risk for MACCE (LogRank: 14.406, p = 0.003), while Group I and Group III patients had higher risk for major bleeding (LogRank: 12.290, p = 0.006). On Cox regression, presence of both conditions independently increased MACCE risk (p = 0.001), while TTR <65% alone and the presence of both conditions were independently associated with major bleeding (p = 0.004 and p = 0.028, respectively). CONCLUSIONS: There was a synergic impact of oral anticoagulation control and renal function in determining major adverse events in AF patients undergoing PCI-S. Use of poor anticoagulation control and impaired renal function in combination would help identify AF patients undergoing PCI-S at risk for MACCE and/or major bleeding. PMID- 28078449 TI - Social media responses to heat waves. AB - Social network services (SNSs) may benefit public health by augmenting surveillance and distributing information to the public. In this study, we collected Twitter data focusing on six different heat-related themes (air conditioning, cooling center, dehydration, electrical outage, energy assistance, and heat) for 182 days from May 7 to November 3, 2014. First, exploratory linear regression associated outdoor heat exposure to the theme-specific tweet counts for five study cities (Los Angeles, New York, Chicago, Houston, and Atlanta). Next, autoregressive integrated moving average (ARIMA) time series models formally associated heat exposure to the combined count of heat and air conditioning tweets while controlling for temporal autocorrelation. Finally, we examined the spatial and temporal distribution of energy assistance and cooling center tweets. The result indicates that the number of tweets in most themes exhibited a significant positive relationship with maximum temperature. The ARIMA model results suggest that each city shows a slightly different relationship between heat exposure and the tweet count. A one-degree change in the temperature correspondingly increased the Box-Cox transformed tweets by 0.09 for Atlanta, 0.07 for Los Angeles, and 0.01 for New York City. The energy assistance and cooling center theme tweets suggest that only a few municipalities used Twitter for public service announcements. The timing of the energy assistance tweets suggests that most jurisdictions provide heating instead of cooling energy assistance. PMID- 28078450 TI - Genome-wide methylation profiles in primary intracranial germ cell tumors indicate a primordial germ cell origin for germinomas. AB - Intracranial germ cell tumors (iGCTs) are the second most common brain tumors among children under 14 in Japan. The World Health Organization classification recognizes several subtypes of iGCTs, which are conventionally subclassified into pure germinoma or non-germinomatous GCTs. Recent exhaustive genomic studies showed that mutations of the genes involved in the MAPK and/or PI3K pathways are common in iGCTs; however, the mechanisms of how different subtypes develop, often as a mixed-GCT, are unknown. To elucidate the pathogenesis of iGCTs, we investigated 61 GCTs of various subtypes by genome-wide DNA methylation profiling. We showed that pure germinomas are characterized by global low DNA methylation, a unique epigenetic feature making them distinct from all other iGCTs subtypes. The patterns of methylation strongly resemble that of primordial germ cells (PGC) at the migration phase, possibly indicating the cell of origin for these tumors. Unlike PGC, however, hypomethylation extends to long interspersed nuclear element retrotransposons. Histologically and epigenetically distinct microdissected components of mixed-GCTs shared identical somatic mutations in the MAPK or PI3K pathways, indicating that they developed from a common ancestral cell. PMID- 28078452 TI - Do deer and raccoons defecate in the right place? Fitness consequences of vertebrate seed dispersal for a deciduous forest herb. AB - Precision of seed placement in a heterogeneous environment is often assumed to select for the evolution of animal-mediated dispersal systems, but this hypothesis has rarely been tested in a multivariate sense. We quantify the microsite fitness benefits of dispersal by white-tailed deer (Odocoileus virginianus) and raccoons (Procyon lotor) for mayapple (Podophyllum peltatum), a shade-tolerant perennial herb, in deciduous forests of southeastern Ohio, USA. Micro-environmental variables were recorded at dung-deposition microsites, at rooting points of mayapple shoots, and at random (control) points in the forest. Fitness was assessed as the degree of overlap in ordinations of microsites by environmental variables. Mayapple occupied a broad sector (56%) of environment space corresponding to low and mid-slope positions, ravines, and proximity to trees. Deer and raccoon defecation placed dung in 71-74 and 86-95% of environment space, respectively, reaching mayapple microsites in 57-60 and 53-54% of cases. Deer placed dung in mayapple environment space 7-9% more often than predicted by random distribution, and raccoons placed dung in mayapple space 0-5% more often, consistent with only a modest degree of directed dispersal. Thus, the precision hypothesis is only weakly supported. The greatest fitness benefit of vertebrate dispersal appears to be the broad distribution of seeds, thereby increasing the probability of randomly reaching a suitable microsite. Imprecise dispersal suggests that secondary mechanisms of seed movement need to be explored in deciduous forest communities. PMID- 28078451 TI - Slower but not faster unilateral fatiguing knee extensions alter contralateral limb performance without impairment of maximal torque output. AB - PURPOSE: The purpose of the present study was to examine the effects of unilateral fatigue of the knee extensors at different movement velocities on neuromuscular performance in the fatigued and non-fatigued leg. METHODS: Unilateral fatigue of the knee extensors was induced in 11 healthy young men (23.7 +/- 3.8 years) at slower (60 degrees /s; FAT60) and faster movement velocities (240 degrees /s; FAT240) using an isokinetic dynamometer. A resting control (CON) condition was included. The fatigue protocols consisted of five sets of 15 maximal concentric knee extensions using the dominant leg. Before and after fatigue, peak isokinetic torque (PIT) and time to PIT (TTP) of the knee extensors as well as electromyographic (EMG) activity of vastus medialis, vastus lateralis, and biceps femoris muscles were assessed at 60 and 240 degrees /s movement velocities in the fatigued and non-fatigued leg. RESULTS: In the fatigued leg, significantly greater PIT decrements were observed following FAT60 and FAT240 (11-19%) compared to CON (3-4%, p = .002, d = 2.3). Further, EMG activity increased in vastus lateralis and biceps femoris muscle following FAT240 only (8-28%, 0.018 <= p <= .024, d = 1.8). In the non-fatigued leg, shorter TTP values were found after the FAT60 protocol (11-15%, p = .023, d = 2.4). No significant changes were found for EMG data in the non-fatigued leg. CONCLUSION: The present study revealed that both slower and faster velocity fatiguing contractions failed to show any evidence of cross-over fatigue on PIT. However, unilateral knee extensor fatigue protocols conducted at slower movement velocities (i.e., 60 degrees /s) appear to modulate torque production on the non fatigued side (evident in shorter TTP values). PMID- 28078453 TI - A Bump in the Road: An Uncommon Cause of Dysphagia. PMID- 28078454 TI - Measuring Competency Development in Objective Evaluation of Videofluoroscopic Swallowing Studies. AB - Clinical interpretation of videofluoroscopic swallow study (VFSS) has often been criticized for its poor objectivity and inter-rater agreement. In order to address this, objective VFSS measures have been developed, reported and demonstrated to be valid and reliable. However, widespread clinical implementation is lacking. Reasons cited include lack of training and excessive time taken to perform measures. This study investigated competency development in selected standardized objective VFSS measures among speech-language pathologists (SLPs) naive to quantitative measurement. Six novice (no VFSS experience) and four experienced (2-10 years of VFSS experience) SLPs participated in 4 h of training in how to perform selected objective VFSS measures including pharyngeal constriction ratio, maximum pharyngoesophageal opening, pharyngoesophageal opening duration, airway closure duration and total pharyngeal transit time. Each week for eight weeks, participants were asked to independently measure and report three VFSS of patients affected by stroke. By week 8, all SLPs, irrespective of prior experience level, were able to achieve 80% accuracy in measures in comparison to the consensus of three expert clinicians. SLPs' mean time for completion reduced from 50 min in week 1-25 min in week 8. Inter-rater agreement for measures improved across the eight-week period (range ICC = -31.05 to .60 in week 1 to ICC = .71 to .98 in week 8). There was high agreement in location of impairment and consequent management recommendations by week 8. In conclusion, SLPs can reliably learn and incorporate objective VFSS measures within a reasonable time frame. Level of experience has limited influence on the learning curve. PMID- 28078455 TI - Retention of laparoscopic and robotic skills among medical students: a randomized controlled trial. AB - BACKGROUND: Although simulation training beneficially contributes to traditional surgical training, there are less objective data on simulation skills retention. OBJECTIVE: To investigate the retention of laparoscopic and robotic skills after simulation training. METHODS: We present the second stage of a randomized single blinded controlled trial in which 40 simulation-naive medical students were randomly assigned to practice peg transfer tasks on either laparoscopic (N = 20, Fundamentals of Laparoscopic Surgery, Venture Technologies Inc., Waltham, MA) or robotic (N = 20, dV-Trainer, Mimic, Seattle, WA) platforms. In the first stage, two expert surgeons evaluated participants on both tasks before (Stage 1: Baseline) and immediately after training (Stage 1: Post-training) using a modified validated global rating scale of laparoscopic and robotic operative performance. In Stage 2, participants were evaluated on both tasks 11-20 weeks after training. RESULTS: Of the 40 students who participated in Stage 1, 23 (11 laparoscopic and 12 robotic) underwent repeat evaluation. During Stage 2, there were no significant differences between groups in objective or subjective measures for the laparoscopic task. Laparoscopic-trained participants' performances on the laparoscopic task were improved during Stage 2 compared to baseline measured by time to task completion, but not by the modified global rating scale. During the robotic task, the robotic-trained group demonstrated superior economy of motion (p = .017), Tissue Handling (p = .020), and fewer errors (p = .018) compared to the laparoscopic-trained group. Robotic skills acquisition from baseline with no significant deterioration as measured by modified global rating scale scores was observed among robotic-trained participants during Stage 2. CONCLUSION: Robotic skills acquired through simulation appear to be better maintained than laparoscopic simulation skills. CLINICAL TRIAL: This study is registered on ClinicalTrials.gov (NCT02370407). PMID- 28078456 TI - A video presentation on technique of laparoscopic redo of stenotic gastrojejunostomy with hiatal hernioplasty and right crural release in a patient with previous Roux-en-Y gastric bypass. PMID- 28078457 TI - Equal patient satisfaction, quality of life and objective recurrence rate after laparoscopic hiatal hernia repair with and without mesh. AB - INTRODUCTION: Laparoscopic hiatal hernia repair has become standard practice for most surgeons performing antireflux surgery. Hiatal hernia repair consists of cruroplasty with sutures only or additional reinforcement using mesh. Use of mesh was initiated to reduce recurrence rates. Recent analyses show that use of mesh may influence radiologic recurrence rates, but it does not seem to prevent symptomatic recurrences and the need for reoperation. This study compares clinical and radiologic outcomes of primary cruroplasty and cruroplasty with non absorbable mesh after laparoscopic hiatal hernia repair. METHODS: Retrospective analysis of prospectively followed cohort of patients undergoing laparoscopic correction of hiatal hernia type II-IV in two tertiary referral centers was carried out. Radiologic recurrence, symptomatic recurrence, reoperation rate, complications and patient-reported outcome measures were analyzed for all patients. RESULTS: A total of 189 patients were analyzed after laparoscopic hiatal hernia correction with an additional fundoplication [127 (67.2%) primary correction, 62 (32.8%) with mesh reinforcement]. After a mean follow-up of 39.3 months, the overall radiologic recurrence rate was 24.3%, which was equal in both groups [25.8% (mesh) vs 23.6% (no mesh), P = 0.331]. Symptomatic recurrence rate was 13.2% (16.1 vs 11.8%, P = 0.495) and reoperation rate 7.4% (9.7 vs 6.3%), which was comparable between the two groups. Complication rates were equal, and no serious mesh-related complications were reported. Health-related quality of life improved after surgery, dysphagia decreased and patient satisfaction was high for both groups without significant differences. CONCLUSION: Radiologic recurrences, symptomatic recurrences and reoperation rates are equal after laparoscopic hiatal hernia repair with or without non-absorbable mesh reinforcement, irrespective of hernia size and type. Quality of life, dysphagia and patient satisfaction were comparable. No serious mesh-related complications occurred. The results of this study do not support the routine use of mesh in hiatal hernia repair. PMID- 28078458 TI - Superiority of laparoscopic proximal gastrectomy with hand-sewn esophagogastrostomy over total gastrectomy in improving postoperative body weight loss and quality of life. AB - BACKGROUND: Proximal gastrectomy is not widely performed because the procedure is complicated, particularly under laparoscopy. We developed a simple laparoscopic technique of hand-sewn esophagogastrostomy with an anti-reflux mechanism. This study aimed to evaluate and compare the postoperative body weight loss (BWL) and quality of life (QOL) following laparoscopic proximal gastrectomy (LPG) and laparoscopic total gastrectomy (LTG) in patients with upper gastric cancer. METHODS: We retrospectively analyzed patients with stage I upper gastric cancer undergoing LPG or LTG at Kyoto University Hospital between March 2006 and June 2014. The main outcome measures were the % BWL 1 year after gastrectomy, postoperative anastomotic stricture, and reflux esophagitis. Additionally, patient-reported outcomes were evaluated using the Post-Gastrectomy Syndrome Assessment Scale (PGSAS)-45 in patients presenting at the outpatient clinic and exhibiting no recurrence. RESULTS: A total of 62 patients were included in this study (LTG, n = 42 vs. LPG, n = 20). The % BWL at 12 months in the LPG group was less than that in the LTG group (-16.3 vs. -10.7%). Multivariate analysis revealed that LPG was associated with less BWL (P = 0.003). Anastomotic stricture occurred more frequently in the LPG group than in the LTG group (0 vs. 25%). One patient in each group exhibited grade B severity of reflux esophagitis (based on the Los Angeles classification). In the questionnaire survey, LPG was better than LTG in terms of diarrhea and dissatisfaction with symptoms. In terms of reflux symptoms, patients in the LPG group experienced less acid and bile regurgitation symptoms compared with those in the LTG group. CONCLUSIONS: LPG with hand-sewn esophagogastrostomy results in less postoperative BWL and better QOL than LTG despite higher rates of anastomotic stricture. PMID- 28078459 TI - Endotherapy in case of relapse of neoplastic Barrett's esophagus after successful initial endoscopic resection. AB - BACKGROUND: Endotherapy in cases of neoplastic Barrett esophagus (BE) relapse after successful initial endoscopic management is commonly accepted, but few studies analyze this topic and also take into account the metachronous lesions. AIMS: To evaluate the efficiency of endotherapy in the case of neoplastic BE relapse after successful complete endoscopic eradication of neoplastic BE and metaplastic BE. METHODS: Retrospective review of medical records was collected in a computerized and prospective manner between 2000 and 2015, in a single tertiary care center. Recurrence was defined by histological presence of high-grade dysplasia or superficial adenocarcinoma at least 6 months after the end of successful initial endotherapy. RESULTS: Eighteen patients were assessed (1F/17 M). Delay between initial treatment and relapse was 16.6 months (range 6-33). Endotherapy for relapse obtained a sustained and complete remission for 8/18 (44%) patients, with an average endoscopic follow-up of 28 months. The complication rate of endotherapy was 6%. Surgical management was required in 33% (2 pT2N0M0, 2 pTisN0M0, 1 pTm2N0M0 and 1 pTm3N0M0) and salvage radiochemotherapy in 17% (3/18). One patient treated by 6 sessions of ER was considered as a failure given the multiple sessions of endotherapy. Multivariate analysis showed that length of BE (>5 cm), late stenosis adverse events and the quality of vertical margin during initial ER are predictive factors for disease-free survival (p value < 0.01, Hazard Ratio up to 0.076). CONCLUSION: Endotherapy could be a treatment for management of neoplastic BE relapse, but should be carefully used, with strict follow-up. PMID- 28078460 TI - Imbedding pancreaticojejunostomy used in pure laparoscopic pancreaticoduodenectomy for nondilated pancreatic duct. AB - BACKGROUND: LPD has been cautiously regarded as feasible and safe for resection and reconstruction. However, anastomosis of the remnant pancreas is still thought to be a critical obstacle to the dissemination of LPD in general practice. This study presents a new technique of pancreaticojejunostomy for nondilated pancreatic duct and evaluates its safety and reliability. METHODS: From July 2014 to June 2015, a total of 52 patients underwent LPD with the new technique. A modified technique of duct-to-mucosa PJ was performed with transpancreatic interlocking mattress sutures, named the imbedding duct-to-mucosa PJ. Then the morbidity and mortality was calculated. RESULTS: This technique was applied in 52 patients after LPD all with nondilated pancreatic duct (1-3 mm). The mean operation time was 4.6 h (range, 3.5-8.3 h) and the median time for the anastomosis was 37 min (range, 24-53 min). Operative mortality was zero, and morbidity was 21.2 % (n = 11), including hemorrhage (n = 3, 5.8 %), biliary fistula (n = 1, 1.9 %), pulmonary infection (n = 1, 1.9 %), delayed gastric emptying (n = 2, 3.8 %), abdominal abscess caused by biliary fistula or PF formation (n = 2, 3.8 %), and POPF (n = 2, 3.8 %). Two patients developed a pancreatic fistula (one type A, one type B) classified according to the International Study Group on Pancreatic Fistula. CONCLUSIONS: The described technique is a simple and safe reconstruction procedure after LPD, especially for patients with nondilated pancreatic duct. PMID- 28078461 TI - Cost-effectiveness of prophylactic appendectomy: a Markov model. AB - BACKGROUND: Appendectomy is the most common emergency surgery performed in the USA. Removal of a non-inflamed appendix during unrelated abdominal surgery (prophylactic or incidental appendectomy) can prevent the downstream risks and costs of appendicitis. It is unknown whether such a strategy could be cost saving for the health system. METHODS: We considered hypothetical patient cohorts of varying ages from 18 to 80, undergoing elective laparoscopic abdominal and pelvic procedures. A Markov decision model using cost per life-year as the main outcome measure was constructed to simulate the trade-off between cost and risk of prophylactic appendectomy and the ongoing risk of developing appendicitis, with downstream costs and risks. Rates, probabilities, and costs of disease, treatment, and outcomes by patient age and gender were extracted from the literature. Sensitivity analyses were conducted using complications and costs of prophylactic appendectomy. RESULTS: With our base-case assumptions, including added cost of prophylactic appendectomy of $660, we find that prophylactic removal of the appendix is cost saving for males aged 18-27 and females aged 18 28 undergoing elective surgery. The margin of cost savings depends on remaining life-years and increases exponentially with age: a 20-year-old female undergoing elective surgery could save $130 over a lifetime by undergoing prophylactic appendectomy, while a 40-year-old female would lose $130 over a lifetime. When the risk of the prophylactic appendectomy exceeds the risk of laparoscopic appendectomy for appendicitis or the cost exceeds $1080, it becomes more cost saving to forego the prophylactic procedure. CONCLUSIONS: Prophylactic appendectomy can be cost saving for patients younger than age thirty undergoing elective laparoscopic abdominal and pelvic procedures. PMID- 28078462 TI - Assessment of predictive factors for recurrence in laparoscopic ventral hernia repair using a bridging technique. AB - AIM: To assess the long-term incidence and predictive factors for recurrence after laparoscopic ventral hernia repair using a bridging technique. METHODS: The study group consisted of 213 consecutive patients operated by laparoscopy for primary ventral (n = 158) or incisional hernia (n = 55) between 2001 and 2014. Patients had a repair without fascia closure by intra-peritoneal onlay placement of a Parietex(r) composite mesh centred on the defect with an overlap of at least 3 cm. Clinical outcome was assessed by a combination of office consultation, patient's electronic medical file review and telephone interview. RESULTS: There were 144 men and 69 women with a mean age of 55 +/- 12 years and a BMI of 32 +/- 6. With a mean follow-up of 69 +/- 44 months, a recurrent hernia was noted in 16 patients (7.5%). Univariate analysis showed a statistically significant higher recurrence rate in the following conditions: incisional hernia (15%), BMI >= 35 (21%), defect width >4 cm (27%), defect area >20 cm2 (27%), mesh overlap <5 cm (32%) and ratio of mesh area to defect area (M/D ratio) <=12 (48%). Multivariate logistic analysis revealed that M/D ratio was the only independent predictive factor for recurrence (coefficient -0.79, OR 0.46, p < 0.002). With a M/D ratio <=8, between 9 and 12, between 13 and 16, and >=17, the recurrence rate was, respectively, 70, 35, 9 and 0% (p < 0.001). CONCLUSIONS: In laparoscopic repair of ventral hernia using a bridging technique, an overlap of at least 5 cm is not all that is required to prevent hernia recurrence. The M/D ratio is the most important predictive factor for recurrence. A ratio of 13 appears as the threshold under which that technique cannot be recommended and 16 as the threshold over which the risk of recurrence is virtually nil. If a satisfactory M/D ratio cannot be achieved, other surgical repair should be proposed to the patient. PMID- 28078463 TI - Endoscopic vacuum therapy for various defects of the upper gastrointestinal tract. AB - BACKGROUND: Postoperative, iatrogenic or spontaneous upper gastrointestinal defects result in significant morbidity and mortality of the patients. In the last few years, endoscopic vacuum therapy (EVT) has been recognized as a new promising method for repairing upper gastrointestinal defects of different etiology. However, probably due to insufficient data and no commercially available system for EVT of the upper gastrointestinal tract, until the end of 2014, covering of esophageal defects with self-expanding metal stents (SEMS) were still the mainstay of endoscopic therapy. The aim of this article is to review the data available about EVT for various upper gastrointestinal defects. METHODS: A selective literature search was conducted in Medline and PubMed (2007-2016), taking into account all the published case series and case reports reporting on the use of EVT in the management of upper gastrointestinal defects. RESULTS: EVT works through intracorporal application of negative pressure at the defect zone with an electronic controlled vacuum device along a polyurethane sponge drainage. This results in closure of the esophageal defect and internal drainage of the septic focus, simultaneously. Compared to stenting, EVT enables regular viewing of wound conditions with control of the septic focus and adjustment of therapy. Moreover, endoscopical negative pressure is applicable in all esophageal regions (cricopharygeal, tubular, gastroesophageal junction) and in anastomotic anatomic variants. EVT can be used solely as a definite treatment or as a complimentary therapy combined with operative revision. In total, there are published data of more than 200 patients with upper gastrointestinal defects treated with EVT, showing succes rates from 70-100%. CONCLUSION: The available data indicate that EVT is feasible, safe and effective with good short-term and long-term clinical outcomes in the damage control of upper GI-tract leaks. Still, a prospective multi-center study has to be conducted to proof the definite benefit of EVT for patients with esophageal defects. PMID- 28078464 TI - Outcome of stent grafting for esophageal perforations: single-center experience. AB - BACKGROUND: Recent studies showed that stent grafting is a promising technique for treatment of esophageal perforation. However, the evidence of its benefits is still scarce. METHODS: Forty-three consecutive patients underwent stent grafting for esophageal perforation at the Oulu University Hospital, Finland. The main endpoints of this study were early and mid-term mortality. Secondary outcome endpoints were the need of esophagectomy and additional surgical procedures on the esophagus and extraesophageal structures. RESULTS: Patients' mean age was 64.6 +/- 13.4 years. The mean delay to primary treatment was 23 +/- 27 h. The most frequent cause of perforation was Boerhaave's syndrome (46.5%). The thoraco abdominal segment of the esophagus was affected in 58.1% of cases. Minor primary procedures were performed in 25 patients (58.1%) and repeat surgical procedures in 23 patients (53.5%). Forty-nine repeat stent graftings were performed in 22 patients (50%). Two patients (4.7%) underwent esophagectomy, one for unrelenting preprocedural stricture of the esophagus and another for persistent leakage of a perforated esophageal carcinoma. The mean length of stay in the intensive care unit was 6.0 +/- 7.5 days and the in-hospital stay was 24.3 +/- 19.6 days. In hospital mortality was 4.6%. Three-year survival was 67.2%. CONCLUSIONS: Stent grafting seems to be an effective less invasive technique for the treatment of esophageal perforation. Repeat stent grafting and procedures on the pleural spaces are often needed to control the site of perforation and for debridement of surrounding infected structures. Stent grafting allows the preservation of the esophagus in most of patients. The mid-term survival of these patients is suboptimal and requires further investigation. PMID- 28078465 TI - Non-inferiority of minimally invasive oesophagectomy: an 8-year retrospective case series. AB - BACKGROUND: The trend towards laparoscopic surgery seen in other specialties has not occurred at the same pace in oesophagectomy. This stems from concerns regarding compromised oncological clearance, and complications associated with gastric tube necrosis and anastomotic failure. We present our experience of minimally invasive oesophagectomy (MIO) compared to open and hybrid surgery. We aim to ascertain non-inferiority of MIO by evaluating impact on survival, oncological clearance by resection margin and lymph node harvest and post operative complications. METHODS: Data were sourced retrospectively 2008-2015. Three approaches were studied. MIO (3-stage Mckeown), hybrid (2-stage Ivor Lewis, laparoscopy, thoracotomy) and open (2-stage Ivor Lewis). RESULTS: Five-year survival was 54.2%. Surgical approach had no significant impact on survival at any stage of disease (Stage 0/I p = 0.98; stage II p = 0.2; stage III p = 0.76). There was no statistically significant difference in oncological clearance by resection margins between procedures when compared by disease stage (p = 0.49). A higher number of nodes were harvested in hybrid [median 27.5 (6-65)] and open surgeries [median 26 (4-54)] than in MIO [median 20 (7-44)] (p > 0.01). Numbers of nodes resected did not impact risk of recurrence [recurrence, median 25 (6 54), no recurrence, 26 (4-65)] (p = 0.25). Anastomotic strictures (22.4%) and potential leaks (17.9%) were more common in MIO (strictures p > 0.01, leaks p = 0.08), although associated morbidity was lower. Respiratory complications were less common in MIO (2.9%) versus hybrid (13.3%) (p = 0.02). Wound infection and chyle leak were also lower (wound 1.5% MIO 3.5% open, p = 0.6; chyle leak 1.5% MIO, 6.7% hybrid, p = 0.2). CONCLUSIONS: Our results show no negative impact of MIO on survival or oncological clearance. Respiratory and wound complications are lower in MIO, but rates of anastomotic strictures and potential anastomotic leaks are increased. This may be due to the longer length of conduit and subclinical ischaemia at the anastomosis and merits further evaluation. PMID- 28078466 TI - Does stoma site specimen extraction increase postoperative ileostomy complication rates? AB - BACKGROUND: Minimizing incisions has the potential to decrease hernia formation and wound complications following laparoscopic surgery. It is currently unknown if using the stoma site for specimen extraction affects outcomes. This study aims to evaluate the impact of stoma site extraction on postoperative complication rates in laparoscopic colorectal surgery. METHODS: After IRB approval, a retrospective comparative review of 738 consecutive patients (405 M) who underwent laparoscopic colorectal surgery with ileostomy between January 2008 and December 2014 was performed. Patients who had a minimally invasive surgery that required an ileostomy were included. Patients were classified into two groups: stoma site extraction (SSE) or non-stoma site extraction (NSSE) and compared by body mass index (BMI), age, comorbidities, American Society of Anesthesiologists score, length of stay, estimated blood loss, parastomal complications, and hernia rate. RESULTS: The parastomal hernia rate was 10.1% for the SSE group (n = 14) and 4.2% for the NSSE group (n = 25) (p = 0.007). The need for additional surgeries was 7/139 (5.0%) for the SSE group and 27/599 (4.5%) for the NSSE group (p = 0.79). There was no difference in the hernia rate after stoma closure in either group. There was no difference in single incision laparoscopic surgery versus conventional laparoscopy or robotic-assisted laparoscopy on stoma site complications in patients with SSE. SSE, transfusion, and BMI >30 were found to be independent factors associated with increased stoma site complications. CONCLUSION: SSE does increase stoma site complications. SSE should be used with caution, or in conjunction with other techniques to reduce hernias in patients requiring a permanent stoma or with an elevated BMI. The increase in stoma site complications does not translate into additional surgeries or postoperative sequelae following stoma reversal and is a reasonable option in patients requiring a temporary stoma. PMID- 28078467 TI - Clinical characteristics, risk factors and outcomes of asymptomatic rectal neuroendocrine tumors. AB - BACKGROUND: Rectal neuroendocrine tumors (NET) are often asymptomatic and frequently discovered during health examinations. However, data on the risk factors of asymptomatic rectal NETs are lacking. We investigated the risk factors, clinical characteristics and outcomes of asymptomatic rectal NETs discovered during health screening. MATERIALS AND METHODS: Asymptomatic subjects who underwent colonoscopy during routine health screening at a tertiary hospital from March 2009 to July 2014 were reviewed. Subjects with histologically confirmed rectal NETs were compared with healthy controls from the same population. Risk factors for rectal NETs were analyzed by multivariable analysis. Clinical outcomes of the resected NETs were also analyzed. RESULTS: A total of 21,706 Subjects underwent screening colonoscopy during the study period. 3417 were excluded from the study, and 180 rectal NET subjects were compared with 18,109 controls. Multivariable analysis showed that a previous history of malignancy (OR 2.960, 95% CI 1.673-5.237, p < 0.001), hypertriglyceridemia (OR 1.482, 95% CI 1.046-2.100, p = 0.027), higher fasting plasma glucose levels (OR 1.008, 95% CI 1.003-1.014, p = 0.001) and higher carcinoembryonic antigen levels (OR 1.019, 95% CI 1.003-1.035, p = 0.021) were significant risk factors while older age (OR 0.964, 95% CI 0.951-0.977, p < 0.001) was a preventive factor. One hundred and sixty nine subjects had endoscopic resection, five were treated by local surgery and six by radical surgery. Complete resection was achieved in 152 subjects. There were three cases of positive lymph nodes and one metastasis. Histology revealed four lymphatic, five vascular and two cases of perineural invasion. One hundred and fifty seven subjects were followed up for at least 1 year (median 38.6 months, 12-84 months). There were no recurrences during the follow-up period. CONCLUSIONS: Younger age, previous history of malignancy, higher fasting plasma glucose levels and hypertriglyceridemia are significantly associated with rectal NET risk. PMID- 28078468 TI - Surgery of the hallux valgus in an ambulatory setting: a liability risk? AB - INTRODUCTION: The primary objective of the study is to make an inventory of malpractice in hallux valgus surgery in an ambulatory setting and to identify the patient characteristics for a higher risk of malpractice. The secondary objective is creating a methodology for analyzing the medicolegal aspects of a surgery in day case comparing with hospitalization. MATERIALS AND METHODS: The database of the Branchet insurance company was used. A total of 11,000 claims for a period of 11 years (2002-2013) have been investigated. The files of the patients with hallux valgus surgery were isolated from the insurer's database using CCAM codes. The medical director, a medical officer, the legal expert and finally the judge had already analyzed all these cases. The authors reviewed the various documents with a specific questionnaire. RESULTS: We identified 14 cases of claims in relation with hallux valgus 1-day surgery among a total of 138 claims for hallux valgus including all techniques (10%). All patients were female. The mean age was 42.6 years (19-64) in ambulatory patients (AG group) in comparison with 49.5 years (19-73) in hospitalized patients (HG group). Percutaneous techniques were significantly more represented in the AG group (p = 0.002) and scarfs osteotomies in the HG group (p = 0.004). The use of tourniquet seemed to be lower in the AG group, but it was a not significant trend (p = 0.085). In term of anesthesia procedures, no significant differences were seen between the two groups. The comparison of the complications common to both groups showed no significant difference except for insufficient results which were more frequent in the AG group (p = 0.026). The rate of insufficient informed consent seemed to be higher in the AG group, but it was a not significant trend (p = 0.084). DISCUSSION AND CONCLUSION: No specific data regarding claims in relation with hallux valgus 1 day surgery are available to our knowledge in the literature. We did not identify in our study specific complications related to ambulatory procedures except for insufficient results. Hallux valgus 1-day surgery does not seem to expose surgeons to higher medicolegal problems than classical hospitalization. Nevertheless, a specific consent form for ambulatory patients is required to limit claims regarding information. PMID- 28078469 TI - New resistance-associated substitutions and failure of dual oral therapy with daclatasvir and asunaprevir. AB - BACKGROUND: Daclatasvir (DCV) and asunaprevir (ASV) combination therapy has been primarily used in patients without NS5A L31 or Y93 resistance-associated substitutions (RASs) before treatment. We examined the characteristics of patients without these baseline RASs who did not achieve hepatitis C virus eradication with DCV and ASV combination therapy and identified new baseline NS5A RASs that are closely associated with failure of combination therapy. METHODS: Three hundred thirty-five patients with hepatitis C virus genotype 1 infection with no NS5A L31, NS5A Y93, and NS3 D168 RASs before DCV and ASV combination therapy and no history of protease inhibitor therapy were enrolled. All RASs were evaluated by direct sequencing. RESULTS: Sustained virologic response at 12 weeks (SVR12) was achieved in 297 patients (89%). Patients with NS5A Q24, L28, and/or R30 RASs or concomitant NS5A F37 and Q54 RASs had a significantly lower SVR12 rate than patients without these RASs (70% vs 92%, p < 0.001 and 79% vs 92%, p = 0.002 respectively). Multivariate analysis showed that NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs were significantly associated with virologic failure. The SVR12 rate in patients without NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs was 96.2% (202/210). CONCLUSIONS: In patients without NS5A L31 or Y93 RASs, the presence of NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs at the baseline was associated with failure of DCV and ASV combination therapy. The coexistence of baseline RASs other than NS5A L31 and Y93 may affect the therapeutic effectiveness of DCV and ASV combination therapy. PMID- 28078470 TI - Appropriate timing to start and optimal response evaluation of high-dose corticosteroid therapy for patients with acute liver failure. AB - BACKGROUND: Corticosteroid therapy has been commonly administered to patients with acute liver injury (ALI)/acute liver failure (ALF) in Japan to prevent the development of hepatic encephalopathy, but the appropriate timing to start corticosteroid therapy has not been determined and optimal response evaluation of the therapy has not been conducted. We prospectively investigated the optimal timing to start therapy on the established severity indication: the Japan Hepatic Encephalopathy Prediction Model (JHEPM) and prothrombin time (PT). METHODS: This prospective observational study enrolled 469 patients with ALI/ALF from 2004 to 2015. We evaluated 44 patients with ALF on high-dose corticosteroid therapy before hepatic coma development. The predictive performance for coma development was assessed using the receiver operator curve method in both PT and JHEPM probability the day before administering high-dose corticosteroid therapy. RESULTS: Among these patients, nine developed hepatic coma after the therapy. Selection bias was adjusted using propensity score method. High-dose corticosteroid therapy tended to decrease the risk of coma development although there was no statistical significance. The cut-off value of 53%, 1.95, and 39% in JHEPM probability, PT-international normalized ratio (PT-INR), and PT activity, respectively, showed high sensitivity and specificity. CONCLUSIONS: We propose the appropriate timing to start high-dose corticosteroid therapy in patients with ALI/ALF; 40% of JHEPM probability, 1.53 of PT-INR, and 52% of PT because these values were theoretically discriminated at 98% coverage to the patients with coma. Because the study contained selection bias, the appropriate timing for therapy should be confirmed in a future prospective study. PMID- 28078472 TI - Using the Edinburgh Postnatal Depression Scale for women and men-some cautionary thoughts. AB - The objective of the study was to critically consider some of the possible limitations in the Edinburgh Depression Scale (EDS), given that great emphasis is put on the results of this measure within both clinical and research fields. Using findings and discussion points from other studies, as well as from a critical analysis of issues by the authors based upon their clinical and research experience, possible limitations with the scale in nine areas are discussed. Possible limitations include the following: (1) ambiguous items, (2) exclusion of certain types of distress, (3) scoring difficulties, (4) low positive predictive value, (5) frequent use of incorrect cut-off scores, (6) a vast array of validated cut-off scores, (7) validation against a questionable gold-standard, (8) limited anxiety detection and of depressive symptoms in men, and (9) many screen positive women only have transient distress. While the EDS has unquestionably been an extremely valuable instrument in aiding in the recognition of the importance of perinatal mental health, users of the scale should be aware that it, like other measures, has limitations. We discuss possible strategies to overcome these limitations and describe a recent scale that has been developed to surmount these shortcomings more effectively. PMID- 28078471 TI - Effects of estrogen on esophageal function through regulation of Ca2+-related proteins. AB - BACKGROUND: The calcium ion is important for physiological functions in all tissues and organs and essential to many vital functions, including hormone secretion and muscle contraction. The intracellular concentration of calcium is regulated by calcium related proteins such as CaBP-9k, PMCA1, and NCX1. In this study, we investigated the relationship between calcium regulation and esophageal functions such as mucin secretion and smooth muscle contraction. METHODS: To evaluate the influence of sex steroid hormones, immature rats were treated for 3 days with estradiol (E2), progesterone (P4), and their antagonists (ICI 182,780, and RU486). Esophageal function, transcription level, and localization of CaBP 9k, PMCA1, NCX1, ERalpha, and MUC2 were examined in the esophagus. RESULTS: Transcriptional level of Cabp-9k and Muc2 was increased by E2, but not by P4. CaBP-9k, PMCA1, and MUC2 were mainly localized in the mucosal layer. Acidic mucosubstances in the esophagus were increased by E2 and recovered by ICI treatment. Unlike the expression of Cabp-9k, mRNA levels of Pmca1, Ncx1, and Eralpha were only decreased in response to E2, and recovered by ICI co-treatment group. The contraction of the esophagus and mRNA level of Mylk were reduced by E2. Overall, E2 upregulated mucus secretion, but downregulated muscle contraction in the esophagus through regulation of the expression of calcium related genes and the resultant intracellular calcium level. CONCLUSIONS: The regulation of E2 in the function of esophagus may be applied to treat esophageal diseases such as reflux esophagitis, achalasia, and esophageal cancer. PMID- 28078473 TI - Traumatic atlantoaxial rotatory fixation in an adult patient. AB - INTRODUCTION: Atlantoaxial rotational fixation (AARF) is a rare entity in adults, with only a few cases reported in the English literature and often associated with a traumatic mechanism. It is an underdiagnosed condition that must be taken into account in the initial assessment of all craniocervical trauma. Both diagnostic and therapeutic delay may be a potential cause of severe neurological damage or even death of the patient. The therapeutic management is controversial given the difficulty of achieving optimum stability and permanent reduction. METHODS AND RESULTS: A 28-year-old woman was involved in a traffic accident a week before coming to the emergency with rotation and irreducible cervical flexion from trauma and severe neck pain. CT and MRI column were performed and showed a cervical spinal AARF with transverse and alar ligaments intact and preserved atlantoaxial distance (Fielding I). The patient was treated by progressive cervical traction with 5 kg and manual reduction was completed in 24 h. Subsequently, an external immobilization was performed by cervical rigid collar for 16 weeks. The clinical course was good, with the patient regaining full mobility with cervical neck pain improvement. CONCLUSIONS: The purpose of this paper is to show a case of a young woman with a posttraumatic AARF successfully treated conservatively. This case delineates the difficulties in diagnosing this pathology, as well as the challenges encountered in its management. PMID- 28078474 TI - Clinical audit effectively bridges the evidence-practice gap in chronic subdural haematoma management. AB - BACKGROUND: Placement of a subdural drain after drainage of chronic subdural haematoma (CSDH) has been shown to reduce the rate of recurrence in several randomised controlled trials (RCT). The most recently published RCT was from Cambridge, UK, in 2009. Despite class I evidence for the use of subdural drains, it is unclear whether these results have been translated into clinical practice. In this clinical audit we review the use of subdural drains in our institution before and after the publication of the 2009 RCT results. METHODS: A longitudinal retrospective study was performed on all adults having burr holes for CSDH between January 2009 and January 2014. Case notes were analysed to determine subdural drain use, re-operation for CSDH recurrence and post-operative complications. The audit loop was closed with data collected from August 2015 to January 2016. RESULTS: Thirty-one per cent of patients had subdural drains placed at operation. Drain placement was associated with lower reoperation rates (8% vs. 17%, p = 0.021) without increasing complication rates. Drain usage doubled after publication of the Santarius et al. (2009) trial but we observed persisting and significant variability in drain utilisation by supervising consultants. The use of drains in the department increased from 35% to 75% of all cases after presentation of these results. CONCLUSIONS: The use of subdural drains in our unit reduced recurrence rates following drainage of CSDH and reproduced the results of a 2009 clinical trial. Although the use of subdural drains doubled in the post-trial epoch, significant variability remains in practice. Clinical audit provided an effective tool necessary to drive the implementation of subdural drain placement in our unit. PMID- 28078475 TI - 50 years of the International Committee on Taxonomy of Viruses: progress and prospects. AB - We mark the 50th anniversary of the International Committee on Taxonomy of Viruses (ICTV) by presenting a brief history of the organization since its foundation, showing how it has adapted to advancements in our knowledge of virus diversity and the methods used to characterize it. We also outline recent developments, supported by a grant from the Wellcome Trust (UK), that are facilitating substantial changes in the operations of the ICTV and promoting dialogue with the virology community. These developments will generate improved online resources, including a freely available and regularly updated ICTV Virus Taxonomy Report. They also include a series of meetings between the ICTV and the broader community focused on some of the major challenges facing virus taxonomy, with the outcomes helping to inform the future policy and practice of the ICTV. PMID- 28078476 TI - Children with social anxiety and other anxiety disorders show similar deficits in habitual emotional regulation: evidence for a transdiagnostic phenomenon. AB - Deficits in emotion regulation (ER) are an important factor in maintaining social anxiety disorder (SAD) in adults. As SAD and ER problems typically develop during childhood and adolescence, and are maintained dynamically within the parent-child dyad, research on families can help to reveal the role ER plays in the early development of SAD. The current study assessed self-reported habitual ER in dyads of children with SAD (n = 31), children with mixed anxiety disorders (MAD; n = 41) and healthy control children (HC; n = 36), and their parents. Results indicate a transdiagnostic quality of ER in that, children with SAD and children with MAD similarly reported less adaptive and more maladaptive ER strategies than HC children, whereas no group differences in parental ER strategies emerged. Furthermore, children's ER strategies aggressive action, withdrawal and self devaluation and the parental ER strategy reappraisal were associated with social anxiety symptoms. These results suggest that there may be deficits in ER which generalize across childhood anxiety disorders. Our results are discussed in relation to current theories and their implications for treatment of childhood SAD. PMID- 28078477 TI - Information-sharing challenges between adolescents with cancer, their parents and health care providers: a qualitative study. AB - PURPOSE: We aimed to assess the viewpoints, experiences, and preferences within the clinical communication triangle (parent, adolescent, health care team) concerning the information-sharing process for adolescents with cancer. METHODS: This is a qualitative descriptive-exploratory study. Overall, 33 participants were recruited (adolescents diagnosed with cancer aged 15-20 years, their parents, oncologists, and nurses). In-depth semi-structured interviews were conducted and data were analyzed using constant comparative analysis. RESULTS: Data analysis yielded three main themes. Disaffiliation of adolescents in information-sharing process with three subthemes: confusion and unanswered questions; and, seeking information from inferior sources. Barriers to information-sharing with three subthemes: parents as gatekeepers in the information-sharing process, cultural background creating strong barriers for information-sharing, and the negative attitude of the medical team towards information-sharing. The last theme is cornerstones in information-sharing process with three subthemes: trust and honesty to enhance communication between adolescents and the medical team, the necessity of paving the way for information sharing, and the value of gradual information-sharing based on the adolescents need and mental readiness. CONCLUSION: Participants believed that information sharing was insufficient and provided recommendations for facilitating this process. Information-sharing process needs to be gradual and based on the adolescent's need and mental capacity. Future research needs to focus on devising a protocol for information-sharing with adolescents with cancer that accounts for familial and cultural factors, is carefully timed, and provides clearer and more efficacious communication between parents, adolescents, and the health care team. PMID- 28078478 TI - Hypercalcaemia and hypocalcaemia: finding the balance. AB - CALCIUM METABOLISM IN CANCER AND HYPERCALCAEMIA OF MALIGNANCY: The balance between bone formation and resorption may be disrupted in patients with cancer, leading either to increased bone resorption, calcium release, and possibly hypercalcaemia, or to increased bone formation, sequestration of calcium, and possibly hypocalcaemia. In adults, hypercalcaemia of malignancy is most common in patients with tumours that produce factors that induce osteoclast activation and enhance bone resorption. Impaired renal function and increased renal tubular calcium resorption may further affect calcium levels. TREATMENT OF HYPERCALCAEMIA OF MALIGNANCY: Inhibitors of bone resorption, first the bisphosphonates and, later, denosumab, have been shown to be effective in hypercalcaemia treatment. Bisphosphonates (which are administered intravenously) are approved for hypercalcaemia of malignancy and are the current mainstay of treatment, whereas denosumab (which is administered subcutaneously) may offer an option for patients who do not respond to bisphosphonates or suffer from renal insufficiency. HYPOCALCAEMIA: TREATMENT AND PREVENTION: Hypocalcaemia is most common in patients with prostate cancer and osteoblastic bone metastases, but can occur in patients with a variety of tumour types who are receiving inhibitors of bone resorption. While patients often respond to calcium and vitamin D supplementation, prevention should be the aim; at-risk patients should be identified before starting treatment with inhibitors of bone resorption, be closely monitored during at least the first few months of treatment, and receive concomitant calcium and vitamin D supplementation unless hypercalcaemia is present. CONCLUSION: Both hypercalcaemia and hypocalcaemia can be serious if left untreated. It is therefore important that patients with cancer are closely monitored and receive adequate prevention and treatment measures to maintain normal blood calcium levels. PMID- 28078480 TI - Muscarinic acetylcholine receptor-mediated tight junction opening is involved in epiphora in late phase of submandibular gland transplantation. AB - Submandibular gland (SMG) autotransplantation is an effective therapy for treating severe dry eye syndrome. However, epiphora occurs in more than 40% of patients 6 months after operation. We previously found that muscarinic acetylcholine receptor (mAChR) plays a crucial role in regulating SMG secretion partially through the modulation on tight junction (TJ)-based paracellular pathway. Therefore, the present study aimed to investigate the possible involvement of mAChR and TJ in a rabbit long-term model of SMG transplantation. We found that SMG secretion was significantly increased on postoperative days 90 and 180, which imitated epiphora observed in the patients with SMG transplantation. Although the mRNA expression and fluorescence intensity of M1 and M3 mAChR subtypes were reversed to control levels on postoperative days 30, 90, and 180, the content of beta-arrestin2, but not beta-arrestin1, was gradually decreased after transplantation, which suggests that mAChR may be hypersensitive in late phase of SMG transplantation. The width of acinar TJs was enlarged and fluorescence intensity of F-actin in peri-apicolateral membranes were remarkably increased on postoperative days 90 and 180. Topical treatment with atropine gel significantly reduced SMG secretion, TJ width, as well as F-actin intensity in peri-apicolateral membranes on postoperative days 180. Moreover, in a perfused rabbit SMG, carbachol increased salivary secretion, enlarged TJ width, and induced F-actin rearrangement, whereas these responses were inhibited by atropine pretreatment. Taken together, our findings suggest that the hypersensitive mAChR may contribute to epiphora in late phase of SMG transplantation through modulating TJ-based paracellular permeability. PMID- 28078479 TI - Follow-up cancer care: perspectives of Aboriginal and Torres Strait Islander cancer survivors. AB - PURPOSE: The purpose of this study was to explore Indigenous Australian cancer survivors' perspectives of follow-up cancer care and management.. METHODS: This is a qualitative study employing individual interviews with 21 Indigenous cancer survivors (13 females, 8 males) recruited from a rural primary health service and large tertiary hospital in Brisbane, Queensland. Yarning methods were used to conduct semi-structured interviews. Yarning is a culturally appropriate, informal conversational process emphasising the importance of storytelling. RESULTS: Findings describe a range of ways in which follow-up cancer care is experienced with four major categories elucidated, namely: links to tertiary health services, links to primary health services, communication between tertiary and primary health services, and lost in transition. Both positive and negative experiences were described; however, the importance of timely and informative discharge information, continuity of care, good communication between tertiary and primary health services, and strong therapeutic relationships were salient issues raised by participants. CONCLUSIONS: These findings highlight the importance of establishing strong therapeutic relationships between patients and tertiary and primary health professionals. Also important for survivorship is provision of discharge summaries or care plans at discharge for survivors and general practitioners as well as access to a range of allied health services. Alternative means for follow-up could be investigated for regional and rural survivors to facilitate convenient and cost-effective follow-up care. Finally, provision of responsive and flexible follow-up care to cater for the diverse range of needs and preferences of cancer survivors is required. A patient navigator available across the cancer continuum could go some way to addressing this. PMID- 28078481 TI - Defining a New Tumor Dimension in Staging of Papillary Thyroid Carcinoma. AB - BACKGROUND: Cervical lymph node metastasis is a vital factor associated with local recurrence in papillary thyroid carcinoma (PTC). Tumor size is used in the staging of PTC because it represents the tumor load. This study compared two methods of tumor size assessment to predict tumor behavior in the relationship between size and cervical node involvement for patients with PTC. METHODS: The study enrolled 1084 patients who underwent initial thyroid surgery and had a pathologic diagnosis of PTC between 2012 and 2014 at The Second Affiliated Hospital Zhejiang University School of Medicine. Cervical lymph node metastasis (LNM) risk was analyzed according to the clinicopathologic features. For each patient with multifocal disease, two tumor size estimates were used: (1) the dominant focus size and (2) the aggregate size, calculated as the sum of the maximal diameters of all tumor foci. RESULTS: Of the 1084 patients, 294 (27.1%) had multifocal cancer lesions, and 49% of these patients had cervical LNM, compared with 38.1% who had unifocal disease (P = 0.001). The use of aggregate dimension significantly increased the tumor size and reclassified significant numbers of multifocal PTCs to a more advanced T stage. This aggregate dimension took account of all tumor foci and predicted LNM risk at a proportion identical with that for size-matched, unifocal tumors. CONCLUSION: Multifocality together with aggregate tumor size is a more accurate predictor of node status and, by inference, tumor behavior in the relationship between tumor size and cervical node involvement. PMID- 28078482 TI - Irreversible electroporation as treatment of locally advanced and as margin accentuation in borderline resectable pancreatic adenocarcinoma. AB - In recent years, many local ablation technologies based on thermal damage have been used in the treatment of locally advanced pancreatic carcinoma (LAPC) and borderline resectable pancreatic carcinoma (BLRPC). However, they are associated with major complications because of possible vascular and ductal damage. Irreversible electroporation (IRE) is a nonthermal ablation technology that seems safe near vital vascular and ductal structures. IRE could be used as exclusive treatment of LAPC (en situ to IRE) after induction chemotherapy In BLRPC, surgery is not really radical in 6% of patients (microscopic residual) and local recurrences occur in 11-42% of apparent radical resections. IRE could be used as margin accentuation to increase posterior margin during radical surgery in BLRPC. Our outcomes are safety, time to progression. Secondary outcomes are overall survival, pain control and quality of life. We are performing a prospective evaluation of patients undergoing IRE for LAPC or BLRPC since July 2014. We have included patients with non-metastatic LAPC with maximum size <=4 cm (en situ to IRE) and patients with BLRPC (complementary IRE). We have performed induction chemotherapy in both groups. After treatment, patients were evaluated on days 1, 2, 4, 7, 14, 21, 30, 60 and 90 with amylase and lipase serum and abdominal drainage test. Based on Ethics Committee's request, follow-up imaging was performed at the 10th day for safety evaluation, at 30, 60 and 90 days for response evaluation and then every 3 months. Seven patients (two women and five men) underwent IRE. Two patients had LAPC and received en situ to IRE. In five patients affected by BLRPC we performed IRE and pancreatic head resection. In all patients, intraoperative imaging confirmed that the treatment of the whole tumor volume was complete. All seven patients demonstrated nonclinically relevant elevation of their amylase and lipase, which returned normal at 5 days postprocedure. No patient showed evidence of clinical pancreatitis or fistula. No major complications were recorded. Patients with LAPC died of distant metastases 6 month after treatment. At 3- and 6-month follow-up, all patients with BLPRC were alive and disease free. Only one patient has already reached 9-month follow up and is alive and disease free. Our results are only preliminary. However, IRE ablation of LAPC and BLRPC seems a safe and feasible treatment. PMID- 28078483 TI - Theoretical characterization on photoelectric properties of benzothiadiazole- and fluorene-based small molecule acceptor materials for the organic photovoltaics. AB - The upper efficiency of heterojunction organic photovoltaics depends on the increased open-circuit voltage (V oc) and short-circuit current (J sc). So, a higher lowest unoccupied molecular orbital (LUMO) level is necessary for organic acceptor material to possess higher V oc and more photons absorbsorption in the solar spectrum is needed for larger J sc. In this article, we theoretically designed some small molecule acceptors (2~5) based on fluorene (F), benzothiadiazole, and cyano group (CN) referring to the reported acceptor material 2-[{7-(9,9-di-n-propyl-9H-fluoren-2-yl)benzo[c][1,2,5]thiadiazol-4 yl}methylene]malononitrile (1), the crucial parameters affecting photoelectrical properties of compounds 2~5 were evaluated by the density functional theory (DFT) and time dependent density functional theory (TDDFT) methods. The results reveal that compared with 1, 3 and 4 could have the better complementary absorption spectra with P3HT, the increased LUMO level, the improved V oc, and the decreased electronic organization energy (lambda e). From the simulation of transition density matrix, it is very clear that the excitons of molecules 3 and 4 are easier to separate in the material surface. Therefore, 3 and 4 may become potential acceptor candidates for organic photovoltaic cells. In addition, with the increased number of CN, the optoelectronic properties of the molecules show a regular change, mainly improve the LUMO level, energy gap, V oc, and absorption intensity. In summary, reasonably adjusting CN can effectively improve the photovoltaic properties of small molecule acceptors. Graphical Abstract Structure property relationship of small molecule acceptors could be rationally evaluated in the article. The changes of conjugate length and CN are important strategies to alter the photovoltaic properties of small molecule acceptors. Therefore, taking the K12/1 as a reference, we have theoretically designed a series of small molecule acceptors (2-4). The calculated results by means of DFT and TDDFT manifest that molecules 3 and 4 have the better complementary absorption spectra with P3HT, the increased LUMO level, the improved V oc, the decreased electronic organization energy and the easier separation in the material surface than 1. In summary, reasonably increasing conjugate length and decreasing CN can effectively improve the PCE, which will provide a theoretical guideline for the design and synthesis of new small molecule acceptors. PMID- 28078484 TI - The Effect of Surface Charges on the Cellular Uptake of Liposomes Investigated by Live Cell Imaging. AB - PURPOSE: Liposomes have been developed as versatile nanocarriers for various pharmacological agents. The effect of surface charges on the cellular uptake of the liposomes has been studied by various methods using mainly fixed cells with inevitable limitations. Live cell imaging has been proposed as an alternative methods to overcome the limitations of the fixed cell-based analysis. In this study, we aimed to investigate the effects of surface charges on cellular association and internalization of the liposomes using live cell imaging. METHODS: We studied the cellular association and internalization of liposomes with different surface charge using laser scanning confocal microscopy (LSCM) equipped with live cell chamber system. Flow cytometry was also carried out using flow cytometer (FACS) for comparison. RESULTS: All of the cationic, neutral and anionic liposomes showed time-dependent cellular uptake through specific endocytic pathways. In glioblastoma U87MG cells, the cationic and anionic liposomes were mainly taken up via macropinocytosis, while the neutral liposomes mainly via caveolae-mediated endocytosis. In fibroblast NIH/3T3 cells, all of the three liposomes entered into the cell via clathrin-mediated endocytosis. CONCLUSIONS: This study provides a better understanding on the cellular uptake mechanisms of the liposomes, which could contribute significantly to development of liposome-based drug delivery systems. PMID- 28078485 TI - A Simple Method for Improving the Spatial Resolution in Infrared Laser Ablation Mass Spectrometry Imaging. AB - In mass spectrometry imaging of tissues, the size of structures that can be distinguished is determined by the spatial resolution of the imaging technique. Here, the spatial resolution of IR laser ablation is markedly improved by increasing the distance between the laser and the focusing lens. As the distance between the laser and the lens is increased from 1 to 18 m, the ablation spot size decreases from 440 to 44 MUm. This way, only the collimated center of the divergent laser beam is directed on the focusing lens, which results in better focusing of the beam. Part of the laser energy is lost at longer distance, but this is compensated by focusing of the radiation to a smaller area on the sample surface. The long distance can also be achieved by a set of mirrors, between which the radiation travels before it is directed to the focusing lens and the sample. This method for improving the spatial resolution can be utilized in mass spectrometry imaging of tissues by techniques that utilize IR laser ablation, such as laser ablation electrospray ionization, laser ablation atmospheric pressure photoionization, and matrix-assisted laser desorption electrospray ionization. Graphical Abstract ?. PMID- 28078486 TI - Two NADPH: Protochlorophyllide Oxidoreductase (POR) Isoforms Play Distinct Roles in Environmental Adaptation in Rice. AB - BACKGROUND: NADPH: protochlorophyllide oxidoreductase (POR) is an essential enzyme that catalyzes the photoreduction of protochlorophyllide to chlorophyllide, which is ultimately converted to chlorophyll in developing leaves. Rice has two POR isoforms, OsPORA and OsPORB. OsPORA is expressed in the dark during early leaf development; OsPORB is expressed throughout leaf development regardless of light conditions. The faded green leaf (fgl) is a loss of-function osporB mutant that displays necrotic lesions and variegation in the leaves due to destabilized grana thylakoids, and has increased numbers of plastoglobules in the chloroplasts. To investigate whether the function of OsPORA can complement that of OsPORB, we constitutively overexpressed OsPORA in fgl mutant. RESULTS: In the 35S:OsPORA/fgl (termed OPAO) transgenic plants, the necrotic lesions of the mutant disappeared and the levels of photosynthetic pigments and proteins, as well as plastid structure, were recovered in developing leaves under natural long days in the paddy field and under short days in an artificially controlled growth room. Under constant light conditions, however, total chlorophyll and carotenoid levels in the developing leaves of OPAO plants were lower than those of wild type. Moreover, the OPAO plants exhibited mild defects in mature leaves beginning at the early reproductive stage in the paddy field. CONCLUSIONS: The physiological function of OsPORB in response to constant light or during reproductive growth cannot be completely replaced by constitutive activity of OsPORA, although the biochemical functions of OsPORA and OsPORB are redundant. Therefore, we suggest that the two OsPORs have differentiated over the course of evolution, playing distinct roles in the adaptation of rice to the environment. PMID- 28078487 TI - The role of the Nox4-derived ROS-mediated RhoA/Rho kinase pathway in rat hypertension induced by chronic intermittent hypoxia. AB - BACKGROUND: Obstructive sleep apnea syndrome, which is a risk factor for resistant hypertension, is characterized by chronic intermittent hypoxia (CIH) and is associated with many cardiovascular diseases. CIH elicits systemic oxidative stress and sympathetic hyperactivity, which lead to hypertension. Rho kinases (ROCKs) are considered to be major effectors of the small GTPase RhoA and have been extensively studied in the cardiovascular field. Upregulation of the RhoA/ROCK signaling cascade is observed in various cardiovascular disorders, such as atherosclerosis, pulmonary hypertension, and stroke. However, the exact molecular function of RhoA/ROCK in CIH remains unclear and requires further study. OBJECTIVE: This study aimed to investigate the role of the NADPH oxidase 4 (Nox4)-induced ROS/RhoA/ROCK pathway in CIH-induced hypertension in rats. METHODS: Male Sprague-Dawley rats were exposed to CIH for 21 days (intermittent hypoxia of 21% O2 for 60 s and 5% O2 for 30 s, cyclically repeated for 8 h/day). We randomly assigned 56 male rats to groups of normoxia (RA) or vertically implemented CIH together with vehicle (CIH-V), GKT137831 (CIH-G), N-acetyl cysteine (NAC) (CIH-N), or Y27632 (CIH-Y). The rats in the RA group were continuously exposed to room air, whereas the rats in the other groups were exposed to CIH. Systolic blood pressure (BP) was monitored at the beginning of each week. After the experiment, renal sympathetic nerve activity (RSNA) was recorded, and serum and renal tissues were subjected to molecular biological and biochemical analyses. RESULTS: Compared with the BP of RA rats, the BP of CIH-V rats started to increase 2 weeks after the beginning of the experiment, subsequently stabilizing at a high level at the end of the third week. CIH increased both RSNA and oxidative stress. This response was attenuated by treatment of the rats with GKT137831 or NAC. Inhibiting Nox4 activity or ROS production reduced RhoA/ROCK expression. Treatment with Y27632 reduced both BP and RSNA in rats exposed to CIH. CONCLUSION: Hypertension can be induced by CIH in SD rats. The CIH-induced elevation of BP is at least partially mediated via the Nox4-induced ROS/RhoA/ROCK pathway. PMID- 28078488 TI - Hydroxyurea treatment effect on children with sickle cell disease and obstructive sleep apnea. AB - BACKGROUND: While hydroxyurea is the mainstay of treatment for many of the comorbidities associated with sickle cell disease, its effect on obstructive sleep apnea has not been fully investigated. The purpose of this project is to help characterize the effects of hydroxyurea on obstructive sleep apnea in children with sickle cell disease and determine its therapeutic role in the condition. METHODS: Chart review was conducted on two pediatric patients with sickle cell disease who experienced resolution of obstructive sleep apnea following hydroxyurea administration. RESULTS: After undergoing approximately 11 months of hydroxyurea therapy, sleep apnea symptoms improved and obstructive sleep apnea resolution was confirmed by repeat polysomnography in both cases. This resolution was largely secondary to a reduction in the obstructive component of the apnea hypopnea index, highlighting a previously unreported association. CONCLUSIONS: As adenotonsillectomy is associated with significant risks in patients with sickle cell disease, it appears reasonable to consider a period of observation for improvement of obstructive sleep apnea following hydroxyurea administration rather than directly proceeding with surgery. PMID- 28078489 TI - Identification and profiling of conserved and novel microRNAs involved in oil and oleic acid production during embryogenesis in Carya cathayensis Sarg. AB - MicroRNAs (miRNAs) are important regulators of plant development and fruit formation. Mature embryos of hickory (Carya cathayensis Sarg.) nuts contain more than 70% oil (comprising 90% unsaturated fatty acids), along with a substantial amount of oleic acid. To understand the roles of miRNAs involved in oil and oleic acid production during hickory embryogenesis, three small RNA libraries from different stages of embryogenesis were constructed. Deep sequencing of these three libraries identified 95 conserved miRNAs with 19 miRNA*s, 7 novel miRNAs (as well as their corresponding miRNA*s), and 26 potentially novel miRNAs. The analysis identified 15 miRNAs involved in oil and oleic acid production that are differentially expressed during embryogenesis in hickory. Among them, nine miRNA sequences, including eight conserved and one novel, were confirmed by qRT-PCR. In addition, 145 target genes of the novel miRNAs were predicted using a bioinformatic approach. Our results provide a framework for better understanding the roles of miRNAs during embryogenesis in hickory. PMID- 28078491 TI - Prognostic factors in early breast cancer associated with body mass index, physical functioning, physical activity, and comorbidity: data from a nationwide Danish cohort. AB - PURPOSE: To explore the associations between lifestyle-related factors and tumor related prognostic factors in women treated for primary breast cancer, and to detect possible differences between the associations in pre- and postmenopausal women. METHODS: Associations between tumor-related prognostic factors, including the composite endpoint risk of recurrence (RoR), body mass index (BMI), comorbidity (Charlson comorbidity index), basic physical functioning (SF-36), physical activity, smoking, and alcohol consumption were examined with binary logistic regression analysis in a national cohort of 4917 women treated for primary breast cancer. In addition, statistical interactions between predictors and menopausal status were assessed in order to determine if their strength differed significantly as a function of menopausal status. RESULTS: Higher BMI, reduced physical function, reduced physical activity, and greater alcohol consumption were all statistically significantly associated with two or more tumor-related factors indicating a poorer prognosis. Interaction analysis revealed that BMI was significantly stronger associated with RoR among premenopausal women than among postmenopausal women (interaction ip = 0.048). Similarly, a significant association between RoR and physical function was only seen in the premenopausal population (ip = 0.008). This pattern was also seen between RoR and daily alcohol consumption, which only reached statistical significance in the total population and in premenopausal women (ip < 0.001). CONCLUSION: Premenopausal women who are overweight and have poorer physical function have poorer prognosis at the time of diagnosis, suggesting the possible relevance of stratifying adjuvant treatment according to guidelines, BMI, and menopausal status. PMID- 28078490 TI - Podocalyxin as a major pluripotent marker and novel keratan sulfate proteoglycan in human embryonic and induced pluripotent stem cells. AB - Podocalyxin (PC) was first identified as a heavily sialylated transmembrane protein of glomerular podocytes. Recent studies suggest that PC is a remarkable glycoconjugate that acts as a universal glyco-carrier. The glycoforms of PC are responsible for multiple functions in normal tissue, human cancer cells, human embryonic stem cells (hESCs), and human induced pluripotent stem cells (hiPSCs). PC is employed as a major pluripotent marker of hESCs and hiPSCs. Among the general antibodies for human PC, TRA-1-60 and TRA-1-81 recognize the keratan sulfate (KS)-related structures. Therefore, It is worthwhile to summarize the outstanding chemical characteristic of PC, including the KS-related structures. Here, we review the glycoforms of PC and discuss the potential of PC as a novel KS proteoglycan in undifferentiated hESCs and hiPSCs. PMID- 28078493 TI - False-Positive Newborn Screen Using the Beutler Spot Assay for Galactosemia in Glucose-6-Phosphate Dehydrogenase Deficiency. AB - Classical galactosemia is detected through newborn screening by measuring galactose-1-phosphate uridylyltransferase (GALT) in the USA primarily via the Beutler spot assay. We report on an 18-month-old patient with glucose-6-phosphate dehydrogenase (G6PD) deficiency that was originally diagnosed with classical galactosemia. The patient presented with elevated liver function enzymes and bilirubinemia and was immediately treated with soy-based formula. Confirmatory tests revealed deficiency of the GALT enzyme, however, full-sequencing of GALT was normal, suggestive of a different ideology. The Beutler spot assay uses three other enzymatic steps in addition to GALT. A deficiency in either of these enzymes can result in suspected decreased GALT activity when using the Beutler assay. Congenital Disorders of Glycosylation screening for phosphoglucomutase-1 deficiency was negative. Quantitative analysis of G6PD enzyme in red blood cells showed a severe deficiency and a deletion in G6PD. Soy-formula, the standard treatment for galactosemia, has been reported to trigger hemolysis in G6PD deficient patients. G6PD and phosphoglucomutase-1 deficiencies should be considered when confirmatory tests are negative for pathogenic variants in GALT and galactose-1-phosphate level is normal. PMID- 28078492 TI - First Report of bla CTX-M-15-Type ESBL-Producing Klebsiella pneumoniae in Wild Migratory Birds in Pakistan. AB - We investigated wild migratory birds faecal swabs for extended-spectrum beta lactamases-producing Klebsiella pneumoniae (ESBL-K. pneumoniae) from wetland habitats in Pakistan. ESBL-K. pneumoniae were analysed for MDR phenotype, ESBL genotype and genetic diversity. A total of 13 (8.6%) ESBL-K. pneumoniae were recovered. Of these, 8 (61%) isolates were MDR. DNA sequencing confirmed bla CTX M-15 as the dominant ESBL genotype. BOX-PCR fingerprints showed most of the isolates are unrelated. This study is the first to report the wildlife contamination of CTX-M-15-producing K. pneumoniae in Pakistan. Due to long-range migration, these birds could be responsible for trans-boundary spread of multidrug-resistant bacteria. PMID- 28078494 TI - Erratum to: Effect of taurine supplementation on hepatic metabolism and alleviation of cadmium toxicity and bioaccumulation in a marine teleost, red sea bream, Pagrus major. PMID- 28078496 TI - Theoretical and Empirical Comparisons of Methods to Estimate the Size of Hard-to Reach Populations: A Systematic Review. AB - Worldwide, the HIV epidemic is concentrated among hidden populations (i.e., female sex workers, men who have sex with men, and people who inject drugs). To understand the true scope and scale of the HIV epidemic, estimates of the sizes of these populations are needed. Various methods are available to enumerate hidden populations, but the degree of agreement between these methods has not been formally evaluated. We systematically reviewed the peer-reviewed literature to assess the extent to which different population size estimation methods provide the same estimate of a target population. Of the 341 studies identified from our search, 25 met our eligibility criteria. Twenty-one unique methods were documented. The service multiplier method was the most common in the review. Eighty target populations were estimated, covering 16 countries. We observed variable population size estimates, with little agreement between methods. We note trends in the relative performance of individual methods. PMID- 28078495 TI - Economic Context and HIV Vulnerability in Adolescents and Young Adults Living in Urban Slums in Kenya: A Qualitative Analysis Based on Scarcity Theory. AB - Urban slum adolescents and young adults have disproportionately high rates of HIV compared to rural and non-slum urban youth. Yet, few studies have examined youth's perceptions of the economic drivers of HIV. Informed by traditional and behavioral economics, we applied a scarcity theoretical framework to qualitatively examine how poverty influences sexual risk behaviors among adolescents and young adults. Focus group discussions with one hundred twenty youth in Kenyan's urban slums were transcribed, coded, and analyzed using interpretive phenomenology. Results indicated that slum youth made many sexual decisions considered rational from a traditional economics perspective, such as acquiring more sex when resources were available, maximizing wealth through sex, being price-sensitive to costs of condoms or testing services, and taking more risks when protected from adverse sexual consequences. Youth's engagement in sexual risk behaviors was also motivated by scarcity phenomena explained by behavioral economics, such as compensating for sex lost during scarce periods (risk-seeking), valuing economic gains over HIV risks (tunneling, bandwidth tax), and transacting sex as an investment strategy (internal referencing). When scarcity was alleviated, young women additionally described reducing the number of sex partners to account for non-economic preferences (slack). Prevention strategies should address the traditional and behavioral economics of the HIV epidemic. PMID- 28078497 TI - Anti-inflammatory effect of Naravelia zeylanica DC via suppression of inflammatory mediators in carrageenan-induced abdominal oedema in zebrafish model. AB - The traditional herbal medicines are receiving great importance in the health care sector, especially in Indian system of medicine, i.e, Ayurveda. The present study focused on the standardization of Naravelia zeylanica (L.) DC in terms of its active phytochemicals and to evaluate the anti-inflammatory activity of ethanol extract of N. zeylanica (ENZ). An analytical method was developed by high performance liquid chromatography for simultaneous determination of beta sitosterol, lupeol and oleanolic acid in ENZ. The cell viability of ENZ was investigated using MTT assay. IC50 value of ENZ on cell viability was found to be 653.01 ug/mL. To determine the anti-inflammatory activity of ENZ by in vitro method, LPS was added to the macrophage cells to induce activation and ENZ was further added to observe the recovery of inflamed cells. These cells when treated with ENZ, the percentage of viable cells were considerably increased to 74.68%. Loss of mitochondrial membrane potential on treatment with LPS and its recovery by ENZ was studied and found that the number of cells that were damaged on treatment with ENZ + LPS was comparatively lesser than treatment with LPS only. An in vivo anti-inflammatory study was carried out in carrageenan-induced abdominal oedema method in adult zebrafish which revealed the percentage inhibition of inflammation at graded dose levels of ENZ as 23.5% at 100 mg/kg, 62.4% at 200 mg/kg and 87.05% at 350 mg/kg when compared with standard of diclofenac which showed 85% inhibition at 100 mg/kg. The PCR amplification of DNA extracted from adult zebrafish showed that increased concentration of ENZ considerably downregulates the expression of TNF-alpha and iNOS, the mediators of inflammation. PMID- 28078498 TI - Perinatal Exposure to Bisphenol A or Diethylstilbestrol Increases the Susceptibility to Develop Mammary Gland Lesions After Estrogen Replacement Therapy in Middle-Aged Rats. AB - The development of the mammary gland is a hormone-regulated event. Several factors can dysregulate its growth and make the gland more susceptible to cellular transformation. Among these factors, perinatal exposure to xenoestrogens and hormone replacement therapy has been associated with increased risk of developing breast cancer. Here, we assessed the effects induced by estrogen replacement therapy (ERT) in ovariectomized (OVX) middle-aged rats and whether perinatal exposure to diethylstilbestrol (DES) or bisphenol A (BPA) modified these effects in the mammary gland. Pregnant rats were orally exposed to vehicle, 5 MUg DES/kg/day, or 0.5 or 50 MUg BPA/kg/day from gestational day 9 until weaning. Then, 12-month-old offspring were OVX and treated with 17beta-estradiol for 3 months. Morphological changes and the percentage of epithelial cells that proliferated or expressed estrogen receptor alpha (ESR1) and progesterone receptor (PR) were analyzed in mammary gland samples of 15-month-old animals. ERT induced lobuloalveolar hyperplasia and ductal cysts in the mammary gland of middle-aged rats, associated with a higher proliferation index of epithelial cells. Perinatal exposure to DES followed by ERT increased the number of cysts and induced the formation of fibroadenoma and ductal carcinoma in situ, without modifying the expression of ESR1 or PR. Also, after 3 months of ERT, BPA-exposed rats had a higher incidence of ductal hyperplasia and atypical lobular hyperplasia than animals under ERT alone. In conclusion, perinatal exposure to xenoestrogens increases the susceptibility of the mammary gland to develop cysts and hyperplastic lesions when confronted with ERT later in life. PMID- 28078499 TI - Carbonaceous Chondrite Meteorites: the Chronicle of a Potential Evolutionary Path between Stars and Life. AB - The biogenic elements, H, C, N, O, P and S, have a long cosmic history, whose evolution can still be observed in diverse locales of the known universe, from interstellar clouds of gas and dust, to pre-stellar cores, nebulas, protoplanetary discs, planets and planetesimals. The best analytical window into this cosmochemical evolution as it neared Earth has been provided so far by the small bodies of the Solar System, some of which were not significantly altered by the high gravitational pressures and temperatures that accompanied the formation of larger planets and may carry a pristine record of early nebular chemistry. Asteroids have delivered such records, as their fragments reach the Earth frequently and become available for laboratory analyses. The Carbonaceous Chondrite meteorites (CC) are a group of such fragments with the further distinction of containing abundant organic materials with structures as diverse as kerogen-like macromolecules and simpler compounds with identical counterparts in Earth's biosphere. All have revealed a lineage to cosmochemical synthetic regimes. Several CC show that asteroids underwent aqueous alteration of their minerals or rock metamorphism but may yet yield clues to the reactivity of organic compounds during parent-body processes, on asteroids as well as larger ocean worlds and planets. Whether the exogenous delivery by meteorites held an advantage in Earth's molecular evolution remains an open question as many others regarding the origins of life are. Nonetheless, the natural samples of meteorites allow exploring the physical and chemical processes that might have led to a selected chemical pool amenable to the onset of life. Graphical Abstract ?. PMID- 28078500 TI - Effects of different omega-3 sources, fish oil, krill oil, and green-lipped mussel against cytokine-mediated canine cartilage degradation. AB - Our purpose was to evaluate the protective effect of three marine omega-3 sources, fish oil (FO), krill oil (KO), and green-lipped mussel (GLM) against cartilage degradation. Canine cartilage explants were stimulated with either 10 ng/mL interleukin-1beta (IL-1beta) or IL-1beta/oncostatin M (10 ng/mL each) and then treated with various concentrations of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA; 3 and 30 MUg/mL), FO, KO, or GLM (250, 500, and 1000 MUg/mL) for 28 days. Gene expression was then investigated in primary canine chondrocytes. Our results showed that DHA and EPA as well as omega-3 sources could suppress matrix degradation in cytokine-induced cartilage explants by significantly reducing the increase of sulfated glycosaminoglycans (s-GAGs) and preserving uronic acid and hydroxyproline content (except GLM). These agents were not able to reduce IL-1beta-induced IL1B and TNFA expression but were able to down-regulate the expression of the catabolic genes MMP1, MMP3, and MMP13 and up regulate the anabolic genes AGG and COL2A1; FO and KO were especially effective. Our findings indicated that FO and KO were superior to GLM for their protective effect against proteoglycan and collagen degradation. Hence, FO and KO could serve as promising sources of chondroprotective agents. PMID- 28078501 TI - The Tissue Culture Laboratory of Dr. George Otto Gey 60 yrs ago as recalled by a former student. AB - George Otto Gey was a pioneer in tissue culture, having introduced the roller drum, the HeLa cell line, and the use of human fetal cord serum and beef embryo extract. During his career (1920s-1960s), the field of tissue culture was in its infancy and not yet dependent upon commercial biological supply houses. While the early techniques of cell culture have been greatly improved upon, of historical interest may be personal observations of the Gey Tissue Culture Laboratory, Johns Hopkins Medical School, as recalled by a medical student working there in the 1950s. Dr. Gey served as a founding member and executive of the Tissue Culture Commission (TCC) and became the first president of the Tissue Culture Association (TCA). PMID- 28078502 TI - Engagement in health-promoting behaviors and patient-caregiver interdependence in dyads facing advanced cancer: an exploratory study. AB - Diet and exercise are important for the wellbeing of people with cancer and their family caregivers. Unfortunately, little is known about their behaviors over time or factors that may influence their engagement in these behaviors. This exploratory study examined the influence of chronic conditions, symptom distress, and perceived social support on exercise and diet behaviors of patients with advanced cancer and their caregivers using the actor-partner interdependence mediation model (APIMeM) and interdependence theory as guiding frameworks. This secondary analysis uses self-report data from a large RCT (N = 484 patient caregiver dyads) at three time points: baseline data was collected within three months of the diagnosis, at 3 months post-baseline, and 6 months post-baseline. A number of actor effects were observed: patient and caregiver prior exercise and diet were significant predictors of their own future exercise and diet behaviors; more patient-reported social support was associated with less patient exercise; more patient symptom distress was associated with poorer patient diet; and, more caregiver-reported social support was associated with more caregiver exercise and better caregiver diet. Partner effects were also observed: more patient exercise was positively associated with more caregiver exercise; more patient comorbidities were associated with better caregiver diet; more caregiver-reported social support was associated with better patient diet; and, more patient reported social support was associated with better caregiver diet. Despite the challenges of advanced cancer and caregiving, past exercise and diet behavior remained a significant predictor of future behavior. Other health problems and perceptions of social support within the dyad may exert a positive or negative influence on patient/caregiver diet and exercise. PMID- 28078503 TI - Efficacy of pulsed Nd:YAG laser in the treatment of patients with knee osteoarthritis: a randomized controlled trial. AB - The purpose of this study was to investigate the effects of pulsed Nd:YAG laser plus glucosamine/chondroitin sulfate (GCS) in patients with knee osteoarthritis (KOA) by examining changes in pain and knee function, as well as synovial thickness (ST) and femoral cartilage thickness (FCT). Sixty-seven male patients participated, with a mean (SD) age of 53.85 (4.39) years, weight of 84.01 (4.70) kg, height of 171.51 (3.96) cm, and BMI of 28.56 (1.22). Group 1 was treated with high-intensity laser therapy (HILT), GCS, and exercises (HILT + GCS + EX). Group 2 was treated with GCS plus exercises (GCS + EX), and group 3 received placebo laser plus exercises (PL + EX). The outcomes measured were pain level and functional disability using the visual analog scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), respectively. ST and FCT were measured by ultrasound examination. Statistical analyses were performed to compare differences between baseline and after 6 weeks of treatment and then after 3 months of follow-up. Statistical significance was set at p < 0.05. VAS and WOMAC were significantly decreased in all groups after 6 weeks, with nonsignificant differences between 6 weeks and 3 months of follow-up. ST was significantly decreased in the HILT + GCS + EX group posttreatment, with nonsignificant decreases in the GCS + EX and PL + EX groups, as well as nonsignificant differences to FCT in all groups. Overall, pulsed Nd:YAG laser combined with GCS and exercises was more effective than GCS + EX and exercises alone in the treatment of KOA patients. PMID- 28078504 TI - Pulsed dye laser on ecchymoses: clinical and histological assessment. PMID- 28078506 TI - Regulation of p53 acetylation. PMID- 28078505 TI - T2 relaxation time measurements in the brains of scalded rats. AB - This study aimed to evaluate the T2 relaxation time of the brain in severely scalded rats using a magnetic resonance (MR) T2 mapping sequence, and to investigate the correlation between T2 relaxation time and plasma glucose level. Twenty-eight Wistar rats were randomly divided into the scalded group (n=21) and control group (n=7). Magnetic resonance scans were performed with T1WI, T2WI, and T2-mapping sequences in the scalded group; the scans were performed 1 day prior to scalding and 1, 3, 5, and 7 days post-scalding; in addition, identical MR scans were performed in the control group at the same time points. T2-maps were generated and T2 relaxation times were acquired from the following brain regions: the hippocampus, thalamus, caudate-putamen, and cerebrum. Pathological changes of the hippocampus were observed. The plasma glucose level of each rat was measured before each MR scan, and a correlation analysis was performed between T2 relaxation time and plasma glucose level. We found that conventional T1WI and T2WI did not reveal any abnormal signals or morphological changes in the hippocampus, thalamus, caudate-putamen, or cerebrum post-scalding. Both the T2 relaxation times of the selected brain regions and plasma glucose levels increased 1, 3, and 5 days post-scalding, and returned to normal levels 7 days post-scalding. The most marked increase of T2 relaxation time was found in the hippocampus; similar changes were also revealed in the thalamus, caudate-putamen, and cerebrum. No correlation was found between T2 relaxation time and plasma glucose level in scalded rats. Pathological observation of the hippocampus showed edema 1, 3, and 5 days post-scalding, with recovery to normal findings at 7 days post-scalding. Thus, we concluded that T2 mapping is a sensitive method for detecting and monitoring scald injury in the rat brain. As the hippocampus is the main region for modulating a stress reaction, it showed significantly increased water content along with an increased plasma glucose level post-scalding. PMID- 28078507 TI - Quantitative analysis of diffusion-weighted magnetic resonance images: differentiation between prostate cancer and normal tissue based on a computer aided diagnosis system. AB - Diffusion-weighted imaging (DWI) is considered to be one of the dominant modalities used in prostate cancer (PCa) detection and the assessment of lesion aggressiveness, especially for peripheral zone (PZ) PCa. Computer-aided diagnosis (CAD), which is capable of automatically extracting and evaluating image features, can integrate multiple parameters and improve the detection of PCa. In this study, 13 quantitative image features were extracted from DWI by CAD, and diagnostic efficacy was analyzed in both the PZ and transition zone (TZ). The results demonstrated that there was a significant difference (P<0.05) between PCa and non-PCa for nine of the 13 features in the PZ and five of the 13 features in the TZ. Besides, the prediction outcome of CAD had a strong correlation with the DWI scores that were graded by experienced radiologists according to the Prostate Imaging-Reporting and Data System Version 2 (PI-RADS v2). PMID- 28078508 TI - Prioritization of liver MRI for distinguishing focal lesions. AB - Liver cancer is one of the leading causes of cancer-related mortality worldwide. Magnetic resonance imaging (MRI) is a non-invasive imaging technique that is often used by radiologists for diagnosis and surgical planning. Analysis of a large amount of liver MRI data for each patient limits the radiologist's efficiency and may lead to misdiagnoses. The redundant MRI data, especially from dynamic contrast enhanced (DCE) sequences, is also a bottleneck in transmitting the images via the internet or PACS for remote consultancy in a reasonable amount of time. This study included 25 patients (aged between 20 and 70 years) with liver cysts (seven cases), hemangiomas (eight cases), or hepatic cell carcinomas (10 cases). DCE T1WI MRI was performed for all the patients. The diagnosis reference included typical MRI findings and post-surgery pathology. The methods were as follows: (i) MRI sequence pre-processing based on large vessels variation level set method to remove non-liver parts from MRI images; (ii) human visual model features (luminance, motion, and contour) extraction and fusion; (iii) anomaly-based MRI ranking; and (iv) methods assessment with the 25 patients' DCE MRI data. The prioritization methods applied to the DCE images could automatically assimilate and determine the content of the medical images, identifying the liver cysts, hemangiomas, and carcinomas. The average uniformity between radiologists and prioritization with the proposed method was 0.805, 0.838, and 0.818 for cysts, hemangiomas, and carcinomas, respectively, which indicates that the proposed method is an efficient method for liver DCE image prioritization. PMID- 28078509 TI - PSG9 promotes angiogenesis by stimulating VEGFA production and is associated with poor prognosis in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a common malignant solid tumor characterized by rich vascularization. Pregnancy-specific glycoprotein 9 (PSG9) is a member of the carcinoembryonic antigen (CEA)/PSG family and is produced at high levels during pregnancy. We previously identified PSG9 as an HCC-related protein. However, the expression of PSG9 and its regulation during HCC carcinogenesis remain poorly explored. In the present study, we first found that the levels of PSG9 protein were significantly increased in the plasma of HCC patients. PSG9 overexpression also increased the proliferation ability of an HCC cell line. High expression of PSG9 was associated with angiogenesis by accelerating VEGFA expression. In addition, Cox's proportional hazards model analysis revealed that the plasma level of PSG9 was an independent prognostic factor for overall survival. We propose that PSG9 is a novel indicator of prognosis in patients with HCC and could serve as a novel therapeutic target for HCC. Furthermore, our results indicate that PSG9 protein may facilitate the development of HCC by fostering angiogenesis via promoting VEGFA production in cancer cells. PMID- 28078510 TI - Relationship between Framingham risk score and subclinical atherosclerosis in carotid plaques: an in vivo study using multi-contrast MRI. AB - The assessment and management of early-stage atherosclerosis are important for the prevention of cardiovascular disease (CVD). In this study, we used multi contrast magnetic resonance imaging (MRI) to investigate the carotid plaque feature in asymptomatic, at-risk subjects; we also evaluated the correlation between MRI findings and Framingham risk score (FRS). One hundred sixty-six asymptomatic individuals with risk factors for CVD underwent multi-contrast MRI. After the arterial morphology and plaque components were outlined, the differences in carotid plaque burden among the various risk categories were analyzed. The FRS analysis showed that high-risk individuals had thicker vessel wall and higher plaque lipid content than did low risk participants. A substantial proportion of advanced carotid plaques occurred in low and intermediate-risk groups. Multi-contrast MRI may provide incremental value to the FRS in managing asymptomatic at-risk population. PMID- 28078511 TI - Intra-individual comparison of different gadolinium-based contrast agents in the quantitative evaluation of C6 glioma with dynamic contrast-enhanced magnetic resonance imaging. AB - This experiment aimed to compare the ionic (Gadodiamide, Gd-DTPA-BMA) and non ionic (Gadopentetate dimeglumine, Gd-DTPA) gadolinium-based contrast agents (GBCA) in the quantitative evaluation of C6 glioma with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). A C6 glioma model was established in 12 Wistar rats, and magnetic resonance (MR) scans were performed six days after tumor implantation. Imaging was performed using a 3.0-T MR scanner with a 7-inch handmade circular coil. Pre-contrast T1 mapping and dynamic contrast-enhanced T1WI after a bolus injection (0.2 mL s-1) of GBCA at 0.4 mmol kg-1 were performed. Each rat received two DCE-MRI scans, 24 h apart. The first and second scans were performed using Gd-DTPA-BMA and Gd-DTPA, respectively. Image data were processed using the Patlak model. Both K trans and V p maps were generated. Tumors were manually segmented on all 3D K trans and V p maps. Pixel counts and mean values were recorded for use in a paired t-test. Three radiologists independently performed the tumor segmentation and value calculation. The agreements from different observers were subjective to the intra-class correlation coefficient (ICC). Readers demonstrated that the pixel counts of tumors in K trans maps were higher with Gd-DTPA-BMA than with Gd-DTPA (P<0.001, all readers). Although the K trans values were higher with Gd-DTPA-BMA than with Gd-DTPA, there was no statistical significance (P>0.05, all readers). The pixel counts of tumors in V p maps, as well as V p values, showed no obvious difference between the two agents (P>0.05, all readers). Excellent interobserver measurement reproducibility and reliability were demonstrated in the ICC tests. The Gd-DTPA BMA contrast agent had significantly higher pixel counts of glioma in the K trans maps, and an increased tendency for average K trans values, indicating that DCE MRI with Gd-DTPA-BMA may be more suitable and sensitive for the evaluation of glioma. PMID- 28078512 TI - The role of apparent diffusion coefficient values in characterization of solid focal liver lesions: a prospective and comparative clinical study. AB - We evaluated and compared the diagnostic accuracy (DA) of apparent diffusion coefficient (ADC) values with that of lesion-to-liver ADC ratios in the characterization of solid focal liver lesions (FLLs). This prospective study was approved by the Institutional Human Ethics Board, after waiving written informed consent. Diffusion-weighted imaging and other routine magnetic resonance imaging were performed on 142 consecutive patients with suspected liver disease. The mean ADC values and lesion-to-liver ADC ratios were compared between benign and malignant solid FLLs. Receiver operating characteristic analysis was performed. The study participants included 46 patients (28 men, 18 women; mean age, 52.5 years) with 57 solid FLLs (32 malignant and 25 benign FLLs). The mean ADC values and ADC ratios of benign solid FLLs were significantly higher than those of malignant lesions (P<0.01). The difference between the area under the receiver operating characteristic curve of the ADC values (0.699) and ADC ratios (0.752) was not significant. Our study suggests that the DA of the ADC ratio is not significantly higher than that of ADC in characterizing solid FLLs. PMID- 28078513 TI - Determining the roles of the three alcohol dehydrogenases (AdhA, AdhB and AdhE) in Thermoanaerobacter ethanolicus during ethanol formation. AB - Thermoanaerobacter ethanolicus is a promising candidate for biofuel production due to the broad range of substrates it can utilize and its high ethanol yield compared to other thermophilic bacteria, such as Clostridium thermocellum. Three alcohol dehydrogenases, AdhA, AdhB and AdhE, play key roles in ethanol formation. To study their physiological roles during ethanol formation, we deleted them separately and in combination. Previously, it has been thought that both AdhB and AdhE were bifunctional alcohol dehydrogenases. Here we show that AdhE has primarily acetyl-CoA reduction activity (ALDH) and almost no acetaldehyde reduction (ADH) activity, whereas AdhB has no ALDH activity and but high ADH activity. We found that AdhA and AdhB have similar patterns of activity. Interestingly, although deletion of both adhA and adhB reduced ethanol production, a single deletion of either one actually increased ethanol yields by 60-70%. PMID- 28078514 TI - The molecular basis of the organization of repetitive DNA-containing constitutive heterochromatin in mammals. AB - Constitutive heterochromatin is composed mainly of repetitive elements and represents the typical inert chromatin structure in eukaryotic cells. Approximately half of the mammalian genome is made of repeat sequences, such as satellite DNA, telomeric DNA, and transposable elements. As essential genes are not present in these regions, most of these repeat sequences were considered as junk DNA in the past. However, it is now clear that these regions are essential for chromosome stability and the silencing of neighboring genes. Genetic and biochemical studies have revealed that histone methylation at H3K9 and its recognition by heterochromatin protein 1 represent the fundamental mechanism by which heterochromatin forms. Although this molecular mechanism is highly conserved from yeast to human cells, its detailed epigenetic regulation is more complex and dynamic for each distinct constitutive heterochromatin structure in higher eukaryotes. It can also vary according to the developmental stage. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) analysis is a powerful tool to investigate the epigenetic regulation of eukaryote genomes, but non-unique reads are usually discarded during standard ChIP-seq data alignment to reference genome databases. Therefore, specific methods to obtain global epigenetic information concerning repetitive elements are needed. In this review, we focus on such approaches and we summarize the latest molecular models for distinct constitutive heterochromatin types in mammals. PMID- 28078516 TI - Dense gene physical maps of the non-model species Drosophila subobscura. AB - The comparative analysis of genetic and physical maps as well as of whole genome sequences had revealed that in the Drosophila genus, most structural rearrangements occurred within chromosomal elements as a result of paracentric inversions. Genome sequence comparison would seem the best method to estimate rates of chromosomal evolution, but the high-quality reference genomes required for this endeavor are still scanty. Here, we have obtained dense physical maps for Muller elements A, C, and E of Drosophila subobscura, a species with an extensively studied rich and adaptive chromosomal polymorphism. These maps are based on 462 markers: 115, 236, and 111 markers for elements A, C, and E, respectively. The availability of these dense maps will facilitate genome assembly and will thus greatly contribute to obtaining a good reference genome, which is a required step for D. subobscura to attain the model species status. The comparative analysis of these physical maps and those obtained from the D. pseudoobscura and D. melanogaster genomes allowed us to infer the number of fixed inversions and chromosomal evolutionary rates for each pairwise comparison. For all three elements, rates inferred from the more closely related species were higher than those inferred from the more distantly related species, which together with results of relative-rate tests point to an acceleration in the D. subobscura lineage at least for elements A and E. PMID- 28078515 TI - Capturing genomic relationships that matter. AB - There is a strong interrelationship within the cell nucleus between form and function of the genome. This connection is exhibited across multiple hierarchies, ranging from grand-scale positioning of chromosomes and their intersection with specific nuclear functional activities, the segregation of chromosome structure into distinct domains and long-range regulatory contacts that drive spatial and temporal expression patterns of genes. Fifteen years ago, the development of the chromosome conformation capture method placed the nature of specific, long-range regulatory interactions under scrutiny. However, its development and integration with next-generation sequencing technologies has greatly expanded the breadth and scope of what is detected. The sheer scale of data offered by these important advances has come with new and challenging bottlenecks that are both experimental and bioinformatical. Here, we discuss the recent and prospective development and implementation of new methodologies and analytical tools that are allowing an in depth, yet focussed characterisation of genomic contacts that are associated with functional activities in the nucleus. PMID- 28078518 TI - Public policy performance for social development: solar energy approach to assess technological outcome in Mexico City Metropolitan Area. AB - Mexico City Metropolitan Area (MCMA) is the most populated urban area in the country. In 2010, MCMA required 14.8% of total energy domestic demand, but greenhouse gas emissions accounted for 7.7% of domestic emissions. Mexico has massive renewable energy potential that could be harnessed through solar photovoltaic (PV) technology. The problem to explore is the relationship between local and federal public strategies in MCMA and their stance on energy transition concern, social empowerment, new technology appropriation, and the will to boost social development and urban sustainability. A public policy typology was conducted through instruments of State intervention approach, based on political agenda articulation and environmental local interactions. Social equality is encouraged by means of forthright funding and in-kind support and energy policies focus on non-renewable energy subsidies and electric transmission infrastructure investment. There is a lack of vision for using PV technology as a guiding axis for marginalized population development. It is essential to promote economic and political rearrangement in order to level and structure environmental governance. It is essential to understand people's representation about their own needs along with renewable energy. PMID- 28078517 TI - Semivolatile organic compounds in surface microlayer and subsurface water of Dianshan Lake, Shanghai, China: implications for accumulation and interrelationship. AB - Semivolatile organic compounds (SVOCs) in surface microlayer (SML) and subsurface water (SSW) from Dianshan Lake were studied to investigate their occurrence, distributions, as well as enrichment and potential sources. A sample was concentrated by solid-phase micro-extraction (SPME). Identification and quantification were carried out by gas chromatography coupled to mass spectrometry (GC-MS). Total SVOCs concentrations ranged from 25.93 to 47.49 MUg/L in SSW and 38.19 to 77.23 MUg/L in SML. The phthalic acid esters (PAE) concentrations in both SSW and SML are the highest of the total SVOC. The enrichment factors (EFs) of total SVOCs ranged from 0.80 to 2.98, while the highest EF was found in benzyl phthalate and dibutyl phthalate, compounds of PAEs (4.06). The EFs values calculated in this study were consistent with the EFs reported for other water ecosystems. Compared with other place, the EF of PAHs were in the normal level (0.88-2.37). The results of correlation analysis, principal component analysis (PCA) suggested that at least three sources, i.e., agricultural residual pesticides, industrial sewage and miscellaneous sources, were responsible for the presence of SVOCs in Dianshan Lake examined, accounting for 94.16% of the total variance in the dataset. Environmental risk assessment revealed that a majority of SVOCs posed relatively low risks (the values of risk quotient were less than 0.1), while naphthalene, acenaphthene, 2,4 dinitrotoluene, and dibutyl phthalat exhibited moderate risks (values of risk quotient were more than 0.1 but less than 1fore) to aquatic organisms. PMID- 28078519 TI - Decrease in the genotoxicity of metal-contaminated soils with biochar amendments. AB - Biochar amendments, i.e., the solid product of biomass pyrolysis, reduce soil metal availability, which may lower the toxicity of metal-contaminated soils. A direct link between the decrease in soil metal availability and improved plant development is however often difficult to establish, as biochar may induce undesirable side effects on plant growth, e.g., a modification to plant nutrition. In order to investigate toxicity processes at a cellular level, roots of Vicia faba were exposed for 7 days to three metal-contaminated substrates and one control soil, amended with a 0 or 5% (w/w) addition of a wood-derived biochar. Exposure to pure biochar was also tested. Root tip cells were then observed to count the number of micronuclei as an estimation of DNA damage and the number of cells at mitosis stage. Results showed that biochar amendments led to a significant decrease in soil metal availability (Cd, Cu, Ni, Pb, and Zn) and to enhance root development on acidic substrates. The micronucleus frequency in root tip cells was positively correlated and the number of mitotic cells negatively, to the extractability of Zn in soils and to the concentration of Zn in secondary roots. Exposure to pure biochar caused a lower production of roots than most soil substrates, but led to the lowest number of observed micronuclei. In conclusion, biochar amendments can reduce the genotoxicity associated with the presence of metallic contaminants in soils, thereby potentially improving plant growth. PMID- 28078520 TI - Effects of screenhouse cultivation and organic materials incorporation on global warming potential in rice fields. AB - Global rice production will be increasingly challenged by providing healthy food for a growing population at minimal environmental cost. In this study, a 2-year field experiment was conducted to investigate the effects of a novel rice cultivation mode (screenhouse cultivation, SHC) and organic material (OM) incorporation (wheat straw and wheat straw-based biogas residue) on methane (CH4) and nitrous oxide (N2O) emissions and rice yields. In addition, the environmental factors and soil properties were also determined. Relative to the traditional open-field cultivation (OFC), SHC decreased the CH4 and N2O emissions by 6.58 18.73 and 2.51-21.35%, respectively, and the global warming potential (GWP) was reduced by 6.49-18.65%. This trend was mainly because of lower soil temperature and higher soil redox potential in SHC. Although the rice grain yield for SHC were reduced by 2.51-4.98% compared to the OFC, the CH4 emissions and GWP per unit of grain yield (yield-scaled CH4 emissions and GWP) under SHC were declined. Compared to use of inorganic fertilizer only (IN), combining inorganic fertilizer with wheat straw (WS) or wheat straw-based biogas residue (BR) improved rice grain yield by 2.12-4.10 and 4.68-5.89%, respectively. However, OM incorporation enhanced CH4 emissions and GWP, leading to higher yield-scaled CH4 emissions and GWP in WS treatment. Due to rice yield that is relatively high, there was no obvious effect of BR treatment on them. These findings suggest that apparent environmental benefit can be realized by applying SHC and fermenting straw aerobically before its incorporation. PMID- 28078521 TI - Exogenously applied poly-gamma-glutamic acid alleviates salt stress in wheat seedlings by modulating ion balance and the antioxidant system. AB - Salt stress is a main abiotic stress that limits agricultural productivity in many parts of the world. To investigate whether poly-gamma-glutamic acid (gamma PGA) can alleviate the negative effects of salt stress on wheat, a foliar application of 400 mg/L gamma-PGA was applied to wheat seedlings, which were then subjected to 150 mM NaCl. Our results showed that after application of gamma-PGA, the plant height, the plant weight, and the antioxidant enzymes including superoxide dismutase, peroxidase, and catalase were significantly increased compared with the treatment of 150 mM NaCl alone. Meanwhile, gamma-PGA application also resulted in high accumulation of K+ and decreased storage of Na+ in wheat leaves. These results suggest that gamma-PGA treatment may improve salt tolerance of wheat by diminishing ionic imbalances and enhancing antioxidant capacity. Our results indicate that exogenous gamma-PGA could alleviate the damage caused by salt stress. PMID- 28078522 TI - Long-term impact of reduced tillage on water and pesticide flow in a drained context. AB - Influence of more than 20 years (1988-2010) of reduced tillage (RT) practices on water and pesticide balances and dynamics is analyzed and compared to results from a conventional tillage plot (CT). The field study soils are described as silty clay stagnic luvisol, developed on a low permeable schist layer. A drainage network was set up according to French criteria (0.9 m deep, 10 m space) to avoid soil winter waterlogging. Climate is temperate oceanic and drainage generally occurs from November to March. Data were analyzed at yearly, weekly (pesticides) and hourly (water) time steps. Over the long term, cumulated drainage decreases significantly on RT (3999 mm) compared to CT (5100 mm). This differentiation becomes significant from 1999, 10 years after plowing was stopped. Strikingly, hourly drainage peak flows are higher under RT, especially during the second period (2000-2010), associated with low or no base flow. These results suggest a strong influence of the macropore network under RT practice. In particular, drainage peaks are higher at the beginning of the drainage season (mid-October to December). Consistently, pesticides applied in late autumn, which are the most quantified on this site, are often significantly more exported under RT. For atrazine, applied in spring, fluxes are linked to cumulative flow and are de facto higher under CT. For others pesticides, losses appear to be heterogeneous, with generally low or null export rates for spring application. Generally speaking, higher concentrations are measured on RT plot and explain observed exportation rate differences. Finally, there is no clear evidence of correlation between pesticide losses and long-term impacts of RT on hydrodynamics, pointing the importance of studying the short-term effect of tillage on water and especially solute flow. PMID- 28078523 TI - Simple vs six-branches autologous suburethral sling during robot-assisted radical prostatectomy to improve early urinary continence recovery: prospective randomized study. AB - We have recently described the use of a retropubic suburethral autologous sling created and placed during robotic radical prostatectomy (RARP). In this study, we assess the effectiveness of newly designed six-branches compared to two-branches suburethral autologous sling in improving early urinary continence (UC) recovery. 120 patients submitted to RARP were prospectively randomized according to the intraoperative positioning of six-branches (group 1, n = 60) or two-branches autologous sling (group 2, n = 60) obtained by different configuration of a same tract of vas deferens removed. Early UC recovery was assessed at 5 (catheter removal), 10 and 30 days postoperatively through the daily number of pads used and the International Consultation on Incontinence Questionnaire-Urinary Incontinence-Short Form (ICIQ-UI-SF) score. UC was defined as the non-use of pad. Chi square test and Wilcoxon test were used to investigate UC recovery between the two groups. Moreover, post-voiding residual was evaluated in each patient at the same time. At catheter removal, UC rate was in groups 1 and 2, 60 and 35% (p = 0.02); at 10 days 70 and 46% (p = 0.03); at 30 days 87 and 70% (p = 0.04), respectively. One patient in group 1 experienced acute urinary retention at the time of catheter removal and was treated uneventfully with a further 7-day catheterization. These preliminary data indicate that newly designed six-branches suburethral autologous sling is able to increase the rate of early UC recovery compared to the two-arms sling previously described by us. PMID- 28078524 TI - Vesico-urethral anastomosis (VUA) evaluation of short- and long-term outcome after robot-assisted laparoscopic radical prostatectomy (RARP): selective cystogram to improve outcome. AB - The role of a cystogram to assess the vesico-urethral anastomosis (VUA) after robot-assisted laparoscopic radical prostatectomy (RARP) has been debated. Early catheter removal without cystogram was reported to be associated with a trend towards an increased risk of acute urinary retention (AUR). In two cohorts we studied the effects of VUA leakage on cystogram and functional outcome after RARP. Cohort A contained 1390 consecutive men that routinely underwent a cystogram after RARP. Transurethral catheter (TUC) was removed in the absence of VUA leakage or minimal leakage on subsequent repeat cystogram. Outcome was compared to a group of 120 men that underwent cystography 7-10 days after RARP but had the TUC removed independent of cystography findings (cohort B). Outcome was assessed by early clinical follow-up and quality of life (QOL) questionnaires at 6 months. Men in cohort B had an increased risk of AUR and 6 months voiding complaints when compared to cohort A. The incidence of AUR and voiding complaints was associated with grade 2-3 leakage on cystography in cohort B but not in cohort A. Grade 2-3 leakage on cystogram was more likely in men with larger prostates larger and preoperative voiding complaints. Selective cystogram in men with larger prostates and preoperative lower urinary tract symptoms (LUTS) may prevent early AUR and voiding complaints after RARP when prolonged TUC use is applied. PMID- 28078525 TI - Chitosan-ceramide coating on gold nanorod to improve its physiological stability and reduce the lipid surface-related toxicity. AB - Gold nanoparticles are promising materials for many applications that include imaging, drug delivery, and photothermal therapy. However, AuNPs can be unstable and/or toxic. We purposed to improve the stability and reduce toxicity of gold nanorods (AuNR) upon coating with biocompatible polymer, chitosan-ceramide (CS CE), without replacing the original layer, CTAB. CS-CE-coated AuNR was prepared by simple mixing for 24 h and purified by centrifugation. The coating was confirmed by UV-Vis absorption analysis and surface charge and size measurement. We prepared nanorods with CS or CS-CE coating at two different concentrations (5 and 10% AuNR), the resulting in larger nanorods with a more positive surface charge than that of AuNR. We investigated the UV-absorption and protein adsorption of the polymer coated nanorods. Based on the protein adsorption, AuNR CS-CE was found to be more stable under physiological conditions than AuNR-CS. The cell internalization assay revealed that Hela cells internalized higher amounts of AuNR-CS-CE than that of AuNR-CS. Cytotoxicity study revealed that AuNR CS-CE has lower toxicity than AuNR against HeLa cells. The CS-CE coating improved the stability of AuNR under physiological conditions via the hydrophobic interactions between the AuNR lipid surface and the ceramide anchor in the CS backbone as well as. PMID- 28078527 TI - Circulating Endothelial Progenitor Cells in Crohn's Disease: An EPiC in the Making? PMID- 28078526 TI - Effectiveness and Safety of Entecavir or Tenofovir in a Spanish Cohort of Chronic Hepatitis B Patients: Validation of the Page-B Score to Predict Hepatocellular Carcinoma. AB - BACKGROUND: Long-term antiviral therapy has resulted in viral suppression and biochemical response in chronic hepatitis B, although the risk of hepatocellular carcinoma has not been abolished. The Page-B score could be useful to estimate the probability of HCC. AIMS: To analyze the effectiveness and safety of entecavir or tenofovir for more than 4 years and the usefulness of Page-B score in the real-world setting. METHODS: Analysis of Caucasian chronic hepatitis B subjects treated with entecavir or tenofovir from the prospective, multicenter database CIBERHEP. RESULTS: A total of 611 patients were enrolled: 187 received entecavir and 424 tenofovir. Most were men, mean age 50 years, 32% cirrhotic and 16.5% HBeAg-positive. Mean follow-up was 55 (entecavir) and 49 (tenofovir) months. >90% achieved HBV DNA <69 IU/mL and biochemical normalization by months 12 and 36, respectively. Cumulative HBeAg loss and anti-HBe seroconversion were achieved by 33.7 and 23.8%. Four patients lost HBsAg; three HBeAg-positive. Renal function remained stable on long-term follow-up. Fourteen (2.29%) developed HCC during follow-up all of them with baseline Page-B >=10. Nine were diagnosed within the first 5 years of therapy. This contrasts with the 27 estimated by Page B, a difference that highlights the importance of regular HCC surveillance even in patients with virological suppression. CONCLUSIONS: Entecavir and tenofovir achieved high biochemical and virological response. Renal function remained stable with both drugs. A Page-B cut-off >=10 selected all patients at risk of HCC development. PMID- 28078528 TI - Reducing Stress Among Mothers in Drug Treatment: A Description of a Mindfulness Based Parenting Intervention. AB - Background Parenting women with substance use disorder could potentially benefit from interventions designed to decrease stress and improve overall psychosocial health. In this study we assessed whether a mindfulness based parenting (MBP) intervention could be successful in decreasing general and parenting stress in a population of women who are in treatment for substance use disorder and who have infants or young children. Methods MBP participants (N = 59) attended a two-hour session once a week for 12 weeks. Within-group differences on stress outcome measures administered prior to the beginning of the MBP intervention and following the intervention period were investigated using mixed-effects linear regression models accounting for correlations arising from the repeated-measures. Scales assessed for pre-post change included the Perceived Stress Scale-10 (PSS) and the Parenting Stress Index-Short Form (PSI). Results General stress, as measured by the PSS, decreased significantly from baseline to post-intervention. Women with the highest baseline general stress level experienced the greatest change in total stress score. A significant change also occurred across the Parental Distress PSI subscale. Conclusions Findings from this innovative interventional study suggest that the addition of MBP within treatment programs for parenting women with substance use disorder is an effective strategy for reducing stress within this at risk population. PMID- 28078529 TI - Rethinking Preconception Care: A Critical, Women's Health Perspective. AB - Objectives Preconception care aims to provide care to reproductive aged individuals in order to improve pregnancy and birth outcomes. Given that preconception care is a public health priority, it is important to evaluate the evolution of this health paradigm and the promotion of preconception messages that are obtained by the public. We identified online preconception health messages, which were critically assessed through a women's health perspective. Methods We searched for "preconception care" on three major search engines. Websites were included if they were U.S.-based, provided content in English, and mentioned preconception care. Blogs and journal articles were excluded. The final sample included 52 websites. Using a content analysis approach, we assessed the presence of gender bias and identified other emergent themes. Results The majority of websites focused on preconception care for women only (67%). The recommendations centered on: (1) health behaviors for women (e.g., folic acid, drinking, smoking); (2) visiting healthcare providers; and (3) evaluating medical risks. Moreover, most content implied that women desired, or should desire, pregnancy. Overall, the messages used biomedical language and rarely mentioned other important health topics, such as social support and violence. Conclusions The primary messages presented on preconception care websites emphasized biomedical aspects of women's health. The current context of preconception care medicalizes this pre-pregnancy period by defining it as a biomedical condition requiring lifestyle changes and interventions. Additionally, the biases presented in these messages assumed women want and are capable of pregnancies and excluded an integral factor for heteronormative reproduction-men. PMID- 28078530 TI - Evaluation of the Population Pharmacokinetic Properties of Lidocaine and its Metabolites After Long-Term Multiple Applications of a Lidocaine Plaster in Post Herpetic Neuralgia Patients. AB - BACKGROUND AND OBJECTIVES: Lidocaine 5% medicated plaster is the first lidocaine containing product for chronic use. As no previous investigations have been conducted to evaluate the population pharmacokinetics of long-term exposure to lidocaine 5% medicated plasters, further insights into the evaluation of the pharmacokinetic properties of lidocaine and its metabolites were needed for the assessment of its safety. METHODS: The population pharmacokinetic properties of lidocaine and its metabolites were evaluated after multiple applications of lidocaine 5% medicated plasters based on data collected for up to 14.5 months from two phase III clinical trials (up to 2.5 months in the first trial, and up to 12 months in a follow-up trial) in post-herpetic neuralgia patients. Modeling was performed using nonlinear mixed effects as implemented in NONMEM(r) (nonlinear mixed-effect modeling) v.5. A stepwise forward inclusion and backward elimination procedure were used for covariate model building. RESULTS: The model provides reliable estimates of the pharmacokinetic behavior of lidocaine after medicated plaster application. It was validated using simulations and showed adequate predictive properties. Apparent Clearance was estimated to be 48 L/h after application of two or fewer plasters, whereas its value increased to 67 L/h after application of three plasters. Model-based simulations predicted no accumulation of lidocaine or any of its metabolites after long-term exposure of three simultaneous plasters up to 1 year. The variability explained by adding covariates into the model for the long-term exposures of lidocaine following one plaster or three simultaneous plaster applications was found to be very small with respect to the overall between-subject variability. CONCLUSIONS: In conclusion, exposure to lidocaine after the application of the lidocaine medicated plaster was found to be primarily affected by the number of plasters simultaneously applied, i.e., it increased with the number of applied patches, but less than proportionally. No clinically relevant effect of other covariates was found to affect the exposure to lidocaine or its metabolites. As no accumulation was predicted by the model, long-term exposure to lidocaine and its metabolites is not expected to lead to any safety concerns in post-herpetic neuralgia patients. PMID- 28078531 TI - Yeast mixture of liquid beer and cassava pulp with rice straw for the growth of dairy heifers. AB - This study was conducted to determine the effects of mixtures of liquid brewer's yeast (LBY) and cassava pulp (CVP) with rice straw (RS) on feed intake, digestibility, rumen fermentation, and growth of dairy heifers. Sixteen Holstein crossbred heifers (13.8 +/- 1.6 months old, 210 +/- 23 kg body weight (BW)) were randomly allocated to four feeding treatments with four replications, which were 0:0:100 (RS), 0:70:30 (0%LBY), 20:50:30 (20%LBY), and 50:20:30 (50%LBY), respectively, for LBY/CVP/RS on a fresh matter basis. The heifers were offered conventional concentrate at 1.5% initial body weight daily and fed the treatment diets ad libitum. Average daily gain and feed intake were not significantly different among the treatments. The heifers fed 50%LBY had the highest crude protein (CP) intake and DM, OM, and CP digestibility (P < 0.05). The ruminal pH did not differ significantly among treatments, while NH3-N was the highest (P < 0.05) in 50%LBY. Total volatile fatty acid (VFA) concentrations and the molar proportion of each VFA were not significantly different among the treatments. Blood urea nitrogen concentrations of 50%LBY were the highest among the treatments (P < 0.05). The results indicated that 50%LBY improved CP digestibility. PMID- 28078532 TI - Biologic mesh extrusion months after laparoscopic ventral rectopexy: reasons and consequences. PMID- 28078533 TI - Risk factors for intravesical recurrence after nephroureterectomy in patients with upper urinary tract urothelial carcinoma. AB - PURPOSE: To determine major risk factors for bladder cancer (BC) recurrence after nephroureterectomy (Nux) by focusing on the pathologic appearances of tumors in upper urinary tract urothelial carcinomas (UUTUCs). METHODS: We performed 147 Nux procedures between November 2002 and September 2015. Forty-eight patients were excluded because of a history of BC (28 patients), previous or concurrent radical cystectomy (9 patients), neoadjuvant chemotherapy (5 patients), and other reasons (6 patients). We classified UUTUCs into three types: renal pelvic, short-length ureteral, and long-length ureteral cancer; the cutoff for categorizing short- versus long-length ureteral cancer was the median tumor length. Univariate and multivariate analyses with Cox regression methods were performed to calculate hazard ratios (HRs) for BC recurrence using nine clinical covariates, including our new pathologic classification. RESULTS: The median follow-up period for the survivors was 60 months (range 1-157 months). Of 99 patients, 36 (36%) had BC recurrence; of these 36 patients, 30 (85%) experienced recurrence within 2 years and 17 (47%) had invasive BC (>=pT1). Statistical analyses demonstrated that pathologic tumor type was the major significant risk factor for BC recurrence. Long-length (>5 cm) ureteral cancer had the highest risk of BC recurrence compared to other tumor types (multivariate HR 2.1; 95% confidence interval 1.03 4.2). CONCLUSIONS: Our simple classification system based on the tumor's pathologic appearance is useful for predicting BC recurrence. Patients with long length ureteral cancer have a high risk of BC recurrence. PMID- 28078534 TI - Health Care Transition Planning Among Adolescents with Autism Spectrum Disorder. AB - Improving the health care transition process for youth with autism spectrum disorder (ASD) is critically important. This study was designed to examine the overall national transition core outcome among youth with ASD and each of the component measures of health care transition planning. Fewer than 10% of youth with ASD meet the national transition core outcome. Among youth with ASD, there is greater disparity in health care transition planning for non-Hispanic black youth, youth with family income <400% of the federal poverty line, and youth with more severe activity limitation. Continued advocacy, research, and training efforts are needed to reduce disparities in receipt of health care transition planning services for youth with ASD. PMID- 28078535 TI - Tubulin polymerization-stimulating activity of Ganoderma triterpenoids. AB - Tubulin polymerization is an important target for anticancer therapies. Even though the potential of Ganoderma triterpenoids against various cancer targets had been well documented, studies on their tubulin polymerization-stimulating activity are scarce. This study was conducted to evaluate the effect of Ganoderma triterpenoids on tubulin polymerization. A total of twenty-four compounds were investigated using an in vitro tubulin polymerization assay. Results showed that most of the studied triterpenoids exhibited microtuble-stabilizing activity to different degrees. Among the investigated compounds, ganoderic acid T-Q, ganoderiol F, ganoderic acid S, ganodermanontriol and ganoderic acid TR were found to have the highest activities. A structure-activity relationship (SAR) analysis was performed. Extensive investigation of the SAR suggests the favorable structural features for the tubulin polymerization-stimulating activity of lanostane triterpenes. These findings would be helpful for further studies on the potential mechanisms of the anticancer activity of Ganoderma triterpenoids and give some indications on the design of tubulin-targeting anticancer agents. PMID- 28078536 TI - New oral anticoagulants compared to warfarin for perioperative anticoagulation in patients undergoing atrial fibrillation catheter ablation: a meta-analysis of continuous or interrupted new oral anticoagulants during ablation compared to interrupted or continuous warfarin. AB - BACKGROUND: New oral anticoagulants (NOACs) have been shown to be comparable to warfarin in patients with non-valvular atrial fibrillation (AF). This meta analysis was performed to evaluate the efficacy and safety of NOACs for perioperative anticoagulation of AF catheter ablation. METHODS: PubMed, Embase, the Cochrane Library, CNKI, VIP, and SinoMed were searched for articles published up to August 30, 2015. The data were calculated with RevMan 5.2 using a fixed effects model. RESULTS: Nineteen studies with a total of 7996 patients were included in this meta-analysis. NOAC treatment was associated with fewer overall bleeding events than continuous warfarin treatment (RR = 0.78, 95% CI = 0.64 0.95, P = 0.01); similarly, there were fewer overall bleeding events with NOAC treatment than interrupted warfarin treatment (RR = 0.58, 95% CI = 0.44-0.77, P = 0.0002). In the subgroup analyses, the incidence of overall bleeding events (RR = 0.67, 95% CI = 0.48-0.92, P = 0.01) and minor bleeding events (RR = 0.56, 95% CI = 0.37-0.86, P = 0.007) in the interrupted NOAC group was lower than that in the continuous warfarin group. NOAC treatment did not increase the risk of thromboembolic complications compared with warfarin treatment (P > 0.05). CONCLUSIONS: The findings of this meta-analysis suggested that periprocedural NOAC therapy was as effective as continuous warfarin therapy for preventing thromboembolism and had a lower incidence of bleeding complications. Interrupted NOAC therapy during the periprocedural period might result in a lower incidence of bleeding complications compared with continuous NOAC therapy. PMID- 28078537 TI - SIRT2-mediated FOXO3a deacetylation drives its nuclear translocation triggering FasL-induced cell apoptosis during renal ischemia reperfusion. AB - We have found that Fas/FasL-mediated "extrinsic" pathway promoted cell apoptosis induced by renal ischemic injury. This study is to elucidate the upstream mechanism regulating FasL-induced extrinsic pathway during renal ischemia/reperfusion. Results demonstrated that when SIRT2 was activated by renal ischemia/reperfusion, activated SIRT2 could bind to and deacetylate FOXO3a, promoting FOXO3a nuclear translocation which resulted in an increase of nuclear FOXO3a along with FasL expression and activation of caspase8 and caspase3, triggering cell apoptosis during renal ischemia/reperfusion. The administration of SIRT2 inhibitor AGK2 prior to renal ischemia decreased significantly the number of apoptotic renal tubular cells and alleviated ultrastructure injury. These results indicate that inhibition of FOXO3a deacetylation might be a promising therapeutic approach for renal ischemia /reperfusion injury. PMID- 28078538 TI - The Sleep in Caenorhabditis elegans: What We Know Until Now. AB - Sleep, as one of the most important requirements of our brain, has a mystical nature. Despite long-standing studies, the molecular mechanisms and physiological properties of sleep have not been defined well as the complexity of the mammals' brain make it difficult to investigate the mechanisms and properties of sleep. Although some features of sleep have changed during evolution, its existence in such a simple animal, Caenorhabditis elegans, not only signifies the importance of sleep in even simple animals, but also allows the scientist to assess the core mechanism and biological events in an uncomplicated organism. This article reviews the information which exists about the characteristics of sleep in C. elegans, its circadian rhythm, the neurons and neurotransmitters responsible for each state, and the signaling molecules involved. Although much still remains to be resolved about the sleep of C. elegans, the available knowledge helps the scientists to recognize the properties better of this mysterious function of the brain. PMID- 28078539 TI - Unfolding of the myosin head by purealin in glycerol. AB - Purealin is a small bioactive compound obtained from the marine sponge. The compound modulates various types of ATPase activity of myosin from skeletal muscle, cardiac muscle, and smooth muscle. To elucidate the structural basis of these effects of purealin on myosin ATPases, we examined the effect of purealin on the conformation of skeletal muscle myosin in aqueous solution and in glycerol. Analysis of the circular dichroism spectrum of subfragment 1, a single headed fragment of myosin, revealed that in 10% glycerol purealin decreased the beta-sheet content of S1, but in aqueous solution it had little effect on the secondary structure of S1. A myosin monomer conforms to two pear-like globular heads attached to a long tail. Electron microscopy observations with rotary shadowing revealed that purealin unfolded each globular head to an extended single strand. The tips of the unfolded strand bound each other and formed a ring in one molecule. These results suggest that binding of purealin affects the critical parameters of myosin folding. PMID- 28078540 TI - Preplanned safety analysis of the JFMC37-0801 trial: a randomized phase III study of six months versus twelve months of capecitabine as adjuvant chemotherapy for stage III colon cancer. AB - BACKGROUND: Six months of adjuvant chemotherapy is regarded as the standard of care for patients with stage III colon cancer. However, whether longer treatment can improve prognosis has not been fully investigated. We conducted a phase III study comparing 6 and 12 months of adjuvant capecitabine chemotherapy for stage III colon cancer, and report here the results of our preplanned safety analysis. METHODS: Patients aged 20-79 years with curatively resected stage III colon cancer were randomly assigned to receive 8 cycles (6 months) or 16 cycles (12 months) of capecitabine (2500 mg/m2/day on days 1-14 of each 21-day cycle). Treatment exposure and adverse events (AEs) were evaluated. RESULTS: A total of 1304 patients (642 and 636 in the 6-month and 12-month groups, respectively) were analyzed. The most common AE was hand-foot syndrome (HFS). HFS, leukocytopenia, neutropenia, and hyperbilirubinemia (any grade) occurred more frequently in the 12-month group than in the 6-month group. HFS was the only grade >=3 AE to have a significantly higher incidence in the 12-month group (23 vs 17%, p = 0.011). The completion rate for 8 cycles was 72% in both groups, while that for 16 cycles was 46% in the 12-month group. HFS was the most common AE requiring dose reduction and treatment discontinuation. CONCLUSIONS: Twelve months of adjuvant capecitabine demonstrated a higher cumulative incidence of HFS compared to the standard 6-month treatment period, while toxicities after 12 months of capecitabine were clinically acceptable. TRIAL REGISTRATION: UMIN-CTR, UMIN000001367. PMID- 28078541 TI - Glucagon-Like Peptide-1 Receptor Agonist (GLP-1RA) Therapy Adherence for Patients with Type 2 Diabetes in a Medicare Population. AB - INTRODUCTION: Anti-diabetes medication regimen adherence is a clinical challenge in elderly patients with type 2 diabetes (T2D) and other comorbidities associated with aging. Glucagon-like peptide-1 receptor agonists (GLP-1RA) therapies such as exenatide once weekly (QW), exenatide twice daily (BID), and liraglutide once daily (QD) are an increasingly used class of drugs with proven efficacy and tolerability. Real-world evidence on adherence to GLP-1RAs in elderly or disabled patients is limited. To further the understanding of this drug class, the current study examined medication adherence in Medicare patients aged >=65 years with T2D initiating a GLP-1RA. METHODS: This retrospective cohort study used medical and pharmacy claims between 2010 and 2013 for Medicare members in a United States health plan diagnosed with T2D who were new initiators of either exenatide QW (n = 537), exenatide BID (n = 923), or liraglutide QD (n = 3,673). Included patients were between the ages of 65 and 89 and were continuously enrolled for 6 months pre- and post-index. Medication adherence was examined during the post-index period using proportion of days covered (PDC) >=80% and >=90%. RESULTS: A significantly higher percentage of patients receiving exenatide QW had a PDC >=80% (43.2%) versus exenatide BID (39.0%, P < 0.01) and liraglutide QD (35.0%, P < 0.001). The patients receiving exenatide QW were significantly more likely to reach a PDC of >=90% (37.2%, P < 0.001) than those initiating exenatide BID (20.6%) or liraglutide QD (23.3%). CONCLUSIONS: While results from this retrospective study suggest room for improvement in adherence to GLP-1RAs, medication adherence rates for patients initiating therapy with exenatide QW were higher than patients initiating therapy with exenatide BID or liraglutide QD. Further research is needed to validate these findings in other T2D patient populations. FUNDING: AstraZeneca Pharmaceuticals. PMID- 28078542 TI - Glenoid baseplate fixation using hybrid configurations of locked and unlocked peripheral screws. AB - BACKGROUND: The use of peripheral locked screws has reduced glenoid baseplate failure rates in reverse shoulder arthroplasty. However, situations may arise when one or more non-locked screws may be preferred. We aimed to determine if different combinations of locked and non-locked screws significantly alter acute glenoid baseplate fixation in a laboratory setting. MATERIALS AND METHODS: Twenty eight polyurethane trabecular bone surrogates were instrumented with a center screw-type glenoid baseplate and fixated with various combinations of peripheral locked and non-locked screws (1-, 2-, 3- and 4-locked con). Each construct was tested through a 55 degrees arc of abduction motion generating compressive and shear forces across the glenosphere. Baseplate micromotion (MUm) was recorded throughout 10,000 cycles for each model. RESULTS: All constructs survived 10,000 cycles of loading without catastrophic failure. One test construct in the 1 locked fixation group exhibited a measured micromotion >150 MUm (177.6 MUm). At baseline (p > 0.662) and following 10,000 cycles (p > 0.665), no differences were observed in baseplate micromotion for screw combinations that included one, two, three and four peripheral locked screws. The maximum difference in measured micromotion between the extremes of groups (1-locked and 4-locked) was 29 um. CONCLUSIONS: Hybrid peripheral screw fixation using combinations of locked and non-locked screws provides secure glenoid baseplate fixation using a polyurethane bone substitute model. Using a glenosphere with a 10-mm lateralized center of rotation, hybrid baseplate fixation maintains micromotion below the necessary threshold for bony ingrowth. LEVEL OF EVIDENCE: N/A/, basic science investigation. PMID- 28078545 TI - Abstracts 2016. PMID- 28078543 TI - Topiramate Confers Neuroprotection Against Methylphenidate-Induced Neurodegeneration in Dentate Gyrus and CA1 Regions of Hippocampus via CREB/BDNF Pathway in Rats. AB - Methylphenidate (MPH) abuse can cause serious neurological damages. The neuroprotective effects of topiramate (TPM) have been reported already, but its mechanism of action still remains unclear. The current study evaluates in vivo role of CREB/BDNF in TPM protection of the rat hippocampal cells from methylphenidate-induced apoptosis, oxidative stress, and inflammation. A total of 60 adult male rats were divided into six groups. Groups 1 and 2 received normal saline (0.7 ml/rat) and MPH (10 mg/kg) respectively for 14 days. Groups 3 and 4 were concurrently treated with MPH (10 mg/kg) and TPM 50 and 100 mg/kg respectively for 14 days. Groups 5 and 6 were treated with 50 and 100 mg/kg TPM only respectively. After drug administration, open field test (OFT) was used to investigate motor activity. The hippocampus was then isolated and the apoptotic, antiapoptotic, oxidative, antioxidant, and inflammatory factors were measured. Expression of the total and phosphorylated CREB and BDNF in gene and protein levels, and gene expression of Ak1, CaMK4, MAPK3, PKA, and c-Fos levels were also measured. MPH significantly decreased motor activity in OFT. TPM (50 and 100 mg/kg) decreased MPH-induced motor activity disturbance. Additionally, MPH significantly increased Bax protein level, CaMK4 gene expression, lipid peroxidation, catalase activity, mitochondrial GSH, IL-1beta, and TNF-alpha levels in isolated hippocampal cells. Also CREB, in total and phosphorylated forms, BDNF and Bcl-2 protein levels, Ak1, MAPK3, PKA and c-Fos gene expression, superoxide dismutase, glutathione peroxidase, and glutathione reductase activities decreased significantly by MPH. TPM (50 and 100 mg/kg), both in the presence and absence of MPH, attenuated the effects of MPH. Immunohistochemistry data showed that TPM increased localization of the total and phosphorylated forms of CREB in dentate gyrus (DG) and CA1 areas of the hippocampus. It seems that TPM can be used as a neuroprotective agent against apoptosis, oxidative stress, and neuroinflammation induced by frequent use of MPH. This might be probably mediated by the CREB/BDNF and their upstream signaling pathways. PMID- 28078544 TI - Epistaxis during nasotracheal intubation: a randomized trial of the Parker Flex TipTM nasal endotracheal tube with a posterior facing bevel versus a standard nasal RAE endotracheal tube. AB - PURPOSE: Nasotracheal intubation is a widely performed technique to facilitate anesthesia induction during oral, dental, and maxillofacial surgeries. The technique poses several risks not encountered with oropharyngeal intubation, most commonly epistaxis due to nasal mucosal abrasion. The purpose of this study was to test whether the use of the Parker Flex-TipTM (PFT) nasal endotracheal tube (ETT) with a posterior facing bevel reduces epistaxis when compared with the standard nasal RAE ETT with a leftward facing bevel. METHODS: Sixty American Society of Anesthesiologists physical status I and II patients undergoing oral or maxillofacial surgery with nasotracheal intubation were recruited. Patients were randomized to either a standard nasal RAE ETT or a PFT nasal ETT. The ETT was thermosoftened and lubricated for both study groups prior to insertion, and the size of the tube was chosen at the discretion of the attending anesthesiologist. The primary outcome was the incidence of epistaxis, with a secondary outcome of epistaxis severity (scored as none, mild, moderate, or severe). An investigator measured both outcomes five minutes after intubation was completed. RESULTS: Mild or moderate epistaxis was experienced by 22 of 30 (73%) patients in the PFT group compared with 21 of 30 (70%) patients in the standard nasal RAE ETT group (absolute risk reduction, 3%; 95% confidence interval, -19 to 25; P = 0.78). There were no occurrences of severe epistaxis in either group. CONCLUSION: There was no difference in the incidence or severity of epistaxis following nasal intubation using the Parker Flex-Tip nasal ETT when compared with a standard nasal RAE ETT. This trial was registered at ClinicalTrials.gov, identifier: NCT02315677. PMID- 28078546 TI - Postoperative real-time electrocardiography monitoring detects myocardial ischemia: a case report. AB - PURPOSE: This case report outlines the utility and challenges of remote continuous postoperative electrocardiography ECG) monitoring, which is routed through a secure smartphone to provide real-time detection and management of myocardial ischemia. CLINICAL FEATURES: A 42-yr-old male with previous myocardial infarction and angioplasty underwent a radical prostatectomy. At three hours and 45 min postoperatively, remote real-time ECG monitoring was initiated upon the patient's arrival on a regular surgical ward. Monitor alerts were routed to a study clinician's smartphone. About six hours postoperatively, alarms were received and horizontal ST segment depressions were observed. A 12-lead ECG validated the ST segment changes, prompting initiation of a metoprolol iv and a red blood cell transfusion. Approximately seven hours and 30 min postoperatively, the ST segments normalized. The patient was discharged on postoperative day 3 and followed for four years without any sequelae. CONCLUSION: This case report illustrates the use of remote ECG monitoring and clinician response in real time with the use of a smartphone. With each alert, a small ECG strip is transmitted to the smartphone for viewing. In our view, this technology and management system provides a possible means to interrupt myocardial ischemic cascades in real time and prevent postoperative myocardial infarction. PMID- 28078548 TI - All that glitters are not gold! Reactive lymphoid hyperplasia mimicking colorectal liver metastases: description of a case and literature review. PMID- 28078547 TI - ZNF804A rs1344706 interacts with COMT rs4680 to affect prefrontal volume in healthy adults. AB - The biological function of ZNF804A rs1344706, the first genome-wide supported risk variant of schizophrenia, remains largely unknown. Based on the upregulating effect of ZNF804A on the expression of COMT, we hypothesize that ZNF804A may affect grey matter volume (GMV) by interacting with COMT. Voxel-based morphometry was applied to analyze the main and interaction effects of ZNF804A rs1344706 and COMT rs4680 on brain GMV in 274 healthy young human subjects. The GMV of the left dorsolateral prefrontal cortex (DLPFC) showed a significant COMT rs4680 * ZNF804A rs1344706 interaction, manifesting as an inverted U-shape modulation by the presumed dopamine signaling. In COMT Met-allele carriers, the ZNF804A TG heterozygotes showed greater GMV in the left DLPFC than both GG and TT homozygotes. In COMT Val/Val homozygotes, however, the ZNF804A TG heterozygotes exhibited smaller GMV in the left DLPFC than GG homozygotes and comparable GMV with TT homozygotes. These findings suggest that ZNF804A affects the GMV of the prefrontal cortex by interacting with COMT, which may improve our understanding of neurobiological effect of ZNF804A and its association with schizophrenia. PMID- 28078549 TI - Functionalized ionic liquid-assisted chromatography-free synthesis of bis(indolyl)methanes. AB - A chromatography-free synthesis of bis(indolyl)methanes has been developed using sulfonic acid and sulfonyl hydrazine-functionalized ionic liquids as catalyst and scavenger, respectively. The employed excess aldehyde for completion of the reaction was scavenged by sulfonyl hydrazine-functionalized ionic liquid. Purification of products without column chromatography, ease of monitoring and shorter reaction time are the salient features of the developed protocol. The reuse and regeneration of the catalyst and scavenger have been achieved up to 5 and 2 times, respectively, without significant loss of activity. PMID- 28078550 TI - Iodine-mediated sp3 C-H functionalization of methyl ketones: a one-pot synthesis of functionalized indolizines via the 1,3-dipolar cycloaddition reaction between pyridinium ylides and ynones. AB - An efficient transition-metal-free approach toward C-H bond activation by using molecular [Formula: see text]-mediated [Formula: see text] C-H bond functionalization for the synthesis of indolizine derivatives via 1,3-dipolar cycloaddition reaction of nitrogen ylides with ynones is described. PMID- 28078551 TI - The proteolysis adaptor, NblA, binds to the N-terminus of beta-phycocyanin: Implications for the mechanism of phycobilisome degradation. AB - Phycobilisome (PBS) complexes are massive light-harvesting apparati in cyanobacteria that capture and funnel light energy to the photosystem. PBS complexes are dynamically degraded during nutrient deprivation, which causes severe chlorosis, and resynthesized during nutrient repletion. PBS degradation occurs rapidly after nutrient step down, and is specifically triggered by non bleaching protein A (NblA), a small proteolysis adaptor that facilitates interactions between a Clp chaperone and phycobiliproteins. Little is known about the mode of action of NblA during PBS degradation. In this study, we used chemical cross-linking coupled with LC-MS/MS to investigate the interactions between NblA and phycobiliproteins. An isotopically coded BS3 cross-linker captured a protein interaction between NblA and beta-phycocyanin (PC). LC-MS/MS analysis identified the amino acid residues participating in the binding reaction, and demonstrated that K52 in NblA is cross-linked to T2 in beta-PC. These results were modeled onto the existing crystal structures of NblA and PC by protein docking simulations. Our data indicate that the C-terminus of NblA fits in an open groove of beta-PC, a region located inside the central hollow cavity of a PC rod. NblA may mediate PBS degradation by disrupting the structural integrity of the PC rod from within the rod. In addition, M1-K44 and M1-K52 cross links between the N-terminus of NblA and the C-terminus of NblA are consistent with the NblA crystal structure, confirming that the purified NblA is structurally and biologically relevant. These findings provide direct evidence that NblA physically interacts with beta-PC. PMID- 28078552 TI - Pediatric Development of Bosentan Facilitated by Modeling and Simulation. AB - BACKGROUND: Bosentan is approved for use in adult patients with pulmonary arterial hypertension. The primary aim of the pharmacokinetic modeling was the provision of a systematic guidance for study design and enhanced understanding of pharmacokinetics across the entire pediatric age range. METHODS: A physiologically based pharmacokinetic model was developed for the pediatric population; starting from an adult model, the effects of body weight, age, and maturation of relevant metabolizing enzymes were incorporated to extrapolate the pharmacokinetics to children. A pediatric population pharmacokinetic model was developed to identify relevant covariates. RESULTS: Based on model predictions, a dose of 0.5 mg/kg led to an exposure distinguishable from a dose of 2 mg/kg, and an additional blood sampling time point at 2 h (the predicted time of maximum concentration) allowed more precise estimation of bosentan exposure in children. The lower exposure observed in children compared with adults could be explained by maturation-related changes in clearance. Clinical data confirmed the model predictions. CONCLUSIONS: Maturational changes in drug clearance and developmental changes in body weight were identified as key elements of bosentan pharmacokinetics in pediatric patients. Estimating bosentan exposure using physiologically based and population pharmacokinetic modeling and simulation supported dose selection in pediatric patients. Model-based exposure estimates helped in reducing the number of the youngest pediatric patients to be studied. Pharmacokinetic models can provide a systematic guidance for study design and enhanced understanding of pharmacokinetics across the entire pediatric age range. PMID- 28078554 TI - Syntax response-space biases for hands, not feet. AB - A number of studies have shown a relationship between comprehending transitive sentences and spatial processing (e.g., Chatterjee, Trends in Cognitive Sciences, 5(2), 55-61, 2001), in which there is an advantage for responding to images that depict the agent of an action to the left of the patient. Boiteau and Almor (Cognitive Science, 2016) demonstrated that a similar effect is found for pure linguistic information, such that after reading a sentence, identifying a word that had appeared earlier as the agent is faster on the left than on the right, but only for left-hand responses. In this study, we examined the role of lateralized manual motor processes in this effect and found that such spatial effects occur even when only the responses, but not the stimuli, have a spatial dimension. In support of the specific role of manual motor processes, we found a response-space effect with manual but not with pedal responses. Our results support an effector-specific (as opposed to an effector-general) hypothesis: Manual responses showed spatial effects compatible with those in previous research, whereas pedal responses did not. This is consistent with theoretical and empirical work arguing that the hands are generally involved with, and perhaps more sensitive to, linguistic information. PMID- 28078553 TI - Expression of apoptosis-regulatory genes in the hippocampus of rat neonates born to mothers with diabetes. AB - Diabetes during pregnancy impairs the development of the central nervous system (CNS) and causes cognitive and behavioral abnormalities in offspring. However, the exact mechanism by which the maternal diabetes affects the development of the brain remains to be elucidated. The aim of the present study was to investigate the effects of maternal diabetes in pregnancy on the expression of Bcl-2 and Bax genes and the numerical density of degenerating dark neurons (DNs) in the hippocampus of offspring at the first postnatal two weeks. Wistar female rats were maintained diabetic from a week before pregnancy through parturition and male offspring was sacrificed at P0, P7, and P14. Our findings demonstrated a significant down-regulation in the hippocampal expression of Bcl-2 in the diabetic group newborns (P < 0.05). In contrast, the mRNA expression of Bax was markedly up-regulated in the offspring born to diabetic dams at all of studied time-points (P < 0.05). Moreover, we found a striking increase in the numerical density of DNs in the various subfields of hippocampus of diabetic group pups (P < 0.05). The results of the present study revealed that maternal hyperglycemia during gestational period may result in disturbances in the expression of Bcl-2 and Bax genes as two important genes in neuronal apoptosis regulation and induces the production of DNs in the developing hippocampus of neonatal rats. These disturbances may be a reason for the cognitive, structural, and behavioral anomalies observed in offspring born to diabetic mothers. Furthermore, the control of maternal glycaemia by insulin administration in most cases normalized these negative impacts. PMID- 28078555 TI - Control blindness: Why people can make incorrect inferences about the intentions of others. AB - There is limited evidence regarding the accuracy of inferences about intention. The research described in this article shows how perceptual control theory (PCT) can provide a "ground truth" for these judgments. In a series of 3 studies, participants were asked to identify a person's intention in a tracking task where the person's true intention was to control the position of a knot connecting a pair of rubber bands. Most participants failed to correctly infer the person's intention, instead inferring complex but nonexistent goals (such as "tracing out two kangaroos boxing") based on the actions taken to keep the knot under control. Therefore, most of our participants experienced what we call "control blindness." The effect persisted with many participants even when their awareness was successfully directed at the knot whose position was under control. Beyond exploring the control blindness phenomenon in the context of our studies, we discuss its implications for psychological research and public policy. PMID- 28078556 TI - Response readiness modulates the development of association-based automaticity in masked priming. AB - The current study investigated the role of the automatization of stimulus and response (S-R) associations and response readiness in triggering the motor activation for masked primes in two experiments. The automatization of associations was manipulated by employing different types of stimuli, and response readiness was manipulated by varying the relative frequency of Go trials in a modified Go/No-Go task. Compatibility (compatible and incompatible), stimulus type (arrows and parallel lines), and test session (Sessions 1, 2, and 3) were manipulated in a high response-readiness condition (Experiment 1) and in a low response-readiness condition (Experiment 2). Negative compatibility effects (NCEs) occurred regardless of session and experiment in the arrow stimuli condition. However, in the parallel-line stimuli condition, no significant compatibility effect (CE) appeared regardless of the experiment in Sessions 1 and 2, whereas a significant NCE appeared in Experiment 1 but not in Experiment 2 in Session 3. These results are consistent with the claim that motor activation can only occur if the association between specific stimuli and specific responses has been automatized by previous practice, and response readiness can modulate the development of automaticity, but this modulation will have a minimal effect once the association is automatized. The findings also provide experimental evidence for the assumption that the formation of association-based automaticity could be modulated by top-down control (e.g., response readiness). PMID- 28078558 TI - Respiratory syncytial virus associated hospitalizations in preterm infants of 29 to 32 weeks gestational age using a risk score tool for palivizumab prophylaxis. AB - To evaluate the efficacy of palivizumab in infants of 29 to 32 weeks of gestational age (GA) based on a risk score tool developed for Austria. Retrospective single-center cohort study including all preterm infants of 29 (+0) to 32 (+6) weeks of GA born between 2004 and 2012 at a tertiary care university hospital. Data on RSV-related hospitalizations over the first 2 years of life were analyzed and compared between those having received palivizumab and those without. The study population was comprised of 789 of 816 screened infants, of whom 262 (33%) had received palivizumab and 527 (67%) had not. Nine of 107 rehospitalizations (8.4%) in the palivizumab group compared to 32 of 156 rehospitalizations (20.5%) in the group without prophylaxis were tested RSV positive (p = 0.004; OR 0.356 [CI 90% 0.184-0.689]). Proven and calculated RSV hospitalization rate was 3.1% (8/262) in the palivizumab group and 5.9% (31/527) in the group without (p = 0.042; OR 0.504 [CI 90% 0.259-0.981]). Increasing number of risk factors (up to three) increased the RSV hospitalization rate in infants with (6.1%) and without (9.0%) prophylaxis. RSV-associated hospitalizations did not differ between groups with regard to length of stay, severity of infection, age at hospitalization, demand of supplemental oxygen, need for mechanical ventilation, and admission rate to the ICU. A risk score tool developed for infants of 29 to 32 weeks of gestational age led to a reduction of RSV-associated hospitalizations without influencing the severity of disease. PMID- 28078557 TI - Cost-effectiveness analysis of universal screening for carbapenemase-producing Enterobacteriaceae in hospital inpatients. AB - The purpose of this study was to assess the cost-effectiveness of screening all hospital inpatients for carbapenemase-producing Enterobacteriaceae (CPE) at the time of hospital admission, compared to not screening, from a US hospital perspective. We used a linked transmission/Markov model to compare outcomes for a typical hospitalized medical patient, from a community with a colonization prevalence of 0.05%. Outcomes were number of colonized patients, CPE-related clinical infections and deaths, expected quality-adjusted life years (QALYs), cost, and the incremental cost-effectiveness ratio (ICER). Sensitivity analyses were performed to assess the effect of parameter uncertainty, using a willingness to-pay threshold of $100,000 per QALY gained. Screening prevented six CPE colonization cases per 1000 patients (1/1000 colonized with screening, 7/1000 without screening), over half of all symptomatic CPE infections (2/10,000 symptomatic with screening, 5/10,000 symptomatic without screening), and nearly half of all CPE-related deaths (8/100,000 deaths with screening, 15/100,000 deaths without screening). Screening accrued 0.0009 additional QALYs and cost an additional $24.68, compared to not screening, and was cost-effective (ICER $26,283 per QALY gained). Our results were sensitive to uncertainty in prevalence and the number of secondary colonizations per colonized patient. Screening was not cost-effective at a prevalence below 0.015% or if transmission to fewer than 0.9 new patients occurred for each colonized patient. At prevalence levels above 0.3%, screening was cost-saving compared to not screening. Screening inpatients for CPE carriage is likely cost-effective, and may be cost-saving, depending on the local prevalence of carriage. PMID- 28078559 TI - Empirical combination of a beta-lactam to vancomycin may not improve outcomes of methicillin-susceptible Staphylococcus aureus bacteremia, compared to vancomycin monotherapy. AB - To evaluate effect of empirical combination of a beta-lactam to vancomycin and vancomycin monotherapy in Staphylococcus aureus bacteremia (MSSA-B), we conducted a retrospective cohort study. Electronic medical records of individuals who were diagnosed with MSSA-B between January 2005 and February 2015 at a tertiary care center were reviewed. Patients were classified into three groups according to empirical antibiotic regimen (BL group, beta-lactam; VAN group, vancomycin; BV group, combination of beta-lactam and vancomycin), and 30-day all-cause mortality of each group was compared. During the study period, 561 patients with MSSA-B were identified. After exclusion of 198 patients (36 with poly-microbial infection, 114 expired within 2 days, and 48 already received parenteral antibiotics) and a matching process, 46 patients for each group were included. Baseline characteristics were similar except for severity and comorbidity scores. The 30-day mortality for all three groups were not significantly different (BL 4.3%, VAN 6.5%, BV 8.7%; P = 0.909). In a multivariate analysis, type of empirical antibiotic regimen was not statistically associated with 30-day all cause mortality. In comparison with the VAN group, the BV group yielded a HR of 0.579 (95% CI = 0.086-3.890, P = 0.574). Pitt bacteremia score was the only significant factor for mortality. The empirical combination of a beta-lactam to vancomycin was not associated with lower mortality in treating MSSA-B, compared to vancomycin monotherapy. PMID- 28078560 TI - Knockdown of PYCR1 inhibits cell proliferation and colony formation via cell cycle arrest and apoptosis in prostate cancer. AB - Pyrroline-5-carboxylate reductase 1 (PYCR1) is an enzyme involved in cell metabolism, which has been shown to be up-regulated in cancers. However, the functions of PYCR1 in prostate cancers (PCa) are still largely unknown. In the present study, we found that PYCR1 was highly expressed in prostate cancer tissues and then knocked down PYCR1 in PCa cell lines (DU145, PC-3 and LNCap) via lentivirus-mediated gene delivery and analyzed its biological function. Both qRT PCR and western blotting indicated that PYCR1 was suppressed efficiently after sh PYCR1 infection. Further analysis indicated knockdown of PYCR1 significantly inhibited PCa cell growth and colony formation ability. The inhibition effects on growth were likely due to G2/M-phase arrest and enhanced cell apoptosis, as determined by flow cytometer analysis. At last, we verified the expression levels of cell cycle regulatory proteins, including CDK1, CDK2, CDK4 and Cyclin B1 were all downregulated and cell apoptotic-related proteins, including cleaved caspase 3 and cleaved PARP were increased in PCa cells after PYCR1 knockdown. Furthermore, PYCR1 has been shown not to be directly regulated by androgen receptor (AR) levels. These results show the functions of PYCR1 in PCa tumorigenesis for the first time and suggest that PYCR1 might be a good potential therapy approach for treating PCa. PMID- 28078561 TI - Clinical benefit of nanoparticle albumin-bound-paclitaxel in recurrent/metastatic head and neck squamous cell carcinoma resistant to cremophor-based paclitaxel or docetaxel. AB - The clinical benefit of nab-paclitaxel monotherapy for recurrent/metastatic head and neck squamous cell carcinoma (RM-HNSCC) that progressed on other taxanes (cremophor-based paclitaxel or docetaxel) is unknown. A retrospective analysis of patients treated at a single institution with nab-paclitaxel for taxane-resistant RM-HNSCC. The exploratory hypothesis was that nab-paclitaxel would result in clinical benefit (tumor response) in patients with taxane-resistant RM-HNSCC. Twelve patients who were treated with nab-paclitaxel monotherapy for taxane resistant RM-HNSCC and met all eligibility criteria were identified. The majority of patients (n = 9; 75%) received three or more lines of therapy for RM-HNSCC. All patients had platin-resistant, and ten patients (83%) had cetuximab-resistant disease. Patients had RM-HNSCC that progressed on cremophor-based paclitaxel (8), docetaxel (1), or both (3). With prior taxane, the best tumor response was partial (PR) in 4 patients (33%), stable (SD) in 3 (25%), and progression in 5 (42%). The median time-to-progression (TTP) with prior taxane was 1.7 (range 0.7 9.0) months. The median interval from last dose of taxane to first dose of nab paclitaxel was 3 (0.7-31.3) months. With nab-paclitaxel, tumor response occurred in two patients (17%; PR in both) and disease control (PR and SD) occurred in five (42%). Median TTP with nab-paclitaxel was 2.1 months (range 0.6-6.2), and median overall survival was 4.9 months (range 1.9-13.5). nab-Paclitaxel provided clinical benefit in some patients with taxane-resistant RM-HNSCC. The median TTP with nab-paclitaxel and with prior taxane were similar. This exploratory observation warrants further investigation in prospective studies. PMID- 28078563 TI - Changes in first-line injectable disease-modifying therapy for multiple sclerosis: predictors of non-adherence, switching, discontinuation, and interruption of drugs. AB - This study was aimed to describe changes of Disease-Modifying Treatments (DMT) in an Italian cohort of patients with multiple sclerosis (MS) and to identify predictors of therapeutic modifications. Patients with MS and treated with the first-line injectable DMT (interferons-IFNs or glatiramer) between 1/7/2009 and 31/10/2012 were selected from administrative databases of the MS Center of Cagliari (Sardinia, Italy). Socio-demographic, therapeutic, and clinical information was collected in the 6 months preceding the index date. All patients were followed for 36 months to evaluate therapeutic changes in terms of non adherence, switch, temporary discontinuation, and permanent interruption. Predictors of changes were estimated by multivariable regression models. Data on 1698 patients were collected: glatiramer was prescribed in 27% of cases, IFNbeta 1b in 22%, IFNbeta-1a-im in 20%, IFNbeta-1a-sc-44mcg in 19%, and IFNbeta-1a-sc 22mcg in 12%. Non-adherence was observed in 25% of cases, therapeutic switch in 30%, discontinuation in 37%, and permanent interruption in 28%. The risk of non adherence was higher for IFNbeta-1b, compared with IFNbeta-1a-im (adjOR = 1.73). Therapeutic switch occurred especially in patients recently diagnosed (each year from diagnosis causes a decrease of this risk adjHR = 0.97); the risk of discontinuation was higher with EDSS = 4-6 and 7-9 (adjHR = 1.52 and 4.42, respectively). The risk of permanent interruption increased with the augmentation of disability (adjHR = 1.67 and 5.43 for EDSS 4-6 and 7-9). This study mirrored a detailed framework of DMT prescription and identified factors related to changes in the MS therapy. These findings could support healthcare providers in the evaluation and maximization of benefits associated with a long-term DMT. PMID- 28078562 TI - Myotonic dystrophy type 2 and modifier genes: an update on clinical and pathomolecular aspects. AB - Myotonic dystrophy (DM) is the most common adult muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia, and multiorgan involvement. To date, two distinct forms caused by similar mutations in two different genes have been identified: myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2). Aberrant transcription and mRNA processing of multiple genes due to RNA-mediated toxic gain-of function has been suggested to cause the complex phenotype in DM1 and DM2. However, despite clinical and genetic similarities, DM1 and DM2 may be considered as distinct disorders. This review is an update on the latest findings specific to DM2, including explanations for the differences in clinical manifestations and pathophysiology between the two forms of myotonic dystrophies. PMID- 28078564 TI - MRI measurements of brainstem structures in patients with vascular parkinsonism, progressive supranuclear palsy, and Parkinson's disease. AB - Magnetic resonance (MR) measurements of brainstem structures have been reported to be useful in differentiating patients with progressive supranuclear palsy (PSP) from those with Parkinson's disease (PD). The aim of this study was to determine whether quantitative measurements of brainstem structures on MR images can help differentiate vascular parkinsonism (VaP) from degenerative parkinsonism (PD and PSP). Areas of the midbrain and pons, and widths of the superior cerebellar peduncle (SCP) and middle cerebellar peduncle (MCP) were measured in 62 patients with PD, 25 patients with PSP (11 probable and 14 possible), and 24 patients with VaP on T 1-weighted MR images. The midbrain-to-pons area ratio (M/P ratio), MCP-to-SCP width ratio (MCP/SCP ratio), and MR parkinsonism index (MRPI; P/M * MCP/SCP) were calculated. The midbrain area and M/P ratio of patients with VaP (104 and 0.22 mm2, respectively) were smaller than those in patients with PD (121 and 0.24 mm2, respectively) and larger than those in patients with PSP (90 and 0.19 mm2, respectively). The MRPI was significantly larger in patients with PSP (13.6) in comparison with those with PD (10.1) and VaP (10.7). However, the MRPI of patients with VaP was not significantly different from patients with PD. Our study showed that MRPI was useful in differentiating PSP from VaP or PD. Thus, MR imaging measurements of brainstem structures may help differentiate patients with VaP from those with PD and PSP. PMID- 28078565 TI - The influence of sodium on pathophysiology of multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune disease of the central nervous system, and is an important cause of disability in young adults. In genetically susceptible individuals, several environmental factors may play a partial role in the pathogenesis of MS. Some studies suggests that high-salt diet (>5 g/day) may contribute to the MS and other autoimmune disease development through the induction of pathogenic Th17 cells and pro-inflammatory cytokines in both humans and mice. However, the precise mechanisms of pro-inflammatory effect of sodium chloride intake are not yet explained. The purpose of this review was to discuss the present state of knowledge on the potential role of environmental and dietary factors, particularly sodium chloride on the development and course of MS. PMID- 28078566 TI - An eye-tracking controlled neuropsychological battery for cognitive assessment in neurological diseases. AB - Traditional cognitive assessment in neurological conditions involving physical disability is often prevented by the presence of verbal-motor impairment; to date, an extensive motor-verbal-free neuropsychological battery is not available for such purposes. We adapted a set of neuropsychological tests, assessing language, attentional abilities, executive functions and social cognition, for eye-tracking (ET) control, and explored its feasibility in a sample of healthy participants. Thirty healthy subjects performed a neuropsychological assessment, using an ET-based neuropsychological battery, together with standard "paper and pencil" cognitive measures for frontal (Frontal Assessment Battery-FAB) and working memory abilities (Digit Sequencing Task) and for global cognitive efficiency (Montreal Cognitive Assessment-MoCA). Psychological measures of anxiety (State-Trait Anxiety Inventory-Y-STAI-Y) and depression (Beck Depression Inventory-BDI) were also collected, and a usability questionnaire was administered. Significant correlations were observed between the "paper and pencil" screening of working memory abilities and the ET-based neuropsychological measures. The ET-based battery also correlated with the MoCA, while poor correlations were observed with the FAB. Usability aspects were found to be influenced by both working memory abilities and psychological components. The ET based neuropsychological battery developed could provide an extensive assessment of cognitive functions, allowing participants to perform tasks independently from the integrity of motor or verbal channels. Further studies will be aimed at investigating validity and usability components in neurological populations with motor-verbal impairments. PMID- 28078567 TI - The c-Abl inhibitor in Parkinson disease. AB - Parkinson's disease (PD) is an insidious onset neurodegenerative disease affecting approximately 1% of the population over the age of 65. So far available therapies for PD have only aimed at improving or alleviating symptoms, but not at slowing, preventing, and reversing the course of PD. Recently, some studies have indicated that the levels and activation of Abelson non-receptor tyrosine kinase (c-Abl, Abl1) were up-regulated in the brain tissue of patients with PD and demonstrated that c-Abl inhibitors could improve motor behavior, prevent the loss of dopamine neurons, inhibit phosphorylation of Cdk5, regulate alpha-synuclein phosphorylation and clearance, inhibit the tyrosine phosphorylation of parkin and decrease parkin substrate, for example, PARIS (zinc finger protein 746), AIMP2 (aminoacyl-tRNA synthetase-interacting multifunctional protein type2), FBP1 (fuse binding protein 1), and synphilin-1. Therefore, we review the mechanism of the c Abl inhibitor in PD and conclude that c-Abl inhibitors may be a potential treatment in PD and other neurodegenerative disease. PMID- 28078568 TI - Rediagnosing one of Smith's patients (John McCann) with "neuromas tumours" (1849). AB - In 1849, the Irish Professor of Surgery, Sir Robert William Smith, by publishing his "Treatise on the Pathology, Diagnosis and Treatment of Neuroma", collected six previous examples of "general development of neuromatous tumours" and reported three further cases (two personal and one referred) of what is nowadays known as neurofibromatosis. Among these latter cases, there was a 35-year-old cattle-driver, John McCann, who was first admitted at hospital in 1840 because of a large tumour on the right side of his neck thought to be malignant (and a second tumour sublingually) but not operated. McCann was readmitted in 1843 ("in an emaciated state"), because of an immense tumour in his thigh dying few months later "with hepatic symptoms". Smith's post-mortem examination revealed dozens of smaller additional tumours. Based on application of modern diagnostic criteria (to McCann's portrait at second referral) and on pathological grounds (reconsideration of the histopathological report of McCann's neuroma of the thigh), we tentatively hypothesise that this patient could be the earliest (illustrated) example of either: (1) a malignant peripheral nerve sheath tumour (MPNST); (2) neurofibromatosis type 2 (NF2); or (3) schwannomatosis (SWNTS). The progressively enlarging masses, the emaciated state and the later death are in favour of a MPNST (against is the lack of malignant appearance at histopathology); the clinical (and gross pathological) appearance of the tumours as large, rounded, encapsulated, eccentric lesions deflecting the parent nerve over the surface of the tumour is typical of schwannomas (thus, in favour of NF2 or SWTNS). Whatever diagnosis we could consider these tumours could be secondary to a (local) mosaic loss of heterozygosity and ultimately represent type 2 segmental manifestations superimposed on an ordinary autosomal dominant trait (i.e., NF1, NF2 or SWTNS). PMID- 28078569 TI - The computer-based Symbol Digit Modalities Test: establishing age-expected performance in healthy controls and evaluation of pediatric MS patients. AB - Decreased information processing speed (IPS) is frequently reported in pediatric multiple sclerosis (MS) patients. The computerized version of the Symbol Digit Modalities Test (c-SDMT) measures IPS over eight consecutive trials per session and additionally captures changes in performance within the session. Here, we establish normative c-SDMT performance and test-retest reliability in healthy children (HC) and explore differences in the overall c-SDMT-performance between HC and MS patients. This cross-sectional study included 478 HC (237 female, 49.5%) divided into five age groups (2 years each), and 27 MS patients (22 female, 81.5%) aged 8-18 years. The average time to complete the c-SDMT increased with age (|r| 0.70, 95% CI -0.74, -0.64). Test-retest reliability was high (ICC = 0.91) in HC. The total time to complete the c-SDMT did not differ between children with MS and sex- and age- matched HC (p = 0.23). However, MS patients were less likely to show faster performance across all the successive eight trials compared to HC (p = 0.0001). Healthy children demonstrate faster IPS with increasing age, as well as during successive trials of the c-SDMT. The inability of pediatric MS patients to maintain the increase in processing speed over successive trials suggests a reduced capacity for procedural learning, possibly resulting from cognitive fatigue. PMID- 28078570 TI - Micro-RNA expression in muscle and fiber morphometry in myotonic dystrophy type 1. AB - We aimed to explore the cellular action of micro-RNAs that are non-coding-RNAs modulating gene expression, whose expression is dysregulated in myotonic dystrophy (DM1). Basic procedure was to measure the levels of muscle-specific myo miRNAs (miR-1, miR-133a/b, miR-206) in muscle of 12 DM1 patients. Muscle fiber morphometry and a new grading of histopathological severity score were used to compare specific myo-miRNA level and fiber atrophy. We found that the levels of miR-1 and miR-133a/b were significantly decreased, while miR-206 was significantly increased as compared to controls. The histopathological score did not significantly correlate with the levels of myo-miRNAs, even if the lowest levels of miRNA-1 and miRNA-133a/b, and the highest levels of miRNA-206 were observed in patients with either severe histopathological scores or long disease duration. The histopathological score was inversely correlated with disease duration. Nowadays that DM1 muscle biopsies are scanty, since patients are usually diagnosed by genetic analysis, our study offers a unique opportunity to present miRNA expression profiles in muscle and correlate them to muscle morphology in this rare multisystem disorder. Our molecular and morphologic data suggest a post-transcriptional regulatory action of myo-miRNA in DM1, highlighting their potential role as biomarkers of muscle plasticity. PMID- 28078571 TI - Analyzing spatial data from mouse tracker methodology: An entropic approach. AB - Mouse tracker methodology has recently been advocated to explore the motor components of the cognitive dynamics involved in experimental tasks like categorization, decision-making, and language comprehension. This methodology relies on the analysis of computer-mouse trajectories, by evaluating whether they significantly differ in terms of direction, amplitude, and location when a given experimental factor is manipulated. In this kind of study, a descriptive geometric approach is usually adopted in the analysis of raw trajectories, where they are summarized with several measures, such as maximum-deviation and area under the curve. However, using raw trajectories to extract spatial descriptors of the movements is problematic due to the noisy and irregular nature of empirical movement paths. Moreover, other significant components of the movement, such as motor pauses, are disregarded. To overcome these drawbacks, we present a novel approach (EMOT) to analyze computer-mouse trajectories that quantifies movement features in terms of entropy while modeling trajectories as composed by fast movements and motor pauses. A dedicated entropy decomposition analysis is additionally developed for the model parameters estimation. Two real case studies from categorization tasks are finally used to test and evaluate the characteristics of the new approach. PMID- 28078572 TI - A film set for the elicitation of emotion in research: A comprehensive catalog derived from four decades of investigation. AB - Emotions are highly influential to many psychological processes. Indeed, research employing emotional stimuli is rapidly escalating across the field of psychology. However, challenges remain regarding discrete evocation of frequently co-elicited emotions such as amusement and happiness, or anger and disgust. Further, as much contemporary work in emotion employs college students, we sought to additionally evaluate the efficacy of film clips to discretely elicit these more challenging emotions in a young adult population using an online medium. The internet is an important tool for investigating responses to emotional stimuli, but validations of emotionally evocative film clips across laboratory and web-based settings are limited in the literature. An additional obstacle is identifying stimuli amidst the numerous film clip validation studies. During our investigation, we recognized the lack of a categorical database to facilitate rapid identification of useful film clips for individual researchers' unique investigations. Consequently, here we also sought to produce the first compilation of such stimuli into an accessible and comprehensive catalog. We based our catalog upon prior work as well as our own, and identified 24 articles and 295 film clips from four decades of research. We present information on the validation of these clips in addition to our own research validating six clips using online administration settings. The results of our search in the literature and our own study are presented in tables designed to facilitate and improve a selection of highly valid film stimuli for future research. PMID- 28078573 TI - Setting things straight: A comparison of measures of saccade trajectory deviation. AB - In eye movements, saccade trajectory deviation has often been used as a physiological operationalization of visual attention, distraction, or the visual system's prioritization of different sources of information. However, there are many ways to measure saccade trajectories and to quantify their deviation. This may lead to noncomparable results and poses the problem of choosing a method that will maximize statistical power. Using data from existing studies and from our own experiments, we used principal components analysis to carry out a systematic quantification of the relationships among eight different measures of saccade trajectory deviation and their power to detect the effects of experimental manipulations, as measured by standardized effect size. We concluded that (1) the saccade deviation measure is a good default measure of saccade trajectory deviation, because it is somewhat correlated with all other measures and shows relatively high effect sizes for two well-known experimental effects; (2) more generally, measures made relative to the position of the saccade target are more powerful; and (3) measures of deviation based on the early part of the saccade are made more stable when they are based on data from an eyetracker with a high sampling rate. Our recommendations may be of use to future eye movement researchers seeking to optimize the designs of their studies. PMID- 28078574 TI - Assessment of the fate of myocardial necrosis by serial myocardial perfusion imaging. AB - BACKGROUND: Myocardial necrosis after myocardial infarction (MI) is common; extent and severity are however variable. The pattern is recognized by myocardial perfusion imaging (MPI) as fixed perfusion defects (FPD). The fate of such FPD is not well appraised. This study addressed this important issue in a large number of patients undergoing serial MPI in relation to type of intervening therapy. METHODS: Patients with prior MI or MPI-evidence of myocardial necrosis undergoing serial MPI without intervening acute coronary syndromes were included. The fate of necrosis by MPI on per-patient and per-region analysis was analyzed, factoring also the impact of intervening coronary revascularization (CR). RESULTS: A total of 3691 patients with 25,837 regions were identified, including 1413 (38.3%) subjects with 3358 (13.0%) regions exhibiting necrosis. Serial MPI after 29+/-21 months confirmed the persistent presence of myocardial necrosis FPD in the vast majority of patients and regions (86%); the consistency was even higher in the presence of moderate or severe necrosis (99%). Neither type nor site of CR significantly impacted on the presence and extent of myocardial necrosis at multivariable analysis. CONCLUSIONS: The finding of myocardial necrosis by MPI remains highly consistent over time, and is not significantly altered by CR. PMID- 28078575 TI - Molecular imaging of atherosclerosis with integrated PET imaging. AB - Atherosclerotic diseases account for nearly half of all deaths and are leading causes of adult disability. Our understanding of how atherosclerosis leads to cardiovascular disease events has evolved: from a concept of progressive luminal narrowing, to that of sudden rupture and thrombosis of biologically active atheroma. In concert with this conceptual shift, contemporary imaging techniques now allow imaging of biological processes that associate with plaque instability: active calcification and plaque inflammation. This review focuses on opportunities provided by positron emission tomography/computed tomography, to identify these high-risk biological features of atherosclerosis. PMID- 28078576 TI - Feeding Problems and Nutrient Intake in Children with and without Autism: A Comparative Study. AB - OBJECTIVE: To compare parent reported feeding difficulties and nutritional adequacy of children with Autism Spectrum Disorders (ASD) to an age and socio economically matched group of typically developing children. METHODS: The scores on Children's Eating Behavior Inventory (CEBI), three-day food records, anthropometric measures and adequacy of micro- and macro- nutrients were compared for 63 children diagnosed with ASD and 50 typically developing children enrolled from the department of pediatrics of a tertiary care teaching hospital from North India. RESULTS: The majority (79%) of the parents of ASD children reported some concern regarding their feeding behavior as compared to 64% of the parents of typically developing children. As compared to controls, ASD children had significantly higher CEBI scores (97.28 vs. 89.48, t = 3.15, P = 0.002) and more feeding problems (6.42 vs. 2.70, t = 3.74, P = 0.001). Relative to controls, ASD children consumed fewer number of food items (P = 0.022), particularly fruits (P = 0.004), vegetables (P = 0.011), and proteins (P = 0.015); had significantly lower daily intake of potassium (P = 0.001), copper (P = 0.007), and folate (P = 0.001). Although children with autism did not differ significantly from controls on intake of calories, height, weight, or body mass index, significantly greater proportion of ASD children failed to meet the estimated average requirement of thiamine (P = 0.039), vitamin C (P = 0.013), and copper (P = 0.005). CONCLUSIONS: The findings underscore the need for comprehensive assessment and empirically supported interventions for eating problems and dietary deficiencies found in ASD children. PMID- 28078577 TI - Production of the Non-apoptotic Metalloprotease-Cleaved CD95L and Its Cytotoxic Recombinant Counterpart Designed Ig-CD95L. AB - The ligand of CD95, CD95L (also known as FasL or CD178), is a type II transmembrane protein that belongs to the Tumor Necrosis factor (TNF) family (Fig. 1a). This membrane-bound cytokine is mainly expressed at the surface of activated T lymphocytes and natural killer cells, where it is used as an apoptotic factor to eliminate infected and transformed cells (Strasser et al., Immunity 30:180-192, 2009). PMID- 28078578 TI - CD95 Stimulation with CD95L and DISC Analysis. AB - CD95 and its ligand CD95L play a major role in immune surveillance and homeostasis. CD95L is expressed by activated T lymphocytes and NK cells to induce apoptosis in cancer and virus-infected cells. The goal of this chapter is to describe a method used to immunoprecipitate CD95 and analyze its associated protein complex in cells stimulated with a cytotoxic CD95L (i.e., Ig-CD95L). PMID- 28078580 TI - In Vitro Evaluation of the Apoptosis Function in Human Activated T Cells. AB - The apoptosis function can be monitored on human lymphocytes by quantifying the induced-death upon apoptotic stimuli involving either the extrinsic or the intrinsic pathway on in vitro activated T cells. Her, we describe an in vitro assay allowing the monitoring of three different apoptosis pathways: (1) the FAS induced pathway, (2) the activation-induced cell death (AICD), and (3) the death induced by starvation of the cells, called activated-cell autonomous death (ACAD). PMID- 28078579 TI - Immunoprecipitation of Death Inducing Signaling Complex by Caspase-8. AB - Analysis of CD95/Fas complexes by immunoprecipitation has long relied on the monoclonal antibody APO1 or tagged recombinant Fas ligand. Immunoprecipitation is an elegant and efficient procedure to investigate endogenous protein interactions or complexes. Provided that the targeted complex is soluble in mild detergent these complexes can be recovered using protein A/G-coupled Sepharose beads and further analyzed after denaturation and electrophoretic separation by western blotting or mass spectrometry. Herein, we describe in detail the method used in our laboratory to immunoprecipitate and analyze by immunoblot complexes containing caspase-8, using a commercial antibody directed against caspase-8. PMID- 28078581 TI - Proximity Ligation Assay (PLA) to Evaluate DISC and MISC Composition. AB - Distribution of the death receptor CD95 into lipid rafts (aggregation) and/or its internalization may contribute to the implementation of the apoptotic signal at the detriment of the non-apoptotic signaling pathway [1-6]. Also CD95 can form different protein complexes via dynamic protein-protein interactions (PPIs) according to its interaction with soluble or transmembrane CD95L. Therefore, spatiotemporal identification of these PPIs is pivotal to anticipate the signaling pathway implemented in cells stimulated with different forms of CD95L. Also, many disorders result from dysfunctions in terms of PPI subcellular distribution and/or their intensity, rendering evaluation of these features crucial to better understand pathogenesis.In situ proximity ligation assay (PLA) is a methodology that offers the possibility to identify PPIs and to determine where these PPIs occur in subcellular location (Fig. 1). Moreover, based on imaging, this method allows a quantification of PPIs at the cellular level and with a higher specificity than classical immunofluorescence assays. We here describe PLA used to confirm CD95/FADD interaction, a protocol that may serve to highlight other CD95 partners. PMID- 28078582 TI - Fluorometric Methods for Detection of Mitochondrial Membrane Depolarization Induced by CD95 Activation. AB - Mitochondria are key organelles implicated in energy supply and apoptosis. Therefore, tracking mitochondria and measuring their membrane potential is of crucial interest to monitor the CD95-mediated apoptotic signal. In this chapter, we report how we evaluate the drop of the mitochondrial transmembrane potential in leukemic cells and adherent triple negative breast cancer cells exposed to cytotoxic CD95L. We describe a simple, robust, and well-established protocol using classical fluorescent probes, DIOC6(3) and TMRM. Living cells are loaded with these cationic dyes, which accumulate in mitochondria. After CD95 activation, organelle depolarization is assessed using flow cytometry. PMID- 28078583 TI - Generation and Application of Bioluminescent CD95 Ligand Fusion Proteins. AB - The quantitative evaluation of the interaction of soluble CD95L with CD95 is not only important for a detailed understanding of CD95 biology but is also of special relevance for the characterization and development of inhibitors of this interaction. The assembly of a CD95L-CD95 complex capable to recruit intracellular factors not only involves pre-assembly of CD95 molecules in the absence of CD95L but is also modulated by cellular factors such as interaction with the actin cytoskeleton and plasma membrane compartmentation of CD95. Due to these influential variables cell-free methods allow only an inadequate analysis of CD95L binding to cell expressed CD95. To enable easy, sensitive and highly reproducible cellular binding studies for the investigation of the CD95L-CD95 interaction, we generated fusion proteins of soluble CD95L with the luciferase from Gaussia princeps (GpL). The GpL domain contained in the GpL-CD95L fusion proteins does not interfere with CD95 binding and makes the GpL-CD95L fusion proteins highly suitable for cellular binding studies and tracer applications. In this chapter, we report detailed protocols for the production of GpL-CD95L fusion proteins and their use in cellular binding studies. PMID- 28078584 TI - CD95-Mediated Calcium Signaling. AB - Intracellular calcium signals regulate cell function and cell survival by controlling many processes. CD95 engagement results in distinct intracellular calcium signals that control the cell fate, apoptosis, or survival, depending on the ligand (membrane or soluble). Intracellular calcium determination is an exquisite readout to explore the molecular mechanisms elicited by CD95 engagement. The most widely applied methods for studying calcium signaling pathways use fluorescent indicators and imaging methods with fluorescence microscopy. This technical approach, however, requires many precautions that we discuss in this chapter. PMID- 28078585 TI - CD95-Mediated Proton Regulation. AB - The Na+/H+ exchanger NHE1 is at the crossroads of a large diversity of signaling pathways, whose activation modifies the cooperative response of the transporter to intracellular H+ ions. Here we show how the activation of the Na+/H+ exchanger NHE1 by the cleaved ligand of CD95 can be measured. We demonstrate two different methods designed to set intracellular pH at precise values. Then we show how these can be coupled to fast kinetics of lithium transport, which will enable to measure the NHE1 activity like for an enzyme, because they will yield rates of transport. PMID- 28078586 TI - Study of the CD95-Mediated Non-apoptotic Signaling Pathway: PI3K. AB - CD95 is a plasma membrane receptor that belongs to the TNF receptor family (Itoh and Nagata, J Biol Chem 268(15):10932-10937, 1993; Trauth et al., Science 245(4915):301-305, 1989). Accumulating evidence indicate that this so-called death receptor can also trigger non-apoptotic signaling pathways promoting inflammation and oncogenesis (Barnhart et al., Embo J 23(15):3175-3185, 2004; Chen et al., Nature 465(7297):492-496, 2010; Legembre et al., Cell Cycle 3(10):1235-1239, 2004; Legembre et al., EMBO Rep 5(11):1084-1089, 2004; Malleter et al., Cancer Res 73(22):6711-6721, 2013; Tauzin et al., PLoS Biol 9(6):e1001090, 2011). We and others demonstrated that CD95 implements the PI3K signaling pathway through the formation of a molecular complex designated Motility Inducing Signaling Complex (MISC) contributing to cell survival, growth, proliferation, differentiation and motility (Malleter et al., Cancer Res 73(22):6711-6721, 2013; Tauzin et al., PLoS Biol 9(6):e1001090, 2011; Kleber et al., Cancer Cell 13(3):235-248, 2008). This chapter describes how to immunoprecipitate CD95 to characterize MISC involved in PI3K activation. PMID- 28078587 TI - Organelle Separation and Cell Signaling. AB - Recent findings indicate that some signaling hubs coalesce at the surfaces of organelles through the accumulation of ubiquitylated components required for the signal transduction. For instance, ubiquitylated components of the NF-kappaB pathway accumulated at the endoplasmic reticulum while ubiquitylated components of the IRF3 pathway are found at the Golgi apparatus. Here we describe simple methods to observe and assess these ubiquitylated components by immunoblotting using differential centrifugation and in vitro assays. PMID- 28078588 TI - Boyden Chamber Assay to Study of Cell Migration Induced by Metalloprotease Cleaved-CD95L. AB - CD95 receptor, also called Fas or Apo-1, is a member of the tumor necrosis factor receptors (TNF-R) superfamily (Itoh and Nagata, J Biol Chem 268:10932-10937, 1993). Its cognate ligand, CD95L, is a transmembrane cytokine, which can be cleaved by metalloproteases (Matsuno et al., J Rheumatol 28:22-28, 2001; Vargo Gogola et al., Arch Biochem Biophys 408:155-161, 2002; Kiaei et al., Exp Neurol 205:74-81, 2007; Schulte et al., Cell Death Differ 14:1040-1049, 2007) releasing a soluble ligand into the bloodstream. Recent work has shown that this metalloprotease-cleaved CD95L (cl-CD95L) is involved in carcinogenesis (Malleter et al., Cancer Res 73:6711-6721, 2013). Cl-CD95L also fuels the inflammatory process in patients affected by systemic lupus erythematosus by promoting the accumulation of activated T lymphocytes in enflamed organs (Tauzin et al., PLoS Biol 9:e1001090, 2011). This chapter aims at describing the methodology used to measure the chemoattractive effect of cl-CD95L on human cancer cells and lymphocytes. PMID- 28078589 TI - Isolation of Lipid Rafts Through Discontinuous Sucrose Gradient Centrifugation and Fas/CD95 Death Receptor Localization in Raft Fractions. AB - Lipid raft domains, enriched in sphingolipids and cholesterol, serve as sorting platforms and hubs for signal transduction proteins, and show resistance to detergent solubilization. Despite rafts have been involved in survival processes, these membrane domains have also been shown to play a major role in the modulation of death receptor signaling. Here, we describe a detailed protocol for isolating lipid rafts from whole cells by taking advantage of the lipid raft resistance to Triton X-100 solubilization at 4 degrees C, followed by sucrose gradient centrifugation, with subsequent analysis of Fas/CD95 death receptor localization in the raft fractions by immunoblotting. This method is also useful to localize additional proteins in membrane rafts. PMID- 28078590 TI - Quantifying CD95/cl-CD95L Implications in Cell Mechanics and Membrane Tension by Atomic Force Microscopy Based Force Measurements. AB - Atomic force microscopy (AFM) is an invaluable tool to investigate the structure of biological material surfaces by imaging them at nanometer scale in physiological conditions. It can also be used to measure the forces and mechanics from single molecule interaction to cell-cell adhesion. Here, we present a methodology that allows to quantify cell elastic properties (using the Young modulus) and cell membrane tension modulated by CD95/cl-CD95L interactions by coupling nanoindentation and membrane tube pulling using suitably decorated AFM levers. PMID- 28078591 TI - Sketching of CD95 Oligomers by In Silico Investigations. AB - This work aimed at building a 3D model of trimeric apo CD95. By combining different molecular modeling approaches and experimental information, we have been able to obtain a consensual organization of the complex. Our strategy permitted the construction of a plausible trimer, and to sketch the interface between protomers. The final model will guide further experimental investigations and understanding of CD95 structure and functions. PMID- 28078592 TI - Site-Specific Detection of Tyrosine Phosphorylated CD95 Following Protein Separation by Conventional and Phospho-Protein Affinity SDS-PAGE. AB - Phosphorylation of two tyrosines in the death domain of CD95 is a critical mechanism in determining the receptor's choices between cell death and survival signals. Recently, site-specific monoclonal antibodies against phosphorylated tyrosines of CD95 have been generated and used to successfully detect each phosphorylated death domain tyrosine of CD95 directly and separately by immunoblotting. Here we provide detailed protocols and useful tips for a successful site-specific detection of phosphorylated death domain tyrosine of CD95 following a protein separation by sizes (conventional SDS-PAGE) and by degrees of phosphorylation (phospho-protein affinity, mobility shift SDS-PAGE). PMID- 28078593 TI - Detection of S-Acylated CD95 by Acyl-Biotin Exchange. AB - S-acylation is the covalent addition of a fatty acid, most generally palmitate onto cysteine residues of proteins through a labile thioester linkage. The death receptor CD95 is S-palmitoylated and this post-translational modification plays a crucial role on CD95 organization in cellular membranes and thus on CD95-mediated signaling. Here, we describe the nonradioactive detection of CD95 S-acylation by acyl-biotin exchange chemistry in which a biotin is substituted for the CD95 linked fatty acid. This sensitive technique, which depends on the ability of hydroxylamine to specifically cleave the thioester linkage between fatty acids and proteins, relies on three chemical steps: (1) blockage of free thiols of non modified cysteine residues, (2) hydroxylamine-mediated cleavage of thioester linked fatty acids to restore free thiols and (3) biotinylation of free thiols with a thiol reactive biotinylation agent. Resulting biotinylated proteins can be easily purified by an avidin capture and analyzed by SDS-PAGE and immunoblotting. PMID- 28078594 TI - Exploration of Fas S-Nitrosylation by the Biotin Switch Assay. AB - S-nitrosylation is the covalent attachment of nitric oxide radical to the thiol side chain of cysteine. The death receptor Fas/CD95 can be S-nitrosylated in cancer cell lines by NO donors or iNOS activation. This posttranslational modification (PTM) induces Fas aggregation into lipid rafts and enhances FasL mediated signaling and apoptosis. In this report, we describe the detection of Fas S-nitrosylation by the most commonly used method, the biotin switch assay (BSA) technique, that allows the detection of this very labile covalent modification in cells or tissues. Briefly, this technique relies on the ability of ascorbate to reduce the covalent bond between the NO radical and the protein, allowing the exchange of the NO radical with a thiol reactive biotin-HPDP. The biotinylated proteins are then easily purified by using NeutrAvidin resin, separated by SDS-PAGE resolution and analyzed by Western blotting. PMID- 28078595 TI - Method to Measure Sphingomyelin Synthase Activity Changes in Response to CD95L. AB - Sphingomyelin synthases 1 and 2 convert the anti-oncometabolite ceramide to sphingomyelin, the most abundant sphingolipid in plasma membrane. CD95L-induced ceramide increase is associated with the caspase-dependent inhibition of sphingomyelin synthesis, which enhances the mitochondrial route to apoptosis. Knocking down sphingomyelin synthase 1 or inhibiting sphingomyelin synthesis facilitates ceramide accumulation, cytochrome c release from mitochondria, and caspase-9 activation in cancer cell upon CD95L treatment. Here, we describe a method to monitor in situ sphingomyelin synthase activity changes triggered by CD95L. PMID- 28078596 TI - Liquid Chromatography-High Resolution Mass Spectrometry Method to Study Sphingolipid Metabolism Changes in Response to CD95L. AB - Sphingolipids are sphingoid base-containing lipids, among which some metabolites behave as bioactive molecules in various biological processes, including cell death. Whereas ceramide is now viewed as an anti-oncometabolite, leading to cancer cell death, CD95L-induced apoptosis is associated with sphingolipid changes, which likely contribute to caspase-dependent signaling pathway activation. Here, we describe Liquid Chromatography-high resolution mass spectrometry method (LC-HRMS) to analyze sphingolipid metabolism changes triggered by CD95L. PMID- 28078597 TI - CD95 and the MRL-lpr Mouse Model. AB - CD95 (Fas-ligand) is a key mediator of cell death in multiple setting, thus its loss within the MRL-lpr (Faslpr) homozygote mice results in spontaneous autoimmunity. This is characterized by the development of arthritis and immune complex glomerulonephrosis making this strain a useful model for studying systemic lupus erythematosus. Herein we describe a method to exploit the heterozygote offspring of this strain in a model to study the effects of a CD95L blocking peptide on lupus-like disease in vivo. PMID- 28078598 TI - An Interaction Between the Effects of Bilingualism and Cross-linguistic Similarity in Balanced and Unbalanced Bilingual Adults' L2 Mandarin Word-Reading Production. AB - We conducted three experiments investigating in more detail the interaction between the two effects of bilingualism and L1-L2 similarity in the speech performance of balanced and unbalanced bilinguals. In Experiment 1, L1 Mandarin monolinguals and two groups of Hakka and Minnan balanced bilinguals (Hakka: more similar to Mandarin) performed a non-contextual single-character reading task in Mandarin, which required more inhibitory control. The two bilingual groups outperformed the monolinguals, regardless of their L1 background. However, the bilingual advantage was not found in a contextual multi-word task (Experiment 2), but instead the effect of cross-linguistic similarity emerged. Furthermore, in Experiment 3, the Hakka unbalanced bilinguals showed an advantage in the non contextual task, while their Minnan counterparts did not, and the impact of L1-L2 similarity emerged in both tasks. These results unveiled the way the two effects dynamically interplayed depending on the task contexts and the relative degrees of using L1 and L2. PMID- 28078599 TI - Besifloxacin Ophthalmic Suspension 0.6% Compared with Gatifloxacin Ophthalmic Solution 0.3% for the Treatment of Bacterial Conjunctivitis in Neonates. AB - PURPOSE: The aim of this study was to evaluate the safety and efficacy of topical besifloxacin ophthalmic suspension 0.6% compared with gatifloxacin ophthalmic solution 0.3% in the treatment of bacterial conjunctivitis in neonates. METHODS: This was a multicenter, randomized, double-masked, parallel group study. Subjects <=31 days of age with severity grade >=1 (scale 0-3) for both conjunctival discharge and conjunctival hyperemia were randomized to besifloxacin or gatifloxacin instilled three times daily for 7 days, and completed five study visits (three clinic visits and two phone calls). Primary endpoints included clinical resolution (absence of both conjunctival discharge and conjunctival hyperemia) at visit 5 (day 8 or 9) and ocular and non-ocular treatment-emergent adverse events (AEs). Bacterial eradication was a secondary endpoint. RESULTS: Thirty-three subjects were included in the intent-to-treat (ITT) population. All were aged <28 days, with a mean (standard deviation) age of 15.5 days (6.0), and 57.6% were female. Twenty-two subjects had culture-confirmed conjunctivitis in at least one eye (modified ITT [mITT] population), most often with Gram-positive bacteria. Visit 5 clinical resolution and bacterial eradication rates were comparable among besifloxacin- and gatifloxacin-treated study eyes (clinical resolution: 12/16 [75.0%] vs. 12/17 [70.6%] for the ITT population, and 11/13 [84.6%] vs. 7/9 [77.8%] for the mITT population; bacterial eradication: 12/13 [92.3%] vs. 8/9 [88.9%] for the mITT population, respectively). No AEs were reported in the besifloxacin treatment group, and AEs reported in the gatifloxacin group were considered not treatment-related. CONCLUSIONS: In this small study in neonates, both besifloxacin and gatifloxacin appeared effective and safe in the treatment of bacterial conjunctivitis. Larger studies are warranted. PMID- 28078600 TI - Net Budgetary Impact of Ferric Citrate as a First-Line Phosphate Binder for the Treatment of Hyperphosphatemia: A Markov Microsimulation Model. AB - Ferric citrate (FC) has demonstrated efficacy as a phosphate binder and reduces the requirements for erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron in dialysis patients. We developed a net budgetary impact model to evaluate FC vs. other phosphate binders from the vantage of a large dialysis provider. We used a Markov microsimulation model to simulate mutually referential longitudinal effects between serum phosphate and phosphate binder dose; categories of these defined health states. Health states probabilistically determined treatment attendance and utilization of ESA and IV iron. We derived model inputs from a retrospective analysis of incident phosphate binder users from a large dialysis organization (January 2011-June 2013) and incorporated treatment effects of FC from a phase III trial. The model was run over a 1-year time horizon. We considered fixed costs of providing dialysis; costs of administering ESA and IV iron; and payment rates for dialysis, ESAs, and IV iron. In the base-case model, FC had a net budgetary impact (savings) of +US$213,223/year per 100 patients treated vs. standard of care. One-way sensitivity analyses showed a net budgetary impact of up to +US$316,296/year per 100 patients treated when higher hemoglobin levels observed with FC translated into a 30% additional ESA dose reduction, and up to +US$223,281/year per 100 patients treated when effects on missed treatment rates were varied. Two-way sensitivity analyses in which acquisition costs for ESA and IV iron were varied showed a net budgetary impact of +US$104,840 to +US$213,223/year per 100 patients treated. FC as a first-line phosphate binder would likely yield substantive savings vs. standard of care under current reimbursement. PMID- 28078601 TI - Inhibition of Epithelial-Mesenchymal Transition and Metastasis by Combined TGFbeta Knockdown and Metformin Treatment in a Canine Mammary Cancer Xenograft Model. AB - Epithelial mesenchymal transition (EMT) is a process by which epithelial cells acquire mesenchymal properties, generating metastases. Transforming growth factor beta (TGF-beta) is associated with this malignancy by having the ability to induce EMT. Metformin, has been shown to inhibit EMT in breast cancer cells. Based on this evidence we hypothesize that treatment with metformin and the silencing of TGF-beta, inhibits the EMT in cancer cells. Canine metastatic mammary tumor cell line CF41 was stably transduced with a shRNA-lentivirus, reducing expression level of TGF-beta1. This was combined with metformin treatment, to look at effects on cell migration and the expression of EMT markers. For in vivo study, unmodified or TGF-beta1sh cells were injected in the inguinal region of nude athymic female mice followed by metformin treatment. The mice's lungs were collected and metastatic nodules were subsequently assessed for EMT markers expression. The migration rate was lower in TGF-beta1sh cells and when combined with metformin treatment. Metformin treatment reduced N-cadherin and increased E-cadherin expression in both CF41 and TGF-beta1sh cells. Was demonstrated that metformin treatment reduced the number of lung metastases in animals bearing TGF-beta1sh tumors. This paralleled a decreased N-cadherin and vimentin expression, and increased E-cadherin and claudin-7 expression in lung metastases. This study confirms the benefits of TGF-beta1 silencing in addition to metformin as potential therapeutic agents for breast cancer patients, by blocking EMT process. To the best of our knowledge, we are the first to report metformin treatment in cells with TGF-beta1 silencing and their effect on EMT. PMID- 28078602 TI - Sulfatides Primarily Exist in the Substantia Nigra Region of Mouse Brain Tissue. AB - Lipid distribution in the brain is important for many biological functions and has been associated with some brain diseases. The aim of this study was to investigate lipid distribution in different regions of brain tissue in mice. To this end, substantia nigra (SN), caudate putamen (CPu), hippocampus (Hip), hypothalamus (Hyp), and cortex (Cx) tissues of mice were analyzed using direct infusion nanoelectrospray-ion trap mass spectrometry and multivariate analyses. The SN, CPu, Hip, Hyp, and Cx groups showed clear differences in lipid distribution using principal component analysis and a partial least-squares discriminant analysis score plot, and lipid levels were significantly different in different brain regions. In particular, sulfatides were mainly distributed in the SN region. Our results could be used to help understand the functions and mechanisms of lipids in various brain diseases. PMID- 28078604 TI - Authenticity in Anatomy Art. AB - The aim of this paper is to observe the evolution and evaluate the 'realness' and authenticity in Anatomy Art, an art form I define as one which incorporates accurate anatomical representations of the human body with artistic expression. I examine the art of 17th century wax anatomical models, the preservations of Frederik Ruysch, and Gunther von Hagens' Body Worlds plastinates, giving consideration to authenticity of both body and art. I give extra consideration to the works of Body Worlds since the exhibit creator believes he has created anatomical specimens with more educational value and bodily authenticity than ever before. Ultimately, I argue that von Hagens fails to offer Anatomy Art 'real human bodies,' and that the lack of bodily authenticity of his plastinates results in his creations being less pedagogic than he claims. PMID- 28078603 TI - A Comparison of the Anti-Inflammatory Effects of Cis-9, Trans-11 Conjugated Linoleic Acid to Celecoxib in the Collagen-Induced Arthritis Model. AB - Cyclooxygenase (COX)-2 inhibitors, such as celecoxib, for chronic inflammatory disease are associated with adverse health events, while cis-9, trans-11 (c9t11) conjugated linoleic acid (CLA) is anti-inflammatory without adverse events attributed to pure intake. Mechanistically, celecoxib and c9t11 disrupt the arachidonic acid cascade; however, the equivalency of anti-inflammatory effects between these compounds is unknown. Therefore, to test the hypothesis that 0.5% dietary c9t11 reduces inflammation equivalently to a celecoxib dose intended to treat rheumatoid arthritis (RA; 5 mg/kg bw), arthritic mice received diets containing one of the following supplements: 1% corn oil (CO, w/w), 0.5% c9t11 (>91% purity) +0.5% CO, or 1% CO + 0.5, 5, or 50 mg/kg bw celecoxib, and were assessed for changes in arthritic severity over 6 weeks. Overall, arthritic severity in mice fed c9t11 was reduced (34%, P < 0.01) while celecoxib doses (0.5, 5, 50 mg/kg) reduced arthritic severity (16, 56, 48%, respectively) compared to CO-fed arthritic mice. Linear regression of the celecoxib dose response showed 0.5% c9t11 (570 mg/kg bw) reduced arthritic severity equivalently to 1.5 mg/kg celecoxib. Interleukin-6 (IL-6) was increased in paws of arthritic mice fed CO compared to shams, but was decreased in arthritic groups fed 0.5% c9t11 and 5 mg/kg celecoxib, compared to arthritic mice fed CO (Ps <= 0.05). Additionally, paw and plasma IL-10 levels in arthritic mice were decreased by 5 mg/kg celecoxib, but were unaffected by c9t11 compared to CO. Results suggest dietary c9t11 may be an effective adjunct to COX-2 inhibition for treating chronic inflammation. PMID- 28078605 TI - Transcriptional Regulatory Network Analysis for Gastric Cancer Based on mRNA Microarray. AB - We aimed to screen the differential expressed genes (DEGs) and transcriptional factors (TFs) related to gastric cancer. GSE19826 microarray data downloaded from Gene Expression Omnibus was used to identify the differentially expressed genes (DEGs) and PPI network of DEGs were constructed by the Retrieval of Interacting Genes database. Pathway enrichment analysis of DEGs were performed by Gene Set Enrichment Analysis. Then, the transcriptional regulatory network was constructed based on TRANSFAC database. Finally, regulatory impact factor (RIF) of TF was calculated. We identified 446 DEGs including 209 up- and 237 down-regulated genes. These DEGs were mainly significantly enriched in 5 pathways including ECM receptor interaction (p = 0.013899), spliceosome (p = 0.025591), bladder cancer (p = 0.026316), focal adhesion (p = 0.047809) and WNT signaling pathway (p = 0.048077). PPI network with 247 nodes and 913 edges were constructed and COL5A2 was the hub node. Transcriptional regulatory network with 6 differently expressed TFs, 58 non-differently expressed TFs, 44 DEGs and 735 non-DEGs was constructed. Finally, top 5 TFs including CRX, TFAP4, NKX2-1, MYB and RARG with higher ZRIF were screened. The identified DEGs such as COL5A2 and TOP2A, and TFs including EGR2, FOXM1, NKX2-1 and TFAP4 might be the critical genes and TFs for gastric cancer. PMID- 28078607 TI - Structure and Optical Features of Micro/Nanosized Carbon Forms Prepared by Electrochemical Exfoliation. AB - Micro/nanosized carbon materials were prepared by electrochemical exfoliation method in the forms of the colloids and thin films. Scanning electronic microscopy, optical and luminescent microscopy, and Raman scattering and luminescent spectroscopy were applied for characterization of materials. The wide photoluminescence band in the visible spectral region was observed for each of the samples. The shape of the photoluminescence band depends on excitation wavelength and on the size of the particles. At least two components with maxima at ~580 and ~710 nm can be distinguished in the photoluminescence spectra. The relations between the photoluminescence properties and morphology of the samples have been described and discussed. PMID- 28078606 TI - Arterial Stiffness in Aortic Stenosis: Relationship with Severity and Echocardiographic Procedures Response. AB - INTRODUCTION: Aortic stenosis (AS) is more than only a degenerative disease, it could be also an atherosclerotic-like process involving the valve instead of the vessels. Little is known about the relation of arterial stiffness and AS. AIM: We sought to determine wether pulse wave velocity (PWV), is related to AS severity and to the procedures response, both as surgical aortic-valve-replacement (AVR) and trascatheter-aortic-valve-implantation (TAVI). METHODS: 30 patients with severe AS were treated (15 AVR, 15 TAVI). Before the procedures (t0) and after 1 week (t1) echocardiography and PWV were evaluated. RESULTS: On the whole population, subjects with higher PWV showed higher transvalvular pressure gradient at baseline (mean: 56.5 +/- 15.1 vs 45.4 +/- 9.5; peak: 93.3 +/- 26.4 vs 73.3 +/- 14.9, p = 0.02) and, a significantly greater response to the procedures (mean: -42.9 +/- 17.2 vs -27.9 +/- 10.1, peak: -68.7 +/- 29.2 vs -42.8 +/- 16.4, p = 0.02). When the two different procedures groups were separated, data were confirmed only in the TAVI subgroup. CONCLUSIONS: In patients undergoing procedures for AS, PWV is correlated with transvalvular gradient and, in TAVI subjects, is able to predict the echocardiographic response. Baseline evaluation of PWV in patients candidates to TAVI can help the selection of subjects, even if larger and longer studies are needed before definitive conclusion can be drawn. PMID- 28078608 TI - Study on the Polarization of Random Lasers from Dye-Doped Nematic Liquid Crystals. AB - Random lasers from dye-doped nematic liquid crystal (DDNLC) cells with different rubbing methods were observed due to different random ring cavities that were formed. Through constructing cells with different rubbing methods on the forward and backward surfaces of light-emitting sides, we can get two random laser beams with different polarization directions from one DDNLC cell at the same time, and the polarization direction is along the rubbing direction of the light-emitting sides. Additionally, the influence of external electric field on the polarization degree of random lasers was also studied. PMID- 28078609 TI - Enhanced thermophysical properties via PAO superstructure. AB - For the last few years, molten salt nanomaterials have attracted many scientists for their enhanced specific heat by doping a minute concentration of nanoparticles (up to 1% by weight). Likewise, enhancing the specific heat of liquid media is important in many aspects of engineering such as engine oil, coolant, and lubricant. However, such enhancement in specific heat was only observed for molten salts, yet other engineering fluids such as water, ethylene glycol, and oil have shown a decrease of specific heat with doped nanoparticles. Recent studies have shown that the observed specific heat enhancement resulted from unique nanostructures that were formed by molten salt molecules when interacting with nanoparticles. Thus, such enhancement in specific heat is only possible for molten salts because other fluids may not naturally form such nanostructures. In this study, we hypothesized such nanostructures can be mimicked through in situ formation of fabricated nano-additives, which are putative nanoparticles coated with useful organic materials (e.g., polar-group ended organic molecules) leading to superstructures, and thus can be directly used for other engineering fluids. We first applied this approach to polyalphaolefin (PAO). A differential scanning calorimeter (DSC), a rheometer, and a customized setup were employed to characterize the heat capacity, viscosity, and thermal conductivity of PAO and PAO with fabricated nano additives. Results showed 44.5% enhanced heat capacity and 19.8 and 22.98% enhancement for thermal conductivity and viscosity, respectively, by an addition of only 2% of fabricated nanostructures in comparison with pure PAO. Moreover, a partial melting of the polar-group-ended organic molecules was observed in the first thermal cycle and the peak disappeared in the following cycles. This indicates that the in situ formation of fabricated nano-additives spontaneously occurs in the thermal cycle to form nanostructures. Figure of merit analyses have been performed for the PAO superstructure to evaluate its performance for heat storage and transfer media. PMID- 28078610 TI - Optimization of the Return-to-Sport Paradigm After Anterior Cruciate Ligament Reconstruction: A Critical Step Back to Move Forward. AB - Athletes who have sustained an anterior cruciate ligament (ACL) injury often opt for an ACL reconstruction (ACLR) with the goal and expectation to resume sports. Unfortunately, the proportion of athletes successfully returning to sport is relatively low, while the rate of second ACL injury has been reported to exceed 20% after clearance to return to sport, especially within younger athletic populations. Despite the development of return-to-sport guidelines over recent years, there are still more questions than answers on the most optimal return-to sport criteria after ACLR. The primary purpose of this review was to provide a critical appraisal of the current return-to-sport criteria and decision-making processes after ACLR. Traditional return-to-sport criteria mainly focus on time after injury and impairments of the injured knee joint. The return-to-sport decision making is only made at the hypothetical 'end' of the rehabilitation. We propose an optimized criterion-based multifactorial return-to-sport approach based on shared decision making within a broad biopsychosocial framework. A wide spectrum of sensorimotor and biomechanical outcomes should be assessed comprehensively, while the interactions of an individual athlete with the tasks being performed and the environment in which the tasks are executed are taken into account. A layered approach within a smooth continuum with repeated athletic evaluations throughout rehabilitation followed by a gradual periodized reintegration into sport with adequate follow-up may help to guide an individual athlete toward a successful return to sport. PMID- 28078611 TI - Hyperbaric Oxygen Prevents Cognitive Impairments in Mice Induced by D-Galactose by Improving Cholinergic and Anti-apoptotic Functions. AB - Our previous study demonstrated that hyperbaric oxygen (HBO) improved cognitive impairments mainly by regulating oxidative stress, inflammatory responses and aging-related gene expression. However, a method for preventing cognitive dysfunction has yet to be developed. In the present study, we explored the protective effects of HBO on the cholinergic system and apoptosis in D-galactose (D-gal)-treated mice. A model of aging was established via systemic intraperitoneal injection of D-gal daily for 8 weeks. HBO was administered during the last 2 weeks of D-gal injection. Our results showed that HBO in D-gal-treated mice significantly improved behavioral performance on the open field test and passive avoidance task. Studies on the potential mechanisms of this effect showed that HBO significantly reduced oxidative stress and blocked the nuclear factor kappaB pathway. Moreover, HBO significantly increased the levels of choline acetyltransferase and acetylcholine and decreased the activity of acetylcholinesterase in the hippocampus. Furthermore, HBO markedly increased expression of the anti-apoptosis protein Bcl-2 and glial fibrillary acidic protein meanwhile decreased expression of the pro-apoptosis proteins Bax and caspase-3. Importantly, there was a significant reduction in expression of Abeta related genes, such as amyloid precursor protein, beta-site amyloid cleaving enzyme-1 and cathepsin B mRNA. These decreases were accompanied by significant increases in expression of neprilysin and insulin-degrading enzyme mRNA. Moreover, compared with the Vitamin E group, HBO combined with Vitamin E exhibited significant difference in part of the above mention parameters. These findings suggest that HBO may act as a neuroprotective agent in preventing cognitive impairments. PMID- 28078612 TI - Ameliorative Effect of Ginsenoside Rg1 on Lipopolysaccharide-Induced Cognitive Impairment: Role of Cholinergic System. AB - Bacterial endotoxin lipopolysaccharide (LPS) can induce systemic inflammation, and therefore disrupt learning and memory processes. Ginsenoside Rg1, a major bioactive component of ginseng, is shown to greatly improve cognitive function. The present study was designed to further investigate whether administration of ginsenoside Rg1 can ameliorate LPS-induced cognitive impairment in the Y-maze and Morris water maze (MWM) task, and to explore the underlying mechanisms. Results showed that exposure to LPS (500 MUg/kg) significantly impaired working and spatial memory and that repeated treatment with ginsenoside Rg1 (200 mg/kg/day, for 30 days) could effectively alleviate the LPS-induced cognitive decline as indicated by increased working and spatial memory in the Y-maze and MWM tests. Furthermore, ginsenoside Rg1 treatment prevented LPS-induced decrease of acetylcholine (ACh) levels and increase of acetylcholinesterase (AChE) activity. Ginsenoside Rg1 treatment also reverted the decrease of alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) protein expression in the prefrontal cortex (PFC) and hippocampus of LPS-treated rats. These findings suggest that ginsenoside Rg1 has protective effect against LPS-induced cognitive deficit and that prevention of LPS-induced changes in cholinergic system is crucial to this ameliorating effect. PMID- 28078615 TI - Enthusiasm Scientifically Oriented: The Preface for the Special Issue Dedicated to Jan Albrecht. PMID- 28078613 TI - L-F001, a Multifunction ROCK Inhibitor Prevents 6-OHDA Induced Cell Death Through Activating Akt/GSK-3beta and Nrf2/HO-1 Signaling Pathway in PC12 Cells and Attenuates MPTP-Induced Dopamine Neuron Toxicity in Mice. AB - Amounting evidences demonstrated that Rho/Rho-associated kinase (ROCK) might be a novel target for the therapy of Parkinson's disease (PD). Recently, we synthesized L-F001 and revealed it was a potent ROCK inhibitor with multifunctional effects. Here we investigated the effects of L-F001 in PD models. We found that L-F001 potently attenuated 6-OHDA-induced cytotoxicity in PC12 cells and significantly decreased intracellular reactive oxygen species (ROS), prevented the 6-OHDA-induced decline of mitochondrial membrane potential and intracellular GSH levels. In addition, L-F001 increased Akt and GSK-3beta phosphorylation and induced the nuclear Nrf2 and HO-1 expression in a time- and concentration-dependent manner. Moreover, L-F001 restored the levels of p-Akt and p-GSK-3beta (Ser9) as well as HO-1 expression reduced by 6-OHDA. Those effects were blocked by the specific PI3K inhibitor, LY294002, indicating the involvement of Akt/GSK-3beta pathway in the neuroprotective effect of L-F001. In addition, L F001 significantly attenuated the tyrosinehydroxylase immunoreactive cell loss in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced mice PD model. Together, our findings suggest that L-F001 prevents 6-OHDA-induced cell death through activating Akt/GSK-3beta and Nrf2/HO-1 signaling pathway and attenuates MPTP-induced dopaminergic neuron toxicity in mice. L-F001 might be a promising drug candidate for PD. PMID- 28078616 TI - Physician Power to Declare Death by Neurologic Criteria Threatened. AB - BACKGROUND: Three recent lawsuits that address declaration of brain death (BD) garnered significant media attention and threaten to limit physician power to declare BD. METHODS: We discuss these cases and their consequences including: the right to refuse an apnea test, accepted medical standards for declaration of BD, and the irreversibility of BD. RESULTS: These cases warrant discussion because they threaten to: limit physicians' power to determine death; incite families to seek injunctions to continue organ support after BD; and force hospitals to dispense valuable resources to dead patients in lieu of patients with reparable illnesses or injuries. CONCLUSIONS: Physicians, philosophers, religious officials, ethicists, and lawyers must work together to address these issues and educate both the public and medical community about BD. PMID- 28078614 TI - Resistance Exercise Reduces Seizure Occurrence, Attenuates Memory Deficits and Restores BDNF Signaling in Rats with Chronic Epilepsy. AB - Epilepsy is a disease characterized by recurrent, unprovoked seizures. Cognitive impairment is an important comorbidity of chronic epilepsy. Human and animal model studies of epilepsy have shown that aerobic exercise induces beneficial structural and functional changes and reduces the number of seizures. However, little is yet understood about the effects of resistance exercise on epilepsy. We evaluated the effects of a resistance exercise program on the number of seizures, long-term memory and expression/activation of signaling proteins in rats with epilepsy. The number of seizures was quantified by video-monitoring and long-term memory was assessed by an inhibitory avoidance test. Using western blotting, multiplex and enzyme-linked immunosorbent assays, we determined the effects of a 4-week resistance exercise program on IGF-1 and BDNF levels and ERK, CREB, mTOR activation in the hippocampus of rats with epilepsy. Rats with epilepsy submitted to resistance exercise showed a decrease in the number of seizures compared to non-exercised epileptic rats. Memory deficits were attenuated by resistance exercise. Rats with epilepsy showed an increase in IGF-1 levels which were restored to control levels by resistance exercise. BDNF levels and ERK and mTOR activation were decreased in rats with epilepsy and resistance exercise restored these to control levels. In conclusion, resistance exercise reduced seizure occurrence and mitigated memory deficits in rats with epilepsy. These resistance exercise-induced beneficial effects can be related to changes in IGF-1 and BDNF levels and its signaling protein activation. Our findings indicate that the resistance exercise might be included as complementary therapeutic strategy for epilepsy treatment. PMID- 28078617 TI - Changes in the first postoperative night bispectral index of patients after thyroidectomy with different types of primary anesthetic management: a randomized controlled trial. AB - Despite major advances in anesthesia management and developments in anesthetic agents, postoperative sleep disturbances remain dissatisfactory for many patients. We hypothesized that propofol might have a subtle influence on sleep after thyroidectomy compared to sevoflurane. A randomized, single-blinded, controlled trial was conducted at the First Hospital of China Medical University from October 2014 to October 2015. One hundred and twenty-four patients undergoing thyroidectomy were enrolled and received sevoflurane (sevoflurane group) or propofol (propofol group) as anesthesia maintenance. Major assessments were made during the operation (different types of anesthetic management) and on the first postoperative night (sleep status). The primary outcome was postoperative sleep status, measured by the BIS-Vista monitor on the first night after surgery between propofol and sevoflurane groups. A total of 105 patients (79 women, 26 men; mean age 49 years; range 18-65 years) were included in the final study sample. All patients in both groups showed one of the five sleep patterns classified by this trial. The BIS-area under the curve was decreased, the sleep efficiency index was significantly increased, and the durations of postoperative sleep and sleep stage N3 were increased by 110.5 and 36.5 min per patient, respectively, in the propofol compared to the sevoflurane group. Propofol might preserve sleep time immediately after thyroidectomy. Clinical Trials.gov identifier: NCT 02146976. PMID- 28078618 TI - Decreased TAp63 and DeltaNp63 mRNA Levels in Most Human Pituitary Adenomas Are Correlated with Notch3/Jagged1 Relative Expression. AB - Despite recent advances in molecular genetics, the pituitary adenoma initiation, development, progress, and the molecular basis of their unique features are still poorly understood. In this sense, it is proposed that stem cell could be involved in pituitary adenoma tumorigenesis. It is suggested that TP63 has important functions in stem cells, and it may have interplay of TP63 and Notch and its ligand Jagged in this process. This study aimed to evaluate the distinct expression of TP63 isoforms (TAp63 and DeltaNp63), as well as its correlation with Notch3 receptor and its ligand Jagged1 in human pituitary adenomas at the messenger RNA (mRNA) level. We included 77 pituitary adenoma tumor samples from patients who underwent surgical resection. The expression levels of TP63 isoforms (TAp63 and DeltaNp63) and Notch3 and its ligand Jagged1 were evaluated by qRT-PCR using isoform-specific primers. We also evaluated proliferation index immunohistochemically using KI-67 antibody. The expression levels were associated with clinical outcomes, as age, gender, tumor size, and tumor subtype. In summary, we found that mRNA expression of both TP63 isoforms decreased in pituitary adenomas compared with normal pituitary control. On the other hand, there was an increase of relative Notch3 and Jagged1 mRNA expression in the majority of examined samples. The mRNA expression of three genes evaluated was correlated and statistically significantly. There was no significant association between gene expression and the analyzed clinical data. The current study has provided the first time evidence that Tap63 and DeltaNp63 isoforms are underexpressed in most pituitary adenomas. These results are correlated with Notch3 and its ligand Jagged1 overexpression, corroborating previous studies pointing its antagonistic interactions. PMID- 28078620 TI - Education and the Transition to Fatherhood: The Role of Selection Into Union. AB - Although advanced education has been found to be consistently associated with a later transition to parenthood for women, findings about education and the transition to parenthood have been much less consistent for men, and no stylized fact has emerged from the literature. We argue that the inconsistency of findings for men is due to the fact that the selection process involved in union formation has been disregarded in earlier studies. We hypothesize that men's educational attainment consistently and positively affects the transition to fatherhood via higher rates of union formation. We apply multiprocess event-history analysis to data from the Generations and Gender Surveys for 10 European countries. Our results show indeed a consistent positive effect of education on the transition to fatherhood, but it operates chiefly through selection into union. Failing to account for this selection process leads to a major underestimation of the salience of education for the transition to fatherhood. PMID- 28078619 TI - Pancreatic Struma with Papillary Thyroid Carcinoma: a Diagnostic Dilemma. PMID- 28078621 TI - Is Stepfamily Status Associated With Cohabiting and Married Women's Fertility Behaviors? AB - Children from prior relationships potentially complicate fertility decision making in new cohabitations and marriages. On the one hand, the "value of children" perspective suggests that unions with and without stepchildren have similar-and deliberate-reasons for shared childbearing. On the other hand, multipartnered fertility (MPF) research suggests that childbearing across partnerships is often unintended. Using the 2006-2010 National Survey of Family Growth and event-history models, I examine the role of stepfamily status on cohabiting and married women's fertility and birth intendedness, with attention to union type and stepfamily configuration. Adjusting for covariates, women in stepfamily unions are more likely to have a first shared birth in a union than women in unions in which neither partner has children from past relationships, but stepfamily births are less likely to be intended than unintended. Further, this association varies by union type: married women have similar birth risks across stepfamily status, but births are less likely to be intended in marital stepfamilies. For cohabitors, women in a stepfamily are more likely to have a birth than women in nonstepfamily unions, with no differences in intendedness. Configuration (whose children and how many) also matters; for instance, women with one child from a past relationship are more likely to have a birth and to have an intended than unintended birth than women with other stepfamily configurations. It appears that children from either partner's prior relationships influences subsequent fertility decision-making, undermining the utility of the "value of children" perspective for explaining childbearing behaviors in complex families. PMID- 28078623 TI - Identification of Host Fruit Volatiles from Snowberry (Symphoricarpos albus), Attractive to Rhagoletis zephyria Flies from the Western United States. AB - A mixture of behaviorally active volatiles was identified from the fruit of snowberry, Symphoricarpos albus laevigatus, for Rhagoletis zephyria flies reared from snowberry fruit. A nine-component blend containing 3-methylbutan-1-ol (3%), dimethyl trisulfide (1%), 1-octen-3-ol (40%), myrcene (8%), nonanal (9%), linalool (13%), (3E)-4,8-dimethyl-1,3,7-nonatriene (DMNT, 6%), decanal (15%), and beta-caryophyllene (5%) was identified that gave consistent electroantennogram activity and was behaviorally active in flight tunnel tests. In other flight tunnel assays, snowberry flies from two sites in Washington state, USA, displayed significantly greater levels of upwind oriented flight to sources with the snowberry volatile blend compared with previously identified volatile blends from domestic apple (Malus domestica) and downy hawthorn (Crataegus mollis) fruit from the eastern USA, and domestic apple, black hawthorn (C. douglasii) and ornamental hawthorn (C. monogyna) from Washington state. Selected subtraction assays showed that whereas removal of DMNT or 1-octen-3-ol significantly reduced the level of upwind flight, removal of myrcene and beta-caryophyllene, or dimethyl trisulfide alone did not significantly affect the proportion of upwind flights. Our findings add to previous studies showing that populations of Rhagoletis flies infesting different host fruit are attracted to unique mixtures of volatile compounds specific to their respective host plants. Taken together, the results support the hypothesis that differences among flies in their behavioral responses to host fruit odors represent key adaptations involved in sympatric host plant shifts, contributing to host specific mating and generating prezygotic reproductive isolation among members of the R. pomonella sibling species complex. PMID- 28078622 TI - Evidence that polycystins are involved in Hydra cnidocyte discharge. AB - Like other cnidarians, the freshwater organism Hydra is characterized by the possession of cnidocytes (stinging cells). Most cnidocytes are located on hydra tentacles, where they are organized along with sensory cells and ganglion cells into battery complexes. The function of the battery complexes is to integrate multiple types of stimuli for the regulation of cnidocyte discharge. The molecular mechanisms controlling the discharge of cnidocytes are not yet fully understood, but it is known that discharge depends on extracellular Ca2+ and that mechanically induced cnidocyte discharge can be enhanced by the presence of prey extracts and other chemicals. Experiments in this paper show that a PKD2 (polycystin 2) transient receptor potential (TRP) channel is expressed in hydra tentacles and bases. PKD2 (TRPP) channels belong to the TRP channel superfamily and are non-selective Ca2+ channels involved in the transduction of both mechanical and chemical stimuli in other organisms. Non-specific PKD2 channel inhibitors Neo (neomycin) and Gd3+ (gadolinium) inhibit both prey capture and cnidocyte discharge in hydra. The PKD2 activator Trip (triptolide) enhances cnidocyte discharge in both starved and satiated hydra and reduces the inhibition of cnidocyte discharge caused by Neo. PKD1 and 2 proteins are known to act together to transduce mechanical and chemical stimuli; in situ hybridization experiments show that a PKD1 gene is expressed in hydra tentacles and bases, suggesting that polycystins play a direct or indirect role in cnidocyte discharge. PMID- 28078624 TI - Millipede Defensive Compounds Are a Double-Edged Sword: Natural History of the Millipede-Parasitic Genus Myriophora Brown (Diptera: Phoridae). AB - Toxic defensive secretions produced by millipedes in the orders Julida, Spirobolida, Spirostreptida, and Polydesmida are highly repellent to most vertebrate and invertebrate natural enemies, but a few insects have evolved mechanisms to overcome these defenses. We demonstrate that highly specialized parasitic phorid flies in the species-rich genus Myriophora use volatile millipede defensive compounds as kairomones for host location. Of the two predominant quinone components in the defensive blend of juliform millipedes, 2 methoxy-3-methyl-1,4-benzoquinone alone was sufficient to attract adult flies of both sexes; however, a combination of 2-methoxy-3-methyl-1,4-benzoquinone and 2 methyl-1,4-benzoquinone increased attractiveness nearly threefold. We further discuss oviposition behavior, adult and larval feeding habits, life history parameters, and the potential competitive interactions between phorid flies in the genus Myriophora and other millipede-associated insects. PMID- 28078627 TI - Nanostructured Materials Synthesis Using Ultrasound. AB - Recent applications of ultrasound to the production of nanostructured materials are reviewed. Sonochemistry permits the production of novel materials or provides a route to known materials without the need for high bulk temperatures, pressures, or long reaction times. Both chemical and physical phenomena associated with high-intensity ultrasound are responsible for the production or modification of nanomaterials. Most notable are the consequences of acoustic cavitation: the formation, growth, and implosive collapse of bubbles, and can be categorized as primary sonochemistry (gas-phase chemistry occurring inside collapsing bubbles), secondary sonochemistry (solution-phase chemistry occurring outside the bubbles), and physical modifications (caused by high-speed jets, shockwaves, or inter-particle collisions in slurries). PMID- 28078625 TI - Analysis of an N-terminal deletion in subunit a of the Escherichia coli ATP synthase. AB - Subunit a is a membrane-bound stator subunit of the ATP synthase and is essential for proton translocation. The N-terminus of subunit a in E. coli is localized to the periplasm, and contains a sequence motif that is conserved among some bacteria. Previous work has identified mutations in this region that impair enzyme activity. Here, an internal deletion was constructed in subunit a in which residues 6-20 were replaced by a single lysine residue, and this mutant was unable to grow on succinate minimal medium. Membrane vesicles prepared from this mutant lacked ATP synthesis and ATP-driven proton translocation, even though immunoblots showed a significant level of subunit a. Similar results were obtained after purification and reconstitution of the mutant ATP synthase into liposomes. The location of subunit a with respect to its neighboring subunits b and c was probed by introducing cysteine substitutions that were known to promote cross-linking: a_L207C + c_I55C, a_L121C + b_N4C, and a_T107C + b_V18C. The last pair was unable to form cross-links in the background of the deletion mutant. The results indicate that loss of the N-terminal region of subunit a does not generally disrupt its structure, but does alter interactions with subunit b. PMID- 28078626 TI - Time-course investigation of blood-brain barrier permeability and tight junction protein changes in a rat model of permanent focal ischemia. AB - Permanent middle cerebral artery occlusion (pMCAO) is an animal model that is widely used to simulate human ischemic stroke. However, the timing of the changes in the expression of tight junction (TJ) proteins and synaptic proteins associated with pMCAO remain incompletely understood. Therefore, to further explore the characteristics and mechanisms of blood-brain barrier (BBB) damage during cerebral ischemic stroke, we used a pMCAO rat model to define dynamic changes in BBB permeability within 120 h after ischemia in order to examine the expression levels of the TJ proteins claudin-5 and occludin and the synaptic proteins synaptophysin (SYP) and postsynaptic density protein 95 (PSD95). In our study, Evans blue content began to increase at 4 h and was highest at 8 and 120 h after ischemia. TTC staining showed that cerebral infarction was observed at 4 h and that the percentage of infarct volume increased with time after ischemia. The expression levels of claudin-5 and occludin began to decline at 1 h and were lowest at 8 and 120 h after ischemia. The expression levels of SYP and PSD95 decreased from 12 to 120 h after ischemia. GFAP, an astrocyte marker, gradually increased in the cortex penumbra over time post-ischemia. Our study helps clarify the characteristics of pMCAO models and provides evidence supporting the translational potential of animal stroke models. PMID- 28078628 TI - 3D-Printed Drugs for Children-Are We Ready Yet? AB - The first medicine manufactured by three-dimensional (3D) printing was recently approved by the Food and Drug Administration (FDA). The advantages of printing as a manufacturing route enabling more flexibility regarding the dose, and enlarging individual treatment options, have been demonstrated. There is a particular need for flexible drug delivery solutions when it comes to children. Printing as a new pharmaceutical manufacturing technology brings manufacturing closer to the patient and can easily be adjusted to the required dosing scheme, offering more flexibility for treatments. Printing of medicine may therefore become the manufacturing route of choice to provide tailored and potentially on-demand treatments for patients with individual needs. This paper intends to summarize and discuss the state of the art, the crucial aspects which should be taken into account, and the still-open questions, in order to make 3D printing a suitable manufacturing route for pediatric drugs. PMID- 28078629 TI - Effect of Microneedle Type on Transdermal Permeation of Rizatriptan. AB - The present study was aimed to investigate the effect of salient microneedle (MN) geometry parameters like length, density, shape and type on transdermal permeation of rizatriptan (RIZ). Studies were carried out using two types of MN devices viz. AdminPatch(r) arrays (ADM) (0.6, 0.9, 1.2 and 1.5 mm lengths) and laboratory-fabricated polymeric MNs (PMs) of 0.6 mm length. In the case of the PMs, arrays were applied three times at different places within a 1.77-cm2 skin area (PM-3) to maintain the MN density closer to 0.6 mm ADM. Histological studies revealed that PM, owing to their geometry/design, formed wider and deeper microconduits when compared to ADM of similar length. Approximately 4.9- and 4.2 fold increases in the RIZ steady-state flux values were observed with 1.5 mm ADM and PM-3 applications when compared to the passive studies. A good correlation between different dimensionless parameters like the amount of RIZ permeated (C t /C s), thickness (h/L) and surface area (S a/L 2) of the skin was observed with scaling analyses. Numerical simulations provided further information regarding the distribution of RIZ in MN-treated skin after application of different MNs. Overall, the study suggests that MN application enhances the RIZ transdermal permeation and the geometrical parameters of MNs play an important role in the degree enhancement. PMID- 28078630 TI - "Data Not Shown" is No Longer Excusable in Biomedical Publishing. PMID- 28078631 TI - Investigation of Solvent Effects on Photophysical Properties of New Aminophthalimide Derivatives-Based on Methanesulfonate. AB - Novel aminophthalimide derivatives were synthesized starting from (3aR,7aS)-2-(2 hydroxypropyl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (9) , and solvent effects on the photo-physical properties of these newly synthesized aminophthalimide derivatives (compounds 14 and 15) were investigated using UV-Vis absorption spectroscopy, steady-state and time-resolved fluorescence measurements. Both absorption and fluorescence spectra exhibited bathochromic shift with the increased polarity of the solvents for both molecules. Solute solvent interactions were analyzed using the Lippert-Mataga and Bakhshiev polarity functions, and Kamlet-Taft and Catalan multiple linear regression approaches. The results revealed that these two molecules experienced specific interactions. Furthermore, photo-physical parameters were calculated for both molecules in all of the solvents, such as the fluorescence quantum yield, fluorescence lifetime, radiative (kr) and non-radiative (knr) rate constant values. It was observed that the fluorescence quantum yield values decreased linearly with increasing solvent polarity. This study proved the new dyes including isopropyl methanesulfonate group displayed different behavior from previous studies of aminophthalimide derivatives in water. It was recommended that these new dyes having interesting properties by changing solvent can be used various applications such as environmentally sensitive fluorescent probes, labels in biology, laser industry. PMID- 28078632 TI - Fluorescent Carbon Dot as Nanosensor for Sensitive and Selective Detection of Cefixime Based on Inner Filter Effect. AB - Here a simple and sensitive fluorescent assay for detecting Cefixime based on inner filter effect (IFE) has been proven, which is conceptually different from the previously reported CEF fluorescent assays. In this sensing platform, fluorescent carbon dots (CDs) were prepared by one-pot synthesis and was directly used as fluorophore in IFE. The method is based on the complexation reaction between cefixime and palladium ion in the presence of acidic buffer solution (pH 4). The Pd(II)-CEFcomplex was capable of functioning as a powerful absorber in IFE to influence the excitation of fluorophore (CDs). Production Pd(II) CEFcomplex induced the absorption band transition from 310 to 400 nm, which resulted in the complementary overlap with the excitation spectra of CDs. Due to the competitive absorption, the excitation of CDs was significantly weakened, resulting in the quenching of CDs. The present IFE-based sensing strategy showed a good linear relationship from 0.2 * 10-6 M to 8 * 10-6 M (R2 = 0.987) and provided an exciting detection limit of 0.5 * 10-7 (3delta/slope). The proposed method has been successfully applied for the determination of cefixime in raw milk and human urine samples. PMID- 28078633 TI - Benzodiazepine Use and Risk of Developing Alzheimer's Disease: A Case-Control Study Based on Swiss Claims Data. AB - BACKGROUND: A possible association between benzodiazepine use and Alzheimer's disease (AD) has been hypothesized in previous studies. OBJECTIVES: Using claims data from the Helsana Group, a large Swiss health insurance provider, we examined the association between previous benzodiazepine use and the risk of AD. METHODS: We conducted a matched case-control study and identified 1438 incident AD cases between 2013 and 2014 based on recorded first-time use of drugs used to treat AD [i.e., acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and the N-methyl-D-aspartate receptor antagonist memantine] and matched one control to each case on age, sex, index date, and residence (canton). Because the initiation of benzodiazepine use shortly before the AD diagnosis date may occur as a result of symptomatic treatment of prodromal symptoms of early major neurocognitive disorder, we introduced an induction period of 2 years before the AD diagnosis date. Additionally, we categorized medication use by duration of use prior to the index date using prescriptions. We applied conditional logistic regression analyses to calculate odds ratios with 95% confidence intervals and adjusted for use of antidepressants. RESULTS: The crude odds ratio (95% confidence interval) of developing AD for patients starting benzodiazepine treatment was 1.71 (1.17-2.99) in the year before diagnosis and 1.19 (0.82-1.72) in the third year before diagnosis. After accounting for benzodiazepine use initiated during the prodromal phase, benzodiazepine use was not associated with an increased risk of developing AD; long-term benzodiazepine use (>=30 prescriptions) yielded an adjusted odds ratio of 0.78 (0.53-1.14). CONCLUSIONS: After taking into consideration a possible protopathic bias in the 2 years preceding the AD diagnosis date, benzodiazepine use was not associated with an increased risk of developing AD. PMID- 28078634 TI - Natalizumab for Achieving Relapse-Free, T1 Gadolinium-Enhancing-Lesion-Free, and T2 Lesion-Free Status in Japanese Multiple Sclerosis Patients: A Phase 2 Trial Subanalysis. AB - INTRODUCTION: In a phase 2 trial of natalizumab in Japanese patients with relapsing-remitting multiple sclerosis (RRMS), treatment-related changes in relapses, brain lesions, and disability worsening were found to be comparable with those observed in the phase 3 studies of natalizumab in primarily non-Asian RRMS patients. METHODS: This subanalysis of the placebo-controlled phase 2 trial of natalizumab in Japanese RRMS patients (n = 94) evaluated the effects of natalizumab versus placebo on the proportion of patients who achieved relapse free, T1 gadolinium-enhancing (Gd+) lesion-free, and new/newly enlarged T2 lesion free status, defined as "no evidence of inflammatory disease activity" (NEDA) like status, after 24 weeks of treatment. RESULTS: In this subanalysis, significantly more natalizumab-treated than placebo-treated patients achieved NEDA-like status (76.6% vs. 31.9%; P < 0.0001). In addition, the odds ratio (95% confidence interval) for patients on natalizumab to reach NEDA-like status was 6.98 (2.80-17.38) compared with placebo patients. CONCLUSION: These results confirm previous findings indicating that natalizumab is efficacious in Japanese patients with RRMS. FUNDING: Biogen. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01440101. PMID- 28078635 TI - CORR Insights(r): Is There Benefit to Free Over Pedicled Vascularized Grafts in Augmenting Tibial Intercalary Allograft Constructs? PMID- 28078636 TI - CORR Insights(r): False-positive Cultures After Native Knee Aspiration: True or False. PMID- 28078637 TI - Editor's Spotlight/Take 5: Lawnmowers Versus Children: The Devastation Continues. PMID- 28078638 TI - 11C-Methionine positron emission tomography delineates non-contrast enhancing tumor regions at high risk for recurrence in pediatric high-grade glioma. AB - We assessed the prognostic utility of 11C-Methionine positron emission tomography (MET-PET) in pediatric high-grade glioma (HGG). Thirty-one children had 62 MET PET studies. Segmented tumor volumes from co-registered magnetic resonance studies were assessed for concordance with MET-PET uptake using Boolean operations. The tumor volume at diagnosis and treatment failure was assessed relative to MET-PET avid volume. The prognostic impact of MET-PET-delineated non contrast enhancing tumor (NCET) was assessed. NCET was defined as the region of tumor defined by defined by FLAIR which did not enhance but showed MET-PET avidity. MET-PET concordance varied according to magnetic resonance sequence. MET PET rarely added to the tumor volume in most cases. The volume of MET-PET with standardized uptake value >3.0 was differentially distributed at diagnosis, post treatment, and at recurrence. The initial MET-PET region overlapped with recurrent tumor in 90% of the cases. When the proportion of tumor which was NCET was >10%, an earlier time to progression (5.8 months; 95% CI, 1-8.2 vs. 10.5 months; 95% CI, 0.9-NR; p = 0.035) was noted. MET-PET delineates regions at increased risk for recurrence and may improve the definition of failure, prognostic assessment, and target definition for radiotherapy. PMID- 28078639 TI - Low preoperative prognostic nutritional index predicts poor survival in patients with newly diagnosed high-grade gliomas. AB - Preoperative prognostic nutritional index (PNI) has been widely demonstrated to predict survival of patients with malignant tumors. Its utility in predicting outcomes in patients with high-grade gliomas (HGG) remains undefined. A retrospective study of 188 HGG patients was conducted. An optimal PNI cut-off value was applied to stratify patients into high PNI (>=52.55, n = 78) and low PNI (<52.55, n = 110) groups. Univariate and multivariate analysis was performed to identify prognostic factors associated with overall survival (OS) and progression free survival (PFS). The resulting prognostic models were externally validated using a demographic-matched cohort of 130 HGG patients. In the training set, PNI value was negatively correlated with age (p = 0.027) and tumor grade (p = 0.048). Both PFS (8.27 vs. 20.77 months, p < 0.001) and OS (13.57 vs. 33.23 months, p < 0.001) were significantly worse in the low PNI group. Strikingly, patients in high PNI group had a 52% decrease in the risk of tumor progression and 55% decrease of death relative to low PNI. Multivariate analysis further demonstrated PNI as an independent predictor for PFS (HR = 0.62, 95% CI 0.43 0.87) and OS (HR = 0.56, 95% CI 0.38-0.80). The PNI retained independent prognostic value in the validation set for both PFS (p = 0.013) and OS (p = 0.003). On subgroup analysis by tumor grade and treatment modalities, both PFS and OS were better for the patients with high PNI. The PNI is a potentially valuable preoperative marker for the survival of patients following HGG resection. PMID- 28078641 TI - Staple Line Leak After Primary Sleeve Gastrectomy-Risk Factors and Mid-term Results: Do Patients Still Benefit from the Weight Loss Procedure? AB - BACKGROUND: Staple line leak after laparoscopic sleeve gastrectomy (LSG) still represents the most feared complication. The purpose of this study was to investigate whether there are factors that increase the risk for a leakage. Furthermore, we aimed to analyze the impact of a leak on weight change and resolution of comorbidities. METHODS: Since 2005, data from obese patients that undergo bariatric procedures in Germany are prospectively registered. For the current analysis, all adult subjects that had undergone primary LSG from 2005 to 2014 were considered. RESULTS: Overall, 241/15,756 (1.53%) patients experienced a leak. The occurrence of a leakage resulted in a significant increase of the mortality rate (3.7 vs. 0.2%; p < 0.01). Percent excess weight loss did not differ between leak and non-leak patients, both, at 12 (64.2 vs. 60.9%; p = 1.0) and 24 months (68.5 vs. 64.0%, p = 0.86). Similarly, no significant difference was observed for resolution rate of all comorbid conditions. Matched pair analysis confirmed these findings. Multivariable analysis identified operation time, conversion, intraoperative complications, and hypertension and degenerative joint disease as risk factors for a leak. Oversewing the staple line was associated with the lowest risk. CONCLUSION: The postoperative staple line leak after primary LSG significantly increases postoperative morbidity and mortality. We found that there are patient-related factors and operative variables that predispose to leakage after LSG. However, the occurrence of a leakage does not adversely impact the weight loss and resolution of comorbidities in the mid-term. PMID- 28078640 TI - Development of the pediatric quality of life inventory neurofibromatosis type 1 module items for children, adolescents and young adults: qualitative methods. AB - Health-related quality of life (HRQOL) is arguably one of the most important measures in evaluating effectiveness of clinical treatments. At present, there is no disease-specific outcome measure to assess the HRQOL of children, adolescents and young adults with Neurofibromatosis Type 1 (NF1). This study aimed to develop the items and support the content validity for the Pediatric Quality of Life InventoryTM (PedsQLTM) NF1 Module for children, adolescents and young adults. The iterative process included multiphase qualitative methods including a literature review, survey of expert opinions, semi-structured interviews, cognitive interviews and pilot testing. Fifteen domains were derived from the qualitative methods, with content saturation achieved, resulting in 115 items. The domains include skin, pain, pain impact, pain management, cognitive functioning, speech, fine motor, balance, vision, perceived physical appearance, communication, worry, treatment, medicines and gastrointestinal symptoms. This study is limited because all participants are recruited from a single-site. Qualitative methods support the content validity for the PedsQLTM NF1 Module for children, adolescents and young adults. The PedsQLTM NF1 Module is now undergoing national multisite field testing for the psychometric validation of the instrument development. PMID- 28078642 TI - Association Between Subtotal Gastrectomy with Billroth II Anastomosis and Coronary Heart Disease. AB - BACKGROUND: We assessed the risk of coronary heart disease (CHD) after subtotal gastrectomy with Billroth II anastomosis (SGBIIA) for peptic ulcer disease (PUD). METHODS: The Taiwan National Health Insurance Research Database was used, and 6160 patients undergoing SGBIIA for PUD were identified as the surgical cohort. A total of 24,540 patients from the PUD population not undergoing surgery selected by frequency-matching were identified as the non-surgical cohort. All patients were followed until the end of 2011 to measure the incidence of CHD. RESULTS: The cumulative incidence of CHD was lower in patients with SGBIIA than in those without surgery (16.9 vs 22.9 per 1000 person-year, adjusted hazard ratio [aHR] = 0.79, 95% confidence interval [CI] = 0.71-0.88). The risk of CHD, either acute coronary syndrome (ACS) (aHR = 0.83, 95% CI = 0.75-0.91) or other non-ACS CHD (aHR = 0.78, 95% CI = 0.68-0.88), was lower for the SGBIIA cohort than for the non-surgery cohort (aHR = 0.79, 95% CI = 0.71-0.88) after adjusting for age and the comorbidities of hypertension, diabetes mellitus, hyperlipidemia, stroke, congestive heart failure, chronic kidney disease, and chronic obstructive pulmonary disease. CONCLUSIONS: We found SGBIIA is associated with a reduced risk of CHD for PUD patients. PMID- 28078643 TI - Anthropometric Assessment for Bariatric Procedures in the Private Practice of a Registered Dietitian in Colombia. AB - BACKGROUND: Obesity and its consequences have now reached worldwide pandemic proportions. Among treatments, bariatric interventions are the most effective for weight reduction. Here, we describe the change in anthropometric measurements (AMs) of 615 adult bariatric procedure patients seen in the private practice of a registered dietitian (RD) in Bogota, Colombia. METHODS: Observational retrospective study of AMs recorded between 1996 and 2013 for patients who had laparoscopic sleeve gastrectomy (LSG, n = 290), laparoscopic adjustable gastric banding (LAGB, n = 207), and laparoscopic Roux-EN-Y gastric bypass (LRYGB, n = 36) or the non-surgical gastric balloon (GB, n = 82) procedure. Patients had three bimonthly follow-up visits. Paired t tests compared baseline (first) and 6 month (fourth) follow-up visit values. RESULTS: Differences in AMs between the baseline and fourth visits were statistically significant for the surgical interventions. A mean weight loss of 22 kg, equivalent to a 22% total body weight loss, together with significant reduction of the waist-to-height-ratio (WHtR)(p < 0.001) and body mass index (BMI)(p < 0.001), was observed across all procedures. CONCLUSIONS: The use of multiple AMs enables a comprehensive assessment of body composition in patients who undergo bariatric procedures. Our study is a useful resource for international future reference and highlights the impact that the RD can have on understanding and influencing the effectiveness of bariatric procedures. PMID- 28078644 TI - Eight- or 12-Week Treatment of Hepatitis C with Ledipasvir/Sofosbuvir: Real-World Experience in a Large Integrated Health System. AB - BACKGROUND: Second-generation direct-acting antiviral agents are integral to treatment of hepatitis C (HCV) infection. Eight-week courses of ledipasvir/sofosbuvir (LDV/SOF) have been supported in some studies, but data are limited on efficacy in real-world use. Controversy exists regarding applicability of clinical trials to real-world effectiveness. We report virologic responses of patients with HCV genotype 1 infection receiving LDV/SOF for 8 or 12 weeks in a large integrated healthcare system. METHODS: All patients receiving LDV/SOF, without ribavirin, were identified from pharmacy records, and outcomes are reported. Only treatment-naive patients without evidence of cirrhosis and hepatitis C viral load less than 6 million IU/ml were candidates for 8-week therapy. Treatment was at clinician discretion, but delivered by a multidisciplinary team and reviewed for appropriateness and adherence to these criteria by one of the authors, all experienced in hepatitis C treatment. Sustained viral response at 12 weeks (SVR 12) was contrasted between those receiving 8 and those receiving 12 weeks of treatment. RESULTS: Completed prescriptions for LDV/SOF, without ribavirin, as of 30 September 2015 were identified in 1021 patients. Five patients discontinued therapy due to medical reasons and 35 had incomplete follow-up viral load data, thus there were 981 evaluable patients: 377 treated for 8 weeks and 604 treated for 12 weeks. SVR 12 was virtually identical at 93.6 and 93.5%, respectively. Baseline characteristics differed between the two groups, as only treatment-naive, non-cirrhotic, non-HIV infected patients were eligible for an 8-week course of therapy. CONCLUSIONS: Eight-week courses of LDV/SOF are comparable to 12-week courses in real-world use among selected patients supported by a multidisciplinary team. PMID- 28078645 TI - PARP Inhibitors in Reproductive System Cancers: Current Use and Developments. AB - The repair of DNA damage is a critical cellular process governed by multiple biochemical pathways that are often found to be defective in cancer cells. The poly(ADP-ribose) polymerase (PARP) family of proteins controls response to single strand DNA breaks by detecting these damaged sites and recruiting the proper factors for repair. Blocking this pathway forces cells to utilize complementary mechanisms to repair DNA damage. While PARP inhibition may not, in itself, be sufficient to cause tumor cell death, inhibition of DNA repair with PARP inhibitors is an effective cytotoxic strategy when it is used in patients who carry other defective DNA-repair mechanisms, such as mutations in the genes BRCA 1 and 2. This discovery has supported the development of PARP inhibitors (PARPi), agents that have proven effective against various types of tumors that carry BRCA mutations. With the application of next-generation sequencing of tumors, there is increased interest in looking beyond BRCA mutations to identify genetic and epigenetic aberrations that might lead to similar defects in DNA repair, conferring susceptibility to PARP inhibition. Identification of these genetic lesions and the development of screening assays for their detection may allow for the selection of patients most likely to respond to this class of anticancer agents. This article provides an overview of clinical trial results obtained with PARPi and describes the companion diagnostic assays being established for patient selection. In addition, we review known mechanisms for resistance to PARPi and potential strategies for combining these agents with other types of therapy. PMID- 28078646 TI - Mucosal Healing in Ulcerative Colitis: A Comprehensive Review. AB - Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by periods of remission and periods of relapse. Patients often present with symptoms such as rectal bleeding, diarrhea and weight loss, and may require hospitalization and even colectomy. Long-term complications of UC include decreased quality of life and productivity and an increased risk of colorectal cancer. Mucosal healing (MH) has gained progressive importance in the management of UC patients. In this article, we review the endoscopic findings that define both mucosal injury and MH, and the strengths and limitations of the scoring systems currently available in clinical practice. The basic mechanisms behind colonic injury and MH are covered, highlighting the pathways through which different drugs exert their effect towards reducing inflammation and promoting epithelial repair. A comprehensive review of the evidence for approved drugs for UC to achieve and maintain MH is provided, including a section on the pharmacokinetics of anti-tumor necrosis factor (TNF)-alpha drugs. Currently approved drugs with proven efficacy in achieving MH in UC include salicylates, corticosteroids (induction only), calcineurin inhibitors (induction only), thiopurines, vedolizumab and anti-TNFalpha drugs (infliximab, adalimumab, and golimumab). MH is of crucial relevance in the outcomes of UC, resulting in lower incidences of clinical relapse, the need for hospitalization and surgery, as well as reduced rates of dysplasia and colorectal cancer. Finally, we present recent evidence towards the need for a more strict definition of complete MH as the preferred endpoint for UC patients, using a combination of both endoscopic and histological findings. PMID- 28078647 TI - Sitagliptin: A Review in Type 2 Diabetes. AB - The dipeptidyl peptidase-4 inhibitor sitagliptin (Januvia(r); Glactiv(r); Tesavel(r); XeleviaTM) is approved in more than 130 countries worldwide as monotherapy and in combination with other antihyperglycaemic drugs for the treatment of adult patients with type 2 diabetes (T2D). Extensive clinical experience has firmly established the glycaemic efficacy of oral sitagliptin (+/ other antihyperglycaemic drugs) in a broad spectrum of patients with T2D, including obese, elderly and renally impaired patients and those with established cardiovascular (CV) disease (CVD). Sitagliptin is generally well tolerated, with most adverse events being of mild to moderate intensity and relatively few patients discontinuing treatment because of these events. Sitagliptin treatment was not associated with an increased risk for the known CVD risk factors of hypoglycaemia and bodyweight gain. Of note, in the TECOS CV safety trial in patients with T2D and established CVD, sitagliptin was noninferior to placebo in terms of the risk of the 4-point major adverse cardiac event (MACE) outcome, with no increased risk in hospitalization for heart failure. Albeit discussion is equivocal regarding the potential increased risk of pancreatitis and pancreatic cancer with incretin-based therapies (including sitagliptin), no causal link between incretin-based drugs and these events has been established to date. With its convenient once-daily oral regimen, low potential for pharmacokinetic drug drug interactions and good efficacy and safety profiles, including CV safety, sitagliptin remains an important option in the management of patients with T2D. PMID- 28078648 TI - Generation of a Floxed Allele of the Mouse MicroRNA-200 Clusters. AB - MicroRNA-8 and its target gene, u-shaped (ush), regulate body size in Drosophila. As the mouse homolog of the Drosophila miR-8, whether the miR-200 family has similar functions and how they perform their regulatory roles in body size control is unknown. In order to discover the biological function of the miR-200s in vivo, we generated mice lacking the miR-200b/200a/429 gene cluster using the Cre/loxp system. miR-200b/200a/429 null mutant mice were viable, fertile, and showed normal development. PMID- 28078649 TI - Acidogenic Digestion of Pre-pulping Extracts for Production of Fuels and Bioproducts Via Carboxylate Platform Processing. AB - Hemicellulose extracted from wood prior to processing the wood into paper or composite materials can be a resource for the production of biofuels or bioproducts. Mixed microbial cultures are capable of converting biomass into mixed carboxylic acids, which can be purified as products or converted to biofuels or other biochemicals. Mixed cultures are robust conversion systems and do not require added enzymes to hydrolyze biomass to sugars. We produced mixed carboxylic acids using mesophilic and thermophilic fermentation of raw, unconditioned green liquor and hot water hardwood extracts, as well as baseline sugar solutions. Daily samples were taken from the fermentations and analyzed for composition, pH, and gas volume. The extract digestions were capable of hydrolyzing oligomeric hemicellulose without supplemental enzymes and converting all types of released sugars. Lactic acid was prominent in lower pH systems and acetic acid, the main product at more neutral pH. Compared to thermophilic systems, mesophilic fermentations had higher hydrolysis conversion, carbohydrate conversion, acid yields, and selectivity for C3-C7 acids. Carbon balances on the wood extracts closed to within +/-9%. Methane production in all cases was essentially zero. PMID- 28078650 TI - In Vivo Efficacy of Latex from Calotropis procera in Ameliorating Fever Biochemical Characteristics and Plausible Mechanism. AB - Calotropis procera latex fractions possessing anti-inflammatory property were characterized for their biochemical properties, compared for their efficacy in ameliorating fever in rats and their mechanism of action was elucidated. Aqueous fraction and methanol extract (AqDL and MeDL) were derived from the dried latex (DL) and proteins were separated from the fresh latex (LP). Polyacrylamide gel electrophoresis carried out under denaturing conditions showed the presence of proteins with some similarity in LP and AqDL and both of these fractions exhibited proteinase activity by gelatin zymography. A further analysis revealed that only the LP fraction possesses cysteine proteinase activity. Oral administration of both AqDL and MeDL produced a dose-dependent reduction in body temperature in rats where fever was induced by yeast and their effect was comparable to that of standard drug paracetamol while intravenous administration of LP was not so effective. Both AqDL and MeDL produced a significant reduction in the levels of TNF-alpha, PGE2, and immunoreactivity of COX-2 in the hypothalamus as compared to yeast control group. This study shows that both AqDL and MeDL, the orally effective anti-inflammatory fractions of latex, have therapeutic potential in treating various febrile conditions. PMID- 28078651 TI - Fed-Batch Enzymatic Saccharification of High Solids Pretreated Lignocellulose for Obtaining High Titers and High Yields of Glucose. AB - To reduce the distillation costs of cellulosic ethanol, it is necessary to produce high sugar titers in the enzymatic saccharification step. To obtain high sugar titers, high biomass loadings of lignocellulose are necessary. In this study, to overcome the low saccharification yields and the low operability of high biomass loadings, a fed-batch saccharification process was developed using an enzyme reactor that was designed and built in-house. After optimizing the cellulase and biomass feeding profiles and the agitation speed, 132.6 g/L glucose and 76.0% theoretical maximum glucose were obtained from the 60 h saccharification of maleic acid-pretreated rice straw at a 30% (w/v) solids loading with 15 filter paper units (FPU) of Cellic CTec2/g glucan. This study demonstrated that through the proper optimization of fed-batch saccharification, both high sugar titers and high saccharification yields are possible, even with using the high solids loading (i.e., >=30%) with the moderate enzyme loading (i.e., <15 FPU/g glucan). These results could be contributed to improving economic feasibility of the high solids saccharification process in cellulosic fuel and chemical production. PMID- 28078652 TI - Free and Ca-Alginate Beads Immobilized Horseradish Peroxidase for the Removal of Reactive Dyes: an Experimental and Modeling Study. AB - The aim of this work was to remove the dyes Reactive Blue 221 (RB 221) and Reactive Blue 198 (RB 198) of synthetic effluent using the immobilized enzyme horseradish peroxidase (HRP) in Ca-alginate beads. Experimental parameters affecting the dye removal process such as the effect of pH, temperature, hydrogen peroxide concentration, mass capsules, and reuse were evaluated, and a numerical model of mass transfer was developed. A maximum removal of 93 and 75%, respectively, for the dyes RB 221 and RB 198, at pH 5.5 and temperature of 30 degrees C, concentration of hydrogen peroxide of 43.75 MUM for dye RB 221 and 37.5 MUM for the dye of RB 198 was obtained. A removal reaction of 180 min for RB 221 and 240 min for RB 198 was observed. Three reuse cycles of use of immobilized enzyme were achieved for both dyes. The numerical model proposed led to a good fit compared to experimental data. The HRP enzyme immobilized in Ca-alginate capsules showed a great potential for biotechnological applications, especially for the removal of reactive dyes. PMID- 28078653 TI - Meta-analysis of treatment with rabbit and horse antithymocyte globulin for aplastic anemia. AB - Aplastic anemia patients who received rabbit antithymocyte globulin exhibited response and survival rates inferior to those who received horse antithymocyte globulin in several studies. Therefore, we conducted a meta-analysis to compare rabbit and horse antithymocyte globulin as immunosuppressive therapy for aplastic anemia. We searched online databases for studies that compared antithymocyte globulin regimens as first-line treatment for aplastic anemia, including both randomized and non-randomized controlled trials. The early mortality rate at 3 months and overall response rate at 6 months were evaluated. Thirteen studies were included in the analysis. The risk ratio (RR) of early mortality for rabbit vs. horse antithymocyte globulin was 1.33 [95% confidence interval (CI) 0.69 2.57; P = 0.39], with significant heterogeneity. A sensitivity analysis suggested higher early mortality rate in patients who received rabbit antithymocyte globulin. The overall response rate was significantly higher in patients who received horse antithymocyte globulin (RR 1.27; 95% CI 1.05-1.54; P = 0.015). In conclusion, in aplastic anemia patients treated with ATG, early mortality rate was not significantly different in patients receiving horse or rabbit ATG, although a sensitivity analysis showed higher early mortality in the rabbit ATG group. Horse ATG was associated with significantly higher response rate than rabbit ATG. PMID- 28078654 TI - Capuchin monkeys can make and use stone tools. AB - Scientists hoping to elucidate the origin of human stone tool manufacture and use have looked to extant primate species for possible clues. Although some skepticism has been raised, there is clear evidence that today's capuchin monkeys can make and use stone tools. PMID- 28078655 TI - Single-Dose Oritavancin Compared to Standard of Care IV Antibiotics for Acute Bacterial Skin and Skin Structure Infection in the Outpatient Setting: A Retrospective Real-World Study. AB - INTRODUCTION: Cost-containment strategies are shifting the treatment of acute bacterial skin and skin structure infections (ABSSSI) from inpatient to outpatient settings. Current standard of care (SoC) requires multiple-dose regimens, which are associated with high hospitalization rates and high costs. Oritavancin, a new single-dose antibiotic for ABSSSI, may be suitable for outpatient therapy. This analysis evaluates the effectiveness, costs, and resource utilization of oritavancin vs. SoC in a real-world, outpatient setting. METHODS: A single-site, retrospective chart review was conducted of 118 adult patients diagnosed with ABSSSI and treated with either single-dose oritavancin or multi-dose SoC therapy between 6 August 2014 and 30 June 2015. Patients were assigned to two matched cohorts: oritavancin and SoC. Primary clinical effectiveness endpoints was the success (cured or improved) at 5-30 days after the course of antibiotic therapy has been completed. Secondary economic endpoints were total costs and healthcare resource utilization. RESULTS: Oritavancin showed comparable clinical effectiveness vs. multi-dose SoC in the outpatient setting. A similar percentage of patients in the oritavancin (90.2%) and SoC cohorts (77.4%) achieved successful outcomes ("cure" or "improved"), with the cure rate higher for oritavancin (73.2%) vs. SoC (48.4%; P = 0.0315). Oritavancin's clinical effectiveness was consistent across patient subgroups with varying demographic, clinical, and ABSSSI characteristics. Oritavancin was consistently associated with lower costs (per-patient savings $2319) and reduced resource utilization measures, and it required just 1.0 day of therapy vs. 7.2 days for SoC. CONCLUSION: Oritavancin is well suited for the outpatient treatment of ABSSSI. Compared with SoC, oritavancin offers comparable effectiveness, is more economical, and requires fewer healthcare resources. PMID- 28078656 TI - Biosimilars for the Treatment of Cancer: A Systematic Review of Published Evidence. AB - BACKGROUND: Biologic treatments for cancer continue to place a significant economic burden on healthcare stakeholders. Biosimilar therapies may help reduce this burden through cost savings, thereby increasing patient access. OBJECTIVES: The purpose of this study was to collate all published data to assess the weight of available evidence (quantity and quality) for proposed monoclonal antibody biosimilars and intended copies, for the treatment of cancer. METHODS: MEDLINE(r), Embase(r), and ISI Web of Science(r) databases were searched to September 2015. Conference proceedings (17) were searched (2012 to July 2015). Searches of the United States National Library of Medicine ClinicalTrials.gov registry were also conducted. Risk of bias assessments were undertaken to assess data strength and validity. RESULTS: Proposed biosimilars were identified in 23 studies (36 publications) in oncology and ten studies in 14 publications in oncology and chronic inflammatory diseases for bevacizumab, rituximab, and trastuzumab originators. Based on our review of the included published studies, and as inferred from the conclusions of study authors, the identified proposed biosimilars exhibit close similarity to their originators. Published data were also retrieved on intended copies of rituximab. It remains unclear what role these agents may have, as publications on rigorous clinical studies are lacking for these molecules. CONCLUSION: While biosimilar products have the potential to improve patient access to important biologic therapies, robust evidence of outcomes for monoclonal antibody biosimilars in treating cancer patients, including data from comparative efficacy and safety trials, is not yet available in the published literature. Significant data gaps exist, particularly for intended copies, which reinforces the need to maintain a clear differentiation between these molecules and true biosimilars. As more biosimilars become available for use, it will be important for stakeholders to understand fully the robustness of overall evidence used to demonstrate biosimilarity and gain regulatory approval. PMID- 28078658 TI - The Past Does Matter: a Nursing Perspective on Post Traumatic Slave Syndrome (PTSS). AB - Few have reviewed the impact of post traumatic slave syndrome (PTSS) on the issues of inequities, especially as it pertains to mental and physical health. Furthermore, the impact of PTSS on the social determinants of health is an area that has been researched by few investigators. The possibilities that the impact of slavery and/or major stress events in the life of a population can become trans-generational are lost to history. Think about what is taking place in cities around the country and then think about racist socialization (internalized racism) and its impact on our society. Combining these factors with the lack of real medical care and the bias that plagues our medical establishment and society in general, the net result is a society faced with inequities that seem to be unresolvable, simply because we have lost perspective about a major root cause of the problem. PMID- 28078657 TI - Racial and Ethnic Differences in Dietary Intake, Physical Activity, and Body Mass Index (BMI) Among Cancer Survivors: 2005 and 2010 National Health Interview Surveys (NHIS). AB - INTRODUCTION: This paper reports racial/ethnic differences in mean dietary and alcohol intake, physical activity, and body mass index (BMI) among cancer survivors and examines adherence to the American Cancer Society and the US Dietary Guidelines for Americans. METHODS: Data are from the cross-sectional 2005 and 2010 National Health Interview Surveys (NHIS). The total sample of cancer survivors (N = 3367) included non-Hispanic Whites (NHW; N = 2698), non-Hispanic Blacks (NHBs; N = 379), and Hispanics (N = 290). We compared mean reported dietary intake, moderate/vigorous physical activity, and BMI among racial/ethnic groups. Predicted marginals and multivariate logistic regression analysis were used to compare prevalence of non-adherence with recommendations among groups. RESULTS: Among the three racial/ethnic groups, Hispanics had the highest mean intake of vegetables, fiber, and calcium (p = 0.0003; p < 0.0001; p = 0.001). In the logistic regression model adjusting for sociodemographic covariates, smoking and BMI, Hispanics had lower non-adherence to fiber guidelines (OR = 0.38; CI = 0.24-0.58) than NHWs. NHBs had significantly higher non-adherence to vegetable guidelines (OR = 1.63; CI = 1.07-2.47). NHBs and Hispanics had lower non adherence with alcohol guidelines than NHWs (OR = 0.35 and 0.38; CI = 0.18-0.69 and 0.19-0.76, respectively). NHBs and Hispanics were more likely to be overweight/obese (OR = 1.66 and 1.57; CI = 1.24-2.23 and CI = 1.11-2.21, respectively). CONCLUSIONS: There are racial/ethnic differences in certain health behaviors of cancer survivors. However, non-adherence to guidelines is high in all three racial/ethnic groups. Achieving the recommended guidelines for diet, physical activity, and a healthy BMI is a concern for all cancer survivors, indicating the need for intervention among this growing group of at-risk individuals. PMID- 28078659 TI - RETRACTED ARTICLE: Summer Research Training Provides Effective Tools for Underrepresented Minorities to Obtain Doctoral Level Degrees. PMID- 28078660 TI - Racial/Ethnic Disparities in Diabetes Quality of Care: the Role of Healthcare Access and Socioeconomic Status. AB - INTRODUCTION: Blacks, Hispanics, and Asians are disproportionately affected by diabetes. We assessed the state of racial/ethnic disparities in diabetes quality of care in the USA. METHODS: We analyzed cross-sectional data of adults diagnosed with Type 2 diabetes in the nationally representative 2013 Medical Expenditure Panel Survey. Differences in adherence to five diabetes quality of care recommendations (HbA1c twice yearly, yearly foot exam, dilated eye exam, blood cholesterol test, and flu vaccination) were examined by race/ethnicity while controlling for three social determinants of health (health insurance status, poverty, and education) and other demographic variables. RESULTS: Among adults with diabetes in the USA, 74.9% received two or more HbA1c tests, 69.0% had a foot exam, 64.9% had an eye exam, 85.4% had a cholesterol test, and 65.1% received flu vaccination in 2013. Compared to Whites, all were lower for Hispanics; HbA1c tests, eye exam, and flu vaccination were lower for Blacks; HbA1c tests, foot exam, and eye exam were lower for Asians. In adjusted models, the only remaining disparities in quality of care indicators were HbA1c tests for Hispanics (AOR 0.67, CI = 0.47-0.97), Blacks (AOR 0.59, CI = 0.40-0.88), and Asians (AOR 0.47, CI = 0.42-0.99); foot exams for Hispanics (AOR 0.65, CI = 0.47 0.90); and flu vaccination for Blacks (AOR 0.68, CI = 0.49-0.93). CONCLUSION: Lack of insurance coverage and education explained some of the racial/ethnic disparities observed in diabetes quality of care. Improving quality of diabetes care could help reduce rates of diabetes complications, healthcare costs, and mortality. PMID- 28078661 TI - Role of cytokines in host defense against Staphylococcus aureus skin infection. AB - Wound infection caused by Staphylococcus aureus (S. aureus) is a critical clinical problem due to long hospitalization times, significant morbidity and mortality, as well as considerable medical resource consumption. With the emergence of methicillin-resistant S. aureus (MRSA) strains, current antibiotic treatments are becoming ineffective in combatting S. aureus infection. Thus, a novel therapeutic strategy is required. Recent studies discovered that several cytokines in the infected wound area play protective roles against S. aureus infection. This review summarizes recent discoveries regarding the role of cytokines-mediated responses in host defense against S. aureus skin infection, and discusses their implications for future immunotherapy and vaccine development. PMID- 28078662 TI - Low immunoglobulin E flags two distinct types of immune dysregulation. AB - During the last two decades, hyper-immunoglobulin (Ig)E syndromes have been characterized clinically and molecularly in patients with genetically determined primary immunodeficiencies. However, the detection of low IgE levels, defined here as below detection limit in the routine clinical immunology laboratory, has received little attention. We analysed the association of serum IgA, IgM and IgG levels (including IgG subclasses) with low, normal or high serum IgE levels in patients evaluated in a single-centre out-patient immunodeficiency and allergy clinic. The correlation of serum IgE levels with IgG subclasses depended on the clinical phenotype. In patients with immunodeficiencies, IgE correlated with IgG2 and IgG4 but not with IgG3. In contrast, in patients referred for signs of allergy, IgE correlated with IgG3 but not with IgG2. A low IgE result was associated with low IgG3 and IgG4 in allergy referrals, while immunodeficiency referrals with a low IgE result had significantly lower IgG1, IgG2 and IgG4 levels. Hierarchical clustering of non-IgE immunoglobulin profiles (IgM, IgA, IgG, IgG1-4) validated that non-IgE immunoglobulin levels predict the clinic referral, i.e. phenotype, of low-IgE patients. These results suggesto guide the clinical management of patients with low serum IgE levels. PMID- 28078663 TI - Inhibition of heat shock protein 90 exerts an antitumour effect in angiosarcoma: involvement of the vascular endothelial growth factor signalling pathway. AB - BACKGROUND: Angiosarcoma is a rare malignant neoplasm derived from endothelial cells, and because advanced angiosarcoma is resistant to standard chemotherapy its prognosis is poor. Therefore, new therapies are urgently needed. Heat shock protein (HSP)90 has been identified as a molecular chaperone that regulates various cancer-related proteins. Numerous clinical trials are currently testing the effectiveness of HSP90 inhibitors in various types of malignancies. OBJECTIVES: To investigate the role of HSP90 in the pathogenesis of angiosarcoma and whether the inhibition of HSP90 may have antitumour activity. METHODS: The expression of HSP90 protein in angiosarcoma was examined using immunohistochemistry and immunoblotting. The effects of HSP90 inhibition were proven using proliferation, migration and invasion assay in angiosarcoma cells. The mechanism of antitumour effect by HSP90 inhibition was investigated by the transfection of small interfering RNA (siRNA). RESULTS: The levels of HSP90 protein expression in cultured angiosarcoma cell lines were markedly increased compared with those in normal tissue cell lines. Immunohistochemical analyses revealed that the expression of HSP90 protein was strongly detected in angiosarcoma tissues compared with that in normal dermal vessels or senile angioma tissues. Ganetespib, an HSP90 inhibitor, with or without taxanes, inhibited the proliferation of angiosarcoma cells via apoptosis in a dose dependent manner. HSP90 siRNA suppressed the proliferation, migration and invasion of angiosarcoma cells. Knock-down of HSP90 did not suppress vascular endothelial growth factor receptor 2 directly, but selectively suppressed several downstream targets of vascular endothelial growth factor signalling in angiosarcoma cells. CONCLUSIONS: HSP90 could be a novel therapeutic target for angiosarcoma. PMID- 28078664 TI - Behavior analysts in the war on poverty: A review of the use of financial incentives to promote education and employment. AB - Poverty is a pervasive risk factor underlying poor health. Many interventions that have sought to reduce health disparities associated with poverty have focused on improving health-related behaviors of low-income adults. Poverty itself could be targeted to improve health, but this approach would require programs that can consistently move poor individuals out of poverty. Governments and other organizations in the United States have tested a diverse range of antipoverty programs, generally on a large scale and in conjunction with welfare reform initiatives. This paper reviews antipoverty programs that used financial incentives to promote education and employment among welfare recipients and other low-income adults. The incentive-based, antipoverty programs had small or no effects on the target behaviors; they were implemented on large scales from the outset, without systematic development and evaluation of their components; and they did not apply principles of operant conditioning that have been shown to determine the effectiveness of incentive or reinforcement interventions. By applying basic principles of operant conditioning, behavior analysts could help address poverty and improve health through development of effective antipoverty programs. This paper describes a potential framework for a behavior-analytic antipoverty program, with the goal of illustrating that behavior analysts could be uniquely suited to make substantial contributions to the war on poverty. PMID- 28078665 TI - Computerized pharmacy surveillance and alert system for drug-related problems. AB - WHAT IS KNOWN AND OBJECTIVE: Because of the impact of drug-related problems (DRPs) on morbidity and mortality, there is a need for computerized strategies to increase drug safety. The detection and identification of the causes of potential DRPs can be facilitated by the incorporation of a pharmacy warning system (PWS) in the computerized prescriber order entry (CPOE) and its application in the routine validation of inpatient drug therapy. A limited number of studies have evaluated a clinical decision support system to monitor drug treatment. Most of these applications have utilized a small range of drugs with alerts and/or types of alert. The objective of this study was to describe the implementation of a PWS integrated in the electronic medical record (EMR). METHODS: The PWS was developed in 2003-2004. Pharmacological information to generate drug alerts was entered on demographic data, drug dosage, laboratory tests related to the prescribed drug and drug combinations (interactions, duplications and necessary combinations). The PWS was applied in the prescription reviews conducted in patients admitted to the hospital in 2012. RESULTS AND DISCUSSION: Information on 83% of the drugs included in the pharmacopeia was introduced into the PWS, allowing detection of 2808 potential DRPs, representing 79.1% of all potential DRPs detected during the study period. Twenty per cent of PWS DRPs were clinically relevant, requiring pharmacist intervention. WHAT IS NEW AND CONCLUSION: The PWS detected most potential DRPs, thus increasing inpatient safety. The detection ability of the PWS was higher than that reported for other tools described in the literature. PMID- 28078666 TI - Paediatric Erdheim-Chester disease with aggressive skin manifestations. AB - Erdheim-Chester disease (ECD), a type of systemic non-Langerhans cell histiocytosis, is uncommon and characterized by the accumulation of CD68+ CD1a- foamy histiocytes. It is extremely rare in children. The skin lesions of paediatric ECD have not been systemically described before. We report a case of ECD in a 3.5-year-old Chinese boy. The patient presented with generalized skin and bone involvement of 3 years' duration. Marked generalized annular maculopapular lesions with central atrophy were seen. These differed from previously reported adult xanthoma-like papules or periorbital xanthelasma-like lesions. Computed tomography revealed diffuse pulmonary fibrosis and generalized skeletal involvement, including osteolysis and osteosclerosis. The presence of CD68+ CD1a- histiocytes allowed the diagnosis of ECD. According to our review of the literature, this is the paediatric case of ECD with the youngest age of onset. The generalized skin involvement made our case unique in comparison with those previously reported. PMID- 28078667 TI - Philanthropy in health professions education research: determinants of success. AB - CONTEXT: Fund-raising is a new practice in medical education research. OBJECTIVES: This qualitative study explores a cross-sectional analysis of philanthropy in medical education in Canada and Europe and identifies some common characteristics in the fund-raising system, key roles and characteristics of research sites that have had success. METHODS: Medical education research sites that had received donations greater than Can$100 000 were identified by searching publicly available sources. Interviews were conducted with 25 individuals from these and other sites, in four categories: medical education leaders (n = 9); philanthropy-supported chairholders and researchers (n = 5); donors of over Can$100 000 (n = 7), and advancement professionals (n = 4). Interview transcripts were inductively coded to identify themes. RESULTS: Five factors associated with success in accessing philanthropic sources were identified in the sample: support of the organisation's senior leadership; a charismatic champion who motivates donors; access to an advancement office or foundation; impetus to find funds beyond traditional operating budgets, and understanding of the conceptual and practical dimensions of fund-raising. Three types of donor (medical education insider, donor collective and general philanthropist), four faculty roles (trailblazers, rock stars, 'Who? Me?' people and future fund-raisers) and six stages in the fund-raising cycle were also identified. CONCLUSIONS: Philanthropy is a source of funding with the potential to significantly advance education research. Yet competence in fund-raising is not widely developed among medical education research leaders. Successful accessing of philanthropic sources of funding requires the ability to articulate the impact of philanthropy in medical education research in a way that will interest donors. This appears to be challenging for medical education leaders, who tend to frame their work in academic terms and have trouble competing against other fund-raising domains. Medical education research institutes and centres will benefit from developing greater understanding of the conception and practices of fund-raising. PMID- 28078668 TI - Mitochondrial adaptations to exercise in human skeletal muscle: a possible role for cristae density as a determinant of muscle fitness. PMID- 28078669 TI - Maintenance phase in psoralen-ultraviolet A phototherapy of early-stage mycosis fungoides. A critically appraised topic. AB - A 65-year-old patient affected by mycosis fungoides (MF) stage IB achieved complete remission (CR) after a cycle of PUVA phototherapy. The U.S. Cutaneous Lymphoma Consortium (USCLC) guidelines suggest that the patient should be kept in the maintenance phase, defined as a 'period of gradual decrease of frequency of UVL [ultraviolet light] while in clinical remission before discontinuation of phototherapy' by slowly tapering the number of psoralen-ultraviolet A (PUVA) applications over time up to clinical relapse. The USCLC guidelines also suggest a standardized schedule for the maintenance phase. Alternatively, the patient could end PUVA therapy and go straight to follow-up. The aim of this critically appraised topic (CAT) was to determine if a maintenance phase gives a significant benefit in terms of relapse rate (RR) and RFI in patients affected by early-stage MF who had achieved CR under PUVA phototherapy. Embase, PubMed and TRIP databases were searched for 'mycosis fungoides' AND [('photochemotherapy' OR 'puva') OR 'psoralen'] in June 2016. Three articles matched our inclusion criteria and are discussed in this CAT. In this field of research the literature is poor and the reported level of evidence is low. Only one of the studies was conducted prospectively, and none were randomized. No significant difference in terms of reduction in relapse rate or increase in RFI in patients who underwent a PUVA maintenance phase emerged when compared with those who went for simple follow-up. Further randomized clinical trials (RCTs) are required in order to evaluate maintenance phase vs. no treatment before it can be favoured as the standard protocol of treatment in early-stage MF. At the time of writing this paper, we report an ongoing Austrian multicentre RCT (Clinical Trial.gov identifier: NCT01686594) that will hopefully give useful results in this topic. PMID- 28078670 TI - Levator ani muscle avulsion is a risk factor for expulsion within 1 year of vaginal pessary placed for pelvic organ prolapse. AB - OBJECTIVE: The aim of this study was to investigate whether the presence of levator ani muscle (LAM) avulsion is associated with expulsion within 1 year of a vaginal pessary placed for pelvic organ prolapse (POP). METHODS: This was a prospective observational study of consecutive women with symptomatic POP, who had not received treatment for the condition before the consultation and opted for vaginal pessary placement in our center. Volume acquisition was performed before pessary insertion and offline analysis of the 3D/4D transperineal ultrasound volume data was performed. LAM was assessed on maximum pelvic floor muscle contraction (PFMC) and hiatal dimensions were assessed at rest, on PFMC and on maximum Valsalva. Results were compared between women in whom the pessary was retained for 1 year and those in whom the pessary was expelled within 1 year. RESULTS: The datasets of 255 women were analyzed including 147 (57.6%) women who had a vaginal pessary continuously in place over 1 year and 108 (42.4%) with pessary expulsion. Mean age was 63.2 (SD, 9.9) years and median parity was 3 (2 4). Eighteen (7.1%) had Stage I, 164 (64.3%) Stage II, 67 (26.3%) Stage III and six (2.4%) Stage IV POP. Women with vaginal pessary expulsion within 1 year had significantly larger hiatal dimensions at rest and on Valsalva, larger hiatal area during rest, PFMC and Valsalva and higher rate of LAM avulsion (53.7% vs 27.2%, P < 0.01) compared with women in whom the pessary was retained for 1 year. After controlling for potential confounders, LAM avulsion remained a risk factor (OR, 3.18, P < 0.01) of vaginal pessary expulsion within 1 year. CONCLUSIONS: Women in whom a vaginal pessary was expelled within 1 year of placement for POP had a larger hiatus. Presence of LAM avulsion was associated with a three-fold increase in the risk of expulsion of a vaginal pessary within 1 year. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28078672 TI - Determinants for drug survival of methotrexate in patients with psoriasis, split according to different reasons for discontinuation: results of the prospective MTX-CAPTURE. AB - BACKGROUND: As methotrexate (MTX) is a widely used treatment for psoriasis, it is important to gain insight into the reasons for the discontinuation of MTX and to understand the determinants for drug survival. OBJECTIVES: To describe 5-year drug survival for MTX in patients with psoriasis, split according to different reasons for discontinuation, and to identify the determinants for drug survival. METHODS: Data were extracted from a prospective psoriasis registry of patients treated with MTX (MTX-CAPTURE). Drug survival was analysed using Kaplan-Meier estimates and the determinants for discontinuation were analysed using Cox regression analysis. Analyses were split according to the reason for discontinuation: side-effects or ineffectiveness. RESULTS: We included 85 patients treated with MTX, with a maximum treatment duration of 5.2 years. The overall drug survival rates were 63%, 30% and 15% after 1, 3 and 5 years, respectively. The median survival was 1.8 years. Overall, 55 patients (65%) discontinued MTX for the following reasons: side-effects (35%), ineffectiveness (26%), combination of side-effects and ineffectiveness (13%), other reasons (16%) and 11% were lost to follow-up. The most reported side-effects were gastrointestinal symptoms, despite the use of folic acid in 99% of patients. Based on univariate analysis, a high Psoriasis Area and Severity Index score and a high score on the visual analogue scale for disease severity at baseline were possible determinants for a short drug survival. CONCLUSIONS: Drug survival of MTX was low with 15% of patients 'on drug' after 5 years. Side-effects alone or in combination with inadequate disease control were more important in the context of treatment discontinuation than inadequate disease control alone. PMID- 28078671 TI - Melanoma in congenital melanocytic naevi. AB - Congenital melanocytic naevi (CMN) are a known risk factor for melanoma, with the greatest risk currently thought to be in childhood. There has been controversy over the years about the incidence of melanoma, and therefore over the clinical management of CMN, due partly to the difficulties of histological diagnosis and partly to publishing bias towards cases of malignancy. Large cohort studies have demonstrated that melanoma risk in childhood is related to the severity of the congenital phenotype. New understanding of the genetics of CMN offers the possibility of improvement in diagnosis of melanoma, identification of those at highest risk, and new treatment options. We review the world literature and our centre's experience over the last 25 years, including the molecular characteristics of melanoma in these patients and new melanoma incidence and outcome data from our prospective cohort. Management strategies are proposed for presentation of suspected melanoma of the skin and the central nervous system in patients with CMN, including use of oral mitogen-activated protein kinase kinase inhibitors in NRAS-mutated tumours. PMID- 28078673 TI - Training kindergarten students lockdown drill procedures using behavioral skills training. AB - During situations in which a gunman is present on a school campus, lockdowns are initiated until the threat is removed. However, there are no data demonstrating an effective teaching strategy to increase students' correct responding during a lockdown. We evaluated the effectiveness of behavioral skills training (BST) to teach three groups of kindergarten students how to respond during lockdown drills. Results showed that participant groups displayed increases in correct steps and decreases in noise levels after BST was implemented; these effects maintained following training. PMID- 28078674 TI - Wilsonosiphonia gen. nov. (Rhodomelaceae, Rhodophyta) based on molecular and morpho-anatomical characters. AB - Morphological, anatomical, and molecular sequence data were used to assess the establishment and phylogenetic position of the genus Wilsonosiphonia gen. nov. Phylogenies based on rbcL and concatenated rbcL and cox1 loci support recognition of Wilsonosiphonia gen. nov., sister to Herposiphonia. Diagnostic features for Wilsonosiphonia are rhizoids located at distal ends of pericentral cells and taproot-shaped multicellular tips of rhizoids. Wilsonosiphonia includes three species with diagnostic rbcL and cox1 sequences, Wilsonosiphonia fujiae sp. nov. (the generitype), W. howei comb. nov., and W. indica sp. nov. These three species resemble each other in external morphology, but W. fujiae is distinguished by having two tetrasporangia per segment rather than one, W. indica by having abundant and persistent trichoblasts, and W. howei by having few and deciduous trichoblasts. PMID- 28078675 TI - Overexpression of a diacylglycerol acyltransferase gene in Phaeodactylum tricornutum directs carbon towards lipid biosynthesis. AB - Under nutrient deplete conditions, diatoms accumulate between 15% to 25% of their dry weight as lipids, primarily as triacylglycerols (TAGs). As in most eukaryotes, these organisms produce TAGs via the acyl-CoA dependent Kennedy pathway. The last step in this pathway is catalyzed by diacylglycerol acyltransferase (DGAT) that acylates diacylglycerol (DAG) to produce TAG. To test our hypothesis that DGAT plays a major role in controlling the flux of carbon towards lipids, we overexpressed a specific type II DGAT gene, DGAT2D, in the model diatom Phaeodactylum tricornutum. The transformants had 50- to 100-fold higher DGAT2D mRNA levels and the abundance of the enzyme increased 30- to 50 fold. More important, these cells had a 2-fold higher total lipid content and incorporated carbon into lipids more efficiently than the wild type (WT) while growing only 15% slower at light saturation. Based on a flux analysis using 13 C as a tracer, we found that the increase in lipids was achieved via increased fluxes through pyruvate and acetyl-CoA. Our results reveal overexpression of DAGT2D increases the flux of photosynthetically fixed carbon towards lipids, and leads to a higher lipid content than exponentially grown WT cells. PMID- 28078676 TI - The ultrastructural characterization of mitochondria-rich cells as a response to variations in salinity in two types of teleostean pseudobranch: milkfish (Chanos chanos) and Mozambique tilapia (Oreochromis mossambicus). AB - The pseudobranchs of two euryhaline teleost species, the milkfish (Chanos chanos) and the Mozambique tilapia (Oreochromis mossambicus), were studied after acclimization to different salinities using optical and electron microscopy. The milkfish pseudobranch was the lamellae-free type, with separate lamellae along the filaments containing two groups of mitochondria (Mt)-rich cells: chloride cells (CCs) and pseudobranch type cells (PSCs). Conversely, the tilapia pseudobranch was the embedded type, covered with connective tissues and with only one group of Mt-rich PSCs. Chloride cells were identified according to the apical openings and branched tubular networks around randomly distributed and diversely shaped Mt. Pseudobranchs type cells, however, were characterized according to the orderly arrangement of parallel tubules around closely packed Mt; both the tubules and the Mt were distributed in the vascular side of the cell, but were absent from the apical region. Compared with those of seawater (SW)-acclimated milkfish, the pseudobranchial lamellae of freshwater (FW) specimens were longer on average, and the Mt of the CCs had fewer cristae, were less electron-dense, and were often vacuolated. The Mt in the PSCs of FW-acclimated milkfish and tilapia were larger and more electron-dense than those of their SW-acclimated counterparts; in addition, more tubules were found to aggregately surround the Mt and basolateral membranes in the PSCs of fish from the hypo-osmotic environment. Conversely, the PSCs of tilapia were periodic acid-Schiff (PAS)-positive, and Mt in PSCs were concentrated with more parallel arrays of the tubule system than those of milkfish. Therefore, salinity-dependent changes in the ultrastructures of PSCs suggest their potential role in energy metabolism of both lamellae-free and embedded pseudobranchs, whereas the PAS-positive staining characteristics suggest a role in releasing or storaging polysaccharides in the embedded pseudobranch. J. Morphol. 278:390-402, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28078677 TI - Stable and Rapid Thiol Bioconjugation by Light-Triggered Thiomaleimide Ring Hydrolysis. AB - Maleimide-mediated thiol-specific derivatization of biomolecules is one of the most efficacious bioconjugation approaches currently available. Alarmingly, however, recent work demonstrates that the resulting thiomaleimide conjugates are susceptible to breakdown via thiol exchange reactions. Herein, we report a new class of maleimides, namely o-CH2 NHi Pr phenyl maleimides, that undergo unprecedentedly rapid ring hydrolysis after thiol conjugation to form stable thiol exchange-resistant conjugates. Furthermore, we overcome the problem of low shelf lives of maleimide reagents owing to their propensity to undergo ring hydrolysis prior to bioconjugation by developing a photocaged version of this scaffold that resists ring hydrolysis. UV irradiation of thiol bioconjugates formed with this photocaged maleimide unleashes rapid thiomaleimide ring hydrolysis to yield the desired stable conjugates within 1 h under gentle, ice cold conditions. PMID- 28078678 TI - A seamless phase I/II dose-finding trial assessing ingenol disoxate (LEO 43204) for field treatment of actinic keratosis on the scalp. AB - BACKGROUND: Actinic keratosis (AK) is a common sun-related skin condition, which can progress to squamous cell carcinoma and occur in cancerized fields. OBJECTIVES: To investigate in a phase I/II trial the safety and efficacy of ingenol disoxate as topical field therapy for patients with AK on the balding scalp. METHODS: Part 1 was a phase I, open-label, dose-escalation trial investigating up to six doses of ingenol disoxate to determine the maximum tolerated dose (MTD). Part 2 was a phase II, randomized, double-blind, parallel group, vehicle-controlled trial. Patients were randomized 2 : 2 : 1 to receive ingenol disoxate 0.037%, 0.05% or vehicle gel once daily for two consecutive days. Percentage reduction in AK count from baseline, complete clearance (AKCLEAR 100) and partial clearance (>= 75% AK count reduction; AKCLEAR 75) were assessed at week 8. RESULTS: The MTD in part 1 was 0.075% based on a dose-dependent increase in the number and severity of adverse events. Two lower doses of ingenol disoxate gel (0.037%, 0.05%) were assessed in part 2, which showed a reduction in AK count from baseline to week 8 (0.037%, 72.7%; 0.05%, 78.5% vs. vehicle 12.6; P < 0.001), and rates of AKCLEAR 100 and AKCLEAR 75 were significantly higher in active treatment groups compared with vehicle (P <= 0.007). Local skin responses peaked at day 3 and declined rapidly. Adverse events were generally mild to moderate in intensity, and were most commonly application site pain/pruritus. CONCLUSIONS: Ingenol disoxate 0.037% and 0.05% gel was effective and superior to vehicle, and well tolerated as field therapy for AK on the balding scalp. PMID- 28078679 TI - Diet-induced dysmotility and neuropathy in the gut precedes endotoxaemia and metabolic syndrome: the chicken and the egg revisited. PMID- 28078680 TI - Children's preference for mixed- versus fixed-ratio schedules of reinforcement: A translational study of risky choice. AB - Laboratory research has shown that when subjects are given a choice between fixed ratio and bi-valued mixed-ratio schedules of reinforcement, preference typically emerges for the mixed-ratio schedule even with a larger ratio requirement. The current study sought to replicate and extend these findings to children's math problem completion. Using an ABCBC reversal design, four fourth-grade students were given the choice of completing addition problems reinforced on either a fixed-ratio 5 schedule or one of three mixed-ratio schedules; an equivalent mixed ratio (1, 9) schedule, a mixed-ratio (1, 11) schedule with a 20% larger ratio requirement, and an equally lean mixed-ratio (5, 7) schedule without the small fixed-ratio 1 component. This was followed by a reversal back to the preceding phase in which preference for the mixed-ratio schedule had been observed, and a final reversal back to the mixed-ratio (5, 7) phase. Findings were consistent with previous research in that all children preferred the mixed-ratio (1, 9) schedule over the equivalent fixed-ratio 5 schedule. Preference persisted for the leaner mixed-ratio (1, 11) schedule for three of the four children. Indifference or preference for the fixed-ratio 5 alternative was observed in phases containing the mixed-ratio (5, 7) schedule. These results extend previous research on risky choice to children's math problem completion and highlight the importance of a small ratio component in the emergence of preference for bi-valued mixed-ratio schedules. Implications of these results for arranging reinforcement to increase children's academic responding are discussed. PMID- 28078681 TI - Synthesis and stability studies of Ga-67 labeled phosphonium salts. AB - Delocalized lipophilic cations such as tri- and tetra-arylphosphonium are able to diffuse across the mitochondrial membrane, which allows them to selectively accumulate in cells with a high transmembrane potential (DeltaPsim ). The mitochondrial membrane potential of cancer cells and cardiomyocytes has been reported to be significantly higher than that of normal epithelial cells. This feature can be exploited for the selective accumulation of phosphonium derivatives for the purposes of molecular imaging using radionuclides. Four structurally related Ga(III)-phosphonium salts were synthesized and fully characterized and found to be modest in toxicity toward T98G human glioblastoma cells (IC50 > 4 mM). High-activity (100 MBq) analogs containing Ga-67 were also synthesized and their stabilities in phosphate-buffered saline and human serum were determined. PMID- 28078683 TI - Worried about publishing in the "wrong" journal?.... PMID- 28078682 TI - Population pharmacokinetics of intravenous clonidine for sedation during paediatric extracorporeal membrane oxygenation and continuous venovenous hemofiltration. AB - AIMS: Clonidine is used for sedation in the paediatric intensive care unit. Extracorporeal membrane oxygenation (ECMO) provides temporary support if respiratory and cardiac function is threatened. ECMO influences the pharmacokinetics of drugs. Clonidine during paediatric ECMO cannot be effectively titrated as PK data are lacking. The aim of this study is to describe clonidine PK in a particular ECMO system and propose dosing guidelines for children on this particular ECMO circuit. METHODS: All children below the age of 18 years who received clonidine during ECMO were eligible. The pharmacokinetic analysis was conducted by nonlinear mixed effect modelling, which enables to establish the separate influences of determinants on drug blood level and to provide individualized dosing. RESULTS: Twenty-two patients, median age 1 month (IQR 6.4) and weight at inclusion 4 kg (IQR 3.1) were included of whom 90% in addition to ECMO received pre-emptive continuous venovenous hemofiltration to optimize fluid balance. The clonidine clearance rate was two-fold that measured in patients not on ECMO. Clearance increased steeply with postnatal age: at days 6, 8 and 10, respectively 30%, 50% and 70% of the adult clearance rate was reached. The use of diuretics was associated with a lower clearance. The volume of distribution increased by 55% during ECMO support. CONCLUSION: Our findings suggest that a higher dose of clonidine may be needed during ECMO. The PK parameters on ECMO and the dosing guidelines proposed hold the potential to improve sedation practices on ECMO but need to be repeated with different ECMO systems. PMID- 28078684 TI - Characterization of protease and effects of temperature and salinity on the biochemical changes during fermentation of Antarctic krill. AB - BACKGROUND: Despite their abundance, Antarctic krill are underutilized because of numerous difficulties in their commercial processing. Ideally, fermentation technology can be applied to transform them into a popular condiment. In addition to the exploration of protease properties, the present study aimed to evaluate proteinase activity, pH, amino nitrogen, and histamine formation during fermentation at different temperatures and salt treatments. RESULTS: Even though the activity of Antarctic krill protease reached a maximum at 40 degrees C and pH 7, it was stable at 30 degrees C and pH 7-9. Among the metal ions tested, Ca2+ , Mg2+ and K+ increased protease activity, in contrast to Zn2+ and Cu2+ . Within each treatment, the highest protease activity and amino nitrogen content, as well as the lowest histamine level, were observed on day 12 of fermentation. Treatment at 35 degrees C with 180 g kg-1 salt led to the production of maximum amino nitrogen (0.0352 g kg-1 ) and low histamine (<=0.0497 g kg-1 ). CONCLUSION: Krill paste fermented for 12 days at 35 degrees C with 180 g kg-1 salt exhibited the optimal quality and properties, suggesting an efficient method for fermentation of Antarctic krill and other aquatic resources. (c) 2017 Society of Chemical Industry. PMID- 28078685 TI - Peer assessment of professional behaviours in problem-based learning groups. AB - CONTEXT: Peer assessment of professional behaviour within problem-based learning (PBL) groups can support learning and provide opportunities to identify and remediate problem behaviours. OBJECTIVES: We investigated whether a peer assessment of learning behaviours in PBL is sufficiently valid to support decision making about student professional behaviours. METHODS: Data were available for two cohorts of students, in which each student was rated by all of their PBL group peers using a modified version of a previously validated scale. Following the provision of feedback to the students, their behaviours were again peer-assessed. A generalisability study was undertaken to calculate the students' professional behaviour scores, sources of error that impacted the reliability of the assessment, changes in student rating behaviour, and changes in mean scores after the delivery of feedback. RESULTS: Peer assessment of professional learning behaviour was highly reliable for within-group comparisons (G = 0.81-0.87), but poor for across-group comparisons (G = 0.47-0.53). Feedback increased the range of ratings given by assessors and brought their mean ratings into closer alignment. More of the increased variance was attributable to assessee performance than to assessor stringency and hence there was a slight improvement in reliability, especially for comparisons across groups. Mean professional behaviour scores were unchanged. CONCLUSIONS: Peer assessment of professional learning behaviours may be unreliable for decision making outside a PBL group. Faculty members should not draw conclusions from peer assessment about a student's behaviour compared with that of their peers in the cohort, and such a tool may not be appropriate for summative assessment. Health professional educators interested in assessing student professional behaviours in PBL groups might focus on opportunities for the provision of formative peer feedback and its impact on learning. PMID- 28078686 TI - Making the transition to specialist practice as a new FACEM. PMID- 28078687 TI - When angiogenesis is not good enough. PMID- 28078688 TI - When things are not the same: A review of research into relations of difference. AB - Responding to stimuli as same and different can be considered a critical component of a variety of language and academic repertoires. Whereas responding to "sameness" and generalized identity matching (i.e., coordination) have been studied extensively, there appears to be a significant gap in behavior analytic research and educational programs with regard to nonmatching relations or relations of difference. We review research on difference relations from a variety of domains, including comparative psychology, as well as experimental, and translational behavior analysis. We examine a range of studies, including research on the perception of difference and oddity responding, as well as investigations on establishing relational frames of distinction. We present suggestions for future research and describe potential methods for teaching skills related to relations of difference. PMID- 28078696 TI - Facilitating Processes and Extending Boundaries at EJI. PMID- 28078698 TI - Addiction Debates: challenging ideas, challenging ourselves. PMID- 28078700 TI - Introduction to Horizons Review series on neuroimaging. PMID- 28078701 TI - Commentary on Sawangjit et al. (2017): There is still much to be determined before policy makers can choose pharmacy needle and syringe programmes (NSP) confidently over other models of NSP provision. PMID- 28078702 TI - Corrigendum. PMID- 28078703 TI - Selection bias and relationships between alcohol consumption and mortality. PMID- 28078704 TI - Commentary on Trias-Llimos et al. (2017): Birth cohort research-an essential tool to guide public health interventions. PMID- 28078705 TI - Commentary on Des Jarlais et al. (2017): Robust public health policies as a way forward in the HIV epidemic. PMID- 28078706 TI - Commentary on Kosty et al. (2017): Understanding risk classes for cannabis use disorder requires knowledge of exposure, environment and genetic effects. PMID- 28078707 TI - Commentary on McAuley et al. (2017): Naloxone programs must reduce marginalization and improve access to comprehensive emergency care. PMID- 28078708 TI - Blood vessel formation during tail regeneration in the leopard gecko (Eublepharis macularius): The blastema is not avascular. AB - Unique among amniotes, many lizards are able to self-detach (autotomize) their tail and then regenerate a replacement. Tail regeneration involves the formation of a blastema, an accumulation of proliferating cells at the site of autotomy. Over time, cells of the blastema give rise to most of the tissues in the replacement tail. In non-amniotes capable of regenerating (such as urodeles and some teleost fish), the blastema is reported to be essentially avascular until tissue differentiation takes place. For tail regenerating lizards less is known. Here, we investigate neovascularization during tail regeneration in the leopard gecko (Eublepharis macularius). We demonstrate that the gecko tail blastema is not an avascular structure. Beginning with the onset of regenerative outgrowth, structurally mature (mural cell supported) blood vessels are found within the blastema. Although the pattern of blood vessel distribution in the regenerate tail differs from that of the original, a hierarchical network is established, with vessels of varying luminal diameters and wall thicknesses. Using immunostaining, we determine that blastema outgrowth and tissue differentiation is characterized by a dynamic interplay between the pro-angiogenic protein vascular endothelial growth factor (VEGF) and the anti-angiogenic protein thrombospondin-1 (TSP-1). VEGF-expression is initially widespread, but diminishes as tissues differentiate. In contrast, TSP-1 expression is initially restricted but becomes more abundant as VEGF-expression wanes. We predict that variation in the neovascular response observed between different regeneration-competent species likely relates to the volume of the blastema. J. Morphol. 278:380-389, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28078709 TI - Expression of transcription factors divides retinal ganglion cells into distinct classes. AB - Retinal ganglion cells (RGCs) are tasked with transmitting all light information from the eye to the retinal recipient areas of the brain. RGCs can be classified into many different types by morphology, gene expression, axonal projections, and functional responses to different light stimuli. Ultimately, these classification systems should be unified into an all-encompassing taxonomy. Toward that end, we show here that nearly all RGCs express either Islet-2 (Isl2), Tbr2, or a combination of Satb1 and Satb2. We present gene expression data supporting the hypothesis that Satb1 and Satb2 are expressed in ON-OFF direction-selective (DS) RGCs, complementing our previous work demonstrating that RGCs that express Isl2 and Tbr2 are non-DS and non-image-forming, respectively. Expression of these transcription factors emerges at distinct embryonic ages and only in postmitotic cells. Finally, we demonstrate that these transcription factor-defined RGC classes are born throughout RGC genesis. PMID- 28078710 TI - Cancer Stem Cells (CSCs) in melanoma: There's smoke, but is there fire? AB - Cancer stem cells (CSCs), also called Tumor Initiating Cells (TICs), can be defined as cancer cells that are present within solid tumors or hematological cancers, which have characteristics associated with normal stem cells, but which can give rise to all cell types found in a particular cancer sample. CSCs, therefore, are transformed stem cells, which can self-renew, differentiate into diverse progenies, and drive continuous tumor growth (Kreso & Dick, , Cell Stem Cell, 14:275-291; Schatton et al., , Nature, 451:345-349; Villani, Sabbatino, Ferrone, & Ferrone, , Melanoma Management, 2:109-114; Zhou et al., , Drug Discovery, 8:806-823) (Fig. ). [Figure: see text]. PMID- 28078711 TI - Systematics of Cladophora spp. (Chlorophyta) from North Carolina, USA, based upon morphology and DNA sequence data with a description of Cladophora subtilissima sp. nov. AB - Identification of Cladophora species is challenging due to conservation of gross morphology, few discrete autapomorphies, and environmental influences on morphology. Twelve species of marine Cladophora were reported from North Carolina waters. Cladophora specimens were collected from inshore and offshore marine waters for DNA sequence and morphological analyses. The nuclear-encoded rRNA internal transcribed spacer regions (ITS) were sequenced for 105 specimens and used in molecular assisted identification. The ITS1 and ITS2 region was highly variable, and sequences were sorted into ITS Sets of Alignable Sequences (SASs). Sequencing of short hyper-variable ITS1 sections from Cladophora type specimens was used to positively identify species represented by SASs when the types were made available. Secondary structures for the ITS1 locus were also predicted for each specimen and compared to predicted structures from Cladophora sequences available in GenBank. Nine ITS SASs were identified and representative specimens chosen for phylogenetic analyses of 18S and 28S rRNA gene sequences to reveal relationships with other Cladophora species. Phylogenetic analyses indicated that marine Cladophorales were polyphyletic and separated into two clades, the Cladophora clade and the "Siphonocladales" clade. Morphological analyses were performed to assess the consistency of character states within species, and complement the DNA sequence analyses. These analyses revealed intra- and interspecific character state variation, and that combined molecular and morphological analyses were required for the identification of species. One new report, Cladophora dotyana, and one new species Cladophora subtilissima sp. nov., were revealed, and increased the biodiversity of North Carolina marine Cladophora to 14 species. PMID- 28078712 TI - Comparative study on fatty acid composition of olive (Olea europaea L.), with emphasis on phytosterol contents. AB - The present study was designed to determine the fatty acid composition and phytosterol contents of Turkish native olive cultivars, namely Kilis Yaglik and Nizip Yaglik cv. In this context, olive fruits from 34 locations were sampled and then screened for their components in comparison. Fifteen different fatty acids were found in both olive oils. In the order of abundance, the most important ones were oleic acid (18:1) > palmitic acid (16:0) > linoleic acid (18:2) > stearic acid (18:0). Significant differences were observed in the contents of oleic acid (18:1), palmitic acid (16:0), linoleic acid (18:2) but not for stearic acid content in comparison both oils (p < 0.01). There were significant differences in terms of unsaturated fatty acids, saturated fatty acids and polyunsaturated fatty acids (p < 0.01). The seven phytosterols - cholesterol, campesterol, stigmasterol, beta-sitosterol, Delta-5-avenasterol, Delta-7-stigmastenol and Delta-7-avenasterol - were studied in both oil sources. The predominant sterols were beta-sitosterol, Delta5-avenasterol and campesterol in the samples analysed. However, no significant differences were found in the levels of the phytosterols between the two olive cultivars. PMID- 28078713 TI - The Novel mTOR Complex 1/2 Inhibitor P529 Inhibits Human Lung Myofibroblast Differentiation. AB - Idiopathic pulmonary fibrosis is a progressive and deadly disorder with very few therapeutic options. Palomid 529 (8-(1-hydroxyethyl)-2-methoxy-3-(4 methoxybenzyloxy)-benzo[c]chromen-6-one; P529) is a novel dual inhibitor of mechanistic target of rapamycin complex 1/2 (mTORC1/2). In these studies, we investigated the effect of P529 on TGF-beta-dependent signaling and myofibroblast differentiation. TGF-beta-induced phosphorylation of the mTORC1 targets, p70 S6 kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), were both dose dependently inhibited by P529 in human lung fibroblasts with maximal inhibition occurring between 10 and 20 MUM. mTORC2 mediated phosphorylation of Akt at the S473 site was partially inhibited with a similar dose dependency, as was TGF-beta-induced myofibroblast differentiation. Protein levels of TGF-beta-induced fibronectin and collagen were similarly decreased by P529. At this dose, there was also inhibition of mRNA transcript levels for Col1 and alpha-SMA, suggesting inhibition of transcriptional activation. However, there was no effect of P529 on canonical TGF-beta-induced Smad signaling, as assessed by receptor-associated Smad2/3 phosphorylation, Smad2/3/4 translocation, or Smad-driven gene expression, as assessed by Smad binding element driven luciferase. Conversely, activation of mTORC1/2 signaling was dependent on TGF-beta type I receptor (ALK5) signaling and on Smad2/3 expression. P529 treatment disrupted TGF-beta-induced actin stress fiber formation during myofibroblast differentiation, the deposition of new extracellular fibronectin matrix, and linear wound closure by fibroblasts. Likewise, mTOR knockdown inhibited TGF-beta-induced myofibroblast differentiation. In conclusion, P529 inhibits TGF-beta-induced myofibroblast differentiation, actin stress fiber formation, and matrix protein expression and deposition. Inhibition of mTORC1/2 by P529 may be a promising approach to inhibit in vivo fibrosis. J. Cell. Biochem. 118: 2241-2249, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28078714 TI - Percutaneous Closure of Post-Infarction Ventricular Septal Defects-An Over Decade long Experience. AB - OBJECTIVES: To report an over decade-long experience with percutaneous post infarction ventricular septal defect (PIVSD) closure. BACKGROUND: PIVSDs remains a major clinical challenge with extremely high mortality. Data concerning interventional closure of PIVSD is scarce. METHODS: All percutaneous PIVSD closures performed between 2003 and 2016 in 8 participating centres were identified. Data concerning patients and procedures was acquired. Patients were divided into two groups, based on the time interval between VSD diagnosis and closure (<=14 days-acute phase, >14 days-non-acute phase). RESULTS: Twenty-one percutaneous PIVSD closures were performed on 20 patients (9 females, mean age: 70 years). Mean interval between the diagnosis and the procedure was 182.6 +/- 500 days (range: 7-2228). Defects were mostly located in apical (55%) segments of the septum. In 7 cases (33%) the procedure was performed in the acute phase. The closure was technically successful in 17 cases (81%). Four patients died within 48 hours after the procedure. 30-days survival rate of the entire cohort was 70%. Univariate analysis revealed impact of technical success of the procedure (HR 0.13, CI 0.03-0.68 P = 0.016) and white blood cell count (HR 1.36 per unit increase, CI 1.1-1.69, P = 0.005) on 30-day mortality. CONCLUSIONS: In a selected population of patients percutaneous PIVSD closure is feasible and provides satisfactory survival rate. Procedural success has a protective impact on survival. Timing of the closure remains controversial. Procedure in the non-acute phase carries lower mortality, but at the same time introduces a selection bias. Larger registry-based studies are required. PMID- 28078716 TI - Incorporating food web dynamics into ecological restoration: a modeling approach for river ecosystems. AB - Restoration is frequently aimed at the recovery of target species, but also influences the larger food web in which these species participate. Effects of restoration on this broader network of organisms can influence target species both directly and indirectly via changes in energy flow through food webs. To help incorporate these complexities into river restoration planning, we constructed a model that links river food web dynamics to in-stream physical habitat and riparian vegetation conditions. We present an application of the model to the Methow River, Washington, USA, a location of on-going restoration aimed at recovering salmon. Three restoration strategies were simulated: riparian vegetation restoration, nutrient augmentation via salmon carcass addition, and side channel reconnection. We also added populations of nonnative aquatic snails and fish to the modeled food web to explore how changes in food web structure mediate responses to restoration. Simulations suggest that side channel reconnection may be a better strategy than carcass addition and vegetation planting for improving conditions for salmon in this river segment. However, modeled responses were strongly sensitive to changes in the structure of the food web. The addition of nonnative snails and fish modified pathways of energy through the food web, which negated restoration improvements. This finding illustrates that forecasting responses to restoration may require accounting for the structure of food webs, and that changes in this structure, as might be expected with the spread of invasive species, could compromise restoration outcomes. Unlike habitat-based approaches to restoration assessment that focus on the direct effects of physical habitat conditions on single species of interest, our approach dynamically links the success of target organisms to the success of competitors, predators, and prey. By elucidating the direct and indirect pathways by which restoration affects target species, dynamic food web models can improve restoration planning by fostering a deeper understanding of system connectedness and dynamics. PMID- 28078715 TI - mTORC2 regulates multiple aspects of NKT-cell development and function. AB - Invariant NKT (iNKT) cells bridge innate and adaptive immunity by rapidly secreting cytokines and lysing targets following TCR recognition of lipid antigens. Based on their ability to secrete IFN-gamma, IL-4 and IL-17A, iNKT cells are classified as NKT-1, NKT-2, and NKT-17 subsets, respectively. The molecular pathways regulating iNKT-cell fate are not fully defined. Recent studies implicate Rictor, a required component of mTORC2, in the development of select iNKT-cell subsets, however these reports are conflicting. To resolve these questions, we used Rictorfl/fl CD4cre+ mice and found that Rictor is required for NKT-17 cell development and normal iNKT-cell cytolytic function. Conversely, Rictor is not absolutely required for IL-4 and IFN-gamma production as peripheral iNKT-cells make copious amounts of these cytokines. Overall iNKT-cell numbers are dramatically reduced in the absence of Rictor. We provide data indicating Rictor regulates cell survival as well as proliferation of developing and mature iNKT cells. Thus, mTORC2 regulates multiple aspects of iNKT-cell development and function. PMID- 28078717 TI - A whole lamella perspective on the origin of the epidermal free margin of Anolis (Reptilia: Dactyloidae) toe pads. AB - Anoline lamellae terminate in an epidermal free margin carrying the majority of its setae. How the free margin is extruded from the body of the scale is not well understood. Two hypotheses have been advanced to account for it, one advocating distal migration of the outer epidermal layers relative to the body of the lamella, and the other proposing regression of the dermal core. Available evidence provides partial support for both. We assembled a series of specimens of Anolis grahami representing all shedding cycle stages, and prepared histological sections of the toe pads to allow measurement of appropriate lamellar components through the shedding cycle. Through its proliferative phases the lamellae increase markedly in length, with the distance between the distal tip of the dermal core and that of the lamella accounting for most of this, indicating that epidermal extrusion is responsible for production of the new free margin. The dermal core showed no evidence of regression. Concomitant with epidermal extrusion, the lacunar cells on the inner lamellar face hypertrophy and keep pace with the increasing thickness of the outer lamellar face resulting from the lengthening of the replacement setae. The integrated changes observed are consistent with continuity of functioning and alignment of the exposed setal carpet of the outer epidermal generation while ensuring that the new setal carpet is fully aligned and functional immediately after shedding. At shedding the original proportions of the lamellae are restored. Development of the new free margin results from a combination of distal displacement of Oberhautchen cells along with arrested maturation of the epidermis in this region. Changes in length of the lamellae during the proliferative stages may impact the overall size of the adhesive toe pad, which may have consequences for assessments of the relationship between whole animal clinging ability and adhesive pad area. J. Morphol. 278:360-368, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28078718 TI - Fabric-based alkaline direct formate microfluidic fuel cells. AB - Fabric-based microfluidic fuel cells (MFCs) serve as a novel, cost-efficient alternative to traditional FCs and batteries, since fluids naturally travel across fabric via capillary action, eliminating the need for an external pump and lowering production and operation costs. Building on previous research with Y shaped paper-based MFCs, fabric-based MFCs mitigate fragility and durability issues caused by long periods of fuel immersion. In this study, we describe a microfluidic fabric-based direct formate fuel cell, with 5 M potassium formate and 30% hydrogen peroxide as the anode fuel and cathode oxidant, respectively. Using a two-strip, stacked design, the optimized parameters include the type of encasement, the barrier, and the fabric type. Surface contact of the fabric and laminate sheet expedited flow and respective chemical reactions. The maximum current (22.83 mA/cm2 ) and power (4.40 mW/cm2 ) densities achieved with a 65% cotton/35% polyester blend material are a respective 8.7% and 32% higher than previous studies with Y-shaped paper-based MFCs. In series configuration, the MFCs generate sufficient energy to power a handheld calculator, a thermometer, and a spectrum of light-emitting diodes. PMID- 28078719 TI - Carbon-Nanotube-Supported Bio-Inspired Nickel Catalyst and Its Integration in Hybrid Hydrogen/Air Fuel Cells. AB - A biomimetic nickel bis-diphosphine complex incorporating the amino acid arginine in the outer coordination sphere was immobilized on modified carbon nanotubes (CNTs) through electrostatic interactions. The functionalized redox nanomaterial exhibits reversible electrocatalytic activity for the H2 /2 H+ interconversion from pH 0 to 9, with catalytic preference for H2 oxidation at all pH values. The high activity of the complex over a wide pH range allows us to integrate this bio inspired nanomaterial either in an enzymatic fuel cell together with a multicopper oxidase at the cathode, or in a proton exchange membrane fuel cell (PEMFC) using Pt/C at the cathode. The Ni-based PEMFC reaches 14 mW cm-2 , only six-times-less as compared to full-Pt conventional PEMFC. The Pt-free enzyme based fuel cell delivers ~2 mW cm-2 , a new efficiency record for a hydrogen biofuel cell with base metal catalysts. PMID- 28078720 TI - The intrinsically disordered linker of E. coli SSB is critical for the release from single-stranded DNA. AB - The Escherichia coli single stranded DNA binding protein (SSB) is crucial for DNA replication, recombination and repair. Within each process, it has two seemingly disparate roles: it stabilizes single-stranded DNA (ssDNA) intermediates generated during DNA processing and, forms complexes with a group of proteins known as the SSB-interactome. Key to both roles is the C-terminal, one-third of the protein, in particular the intrinsically disordered linker (IDL). Previously, they have shown using a series of linker deletion mutants that the IDL links both ssDNA and target protein binding by mediating interactions with the oligosaccharide/oligonucleotide binding fold in the target. In this study, they examine the role of the linker region in SSB function in a variety of DNA metabolic processes in vitro. Using the same linker mutants, the results show that in addition to association reactions (either DNA or protein), the IDL is critical for the release of SSB from DNA. This release can be under conditions of ssDNA competition or active displacement by a DNA helicase or recombinase. Consistent with their previous work these results indicate that SSB linker mutants are defective for SSB-SSB interactions, and when the IDL is removed a terminal SSB-DNA complex results. Formation of this complex inhibits downstream processing of DNA by helicases such as RecG or PriA as well as recombination, mediated by RecA. A model, based on the evidence herein, is presented to explain how the IDL acts in SSB function. PMID- 28078721 TI - Use of the fluorescent dye tetramethylrhodamine methyl ester perchlorate for mitochondrial membrane potential assessment in human spermatozoa. AB - Mitochondrial membrane potential (DeltaPsim) is an indicator of sperm quality and its evaluation complements the standard semen analysis. The fluorescent dye JC-1 has been widely used to assess sperm DeltaPsim; however, some problems have been detected under certain experimental conditions. Another fluorescent compound, tetramethylrhodamine methyl ester perchlorate (TMRM), has been used in somatic cells and bovine spermatozoa but not in human spermatozoa. TMRM accumulates in hyperpolarised mitochondria and the fluorescence intensity of this compound correlates with DeltaPsim. Thus, the aim of this study was to evaluate and validate the usefulness of the fluorescent dye TMRM for measuring sperm DeltaPsim. The results showed that TMRM accurately detects sperm populations displaying either high or low DeltaPsim. Moreover, TMRM was able to measure sperm DeltaPsim under the experimental conditions in which JC-1 had previously presented difficulties. Differences in DeltaPsim according to sperm and semen quality were properly detected and a positive correlation between DeltaPsim and conventional semen parameters was observed. Finally, a positive correlation was found between the DeltaPsim measurement by TMRM and by the widely used JC-1. In conclusion, TMRM is a simple, time-effective method, easy to set in laboratories equipped with flow cytometry technology, and can accurately detect changes in DeltaPsim with efficiency comparable to JC-1 without its limitations. PMID- 28078724 TI - Application of multi-block analysis and mixture design with process variable for development of chocolate cake containing yacon (Smallanthus sonchifolius) and maca (Lepidium meyenii). AB - BACKGROUND: In this study, a chocolate cake formulation was developed with partial substitution of wheat flour by yacon and maca flour. A simplex-centroid design was applied to determine the proportions of the three flours, and the amount of water was included as a process variable at three distinct levels. According to the overall acceptability of the cakes, the tasters were separated into two groups using k-means. RESULTS: After segmentation, regression models were constructed for overall acceptability of each group; R2adjusted values of 92.5% for group 1 and 98.9% for group 2 were obtained. Using the sequential simplex method an optimized formulation was determined for group 1 (0.49 kgwheat kg-1total flour , 0.37 kgyacon kg-1total flour , 0.14 kgmaca kg-1total flour and 140.0 mL of water) and another for group 2 (0.35 kgwheat kg-1total flour , 0.65 kgyacon kg-1total flour and 120.0 mL of water). In addition to these formulations, a third formulation was proposed with a greater maca proportion (0.32 kgmaca kg-1total flour ), which does not significantly alter the overall acceptability of both groups. The three optimized formulations and two control formulations were evaluated through free-choice profiling. The data were evaluated using the multi-block method common components and specific weights analysis (CCSWA). CONCLUSION: It was observed that a greater proportion of maca intensified brownness and burnt aroma and taste, whereas a larger proportion of yacon produced a better appearance, softness, sweetness and chocolate flavor. (c) 2017 Society of Chemical Industry. PMID- 28078722 TI - SSB and the RecG DNA helicase: an intimate association to rescue a stalled replication fork. AB - In E. coli, the regression of stalled DNA replication forks is catalyzed by the DNA helicase RecG. One means of gaining access to the fork is by binding to the single strand binding protein or SSB. This interaction occurs via the wedge domain of RecG and the intrinsically disordered linker (IDL) of SSB, in a manner similar to that of SH3 domains binding to PXXP motif-containing ligands in eukaryotic cells. During loading, SSB remodels the wedge domain so that the helicase domains bind to the parental, duplex DNA, permitting the helicase to translocate using thermal energy. This translocation may be used to clear the fork of obstacles, prior to the initiation of fork regression. PMID- 28078725 TI - Chiral Amplification by Self-Assembly of Neutral Luminescent Platinum(II) Complexes. AB - Two novel enantiomerically pure chiral ligands and the corresponding neutral PtII complexes have been synthetized and characterized. The self-assembly properties of the complexes have been investigated using different morphological and photophysical techniques. The two enantiomeric complexes, 4 a and 4 b, show high tendency to self-assemble into chiral supramolecular aggregates with right (P) and left-handed (M) helical configurations, respectively, as proven by SEM and absorption circular dichroism. The formation of such organized structures is driven by the formation of metallophilic and pi-pi interactions between spatially close Pt complexes with an enhancement of the chiro-optical properties in the solid state. PMID- 28078723 TI - Real-world use, effectiveness and safety of anti-viral treatment in chronic hepatitis C genotype 3 infection. AB - BACKGROUND: Treatment of chronic hepatitis C genotype 3 (GT3) is more challenging compared with other genotypes. Since 2014, several new treatment regimens have been approved but sometimes based on limited data. AIM: To validate the use, effectiveness and safety of anti-viral treatment in chronic hepatitis C genotype 3 infection under real-word conditions. METHODS: The German Hepatitis C-Registry is a large national non-interventional real-world study for patients with chronic hepatitis C. A total of 1322 GT3 patients were enrolled (211 untreated and 1111 treated patients). RESULTS: Between February 2014 and September 2015, five different treatment strategies have been used (PegIFN+RBV, PegIFN+RBV+SOF, SOF+RBV, DCV+SOF+/-RBV, LDV/SOF+/-RBV). Treatment uptake and use of treatment concepts changed markedly and rapidly during the study influenced by new approvals, guideline recommendations, and label updates. PegIFN-based therapies constantly declined while DCV-based therapies increased with one interruption after the approval of LDV/SOF, which was frequently used until new guidelines recommended not using this combination for GT3. Per-protocol SVR ranged from 80.9% in the PegIFN+RBV group to 96.1% in PegIFN+RBV+SOF treated patients. Treatment-experienced patients with cirrhosis showed a suboptimal SVR of 68% for SOF+RBV but a high SVR of 90-95% for DCV+SOF+/-RBV. The safety analysis showed more adverse events and a stronger decline of haemoglobin for RBV containing regimens. CONCLUSIONS: Real-world data can validate the effectiveness and safety for treatment regimens that had previously been approved with limited data, in particular for specific subgroups of patients. The present study demonstrates how rapid new scientific data, new treatment guidelines, new drug approvals and label changes are implemented into routine clinical practice today. PMID- 28078726 TI - Dissecting the Cytochrome P450 1A2- and 3A4-Mediated Metabolism of Aflatoxin B1 in Ligand and Protein Contributions. AB - Aflatoxin B1 (AFB1) is a chemically intriguing compound because it has several potential sites of metabolism (SOMs), although only some of them are observed experimentally. Cytochrome P450 (CYP) 3A4 and 1A2 are the major isoforms involved in its metabolism. Here, we systematically investigate reactivity and accessibility of all possible SOMs in these two CYPs to elucidate AFB1 metabolism. DFT calculations were used to determine activation energies for each possible reaction. Aliphatic hydroxylation on position 9A and 3alpha are energetically favored, whereas position 9 is the preferred site for epoxidation. Docking studies, molecular dynamics (MD) simulations, and free energy (MM/GBSA) calculations were applied to elucidate the accessibility of each SOM. The most stable binding modes in CYP3A4 favor the formation of the 3alpha-hydroxylated and 8,9-exo-epoxide metabolites. Conversion of the methoxy group is also sterically possible, but not observed experimentally due to its low reactivity. In the CYP1A2 active site, AFB1 cannot orient position 3 towards the catalytic center, whereas the 8,9-exo-epoxide and 9A-hydroxylated metabolites are formed from the most stable and the 8,9-endo-epoxide from a less stable binding mode, respectively. The results agree with experimental data and suggest that both reactivity and the shape of the enzyme active site need to be considered to understand the distribution of SOMs and to improve current SOM prediction methods. PMID- 28078728 TI - Radical and Diradical Formation in Naphthalene Diimides through Simple Chemical Oxidation. AB - We successfully synthesized, for the first time, a naphthalene diimide (NDI) radical and diradical by simple chemical oxidation using lead(IV) dioxide. The formation of the (di)radical is confirmed by UV/Vis/NIR absorption, 1 H NMR, and electron paramagnetic resonance (EPR) measurements. In particular, temperature dependent EPR, SQUID (superconducting quantum interference device) measurements, and quantum calculations demonstrated that the generated NDI diradical has a singlet diradical character of y=0.69 in the ground state. Subsequent characterization of this (di)radical revealed its stabilities, large two-photon absorption cross-section, and short excited-state lifetime. PMID- 28078727 TI - Second cancer incidence in primary mediastinal B-cell lymphoma treated with methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin regimen with or without rituximab and mediastinal radiotherapy: Results from a monoinstitutional cohort analysis of long-term survivors. AB - Our aim is to assess the incidence of second cancer in long-time surviving primary mediastinal B-cell lymphoma (PMBCL) patients treated with combined radiochemoimmunotherapy (standard methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin with rituximab and mediastinal radiation therapy at a dose of 30 to 36 Gy). For this purpose, 92 points were evaluated. After a median overall survival of 137 months (range 76-212), we recorded second cancer in 3 of 80 long-surviving patients (3.75%) with cumulative incidence of 3.47% at 15 years and 11% at 17 years, with a 17-year second cancer-free survival of 82%. We observed 2 papillary thyroid cancers with a standardized incidence ratio (SIR) of 7.97 and an absolute excess risk (AER) of 17. 84 and 1 acute myeloid leukemia (AML) with an SIR of 66.53 and an AER of 10.05. No breast cancer occurred. Although we should take into account the limits of the proposed statistical analysis, combined modality treatment was related to a significant SIR and AER for thyroid cancer and acute myeloid leukemia. PMID- 28078729 TI - Achieving Full Scope of Practice Readiness Using Evidence for Psychotherapy Teaching in Web and Hybrid Approaches in Psychiatric Mental Health Advanced Practice Nursing Education. AB - : Radical changes in role, education, and practice have affected how education of advance practice nurses and practice deliverables occur. PURPOSE: This article examines the effects of distance education upon the teaching/learning of psychotherapy in integrating Web-based technology and platforms. DESIGN AND METHODS: With the advent and proliferation of online programs of study, the question begs: How do distance-linked programs successfully introduce, practice, and supervise one-to-one and group psychotherapy training? FINDINGS: By employing evidence-based education strategies, technology, and strong interpersonal skills and evidence-based therapies, a charter Psychiatric Mental Health Nurse Practitioner Doctor of Nursing Practice program paved an innovative and successful path. PRACTICE IMPLICATIONS: In that program, they prepared their students for full scope of practice, upon graduation, inclusive of psychotherapy as well as the other highly demanding and compressed requirements of the 3-year program. This article explores that journey and its recommendations for application derived from this 2010 cohort. PMID- 28078730 TI - A fern AINTEGUMENTA gene mirrors BABY BOOM in promoting apogamy in Ceratopteris richardii. AB - Asexual reproduction is widespread in land plants, including ferns where 10% of all species are obligate asexuals. In these ferns, apogamous sporophytes are generated directly from gametophytes, bypassing fertilization. In the model fern Ceratopteris richardii, a sexual species, apogamy can be induced by culture on high sugar media. BABY BOOM (BBM) genes in angiosperms are known to promote somatic embryogenesis, which like apogamy produce sporophytes without fertilization. Here, a Brassica napus BBM (BnBBM) was used to investigate genetic similarity between apogamy in ferns and somatic embryogenesis in angiosperms. A C. richardii transcriptome was constructed from which one AINTEGUMENTA-LIKE unigene, CrANT, was identified. Whole mount in situ hybridization showed that CrANT is expressed in sperm and fertilized eggs. Phylogenetic analysis grouped CrANT with other non-seed-plant ANT genes to the euANT clade but in a branch separate from BBM genes. Overexpression of CrANT or BnBBM promotes apogamy in C. richardii without sugar supplement. CrANT knockdown gametophytes responded weakly to sugar for apogamy promotion. Theses results suggest some genetic conservation between apogamy and somatic embryogenesis and that such asexual reproduction may be ancient. PMID- 28078732 TI - A fleshy growth below the nail plate in an elderly man. PMID- 28078731 TI - Rapid automated landmarking for morphometric analysis of three-dimensional facial scans. AB - Automated phenotyping is essential for the creation of large, highly standardized datasets from anatomical imaging data. Such datasets can support large-scale studies of complex traits or clinical studies related to precision medicine or clinical trials. We have developed a method that generates three-dimensional landmark data that meet the requirements of standard geometric morphometric analyses. The method is robust and can be implemented without high-performance computing resources. We validated the method using both direct comparison to manual landmarking on the same individuals and also analyses of the variation patterns and outlier patterns in a large dataset of automated and manual landmark data. Direct comparison of manual and automated landmarks reveals that automated landmark data are less variable, but more highly integrated and reproducible. Automated data produce covariation structure that closely resembles that of manual landmarks. We further find that while our method does produce some landmarking errors, they tend to be readily detectable and can be fixed by adjusting parameters used in the registration and control-point steps. Data generated using the method described here have been successfully used to study the genomic architecture of facial shape in two different genome-wide association studies of facial shape. PMID- 28078733 TI - Therapeutic Apheresis in Immunologic Renal and Neurological Diseases. AB - Since the mid 1970s, when membrane modules became available, plasma separation techniques have gained in importance especially in the past few years. The advantages of this method are a complete separation of the corpuscular components from the plasma and due to increased blood flow rate and higher efficacy. Systemic autoimmune diseases based on an immune pathogenesis produce autoantibodies and circulating immune complexes, which cause inflammation in the tissues of various organs. In most cases, these diseases have a poor prognosis without treatment. Therapeutic apheresis (TA) in combination with immunosuppressive therapies has led to a steady increase in survival rates over the last 40 years. The updated information on immunology and molecular biology of different immunologic diseases are discussed in relation to the rationale for apheresis therapy and its place in combination with other modern treatments. The different diseases can be treated by various apheresis methods such as therapeutic plasma exchange (TPE) with substitution solution, or with online plasma or blood purification using adsorption columns, which contain biological or non-biological agents. Here, the authors provide an overview of the most important pathogenic aspects indicating that TA can be a supportive therapy in systemic autoimmune diseases such as renal and neurological disorders. For the immunological diseases that can be treated with TA, the guidelines of the German Working Group of Clinical Nephrology and of the Apheresis Committee of the American Society for Apheresis are cited. PMID- 28078734 TI - Coronary Procedures After TAVI With the Self-Expanding Aortic Bioprosthesis Medtronic CoreValveTM, Not an Easy Matter. AB - OBJECTIVES: To evaluate the feasibility of coronary procedures after transcatheter aortic valve implantation (TAVI) with the CoreValveTM device. BACKGROUND: Due to its design, CoreValveTM prosthesis may interfere with coronary procedures. Data on this issue are sparse. METHODS: Between 2007 and 2015, 550 patients underwent CoreValveTM TAVI in our hospital. Among them, 16 underwent coronary angiogram after TAVI and were included in our retrospective study. For each patient, we compared the characteristics of coronary angiograms performed before and after TAVI. RESULTS: Coronary angiogram was deemed successful in 9 patients. The mean number of different catheters used in attempts to cannulate the coronary arteries was 3.6 +/- 1.4 and the rate of selective intubation was low. Fluoroscopy time (13.2 +/- 5.8 vs. 7.2 +/- 4.6 min, P = 0.003), dose area product (5,347 +/- 4,919 vs. 3,433 +/- 3,420 cGy/m2 , P = 0.004), and contrast volume (157.7 +/- 69.6 vs. 108.3 +/- 42.6 mL, P = 0.006) were more important in coronary angiograms performed after CoreValveTM implantation. Percutaneous coronary intervention was successfully performed in 6 out of 7 patients who required it. CONCLUSION: Coronary procedures after CoreValveTM TAVI are feasible, but challenging. This problem is currently rare but will be more common as the indications of TAVI are expanded to younger patients with longer life expectancies. Recommendations for post-TAVI coronary procedures are needed, particularly for centers unfamiliar with the management of post-TAVI patients. PMID- 28078735 TI - Manganese-Catalyzed Multicomponent Synthesis of Pyrimidines from Alcohols and Amidines. AB - The development of catalytic reactions for synthesizing different compounds from alcohols to save fossil carbon feedstock and reduce CO2 emissions is of high importance. Replacing rare noble metals with abundantly available 3d metals is equally important. We report a manganese-complex-catalyzed multicomponent synthesis of pyrimidines from amidines and up to three alcohols. Our reaction proceeds through condensation and dehydrogenation steps, permitting selective C-C and C-N bond formations. beta-Alkylation reactions are used to multiply alkylate secondary alcohols with two different primary alcohols to synthesize fully substituted pyrimidines in a one-pot process. Our PN5 P-Mn-pincer complexes efficiently catalyze this multicomponent process. A comparison of our manganese catalysts with related cobalt catalysts indicates that manganese shows a reactivity similar to that of iridium but not cobalt. This analogy could be used to develop further (de)hydrogenation reactions with manganese complexes. PMID- 28078736 TI - Investigation of underlying comorbidities as risk factors for symptomatic human hepatitis E virus infection. AB - BACKGROUND: Symptomatic Hepatitis E virus (HEV) infection occurs in few infected subjects, and the risk factors are not completely known. AIM: To explore the risk factors for adverse clinical outcomes in acute HEV infections. METHODS: A large retrospective study was conducted. The baseline characteristics, clinical outcomes, and laboratory data of 512 acute HEV infection cases were analysed using logistic regression models. RESULTS: All patients exhibited autochthonous sporadic HEV infections, and most were elderly. Their symptoms varied from asymptomatic to severe liver diseases. In all, 215 patients (42.0%) had liver failure and/or decompensation, and 45 (8.2%) patients died within 3 months. Nearly 60% of patients had underlying chronic liver diseases (CLDs), 20% were cirrhotic, and various extrahepatic underlying comorbidities were common. The logistic regression analysis revealed that underlying CLDs, especially cirrhosis, were closely associated with disease severity (OR = 8.78, P < 0.001) but not with mortality in patients with severe liver diseases. In addition to the known factors, including an old age, the male gender and CLDs, we identified pre existing extrahepatic tumours, diabetes, and chronic respiratory and renal diseases as novel independent predictors for adverse clinical outcomes. Importantly, patients without these four extrahepatic comorbidities showed a much lower mortality rate (4.2%, P < 0.001) than patients with one (18.5%) or more comorbidities (34.5%). CONCLUSIONS: Previous comorbidities, including tumours, diabetes, and chronic liver, lung and kidney diseases, were independent risk factors for adverse outcomes, especially mortality, in acute HEV infections. This study provides valuable data for improving the prevention and control of HEV infection. PMID- 28078737 TI - Three-dimensional assessment of umbilical vein deviation angle for prediction of liver herniation in left-sided congenital diaphragmatic hernia. AB - OBJECTIVES: To introduce a new sonographic marker of intrathoracic liver herniation in fetuses with left-sided congenital diaphragmatic hernia (CDH). METHODS: In a consecutive series of fetuses with isolated CDH, an ultrasound volume of the fetal abdomen was acquired. On this volume, offline calculation of the angle formed by the midline of the abdomen (joining the center of the vertebral body to the abdominal insertion of the umbilical cord) and a second line joining the center of the vertebral body to the intra-abdominal convexity of the umbilical vein was carried out to give the umbilical vein deviation angle (UVDA). The UVDA was measured in a group of normal fetuses selected as controls. At follow-up, the presence of liver herniation was investigated in all cases of CDH. UVDA values were compared between the CDH group and controls, and between CDH 'liver-up' vs 'liver-down' cases. A receiver-operating characteristics (ROC) curve was constructed to identify a cut-off value of the UVDA with the highest accuracy in predicting liver herniation in the CDH group. RESULTS: Between 2009 and 2015, 22 cases of left-sided CDH were included in the study group, of which nine cases had liver herniation. Eighty-eight normal fetuses were recruited as controls. The UVDA was significantly higher in the cases vs controls (15.25 +/- 7.91 degrees vs 7.68 +/- 1.55 degrees ; P < 0.0001). Moreover, the UVDA was significantly increased in CDH fetuses with liver-up vs liver-down (21.77 +/- 8.79 degrees vs 10.75 +/- 2.10 degrees ; P < 0.0001). On ROC curve analysis the UVDA showed good prediction of liver herniation (area under the ROC curve, 0.94; P < 0.0001) with the best cut-off of 15.2 degrees , yielding a sensitivity of 89% and a specificity of 100% (P < 0.0001). CONCLUSIONS: In fetuses with CDH, umbilical vein bowing may be quantified by measuring the UVDA using three dimensional ultrasound. This sonographic marker seems to be an accurate predictor of liver herniation in left-sided CDH. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28078738 TI - Dorsal pallidal neurons directly link the nidopallium and midbrain in the zebra finch (Taeniopygia guttata). AB - The dorsal pallidum in birds is considered similar, if not homologous, to the globus pallidus (GP) of mammals. The dorsal pallidum projects to both thalamic and midbrain targets similar to the direct and indirect pathways arising from the internal and external segments of the GP. In the present study, retrograde and anterograde tracing studies revealed a previously undescribed projection of the avian dorsal pallidum. This arises from a specific dorsomedial component, which terminates in the intercollicular nucleus and partly surrounds the avian equivalent of the central nucleus of the inferior colliculus. The respiratory vocal dorsomedial nucleus of the intercollicular complex, however, does not receive these projections. The somata of the pallidal neurons retrogradely labeled from injections in the intercollicular nucleus were large and generally multipolar and had extensive, sparsely branching central processes (presumptive dendrites) that together extended up to 2 mm dorsally into the intermediate and caudomedial nidopallium. The size and morphology of these neurons were similar to those of large pallidal neurons labeled by calretinin immunoreactivity, which could be co-localized to the same cells. Thus, rather than being directly involved in the control of movement, the large dorsomedial neurons of the caudal dorsal pallidum may be involved in sensory processing, in that they provide an unusual direct link between sensory (auditory/somatosensory) regions of the nidopallium and sensory regions of the intercollicular nucleus of the midbrain. J. Comp. Neurol. 525:1731-1742, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28078739 TI - Silver-Catalyzed Chemoselective [4+2] Annulation of Two Isocyanides: A General Route to Pyridone-Fused Carbo- and Heterocycles. AB - A silver-catalyzed chemoselective [4+2] annulation of aryl and heteroaryl isocyanides with alpha-substituted isocyanoacetamides was developed for the facile and efficient synthesis of 2-aminoquinolones, naphthyridines, and phenanthrolines. A mechanism for this multistep domino reaction is proposed on the basis of a 13 C-labeling experiment, according to which an unprecedented chemoselective heterodimerization of two different isocyanides generates an alpha amidoketenimine intermediate, which undergoes 1,3-amino migration to form an alpha-imidoylketene, followed by 6 pi electrocyclization. PMID- 28078740 TI - SimLabel: a graphical user interface to simulate continuous wave EPR spectra from site-directed spin labeling experiments. AB - Site-directed spin labeling (SDSL) combined with continuous wave electron paramagnetic resonance (cw EPR) spectroscopy is a powerful technique to reveal, at the residue level, structural transitions in proteins. SDSL-EPR is based on the selective grafting of a paramagnetic label on the protein under study, followed by cw EPR analysis. To extract valuable quantitative information from SDSL-EPR spectra and thus give reliable interpretation on biological system dynamics, numerical simulations of the spectra are required. Such spectral simulations can be carried out by coding in MATLAB using functions from the EasySpin toolbox. For non-expert users of MATLAB, this could be a complex task or even impede the use of such simulation tool. We developed a graphical user interface called SimLabel dedicated to run cw EPR spectra simulations particularly coming from SDSL-EPR experiments. Simlabel provides an intuitive way to visualize, simulate, and fit such cw EPR spectra. An example of SDSL-EPR spectra simulation concerning the study of an intrinsically disordered region undergoing a local induced folding is described and discussed. We believe that this new tool will help the users to rapidly obtain reliable simulated spectra and hence facilitate the interpretation of their results. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28078741 TI - Effect of an art brut therapy program called go beyond the schizophrenia (GBTS) on prison inmates with schizophrenia in mainland China-A randomized, longitudinal, and controlled trial. AB - : Creative arts therapies are proven to promote an interconnection between body and mind, but there are major obstacles for providing therapeutic services in prisons due to inmates' inherent mistrust for verbal disclosure and rigid self defenses, especially among inmates with schizophrenia. Thus, we developed a structured and quantitative art brut therapy program called go beyond the schizophrenia to actually measure the benefits of art therapy on prison inmates in mainland China. Upon completion of the program, the intervention group reported a decrease in anxiety, depression, anger, and negative psychiatric symptoms and showed better compliance with rules, socialization with peers, compliance with medications, and regular sleeping patterns after 16 weekly sessions of go beyond the schizophrenia. This article concludes that the art brut therapy was effective for the inmates with schizophrenia in mainland China and provides encouraging data on how to enhance mental health for inmates with schizophrenia. KEY PRACTITIONER MESSAGE: Art brut therapy can reduce emotional distress and negative psychiatric symptoms among Chinese inmates. Arts brut therapy can enhance Chinese inmates' compliance with rules, socialization with peers, compliance with medicines, and regular sleeping patterns. Arts brut therapy in conjunction with medication is highly recommended for recovery of Chinese inmates with schizophrenia, especially for patients with negative symptoms. PMID- 28078742 TI - Taxonomic revision of the Agaraceae with a description of Neoagarum gen. nov. and reinstatement of Thalassiophyllum. AB - We confirmed the monophyly of the Agaraceae based on phylogenetic analyses of six mitochondrial and six chloroplast gene sequences from Agarum, Costaria, Dictyoneurum, and Thalassiophyllum species, as well as representative species from other laminarialean families. However, the genus Agarum was paraphyletic, comprising two independent clades, A. clathratum/A. turneri and A. fimbriatum/A. oharaense. The latter clade was genetically most closely related to Dictyoneurum spp., and morphologically, the species shared a flattened stipe bearing fimbriae (potential secondary haptera) in the mid- to upper portion. The phylogenetic position of Thalassiophyllum differed between the two datasets: in the chloroplast gene phylogeny, Thalassiophyllum was included in the A. clathratum/A. turneri clade, but in the mitochondrial gene phylogeny, it formed an independent clade at the base of the Agaraceae, the same position it took in the phylogeny when the data from both genomes were combined despite a larger number of bp being contributed by the chloroplast gene sequences. Considering the remarkable morphological differences between Thalassiophyllum and other Agaraceae, and the molecular support, we conclude that Thalassiophyllum should be reinstated as an independent genus. Dictyoneurum reticulatum was morphologically distinguishable from D. californicum due to its midrib, but because of their close genetic relationship, further investigations are needed to clarify species-level taxonomy. In summary, we propose the establishment of a new genus Neoagarum to accommodate A. fimbriatum and A. oharanese and the reinstatement of the genus Thalassiophyllum. PMID- 28078743 TI - Bivalent 14-mer peptide ligands of CXCR4 with polyproline linkers with anti chemotactic activity against Jurkat cells. AB - Interaction of CXCR4 with its endogenous ligand, stromal-cell derived factor-1 (SDF-1)/CXCL12, induces various physiological functions involving chemotaxis. Bivalent ligands with a polyproline helix bearing a cyclic pentapeptide, FC131, were previously shown to have higher binding affinities for CXCR4 than the corresponding monovalent ligands. Bivalent ligands based on a 14-mer peptide T140 derivative with polyproline linkers have been designed and synthesized. The activity of these peptides as well as the effect of bivalency of the ligand on CXCR4 binding has been assessed. The binding affinity of these series of bivalent ligands is increased as the linker length increases up to the 12-/15-mer proline linker. The inhibitory activity against chemotaxis on Jurkat cells also depends on the linker length. The T140-derived bivalent ligands with the 9- and 12-mer proline linkers showed the most effective inhibition against chemotaxis at 1000 nM, which is even higher than that of known CXCR4 antagonists in the monomer structure. The effective metastatic inhibition by bivalent T140 derivatives indicates the therapeutic potential. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd. PMID- 28078744 TI - Escape from rich-to-lean transitions: Stimulus change and timeout. AB - Extended pausing during discriminable transitions from rich-to-lean conditions can be viewed as escape (i.e., rich-to-lean transitions function aversively). In the current experiments, pigeons' key pecking was maintained by a multiple fixed ratio fixed-ratio schedule of rich or lean reinforcers. Pigeons then were provided with another, explicit, mechanism of escape by changing the stimulus from the transition-specific stimulus used in the multiple schedule to a mixed schedule stimulus (Experiment 1) or by producing a period of timeout in which the stimulus was turned off and the schedule was suspended (Experiment 2). Overall, escape was under joint control of past and upcoming reinforcer magnitudes, such that responses on the escape key were most likely during rich-to-lean transitions, and second-most likely during lean-to-lean transitions. Even though pigeons pecked the escape key, they paused before doing so, and the latency to begin the fixed ratio (i.e., the pause) remained extended during rich-to-lean transitions. These findings suggest that although the stimulus associated with rich-to-lean transitions functioned aversively, pausing is more than simply escape responding from the stimulus. PMID- 28078745 TI - The effect of structural empowerment of nurses on quality outcomes in hospitals: a scoping review. AB - AIM: To assess and synthesise studies reporting direct associations between the structural empowerment of frontline nurses and quality outcomes, and to identify gaps in the current literature. BACKGROUND: The empowerment of nurses seems essential for delivering high-quality patient care. Understanding the relationship between empowerment and quality outcomes would enable nurse managers to make informed choices on improving the quality of care. METHODS: A scoping review examining the relationship between the structural empowerment of nurses and the quality, effectiveness, safety, efficiency and patient-centredness of care in hospitals. Searching in MEDLINE, CINAHL, Business Source Premier and Embase identified 672 potentially relevant articles. Independent selection, quality assessment, data extraction and analysis were completed. RESULTS: Twelve cross-sectional studies originating from North America were included. These studies showed a variety of quality outcomes and statistics used. All studies reported positive associations between the structural empowerment of nurses, nurse assessed quality of care and patient safety climate, and work and unit effectiveness. CONCLUSIONS: Nurses having access to empowering structures positively affects the quality outcomes, i.e. quality, effectiveness, safety, efficiency and patient-centredness of patient care in hospitals. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers and leaders should ensure empowering work conditions for nurses in order to increase hospitals' quality of patient care. PMID- 28078746 TI - A Gly65Val substitution in an actin, GhACT_LI1, disrupts cell polarity and F actin organization resulting in dwarf, lintless cotton plants. AB - Actin polymerizes to form part of the cytoskeleton and organize polar growth in all eukaryotic cells. Species with numerous actin genes are especially useful for the dissection of actin molecular function due to redundancy and neofunctionalization. Here, we investigated the role of a cotton (Gossypium hirsutum) actin gene in the organization of actin filaments in lobed cotyledon pavement cells and the highly elongated single-celled trichomes that comprise cotton lint fibers. Using mapping-by-sequencing, virus-induced gene silencing, and molecular modeling, we identified the causative mutation of the dominant dwarf Ligon lintless Li1 short fiber mutant as a single Gly65Val amino acid substitution in a polymerization domain of an actin gene, GhACT_LI1 (Gh_D04G0865). We observed altered cell morphology and disrupted organization of F-actin in Li1 plant cells by confocal microscopy. Mutant leaf cells lacked interdigitation of lobes and F-actin did not uniformly decorate the nuclear envelope. While wild-type lint fiber trichome cells contained long longitudinal actin cables, the short Li1 fiber cells accumulated disoriented transverse cables. The polymerization-defective Gly65Val allele in Li1 plants likely disrupts processive elongation of F-actin, resulting in a disorganized cytoskeleton and reduced cell polarity, which likely accounts for the dominant gene action and diverse pleiotropic effects associated with the Li1 mutation. Lastly, we propose a model to account for these effects, and underscore the roles of actin organization in determining plant cell polarity, shape and plant growth. PMID- 28078747 TI - Granulocyte-Monocyte Apheresis as an Adjuvant Therapy to Anti-Tumor Necrosis Factor Drugs for Ulcerative Colitis. AB - Biologic anti-tumor necrosis factor (TNF) drugs have demonstrated their efficacy for the treatment of ulcerative colitis. Nevertheless, some patients will not respond to this therapy or will develop loss of response. Leukapheresis is the main non-pharmacological therapy for some immune-mediated diseases. The aim of our study was to describe our experience with this therapy in ulcerative colitis patients after loss of response to anti-TNF treatment. Leukapheresis was indicated in four patients with left-sided or extensive colitis because of partial response to biological therapy or secondary loss of response to it. All patients received 8 to 10 sessions in an intensive regimen. Globally, a decrease in the Mayo score was observed. The overall response rate was 50% with one patient who displayed sustained response. No patients have required colectomy during follow-up. Adjuvant treatment with leukapheresis in patients with inadequate response to anti-TNF treatment showed some beneficial effect, although of limited duration, in patients with ulcerative colitis. PMID- 28078748 TI - Low-Temperature Hydrogenation of Carbon Dioxide to Methanol with a Homogeneous Cobalt Catalyst. AB - Herein we describe the first homogeneous non-noble metal catalyst for the hydrogenation of CO2 to methanol. The catalyst is formed in situ from [Co(acac)3 ], Triphos, and HNTf2 and enables the reaction to be performed at 100 degrees C without a decrease in activity. Kinetic studies suggest an inner-sphere mechanism, and in situ NMR and MS experiments reveal the formation of the active catalyst through slow removal of the acetylacetonate ligands. PMID- 28078749 TI - Total Phosphate Elimination is Negatively Associated With Increased Serum Fibroblast Growth Factor 23 Levels in Patients who Undergo Peritoneal Dialysis. AB - As fibroblast growth factor 23 (FGF23) has been shown to induce cardiovascular disease directly in patients with chronic kidney disease, identification of factors and treatments that can modulate serum FGF23 (sFGF23) level is clinically important. This retrospective longitudinal study investigated factors that modulate sFGF23 in 49 patients who underwent peritoneal dialysis (PD). sFGF23 ratio (sFGF23 at 18 months/baseline sFGF23) was used as an indicator of changes in sFGF23 level. Total phosphate elimination was the sum of both renal phosphate excretion and dialysate phosphate elimination. In multivariate analysis, log sFGF23 ratio was associated negatively with total phosphate elimination and the use of cinacalcet at baseline, and positively with the use of vitamin D receptor activators at baseline, even after adjusting for potential confounding factors. Our study indicates that maintaining phosphate elimination can prevent increased sFGF23, thereby preventing cardiovascular events in patients who undergo PD. PMID- 28078750 TI - Metabolic adaptation of colonic microbiota to galactooligosaccharides: a proof-of concept-study. AB - BACKGROUND: Prebiotics have been shown to reduce abdominal symptoms in patients with functional gut disorders, despite that they are fermented by colonic bacteria and may induce gas-related symptoms. AIM: To investigate changes in the metabolic activity of gut microbiota induced by a recognised prebiotic. METHODS: Healthy subjects (n = 20) were given a prebiotic (2.8 g/day HOST-G904, HOST Therabiomics, Jersey, Channel Islands) for 3 weeks. During 3-day periods immediately before, at the beginning and at the end of the administration subjects were put on a standard diet (low fibre diet supplemented with one portion of high fibre foods) and the following outcomes were measured: (i) number of daytime gas evacuations for 2 days by means of an event marker; (ii) volume of gas evacuated via a rectal tube during 4 h after a test meal; and (iii) microbiota composition by faecal Illumina MiSeq sequencing. RESULTS: At the beginning of administration, HOST-G904 significantly increased the number of daily anal gas evacuations (18 +/- 2 vs. 12 +/- 1 pre-administration; P < 0.001) and the volume of gas evacuated after the test meal (236 +/- 23 mL vs. 160 +/- 17 mL pre-administration; P = 0.006). However, after 3 weeks of administration, these effects diminished (11 +/- 2 daily evacuations, 169 +/- 23 mL gas evacuation). At day 21, relative abundance of butyrate producers (Lachnospiraceae) correlated inversely with the volume of gas evacuated (r = 0.52; P = 0.02). CONCLUSION: The availability of substrates induces an adaptation of the colonic microbiota activity in bacterial metabolism, which produces less gas and associated issues. Clinical trials.gov NCT02618239. PMID- 28078751 TI - Cardiac remodeling in normotensive pregnancy and in pregnancy complicated by hypertension: systematic review and meta-analysis. AB - OBJECTIVE: The aim of this systematic review and meta-analysis was to describe comprehensively the pattern of cardiac remodeling during normotensive human singleton pregnancy and to compare it with that of pregnancy complicated by hypertension. METHODS: We performed a meta-analysis of the current literature on cardiac remodeling during normotensive and complicated pregnancies. Literature was retrieved from PubMed (NCBI) and EMBASE (Ovid) databases. Included studies needed to report a reference measurement (matched non-pregnant control group, prepregnancy or postpartum) and measurements made during predetermined gestational-age intervals. Mean differences between reference and pregnancy data were calculated using the random-effects model described by DerSimonian and Laird. RESULTS: Forty-eight studies were included in the meta-analysis, with publication dates ranging from 1977 to 2016. During normotensive pregnancy, most geometric indices started to increase in the second trimester. Left ventricular mass (LVM) increased by 28.36 (95% CI, 19.73-37.00) g (24%), and relative wall thickness (RWT) increased by 0.03 (95% CI, 0.02-0.05) (10%) compared with those in the reference group. During hypertensive pregnancy, LVM and RWT increased more than during normotensive pregnancy (92 (95% CI, 75.46-108.54) g (95%) and 0.14 (95% CI, 0.09-0.19) (56%), respectively). CONCLUSIONS: During normotensive pregnancy, most cardiac geometric indices change from the second trimester onwards. Both LVM and RWT increase, by 20% and 10%, respectively, consistent with concentric rather than eccentric remodeling. Cardiac adaptation in hypertensive pregnancy deviates from that in healthy pregnancy by a greater change in LVM (95% increase from reference) and RWT (56% increase from reference). Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28078752 TI - Two New Copper Borates with Mesoscale Cubic Supramolecular Cages Assembled from {Cu4 @B20 } Clusters. AB - Two new copper borates, namely H6 [(MU4 -O)Cu4 @B20 O32 (OH)8 ]?25 H2 O (1) and H6 [(MU4 -O)Cu4 @B20 O32 (OH)8 ]?34 H2 O?8 H3 BO3 (2), with 3D supramolecular framework have been made under solvothermal conditions, which built by novel cubic supramolecular cages with mesoscale cavities via the H-bondings. Interestingly, the cage is assembled by [(MU4 -O)Cu4 @B20 O32 (OH)8 ] ({Cu4 @B20 }) cluster units with different point-group symmetry. Owing to extra H3 BO3 molecules participated in building the supramolecular framework, 2 has a larger cubic cage size and higher non-framework volume, leading to the cage size extended to mesoporous size set as a version of ''1 plus". PMID- 28078753 TI - Photoredox-Catalysed Decarboxylative Alkylation of N-Heteroarenes with N (Acyloxy)phthalimides. AB - An iridium photoredox catalyst in combination with either a stoichiometric amount of Bronsted acid or a catalytic amount of Lewis acid is capable of catalyzing regioselective alkylation of N-heteroarenes with N-(acyloxy)phthalimides at room temperature under irradiation. A broad range of N-heteroarenes can be alkylated using a variety of secondary, tertiary, and quaternary carboxylates. Mechanistic studies suggest that an IrII /IrIII redox catalytic cycle is responsible for the observed reactivity. PMID- 28078754 TI - Evaluating the core microbiota in complex communities: A systematic investigation. AB - The study of complex microbial communities poses unique conceptual and analytical challenges, with microbial species potentially numbering in the thousands. With transient or allochthonous microorganisms often adding to this complexity, a 'core' microbiota approach, focusing only on the stable and permanent members of the community, is becoming increasingly popular. Given the various ways of defining a core microbiota, it is prudent to examine whether the definition of the core impacts upon the results obtained. Here we used complex marine sponge microbiotas and undertook a systematic evaluation of the degree to which different factors used to define the core influenced the conclusions. Significant differences in alpha- and beta-diversity were detected using some but not all core definitions. However, findings related to host specificity and environmental quality were largely insensitive to major changes in the core microbiota definition. Furthermore, none of the applied definitions altered our perception of the ecological networks summarising interactions among bacteria within the sponges. These results suggest that, while care should still be taken in interpretation, the core microbiota approach is surprisingly robust, at least for comparing microbiotas of closely related samples. PMID- 28078755 TI - Modulation of host cell SUMOylation facilitates efficient development of Plasmodium berghei and Toxoplasma gondii. AB - SUMOylation is a reversible post translational modification of proteins that regulates protein stabilization, nucleocytoplasmic transport, and protein-protein interactions. Several viruses and bacteria modulate host SUMOylation machinery for efficient infection. Plasmodium sporozoites are infective forms of malaria parasite that invade mammalian hepatocytes and transforms into exoerythrocytic forms (EEFs). Here, we show that during EEF development, the distribution of SUMOylated proteins in host cell nuclei was significantly reduced and expression of the SUMOylation enzymes was downregulated. Plasmodium EEFs destabilized the host cytoplasmic protein SMAD4 by inhibiting its SUMOylation. SUMO1 overexpression was detrimental to EEF growth, and insufficiency of the only conjugating enzyme Ubc9/E2 promoted EEF growth. The expression of genes involved in suppression of host cell defense pathways during infection was reversed during SUMO1 overexpression, as revealed by transcriptomic analysis. The inhibition of host cell SUMOylation was also observed during Toxoplasma infection. We provide a hitherto unknown mechanism of regulating host gene expression by Apicomplexan parasites through altering host SUMOylation. PMID- 28078756 TI - Infections in non-splenectomized persistent or chronic primary immune thrombocytopenia adults: risk factors and vaccination effect. AB - : Essentials The risk factors for infection in immune thrombocytopenia are not well known. We conducted a national pharmacoepidemiological study. Pulmonary disease, corticosteroids and rituximab were the main risk factors for infections. Pneumococcal and influenza vaccines were protective against infections. SUMMARY: Introduction Risk factors for infection and protective effect of vaccines in immune thrombocytopenia (ITP) patients in the era of rituximab therapy are unknown. Objectives To assess the risk factors for serious and non-serious infections (respectively, SIs and NSIs) in non-splenectomized adults treated for persistent or chronic primary ITP, including the effect of pneumococcal and influenza vaccines. Patients/Methods The population was the 2009-2012 FAITH cohort (n = 1805), which is the cohort of all incident (newly diagnosed) primary ITP adults treated > 3 months in France built into the national health insurance database (SNIIRAM). SIs were hospitalizations with any infection as the primary diagnosis code. NSIs were identified using out-of-hospital antibiotic dispensing. Cox models were performed. Results Incidence rates were 6.3/100 patient-years (95% confidence interval [CI], 5.4-7.4) for SIs (lower respiratory tract in 42.8% of the cases) and 100.5/100 patient-years (95% CI, 95.0-106.3) for NSIs. In multivariate analyses, increasing age and chronic pulmonary disease were associated with both SI and NSI occurrence. The hazard ratios (HRs) for corticosteroids and rituximab were, respectively, 3.83 (95% CI, 2.76-5.31) and 2.60 (95% CI, 1.67-4.03) for SIs and 2.46 (95% CI, 2.19-2.76) and 1.49 (95% CI, 1.28-1.74) for NSIs. Pneumococcal vaccine showed a protective effect for both SIs and NSIs (0.38 [95% CI, 0.20-0.73] and 0.52 [95% CI, 0.43-0.65], respectively), as did influenza vaccine (0.42 [95% CI, 0.27-0.64] and 0.49 [95% CI, 0.41-0.59], respectively). Conclusions Chronic pulmonary disease, corticosteroids and rituximab are the main risk factors for infections, whereas pneumococcal and influenza vaccines are protective against SIs and NSIs. PMID- 28078757 TI - Lamellar events related to insulin-like growth factor-1 receptor signalling in two models relevant to endocrinopathic laminitis. AB - BACKGROUND: Insulin dysregulation, obesity, and exposure to high-nonstructural carbohydrate (NSC) forage are risk factors for equine metabolic syndrome associated laminitis (EMSAL); high systemic insulin concentrations in EMSAL are proposed to induce cellular dysregulation in the digital lamellae through activation of the insulin-like growth factor-1 receptor. OBJECTIVES: To use a dietary challenge model (DCM) and a euglycaemic-hyperinsulinaemic clamp (EHC) model to assess lamellar growth factor-related signalling. STUDY DESIGN: Lamellar phospho (P)-protein concentrations of signalling proteins important in growth factor-related signalling were assessed in 2 models: 1) lean and obese ponies on a low- or high-NSC diet; and 2) EHC model using Standardbred horses. METHODS: Ponies stratified for body condition (lean [LN, n = 11] and obese [OB, n = 11]) were exposed to a low-NSC diet (LO, n = 5 per group for LN LO and OB LO) or a high NSC diet (HI, n = 6 per group for LN HI and OB HI groups) for 7 days. For the EHC model, horses were administered insulin (constant rate infusion [6 mIU/kg bwt/min] combined with 50% dextrose, EHC group, n = 8)] or saline (0.57 mL/kg bwt/h, CON group, n = 8) for 48 h. Immunoblotting was employed to assess concentrations of activated/phosphorylated and total protein for members of the PI3K/Akt/mTORC1 and Ras/ERK pathways in lamellar samples from both models. RESULTS: In the DCM, lamellar P-(Ser 240/244) RPS6 was increased in OB HI ponies (vs. OB LO, P<0.05); positive correlations existed (P<0.05; r>0.5) between Day 7 basal serum insulin concentrations and lamellar concentrations of P-p70S6K and P (Ser 240/244) RPS6. In the EHC model, lamellar concentrations of P-Akt, P-p70S6K, P-ERK 1/2, P-p90RSK, and both P-(Ser 235/236) and P-(Ser 240/244) RPS6 were increased in the EHC group (vs. CON, P<0.05). MAIN LIMITATIONS: The primary limitations of this study are the small number of animals per group in the DCM study, and the fact that many animals did not develop laminitis as that was not the endpoint of either study. CONCLUSIONS: These results support further investigation of mTORC1/RPS6 signalling as a potential therapeutic target(s) in EMSAL. The Summary is available in Chinese - see Supporting Information. PMID- 28078758 TI - Periconceptional maternal 'high fish and olive oil, low meat' dietary pattern is associated with increased embryonic growth: The Rotterdam Periconceptional Cohort (Predict) Study. AB - OBJECTIVE: To investigate the association between periconceptional maternal dietary pattern and first-trimester embryonic growth. METHODS: This was a prospective cohort study of 228 women with a singleton ongoing pregnancy, of which 135 were strictly dated spontaneous pregnancies and 93 were pregnancies achieved after in-vitro fertilization or intracytoplasmatic sperm injection (IVF/ICSI). All women underwent serial transvaginal three-dimensional ultrasound (3D-US) examinations from 6 + 0 to 13 + 0 weeks' gestation. Crown-rump length (CRL) and embryonic volume (EV) measurements were performed using a virtual reality system. Information on periconceptional maternal dietary intake was collected via food frequency questionnaires. Principal component analysis was performed to identify dietary patterns. Associations between dietary patterns and CRL and EV trajectories were investigated using linear mixed models adjusted for potential confounders. RESULTS: A median of five (range, one to seven) 3D-US scans per pregnancy were performed. Of 1162 datasets, quality was sufficient to perform CRL measurements in 991 (85.3%) and EV measurements in 899 (77.4%). A dietary pattern comprising high intake of fish and olive oil and a very low intake of meat was identified as beneficial for embryonic growth. In strictly dated spontaneous pregnancies, strong adherence to the 'high fish and olive oil, low meat' dietary pattern was associated with a 1.9 mm (95% CI, 0.1-3.63 mm) increase in CRL (+14.6%) at 7 weeks and a 3.4 mm (95% CI, 0.2-7.81 mm) increase (+6.9%) at 11 weeks, whereas EV increased by 0.06 cm3 (95% CI, 0.01-0.13 cm3 ) (+20.4%) at 7 weeks and 1.43 cm3 (95% CI, 0.99-1.87 cm3 ) (+14.4%) at 11 weeks. No significant association was observed in the total study population or in the IVF/ICSI subgroup. CONCLUSION: Periconceptional maternal adherence to a high fish and olive oil, low meat dietary pattern is positively associated with embryonic growth in spontaneously conceived pregnancies. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28078759 TI - Bufalin, a bufanolide steroid from the parotoid glands of the Chinese toad, inhibits L-type Ca2+ channels and contractility in rat ventricular myocytes. AB - Bufalin is a bufanolide steroid compound in Chan Su. Chan Su is a traditional Chinese medicine prepared from the dried white secretion of the auricular and skin glands of toads and has been used as an oriental drug. However, the effect of bufalin on cardiac function and its underlying cellular mechanisms remain unclear. Here, we explore the cellular mechanisms of bufalin on myocardial protection via the whole-cell patch-clamp recording and video-based edge detection system. Exposure to bufalin resulted in a concentration-dependent blockade of ICa-L , with the half-maximal inhibitory concentration (IC50 ) of 60 MUm and the maximal inhibitory effect of 71.50 +/- 2.67%. Bufalin at 100 MUm reduced cell shortening by 33.83 +/- 4.01%. Bufalin restrained L-type Ca2+ channels conductance, and contractility in rat ventricular myocytes. Thus, the protective effects of bufalin on the heart may be determined by the inhibitory effect on ICa-L and the negative inotropic action caused by the decrease of intracellular Ca2+ in rat myocardial cells. PMID- 28078760 TI - A Study of volumetric variations of basal nuclei in the normal human brain by magnetic resonance imaging. AB - Knowledge of the effects of healthy aging on brain structures is necessary to identify abnormal changes due to diseases. Many studies have demonstrated age related volume changes in the brain using MRI. 60 healthy individuals who had normal MRI aged from 20 years to 80 years were examined and classified into three groups: Group I: 21 persons; nine males and 12 females aging between 20-39 years old. Group II: 22 persons; 11 males and 11 females aging between 40-59 years old. Group III: 17 persons; eight males and nine females aging between 60-80 years old. Volumetric analysis was done to evaluate the effect of age, gender and hemispheric difference in the caudate and putamen by the slicer 4.3.3.1 software using 3D T1-weighted images. Data were analyzed by student's unpaired t test, ANOVA and regression analysis. The volumes of the measured and corrected caudate nuclei and putamen significantly decreased with aging in males. There was a statistically insignificant relation between the age and the volume of the measured caudate nuclei and putamen in females but there was a statistically significant relation between the age and the corrected caudate nuclei and putamen. There was no significant difference on the caudate and putamen volumes between males and females. There was no significant difference between the right and left caudate nuclei volumes. There was a leftward asymmetry in the putamen volumes. The results can be considered as a base to track individual changes with time (aging and CNS diseases). Clin. Anat. 30:175-182, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28078761 TI - Venous intravasation during evaluation of tubal patency by ultrasound contrast imaging. PMID- 28078762 TI - Competence in the use of supraglottic airways by Australian surf lifesavers for cardiac arrest ventilation in a manikin. AB - OBJECTIVES: Lifesavers in Australia are taught to use pocket mask (PM) rescue breathing and bag valve mask (BVM) ventilation, despite evidence that first responders might struggle with these devices. Novices have successfully used the Laryngeal Mask Airway (LMA) Supreme and iGel devices previously, but there has been no previous comparison of the ability to train lifesavers to use the supraglottic airways compared to standard techniques for cardiac arrest ventilation. METHODS: The study is a prospective educational intervention whereby 113 lifesavers were trained to use the LMA and iGel supraglottic airways. Comparisons were made to standard devices on plastic manikins. Successful ventilation was defined as achieving visible chest rise. RESULTS: The median time to first effective ventilation was similar between the PM (16 s, 95% confidence interval 16-17 s), BVM (17 s, 16-17 s) and iGel devices (18 s, 16-20 s), but longer for the LMA (36 s, 33-38 s). The iGel frequently failed to achieve ventilation (10%) compared with the PM (1%, P < 0.01) and LMA (3%, P < 0.01) but was not worse than the BVM (3%, P < 0.57). Hands-off time was similar between the BVM, LMA and iGel (10 s for each device), but worse for the PM (13 s, P = 0.001). CONCLUSION: Lifesavers using the PM and BVM perform ventilation for cardiopulmonary resuscitation well. There appears to be a limited role for supraglottic airway devices because of limitations in terms of time to first effective ventilation and reliability. Clinical validation of manikin data with live resuscitation performance is required. PMID- 28078764 TI - Photoisomerization of a Chiral Imine Molecular Switch Followed by Matrix Isolation VCD Spectroscopy. AB - Characterizing the stereochemistry of transient photoisomerization products remains a big challenge for the design of molecular machines, such as unidirectional molecular motors. Often these states are not stable long enough to be characterized in detail using conventional spectroscopic tools. The structurally simple camphorquinone imine 1 serves to illustrate the advantage of combining the matrix-isolation technique with vibrational circular dichroism (VCD) spectroscopy for the investigation of photoisomerizations of chiral molecules. In particular, it is shown that both (E)- and (Z)-1 can be generated photochemically at cryogenic temperatures in an argon matrix, and more importantly, that the stereochemistry of both switching states can be characterized reliably. PMID- 28078763 TI - Development and feasibility testing of the Pediatric Emergency Discharge Interaction Coding Scheme. AB - BACKGROUND: Discharge communication is an important aspect of high-quality emergency care. This study addresses the gap in knowledge on how to describe discharge communication in a paediatric emergency department (ED). OBJECTIVE: The objective of this feasibility study was to develop and test a coding scheme to characterize discharge communication between health-care providers (HCPs) and caregivers who visit the ED with their children. DESIGN: The Pediatric Emergency Discharge Interaction Coding Scheme (PEDICS) and coding manual were developed following a review of the literature and an iterative refinement process involving HCP observations, inter-rater assessments and team consensus. SETTING AND PARTICIPANTS: The coding scheme was pilot-tested through observations of HCPs across a range of shifts in one urban paediatric ED. MAIN VARIABLES STUDIED: Overall, 329 patient observations were carried out across 50 observational shifts. Inter-rater reliability was evaluated in 16% of the observations. The final version of the PEDICS contained 41 communication elements. RESULTS: Kappa scores were greater than .60 for the majority of communication elements. The most frequently observed communication elements were under the Introduction node and the least frequently observed were under the Social Concerns node. HCPs initiated the majority of the communication. CONCLUSION: Pediatric Emergency Discharge Interaction Coding Scheme addresses an important gap in the discharge communication literature. The tool is useful for mapping patterns of discharge communication between HCPs and caregivers. Results from our pilot test identified deficits in specific areas of discharge communication that could impact adherence to discharge instructions. The PEDICS would benefit from further testing with a different sample of HCPs. PMID- 28078765 TI - A typical presentation of primary pulmonary epithelioid sarcoma misdiagnosed as non-small cell lung cancer. PMID- 28078767 TI - Retraction statement: "Huntington's Disease: Characteristics of Fallers" by Shannon Williams et al. PMID- 28078766 TI - Lost in transformation? Reviving ethics of care in hospital cultures of evidence based healthcare. AB - Drawing on previous empirical research, we provide an exemplary narrative to illustrate how patients have experienced hospital care organized according to evidence-based fast-track programmes. The aim of this paper was to analyse and discuss if and how it is possible to include patients' individual perspectives in an evidence-based practice as seen from the point of view of nursing theory. The paper highlights two conflicting courses of development. One is a course of standardization founded on evidence-based recommendations, which specify a set of rules that the patient must follow rigorously. The other is a course of democratization based on patients' involvement in care. Referring to the analysis of the narrative, we argue that, in the current implementation of evidence-based practice, the proposed involvement of patients resembles empty rhetoric. We argue that the principles and values from evidence-based medicine are being lost in the transformation into the current evidence-based hospital culture which potentially leads to a McDonaldization of nursing practice reflected as 'one best way'. We argue for reviving ethics of care perspectives in today's evidence practice as the fundamental values of nursing may potentially bridge conflicts between evidence-based practice and the ideals of patient participation thus preventing a practice of 'McNursing'. PMID- 28078768 TI - Microphysiological Systems ("Organs-on-Chips") for Drug Efficacy and Toxicity Testing. PMID- 28078769 TI - Interleukin-1alpha induced release of interleukin-8 by human bronchial epithelial cells in vitro: assessing mechanisms and possible treatment options. AB - Survival after lung transplantation is hampered by chronic lung allograft dysfunction (CLAD). Persistently elevated BAL-neutrophilia is observed in some patients despite treatment with azithromycin, which may be induced by IL-1alpha. Our aim is to establish an in vitro model, assess mechanistic pathways and test different therapeutic strategies of IL-1alpha-induced release of IL-8 by human bronchial epithelial cells. Bronchial epithelial cells (16HBE) were stimulated with IL-1alpha with or without azithromycin or dexamethasone. IL-8 protein was analyzed in cell supernatant. Different MAP kinases (p38, JNK, ERK1/2 , Ikappabeta) and targets known to be involved in tumor formation (PI3K, Akt) were investigated. Finally, different treatment options were tested for their potential inhibitory effect. IL-1alpha induced IL-8 in bronchial epithelial cells, which was dose-dependently inhibited by dexamethasone but not by azithromycin. IL-1alpha induced p38 and Akt phosphorylation, but activation of these MAPK was not inhibited by dexamethasone. JNK, ERK1/2 , Ikappabeta and PI3K were not activated. None of the tested drugs reduced the IL-1alpha induced IL-8 production. We established an in vitro model wherein steroids inhibit the IL 1alpha-induced IL-8 production, while azithromycin was ineffective. Despite using this simple in vitro model, we could not identify a new treatment option for azithromycin-resistant airway neutrophilia. PMID- 28078771 TI - The see-saw of immune dysregulation association of diverse organ autoimmune conditions in a woman. Evolution over twenty-seven years. PMID- 28078772 TI - Skin cleansing and emolliating for older people: A quasi-experimental pilot study. AB - AIMS: The aims of this study were to (i) assess the effect of low-cost hygiene and emollient regimens on the skin barrier function (SBF) of people aged >65 year with xerosis (dry skin) on their lower legs; (ii) to assess the utility of portable measures of skin barrier function in terms of stratum corneum hydration (SCH) and transepidermal water loss (TEWL) in community settings; and iii) to provide evidence for a randomised controlled trial on the treatment of adults in a resource-poor country with dry skin on their lower legs which causes and exacerbates the skin disease podoconiosis (non-filarial elephantiasis). BACKGROUND: Age increases the risk of impaired skin barrier function which can precipitate skin breakdown. Older skin is frequently characterised by troublesome xerosis and pruritus (itching). Hygiene and emollient practices are central to maintaining skin integrity but are currently under-researched. METHOD: A quasi experimental pilot study of five combinations of cleansing and emollient interventions was applied to the xerotic lower legs of ten participants with no skin disease for five consecutive days. Stratum corneum hydration and transepidermal water loss were measured at baseline and day six. Products were chosen because of effectiveness, low cost and availability in a poor-resource country. RESULTS: The greatest difference in transepidermal water loss pre intervention-postintervention was indicated by the regimen of soapy water, 2% glycerine soak and VaselineTM (mean 1.14, SD 1.27). This regimen also indicated the greatest difference in stratum corneum hydration (mean 7.92, SD 3.93). The improvement in stratum corneum hydration was significantly greater than for the control (p = .011), soap (p = .050) or water soak (p = .011). CONCLUSION: A regimen of washing skin with soapy water, soaking in 2% glycerine for 30 min and applying VaselineTM has a beneficial effect on the skin barrier function in older people. The study supports previous findings on the positive effects of glycerine on skin barrier function. IMPLICATIONS FOR PRACTICE AND RESEARCH: Skin barrier function in older people can be improved using a regimen of washing, soaking in 2% glycerine and applying VaselineTM . PMID- 28078770 TI - Synthetic plant virology for nanobiotechnology and nanomedicine. AB - Nanotechnology is a rapidly expanding field seeking to utilize nano-scale structures for a wide range of applications. Biologically derived nanostructures, such as viruses and virus-like particles (VLPs), provide excellent platforms for functionalization due to their physical and chemical properties. Plant viruses, and VLPs derived from them, have been used extensively in biotechnology. They have been characterized in detail over several decades and have desirable properties including high yields, robustness, and ease of purification. Through modifications to viral surfaces, either interior or exterior, plant-virus-derived nanoparticles have been shown to support a range of functions of potential interest to medicine and nano-technology. In this review we highlight recent and influential achievements in the use of plant virus particles as vehicles for diverse functions: from delivery of anticancer compounds, to targeted bioimaging, vaccine production to nanowire formation. WIREs Nanomed Nanobiotechnol 2017, 9:e1447. doi: 10.1002/wnan.1447 For further resources related to this article, please visit the WIREs website. PMID- 28078773 TI - Ligand-Enabled Alkynylation of C(sp3 )-H Bonds with Palladium(II) Catalysts. AB - The palladium(II)-catalyzed beta- and gamma-alkynylation of amide C(sp3 )-H bonds is enabled by pyridine-based ligands. This alkynylation reaction is compatible with substrates containing alpha-tertiary or alpha-quaternary carbon centers. The beta-methylene C(sp3 )-H bonds of various carbocyclic rings were also successfully alkynylated. PMID- 28078774 TI - Cytology of rheumatoid pleuritis. PMID- 28078775 TI - Comparison of three surgical approaches for staging lymphadenectomy in high-risk endometrial cancer. AB - OBJECTIVE: To compare laparotomy, laparoscopy, and robotic surgical approaches to lymphadenectomy for high-risk endometrial cancer staging. METHODS: A retrospective cohort study enrolled patients who underwent surgery for pathologic high-risk endometrial carcinoma at the University Health Network, Toronto, Canada, between January 1, 2005 and December 31, 2013. The primary outcome, the median number of nodes retrieved, was compared based on surgical technique. The secondary outcome was the detection of metastatic nodes. RESULTS: A total of 176 patients who underwent surgery for high-risk endometrial cancer were included, of whom 147 (83.5%) had pelvic and 78 (44.3%) had para-aortic lymphadenectomy. Laparotomy, laparoscopy, and robotic approaches were applied for 69 (39.2%), 44 (25.0%), and 63 (35.8%) patients, respectively. Minimally-invasive staging was associated with an increased proportion of patients undergoing pelvic lymphadenectomy compared with laparotomy (P=0.005). The median number of nodes removed in the pelvis and para-aortic regions did not differ between surgical approaches. The detection of metastatic nodes was also similar between the groups. Increased blood loss (P<0.001) and longer hospital admission (P<0.001) were observed with laparotomy procedures. CONCLUSION: All three techniques demonstrated adequate staging of high-risk endometrial carcinoma. Based on improved peri-operative outcomes, the use of minimally-invasive techniques is advocated where appropriate. PMID- 28078776 TI - Performance of the ForenSeqTM DNA Signature Prep kit on highly degraded samples. AB - Next generation sequencing (NGS) is the emerging technology in forensic genomics laboratories. It offers higher resolution to address most problems of human identification, greater efficiency and potential ability to interrogate very challenging forensic casework samples. In this study, a trial set of DNA samples was artificially degraded by progressive aqueous hydrolysis, and analyzed together with the corresponding unmodified DNA sample and control sample 2800 M, to test the performance and reliability of the ForenSeqTM DNA Signature Prep kit using the MiSeq Sequencer (Illumina). The results of replicate tests performed on the unmodified sample (1.0 ng) and on scalar dilutions (1.0, 0.5 and 0.1 ng) of the reference sample 2800 M showed the robustness and the reliability of the NGS approach even from sub-optimal amounts of high quality DNA. The degraded samples showed a very limited number of reads/sample, from 2.9-10.2 folds lower than the ones reported for the less concentrated 2800 M DNA dilution (0.1 ng). In addition, it was impossible to assign up to 78.2% of the genotypes in the degraded samples as the software identified the corresponding loci as "low coverage" (< 50x). Amplification artifacts such as allelic imbalances, allele drop outs and a single allele drop in were also scored in the degraded samples. However, the ForenSeqTM DNA Sequencing kit, on the Illumina MiSeq, was able to generate data which led to the correct typing of 5.1-44.8% and 10.9-58.7% of 58 of the STRs and 92 SNPs, respectively. In all trial samples, the SNP markers showed higher chances to be typed correctly compared to the STRs. This NGS approach showed very promising results in terms of ability to recover genetic information from heavily degraded DNA samples for which the conventional PCR/CE approach gave no results. The frequency of genetic mistyping was very low, reaching the value of 1.4% for only one of the degraded samples. However, these results suggest that further validation studies and a definition of interpretation criteria for NGS data are needed before implementation of this technique in forensic genetics. PMID- 28078777 TI - Iron-Catalyzed Mild and Selective Hydrogenative Cross-Coupling of Nitriles and Amines To Form Secondary Aldimines. AB - The first example of a base-metal-catalyzed homogeneous hydrogenative coupling of nitriles and amines to selectively form secondary cross-imines is reported. The reaction is catalyzed under mild conditions by a well-defined (iPr PNP)Fe(H)Br(CO) pincer pre-catalyst and catalytic tBuOK. PMID- 28078778 TI - Texting preferences in a Paediatric residency. AB - PURPOSE: Text messaging is ubiquitous among residents, but remains an underused educational tool. Though feasibility has been demonstrated, evidence of its ability to improve standardised test scores and provide insight on resident texting preferences is lacking. The authors set out to evaluate: (1) satisfaction with a hybrid question-and-answer (Q&A) texting format; and (2) pre-/post paediatric in-training exam (ITE) performance. METHODS: A prospective study with paediatrics and internal medicine-paediatrics residents. Residents were divided into subgroups: adolescent medicine (AM) and developmental medicine (DM). Messages were derived from ITE questions and sent Monday-Friday with a 20 per cent variance in messages specific to the sub-group. Residents completed surveys gauging perceptions of the programme, and pre- and post-programme ITE scores were analysed. RESULTS: Forty-one residents enrolled and 32 (78%) completed a post programme survey. Of those, 21 (66%) preferred a Q&A format with an immediate text response versus information-only texts. The percentage change in ITE scores between 2013 and 2014 was significant. Comparing subgroups, there was no significant difference between the percentage change in ITE scores. Neither group performed significantly better on either the adolescent or developmental sections of the ITE. Text messaging... remains an underused educational tool CONCLUSIONS: Overall, participants improved their ITE scores, but no improvement was seen in the targeted subgroups on the exam. Although Q&A texts are preferred by residents, further assessment is required to assess the effect on educational outcomes. PMID- 28078779 TI - Association between Zika virus and fetopathy: a prospective cohort study in French Guiana. AB - OBJECTIVE: To establish the incidence of fetal central nervous system (CNS) anomalies (including microcephaly), signs of congenital infection and fetal loss in pregnant women infected with Zika virus (ZIKV) and non-infected pregnant women in western French Guiana. METHODS: This prospective cohort study was conducted between 1 January and 15 July 2016. We evaluated and compared clinical and fetal ultrasound examinations of 301 pregnant women with biological confirmation of ZIKV infection and 399 pregnant women who were negative for ZIKV infection. RESULTS: Overall, the total number of fetuses with CNS involvement was higher in the infected than in the control group (9.0% vs 4.3%; relative risk, 2.11 (95% CI, 1.18-4.13)). Anomalies of the corpus callosum and presence of cerebral hyperechogenicities were significantly more common in the infected group. There was an increased risk of microcephaly in the infected compared with the control group (1.7% vs 0.3%; relative risk, 6.63 (95% CI, 0.78-57.83)), although this was not statistically significant. When the mother was infected during the first or second trimester, there was a greater risk of severe CNS involvement, more signs of infection and intrauterine fetal death than with infection in the third trimester. The rate of vertical transmission in the exposed group was 10.9%. CONCLUSION: ZIKV infection during pregnancy is associated with a significant risk of fetal CNS involvement and intrauterine fetal death, particularly when infection occurs during the first or second trimesters. Microcephaly was not present in every case of congenital ZIKV syndrome that we observed. Until more is known about this disease, it is paramount to evaluate suspected cases by detailed neurosonography on a monthly basis, paying particular attention to the corpus callosum and the presence of hyperechogenic foci. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28078780 TI - In vitro anti-tubulin effects of mebendazole and fenbendazole on canine glioma cells. AB - Benzimidazole anthelmintics have reported anti-neoplastic effects both in vitro and in vivo. The purpose of this study was to evaluate the in vitro chemosensitivity of three canine glioma cell lines to mebendazole and fenbendazole. The mean inhibitory concentration (IC50 ) (+/-SD) obtained from performing the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay after treating J3T, G06-A, and SDT-3G cells for 72 h with mebendazole were 0.030 +/- 0.003, 0.080 +/- 0.015 and 0.030 +/- 0.006 MUM respectively, while those for fenbendazole were 0.550 +/- 0.015, 1.530 +/- 0.159 and 0.690 +/- 0.095 MUM; treatment of primary canine fibroblasts for 72 h at IC50 showed no significant effect. Immunofluorescence studies showed disruption of tubulin after treatment. Mebendazole and fenbendazole are cytotoxic in canine glioma cell lines in vitro and may be good candidates for treatment of canine gliomas. Further in vivo studies are required. PMID- 28078781 TI - A novel conversion method for radiographic guide into surgical guide. AB - BACKGROUND: The study proposed a novel method for converting a radiographic guide into a surgical guide and evaluated its accuracy. MATERIALS AND METHODS: Radiographic guide was reformed with the addition of index rods for geometric conversion method (GCM). Planning implants were projected on geometric projection planes, and the implant positions were measured. The radiographic guide was converted into surgical guide using a generic bench drill machine with GCM data. Two experiments were designed to validate the GCM. (1) In vitro test: Twenty implants were placed on five edentulous dental models by using the GCM (group 1) and Stereolithography (SLA) method (group 2), respectively. The deviations of planned and placed implant were calculated, and the precision error (PE) value was calculated to evaluate the stability of the GCM and SLA. (2) In vivo test: Nine edentulous subjects were selected for clinical implant surgery with the GCM guide. Two level of the index rods of radiographic guides were prepared for surgical guides forming. The differences between the planned and actual implants were calculated in implant head, apex, and angulation. RESULTS: The in vitro test revealed no significant differences in the planned and placed angulations between groups 1 and 2 (P > .05). The PE was not significantly different between groups 1 and 2 (P > .05). The in vivo test revealed a successful treatment of the subjects, and 16 implant sites were evaluated. The results indicated that GCM guide could achieve the three-dimensional (3D) offset deviations of 1.03 +/- 0.27 mm and 1.17 +/- 0.24 mm at the implant head and apex, respectively, and 1.37 degrees +/- 0.21 degrees for the 3D angulation. CONCLUSION: The novel method for converting a radiographic guide into a surgical guide appears accurate and stable compared with SLA. PMID- 28078782 TI - PACMANS: A bioinformatically informed algorithm to predict, design, and disrupt protease-on-protease hydrolysis. AB - Multiple proteases in a system hydrolyze target substrates, but recent evidence indicates that some proteases will degrade other proteases as well. Cathepsin S hydrolysis of cathepsin K is one such example. These interactions may be uni- or bi-directional and change the expected kinetics. To explore potential protease-on protease interactions in silico, a program was developed for users to input two proteases: (1) the protease-ase that hydrolyzes (2) the substrate, protease. This program identifies putative sites on the substrate protease highly susceptible to cleavage by the protease-ase, using a sliding-window approach that scores amino acid sequences by their preference in the protease-ase active site, culled from MEROPS database. We call this PACMANS, Protease-Ase Cleavage from MEROPS ANalyzed Specificities, and test and validate this algorithm with cathepsins S and K. PACMANS cumulative likelihood scoring identified L253 and V171 as sites on cathepsin K subject to cathepsin S hydrolysis. Mutations made at these locations were tested to block hydrolysis and validate PACMANS predictions. L253A and L253V cathepsin K mutants significantly reduced cathepsin S hydrolysis, validating PACMANS unbiased identification of these sites. Interfamilial protease interactions between cathepsin S and MMP-2 or MMP-9 were tested after predictions by PACMANS, confirming its utility for these systems as well. PACMANS is unique compared to other putative site cleavage programs by allowing users to define the proteases of interest and target, and can also be employed for non-protease substrate proteins, as well as short peptide sequences. PMID- 28078783 TI - New propolis type from north-east Brazil: chemical composition, antioxidant activity and botanical origin. AB - BACKGROUND: Propolis is a bee product with wide diversity of biological activity. It has a complex composition, which is dependent on its botanical source. The present study aimed to determine the chemical profile, antioxidant activity and botanical origin of two samples of a propolis type from two locations of the state of Rio Grande do Norte (RN, north-east Brazil). RESULTS: The standard chemical characteristics of the RN propolis are similar or superior to the internationally marketed Brazilian green propolis. RN propolis from two locations have high antioxidant activity, corresponding to 10% (municipality of Afonso Bezerra) and 13% (municipality of Alto do Rodrigues) of quercetin activity by the 2,2-diphenyl-1-picrylhydrazyl method and to 15% (both locations) by the beta carotene discoloration method. High-performance liquid chromatography with diode array detection (HPLC-DAD)-electrospray ionization-tandem mass spectrometry analyses revealed that most constituents of the RN propolis are flavonoids, mainly flavonols and chalcones. HPLC-DAD analysis of ethanol extracts revealed a great similarity between the chemical profile of RN propolis and shoot apices of 'jurema-preta' (Mimosa tenuiflora, Leguminosae, Mimosoideae). CONCLUSION: 'Jurema preta' shoot apices are likely resin sources of RN propolis. The chemical characteristics and antioxidant property of RN propolis provide promising prospects for the introduction of this type of propolis into the apicultural market. (c) 2017 Society of Chemical Industry. PMID- 28078784 TI - Rumination in Patients with Binge-Eating Disorder and Obesity: Associations with Eating-Disorder Psychopathology and Weight-bias Internalization. AB - Overvaluation of shape and weight in binge-eating disorder (BED) is associated with greater eating-disorder psychopathology and greater weight-bias internalization, which are-in turn-associated with poorer mental and physical health. Little is known, however, about the significance of other cognitive processes, such as rumination, in BED. This study examined rumination and overvaluation of shape/weight with eating-disorder psychopathology and weight bias internalization among 237 treatment-seeking patients with BED and comorbid obesity. Hierarchical multiple regressions indicated that rumination was associated with eating-disorder psychopathology and weight-bias internalization above and beyond the influence of overvaluation of shape/weight. Findings suggest that, among patients with BED/obesity, rumination is an important cognitive process associated with severity of eating-disorder psychopathology even after accounting for overvaluation of shape/weight. Patients with greater rumination might be more likely to dwell on weight-based discrimination experiences and internalize these negative attitudes. Additional controlled examination could determine whether rumination represents another potential target for BED/obesity treatment. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 28078785 TI - Risks of ocean acidification in the California Current food web and fisheries: ecosystem model projections. AB - The benefits and ecosystem services that humans derive from the oceans are threatened by numerous global change stressors, one of which is ocean acidification. Here, we describe the effects of ocean acidification on an upwelling system that already experiences inherently low pH conditions, the California Current. We used an end-to-end ecosystem model (Atlantis), forced by downscaled global climate models and informed by a meta-analysis of the pH sensitivities of local taxa, to investigate the direct and indirect effects of future pH on biomass and fisheries revenues. Our model projects a 0.2-unit drop in pH during the summer upwelling season from 2013 to 2063, which results in wide ranging magnitudes of effects across guilds and functional groups. The most dramatic direct effects of future pH may be expected on epibenthic invertebrates (crabs, shrimps, benthic grazers, benthic detritivores, bivalves), and strong indirect effects expected on some demersal fish, sharks, and epibenthic invertebrates (Dungeness crab) because they consume species known to be sensitive to changing pH. The model's pelagic community, including marine mammals and seabirds, was much less influenced by future pH. Some functional groups were less affected to changing pH in the model than might be expected from experimental studies in the empirical literature due to high population productivity (e.g., copepods, pteropods). Model results suggest strong effects of reduced pH on nearshore state-managed invertebrate fisheries, but modest effects on the groundfish fishery because individual groundfish species exhibited diverse responses to changing pH. Our results provide a set of projections that generally support and build upon previous findings and set the stage for hypotheses to guide future modeling and experimental analysis on the effects of OA on marine ecosystems and fisheries. PMID- 28078786 TI - V1 connections reveal a series of elongated higher visual areas in the California ground squirrel, Otospermophilus beecheyi. AB - For studies of visual cortex organization, mouse is becoming an increasingly more often used model. In addition to its genetic tractability, the relatively small area of cortical surface devoted to visual processing simplifies efforts in relating the structure of visual cortex to visual function. However, the nature of this compact organization can make some comparisons to the much larger non human primate visual cortex difficult. The squirrel, as a highly visual rodent offers a useful means for better understanding how mouse and monkey cortical organization compares. More in line with primates than their nocturnal rodent cousin, squirrels rely much more on sight and have evolved a larger expanse of cortex devoted to visual processing. To reveal the detailed organization of visual cortex in squirrels, we injected a highly sensitive monosynaptic retrograde tracer (glycoprotein deleted rabies virus) into several locations of primary visual cortex (V1) in California ground squirrels. The resulting pattern of connectivity revealed an organizational scheme in the squirrel that retains some of the basic features of the mouse visual cortex along the medial and posterior borders of V1, but unlike mouse has an elaborate and extensive pattern laterally that is more similar to the early visual cortex organization found in monkeys. In this way, we show that the squirrel can serve as a useful model for comparison to both mouse and primate visual systems, and may help facilitate comparisons between these two very different yet widely used animal models of visual processing. PMID- 28078787 TI - Targeting nasopharyngeal carcinoma by artesunate through inhibiting Akt/mTOR and inducing oxidative stress. AB - Drug repurposing has become an alternative therapeutic strategy for cancer treatment given the known pharmacokinetics and toxicity. The inhibitory effects of artesunate have been reported in various cancers. In this work, we investigated the effects of artesunate in nasopharyngeal carcinoma (NPC). We demonstrate that artesunate significantly inhibits proliferation via arresting NPC cells at G2/M phase. It also induces apoptosis through caspase-dependent and mitochondria-independent pathways in multiple NPC cell lines. The combination of artesunate and cisplatin is synergistic in targeting NPC cells in in vitro cellular culture system and in vivo xenograft tumor models. Artesunate inhibits phosphorylation of essential molecules involved in Akt/mTOR pathway in NPC cells, such as Akt, mTOR, and 4EBP1, and its inhibitory effects are partially abolished by overexpression of constitutively active Akt. In addition, artesunate also induces mitochondrial dysfunction and oxidative stress via inhibiting mitochondrial respiration, increasing levels of mitochondrial superoxide and cellular reactive oxygen species (ROS), leading to decreased ATP levels. Two ROS scavengers partially abolish the inhibitory effects of artesunate in NPC cells. These data suggest that both inhibition of Akt/mTOR pathway and induction of ROS are required for the action of artesunate in NPC cells. Our work demonstrates that artesunate is a potential candidate for NPC treatment. Our work also highlights the critical roles of Akt/mTOR pathway and mitochondrial function in NPC cells. PMID- 28078788 TI - Violence involvement among nightlife patrons: The relative role of demographics and substance use. AB - The nightlife setting is a risk context for violence involvement that ultimately may cause severe injuries and fatalities. Few studies have examined associations between alcohol and illicit substance use with physical violence involvement among nightlife patrons. The aim of the current study was to investigate the relative role of demographics and substance use characteristics for nightlife violence involvement among Norwegian nightlife patrons. A cross-sectional self completion survey was conducted outside 12 licensed premises in Oslo (n = 1099, response rate = 76%) and each respondent's BAC level was measured by a breathalyzer and registered on the questionnaire. A total of 103 individuals (10%) reported that they had been involved in physical violence when they were consuming alcohol in the nightlife setting during the last 12 months. Uni-variate results showed that patrons who had been involved in violence were more likely to present a BAC level above 1.000/00 than those who had not been involved. The prevalence of last year illicit substance use was overall high, especially in the violence-involved group. The most important factors associated with violence involvement in multivariate analysis were a high frequency of last year alcohol intoxication and last year illicit substance use. Women and those with high education had a lower risk of violence involvement. The implications for preventive initiatives are that these need to focus on factors additional to alcohol restrictions. Preventive efforts targeted to specific patron groups and measures targeting patrons who are more likely to use illicit substances may hold promise. Aggr. Behav. 43:398-407, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28078790 TI - Cavum septi pellucidi (CSP) ratio: a marker for partial agenesis of the fetal corpus callosum. AB - OBJECTIVE: While complete agenesis of the corpus callosum is often suspected on fetal ultrasound due to absence of the cavum septi pellucidi (CSP), suspicion of partial agenesis of the corpus callosum (pACC) is a challenge since the CSP is almost always present. The aim of this study was to measure the length and width of the CSP and calculate the length-to-width ratio (CSP ratio), and compare these between fetuses with pACC and normal fetuses. METHODS: In this retrospective case control study, the length and width of the CSP were measured in the axial plane of the fetal head, and the CSP length-to-width ratio calculated, in 323 normal fetuses and in 20 fetuses with pACC between 20 and 34 weeks' gestation. From the normal population we constructed reference ranges in relation to biparietal diameter (BPD). For all fetuses we calculated Z-scores for the CSP ratio. RESULTS: In the normal population, the length and width of the CSP increased with increasing BPD, while the CSP ratio decreased. The CSP was short (< 5th centile) in 85% (17/20) of fetuses with pACC and wide (> 95th centile) in 65% (13/20). The CSP ratio was small (< 5th centile) in 95% (19/20) of pACC fetuses, with 16/20 (80%) having a ratio below an empirical cut-off of 1.5. Analysis of Z-scores showed that fetuses with pACC had a significantly smaller CSP ratio (P < 0.0001) compared with the normal population. CONCLUSIONS: Fetuses with a normal-sized corpus callosum have a rectangular-shaped CSP, with a CSP ratio > 1.5 in the second half of gestation. Most fetuses with pACC have an abnormally shaped, wide and short CSP, with a decreased CSP ratio. This simple ratio has the potential to identify fetuses at high risk for pACC. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28078789 TI - "Breastfeeding" without baby: A longitudinal, qualitative investigation of how mothers perceive, feel about, and practice human milk expression. AB - Most American mothers who produce human milk (HM) now pump in place of some or all feeding at the breast, and most American infants are now fed pumped HM. We aimed to investigate mothers' perceptions of, attitudes toward, and practices for pumping and providing pumped HM. Results related to pumping are reported here. We conducted in-depth, semi-structured interviews among a diverse sample of 20 mothers who pumped, following each from pregnancy through infant HM-feeding cessation up to 1 year postpartum. Data were analyzed using thematic analysis with Atlas.ti. Mothers' reasons for pumping changed over time and reflected their needs and desires (e.g., latch difficulty, return to work, and increasing their milk supply). Mothers reported that pump type and quality were important to pumping success and that pumping was time-consuming, costly, and unpleasant compared to feeding at the breast. Regardless of how often mothers pumped, most felt pumping was necessary to meet their infant HM-feeding goals and was a welcome means of sharing with other caregivers the bonding opportunity and tasks they associated with feeding infants. Mothers interpreted output from pumping sessions to understand their ability to provide enough milk to meet their infants' needs. Mothers' reasons for pumping may signal constraints to infant HM feeding that may be addressed with policy changes. Mothers' attitudes and perceptions toward pumping indicate that, although pumping fills important and welcome roles for many mothers, the reality of its practice may make it an unacceptable or infeasible substitute for some. PMID- 28078791 TI - Effects of stem cell transplantation on bone mineral density and vitamin D status in children with thalassemia major. AB - HSCT is a curative treatment in TM, but conditioning and immunosuppressive treatment may affect bone metabolism. In this retrospective study, we aimed to compare BMD, vitamin D status, and growth in children with TM who underwent HSCT to those in children with TD TM. Twenty-three children with TM who underwent HSCT (mean age 7.1 years [1.03-14.7]) and 24 children with TD thalassemia (mean age 9.8 years [1.6-14]) were recruited. Lumbar spine BMD of TD thalassemia patients was higher than those in patients who had HSCT at both baseline and second-year assessments (P=.009, P<.001, respectively). However, BMD Z scores or serum 25-OH vitamin D levels were not different in two groups. Being >10 years of age was a significant risk factor for low BMD, height, and weight Z score for both groups. Patients who underwent HSCT with Pesaro risk class II or III had higher risk for low BMD compared to those risk class I patients (P=.044). In conclusion, children with TM who were >10 years at HSCT are at risk for low BMD and growth retardation. HSCT had no effect on BMD deficit in children with TM. PMID- 28078792 TI - Synthesis of 1-Difluoroalkylated Isoquinolines via Palladium-Catalyzed Radical Cascade Difluoroalkylation-Cyclization of Vinyl Isocyanides with Bromodifluoroacetic Derivatives. AB - A general method was developed for the synthesis of 1-difluoroalkyl isoquinolines via the palladium-catalyzed radical cascade difluoroalkylation-cyclization of vinyl isocyanides with bromodifluoroacetic derivatives. The difluoroalkylated cyclization products were readily converted to various other valuable gem difluoro-containing compounds. PMID- 28078793 TI - Insights into nuclear dynamics using live-cell imaging approaches. AB - The nucleus contains the genetic blueprint of the cell and myriad interactions within this subcellular structure are required for gene regulation. In the current scientific era, characterization of these gene regulatory networks through biochemical techniques coupled with systems-wide 'omic' approaches has become commonplace. However, these strategies are limited because they represent a mere snapshot of the cellular state. To obtain a holistic understanding of nuclear dynamics, relevant molecules must be studied in their native contexts in living systems. Live-cell imaging approaches are capable of providing quantitative assessment of the dynamics of gene regulatory interactions within the nucleus. We survey recent insights into what live-cell imaging approaches have provided the field of nuclear dynamics. In this review, we focus on interactions of DNA with other DNA loci, proteins, RNA, and the nuclear envelope. WIREs Syst Biol Med 2017, 9:e1372. doi: 10.1002/wsbm.1372 For further resources related to this article, please visit the WIREs website. PMID- 28078794 TI - The Cobalt cyclo-P4 Sandwich Complex and Its Role in the Formation of Polyphosphorus Compounds. AB - A synthetic approach to the sandwich complex [Cp'''Co(eta4 -P4 )] (2) containing a cyclo-P4 ligand as an end-deck was developed. Complex 2 is the missing homologue in the series of first-row cyclo-Pn sandwich complexes, and shows a unique tendency to dimerize in solution to form two isomeric P8 complexes [(Cp'''Co)2 (MU,eta4 :eta2 :eta1 -P8 )] (3 and 4). Reactivity studies indicate that 2 and 3 react with further [Cp'''Co] fragments to give [(Cp'''Co)2 (MU,eta2 :eta2 -P2 )2 ] (5) and [(Cp'''Co)3 P8 ] (6), respectively. Furthermore, complexes 2, 3, and 4 thermally decompose forming 5, 6, and the P12 complex [(Cp'''Co)3 P12 ] (7). DFT calculations on the P4 activation process suggest a eta3 -P4 Co complex as the key intermediate in the synthesis of 2 as well as in the formation of larger polyphosphorus complexes via a unique oligomerization pathway. PMID- 28078795 TI - A continuous-infusion dynamic MRI model at 3.0 Tesla for the serial quantitative evaluation of microvascular proliferation in an animal model of glioblastoma multiforme. AB - PURPOSE: To develop a continuous-infusion dynamic MRI technique to characterize tumor-associated microvascular proliferation (MVP) in a rat brain model of glioblastoma multiforme. METHODS: The proposed model assumes effects due to tumor associated MVP (eg, vascular permeability, Ktrans ; intravascular plasma fraction, vp ) cannot be individually separated and solves for a single parameter (kvasc ) that quantifies the T1 -weighted contrast enhancement from dynamic images acquired during continuous contrast agent (CA) infusion. Untreated C6 tumor-bearing animals (N = 6) were serially imaged on postoperative days (PODs) 14 and 18 with a 3 Tesla clinical scanner utilizing a dynamic spatial and temporal resolution of 0.38 * 0.38 * 1.5 mm3 and 3.47 s, respectively. RESULTS: An association was present between PODs 14 and 18 for median tumor kvasc (Pearson's r = 0.94, P = 0.0052) and CA concentration ([CA], derived from pre- and postcontrast R1 maps; r = 0.94, P = 0.0054). On POD 18, there was a voxel based association between kvasc and [CA] within each tumor (0.45 < r < 0.82, P < 0.001). However, voxel-based subregions demonstrated a reduced association between kvasc and [CA] (N = 5; -0.08 < r < 0.22, P > 0.05) or an inverse association (N = 1; r = -0.28, P = 0.001), indicating differences between locations of vascular permeability and subsequent CA pooling in tumors. CONCLUSION: The continuous-infusion method may provide a quantitative measure for characterizing and monitoring tumor-associated MVP. Magn Reson Med 78:1824-1838, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28078796 TI - Hyperparathyroidism caused by distant pulmonary lesions and parathyromatosis after ethanol injection/parathyroidectomy for secondary hyperparathyroidism. AB - Secondary hyperparathyroidism (SHPT) treatment includes parathyroidectomy and percutaneous ethanol injection therapy (PEIT), which are invasive procedures. The condition in which benign hyperfunctioning parathyroid tissue is distributed throughout the neck and mediastinum is termed parathyromatosis. Here, we present the case of a 51-year-old woman who began hemodialysis in 1986 due to chronic kidney disease of unknown etiology and developed SHPT in 1999. She underwent 6 rounds of PEIT followed by total a parathyroidectomy with partial forearm autotransplantation. Between 2011 and 2013, surgeons removed several nodules from her pulmonary and cervical regions and the transplanted masses from her forearm; all showed hyperplasia but exhibited no histological evidence of malignancy. Damage to the parathyroid capsule after repeated PEITs may cause local cervical recurrence and pulmonary lesions, although distant lesions are extremely rare in SHPT. This case is of interest due to the possible association between PEIT and parathyromatosis and distal lesions. PMID- 28078797 TI - In-situ incubation of iron-sulfur mineral reveals a diverse chemolithoautotrophic community and a new biogeochemical role for Thiomicrospira. AB - Sulfide mineral precipitation occurs at mid-ocean ridge (MOR) spreading centers, both in the form of plume particles and seafloor massive sulfide structures. A common constituent of MOR is the iron-bearing sulfide mineral pyrrhotite, which was chosen as a substrate for in-situ incubation studies in shallow waters of Catalina Island, CA to investigate the colonization of iron-oxidizing bacteria. Microbial community datasets were obtained from in-situ incubated pyrrhotite, allowing for direct comparison to microbial communities of iron-sulfides from active and inactive chimneys in deep-sea environments. Unclassified Gammaproteobacteria and Alphaproteobacteria (Magnetovibrio) largely dominated the bacterial community on pyrrhotite samples incubated in the water column while samples incubated at the surface sediment showed more even dominance by Deltaproteobacteria (Desulfobulbus), Gammaproteobacteria (Piscirickettsiaceae), Alphaproteobacteria (Rhodobacteraceae), and Bacteroidetes (Flavobacteriia). Cultivations that originated from pyrrhotite samples resulted in the enrichment of both, sheath-forming and stalk-forming Zetaproteobacteria. Additionally, a putative novel species of Thiomicrospira was isolated and shown to grow autotrophically with iron, indicating a new biogeochemical role for this ubiquitous microorganism. PMID- 28078799 TI - Specifying a State Guaranteed Health Benefits package for Kazakhstan: lessons for emerging economies and middle-income countries. AB - The Government of Kazakhstan is engaged in a "root and branch" modernisation of the health care sector. One aspect of the raft of modernisation programmes was to revisit the State Guaranteed Health Benefits Package, with the aim to review citizen entitlements to healthcare. This paper reviews the ongoing evolution of the planning of the health benefits package in Kazakhstan, with the main challenges encountered, and critical lessons learned, to be considered for similar attempts elsewhere. The main conclusions are that: the design process requires a blend of technical and socio-political analysis, because it attracts public interest, and therefore political risks; the scale and burden of analysis need to be kept to manageable proportions; and the relationship between the benefits package and funding modalities needs to be carefully managed by the State, to ensure access to declared entitlements to all members, including the most vulnerable, while keeping the package financially feasible. (c) 2017 The Authors. International Journal of Health Planning and Management published by John Wiley & Sons, Ltd. PMID- 28078798 TI - Systematic review with meta-analysis: rifaximin is effective and safe for the treatment of small intestine bacterial overgrowth. AB - BACKGROUND: Small intestinal bacterial overgrowth (SIBO) is a heterogeneous syndrome, characterised by an increased number and/or abnormal type of bacteria in the small bowel. Over the past decades, rifaximin has gained popularity for this indication despite its use is not evidence based. AIM: To perform a systematic review and meta-analysis to summarise evidence about the efficacy and safety of rifaximin to eradicate SIBO in adult patients. METHODS: MEDLINE, EMBASE, CCRCT, Scopus and Web of Science were searched from inception to March 16, 2015 for RCTs and observational studies. Furthermore, abstract books of major European, American and Asian gastroenterological meetings were also examined. RESULTS: Thirty-two studies involving 1331 patients were included. The overall eradication rate according to intention-to-treat analysis was 70.8% (95% CI: 61.4 78.2; I2 = 89.4%) and to per protocol analysis 72.9% (95% CI: 65.5-79.8; I2 = 87.5%). Meta-regression identified three covariates (drug dose, study design and co-therapy) independently associated with an increased eradication rate. The overall rate of adverse events was 4.6% (95% CI: 2.3-7.5; I2 = 63.6%). In the subset of studies (n= 10) allowing the analysis, improvement or resolution of symptoms in patients with eradicated SIBO was found to be 67.7% (95% CI: 44.7 86.9; I2 = 91.3%). CONCLUSIONS: Rifaximin treatment seems to be effective and safe for the treatment of SIBO. However, the quality of the available studies is generally poor. Well-designed RCTs are needed to substantiate these findings and to establish the optimal regimen. PMID- 28078800 TI - Ghrelin ameliorates blood-brain barrier disruption during systemic hypoxia. AB - NEW FINDINGS: What is the central question of this study? Is an anti-oedematous effect of ghrelin associated with increased expression of tight junction proteins in the hypoxic brain? What is the main finding and its importance? We showed that injection of ghrelin during acute and chronic systemic hypoxia is associated with increased expression of tight junction proteins and protection of the blood-brain barrier. Ghrelin appears to be a new therapeutic strategy for protection of the blood-brain barrier from disruption and prevention of brain oedema in hypoxic conditions. The blood-brain barrier, which serves to protect the homeostasis of the CNS, is formed by tight junction proteins. Several studies have indicated that systemic hypoxia leads to cerebral oedema through disruption of tight junction proteins, such as occludin and zonula occludens-1 (ZO-1). According to our previous studies, ghrelin attenuates cerebral oedema in the hypoxic brain. However, the mechanism is not completely understood. The present study was designed to determine the effect of ghrelin on occludin and ZO-1 in the hypoxic brain. Adult male Wistar rats were divided into acute and chronic control, acute or chronic hypoxia, and ghrelin-treated acute or chronic hypoxia groups. Hypoxic groups were kept in a hypoxic chamber (10-11% O2 ) for 2 (acute) or 10 days (chronic). Effects of ghrelin on occludin and ZO-1 protein levels were assessed using Western blotting. Western blot analysis revealed that the protein expression of ZO-1 and occludin decreased significantly in acute and chronic hypoxia. Ghrelin significantly increased ZO-1 protein expression in both acute and chronic hypoxia (P < 0.05). Ghrelin also increased occludin protein expression in chronic hypoxia (P < 0.05) but did not effectively change it in acute hypoxia. Our data showed that ghrelin injection maintains occludin and ZO-1 tight junction proteins, which may improve the integrity of the blood-brain barrier in hypoxic conditions. PMID- 28078801 TI - ABNORMAL POLLEN VACUOLATION1 (APV1) is required for male fertility by contributing to anther cuticle and pollen exine formation in maize. AB - Anther cuticle and pollen exine are the major protective barriers against various stresses. The proper functioning of genes expressed in the tapetum is vital for the development of pollen exine and anther cuticle. In this study, we report a tapetum-specific gene, Abnormal Pollen Vacuolation1 (APV1), in maize that affects anther cuticle and pollen exine formation. The apv1 mutant was completely male sterile. Its microspores were swollen, less vacuolated, with a flat and empty anther locule. In the mutant, the anther epidermal surface was smooth, shiny, and plate-shaped compared with the three-dimensional crowded ridges and randomly formed wax crystals on the epidermal surface of the wild-type. The wild-type mature pollen had elaborate exine patterning, whereas the apv1 pollen surface was smooth. Only a few unevenly distributed Ubisch bodies were formed on the apv1 mutant, leading to a more apparent inner surface. A significant reduction in the cutin monomers was observed in the mutant. APV1 encodes a member of the P450 subfamily, CYP703A2-Zm, which contains 530 amino acids. APV1 appeared to be widely expressed in the tapetum at the vacuolation stage, and its protein signal co-localized with the endoplasmic reticulum (ER) signal. RNA-Seq data revealed that most of the genes in the fatty acid metabolism pathway were differentially expressed in the apv1 mutant. Altogether, we suggest that APV1 functions in the fatty acid hydroxylation pathway which is involved in forming sporopollenin precursors and cutin monomers that are essential for the development of pollen exine and anther cuticle in maize. PMID- 28078803 TI - Why do they care? Narratives of physician volunteers on motivations for participation in short-term medical missions abroad. AB - BACKGROUND: Short-term medical missions (STMMs) refer to the provision of direct pro bono medical services in lower and middle income countries for periods ranging from days to a few weeks by physicians from rich countries. Survey data have provided limited information on demographic and professional profiles of physicians as well as monetary and manpower inputs. Understanding why physicians participate, however, remains incomplete. The study's objective was to elicit physicians' motivations directly. METHODS: Semi-structured interviews of physicians identified through snowball recruiting were conducted to explore motivational themes and then analyzed using narrative software employing directed content analysis methodology. RESULTS: Twenty physicians from varying backgrounds and specialties were interviewed. Responses identified aspects of the decision to participate and the relative influence of economic, diplomatic, value-related, and emotive constructs. CONCLUSION: Personality traits may be more influential to participation than demographic, professional, or socioeconomic determinants. Word of-mouth recruitment appears to underlie the increase in STMM activity, facilitated by information technology. Reported key motivators for physician participation in STMMs tend to parallel schools of thought regarding philanthropy and volunteering and include satisfaction from helping in challenging conditions of limited resources, learning experiences, appreciation from patients, sense of renewal, and the legacy effect of teaching. PMID- 28078802 TI - Evaluation of PVA biodegradable electric conductive membranes for nerve regeneration in axonotmesis injuries: the rat sciatic nerve animal model. AB - The therapeutic effect of three polyvinyl alcohol (PVA) membranes loaded with electrically conductive materials - carbon nanotubes (PVA-CNTs) and polypyrrole (PVA-PPy) - were tested in vivo for neuro-muscular regeneration after an axonotmesis injury in the rat sciatic nerve. The membranes electrical conductivity measured was 1.5 +/- 0.5 * 10-6 S/m, 579 +/- 0.6 * 10-6 S/m, and 1837.5 +/- 0.7 * 10-6 S/m, respectively. At week-12, a residual motor and nociceptive deficit were present in all treated groups, but at week-12, a better recovery to normal gait pattern of the PVA-CNTs and PVA-PPy treated groups was observed. Morphometrical analysis demonstrated that PVA-CNTs group presented higher myelin thickness and lower g-ratio. The tibialis anterior muscle, in the PVA-PPy and PVA-CNTs groups showed a 9% and 19% increase of average fiber size area and a 5% and 10% increase of the "minimal Feret's diameter," respectively. No inflammation, degeneration, fibrosis or necrosis were detected in lung, liver, kidneys, spleen, and regional lymph nodes and absence of carbon deposits was confirmed with Von Kossa and Masson-Fontana stains. In conclusion, the membranes of PVA-CNTs and PVA-PPy are biocompatible and have electrical conductivity. The higher electrical conductivity measured in PVA-CNTs membrane might be responsible for the positive results on maturation of myelinated fibers. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1267-1280, 2017. PMID- 28078805 TI - Three-Dimensional MoS2 @CNT/RGO Network Composites for High-Performance Flexible Supercapacitors. AB - Two-dimensional atomically thick materials, reduced graphene oxide (RGO), and layered molybdenum disulfide (MoS2 ) have been investigated as potential novel energy storage materials because of their distinct physicochemical properties. These materials suffer, however, from rapid capacity decay and low rate capability. This study describes a facile, binder-free approach to fabricate large-scale, 3D network structured MoS2 @carbon nanotube (CNT)/RGO composites for application in flexible supercapacitor devices. The as-obtained composites possess a hierarchical porosity, and an interconnected framework. The electrochemical supercapacitive measurements of the MoS2 @CNT/RGO electrode show a high specific capacitance of 129 mF cm-2 at 0.1 mA cm-2 . The symmetric supercapacitor devices based on the as-obtained composites exhibit a long lifetime (94.7 % capacitance retention after 10 000 cycles), and a high electrochemical performance (29.7 mF cm-2 ). The present experimental findings will lead to scalable, binder-free synthesis of MoS2 @CNT/RGO hybrid electrodes, with enhanced, flexible, supercapacitive performance, in portable and wearable energy storage devices. PMID- 28078804 TI - A low-protein diet induces body weight loss and browning of subcutaneous white adipose tissue through enhanced expression of hepatic fibroblast growth factor 21 (FGF21). AB - SCOPE: Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic candidate for the treatment of obesity. Since FGF21 production is regulated by various nutritional factors, we analyze the impact of low protein intake on circulating levels of this growth hormone in mice and in a sub cohort of the PREDIMED (Prevencion con Dieta Mediterranea) trial. We also describe the role of hepatic FGF21 in metabolic adaptation to a low-protein diet (LPD). METHODS AND RESULTS: We fed control and liver-specific Fgf21 knockout (LFgf21KO) mice a LPD. This diet increased FGF21 production by inducing its overexpression in liver, and this correlated with a body weight decrease without changes in food intake. The LPD also caused FGF21-dependent browning in subcutaneous white adipose tissue (scWAT), as indicated by an increase in the expression of uncoupling protein 1 (UCP1). In a subgroup of 78 individuals from the PREDIMED trial, we observed an inverse correlation between protein intake and circulating FGF21 levels. CONCLUSION: Our results reinforce the involvement of FGF21 in coordinating energy homeostasis under a range of nutritional conditions. Moreover, here we describe an approach to increase the endogenous production of FGF21, which if demonstrated functional in humans, could generate a treatment for obesity. PMID- 28078806 TI - Prognostic factors of hepatocellular carcinoma patients with portal vein tumor thrombosis treated with transcatheter arterial chemoembolization. AB - AIM: To investigate the factors that influence survival of hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) following transarterial chemoembolization (TACE). METHODS: Retrospectively enrolled HCC patients with PVTT (n = 57). Patients received TACE, and the local tumor response was evaluated by modified response evaluation criteria in solid tumor (mRECIST). Overall survival and disease progression were evaluated using Kaplan-Meier survival curves. Prognostic factors were determined by multivariate Cox regression analysis. RESULTS: Following TACE, the median survival times was 8.3 months in HCC patients with PVTT. The median survival time was 3.1 months for patients with progressive disease following TACE and was 11.3 months for patients with complete response or partial response. The one-year rate of survival for patients with progressive disease was 5.0% and was lower than in patients with complete response or partial response (20.0%, P < 0.001). Multivariate analysis indicated that the presence of ascites, arteriovenous fistula and TACE response were significant factors for prognosis. The presence of early (<2 weeks) or late (>=2 weeks) PVTT was not a prognostic factor. CONCLUSION: Our study indicates that TACE is feasible and potentially efficacious in HCC patients with PVTT, and identifies factors that may predict the prognosis of these patients. PMID- 28078807 TI - Traumatized muscle-derived multipotent progenitor cells recruit endothelial cells through vascular endothelial growth factor-A action. AB - Traumatized muscle, such as that debrided from blast injury sites, is considered a promising and convenient tissue source for multipotent progenitor cells (MPCs), a population of adult mesenchymal stem cell (MSC)-like cells. The present study aimed to assess the regenerative therapeutic potential of human traumatized muscle-derived MPCs, e.g., for injury repair in the blast-traumatized extremity, by comparing their pro-angiogenic potential in vitro and capillary recruitment activity in vivo to those of MSCs isolated from human bone marrow, a widely-used tissue source. MPCs were tested for their direct and indirect effects on human microvascular endothelial cells (ECs) in vitro. The findings reported here showed that MPC-conditioned culture medium (MPC-CM), like MSC-CM, promoted EC-cord network branching. Silent (si)RNA-mediated silencing of vascular endothelial growth factor-A (VEGF-A) expression in MPCs attenuated this effect. In a chick embryonic chorioallantoic membrane in vivo angiogenesis assay, MPCs encapsulated in photocrosslinked gelatin scaffold recruited blood vessels more efficiently than either MSCs or human foreskin fibroblasts. Together, these findings support the potential application of traumatized muscle-derived MPCs in cell-based regenerative medicine therapies as a result of their influence on EC organization. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28078808 TI - Minimum sample sizes for population genomics: an empirical study from an Amazonian plant species. AB - High-throughput DNA sequencing facilitates the analysis of large portions of the genome in nonmodel organisms, ensuring high accuracy of population genetic parameters. However, empirical studies evaluating the appropriate sample size for these kinds of studies are still scarce. In this study, we use double-digest restriction-associated DNA sequencing (ddRADseq) to recover thousands of single nucleotide polymorphisms (SNPs) for two physically isolated populations of Amphirrhox longifolia (Violaceae), a nonmodel plant species for which no reference genome is available. We used resampling techniques to construct simulated populations with a random subset of individuals and SNPs to determine how many individuals and biallelic markers should be sampled for accurate estimates of intra- and interpopulation genetic diversity. We identified 3646 and 4900 polymorphic SNPs for the two populations of A. longifolia, respectively. Our simulations show that, overall, a sample size greater than eight individuals has little impact on estimates of genetic diversity within A. longifolia populations, when 1000 SNPs or higher are used. Our results also show that even at a very small sample size (i.e. two individuals), accurate estimates of FST can be obtained with a large number of SNPs (>=1500). These results highlight the potential of high-throughput genomic sequencing approaches to address questions related to evolutionary biology in nonmodel organisms. Furthermore, our findings also provide insights into the optimization of sampling strategies in the era of population genomics. PMID- 28078809 TI - Three-year analysis of repeated laboratory tests for the markers total cholesterol, ferritin, vitamin D, vitamin B12 , and folate, in a large research and teaching hospital in Italy. AB - RATIONALE, AIMS AND OBJECTIVES: The increasing number of diagnostic tests requests all over the world is a problem that can partially be explained by inappropriate testing. Impact on the total costs of health systems becomes relevant when tests are performed in a large amount. In this paper, retesting of total cholesterol, ferritin, vitamin B12 , vitamin D, and folate is assessed. METHODS: The Quality Unit of Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano (Fondazione) decided to perform a first assessment of the appropriate use of the laboratory tests cholesterol, ferritin, vitamin B12 , vitamin D, and folate focusing on the retesting interval for the same patient in the time period January 1, 2012, to December 31, 2014, in every care setting. The minimum retesting intervals were chosen following the ACB recommendations. The Fondazione is a research and teaching hospital with 3 emergency units (adult, pediatric, and obstetric), kidney, liver, lung, cornea, and bone marrow transplant centers and a medical school. Record linkage of laboratory records selected for the time interval January 1, 2012, to December 31, 2014, was applied using tax code. For each marker, the distribution of retesting intervals was evaluated for every year and the total period. With the same record linkage variable, requests on inpatients were identified from hospital discharge records. A cost analysis of inappropriate retesting was performed for every test. RESULTS: We examined 466 035 requests for 113 019 patients. Proportions of tests judged potentially inappropriate varied between 8.1% for 1,25-dihydroxy vitamin D and 37.1% for total cholesterol. The rates of inappropriate tests from year to year never showed significant decrease, and the maximum increase corresponded to an odds ratio of 1.85 (95% CI, 1.36-2.51) for 1,25-dihydroxy vitamin D from 2012 to 2013. Calculated loss of money was approximately ?500 000 in the 3 years. CONCLUSIONS: Inappropriate requests represent a waste of time and money resources. Our analysis highlighted economically unacceptable rates of inappropriate retesting, with no evidence of decreasing trend. Actions to raise awareness in clinicians or automated electronic solutions are necessary to limit unnecessary test repetitions. PMID- 28078810 TI - Anti-HCV Activity from Semi-purified Methanolic Root Extracts of Valeriana wallichii. AB - Hepatitis C virus (HCV) is a serious global health problem affecting approximately 130-150 million individuals. Presently available direct-acting anti HCV drugs have higher barriers to resistance and also improved success rate; however, cost concerns limit their utilization, especially in developing countries like India. Therefore, development of additional agents to combat HCV infection is needed. In the present study, we have evaluated anti-HCV potential of water, chloroform, and methanol extracts from roots of Valeriana wallichii, a traditional Indian medicinal plant. Huh-7.5 cells infected with J6/JFH chimeric HCV strain were treated with water, chloroform, and methanol extracts at different concentrations. Semi-quantitative reverse transcription polymerase chain reaction result demonstrated that methanolic extract showed reduction in HCV replication. The methanolic extract was fractionated by thin layer chromatography, and the purified fractions (F1, F2, F3, and F4) were checked for anti-HCV activity. Significant viral inhibition was noted only in F4 fraction. Further, intrinsic fluorescence assay of purified HCV RNA-dependent RNA polymerase NS5B in the presence of F4 resulted in sharp quenching of intrinsic fluorescence with increasing amount of plant extract. Our results indicated that methanolic extract of V. wallichii and its fraction (F4) inhibited HCV by binding with HCV NS5B protein. The findings would be further investigated to identify the active principle/lead molecule towards development of complementary and alternative therapeutics against HCV. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28078811 TI - The effects of nanomaterials on blood coagulation in hemostasis and thrombosis. AB - The blood coagulation balance in the organism is achieved by the interaction of the blood platelets (PLTs) with the plasma coagulation system (PCS) and the vascular endothelial cells. In healthy organism, these systems prevent thrombosis and, in events of vascular damage, enable blood clotting to stop bleeding. The dysregulation of hemostasis may cause serious thrombotic and/or hemorrhagic pathologies. Numerous engineered nanomaterials are being investigated for biomedical purposes and are unavoidably exposed to the blood. Also, nanomaterials may access vascular system after occupational, environmental, or other types of exposure. Thus, it is essential to evaluate the effects of engineered nanomaterials on hemostasis. This review focuses on investigations of nanomaterial interactions with the blood components involved in blood coagulation: the PCS and PLTs. Particular emphases include the pathophysiology of effects of nanomaterials on the PCS, including the kallikrein-kinin system, and on PLTs. Methods for investigating these interactions are briefly described, and a review of the most important studies on the interactions of nanomaterials with plasma coagulation and platelets is provided. WIREs Nanomed Nanobiotechnol 2017, 9:e1448. doi: 10.1002/wnan.1448 For further resources related to this article, please visit the WIREs website. PMID- 28078812 TI - Gentiana scabra Bunge. Formula for Herpes Zoster: Biological Actions of Key Herbs and Systematic Review of Efficacy and Safety. AB - This study reviewed the biological action of key herbs and evaluated systematically the efficacy and safety of oral Gentiana formula for herpes zoster (HZ). Experimental studies relevant to HZ were identified in PubMed. Randomized controlled trials using Gentiana formula for HZ were identified from nine English and Chinese databases. The primary outcome was evaluation of pain. Potential risk of bias was assessed. Meta-analysis was conducted using mean difference or risk ratio with 95% confidence intervals. Key herbs Gentiana scabra Bunge, Gentiana triflora Pall, Scutellaria baicalensis Georgi, and Gardenia jasminoides Ellis have shown antiinflammatory actions through inhibition of inflammatory cytokines and pro-inflammatory enzymes. Twenty-six clinical studies, involving 2955 participants, were included. Modified Gentiana formula resolved pain earlier than pharmacotherapy when used alone or combined with topical Chinese herbal medicine. Incidence of postherpetic neuralgia was lower (risk ratio 0.14, 95% confidence interval 0.03 to 0.74) with modified Gentiana formula plus topical Chinese herbal medicine. Mild adverse events were reported. Antiinflammatory actions of key herbs of Gentiana formula may explain clinical benefit in hastening pain relief and decreasing postherpetic neuralgia. Few adverse events were reported. Findings were limited by study quality and diversity in intervention and comparator dosage. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28078813 TI - Host defense peptide-derived privileged scaffolds for anti-infective drug discovery. AB - 'Privileged scaffolds' are molecular frameworks which have been successfully exploited for small molecule drug discovery. Peptide privileged scaffolds, featuring a strictly conserved multiple-disulfide framework and high variability in the rest of the sequence, display a broad range of biological effects, including antimicrobial and antiviral activity. Unlike small molecules, however, the cost of manufacturing these peptides is high, and their synthesis challenging. We previously described a simplified privileged scaffold corresponding to the gamma-core of human beta-defensin-3 (HBD3). The gamma-core is a common structural signature found in virtually all host defense peptides (HDPs) stabilized by multiple disulfides, and we showed that for HBD3, it represents the evolutionary starting point of the full-length molecule and, thus, is itself a primordial HDP. Accordingly, we showed that the peptide folded rapidly and was stable in human serum, and displayed many of the biological activities of HBD3. We report here that in addition to the previously reported antibacterial activity on planktonic bacteria, the gamma-core peptide is active against biofilm formation and maturation. We also show that it is readily cell penetrant, like HBD3, although with a different mechanism, which is independent from CD98. Overall, the potency of the single-disulfide, 23-amino acid gamma-core is comparable with the full-length peptide across the whole spectrum of examined properties, and the peptide is not toxic to human cells. The HBD3 gamma-core peptide may therefore represent the first example of an economically viable lead peptide derived from a HDP privileged scaffold. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd. PMID- 28078814 TI - Life threatening nutritional deficiencies in a dialysis patient. AB - Nutritional deficiencies are very common among the patient on chronic hemodialysis. But they can be easily overlooked or misdiagnosed. Deficiencies of trace elements and phosphorous is rare among this patient population but if neglected can lead to catastrophic effects. We describe a case report of a patient with ESRD recently started on outpatient maintenance hemodialysis, who presented with life threatening muscular weakness with respiratory failure requiring prolonged mechanical ventilation. On initial workup, it was unclear what the cause of her weakness was, however, further investigations showed undetectable phosphorous levels as well as very low levels of trace elements. Replacement of these compounds to normal levels led to marked improvement in the clinical picture. On further evaluation, the patient was also found to be profoundly depressed with poor appetite even prior to initiation of hemodialysis. This case report highlights the importance of early diagnosis of depression and malnutrition in patients on chronic hemodialysis, as severe depression can contribute to malnutrition and life threatening deficiencies of organic as well as inorganic compounds, which may cause life threatening complications as evidenced in this patient. PMID- 28078815 TI - Repeat measurements of uterine artery pulsatility index, mean arterial pressure and serum placental growth factor at 12, 22 and 32 weeks in prediction of pre eclampsia. AB - OBJECTIVE: To investigate the potential value of repeat measurements of uterine artery pulsatility index (UtA-PI), mean arterial pressure (MAP) and serum placental growth factor (PlGF) at 12, 22 and 32 weeks' gestation in the prediction of pre-eclampsia (PE) developing after 32 weeks. METHODS: Data were derived from prospective screening for adverse obstetric outcomes in women attending their routine hospital visit at 11-13, 19-24 and/or 30-34 weeks' gestation in two maternity hospitals in England. UtA-PI, MAP and PlGF were measured. Bayes' theorem was used to combine the a-priori risk from maternal factors with UtA-PI, MAP and PlGF multiples of the median values. The performance of screening for PE developing after the 30-34-week visit by UtA-PI, MAP and PlGF measured at 11-13, 19-24 and 30-34 weeks and their combinations was examined. RESULTS: Screening at 30-34 weeks by UtA-PI, MAP and PlGF detected, at a 10% false-positive rate, 79%, 86% and 92% of preterm PE and 42%, 50% and 56% of term PE. The addition of biomarker values at 11-13 and/or 19-24 weeks was not associated with any improvement in the detection rate of preterm PE; in the case of term PE, there was a marginal (< 2%) improvement in detection for UtA-PI and MAP and a modest improvement of about 5% for PlGF. CONCLUSION: Measurements of UtA-PI, MAP and PlGF in the first and/or second trimester have a small or no effect on improving the prediction of PE provided by screening in the early third trimester. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28078816 TI - Smoking and orthopaedic surgery: Does the evidence support rationing of care? PMID- 28078817 TI - Birth of puppies of predetermined sex after artificial insemination with a low number of sex-sorted, frozen-thawed spermatozoa in field conditions. AB - The aim of this study was to evaluate fertility and sex ratios after artificial insemination in dogs under field conditions. Semen was cryopreserved as unsorted (control) or was separated into X- and Y-chromosome-bearing sperm using a cell sorter. Sixty female dogs were inseminated with frozen-thawed spermatozoa of 100 * 106 unsorted (a dose in practice) and 4 * 106 sorted (X and Y group, respectively). A total of 20 dogs became pregnant and 126 puppies were born from the three groups. The percentage of parturition was similar for the X (5/20; 25.0%) and Y (4/20; 20.0%) group (P > 0.05), but lower than controls (11/20; 55.0%) (P < 0.05). Ultimately 28 out of the 32 puppies produced from X group were female (87.5%) and 19/22 (86.4%) puppies of Y group were male. In contrast, sex ratio (51.4% to 48.6%) in the control was significantly different from the X, Y group (P < 0.05). However, male and female puppies in the control had similar birth weights and weaning weights to those from the X and Y groups. This preliminary information indicated that normal puppies of predicted sex can be produced with low numbers of sorted cryopreserved dog spermatozoa at a farm level, making sperm-sexing technology potentially applicable for elite breeding units. PMID- 28078818 TI - Objectively diagnosing rumination syndrome in children using esophageal pH impedance and manometry. AB - BACKGROUND: Rumination syndrome is characterized by recurrent regurgitation of recently ingested food into the mouth. Differentiation with other diagnoses and gastroesophageal reflux disease (GERD) in particular, is difficult. Recently, objective pH-impedance (pH-MII) and manometry criteria were proposed for adults. The aim of this study was to determine diagnostic ambulatory pH-MII and manometry criteria for rumination syndrome in children. METHODS: Clinical data and 24-hour pH-MII and manometry recordings of children with a clinical suspicion of rumination syndrome were reviewed. Recordings were analyzed for retrograde bolus flow extending into the proximal esophagus. Peak gastric and intraesophageal pressures closely related to these events were recorded and checked for a pattern compatible with rumination. Events were classified into primary, secondary, and supragastric belch-associated rumination. KEY RESULTS: Twenty-five consecutive patients (11 males, median age 13.3 years [IQR 5.9-15.8]) were included; recordings of 18 patients were suitable for analysis. Rumination events were identified in 16/18 patients, with 50% of events occurring <30 minutes postprandially. Fifteen of 16 patients showed >=1 gastric pressure peak >30 mmHg, while only 50% of all events was characterized by peaks >30 mmHg and an additional 20% by peaks >25 mmHg. Four patients had evidence of acid GERD, all showing secondary rumination. CONCLUSIONS AND INFERENCES: Combined 24-hour pH-MII and manometry can be used to diagnose rumination syndrome in children and to distinguish it from GERD. Rumination patterns in children are similar compared with adults, albeit with lower gastric pressure increase. We propose a diagnostic cutoff for gastric pressure increase >25 mmHg associated with retrograde bolus flow into the proximal esophagus. PMID- 28078819 TI - Live donor liver transplantation for a child presented with severe hepatopulmonary syndrome and nodular liver lesions due to Abernethy malformation. AB - A 15-year-old boy first presented with severe lung lesions and hypoxia and he was considered as a lung transplant candidate. Upon evaluation, hepatopulmonary syndrome, multiple nodular liver lesions, and Abernethy type 1b malformation were diagnosed. The patient underwent successful right lobe live donor liver transplantation, and all of the symptoms disappeared soon after the transplant. He is currently alive and well with excellent liver and lung functions 4 years after surgery. PMID- 28078821 TI - Collateral fattening: When a deficit in lean body mass drives overeating. AB - In his last review entitled "Some Adventures in Body Composition," Gilbert Forbes reminded us that "lean body mass and body fat are in a sense companions." To what extent the lean body mass (or fat-free mass) component in this companionship impacts on energy intake is rarely a topic for discussion, amid a dominant adipocentric view of appetite control. Yet an analysis of the few human studies that have investigated the relationships between objectively measured food intake and body composition reveals a potentially important role for both an increase and a decrease in fat-free mass in the drive to eat. These studies are highlighted here, together with the implications of their findings for research directed as much toward the elucidation of peripheral signals and energy-sensing mechanisms that drive hunger and appetite, as toward understanding the mechanisms by which dieting and sedentariness predispose to fatness. PMID- 28078820 TI - Improvement of the in vivo cellular repopulation of decellularized cardiovascular tissues by a detergent-free, non-proteolytic, actin-disassembling regimen. AB - Low immunogenicity and high repopulation capacity are crucial determinants for the functional and structural performance of acellular cardiovascular implants. The present study evaluates a detergent-free, non-proteolytic, actin disassembling regimen (BIO) for decellularization of heart valve and vessel grafts, particularly focusing on their bio-functionality. Rat aortic conduits (rAoC; n = 89) and porcine aortic valve samples (n = 106) are decellularized using detergents (group DET) or the BIO regimen. BIO decellularization results in effective elimination of cellular proteins and significantly improves removal of DNA as compared with group DET, while the extracellular matrix (ECM) structure as well as mechanical properties are preserved. The architecture of rAoC in group BIO allows for improved bio-functionalization with fibronectin (FN) in a standardized rat implantation model: BIO treatment significantly increases speed and amount of autologous medial cellular repopulation in vivo (p < 0.001) and decreases the formation of hyperplastic intima (p < 0.001) as compared with FN coated DET-decellularized grafts. Moreover, there are no signs of infiltration with inflammatory cells. The present biological, detergent-free, non-proteolytic regimen balances effective decellularization and ECM preservation in cardiovascular grafts, and provides optimized bio-functionality. Additionally, this study implies that the actin-disassembling regimen may be a promising approach for bioengineering of acellular scaffolds from other muscular tissues, as for example myocardium or intestine. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28078822 TI - Development and testing of a grasper for NOTES powered by variable stiffness pneumatic actuation. AB - BACKGROUND: In natural orifice transluminal endoscopic surgery (NOTES) the peritoneal cavity is reached through natural orifices (mouth, rectus and transvaginal duct), by means of little cuttings in the walls of hollow organs. Due to narrow spaces, NOTES needs robotic systems to assure operation/movement precision and patient safety. Variable stiffness actuation (VSA) assures both requirements. METHODS: The authors developed a grasper for NOTES, provided with VSA, to use as an end-effector for snail robot devices. The present paper deals with basic concepts of VSA and describes the design and architecture of the grasper. Characterization and functional experiments were performed and results analysed. RESULTS: A finite element model developed for the actuator design was validated, performance grasper characteristic curves were obtained, VSA was validated, and the gripping capability of several objects was assessed. CONCLUSION: The grasper satisfies technical design specifications. On the basis of the results obtained, a control system can be developed to test grasper in a simulated surgery environment. PMID- 28078823 TI - Hippo vs. Crab: tissue-specific functions of the mammalian Hippo pathway. AB - The Hippo signaling pathway is a vital suppressor of tumorigenesis that is often inactivated in human cancers. In normal cells, the Hippo pathway is triggered by external forces such as cell crowding, or changes to the extracellular matrix or cell polarity. Once activated, Hippo signaling down-regulates transcription supported by the paralogous cofactors YAP1 and TAZ. The Hippo pathway's functions in normal and cancer biology have been dissected by studies of mutant mice with null or conditional tissue-specific mutations of Hippo signaling elements. In this review, we attempt to systematically summarize results that have been gleaned from detailed in vivo characterizations of these mutants. Our goal is to describe the physiological roles of Hippo signaling in several normal organ systems, as well as to emphasize how disruption of the Hippo pathway, and particularly hyperactivation of YAP1/TAZ, can be oncogenic. PMID- 28078824 TI - Corrigendum. PMID- 28078825 TI - Ethanol combined with heparin as a locking solution for the prevention of catheter related blood stream infections in hemodialysis patients: A prospective randomized study. AB - INTRODUCTION: Ethanol lock solution has been mainly administered in paediatric and home parenteral nutrition patients in order to prevent catheter related blood stream infections (CRBSI). Its utility in hemodialysis (HD) patients with non tunneled-uncuffed catheter (NTC) has been poorly explored. METHODS: We conducted a prospective randomized study in chronic HD patients requiring a newly inserted NTC-while awaiting for the maturation of an already established arteriovenous fistula (AVF) or arteriovenous graft (AVG) or tunneled-cuffed catheter insertion. Patients were randomized in two groups: Group A, where the lock solution was ethanol 70% + unfractionated heparin 2000 U/mL and group B, that received only unfractionated heparin 2000 U/mL. Primary end point was CRBSIs whereas exit site infections, thrombotic and bleeding episodes were the secondary end points. FINDINGS: One hundred three HD patients were enrolled in the study (group A, n = 52; group B, n = 51). The median number of catheter days was 32 for group A (range: 23-39) and 34 (range: 27-40) for group B with no statistically significant difference between the two groups. Group A (ethanol + heparin) demonstrated 4/52 episodes (7.69%) of CRBSI whereas Group B (heparin) 11/51 episodes (21.57%) (P = 0.04). CRBSI rates per 1000 catheter days were 2.53/1000 catheter days for group A and 6.7/1000 catheter days for group B (P = 0.04). Mean cumulative infection-free catheter survival in the ethanol group did not differ significantly compared to the heparin group (log-rank test = 2.99, P = 0.08). Thrombotic episodes did not differ between the two groups. DISCUSSION: Locking of NTCs in HD patients with ethanol 70% + unfractionated heparin reduces CRBSI rates without increasing the thrombotic episodes. PMID- 28078826 TI - The impact of pH inhomogeneities on CHO cell physiology and fed-batch process performance - two-compartment scale-down modelling and intracellular pH excursion. AB - Due to high mixing times and base addition from top of the vessel, pH inhomogeneities are most likely to occur during large-scale mammalian processes. The goal of this study was to set-up a scale-down model of a 10-12 m3 stirred tank bioreactor and to investigate the effect of pH perturbations on CHO cell physiology and process performance. Short-term changes in extracellular pH are hypothesized to affect intracellular pH and thus cell physiology. Therefore, batch fermentations, including pH shifts to 9.0 and 7.8, in regular one compartment systems are conducted. The short-term adaption of the cells intracellular pH are showed an immediate increase due to elevated extracellular pH. With this basis of fundamental knowledge, a two-compartment system is established which is capable of simulating defined pH inhomogeneities. In contrast to state-of-the-art literature, the scale-down model is included parameters (e.g. volume of the inhomogeneous zone) as they might occur during large-scale processes. pH inhomogeneity studies in the two-compartment system are performed with simulation of temporary pH zones of pH 9.0. The specific growth rate especially during the exponential growth phase is strongly affected resulting in a decreased maximum viable cell density and final product titer. The gathered results indicate that even short-term exposure of cells to elevated pH values during large-scale processes can affect cell physiology and overall process performance. In particular, it could be shown for the first time that pH perturbations, which might occur during the early process phase, have to be considered in scale-down models of mammalian processes. PMID- 28078827 TI - FAM83 family oncogenes are broadly involved in human cancers: an integrative multi-omics approach. AB - The development of novel targeted therapies for cancer treatment requires identification of reliable targets. FAM83 ('family with sequence similarity 83') family members A, B, and D were shown recently to have oncogenic potential. However, the overall oncogenic abilities of FAM83 family genes remain largely unknown. Here, we used a systematic and integrative genomics approach to investigate oncogenic properties of the entire FAM83 family members. We assessed transcriptional expression patterns of eight FAM83 family genes (FAM83A-H) across tumor types, the relationship between their expression and changes in DNA copy number, and the association with patient survival. By comparing the gene expression levels of FAM83 family members in cancers from 17 different tumor types with those in their corresponding normal tissues, we identified consistent upregulation of FAM83D and FAM83H across the majority of tumor types, which is largely driven by increased DNA copy number. Importantly, we found also that a higher expression level of a signature of FAM83 family members was associated with poor prognosis in a number of human cancers. In breast cancer, we found that alterations in FAM83 family genes correlated significantly with TP53 mutation, whereas significant, but inverse correlation was observed with PIK3CA and CDH1 (E cadherin) mutations. We also identified that expression levels of 55 proteins were significantly associated with alterations in FAM83 family genes including a decrease in GATA3, ESR1, and PGR proteins in tumors with alterations in FAM83. Our results provide strong evidence for a critical role of FAM83 family genes in tumor development, with possible relevance for therapeutic target development. PMID- 28078828 TI - Biomarkers upon discontinuation of renal replacement therapy predict 60-day survival and renal recovery in critically ill patients with acute kidney injury. AB - INTRODUCTION: There is no consensus on the specific indications for weaning critically ill patients with acute kidney injury (AKI) off renal replacement therapy (RRT). This study aimed to explore the prognostic value of several biomarkers measured upon discontinuation of RRT for their value in predicting 60 day survival and renal recovery in an effort to add knowledge to the decision making process regarding RRT withdrawal. METHODS: We prospectively enrolled 102 patients with AKI who required RRT from the intensive care unit. Serum osteopontin (sOPN), serum interleukin 6 (sIL-6), serum cystatin C (sCysC), sIL 18, serum neutrophil gelatinase-associated lipocalin and urinary IL-18 and urinary neutrophil gelatinase-associated lipocalin were measured upon discontinuation of RRT. Patients were followed up at 60 days for survival and renal recovery. FINDINGS: Patients who survived showed lower levels of all serum and urinary biomarkers. Serum OPN (OR 1.029, 95% CI 1.013-1.047, P = 0.001), diabetes (OR 23.157, 95% CI 4.507-118.981, P < 0.001) and APACHE II score (OR 1.308, 95% CI 1.121-1.527, P = 0.001) were independent predictors of 60-day mortality. Patients whose sOPN values fell within the highest and middle tertiles showed 5.25- and 2.31-fold increased risks of mortality, respectively, compared with that of patients in the lowest tertile. The addition of sOPN to the clinical model resulted in significant net reclassification improvement of 0.453 (P = 0.026) and an integrated discriminative index of 0.155 (P = 0.032). Lower levels of sOPN and sIL-6 were associated with greater odds of 60-day survival (AUC 0.812 and 0.741). The AUC value for predicting survival reached its highest level when all biomarkers were combined with urine output (UO) and urinary and serum creatinine upon discontinuation of RRT (0.882). Lower sCysC performed as well as higher UO in predicting 60-day renal recovery with the greatest AUC of 0.743. DISCUSSION: Upon discontinuation of RRT, serum and urinary biomarkers, particularly sOPN, may predict 60-day survival and renal recovery in critically ill patients with AKI. The serum levels of OPN, IL-6 and CysC may be useful when considering withdrawal of RRT on the basis of conventional indicators. PMID- 28078829 TI - Sensitivity to insulin and its kinetics. PMID- 28078830 TI - Why fat suits do not advance the scientific study of weight stigma. PMID- 28078831 TI - Perception on the abortion laws in Sri Lanka: A community based study in the city of Colombo AB - Introduction: Abortion is legally permitted in Sri Lanka, only if it is performed to save the mother's life. However, it is estimated that a large number of induced abortions take place in Sri Lanka. Knowledge and attitudes towards induced abortion in the society are key issues influencing the policy response towards changes in the law. This study aimed to assess the knowledge and attitudes of adults towards induced abortion in Sri Lanka. Methods: Six Grama Niladhari Divisions (GNDs) and five to eight housing clusters from each GND were selected from Thimbirigasyaya Divisional Secretariat Division using multi stage stratified random sampling. Fifty households were systematically selected from each GND. An interview was scheduled among 743 residents aged between 19 to 49 years of age after receiving written informed consent. Results: Only 11% of the respondents knew the situations in which abortion was legal in Sri Lanka. Approximately one tenth of the respondents (11%) did not agree with the current law which allows an induced abortion only to save the life of the mother. However, a majority agreed to legalization of abortion for rape (65%), incest (55%) and pregnancies with lethal fetal abnormalities (53%). Less than one tenth of respondents agreed with legalisation of induced abortion for other reasons such as con-traceptive failure (6%), poor economic conditions (7%) and, on request (4%). Conclusions: Although the society rejects abortion on request majority are in favour of allowing abortions for rape, incest and fetuses with lethal abnormalities. PMID- 28078832 TI - Pattern of clinical benign euthyroid goitre in a tertiary care center in the Central Province of Sri Lanka from 1981-2011 AB - Objectives: To describe the pattern of clinical euthyroidgoitre in a tertiary care unit in Sri Lanka before and after iodination of salt in Sri Lanka. Methods: We reviewed our thirty-one year computerised database of patients with goitres, spanning iodination in 1995. Results: Prevalence of euthyroid clinical simple diffuse goitre did not reduce during the first thirteen years (p=0.822). However, it reduced in the latter four years from 2008 to 2011. There is significant reduction of prevalence in the younger age groups (p<0.001). A significant reduction of nodular change was observed in all groups within seven years after iodination (p<0.001). Conclusions: There was a significant reduction in the prevalence of clinical nodularity in the post-iodination era in all age groups. Reduction in prevalence of clinical euthyroid simple diffuse goitre was observed only during the period 2008-2011. PMID- 28078833 TI - Clinical profile and outcome of patients with severe sepsis treated in an intensive care unit in India AB - Introduction: Sepsis is the leading cause of intensive care unit (ICU) admissions and is associated with high mortality. Objectives: To identify the incidence, risk factors and outcome of patients with severe sepsis and septic shock. Methods: A prospective observational study was done in a multidisciplinary ICU over a period of 18 months. We included all adult patients admitted to ICU with features of severe sepsis and septic shock as per SCCM/ACCP guidelines. Data related to demography, co-existing illnesses, parameters to assess Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores, other relevant laboratory data, source of infection, organ failures and supportive measures given were recorded. Primary outcome data on mortality was collected and secondary outcome data on ventilator days, ICU length of stay (ALOS) and ventilator free days were recorded. Results: A total of 1162 patients were screened and 356 patients had severe sepsis. Incidence of severe sepsis was 30.6% and mortality rate was 51.6%. APACHEII (23.37 +/- 9.47) and SOFA (7.58 +/- 4.05) scores at admission were high. Most common source of infection was from the respiratory tract (37.2%) followed by urinary tract (10.3%) and intra-abdominal (9.5%) infections. About 63% of patients required ventilator support, 25.5% of patients required vasopressor support despite adequate fluid resuscitation and one third of patients required renal replacement therapy (35.7%). Haematocrit, total leucocyte count, serum bilirubin and SOFA scores were significantly higher among non-survivors. Conclusions: Incidence of severe sepsis was high and was associated with a poor patient outcome in an ICU in India. PMID- 28078834 TI - Magnetic resonance imaging findings of patients with suspected tuberculosis from a tertiary care centre in Sri Lanka AB - Introduction: Spinal tuberculosis (TB) is a relatively common cause for spinal pathology in Sri Lanka and a common indication for magnetic resonance imaging (MRI). Objectives: The objective of the study was to describe the MRI imaging pattern of spinal TB in a series of patients. Methods: One hundred and nine patients with clinically confirmed spinal tuberculosis who had undergone MRI scans at the National Hospital of Sri Lanka from 2012-2016 were included in the study. Results: The commonest vertebral level of spinal TB involvement was at L4/5 level, followed by L5/S1 level. L5 vertebral body involvement was the commonest and L4 was second commonest. Single level involvement (68.8%) was commoner than multiple (31.2%) involvement or contiguous involvement. Wedging (24.8%), erosions (89%), end plate changes (96.3%), canal stenosis (77.1%), paravertebral collection (65.1%), prevertebral collection (39.4%), psoas abscess (23.9%) and epidural collection (45.9%) were noted. No significant difference was seen between females and males. Conclusions: Spinal tuberculosis commonly involves L4/5 level. PMID- 28078835 TI - Pathological characteristics of fifty patients with renal amyloidosis in Sri Lanka AB - Renal involvement is the most important cause of morbidity and mortality in systemic amyloidosis. This retrospective analysis was conducted to analyse the clinico-pathological characteristics of renal amyloidosis in a group of Sri Lankan patients undergoing renal biopsy. Renal amyloidosis was observed in 50/ 9712 (0.5%) renal biopsies. The underlying cause for amyloidosis was not known in most. Of the known causes multiple myeloma was the commonest. Nephrotic range proteinuria was the most common clinical outcome and most had grade I to III chronic kidney disease at the time of diagnosis. Glomerulosclerosis was associated with the deterioration of renal function. PMID- 28078836 TI - Duodenal xanthelasmata PMID- 28078837 TI - Endocarditis in melioidosis PMID- 28078838 TI - Dengue fever associated with extreme reactive thrombocytosis PMID- 28078839 TI - Widespread membrane potential changes and cardiorespiratory synchronization involved in anxiety and sleep-wake transitions. AB - Located within the ascending reticular activating system are nuclei which release neurotransmitters such as acetylcholine, serotonin, dopamine, and norepinephrine. These nuclei have widespread projections that extend into the limbic system and throughout cortex. Activation of these neurotransmitters during awake states leads to arousal, while inhibition leads to the loss of consciousness experienced during slow-wave sleep. Previously, we proposed a mechanism in which cardiorespiratory synchronization may underlie the widespread hyperpolarization that occurs throughout the brain during slow-wave sleep. We further propose that a similar homeostatic mechanism may be involved in sleep-wake transitions and maintaining various arousal states including rapid eye movement sleep, waking, and anxiety. Widespread depolarization associated with more rapid, shallow breathing and desynchronized cardiorespiratory oscillatory activity may underlie waking, anxiety, and rapid eye movement sleep states. The exact voltage values of these widespread membrane potential changes remain unknown and possibly highly variable between different neural areas and cell types. Here, we place these consciousness states on a spectrum of approximated widespread membrane potential values with anxiety states being the most depolarized, followed by waking states, and rapid eye movement sleep. We propose that although these widespread membrane potential changes are minor, they may underlie transitions between and maintenance of varying levels of arousal. Further research on these mechanisms could provide insights into how the brain functions. This homeodynamic arousal mechanism involves the established feed-forward and feedback signaling between the ascending reticular activating system and the hypothalamus, as well as the modulation by cardiorespiratory oscillatory feedback from the body. Understanding the basic mechanisms responsible for the states of sleep, waking, and anxiety could lead to better treatment options in health and disease. PMID- 28078840 TI - Mast cell and cancer with special emphasis on il-37 an anti-inflammatory and inhibitor of innate immunity: new frontiers. AB - Mast cells (MCs) are mediators of allergy and inflammation and participate in the growth of cancer cells. MCs can promote both neoangiogenesis and tumor growth. They increase in the stroma of certain tumors where they can be recruited by tumor-derived chemoattractants, such as monocyte chemotactic protein-1 (MCP-1), RANTES and stem cell factor (SCF) to selectively secrete inflammatory molecules including chemical mediators and cytokines (TNF, IL-6 and IL-1). However, MC differentiation pathways and heterogeneity in cancer are still poorly understood. Human interleukin 1 (IL-1) plays a pivotal role in the pathogenesis of many diseases and functions, including host response to microbial invasion, injury inflammatory processes, immunologic challenges and cancer. Inflammation around the tumor includes the infiltration of mast cells and facilitates cancer growth. MCs are activated by IL-1 which can be produced by certain cancer cells and stimulate the stromal cells to selectively release IL-6, contributing to the development of Th-17 cells and increasing inflammation. IL-37, mainly generated by macrophage cell line, is an IL-1 family member which binds IL-18 receptor alpha (IL-18Ralpha) chain, and acts as a natural inhibitor of immune responses. IL-37 down-regulates cJun induced by IL-1, pro-inflammatory signals and reduces the expression of the mitogen-activated protein kinase (MAPK) p38alpha, STAT transcription factors and p53, affecting cellular differentiation and proliferation. In the present study we report the relationship between inflammatory mast cells, cancer and the beneficial effect of IL-37. PMID- 28078841 TI - Differential expression and distribution of cytokeratins and vimentin in buccal pouch mucosal cells during real-time cell proliferation: research based on a porcine model. AB - In recent years, buccal pouch oral mucosa cells were used as a source of potential biological grafting material in advanced tissue engineering. However, there are several limitations in the process of graft fabrication: donor and recipient patient availability as well as an incomplete knowledge of in vitro procedures related to tissue surgical recovery, in vitro cell culture (IVC) and/or tissue processing in "human somatic cell therapy." Therefore, the animal model for oral mucosa grafting is still recognized as a source for xenografts and a useful model for biomedical research. In this study, the porcine buccal pouch oral mucosa cells were used in analysis of the stromalization/epithelialization process during short-term, in vitro real-time cell proliferation. We evaluated cytokeratin 18 (CK18), cytokeratin 8 + 18 + 19 (panCK), and vimentin (Vim) expression as epithelial and stromal cell markers, respectively. The porcine buccal pouch oral mucosa cells were cultured in vitro for 168 h, and the protein expression/ distribution was analyzed every 24 h during real-time cell proliferation. In our analysis of protein expression using fluorescence intensity (FI), followed by confocal microscopic observations, we found the highest expression of CK18 occurred after 24 h of IVC, panCK after 72 h, and Vim after 48 h of IVC, as compared to other cultivation periods. We also found a substantial increase in Vim expression (3-4 fold) as compared to CK18 and panCK, and all of the investigated proteins were distributed in the cellular cytoplasm. The lag phase of cell proliferation occurred during the first 24 h of IVC, whereas the log phase was observed between 24 h-120 h of IVC. Throughout 7 days of IVC, statistically significant differences were found in Cell Index (CI) of the analyzed cells. Increased Vim expression in buccal pouch oral mucosa cells, as compared to CK18 and panCK, suggested that the stromal cells substantially predominated during in vitro cell cultivation. This may be a result of significant specificity of porcine oral mucosa cells isolated from the buccal pouch. PMID- 28078842 TI - Remission effect of vitamin C on isoflurane-induced apoptosis and its mechanism. AB - This study aims to discuss the remission effect of vitamin C on isoflurane induced apoptosis of rats and its possible mechanism of action, to provide a theoretical basis for postoperative cognitive impairment. Reactive oxygen species (ROS) detection, adenosine triphosphate (ATP) test, MTT method and Morris water maze were applied for detection tests. For data statistics, double factor analysis of variance (ANOVA) and post hoc Bonferroni test were adopted. It was found that vitamin C could slow down the isoflurane-induced accumulation of ROS in H4-APP cells; moreover, it could relieve the activation of caspase-3 and increase cell survival rate to inhibit the occurrence of apoptosis, indicating that ROS was the source of cell toxicity. On the other hand, vitamin C could protect the cells with its antioxidant effect. It was proved that vitamin C could remit isoflurane-induced apoptosis and relieve the decline in learning and memory ability of rats. PMID- 28078843 TI - Association between expression of cumulus expansion markers and real-time proliferation of porcine follicular granulosa cells in a primary cell culture model. AB - Folliculogenesis is a compound process that involves both ovarian follicle growth and oocyte development, which is tightly attached to the follicular wall. During this process, cells that form the follicle structure undergo substantial morphological and molecular modifications that finally lead to differentiation and specialization of ovarian follicular cells. The differentiation of ovarian cells encompasses formation of follicle, which is composed of theca (TCs), mural granulosa (GCs), and cumulus cells (CCs). It was previously hypothesized that GCs and CCs represent undifferentiated and highly specialized follicular cells, respectively, which may have similar primordial cell origins. In this study, we investigated the expression pattern of cumulus expansion markers such as COX2, HAS2, PTX3, and TSG6 in porcine GCs during short-term, in vitro culture. We hypothesized that these genes may display an important function in GCs in relation to cellular real-time proliferation. The expression pattern of COX2, HAS2, PTX3, and TSG6 was evaluated after using RT-qPCR in relation to confocal microscopy observations of protein expression and distribution during real-time proliferation of porcine follicular GCs. The COX2 and HAS2 mRNAs were highly expressed after 120 h of in vitro culture (IVC), whereas PTX3 and TSG6 mRNAs were increased during the first 24-48 h of IVC (P less than 0.001, P less than 0.01). Conversely, all of the encoded proteins were highly expressed after 144-168 h of IVC as compared to other culture periods (P less than 0.001, P less than 0.01). When analyzing the realtime proliferation of GCs in vitro, we observed a logarithmic increase of cell proliferation between 0 h and 120 h of IVC. However, after 120-168 h of IVC, the cells reached the lag phase of proliferation. Since it is well accepted that porcine GCs undergo luteinization shortly after 24-48 h of IVC, the expression pattern of investigated genes indicated that Cox2 and Has2 are independent from the LH surge, but their increased levels may be upregulated by cell proliferation in vitro. Moreover, higher expression of PTX3 and TSG6 during first 24 h and/or 48 h of IVC suggested that their levels are accompanied by porcine GCs luteinization process. PMID- 28078844 TI - A natural formula containing lactoferrin, Equisetum arvensis, soy isoflavones and vitamin D3 modulates bone remodeling and inflammatory markers in young and aged rats. AB - A pivotal role in osteoporosis development is played by radical oxygen species (ROS), the increased production of which is related to inhibited osteoblastic activity and bone formation. A new field of research could involve medicinal plants with antioxidant and protective effects in osteoporosis. Furthermore, considering the multifactorial metabolic aspects of osteoporosis, the pharmacological association of multiple medicinal plants could improve patient response. The aim of the present study is to evaluate in vitro and in vivo the protective effects of a natural formula containing lactoferrin 12%, Equisetum arvensis ES 54%, soy isoflavones 34% and vitamin D3 0.002%, in PBMC and C2C12 cells and in the bone matrix of young (3-month-old) and aged (12-month-old) female Sprague-Dawley rats, following chronic (21 days) administration. In this context, we assayed the activities of several inflammation and bone homeostasis mediators, such as IL-6, TNFalpha, PGE2, osteoprotegerin, RANK, RANKL and NFkB. In vitro studies showed that natural formula (5-1000MUg/ml) was able to significantly inhibit ROS and PGE2 production. In the same concentration range, the natural formula inhibited both TNFalpha and IL-6 gene expression. In the in vivo studies, we administered to young and aged female rats the natural formula at 5mg/rat for 21 days, finding a significant reduction in inflammatory PGE2 and NFkB activity. Nevertheless, we observed a significant increase in osteoprotegerin/RANKL ratio only in aged rats, compared to the respective control group. In conclusion, our findings corroborate the rational use of natural formula in the prevention and management of osteoporotic disease. PMID- 28078845 TI - Effect of low energy light irradiation by light emitting diode on U937 cells. AB - Photobiomodulation (PBM) can induce a set of different biological modulators either in vitro or in vivo. Experimental evidence has highlighted the role of light effects on the mechanisms related to inflammation, apoptosis and autophagy. The goal of this project was the evaluation of PBM on U937, an established cell line of histiocytic lymphoma origin. Several aspects of modulation of proinflammatory pathways were analyzed and autophagic and proapoptotic mechanisms related to low laser light exposure of cells were studied. As a source of low energy light emission, we used an NIR-LED device, characterized by an 880 nm wavelength as light source. Flow cytometry analysis was performed on supernatants of controls and treated U937 cells to detect inflammatory cytokine levels. In order to evaluate NF-kB and caspase3 expressions, Western blot analysis was performed according to standard procedures. In this report, we show the effect of PBM on a monocyte/macrophage established tumor cell line (U-937). We demonstrate that LED exposure, in the presence or absence of lipopolysaccharide (LPS), activates cell degranulation, increased expression of Interleukin-8 (IL-8) and modulation of beta galactosidase activity. Evidence shows that the well-known pro inflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NF kB) and the apoptotic marker (caspase3/cleaved-caspase3 ratio) are up-regulated in response to a proinflammatory biochemical pathway. PMID- 28078846 TI - miR-2861 is involved in osteogenic commitment of human periodontal ligament stem cells grown onto 3D scaffold. AB - miR-2861 endorsing osteoblast differentiation through the overexpression of Runt related transcription factor 2 (RUNX2) protein has been recently described. In this study we evaluated: the performance of living construct, composed by human Periodontal Ligament Stem Cells (hPDLSCs) and 3D scaffold (EXg), and the behaviour of miR-2861/RUNX2 expression pathway on the osteogenic commitment. Human PDLSCs were seeded with and without EXg scaffold and cultured under basal and osteogenic conditions. Morphological features, adhesiveness and differentiation abilities were analysed using scanning electron and confocal laser scanning microscopy. Time-course of RUNX2, ALP, OPN and miR-2861 were evaluated through RT-PCR analysis. Our results highlighted that the osteogenic differentiation was mostly obvious in the hPDLSCs, grown onto 3D scaffold in presence of osteoinductive medium. Moreover, the overexpression of miR-2861 and RUNX2 in hPDLSCs cultured in presence of EXg under osteogenic and standard conditions was demonstrated. In synthesis, the increased expression of miR 2861/RUNX2 provides new insights regarding miRNA signaling network in the presence of scaffold providing an additional method to evaluate the performance of biomaterial in bone regeneration. PMID- 28078847 TI - Real-time shear wave elastrography and APRI index for evaluating autoimmune hepatitis fibrosis. AB - The objective of this study was to investigate the significance of real-time supersonic shear imaging (SSI) and serum biochemical index in evaluating the degree of autoimmune hepatitis fibrosis. Retrospective analysis was carried out to study 291 cases of patients with autoimmune hepatitis, and discuss the value of SSI application, APRI index and bilirubin on autoimmune hepatitis. The area under the receiver operating characteristic curve (AUROC) was taken for statistical analysis to determine its diagnostic accuracy. In the high degree of hepatic fibrosis, the hepatic SSI measured value of autoimmune hepatitis positively correlated to ALT, AST, APRI ratio, AST and AST/ALT. The SSI measured value significantly and positively correlated to the degree of hepatic fibrosis (r=0.598, p=0 less than 0.01). In chronic hepatic fibrosis, the elasticity values of AIH, PBC, AIH-PBC overlap syndrome (OS) were in a rising trend, and the difference in the elasticity value of each fibrosis stage was statistically significant (P less than 0.01). Hepatic SSI measured value was employed to respectively detect the AUROC of S3 stage and S4 stage for AIH, PBC, and AIR-PBC OS groups, which resulted as being higher than the APRI index detected in S3 stage and S4 stage. SSI measured index had better diagnostic significance than APRI index on hepatic fibrosis for AIH, PBC and AIH-PBC OS groups. PMID- 28078848 TI - Clinical effects of thermotherapy in combination with intracavitary infusion of traditional Chinese medicine in the treatment of malignant pleural effusion. AB - Malignant fluid, a commonly seen tumor associated complication, mainly includes peritoneal effusion, malignant pleural effusion and pericardial effusion. It can produce huge negative influence on the quality of life of patients and even lead to death. Treatment of malignant effusion is one of the effective measures for improving life expectancy of patients. To evaluate the effect of thermotherapy in combination with intracavitary infusion of Kangai injection in treating malignant pleural effusion, 195 patients who received treatment from April 2010 to October 2014 in the First Affiliated Hospital of Zhengzhou University were selected and divided into an observation group and two control groups (group A and B). The observation group was treated by thermotherapy in combination with intracavitary infusion of kangai injection. Control group A was treated by intracavitary infusion of kangai injection and control group B was treated by hyperthermal perfusion in combination with intracavity chemotherapy. Clinical effects, quality of life, treatment safety and untoward reactions were compared between the groups. It was found that differences of WBC, RBC and PLT levels before and after treatment had no statistical significance comparisons within group and comparisons between groups (P>0.05); hepatic and renal functions of the groups had no remarkable difference before or after treatment (P>0.05). The clinical effect of the observation group was superior to that of control groups A and B (P less than 0.05); the Karnofsky performance status (KPS) score of the observation group was much higher than that of control groups A and B (79.34+/-10.58 vs 71.11+/-9.64), but the difference of the ZPS score between groups had no statistical significance (P>0.05). It can be concluded that thermotherapy in combination with intracavitary infusion of traditional Chinese medicine can be safely applied as it has positive effects and remarkably improves quality of life, therefore it is clinically worth promoting. PMID- 28078849 TI - Effects of carbomer eye drops in combination with orthokeratology lens in treating adolescent myopia. AB - To investigate the effects of carbomer eye drops (CED) during long-time wearing of overnight orthokeratology lens of adolescents with myopia, 260 teenagers with myopia treated in the Henan Provincial People?s Hospital from June 2012 to August 2014 and followed-up for more than 2 years were enrolled. All the patients underwent regular fitting of orthokeratology lens. They were divided into a CED (Vidisic) group (130 cases, 260 eyes treated with CED) and rewetting drops (RD) (Baushe and Lomb) group (130 cases, 260 eyes treated with RD). The effects in the two groups were observed. The incidence of corneal epithelial defects one day, one week and one month after treatment of the CED group was lower than that of the RD group, and the difference was statistically significant (P less than 0.05); the tear break up time (TBUT) of the CED group was higher than that of the RD group at different time points, and the difference had statistical significance (P less than 0.05); the difference of the value of Schirmer I test between the two groups had no statistical significance (P>0.05). It is concluded that carbomer eye drops can stabilize tear film and protect and repair corneal epithelium during the wearing of orthokeratology lens. PMID- 28078850 TI - Acupuncture in endocrine disorders: a critical appraisal. AB - Acupuncture is an integral part of ancient Chinese medical practice. The technique has been used extensively in pain relief and is being tried for many other chronic conditions. Industrial development and affluence lead to the increase in the prevalence of many endocrine disorders such as diabetes, obesity, and polycystic ovarian disease. The rising prevalence of the endocrine morbidity is observed in both the developing and developed nations. The management of these disorders involves major lifestyle modification coupled with a long-term drug intake. In such situations, patients often look at alternative therapeutic options existing in complementary and alternative medicine. The globalization of the world medical practice has led to the spread of acupuncture beyond China to other parts of the world. Acupuncture has been tried extensively in the management of various endocrine disorders with inconsistent results. In this review, we highlight the principles of acupuncture and its role in the management of various endocrine disorders. PMID- 28078851 TI - Mechanism of serum miR-21 in the pathogenesis of familial and triple negative breast cancer. AB - The aim of this study was to clarify the mechanism of miR-21 in familial and triple-negative breast cancer (TNBC) by exploring the expression of serum miR-21. The sera were collected from healthy women at high risk of breast cancer. miR-39 was employed as the external reference, and real-time fluorescence quantitative PCR was used to detect the expression of serum miR-21 in 77 subjects. The miR-21 expression of the familial breast cancer group, TNBC group, and breast cancer high risk group were significantly higher than those in the normal control group and other breast cancer groups (P less than 0.01). A high serum miR-21 expression level was associated with lymph node metastasis and Ki67 expression (P less than 0.01). Serum miR-21 was closely associated with TNBC and familial breast cancer, and its expression was associated with genetic expression, degree of malignancy, and prognosis. PMID- 28078852 TI - Cell-based therapies for experimental diabetic nephropathy: a systematic review and meta-analysis. AB - Study has shown that stem cell?based therapies are promising strategies in the treatment of several chronic diseases, but their overall benefit in the treatment of diabetic nephropathy (DN) remains controversial. The purpose of this study is to summarize the evidence of the effect of cell-based therapy in the treatment of DN to guide future clinical trials. We searched PubMed, EmBase, and the Cochrane Library for studies from the inception of cell-based therapies up to July 2015. We included animal trials that reported the effects of cell-based therapy on kidney function, cardiovascular risk factors, and body factors. A random-effects model was used to process the data, and the standard mean difference (SMD) was used to evaluate the efficacy of cell-based therapy. We included eight studies that reported data on 159 mice. Overall, we noted that cell-based therapies were associated with significantly reduced plasma creatinine level (P = 0.003), glomerular filtration rate (P less than 0.001), plasma glucose level (P = 0.004), serum cholesterol level (P = 0.010), serum triglyceride level (P = 0.032), plasma urea level (P less than 0.001), proteinuria (P = 0.008), and Cl- fractional excretion (P = 0.023). Furthermore, cell-based therapies were associated with lower kidney weight (P = 0.003), and kidney/body weight (P = 0.004). A sensitivity analysis suggested that cell-based therapy might play an important role in increased body weight. In conclusion, cell-based therapies significantly improve kidney function, cardiovascular risk factors, and body factors in the treatment of DN. PMID- 28078853 TI - Oxidative stress in asthma: a distinct clinical and pathologic feature? AB - Asthma is a type of chronic airway inflammation. Corticosteroids are inadequate for asthma therapy. However, it remains unclear whether oxidative stress is a distinct clinical and pathologic feature in asthma. We reviewed the articles on asthma-associated oxidative stress. The exposures to airborne allergens, such as house dust mite (HDM) and birch pollen, may not only trigger innate and adaptive immune responses but also cause oxidative stress damage in the airways. Allergen induced reactive oxygen species (ROS) is involved in p38 MAPK, phosphoinositide-3 kinase (PI3K)/Akt and nuclear factor erythroid 2-related factor (Nrf2) kinase pathway signaling. Airborne particulate matter (PM) is an important environmental contaminant and is related to asthma development through increasing oxidative stress in the airways. Whether oxidative stress status is associated with the degree of asthma is needed to be further studied. Oxidative stress-induced corticosteroid insensitivity was associated with p38 MAPK, PI3K/Akt and Nrf2 signaling, and inhibited histone deacetylase 2 (HDAC2) activity and corticosteroid receptor (GR) function. Antioxidant treatments may be useful for oxidative stress in asthma. PMID- 28078854 TI - Changes of expression of estrogen and progestrone receptors, human epithelial growth factor receptor 2 and Ki-67 after neoadjuvant chemotherapy in the treatment of breast cancer. AB - Recent studies suggest that the development and prognosis of breast cancer is in close correlation to molecular subtype of breast cancer. Neoadjuvant chemotherapy has been extensively applied in the treatment of local breast cancer in advanced stage. In order to verify the correlation between expression changes of estrogen receptor, progestrone receptor, human epithelial growth factor receptor 2 and Ki 67 after neoadjuvant chemotherapy and neoadjuvant chemotherapy, we studied 120 patients with stage IIAIIIC breast cancer who underwent neoadjuvant chemotherapy in Binzhou Medical University Hospital, Shandong, China from February 2011 to February 2015. Clinical characteristics were retrospectively analyzed. The expression of estrogen receptor, progesterone receptor, human epithelial growth factor receptor 2 and Ki-67 of patients were detected using the immunohistochemical method before and after neoadjuvant chemotherapy. The results suggest that the overall remission rate of neoadjuvant chemotherapy was 76.7% (92/120) of which 16.7% (20/120) of cases had complete remission, 60% (72/120) had partial remission and 23.3% (28/120) were stable. There were no cases of progressive disease. The property of estrogen receptor and the expression of Ki 67 of primary tumor were correlated to the remission rate of neoadjuvant chemotherapy (P less than 0.05). The expression of Ki-67 had a significant decline after neoadjuvant chemotherapy, and the difference had statistical significance (P less than 0.05). The difference in expression of estrogen receptor, progesterone receptor and human epithelial growth factor receptor 2 before and after neoadjuvant chemotherapy had statistical significance (P > 0.05). Hence, it can be concluded that breast cancer patients with negative estrogen receptor expression and high Ki-67 expression before neoadjuvant chemotherapy can achieve better curative effects. Neoadjuvant chemotherapy cannot change the expression states of estrogen receptor, progesterone receptor and human epithelial growth factor receptor 2, but it can lower the expression level of Ki-67. Ki-67 can also be used for predicting the curative effect of neoadjuvant chemotherapy. PMID- 28078855 TI - The impact of electromagnetic field at a frequency of 50 Hz and a magnetic induction of 2.5 mT on viability of pineal cells in vitro. AB - The impact of electromagnetic fields (EMF) on the pineal gland has been described in numerous studies, but many questions still remain unanswered. The aim of the experiment described in this study was to evaluate the effect of EMF on the viability of the pineal gland cells of pig in vitro. Primary culture of the pineal gland cells has been exposed to the influence of an EMF at a frequency of 50 Hz with 1, 2 or 3 hours and for 3 hours every 2 or 3 days. After the experiment, viability of cells was assessed by MTT assay and compared to a control culture not exposed to electromagnetic fields. We noticed that in respect to the control, exposure of the cells to the EMF induced a significant increase in viability of cells at 2 and 3 hours of exposure. After three days of 3-hour exposure to EMF, we observed a significant decrease in cell viability in relation to the control. The results of these studies suggest that EMF can have a significant biological effect on the cells of the pineal gland in a time dependent exposure to its action. PMID- 28078856 TI - Decreased immunoreactivity of visfatin in the pancreas and liver of rats with renovascular hypertension. AB - Hypertension is one of the major endocrine and metabolic disorders, in which visfatin plays a significant role. The objective of this study was to evaluate the immunoreactivity of visfatin in pancreas and liver of ?two kidney, one clip? (2K1C) renovascular hypertension model in rats. The studies were carried out on the pancreas and liver of rats. After a 6-week period of the renal artery clipping procedure, 2K1C rats developed a stable hypertension. Paraffin sections were stained with hematoxylin and eosin (for general histological examination) and processed for immunolocalization of visfatin. The intensity of immunohistochemical reaction was measured using Nikon NIS-Elements Advanced Research software. The hypertension significantly weakened the immunohistochemical reaction exhibiting visfatin in the pancreas and liver of hypertensive rats, compared to control animals. The changes induced by hypertension in the visfatin-containing cells in the pancreas and liver of the rats are discussed and needs further study. PMID- 28078857 TI - Effects of sevoflurane on cardiopulmonary function in patients undergoing coronary artery bypass. AB - The objective of the current study was to investigate effects of sevoflurane on cardiopulmonary function in patients undergoing coronary artery bypass grafting (CABG). In this study, 60 cases of patients with coronary heart disease (CHD) were selected and randomly divided into the sevoflurane group (group S) and the control group C (group C) with 30 cases in each group. The two groups received intravenous anesthesia. The patients of group C were only given oxygen mask and physiological saline to keep vein open; while the patients of group S were administered with 1% sevoflurane immediately after the beginning of cardiopulmonary bypass (CPB) until the end of the treatment. The cardiopulmonary functions at 30 min before operation (T0), postoperative 2 h (T1), 6h (T2), 24h (T3) and 48 (T4) were observed. The mean arterial pressure (MAP) of the group S at T1, T2, T3 was lower than that of the group C, as were the heart rate (HR) and left ventricular ejection fraction (LVEF). The creatine kinase isoenzyme (CK-MB) during T1 to T4 in the group S was less than that of the group C, and there were significant differences between the two groups (P less than 0.05). The tidal volume (Vt), vital capacity (Vc) and oxygenation index (PaO2/FiO2) of the two groups during T1 and T2 were decreased, while respiratory frequency (RR) and alveolar-arterial blood oxygen partial pressure (PA-aO2) were increased and they began to decrease during T3 and T4. Vt and Vc of the group S were higher during T1 and T2 periods than those of the group C, while RR was lower than that of the group C; PaO2 / FiO2 during T1 to T4 period of group S was higher than that of group C, while PA-aO2 was significantly lower than that of the control group (P less than 0.05). In conclusion, although LVEF was not improved in the sevoflurane group, sevoflurane may contribute to stabilizing the cardiopulmonary function and preventing from myocardial injury. PMID- 28078858 TI - Use of Lactated Ringer?s solution does not eliminate the risk of strong ion difference-related metabolic acidosis following on-pump cardiac surgery. AB - There is a growing interest in the effects of plasma sodium levels on postoperative outcomes. A trend of using balanced crystalloid solutions is based on the extensive data on chloride and the strong ion difference-related acidosis. However, effects of sodium are often overlooked in this context. The aim of the study was to establish the effects of the routine use of Lactated Ringer?s Solution (RL) on postoperative changes in sodium concentrations and whether these changes result in metabolic acidosis. We performed database analysis of 358 consecutive elective on-pump cardiac surgery cases in a tertiary referral university hospital. Approval from the institutional ethics committee was obtained for this study. Intraoperative fluid balance was 2726+/-1073 ml and the total volume of intravenous infusions in the first 24 hours was 5865 (+/-1073) ml, 95% of which was RL; 58% of the patients had metabolic acidosis with a base excess below (?)2 mmol L?1 on arrival at the intensive care unit. There was a significant correlation between a strong ion difference and base excess (p less than 0.01). A significant improvement in metabolic acidosis was noted within the first 24 hours, from a base excess of (?)2.49+/-2.8 to 0.32+/-2.6 mmol L?1 (p less than 0.001). All of the improvement in the base excess is explained by a change in the strong ion difference from the mean value of 31+/-4.3 to 34.2+/-3.6 mmol L?1 (p less than 0.001). Changes in the strong ion difference were primarily driven by changes in the serum sodium concentration, which were three-fold higher compared to those of chloride [?2.36 (+/-2.6) mmol L?1 (p less than 0.001) and 0.84 (+/-3.2) mmol L?1, respectively (p = 0.01)]. In conclusion, our data confirm that there is a direct correlation between a strong ion difference and base excess following on-pump cardiac surgery. The use of RL prevented significant hyperchloraemia, but did not eliminate the risk of strong ion difference-related metabolic acidosis. The change in the strong ion difference was primarily linked to perioperative changes in the serum sodium concentration. PMID- 28078859 TI - Role of vitacamphore in improving central pro-inflammatory cytokines following transient global ischemia. AB - Pro-inflammatory cytokines (PICs) including interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are responsive to ischemic stress. This process thereby modulates the responsiveness of many cell types under diseased conditions. The current study was to examine the role played by vitacamphore (VCP) in regulating the levels of PICs and protein expression of PIC receptors in the cerebral cortex and hippocampus of rats after cardiac arrest (CA)-induced transient global ischemia. CA was induced by asphyxia followed by cardiopulmonary resuscitation (CPR) in rats. ELISA and Western blot analyses were employed to determine PICs and their receptors in the cortex and hippocampus. Our results show that IL-1beta, IL-6 and TNF-alpha were significantly elevated in the cortex and hippocampus after CA. This was accompanied with increasing of PIC receptors, namely IL-1R, IL-6R and TNFR1. Systemic injection of VCP attenuated amplification of PIC signal pathway in these brain regions. VCP also improved Neurological Severity Score and brain tissue edema in CA rats. Notably, VCP resulted in a significant increase in survival of CA rats as compared with controls. In conclusion, VCP is likely to play a beneficial role in modulating transient global ischemia induced by CA via PIC signal mechanisms. PMID- 28078860 TI - Effects of two different anesthetic methods on cellular immunity of patients after liver cancer resection. AB - This study aims to investigate the effects of epidural block in combination with general anesthesia and general anesthesia alone on the immune function of patients undergoing primary liver cancer resection. Twenty-four patients with liver cancer who received treatment in the Third Hospital of Harbin Medical University, Heilongjiang, China, were enrolled and randomly allocated into group A and group B, with 12 in each group. The data on the T lymphocyte subpopulation, pro-inflammatory cytokines and antiinflammatory cytokines were recorded before, immediately after and 24 h after liver cancer resection to compare differences and changes. It was found that CD4+ of patients who underwent combined anesthesia decreased after surgery and CD8+ of those patients was lower than that of the general anesthesia group. The content of interleukin (IL)-10 of patients who underwent general anesthesia combined with epidural block showed a decreasing tendency immediately after surgery, but increased 24 h after surgery, and the increase was greater than that of the general anesthesia group; furthermore, those patients had lower levels of IL-1beta and interferon (IFN)-gamma. In addition, patients who underwent epidural block and general anesthesia had a higher ratio of IFN-gamma to IL-4 (Th1/Th2). These findings suggest that general anesthesia combined with epidural block has little passive influence on the cellular immunity of the body and can be selected as an anesthetic approach for patients with liver cancer. PMID- 28078861 TI - Interleukin-6 and interleukin-8 in diagnosing neonatal septicemia. AB - Neonatal septicemia (NS) is a common cause of death of newborn infants, hence early diagnosis and treatment are of the utmost importance. However, lack of specific clinical symptoms and late detection delay a correct diagnosis. It is therefore of great importance to establish auxiliary indexes for the early diagnosis of NS. To evaluate the value of interleukin (IL-6 and IL-8) in the diagnosis of NS, a prospective study was carried out. Seventy-five newborns who developed septicemia and received treatment in our hospital from January 2013 to December 2014 were selected as research subjects; also, 50 healthy newborns were set as a control group. The levels of serum IL-6 and IL-8 were compared between the two groups. Results demonstrated that levels of C-reactive protein (CRP), IL 6 and IL-8 of the septicemia group were higher than those of the control group on admission, although the difference had no statistical significance (P less than 0.05); the septicemia group had higher sequential organ failure assessment (SOFA) scores but lower pediatric critical illness scores (PCIS) compared to the control group (P less than 0.05); levels of CRP, IL-6 and IL-8 were in positive correlation to the SOFA scores and in negative correlation to PCIS. Analysis of receiver operating characteristics (ROC) curve demonstrated that the sensitivity, specificity and accuracy were 85.7%, 80.2% and 81.8%, respectively, when IL-6 level was set as 32 pg/mL, 78.1%, 64.2% and 66.9%, respectively when IL-8 level was set as 54 pg/mL, and 71.4%, 86.3% and 82.7% respectively, when detection of IL-6 and IL-8 were combined together. Hence it can be concluded that: IL-6 and IL 8 are involved in inflammatory reactions; levels of IL-6 and IL-8 were correlated to the severity of the infection; the value of IL-6 is higher than that of IL-8 in the diagnosis of neonatal septicemia and the combined detection of IL-6 and IL 8 can improve the accuracy of the diagnosis of neonatal septicemia. PMID- 28078862 TI - A placebo-controlled trial of a proprietary lipid-lowering nutraceutical supplement in the management of dyslipidemia. AB - There is an ever growing emergence in the popularity of patient-driven care. As this health and wellness model grows, inquiries into diet, lifestyle, and supplemental approaches will continue to become a focal point for the healthcare consumer. Because of this, the aim of this study is to determine the tolerability, and overall effectiveness of a proprietary multi-ingredient lipid lowering supplement in subjects with dyslipidemia. Forty participants were recruited for a single-center, double-blind randomized, placebocontrolled trial. Study participants were recruited between December 2014 and March 2015. Initial screening included a physical examination, renal and hepatic function, serum lipid, serum electrolytes, complete blood counts, and urine analysis. The 40 participants were randomly assigned to receive either the proprietary multi ingredient lipid-lowering supplement (PMILLS) n= 20 or placebo n= 20. The trial consisted of a screening visit, a two-week run-in, and a four-month treatment period. Samples were taken at baseline, one month and four months of treatment. Results from the trial showed that the PMILLS significantly reduced total cholesterol (TC), low density lipoprotein (LDL-C), very low density lipoprotein (VLDL-C), oxidized LDL (oxLDL), Apo-lipoprotein B, triglycerides (TG), LDL particle number (LDL-P), heart rate, and diastolic blood pressure compared to placebo at one month and four months. The PMILLS significantly increased high density lipoprotein (HDL) particle number (HDL-P), and low density lipoprotein (LDL) particle size from dense type III and IV to larger type I and II LDL particle, compared to placebo at one month and four months. In addition, the PMILLS significantly reduced high sensitivity C-reactive protein (hs-CRP), tumor necrosis alpha (TNF-alpha), and interleukin 6 (IL-6) within the treatment group from baseline. There were no adverse effects noted in the treatment group after four months of supplementation. The present study demonstrates this PMILLS improves all relevant lipid parameters, such as particle numbers and particles sizes, as well as showing a significant reduction in inflammatory markers linked to cardiovascular health. With such combined changes in lipids, lipid sub fractions, and inflammation, which are considered among the most effective means of reducing coronary heart disease (CHD), this PMILLS represents a new addition to safe and effective lipid-modifying strategies. PMID- 28078863 TI - Nasal irrigation with Nasir(r) in children: a preliminary experience on nasal cytology. AB - Allergic rhinitis (AR) and upper airway respiratory infections are frequent in children, and both have a relevant impact on some social aspects, including school attendance and performance, sleep, quality of life (also of the parents), and costs. Saline nasal irrigation is widely employed to reduce nasal congestion and mucopurulent secretion, to stimulate cleansing of the nasal and paranasal cavities, and to induce restoration of mucociliary clearance. The present study evaluated the effects of nasal irrigation on nasal cytology, using the new device Nasir(r) in 66 children (40 males, 26 females, mean age 7.31+/-1.7 years, age range 4-17 years) with allergic rhinitis. The patients were treated with nasal irrigation with warm (36 degrees C) Nasir(r) (250 mL sacs of premixed solution): one sac twice daily for 12 days. Nasal irrigation significantly reduced the neutrophilic infiltrate (baseline median value 2.8+/-0.7; post treatment value 2+/-0.5; p less than 0.05). In addition, there was a reduction of eosinophil infiltrate (T0= 3.2+/-1.1; T1= 2.6+/-1.2; p= less than 0.05). There was no significant change with regard to bacteria (T0= 2.7+/-0.9; T1= 2.3+/-1.02; p= 0.17). In conclusion, this pilot study reports that nasal irrigation with Nasir(r) might be useful to attenuate upper airway inflammation. PMID- 28078864 TI - Human herpesviruses-6 and -7 encephalitis in immunocompetent infants: are they really so uncommon? AB - Human herpesviruses-6 and -7 (HHV-6 and 7) are considered uncommon causes of central nervous system infection and may occasionally cause encephalitis in young infants, however, the clinical syndrome and incidence are not well defined. In immunosuppressed hosts, reactivation is associated with a worse outcome such as encephalitis, hepatitis, or graft rejection. In immunocompetent hosts, this persistent infection is generally of no consequence. We report 4 cases of immunocompetent critically ill children, affected by HHV-6 and -7 encephalitis, admitted to our Pediatric Intensive Care Unit. In three patients, herpesvirus polymerase chain reaction in blood and cerebrospinal fluid was positive for HHV- 6, while one patient was positive for HHV-7. In our cases, a typical clinical picture of viral infection was not present but neurological symptoms were predominant. In all 4 children, neurological involvement rapidly regressed after acyclovir therapy. In this report, we offer evidence that HHV-6 and -7 primary infections can cause several clinical manifestations, such as encephalitis, also in immunocompetent hosts. In our experience, children with neurological symptoms suggestive of viral encephalitis should be fully investigated for these two viruses. PMID- 28078865 TI - Parasympathetic nervous system involvement in food allergy: description of a paediatric case. AB - The latest research data emphasize the interaction between the nervous and the immune systems. It has been demonstrated that the central nervous system (CNS) can be involved secondarily due to blood brain barrier (BBB) disruption via pro inflammatory cytokines released in allergy. More recently it was demonstrated that the parasympathetic nervous system (PNS) could also be equally involved in models of peripheral inflammation such as food allergy; although this last clinical presentation has rarely been described. Herein, the authors report the case of a five-year-old Caucasian female who was admitted to our Pediatric Acute and Emergency Operative Unit for cyclic vomiting. Her vomiting, which was preceded by objective torque vertigo, headache and weakness, had been recurring with constant frequency every two months since she was 3 years old. After a complex diagnostic flow-chart, it was found that this spectrum of neurologic symptoms was due to a food allergy syndrome, which postulates some etiopathogenic hypotheses to explain the relationship between the two mentioned diseases. PMID- 28078866 TI - Favourably effective formulation of sodium iodide and salicylic acid plus professional hygiene in patients affected by desquamative gingivitis. AB - The aim of this prospective pilot study was to evaluate the efficiency of an oral hygiene protocol, in combination with a solution of sodium iodide associated to salicylic acid (SISA), in patients affected by desquamative gingivitis (DG). Twenty patients not totally responding to conventional topical therapies, were selected. They received oral hygiene instructions with non-surgical periodontal therapy in a 21-day cohort study (during 3 weekly appointments). The SISA was used at the end of each session, with an impregnated gauze (with 5 ml of the solution) applied for 15 minutes for the upper jaw, and for a further 15 minutes with a new gauze for the lower. Evaluated clinical outcome variables included the full mouth plaque (FMPS) and bleeding (FMBS) scores, probing depth, patient related outcome and clinical gingival signs. Two months after concluding the planned protocol, a statistically significant reduction was observed for FMPS (P=0.032), FMBS (P=0.038), reported pain (P=0.000) and gingival clinical improvement (P=0.005). Topical application of SISA and professional oral hygiene procedures are connected with improvement of gum status, and decrease of related pain in subjects affected by severe DG. PMID- 28078867 TI - Plasma endocannabinoid behaviour in total knee and hip arthroplasty. AB - Endocannabinoids are a class of lipid mediators involved in a wide range of physiological pathways including pain perception, and immunological defences. In particular, the involvement of endocannabinoids in bone metabolism and bone resorption has recently been studied. Moreover, one study on total knee arthroplasty describes the probable role of endocannabinoids in pain perception after surgery. The aim of the present study was to evaluate variations of endocannabinoid concentrations in patients undergoing total hip or total knee arthroplasty before and after surgery. Sera from 23 patients were collected at three different times: before surgery and at two different times during rehabilitation, and endocannabinoids were quantified by HPLC-MS/MS analysis. Mean values of endocannabinoids in presurgical serum samples were: 6.11+/-0.5 ng/ml for N-palmitoylethanolamide, 1.39+/-0.08ng/ml for N-stearoylethanolamide, 4.84+/ 0.04 ng/ml for N-oleoylethanolamide, 0.44+/-0.03ng/ml for N arachidonoylethanolamide, 0.84+/-0.05ng/ml for N-linoleoylethanolamide, 0.17+/ 0.01ng/ml for N-alpha-linolenoylethanolamide. Statistical analysis showed a significant decrease of all the endocannabinoids after surgery, while there were no remarkable differences between total hip and total knee arthroplasties or between genders. Moreover, the results show no significant correlation between endocannabinoid concentrations and C-reactive protein and Erythrocyte sedimentation rate. The present study shows for the first time a specific and univocal behaviour of six endocannabinoids and N-acylethanolamides in orthopaedic surgery, suggesting the endocannabinoid system as a possible pharmacological target for presurgical therapeutics. PMID- 28078868 TI - Minoxidil dose response study in female pattern hair loss patients determined to be non-responders to 5% topical minoxidil. AB - Topical minoxidil is the only US FDA approved drug for the treatment of female pattern hair loss (FPHL). 5% minoxidil foam is only effective at re-growing hair in a minority of women (approximately 40%). Thus, the majority of FPHL patients remain untreated. Previously, we demonstrated that nonresponders to 5% minoxidil have low metabolism of minoxidil in hair follicles. As such, we hypothesized that increasing the dosage of topical minoxidil to low metabolizers would increase the number of responders without increasing the incidence of adverse events. In this study, we recruited FPHL subjects that were identified as non-responders to 5% topical minoxidil utilizing the previously validated assay for minoxidil response. Subjects were treated for 12 weeks with a novel 15% topical minoxidil solution. At 12 weeks, 60% of subjects achieved a clinically significant response based on target area hair counts (>13.7% from baseline), as well as significant improvement in global photographic assessment. None of the subjects experienced significant hemodynamic changes or any other adverse events. To the best of our knowledge, this is the first study to demonstrate the potentially beneficial effect of a higher dosage of minoxidil in FPHL subjects who fail to respond to 5% minoxidil. PMID- 28078869 TI - High level laser therapy for the treatment of lower back pain: clinical efficacy and comparison of different wavelengths. AB - High energy laser therapy (HELT) could be a new alternative treatment for lower back pain (LBP), which is a significant public health problem. Nevertheless, differences between the various light waves of HELT have not yet been fully researched. Sixty-six patients with lower back pain were treated using a high energy laser therapy. They were randomized into three different protocols which differed according to wave length (650 nm, 810 nm and TRIAX, which is simultaneous emission of 810 nm, 980 nm e 1064 nm). The other parameters remained constant (5 W and 50 J/cm2 for ten daily sessions). The visual analogue scale (VAS), the Roland Scale, and the Oswestry Score were measured before treatment (T0), and at end of the treatment session (T1) and 1 month (T1), 2 months (T2) and 4 months of follow-up (T4). In each group we verified a statistically significant improvement over time and that there was a relationship between the time and treatment (p less than 0.01). At T1 for all wavelengths we found a statistically significant improvement of three scores (p less than 0.01), which was maintained up to T4. The group treated with 810 nm HELT, showed a better remission of pain on the VAS scale, and disability on the Oswestry Scale at T4 (p=0.01). Comparing T0-T1 the variation in the Roland Score was significant in the patients treated with 810 nm (p less than 0.01). All the wavelengths analyzed proved to be efficacious for LBP. The greater efficacy of 810 nm in promoting nerve regeneration and in modulating the nociception transmission could explain the better outcomes. PMID- 28078870 TI - Assessing the association between 25-OH vitamin D levels and ROMA score in a population of obese women. AB - The ?Risk of Malignancy Algorithm? (ROMA) combines the diagnostic power of the CA125 and HE4 markers with menopausal status to predict the risk for developing epithelial ovarian cancer (EOC). The aim of this study was to evaluate the association between 25-OH vitamin D levels and ROMA score in obese women. One hundred and eighteen patients with a Body Mass Index (BMI) > 30 kg/m2 (Group 1) and 80 women with a BMI less than 25 kg / m2 (Group 2) were studied. The 25-OH vitamin D was quantified with LUMIPULSE(r) G 1200. As a threshold value, identified by ROC curve analysis, 20.2 ng/ mL (sensitivity 73.3%, specificity 84%) was chosen corresponding to the limit between sufficient and insufficient 25 OH vitamin D according to the World Health Organization (WHO). Low 25-OH vitamin D levels were observed in 64% of obese women and in 11% of normal-weight women (p less than 0.001). ROMA score above 13% was detected only in obese women (19%). An association between low levels of 25-OH vitamin D and ROMA score was observed. Indeed, 64% of obese women with ROMA score >13% had concomitant insufficient levels of 25-OH vitamin D, while only 36% of obese women with ROMA score >13% had sufficient 25-OH vitamin D levels (p less than 0.0001). This study suggests that the deficiency of 25- OH vitamin D in obese women has a possible correlation with high ROMA score. PMID- 28078871 TI - Anti-plaque and antimicrobial efficiency of different oral rinses in a 3-day plaque accumulation model. AB - The idea of incorporating a mouthrinse with normal tooth brushing could be a useful adjunct to oral hygiene. Despite the principle nature of the toothpaste vehicle, most alcohol-based chemical plaque-control agents have been evaluated and later formulated in the mouthrinse vehicle. The current study was aimed to investigate the persistence of antimicrobial action and plaque inhibitory properties of a new alcohol-free mouthrinse when compared with positive control, chlorhexidine 0.12% and placebo control, physiologic saline solution mouthrinses. The evaluation of the antimicrobial activity was performed by saliva samples collected during the 3 days of usage. The results of this study indicate that this new oral rinse has an equivalent plaque inhibitory action to chlorhexidine, and the plaque inhibitory action of the rinse appears to be derived from a persistence of antimicrobial action in the mouth. Furthermore, no side effects were reported during the study, and the additional benefit of no alcohol presence in the rinse solution. PMID- 28078872 TI - Molecular characterization and antibiotic resistance of salmonella serovars isolated in the Apulia region of Italy. AB - During the period January 2013-December 2015, 175 cases of human salmonellosis were reported in the Apulia Region of Italy. The aim of this study was to characterize salmonella strains from the standpoints of serovars prevalence, antimicrobial resistance and clonal origin. The serological typing was performed by agglutination against antisera followed by a multiplex polymerase chain reaction (m-PCR). The obtained results were analyzed following the Kauffmann White scheme. Susceptibility to antimicrobial agents was tested using the disk diffusion method on Muller-Hinton agar plates. All strains were tested by pulsed field gel electrophoresis (PFGE) according to the PulseNet protocol, and cluster analysis was performed using BioNumerics software. It was found that the most prevalent isolated serovars were in order: i) S.Enteritidis, ii) S.Typhimurium and iii) S. 4,[5],12:i:?. The most common resistances were: i) Ampicillin (A) (38%), ii) Amoxicillin/Clavulanic Acid (AmC) (11%), iii) Streptomycin (S) (19%), iv) Sulphonamides (Su) (19%), v) Tetracycline (T) (30%), and vi) Piperacillin (Pip) (25%). Ten multidrugresistant (MDR) patterns were identified among the isolates, and the two most diffused ones were ASSuT and ASSuTPip, respectively. MDR patterns were predominantly expressed by Salmonella Typhimurium and Salmonella 4,[5],12:i:-. Molecular typing by PFGE yielded 60 different macrorestriction profiles among 33 serotypes. PMID- 28078873 TI - Fine needle aspiration cytology of 650 thyroid nodules operated for multinodular goiter: a cyto-histological correlation based on the new Italian cytological classification (siapec 2014). AB - The new Italian cytological classification (SIAPEC 2014) of thyroid nodules, in line with those of Bethesda and BTA-RCPath, replaces the previous TIR3 class with two new classes (TIR3A and TIR3B), which correspond to different risks of malignancy and clinical actions required. The present study was conducted to evaluate the diagnostic accuracy of the new SIAPEC classification as opposed to its previous version (SIAPEC 2007). Preoperative cytology was compared with the final histology obtained from 650 consecutive patients who underwent total thyroidectomy for multinodular goiter. Of this total, 434 patients (group A) had their cytological diagnosis based on the old SIAPEC 2007 classification and 216 patients (group B) had their cytological diagnosis based on the SIAPEC 2014 classification. In group A 111 patients (25.6%) had a TIR3 diagnosis, while in group B 52 patients (24.1%) received a TIR3 diagnosis, of whom 30 had TIR3A and 22 had TIR3B. In group A, 46 (41.4%) out of the 111 patients with TIR3 diagnosis had, based on histology, a thyroid carcinoma. In group B, only 2 (6.7%) out of 30 patients with TIR3A diagnosis had a thyroid carcinoma. This rate of malignancy was significantly lower (p less than 0.001) than that observed in patients with TIR3B diagnosis, in which 12 (54.5%) out of 22 patients had a carcinoma. The observations here reported show that, in respect to the previous version, the new Italian cytological classification provides greater diagnostic accuracy for detecting thyroid nodule malignancy. PMID- 28078874 TI - Tendonitis of the rotator cuff treated with extracorporeal shock wave therapy: radiographic monitoring to identify prognostic factors for disintegration. AB - Extracorporeal shock wave therapy (ESWT) is widely used for calcific tendonitis of the shoulder. The initial rationale for this therapy was to break the calcification, but this effect does not always occur. To date, we do not know how calcifications evolve or why they may be less responsive to the action of the shock waves. One hundred and seventy-four shoulders with calcific tendinitis were prospectively evaluated before and after ESWT, using the radiographic classifications according to Gartner and Heyer, to Bosworth and to Mole. Three months after ESWT therapy, we observed the disappearance of calcification in 36.8% of the shoulders, a reduction in size in 21.8% and no change in 41.4%. The calcifications that disappeared were large according to Bosworth (p=0.004). The probability of disappearance of calcification increased with increasing age (p=0.011), for medium calcifications according to Bosworth (p=0.001), and calcifications of type A according to Mole (p=0.043). The results of our study suggest that the radiographic aspects of calcific tendonitis of the rotator cuff could influence the disruptive effects after ESWT. With this knowledge we could define the timing of treatment and therapeutic choice for each patient. PMID- 28078875 TI - Circulating sRAGE in the diagnosis of osteolytic bone metastasis. AB - Despite the clinical importance of metastasis to the skeleton, the diagnostic tools for early detection and monitoring of bone metastasis lack sensitivity and specificity. We evaluated a promising new serum biomarker, the soluble form of the Receptor of Advanced Glycosylated End-products (sRAGE). sRAGE is involved in the Wnt-signaling pathway, and has been reported to reduce the risk of cancer. We investigated the diagnostic potential of sRAGE to improve the detection and monitoring of bone metastasis. We measured sRAGE in the serum of control healthy subjects, patients with primary tumors and patients with bone metastasis. sRAGE was also correlated with the Wnt inhibitors DKK-1 and sclerostin, the bone resorption markers MMP-2, MMP-9 and TRAP5, and the metastatic marker survivin. sRAGE was significantly lower in primary tumor and metastatic patients than in healthy subjects. sRAGE also showed a strong negative correlation with DKK-1, sclerostin, MMP-2, MMP-9, TRAP5b and survivin. These results indicated that sRAGE might play a protective role in bone metastasis progression, and it may diagnostic significance for detecting and monitoring osteolytic metastases. PMID- 28078876 TI - Comparative molecular analysis of bacterial species associated with periodontal disease. AB - Periodontal disease is an inflammatory disorder affecting the supporting teeth structures, including gingiva, periodontal ligament and alveolar bone, causing loss of connective tissue, reabsorption of alveolar bone and formation of periodontal pockets. The aim of this study is to find a correlation between bacterial growth and periodontal disease. Fifty-seven patients aged between 21 and 65 years, median age 46 years, were enrolled. According to gingival pocket depth, ranging from 3 to 7 mm, patients were divided into two groups: the first (30 patients, 53%) with deep pockets 3 5 mm and the second (27 patients, 47%) less than 5 mm. The samples taken were processed for microbiological analysis by absolute quantitative real-time Taq-Man technique. Patients affected by periodontal disease were 32 (56%) and patients with gingival bleeding were 35 (61%). This data showed that the presence, the type and the bacterial load in gingival pockets were strongly correlated with gingival depth, periodontal disease and gingival bleeding. Quantitative microbiological analysis is a key point to improve patient compliance, allowing to choose the specific antibiotic treatment. avoiding antibiotic resistance and ensuring the successful outcome of therapy for periodontal disease. PMID- 28078877 TI - Congenital muscular dystrophy and epilepsy: a prospective case series of pediatric patients. AB - Congenital Muscular Dystrophies (CMDs) can be considered as a heterogeneous group of diseases characterized by marked weakness, generalized hypotonia and joint contractures. They are divided into pure and classical forms, without ocular and cerebral involvement, and complex forms, which are associated with cerebral abnormalities. Seizures have rarely been described in the pure forms while they seem to occur more frequently in complex forms. The aim of our study was to evaluate the incidence of seizure in CMD. Herein, the authors describe 16 cases of congenital muscular dystrophy (CMD) associated with different kinds of epileptic events, in order to study the pathogenic connection between the two clinical manifestations. In all described patients we reviewed the clinical, neurophysiologic, and neuroimaging data to determine any associations with epilepsy. The patients were divided into two groups: 14 cases with merosin positive CMD in one group and 2 patients with Walker Warburg syndrome (WWS) in the second group. In our study we found that in the first group, one benign myoclonic epilepsy (BME), one benign febrile convulsions had occurred. Also in one patient, the EEG revealed a moderately high voltage slow background with diffuse sharp waves reaching 300mV in amplitude with no clinical signs. In the merosin positive CMD patients, the presence of two different epileptic diseases, benign myoclonic epilepsy (BME) in one and febrile convulsion with tonic clinic seizures, may represent a new expression of merosine-positive congenital muscular disease (PCMD) in which the deficiency of an undiscovered muscular protein with a cerebral isoform may be the cause of epileptic events in this group of patients. PMID- 28078878 TI - Vitamin a decreases after a maximal incremental stress test in non-professional male runners with low aerobic performance. AB - The data on the effects of aerobic training on plasma antioxidant vitamins are conflicting. Additionally, most studies focus on the oxidative profiles of professional athletes, but limited information is available for amateur athlete populations. The aim of this study was to evaluate the effects of high-intensity exercise on antioxidant vitamins in non-professional runners with varying levels of aerobic power. Eighty-one male runners underwent an incremental test to exhaustion. The study population was then divided into the following tertiles according to VO2max: Group L (LowVO2max, less than 44.2 mLkg-1min-1), Group M (MediumVO2max, 44.2-49.7 mLkg-1min-1) and Group H (HighVO2max, >49.7). Comparative analyses were performed between Groups L and H. The total antioxidant capacity (TAC), Vitamin (Vit) E, Vitamin A, beta-carotene, lycopene and thiobarbituric acid-reactive substances (TBARS) were determined before and 60 min after exercise testing. After the stress test, Vit A decreased and TBARS increased in Group L, whereas no changes in the vitamin concentrations, TAC induction and TBARS reduction were observed in group H. In individuals with low VO2max, an incremental test determined lipid-peroxidation and Vitamin A consumption, whereas H Group increases TAC that buffer TBARS production. PMID- 28078879 TI - Zenker diverticulum in the right side of the neck resembling a thyroid mass at ultrasound. AB - Zenker?s diverticulum represents the most common form of pharyngo-oesophageal diverticula usually occurring on the left side of the neck. Due to its anatomical proximity to the thyroid, it can mimic a thyroid mass. Here we describe the case of an asymptomatic 49-year-old man referred to the Thyroid Clinic of the Policlinico Umberto I Hospital-?Sapienza? University of Rome for thyroid sonography due to a family history of autoimmune thyroid disease. The patient?s thyroid blood tests did not reveal any abnormalities. The sonographic examination showed a dishomogeneus and hypoechoic thyroid gland. In addition, in the third middle of the right lobe, a mass (with a diameter greater than 26 mm), with heterogeneous internal echogenicity, hypoechoic margins and internal hyperechoic spots was recorded, with no appreciable flow at the Doppler evaluation. The TI RADS score was 4c. Hence, the patient underwent ultrasound-guided fine-needle aspiration cytology that revealed the presence of squamous cells without cytological atypia, erythrocytes, muscular and vegetable fibres, colonies of bacteria in the absence of inflammatory infiltrate. This was consistent with the diagnostic hypothesis of oesophagus diverticulum, which was confirmed by means of a barium-swallow oesophagography. This case report underlines the possibility that a suspicious thyroid mass may result from a Zenker?s diverticulum, even if located on the right side, especially if the lesion has a heterogeneous echo texture, a hypoechoic rim and internal hyperechoic spots. PMID- 28078881 TI - Varicella zoster virus as a cause of infectious encephalitis in a cohort of Sri Lankan patients PMID- 28078880 TI - Orthodontic forces modulate insulin-like growth factor binding protein-5 changes in gingival crevicular fluid. AB - Orthodontic tooth movement results from the response of the periodontal tissue to orthodontic force, which leads to modeling and remodeling of the surrounding alveolar bone. The response is considered to occur through the activation of specific signaling pathways, many of which are known, all acting to ultimately result in tooth movement. Much is known about the actions of these two cells, and the signaling pathways that affect them, both in bone and orthodontic literature, however, to date, little work has been carried out to examine the effect of the insulin-like growth factor binding proteins (IGFBP) in orthodontics. Therefore, we investigated the presence of IGFBP-5 in the gingival crevicular fluid (GCF) of 6 healthy subjects, and assessed the effects of orthodontic treatment on the levels and molecular state of this protein. PMID- 28078882 TI - Real time surveillance of dengue fever - a preliminary study PMID- 28078883 TI - Flexible Multistate Data Storage Devices Fabricated Using Natural Lignin at Room Temperature. AB - The growing interest in bioinspired and sustainable electronics has induced research on biocompatible and biodegradable materials. However, conventional electronic devices have been restricted due to their nonbiodegradable and sometimes harmful and toxic materials, which can even cause environmental issues. Here, we report a resistive switching random access memory (ReRAM) device based on lignin, which is a biodegradable waste product of the paper industry. The active layer of the device can be easily formed using a simple solution process on a plastic substrate. The memory devices show stable bipolar resistive switching behavior with good endurance and retention. Appropriate control of the maximum reset voltage and compliance current can yield multibit data storage capability with at least four resistance states, which can be exploited to realize a high-density memory device. The resistive switching mechanism may be a result of formation and rupture of carbon-rich filaments. These results suggest that lignin is a promising candidate material for an inexpensive and environmentally benign ReRAM device. We believe that this study can initiate a new route toward development of biocompatible and flexible electronics. PMID- 28078884 TI - Construction of Three-Dimensional Hemin-Functionalized Graphene Hydrogel with High Mechanical Stability and Adsorption Capacity for Enhancing Photodegradation of Methylene Blue. AB - A three-dimensional hemin-functionalized graphene hydrogel (Hem/GH) was prepared by a facile self-assembly approach. The as-prepared Hem/GH showed good mechanical strength with a storage modulus of 609-642 kPa and a high adsorption capacity to organic dye contaminants (341 mg g-1 for rhodamine B). Moreover, Hem/GH could be used as a photosensitizer for the photocatalytic degradation of organic dyes and displayed superior photodegradation activity of methylene blue (MB). This result was better than that of counterparts such as graphene hydrogel (GH) and commercial catalyst P25. The excellent cycling performance of the Hem/GH was well maintained even after multiple cycles on adsorption process and photocatalytic reaction. Interestingly, after the photodegradation of MB, a light-induced pH change of the solution from alkaline pH 8.99 to acidic pH 3.82 was observed, and 10 wt % total organic carbon remained. The liquid chromatography/time-of-flight mass spectrometry (LC/TOF-MS) analysis confirmed the generation of acidic degradation products. The photocatalytic mechanism was further investigated by trapping experiments, which revealed that the MB degradation was driven mainly by the participation of O2*- radicals in the photocatalytic reaction. As an extended application, visually intuitive observation showed the as-prepared Hem/GH also had strong antibacterial properties. These results suggest that Hem/GH could be potentially used for practical application due to its high adsorption ability, excellent photocatalytic activity, and strong antibacterial properties. PMID- 28078885 TI - An Ambipolar BODIPY Derivative for a White Exciplex OLED and Cholesteric Liquid Crystal Laser toward Multifunctional Devices. AB - A new interface engineering method is demonstrated for the preparation of an efficient white organic light-emitting diode (WOLED) by embedding an ultrathin layer of the novel ambipolar red emissive compound 4,4-difluoro-2,6-di(4 hexylthiopen-2-yl)-1,3,5,7,8-pentamethyl-4-bora-3a,4a-diaza-s-indacene (bThBODIPY) in the exciplex formation region. The compound shows a hole and electron mobility of 3.3 * 10-4 and 2 * 10-4 cm2 V-1 s-1, respectively, at electric fields higher than 5.3 * 105 V cm-1. The resulting WOLED exhibited a maximum luminance of 6579 cd m-2 with CIE 1931 color coordinates (0.39; 0.35). The bThBODIPY dye is also demonstrated to be an effective laser dye for a cholesteric liquid crystal (ChLC) laser. New construction of the ChLC laser, by which a flat capillary with an optically isotropic dye solution is sandwiched between two dye-free ChLC cells, provides photonic lasing at a wavelength well matched with that of a dye-doped planar ChLC cell. PMID- 28078886 TI - Enhanced Activity for Hydrogen Evolution Reaction over CoFe Catalysts by Alloying with Small Amount of Pt. AB - The hydrogen evolution reaction highly relied on Pt electrocatalysts, with high activity and stability. In the past few years, a host of efforts have been made in the development of novel platinum nanostructures with a low amount of Pt because the scarcity and high price of Pt hinder its practical applications. Here, we report the preparation of PtCoFe@CN electrocatalysts with a remarkably reduced Pt loading amount of 4.60% by annealing Pt-doped metal-organic frameworks (MOFs). The electrocatalyst demonstrated an outstanding performance with only 45 mV overpotential to achieve the 10 mA cm-2 current density, which is quite close to that of the commercial 20% Pt/C catalyst. The enhanced catalytic capability is originated from the modification of the electronic structures of CoFe by alloying with Pt. The results indicate that robust and superstable alloy electrocatalysts which contain a very small amount of noble metal could be prepared by annealing noble metal-doped MOFs. PMID- 28078887 TI - Electrospun Regenerated Cellulose Nanofiber Membranes Surface-Grafted with Water Insoluble Poly(HEMA) or Water-Soluble Poly(AAS) Chains via the ATRP Method for Ultrafiltration of Water. AB - Electrospun nanofiber membranes (ENMs) have demonstrated promising applications for water purification primarily due to high water flux and low degree of fouling. However, the equivalent/apparent pore sizes of as-electrospun ENMs are in microns/submicrons; therefore, the ENMs can only be directly utilized for microfiltration applications. To make regenerated cellulose (RC) ENMs for ultrafiltration applications, atom transfer radical polymerization (ATRP) was studied to graft polymer chains onto the surface of RC nanofibers; specifically, monomers of 2-hydroxyethyl methacrylate (HEMA) and sodium acrylate (AAS) were selected for surface-grafting water-insoluble and water-soluble polymer chains onto RC nanofibers, respectively. With prolonging of the ATRP reaction time, the resulting surface-modified RC ENMs had reduced pore sizes. The water-insoluble poly(HEMA) chains coated the surface of RC nanofibers to make the fibers thicker, thus decreasing the membrane pore size and reducing permeability. On the other hand, the water-soluble poly(AAS) chains did not coat the surface of RC nanofibers; instead, they partially filled the pores to form gel-like structures, which served to decrease the effective pore size, while still providing elevated permeability. The surface-modified RC ENMs were subsequently explored for ultrafiltration of ~40 nm nanoparticles and ~10 nm bovine serum albumin (BSA) molecules from water. The results indicated that the HEMA-modified RC membranes could reject/remove more than 95% of the nanoparticles while they could not reject any BSA molecules; in comparison, the AAS-modified RC membranes had complete rejection of the nanoparticles and could even reject ~58% of the BSA molecules. PMID- 28078888 TI - Low-Temperature Wet Conformal Nickel Silicide Deposition for Transistor Technology through an Organometallic Approach. AB - The race for performance of integrated circuits is nowadays facing a downscale limitation. To overpass this nanoscale limit, modern transistors with complex geometries have flourished, allowing higher performance and energy efficiency. Accompanying this breakthrough, challenges toward high-performance devices have emerged on each significant step, such as the inhomogeneous coverage issue and thermal-induced short circuit issue of metal silicide formation. In this respect, we developed a two-step organometallic approach for nickel silicide formation under near-ambient temperature. Transmission electron and atomic force microscopy show the formation of a homogeneous and conformal layer of NiSix on pristine silicon surface. Post-treatment decreases the carbon content to a level similar to what is found for the original wafer (~6%). X-ray photoelectron spectroscopy also reveals an increasing ratio of Si content in the layer after annealing, which is shown to be NiSi2 according to X-ray absorption spectroscopy investigation on a Si nanoparticle model. I-V characteristic fitting reveals that this NiSi2 layer exhibits a competitive Schottky barrier height of 0.41 eV and series resistance of 8.5 Omega, thus opening an alternative low-temperature route for metal silicide formation on advanced devices. PMID- 28078889 TI - Quantification of Free Polyelectrolytes Present in Colloidal Suspension, Revealing a Source of Toxic Responses for Polyelectrolyte-Wrapped Gold Nanoparticles. AB - Polyelectrolyte (PE) wrapping of colloidal nanoparticles (NPs) is a standard method to control NP surface chemistry and charge. Because excess polyelectrolytes are usually employed in the surface modification process, it is critical to evaluate different purification strategies to obtain a clean final product and thus avoid ambiguities in the source of effects on biological systems. In this work, 4 nm diameter gold nanoparticles (AuNPs) were wrapped with 15 kDa poly(allylamine hydrochloride) (PAH), and three purification strategies were applied: (a) diafiltration or either (b) one round or (c) two rounds of centrifugation. The bacterial toxicity of each of these three PAH-AuNP samples was evaluated for the bacterium Shewanella oneidensis MR-1 and is quantitatively correlated with the amount of unbound PAH molecules in the AuNP suspensions, as judged by X-ray photoelectron spectroscopy, nuclear magnetic resonance experiments and quantification using fluorescent assay. Dialysis experiments show that, for a 15 kDa polyelectrolyte, a 50 kDa dialysis membrane is not sufficient to remove all PAH polymers. Together, these data showcase the importance of choosing a proper postsynthesis purification method for polyelectrolyte-wrapped NPs and reveal that apparent toxicity results may be due to unintended free wrapping agents such as polyelectrolytes. PMID- 28078890 TI - Metamorphosis Affects Metal Concentrations and Isotopic Signatures in a Mayfly (Baetis tricaudatus): Implications for the Aquatic-Terrestrial Transfer of Metals. AB - Insect metamorphosis often results in substantial chemical changes that can alter contaminant concentrations and fractionate isotopes. We exposed larval mayflies (Baetis tricaudatus) and their food (periphyton) to an aqueous zinc gradient (3 340 MUg Zn/l) and measured zinc concentrations at different stages of metamorphosis: larval, subimago, and imago. We also measured changes in stable isotopes (delta15N and delta13C) in unexposed mayflies. Larval zinc concentrations were positively related to aqueous zinc, increasing 9-fold across the exposure gradient. Adult zinc concentrations were also positively related to aqueous zinc, but were 7-fold lower than larvae. This relationship varied according to adult substage and sex. Tissue concentrations in female imagoes were not related to exposure concentrations, but the converse was true for all other stage-by-sex combinations. Metamorphosis also increased delta15N by ~0.80/00, but not delta13C. Thus, the main effects of metamorphosis on insect chemistry were large declines in zinc concentrations coupled with increased delta15N signatures. For zinc, this change was largely consistent across the aqueous exposure gradient. However, differences among sexes and stages suggest that caution is warranted when using nitrogen isotopes or metal concentrations measured in one insect stage (e.g., larvae) to assess risk to wildlife that feed on subsequent life stages (e.g., adults). PMID- 28078891 TI - Is Biodegradable Plastic Mulch the Solution to Agriculture's Plastic Problem? PMID- 28078892 TI - Dynamical Transitions at Low Temperatures in the Nearest Hydration Shell of Phospholipid Bilayers. AB - For the so-called dynamical transition from harmonic to anharmonic (or diffusive) motions in biological systems, the presence of hydration water is important. To explain the molecular mechanism of this transition, the information on molecular motions in the nearest hydration shell would be helpful. In this work, to study molecular motions in the nearest hydration shell of spin-labeled model biological membranes, a pulsed version of electron paramagnetic resonance, electron spin echo envelope modulation (ESEEM) spectroscopy, is used. For hydration by deuterium water, the 2H ESEEM frequency spectra resemble the solid-state 2H NMR line shape that is widely used for structural and dynamical studies. Two types of model membranes were investigated and compared: bilayers consisting of unsaturated lipid 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and bilayers consisting of fully saturated lipid 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC). The lipid chain packing for the POPC bilayer is known to be more defective than that for the DPPC bilayer. For both the POPC and the DPPC bilayers, the 2H ESEEM NMR-like spectra showed a sharp narrowing between 180 and 190 K. From the other side, in both bilayers at 188 K, an inflection was observed for the temperature dependence of molecular motions detected by the spin relaxation of spin labels in the bilayer interior. It was concluded that dynamical transition in the bilayer interior is accompanied by an onset of isotropic water molecular dynamics in the nearest hydration shell of the bilayer with a rate of ~105 s-1. Also, the 2H ESEEM NMR-like spectra in the POPC bilayer showed slight changes above 100 K that could be ascribed to another dynamical transition resulting in the appearance of restricted orientational motion of water molecules. These data also are interrelated with spin relaxation of spin labels in the POPC bilayer interior and support the hypothesis ascribing the transition at 100 K to excessive lipid chain flexibility. PMID- 28078893 TI - Direct alpha-Arylation/Heteroarylation of 2-Trifluoroboratochromanones via Photoredox/Nickel Dual Catalysis. AB - Utilizing photoredox/nickel dual catalysis, diverse flavanones have been synthesized by coupling novel 2-trifluoroboratochromanone building blocks with aryl and heteroaryl bromide partners. The newly reported trifluoroboratochromanones can be easily accessed from the corresponding chromones on multigram scale. This represents a general route for accessing natural and unnatural flavanones that were previously formed through a synthetically more restrictive ring closure route from chalcone precursors. PMID- 28078894 TI - Synthesis of Sulfones and Sulfonamides via Sulfinate Anions: Revisiting the Utility of Thiosulfonates. AB - Simple and high-yielding strategies for the production of a variety of sulfones and sulfonamides, using thiosulfonates synthesized by copper-catalyzed aerobic dimerization, are reported. Although thiosulfonates are an old class of compound, practical methods for their synthesis and utilization have not been rigorously developed. In this study, we revisit the reactions of easily accessible thiosulfonates to form sulfinate anions. Because of the similar reactivity of thiosulfonates and metal sulfinates derived from toxic SO2, thiosulfinates are proposed to be stable, nontoxic alternatives to metal sulfinate salts. PMID- 28078895 TI - Enantioselective alpha-Hydroxylation by Modified Salen-Zirconium(IV)-Catalyzed Oxidation of beta-Keto Esters. AB - The highly enantioselective alpha-hydroxylation of beta-keto esters using cumene hydroperoxide (CHP) as the oxidant was realized by a chiral (1S,2S) cyclohexanediamine backbone salen-zirconium(IV) complex as the catalyst. A variety of corresponding chiral alpha-hydroxy beta-keto esters were obtained in excellent yields (up to 99%) and enantioselectivities (up to 98% ee). The zirconium-catalyzed enantioselective alpha-hydroxylation of beta-keto esters was scalable, and the zirconium catalyst was recyclable. The reaction can be performed in gram scale, and corresponding chiral products were acquired in 95% yield and 99% ee. PMID- 28078896 TI - [The incidence, mortality and risk factors of prostate cancer]. AB - Prostate cancer is a serious oncological disease in males. There has been a significant escalation in the incidence of this malignancy in the Czech Republic and in developed countries of Europe recently. Conversely, in countries with an altered health system, a minor increase in new cases of this disease is recorded. The causes of the high incidence of prostate cancer in developed countries appear to be the introduction of the prostate specific antigen (PSA) test and prostate biopsy, an aging population, and the consequent increased risk of cancer. The possible contribution of physical and chemical carcinogens associated with environmental pollution and negative lifestyle changes should not be forgotten either. The mortality rate for prostate cancer remains stable, with a slight decline in recent years. The article provides an overview of trends in the incidence and mortality of prostate cancer in the Czech Republic and Europe. PMID- 28078897 TI - [Epidemiological significance of the metabolic syndrome]. AB - From an epidemiological point of view, the metabolic syndrome is a group of risk factors causally, rather than coincidentally, related to insulin resistance. The metabolic syndrome is a condition with relatively high prevalence rates in both the Czech Republic and in other developed countries. There is a clear trend of increasing prevalence in both sexes depending on age. In the Czech Republic, the syndrome is less common in females (25.5%) than in males (37.6%). Epidemiological studies found white (Europoid race) males to be at higher risk due to abdominal obesity. The definition of the metabolic syndrome has evolved over time and helps to identify individuals at high risk of developing cardiovascular disease and type 2 diabetes, hence the use of the term cardiometabolic syndrome. Early detection of metabolic syndrome symptoms including insulin resistance should be performed mainly by general practitioners as part of regular check-ups. PMID- 28078898 TI - [Differential diagnosis of the viral etiology of suspected mumps in a population with high vaccine coverage]. AB - AIM: In this study, buccal swabs from patients with the clinical picture of parotitis epidemica in whom mumps virus (MV) infection was not confirmed by direct detection or serologically were tested. The aim was to detect by molecular methods nucleic acids (NAs) of other respiratory viruses possibly involved in salivary gland swelling. At the same time, paired sera, if available, were tested. MATERIAL AND METHODS: The study group consisted of 72 buccal swabs from patients of the Clinic of infectious, tropical, and parasitic diseases, Na Bulovce Hospital. Paired sera were available from ten patients. Samples were collected in 2013 to 2015. Buccal swabs were tested by PCR for the presence of NAs of adenoviruses (AdV), bocaviruses (hBoV), parainfluenza viruses of types 1-4 (HPIV), human metapneumovirus (hMPV), coronaviruses (HCoV: NL63, OC43, HKU1, and 229E), respiratory syncytial virus (RSV), influenza A virus, influenza B virus, and Epstein-Barr virus (EBV). Paired sera were screened by the complement fixation test (AdV and influenza A and B viruses), hemagglutination inhibition test (HPIV types 2 and 3), ELISA (AdV, EBV), and immunofluorescence (EBV). RESULTS: NAs from viruses other than the mumps virus were detected in 27 of 72 patients with clinical symptoms of parotitis epidemica, and serological tests revealed etiological links with parainfluenza viruses in three more cases. Overall, 30 (41.7%) of 72 patients with suspected mumps tested positive for one or more viruses from the study panel. The most commonly detected viruses were AdV 11/72 (15.3%), EBV 9/72 (12.5%), and HPIV 3/72 (4.2%), but influenza A virus (H3N2) 1/72 (1.4%) was also found. Some patients tested positive for more than one virus: 2/72 (3%) for AdV plus hBoV and 1/72 (1.4%) for HPIV plus HCoV. In addition, examination of paired sera revealed HPIV positivity in three more patients. PCR and serology detected etiological link with HPIV in six (8.3%) of 72 patients tested. CONCLUSION: In our study group, nearly 42% of patients with the clinical picture of parotitis epidemica in whom mumps virus (MV) infection was not confirmed by direct detection or serologically tested positive for viruses other than the mumps virus. Thorough laboratory diagnosis of suspected mumps in vaccinated persons is important not only for the treatment of patients and adoption of isolation and other measures, but also for a better understanding of the epidemiology of the disease and outcomes of the immunisation programmes. PMID- 28078899 TI - [Factors modifying cord blood IgE levels - a pilot study]. AB - AIM: The complex influence of internal and external environmental factors on the individual and his/her immune system and the lack of suitable markers to assess and reduce the risk of the development of allergies during the lifetime can explain the continuous increase in the number of people affected by some form of allergy. According to the results of some studies, cord blood IgE level could be a useful early marker for assessing the risk of atopic diseases, but the studies showed controversial results. In addition, several authors discuss the origin of these antibodies (synthesis in utero, peripartum contamination from maternal blood or placental transfer). The aim of our pilot study was to investigate the possible influence of modifying factors on cord blood IgE level. MATERIAL AND METHODS: Our group of patients consisted of 184 retrospectively selected neonates (98 boys, 53.3% and 86 girls, 46.7%) from whom cord blood was collected and cord blood IgE level was measured 25 years ago (PRIST method). The impact of selected modifying factors (sex, type of delivery or month of birth) on cord blood IgE level was assessed retrospectively. RESULTS: Higher cord blood IgE levels were found in boys than in girls, in neonates born by Caesarean section than in those born by natural delivery, and in those born in the winter months than in other seasons of the year. Our findings are in agreement with those of other authors. CONCLUSION: Based on our results and those of others, we assume that the selected factors affect the cord blood IgE levels to varying degrees. These facts should be taken into consideration while interpreting the cord blood IgE levels. PMID- 28078900 TI - Prevalence of Mycoplasma hominis and Ureaplasma urealyticum in women undergoing an initial infertility evaluation. AB - AIMS: Mycoplasma hominis and Ureaplasma urealyticum are potentially pathogenic bacterial species that are frequently isolated from the urogenital tract of women. These pathogens could be responsible for various genitourinary diseases and have been associated with adverse pregnancy outcomes and female fertility problems. The aim of this study was to analyse the presence of M. hominis and U. urealyticum in the cervical canal of uterus of women with and without fertility problems. METHODS: Endocervical swabs obtained from women with reproductive problems and fertile women were tested by both cultivation and polymerase chain reaction. The antimicrobial susceptibility to the azithromycin, ciprofloxacin, doxycycline and erythromycine of the isolated strains of M. hominis and U. urealyticum was also tested by the microdilution broth method. RESULTS: A total of 111 women with fertile problems were examined. U. urealyticum was detected in samples from 44 (39.6%) women. M. hominis was detected in significantly fewer samples, i.e. only from 9 (8.1%) samples. From these, 6 (5.4%) women were positive for both microorganisms. The fertile group consisted from 23 women. The presence of U. urealyticum was detected in 8 (34.7%) of them. M. hominis was detected only in the mixture with U. urealyticum in 3 (13.0%) cases. The most effective antibiotic against both species in our study was doxycycline. CONCLUSION: The results show slightly higher incidence of M. hominis and U. urealyticum in the genitourinary tract of women with fertility problems compare with control group. The potential negative effect of these species on the reproduction ability of women was not observed. PMID- 28078901 TI - [Recurrent meningitis and inherited complement deficiency]. AB - Complement deficiency represents 5% of primary immunodeficiencies worldwide. A total of seven patients with deficiencies of the classical complement pathway were reported in the Czech Republic by the end of 2015. Typical manifestations of complement deficiency are recurrent meningitis, other bacterial infections, autoimmunity and kidney disease.Two case reports are presented of patients with molecularly confirmed C7 (compound heterozygote, c.663_644del in exon 6 and c.2350+2T:>C in intron 16) and C8 (homozygous c.1282C>T in exon 9) deficiency. The first patient had four attacks of meningococcal meningitis and an episode of pneumonia of unknown aetiology in childhood. The second had six attacks of meningitis. He also suffered from recurrent infections (otitis media, tonsillitis, chronic mucopurulent rhinitis and subsequent pansinusitis complicated by nasal polyposis) since childhood. No autoimmune disease was documented in either patient. They both received meningococcal and pneumococcal vaccines. Antibiotic prophylaxis was used only in the second patient, leading to a decline in the number of ENT infections.Complement deficiency should be suspected in patients with recurrent meningococcal infections, especially if combined with other infections caused by encapsulated bacteria or autoimmunity diseases. Prophylaxis with conjugate polysaccharide vaccines is recommended and antibiotic prophylaxis should be considered in individual cases. PMID- 28078902 TI - An updated approach to viral hepatitis E. AB - Viral hepatitis E (VHE) is considered to be the most common acute viral hepatitis worldwide. Since the 1980s, VHE has been reported in developing countries. Although VHE is not a reportable disease in many developed countries, it is evidently on the rise even in these countries [1].In Europe, VHE is no longer an imported disease and efforts have been made to map VHE cases in both humans and animals to be able to update the recommendations for VHE prevention, risk assessment for blood product and organ transplants recipients, prevention strategies for severe and chronic VHE, and laboratory test algorithms. PMID- 28078903 TI - [IGRA methods in the routine operation - QuantiFERON(r)-TB Gold or T-SPOT.TB?] AB - For indirect diagnosis of tuberculosis, two commercial IGRA (Interferon Gamma Release Assay) assays are available - primal QuantiFERON(r)-TB Gold test, new version QuantiFERON(r)-TB Gold Plus test (four tube, differentiation in activity CD4+ a CD8+) and T-SPOT(r).TB test. Both methods are based on the same principle, but their workflows are different. In this article, both assays are compared on the collection of 284 patients. Inter-rate agreement measure showed 81.3% consistency and Cohens kappa index was calculated as 0.72. In case of discrepancy between IGRA and other methods (clinical aspects, X-ray diagnostic, etc.), results should be confirmed by second IGRA assay for correct interpretation. PMID- 28078904 TI - Malonyl-CoA pathway: a promising route for 3-hydroxypropionate biosynthesis. AB - 3-Hydroxypropionate (3HP) is an attractive platform chemical, serving as a precursor to a variety of commodity chemicals like acrylate and acrylamide, as well as a monomer of a biodegradable plastic. To establish a sustainable way to produce these commercially important chemicals and materials, fermentative production of 3HP is widely investigated in recent years. It is reported that 3HP can be produced from several intermediates, such as glycerol, malonyl-CoA, and beta-alanine. Among all these biosynthetic routes, the malonyl-CoA pathway has some distinct advantages, including a broad feedstock spectrum, thermodynamic feasibility, and redox neutrality. To date, this pathway has been successfully constructed in various species including Escherichia coli, yeast and cyanobacteria, and optimized through carbon flux redirection, enzyme screening and engineering, and an increasing supply of energy and cofactors, resulting in significantly enhanced 3HP titer up to 40 g/L. These results show the feasibility of commercial manufacturing of 3HP and its derivatives in the future. PMID- 28078905 TI - Correction to: Small intestinal malabsorption in chronic alcoholism: a retrospective study of alcoholic patients by the 14C-D-xylose breath test. PMID- 28078906 TI - Arduino-based noise robust online heart-rate detection. AB - This paper introduces a noise robust real time heart rate detection system from electrocardiogram (ECG) data. An online data acquisition system is developed to collect ECG signals from human subjects. Heart rate is detected using window based autocorrelation peak localisation technique. A low-cost Arduino UNO board is used to implement the complete automated process. The performance of the system is compared with PC-based heart rate detection technique. Accuracy of the system is validated through simulated noisy ECG data with various levels of signal to noise ratio (SNR). The mean percentage error of detected heart rate is found to be 0.72% for the noisy database with five different noise levels. PMID- 28078907 TI - The diagnostic value of confocal laser endomicroscopy for gastric cancer and precancerous lesions among Asian population: a system review and meta-analysis. AB - OBJECTIVE: The objective of this study is to evaluate the diagnostic value of confocal laser endomicroscopy (CLE) in detection of gastric cancer (GC), gastric intraepithelial metaplasia (GIM), and gastric intraepithelial neoplasia (GIN) lesions. METHOD: PubMed, the Cochrane Library, and Wangfang databases were searched to include eligible articles about CLE in detection of gastric lesions. After study selection, quality assessment and data extraction conducted by two reviewers independently, meta-analysis was performed by Meta-Disc 1.4. The pooled sensitivity and specificity was calculated, receiver operating characteristic (ROC) curve was constructed, and the area under ROC curve (AUC) was calculated. RESULTS: Twenty-three studies evaluating the diagnostic value of CLE were included. For the diagnosis of GC lesions, the pooled sensitivity, specificity, and AUC were 91% (88-94%), 99% (99-99%), and 0.9513, respectively. For the diagnosis of lesions, the pooled sensitivity, specificity, and AUC were 92% (90 94%), 97% (96-98%), and 0.9774, respectively. For the diagnosis of GIN lesions, the pooled sensitivity, specificity and AUC were 81% (75-85%), 98% (97-98%), and 0.9204, respectively. CONCLUSIONS: CLE can provide an accurate diagnosis with high sensitivity and specificity for GC, GIM, and GIN lesions. The results should be confirmed by well-designed, multi-centered, randomized controlled, and double blinded trials with large samples. PMID- 28078908 TI - Comparison of wrist-worn and hip-worn activity monitors under free living conditions. AB - PURPOSE: Current recommendations state that individuals engage in 150 min of moderate or 75 min of vigorous intensity physical activity (PA) each week. Commercial PA monitors are becoming popular for everyday use. The accuracy of these devices, however, is not well understood. We sought to examine the accuracy of two commercial devices, one wrist and one hip-worn, under free-living conditions. METHODS: Twenty-two subjects wore two commercially available devices and one ActiGraph (AG) for seven consecutive days under normal activity. RESULTS: Mean steps per day between all three devices differed significantly. No differences were found in moderate-to-vigorous intensity physical activity (MPVA). Daily energy expenditure (EE) also differed significantly between the AG and the commercial devices. Bland-Altman analysis found poor agreement between the AG and the commercial devices with regards to steps and EE, but good agreement in MVPA. CONCLUSION: Results suggest that the commercial devices are less accurate in estimating steps and EE. These devices did show good agreement with regards to MVPA, suggesting that they may provide useful feedback for individuals seeking to achieve the current PA guidelines for MVPA. Improvements are needed with regards to steps and EE estimation. PMID- 28078909 TI - Apparent treatment-resistant hypertension - patient-physician relationship and ethical issues. AB - BACKGROUND: Poor drug adherence is a major cause of apparent treatment-resistant hypertension. As a consequence, several methods have been developed and attempted implemented in clinical practice to reveal non-adherence and to monitor drug adherence. There are, however, several hitherto unresolved ethical aspects regarding potential methods for drug monitoring in these patients. RESULTS: The most striking challenge is the balance between patient autonomy and the physician's desire for the patient to adhere to the prescribed therapy. Also, methods for monitoring must only be implemented in the treatment of well-informed and consenting patients. Major resources are used on non-adherent patients; how long the physician should encourage continuation of treatment is an important question. CONCLUSIONS: We believe that physicians should reflect and discuss these potential challenges, and that patient education, information and a solid patient-physician relationship are essential for achieving drug adherence. Methods for monitoring adherence represent, however, a useful and often necessary supplement. PMID- 28078910 TI - Gain of chromosome 1q portends worse prognosis in multiple myeloma despite novel agent-based induction regimens and autologous transplantation. AB - We aimed to identify whether the use of autologous hematopoietic cell transplantation (HCT) impacts outcomes for multiple myeloma patients with gains of chromosome 1q (+1q). We retrospectively identified 95 patients, 21% having +1q. For patients with +1q, the overall response rate to induction was 85%, with 40% having >= VGPR and 20% achieving a CR, similar to non +1q patients (p = .64). The median PFS from diagnosis with +1q was 2.1 years (95% CI: 1.2-not reached (NR)) vs 4.3 years (95% CI: 3.3 yrs-NR) without +1q (p = .003). Median OS from diagnosis was 4.4 years (95% CI: 2.9-NR) vs not reached, respectively (p = .005). On molecular analysis using the Foundation One Heme assay, the most common mutations seen in +1q patients included TP53 (38%) and KRAS (25%). Overall, gain of 1q portends worse PFS and OS which was not negated by auto HCT. Such patients will likely require additional therapy to improve their survival. PMID- 28078911 TI - C5a Increases the Injury to Primary Neurons Elicited by Fibrillar Amyloid Beta. AB - C5aR1, the proinflammatory receptor for C5a, is expressed in the central nervous system on microglia, endothelial cells, and neurons. Previous work demonstrated that the C5aR1 antagonist, PMX205, decreased amyloid pathology and suppressed cognitive deficits in two Alzheimer's Disease (AD) mouse models. However, the cellular mechanisms of this protection have not been definitively demonstrated. Here, primary cultured mouse neurons treated with exogenous C5a show reproducible loss of MAP-2 staining in a dose-dependent manner within 24 hr of treatment, indicative of injury to neurons. This injury is prevented by the C5aR1 antagonist PMX53, a close analog of PMX205. Furthermore, primary neurons derived from C5aR1 null mice exhibited no MAP-2 loss after exposure to the highest concentration of C5a tested. Primary mouse neurons treated with both 100 nM C5a and 5 uM fibrillar amyloid beta (fAbeta), to model what occurs in the AD brain, showed increased MAP 2 loss relative to either C5a or fAbeta alone. Blocking C5aR1 with PMX53 (100 nM) blocked the loss of MAP2 in these primary neurons to the level seen with fAbeta alone. Similar experiments with primary neurons derived from C5aR1 null mice showed a loss of MAP-2 due to fAbeta treatment. However, the addition of C5a to the cultures did not enhance the loss of MAP-2 and the addition of PMX53 to the cultures did not change the MAP-2 loss in response to fAbeta. Thus, at least part of the beneficial effects of C5aR1 antagonist in AD mouse models may be due to protection of neurons from the toxic effects of C5a. PMID- 28078912 TI - Unaltered Glutamate Transporter-1 Protein Levels in Aquaporin-4 Knockout Mice. AB - Maintenance of glutamate and water homeostasis in the brain is crucial to healthy brain activity. Astrocytic glutamate transporter-1 (GLT1) and aquaporin-4 (AQP4) are the main regulators of extracellular glutamate and osmolarity, respectively. Several studies have reported colocalization of GLT1 and AQP4, but the existence of a physical interaction between the two has not been well studied. Therefore, we used coimmunoprecipitation to determine whether a strong interaction exists between these two important molecules in mice on both a CD1 and C57BL/6 background. Furthermore, we used Western blot and immunohistochemistry to examine GLT1 levels in AQP4 knockout (AQP4-/-) mice. An AQP4-GLT1 precipitate was not detected, suggesting the lack of a strong physical interaction between AQP4 and GLT1. In addition, GLT1 protein levels remained unaltered in tissue from CD1 and C57BL/6 AQP4-/- mice. Finally, immunohistochemical analysis revealed that AQP4 and GLT1 do colocalize, but only in a region-specific manner. Taken together, these findings suggest that AQP4 and GLT1 do not have a strong physical interaction between them and are, instead, differentially regulated. PMID- 28078913 TI - Silibinin-loaded magnetic nanoparticles inhibit hTERT gene expression and proliferation of lung cancer cells. AB - Nanoparticle-based targeted drug delivery has the potential for rendering silibinin specifically at the favorite site using an external magnetic field. Also, it can circumvent the pitfalls of poor solubility. For this purpose, silibinin-loaded magnetic nanoparticles are fabricated, characterized and evaluated cytotoxicity and hTERT gene expression in A549 lung cancer cell line. silibinin-loaded PLGA-PEG-Fe3O4 had dose- and time-dependent cytotoxicity than pure silibinin. Additionally, hTERT expression is more efficiently reduced with increasing concentrations of nanosilibinin than pure silibinin. The present study indicates that PLGA-PEG-Fe3O4 nanoparticles, as an effective targeted carrier, can make a promising horizon in targeted lung cancer therapy. PMID- 28078914 TI - Appropriate Patient Selection for Carotid Revascularization Procedures is Urgently Needed. AB - The identification/selection of appropriate patient subgroups with asymptomatic carotid artery stenosis and the performance of prophylactic carotid endarterectomy (CEA)/carotid artery stenting (CAS) exclusively on these asymptomatic patient subgroups is currently one of the "hottest" topics in vascular surgery. It is now clear that offering CEA/CAS to asymptomatic carotid patients based only on the degree of carotid stenosis is unjustified and scientifically flawed. On the other hand, offering only best medical therapy to every asymptomatic patient, irrespective of certain high-risk criteria (such as the detection of microemboli by transcranial Doppler, intraplaque hemorrhage, silent embolic infarcts on brain computed tomography/magnetic resonance imaging, elevated biomarkers, family history), is equally wrong. The validation of specific measures to identify those asymptomatic patients at high risk for developing symptoms is crucial to achieve optimal use of carotid interventions and avoid wasting stroke prevention resources. PMID- 28078915 TI - Synthesis and characterization of thermosensitive poly(N-vinylcaprolactam)-g collagen. AB - In this study, we synthesized poly(N-vinylcaprolactam)-g-collagen (PNVCL-g-Col) by grafting collagen with carboxyl group-terminated thermosensitive PNVCL-COOH. The resulting biopolymer was evaluated for its structural, thermal, and rheological properties. Aqueous solutions of PNVCL-g-Col exhibited a temperature dependent phase transition around human physiological temperature (at ~38.5 degrees C), and temperature-dependent tunability. PNVCL-g-Col exhibited temperature-dependent release of the model drugs, lidocaine hydrochloride and bovine serum albumin. Thus, PNVCL-g-Col biopolymer may have wide potential use in various biomedical applications, including controlled release and tissue engineering. PMID- 28078916 TI - In vivo protection studies of bis-quaternary 2-(hydroxyimino)- N-(pyridin-3-yl) acetamide derivatives (HNK oximes) against tabun and soman poisoning in Swiss albino mice. AB - The study reports antidotal efficacy of three HNK [ bis quaternary 2 (hydroxyimino)-N-(pyridin-3yl) acetamide derivatives] and pralidoxime (2-PAM), against soman and tabun poisoning in Swiss albino mice. Protection index (PI) was determined (treatment doses: HNK oximes, *0.20 of their median lethal dose (LD50) and 2-PAM, 30 mg/kg, intramuscularly (im)) together with atropine (10 mg/kg, intraperitoneally). Probit log doses with difference of 0.301 log of LD50 of the nerve agents administered and inhibition of acetylcholinesterase (AChE) activity by 50% (IC50) was calculated at optimized time in brain and serum. Using various doses of tabun and soman (subcutaneously (sc)), in multiples of their IC50, AChE reactivation ability of the oximes was studied. Besides, acute toxicity (0.8* LD50, im, 24 h postexposure) of HNK-102 and 2-PAM was also compared by determining biochemical, hematological variables and making histopathological observations. Protection offered by HNK-102 against tabun poisoning was found to be four times higher compared to 2-PAM. However, nearly equal protection was noted with all the four oximes against soman poisoning. HNK-102 reactivated brain AChE activity by 1.5 times more than 2-PAM at IC50 dose of soman and tabun. Acute toxicity studies of HNK-102 and 2-PAM showed sporadic changes in urea, uric acid, aspartate aminotransferase, and so on compared to control group, however, not supported by histopathological investigations. The present investigation showed superiority of newly synthesized HNK-102 oxime over standard 2-PAM, as a better antidote, against acute poisoning of tabun (4.00 times) and soman (1.04 times), in Swiss albino mice. PMID- 28078918 TI - Dietary practices of children and adolescents with Down syndrome. AB - The aim of this study was to assess dietary intake, breastfeeding history, weight at birth and current weight in children and adolescents with Down syndrome (DS). Therefore, a cross-sectional, controlled study with 19 DS participants and 19 controls without DS matched by gender and age was performed. Except for vitamin D, a lower or the same frequency of insufficient intake in other micronutrients was noted in participants compared with controls. The DS group had a reduced exclusive breastfeeding duration and increased carbohydrate and caloric intake. The consumption of micronutrients in both groups reinforced the current trend of excessive sodium consumption and insufficient intake of calcium, some B complex vitamins and water by children and adolescents. PMID- 28078919 TI - Cultural competence in medical education: A questionnaire study of Danish medical teachers' perceptions of and preparedness to teach cultural competence. AB - AIMS: The cultural competence training of healthcare professionals is a key element in ensuring the quality of both the access and delivery of healthcare to increasingly ethnically diverse populations. The aim of this study is to investigate Danish medical teachers' opinions about cultural competence, their willingness to receive training and preparedness to teach cultural competence topics. METHODS: The survey was sent to medical teachers, clinical teachers and external lecturers who teach in the medical programme at the University of Copenhagen. A total of 1400 medical teachers received the survey, and 199 responded. The response rate is 14%. Data were analysed through descriptive calculations, and answers to open-ended questions were coded using content analysis. RESULTS: Results showed that 82.4% of the informants agreed or strongly agreed that the medical education programme should include training on cultural issues, and 60.3% agreed or strongly agreed that students should be assessed on their cultural competence skills. Regarding preparedness to teach a diverse classroom, 88.4% felt somewhat or very prepared to engage and motivate all students. About 70% were interested in receiving training on cultural competence. CONCLUSIONS: Generally, there is interest in and acknowledgement of the importance of cultural competence in Danish medical education among teachers at the University of Copenhagen. This creates an opportunity to implement cultural competence in the medical curriculum, training of teachers and strengthening the diversity sensitivity of the organisation. However, support for this programme by management and the allocation of an appropriate level of resources is a prerequisite to the success of the programme. PMID- 28078920 TI - Do predictors of return to work and recurrence of work disability due to mental disorders vary by age? A cohort study. AB - BACKGROUND: The extent to which predictors of return to work (RTW) and recurrence of work disability episodes vary by age group is not well understood. METHODS: We examined the associations of sociodemographic and clinical factors with RTW and recurrence after mental-disorder-related work disability episodes in a cohort of 10,496 Finnish public sector employees. Disability records were derived from national disability registers between 2005 and 2011. Effect modification by age was examined in age groups of 21-34, 35-50 and >50 years. RESULTS: A total of 16,551 disability episodes from mental disorders were recorded. The likelihood of RTW was elevated in age group 21-34 (hazard ratio (HR) = 1.36, 95% confidence interval (CI) = 1.28-1.46) and 35-50 years (HR = 1.22, 95% CI = 1.18-1.26) compared to age group >50 years. The risk of a recurrent episode of work disability was higher in age groups >50 (HR = 1.29, 95% CI = 1.09-1.52) and 35-50 years (HR = 1.20, 95% CI = 1.03-1.41) compared to the youngest age group. Employees with depressive disorders were less likely to RTW than employees with neurotic, stress-related and somatoform disorders, and this difference increased with age. Low education was associated with increased risk of recurrent work disability episode in age groups of 50 years or younger, while no such association was observed in age group >50 years. CONCLUSIONS: The importance of depressive symptoms over neurotic, stress-related and somatoform disorders as predictors of delayed RTW increases with age, whereas educational differences in the recurrence of an episode diminish by age. PMID- 28078922 TI - Diary. PMID- 28078921 TI - Regional differences in mortality, hospital discharges and primary care contacts for cardiovascular disease. AB - AIMS: Surveillance of geographical variations in cardiovascular health is important in order to achieve the objectives of reducing regional health disparities. We aimed to explore differences in cardiovascular disease (CVD) mortality and prevalence of CVD diagnoses made in primary and in-patient care, as well as risk factor distribution by geographic regions (urban/rural) in Iceland. METHODS: From nationwide health registers, we obtained data on CVD mortalities ( N = 7113), primary healthcare CVD contacts ( N = 58,246) and hospital CVD discharges ( N = 14,039), as well as data on CVD risk factors from a national health survey ( N = 5909; response rate 60.3%). Age-standardised annual mortality, primary healthcare contact and hospital discharge rates due to CVD were calculated per 100,000 population inside (urban) and outside (rural) the Capital Area (CA). Logistic regression was used to explore regional differences in CVD risk factors. RESULTS: We observed slightly higher total CVD mortality rates among women outside compared to inside the CA (Standardised Rate Ratio (SRR) 1.06 (95% confidence interval (CI) 1.05-1.07)), particularly due to atrial fibrillation (SRR 1.47 (95% CI 1.46-1.48)), heart failure (SRR 1.29 (95% CI 1.27 1.31)) and ischemic heart disease (SRR 1.11 (95% CI 1.10-1.12)), while reduced mortality risk for cerebrovascular disease (SRR 0.81 (95% CI 0.80-0.83)). The rates of hospital discharges and primary care contacts for these diseases, as well as prevalence of several modifiable risk factors, were generally higher outside the CA, particularly among women. CONCLUSIONS: The higher prevalence of modifiable risk factors and CVD in rural areas, especially among women, calls for refined treatment and health-promoting efforts in rural areas. PMID- 28078935 TI - Tracking Decrement as a Result of Grip Holding Endurance. AB - This study explores the feasibility of using the static strength and endurance relationships suggested by Rohmert in 1960 to predict pursuit tracking performance, Ten male subjects are tested on a pursuit rotor before and after being subjected to specific levels of loading on a grip holding device. The loading corresponded to specific levels of each subject's maximum endurance as determined from Rohmert's strength and endurance equation. The hypotheses are: (a) predetermined schedules of strength expenditure cause a systematic decrement in tracking efficiency; and (b) the process of recovering efficiency is dependent upon the expenditure schedules. Resulting data support these hypotheses, suggesting that tracking efficiency can be reliably predicted using some of the strength and endurance relationships postulated by Rohmert. PMID- 28078936 TI - The Luminous Intensity Requirements of Vehicle Front Lights for Use in Towns. AB - Previous studies suggest that the use of the dipped headlights on urban traffio routes lit by street lighting is undesirable because of glare, yet it is often contended that present marker lights are not adequately conspicuous. An investigation was therefore carried out, using appraisal techniques, to determine the intensity of vehicle front lights which will be adequately conspicuous without being too bright. It was found that the intensity requirements were largely independent of observer attributes, the luminance of the road surface and its surrounds and the number and movement of the vehicles. However, the results suggest that conspicuity and brightness are different attributes of a light. While both increased with increasing luminous intensity, the observers found that, for a given intensity, a larger source was the more conspicuous but that a smaller caused t he more discomfort. Optimum lighting appears to be a town beam, based on dimming the present dipped headlight, giving a straight ahead intensity of 80 ed. If the light is based on the small diameter marker light this value needs to be doubled to give adequate conspicuity, but then this light will be regarded as too bright in about one observation in twenty. PMID- 28078943 TI - How can we apply the use of surface-enhanced Raman scattering nanoparticles in tumor imaging? PMID- 28078944 TI - Rethinking the relationship between socio-economic status and health: Making the case for sociological theory in health inequality research. AB - AIM: The aim of this study is to analyse previous explanations of social inequality in health and argue for a closer integration of sociological theory into future empirical research. METHODS: We examine cultural-behavioural, materialist, psychosocial and life-course approaches, in addition to fundamental cause theory. Giddens' structuration theory and a neo-materialist approach, inspired by Bruno Latour, Gilles Deleuze and Felix Guattari, are proposed as ways of rethinking the causal relationship between socio-economic status and health. CONCLUSIONS: Much of the empirical research on health inequalities has tended to rely on explanations with a static and unidirectional view of the association between socio-economic status and health, assuming a unidirectional causal relationship between largely static categories. We argue for the use of sociological theory to develop more dynamic models that enhance the understanding of the complex pathways and mechanisms linking social structures to health. PMID- 28078945 TI - Influences of population size and density on birthplace effects. AB - Contextual influences on talent development (e.g., birthplace effects) have become a topic of interest for sport scientists. Birthplace effects occur when being born in a certain city size leads to participation or performance advantages, typically for those born in smaller or mid-sized cities. The purpose of this study was to investigate birthplace effects in Portuguese volleyball players by analysing city size, as well as population density - an important but infrequently used variable. Participants included 4062 volleyball players (Mage = 33), 53.2% of whom were men. Using Portuguese national census data from 1981, we compared participants (within each sex) across five population categories. In addition, we used ANOVAs to study expertise and population density. Results indicated that men and women athletes born in districts of 200,000-399,999 were 2.4 times more likely to attain elite volleyball status, while all other districts decreased the odds of expert development. For men, being born in high density areas resulted in less chance of achieving expertise, whereas there were no differences for women. The results suggest that athletes' infrastructure and social structure play an important role in talent development, and that these structures are influenced by total population and population density, respectively. PMID- 28078947 TI - Monitoring of Plasmodium infection in humans and potential vectors of malaria in a newly emerged focus in southern Iran. AB - Despite control programs, which aim to eliminate malaria from Iran by 2025, transmission of malaria has not been removed from the country. This study aimed to monitor malaria from asymptomatic parasitaemia and clinical cases from about one year of active case surveillance and potential vectors of malaria in the newly emerged focus of Mamasani and Rostam, southern Iran during 2014-2015. Samples were collected and their DNAs were extracted for Polymerase Chain Reaction (PCR) assay using specific primers for detection of Plasmodium species. The Annual Parasite Incidence rate (API) was three cases per 1,000 population from 2,000 individuals in three villages. Parasites species were detected in 9 out of the 4,000 blood smear samples among which, 6 cases were indigenous and had no history of travels to endemic areas of malaria. Also, the prevalence rate of asymptomatic parasites was about 0.3%. Overall, 1073 Anopheles spp. were caught from 9 villages. Totally, 512 female samples were checked by PCR, which indicated that none of them was infected with Plasmodium. Despite new malaria local transmission in humans in Mamasani and Rostam districts, no infection with Plasmodium was observed in Anopheles species. Because of neighboring of the studied area to the re-emerged focus in Fars province (Kazerun) and important endemic foci of malaria in other southern provinces, such as Hormozgan and Kerman, monitoring of the vectors and reservoir hosts of Plasmodium species would be unavoidable. Application of molecular methods, such as PCR, can simplify access to the highest level of accuracy in malaria researches. PMID- 28078948 TI - Care seeking for children with fever/cough or diarrhoea in Nepal: equity trends over the last 15 years. AB - AIMS: Childhood illnesses such as diarrhoea and pneumonia remain major contributors to child mortality globally and need to be continually targeted in pursuit of universal health coverage. This study analyses time trends in the prevalence of fever/cough and diarrhoea in Nepal and applies an equity lens in order to identify disadvantaged groups. METHODS: Data from the Nepal Demographic Health Surveys of 2001, 2006, and 2011, together with data from the most recent Multiple Indicator Cluster Survey of 2014 performed in Nepal, were utilized for analysis. RESULTS: Analyses revealed improvements (lower prevalence) of diarrhoea and fever/cough in children under five in Nepal over the last 15 years, with an equitable distribution of symptoms over socio-economic determinants. There was, however, a marked and maintained inequity in care seeking for these symptoms, with less educated mothers and those from poor households being only approximately half as likely to seek care for their children. CONCLUSIONS: Results highlight the persisting need for targeting care-seeking and societal barriers to treatment in order to achieve universal health access. PMID- 28078949 TI - Nature-inspired DNA switches: applications in medicine. PMID- 28078950 TI - Magnetic nanoparticles-based drug and gene delivery systems for the treatment of pulmonary diseases. AB - Magnetic nanoparticles (MNPs) have gained much attention due to their unique properties such as biocompatibility and biodegradability as well as magnetic and heat-medicated characteristics. Due to these inherent properties, MNPs have been widely used in various biomedical applications including targeted drug delivery and hyperthermia-based therapy. Hyperthermia is a promising approach for the thermal activation therapy of several diseases, including pulmonary diseases. Additionally, due to their large loading capacity and controlled release ability, several MNP-based drug delivery systems have been emerged for treatment of cystic fibrosis and lung cancer. This review provides an overview on the unique properties of MNPs and magnetic-mediated hyperthermia with emphasis on the recent biomedical applications of MNPs in treatment of both lung cancer and cystic fibrosis. PMID- 28078952 TI - Recent advances in green nanoparticulate systems for drug delivery: efficient delivery and safety concern. AB - Nanotechnology manipulates therapeutic agents at the nanoscale for the development of nanomedicines. However, there are current concerns over nanomedicines, mainly related to the possible toxicity of nanomaterials used for health medications. Due to their small size, they can enter the human body more readily than larger sized particles. Green chemistry encompasses the green synthesis of drug-loaded nanoparticles by reducing the use of hazardous materials in the synthesis process, thus reducing the adverse health impacts of pharmaceutics. This would greatly expand their potential in biomedical treatments. This review highlights the potential risks of nanomedicine formulations to health, delivery routes of green nanomedicines, recent advances in the development of green nanoscale systems for biomedical applications and future perspectives for the green development of nanomedicines. PMID- 28078953 TI - Evidence-Based Strategies for Shortening Informed Consent Forms in Clinical Research. AB - Long informed consent forms (ICFs) remain commonplace, yet they can negatively affect potential participants' understanding of clinical research. We aimed to build consensus among six groups of key stakeholders on advancing the use of shorter ICFs in clinical research. Partnering with the HIV Prevention Trials Network (HPTN), we used a modified Delphi process with semistructured interviews and online surveys. Concerns about redundancy of information were common. Respondents supported three strategies for reducing ICF length: (a) 91% agreed or strongly agreed with grouping study procedures by frequency, (b) 91% were comfortable or very comfortable with placing supplemental information into appendices, and (c) 93% agreed or strongly agreed with listing duplicate side effects only once. Implementing these strategies will facilitate adoption of the proposed changes to U.S. regulations on ICF length, should they be enacted. PMID- 28078954 TI - Nanovesicle delivery to the liver via retinol binding protein and platelet derived growth factor receptors: how targeting ligands affect biodistribution. AB - AIM: Nanovesicles (NVs) conjugating ligands can deliver to the specific nidus. We designed a nanosystem targeting the injectable niosomes to liver for examining biodistribution. METHODOLOGY: Vitamin A and antiplatelet-derived growth factor receptor antibody were employed as the ligands to be taken by hepatic stellate cells. The biodistribution in rats was visualized by bioimaging. RESULTS: A significant liver accumulation was detected for antibody-embedded NVs at 2 h after dosing. The vitamin A embedded NVs exhibited a delayed targeting to the liver (5 h). The spleen, intestine and kidneys were the nontargeted organs where the vitamin A loaded niosomes largely accumulated. The antibody-loaded NVs could deliver to the spleen, kidneys and lungs. The antibody-loaded nanocarriers increased silibinin uptake to lungs by fourfold than the plain NVs. CONCLUSION: The results have practical application for better designing of active targeting nanocarriers. PMID- 28078966 TI - Visual and cross-modal cues increase the identification of overlapping visual stimuli in Balint's syndrome. AB - INTRODUCTION: Cross-modal interactions improve the processing of external stimuli, particularly when an isolated sensory modality is impaired. When information from different modalities is integrated, object recognition is facilitated probably as a result of bottom-up and top-down processes. The aim of this study was to investigate the potential effects of cross-modal stimulation in a case of simultanagnosia. METHOD: We report a detailed analysis of clinical symptoms and an 18F-fluorodeoxyglucose (FDG) brain positron emission tomography/computed tomography (PET/CT) study of a patient affected by Balint's syndrome, a rare and invasive visual-spatial disorder following bilateral parieto occipital lesions. An experiment was conducted to investigate the effects of visual and nonvisual cues on performance in tasks involving the recognition of overlapping pictures. Four modalities of sensory cues were used: visual, tactile, olfactory, and auditory. RESULTS: Data from neuropsychological tests showed the presence of ocular apraxia, optic ataxia, and simultanagnosia. The results of the experiment indicate a positive effect of the cues on the recognition of overlapping pictures, not only in the identification of the congruent valid-cued stimulus (target) but also in the identification of the other, noncued stimuli. All the sensory modalities analyzed (except the auditory stimulus) were efficacious in terms of increasing visual recognition. CONCLUSIONS: Cross-modal integration improved the patient's ability to recognize overlapping figures. However, while in the visual unimodal modality both bottom-up (priming, familiarity effect, disengagement of attention) and top-down processes (mental representation and short-term memory, the endogenous orientation of attention) are involved, in the cross-modal integration it is semantic representations that mainly activate visual recognition processes. These results are potentially useful for the design of rehabilitation training for attentional and visual perceptual deficits. PMID- 28078967 TI - The glycocalyx regulates the uptake of nanoparticles by human endothelial cells in vitro. AB - AIM: To assess the role of the endothelial glycocalyx (eGCX) for the uptake of nanoparticles by endothelial cells. METHODS: The expression of the eGCX on cultured human umbilical vein endothelial cells was determined by immunostaining of heparan sulfate. Enzymatic degradation of the eGCX was achieved by incubating the cells with eGCX-shedding enzymes. The uptake of 50-nm polystyrene nanospheres was quantified by confocal microscopy. RESULTS: Human umbilical vein endothelial cells expressed a robust eGCX when cultured for 10 days. The uptake of both carboxylated and aminated polystyrene nanospheres was significantly increased in cells in which the glycocalyx was enzymatically degraded, while it remained at a low level in cells with an intact glycocalyx. CONCLUSION: The eGCX constitutes a barrier against the internalization of blood-borne nanoparticles by endothelial cells. PMID- 28078968 TI - Sublime frequencies: The construction of sublime listening experiences in the sonification of scientific data. AB - In the past two decades, the sonification of scientific data - an auditory equivalent of data visualization in which data are turned into sounds - has become increasingly widespread, particularly as an artistic practice and as a means of popularizing science. Sonification is thus part of the recent trend, discussed in public understanding of science literature, towards increased emphasis on 'interactivity' and 'crossovers' between science and art as a response to the perceived crisis in the relationship between the sciences and their publics. However, sonification can also be understood as the latest iteration in a long tradition of theorizing the relations between nature, science and human experience. This article analyses the recent public fascination with sonification and argues that sonification grips public imaginations through the promise of sublime experiences. I show how the 'auditory sublime' is constructed through varying combinations of technological, musical and rhetorical strategies. Rather than maintain a singular conception of the auditory sublime, practitioners draw on many scientific and artistic repertoires. However, sound is often situated as an immersive and emotional medium in contrast to the supposedly more detached sense of vision. The public sonification discourse leaves intact this dichotomy, reinforcing the idea that sound has no place in specialist science. PMID- 28078969 TI - What caused the flood? Controversy and closure in the Hurricane Katrina disaster. AB - Causal attribution for one of the largest disasters in American history has undergone three major shifts. From August 2005 through November 2009, the principal explanation of the flooding of New Orleans was characterized by three distinguishable phases - reactive, organizational, and legal - as the catastrophic events of Hurricane Katrina were ascribed to natural, geotechnical, and environmental causes. From a monstrous storm, to failed levees, and ultimately the loss of wetlands through an insidious shipping channel, 'what happened' should be viewed as a technoscientific development in which media and litigation processes transformed the structural conditions for the production of knowledge claims. Video ethnography is used to examine causal transitions as structural conditions of inquiry changed. Levees - the most important symbol of failure - shifted from cause to consequence. Understanding of disaster cycled from nature to humans, and to nature once more. PMID- 28078970 TI - Scandals, audits, and fictions: Linking climate change to Mexican forests. AB - Over the past 10 years, Mexican officials and scientists have promoted the project of protecting Mexican forests in order to mitigate climate change, forests acting to absorb carbon dioxide from the atmosphere. This article compares existing policies around mass reforestation and markets for environmental services, and their relationships to a policy in construction - Reduced Emissions through Degradation and Deforestation. Mass reforestation policies collapsed in the face of politicized audits and stories about corruption; markets for environmental services continued with little criticism, stabilized in part by the charisma of Reduced Emissions through Degradation and Deforestation policies. I explain the collapse of mass reforestation policies as being due to failed knowledge performances by officials and scientists; such failures are assessed by more or less skeptical publics who expect specific ways of performing credible public knowledge. Areas of nonknowledge can be tamed as calculable uncertainty, or alternatively transformed into ontological indeterminacy, scandals, and stories of corruption. Areas of nonknowledge are not pathological: they may support, as well as undermine, climate science, the authority of institutions, or the credibility of carbon accounts. PMID- 28078972 TI - The predictive state: Science, territory and the future of the Indian climate. AB - Acts of scientific calculation have long been considered central to the formation of the modern nation state, yet the transnational spaces of knowledge generation and political action associated with climate change seem to challenge territorial modes of political order. This article explores the changing geographies of climate prediction through a study of the ways in which climate change is rendered knowable at the national scale in India. The recent controversy surrounding an erroneous prediction of melting Himalayan glaciers by the Intergovernmental Panel on Climate Change provides a window onto the complex and, at times, antagonistic relationship between the Panel and Indian political and scientific communities. The Indian reaction to the error, made public in 2009, drew upon a national history of contestation around climate change science and corresponded with the establishment of a scientific assessment network, the Indian Network for Climate Change Assessment, which has given the state a new platform on which to bring together knowledge about the future climate. I argue that the Indian Network for Climate Change Assessment is indicative of the growing use of regional climate models within longer traditions of national territorial knowledge-making, allowing a rescaling of climate change according to local norms and practices of linking scientific knowledge to political action. I illustrate the complex co-production of the epistemic and the normative in climate politics, but also seek to show how co-productionist understandings of science and politics can function as strategic resources in the ongoing negotiation of social order. In this case, scientific rationalities and modes of environmental governance contribute to the contested epistemic construction of territory and the evolving spatiality of the modern nation state under a changing climate. PMID- 28078973 TI - Actor-Network Theory and methodology: Just what does it mean to say that nonhumans have agency? AB - Actor-Network Theory is a controversial social theory. In no respect is this more so than the role it 'gives' to nonhumans: nonhumans have agency, as Latour provocatively puts it. This article aims to interrogate the multiple layers of this declaration to understand what it means to assert with Actor-Network Theory that nonhumans exercise agency. The article surveys a wide corpus of statements by the position's leading figures and emphasizes the wider methodological framework in which these statements are embedded. With this work done, readers will then be better placed to reject or accept the Actor-Network position - understanding more precisely what exactly it is at stake in this decision. PMID- 28078974 TI - A deviation from standard design? Clinical trials, research ethics committees, and the regulatory co-construction of organizational deviance. AB - Focusing on the high-profile drug disaster at London's Northwick Park Hospital in 2006, this article explores how such an event can be seen as an example of organizational deviance co-constructed between the company running the research and the research ethics committee which approved the trial. This deviance was the result of the normalization of a specific dosing practice in the broader regulatory field, allowing the researchers and regulators to take a risky dosing strategy for granted as best practice. Drawing on the work of Diane Vaughan, this article uses interview data with researchers and members of the research ethics committee concerned as well as documentary material, to show how work group cultures between regulators and those they are intended to oversee are maintained, and how the culturally embedded assumptions of such work groups can result in organizational and regulatory deviance. PMID- 28078975 TI - The Uniformity Illusion. AB - Vision in the fovea, the center of the visual field, is much more accurate and detailed than vision in the periphery. This is not in line with the rich phenomenology of peripheral vision. Here, we investigated a visual illusion that shows that detailed peripheral visual experience is partially based on a reconstruction of reality. Participants fixated on the center of a visual display in which central stimuli differed from peripheral stimuli. Over time, participants perceived that the peripheral stimuli changed to match the central stimuli, so that the display seemed uniform. We showed that a wide range of visual features, including shape, orientation, motion, luminance, pattern, and identity, are susceptible to this uniformity illusion. We argue that the uniformity illusion is the result of a reconstruction of sparse visual information (from the periphery) based on more readily available detailed visual information (from the fovea), which gives rise to a rich, but illusory, experience of peripheral vision. PMID- 28078976 TI - Beyond Purity. AB - Previous studies support a link between moral disgust and impurity, whereas anger is linked to harm. We challenged these strict correspondences by showing that disgust is activated in response to information about moral character, even for harm violations. By contrast, anger is activated in response to information about actions, including their moral wrongness and consequences. Study 1 examined disgust and anger in response to an action that suggests bad moral character (animal cruelty) versus an action that is seen as inherently more wrong (domestic abuse). Animal cruelty was associated with more disgust than domestic abuse was, whereas domestic abuse was associated with more anger. Studies 2 and 3 manipulated character by varying the agent's desire to cause harm and also varied the action's harmful consequences. Desire to harm predicted only disgust (controlling for anger), whereas consequences were more closely related to anger (controlling for disgust). Taken together, these results indicate that disgust arises in response to evidence of bad moral character, not just to impurity. PMID- 28078977 TI - Emotion-Cognition Interaction in Nonhuman Primates: Cognitive Avoidance of Negative Stimuli in Baboons (Papio papio) AB - It is well established that emotion and cognition interact in humans, but such an interaction has not been extensively studied in nonhuman primates. We investigated whether emotional value can affect nonhuman primates' processing of stimuli that are only mentally represented, not visually available. In a short term memory task, baboons memorized the location of two target squares of the same color, which were presented with a distractor of a different color. Through prior long-term conditioning, one of the two colors had acquired a negative valence. Subjects were slower and less accurate on the memory task when the targets were negative than when they were neutral. In contrast, subjects were faster and more accurate when the distractors were negative than when they were neutral. Some of these effects were modulated by individual differences in emotional disposition. Overall, the results reveal a pattern of cognitive avoidance of negative stimuli, and show that emotional value alters cognitive processing in baboons even when the stimuli are not physically present. This suggests that emotional influences on cognition are deeply rooted in evolutionary continuity. PMID- 28078979 TI - Biotechnological Patents Applications of the Deuterium Oxide in Human Health. AB - BACKGROUND: Deuterium oxide is a molecule that has been used for decades in several studies related to human health. Currently, studies on D2O have mobilized a "Race for Patenting" worldwide. Several patents have been registered from biomedical and technological studies of D2O showing the potential of this stable isotope in industry and health care ecosystems. METHODS: Most of the patents related to the applications of the deuterium oxide in human health have been summarized in this review. The following patents databases were consulted: European Patent Office (Espacenet), the United States Patent and Trademark Office (USPTO), the United States Latin America Patents (LATIPAT), Patent scope -Search International and National Patent Collections (WIPO), Google Patents and Free Patents Online. RESULTS: With this review, the information was collected on recent publications including 22 patents related to deuterium oxide and its applications in different areas. CONCLUSION: This review showed that deuterium oxide is a promising component in different areas, including biotechnology, chemistry and medicine. In addition, the knowledge of this compound was covered, reinforcing its importance in the field of biotechnology and human health. PMID- 28078978 TI - Preschoolers Flexibly Adapt to Linguistic Input in a Noisy Channel. AB - Because linguistic communication is inherently noisy and uncertain, adult language comprehenders integrate bottom-up cues from speech perception with top down expectations about what speakers are likely to say. Further, in line with the predictions of ideal-observer models, past results have shown that adult comprehenders flexibly adapt how much they rely on these two kinds of cues in proportion to their changing reliability. Do children also show evidence of flexible, expectation-based language comprehension? We presented preschoolers with ambiguous utterances that could be interpreted in two different ways, depending on whether the children privileged perceptual input or top-down expectations. Across three experiments, we manipulated the reliability of both their perceptual input and their expectations about the speaker's intended meaning. As predicted by noisy-channel models of speech processing, results showed that 4- and 5-year-old-but perhaps not younger-children flexibly adjusted their interpretations as cues changed in reliability. PMID- 28078981 TI - Resilience to Alzheimer's Disease: The Role of Physical Activity AB - BACKGROUND: Although Alzheimer's disease (AD) is a neurodegenerative pathology characterized by accumulation of beta-amyloid plaques and neurofibrillary tangles at cerebral level, recent studies highlighted that AD might be the result of many altered physiological processes occurring at whole-organism level. The ability to adapt to stressors by "bending" but not "breaking" can be considered as "resilience". Individuals incline to withstand such pathophysiological challenges, can be considered more resilient than those that do not. Noticeably, recent literature provide evidence of several exercise-induced positive effects in AD patients including improved brain plasticity, increased adrenal sensitivity, increased vascular health, ameliorations of nitric oxide bioavailability and mitochondrial function. This review explores what resilience means in the AD milieu and the physiological mechanisms by which physical activity may mediate positive adaptative processes that enhance resilience. METHODS: A comprehensive PubMed search was conducted to identify studies about the role of exercise in AD resiliency. The following terminology was applied: Alzheimer resilience, brain resilience, metabolic resilience, cardiovascular resilience, mitochondrial resilience and exercise resilience. RESULTS: Seventy three studies were included. Five papers defined Alzheimer's resilience, 15 papers brain resilience, 5 cardiovascular resilience, 1 metabolic resilience, 11 mitochondrial resilience, and 7 exercise resilience. Other twenty-six paper were identified from reference list of authors' knowledge. CONCLUSION: Knowing that disturbances in brain, neuroendocrine, vascular and mitochondria metabolism are important events in neurodegeneration and dementia development, the ability of exercise to trigger adaptive mechanisms might represent an important non pharmacological strategy to improve resilience to AD. PMID- 28078980 TI - Bioremediation of Toxic Heavy Metals: A Patent Review. AB - BACKGROUND: The global industrialization is fulfilling the demands of modern population at the cost of environmental exposure to various contaminants including heavy metals. These heavy metals affect water and soil quality. Moreover, these enter into the food chain and exhibit their lethal effects on the human health even when present at slightly higher concentration than required for normal metabolism. To the worst of their part, the heavy metals may become carcinogenic. Henceforth, the efficient removal of heavy metals is the demand of sustainable development. Remedy: Bioremediation is the 'green' imperative technique for the heavy metal removal without creating secondary metabolites in the ecosystem. The metabolic potential of several bacterial, algal, fungal as well as plant species has the efficiency to exterminate the heavy metals from the contaminated sites. Different strategies like bioaccumulation, biosorption, biotransformation, rhizofilteration, bioextraction and volatilization are employed for removal of heavy metals by the biological species. Bioremediation approach is presenting a splendid alternate for conventional expensive and inefficient methods for the heavy metal removal. CONCLUSION: The patents granted on the bioremediation of toxic heavy metals are summarized in the present manuscript which supported the applicability of bioremediation technique at commercial scale. However, the implementation of the present information and advanced research are mandatory to further explore the concealed potential of biological species to resume the originality of the environment. PMID- 28078982 TI - Phytochemicals - A Novel and Prominent Source of Anti-cancer Drugs Against Colorectal Cancer. AB - BACKGROUND & AIM: Colorectal cancer (CRC) is a malignant disease whose incidence and mortality rates are greatly influenced by environmental factors. Under treatment of CRC such as a poor diagnostic evaluation, less aggressive surgery, less intensive chemotherapy results in metastasizing of the primary tumor cells and recurrence of cancer. Prolonged chemotherapy treatment against cancer is hazardous to the patients, which also limits its use in cancer therapy. Current research in developing a novel anti-cancer agent, direct towards finding a better antimetastatic and an anti-invasive drug with reduced side effects. METHOD & RESULTS: In this direction, plant derived chemical compounds or phytochemical act as a prominent source of new compounds for drug development. Phytochemicals have a multi-action and a multi-target capacity, and has gained attention among the research communities from last two decades. Epidemiological study shows a direct relationship between a diet and CRC development. A diet rich in plant based products such as vegetables, fruits and cereals is known to prevent CRC development. This review is an effort to explore more about the potential phytochemicals in CRC prevention and also in CRC treatment. CONCLUSION: Here, we have discussed few phytochemicals actively used in CRC research and are in clinical trials against CRC. We have explored more on some of these phytochemicals which can act as a source for new drug or can act as a lead compound for further modifications during the drug development against cancer. PMID- 28078983 TI - Cutaneous Larva Migrans. AB - BACKGROUND: Cutaneous larva migrans is one of the most common skin diseases reported in travelers returning from tropical regions. Western physicians, however, are often not familiar of this condition. OBJECTIVE: To review in depth the epidemiology, pathophysiology, clinical manifestations, complications, and treatment of cutaneous larva migrans. METHODS: A PubMed search was completed in Clinical Queries using the key term "cutaneous larva migrans". The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. Patents were searched using the key term "cutaneous larva migrans" from www.google.com/patents, www.uspto.gov, and www.freepatentsonline.com. RESULTS: Cutaneous larva migrans is a zoonotic infestation caused by penetration and migration in the epidermis of filariform larva of different kinds of animal hookworms through contact with feces of infected animals. Cutaneous larva migrans is endemic in tropical and subtropical regions. Clinically, cutaneous larva migrans is characterized by an intensely pruritic erythematous migrating tortuous or serpiginous, slightly raised track. The diagnosis is mainly clinical, based on the history of travel to an endemic area and exposure to contaminated soil/sand and the characteristic serpiginous track. Treatment options as well as recent patents related to the management of cutaneous larva migrans are also discussed. Compared with oral antihelminthics, topical treatment over the affected area is less effective. Oral ivermectin is the treatment of choice. CONCLUSION: The pruritic serpiginous track is pathognomonic. Oral ivermectin is the treatment of choice. PMID- 28078984 TI - Rasburicase-Induced Methemoglobinemia in a Patient with Glucose-6- Phosphate Dehydrogenase Deficiency. AB - BACKGROUND: Rasburicase is commonly used in patients with hematologic malignancies for tumor lysis syndrome prophylaxis and management. Methemoglobinemia is a serious rare adverse effect of rasburicase, more common in patients with G6PD deficiency. Prompt diagnosis and appropriate management of this condition can make the difference between successful recovery and significant morbidity. Here we discuss the link of rasburicase with methemoglobinemia and the pathophysiology behind increased incidence of this side effect in G6PD deficient patients. METHODS: We report the case of a 73-year-old African American man who developed methemoglobinemia on rasburicase treatment, who was later confirmed to be G6PD deficient. We reviewed the literature using Pubmed and Google Scholar using the following key words: "methemoglobinemia", "rasburicase", "urate oxidase", tumor lysis syndrome", G6PD deficiency", "hemolytic anemia" and "hyperuricemia". RESULTS: Rasburicase-induced methemoglobinemia is more common in patients with G6PD deficiency, and rasburicase is therefore contraindicated in these patients. Clinical presentation includes cyanosis, pallor, methemoglobin levels of 8-12%, and oxygen saturation gap which is evident from ABG analysis, though pulse oximetry is normal. Treatment consists of oxygen supplementation, ascorbic acid and blood transfusion. Importantly, methylene blue is avoided as therapy in G6PD deficiency as it can worsen the methemoglobinemia. CONCLUSION: Rasburicase-induced methemoglobinemia is a serious concern, especially in African- American patients. It should be considered when clinical signs and symptoms are present. Knowledge of this side effect is important in early diagnosis and successful management of the condition. PMID- 28078985 TI - Designing Isoform-selective Inhibitors Against Classical HDACs for Effective Anticancer Therapy: Insight and Perspectives from In Silico. AB - Histone deacetylase inhibitors, the small molecules modulating the biological activity of histone deacetylases are emerging as potent chemotherapeutic agents. Despite their considerable therapeutic benefits in disease models, the lack of isoform specificity culminates in debilitating off target effects, raising serious concerns regarding their applicability. This emphasizes the pressing and unmet medical need of designing isoform selective inhibitors for safe and effective anticancer therapy. Keeping these grim facts in view, the current article sheds light on structural basis of off-targeting. Furthermore, the article discusses extensively the role of in silico strategies such as Molecular Docking, Molecular Dynamics Simulation and Energetically-optimized structure based pharmacophore approach in designing on-target inhibitors against classical HDACs. PMID- 28078986 TI - Cultivating a Trauma Awareness Culture in the Addictions. AB - BACKGROUND: Research evidence points to the high prevalence of trauma exposure and post traumatic stress among addicted individuals, their families and the professionals responsible for their treatment. OBJECTIVE: The purpose of this review is to enhance understanding of the continuing effects of trauma and its impact on the lives of people with addiction problems as well as on the professionals who strive to provide support and care for them. METHOD: Review of twenty eight articles on traumatic experiences in individuals and families facing addiction problems as well as on traumatic stress in addiction professionals. Eligibility criteria were: publication in a peer-reviewed journal dating from 1990 to present; articles written in the English language; quantitative or qualitative design aiming to explore the lived experience of trauma and the recovery process from it. RESULTS: It is argued that for service providers to be able to help patients restore purpose and meaning in the recovery process, it is important to be aware of the trauma dynamics implicated in the long history of the addiction problems. Professionals' difficulty to process their emotions may lead to disengagement or overinvolvement and the adoption of maladaptive roles. Strong and unexpected emotional reactions in the professional may be a clue to the presence of masked trauma. CONCLUSION: Ongoing training on trauma dynamics, self-care and clinical supervision may deepen professionals' understanding of the impact of trauma on their work culture and protect them from the risk of secondary traumatic stress. PMID- 28078987 TI - Role of Proinflammatory Cytokines in Dopaminergic System Disturbances, Implications for Anhedonic Features of MDD. AB - Anhedonia, characterized by a loss of interest and/or pleasure in previously enjoyable activities, is an important diagnostic criterion of Major Depressive Disorder (MDD). Converging evidence implicates a causal relationship between proinflammatory cytokines and behavioural disturbances that characterize anhedonia in the context of MDD. Additionally, anhedonia has been implicated in disturbances of key central dopaminergic modulatory pathways. Emerging research into the roles of tetrahydrobiopterin, a cytokine-targeted co-enzyme in the synthesis of dopamine, and kynurenine, a product of inflammation-sensitive breakdown of tryptophan via indoleamine 2, 3-dioxygenase, have shed new light into the role of inflammation in mediating anhedonic behaviours. The following narrative review is not meant to be comprehensive, but highlights the roles of both tetrahydrobiopterin and kynurenine pathways in anhedonia, and discusses a potential mechanism of action via oxidative stress and excitotoxicity. Treatment implications are discussed, with an emphasis on anti-inflammatories as complements to current treatments of anhedonia and MDD. PMID- 28078988 TI - BDNF/NF-kappaB Signaling in the Neurobiology of Depression. AB - BACKGROUND: Mood disorders, consisting of unipolar and bipolar depression, are complex diseases characterized by depressed mood and anhedonia. These core symptoms are accompanied in a varying manner by anxiety, several neurovegetative symptoms and cognitive impairment. Mood disorders are characterized by decreases in neurogenesis, alteration in synaptic structure and synaptic transmission, all of them regulated by BDNF, a neurotrophin that performs multiple functions in the adult central nervous system. Many evidences show that BDNF is critically decreased in mood disorders and plays an essential role in most anti-depressant treatments. In turn, the transcription factor NF-kB has recently emerged as an important player in the pathophysiology of depression, with roles in neurogenesis, synaptic transmission and plasticity. METHODOLOGY: We review the bidirectional interactions between BDNF and NF-kB signaling pathways. RESULTS AND CONCLUSIONS: We discuss a potential beneficial effect of a positive feedback loop between BDNF and NF-kB activated pathways in antidepressant action. This could be transduced into the identification of downstream NF-kB gene targets able to potentiate antidepressant mechanisms, thus guiding the development of novel and faster acting antidepressant drugs. PMID- 28078989 TI - A Comprehensive Review of mTOR-Inhibiting Pharmacotherapy for the Treatment of Non-Infectious Uveitis. AB - BACKGROUND: Non-infectious uveitis is a sight-threatening inflammatory disease that often necessitates prolonged use of high-dose corticosteroids, resulting in significant systemic side effects. There is a need for efficacious steroid sparing immunomodulatory therapy for these patients, and the mTOR inhibitors (sirolimus and everolimus) may be contenders for this role. METHODS: A comprehensive review of preclinical and clinical research on mTOR inhibitors for non-infectious uveitis was performed. Articles were identified by a search of MEDLINE (PubMed/OVID) and EMBASE (OVID) the terms (uveitis OR non-infectious uveitis) AND (mTOR inhibitor OR sirolimus OR everolimus). Assessment of study aims, methods, efficacy outcomes and adverse events was performed. RESULTS: Seven pre-clinical and nine clinical studies were identified. One study in each group was on everolimus, the rest sirolimus. Preclinical studies have been performed in rabbit, rat, mouse and in-vitro models. Clinical studies range from comparative open-label trials to case reports, with reported clinical efficacy ranging from 40% to 100% depending on endpoint assessed. The overall rate of drug-related adverse events (such as ocular irritation, visual floaters, nausea and vomiting) was 0.640 events per patient-year with sirolimus, and 0.111 events per patient year with everolimus. CONCLUSION: Published evidence suggests that sirolimus and everolimus may be useful in the management of noninfectious uveitis. Both appear to be well tolerated, especially when locally administered. Further high-quality RCTs adopting standardised end-points are required to definitively determine the efficacy of each agent. PMID- 28078990 TI - Mass Spectrometry Imaging in Nanomedicine: Unraveling the Potential of MSI for the Detection of Nanoparticles in Neuroscience. AB - Mass spectrometry imaging (MSI) can uniquely detect thousands of compounds allowing both their identification and localization within biological tissue samples. MSI is an interdisciplinary science that crosses the borders of physics, chemistry and biology, and enables local molecular analysis at a broad range of length scales: From the subcellular level to whole body tissue sections. The spatial resolution of some mass spectrometers now allows nano-scale research, crucial for studies in nanomedicine. Recent developments in MSI have enabled the optimization and localization of drug delivery with nanoparticles within the body and in specific organs such as kidney, liver and brain. Combining MSI with nanomedicine has vast potential, specifically in the treatment of neurological disorders, where effective drug delivery has been hampered by the blood-brain barrier. This review provides an introduction to MSI and its different technologies, with the application of MSI to nanomedicine and the different possibilities that MSI offers to study molecular signals in the brain. Finally, we provide an outlook for the future and exciting potential of MSI in nanoparticle-related research. PMID- 28078991 TI - Vegetable Organosulfur Compounds and their Health Promoting Effects. AB - BACKGROUND: Trends in modern pharmaceutical science show an increase in demand for new drugs and diet supplements derived from natural products, while during the last decades, great research is conducted regarding the natural compounds and their medicinal and bioactive properties. Organosulfur compounds are present in many plants and their bioactive properties have been used in folk and traditional medicine throughout the centuries. Not until recently, modern science confirmed and revealed the chemical compounds that are responsible for these properties, the chemistry involved in their biosynthesis and the main mechanisms of action. OBJECTIVE: In the present review, the organosulfur compounds of vegetable origin and their health effects are presented, focusing on the chemical composition of their main compounds, their biosynthesis and the mechanisms involved in their health effects. Sulfur compound sources presented include mainly vegetable species belonging to Allium genus and Brassicaceae family. CONCLUSION: Organosulfur compounds of vegetable sources are very important in human diet, and their regular consumption has a beneficial contribution to health and well-being. Moreover, their medicinal properties and therapeutic effects have been described thousands of years ago, while they constitute an important ingredient in traditional medicines and preparations. However, not until recently, the mechanisms of action of organosulfur compounds have started to unravel, with promising results for further exploitation of these significant bioactive compounds in drug development and novel nutraceutical products. This review reveals the numerous biological activities of organosulfur compounds of vegetable origin, while it also presents the results of recent clinical studies and trials. PMID- 28078992 TI - Smoking and Eye Pathologies. A Systemic Review. Part II. Retina Diseases, Uveitis, Optic Neuropathies, Thyroid-Associated Orbitopathy. AB - BACKGROUND: Tobacco smoking has detrimental influence on human health. AIM: The analysis of influence of tobacco smoking on retina diseases, uveitis, optic neuropathies, and thyroidassociated orbitopathy in adults and children. METHODS: A comprehensive review of the literature performed through MEDLINE and PubMed searches, covering the years 2000-2016. RESULTS: In adults, tobacco smoking is a strong risk factor for age-related macular degeneration, polypoidal choroidal vasculopathy, uveitis and inflamed cystoid macular edema as well as Grave's ophthalmopathy. Tobacco smoking reduces thickness of the retina and choroid, plays a role in episcleritis, sclerits, tobacco optic neuropathy, and Leber's hereditary optic neuropathy. In children, maternal smoking is a significant risk factor for stages 3 and 4 retinopathy of prematurity, optic nerve hypoplasia among babies with a birth weight over 2500 g and thinner retinal nerve fiber layer. CONCLUSION: Tobacco smoking plays an important role in the pathogenesis of many posterior eye segment diseases leading to blindness in adults and children. PMID- 28078993 TI - miRNAs: New Biomarkers and Therapeutic Targets in Dementia. AB - BACKGROUND: Dementia is a complex pathological state that affects millions of individuals worldwide and is responsible for a huge socioeconomic burden, making it a major health concern of current times. Given the impact of dementia in both patients and caregivers, it is crucial to fully clarify the molecular mechanisms underlying dementia-associated disorders, since without this knowledge our ability to correctly diagnose and treat these diseases is severely hampered. METHODS: Epigenetic mechanisms, such as miRNA-mediated post-transcriptional regulation, have been reported to play a role in dementia pathogenesis. Given their ability to bind complementary mRNA sequences, miRNAs are able to induce temporary or permanent translation repression of their mRNA targets. RESULTS: Consequently, changes in miRNA levels may contribute to alterations in the expression of dementiarelated proteins, impacting the course of the disease. Conversely, studies have also reported that some of these proteins are able to regulate the biogenesis and transport of miRNAs, hinting at novel disease-related mechanisms that are now beginning to be explored. These findings have made miRNAs both interesting tools and promising targets in the design of novel therapeutic strategies. Moreover, the discovery of circulating miRNAs, which are released by cells of various tissues, including the brain, and travel in membrane-bound vesicles found in most biofluids, opened new possibilities concerning the usefulness of miRNAs as biomarkers of disease. CONCLUSION: In this context, the major aim of this review is to discuss the relevance of these small non-coding RNAs in dementia, focusing on their role as gene expression regulators, their potential as biomarkers of dementia subtype and stage, and the hypothesis of using miRNA modulation as an innovative therapeutic approach to treat dementia related disorders. PMID- 28078994 TI - Modulation of Tumour-Related Signaling Pathways by Natural Pentacyclic Triterpenoids and their Semisynthetic Derivatives. AB - Pentacyclic triterpenoids are a large class of natural isoprenoids that are widely biosynthesized in higher plants. These compounds are potent anticancer agents that exhibit antiproliferative, antiangiogenic, antiinflammatory and proapoptotic activities. Although their effects on multiple pathways have been reported, unifying mechanisms of action have not yet been established. To date, a huge number of semisynthetic derivatives have been synthesized in different laboratories on the basis of triterpenoid scaffolds, and many have been assayed for their biological activities. The present review focuses on natural triterpenoids of the oleanane-, ursane- and lupane-types and their semisynthetic derivatives. Here, we summarize the diverse cellular and molecular targets of these compounds and the signal pathways involved in the performance of their antitumour actions. Among the most relevant mechanisms involved are cell cycle arrest, apoptosis and autophagy triggered by the effect of triterpenoids on TGF beta and HER cell surface receptors and the downstream PI3KAkt- mTOR and IKK/NF kB signaling axis, STAT3 pathway and MAPK cascades. PMID- 28078995 TI - Sphingolipids in Genetic and Acquired Forms of Chronic Kidney Diseases. AB - Sphingolipids (SLs) regulate apoptosis, proliferation, and stress response. SLs, including ceramide, glycosphingolipids (glucosylceramide, lactosylceramide, and gangliosides) and sphingosine-1-phosphate (S1P), play a role in the pathogenesis and progression of genetic (lysosomal storage disease, congenital nephrotic syndrome and polycystic kidney disease) and non-genetic forms of chronic kidney diseases (CKDs). SLs metabolism defects promote complications (cardiovascular events, etc.) via oxidant stress in CKDs. A balancing role of apoptotic SLs and anti-apoptotic S1P is crucial in the regulation of glomerular injury and complications associated with CKDs. Interaction between SLs, endothelial function and reninangiotensin- aldosterone system (RAAS) plays an important role in the regulation of glomerular injury. SLs affect mitochondrial function that regulate the opening of mitochondrial permeability transition (MPT) pore, mitochondrial outer membrane permeability (MOMP), generation of reactive oxygen species (ROS), and expression of BcL-2 family proteins, which result in cytochrome c release and caspase activation, leading to apoptosis, and regulate glomerular cell proliferation or renal fibrosis. This review article summarizes the current evidence supporting a role of SLs metabolism defects in the pathogenesis and progression of glomerular injury and discusses a role of mitochondria, including MPT pore, MOMP, ROS generation, BcL-2 family proteins, interaction between SLs, endothelial function and RAAS, and SLs-induced downstream signaling events in CKDs. Crosstalk between these factors plays a role in the pathogenesis and progression of CKDs. Therapeutic strategy of targeting SLs metabolism defects for CKDs through modulation of the enzymes responsible for SLs metabolism defects is also discussed. PMID- 28078996 TI - Kinase Inhibitors in Multitargeted Cancer Therapy. AB - The old-fashioned anticancer approaches, aiming at arresting cancer cell proliferation interfering with non-specific targets (e.g. DNA), have been replaced, in the last decades, by more specific target oriented ones. Nonetheless, single-target approaches have not always led to optimal outcomes because, for its complexity, cancer needs to be tackled at various levels by modulation of several targets. Although at present, combinations of individual singletarget drugs represent the most clinically practiced therapeutic approaches, the modulation of multiple proteins by a single drug, in accordance with the polypharmacological strategy, has become more and more appealing. In the perspective of a multi-target approach, the closely related evolutionary members of the tyrosine kinase family are ideal candidates. Indeed, tyrosine kinase activities are not only critical in tumor phenotype maintenance, but also modulate several functions in the tumor microenvironment. Consequently, several multikinase inhibitors were approved in the last decade, and many new molecules are currently in preclinical or clinical development. In the present review we report on the most widely FDA-approved multitargeted drugs, discussing about their mechanism of action and outlining the clinical trials that have brought them to approval. PMID- 28078997 TI - Lipoprotein (a) and Cardiovascular Risk: The Show Must go on. AB - Lipoprotein (a) [Lp(a)] is an independent but moderate, predictor for coronary heart disease (CHD) prevalence and severity. Several established and emerging cardiovascular (CV) risk factors including age, gender, ethnicity, smoking, dyslipidemia, hypertension, obesity, type 2 diabetes mellitus, alcohol consumption, arterial stiffness and hyperuricemia have been linked to Lp(a) metabolism. Apart from CHD, Lp(a) has been also associated with non-cardiac vascular diseases and diseases associated with increased CV risk such as chronic kidney disease, metabolic syndrome, non-alcoholic fatty liver disease, erectile dysfunction, obstructive sleep apnea syndrome, inflammatory bowel diseases and human immunodeficiency virus infection. The above data are discussed in the present narrative review. Several guidelines suggest the clinical use of Lp(a) in (re)defining vascular risk, especially in asymptomatic individuals at intermediate or high CV risk and those with a family history of premature CHD. By improving individuals risk stratification, Lp(a) may contribute to a better secondary prevention strategy. However, there is still a need to establish a standardized method to measure Lp(a) as well as selective potent therapies for lowering Lp(a). This will support conducting large randomized trials in order to establish whether lowering circulating Lp(a) levels will result in a significant reduction in CV events. PMID- 28078999 TI - HDACs and HDAC Inhibitors in Urothelial Carcinoma - Perspectives for an Antineoplastic Treatment. AB - Histone deacetylases (HDACs) influence diverse cellular processes and may contribute to tumor development and progression by multiple mechanisms. Class I HDACs are often overexpressed in cancers contributing to a genome-wide epigenetic state permitting increased proliferation, and diminished apoptosis and cell differentiation. Class IIA and IIB isoenzymes may likewise contribute to tumorigenesis as components of specific intranuclear repressor complexes or regulators of posttranslational protein modifications. As HDAC inhibitors may counteract these tumorigenic effects several of these compounds are currently tested in clinical trials. HDAC inhibitors are also considered for urothelial carcinoma, where novel therapeutic drugs are urgently required. However, only modest antineoplastic activity has been observed with isoenzyme-unspecific pan HDAC inhibitors. Therefore, inhibition of specific HDAC isoenzymes might be more efficacious and tumor-specific. Here, we systematically review knowledge on the expression, function and suitability as therapeutic targets of the 11 classical HDACs in UC. Overall, the class I HDACs HDAC1 and HDAC2 are the most promising targets for antineoplastic treatment. In contrast, targeting HDAC8 and HDAC6 is likely to be of minor relevance in urothelial carcinoma. Class IIA HDACs like HDAC4 require further study, since their downregulation rather than upregulation could be involved in urothelial carcinoma pathogenesis. PMID- 28078998 TI - Lipoprotein(a) Management: Pharmacological and Apheretic Treatment. AB - Lipoprotein (a) [Lp(a)] is a low-density lipoprotein (LDL)-like particle with an additional apolipoprotein, apolipoprotein (a), [apo(a)] attached to apolipoprotein B. Recent epidemiologic and Mendelian randomization studies have provided evidence that Lp(a) is causally related to the pathogenesis of atherosclerosis and cardiovascular disease (CVD). The risk association between Lp(a) concentrations and CVD is still controversial but seems to be continuous and without an obvious threshold Lp(a) level. Circulating concentrations of Lp(a) are genetically determined; desirable levels are < 50 mg/dl. A plasma concentration of 60 mg/dl is associated with an odds ratio for coronary heart disease of about 1.5 after adjustment for other cardiovascular risk factors. Extended-release niacin is an option for decreasing elevated Lp(a) levels (by ~20 30%) but it is often poorly tolerated. Dietary measures, exercise and lipid lowering drugs such as statins and ezetimibe are without significant effect. In patients with severe progressive CVD and very high Lp(a) levels, lipoprotein apheresis can decrease Lp(a) concentrations. The method is expensive and impractical for most patients and its feasibility depends mainly on the healthcare reimbursement system. Since no established treatment reduces Lp(a) without influencing other lipoproteins, there has been no trial that evaluated whether decreasing Lp(a) concentrations translates to clinical benefits. Recently, an antisense oligonucleotide against apo(a), IONIS-APO(a)Rx, has been shown to selectively decrease Lp(a) by almost 80%. A phase 2 study with this drug has been completed in late 2015 and results are expected to be published soon. PMID- 28079000 TI - Application of monoterpenoids and their derivatives for treatment of neurodegenerative disorders. AB - Neurodegenerative disorders (NDDs) like Alzheimer disease, Parkinson's disease and Huntington's disease are a heterogeneous group of disorders with the progressive and severe loss of neurons. There are no full proof cures for these diseases, and only medicines are available that can alleviate some of the symptoms. Developing effective treatments for the NDDs is a difficult but necessary task. Hence, the investigation of monoterpenoids which modulate targets applicable to many NDDs is highly relevant. Many monoterpenoids have demonstrated promising neuroprotective activity mediated by various systems. It can form the basis for elaboration of agents which will be useful both for the alleviation of symptoms of NDDs and for the treatment of diseases progression and also for prevention of neurodegeneration. The further developments including detections of monoterpenoids and their derivatives with high neuroprotective or neurotrophic activity as well as the results of qualified clinical trials are needed to draw solid conclusions regarding the efficacy of these agents. PMID- 28079001 TI - Application of Organic Monolithic Materials to Enantioseparation in Capillary Separation Techniques. AB - This review article is primarily focused on the state-of-the-art of enantioseparations on organic monolithic materials. The article gives an overview of the chiral stationary phases and its application in capillary electrochromatography (CEC), and capillary- and nano-liquid chromatography (cLC and nLC). Since thousands of publications have been emerged from 2000's and citing all these papers would extend the scope of this review; then, recent developments from last 10 years (2006 to 2016) will be mentioned. Mostly, stationary phases based on copolymers obtained from chiral functional monomers and surface modifications of organic monoliths with chiral ligands will be discussed. The effective application of these chiral separation methodologies in several analysis areas will be also included. PMID- 28079002 TI - Neurotoxicity Associated with Platinum-Based Anti-Cancer Agents: What are the Implications of Copper Transporters? AB - Platinum-based anti-cancer agents, which include cisplatin, carboplatin and oxaliplatin, are an important class of drugs used in clinical setting to treat a variety of cancers. The cytotoxic efficacy of these drugs is mediated by the formation of inter-strand and intrastrand crosslinks, or platinum adducts on nuclear DNA. There is also evidence demonstrating that mitochondrial DNA is susceptible to platinum-adduct damage in dorsal root ganglia neurons. Although all platinum-based agents form similar DNA adducts, they are quite different in terms of activation, systemic toxicity and tolerance. Platinum-based agents are well known for their neurotoxicity and gastrointestinal side-effects which are major causes for dose limitation and treatment discontinuation compromising the efficacy of anti-cancer treatment. Accumulating evidence in non-neuronal cells shows that the copper transport system is associated with platinum drug sensitivity and resistance. There is minimal research concerning the role of copper transporters within the central and peripheral nervous systems. It is unclear whether neurons are more sensitive to platinum-based drugs, are insufficient in drug clearance, or whether platinum accumulation affects intracellular copper status and coppermediated functions. Understanding these mechanisms is important as neurotoxicity is the predominant side-effect of platinum-based chemotherapy. This review highlights the role of copper transpor ters in drug influx, differences in drug activation and side-effects caused by platinum-based agents, as well as their association with central and peripheral neuropathies and gastrointestinal toxicities. PMID- 28079003 TI - Colorectal Cancer Chemotherapy: The Evolution of Treatment and New Approaches. AB - Colorectal cancer (CRC) is one the greatest contributors to cancer related mortality. Although 5 year survival rate for patients at the early stage of CRC (stages I and II) is above 60%, more than 50% of patients are diagnosed at or beyond stage III when distant metastasis has already occurred, in which case 5 year survival rate drops to 10%. Chemotherapeutic intervention coupled with surgery is the backbone of metastatic CRC treatment and the only means of enhanced survival. For decades following its discovery, an antimetabolite 5- fluorouracil (5-FU) was the only chemotherapeutic agent available to successfully improve 12 month survival in CRC patients. Treatment of metastatic CRC has been considered palliative for many years; aiming to increase the duration and quality of the patient's remaining life, with little hope of cure, highlighting the need for novel DNA and RNA targeted therapies in the treatment of CRC. Over the last several decades, combinations of several chemotherapeutic agents have been incorporated into routine clinical practice. Combination regimes incorporating irinotecan, a semisynthetic inhibitor of topoisomerase, oxaliplatin, a third generation platinum compound that causes mitotic arrest via the formation of DNA adducts, and capecitabine, a 5-FU prodrug, are now all established options for use as first-line, second-line and sequential treatment of CRC. This review provides a brief overview of the evolution of CRC chemotherapy as well as new and emerging treatment options. PMID- 28079004 TI - Foodborne Giardiasis: Is There Any Relationship Between food Handlers and Transmission of Giardia duodenalis? AB - BACKGROUND: The foodborne diseases are amongst the main causes of morbidity and mortality in the human communities. Giardia duodenalis, the causative agent of giardiasis, is one of the foodborne parasites, which has public health importance. The aim of the current study was to assess the prevalence of G. duodenalis among food handlers in Andimeshk County, southwest of Iran. MATERIALS AND METHODS: This cross-sectional study was undertaken among 480 food handlers in 2015. The collected stool specimens were investigated using direct saline smear, Lugol's iodine- staining, and sucrose flotation methods. RESULTS: The overall prevalence of G. duodenalis in the examined participants was 12 (2.5%). The higher prevalence 75% (9/12) was found among participants with medium and low levels of education and 25% (3/12) belonged to those with high level of education. Direct microscopic examinations revealed two (0.4%) positive cases infected with Hymenolepis nana, with one of them showing mixed infection with G. duodenalis. CONCLUSION: Based on the obtained results, infected food handlers could be a potential source of intestinal parasitic infections, and transmission can occur through contaminated food. Therefore, we suggest that food handlers training programs should be implemented to increase the awareness of food handlers and reduce the transmission of intestinal parasites. PMID- 28079005 TI - Dendritic Cells Modulate Iron Homeostasis and Inflammatory Abilities Following Quercetin Exposure. AB - BACKGROUND: Fruits and vegetables are rich in plant polyphenols, whose consumption is encouraged in healthy dietary regimes due to their antioxidants and anti-inflammatory effects. These organic molecules exhibit numerous properties including phylochelation; the ability to complex metal ions, including highly reactive iron. Among polyphenols, we focused our attention on quercetin that previously demonstrated its ability to reduce dendritic cells (DCs) inflammatory cytokine secretion and antigen presentation following LPS exposure. Dendritic cell inflammatory response is also associated with modulation of several iron metabolism related genes. OBJECTIVE: To characterize the axis between quercetin exposure and iron extracellular transport that may explain polyphenol anti-inflammatory abilities. METHOD: Bone marrow derived DCs were exposed to 25MUM of quercetin on day 7 and treated with 1 MUg/mL of LPS on day 8. The relation between quercetin exposure and the expression level of genes involved in iron homeostasis was addressed by qPCR. The axis between iron export and quercetin exposure was confirmed in vitro and in vivo using quercetin gavage and quercetin-enriched diet. RESULTS: Here we demonstrate that DCs, exposed to quercetin, activate a pattern of genes that increase extracellular iron export, resulting in an overall decrease in the intracellular iron content and consequent diminished inflammatory abilities. This DCs phenotype is consistent with anti inflammatory phenotype of the mucosal resident DCs, the ones most commonly exposed to polyphenols. CONCLUSIONS: Iron balance is a crucial checkpoint for DCs inflammatory abilities. Quercetin-enriched nutritional regimes that favor DCs extracellular iron transport could reduce the incidence of chronic inflammatory syndromes. PMID- 28079006 TI - A New Vaccine Delivery Vehicle and Adjuvant Candidate: Bordetella pertussis Inactivated Whole Cells Entrapped in Alginate Microspheres. AB - There is no doubt about the whole cell pertussis vaccine efficacy, but it is necessary to improve the vaccine quality specially to decrease its toxicity by obtaining good immunogenicity with low bacterial content. In this work, under optimum condition inactivated B. pertussis bacteria cells entrapped with alginate microparticles were fabricated and in vivo immunogenicity and ptency of new microparticle based vaccine were evaluated in mice. Microspheres loaded with inactive B. pertussis bacterium cells were prepared via an emulsification method and analyzed for morphology, size, polydispersity index, loading efficiency, loading capacity, release profile and in vivo potency. The inactivated bacterial suspension mixture prepared in this work was nontoxic and showed potent ED50 (1:333 of human dose) and preserved agglutinins 1, 2, 3. The optimum conditions for the preparation of microparticles were achieved at alginate concentration 3.8% (w/v), CaCl2 8% (w/v), PLL 0.1% (w/v), lipophilic surfactant 0.22 (%w/v), hydrophilic surfactant 3.6 (%w/v), cross linking time 3min, homogenization rate 600 rpm, and alginate to CaCl2 solution ratio 4. Both empty and B. pertussis loaded microparticles exhibited smooth surface texture and relatively spherical shape. The B. pertussis encapsulated microspheres fabricated under optimized conditions showed mean particle size 151.1 MUm, polydispersity index 0.43, loading efficiency 89.6%, loading capacity 36.3%, and relatively constant release rate lasted to 15 days. In vivo immunogenicity and protection study against wild type challenge showed strongly higher potency (approximately 2.5 fold) of encapsulated B. pertussis organisms than non-encapsulated conventional aluminum hydroxide adsorbed vaccine. It can be concluded that microencapsulation of inactive B. pertussis cells appears to be a suitable approach for improving the wP vaccine quality, specially by obtaining good immunogenicity with low bacterial content. PMID- 28079007 TI - Novel Therapies Targeting Cardioprotection and Regeneration. AB - Cardiovascular disease is the leading cause of death worldwide. The heart is susceptible to pathologies that impact the myocardium directly, such as myocardial infarction and consequent heart failure, as well as conditions with indirect cardiac effects, such as cancer treatment-related cardiotoxicity. As the contractile cells of the heart, cardiomyocytes are essential for normal cardiac function. Various stress stimuli may result in transient damage or cell death in cardiomyocytes through apoptosis, necrosis or maladaptive autophagy. Moreover, cardiomyocytes are unable to regenerate; thus, lost cells are replaced with fibrotic tissue, with a potentially severe impact on myocardial function. Several therapeutic agents and strategies to reduce cardiomyocyte damage are currently available. This manuscript reviews the state of the art regarding novel cardioprotective endogenous peptides, such as neuregulin-1, angiotensin-(1-9), growth/differentiation factor-11, growth/differentiation factor- 15 and insulin like growth factor-1. We discuss their protective effects and therapeutic potential in cardiovascular diseases and the current challenges to harnessing their full cardioprotective power. We also explore targeting of exosomes as a cardioprotective approach along with the therapeutic potential of cardiac regeneration strategies. Further advances associated with these molecules and cardioprotective approaches may provide more effective therapies to attenuate or prevent cardiomyocyte death, thereby preserving the myocardium. PMID- 28079008 TI - Walking a Tightrope: A Perspective of Resveratrol Effects on Breast Cancer. AB - It is an acknowledged fact that health benefits are derived from fruit- and vegetables-enriched diets. In particular, polyphenols, compounds bearing one or more hydroxyl groups attached to an aromatic ring, are ascribed for most of such beneficial effects. Among them, resveratrol, a phytoalexin found in numerous plant species, and more notably in grapes, has widely piqued the interest of the scientific community by virtue of its anti-aging, anti-inflammatory and anti oxidant properties. Moreover, evidence claiming resveratrol ability to hinder processes underlying all the three steps of carcinogenesis (tumor initiation, progression and metastasization) has propelled an incredibly massive number of studies aimed at enquiring its eventual clinical potential in the fight against cancer. However, despite a large body of data pointing to the advantages of dietary resveratrol intake in respect of certain disease conditions, and cancer inter alia, its real position still remains quite ambiguous. In this uncertain scenario, the present review focuses its attention on the highly entangled relationship between resveratrol and breast cancer, attempting to shape the plethora of controversial results stemming from studies carried out on several in vitro and in vivo breast cancer models. Coping with such a tricky matter, there are so many variabilities concerning both resveratrol itself (dosage, administration, bioavailabilty, among others) and the unique molecular traits of each specific breast cancer subtype that must be taken into account when facing the dilemma: "might resveratrol be protective against breast cancer or does it rather fuel it?". PMID- 28079009 TI - Emerging Roles of Calreticulin in Cancer: Implications for Therapy. AB - Calreticulin (CRT), initially identified as a ubiquitous calcium-binding protein in the endoplasmic reticulum, has emerged as a multifunctional protein with roles in calcium homeostasis, molecular chaperoning and cell adhesion. Emerging evidence suggests its involvement in tumorigenesis facilitating proliferation, migration, and adhesion. CRT translocated to the cell surface (ecto-CRT) serves as a phagocytic signal for immunogenic cell death (ICD) mediated through dendritic cells (DCs) and cytotoxic T-cell activation thereby making tumors susceptible to immunotherapy-based anti-cancer strategies. CRT is now regarded as one of the most potent danger-associated molecular patterns (DAMPs) with the ecto CRT triggering restoration of homeostasis by immune stimulation. A recently identified novel transacetylase activity of CRT adds a new dimension to its multi faceted involvement in cancer by virtue of polyphenolic acetates (PA): CRT transacetylase (CRTase) system which results in hyperacetylation of target proteins, thereby mimicking the effects of Histone deacetylase inhibitors (HDACi). Since protein acetylation is one of the crucial post-translational modifications (PTMs) influencing the epigenetic regulation and signal transduction, CRT can be a potential target for developing anticancer therapeutics and preventive strategies by employing pharmacologically compatible semi-synthetic acetyl donors like polyphenolic acetates and other agents. PMID- 28079010 TI - Discovery of Natural Proteasome Inhibitors as Novel Anticancer Therapeutics: Current Status and Perspectives. AB - Natural products serve as a main resource for drug discovery. The ubiquitin proteasome system (UPS) is one of the primary intracellular protein degradation systems, which is responsible for the degradation of most short-lived, mis-folded and aged proteins. The proteasome is a validated target for cancer treatment, since cancer cells are more reliant on high levels of proteasome activity to maintain the dynamic protein homeostasis required for enhanced metabolism and unrestricted proliferation. Encouraged by success of bortezomib in the treatment of multiple myeloma, several second-generation proteasome inhibitors have been developed based on natural resources, and are being tested in various clinical settings. In this paper, we reviewed the most widely investigated proteasome inhibitors, including their natural product origins, compound-discovery and optimization, as well as their current status in both preclinical and clinical studies. PMID- 28079011 TI - Molecular Mechanisms of Anticancer Effects of Phytoestrogens in Breast Cancer. AB - Phytoestrogens derived from plants exert estrogenic as well as antiestrogenic effects and multiple actions within breast cancer cells. Chemopreventive properties of phytoestrogens have emerged from epidemiological observations. In recent clinical research studies, phytoestrogens are safe and may even protect against breast cancer. In this brief review, the molecular mechanisms of phytoestrogens on regulation of cell cycle, apoptosis, estrogen receptors, cell signaling pathways, and epigenetic modulations in relation to breast cancer are discussed. Phytoestrogens have a preferential affinity for estrogen receptor (ER) beta, which appears to be associated with antiproliferative and anticarcinogenic effects. Moreover, while phytoestrogens not only inhibit ER-positive but also ER negative breast cancer cells, the possibility of epigenetic modulation playing an important role is also discussed. In conclusion, as there are multiple targets and actions of phytoestrogens, extensive research is still necessary. However, due to low toxicity, low cost, and easy availability, their potent chemoprevention effects deserve further study. PMID- 28079012 TI - Antioxidant Peptides from Terrestrial and Aquatic Plants Against Cancer. AB - Cancer is the leading cause of morbidity and mortality worldwide. Therefore, the search for new and less aggressive treatments is currently the focus of the anticancer research. An attractive alternative for this purpose is the use of bioactive peptides from plants. Plants live everywhere on Earth, both on land and in water, and they are a major source of diverse molecules with pharmacological potential as antioxidant peptides. Hence, this review focuses on the importance of the antioxidant activity of terrestrial and aquatic plant peptides against cancer throughout several mechanisms. The influence of the antioxidant activity of peptides by different factors such as molecular weight and amino acid composition as a crucial factor for anticancer activity is also revised. Furthermore, the relation of antioxidant activity with anticancer property as well as safety and legal aspects of protein hydrolysates and bioactive peptides for their use in cancer treatments is discussed. PMID- 28079014 TI - Predicting Cognitive Decline across Four Decades in Mutation Carriers and Non carriers in Autosomal-Dominant Alzheimer's Disease. AB - OBJECTIVES: The aim of this study was to investigate cognitive performance including preclinical and clinical disease course in carriers and non-carriers of autosomal-dominant Alzheimer's disease (adAD) in relation to multiple predictors, that is, linear and non-linear estimates of years to expected clinical onset of disease, years of education and age. METHODS: Participants from five families with early-onset autosomal-dominant mutations (Swedish and Arctic APP, PSEN1 M146V, H163Y, and I143T) included 35 carriers (28 without dementia and 7 with) and 44 non-carriers. All participants underwent a comprehensive clinical evaluation, including neuropsychological assessment at the Memory Clinic, Karolinska University Hospital at Huddinge, Stockholm, Sweden. The time span of disease course covered four decades of the preclinical and clinical stages of dementia. Neuropsychological tests were used to assess premorbid and current global cognition, verbal and visuospatial functions, short-term and episodic memory, attention, and executive function. RESULTS: In carriers, the time-related curvilinear trajectory of cognitive function across disease stages was best fitted to a formulae with three predictors: years to expected clinical onset (linear and curvilinear components), and years of education. In non-carriers, the change was minimal and best predicted by two predictors: education and age. The trajectories for carriers and non-carriers began to diverge approximately 10 years before the expected clinical onset in episodic memory, executive function, and visuospatial function. CONCLUSIONS: The curvilinear trajectory of cognitive functions across disease stages was mimicked by three predictors in carriers. In episodic memory, executive and visuospatial functions, the point of diverging trajectories occurred approximately 10 years ahead of the clinical onset compared to non-carriers. (JINS, 2017, 23, 195-203). PMID- 28079013 TI - Natural Product Inhibitors of Topoisomerases: Review and Docking Study. AB - Since ancient times, natural products have been used in treating various diseases effectively and safely. Nowadays, these natural compounds are submitted to sophisticated methodologies from isolation, computing, analytical, and even serving as pharmacophore suggestions for synthesis. The substances extracted from marine species, plants, and microorganisms present activities beneficial to our health, including protection against malignant tumors. The topoisomerase enzymes play an important role in DNA metabolism, and searching for enzyme inhibitors is an important target in the search for new anticancer drugs. This review discusses this problem, reporting research involving alkaloids, terpenes, flavonoids, xanthones, coumarins, acetogenins, and in addition, includes a docking study with our Brazilian diterpenes to topoisomerases I and II. The better compound, the trachylobane 1, forms one hydrogen bond when submitted to docking with Topo I (with the ASP533 residue) and two with residues in Topo II (THR213 and TYR188). The difference observed in the energy of formation can be attributed to hydrogen bond interactions. The difference observed in the energy of formation can be attributed to hydrogen-bond interactions. PMID- 28079015 TI - Chemometrics Expertise in the Links Between Ecotoxicity and Physicochemical Features of Silver Nanoparticles: Environmental Aspects. AB - Studies of the ecotoxicological aspects of nanomaterials in aquatic environments are scarce. Given the growing variety of nanoparticles (NPs), along with the diversity of aquatic species and environments, the key to promoting sound risk assessment in nanoecotoxicology is understanding the mechanisms that govern the fate of NPs in aquatic environments and their behavior at the NP-biota interface. In this paper, data collected from the literature on ecotoxicological effects observed in aquatic species is discussed and analyzed using multivariate statistics techniques. We expand the knowledge of the environmental impact of silver NPs (AgNPs) by testing the acute toxicity of 47 AgNPs on crustacean eukaryotic organisms (Daphnia magna, Thamnocephalus platyurus, and D. galeata). Physicochemical properties, stabilization agents, toxicological end points, and test media were monitored as adding-outcome factors for the evaluation of environmental effects due to exposure to NPs. The chemometrics expertise performed by the use of hierarchical and nonhierarchical cluster analysis and principal component analysis revealed specific links between the ecotoxicology and the physicochemical features of NPs and helped in creating specific patterns of NPs discriminated by ecotoxicity levels and physicochemical parameters. PMID- 28079016 TI - Fast-HPLC Fingerprinting to Discriminate Olive Oil from Other Edible Vegetable Oils by Multivariate Classification Methods. AB - A new analytical method for the differentiation of olive oil from other vegetable oils using reversed-phase LC and applying chemometric techniques was developed. A 3 cm short column was used to obtain the chromatographic fingerprint of the methyl-transesterified fraction of each vegetable oil. The chromatographic analysis took only 4 min. The multivariate classification methods used were k nearest neighbors, partial least-squares (PLS) discriminant analysis, one-class PLS, support vector machine classification, and soft independent modeling of class analogies. The discrimination of olive oil from other vegetable edible oils was evaluated by several classification quality metrics. Several strategies for the classification of the olive oil were used: one input-class, two input-class, and pseudo two input-class. PMID- 28079017 TI - Phenol Contaminated Water Treatment on Several Modified Dimensionally Stable Anodes. AB - Phenolic compounds are some of the most common hazardous organics in wastewater. Removal of these pollutants is important. Physiochemical method such as electrochemical oxidation on dimensionally stable anodes is more convenient in removing such organic pollutants. Therefore, this study focuses on development of three different anodes for phenol contaminated water treatment. The performances of steel/IrO2, steel/IrO2-Sb2O3, and Ti/IrO2-Sb2O3 anodes were tested and compared. Nearly 50, 76, and 84% of chemical oxygen demand removal efficiencies were observed for steel/IrO2, steel/IrO2-Sb2O3, and Ti/IrO2-Sb2O3 anodes, respectively. The formation of intermediates was monitored for three anodes and the Ti/IrO2-Sb2O3 anode showed the most promising results. Findings suggest that the developed anode materials can enhance phenol oxidation efficiency and that mixed metal oxide layer has major influence on the anode. Among the selected metal oxide mixtures IrO2-Sb2O3 was the most suitable under given experimental conditions. PMID- 28079018 TI - Methyl Red Decolorization Efficiency of a Korea Strain of Aspergillus sp. Immobilized into Different Polymeric Matrices. AB - Intensive research studies have revealed that fungal decolorization of dye wastewater is a promising replacement for the current process of dye wastewater decolorization. The authors isolated an Aspergillus sp. from the effluent of a textile industry area in Korea and assessed the effects of a variety of operational parameters on the decolorization of methyl red (MR) by this strain of Aspergillus sp. This Aspergillus sp. was then immobilized by entrapment in several polymeric matrices and the effects of operational conditions on MR decolorization were investigated again. The optimal decolorization activity of this Aspergillus sp. was observed in 1% glucose at a temperature of 37 degrees C and pH of 6.0. Furthermore, stable decolorization efficiency was observed when fungal biomass was immobilized into alginate gel during repeated batch experiment. These results suggest that the Aspergillus sp. isolated in Korea could be used to treat industrial wastewaters containing MR dye. PMID- 28079020 TI - This Issue at a Glance. PMID- 28079019 TI - An efficient targeted nuclease strategy for high-resolution mapping of DNA binding sites. AB - We describe Cleavage Under Targets and Release Using Nuclease (CUT&RUN), a chromatin profiling strategy in which antibody-targeted controlled cleavage by micrococcal nuclease releases specific protein-DNA complexes into the supernatant for paired-end DNA sequencing. Unlike Chromatin Immunoprecipitation (ChIP), which fragments and solubilizes total chromatin, CUT&RUN is performed in situ, allowing for both quantitative high-resolution chromatin mapping and probing of the local chromatin environment. When applied to yeast and human nuclei, CUT&RUN yielded precise transcription factor profiles while avoiding crosslinking and solubilization issues. CUT&RUN is simple to perform and is inherently robust, with extremely low backgrounds requiring only ~1/10th the sequencing depth as ChIP, making CUT&RUN especially cost-effective for transcription factor and chromatin profiling. When used in conjunction with native ChIP-seq and applied to human CTCF, CUT&RUN mapped directional long range contact sites at high resolution. We conclude that in situ mapping of protein-DNA interactions by CUT&RUN is an attractive alternative to ChIP-seq. PMID- 28079024 TI - A Simple Vista en Este Numero. PMID- 28079022 TI - Lifitegrast for the Treatment of Dry Eye Disease: Results of a Phase III, Randomized, Double-Masked, Placebo-Controlled Trial (OPUS-3). AB - PURPOSE: Lifitegrast is a lymphocyte function-associated antigen-1 antagonist developed to reduce inflammation in dry eye disease (DED). We report the results of OPUS-3 (NCT02284516), a phase III study evaluating the efficacy and safety of lifitegrast versus placebo in participants with DED. DESIGN: Twelve-week, phase III, randomized, double-masked, multicenter, placebo-controlled study. PARTICIPANTS: Adults aged >=18 years with Schirmer tear test (without anesthesia) >=1 and <=10 mm, corneal fluorescein staining score >=2.0 (0-4 scale), eye dryness score (EDS) >=40 (0-100 visual analogue scale [VAS]), and history of artificial tear use within 30 days of study entry. METHODS: After a 14-day placebo run-in, participants were randomized 1:1 to lifitegrast ophthalmic solution 5.0% or placebo twice daily for 84 days. MAIN OUTCOME MEASURES: The primary efficacy end point was change from baseline to day 84 in EDS. Key secondary efficacy end points were change from baseline to days 42 and 14 in EDS. Other secondary efficacy end points included additional VAS items (burning/stinging, itching, foreign body sensation, eye discomfort, photophobia, pain), ocular discomfort score (ODS), and safety/tolerability of lifitegrast versus placebo. RESULTS: In the study, 711 participants were randomized: placebo, 356; lifitegrast, 355 (intention-to-treat [ITT] population). At day 84, lifitegrast-treated participants experienced significantly greater improvement from baseline in EDS versus those receiving placebo (treatment effect [TE], 7.16; 95% confidence interval [CI], 3.04-11.28; P = 0.0007). Mean changes from baseline in EDS also significantly favored lifitegrast on days 42 (TE, 9.32; 95% CI, 5.44 13.20; P < 0.0001) and 14 (TE, 7.85; 95% CI, 4.33-11.37; P < 0.0001). No statistically significant differences were observed in ODS between treatment groups at days 84, 42, or 14. A greater improvement was observed in lifitegrast treated participants at day 42 in itching (nominal P = 0.0318), foreign body sensation (nominal P = 0.0418), and eye discomfort (P = 0.0048) versus participants receiving placebo. Most treatment-emergent adverse events were mild to moderate in severity; no serious ocular adverse events were reported. CONCLUSIONS: Lifitegrast significantly improved symptoms of eye dryness, as measured by EDS, versus placebo in participants with DED. Improvement in EDS was observed as early as day 14. Lifitegrast appeared well tolerated. PMID- 28079025 TI - ? PMID- 28079026 TI - A review of compliant transmission mechanisms for bio-inspired flapping-wing micro air vehicles. AB - Flapping-wing micro air vehicles (FWMAVs) are a class of unmanned aircraft that imitate flight characteristics of natural organisms such as birds, bats, and insects, in order to achieve maximum flight efficiency and manoeuvrability. Designing proper mechanisms for flapping transmission is an extremely important aspect for FWMAVs. Compliant transmission mechanisms have been considered as an alternative to rigid transmission systems due to their lower the number of parts, thereby reducing the total weight, lower energy loss thanks to little or practically no friction among parts, and at the same time, being able to store and release mechanical power during the flapping cycle. In this paper, the state of-the-art research in this field is dealt upon, highlighting open challenges and research topics. An optimization method for designing compliant transmission mechanisms inspired by the thoraxes of insects is also introduced. PMID- 28079023 TI - Incidence and Growth of Geographic Atrophy during 5 Years of Comparison of Age Related Macular Degeneration Treatments Trials. AB - PURPOSE: To estimate the incidence, size, and growth rate of geographic atrophy (GA) during 5 years of follow-up among participants in the Comparison of Age Related Macular Degeneration Treatments Trials (CATT). DESIGN: Cohort within a clinical trial. PARTICIPANTS: Participants included in CATT. METHODS: A total of 1185 CATT participants were randomly assigned to ranibizumab or bevacizumab treatment and to 3 treatment regimens. Participants were released from protocol treatment at 2 years and examined at approximately 5 years (N = 647). Two masked graders assessed the presence and size of GA in digital color photographs (CPs) and fluorescein angiograms (FAs) taken at baseline and years 1, 2, and 5. Cox proportional hazard models were used to identify risk factors for incidence of GA. Annual change in the square root of the total area of GA was the measure of growth. Multivariate linear mixed models including baseline demographic, treatment, and ocular characteristics on CP/FA and optical coherence tomography (OCT) as candidate risk factors were used to estimate adjusted growth rates, standard errors (SEs), and 95% confidence intervals (CIs). MAIN OUTCOME MEASURES: Geographic atrophy incidence and growth rate. RESULTS: Among the 1011 participants who did not have GA at baseline and had follow-up images gradable for GA, the cumulative incidence was 12% at 1 year, 17% at 2 years, and 38% at 5 years. At baseline, older age, hypercholesterolemia, worse visual acuity, larger choroidal neovascularization (CNV) area, retinal angiomatous proliferation (RAP) lesion, GA in the fellow eye, and intraretinal fluid were associated with a higher risk of incident GA. Thicker subretinal tissue complex and presence of subretinal fluid were associated with less GA development. The overall GA growth rate was 0.33 mm/year (SE, 0.02 mm/year). Eyes treated with ranibizumab in the first 2 years of the clinical trial had a higher growth rate than eyes treated with bevacizumab (adjusted growth rate, 0.38 vs. 0.28 mm/year; P = 0.009). Geographic atrophy in the fellow eye, hemorrhage, and absence of sub-retinal pigment epithelium fluid at baseline were associated with a higher growth rate. CONCLUSIONS: Development of GA is common 5 years after initiating therapy. Several risk factors identified at 2 years of follow-up persist at 5 years of follow-up. PMID- 28079027 TI - The properties of ultrapure delafossite metals. AB - Although they were first synthesized in chemistry laboratories nearly fifty years ago, the physical properties of the metals PdCoO2, PtCoO2 and PdCrO2 have only more recently been studied in detail. The delafossite structure contains triangular co-ordinated atomic layers, and electrical transport in the delafossite metals is strongly 2D. Their most notable feature is their in-plane conductivity, which is amazingly high for oxide metals. At room temperature, the conductivity of non-magnetic PdCoO2 and PtCoO2 is higher per carrier than those of any alkali metal and even the most conductive elements, copper and silver. At low temperatures the best crystals have resistivities of a few nOmega cm, corresponding to mean free paths of tens of microns. PdCrO2 is a frustrated antiferromagnetic metal, with magnetic scattering contributing to the resistivity at high temperatures and small gaps opening in the Fermi surface below the Neel temperature. There is good evidence that electronic correlations are weak in the Pd/Pt layers but strong in the Co/Cr layers; indeed the Cr layer in PdCrO2 is thought to be a Mott insulator. The delafossite metals therefore act like natural heterostructures between strongly correlated and nearly free electron sub systems. Combined with the extremely high conductivity, they provide many opportunities to study electrical transport and other physical properties in new regimes. The purpose of this review is to describe current knowledge of these fascinating materials and set the scene for what is likely to be a considerable amount of future research. PMID- 28079028 TI - Observation of ultrasharp metamagnetic jumps in polycrystalline Er2Cu2O5. AB - The observation of ultrasharp metamagnetic jumps in the field variation of magnetization (M versus H) data for the highly insulating metal oxide Er2Cu2O5 is investigated. The compound orders antiferromagnetically below about T N1 = 28 K and shows conventional 'not-so-sharp' metamagnetism around 13 kOe on the field increasing leg in the polycrystalline sample. The uniqueness of the ultrasharp jumps in Er2Cu2O5 resides in the fact that they are only observed in the field decreasing segment of the magnetization curve. We observe that the jumps are affected by the sweep rate of the magnetic field, similarly to several other systems that show such ultrasharp jumps. Er2Cu2O5 shows a considerable amount of thermo-remanent magnetization when it is cooled in a field that is higher than the critical field of 13 kOe. Our analysis indicates that above 13 kOe the system remains phase separated, with the coexistence of antiferromagnetic and field induced ferromagnetic-like phases. The jumps in the return leg occur because of the shear-dominated martensitic-like phase transition of the ferromagnetic-like phase to an antiferromagnetic phase, and interfacial strain plays a major role in the observed jumps. PMID- 28079029 TI - Coulomb matrix elements in multi-orbital Hubbard models. AB - Coulomb matrix elements are needed in all studies in solid-state theory that are based on Hubbard-type multi-orbital models. Due to symmetries, the matrix elements are not independent. We determine a set of independent Coulomb parameters for a d-shell and an f-shell and all point groups with up to 16 elements (O h , O, T d , T h , D 6h , and D 4h ). Furthermore, we express all other matrix elements as a function of the independent Coulomb parameters. Apart from the solution of the general point-group problem we investigate in detail the spherical approximation and first-order corrections to the spherical approximation. PMID- 28079030 TI - Neuromusculoskeletal model self-calibration for on-line sequential bayesian moment estimation. AB - OBJECTIVE: Neuromusculoskeletal models involve many subject-specific physiological parameters that need to be adjusted to adequately represent muscle properties. Traditionally, neuromusculoskeletal models have been calibrated with a forward-inverse dynamic optimization which is time-consuming and unfeasible for rehabilitation therapy. Non self-calibration algorithms have been applied to these models. To the best of our knowledge, the algorithm proposed in this work is the first on-line calibration algorithm for muscle models that allows a generic model to be adjusted to different subjects in a few steps. APPROACH: In this paper we propose a reformulation of the traditional muscle models that is able to sequentially estimate the kinetics (net joint moments), and also its full self-calibration (subject-specific internal parameters of the muscle from a set of arbitrary uncalibrated data), based on the unscented Kalman filter. The nonlinearity of the model as well as its calibration problem have obliged us to adopt the sum of Gaussians filter suitable for nonlinear systems. MAIN RESULTS: This sequential Bayesian self-calibration algorithm achieves a complete muscle model calibration using as input only a dataset of uncalibrated sEMG and kinematics data. The approach is validated experimentally using data from the upper limbs of 21 subjects. SIGNIFICANCE: The results show the feasibility of neuromusculoskeletal model self-calibration. This study will contribute to a better understanding of the generalization of muscle models for subject-specific rehabilitation therapies. Moreover, this work is very promising for rehabilitation devices such as electromyography-driven exoskeletons or prostheses. PMID- 28079031 TI - Prevalence of ADHD among 7-9-Year-Old Children in Israel. A Comparison between Jewish and Arab Populations. AB - INTRODUCTION: The world prevalence of ADHD ranges between 5-10%. The prevalence in Israel was generally studied from prescriptions of methylphenidate and not from cohorts of children. METHODS: We assessed the prevalence of ADHD among a cohort of early school age children in the Jewish and Arab populations using DSM IV criteria and evaluated the difference between teachers' and parental assessment. We also studied in the Jewish population the differences in several social-behavioral parameters between children with and without ADHD. RESULTS: The rate of ADHD among the Jewish children was 9.5% and among the Arab children it was significantly lower - 7.35%. Teachers' evaluation in the Jewish population was 2.3 times higher than parental evaluation but in the Arab population it was closer to that of the parents, being only 12% higher. In addition, there were more regulatory, behavioral and learning problems among the Jewish children with ADHD compared to children without ADHD. CONCLUSIONS: The rates of ADHD in school age children among both Jews and Arabs fall within the average rate in other countries. The high difference between teachers' and parental assessment of ADHD in the Jewish population emphasizes that ADHD diagnosis should rely on the joint behavioral assessment of both. The prevalence of ADHD in Jewish early school age children is slightly higher than in Arab children and the inattentive type is the most common. There is a discrepancy between teachers' and parents' evaluation of children's behavior in the Jewish population, but this discrepancy is less in the Arab population. PMID- 28079032 TI - Burnout of Formal Caregivers of Children with Cerebral Palsy. AB - BACKGROUND: Burnout syndrome is under-researched within caregivers (CGs) of children with cerebral palsy. The primary aim was to determine the burnout level of formal CGs of children with cerebral palsy (G1) and to compare it with a control group (G2) of professional pediatric nurses, and second, to correlate the level of depression and anxiety with the burnout level. METHOD: In a total sample of 60 CGs, the Maslach Burnout Inventory Human Services Survey (MBI-HSS), consisting of three structural units - emotional exhaustion (MBIEE) subscale, depersonalization (MBI-DP) subscale and personal accomplishment (MBI-PA) subscale - was used to measure burnout. The Beck Anxiety Inventory (BAI) was used for the assessment of anxiety, and the Beck Depression Inventory (BDI) for depression. RESULTS: A significant difference was shown on the MBI-EE subscale and on the BDI test (p<0.05), in both cases higher scores were obtained by G1. High burnout was observed in all subscales, on the MBI-EE subscale registered 50% of CGs in G1, and 17% in control G2. Correlation of the MBI-EE subscale with BDI and BAI tests was highly significant (p<0.01). CONCLUSIONS: These findings indicate the need for future research aimed at formulating preventive strategies for caregivers' mental health. Better care for caregivers would provide them with better professional satisfaction, and consequently would lead to better care for patients. PMID- 28079033 TI - The Role of Maternal Distress in the Report of Behavioral and Emotional Problems among Children with Chronic Disabilities. AB - BACKGROUND: Assessments of psychological symptoms in children often rely on caregivers' (usually mothers') reports. However, the reliability may be affected by the caregivers' own emotional distress (ED). The main objectives of this study were to assess the variability in ED of mothers of children with chronic physical disabilities, and its association with the ratings of their children's emotional and behavioral problems. METHODS: Medical data of children diagnosed with chronic disabilities were analyzed (N = 72). Mothers completed the 12-item General Health Questionnaire (12-GHQ) to measure ED and the Child Behavior Checklist (CBCL) to assess children's emotional and behavioral problems Mothers' ED scores were compared with communitybased counterparts with similar socio-demographic characteristics (N = 657) from the Israel National Health Survey (INHS). RESULTS: Mothers of children with chronic physical disabilities had higher levels of ED compared to mothers in the general population. About 20% of the sample mothers had 12-GHQ scores compatible with DSM- IV depression or anxiety disorders. No differences in ED were found according to the type of child's disability or IQ score. Marked differences in CBCL scores were reported by mothers with high versus low ED, controlling for baseline maternal and child characteristics. CONCLUSIONS: High levels of maternal ED were associated with mothers' reports on child's behavioral and emotional problems.This may contaminate the reliability of parental reports on their child's psychological state. PMID- 28079034 TI - Enhancing Children's Resilience in Schools to Confront Trauma: The Impact on Teachers. AB - BACKGROUND: Children's exposure to stressful events requires effective interventions to strengthen adaptive development. Expanding the teachers' role to deliver resilience-focused interventions has been shown to enhance children's coping and to have a positive impact on the teachers themselves. METHOD: This study compared the self-efficacy and perceived performance of 48 teachers following the implementation of such an intervention with 52 control teachers. RESULTS: Trained teachers reported higher self-efficacy and perceived performance. Associations between years of experience, perceived performance and self-efficacy are discussed. CONCLUSIONS: This study provides further evidence on the positive impact of teacher-delivered interventions on teachers' performance and self-efficacy. Future studies should replicate this design with a larger sample to examine stages of professional experience, grades, before-after measures, association with students' coping and include male teachers. PMID- 28079036 TI - Parent-child Communication-centered Rehabilitative Approach for Pediatric Functional Somatic Symptoms. AB - BACKGROUND: Functional somatic symptoms (FSS) are a type of somatization phenomenon. Integrative rehabilitation approaches are the preferred treatment for pediatric FSS. Parental roles in the treatment process have not been established. STUDY AIMS: to present 1) a parent-focused treatment (PFT) for pediatric FSS and 2) the approach's preliminary results. METHODS: The sample included 50 children with physical disabilities due to FSS. All children received PFT including physical and psychological therapy. A detailed description of the program's course and guiding principles is provided. OUTCOME MEASURES: FSS extinction and age-appropriate functioning. RESULTS: Post-program, 84% of participants did not exhibit FSS and 94% returned to age-appropriate functioning. At one-year follow up, only 5% of participants experienced symptom recurrence. No associations were found between pre-admission symptoms and intervention duration. CONCLUSION: PFT is beneficial in treating pediatric FSS. Therefore, intensive parental involvement in rehabilitation may be cardinal. PMID- 28079035 TI - Parents' and Teachers' Perceptions of Abnormal Attention Span of Elementary School-Age Children. AB - BACKGROUND: To determine teacher and parental perception of minimal expected sustained attention span during various daily tasks among elementary school children. METHODS: 54 parents and 47 teachers completed the attention span questionnaire (AtSQ) that was developed for this study. The AtSQ consists of 15 academic and leisure tasks that require a child's sustained attention. The study focused on third and fourth graders in Israel. RESULTS: There was a high degree of variability among teachers and parents in their responses to the AtSQ. The expected attention span of children as judged by parents was higher and more varied compared to teachers, and higher for girls than for boys. CONCLUSIONS: Our results indicate poor agreement in cutoff values for sustained attention span between teachers and parents and within each group. PMID- 28079037 TI - Individual Psychotherapy ("Talking Therapy"): A Survey of Attitudes among Residents & Specialists in Psychiatry, Israel 2010-2011. AB - BACKGROUND: Individual psychotherapy is an efficient tool and an integral part of psychiatric treatment. However, its status among psychiatrists in Israel has never been explored. OBJECTIVES: To explore and map the attitudes of psychiatrists in Israel regarding psychotherapy and psychotherapy training during residency, with comparisons between residents vs. specialists, peripheral vs. central institutions and mental health vs. medical centers. METHOD: We conducted a cross-sectional survey to examine the attitudes toward individual psychotherapy. The questionnaire was delivered via email and direct approach to psychiatrists in Israel. RESULTS: The survey was completed by 229 of 1,502 registered psychiatrists (15.3%). While 96% (n=218) had positive attitudes towards psychotherapy, 93.1% (n=215) thought psychotherapy was less available than pharmacotherapy. Psychiatrists from peripheral institutions prefer cognitive behavioral therapy, while psychiatrists from central institutions prefer dynamic psychotherapy. Psychiatrists from mental health centers use more dynamic psychotherapy compared to psychiatrists from medical centers. The number of dynamic psychotherapy treatments psychiatrists delivered during their residencies has been decreasing over time, meaning residents today deliver fewer dynamic psychotherapy treatments compared to the number of treatments specialists delivered during their residencies. Additionally, 97.4% (n=225) believed psychotherapy training should be included in the psychiatric residency and 87.3% thought that the training should be improved to a great extent. CONCLUSIONS: The survey demonstrates mixed but overall positive attitudes towards psychotherapy among psychiatrists in Israel. The findings should be taken into consideration by psychiatrists who design the residency program and by policy makers who are in charge of the mental health reform in Israel, or the psychotherapy usage and therapeutic potential may diminish, as has happened in other countries. PMID- 28079038 TI - Comorbidity of Post-traumatic Stress Symptoms and Depressive Symptoms among Obstetric Nurses with Perinatal Death Exposure. AB - BACKGROUND: Mental health and well-being among obstetric nurses after perinatal death is understudied. The primary goal of this study is to explore the comorbidity of post-traumatic stress disorder (PTSD) symptoms and depressive symptoms among obstetric nurses. In addition, we explore associations between personal resources - coping self-efficacy and active social support - and comorbidity symptoms. METHOD: One hundred and twenty-five obstetric nurses who represent 25% of the entire population of Israeli obstetric nurses completed self report questionnaires regarding demographic data, coping self-efficacy, active social support, history of exposure to traumatic events, PTSD symptoms and depressive symptoms. RESULTS: An elevated risk of PTSD among obstetric nurses was positively associated with an elevated risk of depression and age while negatively associated with coping self-efficacy. CONCLUSIONS: These findings may suggest that nurse educators, administrators and leaders in the midwifery practice should promote stress intervention, supportive clinical environments and educational programs among obstetric nurses. PMID- 28079039 TI - Simulation of Mental Disorders: I. Concepts, Challenges and Animal Models. AB - The complexity of the human brain and the difficulties in identifying and dissecting the biological, social and contextual underpinnings of mental functions confound the study of the etiology and pathophysiology of mental disorders. Large-scale computer simulation of the human brain was recently proposed as a method to circumvent some of these difficulties. In this two partpaper, we discuss selected conceptual and pragmatic issues pertaining to the mental illness simulation in general and computer simulation in particular. We address the merits and limitations of two generic types of simulation vehicles, biological simulation in animal models (Part I) and virtual simulation in computer models (Part II), in the study of mental disorders in humans. We point to the need to tailor the vehicle and method of simulation to the goal of the simulation, and suggest future directions for maximizing the utility of mental illness simulation. We argue that at the current state of knowledge, the biological-phenomenological gap in understanding mental disorders markedly limits the ability to generate high-fidelity biological and computational models of mental illness. Simulation focusing on limited realistic objectives, such as mimicking selected distinct biological and phenomenological attributes of specific mental symptoms, may however serve as a useful tool in exploring mental disorders. PMID- 28079040 TI - Simulation of Mental Disorders: II. Computer Models, Purposes and Future Directions. AB - The complexity of the human brain and the difficulties in identifying and dissecting the biological, social and contextual underpinnings of mental functions confound the study of the etiology and pathophysiology of mental disorders. Simulating mental disorders in animal models or in computer programs may contribute to the understanding of such disorders. In the companion paper (30), we discussed selected concepts and pragmatics pertaining to mental illness simulation in general, and then focused on issues pertaining to animal models of mental disease. In this paper, we focus on selected aspects of the merits and limitations of the use of large scale computer simulation in investigating mental disorders. We argue that at the current state of knowledge, the biological phenomenological gap in understanding mental disorders markedly limits the ability to generate high-fidelity computational models of mental illness. We conclude that similarly to the animal model approach, brain simulation focusing on limited realistic objectives, such as mimicking the emergence of selected distinct attributes of specific mental symptoms in a virtual brain or parts thereof, may serve as a useful tool in exploring mental disorders. PMID- 28079041 TI - Ophthalmic abnormalities in children with dyslexia: A look at current research. PMID- 28079042 TI - Study of interleukin-6 and interleukin-8 levels in patients with neurological manifestations of dengue. AB - CONTEXT: Pro-inflammatory markers play a key role in the pathogenesis of various Flavivirus infection. AIM: In this study, we evaluated the role of these markers in neurological manifestations of dengue. SETTINGS AND DESIGNS: Consecutive dengue cases with different neurological manifestations who presented between August 2012 and July 2014 were studied in hospital-based case-control study. MATERIALS AND METHODS: Interleukin (IL-6) and IL-8 level were measured in serum and cerebrospinal fluid (CSF) of dengue cases with different neurological manifestations and also in age- and sex-matched controls. Level was analyzed with various parameters and outcomes. STATISTICAL ANALYSIS: Statistical analysis was done using SPSS version 16.0 by applying appropriate statistical methods. P < 0.05 considered statistically significant. RESULTS: Out of the 40 enrolled cases of dengue with neurological manifestations, 29 had central nervous system and 11 had peripheral nervous system (CNS/PNS) manifestations. In CNS group, both IL-6 and IL-8 (CSF and serum) were significantly elevated (P < 0.001), whereas CSF IL 6 (P = 0.008), serum IL-6 (P = 0.001), and serum IL-8 (P = 0.005) were significantly elevated in PNS group. CSF IL-6, serum IL-6, and IL-8 were significantly elevated in poor outcome patients in CNS group (P < 0.05). CSF IL-6 and IL-8 were significantly elevated in CSF dengue positive cases as compared to CSF negative patients (P < 0.05). Cytokine level was not significantly correlated with neuroimaging abnormality in CNS group. Nine patients died and the remainder recovered. CONCLUSION: Elevated level of IL-6 and IL-8 is associated with different neurological manifestations and poor outcome, but whether they are contributing to neuropathogenesis or simply a correlate of severe disease remains to be determined. PMID- 28079043 TI - Gossypibomas in India - A systematic literature review. AB - PURPOSE OF REVIEW: Gossypibomas remain a dreaded and unwanted complication of surgical practice. Despite significant interest and numerous guidelines, the number of reported cases remains sparse due to various factors, including potential legal implications. Herein, we review related data from India to ascertain if the problem is better or worse than that reported in world literature. MATERIALS AND METHODS: A literature search was performed on PubMed and Google Scholar, to collect and analyze all case reports and case reviews regarding the condition in India. RESULTS: On analysis of the results, there were 100 publications reporting a total of 126 events. The average patient age was 38.65 years. Average time to discovery was 1225.62 days. Forty-nine percent of reported cases were discovered within the 1 st year. The most common clinical features were pain (73.8%), palpable mass (47.6%), vomiting (35%), abdominal distention (26%), and fever (12.6%). Spontaneous expulsion of the gossypiboma was noted in five cases (3.96%). Transmural migration was seen in 36 cases (28.57%). CONCLUSIONS: Despite advancements in surgical approaches and preventive measures, gossypibomas continue to be a cause of significant morbidity. A safe working culture, open communication, teamwork, and an accurate sponge count remain our best defence against this often unpredictable complication of surgery. PMID- 28079044 TI - Chorea as unusual complication of fungicide poisoning. AB - Chorea is a rare manifestation of poisoning. We report an index case of a young woman who developed generalized chorea following propiconazole toxin ingestion. As large series on neurological complications of toxic compounds are difficult to be compiled, it is of interest to report our experience. This report adds one more compound to the increasing list of toxic chorea. PMID- 28079045 TI - Hernia of the umbilical cord associated with a patent omphalomesenteric duct. AB - Congenital hernia of the cord is a different type of ventral abdominal wall defect in which the bowel usually herniates into the base of normally inserted umbilical cord through a patent umbilical ring. It is rare congenital anomaly with incidence of 1 in 5000. Although it was described as a distinct entity since 1920s it is often misdiagnosed as a small omphalocele. We present an unusal case of term male newborn with umbilical cord hernia associated with patent omphalomesenteric duct. The diagnose was made after birth despite antenatal ultrasound scans and it is managed successfully with uneventful recovery. If this is missdiagnosed, it could cause iatrogenic atresia of the ileum by clamping the umbilical cord after birth. PMID- 28079046 TI - Stroke mimic: Perfusion magnetic resonance imaging of a patient with ictal paralysis. PMID- 28079047 TI - Reply to Letter to Editor regarding the article, "Stroke mimic: Perfusion magnetic resonance imaging of a patient with ictal paralysis". PMID- 28079048 TI - Delivering efficient liver-directed AAV-mediated gene therapy. PMID- 28079049 TI - Lateralization index but not contralateral suppression at adrenal vein sampling predicts improvement in blood pressure after adrenalectomy for primary aldosteronism. AB - Adrenal vein sampling (AVS) is essential in differentiating unilateral from bilateral sources of aldosterone excess in primary aldosteronism (PA). However, its ability to predict blood pressure (BP) improvement after adrenalectomy has not been well studied. This is a retrospective observational study of 119 patients who underwent AVS by sequential technique followed by adrenalectomy for PA at the Hospital of the University of Pennsylvania from 1997 to 2015. Median age was 52 years (interquartile range 44-59), 67% were male and median duration of hypertension was 10 (interquartile range 6-20) years. A total of 76% and 90% of patients experienced BP improvement at 0-6 months or at any time point after surgery, respectively. Lateralization index (LI) >8, but not the presence of contralateral suppression, was significantly associated with BP improvement after surgery by multivariate logistic regression analysis adjusted for potential confounders (odds ratio (95% confidence interval): 17.1 (1.7-171.6) and 6.39 (0.06-641.8), respectively). A prediction score was created by covariates that was significantly associated with BP improvement in logistic regression analysis (duration of hypertension, body mass index, preoperative systolic BP and number of antihypertensive medications). Receiver-operating characteristic curve analyses showed that the addition of LI >8 to the score increased its ability to predict BP improvement (area under the curve 0.73-0.80). In conclusion, LI is useful in predicting improvement in BP after adrenalectomy for PA. The results of this study suggest that patients with long-standing severe hypertension may still benefit from surgery if LI >8. PMID- 28079050 TI - Bipolar radiofrequency renal denervation with the Vessix catheter in patients with resistant hypertension: 2-year results from the REDUCE-HTN trial. PMID- 28079052 TI - Corrigendum: Contrasting effects of nitrogen and phosphorus addition on soil respiration in an alpine grassland on the Qinghai-Tibetan Plateau. PMID- 28079051 TI - Integrated crop management practices for maximizing grain yield of double-season rice crop. AB - Information on maximum grain yield and its attributes are limited for double season rice crop grown under the subtropical environment. This study was conducted to examine key characteristics associated with high yielding double season rice crop through a comparison between an integrated crop management (ICM) and farmers' practice (FP). Field experiments were conducted in the early and late seasons in the subtropical environment of Wuxue County, Hubei Province, China in 2013 and 2014. On average, grain yield in ICM was 13.5% higher than that in FP. A maximum grain yield of 9.40 and 10.53 t ha-1 was achieved under ICM in the early- and late-season rice, respectively. Yield improvement of double-season rice with ICM was achieved with the combined effects of increased plant density and optimized nutrient management. Yield gain of ICM resulted from a combination of increases in sink size due to more panicle number per unit area and biomass production, further supported by the increased leaf area index, leaf area duration, radiation use efficiency, crop growth rate, and total nitrogen uptake compared with FP. Further enhancement in the yield potential of double-season rice should focus on increasing crop growth rate and biomass production through improved and integrated crop management practices. PMID- 28079053 TI - Molecular evidence for the involvement of a polygalacturonase-inhibiting protein, GhPGIP1, in enhanced resistance to Verticillium and Fusarium wilts in cotton. AB - Polygalacturonase-inhibiting protein (PGIP), belonging to a group of plant defence proteins, specifically inhibits endopolygalacturonases secreted by pathogens. Herein, we showed that purified GhPGIP1 is a functional inhibitor of Verticillium dahliae and Fusarium oxysporum f. sp. vasinfectum, the two fungal pathogens causing cotton wilt. Transcription of GhPGIP1 was increased in cotton upon infection, wounding, and treatment with defence hormone and H2O2. Resistance by GhPGIP1 was examined by its virus-induced gene silencing in cotton and overexpression in Arabidopsis. GhPGIP1-silenced cotton was highly susceptible to the infections. GhPGIP1 overexpression in transgenic Arabidopsis conferred resistance to the infection, accompanied by enhanced expression of pathogenesis related proteins (PRs), isochorismate synthase 1 (ICS1), enhanced disease susceptibility 1 (EDS1), and phytoalexin-deficient 4 (PAD4) genes. Transmission electron microscopy revealed cell wall alteration and cell disintegration in plants inoculated with polygalacturonase (PGs), implying its role in damaging the cell wall. Docking studies showed that GhPGIP1 interacted strongly with C terminal of V. dahliae PG1 (VdPG1) beyond the active site but weakly interacted with C-terminal of F. oxysporum f. sp. vasinfectum (FovPG1). These findings will contribute towards the understanding of the roles of PGIPs and in screening potential combat proteins with novel recognition specificities against evolving pathogenic factors for countering pathogen invasion. PMID- 28079054 TI - Local dimensionality determines imaging speed in localization microscopy. AB - Localization microscopy allows biological samples to be imaged at a length scale of tens of nanometres. Live-cell super-resolution imaging is rare, as it is generally assumed to be too slow for dynamic samples. The speed of data acquisition can be optimized by tuning the density of activated fluorophores in each time frame. Here, we show that the maximum achievable imaging speed for a particular structure varies by orders of magnitude, depending on the sample dimensionality (that is, whether the sample is more like a point, a strand or an extended structure such as a focal adhesion). If too high an excitation density is used, we demonstrate that the analysis undergoes silent failure, resulting in reconstruction artefacts. We are releasing a tool to allow users to identify areas of the image in which the activation density was too high and correct for them, in both live- and fixed-cell experiments. PMID- 28079055 TI - Intestinal microbiota as a tetrahydrobiopterin exogenous source in hph-1 mice. AB - Tetrahydrobiopterin (BH4) is a cofactor of a number of regulatory enzymes. Although there are no known BH4 exogenous sources, the tissue content of this biopterin increases with age in GTP cyclohydrolase 1-deficient hyperphenylalaninemia-1 (hph-1) mice. Since certain bacteria are known to generate BH4, we hypothesize that generation of this biopterin by the intestinal microbiota contributes to its tissue increase in hph-1 adult mice. The goal of this study was to comparatively evaluate hph-1 mice and wild-type C57Bl/6 controls for the presence of intestinal BH4-producing bacteria. Newborn and adult mice fecal material was screened for 6-pyruvoyltetrahydropterin synthase (PTPS-2) an enzyme only present in BH4-generating bacteria. Adult, but not newborn, wild type control and hph-1 mouse fecal material contained PTPS-2 mRNA indicative of the presence of BH4-generating bacteria. Utilizing chemostat-cultured human fecal bacteria, we identified the PTPS-2-producing bacteria as belonging to the Actinobacteria phylum. We further confirmed that at least two PTPS-2-producing species, Aldercreutzia equolifaciens and Microbacterium schleiferi, generate BH4 and are present in hph-1 fecal material. In conclusion, intestinal Actinobacteria generate BH4. This finding has important translational significance, since manipulation of the intestinal flora in individuals with congenital biopterin deficiency may allow for an increase in total body BH4 content. PMID- 28079056 TI - Endurance and Cycle-to-cycle Uniformity Improvement in Tri-Layered CeO2/Ti/CeO2 Resistive Switching Devices by Changing Top Electrode Material. AB - Resistance switching characteristics of CeO2/Ti/CeO2 tri-layered films sandwiched between Pt bottom electrode and two different top electrodes (Ti and TaN) with different work functions have been investigated. RRAM memory cells composed of TaN/CeO2/Ti/CeO2/Pt reveal better resistive switching performance instead of Ti/CeO2/Ti/CeO2/Pt memory stacks. As compared to the Ti/CeO2 interface, much better ability of TaN/CeO2 interface to store and exchange plays a key role in the RS performance improvement, including lower forming/SET voltages, large memory window (~102) and no significant data degradation during endurance test of >104 switching cycles. The formation of TaON thinner interfacial layer between TaN TE and CeO2 film is found to be accountable for improved resistance switching behavior. Partial charge density of states is analyzed using density functional theory. It is found that the conductive filaments formed in CeO2 based devices is assisted by interstitial Ti dopant. Better stability and reproducibility in cycle to-cycle (C2C) resistance distribution and Vset/Vreset uniformity were achieved due to the modulation of current conduction mechanism from Ohmic in low field region to Schottky emission in high field region. PMID- 28079057 TI - Functional MRI of the Reserpine-Induced Putative Rat Model of Fibromyalgia Reveals Discriminatory Patterns of Functional Augmentation to Acute Nociceptive Stimuli. AB - Functional neuroimaging, applied to pre-clinical models of chronic pain, offers unique advantages in the drive to discover new treatments for this prevalent and oppressive condition. The high spatial and temporal resolution of fMRI affords detailed mapping of regional pharmacodynamics that underlie mechanisms of pain suppression by new analgesics. Despite evidence supporting the translational relevance of this approach, relatively few studies have investigated fMRI abnormalities in rodent models of chronic pain. In this study, we used fMRI to map the BOLD response in a recently developed putative rat model of fibromyalgia to innocuous and acute nociceptive stimuli by applying a step-wise graded electrical forepaw stimulation paradigm, with comparison to healthy controls. We observed discriminatory functional signatures (p < 0.001) to 2 mA electrical forepaw stimulation, found to be innocuous in the control group. As such, this translational approach provides sensitive and quantitative neural correlates of the underlying chronic disease. The regional patterns of functional augmentation were found to be concordant with previous studies of nociception in the anaesthetised rat brain, supporting the specificity of this approach in the study of altered central pain processing in reserpine induced myalgia. The methodology introduced in this work represents a novel platform for emerging treatment evaluation in highly experimentally controlled conditions. PMID- 28079058 TI - Of dogs and men. PMID- 28079059 TI - Co-Variation of Peripheral Levels of miR-1202 and Brain Activity and Connectivity During Antidepressant Treatment. AB - MicroRNAs are short non-coding molecules that play a major role in regulating gene expression. Peripheral levels of miR-1202 have been shown to predict and mediate antidepressant response. However, it is not clear to what extent these peripheral measures reflect central neural changes in vivo. We approached this problem with the combined use of peripheral miR-1202 measures and neuroimaging. At baseline and after 8 weeks of desvenlafaxine (50-100 mg die), 20 patients were scanned with 3T magnetic resonance imaging, first at rest then during the Go/NoGo task, a classical test of response inhibition. Blood samples were collected at both time points. During resting state, lower baseline miR-1202 levels were predictive of increased connectivity from T0 to T8 between the posterior cingulate and the prefrontal, parietal, and occipital cortices. Changes in miR 1202 levels following desvenlafaxine treatment were negatively correlated with changes in activity in right precuneus within the default-mode network, and in connectivity between the posterior cingulate and the temporal and prefrontal cortices, and the precuneus. During the Go/NoGo task, baseline miR-1202 levels and changes in these levels were correlated with activity changes in different regions, including bilateral prefrontal, insular, cingulate, and temporal cortices, and left putamen and claustrum. Finally, secondary analyses in a subset of patients showed a trend for a significant correlation between miR-1202 levels and glutamate levels measured by spectroscopy. Changes in peripheral miR-1202 levels were therefore associated with changes in brain activity and connectivity in a network of brain regions associated with depression and antidepressant response. These effects may be mediated by the glutamatergic system. PMID- 28079060 TI - Intranasal Lactoferrin Enhances alpha-Secretase-Dependent Amyloid Precursor Protein Processing via the ERK1/2-CREB and HIF-1alpha Pathways in an Alzheimer's Disease Mouse Model. AB - Growing evidence suggests that lactoferrin (Lf), an iron-binding glycoprotein, is a pleiotropic functional nutrient. In addition, Lf was recently implicated as a neuroprotective agent. These properties make Lf a valuable therapeutic candidate for the treatment of Alzheimer's disease (AD). However, the mechanisms regulating the physiological roles of Lf in the pathologic condition of AD remain unknown. In the present study, an APPswe/PS1DE9 transgenic mouse model of AD was used. We explored whether intranasal human Lf (hLf) administration could reduce beta amyloid (Abeta) deposition and ameliorate cognitive decline in this AD model. We found that hLf promoted the non-amyloidogenic metabolism of amyloid precursor protein (APP) processing through activation of alpha-secretase a-disintegrin and metalloprotease10 (ADAM10), resulting in enhanced cleavage of the alpha-COOH terminal fragment of APP and the corresponding elevation of the NH2-terminal APP product, soluble APP-alpha (sAPPalpha), which consequently reduced Abeta generation and improved spatial cognitive learning ability in AD mice. To gain insight into the molecular mechanism by which Lf modulates APP processing, we evaluated the involvement of the critical molecules for APP cleavage and the signaling pathways in N2a cells stably transfected with Swedish mutant human APP (APPsw N2a cells). The results show that the ERK1/2-CREB and HIF-1alpha signaling pathways were activated by hLf treatment, which is responsible for the expression of induced ADAM10. Additional tests were performed before suggesting the potential use of hLf as an antioxidant and anti-inflammatory. These findings provide new insights into the sources and mechanisms by which hLf inhibits the cognitive decline that occurs in AD via activation of ADAM10 expression in an ERK1/2-CREB and HIF-1alpha-dependent manner. PMID- 28079062 TI - Does retinal configuration make the head and eyes of foveate birds move? AB - Animals move their heads and eyes to compensate for movements of the body and background, search, fixate, and track objects visually. Avian saccadic head/eye movements have been shown to vary considerably between species. We tested the hypothesis that the configuration of the retina (i.e., changes in retinal ganglion cell density from the retinal periphery to the center of acute vision fovea) would account for the inter-specific variation in avian head/eye movement behavior. We characterized retinal configuration, head movement rate, and degree of eye movement of 29 bird species with a single fovea, controlling for the effects of phylogenetic relatedness. First, we found the avian fovea is off the retinal center towards the dorso-temporal region of the retina. Second, species with a more pronounced rate of change in ganglion cell density across the retina generally showed a higher degree of eye movement and higher head movement rate likely because a smaller retinal area with relatively high visual acuity leads to greater need to move the head/eye to align this area that contains the fovea with objects of interest. Our findings have implications for anti-predator behavior, as many predator-prey interaction models assume that the sensory system of prey (and hence their behavior) varies little between species. PMID- 28079063 TI - Horizon 2020: Funds to help Eastern Europe close the gap. PMID- 28079061 TI - Progressive Decline in Hippocampal CA1 Volume in Individuals at Ultra-High-Risk for Psychosis Who Do Not Remit: Findings from the Longitudinal Youth at Risk Study. AB - Most individuals identified as ultra-high-risk (UHR) for psychosis do not develop frank psychosis. They continue to exhibit subthreshold symptoms, or go on to fully remit. Prior work has shown that the volume of CA1, a subfield of the hippocampus, is selectively reduced in the early stages of schizophrenia. Here we aimed to determine whether patterns of volume change of CA1 are different in UHR individuals who do or do not achieve symptomatic remission. Structural MRI scans were acquired at baseline and at 1-2 follow-up time points (at 12-month intervals) from 147 UHR and healthy control subjects. An automated method (based on an ex vivo atlas of ultra-high-resolution hippocampal tissue) was used to delineate the hippocampal subfields. Over time, a greater decline in bilateral CA1 subfield volumes was found in the subgroup of UHR subjects whose subthreshold symptoms persisted (n=40) and also those who developed clinical psychosis (n=12), compared with UHR subjects who remitted (n=41) and healthy controls (n=54). No baseline differences in volumes of the overall hippocampus or its subfields were found among the groups. Moreover, the rate of volume decline of CA1, but not of other hippocampal subfields, in the non-remitters was associated with increasing symptom severity over time. Thus, these findings indicate that there is deterioration of CA1 volume in persistently symptomatic UHR individuals in proportion to symptomatic progression. PMID- 28079064 TI - Lasing action from photonic bound states in continuum. AB - In 1929, only three years after the advent of quantum mechanics, von Neumann and Wigner showed that Schrodinger's equation can have bound states above the continuum threshold. These peculiar states, called bound states in the continuum (BICs), manifest themselves as resonances that do not decay. For several decades afterwards the idea lay dormant, regarded primarily as a mathematical curiosity. In 1977, Herrick and Stillinger revived interest in BICs when they suggested that BICs could be observed in semiconductor superlattices. BICs arise naturally from Feshbach's quantum mechanical theory of resonances, as explained by Friedrich and Wintgen, and are thus more physical than initially realized. Recently, it was realized that BICs are intrinsically a wave phenomenon and are thus not restricted to the realm of quantum mechanics. They have since been shown to occur in many different fields of wave physics including acoustics, microwaves and nanophotonics. However, experimental observations of BICs have been limited to passive systems and the realization of BIC lasers has remained elusive. Here we report, at room temperature, lasing action from an optically pumped BIC cavity. Our results show that the lasing wavelength of the fabricated BIC cavities, each made of an array of cylindrical nanoresonators suspended in air, scales with the radii of the nanoresonators according to the theoretical prediction for the BIC mode. Moreover, lasing action from the designed BIC cavity persists even after scaling down the array to as few as 8-by-8 nanoresonators. BIC lasers open up new avenues in the study of light-matter interaction because they are intrinsically connected to topological charges and represent natural vector beam sources (that is, there are several possible beam shapes), which are highly sought after in the fields of optical trapping, biological sensing and quantum information. PMID- 28079065 TI - Ecology: Invasive wild pigs spread across US. PMID- 28079066 TI - Medical devices: Mini machines deliver drugs. PMID- 28079068 TI - Microbiology: Bacterial explorers move fast. PMID- 28079070 TI - Biomaterials: Silk gland mimic spins strong fibres. PMID- 28079071 TI - Optical physics: Supercavity lasing. PMID- 28079072 TI - Physiology: How alcohol ramps up hunger signals. PMID- 28079073 TI - Fluid dynamics: Water flows out of touch. PMID- 28079074 TI - Climate change: Save last cloud forests in western Andes. PMID- 28079076 TI - Neuroscience: Age sees boost in facial recognition. PMID- 28079075 TI - Hydroclimate changes across the Amazon lowlands over the past 45,000 years. AB - Reconstructing the history of tropical hydroclimates has been difficult, particularly for the Amazon basin-one of Earth's major centres of deep atmospheric convection. For example, whether the Amazon basin was substantially drier or remained wet during glacial times has been controversial, largely because most study sites have been located on the periphery of the basin, and because interpretations can be complicated by sediment preservation, uncertainties in chronology, and topographical setting. Here we show that rainfall in the basin responds closely to changes in glacial boundary conditions in terms of temperature and atmospheric concentrations of carbon dioxide. Our results are based on a decadally resolved, uranium/thorium-dated, oxygen isotopic record for much of the past 45,000 years, obtained using speleothems from Paraiso Cave in eastern Amazonia; we interpret the record as being broadly related to precipitation. Relative to modern levels, precipitation in the region was about 58% during the Last Glacial Maximum (around 21,000 years ago) and 142% during the mid-Holocene epoch (about 6,000 years ago). We find that, as compared with cave records from the western edge of the lowlands, the Amazon was widely drier during the last glacial period, with much less recycling of water and probably reduced plant transpiration, although the rainforest persisted throughout this time. PMID- 28079077 TI - Climate science: The resilience of Amazonian forests. PMID- 28079080 TI - Cancer: 'Old' cells linked to drug side effects. PMID- 28079079 TI - Emissions: Step on the natural gas for German cars. PMID- 28079082 TI - Planetary science: Many collisions made the Moon. PMID- 28079081 TI - Sideband cooling beyond the quantum backaction limit with squeezed light. AB - Quantum fluctuations of the electromagnetic vacuum produce measurable physical effects such as Casimir forces and the Lamb shift. They also impose an observable limit-known as the quantum backaction limit-on the lowest temperatures that can be reached using conventional laser cooling techniques. As laser cooling experiments continue to bring massive mechanical systems to unprecedentedly low temperatures, this seemingly fundamental limit is increasingly important in the laboratory. Fortunately, vacuum fluctuations are not immutable and can be 'squeezed', reducing amplitude fluctuations at the expense of phase fluctuations. Here we propose and experimentally demonstrate that squeezed light can be used to cool the motion of a macroscopic mechanical object below the quantum backaction limit. We first cool a microwave cavity optomechanical system using a coherent state of light to within 15 per cent of this limit. We then cool the system to more than two decibels below the quantum backaction limit using a squeezed microwave field generated by a Josephson parametric amplifier. From heterodyne spectroscopy of the mechanical sidebands, we measure a minimum thermal occupancy of 0.19 +/- 0.01 phonons. With our technique, even low-frequency mechanical oscillators can in principle be cooled arbitrarily close to the motional ground state, enabling the exploration of quantum physics in larger, more massive systems. PMID- 28079084 TI - African elephants: Scale up elephant anti-poaching funds. PMID- 28079086 TI - Conservation: Effects of wildlife trade mapped. PMID- 28079085 TI - Endangered species: Illegal lemur trade grows in Madagascar. PMID- 28079087 TI - Announcement: Nature launches five new journals for 2017. PMID- 28079088 TI - Compare voting systems to improve them. PMID- 28079089 TI - Behind New Zealand's wild plan to purge all pests. PMID- 28079090 TI - Deceptive curcumin offers cautionary tale for chemists. PMID- 28079091 TI - Chinese AI company plans to mine health data faster than rivals. PMID- 28079093 TI - Tilikum dies, US antibiotic ban and a Nazi-science probe. PMID- 28079092 TI - Brexit offers rare chance to make Britain greener. PMID- 28079095 TI - Legendary radio telescope hangs in the balance. PMID- 28079094 TI - Gene-edited cows, rogue clinics, speedier drug approvals: the challenges facing Trump's FDA chief. PMID- 28079096 TI - Corrections. PMID- 28079097 TI - Fantasy politics over fetal-tissue research. PMID- 28079098 TI - Google reveals secret test of AI bot to beat top Go players. PMID- 28079099 TI - 'Nature-based solutions' is the latest green jargon that means more than you might think. PMID- 28079100 TI - Where science and nonsense collide. PMID- 28079102 TI - Corrigendum: Ultra-sensitive droplet digital PCR for detecting a low-prevalence somatic GNAQ mutation in Sturge-Weber syndrome. PMID- 28079101 TI - Comparing GWAS Results of Complex Traits Using Full Genetic Model and Additive Models for Revealing Genetic Architecture. AB - Most of the genome-wide association studies (GWASs) for human complex diseases have ignored dominance, epistasis and ethnic interactions. We conducted comparative GWASs for total cholesterol using full model and additive models, which illustrate the impacts of the ignoring genetic variants on analysis results and demonstrate how genetic effects of multiple loci could differ across different ethnic groups. There were 15 quantitative trait loci with 13 individual loci and 3 pairs of epistasis loci identified by full model, whereas only 14 loci (9 common loci and 5 different loci) identified by multi-loci additive model. Again, 4 full model detected loci were not detected using multi-loci additive model. PLINK-analysis identified two loci and GCTA-analysis detected only one locus with genome-wide significance. Full model identified three previously reported genes as well as several new genes. Bioinformatics analysis showed some new genes are related with cholesterol related chemicals and/or diseases. Analyses of cholesterol data and simulation studies revealed that the full model performs were better than the additive-model performs in terms of detecting power and unbiased estimations of genetic variants of complex traits. PMID- 28079103 TI - Erratum: Antigen-affinity controls pre-germinal center B cell selection by promoting Mcl-1 induction through BAFF receptor signaling. PMID- 28079107 TI - Phenotyping for the dynamics of field wheat root system architecture. AB - We investigated a method to quantify field-state wheat RSA in a phenotyping way, depicting the 3D topology of wheat RSA in 14d periods. The phenotyping procedure, proposed for understanding the spatio-temporal variations of root-soil interaction and the RSA dynamics in the field, is realized with a set of indices of mm scale precision, illustrating the gradients of both wheat root angle and elongation rate along soil depth, as well as the foraging potential along the side directions. The 70d was identified as the shifting point distinguishing the linear root length elongation from power-law development. Root vertical angle in the 40 mm surface soil layer was the largest, but steadily decreased along the soil depth. After 98d, larger root vertical angle appeared in the deep soil layers. PAC revealed a stable root foraging potential in the 0-70d period, which increased rapidly afterwards (70-112d). Root foraging potential, explained by MaxW/MaxD ratio, revealed an enhanced gravitropism in 14d period. No-till post paddy wheat RLD decreased exponentially in both depth and circular directions, with 90% roots concentrated within the top 20 cm soil layer. RER along soil depth was either positive or negative, depending on specific soil layers and the sampling time. PMID- 28079106 TI - Extreme mitochondrial variation in the Atlantic gall crab Opecarcinus hypostegus (Decapoda: Cryptochiridae) reveals adaptive genetic divergence over Agaricia coral hosts. AB - The effectiveness of migration in marine species exhibiting a pelagic larval stage is determined by various factors, such as ocean currents, pelagic larval stage duration and active habitat selection. Direct measurement of larval movements is difficult and, consequently, factors determining the gene flow patterns remain poorly understood for many species. Patterns of gene flow play a key role in maintaining genetic homogeneity in a species by dampening the effects of local adaptation. Coral-dwelling gall crabs (Cryptochiridae) are obligate symbionts of stony corals (Scleractinia). Preliminary data showed high genetic diversity on the COI gene for 19 Opecarcinus hypostegus specimens collected off Curacao. In this study, an additional 176 specimens were sequenced and used to characterize the population structure along the leeward side of Curacao. Extremely high COI genetic variation was observed, with 146 polymorphic sites and 187 unique haplotypes. To determine the cause of this high genetic diversity, various gene flow scenarios (geographical distance along the coast, genetic partitioning over depth, and genetic differentiation by coral host) were examined. Adaptive genetic divergence across Agariciidae host species is suggested to be the main cause for the observed high intra-specific variance, hypothesised as early signs of speciation in O. hypostegus. PMID- 28079108 TI - Improving the Concentrations of the Active Components in the Herbal Tea Ingredient, Uraria crinita: The Effect of Post-harvest Oven-drying Processing. AB - Uraria crinita is widely used as a popular folk drink; however, little is known about how the post-harvest operations affect the chemical composition and bioactivity of UC. We assessed three drying methods (Oven-drying, Air-drying, Sun drying), as well as the Oven-drying temperature using metabolomics approaches and bioactivity assays. The samples processed at 40 degree show a greater effect on the levels of estrogen receptor-alpha activity and nuclear factor erythroid 2 related factor 2 activity, anti-oxidative activity, and cyclooxygenase-2 inhibition compared with the other samples. A multivariate analysis showed a clear separation between the 40 degree Oven-dried samples and the other samples, which is consistent with the results of bioactivity assay. These results are ascribed to at least two-fold increase in the concentrations of flavonoids, spatholosineside A and triterpenoids in the oven-dried samples compared with the other groups. The proposed Oven-drying method at 40 degree results in an improved quality of UC. PMID- 28079109 TI - A kind of universal quantum secret sharing protocol. AB - Universality is an important feature, but less researched in quantum communication protocols. In this paper, a kind of universal quantum secret sharing protocol is investigated. Firstly, we design a quantum secret sharing protocol based on the Borras-Plastino-Batle (BPB) state. Departing from previous research, our protocol has a salient feature in that participants in our protocol only need projective measurement instead of any unitary operations. It makes our protocol more flexible. Secondly, universality of quantum communication protocols is studied for the first time. More specifically, module division of quantum communication protocols and coupling between different modules are discussed. Our aforementioned protocol is analyzed as an example. On one hand, plenty of quantum states (the BPB-class states and the BPB-like-class states, which are proposed in this paper) could be used as carrier to perform our protocol. On the other hand, our protocol also could be regarded as a quantum private comparison protocol with a little revision. These features are rare for quantum communication protocols, and make our protocol more robust. Thirdly, entanglements of the BPB-class states are calculated in the Appendix. PMID- 28079104 TI - Longitudinal measurement and hierarchical classification framework for the prediction of Alzheimer's disease. AB - Accurate prediction of Alzheimer's disease (AD) is important for the early diagnosis and treatment of this condition. Mild cognitive impairment (MCI) is an early stage of AD. Therefore, patients with MCI who are at high risk of fully developing AD should be identified to accurately predict AD. However, the relationship between brain images and AD is difficult to construct because of the complex characteristics of neuroimaging data. To address this problem, we present a longitudinal measurement of MCI brain images and a hierarchical classification method for AD prediction. Longitudinal images obtained from individuals with MCI were investigated to acquire important information on the longitudinal changes, which can be used to classify MCI subjects as either MCI conversion (MCIc) or MCI non-conversion (MCInc) individuals. Moreover, a hierarchical framework was introduced to the classifier to manage high feature dimensionality issues and incorporate spatial information for improving the prediction accuracy. The proposed method was evaluated using 131 patients with MCI (70 MCIc and 61 MCInc) based on MRI scans taken at different time points. Results showed that the proposed method achieved 79.4% accuracy for the classification of MCIc versus MCInc, thereby demonstrating very promising performance for AD prediction. PMID- 28079111 TI - Killing the old: cell senescence in atherosclerosis. PMID- 28079110 TI - Left ventricular noncompaction cardiomyopathy: cardiac, neuromuscular, and genetic factors. AB - Left ventricular hypertrabeculation (LVHT) or noncompaction is a myocardial abnormality of unknown aetiology, frequently associated with monogenic disorders, particularly neuromuscular disorders, or with chromosomal defects. LVHT is diagnosed usually by echocardiography by the presence of a bilayered myocardium consisting of a thick, spongy, noncompacted endocardial layer and a thin, compacted, epicardial layer. The pathogenesis of LVHT is unsolved, and the diagnostic criteria, prognosis, and optimal treatment of patients with LVHT are under debate. LVHT is categorized as distinct primary genetic cardiomyopathy by the AHA and as unclassified cardiomyopathy by the ESC. LVHT is usually asymptomatic, but can be complicated by heart failure, thromboembolism, or ventricular arrhythmias, including sudden cardiac death. Mortality of patients with LVHT ranges from 5% to 47%. Anticoagulation is indicated if atrial fibrillation, severe heart failure, previous embolism, or intracardiac thrombus formation are present. In patients with LVHT with late gadolinium enhancement, an implantable cardioverter-defibrillator might be considered if systolic dysfunction, a family history of sudden cardiac death, nonsustained ventricular tachycardia, or previous syncope is additionally present. In this Review, we discuss the current findings on the aetiology and pathophysiology of LVHT, and provide an overview of the diagnosis, available treatment, and prognosis of this cardiomyopathy. PMID- 28079112 TI - Microbes can help explain the evolution of host altruism. AB - The evolution of altruistic behaviour, which is costly to the donor but beneficial for the recipient, is among the most intriguing questions in evolutionary biology. Several theories have been proposed to explain it, including kin selection, group selection and reciprocity. Here we propose that microbes that manipulate their hosts to act altruistically could be favoured by selection, and may play a role in the widespread occurrence of altruism. Using computational models, we find that microbe-induced altruism can explain the evolution of host altruistic behaviour under wider conditions than host-centred theories, including in a fully mixed host population, without repeating interactions or individual recognition. Our results suggest that factors such as antibiotics that kill microbes might negatively affect cooperation in a wide range of organisms. PMID- 28079115 TI - Kidney stones. PMID- 28079114 TI - Discovering potential serological biomarker for chronic Hepatitis B Virus-related hepatocellular carcinoma in Chinese population by MAL-associated serum glycoproteomics analysis. AB - The accuracy of current biomarkers for the diagnosis of hepatocellular carcinoma (HCC), especially chronic Hepatitis B Virus (HBV)-related HCC, is limited. Recent progress in glycoproteomics has provided a novel platform for screening novel serological biomarkers of HCC. In this study, lectin affinity chromatography by Maackia amurensis lectin (MAL) and iTRAQ combined with mass spectrometric analysis were performed to enrich and identify the glycoprotein fractions in serum samples from HBV-related HCC patients and from healthy controls. Seventeen differential MAL-associated glycoproteins were identified. Among them, Galectin 3 binding protein (Gal-3BP) was selected for further evaluated by ELISA analysis and showed a high diagnostic potential of HBV-related HCC, with the AUC of 0.898 and a sensitivity, specificity and accuracy of 80.00%, 93.75% and 86.88%, respectively. Moreover, we constructed a predictive model through the combined use of serum Gal-3BP and Alpha Fetoprotein (AFP), which improved the sensitivity (from 87.5% to 95%), specificity (from 93.75% to 95%) and accuracy (from 90.63% to 95%) of diagnosing early HCC. These data suggested serum Gal-3BP level is a promising biomarker to identify HBV-related HCC and the combined use of serum Gal 3BP and AFP improves the diagnostic potential of HBV-HCC compared with AFP alone in current clinical practice. PMID- 28079113 TI - Congenital hearing loss. AB - Congenital hearing loss (hearing loss that is present at birth) is one of the most prevalent chronic conditions in children. In the majority of developed countries, neonatal hearing screening programmes enable early detection; early intervention will prevent delays in speech and language development and has long lasting beneficial effects on social and emotional development and quality of life. A diagnosis of hearing loss is usually followed by a search for an underlying aetiology. Congenital hearing loss might be attributed to environmental and prenatal factors, which prevail in low-income settings; congenital infections, particularly cytomegalovirus infection, are also a common risk factor for hearing loss. Genetic causes probably account for the majority of cases in developed countries; mutations can affect any component of the hearing pathway, in particular, inner ear homeostasis (endolymph production and maintenance) and mechano-electrical transduction (the conversion of a mechanical stimulus into electrochemical activity). Once the underlying cause of hearing loss is established, it might direct therapeutic decision making and guide prevention and (genetic) counselling. Management options include specific antimicrobial therapies, surgical treatment of craniofacial abnormalities and implantable or non-implantable hearing devices. An improved understanding of the pathophysiology and molecular mechanisms that underlie hearing loss and increased awareness of recent advances in genetic testing will promote the development of new treatment and screening strategies. PMID- 28079116 TI - Katanin p80, NuMA and cytoplasmic dynein cooperate to control microtubule dynamics. AB - Human mutations in KATNB1 (p80) cause severe congenital cortical malformations, which encompass the clinical features of both microcephaly and lissencephaly. Although p80 plays critical roles during brain development, the underlying mechanisms remain predominately unknown. Here, we demonstrate that p80 regulates microtubule (MT) remodeling in combination with NuMA (nuclear mitotic apparatus protein) and cytoplasmic dynein. We show that p80 shuttles between the nucleus and spindle pole in synchrony with the cell cycle. Interestingly, this striking feature is shared with NuMA. Importantly, p80 is essential for aster formation and maintenance in vitro. siRNA-mediated depletion of p80 and/or NuMA induced abnormal mitotic phenotypes in cultured mouse embryonic fibroblasts and aberrant neurogenesis and neuronal migration in the mouse embryonic brain. Importantly, these results were confirmed in p80-mutant harboring patient-derived induced pluripotent stem cells and brain organoids. Taken together, our findings provide valuable insights into the pathogenesis of severe microlissencephaly, in which p80 and NuMA delineate a common pathway for neurogenesis and neuronal migration via MT organization at the centrosome/spindle pole. PMID- 28079117 TI - High-field transport properties of a P-doped BaFe2As2 film on technical substrate. AB - High temperature (high-Tc) superconductors like cuprates have superior critical current properties in magnetic fields over other superconductors. However, superconducting wires for high-field-magnet applications are still dominated by low-Tc Nb3Sn due probably to cost and processing issues. The recent discovery of a second class of high-Tc materials, Fe-based superconductors, may provide another option for high-field-magnet wires. In particular, AEFe2As2 (AE: Alkali earth elements, AE-122) is one of the best candidates for high-field-magnet applications because of its high upper critical field, Hc2, moderate Hc2 anisotropy, and intermediate Tc. Here we report on in-field transport properties of P-doped BaFe2As2 (Ba-122) thin films grown on technical substrates by pulsed laser deposition. The P-doped Ba-122 coated conductor exceeds a transport Jc of 105 A/cm2 at 15 T for main crystallographic directions of the applied field, which is favourable for practical applications. Our P-doped Ba-122 coated conductors show a superior in-field Jc over MgB2 and NbTi, and a comparable level to Nb3Sn above 20 T. By analysing the E - J curves for determining Jc, a non Ohmic linear differential signature is observed at low field due to flux flow along the grain boundaries. However, grain boundaries work as flux pinning centres as demonstrated by the pinning force analysis. PMID- 28079118 TI - Thermal grill conditioning: Effect on contact heat evoked potentials. AB - The 'thermal grill illusion' (TGI) is a unique cutaneous sensation of unpleasantness, induced through the application of interlacing warm and cool stimuli. While previous studies have investigated optimal parameters and subject characteristics to evoke the illusion, our aim was to examine the modulating effect as a conditioning stimulus. A total of 28 healthy control individuals underwent three testing sessions on separate days. Briefly, 15 contact heat stimuli were delivered to the right hand dorsum, while the left palmar side of the hand was being conditioned with either neutral (32 degrees C), cool (20 degrees C), warm (40 degrees C), or TGI (20/40 degrees C). Rating of perception (numeric rating scale: 0-10) and evoked potentials (i.e., N1 and N2P2 potentials) to noxious contact heat stimuli were assessed. While cool and warm conditioning decreased cortical responses to noxious heat, TGI conditioning increased evoked potential amplitude (N1 and N2P2). In line with other modalities of unpleasant conditioning (e.g., sound, visual, and olfactory stimulation), cortical and possibly sub-cortical modulation may underlie the facilitation of contact heat evoked potentials. PMID- 28079120 TI - In situ imaging of microstructure formation in electronic interconnections. AB - The development of microstructure during melting, reactive wetting and solidification of solder pastes on Cu-plated printed circuit boards has been studied by synchrotron radiography. Using Sn-3.0Ag-0.5Cu/Cu and Sn-0.7Cu/Cu as examples, we show that the interfacial Cu6Sn5 layer is present within 0.05 s of wetting, and explore the kinetics of flux void formation at the interface between the liquid and the Cu6Sn5 layer. Quantification of the nucleation locations and anisotropic growth kinetics of primary Cu6Sn5 crystals reveals a competition between the nucleation of Cu6Sn5 in the liquid versus growth of Cu6Sn5 from the existing Cu6Sn5 layer. Direct imaging confirms that the beta-Sn nucleates at/near the Cu6Sn5 layer in Sn-3.0Ag-0.5Cu/Cu joints. PMID- 28079119 TI - Interleukin-32 Gamma Stimulates Bone Formation by Increasing miR-29a in Osteoblastic Cells and Prevents the Development of Osteoporosis. AB - Interleukin-32 gamma (IL-32gamma) is a recently discovered cytokine that is elevated in inflamed tissues and contributes to pathogenic features of bone in human inflammatory rheumatic diseases. Nevertheless, the role of IL-32gamma and its direct involvement in bone metabolism is unclear. We investigated the molecular mechanism of IL-32gamma in bone remodeling and the hypothetical correlation between IL-32gamma and disease activity in osteoporosis patients. Transgenic (TG) mice overexpressing human IL-32gamma showed reduced bone loss with advancing age, increased bone formation, and high osteogenic capacity of osteoblast compared to wild-type (WT) mice through the upregulation of miR-29a, which caused a reduction of Dickkopf-1 (DKK1) expression. IL-32gamma TG mice were protected against ovariectomy (OVX)induced osteoporosis compared with WT mice. Decreased plasma IL-32gamma levels were associated with bone mineral density (BMD) in human patients linked to increased DKK1 levels. These results indicate that IL-32gamma plays a protective role for bone loss, providing clinical evidence of a negative correlation between IL-32gamma and DKK1 as bone metabolic markers. PMID- 28079121 TI - Local geology controlled the feasibility of vitrifying Iron Age buildings. AB - During European prehistory, hilltop enclosures made from polydisperse particle and-block stone walling were exposed to temperatures sufficient to partially melt the constituent stonework, leading to the preservation of glassy walls called 'vitrified forts'. During vitrification, the granular wall rocks partially melt, sinter viscously and densify, reducing inter-particle porosity. This process is strongly dependent on the solidus temperature, the particle sizes, the temperature-dependence of the viscosity of the evolving liquid phase, as well as the distribution and longevity of heat. Examination of the sintering behaviour of 45 European examples reveals that it is the raw building material that governs the vitrification efficiency. As Iron Age forts were commonly constructed from local stone, we conclude that local geology directly influenced the degree to which buildings were vitrified in the Iron Age. Additionally, we find that vitrification is accompanied by a bulk material strengthening of the aggregates of small sizes, and a partial weakening of larger blocks. We discuss these findings in the context of the debate surrounding the motive of the wall builders. We conclude that if wall stability by bulk strengthening was the desired effect, then vitrification represents an Iron Age technology that failed to be effective in regions of refractory local geology. PMID- 28079122 TI - Environmental DNA metabarcoding reveals local fish communities in a species-rich coastal sea. AB - Environmental DNA (eDNA) metabarcoding has emerged as a potentially powerful tool to assess aquatic community structures. However, the method has hitherto lacked field tests that evaluate its effectiveness and practical properties as a biodiversity monitoring tool. Here, we evaluated the ability of eDNA metabarcoding to reveal fish community structures in species-rich coastal waters. High-performance fish-universal primers and systematic spatial water sampling at 47 stations covering ~11 km2 revealed the fish community structure at a species resolution. The eDNA metabarcoding based on a 6-h collection of water samples detected 128 fish species, of which 62.5% (40 species) were also observed by underwater visual censuses conducted over a 14-year period. This method also detected other local fishes (>=23 species) that were not observed by the visual censuses. These eDNA metabarcoding features will enhance marine ecosystem-related research, and the method will potentially become a standard tool for surveying fish communities. PMID- 28079124 TI - Axisymmetric rotational stagnation point flow impinging radially a permeable stretching/shrinking surface in a nanofluid using Tiwari and Das model. AB - In this paper, the problem of normal impingement rotational stagnation-point flow on a radially permeable stretching sheet in a viscous fluid, recently studied in a very interesting paper, is extended to a water-based nanofluid. A similarity transformation is used to reduce the system of governing nonlinear partial differential equations to a system of ordinary differential equations, which is then solved numerically using the function bvp4c from Matlab. It is found that dual (upper and lower branch) solutions exist for some values of the governing parameters. From the stability analysis, it is found that the upper branch solution is stable, while the lower branch solution is unstable. Sample velocity and temperature profiles along both solution branches are graphically presented. PMID- 28079123 TI - TRIM22-Mediated Apoptosis is Associated with Bak Oligomerization in Monocytes. AB - Monocyte apoptosis is a key mechanism that orchestrates host immune responses during sepsis. TRIM22 is constitutively expressed at high levels in monocytes and plays important roles in the antiviral response and inflammation. Overexpression of TRIM22 interferes with the clonogenic growth of monocytic cells, suggesting that TRIM22 may regulate monocyte survival. However, the effect of TRIM22 on monocyte apoptosis remains unknown. In the present report, lipopolysaccharides (LPS)-primed human peripheral blood monocytes expressing higher levels of TRIM22 were more sensitive to apoptosis. This phenomenon was also observed in TRIM22 overexpressing THP-1 monocytes and was associated with the activation of caspase 9 and caspase-3, as well as the increased expression and oligomerization of the pro-apoptotic protein Bak. Similar expression patterns of TRIM22 and Bak were also observed in LPS-primed, apoptotic human peripheral blood monocytes. In addition, the deletion of either the RING domain or the SPRY domain of TRIM22 significantly attenuated TRIM22-mediated monocyte apoptosis and decreased Bak expression and oligomerization. Furthermore, in monocytes from septic patients, TRIM22 levels were down-regulated and positively correlated with Bak levels. Taken together, these results indicate that TRIM22 plays a critical role in monocyte apoptosis by regulating Bak oligomerization and may have a potential function in the pathogenesis of sepsis. PMID- 28079125 TI - Establishment of a integrative multi-omics expression database CKDdb in the context of chronic kidney disease (CKD). AB - Complex human traits such as chronic kidney disease (CKD) are a major health and financial burden in modern societies. Currently, the description of the CKD onset and progression at the molecular level is still not fully understood. Meanwhile, the prolific use of high-throughput omic technologies in disease biomarker discovery studies yielded a vast amount of disjointed data that cannot be easily collated. Therefore, we aimed to develop a molecule-centric database featuring CKD-related experiments from available literature publications. We established the Chronic Kidney Disease database CKDdb, an integrated and clustered information resource that covers multi-omic studies (microRNAs, genomics, peptidomics, proteomics and metabolomics) of CKD and related disorders by performing literature data mining and manual curation. The CKDdb database contains differential expression data from 49395 molecule entries (redundant), of which 16885 are unique molecules (non-redundant) from 377 manually curated studies of 230 publications. This database was intentionally built to allow disease pathway analysis through a systems approach in order to yield biological meaning by integrating all existing information and therefore has the potential to unravel and gain an in-depth understanding of the key molecular events that modulate CKD pathogenesis. PMID- 28079126 TI - Detecting N6-methyladenosine sites from RNA transcriptomes using ensemble Support Vector Machines. AB - As one of the most abundant RNA post-transcriptional modifications, N6 methyladenosine (m6A) involves in a broad spectrum of biological and physiological processes ranging from mRNA splicing and stability to cell differentiation and reprogramming. However, experimental identification of m6A sites is expensive and laborious. Therefore, it is urgent to develop computational methods for reliable prediction of m6A sites from primary RNA sequences. In the current study, a new method called RAM-ESVM was developed for detecting m6A sites from Saccharomyces cerevisiae transcriptome, which employed ensemble support vector machine classifiers and novel sequence features. The jackknife test results show that RAM-ESVM outperforms single support vector machine classifiers and other existing methods, indicating that it would be a useful computational tool for detecting m6A sites in S. cerevisiae. Furthermore, a web server named RAM-ESVM was constructed and could be freely accessible at http://server.malab.cn/RAM-ESVM/. PMID- 28079127 TI - Functional Nanoarchitectures For Enhanced Drug Eluting Stents. AB - Different strategies have been investigated to allow for optimum duration and conditions for endothelium healing through the enhancement of coronary stents. In this study, a nanoarchitectured system is proposed as a surface modification for drug eluting stents. Highly oriented nanotubes were vertically grown on the surface of a new Ni-free biocompatible Ti-based alloy, as a potential material for self-expandable stents. The fabricated nanotubes were self-grown from the potential stent substrate, which are also proposed to enhance endothelial proliferation while acting as drug reservoir to hinder Vascular Smooth Muscle Cells (VSMC) proliferation. Two morphologies were synthesized to investigate the effect of structure homogeneity on the intended application. The material was characterized by field-emission scanning electron microscope (FESEM), X-ray diffraction (XRD), Raman spectroscopy, energy dispersive X-ray spectroscopy (EDX), and X-ray photoelectron spectroscopy (XPS). Nanoindentation technique was used to study the mechanical properties of the fabricated material. Cytotoxicity and proliferation studies were performed and compared for the two fabricated nanoarchitectures, versus smooth untextured samples, using in-vitro cultured endothelial cells. Finally, the drug loading capacity was experimentally studied and further supported by computational modeling of the release profile. PMID- 28079128 TI - Parallel-META 3: Comprehensive taxonomical and functional analysis platform for efficient comparison of microbial communities. AB - The number of metagenomes is increasing rapidly. However, current methods for metagenomic analysis are limited by their capability for in-depth data mining among a large number of microbiome each of which carries a complex community structure. Moreover, the complexity of configuring and operating computational pipeline also hinders efficient data processing for the end users. In this work we introduce Parallel-META 3, a comprehensive and fully automatic computational toolkit for rapid data mining among metagenomic datasets, with advanced features including 16S rRNA extraction for shotgun sequences, 16S rRNA copy number calibration, 16S rRNA based functional prediction, diversity statistics, bio marker selection, interaction network construction, vector-graph-based visualization and parallel computing. Application of Parallel-META 3 on 5,337 samples with 1,117,555,208 sequences from diverse studies and platforms showed it could produce similar results as QIIME and PICRUSt with much faster speed and lower memory usage, which demonstrates its ability to unravel the taxonomical and functional dynamics patterns across large datasets and elucidate ecological links between microbiome and the environment. Parallel-META 3 is implemented in C/C++ and R, and integrated into an executive package for rapid installation and easy access under Linux and Mac OS X. Both binary and source code packages are available at http://bioinfo.single-cell.cn/parallel-meta.html. PMID- 28079129 TI - CircRNA_000203 enhances the expression of fibrosis-associated genes by derepressing targets of miR-26b-5p, Col1a2 and CTGF, in cardiac fibroblasts. AB - Circular RNAs (circRNAs) participate in regulating gene expression in diverse biological and pathological processes. The present study aimed to investigate the mechanism underlying the modulation of circRNA_000203 on expressions of fibrosis associated genes in cardiac fibroblasts. CircRNA_000203 was shown upregulated in the diabetic mouse myocardium and in Ang-II-induced mouse cardiac fibroblasts. Enforced-expression of circRNA_000203 could increase expressions of Col1a2, Col3a1 and alpha-SMA in mouse cardiac fibroblasts. RNA pull-down and RT-qPCR assay indicated that circRNA_000203 could specifically sponge miR-26b-5p. Dual luciferase reporter assay revealed that miR-26b-5p interacted with 3'UTRs of Col1a2 and CTGF, and circ_000203 could block the interactions of miR-26b-5p and 3'UTRs of Col1a2 and CTGF. Transfection of miR-26b-5p could post-transcriptionaly inhibit expressions of Col1a2 and CTGF, accompanied with the suppressions of Col3a1 and alpha-SMA in cardiac fibroblasts. Additionally, over-expression of circRNA_000203 could eliminate the anti-fibrosis effect of miR-26b-5p in cardiac fibroblasts. Together, our results reveal that suppressing the function of miR 26b-5p contributes to the pro-fibrosis effect of circRNA_000203 in cardiac fibroblasts. PMID- 28079130 TI - Association of nsv823469 copy number loss with decreased risk of chronic obstructive pulmonary disease and pulmonary function in Chinese. AB - It is highly possible that copy number variations (CNVs) in susceptible regions have effects on chronic obstructive pulmonary disease (COPD) development, while long noncoding RNA (lncRNAs) have been shown to cause COPD. We hypothesized that the common CNV, named nsv823469 located on 6p22.1, and covering lncRNAs (major histocompatibility complex, class I, A (HLA-A) and HLA complex group 4B (HCG4B)) has an effect on COPD risk. This association was assessed through a two-stage case-control study, and was further confirmed with COPD and pulmonary function based family analyses, respectively. The copy number loss (0-copy/1-copy) of nsv823469 significantly decreased risk of COPD compared with normal (2-copy) (OR = 0.77, 95% CI = 0.69-0.85). The loss allele, inducing copy number loss of nsv823469, has a tendency to transmit to offspring or siblings (P = 0.010) and is associated with forced expiratory volume in 1 second (FEV1) (P = 0.030). Furthermore, the copy number loss of nsv823469 in normal pulmonary tissue decreases the expression levels of HCG4B (r = 0.315, P = 0.031) and HLA-A (r = 0.296, P = 0.044). Our data demonstrates that nsv823469 plays a role in COPD and pulmonary function inheritance by potentially altering expression of HCG4B. PMID- 28079131 TI - Matrix Metallopeptidase-2 Gene rs2287074 Polymorphism is Associated with Brick Tea Skeletal Fluorosis in Tibetans and Kazaks, China. AB - Brick tea skeletal fluorosis is still a public health issue in the north-western area of China. However its pathogenesis remains unknown. Our previous study reveals that the severity of skeletal fluorosis in Tibetans is more serious than that in Kazaks, although they have similar fluoride exposure, suggesting the onset of brick tea type skeletal fluorosis might be genetically influenced. Here we show that MMP-2 rs2287074 SNP (G/A), but not rs243865, was associated with Brick tea type fluorosis in Tibetans and Kazaks, China. The trend test reveals a decline in probability for skeletal fluorosis with increasing number of A alleles in Tibetans. After controlling potential confounders, AA genotype had about 80 percent lower probability of developing skeletal fluorosis than GG genotype in Tibetans (odds ratio = 0.174, 95% CI: 0.053, 0.575), and approximately 53 percent lower probability in Kazaks (odds ratio = 0.462, 95% CI: 0.214, 0.996). A meta analysis shows that the AA genotype had approximately 63 percent lower odds (odds ratio = 0.373, 95% CI: 0.202, 0.689) compared with GG genotype within the two ethnicities. A significant correlation was also found between the genotype of MMP2 rs2287074 and skeletal fluorosis severity. Therefore, the A allele of MMP2 rs2287074 could be a protective factor for brick tea skeletal fluorosis. PMID- 28079132 TI - Critical role for CaFEN1 and CaFEN12 of Candida albicans in cell wall integrity and biofilm formation. AB - Sphingolipids are involved in several cellular functions, including maintenance of cell wall integrity. To gain insight into the role of individual genes of sphingolipid biosynthetic pathway, we have screened Saccharomyces cerevisiae strains deleted in these genes for sensitivity to cell wall perturbing agents calcofluor white and congo red. Only deletants of FEN1 and SUR4 genes were found to be sensitive to both these agents. Candida albicans strains deleted in their orthologs, CaFEN1 and CaFEN12, respectively, also showed comparable phenotypes, and a strain deleted for both these genes was extremely sensitive to cell wall perturbing agents. Deletion of these genes was reported earlier to sensitise cells to amphotericin B (AmB), which is a polyene drug that kills the cells mainly by binding and sequestering ergosterol from the plasma membrane. Here we show that their AmB sensitivity is likely due to their cell wall defect. Further, we show that double deletant of C. albicans is defective in hyphae formation as well as biofilm development. Together this study reveals that deletion of FEN1 and SUR4 orthologs of C. albicans leads to impaired cell wall integrity and biofilm formation, which in turn sensitise cells to AmB. PMID- 28079133 TI - Mechanical Transgressive Segregation and the Rapid Origin of Trophic Novelty. AB - Hybrid phenotypes are often intermediate between those of parental species. However, hybridization can generate novel phenotypes when traits are complex. For instance, even when the morphologies of individual musculo-skeletal components do not segregate outside the parental range in hybrid offspring, complex functional systems can exhibit emergent phenotypes whose mechanics exceed the parental values. To determine if transgression in mechanics could facilitate divergence during an adaptive radiation, we examined three functional systems in the trophic apparatus of Lake Malawi cichlid fishes. We conducted a simulation study of hybridization between species pairs whose morphology for three functional systems was empirically measured, to determine how the evolutionary divergence of parental species influences the frequency that hybridization could produce mechanics that transgress the parental range. Our simulations suggest that the complex mechanical systems of the cichlid trophic apparatus commonly exhibit greater transgression between more recently diverged cichlid species. Because (1) all three mechanical systems produce hybrids with transgressive mechanics in Lake Malawi cichlids, (2) hybridization is common, and (3) single hybrid crosses often recapitulate a substantial diversity of mechanics, we conclude that mechanical transgressive segregation could play an important role in the rapid accumulation of phenotypic variation in adaptive radiations. PMID- 28079134 TI - Topological features of vector vortex beams perturbed with uniformly polarized light. AB - Optical singularities manifesting at the center of vector vortex beams are unstable, since their topological charge is higher than the lowest value permitted by Maxwell's equations. Inspired by conceptually similar phenomena occurring in the polarization pattern characterizing the skylight, we show how perturbations that break the symmetry of radially symmetric vector beams lead to the formation of a pair of fundamental and stable singularities, i.e. points of circular polarization. We prepare a superposition of a radial (or azimuthal) vector beam and a uniformly linearly polarized Gaussian beam; by varying the amplitudes of the two fields, we control the formation of pairs of these singular points and their spatial separation. We complete this study by applying the same analysis to vector vortex beams with higher topological charges, and by investigating the features that arise when increasing the intensity of the Gaussian term. Our results can find application in the context of singularimetry, where weak fields are measured by considering them as perturbations of unstable optical beams. PMID- 28079135 TI - Predicting drug-target interactions by dual-network integrated logistic matrix factorization. AB - In this work, we propose a dual-network integrated logistic matrix factorization (DNILMF) algorithm to predict potential drug-target interactions (DTI). The prediction procedure consists of four steps: (1) inferring new drug/target profiles and constructing profile kernel matrix; (2) diffusing drug profile kernel matrix with drug structure kernel matrix; (3) diffusing target profile kernel matrix with target sequence kernel matrix; and (4) building DNILMF model and smoothing new drug/target predictions based on their neighbors. We compare our algorithm with the state-of-the-art method based on the benchmark dataset. Results indicate that the DNILMF algorithm outperforms the previously reported approaches in terms of AUPR (area under precision-recall curve) and AUC (area under curve of receiver operating characteristic) based on the 5 trials of 10 fold cross-validation. We conclude that the performance improvement depends on not only the proposed objective function, but also the used nonlinear diffusion technique which is important but under studied in the DTI prediction field. In addition, we also compile a new DTI dataset for increasing the diversity of currently available benchmark datasets. The top prediction results for the new dataset are confirmed by experimental studies or supported by other computational research. PMID- 28079136 TI - SNP rs11185644 of RXRA gene is identified for dose-response variability to vitamin D3 supplementation: a randomized clinical trial. AB - The level of serum 25-Hydroxyvitamin D [25(OH)D] has high heritability, suggesting that genes may contribute to variations in serum 25(OH)D level and vitamin D dose-response. As vitamin D deficiency has been linked to numerous diseases, understanding how genetic variation contributes to vitamin D dose response is important for personalized vitamin D treatment and cost-effective disease prevention. To identify genetic variants responsible for vitamin D status and dose-response, we performed two vitamin D3 and calcium clinical supplementation trials in 2,207 postmenopausal Caucasian women. We examined the association of 291 SNPs with baseline serum 25(OH)D levels and 25(OH)D dose response. Five SNPs, rs10500804 (P = 4.93 * 10-7), rs2060793 (P = 6.63 * 10-7), rs10741657 (P = 1.49 * 10-6), rs10766197 (P = 1.05 * 10-5) and rs11023380 (P = 7.67 * 10-5) in the CYP2R1 gene, as well as 6 SNPs, rs4588 (P = 7.86 * 10-7), rs2298850 (P = 1.94 * 10-6), rs1155563 (P = 6.39 * 10-6), rs705119 (P = 2.80 * 10 5), rs705120 (P = 1.08 * 10-4) and rs222040 (P = 1.59 * 10-4) in the GC gene were associated with baseline serum 25(OH)D levels. SNP rs11185644 near the RXRA was significantly associated with 25(OH)D dose-response (P = 1.01 * 10-4). Our data suggest that polymorphisms in the CYP2R1 and GC gene may contribute to variation in baseline serum 25(OH)D concentration, and that polymorphism rs11185644 may contribute to variation in 25(OH)D dose-response in healthy postmenopausal Caucasian women. PMID- 28079137 TI - X-ray Structure and Enzymatic Activity Profile of a Core Papain-like Protease of MERS Coronavirus with utility for structure-based drug design. AB - Ubiquitin-like domain 2 (Ubl2) is immediately adjacent to the N-terminus of the papain-like protease (PLpro) domain in coronavirus polyproteins, and it may play a critical role in protease regulation and stability as well as in viral infection. However, our recent cellular studies reveal that removing the Ubl2 domain from MERS PLpro has no effect on its ability to process the viral polyprotein or act as an interferon antagonist, which involves deubiquitinating and deISGylating cellular proteins. Here, we test the hypothesis that the Ubl2 domain is not required for the catalytic function of MERS PLpro in vitro. The X ray structure of MERS PLpro-?Ubl2 was determined to 1.9 A and compared to PLpro containing the N-terminal Ubl2 domain. While the structures were nearly identical, the PLpro-?Ubl2 enzyme revealed the intact structure of the substrate binding loop. Moreover, PLpro-?Ubl2 catalysis against different substrates and a purported inhibitor revealed no differences in catalytic efficiency, substrate specificity, and inhibition. Further, no changes in thermal stability were observed between enzymes. We conclude that the catalytic core of MERS PLpro, i.e. without the Ubl2 domain, is sufficient for catalysis and stability in vitro with utility to evaluate potential inhibitors as a platform for structure-based drug design. PMID- 28079138 TI - Spatiotemporal Pattern of PM2.5 Concentrations in Mainland China and Analysis of Its Influencing Factors using Geographically Weighted Regression. AB - Based on annual average PM2.5 gridded dataset, this study first analyzed the spatiotemporal pattern of PM2.5 across Mainland China during 1998-2012. Then facilitated with meteorological site data, land cover data, population and Gross Domestic Product (GDP) data, etc., the contributions of latent geographic factors, including socioeconomic factors (e.g., road, agriculture, population, industry) and natural geographical factors (e.g., topography, climate, vegetation) to PM2.5 were explored through Geographically Weighted Regression (GWR) model. The results revealed that PM2.5 concentrations increased while the spatial pattern remained stable, and the proportion of areas with PM2.5 concentrations greater than 35 MUg/m3 significantly increased from 23.08% to 29.89%. Moreover, road, agriculture, population and vegetation showed the most significant impacts on PM2.5. Additionally, the Moran's I for the residuals of GWR was 0.025 (not significant at a 0.01 level), indicating that the GWR model was properly specified. The local coefficient estimates of GDP in some cities were negative, suggesting the existence of the inverted-U shaped Environmental Kuznets Curve (EKC) for PM2.5 in Mainland China. The effects of each latent factor on PM2.5 in various regions were different. Therefore, regional measures and strategies for controlling PM2.5 should be formulated in terms of the local impacts of specific factors. PMID- 28079139 TI - Blood Occludin Level as a Potential Biomarker for Early Blood Brain Barrier Damage Following Ischemic Stroke. AB - Concern about intracerebral hemorrhage (ICH) is the primary reason for withholding tPA therapy from patients with ischemic stroke. Early blood brain barrier (BBB) damage is the major risk factor for fatal post-thrombolysis ICH, but rapidly assessing BBB damage before tPA administration is highly challenging. We recently reported that ischemia induced rapid degradation of tight junction protein occludin in cerebromicrovessels. The present study investigates whether the cleaved occludin is released into the blood stream and how blood occludin levels correlate to the extent of BBB damage using a rat model of ischemic stroke. Cerebral ischemia induced a time-dependent increase of blood occludin with a sharp increase at 4.5-hour post-ischemia onset, which concurrently occurred with the loss of occludin from ischemic cerebral microvessels and a massive BBB leakage at 4.5-hour post-ischemia. Two major occludin fragments were identified in the blood during cerebral ischemia. Furthermore, blood occludin levels remained significantly higher than its basal level within the first 24 hours after ischemia onset. Our findings demonstrate that blood occludin levels correlate well with the extent of BBB damage and thus may serve as a clinically relevant biomarker for evaluating the risk of ICH before tPA administration. PMID- 28079140 TI - Methionine residues around phosphorylation sites are preferentially oxidized in vivo under stress conditions. AB - Protein phosphorylation is one of the most prevalent and well-understood protein modifications. Oxidation of protein-bound methionine, which has been traditionally perceived as an inevitable damage derived from oxidative stress, is now emerging as another modification capable of regulating protein activity during stress conditions. However, the mechanism coupling oxidative signals to changes in protein function remains unknown. An appealing hypothesis is that methionine oxidation might serve as a rheostat to control phosphorylation. To investigate this potential crosstalk between phosphorylation and methionine oxidation, we have addressed the co-occurrence of these two types of modifications within the human proteome. Here, we show that nearly all (98%) proteins containing oxidized methionine were also phosphoproteins. Furthermore, phosphorylation sites were much closer to oxidized methionines when compared to non-oxidized methionines. This proximity between modification sites cannot be accounted for by their co-localization within unstructured clusters because it was faithfully reproduced in a smaller sample of structured proteins. We also provide evidence that the oxidation of methionine located within phosphorylation motifs is a highly selective process among stress-related proteins, which supports the hypothesis of crosstalk between methionine oxidation and phosphorylation as part of the cellular defence against oxidative stress. PMID- 28079142 TI - The prognostic role of EGFR-TKIs for patients with advanced non-small cell lung cancer. AB - Clinical trials have shown that epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) did not improve the survival of patients with EGFR-mutated non-small cell lung cancer (NSCLC) because of the high crossover of treatments. Realistically, the role of EGFR-TKIs in NSCLC with mutated EGFR is not well known. We retrospectively analysed data from patients with recurrent or metastatic NSCLC. Clinical prognostic factors were identified by Cox proportional hazards modelling. Among 503 patients, the median overall survival (OS) for all of patients was 11.7 months. Cox analysis showed that PS 0-1, recurrent disease, EGFR mutations, or EGFR-TKI treatment were associated with improved OS. In patients with EGFR-activating mutations, Cox analysis showed that patients with adenocarcinoma, recurrent disease, or EGFR-TKI treatment had significantly longer survival. Patients with EGFR-activating mutations who received EGFR-TKI therapy had a median OS of 24.3 months, which was significantly longer than those who had not received EGFR-TKI therapy (10.8 months). Patients with wild-type EGFR had a median OS of 9.7 months and Cox analysis showed that PS score and disease type were independent predictors. EGFR-TKI therapy is an independently prognostic factor for NSCLC with mutated EGFR. A more effective therapy is needed for patients with wild-type EGFR. PMID- 28079141 TI - Development of a 690 K SNP array in catfish and its application for genetic mapping and validation of the reference genome sequence. AB - Single nucleotide polymorphisms (SNPs) are capable of providing the highest level of genome coverage for genomic and genetic analysis because of their abundance and relatively even distribution in the genome. Such a capacity, however, cannot be achieved without an efficient genotyping platform such as SNP arrays. In this work, we developed a high-density SNP array with 690,662 unique SNPs (herein 690 K array) that were relatively evenly distributed across the entire genome, and covered 98.6% of the reference genome sequence. Here we also report linkage mapping using the 690 K array, which allowed mapping of over 250,000 SNPs on the linkage map, the highest marker density among all the constructed linkage maps. These markers were mapped to 29 linkage groups (LGs) with 30,591 unique marker positions. This linkage map anchored 1,602 scaffolds of the reference genome sequence to LGs, accounting for over 97% of the total genome assembly. A total of 1,007 previously unmapped scaffolds were placed to LGs, allowing validation and in few instances correction of the reference genome sequence assembly. This linkage map should serve as a valuable resource for various genetic and genomic analyses, especially for GWAS and QTL mapping for genes associated with economically important traits. PMID- 28079143 TI - Lethal/sublethal responses of Daphnia magna to acute norfloxacin contamination and changes in phytoplankton-zooplankton interactions induced by this antibiotic. AB - Although the well-known antibiotic norfloxacin (NOR) is recognized as an important environmental pollutant, little is known about its impacts on ecological processes, particularly on species interactions. In this paper, we quantified Daphnia magna (Crustacea, Cladocera) responses in mortality rate at lethal NOR concentrations (0, 25, 50, 100, 200, 300 and 400 mg L-1), and in heartbeat rate, swimming behavior and feeding rate (on the green alga Chlorella pyrenoidosa) at sublethal NOR concentrations (0, 25, 50 and 100 mg L-1) to determine the effects of this antibiotic in plankton systems. In 96-h-long lethal experiment, mortality rates of D. magna increased significantly with increasing NOR concentration and exposure time. In sublethal experiments, heartbeat rate decreased, while time ratio of vertical to horizontal swimming (TVH) and the duration of quiescence increased in D. magna individuals exposed to increasing NOR concentrations after 4 and 12 h of exposure. These collectively led to decreases in both average swimming ability and feeding rate, consistent with the positive relationship between average swimming ability and feeding rate. Overall, results indicate that, by affecting zooplankton heartbeat rate and behavior, NOR decreased feeding efficiency of D. magna even at low doses, therefore, it might seriously compromise ecosystem health and function. PMID- 28079145 TI - Galectin-3 as a marker of interstitial atrial remodelling involved in atrial fibrillation. AB - Remodelling in the atria could appear as a result of hypertension, diabetes or ischaemic heart disease. Galectin-3 (Gal-3) is a mediator of profibrotic pathways and a potential biomarker of cardiac remodelling. We prospectively recruited consecutive patients undergoing elective cardiac surgery. Preoperative Gal-3 levels were determined from serum samples, and the presence of fibrosis was assessed from atrial appendage tissue samples obtained during cardiac surgery. We included 100 patients with aortic valve or ischaemic heart diseases and 15 controls with permanent AF. Gal-3 levels were associated with sex, left atrial volume, previous cardiac disease, diabetes mellitus, hypertension, NYHA and NT proBNP. We observed differences in serum Gal-3 concentrations between patients and controls with permanent AF (p = 0.020). We performed ROC curves related to fibrosis and established a cutoff point for Gal-3 >13.65 ng/ml. Multivariate analyses showed previous cardiac disease, NYHA scale and high Gal-3 to be independent predictors of fibrosis. After adjustment for confounding factors, atrial fibrosis remained the only independent factor for the development of AF (p = 0.022). High Gal-3 serum levels predict fibrosis of the atrial appendage. NYHA scale and previous cardiac disease were also associated with tissue fibrosis in patients undergoing surgery. Atrial fibrosis was the only independent predictor for post-operative AF occurrence in our model after correcting for confounding factors. PMID- 28079144 TI - IGF-IR cooperates with ERalpha to inhibit breast cancer cell aggressiveness by regulating the expression and localisation of ECM molecules. AB - IGF-IR is highly associated with the behaviour of breast cancer cells. In ERalpha positive breast cancer, IGF-IR is present at high levels. In clinical practice, prolonged treatment with anti-estrogen agents results in resistance to the therapy with activation of alternative signaling pathways. Receptor Tyrosine Kinases, and especially IGF-IR, have crucial roles in these processes. Here, we report a nodal role of IGF-IR in the regulation of ERalpha-positive breast cancer cell aggressiveness and the regulation of expression levels of several extracellular matrix molecules. In particular, activation of IGF-IR, but not EGFR, in MCF-7 breast cancer cells results in the reduction of specific matrix metalloproteinases and their inhibitors. In contrast, IGF-IR inhibition leads to the depletion by endocytosis of syndecan-4. Global important changes in cell adhesion receptors, which include integrins and syndecan-4 triggered by IGF-IR inhibition, regulate adhesion and invasion. Cell function assays that were performed in MCF-7 cells as well as their ERalpha-suppressed counterparts indicate that ER status is a major determinant of IGF-IR regulatory role on cell adhesion and invasion. The strong inhibitory role of IGF-IR on breast cancer cells aggressiveness for which E2-ERalpha signaling pathway seems to be essential, highlights IGF-IR as a major molecular target for novel therapeutic strategies. PMID- 28079147 TI - Flood dynamics in urbanised landscapes: 100 years of climate and humans' interaction. AB - Raising interest in the interaction between humans and climate drivers to understand the past and current development of floods in urbanised landscapes is of great importance. This study presents a regional screening of land-use, rainfall regime and flood dynamics in north-eastern Italy, covering the timeframe 1900-2010. This analysis suggests that, statistically, both climate and land-use have been contributing to a significant increase of the contribution of short duration floods to the increase in the number of flooded locations. The analysis also suggests that interaction arises, determining land-use dynamics to couple with climatic changes influencing the flood aggressiveness simultaneously. Given that it is not possible to control the climatic trend, an effective disaster management clearly needs an integrated approach to land planning and supervision. This research shows that land management and planning should include the investigation of the location of the past and future social and economic drivers for development, as well as past and current climatic trends. PMID- 28079146 TI - Nitrosative Stress-Induced Disruption of Baroreflex Neural Circuits in a Rat Model of Hepatic Encephalopathy: A DTI Study. AB - The onset of hepatic encephalopathy (HE) in liver failure is associated with high mortality; the underlying mechanism is undecided. Here we report that in an acute liver failure model employing intraperitoneal administration of thioacetamide in Sprague-Dawley rats, diffusion weighted imaging revealed a progressive reduction in apparent diffusion coefficient in the brain stem. Diffusion tensor imaging further showed that the connectivity between nucleus tractus solitarii (NTS), the terminal site of baroreceptor afferents in brain stem and rostral ventrolateral medulla (RVLM), the origin of sympathetic innervation of blood vessels, was progressively disrupted until its disappearance, coincidental with the irreversible cessation of baroreflex-mediated sympathetic vasomotor tone signifying clinically the occurrence of brain death. In addition, superoxide, nitric oxide, peroxynitrite and ammonia levels in the NTS or RVLM were elevated, alongside swelling of astroctytes. A scavenger of peroxynitrite, but not an antioxidant, delivered intracisternally reversed all these events. We conclude that nitrosative stress because of augmented peroxynitrite related to accumulation of ammonia and swelling of astrocytes in the NTS or RVLM, leading to cytotoxic edema in the brain stem and severance of the NTS-RVLM connectivity, underpins the defunct baroreflex-mediated sympathetic vasomotor tone that accounts for the high mortality associated with HE. PMID- 28079148 TI - Modulation of snow reflectance and snowmelt from Central Asian glaciers by anthropogenic black carbon. AB - Deposited mineral dust and black carbon are known to reduce the albedo of snow and enhance melt. Here we estimate the contribution of anthropogenic black carbon (BC) to snowmelt in glacier accumulation zones of Central Asia based on in-situ measurements and modelling. Source apportionment suggests that more than 94% of the BC is emitted from mostly regional anthropogenic sources while the remaining contribution comes from natural biomass burning. Even though the annual deposition flux of mineral dust can be up to 20 times higher than that of BC, we find that anthropogenic BC causes the majority (60% on average) of snow darkening. This leads to summer snowmelt rate increases of up to 6.3% (7 cm a-1) on glaciers in three different mountain environments in Kyrgyzstan, based on albedo reduction and snowmelt models. PMID- 28079149 TI - Subwavelength grating as both emission mirror and electrical contact for VCSELs in any material system. AB - Semiconductor-metal subwavelength grating (SMSG) can serve a dual purpose in vertical-cavity surface-emitting lasers (VCSELs), as both optical coupler and current injector. SMSGs provide optical as well as lateral current confinement, eliminating the need for ring contacts and lateral build-in optical and current confinement, allowing their implementation on arbitrarily large surfaces. Using an SMSG as the top mirror enables fabrication of monolithic VCSELs from any type of semiconductor crystal. The construction of VCSELs with SMSGs requires significantly less p-type material, in comparison to conventional VCSELs. In this paper, using a three-dimensional, fully vectorial optical model, we analyse the properties of the stand-alone SMSG in a number of semiconductor materials for a broad range of wavelengths. Integrating the optical model with thermal and electrical numerical models, we then simulate the threshold operation of an exemplary SMSG VCSEL. PMID- 28079150 TI - Sustained kidney biochemical derangement in treated experimental diabetes: a clue to metabolic memory. AB - The occurrence of biochemical alterations that last for a long period of time in diabetic individuals even after adequate handling of glycemia is an intriguing phenomenon named metabolic memory. In this study, we show that a kidney pathway is gradually altered during the course of diabetes and remains persistently changed after late glycemic control in streptozotocin-induced diabetic rats. This pathway comprises an early decline of uric acid clearance and pAMPK expression followed by fumarate accumulation, increased TGF-beta expression, reduced PGC 1alpha expression, and downregulation of methylation and hydroxymethylation of mitochondrial DNA. The sustained decrease of uric acid clearance in treated diabetes may support the prolonged kidney biochemical alterations observed after tight glycemic control, and this regulation is likely mediated by the sustained decrease of AMPK activity and the induction of inflammation. This manuscript proposes the first consideration of the possible role of hyperuricemia and the underlying biochemical changes as part of metabolic memory in diabetic nephropathy development after glycemic control. PMID- 28079151 TI - Discovery and Mechanistic Characterization of Selective Inhibitors of H2S producing Enzyme: 3-Mercaptopyruvate Sulfurtransferase (3MST) Targeting Active site Cysteine Persulfide. AB - Very recent studies indicate that sulfur atoms with oxidation state 0 or -1, called sulfane sulfurs, are the actual mediators of some physiological processes previously considered to be regulated by hydrogen sulfide (H2S). 3 Mercaptopyruvate sulfurtransferase (3MST), one of three H2S-producing enzymes, was also recently shown to produce sulfane sulfur (H2Sn). Here, we report the discovery of several potent 3MST inhibitors by means of high-throughput screening (HTS) of a large chemical library (174,118 compounds) with our H2S-selective fluorescent probe, HSip-1. Most of the identified inhibitors had similar aromatic ring-carbonyl-S-pyrimidone structures. Among them, compound 3 showed very high selectivity for 3MST over other H2S/sulfane sulfur-producing enzymes and rhodanese. The X-ray crystal structures of 3MST complexes with two of the inhibitors revealed that their target is a persulfurated cysteine residue located in the active site of 3MST. Precise theoretical calculations indicated the presence of a strong long-range electrostatic interaction between the persulfur anion of the persulfurated cysteine residue and the positively charged carbonyl carbon of the pyrimidone moiety of the inhibitor. Our results also provide the experimental support for the idea that the 3MST-catalyzed reaction with 3 mercaptopyruvate proceeds via a ping-pong mechanism. PMID- 28079152 TI - A novel toolbox for the in vitro assay of hepatitis D virus infection. AB - Hepatitis D virus (HDV) is a defective RNA virus that requires the presence of hepatitis B virus (HBV) for its life cycle. The in vitro HDV infection system is widely used as a surrogate model to study cellular infection with both viruses owing to its practical feasibility. However, previous methods for running this system were less efficient for high-throughput screening and large-scale studies. Here, we developed a novel method for the production of infectious HDV by adenoviral vector (AdV)-mediated transduction. We demonstrated that the AdV-based method yields 10-fold higher viral titers than the transient-transfection approach. The HDV-containing supernatant derived from AdV-infected Huh7 cells can be used as the inoculum in infectivity assays without requiring further concentration prior to use. Furthermore, we devloped a chemiluminescent immunoassay (HDV-CLEIA) to quantitatively determine intracellular HDAg with a dynamic range of 5-11,000 pg/mL. HDV-CLEIA can be used as an alternative approach to assess HDV infection. The advantages of our updated methodology were demonstrated through in vitro HDV infection of HepaRG cells and by evaluating the neutralization activity using antibodies that target various regions of the HBV/HDV envelope proteins. Together, the methods presented here comprise a novel toolbox of in vitro assays for studying HDV infection. PMID- 28079153 TI - NF-kappaB activation is critical for bacterial lipoprotein tolerance-enhanced bactericidal activity in macrophages during microbial infection. AB - Tolerance to bacterial components represents an essential regulatory mechanism during bacterial infection. Bacterial lipoprotein (BLP)-induced tolerance confers protection against microbial sepsis by attenuating inflammatory responses and augmenting antimicrobial activity in innate phagocytes. It has been well documented that BLP tolerance-attenuated proinflammatory cytokine production is associated with suppressed TLR2 signalling pathway; however, the underlying mechanism(s) involved in BLP tolerance-enhanced antimicrobial activity is unclear. Here we report that BLP-tolerised macrophages exhibited accelerated phagosome maturation and enhanced bactericidal activity upon bacterial infection, with upregulated expression of membrane-trafficking regulators and lysosomal enzymes. Notably, bacterial challenge resulted in a strong activation of NF kappaB pathway in BLP-tolerised macrophages. Importantly, activation of NF-kappaB pathway is critical for BLP tolerance-enhanced antimicrobial activity, as deactivation of NF-kappaB in BLP-tolerised macrophages impaired phagosome maturation and intracellular killing of the ingested bacteria. Finally, activation of NF-kappaB pathway in BLP-tolerised macrophages was dependent on NOD1 and NOD2 signalling, as knocking-down NOD1 and NOD2 substantially inhibited bacteria-induced activation of NF-kappaB and overexpression of Rab10 and Acp5, two membrane-trafficking regulators and lysosomal enzymes contributed to BLP tolerance-enhanced bactericidal activity. These results indicate that activation of NF-kappaB pathway is essential for BLP tolerance-augmented antimicrobial activity in innate phagocytes and depends primarily on both NOD1 and NOD2. PMID- 28079154 TI - Local anesthesia for transrectal ultrasound-guided biopsy of the prostate: A meta analysis. AB - A meta-analysis was performed to evaluate the efficacy of local anesthesia in alleviating pain during prostate biopsy. We searched relevant articles in PubMed and Embase. The included studies should be randomized controlled trials (RCT) using local anesthesia to alleviate pain during biopsy, which was recorded by a pain scale. Analgesic efficacy of different local anesthesia techniques were analyzed, including intrarectal local anesthesia (IRLA), periprostatic nerve block (PNB), pelvic plexus block (PPB) and intraprostatic local anesthesia (IPLA). We included 46 RCTs. PNB significantly reduced pain score compared with placebo (-1.27 [95% confidence interval [95% CI] -1.72, -0.82]) or no injection ( 1.01 [95% CI -1.2, -0.82]). IRLA with prilocaine-lidocaine cream could also reduced pain (-0.45 [95% CI -0.76, -0.15]), while the IRLA with lidocaine gel was not effective (-0.1 [95% CI -0.24, 0.04]). PNB lateral to the neurovascular bundle had better analgesic effect than at prostate apex (P = 0.02). Combination use of PPB and IRLA considerably alleviated pain of patients compared with the combination of PNB and IRLA (-1.32 [95% CI -1.59, -1.06]). In conclusion, local anesthesia could alleviate patients' pain during the prostate biopsy. PNB was not so effective as PPB. PMID- 28079155 TI - Dietary phytochemical PEITC restricts tumor development via modulation of epigenetic writers and erasers. AB - Dietary intake of bioactive phytochemicals including the cruciferous vegetable derivative phenethyl isothiocyanate (PEITC) can reduce risk of human cancers, but possible epigenetic mechanisms of these effects are yet unknown. We therefore sought to identify the molecular basis of PEITC-mediated epigenetic tumor restriction. Colon cancer cells treated with low-dose PEITC for >1 month exhibited stable alterations in expression profile of epigenetic writers/erasers and chromatin-binding of histone deacetylases (HDACs) and Polycomb-group (PcG) proteins. Sustained PEITC exposure not only blocked HDAC binding to euchromatin but was also associated with hypomethylation of PcG target genes that are typically hypermethylated in cancer. Furthermore, PEITC treatment induced expression of pro-apoptotic genes in tumor cells, which was partially reversed by overexpression of PcG member BMI-1, suggesting opposing roles for PEITC and PcG proteins in control of tumor progression. These data demonstrate that PEITC regulates chromatin binding of key epigenetic writers/erasers and PcG complexes to restrict tumor development. PMID- 28079156 TI - A mucin-like peptide from Fasciola hepatica instructs dendritic cells with parasite specific Th1-polarizing activity. AB - Fasciolosis is a trematode zoonosis of interest in public health and cattle production. We report here the immunostimulatory effect of a 66 mer mucin-like peptide from Fasciola hepatica (Fhmuc), which synergizes with lipopolysaccharide (LPS) to promote dendritic cell (DC) maturation, endowing these cells with Th1 polarizing capacity. Exposure of DCs to Fhmuc in presence of LPS induced enhanced secretion of pro-inflammatory cytokines and expression of co-stimulatory molecules by DCs, promoting their T cell stimulatory capacity and selectively augmenting IFN-gamma secretion by allogeneic T cells. Furthermore, exposure of DCs to Fhmuc augmented LPS-induced Toll-like receptor (TLR) 4 expression on the cell surface. Finally, Fhmuc-conditioned DCs induced parasite specific-adaptive immunity with increased levels of IFN-gamma secreted by splenocytes from vaccinated animals, and higher parasite-specific IgG antibodies. However, Fhmuc treated DC conferred modest protection against F. hepatica infection highlighting the potent immuno-regulatory capacity of the parasite. In summary, this work highlights the capacity of a mucin-derived peptide from F. hepatica to enhance LPS-maturation of DCs and induce parasite-specific immune responses with potential implications in vaccination and therapeutic strategies. PMID- 28079157 TI - Feeling Touched: Emotional Modulation of Somatosensory Potentials to Interpersonal Touch. AB - Although the previous studies have shown that an emotional context may alter touch processing, it is not clear how visual contextual information modulates the sensory signals, and at what levels does this modulation take place. Therefore, we investigated how a toucher's emotional expressions (anger, happiness, fear, and sadness) modulate touchee's somatosensory-evoked potentials (SEPs) in different temporal ranges. Participants were presented with tactile stimulation appearing to originate from expressive characters in virtual reality. Touch processing was indexed using SEPs, and self-reports of touch experience were collected. Early potentials were found to be amplified after angry, happy and sad facial expressions, while late potentials were amplified after anger but attenuated after happiness. These effects were related to two stages of emotional modulation of tactile perception: anticipation and interpretation. The findings show that not only does touch affect emotion, but also emotional expressions affect touch perception. The affective modulation of touch was initially obtained as early as 25 ms after the touch onset suggesting that emotional context is integrated to the tactile sensation at a very early stage. PMID- 28079158 TI - Aryl hydrocarbon receptor (AhR)-dependent regulation of pulmonary miRNA by chronic cigarette smoke exposure. AB - The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor historically known for its toxic responses to man-made pollutants such as dioxin. More recently, the AhR has emerged as a suppressor of inflammation, oxidative stress and apoptosis from cigarette smoke by mechanisms that may involve the regulation of microRNA. However, little is known about the AhR regulation of miRNA expression in the lung in response to inhaled toxicants. Therefore, we exposed Ahr-/- and Ahr+/- mice to cigarette smoke for 4 weeks and evaluated lung miRNA expression by PCR array. There was a dramatic regulation of lung miRNA by the AhR in the absence of exogenous ligand. In response to cigarette smoke, there were more up-regulated miRNA in Ahr-/- mice compared to Ahr+/- mice, including the cancer-associated miRNA miR-96. There was no significant change in the expression of the AhR regulated proteins HuR and cyclooxygenase-2 (COX-2). There were significant increases in the anti-oxidant gene sulfiredoxin 1 (Srxn1) and FOXO3a- predicted targets of miR-96. Collectively, these data support a prominent role for the AhR in regulating lung miRNA expression. Further studies to elucidate a role for these miRNA may further uncover novel biological function for the AhR in respiratory health and disease. PMID- 28079160 TI - Tempo of magma degassing and the genesis of porphyry copper deposits. AB - Porphyry deposits are copper-rich orebodies formed by precipitation of metal sulphides from hydrothermal fluids released from magmatic intrusions that cooled at depth within the Earth's crust. Finding new porphyry deposits is essential because they are our largest source of copper and they also contain other strategic metals including gold and molybdenum. However, the discovery of giant porphyry deposits is hindered by a lack of understanding of the factors governing their size. Here, we use thermal modelling and statistical simulations to quantify the tempo and the chemistry of fluids released from cooling magmatic systems. We confirm that typical arc magmas produce fluids similar in composition to those that form porphyry deposits and conclude that the volume and duration of magmatic activity exert a first order control on the endowment (total mass of deposited copper) of economic porphyry copper deposits. Therefore, initial magma enrichment in copper and sulphur, although adding to the metallogenic potential, is not necessary to form a giant deposit. Our results link the respective durations of magmatic and hydrothermal activity from well-known large to supergiant deposits to their metal endowment. This novel approach can readily be implemented as an additional exploration tool that can help assess the economic potential of magmatic-hydrothermal systems. PMID- 28079159 TI - SOCS1 favors the epithelial-mesenchymal transition in melanoma, promotes tumor progression and prevents antitumor immunity by PD-L1 expression. AB - Silencing of SOCS1 protein with shRNAi lentivirus (shR-SOCS1) led to partial reversion of the tumorigenic phenotype of B16F10-Nex2 melanoma cells. SOCS1 silencing inhibited cell migration and invasion as well as in vitro growth by cell cycle arrest at S phase with increased cell size and nuclei. Down-regulation of SOCS1 decreased the expression of epidermal growth factor receptor, Ins Ralpha, and fibroblast growth factor receptors. The present work aimed at analyzing the SOCS1 cell signaling and expression of proteins relevant to tumor development. An RNA microarray analysis of B16F10-Nex2 melanoma cells with SOCS1 silenced by shRNAi-SOCS1 was undertaken in comparison with cells transduced with the empty vector. Among 609 differentially expressed genes, c-Kit, Met and EphA3 cytokine/tyrosine-kinase (TK) receptors were down regulated. A significant decrease in the expression of TK receptors, the phosphorylation of mediators of ERK1/2 and p38 pathways and STAT3 (S727) were observed. Subcutaneous immunization with shR-SOCS1-transduced viable tumor cells rendered protection against melanoma in a syngeneic model, with decreased expression of PD-L1 and of matrix metallo proteinases (MMPs) and CD-10 in those cells. The present work shows the role of SOCS1 in murine melanoma development and the potential of SOCS1-silenced tumor cells in raising an effective anti-melanoma immune response. PMID- 28079161 TI - Micro-Structured Two-Component 3D Metamaterials with Negative Thermal-Expansion Coefficient from Positive Constituents. AB - Controlling the thermal expansion of materials is of great technological importance. Uncontrolled thermal expansion can lead to failure or irreversible destruction of structures and devices. In ordinary crystals, thermal expansion is governed by the asymmetry of the microscopic binding potential, which cannot be adjusted easily. In artificial crystals called metamaterials, thermal expansion can be controlled by structure. Here, following previous theoretical work, we fabricate three-dimensional (3D) two-component polymer micro-lattices by using gray-tone laser lithography. We perform cross-correlation analysis of optical microscopy images taken at different sample temperatures. The derived displacement-vector field reveals that the thermal expansion and resulting bending of the bi-material beams leads to a rotation of the 3D chiral crosses arranged onto a 3D checkerboard pattern within one metamaterial unit cell. These rotations can compensate the expansion of the all positive constituents, leading to an effectively near-zero thermal length-expansion coefficient, or over compensate the expansion, leading to an effectively negative thermal length expansion coefficient. This evidences a striking level of thermal-expansion control. PMID- 28079162 TI - Glucose tolerance in mice exposed to light-dark stimulus patterns mirroring dayshift and rotating shift schedules. AB - Glucose tolerance was measured in (nocturnal) mice exposed to light-dark stimulus patterns simulating those that (diurnal) humans would experience while working dayshift (DSS) and 2 rotating night shift patterns (1 rotating night shift per week [RSS1] and 3 rotating night shifts per week [RSS3]). Oral glucose tolerance tests were administered at the same time and light phase during the third week of each experimental session. In contrast to the RSS1 and RSS3 conditions, glucose levels reduced more quickly for the DSS condition. Glucose area-under-the-curve measured for the DSS condition was also significantly less than that for the RSS1 and RSS3 conditions. Circadian disruption for the 3 light-dark patterns was quantified using phasor magnitude based on the 24-h light-dark patterns and their associated activity-rest patterns. Circadian disruption for mice in the DSS condition was significantly less than that for the RSS1 and RSS3 conditions. This study extends previous studies showing that even 1 night of shift work decreases glucose tolerance and that circadian disruption is linked to glucose tolerance in mice. PMID- 28079163 TI - Steady-state and dynamic network modes for perceptual expectation. AB - Perceptual expectation can attenuate repetition suppression, the stimulus-induced neuronal response generated by repeated stimulation, suggesting that repetition suppression is a top-down modulatory phenomenon. However, it is still unclear which high-level brain areas are involved and how they interact with low-level brain areas. Further, the temporal range over which perceptual expectation can effectively attenuate repetition suppression effects remains unclear. To elucidate the details of this top-down modulatory process, we used two short and long inter-stimulus intervals for a perceptual expectation paradigm of paired stimulation. We found that top-down modulation enhanced the response to the unexpected stimulus when repetition suppression was weak and that the effect disappeared at 1,000 ms prior to stimulus exposure. The high-level areas involved in this process included the left inferior frontal gyrus (IFG_L) and left parietal lobule (IPL_L). We also found two systems providing modulatory input to the right fusiform face area (FFA_R): one from IFG_L and the other from IPL_L. Most importantly, we identified two states of networks through which perceptual expectation modulates sensory responses: one is a dynamic state and the other is a steady state. Our results provide the first functional magnetic resonance imaging (fMRI) evidence of temporally nested networks in brain processing. PMID- 28079164 TI - Corrigendum: Construction and application of a co-expression network in Mycobacterium tuberculosis. PMID- 28079165 TI - Oriented and Ordered Biomimetic Remineralization of the Surface of Demineralized Dental Enamel Using HAP@ACP Nanoparticles Guided by Glycine. AB - Achieving oriented and ordered remineralization on the surface of demineralized dental enamel, thereby restoring the satisfactory mechanical properties approaching those of sound enamel, is still a challenge for dentists. To mimic the natural biomineralization approach for enamel remineralization, the biological process of enamel development proteins, such as amelogenin, was simulated in this study. In this work, carboxymethyl chitosan (CMC) conjugated with alendronate (ALN) was applied to stabilize amorphous calcium phosphate (ACP) to form CMC/ACP nanoparticles. Sodium hypochlorite (NaClO) functioned as the protease which decompose amelogenin in vivo to degrade the CMC-ALN matrix and generate HAP@ACP core-shell nanoparticles. Finally, when guided by 10 mM glycine (Gly), HAP@ACP nanoparticles can arrange orderly and subsequently transform from an amorphous phase to well-ordered rod-like apatite crystals to achieve oriented and ordered biomimetic remineralization on acid-etched enamel surfaces. This biomimetic remineralization process is achieved through the oriented attachment (OA) of nanoparticles based on non-classical crystallization theory. These results indicate that finding and developing analogues of natural proteins such as amelogenin involved in the biomineralization by natural macromolecular polymers and imitating the process of biomineralization would be an effective strategy for enamel remineralization. Furthermore, this method represents a promising method for the management of early caries in minimal invasive dentistry (MID). PMID- 28079167 TI - Corrigendum: Integration and Typologies of Vulnerability to Climate Change: A Case Study from Australian Wheat Sheep Zones. PMID- 28079166 TI - Oxytocin biases men but not women to restore social connections with individuals who socially exclude them. AB - We normally react to individuals who exclude us socially by either avoiding them or increasing our attempts to interact with them. The neuropeptide oxytocin can promote social bonds and reduce social conflict and we therefore investigated whether it facilitates more positive social responses towards individuals who exclude or include us. In a double-blind, placebo-controlled, between-subject design 77 healthy Chinese male and female participants received intranasal oxytocin (40 IU) or placebo before playing a modified virtual ball-tossing game with three fictitious partners who either showed exclusion, inclusion or neutral behavioral interactions with them. Results showed that both male and female subjects threw the ball more often to individuals who excluded rather than included them, although oxytocin did not alter this or awareness/feelings of exclusion or inclusion. However, when subjects returned a week later males, but not females, in the oxytocin group exhibited an increased liking for, and preference for playing again with, players who had previously excluded them. This oxytocin effect was positively associated with independent traits. Our findings suggest that in a collectivist culture oxytocin may promote the desire of males, but not females, with a stronger independent orientation to rebuild social connections with individuals who have previously excluded them. PMID- 28079168 TI - Molecular dynamics studies unravel role of conserved residues responsible for movement of ions into active site of DHBPS. AB - 3,4-dihydroxy-2-butanone-4-phosphate synthase (DHBPS) catalyzes the conversion of D-ribulose 5-phosphate (Ru5P) to L-3,4-dihydroxy-2-butanone-4-phosphate in the presence of Mg2+. Although crystal structures of DHBPS in complex with Ru5P and non-catalytic metal ions have been reported, structure with Ru5P along with Mg2+ is still elusive. Therefore, mechanistic role played by Mg2+ in the structure of DHBPS is poorly understood. In this study, molecular dynamics simulations of DHBPS-Ru5P complex along with Mg2+ have shown entry of Mg2+ from bulk solvent into active site. Presence of Mg2+ in active site has constrained conformations of Ru5P and has reduced flexibility of loop-2. Formation of hydrogen bonds among Thr-108 and residues - Gly-109, Val-110, Ser-111, and Asp-114 are found to be critical for entry of Mg2+ into active site. Subsequent in silico mutations of residues, Thr-108 and Asp-114 have substantiated the importance of these interactions. Loop-4 of one monomer is being proposed to act as a "lid" covering the active site of other monomer. Further, the conserved nature of residues taking part in the transfer of Mg2+ suggests the same mechanism being present in DHBPS of other microorganisms. Thus, this study provides insights into the functioning of DHBPS that can be used for the designing of inhibitors. PMID- 28079169 TI - Abnormalities of regional brain function in Parkinson's disease: a meta-analysis of resting state functional magnetic resonance imaging studies. AB - There is convincing evidence that abnormalities of regional brain function exist in Parkinson's disease (PD). However, many resting-state functional magnetic resonance imaging (rs-fMRI) studies using amplitude of low-frequency fluctuations (ALFF) have reported inconsistent results about regional spontaneous neuronal activity in PD. Therefore, we conducted a comprehensive meta-analysis using the Seed-based d Mapping and several complementary analyses. We searched PubMed, Embase, and Web of Science databases for eligible whole-brain rs-fMRI studies that measured ALFF differences between patients with PD and healthy controls published from January 1st, 2000 until June 24, 2016. Eleven studies reporting 14 comparisons, comparing 421 patients and 381 healthy controls, were included. The most consistent and replicable findings in patients with PD compared with healthy controls were identified, including the decreased ALFFs in the bilateral supplementary motor areas, left putamen, left premotor cortex, and left inferior parietal gyrus, and increased ALFFs in the right inferior parietal gyrus. The altered ALFFs in these brain regions are related to motor deficits and compensation in PD, which contribute to understanding its neurobiological underpinnings and could serve as specific regions of interest for further studies. PMID- 28079171 TI - Comfortable, high-efficiency heat pump with desiccant-coated, water-sorbing heat exchangers. AB - Comfortable, efficient, and affordable heating, ventilation, and air conditioning systems in buildings are highly desirable due to the demands of energy efficiency and environmental friendliness. Traditional vapor-compression air conditioners exhibit a lower coefficient of performance (COP) (typically 2.8-3.8) owing to the cooling-based dehumidification methods that handle both sensible and latent loads together. Temperature- and humidity-independent control or desiccant systems have been proposed to overcome these challenges; however, the COP of current desiccant systems is quite small and additional heat sources are usually needed. Here, we report on a desiccant-enhanced, direct expansion heat pump based on a water sorbing heat exchanger with a desiccant coating that exhibits an ultrahigh COP value of more than 7 without sacrificing any comfort or compactness. The pump's efficiency is doubled compared to that of pumps currently used in conventional room air conditioners, which is a revolutionary HVAC breakthrough. Our proposed water-sorbing heat exchanger can independently handle sensible and latent loads at the same time. The desiccants adsorb moisture almost isothermally and can be regenerated by condensation heat. This new approach opens up the possibility of achieving ultrahigh efficiency for a broad range of temperature- and humidity control applications. PMID- 28079170 TI - Growth and Morbidity of Gambian Infants are Influenced by Maternal Milk Oligosaccharides and Infant Gut Microbiota. AB - Human milk oligosaccharides (HMOs) play an important role in the health of an infant as substrate for beneficial gut bacteria. Little is known about the effects of HMO composition and its changes on the morbidity and growth outcomes of infants living in areas with high infection rates. Mother's HMO composition and infant gut microbiota from 33 Gambian mother/infant pairs at 4, 16, and 20 weeks postpartum were analyzed for relationships between HMOs, microbiota, and infant morbidity and growth. The data indicate that lacto-N-fucopentaose I was associated with decreased infant morbidity, and 3'-sialyllactose was found to be a good indicator of infant weight-for-age. Because HMOs, gut microbiota, and infant health are interrelated, the relationship between infant health and their microbiome were analyzed. While bifidobacteria were the dominant genus in the infant gut overall, Dialister and Prevotella were negatively correlated with morbidity, and Bacteroides was increased in infants with abnormal calprotectin. Mothers nursing in the wet season (July to October) produced significantly less oligosaccharides compared to those nursing in the dry season (November to June). These results suggest that specific types and structures of HMOs are sensitive to environmental conditions, protective of morbidity, predictive of growth, and correlated with specific microbiota. PMID- 28079173 TI - New experimental evidence to support roaming in the reaction Cl + isobutene (i C4H8). AB - The reaction Cl + isobutene (i-C4H8) was reported by Suits et al. to proceed via, in addition to abstraction, an addition-elimination path following a roaming excursion of Cl; a near-zero translational energy release and an isotropic angular distribution observed at a small collision energy characterized this mechanism. We employed a new experimental method to further characterize this roaming mechanism through observation of the internal distribution of HCl (v, J) and their temporal behavior upon irradiation of a mixture of Cl2C2O2 and i-C4H8 in He or Ar buffer gas. With 1-3 Torr buffer gas added to approach the condition of small collision energy, the intensities of emission of HCl (v = 1, 2) and the HCl production rates increased significantly; Ar shows a more significant effect than He because Ar quenches Cl more efficiently to reduce the collisional energy and facilitate the roaming path. According to kinetic modeling, the rate of addition-elimination (roaming) increased from kE ~ 2 * 105 s-1 when little buffer gas was present to ~1.9 * 106 s-1 when 2-3 Torr of Ar was added, and the branching ratio for formation of [HCl (v = 2)]/[HCl (v = 1)] increased from 0.02 +/- 0.01 for abstraction to 0.06 +/- 0.01 for roaming. PMID- 28079172 TI - 25(OH)D and 1,25(OH)D vitamin D fails to predict sepsis and mortality in a prospective cohort study. AB - The clinical role of vitamin D in sepsis and mortality prediction is controversially discussed. Therefore, we conducted a prospective cohort study on standard care wards, including 461 patients with suspected sepsis fulfilling two or more SIRS criteria. On the first and third day after onset of SIRS symptoms levels of 25(OH)D, 1,25(OH)D and sepsis biomarkers were analysed for their predictive capacity for identifying infection, bacteraemia and an elevated mortality risk. Additionally, several SNPs associated with vitamin D metabolism were evaluated. Bacteraemic patients (28.5%) presented with significantly lower 1,25(OH)D levels than SIRS patients without bacteraemia on the first and third day, while 25(OH)D did not show a predictive capacity. No significant differences of either 1,25(OH)D or 25(OH)D levels were found between SIRS patients with and without infections or between survivors and non-survivors. Sepsis biomarkers, including procalcitonin and CRP, showed a significantly higher discriminatory capacity for these classification tasks. The vitamin D metabolism-related SNPs analysed did not indicate any association with our outcome measures. In conclusion, 1,25(OH)D but not 25(OH)D showed a minor discriminatory value for the prediction of bacteraemia that was inferior to CRP and PCT but both failed to predict sepsis and mortality in a prospective cohort of SIRS patients. PMID- 28079175 TI - Interstitial atoms enable joint twinning and transformation induced plasticity in strong and ductile high-entropy alloys. AB - High-entropy alloys (HEAs) consisting of multiple principle elements provide an avenue for realizing exceptional mechanical, physical and chemical properties. We report a novel strategy for designing a new class of HEAs incorporating the additional interstitial element carbon. This results in joint activation of twinning- and transformation-induced plasticity (TWIP and TRIP) by tuning the matrix phase's instability in a metastable TRIP-assisted dual-phase HEA. Besides TWIP and TRIP, such alloys benefit from massive substitutional and interstitial solid solution strengthening as well as from the composite effect associated with its dual-phase structure. Nanosize particle formation and grain size reduction are also utilized. The new interstitial TWIP-TRIP-HEA thus unifies all metallic strengthening mechanisms in one material, leading to twice the tensile strength compared to a single-phase HEA with similar composition, yet, at identical ductility. PMID- 28079174 TI - Alleviating liver failure conditions using an integrated hybrid cryogel based cellular bioreactor as a bioartificial liver support. AB - Conventionally, some bioartificial liver devices are used with separate plasmapheresis unit to separate out plasma from whole blood and adsorbent column to detoxify plasma before it passes through a hepatocytes-laden bioreactor. We aim to develop a hybrid bioreactor that integrates the separate modules in one compact design improving the efficacy of the cryogel based bioreactor as a bioartificial liver support. A plasma separation membrane and an activated carbon cloth are placed over a HepG2-loaded cryogel scaffold in a three-chambered bioreactor design. This bioreactor is consequently connected extracorporeally to a rat model of acute liver failure for 3 h and major biochemical parameters studied. Bilirubin and aspartate transaminase showed a percentage decrease of 20 60% in the integrated bioreactor as opposed to 5-15% in the conventional setup. Urea and ammonia levels which showed negligible change in the conventional setup increase (40%) and decrease (18%), respectively in the integrated system. Also, an overall increase of 5% in human albumin in rat plasma indicated bioreactor functionality in terms of synthetic functions. These results were corroborated by offline evaluation of patient plasma. Hence, integrating the plasmapheresis and adsorbent units with the bioreactor module in one compact design improves the efficacy of the bioartificial liver device. PMID- 28079176 TI - Adductor canal block versus femoral nerve block for total knee arthroplasty: a meta-analysis of randomized controlled trials. AB - Femoral nerve blocks (FNB) can provide effective pain relief but result in quadriceps weakness with increased risk of falls following total knee arthroplasty (TKA). Adductor canal block (ACB) is a relatively new alternative providing pure sensory blockade with minimal effect on quadriceps strength. The meta-analysis was designed to evaluate whether ACB exhibited better outcomes with respect to quadriceps strength, pain control, ambulation ability, and complications. PubMed, Embase, Web of Science, Wan Fang, China National Knowledge Internet (CNKI) and the Cochrane Database were searched for RCTs comparing ACB with FNB after TKAs. Of 309 citations identified by our search strategy, 12 RCTs met the inclusion criteria. Compared to FNB, quadriceps maximum voluntary isometric contraction (MVIC) was significantly higher for ACB, which was consistent with the results regarding quadriceps strength assessed with manual muscle strength scale. Moreover, ACB had significantly higher risk of falling versus FNB. At any follow-up time, ACB was not inferior to FNB regarding pain control or opioid consumption, and showed better range of motion in comparison with FNB. ACB is superior to the FNB regarding sparing of quadriceps strength and faster knee function recovery. It provides pain relief and opioid consumption comparable to FNB and is associated with decreased risk of falls. PMID- 28079177 TI - Species-dependent variation in sensitivity of Microcystis species to copper sulfate: implication in algal toxicity of copper and controls of blooms. AB - Copper sulfate is a frequently used reagent for Microcystis blooms control but almost all the previous works have used Microcystis aeruginosa as the target organism to determine dosages. The aim of this study was to evaluate interspecific differences in the responses of various Microcystis species to varying Cu2+ concentrations (0, 0.05, 0.10, 0.25, and 0.50 mg L-1). The half maximal effective concentration values for M. aeruginosa, M. wesenbergii, M. flos aquae, and M. viridis were 0.16, 0.09, 0.49, and 0.45 mg L-1 Cu2+, respectively. This showed a species-dependent variation in the sensitivity of Microcystis species to copper sulfate. Malonaldehyde content did not decrease with increasing superoxide dismutase content induced by increasing Cu2+, suggesting that superoxide dismutase failed to reduce Cu2+ damage in Microcystis. Considering the risk of microcystin release when Microcystis membranes are destroyed as a result of Cu2+ treatment and the stimulation effects of a low level of Cu2+ on growth in various species, our results suggest that copper sulfate treatment for Microcystis control could be applied before midsummer when M. aeruginosa and M. viridis are not the dominant species and actual amount of Cu2+ used to control M. wesenbergii should be much greater than 0.10 mg L-1. PMID- 28079178 TI - Significance of oxygen transport through aquaporins. AB - Aquaporins are membrane integral proteins responsible for the transmembrane transport of water and other small neutral molecules. Despite their well acknowledged importance in water transport, their significance in gas transport processes remains unclear. Growing evidence points to the involvement of plant aquaporins in CO2 delivery for photosynthesis. The role of these channel proteins in the transport of O2 and other gases may also be more important than previously envisioned. In this study, we examined O2 permeability of various human, plant, and fungal aquaporins by co-expressing heterologous aquaporin and myoglobin in yeast. Two of the most promising O2-transporters (Homo sapiens AQP1 and Nicotiana tabacum PIP1;3) were confirmed to facilitate O2 transport in the spectrophotometric assay using yeast protoplasts. The over-expression of NtPIP1;3 in yeasts significantly increased their O2 uptake rates in suspension culture. In N. tabacum roots subjected to hypoxic hydroponic conditions, the transcript levels of the O2-transporting aquaporin NtPIP1;3 significantly increased after the seven-day hypoxia treatment, which was accompanied by the increase of ATP levels in the apical root segments. Our results suggest that the functional significance of aquaporin-mediated O2 transport and the possibility of controlling the rate of transmembrane O2 transport should be further explored. PMID- 28079179 TI - Transcriptome and network analyses in Saccharomyces cerevisiae reveal that amphotericin B and lactoferrin synergy disrupt metal homeostasis and stress response. AB - Invasive fungal infections are difficult to treat. The few available antifungal drugs have problems with toxicity or efficacy, and resistance is increasing. To overcome these challenges, existing therapies may be enhanced by synergistic combination with another agent. Previously, we found amphotericin B (AMB) and the iron chelator, lactoferrin (LF), were synergistic against a range of different fungal pathogens. This study investigates the mechanism of AMB-LF synergy, using RNA-seq and network analyses. AMB treatment resulted in increased expression of genes involved in iron homeostasis and ATP synthesis. Unexpectedly, AMB-LF treatment did not lead to increased expression of iron and zinc homeostasis genes. However, genes involved in adaptive response to zinc deficiency and oxidative stress had decreased expression. The clustering of co-expressed genes and network analysis revealed that many iron and zinc homeostasis genes are targets of transcription factors Aft1p and Zap1p. The aft1Delta and zap1Delta mutants were hypersensitive to AMB and H2O2, suggesting they are key regulators of the drug response. Mechanistically, AMB-LF synergy could involve AMB affecting the integrity of the cell wall and membrane, permitting LF to disrupt intracellular processes. We suggest that Zap1p- and Aft1p-binding molecules could be combined with existing antifungals to serve as synergistic treatments. PMID- 28079181 TI - Erratum: Condensed-matter equation of states covering a wide region of pressure studied experimentally. PMID- 28079180 TI - The Herbivore-Induced Plant Volatiles Methyl Salicylate and Menthol Positively affect Growth and Pathogenicity of Entomopathogenic Fungi. AB - Some herbivore-induced-plant volatiles (HIPVs) compounds are vital for the functioning of an ecosystem, by triggering multi-trophic interactions for natural enemies, plants and herbivores. However, the effect of these chemicals, which play a crucial role in regulating the multi-trophic interactions between plant herbivore-entomopathogenic fungi, is still unknown. To fill this scientific gap, we therefore investigated how these chemicals influence the entomopathogenic fungi growth and efficacy. In this study, Lipaphis erysimi induced Arabidopsis thaliana HIPVs were collected using headspace system and detected with GC-MS, and then analyzed the effects of these HIPVs chemicals on Lecanicillium lecanii strain V3450. We found that the HIPVs menthol and methyl salicylate at 1 and 10 nmol.ml-1 improved many performance aspects of the fungus, such as germination, sporulation, appressorial formation as well as its pathogenicity and virulence. These findings are not only important for understanding the multi-trophic interactions in an ecosystem, but also would contribute for developing new and easier procedures for conidial mass production as well as improve the pathogenicity and virulence of entomopathogenic fungi in biological pest management strategies. PMID- 28079183 TI - Corrigendum: nanoSQUID operation using kinetic rather than magnetic induction. PMID- 28079182 TI - Physical Health Indicators Improve Prediction of Cardiovascular and All-cause Mortality among Middle-Aged and Older People: a National Population-based Study. AB - The effectiveness of established methods for stratifying cardiovascular risk, for example, the Framingham risk score (FRS), may be improved by adding extra variables. This study evaluated the potential benefits of adding physical health indicators (handgrip strength, walking speed, and peak expiratory flow) to the FRS in predicting cardiovascular and all-cause mortality by using a nationwide population-based cohort study data. During median follow-up of 4.1 years, 67 of 911 study subjects had died. In Cox regression analysis, all additional physical health indicators, except walking speed, significantly predicted cardiovascular and all-cause mortality (P < 0.05). Compared with the conventional FRS, c statistics were significantly increased when dominant handgrip strength or relative handgrip strength (handgrip strength adjusted for body mass index), or combination with walking speed or peak expiratory flow were incorporated into the FRS prediction model, both in the whole cohort and also in participants who did not have prevalent cardiovascular diseases at baseline. In conclusion, dominant or relative handgrip strength are simple and inexpensive physical health indicators that substantially improve the accuracy of the FRS in predicting cardiovascular and all-cause mortality among middle-aged and older people. PMID- 28079184 TI - Development of a novel model of hypertriglyceridemic acute pancreatitis in mice. AB - The morbidity rate of hypertriglyceridemic acute pancreatitis (HTG-AP) increased rapidly over the last decade. However an appropriate animal model was lacking to recapitulate this complicated human disease. We established a novel mice model of HTG-AP by poloxamer 407 (P-407) combined with caerulein (Cae). In our study, serum triglyceride levels of P-407 induced mice were elevated in a dose-dependent manner, and the pancreatic and pulmonary injuries were much severer in HTG mice than normal mice when injected with conventional dose Cae (50 ug/kg), what's more, the severity of AP was positively correlative with duration and extent of HTG. In addition, we found that a low dose Cae (5 ug/kg) could induce pancreatic injury in HTG mice while there was no obvious pathological injury in normal mice. Finally, we observed that HTG leaded to the increased infiltrations of macrophages and neutrophils in mice pancreatic tissues. In conclusion, we have developed a novel animal model of HTG-AP that can mimic physiological, histological, clinical features of human HTG-AP and it could promote the development of therapeutic strategies and advance the mechanism research on HTG AP. PMID- 28079185 TI - High-efficiency tri-band quasi-continuous phase gradient metamaterials based on spoof surface plasmon polaritons. AB - A high-efficiency tri-band quasi-continuous phase gradient metamaterial is designed and demonstrated based on spoof surface plasmon polaritons (SSPPs). High efficiency polarizaiton conversion transmission is firstly achieved via tailoring phase differece between the transmisive SSPP and the space wave in orthogonal directions. As an example, a tri-band circular-to-circular (CTC) polarization conversion metamateiral (PCM) was designed by a nonlinearly dispersive phase difference. Using such PCM unit cell, a tri-band quasi-continuous phase gradient metamaterial (PGM) was then realized by virtue of the Pancharatnam-Berry phase. The distribution of the cross-polarization transmission phase along the x direction is continuous except for two infinitely small intervals near the phases 0 degrees and 360 degrees , and thus the phase gradient has definition at any point along the x-direction. The simulated normalized polarization conversion transmission spectrums together with the electric field distributions for circularly polarized wave and linearly polarized wave demonstrated the high efficiency anomalous refraction of the quasi-continuous PGM. The experimental verification for the linearly polarized incidence was also provided. PMID- 28079187 TI - A spiking neural network model of 3D perception for event-based neuromorphic stereo vision systems. AB - Stereo vision is an important feature that enables machine vision systems to perceive their environment in 3D. While machine vision has spawned a variety of software algorithms to solve the stereo-correspondence problem, their implementation and integration in small, fast, and efficient hardware vision systems remains a difficult challenge. Recent advances made in neuromorphic engineering offer a possible solution to this problem, with the use of a new class of event-based vision sensors and neural processing devices inspired by the organizing principles of the brain. Here we propose a radically novel model that solves the stereo-correspondence problem with a spiking neural network that can be directly implemented with massively parallel, compact, low-latency and low power neuromorphic engineering devices. We validate the model with experimental results, highlighting features that are in agreement with both computational neuroscience stereo vision theories and experimental findings. We demonstrate its features with a prototype neuromorphic hardware system and provide testable predictions on the role of spike-based representations and temporal dynamics in biological stereo vision processing systems. PMID- 28079186 TI - Extracellular vesicle mediated intercellular communication at the porcine maternal-fetal interface: A new paradigm for conceptus-endometrial cross-talk. AB - Exosomes and microvesicles are extracellular vesicles released from cells and can contain lipids, miRNAs and proteins that affect cells at distant sites. Recently, microvesicles containing miRNA have been implicated in uterine microenvironment of pigs, a species with unique epitheliochorial (non-invasive) placentation. Here we report a novel role of conceptus-derived exosomes/microvesicles (hereafter referred to as extracellular vesicles; EVs) in embryo-endometrial cross-talk. We also demonstrate the stimulatory effects of EVs (PTr2-Exo) derived from porcine trophectoderm-cells on various biological processes including the proliferation of maternal endothelial cells (PAOEC), potentially promoting angiogenesis. Transmission immuno-electron microscopy confirmed the presence of EVs in tissue biopsies, PTr2-Exo and PAOEC-derived EVs (PAOEC-Exo). RT-PCR detected 14 select miRNAs in CD63 positive EVs in which miR-126-5P, miR-296-5P, miR-16, and miR-17 5P were the most abundant angiogenic miRNAs. Proteomic analysis revealed EV proteins that play a role in angiogenesis. In-vitro experiments, using two representative cell lines of maternal-fetal interface, demonstrated bidirectional EVs shuttling between PTr2 and PAOEC cells. Importantly, these studies support the idea that PTr2-Exo and PAOEC-Exo containing select miRNAs and proteins can be successfully delivered to recipient cells and that they may have a biological role in conceptus-endometrial cross-talk crucial for the pregnancy success. PMID- 28079188 TI - Proteome Response of Chicken Embryo Fibroblast Cells to Recombinant H5N1 Avian Influenza Viruses with Different Neuraminidase Stalk Lengths. AB - The variation on neuraminidase (NA) stalk region of highly pathogenic avian influenza H5N1 virus results in virulence change in animals. In our previous studies, the special NA stalk-motif of H5N1 viruses has been demonstrated to play a significant role in the high virulence and pathogenicity in chickens. However, the molecular mechanisms underlying the pathogenicity of viruses with different NA stalk remain poorly understood. This study presents a comprehensive characterization of the proteome response of chicken cells to recombinant H5N1 virus with stalk-short NA (rNA-wt) and the stalkless NA mutant virus (rSD20). 208 proteins with differential abundance profiles were identified differentially expressed (DE), and these proteins were mainly related to stress response, transcription regulation, transport, metabolic process, cellular component and cytoskeleton. Through Ingenuity Pathways Analysis (IPA), the significant biological functions of DE proteins represented included Post-Translational Modification, Protein Folding, DNA Replication, Recombination and Repair. It was interesting to find that most DE proteins were involved in the TGF-beta mediated functional network. Moreover, the specific DE proteins may play important roles in the innate immune responses and H5N1 virus replication. Our data provide important information regarding the comparable host response to H5N1 influenza virus infection with different NA stalk lengths. PMID- 28079190 TI - Corrigendum: Knockout of Foxp2 disrupts vocal development in mice. PMID- 28079191 TI - Enhanced Radiation-tolerant Oxide Dispersion Strengthened Steel and its Microstructure Evolution under Helium-implantation and Heavy-ion Irradiation. AB - The world eagerly needs cleanly-generated electricity in the future. Fusion reactor is one of the most ideal energy resources to defeat the environmental degradation caused by the consumption of traditional fossil energy. To meet the design requirements of fusion reactor, the development of the structural materials which can sustain the elevated temperature, high helium concentration and extreme radiation environments is the biggest challenge for the entire material society. Oxide dispersion strengthened steel is one of the most popular candidate materials for the first wall/blanket applications in fusion reactor. In this paper, we evaluate the radiation tolerance of a 9Cr ODS steel developed in China. Compared with Ferritic/Martensitic steel, this ODS steel demonstrated a significantly higher swelling resistance under ion irradiation at 460 degrees C to 188 displacements per atom. The role of oxides and grain boundaries on void swelling has been explored. The results indicated that the distribution of higher density and finer size of nano oxides will lead a better swelling resistance for ODS alloy. The original pyrochlore-structured Y2Ti2O7 particles dissolved gradually while fine Y-Ti-O nano clusters reprecipitated in the matrix during irradiation. The enhanced radiation tolerance is attributed to the reduced oxide size and the increased oxide density. PMID- 28079189 TI - Maintenance and Representation of Mind Wandering during Resting-State fMRI. AB - Major advances in resting-state functional magnetic resonance imaging (fMRI) techniques in the last two decades have provided a tool to better understand the functional organization of the brain both in health and illness. Despite such developments, characterizing regulation and cerebral representation of mind wandering, which occurs unavoidably during resting-state fMRI scans and may induce variability of the acquired data, remains a work in progress. Here, we demonstrate that a decrease or decoupling in functional connectivity involving the caudate nucleus, insula, medial prefrontal cortex and other domain-specific regions was associated with more sustained mind wandering in particular thought domains during resting-state fMRI. Importantly, our findings suggest that temporal and between-subject variations in functional connectivity of above mentioned regions might be linked with the continuity of mind wandering. Our study not only provides a preliminary framework for characterizing the maintenance and cerebral representation of different types of mind wandering, but also highlights the importance of taking mind wandering into consideration when studying brain organization with resting-state fMRI in the future. PMID- 28079192 TI - Differential cytotoxic effects of graphene and graphene oxide on skin keratinocytes. AB - Impressive properties make graphene-based materials (GBMs) promising tools for nanoelectronics and biomedicine. However, safety concerns need to be cleared before mass production of GBMs starts. As skin, together with lungs, displays the highest exposure to GBMs, it is of fundamental importance to understand what happens when GBMs get in contact with skin cells. The present study was carried out on HaCaT keratinocytes, an in vitro model of skin toxicity, on which the effects of four GBMs were evaluated: a few layer graphene, prepared by ball milling treatment (FLG), and three samples of graphene oxide (GOs, a research grade GO1, and two commercial GOs, GO2 and GO3). Even though no significant effects were observed after 24 h, after 72 h the less oxidized compound (FLG) was the less cytotoxic, inducing mitochondrial and plasma-membrane damages with EC50s of 62.8 MUg/mL (WST-8 assay) and 45.5 MUg/mL (propidium iodide uptake), respectively. By contrast, the largest and most oxidized compound, GO3, was the most cytotoxic, inducing mitochondrial and plasma-membrane damages with EC50s of 5.4 and 2.9 MUg/mL, respectively. These results suggest that only high concentrations and long exposure times to FLG and GOs could impair mitochondrial activity associated with plasma membrane damage, suggesting low cytotoxic effects at the skin level. PMID- 28079194 TI - Corrigendum. AB - [This corrects the article DOI: 10.1177/2055102915615046.]. PMID- 28079193 TI - ECG non-specific ST-T and QTc abnormalities in patients with systemic lupus erythematosus compared with rheumatoid arthritis. AB - OBJECTIVES: Cardiovascular disease (CVD) is a leading cause of death in systemic lupus erythematosus (SLE) and in rheumatoid arthritis (RA). Although only explored in one study, ECG non-specific ST-T abnormalities, in addition to corrected QT-interval (QTc) prolongation, were recently reported in an SLE inception cohort. Importantly, these ECG abnormalities are known predictors of CVD mortality in the general population, yet their prevalence in patients with established SLE has not been evaluated. METHODS: We cross-sectionally investigated the presence of non-specific ST-T and QTc abnormalities in 50 patients with SLE, predominantly Hispanic and black, without CVD or SLE-related cardiac involvement and compared them with 139 patients with RA without CVD. Demographics, disease-specific characteristics and CVD risk factors were ascertained and adjusted for. RESULTS: Patients with SLE (mean age 36+/-13 years, 92% women, 6 years median disease duration, 96% Hispanics and blacks) had a 3.3 fold higher adjusted prevalence of non-specific ST-T abnormalities (56% vs 17%; p <0.0001) compared with RA, despite the older age and higher percentage of men in the RA group. The QTc was 26 ms longer in SLE compared with RA (p=0.002) in the setting of a higher percentage of women, blacks, Hispanics and higher C reactive protein levels in the SLE group. CONCLUSIONS: This study demonstrates a high prevalence of ECG abnormalities in predominantly Hispanic and black patients with SLE. Longitudinal evaluation of the progression to potentially life-threatening arrhythmias and/or cardiovascular events is warranted. PMID- 28079195 TI - A pH-responsive molecular capsule with an acridine shell: catch and release of large hydrophobic compounds. AB - Unlike common polyaromatic hydrocarbons, acridine is a characteristic compound bearing both pi-stackable large surfaces and a protonable nitrogen atom. Here we report the first synthesis of a supramolecular capsule with multiple acridine panels. In water, the assembly and disassembly of the capsule reversibly occur under neutral and acidic conditions, respectively (>=10 cycles). Notably, the pH responsive capsule encapsulates a variety of large hydrophobic compounds (up to 1.6 nm in diameter) such as coumarins, metallophthalocyanines and subphthalocyanine in neutral water and subsequently releases them by simple addition of acid. PMID- 28079196 TI - Ultra-fast charge migration competes with proton transfer in the early chemistry of H2O. AB - Oxidation by the ultra-short lived radical cation of water, H2O+, can potentially take place at the interface of water and numerous heterogeneous systems involved in radiation therapy, energy and environmental industries. The oxidation processes induced by H2O+ can be mimicked in highly concentrated solutions where the nearest neighbors of H2O+ may be molecules other than water. The reactivity of H2O+ and D2O+ is probed in hydrogenated and deuterated sulfuric acid solutions of various concentrations. The oxidized solute, sulfate radical, is observed at 7 ps and remarkably higher yields are found in deuterated solutions. The isotopic effects reveal the competition between two ultrafast reactions: proton transfer toward H2O (D2O) and electron transfer from HSO4- to H2O+ (D2O+). Density functional theory simulations decipher the electron transfer mechanism: it proceeds via sub-femtosecond charge migration and is not affected by isotopic substitution. This work definitively demonstrates why direct oxidation triggered by H2O+ can be competitive with proton transfer. PMID- 28079197 TI - Temperature responsive lipid liquid crystal layers with embedded nanogels. AB - Polymer nanogels are embedded within layers consisting of a nonlamellar liquid crystalline lipid phase to act as thermoresponsive controllers of layer compactness and hydration. As the nanogels change from the swollen to the collapsed state via a temperature trigger, they enable on-demand release of water from the mixed polymer-lipid layer while the lipid matrix remains intact. Combining stimuli-responsive polymers with responsive lipid-based mesophase systems opens up new routes in biomedical applications such as functional biomaterials, bioanalysis and drug delivery. PMID- 28079199 TI - Structural influence of proteins upon adsorption to MoS2 nanomaterials: comparison of MoS2 force field parameters. AB - Molybdenum disulfide (MoS2) has recently emerged as a promising nanomaterial in a wide range of applications due to its unique and impressive properties. For example, MoS2 has gained attention in the biomedical field because of its ability to act as an antibacterial and anticancer agent. However, the potential influence of this exciting nanomaterial on biomolecules is yet to be extensively studied. Molecular dynamics (MD) simulations are invaluable tools in the examination of protein interactions with nanomaterials such as MoS2. Previous protein MD studies have employed MoS2 force field parameters which were developed to accurately model bulk crystal structures and thermal heat transport but may not necessarily be amendable to its properties at the interface with biomolecules. By adopting a newly developed MoS2 force field, which was designed to better capture its interaction with water and proteins, we have examined the changes in protein structures between the original and refitted MoS2 force field parameters of three representative proteins, polyalanine (alpha-helix), YAP65 WW-domains (beta sheet), and HP35 (globular protein) when adsorbed onto MoS2 nanomaterials. We find that the original force field, with much larger van der Waals (vdW) contributions, resulted in more dramatic protein structural damage than the refitted parameters. Importantly, some denaturation of the protein tertiary structure and the local secondary structure persisted with the refitted force field albeit overall less severe MoS2 denaturation capacity was found. This work suggests that the denaturation ability of MoS2 to the protein structure is not as dire as previously reported and provides noteworthy findings on the dynamic interactions of proteins with this emergent material. PMID- 28079198 TI - Oligomerization of FVFLM peptides and their ability to inhibit beta amyloid peptides aggregation: consideration as a possible model. AB - Preeclampsia, a pregnancy-specific disorder, shares typical pathophysiological features with protein misfolding disorders including Alzheimer's disease. Characteristic for preeclampsia is the involvement of multiple proteins of which fragments of SERPINA1 and beta-amyloid co-aggregate in urine and placenta of preeclamptic women. To explore the biophysical basis of this interaction, we investigated the multidimensional efficacy of the FVFLM sequence in SERPINA1, as a model inhibitory agent of beta-amyloid aggregation. After studying the oligomerization of FVFLM peptides using all-atom molecular dynamics simulations with the GROMOS43a1 force field and explicit water, we report that FVFLM can aggregate and its aggregation is spontaneous with a remarkably faster rate than that recorded for KLVFF (aggregation "hot-spot" from beta-amyloid). The fast kinetics of FVFLM aggregation was found to be driven primarily by core-like aromatic interactions originating from the anti-parallel orientation of complementarily uncharged strands. The conspicuously stable aggregation mechanism observed for FVFLM peptides is found not to conform to the popular 'dock-lock' scheme. We also found high propensity of FVFLM for KLVFF binding. When present, FVFLM disrupts the beta-amyloid aggregation pathway and we propose that FVFLM like peptides might be used to prevent the assembly of full-length Abeta or other pro-amyloidogenic peptides into amyloid fibrils. PMID- 28079200 TI - A molecular dynamics study of the interaction of water with the external surface of silicalite-1. AB - The interaction of water with the hydroxylated (010) surface of silicalite-1 was studied by classical molecular dynamics simulations. Interatomic interactions in the system were described using a set of effective potentials combining well tested BKS and SPC models. The extended force field is shown to correctly reproduce the structural, energy, and dynamical characteristics of the silica surface OH groups. The interaction of water with the hydrophilic silanols leads to an ordering of H2O molecules in the vicinity of the surface. The ordering is found to be limited to two molecular layers extending to 7 A above the surface. Despite the hydrophobic nature of the silicalite structure and the presence of hydrophilic surface sites, water molecules are capable of penetrating the porous silicalite system, where they form an H-bonded network blocking further access to the bulk. Water uptake by the zeolite was computed to be small in the time-scale of the simulations. The vibrational dynamics of the surface OH groups and adsorbed water molecules is discussed in detail. In agreement with the results of spectroscopic experiments, water molecules in the ordered surface layer have a spectral signature different from that of molecules more distant from the surface. PMID- 28079201 TI - The driving force for Pi-bond localization and bond alternation in trisannelated benzenes. AB - To investigate the factors that may cause bond length alternation and pi-bond localization in annelated benzenes, ab initio valence bond calculations were performed. The results reveal that the bond length alternation of annelated benzene is determined by the strain-induced hybridization change from the partially optimized geometries, in which the central benzene ring is constrained to a regular hexagon, to the equilibrium geometries rather than the previously recognized re-hybridization effect that the carbon atoms in the central ring are deviated from sp2 hybridization. Meanwhile, the pi-pi interaction also provides a sort of driving force, which facilitates bond length alternation, which in turn magnifies pi-bond localization. A subsequent potential energy curve study shows that sigma-strain and pi-pi interactions have different mechanisms for the effect. PMID- 28079202 TI - Oligomer formation of a tea polyphenol, EGCG, on its sensing molecule 67 kDa laminin receptor. AB - Green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) has been attributed to the activation of its cell surface sensing receptor 67 kDa laminin receptor (67LR). However, the action of EGCG to activate 67LR remains unknown. Here we show that EGCG undergoes oligomer formation on its surface receptor 67LR. PMID- 28079203 TI - Complexation of short ds RNA/DNA oligonucleotides with Gemini micelles: a time resolved SAXS and computational study. AB - Gene therapy is based on nucleic acid delivery to pathogenic cells in order to modulate their gene expression. The most used non viral vectors are lipid-based nanoaggregates, which are safer than viral carriers and have been shown to assemble easily with both DNA and RNA. However, the transfection efficiency of non viral carriers still needs to be improved before intensive practise in clinical trials can be implemented. For this purpose, the in depth characterization of the complexes formed by nucleic acids and their transporters is of great relevance. In particular, information on the structure and assembly mechanism can be useful to improve our general knowledge of these artificial transfection agents. In this paper, the complexation mechanism of short interfering RNA and DNA molecules (siRNA and siDNA, respectively) with cationic micelles is investigated by combining small angle X-ray scattering experiments and molecular dynamics simulations. Micelles were obtained by Gemini surfactants with different spacer lengths (12-3-12, 12-6-12). The siRNA and siDNA used were double strand molecules characterized by the same length and homologous sequence, in order to perform a close comparison. We showed that complexes appear in solution immediately after mixing and, therefore, the investigation of complex formation requires fast experimental techniques, such as time resolved synchrotron SAXS (Tr-SAXS). The obtained systems had internal arrangement constituted by layers of squeezed micelles alternating the nucleic acids. Both SAXS and MD analyses allowed us to evaluate the mean size of complexes in the range of a few nanometers, with looser and less ordered stacking for the DNA containing aggregates. PMID- 28079204 TI - Quantum ergodicity breaking in semi-classical electron transfer dynamics. AB - Can the statistical properties of single-electron transfer events be correctly predicted within a common equilibrium ensemble description? This fundamental in nanoworld question of ergodic behavior is scrutinized within a very basic semi classical curve-crossing problem. It is shown that in the limit of non-adiabatic electron transfer (weak tunneling) well-described by the Marcus-Levich-Dogonadze (MLD) rate the answer is yes. However, in the limit of the so-called solvent controlled adiabatic electron transfer, a profound breaking of ergodicity occurs. Namely, a common description based on the ensemble reduced density matrix with an initial equilibrium distribution of the reaction coordinate is not able to reproduce the statistics of single-trajectory events in this seemingly classical regime. For sufficiently large activation barriers, the ensemble survival probability in a state remains nearly exponential with the inverse rate given by the sum of the adiabatic curve crossing (Kramers) time and the inverse MLD rate. In contrast, near to the adiabatic regime, the single-electron survival probability is clearly non-exponential, even though it possesses an exponential tail which agrees well with the ensemble description. Initially, it is well described by a Mittag-Leffler distribution with a fractional rate. Paradoxically, the mean transfer time in this classical on the ensemble level regime is well described by the inverse of the nonadiabatic quantum tunneling rate on a single particle level. An analytical theory is developed which perfectly agrees with stochastic simulations and explains our findings. PMID- 28079205 TI - Reversible control of solubility using functionalized nanoparticles. AB - The paper provides a novel method for the reversible control of solubility by use of functionalized nanoparticles. The nanoparticles are functionalized with functional groups that can act as a co-solvent or anti-solvent and thus can induce either dissolution or crystallization. The process is reversible, as the solution will go back to its original state when the nanoparticles are removed. The use of magnetic nanoparticles facilitates this reversibility. Reductions in solubility (and thus crystallization) were demonstrated for d-mannitol-water, sodium chloride-water and fenofibrate-ethyl acetate systems. An increase in solubility (and thus dissolution) was demonstrated for the benzoic acid-water system and the 4-nitrophenol-water system. Reversible manipulation of solubility can be used to reduce solvent usage in dissolution and crystallization by elimination of the need for an antisolvent or co-solvent. PMID- 28079206 TI - Freestanding MoO2/Mo2C imbedded carbon fibers for Li-ion batteries. AB - Flexible and freestanding MoO2/Mo2C imbedded carbon fibers (MoO2/Mo2C ICFs) have been successfully synthesized via an integrated procedure including electrospinning, thermo-plastication in air and reduction/carbonization at high temperature. A series of techniques such as SEM, TEM, N2 adsorption-desorption analysis, XRD, TGA, IR and XPS have been employed to systemically characterize the MoO2/Mo2C ICFs. In particular, it is observed that the MoO2/Mo2C ICFs derived from phosphomolybdic acid have more highly porous structures than those derived from molybdic acid. Most impressively, the obtained MoO2/Mo2C ICFs are directly used as binder- and current collector-free anode materials for LIBs, which exhibit desirable rate capability and satisfactory cycling performance. The electrochemical investigations illustrated that the MoO2/Mo2C ICFs could deliver an initial discharging capacity of 1422.0 mA h g-1 with an original coulombic efficiency of 63.3%, and the subsequent reversible capacity could reach as high as 1103.6 mA h g-1 even after 70 cycles at a current density of 0.1 A g-1. Such a capacity is larger than the theoretical capacity of MoO2 (838 mA h g-1) and pure carbon fibers (460.5 mA h g-1). More importantly, the MoO2/Mo2C ICFs exhibited an excellent rate performance with a capacity of 445.4 mA h g-1 even at a charging current density of 1.6 A g-1. The remarkable enhancement in rate capability and long cycling performance resulted from a synergistic effect between the MoO2 nanoparticles and porous carbon fiber matrix. This methodology can be widely extended to fabricate other metal oxide/carbon composites for significant energy storage and conversion applications. PMID- 28079207 TI - Hysteresis phenomena in perovskite solar cells: the many and varied effects of ionic accumulation. AB - The issue of hysteresis in perovskite solar cells has now been convincingly linked to the presence of mobile ions within the perovskite layer. Here we test the limits of the ionic theory by attempting to account for a number of exotic characterization results using a detailed numerical device model that incorporates ionic charge accumulation at the perovskite interfaces. Our experimental observations include a temporary enhancement in open-circuit voltage following prolonged periods of negative bias, dramatically S-shaped current voltage sweeps, decreased current extraction following positive biasing or "inverted hysteresis", and non-monotonic transient behaviours in the dark and the light. Each one of these phenomena can be reproduced and ultimately explained by our models, providing further evidence for the ionic theory of hysteresis as well as valuable physical insight into the factors that coincide to bring these phenomena about. In particular we find that both interfacial recombination and carrier injection from the selective contacts are heavily affected by ionic accumulation, and are essential to explaining the non-monotonic voltage transients and S-shaped J-V curves. Inverted hysteresis is attributed to the occurrence of "positive" ionic accumulation, which may also be responsible for enhancing the stabilized open-circuit voltage in some perovskite cells. PMID- 28079208 TI - Controlled assembly of single colloidal crystals using electro-osmotic micro pumps. AB - We assemble charged colloidal spheres at deliberately chosen locations on a charged unstructured glass substrate utilizing ion exchange based electro-osmotic micro-pumps. Using microscopy, a simple scaling theory and Brownian dynamics computer simulations, we systematically explore the control parameters of crystal assembly and the mechanisms through which they depend on the experimental boundary conditions. We demonstrate that crystal quality depends crucially on the assembly distance of the colloids. This is understood as resulting from the competition between inward transport by the electro-osmotic pump flow and the electro-phoretic outward motion of the colloids. Optimized conditions include substrates of low and colloids of large electro-kinetic mobility. Then a sorting of colloids by size is observed in binary mixtures with larger particles assembling closer to the ion exchanger beads. Moreover, mono-sized colloids form defect free single domain crystals which grow outside a colloid-free void with facetted inner crystal boundaries centered on the ion exchange particle. This works remarkably well, even with irregularly formed ion exchange resin splinters. PMID- 28079209 TI - Dynamic phase change and local structures in IL-containing mixtures: classical MD simulations and experiments. AB - The dynamic phase change between a homogeneous mixture and a liquid-liquid biphase and separation of phases are explored in three-component mixtures composed of 1-butyl-3-methylimidazolium hexafluorophosphate ([Bmim][PF6]), 1 butyl-3-methylimidazolium tetrafluoroborate ([Bmim][BF4]), and water through a classical simulation method and experiment. Different experimental and theoretical tools, including density measurement, dynamic light scattering study, radial distribution, mean square displacement, an interstice model, and statistical function, are used to describe the structural modifications of the ions as a function of solution concentration. An analysis of the relation between the phase and the state of the component ions indicates that the phase separation pattern is governed by the hydrophilicity/hydrophobicity of anions. We proposed the existence of a critical point, that is, 1 : 3 : 8 for [Bmim][PF6]/[Bmim][BF4]/H2O (mole fraction). Before this critical point, obvious phase separation was seen in the mixtures. The separation phase became homogeneous with the addition of [Bmim][BF4] after this critical point. However, this homogeneous mixed solution was phase separated again upon the addition of [Bmim][PF6] or water. The existing nanostructures were present in the [Bmim][PF6]/[Bmim][BF4]/H2O mixtures, and their size abruptly decreased close to the critical point. We provided evidence of the formation of double salt ionic liquids of [Bmim][PF6]0.25[BF4]0.75.2H2O and discussed the interactions involved in these systems by examining their physicochemical properties. The ionic phase response of such three-component mixtures could be useful in various applications, especially in the dynamic control of extraction/separation processing. PMID- 28079210 TI - Probing nonlinear optical coefficients in self-assembled peptide nanotubes. AB - Self-assembled l,l-diphenylalanine (FF) peptide micro/nanotubes represent a class of biomimetic materials with a non-centrosymmetric crystal structure and strong piezoelectricity. The peptide nanotubes synthesized by a liquid phase method yield tube lengths in the hundreds of micron range, inner diameters in the few hundred nanometer range, and outer diameters in the 5-15 MUm range. Second harmonic generation (SHG) polarimetry from individual self-assembled FF nanotubes is used to obtain the nonlinear (NLO) optical coefficients as a function of the tube diameter and thermal treatment. The ratio of the shear to the longitudinal component (d15/d33) of the NLO coefficient increases with the diameter of the tubes. One of the transverse components of the nonlinear coefficient is found to be negative, and its magnitude with respect to the longitudinal component increases with the tube diameter. Thermal treatment of individual FF tubes has a similar effect upon increasing the diameter of the tubes in SHG polarimetry. Concurrent Raman scattering measurements from individual FF tubes show a distinct change in the low frequency (100 cm-1) region with the diameter of the tubes reflecting subtle effects of water. PMID- 28079211 TI - Electrolyte-controlled discharge product distribution of Na-O2 batteries: a combined computational and experimental study. AB - Tuning the composition of discharge products is an important strategy to reduce charge potential, suppress side reactions, and improve the reversibility of metal oxygen batteries. In the present study, first-principles calculations and experimental confirmation were performed to unravel the influence of O2 pressure, particle size, and electrolyte on the composition of charge products in Na-O2 batteries. The electrolytes with medium and high donor numbers (>12.5) are favorable for the formation of sole NaO2, while those with low donor numbers (<12.5) may permit the formation of Na2O2 by disproportionation reactions. Our comparative experiments under different electrolytes confirmed the calculation prediction. Our calculations indicated that O2 pressure and particle size hardly affect discharge products. On the electrode, only one-electron-transfer electrochemical reaction to form NaO2 takes place, whereas two-electron-transfer electrochemical and chemical reactions to form Na2O2 and Na3O4 are prevented in thermodynamics. The present study explains why metastable NaO2 was identified as a sole discharge product in many experiments, while thermodynamically more stable Na2O2 was not observed. Therefore, to achieve low overpotential, a high-donor number electrolyte should be applied in the discharge processes of Na-O2 batteries. PMID- 28079212 TI - Direct digestion of living cells via a gel-based strategy for mass spectrometric analysis. AB - A novel sample preparation method was established for proteomic analysis, during which living cells were absorbed into vacuum-dried polyacrylamide gel and directly digested into peptides for subsequent LC-MS/MS assays. As a consequence, both of the steps for cell lysis and protein extraction involved in a conventional digestion method were skipped. PMID- 28079213 TI - A computational mechanistic investigation into the reduction of Pt(iv) prodrugs with two axial chlorides by biological reductants. AB - It is widely reported that the Pt(iv) prodrugs with two axial chlorido ligands are reduced by biological reductants via a chloride-bridged inner-sphere mechanism. By contrast, in this contribution, we demonstrate that although this approach might be true for the reductants with sulphur donors, the reduction by ascorbates preferentially occurs via an outer sphere mechanism. PMID- 28079214 TI - Estimating carrier relaxation times in the Ba8Ga16Ge30 clathrate in the extrinsic regime. AB - We used a semi-empirical method to extract carrier relaxation times at different temperatures (tau(T)) in thermoelectric materials from a combination of experimental results and first-principles calculations. The methodology is based on the Boltzmann transport equation formalism within the relaxation time approximation. It can be applied to single crystals and polycrystalline materials. We applied the method to investigate the electronic transport properties of the clathrate compound Ba8Ga16Ge30 type-I. The calculations indicate that the carrier relaxation process in single crystals is dominated by electron-phonon scattering (tau ? T-3/2), while in polycrystalline materials scattering at grain boundaries dominates (tau ~ cte). The Seebeck coefficient, electrical conductivity, and electron heat conduction are in consistent agreement with experiment. Furthermore, the Slack relation for lattice heat conductivity was successfully applied to the material. The calculated figure of merit is in good agreement with experimental results. PMID- 28079215 TI - Selective-releasing-affected lubricant mechanism of a self-assembled MoS2/Mo-S-C nanoperiod multilayer film sliding in diverse atmospheres. AB - A self-assembled MoS2/Mo-S-C multilayer film prepared by r.f. co-sputtering of MoS2 and graphite targets was tribotested in diverse sliding atmospheres, and the lubricant mechanism and its correlations to the selective releasing behavior of non-lubricant component were analyzed in detail. Based on the analysis of composition and structural transformation of transferred materials by Raman and HRTEM characterizations, selective releasing behavior according to the sliding atmospheres were found to be particularly apparent in vacuum and dry inert atmospheres. Under these conditions, a-C in graphitic form was selectively released outwards from the topmost surfaces of contacts, leaving MoS2 layers finely reordered in (002) orientation playing a lubricant role. Composition and structural transformation were observed not only on the topmost surface of wear track but also on the underlying layer at a thickness of tens of nanometers. Moreover, it was found that the selective releasing of a-C initiated from the center of contacts with higher pressure, and then developed toward the edges, resulting in a gradual change in the composition and microstructure of the transferred materials from the well-aligned MoS2 layers in the center to the graphitic a-C dominant composites at the edges. The short running-in periods and low-friction performance in all the tribotests suggested that the initial preference of MoS2-riched sublayers in (002) orientation may facilitate the formation of shearless tribofilms and therefore provide a feasible way of structural tailoring in the MoS2-based lubricant films for an improved triboactive response. PMID- 28079216 TI - One-step hydroprocessing of fatty acids into renewable aromatic hydrocarbons over Ni/HZSM-5: insights into the major reaction pathways. AB - For high caloricity and stability in bio-aviation fuels, a certain content of aromatic hydrocarbons (AHCs, 8-25 wt%) is crucial. Fatty acids, obtained from waste or inedible oils, are a renewable and economic feedstock for AHC production. Considerable amounts of AHCs, up to 64.61 wt%, were produced through the one-step hydroprocessing of fatty acids over Ni/HZSM-5 catalysts. Hydrogenation, hydrocracking, and aromatization constituted the principal AHC formation processes. At a lower temperature, fatty acids were first hydrosaturated and then hydrodeoxygenated at metal sites to form long-chain hydrocarbons. Alternatively, the unsaturated fatty acids could be directly deoxygenated at acid sites without first being saturated. The long-chain hydrocarbons were cracked into gases such as ethane, propane, and C6-C8 olefins over the catalysts' Bronsted acid sites; these underwent Diels-Alder reactions on the catalysts' Lewis acid sites to form AHCs. C6-C8 olefins were determined as critical intermediates for AHC formation. As the Ni content in the catalyst increased, the Bronsted-acid site density was reduced due to coverage by the metal nanoparticles. Good performance was achieved with a loading of 10 wt% Ni, where the Ni nanoparticles exhibited a polyhedral morphology which exposed more active sites for aromatization. PMID- 28079217 TI - Cisplatin-induced self-assembly of graphene oxide sheets into spherical nanoparticles for damaging sub-cellular DNA. AB - This report describes the hitherto unobserved cisplatin induced self-assembly of 2D-graphene oxide sheets into 3D-spherical nano-scale particles. These nanoparticles can encompass dual DNA damaging drugs simultaneously. A combination of confocal microscopy, gel electrophoresis and flow cytometry studies clearly demonstrated that these novel nanoparticles can internalize into cancer cells by endocytosis, localize into lysosomes, and damage DNA, leading to apoptosis. Cell viability assays indicated that these nanoparticles were more cytotoxic towards cancer cells compared to healthy cells. PMID- 28079219 TI - Internal dynamics in helical molecules studied by X-ray diffraction, NMR spectroscopy and DFT calculations. AB - The conformational behaviour of a prototype helical molecule, [6]helicene, and its derivatives was studied in solution and the solid state. Available crystal structures of [6]helicene revealed surprisingly large flexibility of this molecule and variable-temperature NMR experiments provided unusual temperature dependence of chemical shifts of hydrogen, carbon and fluorine atoms in the peripheral aromatic rings of [6]helicene and tetrafluoro[6]helicene. These chemical shift changes were interpreted as a consequence of the helicene 'pitch' opening with elevated temperature, and the experimental data were corroborated by DFT calculations of the chemical shift dependence on the helicene conformation and by variable-temperature DFT molecular dynamics simulations. PMID- 28079218 TI - Zinc ion-induced conformational changes in new Delphi metallo-beta-lactamase 1 probed by molecular dynamics simulations and umbrella sampling. AB - The hydrolysis of a beta-lactam core ring caused by new Delphi metallo-beta lactamase 1 (NDM-1) with the help of two zinc cofactors induces significant resistance toward beta-lactam antibiotics. Molecular dynamics (MD) simulations and the umbrella sampling method are integrated to study the conformational change mechanism of NDM-1 mediated by zinc ion binding. The statistical analyses of interaction contacts of the antibiotic ampicillin (AMP) with residues based on MD trajectories suggest that two Zn ions are essential for maintaining the binding of AMP with NDM-1. Umbrella sampling simulations further reveal that double-Zn coordination exerts strong restriction on the motions of loop L10 relative to loops L3 and L4. Principal component (PC) analysis also demonstrates that zinc ion binding totally inhibits the motion extent of NDM-1 and changes internal motion modes in NDM-1. We expect that the current study can provide significant dynamical information involving conformational changes of NDM-1 for the development of efficient inhibitors to decrease drug resistance of NDM-1 toward antibiotics. PMID- 28079220 TI - Facile pentagon formation in the dissociation of polyaromatics. AB - Energetic processing of gaseous polycyclic aromatic hydrocarbons (PAHs) plays a pivotal role in the chemistries of inter- and circumstellar environments, certain planetary atmospheres, and also in the chemistry of combustion and soot formation. Although the precursor PAH species have been extensively characterized, the products from these gaseous breakdown reactions have received far less attention. It has been particularly challenging to accurately determine their molecular structure in gas-phase experiments, where comparisons against theoretical modeling are best made. Here we report on a combined experimental and theoretical study of the dissociative ionization of two nitrogen containing polycyclic aromatic hydrocarbons of C13H9N composition, acridine and phenanthridine. The structures of HCN-loss fragments are resolved by infrared multiple-photon dissociation (IRMPD) spectroscopy of the mass-isolated products in an ion trap mass spectrometer. Quantum-chemical computations as well as reference IRMPD spectra are employed to unambiguously identify the molecular structures. Furthermore, computations at the density functional level of theory provide insight into chemical pathways leading to the observed products. Acenaphthylene+ and benzopentalene+ - two aromatic species containing pentagons - are identified as the main products, suggesting that such species are easily formed and may be abundant in regions where thermal or photoprocessing of polyaromatics occurs. PMID- 28079221 TI - Sizing and Eddy currents in magnetic core nanoparticles: an optical extinction approach. AB - Optical extinction is a handy and ubiquitous technique that allows us to study colloidal nanoparticles in their native state. The typical analysis of the extinction spectrum can be extended in order to obtain structural information of the sample such as the size distribution of the cores and the thickness of the coating layers. In this work the extinction spectra of Fe3O4, Fe3O4@Au, and Fe3O4@SiO2@Au single and multilayer nanoparticles are obtained by solving full Mie theory with a frequency dependent susceptibility derived from the Gilbert equation and considering the effect of Eddy currents. The results are compared with non-magnetic Mie theory, magnetic dipolar approximation and magnetic Mie theory without Eddy currents. The particle size-wavelength ranges of validity of these different approaches are explored and novel results are obtained for Eddy current effects in optical extinction. These results are used to obtain particle size and shell thickness information from the experimental extinction spectra of Fe3O4 and Fe3O4@Au nanoparticles in good agreement with TEM results, and to predict the plasmon peak parameters for Fe3O4@SiO2@Au three layer nanoparticles. PMID- 28079222 TI - Infrared characterisation of acetonitrile and propionitrile aerosols under Titan's atmospheric conditions. AB - Pure, crystalline acetonitrile (CH3CN) and propionitrile (CH3CH2CN) particles were formed in a collisional cooling cell allowing for infrared (IR) signatures to be compiled from 50 to 5000 cm-1. The cell temperature and pressure conditions were controlled to simulate Titan's lower atmosphere (80-130 K and 1-100 mbar), allowing for the comparison of laboratory data to the spectra obtained from the Cassini-Huygens mission. The far-IR features confirmed the morphology of CH3CN aerosols as the metastable beta-phase (monoclinic) ice, however, a specific crystalline phase for CH3CH2CN could not be verified. Mie theory and the literature complex refractive indices enabled of the experimental spectra to be modelled. The procedure yielded size distributions for CH3CN (55-140 nm) and CH3CH2CN (140-160 nm) particles. Effective kinetic profiles, tracing the evolution of aerosol band intensities, showed that condensation of CH3CH2CN proceeded at twice the rate of CH3CN aerosols. In addition, the rate of CH3CH2CN aerosol depletion via lateral diffusion of the particles from the interrogation volume was approximately 50% faster than that of CH3CN. The far-IR spectra recorded for both nitrile aerosols did not display absorption profiles that could be attributed to the unassigned 220 cm-1 feature, which has been observed to fluctuate seasonally in the spectra obtained from Titan's atmosphere. PMID- 28079223 TI - Ultrafast energy and electron transfers in structurally well addressable BODIPY porphyrin-fullerene polyads. AB - Two electron transfer polyads built upon [C60]-[ZnP]-[BODIPY] (1) and [ZnP] [ZnP](-[BODIPY])(-[C60]) (2), where [C60] = N-methyl-2-phenyl-3,4 fulleropyrrolidine, [BODIPY] = boron dipyrromethane, and [ZnP] = zinc(ii) porphyrin, were synthesized along with their corresponding energy transfer polyads [ZnP]-[BODIPY] (1a) and [ZnP]-[ZnP]-[BODIPY] (2a) as well as relevant models. These polyads were studied using cyclic voltammetry, DFT computations, steady state and time-resolved fluorescence spectroscopy, and fs transient absorption spectroscopy. The rates for energy transfer, kET, [BODIPY]* -> [ZnP] are ~2.8 * 1010 s-1 for both 1a and 2a, with an efficiency of 99%. Concurrently, the fast appearance of the [C60]- anion for 1 and 2 indicates that the charge separation occurs on the 20-30 ps timescale with the rates of electron transfer, ket, [ZnP]*/[C60] -> [ZnP]+/[C60]- of ~0.9 * 1010 to ~3.8 * 1010 s-1. The latter value is among the fastest for these types of polyads. Conversely, the charge recombination operates on the ns timescale. These rates are comparable to or faster than those reported for other more flexible [C60]-[ZnP]-[BODIPY] polyads, which can be rationalized by the donor-acceptor separations. PMID- 28079224 TI - Suitability of N-propanoic acid spiropyrans and spirooxazines for use as sensitizing dyes in dye-sensitized solar cells. AB - This work deals with the fabrication and evaluation of color-changing dye sensitized solar cells (DSSCs) that include N-propanoic acid-functionalized spiropyrans and spirooxazines as sensitizing dyes. We investigated the photophysical properties of these compounds in various solvents and pH conditions using UV-Vis spectroscopy, and their behavior on TiO2 photoanode surfaces using a combination of UV-Vis and FT-IR. Their performance as sensitizing dyes for DSSCs was also analyzed. This study revealed a number of unique properties for this class of compounds that affect their performance as both photochromic compounds and DSSC sensitizers, which allow for future creation of efficient photochromic DSSCs. PMID- 28079225 TI - Bioconjugation strategies to couple supramolecular exo-functionalized palladium cages to peptides for biomedical applications. AB - Supramolecular Pd2L4 cages (L = ligand) hold promise as drug delivery systems. With the idea of achieving targeted delivery of the metallacages to tumor cells, the bioconjugation of exo-functionalized self-assembled Pd2L4 cages to peptides following two different approaches is reported for the first time. The obtained bioconjugates were analyzed and identified by high-resolution mass spectrometry. PMID- 28079226 TI - In silico kinetics of alkaline hydrolysis of 1,3,5-trinitro-1,3,5-triazinane (RDX): M06-2X investigation. AB - Alkaline hydrolysis of RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine), as one of the most promising methods for nitrocompound remediation, was investigated computationally at the PCM(Pauling)/M06-2X/6-311++G(d,p) level of theory. Computational simulation shows that RDX hydrolysis is a highly exothermic multistep process involving initial deprotonation and nitrite elimination, cycle cleavage, further transformation of cycle-opened intermediates to end products caused by a series of C-N bond ruptures, hydroxide attachments, and proton transfers. Computationally predicted products of RDX hydrolysis such as nitrite, nitrous oxide, formaldehyde, formate, and ammonia correspond to experimentally observed ones. Accounting of specific hydration of hydroxide is critical to create an accurate kinetic model for alkaline hydrolysis. Simulated kinetics of the hydrolysis are in good agreement with available experimental data. A period of one month is necessary for 99% RDX decomposition at pH 10. Computations predict significant increases of the reaction rate of hydrolysis at pH 11, pH 12, and pH 13. PMID- 28079227 TI - Excited state properties of beta-carotene analogs incorporating a lactone ring. AB - Carotenoids possessing a carbonyl group along their polyene backbone exhibit unique excited state properties due to the occurrence of intramolecular charge transfer (ICT) in the excited state. In fact, the ICT characteristics of naturally occurring carbonyl carotenoids play an essential role in the highly efficient energy transfer that proceeds in aquatic photosynthetic antenna systems. In the present study, we synthesized two short-chain polyene carotenoids incorporating a lactone ring, denoted as BL-7 and BL-8, having seven and eight conjugated double bonds (n = 7 and 8), respectively. The excited state properties of these compounds were directly compared to those of their non-carbonyl counterparts to clarify the role of the carbonyl group in the generation of ICT. The energies of the optically allowed S2 states for BL-7 and BL-8 were found to be more than 0.3 eV (2400 cm-1) below those of non-carbonyl short beta-carotene homologs. Ultrafast spectroscopic data demonstrated various solvent polarity induced effects, including the appearance of stimulated emission in the near-IR region in the case of BL-7, and significant lifetime shortening of the lowest lying singlet S1 excited states of both BL-7 and BL-8. These results suggest that these compounds exhibit ICT characteristics. PMID- 28079228 TI - Attenuated recovery of contractile function in aging hearts following global ischemia/reperfusion: Role of extracellular HSP27 and TLR4. AB - BACKGROUND: While cardiac functional recovery is attenuated in the elderly following cardiac surgery with obligatory global myocardial ischemia/reperfusion (I/R), the underlying mechanism remains incompletely understood. We observed previously that human and mouse myocardium releases heat shock protein (HSP) 27 during global I/R. Extracellular HSP27 induces myocardial inflammatory response and plays a role in post-ischemic cardiac dysfunction in adult mouse hearts. OBJECTIVE: This study was to determine the role of extracellular HSP27 and Toll like receptor 4 (TLR4) in the attenuated functional recovery in aging mouse hearts following global I/R. METHODS AND RESULTS: Hearts isolated from aging (18 24 months) and adult (4-6 months) mice were subjected to ex vivo global I/R. Augmented release of HSP27 in aging hearts is associated with greater production of cytokines (TNF-alpha and IL-1beta) and worse functional recovery. Anti-HSP27 suppressed the inflammatory response and markedly improved functional recovery in aging hearts. Perfusion of recombinant HSP27 to aging hearts resulted in greater cytokine production and more severe contractile depression in comparison to adult hearts. TLR4 deficiency abolished cytokine production and functional injury in aging hearts exposed to recombinant HSP27. Interestingly, aging hearts had higher TLR4 protein levels and displayed enhanced TLR4-mediated NF-kappaB activation following HSP27 stimulation or I/R. CONCLUSION: Extracellular HSP27 and TLR4 jointly enhance the inflammatory response and hamper functional recovery following I/R in aging hearts. The enhanced inflammatory response to global I/R and attenuated post-ischemic functional recovery in aging hearts is due, at least in part, to augmented myocardial release of HSP27 and elevated myocardial TLR4 levels. PMID- 28079230 TI - "Doctor of men and souls". PMID- 28079231 TI - Primary neuroendocrine neoplasm of the esophagus - Report of 14 cases from a single institute and review of the literature. AB - BACKGROUND: : Most prevalent esophageal neoplasm is squamous cell carcinoma and adenocarcinoma. Other tumors are uncommon and poorly studied. Primary neuroendocrine esophageal neoplasm is a rare carcinoma and most of its therapy management is based on lung neuroendocrine studies. Neuroendocrine tumors can be clustered in the following subtypes: high grade (small cell carcinoma or large cell carcinoma) and low grade (carcinoids). OBJECTIVE:: The present study aims to assess clinical and pathological neuroendocrine esophageal tumors in a single oncologic center. METHODS:: A retrospective analysis of patients and review of the literatures was performed. RESULTS:: Fourteen patients were identified as neuroendocrine tumors, 11 male and 3 female patients. Mean age was 67.3 years old. Ten patients were classified as small cell, 3 as large cell and 1 as carcinoid. Four patients presented squamous cell carcinoma simultaneously and 1 also presented adenocarcinoma. Main sites of metastasis were liver, peritoneum, lung and bones. Most patients died before 2 years of follow-up. Patient with longer survival died at 35 months after diagnosis. CONCLUSION:: Neuroendocrine esophageal tumors are rare; affect mainly men in their sixties or seventies. High grade tumors can be mixed to other subtypes neoplasms, such as adenocarcinoma and squamous cell carcinoma. Most of these patients have poor overall survival rates. PMID- 28079229 TI - The transcription factor XBP1 in memory and cognition: Implications in Alzheimer disease. AB - X-box binding protein 1 (XBP1) is a unique basic region leucine zipper transcription factor isolated two decades ago in a search for regulators of major histocompatibility complex class II gene expression. XBP1 is a very complex protein regulating many physiological functions, including immune system, inflammatory responses, and lipid metabolism. Evidence over the past few years suggests that XBP1 also plays important roles in pathological settings since its activity as transcription factor has profound effects on the prognosis and progression of diseases such as cancer, neurodegeneration, and diabetes. Here we provide an overview on recent advances in our understanding of this multifaceted molecule, particularly in regulating synaptic plasticity and memory function, and the implications in neurodegenerative diseases with emphasis on Alzheimer disease. PMID- 28079232 TI - Predictive features for histology of gastric subepithelial lesions. AB - BACKGROUND : - Gastric subepithelial lesion is a relatively common diagnosis after routine upper endoscopy. The diagnostic workup of an undetermined gastric subepithelial lesion should take into consideration clinical and endoscopic features. OBJECTIVE: - We aimed to investigate the association between patients' characteristics, endoscopic and echographic features with the histologic diagnosis of the gastric subepithelial lesions. METHODS: - This is a retrospective study with 55 patients, who were consecutively diagnosed with gastric subepithelial lesions, from October 2008 to August 2011. Patients' characteristics, endoscopic and echografic features of each gastric subepithelial lesion were analysed. Histologic diagnosis provided by EUS-guided fine needle aspiration or endoscopic/surgical resection was used as gold standard. RESULTS: - The probability of gastrointestinal stromal tumors to be located in the cardia was low (4.5%), while for leiomyoma it was high (>95%). In addition, there was a higher risk of gastrointestinal stromal tumors in patients older than 57 years (OR 8.9; 95% CI), with lesions >=21 mm (OR 7.15; 95% CI), located at 4th layer (OR 18.8; 95% CI), with positive Doppler sign (OR 9; 95% CI), and irregular outer border (OR 7.75; 95% CI). CONCLUSION: - The location of gastric subepithelial lesions in the gastric cardia lowers the risk of gastrointestinal stromal tumors. While gastric subepithelial lesions occurring in elderly patients, located in the gastric body, with positive Doppler signal and irregular outer border increase the risk of gastrointestinal stromal tumors. PMID- 28079233 TI - Suspected blood indicator in capsule endoscopy: a valuable tool for gastrointestinal bleeding diagnosis. AB - BACKGROUND: Small bowel bleeding is a leading indication for small bowel capsule endoscopy. The Suspected Blood Indicator (SBI) is a software feature directed to automatically detect bleeding lesions during small bowel capsule endoscopy. OBJECTIVE: - We aimed to assess SBI diagnostic accuracy for small bowel haemorrhage or potentially bleeding lesions during small bowel capsule endoscopy for small bowel bleeding. Methods - Single-centre retrospective study including 281 consecutive small bowel capsule endoscopy performed for small bowel bleeding during 6 years. The investigators marked lesions with high bleeding potential (P2), such as angioectasias, ulcers and tumours, as well as active bleeding during regular small bowel capsule endoscopy viewing with PillCam SB2(r). All small bowel capsule endoscopy were independently reviewed by another central reader using SBI. RESULTS: - Among the 281 patients, 29 (10.3%) presented with active haemorrhage while 81 (28.9%) presented with a P2 lesion. The most frequently observed P2 lesions were angioectasias (52), ulcers (15), polyps (7) and ulcerated neoplasias (7). SBI showed a 96.6% (28/29) sensitivity for active small bowel bleeding, with a 97.7% negative predictive value. Regarding P2 lesions, the SBI displayed an overall sensitivity of 39.5%, being highest for ulcerated neoplasias (100%), but significantly lower for angioectasias (38.5%) or ulcers (20.0%). CONCLUSION: Although SBI sensitivity for the automatic detection of potentially bleeding lesions was low, it effectively detected active small bowel bleeding with very high sensitivity and negative predictive value. PMID- 28079234 TI - Evaluation of endoscopic secondary prophylaxis in children and adolescents with esophageal varices. AB - BACKGROUND: - Bleeding of esophageal varices is the main cause of morbidity and mortality in children and adults with portal hypertension and there are few studies involving secondary prophylaxis in children and adolescents. OBJECTIVE: - To evaluate the efficacy of endoscopic secondary prophylaxis in prevention of upper gastrointestinal bleeding in children and adolescents with esophageal varices. METHODS: - This is a prospective analysis of 85 patients less than 18 years of age with or without cirrhosis, with portal hypertension. Participants underwent endoscopic secondary prophylaxis with sclerotherapy or band ligation. Eradication of varices, incidence of rebleeding, number of endoscopic sessions required for eradication, incidence of developing gastric fundus varices and portal hypertensive gastropathy were evaluated. RESULTS: - Band ligation was performed in 34 (40%) patients and sclerotherapy in 51 (60%) patients. Esophageal varices were eradicated in 81.2%, after a median of four endoscopic sessions. Varices relapsed in 38 (55.1%) patients. Thirty-six (42.3%) patients experienced rebleeding, and it was more prevalent in the group that received sclerotherapy. Gastric varices and portal hypertensive gastropathy developed in 38.7% and 57.9% of patients, respectively. Patients undergoing band ligation showed lower rebleeding rates (26.5% vs 52.9%) and fewer sessions required for eradication of esophageal varices (3.5 vs 5). CONCLUSION: - Secondary prophylaxis was effective in eradicating esophageal varices and controlling new upper gastrointestinal bleeding episodes due to the rupture of esophageal varices. Band ligation seems that resulted in lower rebleeding rates and fewer sessions required to eradicate varices than did sclerotherapy. PMID- 28079235 TI - Quality of life in swallowing of the elderly patients affected by stroke. AB - BACKGROUND: - The elderly population faces many difficulties as a result of the aging process. Conceptualize and evaluate their life quality is a challenge, being hard to characterize the impact on daily activities and on functional capacity. The stroke is one of the most disabling neurological diseases, becoming a public health problem. As an aggravating result, there is dysphagia, a disorder that compromises the progression of the food from the mouth to the stomach, causing clinical complications to the individual. OBJECTIVE: - Characterize the life quality of the elderly swallowing affected by stroke. METHODS: - Cross sectional study conducted at the University Hospital, attended by 35 elderly with stroke, being 19 women and 16 men, with age between 60 and 90 years old, that self-reported satisfactory overall clinical picture. It was applied the Quality of Life Swallowing protocol. The data were statistically analyzed, by means of ANOVA tests, Spearman correlation, t test, with significance level of 5%. RESULTS: - The mean age was 69.5 years; as for the scores obtained by the 35 participants in the 11 domains of the protocol, it was observed a change in score indicating severe to moderate impact in quality of life related to self-reported swallowing (31.8% to 59.5%); the domain that most interfered was the feeding time (31.8%). CONCLUSION: - Elderly affected by stroke that present dysphagia has low scores in quality of life related to swallowing. PMID- 28079236 TI - Residual gastric volume evaluation with ultrasonography after ingestion of carbohydrate- or carbohydrate plus glutamine-enriched beverages: a randomized, crossover clinical trial with healthy volunteers. AB - BACKGROUND: - Abbreviation of preoperative fasting to 2 hours with maltodextrin (CHO)-enriched beverage is a safe procedure and may enhance postoperative recovery. Addition of glutamine (GLN) to CHO beverages may include potential benefits to the metabolism. However, by adding a nitrogenous source to CHO beverages, gastric emptying may be delayed and increase the risk of bronchoaspiration during anesthesia. OBJECTIVE: - In this study of safety, we aimed at investigating the residual gastric volume (RGV) 2 hours after the intake of either CHO beverage alone or CHO beverage combined with GLN. METHODS: - We performed a randomized, crossover clinical trial. We assessed RGV by means of abdominal ultrasonography (US) in 20 healthy volunteers (10 males and 10 females) after an overnight fast of 8 hours. Then, they were randomized to receive 600 mL (400 mL immediately after US followed by another 200 mL 2 hours afterwards) of either CHO (12.5% maltodextrin) or CHO-GLN (12.5% maltodextrin plus 15 g GLN). Two sequential US evaluations were done at 120 and 180 minutes after ingestion of the second dose. The interval of time between ingestion of the two types of beverages was 2 weeks. RESULTS: - The mean (SD) RGV observed after 8 hours fasting (13.56+/-13.25 mL) did not statistically differ (P>0.05) from the RGV observed after ingesting CHO beverage at both 120 (16.32+/-11.78 mL) and 180 minutes (14.60+/-10.39 mL). The RGV obtained at 120 (15.63+/-18.83 mL) and 180 (13.65+/-10.27 mL) minutes after CHO-GLN beverage also was not significantly different from the fasting condition. CONCLUSION: - The RGV at 120 and 180 minutes after ingestion of CHO beverage combined with GLN is similar to that observed after an overnight fast. PMID- 28079237 TI - Celiac disease prevalence is not increased in patients with functional dyspepsia. AB - BACKGROUND: - Previous evidence trying to assess the risk of celiac disease among dyspeptic patients has been inconclusive, showing in some cases notorious discrepancies. OBJECTIVE: - To determine the prevalence of celiac disease in patients with dyspepsia compared to healthy controls without dyspepsia. METHODS : - Adult patients under evaluation for dyspepsia were invited to participate. These patients were offered an upper gastrointestinal endoscopy with duodenal biopsies. On the other hand, asymptomatic adult volunteers who performed a preventive visit to their primary care physician were invited to participate and agreed to undertake an upper gastrointestinal endoscopy with duodenal biopsies as well. Those patients with histologic signs of villous atrophy were furtherly evaluated and serological tests were performed in order to determine celiac disease diagnosis. Celiac disease prevalence was compared between groups. RESULTS: - Overall, 320 patients with dyspepsia and 320 healthy controls were recruited. There were no significant differences in terms of gender or age between groups. Celiac disease diagnosis was made in 1.25% (4/320) of patients in the dyspepsia group versus 0.62% (2/320) in the control group. CONCLUSION: - Patients with dyspepsia who underwent routine duodenal biopsies did not show an increased risk for celiac disease when compared to healthy individuals. PMID- 28079238 TI - Human leukocyte antigen HLADRB1 determinants susceptibility to gastroesophageal reflux disease. AB - BACKGROUND: - Gastroesophageal reflux disease (GERD) is characterized by diverse symptoms. There is an evidence for a genetic component to GERD as supported by familial aggregation of this disease. OBJECTIVE: - To investigate whether certain human leucocyte antigen genes HLA-DRB1 are associated with GERD. METHODS: - Patients and controls were prospectively recruited from GIT center at Al-Kindy Teaching Hospital (Baghdad-Iraq) between January 2014 and July 2016. Sixty Iraqi Arab Muslims patients with a history of heartburn and dyspepsia compared with 100 Iraqi Arab Muslims controls. All study patients and control groups underwent upper gastrointestinal endoscopic examinations and their serums were analyzed for CagA antibodies Immunoglobulin G (IgG) for H. pylori. HLA-DRB1 genotyping were done to both groups. RESULTS: - A total of 60 patients with erosive gastritis; GERD (Grade II and III) were evaluated, together with 100 controls. There is a significant increase of H. pylori infection (P=0.0001) in GERD patients than control group. HLA-DRB1* 15:01 was significantly increased in GERD patients in comparison with control group and an increased frequency of HLADRB1*11:01 in control group compared with patients group. CONCLUSION: - There is an association between HLA-DRB1 *15:01 in GERD patients with H. pylori positive patients. PMID- 28079239 TI - Prevalence of dyspeptic symptoms and heartburn of adults in Belo Horizonte, Brazil. AB - BACKGROUND: - Medical literature has shown dyspepsia and heartburn-related symptoms occur among 15% to 40% of the population. These symptoms can occur at any age and are more prevalent in women. OBJECTIVE: - Investigate the prevalence of dyspeptic symptoms and heartburn among individuals over 18. METHODS: - Individuals over 18 were randomly selected in public venues in Belo Horizonte/MG to participate. A standardized questionnaire that included questions related to social-demographic characteristics, eating habits, digestive symptoms, medical appointments, medications, exams, previous surgeries and comorbidities was applied. A questionnaire about functional dyspepsia diagnosis (Rome III) was also applied. RESULTS: - A total of 548 individuals were interviewed. Among these, 58.4% were women, 59.3% were white, 55.9% were single and the average age was 36 years. Within this group, 376 individuals (68.6%) declared to have some symptom and/or use medication to relieve dyspepsia symptoms, and for these patients were applied the Rome III questionnaire. Based on the diagnostic criteria for the questionnaire proposed by the Rome III consensus, the symptom of postprandial fullness was reported by 6.7% of the individuals, early satiety (3.5%) and epigastric pain (10.6%). The overlap of these symptoms was very frequent. The prevalence of functional dyspepsia was 10.6% (postprandial discomfort syndrome (8.2%) and epigastric pain syndrome (2.4%). Among all participants, 52.5% reported heartburn, and 11.1% presented this symptom at least once a week. The most used drug was omeprazole. CONCLUSION: - The prevalence of dyspeptic symptoms and heartburn among a Brazilian adult urban population is similar to those described in other countries. PMID- 28079240 TI - New index for the diagnosis of liver fibrosis in Schistosomiasis mansoni. AB - BACKGROUND: - Periportal fibrosis is the major pathological consequence of the Schistosoma mansoni infection. OBJECTIVE: - To evaluate the accuracy of serum markers and to construct an index to assess fibrosis. METHODS: - Patients (n=116) with schistosomiasis were evaluated by ultrasound scan and measurements of serum levels of aminotransferases, gamma-glutamyl transferase, alkaline phosphatase, hyaluronic acid, cytokines and platelets. Ultrasound images were used to evaluate the fibrosis using Niamey's classification and identified 19 patients without periportal fibrosis (patterns A and B), 48 with mild to moderate fibrosis (C and D) and 49 with advanced fibrosis (E and F). RESULTS: - Using multivariate analysis, a model was created, which involved alkaline phosphatase and platelets and could separate patients with different patterns of fibrosis. This index showed a better performance in separating patients without fibrosis from with advanced periportal fibrosis. The biological index showed an area under the ROC curve of 1.000. Using values below the lowest or above the highest cut-off point, the presence or absence of advanced fibrosis could be predicted in all patients. CONCLUSION: - The index constructed can be used to separate patients with different patterns of periportal fibrosis, specially to predict advanced fibrosis in schistosomiasis patients. PMID- 28079241 TI - Is there an association between vitamin D and liver fibrosis in patients with chronic hepatitis C? AB - BACKGROUND: - Vitamin D is known for its immunomodulatory, anti-inflammatory and antifibrotic properties, which are quite relevant in the pathogenesis and treatment of many causes of chronic liver disease. OBJECTIVE: - This study aimed to evaluate the association between serum vitamin D levels and the histopathological findings in patients with chronic hepatitis C virus infection. METHODS: - Cross-sectional study composed of patients with chronic hepatitis C. All patients underwent vitamin D 25 dosage and anthropometric data analysis. Liver biopsy was performed in a maximum 36-month period before inclusion in the study. RESULTS: - Of the 74 patients included in the study, 45 (60.8%) were women, mean age was 57.03+/-9.24 years, and 63 (85.1%) were white. No association was observed between the serum levels of vitamin D and inflammatory activity (P=0.699) nor with the degree of liver fibrosis (P=0.269). CONCLUSION: - In this study, no association was observed between vitamin D and inflammatory activity, as well as the degree of liver fibrosis, in patients with chronic hepatitis C. PMID- 28079242 TI - Application of BAROS' questionnaire in obese patients undergoing bariatric surgery with 2 years of evolution. AB - BACKGROUND:: -In recent decades, the high prevalence of obesity in the general population has brought serious concerns in terms of public health. Contrarily to conventional treatment involving dieting and physical exercising, often ineffective in generating long term results, bariatric opera-tions have been an effective method for sustained weight loss in morbidly obese individuals. The Bariatric Analysis and Reporting Outcome System (BAROS) is an objective and recognized system in the overall evaluation of results after bariatric surgery. OBJECTIVE: - To investigate results concerning a casuistic of morbidly obese patients undergoing bariatric surgery over a 2-year follow-up in terms of weight loss, related medical conditions, safety and changes in quality of life. METHODS: - A total of 120 obese (17 male and 103 female) patients, who underwent bariatric surgery, were assessed and investigated using the BAROS system after a 2- year follow-up. RESULTS: - Patients obtained a mean excess weight loss of 74.6 (+/ 15.9) % and mean body mass index reduction of 15.6 (+/-4.4) Kg/m2. Pre-surgical comorbidities were present in 71 (59%) subjects and they were totally (86%) or partially (14%) resolved. Complications resulting specifically from the surgical procedure were observed in 4.2% of cases (two bowel obstructions requiring re operation, and three stomal stenosis treated with endoscopic dilation). Sixteen subjects (13% of total number of patients) presented minor clinical complications managed through outpatient care. The final scores for the BAROS questionnaire showcased excellent to good results in 99% of cases (excellent 44%, very good 38%, good 23%, acceptable 1%). CONCLUSION: - According to the BAROS questionnaire, bariatric surgery is a safe and effective method for managing obesity and associated clinical comorbidities, allowing for satisfactory results after a 2-year follow-up. Future studies should address other clinical and psychosocial variables that impact outcome as well as allow for longer follow ups. PMID- 28079243 TI - Serum levels of vitamin A, visual function and ocular surface after bariatric surgery. AB - BACKGROUND : - Bariatric surgery is the most effective treatment for severe obesity, but the surgery increases the risk of developing nutritional deficiencies, such as vitamin A deficiency. In human metabolism, vitamin A plays a role in vision. OBJECTIVE: - To evaluate serum vitamin A, visual function and ocular surface of patients undergoing bariatric surgery. METHODS: - A cross sectional and analytical study was conduced with 28 patients undergoing bariatric surgery for at least 6 months. Ophthalmologic evaluation was done through color vision test, contrast sensitivity test, ocular surface tests and confocal microscopy, as well as vitamin A serum measurement. RESULTS: - Vertical sleeve gastrectomy was performed in seven (25.0%) patients and Roux -en-Y gastric by pass in 21 (75.0%). Mean serum vitamin A level was 1.7+/-0.5 umoL/L. Most patients (60.7%) had symptoms of dry eye. Five (17.9%) patients had contrast sensitivity impairment and 18 (64.3%) color vision changes. In the group of patients undergoing Roux -en-Y gastric by-pass , mean vitamin A levels were 1.8+/ 0.6 umoL/L, whereas they were 1.7+/-0.5 umoL/L in patients submitted to the restrictive technique vertical sleeve gastrectomy . The analysis of the influence of serum levels of vitamin A in the visual function and ocular surface was performed by Pearson correlation test and there was no significant correlation between any of the variables and vitamin A. CONCLUSION: - There was no influence of the bariatric surgery technique used on serum vitamin A levels, on the visual function or on the ocular surface. Moreover, there was no correlation between serum levels of vitamin A and the visual function or the ocular surface changes. PMID- 28079244 TI - Preoperative multidisciplinary program for bariatric surgery: a proposal for the Brazilian Public Health System. AB - BACKGROUND: - Bariatric surgery has become the gold standard treatment for morbid obesity, but access to surgery remains difficult and low compliance to postoperative follow-up is common. To improve outcomes, enable access and optimize follow-up, we developed a multidisciplinary preoperative approach for bariatric surgery. OBJECTIVE: - To determine the impact of this program in the outcomes of bariatric surgery in the Brazilian public health system. METHODS: - A prospective evaluation of the individuals who underwent a preoperative multidisciplinary program for bariatric surgery and comparison of their surgical outcomes with those observed in the prospectively collected historical database of the individuals who underwent surgery before the beginning of the program. RESULTS: - There were 176 individuals who underwent the multidisciplinary program and 226 who did not. Individuals who underwent the program had significantly lower occurrence of the following variables: hospital stay; wound dehiscence; wound infection; pulmonary complications; anastomotic leaks; pulmonary thromboembolism; sepsis; incisional hernias; eventrations; reoperations; and mortality. Both loss of follow-up and weight loss failure were also significantly lower in the program group. CONCLUSION: - The adoption of a comprehensive preoperative multidisciplinary approach led to significant improvements in the postoperative outcomes and also in the compliance to the postoperative follow-up. It represents a reproducible and potentially beneficial approach within the context of the Brazilian public health system. PMID- 28079245 TI - Gastric and jejunal histopathological changes in patients undergoing bariatric surgery. AB - BACKGROUND: - Morbid obesity is a multifactorial disease that is increasingly treated by surgery. OBJECTIVE: - To evaluate gastric histopathological changes in obese, and to compare with patients who underwent gastrojejunal bypass and the jejunal mucosa after the surgery. METHODS: - This is an observational study performed at a tertiary public hospital, evaluating endoscopic biopsies from 36 preoperative patients and 35 postoperative. RESULTS: - In the preoperative group, 80.6% had chronic gastritis, which was active in 38.9% (77.1% and 20.1%, respectively, in the postoperative). The postoperative group had a significant reduction in Helicobacter pylori infection (P=0.0001). A longer length of the gastric stump and a time since surgery of more than two years were associated with Helicobacter pylori infection. The jejunal mucosa was normal in 91.4% and showed slight nonspecific chronic inflammation in 8.6%. CONCLUSION: - There was a reduction in the incidence of Helicobacter pylori infection in the postoperative group. A longer length of the gastric stump and longer time elapsed since surgery were associated with Helicobacter pylori infection. The jejunal mucosa was considered normal in an absolute majority of patients. PMID- 28079246 TI - Is total lymphocyte count related to nutritional markers in hospitalized older adults? AB - BACKGROUND: - Older patients are commonly malnourished during hospital stay, and a high prevalence of malnutrition is found in hospitalized patients aged more than 65 years. OBJECTIVE: - To investigate whether total lymphocyte count is related to other nutritional markers in hospitalized older adults. METHODS: - Hospitalized older adults (N=131) were recruited for a cross-sectional study. Their nutritional status was assessed by the Nutritional Risk Screening (NRS), anthropometry, and total lymphocyte count. The statistical analyses included the chi-square test, Fisher's exact test, and Mann-Whitney test. Spearman's linear correlation coefficient determined whether total lymphocyte count was correlated with the nutritional markers. Multiple linear regression determined the parameters associated with lymphocyte count. The significance level was set at 5%. RESULTS: - According to the NRS, 41.2% of the patients were at nutritional risk, and 36% had mild or moderate depletion according to total lymphocyte count. Total lymphocyte count was weakly correlated with mid-upper arm circumference (r=0.20507); triceps skinfold thickness (r=0.29036), and length of hospital stay (r= -0.21518). Total lymphocyte count in different NRS categories differed significantly: older adults who were not at nutritional risk had higher mean and median total lymphocyte count (P=0.0245). Multiple regression analysis showed that higher lymphocyte counts were associated with higher triceps skinfold thicknesses and no nutritional risk according to the NRS. CONCLUSION: - Total lymphocyte count was correlated with mid-upper arm circumference, triceps skinfold thickness, and nutritional risk according to the NRS. In multiple regression the combined factors that remained associated with lymphocyte count were NRS and triceps skinfold thickness. Therefore, total lymphocyte count may be considered a nutritional marker. Other studies should confirm these findings. PMID- 28079247 TI - Dynamic location changes of Bub1-phosphorylated-H2AThr133 with CENH3 nucleosome in maize centromeric regions. AB - The genomic stability of all organisms requires precise cell division with proper chromosome orientation. The Bub1-H2Aph-Sgo1 pathway and spindle assembly checkpoint (SAC) components have been identified in yeast and mammals that are important for sister centromere orientation and chromosome segregation. However, their roles in plants are not clear. Maize meiotic mutants and minichromosomes were used to study the role of H2AThr133 phosphorylation and SAC components in sister centromere orientation and chromosome segregation. Unlike previously reported, SAC protein Bub1-Sgo1 recruitment was independent of Rec8 in maize and did not play a role in centromere protection in meiosis I. Chromatin immunoprecipitation sequencing analysis with immnolocalization results indicate most CENH3 nucleosomes contain phosphorylated H2AThr133 in centromeric regions. H2AThr133ph spreads to encompass centromeric regions including the inner centromeric and pericentromeric regions during (pro)metaphase. The presence and localization of SAC components and H2AThr133ph on maize lines containing sister chromatids separate precociously in anaphase I revealed no direct role of these proteins on centromere orientation in meiosis I . This work sheds light on the relationship between H2AThr133ph and CENH3 nucleosome in plants, and the phosphorylation with dynamic location changes in centomeric regions suggests temporal and spatial regulation roles for H2A phosphorylation in chromosome segregation. PMID- 28079249 TI - Fractal analysis of visual search activity for mass detection during mammographic screening. AB - PURPOSE: The objective of this study was to assess the complexity of human visual search activity during mammographic screening using fractal analysis and to investigate its relationship with case and reader characteristics. METHODS: The study was performed for the task of mammographic screening with simultaneous viewing of four coordinated breast views as typically done in clinical practice. Eye-tracking data and diagnostic decisions collected for 100 mammographic cases (25 normal, 25 benign, 50 malignant) from 10 readers (three board certified radiologists and seven Radiology residents), formed the corpus for this study. The fractal dimension of the readers' visual scanning pattern was computed with the Minkowski-Bouligand box-counting method and used as a measure of gaze complexity. Individual factor and group-based interaction ANOVA analysis was performed to study the association between fractal dimension, case pathology, breast density, and reader experience level. The consistency of the observed trends depending on gaze data representation was also examined. RESULTS: Case pathology, breast density, reader experience level, and individual reader differences are all independent predictors of the complexity of visual scanning pattern when screening for breast cancer. No higher order effects were found to be significant. CONCLUSIONS: Fractal characterization of visual search behavior during mammographic screening is dependent on case properties and image reader characteristics. PMID- 28079248 TI - Inhibition of matrix metalloproteinase-9 by a barbiturate-nitrate hybrid ameliorates dextran sulphate sodium-induced colitis: effect on inflammation related genes. AB - BACKGROUND AND PURPOSE: Matrix metalloproteinase-9 (MMP-9) is up-regulated in ulcerative colitis and implicated in the pathology of the disease. In this study, we have examined the effects of a barbiturate-based MMP inhibitor incorporating a nitric oxide donor/mimetic group (dinitrate-barbiturate) on the intestinal injury induced by dextran sulphate sodium (DSS). EXPERIMENTAL APPROACH: In vivo experiments were carried out using male Wistar rats given 5% DSS ad libitum in drinking water. The dinitrate-barbiturate, non-nitrate equivalent, nitrate side chains alone or vehicle were administered rectally, twice daily. MMP-9 release was measured by gelatin zymography, and analysis of gene expression was carried out using RT-qPCR. TaqMan low density arrays were used to evaluate the expression of 91 inflammatory genes in the rat colon. KEY RESULTS: The dinitrate-barbiturate inhibited the induction and activity of MMP-9 during DSS colitis in the rat. This occurred in association with significant reductions in the colitic response to DSS as assessed by an established clinical disease activity index and a pathological colitis grade score. The compound modified expression rates of numerous inflammation-related genes in the colon. CONCLUSIONS AND IMPLICATIONS: This study demonstrated the efficacy of the dinitrate-barbiturate in DSS-induced colitis. Therefore, barbiturate-nitrate hybrids may be developed as a promising anti-inflammatory approach to the treatment of inflammatory bowel disease. PMID- 28079250 TI - Use of the ketogenic diet in the neonatal intensive care unit-Safety and tolerability. AB - Drug-resistant epilepsy poses a challenge in neonatal patients, especially those in the neonatal intensive care unit (NICU), who have various secondary comorbidities. We present results of four children with a history of drug resistant epilepsy for whom a ketogenic diet was initiated and used in the NICU. A nonfasting induction into ketosis over 1-2 weeks was utilized, with gradual increases in the ketogenic ratio every 2-3 days. Data were collected retrospectively from a database, which included medical history, daily progress notes, relevant laboratory data, and imaging and diagnostic information. The ketogenic diet was well tolerated in all cases. The most common side effects observed were constipation, hypoglycemia, and weight loss. Serum beta hydroxybutyrate levels demonstrated improved reliability as a marker of ketosis when compared to urine ketones in this population. Perceived benefits to the infants included improved seizure control, increased alertness, and decreased need for invasive respiratory support. These cases demonstrate that the use of the ketogenic diet for treatment of neonatal encephalopathy and refractory epilepsy can be undertaken safely in the NICU and is well tolerated by carefully screened neonates and infants. PMID- 28079251 TI - Maturation-associated gene expression profiles along normal human bone marrow monopoiesis. AB - Human monopoiesis is a tightly coordinated process which starts in the bone marrow (BM) haematopoietic stem cell (HSC) compartment and leads to the production of circulating blood mature monocytes. Although mature monocytes/macrophages have been extensively studied in both normal or inflammatory conditions, monopoiesis has only been assessed in vitro and in vivo animal models, due to low frequency of the monocytic precursors in the normal human BM. Here we investigated the transcriptional profile along normal human BM monopoiesis. Five distinct maturation-associated stages of monocytic precursors were identified and isolated from (fresh) normal human BM through fluorescence activated cell sorting, and the gene expression profile (GEP) of each monocytic precursor subset was analysed by DNA-oligonucleotide microarrays. Overall, >6000 genes (18% of the genes investigated) were expressed in >=1 stage of BM monopoiesis at stable or variable amounts, showing early decrease in cell proliferation with increased levels of expression of genes linked with cell differentiation. The here-defined GEP of normal human BM monopoiesis might contribute to better understand monocytic differentiation and the identification of novel monocytic candidate markers, while also providing a frame of reference for the study of monocytic maturation in both neoplastic and non-neoplastic disease conditions involving monocytic precursor cells. PMID- 28079252 TI - Outcomes of surgical shunts and transjugular intrahepatic portasystemic stent shunts for complicated portal hypertension. AB - BACKGROUND: Transjugular intrahepatic portasystemic stent shunt (TIPSS), instead of surgical shunt, has become the standard treatment for patients with complicated portal hypertension. This study compared outcomes in patients who underwent TIPSS or surgical shunting for complicated portal hypertension. METHODS: This was a retrospective study of all consecutive patients who received portasystemic shunts from 1994 to 2014 at a single institution. Patients who underwent surgical shunting were compared with those who had a TIPSS procedure following one-to-one propensity score matching. The primary study endpoints were overall survival and shunt failure, defined as major variceal rebleeding, relapse of refractory ascites, irreversible shunt occlusion, liver failure requiring liver transplantation, or death. RESULTS: A total of 471 patients received either a surgical shunt or TIPSS. Of these, 334 consecutive patients with cirrhosis who underwent elective surgical shunting (34) or TIPSS (300) for repeated variceal bleeding or refractory ascites were evaluated. Propensity score matching yielded 31 pairs of patients. There were no between-group differences in morbidity and 30 day mortality rates. However, shunt failure was less frequent after surgical shunting than TIPSS (6 of 31 versus 16 of 31; P = 0.016). The 5-year shunt failure-free survival (77 versus 15 per cent; P = 0.008) and overall survival (93 versus 42 per cent; P = 0.037) rates were higher for patients with surgical shunts. Multivariable analysis revealed that a Model for End-Stage Liver Disease (MELD) score exceeding14 and TIPSS were independently associated with shunt failure. In patients with MELD scores of 14 or less, the 5-year overall survival rate remained higher after surgical shunting than TIPSS (100 versus 40 per cent; P < 0.001). CONCLUSION: Surgical shunting achieved better results than TIPSS in patients with complicated portal hypertension and low MELD scores. PMID- 28079254 TI - Pharmacological treatment of vascular risk factors for reducing mortality and cardiovascular events in patients with abdominal aortic aneurysm. AB - BACKGROUND: Pharmacological prophylaxis has been proven to reduce the risk of cardiovascular events in individuals with atherosclerotic occlusive arterial disease. However, the role of prophylaxis in individuals with abdominal aortic aneurysm (AAA) remains unclear. Several studies have shown that despite successful repair, those people with AAA have a poorer rate of survival than healthy controls. People with AAA have an increased prevalence of coronary heart disease and risk of cardiovascular events. Despite this association, little is known about the effectiveness of pharmacological prophylaxis in reducing cardiovascular risk in people with AAA. This is an update of a Cochrane review first published in 2014. OBJECTIVES: To determine the long-term effectiveness of antiplatelet, antihypertensive or lipid-lowering medication in reducing mortality and cardiovascular events in people with abdominal aortic aneurysm (AAA). SEARCH METHODS: For this update the Cochrane Vascular Information Specialist (CIS) searched the Cochrane Vascular Specialised Register (14 April 2016). In addition, the CIS searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 3) and trials registries (14 April 2016) and We also searched the reference lists of relevant articles. SELECTION CRITERIA: Randomised controlled trials in which people with AAA were randomly allocated to one prophylactic treatment versus another, a different regimen of the same treatment, a placebo, or no treatment were eligible for inclusion in this review. Primary outcomes included all-cause mortality and cardiovascular mortality. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, and completed quality assessment and data extraction. We resolved any disagreements by discussion. Only one study met the inclusion criteria of the review, therefore we were unable to perform meta-analysis. MAIN RESULTS: No new studies met the inclusion criteria for this update. We included one randomised controlled trial in the review. A subgroup of 227 participants with AAA received either metoprolol (N = 111) or placebo (N = 116). There was no clear evidence that metoprolol reduced all-cause mortality (odds ratio (OR) 0.17, 95% confidence interval (CI) 0.02 to 1.41), cardiovascular death (OR 0.20, 95% CI 0.02 to 1.76), AAA-related death (OR 1.05, 95% CI 0.06 to 16.92) or increased nonfatal cardiovascular events (OR 1.44, 95% CI 0.58 to 3.57) 30 days postoperatively. Furthermore, at six months postoperatively, estimated effects were compatible with benefit and harm for all-cause mortality (OR 0.71, 95% CI 0.26 to 1.95), cardiovascular death (OR 0.73, 95% CI 0.23 to 2.39) and nonfatal cardiovascular events (OR 1.41, 95% CI 0.59 to 3.35). Adverse drug effects were reported for the whole study population and were not available for the subgroup of participants with AAA. We considered the study to be at a generally low risk of bias. We downgraded the quality of the evidence for all outcomes to low. We downgraded the quality of evidence for imprecision as only one study with a small number of participants was available, the number of events was small and the result was consistent with benefit and harm. AUTHORS' CONCLUSIONS: Due to the limited number of included trials, there is insufficient evidence to draw any conclusions about the effectiveness of cardiovascular prophylaxis in reducing mortality and cardiovascular events in people with AAA. Further good-quality randomised controlled trials that examine many types of prophylaxis with long-term follow-up are required before firm conclusions can be made. PMID- 28079253 TI - Epithelial-mesenchymal transition (EMT): A biological process in the development, stem cell differentiation, and tumorigenesis. AB - The lineage transition between epithelium and mesenchyme is a process known as epithelial-mesenchymal transition (EMT), by which polarized epithelial cells lose their adhesion property and obtain mesenchymal cell phenotypes. EMT is a biological process that is often involved in embryogenesis and diseases, such as cancer invasion and metastasis. The EMT and the reverse process, mesenchymal epithelial transition (MET), also play important roles in stem cell differentiation and de-differentiation (or reprogramming). In this review, we will discuss current research progress of EMT in embryonic development, cellular differentiation and reprogramming, and cancer progression, all of which are representative models for researches of stem cell biology in normal and in diseases. Understanding of EMT and MET may help to identify specific markers to distinguish normal stem cells from cancer stem cells in future. PMID- 28079255 TI - Moonlighting at replication forks - a new life for homologous recombination proteins BRCA1, BRCA2 and RAD51. AB - Coordination between DNA replication and DNA repair ensures maintenance of genome integrity, which is lost in cancer cells. Emerging evidence has linked homologous recombination (HR) proteins RAD51, BRCA1 and BRCA2 to the stability of nascent DNA. This function appears to be distinct from double-strand break (DSB) repair and is in part due to the prevention of MRE11-mediated degradation of nascent DNA at stalled forks. The role of RAD51 in fork protection resembles the activity described for its prokaryotic orthologue RecA, which prevents nuclease-mediated degradation of DNA and promotes replication fork restart in cells challenged by DNA-damaging agents. Here, we examine the mechanistic aspects of HR-mediated fork protection, addressing the crosstalk between HR and replication proteins. PMID- 28079256 TI - Characterization of chronic HCV infection in Northwest Spain: Impact of the treatment strategic plan of the Spanish National Health Service on HCV cure. AB - The aim of the study was to characterize HCV infection in Northwest Spain and assess the impact of the Spanish Strategic Plan to cure HCV infection. Overall, 387 patients were included (60.9% HIV/HCV coinfected and 28.2% cirrhotic). Of these, 72.9% of patients that were recognized as priority for HCV treatment according to the Spanish Strategic Plan (>=F2, transplant or extrahepatic manifestations), initiated treatment during 2015. Globally, SVR12 was achieved in 96.5% of patients. The implementation of the Spanish Strategic Plan has been critical to advance in HCV cure, but 27.1% of priority patients still remain awaiting HCV treatment initiation. PMID- 28079257 TI - Technical Note: A safe, cheap, and easy-to-use isotropic diffusion MRI phantom for clinical and multicenter studies. AB - PURPOSE: Since Diffusion Weighted Imaging (DWI) data acquisition and processing are not standardized, substantial differences in DWI derived measures such as Apparent Diffusion Coefficient (ADC) may arise which are related to the acquisition or MRI processing method, but not to the sample under study. Quality assurance using a standardized test object, or phantom, is a key factor in standardizing DWI across scanners. METHODS: Current diffusion phantoms are either complex to use, not available in larger quantities, contain substances unwanted in a clinical environment, or are expensive. A diffusion phantom based on a polyvinylpyrrolidone (PVP) solution, together with a phantom holder, is presented and compared to existing diffusion phantoms for use in clinical DWI scans. An ADC vs. temperature calibration curve was obtained. RESULTS: ADC of the phantom (808 to 857 +/- 0.2 mm2 /s) is in the same range as ADC values found in brain tissue. ADC measurements are highly reproducible across time with an intra-class correlation coefficient of > 0.8. ADC as function of temperature (in Kelvin) can be estimated as ADCm(T)=[exp(-7.09).exp-2903.81T-1293.55] with a total uncertainty (95% confidence limit) of +/- 1.7%. CONCLUSION: We present an isotropic diffusion MRI phantom, together with its temperature calibration curve, that is easy-to-use in a clinical environment, cost-effective, reproducible to produce, and that contains no harmful substances. PMID- 28079258 TI - Combined effect of therapeutic strategies for bleeding injury on early survival, transfusion needs and correction of coagulopathy. AB - BACKGROUND: The combined effects of balanced transfusion ratios and use of procoagulant and antifibrinolytic therapies on trauma-induced exsanguination are not known. The aim of this study was to investigate the combined effect of transfusion ratios, tranexamic acid and products containing fibrinogen on the outcome of injured patients with bleeding. METHODS: A prospective multicentre observational study was performed in six level 1 trauma centres. Injured patients who received at least 4 units of red blood cells (RBCs) were analysed and divided into groups receiving a low (less than 1 : 1) or high (1 or more : 1) ratio of plasma or platelets to RBCs, and in receipt or not of tranexamic acid or fibrinogen products (fibrinogen concentrates or cryoprecipitate). Logistic regression models were used to assess the effect of transfusion strategies on the outcomes 'alive and free from massive transfusion' (at least 10 units of RBCs in 24 h) and early 'normalization of coagulopathy' (defined as an international normalized ratio of 1.2 or less). RESULTS: A total of 385 injured patients with ongoing bleeding were included in the study. Strategies that were independently associated with an increased number of patients alive and without massive transfusion were a high platelet to RBC ratio (odds ratio (OR) 2.67, 95 per cent c.i. 1.24 to 5.77; P = 0.012), a high plasma to RBC ratio (OR 2.07, 1.03 to 4.13; P = 0.040) and treatment with tranexamic acid (OR 2.71, 1.29 to 5.71; P = 0.009). No strategies were associated with correction of coagulopathy. CONCLUSION: A high platelet or plasma to RBC ratio, and use of tranexamic acid were associated with a decreased need for massive transfusion and increased survival in injured patients with bleeding. Early normalization of coagulopathy was not seen for any transfusion ratio, or for use of tranexamic acid or fibrinogen products. PMID- 28079259 TI - Three-point transfusion risk score in hepatectomy. AB - BACKGROUND: Perioperative red blood cell transfusions are required in up to 23 per cent of patients undergoing hepatectomy. Previous research has developed three transfusion risk scores to assess risk of perioperative red blood cell transfusion. Here, the performance of these transfusion risk scores was evaluated in a multicentre cohort of patients who underwent hepatectomy and compared with that of a simplified transfusion risk score. METHODS: A database of patients undergoing hepatectomy at four specialized centres between 2008 and 2012 was developed. External validity was assessed by discrimination and calibration. Discrimination was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC). Calibration was evaluated by the degree of agreement between predicted and actual red blood cell transfusion probabilities. A simplified transfusion risk score using variables common to the three models was created, and discrimination and calibration were evaluated. RESULTS: There were 1287 patients included in this study, with 341 (26.5 per cent) receiving a red blood cell transfusion. Discriminative ability was similar between the three transfusion risk scores, with AUCs of 0.66-0.68 and good calibration. A new three point risk score was developed based on factors present in all models: haemoglobin 12.5 g/dl or less, primary liver malignancy and major resection (at least 4 segments). Discriminative ability and calibration of the three-point model were similar to those of the three existing models, with an AUC of 0.66. CONCLUSION: The three-point transfusion risk score simplifies assessment of perioperative transfusion risk in hepatectomy without sacrificing predictive ability. PMID- 28079260 TI - An experimentally validated couch and MLC tracking simulator used to investigate hybrid couch-MLC tracking. AB - PURPOSE/OBJECTIVE: Couch and MLC tracking are two novel techniques to mitigate intrafractional tumor motion on a conventional linear accelerator, but both techniques still have residual dosimetric errors. Here, we first propose and experimentally validate a software tool to simulate couch and MLC tracking, and then use the simulator to study hybrid couch-MLC tracking for improved tracking performance. MATERIALS AND METHODS: The tracking simulator requires a treatment plan and a motion trajectory as input and simulates the delivered monitor units and motion of all accelerator parts as function of time. The simulator outputs accelerator log files synchronized with the target motion as well as the MLC exposure error, which is a simple dose error surrogate. A series of couch and MLC tracking experiments were used to determine appropriate parameters for the simulator dynamics and to validate the simulator by its ability to reproduce the experimental tracking accuracy. Three hybrid couch-MLC tracking strategies were investigated. All strategies divided the target motion in beam's eye view into motion perpendicular and parallel to the MLC leaves. In the hybrid strategies, couch tracking compensated for the following target motion components (in order of decreasing couch tracking contribution): (a) all perpendicular motion, (b) residual perpendicular motion less than half a leaf width, and (c) persistent residual perpendicular motion that was stable at a time scale of 1s. MLC tracking compensated for the remaining target motion. All tracking strategies were simulated with two prostate and two lung cancer single-arc VMAT plans using 695 prostate trajectories and 160 lung tumor trajectories. The tracking error was quantified as the MLC exposure error. The couch motion was quantified as the mean speed, acceleration, and jerk of the couch. RESULTS: The simulator reproduced the experimental gantry position with a mean (maximum) root-mean-square (rms) error of 0.07 degrees (0.2 degrees ). The geometrical rms tracking error was reproduced with mean (maximum) absolute errors of 0.20 mm(0.23 mm) and 0.1 mm(0.23 mm) for MLC tracking parallel and perpendicular to the MLC leaves, and 0.40 mm(0.46 mm), 0.09 mm(0.25 mm), and 0.20 mm(0.46 mm) for couch tracking in the left-right, anterior-posterior, and cranio-caudal directions. The MLC exposure error of VMAT MLC tracking was reproduced with a mean absolute error of 5.6%. All hybrid tracking strategies reduced the couch motion relative to pure couch tracking and improved the tracking accuracy compared with pure MLC tracking. The mean MLC exposure error reduction relative to no tracking was 66.6% (couch tracking), 72.9% (hybrid (1)), 70.2% (2), 59.1% (3), and 55.6% (MLC tracking) for lung tumor motion and 76.5% (couch tracking), 76.1% (1), 74.3% (2), 72.3% (3), and 35.9% (MLC tracking) for prostate motion. For prostate motion, pure MLC tracking resulted in rather large MLC exposure errors that were more than halved with all hybrid tracking strategies. CONCLUSION: A couch and MLC tracking simulator was developed and experimentally validated against a series of tracking experiments. All hybrid couch-MLC tracking strategies improved MLC tracking. Two strategies also improved couch tracking of lung tumors. In particular, MLC tracking of prostate may be greatly improved by a modest degree of couch motion. PMID- 28079261 TI - Effect of parthanatos on ropivacaine-induced damage in SH-SY5Y cells. AB - Ropivacaine is one of the most common but toxic local anaesthetics, and the mechanisms underlying its neurotoxicity are still largely unknown. This study was conducted to prepare a ropivacaine-induced neuronal injury model and research the effects of ropivacaine on PARP-1 activation and nicotinamide adenine dinucleotide (NAD)+ depletion. The cell death and apoptosis of ropivacaine-induced SH-SY5Y cells were detected with flow cytometry. The lactate dehydrogenase cycling reaction measured the NAD+ level, and western blots were used to analyze the expression levels of PARP-1 and apoptosis-inducing factor (AIF) after ropivacaine treatments with different concentrations and durations. A PARP-1 inhibitor (PJ 34) was used to confirm the relationship between PARP-1 activation and NAD+ depletion. Hoechst 33258 nuclear staining and a mitochondrial membrane potential (Deltapsim) assay were used to detect the role of exogenous NAD+ in ropivacaine induced neuronal injury. Ropivacaine-induced SH-SY5Y cell death and apoptosis, PARP-1 activation, and AIF increase as well as intracellular NAD+ depletion occurred in a time- and concentration-dependent manner (P<.05). PARP-1 activation led to NAD+ depletion (P<.05). Exogenous NAD+ impaired ropivacaine-induced nuclear injury (P<.05). Ropivacaine treatment induced PARP-1 activation and NAD+ depletion (P<.05). Parthanatos (PARP-1-dependent cell death) was definitely involved in ropivacaine-induced neuronal injury, and exogenous NAD+ may be a novel therapeutic method for parthanatos-dependent neuronal injury. PMID- 28079262 TI - Pediatric Obesity: Pharmacokinetic Alterations and Effects on Antimicrobial Dosing. AB - Limited data exist for appropriate drug dosing in obese children. This comprehensive review summarizes pharmacokinetic (PK) alterations that occur with age and obesity, and these effects on antimicrobial dosing. A thorough comparison of different measures of body weight and specific antimicrobial agents including cefazolin, cefepime, ceftazidime, daptomycin, doripenem, gentamicin, linezolid, meropenem, piperacillin-tazobactam, tobramycin, vancomycin, and voriconazole is presented. PubMed (1966-July 2015) and Cochrane Library searches were performed using these key terms: children, pharmacokinetic, obesity, overweight, body mass index, ideal body weight, lean body weight, body composition, and specific antimicrobial drugs. PK studies in obese children and, if necessary, data from adult studies were summarized. Knowledge of PK alterations stemming from physiologic changes that occur with age from the neonate to adolescent, as well as those that result from increased body fat, become an essential first step toward optimizing drug dosing in obese children. Excessive amounts of adipose tissue contribute significantly to body size, total body water content, and organ size and function that may modify drug distribution and clearance. PK studies that evaluated antimicrobial dosing primarily used total (or actual) body weight (TBW) for loading doses and TBW or adjusted body weight for maintenance doses, depending on the drugs' properties and dosing units. PK studies in obese children are imperative to elucidate drug distribution, clearance, and, consequently, the dose required for effective therapy in these children. Future studies should evaluate the effects of both age and obesity on drug dosing because the incidence of obesity is increasing in pediatric patients. PMID- 28079263 TI - Comparison of Rates of Nephrotoxicity Associated with Vancomycin in Combination with Piperacillin-Tazobactam Administered as an Extended versus Standard Infusion. AB - STUDY OBJECTIVE: Despite recent reports of relatively high rates (16-37%) of acute kidney injury (AKI) in patients receiving the combination of intravenous piperacillin-tazobactam (PTZ) and vancomycin, data are limited evaluating the impact of PTZ infusion strategy on the occurrence of nephrotoxicity. The objective of this study was to compare the rates of nephrotoxicity in patients receiving vancomycin in combination with PTZ administered as an extended infusion (EI) versus a standard infusion (SI). DESIGN: Single-center, retrospective, matched-cohort study. SETTING: Large academic tertiary care hospital. PATIENTS: Two hundred eighty adults with a creatinine clearance (CrCl) of 40 ml/minute or higher who received at least 96 hours of vancomycin plus PTZ EI (140 patients) or vancomycin plus PTZ SI (140 patients) between January 1, 2009, and December 31, 2011, and between January 1, 2013, and December 31, 2014 (year 2012 was skipped due the closure of inpatient units following Superstorm Sandy); 48 patients in each group were admitted to the intensive care unit. MEASUREMENTS AND MAIN RESULTS: The median age of all patients was 67 (interquartile range [IQR] 54-77) years, and CrCl was 75 (IQR 55-107) ml/minute. Nephrotoxicity was assessed by the risk, injury, failure, loss, and end-stage kidney disease (RIFLE) and Acute Kidney Injury Network (AKIN) criteria. Rates of AKI, according to these criteria, were similar between groups: 17.9% versus 17.1% (p=1) and 32.9% versus 29.3% (p=0.596) for the PTZ EI and PTZ SI groups, respectively. When controlling for residual differences between groups in a conditional logistic regression analysis, no association was observed between receipt of PTZ EI and RIFLE-defined AKI (odds ratio 0.522, 95% confidence interval 0.043-6.295, p=0.609). Time to onset of nephrotoxicity was 4 (IQR 3-6) days, with no significant difference noted between groups (p=0.887). CONCLUSION: Our findings suggest a similar rate of nephrotoxicity between patients who received vancomycin in combination with PTZ EI versus PTZ SI. These results need to be further validated in a prospective randomized controlled study. PMID- 28079264 TI - Electromagnetic computation and modeling in MRI. AB - Electromagnetic (EM) computational modeling is used extensively during the development of a Magnetic Resonance Imaging (MRI) scanner, its installation, and use. MRI, which relies on interactions between nuclear magnetic moments and the applied magnetic fields, uses a range of EM tools to optimize all of the magnetic fields required to produce the image. The main field magnet is designed to exacting specifications but challenges in manufacturing, installation, and use require additional tools to maintain target operational performance. The gradient magnetic fields, which provide the primary signal localization mechanism, are designed under another set of complex design trade-offs which include conflicting imaging performance specifications and patient physiology. Gradients are largely impervious to external influences, but are also used to enhance main field operational performance. The radiofrequency (RF) magnetic fields, which are used to elicit the signals fundamental to the MR image, are a challenge to optimize for a host of reasons that include patient safety, image quality, cost optimization, and secondary signal localization capabilities. This review outlines these issues and the EM modeling used to optimize MRI system performance. PMID- 28079265 TI - Chimeric Antigen Receptor T Cells in Hematologic Malignancies. AB - Patients with B-cell hematologic malignancies who progress through first- or second-line chemotherapy have a poor prognosis. Early clinical trials with autologous anti-CD19 chimeric antigen receptor (CAR) T cells have demonstrated promising results for patients who have relapsed or refractory disease. Lymphodepleting conditioning regimens, including cyclophosphamide, fludarabine, pentostatin, bendamustine, interleukin-2, and total body irradiation, are often administered before the infusion of CAR T cells, allowing for greater T-cell expansion. The major toxicity associated with CAR T-cell infusions is cytokine release syndrome (CRS), a potentially life-threatening systemic inflammatory disorder. The quick onset and progression of CRS require rapid detection and intervention to reduce treatment-related mortality. Management with tocilizumab can help ameliorate the symptoms of severe CRS, allowing steroids, which diminish the expansion and persistence of CAR T cells, to be reserved for tocilizumab refractory patients. Other toxicities of CAR T-cell therapy include neutropenia and/or febrile neutropenia, infection, tumor lysis syndrome, neurotoxicity and nausea/vomiting. A review of patients' medications is imperative to eliminate medications that may contribute to treatment-related toxicities. Studies are ongoing to help optimize patient selection, preparation, safety, and management of individuals receiving CAR T cells. Long-term follow-up will help establish the place of CAR T cells in therapy. PMID- 28079266 TI - Risk of Mortality in Elderly Nursing Home Patients with Depression Using Paroxetine. AB - OBJECTIVE: Among selective serotonin reuptake inhibitors (SSRIs), paroxetine is strongly anticholinergic and might lead to a higher risk of adverse outcomes such as mortality. This study examined the risk of mortality in depressed elderly nursing home patients using paroxetine and other SSRIs. METHODS: This study used 2007-2010 Minimum Data Set-linked Medicare data and a propensity score (PS) matched retrospective cohort study design to achieve the study objective. New users of paroxetine and other SSRIs were followed until they reached the end of the follow-up period (1 year), switched to a different antidepressant class, used psychotherapy, or had a gap of more than 15 days in the use of index antidepressant class, whichever occurred earlier. A robust Cox proportional hazard (PH) model was used to evaluate the risk of mortality associated with the use of paroxetine and other SSRIs in depressed elderly nursing home residents. RESULTS: The PS matching yielded 4620 patients each in the two treatment groups. The unadjusted incidence of mortality was 269 (2.9%) for paroxetine and 288 (3.1%) for other SSRIs users in the matched cohort. The robust Cox PH model did not find any significant difference in the risk mortality between the two groups (hazard ratio 1.01; 95% confidence interval 0.86-1.19). CONCLUSIONS: This study did not find any significant difference in the risk of mortality between users of paroxetine and other SSRIs among elderly nursing home patients with depression. There is a need for further evaluation of other adverse effects of paroxetine due to its anticholinergic effects in the geriatric population. PMID- 28079267 TI - Estimating 4D-CBCT from prior information and extremely limited angle projections using structural PCA and weighted free-form deformation for lung radiotherapy. AB - PURPOSE: To investigate the feasibility of using structural-based principal component analysis (PCA) motion-modeling and weighted free-form deformation to estimate on-board 4D-CBCT using prior information and extremely limited angle projections for potential 4D target verification of lung radiotherapy. METHODS: A technique for lung 4D-CBCT reconstruction has been previously developed using a deformation field map (DFM)-based strategy. In the previous method, each phase of the 4D-CBCT was generated by deforming a prior CT volume. The DFM was solved by a motion model extracted by a global PCA and free-form deformation (GMM-FD) technique, using a data fidelity constraint and deformation energy minimization. In this study, a new structural PCA method was developed to build a structural motion model (SMM) by accounting for potential relative motion pattern changes between different anatomical structures from simulation to treatment. The motion model extracted from planning 4DCT was divided into two structures: tumor and body excluding tumor, and the parameters of both structures were optimized together. Weighted free-form deformation (WFD) was employed afterwards to introduce flexibility in adjusting the weightings of different structures in the data fidelity constraint based on clinical interests. XCAT (computerized patient model) simulation with a 30 mm diameter lesion was simulated with various anatomical and respiratory changes from planning 4D-CT to on-board volume to evaluate the method. The estimation accuracy was evaluated by the volume percent difference (VPD)/center-of-mass-shift (COMS) between lesions in the estimated and "ground-truth" on-board 4D-CBCT. Different on-board projection acquisition scenarios and projection noise levels were simulated to investigate their effects on the estimation accuracy. The method was also evaluated against three lung patients. RESULTS: The SMM-WFD method achieved substantially better accuracy than the GMM-FD method for CBCT estimation using extremely small scan angles or projections. Using orthogonal 15 degrees scanning angles, the VPD/COMS were 3.47 +/- 2.94% and 0.23 +/- 0.22 mm for SMM-WFD and 25.23 +/- 19.01% and 2.58 +/- 2.54 mm for GMM-FD among all eight XCAT scenarios. Compared to GMM-FD, SMM-WFD was more robust against reduction of the scanning angles down to orthogonal 10 degrees with VPD/COMS of 6.21 +/- 5.61% and 0.39 +/- 0.49 mm, and more robust against reduction of projection numbers down to only 8 projections in total for both orthogonal-view 30 degrees and orthogonal-view 15 degrees scan angles. SMM WFD method was also more robust than the GMM-FD method against increasing levels of noise in the projection images. Additionally, the SMM-WFD technique provided better tumor estimation for all three lung patients compared to the GMM-FD technique. CONCLUSION: Compared to the GMM-FD technique, the SMM-WFD technique can substantially improve the 4D-CBCT estimation accuracy using extremely small scan angles and low number of projections to provide fast low dose 4D target verification. PMID- 28079268 TI - Renoprotective effect of Hypericum perforatum against diabetic nephropathy in rats: Insights in the underlying mechanisms. AB - Oxidative stress and inflammation play a key role in the initiation and progression of diabetic nephropathy (DN). The present study aimed to investigate the possible protective effect of hypericum perforatum (HP) against DN. Rats were allocated into six groups: control, received normal saline; diabetic untreated (DM), received single dose of streptozotocin (STZ) after injection of nicotinamide (NA); gliclazide, received STZ,NA + gliclazide (10 mg/kg); DM + HP50, DM + HP100, DM + HP200, received STZ,NA and HP 50, 100, 200 mg/kg, respectively. Gliclazide and HP were administered daily via gavage for 8 weeks. Serum glucose, insulin, kidney function and histopathological picture were assessed. Furthermore, oxidative/nitrosative stress, inflammatory cytokines, apoptotic and fibrotic markers were measured. Diabetic untreated group showed increase in serum glucose, urea, creatinine with albuminurea. Renal expression of protein for nuclear factor kappa-B (NF-kB), renal expression of inducible nitric oxide synthase (iNOS), cyclooxygenase II (COXII), collagen IV, fibronectin were elevated. Malondialdehyde (MDA), nitric oxide (NO), tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), intracellular adhesion molecule (ICAM 1), monocellular chemoattractant protein-1 (MCP-1), tumour growth factor- beta (TGF-beta), caspase-3 and cytochrome c contents were also increased consequently with decline of serum insulin, expression of peroxisome proliferator-activated receptor (PPARgamma), renal reduced glutathione (GSH) content and superoxide dismutase (SOD) activity. Treatment with either gliclazide or HP mitigated the deleterious effects of STZ on the tested parameters. These findings indicate for the first time that HP may have a renoprotective effect against DN through reduction of oxidative/nitrosative stress, enhancement of antioxidant defense mechanisms, decline of inflammatory cytokines, antifibrotic, antiapoptotic and blood glucose lowering properties. PMID- 28079269 TI - Ledipasvir plus sofosbuvir as salvage therapy for HCV genotype 1 failures to prior NS5A inhibitors regimens. AB - There is little information on retreatment efficacy and predictors of the combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir) for patients who fail to respond to NS5A inhibitors. NS5A resistance variants are known to persist for long periods after such treatment. Here, we evaluated 54 patients with chronic HCV genotype 1b infection, free of decompensated cirrhosis, and hepatocellular carcinoma, for sustained virological response after 12 weeks (SVR12) of once-daily treatment with 90 mg ledipasvir and 400 mg sofosbuvir. Intention-to-treat analysis showed SVR12 of 70%. Using ultra-deep sequencing, non responder to ledipasvir/sofosbuvir showed no change in the rates of detection of NS5A and NS5B resistant-variants at re-elevation of viral loads, relative to baseline. According to response to prior treatment, SVR12 rates were 18, 69, 94, and 100% in non response, viral breakthrough, relapse, and discontinuation due to adverse events, respectively. SVR12 rates in non response were significantly lower than those of the others. Multivariate analysis identified response to previous treatment (failure except for non response) and FIB4 index (<3.25) as significant determinants of SVR12. The SVR12 rates were significantly lower in patients with FIB4 index of >=3.25 and had not responded to prior treatment, relative to others. The specificity, and positive- and negative-predictive values were high for prediction of poor response based on the combination of two predictors. In conclusion, our study indicated that ledipasvir/sofosbuvir is a potentially useful salvage treatment for patients who fail prior NS5A inhibitors based therapy. Response to prior treatment was an important predictor of retreatment efficacy. PMID- 28079270 TI - Treatment of Adults with Idiopathic Recurrent Pericarditis: Novel Use of Immunotherapy. AB - Idiopathic recurrent pericarditis (IRP) can be challenging to treat. Even after guideline-directed first-line treatment consisting of aspirin (ASA) or a nonsteroidal antiinflammatory drug (NSAID) in combination with colchicine therapy, recurrences still occur in greater than 20% of patients. Many patients then require treatment with long-term corticosteroids, which is not a favorable option due to their short- and long-term adverse effects. Because it is theorized that the pathophysiology of IRP may possess autoimmune sequelae, the use of immunotherapy for the treatment of IRP has emerged. In this review, we describe the literature associated with immunotherapy used to treat IRP in an adult population as well as provide an overview of the safety and monitoring parameters for each agent. The most common immunotherapies used after patients have had multiple recurrences of IRP are anakinra, intravenous immunoglobulin (IVIG), and azathioprine. In most cases, these immunotherapies are adjunctive therapy, with the goal of tapering and discontinuing immunosuppressive corticosteroids. After reviewing the data, anakinra resulted in more patients discontinuing corticosteroids and prevented further recurrences of pericarditis. IVIG resulted in symptom resolution and no further recurrences in most of the patients. Azathioprine was associated with more than half of patients becoming recurrence free; however, many patients required a restart of corticosteroids due to recurrence. Clinicians should be aware of the adverse effects of immunotherapy, ranging from mild gastrointestinal events to risk of infection and serious blood dyscrasias that may require diligent monitoring. The use of immunotherapy for the treatment of adults with IRP should be restricted to patients who have multiple recurrences. Ideally, immunotherapy would be adjunctive to first-line combination therapy with ASA/NSAID plus colchicine, with the goal of tapering and discontinuing immunosuppressive corticosteroids. Furthermore, clinicians should consider cost, drug-drug and drug-disease interactions, and safety, as well as the quality of the retrospective evidence before considering any immunotherapy. PMID- 28079271 TI - Uptake and elimination kinetics of the biocide triclosan and the synthetic musks galaxolide and tonalide in the earthworm Dendrobaena veneta when exposed to sewage sludge. AB - Sewage sludge is an important amendment that enriches soils with organic matter and provides plants with nutrients such as nitrogen and phosphorus. However, knowledge on the fate and effects of organic pollutants present in the sludge on soil organisms is limited. In the present study, the uptake of triclosan, galaxolide, and tonalide in the earthworm Dendrobaena veneta was measured 1 wk after amendment of agricultural soil with sewage sludge, while elimination kinetics were assessed over a 21-d period after transferring worms to clean soil. After 1-wk exposure, earthworms had accumulated 2.6 +/- 0.6 MUg g-1 galaxolide, 0.04 +/- 0.02 MUg g-1 tonalide, and 0.6 +/- 0.2 MUg g-1 triclosan. Both synthetic musks were efficiently excreted and below the limit of quantification after 3 and 14 d of depuration for tonalide and galaxolide, respectively. Triclosan concentrations, on the other hand, did not decrease significantly over the depuration period, which may lead to the transfer of triclosan in the food web. Environ Toxicol Chem 2017;36:2068-2073. (c) 2017 SETAC. PMID- 28079272 TI - Salinity, dissolved organic carbon, and interpopulation variability hardly influence the accumulation and effect of copper in Mytilus edulis. AB - To improve the ecological relevance of environmental risk assessment, an improved understanding is needed of 1) the influence of environmental conditions on the toxicity of pollutants, and 2) the effect of these factors in combination with possible interpopulation variability. The influences of salinity and dissolved organic carbon (DOC) on the accumulation and effect of copper (Cu) to settled mussels were investigated with mussels from a North Sea and a Baltic Sea population. We found that both populations were equally Cu-sensitive, even though the Baltic Sea population lives in suboptimal conditions. Baltic Sea mussels, however, accumulated more Cu. This suggests that these populations may have different ways of coping with excess Cu. The influence of salinity on Cu toxicity to settled mussels was limited for both populations. An increase in DOC did not decrease the Cu accumulation or effect in either population. This suggests that DOC-Cu complexes are bioavailable for settled mussels. These findings are in contrast with previous research which indicated that DOC decreased the toxicity and accumulation of Cu in the D-larvae life stage. As a consequence, the mussel larval stage is not the most Cu-sensitive life stage at high DOC concentrations. Furthermore, a DOC correction factor for Cu toxicity cannot be used for settled mussels. This should be accounted for in future marine Cu environmental risk assessment. Environ Toxicol Chem 2017;36:2074-2082. (c) 2017 SETAC. PMID- 28079273 TI - Abnormal fetal muscle forces result in defects in spinal curvature and alterations in vertebral segmentation and shape. AB - The incidence of congenital spine deformities, including congenital scoliosis, kyphosis, and lordosis, may be influenced by the in utero mechanical environment, and particularly by fetal movements at critical time-points. There is a limited understanding of the influence of fetal movements on spinal development, despite the fact that mechanical forces have been shown to play an essential role in skeletal development of the limb. This study investigates the effects of muscle forces on spinal curvature, vertebral segmentation, and vertebral shape by inducing rigid or flaccid paralysis in the embryonic chick. The critical time points for the influence of fetal movements on spinal development were identified by varying the time of onset of paralysis. Prolonged rigid paralysis induced severe defects in the spine, including curvature abnormalities, posterior and anterior vertebral fusions, and altered vertebral shape, while flaccid paralysis did not affect spinal curvature or vertebral segmentation. Early rigid paralysis resulted in more severe abnormalities in the spine than later rigid paralysis. The findings of this study support the hypothesis that the timing and nature of fetal muscle activity are critical influences on the normal development of the spine, with implications for the understanding of congenital spine deformities. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2135-2144, 2017. PMID- 28079276 TI - Dermal TDI exposure is not associated with lung cancer risk. PMID- 28079275 TI - Non-malignant respiratory disease among workers in industries using styrene-A review of the evidence. AB - BACKGROUND: Asthma and obliterative bronchiolitis (OB) cases have occurred among styrene-exposed workers. We aimed to investigate styrene as a risk factor for non malignant respiratory disease (NMRD). METHODS: From a literature review, we identified case reports and assessed cross-sectional and mortality studies for strength of evidence of positive association (i.e., strong, intermediate, suggestive, none) between styrene exposure and NMRD-related morbidity and mortality. RESULTS: We analyzed 55 articles and two unpublished case reports. Ten OB cases and eight asthma cases were identified. Six (75%) asthma cases had abnormal styrene inhalation challenges. Thirteen (87%) of 15 cross-sectional studies and 12 (50%) of 24 mortality studies provided at least suggestive evidence that styrene was associated with NMRD-related morbidity or mortality. Six (66%) of nine mortality studies assessing chronic obstructive pulmonary disease-related mortality indicated excess mortality. CONCLUSIONS: Available evidence suggests styrene exposure is a potential risk factor for NMRD. Additional studies of styrene-exposed workers are warranted. Am. J. Ind. Med. 60:163-180, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28079277 TI - Whole-body vibration exposure of occupational horseback riding in agriculture: A ranching example. AB - BACKGROUND: Horse riding is common in many occupations; however, there is currently no research evaluating exposure to whole-body vibration and mechanical shock on horseback. METHODS: Whole-body vibration was measured on a cattle rancher during two 30 min horseback rides using a tri-axial accelerometer mounted on a western saddle. Vibration was summarized into standardized metrics, including the 8 hr equivalent root-mean-squared acceleration (A[8]) and the daily 4th power vibration dose value (VDV). The resulting exposures were compared to the exposure limit and action values provided by European Union Directive 2002/44/EC. RESULTS: The highest vibration for both rides was in the vertical axis, with average A(8) and VDV of 0.56 m/s2 and 26.24 m/s1.75 , respectively. The A(8) value indicated moderate risk while the VDV suggested high risk of harmful health effects. CONCLUSIONS: Exposure to whole-body vibration and mechanical shock during occupational horseback riding may pose deleterious health risks and increased susceptibility to low back pain. Am. J. Ind. Med. 60:215-220, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28079278 TI - Corporate corruption of science-Another asbestos example. AB - BACKGROUND: Kelsh et al. [2007]: Occup Med (Lond) 57:581-589 published a paper reanalyzing one of the few data sources publicly available on mesothelioma amongst brake workers, the Australian Mesothelioma Surveillance Registry (AMSR). This reanalysis was commissioned by lawyers representing the automobile manufacturing companies and did not align with an independent analysis published by Leigh and Driscoll [2003]: Occup Environ Health 9:206-217. METHODS: We sought to reevaluate the AMSR data ourselves to understand how the company-sponsored research categorized the data. RESULTS: In our re-analysis of the 78 brake related folios in the AMSR, we determined that 57 were employed brake mechanics, 35 were employed brake mechanics with no other asbestos exposure besides brake work or repair, and 41 of these cases had no other asbestos exposure besides brake work or repair. Our classifications differed significantly from Kelsh et al. CONCLUSIONS: We discuss how Kelsh et al. methodically reduced the relevant cases by following overly stringent criteria for inclusion. Am. J. Ind. Med. 60:152-162, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28079280 TI - Cryptosporidiosis outbreak at an academic animal research laboratory-Colorado, 2014. AB - BACKGROUND: After cryptosporidiosis was reported in three workers caring for preweaned calves at an academic research laboratory, we sought to identify cases, determine risk factors, and implement control measures. METHODS: A cryptosporidiosis case was defined as diarrhea duration >=72 hr, abdominal cramps, or vomiting in an animal research laboratory worker during July 14-July 31. A confirmed case had laboratory evidence of Cryptosporidium infection. Staff were interviewed regarding illness, potential exposures, training, and personal protective equipment (PPE) standard operating procedures (SOPs). RESULTS: The cryptosporidiosis attack rate (AR) was 74% (20/27); five were laboratory confirmed. Median job training was 2 hr including respiratory-fit testing. No SOPs existed for doffing PPE. AR for workers who removed their gloves first was 84% (16/19) compared with 20% (1/5) for workers who removed gloves last (risk ratio = 4.2; P < 0.02). CONCLUSIONS: This outbreak highlights the importance of adequate training, enforced proper PPE procedures, and promoting a culture of safety. Am. J. Ind. Med. 60:208-214, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28079279 TI - Evaluating predictors of lead exposure for activities disturbing materials painted with or containing lead using historic published data from U.S. workplaces. AB - OBJECTIVES: We evaluated predictors of differences in published occupational lead concentrations for activities disturbing material painted with or containing lead in U.S. workplaces to aid historical exposure reconstruction. METHODS: For the aforementioned tasks, 221 air and 113 blood lead summary results (1960-2010) were extracted from a previously developed database. Differences in the natural log transformed geometric mean (GM) for year, industry, job, and other ancillary variables were evaluated in meta-regression models that weighted each summary result by its inverse variance and sample size. RESULTS: Air and blood lead GMs declined 5%/year and 6%/year, respectively, in most industries. Exposure contrast in the GMs across the nine jobs and five industries was higher based on air versus blood concentrations. For welding activities, blood lead GMs were 1.7 times higher in worst-case versus non-worst case scenarios. CONCLUSIONS: Job, industry, and time-specific exposure differences were identified; other determinants were too sparse or collinear to characterize. Am. J. Ind. Med. 60:189-197, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28079281 TI - Response to Goodman et al. PMID- 28079282 TI - Troubling issues at the frontier of animal tracking for conservation and management. PMID- 28079283 TI - Rab8A regulates insulin-stimulated GLUT4 translocation in C2C12 myoblasts. AB - Rab proteins are important regulators of GLUT4 trafficking in muscle and adipose cells. It is still unclear which Rabs are involved in insulin-stimulated GLUT4 translocation in C2C12 myoblasts. In this study, we detect the colocalization of Rab8A with GLUT4 and the presence of Rab8A at vesicle exocytic sites by TIRFM imaging. Overexpression of dominant-negative Rab8A (T22N) diminishes insulin stimulated GLUT4 translocation, while constitutively active Rab8A (Q67L) augments it. In addition, knockdown of Rab8A inhibits insulin-stimulated GLUT4 translocation, which is rescued by replenishment of RNAi-resistant Rab8A. Together, these results indicate an indispensable role for Rab8A in insulin regulated GLUT4 trafficking in C2C12 cells. PMID- 28079284 TI - Controlling the Helix Handedness of alphaalphabeta-Peptide Foldamers through Sequence Shifting. AB - Peptide foldamers containing both cis-beta-aminocyclopentanecarboxylic acid and alpha-amino acid residues combined in various sequence patterns (alphaalphabeta, alphaalphaalphabeta, alphabetaalphaalphabeta, and alphaalphabetaalphaalphaalphabeta) were screened using CD and NMR spectroscopy for the tendency to form helices. alphaalphabeta-Peptides were found to fold into an unprecedented and well-defined 16/17/15/18/14/17-helix. By extending the length of the sequence or shifting a fragment of the sequence from one terminus to another in alphaalphabeta-peptides, the balance between left-handed and right handed helix populations present in the solution can be controlled. Engineering of the peptide sequence could lead to compounds with either a strong propensity for the selected helix sense or a mixture of helical conformations of opposite senses. PMID- 28079285 TI - A pathway-based association study reveals variants from Wnt signalling genes contributing to asthma susceptibility. AB - BACKGROUND: Genetic susceptibility to asthma is currently linked to a handful of genes which have a limited ability to predict the overall disease risk, suggesting the existence of many other genes involved in disease development. Accumulated evidence from association studies in genes related by biological pathways could reveal novel asthma genes. OBJECTIVE: To reveal novel asthma susceptibility genes by means of a pathway-based association study. METHODS: Based on summary data from a previous a genomewide association study (GWAS) of asthma, we first identified significant biological pathways using a gene-set enrichment analysis. We then mapped all tested single nucleotide polymorphisms (SNPs) on the genes contributing to significant pathways and prioritized those with a disproportionate number of nominal significant associations for further studies. For those prioritized genes, association studies were performed for selected SNPs in independent case-control samples (n = 1765) using logistic regression models, and results were meta-analysed with those from the GWAS. RESULTS: Two biological processes were significantly enriched: the cytokine cytokine receptor interaction (P = 0.002) and the Wnt signalling (P = 0.012). From the 417 genes interacting in these two pathways, 10 showed an excess of nominal associations, including a known asthma susceptibility locus (encoding SMAD family member 3) and other novel candidate genes. From the latter, association studies of 14 selected SNPs evidenced replication in a locus near the frizzled class receptor 6 (FZD6) gene (P = 9.90 * 10-4 ), which had a consistent direction of effects with the GWAS findings (meta-analysed odds ratio = 1.49; P = 5.87 * 10-6 ) and was in high linkage disequilibrium with expression quantitative trait loci in lung tissues. CONCLUSIONS AND CLINICAL RELEVANCE: This study revealed the importance of two biological pathways in asthma pathogenesis and identified a novel susceptibility locus near Wnt signalling genes. PMID- 28079286 TI - Design, synthesis, biological evaluation, and 3D-QSAR analysis of podophyllotoxin dioxazole combination as tubulin targeting anticancer agents. AB - The advancement of cancer-fighting drugs has never been a simple linear process. Those drug design professionals begin to find inspiration from the nature after failing to find the ideal products by creative drug design and high-throughput screening. To obtain new molecules for inhibiting tubulin, podophyllotoxin was adopted as the leading compound and 1,3,4-oxadiazole was brought in to the C-4 site of podophyllotoxin in this research. A series of seventeen podophyllotoxin derived esters have been achieved and then evaluated their antitumor activities against four different cancer cell lines: A549, MCF-7, HepG2, and HeLa. Among all the compounds, compound 7c showed the best antiproliferating properties with IC50 = 2.54 +/- 0.82 MUm against MCF-7 cancer cell line. It was obvious that the content of ROS grew significantly in MCF-7 in a way depending on the dosage. The time- and dose-dependent cell cycle assays revealed that compound 7c could apparently block cell cycle in the phase of G2/M along with the upregulation of cyclin A2 and CDK2 protein. According to further studies, confocal microscopy experiment has certified that compound 7c could restrain cancer from growing by blocking the polymerization of microtubule. Meanwhile, compound 7c could be ideally integrated with the colchicine site of tubulin. In future, it would be feasible to selectively design tubulin inhibitors with the help of 3D-QSAR. This means that it is hopeful to develop compound 7c as a potential agent against cancer due to its biological characteristics. PMID- 28079287 TI - Triarylmethane Dyes for Artificial Repellent Cotton Fibers. AB - Families of new hydrophobic and/or oleophobic triarylmethane dyes possessing long hydrocarbon or polyfluorinated chains have been prepared. When covalently grafted on to cotton fabric, these dyes give rise to a new type of colored superhydrophobic fibers. PMID- 28079288 TI - Surface-Enhanced Raman Spectra Promoted by a Finger Press in an All-Solid-State Flexible Energy Conversion and Storage Film. AB - Electrochemically up-regulated surface-enhanced Raman spectroscopy (E-SERS) effectively increases Raman signal intensities. However, the instrumental requirements and the conventional measurement conditions in an electrolyte cell have hampered its application in fast and on-site detection. To circumvent the inconveniences of E-SERS, we propose a self-energizing substrate that provides electrical potential by converting film deformation from a finger press into stored electrical energy. The substrate combines an energy conversion film and a SERS-active Ag nanowire layer. A composite film prepared from a piezoelectric polymer matrix and surface-engineered rGO that simultaneously presents high permittivity and low dielectric loss is the key component herein. Using our substrate, increased E-SERS signals up to 10 times from a variety of molecules were obtained in the open air. Various tests on real-life sample surfaces demonstrated the potentials of the substrate in fast on-site detection. PMID- 28079289 TI - Apocrine Metaplasia Found at MR Biopsy: Is There Something to be Learned? AB - The purpose of this study was to determine (a) the frequency of apocrine metaplasia (ApoM) found on MR core biopsy of suspicious findings, and (b) to determine if there are specific MR imaging features that might obviate the need for biopsy. This HIPAA-compliant retrospective study was performed under IRB exemption for quality assurance studies. Patient demographics, MR imaging features, and pathology were reviewed. Breast lesions which underwent MR-guided biopsy, yielding ApoM on pathology analysis were included. Retrospective review of MR imaging features of these lesions was performed by two radiologists blinded to pathology results except for the presence of ApoM. Imaging features on MR assessed included location, size, morphology, T1 and T2 signals, and enhancement kinetics. Full pathology results were subsequently reviewed during data analysis. The pathology slides and imaging was subsequently reviewed by two fellowship trained radiologists and a breast pathologist to categorize the finding of ApoM into target lesion (imaging corresponds to size of lesion on pathology) versus incidental lesion. Target lesion characteristics were assessed to determine specific MRI features of ApoM. Between January 2011 to November 2012, 155 distinct breast lesions suspicious for malignancy successfully underwent MR guided biopsy. Of the 155 lesions biopsied, 123 (79%) were benign and 32 (21%) were malignant. Of the 123 benign biopsies, ApoM was found in 57 (46%), of which 35 (61%) had no associated atypia and 22 (39%) had associated atypia. Of the 32 malignant biopsies, three (9%) had associated ApoM (DCIS in two cases and DCIS/LCIS in one case). Of the 60 cases with ApoM, only 11 (18.3%) were target lesions and 49 were incidental lesions (81.7%). Of the 60 cases with ApoM, 35 (58%) were masses (average size 0.8 cm for both with or without atypia) and 25 (42%) were nonmass enhancement (NME) (average size 2.1 cm with and 1.0 cm without atypia). Only five (14%) of 35 masses demonstrated spiculated margins, of which four were associated with atypia (80%). Of 22 lesions with atypia or other high risk lesion, 14 (64%) were masses, most commonly with irregular margins (64%). Of the 12 T2 hyperintense lesions, only two (1.7)% had associated atypia or high risk lesion, and none were associated with malignancy. Of the 11 target lesions, seven were T2 hyperintense. Enhancement kinetics were variable: 30 (50%) showed mixed persistent and plateau kinetics, eight (13%) persistent delayed enhancement, 10 (17%) plateau kinetics, four (7%) washout kinetics, and eight (13%) were below threshold for kinetic analysis. ApoM is a common benign pathologic result at MR-guided core biopsy for both masses and NME accounting for 39% of all biopsy results in this series. Although there is considerable variability in imaging characteristics on MR, our results suggest biopsy may be safely obviated for lesions that are subcentimeter T2 hyperintense areas of NME and short term follow-up imaging may be a reasonable alternative for these lesions. PMID- 28079290 TI - Clamped Hybridization Chain Reactions for the Self-Assembly of Patterned DNA Hydrogels. AB - DNA hydrogels hold great potential for biological and biomedical applications owing to their programmable nature and macroscopic sizes. However, most previous studies involve spontaneous and homogenous gelation procedures in solution, which often lack precise control. A clamped hybridization chain reaction (C-HCR)-based strategy has been developed to guide DNA self-assembly to form macroscopic hydrogels. Analogous to catalysts in chemical synthesis or seeds in crystal growth, we introduced DNA initiators to induce the gelation process, including crosslinked self-assembly and clamped hybridization in three dimensions with spatial and temporal control. The formed hydrogels show superior mechanical properties. The use of printed, surface-confined DNA initiators was also demonstrated for fabricating 2D hydrogel patterns without relying on external confinements. This simple method can be used to construct DNA hydrogels with defined geometry, composition, and order for various bioapplications. PMID- 28079291 TI - Prognostic Value of PD-L1 in Breast Cancer: A Meta-Analysis. AB - Programmed cell death 1 ligand 1 (PD-L1) is a promising therapeutic target for cancer immunotherapy. However, the correlation between PD-L1 and breast cancer survival remains unclear. Here, we present the first meta-analysis to investigate the prognostic value of PD-L1 in breast cancer. We searched Pubmed, Embase, and Cochrane Central Register of Controlled Trials databases for relevant studies evaluating PD-L1 expression and breast cancer survival. Fixed- and random-effect meta-analyses were conducted based on heterogeneity of included studies. Publication bias was evaluated by funnel plot and Begg's test. Overall, nine relevant studies with 8583 patients were included. PD-L1 overexpression was found in 25.8% of breast cancer patients. PD-L1 (+) associated with several high-risk prognostic indicators, such as ductal cancer (p = 0.037), high tumor grade (p = 0.000), ER negativity (p = 0.000), PR negativity (p = 0.000), HER2 positivity (p = 0.001) and aggressive molecular subtypes (HER2-rich and Basal-like p = 0.000). PD-L1 overexpression had no significant impact on metastasis-free survival (HR 0.924, 95% CI = 0.747-1.141, p = 0.462), disease-free survival (HR 1.122, 95% CI = 0.878-1.434, p = 0.357) and overall specific survival (HR 0.837, 95% CI = 0.640 1.093, p = 0.191), but significantly correlated with shortened overall survival (HR 1.573, 95% CI = 1.010-2.451, p = 0.045). PD-L1 overexpression in breast cancer associates with multiple clinicopathological parameters that indicated poor outcome, and may increase the risk for mortality. Further standardization of PD-L1 assessment assay and well-controlled clinical trials are warranted to clarify its prognostic and therapeutic value. PMID- 28079293 TI - Vaccination management in children and adults with mastocytosis. PMID- 28079294 TI - Locus on chromosome 16 is significantly associated with increased tendency to lose pups in females of the RR/Sgn inbred mouse strain. AB - Females of the inbred mouse strain RR/Sgn have an apparent tendency to lose pups during rearing. To identify genes underlying this abnormal maternal phenotype, we performed quantitative trait loci (QTL) mapping in 349 (C57BL/6 J * RR/Sgn) F1 * RR/Sgn backcross mice and identified one significant and one suggestive QTL on chromosomes 16 and 4, respectively. We assigned the gene symbol nurturing ability QTL 3 (Naq3) to the QTL on chromosome 16. Twenty of the 21 mothers who lost entire litters were homozygous for RR/Sgn allele at Naq3; i.e., the significant association of Naq3 with pup loss was further confirmed by binomial tests. We tentatively propose that Mapk1, Kalrn, and Vps8 are potential candidate genes for Naq3. PMID- 28079292 TI - Germ cell tumors: Insights from the Drosophila ovary and the mouse testis. AB - Ovarian and testicular germ cell tumors of young adults are thought to arise from defects in germ cell development, but the molecular mechanisms underlying malignant transformation are poorly understood. In this review, we focus on the biology of germ cell tumor formation in the Drosophila ovary and the mouse testis, for which evidence supports common underlying mechanisms, such as blocking initiation into the differentiation pathway, impaired lineage progression, and sexual identity instability. We then discuss how these concepts inform our understanding of the disease in humans. Mol. Reprod. Dev. 84: 200-211, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28079295 TI - Hypophosphatemia predicts a failure to recover from adefovir-related renal injury after dose reduction in lamivudine-resistant hepatitis B patients. AB - AIM: In chronic hepatitis B patients receiving 10 mg adefovir, dose reduction is recommended when renal injury appears. However, recovery is not always achieved and markers that recommend switching to another antiviral agent are unknown. We investigated adefovir-related renal injury, recovery after dose reduction, and their predictors. METHODS: The renal injury in 77 chronic hepatitis B patients receiving 10 mg adefovir and recovery after dose reduction to alternate day administration in those with adefovir-related renal injury were assessed. The predictors for >20% estimated glomerular filtration rate (eGFR) decline following treatment with 10 mg adefovir and for >20% eGFR recovery after dose reduction were investigated. RESULTS: The adefovir dose was reduced in 26 patients (34%) at 59 +/- 30 (mean +/- standard deviation) months of 10 mg adefovir treatment because of decreases in eGFR (cumulative incidence 27%), serum phosphorus (9%), and uric acid (16%) levels, and increases in alkaline phosphatase (20%), bone type alkaline phosphatase (18%), urinary alpha1-microglobulin (18%), and urinary N-acetyl-beta-D-glucosaminidase (18%) levels. The only significant predictor for >20% eGFR decline was age >=50 years at the start of 10 mg adefovir treatment. The cumulative eGFR recovery rate was 42% at 42 +/- 27 months after dose reduction, and >=2.5 mg/dL serum phosphorus level at dose reduction was the only significant predictor for >20% eGFR recovery after dose reduction. CONCLUSION: Patients aged >=50 years are predisposed to adefovir-related renal injury and switching to another antiviral agent rather than adefovir dose reduction is recommended when hypophosphatemia is observed. PMID- 28079296 TI - Elasticity in Macrophage-Synthesized Biocrystals. AB - Supramolecular crystalline assembly constitutes a rational approach to bioengineer intracellular structures. Here, biocrystals of clofazimine (CFZ) that form in vivo within macrophages were measured to have marked curvature. Isolated crystals, however, showed reduced curvature suggesting that intracellular forces bend these drug crystals. Consistent with the ability of biocrystals to elastically deform, the inherent crystal structure of the principal molecular component of the biocrystals-the hydrochloride salt of CFZ (CFZ-HCl)-has a corrugated packing along the (001) face and weak dispersive bonding in multiple directions. These characteristics were previously found to be linked to the elasticity of other organic crystals. Internal stress in bent CFZ-HCl led to photoelastic effects on the azimuthal orientation of polarized light transmittance. We propose that elastic, intracellular crystals can serve as templates to construct functional microdevices with different applications. PMID- 28079297 TI - The Effectiveness of Diclofenac Sodium in the Treatment of Mondor's Disease of the Breast: The Topical Patch Compared to the Oral Capsules. AB - Mondor's disease of the breast is a rare, benign sclerosing superficial thrombophlebitis of the subcutaneous veins of the anterior or lateral chest wall, which is treated conservatively. We aim in this study to evaluate the outcome and effectiveness of our treatment protocol using oral diclofenac sodium and topical diclofenac sodium patch in 172 patients. A retrospective database analysis of 172 female patients between January 2001 and December 2010 was done. The treatment protocol consisted of group 1: treatment by oral diclofenac sodium 100 mg once daily for 3 weeks. Group 2: treatment by diclofenac sodium patches for 8 hours twice daily (morning and evening) for 1 week. The patients were instructed to document the time as soon as pain relief is achieved following the patch application and the intake of the oral dose. The incidence rate was 2.49%. Diclofenac sodium patch was statistically found to be significantly better in subsiding the inflammatory process of the veins, relieving the pain, and enhancing faster healing rate. We conclude that diclofenac sodium patch showed a promising role in the treatment of Mondor's disease of the breast by significantly decreasing the inflammatory process due to its transdermal migration action within a short period and the ability to reach a high local concentration. It achieved the best results for rapid relief of pain and disease regression compared to the oral capsules. Therefore, our protocol was changed to implement diclofenac sodium patch as the first choice in treating Mondor's disease of the breast. PMID- 28079298 TI - From phosphoproteins to phosphoproteomes: a historical account. AB - The first phosphoprotein (casein) was discovered in 1883, yet the enzyme responsible for its phosphorylation was identified only 130 years later, in 2012. In the intervening time, especially in the last decades of the 1900s, it became evident that, far from being an oddity, phosphorylation affects the majority of eukaryotic proteins during their lifespan, and that this reaction is catalysed by the members of a large family of protein kinases, susceptible to a variety of stimuli controlling nearly every aspect of life and death. The aim of this review is to present a historical account of the main steps of this spectacular revolution, which transformed our conception of a biochemical reaction originally held as a sporadic curiosity into the master mechanism governing cell regulation, and, if it is perturbed, causing cell dysregulation. PMID- 28079299 TI - A platinum blue complex exerts its cytotoxic activity via DNA damage and induces apoptosis in cancer cells. AB - Here, we describe the characteristics of a Pt-blue complex [Pt4 (2-atp)8 (H2 O)(OH)] (2-atp: 2-aminothiophenol) as a prodrug for its DNA-binding properties and its use in cancer therapy. The nature of the interaction between the Pt-blue complex and DNA was evaluated based on spectroscopic measurements, the electronic absorption spectra, thermal behavior, viscosity, fluorometric titration, and agarose gel electrophoresis. Our results suggested that the compound was able to partially intercalate DNA and appeared to induce both single- and double-stranded breaks (DBS) on DNA in vitro, but no DSBs in cells. The ability of the compound to induce DNA damage was dependent on reactive oxygen species (ROS) in vitro. There was also elevated formation of ROS and SOD expression in response to drug treatment in cell culture. The complex was found to be more cytotoxic to cancer cells in comparison with noncancer controls using WST-1 assay. The mean of cell death was determined to be apoptosis as assessed via biochemical, morphological, and molecular observations, including DNA condensation/fragmentation analysis, live cell imaging microscopy, TUNEL analyses, and increase in the levels of pro apoptotic genes such as Bag3, Bak, Bik, Bmf, and Hrk. Hence, the Pt-blue complex under study grants premise for further studies. PMID- 28079300 TI - Assessing the accuracy of the OMRON HEM-907XL oscillometric blood pressure measurement device in patients with nondialytic chronic kidney disease. AB - The OMRON HEM-907XL is a commercial oscillometric blood pressure (BP) monitor that was used in the Systolic Blood Pressure Intervention Trial (SPRINT), in which 28% of participants had chronic kidney disease (CKD). This study examined the accuracy of the monitor in nondialytic patients with CKD. Eighty-seven patients met inclusion criteria. The authors used a modified Association for the Advancement of Medical Instrumentation (AAMI) protocol, with one observer recording measurements from the monitor and two blinded physicians obtaining simultaneous aneroid values by auscultation. Using AAMI method 1, there was a 2.5+/-9.5 mm Hg difference in OMRON and aneroid systolic BP, and a -1.6+/-6.5 mm Hg difference in diastolic BP. Using AAMI method 2, there was a 5.1+/-7.4 mm Hg difference in systolic BP and a -0.2+/-5.4 mm Hg difference in diastolic BP. In patients with CKD, the OMRON HEM-907XL appears to be accurate for measuring diastolic BP, but did not perform as well for systolic BP. PMID- 28079301 TI - Case Study for Lean Management in the Public Sector: Improving Combination Product Review at the Food & Drug Administration. PMID- 28079302 TI - Molecular basis for covalent inhibition of glyceraldehyde-3-phosphate dehydrogenase by a 2-phenoxy-1,4-naphthoquinone small molecule. AB - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has recently gained attention as an antiprotozoan and anticancer drug target. We have previously identified 2 phenoxy-1,4-naphthoquinone as an inhibitor of both Trypanosoma brucei and human GAPDH. Herein, through multiple chemical, biochemical, and biological studies, and through the design of analogs, we confirmed the formation of a covalent adduct, we clarified the inhibition mechanism, and we demonstrated antitrypanosomal, antiplasmodial, and cytotoxic activities in cell cultures. The overall results lent support to the hypothesis that 2-phenoxy-1,4-naphthoquinone binds the GAPDH catalytic cysteine covalently through a phenolate displacement mechanism. By investigating the reactivity of 2-phenoxy-1,4-naphthoquinone and its analogs with four GAPDH homologs, we showed that the covalent inhibition is not preceded by the formation of a strong non-covalent complex. However, an up to fivefold difference in inactivation rates among homologs hinted at structural or electrostatic differences of their active sites that could be exploited to further design kinetically selective inhibitors. Moreover, we preliminarily showed that 2-phenoxy-1,4-naphthoquinone displays selectivity for GAPDHs over two other cysteine-dependent enzymes, supporting its suitability as a warhead starting fragment for the design of novel inhibitors. PMID- 28079303 TI - Mononuclear Clusterfullerene Single-Molecule Magnet Containing Strained Fused Pentagons Stabilized by a Nearly Linear Metal Cyanide Cluster. AB - Fused-pentagons results in an increase of local steric strain according to the isolated pentagon rule (IPR), and for all reported non-IPR clusterfullerenes multiple (two or three) metals are required to stabilize the strained fused pentagons, making it difficult to access the single-atom properties. Herein, we report the syntheses and isolations of novel non-IPR mononuclear clusterfullerenes MNC@C76 (M=Tb, Y), in which one pair of strained fused-pentagon is stabilized by a mononuclear cluster. The molecular structures of MNC@C76 (M=Tb, Y) were determined unambiguously by single-crystal X-ray diffraction, featuring a non-IPR C2v (19138)-C76 cage entrapping a nearly linear MNC cluster, which is remarkably different from the triangular MNC cluster within the reported analogous clusterfullerenes based on IPR-obeying C82 cages. The TbNC@C76 molecule is found to be a field-induced single-molecule magnet (SMM). PMID- 28079304 TI - Localized measurements of physical parameters within human sperm cells obtained with wide-field interferometry. AB - We developed a new method to identify the separate cellular compartments in the optical path delay (OPD) maps of un-labeled spermatozoa. This was conducted by comparing OPD maps of fixed, un-labeled spermatozoa to bright field images of the same cells following labeling. The labeling enabled us to identify the acrosomal and nuclear compartments in the corresponding OPD maps of the cells. We then extracted the refractive index maps of fixed cells by dividing the OPD maps of spermatozoa by the corresponding thickness maps of the same cells, obtained with AFM. Finally, the dry mass of the head, nucleus and acrosome of un-labeled immobile spermatozoa, was measured. This method provides the ability to quantitatively measure the dry mass of cellular compartments within human spermatozoa. We expect that these measurements will assist label-free selection of sperm cells for fertilization. PMID- 28079305 TI - Gallium enhances reconstructive properties of a calcium phosphate bone biomaterial. AB - Calcium phosphate (CaP)-based biomaterials are commonly used in bone reconstructive surgery to replace the damaged tissue, and can also serve as vectors for local drug delivery. Due to its inhibitory action on osteoclasts, the semi-metallic element gallium (Ga) is used for the systemic treatment of disorders associated with accelerated bone resorption. As it was demonstrated that Ga could be incorporated in the structure of CaP biomaterials, we investigated the biological properties of Ga-loaded CaP biomaterials. Culturing bone cells on Ga-CaP, we observed a decrease in osteoclast number and a downregulation of late osteoclastic markers expression, while Ga-CaP upregulated the expression of osteoblastic marker genes involved in the maturation of bone matrix. We next investigated in vivo bone reconstructive properties of different Ga-loaded biomaterials using a murine bone defect healing model. All implanted biomaterials showed a good osseointegration into the surrounding host tissue, accompanied by a successful bone ingrowth and bone marrow reconstruction, as evidenced by histological analysis. Moreover, quantitative micro-computed tomography analysis of implants revealed that Ga enhanced total defect filling. Lastly, we took advantage for the first time of a particular mode of non-linear microscopy (second harmonic generation) to quantify in vivo bone tissue reconstruction within a CaP bone substitute. By doing so, we showed that Ga exerted a positive impact on mature organized collagen synthesis. As a whole, our data support the hypothesis that Ga represents an attractive additive to CaP biomaterials for bone reconstructive surgery. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28079306 TI - Open Dislocation of Ankle without Fracture Treated with an External Fixator. AB - Ankle dislocations are orthopedic emergencies that require immediate treatment to avoid neurovascular impairment. They are usually accompanied by one or more comminuted fractures of the ankle mortis. In rare circumstances, such as high energy trauma, the ankle dislocations may not be accompanied by concomitant malleolar fractures and, thus, are named "pure ankle dislocations". We presented a very rare and interesting case of an open medial dislocation of the ankle without associated fracture in an 18-year-old man with no known predisposing risk factors. The patient was admitted to the emergency department after sustaining a catastrophic trampoline accident resulting in severe inversion of the right ankle. The patient was treated with an external fixator and was mobilized early in the post-surgical course. Despite initial presentation that revealed lack of posterior tibial pulse, the post-surgical course was uneventful, with full functional recovery and joint mobility. The primary goals of treatment are immediate reduction of the joint and relief of neurovascular stress. External fixation is a prompt, fairly easy treatment that one should keep in mind in pure ankle dislocations. Nonetheless, ligamentous restoration and early mobilization were the key elements as seen in our case for full functional recovery. PMID- 28079307 TI - Coordination of KrF2 to a Naked Metal Cation, Mg2. AB - Examples of coordination compounds in which KrF2 functions as a ligand are very rare. In contrast, XeF2 provides a rich coordination chemistry with a variety of main-group and transition metal cations. The reactions of Mg(AsF6 )2 and KrF2 in HF or BrF5 solvent have afforded [Mg(KrF2 )4 (AsF6 )2 ] and [Mg(KrF2 )4 (AsF6 )2 ]?2 BrF5 , respectively, the first examples of a metal cation ligated by KrF2 . Their X-ray crystal structures and Raman spectra show that the KrF2 ligands and [AsF6 ]- anions are F-coordinated to a naked Mg2+ cation. Quantum-chemical calculations are consistent with essentially non-covalent ligand-metal bonding. These compounds significantly extend the XeF2 -KrF2 analogy and the limited chemistry of krypton by introducing a new class of coordination compound in which KrF2 functions as a ligand towards a naked metal cation. PMID- 28079309 TI - Bioactive injectable aggregates with nanofibrous microspheres and human dental pulp stem cells: A translational strategy in dental endodontics. AB - Regeneration of the pulp-dentin complex with stem cells is a potential alternative to conventional root canal treatments. Human dental pulp stem cells (hDPSCs) have been extensively studied because of their ability to proliferate and differentiate into mineralized dental and non-dental tissues. Here we combined hDPSCs with two types of injectable poly-l-lactic acid (PLLA) microsphere with a nanofibrous or smooth surface to form bioactive injectable aggregates, and examined their ability to promote pulp regeneration in the root canal in an in vivo model. We investigated the biocompatibility, biosafety and odontogenic potential of fibrous (F-BIM) and smooth bioactive injectable microspheres (S-BIM) in vitro and in vivo. Our results demonstrated that PLLA microspheres and hDPSCs were able to form bioactive injectable aggregates that promoted dentin regeneration in both in vitro and in vivo models. Our results suggest that F-BIM and S-BIM may induce dentinogenesis upon in vivo grafting, and propose that the potential usefulness of the microsphere-hDPSC aggregates described here should be evaluated in clinical settings. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28079308 TI - Greater temperature sensitivity of plant phenology at colder sites: implications for convergence across northern latitudes. AB - Warmer temperatures are accelerating the phenology of organisms around the world. Temperature sensitivity of phenology might be greater in colder, higher latitude sites than in warmer regions, in part because small changes in temperature constitute greater relative changes in thermal balance at colder sites. To test this hypothesis, we examined up to 20 years of phenology data for 47 tundra plant species at 18 high-latitude sites along a climatic gradient. Across all species, the timing of leaf emergence and flowering was more sensitive to a given increase in summer temperature at colder than warmer high-latitude locations. A similar pattern was seen over time for the flowering phenology of a widespread species, Cassiope tetragona. These are among the first results highlighting differential phenological responses of plants across a climatic gradient and suggest the possibility of convergence in flowering times and therefore an increase in gene flow across latitudes as the climate warms. PMID- 28079310 TI - Happy Birthday Kataoka-sensei! PMID- 28079311 TI - Editorial. PMID- 28079312 TI - Rewarding peer-review work: the Publons initiative. PMID- 28079313 TI - Postischemic Inflammation in Acute Stroke. AB - Cerebral ischemia is caused by arterial occlusion due to a thrombus or an embolus. Such occlusion induces multiple and concomitant pathophysiological processes that involve bioenergetic failure, acidosis, loss of cell homeostasis, excitotoxicity, and disruption of the blood-brain barrier. All of these mechanisms contribute to neuronal death, mainly via apoptosis or necrosis. The immune system is involved in this process in the early phases after brain injury, which contributes to potential enlargement of the infarct size and involves the penumbra area. Whereas inflammation and the immune system both exert deleterious effects, they also contribute to brain protection by stimulating a preconditioning status and to the concomitant repair of the injured parenchyma. This review describes the main phases of the inflammatory process occurring after arterial cerebral occlusion, with an emphasis on the role of single mediators. PMID- 28079314 TI - SCN1A Gene Mutation and Adaptive Functioning in 18 Vietnamese Children with Dravet Syndrome. AB - BACKGROUND AND PURPOSE: Dravet syndrome is a rare and severe type of epilepsy in infants. The heterogeneity in the overall intellectual disability that these patients suffer from has been attributed to differences in genetic background and epilepsy severity. METHODS: Eighteen Vietnamese children diagnosed with Dravet syndrome were included in this study. SCN1A variants were screened by direct sequencing and multiplex ligation-dependent probe amplification. Adaptive functioning was assessed in all patients using the Vietnamese version of the Vineland Adaptive Behavior Scales, and the results were analyzed relative to the SCN1A variants and epilepsy severity. RESULTS: We identified 13 pathogenic or likely pathogenic variants, including 6 that have not been reported previously. We found no correlations between the presence or type of SCN1A variants and the level of adaptive functioning impairment or severity of epilepsy. Only two of nine patients aged at least 5 years had an adaptive functioning score higher than 50. Both of these patients had a low frequency of convulsive seizures and no history of status epilepticus or prolonged seizures. The remaining seven had very low adaptive functioning scores (39 or less) despite the variability in the severity of their epilepsy confirming the involvement of factors other than the severity of epilepsy in determining the developmental outcome. CONCLUSIONS: Our study expands the spectrum of known SCN1A variants and confirms the current understanding of the role of the genetic background and epilepsy severity in determining the developmental outcome of Dravet syndrome patients. PMID- 28079315 TI - Migraine Susceptibility Genes in Han Chinese of Fujian Province. AB - BACKGROUND AND PURPOSE: Five single-nucleotide polymorphisms (SNPs) (rs4379368, rs10504861, rs10915437, rs12134493 and rs13208321) were recently identified in a Western population with migraine. These migraine-associated SNPs have not been evaluated in a Han Chinese population. This study investigated the associations of specific SNPs with migraine in a Han population. METHODS: This was a case control study of Han Chinese residing in Fujian Province. Polymerase chain reaction-restriction-fragment-length polymorphism analysis and direct sequencing were used to characterize the relationships of SNPs in a control group of 200 subjects and in a migraine group of 201 patients. RESULTS: The frequencies of the five SNPs did not differ between patients with migraine and healthy non migraine controls. However, subgroup analysis indicated certain SNPs were more strongly associated with migraine with aura or migraine without aura than with controls. The CT genotype of rs4379368 was more common in migraine patients with aura (75%) than in migraine patients without aura (47.9%) and controls (48.5%) (p<0.05), and the TT genotype of rs10504861 was more common in migraine patients with aura than in controls (8.3% vs. 0.5%) (p<0.05). Meanwhile, the CC genotype of rs12134493 was less common in migraine patients without aura than in controls (80.6% vs. 88%) (p<0.05). CONCLUSIONS: Our findings suggest that the rs4379368 and rs10504861 SNPs are markers for susceptibility to migraine with aura and that rs12134493 is a marker for the risk of migraine without aura in this Han population. Future studies should further explore if these associations vary by ethnicity. PMID- 28079316 TI - Clinical Characteristics and Treatment Response of Peripheral Neuropathy in the Presence of Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome): Experience at a Single Tertiary Center. AB - BACKGROUND AND PURPOSE: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic small-vessel vasculitis accompanied by asthma, eosinophilia, and eosinophilic inflammation of various tissues including the peripheral nerves. This study investigated the clinical course and long-term outcomes of peripheral neuropathy in patients with EGPA. METHODS: Seventy-one patients with physician diagnosed EGPA were identified at Samsung Medical Center between January 1995 and April 2014. Sixty-one of these patients were followed-up for more than 1 year and received corticosteroid therapy with or without intravenous cyclophosphamide pulse therapy for 6 to 18 months. Medical records of the 61 patients including demographic data, clinical features, laboratory and pathological findings, treatments, and outcomes were reviewed. RESULTS: Peripheral neuropathy as a manifestation of EGPA was present in 46 (75%) of the 61 patients. The mean follow up duration of the patients with neuropathy was 6.4 years (range 1.2-18.8 years). The scores on the neurological functional disability scale before and after the combination treatment with corticosteroid and cyclophosphamide were 2.43+/-0.86 and 0.54+/-0.95 (mean+/-SD; p<0.001), respectively. The peripheral neuropathy relapsed in one patient. CONCLUSIONS: The long-term clinical outcome of peripheral neuropathy in patients with EGPA receiving initial corticosteroid and cyclophosphamide combination therapy was favorable with a very low relapse rate. PMID- 28079317 TI - Human Umbilical Cord Blood CD34-Positive Cells as Predictors of the Incidence and Short-Term Outcome of Neonatal Hypoxic-Ischemic Encephalopathy: A Pilot Study. AB - BACKGROUND AND PURPOSE: Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of neurological handicap in developing countries. Human umbilical cord blood (hUCB) CD34-positive (CD34+) stem cells exhibit the potential for neural repair. We tested the hypothesis that hUCB CD34+ stem cells and other cell types [leukocytes and nucleated red blood cells (NRBCs)] that are up-regulated during the acute stage of perinatal asphyxia (PA) could play a role in the early prediction of the occurrence, severity, and mortality of HIE. METHODS: This case-control pilot study investigated consecutive neonates exposed to PA. The hUCB CD34+ cell count in mononuclear layers was assayed using a flow cytometer. Twenty full-term neonates with PA and 25 healthy neonates were enrolled in the study. RESULTS: The absolute CD34+ cell count (p=0.02) and the relative CD34+ cell count (CD34+%) (p<0.001) in hUCB were higher in the HIE patients (n=20) than the healthy controls. The hUCB absolute CD34+ cell count (p=0.04), CD34+% (p<0.01), and Hobel risk scores (p=0.04) were higher in patients with moderate-to-severe HIE (n=9) than in those with mild HIE (n=11). The absolute CD34+ cell count was strongly correlated with CD34+% (p<0.001), Hobel risk score (p=0.04), total leukocyte count (TLC) (p<0.001), and NRBC count (p=0.01). CD34+% was correlated with TLC (p=0.02). CONCLUSIONS: hUCB CD34+ cells can be used to predict the occurrence, severity, and mortality of neonatal HIE after PA. PMID- 28079318 TI - Duchenne Muscular Dystrophy and Becker Muscular Dystrophy Confirmed by Multiplex Ligation-Dependent Probe Amplification: Genotype-Phenotype Correlation in a Large Cohort. AB - BACKGROUND AND PURPOSE: Studies of cases of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) confirmed by multiplex ligation-dependent probe amplification (MLPA) have determined the clinical characteristics, genotype, and relations between the reading frame and phenotype for different countries. This is the first such study from India. METHODS: A retrospective genotype-phenotype analysis of 317 MLPA-confirmed patients with DMD or BMD who visited the neuromuscular clinic of a quaternary referral center in southern India. RESULTS: The 317 patients comprised 279 cases of DMD (88%), 32 of BMD (10.1%), and 6 of intermediate phenotype (1.9%). Deletions accounted for 91.8% of cases, with duplications causing the remaining 8.2%. There were 254 cases of DMD (91%) with deletions and 25 (9%) due to duplications, and 31 cases (96.8%) of BMD with deletions and 1 (3.2%) due to duplication. All six cases of intermediate type were due to deletions. The most-common mutation was a single-exon deletion. Deletions of six or fewer exons constituted 68.8% of cases. The deletion of exon 50 was the most common. The reading-frame rule held in 90% of DMD and 94% of BMD cases. A tendency toward a lower IQ and earlier wheelchair dependence was observed with distal exon deletions, though a significant correlation was not found. CONCLUSIONS: The reading-frame rule held in 90% to 94% of children, which is consistent with reports from other parts of the world. However, testing by MLPA is a limitation, and advanced sequencing methods including analysis of the structure of mutant dystrophin is needed for more-accurate assessments of the genotype-phenotype correlation. PMID- 28079319 TI - Erratum to: Ataxia with Oculomotor Apraxia Type 1 without Oculomotor Apraxia: A Case Report. AB - This corrects the article on p. 126 in vol. 12, PMID: 26541496. PMID- 28079321 TI - [2016, increasing the online visibility of Archivos]. PMID- 28079320 TI - [Work and health in Portugal 2016: first report on occupational health in Portugal]. PMID- 28079322 TI - [Incidence of non-work-related sickness absence in Spain by economic activity of the company]. AB - INTRODUCTION: The management of sickness absence due to non-work-related diseases in Spain has typically focused on the control of its duration. The goal of this study was to provide estimates for the incidence of sickness absence due to nonwork-related diseases by economic activity to help shift the focus of management of sickness absence towards prevention. METHODS: Retrospective study based on 646,337 workers and 133,812 episodes of sickness absence started in 2009, from the Working Continuous Life Sample. Incidence rate and its 95% confidence interval (CI) were calculated using Poisson regression models, crude and adjusted for age, company size, and occupational category, separately for men and women. RESULTS: The overall incidence rate was 29.8 per 100 person-years; 24.7 (95%CI: 24.5-24.9) in men and 36.3 (36.0- 36.5) in women. By economic activity, the highest crude incidence rates in men were found in "Water supply, sanitation and wastes" (35.4) and "Health activities" (33.9); for women, "Health activities" (48.3), "Public administration" (41.2) and "Transportation and storage" (41.0) were the highest sectors. CONCLUSIONS: Companies can compare their sickness absence incidence rates to these benchmark values to determine if they are within the expected reference range, which may guide management decisions more towards the prevention of sickness absence. PMID- 28079323 TI - [Fitness for duty and psychophysical fitness in hazardous occupations]. PMID- 28079324 TI - [The informal economy: an occupational health issue]. AB - Informal economy must be differentiated from concepts such as informal employment and the informal sector, each with its own characteristics. There are several types of informal workers that are grouped into several categories according to their work. The families of these workers are grouped into vulnerable job, which is also not beneficial for health coverage. Informal working conditions mean great morbidity resulting in economic losses and a large number of quality adjusted life year, especially among young populations and women. Health policies are needed to reduce socio-economic inequalities, improve the training of health professionals and the accessibility of health services to these workers. PMID- 28079325 TI - Scientific research-based evidence used in drug promotion material distributed in Sri Lanka PMID- 28079326 TI - Estimation of provider cost and the out of pocket expenditure for cataract surgery at a base hospital PMID- 28079327 TI - Inguinal ureteral hernia PMID- 28079328 TI - Re: HLA- B27 allele frequency in Sri Lankan patients with spondyloarthritides PMID- 28079329 TI - 10-Year Outcomes in Localized Prostate Cancer. PMID- 28079330 TI - Authors reply re: HLA-B27 allele frequency in Sri Lankan patients with spondyloarthritides PMID- 28079331 TI - 10-Year Outcomes in Localized Prostate Cancer. PMID- 28079332 TI - 10-Year Outcomes in Localized Prostate Cancer. PMID- 28079333 TI - 10-Year Outcomes in Localized Prostate Cancer. PMID- 28079334 TI - Adjunctive Azithromycin Prophylaxis for Cesarean Delivery. PMID- 28079335 TI - Adjunctive Azithromycin Prophylaxis for Cesarean Delivery. PMID- 28079336 TI - Chronic Cough. PMID- 28079337 TI - Chronic Cough. PMID- 28079338 TI - A single institute's experience on melanoma prognosis: a long-term follow-up. AB - BACKGROUND: The prognosis of cutaneous melanoma is correlated to histopathologic parameters such as Breslow thickness, the presence of mitosis, ulceration and lymphatic involvement at the moment of the diagnosis. On the other hand, the prognostic value of parameters such as age, sex, and tumor localization are still a matter of debate. We evaluated herein the prognostic factors in melanoma patients during a long-term follow-up (60 months). METHODS: Melanoma patients presenting stage IB-III at diagnosis were included. Breslow thickness, ulceration, lymphatic involvement, patients' age, sex and tumor localization were correlated to patients' prognosis. Univariate Cox regressions and multivariate Cox proportional-hazards regression were performed. Successively, Kaplan-Meier was used for variables significantly associated with overall melanoma survival. RESULTS: A total of 115 melanoma patients were included in this study. During follow-up 82 (72.17%) patients survived and 33 (28.7%) died. In our dataset, Breslow thickness >2 mm (P=0.0007), patients age >50 years (P=0.005) and positive sentinel lymph node (P=0.0003) seem to be the most important variables correlated with the presence of metastases at 5 years follow-up. However distant metastases were also observed during follow-up in 14/26 patients presenting negative sentinel lymph node at diagnosis. CONCLUSIONS: Given the vital importance of target drugs and the newly introduced immunotherapies in cutaneous melanoma management, we would suggest that mutational analyses should also be extended to the subgroup of patients presenting microstaging parameters related to a poor prognosis in a long-term follow-up of 60 months. PMID- 28079339 TI - Survey of bullous pemphigoid in an Italian university hospital: clinical epidemiological characteristics and follow-up. AB - BACKGROUND: The clinical-epidemiological characteristics and course of bullous pemphigoid in the general population is not clear. Few studies have been performed to date, and only one in the Italian population more than ten years ago. We decided to evaluate the characteristics and outcome of patients admitted for a bullous pemphigoid at our Hospital in the last 4 years. METHODS: We retrospectively reviewed the last 4 years' medical records of the Department of Dermatology of the University of Bologna, identifying all patients with histological and immunological data typical for bullous pemphigoid. The patients were contacted and, whenever possible, re-evaluated clinically and serologically. Finally, we made a reviews of therapies administered in these cases. RESULTS: We identified 53 patients with a diagnosis of sub-epidermal autoimmune blistering disease. At re-evaluation, resolution of the disease was observed in 13 cases (24.52%) while the disease persisted in 32 cases. An improvement was observed in 35 (66.03%) patients, a worsening was observed in 3 (5.66%) patients, while the class did not change in 5 (9.43%) patients. All patients received systemic steroids as first line therapy, although most patients underwent more than one therapy. Fifteen patients received systemic steroid therapy alone, 22 patients received azathioprin, 16 patients received methotrexate, all patients received a prescription of topical steroid. Twenty-eight patients had abnormal values of eosinophilia, extremely susceptible to systemic steroid therapy. CONCLUSIONS: The findings of our study differ slightly from data collected by other authors in literature. Methotrexate is the drug of choice in terms of efficacy, practicality, cost and tolerability, particularly in the elderly population. PMID- 28079340 TI - Serum tryptase levels in melanoma patients: case-control study and review of the literature. AB - BACKGROUND: Serum tryptase results from the constant release of the enzyme from mast cells and serum tryptase levels are commonly considered to be related to the total number of mast cells. They are increased in several malignancies, as pancreatic carcinoma, angiosarcoma, hepatic carcinoma and proliferative and/or non- proliferative hematological disorders. Contrariwise, it has been reported that the number of tryptase+ and chymase+ mast cells was lower in deeply invasive melanoma compared to in-situ melanoma and dysplastic nevi. Considering the underlying pathophysiological linkages between mast cells and melanocytes and that serum tryptase is related to angiogenesis, tissue-degrading proprieties and metastatization, we have decided to evaluate serum tryptase levels in melanoma patients and in a healthy control. METHODS: We performed a case-control study evaluating serum tryptase in melanoma and in healthy group. Starting from an initial general analysis, we have performed a sub-analysis for each sample. RESULTS: In general population serum tryptase was statistically higher in elderly patients. Generally, in melanoma patients, median serum tryptase was in lower normal range. We found a decreasing of serum tryptase levels from the healthy control to thin (<= 1.00 mm Breslow thickness), reaching the lowest levels in thicker melanoma (>= 1.01 m Breslow thickness), in ulcerated and metastatic melanoma. CONCLUSION: Tryptase may have a protective role in melanoma or, conversely, it may play a role in the early stage of the tumorigenesis. Serum tryptase is an easy and useful biomarker to better investigate melanoma biology. PMID- 28079341 TI - Graves' Disease. PMID- 28079342 TI - Graves' Disease. PMID- 28079343 TI - Hepatic Encephalopathy. PMID- 28079344 TI - Hepatic Encephalopathy. PMID- 28079345 TI - Towards reducing the risk of new onset diabetes after pancreatitis. AB - Metabolic abnormalities due to acute and chronic pancreatitis are common. In particular, post-pancreatitis diabetes mellitus (PPDM) is increasingly recognized as a distinct clinical entity. However, most of the research in this field is focused on unravelling the pathogenesis of PPDM whereas research frontiers are rarely extended to reducing the risk of new onset diabetes after pancreatitis (NODAP). The recent development and validation of the PERSEUS score paved the way to identifying individuals after acute pancreatitis who are at high risk of developing NODAP. This article discusses the PERSEUS score and other evidence that may inform the development of guidelines on reducing the burden of PPDM. PMID- 28079346 TI - Increasing role for modified bismuth-containing quadruple therapies for Helicobacter pylori eradication. PMID- 28079347 TI - Diagnostic challenges of symptomatic uncomplicated diverticular disease. AB - Colonic diverticulosis is a common condition in Western industrialized countries occurring in up to 65% of people over the age of 60 years. Only a minority of these subjects (about 10-25%) experience symptoms, fulfilling Rome III Diagnostic Criteria for irritable bowel syndrome (IBS) diagnosis (IBS-like symptoms) in 10% to 66% of cases. Symptomatic uncomplicated diverticular disease (SUDD) is a syndrome characterized by recurrent abdominal symptoms attributed to diverticula in the absence of macroscopically evident alterations other than the presence of diverticula. Due to the different peak of incidence, the overlap between SUDD and IBS is predominantly present in middle-aged or older patients. In these cases, it is very complex to establish if the symptoms are related to the presence of diverticula or due to an overlapping IBS. In fact, the link between gastrointestinal symptoms and diverticula is unclear, and the mechanism by which diverticula may induce the development of IBS-like symptoms remains to be elucidated. Currently, the etiology and pathophysiology of SUDD, particularly when IBS-like symptoms are present, are not completely understood, and thus these two entities remain a diagnostic challenge not only for the general practitioner but also for the gastroenterologist. Although many issues remain open and unresolved, some minimize the importance of a distinction of these two entities as dietary and pharmacological management may be largely overlapping. PMID- 28079348 TI - Mental Illness and the Criminal Justice System. PMID- 28079349 TI - Interleukin-13 receptor alpha 2 as a marker of poorer prognosis in high-grade astrocytomas. AB - BACKGROUND: Interleukin-13 receptor alpha 2 (IL13Ralpha2) is considered a prognostic marker for gliomas according to the World Health Organization (WHO) grade. However, the expression levels of the marker vary from case to case, even within the same grade. We investigated whether IL13Ralpha2 could serve as a predictor of poorer prognosis in gliomas. METHODS: mRNA expression of IL13Ralpha2 was measured using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 52 formalin-fixed paraffin-embedded glioma samples (4 pilocytic astrocytomas, 9 diffuse astrocytomas, 12 anaplastic astrocytomas, and 27 glioblastomas, grade IV). The expression levels were compared with regard to WHO grade, MIB-1 index, patient's age, and overall survival. RESULTS: Real time qRT-PCR showed that IL13Ralpha2 is expressed in a subset of cases with a progressive increase from low- to high-grade astrocytomas (HGAs). The expression had a significant positive correlation with the MIB-1 index and advanced patient age at diagnosis. The overall survival (OS) of patients who had HGAs with higher levels of IL13Ralpha2 expression was significantly lower than the OS of those with HGAs with lower levels of IL13Ralpha2. In the 39 HGA cases studied, the median survival benefit in the lower expression group was 167.4 months. The median OS (mOS) in HGA group with lower IL13Ralpha2 expression was 186.4 months, while the mOS in the group with higher IL13Ralpha2 expression was 18.6 months (P=0.033). The hazard ratio, adjusted by fitting the Cox proportional hazard models for the mOS in the HGAs with higher IL13Ralpha2 levels and the HGGs with lower IL13Ralpha2 levels, was 5.97 (95% CI: 1.76 to 20.32). CONCLUSIONS: The results showed that IL13Ralpha2 may be used as a marker of poorer prognosis in HGAs, even among tumors of the same grade. PMID- 28079350 TI - Transcranial approach in giant pituitary adenomas: results and outcome in a modern series. AB - BACKGROUND: Today, transcranial (TC) approach indications are particularly rare in pituitary adenomas (PA), representing 1.1% of all PA surgeries in our experience. In these rare and selected cases, the complications, advantages, and disadvantages of TC approach were also analyzed. METHODS: 19 cases of giant PA (>=40 mm) operated via TC approach alone or combined with transsphenoidal (TS) approach between 2000 and 2016 were selected. RESULTS: The most frequently observed symptom was visual disturbance. Most PA (79%) were non-secreting. Only one tumor was aggressive. Maximal diameter average was 51.5 mm. Tumor removal was total, subtotal and partial in respectively 21%, 68.5%, and 10.5% of cases. Mean follow-up was 57 months. No recurrence was observed after total tumor removal. Visual improvement was observed in 53% of patients. Visual impairment rate was 21% after TC approach. New cases of panhypopituitarism were reported in 26.5% of patients in the TC approach. Total (including definitive and transient) postoperative diabetes insipidus occurred in 42% of patients in the TC approach. Ischemic and hemorrhagic complications were observed in 16% and 10.5% of patients, respectively, in the TC approach. Preoperative neurocognitive disturbance was identified in 31.5% of patients and only 16.5% of them showed postoperative improvement. Neurocognitive examination showed impaired results in 7.5% of patients with normal preoperative examination. CONCLUSIONS: TC approach remains a requirement in giant and invasive PAs non-accessible via TS approach. However, the high morbidity associated with TC approach, including ischemic complications and visual impairment, has to be balanced with patient preoperative symptoms, and benign features of the tumor. PMID- 28079351 TI - Effect of age on outcomes and practice patterns for patients with anterior communicating artery aneurysms. AB - BACKGROUND: With widespread utilization of noninvasive imaging, small enraptured anterior communicating artery (AcoA) aneurysms are increasingly detected in the general population, particularly in elderly patients. We investigated the association between age and clinical characteristics and outcomes of patients with unruptured AcoA aneurysms. METHODS: Between January 2008 and May 2016, information on 179 consecutive patients with unruptured AcoA aneurysms was obtained and included demographic data, aneurysm features, risk factors for formation and rupture, treatment type, complications, and follow-up information. A 2-tailed t test was used for continuous data and the chi-square test for categorical variables. Statistical significance was set at P value < 0.05. RESULTS: There were 76 patients 65 and older (42.5%) and 103 younger than 65 (57.5%). Conservative management was more common in older patients (67.1% vs 41.7%, P=0.001). Endovascular treatment was more commonly used in the older population (80% vs 61% of the treated aneurysms in older and younger group, P=0.16). Treatment-related complications were 8% but resulted in permanent neurological deficits in one patient (1.2%). Among conservatively treated aneurysms, three (3.2%) ruptured at follow-up resulting in patient death in two cases (2.4%). All three ruptures occurred in elderly patients. CONCLUSIONS: With a modern approach that emphasizes endovascular therapy, especially in older individuals, unruptured AcoA aneurysms can be treated with a very low morbidity. Among patients with small aneurysms for which treatment was not deemed indicated or necessary, the rate of rupture at follow-up was not negligible, with 5.8% of older patients experiencing bleeding from the aneurysm. PMID- 28079352 TI - The way forward in Italy for iodine. AB - Italy is dealing with iodine deficiency since ancient times. In 1848 an ad hoc committee appointed by the king of Sardinia, identified extensive areas afflicted by endemic goiter and endemic cretinism in Piedmont, Liguria and Sardinia. Since then many epidemiological studies have been conducted in our country. These showed that iodine deficiency was present not only in mountain areas but also in coastal areas. In 1972 the iodization of salt at 15 mg/kg was allowed by law and iodized salt was distributed on request to selected endemic areas. Five years later the distribution was extended to the whole country. However the sale of iodized salt was not mandatory at that time and only a small fraction of the Italian population started using iodized salt. In 1991 the content of iodine in the salt was raised to 30 mg/kg and in 2005 a nationwide salt iodization program was finally implemented. Some years later a nationwide monitoring program of iodine prophylaxis was also implemented. Since 2005 the sale of iodized salt in Italian supermarkets has increased (34% in 2006, 55% in 2012), although it has been observed that the use of iodized salt is still low in the communal eating areas and in the food industry. These data are coherent with recent epidemiological studies showing that some regions in our country are still characterized by mild iodine deficiency and a high frequency of goiter and other iodine deficiency disorders. This implies that further efforts should be made to successfully correct iodine deficiency in Italy. PMID- 28079353 TI - Historical aspects of iodine deficiency control. AB - In 1895, iodine was characterized as an essential element of thyroid tissue by Baumann. The efficacy of iodine to prevent goiter was demonstrated by Marine in Northern USA in 1916-1920. Severe endemic goiter and cretinism had been almost entirely eliminated from continental Western Europe and Northern America before the 1930's; however large populations elsewhere and even some places in Western Europe (Sicily) were still affected up to the 2000's. Public health consequences of iodine deficiency are not limited to endemic goiter and cretinism. Iodine deficiency disorders include also increased neonatal death rate and decreased intellectual development, although these consequences are not included in the current estimation of the Global Burden Disease related to iodine deficiency. Severe iodine deficiency as a public health problem is now largely under control worldwide, but can still affect isolated places, in hard-to-reach and/or politically neglected populations. We emphasize the importance of maintaining international cooperation efforts, in order to monitor iodine status where iodine deficiency is now adequately controlled, and identify at-risk population where it is not. The goal should be now global eradication of severe iodine deficiency. Commercial distribution of iodized salt remains the most appropriate strategy. A randomized clinical trial in New Guinea clearly showed in the 1970's that correcting severe iodine deficiency early in pregnancy prevents endemic neurological cretinism. This supports the essential role of thyroid hormones of maternal origin on the normal fetal development, during the first trimester of pregnancy (i.e. when fetal thyroid is still not functional). A randomized clinical trial in Congo (RD) in the 1970's also showed that correcting severe iodine deficiency during pregnancy prevents myxoedematous cretinism, particularly prevalent in affected Congolese areas. PMID- 28079354 TI - Effect of excess iodine intake on thyroid on human health. AB - The recommended daily intake of iodide, is 150 MUg for adolescents and adults, 250 MUg for pregnancy and lactation. Thyroid gland is an effective collector of iodine. The active iodine uptake along the basolateral membrane of thyroid cell is followed by its transport to the apical edge of the cell and then to the follicle lumen. TSH acts through cAMP and stimulates NIS gene expression and protein synthesis. The major proportion of iodine in the thyroid gland is bound to Thyroglobulin. The non-organic intrathyroidal iodine is usually low, but significantly greater compared to plasma. Large doses of iodine reduce both the uptake and the organification (Wolff-Chaikoff effect) and cause partial inhibition of Tg proteolysis. The thyroid gland has several protective mechanisms resulting on the maintenance of normal thyroid function despite wide fluctuations of the daily iodine intake. Ingestion of several commonly used drugs and food conservatives results in acute or chronic excessive iodine intake. Failure to escape from the iodine induced organification inhibition can cause hypothyroidism, which is temporary and subsides after iodine exposure ceases. Iodine excess may also establish a status of excessive thyroid hormone synthesis and release, thus inducing autonomic thyroid function in iodopenic areas or can contribute to the development of iodine-induced hyperthyroidism in iodine abundant areas. The anti-arrhythmic Amiodarone, is a benzofuranic product with a very high iodine content, is associated with either hypo- or hyperthyroidism development. In the presence of defective auto-protective mechanisms, excessive iodine ingestion can divert the normal thyroid function. PMID- 28079355 TI - Self-Assembled Architectures of Alkynylplatinum(II) Amphiphiles and Their Structural Optimization: A Balance of the Interplay Among Pt...Pt, pi-pi Stacking, and Hydrophobic-Hydrophobic Interactions. AB - A series of alkynylplatinum(II) terpyridine complexes with triethylene glycol units was synthesized, and their self-assembly properties were investigated in solution by UV-vis absorption, emission, and 1H NMR spectroscopy. The aggregation behaviors of several water-soluble complexes were investigated in aqueous media. Some of them were found to give rise to uniform fibers, suggesting the important role that triethylene glycol units has in regulating their self-assembly properties. Further modifications of these structures through the incorporation of alkyl chains and changes in counter-anions have rendered the complexes more amphiphilic in nature, and the effect of their alkyl chain lengths was studied and optimized. The distinguishable color and spectral changes upon variations in solvent compositions might have potential applications in developing colorimetric and luminescent probes for the detection of microenvironment change. Furthermore, an optimum chain length, i.e., n-butyl chain, is required for the formation of stable and ordered nanostructures. This represents a delicate balance among Pt...Pt, pi-pi stacking, and hydrophobic-hydrophobic interactions and provides guiding principles into the construction of supramolecular materials with practical applications. PMID- 28079356 TI - Highly CO2-Tolerant Cathode for Intermediate-Temperature Solid Oxide Fuel Cells: Samarium-Doped Ceria-Protected SrCo0.85Ta0.15O3-delta Hybrid. AB - Susceptibility to CO2 is one of the major challenges for the long-term stability of the alkaline-earth-containing cathodes for intermediate-temperature solid oxide fuel cells. To alleviate the adverse effects from CO2, we incorporated samarium-stabilized ceria (SDC) into a SrCo0.85Ta0.15O3-delta (SCT15) cathode by either mechanical mixing or a wet impregnation method and evaluated their cathode performance stability in the presence of a gas mixture of 10% CO2, 21% O2, and 69% N2. We observed that the CO2 tolerance of the hybrid cathode outperforms the pure SCT15 cathode by over 5 times at 550 degrees C. This significant enhancement is likely attributable to the low CO2 adsorption and reactivity of the SDC protective layer, which are demonstrated through thermogravimetric analysis, energy-dispersive spectroscopy, and electrical conductivity study. PMID- 28079357 TI - Tetracarboxylated Azobenzene/Polymer Supramolecular Assemblies as High Performance Multiresponsive Actuators. AB - Multistimuli-responsive polymers are materials of emerging interest but synthetically challenging. In this work, supramolecular assembly was employed as a facile and effective approach for constructing 3,3',5,5' azobenzenetetracarboxylic acid (H4abtc)/poly(diallyldimethylammonium chloride) (PDAC) supramolecules. Structural transformations of H4abtc can be induced by light, mechanical force, and heat and influenced by free volume. Thus, the fabricated free-standing H4abtc/PDAC film underwent bending/unbending movements upon treatment with light, humidity, or temperature, as asymmetric structural transformations on either side of the film generated asymmetric contraction/stretching forces. Fast rates of shape recovery were achieved for the film on exposure to gently flowing humid nitrogen. The bending/unbending motions are controllable, reversible, and repeatable. Hence, this light-, humido-, and thermo-responsive film has great potential in device applications for advanced functions. PMID- 28079358 TI - Cellulose Nanofibril Aerogels: Synergistic Improvement of Hydrophobicity, Strength, and Thermal Stability via Cross-Linking with Diisocyanate. AB - A facile gelation cross-linking approach was devised to fabricate meso- and macroporous cellulose nanofibril (CNF) aerogels with multiple improved properties. CNF hydrogels made using a freezing-thawing method with a 94 kPa modulus were solvent exchanged with acetone and then cross-linked with methylene diphenyl diisocyanate (MDI) to produce aerogels with significantly improved compressive properties that follow a power law increment against aerogel density with impressive 1.69, 2.49, and 1.43 scaling factors for Young's modulus, yield stress, and ultimate stress, respectively. The optimally cross-linked aerogels had nearly tripled specific surface area (228 m2/g) and doubled pore volume (1 m3/g) from numerous new 9-12 nm wide mesopores as well as significantly improved thermal stability (43% char residue at 500 C vs 9.1% for un-cross-linked aerogel). Cross-linking also made the amphiphilic CNF aerogel highly hydrophobic and capable of completely separating chloroform from water via simple filtration. These nanocellulose aerogels show great promise for efficient and continuous separation of oils and hydrophobic liquids from water. PMID- 28079359 TI - Pristine Graphene Electrode in Hydrogen Evolution Reaction. AB - Graphene, the sp2 carbonaceous two-dimensional (2D) material, is gaining more attention in recent electrochemical studies. However, this atomic thick electrode usually suffers with surface contamination and poor electrochemical endurance. To overcome the drawbacks, we developed a PMMA-assisted, flipped transfer method to fabricate the graphene electrode with pristine surface and prolonged lifetime in hydrogen evolution reaction (HER). The HER performances of the single-layer graphene (SLG) were evaluated on various insulating and conductive substrates, including SiO2, polymers, SLG, highly oriented pyrolytic graphite (HOPG), and copper. The parallel Tafel slopes of SLG, bilayer graphene (BLG), and HOPG suggest they share the same electrochemical activities deriving from the sp2 carbon basal plane. Moreover, the atomic barriers, both for SLG and the single layer h-BN (SLBN), are semitransparent in HER for the underneath copper, providing a new perspective for the 2D materials to protect and couple with the other electrochemical catalysts. PMID- 28079360 TI - Solution-Processed Organic Thin-Film Transistor Arrays with the Assistance of Laser Ablation. AB - A key step toward commercialization of organic thin-film transistors (OTFTs) is to manufacture large-area OTFT arrays with desired uniform device performance. In this work, for the first time, solution-processed OTFT arrays were fabricated with the assistance of laser ablation. The source-drain electrodes and the whole devices were patterned by precise control of laser intensity and process path. Compared with traditional methods, this approach significantly simplifies the fabrication process of OTFT arrays with high quality and high yield. A careful selection of laser processing parameters is key to obtaining high quality and high performance OTFT arrays. The grazing incidence X-ray diffraction experiments and device performance tests ensured the selection of proper laser ablation intensity. Eventually, the OTFT arrays on silicon wafer and ITO glass exhibited uniform electrical characteristics with the mean mobility of 0.16 and 0.10 cm2 V 1 s-1, respectively. These results demonstrated that the laser ablation process provides a promising tool to simplify the fabrication of solution-processed OTFT arrays with low cost and high yield, which has great potential in upscaling of high performance OTFT arrays for display and circuits. PMID- 28079361 TI - Controllable Synthesis of a Smart Multifunctional Nanoscale Metal-Organic Framework for Magnetic Resonance/Optical Imaging and Targeted Drug Delivery. AB - As a result of their extraordinarily large surfaces and well-defined pores, the design of a multifunctional metal-organic framework (MOF) is crucial for drug delivery but has rarely been reported. In this paper, a novel drug delivery system (DDS) based on nanoscale MOF was developed for use in cancer diagnosis and therapy. This MOF-based tumor targeting DDS was fabricated by a simple postsynthetic surface modification process. First, magnetic mesoporous nanomaterial Fe-MIL-53-NH2 was used for encapsulating the drug and served as a magnetic resonance contrast agent. Moreover, the Fe-MIL-53-NH2 nanomaterial exhibited a high loading capacity for the model anticancer drug 5-fluorouracil (5 FU). Subsequently, the fluorescence imaging agent 5-carboxyfluorescein (5-FAM) and the targeting reagent folic acid (FA) were conjugated to the 5-FU-loaded Fe MIL-53-NH2, resulting in the advanced DDS Fe-MIL-53-NH2-FA-5-FAM/5-FU. Owing to the multifunctional surface modification, the obtained DDS Fe-MIL-53-NH2-FA-5 FAM/5-FU shows good biocompatibility, tumor enhanced cellular uptake, strong cancer cell growth inhibitory effect, excellent fluorescence imaging, and outstanding magnetic resonance imaging capability. Taken together, this study integrates diagnostic and treatment aspects into a single platform by a simple and efficient strategy, aiming for facilitating new possibilities for MOF use for multifunctional drug delivery. PMID- 28079363 TI - Fluorescence Development of Latent Fingerprint with Conjugated Polymer Nanoparticles in Aqueous Colloidal Solution. AB - Poly(p-phenylenevinylene) (PPV) nanoparticles in aqueous colloidal solution have been prepared via a modified Wessling method, with the addition of surfactant. The fluorescent colloidal solution was used as the developing solution to develop the fingerprints on different substrates. The developing process was accomplished simply by immersing the substrates into developing solution and then taking out, followed by rinsing with deionized water. The initial study about the fingerprints on the adhesive tapes showed that the developing solution is very effective in fluorescence development on both fresh and aged visible fingerprints; and such an effect was negligibly affected by treating the fingerprints with water or other organic solvents, whether before developing or after. Further study on latent fingerprints (LFPs) demonstrated that PPV nanoparticles in colloidal solution have high sensitivity in developing fingerprints to give very clearly fluorescent patterns. At least 6 months of storage of the colloidal solution did not reduce the developing effect; and each developing solution (3.6 mg/mL, 5.0 mL) can be used to develop at least 30 fingerprints without sacrificing the legibility of the pattern. The preliminary mechanism investigation suggested that selectivity achieved toward the ridge of the fingerprint is very likely due to the affinity between PPV molecules and oily secretions of the fingerprints. Digital magnification of the developed fingerprints provided more details about the fingerprint. PMID- 28079362 TI - Intensive Study on the Catalytical Behavior of N-Methylphenothiazine as a Soluble Mediator to Oxidize the Li2O2 Cathode of the Li-O2 Battery. AB - Aprotic Li-O2 batteries have attracted worldwide interest owing to their ultrahigh theoretical energy density. However, the practical Li-O2 batteries still suffer from high charge overpotential and low energy efficiency resulting from the sluggish kinetics in electrochemically oxidizing the insulating lithium peroxide (Li2O2). Recently, dissolved redox mediators in the electrolyte have enabled the effective catalytic oxidation of Li2O2 at the liquid-solid interface. Here, we report that the incorporation of N-methylphenothiazine (MPT), as a redox shuttle in Li-O2 batteries, provides a dramatic reduction in charge overpotential to 0.67 V and an improved round-trip efficiency close to 76%. Moreover, the efficacy of MPT in Li-O2 cells was further investigated by various characterizations. On charging, MPT+ cations are first generated electrochemically at the cathode surface and subsequently oxidize the solid discharge products Li2O2 through a chemical reaction. Furthermore, the presence of MPT has been demonstrated to improve the cycling stability of the cells and suppress side reactions arising from carbon and electrolytes at high potentials. PMID- 28079364 TI - DNA Modified Fe3O4@Au Magnetic Nanoparticles as Selective Probes for Simultaneous Detection of Heavy Metal Ions. AB - Driven by the urgent need to detect trace heavy metal ions in various real water samples, this article demonstrates for the first time an electrochemical biosensor based on DNA modified Fe3O4@Au magnetic nanoparticles (NPs). Three DNA probes are designed to contain certain mismatched base pairs. One is thiolated and modified on the surface of Fe3O4@Au NPs (DNA 1). The other two probes (DNA 2 and 3) are labeled with two independent electrochemical species. Stable structures of cytosine-Ag+-cytosine and thymine-Hg2+-thymine formed in the presence of Ag+ and Hg2+ can assist the hybridization of DNA 1/DNA 2 and DNA 1/DNA 3, which locate corresponding electrochemical species onto the surface of the magnetic NPs. The achieved nanocomposites are then used as selective electrochemical probes for the detection of heavy metal ions by recording the square wave voltammetry signals. Simultaneous detection of Ag+ and Hg2+ is demonstrated without significant interference, and their individual high sensitivities are fundamentally preserved, which meet the requirements of U.S. Environmental Protection Agency (USEPA). Furthermore, the proposed method has been challenged by various real water samples. The results confirm the DNA modified magnetic NPs based sensing method may have potential applications for the monitoring of heavy metal ions in real sample analysis. PMID- 28079365 TI - Twist and Shout: Single-Molecule Mechanochemistry. AB - Chemical reactions can be accelerated by various means, including applied mechanical forces. If the direction of the force does not project well onto the desired reaction coordinate, then only poor acceleration is achieved. Recent developments in single polymer mechanics illustrate how to overcome this limitation, in a simple cis-trans isomerization reaction. Generalizing the approach, synthetic chemistry can be used to attach tethers to different parts of reacting molecular fragments to direct the force usefully. This Perspective explores the prospects for using applied mechanical forces to create exciting new chemistries. For example, it is possible to imagine making polymers that sense mechanical forces within hard-to-reach places, like biological cells, or using mechanical forces to make nanoscale electrical devices using conjugated polymers. PMID- 28079366 TI - The Neonicotinoid Insecticide Thiacloprid Impacts upon Bumblebee Colony Development under Field Conditions. AB - The impacts of pesticides, and in particular of neonicotinoids, on bee health remain much debated. Many studies describing negative effects have been criticized as the experimental protocol did not perfectly simulate real-life field scenarios. Here, we placed free-flying bumblebee colonies next to raspberry crops that were either untreated or treated with the neonicotinoid thiacloprid as part of normal farming practice. Colonies were exposed to the raspberry crops for a two week period before being relocated to either a flower-rich or flower-poor site. Overall, exposed colonies were more likely to die prematurely, and those that survived reached a lower final weight and produced 46% fewer reproductives than colonies placed at control farms. The impact was more marked at the flower rich site (all colonies performed poorly at the flower poor site). Analysis of nectar and pollen stores from bumblebee colonies placed at the same raspberry farms revealed thiacloprid residues of up to 771 ppb in pollen and up to 561 ppb in nectar. The image of thiacloprid as a relatively benign neonicotinoid should now be questioned. PMID- 28079367 TI - Robust, Responsive, and Targeted PLGA Anticancer Nanomedicines by Combination of Reductively Cleavable Surfactant and Covalent Hyaluronic Acid Coating. AB - PLGA-based nanomedicines have enormous potential for targeted cancer therapy. To boost their stability, targetability, and intracellular drug release, here we developed novel multifunctional PLGA anticancer nanomedicines by combining a reductively cleavable surfactant (RCS), vitamin E-SS-oligo(methyl diglycol l glutamate), with covalent hyaluronic acid (HA) coating. Reduction-sensitive HA coated PLGA nanoparticles (rHPNPs) were obtained with small sizes of 55-61 nm and zeta potentials of -26.7 to -28.8 mV at 18.4-40.3 wt % RSC. rHPNPs were stable against dilution and 10% FBS while destabilized under reductive condition. The release studies revealed significantly accelerated docetaxel (DTX) release in the presence of 10 mM glutathione. DTX-rHPNPs exhibited potent and specific antitumor effect to CD44 + A549 lung cancer cells (IC50 = 0.52 MUg DTX equiv/mL). The in vivo studies demonstrated that DTX-rHPNPs had an extended circulation time and greatly enhanced tolerance in mice. Strikingly, DTX-rHPNPs completely inhibited growth of orthotopic human A549-Luc lung tumor in mice, leading to a significantly improved survival rate and reduced adverse effect as compared to free DTX. This study highlights that advanced nanomedicines can be rationally designed by combining functional surfactants and surface coating. PMID- 28079368 TI - Ligand Design for Isomer-Selective Oxorhenium(V) Complex Synthesis. AB - Recently, N,N-trans Re(O)(LN-O)2X (LN-O = monoanionic N-O chelates; X = Cl or Br prior to being replaced by solvents or alkoxides) complexes have been found to be superior to the corresponding N,N-cis isomers in the catalytic reduction of perchlorate via oxygen atom transfer. However, reported methods for Re(O)(LN-O)2X synthesis often yield only the N,N-cis complex or a mixture of trans and cis isomers. This study reports a geometry-inspired ligand design rationale that selectively yields N,N-trans Re(O)(LN-O)2Cl complexes. Analysis of the crystal structures revealed that the dihedral angles (DAs) between the two LN-O ligands of N,N-cis Re(O)(LN-O)2Cl complexes are less than 90 degrees , whereas the DAs in most N,N-trans complexes are greater than 90 degrees . Variably sized alkyl groups (-Me, -CH2Ph, and -CH2Cy) were then introduced to the 2-(2'-hydroxyphenyl) 2-oxazoline (Hhoz) ligand to increase steric hindrance in the N,N-cis structure, and it was found that substituents as small as -Me completely eliminate the formation of N,N-cis isomers. The generality of the relationship between N,N trans/cis isomerism and DAs is further established from a literature survey of 56 crystal structures of Re(O)(LN-O)2X, Re(O)(LO-N-N-O)X, and Tc(O)(LN-O)2X congeners. Density functional theory calculations support the general strategy of introducing ligand steric hindrance to favor synthesis of N,N-trans Re(O)(LN-O)2X and Tc(O)(LN-O)2X complexes. This study demonstrates the promise of applying rational ligand design for isomeric control of metal complex structures, providing a path forward for innovations in a number of catalytic, environmental, and biomedical applications. PMID- 28079369 TI - Muropeptide Binding and the X-ray Structure of the Effector Domain of the Transcriptional Regulator AmpR of Pseudomonas aeruginosa. AB - A complex link exists between cell-wall recycling/repair and the manifestation of resistance to beta-lactam antibiotics in many Enterobacteriaceae and Pseudomonas aeruginosa. This process is mediated by specific cell-wall-derived muropeptide products. These muropeptides are internalized into the cytoplasm and bind to the transcriptional regulator AmpR, which controls the cytoplasmic events that lead to expression of beta-lactamase, an antibiotic-resistance determinant. The effector-binding domain (EBD) of AmpR was purified to homogeneity. We document that the EBD exists exclusively as a dimer, even at a concentration as low as 1 MUM. The EBD binds to the suppressor ligand UDP-N-acetyl-beta-d-muramyl-l-Ala gamma-d-Glu-meso-DAP-d-Ala-d-Ala and binds to two activator muropeptides, N acetyl-beta-d-glucosamine-(1->4)-1,6-anhydro-N-acetyl-beta-d-muramyl-l-Ala-gamma d-Glu-meso-DAP-d-Ala-d-Ala and 1,6-anhydro-N-acetyl-beta-d-muramyl-l-Ala-gamma-d Glu-meso-DAP-d-Ala-d-Ala, as assessed by non-denaturing mass spectrometry. The EBD does not bind to 1,6-anhydro-N-acetyl-beta-d-muramyl-l-Ala-gamma-d-Glu-meso DAP. This binding selectivity revises the dogma in the field. The crystal structure of the EBD dimer was solved to 2.2 A resolution. The EBD crystallizes in a "closed" conformation, in contrast to the "open" structure required to bind the muropeptides. Structural issues of this ligand recognition are addressed by molecular dynamics simulations, which reveal significant differences among the complexes with the effector molecules. PMID- 28079370 TI - Substituted Polyesters by Thiol-Ene Modification: Rapid Diversification for Therapeutic Protein Stabilization. AB - Many proteins, especially those used as therapeutics, are unstable to storage and shipping temperatures, leading to increased costs in research and industry. Therefore, the design and synthesis of novel stabilizers is an important area of investigation. Herein we report new degradable polymers that stabilize proteins to environmental stressors such as refrigeration and elevated temperature. Specifically, polycaprolactones with different pendant groups were synthesized and surveyed for their ability to stabilize an important therapeutic protein to storage and shipping conditions. Ring-opening polymerization (ROP) of an allyl substituted caprolactone monomer was carried out using the organocatalyst 1,5,7 triazabicyclo[4.4.0]dec-5-ene (TBD) to yield a well-defined, alkene-substituted degradable polymer, which was used as a common backbone to control for the degree of polymerization. Relevant side chains such as trehalose, lactose, glucose, carboxybetaine, and oligo(ethylene glycol) were installed via postpolymerization thiol-ene reactions. These degradable polymers were then employed as excipients for the stabilization of the therapeutic protein granulocyte colony-stimulating factor (G-CSF) against storage at 4 degrees C and shipping temperatures of 60 degrees C. The best stabilization was observed using the trehalose- and zwitterion- substituted polyesters. Both the trehalose- and carboxybetaine substituted pCL were further investigated with regard to molecular weight dependence, and it was found that the molecular weight was minimally important for stabilization to refrigeration, but critical for G-CSF stabilization at elevated temperatures. Both high performing zwitterionic and trehalose polyesters were also degraded, and the polymers and degradation products were shown to be noncytotoxic. This work provides potential biocompatible polymers for stabilization of the important therapeutic G-CSF, as well as a general platform for the future discovery of new polymeric protein stabilizers. PMID- 28079372 TI - Effect of Water Coordination on Luminescent Properties of Pyrazine-Bridged Dinuclear Cu(I) Complexes. AB - Two luminescent pyrazine-bridged dinuclear Cu(I) complexes, namely, [{Cu(PPh3)2(H2O)}(MU-MeOpyz){Cu(PPh3)2(CH3CN)}](BF4)2 and [{Cu(PPh3)2(H2O)}(MU MeOpyz){Cu(PPh3)2(H2O)}](BF4)2 (H2O-Cu2-AN and H2O-Cu2-H2O; PPh3 = triphenylphosphine, MeOpyz = 2-methoxypyrazine), were successfully synthesized and characterized by single-crystal X-ray diffraction and luminescence measurements. X-ray analysis revealed that the water molecules are coordinated to both Cu(I) ions to form almost the same P2N1O1 coordination structure in H2O-Cu2 H2O, whereas one of the two Cu ions in H2O-Cu2-AN was coordinated by acetonitrile instead of water to form a different P2N2 coordination environment. The asymmetric H2O-Cu2-AN exhibits very bright yellow-green emission with a high emission quantum yield (lambdaem = 550 nm, Phi = 0.70) at room temperature in the solid state in spite of the coordination of water molecule, which usually tends to deactivate the emissive state through O-H vibration. The intense emission at room temperature is a result of thermally activated delayed fluorescence, and the remarkable temperature dependence of emission lifetimes indicates the existence of unique multiple emission states for the asymmetric dinuclear complex. In contrast, the emission of H2O-Cu2-H2O was observed at longer wavelengths with remarkably a lower quantum yield (lambdaem = 580 nm, Phi = 0.05). Time-dependent density functional theory calculations suggested that the emission could result from the metal-to-ligand charge-transfer transition state. However, it could be rapidly deactivated by the structural distortion around the Cu ion with a less bulky coordination environment in H2O-Cu2-H2O. PMID- 28079371 TI - Binding Pose Flip Explained via Enthalpic and Entropic Contributions. AB - The anomalous binding modes of five highly similar fragments of TIE2 inhibitors, showing three distinct binding poses, are investigated. We report a quantitative rationalization for the changes in binding pose based on molecular dynamics simulations. We investigated five fragments in complex with the transforming growth factor beta receptor type 1 kinase domain. Analyses of these simulations using Grid Inhomogeneous Solvation Theory (GIST), pKA calculations, and a tool to investigate enthalpic differences upon binding unraveled the various thermodynamic contributions to the different binding modes. While one binding mode flip can be rationalized by steric repulsion, the second binding pose flip revealed a different protonation state for one of the ligands, leading to different enthalpic and entropic contributions to the binding free energy. One binding pose is stabilized by the displacement of entropically unfavored water molecules (binding pose determined by solvation entropy), ligands in the other binding pose are stabilized by strong enthalpic interactions, overcompensating the unfavorable water entropy in this pose (binding pose determined by enthalpic interactions). This analysis elucidates unprecedented details determining the flipping of the binding modes, which can elegantly explain the experimental findings for this system. PMID- 28079373 TI - Energetics of the S2 State Spin Isomers of the Oxygen-Evolving Complex of Photosystem II. AB - The S2 redox intermediate of the oxygen-evolving complex in photosystem II is present as two spin isomers. The S = 1/2 isomer gives rise to a multiline electron paramagnetic resonance (EPR) signal at g = 2.0, whereas the S = 5/2 isomer exhibits a broad EPR signal at g = 4.1. The electronic structures of these isomers are known, but their role in the catalytic cycle of water oxidation remains unclear. We show that formation of the S = 1/2 state from the S = 5/2 state is exergonic at temperatures above 160 K. However, the S = 1/2 isomer decays to S1 more slowly than the S = 5/2 isomer. These differences support the hypotheses that the S3 state is formed via the S2 state S = 5/2 isomer and that the stabilized S2 state S = 1/2 isomer plays a role in minimizing S2QA- decay under light-limiting conditions. PMID- 28079374 TI - Ultrafast Dynamics of Hydrogen Bond Breaking and Making in the Excited State of Fluoren-9-one: Time-Resolved Visible Pump-IR Probe Spectroscopic Study. AB - The fluoren-9-one (FL) molecule, with a single hydrogen bond-accepting site (C?O group), has been used as a probe for investigation of the dynamics of a hydrogen bond in its lowest excited singlet (S1) state using the subpicosecond time resolved visible pump-IR probe spectroscopic technique. In 1,1,1,3,3,3 hexafluoroisopropanol (HFIP), a strong hydrogen bond-donating solvent, the formation of an FL-alcohol hydrogen-bonded complex in the ground electronic (S0) state is nearly complete, with a negligible concentration of the FL molecule remaining free in solution. In addition to the presence of a band due to the hydrogen-bonded complex in the transient IR spectrum recorded immediately after photoexcitation of FL in HFIP solution, appearance of the absorption band due to a free C?O stretch provides confirmatory evidence of ultrafast photodissociation of hydrogen bonds in some of the complexes formed in the S0 state. The peak-shift dynamics of the C?O stretch bands reveal two major relaxation pathways, namely, vibrational relaxation in the S1 state of the free FL molecules and the solvent reorganization process in the hydrogen-bonded complex. The latter process follows bimodal exponential dynamics involving hydrogen bond-making and hydrogen bond reorganization processes. The similar lifetimes of the S1 states of the FL molecules, both free and hydrogen-bonded, suggest establishment of a dynamic equilibrium between these two species in the excited state. However, investigations in two other weaker hydrogen bond-donating solvents, namely, trifluoroethanol (TFE) and perdeuterated methanol (CD3OD), reveal different features of peak-shift dynamics because of the prominence of the vibrational relaxation process over the hydrogen bond-reorganization process during the early time. PMID- 28079375 TI - Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide. AB - In recent years, there has been an increased interest in using macrocyclic compounds for drug discovery and development. For docking of these commonly large and flexible compounds to be addressed, a screening and a validation set were assembled from the PDB consisting of 16 and 31 macrocycle-containing protein complexes, respectively. The macrocycles were docked in Glide by rigid docking of pregenerated conformational ensembles produced by the macrocycle conformational sampling method (MCS) in Schrodinger Release 2015-3 or by direct Glide flexible docking after performing ring-templating. The two protocols were compared to rigid docking of pregenerated conformational ensembles produced by an exhaustive Monte Carlo multiple minimum (MCMM) conformational search and a shorter MCMM conformational search (MCMM-short). The docking accuracy was evaluated and expressed as the RMSD between the heavy atoms of the ligand as found in the X-ray structure after refinement and the poses obtained by the docking protocols. The median RMSD values for top-scored poses of the screening set were 0.83, 0.80, 0.88, and 0.58 A for MCMM, MCMM-short, MCS, and Glide flexible docking, respectively. There was no statistically significant difference in the performance between rigid docking of pregenerated conformations produced by the MCS and direct docking using Glide flexible docking. However, the flexible docking protocol was 2-times faster in docking the screening set compared to that of the MCS protocol. In a final study, the new Prime-MCS method was evaluated in Schrodinger Release 2016-3. This method is faster compared that of to MCS; however, the conformations generated were found to be suboptimal for rigid docking. Therefore, on the basis of timing, accuracy, and ease of set up, standard Glide flexible docking with prior ring-templating is recommended over current gold standard protocols using rigid docking of pregenerated conformational ensembles. PMID- 28079376 TI - Synthesis, Structures, and CO Release Capacity of a Family of Water-Soluble PhotoCORMs: Assessment of the Biocompatibility and Their Phototoxicity toward Human Breast Cancer Cells. AB - Two manganese(I) carbonyl complexes derived from 2-(pyridyl)benzothiazole (pbt) and 1,10-phenanthroline (phen) release carbon monoxide (CO) under low-power broad band visible-light illumination. CO photorelease from [Mn(CO)3(pbt)(PTA)]CF3SO3 (1, where PTA = 1,3,5-triaza-7-phosphaadamantane) is accompanied by an emergence of a strong fluorescence around 400 nm from almost nonfluorescent preirradiated 1. However, [Mn(CO)3(phen)(PTA)]CF3SO3 (2) showed no such phenomenon upon prolonged illumination under similar experimental conditions. The two analogous rhenium(I) complexes, namely, [Re(CO)3(pbt)(PTA)]CF3SO3 (3) and [Re(CO)3(phen)(PTA)]CF3SO3 (4), have also been synthesized and characterized to compare their photo properties with the manganese congeners. Complexes 3 and 4 exhibit moderate CO release upon irradiation with low-power UV light. All four complexes are highly soluble in anaerobic/aerobic aqueous media and are also considerably more stable when kept under dark conditions. The inherently luminescent rhenium complex 3 was utilized to demonstrate cellular internalization of these types of compounds by MDA-MB-231 (human breast cancer) cells, while the two biocompatible manganese(I) complexes (1 and 2) have been applied to assess the cell viability of these malignant cells upon CO delivery. PMID- 28079378 TI - Dibenzofurans and Pseudodepsidones from the Lichen Stereocaulon paschale Collected in Northern Quebec. AB - Chemical investigation of the methanol extract of the lichen Stereocaulon paschale collected in Nunavik, Canada, led to the isolation and identification of two new dibenzofurans (1 and 3) and 11 known lichen metabolites. The structures of the new compounds were established by analysis of 1D and 2D NMR spectroscopic and high-resolution mass spectrometric data. Herein, the first isolation of ascomatic acid dibenzofuran derivatives (1-3) from a whole lichen organism is reported. In addition, some of the isolated metabolites showed antibacterial activity against the oral pathogens Porphyromonas gingivalis and Streptococcus mutans. PMID- 28079379 TI - Formation of Zintl Ions and Their Configurational Change during Sodiation in Na Sn Battery. AB - Despite their large theoretical storage capability, Na-Sn batteries exhibit poor round-trip energy efficiencies as compared to Li-Si batteries. Here, we report the results of a comprehensive study to elucidate how and why Na-Sn batteries exhibit such a low energy efficiency. As a convincing evidence for this behavior, we observed that the resistivity of the Sn anode increased by 8 orders of magnitude during in situ sodiation experiments, which is attributed to the formation of electrically resistive Zintl ions in the sodiated Sn. Continual sodiation induced the development of residual stresses at the Sn anode and caused the distortion of Zintl ions from their ideal configuration. This distortion caused a change in the electronic structure, resulting in the increased resistivity of the sodiated Sn. Our findings offer some solutions that can be used to improve the energy efficiency of Na-Sn batteries. PMID- 28079380 TI - Extraordinarily Rapid Rise of Tiny Bubbles Sliding beneath Superhydrophobic Surfaces. AB - Tiny bubbles readily stick onto substrates owing to contact angle hysteresis (CAH). Nevertheless, they can slide slowly on a tilted surface with ultralow CAH because capillarity is overcome by buoyancy. It is surprising to observe experimentally that bubbles of 3-15 MUL (diameter 1.79-3.06 mm) slide beneath a tilted superhydrophobic surface at a vertical ascent rate faster than that of freely rising ones of high Reynold numbers ~O(102). As the tilting angle increases, the drag coefficient remains essentially the same as that of a freely rising bubble, but the frontal area of the flat bubble rises monotonically. Nonetheless, the frontal area of the sliding bubble always stays much smaller than that of a freely rising bubble. Consequently, the small drag force associated with the sliding bubbles is attributed to their substantially small frontal areas on superhydrophobic surfaces. PMID- 28079381 TI - Gold-Catalyzed Regiodivergent [2 + 2 + 2]-Cycloadditions of Allenes with Triazines. AB - Gold-catalyzed regiodivergent cycloadditions of functionalized allenes with 1,3,5 triazines, providing diverse N-heterocycles in moderate to excellent yields under mild reaction conditions, are reported. Importantly, different types of allenes exhibit distinct selectivity and reactivity for the reactions. Mechanistic investigations reveal that all of the cycloadditions proceed through a stepwise [2 + 2 + 2]-cycloaddition process. PMID- 28079382 TI - Single-Molecule Transport at a Rectifying GaAs Contact. AB - In most single- or few-molecule devices, the contact electrodes are simple ohmic resistors. Here we describe a new type of single-molecule device in which metal and semiconductor contact electrodes impart a function, namely, current rectification, which is then modified by a molecule bridging the gap. We study junctions with the structure Au STM tip/X/n-GaAs substrate, where "X" is either a simple alkanedithiol or a conjugated unit bearing thiol/methylthiol contacts, and we detect current jumps corresponding to the attachment and detachment of single molecules. From the magnitudes of the current jumps we can deduce values for the conductance decay constant with molecule length that agree well with values determined from Au/molecule/Au junctions. The ability to impart functionality to a single-molecule device through the properties of the contacts as well as through the properties of the molecule represents a significant extension of the single-molecule electronics "tool-box". PMID- 28079383 TI - Structure and Interaction in the pH-Dependent Phase Behavior of Nanoparticle Protein Systems. AB - The pH-dependent structure and interaction of anionic silica nanoparticles (diameter 18 nm) with two globular model proteins, lysozyme and bovine serum albumin (BSA), have been studied. Cationic lysozyme adsorbs strongly on the nanoparticles, and the adsorption follows exponential growth as a function of lysozyme concentration, where the saturation value increases as pH approaches the isoelectric point (IEP) of lysozyme. By contrast, irrespective of pH, anionic BSA does not show any adsorption. Despite having a different nature of interactions, both proteins render a similar phase behavior where nanoparticle-protein systems transform from being one-phase (clear) to two-phase (turbid) above a critical protein concentration (CPC). The measurements have been carried out for a fixed concentration of silica nanoparticles (1 wt %) with varying protein concentrations (0-5 wt %). The CPC is found to be much higher for BSA than for lysozyme and increases for lysozyme but decreases for BSA as pH approaches their respective IEPs. The structure and interaction in these systems have been examined using dynamic light scattering (DLS) and small-angle neutron scattering (SANS). The effective hydrodynamic size of the nanoparticles measured using DLS increases with protein concentration and is related to the aggregation of the nanoparticles above the CPC. The propensity of the nanoparticles to aggregate is suppressed for lysozyme and enhanced for BSA as pH approached their respective IEPs. This behavior is understood from SANS data through the interaction potential determined by the interplay of electrostatic repulsion with a short range attraction for lysozyme and long-range attraction for BSA. The nanoparticle aggregation is caused by charge neutralization by the oppositely charged lysozyme and through depletion for similarly charged BSA. Lysozyme-mediated attractive interaction decreases as pH approaches the IEP because of a decrease in the charge on the protein. In the case of BSA, a decrease in the BSA-BSA repulsion enhances the depletion attraction between the nanoparticles as pH is shifted toward the IEP. The morphology of the nanoparticle aggregates is found to be mass fractal. PMID- 28079385 TI - [Influence of drug concentration and blending technology on the content uniformity of mixture for low dose warfarin tablets]. AB - Warfarin is a drug with narrow therapeutic index. Individualization of dose and thorough therapy monitoring is compensated by long time use in praxis and low therapy cost. Considering the low dose usually administered, critical parameter of solid dosage form is its uniformity of content. It has to not only meet the criteria set by pharmacopoeia, but to meet them on statisticall significant level also.This experimental study asseses impact of warfarin concentration and blending time after adition of lubricant on uniformity of content of mixtures and tablets made of them. It concludes, that concentration in 2-2,7% range is optimal and its increase or decrease has a negative effect on uniformity of content. It also confirms 5 minutes of blending after lubricant addition to be adequate, as employing longer blending times leads to mixture overblending.Key words: content uniformity warfarin blending time narrow therapeutic index. PMID- 28079384 TI - Hypoxia and H2O2 Dual-Sensitive Vesicles for Enhanced Glucose-Responsive Insulin Delivery. AB - A glucose-responsive closed-loop insulin delivery system mimicking pancreas activity without long-term side effect has the potential to improve diabetic patients' health and quality of life. Here, we developed a novel glucose responsive insulin delivery device using a painless microneedle-array patch containing insulin-loaded vesicles. Formed by self-assembly of hypoxia and H2O2 dual-sensitive diblock copolymer, the glucose-responsive polymersome-based vesicles (d-GRPs) can disassociate and subsequently release insulin triggered by H2O2 and hypoxia generated during glucose oxidation catalyzed by glucose specific enzyme. Moreover, the d-GRPs were able to eliminate the excess H2O2, which may lead to free radical-induced damage to skin tissue during the long-term usage and reduce the activity of GOx. In vivo experiments indicated that this smart insulin patch could efficiently regulate the blood glucose in the chemically induced type 1 diabetic mice for 10 h. PMID- 28079386 TI - Level of understanding of medical terms among italian students. AB - Problems related to medical treatment and health literacy are nowadays a considerable difficulty, particularly if awareness of them is low. There is still a lack of information about students understanding of medical recommendations. The aim of this work was to determine the understanding of medical terms among Italian students and to find out if there is any relation between understanding and age, gender, education or parental occupation. The research was realized via questionnaires in the Marche region of Central Italy in 2015. Students were chosen at random from grammar schools, vocational schools and the local university. 387 completed questionnaires were subsequently evaluated. The level of understanding of medical terms among students was quite poor. Most of the terms included in the study were known to only a third of respondents on average. A significant link between the comprehension of medical terms and education level or parental occupation was observed, especially in the terms that are not commonly used. Nevertheless, no relation between knowledge of medical terms and gender was found. This topic, which requires attention, should be investigated because of correct implementation of preventive medicine programs.Key words: medical terms Italian students correct use of medicine risk. PMID- 28079387 TI - Fractal aspects of the flow and shear behaviour of free-flowable particle size fractions of pharmaceutical directly compressible excipient sorbitol. AB - Flowability of powder excipients is directly influenced by their size and shape although the granulometric influence of the flow and shear behaviour of particulate matter is not studied frequently. In this work, the influence of particle size on the mass flow rate through the orifice of a conical hopper, and the cohesion and flow function was studied for four free-flowable size fractions of sorbitol for direct compression in the range of 0.080-0.400 mm. The particles were granulometricaly characterized using an optical microscopy; a boundary fractal dimension of 1.066 was estimated for regular sorbitol particles. In the particle size range studied, a non-linear relationship between the mean particle size and the mass flow rate Q10 (g/s) was detected having amaximum at the 0.245mm fraction. The best flow properties of this fraction were verified with aJenike shear tester due to the highest value of flow function and the lowest value of the cohesion. The results of this work show the importance of the right choice of the excipient particle size to achieve the best flow behaviour of particulate material.Key words: flowability size fraction sorbitol for direct compaction Jenike shear tester fractal dimension. PMID- 28079388 TI - [Effect of EUDRAGIT(r) RS on the release behaviour of theophylline solid dispersions]. AB - The purpose of this study was to extend the release of theophylline using Eudragit(r) RS 100 and Eudragit(r) RSPO as carriers. Solid dispersions of theophylline were prepared by the solvent evaporation technique using Eudragit(r) RS 100, Eudragit(r) RSPO and their blend in various drug : polymer ratios. The prepared solid dispersions were characterized with respect to entrapment efficiency, solubility and recovery yield. In vitro drug release of theophylline from the solid dispersions was evaluated in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) without enzymes. Solubility studies demonstrated a decrease in the solubility of the drug from the solid dispersions. The solubilities of pure drug and solid dispersions were lowered in SGF compared to SIF. Solid dispersions prepared with Eudragit(r) RS 100 entrapped a greater amount of theophylline in comparison to those with Eudragit(r) RSPO or the polymer blends and were able to extend the release of theophylline over 24 hrs. Formulation SD4 released 95.52% of the drug in SIF and 93.56% in SGF. Hence, it was selected as the optimized formulation because it was able to extend the release of theophylline over 24 hrs.Key words: solid dispersion extended release Eudragit(r) drug release. PMID- 28079389 TI - UPPER EYELID INJURY WITH PARTIAL LOSS. CASE REPORT. AB - In case of an upper eyelid injury with loss of tissue, it is very important to perform reconstruction to restore protection of the cornea and bulbus. Depending on the size and location of the defect the most suitable reconstructive technique is chosen. This case report presents a patient with a partial loss of the upper eyelid. The defect was reconstructed with a transposition skin flap to cover the ear cartilage graft. The missing conjunctiva was partially reconstructed by its mobilization from the fornix, and a part of the defect was left to heal by spontaneous epithelisation. This procedure provides an alternative solution for defects in the lateral part of the upper eyelid. PMID- 28079390 TI - TRIDIMENSIONAL DOPPLER ASSESSMENT: A RELIABLE, NON-INVASIVE AND COST-EFFECTIVE METHOD FOR PREOPERATIVE PERFORATOR ASSESSMENT IN DIEP FLAP. AB - BACKGROUND: The preoperative perforator mapping is an important step in autologous breast reconstruction, making the flap raising safer, more predictable and time-saving. Although the Doppler exam has proven to be less accurate in locating perforators compared with colour duplex sonography and CTA, it will probably remain of importance in clinical practice. The aim of this paper is to share some advices on how to perform a Doppler exam in preoperative evaluation of a DIEAp flap, increasing its reliability in location of the perforators. METHODS: The study was carried-out preoperatively on 26 consecutive patients. For the evaluation of the matching between Doppler Dot and operative finding was used a Cartesian coordinate systemResults: We have marked preoperatively 145 perforators in 26 patients for a total of 52 semi-abdomens. An average of 5.6 vessels per patient were marked. Of these, 80 (55.17%) were found between 0-1 cm, 36 (24.82%) between 1-2 cm and 5 (3.4%) of these more than 2 cm from each other. We had 24 (16.55%) false positives in which there was no correspondence between the signal and the intraoperative finding. CONCLUSION: Although the Doppler exam may not provide the same anatomic details as the other newer modalities, such as CTA and MRA, the HHD remains a very useful and important tool for autologous reconstruction. We recommend performing this exam in our standardized and reproducible method to improve the reliability.. PMID- 28079391 TI - OUR PRELIMINARY EXPERIENCE WITH A NEW METHOD OF DIEAp FLAP DISSECTION. AB - BACKGROUND: The abdominal tissue is an ideal source for autologous breast reconstruction. We propose a new approach for intramuscular dissection of a DIEP flap in this paper. METHODS: A total of 84 women underwent breast reconstruction after mastectomy. From this group, 49 patients were treated with traditional DIEP flap of which 21 had unilateral procedure and 28 had bilateral procedure. This new type of dissection was performed in 35 women, with unilateral approach in 14 cases and bilateral approach in 21 cases. RESULTS: The statistical differences are not significant in the two groups with regards to complications (p > 0.1). Mean operative time in this new approach was 3 hours and 10 minutes per flap. Mean operative time in the traditional dissection of DIEP was 3 hours and 41 minutes per flap. The operative time of the new approach is significantly shorter than the dissection of the traditional DIEP flap (p < 0.01). CONCLUSION: The approach to DIEP flap dissection proposed by the authors is a new concept in autologous breast reconstruction. In this type of dissection no fascia is resected and it is more reliable than a traditional DIEP flap for the ease of dissection and for the presence of a small protective cuff of muscle around the vessel with a lower risk of perforator injury.It is a reproducible option of dissection, useful also in less experienced hands and it is a time reducing technique compared with the traditional DIEP flap. PMID- 28079392 TI - Lipomodelling - advanced technique for the correction of Congenital hypoplastic breast malformations and deformities. AB - A variety of surgical techniques has been used to correct hypoplastic breast malformations and deformities, including tissue expanders, breast implants, custom chest wall implants, mammary gland remodelling, as well as locoregional or free flap. Case series of successful breast reconstruction using lipomodelling technique in one patient with severe Polands syndrome and two patients with tuberous breasts are reported together with literature review. No surgical complications were observed and ultrasound examination did not reveal any pathology in breast tissue other than oil pseudocysts postoperatively. In both malformations, submammary fold was moved downwards. Moreover, the lower part of the breast and areolar herniation was corrected in tuberous breast, and in Polands syndrome, the areolar complex was significantly shifted downwards and laterally. In comparison with other reconstructive techniques, lipomodelling allows for the breast correction to begin in early adolescence. Further growth of the unaffected breast may be effectively corrected by subsequent lipomodelling session. This technique appears to change the overall approach to the management of hypoplastic breast and chest wall malformations. PMID- 28079393 TI - Reconstruction of large facial and orbital defects by combining free flap transfer with craniofacial prosthesis. AB - The reconstruction of complex craniofacial and orbital defects should satisfactorily restore functional and aesthetic integrity. Autologous reconstruction of nasal, periorbital and auricular facial subunits as a whole using a locoregional or a free flap is very challenging and the results are not sometimes ideal. With advanced technologies that are currently available it is possible to plan and produce authentic facial prosthesis that can satisfactory substitute these facial subunits. We demonstrate an alternative reconstructive concept for complex craniofacial defects based on a free flap combined with a facial prosthesis for the replacement of periorbital or auricular facial subunits. This approach was used in two patients with very satisfactory results. Combination of a free flap with a facial prosthesis may become a preferable approach for the reconstruction of complex craniofacial defects. Clinical outcomes of the reconstructions may be enhanced respecting the principle of aesthetic facial subunits. PMID- 28079395 TI - Diagnostic performance of wrist magnetic resonance (MR) arthrography: comparison of three-dimensional isotropic T1 weighted fast spin-echo MR arthrography and two dimensional MR arthrography. AB - OBJECTIVE: To compare the diagnostic performance of direct wrist MR arthrography (D-MRA) with two-dimensional (2D) T1 weighted fast spin-echo (FSE) and three dimensional (3D) isotropic T1 weighted FSE sequences for detecting triangular fibrocartilage (TFC) central perforations and scapholunate ligament (SLL) and lunotriquetral ligament (LTL) tears. METHODS: 26 patients who had undergone pre operative wrist D-MRA with 2D and 3D isotropic T1 weighted FSE sequences and subsequent arthroscopic surgeries were included. Each MRI sequence was independently evaluated and scored by two readers retrospectively for the presence of TFC central perforations and SLL and LTL tears. Arthroscopic findings were used as the reference standard. Diagnostic performance was evaluated by using the area under the receiver operating characteristic curve. The sensitivity, specificity and accuracy of both sequences for diagnosing the injuries were calculated. RESULTS: Arthroscopic surgery revealed 21 TFC central perforations, 7 SLL tears and 3 LTL tears. The area under the receiver operating characteristic curve value of 2D and 3D for central perforations in TFC and tears in SLL and LTL was identical or similar (0.667-0.947). The sensitivity, specificity and accuracy of both sequences for diagnosing the injury of each structure were not significantly different (TFC, 90.5/80/88.5% for both readers/sequences; SLL, 100/89.5/92.3% for both readers' 2D and Reader A's 3D, and 85.7/89.5/88.5% for Reader B's 3D; LTL, 66.7/100/96.2% for both readers' 2D and 33.3/100/92.3% for both readers' 3D). Interobserver agreements were substantial to excellent. CONCLUSION: In wrist D-MRA, the diagnostic performances of 3D isotropic and 2D T1 weighted FSE sequences are comparable for TFC central perforations and SLL and LTL tears. Advances in knowledge: The diagnostic performance of 3D isotropic T1 weighted FSE D-MRA and that of 2D T1 weighted FSE D-MRA were not significantly different in the diagnosis of central perforations in the TFC and tears in the SLL and LTL. 3D isotropic T1 weighted FSE D-MRA has potential for substituting 2D imaging. PMID- 28079394 TI - The Positive Emotions after Acute Coronary Events behavioral health intervention: Design, rationale, and preliminary feasibility of a factorial design study. AB - BACKGROUND: Positive psychological constructs, such as optimism, are associated with greater participation in cardiac health behaviors and improved cardiac outcomes. Positive psychology interventions, which target psychological well being, may represent a promising approach to improving health behaviors in high risk cardiac patients. However, no study has assessed whether a positive psychology intervention can promote physical activity following an acute coronary syndrome. OBJECTIVE: In this article we will describe the methods of a novel factorial design study to aid the development of a positive psychology-based intervention for acute coronary syndrome patients and aim to provide preliminary feasibility data on study implementation. METHODS: The Positive Emotions after Acute Coronary Events III study is an optimization study (planned N = 128), subsumed within a larger multiphase optimization strategy iterative treatment development project. The goal of Positive Emotions after Acute Coronary Events III is to identify the ideal components of a positive psychology-based intervention to improve post-acute coronary syndrome physical activity. Using a 2 * 2 * 2 factorial design, Positive Emotions after Acute Coronary Events III aims to: (1) evaluate the relative merits of using positive psychology exercises alone or combined with motivational interviewing, (2) assess whether weekly or daily positive psychology exercise completion is optimal, and (3) determine the utility of booster sessions. The study's primary outcome measure is moderate-to-vigorous physical activity at 16 weeks, measured via accelerometer. Secondary outcome measures include psychological, functional, and adherence-related behavioral outcomes, along with metrics of feasibility and acceptability. For the primary study outcome, we will use a mixed-effects model with a random intercept (to account for repeated measures) to assess the main effects of each component (inclusion of motivational interviewing in the exercises, duration of the intervention, and inclusion of booster sessions) from a full factorial model controlling for baseline activity. Similar analyses will be performed on self report measures and objectively-measured medication adherence over 16 weeks. We hypothesize that the combined positive psychology and motivational interviewing intervention, weekly exercises, and booster sessions will be associated with superior physical activity. RESULTS: Thus far, 78 participants have enrolled, with 72% of all possible exercises fully completed by participants. CONCLUSION: The Positive Emotions after Acute Coronary Events III study will help to determine the optimal content, intensity, and duration of a positive psychology intervention in post-acute coronary syndrome patients prior to testing in a randomized trial. This study is novel in its use of a factorial design within the multiphase optimization strategy framework to optimize a behavioral intervention and the use of a positive psychology intervention to promote physical activity in high-risk cardiac patients. PMID- 28079396 TI - Does brain creatine content rely on exogenous creatine in healthy youth? A proof of-principle study. AB - It has been hypothesized that dietary creatine could influence cognitive performance by increasing brain creatine in developing individuals. This double blind, randomized, placebo-controlled, proof-of-principle study aimed to investigate the effects of creatine supplementation on cognitive function and brain creatine content in healthy youth. The sample comprised 67 healthy participants aged 10 to 12 years. The participants were given creatine or placebo supplementation for 7 days. At baseline and after the intervention, participants undertook a battery of cognitive tests. In a random subsample of participants, brain creatine content was also assessed in the regions of left dorsolateral prefrontal cortex, left hippocampus, and occipital lobe by proton magnetic resonance spectroscopy (1H-MRS) technique. The scores obtained from verbal learning and executive functions tests did not significantly differ between groups at baseline or after the intervention (all p > 0.05). Creatine content was not significantly different between groups in left dorsolateral prefrontal cortex, left hippocampus, and occipital lobe (all p > 0.05). In conclusion, a 7 day creatine supplementation protocol did not elicit improvements in brain creatine content or cognitive performance in healthy youth, suggesting that this population mainly relies on brain creatine synthesis rather than exogenous creatine intake to maintain brain creatine homeostasis. PMID- 28079397 TI - Mixed compared with single-source proteins in high-protein diets affect kidney structure and function differentially in obese fa/fa Zucker rats. AB - Questions remain regarding the potential negative effects of dietary high protein (HP) on kidney health, particularly in the context of obesity in which the risk for renal disease is already increased. To examine whether some of the variability in HP effects on kidney health may be due to source of protein, obese fa/fa Zucker rats were given HP (35% of energy from protein) diets containing either casein, soy protein, or a mixed source of animal and plant proteins for 12 weeks. Control lean and obese rats were given diets containing casein at normal protein (15% of energy from protein) levels. Body weight and blood pressure were measured, and markers of renal structural changes, damage, and function were assessed. Obesity alone resulted in mild renal changes, as evidenced by higher kidney weights, proteinuria, and glomerular volumes. In obese rats, increasing the protein level using the single, but not mixed, protein sources resulted in higher renal fibrosis compared with the lean rats. The mixed-protein HP group also had lower levels of serum monocyte chemoattractant protein-1, even though this diet further increased kidney and glomerular size. Soy and mixed-protein HP diets also resulted in a small number of damaged glomeruli, while soy compared with mixed-protein HP diet delayed the increase in blood pressure over time. Since obesity itself confers added risk of renal disease, an HP diet from mixed protein sources that enables weight loss but has fewer risks to renal health may be advantageous. PMID- 28079398 TI - Feasibility evaluation of diffusion-weighted imaging using an integrated MRI radiotherapy system for response assessment to neoadjuvant therapy in rectal cancer. AB - OBJECTIVE: To evaluate the feasibility of on-board diffusion-weighted imaging (DWI) with an integrated low-field MRI radiotherapy system to assess responses to neoadjuvant chemoradiation (NAC) in rectal cancer. METHODS: A spin echo-based planar imaging diffusion sequence on a 0.35-T MRI radiotherapy system was acquired over the course of NAC. The apparent diffusion coefficients (ADCs) from the tumour regions of interest (ROIs) were calculated. A functional diffusion map (fDM) was created showing a pixelwise ADC analysis of the ROI over the course of treatment. Surgical pathology was correlated with ADC data. RESULTS: Consecutive patients treated on a 0.35-T MRI radiotherapy system were evaluated. Patient A had the worst pathological response to NAC with a tumour regression score of 1 and was the only patient with a negative slope in the change of ADC values over the entire course of NAC, and during both the first and second half of NAC. The fDM from the first half of NAC for Patient A showed discrete dark areas in the tumour ROI, reflecting subregions with decreasing ADC values during NAC. Patient C had the most favourable pathological response to NAC with a Grade 3 response and was the only patient who had an increase in the slope in the change of ADC values from the first to the second half of NAC. CONCLUSION: DWI using a low field MRI radiotherapy system for evaluating the responses to NAC is feasible. Advances in knowledge: ADC values obtained using a 0.35-T MRI radiotherapy system over the course of NAC for rectal cancer correlate with pathological responses. PMID- 28079399 TI - Safety and Efficacy of Tissue Plasminogen Activator and DNase for Complicated Pleural Effusions Secondary to Abdominal Pathology. AB - RATIONALE: Exudative pleural effusions may arise secondary to inflammation of intra-abdominal structures. Pleural space loculations can complicate these effusions, preventing adequate chest tube drainage and leading to consideration of surgical intervention. Previous studies have demonstrated that intrapleural administration of tissue plasminogen activator (tPA) combined with human recombinant DNase can improve fluid drainage and reduce surgery for patients with loculated parapneumonic effusions; however, the efficacy of this treatment has not been evaluated for complicated pleural effusions attributed to intra abdominal inflammation. OBJECTIVES: We assessed the safety and efficacy of tPA/DNase for 17 pleural effusions associated with nonmalignant intra-abdominal pathology that did not drain adequately after placement of one or more chest tubes. METHODS: Efficacy was measured by comparing post- to pretreatment fluid drainage rates, volumetric assessment of pleural fluid on radiographic images before and after treatment, and clinical improvement, including the need for surgical intervention. Symptomatic relief was assessed using the Borg scale for breathlessness. MEASUREMENTS AND MAIN RESULTS: After a median of two doses of tPA/DNase, 23.5% of patients had chest pain and none had pleural bleeding. The volume of pleural fluid drained increased from a median of 325 ml to 890 ml per 24 hours after therapy (P = 0.018). The area of pleural space opacity on chest radiographs decreased from a median of 42.8-17.8% of the hemithorax (P = 0.001). tPA/DNase reduced the pleural fluid volume on chest computed tomographic imaging from a median of 294.4 ml to 116.1 ml. Borg scores improved from a median of 3 (interquartile range = 1-6) to 0 (interquartile range = 0-2) after therapy (P = 0.001). The median duration of chest tube placement and hospital stay were 4 and 11 days, respectively. Two patients required surgical intervention for lung entrapment. Overall, treatment was considered successful for 88.2% of patients. CONCLUSIONS: This retrospective case series suggests that intrapleural tPA/DNase can be safe and effective for patients with complicated pleural effusions attributed to abdominal pathology that do not drain adequately after chest tube placement. Additional studies are needed to determine whether the combination of tPA and DNase is more effective than tPA for this indication. PMID- 28079400 TI - Dysphagia therapy post stroke: An exploration of the practices and clinical decision-making of speech-language pathologists in Australia. AB - PURPOSE: A variety of dysphagia management options are available for the treatment of dysphagia following a stroke, however, it is unknown which of these approaches are most commonly utilised by Australian speech-language pathologists (SLPs) and whether particular factors influence decision-making. METHOD: The aim of this study was to investigate, through an online survey, the treatment practices of SLPs in Australia for the treatment of dysphagia post-stroke and identify the factors influencing treatment decisions. RESULT: A total of 118 SLPs completed the online survey. Descriptive statistics identified large variability in the dysphagia treatments utilised, with all 24 therapies listed in the online survey reported as being routinely used. Compensatory therapies were ranked as being utilised more frequently than rehabilitative approaches, with six of the seven highly utilised therapies being compensatory in nature. A client's cognitive capacity was the most prominent factor influencing SLPs' treatment decisions. CONCLUSION: This study provides insight into the practices of SLPs in Australia for the treatment of dysphagia following stroke and discusses potential for shifts in practice. It highlights the complexity involved in the decision making process and that clinicians consider evidence, as well as client, clinician and service factors, when selecting between the range of options available. PMID- 28079401 TI - HEMO2life as a protective additive to Celsior solution for static storage of donor hearts prior to transplantation. AB - BACKGROUND: Prior to heart transplantation, static storage of donor hearts is currently limited to 4-5 h, despite profound hypothermia (4-8 degrees C). Because heart transplantation is an emergency procedure, improved protection to extend safe storage duration would be advantageous. We investigated whether the naturally respiratory pigment HEMO2life(r), which is effective at hypothermia for the passive release of oxygen via oxygen gradient, could improve long-term preservation. METHODS: Isolated Langendorff-perfused rat hearts (n = 12/group) were equilibrated (20 min) and function (left ventricular developed pressure: LVDP) measured by intraventricular balloon before arrest with cold (7.5 degrees C) Celsior(r) solution, either alone (control) or with the addition of HEMO2life(r) (Hemarina SA, Morlaix, France) at 1 g/L. Cold storage lasted 8 h prior to reperfusion (60 min) and recovery (as % of pre-ischemic function) was assessed. Hearts (minced and homogenized) were also assessed by TTC staining as a measure of viability and two hearts from each group were sliced and assessed by TTC staining for infarct size. Values are expressed as mean +/- standard error of mean and analyzed by Student's t-test. RESULTS: Hearts recovered rapidly in both groups to a plateau by 20 min of reperfusion; control and HEMO2life(r) final recovery (60 min) was 45 +/- 2% and 57 +/- 1% (P < 0.05) respectively. Left ventricular end-diastolic pressure recovered to a similar extent in both groups (between 31 to 35 mmHg), as did heart rate (final recovery between 84 to 89% pre ischemic value); however, coronary flow was significantly (P < 0.05) higher in HEMO2life(r) group (7.5 +/- 0.7 ml/min) compared to control (5.4 +/- 0.4 ml/min). Viability and infarct size measurements were similar between groups. CONCLUSION: The addition of the natural oxygen releasing pigment HEMO2life(r) to Celsior(r) preservation solution significantly improved post-ischemic recovery of heart function. This additive may have major therapeutic potential for clinical heart transplantation. PMID- 28079402 TI - Sexual dysfunction in premenopausal women could be related to hormonal profile. AB - Female sexual dysfunction (FSD) is a public health problem that affects women's quality of life. Although the relationship between some hormones and the FSD has been described, it is not well established for all hormones. Therefore, the aim of our study was to evaluate the association between hormonal dysfunction and sexual dysfunction in premenopausal women. We performed a cross-sectional study with 60 patients with regular menstrual cycles, with age ranging from 18 to 44 years, with previous diagnosis of FSD. All patients were evaluated using the female sexual function index (FSFI) questionnaire and had the levels of total testosterone, prolactin (PRL), thyroid-releasing hormone and free testosterone index measured. Among the 60 patients, 43 (71.7%) were diagnosed with hypoactive sexual desire disorder (HSDD), 9 (15%) had anorgasmy and 8 (3.3%) had sexual pain dysfunction. Hormonal evaluation, demonstrated that 79.1% of patients with HSDD, 78.4% of patients with anorgasmy and 50% of patients with sexual pain dysfunction had female androgen insensitivity. We can conclude that there is an important association between low levels of total and free testosterone and FSD. This finding offers a new alternative for diagnosis and treatment of HSDD. Moreover, given the potential role of androgens in sexual function, randomized controlled trials with adequate long-term follow-up are essential to confirm its possible effect. PMID- 28079403 TI - Orofacial function and monitoring of oral care in amyotrophic lateral sclerosis. AB - OBJECTIVE: The aim was to assess orofacial function and monitor oral care in patients with amyotrophic lateral sclerosis (ALS) to maintain oral comfort and oral health. MATERIALS AND METHODS: A case series of 14 patients newly diagnosed with ALS accepted to participate in a quality improvement project. After initial examinations, baseline oral conditions were obtained and the patients were seen every 3 months. Nordic Orofacial Test-Screening (NOT-S) was used for evaluation of orofacial function. RESULTS: Patients were grouped according to initial symptoms in a bulbar group and a spinal group with eight and six patients, respectively. The mean age at diagnosis was 62.8 years. All were dentate with a mean of 26.7 natural teeth. Most patients had very good oral and dental conditions. As expected, orofacial functions were differently affected in the two groups; at initial NOT-S registration, the mean total score was 5.6 (range 3-8 domains) in the bulbar group and 0.7 (0-2 domains) in the spinal group. At final registration, the corresponding figures were 6.1 and 3.2. Oral and dental aids were introduced according to need. CONCLUSIONS: In the bulbar group, several orofacial functions became impaired at an early stage of disease development, and at final registrations many vital orofacial functions were severely compromised. The spinal group was less severely affected orally. However, all individuals irrespective of type of initial symptoms needed assistance in performing oral hygiene measures in the latter part of the disease period. Good oral health and oral comfort could be maintained in all participants and no other dental treatment was needed. PMID- 28079404 TI - Free amino acids in fibromyalgia syndrome: relationship with clinical picture. AB - The objectives of our study were to evaluate free amino acid (FAA) concentrations in the serum of patients affected by fibromyalgia syndrome (FMS) and to determine the relationships between FAA levels and FMS clinical parameters. Thus, serum amino acid concentrations were quantified (HPLC analysis) in 23 females with fibromyalgia (according to the American College of Rheumatology classification criteria) and 20 healthy females. The results showed significantly higher serum concentrations of aspartate, cysteine, glutamate, glycine, isoleucine, leucine, methionine, ornithine, phenylalanine, sarcosine, serine, taurine, tyrosine and valine in FMS patients vs. healthy controls. Patients with higher Fibromyalgia Impact Questionnaire (FIQ) scores showed increased levels of alanine, glutamine, isoleucine, leucine, phenylalanine, proline and valine. In conclusion, our results indicate an imbalance in some FAAs in FMS patients. Increased Glu is particularly interesting, as it could explain the deficit in monoaminergic transmission involved in pain. PMID- 28079405 TI - Posttraumatic growth following pregnancy termination for fetal abnormality: the predictive role of coping strategies and perinatal grief. AB - BACKGROUND: Research about termination for fetal abnormality (TFA) suggests that it is a traumatic event with potential negative psychological consequences. However, evidence also indicates that following traumatic events individuals may experience growth. Although TFA's negative psychological outcomes are well documented, little is known of the potential for growth following this event. Therefore, the study's objectives were to measure posttraumatic growth (PTG) post TFA, examine the relationship between PTG, perinatal grief and coping, and determine the predictors of PTG. DESIGN: An online, retrospective survey was conducted with 161 women. METHODS: Eligible participants were women over 18 who had undergone TFA. Participants were recruited from a support organisation. They completed the Brief COPE, Short Perinatal Grief Scale and Posttraumatic Growth Inventory. Data were analysed using regression analyses. RESULTS: Moderate levels of PTG were observed for "relating to others," "personal strengths" and "appreciation of life." "Positive reframing" was a significant predictor of PTG. Despite using mainly "adaptive" coping strategies, women's grief levels were high. CONCLUSIONS: "Adaptive" coping strategies such as, "positive reframing" are relevant to TFA. They may act as protective factors against distress and as foundations for growth, implicating that interventions such as Cognitive Behavioural Therapy, which aim to reframe women's experience, may be beneficial. PMID- 28079406 TI - Predictive factors of depression symptoms among adolescents in the 18-month follow-up after Wenchuan earthquake in China. AB - BACKGROUND: It is unclear about the change and risk factors of depression among adolescent survivors after earthquake. AIMS: This study aimed to explore the change of depression, and identify the predictive factors of depression among adolescent survivors after the 2008 Wenchuan earthquake in China. METHODS: The depression among high school students at 6, 12 and 18 months after the Wenchuan earthquake were investigated. The Beck Depression Inventory (BDI) was used in this study to assess the severity of depression. RESULTS: Subjects included 548 student survivors in an affected high school. The rates of depression among the adolescent survivors at 6-, 12- and 18-month after the earthquake were 27.3%, 42.9% and 33.3%, respectively, for males, and 42.9%, 61.9% and 53.4%, respectively, for females. Depression symptoms, trauma-related self-injury, suicidal ideation and PTSD symptoms at the 6-month follow-up were significant predictive factors for depression at the 18-month time interval following the earthquake. CONCLUSIONS: This study highlights the need for considering disaster related psychological sequela and risk factors of depression symptoms in the planning and implementation of mental health services. Long-term mental and psychological supports for victims of natural disasters are imperative. PMID- 28079407 TI - Noninvasive evaluation of gastric emptying and gastric wall thickness in SLE patients. AB - OBJECTIVE: The objective of this study is to evaluate the gastric emptying in patients with systemic lupus erythematosus (SLE) with gastrointestinal involvement using three-dimensional (3D) ultrasonography. METHODS: The gastric emptying times at 25% (T1), 50% (T2), and 75% (T3) of SLE patients with gastrointestinal involvement (n = 40) and healthy controls (n = 80) were evaluated and compared. In addition, the correlations among the gastric wall thickness, SLE disease activity index (SLEDAI), and upper gastrointestinal symptoms were calculated. RESULTS: The gastric wall thickness was correlated with the SLEDAI (r = 0.928, p < 0.001) and the upper gastrointestinal symptom index (r = 0.848, p < 0.001). The emptying times T1, T2, and T3 of the SLE patients were 17.08 +/- 2.65 min (mean +/- standard deviation), 39.85 +/- 6.54 min, and 83.58 +/- 7.12 min, respectively. For healthy controls, they were 19.65 +/- 5.39 min, 41.08 +/- 7.51 min, and 70.34 +/- 8.03 min. The T1 of the SLE patients was shorter (p < 0.01), while the T3 was longer (p < 0.001). Moreover, T3 in the SLE group had the best correlation with the upper gastrointestinal symptom index (r = 0.553, p < 0.001). T1 in the SLE group was anti-correlated with early satiety (r = -0.366, p < 0.05). CONCLUSIONS: Combining the emptying times T1 and T3, as well as the gastric wall thickness, the SLEDAI and the upper gastrointestinal symptoms index can provide accurate clinical diagnosis of SLE with gastric involvement. PMID- 28079408 TI - An ecological approach to hearing-health promotion in workplaces. AB - OBJECTIVE: To develop and assess use, acceptability and feasibility of an ecological hearing conservation programme for workplaces. DESIGN: A school-based public health hearing preservation education programme (Dangerous Decibels(r)) was adapted for workplaces using the Multi-level Approach to Community Health (MATCH) Model. The programme was delivered in small manufacturing companies and evaluated using a questionnaire before the training and at one week and two months after training. STUDY SAMPLE: Workers (n = 56) from five small manufacturing companies were recruited. RESULTS: There was a significant improvement in knowledge, attitudes and behaviour of workers at the intrapersonal level; in behaviour motivation and safety culture at the interpersonal and organisational levels; and an overall improvement in hearing-health behaviour after two months post-intervention. CONCLUSIONS: The developed programme offers a simple, interactive and theory-based intervention that is well accepted and effective in promoting positive hearing-health behaviour in workplaces. PMID- 28079410 TI - The importance of adhering to high standards of research ethics. PMID- 28079409 TI - Promoting awareness of neonatal menstruation. AB - Neonatal uterine bleeding (NUB) has been carefully studied in the past through case reports, small series, clinical cohort studies, pathology investigations of fetal and neonatal. Following a historical recount, this review summarizes biological mechanisms conditioning NUB, starting from the persistence till birth of an 'ontogenetic progesterone resistance' (OPR), causing decreased responsiveness of target tissues to bioavailable progesterone. Several pregnancy related conditions, such as preeclampsia, fetal growth restriction, prematurity, post-maturity and even Rhesus or ABO incompatibility, influence the occurrence of NUB. It seems therefore that the phenomenon is precipitated by chronic fetal distress. When present, OPR may persists until telarche; as a consequence, if pregnancy occurs in early teenage, the disorder known as "defective deep placentation" may ensue, increasing the risk of obstetrical syndromes. In the presence of NUB, retrograde shedding into the peritoneal cavity of endometrial stem/progenitor and niche cells may occur. There, given the right environment, these cells can survive and become activated at the time of telarche, causing the specific phenotype of early-onset endometriosis. In conclusion, neonatal menstruation is a fetal distress indicator and can alter the incidence of a variety of pathological conditions later in life. For this reason, it should be carefully recorded and the parents informed. PMID- 28079411 TI - Enteral tube feeding: using good practice to prevent infection. AB - Enteral tube feeding is the delivery of nutritionally complete feed via a tube into the gut. It is used for patients who are unable to meet their nutritional needs orally. Enteral feeding can be given through a variety of different tubes that access the gastrointestinal tract either via the stomach or the small bowel. The contamination of enteral feed can often be overlooked as a source of bacterial infection. Enteral feeds can become contaminated in a variety of different ways. Most often infections result in extended lengths of stay in hospital and patients also need additional therapies and treatments in order to resolve these infections. Healthcare-associated infections not only affect the patients who acquire them but also have an impact on the staff involved in their care. Each acute trust will have its own local policies and guidelines regarding enteral feeding and infection control and prevention. These local documents will be based on national initiatives and guidelines. It is important for nurses to refer to their local policies and guidelines before they start a patient on enteral feeding to ensure that they are doing so in the safest manner possible. Nurses' practice is key to preventing bacterial contamination in such patients. PMID- 28079412 TI - Towards resilience and wellbeing in nurses. AB - Nursing is a physically and emotionally demanding profession. High role expectations and difficult working conditions place some nurses at risk of burnout and stress-related illness. In spite of the challenges in the current healthcare system, nurses continue to deliver high-quality patient care, retain resilience and progress professionally in the face of adversity. This article provides an overview, with discussion of the evidence in the literature, of some of the suggested methods to improve resilience and enhance staff wellbeing in the nursing profession at an individual and organisational level. PMID- 28079413 TI - Striving for a good standard of maths for potential student nurses. AB - This article explores some of the issues surrounding numerical competence for potential pre-registration children's nursing students, with examples of success and failure, at the University of Hertfordshire. With poor numerical ability causing concern in the UK, and the effect of low competence on patient safety when calculating drug dosages in healthcare, this article considers some of the literature surrounding numerical ability, confidence and anxiety, along with considering whether a 'C' grade at GCSE is a suitable marker for assessing numerical competence before starting a pre-registration nursing programme. PMID- 28079414 TI - Ineligibility criteria and deprivation of liberty in relation to guardianship. AB - Richard Griffith, Senior Lecturer in Health Law at Swansea University, discusses how the law surrounding deprivation of liberty safeguards relates to a person who is the subject of a guardianship order. PMID- 28079415 TI - 2017: nursing in the New Year. PMID- 28079416 TI - Patient deaths and learning. PMID- 28079417 TI - The experiences of black and minority ethnic nurses working in the UK. AB - Evidence suggests that black and minority ethnic (BME) midwives are more likely to face fitness to practise hearings than white registrants and BME NHS staff are less likely to be in senior positions. This literature review critically evaluates the literature published since a systematic review on the topic was conducted in 2005. It found that BME nurses and midwives, especially those who registered abroad and subsequently came to live and work in the UK are 'underemployed' and consequently expressed feelings of loss of self-confidence. This was further compounded by accounts of excessive scrutiny and punishment. Many felt excluded from white networks of power and opportunities for staff development and promotion. The literature also describes experiences of covert as well as overt racism between the white majority and BME staff as well as 'horizontal racism' between BME staff of differing ethnicities. PMID- 28079418 TI - Memories of Nursing: nurses' social status and origins of the RNNH. PMID- 28079419 TI - What do we know about emotional labour in nursing? A narrative review. AB - Nurses have to manage their emotions and the expression of emotion to perform best care, and their behaviours pass through emotional labour (EL). However, EL seems to be an under-appreciated aspect of caring work and there is no synthetic portrait of literature about EL in the nursing profession. This review was conducted to synthesise and to critically analyse the literature in the nursing field related to EL. Twenty-seven papers were included and analysed with a narrative approach, where two main themes were found: EL strategies and EL antecedents and consequences. Hence, EL is a multidimensional, complex concept and it represents a nursing competence to provide the best care. Moreover, nurses have a high awareness of EL as a professional competence, which is a fundamental element to balance engagement with an appropriate degree of detachment to accomplish tasks for best practice, and to provide high-quality patient care. PMID- 28079420 TI - International nursing: reflections on working in Sierra Leone. AB - Registered Nurse, 4626 (AE) Sqn, RAuxAF, RAF Brize Norton/Nurse Practitioner, Center Parcs Sherwood Forest, Nottinghamshire looks back over her time working in A&E in Sierra Leone. PMID- 28079421 TI - Leg Club scholarships: from global learning to local implementation. PMID- 28079422 TI - Examining an alcohol health worker service's patient coverage. AB - Alcohol health workers (AHWs) have been found to be effective at reducing alcohol related hospital admissions, but there is still a paucity of evidence in keys areas. This was the first study to investigate what percentage of patients referred to an AHW service by alcohol screening tools are actually seen by the AHWs. The study-based in a large teaching hospital in the north of England-also investigated the impact of social deprivation on service usage. Research data came from a patient database and semi-structured interviews with AHWs. Further research is required to better understand the 'harm paradox' of patients' differential susceptibility to alcohol-related harm and how this might impact AHW service patient flow. PMID- 28079423 TI - Nurse education and the development of the nursing associate role. AB - Emeritus Professor Alan Glasper, from the University of Southampton, discusses the recently launched curriculum for nursing associates and what this might mean for the delivery of care. PMID- 28079424 TI - Career development for all ages. AB - Sam Foster, Chief Nurse at Heart of England NHS Foundation Trust, considers the issues around career progression and staff retention and how they differ between generations. PMID- 28079425 TI - Ensuring care quality at a time of diminishing resources. AB - John Tingle, Reader in Health Law at Nottingham Trent University, discusses the Care Quality Commission's State of Health Care report, in the light of some important clinical negligence trends and reports on major safety failures. PMID- 28079427 TI - Effect of functional electrical stimulation on cardiovascular outcomes in patients with chronic heart failure. AB - Background/design Functional electrical stimulation of lower limb muscles is an alternative method of training in patients with chronic heart failure (CHF). Although it improves exercise capacity in CHF, we performed a randomised, placebo controlled study to investigate its effects on long-term clinical outcomes. Methods We randomly assigned 120 patients, aged 71 +/- 8 years, with stable CHF (New York Heart Association (NYHA) class II/III (63%/37%), mean left ventricular ejection fraction 28 +/- 5%), to either a 6-week functional electrical stimulation training programme or placebo. Patients were followed for up to 19 months for death and/or hospitalisation due to CHF decompensation. Results At baseline, there were no significant differences in demographic parameters, CHF severity and medications between groups. During a median follow-up of 383 days, 14 patients died (11 cardiac, three non-cardiac deaths), while 40 patients were hospitalised for CHF decompensation. Mortality did not differ between groups (log rank test P = 0.680), while the heart failure-related hospitalisation rate was significantly lower in the functional electrical stimulation group (hazard ratio (HR) 0.40, 95% confidence interval (CI) 0.21-0.78, P = 0.007). The latter difference remained significant after adjustment for prognostic factors: age, gender, baseline NYHA class and left ventricular ejection fraction (HR 0.22, 95% CI 0.10-0.46, P < 0.001). Compared to placebo, functional electrical stimulation training was associated with a lower occurrence of the composite endpoint (death or heart failure-related hospitalisation) after adjustment for the above mentioned prognostic factors (HR 0.21, 95% CI 0.103-0.435, P < 0.001). However, that effect was mostly driven by the favourable change in hospitalisation rates. Conclusions In CHF patients, 6 weeks functional electrical stimulation training reduced the risk of heart failure-related hospitalisations, without affecting the mortality rate. The beneficial long-term effects of this alternative method of training require further investigation. PMID- 28079428 TI - The first 6 weeks of recovery after primary total hip arthroplasty with fast track. AB - Background and purpose - Fast-track protocols have been introduced worldwide to improve the recovery after total hip arthroplasty (THA). These protocols have reduced the length of hospital stay (LOS), and THA in an outpatient setting is also feasible. However, less is known regarding the first weeks after THA with fast track. We examined patients' experiences of the first 6 weeks after hospital discharge following inpatient and outpatient THA with fast track. Patients and methods - In a prospective cohort study, 100 consecutive patients who underwent THA surgery in a fast-track setting between February 2015 and October 2015 received a diary for 6 weeks. This diary contained various internationally validated questionnaires including HOOS-PS, OHS, EQ-5D, SF-12, and ICOAP. In addition, there were general questions regarding pain, the wound, physiotherapy, and thrombosis prophylaxis injections. Results - 94 patients completed the diary, 42 of whom were operated in an outpatient setting. Pain and use of pain medication had gradually decreased during the 6 weeks. Function and quality of life gradually improved. After 6 weeks, 91% of all patients reported better functioning and less pain than preoperatively. Interpretation - Fast track improves early functional outcome, and the PROMs reported during the first 6 weeks in this study showed continued improvement. They can be used as a baseline for future studies. The PROMs reported could also serve as a guide for staff and patients alike to modify expectations and therefore possibly improve patient satisfaction. PMID- 28079429 TI - Association between late effects assessed by physicians and quality of life reported by head-and-neck cancer survivors. AB - BACKGROUND: Many survivors of head-and-neck cancer (HNC) suffer from late effects. Their overall quality of life deteriorates during treatment, followed by a slow recovery up to five years after treatment. We examined the association between the severity of physician-assessed late effects and the health-related quality of life (HRQoL) reported by survivors of HNC. MATERIAL AND METHODS: The analysis was based on data collected during follow-up for 136 survivors of cancer in the oral cavity, pharynx, larynx, or salivary glands. Physicians' assessments of dysphagia, xerostomia, fibrosis, and hoarseness, derived from reports to of the Danish Head and Neck Cancer Group database and patient-reported overall quality of life and social, role, emotional, cognitive, and physical functioning reported on the European Organization for Research and Treatment of Cancer questionnaire. Linear regression models were used to examine the association between the severity of each late effect and HRQoL. RESULTS: Quality of life was decreased among patients with moderate to severe dysphagia compared to patients without dysphagia (-16 points; 95% CI -21;-3). Also role functioning (-20 points; 95% CI -38;-2), emotional functioning (-19 points; 95% CI -34;-4) and social functioning (-27 points; 95% CI -41;-13) decreased compared with patients without dysphagia. Mild dysphagia was also associated with decreased overall quality of life (-12 points; 95% CI -21;-3). Moderate to severe hoarseness was significantly associated with poorer social functioning (-25 points; 95% CI -41;-10). There was no association between fibrosis or xerostomia and HRQoL. CONCLUSION: Physician assessed moderate to severe hoarseness and mild, moderate, or severe dysphagia are associated with clinically relevant decreases in patient-reported quality of life and functioning. Fibrosis and xerostomia of any severity were not associated with changes in any scale of functioning in this study population. PMID- 28079430 TI - Multimodal prehabilitation improves functional capacity before and after colorectal surgery for cancer: a five-year research experience. AB - BACKGROUND: Multimodal prehabilitation is a preoperative conditioning intervention in form of exercise, nutritional assessment, whey protein supplementation, and anxiety-coping technique. Despite recent evidence suggesting that prehabilitation could improve functional capacity in patients undergoing colorectal surgery for cancer, all studies were characterized by a relatively small sample size. The aim of this study was to confirm what was previously found in three small population trials. MATERIAL AND METHODS: Data of 185 participants enrolled in a pilot single group study and two randomized control trials conducted at the McGill University Health Center from 2010 to 2015 were reanalyzed. Subjects performing trimodal prehabilitation (exercise, nutrition, and coping strategies for anxiety) were compared to the patients who underwent the trimodal program only after surgery (rehabilitation/control group). Functional capacity was assessed with the six-minute walk test (6MWT), a measure of the distance walked over six minutes (6MWD). A significant functional improvement was defined as an increase in 6MWD from baseline by at least 19 m. Changes in 6MWD before surgery, at four and eight weeks were compared between groups. RESULTS: Of the total study population, 113 subjects (61%) underwent prehabilitation. Changes in 6MWD in the prehabilitation group were higher compared to the rehabilitation/control group during the preoperative period {30.0 [standard deviation (SD) 46.7] m vs. -5.8 (SD 40.1) m, p < 0.001}, at four weeks [-11.2 (SD 72) m vs. -72.5 (SD 129) m, p < 0.01], and at eight weeks [17.0 (SD 84.0) m vs. -8.8 (SD 74.0) m, p = 0.047]. The proportion of subjects experiencing a significant preoperative improvement in physical fitness was higher in those patients who underwent prehabilitation [68 (60%) vs. 15 (21%), p < 0.001]. CONCLUSION: In large secondary analysis, multimodal prehabilitation resulted in greater improvement in walking capacity throughout the whole perioperative period when compared to rehabilitation started after surgery. PMID- 28079431 TI - Vagus Nerve Stimulation in Intractable Epilepsy Associated With SCN1A Gene Abnormalities. AB - Mutations in the SCN1A gene cause a spectrum of epilepsy syndromes. There are 2 syndromes that are on the severe end of this spectrum. The classic severe form, Dravet syndrome, is an epileptic encephalopathy of childhood, causing cognitive decline as well as intractable seizures. Severe Myoclonic Epilepsy of Infancy Borderline (SMEIB) is a term used to include cases with similar severities as those with Dravet syndrome, but lacking a single feature of classic severe myoclonic epilepsy of infancy. Vagus nerve stimulation is a nonpharmacologic treatment for intractable epilepsy. A retrospective review was conducted of patients with deleterious SCN1A mutations who had vagus nerve stimulation placement for treatment of their intractable epilepsy. These children had onset of their epilepsy between 3 and 29 months of age. Seizure control was assessed 6 months after implantation. Twenty patients are included in the study, with 12 implanted at our institution. Nine of the 12 patients implanted at our institution, who had confirmed pre- and post-implantation seizure assessments, showed improvement in seizure control, which was defined as >50% reduction in generalized tonic-clonic seizures, and 4 of those 12 reported improvement in cognitive or speech development. Seven of the 8 patients not implanted at our institution reported subjective benefit, with 4 relating "marked improvement" or seizure freedom. Vagus nerve stimulation appears to impart a benefit to children with deleterious SCN1A gene abnormalities associated with intractable epilepsy. PMID- 28079432 TI - Primary tumors of the facial nerve misdiagnosed: a case series and review of the literature. AB - CONCLUSION: Unusual primary tumors of the facial nerve should be considered in patients with progressive facial paralysis, especially if this is accompanied by hearing loss or vertigo. Misdiagnosis could increase the difficulties of operation, diminish the chance of facial nerve reconstruction, and increase the likelihood of poor reconstructive outcomes. OBJECTIVE: This paper was to determine the characteristics of facial nerve primary tumors misdiagnosed as tumor-free conditions many years prior, and to describe appropriate treatments. METHODS: The cases of 11 Chinese patients with misdiagnosed primary tumors of the facial nerve were reviewed; every one had been misdiagnosed for more than 8 years. All patients presented with progressive or complete facial paralysis and hearing loss, with or without vertigo. The pre- and post-operative images (including CT scans of the temporal bone) and MRI data were reviewed. RESULTS: All tumors were completely resected using the translabyrinthine or transmastoid approach and were confirmed to be primary tumors of the facial nerve. Facial hypoglossal nerve anastomosis failed because fibrosis developed at the end of the facial nerve in one patient whom this study sought to manage in two stages. One patient accepted facial-hypoglossal nerve anastomosis of two-stage and patient status improved to House-Brackmann (H-B) grade V from H-B grade VI. The other nine patients chose not to undergo reconstruction. PMID- 28079433 TI - PET imaging of cannabinoid type 2 receptors with [11C]A-836339 did not evidence changes following neuroinflammation in rats. AB - Cannabinoid type 2 receptors (CB2R) have emerged as promising targets for the diagnosis and therapy of brain pathologies. However, no suitable radiotracers for accurate CB2R mapping have been found to date, limiting the investigation of the CB2 receptor expression using positron emission tomography (PET) imaging. In this work, we report the evaluation of the in vivo expression of CB2R with [11C]A 836339 PET after cerebral ischemia and in two rat models of neuroinflammation, first by intrastriatal LPS and then by AMPA injection. PET images and in vitro autoradiography showed a lack of specific [11C]A-836339 uptake in these animal models demonstrating the limitation of this radiotracer to image CB2 receptor under neuroinflammatory conditions. Further, using immunohistochemistry, the CB2 receptor displayed a modest expression increase after cerebral ischemia, LPS and AMPA models. Finally, [18F]DPA-714-PET and immunohistochemistry demonstrated decreased neuroinflammation by a selective CB2R agonist, JWH133. Taken together, these findings suggest that [11C]A-836339 is not a suitable radiotracer to monitor in vivo CB2R expression by using PET imaging. Future studies will have to investigate alternative radiotracers that could provide an accurate binding to CB2 receptors following brain inflammation. PMID- 28079436 TI - ? PMID- 28079435 TI - Bioelectrical impedance analysis of head and neck cancer patients at presentation. AB - CONCLUSION: Finnish head and neck cancer (HNC) patients show signs of severe malnutrition already at presentation, measured by bioelectric impedance analysis (BIA). BIA may be a practical method to detect malnutrition, analyze body composition, and to identify high-risk patients in this population. OBJECTIVES: BIA is a validated method for evaluating body composition and detecting malnutrition. Low phase angle (PA) is associated with increased mortality and morbidity. Vector analysis (BIVA) provides a qualitative measure for hydration and cell mass, independent of body size. This study describes BIA results in Finnish HNC patients at presentation. METHODS: Forty-one newly-diagnosed HNC patients at the Helsinki University Hospital were included. BIA measures (resistance, reactance, PA, fat-free mass index [FFMI], and fat mass index [FMI]), body mass index (BMI), and Charlson Comorbidity Index (CCI) were determined. RESULTS: The majority of patients were men (78%), with a normal average BMI of 25.2. Low FFMI was seen in 44% of women and 28% of men. The PA (median = 4.6; IQ range = 4-5) was lower than the reference values in 76% (n = 31) of cases. In BIVA, only 13 (32%) of the patients were within normal range and 15 (37%) were plotted in the quadrant indicating malnutrition. PMID- 28079434 TI - Previous pregnancy outcomes and subsequent pregnancy anxiety in a Quebec prospective cohort. AB - INTRODUCTION: Pregnancy anxiety is an important psychosocial risk factor that may be more strongly associated with adverse birth outcomes than other measures of stress. Better understanding of the upstream predictors and causes of pregnancy anxiety could help to identify high-risk women for adverse maternal and infant outcomes. The objective of the present study was to measure the associations between five past pregnancy outcomes (live preterm birth (PTB), live term birth, miscarriage at <20 weeks, stillbirth at >=20 weeks, and elective abortion) and pregnancy anxiety at three trimesters in a subsequent pregnancy. METHODS: Analyses were conducted using data from the 3D Cohort Study, a Canadian birth cohort. Data on maternal demographic characteristics and pregnancy history for each known previous pregnancy were collected via interviewer-administered questionnaires at study entry. Pregnancy anxiety for the index study pregnancy was measured prospectively by self-administered questionnaire following three prenatal study visits. RESULTS: Of 2366 participants in the 3D Study, 1505 had at least one previous pregnancy. In linear regression analyses with adjustment for confounding variables, prior live term birth was associated with lower pregnancy anxiety in all three trimesters, whereas prior miscarriage was significantly associated with higher pregnancy anxiety in the first trimester. Prior stillbirth was associated with greater pregnancy anxiety in the third trimester. Prior elective abortion was significantly associated with higher pregnancy anxiety scores in the first and second trimesters, with an association of similar magnitude observed in the third trimester. DISCUSSION: Our findings suggest that the outcomes of previous pregnancies should be incorporated, along with demographic and psychosocial characteristics, into conceptual models framing pregnancy anxiety. PMID- 28079437 TI - ? PMID- 28079438 TI - ? PMID- 28079440 TI - ? PMID- 28079439 TI - Experience of patients waiting for a hip or pelvic fracture surgery - a qualitative study AB - Background: In Swiss hospitals, patients are waiting for a hip fracture surgery due to a variety of reasons, despite the guidelines recommending a rapid surgical treatment. Quantitative studies show that long delays have a negative impact on the physical and psychological health. Caregivers are confronted directly with waiting patients. Often they feel insecure and helpless, because little is known about how patients experience their waiting period. Aim: In order to derive implications for nursing care, the study describes the experiences of patients with hip fracture while waiting for this specific surgery. Method: A qualitative approach with semi-structured interviews was chosen. The data were analysed with the open coding method by Saldana. Results: Due to recruitment problems, patients with pelvic fracture were subsequently included. The participants - 33 to 89 year old - had an average waiting time of 68 hours. This condition has been perceived as a standstill and waste of time. Adequate information and attentive care, improved the confidence in the medical team and understanding of the situation, eased the waiting period, while physical and psychological distress such as pain, immobility or worries influenced it negatively. Under these circumstances, patients could hardly occupy themselves. They let time pass and appreciated distraction by their relatives. Conclusions: Consequently, reliable, consistent information and a compassionate, attentive care are core elements in caring for patients with delayed surgery. PMID- 28079441 TI - ? PMID- 28079442 TI - ? PMID- 28079443 TI - Breastfeeding in Women Having Experienced Childhood Sexual Abuse. AB - BACKGROUND: Childhood sexual abuse (CSA) can have a serious effect on general and obstetric health. Breastfeeding includes several triggers for memories of abuse experiences, which will likely influence decisions about breastfeeding and its implementation in daily life. This is important since breastfeeding improves maternal well-being and bonding with the child. Research aim: As breastfeeding strongly influences the long-term health of children, we investigated experiences with breastfeeding in women with a history of CSA. METHODS: Data on breastfeeding were collected within a research project designed to compare labor and delivery experiences in women with a history of CSA to women without such antecedents. Data from 85 women having experienced CSA and 170 controls pair-matched for maternal age, children's age, and nationality were evaluated. The clinical record of pregnancy and a self-administered questionnaire were used to collect data. RESULTS: Although the prevalence of breastfeeding was similar in women with and without CSA experiences (96.5% vs. 90.6%), women exposed to CSA more often described complications associated with breastfeeding (77.7% vs. 67.1%, p = .08). Mastitis (49.4% vs. 27.6%, p < .01) and pain (29.4% vs. 18.8%, p = .15) were reported significantly more often by women after CSA. For 20% of women after CSA, breastfeeding was a trigger for memories of CSA. Furthermore, 58% of women with CSA reported dissociation when breastfeeding. CONCLUSION: In addition to the growing list of potential health consequences of CSA experience, this experience seems to be associated with an increased number of problems when breastfeeding. However, most women with a history of CSA intend to breastfeed despite particular challenges related to CSA. A support protocol tailored to the specific needs of these women during pregnancy and the lactation period may help to improve breastfeeding and the early mother-child relationship. PMID- 28079445 TI - ESFM/Hill's Award given at feline day in Ghent. PMID- 28079446 TI - ESFM Feline Symposium 2009. PMID- 28079448 TI - AAFP Position statements. PMID- 28079447 TI - Corrigendum to 'Interference of iohexol with radioiodine thyroid uptake in the hyperthyroid cat' [ Journal of Feline Medicine and Surgery 10, 460-465]. PMID- 28079449 TI - Minutes of the European Society of Feline Medicine (ESFM) Annual Members Meeting held at the Sheraton Hotel, Edinburgh on Saturday, 27 September, 2008 beginning at 12.30 pm. PMID- 28079450 TI - Feline Congress 2008. PMID- 28079451 TI - Feline activities 2008 and VPAT Congress 2008. PMID- 28079452 TI - The 13th Nestle Purina Nutrition Forum. PMID- 28079453 TI - ESFM Feline Symposium. PMID- 28079454 TI - ESFM - Voorjaarsdagen Feline Symposium 2008. PMID- 28079455 TI - Emergence of Resistance to Fungicides: The Role of Fungicide Dose. AB - Resistance to antimicrobial drugs allows pathogens to survive drug treatment. The time taken for a new resistant mutant to reach a population size that is unlikely to die out by chance is called "emergence time." Prolonging emergence time would delay loss of control. We investigate the effect of fungicide dose on the emergence time in fungal plant pathogens. A population dynamical model is combined with dose-response data for Zymoseptoria tritici, an important wheat pathogen. Fungicides suppress sensitive pathogen population. This has two effects. First, the rate of appearance of resistant mutants is reduced, hence the emergence takes longer. Second, more healthy host tissue becomes available for resistant mutants, increasing their chances to invade and accelerates emergence. In theory, the two competing effects may lead to a non-monotonic dependence of the emergence time on fungicide dose that exhibits a minimum. But according to field data, fungicides are unable to reduce the fungicide-sensitive population strongly enough even at high doses. Hence, for full resistance over realistic ranges of pathogen's life history and fungicide dose-response parameters, emergence time decreases monotonically with increasing dose. For partial resistance, there can be cases within a limited parameter range, when emergence decelerates at higher doses. PMID- 28079458 TI - Leadership, Economics & Strategic Thinking: Moving Forward in Feline Practice. PMID- 28079456 TI - Overexpression of TIFY genes promotes plant growth in rice through jasmonate signaling. AB - Because environmental stress can reduce crop growth and yield, the identification of genes that enhance agronomic traits is increasingly important. Previous screening of full-length cDNA overexpressing (FOX) rice lines revealed that OsTIFY11b, one of 20 TIFY proteins in rice, affects plant size, grain weight, and grain size. Therefore, we analyzed the effect of OsTIFY11b and nine other TIFY genes on the growth and yield of corresponding TIFY-FOX lines. Regardless of temperature, grain weight and culm length were enhanced in lines overexpressing TIFY11 subfamily genes, except OsTIFY11e. The TIFY-FOX plants exhibited increased floret number and reduced days to flowering, as well as reduced spikelet fertility, and OsTIFY10b, in particular, enhanced grain yield by minimizing decreases in fertility. We suggest that the enhanced growth of TIFY-transgenic rice is related to regulation of the jasmonate signaling pathway, as in Arabidopsis. Moreover, we discuss the potential application of TIFY overexpression for improving crop yield. PMID- 28079459 TI - Feline Congress, 2009. PMID- 28079460 TI - Development of a version of the self-ordered pointing task: a working memory task for Brazilian preschoolers. AB - OBJECTIVE: Working memory is a fundamental cognitive function and is predictive of outcomes and achievement in a wide range of domains from an early age. The focus of this study was to develop a computerized Brazilian version of the Self Ordered Pointing Task (SOPT) for preschoolers and to provide initial normative and validation data for this task. METHODS: The sample of the present study was composed of 248 children aged 3 (n = 41), 4 (n = 88) and 5 (n = 119) years from 13 private and public schools in Belo Horizonte. Children were evaluated with the SOPT and the Columbia Mental Maturity Scale (CMMS), a measure of intelligence, and their parents completed the Brazilian Criterion of Economic Classification (CCEB) to assess their SES. A subsample of parents of 184 children also filled the Child Behavior Checklist for Ages 11/2-5 years (CBCL 11/2-5), a measure of psychopathology. RESULTS: A multiple regression analysis found chronological age, intelligence, and SES to be predictive of performance on the SOPT. Furthermore, five-year olds performed better than three- and four-year olds in the task. A difference between children in private and public kindergartens also emerged. Additionally, SOPT performance was negatively correlated with Internalizing, Externalizing, and Total psychopathological problems, as well as to several other psychopathological measures as accessed by the CBCL, although the correlations were small. CONCLUSION: Taken together, this study provides initial normative and validation data for the SOPT, but further validation studies are needed. PMID- 28079461 TI - Building the Evidence Base for Tele-Emergency Care: Efforts to Identify a Standardized Set of Outcome Measures. AB - BACKGROUND: To enhance the quality of emergency department (ED) care, some rural hospitals have adopted the use of telemedicine (tele-ED). Without a common set of metrics, it is difficult to quantify the impact of this technology. INTRODUCTION: To address this limitation, the Health Resources and Services Administration funded the identification and testing of a core set of measures that could be used to build a business case for the value of tele-ED care. METHODS: A comprehensive environmental scan was conducted to identify existing measures relevant to assessing ED care and the use of telemedicine. Identified measures were assessed against a set of criteria and pilot tested in rural hospitals. RESULTS: The environmental scan identified numerous ED-specific measures and a limited set of telehealth-specific measures, but no clearly defined measures specific to tele-ED. Applying evaluation criteria to the measures revealed that few have a well-established evidence base, and fewer have undergone the rigorous testing needed to establish statistical reliability and validity. Nevertheless, a parsimonious set of measures was identified that met many of the evaluation criteria. Pilot testing indicated that collecting data using these measures was feasible. DISCUSSION: For tele-ED benefits to be widely acknowledged, more research is required to demonstrate that care delivered using tele-ED care is as high quality, if not more so, than in-person care. This requires researchers to consistently use a set of clearly defined measures. CONCLUSION: The use of clearly defined and standardized measures will aid interpretation and permit replication in multiple studies, furthering acceptance of study findings. PMID- 28079462 TI - Establishing the standard method of cochlear implant in Rongchang pig. AB - CONCLUSIONS: In this investigation, a large mammal, Rongchang pigs were used to successfully establish a research platform for cochlear implant study on the routine use of it in clinic. OBJECTIVE: The aim of this study was to establish a standard method of cochlear implant in a large mammal-pig. METHODS: Rongchang pigs were selected, then divided into two groups: normal-hearing group (Mitf +/+) and mutation group with hearing loss (Mitf -/-). Cochlear implants were used and ABR and EABR were recorded. The implanted electrodes were observed by X-ray and HE stains. RESULTS: The success with cochlear implant and the best electrode position could be defined in all animals, the coiling of the cochlea reached 1.5 1.75 turns. Immediately after the operation of cochlear implants, the ABR threshold of the operated ear (right) could not be derived for each frequency at 120 dB SPL. Moreover, 7 days after surgery, the low-frequency ABR threshold of the operated ear (right) could be derived partly at 100 dB SPL, but the high frequency ABR threshold could not be derived at 120 dB SPL. Immediately or 1 week after cochlear implants, the EABR threshold was 90 CL in the Mitf +/+ group. This was obviously lower than the 190 CL in the Mitf -/- group. PMID- 28079463 TI - Influence of ABCB1 polymorphisms and serum concentrations on venlafaxine response in patients with major depressive disorder. AB - BACKGROUND: The pharmacokinetics and the pharmacodynamics of antidepressants show large inter-individual variations which result in unpredictable clinical responses. AIM: The aim of the study was to examine the effect of ABCB1 polymorphisms and the serum concentrations on the efficacy and tolerability of venlafaxine in patients with major depressive disorder (MDD). METHODS: Fifty-two outpatients who met the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria for MDD were recruited for the study. The severity of depression was assessed using the 17-item Hamilton Rating Scale for Depression scale (HDRS17) and tolerability was assessed based on a query regarding side-effects for 6 weeks. The ABCB1 C3435T/A and G2677T/A polymorphisms were genotyped by PCR/RFLP and steady-state serum venlafaxine concentrations were measured by high-performance liquid chromatography. RESULTS: Patients with the TT genotype for the C3435T and the TT/TA genotype for the G2677T/A polymorphism showed significantly higher frequencies in venlafaxine-induced akathisia. This relationship was not observed for efficacy. As regards serum venlafaxine concentrations, patient groups showed no significant differences in efficacy and tolerability. CONCLUSION: The results suggest that individuals with the TT-TT/TA genotypes for the C3435T-G2677T/A polymorphisms of ABCB1 may be pre-disposed to a risk of akathisia. PMID- 28079464 TI - First ABCD & Merial Young Scientist Award. PMID- 28079466 TI - WSAVA Preconference Day Wednesday 20 August 2008 UCD Veterinary Sciences Centre, University College Dublin, Bellfield, Dublin 4, Ireland. PMID- 28079468 TI - The Congress of the European College of Veterinary Internal Medicine . Companion Animals. PMID- 28079467 TI - AAFP Veterinarian Membership Benefits. PMID- 28079470 TI - Rise in ambient temperature predisposes aging, male Japanese patients to renal colic episodes due to upper urolithiasis. AB - OBJECTIVE: Urolithiasis is a common urological problem, and its incidence has been increasing worldwide, including in Japan. Relationships between stone etiology and rise in ambient temperature have been reported, but it remains unclear how age and gender affect these relationships. MATERIALS AND METHODS: A retrospective examination was conducted of the medical archives of 1005 patients (aged >=15 years) with acute renal colic diagnosed with urolithiasis upon image examination who consecutively visited emergency departments in three hospitals. The patients were categorized into six groups according to age: younger than 30, 30-39, 40-49, 50-59, 60-69, and 70 years and older. The net difference and fold increase in the number of patients in summer (July to September) versus in winter (December to February) were calculated. RESULTS: Overall, the actual number of the patients varied according to the temperature rise throughout the year and among the age groups. Net increases in the number of patients were observed in all age groups for both genders, apart from 30-39-year-old women. The age group of 50-59 years considerably outnumbered all other groups. A significant statistical correlation was detected between the fold increase and male aging using Spearman's rank correlation analysis (rho = 0.94, p = 0.017), but not in females (rho = -0.03, p = 1). CONCLUSIONS: These results support a positive association between ambient temperature rise and increase in the incidence of renal colic due to urolithiasis in Japan, and indicate that aging and gender affect the association differently. PMID- 28079471 TI - Pre-implant modeling of depth lead placement in white matter for maximizing the extent of cortical activation during direct neurostimulation therapy. AB - INTRODUCTION: The objective of this work was to predict preoperatively the maximum extent to which direct stimulation therapy can propagate through an epileptic circuit for stabilizing refractory focal-onset epilepsy. A pre-surgical workflow is presented which comprises a computationally intensive process for calculating the volume of cortical activation (VOCA) surrounding cylindrical depth contacts virtually placed in white matter. The process employs an activation function (AF) derived from cable modeling of an axon. The AF was extrapolated to describe the three-dimensional activation of axon bundles facilitated by patient-specific diffusion tensor imaging (DTI). METHODS: The modeling process consisted of the following steps: (1) acquisition of structural MRI and DTI; (2) computation of the electric potential using the finite element method; (3) analysis of the effect of the modeled electric field on depolarizing axon bundles using the AF; (4) predicting distant cortical activation by strategically placing the AF seeds for creating a modulated circuit tractography (MCT) map; and finally, (5) post-implant in vivo validation using Subtracted Activated SPECT (SAS). RESULTS: The pre-implant simulation calculated non spherical volumetric regions around the contacts representing areas of hyperpolarization and depolarization. Furthermore, the generated MCT map predicted the extent to which white matter connected epileptic sources were influenced during direct stimulation therapy. Validation of this map was demonstrated post-implantation employing RNS electrocorticography and SAS. The latter technique captured transient alterations in blood flow synched to neural metabolism potentially distant to the stimulated contacts. CONCLUSION: This pre implant modeling system offers the potential for predicting optimal depth lead implant sites with a limited set of contacts for modulating the maximal extent of a refractory epileptogenic network. PMID- 28079472 TI - Polymorphisms of RPS6KB1 and CD86 associates with susceptibility to multiple sclerosis in Iranian population. AB - OBJECTIVE: Multiple sclerosis (MS) is the most prevalent disorder of nervous system inflammation which involves demyelination of spinal cord; this process depends on both environmental and genetic susceptibility factors. In the present study, we examined the association between two SNPs in RPS6KB1 (rs180515) and CD86 (rs9282641) with MS in Iranian population. RPS6KB1gene encodes p70S6K1 protein which plays a key role in mTOR signaling pathway, while CD86 gene codes a membrane protein type I which belongs to immunoglobulin super family act on co stimulation signaling pathway. METHODS: In this case-control study 130 patients with MS and 128 matched healthy controls were enrolled, genomic DNA was isolated and genotyping was performed using mismatched PCR-RFLP. The results were finally analyzed using SPSS. RESULTS: Our results showed significant difference in allelic frequency of SNP rs180515 among cases and controls (P = 0.004). For this variation, AA genotype was shown to have protective effect (P = 0.016 and OR = 0.6), while GG genotype was a susceptive genotype to MS (P = 0.04 and OR = 2.2). Allelic frequency of SNP rs9282641 also showed significant difference between cases and controls (P = 0.006). For this SNP, AG genotype had predisposing effect (P = 0.04, OR = 2.3), and GG genotype showed protective (P = 0.01, OR = 0.411). CONCLUSION: We successfully replicated the association of two novel SNPs introduced by a GWAS study, and MS in the Iranian population. This result can open ways for better understanding the mechanisms involved in MS. PMID- 28079474 TI - Erratum. PMID- 28079473 TI - Protective immunity against influenza in HLA-A2 transgenic mice by modified vaccinia virus Ankara vectored vaccines containing internal influenza proteins. AB - BACKGROUND: The emergence of novel strains of influenza A viruses with hemagglutinins (HAs) that are antigenically distinct from those circulating in humans, and thus have pandemic potential, pose concerns and call for the development of more broadly protective influenza vaccines. In the present study, modified vaccinia virus Ankara (MVA) encoding internal influenza antigens were evaluated for their immunogenicity and ability to protect HLA-A2.1 transgenic (AAD) mice from infection with influenza viruses. METHODS: MVAs expressing NP (MVA-NP), M1 (MVA-M1) or polymerase PB1 (MVA-PB1) of A/California/4/09 (CA/09) virus were generated and used to immunize AAD mice. Antibodies and CD8+T cell responses were assessed by ELISA and ELISPOT, respectively, and challenge experiments were performed by infecting vaccinated mice with CA/09 virus. RESULTS: CD8+T cells specific to immunodominant and subdominant epitopes on the internal influenza proteins were elicited by MVA-based vectors in AAD mice, whereas influenza-specific antibodies were detected only in MVA-NP-immunized mice. Both M1- and NP-based MVA vaccines, regardless of whether they were applied individually or in combination, conferred protection against lethal influenza virus challenge. CONCLUSION: Our data further emphasize the promising potential of MVA vector expressing internal antigens toward the development of a universal influenza vaccine. PMID- 28079475 TI - Hyperbaric oxygen therapy is safe and effective for the treatment of sleep disorders in children with cerebral palsy. AB - OBJECTIVE: To observe the effects of hyperbaric oxygen (HBO2) therapy on the treatment of sleep disorders and its safety in children with cerebral palsy (CP). METHODS: A total of 71 recruited children were divided into two groups based on age: group 1, aged between 2 and 4 years; and group 2, aged between 4 and 6 years. The effects of HBO2 therapy on sleep quality were observed. RESULTS: The total sleep items (TSIs) were significantly different in the two groups between pre-HBO2, post 10 HBO2 sessions, and post 20 HBO2 sessions (p < 0.01). A total of 15/38 (39.5%) participants in group 1 and 8/21 (38.0%) in group 2 presented difficulty in falling asleep; 17/38 (44.7%) in group 1 and 4/21 (19.0%) in group 2 had a short duration of sleep during the night; and 20/38 (52.6%) in group 1 and 11/21 (52.4%) in group 2 woke up easily in the night. No significant difference in the average TSIs in 59 participants was found after 10 HBO2 sessions. Eight participants had insomnia after the first 5 sessions, and three in group 2 had nocturnal hyperkinesia after 15 sessions. A seizure during decompression was observed in 2/59 participants (2/419 sessions). DISCUSSION: These results indicate that HBO2 therapy is beneficial to improve sleep and is safe for children with CP; however, further studies are necessary to explore the mechanisms of HBO2 on sleep. PMID- 28079476 TI - Mimiviruses and the Human Interferon System: Viral Evasion of Classical Antiviral Activities, But Inhibition By a Novel Interferon-beta Regulated Immunomodulatory Pathway. AB - In this review we discuss the role of mimiviruses as potential human pathogens focusing on clinical and evolutionary evidence. We also propose a novel antiviral immunomodulatory pathway controlled by interferon-beta (IFN-beta) and mediated by immune-responsive gene 1 (IRG1) and itaconic acid, its product. Acanthamoeba polyphaga Mimivirus (APMV) was isolated from amoebae in a hospital while investigating a pneumonia outbreak. Mimivirus ubiquity and role as protist pathogens are well understood, and its putative status as a human pathogen has been gaining strength as more evidence is being found. The study of APMV and human cells interaction revealed that the virus is able to evade the IFN system by inhibiting the regulation of interferon-stimulated genes, suggesting that the virus and humans have had host-pathogen interactions. It also has shown that the virus is capable of growing on IFN-alpha2, but not on IFN-beta-treated cells, hinting at an exclusive IFN-beta antiviral pathway. Our hypothesis based on preliminary data and published articles is that IFN-beta preferentially upregulates IRG1 in human macrophagic cells, which in turn produces itaconic acid. This metabolite links metabolism to antiviral activity by inactivating the virus, in a novel immunomodulatory pathway relevant for APMV infections and probably to other infectious diseases as well. PMID- 28079477 TI - Waste Gas Treatment in Biofilters. AB - Biofiltration of polluted gas streams containing malodorous triethylamine (TEA) was studied. The experiments were conducted in a laboratory-scale reactor with a mixture of sieved compost and chaff particles as the filter material on which the microorganisms were immobilized. The concentrations of TEA in the inlet gas varied from 0.32 to 3.45 g/m3 (78 ppmv to 841 ppmv), while the superficial velocity of the inlet gas ranged from 60.1 to 322.2 m/hr. The removal efficiency of triethylamine in the biofilter decreased as the gas velocity or TEA concentration in the inlet gas increased. Moreover, the elimination capacity of this biofilter could reach up to 140 g/(m3 hr). When the loading of TEA exceeded this critical value, substrate inhibition occurred and the elimination capacity decreased. A mathematical model predicting the removal efficiency of the pollutant was also developed in this study. The inhibitory effect of the substrate on the growth rate of the biomass was considered in this model. The proposed model could accurately represent the experimental data obtained in this study. PMID- 28079478 TI - Real World Vehicle Emissions: A Summary of the Fifth Coordinating Research Council On-Road Vehicle Emissions Workshop. PMID- 28079479 TI - Understanding and Reducing the Indoor Concentration of Submicron Particles at a Commercial Building in Southern California. AB - Submicron particles play a major role in soiling processes and contribute to corrosion, current leakage and shorts in electronic equipment. For more than a year, optical particle counters have been used to continuously measure the concentrations of submicron particles at a telecommunications facility in Southern California. Separate instruments have simultaneously sampled at four locations: the outdoor air intake, immediately upstream of the HVAC filters, immediately downstream of the HVAC filters, and inside the office. The indoor concentrations can be explained in the context of a one-compartment mass balance model. Key parameters in the model (e.g., the air exchange rate) were monitored throughout the sampling period. In the latter part of this study, the particle counters were used as feedback elements in the HVAC system. An estimate of the concentration of indoor submicron particles, based on measurements of outdoor submicron particles, has been used as a control variable. When this variable exceeds a preset value, the outdoor air damper is partially closed, reducing the amount of outdoor air entering the building. That is, the position of the damper is based on the concentration of outdoor particles as well as the outdoor temperature. As a consequence, the average indoor concentration of submicron particles has been significantly reduced within this facility. PMID- 28079480 TI - Nutrient Limitation in a Compost Biofilter Degrading Hexane. AB - A laboratory-scale compost-based biofilter was operated over a six-month period to study the requirements for removal of n-hexane from air. Hexane is a relatively short chain aliphatic hydrocarbon with a high Henry's coefficient and a low water solubility. Acclimation of the biofilter was slow, but removal efficiencies around 80% were achieved after one month of operation. However, performance decreased during the next two months of operation to 50% removal efficiency. Nutrient limitation was proposed as a reason for the decrease in reactor performance. After the addition of a concentrated nitrogen solution, reactor performance increased almost immediately to >99%. Removal efficiency remained above 99% for the following two months of operation at inlet concentrations of 0.7 g/m3 (200 ppmv), at superficial bed velocities approaching 50 m/h, and empty bed residence times of about one minute. Thus, nutrient availability may well limit biofilter performance even in compost- based units. It was shown that nutrients can be added effectively in a soluble form if compost quality is poor and a method is proposed for the evaluation of compost quality. PMID- 28079481 TI - Emissions of Trace Products of Incomplete Combustion from a Pilot-Scale Incinerator Secondary Combustion Chamber. AB - Experiments were performed on a 73 kW rotary kiln incinerator simulator equipped with a 73 kW secondary combustion chamber (SCC) to examine emissions of products of incomplete combustion (PICs) resulting from incineration of carbon tetrachloride (CC14) and dichloromethane (CH2C12). Species were measured using an on-line gas chromatograph (GC) system capable of measuring concentrations of eight species of volatile organic compounds (VOCs) in a near-realtime fashion. Samples were taken at several points within the SCC, to generate species profiles with respect to system residence time. For the experiments, the afterburner on the SCC was operated at conditions ranging from fuel-rich to fuellean, while the kiln was operated at a constant set of conditions. Results indicate that combustion of CH2C12 produces higher levels of measured PICs than combustion of CC14, particularly 1, 2 dichlorobenzene, and to a lesser extent, monochlorobenzene. Benzene emissions were predominantly affected by the afterburner air/fuel ratio regardless of whether or not a surrogate waste was being fed. PMID- 28079482 TI - Interlaboratory and Intralaboratory Variability in the Analysis of Mercury in Coal. AB - With the passage of the 1990 Clean Air Act Amendments (CAAA), accurate determination of the concentration of mercury in coal has become an increasingly important issue. To address this issue, CONSOL R&D conducted a round robin analytical program to determine the interlaboratory and intralaboratory variability in the measurement of mercury in coal. CONSOL supplied homogeneous splits of Pittsburgh and Illinois #6 seam coals, and the NIST 1632b coal standard to eleven laboratories, twice each, over a one-year period. A twelfth laboratory analyzed the coals once. A European coal standard, certified for mercury, was analyzed at the completion of the round robin study to evaluate accuracy. The round robin participants included representatives from industry, government, and academia. The laboratories, which are experienced in mercury-in-coal analysis, used various state-of-the-art sample preparation and analysis procedures in the study. The round robin results indicate that a substantial level of variability exists in the mercury-in-coal determination. Earlier studies1 found similar results. The relative intralaboratory repeatability was 0.02 ppm and the relative interlaboratory reproducibility ranged from 0.04 to 0.05 ppm. The study showed that laboratory variability can be greatly skewed by outlier values. Fifty-six percent of the results for the European coal standard fell within a 95% confidence interval of the standard (0.138 +/- 0.11 ppm). These results indicate that accuracy is not method-dependent. PMID- 28079483 TI - Airborne Lidar Measurements of a Smoke Plume Produced by a Controlled Burn of Crude Oil on the Ocean. AB - An airborne lidar was used to study the smoke plume from the burning of a controlled oil spill on the ocean. The ratio of the amount of light (at a wavelength, lambda, of 0.532 u.m) backscattered by the smoke to the amount of light extinguished by the smoke was determined by measuring the strength of a laser beam after it had passed through the smoke plume, been reflected from the ocean, and passed through the smoke plume again, and comparing this to the strength of the laser beam reflected directly from the ocean. The optical depth of the smoke (at lambda = 0.532 um) was typically between 0.2 and 0.5. The mass fluxes of smoke particles that passed through four vertical cross sections of the (nonsteady state) smoke plume were estimated from lidar measurements to be 142, 175, 423, and 414 g s-1, compared to an average smoke mass production rate of ~770 g s-1. The spatial distribution of smoke mass along the long axis of the plume was also estimated from the lidar measurements; derived smoke mass concentrations were generally <300 ug m-3, with a few isolated values up to ~800 ug m-3. PMID- 28079484 TI - Comparison of Outdoor and Classroom Ozone Exposures for School Children in Mexico City. AB - To evaluate methods of reducing exposure of school children in southwest Mexico City to ambient ozone, outdoor ozone levels were compared to indoor levels under three distinct classroom conditions: windows/doors open, air cleaner off; windows/doors closed, air cleaner off; windows/ doors closed, air cleaner on. Repeated two-minute average measurements of ozone were made within five minutes of each other inside and outside of six different school classrooms while children were in the room. Outdoor ozone two-minute average levels varied between 64 and 361 ppb; mean outdoor levels were above 160 ppb for each of the three conditions. Adjusting for outdoor relative humidity, for a mean outdoor ozone concentration of 170 ppb, the mean predicted indoor ozone concentrations were 125.3 (+/-5.7) ppb with windows/doors open; 35.4 (+/-4.6) ppb with windows/ doors closed, air cleaner off; and 28.9 (+/-4.3) ppb with windows/ doors closed, air cleaner on. The mean predicted ratios of indoor to outdoor ozone concentrations were 0.71 (+/-0.03) with windows/doors open; 0.18 (+/-0.02) ppb with windows/doors closed, air cleaner off; and 0.15 (+/-0.02) ppb with windows/doors closed, air cleaner on. As outdoor ozone concentrations increased, indoor ozone concentrations increased more rapidly with windows and doors open than with windows and doors closed. Ozone exposure in Mexican schools may be significantly reduced, and can usually be kept below the World Health Organization (WHO) guideline of 80 ppb, by closing windows and doors even when ambient ozone levels reach 30Q ppb or more. PMID- 28079485 TI - Prediction of IM240 Mass Emissions Using Portable Exhaust Analyzers. AB - Inspection and maintenance programs for motor vehicles in the United States increasingly use loaded mode mass emissions testing (IM240). A method was developed to predict mass emission rates and mass emission changes, particularly from repair benefits, using a low-cost, portable four-gas non-dispersive infrared (NDIR) vehicle exhaust gas analyzer. A single vehicle was tested several times with the analyzer while on the dynamometer and undergoing successive repairs. Excellent correlations for CO and HC were observed. Five vehicles were measured using an on-road driving loop before and after emissions-related repairs, while another three vehicles were tested with no repairs performed. The on-road concentration data used to guide the repair process were converted to grams per gallon; when divided by estimated miles per gallon, this gave grams per mile emissions for comparison to IM240. Correlation coefficients (r2) of 0.87 for CO and 0.76 for HC were achieved for the 13 tests. The linear correlations between IM240 and emissions measured by this method would allow repair facilities to perform a relatively inexpensive test for diagnostic purposes and to estimate repair effectiveness without the need for a dynamometer. PMID- 28079486 TI - Corrigendum. PMID- 28079487 TI - Adopting universal testing for HIV in intensive care for patients admitted with severe pneumonia: results from our change in practice. AB - Early identification of HIV infection is of obvious benefit to patients' health, yet many remain unaware of their diagnosis, with detrimental consequences. Current guidelines suggest patients with pneumonia are offered an HIV test. Early diagnosis of HIV infection in critically ill patients within intensive care is vital in reducing mortality and morbidity. In 2015, we established automated HIV testing for patients with pneumonia admitted to our intensive care unit. Prior to our change in practice, our HIV testing rate in patients with pneumonia was 29% within two weeks of admission. After implementation, 80% of patients with pneumonia were tested for HIV within 48 h (73% with 24 h). This intervention also facilitated an early and unexpected HIV diagnosis in one patient, which then allowed prompt tailored therapy and was a significant factor in their survival. Based on our success, we suggest other centres may benefit from employing a similar automated HIV testing system, especially in targeted patient groups such as severe pneumonia. PMID- 28079488 TI - Association analysis of ANK3 variants with bipolar disorder in the Korean population. AB - BACKGROUND: Bipolar disorder (BD) is a major psychiatric disorder characterized by alternating mood episodes, including major depressive, hypomanic, and manic episodes. Previous genetic studies of BD have reported several genes as potentially associated with BD. The ANK3 gene has been identified as a possible BD susceptibility gene in genome-wide association analyses. AIMS: The goal of the present study was to evaluate the association of ANK3 variants with BD in the Korean population. METHODS: Based on previous results, two single nucleotide polymorphisms (SNPs), rs1938526 and rs10994336, were selected in the ANK3 gene. The study included 287 BD patients and 340 healthy controls. Case-control association and case-control haplotype analyses of the two ANK3 variants were performed. RESULTS: No significant association was found of either single SNP with BD by case-control association analysis. However, rs1938526 and rs10994336 showed a significant association (overall p = 3.6 * 10-11; permutation p = 0) in a case-control haplotype analysis. CONCLUSIONS: The haplotype analysis results suggest that ANK3 variants rs1938526 and rs10994336 may confer susceptibility for BD in the Korean population. Association analysis revealed a probable genetic difference between Korean and Caucasian populations in the degree of ANK3 involvement in BD pathogenesis. PMID- 28079489 TI - Editorial. PMID- 28079491 TI - The Problem of University Courses on Infinitesimal Calculus and Their Demarcation from Infinitesimal Calculus in High Schools - ERRATUM. AB - In the above mentioned article [1] unfortunately the names of the translators of Toeplitz's lecture were omitted. The correct title is: The Problem of University Courses on Infinitesimal Calculus and Their Demarcation from Infinitesimal Calculus in High Schools Otto Toeplitz Translated into English by Michael N. Fried and Hans Niels Jahnke. PMID- 28079490 TI - Paris vs. Prague: A "Suspicion of Fraud": Ernst Mach Argues over Photographs and Epistemological Prerequisites. AB - Argument In spring 1888, an anonymous critic raised severe doubts about Ernst Mach's and Peter Salcher's studies, published one year before, on the processes in the air caused by very rapid projectiles. Paraphrasing the experiments for the French popular science magazine La Nature, the critic insinuated that the photographs upon which Mach and Salcher's argument were ostensibly based must have been of such low quality that they did not allow any well-founded conclusion. The critic did not deny the phenomena Mach and Salcher had presented in their article; he denied that the photographs taken in the course of the experiments could permit any observation of the phenomena. I take the resulting quarrel as a window into the actors' ideas on the requirements of "good observations" and the role of technical devices in this case. In particular I enquire how the various arguments relate to Lorraine Daston's and Peter Galison's framing of photography as an emblem of "mechanical objectivity." We will see that in the case under debate, actors considered naked-eye observation, observation by telescope and photography mainly with regard to the challenges of the particular research object. PMID- 28079492 TI - Working with Instruments: Ernst Mach as Material Epistemologist, a Short Introduction. AB - With the death of Ernst Mach on February 19, 1916, one day after his seventy eighth birthday, a question finally became explicit that had been looming for some time. It was as simple as it was fundamental: who, in the end, was this man, a scientist or a philosopher? The importance of this question for contemporaries can easily be gleaned from the obituaries that appeared in the weeks following Mach's death: one in the Physikalische Zeitschrift, written by Albert Einstein, and another in the Archiv fur die Geschichte der Philosophie, written by Mach's former student Heinrich Gomperz. They both addressed this critical issue in plain words. Einstein stressed that Mach "was not a philosopher who chose the natural sciences as the object of his speculation, but a many-sided, interested, diligent scientist who also took visible pleasure in detailed questions outside the burning issues of general interest" (Einstein 1916, 104; translation cited in Blackmore 1992, 158). Gomperz in turn first emphasized the great loss science had experienced with Mach's death, asking subsequently whether "the suffering science is physics or philosophy?" (Gomperz 1916, 321). His answer broadly followed Einstein's conclusion; relying on Mach's own words, he reminded his readers that Mach never claimed to be a philosopher, but merely was looking for a viewpoint that transcended the disciplinary constraints of particular scientific activities. PMID- 28079493 TI - Ernst Mach Invents a New Sphygmograph. AB - Argument The sphygmograph as designed and tested by Jules-Etienne Marey - an apparatus destined to write pulse tracings on paper - revolutionized medical diagnostics in the early 1860s. Since the accuracy with which this device registered and objectified the pulse was controversial from the outset, the young scholar Ernst Mach (soon to become a leading theoretician and philosopher) decided to thoroughly examine Marey's sphygmograph. The investigation led to the invention of an alternative, truly Machian, sphygmograph. Mach's sphygmograph had originated in the regime of theoretical and applied physics, whereas the instrument invented by Marey had been rooted in the regime of experimental physiology. This one type of instrument thus serves as the focal object of a comparative study of two antagonistic epistemological approaches to sphygmography. PMID- 28079494 TI - Remarks on Scientific Applications of Photography. AB - It is undisputed that all scientific knowledge proceeds from sense perception. And the way in which sense perception is fostered by the graphic arts generally, and in particular by photography (stereoscopy included), likewise needs no further explanation here. PMID- 28079495 TI - On the Principle of Temporal Diminution in Serial Photography. AB - In some cases our sensory organs are no longer capable of rendering processes in the external world perceptible to us. Their inadequacy expresses itself, for example, in phenomena that involve the kind of expansion of space and time in which the conditions for summary perception are no longer at all present. The resources that aid our immediate sense perception in these circumstances will thus be charged with the task of expanding or diminishing space and time to the extent that the contiguity and succession of events is comprehensible to us. The microscope is thus essentially based upon the principle of spatial expansion, the map on that of spatial diminution. The pertinent contrivances for these purposes are largely derived from the graphic arts. How stereoscopy and instantaneous photography, which is based on temporal expansion, facilitate our perception! In spite of the multifarious applications of photography, one has yet to take the step of employing it in the opposite direction, namely as a means of temporal diminution. We demonstrate that phenomena that take place in too ephemeral and too rapid a succession for our eyes can, with the help of instantaneous photographs in series, be analyzed with our senses as the event passes in a comparatively longer time. Quite analogously, we could also compress into a small duration the moments of an event separated widely from one another in time and thereby give our perception an understanding of the nature thereof. PMID- 28079496 TI - On the Theory of the Sphygmograph. AB - Many debates have already taken place on the reliability of the results obtained by means of sphygmographs. The following remarks may contribute to clarify some still unsettled points. PMID- 28079497 TI - Meanings of Waves: Electroencephalography and Society in Mexico City, 1940-1950. AB - Argument This paper focuses on the uses of electroencephalograms (EEGs) in Mexico during their introductory decade from 1940 to 1950. Following Borck (2006), I argue that EEGs adapted to fit local circumstances and that this adjustment led to the consolidation of different ways of making science and the emergence of new objects of study and social types. I also maintain that the way EEGs were introduced into the institutional networks of Mexico entangled them in discussions about the objective and juridical definitions of social groups, thereby preempting concerns about their technical and epistemic limitations. This ultimately enabled the use of EEGs as normative machines and dispositifs. To this end, the paper follows the arrival of EEGs and the creation of institutional networks then analyzes the extent to which the styles of thinking behind the uses of EEGs and attempts to reify a notion of normal electrical brain behavior particularly by applying EEGs to a community of Otomi Indians-correlated with the difficulties of defining the socio-anthropological notions that articulated legal and disciplinary projects of the time. Finally, it unveils the shortcomings of alternative attempts to define a brain model and to resist the production of ontological determinations. PMID- 28079498 TI - How Place and Audience Matter: Perspectives on Mathematics Plural Identities from Late 1950s French and English Middle School Textbooks. AB - Argument In this paper, I argue that studying school textbooks is a fruitful way to investigate mathematical conceptions in different national contexts. These sources give access to the written production of an extended mathematical milieu whose members write for various audiences. By studying the case of late 1950s French and English textbooks issued for a growing audience of 11- to 15-year-old pupils, I show that a plurality of conceptions was projected at the time onto pupils and their teachers in both national contexts. I link this diversity to contemporaneous debates regarding mathematics teaching and argue that textbooks themselves have to be considered as active agents of such debates. PMID- 28079499 TI - Notification that new names of prokaryotes, new combinations, and new taxonomic opinions have appeared in volume 66, part 9, of the IJSEM. PMID- 28079500 TI - Efficacy and safety of tofacitinib in older and younger patients with rheumatoid arthritis. AB - OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We evaluated the efficacy and safety of tofacitinib 5 or 10 mg twice daily (BID), in patients with moderate to severe RA, aged >=65 and <65 years. METHODS: Data were pooled from five Phase 3 trials and, separately, from two open-label long-term extension (LTE) studies (data cut-off April, 2012). Patients received tofacitinib, or placebo (Phase 3 only), with/without conventional synthetic DMARDs (mainly methotrexate). Clinical efficacy outcomes from Phase 3 studies were evaluated at Month 3. Safety evaluations using pooled Phase 3 data (Month 12) and pooled LTE data (Month 24) compared exposure-adjusted incidence rates (IRs; with 95% confidence intervals [CIs]), in older versus younger patients. RESULTS: In Phase 3 and LTE studies, 15.3% (475/3111) and 16.1% (661/4102) of patients, respectively, were aged >=65 years. Consequently, exposure to tofacitinib was lower in older versus younger patients in Phase 3 (259.2 vs. 1554.9 patient years [pt-yrs]) and LTE (962.1 vs. 5071.7 pt-yrs) studies. Probability ratios for ACR responses and HAQ-DI improvement from baseline >=0.22 (Month 3) favoured tofacitinib and were similar in older and younger patients, with overlapping CIs. IRs for SAEs and discontinuations due to AEs were generally numerically higher in older versus younger patients, irrespective of treatment. CONCLUSIONS: Older patients receiving tofacitinib 5 or 10 mg BID had a similar probability of ACR20 or ACR50 response and, due to comorbidities, a numerically higher risk of SAEs and discontinuations due to AEs compared with younger patients. PMID- 28079501 TI - Clinical efficacy of oral alendronate in ankylosing spondylitis: a randomised placebo-controlled trial. AB - OBJECTIVES: A prospective, double blind, randomised, placebo controlled trial over 2 years was performed to test the efficacy of alendronate, an oral aminobisphosphonate, in improving symptoms and arrest disease progression in patients with mild to severe ankylosing spondylitis (AS). METHODS: 180 patients with AS were randomised to receive weekly alendronate 70 mg or placebo (1:1 randomisation). BAS-G was the primary outcome measure with Bath indices as secondary outcomes. Vertebral x-rays were performed at 0 and 24 months. Biomarkers (including CRP, IL-1beta, IL6, VEGF, MMP-1, and MMP-3) were collected during the first 12 months. RESULTS: There was no significant difference between the placebo and treatment groups in any of the recorded outcomes over the 2 years including clinical indices, biomarkers, and radiology. The change in BAS-G, the primary outcome measure, was -0.21 for the treatment group and -0.42 for the placebo group p=0.57. Change in all other clinical outcome measures were also non significant; BASDAI p=0.86, BASFI p=0.37, BASMI p=0.021. Sub-group analysis of those subjects with a baseline BASDAI >4 were also non-significant. CONCLUSIONS: This prospective study demonstrates that alendronate 70mg weekly for 2 years was no more efficacious than placebo in improving clinical or laboratory measures of disease activity or measures of physical impact in subjects with mild to severe active AS. TRIAL REGISTRATION: ID SRCTN12308164, registered on 15.12.2015. PMID- 28079502 TI - Subcutaneous panniculitis-like T-cell lymphoma with haemophagocytic syndrome during tocilizumab therapy for juvenile idiopathic arthritis. PMID- 28079503 TI - Novel evidences of atypical manifestations in cryopyrin-associated periodic syndromes. AB - OBJECTIVES: Cryopyrin-associated periodic syndromes (CAPS) usually start during infancy as an urticarial-like rash and a marked acute phase response, with additional manifestations appearing during its evolution. The aim of this study was to expand the clinical diversity of CAPS by the description of novel atypical features. METHODS: Clinical data were collected from patients' medical charts. Sanger sequencing analyzed NLRP3. Response to anti-IL-1 blockade was evaluated by clinical assessments and by measurements of laboratory parameters. RESULTS: Seventeen patients from two families (A and B), carrying the p.Ala439Thr and p.Arg260Trp NLRP3 mutations respectively, were enrolled. The disease was unexpectedly atypical in all members of Family A, with a 16-year-old asymptomatic carrier, and onset in adulthood associated with absence of skin lesions in four affected members. Surprisingly, one patient from each family suffered from severe haemorrhagic cystitis due to AA amyloidosis in the urinary bladder. Members of Family B displayed a classical phenotype, with two patients suffering from olfactive disorders. CONCLUSIONS: Our evidence suggests that CAPS may occasionally be presented as a late-onset, recurrent inflammatory disease without urticarial-like rash. In some patients, AA amyloidosis in strange locations like urinary bladder may complicate the clinical course. The response to IL-1 blockade in these atypical CAPS was similar to that described in classical forms. Consequently, we suggest that CAPS should be included in the differential diagnosis of adult patients with unexplained, recurrent inflammatory diseases, and once confirmed, the early initiation of anti-IL-1 blockade will probably prevent the development of life-threatening complications. PMID- 28079504 TI - Anti-carbonic anhydrase autoantibodies and serum beta-2 microglobulin correlate with the ClinESSDAI score in patients with Sjogren's syndrome. PMID- 28079505 TI - Glucocorticoid withdrawal in polymyalgia rheumatica: the theory versus the practice. PMID- 28079507 TI - Do MicroRNAs have a key epigenetic role in osteoarthritis and in mechanotransduction? AB - Osteoarthritis (OA) is the most common degenerative disease affecting joint tissues. The pathogenesis of OA is complex and poorly understood, as well as the multiple factors contributing to its development and progression. Accumulating evidence has suggested that microRNAs (miRNAs) play an important role as regulators of cartilage biology and in the pathogenesis of OA. It has been demonstrated that mechanical loading, important for the regulation of cartilage metabolism, affects miRNAs expression. Furthermore, miRNAs present in human plasma and in synovial fluid could represent promising biological markers for OA. Herein, we have reviewed the current state of research on miRNAs in cartilage homeostasis and OA pathogenesis and their potential clinical applications. PMID- 28079506 TI - Response of human rheumatoid arthritis osteoblasts and osteoclasts to adiponectin. AB - OBJECTIVES: Adiponectin is an effector molecule in the pathophysiology of rheumatoid arthritis, e.g. by inducing cytokines and matrix degrading enzymes in synovial fibroblasts. There is growing evidence that adiponectin affects osteoblasts and osteoclasts although the contribution to the aberrant bone metabolism in rheumatoid arthritis is unclear. Therefore, the adiponectin effects on rheumatoid arthritis-derived osteoblasts and osteoclasts were evaluated. METHODS: Adiponectin and its receptors were examined in bone tissue. Primary human osteoblasts and osteoclasts were stimulated with adiponectin and analysed using realtime polymerase chain-reaction and immunoassays. Effects on matrix production by osteoblasts and differentiation and resorptive activity of osteoclasts were examined. RESULTS: Immunohistochemistry of rheumatoid arthritis bone tissue showed adiponectin expression in key cells of bone remodelling. Adiponectin altered gene expression and cytokine release in osteoblasts and increased IL-8 secretion by osteoclasts. Adiponectin inhibited osterix and induced osteoprotegerin mRNA in osteoblasts. In osteoclasts, MMP-9 and tartrate resistant acid phosphatase expression was increased. Accordingly, mineralisation capacity of osteoblasts decreased whereas resorptive activity of osteoclasts increased. CONCLUSIONS: The results confirm the proinflammatory potential of adiponectin and support the idea that adiponectin influences rheumatoid arthritis bone remodelling through alterations in osteoblast and osteoclast. PMID- 28079508 TI - Management of dyslipidaemia in high-risk patients with recent-onset rheumatoid arthritis: targets still not met despite specific recommendations. Results from the ESPOIR cohort during the first five years of follow-up. AB - OBJECTIVES: Reduction of LDL-cholesterol (LDLc) is essential to decrease the cardiovascular mortality in rheumatoid arthritis (RA). Between 2005 and 2010, French recommendations for dyslipidaemia defined the LDLc target based on the number of cardiovascular risk factors. In 2006, it was recommended to consider LDLc objectives with RA being counted as an additional cardiovascular risk factor. Our objective was to assess lipid target achievement between 2006 and 2010 in a cohort of patients with recent-onset RA. METHODS: 814 patients were included between 2002 and 2005 in a French cohort of patients with early arthritis and a high probability of RA (ESPOIR). Repeated cross-sectional analyses for cardiovascular risk factors, cholesterol levels were performed every year from 2006 to 2010 to determine lipid profile and achievement of the LDLc goal according to the French guidelines. RESULTS: On the 620 patients analysed at the first point, 77% were female, 89.8% fulfilled the ACR criteria for RA and 2.7% received a statin. The proportion of patients failing to achieve the LDLc target did not improve following the publication of specific RA guidelines in 2006 (15.3 to 22.5% between 2006 and 2010). In patients with the highest cardiovascular risk, more than 58% did not reach the LDLc target. CONCLUSIONS: Specific recommendations for RA published in 2006 decreased LDLc target but did not improve management of dyslipidaemia in daily life which remained suboptimal particularly in patients at highest risk. PMID- 28079509 TI - Excellent balance skills despite active and inactive juvenile idiopathic arthritis - unexpected results of a cross-sectional study. AB - OBJECTIVES: Postural control (PC) is fundamental for human movements. Different factors, such as injuries or diseases, can adversely affect PC. The purpose of this study was to evaluate PC in juvenile idiopathic arthritis (JIA) patients with different disease activity levels in comparison to healthy peers. METHODS: JIA patients with active and inactive lower limb joints (n=36 each group) were examined. Both groups have been on medication and have had physiotherapy for at least 5 years. For comparison, an age- and gender-matched healthy control group (CG; n=36) participated. PC was measured bipedal on a balance-board (S3-Check, TST, Grobetahoeflein), with an instable tilting between left and right. The parameters of interest were the best results of Stability Index (STI), Sensorimotor Index (SMI) and Symmetry Index (SYI) out of 4 test trials as well as JIA disease-related variables. Data were analysed with descriptive statistics, comparison of averages, linear regression and correlations (p<0.05). RESULTS: The three groups showed no differences in anthropometric characteristics and SYI (p>0.05). In both JIA groups, STI and SMI were lower than indices of CG (p<0.05), indicating better stability and motor control. Balance indices did not differ between active and inactive JIA patients (p>0.05). CONCLUSIONS: JIA patients showed better PC than CG. Possible explanations are an increased body-awareness due to long-term physiotherapy and daily coordination training due to compensatory movements. The positive results highlight the success of individual, interdisciplinary treatment in JIA and can be used to promote recommendations for safe sport participation. PMID- 28079510 TI - A comparison of discontinuation rates of tofacitinib and biologic disease modifying anti-rheumatic drugs in rheumatoid arthritis: a systematic review and Bayesian network meta-analysis. AB - OBJECTIVES: The purpose of this study was to compare the discontinuation rates of tofacitinib and biologics (tumour necrosis factor inhibitors (TNFi), abatacept, rituximab, and tocilizumab) in rheumatoid arthritis (RA) patients considering inadequate responses (IRs) to previous treatment(s). METHODS: Randomised controlled trials of tofacitinib and biologics - reporting at least one total discontinuation, discontinuation due to lack of efficacy (LOE), and discontinuation due to adverse events (AEs) - were identified through systematic review. The analyses were conducted for patients with IRs to conventional synthetic disease-modifying anti-rheumatic drugs (cDMARDs) and for patients with biologics-IR, separately. Bayesian network meta-analysis was used to estimate rate ratio (RR) of a biologic relative to tofacitinib with 95% credible interval (CrI), and probability of RR being <1 (P[RR<1]). RESULTS: The analyses of 34 studies showed no significant differences in discontinuation rates between tofacitinib and biologics in the cDMARDs-IR group. In the biologics-IR group, however, TNFi (RR 0.17, 95% CrI 0.01-3.61, P[RR<1] 92.0%) and rituximab (RR 0.20, 95% CrI 0.01-2.91, P[RR<1] 92.3%) showed significantly lower total discontinuation rates than tofacitinib did. Despite the difference, discontinuation cases owing to LOE and AEs revealed that tofacitinib was comparable to the biologics. CONCLUSIONS: The comparability of discontinuation rate between tofacitinib and biologics was different based on previous treatments and discontinuation reasons: LOE, AEs, and total (due to other reasons). Therefore, those factors need to be considered to decide the optimal treatment strategy. PMID- 28079511 TI - Circulating carotenoids and subsequent risk of rheumatoid arthritis in women. AB - OBJECTIVES: The aim of the present study was to examine the associations between circulating carotenoids and future risk of rheumatoid arthritis (RA). METHODS: We conducted a nested case-control study consisting of 227 incident RA cases and 671 matched controls with prospectively measured plasma carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene and lutein/zeaxanthin) levels in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II). Each incident RA case was matched with 3 healthy controls. Serologic phenotype of RA was determined by rheumatoid factor or anti-citrullinated peptide antibody (ACPA) obtained by chart review. Multivariable logistic regressions were used to estimate odds ratios (OR) and 95% confident intervals (95% CI) for RA risk associated with each circulating carotenoid after adjusting for matching factors and other covariates. RESULTS: The median time from blood draw until RA diagnosis was 8.6 years. In the multivariable models, no significant associations were found between any plasma carotenoids and risk of RA. We further examined the associations for two subtypes of RA, and found associations of circulating alpha carotene and beta-carotene with reduced risk of seronegative RA. After correction for multiple comparisons using the Bonferroni method, the findings did not reach statistical significance. CONCLUSIONS: Circulating carotenoids levels are not associated with reduced risk of RA. Further investigations using large prospective cohorts are needed to confirm our findings. PMID- 28079514 TI - ESRD: epidemiology and treatment in developing countries in Southeast Asia. PMID- 28079512 TI - Long-term treatment response in rheumatoid arthritis patients starting adalimumab or etanercept with or without concomitant methotrexate. AB - OBJECTIVES: To observe long-term clinical response and drug survival in a prospective two-year cohort study in rheumatoid arthritis (RA) patients starting adalimumab or etanercept treatment, with or without methotrexate (MTX), after failure of conventional DMARD therapy, including MTX. METHODS: Disease activity score of 28 joints (DAS28) and Health Assessment Questionnaire (HAQ) were collected of 873 consecutive RA patients, treated with adalimumab or etanercept, prospectively at baseline, 4, 16, 28, 40, 52, 78 and 104 weeks of biological therapy. Sustained minimal disease activity (MDA), DAS28 <2.6 for at least 24 consecutive weeks, biological discontinuation, DeltaHAQ and DeltaDAS28 were compared between patients treated with or without concomitant MTX for etanercept and adalimumab separately. RESULTS: More patients treated with adalimumab and MTX (42%) achieved sustained MDA than patients without MTX (18%). The hazard ratio (HR) was 2.3 [1.4-3.9]. No significant difference was found in etanercept treatment (with MTX 33% vs. 28% without MTX), HR 1.1 [0.8-1.6]. More patients treated without MTX discontinued treatment than patients with MTX co-treatment in adalimumab (HR 2.1 [1.5-3.0]) and etanercept (HR 1.9 [1.0-3.4]). The mean decrease in DAS28 over time was higher for patients treated with MTX in adalimumab (regression coefficient (RC): 0.57, p<0.001), but was not significantly different in etanercept treatment (RC 0.05, p=0.427). No significant differences were found in DeltaHAQ. CONCLUSIONS: Treatment discontinuation is lower in patients treated with MTX in both adalimumab and etanercept treatment. However, considering good clinical response, in contrast to etanercept, a synergetic effect of MTX is observed only in adalimumab treatment. PMID- 28079513 TI - High-dose aspirin for Kawasaki disease: outdated myth or effective aid? AB - OBJECTIVES: To compare the efficacy and safety of intravenous immunoglobulin (IVIG) plus high-dose aspirin (HDA) vs. IVIG plus low-dose aspirin (LDA) for the treatment of Kawasaki disease, with an emphasis on coronary artery outcomes. METHODS: This study was a retrospective, medical record review of paediatric patients with Kawasaki disease comparing 6 centres that routinely used HAD for initial treatment and 2 that used LDA in 2004-2013. Treatment response and adverse events were compared. The primary outcome measure was the occurrence of coronary aneurysm at the subacute or convalescent stage. RESULTS: The cohort included 358 patients, of whom 315 were initially treated with adjunctive HDA and 43 with LDA. There were no demographic differences between the groups. Coronary aneurysms occurred in 10% (20/196) of the HDA group and 4% (1/24) of the LDA group (p=0.34). Equivalence tests indicate it is unlikely that the risk of coronary aneurysm in LDA exceeds HDA by more than 3.5%. There were no significant between-group differences in the need for glucocorticoid pulse therapy or disease recurrence. Coronary ectasia rate and hospitalisation time were significantly greater in the HDA group. Adverse events were similar in the two groups. CONCLUSIONS: We found no significant clinical benefit in using IVIG+HDA in Kawasaki disease compared to IVIG+LDA. The use of adjunctive HDA in this setting should be reconsidered. PMID- 28079515 TI - Efficacy and safety of subcutaneous versus intravenous bortezomib in multiple myeloma: a meta-analysis?. AB - PURPOSE: We performed this meta-analysis to compare the efficacy and safety between two different administration routes of bortezomib, subcutaneous and intravenous. METHODS: Six retrospective studies and three randomized controlled trials (RCTs) were included in our study. Data from retrospective studies or RCTs were pooled and displayed in their corresponding subgroup, retrospective studies subgroup or RCTs subgroup. We comprehensively compared the overall response rate (ORR) and the incidence of adverse events between subcutaneous and intravenous bortezomib. RESULTS: We did not find statistical difference in ORR between the two administration routes. The pooled RRs for ORR were 0.99 (95% CI = 0.79 - 1.25, p = 0.95; retrospective studies subgroup) and 1.02 (95% CI = 0.93 - 1.11, p = 0.69; RCTs subgroup). Compared with intravenous bortezomib, the subcutaneous bortezomib reduced the incidence of peripheral neuropathy, both any grade and grade >= 3. The pooled RRs for any grade of peripheral neuropathy were 0.33 (95% CI = 0.15 - 0.71, p = 0.004; retrospective studies subgroup) and 0.55 (95% CI = 0.31 - 0.97, p = 0.04; RCTs subgroup), and for peripheral neuropathy grade >= 3 were 0.40 (95% CI = 0.16 - 0.95, p = 0.04; retrospective trials subgroup) and 0.39 (95% CI = 0.19 - 0.80, p = 0.01; RCTs subgroup). Only retrospective trials subgroup found that the incidence of thrombocytopenia and renal and urinary disorders were lower in subcutaneous bortezomib than in intravenous, with the pooled RRs 0.46 (95% CI = 0.29 - 0.72, p = 0.0007; retrospective trials subgroup) and 0.23 (95% CI = 0.09 - 0.56, p = 0.001; retrospective trials subgroup), respectively. The RCTs subgroup did not find statistical differences in these two adverse events. CONCLUSIONS: Subcutaneous bortezomib did not significantly reduce therapeutic efficacy but resulted in a lower incidence of peripheral neuropathy than intravenous bortezomib. Compared with intravenous bortezomib, subcutaneous bortezomib might reduce the incidence of thrombocytopenia and renal and urinary disorders, but this needs more clinical trials to confirm.?. PMID- 28079516 TI - Adequate exposure to tacrolimus with sublingual administration in pediatric liver transplant patients. PMID- 28079518 TI - Angiotensin receptor blockers and the risk of cancer: data mining of a spontaneous reporting database and a claims database?. AB - OBJECTIVE: The aim of this study was to examine the associations between angiotensin receptor blockers (ARBs) and the risk of 10 major cancers by employing different pharmacoepidemiological assessments. MATERIALS AND METHODS: Data from the first quarter of 2004 through 2012 were downloaded from the US Food and Drug Administration Adverse Event Reporting System (FAERS). The reporting odds ratio (ROR) and information component (IC) were used to detect the signals. Furthermore, symmetry analysis was applied to the claims database to identify the risk of cancer after using ARBs from January 2005 to July 2013. RESULTS: Significant inverse associations were found for all cancer types assessed as a whole (ROR: 0.78, 95% confidence interval (CI): 0.75 - 0.80; IC: -0.36, 95% CI: 0.40 to -0.31) in the analyses of FAERS database. Likewise, significant inverse association was found for all cancer types assessed as a whole (adjusted sequence ratio: 0.89, 95% CI: 0.82 - 0.96) in claims database. In addition, a significantly decreased risk for breast cancer and increased risks for pancreatic and prostate cancer were found in patients treated with ARBs in the analyses of individual cancers. CONCLUSIONS: Significant inverse association was found between ARB use and all cancer types assessed as a whole. However, in the analyses of individual cancers, the risks of ARB-induced cancer may differ according to cancer site. It may be reasonable to assume that the risks of ARB induced cancer may differ according to cancer site.?. PMID- 28079517 TI - Pharmacokinetic and bioequivalence study comparing a candesartan cilexetil/rosuvastatin calcium fixed-dose combination with the concomitant administration of candesartan cilexetil and rosuvastatin calcium in healthy Korean subjects?. AB - CONTEXT: A fixed-dose combination (FDC) of candesartan and rosuvastatin was recently developed for the treatment of cardiovascular disease and expected to enhance patient compliance. OBJECTIVE: This study was performed to compare the single-dose pharmacokinetic properties and tolerability of DP-R208 (candesartan and rosuvastatin FDC) to those of each component administered alone in healthy Korean male volunteers. MATERIALS AND METHODS: A total of 40 healthy Korean volunteers were enrolled in this randomized, open-label, single-dose, two treatment, two-way crossover study. During each treatment period, subjects received the test formulation (FDC tablet containing candesartan and rosuvastatin) or reference formulation (co-administration of candesartan and rosuvastatin). Plasma samples were collected pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, and 48 hours post-dose. Safety and tolerability were assessed by the evaluation of adverse events (AEs), physical examinations, laboratory assessments, 12-lead electrocardiograms (ECGs), and vital sign measurements. RESULTS: The 90% confidence intervals (CIs) of the geometric least-square mean ratios of Cmax, AUClast, and AUCinf were 0.86 - 1.00, 0.92 - 1.04, and 0.92 - 1.03 for candesartan, and 0.88 - 1.06, 0.91 - 1.08, and 0.91 - 1.03 for rosuvastatin, respectively. All of the AEs were mild, and there was no significant difference in the incidence of AEs between the formulations. Furthermore, the pharmacokinetic properties of the test and reference formulations met the regulatory criteria for bioequivalence. Discussion and conclusion: Both formulations were safe and well tolerated, and no significant difference was observed in the safety assessments of the treatments.?. PMID- 28079519 TI - Trends in antimicrobial susceptibility for azithromycin and ceftriaxone in Neisseria gonorrhoeae isolates in Amsterdam, the Netherlands, between 2012 and 2015. AB - Resistance of Neisseria gonorrhoeae to azithromycin and ceftriaxone has been increasing in the past years. This is of concern since the combination of these antimicrobials is recommended as the first-line treatment option in most guidelines. To analyse trends in antimicrobial resistance, we retrospectively selected all consultations with a positive N. gonorrhoeae culture at the sexually transmitted infection clinic, Amsterdam, the Netherlands, from January 2012 through September 2015. Minimum inhibitory concentrations (MICs) for azithromycin and ceftriaxone were analysed per year, and determinants associated with decreased susceptibility to azithromycin (MIC > 0.25 mg/L) or ceftriaxone (MIC > 0.032 mg/L) were assessed. Between 2012 and 2015 azithromycin resistance (MIC > 0.5 mg/L) was around 1.2%, the percentage of isolates with intermediate MICs (> 0.25 and <= 0.5 mg/L) increased from 3.7% in 2012, to 8.6% in 2015. Determinants associated with decreased azithromycin susceptibility were, for men who have sex with men (MSM), infections diagnosed in the year 2014, two infected sites, and HIV status (HIV; associated with less decreased susceptibility); for heterosexuals this was having >= 10 sex partners (in previous six months). Although no ceftriaxone resistance (MIC > 0.125 mg/L) was observed during the study period, the proportion of isolates with decreased ceftriaxone susceptibility increased from 3.6% in 2012, to 8.4% in 2015. Determinants associated with decreased ceftriaxone susceptibility were, for MSM, infections diagnosed in 2014, and pharyngeal infections; and for heterosexuals, infections diagnosed in 2014 or 2015, being of female sex, and having >= 10 sex partners. Continued decrease of azithromycin and ceftriaxone susceptibility will threaten future treatment of gonorrhoea. Therefore, new treatment strategies are warranted. PMID- 28079520 TI - Genetic characterisation of novel, highly pathogenic avian influenza (HPAI) H5N6 viruses isolated in birds, South Korea, November 2016. AB - A novel genotype of H5N6 influenza viruses was isolated from migratory birds in South Korea during November 2016. Domestic outbreaks of this virus were associated with die-offs of wild birds near reported poultry cases in Chungbuk province, central South Korea. Genetic analysis and animal studies demonstrated that the Korean H5N6 viruses are highly pathogenic avian influenza (HPAI) viruses and that these viruses are novel reassortants of at least three different subtypes (H5N6, H4N2 and H1N1). PMID- 28079521 TI - Isoform-specific subcellular localization and function of protein kinase A identified by mosaic imaging of mouse brain. AB - Protein kinase A (PKA) plays critical roles in neuronal function that are mediated by different regulatory (R) subunits. Deficiency in either the RIbeta or the RIIbeta subunit results in distinct neuronal phenotypes. Although RIbeta contributes to synaptic plasticity, it is the least studied isoform. Using isoform-specific antibodies, we generated high-resolution large-scale immunohistochemical mosaic images of mouse brain that provided global views of several brain regions, including the hippocampus and cerebellum. The isoforms concentrate in discrete brain regions, and we were able to zoom-in to show distinct patterns of subcellular localization. RIbeta is enriched in dendrites and co-localizes with MAP2, whereas RIIbeta is concentrated in axons. Using correlated light and electron microscopy, we confirmed the mitochondrial and nuclear localization of RIbeta in cultured neurons. To show the functional significance of nuclear localization, we demonstrated that downregulation of RIbeta, but not of RIIbeta, decreased CREB phosphorylation. Our study reveals how PKA isoform specificity is defined by precise localization. PMID- 28079522 TI - Protection from within. AB - The development of the tsetse fly immune system relies on a cue from an endosymbiotic bacterium called Wigglesworthia. PMID- 28079524 TI - Spatial heterogeneity in the time and frequency properties of skin perfusion. AB - Pathological alterations of the microcirculatory system can be identified by measuring the temporal and spectral properties of laser Doppler flowmetry (LDF) signals acquired on the skin, and their changes following physiological stimulation. A wide range of stimulation protocols and measurement locations is observed in literature. Researchers often use non-invasive stimulation techniques, such as post-occlusive hyperaemia, cold tests, and local heating. As concerns the stimulation/recording sites, the forearm, fingers, and toes are typically selected to conduct microcirculation studies. However, recent clinical investigations showed that different anatomical sites present dissimilar blood flow patterns. Therefore, studies involving the comparison of LDF data, obtained from various anatomical locations, and thus subjected to the intrinsic heterogeneity of the microcirculation, may be methodologically inaccurate. At the moment, no consensus has been reached upon the optimal measurement location, the stimulation pattern, and the physiological parameters of interest. The aim of this study is to quantitatively characterize the heterogeneity of the peripheral perfusion at different anatomical locations: the index finger, the forearm, and the hallux. The skin microvascular system exhibits a complex vasodilatory response in the temporal domain, upon local heating. This physiological reactive hyperaemia comprises two effects: a fast transient response, correlated to neural activation, named axon reflex, followed by a slower hyperaemic plateau, mediated by the release of nitric oxide. In this work, we compare the vasodilatory reaction to heating at the different sites, based on a parametric representation of the perfusion signal. Moreover, skin blood flow is characterized by several components fluctuating at different time scales. Time-frequency decomposition of LDF signals allows to quantitatively evaluate the relative contribution of known physiological mechanisms to the regulation of the peripheral circulation. For this reason, we analyze the wavelet transform coefficients of LDF signals at baseline, to assess potential spatial heterogeneities of the perfusion power spectra among the aforementioned anatomical locations. PMID- 28079525 TI - A model-based 3D patient-specific pre-treatment QA method for VMAT using the EPID. AB - This study reports the development and validation of a model-based, 3D patient dose reconstruction method for pre-treatment quality assurance using EPID images. The method is also investigated for sensitivity to potential MLC delivery errors. Each cine-mode EPID image acquired during plan delivery was processed using a previously developed back-projection dose reconstruction model providing a 3D dose estimate on the CT simulation data. Validation was carried out using 24 SBRT VMAT patient plans by comparing: (1) ion chamber point dose measurements in a solid water phantom, (2) the treatment planning system (TPS) predicted 3D dose to the EPID reconstructed 3D dose in a solid water phantom, and (3) the TPS predicted 3D dose to the EPID and our forward predicted reconstructed 3D dose in the patient (CT data). AAA and AcurosXB were used for TPS predictions. Dose distributions were compared using 3%/3 mm (95% tolerance) and 2%/2 mm (90% tolerance) gamma-tests in the planning target volume (PTV) and 20% dose volumes. The average percentage point dose differences between the ion chamber and the EPID, AcurosXB, and AAA were 0.73 +/- 1.25%, 0.38 +/- 0.96% and 1.06 +/- 1.34% respectively. For the patient (CT) dose comparisons, seven (3%/3 mm) and nine (2%/2 mm) plans failed the EPID versus AAA. All plans passed the EPID versus Acuros XB and the EPID versus forward model gamma-comparisons. Four types of MLC sensitive errors (opening, shifting, stuck, and retracting), of varying magnitude (0.2, 0.5, 1.0, 2.0 mm), were introduced into six different SBRT-VMAT plans. gamma-comparisons of the erroneous EPID dose and original predicted dose were carried out using the same criteria as above. For all plans, the sensitivity testing using a 3%/3 mm gamma-test in the PTV successfully determined MLC errors on the order of 1.0 mm, except for the single leaf retraction-type error. A 2%/2 mm criteria produced similar results with two more additional detected errors. PMID- 28079523 TI - Symbiont-induced odorant binding proteins mediate insect host hematopoiesis. AB - Symbiotic bacteria assist in maintaining homeostasis of the animal immune system. However, the molecular mechanisms that underlie symbiont-mediated host immunity are largely unknown. Tsetse flies (Glossina spp.) house maternally transmitted symbionts that regulate the development and function of their host's immune system. Herein we demonstrate that the obligate mutualist, Wigglesworthia, up regulates expression of odorant binding protein six in the gut of intrauterine tsetse larvae. This process is necessary and sufficient to induce systemic expression of the hematopoietic RUNX transcription factor lozenge and the subsequent production of crystal cells, which actuate the melanotic immune response in adult tsetse. Larval Drosophila's indigenous microbiota, which is acquired from the environment, regulates an orthologous hematopoietic pathway in their host. These findings provide insight into the molecular mechanisms that underlie enteric symbiont-stimulated systemic immune system development, and indicate that these processes are evolutionarily conserved despite the divergent nature of host-symbiont interactions in these model systems. PMID- 28079526 TI - A measurement-based generalized source model for Monte Carlo dose simulations of CT scans. AB - The goal of this study is to develop a generalized source model for accurate Monte Carlo dose simulations of CT scans based solely on the measurement data without a priori knowledge of scanner specifications. The proposed generalized source model consists of an extended circular source located at x-ray target level with its energy spectrum, source distribution and fluence distribution derived from a set of measurement data conveniently available in the clinic. Specifically, the central axis percent depth dose (PDD) curves measured in water and the cone output factors measured in air were used to derive the energy spectrum and the source distribution respectively with a Levenberg-Marquardt algorithm. The in-air film measurement of fan-beam dose profiles at fixed gantry was back-projected to generate the fluence distribution of the source model. A benchmarked Monte Carlo user code was used to simulate the dose distributions in water with the developed source model as beam input. The feasibility and accuracy of the proposed source model was tested on a GE LightSpeed and a Philips Brilliance Big Bore multi-detector CT (MDCT) scanners available in our clinic. In general, the Monte Carlo simulations of the PDDs in water and dose profiles along lateral and longitudinal directions agreed with the measurements within 4%/1 mm for both CT scanners. The absolute dose comparison using two CTDI phantoms (16 cm and 32 cm in diameters) indicated a better than 5% agreement between the Monte Carlo-simulated and the ion chamber-measured doses at a variety of locations for the two scanners. Overall, this study demonstrated that a generalized source model can be constructed based only on a set of measurement data and used for accurate Monte Carlo dose simulations of patients' CT scans, which would facilitate patient-specific CT organ dose estimation and cancer risk management in the diagnostic and therapeutic radiology. PMID- 28079527 TI - Binary moving-blocker-based scatter correction in cone-beam computed tomography with width-truncated projections: proof of concept. AB - This paper proposes a binary moving-blocker (BMB)-based technique for scatter correction in cone-beam computed tomography (CBCT). In concept, a beam blocker consisting of lead strips, mounted in front of the x-ray tube, moves rapidly in and out of the beam during a single gantry rotation. The projections are acquired in alternating phases of blocked and unblocked cone beams, where the blocked phase results in a stripe pattern in the width direction. To derive the scatter map from the blocked projections, 1D B-Spline interpolation/extrapolation is applied by using the detected information in the shaded regions. The scatter map of the unblocked projections is corrected by averaging two scatter maps that correspond to their adjacent blocked projections. The scatter-corrected projections are obtained by subtracting the corresponding scatter maps from the projection data and are utilized to generate the CBCT image by a compressed sensing (CS)-based iterative reconstruction algorithm. Catphan504 and pelvis phantoms were used to evaluate the method's performance. The proposed BMB-based technique provided an effective method to enhance the image quality by suppressing scatter-induced artifacts, such as ring artifacts around the bowtie area. Compared to CBCT without a blocker, the spatial nonuniformity was reduced from 9.1% to 3.1%. The root-mean-square error of the CT numbers in the regions of interest (ROIs) was reduced from 30.2 HU to 3.8 HU. In addition to high resolution, comparable to that of the benchmark image, the CS-based reconstruction also led to a better contrast-to-noise ratio in seven ROIs. The proposed technique enables complete scatter-corrected CBCT imaging with width truncated projections and allows reducing the acquisition time to approximately half. This work may have significant implications for image-guided or adaptive radiation therapy, where CBCT is often used. PMID- 28079529 TI - Leveraging the Skills of Nurses and the Power of Language Nutrition to Ensure a Better Future for Children. AB - BACKGROUND: Early language exposure is critical for language acquisition and significantly influences a child's literacy skills. However, preterm infants may experience language deprivation in the neonatal intensive care unit. Nurses are vital to helping parents understand their critical role in early language development. PURPOSE: To discuss the impact of language-rich interactions and interventions that promote early language exposure, or Language Nutrition, by parents and caregivers on the long-term developmental, language, and educational outcomes of high-risk infants. METHODS/SEARCH STRATEGY: A literature search was conducted using PubMed and Web of Science to identify articles that examined the influence of language interactions with high-risk infants on developmental outcomes. Recent campaigns touting the importance of early language exposure were identified through the Bridging the Word Gap Research Network. FINDINGS/RESULTS: Increasing preterm infants' exposure to Language Nutrition improves their language development, promotes parent-infant attachment, and decreases parent stress. In addition, it may result in greater neuroplasticity and volume of the auditory cortex. Several campaigns have been developed to increase children's access to Language Nutrition and can be implemented into everyday pediatric and neonatal care. IMPLICATIONS FOR PRACTICE: Pediatric, neonatal nurses and advanced practice nurses are uniquely positioned to play a transformational role in high risk infants' developmental trajectory by educating parents about the importance of Language Nutrition and supporting parents as they engage with their infant. IMPLICATIONS FOR RESEARCH: Studies investigating the population-level impact of interventions aimed at increasing infants' access to Language Nutrition as well as studies identifying effective ways to communicate messages about Language Nutrition are warranted. PMID- 28079528 TI - Assessing the evolution of redundancy/synergy of spontaneous variability regulation with age. AB - OBJECTIVE: We exploited a model-based Wiener-Granger causality method in the information domain for the evaluation of the transfer entropy (TE) and interaction TE (ITE), the latter taken as a measure of the net balance between redundancy and synergy, to describe the interactions between the spontaneous variability of heart period (HP) and systolic arterial pressure (SAP) and the effect of respiration (R) on both variables. APPROACH: Cardiac control was typified via the genuine TE from SAP to HP, that from R to HP, and the ITE from SAP and R to HP, while vascular control was characterized via the genuine TE from HP to SAP, that from R to SAP, and the ITE from HP and R to SAP. The approach was applied to study age-related modifications of cardiac and vascular controls in a cohort of 100 healthy humans (age from 21 to 70 years, 54 males) recorded at supine rest (REST) and during active standing (STAND). A surrogate approach was exploited to test the significance of the computed quantities. MAIN RESULTS: Trends of the genuine information transfer with age, already present in literature, were here confirmed. We originally found that: (i) at REST redundancy was predominant over synergy in both vascular and cardiac controls; (ii) the predominance of redundancy of the cardiac control was not affected by postural challenge, while STAND reduced redundancy of vascular control; (iii) the net redundancy of the cardiac control at REST gradually decreased with age, while that of vascular control remained stable; (iv) during STAND net redundancy of both cardiac and vascular controls was stable with age. SIGNIFICANCE: The study confirms the relevance of computing genuine information transfer in cardiovascular control analysis and stresses the importance of evaluating the ITE to quantify the degree of redundancy of physiological mechanisms operating to maintain cardiovascular homeostasis. PMID- 28079530 TI - Can Intoxication Status Be Used as a Prediction Tool for Manner of Death?: A Comparison of the Intoxication Status in Violent Suicides and Homicides. AB - Determining the manner of death in medicolegal death investigations can be difficult. The investigator relies on many facets of death investigation, including the circumstances of death and autopsy examination. A study was designed to analyze whether the intoxication status of the decedent could be used as another tool in death investigations. The intoxication status of violent (nonoverdose or poisoning) suicides and homicides was retrospectively reviewed and compared. A total of 625 deaths were identified, including 366 suicides and 259 homicides. Age, sex, cause of death, and intoxication status, including the specific drugs present, were analyzed. Gunshot wounds were the most common cause of death in both groups, with hanging being the second most common cause in suicides and sharp force injuries in homicides. Analysis found that although the overall intoxication status for suicides versus homicides did not differ significantly, certain drugs were more prevalent in one group over the other. Specifically, illicit drugs, that is, heroin, cocaine, and methamphetamine, were more likely to be present in homicides, whereas antidepressants or antipsychotics, benzodiazepines, and zolpidem were more common in suicides. PMID- 28079531 TI - The Effect of Albumin and Platelet-Poor Plasma Supplemented Botulinum A Toxin on Bioavaliability: An Experimental Rabbit Model. AB - Today, botulinum toxin is commonly used for cosmetic purposes throughout the world. Despite various agents reducing the efficiency of toxin are well defined, the studies related to increasing the bioavailability are limited. The purpose of our study is to assess the effect of the preparation of toxin by diluting with platelet-poor plasma (PPP) and/or albumin instead of standard dilution (saline) on bioavailability in cosmetic-purpose botulinum toxin applications.In the study, 24 New Zealand rabbits were used. Right anterior auricular muscle was preferred for toxin injections. Subjects were divided in 4 groups and in every group; botulinum A toxin (BTxA) that was prepared by different dilution methods was injected. 2.5 U saline-diluted BTxA was injected to the subjects in group 1, 2.5 U ready-to-use rabbit albumin-diluted BTxA was injected to group 2 and 2.5 U autologous PPP-diluted BTxA was injected to group 3 and pure saline was injected to group 4.Before the injection (0th week) and in the second, sixth, and 12th weeks after the injection, visual and electroneuromyographic evaluations of the ears of the subjects were performed.In the second week, median amplitude levels in group 2 were significantly found lower than other groups.In the sixth week, median amplitude levels in group 1 were significantly found lower than other groups.In 12th week, no significant difference was found among all the groups in terms of median amplitude levels.Visual findings were also correlated with electroneuromyographic findings.It was observed that the dilution of BTxA with albumin had caused a stronger paralysis when compared to dilution with saline or PPP at the beginning (second week); however, in the following weeks (sixth week), it was seen that dilution with saline had maintained paralysis better when compared with other dilution methods.In cosmetic BTxA applications, dilution of the toxin with albumin or PPP instead of standard dilution has no positive effect on bioavailability and such modifications regarding this kind of dilution are found unsuitable. Further studies are needed to directly relate the results with clinical applications. PMID- 28079532 TI - Course Review: Cadaveric Hand Trauma Course. AB - The St Thomas' Cadaveric Hand Trauma course is described and evaluated. PMID- 28079533 TI - National and Regional Differences in 32,248 Postmastectomy Autologous Breast Reconstruction Using the Updated National Inpatient Survey. AB - BACKGROUND: The incidence of breast cancer (BC) cases has increased significantly. The number of breast reconstruction (BR) procedures performed has mirrored this trend. Although implant-only procedures remain the most commonly used type of immediate BR, autologous techniques involving donor sites account for approximately 20%. The aim of this study was to assess national and regional trends in different types of autologous BR. METHODS: Using the Nationwide Inpatient Sample database (2008 to 2012), data on BC and mastectomy rates, type of autologous BR, and sociodemographics were obtained and analyzed. Furthermore, national and regional trends over time for autologous BR were plotted and analyzed. RESULTS: A total of 427,272 patients diagnosed with BC or at increased risk of BC were included in the study. A total of 343,163 (80.3%) patients underwent mastectomy and, within this group, 148,700 (43.3%) patients underwent immediate BR. Of these, 32,249 (21.7%) patients underwent an autologous BR (not solely implant based) and 118,258 (78.3%) implant-based BR. Most autologous BRs were performed in the Southern region (37.4%). When stratified into flap types, most pedicled transverse rectus abdominis muscle (TRAM), free TRAM, and other flaps were performed in the Northeast region, whereas most deep inferior epigastric perforator (DIEP) and latissimus dorsi (LD) flaps were performed in the Southern region. Subgroup analysis demonstrated a significant increasing trend for both LD and DIEP flaps, both nationally (P < 0.001) and regionally (P < 0.001). Pedicled TRAM and free TRAM reconstructions decreased significantly both on national and regional level. CONCLUSIONS: Autologous BR demonstrated a significant positive trend over time in the Southern region (P < 0.001). The DIEP and LD flaps increased significantly over time, both nationally and regionally. PMID- 28079534 TI - Practical efficacy of olmesartan versus azilsartan in patients with hypertension: a multicenter randomized-controlled trial (MUSCAT-4 study). AB - BACKGROUND: Olmesartan and azilsartan, angiotensin II receptor blockers (ARBs), are expected to decrease blood pressure more than the other ARBs. We conducted randomized-controlled trials to compare the practical efficacy of olmesartan with azilsartan. METHODS: Eighty-four patients treated with the conventional ARBs for more than 3 months were assigned randomly to receive either 20 mg of olmesartan (olmesartan medoxomil, OL group) or 20 mg of azilsartan (azilsartan, not azilsartan medoxomil, AZ group) once daily for 16 weeks. The practical efficacy on blood pressure was compared between the OL and AZ groups. RESULTS: Office blood pressure of both groups decreased significantly (OL group: 152/86-141/79 mmHg, P<0.05, AZ group: 149/83-135/75 mmHg; P<0.05). Diastolic home blood pressure in the AZ group decreased significantly (79+/-9-74+/-7 mmHg; P<0.05), but not in the OL group (79+/-11-75+/-10 mmHg; P=0.068). However, there were no significant differences between the groups. The dosage of olmesartan and azilsartan increased significantly and slightly for 16 weeks (OL group: 20.3-23.1 mg; P<0.05, AZ group: 20.5-23.2 mg; P<0.05), without a significant difference between groups. Furthermore, there were no significant differences in renal function, lipid profiles, brain natriuretic peptide, soluble fms-like tyrosine kinase-1, and urinary L-type fatty acid-binding protein between the two groups. CONCLUSION: Both olmesartan and azilsartan equally reduced blood pressures. Both olmesartan and azilsartan showed a renoprotective effect and were well tolerated without any major adverse events. PMID- 28079535 TI - Heterozygous Deletion of Chorein Exons 70-73 and GNA14 Exons 3-7 in a Brazilian Patient Presenting With Probable Tau-Negative Early-Onset Alzheimer Disease. PMID- 28079536 TI - Non-vitamin K antagonist oral anticoagulants in patients with severe inherited thrombophilia: a series of 33 patients. AB - : The aim of the study was to investigate whether treatment with non-vitamin K antagonist oral anticoagulants (NOACs) is effective and well tolerated in real life patients following venous thromboembolism (VTE) associated with severe inherited thrombophilia. We evaluated 33 consecutive patients with severe inherited thrombophilia, defined as the presence of deficiencies in protein C, protein S, or anti-thrombin, homozygous factor V Leiden and prothrombin G20210A mutations, or combined defects. The patients were recruited from March 2010 to December 2015 and followed till July 2016. Rivaroxaban was used in 23 patients (70%), whereas dabigatran and apixaban were used in 4 patients each. During a median 21 (range 8-34) months' follow-up, three recurrent VTE episodes (9%) were observed. Deep vein thrombosis recurred after 6 months on rivaroxaban in a protein S-deficient 32-year-old woman who had heavy menstrual bleeding resulting in interruptions of therapy. A long journey preceded deep vein thrombosis recurrence after 12 months of rivaroxaban use in a 59-year-old obese man homozygous for prothrombin 20210A mutation. The third recurrent VTE following anticoagulation withdrawal prior to surgery and during hospitalization was observed in a 56-year-old woman with protein S deficiency and heterozygous factor V Leiden. The three patients continued use of NOACs, apixaban, dabigatran, and rivaroxaban, respectively. This largest real-life series of patients with severe thrombophilia receiving NOACs indicates that such patients could be safely and effectively treated with NOACs. Lower efficacy was observed in protein S deficiency. Recurrent VTE was mostly related with nonadherence, which highlights an important role of regular intake of NOACs in high-risk patients. PMID- 28079537 TI - Successful total hip replacement with sequential administration of bypassing agents in an adolescent boy with hemophilia A and high inhibitor titers. AB - : There are only a few reports of total hip replacement in patients with hemophilia A and inhibitors. We performed total hip replacement in an 18-year-old adolescent boy who had high inhibitor titers since infancy. Recombinant factor VIIa (NovoSeven) was used as a bypass agent during the surgery. There was no excessive introperative bleeding; however, postsurgical bleeding occurred and was controlled by sequential administration of recombinant factor VIIa and activated prothrombin complex concentrate (FEIBA). This is the first report of this treatment modality in such a major surgery. Sequential bypassing agent therapy can be effective for treating refractory bleeding in hemophilia patients who have high inhibitor titers but require major surgery. PMID- 28079538 TI - Antimicrobial Therapy for Pyogenic Liver Abscess Secondary to Streptococcus intermedius Bacteremia. PMID- 28079539 TI - Preoperative Ketoconazole Therapy for Primary Bilateral Adrenocorticotropic Hormone-Independent Macronodular Adrenal Hyperplasia Syndrome. PMID- 28079540 TI - Intravenous Immunoglobulin for Mixed Connective Tissue Disease Presenting With Bilateral Trigeminal Neuropathy. PMID- 28079541 TI - When and How Did Arantius Learn to Perform the Famous Tagliacotian Technique of Nose Reconstruction? PMID- 28079543 TI - A novel anti-HIV immunotherapy to cure HIV. PMID- 28079542 TI - Development and Validation of a Multi-institutional Preoperative Nomogram for Predicting Grade of Dysplasia in Intraductal Papillary Mucinous Neoplasms (IPMNs) of the Pancreas: A Report from The Pancreatic Surgery Consortium. AB - OBJECTIVE: Previous nomogram models for patients undergoing resection of intraductal papillary mucinous neoplasms (IPMNs) have been relatively small single-institutional series. Our objective was to improve upon these studies by developing and independently validating a new model using a large multiinstitutional dataset. SUMMARY BACKGROUND DATA: IPMNs represent the most common radiographically identifiable precursor lesions of pancreatic cancer. They are a heterogenous group of neoplasms in which more accurate markers of high grade dysplasia or early invasive carcinoma could help avoid unnecessary surgery in 1 case and support potentially curative intervention (resection) in another. METHODS: Prospectively maintained databases from 3 institutions were queried for patients who had undergone resection of IPMNs between 2005 and 2015. Patients were separated into main duct [main and mixed-type (MD)] and branch duct (BD) types based on preoperative imaging. Logistic regression modeling was used on a training subset to develop 2 independent nomograms (MD and BD) to predict low risk (low- or intermediate-grade dysplasia) or high-risk (high-grade dysplasia or invasive carcinoma) disease. Model performance was then evaluated using an independent validation set. RESULTS: We identified 1028 patients who underwent resection for IPMNs [MD: n = 454 (44%), BD: n = 574 (56%)] during the 10-year study period. High-risk disease was present in 487 patients (47%). Patients with high-risk disease comprised 71% and 29% of MD and BD groups, respectively (P <0.0001). MD and BD nomograms were developed on the training set [70% of total (n = 720); MD: n = 318, BD: n = 402] and validated on the test set [30% (n = 308); MD: n = 136, BD: n = 172]. The presence of jaundice was almost exclusively associated with high-risk disease (57 of 58 patients, 98%). Cyst size >3.0 cm, solid component/mural nodule, pain symptoms, and weight loss were significantly associated with high-risk disease. C-indices were 0.82 and 0.81 on training and independent validation sets, respectively; Brier scores were 0.173 and 0.175, respectively. CONCLUSIONS: For patients with suspected IPMNs, we present an independently validated model for the prediction of high-risk disease. PMID- 28079544 TI - Discontinuation of treatment and adverse events in an Italian cohort of patients on dolutegravir. PMID- 28079545 TI - Efficacy and tolerability of dolutegravir and two nucleos(t)ide reverse transcriptase inhibitors in HIV-1-positive, virologically suppressed patients. PMID- 28079546 TI - We should monitor the population-level effects of preexposure prophylaxis. PMID- 28079547 TI - The Evolution of Burn Injury Management: Using Dehydrated Human Amnion/Chorion Membrane Allografts in Clinical Practice. PMID- 28079548 TI - History and Advancement of Burn Treatments. AB - Advances in burn care have accelerated within the last 50 years. The principal modalities of and approaches to burn treatment include dressings, antimicrobials, fluid resuscitation, burn wound excision, skin grafting, and use of skin substitutes. This review presents a historical outline of these approaches, their current status, and prospects for the future of burn care. PMID- 28079549 TI - Contemporary Methods Allowing for Safe and Convenient Use of Amniotic Membrane as a Biologic Wound Dressing for Burns. AB - Partial-thickness burns involve damage to the upper layer of skin, which leaves nerve endings exposed, and therefore represent the most painful of several categories of thermal injuries. Historically, partial-thickness burns were treated conservatively by debriding the blisters, by daily tubbing and washing, and the application of new bandages with topical medications. Human amniotic membrane has been used for centuries as a biological wound dressing. In the past 20 years, there has been an increasing body of literature addressing the use of amniotic tissue in chronic wounds and burns. In this review, we present an overview of the use of amniotic membrane in the treatment of burns including processing methods and early clinical use. We believe that amniotic membranes have great potential in improving burn wound care in the future. Standardized processing methods and terminal sterilization ensure safety and allow the material to be available for use by health care providers around the world in clinical trials and for patient care. PMID- 28079550 TI - The Use of Dehydrated Human Amnion/Chorion Membranes in the Treatment of Burns and Complex Wounds: Current and Future Applications. AB - Historically, biologic materials found in nature have been used for a wide variety of medicinal purposes, although their widespread use may be limited due to challenges in obtaining and properly preparing the material for safe clinical use. Amniotic membrane has long been recognized to possess unique properties favorable for healing. Dehydrated human amnion/chorion membrane allografts are commercially available for use in multiple sizes and configurations applicable for a variety of clinical settings and presentations. The purpose of this article is to review the therapeutic properties of amniotic membrane. PMID- 28079551 TI - Current Techniques for Burn Reconstruction: Using Dehydrated Human Amnion/Chorion Membrane Allografts as an Adjunctive Treatment Along the Reconstructive Ladder. AB - The reconstructive ladder is a term coined by reconstructive plastic surgeons to describe levels of increasingly complex management of wounds. The first rungs of the ladder is allowing the wound to heal by secondary intention, advancing up the ladder to direct tissue closure, with skin grafting and tissue transfer (flaps) comprising the higher rungs. Skin grafting and tissue transfer (flaps) at the middle and higher rungs of the ladder are often necessary for the treatment of complex burn injuries. Our purpose is to describe how dehydrated human amnion/chorion membrane allografts may be used as an adjunctive treatment. PMID- 28079552 TI - Clinical Experience: Using Dehydrated Human Amnion/Chorion Membrane Allografts for Acute and Reconstructive Burn Care. AB - Amniotic membrane is immunologically privileged and is a reservoir of growth factors and cytokines known to modulate inflammation and enhance the healing process, while also possessing antimicrobial, antifibrosis, and antiscarring properties. These properties establish a strong argument for using amniotic membrane derived products as a treatment for burns. The purpose of this article is to describe the use of commercially available dehydrated human amnion/chorion membrane allografts in patients with partial-thickness and full-thickness burns. PMID- 28079553 TI - End of life decisions in heart failure: to turn off the intracardiac device or not? AB - PURPOSE OF REVIEW: Heart failure is a significant public health concern around the world. Implantable cardioverter defibrillators with or without cardiac resynchronization therapy (CRT-D) have proven survival benefit. As patients progress to end-stage disease, management shifts to palliative care, and cardiologists are often confronted with how to best manage these devices. RECENT FINDINGS: Studies suggest that up to one-third of patients with an implantable cardioverter defibrillator receive painful shocks in the last 24 h of life. Disabling pacing or resynchronization devices may further weaken the heart function and expedite death, particularly if the patient has no underlying ventricular rhythm. Is it ethical or legal to discontinue functions of the implantable device? The discussion and the decision to be made are whether to continue both pacing and tachyarrhythmia therapies, disable tachyarrhythmia therapies while maintaining pacing, or discontinue both. SUMMARY: The decision to disable all or parts of the device function is ultimately up to the patient. To avoid painful shocks near the end of life, it is recommended that tachyarrhythmia therapies be turned off when the patient is being treated palliatively. After informed discussion, withdrawing the resynchronization or pacing device option is also acceptable if requested by the patient regardless of the potential outcomes. PMID- 28079554 TI - Latest evidence on transcatheter aortic valve implantation vs. surgical aortic valve replacement for the treatment of aortic stenosis in high and intermediate risk patients. AB - PURPOSE OF REVIEW: The goal of this review is to summarize the current evidence supporting the use of transcatheter aortic valve implantation (TAVI) in high and intermediate-risk patients. The focus is on the five randomized controlled trials comparing TAVI with surgical aortic valve replacement (SAVR) published to date, as well as two recent meta-analyses. RECENT FINDINGS: TAVI has profoundly transformed the treatment of elderly patients presenting with symptomatic severe aortic stenosis. In experienced hands, the procedure has become well tolerated and the results more predictable. So far, two trials using two different devices [Placement of Aortic Transcatheter Valve (PARTNER) 1A and US CoreValve High Risk] have shown that TAVI is able to compete in terms of mortality with SAVR in high risk patients. These findings have been extended to the intermediate-risk population in two recently published randomized controlled trials [PARTNER 2 and Nordic Aortic Valve Intervention (NOTION)]. The two meta-analyses suggested improved survival in both high and intermediate-risk patients during the first 2 years following the intervention. The survival benefit was only found in patients treated via the transfemoral access, and appeared more pronounced in women. SUMMARY: Individual randomized trials enrolling high and intermediate-risk patients have established the noninferiority of TAVI in comparison with SAVR, whereas subsequent meta-analyses suggest superiority of transfemoral TAVI in terms of a sustained survival benefit 2 years after valve implantation irrespective of the surgical risk category. The benefit of TAVI appears more pronounced in women than in men. PMID- 28079555 TI - Epidural Labor Analgesia and Maternal Fever. AB - Women receiving an epidural for labor analgesia are at increased risk for intrapartum fever. This relationship has been supported by observational, before and after, and randomized controlled trials. The etiology is not well understood but is likely a result of noninfectious inflammation as studies have found women with fever have higher levels of inflammatory markers. Maternal pyrexia may change obstetric management and women are more likely to receive antibiotics or undergo cesarean delivery. Maternal pyrexia is associated with adverse neonatal outcomes. With these consequences, understanding and preventing maternal fever is imperative. PMID- 28079556 TI - Cardiac Arrest: Obstetric CPR/ACLS. AB - In contrast with other high-resource countries, maternal mortality has seen an increase in the United States. Caring for pregnant women in cardiac arrest may prove uniquely challenging given the rarity of the event coupled by the physiological changes of pregnancy. Optimization of resuscitative efforts warrants special attention as described in the 2015 American Heart Association's "Scientific Statement on Maternal Cardiac Arrest." Current recommendations address a variety of topics ranging from the basic components of chest compressions and airway management to some of the logistical complexities and operational challenges involved in maternal cardiac arrest. PMID- 28079557 TI - Dobutamine aggravates haemodynamic deterioration induced by pleural effusion: A randomised controlled porcine study. AB - BACKGROUND: Pleural effusion is a common finding in critically ill patients and may contribute to circulatory instability and the need for inotropic support. OBJECTIVE: We hypothesised that dobutamine would affect the physiological determinants preload, afterload, contractility and changes of inferior vena cava characteristics during experimental pleural effusion. DESIGN: A randomised, controlled laboratory study. SETTING: Animal laboratory, conducted from March 2013 to May 2013. ANIMALS: Twenty-four Landrace and Yorkshire female piglets (21.3 +/- 1.7 kg). INTERVENTION: Twenty piglets were included in the analyses. After inducing bilateral pleural effusion (30 ml kg), the piglets were block randomised to either incremental dobutamine infusion (n = 10) or control (n = 10). MAIN OUTCOME MEASURES: Ultrasonographic measures of left ventricular end diastolic area, left ventricular afterload, left ventricular fractional area change and inferior vena cava diameter and distensibility were used to assess the basic physiological effect of incremental dobutamine administration during experimental pleural effusion. RESULTS: In the dobutamine group, preload, measured as left ventricular end-diastolic area, decreased from 11.3 +/- 2.0 cm after creation of the pleural effusion to 8.1 +/- 1.5 cm at a dobutamine infusion rate of 20 MUg kg min (P < 0.001). In the same period, central venous pressure and the expiratory diameter of the inferior vena cava decreased from 9 +/- 3 to 7 +/- 4 mmHg (P < 0.001) and from 1.1 +/- 0.2 to 0.9 +/- 0.1 cm (P = 0.008), respectively. CONCLUSION: In a porcine model of pleural effusion, dobutamine affected basic haemodynamic determinants substantially by decreasing left ventricular preload. Changes in central venous pressure and inferior vena cava characteristics were minimal, discouraging their use as indices of preload. This study underlines the significance of evaluating basic haemodynamic determinants to avoid inappropriate, potentially harmful treatment. PMID- 28079558 TI - Once-daily tacrolimus in liver transplantation: a 'me-too drug', or a therapeutic advantage. AB - PURPOSE OF REVIEW: To provide latest information on differences between standard tacrolimus (TAC BID) and slow-released formulation of tacrolimus (Advagraf) in liver transplantation (LTx), and to discuss the latter's therapeutic value as a distinct entity. RECENT FINDINGS: Two articles on de-novo studies, several on conversion and one on survival analysis from the European Liver Transplant Registry published recently showed that low-dose Advagraf immediately after transplantation provided same protection to the kidney as standard dose delayed until day 5, and was associated with lower rejection rate; to maintain the same trough level after late conversion to Advagraf, an approximately 1.25-fold higher dose was needed on average; if studied by questionnaire, conversion improved medication adherence; and registry data provided evidence of long-term survival benefit of Advagraf over TAC BID (7 and 8% graft and patient survival rates over a 3-year period; P < 0.002 and P < 0.003, respectively). SUMMARY: Pharmacokinetic differences between TAC BID and Advagraf translate into less interpatient and intrapatient variability and improve adherence. If survival benefit of Advagraf administration de novo after LTx as demonstrated by the European Liver Transplant Registry analysis is confirmed in an independent cohort, Advagraf will leave the area of the 'me-too' drugs to become the immunosuppressant of choice. PMID- 28079560 TI - Prenatal exposures and the development of childhood wheezing illnesses. AB - PURPOSE OF REVIEW: To critically evaluate and summarize studies published between July 2015 and June 2016 linking prenatal exposures and the onset of childhood wheezing illnesses and to discuss future research directions in this field. RECENT FINDINGS: The aggregated evidence indicates a consistent detrimental effect of prenatal exposure to parental smoking, outdoor air pollution, and maternal stress on childhood wheezing illnesses. Less consistent evidence suggests an adverse impact of maternal obesity during pregnancy and prenatal exposure to antibiotics on these outcomes. There is insufficient evidence to support an association between in-utero exposure to acetaminophen or prenatal levels of specific nutrients (such as vitamin D, folic acid, or polyunsaturated fatty acids) and childhood wheezing illnesses. SUMMARY: Several common potentially modifiable prenatal exposures appear to be consistently associated with childhood wheezing illnesses (e.g. parental smoking, outdoor air pollution, and maternal stress). However, the effect of many other prenatal exposures on the onset of childhood wheezing illnesses remains unclear. The existing scientific evidence from the past year does not allow us to make any new recommendations on primary prevention measures. Intervention studies will best demonstrate whether changing the prenatal environment can prevent childhood wheezing illnesses and asthma. PMID- 28079561 TI - 'Single-checked' Patient Group Directions during initial nurse assessment within paediatric emergency departments of the UK and Ireland. AB - OBJECTIVE: Double checking medications at initial assessment within paediatric emergency departments (EDs) has the potential to delay patient flow, and doubt has been cast on the efficacy of double checking in all but high-risk medications. We aimed to benchmark current practice for the use of Patient Group Direction (PGD) medications at initial assessment in EDs within the Paediatric Emergency Research UK and Ireland (PERUKI) network, with a focus on the use of 'single-checker' PGDs. METHODS: Online survey was distributed to the research representative at each PERUKI site. The survey was open for 5 weeks (from March 2015 to April 2015) and was completed by any appropriate clinician within the site. RESULTS: The response rate was 84% (36/43 EDs). From these, 22 out of 36 (61%) EDs were using single-checker PGDs. The commonest single-checked medications in use were paracetamol and ibuprofen for pain. Among PERUKI sites, 21.9% of EDs reported drug errors related to standard (double-checked) PGDs, whereas 13.6% of those with single-checked PGDs reported drug errors (Fisher's exact test with significance level of 0.05, P=0.501). The commonest errors reported were duplicated dose, incorrect weight, incorrect volume drawn up, contraindication missed. CONCLUSION: Single-checker PGDs are currently in use in nearly two-thirds of PERUKI sites. No evidence of increased medication errors was reported with this practice; however, more detailed studies are required to support this finding and to inform best practice. PMID- 28079559 TI - Strategies to alter the natural history of childhood asthma. AB - PURPOSE OF REVIEW: Asthma exhibits significant heterogeneity in occurrence and severity over the lifespan. Our goal is to discuss recent evidence regarding determinants of the natural history of asthma during childhood, and review the rationale behind and status of major efforts to alter its course. RECENT FINDINGS: Variations in microbial exposures are associated with risk of allergic disease, and the use of bacterial lysates may be a promising preventive strategy. Exposure to air pollution appears to be particularly damaging in prenatal and early life, and interventions to reduce pollution are feasible and result in clinical benefit. E-cigarette use may have a role in harm reduction for conventional cigarette smokers with asthma, but has undefined short-term and long term effects that must be clarified. Vitamin D insufficiency over the first several years of life is associated with risk of asthma, and vitamin D supplementation reduces the risk of severe exacerbations. SUMMARY: The identification of risk factors for asthma occurrence, persistence and severity will continue to guide efforts to alter the natural history of the disease. We have reviewed several promising strategies that are currently under investigation. Vitamin D supplementation and air pollution reduction have been shown to be effective strategies and warrant increased investigation and implementation. PMID- 28079562 TI - Can an age-adjusted D-dimer level be adopted in managing venous thromboembolism in the emergency department? A retrospective cohort study. AB - INTRODUCTION: Patients suspected of having venous thromboembolism (VTE), with a low pretest probability, undergo D-dimer testing. A negative D-dimer, in a low risk patient rules out VTE with a high degree of certainty because of its high sensitivity. It is, however, a poorly specific test, and the absolute value increases with age. The aim of this study was to establish whether an age adjusted D-dimer could be safely used instead of a standard cut-off level in low risk patients over the age of 50 years. PATIENTS AND METHODS: This was a retrospective review of 1649 patients with suspected VTE whose D-dimer levels were analysed. In low-risk patients (defined as 'VTE unlikely' using the dichotomized Wells' scores), the outcomes in terms of confirmed VTE diagnosis, hospital admission and investigations using an age-adjusted D-dimer level (measured in D-dimer units) of 5* the age for patients over 50 years of age and 250 ng/ml for patients younger than 50 years of age, was compared with the cut off standard level (230 ng/ml in all patients). RESULTS: Of the total group of patients in the VTE unlikely group, the proportion of patients with a negative D dimer when using the standard cut-off was 64.9% (859/1324). A further 130 patients had a negative D-dimer when the age-adjusted cut-off was used, increasing the proportion of all patients in whom VTE could be excluded without imaging to 74.7% (989/1324).For those patients of 75 years or older, the proportion of patients in whom VTE could be excluded without imaging increased from only 91/242 (37.6%) when using the standard D-dimer cut-off to 154/242 (63.6%) when the age-adjusted cut-off was used.These changes occurred without any additional false-negative findings. CONCLUSION: For patients over the age of 50 years suspected of having VTE with a low pretest probability, increasing the D dimer cut-off level to 5* the age increases the proportion of patients in whom VTE can safely be excluded without radiological imaging. PMID- 28079563 TI - Cancer-related cognitive impairment. PMID- 28079565 TI - Anesthetics, the Ryanodine Receptors, and the Heart. PMID- 28079564 TI - An Anesthesiologist's Perspective on the History of Basic Airway Management: The "Artisanal Anesthetic" Era: 1846 to 1904. AB - This second installment of the history of basic airway management covers the early-artisanal-years of anesthesia from 1846 to 1904. Anesthesia was invented and practiced as a supporting specialty in the context of great surgical and medical advances. The current-day anesthesia provider tends to equate the history of airway management with the history of intubation, but for the first 58 yr after the introduction of ether anesthesia, airway management was provided by basic airway techniques with or without the use of a face mask. The jaw thrust and chin lift were described in the artisanal years and used primarily with inhalation anesthesia in the spontaneously breathing patient and less often with negative-pressure ventilation in the apneic victim. Positive-pressure ventilation and intubation stayed at the fringes of medical practice, and airway techniques and devices were developed by trial and error. At the beginning of the 20th century, airway management and anesthetic techniques lagged behind surgical requirements. PMID- 28079567 TI - Cardiac Calcium Release Channel (Ryanodine Receptor 2) Regulation by Halogenated Anesthetics. AB - BACKGROUND: Halogenated anesthetics activate cardiac ryanodine receptor 2 mediated sarcoplasmic reticulum Ca release, leading to sarcoplasmic reticulum Ca depletion, reduced cardiac function, and providing cell protection against ischemia-reperfusion injury. Anesthetic activation of ryanodine receptor 2 is poorly defined, leaving aspects of the protective mechanism uncertain. METHODS: Ryanodine receptor 2 from the sheep heart was incorporated into artificial lipid bilayers, and their gating properties were measured in response to five halogenated anesthetics. RESULTS: Each anesthetic rapidly and reversibly activated ryanodine receptor 2, but only from the cytoplasmic side. Relative activation levels were as follows: halothane (approximately 4-fold; n = 8), desflurane and enflurane (approximately 3-fold,n = 9), and isoflurane and sevoflurane (approximately 1.5-fold, n = 7, 10). Half-activating concentrations (Ka) were in the range 1.3 to 2.1 mM (1.4 to 2.6 minimum alveolar concentration [MAC]) with the exception of isoflurane (5.3 mM, 6.6 minimum alveolar concentration). Dantrolene (10 MUM with 100 nM calmodulin) inhibited ryanodine receptor 2 by 40% but did not alter the Ka for halothane activation. Halothane potentiated luminal and cytoplasmic Ca activation of ryanodine receptor 2 but had no effect on Mg inhibition. Halothane activated ryanodine receptor 2 in the absence and presence (2 mM) of adenosine triphosphate (ATP). Adenosine, a competitive antagonist to ATP activation of ryanodine receptor 2, did not antagonize halothane activation in the absence of ATP. CONCLUSIONS: At clinical concentrations (1 MAC), halothane desflurane and enflurane activated ryanodine receptor 2, whereas isoflurane and sevoflurane were ineffective. Dantrolene inhibition of ryanodine receptor 2 substantially negated the activating effects of anesthetics. Halothane acted independently of the adenine nucleotide-binding site on ryanodine receptor 2. The previously observed adenosine antagonism of halothane activation of sarcoplasmic reticulum Ca release was due to competition between adenosine and ATP, rather than between halothane and ATP. PMID- 28079566 TI - Retesting the Hypothesis of a Clinical Randomized Controlled Trial in a Simulation Environment to Validate Anesthesia Simulation in Error Research (the VASER Study). AB - BACKGROUND: Simulation has been used to investigate clinical questions in anesthesia, surgery, and related disciplines, but there are few data demonstrating that results apply to clinical settings. We asked "would results of a simulation-based study justify the same principal conclusions as those of a larger clinical study?" METHODS: We compared results from a randomized controlled trial in a simulated environment involving 80 cases at three centers with those from a randomized controlled trial in a clinical environment involving 1,075 cases. In both studies, we compared conventional methods of anesthetic management with the use of a multimodal system (SAFERsleep; Safer Sleep LLC, Nashville, Tennessee) designed to reduce drug administration errors. Forty anesthesiologists each managed two simulated scenarios randomized to conventional methods or the new system. We compared the rate of error in drug administration or recording for the new system versus conventional methods in this simulated randomized controlled trial with that in the clinical randomized controlled trial (primary endpoint). Six experts were asked to indicate a clinically relevant effect size. RESULTS: In this simulated randomized controlled trial, mean (95% CI) rates of error per 100 administrations for the new system versus conventional groups were 6.0 (3.8 to 8.3) versus 11.6 (9.3 to 13.8; P = 0.001) compared with 9.1 (6.9 to 11.4) versus 11.6 (9.3 to 13.9) in the clinical randomized controlled trial (P = 0.045). A 10 to 30% change was considered clinically relevant. The mean (95% CI) difference in effect size was 27.0% (-7.6 to 61.6%). CONCLUSIONS: The results of our simulated randomized controlled trial justified the same primary conclusion as those of our larger clinical randomized controlled trial, but not a finding of equivalence in effect size. PMID- 28079568 TI - Two-Dimensional and Three-Dimensional Transperineal Ultrasound Findings in Women With High-Pressure Voiding After Midurethral Sling Placement. AB - OBJECTIVES: The aim of this study was to evaluate dynamic two-dimensional (2D) and 3D transperineal pelvic ultrasound findings with urodynamic studies in women with lower urinary tract symptoms after midurethral sling placement. METHODS: On 2D images, the sling position, and on 3D imaging the sling angle, urethral diameter, urethral height, and urethral cross sectional area were recorded with and without Valsalva. Patients were categorized into 3 groups based on 2D imaging: group 1-at rest, the sling lies parallel to the urethral lumen, and during Valsalva, the sling becomes C shaped; group 2-both at rest and during Valsalva, the sling runs parallel to the urethral lumen; group 3-at rest, the sling is C shaped, and during Valsalva, this curved shape is maintained. For analytical purposes, G3 was compared with G1+2. Multiple logistic regressions were used to evaluate the association between transperineal pelvic ultrasound and urodynamic study. RESULTS: Univariate analyses to examine the relationships between high-pressure voiding, and each variable revealed that Valsalva sling angle, G3 versus G1+2, and sling position as percentage of the urethral length yielded significant findings (odds ratio, 95% confidence interval, P value for each, respectively: 1.037, 1.001-1.074, 0.04; 11.67, 2.116-64.31, 0.004; and 0.952, 0.911-0.994, 0.02). When including G3 versus G1+2, Valsalva sling angle, and percentage into the regression model, we concluded that there was only statistically significant association between groups and high-pressure voiding (odds ratio, 6.85; 95% confidence interval, 1.12-42.04; P = 0.03). CONCLUSIONS: Transperineal ultrasound can help to predict women with high-pressure voiding after midurethral sling and thus may aid in the diagnosis of partial bladder outlet obstruction. PMID- 28079569 TI - Standing Vs Supine; Does it Matter in Cough Stress Testing? AB - OBJECTIVES: The aim of this study was to compare the sensitivity of cough stress test in the standing versus supine position in the evaluation of incontinent females. METHODS: We performed a prospective observational study of women with the chief complaint of urinary incontinence (UI) undergoing a provocative cough stress test (CST). Subjects underwent both a standing and a supine CST. Testing order was randomized via block randomization. Cough stress test was performed in a standard method via backfill of 200 mL or until the subject described strong urge. The subjects were asked to cough, and the physician documented urine leakage by direct observation. The gold standard for stress UI diagnosis was a positive CST in either position. RESULTS: Sixty subjects were enrolled, 38 (63%) tested positive on any CST, with 38 (63%) positive on standing compared with 29 (28%) positive on supine testing. Nine women (15%) had positive standing and negative supine testing. No subjects had negative standing with positive supine testing. There were no significant differences in positive tests between the 2 randomized groups (standing first and supine second vs. supine first and standing second). When compared with the gold standard of any positive provocative stress test, the supine CST has a sensitivity of 76%, whereas the standing CST has a sensitivity of 100%. CONCLUSIONS: The standing CST is more sensitive than the supine CST and should be performed in any patient with a complaint of UI and negative supine CST. The order of testing either supine or standing first does not affect the results. PMID- 28079570 TI - Incidental Gallbladder Cancer Visualized From Posttreatment 131I Whole-Body Scan: Reply. PMID- 28079571 TI - Spontaneous Intracranial Hypotension With Site of Leak Detected Only After 111In DTPA Cisternogram. AB - A 54-year-old man with a 3-week history of orthostatic headache and acute on chronic subdural hematoma presented with imaging findings suggestive of spontaneous intracranial hypotension. Three myelograms were negative for leak, and nontargeted epidural blood patches did not result in symptom relief. A cerebrospinal fluid leak study using In-DTPA with SPECT/CT demonstrated a focal area of asymmetric activity at the left C2 nerve root. A left C2 root tie-off, targeted epidural blood patch, and Dura seal glue resulted in resolution of patient symptomatology highlighting the importance of fused SPECT/CT images in detection of an occult cerebral spinal fluid leak. PMID- 28079572 TI - Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE): A Pilot Study in Alcohol-dependent Women. AB - OBJECTIVES: Posttraumatic stress disorder (PTSD) and substance use disorders are highly comorbid. Effective treatments are largely lacking. This pilot study evaluated the safety and feasibility of a novel intervention, Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE), in preparation for a randomized controlled trial. METHODS: Twenty-two treatment seeking women with current DSM-IV-TR PTSD and alcohol dependence (AD) were recruited. Participants received COPE. Safety and feasibility were evaluated, as were efficacy-related outcomes: PTSD and depression symptom severity, alcohol use, craving, and dependence severity. RESULTS: No adverse events occurred. COPE was implemented in routine clinical practice. Among the assessed women, 95.8% were eligible to participate. Treatment attendance and completion were higher than in previous studies. Post treatment, all efficacy-related outcomes, including PTSD and depression symptom severity, alcohol use, craving, and dependence severity, were significantly reduced. CONCLUSIONS: COPE was safe and feasible to use. Concerns that trauma-focused, exposure-based therapy might promote relapse in this population appear unwarranted. Our findings provide initial evidence suggestive of COPE efficacy for comorbid PTSD and AD in women. These results provide a strong rationale for investigating the efficacy of COPE for comorbid PTSD and AD in women in a randomized controlled trial. PMID- 28079573 TI - Medically Assisted Withdrawal (Detoxification): Considering the Mother-Infant Dyad. AB - Recommendations for opioid agonist pharmacotherapy and against medically assisted withdrawal were based upon early reports that associated withdrawal with maternal relapse and fetal demise. Data from recent case series have called these recommendations into question. Although these data do not support an association between medically assisted withdrawal and fetal demise, relapse remains a significant clinical concern with reported rates ranging from 17% to 96% (average 48%). Given the high loss to follow-up in these studies, the actual relapse rate is likely even greater. Furthermore, while medically assisted withdrawal is being proposed as a public health strategy to reduce neonatal abstinence syndrome (NAS), current data do not support a reduction in NAS with medically assisted withdrawal relative to opioid agonist pharmacotherapy. Overall, the data do not support either benefit of medically assisted withdrawal or equivalence to opioid agonist pharmacotherapy for the maternal-newborn dyad. Medically assisted withdrawal increases the risk of maternal relapse and poor treatment engagement and does not improve newborn health. Treatment of chronic maternal disease, including opioid agonist disorder, should be directed toward optimal long-term outcome. PMID- 28079574 TI - Prognostic Impact of MUM1/IRF4 Expression in Burkitt Lymphoma (BL): A Reappraisal of 88 BL Patients in Japan. AB - MUM1/IRF4 expression is detected in 18% to 41% of Burkitt lymphoma (BL). However, only a few studies of MUM1-positive (MUM1) BL have been reported, and its characteristics still remain controversial. To highlight the features of MUM1 BL, we compared the clinicopathologic characteristics of 37 cases of MUM1 and 51 cases of MUM1-negative (MUM1) BL in Japan. Compared with MUM1 BL, patients with MUM1 BL showed significantly younger onset (P=0.0062) and a higher ratio of females (P=0.013). We have also revealed the difference in the involved sites. The MUM1 group showed lower incidences of involvement of stomach (P=0.012) and tonsil (P=0.069). There was a more tendency in MUM1 group to involve colon (P=0.072), breast (P=0.073), and kidney (P=0.073). Regarding the prognosis, a trend toward a lower overall survival for MUM1 group was noted (P=0.089). Notably, comparing MUM1 and MUM1 BL cases of adults (age16 y old and above), the former showed significantly worse prognosis (P=0.041). Among the BL patients treated with the intensive chemotherapy, a standard therapy for BL, MUM1 cases showed worse prognosis (P=0.056). In conclusion, MUM1 BL showed worse prognosis, particularly in adult cases, compared with MUM1 BL. In addition, the difference of the onset age, sex ratio, and involved sites between the 2 groups was noted. Our results demonstrate that MUM1 expression might predict worse prognosis of BL, and MUM1 BL should be distinguished from MUM1 BL. PMID- 28079575 TI - Cystic Biliary Atresia and Choledochal Cysts Are Distinct Histopathologic Entities. AB - Cystic biliary atresia (CBA), a rare cystic expansion of atretic extrahepatic bile ducts in young infants, overlaps in age at presentation and imaging features with early choledochal cysts (CC). Treatment and prognosis differ; histologic differences are unsettled. We compared 10 patients with CBA, 1975 to 2015, to an age-similar cohort of 13 infants, and to older patients who had surgery for CC. Operative details, imaging, and clinical courses were correlated to pathologic specimens. Immunostains for smooth muscle actin and myosin heavy chain were used to evaluate cyst walls and atretic segments. CBA cysts typically lacked epithelium and inflammation; cyst walls had an inner, dense cicatricial layer associated with myofibroblastic (MF) hyperplasia that often delaminated producing a grossly visible inner cyst wall. Seven proximal biliary remnants in CBA featured circumferential peribiliary MF hyperplasia/fibrosis with little or no inflammation, similar to isolated BA. Extrahepatic atresia was usually both proximal and distal to the cyst. Features in 10/13 CC from infants and 8/8 CC in older patients had mostly preserved uninjured epithelium and no subepithelial cicatrix. Mural smooth muscle (absent in CBA) was present to some extent in CC at all ages. Unexpectedly, focal MF hyperplasia and laminar sclerosis was present in a few CC in infants, resembling CBA. CBA and infant CC are distinct histologic entities that occasionally overlap. CBA bile duct injury mimics non-CBA. Cystification is an aberrant manifestation of stromal proliferation in BA. The current management approach assuming CBA and CC in infants are 2 separate disease processes is supported but caution is advised. PMID- 28079576 TI - Mixed Gangliocytoma-Pituitary Adenoma: Insights on the Pathogenesis of a Rare Sellar Tumor. AB - Gangliocytomas originating in the sellar region are rare; most are tumors composed of gangliocytic and pituitary adenomatous elements, forming the so called mixed gangliocytoma-pituitary adenoma. The majority of mixed gangliocytoma adenomas are associated with endocrinopathies, mainly acromegaly and less often Cushing disease and hyperprolactinemia. In the present study, 10 cases of mixed gangliocytoma and somatotroph adenomas were evaluated for patterns of cellular differentiation and expression of lineage-specific transcription factors. The tumors were characterized by immunohistochemistry for pituitary hormones, cytokeratins, Pit-1, and the neuronal markers NeuN, neurofilaments (NFP), and MAP2. Double-labeling immunohistochemistry for Pit-1/GH, Pit-1/NFP, Pit-1/MAP2, and NeuN/GH was performed in 9/10 tumors. Our data demonstrate that both adenomatous and ganglionic cells express the acidophilic lineage transcription factor Pit-1. Although mixed gangliocytomas and somatotroph adenomas show histologically distinct cellular populations, there is at least a small population of cells that coexpress the Pit-1 transcription factor and neuronal associated cytoskeletal proteins favoring the theory of transdifferentiation of neuroendocrine cells into neuronal elements of these mixed tumors. PMID- 28079578 TI - The Liability of a Glowing Reference. PMID- 28079577 TI - Transdifferentiation of Neuroendocrine Cells: Gangliocytoma Associated With Two Pituitary Adenomas of Different Lineage in MEN1. AB - Gangliocytomas are rare and benign neuronal cell tumors, mostly found in the hypothalamic and sellar regions. Their histogenesis is still the subject of discussions. Herein we present a unique case of a pituitary gangliocytoma associated with a prolactinoma and a corticotroph adenoma in a patient affected by MEN1. The histologic study revealed shared features between adenomatous and neuronal cells, supporting the etiological hypothesis of a common origin or a phenomenon of transdifferentiation. Furthermore, gangliocytoma could be a new tumor related to MEN1. The clinical and histologic observations are discussed and the literature on the topic is reviewed. PMID- 28079579 TI - Detailed 2-Dimensional and 3-Dimensional Transesophageal Evaluation of the Aortic Root and Aortic Valve in Complex Type A Dissections. PMID- 28079580 TI - A Predictive Model for Extended Postanesthesia Care Unit Length of Stay in Outpatient Surgeries. AB - BACKGROUND: A predictive model that can identify patients who are at an increased risk for prolonged postanesthesia care unit (PACU) stay could help optimize resource utilization and case sequencing. Although previous studies identified some predictors, there is not a model that only utilizes various patients demographic and comorbidities, that are already known preoperatively, and that may affect PACU length of stay for outpatient procedures requiring the care of an anesthesiologist. METHODS: We collected data from 4151 patients at a single institution from 2014 to 2015. The data set was split into a training set (cases before 2015) and a test set (cases during 2015). Bootstrap samples were chosen (R = 1000 replicates) and a logistic regression model was built on the samples using a combined method of forward selection and backward elimination based on the Akaike Information Criterion. The trained model was applied to the test set. Model performance was evaluated with the area under the receiver operating characteristic (ROC) Curve (AUC) for discrimination and the Hosmer-Lemeshow (HL) test for goodness-of-fit. RESULTS: The final model had 5 predictor variables for prolonged PACU length of stay, which included the following: morbid obesity, hypertension, surgical specialty, primary anesthesia type, and scheduled case duration. The model had an AUC value of 0.754 (95% confidence interval 0.733 0.774) on the training set and 0.722 (95% confidence interval 0.698-0.747) on the test set, with no difference between the 2 ROC curves (P = .06). The model had good calibration for the data in both the training and test data set indicated by nonsignificant P values from the HL test (P = .211 and .719 for the training and test set, respectively). CONCLUSIONS: We developed a predictive model with excellent discrimination and goodness-of-fit that can help identify those at higher odds for extended PACU length of stay. This information may help optimize case-sequencing methodologies. PMID- 28079581 TI - Assessing the Impact of the Anesthesia Medication Template on Medication Errors During Anesthesia: A Prospective Study. AB - BACKGROUND: Medication errors continue to be a significant source of patient harm in the operating room with few concrete countermeasures. The organization and identification of medication syringes may have an impact on the commission of medication errors in anesthesia, so a team of physicians and designers at the University of Washington created the Anesthesia Medication Template (AMT) to define a formal way of organizing the anesthesia workspace. The purpose of this study is to assess the ability of the AMT to reduce perioperative medication errors by anesthesia providers. METHODS: This study evaluated the AMT in 2 phases: (1) 41 anesthesia providers administered medications in 2 prospective, randomized operating room simulations with or without the AMT, while medication errors were directly observed; and (2) around 200 providers prospectively self reported medication errors from all anesthetizing locations during a 2-year period at Seattle Children's Hospital, an academic, pediatric medical center. RESULTS: In simulated emergencies, the odds of medication dosing errors using the AMT were 0.21 times the odds of medication dosing errors without AMT (95% confidence interval [CI], 0.07, 0.66), controlling for scenario, session, training level, and years at training level. During the year after implementation of the AMT, the mean monthly error rate for all reported medication errors that reached patients decreased from 1.24 (95% CI, 0.85-1.79) to 0.65 (95% CI, 0.39 1.09) errors per 1000 anesthetics. The mean monthly error rate of reported swap, preparation, miscalculation, and timing errors decreased from 0.97 (95% CI, 0.64 1.48) to 0.35 (95% CI, 0.17-0.70) errors per 1000 anesthetics. Medication errors that resulted in patient harm did not change after implementation of the AMT. CONCLUSIONS: Standardizing medication organization with the AMT is an intuitive, low-cost strategy with the potential to improve patient safety through reducing medication errors by anesthesia providers. PMID- 28079582 TI - Landmark-Guided and Ultrasound-Guided Approaches for Trochanteric Bursa Injection: A Cadaveric Study. AB - BACKGROUND: Trochanteric bursa (TB) injection with local anesthetic and corticosteroid is a treatment for patients suffering from greater trochanteric pain syndrome. Both landmark (LM)-guided and ultrasound (US)-guided methods have been used, but their accuracies have not been determined. This study examined the accuracy of these injections with cadaveric dissection. METHODS: Twenty-four hip specimens were randomized to receive TB injections with methylene blue under either LM-guided or US-guided approach. After dissection, the locations of the dye were classified into 3 categories: intrabursal, extrabursal, or combined intrabursal and extrabursal. The presence of dye in the intrabursal space with or without extrabursal leak was considered a successful injection. Accuracy was defined as the percentage of successful injection. RESULTS: The accuracies of the LM-guided and US-guided injection were 0.67 (95% confidence interval 0.35-0.90) and 0.92 (95% confidence interval 0.62-1.00), respectively, with no significant difference. CONCLUSIONS: This is the first cadaveric study examining the accuracy of both the US-guided and LM-guided techniques for TB injection. Future clinical studies are required to compare the outcomes of LM-guided and US-guided greater trochanteric pain syndrome injection. PMID- 28079583 TI - Induction. PMID- 28079584 TI - The Development and Implementation of Cognitive Aids for Critical Events in Pediatric Anesthesia: The Society for Pediatric Anesthesia Critical Events Checklists. AB - Cognitive aids such as checklists are commonly used in modern operating rooms for routine processes, and the use of such aids may be even more important during critical events. The Quality and Safety Committee of the Society for Pediatric Anesthesia (SPA) has developed a set of critical-event checklists and cognitive aids designed for 3 purposes: (1) as a repository of the latest evidence-based and expert opinion-based information to guide response and management of critical events, (2) as a source of just-in-time information during critical events, and (3) as a method to facilitate a shared understanding of required actions among team members during a critical event. Committee members, who represented children's hospitals from across the nation, used the recent literature and established guidelines (where available) and incorporated the expertise of colleagues at their institutions to develop these checklists, which included relevant factors to consider and steps to take in response to critical events. Human factors principles were incorporated to enhance checklist usability, facilitate error-free accomplishment, and ensure a common approach to checklist layout, formatting, structure, and design.The checklists were made available in multiple formats: a PDF version for easy printing, a mobile application, and at some institutions, a Web-based application using the anesthesia information management system. After the checklists were created, training commenced, and plans for validation were begun. User training is essential for successful implementation and should ideally include explanation of the organization of the checklists; familiarization of users with the layout, structure, and formatting of the checklists; coaching in how to use the checklists in a team environment; reviewing of the items; and simulation of checklist use. Because of the rare and unpredictable nature of critical events, clinical trials that use crisis checklists are difficult to conduct; however, recent and future simulation studies with adult checklists provide a promising avenue for future validation of the SPA checklists. This article will review the developmental steps in producing the SPA crisis checklists, including creation of content, incorporation of human factors elements, and validation in simulation. Critical-events checklists have the potential to improve patient care during emergency events, and it is hoped that incorporating the elements presented in this article will aid in successful implementation of these essential cognitive aids. PMID- 28079587 TI - Review of the Alternatives to Epidural Blood Patch for Treatment of Postdural Puncture Headache in the Parturient. AB - Labor neuraxial anesthesia is commonly used in the parturient, and postdural puncture headache is the most common complication of the technique. Although epidural blood patch is the best treatment, there are some patients in whom this treatment is refused or contraindicated. The goal of this article is to review the efficacy of the most studied alternate modalities to treat postdural puncture headache. This will include a discussion of the various oral or intravenous therapies and the non-blood-containing epidural injections. Last, the evidence behind interventional pain modalities and acupuncture will be examined. PMID- 28079588 TI - The Cricoid Force Necessary to Occlude the Esophageal Entrance: Is There a Gender Difference? AB - BACKGROUND: We tested the hypothesis whether gender differences exist in the applied cricoid force necessary to prevent regurgitation. Real-time visual and dynamic means were used to assess the effectiveness of different applied cricoid forces in occluding the esophageal entrance in men (group 1) and in women (group 2). METHODS: In anesthetized and paralyzed patients, the glottis and esophageal entrance were visualized with a Glidescope video laryngoscope. Trained operators performed cricoid pressure (CP) and gastric tube insertion trials. Successful gastric tube insertion in the presence of CP was considered ineffective CP, whereas unsuccessful insertion was considered effective CP. The applied cricoid forces were measured with a novel instrument, the cricometer. The first patient in each group received 20 N. The applied cricoid force in successive patients was determined by the response of the previous patient within the same group, using the up-and-down sequential allocation technique. RESULTS: In the 30 men and 30 women who qualified for the study, the median cricoid force (cricoid force = 50) that occluded the esophageal entrance was 30.8 N (95% confidence interval = 28.15 33.5) in men, and 18.7 N in women (95% confidence interval = 17.1-20.3; P < .0001). Patency of the esophageal entrance was observed when CP was not applied and when inadequate forces that allowed successful esophageal cannulation were used. CONCLUSIONS: The current study provides evidence that the median force necessary to occlude the esophageal entrance to prevent regurgitation is less in women compared with men. Applying the appropriate cricoid force in women should also decrease airway-related problems that tend to occur with the use of excessive forces. The findings of the current study may only be applicable to patients with normal body habitus. PMID- 28079589 TI - In Vogue: Ketamine for Neuroprotection in Acute Neurologic Injury. AB - Neurologic deterioration following acute injury to the central nervous system may be amenable to pharmacologic intervention, although, to date, no such therapy exists. Ketamine is an anesthetic and analgesic emerging as a novel therapy for a number of clinical entities in recent years, including refractory pain, depression, and drug-induced hyperalgesia due to newly discovered mechanisms of action and new application of its known pharmacodynamics. In this focused review, the evidence for ketamine as a neuroprotective agent in stroke, neurotrauma, subarachnoid hemorrhage, and status epilepticus is highlighted, with a focus on its applications for excitotoxicity, neuroinflammation, and neuronal hyperexcitability. Preclinical modeling and clinical applications are discussed. PMID- 28079590 TI - The Evaluation of Corneal Fragility After UVA/Riboflavin Crosslinking. AB - PURPOSE: To evaluate the fragility of cornea after UVA/riboflavin crosslinking (CXL). METHODS: Sixty New Zealand rabbits received UVA/riboflavin crosslinking treatment (wavelength 365 nm, irradiance 3.0 mW/cm, and total dose 5.4 J/cm) on right eyes. Animals were sacrificed before and immediately after treatment (day 0), day 1, 3, 7, and 28 after treatment. A 4*10 mm corneal strip for biomechanical evaluation was harvested after sacrifice. The corneal fragility was evaluated by measurement of elongation rate, whereby the elongation rate equals elongation length/baseline length. RESULTS: The Youngs modulus and maximal stress were 1.41+/-0.51 MPa and 5.56+/-1.84 MPa before CXL, and increased to 2.31+/-0.68 MPa (P=0.008) and 9.25+/-2.74 MPa (P=0.04), respectively, on day 0, then maintained a stable level within a 28 days follow-up. The elongation rate was 62.04+/-9.34% before CXL and decreased to 48.95%+/-8.24% (P=0.02) on day 0, then maintained a stable level within a 28 days follow-up. CONCLUSIONS: This study showed an increase in the corneal fragility after UVA/riboflavin crosslinking along with an increase in the corneal stiffness. A long-term follow-up should be taken to evaluate the potential deleterious effect of the increasing corneal fragility after UVA/riboflavin crosslinking. PMID- 28079591 TI - Point-of-care diagnostics: extending the laboratory network to reach the last mile. AB - PURPOSE OF REVIEW: More point-of-care (POC) diagnostic tests are becoming available for HIV diagnosis and treatment in resource-limited settings. These novel technologies have the potential to foster decentralized HIV care and treatment for the benefit of clinical laboratories, HIV clinics, and HIV-infected patients. There continue to be many business, technological, and operational challenges that limit product development and regulatory approval, which limits products available for the required operational and cost-effectiveness studies and delays policy adoption and implementation. RECENT FINDINGS: Although the rapid HIV diagnostic test has been widely successful, the pathways for POC CD4 cell count and HIV viral load assay analyzers have been more challenging. We describe significant hurdles for product development, approval, and implementation, which include the business case, technical development, clinical impact, and integrating laboratory and clinical networks. SUMMARY: The objective of this review is to highlight the obstacles for developing and implementing appropriate strategies for POC HIV testing assays to improve the clinical services for HIV-infected patients in resource-limited settings. PMID- 28079592 TI - Implementation science: the laboratory as a command centre. AB - PURPOSE OF REVIEW: Recent advances in point-of-care technologies to ensure universal access to affordable quality-assured diagnostics have the potential to transform patient management, surveillance programmes, and control of infectious diseases. Decentralization of testing can put tremendous stresses on fragile health systems if the laboratory is not involved in the planning, introduction, and scale-up strategies. RECENT FINDINGS: The impact of investments in novel technologies can only be realized if these tests are evaluated, adopted, and scaled up within the healthcare system with appropriate planning and understanding of the local contexts in which these technologies will be used. SUMMARY: In this digital age, the laboratory needs to take on the role of the Command Centre for technology introduction and implementation. Implementation science is needed to understand the political, cultural, economic, and behavioural context for technology introduction. The new paradigm should include: building a comprehensive system of laboratories and point-of-care testing sites to provide quality-assured diagnostic services with good laboratory-clinic interface to build trust in test results and linkage to care; building and coordinating a comprehensive national surveillance and communication system for disease control and global health emergencies; conducting research to monitor the impact of new tools and interventions on improving patient care. PMID- 28079593 TI - Improving the clinic-laboratory-interface in the context of HIV diagnosis, treatment, and monitoring. AB - PURPOSE OF REVIEW: Laboratory support is central to clinical medicine. The present review focuses on the health systems strengthening needs of the clinic laboratory-interface (CLI) in developing countries within the context of HIV diagnosis, treatment, and monitoring. RECENT FINDINGS: Although significant improvements have been made in reducing error rates in the analytical phase of pathology services within laboratories, there remain substantial deficits in both the preanalytic and postanalytic phases of the entire value chain that require strengthening. Recent interventions have largely aimed at improving the CLI focus through technological advancements. Although these are important, addressing CLI deficiencies within the context of the World Health Organization's health systems strengthening building blocks has been relatively neglected, and data are very limited in resource-limited countries. Broad health systems strengthening in the CLI is required. The present study reviews the key elements of the CLI associated with poor laboratory functioning, and proposes specific areas for improvement. The present study discuss case studies in South Africa and India, as well as reviewing data supporting interventions in public health clinics to improve the CLI. SUMMARY: The CLI is a neglected area of the laboratory value chain. Reducing errors and increasing efficiencies will improve the laboratory service to patients. PMID- 28079594 TI - Impact of Concurrent Medication Use on Pancreatic Cancer Survival-SEER-Medicare Analysis. AB - OBJECTIVES: Preclinical studies have suggested that non-antineoplastic medication use may impact pancreatic cancer biology. We examined the association of several medication classes on pancreatic cancer survival in a large medical claims database. MATERIALS AND METHODS: Histologically confirmed pancreatic adenocarcinoma diagnosed between 2006 and 2009 were analyzed from the Surveillance, Epidemiology, and End Results-Medicare database with available part D data. Drug use was defined as having 2 prescriptions filled within 12 months of pancreatic cancer diagnosis. The following medication classes/combinations were analyzed: beta-blocker, statin, insulin, metformin, thiazolidinedione, warfarin, heparin, beta-blocker/statin, metformin/statin, and beta-blocker/metformin. Multivariable Cox proportional hazard models adjusting for age, sex, race, stage at diagnosis, site of cancer, and Charlson comorbidity index were constructed to test the association between medication classes and overall survival. RESULTS: A total of 13,702 patients were included in the study; median age 76 years, 42.5% males, 77.1% white. The most common anatomic site and stage at diagnosis were head of the pancreas (49.9%) and stage 4 (49.6%), respectively. Ninety-four percent of patients died in the follow-up period (median overall survival 5.3 mo). Multivariable Cox regression analysis showed that use of beta-blockers, heparin, insulin, and warfarin were significantly associated with improved survival (P<0.05 for each one), whereas metformin, thiazolidinedione, statin, and combination therapies were not. CONCLUSIONS: In this study, use of beta-blockers, heparin, insulin, and warfarin were associated with improved survival in patients with pancreatic cancer. Additional studies are needed to validate these findings in the clinical setting. PMID- 28079595 TI - Acetylated cyclophilin A is a major mediator in hypoxia-induced autophagy and pulmonary vascular angiogenesis. AB - BACKGROUND: Autophagy is a major intracellular degradation and recycling process that maintains cellular homeostasis, which is involved in structural and functional abnormalities of pulmonary vasculature in hypoxic pulmonary arterial hypertension (HPAH). Cyclophilin A (CyPA) is a secreted, oxidative stress-induced factor. Its role in inducing autophagy and augmenting endothelial cell dysfunction has never been explored. METHODS: Lungs from rats exposed to chronic hypoxia were examined for autophagy with electron microscopy, western blotting, and fluorescence microscopy. RESULTS: Activated autophagy was seen in the endothelium of the pulmonary artery from experimental rat models of HPAH and cultured bovine pulmonary arterial endothelial cells under hypoxia. Inhibiting autophagy attenuated the pathological progression of HPAH and repressed endothelial cell migration and angiogenesis. We also showed that CyPA was upregulated and acetylated under hypoxia and led to the abnormal occurrence of autophagy through its interaction with autophagy protein 5 and autophagy protein 7. Moreover, acetylated CyPA was essential for the excessive proliferation, migration, and tube formation networks of pulmonary arterial endothelial cells. CONCLUSION: Our results indicate the crucial role of acetylated CyPA in the abnormal occurrence of autophagy and subsequent pulmonary vascular angiogenesis. PMID- 28079596 TI - Statistical analysis as a cause of white-coat hypertension. PMID- 28079597 TI - Histologic Findings of Severe/Therapy-Resistant Asthma From Video-assisted Thoracoscopic Surgery Biopsies. AB - The histologic changes occurring in severe/therapy-resistant asthma (SA) as defined by the European Respiratory Society/American Thoracic Society guidelines, particularly at the level of the distal airways are unknown. This study describes the clinical, radiologic, and histologic characteristics of 29 SA patients who underwent video-assisted thoracoscopic surgery lung biopsy. Pathologic observations were correlated with clinical features, especially the presence of autoimmune disease (AID) (15/29, 51.7%). Ten biopsies (10/29, 34.5%) showed only small airway manifestations of asthma, whereas in 19 (65.5%) asthmatic granulomatosis, manifested by asthmatic bronchiolitis supplemented by an alveolar septal mononuclear infiltrates with non-necrotizing granulomas, was present. SA patients without asthmatic granulomatosis showed more striking small airway injury, subbasement membrane thickening, and neutrophilic infiltrates. Cases with concurrent AID had a tendency to more parenchymal eosinophilic inflammation, more bronchiolocentric granulomas, and a suggestion of increased responsivity to nonsteroidal immunosuppressive therapy. Histologic examination of video-assisted thoracoscopic surgery lung biopsies in SA demonstrates diverse pathologies including cases associated with granulomatous inflammation in addition to eosinophilic infiltrates. This spectrum of histologies may link to a high incidence of AID. PMID- 28079598 TI - Interobserver Agreement in Endometrial Carcinoma Histotype Diagnosis Varies Depending on The Cancer Genome Atlas (TCGA)-based Molecular Subgroup. AB - The Cancer Genome Atlas recently identified a genomic-based molecular classification of endometrial carcinomas, with 4 molecular categories: (1) ultramutated (polymerase epsilon [POLE] mutated), (2) hypermutated (microsatellite instability), (3) copy number abnormalities-low, and (4) copy number abnormalities-high. Two studies have since proposed models to classify endometrial carcinomas into 4 molecular subgroups, modeled after The Cancer Genome Atlas, using simplified and more clinically applicable surrogate methodologies. In our study, 151 endometrial carcinomas were molecularly categorized using sequencing for the exonuclease domain mutations (EDM) of POLE, and immunohistochemistry for p53 and mismatch repair (MMR) proteins. This separated cases into 1 of 4 groups: (1) POLE EDM, (2) MMR-D, (3) p53 wildtype (p53 wt), or (4) p53 abnormal (p53 abn). Seven gynecologic pathologists were asked to assign each case to one of the following categories: grade 1 to 2 endometrioid carcinoma (EC), grade 3 EC, mucinous, serous carcinoma (SC), clear cell, dedifferentiated, carcinosarcoma, mixed, and other. Consensus diagnosis among all 7 pathologists was highest in the p53 wt group (37/41, 90%), lowest in the p53 abn group (14/36, 39%), and intermediate in the POLE EDM (22/34, 65%) and MMR-D groups (23/40, 58%). Although the majority of p53 wt endometrial carcinomas are grade 1 to 2 EC (sensitivity: 90%), fewer than half of grade 1 to 2 EC fell into the p53 wt category (positive predictive value: 42%). Pure SC almost always resided in the p53 abn group (positive predictive value: 96%), but it was insensitive as a marker of p53 abn (sensitivity 64%) and the reproducibility of diagnosing SC was suboptimal. The limitations in the precise histologic classification of endometrial carcinomas highlights the importance of an ancillary molecular-based classification scheme. PMID- 28079599 TI - Steatohepatitis-like Changes in Focal Nodular Hyperplasia, A Finding to Distinguish From Steatohepatitic Variant of Hepatocellular Carcinoma. AB - Steatohepatitis-like change has not been described in focal nodular hyperplasia (FNH). Steatohepatitis-like change in FNH may show overlapping features with steatohepatitic variant of hepatocellular carcinoma (HCC). This problem can be compounded if seen in FNH with widened cell plates or hepatocyte rosettes, other features that can also be seen in HCC. This study examined steatotic FNHs for the frequency of steatohepatitis-like change, especially in the setting of FNH with rosettes and/or widened cell plates. Thirty-three resection specimens of steatotic FNH from 3 institutions were evaluated for degree of steatosis, background liver steatosis, ductular reaction, and lymphocytic infiltrate, as well as presence of thick fibrous bands, thick-walled vessels, ballooned hepatocytes, Mallory-Denk bodies, dilated sinusoids, hepatocyte rosettes, and thick hepatic plates. Steatosis was distributed along fibrous septa as well as diffusely throughout the FNH. Steatohepatitis-like changes were focally present in 54% (18 cases). Thick plates>3 cells were focally found in 14 cases (42%); rosettes were common (70%). All cases showed at least 2 of the histologic features highly suggestive for the diagnosis of FNH such as thick bands of fibrosis, thick-walled vessels and/or ductular reaction and the typical map-like pattern of glutamine synthetase immunostaining. More than half of fatty FNH examined for this study had features of at least focal steatohepatitis-like changes. This finding should not be confused with steatohepatitic variant of HCC. Common typical features of FNH including thick-walled vessels, ductular reaction and thick fibrous bands are helpful for discrimination of FNH from HCC. PMID- 28079600 TI - Acute administration of cyclosporine A does not impair attention or memory performance in healthy men. AB - There is clinical and experimental evidence that treatment with immunosuppressive and antiproliferative drugs such as the calcineurin inhibitor cyclosporine A (CsA) is associated with mental health problems and neuropsychological disturbances in patients. However, it remains unclear whether and to what extent cognitive functions such as memory and attention processes are affected by the pharmacological treatment. This is partly because of the fact that it is difficult to refer the observed neuropsychological disturbances in patients to the drug itself, to drug-induced immune suppression, or to interaction with other medication or comorbidities. Thus, in a double-blind study with healthy male participants (n=30), we investigated whether short-term intake of therapeutic doses of CsA (4*2.5 mg/kg) affects attention, working memory performance, and anxiety levels, measured with the Tests of Attentional Performance and the State Trait Anxiety Inventory. The data indicate that short-term CsA-administration and subsequent suppression in interleukin-2 production are accompanied neither by a decrease in attention or memory performance nor by increased anxiety levels in healthy male volunteers, suggesting that the short-term intake of CsA does not impair cognitive functioning. Further studies in healthy humans are needed to determine neurocognitive functions and mood states after short-term or subchronic treatment with different immunosuppressive and antiproliferative drugs. PMID- 28079601 TI - Infliximab Optimization Based on Therapeutic Drug Monitoring in Pediatric Inflammatory Bowel Disease. AB - BACKGROUND: Infliximab (IFX) is an effective treatment for the management of moderate to severe inflammatory bowel disease (IBD). Low-serum IFX levels are associated with the development of antibodies to IFX (ATI), which subsequently associated with clinical relapse and increased morbidity. The primary purpose of this study is to examine the relation between dose and interval to IFX level. Secondary goal is to evaluate the relation between IFX level and ATI in a pediatric IBD population. METHODS: We performed a retrospective chart review of all children diagnosed with IBD and treated with IFX at a tertiary care pediatric IBD center. We performed our analysis based on prescribed dosing intervals and rounded dose up to 5 or 10 mg/kg as indicated in clinical practice. RESULTS: Our study included 278 samples from 129 children on IFX. ATI were detected in 37 samples (13.3%). Low IFX levels (<3 MUg/mL) were detected in 37.2% of children receiving IFX. Samples with ATI present had significantly lower levels of IFX than samples in which ATI were not present. For the dose 5 mg/kg, Q6 dosing had significantly higher IFX levels than Q8 dosing (P = 0.009). Higher IFX levels were seen with interval shortening rather than dose escalation. CONCLUSIONS: We demonstrate that low IFX levels are associated with development of immunogenicity to IFX as measured by ATI. We demonstrate that interval shortening rather than dose escalation results in higher IFX levels. We suggest that given the high number of IFX levels below 3 MUg/mL in patients, early IFX level evaluation or primary initiation of Q6 week dosing be considered. PMID- 28079603 TI - Genital use of talc and risk of ovarian cancer: a meta-analysis. AB - Some epidemiological studies suggest an association between genital use of talc powders and increased risk of ovarian cancer, but the evidence is not consistent. We performed a meta-analysis of epidemiological studies to formally evaluate this suspected association. A systematic search was conducted in Medline, Embase, and Scopus, leading to the identification of 24 case-control studies and three cohort studies. In the meta-analysis, we used a random-effect model to calculate summary estimates of the association between genital use of talc and occurrence of ovarian cancer. We assessed potential sources of between-study heterogeneity and presence of publication bias. The summary relative risk (RR) for ever use of genital talc and ovarian cancer was 1.22 [95% confidence interval (CI): 1.13 1.30]. The RR for case-control studies was 1.26 (95% CI: 1.17-1.35) and for cohort studies was 1.02 (95% CI: 0.85-1.20, Pheterogeneity=0.007). Serous carcinoma was the only histologic type for which an association was detected (RR: 1.24; 95% CI: 1.15-1.34). There was a weak trend in RR with duration and frequency of genital talc use. This meta-analysis resulted in a weak but statistically significant association between genital use of talc and ovarian cancer, which appears to be limited to serous carcinoma with suggestion of dose response. The heterogeneity of results by study design however, detracts from a causal interpretation of this association. PMID- 28079604 TI - Prior Use of Calcium Channel Blockers Is Associated With Decreased Mortality in Critically Ill Patients With Sepsis: A Prospective Observational Study. AB - OBJECTIVES: Experimental studies suggest that calcium channel blockers can improve sepsis outcome. The aim of this study was to determine the association between prior use of calcium channel blockers and the outcome of patients admitted to the ICU with sepsis. DESIGN: A prospective observational study. SETTING: The ICUs of two tertiary care hospitals in the Netherlands. PATIENTS: In total, 1,060 consecutive patients admitted with sepsis were analyzed, 18.6% of whom used calcium channel blockers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Considering large baseline differences between calcium channel blocker users and nonusers, a propensity score matched cohort was constructed to account for differential likelihoods of receiving calcium channel blockers. Fifteen plasma biomarkers providing insight in key host responses implicated in sepsis pathogenesis were measured during the first 4 days after admission. Severity of illness over the first 24 hours, sites of infection and causative pathogens were similar in both groups. Prior use of calcium channel blockers was associated with improved 30-day survival in the propensity-matched cohort (20.2% vs 32.9% in non calcium channel blockers users; p = 0.009) and in multivariate analysis (odds ratio, 0.48; 95% CI, 0.31-0.74; p = 0.0007). Prior calcium channel blocker use was not associated with changes in the plasma levels of host biomarkers indicative of activation of the cytokine network, the vascular endothelium and the coagulation system, with the exception of antithrombin levels, which were less decreased in calcium channel blocker users. CONCLUSIONS: Prior calcium channel blocker use is associated with reduced mortality in patients following ICU admission with sepsis. PMID- 28079605 TI - Delirium in Critically Ill Children: An International Point Prevalence Study. AB - OBJECTIVES: To determine prevalence of delirium in critically ill children and explore associated risk factors. DESIGN: Multi-institutional point prevalence study. SETTING: Twenty-five pediatric critical care units in the United States, the Netherlands, New Zealand, Australia, and Saudi Arabia. PATIENTS: All children admitted to the pediatric critical care units on designated study days (n = 994). INTERVENTION: Children were screened for delirium using the Cornell Assessment of Pediatric Delirium by the bedside nurse. Demographic and treatment-related variables were collected. MEASUREMENTS AND MAIN RESULTS: Primary study outcome measure was prevalence of delirium. In 159 children, a final determination of mental status could not be ascertained. Of the 835 remaining subjects, 25% screened positive for delirium, 13% were classified as comatose, and 62% were delirium-free and coma-free. Delirium prevalence rates varied significantly with reason for ICU admission, with highest delirium rates found in children admitted with an infectious or inflammatory disorder. For children who were in the PICU for 6 or more days, delirium prevalence rate was 38%. In a multivariate model, risk factors independently associated with development of delirium included age less than 2 years, mechanical ventilation, benzodiazepines, narcotics, use of physical restraints, and exposure to vasopressors and antiepileptics. CONCLUSIONS: Delirium is a prevalent complication of critical illness in children, with identifiable risk factors. Further multi-institutional, longitudinal studies are required to investigate effect of delirium on long-term outcomes and possible preventive and treatment measures. Universal delirium screening is practical and can be implemented in pediatric critical care units. PMID- 28079606 TI - Relationship Between Alternative Resuscitation Strategies, Host Response and Injury Biomarkers, and Outcome in Septic Shock: Analysis of the Protocol-Based Care for Early Septic Shock Study. AB - OBJECTIVES: The Protocol-based Care for Early Septic Shock trial found no differences across alternative resuscitation strategies in all-cause mortality. A separate aim was to determine whether differences in resuscitation strategies affected trajectories of biomarkers of key pathways associated with downstream clinical outcomes of sepsis and whether there were differences in survival across treatment arms for patients with different baseline biomarker profiles. DESIGN: Secondary analysis of a large randomized clinical trial. SETTING: Thirty-one U.S. hospitals. PATIENTS: Six hundred twenty-eight patients with septic shock. INTERVENTIONS: Two resuscitation protocols versus usual care. MEASUREMENTS AND MAIN RESULTS: We measured a panel of biomarkers representing four pathophysiologic domains: "inflammation" (tumor necrosis factor, interleukin-6, and -10); "coagulation" (D-dimers, thrombin-antithrombin complex); "oxidative stress" (urine isoprostane); and "tissue hypoxia" (lactate) at 0, 6, 24, and 72 hours after treatment. We analyzed whether alternative resuscitation strategies affected biomarker trajectories over 72 hours and whether effects on 90-day hospital mortality varied by baseline (time 0) biomarker profiles-both using regression models with interaction terms for treatment arms. For all baseline biomarkers, higher concentrations were associated with increased risk of death by 90 days. However, there was no significant effect of treatment assignment on subsequent biomarker trajectories. We did find evidence for heterogeneity of treatment effect of protocol-based care on mortality for patients with different baseline [interleukin-6] and [interleukin-6] * [interleukin-10] profiles, whereas patients with the lowest quartiles fared better with protocol-based care (odds ratios, 0.32 [0.13-075]; p = 0.01 and 0.32 [0.14-0.73]; p = 0.01, respectively). CONCLUSIONS: In patients with septic shock, alterations in inflammation, coagulation, oxidative stress, and tissue hypoxia are common and associated with adverse outcomes but are not influenced by protocol-based resuscitation compared with usual care. However, contrary to expectation, protocol-based resuscitation appeared to be superior in patients with lower concentrations of inflammatory biomarkers. The mechanisms responsible for this effect are unclear. PMID- 28079607 TI - Mapping Regional Differences of Local Pressure-Volume Curves With Electrical Impedance Tomography. AB - OBJECTIVES: Lung-protective mechanical ventilation aims to prevent alveolar collapse and overdistension, but reliable bedside methods to quantify them are lacking. We propose a quantitative descriptor of the shape of local pressure volume curves derived from electrical impedance tomography, for computing maps that highlight the presence and location of regions of presumed tidal recruitment (i.e., elastance decrease during inflation, pressure-volume curve with upward curvature) or overdistension (i.e., elastance increase during inflation, downward curvature). DESIGN: Secondary analysis of experimental cohort study. SETTING: University research facility. SUBJECTS: Twelve mechanically ventilated pigs. INTERVENTIONS: After induction of acute respiratory distress syndrome by hydrochloric acid instillation, animals underwent a decremental positive end expiratory pressure titration (steps of 2 cm H2O starting from >= 26 cm H2O). MEASUREMENTS AND MAIN RESULTS: Electrical impedance tomography-derived maps were computed at each positive end-expiratory pressure-titration step, and whole-lung CT taken every second steps. Airway flow and pressure were recorded to compute driving pressure and elastance. Significant correlations between electrical impedance tomography-derived maps and positive end-expiratory pressure indicate that, expectedly, tidal recruitment increases in dependent regions with decreasing positive end-expiratory pressure (p < 0.001) and suggest that overdistension increases both at high and low positive end-expiratory pressures in nondependent regions (p < 0.027), supporting the idea of two different scenarios of overdistension occurrence. Significant correlations with CT measurements were observed: electrical impedance tomography-derived tidal recruitment with poorly aerated regions (r = 0.43; p < 0.001); electrical impedance tomography-derived overdistension with nonaerated regions at lower positive end-expiratory pressures and with hyperaerated regions at higher positive end-expiratory pressures (r >= 0.72; p < 0.003). Even for positive end expiratory pressure levels minimizing global elastance and driving pressure, electrical impedance tomography-derived maps showed nonnegligible regions of presumed overdistension and tidal recruitment. CONCLUSIONS: Electrical impedance tomography-derived maps of pressure-volume curve shapes allow to detect regions in which elastance changes during inflation. This could promote individualized mechanical ventilation by minimizing the probability of local tidal recruitment and/or overdistension. Electrical impedance tomography-derived maps might become clinically feasible and relevant, being simpler than currently available alternative approaches. PMID- 28079609 TI - Mesenchymal stem cells induce epithelial mesenchymal transition in melanoma by paracrine secretion of transforming growth factor-beta. AB - Mesenchymal stem cells (MSCs) are considered for potential use as an ideal vehicle to efficiently deliver therapeutic agents in treatment against cancers including melanoma. However, emerging evidence indicates that MSCs promote tumor growth and progression. Therefore, a comprehensive understanding of the role of MSCs is very important to evaluate the MSCs-based therapy in melanoma. B16 melanoma cells treated by MSC conditioned medium (CM), showed significantly enhanced migration and invasion, which was also confirmed in a lung metastasis mice model in vivo. Later, it was found that MSC CM induced an epithelial mesenchymal transition (EMT) in B16 cells. The ELISA assay showed that transforming growth factor-beta (TGF-beta) was secreted by MSCs and EMT was also induced by recombinant TGF-beta in B16 melanoma cells, which suggests the important role of TGF-beta in mediating EMT caused by MSC CM. When TGF-beta signaling was inhibited by SB431542, the EMT process was significantly eliminated in vitro and in xenograft tumors in vivo. Snail, as a downstream target of TGF beta signaling and an EMT regulator, was upregulated by MSC CM and inhibited by SB431542, which confirms the key role of TGF-beta signaling in EMT induced by MSC CM in B16 cells. Taken together, this study shows that MSC induces EMT in melanoma cells in a paracrine manner, which might be mediated by the TGF beta/Snail signaling pathway. Thus, caution should be exercised when considering MSCs-based therapy in melanoma and also in other cancers. Targeting TGF-beta signaling and Snail could be further investigated as potential therapeutic approaches for melanoma. PMID- 28079610 TI - Influence of the Localization of Frontal Bone Defects on Primary Stability Values of 2 Different Implant Designs: An In Vitro Study. AB - OBJECTIVES: The aim of this study was to determine the influence of different frontal bone defect localizations on primary stability values of 2 different implant designs. MATERIALS AND METHODS: Eight cow rib segments were prepared before implant installation, as 2 segments with coronal, 2 with middle, and 2 with apical defects and 2 with control. Thirty-two cylindrical and 32 tapered implants were placed in the remaining 4 segments. Implant stability measurements were performed using electronic percussive testing and resonance frequency analysis. RESULTS: No significance was detected between the stability values of the 2 implant designs except the implant stability quotient (ISQ) of control groups. The tapered implants control group showed significantly higher lateral ISQs compared with cylindrical implants (P = 0.033). For both implant types, stability values were significantly lower in coronal defects (P < 0.01). No significant differences were detected in other defect types. CONCLUSION: Within the limitations of this study, it may be concluded that coronal defects may influence primary stability negatively, compared with middle and apical defects. Although statistically not significant, coronal defects caused lower primary stability values with the tapered design compared with parallel design. PMID- 28079611 TI - It Is Just Attention-Deficit Hyperactivity Disorder...or Is It? AB - CASE: Carly is a 5-year-old girl who presents for an interdisciplinary evaluation due to behaviors at school and home suggestive of attention-deficit hyperactivity disorder (ADHD). Parent report of preschool teacher concerns was consistent with ADHD. Psychological testing showed verbal, visual-spatial, and fluid reasoning IQ scores in the average range; processing speed and working memory were below average. Carly's behavior improved when her mother left the room, and she was attentive during testing with a psychologist. Tests of executive function (EF) skills showed mixed results. Working memory was in the borderline range, although scores for response inhibition and verbal fluency were average. Parent ratings of ADHD symptoms and EF difficulties were elevated.Carly's parents recently separated; she now lives with her mother and sees her father on weekends. Multiple caregivers with inconsistent approaches to discipline assist with child care while her mother works at night as a medical assistant. Family history is positive for ADHD and learning problems in her father. Medical history is unremarkable. Review of systems is significant for nightly mouth breathing and snoring, but no night waking, bruxism, or daytime sleepiness. She has enlarged tonsils and a high-arched palate on physical examination.At a follow-up visit, parent rating scales are consistent with ADHD-combined type; teacher rating scales support ADHD hyperactive-impulsive type. Snoring has persisted. A sleep study indicated obstructive sleep apnea. After adenotonsillectomy, Carly had significant improvement in ADHD symptoms. She developed recurrence of behavior problems 1 year after the surgery. PMID- 28079612 TI - Thrombopoietin as Early Biomarker of Disease Severity in Patients With Acute Pancreatitis. AB - OBJECTIVES: To study the concentrations of thrombopoietin (TPO), a growth factor recently involved in the pathogenesis of experimental acute pancreatitis (AP), and its potential role as an early diagnostic and prognostic biomarker in patients with AP. METHODS: Thrombopoietin was measured in 44 AP patients, 18 patients with nonpancreatic acute abdominal pain, and 18 healthy volunteers. Acute pancreatitis severity was classified on the basis of the 2012 International Atlanta Symposium on Acute Pancreatitis criteria. RESULTS: Thrombopoietin levels did not differ between AP patients and control subjects, whereas these were higher in patients with moderately severe or severe AP compared with those with mild AP. Receiver operating characteristic curve analysis of TPO for severe AP diagnosis showed an area under the curve of 0.80. A cutoff value of 31.48 pg/mL showed the highest sensitivity, allowing to rule out severe AP when TPO was lower, whereas TPO higher than 98.23 pg/mL was associated with severe AP with high specificity (93.5%). Furthermore, TPO levels were greater in AP patients developing organ dysfunction or sepsis and in nonsurvivors compared with survivors. CONCLUSIONS: Our data provide the first evidence for TPO as potential early prognostic biomarker in AP patients. High TPO levels at hospital admission may predict organ dysfunction, sepsis, and fatal outcome in AP patients. PMID- 28079613 TI - CENTRIPETAL MOVEMENT OF THE CAPILLARIES IN THE CENTRAL MACULAR REGION AFTER INTERNAL LIMITING MEMBRANE PEELING. AB - PURPOSE: To report a case that showed centripetal movements of the capillaries in the central macular region after vitrectomy with internal limiting membrane peeling. METHODS: A 57-year-old pseudophakic woman underwent successful vitrectomy with internal limiting membrane peeling and air tamponade for a vitreomacular traction. Optical coherence tomography angiographic images of the 3 mm * 3 mm inner retinal vascular plexus were examined preoperatively and at 3 months postoperatively. The changes in 93 corresponding bifurcations of the capillaries were assessed. RESULTS: The majority of the bifurcations were displaced towards the fovea at 3 months after the vitrectomy with internal limiting membrane peeling. CONCLUSION: Optical coherence tomography angiography was used to help visualize the centripetal movement of the inner retina around the fovea after the vitrectomy with internal limiting membrane peeling. PMID- 28079614 TI - The role of gene-environment interplay in occupational and environmental diseases: current concepts and knowledge gaps. AB - PURPOSE OF REVIEW: The interplay between genetic susceptibilities and environmental exposures in the pathogenesis of a variety of diseases is an area of increased scientific, epidemiologic, and social interest. Given the variation in methodologies used in the field, this review aims to create a framework to help understand occupational exposures as they currently exist and provide a foundation for future inquiries into the biological mechanisms of the gene environment interactions. Understanding of this complex interplay will be important in the context of occupational health, given the public health concerns surrounding a variety of occupational exposures. RECENT FINDINGS: Studies found evidence that suggest genetics influence the progression of disease postberyllium exposure through genetically encoded major histocompatibility complex, class II, DP alpha 2 (HLA-DP2)-peptide complexes as it relates to T-helper cells. This was characterized at the molecular level by the accumulation of Be-responsive CD4 T cells in the lung, which resulted in posttranslational change in the HLA-DPB1 complex. SUMMARY: These studies provide important evidence of gene-environment association, and many provide insights into specific pathogenic mechanisms. The following includes a review of the literature regarding gene-environment associations with a focus on pulmonary diseases as they relate to the workplace. PMID- 28079615 TI - Neuromuscular weakness in chronic obstructive pulmonary disease: chest wall, diaphragm, and peripheral muscle contributions. AB - PURPOSE OF REVIEW: Chronic obstructive lung disease affects the lung parenchyma and airways leading to well described effects in respiratory function. This review describes the current knowledge and advances regarding neuromuscular function and chest wall mechanics, which are affected in chronic obstructive pulmonary disease (COPD). RECENT FINDINGS: In COPD, progressive lung hyperinflation becomes constrained by a chest wall with decreasing capacity to expand, resulting in respiratory muscle inefficiency. There is evidence of neuromuscular uncoupling, that is, the respiratory muscle is unable to increase its output in proportion to increasing neural signals. COPD patients also have evidence of altered peripheral muscles function. The end effect of all these pathological changes is neuromuscular weakness. SUMMARY: Respiratory and peripheral muscles dysfunction is found in patients with COPD. This manifests clinically as dyspnea, poor exercise capacity, and decreased quality of life. We have clear evidence that rehabilitation helps several aspects of patients with COPD. Further understanding of the physiopathology is needed to improve our therapeutic and rehabilitation strategies. PMID- 28079616 TI - Evaluation of an Outpatient Rehabilitative Program to Address Mobility Limitations Among Older Adults. AB - Live Long Walk Strong is a clinical demonstration program for community-dwelling older patients. It was designed to be consistent with current fall prevention guidelines and reimbursed under the Medicare model. Patients were screened within primary care and referred to a physiatrist followed by systematic assessment and treatment within an outpatient rehabilitative care setting. The treatment included behavioral modification, fall prevention education, community/home exercise integration, and exercise targeting strength, power, flexibility, balance, and endurance. Treatment duration and frequency varied with each patient based on baseline presentation, clinical judgment, and patient preference. Program feasibility and preliminary effectiveness were evaluated by assessing participation and changes in physical performance, respectively. There were 266 patients referred to the program, and 147 were willing to participate. Of these, 116 patients completed all scheduled visits (10.8 +/- 3.9 visits). The noncompleters (n = 31) had a higher rate of falls in the previous 6 months and lower baseline Short Physical Performance Battery composite score. At the completion of care, the adjusted mean change in Short Physical Performance Battery was 1.66 units, surpassing a large clinically meaningful threshold (1 unit). The Live Long Walk Strong program appears to be feasible to implement and demonstrates preliminary effectiveness in enhancing mobility among older adults. PMID- 28079617 TI - Manipulation of the Endocannabinoid System in Colitis: A Comprehensive Review. AB - BACKGROUND: Inflammatory bowel disease (IBD) is a lifelong disease of the gastrointestinal tract whose annual incidence and prevalence is on the rise. Current immunosuppressive therapies available for treatment of IBD offer limited benefits and lose effectiveness, exposing a significant need for the development of novel therapies. In the clinical setting, cannabis has been shown to provide patients with IBD symptomatic relief, although the underlying mechanisms of their anti-inflammatory effects remain unclear. METHODS: This review reflects our current understanding of how targeting the endocannabinoid system, including cannabinoid receptors 1 and 2, endogenous cannabinoids anandamide and 2 arachidonoylglycerol, atypical cannabinoids, and degrading enzymes including fatty acid amide hydrolase and monoacylglycerol lipase, impacts murine colitis. In addition, the impact of cannabinoids on the human immune system is summarized. RESULTS: Cannabinoid receptors 1 and 2, endogenous cannabinoids, and atypical cannabinoids are upregulated in inflammation, and their presence and stimulation attenuate murine colitis, whereas cannabinoid receptor antagonism and cannabinoid receptor deficient models reverse these anti-inflammatory effects. In addition, inhibition of endocannabinoid degradation through monoacylglycerol lipase and fatty acid amide hydrolase blockade can also attenuate colitis development, and is closely linked to cannabinoid receptor expression. CONCLUSIONS: Although manipulation of the endocannabinoid system in murine colitis has proven to be largely beneficial in attenuating inflammation, there is a paucity of human study data. Further research is essential to clearly elucidate the specific mechanisms driving this anti-inflammatory effect for the development of therapeutics to target inflammatory disease such as IBD. PMID- 28079618 TI - Diffusion-weighted MRI Enables to Accurately Grade Inflammatory Activity in Patients of Ileocolonic Crohn's Disease: Results from an Observational Study. AB - BACKGROUND: Diffusion-weighted imaging (DWI) is a novel technique to evaluate bowel inflammation in Crohn's disease (CD). It remains unclear whether DWI could differentiate grades of inflammation activity and add to the accuracy of conventional magnetic resonance enterography (MRE) in defining disease activity. We aimed to assess the accuracy of DWI for evaluating ileocolonic CD inflammation compared with conventional MRE, using ileocolonoscopy as reference standard. METHODS: This was an observational study of CD patients who underwent both ileocolonoscopy and MRE with DWI. The conventional MRE and DWI findings of the ileocolon were scored from 0 to 3. The respective segment endoscopic disease activity was scored by simplified endoscopic score for Crohn's disease (SES-CD) and was graded as inactive (0-2), mild (3-6) or moderate-severe (>=7). RESULTS: One hundred eighty-five bowel segments from 43 consecutive CD patients were evaluated and included inactive (n = 86), mild (n = 72), and moderate-severe (n = 27) ileo-colonic segments. The area under the receiver operating characteristics curve (AUC) of 0.973 for apparent diffusion coefficient (ADC) to differentiate active from inactive CD was significantly higher than those of conventional MRE parameters (AUC between 0.840 and 0.940). Higher accuracy of ADC (AUC = 0.919) for differentiating inactive-mild from moderate-severe CD was also shown compared with that of conventional MRE parameters (AUC between 0.868 and 0.915). ADC values demonstrated strongest correlation with SES-CD (r = -0.880) comparing to DWI SI and conventional MRE parameters (r between 0.787 and 0.867). CONCLUSIONS: DWI enables to accurately grade inflammatory activity in patients of ileocolonic CD and may be better suited than conventional MRE for monitoring the activity of CD. PMID- 28079620 TI - Clostridium difficile Infection and Risk of Colectomy in Patients with Inflammatory Bowel Disease: A Bias-adjusted Meta-analysis. AB - BACKGROUND: Clostridium difficile infection (CDI) is a common complication of inflammatory bowel diseases (IBDs) and is associated with worse outcome. Variable rates of colectomy have been reported among IBD complicated by CDI. We conducted a systematic review and meta-analysis of studies to assess the association between CDI and colectomy among patients with IBD. METHODS: The literature was systematically searched using PubMed from inception through April 2016. Studies were limited to cohort, case-control, and cross-sectional studies reporting colectomy risk stratified by CDI in patients with IBD. We estimated summary ORs and 95% CIs using the quality-effects model. Study quality was assessed using an adaptation of the Newcastle-Ottawa scale. RESULTS: Six studies were included in the meta-analysis, comprising 8 data sets. Results from meta-analysis showed that CDI was a significant risk factor for colectomy among patients with IBD, mainly patients with ulcerative colitis, almost doubling the odds (OR 1.90; 95% CI, 1.23 2.93). There was significant heterogeneity across studies (Q = 22.02, P < 0.001; I = 68%). Funnel plots were grossly asymmetrical. Results of sensitivity analysis restricting studies to those reporting ulcerative colitis only and studies using laboratory tests to confirm CDI were consistent with the result from the main analysis. CONCLUSIONS: CDI is a significant risk factor for colectomy in patients with IBD. Further research is needed to investigate the attributable risks of surgery due to CDI among patients with Crohn's disease. PMID- 28079619 TI - The Importance and Challenges of Dietary Intervention Trials for Inflammatory Bowel Disease. AB - Inflammatory bowel disease is believed to be caused by a combination of genetic and environmental stimuli such as our diet. Diets high in meat and fats and low in fruits and vegetables have been associated with new-onset inflammatory bowel disease. This has triggered interest in using dietary modification as a treatment. The 3 principle models of dietary intervention are supplementation with selected dietary components, exclusion of selected dietary components, or use of dietary formulas in place of a normal diet. Despite the high level of interest in dietary interventions as a treatment for inflammatory bowel disease, few well-designed clinical trials have been conducted to firmly establish the optimal diet to induce or maintain remission. This may be in part related to the challenges of conducting dietary intervention trials. This review examines these challenges and potential approaches to be used in dietary intervention trials. PMID- 28079621 TI - Effects of Education and Information on Vaccination Behavior in Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Despite the existence of international guidelines, vaccination in patients with inflammatory bowel disease (IBD) has not been integrated optimally. We developed a thorough education program, and compared its influence on vaccination rates with routine clinical practice in a tertiary IBD center. METHODS: Between December 2014 and March 2015, we included 505 consecutive patients with IBD visiting our outpatient clinic (53% men, 72% Crohn's disease, median age 44 years). Vaccination data, including hepatitis B, influenza, pneumococcus, tetanus, and varicella zoster virus, as well as demographic data, were collected by a fellow in training or a certified gastroenterologist. Thereafter, patients were randomly assigned to group A receiving routine clinical practice or intervention group B receiving additional education by the IBD nurse with help of an information brochure and vaccination card. Vaccination status was reassessed 8 months later. RESULTS: At baseline, 32% of patients were vaccinated according to the guidelines. The remaining 346 patients were randomized to group A (n = 206) or intervention group B (n = 140). Eight months after randomization, 33% of intervention group B versus 6% of group A followed vaccination recommendations and differences were significant for each vaccine (all P < 0.001). A higher educational level was independently associated with better compliance to pneumococcal vaccination (P = 0.008) and to the guidelines overall (P < 0.001). However, the educational intervention was the only consistent factor independently associated with improved compliance to each individual vaccination recommendation (all P <= 0.023). CONCLUSIONS: Introduction of thorough vaccination education significantly increased compliance to vaccination guidelines. However, further education of patients and health care providers remains necessary. PMID- 28079622 TI - Prevalence and Determinants of Job Stress in Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Psychosocial factors have been shown to predict a poor disease course in patients with inflammatory bowel disease (IBD), but whether this applies to job stress is currently unknown. We assessed the prevalence of job stress and its correlates in a large cohort of patients with IBD. METHODS: We included all adult, professionally active patients enrolled between 2006 and 2015 in the Swiss IBD Cohort. Job stress was measured through the self-report effort-reward imbalance ratio and overcommitment (OC) to work questionnaires. We used multiple linear regressions to assess association with sociodemographic, lifestyle, psychosocial, and disease-related factors. RESULTS: Altogether 1656 patients completed the questionnaires (905 Crohn's disease and 751 ulcerative colitis/IBD unclassified). Only 91 (5.7%) of patients had an effort-reward imbalance ratio >1. Effort-reward imbalance and OC scores were higher in full-time versus part time employees (coef = 0.050, P = 0.002; coef = 0.906, P < 0.001) and among those absent from the workplace in the previous 3 months (coef = 0.049, P = 0.010; coef = 1.062, P < 0.001). Higher OC scores were associated with sex (women vs. men: coef = 0.568, P = 0.014), being in a relationship (coef = 0.805, P = 0.001), higher level of occupation (director vs. trainee: coef = 1.447, P < 0.001), and extraintestinal manifestations (coef = 0.623, P = 0.005). Patients hospitalized in the previous 12 months had lower OC scores (coef = 0.560, P = 0.038). CONCLUSIONS: The average level of job stress seems to be remarkably low in patients with IBD from Switzerland. The clinician should turn attention especially to women, full-time employees with a high level of education, and patients with extraintestinal manifestations to identify those with the most vulnerability to suffer from job stress. PMID- 28079623 TI - The Ileitis of Ulcerative Colitis. Why Is It Not Crohn's Disease? PMID- 28079624 TI - Damage of the Mucus Layer: The Possible Shared Critical Common Cause for Both Inflammatory Bowel Disease (IBD) and Irritable Bowel Syndrome (IBS). PMID- 28079625 TI - Older Age- and Health-related Quality of Life in Inflammatory Bowel Diseases. AB - BACKGROUND: The burden of inflammatory bowel disease (IBD) in the older population is increasing. Older-onset disease is associated with reduced use of immunosuppressive medications. In addition, older patients may be more vulnerable to the effect of disease-related symptoms and consequently may experience worse health-related quality of life (HRQoL) compared with younger patients. METHODS: This prospective study included a cohort of patients with Crohn's disease and ulcerative colitis recruited from a single center. All patients completed the Short Inflammatory Bowel Disease Questionnaire (SIBDQ) and the short form-12 (SF 12) questionnaire yielding general physical health (PCS) and mental health component scale subscores (MCS). Patients older than 60 years were compared with those younger than 60 years using multivariable regression analysis. RESULTS: Our study included 1607 patients, among whom 186 were older than 60 at the time of assessment. Older patients were more likely to have isolated colonic disease and less likely to use immunosuppressive therapy. On multivariable analysis, older patients with IBD had higher SIBDQ (2.34, 95% confidence interval, 0.82-3.87) and SF-12 mental subscores (3.78, 95% confidence interval, 2.26-5.30), but lower physical HRQoL (-1.80, 95% confidence interval, -3.21 to -0.38). There was no difference in the SIBDQ and PCS scores between older patients and newly diagnosed IBD or with established disease. CONCLUSIONS: Older age was associated with modestly higher SIBDQ and mental HRQoL scores, but lower physical HRQoL. Comprehensive care of the older patient with IBD should include assessment of factors impairing physical quality of life to ensure appropriate interventions. PMID- 28079626 TI - Complications and Disease Recurrence After Primary Ileocecal Resection in Pediatric Crohn's Disease: A Multicenter Cohort Analysis. AB - BACKGROUND: Studies on the outcome of ileocecal resection in pediatric Crohn's disease (CD) have a limited follow-up and fail to assign predictors of adverse outcomes. Therefore, we aimed to investigate (I) the complication and disease recurrence rates and (II) identify risk factors for these adverse outcomes after ileocecal resection for pediatric CD. METHODS: This is a retrospective cohort analysis of all children (<18 years) that underwent ileocecal resection as first intestinal resection for CD derived from 7 tertiary hospitals in the Netherlands (1990-2015). Risk factors were identified using multivariable analysis. RESULTS: In total, 122 children were included (52% male; median age 15.5 years [interquartile range 14.0-16.0]). Severe postoperative complications rate was 10%. Colonic disease (odds ratio: 5.6 [95% confidence interval {CI}: 1.3-26.3], P = 0.024), microscopically positive resection margins (odds ratio: 10.4 [95% CI: 1.1-100.8] P = 0.043), and emergency surgery (odds ratio: 6.8 [95% CI: 1.1-42.2], P = 0.038) were risk factors for severe complications. Clinical and surgical recurrence rates after 1, 5 and 10 years were 19%, 49%, 71% and 2%, 12%, 22%, respectively. Female sex (hazard ratio [HR]: 2.1 [95% CI: 1.1-3.8], P = 0.023) was a risk factor for clinical recurrence, whereas ileocecal disease (HR: 3.9 [95% CI: 1.2-12.5], P = 0.024) and microscopically positive resection margins (HR: 9.6 [95% CI: 1.2-74.5], P = 0.031) were risk factors for surgical recurrence. Immediate postoperative therapy reduced the risk of both clinical (HR: 0.3 [95% CI: 0.1-0.6], P = 0.001) and surgical (HR: 0.5 [95% CI: 0.1-0.9], P = 0.035) recurrence. CONCLUSIONS: Ileocecal resection is an effective and durable treatment of pediatric CD, although postoperative complications occur frequently. Postoperative therapy may be started immediately to prevent disease recurrence. PMID- 28079627 TI - Inactivation of Digestive Proteases and Degradation of Mucus: The Possible Key Factors That Determined the Different Effects on the Gut by Antibiotics. PMID- 28079628 TI - Interleukin-6 is increased in plasma and cerebrospinal fluid of community dwelling domestic dogs with acute ischaemic stroke. AB - Inflammatory cytokines are potential modulators of infarct progression in acute ischaemic stroke, and are therefore possible targets for future treatment strategies. Cytokine studies in animal models of surgically induced stroke may, however, be influenced by the fact that the surgical intervention itself contributes towards the cytokine response. Community-dwelling domestic dogs suffer from spontaneous ischaemic stroke, and therefore, offer the opportunity to study the cytokine response in a noninvasive set-up. The aims of this study were to investigate cytokine concentrations in plasma and cerebrospinal fluid (CSF) in dogs with acute ischaemic stroke and to search for correlations between infarct volume and cytokine concentrations. Blood and CSF were collected from dogs less than 72 h after a spontaneous ischaemic stroke. Infarct volumes were estimated on MRIs. Interleukin (IL)-2, IL-6, IL-8, IL-10 and tumour necrosis factor in the plasma, CSF and brain homogenates were measured using a canine-specific multiplex immunoassay. IL-6 was significantly increased in plasma (P=0.04) and CSF (P=0.04) in stroke dogs compared with healthy controls. The concentrations of other cytokines, such as tumour necrosis factor and IL-2, were unchanged. Plasma IL-8 levels correlated significantly with infarct volume (Spearman's r=0.8, P=0.013). The findings showed increased concentrations of IL-6 in the plasma and CSF of dogs with acute ischaemic stroke comparable to humans. We believe that dogs with spontaneous stroke offer a unique, noninvasive means of studying the inflammatory processes that accompany stroke while reducing confounds that are unavoidable in experimental models. PMID- 28079629 TI - Duration of pneumonia therapy and the role of biomarkers. AB - PURPOSE OF REVIEW: Increasing antimicrobial resistance is a worldwide phenomenon that is threatening public health. Lower respiratory infections are one of the leading causes of morbidity that contribute to antibiotic consumption and thus the emergence of multidrug-resistant microbial strains. The goal of shortening antibiotic regimens' duration in common bacterial infections has been prioritized by antimicrobial stewardship programs as an action against this problem. RECENT FINDINGS: Data coming from randomized controlled trials, meta-analyses, and systematic reviews support the shortening of antimicrobial regimens in community acquired, hospital-acquired, and ventilator-associated pneumonia. Short schedules have been proven at least as effective as long ones in terms of antimicrobial free days and clinical cure. Procalcitonin-based algorithms have been validated as well tolerated and cost-effective tools for the duration of pneumonia therapy reduction. SUMMARY: Shortening the duration of antibiotic regimens in pneumonia seems a reasonable strategy for reducing selective pressure driving antimicrobial resistance and costs provided that clinical cure is guaranteed. Procalcitonin based protocols have been proven essentially helpful in this direction. VIDEO ABSTRACT. PMID- 28079630 TI - 18F-Fluorodeoxyglucose positron emission tomography and infectious diseases: current applications and future perspectives. AB - PURPOSE OF REVIEW: 18F-Fluorodeoxyglucose positron emission tomography/computed tomography is a well-established technique for diagnosis and management of a number of neoplastic conditions. However, in recent years the body of literature regarding its potential role in infectious diseases has progressively increased, with promising results. RECENT FINDINGS: So far 18F-fluorodeoxyglucose positron emission tomography/computed tomography has a well-established role and is recommended by guidelines only in a few settings, such as prosthetic valve endocarditis, vascular device infections, and chronic osteomyelitis. However, even the lack of large, prospective randomized trials, an increasing number of small series and case reports suggest a potential role in the diagnosis, disease staging, and monitoring of treatment response of several other infective conditions. SUMMARY: In this article, we summarize the available evidence and potential future applications of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in the diagnosis and management of infectious diseases. PMID- 28079631 TI - The role of methicillin-resistant Staphylococcus aureus in skin and soft tissue infections. AB - PURPOSE OF REVIEW: Methicillin-resistant Staphylococcus aureus (MRSA) has become a major public health issue worldwide over the last years. MRSA is frequently implicated in the development of skin and soft tissue infections, leading to significant increases in morbidity, mortality and overall healthcare costs. RECENT FINDINGS: In order to face the threat of MRSA, major changes in clinical management of skin and soft tissue infections are required. The identification of populations at risk for the acquisition of infections due to MRSA, together with the improvement of the diagnostic techniques, is paramount. Moreover, a number of new antimicrobials with activity against MRSA have been recently developed and approved for the treatment of skin and soft tissue infections, however, the use of the new drugs in the wide clinical practice remains limited. SUMMARY: We reviewed the current epidemiology of MRSA in skin and soft tissue infections, with particular focus on implications for clinical management. The potential role of new antibiotic options against MRSA infections is also discussed. PMID- 28079632 TI - Interrater and Test-Retest Reliability and Minimal Detectable Change of the Balance Evaluation Systems Test (BESTest) and Subsystems With Community-Dwelling Older Adults. AB - BACKGROUND AND PURPOSE: Falls are a common cause of injuries and hospital admissions in older adults. Balance limitation is a potentially modifiable factor contributing to falls. The Balance Evaluation Systems Test (BESTest), a clinical balance measure, categorizes balance into 6 underlying subsystems. Each of the subsystems is scored individually and summed to obtain a total score. The reliability of the BESTest and its individual subsystems has been reported in patients with various neurological disorders and cancer survivors. However, the reliability and minimal detectable change (MDC) of the BESTest with community dwelling older adults have not been reported. The purposes of our study were to (1) determine the interrater and test-retest reliability of the BESTest total and subsystem scores; and (2) estimate the MDC of the BESTest and its individual subsystem scores with community-dwelling older adults. METHODS: We used a prospective cohort methodological design. Community-dwelling older adults (N = 70; aged 70-94 years; mean = 85.0 [5.5] years) were recruited from a senior independent living community. Trained testers (N = 3) administered the BESTest. All participants were tested with the BESTest by the same tester initially and then retested 7 to 14 days later. With 32 of the participants, a second tester concurrently scored the retest for interrater reliability. Testers were blinded to each other's scores. Intraclass correlation coefficients [ICC(2,1)] were used to determine the interrater and test-retest reliability. Test-retest reliability was also analyzed using method error and the associated coefficients of variation (CVME). MDC was calculated using standard error of measurement. RESULTS: Interrater reliability (N = 32) of the BESTest total score was ICC(2, 1) = 0.97 (95% confidence interval [CI], 0.94-0.99). The ICCs for the individual subsystem scores ranged from 0.85 to 0.94. Test-retest reliability (N = 70) of the BESTest total score was ICC(2,1) = 0.93 (95% CI, 0.89-0.96). ICCs for the individual subsystem scores ranged from 0.72 to 0.89. The CVME (N = 70) of the BESTest total score was 4.1%. The CVME for the subsystem scores ranged from 5.0% to 10.7%. MDC (N = 70) for the BESTest total score at the 95% CI was 7.6%, or 8.2 points. MDC at the 95% CI for subsystem scores ranged from 11.7% to 19.0% (2.1-3.4 points). DISCUSSION: Results demonstrated generally good to excellent interrater and test retest reliability in both the BESTest total and subsystem scores with community dwelling older adults. CONCLUSIONS: The BESTest total and individual subsystem scores demonstrate good to excellent interrater and test-retest reliability with community-dwelling older adults. A change of 7.6% (8.2 points) or more in the BESTest total and a percentage change ranged from 11.7% to 19.0% (2.1-3.4 points) in the subsystem scores are suggested for clinicians to be 95% confident of true change when evaluating change in this population. PMID- 28079633 TI - Criterion-Referenced Values of Grip Strength and Usual Gait Speed Using Instrumental Activities of Daily Living Disability as the Criterion. AB - BACKGROUND AND PURPOSE: Current evidence suggests that grip strength and usual gait speed (UGS) are important predictors of instrumental activities of daily living (IADL) disability. Knowing the optimum cut points of these tests for discriminating people with and without IADL disability could help clinicians or researchers to better interpret the test results and make medical decisions. The purpose of this study was to determine the cutoff values of grip strength and UGS for best discriminating community-dwelling older adults with and without IADL disability, separately for men and women, and to investigate their association with IADL disability. METHODS: We conducted secondary data analysis on a national dataset collected in the Sarcopenia and Translational Aging Research in Taiwan (START). The data used in this study consisted of health data of 2420 community dwelling older adults 65 years and older with no history of stroke and with complete data. IADL disability was defined as at least 1 IADL item scored as "need help" or "unable to perform." Receiver operating characteristics analysis was used to estimate the optimum grip strength and UGS cut points for best discriminating older adults with/without IADL disability. The association between each physical performance (grip strength and UGS) and IADL disability was assessed with odds ratios (ORs). RESULTS AND DISCUSSION: With IADL disability as the criterion, the optimal cutoff values of grip strength were 28.7 kg for men and 16.0 kg for women, and those for UGS were 0.76 m/s for men and 0.66 m/s for women. The grip strength test showed satisfactory discriminant validity (area under the curve > 0.7) in men and a strong association with IADL disability (OR > 4). Our cut points using IADL disability as the criterion were close to those indicating frailty or sarcopenia. CONCLUSIONS: Our reported cutoffs can serve as criterion-referenced values, along with those previously determined using different indicators, and provide important landmarks on the performance continua of older adults' grip strength and UGS. These landmarks could be useful in interpreting test results, monitoring changes in performance, and identifying individuals requiring timely intervention. For identifying older adults at risk of IADL disability, grip strength is superior to UGS. PMID- 28079634 TI - Characteristics of Patients With Satisfactory Functional Gain Following Total Joint Arthroplasty in a Postacute Rehabilitation Setting. AB - BACKGROUND AND PURPOSE: Total joint arthroplasty (TJA) is an effective and successful treatment of osteoarthritis of the hip and knee as quantified by several measures, such as pain relief, improved walking, improved self-care, functions, and increased quality of life. Data are lacking as to the definition of a satisfactory functional gain in a postacute setting and identifying the characteristics of older patients with TJA who may achieve that gain. Our aim was to characterize patients who may achieve a satisfactory functional gain in a postacute rehabilitation setting following TJA. METHODS: This was a retrospective study of 180 patients with TJA admitted during 2010-2013. The main outcome measures were the Functional Independence Measure (FIM), the Montebello Rehabilitation Factor Score (MRFS) on the motor FIM, and the Timed Get Up and Go Test. Satisfactory functional gain was defined as an mFIM MRFS score above median score. Comparisons of clinical and demographic characteristics between patients who achieved a satisfactory functional gain versus those who did not were performed by the Mann-Whitney U test and the chi test. RESULTS: The proportion of patients who achieved a satisfactory functional gain was similar in the total knee arthroplasty and total hip arthroplasty (THA) groups. The most significant characteristic of patients who achieved a satisfactory functional gain was their admission functional ability. Age negatively impacted the ability to achieve a satisfactory functional gain in patients with THA. CONCLUSION: Functional level on admission is the best predictive factor for a better rehabilitation outcome for patients with TJA. Age negatively affects functional gain in patients with THA. PMID- 28079635 TI - Influences of Age, Obesity, and Adverse Drug Effects on Balance and Mobility Testing Scores in Ambulatory Older Adults. AB - BACKGROUND AND PURPOSE: The adverse effects of drugs may influence results on tests of mobility and balance, but the drug-specific impact is not identified when using these tests. We propose that a quantitative drug index (QDI) will assist in assessing fall risk based on these tests, when combined with other fall risk variables. METHODS: Fifty-seven community-dwelling older adults who could walk independently on a treadmill and had Mini-Mental State Examination (MMSE) scores equal to or greater than 24 participated. Mobility and balance outcome measures included the Balance Evaluation Systems Test (BESTest), Berg Balance Scale (BBS), Timed Up and Go (TUG) and cognitive dual task TUG (TUGc). Fall history, current drug list, and Activity-Specific Balance Confidence (ABC) scale scores were also collected. Body mass index (BMI) was calculated. The QDI was derived from the drug list for each individual, and based on fall-related drug adverse effects. Multiple linear regression analyses were conducted using age, BMI, and QDI as predictor variables for determining mobility and balance test scores, and ABC scale scores. Subsequently, participants were divided into (QDI = 0) low-impact drug group (LIDG) and (QDI > 0) high-impact drug group (HIDG) for Mann-Whitney 2-group comparisons. RESULTS: Age, BMI, and QDI were all significant (P < .001) independent variables in multiple regression analyses for mobility and balance test scores, but not for the ABC scale. Separately, the 2 group comparisons for the BESTest, BBS, TUG, and TUGc demonstrated that HIDG scored significantly (P < .05) worse on these tests compared with the LIDG. Drug counts were also significantly higher for the HIDG than for the LIDG. In contrast, age, BMI, MMSE, and reported falls in the last 12 months were not significantly different between groups. CONCLUSION: Age, BMI, and QDI-all contributed independently to the mobility and balance test scores examined, and may provide health care professionals a screening tool to determine whether additional mobility and balance testing is required. In addition, the QDI is a more precise marker of adverse effects of drugs compared with drug counts, as the latter does not quantitate the influence of drugs on physiologic function. PMID- 28079636 TI - Reconstruction of a Postoperative Mohs Defect of the Upper Cutaneous and Vermilion Lip Involving Cupid's Bow. PMID- 28079637 TI - LN2, CD10, and Ezrin Do Not Distinguish Between Atypical Fibroxanthoma and Undifferentiated Pleomorphic Sarcoma or Predict Clinical Outcome. AB - BACKGROUND: Atypical fibroxanthoma (AFX) is a rare cutaneous spindled cell neoplasm. For both diagnostic and therapeutic purposes, it is important to distinguish AFX from other poorly differentiated tumors, including undifferentiated pleomorphic sarcoma (UPS). OBJECTIVE: The authors aimed to identify the clinical, histologic, and immunohistochemical expression of LN2, ezrin, and CD10 in AFX and UPS tumors. METHODS AND MATERIALS: The authors retrospectively examined the charts of patients with AFX and UPS treated with Mohs micrographic surgery (MMS) at 2 academic institutions. Patient demographics, tumor characteristics, and clinical course data were collected. Immunohistochemical stains were performed on primary and recurrent AFX and UPS tumors with monoclonal antibodies against the B-cell marker LN2 (CD74), CD10, and ezrin. RESULTS: In the series of 169 patients with AFX included in this study, local recurrence was rare at 3%. In contrast, the seven patients with UPS had an aggressive clinical course with 1 local recurrence and 2 distant metastases. Immunohistochemistry staining for ezrin, LN2, and CD10 were similar in AFX and UPS tumors. CONCLUSION: AFX can be treated with MMS with rare instances of recurrence. Undifferentiated pleomorphic sarcoma has a more aggressive clinical course with increased risk for recurrence and metastasis. Staining with ezrin, LN2, and CD10 did not differentiate AFX or UPS tumors. PMID- 28079638 TI - The Effect of Waxing Versus Shaving on the Efficacy of Laser Hair Removal. AB - BACKGROUND: Excessive hair is undesirable and represents both a social and emotional burden, especially among females. Laser hair removal (LHR) has gained popularity in the past 2 decades. It is a common practice to instruct patients not to pluck or wax their hair before undergoing LHR; only shaving is allowed to improve the efficacy of the LHR. OBJECTIVE: To compare the percentage of hair reduction in preshaved versus prewax epilated axillae after LHR in healthy adult Saudi females. METHODS AND MATERIALS: This study is a quantitative experimental pilot clinical trial. Twenty female volunteers were enrolled into this study; all underwent 3 laser sessions using a long-pulsed alexandrite laser. Their left axilla was prewaxed and right axilla was preshaved immediately before laser treatment. Hair was counted manually before and 6 months after the third laser session. RESULTS: The right and left axillae both showed significant hair reduction, between the first session and the hair count 6 months after the third laser session. However, there was no statistically significant difference between these 2 means (p = .44). CONCLUSION: There is no statistical difference in hair reduction after LHR whether the area is preshaved or prewax epilated. PMID- 28079639 TI - Batten Stitch: A Tissue-Sparing Technique for Correction of an Inverted Dog-Ear. PMID- 28079640 TI - Comparison of the American Joint Committee on Cancer Seventh Edition and Brigham and Women's Hospital Cutaneous Squamous Cell Carcinoma Tumor Staging in Immunosuppressed Patients. AB - BACKGROUND: The American Joint Committee on Cancer 7th edition (AJCC-7) and Brigham and Women's Hospital (BWH) staging criteria for cutaneous squamous cell carcinoma (cSCC) have not been validated in immunosuppressed patients. OBJECTIVE: To compare the AJCC-7 and BWH staging systems for cSCCs in immunosuppressed patients. MATERIALS AND METHODS: A single-institution retrospective cohort study of cSCCs in immunosuppressed patients. Risks of local recurrence (LR), nodal metastasis (NM), in-transit metastasis, and any poor outcome (PO) were compared among AJCC-7 and BWH tumor T stages. RESULTS: One hundred six patients had 412 primary invasive cSCCs. Eighty-five percent were AJCC-7 T1, and 15% T2. Risks of NM and PO for AJCC-7 T1 versus T2 were 0.9% versus 5% and 12.8% versus 23.3%, respectively, p < .05. Eighty-one percent of tumors were BWH T1, 18% T2a, 1% T2b, and 0.2% T3. Risk of LR for BWH T1 versus T2a was 11.4% versus 20.3%, p < .01. Risk of NM increased from 0.3% for T1 to 4.1%, 25%, and 100% for T2a, T2b, and T3, p < .05. Ninety percent of PO occurred in low-stage BWH T1/T2a. CONCLUSION: Low T-stage cSCCs account for most POs. Brigham and Women's Hospital staging criteria better risk stratifies cSCCs in immunosuppressed patients for risk of NM and LR. PMID- 28079641 TI - World Health Organization Framework: Multimodal Hand Hygiene Strategy in Piedmont (Italy) Health Care Facilities. AB - OBJECTIVES: In 2009, the World Health Organization (WHO) introduced the "Hand Hygiene Self-Assessment Framework" (HHSAF) to evaluate the level of the application of the Multimodal Hand Hygiene Improvement Strategy (MHHIS), which defines preventive interventions, standards, and tools conceived to improve hand hygiene in healthcare facilities. The aim of our study was to evaluate the implementation of the MHHIS in Piedmont healthcare units in 2014 using the HHSAF document. METHODS: Our surveillance was performed through collection and analysis of the data from 50 Piedmont healthcare facilities recorded through the HHSAF in 2014. The HHSAF describes the hand hygiene level evaluating the following 5 parameters: system changes, education/staff training, evaluation and feedback, reminders in the workplace, and promotion of an institutional safety climate. RESULTS: We reported that 70.4% of the healthcare facilities involved in the study achieved the intermediate hand hygiene level, 19% the advanced level, and 11% the basic level. No facility exhibited an inadequate level of WHO multimodal implementation. Only 55% of the healthcare units provided information about hand hygiene to patients, and only 15% actively involved patients and their families. CONCLUSIONS: The implementation of the MHHIS has achieved important results all over the world in terms of hand hygiene. Piedmont has reached an overall good level, particularly in terms of the supply and availability of hand washing products and staff education. Our results revealed, however, some critical issues related to direct and indirect monitoring of hand hygiene, providing reminders and the active involvement of patients, family members, and caregivers.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 28079642 TI - An Evaluation of a Competency-Based Public Health Training Program for Public Health Professionals in Kansas. AB - CONTEXT: Less than one-third of the US public health workforce has formal training in public health. Academic-public health agency partnerships aimed at addressing the nation's workforce challenges have shown great promise. OBJECTIVE: To evaluate the effectiveness of a piloted competency-based public health training program formed out of an academic-public health agency partnership. DESIGN: Mixed-methods design using pre- and postworkshop surveys and quizzes, open-ended questions, and document review. SETTING: Large, urban local health department located in south central Kansas. MAIN OUTCOME MEASURES: Participant satisfaction with training, knowledge change, self-report application of new knowledge, and organizational change. RESULTS: Participants reported high satisfaction with the training program and valued the hands-on, practical approach used. Participation increased knowledge and confidence in public health competency areas covered in the program. At 3-month follow-up, 90% of participants reported applying new knowledge and skills in their primary job duties. At the organizational level, 3 major policy changes aimed at sustaining the program were implemented following its launch. CONCLUSION: Incorporating tailored, theory-driven approaches to trainings and collaborating with health department leadership to identify policy opportunities that help sustain the training program within the agency is recommended. Findings from this evaluation demonstrate the success of an academic-agency partnership's effort to develop and implement at a large, urban local health department. PMID- 28079644 TI - Functional Characteristics of Health Coalitions in Local Public Health Systems: Exploring the Function of County Health Councils in Tennessee. AB - CONTEXT: Partnerships are emerging as critically important vehicles for addressing health in local communities. Coalitions involving local health departments can be viewed as the embodiment of a local public health system. Although it is known that these networks are heavily involved in assessment and community planning activities, limited studies have evaluated whether health coalitions are functioning at an optimal capacity. OBJECTIVE: This study assesses the extent to which health coalitions met or exceeded expectations for building functional capacity within their respective networks. DESIGN: An evaluative framework was developed focusing on 8 functional characteristics of coalitions previously identified by Erwin and Mills. Twenty-nine indicators were identified that served as "proxy" measures of functional capacity within health coalitions. SETTING AND PARTICIPANTS: Ninety-three County Health Councils (CoHCs) in Tennessee. MAIN OUTCOME MEASURE(S): Diverse member representation; formal rules, roles, and procedures; open, frequent interpersonal communication; task-focused climate; council leadership; resources; active member participation; and external linkages were assessed to determine the level of functionality of CoHCs. Scores across all CoHCs were analyzed using descriptive statistics such as frequency distributions, measures of central tendency, and measures of variability. Data were analyzed using SAS 9.3. RESULTS: Of 68 CoHCs (73% response rate), the total mean score for the level of functional characteristics was 30.5 (median = 30.5; SD = 6.3; range, 18-44). Of the 8 functional characteristics, CoHCs met or exceeded all indicators associated with council leadership, tasked-focused climate, and external linkages. Lowest scores were for having a written communications plan, written priorities or goals, and opportunities for training. CONCLUSION: This study advances the research on health coalitions by establishing a process for quantifying the functionality of health coalitions. Future studies will be conducted to examine the association between health coalition functional capacity, local health departments' community health assessment and planning efforts, and changes in community health status. PMID- 28079643 TI - Validation of Retention in HIV Care Status Using the New York City HIV Surveillance Registry and Clinical Care Data From a Large HIV Care Center. AB - CONTEXT: Improving retention in care is a key element of the National HIV/AIDS Strategy (NHAS). However, definitions for measuring retention in care are not standardized. OBJECTIVE: To compare measures of retention based on both clinic visit data and HIV laboratory surveillance data. DESIGN: Retrospective cohort study. SETTING: New York City (NYC), New York. PARTICIPANTS: We matched adult patients with HIV infection seen at the Spencer Cox Center for Health (SCC) in 2010 or 2011 with the NYC HIV Surveillance Registry. MAIN OUTCOME MEASURES: Retention in care was measured on the basis of SCC electronic medical record (EMR) data (>=1 medical visits in 2012) and Surveillance Registry data (>=2 CD4/viral load [VL] tests >=90 days apart in 2012). RESULTS: There were 5746 adult HIV-infected patients seen at SCC between 2010 and 2011 who matched with the Surveillance Registry. Seventy-eight percent (n = 4469) had 1 or more medical visits at SCC in 2012 and were considered retained on the basis of the EMR definition, among which 3831 (86%) met the surveillance definition for retention in care. Patients who did not have a medical visit at SCC in 2012 (n = 1277) were lost to care in NYC (n = 485; 36%), engaged in care at an alternate provider (n = 622; 49%), or died after their last SCC visit (n = 197; 15%). IMPLICATIONS: This study is an important comparison of laboratory surveillance versus clinic visit based measures of retention in care in an urban setting with the largest HIV epidemic in the country. Collaborative projects between local health departments and clinical care providers can help validate the care status of patients and inform the allocation of resources to reengage patients who are lost to care. CONCLUSION: The combined use of laboratory and clinic visit-based data to measure retention in care provides a more accurate representation of the care status of HIV-infected patients than use of a single data source alone. Routine sharing of data by public health institutions and clinical care providers would help target resources toward reengaging patients who are lost to care in jurisdictions with universal HIV-related laboratory reporting. PMID- 28079645 TI - The Role of Patient Navigators in Building a Medical Home for Multiply Diagnosed HIV-Positive Homeless Populations. AB - CONTEXT: People living with human immunodeficiency virus (HIV) (PLWH) who are most at risk for falling out of HIV primary care and detectable viral loads include homeless and unstably housed individuals and those codiagnosed with behavioral health disorders. The patient-centered medical home (PCMH) is a model that promotes provision of comprehensive, patient-centered, accessible, coordinated, and quality care for patients. This initiative provided patient navigation to HIV-positive homeless and unstably housed individuals codiagnosed with a mental health or substance use disorder as a means to create an adapted PCMH to meet the specific needs of this population. OBJECTIVE: The purpose of this analysis was to characterize the roles and responsibilities of patient navigators as part of an effort to create a medical home for homeless and unstably housed PLWH with behavioral health comorbidities. DESIGN: Eighty-one in depth interviews with clinic staff and 2 focus groups with patient navigators were conducted. Content analysis was performed to identify key roles and responsibilities of the patient navigators. RESULTS: Patient navigators played an important role in creating a PCMH by working with clients to schedule and complete appointments, develop comprehensive care plans, forging critical relationships with providers both within and outside of health care systems, providing holistic support to increase patient self-management, and assisting in achieving housing stability. CONCLUSIONS: It may be necessary to adapt the traditional PCMH model to effectively meet the social, behavior health, and medical needs of homeless and unstably housed PLWH with behavioral health comorbidities. A patient navigator who can invest time in supporting and connecting these patients to needed services may be a key component in creating an effective PCMH for this population. These findings highlight the roles and tasks of patient navigators that may contribute to developing a PCMH specific to homeless and unstably housed PLWH with mental health and substance use comorbidities. Implementation of such a model has the potential to improve health outcomes (such as retention in care and viral suppression) for particularly vulnerable PLWH and thereby reduce the burden of HIV infection. PMID- 28079646 TI - Public Health Agency Accreditation Among Rural Local Health Departments: Influencers and Barriers. AB - OBJECTIVE: Health department accreditation is a crucial strategy for strengthening public health infrastructure. The purpose of this study was to investigate local health department (LHD) characteristics that are associated with accreditation-seeking behavior. This study sought to ascertain the effects of rurality on the likelihood of seeking accreditation through the Public Health Accreditation Board (PHAB). DESIGN: Cross-sectional study using secondary data from the 2013 National Association of County & City Health Officials (NACCHO) National Profile of Local Health Departments Study (Profile Study). SETTING: United States. PARTICIPANTS: LHDs (n = 490) that responded to the 2013 NACCHO Profile Survey. MAIN OUTCOME MEASURES: LHDs decision to seek PHAB accreditation. RESULTS: Significantly more accreditation-seeking LHDs were located in urban areas (87.0%) than in micropolition (8.9%) or rural areas (4.1%) (P < .001). LHDs residing in urban communities were 16.6 times (95% confidence interval [CI], 5.3 52.3) and micropolitan LHDs were 3.4 times (95% CI, 1.1-11.3) more likely to seek PHAB accreditation than rural LHDs (RLHDs). LHDs that had completed an agency wide strategic plan were 8.5 times (95% CI, 4.0-17.9), LHDs with a local board of health were 3.3 times (95% CI, 1.5-7.0), and LHDs governed by their state health department were 12.9 times (95% CI, 3.3-50.0) more likely to seek accreditation. The most commonly cited barrier was time and effort required for accreditation application exceeded benefits (73.5%). CONCLUSION: The strongest predictor for seeking PHAB accreditation was serving an urban jurisdiction. Micropolitan LHDs were more likely to seek accreditation than smaller RLHDs, which are typically understaffed and underfunded. Major barriers identified by the RLHDs included fees being too high and the time and effort needed for accreditation exceeded their perceived benefits. RLHDs will need additional financial and technical support to achieve accreditation. Even with additional funds, clear messaging of the benefits of accreditation tailored to RLHDs will be needed. PMID- 28079647 TI - Using Public Health Data for Soil Pb Hazard Management in Ohio. AB - OBJECTIVES: To evaluate how frequently elevated soil lead (Pb) hazards (>=400 ppm Pb) were identified in existing blood Pb site investigations in Ohio. DESIGN: This study evaluated 3050 site investigations from the Ohio Department of Health for children with blood Pb levels at or above 10 MUg dL that contained bare soil Pb data. SETTING: Data were collected from existing databases maintained by the Ohio Department of Health. PARTICIPANTS: All data were de-identified prior to analysis. The data used included blood Pb level test results for children (18 years or younger) in Ohio, with most data coming from children younger than 6 years. MAIN OUTCOME MEASURES: The main outcome measures were blood Pb levels and identified Pb concentrations in environmental media, including soil, paint, and dust. METHODS: Data were organized and summarized according to county. Summary statistics were generated on the basis of type of environmental media and county. RESULTS: Soil samples were collected in approximately 5% of all blood Pb cases in Ohio between 1999 and 2015. Median bare soil Pb was 1030 mg Pb kg (range, 0-345 021 mg Pb kg soil). Fifty-six of Ohio's 88 counties had at least 1 soil sample above 10 000 ppm (mg Pb kg). Multiple Pb hazards were identified, including bare soil (74% frequency), deteriorated exterior Pb paint (74%), deteriorated interior Pb paint (72%), and settled Pb dust (72%). Bare soil collected from identified dripline areas contained 2638 ppm Pb above soils collected from bare soil play areas (P = .02). Ninety assessments (3%) contained a bare soil hazard, with no other identified hazards. No trend was found comparing county mean or median Pb with county population. Previously identified high-risk counties for elevated blood Pb levels did not have an elevated prevalence of bare soil Pb hazards compared with other counties (P = .64). CONCLUSIONS: Site investigators should anticipate finding and managing elevated bare soil Pb in locations throughout Ohio. When communicating with the public about bare soil Pb hazards, practitioners and policy makers should emphasize the importance of addressing all potential Pb exposure sources. Findings demonstrate the importance of the individual home environment for exposure, as previously identified high-risk counties for elevated blood Pb levels were not different from other counties. PMID- 28079648 TI - Acute Response of the Infraspinatus and Biceps Tendons to Pitching in Youth Baseball. AB - PURPOSE: Youth baseball frequently results in repetitive strain injuries. Quantitative ultrasound allows real-time imaging with the ability to identify acute markers of tendon change. The study objective was to determine acute quantitative ultrasound changes in the long head of the biceps and infraspinatus tendons of the throwing and nonthrowing shoulders during a pitching performance. We hypothesized the tendons of the pitching arm would exhibit an increased width and decreased echogenicity after pitching and that tendons of the nonpitching arm would not demonstrate such changes. METHODS: Fifty youth baseball players, ages 9 14 yr, engaged in a simulated pitching performance that consisted of 50 pitches. Subjects underwent serial quantitative ultrasound imaging of the infraspinatus and the long head of the biceps before pitching and after 25 and 50 pitches were thrown. RESULTS: Testing of the change in tendon width revealed the infraspinatus (0.21 mm) and long head of the biceps tendons (0.18 mm) in the throwing shoulder had statistically significant increases (P = 0.03) in tendon width as an acute response to throwing 50 pitches, without such changes in the nonthrowing shoulder (P > 0.05). No tendon width change was found at 25 pitches in either arm or tendon (P > 0.05). No associated changes in echogenicity were found at any time point (P > 0.05). CONCLUSION: The results of this study suggest that pitching acutely increases tendon width in two biomechanically important tendons of the shoulder as early as the 50 pitch mark. This change could be a normal physiological response or a potential warning sign of future pathology and requires further study. PMID- 28079649 TI - Factors Affecting the Ability of People With Diabetes to Avoid Hypoglycemia. AB - BACKGROUND: Hypoglycemia is recognized as a limiting factor in diabetes management. Fear of experiencing hypoglycemia may lead to lower quality of life, impaired glycemic control, and emotional distress, all of which impair the ability of patients to self-manage their diabetes effectively. Problem solving is central to diabetes self-management and may help patients achieve effective self care of their disease. PURPOSE: The aim of this study was to investigate the ability of people with diabetes to avoid hypoglycemia and to explore associated factors. METHODS: A cross-sectional, descriptive design was used for the study. Data were collected using a demographic and disease characteristics datasheet, the Hypoglycemic Problem Solving Scale, and the Disease-Associated Negative Mood Scale. RESULTS: Three hundred thirteen participants were recruited, with a mean age of 55.49 years. The average item score for the questions on hypoglycemic problem-solving ability was 2.43 (SD = 0.75). In comparing Hypoglycemic Problem Solving Scale subscales, participants scored highest on the problem orientation subscales and lowest on the problem-solving skills subscales. Multiple regression analysis revealed that being younger and unmarried and having a higher level of education, a diagnosis of Type 1 diabetes, and a lower negative mood score were each significantly associated with greater problem-solving ability as regards hypoglycemic events. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: We suggest that patients with diabetes, especially those who are older or with lower levels of education, receive disease-related psychological interventions and that healthcare professionals teach problem-solving abilities in conjunction with hypoglycemia management. PMID- 28079650 TI - PNEUMATIC DISPLACEMENT OF LIMITED TRAUMATIC SUBMACULAR HEMORRHAGE WITHOUT TISSUE PLASMINOGEN ACTIVATOR: A CASE SERIES. AB - PURPOSE: To evaluate the efficacy of intravitreal gas (perfluoropropane, C3F8) assisted displacement of submacular hemorrhage (SMH) secondary to recent or old blunt trauma. METHODS: An interventional case series of three patients who presented with SMH after blunt trauma, ranging from 2 days to 2 weeks back. All three patients were treated with an intravitreal injection of 0.3 cc of 100% C3F8 with anterior chamber paracentesis. Strict prone position was advised for 2 weeks with a minimum of 6 to 8 hours per day. Documentation was done with serial recording of corrected distance visual acuity, fundus photographs, and spectral domain optical coherence tomography both before and after intervention. RESULTS: The follow-up period ranged from 2 weeks to 3 months. All patients showed a significant displacement of SMH with recovery of the normal foveal contour; foveal thinning was noted in 2 cases. Best spectacle-corrected visual acuity improved from counting finger at 1 m to 20/30 in Case 1 and counting finger 3 m to 20/40 in Case 2. In Case 3, the visual acuity remained unchanged from the preoperative 20/60 which could be attributed to the presence of a choroidal rupture in the foveal area that became evident after the displacement of SMH. CONCLUSION: Pneumatic displacement is an effective technique in the management of SMH due to recent or old blunt trauma. PMID- 28079651 TI - BRANCH RETINAL VEIN OCCLUSION SECONDARY TO A RETINAL ARTERIOLAR MACROANEURYSM: A NOVEL MECHANISM SUPPORTED BY MULTIMODAL IMAGING. AB - BACKGROUND/PURPOSE: To report a case of a branch retinal vein occlusion secondary to a retinal arteriolar macroaneurysm (RAM). METHODS: Retrospective case report describing examination findings, treatment outcome and unique multimodal imaging features demonstrated on fluorescein angiography, optical coherence tomography, optical coherence tomography angiography and adaptive optics photography of the retinal vessels and RAM. RESULTS: A 61-year-old man presented with 20/200 vision in the right eye because of a branch retinal vein occlusion secondary to a RAM. After sector panretinal photocoagulation and a course of 24 intravitreal antivascular endothelial growth factor injections over 4 years, visual acuity improved to 20/25. Fluorescein angiography showed filling of the RAM even after 4 years. Optical coherence tomography angiography demonstrated venous collateral vessels in both the superficial and deep capillary plexuses, and adaptive optics imaging revealed a gap between the RAM wall and occluded vein. CONCLUSION: Multimodal imaging of this unusual presentation illustrated a novel mechanism of branch retinal vein occlusion in which a primary RAM adjacent to the junction of two retinal veins led to obstruction of venous flow without evidence of direct compression. This supports the theory that perianeurysmal microenvironment changes may be of importance in the pathogenesis of venous occlusion. PMID- 28079652 TI - Long-Term Survival and Causes of Late Death in Children Treated With Extracorporeal Membrane Oxygenation. AB - OBJECTIVE: Extracorporeal membrane oxygenation has been used in patients with severe circulatory or respiratory failure since the 1970s, but the knowledge on long-term survival in this group is scarce. The aim of the present study was to investigate the 10-year survival rates and causes of late death in children treated with extracorporeal membrane oxygenation. DESIGN: Single-center, retrospective cohort study. SETTING: Tertiary referral center for extracorporeal life support. PATIENTS: Neonatal and pediatric patients treated with extracorporeal membrane oxygenation from 1987 to December 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Survival status was obtained from the national Causes of Death registry. Patient background data along with data on survival and causes of death were collected. Survival rates were calculated using the Kaplan-Meier method. Of 400 subjects, 76% survived to discharge. The median follow-up time in survivors was 7.2 years. There was a high mortality rate within the first months after discharge. In the group of patients who survived the first 90 days after treatment, the 10-year survival rates were 93% in neonates and 89% in pediatric patients and were particularly beneficial in patients whose indication for extracorporeal membrane oxygenation was meconium aspiration syndrome, trauma, or infectious diseases. Late deaths were seen in some diagnostic groups, but the Kaplan-Meier curves plateaued over time. CONCLUSIONS: Children who survive the first months after treatment with extracorporeal membrane oxygenation have a high long-term survival rate. The prognosis is especially favorable in patients with reversible conditions. PMID- 28079653 TI - Comparison of Impact of Monocular and Integrated Binocular Visual Fields on Vision-related Quality of Life. AB - PURPOSE OF THE STUDY: The purpose of the study was to investigate the relationship between vision-related quality of life (VRQOL) and mean deviation (MD) of the monocular visual field and integrated binocular visual field (IBVF). METHODS: One hundred eighty VFs (90 pairs) obtained from 90 patients with normal tension glaucoma were included. VRQOL was evaluated using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25). IBVF was calculated using maximal sensitivity and binocular summation and IBVF MD was calculated. Multiple linear regression analysis was used to assess the impact of IBVF deficit on VRQOL after adjusting for confounding factors. These results were compared to those of monocular visual field. RESULTS: Mean subject age was 59.4 years. The average MD of maximal sensitivity was significantly higher than that of binocular summation, the better eye, and the worse eye (-3.27, -3.78, -3.96, and -8.66 dB, respectively, P<0.001). Rasch-analyzed NEI VFQ-25 subscales and composite scores were significantly correlated with IBVF deficit. The impact that IBVF had on VRQOL was similar to that of the better eye (R of 0.431, 0.422, and 0.422 for MD of the better eye, binocular summation, and maximal sensitivity, respectively). In contrast, the worse eye showed the least correlation with VRQOL (0.363). CONCLUSIONS: The impact of IBVF on VRQOL was similar to that of the better eye irrespective of integration method. Therefore, better eye MD could be a good indicator for VRQOL. PMID- 28079654 TI - Retinal Oximetry in Subjects With Glaucomatous Hemifield Asymmetry. AB - PURPOSE: Although some studies suggest a strong link between retinal vessel oxygenation and damage to the retinal nerve fiber layer (RNFL) seen in glaucoma, it has yet to be conclusively proven. This study compares intraocular retinal oximetry in glaucomatous eyes displaying asymmetrically affected hemifields across different subgroups of glaucoma, namely primary angle closure glaucoma (PACG), primary open-angle glaucoma (POAG), and normal tension glaucoma (NTG). METHODS: In this prospective cross-sectional study, 99 patients (PACG, n=28; POAG, n=37; NTG, n=34) underwent retinal oxygenation and vessel caliber measurements using the Oxymap T1 Retinal Oximeter, Cirrus optical coherence tomography, and Humphrey visual field testing. For the comparison between different subtypes of glaucoma, an analysis of variance with Bonferroni method was performed. Intraeye differences were compared with a paired t test. Determination of the more affected and less affected hemifield was made using the Humphrey visual field pattern deviation plot. RESULTS: Considering the mean deviation and Advanced Glaucoma Interventional Study score, the visual field defects were milder in NTG as compared with POAG and PACG (P<0.05).Arteriole diameter was smaller in the more affected hemifield compared with the less affected hemifield in patients with PACG (109.30+/-18.07 vs. 120.57+/-17.92; P=0.023) and NTG (109.36+/-13.79 vs. 117.46+/-17.72; P=0.04). The more affected hemifield had a significantly thinner RNFL than the less affected hemifield in patients across all 3 groups, though this was only significant in PACG (P=0.02) and NTG patients (P<0.01). In all 3 groups, although the less affected hemifield tended to have a marginally higher arteriole and venule oxygen saturation than the more affected hemifield, no statistical significance was reached. There were no significant differences in arteriovenous difference between the more and less affected hemifield in all 3 groups. CONCLUSIONS: In our study, localized visual field losses were not associated with changes in retinal oximetry but were associated with narrower retinal arteriolar diameters in PACG and NTG. The RNFL was thinner in the more affected hemifield in these 2 groups but this was not so marked in the POAG sample, possibly limiting our ability to find a difference in arteriolar diameter there. PMID- 28079655 TI - Microarchitecture of Schlemm Canal Before and After Selective Laser Trabeculoplasty in Enhanced Depth Imaging Optical Coherence Tomography. AB - PURPOSE: To characterize the in vivo effect of selective laser trabeculoplasty (SLT) on the Schlemm canal (SC) in eyes with primary open-angle glaucoma (POAG). MATERIALS AND METHODS: Eighty-one serial horizontal enhanced depth imaging optical coherence tomograph B-scans (interval between B-scans, ~35 MUm) of the nasal corneoscleral limbus were obtained before and 4 weeks after SLT. Fifty B scans in the overlapping regions before and after SLT were selected for analysis based on the structures of aqueous and blood vessels as landmarks. The SC cross sectional area (CSA) was measured in each selected B-scan and averaged to generate the mean SC CSA of the eye. SC volume in the overlapping region was calculated using commercially available 3-dimensional reconstruction software. The mean SC CSA and SC volume were compared between pre-SLT and post-SLT B-scans. Correlation analysis was performed between SC CSA changes and intraocular pressure (IOP) changes. RESULTS: Thirteen POAG eyes (13 patients) were included for analysis (mean age, 68.2+/-9.2 y). After SLT, the mean IOP was reduced from 19.8+/-7.6 to 14.4+/-3.8 mm Hg (P=0.003); the mean SC CSA increased by 8%, from 2478+/-550 to 2682+/-598 MUm (P=0.029); and the mean SC volume increased from 4,304,592+/-954,777 to 4,658,250+/-1,039,956 MUm (P=0.029). Increase in SC CSA had a significant positive correlation with IOP reduction after SLT (P=0.023, R=0.622). CONCLUSIONS: SLT expands SC in POAG patients and even more so with greater IOP reduction after SLT. Post-SLT expansion of SC may be due to increased trabecular aqueous outflow, IOP decrease, or structural changes in trabecular meshwork resulting from SLT. PMID- 28079656 TI - Endoscopic Cyclophotocoagulation for the Treatment of Glaucoma in Boston Keratoprosthesis Type II Patient. AB - We describe the surgical technique of endoscopic cyclophotocoagulation in a Boston keratoprosthesis type II patient. This patient with ocular cicatricial pemphigoid had pars plana endoscopic cyclophotocoagula through wounds created in the eyelids. PMID- 28079658 TI - Normal-Tension Glaucoma and Low Cerebrospinal Fluid Pressure. PMID- 28079657 TI - Diagnostic Capability of Peripapillary Retinal Volume Measurements in Glaucoma. AB - PURPOSE: To determine the diagnostic capability of spectral domain optical coherence tomography peripapillary retinal volume (RV) measurements. MATERIALS AND METHODS: A total of 156 patients, 89 primary open-angle glaucoma and 67 normal subjects, were recruited. Spectral domain optical coherence tomography peripapillary RV was calculated for 4 quadrants using 3 annuli of varying scan circle diameters: outer circumpapillary annuli of circular grids 1, 2, and 3 (OCA1, OCA2, OCA3). Area under the receiver operating characteristic curves and pairwise comparisons of receiver operating characteristic (ROC) curves were performed to determine which quadrants were best for diagnosing primary open angle glaucoma. The pairwise comparisons of the best ROC curves for RV and retinal nerve fiber layer (RNFL) were performed. The artifact rates were analyzed. RESULTS: Pairwise comparisons showed that the smaller annuli OCA1 and OCA2 had better diagnostic performance than the largest annulus OCA3 (P<0.05 for all quadrants). OCA1 and OCA2 had similar diagnostic performance, except for the inferior quadrant which was better for OCA1 (P=0.0033). The pairwise comparisons of the best ROC curves for RV and RNFL were not statistically significant. RV measurements had lower rates of artifacts at 7.4% while RNFL measurements had higher rates at 42.9%. CONCLUSIONS: Peripapillary RV measurements have excellent ability for diagnosing not only glaucoma patients but also a subset of early glaucoma patients. The inferior quadrant of peripapillary annulus OCA1 demonstrated the best diagnostic capability for both glaucoma and early glaucoma. The diagnostic ability of RV is comparable with that of RNFL parameters in glaucoma but with lower artifact rates. PMID- 28079659 TI - Suspected Malignant Hyperthermia in the Setting of Hypothermic Circulatory Arrest for Type A Aortic Dissection Repair: A Case Report. AB - Malignant Hyperthermia (MH) is a life-threatening biochemical process of hypermetabolism brought about in susceptible individuals by a triggering drug or event. Type A aortic dissections are surgical emergencies requiring cardiopulmonary bypass and frequently deep hypothermic circulatory arrest. We present a case of suspected MH in a patient undergoing emergent repair of a type A aortic dissection. Upon arrival at our institution, the patient had multiple signs of MH. However, no known triggering agent had been administered. Eventually, the unique physiologic changes of cardiopulmonary bypass provided strong support for the diagnosis of MH and dantrolene was administered, effectively treating the episode. PMID- 28079660 TI - Anesthetic Management of a Child With Jeune Syndrome for Tracheotomy: A Case Report. AB - Jeune syndrome is a rare autosomal-recessive skeletal disorder. Anesthetic management of these patients is often difficult because of thoracic and lung hypoplasia. A 5-month-old boy with Jeune syndrome was scheduled to undergo a tracheotomy. Despite 5-minute preoxygenation with continuous positive airway pressure, the patient's oxygen saturation rapidly dropped during the induction of anesthesia. The continuous positive airway pressure should have been titrated to effective tidal volume during preoxygenation to recruit the patient's functional residual capacity and to prevent desaturation. During tracheotomy, volume controlled ventilation with a high respiratory rate and sufficient inspiratory time effectively improved the patient's respiratory status. PMID- 28079661 TI - Femoral Neuropathy Following Spontaneous Retroperitoneal Hemorrhage After Cardiac Surgery: A Case Report. AB - A woman underwent ascending aortic aneurysm repair, aortic root and valve replacement, and coronary artery bypass grafting. Her postoperative course was complicated by stroke and status epilepticus. With supportive care and antiepileptics, her neurologic status improved. Intravenous heparin and aspirin were initiated. On postoperative day 13, she developed a large retroperitoneal hematoma with femoral neuropathy. Because her hematoma was not amenable to percutaneous drainage or surgical evacuation, and considering her comorbidities, a conservative approach was elected. Anticoagulation was held but not reversed, and she was transfused. Her impairment resolved fully after 3 days, and anticoagulation was restarted in staggered fashion. PMID- 28079662 TI - Recognition of a Thoracic Epidural Hematoma in the Setting of Transient Paralysis: A Case Report. AB - A 71-year-old woman on aspirin presented for a distal pancreatectomy, splenectomy, and partial colectomy with a T8/9 epidural catheter placed preoperatively in 3 attempts. Prophylactic 5000 units of subcutaneous heparin were given before the procedure. After catheter removal on postoperative day 2, the patient developed transient bilateral lower extremity paralysis, with near complete recovery within 30 minutes. An urgent MRI revealed a T4-T8 epidural hematoma prompting an emergent T3-T8 laminectomy. This case presentation highlights the need for heightened awareness regarding complications related to neuraxial analgesia in patients receiving unfractionated heparin for thromboembolism prophylaxis with concurrent aspirin use. PMID- 28079663 TI - General Anesthesia and Fabry Disease: A Case Report. AB - Fabry disease is an inherited X-linked disorder characterized by the absence (in men) or deficiency (in women) in alpha-galactosidase A activity that causes a progressive accumulation of glycosphingolipids within lysosomes of cells of all the major organ systems. The subsequent organ damage that manifests in childhood and early adulthood presents a widely variable clinical picture of pain, hypertension, and cardiac, renal, nervous system, and lung dysfunction. We present 2 female patients with Fabry disease who required general anesthesia twice for gynecological and trauma surgery, respectively, and discuss their perioperative management based on new information in the medical literature. PMID- 28079664 TI - Multidose Adenosine Used to Facilitate Microsurgical Clipping of a Cerebral Aneurysm Complicated by Intraoperative Rupture: A Case Report. AB - In some cases of cerebral aneurysm clipping, direct clip application to the aneurysm neck may be difficult or the aneurysm may rupture unexpectedly. In these cases, a clip may be temporarily applied to the parent artery to reduce aneurysmal wall tension, facilitate permanent clip placement, or control bleeding if the aneurysm ruptures. In certain circumstances, even applying a temporary clip may be challenging. We present a case in which the aneurysm ruptured and IV administration of adenosine was required to facilitate clipping. This case suggests that administering multiple consecutive precalculated doses of adenosine may be a safe method to manage aneurysmal rupture. PMID- 28079665 TI - Anesthetic Management of a Patient With Antimuscle-Specific Kinase Antibody Positive Myasthenia Gravis Undergoing an Open Cholecystectomy: A Case Report. AB - Myasthenia gravis (MG) is an autoimmune disease characterized by the production of antibodies against the acetylcholine receptor, muscle-specific kinase (MuSK), or other proteins at the neuromuscular junction. MG with antibodies against MuSK (MuSK-MG) has been described recently. Here, we report the first case of anesthetic management of a patient with MuSK-MG undergoing an open cholecystectomy. In our case, propofol and remifentanil-based anesthesia were used for successful management without using muscle relaxants. Patients with MuSK MG have predominantly ocular, bulbar, and respiratory symptoms that may increase the risk of aspiration. Anesthesiologists need to pay attention to perioperative respiratory failure and respiratory crisis. PMID- 28079666 TI - Intravenous Tissue Plasminogen Activator Administration for Ischemic Stroke 1 Hour After Epidural Catheter Removal: A Case Report. AB - Anticoagulation after a recent neuraxial procedure poses risk for development of spinal hematoma. Clinical evidence supports prompt IV tissue plasminogen activator administration after onset of ischemic stroke. There is an absence of data regarding emergency fibrinolytic therapy for patients experiencing a stroke with recent neuraxial procedures, resulting in highly disparate, nonevidence based guidelines. This report describes a patient who developed ischemic stroke when receiving postoperative epidural analgesia. Tissue plasminogen activator was emergently administered 1 hour after epidural catheter removal with a favorable recovery. The patient and his family reviewed the manuscript, and written consent to publish this case report was obtained from the patient. PMID- 28079667 TI - Stage of fibrosis and portal pressure correlation in nonalcoholic steatohepatitis. AB - BACKGROUND: Hepatic venous pressure gradient (HVPG) measurement correlates with staging of liver fibrosis. Patients with nonalcoholic steatohepatitis (NASH) have a different pattern of fibrosis compared with hepatitis C virus (HCV) with possible alterations in pressures. AIM: The aim of this study was to compare portal pressures with the stage of fibrosis in NASH in comparison with other liver diseases. PATIENTS AND METHODS: Records of all patients who had undergone transjugular liver biopsy with pressure measurements between January 2001 and June 2013 were reviewed. Wedge hepatic venous pressure (WHVP) and HVPG were compared with stages of fibrosis in liver diseases of different etiologies. RESULTS: Among 142 patients included in this study, the liver disease etiology was as follows: HCV (26.6%) and NASH (24.6%), with the remaining (38.7%) grouped under other categories. The mean age of the patients was 51.2+/-11.5 years, with more men with HCV (73.1%) compared with NASH (51.4%) in terms of etiology (P=0.046). There were strong correlations between the stage of fibrosis with both the HVPG (r=0.64; P<0.0001) and the WHVP (r=0.63; P<0.0001) in NASH patients. Compared with HCV patients, NASH patients had a lower HVPG (3.4+/-2.4 vs. 7.5+/ 11 mmHg/stage; P=0.01) with a coefficient estimate of -0.24 (P=0.017) and WHVP (9.6+/-5.5 vs. 14.6+/-15.2 mmHg/stage; P=0.03) for the stage of fibrosis. CONCLUSION: HVPG and WHVP measurements were strongly correlated with stages of fibrosis in NASH. Patients with NASH had lower HVPG and WHVP for each stage of fibrosis compared with HCV patients. This raises the concern of underestimation of pressures by HVPG in NASH etiology for the stage of disease or increased fibrosis despite lower pressures in them. PMID- 28079671 TI - Outcomes of Exercise Training Following the Use of a Birthing Ball During Pregnancy and Delivery. AB - Fournier, D, Feeney, G, and Mathieu, M-E. Outcomes of exercise training following the use of a birthing ball during pregnancy and delivery. J Strength Cond Res 31(7): 1941-1947, 2017- Using a birthing ball (BB) is an exercise form that is growing in popularity. Improved delivery outcomes have been recently reported with as little a 6-8 hours of training per week; however, little is known regarding lower and higher training levels. The aim of this study was to document whether more time spent training with a BB resulted in improved delivery outcomes for the mother and the newborn. This quasi-experimental study was conducted with a sample of women who participated in 1 to 28 supervised exercise classes during pregnancy according to the Ballon Forme program offered in nonclinical settings (http://ballonforme.com), with the option of completing the supervised BB exercises performed at home. Thirty women who gave birth naturally were included in the study. Mean BB training time was 22.3 hours (SD = 16.6 hours). A greater BB training time was significantly associated with shorter labor duration (r = 0.408; p = 0.031) and specific stages of labor (stage 1 [dilatation/active stage] [r = -0.372; p = 0.043] and stage 2 [expulsion] [r = -0.415; p = 0.028]). Increased participation in BB supervised classes was more closely associated with quicker deliveries than those of home based BB exercises. No associations between training time and adverse effects of labor parameters or the baby's health were noted. Greater involvement in BB training seems to lead to quicker deliveries than lower levels of involvement; it also has the benefit of supervised practice. PMID- 28079672 TI - Unexplored Opportunities: Thoughts on Research to Improve Availability and Access to Sexual Health Services for Young Men Who Have Sex With Men. PMID- 28079673 TI - Differences in Use of High-quality and Low-quality Hospitals Among Working-age Individuals by Insurance Type. AB - BACKGROUND: Research suggests that individuals with Medicaid or no insurance receive fewer evidence-based treatments and have worse outcomes than those with private insurance for a broad range of conditions. These differences may be due to patients' receiving care in hospitals of different quality. RESEARCH DESIGN: We used the Healthcare Cost and Utilization Project State Inpatient Databases 2009-2010 data to identify patients aged 18-64 years with private insurance, Medicaid, or no insurance who were hospitalized with acute myocardial infarction, heart failure, pneumonia, stroke, or gastrointestinal hemorrhage. Multinomial logit regressions estimated the probability of admissions to hospitals classified as high, medium, or low quality on the basis of risk-adjusted, in-hospital mortality. RESULTS: Compared with patients who have private insurance, those with Medicaid or no insurance were more likely to be minorities and to reside in areas with low-socioeconomic status. The probability of admission to high-quality hospitals was similar for patients with Medicaid (23.3%) and private insurance (23.0%) but was significantly lower for patients without insurance (19.8%, P<0.01) compared with the other 2 insurance groups. Accounting for demographic, socioeconomic, and clinical characteristics did not influence the results. CONCLUSIONS: Previously noted disparities in hospital quality of care for Medicaid recipients are not explained by differences in the quality of hospitals they use. Patients without insurance have lower use of high-quality hospitals, a finding that needs exploration with data after 2013 in light of the Affordable Care Act, which is designed to improve access to medical care for patients without insurance. PMID- 28079674 TI - Borderline intellectual functioning: an update. AB - PURPOSE OF REVIEW: Borderline intellectual functioning (BIF) is a descriptive v code that is often used, especially in forensic settings, as if it were a full fledged disorder. Various historical and other aspects of this classification are reviewed, and commentary is made on the question of whether to upgrade BIF to a regular psychiatric category, or to eliminate it by folding it into an already recently expanded category of intellectual developmental disorder (IDD). RECENT FINDINGS: Full-scale intelligence quotient (IQ) is an outmoded concept that is decreasingly being used. For example, DSM-5 states that measures of 'executive functioning' (reasoning, planning, consequential thinking, attention, self regulation, and so on) are often more meaningful that full-scale IQ as diagnostic indicators of IDD. Even the definition of BIF in DSM-5 no longer specifies an IQ score range. SUMMARY: BIF is a descriptive v-code (rather than a typical psychiatric category), which started out as a sub-type of IDD (formerly mental retardation or intellectual disability) but morphed into its current status when the IQ ceiling for IDD was changed from minus one standard deviation (85) to minus two standard deviations (70). It has been suggested that, as people with BIF often have adjustment problems, the BIF category be elevated to the status of a formal psychiatric disorder. In this article, a contrary opinion is expressed, namely that the BIF category be dropped. PMID- 28079675 TI - Recent advances in the management of neuropsychiatric symptoms in dementia. AB - PURPOSE OF REVIEW: The present article addresses intriguing questions related to the clinical intervention in distinct neuropsychiatric syndromes of patients with dementia. RECENT FINDINGS: We reviewed 154 articles published between 2015 and 2016 targeting psychopharmacological and nonpharmacological interventions, and safety-tolerability concerns. We selected 115 articles addressing the purpose of this study. Of these, 33 were chosen because they were dedicated to subtopics: agitation (42), depression (33), apathy (18), sleep disorders/anxiety (8), and psychosis (4). Clinical studies using both pharmacological (70) and nonpharmacological (37) interventions were considered; others were included for theoretical support. Regarding the methodological design, we found double-blind RCTs (17), single-blinded RCTs (4), open-label studies (18), case reports (5), cross-sectional or cohort studies (25), epidemiological papers (2), and expert reviews (44). This observation raises concerns about the overall methodological adequacy of a substantial proportion of studies in this field, which limits the potential of generalization of the findings. Finally, 18 studies were designed to determine safety-tolerability issues of psychotropic medications (6 were discussed). SUMMARY: Effective and well tolerated treatment of neuropsychiatric syndromes in dementia remains a critically unsolved challenge. We understand that this is an extremely important area of research, and critically required to guide clinical decisions in geriatric neuropsychiatry. PMID- 28079676 TI - Multiple Conditions Increase Preventable Crash Risks Among Truck Drivers in a Cohort Study. AB - OBJECTIVE: This study aims to quantify the crash risk for truck drivers with multiple comorbid medical conditions, after adjusting for confounders. METHODS: This retrospective cohort of 38,184 drivers evaluated concomitant medical conditions and subsequent crash data between January 1, 2005, and October 31, 2012. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated for any cause and preventable crashes of varying severity. RESULTS: Drivers with three or more medical conditions had a significantly increased risk of preventable Department of Transportation (DOT) reportable crashes (HR = 2.53, 95% CI = 1.65 to 3.88) and preventable crashes with injuries (HR = 2.23, 95% CI = 1.09 to 5.31) after adjustment for covariates. Similarly, adjusted HRs were 2.55 (95% CI = 1.37 to 4.73) for any cause DOT-reportable crashes and 3.21 (95% CI = 1.18 to 8.75) for any cause crashes with injuries. CONCLUSIONS: Having three concomitant medical conditions may be a statistically significant risk factor for preventable and any cause DOT-reportable crashes and crashes with injuries. PMID- 28079677 TI - Cadaveric Testing of Robot-Assisted Access to the Internal Auditory Canal for Vestibular Schwannoma Removal. AB - HYPOTHESIS: An image-guided robotic system can safely perform the bulk removal of bone during the translabyrinthine approach to vestibular schwannoma (VS). BACKGROUND: The translabyrinthine approach to VS removal involves extensive manual milling in the temporal bone to gain access to the internal auditory canal (IAC) for tumor resection. This bone removal is time consuming and challenging due to the presence of vital anatomy (e.g., facial nerve) embedded within the temporal bone. A robotic system can use preoperative imaging and segmentations to guide a surgical drill to remove a prescribed volume of bone, thereby preserving the surgeon for the more delicate work of opening the IAC and resecting the tumor. METHODS: Fresh human cadaver heads were used in the experiments. For each trial, the desired bone resection volume was planned on a preoperative computed tomography (CT) image, the steps in the proposed clinical workflow were undertaken, and the robot was programmed to mill the specified volume. A postoperative CT scan was acquired for evaluation of the accuracy of the milled cavity and examination of vital anatomy. RESULTS: In all experimental trials, the facial nerve and chorda tympani were preserved. The root mean squared surface accuracy of the milled cavities ranged from 0.23 to 0.65 mm and the milling time ranged from 32.7 to 57.0 minute. CONCLUSION: This work shows feasibility of using a robot-assisted approach for VS removal surgery. Further testing and system improvements are necessary to enable clinical translation of this technology. PMID- 28079678 TI - Sound Localization in Patients With Congenital Unilateral Conductive Hearing Loss With a Transcutaneous Bone Conduction Implant. AB - OBJECTIVE: There is no consensus regarding the benefit of implantable hearing aids in congenital unilateral conductive hearing loss (UCHL). This study aimed to measure sound source localization performance in patients with congenital UCHL and contralateral normal hearing who received a new bone conduction implant. STUDY DESIGN: Evaluation of within-subject performance differences for sound source localization in a horizontal plane. SETTING: Tertiary referral center. PATIENTS: Five patients with atresia of the external auditory canal and contralateral normal hearing implanted with transcutaneous bone conduction implant at the Medical University of Vienna were tested. INTERVENTION: Activated/deactivated implant. MAIN OUTCOME MEASURE: Sound source localization test; localization performance quantified using the root mean square (RMS) error. RESULTS: Sound source localization ability was highly variable among individual subjects, with RMS errors ranging from 21 to 40 degrees. Horizontal plane localization performance in aided conditions showed statistically significant improvement compared with the unaided conditions, with RMS errors ranging from 17 to 27 degrees. The mean RMS error decreased by a factor of 0.71 (p < 0.001). CONCLUSION: Analysis revealed improved sound localization performance in a horizontal plane with the activated transcutaneous bone conduction implant. Some patients with congenital UCHL might be capable of developing improved horizontal plane localization abilities with the binaural cues provided by this device. PMID- 28079679 TI - Influence of Behavior on Complications of Osseointegrated Bone Conduction Devices in Children. AB - OBJECTIVE: Compare incidences of complications following implantation of osseointegrated bone conduction devices (OBCD) between children with and without behavioral disorders. STUDY DESIGN: Case series with chart review. SETTING: Tertiary referral center otology and neurotology practice. PATIENTS: Pediatric patients who underwent implantation of OBCD between May 2009 and July 2014 at Arkansas Children's Hospital. INTERVENTIONS: Implantation with Cochlear BAHA 200 series, Cochlear BAHA BI300, or Oticon OBCD. MAIN OUTCOME MEASURES: Osseointegration failure (OIF) with resulting loss of flange-fixture and/or skin and soft tissue reactions. RESULTS: The total rate of complications was 66.2%, with the majority being minor complications (39.4%). There was no difference in the total rate of complication (p = 0.461), minor complications (p = 0.443), major complications (p = 0.777), and minor and major complications (p = 0.762) between the control group and children with behavioral disorders. CONCLUSION: Behavior was not observed to influence the incidence of OIF or skin/soft tissue reactions after implantation of OBCD in pediatric patients. PMID- 28079680 TI - Middle-Ear Sound Transmission Under Normal, Damaged, Repaired, and Reconstructed Conditions. AB - HYPOTHESIS: We hypothesize that current clinical treatment strategies for the disarticulated or eroded incus have the effect of combining the incus and stapes of the human middle ear (ME) into one rigid structure, which, while capable of adequately transmitting lower-frequency sounds, fails for higher frequencies. BACKGROUND: ME damage causes conductive hearing loss (CHL) and while great progress has been made in repairing or reconstructing damaged MEs, the outcomes are often far from ideal. METHODS: Temporal bones (TBs) from human cadavers, a laser Doppler vibrometer (LDV), and a fiber-optic based micro-pressure sensor were used to characterize ME transmission under various ME conditions: normal; with a disarticulated incus; repaired using medical glue; or reconstructed using a partial ossicular replacement prosthesis (PORP). RESULTS: Repairing the disarticulated incus using medical glue, or replacing the incus using a commercial PORP, provided similar restoration of ME function including almost perfect function at frequencies below 4 kHz, but with more than a 20-dB loss at higher frequencies. Associated phase responses under these conditions sometimes varied and seemed dependent on the degree of coupling of the PORP to the remaining ME structure. A new ME-prosthesis design may be required to allow the stapes to move in three-dimensional (3-D) space to correct this deficiency at higher frequencies. CONCLUSIONS: Fixation of the incus to the stapes or ossicular reconstruction using a PORP limited the efficiency of sound transmission at high frequencies. PMID- 28079681 TI - Internal Jugular Vein Compression: A Novel Approach to Mitigate Blast Induced Hearing Injury. AB - HYPOTHESIS: Internal jugular vein (IJV) compression before blast injury will lead to reduced risk of traumatic hearing injury following exposure to a blast injury. BACKGROUND: IJV compression and its effects on not only intracranial, but also intracochlear pressure may potentiate blast induced hearing injury, therefore, precluding its use as a prophylactic therapy for blast induced traumatic brain injury. METHODS: Twenty Sprague Dawley rats were exposed to a 17.9 +/- 0.4 PSI (195.8 dB SPL) right sided shock wave in which 10 had application of a custom IJV compression collar before injury. All rodents received baseline and post blast injury otoacoustic emission (OAE) and auditory brainstem response (ABR) testing followed by cochlear histology. RESULTS: IJV compression was shown to significantly reduce ABR and OAE threshold shifts in comparison to the non intervention group by: 14.9 +/- 4.8 dB (right ear ABR 0.5 kHz Day 1 post blast, p = 0.01), 13.1 +/- 4.9 dB (right ear ABR 4 kHz Day 1 post blast, p = 0.04), 16.5 +/- 4.5 dB (right ear ABR click Day 1 post blast, p = 0.003), 12.1 +/- 4.6 dB (right ear ABR click Day 6 post blast, p = 0.04), and 14.0 +/- 3.2 dB (both ears OAE 3.2-10 kHz, p < 0.0001). Also, those animals with collar application had a greater number of total hair cells per mm from 70 to 100% distance from the cochlear apex following blast injury in comparison to those without intervention (blast: 211.8 +/- 27.5 versus blast+collar: 355.5 +/- 39.5 [p = 0.0002]). CONCLUSION: This study supports the use of IJV compression in a pre-clinical model as a new prophylactic mechanism to combat blast induced hearing injury. PMID- 28079682 TI - Comparing Short-term Complications of Inpatient Versus Outpatient Single-level Anterior Cervical Discectomy and Fusion: An Analysis of 6940 Patients Using the ACS-NSQIP Database. AB - STUDY DESIGN: Multicenter propensity score-adjusted retrospective cohort study. OBJECTIVE: To determine baseline 30-day complication rates for anterior cervical discectomy and fusion (ACDF) and compare clinical complications for patients undergoing single-level ACDFs between inpatient and outpatient settings. SUMMARY OF BACKGROUND DATA: ACDF remains the most common procedure in the treatment of a variety of cervical disc pathologies, making it a focus of quality improvement initiatives. Outpatient single-level ACDFs are becoming more common and offer advantages including reducing nosocomial infections and costs, as well as improved patient satisfaction. MATERIALS AND METHODS: The 2011-2013 NSQIP datasets were queried to identify all patients who underwent single-level ACDF procedures using current procedural terminology codes. Outpatient and inpatient cohorts were matched 1:1 using propensity score analysis to assess short-term outcomes. The outcomes assessed included 30-day medical and surgical complications, reoperation, readmission, and mortality. RESULTS: In total, 6940 patients underwent a single-level ACDF with an overall complication rate of 4.2%. A total of 5162 patients (74.4%) had an inpatient hospital stay after surgery, whereas 1778 patients (25.6%) had outpatient surgery. After matching based on preoperative and operative characteristics to account for potential confounders, the overall complication rate was higher in the inpatient arm compared with the outpatient arm (2.5% vs. 1.2%; P=0.003). The 30-day readmission rate was also higher but not significant in the inpatient group than the outpatient group (2.2% vs. 1.8%; P=0.355). Mortality was the same with 0.1% in both groups (P=0.564). CONCLUSIONS: Patients undergoing outpatient single-level ACDF had a lower 30-day complication rates than those undergoing it in the inpatient setting. Outpatient surgery for single-level ACDF is safe and a favorable option for suitable patients. LEVEL OF EVIDENCE: Level 3. PMID- 28079683 TI - Factors Associated With Graft Detachment After Primary Descemet Stripping Automated Endothelial Keratoplasty. AB - PURPOSE: To identify risk factors associated with postoperative graft detachment after Descemet stripping automated endothelial keratoplasty (DSAEK). METHODS: In this retrospective institutional cohort study, the study group included all consecutive eyes that underwent primary DSAEK between January 2005 and October 2015 at Villa Serena-Villa Igea private hospitals (Forli, Italy) and developed postoperative graft detachment (n = 45). The control group included all eyes that underwent primary DSAEK during the same period and did not develop graft detachment (n = 1167). The main outcome measure was whether or not postoperative graft detachment occurred. RESULTS: Main indications for surgery included Fuchs endothelial dystrophy (525/1212 = 41%), pseudophakic bullous keratopathy (422/1212 = 35%), and a failed penetrating keratoplasty (PK) graft (190/1212 = 16%). Postoperative graft detachment occurred in 45 of 1212 (3.7%) eyes. Medically treated glaucoma, previous trabeculectomy, previous aqueous shunt procedure, and failed PK were all associated with an increased risk for graft detachment in univariate analysis. No particular lens status at the time of graft implantation was significantly associated with graft detachment, including the presence of an anterior chamber intraocular lens [odds ratio (OR), 1.5; 95% confidence interval (CI), 0.35-6.46, P = 0.58] or aphakia at the time of graft transplantation (OR, 1.37; 95% CI, 0.41-4.57, P = 0.74). Cataract removal during surgery was not associated with an increased risk for detachment (OR, 0.77; 95% CI, 0.39-1.5, P = 0.47). Previous trabeculectomy (OR, 4.21; 95% CI, 1.53-11.56, P = 0.005) and a previous failed PK graft (OR, 3.04; 95% CI, 1.6-5.78, P = 0.001) were the only independent risk factors for graft detachment in multivariate analyses. CONCLUSIONS: Previous PK and trabeculectomy are independent risk factors for postoperative graft detachment in primary DSAEK. PMID- 28079684 TI - The cif Virulence Factor Gene Is Present in Isolates From Patients With Pseudomonas aeruginosa Keratitis. AB - PURPOSE: To determine whether the cif gene is present in pathogenic Pseudomonas aeruginosa isolates from patients with bacterial keratitis at Aravind Eye Hospital, a referral eye care center in southern India, and from corresponding environmental isolates. METHODS: Polymerase chain reaction amplification was performed on strains of P. aeruginosa isolated from ocular infections and environmental soil samples were collected from the area surrounding Aravind Eye Hospital. DNA sequencing of 16S ribosomal DNA amplicons was performed to verify strain identity. RESULTS: We determined that 45 of 48 patient isolates carry a genomic copy of cif. Analysis of a catalog of environmental strains previously isolated from the surrounding area revealed that only 4 of 10 P. aeruginosa strains and 1 of 14 strains of related species carry the cif gene. CONCLUSIONS: This is the first study to show that P. aeruginosa strains with ocular pathogenicity carry the cif gene and that the presence of this gene may be enriched over its prevalence in the environment. Taken together, these results suggest a potential role for Cif in acute bacterial keratitis. PMID- 28079685 TI - Asymmetric Deep Stromal Keratopathy in a Patient With Multiple Myeloma. AB - PURPOSE: To report a case of asymmetric deep stromal keratopathy in a patient with multiple myeloma. METHODS: Case report and literature review. RESULTS: An 85 year-old woman was found to have progressive visually significant left-sided deep stromal opacity in the setting of monoclonal gammopathy. Hematologic workup resulted in a diagnosis of IgG kappa multiple myeloma. Histopathology was significant for semicrystalline deposits in the posterior stroma. The patient's visual acuity improved to 20/50 7 months after penetrating keratoplasty. A similar deep stromal lesion appeared in the right eye 2 years after initial presentation. CONCLUSIONS: We present an unusual case of paraproteinemic keratopathy with a uniquely asymmetric presentation that resulted in a diagnosis of multiple myeloma. PMID- 28079686 TI - Number of Bacteria and Time of Coincubation With Bacteria Required for the Development of Acanthamoeba Keratitis. AB - PURPOSE: We hypothesized that bacteria may be a factor contributing to the development of Acanthamoeba keratitis (AK). We investigated interactions between Acanthamoeba and Pseudomonas aeruginosa for the development of keratitis in rabbit corneas. METHODS: Acanthamoeba castellanii (ATCC50492) and P. aeruginosa (PAO-1) were used. Two densities of P. aeruginosa (high, 1 * 10/mL; low, 3 * 10/mL) and 2 durations of coincubation (long, 6 h; short, 2 h) of Acanthamoeba with 1 * 10/mL of P. aeruginosa were tested. Acanthamoeba alone or Acanthamoeba coincubated with P. aeruginosa was inoculated into rabbit corneas. After inoculation, levofloxacin (LVFX) eye drops were administered. The clinical score of the cornea was evaluated after inoculation. RESULTS: Acanthamoeba alone did not produce keratitis during a 5-day observation period. Rabbit corneas inoculated with Acanthamoeba coincubated with low-density P. aeruginosa followed by topical LVFX were clear with few infiltrates. Corneas inoculated with Acanthamoeba coincubated with high-density P. aeruginosa followed by LVFX treatment developed severe keratitis, and clinical scores were significantly higher compared with high-density P. aeruginosa alone followed by LVFX treatment (scores 7, 9.6, 8.5 vs. 3, 3.5, 3.25 on days 1-3, all P < 0.01). The long (6 h) coincubation time of Acanthamoeba with high-density P. aeruginosa resulted in more severe keratitis compared with short (2 h) coincubation (scores, 9.7, 12.7, 12.1, 9.8, 8.7 vs. 7, 9.6, 8.5, 6.9, 5.6 on days 1-5, all P < 0.01). CONCLUSIONS: These results suggest that the presence of bacteria is essential and a critical number of bacteria is required for the development of AK. The time of coexistence with bacteria may be an important determinant of the severity of AK. PMID- 28079687 TI - Periocular Amyloidosis Manifesting as Pseudopemphigoid Treated With Mitomycin C. AB - PURPOSE: To describe an unusual cicatrizing manifestation of periocular amyloid and the utility of adjuvant antimetabolite therapy. METHODS: This is a case report of a 49-year old woman with progressive bilateral upper lid ptosis, who was found to have bilateral inferior forniceal masses with thickening of the conjunctiva. Conjunctival and eyelid biopsies showed evidence of amyloid deposition. Systemic evaluation did not reveal any evidence of systemic amyloidosis. Her blepharoptosis continued to deteriorate, and she underwent bilateral sequential upper lid ptosis correction surgery and debulking procedures. Subsequently, she developed severe and progressive cicatricial conjunctivitis with extensive symblepharon formation in all 4 fornices and restriction of ocular motility, simulating a clinical picture of ocular mucous membrane pemphigoid. RESULTS: She was treated surgically by division of symblepharon augmented with application of topical mitomycin C intraoperatively. This has been partially successful in freeing up differential movement between her lid and her eye and consequently improving eye protection and lubrication. CONCLUSIONS: Pseudopemphigoid represents a rare manifestation of periocular amyloid. Risks and benefits of surgical procedures in this context need to be carefully weighed to minimize the risk of secondary complications. Topical mitomycin C may be considered as a relatively safe adjunct in managing the cicatricial component of the disease. PMID- 28079688 TI - Retrospective Comparative Study of Topical Interferon alpha2b Versus Mitomycin C for Primary Ocular Surface Squamous Neoplasia. AB - PURPOSE: To compare the efficacy and safety of topical interferon alpha 2b (IFNalpha2b) and mitomycin C (MMC) for ocular surface squamous neoplasia. METHODS: In this retrospective study, medical records of 51 eyes of 50 patients with a diagnosis of primary ocular surface squamous neoplasia were included. All cases were treated with either topical IFNalpha2b (1 million IU/mL) or MMC (0.4 mg/mL) 4 times a day. The primary outcome measure was frequency of clinical resolution of tumors along with failure and recurrence rates after treatment. Other outcome measures included the duration of treatment and adverse effects associated with both topical therapies. RESULTS: Twenty-six eyes were treated with topical IFNalpha2b and 25 eyes were treated with topical MMC. A complete response was achieved in 23 (89%) and 23 (92%) eyes with topical IFNalpha2b and MMC, respectively (P = 0.67). The median time to lesion resolution was significantly different between the groups (median 3.5 months in the IFNalpha2b group and 1.5 months in the MMC group) with an average difference of 1.7 months (P < 0.005). Five (10%) of 51 patients showed no or partial response to topical therapy. Subsequently, they underwent surgical excision. Adverse effects occurred in 3 (12%) patients using IFNalpha2b and 22 (88%) patients using MMC (P < 0.005). CONCLUSIONS: Both IFNalpha2b and MMC seemed to be equally effective topical monotherapies. Despite a prolonged time to lesion resolution, IFNalpha2b-treated eyes had better safety and tolerance in comparison with MMC-treated eyes. PMID- 28079689 TI - Scanning Electron Microscope Analysis of Stromal Surface Regularity in DSAEK Using Manual or Automated Microkeratomes or DMEK. AB - PURPOSE: To analyze differences in the stromal bed according to the method used to obtain the disc for endothelial transplant with 1) an automated microkeratome for Descemet stripping automated endothelial keratoplasty (DSAEK), 2) homogeneous dissection of Descemet membrane (Descemet membrane endothelial keratoplasty [DMEK]), or 3) a manual microkeratome used for DSAEK. METHODS: We analyzed the stromal bed of 25 consecutive corneas used for endothelial transplantation, divided into 3 groups: 1) 11 samples cut with an automated microkeratome, 2) 5 samples used for DMEK, 3) 9 samples cut with a manual microkeratome. A scanning electron microscope was used to obtain an image of the center of the stromal bed. The irregularity index of the surface complementary to the stromal surface of the disc obtained for grafting was calculated with the Canny algorithm (0: completely smooth; 1: completely irregular). RESULTS: At all thresholds studied (20, 30, 50, and 70), the mean irregularity index for group C (35.2, 24.4, 13.7, and 8.8, respectively) was higher than that of group A (26.2, 14.8, 6.7, and 4.0, respectively), which in turn was higher than that of group B (7.0, 4.2, 2.4, and 1.8, respectively). Differences were statistically significant among all groups and for all thresholds. CONCLUSIONS: Irregularity of the stromal bed after any dissection can be quantified using the Canny method. The use of an automated microkeratome for DSAEK reduces irregularity and helps obtain a surface more similar to that obtained with DMEK than with a manual microkeratome. PMID- 28079690 TI - Noncontact Evaluation of Corneal Grafts: Swept-Source Fourier Domain OCT Versus High-Resolution Scheimpflug Imaging. AB - PURPOSE: To study the reliability and repeatability of anterior segment measurements in patients who underwent penetrating keratoplasty with swept light source Fourier domain anterior segment optical coherence tomography (SS-OCT) in comparison with a high-resolution Scheimpflug camera. METHODS: Keratometry (K) and elevation data of the anterior and posterior corneal surfaces, central corneal thickness, and anterior chamber depth were determined in 56 postkeratoplasty eyes (mean age: 59.6 +/- 16.5 yrs) with SS-OCT (CASIA SS-1000; Tomey) followed by Scheimpflug photography (Pentacam High Resolution; Oculus). Examinations were also performed on 48 right eyes of 48 age-matched healthy subjects (mean age: 66.3 +/- 7.0 yrs). RESULTS: A statistically significant difference was detected between both tomographers in anterior flat K [1.7 +/- 4.92 diopters (D)], posterior astigmatism (1.32 +/- 5.7 D) and elevation (6.65 +/ 14.07 MUm), and central corneal thickness (27.39 +/- 90.81 MUm) and anterior chamber depth values (0.14 +/- 0.66 mm) in patients who had undergone corneal transplantation (P < 0.05). In the postkeratoplasty group, repeatability of SS OCT was higher for every anterior segment parameter in comparison with the Pentacam. In corneal grafts, the variability between 3 consecutive measurements on the same subject was remarkably lower for every parameter while using SS-OCT. CONCLUSIONS: In patients who had undergone corneal transplantation, SS-OCT provided more reliable and repeatable anterior segment evaluations when compared with the rotating Scheimpflug system. Our findings suggested that the tested high resolution swept-source OCT system is a comprehensive and precise diagnostic tool for postoperative follow-up of patients who have undergone penetrating keratoplasty. PMID- 28079691 TI - Lutein and Brilliant Blue-Based Dye for Donor Preparation and Transplantation in Descemet Membrane Endothelial Keratoplasty. AB - PURPOSE: Trypan blue (TB) is used for visualization of the endothelium-Descemet membrane graft during Descemet membrane endothelial keratoplasty (DMEK). However, TB is assumed to have a dose-dependent toxic effect on the corneal endothelium. We retrospectively compared a lutein/zeaxanthin and Brilliant Blue (LZ/BB)-based dye for preparation and transplantation of the graft in DMEK to TB. METHODS: In 20 patients, a dye composed of 1% LZ /0.025% BB was used, and in 22 patients, 0.06% TB was used for graft visualization in DMEK. We evaluated the rebubbling rate, best spectacle-corrected visual acuity (BSCVA), central corneal thickness (CCT), and endothelial cell density (ECD) before and 3 and 6 months after transplantation. RESULTS: Staining of endothelium-Descemet membrane with LZ/BB was faint but sufficient. There was no significant difference between both groups, except in CCT after 3 months, which was lower in the LZ/BB group (P = 0.02). In the LZ/BB group, BSCVA improved from 0.48 +/- 0.39 before DMEK to 0.19 +/- 0.09 after 6 months (P < 0.05) (20% rebubbling rate). Donor ECD decreased from 2735 +/- 259 cells/m preoperatively to 1876 +/- 316 cells/mm (P < 0.0001) at 6 months (31.4%). CCT decreased from 642 +/- 130 MUm preoperatively to 519.8 +/- 38 MUm (P < 0.0001) at 6 months. In the TB group, BSCVA improved from 0.43 +/- 0.27 to 0.17 +/- 0.14 (P = 0.0003) at 6 months (30% rebubbling rate). ECD decreased from 2825 +/- 263 to 1777 +/- 302 cells/mm (P < 0.0001) after 6 months (36.3%), CCT from 638 +/- 48 MUm preoperatively to 531 +/- 48 MUm (P < 0.0001) at 6 months. CONCLUSIONS: LZ/BB-based dyes are suitable for DMEK with outcomes comparable to TB. However, available formulas result in faint staining, discouraging their routine use in donors with assumed difficult preparation. PMID- 28079692 TI - Keratoconus and Bowman Layer Transplantation. PMID- 28079693 TI - Conjunctival Autograft Versus Amniotic Membrane Transplantation Following Double Pterygium Excision: A Randomized Trial. PMID- 28079694 TI - Eventual Endothelial Failure After Initial Corneal Clearing After a Detached Endothelial Graft in Fuchs Dystrophy. PMID- 28079696 TI - Fellowship Review: Laclinic Aesthetic Surgery Fellowship. PMID- 28079697 TI - Infectious Loss of Tissue Expanders in Breast Reconstruction: Are We Treating the Right Organisms? AB - BACKGROUND: Postoperative infections following tissue expander-based breast reconstruction represent a significant threat to the reconstructive process. Studies have found the incidence to be as high as 29%. There has been abundant research into the risk factors associated with these infections, although very few studies have focused on the causative organisms. The purpose of this study was to investigate the bacterial flora associated with tissue expander infections after breast reconstruction. METHODS: A retrospective analysis of all patients who underwent tissue expander-based breast reconstruction at our institution between February 2010 and April 2013 was conducted. The medical records were reviewed for demographic information, medical history, operative technique, postoperative course, and culture results. Descriptive data analysis was then performed. RESULTS: A total of 56 tissue expander infections were identified in 49 patients during the study period. 41.1% of the cultures grew gram-positive organisms, whereas 28.6% grew gram-negative species. The 2 most common organisms were Staphylococcus aureus (17.9%) and Staphylococcus epidermidis (14.3%). Pseudomonas aeruginosa was the most frequent gram-negative species and was also the third most frequent organism cultured (10.9%). DISCUSSION: Due to the high rate of infection in breast reconstruction patients, adequate perioperative prophylaxis is necessary. The surgeon must also be prepared to treat patients who may return with infection postoperatively. Although the majority of our infections were secondary to normal skin flora, a significant proportion were caused by gram-negative species. Given these results, the empiric antibiotic of choice for postoperative infections should be reconsidered to cover for these various organisms. PMID- 28079698 TI - Pediatric Hand Surgery in Global Health: The Role for International Outreach. AB - PURPOSE: There is emerging interest in hand surgery and global health. This was emphasized at the 2015 presidential address at the American Society for Surgery of Hand. Children are prioritized because of their increased risk for trauma and higher potential for better outcomes. This study aims to identify how hand surgical volunteer programs can benefit the pediatric hand surgical landscape in global health. There has been no literature review to date. METHODS: This institutional review board-approved review systematically searched PubMed, Embase, Medline, African Journal Online, and the Journal of Hand Surgery. A scoping review methodology was selected to allow mapping of a body of literature by topic, include a greater range of study designs, and provide a descriptive overview of the reviewed material. All studies published between 2000 to March 2016 relevant to pediatric hand surgery in global health were included. Preferred Reporting Items for Systematic Reviews and Meta-Analyses was used to record the search results. RESULTS: Six hundred sixty-eight citations were reviewed, with 10 studies that satisfied the inclusion criteria. Hand trauma (70%), congenital anomalies (30%), tumors (20%), surgical technique (50%), and international outreach recommendation (30%) were common themes. Targeting prevention (50%), international outreach education (30%), and building on previous studies to validate findings study (10%) were identified as gaps. PMID- 28079699 TI - A New Technique for Total Reconstruction of the Lower Lid. AB - BACKGROUND: Although several methods have been described for total lower eyelid reconstruction, it remains as a major challenge in reconstructive surgery. Here, we present a new technique, the Mutaf unequal Z-plasty procedure for reconstruction of defects of the lower eyelid. METHODS: In this technique, 2 skin flaps designed in an unequal Z-plasty manner are used to provide skin coverage. Except for 2 patients whose additional upper eyelid defects were closed with Fricke flap, all patients were reconstructed with Mutaf unequal Z-plasty procedure. The conjunctival and tarsal defects are reconstructed with composite chondrocutaneous from the ear, mucochondral grafts, harvested from the nasal septum. In over 12 years, this new technique was used in 24 patients, 13 men and 11 women, with total and subtotal lower eyelid defects that resulted from excision of basal cell carcinomas. The age range of the patients was between 45 and 72 years. RESULTS: There was no complication such as ocular irritation or postoperative epiphora because of ectropion or entropion; all patients healed uneventfully. A mean follow-up of 4.7 +/- 2.15 years (between 1 and 9 years) revealed a functionally and cosmetically satisfactory total lower eyelid reconstruction in all patients. CONCLUSIONS: This new technique seems to be a useful alternative for reconstruction of total and subtotal lower eyelid defects. The procedure seems to be superior since it requires considerably shorter operating time with no risk of flap failure. Moreover, this technique offers an excellent color and textural match for the reconstruction of total and subtotal lower eyelid defects extending the infraorbital area. PMID- 28079700 TI - The Chimera Flap: A Quarter Century Odyssey. AB - Incredibly complicated multidimensional defects have always strained the ingenuity of the reconstructive surgeon. Secondary perhaps to vascularized composite allotransplantation as a solution to this dilemma, the compound flap has been developed to be a more useful and available alternative. Their greatest versatility has been proven by its subtype, the chimera flap. The chimera flap itself consists of multiple flaps, the latter possibly composed of bone, skin, muscle, and so on, where each part has an independent vascular supply, and each part is independent of any physical interconnection whatsoever with the other components, except where joined ultimately only to a common vascular pedicle. An appellation for this concept was first introduced a quarter century ago in this very journal, a time frame now the impetus for a recapitulation of its origin and subsequent history that proves that it has eventually withstood the test of time and has been successfully assimilated into the reconstructive repertoire. PMID- 28079701 TI - Ex Vivo Assessment of Coronary Atherosclerotic Plaque by Grating-Based Phase Contrast Computed Tomography: Correlation With Optical Coherence Tomography. AB - OBJECTIVES: The aim of this study was to determine the diagnostic accuracy of grating-based phase-contrast computed tomography (gb-PCCT) to classify and quantify coronary vessel characteristics in comparison with optical coherence tomography (OCT) and histopathology in an ex vivo setting. MATERIALS AND METHODS: After excision from 5 heart specimens, 15 human coronary arteries underwent gb PCCT examination using an experimental imaging setup consisting of a rotating molybdenum anode x-ray tube, a Talbot-Lau grating interferometer, and a single photon counting detector. Subsequently, all vessels were imaged by OCT and histopathologically processed. Optical coherence tomography, gb-PCCT, and histopathology images were manually matched using anatomical landmarks. Optical coherence tomography and gb-PCCT were reviewed by 2 independent observers blinded to histopathology. Vessel, lumen, and plaque area were measured, and plaque characteristics (lipid rich, calcified, and fibrous) were determined for each section. Measures of diagnostic accuracy were derived, applying histopathology as the standard of reference. RESULTS: Of a total of 286 assessed cross sections, 241 corresponding sections were included in the statistical analysis. Quantitative measures derived from gb-PCCT were significantly higher than from OCT (P < 0.001) and were strongly correlated with histopathology (Pearson r >=0.85 for gb-PCCT and >=0.61 for OCT, respectively). Results of Bland-Altman analysis demonstrated smaller mean differences between OCT and histopathology than for gb-PCCT and histopathology. Limits of agreement were narrower for gb PCCT with regard to lumen area, for OCT with regard to plaque area, and were comparable with regard to vessel area. Based on histopathology, 228/241 (94.6%) sections were classified as fibrous, calcified, or lipid rich. The diagnostic accuracy of gb-PCCT was excellent for the detection of all plaque components (sensitivity, >=0.95; specificity, >=0.94), whereas the results for OCT showed sensitivities of >=0.73 and specificities of >=0.66. CONCLUSIONS: In this ex vivo setting, gb-PCCT provides excellent results in the assessment of coronary atherosclerotic plaque characteristics and vessel dimensions in comparison to OCT and histopathology. Thus, the technique may serve as adjunct nondestructive modality for advanced plaque characterization in an experimental setting. PMID- 28079702 TI - Radiomic Analysis Reveals Prognostic Information in T1-Weighted Baseline Magnetic Resonance Imaging in Patients With Glioblastoma. AB - OBJECTIVES: The aim of this study was to investigate whether radiomic analysis with random survival forests (RSFs) can predict overall survival from T1-weighted contrast-enhanced baseline magnetic resonance imaging (MRI) scans in a cohort of glioblastoma multiforme (GBM) patients with uniform treatment. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board and informed consent was waived. The MRI scans from 66 patients with newly diagnosed GBM from a previous prospective study were analyzed. Tumors were segmented manually on contrast-enhanced 3-dimensional T1-weighted images. Using these segmentations, P = 208 quantitative image features characterizing tumor shape, signal intensity, and texture were calculated in an automated fashion. On this data set, an RSF was trained using 10-fold cross validation to establish a link between image features and overall survival, and the individual risk for each patient was predicted. The mean concordance index was assessed as a measure of prediction accuracy. Association of individual risk with overall survival was assessed using Kaplan-Meier analysis and a univariate proportional hazards model. RESULTS: Mean overall survival was 14 months (range, 0.8-85 months). Mean concordance index of the 10-fold cross-validated RSF was 0.67. Kaplan-Meier analysis clearly distinguished 2 patient groups with high and low predicted individual risk (P = 5.5 * 10). Low predicted individual mortality was found to be a favorable prognostic factor for overall survival in a univariate Cox proportional hazards model (hazards ratio, 1.038; 95% confidence interval, 1.015 1.062; P = 0.0059). CONCLUSIONS: This study demonstrates that baseline MRI in GBM patients contains prognostic information, which can be accessed by radiomic analysis using RSFs. PMID- 28079703 TI - Metal Artifact Reduction Magnetic Resonance Imaging Around Arthroplasty Implants: The Negative Effect of Long Echo Trains on the Implant-Related Artifact. AB - OBJECTIVES: Long echo train length (ETL) is an often recommended but unproven technique to decrease metal artifacts on magnetic resonance imaging (MRI) scans. Therefore, we quantitatively and qualitatively assessed the effects of ETL on metal artifact on MRI scans using a cobalt-chromium-containing arthroplasty implant system. MATERIALS AND METHODS: Using a total ankle arthroplasty system implanted into a human cadaver ankle and a clinical 1.5 T MRI system, turbo spin echo (TSE) pulse sequences were acquired with ETL ranging from 3 to 23 and receiver bandwidth (BW) from 100 to 750 Hz/pixel, whereas effective echo time and spatial resolution were controlled. A compressed sensing slice encoding for metal artifact correction TSE prototype pulse sequence was used as reference standard. End points included the total implant-related artifact area and implant-related signal void areas. Two raters evaluated the overall image quality and preference across varying BW and ETL. Two-factor analysis of variance, Friedman test, Kruskal-Wallis test, and Pearson correlation were used. P values of less than 0.05 were considered statistically significant. RESULTS: The total implant related artifact area ranged from 0.119 for compressed sensing slice encoding for metal artifact correction (BW, 600 Hz/pixel; ETL, 3) to 0.265 for TSE (BW, 100 Hz/pixel; ETL, 23). Longer ETL significantly increases the total implant-related artifact area (P = 0.0004), whereas it decreased with increasing BW (P < 0.0001). Implant-related signal void areas were not significantly affected by larger echo train length, but reduced with higher BW (P < 0.0001). Readers had a significant preference for images with high BW and short ETL (P < 0.0001). CONCLUSIONS: High receiver BW is the most effective parameter for reduction of arthroplasty implant induced metal artifact on MRI scans, whereas in contradiction to prevalent notions, long echo trains fail to reduce implant-related metal artifacts, but in fact cause degradation of image quality around the implant with resultant larger appearing total metal artifacts. PMID- 28079704 TI - Modeling Perceived Exertion during Graded Arm Cycling Exercise in Spinal Cord Injury. AB - PURPOSE: RPE may be useful for exercise testing and prescription in individuals with spinal cord injury (SCI), although the roles of differentiated central and peripheral fatigue during exercise are not clear. We aimed to model differentiated RPE responses during graded arm cycling in individuals with SCI and to describe their relationship to cardiorespiratory outcomes. METHODS: Thirty six individuals with SCI (13 paraplegia and 23 tetraplegia) completed a maximal graded arm cycling exercise test to volitional exhaustion (5 W.min paraplegia; 10 W.min tetraplegia). Participants were asked to report central RPE (CRPE) and peripheral RPE (PRPE) every minute using the Borg category ratio (CR10) scale until termination of exercise. Heart rate and breath-by-breath respiratory outcomes were collected throughout the exercise test. Ventilatory threshold (VT) was assessed using the ventilatory equivalents method. RESULTS: Cardiorespiratory indices increased linearly during graded arm exercise. By contrast, both CRPE and PRPE responses were best fit to a quadratic model with positively accelerating growth in individuals with paraplegia (P < 0.01) and tetraplegia (P < 0.05). PRPE developed faster than CRPE in individuals with tetraplegia (P < 0.01). Individuals with paraplegia had accelerated CRPE (P < 0.05) and PRPE (P < 0.05) responses compared with tetraplegia, but not when considering only individuals who reached VT. PRPE was higher than CPRE only in the late stages (80%-100% test duration; P < 0.05) in both groups when only considering individuals who reached VT. CONCLUSIONS: PRPE develops faster than CRPE in individuals with tetraplegia in a nonlinear fashion, despite linear increases in cardiorespiratory responses during graded arm cycling. Although there is promise to use differentiated RPE for exercise testing and prescription within the SCI population, our results indicate that there are differences in how individuals with tetraplegia perceive peripheral versus central exertion. PMID- 28079705 TI - Prescribed Drinking Leads to Better Cycling Performance than Ad Libitum Drinking. AB - : Drinking ad libitum during exercise often leads to dehydration ranging from -1% to -3% of body weight. PURPOSE: This article aimed to study the effect of a prescribed hydration protocol matching fluid losses on a simulated 30-km criterium-like cycling performance in the heat (31.6 degrees C +/- 0.5 degrees C). METHODS: Ten elite heat-acclimatized male endurance cyclists (30 +/- 5 yr, 76.5 +/- 7.2 kg, 1.81 +/- 0.07 m, VO2peak = 61.3 +/- 5.2 mL.min.kg, body fat = 10.5% +/- 3.3%, Powermax = 392 +/- 33 W) performed three sets of criterium-like cycling, which consisted of a 5-km cycling at 50% power max followed by a 5-km cycling all out at 3% grade (total 30 km). Participants rode the course on two separate occasions and in a counterbalanced order, during either ad libitum drinking (AD; drink water as much as they wished) or prescribed drinking (PD; drink water every 1 km to much fluid losses). To design the fluid intake during PD, participants performed a familiarization trial to calculate fluid losses. RESULTS: After the exercise protocol, the cyclist dehydrated by -0.5% +/- 0.3% and -1.8% +/- 0.7% of their body weight for the PD and AD trial, respectively. The mean cycling speed for the third bout of the 5-km hill cycling was greater in the PD trial (30.2 +/- 2.4 km.h) compared with the AD trial (28.8 +/- 2.6 km.h) by 5.1% +/- 4.8% (P < 0.05). Gastrointestinal, mean skin, and mean body temperatures immediately after the last hill climbing were greater in the AD compared with the PD trial (P < 0.05). Overall, sweat sensitivity during the three climbing bouts was lower in the AD (15.6 +/- 5.7 g.W.m) compared with the PD trial (22.8 +/- 3.4 g.W.m, P < 0.05). CONCLUSION: The data suggested that PD to match fluid losses during exercise in the heat provided a performance advantage because of lower thermoregulatory strain and greater sweating responses. PMID- 28079707 TI - Effect of Number of Sprints in an SIT Session on Change in VO2max: A Meta analysis. AB - PURPOSE: Recent meta-analyses indicate that sprint interval training (SIT) improves cardiorespiratory fitness (VO2max), but the effects of various training parameters on the magnitude of the improvement remain unknown. The present meta analysis examined the modifying effect of the number of sprint repetitions in an SIT session on improvements in VO2max. METHODS: The databases PubMed and Web of Science were searched for original studies that have examined pre- and posttraining VO2max in adults after >=2 wk of training consisting of repeated (>=2) Wingate-type cycle sprints, published up to May 1, 2016. Articles were excluded if they were not in English; if they involved patients, athletes, or participants with a mean baseline VO2max of >55 mL.kg.min or a mean age <18 yr; and if an SIT trial was combined with another intervention or used intervals shorter than 10 s. A total of 38 SIT trials from 34 studies were included in the meta-analysis. Probabilistic magnitude-based inferences were made to interpret the outcome of the analysis. RESULTS: The meta-analysis revealed a likely large effect of a typical SIT intervention on VO2max (mean +/- 90% confidence limits = 7.8% +/- 4.0%) with a possibly small modifying effect of the maximum number of sprint repetitions in a training session (-1.2% +/- 0.8% decrease per two additional sprint repetitions). Apart from possibly small effects of baseline VO2max and age, all other modifying effects were unclear or trivial. CONCLUSION: We conclude that the improvement in VO2max with SIT is not attenuated with fewer sprint repetitions, and possibly even enhanced. This means that SIT protocols can be made more time efficient, which may help SIT to be developed into a viable strategy to impact public health. PMID- 28079706 TI - Ibuprofen before Exercise Does Not Prevent Cortical Bone Adaptations to Training. AB - : Using a nonsteroidal anti-inflammatory drug (NSAID) before a single bout of mechanical loading can reduce bone formation response. It is unknown whether this translates to an attenuation of bone strength and structural adaptations to exercise training. PURPOSE: This study aimed to determine whether nonsteroidal anti-inflammatory drug use before exercise prevents increases in bone structure and strength in response to weight-bearing exercise. METHODS: Adult female Wistar rats (n = 43) were randomized to ibuprofen (IBU) or vehicle (VEH) and exercise (EX) or sedentary (SED) groups in a 2 * 2 (drug and activity) ANCOVA design with body weight as the covariate, and data are reported as mean +/- SE. IBU drops (30 mg.kg BW) or VEH (volume equivalent) were administered orally 1 h before the bout of exercise. Treadmill running occurred 5 d.wk for 60 min.d at 20 m.min with a 5 degrees incline for 12 wk. Micro-CT, mechanical testing, and finite element modeling were used to quantify bone characteristics. RESULTS: Drug-activity interactions were not significant. Exercise increased tibia cortical cross sectional area (EX = 5.67 +/- 0.10, SED = 5.37 +/- 0.10 mm, P < 0.01) and structural estimates of bone strength (Imax: EX = 5.16 +/- 0.18, SED = 4.70 +/- 0.18 mm, P < 0.01; SecModPolar: EX = 4.01 +/- 0.11, SED = 3.74 +/- 0.10 mm, P < 0.01). EX had increased failure load (EX = 243 +/- 9, SED = 202 +/- 7 N, P < 0.05) and decreased distortion in response to a 200-N load (von Mises stress at tibia-fibula junction: EX = 48.2 +/- 1.3, SED = 51.7 +/- 1.2 MPa, P = 0.01). There was no effect of ibuprofen on any measurement tested. Femur results revealed similar patterns. CONCLUSION: Ibuprofen before exercise did not prevent the skeletal benefits of exercise in female rats. However, exercise that engenders higher bone strains may be required to detect an effect of ibuprofen. PMID- 28079708 TI - Parenteral nutrition in the critically ill. AB - PURPOSE OF REVIEW: Feeding guidelines have recommended early, full nutritional support in critically ill patients to prevent hypercatabolism and muscle weakness. Early enteral nutrition was suggested to be superior to early parenteral nutrition. When enteral nutrition fails to meet nutritional target, it was recommended to administer supplemental parenteral nutrition, albeit with a varying starting point. Sufficient amounts of amino acids were recommended, with addition of glutamine in subgroups. Recently, several large randomized controlled trials (RCTs) have yielded important new insights. This review summarizes recent evidence with regard to the indication, timing, and dosing of parenteral nutrition in critically ill patients. RECENT FINDINGS: One large RCT revealed no difference between early enteral nutrition and early parenteral nutrition. Two large multicenter RCTs showed harm by early supplementation of insufficient enteral nutrition with parenteral nutrition, which could be explained by feeding induced suppression of autophagy. Several RCTs found either no benefit or harm with a higher amino acid or caloric intake, as well as harm by administration of glutamine. SUMMARY: Although unanswered questions remain, current evidence supports accepting low macronutrient intake during the acute phase of critical illness and does not support use of early parenteral nutrition. The timing when parenteral nutrition can be initiated safely and effectively is unclear. PMID- 28079709 TI - Meaningful Use of Electronic Health Records by Outpatient Physicians and Readmissions of Medicare Fee-for-Service Beneficiaries. AB - BACKGROUND: Nearly one-fifth of hospitalized Medicare fee-for-service beneficiaries are readmitted within 30 days. Participation in the Meaningful Use initiative among outpatient physicians may reduce readmissions. OBJECTIVE: To evaluate the impact of outpatient physicians' participation in Meaningful Use on readmissions. SUBJECTS AND RESEARCH DESIGN: The study population included 90,774 Medicare fee-for-service beneficiaries from New York State (2010-2012). We compared changes in the adjusted odds of readmission for patients of physicians who participated in Meaningful Use-stage 1, before and after attestation as meaningful users, with concurrent patients of matched control physicians who used paper records or electronic health records without Meaningful Use participation. Three secondary analyses were conducted: (1) limited to patients with 3+ Elixhauser comorbidities; (2) limited to patients with conditions used by Medicare to penalize hospitals with high readmission rates (acute myocardial infarction, congestive heart failure, and pneumonia); and (3) using only patients of physicians with electronic health records who were not meaningful users as the controls. MAIN OUTCOME: Thirty-day readmission. RESULTS: Patients of Meaningful Use physicians had 6% lower odds of readmission compared with patients of physicians who were not meaningful users, but the estimate was not statistically significant (odds ratio: 0.94, 95% confidence interval, 0.88-1.01). Estimated odds ratios from secondary analyses were broadly consistent with our primary analysis. CONCLUSIONS: Physician participation in Meaningful Use was not associated with reduced readmissions. Additional studies are warranted to see if readmissions decline in future stages of Meaningful Use where more emphasis is placed on health information exchange and outcomes. PMID- 28079710 TI - Electronic Health Record Data Versus the National Health and Nutrition Examination Survey (NHANES): A Comparison of Overweight and Obesity Rates. AB - BACKGROUND: Estimating population-level obesity rates is important for informing policy and targeting treatment. The current gold standard for obesity measurement in the United States-the National Health and Nutrition Examination Survey (NHANES)-samples <0.1% of the population and does not target state-level or health system-level measurement. OBJECTIVE: To assess the feasibility of using body mass index (BMI) data from the electronic health record (EHR) to assess rates of overweight and obesity and compare these rates to national NHANES estimates. RESEARCH DESIGN: Using outpatient data from 42 clinics, we studied 388,762 patients in a large health system with at least 1 primary care visit in 2011-2012. MEASURES: We compared crude and adjusted overweight and obesity rates by age category and ethnicity (white, black, Hispanic, Other) between EHR and NHANES participants. Adjusted overweight (BMI>=25) and obesity rates were calculated by a 2-step process. Step 1 accounted for missing BMI data using inverse probability weighting, whereas step 2 included a poststratification correction to adjust the EHR population to a nationally representative sample. RESULTS: Adjusted rates of obesity (BMI>=30) for EHR patients were 37.3% [95% confidence interval (95% CI), 37.1-37.5] compared with 35.1% (95% CI, 32.3-38.1) for NHANES patients. Among the 16 different obesity class, ethnicity, and sex strata that were compared between EHR and NHANES patients, 14 (87.5%) contained similar obesity estimates (ie, overlapping 95% CIs). CONCLUSIONS: EHRs may be an ideal tool for identifying and targeting patients with obesity for implementation of public health and/or individual level interventions. PMID- 28079711 TI - Cell Signaling Pathways in Brain Tumors. AB - Primary brain tumors, particularly glioblastoma, are associated with significant morbidity and are often recalcitrant to standard therapies. In recent years, brain tumors have been the focus of large-scale genomic sequencing efforts, providing unprecedented insight into the genomic aberrations and cellular signaling mechanisms that drive these cancers. Discoveries from these efforts have translated into novel diagnostic algorithms, biomarkers, and therapeutic strategies in Neuro-Oncology. However, the cellular mechanisms that drive brain tumors are heterogeneous and complex: applying this new knowledge to improve patient outcomes remains a challenge. Efforts to characterize and target these molecular vulnerabilities are evolving. PMID- 28079712 TI - A Comprehensive Review of Genomics and Noncoding RNA in Gliomas. AB - Glioblastoma (GBM) is the most malignant primary adult brain tumor. In spite of our greater understanding of the biology of GBMs, clinical outcome of GBM patients remains poor, as their median survival with best available treatment is 12 to 18 months. Recent efforts of The Cancer Genome Atlas (TCGA) have subgrouped patients into 4 molecular/transcriptional subgroups: proneural, neural, classical, and mesenchymal. Continuing efforts are underway to provide a comprehensive map of the heterogeneous makeup of GBM to include noncoding transcripts, genetic mutations, and their associations to clinical outcome. In this review, we introduce key molecular events (genetic and epigenetic) that have been deemed most relevant as per studies such as TCGA, with a specific focus on noncoding RNAs such as microRNAs (miRNA) and long noncoding RNAs (lncRNA). One of our main objectives is to illustrate how miRNAs and lncRNAs play a pivotal role in brain tumor biology to define tumor heterogeneity at molecular and cellular levels. Ultimately, we elaborate how radiogenomics-based predictive models can describe miRNA/lncRNA-driven networks to better define heterogeneity of GBM with clinical relevance. PMID- 28079713 TI - Interrogating IDH Mutation in Brain Tumor: Magnetic Resonance and Hyperpolarization. AB - Magnetic resonance spectroscopy (MRS) offers the possibility to noninvasively quantify 2HG concentration in the brain in the clinic, thereby serving as a valuable tool for patient-stratification as well as targeted treatment monitoring. Recently, hyperpolarized magnetic resonance techniques have opened up new opportunities for metabolic imaging not possible with conventional MRS in the brain. With over 10,000-fold increase in signal-to-noise ratio (SNR), dynamic metabolic processes can be interrogated in vivo with very high specificity by hyperpolarized MRI. In the following article, we will review relevant clinical studies and practical considerations of MRS and hyperpolarized MRS, as well as discuss some promising preclinical hyperpolarization studies to interrogate real time metabolism in IDH mutations in vivo. PMID- 28079714 TI - Radiomic Phenotyping in Brain Cancer to Unravel Hidden Information in Medical Images. AB - Radiomics is a new area of research in the field of imaging with tremendous potential to unravel the hidden information in digital images. The scope of radiology has grown exponentially over the last two decades; since the advent of radiomics, many quantitative imaging features can now be extracted from medical images through high-throughput computing, and these can be converted into mineable data that can help in linking imaging phenotypes with clinical data, genomics, proteomics, and other "omics" information. In cancer, radiomic imaging analysis aims at extracting imaging features embedded in the imaging data, which can act as a guide in the disease or cancer diagnosis, staging and planning interventions for treating patients, monitor patients on therapy, predict treatment response, and determine patient outcomes. PMID- 28079715 TI - From K-space to Nucleotide: Insights Into the Radiogenomics of Brain Tumors. AB - Radiogenomics is a relatively new and exciting field within radiology that links different imaging features with diverse genomic events. Genomics advances provided by the Cancer Genome Atlas and the Human Genome Project have enabled us to harness and integrate this information with noninvasive imaging phenotypes to create a better 3-dimensional understanding of tumor behavior and biology. Beyond imaging-histopathology, imaging genomic linkages provide an important layer of complexity that can help in evaluating and stratifying patients into clinical trials, monitoring treatment response, and enhancing patient outcomes. This article reviews some of the important radiogenomic literatures in brain tumors. PMID- 28079716 TI - Promotion of Research on the HIV Continuum of Care in the United States: The CFAR HIV Continuum of Care/ECHPP Working Group. PMID- 28079717 TI - "Out of Care" HIV Case Investigations: A Collaborative Analysis Across 6 States in the Northwest US. AB - BACKGROUND: HIV care continuum estimates derived from laboratory surveillance typically assume that persons without recently reported CD4 count or viral load results are out of care. METHODS: We conducted a multistate project (Alaska, Idaho, Montana, Oregon, Washington, and Wyoming) to ascertain the status of HIV cases that appeared to be out of care during a 12-month period. We used laboratory surveillance to identify cases in all states but Idaho, where viral load reporting is not mandatory, requiring us to rely on clinic records. After complete investigation, we assigned each case one of the following dispositions: moved out of state, died, in HIV care, no evidence of HIV care, or data error. RESULTS: We identified 3866 cases with no CD4 count or viral load result in a >=12-month period during 2012-2014, most (85%) of which were in Washington or Oregon. A median of 43% (range: 20%-67%) of cases investigated in each state had moved, 9% (0%-16%) had died, and 11% (8%-33%) were in care during the 12-month surveillance period. Only 28% of investigated cases in the region and a median of 30% (10%-57%) of investigated cases in each state had no evidence of care, migration, or death after investigation. CONCLUSIONS: Most persons living with HIV in the Northwest United States who appear to be out of care based on laboratory surveillance are not truly out of care. Our findings highlight the importance of improving state surveillance systems to ensure accurate care continuum estimates and guide Data to Care efforts. PMID- 28079718 TI - Longitudinal HIV Care Trajectories in North Carolina. AB - BACKGROUND: Long-term HIV care and treatment engagement is required for maximal clinical and prevention benefits, but longitudinal care patterns are poorly understood. We used the last 10 years' worth of HIV surveillance data from North Carolina to describe longitudinal HIV care trajectories from diagnosis. METHODS: We conducted a retrospective, population-based cohort study of all persons newly diagnosed with HIV in North Carolina between March 31, 2006 and March 31, 2015 (N = 16,207). We defined HIV care attendance in each 3-month and 6-month interval after diagnosis as the presence of viral load and/or CD4 records (care visit proxies) in the interval. We used group-based trajectory modeling to identify common care trajectories and baseline predictors thereof. RESULTS: A predicted 26% of newly HIV-diagnosed persons showed consistently high care attendance over time; ~16% exhibited steadily declining attendance; ~26% showed consistently low attendance; ~17% had initially weak attendance with an increase starting ~1.5 year later; and ~15% showed initially weak attendance with an increase starting ~3 years later. Older age at diagnosis was protective against all suboptimal trajectories (with the "consistently high" pattern as referent), and being a man who has sex with men was protective against 3 of the 4 suboptimal patterns. CONCLUSIONS: As measured by surveillance-based laboratory proxies, most newly HIV diagnosed persons exhibited suboptimal care trajectories, but there was wide variation in the particular pathways followed. The insights provided by this analytical approach can help to inform the design of epidemic models and tailored interventions, with the ultimate goal of improving HIV care engagement and transmission prevention. PMID- 28079719 TI - Feasibility of Using HIV Care-Continuum Outcomes to Identify Geographic Areas for Targeted HIV Testing. AB - BACKGROUND: Improved detection and linkage to care of previously undiagnosed HIV infections require innovative approaches to testing. We sought to determine the feasibility of targeted HIV testing in geographic areas, defined by continuum of care parameters, to identify HIV-infected persons needing linkage or engagement in care. METHODS: Using HIV surveillance data from Washington, DC, we identified census tracts that had an HIV prevalence >1% and were either above (higher risk areas-HRAs) or below (lower risk areas-LRAs) the median for 3 indicators: monitored viral load, proportion of persons out of care (OOC), and never in care. Community-based HIV rapid testing and participant surveys were conducted in the 20 census tracts meeting the criteria. Areas were mapped using ArcGIS, and descriptive and univariate analyses were conducted comparing the areas and participants. RESULTS: Among 1471 persons tested, 28 (1.9%) tested HIV positive; 2.1% in HRAs vs. 1.7% in LRAs (P = 0.57). Higher proportions of men (63.7% vs. 56.7%, P = 0.007) and fewer blacks (91.0% vs. 94.6%, P = 0.008) were tested in LRAs vs. HRAs; no differences were observed in risk behaviors between the areas. Among HIV-positive participants, 54% were new diagnoses (n = 9) or OOC (n = 6), all were Black, 64% were men with a median age of 51 years. CONCLUSIONS: Although significant differences in HIV seropositivity were not observed between testing areas, our approach proved feasible and enabled identification of new diagnoses and OOC HIV-infected persons. This testing paradigm could be adapted in other locales to identify areas for targeted HIV testing and other reengagement efforts. PMID- 28079720 TI - !Solo Se Vive Una Vez! (You Only Live Once): A Pilot Evaluation of Individually Tailored Video Modules Aiming to Increase HIV Testing Among Foreign-Born Latino Men. AB - BACKGROUND: Although Latinos living in the United States are disproportionately affected by HIV, the development, implementation, and evaluation of HIV prevention, testing, and linkage to care interventions lag behind efforts occurring in other communities. To address sociocultural barriers to testing, we developed a multilevel intervention. This study is a pilot evaluation of the individual-level component of the intervention-animated video modules that address specific barriers to HIV testing common among foreign-born Latino men. METHODS: We conducted a survey assessing HIV risk and barriers to testing with a convenience sample of 104 foreign-born Latino men in Baltimore, MD, who had not tested for HIV within the past year. Intention to test in the next 3 months was measured before and after viewing an intervention module selected based on survey responses. RESULTS: Fifty-two (50.0%) participants had never tested for HIV. Of the participants who had previously tested for HIV, the mean time since their last test was 3.48 years (SD = 3.55). Participants' intention to test for HIV significantly increased after watching the module (t = -8.28, P < 0.001). Increased intention to test was not associated with any socio-demographic characteristics (ie, age, country of origin) or reported sexual behaviors (ie, number of sex partners in the past year). DISCUSSION: These results suggest that our culturally sensitive, individually tailored intervention can be an additional tool to encourage HIV testing among previously untested foreign-born Latino men, one of the demographic groups at highest risk for delayed HIV diagnosis in the United States. PMID- 28079721 TI - An Exploratory Study to Assess Individual and Structural Level Barriers Associated With Poor Retention and Re-engagement in Care Among Persons Living With HIV/AIDS. AB - BACKGROUND: Retention in care is the most challenging step along the HIV care continuum. Many patients who engage in care and achieve viral suppression have care interruptions, characterized by moving in and out of care ("churn"). Poor retention has clinical consequences and contributes to new HIV transmissions, but how to predict or prevent it remains elusive. This study sought to understand the relationship between individual- and structural-level barriers, and poor retention for persons living with HIV/AIDS in Atlanta, GA. METHODS: We administered a survey, through interviews, with HIV-infected patients continuously retained in care for 6 years ("continuously retained," n = 32) and patients with recent gaps in care ("unretained" n = 27). We assessed individual level protective factors for successful engagement (self-efficacy, resilience, perceived social support, and disclosure), risk factors for poor engagement (substance use, mental illness, and stigma), and structural/systemic-level barriers (financial and housing instability, transportation, food insecurity, communication barriers, and incarceration history). Chi-square and Mann-Whitney U tests were used to compare the 2 populations. RESULTS: Both continuously retained and unretained populations had high rates of prior viral suppression but few unretained patients were virologically suppressed upon return to care (11%). Younger age, crack cocaine use, food insecurity, financial instability, housing instability, and phone number changes in the past year were significantly more likely to be present in the unretained population. CONCLUSIONS: Our findings suggest the need for targeted risk assessment tools to predict the highest-risk patients for poor retention whereby public health interventions can be directed to those individuals. PMID- 28079722 TI - Development and Preliminary Pilot Testing of a Peer Support Text Messaging Intervention for HIV-Infected Black Men Who Have Sex With Men. AB - BACKGROUND: Black men who have sex with men (MSM) are disproportionately infected with HIV and are less well retained along the HIV continuum of care. We report on the feasibility of a peer support text messaging intervention designed to increase retention in HIV care and HIV medication adherence among HIV-infected black men who have sex with men. METHODS: Based on formative research, a cell phone app was developed to support a peer-based text messaging intervention. The app allowed the researchers to view text messages sent between mentors and mentees, but did not allow them to view other text messages sent by these phones. Three HIV-infected black men who have sex with men were recruited to serve as volunteer peer mentors. They were trained in motivational techniques, peer support skills, and skills for improving appointment attendance and medication adherence. Mentees (N = 8) received the intervention for 1 month. Mentees completed a postintervention survey and interview. RESULTS: The peer mentor text messaging intervention was feasible. Mentors delivered support in a nonjudgmental, motivational way. However, technical and other implementation problems arose. Some mentees desired more frequent contact with mentors, and mentors reported that other commitments made it difficult at times to be fully engaged. Both mentors and mentees desired more personalized contact (ie, phone calls). CONCLUSIONS: A text messaging peer mentor intervention was feasible. Additional research with a larger sample is needed to determine optimal ways to improve mentors' engagement in the intervention and to determine intervention acceptability and efficacy. In future studies, peer support phone calls could be incorporated. PMID- 28079723 TI - Toward Automating HIV Identification: Machine Learning for Rapid Identification of HIV-Related Social Media Data. AB - INTRODUCTION: "Social big data" from technologies such as social media, wearable devices, and online searches continue to grow and can be used as tools for HIV research. Although researchers can uncover patterns and insights associated with HIV trends and transmission, the review process is time consuming and resource intensive. Machine learning methods derived from computer science might be used to assist HIV domain experts by learning how to rapidly and accurately identify patterns associated with HIV from a large set of social data. METHODS: Using an existing social media data set that was associated with HIV and coded by an HIV domain expert, we tested whether 4 commonly used machine learning methods could learn the patterns associated with HIV risk behavior. We used the 10-fold cross validation method to examine the speed and accuracy of these models in applying that knowledge to detect HIV content in social media data. RESULTS AND DISCUSSION: Logistic regression and random forest resulted in the highest accuracy in detecting HIV-related social data (85.3%), whereas the Ridge Regression Classifier resulted in the lowest accuracy. Logistic regression yielded the fastest processing time (16.98 seconds). CONCLUSIONS: Machine learning can enable social big data to become a new and important tool in HIV research, helping to create a new field of "digital HIV epidemiology." If a domain expert can identify patterns in social data associated with HIV risk or HIV transmission, machine learning models could quickly and accurately learn those associations and identify potential HIV patterns in large social data sets. PMID- 28079725 TI - New Medicine for the U.S. Health Care System: Training Physicians for Structural Interventions. AB - Structural competency provides a language and theoretical framework to promote institutional-level interventions by clinical practitioners working with community organizations, non-health-sector institutions, and policy makers. The special collection of articles on structural competency in this issue of Academic Medicine addresses the need to move from theory to an appraisal of core educational interventions that operationalize the goals of and foster structural competency. In this Commentary, the authors review the role of clinical practitioners in enhancing population-level health outcomes through collaborations with professionals in fields outside medicine, including the social sciences and law. They describe the core elements of structural competency in preclinical and clinical education, as illustrated by the articles of this special collection: perceiving the structural causes of patients' disease, envisioning structural interventions, and cultivating alliances with non-health sector agencies that can implement structural interventions. Finally, the authors argue that preparing trainees to form partnerships will empower them to influence the social determinants of their patients' health and reduce health inequalities. PMID- 28079726 TI - The Charter on Professionalism for Health Care Organizations. AB - In 2002, the Physician Charter on Medical Professionalism was published to provide physicians with guidance for decision making in a rapidly changing environment. Feedback from physicians indicated that they were unable to fully live up to the principles in the 2002 charter partly because of their employing or affiliated health care organizations. A multistakeholder group has developed a Charter on Professionalism for Health Care Organizations, which may provide more guidance than charters for individual disciplines, given the current structure of health care delivery systems.This article contains the Charter on Professionalism for Health Care Organizations, as well as the process and rationale for its development. For hospitals and hospital systems to effectively care for patients, maintain a healthy workforce, and improve the health of populations, they must attend to the four domains addressed by the Charter: patient partnerships, organizational culture, community partnerships, and operations and business practices. Impacting the social determinants of health will require collaboration among health care organizations, government, and communities.Transitioning to the model hospital described by the Charter will challenge historical roles and assumptions of both its leadership and staff. While the Charter is aspirational, it also outlines specific institutional behaviors that will benefit both patients and workers. Lastly, this article considers obstacles to implementing the Charter and explores avenues to facilitate its dissemination. PMID- 28079727 TI - How Supervisor Experience Influences Trust, Supervision, and Trainee Learning: A Qualitative Study. AB - PURPOSE: Appropriate trust and supervision facilitate trainees' growth toward unsupervised practice. The authors investigated how supervisor experience influences trust, supervision, and subsequently trainee learning. METHOD: In a two-phase qualitative inductive content analysis, phase one entailed reviewing 44 internal medicine resident and attending supervisor interviews from two institutions (July 2013 to September 2014) for themes on how supervisor experience influences trust and supervision. Three supervisor exemplars (early, developing, experienced) were developed and shared in phase two focus groups at a single institution, wherein 23 trainees validated the exemplars and discussed how each impacted learning (November 2015). RESULTS: Phase one: Four domains of trust and supervision varying with experience emerged: data, approach, perspective, clinical. Early supervisors were detail oriented and determined trust depending on task completion (data), were rule based (approach), drew on their experiences as trainees to guide supervision (perspective), and felt less confident clinically compared with more experienced supervisors (clinical). Experienced supervisors determined trust holistically (data), checked key aspects of patient care selectively and covertly (approach), reflected on individual experiences supervising (perspective), and felt comfortable managing clinical problems and gauging trainee abilities (clinical). Phase two: Trainees felt the exemplars reflected their experiences, described their preferences and learning needs shifting over time, and emphasized the importance of supervisor flexibility to match their learning needs. CONCLUSIONS: With experience, supervisors differ in their approach to trust and supervision. Supervisors need to trust themselves before being able to trust others. Trainees perceive these differences and seek supervision approaches that align with their learning needs. PMID- 28079728 TI - Surveying Resident and Faculty Physician Knowledge, Attitudes, and Experiences in Response to Public Lead Contamination. AB - Environmental health crises can appear anywhere and without warning. After research revealed a significant incidence of elevated pediatric blood lead levels following a water source change, Genesee County declared a public health emergency in Flint, Michigan. Hospital patients and family members began approaching Hurley Medical Center's physicians with questions regarding the health implications of the lead contamination. Many of the physicians voiced concerns about responding appropriately to patient needs and increasing demands for information. As a result, a Hurley research team decided to conduct an informal survey across training programs to determine the need for added education.Because of heightened patient anxiety, it was necessary for the timeline to progress quickly. In creating the survey, the team's objective was to assess resident and faculty physician knowledge, attitudes, and experiences concerning lead contamination. The results revealed a critical need for supplementary training. Therefore, Hurley embarked on an education campaign for its graduate medical education programs, benefiting physicians and patients alike.Patient and physician needs may change drastically following an environmental health emergency. It is the duty of medical centers to ensure their clinicians are well equipped to confront such threats. As prompt treatment is often a key to positive health outcomes, the authors stress the importance of acting quickly and suggest conducting informal surveys to identify gaps in physician knowledge. Likewise, the authors encourage medical educators nationwide to examine their environmental health curricula. It appears lead-contaminated water is not just a Flint problem but may have far-reaching implications for many cities. PMID- 28079729 TI - Effect of Probiotics on Diarrhea in Children With Severe Acute Malnutrition: A Randomized Controlled Study in Uganda. AB - OBJECTIVES: The aim of the study was to assess the effect of probiotics on diarrhea during in- and outpatient treatment of children with severe acute malnutrition (SAM). METHODS: A randomized, double-blind, placebo-controlled study was conducted involving 400 children admitted with SAM. Patients received 1 daily dose of a blend of Bifidobacterium animalis subsp lactis and Lactobacillus rhamnosus (10 billion colony-forming units, 50:50) or placebo during hospitalization followed by an 8- to 12-week outpatient treatment period, depending on patients' recovery rate. All outcomes were reported for in- and outpatient treatment separately. The primary outcome was number of days with diarrhea during hospitalization. Secondary outcomes included other diarrhea outcomes, pneumonia, weight gain, and recovery. RESULTS: There was no difference in number of days with diarrhea between the probiotic (n = 200) and placebo (n = 200) groups during inpatient treatment (adjusted difference +0.2 days, 95% confidence interval -0.8 to 1.2, P = 0.69); however, during outpatient treatment, probiotics reduced days with diarrhea (adjusted difference -2.2 days 95% confidence interval -3.5 to -0.3, P = 0.025). There were no effects of probiotics on diarrhea incidence and severity or pneumonia, weight gain or recovery during in- or outpatient treatment. Twenty-six patients died in the probiotic versus 20 in the placebo group (P = 0.38). CONCLUSIONS: Bifidobacterium animalis subsp lactis and Lactobacillus rhamnosus had no effect on diarrhea in children with SAM during hospitalization, but reduced the number of days with diarrhea in outpatient treatment by 26%. Probiotics may have a role in follow-up of hospitalized children with SAM or in community-based treatment of malnourished children, but further studies are needed to confirm this. PMID- 28079730 TI - Biomechanical Comparison of Cadaveric and Commercially Available Synthetic Osteoporotic Bone Analogues in a Locked Plate Fracture Model Under Torsional Loading. AB - OBJECTIVES: Biomechanical studies of osteoporotic bone have used synthetic models rather than cadaveric samples because of decreased variability, increased availability, and overall ease of the use of synthetic models. We compared the torsional mechanical properties of cadaveric osteoporotic bone with those of currently available synthetic osteoporotic bone analogues. METHODS: We tested 12 osteoporotic cadaveric humeri and 6 specimens each of 6 types of synthetic analogues. A 5-mm fracture gap model and posterior plating technique with 4.5-mm narrow 10-hole locking compression plate were used. Torque was applied to a peak of +/-10 N.m for 1000 cycles at 0.3 Hz. Data were continuously collected during cyclical and ramped loading with a servohydraulic materials testing system. RESULTS: Cadaveric bone had a 17% failure rate before completing 1000 cycles. Three osteoporotic bone models had 100% failure (P < 0.05), 2 had 17% failure, and 1 had 0% failure before 1000 cycles. Significant differences in the stiffness of the 3 types of synthetic bone models that survived cyclic loading were noted compared with the cadaveric bone model (P < 0.05). Osteoporotic bone analogues had torsional mechanical properties different from those of osteoporotic cadaveric specimens. CONCLUSIONS: The differences between osteoporotic cadaveric humeri and synthetic osteoporotic bone analogues ranged from profound with complete catastrophic failure after a few cycles to subtler differences in stiffness and strain hardening. These findings suggest that different bone analogue models vary substantially in their torsional mechanical properties and might not be appropriate substitutes for cadaveric bone in biomechanical studies of osteoporotic bone. PMID- 28079731 TI - Midterm Radiographic and Functional Outcomes of the Anterior Subcutaneous Internal Pelvic Fixator (INFIX) for Pelvic Ring Injuries. AB - OBJECTIVE: To describe our experience using the anterior internal pelvic fixator (INFIX) for treating pelvic ring injuries. DESIGN: Case Series. SETTING: Level 1 Trauma Center. PATIENTS: Eighty-three patients with pelvic ring injuries were treated with INFIX. Follow-up average was 35 months (range 12-80.33). INTERVENTION: Surgical treatment of pelvic ring injuries included reduction, appropriate posterior fixation, and INFIX placement. OUTCOME MEASUREMENTS: Reduction using the pelvic deformity index and pubic symphysis widening, Majeed functional scores, complications; infection, implant failure, heterotopic ossification (HO), nerve injury, and pain. RESULTS: All patients healed in an appropriate time frame (full weight bearing 12 weeks postoperation). The average pelvic deformity index reduction (injury = 0.0420 +/- 0.0412, latest FU = 0.0254 +/- 0.0243) was 39.58%. The average reduction of pubic symphysis injuries was 56.92%. The average Majeed score of patients at latest follow-up was 78.77 (range 47-100). Complications were 3 infections, 1 case of implant failure, 2 cases implantation too deep, 7 cases of lateral femoral cutaneous nerve irritation, and 3 cases of pain associated with the device. HO was seen in >50% of the patients, correlated with increased age (P < 0.007), injury severity score (P < 0.05) but only 1 case was symptomatic. CONCLUSIONS: The pelvic injuries had good functional and radiological outcomes with INFIX and the appropriate posterior fixation. The downside is removal requiring a second anesthetic, there is a learning curve, HO often occurs, the lateral femoral cutaneous nerve may get irritated which often resolves once the implants are removed. Surgery-specific implants need to be developed. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28079733 TI - "A Tale of Two Planes": Deep Versus Superficial Serratus Plane Block for Postmastectomy Pain Syndrome. AB - INTRODUCTION: Postmastectomy pain syndrome (PMPS) is a significant burden for breast cancer survivors. Although multiple therapies have been described, an evolving field of serratus anterior plane blocks has been described in this population. We describe the addition of the deep serratus anterior plane block (DSPB) for PMPS. METHODS: Four patients with history of PMPS underwent DSPB for anterior chest wall pain. A retrospective review of these patients' outcomes was obtained through postprocedure interviews. RESULTS: Three of the patients previously had a superficial serratus anterior plane block, which was not as efficacious as the DSPB. The fourth patient had a superficial serratus anterior plane that was difficult to separate with hydrodissection but had improved pain control with a DSPB. CONCLUSIONS: We illustrate 4 patients who have benefitted from a DSPB and describe indications that this block may be more efficacious than a superficial serratus plane block. Further study is recommended to understand the intercostal nerve branches within the lateral and anterior muscular chest wall planes. PMID- 28079734 TI - Thoracic Epidural Anesthesia and Prophylactic Three Times Daily Unfractionated Heparin Within an Enhanced Recovery After Surgery Pathway for Colorectal Surgery. AB - BACKGROUND AND OBJECTIVES: Venous thromboembolism (VTE) is a common cause of preventable harm. Perioperative thoracic epidural analgesia (TEA) presents a challenge to optimal VTE prophylaxis. Our primary aim was to characterize missed doses of VTE prophylaxis associated with epidural catheter placement and removal. Our secondary aim was to measure the effect of an enhanced recovery after surgery (ERAS) pathway on the rate of TEA-associated missed VTE prophylaxis. METHODS: We retrospectively reviewed a prospectively collected database of 1264 colorectal surgery patients at a single academic center. Missed preoperative doses between TEA patients and non-TEA patients were compared. Missed postoperative unfractionated heparin (UFH) doses associated with epidural removal were compared before and after implementation of an ERAS program. Other data collected included demographic data, surgical indication, and thrombohemorrhagic complications. RESULTS: Of the 445 TEA patients, 12.6% missed their preoperative heparin doses compared with 8.4% of patients without epidurals (P = 0.017). Of the TEA patients prescribed 3 times daily UFH, 22.5% missed one or more doses associated with epidural removal. The percent of patients missing at least one dose of UFH on epidural removal dropped from 28.1% before ERAS to 17.9% after the ERAS program (P = 0.023). Seven patients developed VTEs. There were zero epidural hematomas. CONCLUSIONS: Thoracic epidural analgesia was associated with a 1.5-fold increased risk of missed dose of preoperative VTE prophylaxis, which was not affected by implementation of an ERAS program. The implementation of an ERAS program reduced missed doses associated with epidural removal. This study highlights the challenge posed by providing VTE prophylaxis in the setting of perioperative neuraxial analgesia. PMID- 28079735 TI - Incidence of Local Anesthetic Systemic Toxicity in Orthopedic Patients Receiving Peripheral Nerve Blocks. AB - BACKGROUND AND OBJECTIVES: Peripheral nerve blocks are increasingly used. However, despite low complication rates, concerns regarding local anesthetic systemic toxicity remain. Although recent studies suggest that this severe complication has decreased considerably, there is a paucity of data about it on a national level. We sought to elucidate the incidence of local anesthetic systemic toxicity on a national level and therefore provide guidance toward the need for preparedness in daily anesthetic practice. METHODS: We searched a large administrative database for patients who received peripheral nerve blocks for total joint arthroplasties from 2006 to 2014. Their discharge and billing data were analyzed for International Classification of Diseases, Ninth Revision, Clinical Modification codes coding for local anesthetic systemic toxicity or surrogate outcomes including cardiac arrest, seizures, and use of lipid emulsion on the day of surgery. Rates for these outcomes were determined cumulatively and over time. RESULTS: We identified 238,473 patients who received a peripheral nerve block within the study period. The cumulative rate of outcomes among these patients in the study period was 0.18%. There was a significant decrease of overall outcome rates between 2006 and 2014. Use of lipid emulsion on the day of surgery increased significantly in total knee replacement from 0.02% 2006 to 0.26% in 2014. CONCLUSIONS: The incidence of local anesthetic systemic toxicity is low but should be considered clinically significant. Since it may cause substantial harm to the patient, appropriate resources and awareness to identify and treat local anesthetic systemic toxicity should be available wherever regional anesthesia is performed. PMID- 28079736 TI - Report on Neurosciences Sessions During the 16th World Congress of Anaesthesiologists (WCA 2016 Hong Kong). PMID- 28079737 TI - Dexmedetomidine Reduces Perioperative Opioid Consumption and Postoperative Pain Intensity in Neurosurgery: A Meta-analysis. AB - BACKGROUND: Dexmedetomidine (DEX) has been administered to patients during neurosurgery. Some studies have found that DEX could reduce perioperative opioid consumption and postoperative pain intensity. However, no firm conclusions have been reached. The purpose of this meta-analysis was to assess the efficacy of DEX for managing pain in neurosurgical patients. MATERIALS AND METHODS: A comprehensive literature review was conducted to identify randomized controlled trials (RCTs) focusing on the effects of DEX on perioperative opioid consumption and postoperative pain intensity in patients undergoing neurosurgery. PubMed, the Web of science, the Cochrane Library, and Scopus were searched. The resulting data were combined to calculate the pooled mean differences (MDs), standard MDs or odds ratios (ORs), and 95% confidence intervals (CIs), as appropriate. Heterogeneity and potential publication bias were assessed. Furthermore, a trial sequential analysis was performed to improve the precision of our findings. RESULTS: A total of 11 published RCTs involving 674 patients undergoing neurosurgery (335 patients, 339 controls) were included in this meta-analysis. There were significant differences in postanesthesia care unit (PACU) visual analog scale scores between the groups (MD=-1.54, 95% CI, -2.33 to 0.75, I=87%, P=0.0001). In addition, there were significant differences in PACU opioid requirements between the treatment and control groups (standard MD=-0.88, 95% CI, -1.74 to 0.02, I=91%, P=0.05). Furthermore, intraoperative opioid consumption was significantly reduced in the treatment group (MD=-127.75, 95% CI, -208.62 to 46.89, I=98%, P=0.002). CONCLUSIONS: DEX could reduce perioperative and PACU opioid consumption as well as postoperative pain intensity. PMID- 28079738 TI - Vision Problems and Reduced Reading Outcomes in Queensland Schoolchildren. AB - PURPOSE: To assess the relationship between vision and reading outcomes in Indigenous and non-Indigenous schoolchildren to determine whether vision problems are associated with lower reading outcomes in these populations. METHODS: Vision testing and reading assessments were performed on 508 Indigenous and non Indigenous schoolchildren in Queensland, Australia divided into two age groups: Grades 1 and 2 (6-7 years of age) and Grades 6 and 7 (12-13 years of age). Vision parameters measured included cycloplegic refraction, near point of convergence, heterophoria, fusional vergence range, rapid automatized naming, and visual motor integration. The following vision conditions were then classified based on the vision findings: uncorrected hyperopia, convergence insufficiency, reduced rapid automatized naming, and delayed visual motor integration. Reading accuracy and reading comprehension were measured with the Neale reading test. The effect of uncorrected hyperopia, convergence insufficiency, reduced rapid automatized naming, and delayed visual motor integration on reading accuracy and reading comprehension were investigated with ANCOVAs. RESULTS: The ANCOVAs explained a significant proportion of variance in both reading accuracy and reading comprehension scores in both age groups, with 40% of the variation in reading accuracy and 33% of the variation in reading comprehension explained in the younger age group, and 27% and 10% of the variation in reading accuracy and reading comprehension, respectively, in the older age group. The vision parameters of visual motor integration and rapid automatized naming were significant predictors in all ANCOVAs (P < .01). The direction of the relationship was such that reduced reading results were explained by reduced visual motor integration and rapid automatized naming results. CONCLUSIONS: Both reduced rapid automatized naming and visual motor integration were associated with poorer reading outcomes in Indigenous and non-Indigenous children. This is an important finding given the recent emphasis placed on Indigenous children's reading skills and the fact that reduced rapid automatized naming and visual motor integration skills are more common in this group. PMID- 28079739 TI - Opinion survey of members of British Society of Children's Orthopaedic Surgery related to specific case scenarios in slipped capital femoral epiphysis. AB - The aim of this study was to assess contemporary management of slipped capital femoral epiphysis (SCFE) by surveying members of the British Society of Children's Orthopaedic Surgery (BSCOS). A questionnaire with five case vignettes was used. Two questions examined the timing of surgery for an acute unstable SCFE in a child presenting at 6 and 48 h after start of symptoms. Two further questions explored the preferred method of fixation in mild and severe stable SCFE. The final question examined the management of the contralateral normal hip. Responses were entered into an Excel spreadsheet and the data was analysed using a chi-test. The response rate was 56% (110/196). Overall, 88% (97/110) responded that if a child presented with an acute unstable SCFE within 6 h, they would treat it within 24 h of presentation, compared with 41% (45/110) for one presenting 48 h after the onset of symptoms (P<0.0001). Overall, 53% (58/110) of surveyed BSCOS members would offer surgery for an unstable SCFE between 1 and 7 days after onset of symptoms. Single screw fixation in situ for mild stable SCFE was advocated by 96% (106/110) with 71% (78/110) using this method for the treatment of severe stable SCFE. Corrective osteotomy is used by 2% (2/110) and 25% (28/110) of respondents for mild and severe stable SCFE, respectively (P<0.0001). Surgeons preferring osteotomy are more likely to perform an intracapsular technique. Prophylactic fixation of the contralateral normal hip was performed by 27% (30/110) of respondents. There are significant differences in opinions between BSCOS members as to the optimal management of SCFE. This reflects the variable recommendations and quality in the current scientific literature. Further research is therefore required to determine best practice and enable consensus to be reached. PMID- 28079740 TI - Venous thromboembolism among pediatric orthopedic trauma patients: a database analysis. AB - Using the 2012 Kids Inpatient Database, we assessed records of pediatric patients (<21 years old) with fractures of the upper limb, lower limb, spine, pelvis, and multiple locations and calculated the overall prevalence of venous thromboembolism (VTE) and associated potential risk factors. 387 (0.68%) of 57 183 patients with one or more fractures were diagnosed with VTE. Children sustaining fractures of the axial skeleton and those with multiple fractures had a higher prevalence of VTE than those with isolated extremity fractures. Associated risk factors included the presence of a central venous catheter. A prospective, multicenter study is needed to confirm our findings. PMID- 28079741 TI - Management of pediatric open tibia fractures with supracutaneous locked plates. AB - We evaluated the novel application of supracutaneous locked plates in pediatric open tibia fractures. Pediatric open tibia fractures stabilized with a locked supracutaneous plate from January 2011 to December 2014 were reviewed. Twenty eight children, mean age 8.9 years, with 29 open tibia fractures were included. Nine of these children who had metaphyseal or metadiaphyseal fractures did not require joint spanning. The mean follow-up duration was 13.5 months. The mean time to uneventful union was 11.46 weeks, with no unacceptable malunion. Supracutaneous locked plates showed early union and no refractures. They could favorably replace tubular external fixators in stabilizing pediatric open tibia fractures. PMID- 28079742 TI - The hybrid method for the treatment of congenital talipes equinovarus: preliminary results on 92 consecutive feet. AB - Over the past 4 years, our pediatric orthopedic unit has developed a new hybrid protocol combining the advantages of Ponseti's method and the French functional physiotherapy method. Sixty-one patients (92 feet) completed treatment. Clubfoot was unilateral in 30 (49.2%) patients and bilateral in 31 (50.8%) patients. The mean Dimeglio score at the start of treatment was 13.5/20 (range: 6/20-19/20). All patients had clinical and radiographic follow-up for at least 2 years (range: 2-4 years). If orthopedic treatment was ineffective and feet showed no improvement, further surgery was performed. Posterior release was performed in eight (8.7%) feet. Clinical evaluation at the last follow-up found a mean dorsal flexion of 20 degrees +/-5 degrees (range: 5 degrees -35 degrees ). The hybrid method is a combination approach applying the strengths of Ponseti's method, that is, serial casting, and the French physiotherapy method, that is, manipulations and radiographs, to achieve long-term correction with a foot that is fully functional and pain free. PMID- 28079743 TI - Normal radiographic parameters in paediatric pelvic radiographs from a Chinese population. AB - : Paediatric pelvic and hip radiographs are a common investigation used when assessing a child for suspected developmental dysplasia of the hip. This report describes an attempt to establish normal values of medial joint space, acetabular index and centre edge angle according to specific age groups and sex in a Chinese population. Patients who had undergone a pelvic radiograph as part of their assessment, but were subsequently found to have normal hips were recruited retrospectively. These patients were grouped according to sex and age; medial joint space, acetabular index and centre edge angle were measured in all radiographs. A mean+/-SD was calculated for each group, and then each age group was tested for statistical significance between the male and the female groups. A total of, 98 patients were recruited, who underwent 188 pelvic radiographs, resulting in images of 376 'normal' hips. The results for medial joint space, acetabular index and centre edge angle for each age and sex group are described. Only the acetabular index requires different reference ranges for male and female patients because of consistent statistical significance between the two groups. It was found that medial joint space remained fairly constant throughout the age groups, whereas the acetabular index decreased and the centre edge angle increased slightly. The reference ranges for the parameters described here are quite different from those established previously in a population of Northern European descent, which could be because of a variety of reasons including genetics, body habitus and measurement technique. We believe that it would be prudent to implement these different ranges when assessing patients of Chinese heritage to optimize care of patients who may suffer as a consequence of not receiving treatment for missed hip dysplasia. LEVEL OF EVIDENCE: Diagnostic Study Level III - Study of nonconsecutive patients (without consistently applying the reference 'gold' standard). PMID- 28079744 TI - Endoscopic Woodward procedure for Sprengel deformity: case report. AB - : Sprengel deformity (SD) results in a limitation of movement of the shoulder girdle and produces an esthetic defect. Our aim is to assess the feasibility and advantages of a minimally invasive endoscopic approach for SD correction. A 4 year-old boy with a Cavendish grade III right SD. The patient underwent an endoscopic Woodward procedure with access through two small incisions at the level of the upper and lower angles of the scapula. Near-symmetrical shoulder elevation was achieved, with an excellent cosmetic result. The endoscopic Woodward procedure is a feasible, effective, and minimally invasive technique in the treatment of SD. LEVEL OF EVIDENCE: V. PMID- 28079746 TI - Sentinel Surveillance for Expedited Partner Therapy Prescriptions Using Pharmacy Data, in 2 New York City Neighborhoods, 2015. AB - BACKGROUND: Expedited partner therapy (EPT) for Chlamydia trachomatis (Ct) is the practice of providing Ct-infected patients with medication, or prescription (prescription-EPT) to deliver to their sex partners without first examining those partners. New York City (NYC) providers commonly use prescription-EPT, yet NYC pharmacists report only occasional receipt of EPT prescriptions. This project assessed the frequency of EPT prescriptions filled in 2 NYC neighborhoods. METHODS: The 2 NYC facilities reporting the most frequent use of prescription-EPT were identified from Ct provider case reports and contacted to ascertain their EPT practices. Providers at the first facility (facility 1) prescribed two 1-g doses of azithromycin, including sex partner treatment on the index patient's electronic prescription. Providers at the second facility (facility 2) gave patients paper prescriptions for sex partners. We reviewed prescriptions filled in 2015 for azithromycin, 1 or 2 g at pharmacies near these facilities; prescriptions indicating partner therapy were classified "EPT prescriptions". RESULTS: Facility 1 providers submitted 112 Ct case reports indicating prescription-EPT, compared with 114 submitted by facility 2 providers. Twelve of 26 identified pharmacies agreed to participate. At 7 pharmacies near facility 1, we found 61 EPT prescriptions from facility 1 and 37 from other facilities. At 5 pharmacies near facility 2, we found only 1 EPT prescription from facility 2 and 3 from other facilities. CONCLUSIONS: Expedited partner therapy prescriptions were received in NYC pharmacies near to EPT-prescribing facilities, but with great variability and at a lower frequency than suggested by provider case reports. Provider EPT prescribing practices may impact the likelihood that partners receive medication and should be further evaluated. PMID- 28079747 TI - How Reliable Is Microscopy and Culture for the Diagnosis of Gonorrhea? An 11-Year Experience from INDIA. AB - Positivity of microscopy and culture was greater (P < 0.0001) in men with urethral discharge syndrome (65.8%) than in women with vaginal/cervical discharge (0.5%), indicating that basic diagnostic tests may not be cost-effective for diagnosis of vaginal/cervical discharge syndrome. Microscopy when compared with culture showed sensitivity, specificity, positive predictive value and negative predictive value of 95.4%, 77.6%, 84.6%, and 95.3%, in men, whereas in women, it was 77.8%, 99.9%, 92.1%, and 99.9%, respectively. PMID- 28079748 TI - Clinical Characteristics of Herpes Simplex Virus Urethritis Compared With Chlamydial Urethritis Among Men. AB - BACKGROUND: The aim of this study was to ascertain the clinical characteristics associated with herpes simplex virus (HSV) urethritis in men and to compare those with chlamydial urethritis. METHODS: We compared clinical and laboratory data from men diagnosed with polymerase chain reaction confirmed HSV urethritis with those of men with chlamydial urethritis presenting to Melbourne Sexual Health Centre between 2000 and 2015. RESULTS: Eighty HSV urethritis cases were identified: 55 (68%, 95% confidence interval, 58-78) were by HSV-1 and 25 (32%, 95% confidence interval, 22-42) by HSV-2. Compared with chlamydial urethritis, men with HSV urethritis were significantly more likely to report severe dysuria (20% vs 0%, P < 0.01) or constitutional symptoms (15% vs 0%, P < 0.01). Men with HSV urethritis were significantly more likely to have meatitis (62% vs 23%, P < 0.01), genital ulceration (37% vs 0%, P < 0.01), or inguinal lymphadenopathy (30% vs 0%, P < 0.01) but less likely to have urethral discharge (32% vs 69%, P < 0.01). There was no significant difference in the proportion of men who had raised (>=5) polymorphonuclear leukocytes per high-powered field between the two groups (P = 0.46). CONCLUSIONS: The clinical presentation of HSV urethritis in men may differ from those of chlamydial urethritis and guide testing for HSV in men presenting with non-gonococcal urethritis. PMID- 28079749 TI - Should Female Partners of Men With Non-Gonococcal Urethritis, Negative for Chlamydia trachomatis and Mycoplasma genitalium, Be Informed and Treated? Clinical Outcomes From a Partner Study of Heterosexual Men With NGU. AB - BACKGROUND: To determine if female partners of men with pathogen-negative non gonococcal urethritis (NGU) are at risk of genital infection. METHODS: Secondary data analysis using health records from a large sexually transmitted disease clinic in Melbourne of 1710 men and their female partners attending on the same day from January 2006 to April 2015. Proportions of female partners with symptoms suggesting genital infection or pelvic inflammatory disease (PID) were determined for: (1) men with NGU and no Chlamydia trachomatis or Mycoplasma genitalium (referred to as pathogen-negative NGU) (n = 91); 2) men with urethral C. trachomatis (n = 176); 3) men with urethral M. genitalium (n = 26); and 4) asymptomatic men (n = 652). RESULTS: Female partners of men with pathogen negative NGU experienced deep pelvic pain (adjusted odds ratio [AOR], 2.2; 95% confidence interval [CI], 1.1-4.4), post coital bleeding (AOR, 2.4; 95% CI, 1.2 4.9), and dysuria (AOR, 3.7; 95% CI, 1.6-8.6) more commonly and were diagnosed with PID more commonly (AOR, 4.8; 95% CI, 2.1-11.3) than the female partners of asymptomatic men. Pelvic inflammatory disease was not more likely to be diagnosed in the female partners of men with genital warts (AOR, 1.4; 95% CI, 0.5-4.4) or candidiasis (AOR, 1.2; 95% CI, 0.4-3.5) than the female partners of asymptomatic men. The female partners of men with chlamydia experienced post coital bleeding more (AOR, 1.9; 95% CI, 1.0-3.6) and were more likely to be diagnosed with PID (AOR, 3.6; 95% CI, 1.6-8.0). CONCLUSIONS: The female partners of men with pathogen-negative NGU may be at increased risk of genital infection, even if a recognised pathogen is not identified in the man. PMID- 28079750 TI - Management of Herpetic Urethritis and Female Partners of Men With Nongonococcal Urethritis. PMID- 28079751 TI - Updates on primary sclerosing cholangitis. PMID- 28079752 TI - Changes in Dorsal Root Ganglion Gene Expression in Response to Spinal Cord Stimulation. AB - BACKGROUND AND OBJECTIVES: Spinal cord stimulation (SCS) has been shown to influence pain-related genes in the spinal cord directly under the stimulating electrodes. There is limited information regarding changes occurring at the dorsal root ganglion (DRG). This study evaluates gene expression in the DRG in response to SCS therapy. METHODS: Rats were randomized into experimental or control groups (n = 6 per group). Experimental animals underwent spared-nerve injury, implantation of lead, and continuous SCS (72 hours). Behavioral assessment for mechanical hyperalgesia was conducted to compare responses after injury and treatment. Ipsilateral DRG tissue was collected, and gene expression quantified for interleukin 1b (IL-1b), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), GABA B receptor 1 (GABAbr1), substance P (subP), Integrin alpha M (ITGAM), sodium/potassium ATP-ase (Na/K ATPase), fos proto oncogene (cFOS), serotonin receptor 3A (5HT3r), galanin (Gal), vasoactive intestinal peptide (VIP), neuropeptide Y (NpY), glial fibrillary acidic protein (GFAP), and brain derived neurotropic factor (BDNF) via quantitative polymerase chain reaction. Statistical significance was established using analysis of variance (ANOVA), independent t tests, and Pearson correlation tests. RESULTS: Expression of IL-1b and IL-6 was reversed following SCS therapy relative to the increase caused by the injury model. Both GABAbr1 and Na/K ATPase were significantly up-regulated upon implantation of the lead, and SCS therapy reversed their expression to within control levels. Pearson correlation analyses reveal that GABAbr1 and Na/K ATPase expression was dependent on the stimulating current intensity. CONCLUSIONS: Spinal cord stimulation modulates expression of key pain-related genes in the DRG. Specifically, SCS led to reversal of IL-1b and IL-6 expression induced by injury. Interleukin 6 expression was still significantly larger than in sham animals, which may correlate to residual sensitivity following continuous SCS treatment. In addition, expression of GABAbr1 and Na/K ATPase was down-regulated to within control levels following SCS and correlates with applied current. PMID- 28079753 TI - Synergistic Effects of Serotonin or Dopamine Combined With Lidocaine at Producing Nociceptive Block in Rats. AB - BACKGROUND: The purpose of this experiment was to investigate the interactions of the local anesthetic lidocaine combined with an agent (serotonin or dopamine) as infiltrative anesthetics. METHODS: Cutaneous analgesia was characterized by the blockade of the cutaneous trunci muscle reflex following 6 skin pinpricks on the rat back. Serotonin or dopamine at producing cutaneous analgesia in a dosage dependent fashion was compared with lidocaine. Drug-drug interactions were calculated using the isobolographic analysis. RESULTS: We revealed that serotonin, dopamine, and lidocaine provoked dose-related cutaneous analgesic effects. On the 50% effective dose basis, the rank of drugs' potency was found to be serotonin (1.70 [1.56-1.85] MUmol) > lidocaine (5.18 [4.67-5.75] MUmol) > dopamine (43.0 [40.9-45.2] MUmol) (P < 0.01). At doses equivalent to their 25%, 50%, and 75% effective doses, serotonin or dopamine elicited a longer duration of action than lidocaine (P < 0.01) on producing cutaneous analgesia. Coadministration of serotonin or dopamine with lidocaine produced a synergistic effect. CONCLUSIONS: The preclinical data showed that serotonin and dopamine produce dose-related cutaneous analgesic effects as an infiltrative anesthetic. Serotonin has a better potency with a much longer duration of action compared with lidocaine at provoking cutaneous analgesia. Serotonin or dopamine as an adjuvant increases the quality of lidocaine in cutaneous analgesia. PMID- 28079754 TI - Ultrasound-Guided Needle Technique Accuracy: Prospective Comparison of Passive Magnetic Tracking Versus Unassisted Echogenic Needle Localization. AB - BACKGROUND AND OBJECTIVES: Ultrasound-guided regional anesthesia facilitates an approach to sensitive targets such as nerve clusters without contact or inadvertent puncture. We compared accuracy of needle placement with a novel passive magnetic ultrasound needle guidance technology (NGT) versus conventional ultrasound (CU) with echogenic needles. METHODS: Sixteen anesthesiologists and 19 residents performed a series of 16 needle insertion tasks each, 8 using NGT (n = 280) and 8 using CU (n = 280), in high-fidelity porcine phantoms. Tasks were stratified based on aiming to contact (target-contact) or place in close proximity with (target-proximity) targets, needle gauge (no. 18/no. 22), and in plane (IP) or out-of-plane (OOP) approach. Distance to the target, task completion by aim, number of passes, and number of tasks completed on the first pass were reported. RESULTS: Needle guidance technology significantly improved distance, task completion, number of passes, and completion on the first pass compared with CU for both IP and OOP approaches (P <= 0.001). Average NGT distance to target was lower by 57.1% overall (n = 560, 1.5 +/- 2.4 vs 3.5 +/- 3.7 mm), 38.5% IP (n = 140, 1.6 +/- 2.6 vs 2.6 +/- 2.8 mm), and 68.2% OOP (n = 140, 1.4 +/- 2.2 vs 4.4 +/- 4.3 mm) (all P <= 0.01). Subgroup analyses revealed accuracy gains were largest among target-proximity tasks performed by residents and for OOP approaches. Needle guidance technology improved first-pass completion from 214 (76.4%) per 280 to 249 (88.9%) per 280, a significant improvement of 16.4% (P = 0.001). CONCLUSIONS: Passive magnetic NGT can improve accuracy of needle procedures, particularly among OOP procedures requiring close approach to sensitive targets, such as nerve blocks in anesthesiology practice. PMID- 28079755 TI - MACULAR PIGMENT DISTRIBUTION RESPONSES TO HIGH-DOSE ZEAXANTHIN SUPPLEMENTATION IN PATIENTS WITH MACULAR TELANGIECTASIA TYPE 2. AB - PURPOSE: To analyze macular pigment (MP) amount and distribution in patients with macular telangiectasia Type 2 receiving oral zeaxanthin supplementation in a randomized, open-label, interventional trial. METHODS: Eight macular telangiectasia Type 2 patients were randomized to 10 mg or 20 mg of zeaxanthin per day. At each visit, best-corrected visual acuity, contrast sensitivity, fundus biomicroscopy, color fundus photography, autofluorescence imaging, optical coherence tomography, and serum carotenoid levels were tested. Patients were assessed at baseline and after 6, 12, 18, and 24 months of zeaxanthin supplementation. Concentration of MP was analyzed and calculated from autofluorescence imaging obtained at 488-nm excitation wavelength. Serum carotenoid levels were obtained using high-performance liquid chromatography. RESULTS: The majority of patients had definite increases in the intensity of hypofluorescent ring of MP, but none of them deposited MP centrally at the fovea. Although some patients noted subjective improvements in vision, no objective improvements could be documented, and there were no changes in foveal optical coherence tomographic features. Yellowish, hypofluorescent crystals appeared in one patient's macular region with no change in visual acuity. These inner retinal crystals disappeared several months after discontinuing her 20-mg zeaxanthin supplement. CONCLUSION: Based on the current study, zeaxanthin supplementation does not result in any visual benefit in patients with macular telangiectasia Type 2 and does not reestablish a normal peaked distribution of MP in the fovea. One patient developed a novel, reversible, crystalline maculopathy in response to zeaxanthin supplementation that was reminiscent of canthaxanthin crystalline maculopathy. PMID- 28079756 TI - OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY CHANGES IN EARLY TYPE 3 NEOVASCULARIZATION AFTER ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT. AB - PURPOSE: To investigate the morphologic changes on optical coherence tomography angiography (OCTA) of treatment-naive Type 3 neovascularization secondary to exudative age-related macular degeneration after 1 year of anti-vascular endothelial growth factor therapy. METHODS: Consecutive patients diagnosed with treatment-naive early-stage Type 3 neovascularization were enrolled in this retrospective study. All patients underwent color fundus photographs/MultiColor (Heidelberg Engineering) imaging, fluorescein angiography, indocyanine green angiography, structural spectral domain OCT, and OCTA Optovue RTVue XR Avanti (Optovue) at baseline, and repeated OCTA and structural spectral domain OCT at Month 12. Qualitative analysis of the 3 * 3 OCTA examinations at baseline and Month 12 was then compared, to assess changes after anti-vascular endothelial growth factor therapy. RESULTS: A total of 15 treatment-naive eyes of 15 consecutive patients were included in the analysis. At 12-month follow-up after pro-re-data anti-vascular endothelial growth factor therapy (5.75 +/- 1.48 injections of ranibizumab, and injections of 6.33 +/- 1.21 of aflibercept), OCTA demonstrated persistence of the deep capillary plexus abnormalities in 13/15 eyes. In the outer retina and choriocapillaris, the initial lesion became undetectable in 7/15 cases, accompanied by choriocapillaris atrophy. The abnormal vascular complex persisted in the form of a tuft-shaped lesion in the outer retinal segmentation in 9/15 eyes, which in the choriocapillaris segmentation was associated with sub-retinal pigment epithelium neovascularization in 8 cases. CONCLUSION: Optical coherence tomography angiography showed that the tuft-shaped abnormal outer retinal lesion, frequently associated with a small clew-like flow signal in the choriocapillaris, after 1 year of anti-vascular endothelial growth factor therapy, either becomes undetectable or develops sub-retinal pigment epithelium neovascularization. PMID- 28079758 TI - Concussion in Ice Hockey: Current Gaps and Future Directions in an Objective Diagnosis. AB - OBJECTIVE: This review provides an update on sport-related concussion (SRC) in ice hockey and makes a case for changes in clinical concussion evaluation. Standard practice should require that concussions be objectively diagnosed and provide quantitative measures of the concussion injury that will serve as a platform for future evidence-based treatment. METHODS: The literature was surveyed to address several concussion-related topics: research in ice hockey related head trauma, current subjective diagnosis, promising components of an objective diagnosis, and current and potential treatments. MAIN RESULTS: Sport related head trauma has marked physiologic, pathologic, and psychological consequences for athletes. Although animal models have been used to simulate head trauma for pharmacologic testing, the current diagnosis and subsequent treatment in athletes still rely on an athlete's motivation to report or deny symptoms. Bias-free, objective diagnostic measures are needed to guide quantification of concussion severity and assessment of treatment effects. Most of the knowledge and management guidelines of concussion in ice hockey are generalizable to other contact sports. CONCLUSIONS: There is a need for an objective diagnosis of SRC that will quantify severity, establish a prognosis, and provide effective evidence-based treatment. Potential methods to improve concussion diagnosis by health care providers include a standardized concussion survey, the King-Devick test, a quantified electroencephalogram, and blood analysis for brain cell specific biomarkers. PMID- 28079757 TI - Pathogenesis of abdominal pain in bowel obstruction: role of mechanical stress induced upregulation of nerve growth factor in gut smooth muscle cells. AB - Abdominal pain is one of the major symptoms in bowel obstruction (BO); its cellular mechanisms remain incompletely understood. We tested the hypothesis that mechanical stress in obstruction upregulates expression of nociception mediator nerve growth factor (NGF) in gut smooth muscle cells (SMCs), and NGF sensitizes primary sensory nerve to contribute to pain in BO. Partial colon obstruction was induced with a silicon band implanted in the distal bowel of Sprague-Dawley rats. Colon-projecting sensory neurons in the dorsal root ganglia (T13 to L2) were identified for patch-clamp and gene expression studies. Referred visceral sensitivity was assessed by measuring withdrawal response to stimulation by von Frey filaments in the lower abdomen. Membrane excitability of colon-projecting dorsal root ganglia neurons was significantly enhanced, and the withdrawal response to von Frey filament stimulation markedly increased in BO rats. The expression of NGF mRNA and protein was increased in a time-dependent manner (day 1-day 7) in colonic SMC but not in mucosa/submucosa of the obstructed colon. Mechanical stretch in vitro caused robust NGF mRNA and protein expression in colonic SMC. Treatment with anti-NGF antibody attenuated colon neuron hyperexcitability and referred hypersensitivity in BO rats. Obstruction led to significant increases of tetrodotoxin-resistant Na currents and mRNA expression of Nav1.8 but not Nav1.6 and Nav1.7 in colon neurons; these changes were abolished by anti-NGF treatment. In conclusion, mechanical stress-induced upregulation of NGF in colon SMC underlies the visceral hypersensitivity in BO through increased gene expression and activity of tetrodotoxin-resistant Na channels in sensory neurons. PMID- 28079759 TI - The QuantiFERON-TB Gold In-Tube Assay in Neuro-Ophthalmology. AB - BACKGROUND: Although QuantiFERON-TB Gold In-Tube (QFT-GIT) testing is regularly used to detect infection with Mycobacterium tuberculosis, its utility in a patient population with a low risk for tuberculosis (TB) has been questioned. The following is a cohort study analyzing the efficacy of QFT-GIT testing as a method for detection of active TB disease in low-risk individuals in a neuro ophthalmologic setting. METHODS: Ninety-nine patients from 2 neuro-ophthalmology centers were identified as having undergone QFT-GIT testing between January 2012 and February 2016. Patients were divided into groups of negative, indeterminate, and positive QFT-GIT results. Records of patients with positive QFT-GIT results were reviewed for development of latent or active TB, as determined by clinical, bacteriologic, and/or radiographic evidence. RESULTS: Of the 99 cases reviewed, 18 patients had positive QFT-GIT tests. Of these 18 cases, 12 had documentation of chest radiographs or computed tomography which showed no evidence for either active TB or pulmonary latent TB infection (LTBI). Four had chest imaging which was indicative of possible LTBI. None of these 18 patients had symptoms of active TB and none developed active TB within the follow-up period. CONCLUSIONS: Based on our results, we conclude that routine testing with QFT-GIT in a low-risk cohort did not diagnose active TB infection. We do not recommend routine QFT-GIT testing for TB low-risk individuals, as discerned through patient and exposure history, ocular examination, and clinical judgment, in neuro-ophthalmology practice. PMID- 28079760 TI - A 31-Year-Old Man With a Ring-Enhancing Brain Lesion. PMID- 28079761 TI - Canadian Laws Are on Target-But Is the Transplant Community? PMID- 28079762 TI - Robotic Versus Laparoscopic Gastric Resection for Primary Gastrointestinal Stromal Tumors >5 cm: A Size-Matched and Location-Matched Comparison. AB - This study compared robotic (RR) and laparoscopic resection (LR) for primary gastrointestinal stromal tumors (GISTs) of the stomach >5 cm. Twelve consecutive patients who underwent RR from 2012 to 2015 were matched for tumor size and location with 24 patients who underwent LR from 2000 to 2012. The median tumor size was 7.1 cm (range, 5.5 to 11.5). GISTs were resected by wedge resection (91.7%) or distal gastrectomy. The median RR operative time was longer than that of LR (162.5 vs. 130 min, respectively; P=0.004). Only 1 LR patient required conversion. The time to flatus and hospital stay were similar between groups. Overall, 3 patients developed minor postoperative complications that were medically treated. Mortality was nil. All resections were R0. No difference was observed in the incidence of recurrence. RR was significantly more expensive (+21.6%) than LR. RR appears to be safe and feasible for GISTs>5 cm, but is associated with longer operative times and greater costs. PMID- 28079763 TI - The Comparison of Etomidate and Propofol Anesthesia in Patients Undergoing Gastrointestinal Endoscopy: A Systematic Review and Meta-Analysis. AB - INTRODUCTION: Etomidate and propofol played an important role in the sedation of patients undergoing gastrointestinal endoscopy. We conducted a systematic review and meta-analysis to compare their efficacy and safety. MATERIALS AND METHODS: PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systematically searched. Randomized controlled trials assessing the effect of etomidate versus propofol for the anesthesia of patients undergoing gastrointestinal endoscopy were included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. The primary outcomes were anesthesia duration and recovery time. Meta-analysis was performed using random-effect model. RESULTS: Six randomized controlled trials involving 1115 patients were included in the meta-analysis. Overall, compared with propofol, etomidate resulted in comparable anesthesia duration [standard mean difference (Std. MD)=-0.03; 95% confidence interval (CI), -0.16 to 0.10; P=0.66], recovery time (Std. MD=0.25; 95% CI, -0.42 to 0.92; P=0.47), mean arterial pressure at intubation (Std. MD=0.44; 95% CI, -0.26 to 1.15; P=0.21), heart pulse at intubation (Std. MD=0.93; 95% CI, -0.69 to 2.55; P=0.26), SPO2 at intubation (Std. MD=-0.52; 95% CI, -1.04 to 0.01; P=0.05), patient satisfaction [odds risk (OR)=0.42; 95% CI, 0.11-1.66; P=0.22], hypotension (OR=0.14; 95% CI, 0.02-1.22; P=0.07), changes of heart rate (OR=0.97; 95% CI, 0.61-1.53; P=0.88), nausea-vomiting (OR=2.02; 95% CI, 0.73-5.57; P=0.17), and the reduction in apnea or hyoxemia (OR=0.39; 95% CI, 0.24-0.64; P=0.0002), and injection pain (OR=0.03; 95% CI, 0.01-0.08; P<0.00001), but the increase in myoclonus (OR=8.54; 95% CI, 3.14-23.20; P<0.0001). CONCLUSIONS: Between etomidate and propofol, no significant difference was revealed regarding anesthesia duration, recovery time, mean arterial pressure at intubation, heart pulse at intubation, SPO2 at intubation, patient satisfaction, hypotension, changes of heart rate and nausea vomiting. Compared with propofol, etomidate showed reduced apnea or hyoxemia, and injection pain, but with an increased myoclonus. PMID- 28079764 TI - Tako-Tsubo cardiomyopathy complicated by paroxysmal supraventricular tachycardia. AB - : We report a case of paroxysmal supraventricular tachycardia complicating Tako Tsubo cardiomyopathy. We hypothesize that increased adrenergic tone supposedly underlying transient apical ballooning syndrome may facilitate the onset of paroxysmal supraventricular tachycardias in predisposed patients. PMID- 28079765 TI - Early recurrence of Tako-Tsubo cardiomyopathy in an elderly woman with amyotrophic lateral sclerosis: different triggers inducing different apical ballooning patterns. AB - : We report the case of early recurrence of Tako-Tsubo cardiomyopathy in an elderly woman with amyotrophic lateral sclerosis triggered by different stressors. A first episode with typical apical ballooning was anticipated by an emotional stress; a second, characterized by systolic anterior motion of the mitral valve associated with mitral regurgitation and severe intra-ventricular gradient, was precipitated by surgical stress and hypovolemia. We therefore hypothesize both a possible link between amyotrophic lateral sclerosis and Tako Tsubo cardiomyopathy, and between different stressors and different Tako-Tsubo patterns. PMID- 28079766 TI - Attempted and Successful Vacuum-Assisted Vaginal Delivery by Prepregnancy Body Mass Index. AB - OBJECTIVE: To examine rates of attempted and successful vacuum-assisted vaginal delivery by prepregnancy body mass index (BMI). METHODS: We conducted a retrospective cohort study of 2,084 women with singleton gestations needing operative delivery assistance and vacuum-eligible (fully dilated, +2 station or greater, 34 weeks of gestation or greater) using 2006-2014 inpatient records. Prepregnancy BMI was categorized as underweight (less than 18.5), normal weight (18.5 to less than 25), overweight (25 to less than 30), or obese (30 or greater). Logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) of attempted and successful vacuum-assisted vaginal delivery by prepregnancy BMI adjusted for age, race, marital status, parity, diabetes, labor induction-augmentation, episiotomy, gestational age, and neonatal birth weight. RESULTS: Thirty-nine percent of women requiring delivery assistance and eligible for a vacuum were overweight or obese, 79% had vacuum attempts, and 95.3% of attempted vacuum-assisted vaginal deliveries were successful. Compared with women who were normal weight prepregnancy (82.8%), women who were overweight or obese were less likely to have vacuum attempted (75.8%, OR 0.71, 95% CI 0.53 0.96 and 71.2%, OR 0.53, 95% CI 0.39-0.74, respectively). Among women with attempted vacuum-assisted vaginal delivery, successful delivery did not differ by prepregnancy BMI (92.6%, OR 0.54, 95% CI 0.21-1.37 for underweight; 94.5%, OR 1.07, 95% CI 0.57-2.00 for overweight; 96.3%, OR 1.09, 95% CI 0.51-2.33 for obese compared with 95.6% among normal-weight women). CONCLUSION: Among women in need of operative delivery assistance, prepregnancy obesity was associated with lower likelihood of attempted vacuum-assisted vaginal delivery but, if attempted, success rates were similar to rates among normal-weight women. With significant morbidity of second-stage cesarean delivery in obese women, research should examine whether vacuum-assisted vaginal delivery may be appropriate for additional obese patients. PMID- 28079767 TI - Primary Gastric Choriocarcinoma Presenting as a Pregnancy of Unknown Location. AB - BACKGROUND: Pregnancy of unknown location presents a diagnostic challenge, in rare occasions leading to the diagnosis of malignancy. We describe a case of beta hCG-secreting nongestational primary gastric choriocarcinoma presenting as a pregnancy of unknown location. CASE: A 37-year-old woman, gravida 4 para 3013, presented with several days of vaginal bleeding and rising beta-hCG level without ultrasound localization of pregnancy. The diagnosis of pregnancy of unknown location was made and methotrexate administered at a beta-hCG level of 7,779 milli-international units/mL. A 40% decrease in beta-hCG level was noted between days 4 and 7. One week later, an inappropriate beta-hCG level rise to 10,937 milli-international units/mL was noted, prompting a second dose of methotrexate and computed tomography imaging, leading to the discovery of gastric and liver lesions. Pathology from gastric biopsies revealed nongestational choriocarcinoma. The patient was treated with chemotherapy, with death from cardiac arrest 7 months after diagnosis. CONCLUSION: Malignancies that can secrete beta-hCG include gestational trophoblastic disease, gonadal and extragonadal germ cell tumors, and malignancies with choriocarcinoma differentiation. Although ectopic pregnancy compromises approximately 2% of first-trimester pregnancy, gestational trophoblastic neoplasia and gestational choriocarcinoma can be seen in 1 of 1,500 and 1 of 20,000 pregnancies, respectively. When beta-hCG levels do not fall appropriately in women undergoing medical management for pregnancy of unknown location, ectopic beta-hCG secretion by a malignancy must be considered. PMID- 28079768 TI - Interpregnancy Interval After Termination of Pregnancy and the Risks of Adverse Outcomes in Subsequent Birth. AB - OBJECTIVE: To assess whether the length of the interpregnancy interval after termination of pregnancy influences the risk of preterm birth, low birth weight, and small-for-gestational-age neonates in a subsequent pregnancy. METHODS: In this register-based study, we included all women (N=19,894) who underwent termination of pregnancy between 2000 and 2009 and whose subsequent pregnancy ended in live singleton delivery. The women were divided into five groups depending on the interpregnancy interval between termination of pregnancy and subsequent conception: interpregnancy interval less than 6 months (n=2,956), 6 to less than 12 months (n=3,203), 12 to less than 18 months (n=2,623), 18 to less than 24 months (n=2,076), and 24 months or greater (n=9,036). The incidences and unadjusted and adjusted risks of preterm birth, low birth weight, and small-for gestational-age neonates were calculated in relation to the different interpregnancy interval lengths, the reference group being that with an interpregnancy interval of 18 to less than 24 months. RESULTS: There was a significant difference in the rate of preterm birth between the group with the interpregnancy interval less than 6 months and the reference group (5.6% compared with 4.0%, respectively, P=.008). After adjusting for nine background factors, an interpregnancy interval of less than 6 months was associated with an increased risk of preterm birth (adjusted odds ratio 1.35, 95% confidence interval 1.02 1.77). No such association emerged in longer interpregnancy interval groups or regarding other adverse events. The possibility of unmeasured confounding cannot be ruled out. CONCLUSION: Slightly but significantly increased estimated risk of preterm delivery in subsequent pregnancy was seen when the interpregnancy interval after termination of pregnancy was less than 6 months. These data emphasize the need for prompt initiation of effective contraception after termination and enable counseling the patient for optimal conception interval. PMID- 28079769 TI - Posttraumatic Stress Disorder Relapse and Clitoral Reconstruction After Female Genital Mutilation. AB - BACKGROUND: Evidence on clitoral reconstruction after female genital mutilation is lacking. CASE: A woman with female genital mutilation experiencing clitoral pain during sex consulted to undergo clitoral reconstruction. The surgery was complicated by a wound infection responsible for severe postoperative pain. Such genital pain made our patient recall the traumatic experience of genital mutilation and experience a relapse of posttraumatic stress disorder symptoms. She reported anxiety; spontaneous, intrusive recurrent memories of the cutting; hypervigilance; and depressed mood. We successfully treated the infection and posttraumatic stress disorder. At 6 months postsurgery, she reported no clitoral pain and improved sexual function. CONCLUSION: Genital pain after clitoral reconstruction may cause recall of memories of the genital mutilation. We recommend multidisciplinary comprehensive psychosexual care and adequate analgesia. PMID- 28079770 TI - Neurodevelopmental Outcomes After Assisted Reproductive Technologies. AB - OBJECTIVE: To compare children's cognitive, motor, and language development at 2 years of age after assisted reproductive technologies (ARTs) relative to natural conception. METHODS: The 3D-Study (2010-2012) is a prospective cohort study, which sought to improve the understanding among perinatal events, obstetric outcomes, and child development. A total of 2,366 pregnant women were recruited, of whom 278 conceived with ART: ovarian stimulation, intrauterine sperm insemination, in vitro fertilization, intracytoplasmic sperm injection, or in vitro maturation. Natural conception was defined as the unassisted establishment of pregnancy. Cognitive, motor, and language neurodevelopmental outcomes were compared between ART and natural conception groups at 24 months using the Bayley Scales of Infant and Toddler Development, 3rd edition, and the MacArthur-Bates Communicative Development Inventories. Adjusted linear regression models evaluated the effect of ART on neurodevelopmental outcomes using natural conception as a reference. RESULTS: A total of 175 children in the ART group (62.9%) and 1,345 children in the natural conception group (64.4%) underwent neurodevelopmental assessment at 24 months postpartum. After adjusting for relevant confounders, children born after ART showed no difference in Bayley scales' cognitive scores (B1 [standard error]=-1.60 [0.9], 95% confidence interval [CI] -3.36 to 0.16), composite motor scores (B1 [standard error]=-1.33 [1.0], 95% CI -3.29 to 0.63), or MacArthur-Bates language scores (B1 [standard error]=-0.28 [2.1], 95% CI -4.39 to 3.83). No difference was observed when independent ART techniques were compared nor when comparing in vivo (ovarian stimulation or intrauterine insemination) or in vitro (in vitro fertilization, intracytoplasmic sperm injection, or in vitro maturation) techniques (P>.05). CONCLUSION: Children born after ART had similar cognitive, motor, and language development as children born after natural conception at 2 years of age. These findings may be useful in the clinical counseling of patients undergoing ART. PMID- 28079771 TI - Advanced Research and Data Methods in Women's Health: Big Data Analytics, Adaptive Studies, and the Road Ahead. AB - Technical advances in science have had broad implications in reproductive and women's health care. Recent innovations in population-level data collection and storage have made available an unprecedented amount of data for analysis while computational technology has evolved to permit processing of data previously thought too dense to study. "Big data" is a term used to describe data that are a combination of dramatically greater volume, complexity, and scale. The number of variables in typical big data research can readily be in the thousands, challenging the limits of traditional research methodologies. Regardless of what it is called, advanced data methods, predictive analytics, or big data, this unprecedented revolution in scientific exploration has the potential to dramatically assist research in obstetrics and gynecology broadly across subject matter. Before implementation of big data research methodologies, however, potential researchers and reviewers should be aware of strengths, strategies, study design methods, and potential pitfalls. Examination of big data research examples contained in this article provides insight into the potential and the limitations of this data science revolution and practical pathways for its useful implementation. PMID- 28079772 TI - Severe Maternal Morbidity Among Hispanic Women in New York City: Investigation of Health Disparities. AB - OBJECTIVE: To investigate differences in severe maternal morbidity between Hispanic mothers and three major Hispanic subgroups compared with non-Hispanic white mothers and the extent to which differences in delivery hospitals may contribute to excess morbidity among Hispanic mothers. METHODS: We conducted a population-based cross-sectional study using linked 2011-2013 New York City discharge and birth certificate data sets (n=353,773). Rates of severe maternal morbidity were calculated using a published algorithm based on diagnosis and procedure codes. Mixed-effects logistic regression with a random hospital specific intercept was used to generate risk-standardized severe maternal morbidity rates for each hospital taking into consideration patient sociodemographic characteristics and comorbidities. Differences in the distribution of Hispanic and non-Hispanic white deliveries were assessed among these hospitals in relation to their risk-adjusted morbidity. Sensitivity analyses were conducted after excluding isolated blood transfusion from the morbidity composite. RESULTS: Severe maternal morbidity occurred in 4,541 deliveries and was higher among Hispanic than non-Hispanic white women (2.7% compared with 1.5%, P<.001); this rate was 2.9% among those who were Puerto Rican, 2.7% among those who were foreign-born Dominican, and 3.3% among those who were foreign-born Mexican. After adjustment for patient characteristics, the risk remained elevated for Hispanic women (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.22-1.66) and for all three subgroups compared with non-Hispanic white women (P<.001). Risk for Hispanic women was attenuated in sensitivity analyses (OR 1.17, 95% CI 1.02-1.33). Risk-standardized morbidity across hospitals varied sixfold. We estimate that Hispanic-non-Hispanic white differences in delivery location may contribute up to 37% of the ethnic disparity in severe maternal morbidity rates in New York City hospitals. CONCLUSION: Hispanic compared with non-Hispanic white mothers are more likely to deliver at hospitals with higher risk-adjusted severe maternal morbidity rates and these differences in site of delivery may contribute to excess morbidity among Hispanic mothers. Our results suggest improving quality at the lowest performing hospitals could benefit both non-Hispanic white and Hispanic women and reduce ethnic disparities in severe maternal morbidity rates. PMID- 28079773 TI - Pregnancies After the Diagnosis of Mild Gestational Diabetes Mellitus and Risk of Cardiometabolic Disorders. AB - OBJECTIVE: To assess the association of subsequent pregnancy with subsequent metabolic syndrome and type II diabetes mellitus after a pregnancy complicated by mild gestational diabetes mellitus (GDM). METHODS: We conducted a prospective observational follow-up study of women with mild GDM randomized from 2002 to 2007 to usual care or dietary intervention and glucose self-monitoring. Women were evaluated 5-10 years after the parent study. Participants were grouped according to the number of subsequent pregnancies (group A, none [reference]; group B, one; group C, two or greater). Serum triglycerides, glucose tolerance, high-density lipoprotein cholesterol, blood pressure, and waist circumference were assessed. Metabolic syndrome was diagnosed by American Heart Association and National Heart Lung and Blood Institute criteria. Multivariable regression was used to estimate adjusted relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: Of 905 eligible women from the original trial, 483 agreed to participate, 426 of whom were included in this analysis. Groups A, B, and C consisted of 212, 143, and 71 women, respectively. Of women with subsequent pregnancies, 32% (69/214) had another pregnancy complicated with GDM. No difference between groups was observed for metabolic syndrome (group A, 34%; group B, 33%; group C, 30%). Subsequent pregnancies were associated with diabetes mellitus outside of pregnancy (group A, 5.2%; group B, 10.5%, RR 2.62, 95% CI 1.16-5.91; group C, 11.3%, RR 2.83, 95% CI 1.06-7.59), and if complicated with GDM (no subsequent GDM pregnancy, RR 1.99, 95% CI 0.82-4.84; subsequent GDM pregnancy, RR 3.75, 95% CI 1.60-8.82). CONCLUSION: In women with prior mild GDM, subsequent pregnancies did not increase the frequency of metabolic syndrome, but subsequent pregnancies with GDM increased the risk of diabetes mellitus outside of pregnancy. PMID- 28079774 TI - A Statewide Progestogen Promotion Program in Ohio. AB - OBJECTIVE: To promote use of progestogen therapy to reduce premature births in Ohio by 10%. METHODS: The Ohio Perinatal Quality Collaborative initiated a quality improvement project in 2014 working with clinics at 20 large maternity hospitals, Ohio Medicaid, Medicaid insurers, and service agencies to use quality improvement methods to identify eligible women and remove treatment barriers. The number of women eligible for prophylaxis, the percent prescribed a progestogen before 20 and 24 weeks of gestation, and barriers encountered were reported monthly. Clinics were asked to adopt protocols to identify candidates and initiate treatment promptly. System-level changes were made to expand Medicaid eligibility, maintain Medicaid coverage during pregnancy, improve communication, and adopt uniform data collection and efficient treatment protocols. Rates of singleton births before 32 and 37 weeks of gestation in Ohio hospitals were primary outcomes. We used statistical process control methods to analyze change and generalized linear mixed models to estimate program effects accounting for known risk factors. RESULTS: Participating sites tracked 2,562 women eligible for treatment between January 1, 2014, and November 30, 2015. Late entry to care, variable interpretation of treatment guidelines, maintenance of Medicaid coverage, and inefficient communication among health care providers and insurers were identified as treatment barriers. Births before 32 weeks of gestation decreased in all hospitals by 6.6% and in participating hospitals by 8.0%. Births before 32 weeks of gestation to women with prior preterm birth decreased by 20.5% in all hospitals, by 20.3% in African American women, and by 17.1% in women on Medicaid. Births before 37 weeks of gestation were minimally affected. Adjusting for risk factors and birth clustering by hospital confirmed a program-associated 13% (95% confidence interval 0.3-24%) reduction in births before 32 weeks of gestation to women with prior preterm birth. CONCLUSION: The Ohio progestogen project was associated with a sustained reduction in singleton births before 32 weeks of gestation in Ohio. PMID- 28079775 TI - Association of Hospital Volume With Racial and Ethnic Disparities in Locally Advanced Cervical Cancer Treatment. AB - OBJECTIVE: To evaluate racial-ethnic disparities in guideline-based care in locally advanced cervical cancer and their relationship to hospital case volume. METHODS: Using the National Cancer Database, we performed a retrospective cohort study of women diagnosed between 2004 and 2012 with locally advanced squamous or adenocarcinoma of the cervix undergoing definitive primary radiation therapy. The primary outcome was the race-ethnicity-based rates of adherence to the National Comprehensive Cancer Network guideline-based care. The secondary outcome was the effect of guideline-based care on overall survival. Multivariable models and propensity matching were used to compare the hospital risk-adjusted rates of guideline-based adherence and overall survival based on hospital case volume. RESULTS: The final cohort consisted of 16,195 patients. The rate of guideline based care was 58.4% (95% confidence interval [CI] 57.4-59.4%) for non-Hispanic white, 53% (95% CI 51.4-54.9%) for non-Hispanic black, and 51.5% (95% CI 49.4 53.7%) for Hispanic women (P<.001). From 2004 to 2012, the rate of guideline based care increased from 49.5% (95% CI 47.1-51.9%) to 59.1% (95% CI 56.9-61.2%) (Ptrend<.001). Based on a propensity score-matched analysis, patients receiving guideline-based care had a lower risk of mortality (adjusted hazard ratio 0.65, 95% CI 0.62-0.68). Compared with low-volume hospitals, the increase in adherence to guideline-based care in high-volume hospitals was 48-63% for non-Hispanic white, 47-53% for non-Hispanic black, and 41-54% for Hispanic women. CONCLUSION: Racial and ethnic disparities in the delivery of guideline-based care are the highest in high-volume hospitals. Guideline-based care in locally advanced cervical cancer is associated with improved survival. PMID- 28079776 TI - Enhanced Recovery Program and Length of Stay After Laparotomy on a Gynecologic Oncology Service: A Randomized Controlled Trial. AB - OBJECTIVE: To estimate whether a rapid recovery program would reduce length of stay among patients undergoing laparotomy on a gynecologic oncology service. METHODS: We conducted a prospective, randomized, controlled trial comparing an enhanced recovery after surgery protocol with routine postoperative care among women undergoing laparotomy on the gynecologic oncology service. Protocol elements included: preoperative counseling, regional anesthesia, intraoperative fluid restriction, and early postoperative ambulation and feeding. A sample size of 50 per group (N=100) was planned to achieve 80% power to detect a two-day difference in our primary outcome, length of hospital stay; secondary outcomes included: total daily narcotics used, time to postoperative milestones, and complications. RESULTS: A total of 112 women were enrolled between 2013 and 2015. Nine patients did not undergo laparotomy and were excluded, leaving 52 and 51 patients in the control and intervention groups, respectively. There was no difference in length of stay between the two groups (median 3.0 in both groups; P=.36). Enhanced recovery after surgery patients used less narcotics on day 0 (10.0 compared with 5.5 morphine equivalents in the control and intervention arms, respectively, P=.09) and day 2 (10.0 compared with 7.5 morphine equivalents, respectively; P=.05); however, there was no statistically significant difference between groups in any of the secondary outcomes. Post hoc analysis based on actual anesthesia received also failed to demonstrate a difference in time to discharge. CONCLUSION: When compared with usual care, introducing a formal enhanced recovery after surgery protocol did not significantly reduce length of stay. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT01705288. PMID- 28079777 TI - It's All How You "Spin" It: Interpretive Bias in Research Findings in the Obstetrics and Gynecology Literature. AB - Scientific publications can be subject to varying degrees of interpretive bias, also known as spin. The rate of spin in randomized controlled trials (RCTs) with nonsignificant primary outcomes in the general obstetrics and gynecology literature is unknown. A decade (January 2006 through December 2015) of the tables of contents of Obstetrics & Gynecology and the American Journal of Obstetrics & Gynecology were screened, with 503 RCTs identified. Limiting assessment to only parallel-group RCTs with a nonsignificant primary outcome (P>=.05) resulted in the identification of 194 studies. The abstracts of the articles reported the primary outcome in 93% of studies with 79% containing a precision estimate but only 25% noting an effect size. The extent of any type of spin occurred in 43% of abstracts and 50% of the main text. In articles that contained spin in the abstract, the more common types were: emphasizing statistically significant secondary results despite a nonsignificant primary outcome (40%); interpreting statistically nonsignificant primary results as showing treatment equivalence or comparable effectiveness (37%); and emphasizing the beneficial effect of the treatment despite statistically nonsignificant results (15%). Half of parallel-group RCTs with nonsignificant primary outcomes published in the two leading journals in general obstetrics and gynecology contains some level of spin. As readers of the medical literature, we should be aware of the concept of spin, the diversity and heterogeneity of spin in the reporting of conclusions, and its effects, particularly when discussing articles that may change clinical practice. PMID- 28079778 TI - Association of Intended Route of Delivery and Maternal Morbidity in Twin Pregnancy. AB - OBJECTIVE: To evaluate maternal morbidity in twin pregnancies according to intended mode of delivery. METHODS: We assembled a 7-year retrospective cohort (2007-2014) of women delivering viable, vertex-presenting twins at or beyond 32 weeks of gestation without contraindication to labor or uterine scar. We classified women as undergoing a trial of labor to attempt vaginal birth or choosing an elective cesarean delivery. Our primary outcome was a measure of composite maternal morbidity including death, postpartum hemorrhage, infection, major procedure, readmission for infection or reoperation, need for dilation and evacuation for hemorrhage or infection, venous thromboembolism, small bowel obstruction or ileus, or intensive care unit admission. Postpartum hemorrhage was defined as estimated blood loss greater than or equal to 1,500 mL or need for transfusion. The rate of lacerations in each group was also determined. Using logistic regression to control for confounders, we examined the odds of maternal morbidity according to intended mode of delivery. RESULTS: Of 2,272 twin pregnancies at or beyond 32 weeks of gestation, 1,140 (50%) met inclusion criteria with 571 (50%) electing cesarean delivery and 569 (50%) undergoing a trial of labor to attempt vaginal birth. Vaginal delivery of both twins was achieved in 74% (n=418) of women choosing a trial of labor. The rate of maternal morbidity was 12.3% in the trial of labor group compared with 9.1% in the elective cesarean delivery group (P=.08, adjusted odds ratio [OR] 1.6, 95% confidence interval [CI] 1.1-2.4). Postpartum hemorrhage was more common among women who attempted vaginal delivery (n=52) compared with those electing cesarean delivery (n=28) with rates of 9.1% compared with 4.9%, respectively (P<.01, adjusted OR 2.2, 95% CI 1.4-3.6) and was responsible for the difference in the composite morbidity rate between groups. CONCLUSION: When adjustment is made for potential confounders, women undergoing a trial of labor with twins experience a higher odds of maternal morbidity than those electing cesarean delivery, primarily as a result of hemorrhage. In pragmatic terms, the tradeoff for a 74% chance of vaginal delivery is a 4% absolute increase in the rate of serious postpartum hemorrhage. PMID- 28079779 TI - Pathologically Diagnosed Placenta Accreta and Hemorrhagic Morbidity in a Subsequent Pregnancy. AB - OBJECTIVE: To identify the relationship between pathologically diagnosed placenta accreta and risk of major morbidity in a subsequent pregnancy. METHODS: We conducted a retrospective cohort study of patients with pathologically diagnosed placenta accreta in an index pregnancy who returned with a subsequent pregnancy at our academic center from 2007 to 2015. Subsequent delivery outcomes included minor, major, or no morbidity. Minor morbidity included estimated blood loss 500 1,500 cc for vaginal and 1,000-1,500 cc for cesarean delivery, transfusion of one to three units of red cells, and minor surgical procedures. Major morbidity included estimated blood loss greater than 1,500 cc, transfusion of greater than three units of red cells, uterine artery embolization, unplanned laparotomy, or hysterectomy. RESULTS: Three hundred thirty-nine patients with pathologically diagnosed accreta did not undergo hysterectomy, and 39 (11.5%) of these returned for subsequent delivery. Of these, 14 (36%) had accretas that had been identified clinically in the index pregnancy. Twenty-one (54%) experienced morbidity in the index pregnancy, 16 of these (76%) minor and five (24%) major. Of patients without morbidity in the first pregnancy, none experienced major morbidity in a subsequent pregnancy, whereas 6 of 21 (29%) with any index morbidity had a subsequent major morbid outcome (P=.02). Of those with a morbid index delivery, 25% had either a clinical or pathologic accreta diagnosis at follow-up compared with none of those who index accreta was nonmorbid (P=.05). CONCLUSION: Risk for major hemorrhagic morbidity after a prior pathologically diagnosed accreta depends on the clinical context. Preparation for major blood loss is indicated after any prior pregnancy complicated by hemorrhage or treatment of retained placenta with a pathologic accreta. PMID- 28079780 TI - Subspecialty Influence on Scientific Peer Review for an Obstetrics and Gynecology Journal With a High Impact Factor. AB - OBJECTIVE: To evaluate whether quality of peer review and reviewer recommendation differ based on reviewer subspecialty in obstetrics and gynecology and to determine the role of experience on reviewer recommendation. METHODS: We performed a retrospective cohort study of reviews submitted to Obstetrics & Gynecology between January 2010 and December 2014. Subspecialties were determined based on classification terms selected by each reviewer and included all major obstetrics and gynecology subspecialties, general obstetrics and gynecology, and nonobstetrics and gynecology categories. Review quality (graded on a 5-point Likert scale by the journal's editors) and reviewer recommendation of "reject" were compared across subspecialties using chi, analysis of variance, and multivariate logistic regression. RESULTS: There were 20,027 reviews from 1,889 individual reviewers. Reviewers with family planning subspecialty provided higher quality peer reviews compared with reviewers with gynecology only, reproductive endocrinology and infertility, gynecologic oncology, and general obstetrics and gynecology specialties (3.61+/-0.75 compared with 3.44+/-0.78, 3.42+/-0.72, 3.35+/-0.75, and 3.32+/-0.81, respectively, P<.05). Reviewers with gynecology only subspecialty recommended rejection more often compared with reviewers with a nonobstetrics and gynecology subspecialty (57.7% compared with 38.7%, P<.05). Editorial Board members recommended rejection more often than new reviewers (68.0% compared with 41.5%, P<.05). Increased adjusted odds of manuscript rejection recommendation were associated with reproductive endocrinology, female pelvic medicine and reconstructive surgery, and gynecology-only reviewer subspecialty (adjusted odds ratio [OR] 1.23 [1.07-1.41], 1.21 [1.05-1.39], and 1.11 [1.02-1.20]). Manuscript rejection recommendation rate was also increased for reviewers who had completed the highest quintile of peer reviews (greater than 195) compared with the lowest quintile (one to seven) (adjusted OR 2.85 [2.60-3.12]). CONCLUSION: Peer review quality differs based on obstetrics and gynecology subspecialty. Obstetrics and gynecology subspecialty and reviewer experience have implications for manuscript rejection recommendation. Reviewer assignment is pivotal to maintaining a rigorous manuscript selection process. PMID- 28079782 TI - Spin. PMID- 28079781 TI - Transcutaneous Nerve Stimulation for Pain Relief During Office Hysteroscopy: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the pain-relieving effect of transcutaneous electrical nerve stimulation (TENS) during office-based hysteroscopy without sedation. METHODS: We conducted a randomized, double-blind, placebo-controlled trial. Participants were randomly assigned to the active TENS, placebo TENS, or control group. The active TENS intervention consisted of a varying high-frequency (80-100 Hz), 400-microseconds, individually adjusted, high-intensity TENS application with two self-adhesive electrodes placed parallel to the spinal cord at the T10 L1 and S2-S4 levels. In the placebo group, participants were connected to the TENS unit but delivering no electrical stimulation. The primary outcome was self reported pain intensity (0-100 mm) measured on a visual analog scale at several stages (entry, contact, biopsy, and residual). The minimum clinically relevant difference for the visual analog scale has been previously reported as 10 mm. Sample size was calculated to provide 80% power to show a 10-mm difference (alpha=0.0125) in the primary outcome. Secondary outcomes included duration of the procedure, vital parameters, vasovagal symptoms, and participant satisfaction index (0-10 rating scale). RESULTS: A total of 138 women (46 per group) participated in the study between January 2016 and April 2016. No differences were found between groups regarding age, weight, body mass index, parity status, menopausal status, or previous hysteroscopy status. Visual analog scale scores highlighted a decrease in pain in the active TENS group compared with the placebo group (entry: -11 mm, 95% confidence interval [CI] -17 to -5; contact: -21.9 mm, 95% CI -30 to -13.9; biopsy: -30.5 mm, 95% CI -47.1 to -13.8, P<.001). Moreover, the reduction in pain reached the minimum clinically relevant difference. Regarding satisfaction, results also revealed differences between active TENS and placebo groups (1.3, 95% CI 0.5-2.2, P=.001). CONCLUSION: Transcutaneous electrical nerve stimulation reduces pain and increases patient satisfaction during office hysteroscopy without sedation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT02647008. PMID- 28079783 TI - What Is New in Global Women's Health? (Part 2): Best Articles From the Past Year. AB - This month we focus on current research in global women's health in obstetrics and gynecology. Drs. Autry and Petersen discuss six recent publications, which are concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. PMID- 28079784 TI - Connect the Dots-February 2017. PMID- 28079785 TI - Antiplatelet Agents and the Prevention of Spontaneous Preterm Birth: A Systematic Review and Meta-analysis. AB - OBJECTIVE: Spontaneous preterm birth is an important cause of neonatal mortality and morbidity. An increasing body of evidence suggests that uteroplacental ischemia plays an important role in the etiology of spontaneous preterm birth. We aimed to study whether antiplatelet agents reduce the risk of spontaneous preterm birth. DATA SOURCES: We included data from an individual participant data meta analysis of studies that had evaluated the effect of antiplatelet agents to reduce preeclampsia (Perinatal Antiplatelet Review of International Studies Individual Participant Data). METHODS OF STUDY SELECTION: The meta-analysis included 31 studies that randomized women to low-dose aspirin-dipyridamole or placebo-no treatment as a primary preventive strategy for preeclampsia. For the current study we analyzed data from 17 trials (28,797 women) that supplied data on type of delivery (spontaneous compared with indicated birth). TABULATION, INTEGRATION, AND RESULTS: Primary endpoints were spontaneous preterm birth at less than 37 weeks, less than 34 weeks, and less than 28 weeks of gestation. We analyzed outcomes for each trial separately using chi statistics and combined in an individual participant data meta-analysis using a binary logistic regression model. Women assigned to antiplatelet treatment compared with placebo or no treatment had a lower risk of spontaneous preterm birth at less than 37 weeks (relative risk [RR] 0.93, 95% confidence interval [CI] 0.86-0.996) and less than 34 weeks of gestation (RR 0.86, 95% CI 0.76-0.99). The RR of having a spontaneous preterm birth at less than 37 weeks of gestation was 0.83 (95% CI 0.73-0.95) for women who have had a previous pregnancy and 0.98 (95% CI 0.89-1.09) for women in their first pregnancy. The treatment effect was stable in all other prespecified subgroups. CONCLUSION: Antiplatelet agents reduce spontaneous preterm birth in pregnant women at risk for preeclampsia. PMID- 28079786 TI - Fatal postoperative systemic pulmonary hypertension in benfluorex-induced valvular heart disease surgery: A case report. AB - RATIONALE: Drug-induced valvular heart disease (DI-VHD) remains an under recognized entity. PATIENT CONCERNS: This report describes a heart valve replacement which was complicated by intractable systemic pulmonary arterial hypertension in a 61-year-old female with severe restrictive mitral and aortic disease. The diagnosis of valvular disease was preceded by a history of unexplained respiratory distress. The patient had been exposed to benfluorex for 6.5 years. DIAGNOSES: The diagnostic procedure documented specific drug-induced valvular fibrosis. INTERVENTIONS: Surgical mitral and aortic valve replacement was performed. OUTCOMES: Heart valve replacement was postoperatively complicated by unanticipated disproportionate pulmonary hypertension. This issue was fatal despite intensive care including prolonged extracorporeal life support. LESSONS: Benfluorex is a fenfluramine derivative which has been marketed between 1976 and 2009. Although norfenfluramine is the common active and toxic metabolite of all fenfluramine derivatives, the valvular and pulmonary arterial toxicity of benfluorex was much less known than that of fenfluramine and dexfenfluramine. The vast majority of benfluorex-induced valvular heart disease remains misdiagnosed as hypothetical rheumatic fever due to similarities between both etiologies. Better recognition of DI-VHD is likely to improve patient outcome. PMID- 28079787 TI - Oral and vulvo-vaginal lichenoid reactions due to mitotane (Lysodren): A case report. AB - BACKGROUND: The purpose of pharmacovigilance (drug safety) is collection, detection, assessment, monitoring, and prevention of adverse effects with pharmaceutical products. It is meant to identify, characterize, prevent, or minimize actual or potential risks relating to medicinal products. To prevent these adverse effects and improve our practice, health professionals have a duty to report side effects to assess this risk and evaluate the benefit/risk requirements. Mitotane (Lysodren) is used for treating adrenocortical carcinoma. Currently, no side effects concerning oral and genital mucosa have been reported. CASE SUMMARY: This case report is about a 50 years old woman. Six months after the initiation on mitotane treatment, she developed erosive lesions located on the oral and vaginal mucosa. These drug reactions were diagnosed as erosive lichen planus by the biopsy. This lichenoid lesions were resistant to the usual treatments, mitotane being at the time not replaceable. CONCLUSION: This case describes an unreported adverse effect of mitotane, it is - to our knowledge - the 1st description of erosive lichenoid drug reaction due to Mitotane. PMID- 28079788 TI - The prevalence of factor VIII and IX inhibitors among Saudi patients with hemophilia: Results from the Saudi national hemophilia screening program. AB - Hemophilia A and B are X-linked diseases that predominantly affect male patients. Patients can develop coagulation factor inhibitors, which exponentially increases the treatment cost. However, the prevalence of factor VIII and IX inhibitors in Saudi Arabia is unclear.This study aimed to determine the Saudi prevalence of factor VIII and IX inhibitors.This 4-year, 7-center, cross-sectional study evaluated the Saudi prevalences of hemophilia A and B. We collected the patients' clinical data, evaluated their disease, and tested for factor inhibitors.We included 202 patients with hemophilia (median age at diagnosis: 0.13 years, range: birth-34.8 years). The patients included 198 male patients (98%), 148 patients with hemophilia A (73.3%), and 54 patients with hemophilia B (26.7%). The patients exhibited severe factor VIII activity (<1%; 121 patients; 5.2%), moderate activity (1-5%; 7 patients; 4.9%), and mild activity (14 patients; 9.9%). Among the patients with care-related data, most patients were treated for episodic bleeding (76.8%) or received prophylaxis (22.6%); 1 patient received both treatments. Among the patients with source-related data, the factor replacements were derived from plasma (48.4%), recombinant concentrates (22.9%), both sources (14.6%), or fresh frozen plasma (14.1%). Factor VIII inhibitors were observed in 43 (29.3%) of the 147 patients, and only 1 of the 54 patients developed factor IX inhibitors. Most patients who developed inhibitors had severe hemophilia (40/44; 90.9%), and inhibitors were also common among patients who received recombinant products (14/43; 32.6%).The Saudi prevalence of factor inhibitors was similar to those among other ethnic populations. PMID- 28079789 TI - The impact of irrigating fluid absorption on blood coagulation in patients undergoing transurethral resection of the prostate: A prospective observational study using rotational thromboelastometry. AB - Although endoscopic transurethral resection of the prostate (TURP) is a well established procedure as a treatment for benign prostatic hyperplasia, its complications remain a concern. Among these, coagulopathy may be caused by the absorption of irrigating fluid. This study aimed to evaluate such phenomenon using a rotational thromboelastometry (ROTEM).A total of 20 patients undergoing TURP participated in this study. A mixture of 2.7% sorbitol-0.54% mannitol solution and 1% ethanol was used as an irrigating fluid, and fluid absorption was measured via the ethanol concentration in expired breath. The effects on coagulation were assessed by pre- and postoperative laboratory blood tests, including hemoglobin, hematocrit, platelet count, international normalized ratio of prothrombin time (PT-INR), activated partial thromboplastin time, electrolyte, and ROTEM.INTEM-clotting time (INTEM-CT) was significantly lengthened by 14% (P = 0.001). INTEM-alpha-angle was significantly decreased by 3% (P = 0.011). EXTEM clot formation time was significantly prolonged by 18% (P = 0.008), and EXTEM maximum clot firmness (EXTEM-MCF) was significantly decreased by 4% (P = 0.010). FIBTEM-MCF was also significantly decreased by 13% (P = 0.015). Moreover, hemoglobin (P < 0.001), hematocrit (P < 0.001), platelet counts (P < 0.001), potassium (P = 0.024), and ionized calcium (P = 0.004) were significantly decreased, while PT-INR (P = 0.001) was significantly increased after surgery. The amount of irrigating fluid absorbed was significantly associated with the weight of resected prostatic tissue (P = 0.001) and change of INTEM-CT (P < 0.001).As shown by the ROTEM analysis, the irrigating fluid absorbed during TURP impaired the blood coagulation cascade by creating a disruption in the coagulation factor activity or by lowering the coagulation factor concentration via dilution. PMID- 28079790 TI - Ecthyma gangrenosum, a skin manifestation of Pseudomonas aeruginosa sepsis in a previously healthy child: A case report. AB - RATIONALE: Ecthyma gangrenosum (Eg) is a necrotic lesion that is mostly seen in immunocompromised patients. It reflects a severe sepsis, possibly caused by Pseudomonas aeruginosa (Pa). PATIENT CONCERNS: A healthy 3-year-old girl admitted to the Pediatric Emergency Department presented a sepsis-associated purpura with neurological and respiratory distress. INTERVENTIONS: An empiric antibiotherapy (anti-meningococcal) was prescribed. DIAGNOSES: Forty-eight hours after admission, blood and wound cultures were positive for Pa. As a result, the decision was made to change the antibiotic therapy.Unfortunately, on day 3, the patient died. Exhaustive immunologic tests are presently being carried out. OUTCOMES: Eg caused by Pa is uncommon in healthy children, and purpura sepsis is usually caused by Neisseria meningitides infection. LESSONS: Eg should be recognized rapidly so that the appropriate treatment can be prescribed as quickly as possible. PMID- 28079791 TI - A possible new approach in the prediction of late gestational hypertension: The role of the fetal aortic intima-media thickness. AB - The aim was to determine the predictive role of combined screening for late-onset gestational hypertension by fetal ultrasound measurements, third trimester uterine arteries (UtAs) Doppler imaging, and maternal history. This prospective study on singleton pregnancies was conducted at the tertiary center of Maternal and Fetal Medicine of the University of Padua during the period between January 2012 and December 2014. Ultrasound examination (fetal biometry, fetal wellbeing, maternal Doppler study, fetal abdominal aorta intima-media thickness [aIMT], and fetal kidney volumes), clinical data (mother age, prepregnancy body mass index [BMI], and parity), and pregnancy outcomes were collected. The P value <0.05 was defined significant considering a 2-sided alternative hypothesis. The distribution normality of variables were assessed using Kolmogorov-Smirnoff test. Data were presented by mean (+/-standard deviation), median and interquartile range, or percentage and absolute values. We considered data from 1381 ultrasound examinations at 29 to 32 weeks' gestation, and in 73 cases late gestational hypertension developed after 34 weeks' gestation. The final multivariate model found that fetal aIMT as well as fetal umbilical artery pulsatility index (PI), maternal age, maternal prepregnacy BMI, parity, and mean PI of maternal UtAs, assessed at ultrasound examination of 29 to 32 weeks' gestation, were significant and independent predictors for the development of gestational hypertension after 34 weeks' gestation. The area under the curve of the model was 81.07% (95% confidence interval, 75.83%-86.32%). A nomogram was developed starting from multivariate logistic regression coefficients. Late-gestational hypertension could be independently predicted by fetal aIMT assessment at 29 to 32 weeks' gestation, ultrasound Doppler waveforms, and maternal clinical parameters. PMID- 28079792 TI - Amplification of HER2 and TOP2A and deletion of TOP2A genes in a series of Taiwanese breast cancer. AB - BACKGROUND: The prognostic relevance of topoisomerase II alpha (TOP2A) copy number change remains not well established. This study is aimed to investigate the frequency and pattern of TOP2A aberrations; to correlate TOP2A alterations with human epidermal growth factor receptor 2 (HER2) status and clinicopathological parameters, and further to explore prognostic value of TOP2A and HER2 status in breast cancer in Taiwan. METHODS: We analyzed tissue samples from 311 invasive carcinomas in tissue microarrays for TOP2A and HER2 status by fluorescent in situ hybridization. RESULTS: TOP2A copy number change is an infrequent genetic event (9.8% amplification and 2.7% deletion) and is present in both HER2-amplified and nonamplified tumors. TOP2A amplification is statistically associated with age >50 at diagnosis (P = 0.016) and HER2 amplification (P < 0.001). HER2 amplification, but not TOP2A amplification, is a predictor of unfavorable prognosis (P = 0.002). Univariate and multivariate analysis showed that higher histologic grading, positive nodal involvement, and HER2 positivity were associated with poorer overall survival. Cytogenetically, double minutes type amplification is the predominant pattern for both genes (HER2: 64% and TOP2A: 93.1%). Homogeneous staining region-type signals of both genes are resistant to RNase digestion, supporting that these were not nuclear accumulation of mRNA transcripts. CONCLUSION: Our results demonstrate the prognostic value of tumor grading, nodal involvement, and HER2 status in Taiwanese breast cancer. TOP2A aberrations are an infrequent event independent of HER2 status, and TOP2A amplification carries no prognostic value. The predictive value of TOP2A aberrations in patients of breast cancer taking athracycline-containing treatment in Taiwan remains to be determined in prospectively well-designed clinical trials. PMID- 28079793 TI - Oral health-related quality of life in pediatric patients under general anesthesia: A prospective study. AB - Our goal was to evaluate how dental treatments under general anesthesia (GA) affect the quality of life by a prospective pair-matched design. Pediatric patients, who had received dental treatments under GA, were enrolled and were asked to complete the Early Childhood Oral Health Impact Scale (ECOHIS) before the treatment and 1 month after the treatment. To shield the observed impacts, a pair-matched control group was performed. Patients in the control group were also required to complete the ECOHIS at these different points in time. In both groups, the items of troubled sleep and oral/dental pain scored highest, whereas avoiding smiling or laughing and avoiding talking scored lowest before the treatment. The total mean score in the 2 groups was 13.1 and 13.7, respectively, and there was no significant statistical difference (P > 0.05). However, the total mean score was 1.9 in the experimental group after the treatment and smaller compared with the control group (1.9 vs. 4.7, P < 0.001). The majority of the items in both groups had an apparent effect size and the total mean effect in the experimental group was greater than that in the control group (85.5% vs. 65.7%, P < 0.001). Therefore, dental treatment under GA could provide better quality of life restoration compared with treatment over multiple visits. PMID- 28079794 TI - Interventional pulmonology for patients with central airway obstruction: An 8 year institutional experience. AB - Patients with central airway obstruction (CAO) may need endobronchial intervention to relieve their symptoms. This report is on a single-center experience of using interventional bronchoscopy in terms of complications and survival. This retrospective study was conducted in a university hospital and involved 614 patients (464 men, 150 women; mean age, 60.2 years) with benign (n = 133) and malignant (n = 481) tracheobronchial disease who received 756 endobronchial intervention procedure during the period 2008 to 2015. Survival was analyzed using the Kaplan-Meier method, while the log-rank test was used for comparisons. A total of 583 patients (95%) achieved endoscopic success after interventional bronchoscopy. Four (0.7%) died within 24 hours of the procedure, while the major morbidities were halitosis (n = 41, 6.7%) and iatrogenic pneumonia (n = 24, 3.9%). Repeat procedures due to recurrent airway obstruction were done on 45 patients with benign conditions and on 60 with malignancies. The median survival after the procedure in patients with lung cancer, other metastatic cancer, and esophageal cancer was 166, 228, and 86 days, respectively. Between patients with inoperable lung cancer and CAO after therapeutic bronchoscopy and patients without CAO, there was no statistically significant difference in survival (P = 0.101). Interventional bronchoscopy is a safe and effective procedure that may be recommended for CAO. Patients with lung metastases have similar lengths of survival as patients with primary lung cancer. Patients with advanced lung cancer and CAO have similar survival as those without CAO. PMID- 28079795 TI - Pancreatic groove cancer. AB - Pancreatic groove cancer is very rare and can be indistinguishable from groove pancreatitis. This study is to clarify the characteristics, clinical features, managements, and survival outcomes of this rare tumor.Brief descriptions were made for each case of pancreatic groove cancer encountered at our institute. Individualized data of pancreatic groove cancer cases described in the literature were extracted and added to our database to expand the study sample size for a more complete analysis.A total of 33 patients with pancreatic groove cancer were included for analysis, including 4 cases from our institute. The median tumor size was 2.7 cm. The most common symptom was nausea or vomiting (89%), followed by jaundice (67%). Duodenal stenosis was noted by endoscopy in 96% of patients. The histopathological examination revealed well differentiated tumor in 43%. Perineural invasion was noted in 90%, and lymphovascular invasion and lymph node involvement in 83%. Overall 1-year survival rate was 93.3%, and 3- or 5-year survival rate was 62.2%, with a median survival of 11.0 months. Survival outcome for the well-differentiated tumors was better than those of the moderate/poorly differentiated ones.Early involvement of duodenum causing vomiting is often the initial presentation, but obstructive jaundice does not always happen until the disease progresses. Tumor differentiation is a prognostic factor for survival outcome. The possibility of pancreatic groove cancer should be carefully excluded before making the diagnosis of groove pancreatitis for any questionable case. PMID- 28079797 TI - Case report: Rapid improvement of crossed cerebellar diaschisis after intravascular laser irradiation of blood in a case of stroke. AB - RATIONALE: Crossed cerebellar diaschisis (CCD) is a poor prognostic factor after stroke because without immediate cerebral reperfusion no further improvements in the patient's condition can be achieved. We investigated the clinical effects of intravascular laser irradiation therapy (ILIB) on CCD and evaluated the therapeutic effect in the sub-acute post-stroke stage. PATIENT CONCERNS: The 77 year-old male with cerebral infarction in the territory of the right anterior cerebral artery only underwent conservative treatment including hydration and aspirin in the acute post-stroke stage. DIAGNOSIS: He was diagnosed as stroke based on the clinical presentations and imaging findings. INTERVENTION: Once the patient was in stable condition, he underwent a daily hour-long ILIB (He-Ne laser) for ten consecutive days during the sub-acute post-stroke stage. OUTCOMES: We used single-photon emission computed tomography (SPECT) before and after intravascular laser irradiation to detect changes in cerebral and cerebellar perfusion. Then, we compared the two images. CCD was detected using the first SPECT. After intervention by ILIB, the second SPECT showed greater perfusion in the affected cerebellar hemisphere. LESSONS: We found that ILIB helped eliminate CCD, which was previously shown to be an untreatable condition using any intervention during the sub-acute post-stroke stage. Stroke patients could therefore greatly benefit from ILIB. PMID- 28079796 TI - Serum microRNA panel for early diagnosis of the onset of hepatocellular carcinoma. AB - Unique change of circulating microRNAs (miRNAs) was recognized to occur in early oncogenesis, which conferred it the potential as biomarkers for early detection of cancer. However, its diagnostic capability for hepatocellular carcinoma (HCC) has not been fully understood. In this study, microarray analysis was applied to screen the initial candidate miRNA from both the supernatants of anoikis resistant cellular models and the sera samples of HCC patients. The selected differentially expressed miRNAs were further verified in 115 HCC patients and 40 health controls by qRT-PCR. Among these, 4 miRNAs (miR-16-2-3p, 92a-3p, 107, and 3126-5p) were significantly changed in HCC patients compared with controls. Logistic regression analysis identified a 3-miRNA panel (miR-92-3p, miR-107, and miR-3126-5p) as valuable diagnostic marker for HCC, especially for early stage patients (AUC = 0.975) and for low-level AFP HCC patients (AUC = 0.971). In addition, the combination of 3-miRNA panel and AFP was even more effective for discriminating the early stage HCC patients (AUC = 0.988) and low-level AFP HCC patients (AUC = 0.989) from control. In conclusion, diagnostic efficacy of the combination of 3-miRNA panel and AFP was powerful for HCC diagnosis, especially in early tumor screening and low-level AFP patients. PMID- 28079798 TI - Clinical and genetic factors associated with warfarin maintenance dose in northern Chinese patients with mechanical heart valve replacement. AB - The effects of genetic variants on warfarin dosing vary among different ethnic groups, especially in the Chinese population. The objective of this study was to recruit patients through a rigorous experimental design and to perform a comprehensive screen to identify gene polymorphisms that may influence warfarin dosing in northern Han Chinese patients with mechanical heart valve replacement. Consenting patients (n = 183) with a stable warfarin dose were included in this study. Ninety-six single nucleotide polymorphisms (SNPs) in 30 genes involved in warfarin pharmacological pathways were genotyped using the Illumina SNP GoldenGate Assay, and their associations with warfarin dosing were assessed using univariate regression analysis with post hoc comparison using least significant difference analysis. Multiple linear regression was performed by incorporating patients' clinical and genetic data to create a new algorithm for warfarin dosing. From the 96 SNPs analyzed, VKORC1 rs9923231, CYP1A2 rs2069514, CYP3A4 rs28371759, and APOE rs7412 were associated with higher average warfarin maintenance doses, whereas CYP2C9 rs1057910, EPHX1 rs2260863, and CYP4F2 rs2189784 were associated with lower warfarin doses (P < 0.05). Multiple linear regression analysis could estimate 44.4% of warfarin dose variability consisting of, in decreasing order, VKORC1 rs9923231 (14.2%), CYP2C9*3 (9.6%), body surface area (6.7%), CYP1A2 rs2069514 (3.7%), age (2.7%), CYP3A4 rs28371759 (2.5%), CYP4F2 rs2108622 (1.9%), APOE rs7412 (1.7%), and VKORC1 rs2884737 (1.4%). In the dosing algorithm we developed, we confirmed the strongest effects of VKORC1, CYP2C9 on warfarin dosing. In the limited sample set, we also found that novel genetic predictors (CYP1A2, CYP3A4, APOE, EPHX1, CYP4F2, and VKORC1 rs2884737) may be associated with warfarin dosing. Further validation is needed to assess our results in larger independent northern Chinese samples. PMID- 28079800 TI - Discrepancy between financial disclosures of authors of clinical practice guidelines and reports by industry. AB - There is a substantial effort to increase the accuracy of conflicts of interest (COI) reporting, and reduce the influence of COI between physicians and industry, especially as it relates to clinical practice guidelines.We used the newly implemented Open Payments dataset to evaluate the accuracy of COI disclosures of authors of clinical practice guidelines that were either newly published or revised within 2014 and were included in the National Guideline Clearinghouse (NGC) website (maintained by the U.S. Department of Health and Human Services). Authors were considered as having inaccurate COI disclosure if they had not reported all companies from which they had received funds >$5000 in the 12 months preceding the guideline's publication.We identified 223 guidelines that were either newly published (109/223; 48.9%) or revised (114/223; 51.1%) within 2014 and were included in the NGC website. Among the 1329 guideline authors with available Open Payments data, 523 received >$5000 from at least 1 healthcare associated entity. However, only 56 out of the 523 authors (10.7%) were found to have accurate COI disclosure. The percentage of authors with accurate COI disclosure in revised guidelines was significantly lower than in newly published guidelines (6.8% vs 14.3%; P < 0.01) and was also found to differ between specialties. Furthermore, authors were less likely to inaccurately disclose "research payments" (37/49, 75.5%) compared to "general payments" (488/559, 87.3%, P = 0.02) as well as "other/associated research funding" (430/506, 85.0%, P = 0.08). No statistically significant association was detected between funding amount and disclosure accuracy.The majority of guideline authors lacked significant COIs, but among authors that received significant funds from at least 1 healthcare-associated entity the frequency of accurate disclosure was low. These findings indicate that the current process of disclosing COIs may be suboptimal and a proactive approach should be adopted in order to minimize COI reporting discrepancies. Furthermore, every effort should be undertaken to ensure the completeness and accuracy of the data recorded in the Open Payments database. PMID- 28079799 TI - Risk factors for recollapse of the augmented vertebrae after percutaneous vertebroplasty for osteoporotic vertebral fractures with intravertebral vacuum cleft. AB - To determine risk factors related to recollapse of the augmented vertebrae after percutaneous vertebroplasty (PVP) for osteoporotic vertebral compression fractures (OVCFs) with intravertebral vacuum cleft (IVC).Fifty-two patients treated with PVP for single OVCFs with the IVC were retrospectively reviewed. The follow-up period was at least 2 years. Vertebral height loss >=15% or kyphotic angle >=10 degrees at the final follow-up in relation to the immediately postoperative values were adopted as a definition of recollapse of the augmented vertebrae. Correlation analysis and multiple logistic regression analyses were performed to elucidate the related clinical or radiological factors for recollapse of the augmented vertebrae including age, gender, bone mineral density, preoperative fracture severity, locations of IVC sign, distribution patterns of polymethylmethacrylate (PMMA), reduction rate, and reduction angle.Assuming the increase of height loss more than 15% as a criterion of recollapse, only cleft filling pattern of PMMA in the IVC area was a significant risk factor for recollapse of the augmented vertebrae (P < 0.01). Assuming >=10 degrees progression of kyphotic angle as a criterion, cleft filling pattern of PMMA and higher values of reduction angle was as 2 significant risk factors for recollapse of the augmented vertebrae (P < 0.01). No significant difference was found in other clinical and radiological factors (P > 0.05).Cleft filling pattern of PMMA and higher values of reduction angle may play an important role in inducing recollapse of the augmented vertebrae after PVP for OVCFs with the IVC. Careful observation of patients with these conditions is necessary to prevent deterioration of their clinical course. PMID- 28079801 TI - Acute necrotizing retinal vasculitis as onset of systemic lupus erythematosus: A case report. AB - RATIONALE: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production, complement activation, and deposition of immune complexes in tissues and organs. SLE can involve any region of the visual system. Although ocular manifestations are not part of the classification criteria for SLE, they can be observed in up to one-third of the patients with SLE. They are rarely reported at the time of disease onset. Retinal vasculitis is usually associated with active generalized disease. Due to its low frequency, we report a case of acute necrotizing retinal vasculitis as onset of SLE. PATIENT CONCERNS AND DIAGNOSIS: A 25-year-old white female was referred to the rheumatology clinic with gradually and rapid deterioration of the vision due to abnormal vessel permeability in the right fundus with edema along the vessels, occlusion of arterial branches in the middle periphery with leakage of the dye in these areas and indentical but less prominent changes with cotton wool spots in the papillomacular area and extensive hemorrhages in the left eye. The onset of malar rash, arthralgias and positive antinuclear, anti-double stranded DNA, anti ribosomal P and anti-beta2 glycoprotein I antibodies with decreased C4 complement levels, as well as the positive lupus-band test confirmed the diagnosis of SLE. INTERVENTIONS: Aggressive immunomodulating therapy with high-dose methylprednisolone, intravenous immunoglobulin, and cyclophosphamide was used for suppression of the disease activity followed by azathioprine as maintaince therapy. OUTCOMES: Substantial improvement and partial resorption of the vasculitic changes, including central retinal artery and vein, was achieved prominently in the left eye. The study was conducted in accordance with the Declaration of Helsinki and written informed consent was obtained from the patient. Because of this, there is no need to conduct special ethic review and the ethical approval is not necessary. LESSONS: Inclusion of ocular manifestations among the classification criteria for SLE would enable earlier establishment of the diagnosis and therapeutic interventions in some instances of SLE. PMID- 28079802 TI - Promoter methylation of yes-associated protein (YAP1) gene in polycystic ovary syndrome. AB - BACKGROUND: DNA methylation modification has been proved to influence the phenotype of polycystic ovary syndrome (PCOS). Genome-wide association studies (GWAS) demonstrate that yes-associated protein (YAP1) genetic sites are associated with PCOS. The study aims to detect the methylation status of YAP1 promoter in ovary granulosa cells (GCs) of PCOS patients and explore novel therapeutic targets for PCOS. METHODS: Randomized controlled trial was applied and a total of 72 women were included in the study, including 36 cases of PCOS patients and 36 cases of health controls. Ovary GCs were extracted from in vitro fertilization embryo transfer. Methylation status of YAP1 promoter was detected by bisulfite sequencing PCR (BSP). Protein and mRNA expression of YAP1 were measured by western blotting and real-time quantitate PCR. RESULTS: Overall methylation level of YAP1 promoter region from PCOS group was significantly lower than that from control group. CpG sites analysis revealed that 12 sites (-443, 431, -403, -371, -331, -120, -49, -5, +1, +9, +15, +22) were significantly hypomethylated in women with PCOS (P < 0.05). A significant upregulation of YAP1 mRNA and protein expression levels was observed. Testosterone concentration could alleviate the methylation status and demonstrate obvious dose-dependent relation. CONCLUSION: Our research achievements manifest that hypomethylation of YAP1 promoter promotes the YAP1 expression, which plays a key role in the pathogenesis and accelerate PCOS. PMID- 28079803 TI - High-resolution endoscopic ultrasound imaging and the number of needle passages are significant factors predicting high yield of endoscopic ultrasound-guided fine needle aspiration for pancreatic solid masses without an on-site cytopathologist. AB - Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is the accurate diagnostic method for pancreatic masses and its accuracy is affected by various FNA methods and EUS equipment. Therefore, we aimed to elucidate the instrumental and methodologic factors for determining the diagnostic yield of EUS-FNA for pancreatic solid masses without an on-site cytopathology evaluation.We retrospectively reviewed the medical records of 260 patients (265 pancreatic solid masses) who underwent EUS-FNA. We compared historical conventional EUS groups with high-resolution imaging devices and finally analyzed various factors affecting EUS-FNA accuracy.In total, 265 pancreatic solid masses of 260 patients were included in this study. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of EUS-FNA for pancreatic solid masses without on-site cytopathology evaluation were 83.4%, 81.8%, 100.0%, 100.0%, and 34.3%, respectively. In comparison with conventional image group, high-resolution image group showed the increased accuracy, sensitivity and specificity of EUS-FNA (71.3% vs 92.7%, 68.9% vs 91.9%, and 100% vs 100%, respectively). On the multivariate analysis with various instrumental and methodologic factors, high-resolution imaging (P = 0.040, odds ratio = 3.28) and 3 or more needle passes (P = 0.039, odds ratio = 2.41) were important factors affecting diagnostic yield of pancreatic solid masses.High-resolution imaging and 3 or more passes were the most significant factors influencing diagnostic yield of EUS-FNA in patients with pancreatic solid masses without an on-site cytopathologist. PMID- 28079804 TI - Aquaporin-4 positive neuromyelitis optica spectrum disorders secondary to thrombopenic purpura: A case report. AB - RATIONALE: Neuromyelitis optica spectrum disorders (NMOSD) is considered as an immune-mediated disorder in the central nervous system (CNS). Numerous autoimmune diseases are frequently complicated with NMOSD and distinct clinical characteristics are noted in NMOSD patients with other autoimmune diseases. However, to our best knowledge, co-occurrence of NMOSD and thrombopenic purpura is rarely identified. PATIENT CONCERNS: We presented a rare case of a 72-year-old female with 6-year history of thrombopenic purpura, and 1-month history of blurred vision as well as chest zonethesia. Anti-aquaporin-4 (AQP4) antibodies was positive in the serum of the patient. DIAGNOSES: With the addition of laboratory findings, iconography findings and physical examination results, the diagnosis of NMOSD was established according to the most recent diagnostic criteria. INTERVENTIONS AND OUTCOMES: With the treatment of intravenous immunoglobulin (IVIg), the patient felt better at discharge without changing of expanded disability status scale (EDSS) score. LESSONS: The case indicates that NMOSD could co-occur with thrombopenic purpura. The disturbance of immune system balance may explain this overlap. Further studies are warranted to reveal the mechanism and to explore whether patients with NMOSD with and without thrombopenic purpura have distinct clinical feature, drug responsiveness or prognosis. PMID- 28079805 TI - Toxicities of different first-line chemotherapy regimens in the treatment of advanced ovarian cancer: A network meta-analysis. AB - BACKGROUND: Ovarian cancer (OC) is the 5th leading cause of cancer-related deaths around the world, and several chemotherapy regimens have been applied in the treatment of OC. We aim to compare toxicities of different chemotherapy regimens in the treatment of advanced ovarian cancer (AOC) using network meta-analysis. METHODS: Literature research in Cochrane Library, PubMed, and EMBASE was performed up to November 2015. Eligible randomized controlled trials (RCTs) of different chemotherapy regimens were included. Network meta-analysis combined direct and indirect evidence to assess pooled odds ratios (ORs) and draw the surface under the cumulative ranking (SUCRA) curves. RESULTS: Thirteen eligible RCTs were included in this network meta-analysis, including 8 chemotherapy regimens (paclitaxel + carboplatin [PC], pegylated liposomal doxorubicin [PLD] + carboplatin, carboplatin, gemcitabine + carboplatin, paclitaxel, PC + epirubicin, PC + topotecan, docetaxel + carboplatin). Gemcitabine + carboplatin regimen exerted higher incidence of anemia when compared with carboplatin and paclitaxel regimens. The incidence of febrile neutropenia of gemcitabine + carboplatin regimen was higher than that of PC, PLD + carboplatin, carboplatin, and PC + topotecan regimens. Topotecan PC + epirubicin regimen had a higher toxicity, comparing with PC, PLD + carboplatin, and PC + topotecan regimens. As for thrombocytopenia, gemcitabine + carboplatin chemotherapy regimen produced an obviously higher toxicity than PC and carboplatin. As for nausea, PLD + carboplatin chemotherapy regimen had a significantly higher toxicity than that of carboplatin chemotherapy regimen. Moreover, when compared with PC and carboplatin chemotherapy regimens, the toxicity of PC + epirubicin was greatly higher to patients with AOC. CONCLUSION: The nonhematologic toxicity of PLD + carboplatin regimen was higher than other regimens, which was clinically significant for the treatment of AOC. PMID- 28079806 TI - The relationship of nonalcoholic fatty liver disease and metabolic syndrome for colonoscopy colorectal neoplasm. AB - Colorectal neoplasm is considered to have a strong association with nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS), respectively. The relationship among NAFLD, MetS, and colorectal neoplasm was assessed in 1793 participants. Participants were divided into 4 groups based on the status of NAFLD and MetS. Relative excess risks of interaction (RERI), attributable proportion (AP), and synergy index (SI) were applied to evaluate the additive interaction. NAFLD and MetS were significantly correlated with colorectal neoplasm and colorectal cancer (CRC), respectively. The incidence of CRC in NAFLD (+) MetS (+) group was significantly higher than other 3 groups. The result of RERI, AP, and SI indicated the significant additive interaction of NAFLD and MetS on the development of CRC. NAFLD and MetS are risk factors for colorectal neoplasm and CRC, respectively. And NAFLD and MetS have an additive effect on the development of CRC. PMID- 28079807 TI - A case report: Distal humeral diaphyseal fracture in a child. AB - RATIONALE: Distal humeral diaphyseal fractures are much less common than supracondylar humeral fractures. The triangular shape and thinner periosteum in the diaphyseal region than in the supracondylar region of the distal diaphysis makes the treatment of diaphyseal fractures difficult. Nonoperative treatment for this fracture is challenging and troublesome; thus, open reduction and internal fixation (OR/IF) is generally recommended. PATIENT CONCERNS: We herein report a distal humeral diaphyseal fracture in a child. A 6-year-old boy fell from a chair, injuring his left elbow. Radiographs were performed at a local clinic. DIAGNOSIS: Unstable diaphyseal shaft fracture of the left humerus. INTERVENTIONS: Because of the severe displacement of the fracture and difficulty maintaining alignment for reduction, we performed OR/IF using an anterior mini-incision approach on the cubital skin line under general anesthesia. OUTCOMES: Displacement of the fracture was reduced easily, and stable fixation was achieved using percutaneous intramedullary Kirschner wires. After immobilization with a long-arm cast for 4 weeks, the cast was removed and range-of-motion exercises were encouraged. At 9 months postoperatively, the range of elbow motion was 0 degrees to 135 degrees . Baumann angle and the carrying angle were 62 degrees and 17 degrees , respectively. According to Flynn criteria, the result was excellent. LESSONS: OR/IF using the herein-described cubital anterior approach seems to be a safe and easily performed procedure for distal humeral diaphyseal fractures, and percutaneous intramedullary Kirschner wires provide reliable fixation in such cases. PMID- 28079808 TI - Diagnosis and treatment of pediatric benign pneumoperitoneum: A case report series of 9 patients. AB - INTRODUCTION: Benign pneumoperitoneum (BPPT) is defined as asymptomatic free intraabdominal air or as pneumoperitoneum without peritonitis. Symptomatic free air requires surgical anagement, but management of asymptomatic pneumoperitoneum is controversial. In this study, we investigate the diagnosis and treatment of BPPT in children. CLINICAL FINDINGS: The clinical data of 9 pediatric patients with BPPT who were admitted to our hospital from January 2000 to January 2015 were retrospectively analyzed to summarize the diagnosis and treatment. Overall, 9 cases were included with 8 males and 1 female, aged from 4 days to 4 years. Among them there were 6 newborns (including 1 premature infant). Patients were all admitted to hospital with the major clinical symptom of abdominal distension, including 2 cases accompanied by tachypnea, 2 cases with vomiting, 1 case with diarrhea, and 2 cases with fever. No previous constipation or obstructive defecation existed. Six newborns had meconium defecation within 24 hours after birth. Physical examination revealed all patients with relaxed abdominal wall except 1 patient with abdominal distension had slight muscle stiffness and hyperactive bowel sounds. Abdominal X-ray suggested free air under the diaphragm in all cases. INTERVENTIONS/OUTCOMES: All patients except for one case of laparotomy were conservatively treated and cured with fasting, infection prevention, rehydration, abdominocentesis, and close observation. Nine cases of patients were all discharged with no death occurrence. After discharge follow-up of 7 months to 6 years was conducted. There was no recurrence of similar symptoms, and children were in good growth and development. CONCLUSION: The diagnosis of BPPT mainly relies on clinical symptoms in patient, careful abdominal examination, abdominal X-ray combined with abdominocentesis, and the exclusion of gastrointestinal perforation for confirmation. Conservative treatment can cure the disease. Attention should be paid to distinguish with surgical pneumoperitoneum to avoid unnecessary surgical exploration. PMID- 28079809 TI - A comparison of the surgical mortality due to colorectal perforation at different hospitals with data from 10,090 cases in the Japanese National Clinical Database. AB - Colorectal perforation has a high rate of mortality. We compared the incidence and fatality rates of colorectal perforation among different hospitals in Japan using data from the nationwide surgical database.Patients were registered in the National Clinical Database (NCD) between January 1st, 2011 and December 31st, 2013. Patients with colorectal perforation were identified from surgery records by examining if acute diffuse peritonitis (ADP) and diseases associated with a high probability of colorectal perforation were noted. The primary outcome measures included the 30-day postsurgery mortality and surgical mortality of colorectal perforation. We analyzed differences in the observed-to-expected mortality (O/E) ratio between the two groups of hospitals, that is, specialized and non-specialized, using the logistic regression analysis forward selection method.There were 10,090 cases of disease-induced colorectal perforation during the study period. The annual average postoperative fatality rate was 11.36%. There were 3884 patients in the specialized hospital group and 6206 in the non specialized hospital group. The O/E ratio (0.9106) was significantly lower in the specialized hospital group than in the non-specialized hospital group (1.0704). The experience level of hospitals in treating cases of colorectal perforation negatively correlated with the O/E ratio.We conducted the first study investigating differences among hospitals with respect to their fatality rate of colorectal perforation on the basis of data from a nationwide database. Our data suggest that patients with colorectal perforation should choose to be treated at a specialized hospital or a hospital that treats five or more cases of colorectal perforation per year. The results of this study indicate that specialized hospitals may provide higher quality medical care, which in turn proves that government policy on healthcare is effective at improving the medical system in Japan. PMID- 28079811 TI - Routine application of lung ultrasonography in the neonatal intensive care unit. AB - The aim of this study was to study the features of lung ultrasonography (LUS) in lung disease and to evaluate the usefulness of LUS in the neonatal intensive care unit (NICU).All of 3405 neonates included in this study underwent an LUS examination. Diagnoses were based on medical history, clinical manifestation, laboratory examination, and signs on chest radiography (CR) and/or computed tomography (CT). A single expert physician performed all LUS examinations.There were 2658 cases (78.9%) with lung disease and 747 cases (21.9%) without lung disease. The main signs of neonates with lung disease on LUS were as follows: absence of A-lines, pleural-line abnormalities, interstitial syndrome, lung consolidation, air bronchograms, pulmonary edema, and lung pulse. These abnormal signs were reduced or eliminated on LUS as patient conditions improved. There were 81 cases that could not be diagnosed as lung disease by CR but were discovered as pneumonia, respiratory distress syndrome (RDS), or transient tachypnea of newborn (TTN) on LUS. Likewise, 23 cases misdiagnosed as RDS by CR were diagnosed as TTN on LUS. Among 212 cases of long-term oxygen dependence (LTOD) that failed to yield signs of pulmonary edema and lung consolidation on CR, 103 cases showed abnormal signs on LUS. Among 747 cases without lung disease, B-lines of 713 neonates (95.4%) could be found within 3 days after birth, and 256 neonates (34.3%) could be observed from 3 days to 1 week after birth. B-lines of 19 cases could be detected from 1 to 2 weeks after birth. The longest time at which B-lines could still be observed was 19 days after birth.LUS has clinical value for the diagnosis of lung disease and the discrimination of causes of LTOP in premature infants, particularly for the diagnosis and identification of RDS and TTN. Moreover, LUS has additional advantages, including its lack of radiation exposure and its ability to noninvasively monitor treatment progress. Therefore, LUS should be routinely used in the NICU. PMID- 28079810 TI - Risk of vertebral compression fractures in multiple myeloma patients: A finite element study. AB - The purpose of this study was to develop and validate a finite element (FE) model to predict vertebral bone strength in vitro using multidetector computed tomography (MDCT) images in multiple myeloma (MM) patients, to serve as a complementing tool to assess fracture risk. In addition, it also aims to differentiate MM patients with and without vertebral compression fractures (VCFs) by performing FE analysis on vertebra segments (T1-L5) obtained from in vivo routine MDCT imaging scans. MDCT-based FE models were developed from the in vitro vertebrae samples and were then applied to the in vivo vertebrae segments of MM patients (n = 4) after validation. Predicted fracture load using FE models correlated significantly with experimentally measured failure load (r = 0.85, P < 0.001). Interestingly, an erratic behavior was observed in patients with fractures (n = 2) and a more gradual change in FE-predicted strength values in patients without fractures (n = 2). Severe geometric deformations were also observed in models that have already attained fractures. Since BMD is not a reliable parameter for fracture risk prediction in MM subjects, it is necessary to use advanced tools such as FE analysis to predict individual fracture risk. If peaks are observed between adjacent segments in an MM patient, it can be safe to conclude that the spine is experiencing regions of structural instability. Such an FE visualization may have therapeutic consequences to prevent MM associated vertebral fractures. PMID- 28079812 TI - The efficacy of elastomeric patient-control module when connected to a balloon pump for postoperative epidural analgesia: A randomized, noninferiority trial. AB - When considering the principles of a pain control strategy by patients, reliable administration of additional bolus doses is important for providing the adequate analgesia and improving patient satisfaction. We compared the efficacy of elastomeric patient-control module (PCM) with conventional PCM providing epidural analgesia postoperatively.A noninferiority comparison was used. Eighty-six patients scheduled for open upper abdominal surgery were randomized to use either an elastomeric or conventional PCM connected to balloon pump. After successful epidural catheter insertion at T6-8 level, fentanyl (15-20 MUg/kg) in 0.3% ropivacaine 100 mL was administered at basal rate 2 mL/h with bolus 2 mL and lock out time 15 minutes. The primary outcome was the verbal numerical rating score for pain.The 95% confidence intervals for differences in pain scores during the first 48 hours postoperatively were <1, indicating noninferiority of the elastomeric PCM. The duration of pump reservoir exhaustion was shorter for the elastomeric PCM (mean [SD], 33 hours [8 hours] vs 40 hours [8 hours], P = 0.0003). There were no differences in the frequency of PCM use, additional analgesics, or adverse events between groups.The elastomeric PCM was as effective as conventional PCM with and exhibited a similar safety profile. PMID- 28079813 TI - Surgical treatment for male prolactinoma: A retrospective study of 184 cases. AB - A total of 184 cases of surgically treated male prolactinoma were analyzed retrospectively to summarize the outcome of this surgical intervention. We analyzed the general characteristics, clinical manifestations, hormone levels, imaging features, preoperative treatments, surgical outcomes, pathology results, and follow-up records for all included patients. The most common clinical manifestations included sexual dysfunction (47.4%), headache (55.9%), and visual disturbance (46.7%). Serum prolactin levels ranged from 150 to 204,952 ng/mL. Tumor size varied from 6 to 70 mm. Pituitary adenomas grew in a parasellar pattern with visual deficits occurring 40.7% of the time. After surgical therapy, 88.6% of patients achieved symptom relief, and 98.4% experienced an immediate postoperative decline in prolactin level. Fifty-seven patients (31.0%) achieved initial remission, and 26 patients (45.6%) experienced recurrence. Hence, our results suggest that in male prolactinoma characterized by a large pituitary diameter and high serum prolactin level, tumor size predicts the degree of gross resection. The prognostic predictors included preoperative tumor growth pattern and Ki-67 index.Citation: Yi-jun S, Mei-ting C, Wei L, Bing X, Yong Y, Ming F, Ren-zhi W. (2016) Surgical treatment for male prolactinoma: a retrospective study of 184 cases. PMID- 28079814 TI - Predictive role of corneal Q-value differences between nasal-temporal and superior-inferior quadrants in orthokeratology lens decentration. AB - BACKGROUND: To investigate the association between pretreatment corneal parameters and orthokeratology lens decentration. METHODS: This retrospective study included a total of 108 eyes in 60 myopia patients, who were divided into a lens-decentration and a control group. Various pretreatment corneal parameters were analyzed by receiver operating characteristic curves (ROC curves), including corneal horizontal and vertical curvatures, diopter, corneal eccentricity (E value), asphericity (Q-value), diameter, and astigmatism, to establish a reliable predictive model for orthokeratology lens decentration. RESULTS: The temporal and inferior quadrants are preferential sides for lens decentration, which was associated with the occurrence of complications such as ghosting and corneal epithelial staining. By further analysis, we revealed lower corneal horizontal curvature and much higher corneal Q-value differences between the nasal-temporal and superior-inferior quadrants in the lens-decentration group compared to the control group (P < 0.05). ROC curve analysis showed that the sum of Q-value differences between the nasal-temporal and superior-inferior quadrants was more sensitive than any other corneal parameters in predicting lens decentration, with an area under the curve of 0.778 and a truncation point of 0.3 (P < 0.001). CONCLUSION: The sum of pretreatment corneal Q-value differences between nasal temporal and superior-inferior quadrants is a convenient and reliable predictor for orthokeratology lens decentration. PMID- 28079815 TI - Morning breathing exercises prolong lifespan by improving hyperventilation in people living with respiratory cancer. AB - Disturbance of oxygen-carbon dioxide homeostasis has an impact on cancer. Little is known about the effect of breath training on cancer patients. Here we report our 10-year experience with morning breathing exercises (MBE) in peer-support programs for cancer survivors.We performed a cohort study to investigate long term surviving patients with lung cancer (LC) and nasopharyngeal cancer (NPC) who practiced MBE on a daily basis. End-tidal breath holding time (ETBHT) after MBE was measured to reflect improvement in alveolar O2 pressure and alveolar CO2 pressure capacity.Patients (female, 57) with a diagnosis of LC (90 patients) and NPC (32 patients) were included. Seventy-six of them were MBE trainees. Average survival years were higher in MBE trainees (9.8 +/- 9.5) than nontrainees (3.3 +/ 2.8). The 5-year survival rate was 56.6% for MBE trainees and 19.6% for nontrainees (RR = 5.371, 95% CI = 2.271-12.636, P < 0.001). Survival probability of the trainees further increased 17.9-fold for the 10-year survival rate. Compared with the nontrainees, the MBE trainees shows no significant differences in ETBHT (baseline, P = 0.795; 1-2 years, P = 0.301; 3-4 years, P = 0.059) at baseline and within the first 4 years. From the 5th year onwards, significant improvements were observed in ETBHT, aCO2%, PaCO2, and PaO2 (P = 0.028). In total, 18 trainees (40.9%) and 20 nontrainees (74.1%) developed new metastasis (RR = 0.315, 95% CI = 0.108-0.919, P = 0.031).MBE might benefit for the long-term survival in patients with LC and NPC due to improvement in hyperventilation. PMID- 28079816 TI - A comparison study between gross tumor volumes defined by preoperative magnetic resonance imaging, postoperative specimens, and tumor bed for radiotherapy after breast-conserving surgery. AB - BACKGROUND: The identification and contouring of target volume is important for breast-conserving therapy. The aim of the study was to compare preoperative magnetic resonance imaging (MRI), postoperative pathology, excised specimens' (ES) size, and tumor bed (TB) delineation as methods for determining the gross tumor volume (GTV) for radiotherapy after breast-conserving surgery (BCS). METHODS: Thirty-three patients with breast cancer who underwent preoperative MRI and radiotherapy after BCS were enrolled. The GTVs determined by MRI, pathology, and the ES were defined as GTVMRI, GTVPAT, and GTVES, respectively. GTVMRI+1 was defined as a 1.0-cm margin around the GTVMRI. The radiation oncologist delineated GTV of the TB (GTVTB) using planning computed tomography according to >=5 surgical clips placed in the lumpectomy cavity (LC). RESULTS: The median GTVMRI, GTVMRI+1, GTVPAT, GTVES, and GTVTB were 0.97 cm (range, 0.01-6.88), 12.58 cm (range, 3.90-34.13), 0.97 cm (range, 0.01-6.36), 15.46 cm (range, 1.15-70.69), and 19.24 cm (range, 4.72-54.33), respectively. There were no significant differences between GTVMRI and GTVPAT, GTVMRI+1 and GTVES, GTVES and GTVTB (P = 0.188, 0.070, and 0.264, respectively). GTVMRI is positively related with GTVPAT. However, neither GTVES nor GTVTB correlated with GTVMRI (P = 0.071 and 0.378, respectively). Furthermore, neither GTVES nor GTVTB correlated with GTVMRI+1 (P = 0.068 and 0.375, respectively). CONCLUSION: When >=5 surgical clips were placed in the LC for BCS, the volume of TB was consistent with the volume of ES. Neither the volume of TB nor the volume of ES correlated significantly with the volume of tumor defined by preoperative MRI. PMID- 28079817 TI - Clinical features of hepatitis B and C virus infections, with high alpha fetoprotein levels but not hepatocellular carcinoma. AB - The appropriate alpha-fetoprotein (AFP) level to confirm hepatocellular carcinoma (HCC) could be 100 ng/mL; however, the clinical significance of falsely elevated AFP in patients without HCC has not been fully studied. We investigated the clinical features and outcome of patients without HCC but with high AFP levels (100 ng/mL), especially with chronic hepatitis B (CHB) or C (CHC).The sample included 124 consecutive patients with CHB (n = 97) or CHC (n = 27), with AFP levels >100 ng/mL and without HCC at baseline. Multivariate Cox proportional regression analysis was performed to determine the factors associated with AFP normalization and HCC development.During the mean 52-month follow-up, the proportion of patients with CHB with AFP normalization (90.7%) was significantly higher than the proportion of patients with CHC (59.3%, P < 0.001). Initial aspartate aminotransferase levels (hazard ratio [HR] = 1.02 per 10 U/L increase, P = 0.021) and antiviral therapy (HR = 2.89, P < 0.001) were significantly associated with AFP normalization. Of the 16 (12.9%) patients who developed HCC, hepatitis B virus infection (HR = 10.82, P = 0.001), initiation of antiviral treatment postenrollment (HR = 0.23, P = 0.030), and AFP normalization within 12 months (HR = 0.13, P = 0.011) were associated with HCC development.CHB and CHC were the most common causes of falsely elevated AFP (>100 ng/mL). With either CHB or CHC, persistent AFP elevation (>12 months), regardless of antiviral treatment, might be an important marker of HCC development. PMID- 28079818 TI - Factors associated with syphilis incidence in the HIV-infected in the era of highly active antiretrovirals. AB - After several years of steady decline, syphilis is reemerging globally as a public health hazard, especially among people living with human immunodeficiency virus (HIV). Syphilis resurgence is observed mainly in men who have sex with men (MSM), yet other transmission groups are affected too. In this manuscript, we study the factors associated with syphilis incidence in the Swiss HIV cohort study in the era of highly effective antiretrovirals. Using parametric interval censored models with fixed and time-varying covariates, we studied the immunological, behavioral, and treatment-related elements associated with syphilis incidence in 3 transmission groups: MSM, heterosexuals, and intravenous drug users. Syphilis incidence has been increasing annually since 2005, with up to 74 incident cases per 1000 person-years in 2013, with MSM being the population with the highest burden (92% of cases). While antiretroviral treatment (ART) in general did not affect syphilis incidence, nevirapine (NVP) was associated with a lower hazard of syphilis incidence (multivariable hazard ratio 0.5, 95% confidence interval 0.2-1.0). We observed that condomless sex and younger age were associated with higher syphilis incidence. Moreover, time-updated CD4, nadir CD4, and CD8 cell counts were not associated with syphilis incidence. Finally, testing frequency higher than the recommended once a year routine testing was associated with a 2-fold higher risk of acquiring syphilis. Condomless sex is the main driver of syphilis resurgence in the Swiss HIV Cohort study; ART and immune reconstitution provide no protection against syphilis. This entails targeted interventions and frequent screening of high-risk populations. There is no known effect of NVP on syphilis; therefore, further clinical, epidemiological, and microbiological investigation is necessary to validate our observation. PMID- 28079819 TI - Efficacy and toxicity of different concurrent chemoradiotherapy regimens in the treatment of advanced cervical cancer: A network meta-analysis. AB - OBJECTIVE: The aim of this study was to compare the efficacy and toxicity of different concurrent chemoradiotherapy (CCRT) regimens in the treatment of advanced cervical cancer (CC) by adopting a network meta-analysis. METHODS: We searched PubMed and Cochrane Library from the inception of these databases to September 2016, and all cohort studies (CSs) related to different CCRT regimens in the treatment of CC were included. A network analysis was adopted to compare the combination of direct and indirect evidence, to analyze the odds ratio (OR), and to draw a surface under the cumulative ranking curve of the efficacy and toxicity of different CCRT regimens for CC. Cluster analyses were used to group each category based on similar treatment regimens. RESULTS: Nineteen CSs were enrolled in this network meta-analysis, including 12 CCRT regimens (radiotherapy [RT], CCRT [cisplatin], CCRT [vinorelbine], CCRT [paclitaxel], CCRT [hydroxyurea], CCRT [cisplatin + FU], CCRT [cisplatin + gemcitabine], CCRT [cisplatin + docetaxel], CCRT [cisplatin + paclitaxel], CCRT [cisplatin + amifostine], CCRT [cisplatin + FU + hydroxyurea], and CCRT [cisplatin + vincristine + bleomycin]). The results of the network meta-analysis showed that regarding efficacy, the overall response rate of CCRT (cisplatin + docetaxel) was higher than RT, and the 5-year overall survival (OS) rate of CCRT (cisplatin + FU + hydroxyurea) was relatively higher than CCRT (hydroxyurea). As for toxicity, CCRT (cisplatin) had a lower incidence of leukopenia than CCRT (hydroxyurea), CCRT (cisplatin + FU) and CCRT (cisplatin + paclitaxel), and the incidences of diarrhea and vomiting in CCRT (cisplatin) were lower than those in CCRT (cisplatin + gemcitabine). Additionally, the cluster analysis showed that CCRT (cisplatin) had relatively lower incidences of both hematotoxicity and gastrointestinal toxicity, and CCRT (paclitaxel) had lower gastrointestinal toxicity than other regimens. CONCLUSION: Our study demonstrated that CCRT (cisplatin + docetaxel) might be the best choice of CCRT regimens in the treatment of CC, and the 5-year OS rate of CCRT (cisplatin + FU + hydroxyurea) might be the highest among these different regimens. CCRT (cisplatin) might have the lowest toxicity among all the CCRT regimens. PMID- 28079820 TI - Hepatoblastoma in an 11-year-old: Case report and a review of the literature. AB - RATIONALE: Hepatoblastoma is a rare malignancy. Approximately 100 cases are diagnosed yearly in the United States. The highest incidence occurs in infants and in children younger than 5 years. Cases involving patients older than 5 years are very rare. We describe the case of a patient who was diagnosed with hepatoblastoma at an atypical age of presentation for this type of malignancy. We also performed Ovid MEDLINE search for hepatoblastoma and epidemiology reports occurring in children between the ages of 5 and 18 years. In this article we review the epidemiology and summarize case reports published between 1997 and 2012 of patients with hepatoblastoma, who were older than 5 years. PATIENT CONCERNS AND DIAGNOSIS: Our patient is an 11 year old boy with stage IV hepatoblastoma with lung and omental metastases at diagnosis. INTERVENTIONS: The patient received 7 cycles of chemotherapy following the treatment plan of COG protocol AHEP 0731, off study. He also had tumor resection and omentectomy and achieved complete remission. OUTCOMES: He later had disease recurrence and after undergoing treatment with different modalities, ultimately died of his disease. Review of SEER program data shows that the incidence of hepatoblastoma in children above the age of 5 years is too infrequent to be calculated. Literature review revealed 13 cases of patients diagnosed at age older than 5 years. Most cases were published due to unusual associations and/or complications. There are no obvious unifying characteristics for these cases, although there may be a slight male preponderance and many patients in this selected series presented with elevated Alpha-fetoprotein. LESSONS: The reported case is rare, given the very low incidence of hepatoblastoma outside of infancy. A systematic review of characteristics and outcomes for patients older than 5 years who are enrolled in cooperative group hepatoblastoma trials may reveal important information about the epidemiology and tumor biology in this rare patient population. PMID- 28079821 TI - Febuxostat-induced agranulocytosis in an end-stage renal disease patient: A case report. AB - INTRODUCTION: Febuxostat, a nonpurine xanthine oxidase inhibitor, is approved as the first-line urate-lowering therapy in gout patients with normal renal function or mild to moderate renal impairment. The most common adverse effects of febuxostat are liver function test abnormalities, diarrhea, and skin rash. However, there is insufficient data in patients with severe renal impairment and end-stage renal disease (ESRD). We report the first case, to our knowledge, in which agranulocytosis developed after febuxostat treatment in an ESRD patient. CLINICAL PRESENTATION: A 67-year-old woman with gout and ESRD received febuxostat 40 mg a day for 2.5 months. She subsequently complicated with febrile neutropenia and the absolute neutrophil count was only 14/MUL. After broad-spectrum antibiotics treatment and no more exposure to febuxostat for 17 days, her infection and neutrophil count recovered. Bone marrow study during neutropenic period showed myeloid hypoplasia without evidence of hematologic neoplasms. CONCLUSION: As febuxostat use may become more common in the population of advanced renal failure, clinicians should be aware of this rare but potentially life-threatening adverse effect. Based on our experience, close monitoring hemogram and immediate discontinuation of this medication may prevent serious consequences. PMID- 28079822 TI - Successfully treated congenital cystic adenomatoid malformation by open fetal surgery: A care-compliant case report of a 5-year follow-up and review of the literature. AB - BACKGROUND: Congenital cystic adenomatoid malformation (CCAM) is a rare hamartomatous cystic lesion. Open fetal surgery currently provides a potential therapeutic option for management of a fetus with CCAM diagnosis. CASE SUMMARY: A 22-year-old G2P0 woman presented at (Equation is included in full-text article.)weeks' gestation for evaluation of a fetus with a left lung lesion and diagnosed as CCAM at (Equation is included in full-text article.)weeks' gestation. Open fetal surgery was performed to resection the lesion at (Equation is included in full-text article.)weeks' gestation under deep maternal general anesthesia. The mother presented at (Equation is included in full-text article.)weeks after open fetal surgery with preterm premature rupture of membranes (PPROM) and underwent cesarean delivery at (Equation is included in full-text article.)weeks' gestation. A vigorous woman infant of 1955 g, with good Apgar score, was delivered. At 1 month, 4 years, and present, 5 years after birth, she has continued to do well without any obvious deficit and both respiration and circulation were well maintained. CONCLUSION: We present one case of CCAM which was cured by open fetal surgery and continued to do well at follow up of 5 years. The success of treatment provided preliminary experience for further carrying out such interventions in China. PMID- 28079823 TI - PET/CT for differentiating between tuberculous peritonitis and peritoneal carcinomatosis: The parietal peritoneum. AB - OBJECTIVES: Tuberculous peritonitis (TBP) mimics peritoneal carcinomatosis (PC). We aimed to investigate the discriminative use of PET/CT findings in the parietal peritoneum. MATERIALS AND METHODS: Parietal peritoneal PET/CT findings from 76 patients with TBP (n = 25) and PC (n = 51) were retrospectively reviewed. The lesion locations were noted as right subdiaphragmatic, left subdiaphragmatic, right paracolic gutters, left paracolic gutters, and pelvic regions. The distribution characteristic consisted of a dominant distribution in the pelvic and/or right subdiaphragmatic region (susceptible area for peritoneal implantation, SAPI) (SAPI distribution), a dominant distribution in the remaining regions (less-susceptible area for peritoneal implantation, LSAPI) (LSAPI distribution), or a uniform distribution. PET morphological patterns were classified as F18-fluorodeoxyglucose (F-FDG) uptake in a long beaded line (string of-beads F-FDG uptake) or in a cluster (clustered F-FDG uptake) or focal F-FDG uptake. CT patterns included smooth uniform thickening, irregular thickening, or nodules. RESULTS: More common findings in the parietal peritoneum corresponding to TBP as opposed to PC were (a) >=4 involved regions (80.0% vs 19.6%), (b) uniform distribution (72.0% vs 5.9%), (c) string-of-beads F-FDG uptake (76.0% vs 7.8%), and (d) smooth uniform thickening (60.0% vs 7.8%) (all P < 0.001), whereas more frequent findings in PC compared with TBP were (a) SAPI distribution (78.4% vs 28.0%), (b) clustered F-FDG uptake (56.9% vs 20.0%), (c) focal F-FDG uptake (21.6% vs 4.0%), (d) irregular thickening (51.0% vs 12.0%), and (e) nodules (21.6% vs 4.0%) (P < 0.001, P < 0.05, P > 0.05, P < 0.05, P > 0.05, respectively). CONCLUSION: Our data show that PET/CT findings in the parietal peritoneum are useful for differentiating between TBP and PC. PMID- 28079824 TI - Inflammatory myofibroblastic tumors of the pancreas in children: A case report and literature review. AB - INTRODUCTION: Inflammatory myofibroblastic tumors are an uncommon neoplasm, which are very rarely located in the pancreas. Clinically and radiologically, this rare pancreatic tumor presents as an abdominal mass lesion that mimics other pancreatic tumors, and should therefore be considered in the differential diagnosis of pancreatic tumors. CLINICAL FINDINGS AND DIAGNOSIS: The 15-year-old boy complained of abdominal pain over the left upper quadrant with intermittent fever for 7 days. Abdominal sonography revealed one cystic lesion with a hyperechoic component in the left upper quadrant of the abdomen. Surgical excision was performed and postoperative findings indicated a pancreatic tail tumor. The pathology indicated inflammatory myofibroblastic tumors. To our knowledge, this patient is a unique case as the tumor was located in the pancreatic tail only, sparing the body. INTERVENTIONS AND OUTCOMES: The patient underwent tumor resection and segmental resection of the transverse colon with simple closure. The patient had no evidence of disease recurrence at 3 years follow-up. CONCLUSION: Inflammatory myofibroblastic tumors of the pancreas in children are extremely rare. Surgical excision is the standard treatment, and corticosteroids use in children need more large-scale studies. PMID- 28079825 TI - The utility of bispectral index monitoring for prevention of rocuronium-induced withdrawal movement in children: A randomized controlled trial. AB - BACKGROUND: This study was designed to determine whether a deep hypnotic state with a bispectral index (BIS) value less than 40 could alleviate withdrawal movement (WM) upon rocuronium injection during anesthesia induction in children. METHODS: Finally, 135 healthy children (3-12 years) scheduled for minor elective surgery were studied. Without premedication, anesthesia was induced with thiopental sodium 5 mg/kg. Patients were randomized into 2 groups (control vs experimental) and then by virtue of rocuronium injection time, patients in the experimental group were allocated into 2 groups, as follows: in the control group (group C; n = 45), rocuronium 0.6 mg/kg was administered at the loss of eyelash reflex; in the 1st experimental group, rocuronium 0.6 mg/kg was administered when BIS fell to less than 40 (group T; n = 45); however, if BIS did not fall below 40 after thiopental sodium administration, manual ventilation was provided with oxygen 6 L/minute using sevoflurane 8% and then rocuronium was administered when BIS fell below 40 (the 2nd experimental group, group S; n = 45). Rocuronium induced WM was evaluated using a 4-point scale (no movement; movement/withdrawal involving the arm only; generalized response, with movement/withdrawal of more than 1 extremity, but no requirement for restraint of the body; and generalized response which required restraint of the body and caused coughing or breath holding). RESULTS: No significant differences were found among the groups for patient characteristics including age, sex, height, and location of venous cannula. However, body weight, height, and body mass index in group S were all smaller than those in group T. The incidence of WM caused by rocuronium was 100% in group C, 95.6% in group T, and 80% in group S, and was significantly lower in group S than in group C. The grade of WM was 3.7 +/- 0.6 in group C, 3.2 +/- 0.9 in group T, and 2.6 +/- 1.0 in group S. It was significantly lower in group T than in group C and significantly lower in group S than in groups C and T. CONCLUSION: The confirmation of a deep hypnotic state with BIS values lower than 40 using BIS monitoring can reduce the grade of rocuronium-induced WMs during anesthesia induction using thiopental sodium or sevoflurane in children. PMID- 28079826 TI - Waist-to-height ratio is the best anthropometric predictor of hypertension: A population-based study with women from a state of northeast of Brazil. AB - The WHO recommends the use of some anthropometric parameters as a screening resource for individuals under cardiometabolic risk. However, in the validation of these indicators, Brazilian women were not included. These women have different anthropometric profile compared to women who integrated the samples of the validation studies. We aimed to verify the accuracy of anthropometric indicators as a resource for the screening of women with hypertension. A cross sectional study, with a probability sample of 3143 women (20-49 years) from the state of Alagoas (northeast of Brazil), was carried out. Hypertension was identified by systolic blood pressure (SBP) >=140 mm Hg and/or diastolic BP >=90 mm Hg and/or regular use of antihypertensive drugs. The anthropometric indicators analyzed were BMI, waist circumference, waist-to-hip ratio, waist-to-height ratio (WHtR), body fat percentage, and conicity index. The accuracy definition of the indicators and the identification of best cut-off points were carried out on the basis of ROC curve analysis and Youden index, respectively. The prevalence of hypertension was 21.8%. All indicators used in hypertension identification had area under the ROC curve (AUC) >0.5. The WHtR with cut-off point of 0.54 was the best performance indicator (AUC = 0.72; P < 0.05; sensitivity = 67%, specificity = 66%). The WHtR with cut-off point of 0.54 has constituted the most accurate indicator in the screening of women with hypertension. In the absence of specific studies and considering the largest ethnic proximity and environmental/epidemiological similarity, the findings now obtained can be extended to women of other Brazilian states, especially those in the Northeastern region. PMID- 28079827 TI - Differentiating malignant from benign gastric mucosal lesions with quantitative analysis in dual energy spectral computed tomography: Initial experience. AB - To investigate the value of quantitative analysis in dual energy spectral computed tomography (DESCT) for differentiating malignant gastric mucosal lesions from benign gastric mucosal lesions (including gastric inflammation [GI] and normal gastric mucosa [NGM]). This study was approved by the ethics committee, and all patients provided written informed consent. A total of 161 consecutive patients (63 with gastric cancer [GC], 48 with GI, and 50 with NGM) who underwent dual-phase contrast enhanced DESCT scans in the arterial phase (AP) and portal venous phase (PVP) were included in this study. Iodine concentration (IC) in lesions was derived from the iodine-based material-decomposition images and normalized to that in the aorta to obtain normalized IC (nIC). The ratios of IC and nIC between the AP and PVP were calculated. Diagnostic confidence for GC and GI was evaluated with reviewing the features including gastric wall thickness, focal, and eccentric on the conventional polychromatic images. All statistical analyses were performed by using statistical software SPSS 17.0 (SPSS, Chicago, IL). IC and nIC in GC differed significantly from those in GI and NGM, except for nICAP in comparing GC with GI. Mean nIC values of GC (0.18 +/- 0.06 in AP and 0.62 +/- 0.16 in PVP) were significantly higher than that of NGM (0.12 +/- 0.03 in AP and 0.37 +/- 0.08 in PVP) (all P < 0.05). There was also significant difference for IC values in GC, GI, and NGM (24.19 +/- 8.27, 19.07 +/- 5.82, and 13.61 +/- 2.52 mg/mL, respectively, in AP and 28.00 +/- 7.01, 24.66 +/- 6.55, and 16.94 +/- 3.06 mg/mL, respectively, in PVP). Based on Receiver Operating Characteristic Curve analysis, nIC and IC in PVP had high sensitivities of 88.89% and 90.48%, respectively, in differentiating GC from NGM, while the sensitivities were 71.43% and 88.89% during AP. Ratios IC and nIC ratios did not provide adequate diagnostic accuracy with their area under curves less than 0.65. With the conventional features, the diagnostic accuracies for GC and GI were 75.0% and 98.0%, respectively. Quantitative analysis of DESCT imaging parameters for gastric mucosa, such as nIC and IC, is useful for differentiating malignant from benign gastric mucosal lesions. PMID- 28079828 TI - Vaccination with 10-valent pneumococcal conjugate vaccine in infants according to HIV status. AB - BACKGROUND: Phase III, open-label, single-center, controlled study in South Africa (ClinicalTrials.gov: NCT00829010) to evaluate immunogenicity, reactogenicity, and safety of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in human immunodeficiency virus (HIV)-infected (HIV+), HIV-exposed-uninfected (HEU), and HIV-unexposed-uninfected (HUU) children. METHODS: Children stratified by HIV status received PHiD-CV primary vaccination (age 6/10/14 weeks; coadministered with routine childhood vaccines) and booster dose (age 9-10 months). Immune responses, assessed using enzyme-linked immunosorbent and functional assays, and safety were evaluated up to 14 months post-booster. RESULTS: Of 83, 101, and 100 children enrolled in HIV+, HEU, and HUU groups, 70, 91, and 93 were included in according-to-protocol immunogenicity cohort. For each vaccine-serotype, percentages of children with antibody concentrations >=0.2 MUg/mL were >=97% 1 month post-primary vaccination and >=98.5% 1 month post-booster (except for 6B and 23F at both timepoints). Post primary vaccination, functional antibody responses were lower in HIV+ children: for each vaccine-serotype, percentages of children with opsonophagocytic activity (OPA) titres >=8 were >=72%, >=81%, and >=79% for HIV+, HEU, and HUU children. Post-booster, >=87% of children in each group had OPA titres >=8. Reactogenicity was similar across groups. Thirty one (37%) HIV+, 25 (25%) HEU, and 20 (20%) HUU children reported >=1 serious adverse event. Five HIV+ and 4 HEU children died. One death (sudden infant death syndrome; HEU group; 3 days post-dose 1) was considered potentially vaccine-related. CONCLUSION: PHiD-CV was immunogenic and well-tolerated in HIV+, HEU, and HUU children, and has the potential to provide substantial benefit irrespective of HIV infection status. PMID- 28079829 TI - Breath-hold and free-breathing F-18-FDG-PET/CT in malignant melanoma-detection of additional tumoral foci and effects on quantitative parameters. AB - During PET/CT acquisition, respiratory motion generates artifacts in the form of breath-related blurring, which may impair lesion detectability and diagnostic accuracy. This observational study was undertaken to verify whether breath-hold F 18-FDG-PET/CT (bhPET) detects additional foci compared to free-breathing PET/CT (fbPET) in cases of malignant melanoma, and to assess the impact of breath holding on standard uptake values (SUV) and metabolic isocontoured volume (mVic40).Thirty-four patients with melanoma were examined. BhPET and fbPET findings of 117 lesions were compared and correlated with standard contrast enhanced (ce) CT and MRI for lesion verification. Quantitative parameters (SUVmax, SUVmean, and mVic40) were assessed for both methods and evaluated by linear regression and Spearman correlation. The impact of lesion size and time interval between investigations was analyzed.In 1 patient, a CT-confirmed liver metastasis was seen only on bhPET but not on fbPET. At bhPET, SUVmax, and SUVmean proved significantly higher and mVic40 significantly lower than at fbPET. The positive effect on SUVmax and SUVmean was more pronounced in smaller lesions, whereas the time interval between bhPET and fbPET did not influence SUV or mVic40.In our patient cohort, bhPET yielded significantly higher SUV and provided improved volumetric lesion definition, particularly of smaller lesions. Also one additional liver lesion was identified. Breath-hold PET/CT is technically feasible, and may become clinically useful when fine quantitative evaluations are needed. PMID- 28079830 TI - Geographic coverage of male circumcision in western Kenya. AB - Voluntary Medical Male Circumcision (VMMC) for human immunodeficiency virus (HIV) prevention has scaled up rapidly among young men in western Kenya since 2008. Whether the program has successfully reached uncircumcised men evenly across the region is largely unknown. Using data from two cluster randomized surveys from the 2008 and 2014 Kenyan Demographic Health Survey (KDHS), we mapped the continuous spatial distribution of circumcised men by age group across former Nyanza Province to identify geographic areas where local circumcision prevalence is lower than the overall, regional prevalence. The prevalence of self-reported circumcision among men 15 to 49 across six counties in former Nyanza Province increased from 45.6% (95% CI = 33.2-58.0%) in 2008 to 71.4% (95% CI = 67.4-75.0%) in 2014, with the greatest increase in men 15 to 24 years of age, from 40.4% (95% CI = 27.7-55.0%) in 2008 to 81.6% (95% CI = 77.2-85.0%) in 2014. Despite the dramatic scale-up of VMMC in western Kenya, circumcision coverage in parts of Kisumu, Siaya, and Homa Bay counties was lower than expected (P < 0.05), with up to 50% of men aged 15 to 24 still uncircumcised by 2014 in some areas. The VMMC program has proven successful in reaching a large population of uncircumcised men in western Kenya, but as of 2014, pockets of low circumcision coverage still existed. Closing regional gaps in VMMC prevalence to reach 80% coverage may require targeting specific areas where VMMC prevalence is lower than expected. PMID- 28079831 TI - Gastric cancer burden of last 40 years in North China (Hebei Province): A population-based study. AB - Gastric cancer (GC) is the second leading cause of cancer death in China. It is well known that Cixian in Hebei Province is one of the highest risk areas of GC in China and worldwide. This study aims to accurate assessment of GC burden and trend in high-risk area (Hebei Province) from 1973 to 2013. The authors analyzed GC data from 21 population-based cancer registries which represented 15.25% of the entire population of Hebei Province. The collected data were stratified by 5 year age groups, gender, and area. Mortality of GC was extracted from national death surveys from 1973 to 1975, 1990 to 1992, 2004 to 2005, and 2011 to 2013. Trend analysis (1988-2013) in a high-risk area (Cixian) used the Joinpoint Model. The age-period-cohort model was used to estimate the effects of age, period, and birth cohort in GC incidence in Cixian from 1988 to 2013. The crude incidence of GC in 2011 to 2013 was 40.37/100,000 (57.53/100,000 in males and 22.55/100,000 in females). The corresponding age-standardized rate by world age-standard population was 32.18/100,000 (48.87/100,000 in males and 17.53/100,000 in females), which was 2.66-fold (2.81-fold in male and 2.34-fold in female) higher than that in the world (12.1/100,000, 17.4/100,000 in males and 7.5/100,000 in females). Males in rural areas had the highest incidence, with an age standardized rate of 70.51/100,000. Gastric cardia cancer was primary anatomical subsite which accounting for 59.59% in GC, followed by gastric corpus (13.92%), gastric antrum (11.43%), gastric fundus (4.99%), and overlapping lesion of gastric (4.17%). The age-standardized rate of mortality from GC displayed a significant downward trend (P = 0.019) in Hebei Province from the 1990s (31.44/100,000) to the 2010s (24.63/100,000). In Cixian, the incidence of GC rose from 1988 (38.25/100,000) to 2009 (65.11/100,000). Cixian, where population-based screening of upper gastrointestinal cancer was performed, experienced the increasing rate of GC from 2000 (37.59/100,000) to 2009 (65.11/100,000) and then had a sharp decrease from 2009 to 2013 (55.30/100,000), with annual percentage change of -6.69%. Gastric cardia cancer had an increasing trend from 1988 (6.88/100,000) to 2013 (26.56/100,000). Both age and birth cohort effects played important roles in these changes. In conclusion, males in rural areas had the highest risk of GC. GC mortality rate decreased from the 1990s in Hebei Province. Endoscopic screening project for GC is an effective method of controlling the disease. PMID- 28079832 TI - Usefulness of low dose chest CT for initial evaluation of blunt chest trauma. AB - We aimed to compare the diagnostic performance and inter-observer consistency between low dose chest CT (LDCT) and standard dose chest CT (SDCT) in the patients with blunt chest trauma.A total of 69 patients who met criteria indicative of blunt chest trauma (77% of male; age range, 16-85) were enrolled. All patients underwent LDCT without intravenous (IV) contrast and SDCT with IV contrast using parameters as following: LDCT, 40 mAs with automatic tube current modulation (ATCM) and 100 kVp (BMI <25, n = 51) or 120 kVp (BMI>25, n = 18); SDCT, 180 mAs with ATCM and 120 kVp. Transverse, coronal, sagittal images were reconstructed with 3-mm slice thickness without gap and provided for evaluation of 3 observers. Reference standard images (transverse, coronal, sagittal) were reconstructed using SDCT data with 1-mm slice thickness without gap. Reference standard was established by 2 experienced thoracic radiologists by consensus. Three observers independently evaluated each data set of LDCT and SDCT.Multiple reader receiver operating characteristic analysis for comparing areas under the ROC curves demonstrated that there was no significant difference of diagnostic performance between LDCT and SDCT for the diagnosis of pulmonary injury, skeletal trauma, mediastinal injury, and chest wall injury (P > 0.05). The intraclass correlation coefficient was measured for inter-observer consistency and revealed that there was good inter-observer consistency in each examination of LDCT and SDCT for evaluation of blunt chest injury (0.8601-1.000). Aortic and upper abdominal injury could not be appropriately compared as LDCT was performed without using contrast materials and this was limitation of this study.The effective radiation dose of LDCT (average DLP = 1.52 mSv?mGy cm) was significantly lower than those of SDCT (7.21 mSv mGy cm).There is a great potential benefit to use of LDCT for initial evaluation of blunt chest trauma because LDCT could maintain diagnostic image quality as SDCT and provide significant radiation dose reduction. A further study of LDCT with IV contrast for evaluation of aortic and upper abdominal injury is needed. PMID- 28079833 TI - The rare ethambutol-induced optic neuropathy: A case-report and literature review. AB - RATIONALE: Ethambutol-induced optic neuropathy (EON) is a well-known complication that results from the use of ethambutol. The ocular manifestations of EON include painless loss of central vision and cecocentral scotomas in the visual field. PATIENT CONCERNS: A 75-year-old Chinese Han man suffered from this rare ocular disorder because he took ethambutol for about 8 months. DIAGNOSES: He was diagnosed as EON based on series of ophthalmic examinations performed. INTERVENTIONS: Since he has stopped taking this drug for 3 months, we just offered some neurotrophic agents to him. OUTCOMES: One month later, he came back for return visit. The ophthalmic examinations indicated recovery of the visual function very well. LESSONS: The EON is a reversible optic neuropathy if the ocular toxicity is monitored closely among the tuberculosis patients that take ethambutol. PMID- 28079834 TI - Intestinal brucellosis associated with celiac artery and superior mesenteric artery stenosis and with ileum mucosa and submucosa thickening: A case report. AB - RATIONALE: Brucellosis is a multisystem infection found worldwide that has a broad range of characteristics, which range from acute fever and hepatomegaly to chronic infections that most commonly affect the central nervous system, cardiovascular system, or skeletal system. Gastrointestinal and splanchnic artery involvements in brucellosis are relatively uncommon. PATIENT CONCERNS: We report a case of brucellosis in an adolescent presenting as intermittent abdominal pain, diarrhea, and fever, with intestinal tract involvement. And stenosis of the celiac artery and the superior mesenteric artery was found after exposed to risk factors of Brucella infection. Splanchnic vessels stenosis and an endothelial lesion may exacerbate the prevalent symptom of abdominal pain, as a form of colic pain, occurring after eating. DIAGNOSES: The patient was diagnosed as brucellosis. The narrowing of the SMA and CA was suspected to be vasculitis secondary to the brucellosis. INTERVENTIONS: The patient was treated with minocycline and rifampicin for 12 weeks totally. OUTCOMES: The gastrointestinal manifestations of brucellosis recovered rapidly under intensive treatment. However, follow-up imaging revealed that the superior mesenteric artery and celiac artery stenosis was unimproved. LESSONS: In brucellosis, gastrointestinal manifestations may be the only observable features of the disease. Splanchnic arterial stenosis is a rare complication of brucellosis. Sonography and computed tomography may be useful for both diagnosis and follow-up. PMID- 28079835 TI - Prognostic factors of Bell's palsy and Ramsay Hunt syndrome. AB - The aim of this study was to compare clinical characteristics, electroneurography (ENoG) results, and functional outcomes of patients with Bell's palsy (BP) and Ramsay Hunt syndrome (RHS).Around 57 patients with BP and 23 patients with RHS were enrolled in this study from January 2010 and September 2015. Both clinical characteristics and ENoG results were recorded at hospital admission. The evaluations of functional outcomes were conducted with House-Brackmann (H-B) grading system at 6-month follow-up.There were no significant differences in age, gender proportion, initial H-B grades, time before commencement of treatment and the presence of comorbid disease in 2 groups. However, the final H-B grades at 6 month follow-up were significantly better in BP patients than RHS patients. The results of ENoG showed that degeneration index (DI) was significantly higher in the RHS group than the BP group. But no significant difference was found in the value of prolonged latency time (PLT) between the 2 groups. In multivariate analysis, age and ENoG DI were independently associated with functional outcome of recovery in the BP group (OR 0.167, 95% CI 0.038-0.622, P = 0.009 and OR 0.289 95% CI 0.107-0.998, P = 0.050, respectively). However, in the RHS group, only ENoG DI was related to the final H-B grades (OR 0.067, 95% CI 0.005-0.882, P = 0.040). Spearman's rank correlation analysis showed that higher age and ENoG DI were related to poorer prognosis in 2 groups (P < 0.05). PLT was related to functional outcomes only in the BP group (rs = 0.460, P < 0.001). The receiver operating characteristic (ROC) of ENoG DI analysis revealed that the cutoff value was 67.0% for BP prognosis and 64.5% for RHS prognosis. What's more, patients with hypertension or diabetes mellitus had both higher final H-B grade and ENoG DI than those without the same comorbidity.Patients with RHS had poorer prognosis than those with BP. Some factors including age, ENoG DI, and the presence of disease influenced recovery from BP and RHS. The present study demonstrated that BP patients with ENoG DI < 67.0% and RHS patients with ENoG DI < 65.5% had a greater opportunity for recovery within half a year. PMID- 28079836 TI - Symptomatic Cytomegalovirus Infections in the First Year of Life: When Is Antiviral Therapy Conceived to Be Justified? AB - All infants treated with antiviral medication for symptomatic congenital (diagnosis <3 weeks) and probably postnatal (>3 weeks) cytomegalovirus infection were characterized with the help of a survey covering all German Pediatric hospitals between 2012 and 2013. We found that >50% of infants treated for cytomegalovirus were classified as probably postnatal cytomegalovirus infection, which was associated with preterm birth and underlying diseases of the immune system, heart or lung. PMID- 28079837 TI - It May Be Too Early to Try to Prove the Effect of Deworming on Tuberculin Reactivity. PMID- 28079838 TI - Re: "It May Be Too Early to Try to Prove the Effect of Deworming on Tuberculin Reactivity". PMID- 28079839 TI - Preparing Pediatric International Travelers for Travelers' Diarrhea: Insights From the Global TravEpiNet. PMID- 28079840 TI - Re: "Preparing Pediatric International Travelers for Travelers' Diarrhea: Insights from the Global TravEpiNet". PMID- 28079841 TI - Staphylococcus schleiferi Meningitis in an Infant. PMID- 28079842 TI - Increased erythrocyte aggregation and oxidative stress in patients with idiopathic interstitial pneumonia. AB - BACKGROUND: Hemorheological properties are important determinants of tissue oxygenation. Although hemorheological alterations in various lung diseases have been well-defined, no information is available about the effects of idiopathic interstitial pneumonia (IIP) on hemorheological parameters. OBJECTIVES: The aim of this study was to investigate hemorheological parameters (erythrocyte deformability, aggregation, and plasma viscosity -PV) and associated oxidative stress indices in patients with IIP. METHODS: The study enrolled 31 patients (9 Idiopathic pulmonary fibrosis (IPF), 10 non-specific Interstitial Pneumonia (NSIP), 12 Cryptogenic Organising Pneumonia (COP) and 33 healthy controls. Erythrocyte deformability and aggregation were measured by an ektacytometer. PV was determined by a cone-plate rotational viscometer and oxidative stress via a commercial kit. RESULTS: Erythrocyte aggregation, total oxidant status (TOS) and oxidative stress index (OSI) of IIP patients were higher than controls whereas erythrocyte deformability, PV and total antioxidant status (TAS) were unaltered. CONCLUSIONS: Increment of oxidative stress in IIP seems to depend on enhancement of oxidants, rather than alteration of antioxidants. The issue that, elevated erythrocyte aggregation may further impair tissue oxygenation by disturbing microcirculation in IIP, may be considered in the follow up and development of new treatment protocols for this disease. PMID- 28079843 TI - The association between BNP, 6MWD test, DLCO% and pulmonary hypertension in sarcoidosis. AB - INTRODUCTION: Pulmonary hypertension (PH) is a feared complication in patients with sarcoidosis.It is an important negative prognostic factor which is reflected as a priority given to these subjects for orthotopic lung transplantation. We evaluated the relationship between BNP, 6MWD test, DLCO% values and the severity of sarcoidosis-associated pulmonary hypertension. METHODS: A retrospective chart review was conducted between January 2010 and January 2015 on consecutive confirmed adult subjects diagnosed with sarcoidosis. Demographics, medical comorbidities, clinical features, pulmonary function tests (PFTs), 6MWD test, transthoracic echocardiography, laboratory investigations, radiographic findings, treatment and outcome data were collected from medical records. Subjects with suspicion for PH (i.e. those with PASP >= 25 mmHg) were included in the study. PH severity was classified using PASP into mild (PASP 25-49 mmHg), moderate (50-69 mmHg) and severe (>=70 mmHg). We evaluated the strength of correlation between BNP, 6MWD test, DLCO% and the severity of PH. The association between variables was performed using Pearson correlation coefficient and results were considered statistically significant if P value was <0.05. RESULTS: Among the 108 cases diagnosed with sarcoidosis, we identified a total of 27 patients (25%) who had an elevated PASP suggestive of PH and met the study inclusion criteria. There was a significant correlation between BNP level (r=0.804, P=0.003), 6MWD test (r= 0.865, P=0.000), DLCO% (r=-0.513, P=0.015) and the PASP in sarcoidosis patients. CONCLUSION: Although these simple tests should not be used as screening tools for suspecting sarcoidosis-associated pulmonary hypertension, they may be of value in following its progression in subjects already diagnosed with pulmonary hypertension. PMID- 28079844 TI - Serum interleukin-6 in systemic sclerosis and its correlation with disease parameters and cardiopulmonary involvement. AB - OBJECTIVE: To assess serum interleukin-6 (IL-6)level in patients with systemic sclerosis (SSc) and its correlations with European Scleroderma Study Group activity score (EUSTAR), Scleroderma Assessment Questionnaire (SAQ), disability index and cardiopulmonary involvement. METHODS: Twenty SSc patients and 10 matched healthy controls were included. Serum IL-6 was measured in patients and controls. Disease activity, status,and disability were assessed.Cardiopulmonary involvement was evaluated by pulmonary function tests (PFTs), six minute walk test, echocardiography, and high resolution computed tomography (HRCT) of chest. RESULTS: Serum level of IL-6 was significantly higher in patients with SSc (6.3+/ 1.4pg/ml) versus healthy controls (3.2+/- 0.4pg/ml) (P=0.002). IL-6 level showed positive correlations with disease duration (r=0.49, P=0.03), EUSTAR score (r=0.64, P=0.002), Index of Respiratory Status "IRS" (r=0.46, P=0.001), Index of Musculoskeletal Status "IMSS" (r=0.45, P=0.049), Index of Vascular Status "IVS" (r=0.39, P=0.04), mean and peak of pulmonary artery pressure (r=0.44 & 0.55, P=0.02 & 0.002 respectively). Negative correlations of IL-6 level with DLCO% (r= 0.49, P=0.006),six minute walk distance (6MWD) (r=-0.52, P= 0.003) and right ventricle fraction area change (r=-0.48, P=0.03) were found, while there were strong positive correlations with HRCT-ground glass score (r=0.77, P=0.0001) and HRCT-fibrosis score (r=0.62, P=0.003). CONCLUSION: IL-6 level is increased in patients with SSc and significantly correlates with EUSTAR score, IRS, DLCO, 6MWD, HRCT scores, and echocardiographic abnormalities of the right side of the heart. These results support the role of IL-6 in the disease activity and in the development of cardiopulmonary manifestations in SSc patients. PMID- 28079845 TI - Predictive value of C-reactive protein and clinically relevant baseline variables in sarcoidosis. AB - BACKGROUND: This study aims to examine the predictive and prognostic implications of C-reactive protein (CRP) and clinically relevant baseline variables in determining treatment indication and disease progression in a large clinical cohort of patients with stable sarcoidosis. METHODS: A retrospective observational study of 328 sarcoidosis patients attending a regional tertiary referral centre over a 26-year period was performed. Clinical, biochemical, radiological and physiological data were analysed according to a clinically relevant dichotomous cutpoint of CRP. Multiple models of logistic regression were used to determine independent predictors of outcome as defined by indication for treatment with corticosteroids, radiological deterioration and physiological progression. RESULTS: 328/409 (80.2%) sarcoidosis patients had baseline serum CRP measured and were suitable for inclusion. Baseline CRP was elevated in 154 (47%). 178 (54.3%) were prescribed corticosteroid treatment during the disease course. Physiological deterioration was demonstrated in 48 (14.6%) patients and radiological progression in 59 (17.9%) patients. High baseline CRP was strongly associated with Lofgren's syndrome (p=<0.001) and reduced FVC% predicted (p=0.012). High CRP was found to be a negative predictor of radiological progression (p=0.046). In a sub-analyses of patients without Lofgren's syndrome (n=223), patients with high baseline CRP were almost twice as likely to receive corticosteroid treatment, OR 1.89 (95% CI 1.04-3.55). Low baseline DLCO% independently predicted the need for corticosteroid treatment (p=<0.001) and physiological decline (p=0.045). CONCLUSIONS: Elevated baseline CRP in sarcoidosis is associated with a good prognosis and is a negative predictive indicator of radiological progression. In patients without Lofgren's syndrome, high CRP and low DLCO% at presentation may identify a subset of patients more likely to develop physiological progression who may benefit from early systemic treatment. PMID- 28079846 TI - Patient confidence and quality of life in idiopathic pulmonary fibrosis and sarcoidosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) and sarcoidosis impact significantly on health-related quality of life (HRQOL). There are few studies on the impact of patient confidence on HRQOL in these conditions. OBJECTIVES: 1. To investigate whether patient confidence is associated with HRQOL, anxiety, depression, dyspnoea or fatigue. 2. To assess if patient confidence is associated with inpatient admissions, access to community healthcare and, for IPF patients, mortality and disease severity. METHODS: Study participants self-completed seven questionnaires: Hospital Anxiety and Depression Scale, EuroQol 5D (EQ5D), King's Brief Interstitial Lung Disease questionnaire, St George's Respiratory Questionnaire, MRC dyspnoea scale, Fatigue Assessment Scale and a non-validated questionnaire assessing patient confidence, symptom duration and access to community healthcare. Lung function and follow-up data were collected from hospital electronic databases. Spearman's rank correlation coefficients were calculated to assess for correlation between patient confidence, questionnaire variables and inpatient admissions. Chi-square tests were performed to assess for association between patient confidence, mortality and disease severity. RESULTS: 75 IPF patients and 69 sarcoidosis patients were recruited to the study. Patient confidence in IPF was significantly negatively correlated with depression and fatigue, and significantly positively correlated with EQ5D scores, but not healthcare outcomes. No associations were found between confidence and any of the variables assessed in sarcoidosis. CONCLUSIONS: Lower levels of confidence in IPF patients are associated with higher levels of depression and fatigue and worse HRQOL. Efforts should be made to improve patient confidence to assess the impact on HRQOL. PMID- 28079847 TI - Relationship Between Abnormalities on High-Resolution Computerized Tomography, Pulmonary Function, and Bronchoalveolar Lavage in Progressive Systemic Sclerosis. AB - : Introduction and aim: Progressive systemic sclerosis (pSS) is a multisystemic connective tissue disease characterized by fibrosis of the skin and internal organs including lung. The mechanisms that leads to progressive lung fibrosis in scleroderma remain obscure. In this study, we aimed to investigate the correlation between HRCT findings and patients' clinical and functional status and the degree of alveolitis based on the BAL resultsMaterials and methods: 65 patients with pSS were evaluated. Thoracic HRCT, pulmonary function tests, and dyspnea measurements were applied, and BAL was performed. The parenchymal abnormalities identified on HRCT were coded, and scored according to Warrick et al. RESULTS: Among parameters investigated, a correlation was found between the number of segments with subpleural cysts and the duration of disease. Also there was a correlation between the HRCT score and patient age whereas no correlation was detected between the duration of the disease, manifestation of the symptoms, and the x-ray findings. A correlation was found between the percentage of neutrophils detected in BAL and the extent of the honeycombing on HRCT. CONCLUSION: This study showed a strong correlation between the extent of x-ray abnormalities and FVC, RV, and DLCO, as well as an increase in the percentage of BAL fluid neutrophils in patients with SSc-PI. PMID- 28079848 TI - High-resolution computed tomography to differentiate chronic diffuse infiltrative lung diseases with chronic multifocal consolidation patterns using logical analysis of data. AB - BACKGROUND: Chronic lung consolidation has a limited number of differential diagnoses requiring distinct managements. The aim of the study was to investigate how logical analysis of data (LAD) can support their diagnosis at HRCT (high resolution computed tomography). METHODS: One hundred twenty-four patients were retrospectively included and classified into 8 diagnosis categories: sarcoidosis (n=35), connective tissue disease (n=21), adenocarcinoma (n=17), lymphoma (n=13), cryptogenic organizing pneumonia (n=11), drug-induced lung disease (n=9), chronic eosinophilic pneumonia (n =7) and miscellaneous (n=11). First, we investigated the patterns and models (association of patterns characterizing a disease) built up by the LAD from combinations of HRCT attributes (n=51). Second, data were recomputed by adding simple clinical attributes (n=14) to the analysis. Third, cluster analysis was performed to explain LAD failures. RESULTS: HRCT models reached a sensitivity >80% and a specificity >90% for adenocarcinoma and chronic eosinophilic pneumonia. The same thresholds were obtained for sarcoidosis, connective tissue disease, and drug-induced lung diseases when clinical attributes were added to HRCT. LAD failed to provide a satisfactory model for lymphoma and cryptogenic organizing pneumonia, with overlap between both diseases shown on cluster analysis. CONCLUSION: LAD provides relevant models that can be used as a diagnosis support for the radiologist. It highlights the need to add clinical data in the analysis due to frequent overlap between diseases at HRCT. PMID- 28079849 TI - Role of serial F-18 FDG PET/CT scans in assessing treatment response and predicting relapses in patients with symptomatic sarcoidosis. AB - : ackground: Monitoring disease activity in sarcoidosis remains a clinical challenge as there is no gold standard. Positron emission tomography (PET) imaging is a novel tool to assess the metabolic activity. There is limited data on the role of serial PET scans in monitoring the disease activity. METHODS: This is a prospective study of 27 sarcoidosis patients treated with systemic corticosteroids. Patients underwent two serial PET/CT scans: one before initiating therapy and the follow up scan at end of therapy. The metabolic response on PET scan was classified as: (a) complete metabolic response (CMR); (b) partial metabolic response (PMR); (c) stable metabolic disease (SMD); and, (d) progressive metabolic disease (PMD). Patients with either CMR or PMR were classified as PET responders while those with SMD or PMD were considered as PET non-responders. All patients were followed at 3, 6 and 12 months after completion of therapy. Relapse rates and relapse-free survival was compared between the various groups. RESULTS: There was significant decline in the median SUVmax of the mediastinal lymph nodes, peripheral lymph nodes and the lung parenchyma in the follow up PET scan. Eight patients achieved CMR, 6 patients achieved PMR while 13 patients were PET non-responders. There was no difference in the clinical remission rates between the responders and non-responders. However, the relapse rate was significantly higher in non-responders vs. responders (61.5% vs. 14.2%, p=0.018). None of the patients who achieved a CMR relapsed during the study period. CONCLUSIONS: Patients with metabolic response on PET scan have significantly fewer relapses as compared to those with no response on PET scan. PMID- 28079850 TI - Challenges in diagnosing Sarcoidosis in tuberculosis endemic regions: Clinical scenario in India. AB - Sarcoidosis is a chronic, systemic disease of unknown etiology that affects multiple organs. The disease was considered rare in developing countries like India. More recently sarcoidosis is being increasingly diagnosed in countries where tuberculosis continues to be endemic. There is a general perception among physicians that the prevalence of sarcoidosis has increased over the last two decades in countries like India. This may be true but could also be related to better awareness of the condition, availability of improved diagnostic facilities and the increased ability of physicians to differentiate it from tuberculosis. In India, diagnosis of tuberculosis is entertained first in patients who may have sarcoidosis and thus, it is very likely for sarcoidosis to be misdiagnosed as tuberculosis, owing to the high prevalence of tuberculosis and clinicoradiological resemblance to the disease. This editorial highlights the challenges in diagnosing tuberculosis in countries where tuberculosis still continues to be endemic. PMID- 28079851 TI - Corticosteroid and cyclophosphamide in acute exacerbation of idiopathic pulmonary fibrosis: a single center experience and literature review. AB - Acute Exacerbation (AEx) is a frequent and severe complication of Idiopathic Pulmonary Fibrosis (IPF). In the absence of consensus regarding treatment, studies evaluating the efficacy of specific therapies, such as corticosteroids and immunosuppresant agents, are needed. In this case series we evaluated the outcome in terms of survival of intravenous pulse doses of high-dose corticosteroid (methylprednisolone 1000 mg per day for 3 consecutive days) followed by montlhy cyclophosphamide administration (maximum 6 doses) in a cohort of patients with AEx-IPF referred to the Respiratory Unit, San Gerardo University Hospital, Monza, Italy, from 2009 to 2013. A total of 11 patients (7 males, median age 65 years) were enrolled. A median of five monthly pulse doses of cyclophosphamide were administered, with four patients receiving all 6 doses. Four patients died before completion. Three patients developed adverse events. Overall survival at 3 months was 73%, at 6 months 63%, at 12 months 55%, at 18 months 45% and at 2 years 27%. In-hospital mortality was 9%. Causes of death were: six respiratory failures from disease progression, one lung cancer and one breast cancer. Two patients received lung transplantation and were excluded from the Kaplan-Meier analysis. In conclusion, combined intravenous pulse doses of high-dose corticosteroid and cyclophosphamide could be a reasonable add-on therapy for AEx-IPF, considering the few side effects and safe profile. A complete and rapid diagnostic work-up associated to the proper management (e.g. support of respiratory failure with non-invasive ventilation) in the right setting, may also have a positive effect on patients' outcome. PMID- 28079852 TI - Ichthyosiform sarcoidosis: report of three cases from Japan and literature review. AB - Cutaneous lesions of sarcoidosis present with various manifestations including specific and non-specific cutaneous lesions. Ichthyosiform sarcoidosis is a rare form of cutaneous sarcoidosis, presenting with asymptomatic, adherent, polygonal scales, mainly appearing on the lower limbs. Ichthyosiform sarcoidosis has a predilection for dark-skinned races, and cases affecting Japanese patients have rarely been reported in English literature. We herein describe three Japanese cases of ichthyosiform sarcoidosis on the lower limbs. All of the patients were female, with an age range of 57-69 years old. Histologically, sarcoidal granulomas were located in the mid- to lower dermis. All cases had scar sarcoidosis on the knees. Furthermore, Case 1 presented with papular sarcoidosis on the back, and Case 3 presented with subcutaneous nodules on the buttock as well as erythema nodosum-like lesions on the lower legs. All patients had lung sarcoidosis, but ocular sarcoidosis was seen in only Case 2. Case 3 showed Heerfordt syndrome with facial nerve paralysis. Histological features showed that the granular layers were scarcely detected in the overlying epidermis; however, filaggrin expression was not decreased. Sarcoidal granulomas accumulated around the sweat glands in one case, whereas those features were not detected in the other two cases. In conclusion, ichthyosiform cutaneous sarcoidosis may be overlooked or misdiagnosed as xerotic dry skin which is frequently found in elderly people, and ichthyosiform cutaneous lesions may be more prevalent than previously estimated. PMID- 28079854 TI - Time-course of Serum Pro-inflammatory Cytokines and Chemokines Levels Observed in Granulomatosis with Polyangiitis: A Case Report. AB - A 77-year-old man visited our hospital with chief complaints of difficulty in hearing, nasal discharge and fever. The patients was diagnosed with otitis media, and his fever continued at approximately 38 degrees C despite the administration of clarithromycin. After that, dyspnea on exertion developed and chest X-ray examination indicated multiple infiltrative shadows. PR3-ANCA levels were high (238-fold of the normal levels), and granulomatosis with polyangiitis (GPA) was diagnosed on the basis of clinical symptoms, laboratory results, and pathological findings. Thus, remission induction therapy was initiated with prednisolone and cyclophosphamide, following which symptoms and imaging findings rapidly improved. Blood concentrations of tumor necrosis factor-alpha, interleukin-8, and growth related oncogene that had been measured since before treatment decreased over time with the improvement of lesions following treatment. PMID- 28079853 TI - Solely lung-involved IgG4-related disease : a case report and review of the literature. AB - By analyzing the clinical data of 1 case of IgG4-related lung disease(IgG4-RLD) and the review of literature, the author investigated the clinical characteristics of IgG4-RLD. IgG4-RLD is a rare disease characterized by significant elevation of serum IgG4 and infiltration of a large number of IgG4+ plasma cells. The clinical manifestations of the disease were nonspecific, and the imaging features were mixed with several types. The disease can only be involved in the lung, but also multiple organ involvement. Solely lung-involved IgG4-RD is not only extremely rare but also easily misdiagnosed as tuberculosis, lung cancer, lymphoma and other common pulmonary diseases. Histopathological examination is the key to the diagnosis of the disease. Corticosteroids are the first choice of treatment, and the overall prognosis is good. PMID- 28079855 TI - Acute sarcoid myopathy: a case report and literature review. AB - Sarcoidosis is a worldwide spread disease with brad clinical spectrum, in which the pulmonary involvement is the main manifestation (more than 90% of cases); nevertheless, extrathoracic symptoms can predominate in the clinical picture and they may even be the first manifestation. One of them is the skeletal muscle involvement that normally is chronic and silent, with poor response to treatment with glucocorticoids. However, in some cases, it has an acute presentation. We present a case of a 61-year-old man with diagnosis of sarcoidosis whe were evaluated for proximal lower limb weakness within few days of evolution. PMID- 28079856 TI - Charles VI of France and Henry VI of England: Familial Sarcoidosis in the Hundred Years' War. AB - Not available. PMID- 28079857 TI - Annexin A11 is associated with pulmonary fibrosis in African American patients with sarcoidosis. AB - Not available. PMID- 28079858 TI - Reticuloendothelial system involvement in untreated sarcoidosis patients as assessed by 18F-FDG PET scanning. AB - Not available. PMID- 28079859 TI - Executive functions in sarcoidosis: a neurocognitive assessment study. AB - Not available. PMID- 28079860 TI - Erratum. AB - In the article "Transcriptional blood signatures of sarcoidosis, sarcoid-like reactions and tubercolosis and their diagnostic implications" which appeared in Volume 33, Issue 3 (2016) of Sarcoidosis, vasculitis and diffuse lung diseases, the title was given incorrectly. The correct title is "Transcriptional blood signatures of sarcoidosis, sarcoid-like reactions and tuberculosis and their diagnostic implications". PMID- 28079861 TI - Endoscopic vs. Surgical Interventions for Painful Chronic Pancreatitis: What is Needed for Future Clinical Trials. AB - The treatment of painful chronic pancreatitis remains controversial. The available evidence from two randomized controlled trials favor surgical intervention, whereas an endotherapy-first approach is widely practiced. Chronic pancreatitis is complex disease with different genetic and environmental factors, different pain mechanisms and different treatment modalities including medical, endoscopic, and surgical. The widely practiced step-up approach remains unproven. In designing future clinical trials there are some important pre-requisites including a more comprehensive pain assessment tool, the optimization of conservative medical treatment and interventional techniques. Consideration should be given to the need of a control arm and the optimal timing of intervention. Pending better designed studies, the practical way forward is to identify subgroups of patients who clearly warrant endotherapy or surgery first, and to design the future clinical trials for the remainder. PMID- 28079862 TI - Extraneuronal pathology in a canine model of CLN2 neuronal ceroid lipofuscinosis after intracerebroventricular gene therapy that delays neurological disease progression. AB - CLN2 neuronal ceroid lipofuscinosis is a hereditary lysosomal storage disease with primarily neurological signs that results from mutations in TPP1, which encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Studies using a canine model for this disorder demonstrated that delivery of TPP1 enzyme to the cerebrospinal fluid (CSF) by intracerebroventricular administration of an AAV TPP1 vector resulted in substantial delays in the onset and progression of neurological signs and prolongation of life span. We hypothesized that the treatment may not deliver therapeutic levels of this protein to tissues outside the central nervous system that also require TPP1 for normal lysosomal function. To test this hypothesis, dogs treated with CSF administration of AAV-TPP1 were evaluated for the development of non-neuronal pathology. Affected treated dogs exhibited progressive cardiac pathology reflected by elevated plasma cardiac troponin-1, impaired cardiac function and development of histopathological myocardial lesions. Progressive increases in the plasma activity levels of alanine aminotransferase and creatine kinase indicated development of pathology in the liver and muscles. The treatment also did not prevent disease-related accumulation of lysosomal storage bodies in the heart or liver. These studies indicate that optimal treatment outcomes for CLN2 disease may require delivery of TPP1 systemically as well as directly to the central nervous system. PMID- 28079863 TI - The modified patient enablement instrument: a Portuguese cross-cultural adaptation, validity and reliability study. AB - Enabling patients with asthma to obtain the knowledge, confidence and skills they need in order to assume a major role in the management of their disease is cost effective. It should be an integral part of any plan for long-term control of asthma. The modified Patient Enablement Instrument (mPEI) is an easily administered questionnaire that was adapted in the United Kingdom to measure patient enablement in asthma, but its applicability in Portugal is not known. Validity and reliability of questionnaires should be tested before use in settings different from those of the original version. The purpose of this study was to test the applicability of the mPEI to Portuguese asthma patients after translation and cross-cultural adaptation, and to verify the structural validity, internal consistency and reproducibility of the instrument. The mPEI was translated to Portuguese and back translated to English. Its content validity was assessed by a debriefing interview with 10 asthma patients. The translated instrument was then administered to a random sample of 142 patients with persistent asthma. Structural validity and internal consistency were assessed. For reproducibility analysis, 86 patients completed the instrument again 7 days later. Item-scale correlations and exploratory factor analysis were used to assess structural validity. Cronbach's alpha was used to test internal consistency, and the intra-class correlation coefficient was used for the analysis of reproducibility. All items of the Portuguese version of the mPEI were found to be equivalent to the original English version. There were strong item scale correlations that confirmed construct validity, with a one component structure and good internal consistency (Cronbach's alpha >0.8) as well as high test-retest reliability (ICC=0.85). The mPEI showed sound psychometric properties for the evaluation of enablement in patients with asthma making it a reliable instrument for use in research and clinical practice in Portugal. Further studies are needed to confirm its responsiveness. PMID- 28079864 TI - Bronchopulmonary dysplasia and pulmonary hypertension: a meta-analysis. AB - OBJECTIVE: Pulmonary hypertension (PH) is a complication of bronchopulmonary dysplasia (BPD) but the true impact of PH in patients with BPD remains unclear. We sought to systematically review and meta-analyze incidence of PH in BPD and compare clinical outcomes of BPD patients with PH to those without PH in preterm infants. STUDY DESIGN: Medline, Embase, PsychINFO and CINAHL were searched from January 2000 through December 2015. Cohort, case-control and randomized studies were included. Case-reports, case-series and letters to editors and studies with high risk of bias were excluded. Study design, inclusion/exclusion criteria, diagnostic criteria for BPD and PH and outcomes were extracted independently by two co-authors. RESULTS: The pooled incidence of PH in patients with BPD (any severity) was 17% (95% confidence interval (CI) 12 to 21; 7 studies) and 24% (95% CI 17 to 30; 9 studies) in moderate-severe BPD. Patients with BPD have higher unadjusted odds of developing PH compared to those without BPD (odds ratio (OR) 3.00; 95% CI 1.18 to 7.66; 4 studies). Patients with BPD and PH were at higher odds of mortality (OR 5.29; 95% CI 2.07 to 13.56; 3 studies) compared with BPD without PH, but there was no significant difference in duration of initial hospitalization, duration of supplemental oxygen requirement or need for home oxygen. No studies included in this review reported on long-term pulmonary or neurodevelopmental outcomes. CONCLUSIONS: PH occurs in one out of 4 to 5 preterm neonates with BPD. Patients with BPD and PH may have higher odds of mortality; however, there is urgent need for high quality studies that control for confounders and provide data on long-term outcomes. PMID- 28079865 TI - Differences in mortality characteristics in neonates with Down's syndrome. AB - OBJECTIVE: Neonates with Down's syndrome (nDS) may have multiple medical issues that place them at increased risk for mortality during the newborn period. Goal of this study was to determine if there are differences in baseline characteristics, medical complications or procedures performed during hospitalization between nDS who survived versus those who died during initial hospitalization. STUDY DESIGN: Data from 2000 to 2014 were reviewed using the Pediatric Health Information Systems (PHIS) database on all DS patients admitted to the hospital <30 days postnatal life. Baseline demographics, medical complications, procedures performed and mortality were recorded. Patients were divided into nDS patients who were discharged alive (nDS-a) versus nDS patients who died (nDS-d). Multivariate logistic analysis with odds ratios was performed to determine significant predictors of death. A P<0.05 was considered significant. RESULTS: A total of 5737 nDS were evaluated. Overall mortality was 7.5% (431/5737). nDS-d were more likely than nDS-a to have a lower birth weight (1.0 (0.9 to 1.0)), presence of a diaphragmatic hernia (6.9 (1.9 to 25.1), or a cardiac diagnosis of a pulmonary venous abnormality (6.8 (1.9 to 24.4)), Ebstein's anomaly (3.2 (1.2 to 8.5)) or left-sided obstructive lesion (2.0 (1.3 to 3.0). nDS-d were more likely to develop hydrops (5.7 (3.5 to 9.5)) and necrotizing enterocolitis (1.7 (1.2 to 2.6)). In addition, nDS-d had significantly higher odds of requiring mechanical ventilation (20.7 (9.9 to 43.1)) or extracorporeal membrane oxygenation (8.7 (4.7 to 16.1)). CONCLUSIONS: A number of characteristics, specifically certain cardiac diagnosis, place nDS at increased risk for mortality. Furthermore, development of specific medical complications or need for particular procedures increases the odds for mortality in nDS. Caregivers should be cognizant that they are taking care of a high-risk population nDS with an increased risk for mortality if these variables are present. PMID- 28079866 TI - Outcomes of twin pregnancies complicated by gestational diabetes: a meta-analysis of observational studies. AB - OBJECTIVE: Gestational diabetes mellitus (GDM) in singleton pregnancy is associated with large for gestational age neonates and adverse perinatal outcomes; however, the impact of GDM in twin pregnancy is unclear. Thus, the aim of this study is to assess the perinatal outcomes of twin pregnancies complicated by GDM by performing a meta-analysis of observational studies. STUDY DESIGN: Studies investigating GDM in twin pregnancy were identified through an online search of three databases: Medline, Embase and Web of Science. Selection criteria comprised full paper observational studies (retrospective or prospective) published in English that examined GDM in twin pregnancy compared with non-GDM twin pregnancy and reported on birth weight and/or adverse perinatal outcomes. Random-effects models with inverse-variance weighting were used to calculate standardized mean differences and unadjusted odds ratios. Sensitivity analyses were carried out to determine the impact of possible maternal confounders (body mass index and age) and GDM diagnostic criteria on perinatal outcomes. RESULTS: Thirteen observational studies were included. GDM twins were born at the same gestation as non-GDM twins, with marginally lower birth weight. There was no difference in the incidence of large or small for gestational age neonates. Although there was no correlation between GDM in twin pregnancy and respiratory distress, neonatal hypoglycemic or low Apgar score, GDM twins had a higher rate of neonatal intensive care unit admission (OR 1.49; 95% confidence interval: 1.10, 2.02; P<0.01). CONCLUSION: Identification and subsequent treatment of GDM in twin pregnancy demonstrates a similar risk of adverse perinatal outcomes compared with non-GDM twin pregnancies. PMID- 28079867 TI - Reducing peripherally inserted central catheters in the neonatal intensive care unit. AB - OBJECTIVE: Our objective was to safely reduce the number of peripherally inserted central catheters (PICCs) inserted in infants with umbilical venous catheter using quality improvement methods. STUDY DESIGN: In a tertiary neonatal intensive care unit, a questionnaire designed to prompt critical thinking around the decision to place a PICC, along with an updated standardized feeding guideline was introduced. PICC insertion in 86 infants with umbilical venous catheter (pre intervention) with birth weight 1000-1500 g were compared with 115 infants (post intervention) using Fisher's exact test. RESULTS: PICC lines inserted after the intervention decreased by 37.5% (67/86; 77.9% vs 56/115; 48.7%; P<0.001). The proportion of central line-associated blood stream infection were 2.49 vs 2.82/1000 umbilical venous catheter days; P=0.91 in the two epochs, respectively. CONCLUSION: Quality improvement methodology was successful in significantly reducing the number of PICCs inserted without an increase in central line associated blood stream infection. PMID- 28079868 TI - CDC123/CAMK1D gene rs12779790 polymorphism and rs10811661 polymorphism upstream of the CDKN2A/2B gene in women with gestational diabetes. AB - OBJECTIVE: Gestational diabetes mellitus (GDM) is carbohydrate intolerance occurring in pregnant women. CDC123/CAMK1D and CDKN2A/2B are associated with increased risk of type 2 diabetes and may affect pancreatic beta cell function. The aim of this study was to examine the association between CDKN2A/2B rs10811661 and CDC123/CAMK1D rs12779790 gene polymorphisms and GDM. STUDY DESIGN: This study included 411 pregnant women. The diagnosis of GDM was based on the International Association of Diabetes and Pregnancy Study Groups criteria. According to the results of their oral glucose tolerance test, the women were divided into two groups: 204 pregnant women with GDM and 207 pregnant women with normal glucose tolerance. RESULTS: There were no statistically significant differences in the distribution of CDC123/CAMK1D rs12779790 genotypes and alleles between women with GDM and healthy pregnant women. However, there was a statistically significant association between the C allele of CDKN2A/2B rs10811661 polymorphism and reduced risk of GDM (C vs T, OR 0.53, 95% CI 0.36 to 0.79, P=0.0014). In the multivariate logistic regression analysis, older age and higher body mass index before pregnancy were independent significant predictors of a higher risk of GDM, while higher number of C alleles (CDKN2A/2B rs10811661) was a protective factor against GDM. CONCLUSION: The results of this study suggest an association between CDKN2A/2B gene rs10811661 polymorphism and GDM. PMID- 28079870 TI - Impact of l-carnitine supplementation on metabolic profiles in premature infants. AB - OBJECTIVE: To describe the influence that of l-carnitine supplementation on acylcarnitine (AC) profiles and hospital outcomes in premature infants. STUDY DESIGN: This study is a secondary analysis of previously reported work. Metabolic profiles were obtained using standard newborn techniques on infants born between 23 and 31 completed weeks of gestation. The profiles were drawn within the first 24 h after birth and on approximately days 7, 28 and 42 of life, or at the time of discharge. A single, central, contract laboratory analyzed and managed the samples. RESULTS: We studied 995 patients; none was subsequently diagnosed with an inborn error of metabolism. l-Carnitine was added to parenteral nutrition in 390 (39%) study subjects; 592 (60%) did not receive supplementation. Non supplemented infants were more likely to develop low levels of free carnitine (FC; <7 MUm) on day 28; (41% vs 5%, P<0.01); and FC values were lower on day 7. Despite higher levels of FC and fewer patients with significant carnitine deficiencies, we found no evidence that l-carnitine supplementation was associated with improved short-term hospital outcomes. CONCLUSION: l-Carnitine supplementation is common in prematurely born neonates and is associated with higher carnitine levels, but is not associated with improved short-term hospital outcomes. PMID- 28079869 TI - Racial and social predictors of longitudinal cervical measures: the Cervical Ultrasound Study. AB - OBJECTIVE: To evaluate whether the racial and socioeconomic disparities are present in adverse cervical parameters, and, if so, when such disparities develop. STUDY DESIGN: A prospective cohort study was conducted. 175 women with a prior preterm birth had up to four endovaginal ultrasounds between gestational weeks 16 and 24 (Cervical Ultrasound Trial of the MFMU). Each sociodemographic factor (race/ethnicity, marital status, insurance funding and education) was examined as a predictor of short cervix or U/funnel shape, using multiple logistic and linear regression. Changes in the cervical length and shape across pregnancy and after pressure were also examined. RESULTS: The strongest associations were seen between race and government-funded insurance and short cervix and U shape per funneling (race and length <25 mm per funnel: adjusted odds ratio (OR) 5.52, 2.24 to 13.63; government-funded insurance and length <30 mm per funnel: adjusted OR 3.10, 1.34 to 7.15). Changes in cervical length were not associated with sociodemographics. CONCLUSION: African-American race and, to a lesser extent, insurance funder, are associated with cervical length and shapes that have been associated with preterm birth, and those properties are present largely early in pregnancy. PMID- 28079871 TI - The relationship between the rising cesarean delivery and postpartum readmission rates. AB - OBJECTIVE: This study seeks to determine if the increasing rate of postpartum readmissions is related to the increasing rate of cesarean delivery. STUDY DESIGN: Readmitted patients were identified in the State Inpatient Databases of California, Florida and New York from 2004 to 2011. Relevant maternal comorbidities, pregnancy complications and intrapartum events were collected using ICD-9 diagnosis and procedure codes. The effects of cesarean delivery were first examined via univariate logistic regression to calculate the odds of readmission by year for patients who had delivered via cesarean section. Then, we used multivariate logistic regression models to isolate the effect of mode of delivery on the odds of readmission by adjusting for the effects of patient demographics, hospital characteristics and maternal comorbidities. RESULTS: Nearly one million deliveries were identified each year, and ~600 000 deliveries per year met inclusion criteria. During this time, the readmission rate increased from 1.72 to 2.16%, and the cesarean delivery rate increased from 30.4 to 33.9%. The odds of readmission for patients delivered via cesarean section decreased yearly, from 1.343 (95% CI: 1.295 to 1.392) in 2004 to 1.046 (95% CI: 1.012 to 1.108) in 2011. In a multivariate model, the odds based on year were 1.032 (95% CI: 1.030 to 1.035), demonstrating an increased odds of readmission over time. When cesarean delivery was added to the model, this odds estimate did not change (OR: 1.031, 95% CI: 1.028 to 1.035), suggesting it did not account for the increased odds of readmission over time, even though cesarean delivery rates increased. However, when maternal comorbidities were added to the model, the odds ratio for year became insignificant (OR: 1.001, 95% CI: 0.998 to 1.005), suggesting that they accounted for the increasing rate of readmissions. CONCLUSIONS: The increasing cesarean delivery rate does not explain the increasing rate of postpartum readmissions. Rather, the increasing postpartum readmission rate appears to be related to maternal comorbidities. PMID- 28079872 TI - Is use of multiple antihypertensive agents to achieve blood pressure control associated with adverse pregnancy outcomes? AB - OBJECTIVE: We assessed whether requiring >1 medication for blood pressure control is associated with adverse pregnancy outcomes. STUDY DESIGN: Retrospective cohort of 974 singletons with chronic hypertension at a tertiary care center. Subjects on >1 antihypertensive agent were compared with those on one agent <20 weeks gestational age with results stratified by average blood pressure (<140/90 and ?140/90 mm Hg) from prenatal visits. The primary maternal outcome was preeclampsia; the primary neonatal outcome was small for gestational age (<10th percentile). RESULT: Among women with blood pressure ?140/90 mm Hg, women on multiple agents had the greatest risk of preeclampsia, severe preeclampsia, antenatal admissions to rule out preeclampsia, preterm birth <35 weeks and composite neonatal adverse outcomes. CONCLUSION: Compared with use of a single agent when blood pressure is ?140/90 mm Hg, use of multiple agents increases adverse risks, while no such finding exists when blood pressure is controlled below 140/90 mm Hg. PMID- 28079873 TI - Major anomalies and birth-weight influence NICU interventions and mortality in infants with trisomy 13 or 18. AB - OBJECTIVE: To describe neonatal intensive care unit (NICU) medical interventions and NICU mortality by birth weight and major anomaly types for infants with trisomy 13 (T13) or 18 (T18). STUDY DESIGN: Retrospective cohort analysis of infants with T13 or T18 from 2005 to 2012 in the Pediatrix Medical Group. We classified infants into three groups by associated anomaly type: neonatal surgical, non-neonatal surgical and minor. Outcomes were NICU medical interventions and mortality. RESULTS: 841 infants were included from 186 NICUs. NICU mortality varied widely by anomaly type and birth weight, from 70% of infants <1500 g with neonatal surgical anomalies to 31% of infants ?2500 g with minor anomalies. Infants ?1500 g without a neonatal surgical anomaly comprised 66% of infants admitted to the NICU; they had the lowest rates of NICU medical interventions and NICU mortality. CONCLUSIONS: Risk stratification by anomaly type and birth weight may help provide more accurate family counseling for infants with T13 and T18. PMID- 28079874 TI - Cerebral modulation of the autonomic nervous system in term infants. AB - OBJECTIVE: Central topography of autonomic nervous system (ANS) function has yet to be fully deciphered. In adults it has been shown to lateralize sympathetic and parasympathetic influence predominantly to the right and left cerebral hemispheres, respectively. We examined functional topography of central ANS in newborn subjects utilizing spectral analysis of heart rate variability (HRV), an established measure of ANS function. STUDY DESIGN: We studied newborns with hypoxic-ischemic encephalopathy participating in a prospective study undergoing a therapeutic hypothermia protocol.We included subjects with continuous heart rate data over the first 3 h of normothermia (post rewarming) and brain magnetic resonance imaging, which was reviewed and scored according to a 4 region scheme. HRV was evaluated by spectral analysis in the low-frequency (0.05 to 0.25 Hz) and high-frequency (0.3 to 1 Hz) ranges. The relationship between injured brain regions and HRV was studied using multiple regressions. RESULTS: Forty eight newborns were included. When examined in isolation, right hemisphere injury had a significant negative effect on HRV (-0.088; 95% CI: -0.225,-0.008). The combination of posterior fossa region injury with right hemispheric injury or left hemispheric injury demonstrated significant positive (0.299; 95% CI: 0.065, 0.518) and negative (-0.475; 95% CI: -0.852, -0.128) influences on HRV, respectively. The association between brain injury location and HRV in the high frequency range did not reach significance. CONCLUSION: Our data support the notion that lateralized cerebral modulation of the ANS, specifically of its sympathetic component, is present in the term newborn, and suggest complex modulation of these tracts by components of the posterior fossa. PMID- 28079876 TI - Cardiac output decreases and systemic vascular resistance increases in newborns placed in the left-lateral position. AB - OBJECTIVE: The objective of the study was to study the effect of short-term left lateral position on cardiovascular parameters in hemodynamically stable newborns. STUDY DESIGN: Cardiac output (CO), stroke volume (SV), systemic vascular resistance index (SVRI) and heart rate (HR) were measured by electric velocimetry in hemodynamically stable newborns without respiratory support in the supine, left-lateral and back-to-supine positions, each kept for 10 min. RESULTS: Thirty two newborns were enrolled, birth weight 2134 (1818 to 2460) g, gestational age 34.5+/-2.4 weeks. CO and SV decreased significantly from supine to left-lateral position (CO supine: 193.4 (168.0 to 229.6) ml kg-1min-1; CO left-lateral: 172.0 (154.9 to 201.6) ml kg-1min-1, P<0.0001; SV supine: 3.0 (2.7 to 4.0) ml; SV left lateral: 2.7 (2.4 to 3.2) ml, P<0.0004). Conversely, SVRI increased in left lateral position: SVRI supine: 18865+/-9244 dyns cm-5 m-2; SVRI left-lateral: 21203+/-10059 dyns cm-5 m-2, P<0.0001). All variables returned to the initial value when infants were back in the supine position. HR and blood pressure did not change. CONCLUSION: In stable infants, CO and SV decrease and SVRI increases, in left-lateral position. PMID- 28079875 TI - Early postnatal illness severity scores predict neurodevelopmental impairments at 10 years of age in children born extremely preterm. AB - OBJECTIVE: A neonatal illness severity score, The Score for Neonatal Acute Physiology-II (SNAP-II), predicts neurodevelopmental impairments at two years of age among children born extremely preterm. We sought to evaluate to what extent SNAP-II is predictive of cognitive and other neurodevelopmental impairments at 10 years of age. STUDY DESIGN: In a cohort of 874 children born before 28 weeks of gestation, we prospectively collected clinical, physiologic and laboratory data to calculate SNAP-II for each infant. When the children were 10 years old, examiners who were unaware of the child's medical history assessed neurodevelopmental outcomes, including neurocognitive, gross motor, social and communication functions, diagnosis and treatment of seizures or attention deficit hyperactivity disorder (ADHD), academic achievement, and quality of life. We used logistic regression to adjust for potential confounders. RESULTS: An undesirably high SNAP-II (?30), present in 23% of participants, was associated with an increased risk of cognitive impairment (IQ, executive function, language ability), adverse neurological outcomes (epilepsy, impaired gross motor function), behavioral abnormalities (attention deficit disorder and hyperactivity), social dysfunction (autistic spectrum disorder) and education related adversities (school achievement and need for educational supports. In analyses that adjusted for potential confounders, Z-scores ?-1 on 11 of 18 cognitive outcomes were associated with SNAP-II in the highest category, and 6 of 18 were associated with SNAP-II in the intermediate category. Odds ratios and 95% confidence intervals ranged from 1.4 (1.01, 2.1) to 2.1 (1.4, 3.1). Similarly, 2 of the 8 social dysfunctions were associated with SNAP-II in the highest category, and 3 of 8 were associated with SNAP-II in the intermediate category. Odds ratios and 95% confidence intervals were slightly higher for these assessments, ranging from 1.6 (1.1, 2.4) to 2.3 (1.2, 4.6). CONCLUSION: Among very preterm newborns, physiologic derangements present in the first 12 postnatal hours are associated with dysfunctions in several neurodevelopmental domains at 10 years of age. We are unable to make inferences about causality. PMID- 28079877 TI - Genome-wide transposon screening and quantitative insertion site sequencing for cancer gene discovery in mice. AB - Transposon-mediated forward genetics screening in mice has emerged as a powerful tool for cancer gene discovery. It pinpoints cancer drivers that are difficult to find with other approaches, thus complementing the sequencing-based census of human cancer genes. We describe here a large series of mouse lines for insertional mutagenesis that are compatible with two transposon systems, PiggyBac and Sleeping Beauty, and give guidance on the use of different engineered transposon variants for constitutive or tissue-specific cancer gene discovery screening. We also describe a method for semiquantitative transposon insertion site sequencing (QiSeq). The QiSeq library preparation protocol exploits acoustic DNA fragmentation to reduce bias inherent to widely used restriction-digestion based approaches for ligation-mediated insertion site amplification. Extensive multiplexing in combination with next-generation sequencing allows affordable ultra-deep transposon insertion site recovery in high-throughput formats within 1 week. Finally, we describe principles of data analysis and interpretation for obtaining insights into cancer gene function and genetic tumor evolution. PMID- 28079878 TI - A complete workflow for high-resolution spectral-stitching nanoelectrospray direct-infusion mass-spectrometry-based metabolomics and lipidomics. AB - Metabolomic and lipidomic studies measure and discover metabolic and lipid profiles in biological samples, enabling a better understanding of the metabolism of specific biological phenotypes. Accurate biological interpretations require high analytical reproducibility and sensitivity, and standardized and transparent data processing. Here we describe a complete workflow for nanoelectrospray ionization (nESI) direct-infusion mass spectrometry (DIMS) metabolomics and lipidomics. After metabolite and lipid extraction from tissues and biofluids, samples are directly infused into a high-resolution mass spectrometer (e.g., Orbitrap) using a chip-based nESI sample delivery system. nESI functions to minimize ionization suppression or enhancement effects as compared with standard electrospray ionization (ESI). Our analytical technique-named spectral stitching measures data as several overlapping mass-to-charge (m/z) windows that are subsequently 'stitched' together, creating a complete mass spectrum. This considerably increases the dynamic range and detection sensitivity-about a fivefold increase in peak detection-as compared with the collection of DIMS data as a single wide mass-to-charge (m/z ratio) window. Data processing, statistical analysis and metabolite annotation are executed as a workflow within the user friendly, transparent and freely available Galaxy platform (galaxyproject.org). Generated data have high mass accuracy that enables molecular formulae peak annotations. The workflow is compatible with any sample-extraction method; in this protocol, the examples are extracted using a biphasic method, with methanol, chloroform and water as the solvents. The complete workflow is reproducible, rapid and automated, which enables cost-effective analysis of >10,000 samples per year, making it ideal for high-throughput metabolomics and lipidomics screening e.g., for clinical phenotyping, drug screening and toxicity testing. PMID- 28079879 TI - The ClusPro web server for protein-protein docking. AB - The ClusPro server (https://cluspro.org) is a widely used tool for protein protein docking. The server provides a simple home page for basic use, requiring only two files in Protein Data Bank (PDB) format. However, ClusPro also offers a number of advanced options to modify the search; these include the removal of unstructured protein regions, application of attraction or repulsion, accounting for pairwise distance restraints, construction of homo-multimers, consideration of small-angle X-ray scattering (SAXS) data, and location of heparin-binding sites. Six different energy functions can be used, depending on the type of protein. Docking with each energy parameter set results in ten models defined by centers of highly populated clusters of low-energy docked structures. This protocol describes the use of the various options, the construction of auxiliary restraints files, the selection of the energy parameters, and the analysis of the results. Although the server is heavily used, runs are generally completed in <4 h. PMID- 28079881 TI - Translational upregulation of Aurora-A by hnRNP Q1 contributes to cell proliferation and tumorigenesis in colorectal cancer. AB - By using RNA-immunoprecipitation assay following next-generation sequencing, a group of cell cycle-related genes targeted by hnRNP Q1 were identified, including Aurora-A kinase. Overexpressed hnRNP Q1 can upregulate Aurora-A protein, but not alter the mRNA level, through enhancing the translational efficiency of Aurora-A mRNA, either in a cap-dependent or -independent manner, by interacting with the 5'-UTR of Aurora-A mRNA through its RNA-binding domains (RBDs) 2 and 3. By ribosomal profiling assay further confirmed the translational regulation of Aurora-A mRNA by hnRNP Q1. Overexpression of hnRNP Q1 promotes cell proliferation and tumor growth. HnRNP Q1/DeltaRBD23-truncated mutant, which loses the binding ability and translational regulation of Aurora-A mRNA, has no effect on promoting tumor growth. The expression level of hnRNP Q1 is positively correlated with Aurora-A in colorectal cancer. Taken together, our data indicate that hnRNP Q1 is a novel trans-acting factor that binds to Aurora-A mRNA 5'-UTRs and regulates its translation, which increases cell proliferation and contributes to tumorigenesis in colorectal cancer. PMID- 28079880 TI - Nonradioactive quantification of autophagic protein degradation with L azidohomoalanine labeling. AB - At present, several assays that use radioisotope labeling to quantify the degradation of long-lived proteins have been developed to measure autophagic flux. Here, we describe a nonradioactive pulse-chase protocol using L azidohomoalanine (AHA) labeling to quantify long-lived protein degradation during autophagy. AHA is used as a surrogate for L-methionine, and, when added to cultured cells grown in methionine-free medium, AHA is incorporated into proteins during de novo protein synthesis. After a chase period to remove short-lived proteins, autophagy is induced by starvation or other stimuli. Cells then undergo a 'click' reaction between the azide group of AHA and a fluorescently tagged alkyne probe. The AHA-containing proteins can then be detected by flow cytometry. This protocol is nonradioactive, sensitive and quantitative, and it is easy to perform. It is also applicable to various cell culture systems. The whole protocol is estimated to take 4-5 d to complete. PMID- 28079882 TI - Stability of the cancer target DDIAS is regulated by the CHIP/HSP70 pathway in lung cancer cells. AB - DNA damage-induced apoptosis suppressor (DDIAS) rescues lung cancer cells from apoptosis in response to DNA damage. DDIAS is transcriptionally activated by NFATc1 and EGF-mediated ERK5/MEF2B, leading to cisplatin resistance and cell invasion. Therefore, DDIAS is suggested as a therapeutic target for lung cancer. Here, we report that DDIAS stability is regulated by E3 U-box ubiquitin ligase carboxyl terminus of HSP70-interacting protein (CHIP)-mediated proteasomal degradation. We first isolated CHIP as an interacting partner of DDIAS by yeast two-hybrid screening. CHIP physically associated with both the N- and C-terminal regions of DDIAS, targeting it for proteasomal degradation and reducing the DDIAS half-life. CHIP overexpression analyses indicated that the tetratrico peptide repeat (TPR) domain and the U-box are required for DDIAS ubiquitination. It is likely that HSP70-bound DDIAS is recruited to the CHIP E3 ligase via the TPR domain, suggesting DDIAS as a client protein of HSP70. In addition, CHIP overexpression in lung cancer cells expressing high DDIAS levels induced significant growth inhibition by enhancing DDIAS degradation. Furthermore, simultaneous CHIP overexpression and DNA damage agent treatment caused a substantial increase in the apoptosis of lung cancer cells. Taken together, these findings indicate that the stability of the DDIAS protein is regulated by CHIP/HSP70-mediated proteasomal degradation and that CHIP overexpression stimulates the apoptosis of lung cancer cells in response to DNA-damaging agents. PMID- 28079883 TI - Cysteamine re-establishes the clearance of Pseudomonas aeruginosa by macrophages bearing the cystic fibrosis-relevant F508del-CFTR mutation. AB - Cystic fibrosis (CF), the most common lethal monogenic disease in Caucasians, is characterized by recurrent bacterial infections and colonization, mainly by Pseudomonas aeruginosa, resulting in unresolved airway inflammation. CF is caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions as a chloride channel in epithelial cells, macrophages, and other cell types. Impaired bacterial handling by macrophages is a feature of CF airways, although it is still debated how defective CFTR impairs bacterial killing. Recent evidence indicates that a defective autophagy in CF macrophages leads to alterations of bacterial clearance upon infection. Here we use bone marrow-derived macrophages from transgenic mice to provide the genetic proof that defective CFTR compromises both uptake and clearance of internalized Pseudomonas aeruginosa. We demonstrate that the proteostasis regulator cysteamine, which rescues the function of the most common F508del-CFTR mutant and hence reduces lung inflammation in CF patients, can also repair the defects of CF macrophages, thus restoring both bacterial internalization and clearance through a process that involves upregulation of the pro-autophagic protein Beclin 1 and re-establishment of the autophagic pathway. Altogether these results indicate that cysteamine restores the function of several distinct cell types, including that of macrophages, which might contribute to its beneficial effects on CF. PMID- 28079884 TI - Lack of collagen XV is protective after ischemic stroke in mice. AB - Collagens are key structural components of basement membranes, providing a scaffold for other components or adhering cells. Collagens and collagen-derived active fragments contribute to biological activities such as cell growth, differentiation and migration. Here, we report that collagen XV knock-out (ColXV KO) mice are resistant to experimental ischemic stroke. Interestingly, the infarcts of ColXV KO mice were as small as those of wild-type (WT) mice thrombolysed with recombinant tissue plasminogen activator (rtPA), the actual treatment for ischemic stroke. Importantly, there were no differences in the architecture of cerebrovascular anatomy between WT and ColXV KO mice. We found a twofold increase of the most potent pro-angiogenic factor, type A vascular growth endothelial factor (VEGF-A) in the ipsilateral cortex of rtPA-treated ischemic WT mice compared with untreated ischemic and sham-operated counterparts. A similar increase of VEGF-A was also found in both rtPA and untreated ischemic ColXV KO mice compared with sham ColXV KO mice. Finally, we evidenced that the levels of ColXV were increased in the plasma of WT mice treated with rtPA compared with untreated ischemic counterparts. Altogether, this study indicates that the lack ColXV is protective after stroke and that the degradation of endothelial ColXV may contribute to the beneficial effect of rtPA after ischemic stroke. The neuroprotection observed in ColXV KO mice may be attributed to the increased VEGF A production following stroke in the ischemic territory. PMID- 28079885 TI - MiRNA182 regulates percentage of myeloid and erythroid cells in chronic myeloid leukemia. AB - The deregulation of lineage control programs is often associated with the progression of haematological malignancies. The molecular regulators of lineage choices in the context of tyrosine kinase inhibitor (TKI) resistance remain poorly understood in chronic myeloid leukemia (CML). To find a potential molecular regulator contributing to lineage distribution and TKI resistance, we undertook an RNA-sequencing approach for identifying microRNAs (miRNAs). Following an unbiased screen, elevated miRNA182-5p levels were detected in Bcr Abl-inhibited K562 cells (CML blast crisis cell line) and in a panel of CML patients. Earlier, miRNA182-5p upregulation was reported in several solid tumours and haematological malignancies. We undertook a strategy involving transient modulation and CRISPR/Cas9 (clustered regularly interspersed short palindromic repeats)-mediated knockout of the MIR182 locus in CML cells. The lineage contribution was assessed by methylcellulose colony formation assay. The transient modulation of miRNA182-5p revealed a biased phenotype. Strikingly, Delta182 cells (homozygous deletion of MIR182 locus) produced a marked shift in lineage distribution. The phenotype was rescued by ectopic expression of miRNA182 5p in Delta182 cells. A bioinformatic analysis and Hes1 modulation data suggested that Hes1 could be a putative target of miRNA182-5p. A reciprocal relationship between miRNA182-5p and Hes1 was seen in the context of TK inhibition. In conclusion, we reveal a key role for miRNA182-5p in restricting the myeloid development of leukemic cells. We propose that the Delta182 cell line will be valuable in designing experiments for next-generation pharmacological interventions. PMID- 28079886 TI - HIV-1 Nef is released in extracellular vesicles derived from astrocytes: evidence for Nef-mediated neurotoxicity. AB - Human immunodeficiency virus-associated neurological disorders (HANDs) affect the majority of AIDS patients and are a significant problem among HIV-1-infected individuals who live longer because of combined anti-retroviral therapies. HIV-1 utilizes a number of viral proteins and subsequent cytokine inductions to unleash its toxicity on neurons. Among HIV-1 viral proteins, Nef is a small protein expressed abundantly in astrocytes of HIV-1-infected brains and has been suggested to have a role in the pathogenesis of HAND. In order to explore its effect in the central nervous system, HIV-1 Nef was expressed in primary human fetal astrocytes (PHFAs) using an adenovirus. Our results revealed that HIV-1 Nef is released in extracellular vesicles (EVs) derived from PHFA cells expressing the protein. Interestingly, HIV-1 Nef release in EVs was enriched significantly when the cells were treated with autophagy activators perifosine, tomaxifen, MG 132, and autophagy inhibitors LY294002 and wortmannin suggesting a novel role of autophagy signaling in HIV-1 Nef release from astrocytes. Next, Nef-carrying EVs were purified from astrocyte cultures and neurotoxic effects on neurons were analyzed. We observed that HIV-1 Nef-containing EVs were readily taken up by neurons as demonstrated by immunocytochemistry and immunoblotting. Furthermore, treatment of neurons with Nef-carrying EVs induced oxidative stress as evidenced by a decrease in glutathione levels. To further investigate its neurotoxic effects, we expressed HIV-1 Nef in primary neurons by adenoviral transduction. Intracellular expression of HIV-1 Nef caused axonal and neurite degeneration of neurons. Furthermore, expression of HIV-1 Nef decreased the levels of phospho-tau while enhancing total tau in primary neurons. In addition, treatment of primary neurons with Nef-carrying EVs suppressed functional neuronal action potential assessed by multielectrode array studies. Collectively, these data suggested that HIV-1 Nef can be a formidable contributor to neurotoxicity along with other factors, which leads to HAND in HIV-1-infected AIDS patients. PMID- 28079887 TI - DRP-1 is required for BH3 mimetic-mediated mitochondrial fragmentation and apoptosis. AB - The concept of using BH3 mimetics as anticancer agents has been substantiated by the efficacy of selective drugs, such as Navitoclax and Venetoclax, in treating BCL-2-dependent haematological malignancies. However, most solid tumours depend on MCL-1 for survival, which is highly amplified in multiple cancers and a major factor determining chemoresistance. Most MCL-1 inhibitors that have been generated so far, while demonstrating early promise in vitro, fail to exhibit specificity and potency in a cellular context. To address the lack of standardised assays for benchmarking the in vitro binding of putative inhibitors before analysis of their cellular effects, we developed a rapid differential scanning fluorimetry (DSF)-based assay, and used it to screen a panel of BH3 mimetics. We next contrasted their binding signatures with their ability to induce apoptosis in a MCL-1 dependent cell line. Of all the MCL-1 inhibitors tested, only A-1210477 induced rapid, concentration-dependent apoptosis, which strongly correlated with a thermal protective effect on MCL-1 in the DSF assay. In cells that depend on both MCL-1 and BCL-XL, A-1210477 exhibited marked synergy with A-1331852, a BCL-XL specific inhibitor, to induce cell death. Despite this selectivity and potency, A-1210477 induced profound structural changes in the mitochondrial network in several cell lines that were not phenocopied following MCL-1 RNA interference or transcriptional repression, suggesting that A-1210477 induces mitochondrial fragmentation in an MCL-1-independent manner. However, A 1210477-induced mitochondrial fragmentation was dependent upon DRP-1, and silencing expression levels of DRP-1 diminished not just mitochondrial fragmentation but also BH3 mimetic-mediated apoptosis. These findings provide new insights into MCL-1 ligands, and the interplay between DRP-1 and the anti apoptotic BCL-2 family members in the regulation of apoptosis. PMID- 28079888 TI - Antiphospholipid antibodies enhance rat neonatal cardiomyocyte apoptosis in an in vitro hypoxia/reoxygenation injury model via p38 MAPK. AB - A significant amount of myocardial damage during a myocardial infarction (MI) occurs during the reperfusion stage, termed ischaemia/reperfusion (I/R) injury, and accounts for up to 50% of total infarcted tissue post-MI. During the reperfusion phase, a complex interplay of multiple pathways and mechanisms is activated, which ultimately leads to cell death, primarily through apoptosis. There is some evidence from a lupus mouse model that lupus IgG, specifically the antiphospholipid (aPL) antibody subset, is pathogenic in mesenteric I/R injury. Furthermore, it has previously been shown that the immunodominant epitope for the majority of circulating pathogenic aPLs resides in the N-terminal domain I (DI) of beta-2 glycoprotein I (beta2GPI). This study describes the enhanced pathogenic effect of purified IgG derived from patients with lupus and/or the antiphospholipid syndrome in a cardiomyocyte H/R in vitro model. Furthermore, we have demonstrated a pathogenic role for aPL containing samples, mediated via aPL beta2GPI interactions, resulting in activation of the pro-apoptotic p38 MAPK pathway. This was shown to be inhibited using a recombinant human peptide of domain I of beta2GPI in the fluid phase, suggesting that the pathogenic anti beta2GPI antibodies in this in vitro model target this domain. PMID- 28079889 TI - Deletion of the BH3-only protein Noxa alters electrographic seizures but does not protect against hippocampal damage after status epilepticus in mice. AB - Several members of the Bcl-2 gene family are dysregulated in human temporal lobe epilepsy and animal studies show that genetic deletion of some of these proteins influence electrographic seizure responses to chemoconvulsants and associated brain damage. The BH3-only proteins form a subgroup comprising direct activators of Bax-Bak that are potently proapoptotic and a number of weaker proapoptotic BH3 only proteins that act as sensitizers by neutralization of antiapoptotic Bcl-2 family members. Noxa was originally characterized as a weaker proapoptotic, 'sensitizer' BH3-only protein, although recent evidence suggests it too may be potently proapoptotic. Expression of Noxa is under p53 control, a known seizure activated pathway, although Noxa has been linked to energetic stress and autophagy. Here we characterized the response of Noxa to prolonged seizures and the phenotype of mice lacking Noxa. Status epilepticus induced by intra-amygdala kainic acid caused a rapid increase in expression of noxa in the damaged CA3 subfield of the hippocampus but not undamaged CA1 region. In vivo upregulation of noxa was reduced by pifithrin-alpha, suggesting transcription may be partly p53 dependent. Mice lacking noxa developed less severe electrographic seizures during status epilepticus in the model but, surprisingly, displayed equivalent hippocampal damage to wild-type animals. The present findings indicate Noxa does not serve as a proapoptotic BH3-only protein during seizure-induced neuronal death in vivo. This study extends the comprehensive phenotyping of seizure and damage responses in mice lacking specific Bcl-2 gene family members and provides further evidence that these proteins may serve roles beyond control of cell death in the brain. PMID- 28079890 TI - Structural insight into an evolutionarily ancient programmed cell death regulator - the crystal structure of marine sponge BHP2 bound to LB-Bak-2. AB - Sponges of the porifera family harbor some of the evolutionary most ancient orthologs of the B-cell lymphoma-2 (Bcl-2) family, a protein family critical to regulation of apoptosis. The genome of the sponge Geodia cydonium contains the putative pro-survival Bcl-2 homolog BHP2, which protects sponge tissue as well as mammalian Hek-293 and NIH-3T3 cells against diverse apoptotic stimuli. The Lake Baikal demosponge Lubomirskia baicalensis has been shown to encode both putative pro-survival Bcl-2 (LB-Bcl-2) and pro-apoptotic Bcl-2 members (LB-Bak-2), which have been implied in axis formation (branches) in L. baicalensis. However, the molecular mechanism of action of sponge-encoded orthologs of Bcl-2 remains to be clarified. Here, we report that the pro-survival Bcl-2 ortholog BHP2 from G. cydonium is able to bind the BH3 motif of a pro-apoptotic Bcl-2 protein, LB-Bak-2 of the sponge L. baicalensis. Furthermore, we determined the crystal structure of BHP2 bound to LB-Bak-2, which revealed that using a binding groove conserved across all pro-survival Bcl-2 proteins, BHP2 binds multi-motif Bax-like proteins through their BH3-binding regions. However, BHP2 discriminates against BH3-only bearing proteins by blocking access to a hydrophobic pocket that is critical for BH3 motif binding in pro-survival Bcl-2 proteins from higher organisms. This differential binding mode is reflected in a structure-based phylogenetic comparison of BHP2 with other Bcl-2 family members, which revealed that BHP2 does not cluster with either Bcl-2 members of higher organisms or pathogen-encoded homologs, and assumes a discrete position. Our findings suggest that the molecular machinery and mechanisms for executing Bcl-2-mediated apoptosis as observed in mammals are evolutionary ancient, with early regulation of apoptotic machineries closely resembling their modern counterparts in mammals rather than Caenorhabditis elegans or drosophila. PMID- 28079891 TI - CRB3 regulates contact inhibition by activating the Hippo pathway in mammary epithelial cells. AB - The loss of contact inhibition is a hallmark of cancer cells. The Hippo pathway has recently been shown to be an important regulator of contact inhibition, and the cell apical polarity determinant protein CRB3 has been suggested to be involved in Hippo signalling. However, whether CRB3 regulates contact inhibition in mammary cells remains unclear, and the underlying mechanisms have not been elucidated. As shown in the present study, CRB3 decreases cell proliferation, promotes apoptosis, and enhances the formation of tight and adherens junctions. Furthermore, we report for the first time that CRB3 acts as an upstream regulator of the Hippo pathway to regulate contact inhibition by recruiting other Hippo molecules, such as Kibra and/or FRMD6, in mammary epithelial cells. In addition, CRB3 inhibits tumour growth in vivo. Collectively, the present study increases our understanding of the Hippo pathway and provides an important theoretical basis for exploring new avenues for breast cancer treatment. PMID- 28079892 TI - HIF-2alpha and Oct4 have synergistic effects on survival and myocardial repair of very small embryonic-like mesenchymal stem cells in infarcted hearts. AB - Poor cell survival and limited functional benefits have restricted mesenchymal stem cell (MSC) efficacy for treating myocardial infarction (MI), suggesting that a better understanding of stem cell biology is needed. The transcription factor HIF-2alpha is an essential regulator of the transcriptional response to hypoxia, which can interact with embryonic stem cells (ESCs) transcription factor Oct4 and modulate its signaling. Here, we obtained very small embryonic-like mesenchymal stem cells (vselMSCs) from MI patients, which possessed the very small embryonic like stem cells' (VSELs) morphology as well as ESCs' pluripotency. Using microarray analysis, we compared HIF-2alpha-regulated gene profiles in vselMSCs with ESC profiles and determined that HIF-2alpha coexpressed Oct4 in vselMSCs similarly to ESCs. However, this coexpression was absent in unpurified MSCs (uMSCs). Under hypoxic condition, vselMSCs exhibited stronger survival, proliferation and differentiation than uMSCs. Transplantation of vselMSCs caused greater improvement in cardiac function and heart remodeling in the infarcted rats. We further demonstrated that HIF-2alpha and Oct4 jointly regulate their relative downstream gene expressions, including Bcl2 and Survivin; the important pluripotent markers Nanog, Klf4, and Sox2; and Ang-1, bFGF, and VEGF, promoting angiogenesis and engraftment. Importantly, these effects were generally magnified by upregulation of HIF-2alpha and Oct4 induced by HIF-2alpha or Oct4 overexpression, and the greatest improvements were elicited after co overexpressing HIF-2alpha and Oct4; overexpressing one transcription factor while silencing the other canceled this increase, and HIF-2alpha or Oct4 silencing abolished these effects. Together, these findings demonstrated that HIF-2alpha in vselMSCs cooperated with Oct4 in survival and function. The identification of the cooperation between HIF-2alpha and Oct4 will lead to deeper characterization of the downstream targets of this interaction in vselMSCs and will have novel pathophysiological implications for the repair of infarcted myocardium. PMID- 28079893 TI - Mitochondrial respiratory dysfunction disturbs neuronal and cardiac lineage commitment of human iPSCs. AB - Mitochondrial diseases are genetically heterogeneous and present a broad clinical spectrum among patients; in most cases, genetic determinants of mitochondrial diseases are heteroplasmic mitochondrial DNA (mtDNA) mutations. However, it is uncertain whether and how heteroplasmic mtDNA mutations affect particular cellular fate-determination processes, which are closely associated with the cell type-specific pathophysiology of mitochondrial diseases. In this study, we established two isogenic induced pluripotent stem cell (iPSC) lines each carrying different proportions of a heteroplasmic m.3243A>G mutation from the same patient; one exhibited apparently normal and the other showed most likely impaired mitochondrial respiratory function. Low proportions of m.3243A>G exhibited no apparent molecular pathogenic influence on directed differentiation into neurons and cardiomyocytes, whereas high proportions of m.3243A>G showed both induced neuronal cell death and inhibited cardiac lineage commitment. Such neuronal and cardiac maturation defects were also confirmed using another patient derived iPSC line carrying quite high proportion of m.3243A>G. In conclusion, mitochondrial respiratory dysfunction strongly inhibits maturation and survival of iPSC-derived neurons and cardiomyocytes; our presenting data also suggest that appropriate mitochondrial maturation actually contributes to cellular fate determination processes during development. PMID- 28079894 TI - MiR-26 enhances chemosensitivity and promotes apoptosis of hepatocellular carcinoma cells through inhibiting autophagy. AB - Hepatocellular carcinoma (HCC) generally possesses a high resistance to chemotherapy. Given that autophagy is an important factor promoting tumor chemoresistance and HCC express low level of miR-26, we aim to investigate the functional role of miR-26 in autophagy-mediated chemoresistance of HCC. We found that chemotherapeutic drug doxorubicin (Dox) induced autophagy but decreased the level of miR-26a/b in HCC cells. Activating autophagy using rapamycin can directly downregulate the level of miR-26a/b in HCC cells. In turn, restoring the expression of miR-26a/b inhibited autophagy induced by Dox and promoted apoptosis in HCC cells. Further mechanistic study identified that miR-26a and miR-26b target ULK1, a critical initiator of autophagy, at post-transcriptional level. Results from 30 cases of patients with HCC also showed that tumor cellular levels of miR-26a and miR-26b are significantly downregulated as compared with the corresponding control tissues and negatively correlated with the protein level of ULK1 but are not correlated to the mRNA level of ULK1. Gain- and loss-of-function assay confirmed that miR-26a/b inhibited autophagic flux at the initial stage through targeting ULK1. Overexpression of miR-26a/b enhanced the sensitivity of HCC cells to Dox and promoted apoptosis via inhibiting autophagy in vitro. Using xenograft models in nude mice, we confirmed that miR-26a/b, via inhibiting autophagy, promoted apoptosis and sensitized hepatomas to Dox treatment in vivo. Our findings demonstrate for the first time that miR-26a/b can promote apoptosis and sensitize HCC to chemotherapy via suppressing the expression of autophagy initiator ULK1, and provide the reduction of miR-26a/b in HCC as a novel mechanism of tumor chemoresistance. PMID- 28079895 TI - TNF-induced chronic inflammation does not affect tumorigenesis driven by p53 loss. PMID- 28079896 TI - Impaired embryonic development in glucose-6-phosphate dehydrogenase-deficient Caenorhabditis elegans due to abnormal redox homeostasis induced activation of calcium-independent phospholipase and alteration of glycerophospholipid metabolism. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a commonly pervasive inherited disease in many parts of the world. The complete lack of G6PD activity in a mouse model causes embryonic lethality. The G6PD-deficient Caenorhabditis elegans model also shows embryonic death as indicated by a severe hatching defect. Although increased oxidative stress has been implicated in both cases as the underlying cause, the exact mechanism has not been clearly delineated. In this study with C. elegans, membrane-associated defects, including enhanced permeability, defective polarity and cytokinesis, were found in G6PD-deficient embryos. The membrane-associated abnormalities were accompanied by impaired eggshell structure as evidenced by a transmission electron microscopic study. Such loss of membrane structural integrity was associated with abnormal lipid composition as lipidomic analysis revealed that lysoglycerophospholipids were significantly increased in G6PD-deficient embryos. Abnormal glycerophospholipid metabolism leading to defective embryonic development could be attributed to the increased activity of calcium-independent phospholipase A2 (iPLA) in G6PD deficient embryos. This notion is further supported by the fact that the suppression of multiple iPLAs by genetic manipulation partially rescued the embryonic defects in G6PD-deficient embryos. In addition, G6PD deficiency induced disruption of redox balance as manifested by diminished NADPH and elevated lipid peroxidation in embryos. Taken together, disrupted lipid metabolism due to abnormal redox homeostasis is a major factor contributing to abnormal embryonic development in G6PD-deficient C. elegans. PMID- 28079898 TI - The current state of implementation science in genomic medicine: opportunities for improvement. AB - PURPOSE: The objective of this study was to identify trends and gaps in the field of implementation science in genomic medicine. METHODS: We conducted a literature review using the Centers for Disease Control and Prevention's Public Health Genomics Knowledge Base to examine the current literature in the field of implementation science in genomic medicine. We selected original research articles based on specific inclusion criteria and then abstracted information about study design, genomic medicine, and implementation outcomes. Data were aggregated, and trends and gaps in the literature were discussed. RESULTS: Our final review encompassed 283 articles published in 2014, the majority of which described uptake (35.7%, n = 101) and preferences (36.4%, n = 103) regarding genomic technologies, particularly oncology (35%, n = 99). Key study design elements, such as racial/ethnic composition of study populations, were underreported in studies. Few studies incorporated implementation science theoretical frameworks, sustainability measures, or capacity building. CONCLUSION: Although genomic discovery provides the potential for population health benefit, the current knowledge base around implementation to turn this promise into a reality is severely limited. Current gaps in the literature demonstrate a need to apply implementation science principles to genomic medicine in order to deliver on the promise of precision medicine.Genet Med advance online publication 12 January 2017. PMID- 28079897 TI - Tsc1 expression by dendritic cells is required to preserve T-cell homeostasis and response. AB - Dendritic cells (DCs) are pivotal to the induction of adaptive T-cell immune responses. Recent evidence highlights a critical role of tuberous sclerosis complex 1 (Tsc1), a primarily upstream negative regulator of mammalian target of rapamycin (mTOR), in DC development, but whether and how Tsc1 directly regulate mature DC function in vivo remains elusive. Here we show that selective disruption of Tsc1 in DCs results in a lymphoproliferative disorder with the spontaneous activation of T cells. Tsc1 deficiency results in the activation of mTORC1-PPARgamma pathway, which leads to the upregulation of neuropilin-1 (Nrp1) expression on DCs to stimulate naive T-cell proliferation. However, Tsc1 deficient DCs have defects in the ability to induce antigen-specific T-cell responses in vitro and in vivo owing to impaired survival during antigen transportation and presentation. Indeed, Tsc1 promotes DC survival through restraining independent mTORC1 and ROS-Bim pathways. Our study identifies Tsc1 as a crucial signaling checkpoint in DCs essential for preserving T-cell homeostasis and response. PMID- 28079899 TI - Genome sequencing and carrier testing: decisions on categorization and whether to disclose results of carrier testing. AB - PURPOSE: We investigated the use of genome sequencing for preconception carrier testing. Genome sequencing could identify one or more of thousands of X-linked or autosomal recessive conditions that could be disclosed during preconception or prenatal counseling. Therefore, a framework that helps both clinicians and patients understand the possible range of findings is needed to respect patient preferences by ensuring that information about only the desired types of genetic conditions are provided to a given patient. METHODS: We categorized gene condition pairs into groups using a previously developed taxonomy of genetic conditions. Patients could elect to receive results from these categories. A Return of Results Committee (RORC) developed inclusion and exclusion criteria for each category. RESULTS: To date, the RORC has categorized 728 gene-condition pairs: 177 are categorized as life span-limiting, 406 are categorized as serious, 93 are categorized as mild, 41 are categorized as unpredictable, and 11 are categorized as adult-onset. An additional 64 gene-condition pairs were excluded from reporting to patients or put on a watch list, generally because evidence that a gene and condition were associated was limited. CONCLUSION: Categorization of gene-condition pairs using our taxonomy simplifies communication regarding patient preferences for carrier information from a genomic test.Genet Med advance online publication 12 January 2017. PMID- 28079900 TI - A curated gene list for reporting results of newborn genomic sequencing. AB - PURPOSE: Genomic sequencing (GS) for newborns may enable detection of conditions for which early knowledge can improve health outcomes. One of the major challenges hindering its broader application is the time it takes to assess the clinical relevance of detected variants and the genes they impact so that disease risk is reported appropriately. METHODS: To facilitate rapid interpretation of GS results in newborns, we curated a catalog of genes with putative pediatric relevance for their validity based on the ClinGen clinical validity classification framework criteria, age of onset, penetrance, and mode of inheritance through systematic evaluation of published evidence. Based on these attributes, we classified genes to guide the return of results in the BabySeq Project, a randomized, controlled trial exploring the use of newborn GS (nGS), and used our curated list for the first 15 newborns sequenced in this project. RESULTS: Here, we present our curated list for 1,514 gene-disease associations. Overall, 954 genes met our criteria for return in nGS. This reference list eliminated manual assessment for 41% of rare variants identified in 15 newborns. CONCLUSION: Our list provides a resource that can assist in guiding the interpretive scope of clinical GS for newborns and potentially other populations.Genet Med advance online publication 12 January 2017. PMID- 28079901 TI - The clinical utility of DNA-based screening for fetal aneuploidy by primary obstetrical care providers in the general pregnancy population. AB - OBJECTIVE: To assess the clinical utility of cell-free DNA (cfDNA)-based screening for aneuploidies offered through primary obstetrical care providers to a general pregnancy population. METHODS: Patient educational materials were developed and validated and providers were trained. Serum was collected for reflexive testing of cfDNA failures. Providers and patients were surveyed concerning knowledge, decision making, and satisfaction. Pregnancy outcome was determined by active or passive ascertainment. RESULTS: Between September 2014 and July 2015, 72 providers screened 2,691 women. The five largest participating practices increased uptake by 8 to 40%. Among 2,681 reports, 16 women (0.6%) were screen-positive for trisomy 21, 18, or 13; all saw genetic professionals. Twelve were confirmed (positive predictive value (PPV), 75%; 95% CI, 48-93%) and four were false-positives (0.15%). Of 150 failures (5.6%), 79% had a negative serum or subsequent cfDNA test; no aneuploidies were identified. Of 100 women surveyed, 99 understood that testing was optional, 96 had their questions answered, and 95 received sufficient information. Pretest information was provided by the physician/certified nurse midwife (55) or office nurse/educator (40); none was provided by genetic professionals. CONCLUSION: This first clinical utility study of cfDNA screening found higher uptake rates, patient understanding of basic concepts, and easy incorporation into routine obstetrical practices. There were no reported cases of aneuploidy among cfDNA test failures.Genet Med advance online publication 12 January 2017. PMID- 28079902 TI - PhenX measures for phenotyping rare genetic conditions. AB - INTRODUCTION: The PhenX Toolkit, an online resource of well-established measures of phenotypes and exposures, now has 16 new measures recommended for assessing rare genetic conditions. MATERIALS AND METHODS: These measures and their protocols were selected by a working group of domain experts with input from the scientific community. RESULTS: The measures, which cover life stages from birth through adulthood, include clinical scales, characterization of rare genetic conditions, bioassays, and questionnaires. Most are broadly applicable to rare genetic conditions (e.g., family history, growth charts, bone age, and body proportions). Some protocols (e.g., sweat chloride test) target specific conditions. DISCUSSION: The rare genetic condition measures complement the existing measures in the PhenX Toolkit that cover anthropometrics, demographics, mental health, and reproductive history. They are directed at research pertaining to common and complex diseases. PhenX measures are publicly available and are recommended to help standardize assessments across a range of biomedical study designs. To facilitate incorporation of measures into human subjects' research, the Toolkit offers data collection worksheets and compatible data dictionaries. CONCLUSION: Widespread use of standard PhenX measures in clinical, translational, and epidemiological research will enable more uniform cross-study comparisons and increase statistical power with the potential for enhancing scientific discovery.Genet Med advance online publication 12 January 2017. PMID- 28079903 TI - Introduction-Standing on each other's shoulders. PMID- 28079906 TI - 4d and 5d bimetal doped tubular silicon clusters Si12M2 with M = Nb, Ta, Mo and W: a bimetallic configuration model. AB - Geometries and electronic properties related to the ground state stabilities of several Si12M2 clusters (M: second-row (Nb and Mo) and third-row (Ta and W) transition metals, and their mixed bimetallic clusters M2: NbMo and TaW) were explored using density functional theory (DFT) computations. The computed results show that two different structural motifs emerge as the global energy minima of such clusters. They are basically singlet tubular structures in either a C2v prism (1A1) or a C6v antiprism (1A1) form. Other structural shapes are also possible for higher-energy isomers and in higher spin states. 58-valence electron systems including Nb2Si12, Ta2Si12, Mo2Si122+, W2Si122+, NbMoSi12+ and TaWSi12+ are thermodynamically stable as C2v prism global minima on the corresponding potential energy surfaces. Clusters containing 60 valence electrons include Mo2Si12, W2Si12, Nb2Si122-, Ta2Si122-, NbMoSi12- and TaWSi12- and they prefer a C6v anti-prism form. In the mixed MoNbSi12 and TaWSi12 open-shell systems, both resulting C2 (2A) and C2v (2A1) forms are nearly degenerate. The formation of Si12M2 clusters in such specific ground state symmetry is explained using the Jellium model and orbital interaction analyses. The investigations lead further to a proposal for a simple model of a bimetallic configuration using the nature of interactions of the transition metal d-d dimeric bond with the Si12 host, to interpret the formation of such M2Si12 clusters. PMID- 28079905 TI - DEVELOPMENT OF DISRUPTIVE BEHAVIORS IN YOUNG CHILDREN: A PROSPECTIVE POPULATION BASED COHORT STUDY. AB - We know relatively little about the development of disruptive behaviors (DBs), and gender differences therein. The objective of this study was to describe the continuity and discontinuity in the degree to which young children in the general population are reported to exhibit specific DBs over time. Data came from the Quebec Longitudinal Study of Child Development. First, the results show that relatively few children exhibit DBs on a frequent basis at 41 months of age. Second, the results show that a majority of children who exhibit a particular DB on a frequent basis at 41 months of age did not do so 1 year earlier. In addition, a majority of children who exhibited a particular DB on a frequent basis at 29 months of age no longer do so 1 year later. Third, gender differences in DBs (boys > girls) are either emerging or at least increasing in magnitude between 29 and 41 months of age. Consistent with the canalization of the behavioral development principle, children who exhibited DBs on a frequent basis at 29 months of age are less likely to stop doing so in the following year if they had exhibited the same behaviors at 17 months of age. PMID- 28079907 TI - Retention of fungal enzyme activity in environmental liquid and filter samples. AB - Fungal biomass can be determined by measuring the beta-N-acetylhexos-aminidase (NAHA) enzyme activity. NAHA, an enzyme present in fungal mycelium and spores, has been detected in inactive, dormant and non-viable cells. Very little information is available on the enzyme activity of different species or retention of the activity under various storage conditions. This study used fluorometry to evaluate the enzyme activity of liquid and filter samples containing spores of four fungal species from genera Penicillium, Cladosporium, Aspergillus, and Acremonium. When fungal spores were stored on a filter, enzyme activity was more stable than when the spores were maintained in suspension for one year. The enzyme activity in suspension samples increased with most of the differences detected between the values at the baseline and 12 months being statistically significant. The results indicate that enzyme activity varies between species. Cladosporium spores had highest NAHA content per spore, whereas Acremonium did not exhibit any detectable enzyme activity even when viability was detected. The results indicated that samples should be stored as dry filter samples. PMID- 28079908 TI - Hot off the press. AB - A personal selection of 32 recent papers is presented covering various aspects of current developments in bioorganic chemistry and novel natural products such as hitorin A from Chloranthus japonicus. PMID- 28079909 TI - The Clinical Utility of Intravenous Immunoglobulin and When to Involve Our Consultants. PMID- 28079910 TI - Human Papillomavirus and the HPV Vaccine: Where Are We Today? AB - Vaccine discussions are an important part of the general pediatrician's day. The human papillomavirus (HPV) vaccine, in particular, has been slow to gain acceptance by the general public. It has recently gained momentum (both positive and negative) on social media, which has led to an increase in questions and concerns from families. It is important that providers are equipped to address these concerns, answer questions, and provide quality information for families to help guide them in their vaccination decisions. Not only is it crucial to be knowledgeable about the vaccines themselves, but providers should also be informed about HPV and its potential disease burden. The HPV vaccine recommendations are also evolving, so it is important to stay abreast with current data to provide the best care for all patients. [Pediatr Ann. 2017;46(1):e2-e5.]. PMID- 28079911 TI - Intravenous Immunoglobulin and Its Clinical Applications. PMID- 28079912 TI - Intravenous Immunoglobulin in the Treatment of Primary Immunodeficiency Diseases. AB - Intravenous immunoglobulin (IVIG) has been used as antibody replacement therapy in primary immunodeficiency diseases (PIDDs) for more than 50 years. Its role as a therapeutic agent has expanded over the past couple of decades as its anti inflammatory and immune-modulatory mechanisms of action have been elucidated. It is now used "off-label" to treat other autoimmune diseases. This article focuses on the role of IVIG in the treatment of PIDDs characterized by absent or deficient antibody production. Replacement doses are given on a monthly basis in these conditions as a prophylactic measure to prevent acute and serious bacterial infections. [Pediatr Ann. 2017;46(1):e8-e12.]. PMID- 28079913 TI - Intravenous Immunoglobulin in the Treatment of Hematologic Disorders in Pediatrics. AB - Intravenous immunoglobulin (IVIG) is pooled immunoglobulin G derived from human blood donors. It was introduced in the early 1980s to treat immunodeficiency disorders. Since then, its use has expanded to other fields such as neurology, rheumatology, and hematology. IVIG has been used to provide passive immunity in qualitative and quantitative immunoglobulin disorders, to neutralize antibodies in immune-mediated diseases, and as an immune modulatory agent. The difficulty of producing IVIG in high quantities, in addition to a growing list of "off-label" indications, has resulted in a worldwide shortage and increase in cost. From a pediatric hematology perspective, IVIG is considered an appropriate therapeutic option in autoimmune cytopenias, sometimes coadministrated with steroids. Its use in other hematologic disorders is questionable, and there is not sufficient evidence to recommend it. This article provides clear information to the general pediatrician about indications for IVIG therapy in children with hematologic disorders. [Pediatr Ann. 2017;46(1):e13-e18.]. PMID- 28079914 TI - Intravenous Immunoglobulin in Pediatric Rheumatology: When to Use It and What Is the Evidence. AB - Intravenous immunoglobulin (IVIG) is given to children with a variety of rheumatologic illnesses. The mechanism of action by which it exerts therapeutic effects is not well understood and likely differs in the medical conditions for which it is given. IVIG is approved by the US Food and Drug Administration and is the standard of care for Kawasaki disease, but most IVIG use in pediatric rheumatology is "off-label. " The literature supports the use of IVIG for juvenile dermatomyositis, although it is unclear whether its use should be limited to those children with more severe or refractory disease. It appears efficacious in the treatment of autoimmune thrombocytopenia secondary to lupus, but its use may be limited by transient responses. Treatment of other categories of pediatric rheumatologic diseases, such as juvenile idiopathic arthritis and non-Kawasaki vasculitides, is not well-established in the literature. This review focuses on current use of IVIG in the treatment of pediatric rheumatologic disorders. [Pediatr Ann. 2017;46(1):e19-e24.]. PMID- 28079915 TI - Intravenous Immunoglobulin for the Treatment of Kawasaki Disease. AB - Standard first-line therapy for Kawasaki disease (KD) consists of intravenous immunoglobulin (IVIG) and aspirin. Current guidelines recommend 2 g/kg of IVIG and 80 to 100 mg/kg of aspirin administered within the first 10 days of illness. This regimen has marked efficacy in preventing the development of coronary artery aneurysms. Approximately 15% to 20% of treated patients require a second dose of IVIG to control the inflammatory process. The role of adjunctive corticosteroid therapy with IVIG and aspirin is evolving, with Japanese studies showing a clear benefit in those patients at highest risk for development of coronary disease. The challenge in North America has been reliable identification of the highest risk patients, which still eludes us because the Japanese scoring systems are ineffective in multiethnic populations. Despite its efficacy, the precise mechanism of IVIG's effect in KD is unclear but probably relates to its ability to down-regulate aspects of the up-regulated inflammatory response in patients with KD. [Pediatr Ann. 2017;46(1):e25-e28.]. PMID- 28079916 TI - Adolescent Shin Pain. AB - Shin pain is a common complaint in adolescent athletes. The term "shin splints" has historically been applied to these patients. Shin splints, more often than not, refers to a stress reaction of the tibia from overuse. Overuse injuries occur when repetitive microtrauma to the bone exceeds the biologic healing potential. Diagnosis is based on typical history and physical examination findings. Plain radiographs and advanced imaging are rarely necessary but can provide valuable prognostic information. Treatment consists of adequate rest and exercise modification. Time to return to sport depends on injury location and severity. Stress fractures have long-term implications on bone health, so modifiable risk factors should be addressed. It is important for primary care physicians to understand the significance of these injuries. [Pediatr Ann. 2017;46(1):e29-e32.]. PMID- 28079917 TI - Did you know Medicare does not usually include a dental benefit? Findings from a multisite investigation of oral health literacy. AB - OBJECTIVES: Medicare does not usually include a dental benefit. Adults who are unaware of this fact risk unanticipated expenses after retirement. This report will explore the sociodemographic and oral health literacy determinants of this knowledge. METHODS: Data came from the Multi-Site Oral Health Literacy Research Study, a survey of patients presenting to two university dental clinics. Sociodemographic descriptors included age, sex, race/ethnicity, education level, and dental insurance status. Oral health literacy was measured by the Rapid Estimate of Adult Literacy in Medicine and Dentistry (REALM-D). RESULTS: Only 34 percent of respondents knew the correct answer to the Medicare question. Knowledge was significantly associated with age, race/ethnicity, education level (bivariate only), and REALM-D score. CONCLUSIONS: Policymakers and those assisting in Medicare enrollment should ensure information regarding dental coverage is communicated in ways that individuals of varying literacy, language, and culture understand what is necessary to make appropriate decisions. PMID- 28079920 TI - Serum microRNA profiles in patients with syphilis. PMID- 28079919 TI - Copper oxide nanoparticles and copper sulphate act as antigenotoxic agents in drosophila melanogaster. AB - The biological reactivity of metal and metal oxide nanomaterials is attributed to their redox properties, which would explain their pro- or anti-cancer properties depending on exposure circumstances. In this sense, copper oxide nanoparticles (CuONP) have been proposed as a potential anti-tumoral agent. The aim of this study was to assess if CuONP can exert antigenotoxic effects using Drosophila melanogaster as an in vivo model. Genotoxicity was induced by two well-known genotoxic compounds, namely potassium dichromate (PD) and ethyl methanesulfonate (EMS). The wing-spot assay and the comet assay were used as biomarkers of genotoxic effects. In addition, changes in the expression of Ogg1 and Sod genes were determined. The effects of CuONP cotreatment were compared with those induced by copper sulfate (CS), an agent releasing copper ions. Using the wing spot assay, CuONP and CS were not able to reduce the genotoxic effects of EMS exposure, but had the ability to decrease the effects induced by PD, reducing the frequency of mutant twin-spots that arise from mitotic recombination. In addition, CuONP and CS were able to reduce the DNA damage induced by PD as determined by the comet assay. In general, similar qualitative antigenotoxic effects were obtained with both copper compounds. The antigenotoxic effects of environmentally relevant and non-toxic doses of CuONP and CS may be explained by their ability to partially restore the expression levels of the repair gene Ogg1 and the antioxidant gene Cu,ZnSod, both of which are inhibited by PD treatment. Environ. Mol. Mutagen. 58:46-55, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28079918 TI - Dose evaluation of lamivudine in human immunodeficiency virus-infected children aged 5 months to 18 years based on a population pharmacokinetic analysis. AB - AIM: The objectives of this study were to characterize age-related changes in lamivudine pharmacokinetics in children and evaluate lamivudine exposure, followed by dose recommendations for subgroups in which target steady state area under the daily plasma concentration-time curve (AUC0-24h ) is not reached. METHODS: Population pharmacokinetic modelling was performed in NONMEM using data from two model-building datasets and two external datasets [n = 180 (age 0.4-18 years, body weight 3.4-60.5 kg); 2061 samples (median 12 per child); daily oral dose 60-300 mg (3.9-17.6 mg kg-1 )]. Steady state AUC0-24h was calculated per individual (adult target 8.9 mg.h l-1 ). RESULTS: A two-compartment model with sequential zero order and first order absorption best described the data. Apparent clearance and central volume of distribution (% RSE) were 13.2 l h-1 (4.2%) and 38.9 l (7.0%) for a median individual of 16.6 kg, respectively. Bodyweight was identified as covariate on apparent clearance and volume of distribution using power functions (exponents 0.506 (20.2%) and 0.489 (32.3%), respectively). The external evaluation supported the predictive ability of the final model. In 94.5% and 35.8% of the children with a body weight >14 kg and <14 kg, respectively, the target AUC0-24h was reached. CONCLUSION: Bodyweight best predicted the developmental changes in apparent lamivudine clearance and volume of distribution. For children aged 5 months-18 years with a body weight <14 kg, the dose should be increased from 8 to 10 mg kg-1 day-1 if the adult target for AUC0-24h is aimed for. In order to identify whether bodyweight influences bioavailability, clearance and/or volume of distribution, future analysis including data on intravenously administered lamivudine is needed. PMID- 28079921 TI - Four cases of exogenous acral pigmentation related to a darkling beetle (coleoptera: tenebrionidae: blaps). PMID- 28079922 TI - IgA tracheobronchial deposits underlie respiratory compromise in neonatal linear IgA bullous dermatosis. PMID- 28079923 TI - Vibrational circular dichroism of a 2,5-diketopiperazine (DKP) peptide: Evidence for dimer formation in cyclo LL or LD diphenylalanine in the solid state. AB - The diastereomer diketopiperazine (DKP) peptides built on phenylalanine, namely, cyclo diphenylalanine LPhe-LPhe and LPhe-DPhe, were studied in the solid phase by vibrational circular dichroism (VCD) coupled to quantum chemical calculations. The unit structure of cyclo LPhe-LPhe in KBr pellets is a dimer bridged by two strong NH...O hydrogen bonds. The intense bisignate signature in the CO stretch region is interpreted in terms of two contributions arising from the free COs of the dimer and the antisymmetrical combination of the bound COs. In contrast, cyclo LPhe-DPhe shows no VCD signal in relation to its symmetric nature. PMID- 28079924 TI - Optimized microwave-assistant extraction combined ultrasonic pretreatment of flavonoids from Periploca forrestii Schltr. and evaluation of its anti-allergic activity. AB - Microwave extraction combined ultrasonic pretreatment of flavonoids from Periploca forrestii Schltr. was investigated in this study, extraction process was first performed in an ultrasonic cleaner, then treated by microwave irradiation. The optimum ultrasonic time of 25 min was selected by single-factor experiments. A response surface methodology has been used to obtain a mathematical model that describes the process and analyzes the significant parameters ethanol concentration 59.92%, liquid to raw materials ratio 21.24 mL/g, microwave radiation time 209.53 s, and microwave power 274.14 w. In these optimum conditions, the yield of flavonoids from P. forrestii (TFPF) could be up to 9.11 +/- 0.08%, which was increased by 14.30 and 19.86% compared microwave extraction and ultrasonic extraction, respectively. In vitro suppress hyaluronidase experimentation showed that TFPF purified using polyamide exhibited good anti-hyaluronidase ability with IC50 value of 1.033 mg/mL, possessing certain anti-antiallergic and potential application prospect in pharmaceutical production of treating inflammation and other related fields. PMID- 28079925 TI - Pregnancy outcome after rituximab treatment before conception in patients affected by severe pemphigus vulgaris/superficialis. PMID- 28079926 TI - Fallen stock data: An essential source of information for quantitative knowledge of equine mortality in France. AB - BACKGROUND: Quantitative information about equine mortality is relatively scarce, yet it could be of great value for epidemiological purposes. In France, data from rendering plants are centralised in the Fallen Stock Data Interchange database (FSDI), managed by the French Ministry of Agriculture, while individual equine data are centralised in the French equine census database, SIRE, managed by the French horse and riding institute (IFCE). OBJECTIVES: To evaluate whether the combined use of the FSDI and SIRE databases can provide representative and accurate quantitative information on mortality for the French equine population and to propose enhancements of these databases to improve the quality of the resulting demographic information. STUDY DESIGN: Descriptive study. METHODS: Mortality ratios for the French equine population were calculated per year between 2011 and 2014 and temporal variations in equine mortality modelled during the same period. Survival analyses were performed on a sample of equines traceable in both the FSDI and SIRE databases. RESULTS: Estimates of the annual mortality ratios varied from 3.02 to 3.40% depending on the years. Survival rates of equines 2-years-old and over differed according to breed categories with the highest median age at death for the ponies. The weekly description of mortality highlighted marked seasonality of deaths whatever the category of equines. Modelling temporal variations in equine mortality also brought to light excess mortality. MAIN LIMITATIONS: Insufficient traceability of equines between the two databases. CONCLUSION: The FSDI database provided an initial approach to equine death ratios on a national scale and an original description of temporal variations in mortality. Improvement in the traceability of equines between the FSDI and SIRE databases is needed to enable their combined use, providing a representative description of equine longevity and a more detailed description of temporal variations in mortality. PMID- 28079928 TI - Relation of serum and vitreous nesfatin-1 concentrations with diabetic retinopathy. AB - OBJECTIVE: Nesfatin-1, belonging to adipokine family, serves as an anti inflammatory mediator. We performed this investigation to evaluate the relation between serum and vitreous nesfatin-1 concentrations with diabetic retinopathy (DR). METHODS: This study was performed in a population of 189 diabetic patients and 48 control subjects. Diabetic patients were then divided into diabetic patients without DR, non-proliferative diabetic retinopathy (NPDR) patients, and proliferative diabetic retinopathy (PDR) patients. RESULTS: Serum and vitreous nesfatin-1 concentrations were significantly lower in the diabetic patients than in the controls. NPDR patients had reduced vitreous nesfatin-1 concentrations compared with patients without DR. In addition, there were significantly lower serum and vitreous nesfatin-1 concentrations in PDR patients compared with the other three groups. Pearson correlation analysis showed that serum nesfatin-1 was negatively correlated with body mass index and fasting plasma glucose in diabetic patients. CONCLUSION: Serum and vitreous nesfatin-1 concentrations were negatively correlated with DR. PMID- 28079927 TI - Developmental programming: Interaction between prenatal BPA and postnatal overfeeding on cardiac tissue gene expression in female sheep. AB - Epidemiologic studies and studies in rodents point to potential risks from developmental exposure to BPA on cardiometabolic diseases. Furthermore, it is becoming increasingly evident that the manifestation and severity of adverse outcomes is the result of interaction between developmental insults and the prevailing environment. Consistent with this premise, recent studies in sheep found prenatal BPA treatment prevented the adverse effects of postnatal obesity in inducing hypertension. The gene networks underlying these complex interactions are not known. mRNA-seq of myocardium was performed on four groups of four female sheep to assess the effects of prenatal BPA exposure, postnatal overfeeding and their interaction on gene transcription, pathway perturbations and functional effects. The effects of prenatal exposure to BPA, postnatal overfeeding, and prenatal BPA with postnatal overfeeding all resulted in transcriptional changes (85-141 significant differentially expressed genes). Although the effects of prenatal BPA and postnatal overfeeding did not involve dysregulation of many of the same genes, they affected a remarkably similar set of biological pathways. Furthermore, an additive or synergistic effect was not found in the combined treatment group, but rather prenatal BPA treatment led to a partial reversal of the effects of overfeeding alone. Many genes previously known to be affected by BPA and involved in obesity, hypertension, or heart disease were altered following these treatments, and AP-1, EGR1, and EGFR were key hubs affected by BPA and/or overfeeding. Environ. Mol. Mutagen. 58:4-18, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28079930 TI - Expression of Concern. PMID- 28079929 TI - The impact of age on psoriasis health care in Germany. AB - INTRODUCTION: Inequality between age groups has been demonstrated in the prescription of biologics, yet systematic real-world data about age-related differences in psoriasis care are missing. OBJECTIVE: To investigate disparities in psoriasis characteristics by age groups and to identify potential impact on psoriasis health care. PATIENTS AND METHODS: Data analysis included 3615 patients from the German psoriasis registry PsoBest, which observes adult patients with moderate-to-severe psoriasis or psoriatic arthritis (PsA) on systemic treatment over a time period of 10 years. RESULTS: With 2376 participants (65.7%), the majority of patients was assigned to the age group 35-64, followed by 776 (21.4%) and 463 (12.8%) for the age groups 18-34 and 65+, respectively. Psoriasis vulgaris was the most frequent form of psoriasis with nearly 90% patients affected. Appearance of psoriasis forms did not differentiate significantly between the age groups except for erythrodermic psoriasis, which was more frequent in the elderly than in patients aged 35-64 (1.9%, P <= 0.048). Nail psoriasis appeared significantly more often in patients aged 35-64 (55.5%, P <= 0.001) and also showed the highest number of nails involved (6.9 +/- 3.3). PsA was less frequent in the age group 18-34 (9.5%, P <= 0.001). This group showed the highest rate of scalp psoriasis (85.8%) compared to the elder age groups (P <= 0.001). Biologicals were used significantly less in younger patients (16.2%) compared to the age groups 35-64 (23.9%, P <= 0.001) and 65+ (21.8%, P <= 0.042). CONCLUSION: Middle-aged patients show higher rates of PsA and nail psoriasis, which may explain age-dependent disparities in health care including the use of systemic treatment. PMID- 28079931 TI - Novel tropical forests: response to global change. PMID- 28079932 TI - The Trojan horse coronatine: the COI1-JAZ2-MYC2,3,4-ANAC019,055,072 module in stomata dynamics upon bacterial infection. PMID- 28079933 TI - Co-expression of peppermint geranyl diphosphate synthase small subunit enhances monoterpene production in transgenic tobacco plants. AB - Monoterpenes are important for plant survival and useful to humans. In addition to their function in plant defense, monoterpenes are also used as flavors, fragrances and medicines. Several metabolic engineering strategies have been explored to produce monoterpene in tobacco but only trace amounts of monoterpenes have been detected. We investigated the effects of Solanum lycopersicum 1-deoxy-d xylulose-5-phosphate synthase (SlDXS), Arabidopsis thaliana geranyl diphosphate synthase 1 (AtGPS) and Mentha * piperita geranyl diphosphate synthase small subunit (MpGPS.SSU) on production of monoterpene and geranylgeranyl diphosphate (GGPP) diversities, and plant morphology by transient expression in Nicotiana benthamiana and overexpression in transgenic Nicotiana tabacum. We showed that MpGPS.SSU could enhance the production of various monoterpenes such as (-) limonene, (-)-linalool, (-)-alpha-pinene/beta-pinene or myrcene, in transgenic tobacco by elevating geranyl diphosphate synthase (GPS) activity. In addition, overexpression of MpGPS.SSU in tobacco caused early flowering phenotype and increased shoot branching by elevating contents of GA3 and cytokinins due to upregulated transcript levels of several plastidic 2-C-methyl-d-erythritol-4 phosphate (MEP) pathway genes, geranylgeranyl diphosphate synthases 3 (GGPPS3) and GGPPS4. Our method would allow the identification of new monoterpene synthase genes using transient expression in N. benthamiana and the improvement of monoterpene production in transgenic tobacco plants. PMID- 28079934 TI - Corrigendum. PMID- 28079935 TI - Regional heritability mapping and genome-wide association identify loci for complex growth, wood and disease resistance traits in Eucalyptus. AB - Although genome-wide association studies (GWAS) have provided valuable insights into the decoding of the relationships between sequence variation and complex phenotypes, they have explained little heritability. Regional heritability mapping (RHM) provides heritability estimates for genomic segments containing both common and rare allelic effects that individually contribute too little variance to be detected by GWAS. We carried out GWAS and RHM for seven growth, wood and disease resistance traits in a breeding population of 768 Eucalyptus hybrid trees using EuCHIP60K. Total genomic heritabilities accounted for large proportions (64-89%) of pedigree-based trait heritabilities, providing additional evidence that complex traits in eucalypts are controlled by many sequence variants across the frequency spectrum, each with small contributions to the phenotypic variance. RHM detected 26 quantitative trait loci (QTLs) encompassing 2191 single nucleotide polymorphisms (SNPs), whereas GWAS detected 13 single SNP trait associations. RHM and GWAS QTLs individually explained 5-15% and 4-6% of the genomic heritability, respectively. RHM was superior to GWAS in capturing larger proportions of genomic heritability. Equated to previously mapped QTLs, our results highlighted genomic regions for further examination towards gene discovery. RHM-QTLs bearing a combination of common and rare variants could be useful enhancements to incorporate prior knowledge of the underlying genetic architecture in genomic prediction models. PMID- 28079936 TI - Mycorrhizal fungi as drivers and modulators of terrestrial ecosystem processes. PMID- 28079937 TI - Cereal immunity against powdery mildews targets RNase-Like Proteins associated with Haustoria (RALPH) effectors evolved from a common ancestral gene. PMID- 28079939 TI - Functional ecology of cryptogams: scaling from bryophyte, lichen, and soil crust traits to ecosystem processes. PMID- 28079938 TI - An enigmatic Hawaiian moth is a missing link in the adaptive radiation of Schiedea. AB - Shifts in pollination may drive adaptive diversification of reproductive systems within plant lineages. The monophyletic genus Schiedea is a Hawaiian lineage of 32 extant species, with spectacular diversity in reproductive systems. Biotic pollination is the presumed ancestral condition, but this key element of the life history and its role in shaping reproductive systems has remained undocumented. We observed floral visitors to two species of Schiedea and conducted field experiments to test pollinator effectiveness. We used choice tests to compare attraction of pollinators to species hypothesized to be biotically vs wind pollinated. Pseudoschrankia brevipalpis (Erebidae), a recently described moth species known only from O'ahu, visited hermaphroditic Schiedea kaalae and S. hookeri and removed nectar from their unique tubular nectary extensions. Pseudoschrankia brevipalpis effectively pollinates S. kaalae; single visits to emasculated flowers resulted in pollen transfer. In choice tests, P. brevipalpis strongly preferred these hermaphroditic species over two subdioecious species capable of wind pollination. A shift from biotic to abiotic pollination is clearly implicated in the diversification of reproductive systems within Schiedea. Abundant pollination by a previously unknown native moth in experimental and restored populations suggests the potential for restoration to re-establish native plant-pollinator interactions critical for production of outcrossed individuals with high fitness. PMID- 28079940 TI - Reproductive modification in forest plantations: impacts on biodiversity and society. AB - 1000 I. 1000 II. 1001 III. 1014 IV. 1015 V. 1016 1016 References 1016 SUMMARY: Genetic engineering (GE) can be used to improve forest plantation productivity and tolerance of biotic and abiotic stresses. However, gene flow from GE forest plantations is a large source of ecological, social and legal controversy. The use of genetic technologies to mitigate or prevent gene flow has been discussed widely and should be technically feasible in a variety of plantation taxa. However, potential ecological effects of such modifications, and their social acceptability, are not well understood. Focusing on Eucalyptus, Pinus, Populus and Pseudotsuga - genera that represent diverse modes of pollination and seed dispersal - we conducted in-depth reviews of ecological processes associated with reproductive tissues. We also explored potential impacts of various forms of reproductive modification at stand and landscape levels, and means for mitigating impacts. We found little research on potential reactions by the public and other stakeholders to reproductive modification in forest plantations. However, there is considerable research on related areas that suggest key dimensions of concern and support. We provide detailed suggestions for research to understand the biological and social dimensions of containment technologies, and consider the role of regulatory and market restrictions that obstruct necessary ecological and genetic research. PMID- 28079941 TI - Changes to Cretaceous surface fire behaviour influenced the spread of the early angiosperms. AB - Angiosperms evolved and diversified during the Cretaceous period. Early angiosperms were short-stature weedy plants thought to have increased fire frequency and mortality in gymnosperm forest, aiding their own expansion. However, no explorations have considered whether the range of novel fuel types that diversified throughout the Cretaceous also altered fire behaviour, which should link more strongly to mortality than fire frequency alone. We measured ignitability and heat of combustion in analogue Cretaceous understorey fuels (conifer litter, ferns, weedy and shrubby angiosperms) and used these data to model palaeofire behaviour. Variations in ignition, driven by weedy angiosperms alone, were found to have been a less important feedback to changes in Cretaceous fire activity than previously estimated. Our model estimates suggest that fires in shrub and fern understories had significantly greater fireline intensities than those fuelled by conifer litter or weedy angiosperms, and whilst fern understories supported the most rapid fire spread, angiosperm shrubs delivered the largest amount of heat per unit area. The higher fireline intensities predicted by the models led to estimates of enhanced scorch of the gymnosperm canopy and a greater chance of transitioning to crown fires. Therefore, changes in fire behaviour driven by the addition of new Cretaceous fuel groups may have assisted the angiosperm expansion. PMID- 28079942 TI - Treatment of capillary malformation using topical timolol combined with 585-nm pulsed dye laser: a prospective, randomized, split-lesion study. PMID- 28079943 TI - Cooperative Activation of Isocyanates by Al-N-Based Active Lewis Pairs and the Generation of a C5 Chain by Simultaneous Formation of Two C-C Bonds. AB - The active Al/N Lewis pair, (Me3 C)2 Al-C(SiMe3 )=C(H)-N(CHMe-CH2 )2 CH2 (2), reacted with isocyanates to afford a fascinating variety of products. One equivalent of Ph-N=C=O yielded by the release of H-C=C-SiMe3 an urea-type ligand which coordinated the Al atom in a chelating manner (4). Dipp-N=C=O gave a similar product, but the bulky substituent hindered the approach of the N-aryl group to Al. A situation similar to that of frustrated Lewis pairs resulted in the coordination of the alkyne to the Al and N atoms (6) by C-H bond activation. Dual insertion was observed upon treatment of 2 with two equivalents of isocyanates (8 to 11). The preferred formation of cyclic oligomers is prevented by the specific cooperative properties of the Lewis pair. A metal-free dimeric isocyanate (13) was formed by hydrolysis. Replacement of the CMe3 groups in 2 by less bulky isobutyl groups (7) afforded the insertion of two isocyanate molecules into the Al-vinyl bonds without alkyne elimination. The resulting highly functionalised compound had a chain formed by two isocyanates and the organic backbone of the Lewis pair. Me3 C-N=C=O and 2 afforded a unique compound (14) in which an isocyanate ligand connects two molecules of 2 by the release of dimethylpiperidine. The combination of a C1 building block and two C2 groups gave an unsaturated branched C5 moiety by the simultaneous formation of two C-C bonds. The molecular structure showed an interaction between an Al atom and a C-C pi bond. PMID- 28079944 TI - An Isolable Silicon Dicarbonate Complex from Carbon Dioxide Activation with a Silylone. AB - The first isolable molecular silicon dicarbonate complex (bis-NHC)Si(CO3 )2 2 (bis-NHC=H2 C[{NC(H)=C(H)N(Dipp)}C:]2 , Dipp=2,6-iPr2 C6 H3 ) was synthesized by facile reaction of the bis-N-heterocyclic carbene stabilized silylone (bis-NHC)Si 1, bearing a zero-valent silicon atom, with carbon dioxide. The monomeric silicon dioxide complex (bis-NHC)SiO2 3 supported by the bis-NHC ligand was proposed as a key intermediate resulting from double oxygenation of the zero-valent silicon atom in 1 by two molar equivalents of CO2 under liberation of CO; its subsequent Lewis acid-base reaction with CO2 leads to 2 which has been fully characterized including an single-crystal X-ray diffraction analysis. Its electronic structure, spectroscopic data and the thermochemistry of the formation have been studied quantum-chemically. PMID- 28079945 TI - Systematic review of site distribution of bone metastases in differentiated thyroid cancer. AB - BACKGROUND: Thyroid cancer is the fastest growing cancer in the United States. A small portion of differentiated thyroid cancers (DTCs; 2% to 13%) develop bone metastases, which can decrease a patient's survival rate by more than 60%. METHODS: A systematic literature search of studies, including patients with DTC with bone metastases, was conducted by following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A case series of patients with DTC diagnosed with bone metastases seen at our institution was also included. RESULTS: A total of 616 bone metastases sites in 317 patients were identified in 14 case series. Ten patients were identified in our institutional case series. The most common sites of metastases are spine (34.6%), pelvis (25.5%), sternum and ribs (18.3%), extremities (10.2%), shoulder girdle (5.4%), and craniomaxillofacial (5.4%). CONCLUSION: The axial skeleton is the primary target of bone metastases in DTC. The relative distribution of bone metastases and red marrow content follow a similar rank. (c) 2017 Wiley Periodicals, Inc. Head Neck 39: 812-818, 2017. PMID- 28079946 TI - Enantioselective and Regiodivergent Addition of Purines to Terminal Allenes: Synthesis of Abacavir. AB - The rhodium-catalyzed atom-economic asymmetric N-selective intermolecular addition of purine derivatives to terminal allenes is reported. Branched allylic purines were obtained in high yields, regioselectivity and outstanding enantioselectivity utilizing a Rh/Josiphos catalyst. Conversely, linear selective allylation of purines could be realized in good to excellent regio- and E/Z selectivity with a Pd/dppf catalyst system. Furthermore, the new methodology was applied to a straightforward asymmetric synthesis of carbocyclic nucleoside abacavir. PMID- 28079947 TI - An Unusually Delocalized Mixed-Valence State of a Cyanidometal-Bridged Compound Induced by Thermal Electron Transfer. AB - The heterometallic complexes trans-[Cp(dppe)FeNCRu(o-bpy)CNFe(dppe)Cp][PF6 ]n (1[PF6 ]n , n=2, 3, 4; o-bpy=1,2-bis(2,2'-bipyridyl-6-yl)ethane, dppe=1,2 bis(diphenylphosphino)ethane, Cp=1,3-cyclopentadiene) in three distinct states have been synthesized and fully characterized. 13+ [PF6 ]3 and 14+ [PF6 ]4 are the one- and two-electron oxidation products of 12+ [PF6 ]2 , respectively. The investigated results suggest that 1[PF6 ]3 is a Class II mixed valence compound. 1[PF6 ]4 after a thermal treatment at 400 K shows an unusually delocalized mixed valence state of [FeIII -NC-RuIII -CN-FeII ], which is induced by electron transfer from the central RuII to the terminal FeIII in 1[PF6 ]4 , which was confirmed by IR spectroscopy, magnetic data, and EPR and Mossbauer spectroscopy. PMID- 28079949 TI - A 11-Steps Total Synthesis of Magellanine through a Gold(I)-Catalyzed Dehydro Diels-Alder Reaction. AB - We have developed an innovative strategy for the formation of angular carbocycles via a gold(I)-catalyzed dehydro Diels-Alder reaction. This transformation provides rapid access to a variety of complex angular cores in excellent diastereoselectivities and high yields. The usefulness of this AuI -catalyzed cycloaddition was further demonstrated by accomplishing a 11-steps total synthesis of (+/-)-magellanine. PMID- 28079948 TI - Induction of Antibodies Directed Against Branched Core O-Mannosyl Glycopeptides Selectivity Complimentary to the ConA Lectin. AB - Mammalian protein O-mannosylation, initiated by attachment of alpha-mannopyranose to Ser or Thr residues, comprise a group of post-translational modifications (PTMs) involved in muscle and brain development. Recent advances in glycoproteomics methodology and the "SimpleCell" strategy have enabled rapid identification of glycoproteins and specific glycosylation sites. Despite the enormous progress made, the biological impact of the mammalian O-mannosyl glycoproteome remains largely unknown to date. Tools are still needed to investigate the structure, role, and abundance of O-mannosyl glycans. Although O mannosyl branching has been shown to be of relevance in integrin-dependent cell migration, and also plays a role in demyelinating diseases, such as multiple sclerosis, a broader understanding of the biological roles of branched O-mannosyl glycans is lacking in part due to the paucity of detection tools. In this work, a glycopeptide vaccine construct was synthesized and used to generate antibodies against branched O-mannosyl glycans. Glycopeptide microarray screening revealed high selectivity of the induced antibodies for branched glycan core structures presented on different peptide backbones, with no cross-reactivity observed with related linear glycans. For comparison, microarray screening of the mannose binding lectin concanavalin A (ConA), which is commonly used in glycoproteomics workflows to enrich tryptic O-mannosyl peptides, showed that the ConA lectin did not recognize branched O-mannosyl glycans. The binding preference of ConA for short linear O-mannosyl glycans was rationalized in terms of molecular structure using crystallographic data augmented by molecular modeling. The contrast between the ConA binding specificity and that of the new antibodies indicates a novel role for the antibodies in studies of protein O-mannosylation. PMID- 28079950 TI - Olefin Insertion into a Pd-F Bond: Catalyst Reactivation Following beta-F Elimination in Ethylene/Vinyl Fluoride Copolymerization. AB - The discrete (phosphinoarenesulfonate)Pd fluoride complex (POBp,OMe )PdF(lutidine), where POBp,OMe =(2-MeOC6 H4 )(2-{2,6-(MeO)2 C6 H3 }C6 H4 )(2-SO3 5-MeC6 H3 )P, inserts vinyl fluoride (VF) to form (POBp,OMe )PdCH2 CHF2 (lutidine) and inserts multiple ethylene (E) units to generate polyethylene that contains -CH2 F chain ends. These results provide strong evidence that the -CHF2 and -CH2 F chain ends in E/VF copolymer generated by (phosphinoarenesulfonate)PdR catalysts form by beta-F elimination of Pd(beta-F-alkyl) species, VF or E insertion of the resulting (PO)PdF species, and subsequent chain growth. These results also imply that beta-F elimination is not an important catalyst deactivation reaction in this system. PMID- 28079951 TI - Water Catalysis of the Reaction between Methanol and OH at 294 K and the Atmospheric Implications. AB - The rate coefficient for the reaction CH3 OH+OH was determined by means of a relative method in a simulation chamber under quasi-real atmospheric conditions (294 K, 1 atm of air) and variable humidity or water concentration. Under these conditions, a quadratic dependence of the rate coefficient for the reaction CH3 OH+OH on the water concentration was found. Thus the catalytic effect of water is not only important at low temperatures, but also at room temperature. The detailed mechanism responsible of the reaction acceleration is still unknown. However, this dependence should be included in the atmospheric global models since it is expected to be important in humid regions as in the tropics. Additionally, it could explain several differences regarding the global and local atmospheric concentration of methanol in tropical areas, for which many speculations about the sinks and sources of methanol have been reported. PMID- 28079952 TI - Regioselectivity Change in the Organocatalytic Enantioselective (3+2) Cycloaddition with Nitrones through Cooperative Hydrogen-Bonding Catalysis/Iminium Activation. AB - The reaction of nitrones with enals through iminium activation can be modulated by using cooperative hydrogen-bonding catalysis to induce the participation of a nitrone ylide (C-N-C) instead of the classical C-N-O dipole. As a consequence, N hydroxypyrrolidines are obtained, rather than the expected isoxazolidines. The reaction proceeds smoothly and high enantioselectivities are observed in all cases. By using the appropriate substrate, polysubstituted pyrrolidines incorporating quaternary stereocenters can be efficiently prepared. PMID- 28079953 TI - Reversible Photoactivated Phosphorescence of Gold(I) Arylethynyl Complexes in Aerated DMSO Solutions and Gels. AB - Phosphorescence in fluid solutions at ambient temperature is usually quenched by molecular oxygen via energy transfer, and singlet oxygen is concomitantly sensitized. The long-lived phosphorescence of a series of AuI arylethynyl complexes with tunable emission energies in aerated dimethyl sulfoxide (DMSO) solutions can be completely and repeatedly switched on by controlled photoirradiation. A trace amount of DMSO oxidation by the sensitized singlet oxygen is proposed to lead to a depletion of molecular oxygen in the local microenvironment of the AuI phosphor in the photoactivation processes. Harnessing the photoactivated phosphorescence and using UV light as a non-contact pen, a writing-erasing-rewriting prototype has been demonstrated with a DMSO gel containing AuI arylethynyl complexes. PMID- 28079954 TI - Conformational SERS Classification of K-Ras Point Mutations for Cancer Diagnostics. AB - Point mutations in Ras oncogenes are routinely screened for diagnostics and treatment of tumors (especially in colorectal cancer). Here, we develop an optical approach based on direct SERS coupled with chemometrics for the study of the specific conformations that single-point mutations impose on a relatively large fragment of the K-Ras gene (141 nucleobases). Results obtained offer the unambiguous classification of different mutations providing a potentially useful insight for diagnostics and treatment of cancer in a sensitive, fast, direct and inexpensive manner. PMID- 28079955 TI - Solubilization of Membrane Proteins into Functional Lipid-Bilayer Nanodiscs Using a Diisobutylene/Maleic Acid Copolymer. AB - Once removed from their natural environment, membrane proteins depend on membrane mimetic systems to retain their native structures and functions. To this end, lipid-bilayer nanodiscs that are bounded by scaffold proteins or amphiphilic polymers such as styrene/maleic acid (SMA) copolymers have been introduced as alternatives to detergent micelles and liposomes for in vitro membrane-protein research. Herein, we show that an alternating diisobutylene/maleic acid (DIBMA) copolymer shows equal performance to SMA in solubilizing phospholipids, stabilizes an integral membrane enzyme in functional bilayer nanodiscs, and extracts proteins of various sizes directly from cellular membranes. Unlike aromatic SMA, aliphatic DIBMA has only a mild effect on lipid acyl-chain order, does not interfere with optical spectroscopy in the far-UV range, and does not precipitate in the presence of low millimolar concentrations of divalent cations. PMID- 28079956 TI - An Exonuclease III-Powered, On-Particle Stochastic DNA Walker. AB - DNA-based machines have attracted rapidly growing interest owing to their potential in drug delivery, biocomputing, and diagnostic applications. Herein, we report a type of exonuclease III (Exo III)-powered stochastic DNA walker that can autonomously move on a spherical nucleic acid (SNA)-based 3D track. The motion is propelled by unidirectional Exo III digestion of hybridized DNA tracks in a burnt bridge mechanism. The operation of this Exo III-propelled DNA walker was monitored in real time and at the single-particle resolution using total internal reflection fluorescence microscopy (TIRF). We further interrogated the morphological effect of the 3D track on the nuclease activity, which suggested that the performance of the DNA walker was critically dependent upon the DNA density and the track conformation. Finally, we demonstrated potential bioanalytical applications of this SNA-based stochastic DNA walker by exploiting movement-triggered cascade signal amplification. PMID- 28079957 TI - Palladium-Catalyzed Remote Aryldifluoroalkylation of Alkenyl Aldehydes. AB - A palladium-catalyzed three-component reaction between fluoroalkyl bromides, arylboronic acids, and alkenyl aldehydes has been developed and provides facile access to 5-, 6-, or 7-difluoroalkylated ketones under very mild reaction conditions. The resultant products can be smoothly converted into CF2 -containing tetrahydronaphthalenes by a novel silver-catalyzed intramolecular decarboxylative cyclization of 5-aryl-2,2-difluoropentanoic acids. PMID- 28079958 TI - An S-Oxygenated [NiFe] Complex Modelling Sulfenate Intermediates of an O2 Tolerant Hydrogenase. AB - To understand the molecular details of O2 -tolerant hydrogen cycling by a soluble NAD+ -reducing [NiFe] hydrogenase, we herein present the first bioinspired heterobimetallic S-oxygenated [NiFe] complex as a structural and vibrational spectroscopic model for the oxygen-inhibited [NiFe] active site. This compound and its non-S-oxygenated congener were fully characterized, and their electronic structures were elucidated in a combined experimental and theoretical study with emphasis on the bridging sulfenato moiety. Based on the vibrational spectroscopic properties of these complexes, we also propose novel strategies for exploring S oxygenated intermediates in hydrogenases and similar enzymes. PMID- 28079959 TI - Removal of Multiple Contaminants from Water by Polyoxometalate Supported Ionic Liquid Phases (POM-SILPs). AB - The simultaneous removal of organic, inorganic, and microbial contaminants from water by one material offers significant advantages when fast, facile, and robust water purification is required. Herein, we present a supported ionic liquid phase (SILP) composite where each component targets a specific type of water contaminant: a polyoxometalate-ionic liquid (POM-IL) is immobilized on porous silica, giving the heterogeneous SILP. The water-insoluble POM-IL is composed of antimicrobial alkylammonium cations and lacunary polyoxometalate anions with heavy-metal binding sites. The lipophilicity of the POM-IL enables adsorption of organic contaminants. The silica support can bind radionuclides. Using the POM SILP in filtration columns enables one-step multi-contaminant water purification. The results show how multi-functional POM-SILPs can be designed for advanced purification applications. PMID- 28079960 TI - Successful medical management of a domestic longhair cat with subdural intracranial empyema and multifocal pneumonia. AB - OBJECTIVE: To describe a case of successful medical management of subdural intracranial empyema and multifocal pneumonia in a domestic longhaired cat. CASE SUMMARY: A 7-year-and-8-month-old male neutered domestic longhair cat presented with tachypnea, respiratory compromise, vestibular ataxia, obtundation, left sided head tilt, and multiple cranial nerve deficits. Neuroanatomical localization was multifocal with central vestibular involvement. Magnetic resonance imaging of the head indicated diffuse subdural empyema, mainly affecting the middle cranial fossa and the right cerebrum. Analysis of cerebrospinal fluid revealed degenerate neutrophils with a mixed population of intracellular bacilli. Computed tomography (CT) of the thorax was suggestive for multifocal pneumonia. Aggressive medical management with IV fluids, oxygen supplementation, mannitol boluses, dexamethasone, and broad-spectrum antimicrobials was initiated. The cat demonstrated gradual improvement within 24 hours following initiation of treatment. General physical and neurological examinations, 9 weeks after initiating treatment, did not reveal any abnormalities. A CT examination performed at this time revealed resolution of the cat's pulmonary lesions. The cat was still free of clinical signs, 9 months after treatment was started. NEW OR UNIQUE INFORMATION PROVIDED: Subdural empyema is infrequently reported in cats and has high mortality rates even following surgical treatment. To the authors' knowledge, this is the first reported case of successful medical management of a cat with subdural empyema and suggests that aggressive medical management should be attempted in cats that are not considered surgical candidates. PMID- 28079961 TI - Highly Porous Thermoelectric Nanocomposites with Low Thermal Conductivity and High Figure of Merit from Large-Scale Solution-Synthesized Bi2 Te2.5 Se0.5 Hollow Nanostructures. AB - To enhance the performance of thermoelectric materials and enable access to their widespread applications, it is beneficial yet challenging to synthesize hollow nanostructures in large quantities, with high porosity, low thermal conductivity (kappa) and excellent figure of merit (z T). Herein we report a scalable (ca. 11.0 g per batch) and low-temperature colloidal processing route for Bi2 Te2.5 Se0.5 hollow nanostructures. They are sintered into porous, bulk nanocomposites (phi 10 mm*h 10 mm) with low kappa (0.48 W m-1 K-1 ) and the highest z T (1.18) among state-of-the-art Bi2 Te3-x Sex materilas. Additional benefits of the unprecedented low relative density (68-77 %) are the large demand reduction of raw materials and the improved portability. This method can be adopted to fabricate other porous phase-transition and thermoelectric chalcogenide materials and will pave the way for the implementation of hollow nanostructures in other fields. PMID- 28079962 TI - Determining Electrochemical Surface Stress of Single Nanowires. AB - Electrochemical surface stress is important in nanomaterials because of their large surface-to-volume ratios, which lead to unique mechanical and electrocatalytic properties, but directly measuring this quantity has been challenging. Here we report on experimental determination of the surface stress, and associated electrochemical processes of a single gold nanowire with an optical imaging technique. We show that surface stress changes linearly and reversibly with the potential between 0 and 0.8 V versus Ag/AgCl, but abruptly with large hysteresis, associated with the oxidation and reduction of the nanowire, between 0.8 and 1.5 V. The potential derivative of the surface stress closely resembles the cyclic voltammograms. We described the observations in terms of anion adsorption and surface oxidation/reduction. This work demonstrates a new approach to study electrochemical processes and the associated surface stress changes of nanomaterials. PMID- 28079963 TI - Nauseas Y Vomitos Durante el Embarazo (Nausea and Vomiting During Pregnancy). PMID- 28079964 TI - BAB-random-C Monomer Sequence via Radical Terpolymerization of Limonene (A), Maleimide (B), and Methacrylate (C): Terpene Polymers with Randomly Distributed Periodic Sequences. AB - A naturally abundant terpene, limonene (A), was radically polymerized with a maleimide derivative (B) and methacrylate (C) in a fluorinated alcohol to give terpolymers with unprecedented BAB-random-C sequences in which the BAB monomer sequence was randomly copolymerized with a C unit. In each binary system, limonene was hardly copolymerized with methacrylate while it was efficiently copolymerized with maleimide to result in a 1:2-alternating BAB periodic sequence, in part due to the penultimate effects and hydrogen-bonding interactions with fluoroalcohol. Methacrylate and maleimide were randomly copolymerized to give copolymers rich in methacrylate units with minimal amounts of maleimide-maleimide sequences. Their terpolymerization resulted in a BAB-r-C sequence as a consequence of the selective BAB polymerization between limonene and maleimide, the random copolymerization between methacrylate and maleimide, and the lack of copolymerization between limonene and methacrylate. PMID- 28079965 TI - Transanal endolaparoscopic circumferential mucosectomy for symptomatic benign rectal stenosis - a video vignette. PMID- 28079966 TI - Updates From the Literature, January/February 2017. PMID- 28079967 TI - Current Resources for Evidence-Based Practice January/February 2017. PMID- 28079968 TI - Salud Vaginal y De La Vulva. PMID- 28079969 TI - Molecular Polygons Probe the Role of Intramolecular Strain in the Photophysics of pi-Conjugated Chromophores. AB - pi-Conjugated segments, chromophores, are the electronically active units of polymer materials used in organic electronics. To elucidate the effect of the bending of these linear moieties on elementary electronic properties, such as luminescence color and radiative rate, we introduce a series of molecular polygons. The pi-system in these molecules becomes so distorted in bichromophores (digons) that these absorb and emit light of arbitrary polarization: any part of the chain absorbs and emits radiation with equal probability. Bending leads to a cancellation of transition dipole moment (TDM), increasing excited-state lifetime. Simultaneously, fluorescence shifts to the red as radiative transitions require mixing of the excited state with vibrational modes. However, strain can become so large that excited-state localization on shorter units of the chain occurs, compensating TDM cancellation. The underlying correlations between shape and photophysics can only be resolved in single molecules. PMID- 28079970 TI - Categorizing the Magnitude and Frequency of Exposure to Uncivil Behaviors: A New Approach for More Meaningful Interventions. AB - PURPOSE: To examine turnover intentions, as well as the prevalence and frequency of uncivil behaviors, from the perspective of registered nurses, respiratory therapists, and imaging professionals, using a new method to categorize exposure magnitude. DESIGN AND METHODS: Data were collected using the 22-item Negative Acts Questionnaire-Revised (NAQ-R). Additional items, informed by Price and Mueller's causal model of turnover, were included, as were select demographic variables. The final sample included 170 healthcare professionals. Descriptive statistics were used to describe the sample, a chi-square test was constructed to test for significant differences in exposure to uncivil behavior based on demographics, and Cochran-Mantel-Haenszel statistics were used to test associations between variables and calculation of raw sum scores to implement a new method of analysis for the NAQ-R, allowing for categorization of exposure magnitude. FINDINGS: Exposure to uncivil behavior was reported more often among nursing staff than other healthcare professionals. Lack of exposure to uncivil behavior was a significant predictor of intention to stay. Perceptual differences were found between nurses prepared at the baccalaureate and associate degree levels. Lastly, no significant correlations between exposure to uncivil behavior and selected demographic variables were found, suggesting that exposure is not dependent upon age, race, unit type, or educational level. CONCLUSIONS: Findings support prior research associating negative organizational climate with higher turnover intentions. Uncivil behavior was reported across the organization, most predominantly among units staffed with nurses. Finally, use of newly defined cutoff points for the NAQ-R provide organizations with the ability to use both subjective and objective data to identify targets of uncivil behaviors to construct meaningful interventions. CLINICAL RELEVANCE: There is a need to develop more meaningful interventions to support targets of uncivil behaviors. Use of the NAQ-R, coupled with the proposed cutoff scores, allows for the identification of targets, the magnitude of exposure, and the construction of meaningful primary, secondary, and tertiary intervention programs that may improve turnover and quality of care. PMID- 28079971 TI - Au/La2 Ti2 O7 Nanostructures Sensitized with Black Phosphorus for Plasmon Enhanced Photocatalytic Hydrogen Production in Visible and Near-Infrared Light. AB - Efficient utilization of solar energy is a high-priority target and the search for suitable materials as photocatalysts that not only can harvest the broad wavelength of solar light, from UV to near-infrared (NIR) region, but also can achieve high and efficient solar-to-hydrogen conversion is one of the most challenging missions. Herein, using Au/La2 Ti2 O7 (BP-Au/LTO) sensitized with black phosphorus (BP), a broadband solar response photocatalyst was designed and used as efficient photocatalyst for H2 production. The optimum H2 production rates of BP-Au/LTO were about 0.74 and 0.30 mmol g-1 h-1 at wavelengths longer than 420 nm and 780 nm, respectively. The broad absorption of BP and plasmonic Au contribute to the enhanced photocatalytic activity in the visible and NIR light regions. Time-resolved diffuse reflectance spectroscopy revealed efficient interfacial electron transfer from excited BP and Au to LTO which is in accordance with the observed high photoactivities. PMID- 28079972 TI - Prevalence of vomiting in dogs with pericardial effusion. AB - BACKGROUND: Pericardial effusion (PE) is common in dogs. Clinical signs may be vague until cardiac tamponade and associated cardiovascular decompensation develops. Vomiting has previously been identified in some dogs, but the actual prevalence of vomiting in dogs with PE is unknown. The purpose of this study is to report the prevalence of vomiting associated with PE, and to determine if vomiting is associated with the underlying cause of effusion, presenting plasma lactate concentration, or volume of PE removed. KEY FINDINGS: The medical records of 49 dogs diagnosed with PE were restrospectively reviewed. Data collected from the medical record included signalment, the presence or absence of vomiting, presenting plasma lactate concentration, and the etiology of the PE. Twenty-five of 49 dogs (51%) identified with PE had recently vomited. Vomiting was more common in dogs with presenting plasma lactate concentration > 5.0 mmol/L (P = 0.02) but was unrelated to the specific etiology of the PE. The volume of PE obtained via pericardiocentesis did not differ (P = 0.79) between dogs with (8.7 +/- 3.4 mL/kg) and without historical vomiting (9.1 +/- 4.3 mL/kg). SIGNIFICANCE: Vomiting is common in dogs with PE, and in particular, dogs with evidence of hypoperfusion. Pericardial effusion should be included as a differential diagnosis in dogs with a history of vomiting that present with weakness or collapse. PMID- 28079974 TI - Findings From a Pilot Study: Bringing Evidence-Based Practice to the Bedside. AB - BACKGROUND: To translate research supporting inpatient care outcomes and provide evidence-based care, registered nurses (RNs) need continuing education and mentoring support to adopt evidence-based practice (EBP). AIMS: The aim of this study was to assess a demonstration project intended to pilot and evaluate a structured EBP education with mentoring innovation for nurses in a multihospital system. METHODS: Nurses from five units in five hospitals were included in an education with mentoring innovation to implement the Johns Hopkins Nursing Evidence-Based Practice Model and the Advancing Research and Clinical practice through close Collaboration (ARCC) Model. To determine outcomes, the EBP beliefs scale (EBPB) and implementation scale (EBPI) were administered before and after the education with mentoring innovation. Eighty-three RNs completed both preintervention surveys. A total of 57 RNs completed the postintervention surveys. In addition, qualitative data were obtained from focus groups involving 24 participants. FINDINGS: Statistical analysis indicated positive movement toward EBP in project participants. Qualitative analysis revealed perceived successes and challenges involved with implementing an evidence-based program, provided logistical lessons learned, and indicated that nurses at all levels of practice require mentoring and coaching to foster EBP sustainment. LINKING EVIDENCE TO ACTION: The engagement of nurses in this project supported professional development and clinical application of evidence at the point of care. The pilot project's outcome informed a decision by health system administrators to fund more nurse driven EBP projects in the five hospitals. This innovative program provides a replicable structure for deployment and appraisal of EBP nursing model implementation. PMID- 28079973 TI - A regulatory BMI1/let-7i/ERK3 pathway controls the motility of head and neck cancer cells. AB - Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK), whose biological activity is tightly regulated by its cellular abundance. Recent studies have revealed that ERK3 is upregulated in multiple cancers and promotes cancer cell migration/invasion and drug resistance. Little is known, however, about how ERK3 expression level is upregulated in cancers. Here, we have identified the oncogenic polycomb group protein BMI1 as a positive regulator of ERK3 level in head and neck cancer cells. Mechanistically, BMI1 upregulates ERK3 expression by suppressing the tumor suppressive microRNA (miRNA) let-7i, which directly targets ERK3 mRNA. ERK3 then acts as an important downstream mediator of BMI1 in promoting cancer cell migration. Importantly, ERK3 protein level is positively correlated with BMI1 level in head and neck tumor specimens of human patients. Taken together, our study revealed a molecular pathway consisting of BMI1, miRNA let-7i, and ERK3, which controls the migration of head and neck cancer cells, and suggests that ERK3 kinase is a potential new therapeutic target in head and neck cancers, particularly those with BMI1 overexpression. PMID- 28079975 TI - Edge States and Topological Phase Transitions in Chains of Dielectric Nanoparticles. AB - Recently introduced field of topological photonics aims to explore the concepts of topological insulators for novel phenomena in optics. Here polymeric chains of subwavelength silicon nanodisks are studied and it is demonstrated that these chains can support two types of topological edge modes based on magnetic and electric Mie resonances, and their topological properties are fully dictated by the spatial arrangement of the nanoparticles in the chain. It is observed experimentally and described how theoretically topological phase transitions at the nanoscale define a change from trivial to nontrivial topological states when the edge mode is excited. PMID- 28079977 TI - Psychosocial changes as correlates of weight regain vs. continued loss within 2 year trials of a self-regulation-focused community-based intervention. AB - Although health-enhancing weight reductions are associated with behavioural treatments initially, a trajectory towards full regain typically begins within 6 9 months. Women with obesity (body mass index = 30-40 kg m-2 ) who lost at least 3% of their baseline weight within two trials of a new cognitive-behavioural treatment incorporating physical activity prior to changes in eating behaviours, and either regained >=50% of that weight over 2 years (Regain group, n=32) or continued to lose weight (ContinuedLoss group, n = 34), were assessed from months 6 to 24 on changes in weight-loss behaviours and psychosocial predictors of those behaviours derived from established behavioural theories. For the Regain group, significant decreases in physical activity and fruit/vegetable intake during months 12-24, from both months 6 to 24 and 12 to 24 in eating- and physical activity-related self-regulation and from months 6 to 24 in eating-related self efficacy (i.e. feelings of ability), were found. No significant behavioural or psychosocial changes were found over those times in the ContinuedLoss group. Changes in self-regulation and self-efficacy completely mediated the relationship between changes in fruit/vegetable intake and group (Regain vs. ContinuedLoss) (McFadden's R 2 = 0.19 and 0.20, respectively), with self-regulation independently contributing to the explained variance. Changes over both months 6 24 and 12-24 in self-regulation significantly mediated the relationship between changes in physical activity and group membership (McFadden's R 2 = 0.24 and 0.27, respectively). Findings suggested that approximately 6 months after treatment initiation would be a suitable time to intervene with some bolstering methods, while approximately 12 months post-initiation would be most applicable for others. PMID- 28079976 TI - Maresin 1 induces a novel pro-resolving phenotype in human platelets. AB - : Essentials Specialized proresolving mediators (SPMs) promote the resolution of inflammation. This study sought to investigate the effects of SPMs on human platelet function. The SPM, Maresin 1, enhanced hemostatic, but suppressed inflammatory functions of platelets. SPMs uniquely regulate platelet function and may represent a new class of antiplatelet agents. SUMMARY: Background Antiplatelet therapy is a cornerstone of modern medical practice and is routinely employed to reduce the likelihood of myocardial infarction, thrombosis and stroke. However, current antiplatelet therapies, such as aspirin, often have adverse side-effects, including increased risk of bleeding, and some patients are relatively 'aspirin-resistant'. Platelets are intimately involved in hemostasis and inflammation, and clinical consequences are associated with excessive or insufficient platelet activation. Objectives A major unmet need in the field of hematology is the development of new agents that safely prevent unwanted platelet activation in patients with underlying cardiovascular disease, while minimizing the risk of bleeding. Here, we investigate the potential of endogenously produced, specialized pro-resolving mediators (SPMs) as novel antiplatelet agents. SPMs are a recently discovered class of lipid-derived molecules that drive the resolution of inflammation without being overtly immunosuppressive. Methods Human platelets were treated with lipoxin A4, resolvin D1, resolvin D2, 17-HDHA or maresin 1 for 15 min, then were subjected to platelet function tests, including spreading, aggregation and inflammatory mediator release. Results We show for the first time that human platelets express the SPM receptors, GPR32 and ALX. Furthermore, our data demonstrate that maresin 1 differentially regulates platelet hemostatic function by enhancing platelet aggregation and spreading, while suppressing release of proinflammatory and prothrombotic mediators. Conclusions These data support the concept that SPMs differentially regulate platelet function and may represent a novel class of antiplatelet agents. SPMs also may play an important role in the resolution of inflammation in cardiovascular diseases. PMID- 28079979 TI - A General Strategy to Enhance the Performance of Dye-Sensitized Solar Cells by Incorporating a Light-Harvesting Dye with a Hydrophobic Polydiacetylene Electrolyte-Blocking Layer. AB - A unique strategy to suppress charge recombination effectively and enhance light harvesting in dye-sensitized solar cells (DSSCs) is demonstrated by the design of a new dipolar organic dye functionalized with a diacetylene unit, which is capable of undergoing a photoinduced crosslinking reaction to generate a hydrophobic polydiacetylene layer. The polydiacetylene layer serves as an electrolyte-blocking layer that effectively blocks the approach of the oxidized redox mediator and suppresses the dark current, and also plays a role in light harvesting owing to efficient energy transfer to the dipolar dyes. A 15 % efficiency improvement was achieved on going from the monomer dye (JSC =13.5 mA cm-2 , Voc =0.728 V, fill factor=0.73, eta=7.17 %) to the crosslinked dye (JSC =14.9 mA cm-2 , Voc =0.750 V, fill factor=0.74, eta=8.27 %) under AM 1.5 conditions. PMID- 28079978 TI - Targeting coagulation factor receptors - protease-activated receptors in idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with a 5-year mortality rate of > 50% and unknown etiology. Treatment options remain limited and, currently, only two drugs are available, i.e. nintedanib and pirfenidone. However, both of these antifibrotic agents only slow down the progression of the disease, and do not remarkably prolong the survival of IPF patients. Hence, the discovery of new therapeutic targets for IPF is crucial. Studies exploring the mechanisms that are involved in IPF have identified several possible targets for therapeutic interventions. Among these, blood coagulation factor receptors, i.e. protease-activated receptors (PARs), are key candidates, as these receptors mediate the cellular effects of coagulation factors and play central roles in influencing inflammatory and fibrotic responses. In this review, we will focus on the controversial role of the coagulation cascade in the pathogenesis of IPF. In the light of novel data, we will attempt to reconciliate the apparently conflicting data and discuss the possibility of pharmacologic targeting of PARs for the treatment of fibroproliferative diseases. PMID- 28079980 TI - Induction of mesenchymal stem cell differentiation in the absence of soluble inducer for cutaneous wound regeneration by a chitin nanofiber-based hydrogel. AB - Transplantation of bone marrow mesenchymal stem cells (BMSCs) has been considered to be a promising strategy for wound healing. However, poor viability of engrafted BMSCs and limited capabilities of differentiation into the desired cell types in wounds often hinder its application. Few studies report the induction of BMSC differentiation into the skin regeneration-related cell types using natural biopolymer, e.g. chitin and its derivative. Here we utilized a chitin nanofiber (CNF) hydrogel as a directive cue to induce BMSC differentiation for enhancing cutaneous wound regeneration in the absence of cell-differentiating factors. First, a 'green' fabrication of CNF hydrogels encapsulating green fluorescence protein (GFP)-transfected rat BMSCs was performed via in-situ physical gelation without chemical cross-linking. Without soluble differentiation inducers, CNF hydrogels decreased the expression of BMSC transcription factors (Oct4 and Klf4) and concomitantly induced their differentiation into the angiogenic cells and fibroblasts, which are indispensable for wound regeneration. In vivo, rat full thickness cutaneous wounds treated with BMSC hydrogel exhibited better viability of the cells than did local BMSC injection-treated wounds. Similar to that of the in vitro result, CNF hydrogels induced BMSCs to differentiate into beneficial cell types, resulting in accelerated wound repair characterized by granulation tissue formation. Our data suggest that three-dimensional CNF hydrogel may not only serve as a 'protection' to improve the viability of exogenous BMSCs, but also provide a functional scaffold capable of enhancing BMSC regenerative potential to promote wound healing. This may help to overcome the current limitations to stem cell therapy that are faced in the field of wound regeneration. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28079981 TI - Inhibiting Solid Tumor Growth In Vivo by Non-Tumor-Penetrating Nanomedicine. AB - Nanomedicine (NM) cannot penetrate deeply into solid tumors, which is partly attributed to the heterogeneous microenvironment and high interstitial fluid pressure of solid tumors. To improve NM efficacy, there has been tremendous effort developing tumor-penetrating NMs by miniaturizing NM sizes or controlling NM surface properties. But progress along the direction of developing tumor penetrating nanoparticle has been slow and improvement of the overall antitumor efficacy has been limited. Herein, a novel strategy of inhibiting solid tumor with high efficiency by dual-functional, nontumor-penetrating NM is demonstrated. The intended NM contains 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a vascular disrupting agent, and doxorubicin (DOX), a cytotoxic drug. Upon arriving at the target tumor site, sustained release of DMXAA from NMs results in disruption of tumor vessel functions, greatly inhibiting the interior tumor cells by cutting off nutritional supply. Meanwhile, the released DOX kills the residual cells at the tumor exterior regions. The in vivo studies demonstrate that this dual functional, nontumor penetrating NM exhibits superior anticancer activity, revealing an alternative strategy of effective tumor growth inhibition. PMID- 28079983 TI - Stretchable Fiber Supercapacitors with High Volumetric Performance Based on Buckled MnO2 /Oxidized Carbon Nanotube Fiber Electrodes. AB - A stretchable fiber supercapacitor (SC) based on buckled MnO2 /oxidized carbon nanotube (CNT) fiber electrode is fabricated by a simple prestraining-then buckling method. The prepared stretchable fiber SC has a specific volumetric capacitance up to 409.4 F cm-3 , which is 33 times that of the pristine CNT fiber based SC, and shows the outstanding stability and repeatability in performance as a stretchable SC. PMID- 28079982 TI - Recombinant soluble apyrase APT102 inhibits thrombosis and intimal hyperplasia in vein grafts without adversely affecting hemostasis or re-endothelialization. AB - : Essentials New strategies are needed to inhibit thrombosis and intimal hyperplasia (IH) in vein grafts (VG). We studied effects of apyrase (APT102) on VGs and smooth muscle and endothelial cells (SMC/EC). APT102 inhibited thrombosis, SMC migration, and IH without impairing hemostasis or EC recovery. Apyrase APT102 is a single-drug approach to inhibit multiple processes that cause VG failure. SUMMARY: Background Occlusion of vein grafts (VGs) after bypass surgery, owing to thrombosis and intimal hyperplasia (IH), is a major clinical problem. Apyrases are enzymes that scavenge extracellular ATP and ADP, and promote adenosine formation at sites of vascular injury, and hence have the potential to inhibit VG pathology. Objectives To examine the effects of recombinant soluble human apyrase, APT102, on platelets, smooth muscle cells (SMCs) and endothelial cells (ECs) in vitro, and on thrombosis and IH in murine VGs. Methods SMC and EC proliferation and migration were studied in vitro. Inferior vena cava segments from donor mice were grafted into carotid arteries of recipient mice. Results APT102 potently inhibited ADP-induced platelet aggregation and VG thrombosis, but it did not impair surgical hemostasis. APT102 did not directly inhibit SMC or EC proliferation, but significantly attenuated the effects of ATP on SMC and EC proliferation. APT102 significantly inhibited SMC migration, but did not inhibit EC migration, which may be mediated, at least in part, by inhibition of SMC, but not EC, migration by adenosine. At 4 weeks after surgery, there was significantly less IH in VGs of APT102-treated mice than in control VGs. APT102 significantly inhibited cell proliferation in VGs, but did not inhibit re-endothelialization. Conclusions Systemic administration of a recombinant human apyrase inhibits thrombosis and IH in VGs without increasing bleeding or compromising re-endothelialization. These results suggest that APT102 has the potential to become a novel, single-drug treatment strategy to prevent multiple pathologic processes that drive early adverse remodeling and occlusion of VGs. PMID- 28079984 TI - Medical application of glycosaminoglycans: a review. AB - The characteristic molecular composition of the different glycosaminoglycans (GAGs) is related to their role as structural components and regulators of a multitude of functions of proteins, cells and tissues in the human body. Therefore, it is not surprising that GAGs are widely used as coating materials for implants, components of 3D-constructs such as tissue engineering scaffolds and hydrogels, but also as diagnostic devices such as biosensors and in controlled release applications. Beside a physisorption or encapsulation of GAGs, these applications often require their chemical modification to allow a stable covalent attachment on surfaces or cross-linking reactions with other molecules. Then, the preservation of the functionality of GAGs under maintenance of their biocompatibility is a challenging task and must be addressed in accordance with the designated field of application. Here, we will give a brief overview on structure and biological functions of GAGs, different methods of their activation and immobilization, the recent progress in GAG-related biomaterials development, as well as some examples of their application in the field of tissue engineering and regenerative medicine. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28079985 TI - One-Pot Bimetallic Pd/Cu-Catalyzed Synthesis of Sulfonamides from Boronic Acids, DABSO and O-Benzoyl Hydroxylamines. AB - A practical and straightforward bimetallic Pd/Cu catalytic system has been developed. This system affords various sulfonamides in one pot from easy-to handle and readily available boronic acids, sulfur dioxide surrogate DABSO and O benzoyl hydroxylamines in high yields. Without additional ligands, the newly developed catalytic system revealed a broad substrate scope for both partners and tolerated a wide array of functional groups even at low catalyst loadings. Furthermore, based on control experiments, a plausible mechanism has been proposed, in which sodium sulfinate has been isolated and identified as the crucial intermediate for this transformation. PMID- 28079986 TI - Establishment of an in vitro three-dimensional model for cartilage damage in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to progressive joint destruction. To further understand the process of rheumatoid cartilage damage, an in vitro model consisting of an interactive tri-culture of synovial fibroblasts (SFs), LPS-stimulated macrophages and a primary chondrocyte based tissue-engineered construct was established. The tissue-engineered construct has a composition similar to that of human cartilage, which is rich in collagen type II and proteoglycans. Data generated from this model revealed that healthy chondrocytes were activated in the presence of SFs and macrophages. The activated chondrocytes subsequently displayed aberrant behaviours as seen in a disease state such as increased apoptosis, decreased gene expression for matrix components such as type II collagen and aggrecan, increased gene expression for tissue-degrading enzymes (MMP-1, -3, -13 and ADAMTS-4, -5), and upregulation of inflammatory mediator gene expression (TNF-alpha, IL-1beta, IL-6 and IKBKB). Additionally, the inclusion of SFs and macrophages in the model enabled both cell types to more closely replicate an in vivo role in mediating cartilage destruction. This is evidenced by extensive matrix loss, detected in the model through immunostaining and biochemical analysis. Subsequent drug treatment with celecoxib has shown that the model was able to respond to the therapeutic effects of this drug by reversing cartilage damage. This study showed that the model was able to recapitulate certain pathological features of an RA cartilage. If properly validated, this model potentially can be used for screening new therapeutic drugs and strategies, thereby contributing to the improvement of anti rheumatic treatment. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28079987 TI - Body-Centered Tetragonal C16 : A Novel Topological Node-Line Semimetallic Carbon Composed of Tetrarings. AB - The present work not only predicts the existence of 3D topological semimetallic carbon allotropes composed of tetrarings, but also provides a likely crystalline structure for the unknown phase produced in the detonation soot. PMID- 28079995 TI - Effects of cell cycle phases on the induction of dental pulp stem cells toward dopaminergic-like cells. AB - Parkinson's disease (PD) is characterized by tremors and cognitive issues, and is due to the death of dopaminergic (DA-ergic) neurons in brain circuits that are responsible for producing neurotransmitter dopamine (DA). Currently, cell replacement therapies are underway to improve upon existing therapeutic approaches such as drug treatments and electrical stimulation. Among the widely available sources, dental pulp stem cells (DPSCs) from deciduous teeth have gained popularity because of their neural crest origin and inherent propensity toward neuronal lineage. Despite the various pre-clinical studies conducted, an important factor yet to be elucidated is the influence of growth phases in a typical trans-differentiation process. This study selected DPSCs at three distinct time points with variable growth phase proportions (G0/G1, S and G2/M) for in vitro trans-differentiation into DA-ergic-like cells. Using commercially available PCR arrays, we identified distinct gene profiles pertaining to cell cycles in these phases. The differentiation outcomes were assessed in terms of morphology and gene and protein expression, as well as with functional assays. It was noted that DPSCs with the highest G0/G1 phase were comparatively the best, representing at least a 2-fold up regulation (p < 0.05) of DA-ergic molecular cues compared to those from the remaining time points. Further investigations in terms of protein expression and DA-release assays also revealed a similar phenomenon (p < 0.05). These findings are expected to provide vital information for consideration in improving standard operating procedures in future cell transplantation work. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28080010 TI - Turmoil in the Health Insurance Marketplaces. AB - The first three years of the Affordable Care Act's Health Insurance Marketplaces have been tumultuous ones, with rapid entry and exit of insurers and recent spikes in premiums. As concerns mount about the stability and viability of the Marketplaces, this brief provides some insight into the forces behind the headlines and presents six options for policymakers to consider. PMID- 28080011 TI - Insurance Coverage and Access to Care Under the Affordable Care Act. AB - This brief details changes in insurance coverage and access to care under the Affordable Care Act. About 20 million individuals gained coverage under the law and access to care improved. Despite these gains, more than 27 million individuals are still uninsured, and many others face barriers in accessing care. As a result of the 2016 elections, the future of the ACA is uncertain. As the next Administration and policymakers debate further health system reforms, they should consider the scope of the ACA's effects on their constituents. PMID- 28080012 TI - Medicaid's future: What Might ACA Repeal Mean? AB - Issue: Republicans in Congress are expected to repeal portions of the Affordable Care Act (ACA) using a fast-track process known as budget reconciliation. Goals: This issue brief examines how repeal legislation could affect Medicaid, the nation's health care safety net, which insured 70 million people in 2016. Findings and Conclusions: Partial-repeal legislation that passed Congress but was vetoed by President Obama in 2016 offers some insight but new legislation could go further. It could repeal the ACA's Medicaid eligibility expansions for adults and children but also roll back other provisions, such as simplified enrollment and improvements in long-term services and supports for beneficiaries with disabilities. Additionally, the Trump Administration could expanduse of demonstration authority to introduce deeper structural changes into Medicaid, such as eligibility restrictions tied to work, required premium contributions and lock-out for nonpayment, annual enrollment periods, and coverage limits and exclusions. Together, these changes would have far-reaching implications for Medicaid's continued role as the nation's safety-net insurer. PMID- 28080019 TI - Controlled Growth of Metal-Organic Framework on Upconversion Nanocrystals for NIR Enhanced Photocatalysis. AB - Development of MOF-based photocatalysts is intriguing research due to their structural flexibility and tremendous catalytic sites, whereas most MOFs only can take use of UV/visible light and lack of response to NIR light. Herein, we present a facile approach to integrate upconversion nanoparticles (UCNPs) with MOF to build a NIR-responsive composite photocatalyst. The MOF shell with controllable thickness can be grown on the UCNPs, thus exhibiting tunable photocatalytic activities under NIR irradiation. Furthermore, we extend visible absorption of the MOF shell by adding -NH2 groups so that the composite photocatalysts have a better utilization of UC emissions and sunlight to improve their activities. The developed composite photocatalysts have been characterized by XRD, TEM, PL, etc., and their photocatalytic performances were systematically explored. The formation and working mechanism of the composite photocatalysts were also elucidated. PMID- 28080020 TI - Biocatalytic Self-Assembly Using Reversible and Irreversible Enzyme Immobilization. AB - Biocatalytic control of molecular self-assembly provides an effective approach for developing smart biomaterials, allowing versatile enzyme-mediated tuning of material structure and properties as well as enabling biomedical applications. We functionalized surfaces with bioinspired polydopamine and polyphenol coatings to study the effects of enzyme surface localization and surface release on the self assembly process. We show how these coatings could be conveniently used to release enzymes for bulk gelation as well as to irreversibly immobilize enzymes for localizing the self-assembly to the surface. The results provide insights to the mode of action of biocatalytic self-assembly relevant to nanofabrication and enzyme-responsive materials. PMID- 28080021 TI - An Ionic Liquid as Interface Linker for Tuning Piezoresistive Sensitivity and Toughness in Poly(vinylidene fluoride)/Carbon Nanotube Composites. AB - Conductive polymer nanocomposites (CPNCs) have emerged as potential alternatives for metallic foil sensors and semiconductor strain gauges. The simultaneous achievement of high piezoresistive sensitivity and large strain ranges for CPNCs currently presents a great challenge and solving this challenge may extend the applications of CPNCs with self-diagnosis capabilities to many structural health monitoring (SHM) systems. This paper reports a facile strategy for fabricating highly piezoresistive and tough poly(vinylidene fluoride) (PVDF) based CPNCs by tuning the interactions between the polymer matrix and multiwalled carbon nanotubes (CNT) using an ionic liquid (IL) as an interface linker/modifier. As a result, the presence of IL achieves homogeneous dispersion of CNTs in PVDF but causes a reduced number of CNT-CNT ohmic contacts with higher electrical contact resistance. According to the lower initial resistivity, piezoresistive sensitivity is greatly improved, and the gauge factor (GF) varies from 7 to 60 upon the addition of IL. It is also shown that IL tunes PVDF-CNT interfacial bonding and, as an effective interface linker/modifier, achieves significantly improved sensing strain ranges (increased from ca. 6 to 21%) and toughness (elongation at break increases from 6 to 130%) of CPNCs. These results substantially advance the understanding of the missing relationship between polymer-filler interface interactions and piezoresistive properties and have important implications for future studies of tuning polymer-filler interface bonding properties and piezoresistive sensitivity. PMID- 28080022 TI - Single-Wall Carbon Nanotube Doping in Lead-Acid Batteries: A New Horizon. AB - The addition of single-wall carbon nanotubes (SWCNT) to lead-acid battery electrodes is the most efficient suppresser of uncontrolled sulfation processes. Due to the cost of SWCNT, we studied the optimization loading of SWCNT in lead acid battery electrodes. We optimized the SWCNT loading concentrations in both the positive and negative plates, separately. Loadings of 0.01% and 0.001% in the positive and negative active masses were studied, respectively. Two volts of lead acid laboratory cells with sulfuric acid, containing silica gel-type electrolytes, were cycled in a 25% and 50% depth-of-discharge (DOD) cycling with a charging rate of C and 2C, respectively, and discharge rates of C/2 and C, respectively. All tests successfully demonstrated an excellent service life up to about 1700 and 1400 cycles for 25% and 50% DOD operations, respectively, at a low loading level of SWCNT. This performance was compared with CNT-free cells and cells with a multiwall carbon nanotube (MWCNT) additive. The outstanding performance of the lead-acid cells with the SWCNT additive is due to the oxidative stability of the positive plates during charging and the efficient reduction in sulfation in both plates while forming conducting active-material matrices. PMID- 28080023 TI - Microbial Nanoscopy: Breakthroughs, Challenges, and Opportunities. AB - Studying the structure, properties, and interactions of microbial cells is key to understanding the functions of the microbiome. Recent advances in nanotechnology have offered new tools to probe microbes at the single-molecule and single-cell levels. In this issue of ACS Nano, Kumar et al. present an atomic force microscopy method that is capable of imaging the nanoscale organization of bacterial proteins in native, curved membranes. This study represents an important step forward in the development of nanoscopy techniques for analyzing biological systems with large curvature and vertical dimensions, such as membrane vesicles and bacterial cells. PMID- 28080024 TI - Direct Fabrication of Micro/Nano-Patterned Surfaces by Vertical-Directional Photofluidization of Azobenzene Materials. AB - Anisotropic movement of azobenzene materials (i.e., azobenzene molecules incorporated in polymer, glass, or supramolecules) has provided significant opportunities for the fabrication of micro/nanoarchitectures. The examples include circular holes, line gaps, ellipsoidal holes, and nanofunnels. However, all of the previous studies have only focused on the lateral directional movement for the structural shaping of azobenzene materials. Herein, we propose structural shaping based on a vertical directional movement of azobenzene materials. To do this, light with oblique incidence, containing normal direction light polarization, was illuminated onto azobenzene materials film contact with patterned elastomeric molds (i.e., PDMS) so that the resulting vertical directional movement of azobenzene materials fills in the cavities of the molds and results in pattern formation. As a result, a range of patterns with sizes of features from micro- to sub-100 nm scale was successfully fabricated in a large area (few cm2), and the structural height was deterministically controlled by simply adjusting irradiation time. In addition to the notable capability of fabricating the single-scale structures, the technique provides a facile way to fabricate complex hierarchical multiscale structures, ensuring its versatility and wide applicability to various applications. As a selected exemplary application of the multiscale structures, a superhydrophobic surface has been successfully demonstrated. PMID- 28080026 TI - Ionic Strength Responsive Sulfonated Polystyrene Opals. AB - Stimuli-responsive photonic crystals (PCs) represent an intriguing class of smart materials very promising for sensing applications. Here, selective ionic strength responsive polymeric PCs are reported. They are easily fabricated by partial sulfonation of polystyrene opals, without using toxic or expensive monomers and etching steps. The color of the resulting hydrogel-like ordered structures can be continuously shifted over the entire visible range (405-760 nm) by changing the content of ions over an extremely wide range of concentration (from about 70 MUM to 4 M). The optical response is completely independent from pH and temperature, and the initial color can be fully recovered by washing the sulfonated opals with pure water. These new smart photonic materials could find important applications as ionic strength sensors for environmental monitoring as well as for healthcare screening. PMID- 28080025 TI - Enabling Energy Efficiency and Polarity Control in Germanium Nanowire Transistors by Individually Gated Nanojunctions. AB - Germanium is a promising material for future very large scale integration transistors, due to its superior hole mobility. However, germanium-based devices typically suffer from high reverse junction leakage due to the low band-gap energy of 0.66 eV and therefore are characterized by high static power dissipation. In this paper, we experimentally demonstrate a solution to suppress the off-state leakage in germanium nanowire Schottky barrier transistors. Thereto, a device layout with two independent gates is used to induce an additional energy barrier to the channel that blocks the undesired carrier type. In addition, the polarity of the same doping-free device can be dynamically switched between p- and n-type. The shown germanium nanowire approach is able to outperform previous polarity-controllable device concepts on other material systems in terms of threshold voltages and normalized on-currents. The dielectric and Schottky barrier interface properties of the device are analyzed in detail. Finite-element drift-diffusion simulations reveal that both leakage current suppression and polarity control can also be achieved at highly scaled geometries, providing solutions for future energy-efficient systems. PMID- 28080027 TI - Asymmetric Pentagonal Metal Meshes for Flexible Transparent Electrodes and Heaters. AB - Metal meshes have emerged as an important class of flexible transparent electrodes. We report on the characteristics of a new class of asymmetric meshes, tiled using a recently discovered family of pentagons. Micron-scale meshes were fabricated on flexible polyethylene terephthalate substrates via optical lithography, metal evaporation (Ti 10 nm, Pt 50 nm), and lift-off. Three different designs were assessed, each with the same tessellation pattern and line width (5 MUm), but with different sizes of the fundamental pentagonal unit. Good mechanical stability was observed for both tensile strain and compressive strain. After 1000 bending cycles, devices subjected to tensile strain showed fractional resistance increases in the range of 8-17%, while devices subjected to compressive strain showed fractional resistance increases in the range of 0-7%. The performance of the pentagonal metal mesh devices as visible transparent heaters via Joule heating was also assessed. Rapid response times (~15 s) at low bias voltage (<=5 V) and good thermal resistance characteristics (213-258 degrees C cm2/W) were found using measured thermal imaging data. Deicing of an ice-bearing glass coupon on top of the transparent heater was also successfully demonstrated. PMID- 28080028 TI - A Grand Avenue to Au Nanocluster Electrochemiluminescence. AB - In most cases of semiconductor quantum dot nanocrystals, the inherent optical and electrochemical properties of these interesting nanomaterials do not translate into expected efficient electrochemiluminescence or electrogenerated chemiluminescence (ECL) because of the surface-state induction effect. Thus, their low ECL efficiencies, while very interesting to explore, limit their applications. As their electrochemistry is not well-defined, insight into their ECL mechanistic details is also limited. Alternatively, gold nanoclusters possess monodispersed sizes with atomic precision, low and well defined HOMO-LUMO energy gaps, and stable optical and electrochemical properties that make them suitable for potential ECL applications. In this Account, we demonstrate strong and sustainable ECL of gold nanoclusters Au25z (i.e., Au25(SR)18z, z = 1-, 0, 1+), Au38(SR)24, and Au144(SR)60, where the ligand SR is 2-phenylethanethiol. By correlation of the optical and electrochemical features of Au25 nanoclusters, a Latimer-type diagram can be constructed to reveal thermodynamic relationships of five oxidation states (Au252+, Au25+, Au250, Au25-, and Au252-) and three excited states (Au25-*, Au250*, and Au25+*). We describe ECL mechanisms and reaction kinetics by means of conventional ECL-voltage curves and novel spooling ECL spectroscopy. Notably, their ECL in the presence of tri-n-propylamine (TPrA), as a coreactant, is attributed to emissions from Au25-* (950 nm, strong), Au250* (890 nm, very strong), and Au25+* (890 nm, very strong), as confirmed by the photoluminescence (PL) spectra of the three Au25 clusters electrogenerated in situ. The ECL emissions are controllable by adjustment of the concentrations of TPrA. and Au25-, Au250, and Au25+ species in the vicinity of the working electrode and ultimately the applied potential. It was determined that the Au25 /TPrA coreactant system should have an ECL efficiency of >50% relative to the Ru(bpy)32+/TPrA, while those of Au250/TPrA and Au25+/TPrA reach 103% and 116%, respectively. Au25-* is the main light emission source for Au25z in the presence of benzoyl peroxide (BPO) as a coreactant, with a relative efficiency of up to 30%. For Au38, BPO leads to the Au38-* excited state, which emits light at 930 nm. In the Au38/TPrA coreactant system, we find that highly efficient light emission at 930 nm is mainly from Au38+* (and also Au383+*), with an efficiency 3.5 times that of the Ru(bpy)32+/TPrA reference. We show that the ECL and PL of the various Au38 charge states, namely, Au382-, Au38-, Au380, Au38+, Au382+, and Au384+, have the same peak wavelength of 930 nm. Finally, we demonstrate ECL with a peak wavelength of 930 nm from the Au144/TPrA coreactant system, which is released from the electrogenerated excited states Au144+* and Au1443+*. In our opinion, these gold nanoclusters represent a new class of effective near-IR ECL emitters, from which applications such as bioimaging, biological testing, and medical diagnosis are anticipated once they are made water-dispersible with hydrophilic capping ligands. PMID- 28080029 TI - One-Step Fabrication of 3D Nanohierarchical Nickel Nanomace Array To Sinter with Silver NPs and the Interfacial Analysis. AB - Three-dimensional (3D) nanohierarchical Ni nanomace (Ni NM) array was fabricated on copper substrate by only one step with electroplating method, the unique structure was covered with Au film (Ni/Au NM) without changing its morphology, and in the following step, it was sintered with silver nanoparticle (Ag NP) paste. The structure of the Ni NM array and its surface morphology were characterized by X-ray diffraction, scanning electron microscope (SEM), and atomic force microscope. The sintered interface was investigated by SEM, transmission electron microscopy, and energy-dispersive X-ray spectroscopy to analyze the sintering mechanism. The results showed that a metallurgical bond was successfully achieved at 250 degrees C without any gas or vacuum shield and extra pressure. The Cu substrate with Ni/Au NM array was able to join with the Ag NP paste without obvious voids. Due to the compatible chemical potential between Ag NPs and Ni/Au NM array, the Au element was able to diffuse into the Ag layer with about 800 nm distance. Based on the excellent 3D nanohierarchical structure, the shear strength of Ni/Au NM array was 6 times stronger than the flat Ni/Au coated substrate. It turned out that the substrate surface played a crucial role in improving the shear strength and sintering efficiency. The 3D Ni NM array had achieved an excellent bonding interface and had great potential application in the microelectronics packaging field. PMID- 28080030 TI - Chemoselective, Enzymatic C-H Bond Amination Catalyzed by a Cytochrome P450 Containing an Ir(Me)-PIX Cofactor. AB - Cytochrome P450 enzymes have been engineered to catalyze abiological C-H bond amination reactions, but the yields of these reactions have been limited by low chemoselectivity for the amination of C-H bonds over competing reduction of the azide substrate to a sulfonamide. Here we report that P450s derived from a thermophilic organism and containing an iridium porphyrin cofactor (Ir(Me)-PIX) in place of the heme catalyze enantioselective intramolecular C-H bond amination reactions of sulfonyl azides. These reactions occur with chemoselectivity for insertion of the nitrene units into C-H bonds over reduction of the azides to the sulfonamides that is higher and with substrate scope that is broader than those of enzymes containing iron porphyrins. The products from C-H amination are formed in up to 98% yield and ~300 TON. In one case, the enantiomeric excess reaches 95:5 er, and the reactions can occur with divergent site selectivity. The chemoselectivity for C-H bond amination is greater than 20:1 in all cases. Variants of the Ir(Me)-PIX CYP119 displaying these properties were identified rapidly by evaluating CYP119 mutants containing Ir(Me)-PIX in cell lysates, rather than as purified enzymes. This study sets the stage to discover suitable enzymes to catalyze challenging C-H amination reactions. PMID- 28080031 TI - A New Approach to Sensitize Antitumor Monofunctional Platinum(II) Complexes via Short Time Photo-Irradiation. AB - Sensitizing the antitumor activity of monofunctional PtII complexes is a reliable approach to developing antitumor agents different from the classic Pt-based drugs. Considering the poor intracellular accumulation of monofunctional PtII complexes, in this study, the photosensitizing monofunctional PtII complex Pt-BA was derived from a weak BODIPY (boron-dipyrromethene)-derived photosensitizer BA, with the purpose to improve its antitumor cytotoxicity via enhancing its intracellular accumulation with a short time photo-irradiation. Photoinduced reactive oxygen species (ROS) determination indicated that the PtII center in Pt BA is able to improve the photoinduced ROS production ability of BA, which makes Pt-BA a mild photosensitizer. Fluorescence imaging disclosed that dark incubation makes Pt-BA accumulate mainly on the surface of cell membrane, and the later short time photo-irradiation (5 min) promotes distinctly the intracellular accumulation of Pt-BA, which has been confirmed by inductively coupled plasma mass spectrometry determination. Flow cytometric Annexin V-FITC assay indicated that the short time irradiation of Pt-BA induces in situ the cell membrane damage, which might finally enhance the intracellular accumulation of this monofunctional complex. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay confirmed that the short time photo-irradiation promotes distinctly the antitumor cytotoxicity of Pt-BA against MCF-7, SGC-7901, A549, and HeLa cell lines. The photopromoted antitumor activity of Pt-BA implies that modifying monofunctional PtII complex as a mild photosensitizer to promote its cell accumulation is a useful approach to sensitizing the antitumor activity of monofunctional PtII complex and renders the possibility of monofunctional PtII prodrugs for precise chemotherapy via only short time photoactivation. PMID- 28080032 TI - Heteroprotein Complex Formation of Bovine Lactoferrin and Pea Protein Isolate: A Multiscale Structural Analysis. AB - Associative electrostatic interactions between two oppositely charged globular proteins, lactoferrin (LF) and pea protein isolate (PPI), the latter being a mixture of vicilin, legumin, and convicilin, was studied with a specific PPI/LF molar ratio at room temperature. Structural aspects of the electrostatic complexes probed at different length scales were investigated as a function of pH by means of different complementary techniques, namely, with dynamic light scattering, small-angle X-ray scattering (SAXS), turbidity measurements, and atomic force microscopy (AFM). Irrespective of the applied techniques, the results consistently displayed that complexation between LF and PPI did occur. In an optimum narrow range of pH 5.0-5.8, a viscous liquid phase of complex coacervate was obtained upon mild centrifugation of the turbid LF-PPI mixture with a maximum Rh, turbidity and the zeta-potential being close to zero observed at pH 5.4. In particular, the SAXS data demonstrated that the coacervates were densely assembled with a roughly spherical size distribution exhibiting a maximum extension of ~80 nm at pH 5.4. Equally, AFM image analysis showed size distributions containing most frequent cluster sizes around 40-80 nm with spherical to elliptical shapes (axis aspect ratio <= 2) as well as less frequent elongated to chainlike structures. The most frequently observed compact complexes, we identify as mainly leading to LF-PPI coacervation, whereas for the less frequent chain-like aggregates, we hypothesize that additionally PPI-PPI facilitated complexes exist. PMID- 28080033 TI - Solvent-Templated Folding of Perylene Bisimide Macrocycles into Coiled Double String Ropes with Solvent-Sensitive Optical Signatures. AB - A series of semirigid perylene bisimide (PBI) macrocycles with varied ring size containing two to nine PBI chromophores were synthesized in a one-pot reaction and their photophysical properties characterized by fluorescence, steady-state, and transient absorption spectroscopy as well as femtosecond stimulated Raman spectroscopy. These macrocycles show solvent-dependent conformational equilibria and excited-state properties. In dichloromethane, the macrocycles prevail in wide stretched conformations and upon photoexcitation exhibit symmetry-breaking charge separation followed by charge recombination to triplet states, which photosensitize singlet oxygen formation. In contrast, in aromatic solvents folding of the macrocycles with a distinct odd-even effect regarding the number of PBI chromophore units was observed in steady-state and time-resolved absorption and fluorescence spectroscopy as well as femtosecond stimulated Raman spectroscopy. These distinctive optical properties are attributable to the folding of the even-membered macrocycles into exciton-vibrational coupled dimer pairs in aromatic solvents. Studies in a variety of aromatic solvents indicate that these solvents embed between PBI dimer pairs and accordingly template the folding of even-membered PBI macrocycles into ropelike folded conformations that give rise to solvent-specific exciton-vibrational couplings in UV-vis absorption spectra. As a consequence of the embedding of solvent molecules in the coiled double-string rope architecture, highly solvent specific intensity ratios are observed for the two lowest-energy exciton-vibrational bands, enabling assignment of the respective solvent simply based on the absorption spectra measured for the tetramer macrocycle. PMID- 28080034 TI - Mechanism of Flavoprotein l-6-Hydroxynicotine Oxidase: pH and Solvent Isotope Effects and Identification of Key Active Site Residues. AB - The flavoenzyme l-6-hydroxynicotine oxidase is a member of the monoamine oxidase family that catalyzes the oxidation of (S)-6-hydroxynicotine to 6 hydroxypseudooxynicotine during microbial catabolism of nicotine. While the enzyme has long been understood to catalyze oxidation of the carbon-carbon bond, it has recently been shown to catalyze oxidation of a carbon-nitrogen bond [Fitzpatrick, P. F., et al. (2016) Biochemistry 55, 697-703]. The effects of pH and mutagenesis of active site residues have now been utilized to study the mechanism and roles of active site residues. Asn166 and Tyr311 bind the substrate, while Lys287 forms a water-mediated hydrogen bond with flavin N5. The N166A and Y311F mutations result in ~30- and ~4-fold decreases in kcat/Km and kred for (S)-6-hydroxynicotine, respectively, with larger effects on the kcat/Km value for (S)-6-hydroxynornicotine. The K287M mutation results in ~10-fold decreases in these parameters and a 6000-fold decrease in the kcat/Km value for oxygen. The shapes of the pH profiles are not altered by the N166A and Y311F mutations. There is no solvent isotope effect on the kcat/Km value for amines. The results are consistent with a model in which both the charged and neutral forms of the amine can bind, with the former rapidly losing a proton to a hydrogen bond network of water and amino acids in the active site prior to the transfer of hydride to the flavin. PMID- 28080035 TI - Fluorescence Turn-On Sensing of DNA Duplex Formation by a Tricyclic Cytidine Analogue. AB - Most fluorescent nucleoside analogues are quenched when base stacked and some maintain their brightness, but there has been little progress toward developing nucleoside analogues that markedly increase their fluorescence upon duplex formation. Here, we report on the design and synthesis of a new tricyclic cytidine analogue, 8-diethylamino-tC (8-DEA-tC), that responds to DNA duplex formation with up to a 20-fold increase in fluorescent quantum yield as compared with the free nucleoside, depending on neighboring bases. This turn-on response to duplex formation is the greatest of any reported nucleoside analogue that can participate in Watson-Crick base pairing. Measurements of the quantum yield of 8 DEA-tC mispaired with adenosine and, separately, opposite an abasic site show that there is almost no fluorescence increase without the formation of correct Watson-Crick hydrogen bonds. Kinetic isotope effects from the use of deuterated buffer show that the duplex protects 8-DEA-tC against quenching by excited state proton transfer. These results, supported by DFT calculations, suggest a rationale for the observed photophysical properties that is dependent on duplex integrity and the electronic structure of the analogue. PMID- 28080036 TI - Lithium Hexamethyldisilazide-Mediated Enolization of Acylated Oxazolidinones: Solvent, Cosolvent, and Isotope Effects on Competing Monomer- and Dimer-Based Pathways. AB - Lithium hexamethyldisilazide (LiHMDS)-mediated enolization of (+)-4-benzyl-3 propionyl-2-oxazolidinone in THF-hydrocarbon mixtures shows unusual sensitivity to the choice of hydrocarbon cosolvent (hexane versus toluene) and to isotopic labeling. Four mechanisms corresponding to monosolvated monomers, trisolvated dimers, octasolvated monomers, and octasolvated dimers were identified. Even under conditions in which the LiHMDS monomer was the dominant observable form, dimer-based metalation was significant. The mechanism-dependent isotope and cosolvent effects are discussed in the context of ground-state stabilization and transition-state tunneling. PMID- 28080037 TI - Global Metabolic Engineering of Glycolytic Pathway via Multicopy Integration in Saccharomyces cerevisiae. AB - The use of renewable feedstocks for producing biofuels and biobased chemicals by engineering metabolic pathways of yeast Saccharomyces cerevisiae has recently become an attractive option. Many researchers attempted to increase glucose consumption rate by overexpressing some glycolytic enzymes because most target biobased chemicals are derived through glycolysis. However, these attempts have met with little success. In this study, to create a S. cerevisiae strain with high glucose consumption rate, we used multicopy integration to develop a global metabolic engineering strategy. Among approximately 350 metabolically engineered strains, YPH499/dPdA3-34 exhibited the highest glucose consumption rate. This strain showed 1.3-fold higher cell growth rate and glucose consumption rate than the control strain. Real-time PCR analysis revealed that transcription levels of glycolysis-related genes such as HXK2, PFK1, PFK2, PYK2, PGI1, and PGK1 in YPH499/dPdA3-34 were increased. Our strategy is thus a promising approach to optimize global metabolic pathways in S. cerevisiae. PMID- 28080038 TI - Tracking Catalyst Redox States and Reaction Dynamics in Ni-Fe Oxyhydroxide Oxygen Evolution Reaction Electrocatalysts: The Role of Catalyst Support and Electrolyte pH. AB - Ni-Fe oxyhydroxides are the most active known electrocatalysts for the oxygen evolution reaction (OER) in alkaline electrolytes and are therefore of great scientific and technological importance in the context of electrochemical energy conversion. Here we uncover, investigate, and discuss previously unaddressed effects of conductive supports and the electrolyte pH on the Ni-Fe(OOH) catalyst redox behavior and catalytic OER activity, combining in situ UV-vis spectro electrochemistry, operando electrochemical mass spectrometry (DEMS), and in situ cryo X-ray absorption spectroscopy (XAS). Supports and pH > 13 strongly enhanced the precatalytic voltammetric charge of the Ni-Fe oxyhydroxide redox peak couple, shifted them more cathodically, and caused a 2-3-fold increase in the catalytic OER activity. Analysis of DEMS-based faradaic oxygen efficiency and electrochemical UV-vis traces consistently confirmed our voltammetric observations, evidencing both a more cathodic O2 release and a more cathodic onset of Ni oxidation at higher pH. Using UV-vis, which can monitor the amount of oxidized Ni+3/+4 in situ, confirmed an earlier onset of the redox process at high electrolyte pH and further provided evidence of a smaller fraction of Ni+3/+4 in mixed Ni-Fe centers, confirming the unresolved paradox of a reduced metal redox activity with increasing Fe content. A nonmonotonic super-Nernstian pH dependence of the redox peaks with increasing Fe content-displaying Pourbaix slopes as steep as -120 mV/pH-suggested a two proton-one electron transfer. We explain and discuss the experimental pH effects using refined coupled (PCET) and decoupled proton transfer-electron transfer (PT/ET) schemes involving negatively charged oxygenate ligands generated at Fe centers. Together, we offer new insight into the catalytic reaction dynamics and associated catalyst redox chemistry of the most important class of alkaline OER catalysts. PMID- 28080039 TI - Using Standing Gold Nanorod Arrays as Surface-Enhanced Raman Spectroscopy (SERS) Substrates for Detection of Carbaryl Residues in Fruit Juice and Milk. AB - In recent years, there have been increasing concerns about pesticide residues in various foods. On the other hand, there is growing attention in utilizing novel nanomaterials as highly sensitive, low-cost, and reproducible substrates for surface-enhanced Raman spectroscopy (SERS) applications. The objective of this study was to develop a SERS method for the rapid detection of pesticides that were extracted from different types of food samples (fruit juice and milk). A new SERS substrate was prepared by assembling gold nanorods into standing arrays on a gold-coated silicon slide. The standing nanorod arrays were neatly arranged and were able to generate a strong electromagnetic field in SERS measurement. The as prepared SERS substrate was utilized to detect carbaryl in acetonitrile/water solution, fruit juices (orange and grapefruit), and milk. The results show that the concentrations of carbaryl spiked in fruit juice and milk were linearly correlated with the concentrations predicted by the partial least-squares (PLS) models with r values of 0.91, 0.88, and 0.95 for orange juice, grapefruit juice, and milk, respectively. The SERS method was able to detect carbaryl that was extracted from fruit juice and milk samples at a 50 ppb level. The detection limits of carbaryl were 509, 617, and 391 ppb in orange juice, grapefruit juice, and milk, respectively. All detection limits are below the maximum residue limits that were set by the U.S. EPA. Moreover, satisfactory recoveries (82-97.5%) were accomplished for food samples using this method. These results demonstrate that SERS coupled with the standing gold nanorod array substrates is a rapid, reliable, sensitive, and reproducible method for the detection of pesticide residues in foods. PMID- 28080041 TI - In Vitro Reconstitution and Optimization of the Entire Pathway to Convert Glucose into Fatty Acid. AB - Glucose and fatty acids play essential physiological roles in nearly all living organisms, and the pathway that converts glucose into fatty acid is pivotal to the central metabolic network. We have successfully reconstituted a pathway that converts glucose to fatty acid in vitro using 30 purified proteins. Through systematic titration and optimization of the glycolytic pathway and pyruvate dehydrogenase, we increased the yield of free fatty acid from nondetectable to a level that exceeded 9% of the theoretical yield. We also reconstituted the entire pentose-phosphate pathway of Escherichia coli and established a pentose phosphate glycolysis hybrid pathway, replacing GAPDH to enhance NADPH availability. Our efforts provide a useful platform for research involving these core biochemical transformations. PMID- 28080040 TI - Insights into Thiol-Aromatic Interactions: A Stereoelectronic Basis for S-H/pi Interactions. AB - Thiols can engage favorably with aromatic rings in S-H/pi interactions, within abiological systems and within proteins. However, the underlying bases for S-H/pi interactions are not well understood. The crystal structure of Boc-l-4 thiolphenylalanine tert-butyl ester revealed crystal organization centered on the interaction of the thiol S-H with the aromatic ring of an adjacent molecule, with a through-space Hthiol...Caromatic distance of 2.71 A, below the 2.90 A sum of the van der Waals radii of H and C. The nature of this interaction was further examined by DFT calculations, IR spectroscopy, solid-state NMR spectroscopy, and analysis of the Cambridge Structural Database. The S-H/pi interaction was found to be driven significantly by favorable molecular orbital interactions, between an aromatic pi donor orbital and the S-H sigma* acceptor orbital (a pi -> sigma* interaction). For comparison, a structural analysis of O-H/pi interactions and of cation/pi interactions of alkali metal cations with aromatic rings was conducted. Na+ and K+ exhibit a significant preference for the centroid of the aromatic ring and distances near the sum of the van der Waals and ionic radii, as expected for predominantly electrostatic interactions. Li+ deviates substantially from Na+ and K+. The S-H/pi interaction differs from classical cation/pi interactions by the preferential alignment of the S-H sigma* toward the ring carbons and an aromatic pi orbital rather than toward the aromatic centroid. These results describe a potentially broadly applicable approach to understanding the interactions of weakly polar bonds with pi systems. PMID- 28080042 TI - Relative Stability of Empty Exohedral Fullerenes: pi Delocalization versus Strain and Steric Hindrance. AB - Predicting and understanding the relative stability of exohedral fullerenes is an important aspect of fullerene chemistry, since the experimentally formed structures do not generally follow the rules that govern addition reactions or the making of pristine fullerenes. First-principles theoretical calculations are of limited applicability due to the large number of possible isomeric forms, for example, more than 50 billion for C60X8. Here we propose a simple model, exclusively based on topological arguments, that allows one to predict the relative stability of exohedral fullerenes without the need for electronic structure calculations or geometry optimizations. The model incorporates the effects of pi delocalization, cage strain, and steric hindrance. We show that the subtle interplay between these three factors is responsible for (i) the formation of non-IPR (isolated pentagon rule) exohedral fullerenes in contrast with their pristine fullerene counterparts, (ii) the appearance of more pentagon-pentagon adjacencies than predicted by the PAPR (pentagon-adjacency penalty rule), (iii) the changes in regioisomer stability due to the chemical nature of the addends, and (iv) the variations in fullerene cage stability with the progressive addition of chemical species. PMID- 28080043 TI - Plasma-Based Water Treatment: Efficient Transformation of Perfluoroalkyl Substances in Prepared Solutions and Contaminated Groundwater. AB - A process based on electrical discharge plasma was tested for the transformation of perfluorooctanoic acid (PFOA). The plasma-based process was adapted for two cases, high removal rate and high removal efficiency. During a 30 min treatment, the PFOA concentration in 1.4 L of aqueous solutions was reduced by 90% with the high rate process (76.5 W input power) and 25% with the high efficiency process (4.1 W input power). Both achieved remarkably high PFOA removal and defluorination efficiencies compared to leading alternative technologies. The high efficiency process was also used to treat groundwater containing PFOA and several cocontaminants including perfluorooctanesulfonate (PFOS), demonstrating that the process was not significantly affected by cocontaminants and that the process was capable of rapidly degrading PFOS. Preliminary investigation into the byproducts showed that only about 10% of PFOA and PFOS is converted into shorter chain perfluoroalkyl acids (PFAAs). Investigation into the types of reactive species involved in primary reactions with PFOA showed that hydroxyl and superoxide radicals, which are typically the primary plasma-derived reactive species, play no significant role. Instead, scavenger experiments indicated that aqueous electrons account for a sizable fraction of the transformation, with free electrons and/or argon ions proposed to account for the remainder. PMID- 28080044 TI - Structural Dependence of the Ising-type Magnetic Anisotropy and of the Relaxation Time in Mononuclear Trigonal Bipyramidal Co(II) Single Molecule Magnets. AB - This paper describes the correlation between Ising-type magnetic anisotropy and structure in trigonal bipyramidal Co(II) complexes. Three sulfur-containing trigonal bipyramidal Co(II) complexes were synthesized and characterized. It was shown that we can engineer the magnitude of the Ising anisotropy using ligand field theory arguments in conjunction with structural parameters. To prepare this series of compounds, we used, on the one hand, a tetradentate ligand containing three sulfur atoms and one amine (NS3tBu) and on the other hand three different axial ligands, namely, Cl-, Br-, and NCS-. The organic ligand imposes a trigonal bipyramidal arrangement with the three sulfur atoms lying in the trigonal plane with long Co-S bond distances. The magnetic properties of the compounds were measured, and ab initio calculations were used to analyze the anisotropy parameters and perform magneto-structural correlations. We demonstrate that a smaller axial zero-field splitting parameter leads to slower relaxation time when the symmetry is strictly axial, while the presence of very weak rhombicity decreases the energy barrier and speeds the relaxation of the magnetization. PMID- 28080045 TI - Crystal Engineering of Hand-Twisted Helical Crystals. AB - A strategy is outlined for the design of hand-twisted helical crystals. The starting point in the exercise is the one-dimensional (1D) plastic crystal, 1,4 dibromobenzene, which is then changed to a 1D elastic crystal, exemplified by 4 bromophenyl 4'-chlorobenzoate, by introduction of a molecular synthon -O-CO- in lieu of the supramolecular synthon Br...Br in the precursor. The 1D elastic crystals are next modified to two-dimensional (2D) elastic crystals, of the type 4-bromophenyl 4'-nitrobenzoate where the halogen bonding and C-H...O hydrogen bonding are well-matched. Finally, varying the interaction strengths in these 2D elastic crystals gives plastic crystals with two pairs of bendable faces but without slip planes. Typical examples are 4-chlorophenyl and 4-bromophenyl 4' nitrobenzoate. This type of 2D plasticity represents a new type of bendable crystals in which plastic behavior is seen with a fair degree of isotropic character in the crystal packing. The presence of two sets of bendable faces, generally orthogonal to each other, allows for the possibility of hand-twisting of the crystals to give grossly helical morphologies. Accordingly, we propose the name hand-twisted helical crystals for these substances. PMID- 28080046 TI - Application of 2-Aminothiazoline-4-carboxylic Acid as a Forensic Marker of Cyanide Exposure. AB - Cyanides are infamous for their highly poisonous properties. Accidental cyanide poisoning occurs frequently, but occasionally, intentional poisonings also occur. Inhalation of fumes generated by fire may also cause cyanide poisoning. There are many limitations in direct analysis of cyanide. 2-Aminothiazoline-4-carboxylic acid (ATCA), a cyanide metabolite, seems to be the only surrogate that is being used in the detection of cyanide because of its stability and its cyanide dependent quality in a biological matrix. Unfortunately, toxicokinetic studies on diverse animal models suggest significant interspecies differences; therefore, the attempt to extrapolate animal models to human models may be unsuccessful. The aim of the present study was to evaluate the use of ATCA as a forensic marker of cyanide exposure. For this purpose, post-mortem materials (blood and organs) from fire victims (n = 32) and cyanide-poisoned persons (n = 3) were collected. The distribution of ATCA in organs and its thermal stability were evaluated. The variability of cyanides in a putrid sample and in the context of their long-term and higher temperature stability was established. The presence of ATCA was detected by using an LC-MS/MS method and that of cyanide was detected spectrofluorimetrically. This is the first report on the endogenous ATCA concentrations and the determination of ATCA distribution in tissues of fire victims and cyanide-poisoned persons. It was found that blood and heart had the highest ATCA concentrations. ATCA was observed to be thermally stable even at 90 degrees C. Even though the cyanide concentration was not elevated in putrid samples, it was unstable during long-term storage and at higher temperature, as expected. The relationship between ATCA and cyanides was also observed. Higher ATCA concentrations were related to increased levels of cyanide in blood and organs (less prominent). ATCA seems to be a reliable forensic marker of exposure to lethal doses of cyanide. PMID- 28080047 TI - Burden of Disease from Rising Coal-Fired Power Plant Emissions in Southeast Asia. AB - Southeast Asia has a very high population density and is on a fast track to economic development, with most of the growth in electricity demand currently projected to be met by coal. From a detailed analysis of coal-fired power plants presently planned or under construction in Southeast Asia, we project in a business-as-usual scenario that emissions from coal in the region will triple to 2.6 Tg a-1 SO2 and 2.6 Tg a-1 NOx by 2030, with the largest increases occurring in Indonesia and Vietnam. Simulations with the GEOS-Chem chemical transport model show large resulting increases in surface air pollution, up to 11 MUg m-3 for annual mean fine particulate matter (PM2.5) in northern Vietnam and up to 15 ppb for seasonal maximum 1 h ozone in Indonesia. We estimate 19 880 (11 400-28 400) excess deaths per year from Southeast Asian coal emissions at present, increasing to 69 660 (40 080-126 710) by 2030. 9000 of these excess deaths in 2030 are in China. As Chinese emissions from coal decline in coming decades, transboundary pollution influence from rising coal emissions in Southeast Asia may become an increasing issue. PMID- 28080048 TI - Wearable Sensors for Personal Monitoring and Estimation of Inhaled Traffic Related Air Pollution: Evaluation of Methods. AB - Physical activity and ventilation rates have an effect on an individual's dose and may be important to consider in exposure-response relationships; however, these factors are often ignored in environmental epidemiology studies. The aim of this study was to evaluate methods of estimating the inhaled dose of air pollution and understand variability in the absence of a true gold standard metric. Five types of methods were identified: (1) methods using (physical) activity types, (2) methods based on energy expenditure, METs (metabolic equivalents of task), and oxygen consumption, (3) methods based on heart rate or (4) breathing rate, and (5) methods that combine heart and breathing rate. Methods were compared using a real-life data set of 122 adults who wore devices to track movement, black carbon air pollution, and physiological health markers for 3 weeks in three European cities. Different methods for estimating minute ventilation performed well in relative terms with high correlations among different methods, but in absolute terms, ignoring increased ventilation during day-to-day activities could lead to an underestimation of the daily dose by a factor of 0.08-1.78. There is no single best method, and a multitude of methods are currently being used to approximate the dose. The choice of a suitable method for determining the dose in future studies will depend on both the size and the objectives of the study. PMID- 28080049 TI - Modeling Diversity in Structures of Bacterial Outer Membrane Lipids. AB - Lipopolysaccharides (LPSs) are vital components of the outer membrane of Gram negative bacteria, and they act as extremely strong stimulators of innate immunity in diverse eukaryotic species. The primary immunostimulatory center of the LPS molecule is lipid A, a disaccharide-bound lipophilic domain. Considering the broad diversity in bacterial species, there are variations in the lipid A structures and their immunogenic potencies. In this work, we model the lipid A structures of eight commensal or human pathogenic bacterial species: Helicobacter pylori, Porphyromonas gingivalis, Bacteroides fragilis, Bordetella pertussis, Chlamydia trachomatis, Campylobacter jejuni, Neisseria meningitidis, and Salmonella minnesota. The membrane properties of these bacterial species were characterized and compared using molecular simulations. The structure-property relationships that emerge from this lipid A molecular library highlight the roles of acyl chain lengths, number of chains, phosphorylation state, membrane composition, and counterion charge in regulating the phase transition temperature of the membrane, diffusion coefficient of the lipids, and membrane thickness. The molecular and structural insights provided reveal the diversity in bacterial outer membrane lipids and their contribution to human disease and immunity. PMID- 28080050 TI - Altering Product Selectivity by Mechanochemistry. AB - Mechanochemical activation achieved by grinding, shearing, pulling, or milling opens unique opportunities in synthetic organic chemistry. Common features are that mechanochemistry facilitates reactions with insoluble reactants, enables high-yielding solvent-free synthetic procedures, and shortens reaction times, among others. However, mechanochemical techniques can also alter chemical reactivity and selectivity compared to the analogous solution-based protocols. As a consequence, solvent-free milling can lead to different product compositions or equilibration mixtures than in solution. Reactions by milling have also allowed the trapping and characterization of elusive intermediates and materials. In this Perspective we highlight a few selected examples that illustrate the value of mechanochemistry in uncovering interesting chemical reactivity, which is often masked in typical liquid-phase synthesis. PMID- 28080051 TI - Prediction of Bond Dissociation Energies/Heats of Formation for Diatomic Transition Metal Compounds: CCSD(T) Works. AB - It was recently reported ( J. Chem. Theory Comput. 2015 , 11 , 2036 - 2052 ) that the coupled cluster singles and doubles with perturbative triples method, CCSD(T), should not be used as a benchmark tool for the prediction of dissociation energies (heats of formation) for the first row transition metal diatomics based on a comparison with the experimental thermodynamic values for a set of 20 diatomics. In the present work the bond dissociation energies as well as the heats of formation for those diatomics have been calculated by the Feller Peterson-Dixon approach at the CCSD(T)/complete basis set (CBS) level of theory including scalar relativistic corrections and correlation of the outer shell of core electrons in addition to the valence electrons. Revised experimental values for the hydrides are presented that are based on new heterolytic R-H bond dissociation energies, which are needed for analysis of the mass spectrometry experiments. The agreement between the calculated bond dissociation energies and the revised experimental values of the hydrides is good. Good agreement of the calculated bond dissociation energies/heats of formation is also found for most of the chlorides, oxides, and sulfides given the experimental error bars from experiment and those of the transition metal atoms in the gas phase. Thus, reliable results can be achieved by the CCSD(T) method at the CBS limit. The use of PW91 orbitals for the CCSD(T) calculations improves the predictions for some compounds with large T1 diagnostics at the HF-CCSD(T) level. The optimized bond distances and calculated vibrational frequencies for the diatomics also agree well with the available experimental values. PMID- 28080052 TI - Mechanochemical Tuning of Pyrene Absorption Spectrum Using Force Probes. AB - Control of absorption spectra in chromophores is a fundamental aspect of many photochemical and photophysical processes as it constitutes the first step of the global photoinduced process. Here we explore the use of mechanical forces to modulate the light absorption process. Specifically, we develop a computational formalism for determining the type of mechanical forces permitting a global tuning of the absorption spectrum. This control extends to the excitation wavelength, absorption bands overlap, and oscillator strength. The determination of these optimal forces permits us to rationally guide the design of new mechano responsive chromophores. Pyrene has been chosen as the case study for applying these computational tools because significant absorption spectra information is available for the chromophore as well as for different strained derivatives. Additionally, pyrene presents a large flexibility, which makes it a good system to test the inclusion of force probes as the strategy to exert forces on the system. PMID- 28080054 TI - Bond Dissociation Energies for Diatomic Molecules Containing 3d Transition Metals: Benchmark Scalar-Relativistic Coupled-Cluster Calculations for 20 Molecules. AB - Benchmark scalar-relativistic coupled-cluster calculations for dissociation energies of the 20 diatomic molecules containing 3d transition metals in the 3dMLBE20 database ( J. Chem. Theory Comput. 2015 , 11 , 2036 ) are reported. Electron correlation and basis set effects are systematically studied. The agreement between theory and experiment is in general satisfactory. For a subset of 16 molecules, the standard deviation between computational and experimental values is 9 kJ/mol with the maximum deviation being 15 kJ/mol. The discrepancies between theory and experiment remain substantial (more than 20 kJ/mol) for VH, CrH, CoH, and FeH. To explore the source of the latter discrepancies, the analysis used to determine the experimental dissociation energies for VH and CrH is revisited. It is shown that, if improved values are used for the heterolytic C H dissociation energies of di- and trimethylamine involved in the experimental determination, the experimental values for the dissociation energies of VH and CrH are increased by 18 kJ/mol, such that D0(VH) = 223 +/- 7 kJ/mol and D0(CrH) = 204 +/- 7 kJ/mol (or De(VH) = 233 +/- 7 kJ/mol and De(CrH) = 214 +/- 7 kJ/mol). The new experimental values agree quite well with the calculated values, showing the consistency of the computation and the measured reaction thresholds. PMID- 28080055 TI - Morphological Transformation of Surface Femtodroplets upon Dissolution. AB - Constructing controllable liquid patterns with high resolution and accuracy is of great importance in droplet depositions for a range of applications. Simple surface chemical micropatterns have been popularly used to regulate the shape of liquid droplets and the final structure of deposited materials. In this work, we study the morphological evolution of a dissolving femtoliter droplet pinned on multiple microdomains. On the basis of minimization of interfacial energy, the numerical simulations predict various symmetric droplet profiles in equilibrium at different liquid volumes. However, our experimental results show both symmetric and asymmetric shapes of droplets due to contact line pinning and symmetry breaking during droplet dissolution. Upon slow volume reduction, the deposited microdroplet arrays on one single type of simple surface prepatterns spontaneously morphed into a series of complex regular 3D shapes. The findings in this work offer insights into design and prepararion of the rich and complex morphology of liquid patterns via simple surface premicropatterns. PMID- 28080053 TI - Lipid-Drug Conjugate for Enhancing Drug Delivery. AB - Lipid-drug conjugates (LDCs) are drug molecules that have been covalently modified with lipids. The conjugation of lipids to drug molecules increases lipophilicity and also changes other properties of drugs. The conjugates demonstrate several advantages including improved oral bioavailability, improved targeting to the lymphatic system, enhanced tumor targeting, and reduced toxicity. Based on the chemical nature of drugs and lipids, various conjugation strategies and chemical linkers can be utilized to synthesize LDCs. Linkers and/or conjugation methods determine how drugs are released from LDCs and are critical for the optimal performance of LDCs. In this review, different lipids used for preparing LDCs and various conjugation strategies are summarized. Although LDCs can be administered without a delivery carrier, most of them are loaded into appropriate delivery systems. The lipid moiety in the conjugates can significantly enhance drug loading into hydrophobic components of delivery carriers and thus generate formulations with high drug loading and superior stability. Different delivery carriers such as emulsions, liposomes, micelles, lipid nanoparticles, and polymer nanoparticles are also discussed in this review. PMID- 28080056 TI - Metadynamics Simulations Distinguish Short- and Long-Residence-Time Inhibitors of Cyclin-Dependent Kinase 8. AB - The duration of drug efficacy in vivo is a key aspect primarily addressed during the lead optimization phase of drug discovery. Hence, the availability of robust computational approaches that can predict the residence time of a compound at its target would accelerate candidate selection. Nowadays the theoretical prediction of this parameter is still very challenging. Starting from methods reported in the literature, we set up and validated a new metadynamics (META-D)-based protocol that was used to rank the experimental residence times of 10 arylpyrazole cyclin-dependent kinase 8 (CDK8) inhibitors for which target-bound X ray structures are available. The application of reported methods based on the detection of the escape from the first free energy well gave a poor correlation with the experimental values. Our protocol evaluates the energetics of the whole unbinding process, accounting for multiple intermediates and transition states. Using seven collective variables (CVs) encoding both roto-translational and conformational motions of the ligand, a history-dependent biasing potential is deposited as a sum of constant-height Gaussian functions until the ligand reaches an unbound state. The time required to achieve this state is proportional to the integral of the deposited potential over the CV hyperspace. Average values of this time, for replicated META-D simulations, provided an accurate classification of CDK8 inhibitors spanning short, medium, and long residence times. PMID- 28080058 TI - Fabrication of PEDOT Nanocone Arrays with Electrochemically Modulated Broadband Antireflective Properties. AB - Ordered nanocone arrays of the electroactive polymer poly(3,4 ethylenedioxythiophene) (PEDOT) were fabricated by the simultaneous oxygen plasma etching of an electrodeposited PEDOT thin film coated with a hexagonally closed packed polystyrene bead monolayer. PEDOT nanocone arrays with an intercone spacing of 200 nm and an average nanocone height of 350 nm exhibited a low broadband reflectivity of <1.5% from 550 to 800 nm. Electrochemical modulation of the oxidation state of the PEDOT nanocone array film was used to change both its ex situ absorption spectrum (electrochromism) and reflection spectrum (electroreflectivity). The sign of the PEDOT nanocone array electroreflectivity was opposite to that observed from unmodified PEDOT thin films; this significant difference is attributed to the unique optical behavior of nanostructured surfaces with an interfacial layer that contains a graded mix of air and highly absorptive nanocones. The combined electrochromic and electroreflective behavior of the antireflective PEDOT nanocone array films should find promising applications in solar energy cells, sensors and other optical devices. PMID- 28080057 TI - Identification of Binding Modes for Amino Naphthalene 2-Cyanoacrylate (ANCA) Probes to Amyloid Fibrils from Molecular Dynamics Simulations. AB - The amino naphthalene 2-cyanoacrylate (ANCA) probe is a kind of fluorescent amyloid binding probe that can report different fluorescence emissions when bound to various amyloid deposits in tissue, while their interactions with amyloid fibrils remain unclear due to the insoluble nature of amyloid fibrils. Here, all atom molecular dynamics simulations were used to investigate the interaction between ANCA probes with three different amyloid fibrils. Two common binding modes of ANCA probes on Abeta40 amyloid fibrils were identified by cluster analysis of multiple simulations. The van der Waals and electrostatic interactions were found to be major driving forces for the binding. Atomic contacts analysis and binding free energy decomposition results suggested that the hydrophobic part of ANCA mainly interacts with aromatic side chains on the fibril surface and the hydrophilic part mainly interacts with positive charged residues in the beta-sheet region. By comparing the binding modes with different fibrils, we can find that ANCA adopts different conformations while interacting with residues of different hydrophobicity, aromaticity, and electrochemical properties in the beta-sheet region, which accounts for its selective mechanism toward different amyloid fibrils. PMID- 28080059 TI - A Computational Approach for Modeling Neutron Scattering Data from Lipid Bilayers. AB - Biological cell membranes are responsible for a range of structural and dynamical phenomena crucial, which are crucial to a cell's well-being and its associated functions. Due to the complexity of cell membranes, lipid bilayer systems are often used as biomimetic models. These systems have led to significant insights into vital membrane phenomena such as domain formation, passive permeation, and protein insertion. Experimental observations of membrane structure and dynamics are, however, limited in resolution, both spatial and temporal. Importantly, computer simulations are starting to play a more prominent role in interpreting experimental results, enabling a molecular understanding of lipid membranes. In particular, the synergy between scattering experiments and simulations offers opportunities for new discoveries in membrane physics, as the length and time scales probed by molecular dynamics (MD) simulations parallel those of experiments. Here, we describe a coarse-grained MD simulation approach that mimics neutron scattering data from large unilamellar lipid vesicles over a range of bilayer rigidities. Specifically, we simulate vesicle form factors and membrane thickness fluctuations determined from small angle neutron scattering (SANS) and neutron spin echo (NSE) experiments, respectively. Our simulations accurately reproduce trends from experiments and lay the groundwork for studies of more complex membrane systems. PMID- 28080060 TI - Pharmacokinetics of the Individual Major Components of Polymyxin B and Colistin in Rats. AB - The pharmacokinetics of polymyxin B1, polymyxin B2, colistin A, and colistin B were investigated in a rat model following intravenous administration (0.8 mg/kg) of each individual component. Plasma and urine concentrations were determined by LC-MS/MS, and plasma protein binding was measured by ultracentrifugation. Total and unbound pharmacokinetic parameters for each component were calculated using noncompartmental analysis. All of the polymyxin components had a similar clearance, volume of distribution, elimination half-life, and urinary recovery. The area under the concentration-time curve for polymyxins B1 and B2 was greater than those of colistins A and B. Colistin A (56.6 +/- 9.25%) and colistin B (41.7 +/- 12.4%) displayed lower plasma protein binding in rat plasma compared to polymyxin B1 (82.3 +/- 4.30%) and polymyxin B2 (68.4 +/- 3.50%). These differences in plasma protein binding potentially equate to significant differences in unbound pharmacokinetics, highlighting the need for more stringent standardization of the composition of commercial products currently available for clinical use. PMID- 28080061 TI - Evaluation of a New Biosensor Based on in Situ Synthesized PPy-Ag-PVP Nanohybrid for Selective Detection of Dopamine. AB - In the present work, in situ synthesis of polypyrrole-silver-polyvinylpyrrolidone (PPy-Ag-PVP) nanohybrid using AgNO3 as an oxidant and polyvinylpyrrolidone (PVP) as a stabilizer and surfactant is demonstrated. The obtained ternary PPy-Ag-PVP nanohybrid was characterized by UV-vis, FT-IR, XRD, Raman, TGA, SEM, and HR-TEM analysis. Further the synthesized PPy-Ag-PVP has been investigated for its selective and sensitive sensing of dopamine (DA). The PPy-Ag-PVP modified glassy carbon electrode shows a reversible electrochemical behavior with superior response for DA. The limit of detection and limit of quantification are found to be 0.0126 and 0.042 MUM (S/N = 3 and 10), respectively, with remarkable sensitivity (7.26 MUA mM-1 cm-2). The practical application of the present modified electrode has been validated by determining the concentration of DA in human urine samples of different age group. PMID- 28080062 TI - Theoretical Prediction on [5]Radialene Sandwich Complexes (CpM)2(C10H10) (Cp = eta5-C5H5; M = Fe, Co, Ni): Geometry, Spin States, and Bonding. AB - [5]Radialene, the missing link for synthesis of radialene family, has been finally obtained via the preparation and decomplexation of the [5]radialene-bis Fe(CO)3 complex. The stability of [5]radialene complex benefits from the coordination with Fe(CO)3 by losing free 1,3-butadiene structures to avoid polymerization. In light of the similar coordination ability of half-sandwiches CpM(Cp = eta5-C5H5; M = Fe, Co, Ni), there is a great possibility that the sandwiched complexes of [5]radialene with CpM are available. Herein, we present the first theoretical prediction on the geometry, spin states and bonding of (CpM)(C10H10) and (CpM)2(C10H10). For M = Fe, Co, Ni, the ground states of (CpM)(C10H10) and (CpM)2(C10H10) are doublet and triplet, singlet and singlet, and doublet and triplet states, where each Fe, Co, and Ni adopts 17, 18, and 19 electron-configuration, respectively. In particular, (CpFe)2(C10H10) and (CpNi)2(C10H10) have considerable open-shell singlet features. Generally the trans isomers of (CpM)2(C10H10) with two CpM fragments on the opposite sides of the [5]radialene plane are apparently more stable than the cis ones with CpM fragments on the same side. However, for the singlet and triplet isomers of (CpNi)2(C10H10) (both cis and trans isomers), the energy differences are relatively small, indicating that these isomers all have the opportunity to exist. Besides, the easy Diels-Alder (DA) dimerization between the [3]dendralene like fragments of (CpM)(C10H10) suggests the great difficulty in isolating the (CpM)(C10H10) monomer. PMID- 28080063 TI - Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity. AB - Novel antimalarial therapeutics that target multiple stages of the parasite lifecycle are urgently required to tackle the emerging problem of resistance with current drugs. Here, we describe the optimization of the 2-anilino quinazoline class as antimalarial agents. The class, identified from publicly available antimalarial screening data, was optimized to generate lead compounds that possess potent antimalarial activity against P. falciparum parasites comparable to the known antimalarials, chloroquine and mefloquine. During the optimization process, we defined the functionality necessary for activity and improved in vitro metabolism and solubility. The resultant lead compounds possess potent activity against a multidrug resistant strain of P. falciparum and arrest parasites at the ring phase of the asexual stage and also gametocytogensis. Finally, we show that the lead compounds are orally efficacious in a 4 day murine model of malaria disease burden. PMID- 28080064 TI - Collective Excitations in Protein as a Measure of Balance Between its Softness and Rigidity. AB - In this article, we elucidate the protein activity from the perspective of protein softness and flexibility by studying the collective phonon-like excitations in a globular protein, human serum albumin (HSA), and taking advantage of the state-of-the-art inelastic X-ray scattering (IXS) technique. Such excitations demonstrate that the protein becomes softer upon thermal denaturation due to disruption of weak noncovalent bonds. On the other hand, no significant change in the local excitations is detected in ligand- (drugs) bound HSA compared to the ligand-free HSA. Our results clearly suggest that the protein conformational flexibility and rigidity are balanced by the native protein structure for biological activity. PMID- 28080065 TI - Level Spectrum and Charge Relaxation in a Silicon Double Quantum Dot Probed by Dual-Gate Reflectometry. AB - We report on dual-gate reflectometry in a metal-oxide-semiconductor double-gate silicon transistor operating at low temperature as a double quantum dot device. The reflectometry setup consists of two radio frequency resonators respectively connected to the two gate electrodes. By simultaneously measuring their dispersive responses, we obtain the complete charge stability diagram of the device. Electron transitions between the two quantum dots and between each quantum dot and either the source or the drain contact are detected through phase shifts in the reflected radio frequency signals. At finite bias, reflectometry allows probing charge transitions to excited quantum-dot states, thereby enabling direct access to the energy level spectra of the quantum dots. Interestingly, we find that in the presence of electron transport across the two dots the reflectometry signatures of interdot transitions display a dip-peak structure containing quantitative information on the charge relaxation rates in the double quantum dot. PMID- 28080066 TI - para-Selective Alkylation of Sulfonylarenes by Cooperative Nickel/Aluminum Catalysis. AB - A method for the para-selective alkylation of a variety of arenesulfonamides and aromatic sulfones with 1-alkenes by cooperative nickel/aluminum catalysis has been developed. Taking advantage of the sulfornyl functionality serving as a removable ortho-directing group, the reaction can be applied to facile access to 1,3-dialkyl-substitued benzenes. PMID- 28080067 TI - Stability, Kinetic, and Mechanistic Investigation of 1,8-Self-Immolative Cinnamyl Ether Spacers for Controlled Release of Phenols and Generation of Resonance and Inductively Stabilized Methides. AB - Three cinnamyl ether spacers (non-methyl, alpha-methyl, and gamma-methyl) for caging of phenols have been synthesized and are physiologically stable. When triggered, the gamma-methyl spacer releases phenols (pKa 7.8 and 9.8) with a t1/2 < 30 s and <2 min in aqueous and aqueous-organic solvent, respectively. The alpha methyl spacer releases a phenol (pKa 7.8) with a t1/2 = 27 and 54 min. For the gamma-methyl spacer, the results suggest the presence of a resonance and inductively stabilized aza-cinnamyl methide. PMID- 28080068 TI - Transition-Metal-Free Redox-Neutral One-Pot C3-Alkenylation of Indoles Using Aldehydes. AB - The synthesis of sensitive beta-alkyl 3-vinylindoles having diverse functional groups with good selectivity remains a challenging task. Keeping the synthetic utility of 3-alkenylindoles in mind, we explored a unique approach to synthesize them from unprotected indoles in a domino fashion. A transition-metal-free C3 alkenylation of indole is reported by using sequential Bronsted acid/base catalysis. Several beta-substituted 3-alkenylindoles and conjugated 1,3-dienes are synthesized by direct coupling of indole and readily available aliphatic aldehydes. Excellent scalability and recycling of benzenesulfinic acid for successive alkenylation reactions up to five times make this method economically viable. PMID- 28080069 TI - Direct Construction of 2,3-Dihydroxy-2,3-diaryltetrahydrofurans via N Heterocyclic Carbene/Base-Mediated Domino Reactions of Aromatic Aldehydes and Vinyl Selenone. AB - A one-pot, stereoselective construction of 2,3-dihydroxy-2,3 diaryltetrahydrofurans has been achieved via N-heterocyclic carbene (NHC)/base mediated domino reactions of aldehydes and vinyl selenone. The products containing two contiguous quaternary hydroxyl functionalities among the three stereocenters are obtained advantageously as either acetals or ketals through the formation of five new chemical bonds in a single operation. This report constitutes an altogether different reactivity of vinyl selenone in comparison with the corresponding sulfones and phosphonates under NHC/base-mediated reactions. PMID- 28080070 TI - Solution Synthesis of Iodine-Doped Red Phosphorus Nanoparticles for Lithium-Ion Battery Anodes. AB - Red phosphorus (RP) is a promising anode material for lithium-ion batteries due to its earth abundance and a high theoretical capacity of 2596 mA h g-1. Although RP-based anodes for lithium-ion batteries have been reported, they were all in the form of carbon-P composites, including P-graphene, P-graphite, P-carbon nanotubes (CNTs), and P-carbon black, to improve P's extremely low conductivity and large volume change during cycling process. Here, we report the large-scale synthesis of red phosphorus nanoparticles (RPNPs) with sizes ranging from 100 to 200 nm by reacting PI3 with ethylene glycol in the presence of cetyltrimethylammonium bromide (CTAB) in ambient environment. Unlike the insulator behavior of commercial RP (conductivity of <10 -12 S m-1), the conductivity of RPNPs is between 2.62 * 10-3 and 1.81 * 10-2 S m-1, which is close to that of semiconductor germanium (1.02 * 10-2 S m-1), and 2 orders of magnitude higher than silicon (5.35 * 10-4 S m-1). Around 3-5 wt % of iodine doping was found in RPNPs, which was speculated as the key to significantly improve the conductivity of RPNPs. The significantly improved conductivity of RPNPs and their uniform colloidal nanostructures enable them to be used solely as active materials for LIBs anodes. The RPNPs electrodes exhibit a high specific capacity of 1700 mA h g-1 (0.2 C after 100 cycles, 1 C = 2000 mA g-1), long cycling life (~900 mA h g-1 after 500 cycles at 1 C), and outstanding rate capability (175 mA h g-1 at the charge current density of 120 A g-1, 60 C). Moreover, as a proof-of-concept example, pouch-type full cells using RPNPs anodes and Li(Ni0.5Co0.3Mn0.2)O2 (NCM-532) cathodes were assembled to show their practical uses. PMID- 28080071 TI - Nanoscale Engineering in VO2 Nanowires via Direct Electron Writing Process. AB - Controlling phase transition in functional materials at nanoscale is not only of broad scientific interest but also important for practical applications in the fields of renewable energy, information storage, transducer, sensor, and so forth. As a model functional material, vanadium dioxide (VO2) has its metal insulator transition (MIT) usually at a sharp temperature around 68 degrees C. Here, we report a focused electron beam can directly lower down the transition temperature of a nanoarea to room temperature without prepatterning the VO2. This novel process is called radiolysis-assisted MIT (R-MIT). The electron beam irradiation fabricates a unique gradual MIT zone to several times of the beam size in which the temperature-dependent phase transition is achieved in an extended temperature range. The gradual transformation zone offers to precisely control the ratio of metal/insulator phases. This direct electron writing technique can open up an opportunity to precisely engineer nanodomains of diversified electronic properties in functional material-based devices. PMID- 28080072 TI - Chiral Catalyst-Directed Dynamic Kinetic Diastereoselective Acylation of Anomeric Hydroxyl Groups and a Controlled Reduction of the Glycosyl Ester Products. AB - A catalytic method is developed for the diastereoselective acylation of the anomeric hydroxyl group in diverse carbohydrates to form either alpha- or beta anomeric esters. While exclusive formation of the beta-isomer was observed in most sugar substrates with one enantiomer of the chiral catalyst, moderate to high alpha-selectivity was obtained by using the other enantiomer of the chiral catalyst. The resulting alpha- and beta-anomeric esters have very different reactivity toward a reduction reaction. PMID- 28080073 TI - Copper-Mediated Domino Cyclization/Trifluoromethylation/Deprotection with TMSCF3: Synthesis of 4-(Trifluoromethyl)pyrazoles. AB - A copper-mediated synthesis of 4-(trifluoromethyl)pyrazoles is described. In one step from readily accessible alpha,beta-alkynic tosylhydrazones, a remarkable domino sequence of cyclization, trifluoromethylation, and detosylation takes place to furnish the 4-CF3 N-H pyrazole cores with good functional group compatibility. The reaction conditions are mild and convenient, at room temperature in air, using the commercially available trifluoromethyltrimethylsilane (TMSCF3) as the CF3 source. The method can be applied to the synthesis of a 4-CF3 analogue of the anti-inflammatory drug celecoxib. PMID- 28080074 TI - Synthesis of Briarane Diterpenoids: Biomimetic Transannular Oxa-6pi electrocyclization Induced by a UVA/UVC Photoswitch. AB - A biomimetic synthesis of briareolate ester B (3) from briareolate ester L (1) via the intermediate briareolate ester G (2) has been achieved through a unique transannular oxa-6pi electrocyclization induced by UVA light. UVC irradiation of 3 triggered a rapid retro-6pi electrocyclization to establish an unprecedented photochromic switch. In the ground state, reaction of 1 led to the formation of a polycyclic gamma-spiroketal gamma-lactone 5, architecturally related to the ether bridged cembranoids of the cladiellin class. PMID- 28080076 TI - Adverse childhood experiences and risk for suicidal behavior in male Iraq and Afghanistan veterans seeking PTSD treatment. AB - OBJECTIVE: Adverse childhood experiences (ACEs) are associated with increased risk for suicide and appear to occur in disproportionately high rates among men who served in the U.S. military. However, research has yet to examine a comprehensive range of ACEs among Iraq/Afghanistan veterans with combat-related posttraumatic stress disorder (PTSD) or whether these premilitary stressors may contribute to suicidal behavior in this highly vulnerable population. METHOD: A sample of 217 men entering a residential program for combat-related PTSD completed measures for ACEs, combat exposure, and lifetime suicidal ideation and attempts. RESULTS: The majority of patients had experienced multiple types of adversity or traumas during childhood/adolescence. In particular, 83.4% endorsed at least 1 ACE category and 41.5% reported experiencing 4 or more ACEs. When accounting for effects of deployment-related stressors, we further found that accumulation of ACEs was uniquely linked with thoughts of suicide or attempts among these patients. Namely, for every 1-point increase on the ACE Questionnaire, veterans' risk of suicidal ideation and attempts increased by 23% and 24%, respectively. CONCLUSION: This brief report provides initial evidence that veterans seeking treatment for combat-related PTSD often have extensive histories of premilitary stressors that may increase suicide risk beyond probable deployment-related traumas. (PsycINFO Database Record PMID- 28080075 TI - Cognitive outcomes in early-treated adults with phenylketonuria (PKU): A comprehensive picture across domains. AB - OBJECTIVE: Phenylketonuria (PKU) is an inherited metabolic disease which affects cognitive functions due to an inability to metabolize phenylalanine which leads to the accumulation of toxic by-products (Phe) in the brain. PKU can be effectively treated with a low phenylalanine diet, but some cognitive deficits remain. Studies have reported impairments, especially for processing speed and executive functions, but there is a lack of comprehensive assessment across cognitive domains. Moreover, it is important to establish outcomes in early treated adults with PKU (AwPKU) who have better metabolic control than groups previously reported in the literature. METHOD: We tested 37 AwPKU with an unprecedented number of tasks (N = 28) and measures (N = 44) and compared results with 30 controls matched for age and education. RESULTS: We found (a) group impairments, particularly in tasks tapping speed of processing and complex executive functions; (b) high variability across participants, with a sizable number of AwPKU with completely normal performance (about 38%); (c) but also a sizable number of participants who were clearly impaired (about 24%); and (d) good performance in tasks tapping verbal learning, verbal memory and orthographic processing, indicating no generalized learning impairment. CONCLUSION: Our results indicate good outcomes, but also that deficits are still present with current treatment policies. (PsycINFO Database Record PMID- 28080077 TI - Dogs' (Canis familiaris) attention to human perception: Influence of breed groups and life experiences. AB - Attending to the perception of others may help individuals gaining information from conspecifics, or help in competitive situations. Dogs (Canis familiaris) are attentive to humans' signals and their attentional state. We investigated whether dogs of different breed groups differ in their ability to pay attention to human's perception, first according to the genetic relatedness between dog breeds, and second according to working style differences. Once dogs had learned to leave forbidden food on the floor, they were confronted with 2 food items to which only they had unrestricted visual access. The owners saw either none or 1 food item through a transparent barrier. Our results showed that dogs pay attention to the perception of humans, whereby differences between breed groups became obvious. Within different genetic groups, ancient and hunting type dogs performed similarly, they were more attentive to their owners' perception than shepherd and the mastiff type dogs. When comparing dogs classified according to their working style, independent workers and family dogs were attentive to the owner's perception, while cooperative workers seemed not. The dogs' choice could not be explained by a general or training induced preference for eating behind an opaque screen, or by an influence of the owner's possible intention to prevent the dog from taking the food item he could see. Our study confirms that dogs are attentive/sensitive to human's perception, but genetic and working style differences among the breeds, as well as dog sport experiences explain part of the variation seen in their performance. (PsycINFO Database Record PMID- 28080078 TI - What to do when scalar invariance fails: The extended alignment method for multi group factor analysis comparison of latent means across many groups. AB - Scalar invariance is an unachievable ideal that in practice can only be approximated; often using potentially questionable approaches such as partial invariance based on a stepwise selection of parameter estimates with large modification indices. Study 1 demonstrates an extension of the power and flexibility of the alignment approach for comparing latent factor means in large scale studies (30 OECD countries, 8 factors, 44 items, N = 249,840), for which scalar invariance is typically not supported in the traditional confirmatory factor analysis approach to measurement invariance (CFA-MI). Importantly, we introduce an alignment-within-CFA (AwC) approach, transforming alignment from a largely exploratory tool into a confirmatory tool, and enabling analyses that previously have not been possible with alignment (testing the invariance of uniquenesses and factor variances/covariances; multiple-group MIMIC models; contrasts on latent means) and structural equation models more generally. Specifically, it also allowed a comparison of gender differences in a 30-country MIMIC AwC (i.e., a SEM with gender as a covariate) and a 60-group AwC CFA (i.e., 30 countries * 2 genders) analysis. Study 2, a simulation study following up issues raised in Study 1, showed that latent means were more accurately estimated with alignment than with the scalar CFA-MI, and particularly with partial invariance scalar models based on the heavily criticized stepwise selection strategy. In summary, alignment augmented by AwC provides applied researchers from diverse disciplines considerable flexibility to address substantively important issues when the traditional CFA-MI scalar model does not fit the data. (PsycINFO Database Record PMID- 28080080 TI - The role of emotional capital during the early years of marriage: Why everyday moments matter. AB - Throughout a marriage couples will share countless ordinary moments together that may seem trivial, but which actually have potential to affirm and strengthen relational bonds. According to theories of emotional capital, the accumulation of shared positive moments in a relationship should serve as an essential resource for protecting the relationship against threats. To date, however, few empirical studies have explored the role emotional capital may play in shaping responses to negative relationship experiences. In the current study, newly married couples completed 3 14-day daily diary tasks assessing emotional capital, negative partner behaviors, and marital satisfaction over a 3-year period, for a total of 42 potential days of diary data. Contrary to predictions, emotional capital on a given day was not associated with reactivity to relationship threats on the following day. However, conceptually replicating prior work, individuals who accumulated more emotional capital on average across the diary tasks did exhibit lower reactivity to daily relationship threats; that is, on days of greater relationship threat (i.e., negative partner behaviors), those spouses who generally accrued more shared positive moments with their partner maintained greater feelings of marital satisfaction compared with spouses who accrued fewer positive moments. These findings contribute to a growing literature illustrating how positive shared activities between partners help sustain relationship quality over time. (PsycINFO Database Record PMID- 28080079 TI - Mother, father, and adolescent self-control and adherence in adolescents with Type 1 diabetes. AB - This study explored whether shared self-control across a family system, including adolescent, mother, and father self-control, as well as the interaction of mother and father self-control, was associated with ease of completing adherence tasks and the completion of adherence behaviors related to the Type 1 diabetes (T1D) regimen. One hundred thirty-seven adolescents (M = 13.48 years), mothers, and fathers completed a self-report measure of self-control, while adolescents also self-reported on ease of completing adherence tasks and the frequency with which they completed adherence tasks. Higher adolescent, mother, father, and the interaction of mother and father self-control were each associated with greater adolescent perceptions of ease of completing adherence tasks. Also, greater adolescent perception of ease of adherence mediated the association of higher adolescent, father, and the interaction of mother and father self-control on more frequent adherence behaviors. The results are consistent with the idea that family members may share the load of self-control within the family system. The results point to the importance of assessing and intervening within the entire family system to support improved quality of life and better adherence to the medical regimen in adolescents with Type 1 diabetes. (PsycINFO Database Record PMID- 28080081 TI - The heart of parenting: Parent HR dynamics and negative parenting while resolving conflict with child. AB - The current study examined parent heart rate (HR) dynamic changing patterns and their links to observed negative parenting (i.e., emotional unavailability and psychological control) during a parent-child conflict resolution task among 150 parent-child dyads (child age ranged from 6 to 12 years, Mage = 8.54 +/- 1.67). Parent HR was obtained from electrocardiogram (ECG) data collected during the parent-child conflict resolution task. Negative parenting was coded offline based on the video recording of the same task. Results revealed that emotionally sensitive parents during the task showed greater HR increases while discussing a conflict and greater HR decreases while resolving the conflict, whereas emotionally unavailable parents showed no changes in HR. However, parent psychological control was not associated with HR dynamics during the task. These findings indicated the physiological underpinnings of parent emotional sensitivity and responsiveness during parent-child interactions. The potential association between HR baseline levels and parenting behaviors was also discussed. (PsycINFO Database Record PMID- 28080082 TI - Parenting and later substance use among Mexican-origin youth: Moderation by preference for a common language. AB - The primary goal of the current study was to test whether parent and adolescent preference for a common language moderates the association between parenting and rank-order change over time in offspring substance use. A sample of Mexican origin 7th-grade adolescents (Mage = 12.5 years, N = 194, 52% female) was measured longitudinally on use of tobacco, alcohol, and marijuana. Mothers, fathers, and adolescents all reported on consistent discipline and monitoring of adolescents. Both consistent discipline and monitoring predicted relative decreases in substance use into early adulthood but only among parent-offspring dyads who expressed preference for the same language (either English or Spanish). This moderation held after controlling for parent substance use, family structure, having completed schooling in Mexico, years lived in the United States, family income, and cultural values. An unintended consequence of the immigration process may be the loss of parenting effectiveness that is normally present when parents and adolescents prefer to communicate in a common language. (PsycINFO Database Record PMID- 28080083 TI - The empathy impulse: A multinomial model of intentional and unintentional empathy for pain. AB - Empathy for pain is often described as automatic. Here, we used implicit measurement and multinomial modeling to formally quantify unintentional empathy for pain: empathy that occurs despite intentions to the contrary. We developed the pain identification task (PIT), a sequential priming task wherein participants judge the painfulness of target experiences while trying to avoid the influence of prime experiences. Using multinomial modeling, we distinguished 3 component processes underlying PIT performance: empathy toward target stimuli (Intentional Empathy), empathy toward prime stimuli (Unintentional Empathy), and bias to judge target stimuli as painful (Response Bias). In Experiment 1, imposing a fast (vs. slow) response deadline uniquely reduced Intentional Empathy. In Experiment 2, inducing imagine-self (vs. imagine-other) perspective taking uniquely increased Unintentional Empathy. In Experiment 3, Intentional and Unintentional Empathy were stronger toward targets with typical (vs. atypical) pain outcomes, suggesting that outcome information matters and that effects on the PIT are not reducible to affective priming. Typicality of pain outcomes more weakly affected task performance when target stimuli were merely categorized rather than judged for painfulness, suggesting that effects on the latter are not reducible to semantic priming. In Experiment 4, Unintentional Empathy was stronger for participants who engaged in costly donation to cancer charities, but this parameter was also high for those who donated to an objectively worse but socially more popular charity, suggesting that overly high empathy may facilitate maladaptive altruism. Theoretical and practical applications of our modeling approach for understanding variation in empathy are discussed. (PsycINFO Database Record PMID- 28080085 TI - Suppression and expression of emotion in social and interpersonal outcomes: A meta-analysis. AB - Emotion expression is critical for the communication of important social information, such as emotional states and behavioral intentions. However, people tend to vary in their level of emotional expression. This meta-analysis investigated the relationships between levels of emotion expression and suppression, and social and interpersonal outcomes. PsycINFO databases, as well as reference lists were searched. Forty-three papers from a total of 3,200 papers met inclusion criteria, allowing for 105 effect sizes to be calculated. Meta analyses revealed that greater suppression of emotion was significantly associated with poorer social wellbeing, including more negative first impressions, lower social support, lower social satisfaction and quality, and poorer romantic relationship quality. Furthermore, the expression of positive and general/nonspecific emotion was related to better social outcomes, while the expression of anger was associated with poorer social wellbeing. Expression of negative emotion generally was also associated with poorer social outcomes, although this effect size was very small and consisted of mixed results. These findings highlight the importance of considering the role that regulation of emotional expression can play in the development of social dysfunction and interpersonal problems. (PsycINFO Database Record PMID- 28080084 TI - Negative affect mediates the relation between trait urgency and behavioral distress tolerance. AB - Distress tolerance is associated with a range of psychopathology and risk-taking behavior. Current research suggests that the behavioral ability to persist at goal-directed behavior when distressed may be malleable. However, little is known about the contributing factors that underlie individual differences in distress tolerance. Trait urgency, or the tendency to act impulsively in the context of acute changes in affect, may predict distress tolerance because the prepotent response to avoid or remove an aversive state may undermine persistence. To date, most research has examined the role of negative urgency, a valenced subfactor of urgency, in relation to distress tolerance. However, the broad trait of urgency may be associated with a greater change in affect that precedes the inability to tolerate distress. The current study examined whether greater changes in negative affect was indeed a mediator in the relationship between trait urgency and behavioral distress tolerance. The effects of both positive and negative urgency on affect change were examined to investigate the potential contribution of the broader urgency trait. The results suggest that a greater change in negative affect over the course of a stressor mediated the association between both subfactors of urgency and distress tolerance. These findings suggest that trait urgency, regardless of valence, may be associated with experiencing greater changes in affect that ultimately undermine the ability to tolerate distress. These findings also highlight important components of distress tolerance that could inform behavioral interventions. (PsycINFO Database Record PMID- 28080086 TI - Attentional capture by taboo words: A functional view of auditory distraction. AB - It is well established that task-irrelevant, to-be-ignored speech adversely affects serial short-term memory (STM) for visually presented items compared with a quiet control condition. However, there is an ongoing debate about whether the semantic content of the speech has the capacity to capture attention and to disrupt memory performance. In the present article, we tested whether taboo words are more difficult to ignore than neutral words. Taboo words or neutral words were presented as (a) steady state sequences in which the same distractor word was repeated, (b) changing state sequences in which different distractor words were presented, and (c) auditory deviant sequences in which a single distractor word deviated from a sequence of repeated words. Experiments 1 and 2 showed that taboo words disrupted performance more than neutral words. This taboo effect did not habituate and it did not differ between individuals with high and low working memory capacity. In Experiments 3 and 4, in which only a single deviant taboo word was presented, no taboo effect was obtained. These results do not support the idea that the processing of the auditory distractors' semantic content is the result of occasional attention switches to the auditory modality. Instead, the overall pattern of results is more in line with a functional view of auditory distraction, according to which the to-be-ignored modality is routinely monitored for potentially important stimuli (e.g., self-relevant or threatening information), the detection of which draws processing resources away from the primary task. (PsycINFO Database Record PMID- 28080088 TI - The effect of reactive emotions expressed in response to another's anger on inferences of social power. AB - Social perception of emotions is influenced by the context in which it occurs. One such context is a social interaction involving an exchange of emotions. The way parties to the interaction are perceived is shaped by the combination of emotions exchanged. This idea was examined by assessing the extent to which expressions of anger toward a target-which, in isolation, are perceived as signals of high social power-are influenced by the target's emotional reaction to it (i.e., reactive emotions). Three studies show that the angry person was perceived as having a higher level of social power when this anger was responded by fear or sadness than when it was responded by neutrality or anger. Study 1 indicated that reactive emotions have a stronger effect on perceived social power when emotions were incongruent with gender stereotypes. Study 2 indicated that these effects are a result of these emotions serving as reactive emotions rather than a benchmark against which the angry person's power is assessed. Study 3 showed that reactive emotions affect perceived social power by serving as signals of the level to which the high social power suggested by the first person's expression is confirmed by its target. Comparing effects of reactive emotions to anger with reactive emotions to sadness, showed that perceived social power of the expresser is determined by the nature of the expression, with some adjustment caused by the reactive emotions. This underscores the importance of social interaction as a context for the social perception of emotions. (PsycINFO Database Record PMID- 28080089 TI - What you like is what you try to get: Attitudes toward emotions and situation selection. AB - Why do people expose themselves to certain emotional stimuli and avoid others? We propose that what people want to feel is linked to attitudes toward emotions. In 3 studies, we show that individuals with more (vs. less) negative attitudes toward an emotion were more (vs. less) likely to avoid stimuli that induce that emotion. People who evaluated disgust (or joy) less favorably than others were less likely to expose themselves to disgusting (or joyful) pictures (Study 1). These links were emotion-specific and could not be explained by differences in state or trait emotion (Study 2) or in emotional reactivity (Study 3). We were further able to show that the choice of emotion-inducing stimuli affected emotional experience in a congruent manner. People with more (vs. less) negative attitudes toward disgust (or sadness) were more likely to avoid disgusting (or sad) stimuli, resulting in more intense experiences of disgust (or sadness; Study 2). Finally, people with more negative attitudes toward disgust chose to avoid more disgusting stimuli, whether attitudes were assessed explicitly or implicitly (Study 3). These findings suggest that people avoid stimuli that induce emotions that they evaluate less favorably, even when such evaluations are not consciously accessible. (PsycINFO Database Record PMID- 28080087 TI - Perceptual salience does not influence emotional arousal's impairing effects on top-down attention. AB - Emotional arousal impairs top-down attentional control while strengthening bottom up attentional biases. In this study, we examined whether top-down impairments due to arousal can be modulated by increasing the perceptual salience of the target stimulus. To examine this question, we briefly displayed positive and negative arousing images prior to the encoding of 2 emotionally neutral items, 1 of which was to be remembered and 1 of which was perceptually salient (the to-be remembered and the salient items were either the same item or different items). Eye tracking was used to measure attention biases during the encoding of the 2 competing neutral items, as well as to measure pupillary responses to the preceding modulator image. Viewing emotional images, regardless of valence, impaired top-down attention to animate stimulus targets (i.e., animals), regardless of perceptual salience. However, these effects on encoding had no influence on recognition memory. Taken together, these findings reveal that exposure to emotionally arousing images impairs top-down attention to animate stimuli, regardless of whether that stimulus is perceptually salient. (PsycINFO Database Record PMID- 28080090 TI - We are sorry, they don't care: Misinterpretation of facial embarrassment displays in Arab-White intergroup contexts. AB - Embarrassment displays show others that one is aware of one's own misbehavior and willing to make up for it. The facial actions of embarrassment, however, are partly similar to those of disinterest, which has an opposite function, signaling that one is not concerned about one's self in relation to others. In the context of negative intergroup relations, embarrassment displays of outgroup members may therefore be misinterpreted as disinterest. In the present research, the authors predicted that Whites would perceive Arab expressions of embarrassment more as disinterest, but embarrassment displays of Whites more as embarrassment. Aggregated Study 1 (N = 1,154) confirms this hypothesis showing that White participants perceived more intense embarrassment in Whites than in Arabs and more intense disinterest in Arabs than in Whites. Studies 2 (n = 193) and 3 (n = 260) include methodological improvements and either largely or fully replicated our findings. Based on this evidence in an Arab-White context, the authors conclude that the affiliative function of embarrassment perception is dependent on the nature of the group context. Finally, they discuss the generalizability of this intergroup emotion bias in which emotional expressions may be perceived as the opposite of what they are intended to display. (PsycINFO Database Record PMID- 28080091 TI - Dynamical systems modeling of early childhood self-regulation. AB - Self-regulation can be conceptualized in terms of dynamic tension between highly probable reactions (prepotent responses) and use of strategies that can modulate those reactions (executive processes). This study investigated the value of a dynamical systems approach to the study of early childhood self-regulation. Specifically, ordinary differential equations (ODEs) were used to model the interactive influences of 115 36-month-olds' executive processes (strategy use) and prepotent responses to waiting to open a gift (desire for the gift and frustration about waiting to open it). Using a pair of coupled second-order ODEs in a nonlinear mixed effects framework, the study tested predictions for specific within- and between-child patterns of prepotent response-executive process coupling. Dynamic modeling results articulated the limits of 36-month olds' strategic efforts. They engaged executive processes when their prepotent responding levels were high, which delayed the resurgence of prepotent responses, but ultimately did not damp prepotent responding over the course of the wait. There was, however, preliminary evidence that the effectiveness of 36-month-olds' self-regulation depended upon child characteristics. Externalizing behavior problems were associated with more regulatory interference. Temperamental negative affectivity was marginally associated with more regulatory inefficiency. Compared with conventional methods of studying self-regulation, dynamic modeling yielded complementary and unique findings, suggesting its potential. (PsycINFO Database Record PMID- 28080093 TI - Psychometric properties of the Short Inventory of Problems (SIP) with adjudicated DUI intervention participants. AB - We used responses of two large samples of court-ordered participants from a statewide alcohol/driving safety program to investigate factor structure, score reliability, and criterion-related validity of the Short Inventory of Problems (SIP). Exploratory and confirmatory factor analyses, using both item-level and subscore-level data, support a one-factor structure for the SIP. Internal consistency score reliability estimates were consistent across samples and high enough to warrant use for making decisions about individuals. Item response theory model calibration of the scale, using a two-parameter logistic model, yielded consistent estimates of location and discrimination (slope) across samples. Estimated scale scores correlated moderately with an independent indicator of alcohol problems and poorly with an indicator of risky driving behavior, lending evidence of convergent and discriminant validity. We judge the SIP as adequately described by a single factor, that the joint person-item scale is coherent, and scores behave consistently across samples. (PsycINFO Database Record PMID- 28080092 TI - Brief online interventions targeting risk and protective factors for increased and problematic alcohol use among American college students studying abroad. AB - Research documents increased and problematic alcohol use during study abroad experiences for college students yet no research documents effective preventive programs with these students. The present randomized controlled trial was designed to prevent increased and problematic alcohol use abroad by correcting misperceptions of peer drinking norms abroad and by promoting positive and healthy adjustment into the host culture (i.e., sojourner adjustment) through brief online personalized feedback interventions. A sample of 343 study abroad college students was randomly assigned to 1 of 4 conditions including a personalized normative feedback intervention (PNF), a sojourner adjustment feedback intervention (SAF), a combined PNF + SAF intervention, and an assessment only control condition. Generalized estimated equation analyses accounting for baseline drinking and consequences revealed an intervention effect for PNF that was mitigated by baseline drinking level, such that PNF was best for those with lighter baseline drinking, but heavier baseline drinkers receiving PNF alone or PNF + SAF drank comparatively similar or more heavily abroad to those in the control condition. However, PNF + SAF condition participants with greater baseline levels of consequences reported comparatively less consequences abroad than their control participants. Thus, PNF alone may be helpful for lighter drinkers at predeparture and the addition of SAF to PNF may help prevent consequences abroad for those reporting more consequences prior to departure abroad. This research represents an important first step in designing and implementing efficacious interventions with at-risk study abroad college students, for which no current empirically based programs exist. (PsycINFO Database Record PMID- 28080094 TI - Lifetime Alcoholics Anonymous attendance as a predictor of spiritual gains in the Relapse Replication and Extension Project (RREP). AB - This study investigated the association between extent of lifetime attendance in Alcoholics Anonymous (AA) and spiritual gains among treatment seeking adults for alcohol use disorder. Participants included 246 individuals from 2 of the 3 sites in the Relapse Replication and Extension Project (Lowman, Allen, Stout, & The Relapse Research Group, 1996). Baseline characteristics included 63% male, 39.9% single, and the average age was 34 years (SD = 8.2). The Alcoholics Anonymous Involvement questionnaire (Tonigan, Connors, & Miller, 1996) was used to assess lifetime AA attendance. The Religious Beliefs & Behaviors Questionnaire (Connors, Tonigan, & Miller, 1996) was used to assess spirituality. Percent days abstinent (PDA) and drinks per drinking day (DPDD) were measured using the Form 90. At baseline, adults with more extensive AA histories were more severely alcohol impaired although they were no older relative to adults with less past AA exposure. Clear patterns of AA engagement were found between the high-low AA history groups over follow-up, with adults with less AA experience reporting less AA participation across a swath of AA-specific measures. Gains in spiritual practices significantly mediated AA-related benefit as measured by PDA and DPDD. Tests for moderated-mediation indicated that the magnitude of the mediational effect of spiritual gains did not differ between high-low AA history groups. Having an extensive AA history did not advantage (or disadvantage) adults in mobilizing future spiritual practices that are prescribed in AA. Clinical assessment of client AA history is important, however, because it predicts both the nature and extent that clients may participate in AA. (PsycINFO Database Record PMID- 28080095 TI - The proximal effects of acute alcohol use on female aggression: A meta-analytic review of the experimental literature. AB - Experimental research on alcohol-related aggression has focused largely upon male participants, providing only a limited understanding of the proximal effects of acute alcohol use on aggression among females extrapolated from the male literature. The current meta-analysis was undertaken to summarize the effects of alcohol, compared to placebo or no alcohol, on female aggression as observed across experimental investigations. A review of the literature yielded 11 articles and 12 effect sizes for further analysis. The overall effect size of alcohol on female aggression was small and reached statistical significance (d = .17, p = .02, 95% confidence interval [.03, .30]). Meta-analytic examination of the experimental literature indicated that alcohol is a significant factor in female aggression. The overall alcohol-aggression effect was smaller than has been observed among male samples. Additional research is required to evaluate the influence of other factors on alcohol-related aggressive responding among female participants. (PsycINFO Database Record PMID- 28080096 TI - Emotion dysregulation explains associations between anxiety sensitivity and hazardous drinking and drinking motives among adult treatment-seeking smokers. AB - Smoking and drinking frequently co-occur. For example, alcohol use is associated with smoking lapses during quit attempts. However, little is known regarding psychological factors explaining drinking among smokers. Anxiety sensitivity is a risk factor associated with hazardous drinking and drinking to cope and/or conform, although little is known about mechanisms underlying such associations. One potential explanatory factor is emotion dysregulation. The current study examined emotion dysregulation as an explanatory factor underlying Anxiety Sensitivity and 5 alcohol-related outcomes: hazardous drinking, alcohol consumption, alcohol problems, coping-oriented drinking, and drinking to conform. Participants for this study were 467 treatment-seeking adult, daily smokers (48.2% women; Mage = 36.7 years, SD = 13.6) who reported smoking an average of 16.5 cigarettes per day. Results indicate significant indirect effects of Anxiety Sensitivity on hazardous drinking via emotion dysregulation, alcohol consumption, alcohol problems, drinking to cope, and drinking to conform. Effects were medium in size. Alternative models testing indirect effects of emotion dysregulation through Anxiety Sensitivity on outcomes, and Anxiety Sensitivity through outcomes on emotion dysregulation were nonsignificant and all had small effect sizes. Follow-up tests examined the path of effects from Anxiety Sensitivity through specific emotion-dysregulation subfactors. Thus, among treatment-seeking smokers, emotion dysregulation may explain the associations of Anxiety Sensitivity with alcohol-related outcomes. This pattern of findings highlights the potential importance of interventions targeting emotion dysregulation among hazardous drinking smokers. (PsycINFO Database Record PMID- 28080097 TI - "You must be lying because I don't understand you: Language proficiency and lie detection:" Correction to Elliott and Leach (2016). AB - Reports an error in "You must be lying because I don't understand you: Language proficiency and lie detection" by Elizabeth Elliott and Amy-May Leach (Journal of Experimental Psychology: Applied, 2016[Dec], Vol 22[4], 488-499). In the Results section, under "Signal detection theory," the first sentence of the second paragraph contains errors. The correct sentence is provided in this erratum. (The following abstract of the original article appeared in record 2016-59419-006.) We examined the impact of interviewees' language proficiencies on observers' lie detection performance. Observers (N = 132) were randomly assigned to make deception judgments about interviewees (N = 56) from Four proficiency groups (i.e., native, advanced, intermediate, and beginner English speakers). Discrimination between lie- and truth-tellers was poorest when observers judged beginner English speakers compared to interviewees from any other proficiency group. Observers were also less likely to exhibit a truth-bias toward nonnative than native English speakers. These results suggest that interviewing individuals in their nonnative languages can create inequalities in the justice system. (PsycINFO Database Record PMID- 28080098 TI - Knowledge of the self-control benefits of high-level versus low-level construal. AB - Research indicates that inducing high-level construal (processing that highlights invariant, essential features) relative to low-level construal (processing that highlights idiosyncratic, peripheral features) promotes self-control (Fujita & Carnevale, 2012). In the present work, we investigate to what extent people recognize the self-control benefits of high-level construal, and explore the consequences of this knowledge. Studies 1 and 2 provide initial evidence that individuals are aware that high-level relative to low-level construal promotes self-control in the dieting domain. Studies 3 and 4 find that individual differences in this knowledge predict self-control success outcomes (i.e., body mass index) among those who are motivated by dieting goals. Examining academics as a domain of self-control, Study 5 demonstrates that those with higher knowledge of construal level's impact on self-control earned higher end-of semester grades to the extent that they were motivated to do well academically. Theoretical and practical implications of these findings are discussed. (PsycINFO Database Record PMID- 28080099 TI - School connectedness and suicidal thoughts and behaviors: A systematic meta analysis. AB - Among the protective factors associated with reduced risk for suicide, scientific inquiries into school connectedness are especially important considering that schools are ideally situated to provide interventions reaching the vast majority of youth. Although there is a wealth of research that supports the association between school connectedness and reduced self-report of adolescents having a suicidal thought or making a suicide attempt, inconsistencies in the way studies have measured and operationalized school connectedness limit synthesis across findings. This meta-analytic study investigates the literature exploring associations between school connectedness and suicidal thoughts and behaviors across general and subpopulations (high risk and sexual minority youth) using a random effects model. Eligible studies examined a measure of school connectedness explicitly referred to as "school connectedness" or "connections at school" in relation to suicidal ideation or suicide attempts among youth enrolled in school (Grades 6-12). Multiple metaregression analyses were conducted to explore the influence of school connectedness measurement variation, as well as participant characteristics. Results, including 16 samples, support that higher school connectedness is associated with reduced reports of suicidal thoughts and behaviors across general (odds ratio [OR] = 0.536), high-risk (OR = 0.603), and sexual minority (OR = 0.608) adolescents. Findings are consistent when analyzed separately for suicidal ideation (OR = 0.529) and suicide attempts (OR = 0.589) and remain stable when accounting for measurement variability. Although limited by its cross-sectional nature, findings support recent calls to increase school connectedness and proffer important implications for screening and intervention efforts conducted in schools. (PsycINFO Database Record PMID- 28080100 TI - Metabolic control and academic achievement over time among adolescents with type 1 diabetes. AB - The relation between metabolic control (HbA1c) and achievement (grade point average [GPA]) was examined over a period of 2.5 years (every 6 months) employing a dynamical systems approach that allowed for the examination of whether HbA1c was associated with change in subsequent GPA and vice versa. Metabolic control tends to deteriorate (i.e., with higher HbA1c reflecting poorer metabolic control) during adolescence. It was hypothesized that these higher levels of HbA1c would limit subsequent increases in GPA. The sample included 252 adolescents (Mbaseline age = 12.49 years, SD = 1.53; 53.6% female) with Type 1 diabetes. Mothers' report and school records provided information on relevant demographics and GPA; medical records provided values of HbA1c. Two simultaneous coupled change equations (i.e., examining current values in 1 variable associated with changes in the other) controlling relevant risk indicators (i.e., age, sex, disease duration, insulin delivery method, IQ) revealed higher levels of HbA1c limited increases in GPA. Higher levels of GPA, however, were not associated with change in HbA1c except for 2 instances where moderation existed by disease duration and IQ. Higher GPA was associated with slower increases in HbA1c over time for youth with shorter disease duration and lower IQ. These results affirm the importance of maintaining good metabolic control to facilitate adequate school performance across the adolescent years. Further, the results suggest that factors related to school achievement may protect adolescents who are newly diagnosed or who have low cognitive ability from subsequent deterioration in metabolic control. (PsycINFO Database Record PMID- 28080101 TI - Racial discrimination and psychological health among Polynesians in the U.S. AB - OBJECTIVES: There is a dearth of research on the mental health of Polynesians residing in the United States. The aims of this study were to examine experiences of racial discrimination, self-esteem, trait anger, satisfaction with life, and psychological well-being among 628 Polynesians (e.g., Native Hawaiian, Tongan, Samoan, Fijian, Tahitian, Maori; 60% women (n = 378) and 40% men (n = 249); mean age = 28.7). METHOD: Measures were administered through an online survey to 628 Polynesians residing in the United States. Comparison analyses between men and women, correlations, and path analyses were analyzed for this Polynesian sample. RESULTS: Polynesian women showed higher levels of self-esteem and lower levels of depression and anxiety. Racial discrimination was inversely correlated with self esteem and satisfaction with life, and positively linked to trait anger, depression, anxiety, and stress. Self-esteem had an indirect effect on the relationship between racial discrimination and satisfaction with life. CONCLUSIONS: Mental health professionals need to be aware of racial discrimination on psychological health and incorporate the value of self-esteem in the psychological treatment of Polynesians. Additional results are provided and implications of these findings are outlined. (PsycINFO Database Record PMID- 28080103 TI - Empirical influence of the multicultural guidelines: A brief report. AB - OBJECTIVE: In 2002, the American Psychological Association (APA) Council of Representatives approved the "Guidelines for Multicultural Education, Training, Research, Practice and Organizational Change for Psychologists." The Guidelines have been downloaded 64,153 times from the APA website from 2007 to 2013, and have been cited nearly 900 times. This suggests that the Guidelines have influenced education, training, research, and practice in psychology. However, it is unclear how the Guidelines have influenced these domains. We conducted a comprehensive literature review to examine how the Guidelines have influenced the field. Articles were coded for several criteria, including whether the Guidelines were cited, the type of research that was conducted, study findings, limitations, and future directions of research. METHOD: The data for this study consisted of 895 empirical articles published since the 2003 publication of the Guidelines. A literature review using the keywords APA and multicultural guidelines were searched in PsycINFO and ERIC databases. Articles were then coded by the research team. RESULTS: Findings from the literature review suggested that although there were a total of 895 articles and books that cited the Guidelines, only 34 met our coding criteria. CONCLUSIONS: Our findings suggest that most of the articles that cited the Guidelines used the citation as a way to document that culture is important to consider. In some cases, other professions cited the Guidelines to argue that their discipline should also attend to culture. However, very few articles focused on framing an investigation around a specific guideline. (PsycINFO Database Record PMID- 28080102 TI - Not just sticks and stones: Indirect ethnic discrimination leads to greater physiological reactivity. AB - OBJECTIVES: We examined the effect of indirect ethnic discrimination on physiological reactivity (i.e., cortisol, blood pressure, heart rate) in Latino emerging adults. METHOD: Participants (N = 32) were randomly assigned to be exposed to indirect ethnic discrimination (experimental condition) or not (control condition) while undergoing a cognitive stress task. RESULTS: Greater total cortisol output was observed in participants in the experimental condition, relative to those in the control condition. No significant differences in heart rate or blood pressure were noted. CONCLUSIONS: Results suggest that witnessing ethnic discrimination affects cortisol recovery responses, but not cardiovascular reactivity. Words that are not intentionally hurtful or directed at a specific person may still "hurt"-affecting biological processes associated with hypothalamic-pituitary-adrenocortical (HPA) axis and potentially leading to long term health consequences. (PsycINFO Database Record PMID- 28080104 TI - Measuring Black men's police-based discrimination experiences: Development and validation of the Police and Law Enforcement (PLE) Scale. AB - OBJECTIVES: Although social science research has examined police and law enforcement-perpetrated discrimination against Black men using policing statistics and implicit bias studies, there is little quantitative evidence detailing this phenomenon from the perspective of Black men. Consequently, there is a dearth of research detailing how Black men's perspectives on police and law enforcement-related stress predict negative physiological and psychological health outcomes. This study addresses these gaps with the qualitative development and quantitative test of the Police and Law Enforcement (PLE) Scale. METHOD: In Study 1, we used thematic analysis on transcripts of individual qualitative interviews with 90 Black men to assess key themes and concepts and develop quantitative items. In Study 2, we used 2 focus groups comprised of 5 Black men each (n = 10), intensive cognitive interviewing with a separate sample of Black men (n = 15), and piloting with another sample of Black men (n = 13) to assess the ecological validity of the quantitative items. For Study 3, we analyzed data from a sample of 633 Black men between the ages of 18 and 65 to test the factor structure of the PLE, as we all as its concurrent validity and convergent/discriminant validity. RESULTS: Qualitative analyses and confirmatory factor analyses suggested that a 5-item, 1-factor measure appropriately represented respondents' experiences of police/law enforcement discrimination. As hypothesized, the PLE was positively associated with measures of racial discrimination and depressive symptoms. CONCLUSIONS: Preliminary evidence suggests that the PLE is a reliable and valid measure of Black men's experiences of discrimination with police/law enforcement. (PsycINFO Database Record PMID- 28080105 TI - Cross-cultural feigning assessment: A systematic review of feigning instruments used with linguistically, ethnically, and culturally diverse samples. AB - The cross-cultural validity of feigning instruments and cut-scores is a critical concern for forensic mental health clinicians. This systematic review evaluated feigning classification accuracy and effect sizes across instruments and languages by summarizing 45 published peer-reviewed articles and unpublished doctoral dissertations conducted in Europe, Asia, and North America using linguistically, ethnically, and culturally diverse samples. The most common psychiatric symptom measures used with linguistically, ethnically, and culturally diverse samples included the Structured Inventory of Malingered Symptomatology, the Miller Forensic Assessment of Symptoms Test, and the Minnesota Multiphasic Personality Inventory (MMPI). The most frequently studied cognitive effort measures included the Word Recognition Test, the Test of Memory Malingering, and the Rey 15-item Memory test. The classification accuracy of these measures is compared and the implications of this research literature are discussed. (PsycINFO Database Record PMID- 28080107 TI - Feasibility and adherence paradigm to ecological momentary assessments in urban minority youth. AB - All adolescents in general, including ethnic and racial minorities, report high levels of cell phone use, making mobile technology a useful tool for assessment and intervention. Known health and education disparities based on minority status motivated us to conduct an in-depth investigation regarding feasibility of and adherence to the ecological momentary assessment (EMA) research protocol, studying daily life of urban minority youth. In addition, this paper presents a methodological approach to conceptualizing and reporting adherence in EMA studies. The sample was comprised of 126 youth (41.3% boys; 40.5% 7th and 59.5% 8th graders; 75.4% African American, and 20.6% Hispanic) who carried a mobile phone for 10 days, including 2 weekends and reported on activities, moods, and attitudes. Mean level of adherence was 81% for momentary and 93.8% for daily assessments; it decreased over time and was higher during the week compared to weekends. Adherence was lower on days when participants reported high levels of negative affect and on days when they were engaged in physical activities. Our findings underscore the importance of differentiating between human and technology-related factors when computing adherence rates and portray adherence as a complex and dynamic construct that can vary across individuals. Specific study recommendations and methodological discussion provide guidelines for designing future studies. (PsycINFO Database Record PMID- 28080106 TI - Validity of the Brief Symptom Inventory-18 (BSI-18) for identifying depression and anxiety in young adult cancer survivors: Comparison with a Structured Clinical Diagnostic Interview. AB - The Brief Symptom Inventory-18 (BSI-18) is widely used to assess psychological symptoms in cancer survivors, but the validity of conventional BSI-18 cut-off scores in this population has been questioned. This study assessed the accuracy of the BSI-18 for identifying significant anxiety and depression in young adult cancer survivors (YACS), by comparing it with a "gold standard" diagnostic interview measure. Two hundred fifty YACS, age 18-40 completed the BSI-18 and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; SCID) interview assessing anxiety and depressive disorders. BSI-18 results were compared with SCID criteria using receiver operating characteristics (ROC) analyses. Forty four participants (17.7%) met criteria for >=1 SCID diagnoses, and an additional 20 (8.0%) met criteria for clinically significant SCID symptoms without a diagnosis. General concordance between the BSI-18 GSI scale and SCID diagnosis was good (AUC = 0.848), but the 2 most widely used BSI-18 case rules failed to identify a majority of survivors with SCID diagnoses, and no alternative BSI-18 cut-off scores met study criteria for clinical screening. Analyses aimed at identifying survivors with significant SCID symptoms or a SCID diagnosis had similar results, as did analyses examining depression and anxiety separately. The BSI-18 shows good overall concordance with a psychiatric interview, but recommended cut-off scores fail to identify a majority of YACS with psychiatric diagnosis. Clinicians should not rely on the BSI-18 alone as a screening measure for YACS. Alternative BSI-18 scoring algorithms optimized for detecting psychiatric symptoms in YACS may be an important step to address this limitation. (PsycINFO Database Record PMID- 28080108 TI - The Brief Problem Monitor-Parent form (BPM-P), a short version of the Child Behavior Checklist: Psychometric properties in Spanish 6- to 8-year-old children. AB - We provide the first validation data on the Spanish version of the Brief Problem Monitor-Parent form (BPM-P), a recently developed abbreviated version of the 120 item Child Behavior Checklist for Ages 6 to 18 (CBCL/6-18) in young schoolchildren. Parents of a community sample of 521 children aged 6-8 answered the CBCL/6-18 yearly, and the 19 BPM-P items were examined; parents also provided different measures of psychopathology. Confirmatory factor analysis of the expected 3-factor model (attention, externalizing, and internalizing) showed adequate fit (root mean square error of approximation, RMSEA <= .057), and measurement invariance across sex and age was observed. Internal consistency for the derived scores was satisfactory (omega >= .83). Concurrent validity with the equivalent scale scores of the original full CBCL/6-18 (r >= .84) and convergent validity with parents' ratings of the Strengths and Difficulties Questionnaire scores (r >= .52) were good. BPM-P scores at age 7 showed good predictive accuracy for discriminating the use of mental health services (OR >= 1.12), functional impairment (B <= -1.25), and the presence of the corresponding disorders diagnosed with an independent clinical interview, both cross sectionally at age 7 and longitudinally at age 8 (OR >= 1.24). The BPM-P provides reliable and valid scores as a very brief follow-up and screening tool for assessing behavioral and emotional problems in young schoolchildren. (PsycINFO Database Record PMID- 28080109 TI - The dynamic range of response set activation during action sequencing. AB - We show that theories of response scheduling for sequential action can be discriminated on the basis of their predictions for the dynamic range of response set activation during sequencing, which refers to the momentary span of activation states for completed and to-be-completed actions in a response set. In particular, theories allow that future actions in a plan are partially activated, but differ with respect to the width of the range, which refers to the number of future actions that are partially activated. Similarly, theories differ on the width of the range for recently completed actions that are assumed to be rapidly deactivated or gradually deactivated in a passive fashion. We validate a new typing task for measuring momentary activation states of actions across a response set during action sequencing. Typists recruited from Amazon Mechanical Turk copied a paragraph by responding to a "go" signal that usually cued the next letter but sometimes cued a near-past or future letter (n-3, -2, -1, 0, +2, +3). The activation states for producing letters across go-signal positions can be inferred from RTs and errors. In general, we found evidence of graded parallel activation for future actions and rapid deactivation of more distal past actions. (PsycINFO Database Record PMID- 28080110 TI - Spoken words can make the invisible visible-Testing the involvement of low-level visual representations in spoken word processing. AB - The notion that processing spoken (object) words involves activation of category specific representations in visual cortex is a key prediction of modality specific theories of representation that contrasts with theories assuming dedicated conceptual representational systems abstracted away from sensorimotor systems. In the present study, we investigated whether participants can detect otherwise invisible pictures of objects when they are presented with the corresponding spoken word shortly before the picture appears. Our results showed facilitated detection for congruent ("bottle" -> picture of a bottle) versus incongruent ("bottle" -> picture of a banana) trials. A second experiment investigated the time-course of the effect by manipulating the timing of picture presentation relative to word onset and revealed that it arises as soon as 200 400 ms after word onset and decays at 600 ms after word onset. Together, these data strongly suggest that spoken words can rapidly activate low-level category specific visual representations that affect the mere detection of a stimulus, that is, what we see. More generally, our findings fit best with the notion that spoken words activate modality-specific visual representations that are low level enough to provide information related to a given token and at the same time abstract enough to be relevant not only for previously seen tokens but also for generalizing to novel exemplars one has never seen before. (PsycINFO Database Record PMID- 28080111 TI - Generalized movement representation in haptic perception. AB - The extraction of spatial information by touch often involves exploratory movements, with tactile and kinesthetic signals combined to construct a spatial haptic percept. However, the body has many tactile sensory surfaces that can move independently, giving rise to the source binding problem: when there are multiple tactile signals originating from sensory surfaces with multiple movements, are the tactile and kinesthetic signals bound to one another? We studied haptic signal combination by applying the tactile signal to a stationary fingertip while another body part (the other hand or a foot) or a visual target moves, and using a task that can only be done if the tactile and kinesthetic signals are combined. We found that both direction and speed of movement transfer across limbs, but only direction transfers between visual target motion and the tactile signal. In control experiments, we excluded the role of explicit reasoning or knowledge of motion kinematics in this transfer. These results demonstrate the existence of 2 motion representations in the haptic system-one of direction and another of speed or amplitude-that are both source-free or unbound from their sensory surface of origin. These representations may well underlie our flexibility in haptic perception and sensorimotor control. (PsycINFO Database Record PMID- 28080112 TI - Beyond trial-by-trial adaptation: A quantification of the time scale of cognitive control. AB - The idea that adaptation to stimulus or response conflict can operate over different time scales takes a prominent position in various theories and models of cognitive control. The mechanisms underlying temporal variations in control are nevertheless poorly understood, which is partly due to a lack of appropriate empirical measures. Inspired by reinforcement learning models, we developed a method to quantify the time scale of control behaviorally, by computing trial-by trial effects that go beyond the preceding trial. Briefly, we extended the congruency sequence effect from 1 trial to multiple trials into the past and quantified the influence of previous trials on current-trial performance as a function of trial distance. The rate at which this influence changes across trials was taken as a measure of the time scale of control. We applied the method to a flanker task with different conflict frequencies and volatility. Results showed that the time scale of control was smaller in rare-conflict and volatile contexts, compared to frequent-conflict and neutral contexts. This is in agreement with theories differentiating transient from sustained control. The method offers new opportunities to reveal temporal differences in control modes and can easily be applied to various empirical paradigms. (PsycINFO Database Record PMID- 28080113 TI - Higher-order cognitive control in dual tasks: Evidence from task-pair switching. AB - In the present study, we combined the psychological refractory period (PRP) paradigm with a novel task-pair switching logic which enabled us to isolate performance costs occurring at the global level of task-pairs. In Experiment 1, in which we used conceptually overlapping responses for Task 1 (T1) and Task 2 (T2), we generated 3 task-pairs by combining 1 of 3 visual tasks (T1) with an auditory task (T2). In addition to worse performance after a short SOA than a long SOA (i.e., PRP effect), we found impaired performance in n - 1 task-pair switches as compared to n - 1 task-pair repetitions (i.e., n - 1 task-pair switch costs), suggesting that task-pairs were activated during dual-task processing. In Experiment 2, we increased the interference between T1 and T2 by using physically overlapping responses and we again observed n - 1 task-pair switch costs. To investigate whether the activation of task-pairs is adjusted by inhibitory control, we looked at the n - 2 task-pair sequence and found performance to be better in n - 2 task-pair repetitions than in n - 2 task-pair switches in both experiments. This n - 2 task-pair repetition benefit was replicated in Experiment 3 in which no immediate task-pair repetitions were included. Hence, the evidence suggests enhanced activation rather than inhibition as a crucial selection mechanism at the global level of dual-task processing. (PsycINFO Database Record PMID- 28080114 TI - Oculomotor and linguistic processing effects in reading dynamic horizontally scrolling text. AB - Two experiments are reported investigating oculomotor behavior and linguistic processing when reading dynamic horizontally scrolling text (compared to reading normal static text). Three factors known to modulate processing time in normal reading were investigated: Word length and word frequency were examined in Experiment 1, and target word predictability in Experiment 2. An analysis of global oculomotor behavior across the 2 experiments showed that participants made fewer and longer fixations when reading scrolling text, with shorter progressive and regressive saccades between these fixations. Comparisons of the linguistic manipulations showed evidence of a dissociation between word-level and sentence level processing. Word-level processing (Experiment 1) was preserved for the dynamic scrolling text condition with no difference in length and frequency effects between scrolling and static text formats. However, sentence-level integration (Experiment 2) was reduced for scrolling compared to static text in that we obtained no early facilitation effect for predictable words under scrolling text conditions. (PsycINFO Database Record PMID- 28080115 TI - Reaching into response selection: Stimulus and response similarity influence central operations. AB - To behave adaptively in complex and dynamic environments, one must link perception and action to satisfy internal states, a process known as response selection (RS). A largely unexplored topic in the study of RS is how interstimulus and interresponse similarity affect performance. To examine this issue, we manipulated stimulus similarity by using colors that were either similar or dissimilar and manipulated response similarity by having participants move a mouse cursor to locations that were either close together or far apart. Stimulus and response similarity produced an interaction such that the mouse trajectory showed the greatest curvature when both were similar, a result obtained under task conditions emphasizing speed and conditions emphasizing accuracy. These findings are inconsistent with symbolic look-up accounts of RS but are consistent with central codes incorporating metrical properties of both stimuli and responses. (PsycINFO Database Record PMID- 28080116 TI - Recognition memory for hue: Prototypical bias and the role of labeling. AB - How does the concurrent use of language affect perception and memory for exemplars? Labels cue more general category information than a specific exemplar. Applying labels can affect the resulting memory for an exemplar. Here 3 alternative hypotheses are proposed for the role of labeling an exemplar at encoding: (a) labels distort memory toward the label prototype, (b) labels guide the level of specificity needed in the current context, and (c) labels direct attention to the label's referent among all possible features within a visual scene. University students were shown hues on object silhouettes that they either labeled with basic color categories, made preference judgments about, or indicated the animacy of its category. Experiments 1 and 2 established that there are response shifts toward the category prototype regardless of labeling, showing a pervasive influence of category knowledge on response bias. They also established an effect of labeling whereby labeling decreases the magnitude of shifts. Experiments 3 and 4 investigated the uniqueness and necessity of language in causing the decreased shift-neither of which proved to be the case. Overall, category-relative bias was pervasive and labeling appears to direct attention to the feature resulting in less biased memory. The results highlight that the context at encoding affects how memory is formed. (PsycINFO Database Record PMID- 28080117 TI - Effects of learned episodic event structure on prospective duration judgments. AB - The field of psychology of time has typically distinguished between prospective timing and retrospective duration estimation: in prospective timing, participants attend to and encode time, whereas in retrospective estimation, estimates are based on the memory of what happened. Prior research on prospective timing has primarily focused on attentional mechanisms to explain timing behavior, but it remains unclear the extent to which memory processes may also play a role. The present studies investigate this issue, and specifically, the role of newly learned encoded event structure. Two structural properties of dynamic event sequences were examined, which are known to modulate retrospective duration estimates: the perceived number of segments and the similarity between them. We found that when duration and episodic event content are both attended to and encoded, more segments and less similarity between them led to longer attributed durations, despite clock duration remaining constant. In contrast, when only duration is attended to, only the number of segments influenced estimated durations. These findings indicate that incidentally or intentionally encoded episodic event structure modulates prospective duration judgments. Based on these and previous findings, implications for the role of memory mechanisms on prospective paradigms are discussed. (PsycINFO Database Record PMID- 28080118 TI - Photos that increase feelings of learning promote positive evaluations. AB - Research shows that when semantic context makes it feel easier for people to bring related thoughts and images to mind, people can misinterpret that feeling of ease as evidence that information is positive. But research also shows that semantic context does more than help people bring known concepts to mind-it also teaches people new concepts. In five experiments, we show that when photos increase these feelings of learning, they also increase positive evaluations. People saw fictitious wine names and evaluated claims about each. Within subjects, wine names appeared with (or without) photos depicting the noun in the names. We found that photos promoted positive evaluations, did so most when they were most likely to help people learn new words, and even led people to think the wines tasted better. Together, these findings fit with the idea that semantic context promotes positive evaluations in part by teaching people new concepts. (PsycINFO Database Record PMID- 28080119 TI - The role of episodic context in retrieval practice effects. AB - The episodic context account of retrieval-based learning proposes that retrieval enhances subsequent retention because people must think back to and reinstate a prior learning context. Three experiments directly tested this central assumption of the context account. Subjects studied word lists and then either restudied the words under intentional learning conditions or made list discrimination judgments by indicating which list each word had occurred in originally. Subjects in both conditions experienced all items for the same amount of time, but subjects in the list discrimination condition were required to retrieve details about the original episodic context in which the words had occurred. Making initial list discrimination judgments consistently enhanced subsequent free recall relative to restudying the words. Analyses of recall organization and retrieval strategies on the final test showed that retrieval practice enhanced temporal organization during final recall. Semantic encoding tasks also enhanced retention relative to restudying but did so by promoting semantic organization and semantically based retrieval strategies during final recall. The results support the episodic context account of retrieval-based learning. (PsycINFO Database Record PMID- 28080120 TI - A goal bias in action: The boundaries adults perceive in events align with sites of actor intent. AB - We live in a dynamic world comprised of continuous events. Remembering our past and predicting future events, however, requires that we segment these ongoing streams of information in a consistent manner. How is this segmentation achieved? This research examines whether the boundaries adults perceive in events, such as the Olympic figure skating routine used in these studies, align with the beginnings (sources) and endings (goals) of human goal-directed actions. Study 1 showed that a group of experts, given an explicit task with unlimited time to rewatch the event, identified the same subevents as one another, but with greater agreement as to the timing of goals than sources. In Study 2, experts, novices familiarized with the figure skating sequence, and unfamiliarized novices performed an online event segmentation task, marking boundaries as the video progressed in real time. The online boundaries of all groups corresponded with the sources and goals offered by Study 1's experts, with greater alignment of goals than sources. Additionally, expertise, but not mere perceptual familiarity, boosted the alignment of sources and goals. Finally, Study 3, which presented novices with the video played in reverse, indicated, unexpectedly, that even when spatiotemporal cues were disrupted, viewers' perceived event boundaries still aligned with their perception of the actors' intended sources and goals. This research extends the goal bias to event segmentation, and suggests that our spontaneous sensitivity toward goals may allow us to transform even relatively complex and unfamiliar event streams into structured and meaningful representations. (PsycINFO Database Record PMID- 28080122 TI - Continuing our organizational mission: A new name for a new time. AB - This editorial explains the need for a new name for the American Orthopsychiatric Association (ORTHO). As ORTHO continues their work into the 21st century, they want to better reflect their global membership and focus, increasing the number of partnerships with individuals and organizations, and commitment to a just society. Therefore, ORTHO is changing their name to the Global Alliance for Behavioral Health and Social Justice. It is crucial to underscore that, although the organizations name is changing, the values and principles that inform their work will remain the same. The mission statement of the Global Alliance for Behavioral Health and Social Justice is "to inform policy, practice, and research to prevent behavioral health disorders and to promote conditions to ensure that people with disorders can be full participants in society." (PsycINFO Database Record PMID- 28080121 TI - Hand matters: Left-hand gestures enhance metaphor explanation. AB - Research suggests that speech-accompanying gestures influence cognitive processes, but it is not clear whether the gestural benefit is specific to the gesturing hand. Two experiments tested the "(right/left) hand-specificity" hypothesis for self-oriented functions of gestures: gestures with a particular hand enhance cognitive processes involving the hemisphere contralateral to the gesturing hand. Specifically, we tested whether left-hand gestures enhance metaphor explanation, which involves right-hemispheric processing. In Experiment 1, right-handers explained metaphorical phrases (e.g., "to spill the beans," beans represent pieces of information). Participants kept the one hand (right, left) still while they were allowed to spontaneously gesture (or not) with their other free hand (left, right). Metaphor explanations were better when participants chose to gesture when their left hand was free than when they did not. An analogous effect of gesturing was not found when their right hand was free. In Experiment 2, different right-handers performed the same metaphor explanation task but, unlike Experiment 1, they were encouraged to gesture with their left or right hand or to not gesture at all. Metaphor explanations were better when participants gestured with their left hand than when they did not gesture, but the right hand gesture condition did not significantly differ from the no-gesture condition. Furthermore, we measured participants' mouth asymmetry during additional verbal tasks to determine individual differences in the degree of right-hemispheric involvement in speech production. The left-over-right-side mouth dominance, indicating stronger right-hemispheric involvement, positively correlated with the left-over-right-hand gestural benefit on metaphor explanation. These converging findings supported the "hand-specificity" hypothesis. (PsycINFO Database Record PMID- 28080123 TI - Treating adult survivors of childhood emotional abuse and neglect: A new framework. AB - This article provides the outline of a new framework for treating adult survivors of childhood emotional abuse and neglect. Component-based psychotherapy (CBP) is an evidence-informed model that bridges, synthesizes, and expands upon several existing schools, or theories, of treatment for adult survivors of traumatic stress. These include approaches to therapy that stem from more classic traditions in psychology, such as psychoanalysis, to more modern approaches including those informed by feminist thought. Moreover, CBP places particular emphasis on integration of key concepts from evidence-based treatment models developed in the past few decades predicated upon thinking and research on the effects of traumatic stress and processes of recovery for survivors. (PsycINFO Database Record PMID- 28080124 TI - Statistical learning of parts and wholes: A neural network approach. AB - Statistical learning is often considered to be a means of discovering the units of perception, such as words and objects, and representing them as explicit "chunks." However, entities are not undifferentiated wholes but often contain parts that contribute systematically to their meanings. Studies of incidental auditory or visual statistical learning suggest that, as participants learn about wholes they become insensitive to parts embedded within them, but this seems difficult to reconcile with a broad range of findings in which parts and wholes work together to contribute to behavior. Bayesian approaches provide a principled description of how parts and wholes can contribute simultaneously to performance, but are generally not intended to model the computations that actually give rise to this performance. In the current work, we develop an account based on learning in artificial neural networks in which the representation of parts and wholes is a matter of degree, and the extent to which they cooperate or compete arises naturally through incidental learning. We show that the approach accounts for a wide range of findings concerning the relationship between parts and wholes in auditory and visual statistical learning, including some findings previously thought to be problematic for neural network approaches. (PsycINFO Database Record PMID- 28080125 TI - Valence in context: Asymmetric reactions to realized gains and losses. AB - The current research documents a novel pattern of preferences across nominally equivalent outcomes. When evaluating the outcome of completed experiences, people are sensitive to the magnitude of component (i.e., gross) gains and losses rather than responding solely to the net outcomes. However, people do not consistently favor outcomes that minimize losses (a pattern consistent with loss aversion), nor those that maximize gains (a pattern consistent with a positivity bias). Instead, preferences are context dependent. Holding net outcomes constant, people prefer positive outcomes that have lower magnitudes of component gains and losses. In contrast, people prefer negative outcomes that have higher magnitudes of component gains and losses. A shift in focus occurs such that people prioritize the contrasting attribute (e.g., negative when the net outcome is positive) in the evaluation process. The article concludes by discussing implications for a broad range of judgments and decisions. (PsycINFO Database Record PMID- 28080126 TI - Know thy enemy: Education about terrorism improves social attitudes toward terrorists. AB - Hatred of terrorists is an obstacle to the implementation of effective counterterrorism policies-it invites indiscriminate retaliation, whereas many of the greatest successes in counterterrorism have come from understanding terrorists' personal and political motivations. Drawing from psychological research, traditional prejudice reduction strategies are generally not well suited to the task of reducing hatred of terrorists. Instead, in 2 studies, we explored education's potential ability to reduce extreme negative attitudes toward terrorists. Study 1 compared students in a college course on terrorism (treatment) with wait-listed students, measuring prosocial attitudes toward a hypothetical terrorist. Initially, all students reported extremely negative attitudes; however, at the end of the semester, treatment students' attitudes were significantly improved. Study 2 replicated the effect within a sample of treatment and control classes drawn from universities across the United States. The present work was part of an ongoing research project, focusing on foreign policy and the perceived threat of terrorism; thus classes did not explicitly aim to reduce prejudice, making the effect of treatment somewhat surprising. One possibility is that learning about terrorists "crowds out" the initial pejorative associations-that is, the label terrorism may ultimately call more information to mind, diluting its initial negative associative links. Alternatively, students may learn to challenge how the label terrorist is being applied. In either case, learning about terrorism can decrease the extreme negative reactions it evokes, which is desirable if one wishes to implement effective counterterrorism policies. (PsycINFO Database Record PMID- 28080127 TI - Are you early or late?: Temporal error monitoring. AB - Temporal judgments regarding a target interval typically produce a nearly normally distributed reproduction times centered on the target with substantial variance. This phenomenon indicates that the majority of our temporal judgments are deviations from the target times, which are assumed to originate from the underlying timing uncertainty. Although humans were found to adapt their decisions in response to timing uncertainty, we do not know if they can accurately judge the direction and degree of their temporal errors. In this study, we asked participants to reproduce durations as accurately as possible. After each reproduction, participants were asked to retrospectively rate their confidence in their temporal estimates and to judge if their response time was earlier or later than the target interval. The results revealed that human participants are aware of both the direction and magnitude of their timing errors, pointing at an informationally rich temporal error monitoring ability. We further show that a sequential diffusion process can account for the detection of direction of errors as well as the qualitative features of the relationship of objective temporal errors with subjective confidence ratings and associated response times. (PsycINFO Database Record PMID- 28080130 TI - Corrigendum. AB - Mueller AM, Rosso C, Entezari V, McKenzie B, Hasebroock A, Della Croce U, Nazarian A, Ramappa AJ, DeAngelis JP. The effect of supraspinatus tears on glenohumeral translations in passive pitching motion. Am J Sports Med. 2014;42(10):2455-2462. (Original DOI: 10.1177/0363546514547348 ) In the above article, an author was inadvertently omitted: Andrea Cereatti, PhD (Department of Information Engineering, Political Sciences and Communication Sciences, University of Sassari, Sassari, Italy). The corrected citation information is as follows: Mueller AM, Rosso C, Entezari V, McKenzie B, Hasebroock A, Cereatti A, Della Croce U, Nazarian A, Ramappa AJ, DeAngelis JP. The effect of supraspinatus tears on glenohumeral translations in passive pitching motion. Am J Sports Med. 2014;42(10):2455-2462. PMID- 28080131 TI - Hypusination of eIF5A as a Target for Antiviral Therapy. PMID- 28080132 TI - Ranting in 2017: Is It Working? PMID- 28080133 TI - Associations Between Internet Attachment, Cyber Victimization, and Internalizing Symptoms Among Adolescents. AB - With increasing frequency of Internet use among adolescents, there are growing concerns about their risk for becoming attached to these forms of communication and increased vulnerability for negative online experiences, including cyber victimization. The effect of these experiences on adolescent mental health is not well understood. In this study, we examine how Internet attachment is related to anxiety and depression and assess the mediating effect of cyber victimization on these associations. Participants included 1,151 middle school students (51.4 percent males) aged 10 to 16 (M = 12.7, SD = 0.93). Structural equation models show that greater Internet attachment was associated with more cyber victimization and greater symptoms of anxiety and depression. Cyber victimization mediated the associations between Internet attachment and anxiety and between Internet attachment and depression. Implications for online awareness efforts are discussed. PMID- 28080135 TI - Characteristics, Properties and Analytical Methods of Amoxicillin: A Review with Green Approach. AB - Bacterial infections are the second leading cause of global mortality. Considering this fact, it is extremely important studying the antimicrobial agents. Amoxicillin is an antimicrobial agent that belongs to the class of penicillins; it has bactericidal activity and is widely used in the Brazilian health system. In literature, some analytical methods are found for the identification and quantification of this penicillin, which are essential for its quality control, which ensures maintaining the product characteristics, therapeutic efficacy and patient's safety. Thus, this study presents a brief literature review on amoxicillin and the analytical methods developed for the analysis of this drug in official and scientific papers. The major analytical methods found were high-performance liquid chromatography (HPLC), ultra performance liquid chromatography (U-HPLC), capillary electrophoresis and iodometry and diffuse reflectance infrared Fourier transform. It is essential to note that most of the developed methods used toxic and hazardous solvents, which makes necessary industries and researchers choose to develop environmental friendly techniques to provide enhanced benefits to environment and staff. PMID- 28080134 TI - Alveolar Epithelial Cell-Derived Mediators: Potential Direct Regulators of Large Airway and Vascular Responses. AB - Bronchial epithelial cells and pulmonary endothelial cells are thought to be the primary modulators of conducting airways and vessels, respectively. However, histological examination of both mouse and human lung tissue reveals that alveolar epithelial cells (AECs) line the adventitia of large airways and vessels and thus are also in a position to directly regulate these structures. The primary purpose of this perspective is to highlight the fact that AECs coat the adventitial surface of every vessel and airway in the lung parenchyma. This localization is ideal for transmitting signals that can contribute to physiologic and pathologic responses in vessels and airways. A few examples of mediators produced by AECs that may contribute to vascular and airway responses are provided to illustrate some of the potential effects that AECs may modulate. PMID- 28080136 TI - Isoniazid: A Review of Characteristics, Properties and Analytical Methods. AB - Isoniazid is a synthetic antimicrobial and one of the most important first-line drugs used in the treatment of tuberculosis. Since it was introduced in the therapy in 1952, the drug remains at the front line of the antituberculosis treatment mainly due to its potency and high selectivity against Mycobacterium tuberculosis. Pharmaceutical analysis and therapeutic drug monitoring of isoniazid in both, pharmaceuticals and biological samples, plays an important role to comprehend aspects regarding to bioavailability, bioequivalence and therapeutic monitoring during patients following-up. In the last case, validated and simple methods are extremely useful for Public Healthy in order to guarantee the drug efficacy, safety and reduce the tuberculosis resistance. Among the available analytical tools, HPLC-based methods coupled to ultraviolet or mass spectroscopy are the most widely used techniques to quantify isoniazid. Therefore, this review highlights the main analytical methods reported in the literature for determination of isoniazid focusing in HPLC-based methods. PMID- 28080138 TI - Corrigendum. AB - McCormick F, Nwachukwu BU, Solomon D, Dewing C, Golijanin P, Gross DJ, Provencher MT. The efficacy of biceps tenodesis in the treatment of failed superior labral anterior posterior repairs. Am J Sports Med. 2014;42(4):820-825. (Original DOI: 10.1177/0363546513520122 ). PMID- 28080139 TI - Corrigendum. AB - Farr J, Tabet SK, Margerrison E, Cole BJ. Clinical, radiographic, and histological outcomes after cartilage repair with particulated juvenile articular cartilage: a 2-year prospective study. Am J Sports Med. 2014;42(6):1417-1425. (Original DOI: 10.1177/0363546514528671 ) In the above article, 2 authors were inadvertently omitted: Cathy S. Carlson, DVM, PhD (Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, USA) and Garry E. Gold, MD (Department of Radiology, Stanford University, Stanford, California, USA). The corrected citation information is as follows: Farr J, Tabet SK, Margerrison E, Carlson CS, Gold GE, Cole BJ. Clinical, radiographic, and histological outcomes after cartilage repair with particulated juvenile articular cartilage: a 2-year prospective study. Am J Sports Med. 2014;42(6):1417-1425. PMID- 28080141 TI - Low concentration of oleic acid exacerbates LPS-induced cell death and inflammation in human alveolar epithelial cells. AB - PURPOSE: The current study aimed to investigate in vitro effects of oleic acid on lipopolysaccharide (LPS)-induced acute lung injury in the human lung epithelial cells (A549). MATERIALS AND METHODS: The cell viability was evaluated by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) tests. Selected gene expression levels were analyzed by Real-Time Quantitative-Polymerase Chain Reaction (RT-qPCR). RESULTS: 24 hours of LPS (100 ng/mL) exposure decreased the cells' viability by 44.6% compared to untreated control. Low concentration (2.5 nM) of oleic acid slightly suppressed the cell survival by 9.1% analyzed 24 hours after incubation. However, oleic acid pretreatment before LPS exposure significantly increased cell survival loss to 63.9%. LPS exposure decreased the expressions of catalase (CAT) and glutathione peroxidase (GPx) mRNA levels by 2.8 and 2.5 fold, respectively. Moreover, pretreatment of the cells with oleic acid strengthened LPS-decreased expressions of CAT and GPx genes by 3.5 and 6.7 fold, respectively. The mRNA expressions of superoxide dismutase (SOD), induced nitric oxide synthase (iNOS), interleukin-1beta, IL-12, COX-2, caspase-3 and caspase-8 were increased by 2.4, 2.2, 2.2, 2.3, 3.0, 2.6, and 2.5 fold, respectively, by LPS, and oleic acid pretreatment significantly potentiated the effect of LPS. CONCLUSION: Oleic acid worsens LPS-induced cell death by potentiating oxidative stress and inflammation in A549 lung epithelial cells. PMID- 28080142 TI - Whole Genome Amplification Provides Suitable Control DNA for Use in DNA Barcoding Applications. PMID- 28080144 TI - A Survey of the Current Situation of Clinical Biobanks in China. AB - The development of biomedical research urgently needs the support of a large number of high-quality clinical biospecimens. Therefore, human biobanks at different levels have been established successively in China and other countries at a significantly increasing pace in recent years. To better understand the general current state of clinical biobanks in China, we surveyed 42 clinical biobanks based in hospitals and collected information involving their management systems, sharing mechanisms, quality control systems, and informational management systems using closed questionnaire methods. Based on our current information, there has not been such a large-scale survey in China. An understanding of the status and challenges current clinical biobanks face will provide valuable insights for the construction and sustainable development of higher quality clinical biobanks. PMID- 28080145 TI - Neuropsychological Predictors of ODD Symptom Dimensions in Young Children. AB - Oppositional defiant disorder (ODD) is a commonly diagnosed childhood behavior disorder, yet knowledge of relations between ODD and early neuropsychological functions, particularly independent of attention deficit/hyperactivity disorder (ADHD), is still limited. In addition, studies have not examined neuropsychological functioning as it relates to the different ODD symptom dimensions. Structural equation modeling was used to investigate how preschool neuropsychological functioning predicted negative affect, oppositional behavior, and antagonistic behavior symptom dimensions of ODD in 224 six-year-old children, oversampled for early behavior problems. Working memory, inhibition, and sustained attention predicted negative affect symptoms of ODD, controlling for ADHD, whereas delay aversion uniquely predicted oppositional behavior, controlling for ADHD. Delay aversion also marginally predicted antagonistic behavior, controlling for ADHD. Results demonstrate that different ODD symptom dimensions may be differentially predicted by different neuropsychological functions. The findings further underscore the importance of future research on ODD to take into account the possible heterogeneity of both symptoms and underlying neuropsychological functioning. PMID- 28080148 TI - Beyond Direct Benefits: Indirect Health Benefits of Social Media Use. PMID- 28080146 TI - Perceptions vs. evidence: therapeutic substitutes for antipsychotics in patients with dementia in long-term care. AB - OBJECTIVE: To compare differences between clinician perceptions of therapeutic substitutes for antipsychotics prescribed to patients with dementia in long term care (LTC) and published evidence. METHODS: A mixed-methods approach that included a drug information search, online survey of 55 LTC clinicians and a comprehensive literature review was used. For 41 pharmacologic antipsychotic substitute candidates identified, LTC clinicians rated the likelihood they would substitute each for patients with dementia and identified non-pharmacologic antipsychotic substitutes. The quality of evidence supporting the most likely antipsychotic substitutes was assessed using a modified GRADE approach. RESULTS: Among 36 (65%) of LTC clinicians responding, the pharmacologic candidates deemed likely or somewhat likely to be substituted for an antipsychotic were: valproic acid, serotonin modulator antidepressants, short-acting benzodiazepines, serotonin reuptake inhibitor antidepressants, alpha-adrenoceptor antagonist, buspirone, acetaminophen, serotonin-norepinephrine reuptake inhibitor antidepressants, memantine, and a cholinesterase inhibitor. High quality evidence supporting these substitutions existed for only memantine and cholinesterase inhibitors, while high quality evidence cautioning against this substitution existed for valproic acid. Activities and music therapy were the most commonly cited non-pharmacologic substitutes but the supporting evidence for each is sparse. CONCLUSION: Perceptions of LTC clinicians regarding substitutes for antipsychotics in LTC patients with dementia vary widely and are often discordant with published evidence. PMID- 28080149 TI - Positive Preferences: The Emotional Valence of What an Avatar Says Matters. AB - This study examined preferences and ascriptions of human control for avatars associated with positive and negative language. An avatar is a graphical representation of an individual user in a virtual world. Users form judgments of other virtual world users based on the appearance and behavior of their avatars in the absence of physical cues. In particular, users have previously displayed sensitivity toward anthropomorphism and verbal behavior of avatars they encounter within virtual environments. Thus far, investigations of language in online and virtual spaces have been limited to specific contexts. University student participants and Amazon Mechanical Turk workers were shown two avatars. Each pair consisted of two out of three possible appearances: a tiger, a male, or a female. Each avatar was aligned with a different text introduction: one containing words of positive emotional valence and the other of negative emotional valence. Participants from both samples preferred avatars associated with positive language, regardless of appearance, but participants did not ascribe human control of an avatar based on either emotional valance or appearance. Significant differences for reported preferences and likeability demonstrate the salience of emotive language as a social cue even in short text introductions for avatars. These findings suggest that those we like and want to be around in virtual environments might not necessarily align with whom we view as human. PMID- 28080150 TI - Motives Matter: Motives for Playing Pokemon Go and Implications for Well-Being. AB - Mobile games such as Pokemon Go have become a major form of entertainment, and yet little is known about why people play the games and how their motives associate with well-being. Although literature on motives for playing video and online games is informative, the findings may not reflect the full spectrum of mobile gaming motives due to some unique affordances of mobile games (e.g., mobility). To catch up with the evolving gaming context, a popular mobile game, Pokemon Go, was taken as an example to explore individuals' mobile gaming motives. A Pokemon Go Motive Scale was developed. Seven motives were identified through factor analyses based on survey data from 262 Pokemon Go players (45 percent women; Mage = 30.71, standard deviation = 7.77): Exercise, Fun, Escapism, Nostalgia, Friendship Maintenance, Relationship Initiation, and Achievement. Both Fun and Friendship Maintenance were positive correlates of well-being, whereas Escapism and Nostalgia were negative correlates. Relationship Initiation was associated with both better and poorer well-being. Implications of the findings are discussed. PMID- 28080152 TI - Ideological Consumerism in Colombian Elections, 2015: Links Between Political Ideology, Twitter Activity, and Electoral Results. AB - Propagation of political ideologies in social networks has shown a substantial impact on voting behavior. Both the contents of the messages (the ideology) and the politicians' influence on their online audiences (their followers) have been associated with such an impact. In this study we evaluate which of these factors exerted a major role in deciding electoral results of the 2015 Colombian regional elections by evaluating the linguistic similarity of political ideologies and their influence on the Twitter sphere. The electoral results proved to be strongly associated with tweets and retweets and not with the linguistic content of their ideologies or politicians' followers in Twitter. Finally, suggestions for new ways to analyze electoral processes are discussed. PMID- 28080154 TI - Biocompatibility assessments for medical devices - evolving regulatory considerations. AB - INTRODUCTION: Biocompatibility assessment provides key data supporting medical device development and marketing. Although regional and international guidance is available, differences in proposed biocompatibility assessments or test methods lead to confusion and inefficiencies in generating the package of supporting nonclinical data. Areas covered: Modifications to available guidance for biological safety testing of medical devices, as described by the International Organisation for Standardisation (ISO) and the US Food and Drug Administration (FDA), have, over time, sometimes increased and sometimes decreased the level of harmonisation in testing requirements. These requirements continue to evolve, as shown by refinements and supplements to existing ISO 10,993 standards, new ISO standards under development and new finalised guidance from the FDA - which shows a shift away from routine testing-based approaches and much greater emphasis on characterisation, with use of existing literature or demonstration of equivalence to established comparator products, where possible. Expert commentary: This article examines the impact of recent changes in guidance for biocompatibility assessment of new medical devices and shows that, although a high level of consistency now occurs in ISO and FDA requirements, there are still areas where a 'standard approach' is not possible, allowing hurdles for global development of medical devices to persist. PMID- 28080153 TI - Long-term Change of Subfoveal Choroidal Thickness in Behcet's Disease Patients with Posterior Uveitis. AB - PURPOSE: To evaluate long-term changes of subfoveal choroidal thickness (SCT) in Behcet's disease (BD) patients with posterior uveitis. METHODS: Changes in SCT measured with enhanced depth imaging optical coherence tomography during quiescent phase were assessed during >24 months in 63 BD patients and control group. RESULTS: Baseline characteristics showed no difference, but the BD group showed poorer visual acuity (p = 0.013) and smaller SCT (p = 0.006) at final examination. Mean SCT in the BD group decreased from 291.0 to 268.1 MUm (p<0.001) during the mean period of 38.5 months. Mean change rate of SCT in the BD group was greater than controls (-7.2 vs 2.0 MUm/year; p<0.001) and was associated with longer active inflammation (p<0.001). Patients with longer disease duration showed smaller baseline SCT (p = 0.03). CONCLUSIONS: In BD patients, choroidal thickness decreased over time, which was associated with length of active inflammation. It suggests intraocular inflammation in BD affects the choroid as well as the retina. PMID- 28080155 TI - Safety of Interferon Alpha-2a in Patients with Severe Ophthalmic Behcet's Disease: Response to Bielefeld et al.'s Letter. AB - Thyroid dysfunction is a common and severe side-effect encountered in up to 40% of patients treated with IFN-alpha-2a. The main two mechanisms by which IFN-alpha 2a induces thyroid dysfunction can be categorized as autoimmune and non autoimmune disease. In the first subgroup, thyroid antibodies are found before treatment initiation, and then patients develop thyroiditis. In the second subgroup, IFN-alpha-2a induces thyroiditis by a direct cytotoxic effect on the thyroid gland; in this case, thyroid antibodies are usually negative. To avoid such complications, patients should undergo routine thyroid screening (thyroid stimulating hormone and thyroid antibodies) prior to IFN-alpha-2a initiation, during the treatment period, and 6 months after treatment withdrawal. PMID- 28080157 TI - Detection of recurrence in early stage endometrial cancer - the role of symptoms and routine follow-up. AB - BACKGROUND: Considerable controversy remains as to the optimal organization of endometrial cancer follow-up. AIM: To evaluate the relationship between the way recurrence was detected and survival after treatment for endometrial cancer. Further, to identify characteristics associated with a pre-scheduled examination in women with symptomatic recurrence. MATERIAL AND METHODS: All women with early stage endometrial cancer during 2005-2009 were included in a population-based historical cohort derived from the Danish Gynecological Cancer Database. Women diagnosed with recurrence within three years after primary surgery and the mode of recurrence detection were identified from hospital charts: asymptomatic recurrence detected at regular follow-up, symptomatic recurrence detected at regular follow-up or symptomatic recurrence detected in between follow-up. Survival of women with symptomatic and asymptomatic disease was compared. Furthermore, characteristics associated with self-referral as compared to presenting symptoms at regular follow-ups were identified using univariate analyses. RESULTS: In total, 183 cases of recurrence (7%) were identified in the cohort of 2612 women. Of these, 65.5% were symptomatic with vaginal bleeding as the most prevalent symptom. Asymptomatic women had a significantly better three year survival rate compared to symptomatic women (80.3% vs. 54.3%, p < 0.01). A total of 2.3% of the entire population had an asymptomatic recurrence. Women diagnosed at a pre-scheduled visit due to symptoms had a higher educational level (p = 0.03) and more often high-risk disease (p = 0.02) than symptomatic women diagnosed at regular follow-up. CONCLUSION: Early stage endometrial cancer carries a low risk of recurrence. Survival appears to be superior in asymptomatic patients, but length-time bias, i.e. the effect of aggressive tumor biology in symptomatic recurrences, may bias results in non-randomized controlled trials. Well educated patients with symptoms of recurrence more often sought medical attendance compared to less educated counterparts. This should be considered if patient-initiated follow-up is the standard care. PMID- 28080158 TI - Diagnosing central lesions of the triangular fibrocartilage as traumatic or degenerative: a review of clinical accuracy. AB - : This study examined the reliability of surgeons' estimations as to whether central lesions of the triangular fibrocartilage complex were traumatic or degenerative. A total of 50 consecutive central triangular fibrocartilage complex lesions were independently rated by ten experienced wrist surgeons viewing high quality arthroscopy videos. The videos were reassessed after intervals of 3 months; at the second assessment surgeons were given the patient's history, radiographs and both, each in a randomized order. Finally, the surgeons assessed the histories and radiographs without the videos. Kappa statistics revealed fair interrater agreement when the histories were added to the videos. The other four modalities demonstrated moderate agreement, with lower Kappa values for the assessment without videos. Intra-rater reliability showed fair agreement for three surgeons, moderate agreement for two surgeons and substantial agreement for five surgeons. It appears that classification of central triangular fibrocartilage complex lesions depends on the information provided upon viewing the triangular fibrocartilage complex at arthroscopy. LEVEL OF EVIDENCE: II. PMID- 28080160 TI - The Whipple Prize. PMID- 28080159 TI - Profile. PMID- 28080167 TI - Best Paper and Poster Presented at Bssh Autumn Meeting 2011. PMID- 28080168 TI - Corneal Melt after Boston Keratoprosthesis: Clinical Presentation, Management, Outcomes and Risk Factor Analysis. AB - PURPOSE: To determine the presentation, risk factors, and outcomes of keratolysis after Boston type I keratoprosthesis (B-KPro). METHODS: Retrospective chart review. RESULTS: A total of 16 (14%) of the 110 eyes (96 patients) which underwent B-KPro implantation developed keratolysis at an average 20 +/- 11 months. Retroprosthetic membrane (RPM), infectious keratitis, and corneal dellen were identified in 31%, 25%, and 13% of corneal melts, respectively. Five eyes had keratolysis without a readily identifiable cause. RPM (odds-ratio, OR = 4.4, p = 0.02) and infectious keratitis (OR = 17.6, p<0.0005) were confirmed as significant risk factors. Retinal detachment (p = 0.001) and choroidal detachment (p = 0.003) were more common in eyes with keratolysis. Management included B-KPro removal or exchange (n = 7), amniotic membrane transplantation (n = 1), tectonic corneal transplantation (n = 2), medical treatment (n = 4), and observation (n = 2). CONCLUSIONS: The risk of keratolysis following B-Kpro increases with the development of RPM and infectious keratitis. Patients with keratolysis had higher complication rates and should receive rigorous monitoring. PMID- 28080170 TI - Presentation to the best candidate in the European board of hand surgery diploma examination 2011. PMID- 28080169 TI - FAMily-Oriented Support (FAMOS): development and feasibility of a psychosocial intervention for families of childhood cancer survivors. AB - BACKGROUND: We developed and tested the feasibility of a manualized psychosocial intervention, FAMily-Oriented Support (FAMOS), a home-based psychosocial intervention for families of childhood cancer survivors. The aim of the intervention is to support families in adopting healthy strategies to cope with the psychological consequences of childhood cancer. The intervention is now being evaluated in a nationwide randomized controlled trial (RCT). METHODS AND DESIGN: FAMOS is based on principles of family systems therapy and cognitive behavioral therapy, and is delivered in six sessions at home. Families were recruited from all four pediatric oncology departments in Denmark after the end of intensive cancer treatment. We evaluated the feasibility of the intervention and of a RCT design for comparing the intervention with usual care. The evaluation was conducted among families enrolled in the study by tracking procedures and parents' evaluations. RESULTS: A total of 68 families (68 mothers, 60 fathers, 68 children with cancer and 73 siblings) were enrolled, with a participation rate of 62% of families. Fathers were highly represented (88% of families); also families with single parents (12%) and parents with basic education (7-12 years of primary, secondary, and grammar school education) were represented (12%). The dropout rate was 12% of families (all in the control group), and two families did not complete the intervention because of relapse. Evaluation by parents in the intervention group showed overall satisfaction with the format, timing, and content of the intervention. CONCLUSION: The results indicate that the FAMOS intervention is feasible in terms of recruitment, retention, and acceptability. The effects of the intervention on post-traumatic stress, depression, anxiety, family functioning, and quality of life will be reported after the nationwide RCT has been completed. PMID- 28080172 TI - Focusing on Participation: A Commentary on "Current Rehabilitation Practices for Children with Cerebral Palsy: Focus and Gaps". PMID- 28080174 TI - The Use of Topical Non-steroidal Anti-inflammatory Drugs for Uveitic Cystoid Macular Edema. AB - The use of topical non-steroidal anti-inflammatory drugs in the management of uveitic cystoid macular edema is controversial. In this letter, we review the literature and report our results from a retrospective case series of 281 patients taking topical nepafenac 0.1% for uveitic cystoid macular edema between 2010 and 2016. Over a 4-month period, there was a modest improvement in best corrected visual acuity (0.66 +/- 3.7 logMAR) and central macular thickness (69.8 +/- 132.5 MUm). Patients with idiopathic anterior uveitis and HLA-B*27-associated anterior uveitis recovered more vision while taking topical nepafenac 0.1%, than those with other uveitides, however, this was not statistically significant. There is a need for controlled prospective studies to evaluate the efficacy of topical non-steroidal anti-inflammatory drugs in the management of uveitic cystoid macular edema. At present, clinicians have little evidence on which to base practice. PMID- 28080175 TI - Combination of adalimumab with lower dose of methylprednisolone in Erdheim Chester disease with systemic involvement. PMID- 28080173 TI - Evaluation of Long-Term Cryostorage of Brain Tissue Sections for Quantitative Histochemistry. AB - Storage of tissue sections for long periods allows multiple samples, acquired over months or years, to be processed together, in the same reagents, for quantitative histochemical studies. Protocols for freezer storage of free floating frozen sections using sucrose with different additives have been reported and assert that storage has no effect on histochemistry, but no quantitative support has been provided. The present study analyzed the efficacy of long-term storage of brain tissue sections at -80C in buffered 15% glycerol. To determine whether histochemical reactivity is affected, we analyzed 11 datasets from 80 monkey brains that had sections stored for up to 10 years. For processing, sections from multiple cases were removed from storage, thawed, and batch-processed at the same time for different histochemical measures, including IHC for neuronal nuclear antigen, parvalbumin, orexin-A, doublecortin, bromodeoxyuridine, the pro-form of brain-derived neurotrophic factor, and damaged myelin basic protein as well as a histochemical assay for hyaluronic acid. Results were quantified using stereology, optical densitometry, fluorescence intensity, or percent area stained. Multiple regression analyses controlling for age and sex demonstrated the general stability of these antigens for up to a decade when stored in 15% glycerol at -80C. PMID- 28080180 TI - Long-term effects on the incidence of second primary cancers in a randomized trial of two and five years of adjuvant tamoxifen. AB - BACKGROUND: Tamoxifen is a well established treatment for breast cancer, but its long-term effects on the incidence of secondary cancers are not fully evaluated. MATERIAL AND METHODS: We have studied 4128 postmenopausal patients with early stage breast cancer who were alive and free of breast cancer recurrence after two years of tamoxifen, and who were randomized to receive totally two or five years of therapy. RESULTS: Compared to patients randomized to two years of tamoxifen the incidence of contralateral breast cancer [hazard ratio (HR) 0.73; 95% CI 0.56 0.96] and of lung cancer (HR 0.45; 95% CI 0.27-0.77), especially squamous cell and small cell lung cancer, were reduced in the five-year group, and similar results were seen when restricting the analysis to the 10-year period after treatment stopped. An increased incidence of endometrial cancer was observed in the five-year group, but the excess risk decreased over time. CONCLUSION: Further studies of the effects of tamoxifen on the risk of different histological types of lung cancer are needed. PMID- 28080181 TI - Conceptualizing patient empowerment in cancer follow-up by combining theory and qualitative data. AB - BACKGROUND: Patient empowerment (PE) may be defined as the opportunity for patients to master issues important to their own health. The aim of this study was to conceptualize PE and how the concept manifests itself for cancer patients attending follow-up, in order to develop a relevant and sensitive questionnaire for this population. MATERIAL AND METHODS: A theoretical model of PE was made, based on Zimmerman's theory of psychological empowerment. Patients who were in follow-up after first line treatment for their cancer (n = 16) were interviewed about their experiences with follow-up. A deductive thematic analysis was conducted to contextualize the theory and find concrete manifestations of empowerment. Data were analyzed to find situations that expressed empowerment or lack of empowerment. We then analyzed what abilities these situations called for and we further analyzed how these abilities fitted Zimmerman's theory. RESULTS: In all, 16 patients from two different hospitals participated in the interviews. PE in cancer follow-up was conceptualized as: (1) the perception that one had the possibility of mastering treatment and care (e.g. the possibility of 'saying no' to treatment and getting in contact with health care when needed); (2) having knowledge and skills regarding, for example treatment, care, plan of treatment and care, normal reactions and late effects, although knowledge and information was not always considered positively; and (3) being able to make the health care system address one's concerns and needs and, for some patients, also being able to monitor one's treatment, tests and care. CONCLUSION: We conceptualized PE based on Zimmerman's theory and empirical data to contextualize the concept in cancer follow-up. When developing a patient reported outcome measure measuring PE for this group of patients, one needs to be attentive to differences in wishes regarding mastery. PMID- 28080182 TI - Multi-Professional Perspectives on Adolescent and Young Adult Oncology Across Europe: An e-Delphi Survey. AB - The aims of this article are to describe the ongoing development of adolescent and young adult (AYA) cancer services within the European Union (EU), and to develop consensus on key areas within the field. This survey used an e-Delphi design. An initial survey was distributed via email to professionals working in Europe. A snowball sampling technique was used to promote distribution. Consensus was sought over three rounds from October 2012 to April 2015. Consensus was defined as >80% agreement ("agree" or "strongly agree"). Sixty professionals participated in round 1, 106 in round 2, and 61 in round 3. Twenty-six countries were represented across all rounds. Consensus was achieved for: the need for national policy guidance, the importance of patient choice, the validity of the International Charter of Rights for Young People, and some aspects of multi disciplinary working. There was 75% agreement on a single definition of the patient age range within AYA cancer care. European professionals with expertise in AYA cancer care reached consensus on key elements of care for this group. The optimal AYA age range remained an elusive topic on which to agree. The broad engagement and interest in AYA cancer across the EU through the European Network for Cancer in Children and Adolescents (ENCCA) network was also demonstrated. PMID- 28080184 TI - Editorial. PMID- 28080183 TI - Palliative Care Scorecard. AB - BACKGROUND: In response to poor healthcare quality outcomes and rising costs, healthcare reform triple aim has increased requirements for providers to demonstrate value to payers, partners, and the public. OBJECTIVE: Electronically automating measurement of the meaningful impact of palliative care (PC) programs on clinical, operational, and financial systems over time is imperative to the success of the field and the goal of development of this automated PC scorecard. DESIGN: The scorecard was organized into a format of quality measures identified by the Measuring What Matters (MWM) project that are defined as important to the team, automatically extracted from the electronic health record, valid, and can be impacted over time. SETTING: The scorecard was initially created using University of Florida Health (UF) data, a new PC program, and successfully applied and implemented at University of Colorado Anschutz Medical Campus (CU), a second institution with a mature PC program. MEASUREMENTS: Clinical metrics are organized in the scorecard based on MWM and described in terms of the metric definition, rationale for selection, measure type (structure, process, or outcome), and whether this represents a direct or proxy measure. RESULTS/CONCLUSIONS: The process of constructing the scorecard helped identify areas within both systems for potential improvement in team structure, clinical processes, and outcomes. In addition, by automating data extraction, the scorecard decreases costs associated with manual data entry and extraction, freeing clinical staff to care for patients and increasing the value of PC delivered to patients. PMID- 28080185 TI - PRESENTATION TO THE BEST CANDIDATE IN THE FESSH DIPLOMA EXAMINATION 2007. PMID- 28080186 TI - Satisfaction with sex life in sexually active heterosexual couples dealing with breast cancer: a nationwide longitudinal study. AB - BACKGROUND: A breast cancer (BC) diagnosis can profoundly affect the sex life of patient and partner within a couple. The purpose of the present study is to examine whether individual and partner sexual functioning, affectionate behavior, emotional closeness and depressive symptoms are associated with change over time in satisfaction with sex life of sexually active heterosexual couples dealing with BC and to explore whether the associations differ between patients and partners after adjustment for basic sociodemographic characteristics, comorbidity and BC treatment. MATERIAL AND METHODS: Women with BC and their male partners participated in a longitudinal study (Time 1, <=4 months after surgery; Time 2, 5 months later). Participants completed items from the PROMIS(r) Sexual Function and Satisfaction measure (version 1.0), two items measuring affectionate behavior, a single item measuring emotional closeness and the Center for Epidemiologic Studies-Depression Scale. Registers provided sociodemographic and medical information. Multilevel models were used, which take the interdependency of couples' scores into account. RESULTS: A total of 287 sexually active couples were included in the analyses. Less vaginal discomfort and more vaginal lubrication were associated with increases in patients' satisfaction with sex life. Patients' and partners' satisfaction increased with higher ratings of their own orgasm ability and of partners' timing of ejaculation. Patients' reports of affectionate behavior were positively associated with their partners' satisfaction, and vice versa for partners. Patients' satisfaction increased the more emotional closeness their partner experienced. Partners' depressive symptoms were negatively associated with their satisfaction. Sociodemographic factors and BC treatment were not significantly associated with change in satisfaction. CONCLUSION: Satisfaction with sex life in sexually active couples dealing with BC needs to be seen as a couple issue. Health professionals should take the partner into account when addressing sexuality issues. Couples' functioning and relationship-related factors may be promising targets for couple interventions. PMID- 28080187 TI - Early life risk factors for testicular cancer: a case-cohort study based on the Copenhagen School Health Records Register. AB - PURPOSE: One established risk factors for testicular cancer is cryptorchidism. However, it remains unclear whether cryptorchidism is a risk factor in itself or whether the two conditions share common causes in early life (estrogen hypothesis), such as birth weight and birth order. The objective of this study is to utilize data from the Copenhagen School Health Records Register (CSHRR) to evaluate cryptorchidism, birth weight and birth order as risk factors for testicular cancer. METHODS: The study population consisted of 408 cases of testicular cancer identified by a government issued identification number linkage of the entire CSHRR with the Danish Cancer Registry and a random subsample of 4819 males from the CSHRR. The study design was case-cohort and the period of follow-up between 2 April 1968 and 31 December 2003. RESULTS: Cryptorchidism was significantly associated with testicular cancer in crude analyses [hazard ratio (HR) = 3.60, 95% CI 2.79-4.65]. Birth weight was inversely associated with testicular cancer and no clear association with birth order was observed. The positive association between cryptorchidism and testicular cancer was only slightly attenuated controlling for birth weight and birth order and stratified on birth cohort (HR = 3.46, 95% CI 2.67-4.48). CONCLUSION: This study confirmed the robustness of the association between cryptorchidism and testicular cancer even after adjustment for birth weight and birth order. Furthermore, the study showed an inverse association between birth weight and testicular cancer. PMID- 28080190 TI - Informatics and Computing. PMID- 28080188 TI - Informatics and Computing. PMID- 28080191 TI - From the Editor-in-Chief: The JALA Special Issues on Robotics in Laboratory Automation. PMID- 28080193 TI - Pioneers in Hand Surgery. PMID- 28080194 TI - GEOFFREY RAYMOND FISK (1916-2007). PMID- 28080195 TI - Presentation to the best candidate in the European board of hand surgery diploma examination 2012. PMID- 28080196 TI - Dr. Dieter Buck-Gramcko. PMID- 28080198 TI - From the Editor-in-Chief: The 2013 JALA Ten: Call for Nominations. PMID- 28080203 TI - Alginate immobilized enrichment culture for atrazine degradation in soil and water system. AB - An atrazine degrading enrichment culture, a consortium of bacteria of genus Bacillus along with Pseudomonas and Burkholderia, was immobilized in sodium alginate and was used to study atrazine degradation in mineral salts medium (MSM), soil and wastewater effluent. Sodium alginate immobilized consortium, when stored at room temperature (24 +/- 5 degrees C), was effective in degrading atrazine in MSM up to 90 days of storage. The survival of bacteria in alginate beads, based on colony formation unit (CFU) counts, suggested survival up to 90 days and population counts decreased to 1/5th on 120 days. Comparison of atrazine degrading ability of the freely suspended enrichment culture and immobilized culture suggested that the immobilized culture took longer time for complete degradation of atrazine as a lag phase of 2 days was observed in the MSM inoculated with alginate immobilized culture. The free cells resulted in complete degradation of atrazine within 6 days, while immobilized cells took 10 days for 100% atrazine degradation. Further, immobilized cultures were able to degrade atrazine in soil and wastewater effluent. Alginate beads were stable and effective in degrading atrazine till 3rd transfer and disintegrated thereafter. The study suggested that immobilized enrichment culture, due to its better storage and application, can be used to degrade atrazine in soil water system. PMID- 28080204 TI - Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1. AB - HuR influences gene expression programs and hence cellular phenotypes by binding to hundreds of coding and noncoding linear RNAs. However, whether HuR binds to circular RNAs (circRNAs) and impacts on their function is unknown. Here, we have identified en masse circRNAs binding HuR in human cervical carcinoma HeLa cells. One of the most prominent HuR target circRNAs was hsa_circ_0031288, renamed CircPABPN1 as it arises from the PABPN1 pre-mRNA. Further analysis revealed that HuR did not influence CircPABPN1 abundance; interestingly, however, high levels of CircPABPN1 suppressed HuR binding to PABPN1 mRNA. Evaluation of PABPN1 mRNA polysomes indicated that PABPN1 translation was modulated positively by HuR and hence negatively by CircPABPN1. We propose that the extensive binding of CircPABPN1 to HuR prevents HuR binding to PABPN1 mRNA and lowers PABPN1 translation, providing the first example of competition between a circRNA and its cognate mRNA for an RBP that affects translation. PMID- 28080205 TI - Laparoscopic Liver Resection of Hepatocellular Carcinoma with a Tumor Size Larger Than 5 cm: Review of 45 Cases in a Tertiary Institution. AB - INTRODUCTION: Although laparoscopic liver resection (LLR) has developed rapidly, its usefulness for the treatment of large tumors is less clear, due to concerns about compromising oncological principles and patient safety. The purpose of this study was to explore the feasibility and safety of LLR for the treatment of hepatocellular carcinoma (HCC) with a tumor size larger than 5 cm. PATIENTS AND METHODS: From January 2007 to December 2014, we performed LLR in 45 patients with HCC with a tumor size >=5 cm. Perioperative outcome, tumor recurrence, and overall patient survival were analyzed. RESULTS: Median age was 60 years (interquartile range [IQR] 52-68) and 64.4% (29/45) were male. Seven patients (15.6%) had larger than 10 cm of HCC. No operative deaths occurred and six of the laparoscopic procedures were converted to open resection (conversion rate 13.3%). Median operation time was 365 minutes (IQR 277-443) and median estimated blood loss (EBL) was 400.0 mL (IQR 275-600). There was no R1 or R2 resection and median resection margin was 19.0 mm (IQR 8.0-33.0). Complications above Clavien-Dindo classification grade III occurred in four patients (8.9%). The median overall follow-up time was 10.7 month (range 1.1-62.1). One-year recurrence free survival (RFS) and overall survival (OS) were 86.0% and 95.5%, and 3-year RFS and OS were 70.7% and 86.0%. CONCLUSION: LLR appears safe and feasible in patients with HCC with a tumor size larger than 5 cm. Expansion of indication for LLR in patients with HCC may be considered. PMID- 28080202 TI - Chemical probes targeting epigenetic proteins: Applications beyond oncology. AB - Epigenetic chemical probes are potent, cell-active, small molecule inhibitors or antagonists of specific domains in a protein; they have been indispensable for studying bromodomains and protein methyltransferases. The Structural Genomics Consortium (SGC), comprising scientists from academic and pharmaceutical laboratories, has generated most of the current epigenetic chemical probes. Moreover, the SGC has shared about 4 thousand aliquots of these probes, which have been used primarily for phenotypic profiling or to validate targets in cell lines or primary patient samples cultured in vitro. Epigenetic chemical probes have been critical tools in oncology research and have uncovered mechanistic insights into well-established targets, as well as identify new therapeutic starting points. Indeed, the literature primarily links epigenetic proteins to oncology, but applications in inflammation, viral, metabolic and neurodegenerative diseases are now being reported. We summarize the literature of these emerging applications and provide examples where existing probes might be used. PMID- 28080206 TI - Probiotics, D-Lactic acidosis, oxidative stress and strain specificity. AB - The existence of an implicit living microscopic world, composed primarily of bacteria, has been known for centuries. The exact mechanisms that govern the contribution of bacteria to human health and disease have only recently become the subject of intense research efforts. Within this very evident shift in paradigms, the rational design of probiotic formulations has led to the creation of an industry that seeks to progress the engineering of probiotic bacteria that produce metabolites that may enhance human host health and prevent disease. The promotion of probiotics is often made in the absence of quality scientific and clinically plausible data. The latest incursions into the probiotic market of claims have posited the amelioration of oxidative stress via potent antioxidant attributes or limiting the administration of probiotics to those species that do not produce D-Lactic acid (i.e., claims that D-Lactic acid acidosis is linked to chronic health conditions) or are strain-specific (shaping an industry point of difference) for appraising a therapeutic effect. Evidence-based research should guide clinical practice, as there is no place in science and medicine that supports unsubstantiated claims. Extravagant industry based notions continue to fuel the imprimatur of distrust and skepticism that is leveled by scientists and clinicians at an industry that is already rife with scientific and medical distrust and questionable views on probiotics. Ignoring scientifically discordant data, when sorting through research innovations and false leads relevant to the actions of probiotics, drives researcher discomfit and keeps the bar low, impeding the progress of knowledge. Biologically plausible posits are obligatory in any research effort; companies formulating probiotics often exhibit a lack of analytical understanding that then fuels questionable investigations failing to build on research capacity. PMID- 28080207 TI - Laparoscopic Gastropleural Fistula Repair: A Minimally Invasive Solution for a Complex Problem. AB - INTRODUCTION: Gastropleural fistula (GPF) is a complex pathology that can present as a result of surgery, trauma, peptic ulcer disease, malignancies, radiation, or chemotherapy. Management typically includes endoscopic or surgical intervention along with intraabdominal or intrathoracic drainage of pre-existing infection. Traditionally, surgical approaches have been through exploratory laparotomy or thoracotomy, subjecting already ill patients to additional morbidity. CASE REPORT: We describe and demonstrate a laparoscopic minimally invasive approach to the management of a GPF with a wedge resection of the stomach, along with a review of the current literature regarding GPF treatment. CONCLUSION: GPF repair can be performed through laparoscopy and may lead to improved patient outcomes and faster recovery. PMID- 28080208 TI - A research program for the socioeconomic impacts of gene editing regulation. AB - Gene editing technologies are a group of recent innovations in plant breeding using molecular biology, which have in common the capability of introducing a site-directed mutation or deletion in the genome. The first cases of crops improved with these technologies are approaching the market; this has raised an international debate regarding if they should be regulated as genetically modified crops or just as another form of mutagenesis under conventional breeding. This dilemma for policymakers not only entails issues pertaining safety information and legal/regulatory definitions. It also demands borrowing tools developed in the field of social studies of science and technology, as an additional basis for sound decision making. PMID- 28080209 TI - Dissipation, half-lives, and mass spectrometric identification of chlorpyrifos and its two metabolites on field-grown collard and kale. AB - The persistence and fate of chlorpyrifos and its two metabolites, chlorpyrifos oxon and the 3, 5, 6-trichloro-2-pyridinol (TCP) break-down product were investigated on kale and collard leaves under field conditions. A simultaneous extraction and quantification procedure was developed for chrorpyrifos and its two main metabolites. Residues of chlorpyrifos, chlorpyrifos oxon, and TCP were determined using a gas chromatograph (GC) equipped with an electron capture detector (GC/ECD). Chlorpyrifos metabolites were detectable up to 23 days following application. Residues were confirmed using a GC equipped with a mass selective detector (GC/MSD) in total ion mode. Initial residues of chlorpyrifos were greater on collard (14.5 ug g-1) than kale (8.2 ug g-1) corresponding to half-lives (T1/2) values of 7.4 and 2.2 days, respectively. TCP, the hydrolysis product, was more persistent on collards with an estimated T1/2 of 6.5 days compared to kale (T1/2 of 1.9 days). PMID- 28080210 TI - Pathogen control at the intestinal mucosa - H2O2 to the rescue. AB - Intestinal infections are a global challenge, connected to malnutrition and inadequate hygiene in developing countries, and to expanding antibiotic resistance in developed countries. In general, a healthy host is capable of fighting off gut pathogens or at least to recover from infections quickly. The underlying protective mechanism, termed colonization resistance, is provided by indigenous commensal communities (microbiota) that are shaped and aided by the host's epithelial and innate immune system. Commensal-pathogen interactions are governed by competition for a suitable niche for replication and stable colonization, nutrient availability, species-specific alterations of the metabolic environment, changes in oxygen tension and release of chemicals and proteinaceous toxins (bacteriocins). This protective intestinal milieu is further reinforced by antimicrobial factors and chemicals secreted by the epithelial barrier, by dendritic cell sensing and by homeostasis between T-cell subsets (Treg/Th17) in the lamina propria. The 3 players (host-microbiota-pathogen) communicate via direct interactions or secreted factors. Our recent manuscript illustrates that reactive oxygen species (ROS) are an integral part of colonization resistance and should be considered an interkingdom antivirulence strategy. PMID- 28080211 TI - Neuromyelitis optica spectrum disorder diagnostic criteria: Sensitivity and specificity are both important. PMID- 28080212 TI - Heterogeneity of Carbapenem Resistance Mechanisms Among Gram-Negative Pathogens in Lebanon: Results of the First Cross-Sectional Countrywide Study. AB - Carbapenem-resistant Gram-negative pathogens have progressively disseminated to different countries worldwide, presenting a serious public health concern. The aims of this study were to determine the prevalence of carbapenem resistance in Gram-negative bacteria in Lebanon, to elucidate molecular mechanisms, and to identify genetic relatedness of incriminated strains. Carbapenem nonsusceptible Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas were collected from 11 Lebanese hospitals in 2012. Antimicrobial susceptibility was assessed with phenotypic tests, genes encoding carbapenemases were screened via PCR-sequencing, and genetic relatedness was examined by PGFE and ERIC-PCR. A total of 398 nonrepetitive carbapenem nonsusceptible isolates were studied, of which 44 were Enterobacteriaceae, 142 were A. baumannii, and 212 were Pseudomonas. Among Enterobacteriaceae, 70.4% carried blaOXA-48-like gene on IncL/M-type plasmids, while acquired AmpC cephalosporinases, extended-spectrum-beta-lactamases, and efflux-pump were additional contributors to carbapenem resistance. Among A. baumannii, 90% produced OXA-23 and GES-11 and carried insertion sequence ISAba1 upstream and adjacent to blaOXA-23 and blaAcinetobacter-derived cephalosporinases. Among Pseudomonas, 16% harbored VIM-2, 4.2% IMP-2, and 1.4% IMP-1 metallo-beta-lactamases. Fingerprint analysis indicated that the spread of OXA-48-like carbapenemases was mostly mediated by horizontal transfer, while OXA 23 and GES-11 diffusion in A. baumannii and VIM-2 diffusion in P. aeruginosa were primarily due to clonal dissemination. This study is the first nationwide investigation of carbapenem resistance in Lebanon, showing low level of resistance in Enterobacteriaceae, and higher levels in A. baumannii and Pseudomonas. With current changes in the region, continuous surveillance of carbapenem resistance is crucial. PMID- 28080214 TI - 1H-NMR-based metabolomic studies of bisphenol A in zebrafish (Danio rerio). AB - Proton nuclear magnetic resonance (1H-NMR) spectroscopy was used to study the response of zebrafish (Danio rerio) to increasing concentrations of bisphenol A (4,4'-(propane-2,2-diyl)diphenol, BPA). Orthogonal partial least squares discriminant analysis (OPLS-DA) was applied to detect aberrant metabolomic profiles after 72 h of BPA exposure at all levels tested (0.01, 0.1, and 1.0 mg/L). The OPLS-DA score plots showed that BPA exposure caused significant alterations in the metabolome. The metabolomic changes in response to BPA exposure generally exhibited nonlinear patterns, with the exception of reduced levels of several metabolites, including glutamine, inosine, lactate, and succinate. As the level of BPA exposure increased, individual metabolite patterns indicated that the zebrafish metabolome was subjected to severe oxidative stress. Interestingly, ATP levels increased significantly at all levels of BPA exposure. In the present study, we demonstrated the applicability of 1H-NMR-based metabolomics to identify the discrete nature of metabolic changes. PMID- 28080213 TI - Campylobacter jejuni transducer like proteins: Chemotaxis and beyond. AB - Chemotaxis, a process that mediates directional motility toward or away from chemical stimuli (chemoeffectors/ligands that can be attractants or repellents) in the environment, plays an important role in the adaptation of Campylobacter jejuni to disparate niches. The chemotaxis system consists of core signal transduction proteins and methyl-accepting-domain-containing Transducer like proteins (Tlps). Ligands binding to Tlps relay a signal to chemotaxis proteins in the cytoplasm which initiate a signal transduction cascade, culminating into a directional flagellar movement. Tlps facilitate substrate-specific chemotaxis in C. jejuni, which plays an important role in the pathogen's adaptation, pathobiology and colonization of the chicken gastrointestinal tract. However, the role of Tlps in C. jejuni's host tissue specific colonization, physiology and virulence remains not completely understood. Based on recent studies, it can be predicted that Tlps might be important targets for developing strategies to control C. jejuni via vaccines and antimicrobials. PMID- 28080215 TI - Laparoscopy-Assisted Duhamel-Z Anastomosis for Total Colonic Aganglionosis: Outcome Assessed by Fecal Continence Evaluation. AB - BACKGROUND: A Z-shaped colorectal side-to-side anastomosis was introduced to improve the Duhamel procedure by eliminating the rectal blind pouch. We retrospectively reviewed all total colonic aganglionosis patients treated by laparoscopy-assisted Duhamel-Z (LapDZ) between 2009 and 2014 focusing on annual fecal continence evaluation scores (CES) as an indicator of outcome. METHODS: LapDZ was performed conventionally. Postoperatively, defecation was regulated with medications and enemas according to our standard protocol. Stool frequency, stool consistency, fecal soiling/incontinence, growth, and severity of enterocolitis were each scored (0-2) to give a total CES (maximum: 10). RESULTS: Eleven subjects (6 males and 5 females) were reviewed. Mean age and mean weight at LapDZ were 10.2 months and 8.4 kg, respectively. Mean length of the aganglionic ileum resected was 19.5 cm. Mean operative time was 6.2 hours. Postoperative recommencement of oral intake took 5.7 days on average. There were no intraoperative complications, no anastomotic leaks or strictures, and no intestinal obstruction. Postoperative blood transfusion was required in 1 case complicated by chronic bleeding. No subject has been constipated postoperatively. Follow-up was for 5 years. The number of subjects who had CES assessments each year was: after 1 year (n = 11), after 2 years (n = 10), after 3 years (n = 10), after 4 years (n = 8), and after 5 years (n = 5). Average annual CES during follow-up were 4.5, 6.1, 7.7, 8.1, and 8.4, respectively. CONCLUSION: LapDZ and strict management of postoperative bowel function may have contributed to improving CES over time. PMID- 28080216 TI - Occurrence of mycotoxins in wheat grains exposed to fungicides on fusarium head blight control in southern Brazil. AB - Mycotoxins occurrence in wheat grains impose risks to human and animal health. The southern Brazil has favorable weather conditions for Fusarium graminearum infections and consequently for mycotoxins accumulation on grains. The goal of this study was to evaluate the behavior of new wheat commercial genotypes to Fusarium Head Blight (FHB), to control performance of new fungicide formulations and their relationship with mycotoxins concentration in grains. The manly mycotoxin occurrence on wheat grains in southern Brazil was deoxynivalenol (DON). Two cultivars showed high DON concentration above the tolerance limits (>3000 MUg kg-1). Many other mycotoxins monitored presented concentrations below method detection limit. Satisfactory levels of fungicide effectiveness were achieved against F. graminearum. Some fungicides promoted a satisfactory decrease on DON accumulation in grains. The best results were obtained when prothioconazole was present. SDHI (Succinate dehydrogenase inhibitors) + QoI (Quinone outside inhibitors) fungicides showed benefic effects at FHB control at field, but it did not promote satisfactory reduction on DON contamination. Fungicides can be used satisfactory for FHB control and reduce DON contamination in grains in southern Brazil. The presence of prothioconazole should be recommended. Some genotypes showed high DON concentration and it was not directly related with FHB severity at field. PMID- 28080218 TI - Temperature dependence of multiple sclerosis mortality rates in the United States. AB - BACKGROUND: It is well known that multiple sclerosis (MS) patients are very sensitive to heat events. However, how MS patients respond to the significant temperature difference between the high- and low-latitude regions is not understood. OBJECTIVE: The goal is to identify the primary factor responsible for the fact that MS mortality rates of the United States is more than three times higher in the northern states than in the southern states. METHODS: Correlation coefficients between the age-adjusted mortality rate of MS as the underlying cause of death and the state average temperature, altitude, latitude, duration of sunshine hours, and solar radiation in the 48 contiguous states were compared. RESULTS: MS mortality rates correlate significantly and inversely with temperatures in the 48 states (correlation coefficient r = -0.812 and significance p = 0.00). Durations of sunshine hours and solar radiation do not correlate significantly with MS mortality rates ( r = -0.245, -0.14, and p = 0.101, 0.342, respectively). CONCLUSION: High environmental temperature is the primary reason for the low MS mortality rates and likely the low MS prevalence in low-latitude regions. Implication of the study result is that benefits of long term heat acclimation through gradual and prolonged exposure to environmental heat for MS patients may be greatly underappreciated. PMID- 28080217 TI - Synergistic Effects of Tetrandrine with Posaconazole Against Aspergillus fumigatus. AB - In our earlier in vitro and in vivo studies, synergistic effects were observed when itraconazole or voriconazole were combined with tetrandrine (TET) against Aspergillus fumigatus, and the synergistic mechanism was related to inhibition of the drug efflux pump. Posaconazole (PCZ) is a broad-spectrum triazole antifungal agent used for the treatment of diverse fungal infections, including aspergillosis and candidiasis. Herein, the antifungal effects of TET are further investigated in vitro and in vivo alone or combined with PCZ against 20 clinical isolates of A. fumigatus. We found that the minimal inhibitory concentrations (MICs) of PCZ were decreased one- to twofold and three- to fivefold across a series of concentration gradients in vitro in presence of TET. Time-killing curves revealed that the synergy was dependent on TET and PCZ concentrations as well as incubation time. The combination could further downregulate the expression of MDR2, MDR3, MDR4, and ATRF in PCZ-resistant strain, however, it has subtle effects on TET-synergized mechanism. In addition, TET in combination with PCZ significantly prolonged mice survival time and reduced kidney and brain tissue burdens in vivo. Our data in vitro and in vivo demonstrate that TET is an effective synergist with azoles against A. fumigates. PMID- 28080220 TI - Predictors of response to first-line immunosuppressive therapy in neuromyelitis optica spectrum disorders. AB - BACKGROUND: Azathioprine (AZA) and mycophenolate mofetil (MMF) are the most commonly used first-line therapies for patients with neuromyelitis optica spectrum disorders (NMOSD). However, some patients experience a relapse following AZA or MMF treatment. OBJECTIVES: To identify factors that predict a response to AZA or MMF in NMOSD. METHODS: We retrospectively evaluated medical records from 116 patients who were initially treated with AZA or MMF for at least 6 months. Poor response was defined as ?2 relapses or ?1 severe relapse. RESULTS: Among the 116 patients, 40 (34%) were classified as poor responders. Logistic regression analyses revealed that a poor response was independently associated with a pre treatment history of a severe attack ( p < 0.001) and a younger age at disease onset ( p = 0.022). Among the 40 patients with a poor response, 29 (73%) switched to rituximab, and only 3 (10%) had a poor response to rituximab. CONCLUSION: Patients with a pre-treatment history of a severe attack and a younger age of onset exhibited an increased risk of a poor response to AZA or MMF therapy. Identifying patients who are unlikely to respond to AZA or MMF therapy may allow for treatment with more potent therapies that improve treatment outcomes. PMID- 28080219 TI - Adipose Tissue Insulin Resistance in Gestational Diabetes. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is a metabolic disorder characterized by insulin resistance (IR) and altered glucose-lipid metabolism. We propose that ectonucleotide pyrophosphate phosphodiesterase-1 (ENPP1), a protein known to induce adipocyte IR, is a determinant of GDM. Our objective was to study ENPP1 expression in adipose tissue (AT) of obese pregnant women with or without GDM, as well as glucose tolerance in pregnant transgenic (Tg) mice with AT specific overexpression of human ENPP1. METHODS: AT biopsies and blood were collected from body mass index-matched obese pregnant women non-GDM (n = 6), GDM (n = 7), and nonpregnant controls (n = 6) undergoing cesarian section or elective surgeries, respectively. We measured the following: (1) Expression of key molecules involved in insulin signaling and glucose-lipid metabolism in AT; (2) Plasma glucose and insulin levels and calculation of homeostasis model assessment of IR (HOMA-IR); (3) Intraperitoneal glucose tolerance test in AtENPP1 Tg pregnant mice. RESULTS: We found that: (1) Obese GDM patients have higher AT ENPP1 expression than obese non-GDM patients, or controls (P = 0.01-ANOVA). (2) ENPP1 expression level correlated negatively with glucose transporter 4 (GLUT4) and positively with insulin receptor substrate-1 (IRS-1) serine phosphorylation, and to other adipocyte functional proteins involved in glucose and lipid metabolism (P < 0.05 each), (3) AT ENPP1 expression levels were positively correlated with HOMA-IR (P = 0.01-ANOVA). (4) Pregnant AT ENPP1 Tg mice showed higher plasma glucose than wild type animals (P = 0.046-t test on area under curve [AUC]glucose). CONCLUSIONS: Our results provide evidence of a causative link between ENPP1 and alterations in insulin signaling, glucose uptake, and lipid metabolism in subcutaneous abdominal AT of GDM, which may mediate IR and hyperglycemia in GDM. PMID- 28080221 TI - Molecular Mechanisms of Antisense Oligonucleotides. AB - In 1987, when I became interested in the notion of antisense technology, I returned to my roots in RNA biochemistry and began work to understand how oligonucleotides behave in biological systems. Since 1989, my research has focused primarily on this topic, although I have been involved in most areas of research in antisense technology. I believe that the art of excellent science is to frame large important questions that are perhaps not immediately answerable with existing knowledge and methods, and then conceive a long-term (multiyear) research strategy that begins by answering the most pressing answerable questions on the path to the long-term goals. Then, a step-by-step research pathway that will address the strategic questions posed must be implemented, adjusting the plan as new things are learned. This is the approach we have taken at Ionis. Obviously, to create antisense technology, we have had to address a wide array of strategic questions, for example, the medicinal chemistry of oligonucleotides, manufacturing and analytical methods, pharmacokinetics and toxicology, as well as questions about the molecular pharmacology of antisense oligonucleotides (ASOs). Each of these endeavors has consumed nearly three decades of scientific effort, is still very much a work-in-progress, and has resulted in hundreds of publications. As a recipient of the Lifetime Achievement Award 2016 granted by the Oligonucleotide Therapeutic Society, in this note, my goal is to summarize the contributions of my group to the efforts to understand the molecular mechanisms of ASOs. PMID- 28080222 TI - Eyes on New Product Development. PMID- 28080224 TI - RIMS Conference Abstracts. PMID- 28080249 TI - Pactrims Invited Lecture / Ordinary Submission. PMID- 28080250 TI - No evidence of disease activity in patients receiving daclizumab versus intramuscular interferon beta-1a for relapsing-remitting multiple sclerosis in the DECIDE study. AB - BACKGROUND: No evidence of disease activity (NEDA) is a composite endpoint being increasingly applied as an outcome measure in clinical trials as well as proposed for individual therapeutic decisions in multiple sclerosis (MS). OBJECTIVE: Assess the proportion of patients with relapsing-remitting MS achieving NEDA in the DECIDE study of daclizumab 150 mg subcutaneous versus intramuscular interferon beta-1a 30 ug for 96-144 weeks. METHODS: NEDA was defined as no relapses, no onset of 12-week confirmed disability progression (CDP), no new/newly enlarging T2 hyperintense lesions (NET2), and no gadolinium-enhancing (Gd+) lesions. Logistic regression models adjusted for baseline covariates compared treatment groups for baseline to week 96, weeks 0-24, and weeks 24-96. RESULTS: From baseline to week 96, more daclizumab versus intramuscular interferon beta-1a patients achieved NEDA (24.6% vs 14.2%; odds ratio (OR; 95% confidence interval): 2.059 (1.592-2.661); p < 0.0001). ORs for clinical NEDA (no relapses, no CDP) and magnetic resonance imaging (MRI) NEDA (no NET2, no Gd+ lesions) were 1.651 (1.357-2.007; p < 0.0001) and 2.051 (1.628-2.582; p < 0.0001), respectively. ORs in favor of daclizumab for weeks 24-96 were consistently higher than for weeks 0-24. CONCLUSION: More daclizumab versus intramuscular interferon beta-1a patients achieved NEDA early in DECIDE, with effects increasing over time. PMID- 28080251 TI - Tetrahedral DNA Nanoparticle Vector for Intracellular Delivery of Targeted Peptide Nucleic Acid Antisense Agents to Restore Antibiotic Sensitivity in Cefotaxime-Resistant Escherichia coli. AB - The bacterial cell wall presents a barrier to the uptake of unmodified synthetic antisense oligonucleotides, such as peptide nucleic acids, and so is one of the greatest obstacles to the development of their use as therapeutic anti-bacterial agents. Cell-penetrating peptides have been covalently attached to antisense agents, to facilitate penetration of the bacterial cell wall and deliver their cargo into the cytoplasm. Although they are an effective vector for antisense oligonucleotides, they are not specific for bacterial cells and can exhibit growth inhibitory properties at higher doses. Using a bacterial cell growth assay in the presence of cefotaxime (CTX 16 mg/L), we have developed and evaluated a self-assembling non-toxic DNA tetrahedron nanoparticle vector incorporating a targeted anti-blaCTX-M-group 1 antisense peptide nucleic acid (PNA4) in its structure for penetration of the bacterial cell wall. A dose-dependent CTX potentiating effect was observed when PNA4 (0-40 MUM) was incorporated into the structure of a DNA tetrahedron vector. The minimum inhibitory concentration (to CTX) of an Escherichia coli field isolate harboring a plasmid carrying blaCTX-M-3 was reduced from 35 to 16 mg/L in the presence of PNA4 carried by the DNA tetrahedron vector (40 MUM), contrasting with no reduction in MIC in the presence of PNA4 alone. No growth inhibitory effects of the DNA tetrahedron vector alone were observed. PMID- 28080252 TI - Editors' note. PMID- 28080254 TI - Wellness and multiple sclerosis: The National MS Society establishes a Wellness Research Working Group and research priorities. AB - BACKGROUND: People with multiple sclerosis (MS) have identified "wellness" and associated behaviors as a high priority based on "social media listening" undertaken by the National MS Society (i.e. the Society). OBJECTIVE: The Society recently convened a group that consisted of researchers with experience in MS and wellness-related research, Society staff members, and an individual with MS for developing recommendations regarding a wellness research agenda. METHOD: The members of the group engaged in focal reviews and discussions involving the state of science within three approaches for promoting wellness in MS, namely diet, exercise, and emotional wellness. RESULTS: That process informed a group-mediated activity for developing and prioritizing research goals for wellness in MS. This served as a background for articulating the mission and objectives of the Society's Wellness Research Working Group. CONCLUSION: The primary mission of the Wellness Research Working Group is the provision of scientific evidence supporting the application of lifestyle, behavioral, and psychosocial approaches for promoting optimal health of mind, body, and spirit (i.e. wellness) in people with MS as well as managing the disease and its consequences. PMID- 28080255 TI - Assessing long-term prognosis improvement as a consequence of treatment pattern changes in MS. AB - OBJECTIVE: To assess whether the age at which multiple sclerosis (MS) patients reach Expanded Disability Status Scale (EDSS) milestones changed as long as new drugs for the treatment of MS became available. METHODS: We evaluated the long term impact of therapies on disability progression assessing whether there is a detectable delay in the age at which patients reached EDSS milestones in more recent years. We used data collected over more than 30 years in the Center of Brescia, Italy. We compared the age at EDSS = 6 among patients diagnosed with relapsing-remitting MS in different time periods, adjusting for age at diagnosis and median interval among EDSS visits, by a multivariate Cox model. RESULTS: A total of 1324 MS patients were included. Patients diagnosed in more recent periods reached EDSS = 6 at an older age: the rate at which patients reached EDSS = 6 in those diagnosed in 1991-1995 was similar to those diagnosed in 1980-1990 (hazard ratio ( HR) = 1.09, p = 0.68) and to those diagnosed in 1996-2000 ( HR = 0.85, p = 0.44), it was reduced by 37% in patients diagnosed in 2001-2005 ( HR = 0.63, p = 0.05), by 46% in patients diagnosed in 2006-2010 ( HR = 0.54, p < 0.02). CONCLUSION: A clear modification of MS course is observed after 2000; among other causes, this can be associated to the changes in the treatment patterns experienced in those years. PMID- 28080258 TI - LACTRIMS Abstracts. PMID- 28080257 TI - Karl Vass, 1958-2012. PMID- 28080259 TI - Plenary Session. PMID- 28080263 TI - MENACTRIMS congress 2016. PMID- 28080262 TI - Processing speed test: Validation of a self-administered, iPad(r)-based tool for screening cognitive dysfunction in a clinic setting. AB - BACKGROUND: Cognitive dysfunction is common in multiple sclerosis (MS) patients and has important consequences for daily activities, yet, unlike motor function, is not routinely assessed in the clinic setting. We developed the Processing Speed Test (PST), a self-administered iPad(r)-based tool to measure MS-related deficits in processing speed. OBJECTIVE: To determine whether the PST is valid for screening cognitive dysfunction by comparing it to the paper-and-pencil Symbol Digit Modalities Test (SDMT). METHODS: We assessed PST test-retest reliability, sensitivity of PST and SDMT in discriminating MS patients from healthy controls (HC), convergent validity between PST and SDMT, correlations between T2 lesion load and PST and SDMT, and PST performance with and without technician present during administration. RESULTS: PST had excellent test-retest reliability, was highly correlated with SDMT, was slightly more sensitive than SDMT in discriminating MS from HC groups, and correlated better with cerebral T2 lesion load than did SDMT. Finally, PST performance was no different with or without a technician in the testing environment. CONCLUSION: PST has advantages over SDMT because of its efficient administration, scoring, and potential for medical record or research database integration. PST is a practical tool for routine screening of processing speed deficits in the MS clinic. PMID- 28080261 TI - Performance of Hispanics and Non-Hispanic Whites on the NIH Toolbox Cognition Battery: the roles of ethnicity and language backgrounds. AB - OBJECTIVE: This study examined the influence of Hispanic ethnicity and language/cultural background on performance on the NIH Toolbox Cognition Battery (NIHTB-CB). METHOD: Participants included healthy, primarily English-speaking Hispanic (n = 93; Hispanic-English), primarily Spanish-speaking Hispanic (n = 93; Hispanic-Spanish), and English speaking Non-Hispanic white (n = 93; NH white) adults matched on age, sex, and education levels. All participants were in the NIH Toolbox national norming project and completed the Fluid and Crystallized components of the NIHTB-CB. T-scores (demographically-unadjusted) were developed based on the current sample and were used in analyses. RESULTS: Spanish-speaking Hispanics performed worse than English-speaking Hispanics and NH whites on demographically unadjusted NIHTB-CB Fluid Composite scores (ps < .01). Results on individual measures comprising the Fluid Composite showed significant group differences on tests of executive inhibitory control (p = .001), processing speed (p = .003), and working memory (p < .001), but not on tests of cognitive flexibility or episodic memory. Test performances were associated with language/cultural backgrounds in the Hispanic-Spanish group: better vocabularies and reading were predicted by being born outside the U.S., having Spanish as a first language, attending school outside the U.S., and speaking more Spanish at home. However, many of these same background factors were associated with worse Fluid Composites within the Hispanic-Spanish group. CONCLUSIONS: On tests of Fluid cognition, the Hispanic-Spanish group performed the poorest of all groups. Socio-demographic and linguistic factors were associated with those differences. These findings highlight the importance of considering language/cultural backgrounds when interpreting neuropsychological test performances. Importantly, after applying previously published NIHTB-CB norms with demographic corrections, these language/ethnic group differences are eliminated. PMID- 28080270 TI - Editorial Note. PMID- 28080282 TI - Dirty Headlights - Frequency and Visibility Effects. AB - To investigate the problem of dirty headlamps, three experiments have been carried out. In the first, dirt layers were systematically collected under various road conditions. The wetness of the road was found markedly to influence the amount of dirt deposited. In the second, light reduction caused by dirt on cars in traffic was measured. It was found that even in dry weather on seemingly clean roads light reduction due to headlamp dirt is normally 10-20%. In bed (slushy) road conditions few cars have light reduction below 50%. Drivers normally do not react to light reduction below 60% In the third experiment, reduction in visibility during night driving was measured as a function of light reduction. Light reduction of 60% causes a 20% reduction of high beam visibility and a 15% reduction of low beam visibility. PMID- 28080264 TI - Convergent and criterion validity of the CogState computerized brief battery cognitive assessment in women with and without breast cancer. AB - OBJECTIVE: Computerized tests have increasingly garnered interest for assessing cognitive functioning due to their potential logistical and financial advantages over traditional 'pencil and-paper' neuropsychological tests. However, psychometric information is necessary to guide decisions about their clinical and research utility with varied populations. We explored the convergent construct validity and criterion validity of the CogState computerized tests in breast cancer survivors, a group known to present with mostly mild, subtle cognitive dysfunction. METHOD: Fifty-three post-menopausal women (26 breast cancer survivors, 27 healthy controls) completed the CogState Brief Battery tests with passed performance checks, conceptually matched traditional neuropsychological tests, and a self-report measure of daily functioning, the Functional Activities Questionnaire. RESULTS: Significant positive correlations were found between the CogState Brief Battery tests and traditional neuropsychological tests, although the traditional tests specifically hypothesized to correlate with CogState tests did not reach statistical significance. Analysis of Covariance results showed preliminary support for criterion validity, as the patient and control groups differed on the traditional test of working memory (Digits Backwards, p = .01), with a trend towards significance for the CogState test of working memory (One Back, p = .02), controlled for age, race, and mood. CONCLUSIONS: The results provide preliminary support for further research to determine if the CogState tests are viable as screening tools to detect subtle cognitive differences between breast cancer survivors and healthy women. Our study was limited by the low base rate of cognitive impairment and small sample size. We recommend further research employing sufficiently powered sample sizes and a longitudinal, repeated measures study design. PMID- 28080285 TI - International Ergonomics Association Minutes of the Fifth General Assembly, held in Amsterdam on the 7th of June, 1973. PMID- 28080287 TI - The Ergonomics Research Society ANNUAL CONFERENCE 1974 ABSTRACTS OF PAPERS. PMID- 28080292 TI - Effect of the endOclear(r) Device on Biofilm in Endotracheal Tubes. AB - BACKGROUND: Organisms trapped in biofilms cause more than 80% of medical infections. Significant investments are being made to develop methods of removing these biofilms. The endOclear(r) device is reported to remove biofilm from endotracheal tubes (ETTs) and to decrease pneumonia rates and ventilator time. METHODS: This was an observational study performed at a university Level 1 trauma center intensive care unit. A series of 40 ETTs were collected at extubation, with half of the patients having been treated daily with the endOclear(r) device. Biofilms were quantified from a standardized point on the distal ETT. The patients' standard and biofilm cultures were reviewed. RESULTS: The mean hours of intubation for the control group was 135 and for the device group 138. This difference was not statistically significant (p = 0.91). Eleven patients in the device group were found to have pneumonia compared with six in the control group (p = 0.34). Ventilator data after device use showed a mean increase of 29.9 cc in tidal volume and a mean decrease in peak pressures of 0.39 cm H2O. Comparisons between biofilm stage or hours of intubation and a diagnosis of pneumonia found no correlation. Only nine of 40 ETTs had congruence between the microbiata of the biofilm and standard bronchoalveolar lavage (BAL) fluid, a divergence rate of 78%. CONCLUSIONS: Comparison of the endOclear(r) group and controls demonstrated a trend toward a higher pneumonia rate in the former. Additionally, the device achieved very small, clinically insignificant, changes in ventilator settings, and no difference was seen in the time on the ventilator. Comparisons between biofilm and standard BAL cultures continue to show the biofilm is more diverse than previously thought. In this study, no statistical significance was found between biofilm stage and the pneumonia rate. This study provides additional evidence that there is no correlation between biofilm stage and duration of intubation. PMID- 28080293 TI - Proximal Contact Repair of Complex Amalgam Restorations. AB - The carving of a complex amalgam restoration may occasionally result in light proximal contact with the adjacent tooth. The purpose of this study was to investigate the strength of complex amalgam restorations repaired with a proximal slot amalgam preparation. Extracted human third molars of similar coronal size were sectioned 1 mm apical to the height of the contour using a saw and were randomly distributed into 9 groups of 10 teeth each. One pin was placed at each line angle of the flattened dentinal tooth surface. A metal matrix band was placed and an admixed alloy was condensed and carved to create a full crown contour but with a flat occlusal surface. A proximal slot was prepared with or without a retention groove and repaired using a single-composition spherical amalgam 15 minutes, 24 hours, one week, or six months after the initial crown condensation. The specimens were stored for 24 hours in 37 degrees C water before fracture at the marginal ridge using a round-ended blade in a universal testing machine. The control group was not repaired. The mean maximum force in newtons and standard deviation were determined per group. Data were analyzed with a 2-way analysis of variance as well as Tukey and Dunnett tests (alpha=0.05). Significant differences were found between groups based on type of slot preparation (p=0.017) but not on time (p=0.327), with no significant interaction (p=0.152). No significant difference in the strength of the marginal ridge was found between any repair group and the unrepaired control group (p>0.076). The proximal repair strength of a complex amalgam restoration was not significantly different from an unrepaired amalgam crown. Placing a retention groove in the proximal slot preparation resulted in significantly greater fracture strength than a slot with no retention grooves. Time of repair had no significant effect on the strength of the repair. PMID- 28080301 TI - Assessing social cognition: age-related changes in moral reasoning in childhood and adolescence. AB - OBJECTIVE: There is increasing recognition that socio-cognitive skills, such as moral reasoning (MR), are affected in a wide range of developmental and neuropsychological conditions. However, the lack of appropriate measures available to neuropsychologists poses a challenge for the direct assessment of these skills. This study sought to explore age-related changes in MR using an innovative visual tool and examine the developmental sensitivity of the task. METHOD: To address some of the methodological limitations of traditional measures of MR, a novel, visual task, the Socio-Moral Reasoning Aptitude Level (So-Moral), was used to evaluate MR in 216 healthy participants aged 6-20 years. RESULTS: The findings show a linear increase in MR from childhood to late adolescence with significant group differences between childhood (6-8 years) and preadolescence (9 11 years), and between early adolescence (12-14 years) and middle adolescence (15 17 years). CONCLUSIONS: Interpreted in light of current brain development research, the results highlight age-related changes in MR that offer insight into typical MR development and opportunities for comparisons with clinical populations. The findings also provide evidence of the potential of the So-Moral as a developmentally appropriate measure of MR throughout childhood and adolescence. PMID- 28080302 TI - The Road to Bribery and Corruption. AB - Major forms of corruption constitute a strong threat to the functioning of societies. The most frequent explanation of how severe corruption emerges is the slippery-slope metaphor-the notion that corruption occurs gradually. While having widespread theoretical and intuitive appeal, this notion has barely been tested empirically. We used a recently developed paradigm to test whether severely corrupt acts happen gradually or abruptly. The results of four experimental studies revealed a higher likelihood of severe corruption when participants were directly given the opportunity to engage in it (abrupt) compared with when they had previously engaged in minor forms of corruption (gradual). Neither the size of the payoffs, which we kept constant, nor evaluations of the actions could account for these differences. Contrary to widely shared beliefs, sometimes the route to corruption leads over a steep cliff rather than a slippery slope. PMID- 28080303 TI - The Development of a Cross-Modal Sense of Body Ownership. AB - In this study, we investigated the contribution of tactile and proprioceptive cues to the development of the sense of body ownership by testing the susceptibility of 4- to 5-year-old children, 8- to 9-year-old children, and adults to the somatic rubber-hand illusion (SRHI). We found that feelings of owning a rubber hand in the SHRI paradigm, as assessed by explicit reports (i.e., questionnaire), are already present by age 4 and do not change throughout development. In contrast, the effect of the illusion on the sense of hand position, as assessed by a pointing task, was present only in 8- to 9-year-old children and adults; the magnitude of such capture increased with age. Our findings reveal that tactile-proprioceptive interactions contributed differently to the two aspects characterizing the SRHI: Although the contribution of such interactions to an explicit sense of self was similar across age groups, their contribution to the more implicit recalibration of hand position is still developing by age 9. PMID- 28080305 TI - Critical review of the building downwash algorithms in AERMOD. AB - : The only documentation on the building downwash algorithm in AERMOD (American Meteorological Society/U.S. Environmental Protection Agency Regulatory Model), referred to as PRIME (Plume Rise Model Enhancements), is found in the 2000 A&WMA journal article by Schulman, Strimaitis and Scire. Recent field and wind tunnel studies have shown that AERMOD can overpredict concentrations by factors of 2 to 8 for certain building configurations. While a wind tunnel equivalent building dimension study (EBD) can be conducted to approximately correct the overprediction bias, past field and wind tunnel studies indicate that there are notable flaws in the PRIME building downwash theory. A detailed review of the theory supported by CFD (Computational Fluid Dynamics) and wind tunnel simulations of flow over simple rectangular buildings revealed the following serious theoretical flaws: enhanced turbulence in the building wake starting at the wrong longitudinal location; constant enhanced turbulence extending up to the wake height; constant initial enhanced turbulence in the building wake (does not vary with roughness or stability); discontinuities in the streamline calculations; and no method to account for streamlined or porous structures. IMPLICATIONS: This paper documents theoretical and other problems in PRIME along with CFD simulations and wind tunnel observations that support these findings. Although AERMOD/PRIME may provide accurate and unbiased estimates (within a factor of 2) for some building configurations, a major review and update is needed so that accurate estimates can be obtained for other building configurations where significant overpredictions or underpredictions are common due to downwash effects. This will ensure that regulatory evaluations subject to dispersion modeling requirements can be based on an accurate model. Thus, it is imperative that the downwash theory in PRIME is corrected to improve model performance and ensure that the model better represents reality. PMID- 28080315 TI - We Know Who Likes Us, but Not Who Competes Against Us. AB - Research on dyadic meta-accuracy suggests that people can accurately judge how their acquaintances feel toward them. However, existing studies have focused exclusively on positive feelings, such as liking. We present the first research on dyadic meta-accuracy for competition, a common dynamic among work colleagues. Data from the sales staff at a car dealership and students working on project teams suggest that the prevailing model of dyadic meta-accuracy breaks down for judgments of competition. For liking, projecting one's own feelings promotes dyadic meta-accuracy because colleagues tend to reciprocate each other's liking. For competition, the tendency to compete against superior performers reduces reciprocity and renders self-projection ineffective. You can accurately estimate how much your colleagues like you, but are unlikely to know how much those same colleagues compete against you. PMID- 28080306 TI - No Clinically Significant Difference Between Adult and Pediatric IKDC Subjective Knee Evaluation Scores in Adults. AB - BACKGROUND: Two versions of the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation form currently exist: the original version (1999) and a recently modified pediatric-specific version (2011). Comparison of the pediatric IKDC with the adult version in the adult population may reveal that either version could be used longitudinally. HYPOTHESIS: We hypothesize that the scores for the adult IKDC and pediatric IKDC will not be clinically different among adult patients aged 18 to 50 years. STUDY DESIGN: Randomized crossover study design. LEVEL OF EVIDENCE: Level 2. METHODS: The study consisted of 100 participants, aged 18 to 50 years, who presented to orthopaedic outpatient clinics with knee problems. All participants completed both adult and pediatric versions of the IKDC in random order with a 10-minute break in between. We used a paired t test to test for a difference between the scores and a Welch's 2-sample t test to test for equivalence. A least-squares regression model was used to model adult scores as a function of pediatric scores, and vice versa. RESULTS: A paired t test revealed a statistically significant 1.6-point difference between the mean adult and pediatric scores. However, the 95% confidence interval (0.54 2.66) for this difference did not exceed our a priori threshold of 5 points, indicating that this difference was not clinically important. Equivalence testing with an equivalence region of 5 points further supported this finding. The adult and pediatric scores had a linear relationship and were highly correlated with an R2 of 92.6%. CONCLUSION: There is no clinically relevant difference between the scores of the adult and pediatric IKDC forms in adults, aged 18 to 50 years, with knee conditions. CLINICAL RELEVANCE: Either form, adult or pediatric, of the IKDC can be used in this population for longitudinal studies. If the pediatric version is administered in adolescence, it can be used for follow-up into adulthood. PMID- 28080323 TI - Oral Adenosine-5'-triphosphate (ATP) Administration Increases Postexercise ATP Levels, Muscle Excitability, and Athletic Performance Following a Repeated Sprint Bout. AB - OBJECTIVE: Oral adenosine-5'-triphosphate (ATP) administration has failed to increase plasma ATP levels; however, chronic supplementation with ATP has shown to increase power, strength, lean body mass, and blood flow in trained athletes. The purpose of this study was to investigate the effects of ATP supplementation on postexercise ATP levels and on muscle activation and excitability and power following a repeated sprint bout. METHODS: In a double-blind, placebo-controlled, randomized design, 42 healthy male individuals were given either 400 mg of ATP as disodium salt or placebo for 2 weeks prior to an exercise bout. During the exercise bout, muscle activation and excitability (ME, ratio of power output to muscle activation) and Wingate test peak power were measured during all sprints. ATP and metabolites were measured at baseline, after supplementation, and immediately following exercise. RESULTS: Oral ATP supplementation prevented a drop in ATP, adenosine-5'-diphosphate (ADP), and adenosine-5'-monophosphate (AMP) levels postexercise (p < 0.05). No group by time interaction was observed for muscle activation. Following the supplementation period, muscle excitability significantly decreased in later bouts 8, 9, and 10 in the placebo group (-30.5, 28.3, and -27.9%, respectively; p < 0.02), whereas ATP supplementation prevented the decline in later bouts. ATP significantly increased Wingate peak power in later bouts compared to baseline (bout 8: +18.3%, bout 10: +16.3%). CONCLUSIONS: Oral ATP administration prevents exercise-induced declines in ATP and its metabolite and enhances peak power and muscular excitability, which may be beneficial for sports requiring repeated high-intensity sprinting bouts. PMID- 28080324 TI - The 40th annual meeting of AMERSA: Highlights, abstracts, and awards. PMID- 28080326 TI - Running the HIV risk. AB - A report from the Health Protection Agency last month revealed that 3,010 men who have sex with men (MSM) were diagnosed with HIV in 2011 - the highest number in any year since the AIDS epidemic began in 1981. PMID- 28080325 TI - Adequacy of Parent-Packed Lunches and Preschooler's Consumption Compared to Dietary Reference Intake Recommendations. AB - BACKGROUND: U.S. preschool children consume inadequate amounts of key nutrients. Understanding the contents of lunches packed by parents and consumed by their children can help identify areas of opportunity for the development of healthy food preferences. OBJECTIVE: To evaluate the nutrient adequacy of lunches packed by parents and consumed by children attending early care and education (ECE) centers. METHODS: Baseline data from 607 parent-child dyads in the "Lunch Is in the Bag" cluster-randomized controlled trial in Central Texas were examined. Foods packed by parents and consumed by children in sack lunches were observed at 30 ECE centers on 2 nonconsecutive days. Mean levels of energy, macronutrients, vitamins, and minerals were estimated with covariate-adjusted multilevel regression models that accounted for center-level clustering and repeated within child measures. RESULTS: Energy (kilocalories) was 602.48 for packed lunches compared to 374.40 for consumed lunches. In packed lunches, percentage of energy as macronutrients for protein (14.8%), carbohydrate (55.9%), and total fat (31.2%) were within the acceptable macronutrient distribution range (AMDR) for the children's ages. Sugar (28.9% of energy) was above the AMDR recommendation. Only a quarter of parents packed 33% or more of the child's dietary reference intake (DRI) for dietary fiber. Over half the parents packed 33% or more of the DRI for vitamin A and calcium, and less than one in 8 packed 33% of the DRI for potassium. Children consistently consumed between 60 and 80% of the nutrients that were packed. CONCLUSIONS: Preschool children rely on parents to present them with healthy food choices, but lunches packed by parents for their preschool children do not consistently provide adequate nutrients. These data and the relationships between the dietary quality of packed and consumed lunches can be useful information to guide nutrition behavior change through targeted interventions. PMID- 28080327 TI - Under pressure. AB - There is something about staying up night after night with a sick relative that can turn one into a pain in the neck. PMID- 28080328 TI - 'Campaign Remains As Urgent As Ever'. AB - Peter Carter, general secretary of the RCN: 'The quality and dignity of care for all our patients is at the heart of everything the nursing profession does. By working together to eliminate poor care and to share the good practice that so many nurses deliver day in, day out, we can make sure that all patients get the quality of care that we would like to receive ourselves. This campaign has highlighted many examples of good practice, and I hope that they will be adopted widely.' PMID- 28080330 TI - Research rules out link between pre-eclampsia and drugs for autoimmune disease. AB - Women with systemic lupus erythematosus have twice the risk of developing pre eclampsia compared with women without autoimmune disease, but the effects of drug use during pregnancy are slight. PMID- 28080332 TI - On a mission to encourage better eating and drinking. AB - Head of nursing for older people Ann Gibbins, left, was one year into her role at Brighton and Sussex University Hospitals NHS Trust when she heard about the Care campaign. PMID- 28080329 TI - HCA Voices Make Council Debut. AB - I have been an RCN member since 2002 when healthcare assistants (HCAs) had to have an NVQ level 3 to join - so I got one. Soon after, with encouragement from the general secretary and chair of congress, I was the first HCA to vote and speak at RCN congress - in a speech in favour of nursery nurses joining the RCN with an NVQ level 2 qualification. PMID- 28080339 TI - Over-diagnosis is a price worth paying for lives saved. AB - The debate about whether the benefits of breast screening outweigh the perceived harms reached fever pitch in October 2011, prompting an independent review. PMID- 28080338 TI - Race is a contributing factor in length of survival for people with kidney cancer. AB - A national study of patients with kidney cancer in the United States has confi rmed that white people consistently have a survival advantage over black people, regardless of tumour character or surgical treatment. PMID- 28080340 TI - Starting out - nurse training initaly was tough boosting but it taught me the essence of care. AB - In my final year of nurse training, I spent eight months in Italy as part of my degree in European nursing. PMID- 28080341 TI - Readers panel - Boosting. AB - Our experts consider a hot topic of the day. PMID- 28080344 TI - One in six mothers who took their baby to a&e had postnatal depression. AB - Mothers who seek treatment at emergency departments for their young infants have a high prevalence of postnatal. PMID- 28080343 TI - Legal advice. AB - All patients, including those who have died, have the right to their personal health information being kept confi dential. PMID- 28080345 TI - Uncommon cold. AB - Everyone has heard of the common cold. Well, I am suffering from the uncommon cold. It is extremely tiresome - much more so than the common cold. And I wish it would clear up and let me get on with my life. PMID- 28080347 TI - Staff lack competence in caring for people with genetic conditions. AB - Nurses appear to have poor knowledge of and clinical skills in genetic health care, suggests a review of the evidence. PMID- 28080346 TI - Getting to the heart of care. AB - Taking up my role as a support nurse at the Cardiomyopathy Association has been a fascinating career move, building on my background in intensive and cardiac care, and vascular surgery. PMID- 28080352 TI - 'The nursing staff were phenomenal'. AB - Garry Brough (pictured) was diagnosed HIV positive in February 1991 and developed AIDS in 1995. He was subsequently hospitalised several times with Karposi's sarcoma, a skin cancer associated with AIDS. PMID- 28080362 TI - Playing to my strengths. AB - Studying for a pre-nursing orthopaedic certifi cate many years ago inspired my interest in health care and a later job working with children excluded from school made me realise I enjoyed working with young people. So my current job as a school nurse assistant fosters both my interests. PMID- 28080363 TI - Review aims to maximise Staff potential. AB - New community roles being developed by Skills for Health will demonstrate the benefi ts that support healthcare staff at bands 1-4 can bring to patient care. PMID- 28080364 TI - HCAs are perfectly placed to provide human sympathy and support. AB - The importance of healthcare assistants in hospitals has undoubtedly grown in recent years. PMID- 28080365 TI - Francis Biley 1958-2012. AB - Francis (Fran) Biley, who has died at the age of 54, was an enthusiastic champion of health and wellbeing in nursing and mental health. PMID- 28080366 TI - Clarification. AB - We have been asked to point out that new RCGP guidance mentioned last week (noticeboard November 21) referred to the former Winterbourne View Hospital, Bristol, and not the BMI Winterbourne Hospital in Dorset. PMID- 28080367 TI - 'Game show' approach to service commissioning was a total sham. AB - I recently attended a clinical commissioning group (CCG) 'consultation' in Kent. It was held in a church building at the back of a remote industrial estate. PMID- 28080370 TI - ? AB - Nurses and healthcare assistants have always worked together as a team and I believe RCN council is no different. PMID- 28080368 TI - Exercise can help to alleviate the fatigue associated with cancer. AB - Aerobic exercise can help to relieve the fatigue that is frequently associated with cancer and its treatment, according to a review of the evidence by Cochrane researchers. PMID- 28080371 TI - News update. AB - The RCN has raised concerns that many healthcare assistants are paid less than the ethical minimum. While the current UK-wide minimum wage is L6.19 per hour, the Living Wage Foundation - which campaigns for minimum wages that refl ect the cost of living - claims the minimum wage should be L8.30 per hour in London and L7.20 per hour in other parts of UK. Commenting during the recent Living Wage Week, RCN general secretary Peter Carter said: 'This affects college members, particularly healthcare assistants in the private sector, who are often paid less than the living wage. Some struggle to make ends meet, forcing them to claim benefi ts.' PMID- 28080372 TI - Voices leadership is all very well, but leaders need people to lead, says jean gray. AB - As we await publication of the report on care failings at Mid Staffordshire NHS Foundation Trust, which is due in the new year, it becomes increasingly clear that the most important issue facing the profession is safe staffi ng levels. PMID- 28080375 TI - Good tidings. AB - Crisis at Christmas is one of the largest volunteering events in the UK - more than 8,000 volunteers and 3,200 guests attended its centres last year. PMID- 28080378 TI - Building the basis for appropriate therapy. AB - Speech and language therapy may not seem a priority treatment for patients in a secure psychiatric hospital, nor one commonly undertaken by care assistants. PMID- 28080380 TI - Safety first on medicines. AB - Aspects of medicines management are increasingly being taken on by healthcare assistants. PMID- 28080382 TI - Courses & resources. AB - Wound care A workshop on wound care for healthcare assistants will be held in Manchester on January 24 and in London on January 31. These will be an opportunity to develop knowledge and skills in wound care, infection control and removing skin closures. The course includes anatomy, physiology and pathophysiology of skin and skin healing, wound dressings, documentation and professional responsibilities. tinyurl.com/cnwb3o4. PMID- 28080384 TI - The importance of remaining watchful. AB - Between November 2011 and March 2012, six senior sisters at the Heart of England NHS Foundation Trust in Birmingham were made 'supervisory to shift' to test different ways of turning the concepts of the Care campaign into reality. PMID- 28080387 TI - 'Nurses suffered in the two world wars and history abandoned them'. AB - Although more than 1,500 nurses lost their lives serving in the two world wars, there is no national memorial to that sacrifice. PMID- 28080388 TI - Post-menopausal women who receive hrt have lower risk of morbidity. AB - Hormone replacement therapy significantly reduces the risk of mortality in post menopausal women, according to the first long-term randomised controlled trial to look at the effects of initiating the therapy early in post-menopause. PMID- 28080389 TI - Elephant ahead. AB - I often use a stretch of motorway where vast new dot matrix signs have been installed. There is one of these monsters on each carriageway at one mile intervals, and they must have cost millions. PMID- 28080390 TI - In search of answers. AB - When the National Nursing Research Unit was founded in 1977, its remit was to conduct robust and independent academic enquiry into key policy questions for the Department of Health. PMID- 28080391 TI - Insulin resistance in obese children reduced significantly by regular aerobic exercise. AB - Twenty minutes of aerobic exercise five days a week can reduce diabetes risk in overweight and obese children, suggests a study of primary school children in the US. PMID- 28080392 TI - Women who have undergone genital mutilation experience impaired sexual function. AB - A study by researchers at King's College London has confirmed that women who have undergone female genital mutilation (FGM) have a significantly impaired sexual quality of life. PMID- 28080393 TI - Vintage charm. AB - It was a touching scene. A nursing home resident in her nineties, frail and in a wheelchair, had been taken along to the shops for a trip out. PMID- 28080396 TI - Voices - The US healthcare system makes Yvonne Coghill appreciate the NHS. AB - By the time you read this, voting for the next president of the United States will have finished. I have been in the US for the past six weeks and the race has been extremely close. PMID- 28080397 TI - The independent commission's key recommendations. AB - ? Use evidence of the benefits nurses have on patient outcomes when planning nursing skill mix. PMID- 28080402 TI - Medicines management. AB - As an independent and supplementary nurse prescriber, is it possible to prescribe pre-emptive medication for end of life care patients? PMID- 28080398 TI - Willis review of nurse education backs shist to all-graduate entry. AB - A UK-wide review of nurse education says the system must produce nurses who have both intelligence and compassion. It says education should encourage nurses to question practice constantly and look for evidence to improve performance. PMID- 28080403 TI - Effectiveness of care pathway is dependent on the practitioner. AB - There has been much discussion about the Liverpool Care Pathway (news October 31). PMID- 28080404 TI - Workforce. AB - Now that the afterglow has faded, it is worth refl ecting on one less positive aspect of preparations for London 2012. PMID- 28080405 TI - An ombudsman would encourage nurses to report concerns. AB - The events at Winterbourne View residential home and failures on the part of the NHS to take up concerns about Sir Jimmy Savile (news October 31) are evidence that whistleblowing policies are not working. PMID- 28080406 TI - Leadership training needs to be offered at all levels. AB - The news of investment in leadership training for nurses and ward leaders over the next three years is probably to be welcomed (news October 10, letters October 24 and October 31), but it depends on how the investment is to be used. PMID- 28080407 TI - Vacating RCN's offices in London would prove to be a false economy. AB - I appreciate why Sue Green might think it sensible for the RCN to vacate its London office in Cavendish Square and relocate to a part of the country where property rental is less expensive (letters October 24). PMID- 28080408 TI - Nurse of the year highlights the value of prison nurses. AB - The work of nurses with prisoners is often overlooked, so it is inspiring to read about nurse of the year Johanne Tomlinson's engagement with inmates at HMP Stafford (features October 10), a category C prison that houses up to 740 male offenders. PMID- 28080409 TI - The experts' view. AB - RCN general secretary Peter Carter: 'There is no truth in the suggestion that because nurses receive training from universities as well as on the ward they become less caring. Improvements will need to be made to the profession in the future, notably in the regulation of healthcare assistants.' PMID- 28080411 TI - Make the time to talk to patients who may be anxious. AB - Patients with dementia can often display behaviour that is perceived to be difficult, such as getting out of bed unexpectedly and leaving wards. PMID- 28080412 TI - If the public wants best care then they must pay for it. AB - Times are tough for nurses. We are working unpaid overtime and through our breaks, and our salaries are decreasing in value. Foundation trusts are discarding Agenda for Change and our job security feels threatened. PMID- 28080413 TI - It is wrong to penalise nurses for the failings of their regulator. AB - The Nursing and Midwifery Council (NMC) has accepted a L20 million grant from the Department of Health to address long-running problem areas, notably the backlog of fitness to practise cases (news October 31). PMID- 28080415 TI - Correction. AB - NMC fees are increasing from L76 to L100 a year, and not to L100 a month, as stated in last week's editorial. We apologise for the error. PMID- 28080416 TI - Clarification about use of water in burns treatment. AB - In response to our article on burns management (art&science September 12), Mark Pittman writes that cold water and cling film are the best remedy for burns (letters September 26). PMID- 28080418 TI - Competence-based education: learning disability nursing in wales. AB - A new era of nursing education has begun in Wales during 2012 based on new standards for pre-registration nursing education published by the Nursing and Midwifery Council ( NMC ). While the article focuses on pre-registration learning disability nursing education, the NMC standards can also be used for adult, mental health and children's nursing education. Partnership working across Wales has resulted in the development of nationally agreed common elements relating to students' ongoing record of achievement of practice competence, student selection and recruitment principles, a generic educational audit format and student evaluation. Details of the NMC standards are provided, with particular examples of their implementation in learning disability nursing education across Wales. PMID- 28080419 TI - Managing anxiety. AB - As a mental health liaison nurse, my role involves assessing psychiatric referrals from emergency departments and general wards. I encounter patients experiencing anxiety and in mental health crisis. PMID- 28080420 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28080425 TI - Taking a stand. AB - Earlier this year, I was trying to encourage nurses in my sector to bid for funding to celebrate Nurses' Day. But I was concerned to discover that those I spoke to felt far too stressed to think beyond job security, pay and pensions. PMID- 28080426 TI - Victory for 'J' in police records case. AB - A nurse who claims her 'excessive pillow plumping' led to an unfair police record has won a landmark court ruling. PMID- 28080428 TI - Readers panel-An issue of jobs for the boys. AB - Our experts consider a hot topic of the day. PMID- 28080429 TI - Starting out - stroke unit placement reinforced an issue belief that nursing is right for me. AB - Nursing is a unique career. Not only does it require the right academic knowledge and practical skills, but it also requires the right attitude. Anyone who wants to enter the profession has to ask themselves: 'Is this the right career for me?' PMID- 28080430 TI - Nurses should consider ethnic background when advising couples about dementia care. AB - Ethnic background influences whether family or formal care is preferred by partners of people with dementia, a study suggests. PMID- 28080432 TI - Will ministers listen to what Willis has to say? AB - The RCN took a risk when it asked former head teacher Lord Willis, a shadow education minister when the Liberal Democrats were in opposition, to conduct a wide-ranging review of nurse education. He could have agreed with the popular view that nursing students do not need degrees to know how to care, and gone along with the prevailing public opinion that moving nursing schools into universities 20 years ago was a mistake. As an MP from 1997 to 2010, he will have heard many complaints from constituents along these lines. PMID- 28080436 TI - 'We are being accused of extermination, but we must fight back'. AB - Rita Doyle, palliative care clinical nurse specialist at Royal Liverpool and Broadgreen University Hospitals NHS Trust, said the newspaper reports have distressed patients and nurses. PMID- 28080434 TI - Clinically indicated catheter replacement is as safe as more frequent removal. AB - Routine removal of peripheral intravenous catheters may not be necessary, suggests an Australian study. PMID- 28080437 TI - Have you got what it takes to commission services for patients? AB - Nurse representation on clinical commissioning group boards was made mandatory last year, and the rules on membership of the boards that will oversee each clinical commissioning group were laid before parliament in July. PMID- 28080438 TI - Maladaptive schemas mediate poor parental attachment and suicidality in college students. AB - In college-aged adults (n = 766), the transition to adulthood may aggravate risk factors for suicidal behavior such as poor parental attachment and maladaptive self-schemas. Because poor parental attachment may facilitate developing maladaptive self-related schemas, this study was designed to determine whether specific maladaptive schemas mediate the relation between poor parental attachment and college students' suicide proneness and ideation. Findings supported this hypothesis. Defectiveness and emotional deprivation schemas, which are consistent with "perceived burdensomeness" and "thwarted belonging," may be important intervention targets for suicide prevention programs. The ongoing role of parental attachment during early adult development is highlighted. PMID- 28080439 TI - Reiki helped me to cope with stress. AB - I recently had cause to require anti-stress therapy after a car accident six months ago. I had several choices of treatment and I decided to choose reiki, which I knew nothing about at the time. PMID- 28080440 TI - The Admiral Nursing Service helps the carer. AB - Following my 'On the move' appearance (News July 7), I felt I should clarify the role of the Admiral Nursing Service in which specialist nurses work in the community to support the carers of people with dementia. PMID- 28080441 TI - Foot notes. AB - A friend of mine used to hate the expression 'it all went pear- shaped'. She still does, for all I know. We tend to avoid the subject these days. PMID- 28080442 TI - Vaccine plans may fail without enough nurses. AB - NURSES HAVE welcomed the announcement of a new meningitis vaccine which could save the lives of thousands but fear there may not be enough nurses or vaccine to deliver the programme. PMID- 28080443 TI - Nursing may be more academic these days - but not if you are Finnish. AB - This month it was my turn once again to renew my UKCC registration. When I came to fill in the section 'Further academic qualifications, degrees or diplomas', I realised that my two degrees, MA and BA, have never been printed on my form. I telephoned the UKCC to ask whether nursing or related degrees only were included to be told that was not the case but that as both of my degrees were obtained at a university in Finland, they could not be recorded on my professional register. PMID- 28080444 TI - Complaints procedure must be clearer. AB - THE PUBLIC must be made more aware of when they can complain to the health service ombudsman (HSO), according to the RCN. PMID- 28080445 TI - Complementary therapies follow Hippocrates. AB - Things have changed considerably since Claire Rayner qualified in 1954. PMID- 28080446 TI - Naturopathy is a different approach to illness. AB - As a naturopath I would like to comment on Ms Rayner's view of naturopathy as quackery. Naturopathy requires a four-year honours degree course and is an established alternative to orthodox medicine with a sound philosophy to support its principles. PMID- 28080447 TI - On the move. AB - Promotions / new appointments. PMID- 28080449 TI - Nurses demand information on GMOs as concern grows. AB - NURSES ARE calling for more information about genetically modified (CM) food so they can answer questions about food safety from the public. PMID- 28080448 TI - Set for care. AB - overnight, unless there were complications. At the same time, their wounds and vaginal blood loss were checked by nurses. PMID- 28080451 TI - Nursing care diluted by support workers. AB - HEALTHCARE assistants (HCAs) are carrying out nursing tasks such as tracheostomy care and administering drugs as health authorities exploit confusion between general care and specialist nursing care to save money. PMID- 28080452 TI - MP calls for clarification of long-term care. AB - AN EARLY DAY motion tabled in the House of Commons this week urges health secretary Frank Dobson (above) to issue new guidance on patients' eligibility for long-term nursing care in light of the Coughlan case ruling. PMID- 28080453 TI - Unfair criteria are blocking access to nursing homes. AB - HEALTH AUTHORITIES (HAs) and social services are enforcing such strict eligibility criteria for nursing home care that patients 'practically have to be dead', a nursing home organisation claimed this week. PMID- 28080454 TI - Standard life. AB - When Neil Armstrong stepped on to the moon 30 years ago, I was up a tree. If he thought he was taking a giant leap, he obviously hadn't straddled the large gap between forking boughs half way up the big yew in our garden. The Sea of Tranquility? Easy. PMID- 28080455 TI - Second rate citizens. AB - Don't be ageist We are all humans who deserve to be given the best possible care regardless of our age. Every age group can put forward a good reason for why they should be given priority. The young have a whole life in front of them. The middle aged are the primarily employed population. The older generation have given a life-time towards the society of today. PMID- 28080456 TI - Ask the experts. AB - I am a newly qualified D grade working on an acute hospital ward with one other nurse and a ward sister. We think the sister has a drink problem she comes in smelling of drink. She sucks mints and uses perfume, so I don't think the patients have noticed. We are worried that patients might be compromised by her drinking, but as we have no real evidence we wonder if something has to happen before we can tell anyone. I am worried about repercussions should my complaint be unfounded. PMID- 28080458 TI - Recruitment 'turns the comer'. AB - THE NUMBER of applicants to diploma courses in England saw a 73 per cent rise on last year's figures. PMID- 28080457 TI - Super model behaviour. AB - EVA HERZICOVA (pictured) was one of five models praised by the National Blood Transfusion Service (NBTS) for giving blood in a photo shoot for the August edition of the style magazine. PMID- 28080459 TI - Euthanasia debate. AB - IF EUTHANASIA were legalised nurses would need specialist training and the protection of the law, says the author of an article on the controversial area. PMID- 28080460 TI - Just tell me why... AB - Well Walter, you were unsuccessful on this occasion.' I was being informed sympathetically by the nursing officer that my attempt to obtain a charge nurse post had crashed on the treacherous rocks of interview. 'Do come and see me if you wish to discuss the matter further,' he added. PMID- 28080461 TI - No minimum standards patients' post-operative. AB - PATIENTS WANT minimum standards for post-operative observations to set down how frequently they should be monitored following surgery. PMID- 28080462 TI - Feedback. AB - The Health and Safety Commission has asked the RCN for its views on a consultation document on genetically modified organisms. The consultation is being carried out to establish whether UK law should be changed. PMID- 28080463 TI - Someone should know how to use sign language. AB - The article 'Audiology and hearing impairment - improving the quality of care' (Art&Science July 14) was very interesting and clearly written. However as the mother of a deaf child who uses total communication - speech, lipreading and British Sign Language, I was amazed that in the section on communication there was no mention of sign language. PMID- 28080464 TI - Autism linked to autoimmune disease. AB - Families with children who have autism have a particularly high incidence of autoimmune diseases, according to American researchers. PMID- 28080465 TI - Guidelines do not affect mothers' use of services. AB - Providing new mothers with Baby Check, an illness scoring system for babies aged up to six months, does not affect use of health services, Scottish researchers say. PMID- 28080466 TI - Depression after stillbirth and further pregnancy. AB - Women who have had a stillbirth might be well advised to delay another conception for 12 months, researchers believe. PMID- 28080467 TI - New adjunctive therapy for intractable epilepsy. AB - Low frequency repetitive transcranial magnetic stimulation (rTMS) might be useful as a non-invasive adjunctive treatment for intractable epilepsy. PMID- 28080468 TI - Beating the habit. AB - As a drugs charity, Addaction long ago recognised the important role that nurses and ex-nurses have to play at our 22 projects around the country. We have nurses working with drug users at many of our projects, as well as former nurses who have become drug workers before moving into management and even on to our executive team. PMID- 28080469 TI - Network offers you the chance to contact other-nurses free of charge. If you want help on any professional matters, please send details to Nursing Standard. PMID- 28080470 TI - 'Eligibility criteria' send shivers down the spine. AB - NOW THEN, when you go on duty today are you going to be delivering skilled specialist care to patients with complex needs? And will you recognise when semi skilled nursing is in order? Indeed, can you identify the difference? Can you say exactly how many hours of care a patient is going to need? What criteria will you be applying? If your work involves contact with nursing homes, that word criteria has probably sent a shiver down your spine. PMID- 28080471 TI - Listings. PMID- 28080472 TI - Spotlight on private cane. AB - An Awful Lot of poppycock has been written and spoken around the subject of private health care. It is one of those areas where everyone has an opinion. The trouble is, the people with the strongest and least complimentary opinions have not always been the ones with the most experience of this area. PMID- 28080473 TI - Fractured neck of femur, the risk factors. AB - On the orthopaedic ward on which I work, a large percentage of trauma/emergency admissions to the ward are the result of falls by older people resulting in fractures of the neck of femur. PMID- 28080474 TI - ? AB - Castaway: staff nurse Carol Baum showed Hull schoolgirl Rachel Clarke how to help her mum get plastered during a fracture clinic demonstration at Hull Royal Infirmary's family day. During the day there were displays by several departments, including pathology, health education and physiotherapy, and youngsters had fun being made up with pretend bruises and wounds. PMID- 28080476 TI - UKCC to survey nurses' ethnic identity. AB - THE UKCC is to compile the first comprehensive statistics on the number of black nurses in the UK. PMID- 28080477 TI - A&E nurses plan to sue over post-traumatic stress. AB - NURSES ARE planning to take their employers to the High Court, claiming that NHS trusts failed to protect them from post-traumatic stress disorder (PTSD). PMID- 28080478 TI - Resources. AB - A resource guide on HIV health promotion with African community groups in England is now available. The guide lists published reports, educational resources, websites, useful contacts and advance information on forthcoming projects. To receive the guide free of charge send a stamped addressed envelope to: National HIV Prevention Information Service Health Education Authority Trevelyan House 30 Great Peter Street London SW12 2HW. PMID- 28080479 TI - Demanding Patients? Analysing The Use of Primary Care Demanding Patients? Analysing The Use of Primary Care Rogers Anne , Hasswll Karen , Nicolaas Gerry , 250pp , L16.99 0-335-20090-7 0335200907. AB - This book examines the policy and sociological explanations for the diverse patterns of service use in primary care. Drawing on empirical data, the book's major interest concerns the interface between the public and primary care. It deals with lay decision making and the importance of these issues in understanding the role of the public in planning services in primary care groups. PMID- 28080481 TI - Complementary Therapies in Context Helen Graham Complementary Therapies in Context Jessica Kingsley 350pp , L16.95 1-85302-6409 1853026409. AB - Helen Graham addresses a wide range of topics and themes which underpin concepts of healing. Part I offers a well informed and succinct overview of perspectives of healing. Ms Graham summarises the key elements of ancient and modern approaches to healing before addressing both Eastern and Western approaches to this topic. This is a fascinating section and places recent developments in medicine within a sociocultural context. PMID- 28080482 TI - Nurse in the house. AB - WHEN KAREN ST.CYR first arrived at her office in the House of Commons, she found some unorthodox nursing equipment. PMID- 28080495 TI - Correction. AB - In 'The ultimate honour' (features October 31), it was reported that breast cancer nurse specialist Gill Donovan, joint winner of the first patient's choice award in 2008, is retiring from her post at Velindre Hospital in Cardiff. Ms Donovan is leaving Velindre, but is not retiring. We are happy to set the record straight. PMID- 28080497 TI - Fundamental values. AB - Changes in health care over the past 30 years, such as the increase in patient throughput and greater complexity of patient need, have undoubtedly affected nursing practice in hospitals. PMID- 28080498 TI - An instrument is only as good as its player. AB - The Liverpool Care Pathway is an excellent map guiding best practice for the terminally ill, but recently relatives have complained about a lack of consultation on decisions to withdraw food and fluids, for example. PMID- 28080501 TI - Let us clarify the type of leadership we want. AB - The prime minister sees better nursing leadership as essential to the NHS. He recently announced that 300 aspiring board-level directors of nursing will get a L2.7 million leadership development programme. A further L37 million will be available to train 10,000 leaders at foundation or mid-career level. PMID- 28080511 TI - Starting out - Managers have a duty to support staff with mental health problems. AB - As someone in their mid-thirties on their second career, I chose mental health nursing because I was eager to help people with mental health difficulties. PMID- 28080512 TI - Safeguarding adults at risk understand neglect and how to promote care and compassion. AB - Officially, neglect is a form of abuse. Government guidance states that abuse can be 'neglect and acts of omission, including ignoring medical or physical care needs, failure to provide access to appropriate health, social care or educational services, the withholding of the necessities of life, such as medication, adequate nutrition and heating' ( Department of Health (DH) and Home Office 2000 ). PMID- 28080515 TI - Fight back. AB - At the RCN UK stewards conference in Birmingham earlier this month, the south west pay consortium was high on the agenda. PMID- 28080516 TI - Readers panel - wading into controversy. AB - Our experts consider a hot topic of the day. PMID- 28080518 TI - Midwives' care can be as safe as physician-led services, and sometimes has better outcomes. AB - Midwife-led maternity care is as safe as physician-led care for women and babies, and may also have additional health benefits, concludes a review of the evidence by UK researchers. PMID- 28080520 TI - Staff in the south west are on the pay front line. AB - The group of trusts in south west England that is seeking to go its own way on pay lost one of its members last week. To the delight of staff, the board of the Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust in Dorset decided to remain with the hundreds of other NHS employers that are happy for terms and conditions to be set nationally rather than by local cabals. PMID- 28080524 TI - Nurses will judge programme's effectiveness. AB - The palliative and end of life learning and development programme for nursing homes will be delivered to nurses in 266 care homes across Northern Ireland by March 31 2013. PMID- 28080526 TI - CNO's blueprint aims to refocus profession on core priorities. AB - At the heart of the chief nursing officer for England's blueprint for nursing is an ambition to unlock the potential of every nurse and develop a culture of compassionate care. PMID- 28080527 TI - Don't ask me .... AB - I am not a stupid person. I read books and stay on top of current affairs. Having children keeps me abreast of popular culture, and I watch television and listen to Radio 4. So why am I a quiz night duffer? PMID- 28080528 TI - Waiting game. AB - 'You used to pay them half a crown. A lot of money in those days, but at least they came.' That was my mother reminiscing about the dark ages of health care, before the NHS. PMID- 28080529 TI - Be a ratings winner. AB - Improving patient experience requires the commitment of staff at every level of an organisation. From the chief executive to volunteers, everyone has a part to play, including the patients themselves wherever possible. PMID- 28080531 TI - Prioritise prevention. PMID- 28080532 TI - I want to help nurses articulate their contribution. AB - By writing the articles in this supplement, we wanted to support nurses in recognising neglect, in understanding the processes that can foster neglect and to offer ideas on how to prevent it. PMID- 28080533 TI - Nurses need to respond promptly to older people's expressions of pain. AB - Nurses use simple questions to assess pain in older patients in hospital, including those who have difficulty communicating, despite the availability of validated pain assessment tools, a qualitative study has found. PMID- 28080534 TI - Voices - The NMC will cut costs to keep registration fees down, says Mark Addison. AB - When the Nursing and Midwifery Council (NMC) voted to increase the registration fee by L24 to L100 a year from February 2013, it was not a decision we made lightly. PMID- 28080540 TI - On the move. AB - Promotions / new appointments. PMID- 28080539 TI - Progesterone test predicts early pregnancy outcome in women with pain or bleeding. AB - A single progesterone measurement can discriminate between a viable and non viable pregnancy in women who have pain or bleeding in the early stages of their pregnancy, an analysis of the evidence has found. PMID- 28080541 TI - Exhaustion during training linked to poor performance in later years. AB - Nursing students who show signs of burnout during training are likely to underperform in their nursing practice after qualifying and experience poor psychological wellbeing, a study in Sweden has revealed. PMID- 28080542 TI - General health checks for adults fail to improve their wellbeing or longevity. AB - A meta-analysis of the evidence by Cochrane researchers has concluded that general health checks - such as those introduced in the UK in 2009 for adults aged 40 to 74 years - are unlikely to be beneficial. PMID- 28080543 TI - Stand up and be. AB - Nurses have a duty to prevent neglect occurring and this entails keeping abreast of current practice, being honest about their own competence and being prepared to report neglectful practices or dangerous organisational systems ( NMC 2008 , 2011 ). PMID- 28080545 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28080548 TI - Nurses shape up on reality show. AB - Two nurses faced their food fears on television in reality show Supersize Versus Superskinny, which aired this week on Channel 4. PMID- 28080547 TI - Anti-smoking policy puts staff at risk. AB - Nurses being asked to confront people breaching NHS hospital smoking bans could be putting their own safety at risk, according to the RCN. PMID- 28080549 TI - Dole queue health danger. AB - There is a wealth of literature showing links between unemployment and ill health. As the government struggles with the economy and attempts to keep people in work, nurses are bracing themselves for the health impact of growing job losses. Last week, the RCN took the opportunity of prime minister Gordon Brown's employment summit to remind politicians that periods of economic downturn historically lead to well documented rises in health problems. PMID- 28080550 TI - Domiciliary oxygen therapy:assessment and management. PMID- 28080553 TI - Small changes can bring big improvements for patients. AB - Further to Alan Halliday's letter (January 7), in my experience as a matron in outpatients the emphasis has already shifted towards a more caring environment. PMID- 28080551 TI - Health unions unite in call for a 2.5-hour cut in the working week. AB - Health unions will renew calls for nurses to work a shorter working week as part of moves to improve working conditions for NHS staff. PMID- 28080555 TI - Overcrowding must lead to compromised patient dignity. AB - It's a bit like Wimbledon. The ball goes back and forth. Alan Halliday wants the focus of the RCN's dignity campaign to switch to outpatients, where he complains that patient dignity is compromised as a matter of course (letters January 7). PMID- 28080556 TI - Webwise. AB - If you are a woman aged 45 to 70, the National Osteoporosis Society website will inform you and may even change your life. Osteoporosis is a condition in which the bones, particularly those of the wrist, hip and spine, become increasingly fragile and prone to fracture. PMID- 28080557 TI - Patient bottlenecks lead to conveyor belt care in outpatient departments. AB - Outpatients would be a great place to work were it not for the hordes of patients booked in to be seen in the morning and afternoon clinics (letters January 7 and 14). PMID- 28080559 TI - Write a practice profile. PMID- 28080558 TI - Providing specialist care for pregnant women with asthma. AB - This article evaluates the care provided by respiratory nurse specialists to pregnant women with asthma. The effect of asthma on pregnancy and the effect of pregnancy on asthma are discussed with reference to relevant literature. This article focuses on education relating specifically to asthma and pregnancy and the personalised asthma action plan. PMID- 28080560 TI - Steps to promote dignity are undermined by target culture. AB - Nurses working in outpatients face the challenge of delivering individualised care in a clinical environment where the patient to trained staff ratio is significantly higher than the typical ward area (letters January 7 and 14). PMID- 28080561 TI - Hospital end of life care is inappropriate and unwanted. AB - Hospitals are far too expensive a burden on the state and a large part of that expense is inappropriate end of life care (editorial and news January 7). Many of the interventions for hospital patients nearing the end of their lives are unwanted, inappropriate, aggressive and highly technical. PMID- 28080562 TI - Adverse reaction. AB - Prescribed drugs undoubtedly save lives but some can also adversely affect mental health. PMID- 28080564 TI - Pre-surgery checklist aims to promote safety. AB - A checklist designed by the World Health Organization to ensure surgical procedures are carried out safely has been welcomed by the International Federation of Perioperative Nurses (IFPN). PMID- 28080565 TI - Alcohol-related presentations. AB - As a second-year adult nursing student on placement in an endocrine and upper gastrointestinal surgical ward, I encounter many patients with alcohol-induced pancreatitis. PMID- 28080563 TI - Every dying patient deserves the best specialist care. AB - The End of Life Care Strategy is an important document, but end of life care planning is unfortunately much more complex than the Commons public accounts committee and your editorial (January 7) would suggest. PMID- 28080567 TI - Climate is growing health threat. AB - Nurses will have to cope with a rising number of people with illnesses related to climate change over the next 50 years, according to a coalition of leading environmental and social justice groups. PMID- 28080566 TI - Graduates turn to public sector careers amid financial uncertainty. AB - A dramatic increase in the number of graduates applying to train as nurses in Newcastle upon Tyne has coincided with the loss of thousands of banking jobs in the city. PMID- 28080568 TI - Good management protects employees from heart disease. AB - Managers who display leadership skills might protect their staff from developing ischaemic heart disease. PMID- 28080569 TI - Beta blockers do not improve surgical clinical outcomes. AB - Evidence does not support the use of beta blockers for the prevention of perioperative clinical outcomes in patients having non-cardiac surgery. PMID- 28080571 TI - Rights of the child. AB - Thirteen-year-old leukaemia patient Hannah Jones was given the 'right to die' last year. That, at least, is what happened according to some newspaper reports. PMID- 28080570 TI - A race for women to support women - and men. AB - Liz Piper raised some interesting issues about Cancer Research UK's Race for Life (reflections December 3). PMID- 28080572 TI - Alcohol and drug use leads to violence among young tourists. AB - International resorts that attract young people feature many of the key risk factors for violence, including large numbers of bars and nightclubs and high levels of substance misuse. PMID- 28080573 TI - High levels of resistance in E. coli urinary infection. AB - With the exception of nitrofurantoin, resistance to drugs commonly used to treat urinary tract infections (UTIs) is extremely high. PMID- 28080575 TI - I learned how body image can affectapatient'smentalstate- Starting out. AB - Jude was a middle-aged woman whose independence had been severely affected by a vulvectomy. I visited her at home, with my mentor, four weeks after her operation. PMID- 28080576 TI - Survey reveals vast differences in practice nurse remuneration. AB - Some experienced practice nurses are receiving less money than newly qualified nurses working in the NHS, a survey of practice nurses has found. PMID- 28080577 TI - Staff on gaza conflict front line commended. AB - Nurses in Gaza and Israel have been sent a message of 'support, fraternity and solidarity' from the RCN during the current conflict. PMID- 28080578 TI - Letter from america. AB - With thousands of providers, a complex payment and reimbursement system and an extreme shortage of primary care doctors, it is difficult to see how the United States health system might compare to ours in the UK. PMID- 28080579 TI - Occupational hazard. AB - Shifts that interfere with diurnal rhythms have been classified as a carcinogen of the same magnitude as ultraviolet light. PMID- 28080580 TI - Respecting the rights of atheist or agnostic patients. AB - The National Secular Society (NSS) is a pressure group that defends the rights of atheists, agnostics and all non-believers. PMID- 28080582 TI - First meeting of new regulatory 'board' proves short and sweet. AB - The new Nursing and Midwifery Council (NMC) held its first, and decidedly succinct, council meeting last week at the regulator's London headquarters, writes Petra Kendall-Raynor. PMID- 28080581 TI - Stress point. AB - A new pharmacy assistant asked me why nurses get stressed over their patients' TTOs. PMID- 28080583 TI - Hold the trade gobbledegook and say it like it is, says Daniel Allen. AB - The best example of a badly named healthcare department is 'ECT suite' because 'suite' implies to me a sofa and a couple of armchairs. PMID- 28080584 TI - Readers panel - Lining private sector pockets. AB - Our experts consider a hot topic of the day. PMID- 28080585 TI - The modest hospital gown. AB - Inter-faith hospital gowns provide alternative attire for patients who wish to cover themselves more extensively than the traditional gown allows. They were the brainchild of Karen Jacob, a linen services manager at Lancashire Teaching Hospitals NHS Foundation Trust. Distributor Interweave Textiles Limited has sold about 1,000 gowns to the NHS over the past two years. PMID- 28080587 TI - New constitution to promote needs and rights of NHS nurses. AB - The Department of Health (DH) is expected to make a pledge towards more nurse training in the new NHS Constitution, which is being launched this week. PMID- 28080586 TI - Guide to spiritual needs of staff and patients aims to clear up confusion. AB - It has been 12 years since healthcare students were given the first 'culturally appropriate' uniforms for NHS staff. The move was considered groundbreaking and recognised that the NHS needs to cater for people differently according to their religious beliefs. PMID- 28080588 TI - Rise in mental health problems predicted as job losses increase. AB - Psychological therapies must be accessible to people who have lost their jobs and are feeling depressed, leading nurses have warned. PMID- 28080589 TI - RCN members to gain more voting power. AB - The voting system at RCN congress could be overhauled to help give members a 'stronger voice' during the college's annual conference. PMID- 28080590 TI - Emergency patients say care is improving. AB - Improved communication between patients and A&E staff, including better information at discharge, has been reported by the Healthcare Commission. PMID- 28080591 TI - Legal blame for fatal infection outbreaks could fall on nurses. AB - More nurses can expect to be blamed for outbreaks of healthcare-associated infections (HCAIs) as a result of high-profile investigations into cases, according to the RCN. PMID- 28080593 TI - Nmc's registration rules are gobbledegook to me. AB - The past three years have been difficult following my forced retirement due to ill health. But at last something positive has come of it. I will no longer be paying a registration fee to the Nursing and Midwifery Council (NMC) for it to send out gobbledegook letters. PMID- 28080595 TI - Senseless suffering of children in the middle east. AB - My heart bleeds for the children in the Middle East. I cannot bear to watch the television news footage of shocked and injured children and young people in Gaza and Israel. PMID- 28080594 TI - Strategies to promote bme staff are not being enforced. AB - The NHS Institute for Innovation and Improvement report Access of BME Staff to Senior Positions in the NHS (news January 14) put a bit of damper on my new year. PMID- 28080596 TI - Mobile phone pests should not be let loose on hospital wards. AB - The woman who answers to the name of Amelie is on the train. I know this because she has told everyone within earshot five times already. And I know lots more about her as well. PMID- 28080597 TI - There is a time and a place for words of endearment. AB - I read with some degree of bemusement your readers panel on how we address patients (reflections January 7). PMID- 28080598 TI - Voices-Dame Chris Beasley outlines a government push to enhance community services. AB - I am pleased to announce that funding has been made available by the Department of Health to support leadership development and to enhance the evidence base of good practice in community services in England. PMID- 28080600 TI - RCN's dignity campaign is relevant to outpatients. AB - Alan Halliday (letters January 7) is so right when he says the need for dignity is as relevant in outpatients as it is in every other care service area. PMID- 28080599 TI - Squeezed by degrees. AB - Much of the debate on nursing education in recent months has focused on the pros and cons of making entry to the profession at degree level only. But many nursing students are worried about more basic issues, such as paying our rent, heating our homes and whether we can afford to stay on our courses. PMID- 28080601 TI - Ear muff acceptance among sawmill workers. AB - A method of ear muff selection has been suggested whereby the attenuation provided by the muff, measured as the SLC80 value, the muff weight and clamping force are combined to provide a rating index. A range of muffs selected on this basis was tested in a number of Australian sawmills to determine their acceptance among the workers in these mills. A specific relationship between the rating index and wearer acceptance was not clearly established, although a number of muffs with the highest indices were favourably rated by wearers and others with the lowest values were rated unfavourably. PMID- 28080602 TI - Memory overload or expectancy effect? 'Hysteresis' revisited. AB - The effects of expectancy and variation in task demand on the rate of human information transmission were studied. Subjects performed an eight-choice key pressing task, attempting to match characters presented singly under both increasing and decreasing demand. The results support previous research indicating that the relationship between the rate of information an individual is able to transmit and task demand depends, at least in part, upon the temporal history of demand. When a relatively high level of demand was imposed, performance failed to recover at the expected rate as demand was reduced. However, this 'hysteresis' effect occurred even when a cue was provided to indicate clearly that a reduction in task demand was imminent, suggesting that an overload of short-term memory, rather than an individual's erroneous expectations regarding demand, is primarily responsible for the effect. PMID- 28080603 TI - A cost analysis method of establishing training criteria. AB - A significant problem encountered in designing operator training programmes is the lack of a method for establishing appropriate training criteria (final performance levels). This paper presents such a method which has been derived on the basis of integrating three relatively distinct technical areas: (1) learning curve modelling, (2) quality assurance concepts, and (3) economic analysis. The information requirements for making training decisions are discussed and sources of that information are proposed. The end result of applying the method is a quantifiable measure of the cost effectiveness of a training programme. PMID- 28080604 TI - The influence of vehicle type on the estimation of velocity while driving. AB - Velocity production in the absence of speedometer information was investigated as a function of car size. In the first experiment three vehicles of different sizes were driven by 30 subjects; in the second experiment a different sample of 20 subjects used their own vehicles, which were classified into two size categories. In both experiments subjects were required to drive under conditions of normal and attenuated auditory feedback. The results indicated a greater production accuracy in small compared with large cars and a tendency for drivers of small cars to make greater use of auditory information. The results are discussed in the context of the relative contribution of different sensory channels to the subjective scale of speed. PMID- 28080605 TI - Obituary. PMID- 28080606 TI - A comparison of colour and visual texture as codes for use as area symbols on thematic maps. AB - Three experiments compared colour and texture as methods of coding area symbols for thematic maps. Most previous research has been limited to displays with, at most, eight codes. This study employed displays containing 16 types of symbol coded either by colour, texture, or a non-redundant combination of the two. Symbols coded by colour, or a combination of colour and texture were much easier to find than symbols coded by texture alone. Point symbols were easier to locate against a coloured background than a textured background. Texture codes may be slightly easier to remember than colour codes but the difference, if any, is small. PMID- 28080607 TI - The need for single registration care homes: the RCN visionThis report discusses the provision of care for people living in nursing and residential homes. It presents the RCN's (1997a) proposals for single registration care homes. In the first of two articles, on page 35 in this week's issue, the authors also examine the statutory framework that currently regulates residential and nursing home provision. PMID- 28080608 TI - New chief for Ashworth. AB - NURSES AT ASHWORTH Special Hospital on Merseyside are hoping for a period of calm, the RCN said last week. PMID- 28080609 TI - Agency alert. AB - IMAGINE THE scene. Monday morning and you are the only qualified nurse on a busy elderly care unit. Of the other three care staff, one is a regular' and the others are from the agency and have never been in the building before. PMID- 28080610 TI - Readers panel. AB - Our experts consider a hot topic of the day. PMID- 28080611 TI - Numeracy skills for intravenous calculations. AB - Aims and intended learning outcomes: This article covers the numeracy skills required in the administration of intravenous (IV) therapy in the acute setting. It begins by considering everyday practice with straightforward prescriptions and progresses to more complex calculations. The article also encourages the practitioner to consider other related features of IV therapy. PMID- 28080612 TI - 'Happiness sessions' help stressed nurses. AB - A NURSE who left the profession because of stress has set up her own company to help other stressed nurses. PMID- 28080615 TI - Nurses told to hand back overpayments. AB - NURSES AT a Scottish health board are taking legal advice after being asked to hand back overpayments made to them I under a management which has been criticised by an independent inquiry. PMID- 28080613 TI - ? AB - June Catterall, nee Salisbury, the first baby born under the NHS on July 5 1948 holds Jack Topping, born July 5 1998 at the same hospital, the North Manchester General Hospital. The event was part of the NHS 50th anniversary celebrations. PMID- 28080616 TI - MPs look into eviction of nursing home residents. AB - THE GOVERNMENT is looking at ways to protect nursing home residents from being evicted abruptly. PMID- 28080618 TI - CHImp is watching: rolling checks designed to make sure national standards are met. AB - A NEW statutory body, the Commission for Health Improvement, (CHImp) is to monitor trusts' performance. PMID- 28080617 TI - ? AB - A NEW publication written by a group of respected policy analysts provides a cool overview of the UK nursing labour market, demonstrating the extent to which every policy change, deal and review affects it in some way. PMID- 28080619 TI - ? AB - New recruit: Jan Anderson joins the cast of the BBC's hit TV series Casualty as new nurse Chloe Hill in the forthcoming series starting in September. PMID- 28080620 TI - New hi-tech standards. AB - CLEAR PERFORMANCE standings to ensure nurses remain up to date with hi-tech equipment are on the way. PMID- 28080621 TI - Clinical governance: senior clinicians to draw up programmes for improving quality. AB - NATIONAL standards, set by NICE and the national service frameworks, will be introduced across the country through clinical governance - tire system for putting the standards into practice locally. PMID- 28080622 TI - Treasury cash offers NHS a fighting chance. AB - THE CASH injection for public services expected this week should provide for more nurse- led services, RCN general secretary Christine Hancock has said. PMID- 28080623 TI - National body needed to solve nursing crisis. AB - A STUDY of the nursing labour market has predicted that government efforts to end nursing shortages will fail. PMID- 28080624 TI - Buying health. AB - THE GOOD NEWS in the government's strategy for the new NHS is the official recognition of the need for nurse involvement in commissioning. 'The bad news is that some influential senior managers have been heard to say that the inclusion of nurses in the White Paper was an afterthought, not planned or thought through, which only happened after extensive lobbying. I do not agree with this, I think it reflected the belated realisation by the government that much high-quality expertise was being lost to the management of the NHS because of the failure to include nurses in commissioning. PMID- 28080625 TI - The need for single registration care homes 1: current provision. AB - Successive governments have committed themselves to care in the community, with emphasis on people staying in their own homes for as long as possible. PMID- 28080626 TI - Persecution of the fifty'somethings. AB - I WONDER how much wastage of skills, knowledge, respect and loyalty occurs when a nurse, on reaching 50- something, is placed on the 'witchhunt hit-list? PMID- 28080627 TI - Trusts block right to see medical notes. AB - MIDWIFE Amanda Shaw is among thousands of angry patients and relatives who claim they have been given the runaround by GPs and hospitals over access to medical records. PMID- 28080629 TI - Protest over private funding. AB - NURSES protested last week against plans to fund hospital developments privately. PMID- 28080628 TI - Sentence for bogus nurse is criticised. AB - THE SYSTEM for checking nurses' registration and qualifications is being tightened up following the case of a bogus nurse, Gloucester Crown Court was told last week. PMID- 28080631 TI - Rewind. AB - A round-up of recent news events. PMID- 28080632 TI - Unexpected peril for gardeners. AB - People who spend a lot of time gardening might be at risk of psittacosis. PMID- 28080633 TI - Opportunity knocks.....will nurses answer?Nurses will have to compete with other professions for the chance to lead the new NHS, says Rudolf Klein. AB - ONE OF THE characteristics of the government's White Paper, The New NHS: Modern Dependable', is that it is strong on long-term aspirations but fuzzily vague about the mechanisms and tools required to achieve its aims. It is an outline sketch, where the details still remain to be filled in. PMID- 28080635 TI - Frameworks for equal standards of care. AB - NATIONAL SERVICE frameworks will set standards for the treatment and care of particular conditions and diseases. PMID- 28080634 TI - Patients' use of denial: coping with the unacceptable. AB - Sigmund Freud ( 1961 ) identified the ego as the reality component of the personality that governs problem solving and rational thinking. As the level of anxiety increases, the strength of the ego is tested, and energy is mobilised to confront the threat. Anna Freud ( 1953 ) identified a number of defence mechanisms which can be used in the face of threat to physical or psychological integrity. Among these defence mechanisms is the commonly used and important mechanism of denial. PMID- 28080636 TI - Lifelong learning keeps skills up to date. AB - NURSES WILL have to take part in continuing professional development (CPD) under clinical governance arrangements. PMID- 28080637 TI - Listings. PMID- 28080638 TI - Self-regulation is to be strengthened. AB - PROFESSIONAL self-regulation will be modernised and strengthened. It will aim to identify possible lapses in quality earlier than under the present system. PMID- 28080639 TI - Learning for life. AB - PARENTS OF children with life-threatening conditions are initally in a state of severe shock. Education is not even on their agenda. PMID- 28080640 TI - Mental health nurses ready to set 'care blueprint'. AB - MENTAL HEALTH nurses have been recruited to an expert group which will be asked to draw up a 'care blueprint' for mental health services across the country. PMID- 28080641 TI - Women who conceal breast lumps. AB - In spite of extensive media coverage, a substantial proportion of women still conceal their breast lumps. PMID- 28080642 TI - Why are we embarrased to talk about pay? AB - UKCC We would like to make it clear that a recent letter from Nursing Standard concerning the UKCC's current survey of selected registrants over the PREP requirements was published and distributed by Nursing Standard and not by the UKCC. The letter is not part of the UKCC's evaluation work. PMID- 28080644 TI - Visiting list will resolve disputes. AB - I was pleased to see coverage of my national campaign on visiting access (News Analysis June 17). PMID- 28080643 TI - Blood pressure and risk of stroke. AB - Even a small reduction in systolic blood pressure could substantially lower the risk of stroke. Chinese researchers undertook a prospective, observational study of nearly 10,000 men and women. PMID- 28080645 TI - NetworkNetwork offers you the chance to contact other nurses free of charge. if you want help with any professional issues, please send details to nursing standard. AB - I work in a small A&E department on the west coast of Scotland and am trying to establish standard advice and treatment for dealing with ticks. I am also trying to collect information on Lymes disease. I would be grateful for any information. PMID- 28080646 TI - Work-related asthma rockets. AB - NURSES ARE ideally placed to help the government in its battle against the alarming rise in occupational asthma, according to an asthma charity. Ministers now consider the problem a health priority. PMID- 28080647 TI - TV appeal for Christie's. AB - MARCELLE LEWIS, a staff nurse at Christie Hospital NHS Trust, Manchester, is getting used to being a 'luvvy' after she appeared in a prime-time television advertisement. PMID- 28080648 TI - Web worries. AB - IN A study funded by the Foundation of Nursing Studies, and available in full on this week's Nursing Standard Online, senior nurses were asked to give their views on computer networks. TTie results were surprisingly upbeat, though tempered with caution. PMID- 28080650 TI - PCGs may not cut management costs. AB - PRIMARY CARE groups are unlikely to reduce NHS management costs, at least in their first few years, according to a King's Fund report. PMID- 28080651 TI - On the move. AB - Promotions / new appointments. PMID- 28080652 TI - Nurse with criminal past loses job offer. AB - A SOMERSET nurse has turned to his MP for justice after he lost a job opportunity clue to a spent conviction. PMID- 28080653 TI - All that glitters is not gold... AB - As the leading employer of nurse expert witnesses, I welcome the work the RCN is doing to improve the standard of this service. Performance in the witness box not only reflects and exposes an individual's credibility, but also publicly demonstrates the professionalism of nurses in general. PMID- 28080654 TI - Size matters. AB - DURING THE admission procedure for people requiring psychiatric hospital care, nursing staff concentrate on the client's current mental health problems. At the same time, the admittance nurse assesses the client's potential for violence. PMID- 28080655 TI - Nurses are not part of the 'medical profession'. AB - I welcome the RCN's call for recognition by the Crown Prosecution Service of RNs as professional witnesses (News July 1). The issues are complex, not least because of differences between expert and professional witnesses. A professional witness gives evidence of fact, while an expert witness gives an opinion in a professional capacity. PMID- 28080656 TI - Sidelines. AB - ? If Lord Stoddard of Swindon ever ends up in hospital, nurses should beware of (ailing hint David. At least, not unless they are sure he won't be offended. The Labour peer is upset at the overfamiliarity of NHS staff who address patients by their first names rather than their surnames. Lord Stoddard is so concerned that he has urged health minister Baroness Jay to issue orders to all NHS hospitals. His Lordship, as he may wish to be described, believes NHS patients should be treated 'like paying customers' and 'customers should be addressed by their surnames and titles unless the use of their Christian name is desired and sanctioned by the customer'. PMID- 28080657 TI - Caring climate will help us to heal. AB - Reflection is widely written and talked about these days, but I wonder to what extent it actually occurs. I recently attended a reflective practice conference, where participants demonstrated the ways in which reflection is used - particularly interesting was the use of poetry, art work and meditation. PMID- 28080658 TI - Climax of speech did not reach audience. AB - It was a privilege to be invited to open the series of reflections on the NHS at the 50th Anniversary Celebration at Westminster Abbey. My title was The vision of dignity and the challenge - respect and care for all'. PMID- 28080661 TI - Welsh assembly goes it alone on regulation of support workers. AB - Healthcare support workers (HCSWs) in Wales are to be regulated for the first time in a historic move by the Welsh Assembly Government. PMID- 28080659 TI - Drop the histrionics and face the facts. AB - In the fallout after the scandal at the Bristol Royal Infirmary, I am incredulous at the attitude of Professor Christopher Maggs (Letters July 1). PMID- 28080662 TI - Margaret haywood 'delighted' as ban is overturned. AB - A whistleblower who was banned from nursing in April for exposing patient neglect in a BBC documentary has been allowed to nurse again. PMID- 28080663 TI - Shoe inserts can reduce serious pain in runners. AB - Running injuries are among the most commonly treated sports-related injuries. PMID- 28080664 TI - HPV vaccines could prevent many cases of penile cancer. AB - Vaccines against human papillomavirus (HPV) are likely to be effective in penile carcinoma. PMID- 28080665 TI - It should be nurses' skills that count, not their gender. AB - Striving to achieve the right gender balance provides an opportunity to re-think the profession and get rid of stereotypical gendered roles (reflections September 30). PMID- 28080667 TI - Personal factors might influence induction rate of labour. AB - More than a quarter of induced labours are not explained by clinical factors, Scottish researchers report. PMID- 28080666 TI - Starting out - I was amazed by the skill and professionalism of paramedics. AB - On my community placement I joined a 12-hour shift at the East Midlands Ambulance Service NHS Trust. I was apprehensive at first, but as we raced to our first emergency, the adrenaline soon overcame any doubts. PMID- 28080668 TI - First aid article further confuses a complicated issue. AB - Articles such as 'Introduction to the nurse's role in providing first aid' (art&science September 30) do notassist or educate the nursing community on their duties and obligations. They serve only to confuse the issues. PMID- 28080670 TI - Leave pay to the experts. AB - The promise of a pay freeze in 2011 should the Conservatives win power did not come as a major surprise when it was announced by shadow chancellor George Osborne last week. Before their annual conference the Tories had said they would be honest about the cuts they would make to government spending, and hinted that public sector pay would be in their sights. PMID- 28080669 TI - Scale detects drug overuse in people with chronic headache. AB - The severity of dependence scale (SDS) reliably detects medication overuse and dependency-like behaviour in people with primary chronic headache. PMID- 28080671 TI - Unions warn of workforce crisis if osborne imposes wage freeze. AB - Nurses' pay could be frozen for the first time in living memory if the Conservative Party wins the next general election, prompting fears of a major recruitment crisis. PMID- 28080672 TI - Your views on public pay freeze. AB - The Conservatives propose a pay freeze for public sector workers if they win next year's general election. Nursing Standard asked nurses how it would affect them. PMID- 28080673 TI - Mobile phones may be useful tools but are banned on wards for a reason. AB - Vincent Tremayne asserts that a mobile phone can be a nursing student's best friend. In the student focus (September 30), he writes: 'Thoughts of buying a fob watch, nursing dictionary, pens and a complete nursing library should be put on hold because you probably own an accessory that can perform all these functions - your mobile phone.' PMID- 28080674 TI - Doctors want limit to nurse prescribing. AB - Nearly eight out of ten psychiatrists have concerns about the clinical safety of mental health nurse prescribers, according to a study. PMID- 28080676 TI - Psychometric tests may be used to recruit staff and students. AB - Nursing students and staff in England will be asked to undergo psychometric tests as part of the recruitment process, Nursing Standard has learned. PMID- 28080675 TI - Reports highlight drug errors in residential care homes. AB - The quality of district and community nursing in care homes will be analysed as part of a broader investigation into residential home care. PMID- 28080677 TI - OutsideIn. AB - Before I reveal what the other boys called me at school, I want to make two things clear. First, the nickname was in no way a reflection on my personal hygiene. And second, it was positively complimentary compared with what some other children were called. PMID- 28080679 TI - RCN survey reveals discrimination persists towards BME staff. AB - Plans to tackle racism in the NHS will be developed by the RCN after a survey of nurses from black and minority ethnic (BME) backgrounds found that they continue to experience discrimination. PMID- 28080680 TI - Cameras aim to deter attacks on nurses. AB - CCTV will be introduced in A&E units across Wales in a bid to protect nurses against violent attacks. PMID- 28080681 TI - Time to decide how to deliver older people's care - and who will fund it. AB - How to fund long-term care is set to be a major issue at next year's general election. PMID- 28080682 TI - Colleagues in a lather for a worthy cause. AB - Nurses scrubbed up to raise funds for their patients at a charity car wash. PMID- 28080683 TI - Narrowed pay gap could erode differences in bands, says RCN. AB - The pay gap between unqualified healthcare assistants (HCAs) and registered nurses will be narrowed if a Conservative government freezes public sector pay. PMID- 28080684 TI - Hepatitis support club launched at hospital. AB - A support group allowing people living with hepatitis B or C to share their experiences was launched this month. PMID- 28080685 TI - Deaf student signs on to register. AB - A deaf nurse is believed to have become the first man whose primary language is British Sign Language to join the Nursing and Midwifery Council register. PMID- 28080686 TI - Potential NHS whistleblowers are being paid off, charity claims. AB - A whistleblowing charity claims some NHS employers are offering large sums of money to buy the silence of staff who raise concerns. PMID- 28080687 TI - Nursing needs an urgent image overhaul to attract more men. AB - The number of men applying for nursing diploma courses has slumped by half, leading to calls for an urgent revamp of the profession's image. PMID- 28080688 TI - On-call rules decision has to be delayed. AB - Plans to introduce standardised pay for nurses working on-call have been delayed. PMID- 28080690 TI - Lansley should come clean on his policy for the NHS. AB - Despite the recent speech by shadow secretary Andrew Lansley at the Conservative Party conference, the electorate remains unclear about Tory policy on the NHS. PMID- 28080689 TI - Honour a patient's request to die without judgement. AB - Nurses who hear a patient asking for assisted dying should really listen. It is wrong to ignore an authentic request, or dismiss it with 'you don't really mean that'. PMID- 28080692 TI - Community mental healthservices are being eroded. AB - Inpatient mental health service users do not receive sufficient support and care from nurses and I am pleased that the Care Quality Commission's 2009 Survey of Mental Health Acute Inpatient Services has highlighted this (news September 30). PMID- 28080693 TI - The best of the week's health-related tv and radio. AB - Our roundup of what's on. PMID- 28080695 TI - Ward to board leadership. AB - Nursing directors are supposed to ensure that clinical quality features frequently on the agendas of NHS board meetings and is monitored at board level. On the face of it, nurse directors are ideally placed to promote clinical quality. After all, nurses and midwives are seen as key to providing quality care. PMID- 28080694 TI - Gram-negative bacterium illustration is misleading. AB - Reading one of my wife's copies of Nursing Standard, I was surprised to see an illustration of a Gram negative bacterium that is misleading (art&science August 5). PMID- 28080696 TI - There are three basic steps to motivating nurses. AB - Further to 'The right incentive' (career development September 30), there is no need for managers to ask individual staff members what motivates us. PMID- 28080697 TI - Voices - Tony Hazell says the four UK countries can learn from each other. AB - When I took on the role of chair of the Nursing and Midwifery Council (NMC) in January, I became aware very quickly of the challenge of being a four-country regulator. PMID- 28080698 TI - Skill mix is the key to retaining experienced staff. AB - Further to the analysis by Tamsin Snow on workforce planning (September 23), I have been in nursing all my working life and have just opted for the 24-hour retirement option at the age of 58. PMID- 28080699 TI - I feel cheated out of a public symbol of three years' work. AB - I have recently qualified after three hard years of study, stress and laughter, and had a wonderful day celebrating with my fellow graduates. PMID- 28080700 TI - Reders panel - alcohol anonymous. AB - Our experts consider a hot topic of the day. PMID- 28080702 TI - 'Staffing levels dictate what i do'. AB - Tayo Onipede manages the renal unit at King's College Hospital, London. PMID- 28080705 TI - Using the mnemonic 'brain attack' in the management of acute stroke. PMID- 28080706 TI - A telling truth. AB - When I was a nursing student I had to tell a man that his wife was dying. As the 'third year' in charge of the ward, I was deemed senior enough to have the unenviable task fall to me. PMID- 28080707 TI - A journey of all-round discovery. AB - The chief nursing officer (CNO) for England's black and minority ethnic (BME) advisory group was established to advise her on policy and practice matters. PMID- 28080709 TI - Management of home emergencies. PMID- 28080708 TI - Give us the resources to lead. AB - Scotland and Wales have begun programmes to support ward sisters and charge nurses, and Northern Ireland has allocated L2 million to provide practical support for them. There is no hint of similar activity in England. PMID- 28080710 TI - The Ergonomics Society ANNUAL CONFERENCE 1976 ABSTRACTS OF PAPERS. PMID- 28080715 TI - Dignity in all we do. AB - The RCN's dignity campaign is encouraging nurses to give respectful and compassionate care at all times. PMID- 28080716 TI - External fixation. AB - As a newly qualified staff nurse working on a trauma ward, I see patients with a variety of fractures. It is often difficult to distinguish between the different types of fractures and the methods of fixation. PMID- 28080717 TI - Correction. AB - There was an error in the last paragraph of Clare Walker's letter (August 5) on the RCN policy change to a neutral position on assisted suicide. Catholic Nursing Association should have read Catholic Medical Association. PMID- 28080718 TI - NHS must go the extra mile. AB - For years, many of the community nurses and midwives who use their own cars for work have been subsidising the NHS. The mileage rates on offer have fallen some way short of the true costs of running a car, which have soared in recent years. PMID- 28080719 TI - Leisure time activity low in men employed in passive jobs. AB - Men who work in passive jobs are less likely to engage in physical leisure activity. PMID- 28080720 TI - Drive to meet targets may undermine learning aims. AB - As a professor of nursing, I read with interest that Imperial College Healthcare NHS Trust in London aims to double the proportion of nurses with degrees from 25 to 50 per cent over the next five years (news July 29). PMID- 28080721 TI - Hundreds of posts in a wide range of specialties are taking three months or more to fill. AB - The statistics also showed there were 1,200 more jobs being advertised in acute, older people's and general care compared to the same time the previous year. PMID- 28080723 TI - Rise in unfilled posts blamed on squeeze on overseas recruitment. AB - Tighter immigration laws are leaving health organisations struggling for staff, particularly to care for older people, the RCN claims. PMID- 28080725 TI - Starting out - conquering your fears is key to helping others overcome theirs. AB - During my time on a surgical ward I was allocated a placement in theatres. As soon as my mentor mentioned it, I felt anxious. I went home and worried all night. I did not know what to expect in theatre. What if I fainted? PMID- 28080724 TI - Yearly medicines management training should be mandatory. AB - A discussion took place at a recent meeting of the Medicines Management Nurses Network Group on the amount of work, time and effort each member of the group had undertaken to reduce the number of reported medication-related errors made by healthcare professionals. PMID- 28080726 TI - Meet students' europe-wide leader. AB - Second-year nursing student Saffron Brown, pictured, will help raise the profile of students across the UK and Europe. PMID- 28080727 TI - Working unpaid overtime is no way to manage workload. AB - Is working extra unpaid hours every week the best way to address heavy workloads (news August 5)? Absolutely not. PMID- 28080730 TI - Methadone prescribing maintenance could be improved, study finds. AB - Important elements of care in provision of methadone maintenance treatment are likely to influence, or indicate, an individual's risk of death. PMID- 28080728 TI - Dig for victory in the worldwide war on fat. AB - I was stressed out by house hunting and still struggling to lose weight when a friend said: 'Make sure your new house has a garden that needs a lot of work. A few hours a week digging flower beds is all you need. Get stuck in to a bit of digging and your weight will drop off.' PMID- 28080731 TI - I disapprove of the policy change on assisted suicide. AB - As an RCN fellow, I share many readers' disappointment about the RCN policy change on assisted suicide. Neutrality signals weak leadership and mixed messages to nurses and patients. PMID- 28080732 TI - Suicide ruling is welcomed, but presents problems too. AB - The Huntington's Disease Association knows only too well that assisted suicide is a complicated issue and fraught with ethical, spiritual and moral dilemmas (news and letters July 29). PMID- 28080735 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28080733 TI - Nurses should beware of putting words in their patients'mouths. AB - While reviewing care plans for patients in care homes recently, I noticed that they were written in the first person singular. PMID- 28080736 TI - Respecting patient choice extends to suicide rights. AB - There is much talk in health care about ensuring that the people we care for have their choices respected. But people in the UK with progressive illnesses are not being offered the choice to die with dignity. PMID- 28080737 TI - RCN is only prepared to take on pre-agenda for change claims. AB - The RCN takes issues of equal pay seriously. However, your article about the college supporting unfair pay claims is misleading (news August 5). PMID- 28080738 TI - Nurses and doctors need to discuss end of life care. AB - I am an RCN fellow and regret the decision of RCN council to adopt a neutral position in the debate on assisted dying. It is questionable whether it is possible to be neutral in such circumstances. Nursing is not carried out in isolation. Nurses are part of a team of practitioners acting in concert for the welfare of patients. PMID- 28080740 TI - Staff suspended over 'anomalies' in A&E waiting time records. AB - A trust investigating irregularities in the recording of A&E waiting times has suspended two of its senior nurses. PMID- 28080739 TI - Developing and implementing an oral care policy and assessment tool. PMID- 28080741 TI - Transition smooth on hours law. AB - The introduction of a European law limiting the number of hours junior doctors can work has gone smoothly and not raised concern among RCN members, according to the college. PMID- 28080742 TI - Student life-Seeing the person. AB - Few people would dispute that education can be an important tool in defeating ageist attitudes. For professionals, however, clinical practice is as important as classroom learning in developing and shaping students' experiences, especially when it comes to caring for older people. PMID- 28080743 TI - Troubled hospital criticised over lack of progress. AB - Efforts to improve care at the troubled Mid Staffordshire NHS Foundation Trust remain blighted by a serious shortage of experienced nurses and a reliance on agency staff. PMID- 28080744 TI - 'We want to go the extra mile'. AB - Guy's and St Thomas' NHS Foundation Trust in London has introduced a range of measures to enhance dignity and respect in patient care. PMID- 28080745 TI - Consultation on alternative therapy regulation launched. AB - Nurses practising acupuncture, or herbal or Chinese medicine, may soon be subject to UK-wide statutory regulation and have to pass an accreditation test. PMID- 28080746 TI - Delivering value for money. AB - World class commissioning (WCC) is a catchphrase made famous by departing health minister Lord Darzi in the Next Stage Review. Such is the importance attached to primary care trusts (PCTs) as commissioners of effective services that the Department of Health (DH) established a major WCC programme for primary care organisations. PMID- 28080747 TI - Leading nurse claims most staff fail to carry out essential checks. AB - The nursing profession needs to confront the failure of nurses to complete essential processes, such as patient observations, a leading nurse director has warned. PMID- 28080749 TI - Crash victim inspired to join profession. AB - Watching healthcare professionals at work as she recovered from a devastating car crash has inspired Rachael Medlock to pursue her dream to be a nurse. PMID- 28080750 TI - Overhaul of mileage allowances will see current system simplified. AB - Recommended mileage rates for NHS staff using personal cars for work could be increased in a bid to simplify the current system, Nursing Standard can reveal. PMID- 28080751 TI - Private healthcare sector shows resilience amid economic gloom. AB - Jennifer Richards is one of a growing number of nurses working in the private sector. PMID- 28080752 TI - Healthcare support staff must be regulated. AB - Every day tens of thousands of dedicated healthcare support workers (HCSWs) provide personal and complex care to patients, often with little supervision and support. PMID- 28080753 TI - Trust's service innovation sees tissue donations soar. AB - Tissue donation at a hospital has increased 40-fold after a nurse combined its bereavement and donation services. PMID- 28080755 TI - Call for probe into deaths from superbug. AB - The Scottish Labour Party is calling for a Scotland-wide investigation into deaths caused by Clostridium difficile. PMID- 28080756 TI - Voices - seize the chance to help shape nursing's future, urges Chris Beasley. AB - The consultation for the prime minister's Commission on the Future of Nursing and Midwifery closed last week and, on behalf of the commission, I would like to thank those of you who responded. There will be more opportunities to get involved in the commission's work through local events over the coming months. PMID- 28080754 TI - David Newnham is living on the wrong side of the digital divide. AB - Everyone says that living in the countryside is good for your health. All those plants pumping out oxygen and coloured a nice, relaxing green. What could be more beneficial? Well, decent mobile phone coverage for a start. PMID- 28080757 TI - 'Improve access to head cancer nurses'. AB - All patients with head and neck cancer should have access to a clinical nurse specialist from diagnosis, a new audit has recommended. PMID- 28080758 TI - Care home sector braced for cuts. AB - The economic downturn could lead to a reduction in the number of long-term care residences, according to Registered Nursing Home Association chief executive officer Frank Ursell. PMID- 28080759 TI - Trusts turn to retired nurses to cope with swine flu pandemic. AB - NHS organisations are reaching out to hundreds of recently retired nurses for help during the influenza A (H1N1) pandemic. PMID- 28080761 TI - Readers panel - painful decisions. AB - Our experts consider a hot topic of the day. PMID- 28080760 TI - Commission analyses submissions on what makes an ideal nurse. AB - The prime minister's Commission on the Future of Nursing and Midwifery is starting to analyse the submissions to its consultation on what makes an ideal nurse. PMID- 28080762 TI - Strategies to improve patients' adherence to medication. PMID- 28080764 TI - A little knowledge can be an irritating thing. AB - There was a time when medical expertise was valued and patients knew little and questioned nothing. Thankfully we have moved on. Patients have a right to an opinion and expect to be given enough information to make informed decisions. PMID- 28080763 TI - WebWise. AB - NHS Choices has set up a swine flu portal for the general public and healthcare professionals. This site is an invaluable and comprehensive resource on influenza A(H1N1) and is being updated on a daily basis during the global pandemic. PMID- 28080765 TI - Health visiting: a critical service. AB - MPs on the House of Commons health committee were surprised recently when then health secretary Alan Johnson suggested that the worsening shortage of health visitors might be partially resolved if they no longer routinely saw individual children and their families. PMID- 28080766 TI - Why does nursing workload spike every ten years? AB - Trends in nursing workload can be analysed by capturing and counting workload data across time. PMID- 28080767 TI - Patients to judge equality council. AB - Patient satisfaction surveys will be used to judge whether the new NHS Equality and Diversity Council is a success, according to the Department of Health (DH). PMID- 28080768 TI - Police, courts and NHS pledge to tackle nurse abuse. AB - Nurses who have been attacked in Suffolk have been promised 'enhanced support' after local authorities signed an agreement to ensure perpetrators are prosecuted where appropriate. PMID- 28080769 TI - No answers. AB - Have you noticed the number of service companies that end their name in 'solutions'? It seems to be the fashion nowadays. PMID- 28080770 TI - Antibiotic resistance in Campylobacter not clinically important. AB - There is no evidence of more severe or prolonged illness in people with quinolone resistant Campylobacter infection, nor evidence of any adverse medium-term consequences. PMID- 28080773 TI - BSc (Hons) in global health and disease. AB - Run by Faculty of Health and Social Care, University of Hull. PMID- 28080771 TI - Risk factors linked to onset of diabetes in later life. AB - Researchers in the United States investigated how lifestyle factors, assessed in combination, relate to the development of diabetes in older adults. In a prospective study over ten years, data on repeated measures of lifestyle factors were collected. PMID- 28080774 TI - The WWDU (Work With Display Units) Conference as a Platform for Occupational Health and Safety in the Past-And as a WWCS (Work With Computer Systems) Conference in the Future. PMID- 28080775 TI - A Comparison of the Legibility of Three Types of Electronic Digital Displays. AB - A series of experiments was carried out to compare the legibility of three different typos of electronic digital display. The three displays, namely the cold cathode, the side illumination and the straight projection types, were examined under varying ambient light levels and viewing positions. The two performance criteria used in the investigations were recognition time for a single digit and accuracy of report of a four digit number. Results indicated that there was little difference between the cold cathode and the straight projection types under the conditions used in the experiment. However, the side illumination display gave a significantly poorer performance score than cither of the two other displays. It was also shown that performance decrements would result if any of the displays wore used in ambient light levels of greater than 22 foot candles. PMID- 28080777 TI - The Design of Non-Linear Scales for Slide Rules. AB - Many school children experience considerable difficulty in reading the 0 scale on conventional slide rules. This investigation sets out to provide design recommendations for a scale of acceptable accuracy which can be understood by children with a wide range of abilities. Eight different scale designs, including the conventional design, were compared at a scale-reading task using secondary modern schoolboys as subjects. The scales were presented in booklet form. Errors in the results are classified as either gross errors, i.e. those caused by misunderstanding, or interpolation errors. Analysis shows that the simplest designs, i.e. those with the fewest gradations and numerals, lead to fewer gross errors, and can be read faster than the conventional design. The simpler designs, however, led to more interpolation errors than the conventional design mainly because interpolation errors were not possible (for three significant figure accuracy) at the lower end of the conventional scales. Inconsistency in the meaning of gradations and numerals in different parts of the scale seems to be the main source of misunderstanding on the conventional design. The recommended scale has gradations at the 0.1 positions and numbering only at the 1,2...10 positions. It is suggested, however, that the introduction of such a simplified scale for school slide rides might meet with some resistance, and a scale with consistent numbering and with gradations at the 0.05 position is recommended as a more acceptable alternative. PMID- 28080778 TI - Mechanical Energy Relationships in Vaulting with a Fibreglass Pole. AB - The performances of the competitors in the polo vault at the 1968 Now Zealand. A.A.A. Championships were studied by means of a motion-picture analysis. For successive stages throughout the best vault recorded by each subject, the subject's kinetic energy of translation, kinetic energy of rotation, potential energy, and total mechanical energy, and the extent of the pole-bend, were computed. Comparison of these parameters between subjects of differing abilities revealed certain characteristics which appeared to be directly associated with the quality of the performance. The best performances were characterised by a pronounced bending of the pole, similar rates of polo-bonding and pole straightening and marked changes in the subject's potential energy and kinetic energy of translation as the pole straightened. PMID- 28080779 TI - Report on an International Event Cost 281/ebea Forum. PMID- 28080781 TI - Improved personal tutor contact with students is complete sense. AB - The news story, 'Personal tutor support from the start reduces student attrition' (September 12), makes complete sense, especially given the high levels of attrition from nursing degree courses. PMID- 28080782 TI - Clinical skills and experience are essential for older people's care. AB - I agree with Bridget Ryan (letters September 5) that simple initiatives such as offering manicures and hand massages can make a world of difference to the inpatient experience. PMID- 28080783 TI - Front line staff would benefit from belonging to a trade union. AB - Nurses are divided over whether the RCN should join the Trades Union Congress (features September 5). PMID- 28080784 TI - PM wants nurses with pretty hats doing 'trolley dolly' rounds. AB - Prime minister David Cameron announced in January that he wanted hourly rounds to be carried out as part of a government drive to improve nursing care (analysis August 22). PMID- 28080785 TI - Regulator to slash number of university inspections. AB - The number of universities receiving inspection visits from the Nursing and Midwifery Council is to be cut drastically, its outgoing chair has said. PMID- 28080786 TI - New posts for well-paid senior staff are the final straw for me. AB - Have you wondered where your pay rise went? Not just on foreign jaunts for ministers, oh no. We are again creating lots of new posts for managers (news September 5). PMID- 28080787 TI - Cameron's care forum chair calls for research into effects of long shists. AB - Nurses should be allowed to take power naps during breaks, according to new guidance on shift patterns due to be published by the RCN next month. PMID- 28080788 TI - A change in attitude is needed towards nurses with disabilities. AB - I have a chronic back condition and my mobility is poor. On qualifying in 2010, I managed to work without taking any sick leave for three months but experienced discriminatory behaviour from colleagues. PMID- 28080789 TI - Athletic achievements should spur us on to meet our own fitness challenge. AB - Four readers panellists were asked if the Olympics and Paralympics will leave a lasting health legacy for the UK (reflections September 12). PMID- 28080790 TI - Rosie Ratcliffe 1944-2012. AB - Renal nurse who died doing what she loved Rosemary (Bud) Downey, known professionally as sister Rosie Ratcliffe, has died aged 67 at Hull Royal Infirmary following a stroke while on duty in the haemodialysis unit. She had been in nursing for 51 years, the past 39 of them as a renal nurse in East Yorkshire. PMID- 28080792 TI - The ideal consultation. AB - The consulting room used to be regarded as the doctor's preserve. Not any longer. Patients are increasingly consulting nurses for advice and treatment, especially in community settings or in the patient's home. PMID- 28080791 TI - Has anyone received support for management strategies training? AB - In these cash-starved times, we nurses, particularly those like myself in specialist practice, should be able to demonstrate our worth. PMID- 28080794 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28080793 TI - World in brief. AB - What's happening in nursing across the globe. PMID- 28080797 TI - Leading centre for research marks 35th year. AB - Nurse academics and policymakers celebrated the 35th anniversary of the influential national nursing research unit in London last week. PMID- 28080798 TI - Webwise. AB - The Museum of Health Care at Kingston in Ontario, Canada, is part of the Ann Baillie Building National Historic Site, a former residence for nursing students built in 1904 in the grounds of Kingston General Hospital. PMID- 28080801 TI - Launch of network for BME leaders. AB - An RCN network comprising former and aspiring black and minority ethnic nurse directors is due to be set up as part of a drive to bolster their dwindling numbers, Nursing Standard has learned. PMID- 28080800 TI - Mid Staffs' L15m deficit sparks financial scrutiny by Monitor. AB - Nurses at the troubled Mid Staffordshire NHS Foundation Trust say they are concerned and surprised after learning their organisation could go into special administration. PMID- 28080802 TI - New health secretary praises NHS workers. AB - Jeremy Hunt (pictured) last week met nurses for the first time since becoming England's health secretary. He was given a tour of St Thomas' Hospital in London and was told about staff training and how nurses look after patients who need extra care. PMID- 28080803 TI - Evidence-based nursing is the cornerstone of our profession. AB - I read with interest nurse Jennie Burch's learning zone article (September 12) on enhanced recovery for patients following colorectal surgery. PMID- 28080804 TI - Nurse prescribers favour seminars to develop skills. AB - Nearly nine out of ten nurse prescribers would attend independent validated educational seminars supported by pharmaceutical companies, a Nursing Standard survey of 2,000 nurses shows. PMID- 28080805 TI - Breakaway success. PMID- 28080807 TI - Women diagnosed with breast cancer who have a high BMI run greater risk of recurrence. AB - Women who are obese when they are diagnosed with the most common form of breast cancer have a higher risk of recurrence and death, suggests a study by American researchers. PMID- 28080808 TI - Balance and strength activities reduce rate of falls in older people. AB - The Lifestyle integrated Functional Exercise (LiFE) approach integrates balance and strength training into normal activities, so that exercises are repeated many times a day. PMID- 28080809 TI - 'I am extremely cautious about the case for regional pay'. AB - Tensions between the Liberal Democrats and the Conservatives have worsened steadily over the summer, and one issue that may provide the catalyst for a split is the future of NHS pay. PMID- 28080810 TI - Manage workplace chaos by building your resilience. AB - Faced with stressful situations, do you go into meltdown or do you adapt and thrive? Overwork, paperwork, and physical and mental exhaustion are part of many nursing jobs, but why do some people cope better than others? PMID- 28080812 TI - Social inequalities have a negative health effect on rich and poor individuals. AB - Living close to a poor area has a negative effect on the health of rich people, suggests an analysis of mortality rates and deprivation in England. PMID- 28080811 TI - All high-risk areas should put measures in place to help address resistance to care. AB - Preventive strategies to reduce resistance to care by patients are required across a range of settings, not just in older people's care, a study by nurse researchers suggests. PMID- 28080813 TI - Waiting room blues. AB - My partner had an altercation recently with two excitable dogs, only one of which belonged to us. Around 70kg of combined dog at speed can cause a lot of damage, especially when they are heading for your chest. PMID- 28080814 TI - Readers panel - Ready for take off. AB - Our experts consider a hot topic of the day. PMID- 28080815 TI - Fine whines. AB - 'Ooh, and my feet at the end of the day. They're so swollen they need their own postcode!' said the waitress. 'I know,' I sympathised. 'Tell me about it.' PMID- 28080816 TI - Our duty of care is from cradle to grave. AB - I recently visited an undertaker friend who was distressed by a body he had received at his chapel of rest. He wanted to know what was happening to nursing, especially the care and respect we show our deceased patients. PMID- 28080817 TI - Changing practice on the basis of evidence. AB - Proving that one nursing intervention or system works better than another has long been a challenge for the profession. Some practice is not grounded in any evidence at all, but rather on a premise that it has always been done in a particular way and is generally considered to be effective. PMID- 28080819 TI - Will the government reshuffle signal a brighter NHS future? AB - The appointment of Jeremy Hunt as health secretary marks not only the end of Andrew Lansley's tenure, but also the halfway point of the coalition government's term in office. PMID- 28080820 TI - Bus ads aim to boost profession's image. AB - An advertising campaign that highlights nurses' unique skills was unveiled on a London bus last week. PMID- 28080821 TI - Voices. AB - More than a thousand buses across the country are now advertising This is Nursing, the RCN's new initiative to promote the nursing profession and tell the public about the challenges you face. PMID- 28080823 TI - Nurses will take lower paid jobs to escape NHS, recruiters claim. AB - Job-seeking nurses have told employers in the independent sector they are willing to take a pay cut to work outside the NHS. PMID- 28080822 TI - Job seekers keen to branch out. AB - Owen Davies, third-year nursing student, University of Surrey 'I am looking to see what is available in the private sector compared with the NHS. But at the end of the day, I just want a job.' PMID- 28080824 TI - A powerful message. PMID- 28080825 TI - Starting out can act as barriers to family bonds i learnt that well-meaning acts. AB - During a second-year placement on a neonatal unit, I helped to look after Abraham, a two-week old boy with congenital heart defects. PMID- 28080827 TI - NMC chair warns council not to rely on fee rise. AB - The outgoing Nursing and Midwifery Council chair warned council members not to base financial decisions on the assumption that the proposed 58 per cent fee increase will be approved. PMID- 28080826 TI - The integumentary system: anatomy, physiology and function of skin. AB - This article, which forms part of the life sciences series, examines the anatomy and physiology of skin, also termed the integumentary system. Skin is composed of two main layers, the epidermis and dermis. The structure of the epidermis and dermis are described and their functions are discussed. Accessory structures, such as nails and hair are also considered. Although many diseases of the skin exist, two common conditions - psoriasis and decubitus ulcers - are described in this article. PMID- 28080828 TI - Lawyer slams vulnerable man's treatment as 'blatant prejudice'. AB - Do not resuscitate orders are frequently being put in the medical files of UK patients with a learning disability without the knowledge or agreement of their families, according to Mencap. PMID- 28080830 TI - People with Parkinson's report little improvement in quality of life following physiotherapy. AB - Physiotherapy has limited benefi ts in people with Parkinson's disease, according to a review of evidence by British researchers. PMID- 28080829 TI - TUC delegates told that 'scroungers' image fuels crime. AB - Hate crimes against people with disabilities are being fuelled by public perceptions that many are 'benefit scroungers', Trades Union Congress delegates heard at their annual conference in Brighton last week. PMID- 28080831 TI - Crossing the line. AB - The dentist is fine about it. And why not? He never does home visits - can you imagine having root canal work at the kitchen table? As long as I can still produce a credit card, why should he care where I live? At the GP surgery, however, it's a different story. PMID- 28080833 TI - From Distillation to Standardization: A French Perspective on the Shaping of Turpentine Spirit (1909-1976). AB - Turpentine is a complex substance of pine resin origin, widely used as a solvent in multiple industries. Attempts to define it, even when elaborated by scientists, have been marked by a whole range of extra-scientific market considerations. While the Pine Institute, a resin chemistry research centre in Bordeaux, succeeded in stabilizing the meaning of the word "turpentine" on the national level in France, its expertise was contested abroad. When the International Organization for Standardization (ISO) Committee 35 tried to establish a new international standard for turpentine, France was accused of protecting its industry by twisting scientific definitions for its own needs. The ISO members clashed over the relationship between trade standards and scientific definitions, at the same time highlighting the epistemological difficulties in constructing both categories. PMID- 28080836 TI - Comments on "Relating Summer Ambient Particulate Sulfur, Sulfur Dioxide, and Light Scattering to Gaseous Tracer Emissions from the MOHAVE Power Project". PMID- 28080834 TI - Low Adherence to Dietary Guidelines in Spain, Especially in the Overweight/Obese Population: The ANIBES Study. AB - OBJECTIVE: The objective of this study was to analyze the dietary intake of the Spanish population according to ponderal status and body fat distribution. METHODS: Data were obtained from ANIBES (Anthropometry, Intake, and Energy Balance in Spain), a cross-sectional study of a nationally representative sample (1013 men, 996 women) of the Spanish population (18-64 years). The final fieldwork was carried out from mid-September to November (three months) 2013. A 3 day dietary record provided information about food and beverage consumption. Height, weight, and waist circumference were assessed, and body mass index (BMI) and waist-height ratio (WHtR) calculated. RESULTS: The Spanish population had a low consumption of fruits and vegetables, cereals, whole cereals, and dairy and high consumption of meat products. Individuals with overweight/obesity (BMI >= 25 kg/m2) and abdominal adiposity (WHtR >= 0.5) showed lower compliance with dietary guidelines. In the male group, adjusting by age, inadequate consumption of cereals (<4 servings/day) and vegetables and fruit (<5 servings/day) was associated with higher risk of overweight (odds ratio [OR] = 1.704, 95% confidence interval [CI], 1.187-2.447, p = 0.001, for cereals and OR = 3.816, 95% CI, 1.947-7.480, p = 0.001, for vegetables and fruits) and abdominal adiposity (OR = 2.081, 95% CI, 1.419-3.053, p = 0.000 and OR = 4.289, 95% CI, 2.108-8.726, p = 0.001, respectively). CONCLUSION: Nutritional campaigns should be conducted to improve the dietary habits of the Spanish population in general, especially men, who have poorer ponderal status and abdominal adiposity, due to their lower adherence to dietary guidelines. PMID- 28080837 TI - Light Scattering Characteristics of Aerosols as a Function of Relative Humidity: Part I-A Comparison of Measured Scattering and Aerosol Concentrations Using the Theoretical Models. AB - The Southeastern Aerosol and Visibility Study (SEAVS) was undertaken to characterize the size-dependent composition, thermodynamic properties, and optical characteristics of the ambient atmospheric particles in the southeastern United States. The field portion of the study was carried out from July 15 to August 25, 1995. As part of the study a relative humidity controlled inlet was built to raise or lower the relative humidity to predetermined levels before the aerosol was passed into an integrating nephelometer or particle-sizing device. Five other integrating nephelometers were operated in various configurations, two of which were fitted with a 2.5 MUm inlet. Fine particle (<2.5 MUm) samplers were operated to measure concentrations of sulfate, nitrate, and ammonium ions, organic and elemental carbon, and fine soil. Mass size distributions were measured with an eight-stage, single orifice cascade impactor. PMID- 28080838 TI - Welcome to a Special Issue from the Specialty Conference on Visual Air Quality, Aerosols, and Global Radiation Balance. PMID- 28080840 TI - Blog gripes. AB - Scoff if you like, but I have only just discovered what a 'blog' is. And having found out, I have been following one of these online threads about modern nurses and their tendency to discriminate. PMID- 28080839 TI - Light Scattering Characteristics of Aerosols at Ambient and as a Function of Relative Humidity: Part II-A Comparison of Measured Scattering and Aerosol Concentrations Using Statistical Models. AB - The eastern United States national parks experience some of the worst visibility conditions in the nation. To study these conditions, the Southeastern Aerosol and Visibility Study (SEAVS) was undertaken to characterize the size-dependent composition, thermodynamic properties, and optical characteristics of the ambient atmospheric particles. It is a cooperative three-year study that is sponsored by the National Park Service and the Electric Power Research Institute and its member utilities. The field portion of the study was carried out from July 15 to August 25, 1995. The study design, instrumental configuration, and estimation of aerosol types from particle measurements is presented in a companion paper. In the companion paper, we compare measurements of scattering at ambient conditions and as functions of relative humidity to theoretical predictions of scattering. In this paper, we make similar comparisons, but using statistical techniques. Statistically derived specific scattering associated with sulfates suggest that a reasonable estimate of sulfate scattering can be arrived at by assuming nominal dry specific scattering and treating the aerosols as an external mixture with ammoniation of sulfate accounted for and by the use of Tang's growth curves to predict water absorption. However, the regressions suggest that the sulfate scattering may be underestimated by about 10%. Regression coefficients on organics, to within the statistical uncertainty of the model, suggest that a reasonable estimate of organic scattering is about 4.0 m2/g. A new analysis technique is presented, which does not rely on comparing measured to model estimates of scattering to evoke an understanding of ambient aerosol growth properties, but rather relies on measurements of scattering as a function of relative humidity to develop actual estimates of f(RH) curves. The estimates of the study average f(RH) curve for sulfates compares favorably with the theoretical f(RH) curve for ammonium bisulfate, which is in turn consistent with the study average sulfate am-moniation corresponding to a molar ratio of NH4/SO4 of approximately one. The f(RH) curve for organics is not significantly different from one, suggesting that organics are weakly to nonhygroscopic. PMID- 28080841 TI - Turning theory into practice. AB - Joy Jones has shown us how managing change requires a good deal of personal stamina, commitment and wisdom. Patient application to a single issue can work wonders. PMID- 28080842 TI - Mid Staffs: how to ensure the mistakes never happen again. AB - NHS organisations must learn from the tragedies that followed cuts in nursing jobs at Stafford Hospital according to England's chief nursing officer Dame Chris Beasley. PMID- 28080843 TI - Landmark deal gives union power to negotiate terms for non-NHS nurses. AB - A landmark recognition agreement has been secured between the RCN and a county council, allowing the college to negotiate terms and conditions for the organisation's nurses. PMID- 28080844 TI - Praise for innovative services. AB - A nurse-led, award-winning bereavement and donor support team has been praised by the prime minister's commission on the future of nursing and midwifery. PMID- 28080845 TI - Fighting talk from midwives. AB - The Royal College of Midwives (RCM) will hold any future Labour government to account about commitments made to the profession. PMID- 28080846 TI - The long road. PMID- 28080847 TI - New regulatory regime will hold managers to account. AB - Managers and non-executive directors could be regulated as a result of the devastating care failures at Mid Staffordshire NHS Foundation Trust. PMID- 28080848 TI - 'Our staff are good people who have been badly led'. AB - Nurses at Mid Staffordshire NHS Foundation Trust will ask patients every two hours if they need pain relief, a drink or toilet assistance. PMID- 28080849 TI - Disseminating best practice through publication in journals. AB - This article, the second in a five-part series, explores the ways in which best practice might be presented successfully through articles published within journals. The article discusses the importance of preparatory research and 'thinking time', the need for an article plan and how to target journals and approach staff. Information and advice is provided on writing, redrafting and dealing with the peer review process. There is an emphasis on consultation and obtaining feedback on the potential article throughout the planning and writing process. PMID- 28080850 TI - Outsidein. AB - I suppose there are people who buy Country Life magazine. I expect they live in vast Georgian houses in Wiltshire. But despite being a frequent reader, I have never paid for a single issue. PMID- 28080851 TI - Voices - Tony Hazell urges nurses to send their views on education to the NMC. AB - This year we have been putting a lot of thought into the nurses of tomorrow as we begin consulting on our proposed changes to pre-registration nurse education. PMID- 28080852 TI - Minister for nursing promises action group to implement commission's 'radical' findings. AB - A future Labour government would implement the recommendations of the prime minister's commission on the future of nursing, health minister Ann Keen has told Nursing Standard. PMID- 28080853 TI - Commission recommendations. AB - 1. Nurses and midwives must declare their commitment to delivering high quality and compassionate care. PMID- 28080854 TI - Nurses must pledge to give quality care. AB - Every nurse and midwife should take a pledge to give high quality and compassionate care, according to the commission on the future of nursing. PMID- 28080856 TI - Trust in my colleagues has been shaken by mid staffs. AB - The Francis report into the failings at Mid Staffordshire NHS Foundation Trust makes for shocking reading. It is clear that there was a failure of management and nursing involving a culture shift, rather than simply a lack of resources. There was a lack of compassion and of basic nursing responsibilities that had nothing to do with understaffing. PMID- 28080857 TI - Webwise. AB - Launched in June 2008, the National Cancer Intelligence Network (NCIN) is the central repository for cancer-related data in the UK, with a number of tools providing information for health professionals, commissioners and public health officials. PMID- 28080858 TI - Better nutrition can come at an affordable price. AB - It was a pleasure to read Lynne Pearce's feature about simple, sensible and cost effective ways to promote nutrition among nursing home residents by offering tempting treats (February 17). PMID- 28080859 TI - Chris Halek mental health nurse 1957- 2010. AB - Mental health nursing has lost one of its most inspirational nursing leaders. Chris Halek RMN, BA (Hons), MPA, director of nursing at Coventry and Warwickshire NHS Partnership Trust, died on February 6 at the age of 53 from ovarian cancer. PMID- 28080861 TI - Putting patients first. AB - It may be a coincidence that the prime minister's nursing commission issued its recommendations just days after Robert Francis published his verdict into why hundreds of patients died unnecessarily at Stafford Hospital. However, the publication of two high-profile reports on the state of nursing in such quick succession could hardly be more timely. PMID- 28080860 TI - Psychosocial care loses out because of time constraints. AB - In his excellent learning zone article (February 17), Mark Haddad concludes that nurses are central to care delivery for people living with depression associated with long-term conditions. He discusses the essential capabilities that healthcare staff need to demonstrate for people to speak candidly about their illnesses. PMID- 28080862 TI - Attrition could be curbed by more high quality mentors. AB - Your analysis article on nursing student attrition rates (February 17) raises concerns about the ways we are training and treating our students. PMID- 28080863 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28080864 TI - A nursing education is about more than writing essays. AB - The analysis article on student attrition (February 17) made for grim reading and I was deeply sorry to read that former student Dan Bartlett's placement reports counted for nothing. PMID- 28080866 TI - Standardised training is key for healthcare assistants. AB - Jayne Thomas says healthcare assistant (HCA) training has always been on the job and should remain so (letters February 17). But a recent study and Nursing Standard survey (news February 10) reveal that many HCAs are not receiving training in personal care or basic hygiene. PMID- 28080867 TI - Smoking cessation after early diagnosis can be beneficial. AB - There is preliminary evidence that smoking cessation after diagnosis of early stage lung cancer improves prognosis. Offering smoking cessation treatment to patients presenting with early stage lung cancer can help. PMID- 28080868 TI - Rectal irrigation for patients with functional bowel disorders. PMID- 28080870 TI - Give sisters visible authority. AB - Prime minister Gordon Brown, pictured, has supported a call for the visible authority of the ward sister to be reinstated. PMID- 28080869 TI - Commission report underlines the need to enhance ward leaders'role. AB - The prime minister's commission on the future of nursing and midwifery has called on the government and the NHS to strengthen nurse leadership at ward and board level. PMID- 28080871 TI - Protein should be added to dietary advice on diabetes. AB - Diets high in animal protein are associated with an increased risk of developing diabetes. There may also be an association for total protein rather than only animal sources. Consumption of energy from protein at the expense of carbohydrate or fat may similarly increase diabetes risk. PMID- 28080873 TI - Wound sepsis reduced when chlorhexidine is used as skin prep. AB - Pre-operative skin cleaning with chlorhexidine-alcohol is superior to povidone iodine for preventing surgical site infections after clean-contaminated surgery. PMID- 28080874 TI - Buddies help find the way. AB - 'We were given a map of the hospital and told to find our own way,' is one comment from a third-year student nurse recalling her experience of a first-year placement. PMID- 28080875 TI - My ambition is to harness nurses'passion and talent. PMID- 28080876 TI - The NHS should take the blame for credibility gap. AB - Much space is devoted to what is wrong with nurse education (editorial, news, analysis and letters February 17). But the issues of student attrition and the credibility of educators are two old chestnuts that have been knocking around for decades. PMID- 28080878 TI - Mixed reception for dual roles. AB - Former NHS chief executive Nigel Crisp wrote to a national newspaper last month calling for more health service staff to be trained to carry out specific tasks. PMID- 28080879 TI - Administering medication to adult patients with dysphagia:part 2. PMID- 28080880 TI - The ultimate gift. PMID- 28080881 TI - Starting out - Time is no barrier to forming a close nurse-patient relationship. AB - My first placement was on a surgical ward. One day I helped a nurse bed bath a patient. I had just come back from my day off and had never seen this patient before. PMID- 28080882 TI - New test can rapidly identify the cause of bacterial sepsis. AB - Definitive identification of bacterial species using a new molecular sepsis assay is highly sensitive, specific and faster than the gold standard culture based method. PMID- 28080883 TI - A good place to be. AB - The largest supplier of graduates to the health service in north east England has a nurse at its helm. Professor Kathleen McCourt is six months into her role as dean of the school of health, community and education at Northumbria University. PMID- 28080884 TI - Assisted suicide guidance wins support of palliative care nurses. AB - Nurses could be prosecuted if they help patients to take their own lives, guidance from the Crown Prosecution Service (CPS) confirms. PMID- 28080885 TI - It seems that the defining role of caring is no longer our domain. AB - NHS boards in Wales are to cut a number of staff at bands 5 and above (news February 17) and replace them with healthcare support workers (HCSWs). Strategic health authorities in England are cutting commissions for nursing students and receptionists are being trained by doctors in their surgeries to adopt nurse roles (news February 15). PMID- 28080886 TI - Readers panel - job security comes at a price. AB - Our experts consider a hot topic of the day. PMID- 28080887 TI - Arthritis specialists being 'under-used'. AB - Specialist nurses can enhance treatment of patients with rheumatoid arthritis, according to an influential group of MPs. PMID- 28080889 TI - Booking a time for treatment. AB - Carrie Ross, pictured, was chemotherapy lead nurse at Harrogate and District NHS Foundation Trust, North Yorkshire, when she had an idea for a staff/patient scheduling system that electronically books patients for their treatments according to the availability and competence of staff. PMID- 28080888 TI - Embarrassing problem? Show it to television viewers. AB - 'You lose all your dignity don't you? How often have we heard those words? Few of us are perfect physical specimens and the disrobing required for many procedures can discourage patients from attending. Like most people, I do my best to keep loss of dignity to a minimum, but I was somewhat nonplussed when preparing to do a smear when the patient asked 'can you do it without looking?' This was a request made in all seriousness and, although I hated to admit to a weakness in my repertoire, I had to say no. PMID- 28080890 TI - Standards body will assess care. AB - An NHS watchdog will begin detailed assessment of care improvements needed at Stafford Hospital this month and says its staffing levels still cause concern. PMID- 28080892 TI - Local pay system in doubt as unions urge staff to opt out. AB - Staff at the only NHS trust with a grading system that differs markedly from Agenda for Change (AfC) are being encouraged by unions to transfer to the national pay bands. PMID- 28080896 TI - TRAUMATIC (FOREIGN BODY) PERICARDITIS IN A TOCO TOUCAN (RAMPHASTOS TOCO). AB - An approximately 10-yr-old, captive-born female toco toucan ( Ramphastos toco ) was presented due to an acute onset of depression and apathy. On visual and physical examination, it showed an abnormal posture and dehydration, respectively. Serum biochemistry revealed hyperuricemia (39.4 mg/dl) and elevated glutamic oxaloacetic transaminase (GOT; 1,050 U/L). Radiographs demonstrated an enlargement of the cardiac silhouette. The bird died 7 days after presentation, despite treatment with enrofloxacin, allopurinol, a preparation of hepatorenal protectors, and complex B vitamins with dextrose. Necropsy revealed severe fibrinohemorrhagic pericarditis with a 15 mm long and 2.5 mm diameter, rigid foreign body in the pericardial exudate. Microscopically, this foreign body was of vegetal origin. PMID- 28080897 TI - RADIOGRAPHIC CARDIAC SILHOUETTE MEASUREMENT IN CAPTIVE LIVINGSTONE'S FRUIT BATS (PTEROPUS LIVINGSTONII). AB - Cardiomyopathies have been increasingly noted in the captive population of Livingstone's fruit bat ( Pteropus livingstonii ). The aim of this study was to produce a set of repeatable quantitative reference measurements that could be used to assess the cardiac size during radiographic examination of this species. Ventro-dorsal and lateral radiographs (n = 129) from a total of 42 individual Livingstone's fruit bats were examined. The control group radiographs (n = 102) consisted of 34 healthy individuals. Radiographic measurements were taken of structures within the thorax and then converted into ratios. These ratios from radiographs (n = 27) were also calculated for eight individuals with diagnosed cardiomyopathy. Vertebral Heart Scores (VHS) were calculated from right lateral radiographs and compared between the two groups. From all the data, only the width of the cardiac silhouette to the width of the thorax (the W : T ratio) in the ventro-dorsal view and the VHS were found to be significantly different between both groups (P < 0.05). The group with cardiomyopathies had a mean W : T ratio of 0.59 (+/-0.005) and a VHS of 9.77 (+/-0.89), while a mean W : T ratio of 0.54 (+/-0.004) and a VHS of 8.71 (+/-0.93) was established for healthy specimens. PMID- 28080899 TI - HEALTH AND NUTRITIONAL ASSESSMENT OF FREE-RANGING EASTERN INDIGO SNAKES (DRYMARCHON COUPERI) IN GEORGIA, UNITED STATES. AB - Clinical pathology and nutritional parameters are useful in evaluating and monitoring threatened and endangered wildlife populations, but reference ranges for most snake species are lacking. From 2001 to 2005, health assessments were performed on 58 eastern indigo snakes (EIS) (Drymarchon couperi) captured in the wild in southeastern Georgia, United States. Health and nutritional assessments performed included hematology, serum biochemistry, fat-soluble vitamins, heavy metals, pesticide contaminants, parasitology, and surveys of other pathogens. Significant differences in total solids, packed cell volume, glucose, blood urea nitrogen, albumin : globulin ratio, amylase, triglycerides, and bile acids between males and females were observed. Additionally, there was a significant difference between liver and kidney concentrations for vitamins A and E. As previously noted in captive EIS, total Ca was elevated in comparison to concentrations reported in other snake species. Parasitism was a common finding in sampled EIS, but the overall health status of this free-ranging population appeared good. A winter-time dermatitis was found in most snakes, which resolved in the summer months. This study represents the first health and nutritional assessment of free-ranging EIS, and provides needed data to guide monitoring and conservation efforts. PMID- 28080901 TI - CEREBELLAR AND MESENCEPHALON NEOPLASIA IN A NILE HIPOPPOTAMUS (HIPPOPOTAMUS AMPHIBIOUS). AB - A 52-yr-old female Nile hippopotamus ( Hippopotamus amphibious ) was presented for acute onset anorexia, depression, lethargy, instability, and weakness in the pelvic limbs. Clinical signs were rapidly progressive, despite empiric therapy with anti-inflammatory medications, resulting in the death of the animal. Gross necropsy evaluation revealed two tan, firm masses in the cerebellum and mesencephalon and a single mass in the right cranial adrenal gland. All three masses had a similar histologic morphology, and immunohistochemical investigation confirmed the general diagnosis of an adenocarcinoma, but the exact cell of origin remains unclear. In addition, there was evidence of neuroendocrine differentiation in the adrenal gland and not in the brain. These findings suggest either two distinct neoplastic populations or a metastasizing adenocarcinoma with focal endocrine differentiation. In dogs, anal sac and clitoral adenocarcinomas have been reported to undergo focal endocrine differentiation, and both can cause widespread metastasis while the primary lesion can be small. A small neoplasm of these glands may have been missed on gross examination. PMID- 28080903 TI - STRESS LEVELS IN CAPTURED RIVER OTTERS (LONTRA CANADENSIS) DECREASED AFTER TRANSPORTATION TO REINTRODUCTION SITES. AB - The level of stress that animals endure during capture, handling, transportation, and release processes is a major concern of animal reintroduction projects. Animals under chronic stress are more susceptible to disease and other deleterious issues that could reduce their survival in a new environment. Northern river otters ( Lontra canadensis ) have been reintroduced in 22 states in the United States and may be susceptible to developing chronic stress during the reintroduction process. We assessed stress levels in five river otters captured from wild populations in Washington, held in captivity for up to 21 days, and then transported to New Mexico for reintroduction. Glucocorticoid levels in fecal samples of all otters tested decreased from when they were held captive in Washington to the time of release. This outcome suggests that habituation to captivity before transport and release may serve to minimize the likelihood of an otter being released while experiencing a potentially burdensome level of stress. PMID- 28080902 TI - A SEROLOGIC AND POLYMERASE CHAIN REACTION SURVEY OF EQUINE HERPESVIRUS IN BURCHELL'S ZEBRAS (EQUUS QUAGGA), HARTMANN'S MOUNTAIN ZEBRAS (EQUUS ZEBRA HARTMANNAE), AND THOMSON'S GAZELLES (EUDORCAS THOMSONII) IN A MIXED SPECIES SAVANNAH EXHIBIT. AB - Reports of equine herpesvirus (EHV) 1 and EHV-9 causing clinical disease in a wide range of species have been well documented in the literature. It is thought that zebras are the natural hosts of EHV-9 both in the wild and in captive collections. Concerns about potential interspecies transmission of EHV-1 and EHV 9 in a mixed species savannah exhibit prompted serologic and polymerase chain reaction surveys. Eighteen Burchell's zebras ( Equus quagga ), 11 Hartmann's mountain zebras ( Equus zebra hartmannae), and 14 Thomson's gazelles ( Eudorcas thomsonii ) cohabitating the same exhibit were examined for EHV-1 virus neutralization titers, and evidence of virus via EHV 1-5 polymerase chain reactions. None of the animals had previous exposure to vaccination with EHV-1 or EHV-4. All tested zebras had positive EHV-1 titers, ranging from 4 to 384. All zebras and Thomson's gazelles had negative polymerase chain reaction results for all targeted equine herpesviruses. EHV-9-specific assays are not available but EHV-1, EHV-4, and EHV-9 cross-react serologically. Positive serology results indicate a potential latent equine herpesvirus in the zebra population, which prompted initiation of an equine herpesvirus vaccine protocol, changes in pregnant zebra mare management, and equine herpesvirus polymerase chain reaction screening prior to shipment to or from the study site. PMID- 28080904 TI - PHOTORECEPTOR DEGENERATION IN A MOUNTAIN LION CUB (PUMA CONCOLOR). AB - An orphaned 4-mo-old female mountain lion cub ( Puma concolor ) was captured along the coastline in Montana de Oro State Park in Los Osos, California, USA. Following suspicion that the cub was visually impaired, ophthalmic examination revealed diffuse bilateral retinal atrophy. Due to a poor prognosis, humane euthanasia was elected. Necropsy and histopathological findings were consistent with photoreceptor degeneration. Based on the cub's signalment, history, and histopathology, a genetic or nutritional etiology was suspected, with the former etiology more strongly supported. To the authors' knowledge, this is the first report of photoreceptor degeneration in a wild felid and should be considered in cases of blindness. PMID- 28080905 TI - PLASMA PROTEIN ELECTROPHORESIS AND SELECT ACUTE PHASE PROTEINS IN HEALTHY BONNETHEAD SHARKS (SPHYRNA TIBURO) UNDER MANAGED CARE. AB - Preventative health care of elasmobranchs is an important but understudied field of aquatic veterinary medicine. Evaluation of inflammation through the acute phase response is a valuable tool in health assessments. To better assess the health of bonnethead sharks ( Sphyrna tiburo ) under managed care, normal reference intervals of protein electrophoresis (EPH) and the acute phase proteins, C-reactive protein (CRP) and haptoglobin (HP), were established. Blood was collected from wild caught, captive raised bonnethead sharks housed at public aquaria. Lithium heparinized plasma was either submitted fresh or stored at -80 degrees C prior to submission. Electrophoresis identified protein fractions with migration characteristics similar to other animals with albumin, alpha-1 globulin, alpha-2 globulin, beta globulin, and gamma globulin. These fractions were classified as fractions 1-5 as fractional contents are unknown in this species. Commercial reagents for CRP and HP were validated for use in bonnethead sharks. Reference intervals were established using the robust method recommended by the American Society for Veterinary Clinical Pathology for the calculation of 90% reference intervals. Once established, the diagnostic and clinical applicability of these reference intervals was used to assess blood from individuals with known infectious diseases that resulted in systemic inflammation and eventual death. Unhealthy bonnethead sharks had significantly decreased fraction 2, fraction 3, and fraction 3:4 ratio and significantly increased fraction 5, CRP, and HP. These findings advance our understanding of elasmobranch acute phase inflammatory response and health and aid clinicians in the diagnosis of inflammatory disease in bonnethead sharks. PMID- 28080906 TI - ORAL SQUAMOUS CELL CARCINOMA IN AN AGED CAPTIVE WHITE RHINOCEROS (CERATOTHERIUM SIMUM). AB - A 48-yr-old captive white rhinoceros ( Ceratotherium simum ) was euthanized due to old age, pododermatitis, and progressive laminitis of the middle toe of the left fore- and hindlimbs. Severe chronic necrotizing periodontitis and dental loss was diagnosed, although food intake prior to death had not decreased. In addition, extensive ulceration of the tongue was noted. Histologically, squamous cell carcinoma of the tongue was diagnosed with chronic severe ulcerative glossitis. Metastatic lesions were not detected. Clinicians should monitor the oral health of aging rhinoceros due to the occult nature of these lesions. PMID- 28080907 TI - UNSEDATED COMPUTED TOMOGRAPHY FOR DIAGNOSIS OF PELVIC CANAL OBSTRUCTION IN A LEOPARD GECKO (EUBLEPHARIS MACULARIUS). AB - An adult leopard gecko ( Eublepharis macularius ) presented for lethargy, hyporexia, weight loss, decreased passage of waste, and a palpable caudal coelomic mass. Computed tomography showed a heterogeneous hyperattenuating (~143 Hounsfield units) structure within the right caudal coelom. The distal colon coprodeum lumen or urinary bladder was hypothesized as the most likely location for the heterogeneous structure. Medical support consisted of warm water and lubricant enema, as well as a heated environment. Medical intervention aided the passage of a plug comprised centrally of cholesterol and urates with peripheral stratified layers of fibrin, macrophages, heterophils, and bacteria. Within 24 hr, a follow-up computed tomography scan showed resolution of the pelvic canal plug. PMID- 28080908 TI - ANTIDOG IgG SECONDARY ANTIBODY SUCCESSFULLY DETECTS IgG IN A VARIETY OF AQUATIC MAMMALS. AB - Serological tests play an important role in the detection of wildlife diseases. However, while there are many commercial assays and reagents available for domestic species, there is a need to develop efficient serological assays for wildlife. In recent years, marine mammals have represented a wildlife group with emerging infectious diseases, such as influenza, brucellosis, and leptospirosis. However, with the exception of disease-agent-specific assays or functional assays, few reports describe the use of antibody detection assays in marine mammals. In an indirect enzyme-linked immunoassay (EIA) or an immunofluorescence assay, antibody is detected using an antitarget species secondary conjugated antibody. The sensitivity of the assay depends on the avidity of the binding reaction between the bound antibody and the detection antibody. A commercial polyclonal antidog IgG conjugated antibody was tested in an EIA for its ability to sensitively detect the IgG of seven marine mammals including sea otter ( Enhydra lutris ), polar bear ( Ursus maritimus ), grey seal ( Halichoerus grypus ), harbor seal ( Phoca vitulina ), northern elephant seal ( Mirounga angustirostris ), California sea lion ( Zalophus californianus ), Pacific walrus ( Odobenus rosmarus ) and one freshwater mammal: Asian small-clawed otter ( Aonyx cinerea ). With the exception of Asian small-clawed sea otters, the detection of IgG in these marine mammals either exceeded or was nearly equal to detection of dog IgG. The use of the tested commercial antidog IgG antibody may be a valid approach to the detection of antibody response to disease in sea mammals. PMID- 28080910 TI - USE OF COMPUTED TOMOGRAPHY FOR INVESTIGATION OF RHINITIS AND SINUSITIS IN A GREATER RHEA (RHEA AMERICANA). AB - Sinusitis is a common finding in avian species; however, it presents unique treatment challenges in ratites. A 6-yr-old male greater rhea ( Rhea americana ) presented acutely with right infraorbital sinus swelling and chemosis. Oral antibiotics were prescribed based on bacterial culture results with incomplete resolution of clinical signs. A computed tomography scan of the skull demonstrated a mixed-density soft tissue mass with extensive destruction of the right nasal bone, hard palate, maxilla, and frontal bone. The affected tissue was surgically resected and histopathology was consistent with inspissated necrotic tissue. Aerobic culture of the mass grew a multidrug-resistant Escherichia coli and was treated with amikacin. Ten months postsurgery, no further clinical signs were observed. Advanced diagnostic imaging with computed tomography and surgical therapy facilitated complete resolution of this resistant bacterial sinusitis in a species that is not typically amenable to frequent handling and restraint. PMID- 28080911 TI - EVALUATION OF IN-HOUSE URINE DIPSTICK, REFERENCE LABORATORY URINALYSIS, AND URINE PROTEIN: CREATININE RATIO FROM A COLONY OF CALLIMICOS (CALLIMICO GOELDII). AB - This study evaluated results from an in-house (IH) laboratory dipstick, a reference laboratory (RL) urinalysis, and urine protein : creatinine (UPC) ratios from callimicos ( Callimico goeldii ). Urine was collected from 25 individuals comprising a single colony under professional care in North America and compared based on laboratory, sex, age class, and presence or absence of a normal urinalysis. Urine specific gravity and pH between laboratories were statistically different. Overall, 56% to 100% of animals had at least a trace amount of protein in their urine. In comparing normal and abnormal urinalyses, IH dipstick protein, RL dipstick protein, RL pH, quantitative protein measurement, and UPC ratios were all statistically different. Eleven animals (44%) had UPC ratios that were >=0.5. Based on results of this study, UPC > 0.3 was found to be abnormal and supportive of renal compromise in callimicos. Higher protein concentrations on the IH dipstick, the quantitative protein concentration, and UPC ratio in the 1- to 4-yr old age class were the only significant age-related differences. There was no association between any categorical variable (glucose, blood, bilirubin, ketones, urobilinogen) and abnormal urinalysis. There were no differences between sexes. Since renal disease is a major cause of morbidity and mortality in this species, the authors recommend including routine urinalyses and UPC ratios as part of preventive care programs for callimicos. These data provide the first published information on urinalysis and UPC ratios in callimicos and will serve as a helpful reference for interpreting results and evaluating patients with renal disease. PMID- 28080912 TI - COMPARISON OF MEDETOMIDINE-KETAMINE AND BUTORPHANOL-AZAPERONE-MEDETOMIDINE IN CAPTIVE BENNETT'S WALLABIES (MACROPUS RUFOGRISEUS). AB - The objective of this study was to compare a traditional partially reversible medetomidine-ketamine sedation with a more reversible butorphanol-azaperone medetomidine combination in Bennett's wallabies ( Macropus rufogriseus ) maintained in a zoological collection. Fourteen animals were divided into two treatment groups. Individuals in group 1 received an intramuscular (i.m.) injection of butorphanol (0.54 +/- 0.05 mg/kg), azaperone (0.22 +/- 0.02 mg/kg), and medetomidine (0.16 +/- 0.02 mg/kg). Individuals in group 2 received an i.m. injection of ketamine (5.43 +/-1.16 mg/kg) with medetomidine (0.05 +/- 0.014 mg/kg). For group 1, sedation was reversed with atipamezole (0.81 +/- 0.069 mg/kg i.m.) and naltrexone (1.08 +/- 0.09 mg/kg i.m.). For group 2, sedation was reversed with atipamezole (0.27 +/- 0.056 mg/kg i.m.). There were no significant differences between the groups in mean time to induction, time spent on gas anesthesia, or time to standing after reversal was administered. Animals in both groups required supplemental gas anesthesia to facilitate intubation. No adverse reactions or effects were noted with either protocol; however, the BAM protocol did not provide sufficient sedation for handling in all animals and may not be suitable for use in this species. PMID- 28080913 TI - LIVER ULTRASONOGRAPHY IN DOLPHINS: USE OF ULTRASONOGRAPHY TO ESTABLISH A TECHNIQUE FOR HEPATOBILIARY IMAGING AND TO EVALUATE METABOLIC DISEASE-ASSOCIATED LIVER CHANGES IN BOTTLENOSE DOLPHINS (TURSIOPS TRUNCATUS). AB - The objective of this study was to establish a comprehensive technique for ultrasound examination of the dolphin hepatobiliary system and apply this technique to 30 dolphins to determine what, if any, sonographic changes are associated with blood-based indicators of metabolic syndrome (insulin greater than 14 MUIU/ml or glucose greater than 112 mg/dl) and iron overload (transferrin saturation greater than 65%). A prospective study of individuals in a cross sectional population with and without elevated postprandial insulin levels was performed. Twenty-nine bottlenose dolphins ( Tursiops truncatus ) in a managed collection were included in the final data analysis. An in-water ultrasound technique was developed that included detailed analysis of the liver and pancreas. Dolphins with hyperinsulinemia concentrations had larger livers compared with dolphins with nonelevated concentrations. Using stepwise, multivariate regression including blood-based indicators of metabolic syndrome in dolphins, glucose was the best predictor of and had a positive linear association with liver size (P = 0.007, R2 = 0.24). Bottlenose dolphins are susceptible to metabolic syndrome and associated complications that affect the liver, including fatty liver disease and iron overload. This study facilitated the establishment of a technique for a rapid, diagnostic, and noninvasive ultrasonographic evaluation of the dolphin liver. In addition, the study identified ultrasound detectable hepatic changes associated primarily with elevated glucose concentration in dolphins. Future investigations will strive to detail the pathophysiological mechanisms for these changes. PMID- 28080914 TI - TRICAINE METHANESULFONATE (MS-222) SEDATION AND ANESTHESIA IN THE PURPLE-SPINED SEA URCHIN (ARBACIA PUNCTULATA). AB - The purple-spined sea urchin ( Arbacia punctulata ) is commonly found in shallow waters of the western Atlantic Ocean from the New England area of the United States to the Caribbean. Sea urchins play a major role in ocean ecology, echinoculture, and biomedical research. Additionally, sea urchins are commonly displayed in public aquaria. Baseline parameters were developed in unanesthetized urchins for righting reflex (time to regain oral recumbency) and spine response time to tactile stimulus. Tricaine methanesulfonate (MS-222) was used to sedate and anesthetize purple-spined sea urchins and assess sedation and anesthetic parameters, including adhesion to and release from a vertical surface, times to loss of response to tactile stimulus and recovery of righting reflex, and qualitative observations of induction of spawning and position of spines and pseudopodia. Sedation and anesthetic parameters were evaluated in 11 individuals in three circumstances: unaltered aquarium water for baseline behaviors, 0.4 g/L MS-222, and 0.8 g/L MS-222. Induction was defined as the release from a vertical surface with the loss of righting reflex, sedation as loss of righting reflex with retained tactile spine response, anesthesia as loss of righting reflex and loss of tactile spine response, and recovery as voluntary return to oral recumbency. MS-222 proved to be an effective sedative and anesthetic for the purple-spined sea urchin at 0.4 and 0.8 g/L, respectively. Sodium bicarbonate used to buffer MS-222 had no measurable sedative effects when used alone. Anesthesia was quickly reversed with transfer of each individual to anesthesia free seawater, and no anesthetic-related mortality occurred. The parameters assessed in this study provide a baseline for sea urchin anesthesia and may provide helpful comparisons to similar species and populations that are in need of anesthesia for surgical procedures or research. PMID- 28080915 TI - DORSAL LAMINECTOMY TO RELIEVE SPINAL CORD COMPRESSION IN A CAPTIVE SYRIAN BEAR (URSUS ARCTOS SYRIACUS). AB - A 19-yr-old captive male Syrian bear ( Ursus arctos syriacus) presented with a right hind limb lameness that progressed to nonambulatory paraparesis over the course of 2 wk. When night enclosure confinement and a short course of glucocorticoids and antibiotics did not lead to improvement, radiographs were performed, followed by cerebrospinal fluid analysis and myelography, revealing a dynamic spinal cord compression at the level of T2-T3. Dorsal laminectomy of both T2 and T3 was performed to allow decompression. The bear recovered uneventfully with first sign of neurological improvement apparent at 10 days postoperatively. Following 6 mo of rehabilitation the bear was walking and using his hind limbs normally. PMID- 28080916 TI - AEROBIC MICROFLORA AND ENDOPARASITES OF FRESHLY SHOT WILD AGOUTI (DASYPROCTA LEPORINA) IN TRINIDAD, WEST INDIES. AB - The agouti ( Dasyprocta leporina ) is a New World wild rodent hunted for its meat in Trinidad and other Latin American countries. Studies on agouti under captive conditions have yielded some data on health-related aspects, but relatively very little is known about their wild counterparts. The environment of the agouti can influence the microflora and parasites harbored by the animals, which may contain zoonotic pathogens. Here, the microflora found on the nasal mucosa and sections of the intestinal tract and endoparasites of freshly shot agouti from various areas of Trinidad are described. Staphylococcus epidermidis , S. intermedius , Bacillus spp., Enterobacter spp. and Escherichia coli comprised the majority of bacteria isolated from the nasal mucosa whereas Escherichia coli , Streptococcus viridans, Bacillus spp. and Klebsiella pneumoniae were predominant in all sections of the intestinal tract. The fungi Aspergillus fumigatus , Aspergillus spp., Candida spp., Penicillium spp., and Mucor spp. were only isolated from the nasal cavity but not in any section of the intestinal tract. The parasites Strongyloides spp., Ascaridia spp., a hookworm, a trematode, and Trichuris spp. were detected at variable frequencies in each of the sections of the intestines (small intestine, large intestine, caecum), whereas Eimeria spp. were found in all sections (76.9%, 10 of 13 agoutis). These wild agoutis were presumably healthy at the time of death and represent animals that hunters may encounter. Some of the detected pathogens and parasites have the potential to cause opportunistic infections or infestations, especially in immune-compromised hosts. PMID- 28080917 TI - RESULTS OF THE MEGAVEREBRATE ANALGESIA SURVEY: GIRAFFE AND HIPPOPOTAMUS. AB - Results of an online survey posted on the American Association of Zoo Veterinarians listserv examined the patterns of analgesic medication and pain management modalities used for captive giraffe and hippopotami. Compiled data included signalment, drugs administered, dosing regimens, subjective efficacy scores, ease of administration, and adverse events. Nineteen institutions exhibiting hippopotami ( Hippopotamus amphibious ) and pygmy hippopotami (Choeropsis liberiensis) and 45 exhibiting giraffe ( Giraffa camelopardalis spp.) responded. Phenylbutazone was the most-commonly administered nonsteroidal anti inflammatory drug (NSAID), followed by flunixin meglumine, but doses varied widely. Eight institutions reported adverse events from NSAID administration. Tramadol was the most-commonly administered opioid followed by butorphanol. Only one adverse event was reported for opioids. Twenty-three of 45 institutions exhibiting giraffe utilized alternative analgesia methods including gabapentin, glucosamine-chondroitin, local anesthetics, and low level laser therapy. Six of 19 institutions exhibiting hippopotami administered omega 3-6 fatty acids, gabapentin, glucosamine-chondroitin, and alpha-2 adrenergics to provide analgesia. While all reporting zoological institutions administered similar drugs, there was substantial variation and diversity in both dosing regimens and frequencies, indicating the need for both preclinical and clinical studies supporting dosing regimens. PMID- 28080918 TI - HIGH PREVALENCE OF INTESTINAL ADENOCARCINOMA IN A CAPTIVE POPULATION OF AMAZON MILK FROG (TRACHYCEPHALUS RESINIFICTRIX). AB - : A series of eight cases of intestinal adenocarcinoma in Amazon milk frog (Trachycephalus resinifictrix) is described. All cases presented with signs of inappetence and weight loss, and evidence of large intestinal distention on gross postmortem, with six of the eight cases showing a grossly visible large intestinal mass. Histologic examination identified the mass as an intestinal adenocarcinoma in all cases. No specific etiologic agent could be identified. This is the first report of neoplasia in the Amazon milk frog, and the first reported series of amphibian gastrointestinal neoplasia. PMID- 28080919 TI - RESTRICTIVE CARDIOMYOPATHY AND SECONDARY CONGESTIVE HEART FAILURE IN A MCDOWELL'S CARPET PYTHON (MORELIA SPILOTA MCDOWELLI). AB - Echocardiography is an established and noninvasive diagnostic tool used in herpetologic cardiology. Various cardiac lesions have been previously described in reptiles with the exception of restrictive cardiomyopathy. In this case report, restrictive cardiomyopathy and congestive heart failure associated with left atrial and sinus venosus dilation were diagnosed in a 2-yr-old captive lethargic McDowell's carpet python ( Morelia spilota mcdowelli), based on echocardiographic, Doppler, and histopathologic examinations. This cardiomyopathy was also associated with thrombosis within the sinus venosus. PMID- 28080920 TI - PHAEOHYPHOMYCOSIS ASSOCIATED WITH OSSIFICATION OF THE SKULL AND CERVICAL VERTEBRAE IN A SWELL SHARK (CEPHALOSCYLLIUM VENTRIOSUM). AB - A female, captive bred, juvenile swell shark ( Cephaloscyllium ventriosum ) was observed swimming in tight circles and rolling. Radiographs and computed tomography of this individual revealed extensive cartilage mineralization of the skull and cranial cervical vertebrae compared with diagnostic images of clinically healthy conspecifics. Gross necropsy and histopathologic examination revealed ossification and fibrosis of the cartilaginous matrix of the skull and cervical vertebrae with deep invasion by a pigmented hyphal fungus. There was no growth on fungal culture, but fungal polymerase chain reaction identified a DNA sequence compatible with Exophiala sp. (99%). Radiographs and computed tomography were helpful to determine a prognosis and course of action for this individual. This case emphasizes the need to include fungal infections as a differential diagnosis when evaluating elasmobranchs with abnormal swimming behaviors and mineralization of the skeletal structures. PMID- 28080921 TI - UTERINE ADENOMYOSIS AND AN ENDOMETRIAL POLYP IN A ROCK HYRAX (PROCAVIA CAPENSIS). AB - An 8-yr-old nulliparous, female rock hyrax ( Procavia capensis ) had intermittent mucoid to bloody discharge late winter-early spring for two consecutive years. Fragments of necrotic tissue, suspected to be vaginal or rectal in origin, were passed on two occasions. Physical examination, radiographs, and ultrasound did not identify the source of the tissue. Exploratory laparotomy and ovariohysterectomy were performed. On histopathology, a diagnosis of adenomyosis with a uterine polyp was made. Postsurgical complications included incisional infection and renal compromise that were medically managed and resolved. No further vaginal discharge was observed. This is the first report of uterine adenomyosis and endometrial polyp in a rock hyrax. PMID- 28080922 TI - SOLITARY OSTEOCHONDROMA OF THE DISTAL THIRD METACARPAL BONE IN A TWO-YEAR-OLD WHITE RHINOCEROS (CERATOTHERIUM SIMUM). AB - A privately owned, 2-yr-old, 600-kg, intact male white rhinoceros presented with a progressive lameness of the left front limb of 8-mo duration with a focal swelling situated over the dorsoproximal aspect of third metacarpophalangeal joint. Radiographs of the affected limb showed a 28 mm * 26 mm exostosis at the dorsodistal third metacarpal bone. Surgical removal of the exostosis was performed and histopathologic examination confirmed a solitary osteochondroma. A follow-up examination 1 yr after surgical removal revealed total abolishment of the left front limb lameness. This report documents the first diagnosis and treatment of solitary osteochondroma in a white rhinoceros. PMID- 28080923 TI - TREATMENT OF RENAL CARCINOMA IN A BINTURONG (ARCTICTIS BINTURONG) WITH NEPHRECTOMY AND A TYROSINE KINASE INHIBITOR. AB - A 13-yr-old female binturong ( Arctictis binturong ) presented with a 1 wk history of decreased appetite. The animal was thin, with hypercalcemia (calcium 12.2 mg/dl). A right renal mass was identified on ultrasound and removed via nephrectomy. Histopathology indicated a renal adenocarcinoma. Treatment with toceranib phosphate, a tyrosine-kinase inhibitor, was initiated and well tolerated by the animal. Four months after initial diagnosis radiographs indicated metastases to the lungs and the animal was euthanized. Necropsy revealed disseminated adenocarcinoma. Although treatment did not prevent metastasis, it was minimally invasive and well tolerated by the animal with minimal side effects. Review of records at the institution revealed that the cause of death for the primary case's dam and sire was disseminated renal carcinoma. These cases suggest that there may be a hereditary component to development of renal neoplasia in binturongs. Renal carcinoma should be considered an aggressive neoplasia in binturongs with a poor prognosis. PMID- 28080924 TI - SELECTED PLASMA BIOCHEMISTRY ANALYTES OF HEALTHY CAPTIVE SULCATA (AFRICAN SPURRED) TORTOISES (CENTROCHELYS SULCATA). AB - The sulcata or African spurred tortoise (Centrochelys sulcata) is a large tortoise species that is commonly kept in zoologic collections and as a pet. The objectives of this study were to establish reference intervals for selected biochemical analytes in clinically healthy captive sulcata tortoises and to evaluate the impact of blood sampling site and sex. Blood samples were collected from 60 tortoises from either the dorsal coccygeal (tail) vein or the subcarapacial venous plexus based on their body size. The packed cell volume and refractometric total solids (TS) were determined. The concentrations of selected plasma biochemical analytes were determined using the VetScan VS2 analyzer and included albumin, aspartate aminotransferase, bile acids, calcium, creatine kinase, globulins, glucose, potassium, sodium, phosphorous, total proteins (TP), and uric acid. The calcium-to-phosphorous ratio was calculated. Reference intervals were determined and evaluated for the potential effects of blood sampling site and sex. There were significant differences (P < 0.05) associated with the blood sampling site in TS, TP, phosphorus, and globulins, with higher values in samples from the tail versus the subcarapacial sampling site. No significant statistical differences were noted in the plasma biochemistry analytes between the sexes. Reading of the globulins by the analyzer failed in 36 of 60 of the samples and was largely associated with the subcarapacial plexus sampling site. The reference intervals defined by the VetScan analyzer in this study can be used for clinical medicine and conservation of this tortoise species. Sampling site was identified as a factor significantly affecting some blood analytes in this study; this factor should thus be taken into consideration when assessing sulcata tortoise health status and using this testing methodology. PMID- 28080925 TI - CARDIAC ASSESSMENT OF ZOO-KEPT, BLACK-TAILED PRAIRIE DOGS (CYNOMYS LUDOVICIANUS) ANESTHETIZED WITH ISOFLURANE. AB - Cardiomyopathy is suggested to be a relatively common disease condition in prairie dogs; however, there are no reports of normal cardiac echosonography and radiology in the prairie dog ( Cynomys spp.). The objective of this study was to report the ultrasonographic and radiographic measurements of the heart, and plasma troponin concentration in captive healthy anesthetized black-tailed prairie dogs ( Cynomys ludovicianus ). Zoo-kept prairie dogs with no signs of cardiac disease (n = 17) were evaluated. Each animal was anesthetized with isoflurane via face mask and a complete clinical assessment was performed, including complete blood cell count and plasma biochemistry, urinalysis, blood gasses, plasma troponin concentration, three-view whole body radiography, and echocardiogram. Standard measurements were taken. Few trivial findings were identified on echocardiographic evaluation. Further research with a larger sample size is needed to determine if these variations are normal, or represent early or mild cardiac disease. The data presented here can aid, with the necessary caution, in evaluating prairie dogs with possible cardiac disease, potentially resulting in earlier diagnosis and more successful treatment. PMID- 28080926 TI - Integrating task analysis into system design: Surveying designers' needs. AB - The authors are presently developing tools to enable software designers to carry out task analyses (TA). The tools will support a methodology comprising techniques for carrying out task analyses and will also take account of integrating the resulting TA information into system design. To support integration and to identify the requirements for TA tools, a group of designers were surveyed. The survey identified how the designers approach design, whether the designers believe TA would be of use to them and how, why and where TA might contribute to design. Finally the designers' views of the desired characteristics of TA tools was sought. This paper outlines the results of this small, detailed survey of what designers want, need and expect from TA tools. PMID- 28080927 TI - Individual differences and the user interface. AB - Individual differences in cognitive functions are relevant in introducing novioes to computing. The interaction between the user and the computer may be improved if these psychological characteristics are taken into account in the design of the user interface and in the design of introductory courses. In.section 1 of this paper an analysis is made of individual differences and of the possibilities of adaptation. The user interface is described as an opportunity for adaptation. Methods of adaptation are systematically related to the changeability of individual differences. Illustrated by an overview of previous experimental work, some principles of adaptation are demonstrated in relation to individual differences on variables that are relevant in human-computer interaction. Prior knowledge of mathematics has been shown to be related to success and failure in learning a programming language, and to motivation for using computers. In section 2 ways to prevent the course drop-out rate by structuring the teaching method are illustrated. Strategies of information processing in the user interface, in relation to metacommunication and teaching, are described in section 3 as another example of an individual difference variable that may be attended to in teaching, resulting in reduction of problem solving time. Some cognitive styles are related to success in programming. The choice of adequate educational examples may improve programming habits, as illustrated in section 4. Style of representation and spatial ability are relevant for the development of mental models of computer system. In section 5 some field studies on teaching novices to work with office systems illustrate these relations. Teaching strategies, educational examples, and metaphors, may neutralize the handicap some novices have because of these variables. PMID- 28080928 TI - JSD and the design of user interface software. AB - Systems analysis and design methods (SADMs), such as Jackson system development (JSD), have been proposed as a means of improving software quality. This is contrasted with the role of improving software usability proposed for human factors (HF). The paper argues the need for an explicit user interface specification stage in system development to ensure the usability of proposed systems. It is suggested that JSD supplemented by the specialist knowledge of HF can support such a specification stage. For HF and JSD to be successfully integrated, contributions from both need to be appropriately timed and structured. A model of the system development process that incorporates HF contributions is proposed. A means by which the HF contributions, in the form of a user interface specification, can be integrated with the JSD specification is developed and illustrated through examples. PMID- 28080929 TI - Designing for user benefit: a methodological cautionary tale. AB - This paper is concerned with the problem of 'losing sight' of the user during the design of human-computer interfaces. A methodological practice is proposed which enables the designer to track the implications of design proposals with respect to both the benefits they confer on the user and their goodness of fit with user characteristics. The methodological practice, which is seen as a technique for early or formative evaluation, is then applied in retrospect to two adaptive prototypes which are currently being incorporated into a Multi-Author Document Preparation System. The results of this process are intended as a methodological cautionary tale for other designers, illustrating the potential consequences of failure to evaluate the implicit assumptions that are being made about users by the designer. PMID- 28080930 TI - The human-computer interface hierarchy model and strategies in system development. AB - With the rapid introduction of computer systems into various practical settings, there has been a great need for theoretical guidance, and for system development strategies. Based on results of research on the organizational interface in Chinese enterprises, a LISREL model of human-computer interface hierarchy was built. Three useful strategies: computer expertise, system connectivity and participation strategies were formulated according to the Interface Hierarchy Model. The implications of the Model and related strategies were highlighted in relation to system development tasks and relative to the macro-ergonomics perspective. PMID- 28080931 TI - Alphanumeric and graphic displays for dynamic process monitoring and control. AB - The use of high resolution graphic display technology provides the control system designer with numerous options for displaying process plant information. This research evaluated the effectiveness of alphanumeric and graphic display formats for presenting system information in a dynamic process plant environment Thirty subjects, divided equally into three groups, were tested on three separate display formats: graphical, digital and multiple representations. The operators' task was to optimize the performance of a simulated fluid processing plant and to detect system failures. Results showed that the multiple display resulted in the best optimization performance and minimized the time required to detect failures. In general, the graphic display produced the worst performance with the digital display exhibiting intermediate results. The decision strategies used by the operators were found to have the greatest impact on performance. The results are discussed in terms of the merits of different display formats for representing system information in a manner appropriate to the operator's task. PMID- 28080932 TI - The implementation and evaluation of a theory for high level cognitive skill acquisition through expert systems modelling techniques. AB - From previous studies by Koubek and Salvendy (1988), it has been established that differences exist in the high level controlled processes between expert (E) and super-expert (SE) subjects on computer program modification tasks. This study examines the implications of this finding by applying modelling techniques via expert systems technology. To examine the hypothesis that the knowledge representation is critical to SE performance, and to indicate how these results might have practical application, two small prototype expert systems were developed using the E and SE knowledge representations respectively. A qualitative analysis reveals significant performance differences between systems attributable to the knowledge representation and suggests a combination of E and SE knowledge be used for construction of a hybrid expert system. The SE knowledge base is a hierarchical structure and is organized under abstract categories, suggesting a breadth first approach. This structure allows for interactions within the program itself and between the program and user environment. The E knowledge base is narrow and task specific, indicating a depth first approach. In conclusion, theoretical and practical implications of this research into SE performance and modelling techniques are discussed. PMID- 28080933 TI - Video analysis in cognitive ergonomics: a methodological perspective. AB - The object of this paper is to discuss the methodological issues associated with using video analysis in the evaluation of Human-Computer Interaction. It is proposed that the mapping between low-level observed events and the high-level goals of the usability evaluation ultimately determines the success of this research technique. The paper firstly addresses the advantages of using video as a data-capture medium in the context of usability evaluations, and secondly, evaluates the use of alternative data capture devices. The process of conducting video analysis is then described. The methodological issues that arise in employing this technique are presented in a format consistent with the execution of any empirical investigation: research design, scoring, data analysis and interpretation of results. The reader is alerted to certain methodological problems associated with the use of video analysis as a means of data collection. The conclusion is drawn that video analysis provides a very powerful data source for the study of human performance in cognitive ergonomics and usability evaluations provided that human factors practitioners attend to the methodological requirements imposed by this technique. PMID- 28080934 TI - Some requirements and suggestions for a methodology to develop knowledge based systems. AB - This paper describes an approach to the creation of a methodology for the development of knowledge based systems. It specifies some requirements and suggests how these requirements might be met. General requirements can be satisfied using a systems approach. More specific ones can be met by viewing an organization as a network of consultations for coordinating expertise. The nature of consultations is described and the form of a possible cognitive model using a blackboard architecture is outlined. The value of the approach is illustrated in terms of certain knowledge elicitation methods. PMID- 28080935 TI - Conference review Simulation in the development of user interfaces. PMID- 28080936 TI - State-space and verbal protocol methods for studying the human operator in process control. AB - This paper presents a variety of methods founded in cognitive science for examining the behaviour of the human operator in process control. The waterbath task described by Crossman and Cooke (1974) and by Moray et al. (1986) is taken as a basic process control laboratory paradigm for applying these methods in an integrated approach. First, the waterbath task itself was analysed and a graphical representation developed to show relations between system variables (various valve and heater settings) and state variables (volume, temperature and flow rate). From this a representation of possible correct knowledge about the waterbath was developed. Second, a classification was made of the different states the waterbath system could be in with respect to an operator's goal state. A state-action diagram identified the correct control action or actions to travel from each state to the goal. This provided a basis for predicting the types of difficulties operators might have. Results of an experiment snowed that the need to coordinate several control actions to reach a goal was a source of difficulty. Subjects consistently misunderstood the relation between variables and performance data showed poorer performance when these variables had to be controlled. Verbal protocol data showed how often and how accurately subjects discussed particular aspects of the waterbath system. It was possible to piece together fragments of a subject's whole system of knowledge. Overall, the methods discussed contrast possible actions and knowledge with actual actions and knowledge. They represent a promising collection of data reduction techniques for studying the human operator in process control. PMID- 28080937 TI - Towards a conception for an engineering discipline of human factors. AB - This paper concerns one possible response of human factors to the need for better user interactions of computer-based systems. The paper is in two parts. Part I examines the potential for human factors to formulate engineering principles. A basic prerequisite for realizing that potential is a conception of the general design problem addressed by human factors. The problem is expressed informally as: 'to design human interactions with computers for effective working'. A conception would provide the set of related concepts which both expressed the general design problem more formally, and which might be embodied in engineering principles. Part II of the paper proposes such a conception and illustrates its concepts. It is offered as an initial and speculative step towards a conception for an engineering discipline of Human Factors. PMID- 28080938 TI - Dynamic analysis of isoinertial lifting technique. AB - The objectives of the study were threefold: (1) to quantify dynamic measures (displacement, velocity, force/acceleration, and power) of a 1.83 m isoinertial lift on an incremental lifting machine (ILM); (2)to identify any gender differences in ILM lifting technique; and (3) to assess the implications of these data for the use of the ILM as a screening device. One hundred and thirty-two military personnel (33 females and 99 males) completed a maximal isoinertial lifting test from a starting height of 0.34 m to a target height of 1.83 m on the ILM. A force transducer attached to the back of the armature provided continuous velocity and displacement data from which the displacement, velocity, acceleration/force, and power profiles were determined. These data were summarized into 37 lift parameters; 33 representing the dynamic components of the lift, and four representing averages taken across the entire lift. The results revealed that the 1.83 m isoinertial lift could be described in three phases: (1) a powerful pulling phase, which incorporated measures of maximal acceleration/force, velocity, and power; 2) a wrist changeover manoeuvre, wherein momentum was required to compensate for minimal force and acceleration values; and (3) a pushing phase, during which second maximal force and acceleration measures were attained. Statistically significant differences were found between genders on various parameters of the technique profiles, suggesting that the testing protocol may have placed different demands on males and females. Females spent a greater proportion of the total lift time in the pushing phase, and had less opportunity to generate power during the pulling phase. The resulting TLM scores may have underestimated the lifting capacity of females. It was recommended that females and males be given independent consideration in the design of ILM lifting protocols. PMID- 28080940 TI - Predicting the transmissibility of a suspension seat. AB - Measurements of the stiffness and the damping of an air suspension seat were made. The seat was loaded with either a person or an equivalent rigid mass, and the effect of the following variables was investigated: duration; vibration magnitude; load on-the seat; seat adjustment. The results obtained with a rigid mass were used in conjunction with previous measurements of the apparent mass of the body and the apparent mass of the legs, to predict the transmissibility of the seat with a person. Good agreement was obtained between measured and predicted seat transmissibilities. PMID- 28080942 TI - Perceived relationship between elements of a complex display. AB - An important aspect of complex control and display layout is the grouping together of functionally related areas. Three experiments on perception of the relationship between elements of a complex display are reported. In the first experiment, subjects were presented with an array of nine plain elements with different element and external aspect ratios as well as different values of solidity of the display. Subjects reported their judgments on the perceived relationship of three groups of three elements which were related in either a horizontal or vertical direction. It was found that both aspect ratios were important in determining the strength of the 'vertically'-related response. Solidity of the display was not important. Two further experiments used display elements from power stations. The first of these experiments used a series of display elements with varying element and external aspect ratios; both of these variables were found to be significant in determining the perceived relationship between elements. However, the results are not as clear as those for the abstract elements used in the first experiment and suggest that more extreme aspect ratios are necessary to ensure that the desired relationships are perceived. The third experiment considered displays in which the elements within the one display were of different sizes. The perceived relationships are further weakened by the inclusion of this factor. PMID- 28080945 TI - Sensations of temperature and humidity during alternative work/rest and the influence of underwear knit structure. AB - The purpose of this study was to evaluate the influence of alternate work/rest and knit structure of underwear on various subjective sensations of temperature and humidity. Underwear manufactured from 100% polypropylene fibres in five different knit structures (1-by-l rib, fleece, fishnet, interlock, double-layer rib) were applied and tested as part of a prototype clothing system. Human testing was done on eight male subjects, and took place at Ta = 5 degrees C, Tdp = - 3.5 degrees C and Va = 0.32ms-1. The test comprized a twice-repeated bout of 40 min cycle exercise (56 Wm-2;. [Vdot]O2 = 1741O2min-1~52+/-4.9% V O2 max) followed by 20 min of rest (OWm-2 0.351 O2 min-1). Alternate work/rest had a significant influence on all temperature and humidity sensations of the body, of the skin-clothing interface, and of the environment. Knit structures of the underwear influenced sensations of humidity significantly, but not sensations of temperature. The various sensations of temperature correlated best with core temperature, whereas the sensations of humidity correlated with skin wettedness. Subjective sensations of wetness of the skin and of the clothing are recommended as a sensitive tool to discriminate between the thermal function of similar garments. PMID- 28080946 TI - Four factor model to describe an isoinertial lift. AB - The objectives of the study were threefold: (1) to develop an empirical description of dynamic factors involved in a test of lifting performance on an Incremental Lifting Machine (TLM) through application of principal components analysis; (2) to conduct gender analyses of the factor structures; and (3) to determine the stability of the structures with repeated sampling. An initial sample of 175 participants (79 females and 96 males) completed a maximal isoinertial lifting test from a starting height of 0.34 m to a target height of 1.83 m. A confirmatory sample of 132 participants (33 females and 99 males) completed the same 1LM test under identical conditions. A force transducer attached to the back of the armature provided continuous displacement data from which displacement, velocity, acceleration, force, and power profiles were determined. These data were summarized into 32 lift parameters, and then subjected to principal components analyses. For the dynamic parameters recorded for the initial sample, a four factor solution accounting for 78.9% of the variance was found to be optimal. Factor one (named Mid-Body Coordination and accounting for 24.7% of the variance) related to the timing and displacement of maximum velocity and power. Factor two (named Maximum Strength) contained maximum force and power measurements and accounted for 22.5% of the variance. Factor three (named Minimum Strength) related to minimum measures of force and power and accounted for 17.2% of the variance. Finally, factor four (named Lower Body Co ordination and accounting for 14.4% of the variance) related to the timing and displacement of maximum force. Descriptions of the factors were developed in terms of their underlying biomechanical relationships. The four factor solution was found to be stable across genders, and it was replicated for the confirmatory sample. It was concluded that these dynamic factors possessed considerable scientific utility for future research. PMID- 28080947 TI - HIV testing intervention development among men who have sex with men in the developed world. AB - HIV testing is a 'gateway' technology, enabling access to treatment and HIV prevention. Biomedical approaches to prevention, such as pre-exposure prophylaxis and treatment as prevention, require accurate and regular HIV test results. HIV testing also represents a powerful 'teachable moment' for behavioural prevention. An increasing range of HIV tests and the emergence of self-managed diagnostic technologies (e.g. self-testing) means there is now considerable diversification of when, where and how results are available to those who test. These changes have profound implications for intervention development and, indeed, health service redesign. This paper highlights the need for better ways of conceptualising testing in order to capitalise on the health benefits that diverse HIV testing interventions will bring. A multidimensional framework is proposed to capture ongoing developments in HIV testing among men who have sex with men and focus on the intersection of: (1) the growing variety of HIV testing technologies and the associated diversification of their pathways into care; (2) psychosocial insights into the behavioural domain of HIV testing; and (3) better appreciation of population factors associated with heterogeneity and concomitant inequities. By considering these three aspects of HIV testing in parallel, it is possible to identify gaps, limitations and opportunities in future HIV testing related interventions. Moreover, it is possible to explore and map how diverse interventions may work together having additive effects. Only a holistic and dynamic framework that captures the increasing complexity of HIV testing is fit for purpose to deliver the maximum public health benefit of HIV testing. PMID- 28080948 TI - ECG Diagnosis: Right Ventricular Myocardial Infarction. PMID- 28080949 TI - Image Diagnosis: Endobronchial Tuberculosis Masquerading as an Endobronchial Tumor with Presentation as Middle Lobe Syndrome. PMID- 28080951 TI - Primary Upper Limb Lymphedema: Case Report of a Rare Pathology. AB - INTRODUCTION: Lymphedema is characterized by a defect in the lymphatic system that causes limb swelling. Impaired uptake and transport of lymphatic fluid through lymphatic vessels causes accumulation of protein-rich fluid in the interstitial spaces, which leads to swelling of the limb. Primary lymphedema often presents at birth. The rare cases that arise after age 35 years are described as lymphedema tarda. The great majority of patients with lymphedema have swelling of the lower limbs-upper limb lymphedema is a rare disorder. CASE PRESENTATION: An 84-year-old woman presented with a 3-year history of unilateral swelling of the right upper limb. There were no constitutional symptoms and no evidence of lymphadenopathy or systemic disease. Blood tests, carcinoembryonic antigen test, computed tomography scans, and venous Doppler ultrasound were all normal. The diagnosis was primary upper limb lymphedema. DISCUSSION: The swelling that occurs in upper limb lymphedema is permanent and usually extends to the hand. About one-third of patients with this condition also present with lower limb lymphedema. Thorough investigations are warranted in cases of unilateral upper limb lymphedema to rule out occult malignancy and systemic disease. PMID- 28080950 TI - Image Diagnosis: A Striking Bleomycin-Induced Skin Toxicity: Flagellate Hyperpigmentation. PMID- 28080953 TI - Childhood Disrupted: How Your Biography Becomes Your Biology, and How You Can Heal. PMID- 28080954 TI - Sjogren Syndrome and Pregnancy: A Literature Review. AB - OBJECTIVES: Autoimmune diseases do not impair fertility, and women with autoimmune diseases who become pregnant are likely to experience more complicated pregnancies than are women without the disease. Pregnancies complicated by these disorders have a high clinical impact on both the pregnancy and the disease. The effect of autoimmune disease on pregnancy differs according to the type of maternal disease, disease activity, severity of organ damage, antibody profile, and drug treatment. Sjogren syndrome is an autoimmune disease with a high prevalence of anti-SS-A (anti-Ro) and anti-SS-B (anti-La) antibodies. Anti-SS-A antibodies are associated with congenital heart block. Data on pregnancy outcomes in primary Sjogren syndrome are scarce. METHODS: We performed a review of the literature regarding pregnancy outcomes in women with Sjogren syndrome. RESULTS: Women with Sjogren syndrome are likely to experience more complications during pregnancy than women without an autoimmune disease. Studies show a high incidence of poor fetal outcomes for these patients. CONCLUSION: Women with Sjogren syndrome require prenatal counseling explaining the risks involved and the need to control the disease well before conception. High-risk pregnancies can be optimally managed by a multidisciplinary team. PMID- 28080955 TI - Leukocytoclastic Vasculitis Secondary to Pyridostigmine (Mestinon): Report of a Possible First Case. AB - INTRODUCTION: Pyridostigmine is an acetylcholinesterase inhibitor commonly used in the treatment of myasthenia gravis. We describe a patient who developed a rash after recently being started on pyridostigmine and give a general review of leukocytoclastic vasculitis. CASE PRESENTATION: A 91-year-old man was diagnosed with ocular myasthenia gravis. He was started on pyridostigmine, and 2 weeks later he developed a rash. The rash was biopsied and found to be secondary to leukocytoclastic vasculitis; the pyridostigmine was stopped, loratadine was started, and the rash resolved. DISCUSSION: Leukocytoclastic vasculitis is commonly caused by a hypersensitivity reaction to medications, or it can be associated with certain medical conditions. We present a brief review of the most common medications and medical conditions known to cause this reaction, but to our knowledge this is the first description of pyridostigmine causing this reaction. PMID- 28080956 TI - ECG Diagnosis: Deep T Wave Inversions Associated with Intracranial Hemorrhage. PMID- 28080957 TI - Understanding Preferences for Osteoporosis Information to Develop an Osteoporosis Patient Education Brochure. AB - CONTEXT: Patient education materials can provide important information related to osteoporosis prevention and treatment. However, available osteoporosis education materials fail to follow best-practice guidelines for patient education. OBJECTIVE: To develop an educational brochure on bone health for adults aged 50 years and older using mixed-method, semistructured interviews. DESIGN: This project consisted of 3 phases. In Phase 1, we developed written content that included information about osteoporosis. Additionally, we designed 2 graphic-rich brochures, Brochure A (photographs) and Brochure B (illustrations). In Phase 2, interviewers presented the text-only document and both brochure designs to 53 participants from an academic Medical Center in the Midwest and an outpatient clinic in the Southeastern region of the US. Interviewers used open- and closed ended questions to elicit opinions regarding the brochures. In Phase 3, using feedback from Phase 2, we revised the brochure and presented it to 11 participants at a third site in the Southeastern US. MAIN OUTCOME MEASURES: Participants' comprehension of brochure text and acceptability of brochure design. RESULTS: We enrolled 64 participants. Most were women, white, and college educated, with an average age of 66.1 years. Participants were able to restate the basic content of the brochure and preferred Brochure A's use of photographs. CONCLUSIONS: Using feedback from older adults, we developed and refined a brochure for communicating bone health information to older adults at risk of osteoporosis and fragility fractures. The methods outlined in this article may serve to guide others in developing health educational brochures for chronic medical conditions. PMID- 28080958 TI - Erratum for Euro Surveill. 2016;21(50). PMID- 28080959 TI - Sentinel surveillance of imported dengue via travellers to Europe 2012 to 2014: TropNet data from the DengueTools Research Initiative. AB - We describe the epidemiological pattern and genetic characteristics of 242 acute dengue infections imported to Europe by returning travellers from 2012 to 2014. The overall geographical pattern of imported dengue (South-east Asia > Americas > western Pacific region > Africa) remained stable compared with 1999 to 2010. We isolated the majority of dengue virus genotypes and epidemic lineages causing outbreaks and epidemics in Asia, America and Africa during the study period. Travellers acted as sentinels for four unusual dengue outbreaks (Madeira, 2012 13; Luanda, 2013; Dar es Salaam, 2014; Tokyo, 2014). We were able to characterise dengue viruses imported from regions where currently no virological surveillance data are available. Up to 36% of travellers infected with dengue while travelling returned during the acute phase of the infection (up to 7 days after symptom onset) or became symptomatic after returning to Europe, and 58% of the patients with acute dengue infection were viraemic when seeking medical care. Epidemiological and virological data from dengue-infected international travellers can add an important layer to global surveillance efforts. A considerable number of dengue-infected travellers are viraemic after arrival back home, which poses a risk for dengue introduction and autochthonous transmission in European regions where suitable mosquito vectors are prevalent. PMID- 28080961 TI - Interoception beyond homeostasis: affect, cognition and mental health. AB - Interoception refers to the sensing of the internal state of one's body. Interoception is distinct from the processing of sensory information concerning external (non-self) stimuli (e.g. vision, hearing, touch and smell) and is the afferent axis to internal (autonomic and hormonal) physiological control. However, the impact of interoception extends beyond homeostatic/allostatic reflexes: it is proposed to be fundamental to motivation, emotion (affective feelings and behaviours), social cognition and self-awareness. This view is supported by a growing body of experimental evidence that links peripheral physiological states to mental processes. Within this framework, the representation of self is constructed from early development through continuous integrative representation of biological data from the body, to form the basis for those aspects of conscious awareness grounded on the subjective sense of being a unique individual. This theme issue of the Philosophical Transactions of the Royal Society B draws together state-of-the-art knowledge concerning theoretical, experimental and clinical facets of interoception with the emphasis on cognitive and affective neuroscience. The multidisciplinary and cross disciplinary perspectives represented in this theme issue disseminate and entrench knowledge about interoception across the scientific community and provide a reference for the conceptualization and further study of interoception across behavioural sciences. PMID- 28080960 TI - Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS) is a pediatric malignacy of muscle with myogenic regulatory transcription factors MYOD and MYF5 being expressed in this disease. Consensus in the field has been that expression of these factors likely reflects the target cell of transformation rather than being required for continued tumor growth. Here, we used a transgenic zebrafish model to show that Myf5 is sufficient to confer tumor-propagating potential to RMS cells and caused tumors to initiate earlier and have higher penetrance. Analysis of human RMS revealed that MYF5 and MYOD are mutually-exclusively expressed and each is required for sustained tumor growth. ChIP-seq and mechanistic studies in human RMS uncovered that MYF5 and MYOD bind common DNA regulatory elements to alter transcription of genes that regulate muscle development and cell cycle progression. Our data support unappreciated and dominant oncogenic roles for MYF5 and MYOD convergence on common transcriptional targets to regulate human RMS growth. PMID- 28080962 TI - 'Bodily precision': a predictive coding account of individual differences in interoceptive accuracy. AB - Individuals differ in their awareness of afferent information from within their bodies, which is typically assessed by a heartbeat perception measure of 'interoceptive accuracy' (IAcc). Neural and behavioural correlates of this trait have been investigated, but a theoretical explanation has yet to be presented. Building on recent models that describe interoception within the free energy/predictive coding framework, this paper applies similar principles to IAcc, proposing that individual differences in IAcc depend on 'precision' in interoceptive systems, i.e. the relative weight accorded to 'prior' representations and 'prediction errors' (that part of incoming interoceptive sensation not accounted for by priors), at various levels within the cortical hierarchy and between modalities. Attention has the effect of optimizing precision both within and between sensory modalities. Our central assumption is that people with high IAcc are able, with attention, to prioritize interoception over other sensory modalities and can thus adjust the relative precision of their interoceptive priors and prediction errors, where appropriate, given their personal history. This characterization explains key findings within the interoception literature; links results previously seen as unrelated or contradictory; and may have important implications for understanding cognitive, behavioural and psychopathological consequences of both high and low interoceptive awareness.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. PMID- 28080963 TI - Is the cardiac monitoring function related to the self in both the default network and right anterior insula? AB - The self has been proposed to be rooted in the neural monitoring of internal bodily signals and might thus involve interoceptive areas, notably the right anterior insula (rAI). However, studies on the self consistently showed the involvement of midline default network (DN) nodes, without referring to visceral monitoring. Here, we investigate this apparent discrepancy. We previously showed that neural responses to heartbeats in the DN encode two different self dimensions, the agentive 'I' and the introspective 'Me', in a whole-brain analysis of magnetoencephalography (MEG) data. Here, we confirm and anatomically refine this result with intracranial recordings (intracranial electroencephalography, iEEG). In two patients, we show a parametric modulation of neural responses to heartbeats by the self-relatedness of thoughts, at the single trial level. A region-of-interest analysis of the insula reveals that MEG responses to heartbeats in the rAI encode the 'I' self-dimension. The effect in rAI was weaker than in the DN and was replicated in iEEG data in one patient out of two. We propose that a common mechanism, the neural monitoring of cardiac signals, underlies the self in both the DN and rAI. This might reconcile studies on the self highlighting the DN, with studies on interoception focusing on the insula.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. PMID- 28080964 TI - Prospective memory mediated by interoceptive accuracy: a psychophysiological approach. AB - Previous studies on prospective memory (PM), defined as memory for future intentions, suggest that psychological stress enhances successful PM retrieval. However, the mechanisms underlying this notion remain poorly understood. We hypothesized that PM retrieval is achieved through interaction with autonomic nervous activity, which is mediated by the individual accuracy of interoceptive awareness, as measured by the heartbeat detection task. In this study, the relationship between cardiac reactivity and retrieval of delayed intentions was evaluated using the event-based PM task. Participants were required to detect PM target letters while engaged in an ongoing 2-back working memory task. The results demonstrated that individuals with higher PM task performance had a greater increase in heart rate on PM target presentation. Also, higher interoceptive perceivers showed better PM task performance. This pattern was not observed for working memory task performance. These findings suggest that cardiac afferent signals enhance PM retrieval, which is mediated by individual levels of interoceptive accuracy.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. PMID- 28080965 TI - Feeling, learning from and being aware of inner states: interoceptive dimensions in neurodegeneration and stroke. AB - Interoception is a complex process encompassing multiple dimensions, such as accuracy, learning and awareness. Here, we examined whether each of those dimensions relies on specialized neural regions distributed throughout the vast interoceptive network. To this end, we obtained relevant measures of cardiac interoception in healthy subjects and patients offering contrastive lesion models of neurodegeneration and focal brain damage: behavioural variant fronto-temporal dementia (bvFTD), Alzheimer's disease (AD) and fronto-insular stroke. Neural correlates of the three dimensions were examined through structural and functional resting-state imaging, and online measurements of the heart-evoked potential (HEP). The three patient groups presented deficits in interoceptive accuracy, associated with insular damage, connectivity alterations and abnormal HEP modulations. Interoceptive learning was differentially impaired in AD patients, evidencing a key role of memory networks in this skill. Interoceptive awareness results showed that bvFTD and AD patients overestimated their performance; this pattern was related to abnormalities in anterior regions and associated networks sub-serving metacognitive processes, and probably linked to well-established insight deficits in dementia. Our findings indicate how damage to specific hubs in a broad fronto-temporo-insular network differentially compromises interoceptive dimensions, and how such disturbances affect widespread connections beyond those critical hubs. This is the first study in which a multiple lesion model reveals fine-grained alterations of body sensing, offering new theoretical insights into neuroanatomical foundations of interoceptive dimensions.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. PMID- 28080966 TI - Active interoceptive inference and the emotional brain. AB - We review a recent shift in conceptions of interoception and its relationship to hierarchical inference in the brain. The notion of interoceptive inference means that bodily states are regulated by autonomic reflexes that are enslaved by descending predictions from deep generative models of our internal and external milieu. This re-conceptualization illuminates several issues in cognitive and clinical neuroscience with implications for experiences of selfhood and emotion. We first contextualize interoception in terms of active (Bayesian) inference in the brain, highlighting its enactivist (embodied) aspects. We then consider the key role of uncertainty or precision and how this might translate into neuromodulation. We next examine the implications for understanding the functional anatomy of the emotional brain, surveying recent observations on agranular cortex. Finally, we turn to theoretical issues, namely, the role of interoception in shaping a sense of embodied self and feelings. We will draw links between physiological homoeostasis and allostasis, early cybernetic ideas of predictive control and hierarchical generative models in predictive processing. The explanatory scope of interoceptive inference ranges from explanations for autism and depression, through to consciousness. We offer a brief survey of these exciting developments.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. PMID- 28080967 TI - Affective touch and attachment style modulate pain: a laser-evoked potentials study. AB - Affective touch and cutaneous pain are two sub-modalities of interoception with contrasting affective qualities (pleasantness/unpleasantness) and social meanings (care/harm), yet their direct relationship has not been investigated. In 50 women, taking into account individual attachment styles, we assessed the role of affective touch and particularly the contribution of the C tactile (CT) system in subjective and electrophysiological responses to noxious skin stimulation, namely N1 and N2-P2 laser-evoked potentials. When pleasant, slow (versus fast) velocity touch was administered to the (non-CT-containing) palm of the hand, higher attachment anxiety predicted increased subjective pain ratings, in the same direction as changes in N2 amplitude. By contrast, when pleasant touch was administered to CT-containing skin of the arm, higher attachment anxiety predicted attenuated N1 and N2 amplitudes. Higher attachment avoidance predicted opposite results. Thus, CT-based affective touch can modulate pain in early and late processing stages (N1 and N2 components), with the direction of effects depending on attachment style. Affective touch not involving the CT system seems to affect predominately the conscious perception of pain, possibly reflecting socio-cognitive factors further up the neurocognitive hierarchy. Affective touch may thus convey information about available social resources and gate pain responses depending on individual expectations of social support.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. PMID- 28080968 TI - Interoception, homeostatic emotions and sympathovagal balance. AB - We briefly review the evidence for distinct neuroanatomical substrates that underlie interoception in humans, and we explain how they substantialize feelings from the body (in the insular cortex) that are conjoined with homeostatic motivations that guide adaptive behaviours (in the cingulate cortex). This hierarchical sensorimotor architecture coincides with the limbic cortical architecture that underlies emotions, and thus we regard interoceptive feelings and their conjoint motivations as homeostatic emotions We describe how bivalent feelings, emotions and sympathovagal balance can be organized and regulated efficiently in the bicameral forebrain as asymmetric positive/negative, approach/avoidance and parasympathetic/sympathetic components. We provide original evidence supporting this organization from studies of cardiorespiratory vagal activity in monkeys and functional imaging studies in healthy humans showing activation modulated by paced breathing and passively viewed emotional images. The neuroanatomical architecture of interoception provides deep insight into the functional organization of all emotional feelings and behaviours in humans.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. PMID- 28080970 TI - Differentiating attention styles and regulatory aspects of self-reported interoceptive sensibility. AB - Based on prior research, multiple discriminable dimensions of interoception have been defined: awareness, accuracy and sensibility. Some investigators defined interoceptive awareness as metacognitive awareness of interoceptive accuracy, assessed as correspondence between subjective confidence in and objective accuracy of one's heartbeat detection. However, metacognitive awareness has been understood quite differently: 'a cognitive set in which negative thoughts/feelings are experienced as mental events, rather than as the self' or as 'error awareness'. Interoceptive sensibility, defined as self-reported interoception, distinguishes self-reported interoception from objective interoceptive accuracy, but does not differentiate between anxiety-driven and mindful attention styles towards interoceptive cues, a distinction of key clinical importance: one attention style is associated with somatization and anxiety disorders; the other has been viewed as healthy, adaptive, resilience enhancing. The self-report Multidimensional Assessment of Interoceptive Awareness was developed to differentiate these attention styles. It has been translated into 16 languages and applied in cross-sectional and longitudinal studies. Findings from these applications suggest that differentiating interoceptive sensibility according to attention style and regulatory aspects (i) provides insights into the psychology of interoceptive awareness, (ii) differentiates between clinically maladaptive and beneficial interoceptive attention, and (iii) helps elucidate therapeutic approaches that claim to provide health benefits by training mindful styles of bodily awareness.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. PMID- 28080971 TI - Interoceptive dimensions across cardiac and respiratory axes. AB - Interoception refers to the sensing of signals concerning the internal state of the body. Individual differences in interoceptive sensitivity are proposed to account for differences in affective processing, including the expression of anxiety. The majority of investigations of interoceptive accuracy focus on cardiac signals, typically using heartbeat detection tests and self-report measures. Consequently, little is known about how different organ-specific axes of interoception relate to each other or to symptoms of anxiety. Here, we compare interoception for cardiac and respiratory signals. We demonstrate a dissociation between cardiac and respiratory measures of interoceptive accuracy (i.e. task performance), yet a positive relationship between cardiac and respiratory measures of interoceptive awareness (i.e. metacognitive insight into own interoceptive ability). Neither interoceptive accuracy nor metacognitive awareness for cardiac and respiratory measures was related to touch acuity, an exteroceptive sense. Specific measures of interoception were found to be predictive of anxiety symptoms. Poor respiratory accuracy was associated with heightened anxiety score, while good metacognitive awareness for cardiac interoception was associated with reduced anxiety. These findings highlight that detection accuracies across different sensory modalities are dissociable and future work can better delineate their relationship to affective and cognitive constructs.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. PMID- 28080969 TI - An active inference theory of allostasis and interoception in depression. AB - In this paper, we integrate recent theoretical and empirical developments in predictive coding and active inference accounts of interoception (including the Embodied Predictive Interoception Coding model) with working hypotheses from the theory of constructed emotion to propose a biologically plausible unified theory of the mind that places metabolism and energy regulation (i.e. allostasis), as well as the sensory consequences of that regulation (i.e. interoception), at its core. We then consider the implications of this approach for understanding depression. We speculate that depression is a disorder of allostasis, whose myriad symptoms result from a 'locked in' brain that is relatively insensitive to its sensory context. We conclude with a brief discussion of the ways our approach might reveal new insights for the treatment of depression.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. PMID- 28080972 TI - Towards a psychophysics of interoceptive processes: the measurement of heartbeat detection. AB - It is difficult to collect objective evidence of interoception. Unlike exteroception, the effective stimuli for interoception are often unknown, and even when identifiable, they are difficult to control experimentally. Furthermore, direct stimulation of the interoceptors is seldom appropriate in human experimentation. Hence, non-invasive behavioural measures of accuracy in heartbeat detection have frequently been adopted to index interoceptive sensitivity. However, there has been little standardization and the two most popular methods for assessing heartbeat detection, heartbeat tracking and two alternative forced choice methods, appear to be biased and of questionable validity. These issues do not arise with other methods that are based on classical psychophysics and that enable subjects to indicate when during the cardiac cycle their heartbeat sensations occur. Not only are these classical methods highly reliable, but they also provide continuous unbiased measures of the temporal locations of heartbeat sensations and the precision with which these sensations are detected.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. PMID- 28080973 TI - Changes in interoceptive processes following brain stimulation. AB - The processing and perception of individual internal bodily signals (interoception) has been differentiated to comprise different levels and processes involved. The so-called heartbeat-evoked potential (HEP) offers an additional possibility to examine automatic processing of cardiac signals. Knowledge on neural structures potentially supporting different facets of interoception is still sparse. One way to get insights into neuroanatomical function is to manipulate the activity of different brain structures. In this study, we used repetitive transcranial magnetic stimulation (rTMS) and a continuous theta-burst protocol to inhibit specific central locations of the interoceptive network including the right anterior insula and the right somatosensory cortices and assessed effects on interoceptive facets and the HEP in 18 male participants. Main results were that inhibiting anterior insula resulted in a significant decline in cardiac and respiratory interoceptive accuracy (IAc) and in a consistent decrease in perception confidence. Continuous theta-burst stimulation (cTBS) over somatosensory cortices reduced only cardiac IAc and affected perception confidence. Inhibiting right anterior insula and right somatosensory cortices increased interoceptive sensibility and reduced the HEP amplitude over frontocentral locations. Our findings strongly suggest that cTBS is an effective tool to investigate the neural network supporting interoceptive processes.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. PMID- 28080974 TI - How the heart speaks to the brain: neural activity during cardiorespiratory interoceptive stimulation. AB - Prominent theories emphasize key roles for the insular cortex in the central representation of interoceptive sensations, but how this brain region responds dynamically to changes in interoceptive state remains incompletely understood. Here, we systematically modulated cardiorespiratory sensations in humans using bolus infusions of isoproterenol, a rapidly acting peripheral beta-adrenergic agonist similar to adrenaline. To identify central neural processes underlying these parametrically modulated interoceptive states, we used pharmacological functional magnetic resonance imaging (phMRI) to simultaneously measure blood oxygenation-level dependent (BOLD) and arterial spin labelling (ASL) signals in healthy participants. Isoproterenol infusions induced dose-dependent increases in heart rate and cardiorespiratory interoception, with all participants endorsing increased sensations at the highest dose. These reports were accompanied by increased BOLD and ASL activation of the right insular cortex at the highest dose. Different responses across insula subregions were also observed. During anticipation, insula activation increased in more anterior regions. During stimulation, activation increased in the mid-dorsal and posterior insula on the right, but decreased in the same regions on the left. This study demonstrates the feasibility of phMRI for assessing brain activation during adrenergic interoceptive stimulation, and provides further evidence supporting a dynamic role for the insula in representing changes in cardiorespiratory states.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. PMID- 28080975 TI - Neural correlates of heart-focused interoception: a functional magnetic resonance imaging meta-analysis. AB - Interoception is the ability to perceive one's internal body state including visceral sensations. Heart-focused interoception has received particular attention, in part due to a readily available task for behavioural assessment, but also due to accumulating evidence for a significant role in emotional experience, decision-making and clinical disorders such as anxiety and depression. Improved understanding of the underlying neural correlates is important to promote development of anatomical-functional models and suitable intervention strategies. In the present meta-analysis, nine studies reporting neural activity associated with interoceptive attentiveness (i.e. focused attention to a particular interoceptive signal for a given time interval) to one's heartbeat were submitted to a multilevel kernel density analysis. The findings corroborated an extended network associated with heart-focused interoceptive attentiveness including the posterior right and left insula, right claustrum, precentral gyrus and medial frontal gyrus. Right-hemispheric dominance emphasizes non-verbal information processing with the posterior insula presumably serving as the major gateway for cardioception. Prefrontal neural activity may reflect both top-down attention deployment and processing of feed-forward cardioceptive information, possibly orchestrated via the claustrum.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. PMID- 28080977 TI - Moorland vegetation burning debates should avoid contextomy and anachronism: a comment on Davies et al. (2016). PMID- 28080976 TI - Respiratory modulation of startle eye blink: a new approach to assess afferent signals from the respiratory system. AB - Current approaches to assess interoception of respiratory functions cannot differentiate between the physiological basis of interoception, i.e. visceral afferent signal processing, and the psychological process of attention focusing. Furthermore, they typically involve invasive procedures, e.g. induction of respiratory occlusions or the inhalation of CO2-enriched air. The aim of this study was to test the capacity of startle methodology to reflect respiratory related afferent signal processing, independent of invasive procedures. Forty-two healthy participants were tested in a spontaneous breathing and in a 0.25 Hz paced breathing condition. Acoustic startle noises of 105 dB(A) intensity (50 ms white noise) were presented with identical trial frequency at peak and on-going inspiration and expiration, based on a new pattern detection method, involving the online processing of the respiratory belt signal. The results show the highest startle magnitudes during on-going expiration compared with any other measurement points during the respiratory cycle, independent of whether breathing was spontaneous or paced. Afferent signals from slow adapting phasic pulmonary stretch receptors may be responsible for this effect. This study is the first to demonstrate startle modulation by respiration. These results offer the potential to apply startle methodology in the non-invasive testing of interoception-related aspects in respiratory psychophysiology.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. PMID- 28080978 TI - The role of fire in UK upland management: the need for informed challenge to conventional wisdoms: a comment on Davies et al. (2016). PMID- 28080979 TI - The peatland vegetation burning debate: keep scientific critique in perspective. A response to Brown et al. and Douglas et al. PMID- 28080981 TI - Phenotypic interactions between tree hosts and invasive forest pathogens in the light of globalization and climate change. AB - Invasive pathogens can cause considerable damage to forest ecosystems. Lack of coevolution is generally thought to enable invasive pathogens to bypass the defence and/or recognition systems in the host. Although mostly true, this argument fails to predict intermittent outcomes in space and time, underlining the need to include the roles of the environment and the phenotype in host pathogen interactions when predicting disease impacts. We emphasize the need to consider host-tree imbalances from a phenotypic perspective, considering the lack of coevolutionary and evolutionary history with the pathogen and the environment, respectively. We describe how phenotypic plasticity and plastic responses to environmental shifts may become maladaptive when hosts are faced with novel pathogens. The lack of host-pathogen and environmental coevolution are aligned with two global processes currently driving forest damage: globalization and climate change, respectively. We suggest that globalization and climate change act synergistically, increasing the chances of both genotypic and phenotypic imbalances. Short moves on the same continent are more likely to be in balance than if the move is from another part of the world. We use Gremmeniella abietina outbreaks in Sweden to exemplify how host-pathogen phenotypic interactions can help to predict the impacts of specific invasive and emergent diseases.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'. PMID- 28080980 TI - Climate forcing of an emerging pathogenic fungus across a montane multi-host community. AB - Changes in the timings of seasonality as a result of anthropogenic climate change are predicted to occur over the coming decades. While this is expected to have widespread impacts on the dynamics of infectious disease through environmental forcing, empirical data are lacking. Here, we investigated whether seasonality, specifically the timing of spring ice-thaw, affected susceptibility to infection by the emerging pathogenic fungus Batrachochytrium dendrobatidis (Bd) across a montane community of amphibians that are suffering declines and extirpations as a consequence of this infection. We found a robust temporal association between the timing of the spring thaw and Bd infection in two host species, where we show that an early onset of spring forced high prevalences of infection. A third highly susceptible species (the midwife toad, Alytes obstetricans) maintained a high prevalence of infection independent of time of spring thaw. Our data show that perennially overwintering midwife toad larvae may act as a year-round reservoir of infection with variation in time of spring thaw determining the extent to which infection spills over into sympatric species. We used future temperature projections based on global climate models to demonstrate that the timing of spring thaw in this region will advance markedly by the 2050s, indicating that climate change will further force the severity of infection. Our findings on the effect of annual variability on multi-host infection dynamics show that the community-level impact of fungal infectious disease on biodiversity will need to be re-evaluated in the face of climate change.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'. PMID- 28080982 TI - Drivers of variation in species impacts for a multi-host fungal disease of bats. AB - Disease can play an important role in structuring species communities because the effects of disease vary among hosts; some species are driven towards extinction, while others suffer relatively little impact. Why disease impacts vary among host species remains poorly understood for most multi-host pathogens, and factors allowing less-susceptible species to persist could be useful in conserving highly affected species. White-nose syndrome (WNS), an emerging fungal disease of bats, has decimated some species while sympatric and closely related species have experienced little effect. We analysed data on infection prevalence, fungal loads and environmental factors to determine how variation in infection among sympatric host species influenced the severity of WNS population impacts. Intense transmission resulted in almost uniformly high prevalence in all species. By contrast, fungal loads varied over 3 orders of magnitude among species, and explained 98% of the variation among species in disease impacts. Fungal loads increased with hibernating roosting temperatures, with bats roosting at warmer temperatures having higher fungal loads and suffering greater WNS impacts. We also found evidence of a threshold fungal load, above which the probability of mortality may increase sharply, and this threshold was similar for multiple species. This study demonstrates how differences in behavioural traits among species-in this case microclimate preferences-that may have been previously adaptive can be deleterious after the introduction of a new pathogen. Management to reduce pathogen loads rather than exposure may be an effective way of reducing disease impact and preventing species extinctions.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'. PMID- 28080984 TI - Modelling coffee leaf rust risk in Colombia with climate reanalysis data. AB - Many fungal plant diseases are strongly controlled by weather, and global climate change is thus likely to have affected fungal pathogen distributions and impacts. Modelling the response of plant diseases to climate change is hampered by the difficulty of estimating pathogen-relevant microclimatic variables from standard meteorological data. The availability of increasingly sophisticated high resolution climate reanalyses may help overcome this challenge. We illustrate the use of climate reanalyses by testing the hypothesis that climate change increased the likelihood of the 2008-2011 outbreak of Coffee Leaf Rust (CLR, Hemileia vastatrix) in Colombia. We develop a model of germination and infection risk, and drive this model using estimates of leaf wetness duration and canopy temperature from the Japanese 55-Year Reanalysis (JRA-55). We model germination and infection as Weibull functions with different temperature optima, based upon existing experimental data. We find no evidence for an overall trend in disease risk in coffee-growing regions of Colombia from 1990 to 2015, therefore, we reject the climate change hypothesis. There was a significant elevation in predicted CLR infection risk from 2008 to 2011 compared with other years. JRA-55 data suggest a decrease in canopy surface water after 2008, which may have helped terminate the outbreak. The spatial resolution and accuracy of climate reanalyses are continually improving, increasing their utility for biological modelling. Confronting disease models with data requires not only accurate climate data, but also disease observations at high spatio-temporal resolution. Investment in monitoring, storage and accessibility of plant disease observation data are needed to match the quality of the climate data now available.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'. PMID- 28080983 TI - Snake fungal disease: an emerging threat to wild snakes. AB - Since 2006, there has been a marked increase in the number of reports of severe and often fatal fungal skin infections in wild snakes in the eastern USA. The emerging condition, referred to as snake fungal disease (SFD), was initially documented in rattlesnakes, where the infections were believed to pose a risk to the viability of affected populations. The disease is caused by Ophidiomyces ophiodiicola, a fungus recently split from a complex of fungi long referred to as the Chrysosporium anamorph of Nannizziopsis vriesii (CANV). Here we review the current state of knowledge about O. ophiodiicola and SFD. In addition, we provide original findings which demonstrate that O. ophiodiicola is widely distributed in eastern North America, has a broad host range, is the predominant cause of fungal skin infections in wild snakes and often causes mild infections in snakes emerging from hibernation. This new information, together with what is already available in the scientific literature, advances our knowledge of the cause, pathogenesis and ecology of SFD. However, additional research is necessary to elucidate the factors driving the emergence of this disease and develop strategies to mitigate its impacts.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'. PMID- 28080985 TI - Emerging oomycete threats to plants and animals. AB - Oomycetes, or water moulds, are fungal-like organisms phylogenetically related to algae. They cause devastating diseases in both plants and animals. Here, we describe seven oomycete species that are emerging or re-emerging threats to agriculture, horticulture, aquaculture and natural ecosystems. They include the plant pathogens Phytophthora infestans, Phytophthora palmivora, Phytophthora ramorum, Plasmopara obducens, and the animal pathogens Aphanomyces invadans, Saprolegnia parasitica and Halioticida noduliformans For each species, we describe its pathology, importance and impact, discuss why it is an emerging threat and briefly review current research activities.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'. PMID- 28080986 TI - Clinical implications of globally emerging azole resistance in Aspergillus fumigatus. AB - Aspergillus fungi are the cause of an array of diseases affecting humans, animals and plants. The triazole antifungal agents itraconazole, voriconazole, isavuconazole and posaconazole are treatment options against diseases caused by Aspergillus However, resistance to azoles has recently emerged as a new therapeutic challenge in six continents. Although de novo azole resistance occurs occasionally in patients during azole therapy, the main burden is the aquisition of resistance through the environment. In this setting, the evolution of resistance is attributed to the widespread use of azole-based fungicides. Although ubiquitously distributed, A. fumigatus is not a phytopathogen. However, agricultural fungicides deployed against plant pathogenic moulds such as Fusarium, Mycospaerella and A. flavus also show activity against A. fumigatus in the environment and exposure of non-target fungi is inevitable. Further, similarity in molecule structure between azole fungicides and antifungal drugs results in cross-resistance of A. fumigatus to medical azoles. Clinical studies have shown that two-thirds of patients with azole-resistant infections had no previous history of azole therapy and high mortality rates between 50% and 100% are reported in azole-resistant invasive aspergillosis. The resistance phenotype is associated with key mutations in the cyp51A gene, including TR34/L98H, TR53 and TR46/Y121F/T289A resistance mechanisms. Early detection of resistance is of paramount importance and if demonstrated, either with susceptibility testing or through molecular analysis, azole monotherapy should be avoided. Liposomal amphotericin B or a combination of voriconazole and an echinocandin are recomended for azole-resistant aspergillosis.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'. PMID- 28080987 TI - Ploidy dynamics and evolvability in fungi. AB - Rapid responses to acute stresses are essential for stress survival and are critical to the ability of fungal pathogens to adapt to new environments or hosts. The rapid emergence of drug resistance is used as a model for how fungi adapt and survive stress conditions that inhibit the growth of progenitor cells. Aneuploidy and loss of heterozygosity (LOH), which are large-scale genome shifts involving whole chromosomes or chromosome arms, occur at higher frequency than point mutations and have the potential to mediate stress survival. Furthermore, the stress of exposure to an antifungal drug can induce elevated levels of LOH and can promote the formation of aneuploids. This occurs via mitotic defects that first produce tetraploid progeny with extra spindles, followed by chromosome mis segregation. Thus, drug exposure induces elevated levels of aneuploidy, which can alter the copy number of genes that improve survival in a given stress or drug. Selection then acts to increase the proportion of adaptive aneuploids in the population. Because aneuploidy is a common property of many pathogenic fungi, including those posing emerging threats to plants, animals and humans, we propose that aneuploid formation and LOH often accompanying it contribute to the rapid generation of diversity that can facilitate the emergence of fungal pathogens to new environmental niches and/or new hosts, as well as promote antifungal drug resistance that makes emerging fungal infections ever more difficult to contain.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'. PMID- 28080990 TI - Food system consequences of a fungal disease epidemic in a major crop. AB - Fungal diseases are major threats to the most important crops upon which humanity depends. Were there to be a major epidemic that severely reduced yields, its effects would spread throughout the globalized food system. To explore these ramifications, we use a partial equilibrium economic model of the global food system (IMPACT) to study a hypothetical severe but short-lived epidemic that reduces rice yields in the countries affected by 80%. We modelled a succession of epidemic scenarios of increasing severity, starting with the disease in a single country in southeast Asia and ending with the pathogen present in most of eastern Asia. The epidemic and subsequent crop losses led to substantially increased global rice prices. However, as long as global commodity trade was unrestricted and able to respond fast enough, the effects on individual calorie consumption were, to a large part, mitigated. Some of the worse effects were projected to be experienced by poor net-rice importing countries in sub-Saharan Africa, which were not affected directly by the disease but suffered because of higher rice prices. We critique the assumptions of our models and explore political economic pressures to restrict trade at times of crisis. We finish by arguing for the importance of 'stress-testing' the resilience of the global food system to crop disease and other shocks.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'. PMID- 28080988 TI - Medical mycology and fungal immunology: new research perspectives addressing a major world health challenge. AB - Fungi cause more than a billion skin infections, more than 100 million mucosal infections, 10 million serious allergies and more than a million deaths each year. Global mortality owing to fungal infections is greater than for malaria and breast cancer and is equivalent to that owing to tuberculosis (TB) and HIV. These statistics evidence fungal infections as a major threat to human health and a major burden to healthcare budgets worldwide. Those patients who are at greatest risk of life-threatening fungal infections include those who have weakened immunity or have suffered trauma or other predisposing infections such as HIV. To address these global threats to human health, more research is urgently needed to understand the immunopathology of fungal disease and human disease susceptibility in order to augment the advances being made in fungal diagnostics and drug development. Here, we highlight some recent advances in basic research in medical mycology and fungal immunology that are beginning to inform clinical decisions and options for personalized medicine, vaccine development and adjunct immunotherapies.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'. PMID- 28080989 TI - Overview of chytrid emergence and impacts on amphibians. AB - Chytridiomycosis is an emerging infectious disease of amphibians that affects over 700 species on all continents where amphibians occur. The amphibian chytridiomycosis system is complex, and the response of any amphibian species to chytrid depends on many aspects of the ecology and evolutionary history of the amphibian, the genotype and phenotype of the fungus, and how the biological and physical environment can mediate that interaction. Impacts of chytridiomycosis on amphibians are varied; some species have been driven extinct, populations of others have declined severely, whereas still others have not obviously declined. Understanding patterns and mechanisms of amphibian responses to chytrids is critical for conservation and management. Robust estimates of population numbers are needed to identify species at risk, prioritize taxa for conservation actions, design management strategies for managing populations and species, and to develop effective measures to reduce impacts of chytrids on amphibians.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'. PMID- 28080991 TI - Minimizing fungal disease deaths will allow the UNAIDS target of reducing annual AIDS deaths below 500 000 by 2020 to be realized. AB - Deaths from AIDS (1 500 000 in 2013) have been falling more slowly than anticipated with improved access to antiretroviral therapy. Opportunistic infections account for most AIDS-related mortality, with a median age of death in the mid-30s. About 360 000 (24%) of AIDS deaths are attributed to tuberculosis. Fungal infections deaths in AIDS were estimated at more than 700 000 deaths (47%) annually. Rapid diagnostic tools and antifungal agents are available for these diseases and would likely have a major impact in reducing deaths. Scenarios for reduction of avoidable deaths were constructed based on published outcomes of the real-life impact of diagnostics and generic antifungal drugs to 2020. Annual deaths could fall for cryptococcal disease by 70 000, Pneumocystis pneumonia by 162 500, disseminated histoplasmosis by 48 000 and chronic pulmonary aspergillosis by 33 500, with approximately 60% coverage of diagnostics and antifungal agents; a total of >1 000 000 lives saved over 5 years. If factored in with the 90-90-90 campaign rollout and its effect, AIDS deaths could fall to 426 000 annually by 2020, with further reductions possible with increased coverage. Action could and should be taken by donors, national and international public health agencies, NGOs and governments to achieve the UNAIDS mortality reduction target, by scaling up capability to detect and treat fungal disease in AIDS.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'. PMID- 28080992 TI - Microevolutionary traits and comparative population genomics of the emerging pathogenic fungus Cryptococcus gattii. AB - Emerging fungal pathogens cause an expanding burden of disease across the animal kingdom, including a rise in morbidity and mortality in humans. Yet, we currently have only a limited repertoire of available therapeutic interventions. A greater understanding of the mechanisms of fungal virulence and of the emergence of hypervirulence within species is therefore needed for new treatments and mitigation efforts. For example, over the past decade, an unusual lineage of Cryptococcus gattii, which was first detected on Vancouver Island, has spread to the Canadian mainland and the Pacific Northwest infecting otherwise healthy individuals. The molecular changes that led to the development of this hypervirulent cryptococcal lineage remain unclear. To explore this, we traced the history of similar microevolutionary events that can lead to changes in host range and pathogenicity. Here, we detail fine-resolution mapping of genetic differences between two highly related Cryptococcus gattii VGIIc isolates that differ in their virulence traits (phagocytosis, vomocytosis, macrophage death, mitochondrial tubularization and intracellular proliferation). We identified a small number of single site variants within coding regions that potentially contribute to variations in virulence. We then extended our methods across multiple lineages of C. gattii to study how selection is acting on key virulence genes within different lineages.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'. PMID- 28080993 TI - Secondary metabolite arsenal of an opportunistic pathogenic fungus. AB - Aspergillus fumigatus is a versatile fungus able to successfully exploit diverse environments from mammalian lungs to agricultural waste products. Among its many fitness attributes are dozens of genetic loci containing biosynthetic gene clusters (BGCs) producing bioactive small molecules (often referred to as secondary metabolites or natural products) that provide growth advantages to the fungus dependent on environment. Here we summarize the current knowledge of these BGCs-18 of which can be named to product-their expression profiles in vivo, and which BGCs may enhance virulence of this opportunistic human pathogen. Furthermore, we find extensive evidence for the presence of many of these BGCs, or similar BGCs, in distantly related genera including the emerging pathogen Pseudogymnoascus destructans, the causative agent of white-nose syndrome in bats, and suggest such BGCs may be predictive of pathogenic potential in other fungi.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'. PMID- 28080994 TI - Global food and fibre security threatened by current inefficiencies in fungal identification. AB - Fungal pathogens severely impact global food and fibre crop security. Fungal species that cause plant diseases have mostly been recognized based on their morphology. In general, morphological descriptions remain disconnected from crucially important knowledge such as mating types, host specificity, life cycle stages and population structures. The majority of current fungal species descriptions lack even the most basic genetic data that could address at least some of these issues. Such information is essential for accurate fungal identifications, to link critical metadata and to understand the real and potential impact of fungal pathogens on production and natural ecosystems. Because international trade in plant products and introduction of pathogens to new areas is likely to continue, the manner in which fungal pathogens are identified should urgently be reconsidered. The technologies that would provide appropriate information for biosecurity and quarantine already exist, yet the scientific community and the regulatory authorities are slow to embrace them. International agreements are urgently needed to enforce new guidelines for describing plant pathogenic fungi (including key DNA information), to ensure availability of relevant data and to modernize the phytosanitary systems that must deal with the risks relating to trade-associated plant pathogens.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'. PMID- 28080995 TI - Rapid emergence of pathogens in agro-ecosystems: global threats to agricultural sustainability and food security. AB - Agricultural ecosystems are composed of genetically depauperate populations of crop plants grown at a high density and over large spatial scales, with the regional composition of crop species changing little from year to year. These environments are highly conducive for the emergence and dissemination of pathogens. The uniform host populations facilitate the specialization of pathogens to particular crop cultivars and allow the build-up of large population sizes. Population genetic and genomic studies have shed light on the evolutionary mechanisms underlying speciation processes, adaptive evolution and long-distance dispersal of highly damaging pathogens in agro-ecosystems. These studies document the speed with which pathogens evolve to overcome crop resistance genes and pesticides. They also show that crop pathogens can be disseminated very quickly across and among continents through human activities. In this review, we discuss how the peculiar architecture of agro-ecosystems facilitates pathogen emergence, evolution and dispersal. We present four example pathosystems that illustrate both pathogen specialization and pathogen speciation, including different time frames for emergence and different mechanisms underlying the emergence process. Lastly, we argue for a re-design of agro-ecosystems that embraces the concept of dynamic diversity to improve their resilience to pathogens. This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'. PMID- 28080997 TI - Tackling emerging fungal threats to animal health, food security and ecosystem resilience. AB - Emerging infections caused by fungi have become a widely recognized global phenomenon. Their notoriety stems from their causing plagues and famines, driving species extinctions, and the difficulty in treating human mycoses alongside the increase of their resistance to antifungal drugs. This special issue comprises a collection of articles resulting from a Royal Society discussion meeting examining why pathogenic fungi are causing more disease now than they did in the past, and how we can tackle this rapidly emerging threat to the health of plants and animals worldwide.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'. PMID- 28080998 TI - Determination of oxycodone and its major metabolites noroxycodone and oxymorphone by ultra-high-performance liquid chromatography tandem mass spectrometry in plasma and urine: application to real cases. AB - BACKGROUND: Oxycodone is a narcotic drug widely used to alleviate moderate and severe acute and chronic pain. Variability in analgesic efficacy could be explained by inter-subject variations in plasma concentrations of parent drug and its active metabolite, oxymorphone. To evaluate patient compliance and to set up therapeutic drug monitoring (TDM), an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) assay was developed and validated for the parent drug and its major metabolites noroxycodone and oxymorphone. METHODS: Extraction of analytes from plasma and urine samples was obtained by simple liquid-liquid extraction. The chromatographic separation was achieved with a reversed phase column using a linear gradient elution with two solvents: acetic acid 1% in water and methanol. The separated analytes were detected with a triple quadrupole mass spectrometer operated in multiple reaction monitoring (MRM) mode via positive electrospray ionization (ESI). RESULTS: Separation of analytes was obtained in less than 5 min. Linear calibration curves for all the analytes under investigation in urine and plasma samples showed determination coefficients (r2) equal or higher than 0.990. Mean absolute analytical recoveries were always above 86%. Intra- and inter-assay precision (measured as coefficient of variation, CV%) and accuracy (measured as % error) values were always better than 13%. Limit of detection at 0.06 and 0.15 ng/mL and limit of quantification at 0.2 and 0.5 ng/mL for plasma and urine samples, respectively, were adequate for the purpose of the present study. CONCLUSIONS: Rapid extraction, identification and quantification of oxycodone and its metabolites both in urine and plasma by UHPLC-MS/MS assay was tested for its feasibility in clinical samples and provided excellent results for rapid and effective drug testing in patients under oxycodone treatment. PMID- 28080996 TI - Mitigating amphibian chytridiomycoses in nature. AB - Amphibians across the planet face the threat of population decline and extirpation caused by the disease chytridiomycosis. Despite consensus that the fungal pathogens responsible for the disease are conservation issues, strategies to mitigate their impacts in the natural world are, at best, nascent. Reducing risk associated with the movement of amphibians, non-amphibian vectors and other sources of infection remains the first line of defence and a primary objective when mitigating the threat of disease in wildlife. Amphibian-associated chytridiomycete fungi and chytridiomycosis are already widespread, though, and we therefore focus on discussing options for mitigating the threats once disease emergence has occurred in wild amphibian populations. All strategies have shortcomings that need to be overcome before implementation, including stronger efforts towards understanding and addressing ethical and legal considerations. Even if these issues can be dealt with, all currently available approaches, or those under discussion, are unlikely to yield the desired conservation outcome of disease mitigation. The decision process for establishing mitigation strategies requires integrated thinking that assesses disease mitigation options critically and embeds them within more comprehensive strategies for the conservation of amphibian populations, communities and ecosystems.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'. PMID- 28080999 TI - Electrochemical depositing rGO-Ti-rGO heterogeneous substrates with higher thermal conductivity and heat transfer performance compared to pure Ti. AB - Titanium (Ti) and its alloys are widely applied in many high strength, light weight applications, but their thermal conductivity is lower compared to that of other metals, which limits their further applications. In this paper, we demonstrated experimentally that rGO-Ti-rGO heterogeneous substrates with higher thermal conductivity, up to ~38.8% higher than Ti, could be fabricated by electrochemical depositing rGO on their surface. The rGO layers are grown on the surface of Ti substrates, with appearance of bedclothes on the beds. The thickness of rGO layers is around 300-500 nm and around 600-1000 nm when deposited for 5 cycles and 10 cycles, respectively. According to the cooling experiment results, as-prepared Ti + rGO substrates can present excellent thermal conduction performance, and reduce the chip temperature close to 3.2 degrees C 13.1 degrees C lower than Ti alloy substrates with the heat flow density of 0.4 3.6 W cm-2. Finally, the approach to electro-chemically deposit hundreds of nanometer rGO layers on the surface of Ti substrates can improve their thermal conductivity and heat transfer performance, which may have further application in the increasing thermal conduction of other metal-alloys, ceramics and polymers. PMID- 28081000 TI - On the development of a VIPARnd radiotherapy 3D polymer gel dosimeter. AB - This work presents an improvement of the VIPARnd ('nd' stands for 'normoxic, double', or VIP) polymer gel dosimeter. The gel composition was altered by increasing the concentration of the monomeric components, N-vinylpyrrolidone (NVP) and N,N'-methylenebisacrylamide (MBA), in co-solvent solutions. The optimal composition (VIPARCT, where 'CT' stands for computed tomography, or VIC) comprised: 17% NVP, 8% MBA, 12% t-BuOH, 7.5% gelatine, 0.007% ascorbic acid, 0.0008% CuSO4 * 5H2O and 0.02% hydroquinone. The following characteristics of VIC were achieved: (i) linear dose range of 0.9_30 Gy, (ii) saturation for radiation doses of over 50 Gy, (iii) threshold dose of about 0.5 Gy, (iv) dose sensitivity of 0.171 Gy-1 s-1, which is roughly 2.2 times higher than that of VIP (for nuclear magnetic resonance measurements). It was also found that VIC is dose rate-independent, and its dose response does not alter if the radiation source is changed from electrons to photons for external beam radiotherapy. The gel responded similarly to irradiation with small changes in radiation energy but was sensitive to larger energy changes. The VIC gel retained temporal stability from 20 h until at least 10 d after irradiation, whereas spatial stability was retained from 20 h until at least 6 d after irradiation. The scheme adopted for VIC manufacturing yields repeatable gels in terms of radiation dose response. The VIC was also shown to perform better than VIP using x-ray computed tomography as a readout method; the dose sensitivity of VIC (0.397 HU Gy-1) was 1.5 times higher than that of VIP. Also, the dose resolution of VIC was better than that of VIP in the whole dose range examined. PMID- 28081001 TI - How assembly matters to catalysis and thermal conductivity mediated by CuO nanoparticles. AB - CuO nanostructures (NSs) of different morphologies were prepared, applied as catalysts for the pyrolysis of sugarcane bagasse (PSCB), and applied for thermally-conductive nanofluids. Both size and shape of the prepared NSs ranged from 5 to 1000 nm, and from nanodots (NDs) to spindle nano-aggregates (NAs), respectively. The catalytic activity of these NSs towards the PSCB was followed up by thermogravimetric analysis (TGA), where they increased the percentage of total weight loss, and lowered the decomposition temperatures of PSCB. The Coats Redfern kinetic model showed a decline in activation energy by 57 and 9-43 kJ mol 1 for NDs and NAs, respectively. Colloidal dispersions of CuO NDs and NAs in monoethylene glycol (MEG) were prepared with volume fractions ([Formula: see text]) of 0.01-0.04%, where thermal conductivity improved with increasing [Formula: see text]. At all values of [Formula: see text], the best enhancements were exerted by NDs. The nature of assembly impacted the catalyzed PSCB and the thermal conductivity of MEG. This behavior depends to a large extent on the NAs that expose a different fraction of crystal facets of different reactivities and surface areas, not on the constituent nanorods (NRs). PMID- 28081002 TI - Symmetry analysis of transport properties in helical superconductor junctions. AB - We study the discrete symmetries satisfied by helical p-wave superconductors with the d-vectors [Formula: see text] or [Formula: see text] and the transformations brought by symmetry operations to ferromagnet and spin-singlet superconductors, which show intimate associations with the transport properties in heterojunctions, including helical superconductors. In particular, the partial symmetries of the Hamiltonian under spin-rotation and gauge-rotation operations are responsible for the novel invariances of the conductance in tunnel junctions and the new selection rules for the lowest current and peculiar phase diagrams in Josephson junctions, which were reported recently. The symmetries of constructed free energies for Josephson junctions are also analyzed, and are consistent with the results from the Hamiltonian. PMID- 28081003 TI - Fe-nitrilotriacetic acid coordination polymer nanowires: an effective sensing platform for fluorescence-enhanced nucleic acid detection. AB - The determination of specific nucleic acid sequences is key in identifying disease-causing pathogens and genetic diseases. In this paper we report the utilization of Fe-nitrilotriacetic acid coordination polymer nanowires as an effective nanoquencher for fluorescence-enhanced nucleic acid detection. The detection is fast and the whole process can be completed within 15 min. This nanosensor shows a low detection limit of 0.2 nM with selectivity down to single base mismatch. This work provides us with an attractive sensing platform for applications. PMID- 28081004 TI - Reverberant shear wave fields and estimation of tissue properties. AB - The determination of shear wave speed is an important subject in the field of elastography, since elevated shear wave speeds can be directly linked to increased stiffness of tissues. MRI and ultrasound scanners are frequently used to detect shear waves and a variety of estimators are applied to calculate the underlying shear wave speed. The estimators can be relatively simple if plane wave behavior is assumed with a known direction of propagation. However, multiple reflections from organ boundaries and internal inhomogeneities and mode conversions can create a complicated field in time and space. Thus, we explore the mathematics of multiple component shear wave fields and derive the basic properties, from which efficient estimators can be obtained. We approach this problem from the historic perspective of reverberant fields, a conceptual framework used in architectural acoustics and related fields. The framework can be recast for the alternative case of shear waves in a bounded elastic media, and the expected value of displacement patterns in shear reverberant fields are derived, along with some practical estimators of shear wave speed. These are applied to finite element models and phantoms to illustrate the characteristics of reverberant fields and provide preliminary confirmation of the overall framework. PMID- 28081005 TI - Mechanical properties and failure behavior of phosphorene with grain boundaries. AB - Using the density-functional tight-binding method, we studied the effect of grain boundaries on the mechanical properties and failure behavior of phosphorene. We found that the high-angle tilt boundaries with a higher density of (5?7) defect pairs (oriented along the armchair direction) are stronger than the low-angle tilt boundaries with a lower defect density, and similarly the high-angle boundaries with a higher density of (4?8) defect pairs (oriented along the zigzag direction) are stronger than the low-angle boundaries with a lower defect density. The failure is due to the rupture of the most pre-strained bonds in the heptagons of the (5?7) defect pair or octagons of the (4?8) pairs. The high-angle grain boundaries are better at accommodating the pre-strained bonds in heptagon and octagon defects, leading to a higher failure stress and strain. The results cannot be described by a Griffith-type fracture mechanics criterion, since this does not take into account the bond pre-stretching. Interestingly, these anomalous mechanical and failure characteristics of tilt grain boundaries in phosphorene are also shared by graphene and hexagonal boron nitride, signifying that they may be universal for 2D materials. The findings revealed here may be useful in tuning the mechanical properties of phosphorene via defect engineering for specific applications. PMID- 28081006 TI - Latent feature representation with depth directional long-term recurrent learning for breast masses in digital breast tomosynthesis. AB - Characterization of masses in computer-aided detection systems for digital breast tomosynthesis (DBT) is an important step to reduce false positive (FP) rates. To effectively differentiate masses from FPs in DBT, discriminative mass feature representation is required. In this paper, we propose a new latent feature representation boosted by depth directional long-term recurrent learning for characterizing malignant masses. The proposed network is designed to encode mass characteristics in two parts. First, 2D spatial image characteristics of DBT slices are encoded as a slice feature representation by convolutional neural network (CNN). Then, depth directional characteristics of masses among the slice feature representations are encoded by the proposed depth directional long-term recurrent learning. In addition, to further improve the class discriminability of latent feature representation, we have devised three objective functions aiming to (a) minimize classification error, (b) minimize intra-class variation within the same class, and (c) preserve feature representation consistency in a central slice. Experimental results have demonstrated that the proposed latent feature representation achieves a higher level of classification performance in terms of receiver operating characteristic (ROC) curves and the area under the ROC curve values compared to performance with feature representation learned by conventional CNN and hand-crafted features. PMID- 28081007 TI - Electronic structure of AlCrN films investigated using various photoelectron spectroscopies and ab initio calculations. AB - The valence band (VB) structures of wurtzite AlCrN (Cr concentration: 0-17.1%), which show optical absorption in the ultraviolet-visible-infrared light region, were investigated via photoelectron yield spectroscopy (PYS), x-ray/ultraviolet photoelectron spectroscopy (XPS/UPS), and ab initio density of states (DOS) calculations. An obvious photoelectron emission threshold was observed ~5.3 eV from the vacuum level for AlCrN, whereas no emission was observed for AlN in the PYS spectra. Comparisons of XPS and UPS VB spectra and the calculated DOS imply that Cr 3d states are formed both at the top of the VB and in the AlN gap. These data suggest that Cr doping could be a viable option to produce new materials with relevant energy band structures for solar photoelectric conversion. PMID- 28081008 TI - Elastic properties of amorphous T 0.75Y0.75B14 (T = Sc, Ti, V, Y, Zr, Nb) and the effect of O incorporation on bonding, density and elasticity (T' = Ti, Zr). AB - We have systematically studied the effect of transition metal valence electron concentration (VEC) of amorphous T 0.75Y0.75B14 (a-T 0.75Y0.75B14, T = Sc, Ti, V, Y, Zr, Nb) on the elastic properties, bonding, density and electronic structure using ab initio molecular dynamics. As the transition metal VEC is increased in both periods, the bulk modulus increases linearly with molar- and mass density. This trend can be understood by a concomitant decrease in cohesive energy. T' = Ti and Zr were selected to validate the predicted data experimentally. A-Ti0.74Y0.80B14 and a-Zr0.75Y0.75B14 thin films were synthesized by high power pulsed magnetron sputtering. Chemical composition analysis revealed the presence of up to 5 at.% impurities, with O being the largest fraction. The measured Young's modulus values for a-Ti0.74Y0.80B14 (301 +/- 8 GPa) and a Zr0.75Y0.75B14 (306 +/- 9 GPa) are more than 20% smaller than the predicted ones. The influence of O incorporation on the elastic properties for these selected systems was theoretically studied, exemplarily in a Ti0.75Y0.75B12.75O1.25. Based on ab initio data, we suggest that a-Ti0.75Y0.75B14 exhibits a very dense B network, which is partly severed in a Ti0.75Y0.75B12.75O1.25. Upon O incorporation, the average coordination number of B and the molar density decrease by 9% and 8%, respectively. Based on these data the more than 20% reduced Young's modulus obtained experimentally for films containing impurities compared to the calculated Young's modulus for a Ti0.75Y0.75B14 (without incorporated oxygen) can be rationalized. The presence of oxygen impurities disrupts the strong B network causing a concomitant decrease in molar density and Young's modulus. Very good agreement between the measured and calculated Young's modulus values is obtained if the presence of impurities is considered in the calculations. The implications of these findings are that prediction efforts regarding the elastic properties of amorphous borides containing oxygen impurities on the at.% level are flawed without taking the presence of impurities into account. PMID- 28081009 TI - Influence of wall thickness and diameter on arterial shear wave elastography: a phantom and finite element study. AB - Quantitative, non-invasive and local measurements of arterial mechanical properties could be highly beneficial for early diagnosis of cardiovascular disease and follow up of treatment. Arterial shear wave elastography (SWE) and wave velocity dispersion analysis have previously been applied to measure arterial stiffness. Arterial wall thickness (h) and inner diameter (D) vary with age and pathology and may influence the shear wave propagation. Nevertheless, the effect of arterial geometry in SWE has not yet been systematically investigated. In this study the influence of geometry on the estimated mechanical properties of plates (h = 0.5-3 mm) and hollow cylinders (h = 1, 2 and 3 mm, D = 6 mm) was assessed by experiments in phantoms and by finite element method simulations. In addition, simulations in hollow cylinders with wall thickness difficult to achieve in phantoms were performed (h = 0.5-1.3 mm, D = 5-8 mm). The phase velocity curves obtained from experiments and simulations were compared in the frequency range 200-1000 Hz and showed good agreement (R 2 = 0.80 +/- 0.07 for plates and R 2 = 0.82 +/- 0.04 for hollow cylinders). Wall thickness had a larger effect than diameter on the dispersion curves, which did not have major effects above 400 Hz. An underestimation of 0.1-0.2 mm in wall thickness introduces an error 4-9 kPa in hollow cylinders with shear modulus of 21-26 kPa. Therefore, wall thickness should correctly be measured in arterial SWE applications for accurate mechanical properties estimation. PMID- 28081010 TI - Biological dose representation for carbon-ion radiotherapy of unconventional fractionation. AB - In carbon-ion radiotherapy, single-beam delivery each day in alternate directions has been common practice for efficient operation, taking advantage of the Bragg peak and the relative biological effectiveness (RBE) for uniform dose conformation to a tumor. Treatments are usually fractionated and treatment plans are evaluated with the total RBE-weighted dose; however, this is of limited relevance to the biological effect. In this study, we reformulate the biologically effective dose (BED) to normalize the dose-fractionation and cell repopulation effects as well as the RBE of treating radiation, based on inactivation of a reference cell line by a reference carbon-ion radiation. The BED distribution virtually represents the biological effect of a treatment regardless of radiation modality or fractionation scheme. We applied the BED formulation to simplistic model treatments and to a preclinical survey for hypofractionation based on an actual prostate cancer treatment with carbon ions. The proposed formulation was demonstrated to be practical and to give theoretical implications. For a prostate cancer treatment in 12 fractions, the distributions of BED and of RBE-weighted dose were very similar. With hypofractionation, while the RBE-weighted dose distribution varied significantly, the BED distribution was nearly invariant, implying that carbon-ion radiotherapy would be effectively insensitive to fractionation. However, treatment evaluation with such a simplistic biological dose is intrinsically limited and must be complemented in practice by clinical experience and biological experiments. PMID- 28081011 TI - Spectrum reconstruction method based on the detector response model calibrated by x-ray fluorescence. AB - Accurate estimation of distortion-free spectra is important but difficult in various applications, especially for spectral computed tomography. Two key problems must be solved to reconstruct the incident spectrum. One is the acquisition of the detector energy response. It can be calculated by Monte Carlo simulation, which requires detailed modeling of the detector system and a high computational power. It can also be acquired by establishing a parametric response model and be calibrated using monochromatic x-ray sources, such as synchrotron sources or radioactive isotopes. However, these monochromatic sources are difficult to obtain. Inspired by x-ray fluorescence (XRF) spectrum modeling, we propose a feasible method to obtain the detector energy response based on an optimized parametric model for CdZnTe or CdTe detectors. The other key problem is the reconstruction of the incident spectrum with the detector response. Directly obtaining an accurate solution from noisy data is difficult because the reconstruction problem is severely ill-posed. Different from the existing spectrum stripping method, a maximum likelihood-expectation maximization iterative algorithm is developed based on the Poisson noise model of the system. Simulation and experiment results show that our method is effective for spectrum reconstruction and markedly increases the accuracy of XRF spectra compared with the spectrum stripping method. The applicability of the proposed method is discussed, and promising results are presented. PMID- 28081012 TI - The lead acceptor in p-type natural 2H-polytype MoS2 crystals evidenced by electron paramagnetic resonance. AB - A low-temperature (T = 1.5-8 K) electron paramagnetic resonance study of p-type 2H-polytype natural MoS2 crystals reveals a previously unreported anisotropic signal of corresponding defect density (spin S = 1/2) ~5 * 1014 cm-3. For the applied magnetic field B//c-axis, the response is comprised of a single central asymmetric Zeeman peak at zero-crossing g = 2.102(1), amid a symmetrically positioned hyperfine doublet of splitting 6.6(2) G. Field angular observations reveal a two-branch g pattern, indicative of a defect of lower than axial symmetry, likely orthorhombic (C 2v). Based on the signal specifics, it is ascribed to a system of decoupled Pb impurities substituting for Mo, the defect operating as an acceptor, with estimated thermal activation energy >10 meV. Supporting theoretical anticipation, the results pinpoint the conduct of the Pb impurity in layered MoS2. PMID- 28081013 TI - Magneto photoluminescence measurements of tungsten disulphide monolayers. AB - Layered transition-metal dichalcogenides have attracted great interest in the last few years. Thinned down to the monolayer limit they change from an indirect band structure to a direct band gap in the visible region. Due to the monolayer thickness the inversion symmetry of the crystal is broken and spin and valley are coupled to each other. The degeneracy between the two equivalent valleys, K and K', respectively, can be lifted by applying an external magnetic field. Here, we present photoluminescence measurements of CVD-grown tungsten disulphide (WS2) monolayers at temperatures of 2 K. By applying magnetic fields up to 7 T in Faraday geometry, a splitting of the photoluminescence peaks can be observed. The magnetic field dependence of the A-exciton, the trion and three bound exciton states is discussed and the corresponding g-factors are determined. PMID- 28081015 TI - The prospects of phosphorene as an anode material for high-performance lithium ion batteries: a fundamental study. AB - To completely understand lithium adsorption, diffusion, and capacity on the surface of phosphorene and, therefore, the prospects of phosphorene as an anode material for high-performance lithium-ion batteries (LIBs), we carried out density-functional-theory calculations and studied the lithium adsorption energy landscape, the lithium diffusion mobility, the lithium intercalation, and the lithium capacity of phosphorene. We also carried out, for the very first time, experimental measurement of the lithium capacity of phosphorene. Our calculations show that the lithium diffusion mobility along the zigzag direction in the valley of phosphorene was about 7 to 11 orders of magnitude faster than that along the other directions, indicating its ultrafast and anisotropic diffusivity. The lithium intercalation in phosphorene was studied by considering various Li n P16 configurations (n = 1-16) including single-side and double-side adsorptions. We found that phosphorene could accommodate up to a ratio of one Li per P atom (i.e. Li16P16). In particular, we found that, even at a high Li concentration (e.g. x = 1 in Li x P), there was no lithium clustering, and the structure of phosphorene (when fractured) is reversible during lithium intercalation. The theoretical value of the lithium capacity for a monolayer phosphorene is predicted to be above 433 mAh g-1, depending on whether Li atoms are adsorbed on the single side or the double side of phosphorene. Our experimental measurement of the lithium capacity for few-layer phosphorene networks shows a reversible stable value of ~453 mAh g-1 even after 50 cycles. Our results clearly show that phosphorene, compared to graphene and other two-dimensional materials, has great promise as a novel anode material for high-performance LIBs. PMID- 28081014 TI - Canny edge-based deformable image registration. AB - This work focuses on developing a 2D Canny edge-based deformable image registration (Canny DIR) algorithm to register in vivo white light images taken at various time points. This method uses a sparse interpolation deformation algorithm to sparsely register regions of the image with strong edge information. A stability criterion is enforced which removes regions of edges that do not deform in a smooth uniform manner. Using a synthetic mouse surface ground truth model, the accuracy of the Canny DIR algorithm was evaluated under axial rotation in the presence of deformation. The accuracy was also tested using fluorescent dye injections, which were then used for gamma analysis to establish a second ground truth. The results indicate that the Canny DIR algorithm performs better than rigid registration, intensity corrected Demons, and distinctive features for all evaluation matrices and ground truth scenarios. In conclusion Canny DIR performs well in the presence of the unique lighting and shading variations associated with white-light-based image registration. PMID- 28081016 TI - Graphene as a flexible template for controlling magnetic interactions between metal atoms. AB - Metal-doped graphene produces magnetic moments that have potential application in spintronics. Here we use density function theory computational methods to show how the magnetic interaction between metal atoms doped in graphene can be controlled by the degree of flexure in a graphene membrane. Bending graphene by flexing causes the distance between two substitutional Fe atoms covalently bonded in graphene to gradually increase and these results in the magnetic moment disappearing at a critical strain value. At the critical strain, a carbon atom can enter between the two Fe atoms and blocks the interaction between relevant orbitals of Fe atoms to quench the magnetic moment. The control of interactions between doped atoms by exploiting the mechanical flexibility of graphene is a unique approach to manipulating the magnetic properties and opens up new opportunities for mechanical-magnetic 2D device systems. PMID- 28081017 TI - Lattice parameters guide superconductivity in iron-arsenides. AB - The discovery of superconducting materials has led to their use in technological marvels such as magnetic-field sensors in MRI machines, powerful research magnets, short transmission cables, and high-speed trains. Despite such applications, the uses of superconductors are not widespread because they function much below room-temperature, hence the costly cooling. Since the discovery of Cu- and Fe-based high-temperature superconductors (HTS), much intense effort has tried to explain and understand the superconducting phenomenon. While no exact explanations are given, several trends are reported in relation to the materials basis in magnetism and spin excitations. In fact, most HTS have antiferromagnetic undoped 'parent' materials that undergo a superconducting transition upon small chemical substitutions in them. As it is currently unclear which 'dopants' can favor superconductivity, this manuscript investigates crystal structure changes upon chemical substitutions, to find clues in lattice parameters for the superconducting occurrence. We review the chemical substitution effects on the crystal lattice of iron-arsenide-based crystals (2008 to present). We note that (a) HTS compounds have nearly tetragonal structures with a-lattice parameter close to 4 A, and (b) superconductivity can depend strongly on the c-lattice parameter changes with chemical substitution. For example, a decrease in c-lattice parameter is required to induce 'in-plane' superconductivity. The review of lattice parameter trends in iron-arsenides presented here should guide synthesis of new materials and provoke theoretical input, giving clues for HTS. PMID- 28081018 TI - Mantle Cell Lymphoma Presenting as a Subcutaneous Soft Tissue Mass With an Unusual Appearance. PMID- 28081019 TI - Adenofibroma in the Uterine Cervix Manifesting as Multilocular Cystic Lesions. AB - Uterine cervical adenofibroma, a very rare benign neoplasm, has rarely been reported in imaging features in the English literature. Herein, we describe a case of uterine cervical adenofibroma that was depicted as a multilocular cystic lesion with enhanced solid portions. PMID- 28081020 TI - Sonographic Findings and Diagnostic Pitfalls in Evaluation for Uterine Rupture in a Case of Fetal Demise and Prior Cesarean Delivery of Unknown Type. AB - A 38-week pregnant patient with history of cesarean delivery was admitted to the hospital for induction of labor after diagnosis of fetal demise. When the clinical picture became concerning for uterine scar dehiscence, an ultrasound was ordered. After targeted ultrasound of the lower uterine segment, the sonographer initially reported thin but intact lower uterine segment and normal positioning of the fetus. By keeping a high level of suspicion, the radiologist analyzed the images submitted and found other clues suggesting possible dehiscence or rupture. Additional images were then obtained, ultimately demonstrating uterine rupture with fetus external to uterus. PMID- 28081021 TI - Endoleak. PMID- 28081022 TI - Luteoma of Pregnancy. PMID- 28081024 TI - Chinese TOC. PMID- 28081023 TI - A Case Study of Hemochromatosis and Conflicting Point Shear Wave Measurements in the Assessment of Liver Fibrosis. AB - There are multiple factors that affect the shear wave speed in the assessment of liver stiffness. In this case report, we present a case of hemochromatosis that has elevated liver stiffness suggestive of significant fibrosis or cirrhosis; however on liver biopsy, no fibrosis was identified. This article will discuss the possibility that liver iron deposition may affect SWE measurements of the liver, leading to inaccurate assessment of liver fibrosis. In these cases, a liver biopsy may be required for accurate liver assessment. PMID- 28081025 TI - Transdermal Scopolamine Withdrawal Syndrome Case Report in the Pediatric Cerebral Palsy Population. AB - Sialorrhea in children with cerebral palsy (CP) results in aspiration, decreased social integration, and poor quality of life. Management options include transdermal anticholinergics such as the scopolamine patch. A controlled clinical trial has proven botulinum toxin (BTX) injections into the salivary glands are an effective alternative to transdermal anticholinergics with a safer side effect profile. Multiple studies of the injections in diverse populations demonstrate reduction in saliva production with improvement in quality of life and decrease in hospitalization-associated costs. The authors describe a 15-year-old boy with spastic quadriplegic CP who developed emesis, nausea, and lethargy 1 day after the first injection of botulinum toxin A (BTX-A) to his salivary glands for sialorrhea management. The authors ascribed his symptoms to scopolamine withdrawal. Given the lack of exposure in the medical literature, there is minimal awareness of the withdrawal syndrome from transdermal scopolamine in children with or without CP, resulting in delayed diagnosis and potential complications. Treatment of the withdrawal syndrome has been successful with meclizine though safety and efficacy has not been established in children younger than 12 despite frequent clinical and over-the-counter use. Prompt diagnosis of the transdermal scopolamine withdrawal syndrome can result in quicker treatment and a shorter hospital stay. PMID- 28081026 TI - The Effect of Nebulized Glycopyrrolate on Posterior Drooling in Patients with Brain Injury: Two Cases of Different Brain Lesions. AB - Posterior drooling, which can lead to substantial respiratory morbidity, including unexplained lung diseases and recurrent pneumonia, is an important issue in the rehabilitation unit. There are various treatment options for posterior drooling, including pharmacologic therapy, oral motor or behavioral therapy, biofeedback, local glandular injection of botulinum toxin, irradiation, and surgery. Among them, nebulized glycopyrrolate has the following advantages: It is noninvasive and is relatively free of central adverse effects because it does not cross the blood-brain barrier unlike other anticholinergics. Although there has been one case report regarding the effectiveness of nebulized glycopyrrolate for drooling in a motor neuron patient, there have not been any reports on its effectiveness for posterior drooling. Herein, we report two cases (an 82-year-old male bilateral hemiplegic stroke patient and a 1-year-old female cerebral palsy infant with bilaterally spastic hemiplegia of posterior drooling treated with nebulized glycopyrrolate) and identify salivary aspiration and the effect of nebulized glycopyrrolate using radionuclide salivagram. Considering its advantages and effectiveness, nebulized glycopyrrolate should be considered as one of the reliable methods to manage posterior drooling in patients with impaired cognition or swallowing difficulties, such as severe brain injury. PMID- 28081027 TI - Physician Burnout in Physical Medicine and Rehabilitation (PM&R): Should We Focus More on Physiatrists' Mission? PMID- 28081028 TI - Second-Order Peer Reviews of Clinically Relevant Articles for the Physiatrist: "Early Physical Therapy Vs Usual Care in Patients with Recent-Onset Low Back Pain" (Fritz JM, Magel JS, McFadden M, et al, JAMA 2015): "Physical Therapy May Not Help Acute Lower Back Pain Sufferers". PMID- 28081029 TI - A Rarely Seen Complication That Causes Increase in Morbidity in Tetraplegic Patients: Zenker Diverticula. AB - Although spinal cord injury (SCI) damages the spinal cord, physiological changes due to SCI can affect many organs and systems of the human body. While respiratory problems are common following cervical SCI, dysphagia is a relatively uncommon secondary complication that occurs after cervical SCI. We report a case of recurrent aspiration pneumonia due to Zenker diverticulum in 26-year-old tetraplegic patient with a chronic history of silent aspirations and dysphagia contributing to functional disability. PMID- 28081030 TI - Ultrasound Findings of Young and Traumatic Amputees With Lower Extremity Residual Limb Pain in Turkey. AB - OBJECTIVE: The current study was designed to document clinical and ultrasound (US) findings of patients with residual limb pain (RLP) after amputation and to investigate the relationship between these findings. MATERIALS AND METHODS: A chart review was performed to identify demographic and clinical data including the age (current and at the time of injury), time since amputation, gender, reason for amputation, affected limb number, side and level of limb loss, and ultrasonographic findings of young and traumatic amputees with RLP. RESULTS: The study included a total of 147 patients. Inflammation and neuroma were the leading pathologies in 20-29 years and 30-39 years age groups, respectively. Inflammation/edema were detected significantly more in patients with <1 year since amputation (P = 0.001). Neuroma was found at a significantly high rate in patients at 1-5 years (P = 0.029) and infection/abscess was more common in patients at >5 years since amputation (P = 0.051). The percentage of neuromas in below-the-knee amputees was significantly higher than in non-below-the-knee amputees (45.8% vs. 28.6%). Neuroma formation was detected in 50% of the patients with land mine-related amputation and at 27% in patients with amputation secondary to other traumatic reasons. Regression analysis showed below-the-knee level amputation to be an associated factor for US abnormality. CONCLUSION: The leading US findings were inflammation/edema, neuroma, and infection/abscess in traumatic amputees with RLP. The US findings might be different in patients according to the time since amputation. Patient with land mine-related amputations may have different US findings. PMID- 28081031 TI - Intracranial hemorrhage recurrence on vitamin K antagonist: severity of the first episode and HASBLED score fail to identify high-risk patients from the CHIRONE study. AB - The most feared complication of vitamin K antagonists (VKAs) treatment is intracranial hemorrhage (ICH). The previously published CHIRONE Study fails to identify risk factors associated with ICH recurrence after VKAs resumption. The aim of this secondary analysis of the study is to evaluate if patients who need surgery or with severe neurological sequelae after the first episode show a higher risk of ICH recurrence. The HASBLED score was used to stratify bleeding risk and to evaluate the distribution of recurrence in relation to each class of risk. The study included 267 patients from 27 Italian centers. The treatment of the index ICH, surgical or medical was recorded; modified Rankin Scale score of 3 or more was used to define patients with severe neurological impairment; HASBLED score of 3 or more was used to identify high bleeding risk patients. During follow-up, 20 patients (7.5%) had ICH recurrence (rate of 2.56 * 100 patient years). No difference in the type of treatment [hazard ratio = 1.5; 95% confidence interval (CI): 0.49-4.74] and neurological impairment with modified Rankin Scale 3 or more (hazard ratio = 0.9; 95% CI: 0.31-2.83) were found in relation to ICH recurrence. The mean HASBLED score was similar between the two groups (P = 0.54). In conclusion, the results of our study suggest that neither the severity of the index ICH at presentation nor the HASBLED clinical prediction rule should be used to assess the risk of recurrence in patients who need VKAs resumption after a previous ICH. PMID- 28081032 TI - A Systematic Review of the Factors Influencing Ethnic Minority Women's Cervical Cancer Screening Behavior: From Intrapersonal to Policy Level. AB - BACKGROUND: Cervical cancer can be prevented by effective screening using Papanicolaou tests, but the utilization rate is lower among ethnic minorities than in the general population. Understanding the factors influencing minorities' use of such screening can aid the design of an appropriate intervention to increase their uptake rate. OBJECTIVE: The aims of this study were to examine the factors that influence ethnic minority women in using cervical cancer screening and the similarities and differences in associated factors across different groups and to explore the interrelationships between the factors identified. METHODS: A literature search was conducted using Ovid MEDLINE, Cumulative Index to Nursing and Allied Health Literature Plus, Scopus, PsycINFO, and PubMed. Furthermore, 1390 articles were retrieved, of which 24 met the inclusion criteria. Critical appraisal was performed by means of a quality assessment tool. The findings were summarized in tabular and narrative forms. RESULTS: The findings showed that certain factors commonly affected ethnic minority women's screening behavior, including knowledge, attitude and perceptions, physician's recommendation, quality of care and service, language, and acculturation. Culture related factors, religion, and acculturation exhibited close interrelationships with the attitude and perceptions factor, resulting in behavioral change. CONCLUSIONS: The review sheds light on how common or unique are the factors across ethnic minorities and how these factors interact to influence behavior. Further studies are warranted to develop and test empirically a comprehensive model leading to a better understanding of the interrelationships between multiple factors. IMPLICATIONS FOR PRACTICE: The model should be useful in informing policy makers about appropriate resource allocation and in guiding the development of culturally relevant programs to increase screening uptake. PMID- 28081033 TI - Performance Aspects and Physiological Responses in Male Amateur Boxing Competitions: A Brief Review. AB - Slimani, M, Chaabene, H, Davis, P, Franchini, E, Cheour, F, and Chamari, K. Performance aspects and physiological responses in male amateur boxing competitions: a brief review. J Strength Cond Res 31(4): 1132-1141, 2017-Boxing is one of the most popular striking combat sports in the world. The aim of this review was to present data concerning performance analysis (time-motion and technical-tactical analysis) and physiological responses (i.e., blood lactate concentration [BLC], heart rate, and oxygen consumption) during novice and elite male simulated and official amateur boxing competitions in any age category. The present review shows that boxing competition is a high-intensity intermittent striking combat sport. Typically, the activity-to-rest ratio was higher in elite (18:1) than in novice (9:1) boxers and significant differences were observed between rounds (first round = 16:1, second round = 8:1, and third round = 6:1) in novice boxers. Thus, total stop-time and total stop-frequency increased over subsequent rounds in novice boxers. The technical-tactical aspects in elite and novice boxing bouts were different between rounds and dependent on the match outcome (i.e., winners vs. losers). Particularly, the current review highlights that triple-punch combinations, total combinations, block- and counter-punch combinations, total punches to the head, technical performance effectiveness, and defensive- and offensive-skills effectiveness may have contributed to win in novice and elite boxing competitions. Higher frequencies of technical movements were also observed in elite compared with novice boxers. From a physiological point of view, BLC increased significantly from postround 1 compared with postround 3 in novice boxing match. BLC was also higher in official than in simulated elite boxing matches in senior compared with junior boxers and in medium heavy-weight category compared with light- and medium-weight categories in junior boxing competition. A higher percentage of maximal heart rate (%HRmax) and maximal oxygen uptake (V[Combining Dot Above]O2max) were reported in round 3 compared with rounds 2 and 1 in elite boxing competition. In conclusion, these data are useful for both technical-tactical and physical conditioning sessions. Coaches and fitness trainers are encouraged to adjust their training according to these particular characteristics, specifically in terms of age, participants' level, weight categories, and combat contest type. PMID- 28081034 TI - The Effects of the Removal of Electronic Devices for 48 Hours on Sleep in Elite Judo Athletes. AB - : This study examined the effects of evening use of electronic devices (i.e., smartphones, etc.) on sleep quality and next-day athletic and cognitive performance in elite judo athletes. Over 6 consecutive days and nights, 23 elite Australian judo athletes were monitored while attending a camp at the Australian Institute of Sport (AIS). In 14 athletes, all electronic devices were removed on days 3 and 4 (i.e., for 48 hours: the "device-restricted group"), whereas 9 were permitted to use their devices throughout the camp (the "control group"). All athletes wore an activity monitor (Readiband) continuously to provide measures of sleep quantity and quality. Other self-reported (diary) measures included time in bed, electronic device use, and rate of perceived exertion during training periods. Cognitive performance (Cogstate) and physical performance (single leg triple hop test) were also measured. When considering night 2 as a "baseline" for each group, removal of electronic devices on nights 3 and 4 (device-restricted group) resulted in no significant differences in any sleep-related measure between the groups. When comparing actigraphy-based measures of sleep to subjective measures, all athletes significantly overestimated sleep duration by 58 +/- 85 minutes (p = 0.001) per night and underestimated time of sleep onset by 37 +/- 72 minutes (p = 0.001) per night. No differences in physical or cognitive function were observed between the groups. CONCLUSION: This study has shown that the removal of electronic devices for a period of two nights (48 hours) during a judo camp does not affect sleep quality or quantity or influence athletic or cognitive performance. PMID- 28081035 TI - Removal of ribonucleotides by p53 protein incorporated during DNA synthesis by HIV-1 reverse transcriptase. AB - OBJECTIVE(S): HIV-1 reverse transcriptase frequently incorporates ribonucleotides into the proviral DNA in macrophages, but not in lymphocytes. The enzyme exerts an efficient ribonucleotide-terminated primer extension capacity. Furthermore, ribonucleotide-editing repair is attenuated in macrophages. Tumor suppressor p53 protein, displaying an intrinsic 3'->5' exonuclease activity, was found to be involved in efficient proofreading of base-base mismatches produced during DNA synthesis. As the presence of proofreading activity is cardinal for the DNA synthesis accuracy, it was of interest to assess whether p53 can serve as a trans acting proofreader for HIV-1 reverse transcriptase during ribonucleotide incorporation. DESIGN: We investigated the potential involvement of cytoplasmic p53 in error correction during insertion of ribonucleotides into DNA by recombinant HIV-1 reverse transcriptase in a p53-proficient and deficient background. METHODS: Primer extension reactions were carried out to elucidate the incorporation and removal of ribonucleotides. RESULTS: The biochemical studies suggest that p53 is involved in a ribonucleotide damage-associated repair mechanism through its capacity to remove preformed 3'-terminal ribonucleotides, to decrease ribonucleotide incorporation and to prevent the 3'-ribo-terminated primer extension during ongoing DNA synthesis by HIV-1 reverse transcriptase. A positive correlation exists between the presence of endogenous p53 and decrease in stable incorporation of ribonucleotides into DNA with p53-harboring lysates of HCT116 cells. p53, by preferential removal of purine over pyrimidine ribonucleotides, may affect the ribonucleotide mutation spectra produced by HIV-1 reverse transcriptase. CONCLUSION: The data implies that p53 can excise incorrect sugar in addition to base mispairs, thereby expanding the role of p53 in the repair of nucleic acids replication errors. PMID- 28081036 TI - One-year mortality of HIV-positive patients treated for rifampicin- and isoniazid susceptible tuberculosis in Eastern Europe, Western Europe, and Latin America. AB - OBJECTIVES: The high mortality among HIV/tuberculosis (TB) coinfected patients in Eastern Europe is partly explained by the high prevalence of drug-resistant TB. It remains unclear whether outcomes of HIV/TB patients with rifampicin/isoniazid susceptible TB in Eastern Europe differ from those in Western Europe or Latin America. METHODS: One-year mortality of HIV-positive patients with rifampicin/isoniazid-susceptible TB in Eastern Europe, Western Europe, and Latin America was analysed and compared in a prospective observational cohort study. Factors associated with death were analysed using Cox regression modelsRESULTS:: Three hundred and forty-one patients were included (Eastern Europe 127, Western Europe 165, Latin America 49). Proportions of patients with disseminated TB (50, 58, 59%) and initiating rifampicin + isoniazid + pyrazinamide-based treatment (93, 94, 94%) were similar in Eastern Europe, Western Europe, and Latin America respectively, whereas receipt of antiretroviral therapy at baseline and after 12 months was lower in Eastern Europe (17, 39, 39%, and 69, 94, 89%). The 1-year probability of death was 16% (95% confidence interval 11-24%) in Eastern Europe, vs. 4% (2-9%) in Western Europe and 9% (3-21%) in Latin America; P < 0.0001. After adjustment for IDU, CD4 cell count and receipt of antiretroviral therapy, those residing in Eastern Europe were at nearly 3-fold increased risk of death compared with those in Western Europe/Latin America (aHR 2.79 (1.15-6.76); P = 0.023). CONCLUSIONS: Despite comparable use of recommended anti-TB treatment, mortality of patients with rifampicin/isoniazid-susceptible TB remained higher in Eastern Europe when compared with Western Europe/Latin America. The high mortality in Eastern Europe was only partially explained by IDU, use of ART and CD4 cell count. These results call for improvement of care for TB/HIV patients in Eastern Europe. PMID- 28081038 TI - Impact of HIV infection and antiretroviral treatment on N-terminal prohormone of brain natriuretic peptide as surrogate of myocardial function. AB - OBJECTIVE: Vasoactive cardiovascular hormones such as the N-terminal prohormone of brain natriuretic peptide (NT-proBNP) are produced upon ventricular stretch and play a central role in neurohumoral pathways of the heart regulating cardiovascular remodeling and volume homeostasis. The impact of HIV infection on these neurohumoral pathways of the heart and its potential reversibility by combinations of antiretroviral therapies remain unclear. METHODS: We assessed serum levels of NT-proBNP in 219 antiretroviral therapy-naive HIV-infected patients with a normal cardiac and renal status at treatment initiation and after attainment of viremic control. RESULTS: Before antiretroviral therapy, NT-proBNP as a surrogate of myocardial function displayed a significant correlation with absolute CD4 cell count (r = -0.31; P < 0.001) as well as with HIV viral load (r = 0.26; P < 0.001). The median levels of NT-proBNP were 80 pg/ml (36-205) in patients with a CD4 cell count less than 200 cells/MUl and 42 pg/ml (20-80; P < 0.001) with a CD4 cell count more than 500 cells/MUl. After viremic control, no statistical correlation was present. CONCLUSION: Higher NT-proBNP levels were observed in treatment-naive patients with low CD4 cell count and high HIV viral load, indicating a subclinical impact of HIV infection on myocardial function. This association is reversible by the initiation of antiretroviral therapy and subsequent viral suppression. PMID- 28081037 TI - Higher CD163 levels are associated with insulin resistance in hepatitis C virus infected and HIV-infected adults. AB - OBJECTIVES: HIV/hepatitis C virus (HCV) coinfection is associated with insulin resistance, but the mechanism is unclear. We hypothesized that intestinal epithelial damage and the consequent monocyte/macrophage activation and inflammation explain this perturbation. DESIGN: Cross-sectional study of 519 adults (220 HIV+/HCV-; 64 HIV-/HCV+; 89 HIV+/HCV+; 146 HIV-/HCV-). METHODS: We used multivariable linear regression to evaluate associations of HIV and HCV with the homeostasis model assessment of insulin resistance (HOMA-IR) and if intestinal fatty (FA) acid binding protein (I-FABP, a marker of gut epithelial integrity), soluble CD14 (sCD14) and soluble CD163 (sCD163) (markers of monocyte/macrophage activation), and IL-6 (an inflammatory cytokine) mediated this association. RESULTS: HIV+/HCV+ and HIV-/HCV+ had greater demographic adjusted HOMA-IR [mean (95% confidence interval (CI)): 1.96 (1.51, 2.54) and 1.65 (1.22, 2.24)] than HIV+/HCV- and HIV-/HCV-[1.41 (1.18, 1.67) and 1.44 (1.17, 1.75), respectively]. After additional adjustment for lifestyle and metabolic factors, HIV+/HCV+ remained associated with 36% (95% CI: 4, 80%) greater HOMA-IR relative to HIV-/HCV-, whereas HIV-/HCV+ and HIV+/HCV- had smaller differences. Adjustment for sCD163 substantially attenuated the difference between HIV+/HCV+ and HIV-/HCV-; adjustment for I-FABP, sCD14, and IL-6 had little effect. Higher sCD163 was independently associated with 19% (95% CI: 7, 33%), 26% (95% CI: 15, 39%), 25% (95% CI: 14, 37%), and 23% (95% CI: 11, 36%) greater HOMA-IR in HIV+/HCV+, HIV-/HCV+, HIV+/HCV-, and HIV-/HCV- (all estimates per doubling of sCD163). I-FABP, sCD14, and IL-6 were not associated with HOMA-IR. CONCLUSION: HIV/HCV coinfection is associated with greater HOMA-IR, even after controlling for demographic, lifestyle, and metabolic factors. sCD163, which appears independent of intestinal epithelial damage and inflammation, partly explains this association. Our findings that the association of sCD163 with HOMA-IR occurred even in the absence of HIV and HCV, indicate that viral and nonviral factors affect sCD163 levels. Its role in insulin resistance needs elucidation. PMID- 28081039 TI - HIV and hypogonadism: a new challenge for young-aged and middle-aged men on effective antiretroviral therapy. AB - Male hypogonadism is poorly defined in people living with HIV. Using a reliable free-testosterone assay, we examined the prevalence and risk factors of male hypogonadism among people living with HIV on effective antiretroviral therapy. Male hypogonadism was found in 12.4% of patients, twice the rate reported in the general population of the same age. Two risk thresholds, namely 5 years of antiretroviral therapy and 19% total body fat, may help to identify patients at risk. PMID- 28081040 TI - Azathioprine Therapy in a Pediatric TPMT-Deficient Patient-Still an Option. AB - We describe the case of a pediatric patient on azathioprine therapy with previously undiagnosed homozygote thiopurine S-methyltransferase (TPMT) deficiency, resulting in myelotoxic thiopurine metabolite levels. The patient was successfully treated with a very low azathioprine dose of 50 mg once a week (4% of standard dose), guided by frequent thiopurine metabolite measurement and a close clinical surveillance. We demonstrate that azathioprine therapy still might be an effective and safe therapeutic option in pediatric thiopurine S methyltransferase-deficient IBD patients. PMID- 28081042 TI - Detection of Hydrocodone and Morphine as Metabolites in Oral Fluid by LC-MS/MS in Patients Prescribed Codeine. AB - A retrospective analysis of oral fluid drug testing results using LC-MS/MS was performed to determine the prevalence rates in oral fluid for codeine (COD) and 3 COD metabolites-morphine (MOR), norhydrocodone (NHC), and hydrocodone (HCOD). Oral fluid samples were collected using Quantisal oral fluid collection device (Immunalysis Inc.) and submitted to Millennium Health, LLC for the routine drug analysis by LC-MS/MS. Consistent with previously published literature, COD was the primary analyte detected in oral fluid after the use of COD. In COD-positive samples, HCOD, MOR, and NHC were detected at rates of 68.4%, 18.4%, and 6.3%, respectively. Concentration ranges of these analytes were 1.0 to >2000 ng/mL for COD, 1.0-20.2 ng/mL for MOR, 1.0-740.0 ng/mL for HCOD, and 2.1-47.5 ng/mL for NHC. In contrast to urine, where HCOD is typically detected as a minor metabolite of COD, HCOD was the most commonly detected metabolite in oral fluid in samples testing positive for COD with reported prescriptions for COD. This observation suggests that care should be taken when interpreting HCOD positives in oral fluid results, and that the use of COD should be considered as one possible explanation for HCOD positives. PMID- 28081041 TI - A Systematic Literature Review Approach to Estimate the Therapeutic Index of Selected Immunosuppressant Drugs After Renal Transplantation. AB - BACKGROUND: Drugs that exhibit close margins between therapeutic and toxic blood concentrations are considered to have a narrow therapeutic index (NTI). The Food and Drug Administration has proposed that NTI drugs should have more stringent bioequivalence standards for approval of generic formulations. However, many immunosuppressant drugs do not have a well-defined therapeutic index (TI). METHODS: We sought to determine whether safety, efficacy, and pharmacokinetic data obtained from the medical literature through a comprehensive literature search could be used to estimate the TI of cyclosporine, tacrolimus, and sirolimus. In this analysis, we considered TI <=2 as a criterion to define a drug as having an NTI. RESULTS: Published literature indicates that cyclosporine has a TI of 2-3, which falls just short of our criteria to be classified as having an NTI. We found sirolimus and tacrolimus to have a therapeutic range of 5-12 ng/mL and of 5-20 ng/mL, respectively, but were unable to calculate the TI. CONCLUSIONS: Although the current literature does not provide a clear indication that these drugs have an NTI, the routine use of therapeutic drug monitoring in clinical practice suggests that more stringent testing of their pharmacokinetic and pharmacodynamic properties should be performed before the approval of generic formulations. PMID- 28081044 TI - Evaluation of the Condom Barriers Scale for Young Black Men Who Have Sex With Men: Reliability and Validity of 3 Subscales. AB - BACKGROUND: Reliable and valid scale measures of barriers to condom use are not available for young black men who have sex with men (YBMSM). The purpose of this study was to evaluate the Condom Barriers Scales for application with YBMSM. METHODS: A clinic-based sample of 600 YBMSM completed a computer-assisted self interview. The primary measure was a 14-item abbreviated version of the Condom Barriers Scale. Reliability and criterion validity were assessed. RESULTS: All 3 subscales were reliable: partner-related barriers (Cronbach alpha=0.73), sensation-related barriers (alpha=0.70), and motivation-related barriers (alpha =0.81). A complete absence of barriers was common: 47.0% (partner-related), 30.7% (sensation-related), and 46.5% (motivation-related). Dichotomized subscales were significantly associated with reporting any condomless insertive anal sex (all Ps < 0.001) and any condomless receptive anal sex (all Ps < 0.001). The subscales were significantly associated with these measures of condomless sex preserved at a continuous level (all Ps <0.001, except for sensation barriers associated with condomless receptive anal sex = 0.03). Further, the subscales were significantly associated with reporting any condom use problems (all Ps <0.001) and a measure of condomless oral sex (all Ps <0.001, except for partner-related barriers=0.31). Finally, the sensation-related barriers subscale was significantly associated with testing positive for Chlamydia and/or gonorrhea (P=0.049). CONCLUSIONS: The 3 identified subscales yielded adequate reliability and strong evidence of validity, thereby suggesting the utility of these brief measures for use in observational and experimental research with YBMSM. PMID- 28081043 TI - The Human Immunodeficiency Virus Endemic: Maintaining Disease Transmission in At Risk Urban Areas. AB - OBJECTIVES: A study of network relationships, geographic contiguity, and risk behavior was designed to test the hypothesis that all 3 are required to maintain endemicity of human immunodeficiency virus (HIV) in at-risk urban communities. Specifically, a highly interactive network, close geographic proximity, and compound risk (multiple high-risk activities with multiple partners) would be required. METHODS: We enrolled 927 participants from two contiguous geographic areas in Atlanta, GA: a higher-risk area and lower-risk area, as measured by history of HIV reporting. We began by enrolling 30 "seeds" (15 in each area) who were comparable in their demographic and behavioral characteristics, and constructed 30 networks using a chain-link design. We assessed each individual's geographic range; measured the network characteristics of those in the higher and lower-risk areas; and measured compound risk as the presence of two or more (of 6) major risks for HIV. RESULTS: Among participants in the higher-risk area, the frequency of compound risk was 15%, compared with 5% in the lower-risk area. Geographic cohesion in the higher-risk group was substantially higher than that in the lower-risk group, based on comparison of geographic distance and social distance, and on the extent of overlap of personal geographic range. The networks in the 2 areas were similar: both areas show highly interactive networks with similar degree distributions, and most measures of network attributes were virtually the same. CONCLUSIONS: Our original hypothesis was supported in part. The higher and lower-risk groups differed appreciably with regard to risk and geographic cohesion, but were substantially the same with regard to network properties. These results suggest that a "minimum" network configuration may be required for maintenance of endemic transmission, but a particular prevalence level may be determined by factors related to risk, geography, and possibly other factors. PMID- 28081045 TI - Changes in the Distribution of Sex Partners in the United States: 2002 to 2011 2013. AB - OBJECTIVE: The purpose of the current analysis is to examine subgroup differences in the distribution of opposite-sex sex partners in the United States across an approximate 10-year period to identify patterns that may inform sexually transmitted infection research and prevention. METHODS: Data were drawn from the 2002 and 2011-2013 National Survey of Family Growth, a US probability-based household survey focusing on sexual and reproductive health. The measures included in this analysis were lifetime opposite-sex sex partners and opposite sex sex partners in the past year. Analyses were conducted separately for men and women. All analyses were conducted in R and R-studio with the "survey" package, focusing on medians, the 80th, and 95th quartile. RESULTS: In 2002, there were significant differences between men and women in median number of lifetime sex partners with men reporting more lifetime partners. However, in the 2011-2013 data, these differences are no longer significant. Still, the findings suggest that the top 20% and top 5% of men are reporting significantly more lifetime partners than their female counterparts. In comparison, partners in the past year remain relatively unchanged for both men and women. CONCLUSIONS: These findings suggest that there were important changes in the distribution of sex partners between 2002 and 2011-2013 that have implications for sexually transmitted infection prevention. Median lifetime partners are no longer different for women and men: however, the distribution of lifetime partners among men is becoming even more skewed. PMID- 28081046 TI - Evaluation of Herpes Simplex Virus Type 2 Serological Tests for Use With Dried Blood Spots in Kenya. AB - We evaluated 2 assays to detect antibodies to herpes simplex virus type 2 in dried blood spots prepared from blood specimens submitted to a reference laboratory in Kenya. Dried blood spots did not perform well with the Kalon herpes simplex virus type 2 assay. Focus HerpeSelect 2 was 98.8% sensitive and 98.9% specific with dried blood spots. PMID- 28081047 TI - The Challenges of Implementing and Evaluating Prescription Expedited Partner Treatment. PMID- 28081049 TI - The First Infant Death Associated With Human Coronavirus NL63 Infection. AB - Human coronavirus NL63 (HCoV-NL63) primarily infects the upper respiratory tract. However, it may cause severe lower respiratory tract infection, and the clinical course may be severe in immunocompromised patients. To our knowledge, child death due to HCoV-NL63 has not been reported. We present a fatal lower respiratory tract disease associated with HCoV-NL63 in a 7-month-old malnourished infant. PMID- 28081048 TI - A Prospective Cohort Study of Common Childhood Infections in South African HIV exposed Uninfected and HIV-unexposed Infants. AB - BACKGROUND: Much evidence of HIV-exposed uninfected (HEU) infant infectious morbidity predates availability of maternal combination antiretroviral therapy and does not control for universal risk factors (preterm birth, low birth weight, suboptimal breastfeeding and poverty). METHODS: This prospective cohort study identified HIV-infected and HIV-uninfected mothers and their newborns from South African community midwife unit. The primary outcome, infectious cause hospitalization or death before 6 months of age, was compared between HEU and HIV unexposed (HU) infants and classified for type and severity using validated study specific case definitions. Adjusted odds ratios (aORs) were calculated by logistic regression including stratified analyses conditioned on breastfeeding. RESULTS: One hundred and seventy-six (94 HEU and 82 HU) mother-infant pairs were analyzed. HIV-infected mothers were older (median, 27.8 vs. 24.7 years; P < 0.01) and HU infants more often breastfed (81/82 vs. 35/94; P < 0.001). Groups were similar for maternal education, antenatal course, household characteristics, birth weight, gestational age and immunizations. The primary outcome occurred in 17 (18%) HEU and 10 (12%) HU infants [aOR, 1.45; 95% confidence interval (CI): 0.44-4.55]. In stratified analysis restricted to breastfed infants, the aOR for hospitalization due to very severe infection or death was 4.2 (95% CI: 1.00-19.2; P = 0.05) for HEU infants. Hospitalization for diarrhea was more common in HEU than HU infants [8/94 (8.5%) vs. 1/82 (1.2%); P = 0.04]. CONCLUSION: The difference between HEU and HU infants in the probability of infectious cause hospitalization or death in the first 6 months of life was not significant. However, among breastfed infants, severe infectious morbidity occurred more often in HEU than HU infants. PMID- 28081050 TI - White Paper of the Society of Computed Body Tomography and Magnetic Resonance on Dual-Energy CT, Part 3: Vascular, Cardiac, Pulmonary, and Musculoskeletal Applications. AB - This is the third of a series of 4 white papers that represent Expert Consensus Documents developed by the Society of Computed Body Tomography and Magnetic Resonance through its Task Force on dual-energy computed tomography. This paper, part 3, describes computed tomography angiography and thoracic, cardiac, vascular, and musculoskeletal clinical applications. At the end of the discussion of each application category (vascular, cardiac, pulmonary, and musculoskeletal), we present our consensus opinions on the current clinical utility of the application and opportunities for further research. PMID- 28081051 TI - Procedure Oriented Torsional Anatomy of the Forearm for Spasticity Injection: Erratum. PMID- 28081052 TI - Identification of Key Transcription Factors Associated with Lung Squamous Cell Carcinoma. AB - BACKGROUND Lung squamous cell carcinoma (lung SCC) is a common type of lung cancer, but its mechanism of pathogenesis is unclear. The aim of this study was to identify key transcription factors in lung SCC and elucidate its mechanism. MATERIAL AND METHODS Six published microarray datasets of lung SCC were downloaded from Gene Expression Omnibus (GEO) for integrated bioinformatics analysis. Significance analysis of microarrays was used to identify differentially expressed genes (DEGs) between lung SCC and normal controls. The biological functions and signaling pathways of DEGs were mapped in the Gene Otology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database, respectively. A transcription factor gene regulatory network was used to obtain insights into the functions of DEGs. RESULTS A total of 1,011 genes, including 539 upregulated genes and 462 downregulated genes, were filtered as DEGs between lung SCC and normal controls. DEGs were significantly enriched in cell cycle, DNA replication, p53 signaling pathway, pathways in cancer, adherens junction, and cell adhesion molecules signaling pathways. There were 57 transcription factors identified, which were used to construct a regulatory network. The network consisted of 736 interactions between 49 transcription factors and 486 DEGs. NFIC, BRCA1, and NFATC2 were the top 3 transcription factors that had the highest connectivity with DEGs and that regulated 83, 82, and 75 DEGs in the network, respectively. CONCLUSIONS NFIC, BRCA1, and NFATC2 might be the key transcription factors in the development of lung SCC by regulating the genes involved in cell cycle and DNA replication pathways. PMID- 28081054 TI - QuickStats: Prevalence* of Untreated Dental Caries? in Permanent Teeth Among Children and Adolescents Aged 6-19 Years, by Age Group - National Health and Nutrition Examination Survey, United States, 2011-2014. AB - During 2011-2014, 13.3% of children and adolescents aged 6-19 years had untreated dental caries in their permanent teeth. The percentage of children and adolescents with untreated dental caries increased with age: 6.1% among those aged 6-11 years, 14.5% among those aged 12-15 years, and 22.6% among those aged 16-19 years. PMID- 28081053 TI - Notes from the Field: Occupational Lead Exposures at a Shipyard - Douglas County, Wisconsin, 2016. PMID- 28081055 TI - State-Level Lifetime Medical and Work-Loss Costs of Fatal Injuries - United States, 2014. AB - Injury-associated deaths have substantial economic consequences in the United States. The total estimated lifetime medical and work-loss costs associated with fatal injuries in 2013 were $214 billion (1). In 2014, unintentional injury, suicide, and homicide (the fourth, tenth, and seventeenth leading causes of death, respectively) accounted for 194,635 deaths in the United States (2). In 2014, a total of 199,756 fatal injuries occurred in the United States, and the associated lifetime medical and work-loss costs were $227 billion (3). This report examines the state-level economic burdens of fatal injuries by extending a previous national-level study (1). Numbers and rates of fatal injuries, lifetime costs, and lifetime costs per capita were calculated for each of the 50 states and the District of Columbia (DC) and for four injury intent categories (all intents, unintentional, suicide, and homicide). During 2014, injury mortality rates and economic burdens varied widely among the states and DC. Among fatal injuries of all intents, the mortality rate and lifetime costs per capita ranged from 101.9 per 100,000 and $1,233, respectively (New Mexico) to 40.2 per 100,000 and $491 (New York). States can engage more effectively and efficiently in injury prevention if they are aware of the economic burden of injuries, identify areas for immediate improvement, and devote necessary resources to those areas. PMID- 28081056 TI - Guidance for Assessment of Poliovirus Vaccination Status and Vaccination of Children Who Have Received Poliovirus Vaccine Outside the United States. AB - In 1988, the World Health Assembly resolved to eradicate poliomyelitis (polio). Since then, wild poliovirus (WPV) cases have declined by >99.9%, from an estimated 350,000 cases of polio each year to 74 cases in two countries in 2015 (1). This decrease was achieved primarily through the use of trivalent oral poliovirus vaccine (tOPV), which contains types 1, 2, and 3 live, attenuated polioviruses. Since 2000, the United States has exclusively used inactivated polio vaccine (IPV), which contains all three poliovirus types (2,3). In 2013, the World Health Organization (WHO) set a target of a polio-free world by 2018 (4). Of the three WPV types, type 2 was declared eradicated in September 2015. To remove the risk for infection with circulating type 2 vaccine-derived polioviruses (cVDPV), which can lead to paralysis similar to that caused by WPV, all OPV-using countries simultaneously switched in April 2016 from tOPV to bivalent OPV (bOPV), which contains only types 1 and 3 polioviruses (5). This report summarizes current Advisory Committee on Immunization Practices (ACIP) recommendations for poliovirus vaccination and provides CDC guidance, in the context of the switch from tOPV to bOPV, regarding assessment of vaccination status and vaccination of children who might have received poliovirus vaccine outside the United States, to ensure that children living in the United States (including immigrants and refugees) are protected against all three poliovirus types. This guidance is not new policy and does not change the recommendations of ACIP for poliovirus vaccination in the United States. Children living in the United States who might have received poliovirus vaccination outside the United States should meet ACIP recommendations for poliovirus vaccination, which require protection against all three poliovirus types by age-appropriate vaccination with IPV or tOPV. In the absence of vaccination records indicating receipt of these vaccines, only vaccination or revaccination in accordance with the age appropriate U.S. IPV schedule is recommended. Serology to assess immunity for children with no or questionable documentation of poliovirus vaccination will no longer be an available option and therefore is no longer recommended, because of increasingly limited availability of antibody testing against type 2 poliovirus. PMID- 28081057 TI - Reducing Potentially Excess Deaths from the Five Leading Causes of Death in the Rural United States AB - In 2014, the all-cause age-adjusted death rate in the United States reached a historic low of 724.6 per 100,000 population (1). However, mortality in rural (nonmetropolitan) areas of the United States has decreased at a much slower pace, resulting in a widening gap between rural mortality rates (830.5) and urban mortality rates (704.3) (1). During 1999-2014, annual age-adjusted death rates for the five leading causes of death in the United States (heart disease, cancer, unintentional injury, chronic lower respiratory disease (CLRD), and stroke) were higher in rural areas than in urban (metropolitan) areas (Figure 1). In most public health regions (Figure 2), the proportion of deaths among persons aged <80 years (U.S. average life expectancy) (2) from the five leading causes that were potentially excess deaths was higher in rural areas compared with urban areas (Figure 3). Several factors probably influence the rural-urban gap in potentially excess deaths from the five leading causes, many of which are associated with sociodemographic differences between rural and urban areas. Residents of rural areas in the United States tend to be older, poorer, and sicker than their urban counterparts (3). A higher proportion of the rural U.S. population reports limited physical activity because of chronic conditions than urban populations (4). Moreover, social circumstances and behaviors have an impact on mortality and potentially contribute to approximately half of the determining causes of potentially excess deaths (5). PMID- 28081059 TI - Notice to Readers: MMWR Weekly Launches Online Manuscript Submission System. AB - The MMWR Weekly is now using MMWR ScholarOne Manuscripts, an online system for manuscript submissions. Launching this system provides comprehensive workflow management and streamlines the Weekly submission process. PMID- 28081058 TI - Leading Causes of Death in Nonmetropolitan and Metropolitan Areas- United States, 1999-2014. AB - PROBLEM/CONDITION: Higher rates of death in nonmetropolitan areas (often referred to as rural areas) compared with metropolitan areas have been described but not systematically assessed. PERIOD COVERED: 1999-2014 DESCRIPTION OF SYSTEM: Mortality data for U.S. residents from the National Vital Statistics System were used to calculate age-adjusted death rates and potentially excess deaths for nonmetropolitan and metropolitan areas for the five leading causes of death. Age adjusted death rates included all ages and were adjusted to the 2000 U.S. standard population by the direct method. Potentially excess deaths are defined as deaths among persons aged <80 years that exceed the numbers that would be expected if the death rates of states with the lowest rates (i.e., benchmark states) occurred across all states. (Benchmark states were the three states with the lowest rates for each cause during 2008-2010.) Potentially excess deaths were calculated separately for nonmetropolitan and metropolitan areas. Data are presented for the United States and the 10 U.S. Department of Health and Human Services public health regions. RESULTS: Across the United States, nonmetropolitan areas experienced higher age-adjusted death rates than metropolitan areas. The percentages of potentially excess deaths among persons aged <80 years from the five leading causes were higher in nonmetropolitan areas than in metropolitan areas. For example, approximately half of deaths from unintentional injury and chronic lower respiratory disease in nonmetropolitan areas were potentially excess deaths, compared with 39.2% and 30.9%, respectively, in metropolitan areas. Potentially excess deaths also differed among and within public health regions; within regions, nonmetropolitan areas tended to have higher percentages of potentially excess deaths than metropolitan areas. INTERPRETATION: Compared with metropolitan areas, nonmetropolitan areas have higher age-adjusted death rates and greater percentages of potentially excess deaths from the five leading causes of death, nationally and across public health regions. PUBLIC HEALTH ACTION: Routine tracking of potentially excess deaths in nonmetropolitan areas might help public health departments identify emerging health problems, monitor known problems, and focus interventions to reduce preventable deaths in these areas. PMID- 28081060 TI - Erratum: Vol. 65, Nos. 50 & 51. AB - In the report "Increases in Drug and Opioid-Involved Overdose Deaths - United States, 2010-2015" in both "TABLE 1. Number and age-adjusted rate of drug overdose deaths* involving natural and semisynthetic opioids? and methadone,S, by sex, age group, race/ethnicity,** U.S. Census region, and selected states?? - United States, 2014 and 2015," and in "TABLE 2. Number and age-adjusted rate of drug overdose deaths* involving synthetic opioids other than methadone? and heroin,S, by sex, age group, race/ethnicity,** U.S. Census region, and selected states?? - United States, 2014 and 2015," the seventh footnote (SS) should have read as follows: "Statistically significant at p<0.05 level. Nonoverlapping confidence intervals based on the gamma method were used if the number of deaths was <100 in 2014 or 2015, and z-tests were used if the number of deaths was >=100 in both 2014 and 2015." PMID- 28081061 TI - Vital Signs: Decrease in Incidence of Diabetes-Related End-Stage Renal Disease among American Indians/Alaska Natives - United States, 1996-2013. AB - BACKGROUND: American Indians and Alaska Natives (AI/AN) have the highest diabetes prevalence among any racial/ethnic group in the United States. Among AI/AN, diabetes accounts for 69% of new cases of end-stage renal disease (ESRD), defined as kidney failure treated with dialysis or transplantation. During 1982-1996, diabetes-related ESRD (ESRD-D) in AI/AN increased substantially and disproportionately compared with other racial/ethnic groups. METHODS: Data from the U.S. Renal Data System, the Indian Health Service (IHS), the National Health Interview Survey, and the U.S. Census were used to calculate ESRD-D incidence rates by race/ethnicity among U.S. adults aged >=18 years during 1996-2013 and in the diabetic population during 2006-2013. Rates were age-adjusted based on the 2000 U.S. standard population. IHS clinical data from the Diabetes Cares and Outcomes Audit were analyzed for diabetes management measures in AI/AN. RESULTS: Among AI/AN adults, age-adjusted ESRD-D rates per 100,000 population decreased 54%, from 57.3 in 1996 to 26.5 in 2013. Although rates for adults in other racial/ethnic groups also decreased during this period, AI/AN had the steepest decline. Among AI/AN with diabetes, ESRD-D incidence decreased during 2006-2013 and, by 2013, was the same as that for whites. Measures related to the assessment and treatment of ESRD-D risk factors also showed more improvement during this period in AI/AN than in the general population. CONCLUSION AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Despite well-documented health and socioeconomic disparities among AI/AN, ESRD-D incidence rates among this population have decreased substantially since 1996. This decline followed implementation by the IHS of public health and population management approaches to diabetes accompanied by improvements in clinical care beginning in the mid-1980s. These approaches might be a useful model for diabetes management in other health care systems, especially those serving populations at high risk. PMID- 28081062 TI - Prevalence of Perceived Food and Housing Security - 15 States, 2013. AB - Recent global (1) and national (2,3) health equity initiatives conclude that the elimination of health disparities requires improved understanding of social context (4,5) and ability to measure social determinants of health, including food and housing security (3). Food and housing security reflect the availability of and access to essential resources needed to lead a healthy life. The 2013 Behavioral Risk Factor Surveillance System (BRFSS) included two questions to assess perceived food and housing security in 15 states.* Among 95,665 respondents, the proportion who answered "never or rarely" to the question "how often in the past 12 months would you say you were worried or stressed about having enough money to buy nutritious meals?" ranged from 68.5% to 82.4% by state. Among 90,291 respondents living in housing they either owned or rented, the proportion who answered "never or rarely" to the question, "how often in the past 12 months would you say you were worried or stressed about having enough money to pay your rent/mortgage?" ranged from 59.9% to 72.8% by state. Food security was reported less often among non-Hispanic blacks (blacks) (68.5%) and Hispanics (64.6%) than non-Hispanic whites (whites) (81.8%). These racial/ethnic disparities were present across all levels of education; housing security followed a similar pattern. These results highlight racial/ethnic disparities in two important social determinants of health, food and housing security, as well as a substantial prevalence of worry or stress about food or housing among all subgroups in the United States. The concise nature of the BRFSS Social Context Module's single-question format for food and housing security makes it possible to incorporate these questions into large health surveys so that social determinants can be monitored at the state and national levels and populations at risk can be identified. PMID- 28081063 TI - State Laws Requiring Hand Sanitation Stations at Animal Contact Exhibits-United States, March-April 2016. AB - In the United States, animal contact exhibits, such as petting zoos and agricultural fairs, have been sources of zoonotic infections, including infections with Escherichia coli, Salmonella, and Cryptosporidium (1-4). The National Association of State Public Health Veterinarians recommends handwashing after contact with animals as an effective prevention measure to disease transmission at these exhibits (4). This report provides a list of states that have used law, specifically statutes and regulations, as public health interventions to increase hand sanitation at animal contact exhibits. The report is based on an assessment conducted by CDC's Public Health Law Program, in collaboration with the Division of Foodborne, Waterborne, and Environmental Diseases in CDC's National Center for Emerging and Zoonotic Infectious Diseases. The assessment found that seven states have used statutes or regulations to require hand sanitation stations at these exhibits (5). Jurisdictions seeking to improve rates of hand sanitation at animal contact exhibits can use this report as a resource in developing their own legal interventions. PMID- 28081064 TI - Using National Inpatient Death Rates as a Benchmark to Identify Hospitals with Inaccurate Cause of Death Reporting - Missouri, 2009-2012. AB - Reporting causes of death accurately is essential to public health and hospital based programs; however, some U.S. studies have identified substantial inaccuracies in cause of death reporting. Using CDC's national inpatient hospital death rates as a benchmark, the Missouri Department of Health and Senior Services (DHSS) analyzed inpatient death rates reported by hospitals with high inpatient death rates in St. Louis and Kansas City metro areas. Among the selected hospitals with high inpatient death rates, 45.8% of death certificates indicated an underlying cause of death that was inconsistent with CDC's Guidelines for Death Certificate completion. Selected hospitals with high inpatient death rates were more likely to overreport heart disease and renal disease, and underreport cancer as an underlying cause of death. Based on these findings, the Missouri DHSS initiated a new web-based training module for death certificate completion based on the CDC guidelines in an effort to improve accuracy in cause of death reporting. PMID- 28081065 TI - Notes from the Field: Pan-Resistant New Delhi Metallo-Beta-Lactamase-Producing Klebsiella pneumoniae - Washoe County, Nevada, 2016. PMID- 28081066 TI - Experimental demonstration of pulse multiplexing and beam combining of four fiber lasers by noncollinear frequency conversion in an LBO crystal. AB - In this work, we provide proof-of-concept experimental realization of pulse multiplexing and beam combining of four pulsed Yb-doped fiber lasers by noncollinear frequency up-conversion in an LBO crystal. An overall conversion efficiency of 51% and up to 29 W average power in a combined 532 nm beam were achieved. These results correspond to an improvement by a factor of 2 compared to the average power extracted from a single fiber amplifier. PMID- 28081067 TI - Guiding terahertz orbital angular momentum beams in multimode Kagome hollow-core fibers. AB - We explore terahertz (THz) orbital angular momentum (OAM) modes supported in multimode Kagome hollow-core fibers. Numerical models are adopted to characterize the effective indices and confinement losses of vector modes over 0.2-0.9 THz, where two low-loss transmission windows are observed. Linearly combining the vector modes, THz OAM states can be generated. Covering a broad bandwidth of 0.25 THz, the purity values of OAM modes are beyond 0.9. Using numerical simulations, the hollow-core THz fibers with one and two rings of Kagome structures are also comparably investigated. We reveal that the OAM purity is dependent upon the confinement performance of THz fiber. PMID- 28081068 TI - Plasmonic wavelength splitter based on a metal-insulator-metal waveguide with a graded grating coupler. AB - A plasmonic wavelength splitter based on a sub-wavelength metal-insulator-metal (MIM) periodic rectangle wrinkle waveguide with a graded grating coupler is theoretically analyzed and experimentally demonstrated. The surface plasmon polaritons (SPPs), excited in the metal grating with wavelength selection, are deflected by the graded difference according to the aplanatic parametric principle. The wave vector of the deflected SPPs meets the phase-matching condition and couples into the periodic rectangle wrinkle waveguide with a plasmonic bandgap. The characteristic of the plasmonic wavelength splitter is simulated by finite difference time domain (FDTD) simulation, which agrees well with the theoretical analysis. By electron beam lithography and ion beam etching process, the plasmonic wavelength splitter was fabricated. The SPPs excited by incident 650 and 832 nm were successfully split and guided to opposite directions of the MIM waveguide with extinction ratios of 27.5 dB and 32.7 dB, respectively, which was observed under an optical microscope using a CCD camera. The proposed wavelength splitter is simple fabricated and has a large coupling aperture by utilizing the graded grating coupler. PMID- 28081069 TI - Photoacoustic imaging of sub-diffraction objects with spectral contrast. AB - Photoacoustic imaging couples the chemical specificity of optical absorption with the viewing depth of ultrasound. Systems based on linear array transducers have the versatility to be applied in various (pre-) clinical scenarios but face a trade-off between viewing depth and image resolution depending on transducer frequency and aperture. We propose here a method to disentangle, with precision, small, closely spaced targets with optical spectral contrast, without impairing the imaging depth. Photoacoustic data sets were recorded at two different optical wavelengths. We accurately recovered object separation distances (mean error=2.3%+/-6%) from the phase difference between signals across the array, down to a spacing of 1/20th of the system's beam-formed lateral resolution. The proposed method may enable the translation of super-resolution microscopy to deep tissue imaging. PMID- 28081070 TI - Second harmonic generation via femtosecond laser fabrication of poled, quasi phase-matched waveguides in fused silica. AB - Second harmonic generation (SHG) is demonstrated in femtosecond laser written waveguides in fused silica through a combination of thermal poling and laser based quasi-phase-matching (QPM) techniques. Quasi-phase-matching was controlled by the periodic erasure of induced nonlinearity through femtosecond laser erasure. A maximum SHG conversion efficiency of 6.6+/-0.5*10-5%/W is reported for the fundamental wavelength of 1552.8 nm with a phase-matching bandwidth of 4.4 nm for a 10.0 mm long waveguide. For a shorter sample, an effective second-order nonlinearity of chi(2)=0.012+/-0.001 pm/V was measured. Chirped QPM structures for wider SHG bandwidths also were demonstrated. Such periodically poled waveguides are promising for introducing nonlinear optical components within the 3D passive optical circuits that can be flexibly formed in fused silica by femtosecond laser writing. PMID- 28081071 TI - Small-period long-period fiber grating with improved refractive index sensitivity and dual-parameter sensing ability. AB - We UV inscribe and characterize a long-period fiber grating with a period of 25 MUm. A series of polarization-dependent dual-peak pairs can be seen in the transmission spectrum, even though only the symmetrical refractive index modification is introduced. The fabricated grating exhibits a lower temperature sensitivity compared with standard long-period gratings and an enhanced refractive index sensitivity of ~312.5 nm/RIU averaged from 1.315 to 1.395, which is more than four-fold higher than standard long-period gratings in this range. The full width at half-maximum of the fabricated grating is only about 0.6 nm, allowing for high-resolution sensing. Moreover, the grating period is so small that the attenuation dip corresponding to a high-order Bragg resonance can also be seen, which can act as a monitor of the unwanted perturbation to realize dual-parameter sensing. PMID- 28081072 TI - V-band gapless OFDM RoF system with power detector down-conversion and novel Volterra nonlinear filtering. AB - This Letter presents a V-band gapless orthogonal frequency division multiplexing (OFDM) RoF system at 60 GHz employing a power detector to support vector signal down-conversion. Additional RF tone is generated and transmitted from a central station to replace the local oscillator at a wireless receiver for power detector down-conversion. To enhance the spectrum efficiency, the gap between the OFDM signal and the RF tone is not needed. However, the down-converted signal will suffer signal-to-signal interference (SSBI). In this Letter, we propose and successfully employ a novel Volterra nonlinear compensation to mitigate SSBI, resulting in a 22% data rate improvement with a bit-loading algorithm. PMID- 28081073 TI - Strip-loaded horizontal slot waveguide. AB - We introduce a novel concept for an optical waveguide called a strip-loaded slot waveguide. It allows an extraordinary confinement of the field in a waveguide with an extremely tiny (vertical) cross section. Unlike conventional slot waveguides, the proposed configuration has potential for very low propagation losses. Its operation is demonstrated at telecommunication wavelengths and, in addition, it is fabricated by means of mass production compatible techniques: atomic layer deposition and nanoimprint replication. The possibility to fabricate the proposed structure with such low-cost techniques opens a new path for a variety of nanophotonics applications. PMID- 28081074 TI - Influence of the photon orbital angular momentum on electric dipole transitions: negative experimental evidence. AB - We describe an experiment of atomic spectroscopy devoted to ascertaining whether the orbital angular momentum (OAM) of photons has the same property of interacting with atoms or molecules as occurs for the spin angular momentum (SAM). In our experiment, rubidium vapors are excited by means of laser radiation with different combinations of OAM and SAM, particularly selected to inhibit or enhance the fluorescence according to the selection rules for the electric dipole transitions between the fundamental state and the first excited doublet. Our results clearly show that an electric-dipole-type transition is insensitive to the OAM value, and provide an original validation of a problem long debated in theoretical works. PMID- 28081075 TI - Dual-focus coherent anti-Stokes Raman scattering microscopy using a compact two beam fiber laser source. AB - We have developed a dual-focus coherent anti-Stokes Raman scattering (CARS) microscope based on a dual output, compact fiber laser source. The underlying concepts of time-multiplexed, two-beam scanning and demultiplexed detection that we already employed for second-harmonic generation are here naturally extended for CARS microscopy. The layout of a robust, all-fiber laser source was reconfigured to provide two outputs, each containing the two colors necessary for the CARS process. The utilization of the design for simultaneously imaging two laterally or axially separated fields of view and, thus, inherently speeding up the image acquisition process, is demonstrated on human artery tissue samples. PMID- 28081076 TI - Spatially-resolved individual particle spectroscopy using photothermal modulation of Mie scattering. AB - We report a photothermal modulation of Mie scattering (PMMS) method that enables concurrent spatial and spectral discrimination of individual micron-sized particles. This approach provides a direct measurement of the "fingerprint" infrared absorption spectrum with the spatial resolution of visible light. Trace quantities (tens of picograms) of material were deposited onto an infrared transparent substrate and simultaneously illuminated by a wavelength-tunable intensity-modulated quantum cascade pump laser and a continuous-wave 532 nm probe laser. Absorption of the pump laser by the particles results in direct modulation of the scatter field of the probe laser. The probe light scattered from the interrogated region is imaged onto a visible camera, enabling simultaneous probing of spatially-separated individual particles. By tuning the wavelength of the pump laser, the IR absorption spectrum is obtained. Using this approach, we measured the infrared absorption spectra of individual 3 MUm PMMA and silica spheres. Experimental PMMS signal amplitudes agree with modeling using an extended version of the Mie scattering theory for particles on substrates, enabling the prediction of the PMMS signal magnitude based on the material and substrate properties. PMID- 28081077 TI - MeV electron acceleration at 1 kHz with <10 mJ laser pulses. AB - We demonstrate laser-driven acceleration of electrons to MeV-scale energies at 1 kHz repetition rate using <10 mJ pulses focused on near-critical density He and H2 gas jets. Using the H2 gas jet, electron acceleration to ~0.5 MeV in ~10 fC bunches was observed with laser pulse energy as low as 1.3 mJ. Increasing the pulse energy to 10 mJ, we measure ~1 pC charge bunches with >1 MeV energy for both He and H2 gas jets. PMID- 28081078 TI - Mid-wave infrared narrow bandwidth guided mode resonance notch filter. AB - We have designed, fabricated, and characterized a guided mode resonance notch filter operating in the technologically vital mid-wave infrared (MWIR) region of the electromagnetic spectrum. The filter provides a bandstop at lambda~4.1 MUm, with a 12 dB extinction on resonance. In addition, we demonstrate a high transmission background (>80%), less than 6% transmission on resonance, and an ultra-narrow bandwidth transmission notch (10 cm-1). Our filter is optically characterized using angle- and polarization-dependent Fourier transform infrared spectroscopy, and simulated using rigorous coupled-wave analysis (RCWA) with excellent agreement between simulations and our experimental results. Using our RCWA simulations, we are able to identify the optical modes associated with the transmission dips of our filter. The presented structure offers a potential route toward narrow-band laser filters in the MWIR. PMID- 28081079 TI - Simple and fast spectral domain algorithm for quantitative phase imaging of living cells with digital holographic microscopy. AB - We present a simple and fast phase aberration compensation method in digital holographic microscopy (DHM) for quantitative phase imaging of living cells. By analyzing the frequency spectrum of an off-axis hologram, phase aberrations can be compensated for automatically without fitting or pre-knowledge of the setup and/or the object. Simple and effective computation makes the method suitable for quantitative online monitoring with highly variable DHM systems. Results from automated quantitative phase imaging of living NIH-3T3 mouse fibroblasts demonstrate the effectiveness and the feasibility of the method. PMID- 28081080 TI - Optimal measurements for resolution beyond the Rayleigh limit. AB - We establish the conditions to attain the ultimate resolution predicted by quantum estimation theory for the case of two incoherent point sources using a linear imaging system. The solution is closely related to the spatial symmetries of the detection scheme. In particular, for real symmetric point spread functions, any complete set of projections with definite parity achieves the goal. PMID- 28081081 TI - Compact broadband polarization beam splitter using a symmetric directional coupler with sinusoidal bends. AB - We design and demonstrate a compact broadband polarization beam splitter (PBS) using a symmetric directional coupler with sinusoidal bends on a silicon-on insulator platform. The sinusoidal bends in our PBS suppress the power exchange between two parallel symmetric strip waveguides for the transverse-electric (TE) mode, while allowing for the maximum power transfer to the adjacent waveguide for the transverse-magnetic (TM) mode. Our PBS has a nominal coupler length of 8.55 MUm, and it has an average extinction ratio (ER) of 12.0 dB for the TE mode, an average ER of 20.1 dB for the TM mode, an average polarization isolation (PI) of 20.6 dB for the through port, and an average PI of 11.5 dB for the cross port, all over a bandwidth of 100 nm. PMID- 28081082 TI - Seedless velocimetry at 100 kHz with picosecond-laser electronic-excitation tagging. AB - Picosecond-laser electronic-excitation tagging (PLEET), a seedless picosecond laser-based velocimetry technique, is demonstrated in non-reactive flows at a repetition rate of 100 kHz with a 1064 nm, 100 ps burst-mode laser. The fluorescence lifetime of the PLEET signal was measured in nitrogen, and the laser heating effects were analyzed. PLEET experiments with a free jet of nitrogen show the ability to measure multi-point flow velocity fluctuations at a 100 kHz detection rate or higher. Both spectral and dynamic mode decomposition analyses of velocity on a Ma=0.8 free jet show two dominant Strouhal numbers around 0.24 and 0.48, respectively, well within the shear-layer flapping frequencies of the free jets. This technique increases the laser-tagging repetition rate for velocimetry to hundreds of kilohertz. PLEET is suitable for subsonic through supersonic laminar- and turbulent-flow velocity measurements. PMID- 28081083 TI - Molecular dispersion spectroscopy based on Fabry-Perot quantum cascade lasers. AB - Two Fabry-Perot quantum cascade lasers are used in a differential dual comb configuration to perform rapidly swept dispersion spectroscopy of low-pressure nitrous oxide with <1 ms acquisition time. Active feedback control of the laser injection current enables simultaneous wavelength modulation of both lasers at kilohertz rates. The system demonstrates similar performance in both absorption and dispersion spectroscopy modes and achieves a noise-equivalent absorption figure of merit in the low 10-4/Hz range. PMID- 28081084 TI - Tailoring supercontinuum generation beyond 2 MUm in step-index tellurite fibers. AB - We report numerical and experimental demonstrations of flexible group-velocity dispersion regimes in step-index tellurite fibers by fine control of the fiber core diameter. Our simple fiber design allowed us to explore various nonlinear propagation regimes beyond 2 MUm, which involved careful control of four-wave mixing processes. Combined with the recent development of 2 MUm fiber lasers, we present an easy way to tailor supercontinuum generation and related coherence features in the high-demand 1.5-3.5 MUm spectral region. PMID- 28081085 TI - Coherent and incoherent seeding of dissipative modulation instability in a nonlinear fiber ring cavity. AB - We investigate the coherent or incoherent seeding of dissipative modulation instability (MI) in a nonlinear fiber ring cavity. By varying wavelength and degree of coherence of the seed signal across the MI gain band, we observe a strong sensitivity of the resulting MI sidebands in terms of bandwidth and amplification. Both spectral and temporal characterizations are performed to reveal intensity coherence properties (over a single round-trip) of the generated temporal patterns. Experimental observations are well confirmed by numerical simulations. Our results provide new insights into the control of dissipative MI through a specific seeding in optical resonators with a moderate free-spectral range. In particular, a large tunability of the subsequent Kerr comb spacing is achieved by means of the early transient stage of seeded MI growth. PMID- 28081086 TI - Random sources for rotating spectral densities. AB - The propagating modes of a wide-sense stationary Schell-like source with arbitrary coherence state and a twist factor are determined. This suggests a convenient practical method for modeling novel classes of twisted partially coherent beam-like fields. The first example discusses the previously introduced twisted anisotropic Gaussian Schell-model source and verifies the feasibility of this method. As a second example, we introduce a new type of twisted partially coherent beam in which a radiated flat-top average intensity pattern remains invariant in shape (but not size) while it twists around the axis upon propagation. PMID- 28081087 TI - Plasmonic non-concentric nanorings array as an unidirectional nano-optical conveyor belt actuated by polarization rotation. AB - We report a nano-optical conveyor belt containing an array of gold plasmonic non concentric nanorings (PNNRs) for the realization of trapping and unidirectional transportation of nanoparticles through rotating the polarization of an excitation beam. The location of hot spots within an asymmetric plasmonic nanostructure is polarization dependent, thus making it possible to manipulate a trapped target by rotating the incident polarization state. In the case of PNNR, the two poles have highly unbalanced trap potential. This greatly enhances the chance of transferring trapped particles between adjacent PNNRs in a given direction through rotating the polarization. As confirmed by three-dimensional finite-difference time-domain analysis, an array of PNNRs forms an unidirectional nano-optical conveyor belt, which delivers target nanoparticles or biomolecules over a long distance with nanometer accuracy. With the capacity to trap and to transfer, our design offers a versatile scheme for conducting mechanical sample manipulation in many on-chip optofluidic applications. PMID- 28081088 TI - AM-to-PM conversion in a resonant microwave optical rectification detector. AB - A LiNbO3-loaded microwave cavity pumped with weakly AM-modulated 30 fs optical pulses was used as a platform to investigate AM-to-PM conversion in the optical rectification process. Theoretical treatment of AM-to-PM conversion (i.e., peak-induced electrical phase deviation betai due to optical power modulation with index m) suggests that the dominant mechanism is self-group velocity modulation due to chi(3) and cascaded chi(2) processes with a value of delta=betai/m=-151 dB, linearly dependent on the optical power at intensities of 6*1010 W/m2 in a 40 mm long LiNbO3 crystal. This is in stark contrast to p-i-n photodiodes which can exhibit an AM-to-PM conversion gain delta>0 dB. In this experiment, we measured values of delta for a resonant optical rectification detector using typical mode-locked Ti:sapphire laser pulses (100 MHz, 30 fs, Pavg~100 mW) and found an instrumentation-limited lower bound of delta~-43.5 dB, independent of the optical power. PMID- 28081089 TI - Direct comparison of two-dimensional and three-dimensional laser-induced fluorescence measurements on highly turbulent flames. AB - This Letter reports the first direct comparison between two-dimensional (2D) and three-dimensional (3D) laser-induced fluorescence (LIF) applied to highly turbulent flames, with the goal of experimentally illustrating the capabilities and limitations of volumetric LIF (VLIF). To accomplish these goals, planar LIF (PLIF) and VLIF measurements were simultaneously performed on turbulent flames based on the CH radical. The PLIF measurements imaged a planar cross-section of the target flames across a 2D field-of-view (FOV) of 42 mm*42 mm. The VLIF measurements imaged the same region in the target flame with a 3D FOV of 42 mm*42 mm*5 mm, with 5 mm being the thickness of the measurement volume. The VLIF signals generated in this volume were captured by five intensified cameras from different perspectives, based on which a 3D tomographic reconstruction was performed to obtain the 3D reconstruction of the CH radical (as a marker of the flame front). The PLIF measurements were then compared to a cross-section of the VLIF measurement to demonstrate the feasibility and accuracy of instantaneous 3D imaging of flame topography and flame surface area in highly turbulent flames. PMID- 28081090 TI - Enhancement cavities for few-cycle pulses. AB - We address the challenge of increasing the bandwidth of high-finesse femtosecond enhancement cavities and demonstrate a broad spectrum spanning 1800 cm 1 (195 nm) at -10 dB around a central wavelength of 1050 nm in an EC with an average finesse exceeding 300. This will benefit a host of spectroscopic applications, including transient absorption spectroscopy, direct frequency comb spectroscopy, and Raman spectroscopy. The pulse circulating in the EC is composed of only 5.4 optical cycles, at a kilowatt-level average power. Together with a suitable gating technique, this paves the way to the efficient generation of multi-megahertz-repetition-rate isolated extreme ultraviolet attosecond pulses via intracavity high-order harmonic generation. PMID- 28081091 TI - Refocus criterion based on maximization of the coherence factor in digital three wavelength holographic interferometry. AB - This Letter presents an alternative approach for image refocusing in digital Fresnel holography. In the literature, a large majority of reported focus detection criteria is based on amplitude contrast or phase contrast. We propose a focus detection criterion based on the speckle phase coherence factor. This factor reaches its maximum value at the best focus distance. At any reconstruction distance, estimation of the coherence factor is based on robust noise estimation from anisotropic diffusion. We propose a theoretical relation to estimate the coherence factor from the measured standard deviation. Experimental results for the case of three-color holographic imaging and interferometry are provided. Experimental results show the suitability of the proposed approach for image plane refocusing. PMID- 28081092 TI - Optical excitation of spin waves in epitaxial iron garnet films: MSSW vs BVMSW. AB - In most of the previous studies of the spin wave optical generation in magnetic dielectrics, the backward volume spin waves were excited. Here we modified the parameters of the circularly polarized optical pump beams emitted by femtosecond laser to reveal surface spin waves in bismuth iron garnet thin film. Beams that are larger than 10 MUm in diameter generate both surface and volume spin waves with only one spectral peak near the ferromagnetic resonance. On the contrary, narrower beams excite predominantly surface spin waves of higher frequency, providing an additional peak in the spin wave spectrum. Thus different interference patterns of the magnetization dynamics are achievable. This may significantly broaden the capabilities of spin wave based devices. PMID- 28081093 TI - Balanced detection for self-mixing interferometry. AB - We propose a new detection scheme for self-mixing interferometry using two photodiodes for implementing a differential acquisition. The method is based on the phase opposition of the self-mixing signal measured between the two laser diode facet outputs. The subtraction of the two outputs implements a sort of balanced detection that improves the signal quality, and allows canceling of unwanted signals due to laser modulation and disturbances on laser supply and transimpedance amplifier. Experimental results demonstrate the benefits of differential acquisition in a system for both absolute distance and displacement vibration measurement. This Letter provides guidance for the design of self mixing interferometers using balanced detection. PMID- 28081094 TI - Graphitic C3N4 as a new saturable absorber for the mid infrared spectral range. AB - The saturable absorption properties of few-layer graphitic carbon nitride (g C3N4) nanosheets near 3 MUm were investigated. A stable Q switched Er:Lu2O3 laser at 2.84 MUm was realized by using a home-made g-C3N4 saturable absorber (SA), generating a pulse duration of 351 ns and an average output power of 1.09 W at a repetition rate of 99 kHz, corresponding to a pulse energy of 11.1 MUJ. Our result indicates a great potential of g-C3N4 as a new SA in the 3 MUm wavelength range. PMID- 28081095 TI - High spatial resolution distributed optical fiber dynamic strain sensor with enhanced frequency and strain resolution. AB - A distributed optical fiber dynamic strain sensor with high spatial and frequency resolution is demonstrated. The sensor, which uses the phi-OTDR interrogation technique, exhibited a higher sensitivity thanks to an improved optical arrangement and a new signal processing procedure. The proposed sensing system is capable of fully quantifying multiple dynamic perturbations along a 5 km long sensing fiber with a frequency and spatial resolution of 5 Hz and 50 cm, respectively. The strain resolution of the sensor was measured to be 40 nepsilon. PMID- 28081096 TI - Pump-probe micro-spectroscopy by means of an ultra-fast acousto-optics delay line. AB - We demonstrate femtosecond pump-probe transient absorption spectroscopy using a programmable dispersive filter as an ultra-fast delay line. Combined with fast synchronous detection, this delay line allows for recording of 6 ps decay traces at 34 kHz. With such acquisition speed, we perform single point pump-probe spectroscopy on bulk samples in 80 MUs and hyperspectral pump-probe imaging over a field of view of 100 MUm in less than a second. The usability of the method is illustrated in a showcase experiment to image and discriminate between two pigments in a mixture. PMID- 28081097 TI - Laser beam self-focusing in turbulent dissipative media. AB - A high-power laser beam propagating through a dielectric in the presence of fluctuations is subject to diffraction, dissipation, and optical Kerr nonlinearity. A method of moments was applied to a stochastic, nonlinear enveloped wave equation to analyze the evolution of the long-term spot radius. For propagation in atmospheric turbulence described by a Kolmogorov-von Karman spectral density, the analysis was benchmarked against field experiments in the low-power limit and compared with simulation results in the high-power regime. Dissipation reduced the effect of self-focusing and led to chromatic aberration. PMID- 28081098 TI - Generation of terahertz optical beating from a simultaneously self-mode-locked Nd:YAG laser at 1064 and 1123 nm. AB - The reflectivity of the output coupler is designed to achieve the synchronously self-mode-locked operation at 1064 and 1123 nm in a diode-end-pumped Nd:YAG laser. Numerical analyses are performed to confirm that the designed output coupler can lead the emission lines to be predominant at 1064 and 1123 nm. Moreover, the crossover of the threshold pump powers for the 1064 and 1123 nm emission lines can be exploited to obtain the single central wavelength of 1064 nm or the single central wavelength of 1123 nm or, simultaneously, dual-central wavelength self-mode-locked operation by finely adjusting the cavity alignment. For the dual-central-wavelength mode-locked emissions, the pulse repetition rate and the pulse duration are 4.5 GHz and 50.8 ps, respectively. The maximum output power can be up to 2.47 W at a pump power of 7.5 W. The synchronization of the 1064 and 1123 nm mode-locked pulses generates the optical beating pulse trains with repetition rates up to 14.7 THz. PMID- 28081099 TI - High-order external cavity modes and restabilization of a laser diode subject to a phase-conjugate feedback. AB - We experimentally report the sequence of bifurcations destabilizing and restabilizing a laser diode with phase-conjugate feedback when the feedback rate is increased. Specifically, we successively observe the initial steady state, undamped relaxation oscillations, quasi-periodicity, chaos, and oscillating solutions at harmonics up to 13 times the external cavity frequency but also the restabilization to a steady state. The experimental results are qualitatively well reproduced by a model that accounts for the time the light takes to penetrate the phase-conjugate mirror. The theory points out that the system restabilizes through a Hopf bifurcation whose frequency is a harmonic of the external cavity frequency. PMID- 28081100 TI - Digital equalization of time-delay array receivers on coherent laser communications. AB - Field conjugation arrays use adaptive combining techniques on multi-aperture receivers to improve the performance of coherent laser communication links by mitigating the consequences of atmospheric turbulence on the down-converted coherent power. However, this motivates the use of complex receivers as optical signals collected by different apertures need to be adaptively processed, co phased, and scaled before they are combined. Here, we show that multiple apertures, coupled with optical delay lines, combine retarded versions of a signal at a single coherent receiver, which uses digital equalization to obtain diversity gain against atmospheric fading. We found in our analysis that, instead of field conjugation arrays, digital equalization of time-delay multi-aperture receivers is a simpler and more versatile approach to accomplish reduction of atmospheric fading. PMID- 28081101 TI - Design of many-body spin states of Rydberg atoms excited to highly tunable magnetic sublevels. AB - Quantum control methodology is presented to design many-body spin states in a spin chain of Rydberg atoms using laser pulses and a magnetic field. A two-photon ladder-type configuration is implemented, which is advantageous due to the combined action of the one-photon and two-photon detunings as control parameters. Many-body spin states are designed consisting of an ensemble of spins encoded in sublevels of Rydberg states and coupled via the van der Waals interactions. PMID- 28081102 TI - Dual-comb coherent Raman spectroscopy with lasers of 1-GHz pulse repetition frequency. AB - We extend the technique of multiplex coherent Raman spectroscopy with two femtosecond mode-locked lasers to oscillators of a pulse repetition frequency of 1 GHz. We demonstrate a spectra of liquids, which span 1100 cm-1 of Raman shifts. At a resolution of 6 cm-1, their measurement time may be as short as 5 MUs for a refresh rate of 2 kHz. The waiting period between acquisitions is improved 10-fold compared to previous experiments with two lasers of 100-MHz repetition frequencies. PMID- 28081103 TI - Robust processing of phase dislocations based on combined unwrapping and inpainting approaches. AB - This Letter proposes a robust processing of phase dislocations to recover continuous phase maps. The approach is based on combined unwrapping and inpainting methods. Phase dislocations are determined using an estimator based on the second order phase gradient. The algorithm is validated using a realistic simulation of phase dislocations, and the phase restoration exhibits only weak errors. A comparison with other inpainting algorithms is also provided, demonstrating the suitability of the approach. The approach is applied to experimental data from off-axis digital holographic interferometry. The phase dislocation from phase data from a wake flow at Mach 0.73 are identified and processed. Excellent phase restoration can be appreciated. PMID- 28081104 TI - Intracavity stretcher for chirped-pulse amplification in high-power laser systems. AB - We present pulse stretching with an intracavity Offner-type pulse stretcher applied to a high-energy, short-pulse laser system. The compact intracavity design, offering a tunable stretching factor, allows the pulses to be stretched to several nanoseconds and, at the same time, to be amplified to 100 MUJ. The stretched pulses have been further amplified with the high-power laser system Polaris and have been recompressed to durations as short as 102 fs, reaching peak powers of 100 TW. Furthermore, the temporal intensity contrast is investigated and compared to the formerly used stretcher setup. PMID- 28081105 TI - Dynamic trapping of a polarization rotation vector soliton in a fiber laser. AB - Ultrafast fiber laser, as a dissipative nonlinear optical system, plays an important role in investigating various nonlinear phenomena and soliton dynamics. Vector features of solitons, including polarization locked and polarization rotation vector solitons (PRVSs), are interesting nonlinear dynamics in ultrafast fiber lasers. Herein, we experimentally reveal the trapping characteristics of PRVSs for the first time, to the best of our best knowledge. We show that, for the conventional soliton trapping in the ultrafast fiber laser, the soliton central wavelengths of the two polarization components are constant at the laser output port. However, it is found that the dynamic trapping can be observed for the PRVS. That is, the peak frequencies along the two orthogonal polarization directions are dynamically alternating, depending on the relative intensities of the two polarization components. The obtained results would further unveil the physical mechanism of PRVSs. PMID- 28081106 TI - Broad-bandwidth, reversible, and high-contrast-ratio optical diode. AB - Fano resonance is widely used to realize high-contrast nonreciprocal transmission. However, resonance-enhanced all-optical diodes (AOD) are bandwidth limited, and their transmission rates are normally low, which restricts realistic application. In this Letter, we analytically and numerically demonstrate that this limitation can be overcome once multistability of cascaded nonlinear cavities is appropriately excited. By precisely molding the transiting of the signal light between multistable states, a high-contrast-ratio, high unidirectional-transmission-rate, and reversal-controllable AOD is achieved with a bandwidth over 2.4 nm, which is about two orders of magnitude wider than the reported results obtained by other methods based on Fano resonances. This approach may pave the way for dynamic control of on-chip all-optical information processing. PMID- 28081107 TI - Electrically pumped continuous-wave 1.3 MUm quantum-dot lasers epitaxially grown on on-axis (001) GaP/Si. AB - We demonstrate the first electrically pumped continuous-wave (CW) III-V semiconductor lasers epitaxially grown on on-axis (001) silicon substrates without offcut or germanium layers, using InAs/GaAs quantum dots as the active region and an intermediate GaP buffer between the silicon and device layers. Broad-area lasers with uncoated facets achieve room-temperature lasing with threshold current densities around 860 A/cm2 and 110 mW of single facet output power for the same device. Ridge lasers designed for low threshold operations show maximum lasing temperatures up to 90 degrees C and thresholds down to 30 mA. PMID- 28081108 TI - Integrated all-optical MIMO demultiplexer for mode- and wavelength-division multiplexed transmission. AB - A photonic integrated circuit performing simultaneous mode and wavelength demultiplexing for few-mode-fiber transmission is demonstrated for the first time. The circuit is realized on an InP-based technological platform; it can handle up to eight mode- and wavelength-division-multiplexed (MDM/WDM) channels and allows all-optical multiple-input-multiple-output processing to unscramble mode mixing generated by fiber propagation. A single arrayed waveguide grating is used to demultiplex the WDM channels carried by all the propagating modes, optimizing circuit complexity, chip area, and operational stability. Combined with an integrated wideband mode multiplexer the circuit is successfully exploited for the transmission of 10 Gbit/s on-off-keying non-return-to-zero channels with a residual cross talk of about -15 dB. PMID- 28081109 TI - Non-axial-scanning multifocal confocal microscopy with multiplexed volume holographic gratings. AB - Confocal imaging techniques offer an optical sectioning capability to acquire three-dimensional information from various volumetric samples by discriminating the desired in-focus signals from the out-of-focus background. However, confocal, in general, requires a point-by-point scan in both the lateral and axial directions to reconstruct three-dimensional images. In addition, axial scanning in confocal is slower than scanning in lateral directions. In this Letter, a non axial-scanning multifocal confocal microscope incorporating multiplexed holographic gratings in illumination and dual detection for depth discrimination is presented. Further, we demonstrate the ability of the proposed confocal microscopy to image ex vivo tissue structures simultaneously at different focal depths without mechanical or electro-optic axial scanning. PMID- 28081110 TI - Light-sheet microscopy in a glass capillary: feedback holographic control for illumination beam correction. AB - Light-sheet microscopy enables fast 3D, high-contrast imaging in biology and colloidal sciences. Recently, the controlled transport of living embryos or small colloids through stable glass capillaries is manifold interesting. Although they hardly impair the sample, glass capillaries spoil the image by generating significant aberrations of the illumination and detection light. Here, we analyze the deflection of illuminating Bessel beams at the capillary by k-spectral shifting, and correct for it by a beam deflector. Using cylindrical lenses for astigmatism compensation on the detection side, we demonstrate 3D line-confocal imaging inside a glass capillary over an axial range of +/-400 MUm. PMID- 28081111 TI - Naked eye picometer resolution in a Michelson interferometer using conjugated twisted beams. AB - Michelson interferometry is one of the most widely used techniques for accuracy measurements. Its main characteristic feature is to infer a displacement in one of the arms of the interferometer from a phase measurement. Two different twisted beams, also called vortex beams, with opposite twisted rotations in each arm of the interferometer interfere in a daisy flower-like pattern. The number of petals is twice the topological charge. Their position depends on the relative phase of the beams. Naked eye detection of 44 pm displacements is achieved. The sensitivity of such an interferometer together with possible further improvements, and applications are then discussed. PMID- 28081112 TI - Electronic states of defect with impurity and infrared emission on black silicon prepared by an ns-laser. AB - It is found that the optimum annealing temperature is about 1000 degrees C for the infrared emission of defect states at room temperature on black silicon (BS) prepared by using a nanosecond-pulsed laser. In addition, it is observed that the suitable annealing time is 6~8 min at 1000 degrees C for the emission on the BS. The crystallizing proceeding in annealing on the BS can be used to explain the above annealing effect. It is interesting that the emission band becomes intensive and broader on the BS prepared in oxygen atmosphere than that prepared in vacuum in the analysis of photoluminescence spectra, where the electronic states localized at the defects from D1 to D4 doped with oxygen play an important role in the emission with the broader band which are obviously enhanced in the room temperature. PMID- 28081113 TI - Reciprocity relation for the vector radiative transport equation and its application to diffuse optical tomography with polarized light. AB - We derive a reciprocity relation for the 3D vector radiative transport equation that describes propagation of polarized light in multiple-scattering media. We then show how this result, together with translational invariance of a plane parallel sample, can be used to efficiently compute the sensitivity kernel of diffuse optical tomography by Monte Carlo simulations. Numerical examples of polarization-selective sensitivity kernels are given. PMID- 28081114 TI - Enhancement of entanglement using cascaded four-wave mixing processes. AB - A maximal joint quadrature squeezing of -6.8+/-0.4 dB is experimentally obtained by a scheme of cascaded four-wave mixing (FWM) processes, which gives strong proof about the inseparability or entanglement between output of the twin beams from the system. Here joint quadrature is the difference between the two quadratures of the twin beam output from the cascaded FWM processes. This result is enhanced by about 3.1 dB, compared with the one of the single FWM process. We also study the gain dependence of the entanglement enhancement in this cascaded system. Theoretical predictions with the considerations of the losses in the experiment are also studied, and a similar trend in the low-gain regime can be found between the experimental results and the theoretical predictions. The scheme of cascaded FWM processes, which can be used to improve or even manipulate the degree of the entanglement between the output fields from the single FWM process, may find its applications in the continuous-variable quantum communication protocols. PMID- 28081115 TI - Circular fringe projection profilometry: erratum. AB - In this erratum, an error in Eq. (14) in our recently published Letter [Opt. Lett.41, 4951 (2016)10.1364/OL.41.004951OPLEDP0146-9592] is corrected. PMID- 28081116 TI - The Sharing Experimental Animal Resources, Coordinating Holdings (SEARCH) Framework: Encouraging Reduction, Replacement, and Refinement in Animal Research. AB - While significant medical breakthroughs have been achieved through using animal models, our experience shows that often there is surplus material remaining that is frequently never revisited but could be put to good use by other scientists. Recognising that most scientists are willing to share this material on a collaborative basis, it makes economic, ethical, and academic sense to explore the option to utilise this precious resource before generating new/additional animal models and associated samples. To bring together those requiring animal tissue and those holding this type of archival material, we have devised a framework called Sharing Experimental Animal Resources, Coordinating Holdings (SEARCH) with the aim of making remaining material derived from animal studies in biomedical research more visible and accessible to the scientific community. We encourage journals, funding bodies, and scientists to unite in promoting a new way of approaching animal research by adopting the SEARCH framework. PMID- 28081117 TI - Interplay between Public Attention and Public Emotion toward Multiple Social Issues on Twitter. AB - This study aims to elucidate the intricate interplay between public attention and public emotion toward multiple social issues. A theoretical framework is developed based on three perspectives including endogenous affect hypothesis, affect transfer hypothesis, and affective intelligence theory. Large-scale longitudinal data with 265 million tweets on five social issues are analyzed using a time series analytical approach. Public attention on social issues can influence public emotion on the issue per se. Social issues interact with one another to attract public attention in both cooperative and competitive ways. Instead of a direct transfer from public emotion to public attention, the public emotion toward a social issue moderates the interaction between the issue and other issue(s). PMID- 28081118 TI - The Cost of War on Public Health: An Exploratory Method for Understanding the Impact of Conflict on Public Health in Sri Lanka. AB - PURPOSE: The direct impact of protracted conflict on population health and development is well understood. However, the extent of a war's impact on long term health, and the opportunity costs, are less well understood. This research sought to overcome this gap by asking whether or not health outcomes in Sri Lanka would have been better in the absence of a 26-year war than they were in the presence of war. METHODS: A counterfactual model of national and district-level health outcomes was created for Sri Lanka for the period 1982 to 2002. At the national level, the model examined life expectancy, infant mortality rate (IMR), and maternal mortality ratios (MMR). At the district level, it looked at IMR and MMR. The model compared outcomes generated by the counterfactual model to actual obtained health outcomes. It looked at the rate of change and absolute values. RESULTS: The analysis demonstrated that war altered both rate of change and absolute health outcomes for the worse. The impact was most clearly evident at the district level. IMR was poorer than predicted in 10 districts; of these 8 were outside of the conflict zone. The MMR was worse than expected in 11 districts of which 9 were not in the conflict zone. Additionally, the rate of improvement in IMR slowed as a result of war in 16 districts whereas the rate of improvement in MMR slowed in 9. CONCLUSION: This project showed that protracted conflict degraded the trajectory of public health in Sri Lanka and hurt population health outside of the conflict zone. It further provided a novel methodology with which to better understand the indirect impact of conflict on population health by comparing what is to what could have been achieved in the absence of war. In so doing, this research responded to two public health challenges by providing a tool through which to better understand the human and opportunity costs of war and by answering a call for new methodologies. PMID- 28081119 TI - Sclerostin Promotes Bone Remodeling in the Process of Tooth Movement. AB - Tooth movement is a biological process of bone remodeling induced by mechanical force. Sclerostin secreted by osteocytes is mechanosensory and important in bone remodeling. However, little is known regarding the role of sclerostin in tooth movement. In this study, models of experimental tooth movement were established in rats and mice. Sclerostin expression was investigated with immunohistochemistry staining, and osteoclastic activity was analyzed with tartrate-resistant acid phosphatase (TRAP) staining. MLO-Y4 osteocyte-like cells underwent uniaxial compression and tension stress or were cultured in hypoxia conditions. Expression of sclerostin was assessed by RT-qPCR and ELISA. MLO-Y4 cells were cultured with recombinant human sclerostin (rhSCL) interference and then co-cultured with RAW264.7 osteoclast precursor cells. Expressions of RANKL and OPG were analyzed by RT-qPCR, and osteoclastic activity was assessed by TRAP staining. During tooth movement, sclerostin was expressed differently in compression and tension sites. In SOST knock-out mice, there were significantly fewer TRAP-positive cells than in WT mice during tooth movement in compression sites. In-vitro studies showed that the expression of sclerostin in MLO-Y4 osteocyte-like cells was not different under a uniaxial compression and tension force, whereas hypoxia conditions significantly increased sclerostin expression in MLO-Y4 cells. rhSCL interference increased the expression of RANKL and the RANKL/OPG ratio in MLO-Y4 cells and the osteoclastic induction ability of MLO-Y4 cells in experimental osteocyte-osteoclast co-culture. These data suggest that sclerostin plays an important role in the bone remodeling of tooth movement. PMID- 28081120 TI - Epidemiology of Chikungunya Virus Outbreaks in Guadeloupe and Martinique, 2014: An Observational Study in Volunteer Blood Donors. AB - BACKGROUND: During Dec-2013, a chikungunya virus (CHIKV) outbreak was first detected in the French-West Indies. Subsequently, the virus dispersed to other Caribbean islands, continental America and many islands in the Pacific Ocean. Previous estimates of the attack rate were based on declaration of clinically suspected cases. METHODS/PRINCIPAL FINDINGS: Individual testing for CHIKV RNA of all (n = 16,386) blood donations between Feb-24th 2014 and Jan-31st 2015 identified 0.36% and 0.42% of positives in Guadeloupe and Martinique, respectively. The incidence curves faithfully correlated with those of suspected clinical cases in the general population of Guadeloupe (abrupt epidemic peak), but not in Martinique (flatter epidemic growth). No significant relationship was identified between CHIKV RNA detection and age-classes or blood groups. Prospective (Feb-2014 to Jan-2015; n = 9,506) and retrospective (Aug-2013 to Feb 2014; n = 6,559) seroepidemiological surveys in blood donors identified a final seroprevalence of 48.1% in Guadeloupe and 41.9% in Martinique. Retrospective survey also suggested the absence or limited "silent" CHIKV circulation before the outbreak. Parameters associated with increased seroprevalence were: Gender (M>F), KEL-1, [RH+1/KEL-1], [A/RH+1] and [A/RH+1/KEL-1] blood groups in Martiniquan donors. A simulation model based on observed incidence and actual seroprevalence values predicted 2.5 and 2.3 days of asymptomatic viraemia in Martiniquan and Guadeloupian blood donors respectively. CONCLUSIONS/SIGNIFICANCE: This study, implemented promptly with relatively limited logistical requirements during CHIKV emergence in the Caribbean, provided unique information regarding retrospective and prospective epidemiology, infection risk factors and natural history of the disease. In the stressful context of emerging infectious disease outbreaks, blood donor-based studies can serve as robust and cost-effective first line tools for public health surveys. PMID- 28081121 TI - Isolation of Novel Trypanosomatid, Zelonia australiensis sp. nov. (Kinetoplastida: Trypanosomatidae) Provides Support for a Gondwanan Origin of Dixenous Parasitism in the Leishmaniinae. AB - The genus Leishmania includes approximately 53 species, 20 of which cause human leishmaniais; a significant albeit neglected tropical disease. Leishmaniasis has afflicted humans for millennia, but how ancient is Leishmania and where did it arise? These questions have been hotly debated for decades and several theories have been proposed. One theory suggests Leishmania originated in the Palearctic, and dispersed to the New World via the Bering land bridge. Others propose that Leishmania evolved in the Neotropics. The Multiple Origins theory suggests that separation of certain Old World and New World species occurred due to the opening of the Atlantic Ocean. Some suggest that the ancestor of the dixenous genera Leishmania, Endotrypanum and Porcisia evolved on Gondwana between 90 and 140 million years ago. In the present study a detailed molecular and morphological characterisation was performed on a novel Australian trypanosomatid following its isolation in Australia's tropics from the native black fly, Simulium (Morops) dycei Colbo, 1976. Phylogenetic analyses were conducted and confirmed this parasite as a sibling to Zelonia costaricensis, a close relative of Leishmania previously isolated from a reduviid bug in Costa Rica. Consequently, this parasite was assigned the name Zelonia australiensis sp. nov. Assuming Z. costaricensis and Z. australiensis diverged when Australia and South America became completely separated, their divergence occurred between 36 and 41 million years ago at least. Using this vicariance event as a calibration point for a phylogenetic time tree, the common ancestor of the dixenous genera Leishmania, Endotrypanum and Porcisia appeared in Gondwana approximately 91 million years ago. Ultimately, this study contributes to our understanding of trypanosomatid diversity, and of Leishmania origins by providing support for a Gondwanan origin of dixenous parasitism in the Leishmaniinae. PMID- 28081122 TI - Novel Bartonella Species in Insectivorous Bats, Northern China. AB - Bartonella species are emerging human pathogens. Bats are known to carry diverse Bartonella species, some of which are capable of infecting humans. However, as the second largest mammalian group by a number of species, the role of bats as the reservoirs of Bartonella species is not fully explored, in term of their species diversity and worldwide distribution. China, especially Northern China, harbors a number of endemic insectivorous bat species; however, to our knowledge, there are not yet studies about Bartonella in bats in China. The aim of the study was to investigate the prevalence and genetic diversity of Bartonella species in bats in Northern China. Bartonella species were detected by PCR amplification of gltA gene in 25.2% (27/107) bats in Mengyin County, Shandong Province of China, including 1/3 Rhinolophus ferrumequinum, 2/10 Rhinolophus pusillus, 9/16 Myotis fimbriatus, 1/5 Myotis ricketti, 14/58 Myotis pequinius. Phylogenetic analysis showed that Bartonella species detected in bats in this study clustered into ten groups, and some might be novel Bartonella species. An association between Bartonella species and bat species was demonstrated and co-infection with different Bartonella species in a single bat was also observed. Our findings expanded our knowledge on the genetic diversity of Bartonella in bats, and shed light on the ecology of bat-borne Bartonella species. PMID- 28081123 TI - Yersinia enterocolitica, a Neglected Cause of Human Enteric Infections in Cote d'Ivoire. AB - BACKGROUND: Enteropathogenic Yersinia circulate in the pig reservoir and are the third bacterial cause of human gastrointestinal infections in Europe. In West Africa, reports of human yersiniosis are rare. This study was conducted to determine whether pathogenic Yersinia are circulating in pig farms and are responsible for human infections in the Abidjan District. METHODOLOGY/PRINCIPAL FINDINGS: From June 2012 to December 2013, pig feces were collected monthly in 41 swine farms of the Abidjan district. Of the 781 samples collected, 19 Yersinia strains were isolated in 3 farms: 7 non-pathogenic Yersinia intermedia and 12 pathogenic Yersinia enterocolitica bioserotype 4/O:3. Farm animals other than pigs and wild animals were not found infected. Furthermore, 2 Y. enterocolitica 4/O:3 strains were isolated from 426 fecal samples of patients with digestive disorders. All 14 Y. enterocolitica strains shared the same PFGE and MLVA profile, indicating their close genetic relationship. However, while 6 of them displayed the usual phage type VIII, the other 8 had the highly infrequent phage type XI. Whole genome sequencing and SNP analysis of individual colonies revealed that phage type XI strains had unusually high rates of mutations. These strains displayed a hypermutator phenotype that was attributable to a large deletion in the mutS gene involved in DNA mismatch repair. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that pathogenic Y. enterocolitica circulate in the pig reservoir in Cote d'Ivoire and cause human infections with a prevalence comparable to that of many developed countries. The paucity of reports of yersiniosis in West Africa is most likely attributable to a lack of active detection rather than to an absence of the microorganism. The identification of hypermutator strains in pigs and humans is of concern as these strains can rapidly acquire selective advantages that may increase their fitness, pathogenicity or resistance to commonly used treatments. PMID- 28081124 TI - Rapid Genotyping of beta-tubulin Polymorphisms in Trichuris trichiura and Ascaris lumbricoides. AB - BACKGROUND: The benzimidazole (BZ) anthelmintics, albendazole (ABZ) and mebendazole (MBZ) are the most common drugs used for treatment of soil transmitted helminths (STHs). Their intensive use increases the possibility that BZ resistance may develop. In veterinary nematodes, BZ resistance is caused by a single nucleotide polymorphism (SNP) in the beta-tubulin isotype 1 gene at codon position 200, 167 or 198, and these SNPs have also been correlated with poor response of human Trichuris trichiura to BZ treatment. It is important to be able to investigate the presence of resistance-associated SNPs in STHs before resistance becomes clinically established. METHODS: The objective of this study was to develop new genotyping assays to screen for the presence of beta-tubulin SNPs in T. trichiura and Ascaris lumbricoides. Rapid, simple and accurate genotyping assays were developed based on the SmartAmp2 method. Primer sets were optimized and selected to distinguish the SNP-variant genotypes. After initial optimization on control plasmids, the feasibility of the assay was assessed in field samples from Haiti and Panama. Finally, spiked fecal samples were assessed to determine the tolerance of Aac polymerase to fecal inhibitors. FINDINGS: Rapid SNP genotyping assays were developed to target beta-tubulin polymorphisms in T. trichiura and A. lumbricoides. The assays showed high sensitivity and specificity in field samples and also demonstrated high tolerance to PCR inhibitors in fecal samples. CONCLUSION: These assays proved to be robust and efficient with the potential to be used as field tools for monitoring SNPs that could be associated with BZ resistance. However, further work is needed to validate the assays on large numbers of field samples before and after treatment. PMID- 28081125 TI - The Neural Representation of Prospective Choice during Spatial Planning and Decisions. AB - We are remarkably adept at inferring the consequences of our actions, yet the neuronal mechanisms that allow us to plan a sequence of novel choices remain unclear. We used functional magnetic resonance imaging (fMRI) to investigate how the human brain plans the shortest path to a goal in novel mazes with one (shallow maze) or two (deep maze) choice points. We observed two distinct anterior prefrontal responses to demanding choices at the second choice point: one in rostrodorsal medial prefrontal cortex (rd-mPFC)/superior frontal gyrus (SFG) that was also sensitive to (deactivated by) demanding initial choices and another in lateral frontopolar cortex (lFPC), which was only engaged by demanding choices at the second choice point. Furthermore, we identified hippocampal responses during planning that correlated with subsequent choice accuracy and response time, particularly in mazes affording sequential choices. Psychophysiological interaction (PPI) analyses showed that coupling between the hippocampus and rd-mPFC increases during sequential (deep versus shallow) planning and is higher before correct versus incorrect choices. In short, using a naturalistic spatial planning paradigm, we reveal how the human brain represents sequential choices during planning without extensive training. Our data highlight a network centred on the cortical midline and hippocampus that allows us to make prospective choices while maintaining initial choices during planning in novel environments. PMID- 28081126 TI - A Pan-Lyssavirus Taqman Real-Time RT-PCR Assay for the Detection of Highly Variable Rabies virus and Other Lyssaviruses. AB - Rabies, resulting from infection by Rabies virus (RABV) and related lyssaviruses, is one of the most deadly zoonotic diseases and is responsible for up to 70,000 estimated human deaths worldwide each year. Rapid and accurate laboratory diagnosis of rabies is essential for timely administration of post-exposure prophylaxis in humans and control of the disease in animals. Currently, only the direct fluorescent antibody (DFA) test is recommended for routine rabies diagnosis. Reverse-transcription polymerase chain reaction (RT-PCR) based diagnostic methods have been widely adapted for the diagnosis of other viral pathogens, but there is currently no widely accepted rapid real-time RT-PCR assay for the detection of all lyssaviruses. In this study, we demonstrate the validation of a newly developed multiplex real-time RT-PCR assay named LN34, which uses a combination of degenerate primers and probes along with probe modifications to achieve superior coverage of the Lyssavirus genus while maintaining sensitivity and specificity. The primers and probes of the LN34 assay target the highly conserved non-coding leader region and part of the nucleoprotein (N) coding sequence of the Lyssavirus genome to maintain assay robustness. The probes were further modified by locked nucleotides to increase their melting temperature to meet the requirements for an optimal real-time RT PCR assay. The LN34 assay was able to detect all RABV variants and other lyssaviruses in a validation panel that included representative RABV isolates from most regions of the world as well as representatives of 13 additional Lyssavirus species. The LN34 assay was successfully used for both ante-mortem and post-mortem diagnosis of over 200 clinical samples as well as field derived surveillance samples. This assay represents a major improvement over previously published rabies specific RT-PCR and real-time RT-PCR assays because of its ability to universally detect RABV and other lyssaviruses, its high throughput capability and its simplicity of use, which can be quickly adapted in a laboratory to enhance the capacity of rabies molecular diagnostics. The LN34 assay provides an alternative approach for rabies diagnostics, especially in rural areas and rabies endemic regions that lack the conditions and broad experience required to run the standard DFA assay. PMID- 28081128 TI - Radiation Exposure from Diagnostic Imaging in a Cohort of Pediatric Transplant Recipients. AB - Recipients of solid organ transplants (SOT) have extensive diagnostic imaging (DI). The purpose of this study was to quantify this exposure. Children from northern Alberta with SOTs at Stollery Children's Hospital, Edmonton, Alberta January 1, 2006, to July 31, 2012, were included. Effective doses of radiation were estimated using published norms for DI performed post-transplant up to October 16, 2014. The 54 eligible children had 6215 DI studies (5628 plain films, 293 computerized tomography (CT) scans, 149 positron emission topography (PET) CT scans, 47 nuclear medicine scans and 98 cardiac catheterizations). Children less than 5 years of age underwent more DI studies than did older children (median (IQR) 140 (66-210) vs 49 (19-105), p = 0.010). Children with post transplant lymphoproliferative disorder (N = 8) had more CT scans (median (IQR) 13 (5.5-36) vs 1 (0-5), p<0.001) and PET-CT scans (median (IQR) 3.5 (1.5-8) vs 0 (0-0), p<0.001) than did other children. The estimated cumulative effective dose attributed to DI studies post-transplant was median (range) 78 (4.1-400) millisievert (mSv), and 19 of 54 children (35%; 95% confidence interval 24-49%) had a dose >100 mSv. In conclusion, a significant proportion of pediatric transplant recipients have sufficient radiation exposure post-transplant for DI to be at potential risk for radiation-induced malignancies. PMID- 28081127 TI - Transient In Vivo Resistance Mechanisms of Burkholderia pseudomallei to Ceftazidime and Molecular Markers for Monitoring Treatment Response. AB - Much is known about the mode of action of drugs and resistance mechanisms under laboratory growth conditions, but research on the bacterial transcriptional response to drug pressure in vivo or efficacious mode of action and transient resistance mechanisms of clinically employed drugs is limited. Accordingly, to assess active alternative metabolism and transient resistance mechanisms, and identify molecular markers of treatment response, the in vivo transcriptional response of Burkholderia pseudomallei 1026b to treatment with ceftazidime in infected lungs was compared to the in vitro bacterial response in the presence of drug. There were 1,688 transcriptionally active bacterial genes identified that were unique to in vivo treated conditions. Of the in vivo transcriptionally active bacterial genes, 591 (9.4% coding capacity) genes were differentially expressed by ceftazidime treatment. In contrast, only 186 genes (2.7% coding capacity) were differentially responsive to ceftazidime treatment under in vitro culturing conditions. Within the genes identified were alternative PBP proteins that may compensate for target inactivation and transient resistance mechanisms, such as beta-lactamses that may influence the potency of ceftazidime. This disparate observation is consistent with the thought that the host environment significantly alters the bacterial metabolic response to drug exposure compared to the response observed under in vitro growth. Notably, this study revealed 184 bacterial genes and ORFs that were unique to in vivo ceftazidime treatment and thus provide candidate molecular markers for treatment response. This is the first report of the unique transcriptional response of B. pseudomallei from host tissues in an animal model of infection and elucidates the in vivo metabolic vulnerabilities, which is important in terms of defining the efficacious mode of action and transient resistance mechanisms of a frontline meliodosis chemotherapeutic, and biomarkers for monitoring treatment outcome. PMID- 28081129 TI - Effects of Kasugamycin on the Translatome of Escherichia coli. AB - It is long known that Kasugamycin inhibits translation of canonical transcripts containing a 5'-UTR with a Shine Dalgarno (SD) motif, but not that of leaderless transcripts. To gain a global overview of the influence of Kasugamycin on translation efficiencies, the changes of the translatome of Escherichia coli induced by a 10 minutes Kasugamycin treatment were quantified. The effect of Kasugamycin differed widely, 102 transcripts were at least twofold more sensitive to Kasugamycin than average, and 137 transcripts were at least twofold more resistant, and there was a more than 100-fold difference between the most resistant and the most sensitive transcript. The 5'-ends of 19 transcripts were determined from treated and untreated cultures, but Kasugamycin resistance did neither correlate with the presence or absence of a SD motif, nor with differences in 5'-UTR lengths or GC content. RNA Structure Logos were generated for the 102 Kasugamycin-sensitive and for the 137 resistant transcripts. For both groups a short Shine Dalgarno (SD) motif was retrieved, but no specific motifs associated with resistance or sensitivity could be found. Notably, this was also true for the region -3 to -1 upstream of the start codon and the presence of an extended SD motif, which had been proposed to result in Kasugamycin resistance. Comparison of the translatome results with the database RegulonDB showed that the transcript with the highest resistance was leaderless, but no further leaderless transcripts were among the resistant transcripts. Unexpectedly, it was found that translational coupling might be a novel feature that is associated with Kasugamycin resistance. Taken together, Kasugamycin has a profound effect on translational efficiencies of E. coli transcripts, but the mechanism of action is different than previously described. PMID- 28081130 TI - Comparative Ability of Oropsylla montana and Xenopsylla cheopis Fleas to Transmit Yersinia pestis by Two Different Mechanisms. AB - BACKGROUND: Transmission of Yersinia pestis by flea bite can occur by two mechanisms. After taking a blood meal from a bacteremic mammal, fleas have the potential to transmit the very next time they feed. This early-phase transmission resembles mechanical transmission in some respects, but the mechanism is unknown. Thereafter, transmission occurs after Yersinia pestis forms a biofilm in the proventricular valve in the flea foregut. The biofilm can impede and sometimes completely block the ingestion of blood, resulting in regurgitative transmission of bacteria into the bite site. In this study, we compared the relative efficiency of the two modes of transmission for Xenopsylla cheopis, a flea known to become completely blocked at a high rate, and Oropsylla montana, a flea that has been considered to rarely develop proventricular blockage. METHODOLOGY/PRINCIPAL FINDINGS: Fleas that took an infectious blood meal containing Y. pestis were maintained and monitored for four weeks for infection and proventricular blockage. The number of Y. pestis transmitted by groups of fleas by the two modes of transmission was also determined. O. montana readily developed complete proventricular blockage, and large numbers of Y. pestis were transmitted by that mechanism both by it and by X. cheopis, a flea known to block at a high rate. In contrast, few bacteria were transmitted in the early phase by either species. CONCLUSIONS: A model system incorporating standardized experimental conditions and viability controls was developed to more reliably compare the infection, proventricular blockage and transmission dynamics of different flea vectors, and was used to resolve a long-standing uncertainty concerning the vector competence of O. montana. Both X. cheopis and O. montana are fully capable of transmitting Y. pestis by the proventricular biofilm dependent mechanism. PMID- 28081131 TI - "I Wasted 3 Years, Thinking It's Not a Problem": Patient and Health System Delays in Diagnosis of Leprosy in India: A Mixed-Methods Study. AB - BACKGROUND: Worldwide, leprosy is one of the major causes of preventable disability. India contributes to 60% of global leprosy burden. With increasing numbers of leprosy with grade 2 disability (visible disability) at diagnosis, we aimed to determine risk factors associated with grade 2 disability among new cases and explore patients and providers' perspectives into reasons for late presentation. METHODOLOGY/PRINCIPAL FINDINGS: This was an explanatory mixed methods study where the quantitative component, a matched case-control design, was followed by a qualitative component. A total of 70 cases (grade 2 disability) and 140 controls (grade 0) matched for age and sex were randomly sampled from new patients registered between January 2013-January 2015 in three districts of Maharashtra (Mumbai, Thane and Amaravati) and interviewed using a structured close ended questionnaire. Eight public health care providers involved in leprosy care and 7 leprosy patients were purposively selected (maximum variation sampling) and interviewed using a structured open-ended interview schedule. Among cases, overall median (IQR) diagnosis delay in months was 17.9(7-30); patient and health system delay was 7(4-16.5) and 5.5(0.9-12.5) respectively; this was significantly higher than the delay in controls. Reasons for delayed presentation identified by the quantitative and qualitative data were: poor awareness of leprosy symptoms, first health care provider visited being private practitioners who were not aware about provision of free leprosy treatment at public health care facilities, reduced engagement and capacity of the general health care system in leprosy control. CONCLUSIONS: Raising awareness in communities and health care providers regarding early leprosy symptoms, engagement of private health care provider in early leprosy diagnosis and increasing capacity of general health system staff, especially targeting high endemic areas that are hotspots for leprosy transmission may help in reducing diagnosis delays. PMID- 28081132 TI - The Janus-faced Nature of miR-22 in Hematopoiesis: Is It an Oncogenic Tumor Suppressor or Rather a Tumor-Suppressive Oncogene? PMID- 28081133 TI - The Power of Malaria Vaccine Trials Using Controlled Human Malaria Infection. AB - Controlled human malaria infection (CHMI) in healthy human volunteers is an important and powerful tool in clinical malaria vaccine development. However, power calculations are essential to obtain meaningful estimates of protective efficacy, while minimizing the risk of adverse events. To optimize power calculations for CHMI-based malaria vaccine trials, we developed a novel non linear statistical model for parasite kinetics as measured by qPCR, using data from mosquito-based CHMI experiments in 57 individuals. We robustly account for important sources of variation between and within individuals using a Bayesian framework. Study power is most dependent on the number of individuals in each treatment arm; inter-individual variation in vaccine efficacy and the number of blood samples taken per day matter relatively little. Due to high inter individual variation in the number of first-generation parasites, hepatic vaccine trials required significantly more study subjects than erythrocytic vaccine trials. We provide power calculations for hypothetical malaria vaccine trials of various designs and conclude that so far, power calculations have been overly optimistic. We further illustrate how upcoming techniques like needle-injected CHMI may reduce required sample sizes. PMID- 28081134 TI - Pain: A Statistical Account. AB - Perception is seen as a process that utilises partial and noisy information to construct a coherent understanding of the world. Here we argue that the experience of pain is no different; it is based on incomplete, multimodal information, which is used to estimate potential bodily threat. We outline a Bayesian inference model, incorporating the key components of cue combination, causal inference, and temporal integration, which highlights the statistical problems in everyday perception. It is from this platform that we are able to review the pain literature, providing evidence from experimental, acute, and persistent phenomena to demonstrate the advantages of adopting a statistical account in pain. Our probabilistic conceptualisation suggests a principles-based view of pain, explaining a broad range of experimental and clinical findings and making testable predictions. PMID- 28081135 TI - Rumor Detection over Varying Time Windows. AB - This study determines the major difference between rumors and non-rumors and explores rumor classification performance levels over varying time windows-from the first three days to nearly two months. A comprehensive set of user, structural, linguistic, and temporal features was examined and their relative strength was compared from near-complete date of Twitter. Our contribution is at providing deep insight into the cumulative spreading patterns of rumors over time as well as at tracking the precise changes in predictive powers across rumor features. Statistical analysis finds that structural and temporal features distinguish rumors from non-rumors over a long-term window, yet they are not available during the initial propagation phase. In contrast, user and linguistic features are readily available and act as a good indicator during the initial propagation phase. Based on these findings, we suggest a new rumor classification algorithm that achieves competitive accuracy over both short and long time windows. These findings provide new insights for explaining rumor mechanism theories and for identifying features of early rumor detection. PMID- 28081136 TI - Task Irrelevant External Cues Can Influence Language Selection in Voluntary Object Naming: Evidence from Hindi-English Bilinguals. AB - We examined if external cues such as other agents' actions can influence the choice of language during voluntary and cued object naming in bilinguals in three experiments. Hindi-English bilinguals first saw a cartoon waving at a color patch. They were then asked to either name a picture in the language of their choice (voluntary block) or to name in the instructed language (cued block). The colors waved at by the cartoon were also the colors used as language cues (Hindi or English). We compared the influence of the cartoon's choice of color on naming when speakers had to indicate their choice explicitly before naming (Experiment 1) as opposed to when they named directly on seeing the pictures (Experiment 2 and 3). Results showed that participants chose the language indicated by the cartoon greater number of times (Experiment 1 and 3). Speakers also switched significantly to the language primed by the cartoon greater number of times (Experiment 1 and 2). These results suggest that choices leading to voluntary action, as in the case of object naming can be influenced significantly by external non-linguistic cues. Importantly, these symbolic influences can work even when other agents are merely indicating their choices and are not interlocutors in bilingual communication. PMID- 28081137 TI - Anillin Phosphorylation Controls Timely Membrane Association and Successful Cytokinesis. AB - During cytokinesis, a contractile ring generates the constricting force to divide a cell into two daughters. This ring is composed of filamentous actin and the motor protein myosin, along with additional structural and regulatory proteins, including anillin. Anillin is a required scaffold protein that links the actomyosin ring to membrane and its organizer, RhoA. However, the molecular basis for timely action of anillin at cytokinesis remains obscure. Here, we find that phosphorylation regulates efficient recruitment of human anillin to the equatorial membrane. Anillin is highly phosphorylated in mitosis, and is a substrate for mitotic kinases. We surveyed function of 46 residues on anillin previously found to be phosphorylated in human cells to identify those required for cytokinesis. Among these sites, we identified S635 as a key site mediating cytokinesis. Preventing S635 phosphorylation adjacent to the AH domain disrupts anillin concentration at the equatorial cortex at anaphase, whereas a phosphomimetic mutant, S635D, partially restores this localization. Time-lapse videomicroscopy reveals impaired recruitment of S635A anillin to equatorial membrane and a transient unstable furrow followed by ultimate failure in cytokinesis. A phosphospecific antibody confirms phosphorylation at S635 in late cytokinesis, although it does not detect phosphorylation in early cytokinesis, possibly due to adjacent Y634 phosphorylation. Together, these findings reveal that anillin recruitment to the equatorial cortex at anaphase onset is enhanced by phosphorylation and promotes successful cytokinesis. PMID- 28081138 TI - Overexpression of Kinesin Family Member 20A Correlates with Disease Progression and Poor Prognosis in Human Nasopharyngeal Cancer: A Retrospective Analysis of 105 Patients. AB - BACKGROUND: Numerous studies have shown Kinesin family member 20A (KIF20A) may play a critical role in the development and progression of cancer. However, the clinical value of KIF20A in nasopharyngeal carcinoma (NPC) is unknown. Here, we investigated the expression pattern of KIF20A in NPC and its correlation with clinicopathological features of patients. METHODS: Real-time PCR and Western blotting were used to quantify KIF20A expression in NPC cell lines and clinical specimens compared with normal controls. KIF20A protein expression was also examined in archived paraffin embedded tumor samples from 105 patients with pathologically confirmed NPC by immunohistochemistry (IHC). Statistical analyses were applied to assess the associations between KIF20A expression and the clinicopathological features and survival outcomes. Effects on migration and invasion were assessed by wound healing and transwell invasion assays after KIF20A silencing. RESULTS: KIF20A was significantly overexpressed at both the mRNA and protein levels in NPC cell lines and human tumor tissues. 45/105 (42.9%) of NPC specimens expressed high levels of KIF20A among the KIF20A detectable cases. Statistical analysis revealed that high KIF20A expression was significantly associated with gender (P = 0.046), clinical stage (P<0.001), T category (P = 0.022), N category (P<0.001), distant metastasis (P = 0.001) and vital status (P = 0.001). Moreover, Higher KIF20A expression patients had shorter overall survival (OS) and progression-free survival (PFS) (P = 0.001 and P = 0.001; log-rank test). In multivariate analysis, KIF20A was an independent prognostic factor for OS and PFS in the entire cohort (P = 0.033, P = 0.008). Knock down of KIF20A expression significantly suppressed NPC cell's migration and invasion. CONCLUSIONS: KIF20A is overexpressed and may serve as an independent prognostic biomarker in NPC. Targeting KIF20A reduces migration and invasion of NPC cells. PMID- 28081139 TI - Long-Latency Somatosensory Evoked Potentials of the Subthalamic Nucleus in Patients with Parkinson's Disease. AB - Somatosensory evoked potentials (SSEPs) are a viable way to measure processing of somatosensory information. SSEPs have been described at the scalp and the cortical level by electroencephalographic, magnetoencephalographic and intracranial cortical recordings focusing on short-latency (SL; latency<40 ms) and long-latency (LL; latency>40 ms) SSEPs as well as by deep brain stimulation (DBS) electrode studies targeting SL-SSEPs. Unfortunately, LL-SSEPs have not been addressed at the subcortical level aside from the fact that studies targeting the characteristics and generators of SSEPs have been neglected for the last ten years. To cope with these issues, we investigated LL-SSEPs of the subthalamic nucleus (STN) in twelve patients with Parkinson's disease (PD) that underwent deep brain stimulation (DBS) treatment. In a postoperative setting, LL-SSEPs were elicited by median nerve stimulation (MNS) to the patient's wrists. Ipsilateral or contralateral MNS was applied with a 3 s inter-stimulus interval. Here, we report about four distinctive LL-SSEPs ("LL-complex" consisting of P80, N100, P140 and N200 component), which were recorded by using monopolar/bipolar reference and ipsi/contralateral MNS. Phase reversal and/or maximum amplitude provided support for the generation of such LL-SSEPs within the STN, which also underscores a role of this subcortical structure in sensory processing. PMID- 28081140 TI - BnLATE, a Cys2/His2-Type Zinc-Finger Protein, Enhances Silique Shattering Resistance by Negatively Regulating Lignin Accumulation in the Silique Walls of Brassica napus. AB - Silique shattering resistance is one of the most important agricultural traits in oil crop breeding. Seed shedding from siliques prior to and during harvest causes devastating losses in oilseed yield. Lignin biosynthesis in the silique walls is thought to affect silique-shattering resistance in oil crops. Here, we identified and characterized B. napus LATE FLOWERING (BnLATE), which encodes a Cys2/His2 type zinc-finger protein. Heterologous expression of BnLATE under the double enhanced CaMV 35S promoter (D35S) in wild-type Arabidopsis plants resulted in a marked decrease in lignification in the replum, valve layer (carpel) and dehiscence zone. pBnLATE::GUS activity was strong in the yellowing silique walls of transgenic lines. Furthermore, the expression pattern of BnLATE and the lignin content gradient in the silique walls at 48 days after pollination (DAP) of 73290, a B. napus silique shattering-resistant line, are similar to those in transgenic Arabidopsis lines expressing BnLATE. Transcriptome sequencing of the silique walls revealed that genes encoding peroxidases, which polymerize monolignols and lignin in the phenylpropanoid pathway, were down-regulated at least two-fold change in the D35S::BnLATE transgenic lines. pBnLATE::BnLATE transgenic lines were further used to identify the function of BnLATE, and the results showed that lignification in the carpel and dehiscence zone of yellowing silique also remarkably decreased compared with the wild-type control, the silique shattering-resistance and expression pattern of peroxidase genes are very similar to results with D35S::BnLATE. These results suggest that BnLATE is a negative regulator of lignin biosynthesis in the yellowing silique walls, and promotes silique-shattering resistance in B. napus through restraining the polymerization of monolignols and lignin. PMID- 28081141 TI - Could a Neuroscientist Understand a Microprocessor? AB - There is a popular belief in neuroscience that we are primarily data limited, and that producing large, multimodal, and complex datasets will, with the help of advanced data analysis algorithms, lead to fundamental insights into the way the brain processes information. These datasets do not yet exist, and if they did we would have no way of evaluating whether or not the algorithmically-generated insights were sufficient or even correct. To address this, here we take a classical microprocessor as a model organism, and use our ability to perform arbitrary experiments on it to see if popular data analysis methods from neuroscience can elucidate the way it processes information. Microprocessors are among those artificial information processing systems that are both complex and that we understand at all levels, from the overall logical flow, via logical gates, to the dynamics of transistors. We show that the approaches reveal interesting structure in the data but do not meaningfully describe the hierarchy of information processing in the microprocessor. This suggests current analytic approaches in neuroscience may fall short of producing meaningful understanding of neural systems, regardless of the amount of data. Additionally, we argue for scientists using complex non-linear dynamical systems with known ground truth, such as the microprocessor as a validation platform for time-series and structure discovery methods. PMID- 28081142 TI - The Global Distribution and Drivers of Alien Bird Species Richness. AB - Alien species are a major component of human-induced environmental change. Variation in the numbers of alien species found in different areas is likely to depend on a combination of anthropogenic and environmental factors, with anthropogenic factors affecting the number of species introduced to new locations, and when, and environmental factors influencing how many species are able to persist there. However, global spatial and temporal variation in the drivers of alien introduction and species richness remain poorly understood. Here, we analyse an extensive new database of alien birds to explore what determines the global distribution of alien species richness for an entire taxonomic class. We demonstrate that the locations of origin and introduction of alien birds, and their identities, were initially driven largely by European (mainly British) colonialism. However, recent introductions are a wider phenomenon, involving more species and countries, and driven in part by increasing economic activity. We find that, globally, alien bird species richness is currently highest at midlatitudes and is strongly determined by anthropogenic effects, most notably the number of species introduced (i.e., "colonisation pressure"). Nevertheless, environmental drivers are also important, with native and alien species richness being strongly and consistently positively associated. Our results demonstrate that colonisation pressure is key to understanding alien species richness, show that areas of high native species richness are not resistant to colonisation by alien species at the global scale, and emphasise the likely ongoing threats to global environments from introductions of species. PMID- 28081143 TI - Engineered Aedes aegypti JAK/STAT Pathway-Mediated Immunity to Dengue Virus. AB - We have developed genetically modified Ae. aegypti mosquitoes that activate the conserved antiviral JAK/STAT pathway in the fat body tissue, by overexpressing either the receptor Dome or the Janus kinase Hop by the blood feeding-induced vitellogenin (Vg) promoter. Transgene expression inhibits infection with several dengue virus (DENV) serotypes in the midgut as well as systemically and in the salivary glands. The impact of the transgenes Dome and Hop on mosquito longevity was minimal, but it resulted in a compromised fecundity when compared to wild type mosquitoes. Overexpression of Dome and Hop resulted in profound transcriptome regulation in the fat body tissue as well as the midgut tissue, pinpointing several expression signatures that reflect mechanisms of DENV restriction. Our transcriptome studies and reverse genetic analyses suggested that enrichment of DENV restriction factor and depletion of DENV host factor transcripts likely accounts for the DENV inhibition, and they allowed us to identify novel factors that modulate infection. Interestingly, the fat body specific activation of the JAK/STAT pathway did not result in any enhanced resistance to Zika virus (ZIKV) or chikungunya virus (CHIKV) infection, thereby indicating a possible specialization of the pathway's antiviral role. PMID- 28081145 TI - Probing the Association between Early Evolutionary Markers and Schizophrenia. AB - Schizophrenia is suggested to be a by-product of the evolution in humans, a compromise for our language, creative thinking and cognitive abilities, and thus, essentially, a human disorder. The time of its origin during the course of human evolution remains unclear. Here we investigate several markers of early human evolution and their relationship to the genetic risk of schizophrenia. We tested the schizophrenia evolutionary hypothesis by analyzing genome-wide association studies of schizophrenia and other human phenotypes in a statistical framework suited for polygenic architectures. We analyzed evolutionary proxy measures: human accelerated regions, segmental duplications, and ohnologs, representing various time periods of human evolution for overlap with the human genomic loci associated with schizophrenia. Polygenic enrichment plots suggest a higher prevalence of schizophrenia associations in human accelerated regions, segmental duplications and ohnologs. However, the enrichment is mostly accounted for by linkage disequilibrium, especially with functional elements like introns and untranslated regions. Our results did not provide clear evidence that markers of early human evolution are more likely associated with schizophrenia. While SNPs associated with schizophrenia are enriched in HAR, Ohno and SD regions, the enrichment seems to be mediated by affiliation to known genomic enrichment categories. Taken together with previous results, these findings suggest that schizophrenia risk may have mainly developed more recently in human evolution. PMID- 28081144 TI - Digital Health: Tracking Physiomes and Activity Using Wearable Biosensors Reveals Useful Health-Related Information. AB - A new wave of portable biosensors allows frequent measurement of health-related physiology. We investigated the use of these devices to monitor human physiological changes during various activities and their role in managing health and diagnosing and analyzing disease. By recording over 250,000 daily measurements for up to 43 individuals, we found personalized circadian differences in physiological parameters, replicating previous physiological findings. Interestingly, we found striking changes in particular environments, such as airline flights (decreased peripheral capillary oxygen saturation [SpO2] and increased radiation exposure). These events are associated with physiological macro-phenotypes such as fatigue, providing a strong association between reduced pressure/oxygen and fatigue on high-altitude flights. Importantly, we combined biosensor information with frequent medical measurements and made two important observations: First, wearable devices were useful in identification of early signs of Lyme disease and inflammatory responses; we used this information to develop a personalized, activity-based normalization framework to identify abnormal physiological signals from longitudinal data for facile disease detection. Second, wearables distinguish physiological differences between insulin-sensitive and -resistant individuals. Overall, these results indicate that portable biosensors provide useful information for monitoring personal activities and physiology and are likely to play an important role in managing health and enabling affordable health care access to groups traditionally limited by socioeconomic class or remote geography. PMID- 28081146 TI - Maternal Nutrition during Pregnancy Affects Testicular and Bone Development, Glucose Metabolism and Response to Overnutrition in Weaned Horses Up to Two Years. AB - INTRODUCTION: Pregnant mares and post-weaning foals are often fed concentrates rich in soluble carbohydrates, together with forage. Recent studies suggest that the use of concentrates is linked to alterations of metabolism and the development of osteochondrosis in foals. The aim of this study was to determine if broodmare diet during gestation affects metabolism, osteoarticular status and growth of yearlings overfed from 20 to 24 months of age and/or sexual maturity in prepubertal colts. MATERIAL AND METHODS: Twenty-four saddlebred mares were fed forage only (n = 12, group F) or cracked barley and forage (n = 12, group B) from mid-gestation until foaling. Colts were gelded at 12 months of age. Between 20 and 24 months of age, all yearlings were overfed (+140% of requirements) using an automatic concentrate feeder. Offspring were monitored for growth between 6 and 24 months of age, glucose homeostasis was evaluated via modified frequently sampled intra veinous glucose tolerance test (FSIGT) at 19 and 24 months of age and osteoarticular status was investigated using radiographic examinations at 24 months of age. The structure and function of testicles from prepubertal colts were analyzed using stereology and RT-qPCR. RESULTS: Post-weaning weight growth was not different between groups. Testicular maturation was delayed in F colts compared to B colts at 12 months of age. From 19 months of age, the cannon bone was wider in B vs F yearlings. F yearlings were more insulin resistant at 19 months compared to B yearlings but B yearlings were affected more severely by overnutrition with reduced insulin sensitivity. The osteoarticular status at 24 months of age was not different between groups. CONCLUSION: In conclusion, nutritional management of the pregnant broodmare and the growing foal may affect sexual maturity of colts and the metabolism of foals until 24 months of age. These effects may be deleterious for reproductive and sportive performances in older horses. PMID- 28081147 TI - Fine Mapping of a Degenerated Abdominal Legs Mutant (Edl) in Silkworm, Bombyx mori. AB - In insects, abdominal appendages, also called prolegs, vary due to adaptive evolution. Mutations on prolegs within species provide insights to better understand the mechanisms underlying appendage development and diversity. In silkworm Bombyx mori, extra-crescents and degenerated abdominal legs (Edl) mutant, belonging to the E pseudoallele group, is a spontaneous mutation that adds crescents and degenerates prolegs on the third abdominal segment (A3). This mutation may be a homeotic transformation of A3 to A2. In this study, the Edl locus was mapped within approximately a 211 Kb region that is 10 Kb upstream of Bmabdominal-A (Bmabd-A). RT-quantitative PCR (RT-qPCR) and Western blot analysis of Bmabd-A expression showed a slight but significant decrease, while the expression of BmUltrabithorax (BmUbx) was up-regulated in the Edl mutant compared to wildtype (Dazao). Moreover, we also found that BmDistal-less (BmDll), which regulated the development of distal proleg structures, was missing at the tips of the A3 prolegs in the Edl mutant compared to BmDll expression in normally developed prolegs in both the wildtype and mutant. Collectively, we identified approximately a 211 Kb region in the Edl locus that regulates BmUbx and Bmabd-A expression and found that changes in BmUbx and Bmabd-A expression may lead to the loss of distal proleg structures in B. mori. PMID- 28081148 TI - Characterization of Multi-Drug Resistant Enterococcus faecalis Isolated from Cephalic Recording Chambers in Research Macaques (Macaca spp.). AB - Nonhuman primates are commonly used for cognitive neuroscience research and often surgically implanted with cephalic recording chambers for electrophysiological recording. Aerobic bacterial cultures from 25 macaques identified 72 bacterial isolates, including 15 Enterococcus faecalis isolates. The E. faecalis isolates displayed multi-drug resistant phenotypes, with resistance to ciprofloxacin, enrofloxacin, trimethoprim-sulfamethoxazole, tetracycline, chloramphenicol, bacitracin, and erythromycin, as well as high-level aminoglycoside resistance. Multi-locus sequence typing showed that most belonged to two E. faecalis sequence types (ST): ST 4 and ST 55. The genomes of three representative isolates were sequenced to identify genes encoding antimicrobial resistances and other traits. Antimicrobial resistance genes identified included aac(6')-aph(2"), aph(3')-III, str, ant(6)-Ia, tetM, tetS, tetL, ermB, bcrABR, cat, and dfrG, and polymorphisms in parC (S80I) and gyrA (S83I) were observed. These isolates also harbored virulence factors including the cytolysin toxin genes in ST 4 isolates, as well as multiple biofilm-associated genes (esp, agg, ace, SrtA, gelE, ebpABC), hyaluronidases (hylA, hylB), and other survival genes (ElrA, tpx). Crystal violet biofilm assays confirmed that ST 4 isolates produced more biofilm than ST 55 isolates. The abundance of antimicrobial resistance and virulence factor genes in the ST 4 isolates likely relates to the loss of CRISPR-cas. This macaque colony represents a unique model for studying E. faecalis infection associated with indwelling devices, and provides an opportunity to understand the basis of persistence of this pathogen in a healthcare setting. PMID- 28081149 TI - Rationale for Further Development of a Vaccine Based on the Circumsporozoite Protein of Plasmodium vivax. PMID- 28081150 TI - The Association of Birth Weight and Infant Growth with Energy Balance-Related Behavior - A Systematic Review and Best-Evidence Synthesis of Human Studies. AB - BACKGROUND: Suboptimal prenatal and early postnatal growths are associated with obesity in later life, but the underlying mechanisms are unknown. The aim of this study was to systematically review the literature that reports on the longitudinal association of (i) birth size or (ii) infant growth with later (i) energy intake, (ii) eating behaviors, (iii) physical activity or (iv) sedentary behavior in humans. METHODS: A comprehensive search of MEDLINE, EMBASE, PsycINFO and The Cochrane Library was conducted to identify relevant publications. We appraised the methodological quality of the studies and synthesized the extracted data through a best-evidence synthesis. RESULTS: Data from 41 publications were included. The quality of the studies was high in three papers, moderate in 11 and low in the large majority (n = 27) of papers appraised. Our best-evidence synthesis indicates that there is no evidence for an association of birth weight with later energy intake, eating behavior, physical activity or sedentary behavior. We found moderate evidence for an association of extreme birth weights (at both ends of the spectrum) with lower physical activity levels at a later age. Evidence for the association of infant growth with energy balance-related behavior was generally insufficient. CONCLUSIONS: We conclude that current evidence does not support an association of early-life growth with energy balance related behaviors in later life, except for an association of extreme birth weights with later physical activity. PMID- 28081151 TI - Human Lacrimal Gland Gene Expression. AB - BACKGROUND: The study of human lacrimal gland biology and development is limited. Lacrimal gland tissue is damaged or poorly functional in a number of disease states including dry eye disease. Development of cell based therapies for lacrimal gland diseases requires a better understanding of the gene expression and signaling pathways in lacrimal gland. Differential gene expression analysis between lacrimal gland and other embryologically similar tissues may be helpful in furthering our understanding of lacrimal gland development. METHODS: We performed global gene expression analysis of human lacrimal gland tissue using Affymetrix (r) gene expression arrays. Primary data from our laboratory was compared with datasets available in the NLM GEO database for other surface ectodermal tissues including salivary gland, skin, conjunctiva and corneal epithelium. RESULTS: The analysis revealed statistically significant difference in the gene expression of lacrimal gland tissue compared to other ectodermal tissues. The lacrimal gland specific, cell surface secretory protein encoding genes and critical signaling pathways which distinguish lacrimal gland from other ectodermal tissues are described. CONCLUSIONS: Differential gene expression in human lacrimal gland compared with other ectodermal tissue types revealed interesting patterns which may serve as the basis for future studies in directed differentiation among other areas. PMID- 28081153 TI - Dermal gammadelta T Cells Do Not Freely Re-Circulate Out of Skin and Produce IL 17 to Promote Neutrophil Infiltration during Primary Contact Hypersensitivity. AB - The role of mouse dermal gammadelta T cells in inflammatory skin disorders and host defense has been studied extensively. It is known that dendritic epidermal T cells (DETC) have a monomorphic gammadelta T cell receptor (TCR) and reside in murine epidermis from birth. We asked if dermal gammadelta cells freely re circulated out of skin, or behaved more like dermal resident memory T cells (TRM) in mice. We found that, unlike epidermal gammadelta T cells (DETC), dermal gammadelta cells are not homogeneous with regard to TCR, express the tissue resident T cell markers CD69 and CD103, bear skin homing receptors, and produce IL-17 and IL-22. We created GFP+: GFP- parabiotic mice and found that dermal gammadelta T cells re-circulate very slowly-more rapidly than authentic alphabeta TCR TRM, but more slowly than the recently described dermal alphabeta TCR T migratory memory cells (TMM). Mice lacking the TCR delta gene (delta-/-) had a significant reduction of 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity (CHS). We created mice deficient in dermal gammadelta T cells but not DETC, and these mice also showed a markedly reduced CHS response after DNFB challenge. The infiltration of effector T cells during CHS was not reduced in dermal gammadelta T cell-deficient mice; however, infiltration of Gr-1+CD11b+ neutrophils, as well as ear swelling, was reduced significantly. We next depleted Gr-1+ neutrophils in vivo, and demonstrated that neutrophils are required for ear swelling, the accepted metric for a CHS response. Depletion of IL-17-producing dermal Vgamma4+ cells and neutralization of IL-17 in vivo, respectively, also led to a significantly reduced CHS response and diminished neutrophil infiltration. Our findings here suggest that dermal gammadelta T cells have an intermediate phenotype of T cell residence, and play an important role in primary CHS through producing IL-17 to promote neutrophil infiltration. PMID- 28081152 TI - Increased Serum Sodium and Serum Osmolarity Are Independent Risk Factors for Developing Chronic Kidney Disease; 5 Year Cohort Study. AB - BACKGROUND: Epidemics of chronic kidney disease (CKD) not due to diabetes mellitus (DM) or hypertension have been observed among individuals working in hot environments in several areas of the world. Experimental models have documented that recurrent heat stress and water restriction can lead to CKD, and the mechanism may be mediated by hyperosmolarity that activates pathways (vasopressin, aldose reductase-fructokinase) that induce renal injury. Here we tested the hypothesis that elevated serum sodium, which reflects serum osmolality, may be an independent risk factor for the development of CKD. METHODS: This study was a large-scale, single-center, retrospective 5-year cohort study at Center for Preventive Medicine, St. Luke's International Hospital, Tokyo, Japan, between 2004 and 2009. We analyzed 13,201 subjects who underwent annual medical examination of which 12,041 subjects (age 35 to 85) without DM and/or CKD were enrolled. This analysis evaluated age, sex, body mass index, abdominal circumference, hypertension, dyslipidemia, hyperuricemia, fasting glucose, BUN, serum sodium, potassium, chloride and calculated serum osmolarity. RESULTS: Elevated serum sodium was an independent risk factor for development of CKD (OR: 1.03, 95% CI, 1.00-1.07) after adjusted regression analysis with an 18 percent increased risk for every 5 mmol/L change in serum sodium. Calculated serum osmolarity was also an independent risk factor for CKD (OR: 1.04; 95% CI, 1.03-1.05) as was BUN (OR: 1.08; 95% CI, 1.06-1.10) (independent of serum creatinine). CONCLUSIONS: Elevated serum sodium and calculated serum osmolarity are independent risk factors for developing CKD. This finding supports the role of limiting salt intake and preventing dehydration to reduce risk of CKD. PMID- 28081154 TI - Sensitization of Radioresistant Prostate Cancer Cells by Resveratrol Isolated from Arachis hypogaea Stems. AB - Resveratrol (RV, 3,4',5-trihydroxystilbene) is naturally produced by a wide variety of plants including grapes and peanuts (Arachis hypogaea). However, the yield of RV from peanut stem and its potential radiosensitizing effects in prostate cancer (PCa) have not been well investigated. In this study, we characterized RV in peanut stem extract (PSE) for the first time and showed that both RV and PSE dose-dependently induced cell death in DOC-2/DAB2 interactive protein (DAB2IP)-deficient PCa cells with the radioresistant phenotype. Furthermore, the combination of radiation with either RV or PSE induced the death of radioresistant PCa cells through delayed repair of radiation-induced DNA double-strand break (DSB) and prolonged G2/M arrest, which induced apoptosis. The administration of RV and PSE effectively enhanced radiation therapy in the shDAB2IP PCa xenograft mouse model. These results demonstrate the promising synergistic effect of RV and PSE combined with radiation in the treatment of radioresistant PCa. PMID- 28081155 TI - Evaluation of Bufadienolides as the Main Antitumor Components in Cinobufacin Injection for Liver and Gastric Cancer Therapy. AB - BACKGROUND: Cinobufacin injection, also known as huachansu, is a preparation form of Cinobufacini made from Cinobufacin extract liquid. Despite that Cinobufacin injection is shown to shrink liver and gastric tumors, improving patient survival and life quality, the effective components in Cinobufacin remain elusive. In this study, we aim to screen antitumor components from Cinobufacin injection to elucidate the most effective antitumor components for treatment of liver and gastric cancers. MATERIALS AND METHODS: High performance liquid chromatography (HPLC) and LC-MS/MS analysis were used to separate and determine the components in Cinobufacin injection. Inhibition rates of various components in Cinobufacin injection on liver and gastric cancer cells were determined with MTT assay; Hepatocellular carcinoma and gastric cancer models were used to assess the antitumor effect of the compounds in vivo. RESULTS: The major constituents in Cinobufacin injection include peptides, nucleic acids, tryptamines and bufotalins. MTT assay revealed that bufadienolides had the best antitumor activity, with peptides being the second most effective components. Bufadienolides showed significant inhibition rates on gastric and hepatocellular tumour growth in vivo. CONCLUSION: Bufadienolides are the most effective components in Cinobufacini injection for the treatment of liver and gastric cancers. This discovery can greatly facilitate further research in improving the therapeutic effects of Cinobufacin injection, meanwhile reducing its adverse reaction. PMID- 28081156 TI - Generation of a Stable Transgenic Swine Model Expressing a Porcine Histone 2B eGFP Fusion Protein for Cell Tracking and Chromosome Dynamics Studies. AB - Transgenic pigs have become an attractive research model in the field of translational research, regenerative medicine, and stem cell therapy due to their anatomic, genetic and physiological similarities with humans. The development of fluorescent proteins as molecular tags has allowed investigators to track cell migration and engraftment levels after transplantation. Here we describe the development of two transgenic pig models via SCNT expressing a fusion protein composed of eGFP and porcine Histone 2B (pH2B). This fusion protein is targeted to the nucleosomes resulting a nuclear/chromatin eGFP signal. The first model (I) was generated via random insertion of pH2B-eGFP driven by the CAG promoter (chicken beta actin promoter and rabbit Globin poly A; pCAG-pH2B-eGFP) and protected by human interferon-beta matrix attachment regions (MARs). Despite the consistent, high, and ubiquitous expression of the fusion protein pH2B-eGFP in all tissues analyzed, two independently generated Model I transgenic lines developed neurodegenerative symptoms including Wallerian degeneration between 3-5 months of age, requiring euthanasia. A second transgenic model (II) was developed via CRISPR-Cas9 mediated homology-directed repair (HDR) of IRES-pH2B-eGFP into the endogenous beta-actin (ACTB) locus. Model II transgenic animals showed ubiquitous expression of pH2B-eGFP on all tissues analyzed. Unlike the pCAG-pH2B eGFP/MAR line, all Model II animals were healthy and multiple pregnancies have been established with progeny showing the expected Mendelian ratio for the transmission of the pH2B-eGFP. Expression of pH2B-eGFP was used to examine the timing of the maternal to zygotic transition after IVF, and to examine chromosome segregation of SCNT embryos. To our knowledge this is the first viable transgenic pig model with chromatin-associated eGFP allowing both cell tracking and the study of chromatin dynamics in a large animal model. PMID- 28081157 TI - Simultaneous Quantitative MRI Mapping of T1, T2* and Magnetic Susceptibility with Multi-Echo MP2RAGE. AB - The knowledge of relaxation times is essential for understanding the biophysical mechanisms underlying contrast in magnetic resonance imaging. Quantitative experiments, while offering major advantages in terms of reproducibility, may benefit from simultaneous acquisitions. In this work, we demonstrate the possibility of simultaneously recording relaxation-time and susceptibility maps with a prototype Multi-Echo (ME) Magnetization-Prepared 2 RApid Gradient Echoes (MP2RAGE) sequence. T1 maps can be obtained using the MP2RAGE sequence, which is relatively insensitive to inhomogeneities of the radio-frequency transmit field, [Formula: see text]. As an extension, multiple gradient echoes can be acquired in each of the MP2RAGE readout blocks, which permits the calculation of [Formula: see text] and susceptibility maps. We used computer simulations to explore the effects of the parameters on the precision and accuracy of the mapping. In vivo parameter maps up to 0.6 mm nominal resolution were acquired at 7 T in 19 healthy volunteers. Voxel-by-voxel correlations and the test-retest reproducibility were used to assess the reliability of the results. When using optimized paramenters, T1 maps obtained with ME-MP2RAGE and standard MP2RAGE showed excellent agreement for the whole range of values found in brain tissues. Simultaneously obtained [Formula: see text] and susceptibility maps were of comparable quality as Fast Low-Angle SHot (FLASH) results. The acquisition times were more favorable for the ME-MP2RAGE (~ 19 min) sequence as opposed to the sum of MP2RAGE (~ 12 min) and FLASH (~ 10 min) acquisitions. Without relevant sacrifice in accuracy, precision or flexibility, the multi-echo version may yield advantages in terms of reduced acquisition time and intrinsic co-registration, provided that an appropriate optimization of the acquisition parameters is performed. PMID- 28081158 TI - "I Do Not Take My Medicine while Hiding" - A Longitudinal Qualitative Assessment of HIV Discordant Couples' Beliefs in Discordance and ART as Prevention in Uganda. AB - BACKGROUND: HIV negative members of serostatus discordant couples are at high risk for HIV acquisition, but few interventions are in place to target them in sub-Saharan Africa. METHODS: In this study, we interviewed 28 couples, 3 times over a period of one year to understand their perceptions and attitudes around discordance, their relationship dynamics, their HIV risk behaviour, their beliefs and attitudes about antiretroviral therapy (ART) and their views of the community perceptions of discordance and treatment for HIV. RESULTS: Findings revealed that at baseline there were multiple complex explanations and interpretations about discordance among discordant couples and their surrounding community. Shifts in beliefs and attitudes about discordance, HIV risk reduction and ART over time were enabled through re-testing negative members of discordant couples and repeat counselling but some beliefs remain solidly embedded in cultural imperatives of the importance of childbearing as well as culturally determined and enforced gender roles. CONCLUSIONS: Interventions that aim to target discordant couples must embrace the complex and dynamic understandings of HIV diagnosis and treatment in context of fluid relationships, and changing beliefs about HIV risk and treatment. PMID- 28081160 TI - Estimates of Abundance and Trend of Chilean Blue Whales off Isla de Chiloe, Chile. AB - Since 1970, blue whales (Balaenoptera musculus) have been seen feeding in the waters off southern Chile during the summer and autumn (December to May). Investigation of the genetic, acoustic and morphological characteristics of these blue whales shows that they are a distinct but unnamed subspecies, called the Chilean blue whales. Photo-identification surveys have been conducted in the waters off northwestern Isla Grande de Chiloe, southern Chile from 2004-2012 and Isla Chanaral, central Chile in 2012. Over this time, 1,070 blue whales were encountered yielding, after photo-quality control, 318 and 267 unique photographs of the left and right side of the flank respectively. Using mark-recapture analysis of left and right side photographs collected from Isla Grande de Chiloe (2004-2012), open population models estimate that ~570-760 whales are feeding seasonally in this region. POPAN superpopulation abundance estimates for the same feeding ground in 2012 are 762 (95% confidence intervals, CI = 638-933) and 570 (95% CI 475-705) for left and right side datasets respectively, very similar to results from closed population models. Estimates of trend revealed strong variation in abundance, peaking in 2009 and [suggesting] fluctuating use in the survey area over time, likely related to the density of their prey. High inter annual return rates suggest a degree of site-fidelity of individuals to Isla Grande de Chiloe and that the number of whales using this feeding ground is relatively small. PMID- 28081159 TI - Osmoregulation in the Halophilic Bacterium Halomonas elongata: A Case Study for Integrative Systems Biology. AB - Halophilic bacteria use a variety of osmoregulatory methods, such as the accumulation of one or more compatible solutes. The wide diversity of compounds that can act as compatible solute complicates the task of understanding the different strategies that halophilic bacteria use to cope with salt. This is specially challenging when attempting to go beyond the pathway that produces a certain compatible solute towards an understanding of how the metabolic network as a whole addresses the problem. Metabolic reconstruction based on genomic data together with Flux Balance Analysis (FBA) is a promising tool to gain insight into this problem. However, as more of these reconstructions become available, it becomes clear that processes predicted by genome annotation may not reflect the processes that are active in vivo. As a case in point, E. coli is unable to grow aerobically on citrate in spite of having all the necessary genes to do it. It has also been shown that the realization of this genetic potential into an actual capability to metabolize citrate is an extremely unlikely event under normal evolutionary conditions. Moreover, many marine bacteria seem to have the same pathways to metabolize glucose but each species uses a different one. In this work, a metabolic network inferred from genomic annotation of the halophilic bacterium Halomonas elongata and proteomic profiling experiments are used as a starting point to motivate targeted experiments in order to find out some of the defining features of the osmoregulatory strategies of this bacterium. This new information is then used to refine the network in order to describe the actual capabilities of H. elongata, rather than its genetic potential. PMID- 28081161 TI - Factors Related with CH4 and N2O Emissions from a Paddy Field: Clues for Management implications. AB - Paddy fields are major sources of global atmospheric greenhouse gases, including methane (CH4) and nitrous oxide (N2O). The different phases previous to emission (production, transport, diffusion, dissolution in pore water and ebullition) despite well-established have rarely been measured in field conditions. We examined them and their relationships with temperature, soil traits and plant biomass in a paddy field in Fujian, southeastern China. CH4 emission was positively correlated with CH4 production, plant-mediated transport, ebullition, diffusion, and concentration of dissolved CH4 in porewater and negatively correlated with sulfate concentration, suggesting the potential use of sulfate fertilizers to mitigate CH4 release. Air temperature and humidity, plant stem biomass, and concentrations of soil sulfate, available N, and DOC together accounted for 92% of the variance in CH4 emission, and Eh, pH, and the concentrations of available N and Fe3+, leaf biomass, and air temperature 95% of the N2O emission. Given the positive correlations between CH4 emission and DOC content and plant biomass, reduce the addition of a carbon substrate such as straw and the development of smaller but higher yielding rice genotypes could be viable options for reducing the release of greenhouse gases from paddy fields to the atmosphere. PMID- 28081162 TI - Beyond Pressure Gradients: The Effects of Intervention on Heart Power in Aortic Coarctation. AB - BACKGROUND: In aortic coarctation, current guidelines recommend reducing pressure gradients that exceed given thresholds. From a physiological standpoint this should ideally improve the energy expenditure of the heart and thus prevent long term organ damage. OBJECTIVES: The aim was to assess the effects of interventional treatment on external and internal heart power (EHP, IHP) in patients with aortic coarctation and to explore the correlation of these parameters to pressure gradients obtained from heart catheterization. METHODS: In a collective of 52 patients with aortic coarctation 25 patients received stenting and/or balloon angioplasty, and 20 patients underwent MRI before and after an interventional treatment procedure. EHP and IHP were computed based on catheterization and MRI measurements. Along with the power efficiency these were combined in a cardiac energy profile. RESULTS: By intervention, the catheter gradient was significantly reduced from 21.8+/-9.4 to 6.2+/-6.1mmHg (p<0.001). IHP was significantly reduced after intervention, from 8.03+/-5.2 to 4.37+/-2.13W (p < 0.001). EHP was 1.1+/-0.3 W before and 1.0+/-0.3W after intervention, p = 0.044. In patients initially presenting with IHP above 5W intervention resulted in a significant reduction in IHP from 10.99+/-4.74 W to 4.94+/-2.45W (p<0.001), and a subsequent increase in power efficiency from 14 to 26% (p = 0.005). No significant changes in IHP, EHP or power efficiency were observed in patients initially presenting with IHP < 5W. CONCLUSION: It was demonstrated that interventional treatment of coarctation resulted in a decrease in IHP. Pressure gradients, as the most widespread clinical parameters in coarctation, did not show any correlation to changes in EHP or IHP. This raises the question of whether they should be the main focus in coarctation interventions. Only patients with high IHP of above 5W showed improvement in IHP and power efficiency after the treatment procedure. TRIAL REGISTRATION: clinicaltrials.gov NCT02591940. PMID- 28081163 TI - Income in Multiple Sclerosis Patients with Different Disease Phenotypes. AB - BACKGROUND: Multiple sclerosis (MS) is a disease with profound heterogeneity in clinical course. OBJECTIVE: To analyze sources and levels of income among MS patients in relation to disease phenotype with a special focus on identifying differences/similarities between primary progressive MS (PPMS) and secondary progressive MS (SPMS). METHODS: A total of 6890 MS patients aged 21-64 years and living in Sweden in 2010 were identified for this cross-sectional study. Descriptive statistics, logistic, truncated linear, and zero-inflated negative binomial regression models were used to estimate differences in income between SPMS, PPMS and relapsing-remitting MS (RRMS) patients. RESULTS: RRMS patients earned almost twice as much as PPMS and SPMS patients (on average SEK 204,500, SEK 114,500, and SEK 79,800 in 2010, respectively). The difference in earnings between PPMS and SPMS was not statistically significant when analyzed with multivariable regression. The estimated odds ratio for PPMS patients to have income from earnings was not significantly different from SPMS patients (95% CI 0.98 to 1.59). PPMS and RRMS patients were less likely to receive benefits when compared to SPMS patients (by 6% and 27% lower, respectively). CONCLUSION: Our findings argue for similarities between PPMS and SPMS and highlight the socioeconomic importance of preventing RRMS patients convert to SPMS. PMID- 28081164 TI - Economic Evaluation of PCSK9 Inhibitors in Reducing Cardiovascular Risk from Health System and Private Payer Perspectives. AB - The introduction of Proprotein covertase subtilisin/kexin type 9 (PCSK9) inhibitors has been heralded as a major advancement in reducing low-density lipoprotein cholesterol levels by nearly 50%. However, concerns have been raised on the added value to the health care system in terms of their costs and benefits. We assess the cost-effectiveness of PCSK9 inhibitors based on a decision-analytic model with existing clinical evidence. The model compares a lipid-lowering therapy based on statin plus PCSK9 inhibitor treatment with statin treatment only (standard therapy). From health system perspective, incremental cost per quality adjusted life years (QALYs) gained are presented. From a private payer perspective, return-on-investment and net present values over patient lifespan are presented. At the current annual cost of $14,000 to $15,000, PCSK9 inhibitors are not cost-effective at an incremental cost of about $350,000 per QALY. Moreover, for every dollar invested in PCSK9 inhibitors, the private payer loses $1.98. Our study suggests that the annual treatment price should be set at $4,250 at a societal willingness-to-pay of $100,000 per QALY. However, we estimate the breakeven price for private payer is only $600 per annual treatment. At current prices, our study suggests that PCSK9 inhibitors do not add value to the U.S. health system and their provision is not profitable for private payers. To be the breakthrough drug in the fight against cardiovascular disease, the current price of PCSK9 inhibitors must be reduced by more than 70%. PMID- 28081165 TI - Urine Concentrating Capacity, Vasopressin and Copeptin in ADPKD and IgA Nephropathy Patients with Renal Impairment. AB - BACKGROUND: Autosomal Dominant Polycystic Kidney Disease (ADPKD) patients have an impaired urine concentrating capacity. Increased circulating vasopressin (AVP) concentrations are supposed to play a role in the progression of ADPKD. We hypothesized that ADPKD patients have a more severely impaired urine concentrating capacity in comparison to other patients with chronic kidney disease at a similar level of kidney function, with consequently an enhanced AVP response to water deprivation with higher circulating AVP concentrations. METHODS: 15 ADPKD (eGFR<60) patients and 15 age-, sex- and eGFR-matched controls with IgA nephropathy (IgAN), underwent a water deprivation test to determine maximal urine concentrating capacity. Plasma and urine osmolality, urine aquaporin-2 (AQP2) and plasma AVP and copeptin (a surrogate marker for AVP) were measured at baseline and after water deprivation (average 16 hours). In ADPKD patients, height adjusted total kidney volume (hTKV) was measured by MRI. RESULTS: Maximal achieved urine concentration was lower in ADPKD compared to IgAN controls (533+/-138 vs. 642+/-148 mOsm/kg, p = 0.046), with particularly a lower maximal achieved urine urea concentration (223+/-74 vs. 299+/-72 mmol/L, p = 0.008). After water deprivation, plasma osmolality was similar in both groups although change in plasma osmolality was more profound in ADPKD due to a lower baseline plasma osmolality in comparison to IgAN controls. Copeptin and AVP increased significantly in a similar way in both groups. AVP, copeptin and urine AQP2 were inversely associated with maximal urine concentrating in both groups. CONCLUSIONS: ADPKD patients have a more severely impaired maximal urine concentrating capacity with a lower maximal achieved urine urea concentration in comparison to IgAN controls with similar endogenous copeptin and AVP responses. PMID- 28081166 TI - Comparison of Criteria for Choosing the Number of Classes in Bayesian Finite Mixture Models. AB - Identifying the number of classes in Bayesian finite mixture models is a challenging problem. Several criteria have been proposed, such as adaptations of the deviance information criterion, marginal likelihoods, Bayes factors, and reversible jump MCMC techniques. It was recently shown that in overfitted mixture models, the overfitted latent classes will asymptotically become empty under specific conditions for the prior of the class proportions. This result may be used to construct a criterion for finding the true number of latent classes, based on the removal of latent classes that have negligible proportions. Unlike some alternative criteria, this criterion can easily be implemented in complex statistical models such as latent class mixed-effects models and multivariate mixture models using standard Bayesian software. We performed an extensive simulation study to develop practical guidelines to determine the appropriate number of latent classes based on the posterior distribution of the class proportions, and to compare this criterion with alternative criteria. The performance of the proposed criterion is illustrated using a data set of repeatedly measured hemoglobin values of blood donors. PMID- 28081167 TI - Bacterial Communities Associated with Houseflies (Musca domestica L.) Sampled within and between Farms. AB - The housefly feeds and reproduces in animal manure and decaying organic substances and thus lives in intimate association with various microorganisms including human pathogens. In order to understand the variation and association between bacteria and the housefly, we used 16S rRNA gene amplicon sequencing to describe bacterial communities of 90 individual houseflies collected within and between ten dairy farms in Denmark. Analysis of gene sequences showed that the most abundant classes of bacteria found across all sites included Bacilli, Clostridia, Actinobacteria, Flavobacteria, and all classes of Proteobacteria and at the genus level the most abundant genera included Corynebacterium, Lactobacillus, Staphylococcus, Vagococcus, Weissella, Lactococcus, and Aerococcus. Comparison of the microbiota of houseflies revealed a highly diverse microbiota compared to other insect species and with most variation in species richness and diversity found between individuals, but not locations. Our study is the first in-depth amplicon sequencing study of the housefly microbiota, and collectively shows that the microbiota of single houseflies is highly diverse and differs between individuals likely to reflect the lifestyle of the housefly. We suggest that these results should be taken into account when addressing the transmission of pathogens by the housefly and assessing the vector competence variation under natural conditions. PMID- 28081168 TI - A Mobile Platform Enables Unprecedented Sanitation Uptake in Zambia. PMID- 28081169 TI - Assessment of a 96-Well Plate Assay of Quantitative Drug Susceptibility Testing for Mycobacterium Tuberculosis Complex in China. AB - OBJECTIVE: To evaluate the performance of the Sensitire MYCOTB MIC Plate (MYCOTB) which could measure the twelve anti-tuberculosis drugs susceptibility on one 96 wells plate. METHODS: A total of 140 MDR-TB strains and 60 non-MDR strains were sub-cultured and 193 strains were finally tested for drug resistance using MYCOTB and agar proportion method (APM) and another 7 strains failed of subculture. The drugs included ofloxacin (Ofx), moxifloxacin (Mfx), rifampin (RFP), amikacin (Am), rifabutin (Rfb), para-aminosalicylic acid (PAS), ethionamide (Eth), isoniazid (INH), kanamycin (Km), ethambutol (EMB), streptomycin (Sm), and cycloserine(Cs). The categorical agreement, conditional agreement, sensitivity and specificity of MYCOTB were assessed in comparison with APM. For strains with inconsistent results between MYCOTB and APM, the drug resistance related gene fragments were amplified and sequenced: gyrA for Ofx and Mfx; rpoB for RFP and Rfb; embB for EMB; rpsl for Sm; katG and the promoter region of inhA for INH, ethA and the promoter region of inhA for Eth. The sequence results were compared with results of MYCOTB and APM to analyze the consistency between sequence results and MYCOTB or APM. RESULTS: The categorical agreement between two methods for each drug ranged from 88.6% to 100%. It was the lowest for INH (88.6%). The sensitivity and specificity of MYCOTB ranged from 71.4% to 100% and 84.3% to 100%, respectively. The sensitivity was lowest for Cs(71.4%), EMB at 10MUg/ml (80.0%) and INH at 10.0MUg/ml (84.6%). The specificity was lowest for Rfb (84.3%). Overall discordance between the two phenotypic methods was observed for 96 strains, of which 63 (65.6%) were found susceptible with APM and resistant with MYCOTB and the remaining 33(34.4%) strains were resistant by APM and susceptible with MYCOTB. 34/52 (65.4%) sequenced APM susceptible and MYCOTB resistant(APM-S/MYCOTB-R) strains had mutations or insertions in the amplified regions. 20/30 (66.7%) sequenced APM resistant and MYCOTB susceptible strains had mutations in the sequenced genes. MICs of twenty-nine of these thirty isolates were equal to or within 1 doubling dilution of the critical concentration. CONCLUSION: MYCOTB had good performance for most of tested drugs and could be used as an alternative to the more labor demanding and longer turnaround time solid culture based DST method for detection of drug susceptibility in China. PMID- 28081170 TI - An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice. AB - Alpha-1 adrenergic receptors mediate adaptive effects in the heart and cardiac myocytes, and a myocyte survival pathway involving the alpha-1A receptor subtype and ERK activation exists in vitro. However, data in vivo are limited. Here we tested A61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8 tetrahydronaphthalen-1-yl]methanesulfonamide), a selective imidazoline agonist for the alpha-1A. A61603 was the most potent alpha-1-agonist in activating ERK in neonatal rat ventricular myocytes. A61603 activated ERK in adult mouse ventricular myocytes and protected the cells from death caused by the anthracycline doxorubicin. A low dose of A61603 (10 ng/kg/d) activated ERK in the mouse heart in vivo, but did not change blood pressure. In male mice, concurrent subcutaneous A61603 infusion at 10 ng/kg/d for 7 days after a single intraperitoneal dose of doxorubicin (25 mg/kg) increased survival, improved cardiac function, heart rate, and cardiac output by echocardiography, and reduced cardiac cell necrosis and apoptosis and myocardial fibrosis. All protective effects were lost in alpha-1A-knockout mice. In female mice, doxorubicin at doses higher than in males (35-40 mg/kg) caused less cardiac toxicity than in males. We conclude that the alpha-1A-selective agonist A61603, via the alpha-1A adrenergic receptor, prevents doxorubicin cardiomyopathy in male mice, supporting the theory that alpha-1A adrenergic receptor agonists have potential as novel heart failure therapies. PMID- 28081171 TI - A Higher Proportion of Metabolic Syndrome in Chinese Subjects with Sleep Disordered Breathing: A Case-Control Study Based on Electrocardiogram-Derived Sleep Analysis. AB - OBJECTIVE: The prevalence of metabolic syndrome (MS) has increased rapidly in Taiwan and worldwide. We aim to determine the association between sleep disordered breathing (SDB) and MS in a Chinese general population. METHODS: This case-control study recruited subjects who have undergone a prospective electrocardiogram-based cardiopulmonary coupling (CPC) sleep spectrogram as part of the periodic health check-ups at the National Taiwan University Hospital. Comprehensive anthropometrics, blood biochemistry, prevalence of MS and its individual components were compared with Bonferroni correction between 40 subjects with SDB, defined as the CPC-derived apnea-hypopnea index (CPC-AHI) >5 event/hour and 80 age- and sex-matched controls, defined as CPC-AHI <1 event/hour. MS was diagnosed based on the Adult Treatment Panel III, with a modification of waist circumference for Asians. RESULTS: Subjects with SDB were more obese with larger waist circumferences (95.1+/-12.9 vs. 87.3+/-6.9, P < .001) and borderline higher BMI (27.0+/-4.9 vs. 24.3+/-2.5, P = .002). Waist circumference was independently associated with the presence of SDB after adjustment for BMI, systolic blood pressure and fasting blood glucose in multiple regression analyses. Subjects with SDB had a higher prevalence of central obesity (72.5% vs. 42.5%, P = .002), hyperglycemia (45.0% vs. 26.3%, P = .04), MS (45.0% vs. 22.5%, P = .01) and number of MS components (2.4 +/- 1.6 vs. 1.7 +/- 1.4, P = .01) than the control group. Waist circumference was significantly correlated with both CPC-AHI (r = .492, P = .0013) and PSG-AHI (r = .699, P < .0001) in the SDB group. CONCLUSIONS: SDB was associated with a higher prevalence of MS and its individual components, notably central obesity, in a Chinese general population. Large-scale screening of high risk population with MS to identify subjects with SDB for appropriate management is warranted. PMID- 28081172 TI - Influence of Corneal Opacity on Intraocular Pressure Assessment in Patients with Lysosomal Storage Diseases. AB - AIMS: To investigate an influence of mucopolysaccharidosis (MPS)- and Morbus Fabry-associated corneal opacities on intraocular pressure (IOP) measurements and to evaluate the concordance of the different tonometry methods. METHODS: 25 MPS patients with or without corneal clouding, 25 Fabry patients with cornea verticillata >= grade 2 and 25 healthy age matched controls were prospectively included into this study. Outcome measures: Goldmann applanation tonometry (GAT); palpatory assessment of IOP; Goldmann-correlated intraocular pressure (IOPg), corneal-compensated intraocular pressure (IOPcc), corneal resistance factor (CRF) and corneal hysteresis (CH) assessed by Ocular Response Analyzer (ORA); central corneal thickness (CCT) and density assessed with Pentacam. Statistical analysis was performed using linear mixed effect models and Spearman correlation coefficients. The concordance between tonometry methods was assessed using Bland Altman analysis. RESULTS: There was no relevant difference between study groups regarding median GAT, IOPg, IOPcc and CCT measurements. The limits of agreement between GAT and IOPcc/IOPg/palpatory IOP in MPS were: [-11.7 to 12.1mmHg], [-8.6 to 15.5 mmHg] and [- 5.4 to 10.1 mmHg] respectively. Limits of agreement were less wide in healthy subjects and Fabry patients. Palpatory IOP was higher in MPS than in healthy controls and Fabry patients. Corneal opacity correlated more strongly with GAT, IOPg, CH, CRF, CCT and corneal density in MPS (r = 0.4, 0.5, 0.5, 0.7, 0.6, 0.6 respectively) than in Fabry patients (r = 0.3, 0.2, -0.03, 0.1, 0.3, -0.2 respectively). In contrast, IOPcc revealed less correlation with corneal opacity than GAT in MPS (r = 0.2 vs. 0.4). CONCLUSIONS: ORA and GAT render less comparable IOP-values in patients suffering from MPS-associated corneal opacity in comparison to Fabry and healthy controls. The IOP seems to be overestimated in opaque MPS-affected corneas. GAT, IOPg and biomechanical parameters of the cornea correlate more strongly with the corneal clouding than IOPcc in MPS patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01695161. PMID- 28081173 TI - Effect of Rifampin on Thyroid Function Test in Patients on Levothyroxine Medication. AB - BACKGROUND: Levothyroxine (LT4) and rifampin (RIF) are sometimes used together; however, no clinical studies have assessed the effects of these drugs on thyroid function or the need to adjust LT4 dose. METHODS: We retrospectively reviewed the records of 71 Korean patients who started RIF during LT4 treatment. Clinically relevant cases that required dose adjustment according to the American Thyroid Association (ATA)/American Association of Clinical Endocrinologists (AACE) guidelines were identified, and risk factors of increased LT4 dose were analyzed. RESULTS: After administering RIF, median serum thyroid-stimulating hormone (TSH) level (2.58 mIU/L, interquartile range [IQR] 0.21-7.44) was significantly higher than that before RIF (0.25 mIU/L, IQR, 0.03-2.62; P < 0.001). An increased LT4 dose was required for 50% of patients in the TSH suppression group for thyroid cancer and 26% of patients in the replacement group for hypothyroidism. Risk factor analysis showed that remaining thyroid gland (odds ratio [OR] 9.207, P = 0.002), the time interval between starting RIF and TSH measurement (OR 1.043, P = 0.019), and baseline LT4 dose per kg body weight (OR 0.364, P = 0.011) were clinically relevant variables. CONCLUSIONS: In patients receiving LT4, serum thyroid function test should be performed after starting RIF treatment. For patients with no remnant thyroid gland and those receiving a lower LT4 dose, close observation is needed when starting RIF and TB medication. PMID- 28081174 TI - Definition of Human Epitopes Recognized in Tetanus Toxoid and Development of an Assay Strategy to Detect Ex Vivo Tetanus CD4+ T Cell Responses. AB - Despite widespread uses of tetanus toxoid (TT) as a vaccine, model antigen and protein carrier, TT epitopes have been poorly characterized. Herein we defined the human CD4+ T cell epitope repertoire by reevaluation of previously described epitopes and evaluation of those derived from prediction of HLA Class II binding. Forty-seven epitopes were identified following in vitro TT stimulation, with 28 epitopes accounting for 90% of the total response. Despite this diverse range of epitopes, individual responses were associated with only a few immunodominant epitopes, with each donor responding on average to 3 epitopes. For the top 14 epitopes, HLA restriction could be inferred based on HLA typing of the responding donors. HLA binding predictions re-identified the vast majority of known epitopes, and identified 24 additional novel epitopes. With these epitopes, we created a TT epitope pool, which allowed us to characterize TT responses directly ex vivo using a cytokine-independent Activation Induced Marker (AIM) assay. These TT responses were highly Th1 or Th2 polarized, which was dependent upon the original priming vaccine, either the cellular DTwP or acellular DTaP formulation. This polarization remained despite the original priming having occurred decades past and a recent booster immunization with a reduced acellular vaccine formulation. While TT responses following booster vaccination were not durably increased in magnitude, they were associated with a relative expansion of CD4+ effector memory T cells. PMID- 28081175 TI - Understanding the Goals of Everyday Instrumental Actions Is Primarily Linked to Object, Not Motor-Kinematic, Information: Evidence from fMRI. AB - Prior research conceptualised action understanding primarily as a kinematic matching of observed actions to own motor representations but has ignored the role of object information. The current study utilized fMRI to identify (a) regions uniquely involved in encoding the goal of others' actions, and (b) to test whether these goal understanding processes draw more strongly on regions involved in encoding object semantics or movement kinematics. Participants watched sequences of instrumental actions while attending to either the actions' goal (goal task), the movements performed (movement task) or the objects used (object task). The results confirmed, first, a unique role of the inferior frontal gyrus, middle temporal gyrus and medial frontal gyrus in action goal understanding. Second, they show for the first time that activation in the goal task overlaps directly with object- but not movement-related activation. Moreover, subsequent parametric analyses revealed that movement-related regions become activated only when goals are unclear, or observers have little action experience. In contrast to motor theories of action understanding, these data suggest that objects-rather than movement kinematics-carry the key information about others' actions. Kinematic information is additionally recruited when goals are ambiguous or unfamiliar. PMID- 28081176 TI - Radiation Induced Apoptosis of Murine Bone Marrow Cells Is Independent of Early Growth Response 1 (EGR1). AB - An understanding of how each individual 5q chromosome critical deleted region (CDR) gene contributes to malignant transformation would foster the development of much needed targeted therapies for the treatment of therapy related myeloid neoplasms (t-MNs). Early Growth Response 1 (EGR1) is a key transcriptional regulator of myeloid differentiation located within the 5q chromosome CDR that has been shown to regulate HSC (hematopoietic stem cell) quiescence as well as the master regulator of apoptosis-p53. Since resistance to apoptosis is a hallmark of malignant transformation, we investigated the role of EGR1 in apoptosis of bone marrow cells; a cell population from which myeloid malignancies arise. We evaluated radiation induced apoptosis of Egr1+/+ and Egr1-/- bone marrow cells in vitro and in vivo. EGR1 is not required for radiation induced apoptosis of murine bone marrow cells. Neither p53 mRNA (messenger RNA) nor protein expression is regulated by EGR1 in these cells. Radiation induced apoptosis of bone marrow cells by double strand DNA breaks induced p53 activation. These results suggest EGR1 dependent signaling mechanisms do not contribute to aberrant apoptosis of malignant cells in myeloid malignancies. PMID- 28081177 TI - First Behavioural Characterisation of a Knockout Mouse Model for the Transforming Growth Factor (TGF)-beta Superfamily Cytokine, MIC-1/GDF15. AB - Macrophage inhibitory cytokine-1 (MIC-1), also known as growth differentiation factor 15 (GDF15), is a stress response cytokine. MIC-1/GDF15 is secreted into the cerebrospinal fluid and increased levels of MIC-1/GDF15 are associated with a variety of diseases including cognitive decline. Furthermore, Mic-1/Gdf15 knockout mice (Mic-1 KO) weigh more, have increased adiposity, associated with increased spontaneous food intake, and exhibit reduced basal energy expenditure and physical activity. The current study was designed to comprehensively determine the role of MIC-1/GDF15 on behavioural domains of male and female knockout mice including locomotion, exploration, anxiety, cognition, social behaviours, and sensorimotor gating. Mic-1 KO mice exhibited a task-dependent increase in locomotion and exploration and reduced anxiety-related behaviours across tests. Spatial working memory and social behaviours were not affected by Mic-1/Gdf15 deficiency. Interestingly, knockout mice formed an increased association with the conditioned stimulus in fear conditioning testing and also displayed significantly improved prepulse inhibition. Overall sex effects were evident for social behaviours, fear conditioning, and sensorimotor gating. This is the first study defining the role of Mic-1/Gdf15 in a number of behavioural domains. Whether the observed impact is based on direct actions of Mic-1/Gdf15 deficiency on the CNS or whether the behavioural effects are mediated by indirect actions on e.g. other neurotransmitter systems must be clarified in future studies. PMID- 28081178 TI - Gender Differences in HIV Care among Criminal Justice-Involved Persons: Baseline Data from the CARE+ Corrections Study. AB - BACKGROUND: HIV-infected individuals recently released from incarceration have suboptimal linkage and engagement in community HIV care. We conducted a study to evaluate an information and communication technology intervention to increase linkage to community care among HIV-infected persons recently involved in the criminal justice (CJ) system. Baseline characteristics including risk behaviors and HIV care indicators are reported and stratified by gender. METHODS: We recruited HIV-infected individuals in the District of Columbia jail and persons with a recent history of incarceration through community and street outreach. Participants completed a baseline computer-assisted personal interview regarding HIV care and antiretroviral treatment (ART) adherence, substance use, and sexual behaviors. CD4 and HIV plasma viral load testing were performed at baseline or obtained through medical records. Data were analyzed for the sample overall and stratified by gender. RESULTS: Of 110 individuals, 70% were community-enrolled, mean age was 40 (SD = 10.5), 85% were Black, and 58% were male, 24% female, and 18% transgender women. Nearly half (47%) had condomless sex in the three months prior to incarceration. Although drug dependence and hazardous alcohol use were highly prevalent overall, transgender women were more likely to have participated in drug treatment than men and women (90%, 61%, and 50% respectively; p = 0.01). Prior to their most recent incarceration, 80% had an HIV provider and 91% had ever taken ART. Among those, only 51% reported >=90% ART adherence. Fewer women (67%) had received HIV medications during their last incarceration compared to men (96%) and transgender women (95%; p = 0.001). Although neither was statistically significant, transgender women and men had higher proportions of baseline HIV viral suppression compared to women (80%, 69%, and 48.0% respectively, p>0.05); a higher proportion of women had a CD4 count <=200 compared to men and transgender women (17%, 8% and 5% respectively; p>0.05). CONCLUSIONS: In this study, HIV-infected persons with recent incarceration in Washington, DC reported important risk factors and co-morbidities, yet the majority had access to HIV care and ART prior to, during, and after incarceration. Self-reported ART adherence was sub-optimal, and while there were not statistically significant differences, CJ-involved women appeared to be at greatest risk of poor HIV outcomes. TRIAL REGISTRATION: Registered on ClinicalTrials.gov on 10/16/2012. Reference number: NCT01721226. PMID- 28081179 TI - Effect of Straw Amendment on Soil Zn Availability and Ageing of Exogenous Water Soluble Zn Applied to Calcareous Soil. AB - Organic matter plays a key role in availability and transformation of soil Zn (zinc), which greatly controls Zn concentrations in cereal grains and human Zn nutrition level. Accordingly, soils homogenized with the wheat straw (0, 12 g straw kg-1) and Zn fertilizer (0, 7 mg Zn kg-1) were buried and incubated in the field over 210 days to explore the response of soil Zn availability and the ageing of exogenous Zn to straw addition. Results indicated that adding straw alone scarcely affected soil DTPA-Zn concentration and Zn fractions because of the low Zn concentration of wheat straw and the high soil pH, and large clay and calcium carbonate contents. However, adding exogenous Zn plus straw increased the DTPA-Zn abundance by about 5-fold and had the similar results to adding exogenous Zn alone, corresponding to the increased Zn fraction loosely bounded to organic matter, which had a more dominant presence in Zn reaction than soil other constituents such as carbonate and minerals in calcareous soil. The higher relative amount of ineffective Zn (~50%) after water soluble Zn addition also occurred, and at the days of 120-165 and 180-210when the natural temperature and rainfall changed mildly, the ageing process of exogenous Zn over time was well evaluated by the diffusion equation, respectively. Consequently, combining crop residues with exogenous water soluble Zn application is promising strategy to maximize the availability of Zn in calcareous soil, but the higher ageing rate of Zn caused by the higher Zn mobility should be considered. PMID- 28081180 TI - PI3Kgamma Deficient NOD-Mice Are Protected from Diabetes by Restoring the Balance of Regulatory to Effector-T-Cells. AB - With a steady increase in its incidence and lack of curative treatment, type 1 diabetes (T1D) has emerged as a major health problem worldwide. To design novel effective therapies, there is a pressing need to identify regulatory targets controlling the balance of autoreactive to regulatory-T-cells (Tregs). We previously showed that the inhibition of the gamma-subunit of the Phosphoinositide-3-kinase (PI3K), significantly suppress autoimmune-diabetes. To further delineate the mechanisms and the selectivity of specific immune modulation by PI3Kgamma-inhibition, we developed a new NOD mouse model of T1D lacking the gamma-subunit of PI3K. Strikingly, the loss of PI3Kgamma protected 92% of the NOD-mice from developing spontaneous diabetes. The NOD.PI3Kgamma-/- mice are protected from insulitis secondary to a defect in CD4 and CD8 autoreactive-T-cells activation and survival. In addition, PI3Kgamma-deficiency promoted Treg generation in-vitro and in-vivo. Furthermore, PI3Kgamma-inhibitor (AS605240) inhibited proliferation and cytokine production of a human CD4+ T-cell clone specific for GAD555-567 peptide that was isolated from a patient with T1D. These studies demonstrate the key role of the PI3Kgamma pathway in regulating autoimmune-diabetes and provide rationales for future devise of anti- PI3Kgamma therapy in T1D. PMID- 28081181 TI - Aronia melanocarpa Extract Ameliorates Hepatic Lipid Metabolism through PPARgamma2 Downregulation. AB - Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. Studies have demonstrated that anthocyanin-rich foods may improve hyperlipidemia and ameliorate hepatic steatosis. Here, effects of Aronia melanocarpa (AM), known to be rich of anthocyanins, on hepatic lipid metabolism and adipogenic genes were determined. AM was treated to C57BL/6N mice fed with high fat diet (HFD) or to FL83B cells treated with free fatty acid (FFA). Changes in levels of lipids, enzymes and hormones were observed, and expressions of adipogenic genes involved in hepatic lipid metabolism were detected by PCR, Western blotting and luciferase assay. In mice, AM significantly reduced the body and liver weight, lipid accumulation in the liver, and levels of biochemical markers such as fatty acid synthase, hepatic triglyceride and leptin. Serum transaminases, indicators for hepatocyte injury, were also suppressed, while superoxide dismutase activity and liver antioxidant capacity were significantly increased. In FL83B cells, AM significantly reduced FFA-induced lipid droplet accumulation. Protein synthesis of an adipogenic transcription factor, peroxisome proliferator-activated receptor gamma2 (PPARgamma2) was inhibited in vivo. Furthermore, transcriptional activity of PPARgamma2 was down-regulated in vitro, and mRNA expression of PPARgamma2 and its downstream target genes, adipocyte protein 2 and lipoprotein lipase were down-regulated by AM both in vitro and in vivo. These results show beneficial effects of AM against hepatic lipid accumulation through the inhibition of PPARgamma2 expression along with improvements in body weight, liver functions, lipid profiles and antioxidant capacity suggesting the potential therapeutic efficacy of AM on NAFLD. PMID- 28081182 TI - Combination of Plant Metabolic Modules Yields Synthetic Synergies. AB - The great potential of pharmacologically active secondary plant metabolites is often limited by low yield and availability of the producing plant. Chemical synthesis of these complex compounds is often too expensive. Plant cell fermentation offers an alternative strategy to overcome these limitations. However, production in batch cell cultures remains often inefficient. One reason might be the fact that different cell types have to interact for metabolite maturation, which is poorly mimicked in suspension cell lines. Using alkaloid metabolism of tobacco, we explore an alternative strategy, where the metabolic interactions of different cell types in a plant tissue are technically mimicked based on different plant-cell based metabolic modules. In this study, we simulate the interaction found between the nicotine secreting cells of the root and the nicotine-converting cells of the senescent leaf, generating the target compound nornicotine in the model cell line tobacco BY-2. When the nicotine demethylase NtomCYP82E4 was overexpressed in tobacco BY-2 cells, nornicotine synthesis was triggered, but only to a minor extent. However, we show here that we can improve the production of nornicotine in this cell line by feeding the precursor, nicotine. Engineering of another cell line overexpressing the key enzyme NtabMPO1 allows to stimulate accumulation and secretion of this precursor. We show that the nornicotine production of NtomCYP82E4 cells can be significantly stimulated by feeding conditioned medium from NtabMPO1 overexpressors without any negative effect on the physiology of the cells. Co-cultivation of NtomCYP82E4 with NtabMPO1 stimulated nornicotine accumulation even further, demonstrating that the physical presence of cells was superior to just feeding the conditioned medium collected from the same cells. These results provide a proof of concept that combination of different metabolic modules can improve the productivity for target compounds in plant cell fermentation. PMID- 28081183 TI - Circulating Cell-Free DNA in Dogs with Mammary Tumors: Short and Long Fragments and Integrity Index. AB - Circulating cell-free DNA (cfDNA) has been considered an interesting diagnostic/prognostic plasma biomarker in tumor-bearing subjects. In cancer patients, cfDNA can hypothetically derive from tumor necrosis/apoptosis, lysed circulating cells, and some yet unrevealed mechanisms of active release. This study aimed to preliminarily analyze cfDNA in dogs with canine mammary tumors (CMTs). Forty-four neoplastic, 17 non-neoplastic disease-bearing, and 15 healthy dogs were recruited. Necrosis and apoptosis were also assessed as potential source of cfDNA on 78 CMTs diagnosed from the 44 dogs. The cfDNA fragments and integrity index significantly differentiated neoplastic versus non-neoplastic dogs (P<0.05), and allowed the distinction between benign and malignant lesions (P<0.05). Even if without statistical significance, the amount of cfDNA was also affected by tumor necrosis and correlated with tumor size and apoptotic markers expression. A significant (P<0.01) increase of Bcl-2 in malignant tumors was observed, and in metastatic CMTs the evasion of apoptosis was also suggested. This study, therefore, provides evidence that cfDNA could be a diagnostic marker in dogs carrying mammary nodules suggesting that its potential application in early diagnostic procedures should be further investigated. PMID- 28081184 TI - Intraocular Pressure-Lowering Effect of Latanoprost Is Hampered by Defective Cervical Lymphatic Drainage. AB - PURPOSE: To evaluate whether defects in cervical lymphatic drainage influence the intraocular pressure (IOP)-lowering effect of latanoprost in patients with primary open-angle glaucoma (POAG) who have undergone unilateral radical neck dissection (uRND). METHODS: We enrolled (1) bilateral POAG patients who had started (bilateral) latanoprost (0.005%) monotherapy prior to their uRND and (2) treatment-naive, bilateral glaucoma suspects (GSs) who had undergone the same surgery. We compared the eyes ipsilateral to the uRND with their fellow eyes in terms of the changes in IOP between the baseline (prior to the uRND) and the follow-up visits (1, 3, and 6 months after the uRND). RESULTS: The study involved 22 eyes of 11 POAG patients and 14 eyes of 7 GSs. In the POAG patients, IOP had increased significantly after surgery in the eyes ipsilateral to the uRND (from 14.7+/-1.4mmHg to 17.1+/-2.2mmHg; P = 0.007). Interestingly, in the eyes contralateral to the uRND, IOP had not changed significantly after surgery (from 14.2+/-1.8mmHg to 14.4+/-2.0mmHg; P = 0.826). In GSs, the eyes ipsilateral to the uRND did not differ significantly from their fellow eyes in terms of post operative IOP change (ipsilateral value: 0.3+/-0.5mmHg, fellow eyes: -0.1+/ 0.7mmHg; P = 0.242). CONCLUSION: In the POAG patients, IOP had increased significantly in the eyes ipsilateral to the uRND. However, it had not changed significantly in the eyes contralateral to the surgery or in the eyes of the GSs. These findings suggest that, latanoprost works, at least in part, by enhancing outflow from the aqueous humor via the uveolymphatic pathway. PMID- 28081186 TI - Mechanical Compression Effects on the Secretion of vWF and IL-8 by Cultured Human Vein Endothelium. AB - Short peripheral catheters are ubiquitous in today's healthcare environment enabling effective delivery of fluids and medications directly into a patient's vasculature. However, complications related to their use, such as short peripheral catheter thrombophlebitis (SPCT), affect up to 80% of hospitalized patients. While indwelling within the vein, the catheters exert prolonged constant pressure upon the endothelium which can trigger inflammation processes. We have developed and studied an in-vitro model of cultured endothelial cells subjected to mechanical compression of modular self-designed weights, and explored their inflammatory response by quantification of two key biomarkers- vWF and IL-8. Evaluation was performed by ELISA immunoassay and processing of vWF labeled immunofluorescence images. We found that application of weights correspond to 272 Pa yielded increased release of vWF and IL-8 up to 150% and 250% respectively, comparing to the exertion of 136 Pa. Analyses of the immunofluorescence images revealed significantly longer and more extracellular vWF-strings as well as higher intensity stained-pixels in cells exposed to elevated pressures. The release of both factors found to be significantly dependent on the extent of the exerted pressure. The research shed a light on the relationship between induced mechanical compression and the pathogenesis of SPCT. Minimizing, let alone eliminating the contact between the catheter and the vein wall will mitigate the pressure acting on the endothelium, thereby reducing the secretion of inflammatory factors and lessen the incidence of SPCT. PMID- 28081185 TI - Upregulated Expression of Transient Receptor Potential Cation Channel Subfamily V Receptors in Mucosae of Patients with Oral Squamous Cell Carcinoma and Patients with a History of Alcohol Consumption or Smoking. AB - OBJECTIVES: Transient receptor potential cation channel (subfamily V, members 1 4) (TRPV1-4) are expressed in skin and neurons and activated by external stimuli in normal mucosae of all oral cavity sites. The oral cavity is exposed to various stimuli, including temperature, mechanical stimuli, chemical substances, and changes in pH, and, notably, the risk factors for oncogenic transformation in oral squamous epithelium are the same as the external stimuli received by TRPV1-4 receptors. Hence, we examined the relationship between oral squamous cell carcinoma (SCC) and TRPV1-4 expression. MATERIALS AND METHODS: Oral SCC patients (n = 37) who underwent surgical resection were included in this study. We investigated the expression of TRPV1-4 by immunohistochemical staining and quantification of TRPV1-4 mRNA in human oral mucosa. In addition, we compared the TRPV1-4 levels in mucosa from patients with SCC to those in normal oral mucosa. RESULTS: The receptors were expressed in oral mucosa at all sites (tongue, buccal mucosa, gingiva, and oral floor) and the expression was stronger in epithelia from patients with SCC than in normal epithelia. Furthermore, alcohol consumption and tobacco use were strongly associated with the occurrence of oral cancer and were found to have a remarkable influence on TRPV1-4 receptor expression in normal oral mucosa. In particular, patients with a history of alcohol consumption demonstrated significantly higher expression levels. CONCLUSION: Various external stimuli may influence the behavior of cancer cells. Overexpression of TRPV1-4 is likely to be a factor in enhanced sensitivity to external stimuli. These findings could contribute to the establishment of novel strategies for cancer therapy or prevention. PMID- 28081187 TI - Perceptual Space of Superimposed Dual-Frequency Vibrations in the Hands. AB - The use of distinguishable complex vibrations that have multiple spectral components can improve the transfer of information by vibrotactile interfaces. We investigated the qualitative characteristics of dual-frequency vibrations as the simplest complex vibrations compared to single-frequency vibrations. Two psychophysical experiments were conducted to elucidate the perceptual characteristics of these vibrations by measuring the perceptual distances among single-frequency and dual-frequency vibrations. The perceptual distances of dual frequency vibrations between their two frequency components along their relative intensity ratio were measured in Experiment I. The estimated perceptual spaces for three frequency conditions showed non-linear perceptual differences between the dual-frequency and single-frequency vibrations. A perceptual space was estimated from the measured perceptual distances among ten dual-frequency compositions and five single-frequency vibrations in Experiment II. The effect of the component frequency and the frequency ratio was revealed in the perceptual space. In a percept of dual-frequency vibration, the lower frequency component showed a dominant effect. Additionally, the perceptual difference among single frequency and dual-frequency vibrations were increased with a low relative difference between two frequencies of a dual-frequency vibration. These results are expected to provide a fundamental understanding about the perception of complex vibrations to enrich the transfer of information using vibrotactile stimuli. PMID- 28081188 TI - Effect of Varroa destructor, Wounding and Varroa Homogenate on Gene Expression in Brood and Adult Honey Bees. AB - Honey bee (Apis mellifera) gene expression related to immunity for hymenoptaecin (AmHym) and defensin-1 (AmDef-1), longevity for vitellogenin (AmVit2) and stem cell proliferation for poly U binding factor 68 kDa (AmPuf68) was compared following Varroa destructor parasitism, buffer injection and injection of V. destructor compounds in its homogenate. In adults, V. destructor parasitism decreased expression of all four genes, while buffer injection decreased expression of AmHym, AmPuf68 and AmVit2, and homogenate injection decreased expression of AmPuf68 and AmVit2 but increased expression of AmDef-1 relative to their respective controls. The effect of V. destructor parasitism in adults relative to the controls was not significantly different from buffer injection for AmHym and AmVit2 expression, and it was not significantly different from homogenate injection for AmPuf68 and AmVit2. In brood, V. destructor parasitism, buffer injection and homogenate injection decreased AmVit2 expression, whereas AmHym expression was decreased by V. destructor parasitism but increased by buffer and homogenate injection relative to the controls. The effect of varroa parasitism in brood was not significantly different from buffer or homogenate injection for AmPuf68 and AmVit2. Expression levels of the four genes did not correlate with detectable viral levels in either brood or adults. The results of this study indicate that the relative effects of V. destructor parasitism on honey bee gene expression are also shared with other types of stresses. Therefore, some of the effects of V. destructor on honey bees may be mostly due to wounding and injection of foreign compounds into the hemolymph of the bee during parasitism. Although both brood and adults are naturally parasitized by V. destructor, their gene expression responded differently, probably the result of different mechanisms of host responses during development. PMID- 28081189 TI - Global Gene Expression Analysis of Cross-Protected Phenotype of Pectobacterium atrosepticum. AB - The ability to adapt to adverse conditions permits many bacterial species to be virtually ubiquitous and survive in a variety of ecological niches. This ability is of particular importance for many plant pathogenic bacteria that should be able to exist, except for their host plants, in different environments e.g. soil, water, insect-vectors etc. Under some of these conditions, bacteria encounter absence of nutrients and persist, acquiring new properties related to resistance to a variety of stress factors (cross-protection). Although many studies describe the phenomenon of cross-protection and several regulatory components that induce the formation of resistant cells were elucidated, the global comparison of the physiology of cross-protected phenotype and growing cells has not been performed. In our study, we took advantage of RNA-Seq technology to gain better insights into the physiology of cross-protected cells on the example of a harmful phytopathogen, Pectobacterium atrosepticum (Pba) that causes crop losses all over the world. The success of this bacterium in plant colonization is related to both its virulence potential and ability to persist effectively under various stress conditions (including nutrient deprivation) retaining the ability to infect plants afterwards. In our previous studies, we showed Pba to be advanced in applying different adaptive strategies that led to manifestation of cell resistance to multiple stress factors. In the present study, we determined the period necessary for the formation of cross-protected Pba phenotype under starvation conditions, and compare the transcriptome profiles of non-adapted growing cells and of adapted cells after the cross-protective effect has reached the maximal level. The obtained data were verified using qRT-PCR. Genes that were expressed differentially (DEGs) in two cell types were classified into functional groups and categories using different approaches. As a result, we portrayed physiological features that distinguish cross-protected phenotype from the growing cells. PMID- 28081190 TI - Inflammatory Activity on Natalizumab Predicts Short-Term but Not Long-Term Disability in Multiple Sclerosis. AB - BACKGROUND: In people with multiple sclerosis treated with interferon-beta or glatiramer acetate, new MRI lesions and relapses during the first year of treatment predict a poor prognosis. OBJECTIVE: To study this association in those receiving natalizumab. METHODS: Data were collected on relapses, new MRI activity, and Modified Rio Score after initiation of natalizumab in an observational cohort of 161 patients with high baseline disability. These were correlated with Expanded Disability Status Scale (EDSS) progression at years 1, 2, 3, and 3-7 after treatment initiation, versus pre-treatment baseline. RESULTS: 46/161 patients had a relapse in the first year and 44/161 had EDSS progression by year 2. Relapses and Modified Rio Score in the first year of treatment predicted EDSS progression at year 1 and 2 after treatment initiation. However, this effect disappeared with longer follow-up. Paradoxically, there was a trend towards inflammatory activity on treatment (first year Modified Rio Score, relapses, and MRI activity) predicting a lower risk of EDSS progression by years 3-7, although this did not reach statistical significance. Those with and without EDSS progression did not differ in baseline age, EDSS, or pre-treatment relapse rate. Relapses in year 0-1 predicted further relapses in years 1-3. CONCLUSIONS: Breakthrough inflammatory activity after natalizumab treatment is predictive of short-term outcome measures of relapses or EDSS progression, but does not predict longer term EDSS progression, in this cohort with high baseline disability. PMID- 28081191 TI - Recreational Physical Activity and Premenstrual Syndrome in Young Adult Women: A Cross-Sectional Study. AB - INTRODUCTION: It is estimated that up to 75% of premenopausal women experience at least one premenstrual symptom and 8-20% meet clinical criteria for premenstrual syndrome. Premenstrual syndrome substantially reduces quality of life for many women of reproductive age, with pharmaceutical treatments having limited efficacy and substantial side effects. Physical activity has been recommended as a method of reducing menstrual symptom severity. However, this recommendation is based on relatively little evidence, and the relationship between physical activity, premenstrual symptoms, and premenstrual syndrome remains unclear. METHODS: We evaluated the relationship between physical activity and premenstrual syndrome and premenstrual symptoms among 414 women aged 18-31. Usual premenstrual symptom experience was assessed with a modified version of the Calendar of Premenstrual Experiences. Total, physical, and affective premenstrual symptom scores were calculated for all participants. Eighty women met criteria for moderate-to-severe premenstrual syndrome, while 89 met control criteria. Physical activity, along with dietary and lifestyle factors, was assessed by self-report. RESULTS: Physical activity was not significantly associated with total, affective, or physical premenstrual symptom score. Compared to the women with the lowest activity, women in tertiles 2 and 3 of activity, classified as metabolic equivalent task hours, had prevalence odds ratios for premenstrual syndrome of 1.5 (95% CI: 0.6-3.7) and 0.9 (95% CI: 0.4-2.4), respectively (p-value for trend = 0.85). CONCLUSIONS: We found no association between physical activity and either premenstrual symptom scores or the prevalence of premenstrual syndrome. PMID- 28081193 TI - Environmental Factors Can Influence Mitochondrial Inheritance in the Saccharomyces Yeast Hybrids. AB - Mitochondria play a critical role in the generation of metabolic energy and are crucial for eukaryotic cell survival and proliferation. In most sexual eukaryotes, mitochondrial DNA (mtDNA) is inherited from only one parent in non Mendelian inheritance in contrast to the inheritance of nuclear DNA. The model organism Saccharomyces cerevisiae is commonly used to study mitochondrial biology. It has two mating types: MATa and MATalpha. Previous studies have suggested that the mtDNA inheritance patterns in hybrid diploid cells depend on the genetic background of parental strains. However, the underlying mechanisms remain unclear. To elucidate the mechanisms, we examined the effects of environmental factors on the mtDNA inheritance patterns in hybrids obtained by crossing S. cerevisiae with its close relative S. paradoxus. The results demonstrated that environmental factors can influence mtDNA transmission in hybrid diploids, and that the inheritance patterns are strain dependent. The fitness competition assay results showed that the fitness differences can explain the mtDNA inheritance patterns under specific conditions. However, in this study, we found that fitness differences cannot fully be explained by mitochondrial activity in hybrids under stress conditions. PMID- 28081192 TI - Circulating Betatrophin Levels and Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: The association between circulating betatrophin levels and gestational diabetes mellitus (GDM) is controversial. The aim of our study was to systematically review available literature linking betatrophin to GDM for a comprehensive understanding of the relationship between circulating betatrophin levels and GDM in human. METHODS: PubMed, The Cochrane Library, Medline and CNKI were searched for studies published up to August 2016. Manual searches of references of the relevant original studies were conducted. Pooled estimates were measured using the fixed or random effect model. Overall effect was reported in a standard mean difference (SMD). All data were analyzed with Review Manager 5.3 and Stata 12.0. RESULTS: Of 25 references reviewed, 8 studies met our inclusion criteria and contributed to meta-analysis. All the studies were used to evaluate the relationship between betatrophin levels in blood and GDM. Betatrophin levels were significantly elevated in women with GDM compared with those without GDM (SMD = 1.05; 95% CI: 0.41-1.68, P = 0.001). This evidence was more consistent among women with betatrophin blood draw during the third trimester (SMD = 1.3, 95% CI: 1-1.61, P < 0.001) and for women BMI >= 28 kg/m2 (SMD = 1.53, 95% CI: 1.30-1.75, P < 0.001). CONCLUSIONS: The evidences from this meta-analysis indicated that the levels of circulating betatrophin were significantly elevated among women with GDM compared with women with normal glucose tolerance, especially with BMI >= 28 kg/m2 and in the third trimester. PMID- 28081194 TI - T Cell Epitope-Containing Domains of Ragweed Amb a 1 and Mugwort Art v 6 Modulate Immunologic Responses in Humans and Mice. AB - BACKGROUND: Ragweed (Ambrosia artemisiifolia) and mugwort (Artemisia vulgaris) are the major cause of pollen allergy in late summer. Allergen-specific lymphocytes are crucial for immune modulation during immunotherapy. We sought to generate and pre-clinically characterise highly immunogenic domains of the homologous pectate lyases in ragweed (Amb a 1) and mugwort pollen (Art v 6) for immunotherapy. METHODS: Domains of Amb a 1 (Amb a 1alpha) and Art v 6 (Art v 6alpha) and a hybrid molecule, consisting of both domains, were designed, expressed in E. coli and purified. Human IgE reactivity and allergenicity were assessed by ELISA and mediator release experiments using ragweed and mugwort allergic patients. Moreover, T cell proliferation was determined. Blocking IgG antibodies and cytokine production in BALB/c mice were studied by ELISA and ELISPOT. RESULTS: The IgE binding capacity and in vitro allergenic activity of the Amb a 1 and Art v 6 domains and the hybrid were either greatly reduced or abolished. The recombinant proteins induced T cell proliferative responses comparable to those of the natural allergens, indicative of retained allergen specific T cell response. Mice immunisation with the hypoallergens induced IL-4, IL-5, IL-13 and IFN-gamma production after antigen-specific in vitro re stimulation of splenocytes. Moreover, murine IgG antibodies that inhibited specific IgE binding of ragweed and mugwort pollen allergic patients were detected. CONCLUSION: Accumulation of T cell epitopes and deletion of IgE reactive areas of Amb a 1 and Art v 6, modulated the immunologic properties of the allergen immuno-domains, leading to promising novel candidates for therapeutic approach. PMID- 28081195 TI - Assessment of Volumetric versus Manual Measurement in Disseminated Testicular Cancer; No Difference in Assessment between Non-Radiologists and Genitourinary Radiologist. AB - BACKGROUND: The aim of this study was to assess the feasibility and reproducibility of semi-automatic volumetric measurement of retroperitoneal lymph node metastases in testicular cancer (TC) patients treated with chemotherapy versus the standardized manual measurements based on RECIST criteria. METHODS: 21 TC patients with retroperitoneal lymph node metastases of testicular cancer were studied with a CT scan of chest and abdomen before and after cisplatin based chemotherapy. Three readers, a surgical resident, a radiological technician and a radiologist, assessed tumor response independently using computerized volumetric analysis with Vitrea software(r) and manual measurement according to RECIST criteria (version 1.1). Intra- and inter-rater variability were evaluated with intra class correlations and Bland-Altman analysis. RESULTS: Assessment of intra observer and inter observer variance proved non-significant in both measurement modalities. In particularly all intraclass correlation (ICC) values for the volumetric analysis were > .99 per observer and between observers. There was minimal bias in agreement for manual as well as volumetric analysis. CONCLUSION: In this study volumetric measurement using Vitrea software(r) appears to be a reliable, reproducible method to measure initial tumor volume of retroperitoneal lymph node metastases of testicular cancer after chemotherapy. Both measurement methods can be performed by experienced non-radiologists as well. PMID- 28081196 TI - How Social Ties Influence Consumer: Evidence from Event-Related Potentials. AB - A considerable amount of marketing research has reported that consumers are more saliently influenced by friends (strong social ties) than by acquaintances and strangers (weak social ties). To shed light on the neural and psychological processes underlying such phenomenon, in this study we designed an amended S1-S2 paradigm (product-[reviewer-review]) that is based on realistic consumer purchase experiences. After incoming all given information (product, reviewer, review), participants were required to state their purchase intentions. The neurocognitive and emotional processes related to friend and stranger stimuli were delineated to suggest how social ties influence consumers during their shopping processes. Larger P2 (fronto-central scalp areas) and P3 (central and posterior-parietal scalp areas) components under stranger condition were elicited successfully. These findings demonstrate that the cognitive and emotional processing of friend and stranger stimuli occurs at stages of neural activity, and can be indicated by the P2 and P3 components. Electrophysiological data also support the hypothesis that different neural and emotional processing magnitude and strength underlie friend and stranger effect in the context of consumer purchase. During this process, the perception of stimuli evoked P2, subsequently emotional processing and attention modulation were activated and indicated by P2 and P3. The friend dominated phenomenon can be interpreted as the result of distinctive neurocognitive and emotional processing magnitude, which suggests that psychological and emotional factors can guide consumer decision making. This study consolidates that event related potential (ERP) methodology is likely to be a more sensitive method for investigating consumer behaviors. From the perspectives of management and marketing, our findings show that the P2 and P3 components can be employed as an indicator to probe the influential factors of consumer purchase intentions. PMID- 28081197 TI - Morphine Withdrawal Modifies Prion Protein Expression in Rat Hippocampus. AB - The hippocampus is a vulnerable brain structure susceptible to damage during aging and chronic stress. Repeated exposure to opioids may alter the brain so that it functions normally when the drugs are present, thus, a prolonged withdrawal might lead to homeostatic changes headed for the restoration of the physiological state. Abuse of morphine may lead to Reacting Oxygen Species induced neurodegeneration and apoptosis. It has been proposed that during morphine withdrawal, stress responses might be responsible, at least in part, for long-term changes of hippocampal plasticity. Since prion protein is involved in both, Reacting Oxygen Species mediated stress responses and synaptic plasticity, in this work we investigate the effect of opiate withdrawal in rats after morphine treatment. We hypothesize that stressful stimuli induced by opiate withdrawal, and the subsequent long-term homeostatic changes in hippocampal plasticity, might modulate the Prion protein expression. Our results indicate that abstinence from the opiate induced a time-dependent and region-specific modification in Prion protein content, indeed during morphine withdrawal a selective unbalance of hippocampal Prion Protein is observable. Moreover, Prion protein overexpression in hippocampal tissue seems to generate a dimeric structure of Prion protein and alpha-cleavage at the hydrophobic domain. Stress factors or toxic insults can induce cytosolic dimerization of Prion Protein through the hydrophobic domain, which in turn, it stimulates the alpha-cleavage and the production of neuroprotective Prion protein fragments. We speculate that this might be the mechanism by which stressful stimuli induced by opiate withdrawal and the subsequent long-term homeostatic changes in hippocampal plasticity, modulate the expression and the dynamics of Prion protein. PMID- 28081198 TI - Molecular Analysis of Chinese Celastrus and Tripterygium and Implications in Medicinal and Pharmacological Studies. AB - Celastrus and Tripterygium species, which are used in traditional Chinese medicine, have attracted much attention due to their anti-tumor promoting and neuroprotective activities, in addition to their applications in autoimmune disorders. However, systematic relationships between them and among species are unclear, and it may disturb their further medicinal utilization. In the present study, the molecular analysis of combined chloroplast and nuclear markers of all Chinese Celastrus and Tripterygium was performed, and clear inter- and intra genus relationships were presented. The result suggests that Tripterygium constitute a natural monophyletic clade within Celastrus with strong support value. Fruit and seed type are better than inflorescence in subgeneric classification. Chinese Celastrus are classified for three sections: Sect. Sempervirentes (Maxim.) CY Cheng & TC Kao, Sect. Lunatus XY Mu & ZX Zhang, sect. nov., and Sect. Ellipticus XY Mu & ZX Zhang, sect. nov. The phylogenetic data was consistent with their chemical components reported previously. Owing to the close relationship, several evergreen Celastrus species are recommended for chemical and pharmacological studies. Our results also provide reference for molecular identification of Chinese Celastrus and Tripterygium. PMID- 28081199 TI - Mesons from Laser-Induced Processes in Ultra-Dense Hydrogen H(0). AB - Large signals of charged light mesons are observed in the laser-induced particle flux from ultra-dense hydrogen H(0) layers. The mesons are formed in such layers on metal surfaces using < 200 mJ laser pulse-energy. The time variation of the signal to metal foil collectors and the magnetic deflection to a movable pin collector are now studied. Relativistic charged particles with velocity up to 500 MeV u-1 thus 0.75 c are observed. Characteristic decay time constants for meson decay are observed, for charged and neutral kaons and also for charged pions. Magnetic deflections agree with charged pions and kaons. Theoretical predictions of the decay chains from kaons to muons in the particle beam agree with the results. Muons are detected separately by standard scintillation detectors in laser-induced processes in ultra-dense hydrogen H(0) as published previously. The muons formed do not decay appreciably within the flight distances used here. Most of the laser-ejected particle flux with MeV energy is not deflected by the magnetic fields and is thus neutral, either being neutral kaons or the ultra dense HN(0) precursor clusters. Photons give only a minor part of the detected signals. PACS: 67.63.Gh, 14.40.-n, 79.20.Ds, 52.57.-z. PMID- 28081200 TI - Fitter Women Did Not Have Attenuated Hemodynamic Responses to Psychological Stress Compared with Age-Matched Women with Lower Levels of Fitness. AB - According to the 'cross stressor adaptation hypothesis', regular exercise acts as a buffer against the detrimental effects of stress. Nevertheless, evidence that higher levels of cardiorespiratory fitness moderate hemodynamic responses to acute psychological stress is inconclusive, especially in women. Women aged 30-50 years (in the mid-follicular phase of the menstrual cycle) with higher (n = 17) and lower (n = 17) levels of fitness were subjected to a Trier Social Stress Test (TSST). Continuous, non-invasive measurements were made of beat-to-beat, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), stroke volume (SV), cardiac output (CO), left ventricular ejection time (LVET), maximum slope, pulse interval (PI) and total peripheral resistance (TPR). Maximal oxygen consumption was significantly (p<0.001) higher in the 'higher fit' women. Lower fit women had higher fasting glucose, resting heart rate, waist to hip ratios and elevated serum triglyceride and cholesterol/ HDL ratios compared with higher fit women (p<0.05 for all). While all measured parameters (for both groups)displayed significant (p<0.001) responses to the TSST, only HR, PI and LVET differed significantly between higher and lower fit women (p<0.001 for all) with the higher fit women having the larger response in each case. It was also found that higher fit women had significantly shorter time to recovery for maximum slope compared with the lower fit women. These findings provide little support for the notion that higher levels of cardiorespiratory fitness result in lower cardiovascular responsivity to psychological stress in women but may indicate that lower fit women have blunted responses to stress. PMID- 28081201 TI - Complex Network Analysis for Characterizing Global Value Chains in Equipment Manufacturing. AB - The rise of global value chains (GVCs) characterized by the so-called "outsourcing", "fragmentation production", and "trade in tasks" has been considered one of the most important phenomena for the 21st century trade. GVCs also can play a decisive role in trade policy making. However, due to the increasing complexity and sophistication of international production networks, especially in the equipment manufacturing industry, conventional trade statistics and the corresponding trade indicators may give us a distorted picture of trade. This paper applies various network analysis tools to the new GVC accounting system proposed by Koopman et al. (2014) and Wang et al. (2013) in which gross exports can be decomposed into value-added terms through various routes along GVCs. This helps to divide the equipment manufacturing-related GVCs into some sub networks with clear visualization. The empirical results of this paper significantly improve our understanding of the topology of equipment manufacturing-related GVCs as well as the interdependency of countries in these GVCs that is generally invisible from the traditional trade statistics. PMID- 28081202 TI - Characterization and Functional Analysis of Five MADS-Box B Class Genes Related to Floral Organ Identification in Tagetes erecta. AB - According to the floral organ development ABC model, B class genes specify petal and stamen identification. In order to study the function of B class genes in flower development of Tagetes erecta, five MADS-box B class genes were identified and their expression and putative functions were studied. Sequence comparisons and phylogenetic analyses indicated that there were one PI-like gene-TePI, two euAP3-like genes-TeAP3-1 and TeAP3-2, and two TM6-like genes-TeTM6-1 and TeTM6-2 in T. erecta. Strong expression levels of these genes were detected in stamens of the disk florets, but little or no expression was detected in bracts, receptacles or vegetative organs. Yeast hybrid experiments of the B class proteins showed that TePI protein could form a homodimer and heterodimers with all the other four B class proteins TeAP3-1, TeAP3-2, TeTM6-1 and TeTM6-2. No homodimer or interaction was observed between the euAP3 and TM6 clade members. Over-expression of five B class genes of T. erecta in Nicotiana rotundifolia showed that only the transgenic plants of 35S::TePI showed altered floral morphology compared with the non-transgenic line. This study could contribute to the understanding of the function of B class genes in flower development of T. erecta, and provide a theoretical basis for further research to change floral organ structures and create new materials for plant breeding. PMID- 28081203 TI - Mechanism and Parameter Optimization of Fenton's Reagent Integrated with Surfactant Pretreatment to Improve Sludge Dewaterability. AB - Sludge dewatering can effectively reduce the volume and mass of sludge for subsequent treatment and disposal. The work validated the potential of Fenton's reagent combined with dodecyl dimethyl benzyl ammonium chloride (DDBAC) in improving sludge dewaterability and proposed the mechanism of joint conditioning. The composite conditioner dosage was optimized using response surface methodology. Results indicated the good conditioning capability of the composite conditioners. The optimum dosages for H2O2, Fe2+, and DDBAC were 44.6, 39.6, and 71.0 mg/g, respectively, at which a sludge cake water content of 59.67% could be achieved. Moreover, a second-order polynomial equation was developed to describe the behavior of joint conditioning. Analysis of the reaction mechanism showed that Fenton oxidation effectively decomposed extracellular polymeric substance (EPS), including loosely bound EPS (LB-EPS) and tightly bound EPS (TB-EPS), into dissolved organics, such as proteins and polysaccharides. The process facilitated the conversion of the bound water into free water. Furthermore, DDBAC further released the bound water through solubilization of TB-EPS and LB-EPS after the Fenton reaction. The bound water content of the sludge conditioned with Fenton's reagent decreased from 3.15 to 1.36 g/g and further decreased to 1.08 g/g with the addition of DDBAC. High-performance liquid chromatography analysis verified that the composite conditioning could oxidize and hydrolyze EPS into low molecular-mass organics (e.g., formic and acetic acid), thereby facilitating the release of bound water. PMID- 28081204 TI - Deletion of ssnA Attenuates the Pathogenicity of Streptococcus suis and Confers Protection against Serovar 2 Strain Challenge. AB - Streptococcus suis serotype 2 (SS2) is a major porcine and human pathogen which causes arthritis, meningitis, and septicemia. Streptococcus suis nuclease A (SsnA) is a recently discovered deoxyribonuclease (DNase), which has been demonstrated to contribute to escape killing in neutrophil extracellular traps (NETs). To further determine the effects of ssnA on virulence, the ssnA deletion mutant (DeltassnA) and its complemented strain (C-DeltassnA) were constructed. The ability of DeltassnA mutant to interact with human laryngeal epithelial cell (Hep-2) was evaluated and it exhibited dramatically decreased ability to adhere to and invade Hep-2 cells. This mutation was found to exhibit significant attenuation of virulence when evaluated in CD1 mice, suggesting ssnA plays a critical role in the pathogenesis of SS2. Finally, we found that immunization with the DeltassnA mutant triggered both antibody responses and cell-mediated immunity, and conferred 80% protection against virulent SS2 challenge in mice. Taken together, our results suggest that DeltassnA represents an attractive candidate for designing an attenuated live vaccine against SS2. PMID- 28081206 TI - Identifying Pleiotropic Genes in Genome-Wide Association Studies for Multivariate Phenotypes with Mixed Measurement Scales. AB - We propose a multivariate genome-wide association test for mixed continuous, binary, and ordinal phenotypes. A latent response model is used to estimate the correlation between phenotypes with different measurement scales so that the empirical distribution of the Fisher's combination statistic under the null hypothesis is estimated efficiently. The simulation study shows that our proposed correlation estimation methods have high levels of accuracy. More importantly, our approach conservatively estimates the variance of the test statistic so that the type I error rate is controlled. The simulation also shows that the proposed test maintains the power at the level very close to that of the ideal analysis based on known latent phenotypes while controlling the type I error. In contrast, conventional approaches-dichotomizing all observed phenotypes or treating them as continuous variables-could either reduce the power or employ a linear regression model unfit for the data. Furthermore, the statistical analysis on the database of the Study of Addiction: Genetics and Environment (SAGE) demonstrates that conducting a multivariate test on multiple phenotypes can increase the power of identifying markers that may not be, otherwise, chosen using marginal tests. The proposed method also offers a new approach to analyzing the Fagerstrom Test for Nicotine Dependence as multivariate phenotypes in genome-wide association studies. PMID- 28081205 TI - Anxiety and Depression in Patients with Traumatic Spinal Cord Injury: A Nationwide Population-Based Cohort Study. AB - BACKGROUND: Traumatic spinal cord injury (tSCI) may involve new-onset anxiety and depression post-discharge. However, long-term population-based studies have lacked access to follow-up conditions in terms of new-onset anxiety and depression. The objective of this study was to estimate the long-term risk of new onset anxiety and depression post-discharge. METHODS: The Longitudinal Health Insurance Database 2000 (LHID2000) from Taiwan's National Health Insurance Research Database was used in this study. Individuals with tSCI were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes of 806 and 952 from 1999-2008. The comparison cohort (other health conditions group) was randomly selected from the LHID2000 and was 1:1 matched by age, sex, index year, and comorbidities to reduce the selection bias. All study participants were retrospectively followed for a maximum of 3 years until the end of follow-up, death, or new-onset anxiety (ICD-9 CM: 309.2-309.4) or depression (ICD-9-CM: 296.2, 296.5, 296.82, 300.4, 309.0 309.1, and 311). Persons who were issued a catastrophic illness card for tSCI were categorized as having a severe level of SCI (Injury Severity Score [ISS] >=16). Poisson regression was used to estimate the incidence rate ratios of anxiety or depression between patients with tSCI and other health conditions. The relative risk of anxiety or depression was estimated using a Cox regression analysis, which was adjusted for potential confounding factors. RESULTS: Univariate analyses showed that the tSCI patients (n = 3556) had a 1.33 times greater incidence of new-onset anxiety or depression (95% confidence interval [CI]: 1.12-1.57) compared to the other health conditions group (n = 3556). After adjusting for potential risk factors, the tSCI patients had a significant 1.29 fold increased risk of anxiety or depression compared to the group with other health conditions (95% CI: 1.09-1.53). Individuals with tSCI, including patients who were under the age of 35, patients who were males, patients who had a low income, and patients without a Charlson Comorbidity Index score, all had a higher long-term risk of anxiety or depression than the other health conditions group (IRRs: 1.84, 1.63, 1.29, and 1.39, respectively). For all tSCI patients, those with an Injury Severity Score (ISS) >=16 had an almost 2-fold higher risk of anxiety or depression (adjusted Hazard Ratio: 1.85; 95% CI: 1.17-2.92) compared to those with ISS <16. CONCLUSIONS: Our findings indicated that tSCI patients have a high risk of anxiety or depression post-discharge, especially among the younger tSCI patients (age <50 years), compared with the other health conditions group. This information could help physicians understand the long-term risk of new-onset anxiety or depression in tSCI patients post-discharge. PMID- 28081207 TI - Myxovirus Resistance Protein A mRNA Expression Kinetics in Multiple Sclerosis Patients Treated with IFNbeta. AB - INTRODUCTION: Interferon-beta (IFNbeta) is the first-line treatment for relapsing remitting multiple sclerosis. Myxovirus resistance protein A (MxA) is a marker of IFNbeta bioactivity, which may be reduced by neutralizing antibodies (NAbs) against IFNbeta. The aim of the study was to analyze the kinetics of MxA mRNA expression during long-term IFNbeta treatment and assess its predictive value. METHODS: A prospective, observational, open-label, non-randomized study was designed in multiple sclerosis patients starting IFNbeta treatment. MxA mRNA was assessed prior to initiation of IFNbeta therapy and every three months subsequently. NAbs were assessed every six months. Assessment of relapses was scheduled every three months during 24 months of follow up. The disease activity was correlated to the pretreatment baseline MxA mRNA value. In NAb negative patients, clinical status was correlated to MxA mRNA values. RESULTS: 119 patients were consecutively enrolled and 107 were included in the final analysis. There was no correlation of MxA mRNA expression levels between baseline and month three. Using survival analysis, none of the selected baseline MxA mRNA cut off points allowed prediction of time to first relapse on the treatment. In NAb negative patients, mean MxA mRNA levels did not significantly differ in patients irrespective of relapse status. CONCLUSION: Baseline MxA mRNA does not predict the response to IFNbeta treatment or the clinical status of the disease and the level of MxA mRNA does not correlate with disease activity in NAb negative patients. PMID- 28081208 TI - Optimizing Training Population Size and Genotyping Strategy for Genomic Prediction Using Association Study Results and Pedigree Information. A Case of Study in Advanced Wheat Breeding Lines. AB - Wheat breeding programs generate a large amount of variation which cannot be completely explored because of limited phenotyping throughput. Genomic prediction (GP) has been proposed as a new tool which provides breeding values estimations without the need of phenotyping all the material produced but only a subset of it named training population (TP). However, genotyping of all the accessions under analysis is needed and, therefore, optimizing TP dimension and genotyping strategy is pivotal to implement GP in commercial breeding schemes. Here, we explored the optimum TP size and we integrated pedigree records and genome wide association studies (GWAS) results to optimize the genotyping strategy. A total of 988 advanced wheat breeding lines were genotyped with the Illumina 15K SNPs wheat chip and phenotyped across several years and locations for yield, lodging, and starch content. Cross-validation using the largest possible TP size and all the SNPs available after editing (~11k), yielded predictive abilities (rGP) ranging between 0.5-0.6. In order to explore the Training population size, rGP were computed using progressively smaller TP. These exercises showed that TP of around 700 lines were enough to yield the highest observed rGP. Moreover, rGP were calculated by randomly reducing the SNPs number. This showed that around 1K markers were enough to reach the highest observed rGP. GWAS was used to identify markers associated with the traits analyzed. A GWAS-based selection of SNPs resulted in increased rGP when compared with random selection and few hundreds SNPs were sufficient to obtain the highest observed rGP. For each of these scenarios, advantages of adding the pedigree information were shown. Our results indicate that moderate TP sizes were enough to yield high rGP and that pedigree information and GWAS results can be used to greatly optimize the genotyping strategy. PMID- 28081209 TI - MTHFR C677T, A1298C and MS A2756G Gene Polymorphisms and Male Infertility Risk in a Chinese Population: A Meta-Analysis. AB - BACKGROUND: Methylenetetrahydrofolate reductase gene (MTHFR C677T and A1298C) and methionine synthase gene (MS A2756G) polymorphisms have shown an association with male infertility risk in several ethnic populations. Although several studies have evaluated these associations in Chinese populations, their small sample sizes and inconsistent outcomes have prevented strong conclusions. Therefore, the present meta-analysis was performed with published studies to evaluate the associations of the three single nucleotide polymorphisms (SNPs) and male infertility in a Chinese population. METHODS: We conducted a search of PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure (CNKI), China biology medical literature (CBM), VIP, and Chinese literature (Wan Fang) databases up to May 31, 2016. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were used to assess the strength of associations with a random-effect model or a fixed-effect model based on the heterogeneity analysis results. Sensitivity analysis was used to confirm the reliability and stability of the meta-analysis. RESULTS: A total of nine studies, including 1,713 cases and 1,104 controls, were included in the meta-analysis. The pooled results indicated that the MTHFR C667T polymorphism was significantly associated with increased risk of male infertility in the Chinese population in the allele model (T vs. C: OR = 1.47, 95%CI = 1.32-1.63), the dominant model (TT + CT vs. CC: OR = 1.51, 95%CI = 1.30-1.77), the additive model (TT vs. CC: OR = 2.08, 95%CI = 1.68-2.58) and the recessive model (TT vs. CT+CC: OR = 1.58, 95%CI = 1.31-1.90), whereas the MTHFR A1298C and MS A2756G polymorphisms were not risk factors. There was no significant heterogeneity in any genotype contrasts among the studies. The sensitivity analysis indicated that the results of this meta-analysis were relatively stable. CONCLUSION: This study suggests that the MTHFR C667T polymorphism may contribute to the genetic susceptibility to male infertility in the Chinese population, whereas MTHFR A1298C and MS A2756G polymorphisms may be unrelated to male infertility. Studies with larger sample sizes and representative population-based cases and well-matched controls are needed to validate our results. PMID- 28081212 TI - Correction: A Stochastic Model of the Yeast Cell Cycle Reveals Roles for Feedback Regulation in Limiting Cellular Variability. AB - [This corrects the article DOI: 10.1371/journal.pcbi.1005230.]. PMID- 28081210 TI - Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice. AB - Orofacial clefting is amongst the most common of birth defects, with both genetic and environmental components. Although numerous studies have been undertaken to investigate the complexities of the genetic etiology of this heterogeneous condition, this factor remains incompletely understood. Here, we describe mutations in the HYAL2 gene as a cause of syndromic orofacial clefting. HYAL2, encoding hyaluronidase 2, degrades extracellular hyaluronan, a critical component of the developing heart and palatal shelf matrix. Transfection assays demonstrated that the gene mutations destabilize the molecule, dramatically reducing HYAL2 protein levels. Consistent with the clinical presentation in affected individuals, investigations of Hyal2-/- mice revealed craniofacial abnormalities, including submucosal cleft palate. In addition, cor triatriatum sinister and hearing loss, identified in a proportion of Hyal2-/- mice, were also found as incompletely penetrant features in affected humans. Taken together our findings identify a new genetic cause of orofacial clefting in humans and mice, and define the first molecular cause of human cor triatriatum sinister, illustrating the fundamental importance of HYAL2 and hyaluronan turnover for normal human and mouse development. PMID- 28081211 TI - Development and Validation of a Clinical Prediction Rule for Bacteremia among Maintenance Hemodialysis Patients in Outpatient Settings. AB - BACKGROUND: To our knowledge, no reliable clinical prediction rule (CPR) for identifying bacteremia in hemodialysis (HD) patients has been established. The aim of this study was to develop a CPR for bacteremia in maintenance HD patients visiting the outpatient department. METHODS: This multicenter cohort study involved consecutive maintenance HD patients who visited the outpatient clinic or emergency room of seven Japanese institutions between August 2011 and July 2013. The outcome measure was bacteremia diagnosed based on the results of blood cultures. The candidate predictors for bacteremia were extracted through a literature review. A CPR for bacteremia was developed using a coefficient-based multivariable logistic regression scoring method, and calibration was performed. The test performance was then assessed for the CPR. RESULTS: Of 507 patients eligible for the study, we analyzed the 293 with a complete dataset for candidate predictors. Of these 293 patients, 48 (16.4%) were diagnosed with bacteremia. At the conclusion of the deviation process, body temperature >= 38.3 degrees C, heart rate >= 125 /min, C-reactive protein >= 10 mg/dL, alkaline phosphatase >360 IU/L, and no prior antibiotics use within the past week were retained and scored. The CPR had a good fit for the model on calibration. The AUC of the CPR was 0.76, and for score CPR >= 2, the sensitivity and specificity were 89.6% and 51.4%, respectively. CONCLUSIONS: We established a simple CPR for bacteremia in maintenance HD patients using routinely obtained clinical information in an outpatient setting. This model may facilitate more appropriate clinical decision making. PMID- 28081213 TI - Transcriptome Profiling to Understand the Effect of Citrus Rootstocks on the Growth of 'Shatangju' Mandarin. AB - To obtain insight into potential mechanisms underlying the influence of rootstock on scion growth, we performed a comparative analysis of 'Shatangju' mandarin grafted onto 5 rootstocks: Fragrant orange (Citrus junons Sieb. ex. Tanaka), Red tangerine (Citrus reticulata Blanco), 'Shatangju' mandarin (Citrus reticulata Blanco), Rough lemon (Citrus jambhiri Lush) and Canton lemon (Citrus limonia Osbeck). The tree size of 'Shatangju' mandarin grafted onto Canton lemon and Rough lemon were the largest, followed by self-rooted rootstock trees, and the lowest tree sizes correspond to ones grafted on Red tangerine and Fragrant orange rootstocks. The levels of indoleacetic acid (IAA) and gibberellin (GA) were significantly and positively related to growth vigor. The differences of gene expression in leaves of trees grafted onto Red tangerine, Canton lemon and 'Shatangju' mandarin were analyzed by RNA-Seq. Results showed that more differentially expressed genes involved in oxidoreductase function, hormonal signal transduction and the glycolytic pathway were enriched in 'Red tangerine vs Canton lemon'. qRT-PCR analysis showed that expression levels of ARF1, ARF8, GH3 and IAA4 were negatively correlated with the growth vigor and IAA content. The metabolism of GA was influenced by the differential expression of KO1 and GA2OX1 in grafted trees. In addition, most of antioxidant enzyme genes were up-regulated in leaves of trees grafted onto Red tangerine, resulting in a higher peroxidase activity. We concluded that different rootstocks significantly affected the expression of genes involved in auxin signal transduction pathway and GA biosynthesis pathway in the grafted plants, and then regulated the hormone levels and their signal pathways. PMID- 28081215 TI - Genome-Wide Association Studies of Multiple Keratinocyte Cancers. AB - There is strong evidence for a role of environmental risk factors involved in susceptibility to develop multiple keratinocyte cancers (mKCs), but whether genes are also involved in mKCs susceptibility has not been thoroughly investigated. We investigated whether single nucleotide polymorphisms (SNPs) are associated with susceptibility for mKCs. A genome-wide association study (GWAS) of 1,666 cases with mKCs and 1,950 cases with single KC (sKCs; controls) from Harvard cohorts (the Nurses' Health Study [NHS], NHS II, and the Health Professionals Follow-Up Study) and the Framingham Heart Study was carried-out using over 8 million SNPs (stage-1). We sought to replicate the most significant statistical associations (p-value<= 5.5x10-6) in an independent cohort of 574 mKCs and 872 sKCs from the Rotterdam Study. In the discovery stage, 40 SNPs with suggestive associations (p value <=5.5x10-6) were identified, with eight independent SNPs tagging all 40 SNPs. The most significant SNP was located at chromosome 9 (rs7468390; p-value = 3.92x10-7). In stage-2, none of these SNPs replicated and only two of them were associated with mKCs in the same direction in the combined meta-analysis. We tested the associations for 19 previously reported basal cell carcinoma-related SNPs (candidate gene association analysis), and found that rs1805007 (MC1R locus) was significantly associated with risk of mKCs (p-value = 2.80x10-4). Although the suggestive SNPs with susceptibility for mKCs were not replicated, we found that previously identified BCC variants may also be associated with mKC, which the most significant association (rs1805007) located at the MC1R gene. PMID- 28081216 TI - Real-Time Monitoring of Placental Oxygenation during Maternal Hypoxia and Hyperoxygenation Using Photoacoustic Imaging. AB - PURPOSE: This preclinical study aimed to evaluate placental oxygenation in pregnant rats by real-time photoacoustic (PA) imaging on different days of gestation and to specify variations in placental oxygen saturation under conditions of maternal hypoxia and hyperoxygenation. MATERIAL AND METHODS: Placentas of fifteen Sprague-Dawley rats were examined on days 14, 17, and 20 of pregnancy with a PA imaging system coupled to high-resolution ultrasound imaging. Pregnant rats were successively exposed to hyperoxygenated and hypoxic conditions by changing the oxygen concentration in inhaled gas. Tissue oxygen saturation was quantitatively analyzed by real-time PA imaging in the skin and 3 regions of the placenta. All procedures were performed in accordance with applicable ethical guidelines and approved by the animal care committee. RESULTS: Maternal hypoxia was associated with significantly greater decrease in blood oxygen saturation (DeltaO2 Saturation) in the skin (70.74% +/-7.65) than in the mesometrial triangle (32.66% +/-5.75) or other placental areas (labyrinth: 18.58% +/- 6.61; basal zone: 13.13% +/-5.72) on different days of pregnancy (P<0.001). DeltaO2 Saturation did not differ significantly between the labyrinth, the basal zone, and the decidua. After the period of hypoxia, maternal hyperoxygenation led to a significant rise in oxygen saturation, which returned to its initial values in the different placental regions (P<0.001). CONCLUSIONS: PA imaging enables the variation of blood oxygen saturation to be monitored in the placenta during maternal hypoxia or hyperoxygenation. This first preclinical study suggests that the placenta plays an important role in protecting the fetus against maternal hypoxia. PMID- 28081214 TI - Cold Pressor Stress Cardiac Magnetic Resonance Myocardial Flow Reserve Is Not Useful for Detection of Coronary Endothelial Dysfunction in Women with Signs and Symptoms of Ischemia and No Obstructive CAD. AB - BACKGROUND: Coronary endothelial function testing using acetylcholine is not routinely available, while non-pharmacological cold pressor testing (CPT) is considered an endothelial stressor. Noninvasive cardiac magnetic resonance imaging (CMRI) myocardial perfusion reserve index (MPRI) can detect coronary microvascular dysfunction (CMD). We evaluated if CPT stress CMRI MPRI could detect invasive coronary endothelial dysfunction. METHODS: Coronary reactivity testing was performed in 189 women with symptoms and signs of ischemic but no obstructive coronary artery disease as previously described plus CPT stress. Subjects also underwent pharmacologic and CPT stress during CMRI (1.5 T). Statistical analysis comparing CPT MPRI between groups was performed by Welch's t test and Mann-Whitney where appropriate. Anderson-Darling test and Levene test were considered to verify the normality and homogeneity of variances assumptions. Correlation analyses between CPT MPRI and both invasive and noninvasive measures of CMD were performed using Spearman correlation. RESULTS: While CPT MPRI correlated with pharmacological stress MPRI, it did not correlate with invasive measures of CMD including invasively measured responses to intracoronary (IC) adenosine, IC acetylcholine, CPT, or IC nitroglycerin. Additionally CPT MPRI was not significantly different between subjects with normal compared to abnormal pharm stress MPRI or normal compared to abnormal invasive CMD parameters. CONCLUSION: Despite correlation with pharmacological stress MPRI, non-invasive CPT MPRI does not appear to be useful for detecting CMD in symptomatic women. PMID- 28081217 TI - Collective Genetic Interaction Effects and the Role of Antigen-Presenting Cells in Autoimmune Diseases. AB - Autoimmune diseases occur when immune cells fail to develop or lose their tolerance toward self and destroy body's own tissues. Both insufficient negative selection of self-reactive T cells and impaired development of regulatory T cells preventing effector cell activation are believed to contribute to autoimmunity. Genetic predispositions center around the major histocompatibility complex (MHC) class II loci involved in antigen presentation, the key determinant of CD4+ T cell activation. Recent studies suggested that variants in the MHC region also exhibit significant non-additive interaction effects. However, collective interactions involving large numbers of single nucleotide polymorphisms (SNPs) contributing to such effects are yet to be characterized. In addition, relatively little is known about the cell-type-specificity of such interactions in the context of cellular pathways. Here, we analyzed type 1 diabetes (T1D) and rheumatoid arthritis (RA) genome-wide association data sets via large-scale, high performance computations and inferred collective interaction effects involving MHC SNPs using the discrete discriminant analysis. Despite considerable differences in the details of SNP interactions in T1D and RA data, the enrichment pattern of interacting pairs in reference epigenomes was remarkably similar: statistically significant interactions were epigenetically active in cell-type combinations connecting B cells to T cells and intestinal epithelial cells, with both helper and regulatory T cells showing strong disease-associated interactions with B cells. Our results provide direct genetic evidence pointing to the important roles B cells play as antigen-presenting cells toward CD4+ T cells in the context of central and peripheral tolerance. In addition, they are consistent with recent experimental studies suggesting that the repertoire of B cell specific self-antigens in the thymus are critical to the effective control of corresponding autoimmune activation in peripheral tissues. PMID- 28081219 TI - Correction: A Novel Diphenylthiosemicarbazide Is a Potential Insulin Secretagogue for Anti-Diabetic Agent. AB - [This corrects the article DOI: 10.1371/journal.pone.0164785.]. PMID- 28081218 TI - Adiponectin Signaling Regulates Lipid Production in Human Sebocytes. AB - Adiponectin plays important roles in metabolic function, inflammation and multiple biological activities in various tissues. However, evidence for adiponectin signaling in sebaceous glands is lacking, and its role remains to be clarified. This study investigated the role of adiponectin in lipid production in sebaceous glands in an experimental study of human sebocytes. We demonstrated that human sebaceous glands in vivo and sebocytes in vitro express adiponectin receptor and that adiponectin increased cell proliferation. Moreover, based on a lipogenesis study using Oil Red O, Nile red staining and thin layer chromatography, adiponectin strongly upregulated lipid production in sebocytes. In three-dimensional culture of sebocytes, lipid synthesis was markedly enhanced in sebocytes treated with adiponectin. This study suggested that adiponectin plays a significant role in human sebaceous gland biology. Adiponectin signaling is a promising target in the clinical management of barrier disorders in which sebum production is decreased, such as in atopic dermatitis and aged skin. PMID- 28081220 TI - Correction: Hierarchy of Dysfunction Related to Dressing Performance in Stroke Patients: A Path Analysis Study. AB - [This corrects the article DOI: 10.1371/journal.pone.0151162.]. PMID- 28081221 TI - Dietary Lipid Sources Influence Fatty Acid Composition in Tissue of Large Yellow Croaker (Larmichthys crocea) by Regulating Triacylglycerol Synthesis and Catabolism at the Transcriptional Level. AB - An 8-week feeding trial was conducted to evaluate the effects of dietary lipid sources on growth performance, fatty acid composition, rate-limiting enzyme activities and gene expression related to lipid metabolism in large yellow croaker (Larmichthys crocea). Five iso-nitrogenous and iso-lipidic experimental diets were formulated to contain different lipid sources, such as fish oil (FO), soybean oil (SO), linseed oil (LO), rapeseed oil (RO) and peanut oil (PO), respectively. Triplicate groups of 50 fish (initial weight 13.77+/-0.07g) were stocked in 15 floating net cages (1.5m*1.5m*2.0m). Fish fed the diets containing RO and LO had lower weight gain and specific growth rates than those fed the FO, SO and PO diets. Survival, feed efficiency, protein efficiency ratio, hepatosomatic index, viscerasomatic index and condition factor were not significantly affected by different dietary lipid sources. Fish fed the diet containing FO had higher lipid content in whole body compared with the other groups, whereas fish fed the SO diet had the lowest muscle lipid content. Fatty acid profiles of muscle and liver reflected the fatty acid composition of the diets. Plasma glucose, triglyceride, and the enzymatic activity of aspartate aminotransferase and alanine aminotransferase were significantly influenced by different dietary lipid sources, while total protein, cholesterol, superoxide dismutase or malondialdehyde in plasma were not affected by the different dietary lipid sources. Fish fed the LO diet had lower adipose triglyceride lipase and fatty acid synthase activities in liver than those fed the diets containing FO and RO, while the LO diet resulted in the highest hepatic carnitine palmitoultransferase-1 activity. Hepatic gene relative expression of adipose triglyceride lipase and carnitine palmitoyltransferase-1 in fish fed PO diet was significantly higher than all other groups, whereas fish fed the SO and LO diets had lower relative expression levels of lipoprotein lipase than the other groups. The highest relative expression levels of fatty acid synthase and acyl-CoA diacylglycerol acyltransferase-2 were observed in the FO group, while the highest relative expression of glucose 6-phosphate dehydrogenase occurred in fish fed the FO and RO diets. In summary, based on the growth performance, FO and SO appear to be suitable lipid sources for large yellow croaker, with the findings of this study also providing a molecular insight into the role of lipid metabolic mechanism in response to different dietary lipid sources. PMID- 28081222 TI - AT7867 Inhibits Human Colorectal Cancer Cells via AKT-Dependent and AKT Independent Mechanisms. AB - AKT is often hyper-activated in human colorectal cancers (CRC). This current study evaluated the potential anti-CRC activity by AT7867, a novel AKT and p70S6K1 (S6K1) dual inhibitor. We showed that AT7867 inhibited survival and proliferation of established (HT-29, HCT116 and DLD-1 lines) and primary human CRC cells. Meanwhile, it provoked caspase-dependent apoptosis in the CRC cells. Molecularly, AT7867 blocked AKT-S6K1 activation in CRC cells. Restoring AKT-S6K1 activation, via expression of a constitutively-active AKT1 ("ca-AKT1"), only partially attenuated AT7867-induced HT-29 cell death. Further studies demonstrated that AT7867 inhibited sphingosine kinase 1 (SphK1) activity to promote pro-apoptotic ceramide production in HT-29 cells. Such effects by AT7867 were independent of AKT inhibition. AT7867-indued ceramide production and subsequent HT-29 cell apoptosis were attenuated by co-treatment of sphingosine-1 phosphate (S1P), but were potentiated with the glucosylceramide synthase (GCS) inhibitor PDMP. In vivo, intraperitoneal injection of AT7867 inhibited HT-29 xenograft tumor growth in nude mice. AKT activation was also inhibited in AT7867 treated HT-29 tumors. Together, the preclinical results suggest that AT7867 inhibits CRC cells via AKT-dependent and -independent mechanisms. PMID- 28081223 TI - High-Intensity Jump Training Is Tolerated during 60 Days of Bed Rest and Is Very Effective in Preserving Leg Power and Lean Body Mass: An Overview of the Cologne RSL Study. AB - PURPOSE: Space agencies are looking for effective and efficient countermeasures for the degrading effects of weightlessness on the human body. The aim of this study was to assess the effects of a novel jump exercise countermeasure during bed rest on vitals, body mass, body composition, and jump performance. METHODS: 23 male participants (29+/-6 years, 181+/-6 cm, 77+/-7 kg) were confined to a bed rest facility for 90 days: a 15-day ambulatory measurement phase, a 60-day six degree head-down-tilt bed rest phase (HDT), and a 15-day ambulatory recovery phase. Participants were randomly allocated to the jump training group (JUMP, n = 12) or the control group (CTRL, n = 11). A typical training session consisted of 4x10 countermovement jumps and 2x10 hops in a sledge jump system. The training group had to complete 5-6 sessions per week. RESULTS: Peak force for the reactive hops (3.6+/-0.4 kN) as well as jump height (35+/-4 cm) and peak power (3.1+/-0.2 kW) for the countermovement jumps could be maintained over the 60 days of HDT. Lean body mass decreased in CTRL but not in JUMP (-1.6+/-1.9 kg and 0+/-1.0 kg, respectively, interaction effect p = 0.03). Resting heart rate during recovery was significantly increased for CTRL but not for JUMP (interaction effect p<0.001). CONCLUSION: Participants tolerated the near-daily high-intensity jump training and maintained high peak forces and high power output during 60 days of bed rest. The countermeasure was effective in preserving lean body mass and partly preventing cardiac deconditioning with only several minutes of training per day. PMID- 28081224 TI - Resveratrol Impairs Glioma Stem Cells Proliferation and Motility by Modulating the Wnt Signaling Pathway. AB - Glioblastoma multiforme (GBM) is a grade IV astrocytoma and the most common form of malignant brain tumor in adults. GBM remains one of the most fatal and least successfully treated solid tumors: current therapies provide a median survival of 12-15 months after diagnosis, due to the high recurrence rate. Glioma Stem Cells (GSCs) are believed to be the real driving force of tumor initiation, progression and relapse. Therefore, better therapeutic strategies GSCs-targeted are needed. Resveratrol is a polyphenolic phytoalexin found in fruits and vegetables displaying pleiotropic health benefits. Many studies have highlighted its chemo preventive and chemotherapeutic activities in a wide range of solid tumors. In this work, we analyzed the effects of Resveratrol exposure on cell viability, proliferation and motility in seven GSC lines isolated from GBM patients. For the first time in our knowledge, we investigated Resveratrol impact on Wnt signaling pathway in GSCs, evaluating the expression of seven Wnt signaling pathway-related genes and the protein levels of c-Myc and beta-catenin. Finally, we analyzed Twist1 and Snail1 protein levels, two pivotal activators of epithelial mesenchymal transition (EMT) program. Results showed that although response to Resveratrol exposure was highly heterogeneous among GSC lines, generally it was able to inhibit cell proliferation, increase cell mortality, and strongly decrease cell motility, modulating the Wnt signaling pathway and the EMT activators. Treatment with Resveratrol may represent a new interesting therapeutic approach, in order to affect GSCs proliferation and motility, even if further investigations are needed to deeply understand the GSCs heterogeneous response. PMID- 28081225 TI - Fighting Ebola: A Window for Vaccine Re-evaluation? PMID- 28081226 TI - Regional Homogeneity Changes in Nicotine Addicts by Resting-State fMRI. AB - OBJECTIVE: To reveal the brain functional changes of nicotine addicts compared with those of non-smokers and explore the objective biomarker for nicotine dependence evaluation. METHODS: A total of 14 smokers and 11 non-smoking controls were recruited for this study. Resting-state functional magnetic resonance imaging and regional homogeneity (ReHo) were applied in the neural activity analysis. Two-sample t-test was performed to examine the voxel-wise difference between the smokers and the controls. Correlation analysis between the ReHo values and the Fagerstrom Test for Nicotine Dependence (FTND) scores were performed to explore the biomarkers for the clinical characteristics of smokers. RESULTS: The ReHo values from the right superior frontal gyrus of the Brodmann's area (BA) 9 to the right middle frontal gyrus and the ReHo value from the left and right precuneus (BA 23) to the left and right middle cingulum gyrus were lower in the smokers than in the non-smokers. The ReHo value in the precuneus (BA 23) was significantly and positively correlated with the FTND score of smokers. CONCLUSION: The ReHo values in the right superior frontal gyrus and left precuneus can be used to separate the smokers from the non-smokers. In particular, the left precuneus is a potential neuroimaging biomarker for nicotine addicts. PMID- 28081227 TI - Diagnostic Accuracy of GeneXpert MTB/RIF Assay in Comparison to Conventional Drug Susceptibility Testing Method for the Diagnosis of Multidrug-Resistant Tuberculosis. AB - Xpert MTB/RIF assay is regarded as a great achievement of modern medicine for the rapid diagnosis of multidrug-resistant tuberculosis (MDR-TB). The main purpose of this study was to determine the performance of Xpert MTB/RIF assay compared to conventional drug susceptibility testing (DST) method for the diagnosis of MDR TB. A comparative cross sectional study was carried out at German-Nepal Tuberculosis Project, Kathmandu, Nepal, from April 2014 to September 2014. A total of 88 culture positive clinical samples (83 pulmonary and 5 extra pulmonary) received during the study period were analyzed for detection of multidrug-resistant tuberculosis by both GeneXpert MTB/RIF assay and conventional DST method. McNemar chi square test was used to compare the performance of Xpert with that of DST method. A p-value of less than 0.05 was considered as statistically significant. Of total 88 culture positive samples, one was reported as invalid while 2 were found to contain nontuberculous Mycobacteria (NTM). Among remaining 85 Mycobacterium tuberculosis culture positive samples, 69 were found to be MDR-TB positive by both methods. The overall sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of GeneXpert MTB/RIF assay were found to be 98.6%, 100%, 100% and 93.8% respectively. Statistically, there was no significant difference between the diagnostic performance of Xpert and conventional DST method for detection of MDR-TB. GeneXpert MTB/RIF assay was found to be highly sensitive, specific and comparable to gold standard conventional DST method for the diagnosis of MDR-TB. PMID- 28081228 TI - Resistance for Genotoxic Damage in Mesenchymal Stromal Cells Is Increased by Hypoxia but Not Generally Dependent on p53-Regulated Cell Cycle Arrest. AB - Adult stem cells including multipotent mesenchymal stromal cells (MSC) acquire a high amount of DNA-damage due to their prolonged lifespan. MSC may exert specific mechanisms of resistance to avoid loss of functional activity. We have previously shown that resistance of MSC is associated with an induction of p53 and proliferation arrest upon genotoxic damage. Hypoxia may also contribute to resistance in MSC due to the low oxygen tension in the niche. In this study we characterized the role of p53 and contribution of hypoxia in resistance of MSC to genotoxic damage. MSC exhibited increased resistance to cisplatin induced DNA damage. This resistance was associated with a temporary G2/M cell cycle arrest, induction of p53- and p21-expression and reduced cyclin B / cdk1-levels upon subapoptotic damage. Resistance of MSC to cisplatin was increased at hypoxic conditions i. e. oxygen <0.5%. However, upon hypoxia the cisplatin-induced cell cycle arrest and expression of p53 and p21 were abrogated. MSC with shRNA mediated p53 knock-down showed a reduced cell cycle arrest and increased cyclin B / cdk1 expression. However, this functional p53 knock down did not alter the resistance to cisplatin. In contrast to cisplatin, functional p53-knock-down increased the resistance of MSC to etoposide. We conclude that resistance of MSC to genotoxic damage is influenced by oxygen tension but is not generally dependent on p53. Thus, p53-dependent and p53-independent mechanisms of resistance are likely to contribute to the life-long functional activity of MSC in vivo. These findings indicate that hypoxia and different resistance pathways contribute to the phenotype that enables the prolonged lifespan of MSC. PMID- 28081229 TI - Statistical Parametric Mapping to Identify Differences between Consensus-Based Joint Patterns during Gait in Children with Cerebral Palsy. AB - Experts recently identified 49 joint motion patterns in children with cerebral palsy during a Delphi consensus study. Pattern definitions were therefore the result of subjective expert opinion. The present study aims to provide objective, quantitative data supporting the identification of these consensus-based patterns. To do so, statistical parametric mapping was used to compare the mean kinematic waveforms of 154 trials of typically developing children (n = 56) to the mean kinematic waveforms of 1719 trials of children with cerebral palsy (n = 356), which were classified following the classification rules of the Delphi study. Three hypotheses stated that: (a) joint motion patterns with 'no or minor gait deviations' (n = 11 patterns) do not differ significantly from the gait pattern of typically developing children; (b) all other pathological joint motion patterns (n = 38 patterns) differ from typically developing gait and the locations of difference within the gait cycle, highlighted by statistical parametric mapping, concur with the consensus-based classification rules. (c) all joint motion patterns at the level of each joint (n = 49 patterns) differ from each other during at least one phase of the gait cycle. Results showed that: (a) ten patterns with 'no or minor gait deviations' differed somewhat unexpectedly from typically developing gait, but these differences were generally small (<=3 degrees ); (b) all other joint motion patterns (n = 38) differed from typically developing gait and the significant locations within the gait cycle that were indicated by the statistical analyses, coincided well with the classification rules; (c) joint motion patterns at the level of each joint significantly differed from each other, apart from two sagittal plane pelvic patterns. In addition to these results, for several joints, statistical analyses indicated other significant areas during the gait cycle that were not included in the pattern definitions of the consensus study. Based on these findings, suggestions to improve pattern definitions were made. PMID- 28081230 TI - Characteristics of HIV-Infected Children at Enrollment into Care and at Antiretroviral Therapy Initiation in Central Africa. AB - BACKGROUND: Despite the World Health Organization (WHO) regularly updating guidelines to recommend earlier initiation of antiretroviral therapy (ART) in children, timely enrollment into care and initiation of ART in sub-Saharan Africa in children lags behind that of adults. The impact of implementing increasingly less restrictive ART guidelines on ART initiation in Central Africa has not been described. MATERIALS AND METHODS: Data are from the Central Africa International Epidemiologic Databases to Evaluate AIDS (IeDEA) pediatric cohort of 3,426 children (0-15 years) entering HIV care at 15 sites in Burundi, DRC, and Rwanda. Measures include CD4 count, WHO clinical stage, age, and weight-for-age Z score (WAZ), each at enrollment into HIV care and at ART initiation. Changes in the medians or proportions of each measure by year of enrollment and year of ART initiation were assessed to capture potential impacts of changing ART guidelines. RESULTS: Median age at care enrollment decreased from 77.2 months in 2004-05 to 30.3 months in 2012-13. The median age at ART initiation (n = 2058) decreased from 83.0 months in 2004-05 to 66.9 months in 2012-13. The proportion of children <=24 months of age at enrollment increased from 12.7% in 2004-05 to 46.7% in 2012 13, and from 9.6% in 2004-05 to 24.2% in 2012-13 for ART initiation. The median CD4 count at enrollment into care increased from 563 (IQR: 275, 901) in 2004-05 to 660 (IQR: 339, 1071) cells/MUl in 2012-13, and the median CD4 count at ART initiation increased from 310 (IQR:167, 600) in 2004-05 to 589 (IQR: 315, 1113) cells/MUl in 2012-13. From 2004-05 to 2012-13, median WAZ improved from -2 (IQR: 3.4, -1.1) to -1 (IQR: -2.5, -0.2) at enrollment in care and from -2 (IQR: -3.8, 1.6) to -1 (IQR: -2.6, -0.4) at ART initiation. DISCUSSION AND CONCLUSION: Although HIV-infected children <=24 months of age accounted for half of all children enrolling in care in our cohort during 2012-13, they represented less than a quarter of all those who were initiated on ART during the same period. Further research is needed to identify barriers to timely diagnosis, linkage to care, and initiation of ART among children with HIV infection. PMID- 28081231 TI - Physical Activity, Energy Expenditure, Nutritional Habits, Quality of Sleep and Stress Levels in Shift-Working Health Care Personnel. AB - BACKGROUND: Among health care personnel working regular hours or rotating shifts can affect parameters of general health and nutrition. We have investigated physical activity, sleep quality, metabolic activity and stress levels in health care workers from both groups. METHODS: We prospectively recruited 46 volunteer participants from the workforce of a University Medical Department of which 23 worked in rotating shifts (all nursing) and 21 non-shift regular hours (10 nursing, 13 clerical staff). All were investigated over 7 days by multisensory accelerometer (SenseWear Bodymedia(r) armband) and kept a detailed food diary. Physical activity and resting energy expenditure (REE) were measured in metabolic equivalents of task (METs). Quality of sleep was assessed as Pittsburgh Sleeping Quality Index and stress load using the Trier Inventory for Chronic Stress questionnaire (TICS). RESULTS: No significant differences were found for overall physical activity, steps per minute, time of exceeding the 3 METs level or sleep quality. A significant difference for physical activity during working hours was found between shift-workers vs. non-shift-workers (p<0.01) and for shift-working nurses (median = 2.1 METs SE = 0.1) vs. non-shift-working clerical personnel (median = 1.5 METs SE = 0.07, p<0.05). Non-shift-working nurses had a significantly lower REE than the other groups (p<0.05). The proportion of fat in the diet was significantly higher (p<0.05) in the office worker group (median = 42% SE = 1.2) whereas shift-working nurses consumed significantly more carbohydrates (median = 46% SE = 1.4) than clerical staff (median = 41% SE = 1.7). Stress assessment by TICS confirmed a significantly higher level of social overload in the shift working group (p<0.05). CONCLUSION: In this prospective cohort study shift-working had no influence on overall physical activity. Lower physical activity during working hours appears to be compensated for during off hours. Differences in nutritional habits and stress load warrant larger scale trials to determine the effect on implicit health-associated conditions. PMID- 28081232 TI - Correction: Population Screening Using Sewage Reveals Pan-Resistant Bacteria in Hospital and Community Samples. AB - [This corrects the article DOI: 10.1371/journal.pone.0164873.]. PMID- 28081233 TI - Differences in Inflammatory Response Induced by Two Representatives of Clades of the Pandemic ST258 Klebsiella pneumoniae Clonal Lineage Producing KPC-Type Carbapenemases. AB - ST258-K. pneumoniae (ST258-KP) strains, the most widespread multidrug-resistant hospital-acquired pathogens, belong to at least two clades differing in a 215 Kb genomic region that includes the cluster of capsule genes. To investigate the effects of the different capsular phenotype on host-pathogen interactions, we studied representatives of ST258-KP clades, KKBO-1 and KK207-1, for their ability to activate monocytes and myeloid dendritic cells from human immune competent hosts. The two ST258-KP strains strongly induced the production of inflammatory cytokines. Significant differences between the strains were found in their ability to induce the production of IL-1beta: KK207-1/clade I was much less effective than KKBO-1/clade II in inducing IL-1beta production by monocytes and dendritic cells. The activation of NLRP3 inflammasome pathway by live cells and/or purified capsular polysaccharides was studied in monocytes and dendritic cells. We found that glibenclamide, a NLRP3 inhibitor, inhibits more than 90% of the production of mature IL-1beta induced by KKBO1 and KK207-1. KK207-1 was always less efficient compared to KKBO-1 in: a) inducing NLRP3 and pro-IL-1beta gene and protein expression; b) in inducing caspase-1 activation and pro-IL-1beta cleavage. Capsular composition may play a role in the differential inflammatory response induced by the ST258-KP strains since capsular polysaccharides purified from bacterial cells affect NLRP3 and pro-IL-1beta gene expression through p38MAPK- and NF-kappaB-mediated pathways. In each of these functions, capsular polysaccharides from KK207-1 were significantly less efficient compared to those purified from KKBO-1. On the whole, our data suggest that the change in capsular phenotype may help bacterial cells of clade I to partially escape innate immune recognition and IL-1beta-mediated inflammation. PMID- 28081234 TI - Racial and Ethnic Disparities in Influenza Vaccination among Adults with Chronic Medical Conditions Vary by Age in the United States. AB - BACKGROUND: People living with chronic health conditions exhibit higher risk for developing severe complications from influenza according to the Centers for Diseases Control and Prevention. Although racial and ethnic disparities in influenza vaccination have been documented, it has not been comprehensively determined whether similar disparities are present among the adult population with at least one such condition. OBJECTIVE: To study if racial and ethnic disparities in relation to influenza vaccination are present in adults suffering from at least one chronic condition and if such inequalities differ between age groups. METHODS: The Medical Expenditure Panel Survey (2011-2012) was used to study the adult population (age >=18) who had at least one chronic health condition. Baseline differences in population traits across racial and ethnic groups were identified using a chi-square test. This was conducted among various age groups. In addition, survey logistic regression was utilized to produce odds ratios of receiving influenza vaccination annually between racial and ethnic groups. RESULTS: The total sample consisted of 15,499 adults living with at least one chronic health condition. The numbers of non-Hispanic whites (whites), non Hispanic blacks (blacks), and Hispanics were 8,658, 3,585, and 3,256, respectively. Whites (59.93%) were found to have a higher likelihood of self reporting their receipt of the influenza vaccine in comparison to the black (48.54%) and Hispanic (48.65%) groups (P<0.001). When examining persons aged 50 64 years and >=65 years, it was noted that the black (54.99%, 62.72%) and Hispanic (53.54%, 64.48%) population had lower rates of influenza vaccine coverage than the white population (59.22%, 77.89) (both P<0.0001). No significant differences between whites and the blacks or Hispanics were found among the groups among adults between 18 and 49 inclusive (P>0.05). After controlling for patient characteristics, the difference in influenza vaccine coverage between whites and the minority groups were no longer significant for adults aged 50-64 years. However, the difference were still statistically significant for those aged >=65 years. CONCLUSIONS: In the United States, there are significant disparities in influenza vaccination by race and ethnicity for adults over 65 years with at least one chronic health condition. Future research is needed to help develop more targeted interventions to address these issues and improve influenza vaccination rates. PMID- 28081235 TI - Comprehensive RNA-Seq Profiling to Evaluate the Sheep Mammary Gland Transcriptome in Response to Experimental Mycoplasma agalactiae Infection. AB - Mycoplasma agalactiae is a worldwide serious pathogen of small ruminants that usually spreads through the mammary route causing acute to subacute mastitis progressing to chronic persistent disease that is hard to eradicate. Knowledge of mechanisms of its pathogenesis and persistence in the mammary gland are still insufficient, especially the host-pathogen interplay that enables it to reside in a chronic subclinical state. This study reports transcriptome profiling of mammary tissue from udders of sheep experimentally infected with M. agalactiae type strain PG2 in comparison with uninfected control animals using Illumina RNA sequencing (RNA-Seq). Several differentially expressed genes (DEGs) were observed in the infected udders and RT-qPCR analyses of selected DEGs showed their expression profiles to be in agreement with results from RNA-Seq. Gene Ontology (GO) analysis revealed majority of the DEGs to be associated with mycoplasma defense responses that are directly or indirectly involved in host innate and adaptive immune responses. Similar RNA-Seq analyses were also performed with spleen cells of the same sheep to know the specific systemic transcriptome responses. Spleen cells exhibited a comparatively lower number of DEGs suggesting a less prominent host response in this organ. To our knowledge this is the first study that describes host transcriptomics of M. agalactiae infection and the related immune-inflammatory responses. The data provides useful information to further dissect the molecular genetic mechanisms underlying mycoplasma mastitis, which is a prerequisite for designing effective intervention strategies. PMID- 28081236 TI - A Key Marine Diazotroph in a Changing Ocean: The Interacting Effects of Temperature, CO2 and Light on the Growth of Trichodesmium erythraeum IMS101. AB - Trichodesmium is a globally important marine diazotroph that accounts for approximately 60 - 80% of marine biological N2 fixation and as such plays a key role in marine N and C cycles. We undertook a comprehensive assessment of how the growth rate of Trichodesmium erythraeum IMS101 was directly affected by the combined interactions of temperature, pCO2 and light intensity. Our key findings were: low pCO2 affected the lower temperature tolerance limit (Tmin) but had no effect on the optimum temperature (Topt) at which growth was maximal or the maximum temperature tolerance limit (Tmax); low pCO2 had a greater effect on the thermal niche width than low-light; the effect of pCO2 on growth rate was more pronounced at suboptimal temperatures than at supraoptimal temperatures; temperature and light had a stronger effect on the photosynthetic efficiency (Fv/Fm) than did CO2; and at Topt, the maximum growth rate increased with increasing CO2, but the initial slope of the growth-irradiance curve was not affected by CO2. In the context of environmental change, our results suggest that the (i) nutrient replete growth rate of Trichodesmium IMS101 would have been severely limited by low pCO2 at the last glacial maximum (LGM), (ii) future increases in pCO2 will increase growth rates in areas where temperature ranges between Tmin to Topt, but will have negligible effect at temperatures between Topt and Tmax, (iii) areal increase of warm surface waters (> 18 degrees C) has allowed the geographic range to increase significantly from the LGM to present and that the range will continue to expand to higher latitudes with continued warming, but (iv) continued global warming may exclude Trichodesmium spp. from some tropical regions by 2100 where temperature exceeds Topt. PMID- 28081237 TI - Co-Occurrence of Asthma and Nephrolithiasis in Children. AB - It has been proposed that epithelial dysfunction and inflammation may predispose patients to kidney stone formation. Asthma is another chronic condition related to epithelial dysfunction and inflammation. We hypothesized that pediatric patients with asthma would have an increased prevalence of nephrolithiasis. Furthermore, we investigated if asthma patients with nephrolithiasis have clinical characteristics and urine profiles that point to mechanisms of stone formation. We evaluated 865 pediatric patients who had a diagnosis of nephrolithiasis. Clinical/demographic data and 24 hour urine samples were compared between asthma + stone (n = 142) and stone only patients. Data from asthmatics without stone were also available for evaluation of medication differences among asthma + stone and asthma only patients. The prevalence of nephrolithiasis in the pediatric population at our institution was 0.08% vs. 0.31% in our pediatric asthmatic population. The prevalence of asthma in our pediatric population was 6.8% vs. 26.7% in our pediatric stone patients. Asthma + stone patients were more likely to be on a combination inhaled corticosteroid + long acting beta agonist inhaler as compared to age/gender/BMI matched asthma patients without stone (29.7% vs. 13.7%, p = 0.0012). 259 kidney stone patients had 24 hour urine samples for comparison. There was no difference in 24 hour urine profiles between asthma + stone and stone only patients. Children with asthma have a 4-fold greater prevalence of kidney stones than the general pediatric population. Similarly, children with kidney stones have a 4-fold greater prevalence of asthma. This correlation may suggest a mechanistic link between asthma and nephrolithiasis. Further investigation is needed to elucidate the pathophysiologic origin of this relationship. PMID- 28081238 TI - Genomic Organization of Repetitive DNA in Woodpeckers (Aves, Piciformes): Implications for Karyotype and ZW Sex Chromosome Differentiation. AB - Birds are characterized by a low proportion of repetitive DNA in their genome when compared to other vertebrates. Among birds, species belonging to Piciformes order, such as woodpeckers, show a relatively higher amount of these sequences. The aim of this study was to analyze the distribution of different classes of repetitive DNA-including microsatellites, telomere sequences and 18S rDNA-in the karyotype of three Picidae species (Aves, Piciformes)-Colaptes melanochloros (2n = 84), Colaptes campestris (2n = 84) and Melanerpes candidus (2n = 64)-by means of fluorescence in situ hybridization. Clusters of 18S rDNA were found in one microchromosome pair in each of the three species, coinciding to a region of (CGG)10 sequence accumulation. Interstitial telomeric sequences were found in some macrochromosomes pairs, indicating possible regions of fusions, which can be related to variation of diploid number in the family. Only one, from the 11 different microsatellite sequences used, did not produce any signals. Both species of genus Colaptes showed a similar distribution of microsatellite sequences, with some difference when compared to M. candidus. Microsatellites were found preferentially in the centromeric and telomeric regions of micro and macrochromosomes. However, some sequences produced patterns of interstitial bands in the Z chromosome, which corresponds to the largest element of the karyotype in all three species. This was not observed in the W chromosome of Colaptes melanochloros, which is heterochromatic in most of its length, but was not hybridized by any of the sequences used. These results highlight the importance of microsatellite sequences in differentiation of sex chromosomes, and the accumulation of these sequences is probably responsible for the enlargement of the Z chromosome. PMID- 28081239 TI - Statistical Modeling Applied to Deformation-Relaxation Processes in a Composite Biopolymer Network Induced by Magnetic Field. AB - This study investigated a methodology based on image processing and statistics to characterize and model the deformation upon controlled and uniform magnetic field and the relaxation under zero field of droplets observed in aqueous solutions of sodium alginate incorporating magnetic maghemite nanoparticles stabilized by adsorption of citrate ions. The changes of droplet geometry were statistically analyzed using a new approach based on the data obtained from optical microscopy, image processing, nonlinear regression, evolutionary optimization, analysis of variance and resampling. Image enhancement and then image segmentation (Gaussian mixture modeling) processes were applied to extract features with reliable information of droplets dimensions from optical micrographs. The droplets deformation and relaxation trends were accurately adjusted by the Kohlrausch Williams-Watts (KWW) function and a mean relaxation time was obtained by fitting the time evolution of geometry parameters. It was found to be proportional to the initial radius of the spherical droplets and was associated to interfacial tension. PMID- 28081240 TI - Oropharyngeal Candidiasis: Fungal Invasion and Epithelial Cell Responses. PMID- 28081241 TI - CD25+CD127+Foxp3- Cells Represent a Major Subpopulation of CD8+ T Cells in the Eye Chambers of Normal Mice. AB - The aim of this study has been to determine whether eye chambers constitute part of the normal migratory pathway of naive CD4+ and CD8+ T cells in mouse and if natural CD4+CD25+Foxp3+ and CD8+CD25+Foxp3+ regulatory T cells are present within these eye compartments. To this aim, the cells obtained from aqueous humor (AH) of normal mice were phenotyped in terms of the expression CD4, CD8, CD25, CD127 and transcription factor Foxp3. The mean percentage of CD8+ T cells in the total AH lymphocyte population was as high as 28.69%; the mean percentage of CD8high and CD8low cells in this population was 34.09% and 65.91%, respectively. The presence of cells with the regulatory phenotype, i.e. CD25+Foxp3+ cells, constituted only 0.32% of CD8+ T cell subset. Regarding the expression of CD25, AH CD8+ T cells were an exceptional population in that nearly 85% of these cells expressed this molecule without concomitant Foxp3 expression. Despite having this phenotype, they should not be viewed as activated cells because most of them co expressed CD127, which indicates that they are naive lymphocytes. With regard to the markers applied in the present research, CD8+CD25+CD127+Foxp3- T cells represent the most numerous subset of AH CD8+ cells. The results suggest that eye chambers in mice are an element in the normal migratory pathway of naive CD8+ T cells. The study presented herein demonstrated only trace presence of CD4+ cells in the eye chambers, as the mean percentage of these cells was just 0.56. Such selective and specific homing of CD8+ and CD4+ cells to the eye chambers is most clearly engaged in the induction and maintenance of ocular immune privilege. PMID- 28081242 TI - Genetic and Clinical Analyses of DOA and LHON in 304 Chinese Patients with Suspected Childhood-Onset Hereditary Optic Neuropathy. AB - Leber hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA), the most common forms of hereditary optic neuropathy, are easily confused, and it is difficult to distinguish one from the other in the clinic, especially in young children. The present study was designed to survey the mutation spectrum of common pathogenic genes (OPA1, OPA3 and mtDNA genes) and to analyze the genotype phenotype characteristics of Chinese patients with suspected childhood-onset hereditary optic neuropathy. Genomic DNA and clinical data were collected from 304 unrelated Chinese probands with suspected hereditary optic neuropathy with an age of onset below 14 years. Sanger sequencing was used to screen variants in the coding and adjacent regions of OPA1, OPA3 and the three primary LHON-related mutation sites in mitochondrial DNA (mtDNA) (m.3460G>A, m.11778G>A and m.14484T>C). All patients underwent a complete ophthalmic examination and were compared with age-matched controls. We identified 89/304 (29.3%) primary mtDNA mutations related to LHON in 304 probands, including 76 mutations at m.11778 (76/89, 85.4% of all mtDNA mutations), four at m.3460 (4/89, 4.5%) and nine at m.14484 (9/89, 10.1%). This result was similar to the mutation frequency among Chinese patients with LHON of any age. Screening of OPA1 revealed 23 pathogenic variants, including 11 novel and 12 known pathogenic mutations. This study expanded the OPA1 mutation spectrum, and our results showed that OPA1 mutation is another common cause of childhood-onset hereditary optic neuropathy in Chinese pediatric patients, especially those with disease onset during preschool age. PMID- 28081243 TI - The Prognostic and Clinicopathological Significance of Tumor-Associated Macrophages in Patients with Gastric Cancer: A Meta-Analysis. AB - OBJECTIVE: Comprehensive studies have investigated the prognostic and clinicopathological value of tumor-associated macrophages (TAMs) in gastric cancer patients, yet results remain controversial. Therefore, we performed a meta analysis to clarify this issue. METHODS: PubMed, Embase, and the Cochrane Library databases were searched to identify eligible studies. We extracted hazard ratios (HRs) and odds ratios (ORs) with their corresponding 95% confidence intervals (95% CIs) to estimate the effect sizes. In addition, subgroup analysis and sensitivity analysis were also conducted. RESULTS: A total of 19 studies involving 2242 patients were included. High generalised TAMs density was significantly associated with poor overall survival (OS) (HR 1.49, 95% CI 1.15 1.95). Subgroup analysis revealed that CD68+ TAMs had no significant effect on OS (HR 1.38, 95% CI 1.00-1.91). High M1 TAMs density was correlated with better OS (HR 0.45, 95% CI 0.32-0.65). By contrast, high density of M2 TAMs was correlated with a poor prognosis for OS (HR 1.48, 95% CI 1.25-1.75). Furthermore, high M2 TAMs density was correlated with larger tumor size, diffuse Lauren type, poor histologic differentiation, deeper tumor invasion, lymph node metastasis, and advanced TNM stage. CONCLUSIONS: Overall, this meta-analysis reveal that although CD68+ TAMs infiltration has the neutral prognostic effects on OS, the M1/M2 polarization of TAMs are predicative factor of prognosis in gastric cancer patients. PMID- 28081244 TI - Fever Is Associated with Reduced, Hypothermia with Increased Mortality in Septic Patients: A Meta-Analysis of Clinical Trials. AB - BACKGROUND: Sepsis is usually accompanied by changes of body temperature (Tb), but whether fever and hypothermia predict mortality equally or differently is not fully clarified. We aimed to find an association between Tb and mortality in septic patients with meta-analysis of clinical trials. METHODS: We searched the PubMed, EMBASE, and Cochrane Controlled Trials Registry databases (from inception to February 2016). Human studies reporting Tb and mortality of patients with sepsis were included in the analyses. Average Tb with SEM and mortality rate of septic patient groups were extracted by two authors independently. RESULTS: Forty two studies reported Tb and mortality ratios in septic patients (n = 10,834). Pearson correlation analysis revealed weak negative linear correlation (R2 = 0.2794) between Tb and mortality. With forest plot analysis, we found a 22.2% (CI, 19.2-25.5) mortality rate in septic patients with fever (Tb > 38.0 degrees C), which was higher, 31.2% (CI, 25.7-37.3), in normothermic patients, and it was the highest, 47.3% (CI, 38.9-55.7), in hypothermic patients (Tb < 36.0 degrees C). Meta-regression analysis showed strong negative linear correlation between Tb and mortality rate (regression coefficient: -0.4318; P < 0.001). Mean Tb of the patients was higher in the lowest mortality quartile than in the highest: 38.1 degrees C (CI, 37.9-38.4) vs 37.1 degrees C (CI, 36.7-37.4). CONCLUSIONS: Deep Tb shows negative correlation with the clinical outcome in sepsis. Fever predicts lower, while hypothermia higher mortality rates compared with normal Tb. Septic patients with the lowest (< 25%) chance of mortality have higher Tb than those with the highest chance (> 75%). PMID- 28081245 TI - Sharp-Tailed Grouse Nest Survival and Nest Predator Habitat Use in North Dakota's Bakken Oil Field. AB - Recent advancements in extraction technologies have resulted in rapid increases of gas and oil development across the United States and specifically in western North Dakota. This expansion of energy development has unknown influences on local wildlife populations and the ecological interactions within and among species. Our objectives for this study were to evaluate nest success and nest predator dynamics of sharp-tailed grouse (Tympanuchus phasianellus) in two study sites that represented areas of high and low energy development intensities in North Dakota. During the summers of 2012 and 2013, we monitored 163 grouse nests using radio telemetry. Of these, 90 nests also were monitored using miniature cameras to accurately determine nest fates and identify nest predators. We simultaneously conducted predator surveys using camera scent stations and occupancy modeling to estimate nest predator occurrence at each site. American badgers (Taxidea taxus) and striped skunks (Mephitis mephitis) were the primary nest predators, accounting for 56.7% of all video recorded nest depredations. Nests in our high intensity gas and oil area were 1.95 times more likely to succeed compared to our minimal intensity area. Camera monitored nests were 2.03 times more likely to succeed than non-camera monitored nests. Occupancy of mammalian nest predators was 6.9 times more likely in our study area of minimal gas and oil intensity compared to the high intensity area. Although only a correlative study, our results suggest energy development may alter the predator community, thereby increasing nest success for sharp-tailed grouse in areas of intense development, while adjacent areas may have increased predator occurrence and reduced nest success. Our study illustrates the potential influences of energy development on the nest predator-prey dynamics of sharp-tailed grouse in western North Dakota and the complexity of evaluating such impacts on wildlife. PMID- 28081246 TI - Nitrosothiol-Trapping-Based Proteomic Analysis of S-Nitrosylation in Human Lung Carcinoma Cells. AB - Nitrosylation of cysteines residues (S-nitrosylation) mediates many of the cellular effects of nitric oxide in normal and diseased cells. Recent research indicates that S-nitrosylation of certain proteins could play a role in tumor progression and responsiveness to therapy. However, the protein targets of S nitrosylation in cancer cells remain largely unidentified. In this study, we used our recently developed nitrosothiol trapping approach to explore the nitrosoproteome of human A549 lung carcinoma cells treated with S-nitrosocysteine or pro-inflammatory cytokines. Using this approach, we identified about 300 putative nitrosylation targets in S-nitrosocysteine-treated A549 cells and approximately 400 targets in cytokine-stimulated cells. Among the more than 500 proteins identified in the two screens, the majority represent novel targets of S nitrosylation, as revealed by comparison with publicly available nitrosoproteomic data. By coupling the trapping procedure with differential thiol labeling, we identified nearly 300 potential nitrosylation sites in about 150 proteins. The proteomic results were validated for several proteins by an independent approach. Bioinformatic analysis highlighted important cellular pathways that are targeted by S-nitrosylation, notably, cell cycle and inflammatory signaling. Taken together, our results identify new molecular targets of nitric oxide in lung cancer cells and suggest that S-nitrosylation may regulate signaling pathways that are critically involved in lung cancer progression. PMID- 28081247 TI - Changes of Oxidative Stress, Glutathione, and Its Dependent Antioxidant Enzyme Activities in Patients with Hepatocellular Carcinoma before and after Tumor Resection. AB - The changes in and relationship between oxidative stress and the glutathione (GSH) antioxidant system in the plasma and tissues of patients with hepatocellular carcinoma (HCC) before and after tumor resection have not been clearly determined. We investigated the changes in oxidative stress, GSH status and its dependent antioxidant enzyme activities in HCC patients before and after tumor resection, and to determine the association of oxidative stress with GSH and its dependent antioxidant enzyme activities in plasma and tissues. This study employed a cross-sectional design. Forty-four men and 16 women with HCC were recruited. Fasting blood was drawn on the day before the tumor resection and one month after the tumor resection. HCC tissue and adjacent normal liver tissue were obtained at the time of surgical resection. Patients had significantly increased plasma malondialdehyde (MDA) and oxidized-low density lipoprotein levels but decreased GSH and oxidized GSH levels before tumor resection compared with the corresponding post-resection values. GSH and trolox equivalent antioxidant capacity (TEAC) levels and activities of GSH peroxidase were significantly increased while MDA level was significantly lower in HCC tissue when compared with the adjacent normal tissue. The pre-resection plasma MDA level was significantly correlated with pre-resection plasma GSH concentration, and MDA level in HCC and adjacent normal tissues. Pre-resection plasma GSH concentration was significantly correlated with GSH and TEAC level in HCC tissue. HCC patients had increased oxidative stress, decreased GSH, and lower dependent antioxidant capacities before tumor resection. However, hepatocellular tumor had increased GSH and TEAC levels as well as GSH peroxidase activities which might protect itself against increased oxidative stress. PMID- 28081248 TI - Low Rice Intake Is Associated with Proteinuria in Participants of Korea National Health and Nutrition Examination Survey. AB - Little is known about the risk factors of proteinuria in the Asian population. On the basis of the association between rice intake patterns and chronic diseases, we hypothesized that rice intake patterns are associated with proteinuria in the Asian population. Data, including data regarding rice intake frequency and dipstick urinalysis results, from the Korea National Health and Nutrition Examination Survey in 1998, 2001, 2005, and 2007 were analyzed. The study involved 19,824 participants who were older than 20 years of age. Low rice intake was defined as consumption of rice <= 1 time/day. Proteinuria was defined as dipstick urinalysis protein >= 1 positive. Among the 19,824 participants, the prevalence of low rice intake and proteinuria were 17.3% and 2.9%, respectively. The low rice intake group showed a higher rate of proteinuria than the non-low rice intake group did (3.8% vs. 2.7%, P < 0.001). In multivariate logistic regression analysis, the odds ratio (OR) of low rice intake for proteinuria was 1.54 (95% confidence interval (CI): 1.25-1.89; P < 0.001). Low rice intake was also independently associated with high blood pressure (OR: 1.43, 95% CI: 1.31 1.56; P < 0.001) and diabetes (OR: 1.43, 95% CI: 1.27-1.62; P < 0.001). In conclusion, low rice intake was found to be independently associated with proteinuria in the Asian population, which might have been affected by the associations of low rice intake with high blood pressure and diabetes. Future prospective studies are needed to confirm the results of this study. PMID- 28081249 TI - Measuring Physical Activity with Hip Accelerometry among U.S. Older Adults: How Many Days Are Enough? AB - INTRODUCTION: Accelerometers are increasingly used in research. Four to 7 days of monitoring is preferred to estimate average activity but may be burdensome for older adults. We aimed to investigate: 1) 7-day accelerometry protocol adherence, 2) demographic predictors of adherence, 3) day of the week effect, and 4) average activity calculated from 7 versus fewer days among older adults. METHODS: We used the 2003-2006 older adult hip accelerometry data from the National Health and Nutrition Examination Survey (NHANES) sample. We determined proportions with 1-7 valid (10-20 hours) wear days and identified wear day correlates using ordinal logistic regression. We determined the day of week effect on 5 accelerometry measures (counts per minute, CPM; % sedentary behavior; % light-lifestyle activity; % moderate-vigorous activity, MVPA; total activity counts) using multivariate linear regression and compared averages estimated over 2 or 3 versus 7 days using correlations, linear regression, and Bland-Altman plots. RESULTS: Among 2,208 participants aged 65+, 85% of participants had >=2 and 44% had 7 valid wear days. Increasing age (p = 0.01) and non-white race (p < 0.001) were associated with fewer days. Daily CPM, % MVPA, and total daily activity counts were similar Monday through Saturday, but significantly lower on Sundays (p < 0.001). Daily % sedentary behavior and % light-lifestyle activity were significantly different on Saturdays (p = 0.04-0.045) and Sundays (p < 0.001) compared to weekdays. Among participants with 7 valid days, 2 or 3 day averages were highly correlated with 7 day averages for all 5 accelerometry measures (2 versus 7 days: r = 0.90-0.93, 3 versus 7 days: r = 0.94-0.96). CONCLUSIONS: Protocols of 2-3 days, adjusting for Sundays (average CPM, % moderate-vigorous activity, and average total daily activity counts) or weekends (% sedentary behavior and % light-lifestyle activity), give reliable estimates of older adult activity. PMID- 28081250 TI - Cutaneous Deficiency of Filaggrin and STAT3 Exacerbates Vaccinia Disease In Vivo. AB - RATIONALE: Defects in filaggrin and STAT3 are associated with atopic dermatitis (AD) and susceptibility to severe skin infection. METHODS: We evaluated skin infection with the current smallpox vaccine, ACAM-2000, in immunosuppressed mice with combined cutaneous deficiency in filaggrin and STAT3. In parallel, early events post-infection with ACAM-2000 were investigated in cultured keratinocytes in which filaggrin expression was knocked down via siRNA. RESULTS: Immunosuppressed, filaggrin-deficient mice, treated with the topical STAT3 inhibitor Stattic(r) prior to ACAM-2000 infection, demonstrated rapid weight loss, prolonged vaccinia burden in skin, and dermatitis. The TGF-beta family ligand activin A was upregulated ten-fold in infected skin. Topically-applied ALK5/TGbetaR1 signaling inhibitor synergized with vaccinia immune globulin (VIG) to promote vaccinia clearance and limit weight loss. In cultured keratinocytes, filaggrin-directed siRNA inhibited programmed necrosis and inflammatory cytokine release induced by ACAM-2000, while viral growth was increased. CONCLUSIONS: Our findings may point to a novel role for filaggrin in early antiviral responses in skin. In wounded skin with underlying barrier defects, chronically elevated activin A levels may contribute to skin remodeling and cutaneous pathogen persistence. Inhibition of ALK5/TGFbetaR1 signaling may provide a novel co therapeutic approach, together with VIG, to limit cutaneous spread of vaccinia. PMID- 28081251 TI - Physical Activity and Sedentary Behaviors Modify the Association between Melanocortin 4 Receptor Gene Variant and Obesity in Chinese Children and Adolescents. AB - Effects of MC4R variants in previous Chinese population studies were inconsistent. Gene-environment interactions might influence the effect of MC4R variants on obesity, which was still unclear. We performed the study to clarify the association of variants near MC4R gene with obesity-related phenotypes and gene-environment interactions in Chinese children and adolescents. Two common variants (rs12970134 and rs17782313) near MC4R were genotyped in 2179 children and adolescents aged 7-18 years in Beijing of China. Associations between the variants and obesity-related phenotypes together with gene-environment interactions were analyzed. The A-alleles of rs12970134 were nominally associated with risk of overweight/obesity (Odds Ratios (OR) = 1.21, 95%CI: 1.03-1.44, P = 0.025) and BMI (beta = 0.33 kg/m2, 95%CI: 0.02-0.63, P = 0.025), respectively. The rs12970134 was also associated with HDL-C (beta = -0.03mmol/L per A-allele, 95%CI: -0.05, -0.01, P = 0.013) independent of BMI. In the further analysis, we found the significant interaction of rs12970134 and physical activity/sedentary behaviors on BMI (Pinteraction = 0.043). The rs12970134 was found to be associated with BMI only in children with physical activity<1h/d and sedentary behaviors >=2h/d (BMI: beta = 1.27 kg/m2, 95%CI: 0.10-2.45, P = 0.034). The association was not detected in their counterparts with physical activity>=1h/d or sedentary behaviors <2h/d. We identified the effect of MC4R rs12970134 on overweight/obesity and BMI, and we also found physical activity and sedentary behaviors modified the association between the rs12970134 and BMI in Chinese children and adolescents. PMID- 28081252 TI - Corn-Soy-Blend Fortified with Phosphorus to Prevent Refeeding Hypophosphatemia in Undernourished Piglets. AB - BACKGROUND: Phosphorus (P) levels in refeeding diets are very important as undernourished children are at risk of hypophosphatemia during refeeding. For this reason, conventional corn-soy-blends (CSB) have been reformulated by the World Food Programme to obtain a mono-calcium-phosphate fortified product (CSB+) and a product further fortified with skim milk powder (CBS++). METHODS: Using a piglet model of undernourished children, we hypothesized that feeding of CSB+, CSB++ or CSB+ with added whey permeate (CSB+/wp) would help to prevent refeeding hypophosphatemia. Pigs were weaned at 4 weeks of age and undernutrition was induced with a nutritionally inadequate pure maize diet for 7 weeks, after which they were refed for 3 weeks with either CSB+ (n = 10), CSB++ (n = 10) or CSB+/wp (n = 10). For reference, a fourth group continued on the maize diet (REF, n = 10). RESULTS: Following induction of undernutrition, body weight and length were 29+/-5% and 67+/-4% (means+/-SD) of values in age-matched pigs fed a nutritionally adequate diet, and the mean serum P level was 1.77+/-0.34 mmol/l. During the first week of refeeding, P levels in the CSB+ pigs decreased to 55% of values before refeeding (P < 0.05) while values in the CSB++ and CSB+/wp pigs were able to maintain their plasma phosphate at a similar level as before refeeding. CONCLUSION: We conclude that fortification of CSB with only monocalcium-phosphate does not prevent hypophosphatemia. Dairy products like skim milk powder or whey permeate may represent relevant sources of phosphorus during refeeding. The content and form of phosphorus in such diets need to be carefully evaluated, and the undernourished piglet may be used to test the efficacy of such diets. PMID- 28081253 TI - Probability of Transmission of Malaria from Mosquito to Human Is Regulated by Mosquito Parasite Density in Naive and Vaccinated Hosts. AB - Over a century since Ronald Ross discovered that malaria is caused by the bite of an infectious mosquito it is still unclear how the number of parasites injected influences disease transmission. Currently it is assumed that all mosquitoes with salivary gland sporozoites are equally infectious irrespective of the number of parasites they harbour, though this has never been rigorously tested. Here we analyse >1000 experimental infections of humans and mice and demonstrate a dose dependency for probability of infection and the length of the host pre-patent period. Mosquitoes with a higher numbers of sporozoites in their salivary glands following blood-feeding are more likely to have caused infection (and have done so quicker) than mosquitoes with fewer parasites. A similar dose response for the probability of infection was seen for humans given a pre-erythrocytic vaccine candidate targeting circumsporozoite protein (CSP), and in mice with and without transfusion of anti-CSP antibodies. These interventions prevented infection more efficiently from bites made by mosquitoes with fewer parasites. The importance of parasite number has widespread implications across malariology, ranging from our basic understanding of the parasite, how vaccines are evaluated and the way in which transmission should be measured in the field. It also provides direct evidence for why the only registered malaria vaccine RTS,S was partially effective in recent clinical trials. PMID- 28081254 TI - Maternal Supply of Cas9 to Zygotes Facilitates the Efficient Generation of Site Specific Mutant Mouse Models. AB - Genome manipulation in the mouse via microinjection of CRISPR/Cas9 site-specific nucleases has allowed the production time for genetically modified mouse models to be significantly reduced. Successful genome manipulation in the mouse has already been reported using Cas9 supplied by microinjection of a DNA construct, in vitro transcribed mRNA and recombinant protein. Recently the use of transgenic strains of mice overexpressing Cas9 has been shown to facilitate site-specific mutagenesis via maternal supply to zygotes and this route may provide an alternative to exogenous supply. We have investigated the feasibility of supplying Cas9 genetically in more detail and for this purpose we report the generation of a transgenic mice which overexpress Cas9 ubiquitously, via a CAG Cas9 transgene targeted to the Gt(ROSA26)Sor locus. We show that zygotes prepared from female mice harbouring this transgene are sufficiently loaded with maternally contributed Cas9 for efficient production of embryos and mice harbouring indel, genomic deletion and knock-in alleles by microinjection of guide RNAs and templates alone. We compare the mutagenesis rates and efficacy of mutagenesis using this genetic supply with exogenous Cas9 supply by either mRNA or protein microinjection. In general, we report increased generation rates of knock-in alleles and show that the levels of mutagenesis at certain genome target sites are significantly higher and more consistent when Cas9 is supplied genetically relative to exogenous supply. PMID- 28081255 TI - Changes in DNA Methylation in Mouse Lungs after a Single Intra-Tracheal Administration of Nanomaterials. AB - AIMS: This study aimed to investigate the effects of nanomaterial (NM) exposure on DNA methylation. METHODS AND RESULTS: Intra-tracheal administration of NM: gold nanoparticles (AuNPs) of 5-, 60- and 250-nm diameter; single-walled carbon nanotubes (SWCNTs) and multi-walled carbon nanotubes (MWCNTs) at high dose of 2.5 mg/kg and low dose of 0.25 mg/kg for 48 h to BALB/c mice. Study showed deregulations in immune pathways in NM-induced toxicity in vivo. NM administration had the following DNA methylation effects: AuNP 60 nm induced CpG hypermethylation in Atm, Cdk and Gsr genes and hypomethylation in Gpx; Gsr and Trp53 showed changes in methylation between low- and high-dose AuNP, 60 and 250 nm respectively, and AuNP had size effects on methylation for Trp53. CONCLUSION: Epigenetics may be implicated in NM-induced disease pathways. PMID- 28081256 TI - Inhibition of Acetyl-CoA Carboxylase 1 (ACC1) and 2 (ACC2) Reduces Proliferation and De Novo Lipogenesis of EGFRvIII Human Glioblastoma Cells. AB - Tumor cell proliferation and migration processes are regulated by multiple metabolic pathways including glycolysis and de novo lipogenesis. Since acetyl-CoA carboxylase (ACC) is at the junction of lipids synthesis and oxidative metabolic pathways, we investigated whether use of a dual ACC inhibitor would provide a potential therapy against certain lipogenic cancers. The impact of dual ACC1/ACC2 inhibition was investigated using a dual ACC1/ACC2 inhibitor as well as dual siRNA knock down on the cellular viability and metabolism of two glioblastoma multiform cancer cell lines, U87 and a more aggressive form, U87 EGFRvIII. We first demonstrated that while ACCi inhibited DNL in both cell lines, ACCi preferentially blunted the U87 EGFRvIII cellular proliferation capacity. Metabolically, chronic treatment with ACCi significantly upregulated U87 EGFRvIII cellular respiration and extracellular acidification rate, a marker of glycolytic activity, but impaired mitochondrial health by reducing maximal respiration and decreasing mitochondrial ATP production efficiency. Moreover, ACCi treatment altered the cellular lipids content and increased apoptotic caspase activity in U87 EGFRvIII cells. Collectively these data indicate that ACC inhibition, by reducing DNL and increasing cellular metabolic rate, may have therapeutic utility for the suppression of lipogenic tumor growth and warrants further investigation. PMID- 28081257 TI - Influence of La3+ Substitution on Structure, Morphology and Magnetic Properties of Nanocrystalline Ni-Zn Ferrite. AB - Lanthanum substituted Ni-Zn ferrite nanoparticles (Ni0.5Zn0.5LaxFe1-xO4; 0.00 <=x<= 1.00) synthesized by sol-gel method were presented. X-ray diffraction patterns reveal the typical single phase spinel cubic ferrite structure, with the traces of secondary phase for lanthanum substituted nanocrystals. In addition, the structural analysis also demonstrates that the average crystallite size varied in the range of 21-25 nm. FTIR spectra present the two prominent absorption bands in the range of 400 to 600 cm-1 which are the fingerprint region of all ferrites. Surface morphology of both substituted and unsubstituted Ni-Zn ferrite nanoparticle samples was studied using FESEM technique and it indicates a significant increase in the size of spherical shaped particles with La3+ substitution. Magnetic properties of all samples were analyzed using vibrating sample magnetometer (VSM). The results revealed that saturation magnetization (Ms) and coercivity (Hc) of La3+ substituted samples has decreased as compared to the Ni-Zn ferrite samples. Hence, the observed results affirm that the lanthanum ion substitution has greatly influenced the structural, morphology and magnetic properties of Ni-Zn ferrite nanoparticles. PMID- 28081258 TI - The Effect of Individual and Neighbourhood Socioeconomic Status on Diabetes Mellitus Survival in Working Age Patients in Taiwan. AB - PURPOSE: Diabetes mellitus (DM) is a global pandemic metabolic disorder. In recent years, the amount of medical resources required for the treatment of diabetes has increased as diabetes rates have gradually risen. The combined effects of individual and neighbourhood socio-economic status (SES) on DM survival rates are still not clear, especially in patients of working age. In this paper, we aim to analyze the combined effects of neighbourhood and individual SES on DM survival rates in patients of working age in Taiwan. METHODS: The study of 23,781 people who were diagnosed with DM by using population-based study between 2002 and 2006. Each sample was followed up for 4 years or as a sensor case. We defined Individual SES and neighbourhood SES by each patient's job category and household income which characterized as advantaged or disadvantaged. Then we compared the survival rates by SES group used Cox proportional hazards model for adjust risk factors. RESULTS: The 4-year overall survival rates of diabetic patients were worst for those with low individual SES who living in advantaged neighbourhoods. After adjustment for patient characteristics, DM patients with high individual SES living in disadvantaged neighbourhoods had the same risk of mortality as those patients with high individual SES living in advantaged neighbourhoods (hazard ratio: 1.11; 95% confidence interval [CI]: 0.81-1.51). The study found that DM patients with low individual SES who live in disadvantaged areas had a greater risk of mortality than those with high SES (odds ratio: 2.57; 95% CI: 2.04-3.24). There were significant differences in survival rates between patients with high individual SES and patients with low individual SES. In contrast, the results did not statistically significant differences in survival rates between advantaged and disadvantaged neighbourhood SES groups. CONCLUSION: DM patients with low individual SES had the worst survival rate, regardless of whether they were living in a high or low SES neighbourhood area. The competitive cause of death, i.e., the fact that complications, rather than DM itself, are often the cause of death, may be the reason for the inverse relationship found between the effects of individual SES and neighbourhood SES on DM survival. We conclude that the socio-economic gradient in survival among DM patients may be the result of differences in access to medical treatment and attributes related to individual SES. PMID- 28081259 TI - Frequency of Propionibacterium acnes Infection in Prostate Glands with Negative Biopsy Results Is an Independent Risk Factor for Prostate Cancer in Patients with Increased Serum PSA Titers. AB - BACKGROUND: Propionibacterium acnes has recently been implicated as a cause of chronic prostatitis and this commensal bacterium may be linked to prostate carcinogenesis. The occurrence of intracellular P. acnes infection in prostate glands and the higher frequency of P. acnes-positive glands in radical prostatectomy specimens from patients with prostate cancer (PCa) than in those from patients without PCa led us to examine whether the P. acnes-positive gland frequency can be used to assess the risk for PCa in patients whose first prostate biopsy, performed due to an increased prostate-specific antigen (PSA) titer, was negative. METHODS: We retrospectively collected the first and last prostate biopsy samples from 44 patients that were diagnosed PCa within 4 years after the first negative biopsy and from 36 control patients with no PCa found in repeated biopsy for at least 3 years after the first biopsy. We evaluated P. acnes positive gland frequency and P. acnes-positive macrophage number using enzyme immunohistochemistry with a P. acnes-specific monoclonal antibody (PAL antibody). RESULTS: The frequency of P. acnes-positive glands was higher in PCa samples than in control samples in both first biopsy samples and in combined first and last biopsy samples (P < 0.001). A frequency greater than the threshold (18.5 and 17.7, respectively) obtained by each receiver operating characteristic curve was an independent risk factor for PCa (P = 0.003 and 0.001, respectively) with odds ratios (14.8 and 13.9, respectively) higher than those of serum PSA titers of patients just before each biopsy (4.6 and 2.3, respectively). The number of P. acnes-positive macrophages did not differ significantly between PCa and control samples. CONCLUSIONS: These results suggested that the frequency of P. acnes positive glands in the first negative prostate biopsy performed due to increased PSA titers can be supportive information for urologists in planning repeated biopsy or follow-up strategies. PMID- 28081261 TI - The Role of TOR1A Polymorphisms in Dystonia: A Systematic Review and Meta Analysis. AB - IMPORTANCE: A number of genetic loci were found to be associated with dystonia. Quite a few studies have been contacted to examine possible contribution of TOR1A variants to the risk of dystonia, but their results remain conflicting. The aim of the present study was to systematically evaluate the effect of TOR1A gene SNPs on dystonia and its phenotypic subtypes regarding the body distribution. METHODS: We performed a systematic review of Pubmed database to identify all available studies that reported genotype frequencies of TOR1A SNPs in dystonia. In total 16 studies were included in the quantitative analysis. Odds ratios (ORs) were calculated in each study to estimate the influence of TOR1A SNPs genotypes on the risk of dystonia. The fixed-effects model and the random effects model, in case of high heterogeneity, for recessive and dominant mode of inheritance as well as the free generalized odds ratio (ORG) model were used to calculate both the pooled point estimate in each study and the overall estimates. RESULTS: Rs1182 was found to be associated with focal dystonia in recessive mode of inheritance [Odds Ratio, OR (95% confidence interval, C.I.): 1.83 (1.14-2.93), Pz = 0.01]. In addition, rs1801968 was associated with writer's cramp in both recessive and dominant modes [OR (95%C.I.): 5.99 (2.08-17.21), Pz = 0.00009] and [2.48 (1.36 4.51), Pz = 0.003) respectively and in model free-approach [ORG (95%C.I.): 2.58 (1.45-4.58)]. CONCLUSIONS: Our meta-analysis revealed a significant implication of rs1182 and rs1801968 TOR1A variants in the development of focal dystonia and writer's cramp respectively. TOR1A gene variants seem to be implicated in dystonia phenotype. PMID- 28081262 TI - Efficacy of Statin Treatment in Early-Stage Chronic Kidney Disease. AB - Chronic kidney disease (CKD) represents a major medical challenge and frequently coexists with cardiovascular disease (CVD), which can be treated by statin trerapy. However, whether statin treatment affects renal progression and outcomes in CKD patients remains unclear. We retrospectively reviewed CKD patients at Gachon University Gil Medical Center from 2003-2013. From a total of 14,497 CKD patients, 858 statin users were paired with non-users and analyze with propensity score matching was performed. The outcomes of this study were creatinine doubling, renal death, all-cause mortality, and interactive factors for composite outcomes. Statins were prescribed to 13.5% of the study subjects. Hazard ratios (HRs) [95% confidence intervals (CIs)] for statin treatment for the doubling of serum creatinine levels were significant only in CKD patients with an estimated glomerular filtration rate (eGFR) >=30 mL/min/1.73 m2, and were 0.744 (0.635 0.873) in the unmatched cohort and 0.767 (0.596-0.986) in the matched cohort. In analyses of secondary outcomes, the HRs (95% CIs) for all-cause mortality were 0.655 (0.502-0.855) in the unmatched cohort and 0.537 (0.297-0.973) in the matched cohort. The HRs (95% CIs) for statin therapy for composite outcomes among patients with and without an eGFR >=30 mL/min/1.73 m2 were 0.764 (0.613-0.952) and 1.232 (0.894-1.697), respectively (P for interaction, 0.017). Thus, statin treatment may have beneficial effects on renal progression and all-cause mortality only for the patients with early- stage CKD. PMID- 28081260 TI - Comparative Genome Sequencing Reveals Within-Host Genetic Changes in Neisseria meningitidis during Invasive Disease. AB - Some members of the physiological human microbiome occasionally cause life threatening disease even in immunocompetent individuals. A prime example of such a commensal pathogen is Neisseria meningitidis, which normally resides in the human nasopharynx but is also a leading cause of sepsis and epidemic meningitis. Using N. meningitidis as model organism, we tested the hypothesis that virulence of commensal pathogens is a consequence of within host evolution and selection of invasive variants due to mutations at contingency genes, a mechanism called phase variation. In line with the hypothesis that phase variation evolved as an adaptation to colonize diverse hosts, computational comparisons of all 27 to date completely sequenced and annotated meningococcal genomes retrieved from public databases showed that contingency genes are indeed enriched for genes involved in host interactions. To assess within-host genetic changes in meningococci, we further used ultra-deep whole-genome sequencing of throat-blood strain pairs isolated from four patients suffering from invasive meningococcal disease. We detected up to three mutations per strain pair, affecting predominantly contingency genes involved in type IV pilus biogenesis. However, there was not a single (set) of mutation(s) that could invariably be found in all four pairs of strains. Phenotypic assays further showed that these genetic changes were generally not associated with increased serum resistance, higher fitness in human blood ex vivo or differences in the interaction with human epithelial and endothelial cells in vitro. In conclusion, we hypothesize that virulence of meningococci results from accidental emergence of invasive variants during carriage and without within host evolution of invasive phenotypes during disease progression in vivo. PMID- 28081263 TI - Molecular and Functional Characterization of Three Odorant-Binding Protein from Periplaneta americana. AB - The American cockroach, Periplaneta americana, is a vector of many pathogenic organisms associated with human diseases. Olfaction plays a crucial role in guiding cockroach behaviors and contributes to their ability to transmit pathogens. Odorant binding proteins (OBPs), abundant in the insect olfactory sensilla, are important for insect olfaction. In this study, three OBP genes, PameOBP1, 2 and 3, were cloned from P. americana. Sequence alignment and phylogenetic analysis revealed that PameOBP1, 2 and 3 belong to the Minus-C OBP, Classic OBP, and Plus-C OBP subfamilies, respectively. Expression pattern and ligand-binding analysis showed that PameOBP1 and 2 were specifically expressed in antennae, and exhibited high binding affinities (Ki < 2 MUM) to farnesene, farnesol, 2-tridecanone, and tetradecane, suggesting roles in volatile perception. Conversely, PameOBP3 was ubiquitously expressed in most of the tissues examined at high levels and displayed very weak binding affinities (Ki > 40 MUM) for all 87 ligands tested. Our study provides insights into the functional diversity of PameOBP genes and provides some volatiles that can potentially be used in behavioral interference of P. americana. PMID- 28081264 TI - The Important Role of Lipid Raft-Mediated Attachment in the Infection of Cultured Cells by Coronavirus Infectious Bronchitis Virus Beaudette Strain. AB - Lipid raft is an important element for the cellular entry of some viruses, including coronavirus infectious bronchitis virus (IBV). However, the exact role of lipid rafts in the cellular membrane during the entry of IBV into host cells is still unknown. In this study, we biochemically fractionated IBV-infected cells via sucrose density gradient centrifugation after depleting plasma membrane cholesterol with methyl-beta-cyclodextrin or Mevastatin. Our results demonstrated that unlike IBV non-structural proteins, IBV structural proteins co-localized with lipid raft marker caveolin-1. Infectivity assay results of Vero cells illustrated that the drug-induced disruption of lipid rafts significantly suppressed IBV infection. Further studies revealed that lipid rafts were not required for IBV genome replication or virion release at later stages. However, the drug-mediated depletion of lipid rafts in Vero cells before IBV attachment significantly reduced the expression of viral structural proteins, suggesting that drug treatment impaired the attachment of IBV to the cell surface. Our results indicated that lipid rafts serve as attachment factors during the early stages of IBV infection, especially during the attachment stage. PMID- 28081265 TI - The Plasmin-Sensitive Protein Pls in Methicillin-Resistant Staphylococcus aureus (MRSA) Is a Glycoprotein. AB - Most bacterial glycoproteins identified to date are virulence factors of pathogenic bacteria, i.e. adhesins and invasins. However, the impact of protein glycosylation on the major human pathogen Staphylococcus aureus remains incompletely understood. To study protein glycosylation in staphylococci, we analyzed lysostaphin lysates of methicillin-resistant Staphylococcus aureus (MRSA) strains by SDS-PAGE and subsequent periodic acid-Schiff's staining. We detected four (>300, ~250, ~165, and ~120 kDa) and two (>300 and ~175 kDa) glycosylated surface proteins with strain COL and strain 1061, respectively. The ~250, ~165, and ~175 kDa proteins were identified as plasmin-sensitive protein (Pls) by mass spectrometry. Previously, Pls has been demonstrated to be a virulence factor in a mouse septic arthritis model. The pls gene is encoded by the staphylococcal cassette chromosome (SCC)mec type I in MRSA that also encodes the methicillin resistance-conferring mecA and further genes. In a search for glycosyltransferases, we identified two open reading frames encoded downstream of pls on the SCCmec element, which we termed gtfC and gtfD. Expression and deletion analysis revealed that both gtfC and gtfD mediate glycosylation of Pls. Additionally, the recently reported glycosyltransferases SdgA and SdgB are involved in Pls glycosylation. Glycosylation occurs at serine residues in the Pls SD-repeat region and modifying carbohydrates are N-acetylhexosaminyl residues. Functional characterization revealed that Pls can confer increased biofilm formation, which seems to involve two distinct mechanisms. The first mechanism depends on glycosylation of the SD-repeat region by GtfC/GtfD and probably also involves eDNA, while the second seems to be independent of glycosylation as well as eDNA and may involve the centrally located G5 domains. Other previously known Pls properties are not related to the sugar modifications. In conclusion, Pls is a glycoprotein and Pls glycosyl residues can stimulate biofilm formation. Thus, sugar modifications may represent promising new targets for novel therapeutic or prophylactic measures against life-threatening S. aureus infections. PMID- 28081266 TI - Human Extravillous Trophoblasts Penetrate Decidual Veins and Lymphatics before Remodeling Spiral Arteries during Early Pregnancy. AB - In humans, the defective invasion of the maternal endometrium by fetal extravillous trophoblasts (EVTs) can lead to insufficient perfusion of the placenta, resulting in pregnancy complications that can put both mother and baby at risk. To study the invasion of maternal endometrium between (W)5.5-12 weeks of gestation by EVTs, we combined fluorescence in situ hybridization, immunofluorescence and immunohistochemistry to determine the presence of (male) EVTs in the vasculature of the maternal decidua. We observed that interstitial mononuclear EVTs directly entered decidual veins and lymphatics from W5.5. This invasion of decidual veins and lymphatics occurred long before endovascular EVTs remodelled decidual spiral arteries. This unexpected early entrance of interstitial mononuclear EVTs in the maternal circulation does not seem to contribute to the materno-placental vascular connection directly, but rather to establish (and expand) the materno-fetal interface through an alternative vascular route. PMID- 28081267 TI - Single Nucleotide Variants of Candidate Genes in Aggrecan Metabolic Pathway Are Associated with Lumbar Disc Degeneration and Modic Changes. AB - INTRODUCTION: Lumbar disc degeneration (LDD) is genetically determined and severity of LDD is associated with Modic changes. Aggrecan is a major proteoglycan in the intervertebral disc and end plate. Progressive reduction of aggrecan is a main feature of LDD and Modic changes. OBJECTIVES: The study investigated the associations of single nucleotide variants (SNVs) of candidate genes in the aggrecan metabolic pathway with the severity of LDD and Modic changes. In-silico functional analysis of significant SNVs was also assessed. METHODS: A descriptive cross sectional study was carried out on 106 patients with chronic mechanical low back pain. T1, T2 sagittal lumbar MRI scans were used to assess the severity of LDD and Modic changes. 62 SNVs in ten candidate genes (ACAN, IL1A, IL1B, IL6, MMP3, ADAMTS4, ADAMTS5, TIMP1, TIMP2 and TIMP3) were genotyped on Sequenom MassARRAY iPLEX platform. Multiple linear regression analysis was carried out using PLINK 1.9 in accordance with additive genetic model. In-silico functional analysis was carried out using Provean, SIFT, PolyPhen and Mutation Taster. RESULTS: Mean age was 52.42+/-9.42 years. 74 (69.8%) were females. The rs2856836, rs1304037, rs17561 and rs1800587 variants of the IL1A gene were associated with the severity of LDD and Modic changes. The rs41270041 variant of the ADAMTS4 gene and the rs226794 variant of the ADAMTS5 gene were associated with severity of LDD while the rs34884997 variant of the ADAMTS4 gene, the rs55933916 variant of the ADAMTS5 gene and the rs9862 variant of the TIMP3 gene were associated with severity of Modic changes. The rs17561 variant of the IL1A gene was predicted as pathogenic by the PolyPhen prediction tool. CONCLUSIONS: SNVs of candidate genes in ACAN metabolic pathway are associated with severity of LDD and Modic changes in patients with chronic mechanical low back pain. Predictions of in-silico functional analysis of significant SNVs are inconsistent. PMID- 28081269 TI - Morphine Does Not Affect Myocardial Salvage in ST-Segment Elevation Myocardial Infarction. AB - Recent studies have proposed intravenous (IV) morphine is associated with delayed action of antiplatelet agents in acute myocardial infarction. However, it is unknown whether morphine results in increased myocardial damage in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). We investigated myocardial salvage index (MSI) to determine whether IV morphine affects myocardial injury adversely in STEMI patients undergoing primary PCI. 299 STEMI patients underwent contrast-enhanced magnetic resonance imaging a median of 3 days after PCI. Infarct size was measured on delayed-enhancement imaging, and area at risk was quantified on T2 weighted imaging. MSI was calculated as '[area at risk-infarct size] X 100 / area at risk'. IV morphine was administrated in 32.1% of patients. Patients treated with morphine had shorter symptom to balloon time and higher prevalence of Thrombolysis in Myocardial Infarction flow grade 0 or 1. The morphine group showed a trend toward larger MSI and infarct size and significantly greater area at risk than the non-morphine group. After propensity score matching (90 pairs), MSI was similar between the morphine and non-morphine group (46.1% versus 43.5%, P = .11), and infarct size and area at risk showed no difference. In propensity score-matched analysis, IV morphine prior to primary PCI in STEMI patients did not cause adverse impacts on myocardial salvage. PMID- 28081270 TI - Outcome and Treatment Effects in Stroke Associated with Acute Cervical ICA Occlusion. AB - BACKGROUND: Endovascular therapy (EVT) with stent retrievers in addition to i.v. thrombolysis (IVT) has proven effective in acute stroke patients with middle cerebral artery (MCA, M1 segment) and distal internal carotid artery (ICA) occlusion. Limited data exist concerning acute cervical ICA occlusion, either alone or in combination with intracranial ICA occlusion (tandem occlusion). Therefore we analyzed outcome and treatment effects in stroke associated with cervical ICA occlusion, with specific focus on the impact of intracranial ICA or M1 patency. METHODS: Seventy-eight patients with cervical ICA occlusion from our local stroke unit registry were analyzed retrospectively. Thrombolysis in Cerebral Infarction (TICI) classification, infarct size, modified Rankin scale (mRS), symptomatic intracerebral hemorrhage (ICH), and death were assessed as outcome parameters. RESULTS: Forty-three patients had isolated cervical ICA occlusion whereas 35 patients presented with extra-/intracranial tandem occlusion. Patients underwent IVT alone (n = 23), combined IVT/EVT (n = 28) or no treatment (n = 27). Treated and untreated patients with tandem occlusion had a worse outcome after 90 days compared to isolated cervical occlusion (OR for moderate outcome 0.29, 0.27-0.88, p = 0.01). Additional EVT improved outcome in patients with tandem occlusion (OR for moderate outcome: 15.43, 1.60-148.90, p = 0.008) but not isolated cervical occlusion (OR 1.33, 0.38-11.60, NS). CONCLUSIONS: In contrast to tandem occlusion, stroke outcome in patients with isolated cervical ICA occlusion was generally more benign and not improved by combined IVT/EVT compared to IVT alone. Intracranial vessel patency may be critical for treatment decision in acute cervical ICA occlusion. PMID- 28081271 TI - Beaver Colony Density Trends on the Chequamegon-Nicolet National Forest, 1987 - 2013. AB - The North American beaver (Castor canadensis) is a managed species in the United States. In northern Wisconsin, as part of the state-wide beaver management program, the Chequamegon-Nicolet National Forest removes beavers from targeted trout streams on U.S. Forest Service lands. However, the success of this management program has not been evaluated. Targeted removals comprise only 3% of the annual beaver harvest, a level of effort that may not affect the beaver population. We used colony location data along Forest streams from 1987-2013 (Nicolet, northeast Wisconsin) and 1997-2013 (Chequamegon, northwest Wisconsin) to assess trends in beaver colony density on targeted trout streams compared to non-targeted streams. On the Chequamegon, colony density on non-targeted trout and non-trout streams did not change over time, while colony density on targeted trout streams declined and then stabilized. On the Nicolet, beaver colony density decreased on both non-targeted streams and targeted trout streams. However, colony density on targeted trout streams declined faster. The impact of targeted trapping was similar across the two sides of the Forest (60% reduction relative to non-targeted trout streams). Exploratory analyses of weather influences found that very dry conditions and severe winters were associated with transient reductions in beaver colony density on non-targeted streams on both sides of the Forest. Our findings may help land management agencies weigh more finely calibrated beaver control measures against continued large-scale removal programs. PMID- 28081268 TI - The Rice Dynamin-Related Protein OsDRP1E Negatively Regulates Programmed Cell Death by Controlling the Release of Cytochrome c from Mitochondria. AB - Programmed cell death (PCD) mediated by mitochondrial processes has emerged as an important mechanism for plant development and responses to abiotic and biotic stresses. However, the role of translocation of cytochrome c from the mitochondria to the cytosol during PCD remains unclear. Here, we demonstrate that the rice dynamin-related protein 1E (OsDRP1E) negatively regulates PCD by controlling mitochondrial structure and cytochrome c release. We used a map-based cloning strategy to isolate OsDRP1E from the lesion mimic mutant dj-lm and confirmed that the E409V mutation in OsDRP1E causes spontaneous cell death in rice. Pathogen inoculation showed that dj-lm significantly enhances resistance to fungal and bacterial pathogens. Functional analysis of the E409V mutation showed that the mutant protein impairs OsDRP1E self-association and formation of a higher-order complex; this in turn reduces the GTPase activity of OsDRP1E. Furthermore, confocal microscopy showed that the E409V mutation impairs localization of OsDRP1E to the mitochondria. The E409V mutation significantly affects the morphogenesis of cristae in mitochondria and causes the abnormal release of cytochrome c from mitochondria into cytoplasm. Taken together, our results demonstrate that the mitochondria-localized protein OsDRP1E functions as a negative regulator of cytochrome c release and PCD in plants. PMID- 28081272 TI - Individual Plasticity of the Shade Response of the Invasive Solidago canadensis in China. AB - To evaluate the population variation, individual plasticity, and local adaptability of Solidago canadensis in response to shade treatment, we conducted a common pots experiment with a total of 150 ramets (5 genets, 15 populations, and 2 treatments) subjected to both control (natural light) and shady treatment (10% of natural light). Shade treatment significantly reduced growth and content of defense metabolites in S. canadensis. Compared to control, shading led to increased height, decreased basal diameter, increased leaf width, increased leaf length, increased chlorophyll content, stronger photosynthetic rate (Pn), stronger stomatal conductance (gs), and lower root to shoot ratio. Three-way analysis of variance revealed geographical origin to significantly affect the basal diameter of S. canadensis, while genotype significantly affected plant height, intercelluar CO2 concentration (Ci), transpiration rate (Tr), and proline content. Significant interactive effects between shade and geographic origin were prevalent for most traits. The phenotypic differentiation coefficient of the plasticity of all traits was below 0.4, indicating that most of all variations can be found among individuals within populations. Phenotypic selection analysis revealed that fitness was significantly positively related to plant height, basal diameter, Ci, total flavonoid content, as well as the plasticity of plant height, leaf length, leaf width, gs, Ci, total flavonoid content, and malondialdehyde content under the control condition. However, subjected to shade, fitness was only significantly positively related to plant height, basal diameter, and the plasticity of basal diameter. Rather than local adaption, these results suggest that individual plasticity played a more prominent role in the shade response of the invasive S. canadensis. PMID- 28081273 TI - Assessing the Impact of Retreat Mechanisms in a Simple Antarctic Ice Sheet Model Using Bayesian Calibration. AB - The response of the Antarctic ice sheet (AIS) to changing climate forcings is an important driver of sea-level changes. Anthropogenic climate change may drive a sizeable AIS tipping point response with subsequent increases in coastal flooding risks. Many studies analyzing flood risks use simple models to project the future responses of AIS and its sea-level contributions. These analyses have provided important new insights, but they are often silent on the effects of potentially important processes such as Marine Ice Sheet Instability (MISI) or Marine Ice Cliff Instability (MICI). These approximations can be well justified and result in more parsimonious and transparent model structures. This raises the question of how this approximation impacts hindcasts and projections. Here, we calibrate a previously published and relatively simple AIS model, which neglects the effects of MICI and regional characteristics, using a combination of observational constraints and a Bayesian inversion method. Specifically, we approximate the effects of missing MICI by comparing our results to those from expert assessments with more realistic models and quantify the bias during the last interglacial when MICI may have been triggered. Our results suggest that the model can approximate the process of MISI and reproduce the projected median melt from some previous expert assessments in the year 2100. Yet, our mean hindcast is roughly 3/4 of the observed data during the last interglacial period and our mean projection is roughly 1/6 and 1/10 of the mean from a model accounting for MICI in the year 2100. These results suggest that missing MICI and/or regional characteristics can lead to a low-bias during warming period AIS melting and hence a potential low-bias in projected sea levels and flood risks. PMID- 28081274 TI - Role of methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in polycystic ovary syndrome risk. AB - Polycystic ovary syndrome is one of the most frequently encountered endocrine malfunctions. Methylenetetrahydrofolate reductase (MTHFR) plays a vital role in folate metabolism, DNA methylation, and RNA synthesis. We carried out a study to investigate the association between MTHFR C677T and A1298C genetic variations and the risk of polycystic ovary syndrome in a Chinese population. We recruited 244 patients and 257 control subjects from an Inner Mongolian Medical University to this hospital-based, case-control study. The genotyping of the MTHFR C677T and A1298C polymorphisms was carried out using polymerase chain reaction coupled with restriction fragment length polymorphism. Using multiple logistic regression analysis, we found that the TT genotype and the T allele of MTHFR C677T carriers showed increased risk of polycystic ovary syndrome compared with the wild-type genotype or allele carriers. The adjusted ORs for the TT genotype and the T allele of MTHFR C677T were 1.84 (1.05-3.26) and 1.38 (1.06-1.81), respectively. Subjects carrying the CC genotype (OR = 3.98, 95%CI = 1.60-11.23) and the C allele (OR = 1.46, 95%CI = 1.07-2.00) of MTHFR A1298C had an elevated risk of polycystic ovary syndrome compared with the AA genotype and A allele carriers. In conclusion, our study suggests that the MTHFR C677T and A1298C polymorphisms may have contributed to the risk of polycystic ovary syndrome in the Chinese women investigated. Further research involving a greater number of individuals is warranted to confirm our results. PMID- 28081275 TI - Role of XRCC1 gene polymorphisms in non-small cell lung cancer cisplatin-based chemotherapy, and their effect on clinical and pathological characteristics. AB - Non-small cell lung cancer (NSCLC) is the most common cancer globally. The XRCC1 protein interacts with ligase and poly(ADP-ribose) polymerase to repair cisplatin induced DNA damage. The authors of previous studies have reported XRCC1 Arg399Gln, Arg280His, and Arg194Trp polymorphisms and advanced NSCLC prognosis, but the results are inconclusive. We investigated the association between clinical outcome and XRCC1 Arg399Gln, Arg280His, and Arg194Trp polymorphisms in advanced NSCLC patients treated with cisplatin. We recruited 252 patients with advanced NSCLC (TNM stages: IIIB and IV) and used polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) to genotype the polymorphisms. Patients with the TT genotype of XRCC1 Arg194Trp showed a significantly better response to chemotherapy than those with the CC genotype. The GA+AA genotype of Arg194Trp was correlated with better response to chemotherapy than the wild-type form. The TT genotype of Arg194Trp was associated with longer survival time than the CC genotype. The TT genotype of Arg194Trp was correlated with lower risk of death from all causes than the CC genotype. The Arg194Trp polymorphisms interacted with squamous cell carcinoma and affected overall survival of advanced NSCLC. However, there was no association between Arg399Gln and Arg280His polymorphisms and response to cisplatin-based chemotherapy and overall survival in advanced NSCLC. The results suggest that the TT genotype of Arg194Trp is significantly associated with better response to chemotherapy and longer overall survival of advanced NSCLC patients than the wild type form. Our investigation offers insight into the influence of XRCC1 gene polymorphisms on the treatment outcome of advanced NSCLC. PMID- 28081276 TI - Correlation and path analysis of biomass sorghum production. AB - Sorghum biomass is an interesting raw material for bioenergy production due to its versatility, potential of being a renewable energy source, and low-cost of production. The objective of this study was to evaluate the genetic variability of biomass sorghum genotypes and to estimate genotypic, phenotypic, and environmental correlations, and direct and indirect effects of seven agronomic traits through path analysis. Thirty-four biomass sorghum genotypes and two forage sorghum genotypes were cultivated in a randomized block design with three replicates. The following morpho-agronomic traits were evaluated: flowering date, stem diameter, number of stems, plant height, number of leaves, green mass production, and dry matter production. There were significant differences at the 1% level for all traits. The highest genotypic correlation was found between the traits green mass production and dry matter production. The path analysis demonstrated that green mass production and number of leaves can assist in the selection of dry matter production. PMID- 28081277 TI - Comparative genomic hybridization analysis of rice dwarf mutants induced by gamma irradiation. AB - Comparative genomic hybridization (CGH) is a powerful tool used to analyze changes in copy number, polymorphisms, and structural variations in the genome. Gene copy number variation (CNV) is a common form of natural diversity in the genome, which can create new genes and alter gene structure. Thus, CNVs may influence phenotypic variation and gene expression. In this study, to detect CNVs, we irradiated rice seeds with gamma rays (300 Gy) and selected two dwarf mutagenized plants, GA-III-189 and -1052, in the M3 generation. These plants were subjected to CGH analysis using Agilent's RICE CGH array. Most of the CNVs identified were less than 10 kb in length. We detected 90 amplified and 18 deleted regions in GA-III-189, and 99 amplified and 11 deleted regions in GA-III 1052. Of note, CNVs were located on chromosome 12 in both GA-III-189 and -1052, which contained 39 commonly amplified regions in 29 genes. The commonly amplified genes included six genes encoding F-box domain-containing proteins. Alterations in these F-box domain-containing genes were confirmed by quantitative RT-PCR. Integration of CGH and gene expression data identified copy number aberrations and novel genes potentially involved in the dwarf phenotype. These CGH and gene expression data may be useful for uncovering the mechanisms underlying the dwarf phenotype. PMID- 28081278 TI - Population structure of Annona crassiflora: an endemic plant species of the Brazilian Cerrado. AB - Habitat fragmentation has numerous consequences, particularly to endemic species, and has a negative impact on the genetic diversity of neglected species, leading to genetic drift. Annona crassiflora Mart. is a species that is endemic to Brazil, and its incidence in the Cerrado biome has decreased. The identification and characterization of its remaining diversity is necessary for its conservation. Our aim was to study the population structure of A. crassiflora populations from different Cerrado regions in Minas Gerais State, Brazil (Corinto, Curvelo, Carmo da Mata, Boa Esperanca, and Paraguacu) using inter simple sequence repeat (ISSR) markers and DNA content. Nuclear DNA content was estimated by flow cytometry using 10 individuals from each population. ISSR markers were used for genotyping accessions in order to study their genetic diversity and population structures. We found considerable genetic variation among populations, with the highest variability observed in the Curvelo population. There was a significant positive correlation between DNA content and latitude (r = 0.46, P = 0. 0003). A Bayesian-based cluster analysis grouped the populations into three clusters, which followed their geographical origins. There was some level of genetic diversity and differentiation among the populations, suggesting the need for a conservation plan for this species. The ISSR markers and DNA content analysis were effective in studying the genetic diversity and population structure of A. crassiflora. PMID- 28081279 TI - Karyotype analysis and ribosomal gene localization of spotted knifejaw Oplegnathus punctatus. AB - The spotted knifejaw, Oplegnathus punctatus, is an important aquaculture fish species in China. To better understand the chromosomal microstructure and the karyotypic origin of this species, cytogenetic analysis was performed using Giemsa staining to identify metaphase chromosomes, C-banding to detect C-positive heterochromatin, silver staining to identify the nucleolus organizer regions (Ag NORs), and fluorescence in situ hybridization (FISH) for physical mapping of the major (18S rDNA) and minor (5S rDNA) ribosomal genes. The species showed a karyotype of 2n = 48 for females, composed of 2 submetacentric and 46 telocentric chromosomes, with a fundamental number (FN) = 50, while the karyotype of males was 2n = 47, composed of 1 exclusive large metacentric, 2 submetacentric, and 44 telocentric chromosomes, with FN = 50. These karyotype results suggest that O. punctatus might have an X1X1X2X2/X1X2Y multiple sex chromosome system. C-positive heterochromatin was distributed in the centromeres of all chromosomal pairs and in the terminal portions of some chromosomes. A single pair of Ag-positive NORs was found to be localized at the terminal regions of the short arms of the subtelocentric chromosome pair, which was supported by FISH of 18S rDNA. After FISH, 5S rDNA were located on the interstitial regions of the smallest telocentric chromosome pair. This study was the first to identify the karyotype of this species and will facilitate further research on karyotype evolution in the order Perciformes. PMID- 28081280 TI - Evaluation on the germplasm of maize (Zea mays L.) landraces from southwest China. AB - Because of their local adaptation and economic factors that limit the adoption of commercial hybrids, farmer-saved maize landraces are still grown over a considerable area concentrated in southwest China. To evaluate the potential of using maize landraces, the germplasm characteristics of 96 landraces from southwest China were evaluated at phenotypic, cellular, and molecular levels. The existence of high phenotypic variation and elite germplasm tolerant to low-N, low P, as well as drought stress was observed. Of the total landraces, 81.25, 7.29, 5.21, and 2.08% were found with 0, 1, 2, 3, and 4 B chromosomes. Using 42 microsatellite (simple sequence repeat) loci, 246 alleles were detected among the landraces. The number of alleles per SSR locus varied from 2 to 10, averaging 5.67 allele per locus, which revealed a high level of genetic diversity of maize landraces in southwest China. Cluster analysis showed that 96 landraces could distinctly be clustered into four groups, which tended to associate with their geographic origins. We propose that the genetic diversity center of maize landraces in southwest China might be in Sichuan. A sharp genetic deviation from Hardy-Weinberg equilibrium was observed from heterozygosity deficiency and a considerable genetic variation was revealed within, rather than among, the landraces. Based on their germplasm characteristics, the innovation and utilization of maize landraces in southwestern China for theoretical and applied research could be achieved by constructing heterosis groups, developing inbred lines with high combining ability, and maintaining the landraces with elite germplasm and B chromosomes using bulked pollen. PMID- 28081281 TI - SHORT-COMMUNICATION Validation of reference genes for real-time quantitative PCR in tambaqui (Colossoma macropomum). AB - Tambaqui, Colossoma macropomum, is the main native freshwater fish in Brazilian aquaculture. Therefore, intensive research pressure has been applied to the species to support new technologies for tambaqui farming. Molecular biology represents a tool that can be used to investigate every field of applied biology, from fish physiology to the effects of climate change. Based on the importance of reference genes for the relative or absolute quantification of gene transcripts, we cloned and sequenced three candidate reference genes in tambaqui (18S ribossomal RNA - 18s, glyceraldehyde-3-phosphate dehydrogenase - gapdh, and actin beta - beta-actin), and validated a set of primers for each gene for use in real time quantitative PCR. The results were evaluated by RefFinder, which indicated that beta-actin is the most suitable reference gene for tambaqui among those studied, followed by 18s. PMID- 28081282 TI - Cloning of three genes involved in the flavonoid metabolic pathway and their expression during insect resistance in Pinus massoniana Lamb. AB - Pinus massoniana Lamb. is an important timber and turpentine-producing tree species in China. Dendrolimus punctatus and Dasychira axutha are leaf-eating pests that have harmful effects on P. massoniana production. Few studies have focused on the molecular mechanisms underlying pest resistance in P. massoniana. Based on sequencing analysis of the transcriptomes of insect-resistant P. massoniana, three key genes involved in the flavonoid metabolic pathway were identified in the present study (PmF3H, PmF3'5'H, and PmC4H). Structural domain analysis showed that the PmF3H gene contains typical binding sites for the 2OG-Fe (II) oxygenase superfamily, while PmF3'5'H and PmC4H both contain the cytochrome P450 structural domain, which is specific for P450 enzymes. Phylogenetic analysis showed that each of the three P. massoniana genes, and the homologous genes in gymnosperms, clustered into a group. Expression of these three genes was highest in the stems, and was higher in the insect-resistant P. massoniana varieties than in the controls. The extent of the increased expression in the insect-resistant P. massoniana varieties indicated that these three genes are involved in defense mechanisms against pests in this species. In the insect-resistant varieties, rapid induction of PmF3H increased the levels of PmF3'5'H and PmC4H expression. The enhanced anti-pest capability of the insect-resistant varieties could be related to temperature and humidity. In addition, these results suggest that these three genes maycontribute to the change in flower color during female cone development. PMID- 28081283 TI - Transcriptome analysis of peach (Prunus persica L. Batsch) during the late stage of fruit ripening. AB - Fruit ripening is a complex developmental process, the details of which remain largely unknown in fleshy fruits. In this paper, the fruit flesh of two peach varieties, "Zhongyou9" (a nectarine; Prunus persica L. Batsch) and its mutant "Hongyu", was analyzed by RNA-seq technology during two stages of ripening at 20 day intervals. One hundred and eighty significant upregulated and two hundred and thirty-five downregulated genes were identified in the experiment. Many of these genes were related to plant hormones, chlorophyll breakdown, accumulation of aroma and flavor volatiles, and stress. To the best of our knowledge, this is the first transcriptome analysis of peach ripening, and our data will be useful for further studies of the molecular basis of fruit ripening. PMID- 28081284 TI - Analysis of the relationship between ribosomal DNA ITS sequences and active components in Rhodiola plants. AB - Rhodiola plants are a valuable resource in traditional Chinese medicine. The objective of this study was to evaluate the correlation between ribosomal DNA internal transcribed spacer (ITS) sequences and the three active components in Rhodiola plants. For this, we determined ITS sequence polymorphisms and the concentrations of active components salidroside, tyrosol, and gallic acid in different Rhodiola species from the Tibetan Plateau. In a total of 23 Rhodiola samples, 16 different haplotypes were defined based on their ITS sequences. Analysis of the active components in these same samples revealed that salidroside was not detected in species with haplotypes H4, H5, or H10, tyrosol was not detected with haplotypes H3, H5, H7, H10, H14, or H15, and gallic acid was detected in with all haplotypes except H14 and H15. In addition, the concentrations of salidroside, tyrosol and gallic acid varied between samples with different haplotypes as well as those with the same haplotype, implying that no significant correlation exists between haplotype and salidroside, tyrosol or gallic acid concentrations. However, a statistically significant positive correlation was observed for among these three active components. PMID- 28081285 TI - Pre-harvest foliar application of ethephon strengthens gibberellins-induced fruit expansion in Pyrus pyrifolia. AB - To identify the roles of ethylene in fruit development in Japanese pear Pyrus pyrifolia 'Niitaka', one of the non-climacteric genotypes, source-sink strength and fruit development during fruit expansion were investigated when ethephon was applied after a conventional gibberellic acid (GA) lanolin paste treatment on the pedicel. The results demonstrate that the conventional GA treatment during the early stage of fruit expansion resulted in larger fruit size and advanced fruit maturation, but pre-harvest foliar application of ethephon only advanced fruit maturation. However, pre-harvest foliar application of ethephon with a preceding conventional GA treatment during the early stage of fruit expansion dramatically improved fruit size and advanced fruit maturation over GA or ethephon alone. Moreover, the early foliar application of ethephon showed a better efficacy in increasing fruit size than the late spraying. A further study revealed that when ethephon was applied after the conventional GA treatment, it improved source-sink strength associated with leaf photosynthesis and the specific rate of [13C] accumulation in fruit, and also strengthened cell expansion more than did GA or ethephon alone. PMID- 28081286 TI - Carbon-Carbon Bond Formation in a Weak Ligand Field: Leveraging Open-Shell First Row Transition-Metal Catalysts. AB - Unique features of earth-abundant transition-metal catalysts are reviewed in the context of catalytic carbon-carbon bond-forming reactions. Aryl-substituted bis(imino)pyridine iron and cobalt dihalide compounds, when activated with alkyl aluminum reagents, form highly active catalysts for the polymerization of ethylene. Open-shell iron and cobalt alkyl complexes have been synthesized that serve as single-component olefin polymerization catalysts. Reduced bis(imino)pyridine iron and cobalt dinitrogen compounds have also been discovered that promote the unique [2+2] cycloaddition of unactivated terminal alkenes. Studies of the electronic structure support open-shell intermediates, a deviation from traditional strong-field organometallic compounds that promote catalytic C-C bond formation. PMID- 28081287 TI - Current insights into the aetiology, pathobiology, and management of local disease recurrence in squamous cell carcinoma of the vulva. AB - : Squamous cell carcinoma of the vulva is predominantly a disease of the elderly, where the mainstay of treatment is radical surgery. Local vulval recurrence (LVR) is a significant problem for these patients, and the rates of recurrence have not improved over the last three decades. Disappointingly, we still lack an understanding of how LVRs develop, and the best approach to prevent and manage the condition. This review discusses recent insights into the key prognostic factors that influence the risk of recurrence, focusing on the role of tumour adjacent non-neoplastic epithelial disorders, which are thought to play a causative role. TWEETABLE ABSTRACT: A review that discusses the key prognostic factors that influence local recurrence in vulval cancer. PMID- 28081288 TI - Short dental implants (6 mm) versus long dental implants (11-15 mm) in combination with sinus floor elevation procedures: 3-year results from a multicentre, randomized, controlled clinical trial. AB - AIM: To test whether the use of short dental implants (6 mm) results in an implant survival rate similar to that with longer implants (11-15 mm) in combination with sinus grafting. METHODS: This multicentre study enrolled 101 patients with partial edentulism in the posterior maxilla and a remaining bone height of 5-7 mm. Included patients were randomly assigned to receive short implants (6 mm; GS/group short) or long implants (11-15 mm) simultaneously with sinus grafting (GG/group graft). Six months after implant placement (IP), implants were loaded with single crowns (PR) and patients were re-examined yearly thereafter. Assessed outcomes included: implant survival, marginal bone level changes (MBL), probing pocket depth (PPD), bleeding on probing (BoP) and plaque accumulation (PCR) during 3 years of loading as well as recording of any adverse effects. In addition to descriptive statistics, statistical analysis has been performed for the two treatment modalities using a non-parametric approach. RESULTS: In 101 patients, 137 implants were placed. At the 3-year follow-up (FU 3), 94 patients with 129 implants were re-examined. The implant survival rate was 100% in both groups. MBL at FU-3 was 0.45 mm (GG) and 0.44 mm (GS) (p > 0.05). A statistically significant loss of MBL was observed in both GG (-0.43 +/- 0.58 mm) and GS (-0.44 +/- 0.56 mm) from IP to FU-3, and from PR to FU-3 in GG (-0.25 +/- 0.58 mm) but not in GS (-0.1 +/- 0.54 mm). PCR and BoP at FU-3 did not show any difference between the groups but for PPD (p = 0.035). CONCLUSIONS: Within the limitations of this study, implants with a length of 6 mm as well as longer implants in combination with a lateral sinus lift may be considered as a treatment option provided a residual ridge height of 5-7 mm in the atrophied posterior maxilla is present. PMID- 28081289 TI - Transgenic cotton expressing Cry10Aa toxin confers high resistance to the cotton boll weevil. AB - Genetically modified (GM) cotton plants that effectively control cotton boll weevil (CBW), which is the most destructive cotton insect pest in South America, are reported here for the first time. This work presents the successful development of a new GM cotton with high resistance to CBW conferred by Cry10Aa toxin, a protein encoded by entomopathogenic Bacillus thuringiensis (Bt) gene. The plant transformation vector harbouring cry10Aa gene driven by the cotton ubiquitination-related promoter uceA1.7 was introduced into a Brazilian cotton cultivar by biolistic transformation. Quantitative PCR (qPCR) assays revealed high transcription levels of cry10Aa in both T0 GM cotton leaf and flower bud tissues. Southern blot and qPCR-based 2-DeltaDeltaCt analyses revealed that T0 GM plants had either one or two transgene copies. Quantitative and qualitative analyses of Cry10Aa protein expression showed variable protein expression levels in both flower buds and leaves tissues of T0 GM cotton plants, ranging from approximately 3.0 to 14.0 MUg g-1 fresh tissue. CBW susceptibility bioassays, performed by feeding adults and larvae with T0 GM cotton leaves and flower buds, respectively, demonstrated a significant entomotoxic effect and a high level of CBW mortality (up to 100%). Molecular analysis revealed that transgene stability and entomotoxic effect to CBW were maintained in T1 generation as the Cry10Aa toxin expression levels remained high in both tissues, ranging from 4.05 to 19.57 MUg g-1 fresh tissue, and the CBW mortality rate remained around 100%. In conclusion, these Cry10Aa GM cotton plants represent a great advance in the control of the devastating CBW insect pest and can substantially impact cotton agribusiness. PMID- 28081290 TI - Membrane microdomains and the cytoskeleton constrain AtHIR1 dynamics and facilitate the formation of an AtHIR1-associated immune complex. AB - Arabidopsis hypersensitive-induced reaction (AtHIR) proteins function in plant innate immunity. However, the underlying mechanisms by which AtHIRs participate in plant immunity remain elusive. Here, using VA-TIRFM and FLIM-FRET, we revealed that AtHIR1 is present in membrane microdomains and co-localizes with the membrane microdomain marker REM1.3. Single-particle tracking analysis revealed that membrane microdomains and the cytoskeleton, especially microtubules, restrict the lateral mobility of AtHIR1 at the plasma membrane and facilitate its oligomerization. Furthermore, protein proximity index measurements, fluorescence cross-correlation spectroscopy, and biochemical experiments demonstrated that the formation of the AtHIR1 complex upon pathogen perception requires intact microdomains and cytoskeleton. Taken together, these findings suggest that microdomains and the cytoskeleton constrain AtHIR1 dynamics, promote AtHIR1 oligomerization, and increase the efficiency of the interactions of AtHIR1 with components of the AtHIR1 complex in response to pathogens, thus providing valuable insight into the mechanisms of defense-related responses in plants. PMID- 28081291 TI - A Bioorganometallic Approach to Study Histidine Kinase Autophosphorylations. AB - Auto-phosphorylation of bacterial histidine kinases PhoR, PhoQ, and EnvZ has been investigated using adenosine-5'-[gamma-ferrocene] triphosphate (Fc-ATP) as a cosubstrate for the first time. The study has been carried out in solution and on surface. Results from biochemical multiplex assay and surface electrochemical/optical methods are consistent, which successfully demonstrates that Fc-ATP is an efficient cosubstrate for histidine kinase auto phosphorylations. The study also has discovered that the concentration of Fc-ATP influences the autophosphorylation efficiency. This developed methodology will provide a powerful tool in studying such biological processes towards further understanding of the involved mechanism. PMID- 28081292 TI - The utility of abbreviated patient-reported outcomes for predicting survival in early stage colorectal cancer. AB - BACKGROUND: Patient-reported outcomes (PROs) are increasingly used in clinical settings. Prior research suggests that PROs collected at baseline may be associated with cancer survival, but most of those studies were conducted in patients with breast or lung cancer. The objective of this study was to determine the correlation between prospectively collected PROs and cancer-specific outcomes in patients with early stage colorectal cancer. METHODS: Patients who had newly diagnosed stage II or III colorectal cancer from 2009 to 2010 and had a consultation at the British Columbia Cancer Agency completed the brief Psychosocial Screen for Cancer (PSSCAN) questionnaire, which collects data on patients' perceived social supports, quality of life (QOL), anxiety and depression, and general health. PROs from the PSSCAN were linked with the Gastrointestinal Cancers Outcomes Database, which contains information on patient and tumor characteristics, treatment details, and cancer outcomes. Cox regression models were constructed for overall survival (OS), and Fine and Gray regression models were developed for disease-specific survival (DSS). RESULTS: In total, 692 patients were included. The median patient age was 67 years (range, 26-95 years), and the majority had colon cancer (61%), were diagnosed with stage III disease (54%), and received chemotherapy (58%). In general, patients felt well supported and reported good overall health and QOL. On multivariate analysis, increased fatigue was associated with worse OS (hazard ratio [HR], 1.99; P = .00007) and DSS (HR, 1.63; P = .03), as was lack of emotional support (OS: HR, 4.36; P = .0003; DSS: HR, 1.92; P = .02). CONCLUSIONS: Although most patients described good overall health and QOL and indicated that they were generally well supported, patients who experienced more pronounced fatigue or lacked emotional support had a higher likelihood of worse OS and DSS. These findings suggest that abbreviated PROs can inform and assist clinicians to identify patients who have a worse prognosis and may need more vigilant follow-up. Cancer 2017;123:1839-1847. (c) 2017 American Cancer Society. PMID- 28081293 TI - Role of Pyridoxal 5'-Phosphate at the Titanium Implant Interface In Vivo: Increased Hemophilicity, Inactive Platelet Adhesion, and Osteointegration. AB - Titanium is the most biocompatible inorganic biomaterial with a long history of use in orthopedic and dental implants. However, promoting rapid and effective bone formation and integration onto etched, rough TiO2 surfaces has been a challenging topic. Here, 21 commercially available molecules are examined that met the following criteria: (1) contain phosphonic acid for stable immobilization onto TiO2 surfaces and (2) have a molecular weight less than 500 Da for negligible coating thickness. Of these molecules, the surface immobilization of pyridoxal 5'-phosphate (PLP), an active form of vitamin B6 , dramatically increases the hemophilic property of the surface and accelerated osteointegration in vivo. Analysis shows that PLP promotes surface binding of serum albumin and other plasma proteins by Schiff-base formations via its aldehyde group, providing a platform suitable for osteoblast adhesion. PLP also retards blood coagulation more than the widely used citric acid at the TiO2 surface. As PLP is capable of maintaining an inactivated status of surface-adsorbed platelets, delayed coagulation at the implant-blood interface allows for sufficient supply of growth factors from blood plasma and migration of osteoblasts. The results suggest that PLP can be widely applicable as a biocompatible, effective coating compound to promote osteointegration of titanium-based implants. PMID- 28081294 TI - Xenogeneic Bio-Root Prompts the Constructive Process Characterized by Macrophage Phenotype Polarization in Rodents and Nonhuman Primates. AB - Tissue or organ regeneration using xenogeneic matrices is a promising approach to address the shortage of donor matrices for allotransplantation. Success of such approach has been demonstrated to correlate with macrophage-mediated fibrotic homeostasis and tissue remodeling. The previous studies have demonstrated that treated dentin matrix (TDM) could be a suitable bioactive substrate for allogeneic tooth root regeneration. This study constructed xenogeneic bioengineered tooth root (bio-root) via a combination of porcine TDM (pTDM) with allogeneic dental follicle cells (DFCs). Macrophage phenotypes are used to evaluate the remodeling process of xenogeneic bio-roots in vitro and in vivo. pTDM can facilitate odontoblast differentiation of human derived DFCs. Xenogeneic bio-roots in rat subcutaneous tissue prompt constructive response via M1 macrophage infiltration during early postimplantation stages and increase restorative M2 phenotype at later stages. After implantation of bio-roots into jaws of rhesus monkeys for six months, periodontal ligament-like fibers accompanied by macrophage polarization are observed, which are positive for COL 1, Periostin, betaIII-tubulin and display such structures as fibroblasts and blood vessels. The reconstructed bio-root possesses biomechanical properties for the dissipation of masticatory forces. These results support that xenogeneic bio root could maintain fibrotic homeostasis during remodeling process and highlight the potential application of xenogeneic matrices in regenerative medicine. PMID- 28081295 TI - Connected component masking accurately identifies the ratio of phagocytosed and cell-bound particles in individual cells by imaging flow cytometry. AB - Innate immune cell-mediated recognition, capture, and engulfment of large particulate targets such as bacteria is known as phagocytosis. This highly dynamic cellular process involves a series of steps including receptor-mediated target binding, phagocytic cup formation, pseudopod extension, and phagosome closure, which depend on distinct actin polymerization events. Using flow cytometry, precise determination of target locations relative to cell membranes (i.e., surface-bound vs. fully engulfed/internalized) during the phagocytic process is difficult to quantify. Here, we describe the application of new analysis features within the IDEAS(r) software to distinguish internalized and surface-bound particles on individual cells with a high degree of accuracy and reproducibility. Through the use of connected component masks, the accurate discrimination of surface-bound beads versus those internalized is clearly demonstrated. In addition, we were able to further analyze the ratio of beads that had been surface-bound or internalized within individual cells. This novel method of analyzing the phagocytic process provides more accurate determination of target-cell interactions that will assist in examination of the signalling events that occur during the various stages of phagocytosis. (c) 2017 International Society for Advancement of Cytometry. PMID- 28081296 TI - Short Synthetic alpha-Helical-Forming Peptide Amphiphiles for Fungal Keratitis Treatment In Vivo. AB - The emergence of fungal keratitis is on the rise globally. However, current antifungal therapeutics are ineffective in severe keratomycosis. Previously reported alpha-helical peptides comprising 8-14 amino acids demonstrate broad spectrum antimicrobial activity both in vitro and in vivo. Here, alpha-helical peptides of the optimized sequences are investigated for antifungal biofilm in vitro and in vivo using a fungal biofilm-caused mouse keratitis model. The peptides with the optimal composition demonstrate higher alpha-helical propensity and improve antifungal activity in dispersing Candida albicans biofilm in vitro. Moreover, the optimized alpha-helical peptides are not only effective in treating C. albicans biofilm-induced keratitis in mice, they are also nontoxic to the mice eyes. These peptides have the potential to be developed as antifungal agents for the treatment of C. albicans biofilm-caused keratitis. PMID- 28081297 TI - First trimester noninvasive fetal RHD genotyping using maternal dried blood spots. AB - OBJECTIVE: This study was aimed to evaluate whether maternal dried blood spots could be a potential source for the noninvasive fetal RHD genotyping, serving as a combined one-step test for both the First Trimester Screen and the fetal RHD genotyping. METHOD: Both the maternal dried blood spots and the peripheral blood samples from 19 RhD-negative pregnant women were obtained during the First Trimester Screen. DNA was extracted and sequential real-time PCRs were performed to determine the fetal RHD genotypes. Fetal RhD serological types were obtained after delivery. This study was approved by the Institutional Review Board, and informed consents were obtained. RESULTS: A total of 19/19 fetal RHD genotyping with maternal DBS were consistent with the follow-up serological RhD test results after birth. Eleven were RhD positive, and eight were RhD negative (RHD deletion or RHD-CE-D = 6, RHD pseudogene = 1, RHDVI = 1). Sensitivity = 100%, specificity = 100%, positive predictive value = 100%, negative predictive value = 100%. A total of 18/19 fetal gender were determined correctly with maternal DBS. One female fetus was falsely determined as male. Sensitivity = 100%, specificity = 91.6%, positive predictive value = 87.5%, negative predictive value = 100%. CONCLUSION: Maternal dried blood spots, with the benefits of flexible sample transportation and processing, could be utilized for the noninvasive prenatal fetal RHD genotyping and potentially be incorporated into the routine First Trimester Screen. Larger scale study is in progress to implement fetal RHD genotyping in routine prenatal care. (c) 2017 John Wiley & Sons, Ltd. PMID- 28081298 TI - Full-Thickness Heart Repair with an Engineered Multilayered Myocardial Patch in Rat Model. AB - In a rat model of right free wall replacement, the transplantation of an engineered multilayered myocardial patch fabricated from a polycaprolactone membrane supporting a chitosan/heart matrix hydrogel induces significant muscular and vascular remodeling and results in a significantly higher right ventricular ejection fraction compared to use of a commercially available pericardium patch. PMID- 28081299 TI - Ultrasound Detection of Regional Oxidative Stress in Deep Tissues Using Novel Enzyme Loaded Nanoparticles. AB - Oxidative stress is a powerful tool that is critical to immune mediated responses in healthy individuals, yet additionally plays a crucial role in development of cancer, inflammatory pathologies, and tissue ischemia. Despite this, there remain relatively few molecular tools to study oxidative stress, particularly in living mammals. To develop an intravenously injectable probe capable of labeling sites of oxidative stress in vivo, 200 nm catalase synthetic hollow enzyme loaded nanospheres (catSHELS) are designed and fabricated using a versatile enzyme nanoencapsulation method. catSHELS catalyze H2 O2 to water and oxygen producing microbubbles that can be detected and imaged using a clinical ultrasound system. catSHELS are optimized in vitro to maximize ultrasound signal and their functionality is demonstrated in rat ischemic renal injury model. Ischemic oxidative injury is induced in a single kidney of normal rats by clamping the renal artery for 1 h followed by 2 h of reperfusion. Imaging of both kidneys is performed following the intravenous bolus injection of 1012 catSHELS of the optimized formulation. There is significant increase in ultrasound signal of the injured kidney relative to controls. This method offers a novel intravenous approach to detect oxidative stress in deep tissues in living animals. PMID- 28081300 TI - Deep caries due to Pre-eruptive intracoronal resorption in a newly erupted primary molar. AB - CASE REPORT: This report describes a rare case of a 19-month-old girl with pre eruptive intracoronal resorption in the lower left first primary molar which had erupted a few weeks earlier and had deep caries. The treatment is described. CONCLUSION: Dentists who treat children must take into consideration the possibility of pre-eruptive lesions in the primary dentition that may cause involvement of the pulp, either before or shortly post-eruption. PMID- 28081301 TI - Ethanol Induces Platelet Apoptosis. AB - BACKGROUND: Alcohol abuse incurs severe medical conditions, such as thrombocytopenia and hemorrhage, but the pathogenesis is not totally understood. Alcohol has been reported to induce apoptosis in eukaryotic cells, such as hepatocyte, nerve cell, corneal fibroblasts. However, it is still unclear whether alcohol induces platelet apoptosis. METHODS: Washed human platelets were pretreated with ethanol (EtOH), and apoptotic events and platelet function were detected. In in vivo experiments, C57BL/6J mice were given EtOH by gavage. Platelet counts, tail bleeding time, and the stomach were examined. RESULTS: EtOH dose dependently induces depolarization of mitochondrial inner transmembrane potential, up-regulation of Bax, down-regulation of Bcl-2, and caspase-3 activation. EtOH does not induce surface expression of P-selectin or PAC-1 binding, whereas significantly reduces collagen-, thrombin-, and ADP-induced platelet aggregation. Moreover, EtOH induces c-Jun NH2-terminal kinase activation. In an in vivo mouse model of the acute alcoholism, EtOH significantly reduces the number of circulating platelets, prolongs the tail bleeding time, and causes gastric mucosa hemorrhage. CONCLUSIONS: These data demonstrate that EtOH induces mitochondria-mediated intrinsic platelet apoptosis, results in the reduction of the number of circulating platelets, and impairs in vivo hemostasis. These findings reveal the possible pathogenesis of hemorrhagic symptoms in patients experiencing acute alcohol intoxication. PMID- 28081302 TI - Education and support needs in patients with head and neck cancer: A multi institutional survey. AB - BACKGROUND: Head and neck cancer (HNC) encompasses a diverse group of tumors, and thus providing appropriate and tailored information to patients before, during, and after treatment is a challenge. The objective of the current study was to characterize the experience and unmet needs of patients with HNC with regard to information and support provision. METHODS: A 28-question, cross-sectional survey was completed by patients treated for HNC at 1 of 4 institutions in New South Wales, Australia (Chris O'Brien Lifehouse and Liverpool, Westmead, and Wollongong hospitals). It consisted of the adapted Kessler Psychological Distress Scale and questions assessing information quality, quantity, and format. RESULTS: A total of 597 patients responded. The mean age of the patients was 58 years (range, 21 94 years) with 284 men and 313 women (1:1.1). The majority of patients reported information concerning the disease process (76%), prognosis (67%), and treatment (77%) was sufficient, and approximately 50% reporting having received little or no information regarding coping with stress and anxiety. A substantial percentage of patients reported receiving minimal information concerning psychosexual health (56%) or the availability of patient support groups (56%). The majority of patients preferred access to multiple modes of information delivery (72%), with the preferred modality being one-on-one meetings with a health educator (37%) followed by internet-based written information (19%). CONCLUSIONS: Patients with HNC are a diverse group, with complex educational and support needs. Patients appear to be given information regarding survivorship topics such as psychological well-being, patient support groups, and psychosexual health less frequently than information concerning disease and treatment. Verbal communication needs to be reinforced by accessible, well-constructed, written and multimedia resources appropriate to the patient's educational level. Cancer 2017;123:1949-1957. (c) 2017 American Cancer Society. PMID- 28081303 TI - The novel fusion transcript NR5A2-KLHL29FT is generated by an insertion at the KLHL29 locus. AB - BACKGROUND: Novel fusion transcripts (FTs) caused by chromosomal rearrangement are common factors in the development of cancers. In the current study, the authors used massively parallel RNA sequencing to identify new FTs in colon cancers. METHODS: RNA sequencing (RNA-Seq) and TopHat-Fusion were used to identify new FTs in colon cancers. The authors then investigated whether the novel FT nuclear receptor subfamily 5, group A, member 2 (NR5A2)-Kelch-like family member 29 FT (KLHL29FT) was transcribed from a genomic chromosomal rearrangement. Next, the expression of NR5A2-KLHL29FT was measured by quantitative real-time polymerase chain reaction in colon cancers and matched corresponding normal epithelia. RESULTS: The authors identified the FT NR5A2 KLHL29FT in normal and cancerous epithelia. While investigating this transcript, it was unexpectedly found that it was due to an uncharacterized polymorphic germline insertion of the NR5A2 sequence from chromosome 1 into the KLHL29 locus at chromosome 2, rather than a chromosomal rearrangement. This germline insertion, which occurred at a population frequency of 0.40, appeared to bear no relationship to cancer development. Moreover, expression of NR5A2-KLHL29FT was validated in RNA specimens from samples with insertions of NR5A2 at the KLHL29 gene locus, but not from samples without this insertion. It is interesting to note that NR5A2-KLH29FT expression levels were significantly lower in colon cancers than in matched normal colonic epithelia (P =.029), suggesting the potential participation of NR5A2-KLHL29FT in the origin or progression of this tumor type. CONCLUSIONS: NR5A2-KLHL29FT was generated from a polymorphism insertion of the NR5A2 sequence into the KLHL29 locus. NR5A2-KLHL29FT may influence the origin or progression of colon cancer. Moreover, researchers should be aware that similar FTs may occur due to transchromosomal insertions that are not correctly annotated in genome databases, especially with current assembly algorithms. Cancer 2017;123:1507-1515. (c) 2017 American Cancer Society. PMID- 28081304 TI - Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: Final results of the National Surgical Adjuvant Study of Breast Cancer 02 trial, a randomized comparative phase 3 study. AB - BACKGROUND: In postoperative patients with breast cancer, the combination of an anthracycline and cyclophosphamide (AC) followed by a taxane is a standard regimen. In the current study, the authors examined whether AC could be safely omitted, and compared the effectiveness of paclitaxel versus docetaxel. METHODS: Female postoperative patients with axillary lymph node-positive breast cancer were eligible for enrollment in this phase 3, open-label, randomized controlled trial at 84 centers in Japan. Patients were randomized to 4 cycles of doxorubicin at a dose of 60 mg/m2 and cyclophosphamide at a dose of 600 mg/m2 (AC) followed by 4 cycles of paclitaxel at a dose of 175 mg/m2 (ACpT) or AC followed by 4 cycles of docetaxel at a dose of 75 mg/m2 (ACdT), or 8 cycles of paclitaxel (PTx) or docetaxel (DTx) every 3 weeks. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival adverse events. The authors adopted a 2 * 2 factorial design to examine the AC containing-regimens (ACpT and ACdT) versus the AC free-regimens (PTx and DTx), and the paclitaxel-containing regimens (ACpT and PTx) versus the docetaxel-containing regimens (ACdT and DTx). RESULTS: Of 1060 patients, 1049 were treated and included in the intention-to treat population. The DFS results did not demonstrate noninferiority between the AC-containing and the AC-free regimens (hazard ratio [HR], 1.19; 95% confidence interval [95% CI], 0.982-1.448 [Pnoninferiority = .30]). Better outcomes were noted in patients treated with the docetaxel-containing regimens compared with the paclitaxel-containing regimens with respect to DFS (HR, 0.72; 95% CI, 0.589 0.875 [P = .0008]) and overall survival (HR, 0.75; 95% CI, 0.574-0.980 [P = .035]). Neutropenia, nausea, and vomiting were found to occur more often in the AC-containing arms, whereas the incidence of edema was greater in the docetaxel containing treatment arms. CONCLUSIONS: Noninferiority in DFS was not demonstrated between the AC-containing and AC-free regimens. Compared with a similar regimen of paclitaxel, docetaxel appeared to increase the DFS. Cancer 2017;123:759-68. (c) 2016 American Cancer Society. PMID- 28081305 TI - Biocompatible Multifunctional Black-Silicon for Implantable Intraocular Sensor. AB - Multifunctional black-silicon (b-Si) integrated on the surface of an implantable intraocular pressure sensor significantly improves sensor performance and reliability in six-month in vivo studies. The antireflective properties of b-Si triples the signal-to-noise ratio and increases the optical readout distance to a clinically viable 12 cm. Tissue growth and inflammation response on the sensor is suppressed demonstrating desirable anti-biofouling properties. PMID- 28081306 TI - Tracheal intubation in patients immobilized by a rigid collar: a comparison of GlideScope and an intubating laryngeal mask airway. AB - BACKGROUND/AIM: Intubation must be rapidly performed with the utmost care in cervical trauma patients. We present the first comparison of GlideScope and an intubating laryngeal mask airway (ILMA) regarding insertion and intubation times, intubation success rates, mucosal damage, need for optimization maneuvers, effects on hemodynamic changes, and postoperative minor complications in a simulated cervical injury with a Philadelphia cervical collar. MATERIALS AND METHODS: Ethics committee approval and patient consent were obtained and 94 American Society of Anesthesiology physical status I or II patients were enrolled in this study. Following standard anesthesia monitoring and induction, the Philadelphia-type cervical collar was applied and patients were subsequently intubated with ILMA or GlideScope. RESULTS: The total intubation success rates were similar between the groups (96%). The insertion (14.9 +/- 10 s vs. 21.9 +/- 6.5 s, respectively; P < 0.001) and intubation (43.5 +/- 13 s vs. 48.4 +/- 11 s; P = 0.02) times for ILMA were longer than for GlideScope. The total intubation times for ILMA were longer than the intubation time for GlideScope (43.5 +/- 13 s vs. 85.6 +/- 13 s; P < 0.001). The mucosal damage was higher in the ILMA group (P = 0.04). The two airway devices increased the heart rate and mean arterial pressure after insertion compared with the postinduction values within groups. CONCLUSION: GlideScope is superior to ILMA in terms of lower insertion and intubation times and lower levels of mucosal damage in cervical collar immobilized patients. PMID- 28081307 TI - The demographics and histopathological features of oral cavity cancers in Turkey. AB - BACKGROUND/AIM: This study aimed to examine the demographics and histopathological features of oral cavity cancers (OCCs) managed in our clinic. MATERIALS AND METHODS: Patients who were diagnosed with OCCs in the Gazi University Otorhinolaryngology Department between the years 1993 and 2013 were retrospectively enrolled in the study. Surgical archive charts and pathology records were reviewed in detail regarding the anatomical and histopathological profiles of the tumors, as well as the demographic data of the patients. RESULTS: Out of 230 patients with OCCs, the most common anatomic location and histopathological diagnosis were found to be the oral tongue (41.4%) and squamous cell carcinoma (SCC) (84.3%), respectively. A marked predominance of SCC was observed in all subsites of the oral cavity except the hard palate location. The mean age at presentation was 55.5 +/- 13.4 years (+/-SD). The male:female ratio was found to be 2.2:1. A male predominance was also present in all subsites except the retromolar trigon. CONCLUSION: OCCs particularly concern the elderly population with a male predominance. The most common location and histopathological type are the oral tongue and SCC, respectively. PMID- 28081308 TI - Exhaled carbon monoxide is a marker of heavy nicotine dependence. AB - BACKGROUND/AIM: Exhaled CO level provides an objective measure of a patient's smoking status. The relationship between CO levels and nicotine dependence is controversial. The aim of this study is to evaluate the relationship between exhaled CO levels and nicotine dependence as well as to demonstrate that exhaled CO levels may be used as a marker of nicotine dependence. MATERIALS AND METHODS: Two hundred eighty-nine patients (132 females, 157 males) were included in the study. Smoking duration, the age of smoking initiation, exhaled CO levels, and Fagerstrom Test for Nicotine Dependence (FTND) scores were recorded. The relationship between FTND scores and exhaled CO levels was investigated. RESULTS: There was a statistically significant correlation between FTND score and exhaled CO levels (P < 0.001). We found that a cut-off score of 7.5 ppm for exhaled CO may be useful as a marker for heavy smoking. The sensitivity and specificity of this cut-off score for exhaled CO was 69.3% and 49.3%, respectively (P < 0.001). CONCLUSION: We found that exhaled CO levels significantly correlated with FTND scores. For patients who are unable to provide reliable answers to questions in the FTND, exhaled CO measurements may be used as an alternative test for estimating the status of heavy smoking. PMID- 28081309 TI - Simulation of cryolipolysis as a novel method for noninvasive fat layer reduction. AB - BACKGROUND/AIM: Regarding previous problems in conventional liposuction methods, the need for development of new fat removal operations was appreciated. In this study we are going to simulate one of the novel methods, cryolipolysis, aimed to tackle those drawbacks. MATERIALS AND METHODS: We think that simulation of clinical procedures contributes considerably in efficacious performance of the operations. To do this we have attempted to simulate temperature distribution in a sample fat of the human body. Using Abaqus software we have presented the graphical display of temperature-time variations within the medium. RESULTS: Findings of our simulation indicate that tissue temperature decreases after cold exposure of about 30 min. It can be seen that the minimum temperature of tissue occurs in shallow layers of the sample and the temperature in deeper layers of the sample remains nearly unchanged. It is clear that cold exposure time of more than the specific time (t > 30 min) does not result in considerable changes. CONCLUSION: Numerous clinical studies have proved the efficacy of cryolipolysis. This noninvasive technique has eliminated some of drawbacks of conventional methods. Findings of our simulation clearly prove the efficiency of this method, especially for superficial fat layers. PMID- 28081310 TI - A simple risk score in acute ST-elevation myocardial infarction: Modified ACEF(age, creatinine, and ejection fraction) score. AB - BACKGROUND/AIM: The aim of this study was to evaluate if the modified ACEF (age, creatinine, and ejection fraction) score is a predictor of major adverse cardiac and cerebrovascular events during 1 year of follow-up in patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI). MATERIALS AND METHODS: We retrospectively enrolled 1632 consecutive patients who were admitted to our emergency department diagnosed with STEMI within 12 h of chest pain and treated with primary PCI. The modified ACEF score, determined with a simplified scoring system, was calculated. The patients were grouped into tertiles according to this score (group I mACEF < 1.03, group II mACEF 1.03-1.37, group III > 1.37) . The clinical and angiographic data were compared among the tertiles. RESULTS: In patients with the highest mACEF tertile, out-of-hospital cardiac arrest (1.3%, 1.8%, and 4.1% consecutively; P = 0.003), Killip class ≥ II (P < 0.001), and cardiogenic shock were more common and ejection fraction was lower (P < 0.001). Moreover, in the 1-year follow-up, there was a statistically significant difference between cardiac mortality, target vessel revascularization, stroke, reinfarction, and major adverse cardiac and cerebrovascular events of the groups, while the rates of stent thrombosis were similar. CONCLUSION: The modified ACEF score is a predictor of cardiac mortality and morbidity during 1-year follow-up. PMID- 28081311 TI - Applying the International Classification of Functioning, Disability, and Health in children with low vision: differences between raters. AB - BACKGROUND/AIM: This study was conducted to analyze the agreement between International Classification of Functioning, Disability, and Health (ICF) raters and to show its applicability in children with low vision. MATERIALS AND METHODS: Twenty children (mean age: 11.70 +/- 1.92 years) were included. To evaluate the independency of the sample, the Northwick Park Activities Daily Living questionnaire was used. The Low Vision Quality of Life Scale was used to evaluate quality of life. An ICF core set was developed to be used in this study. The core set consisted of 13 items for body functions, 3 items for body structures, 36 items for activity and participation, and 12 items for environmental factors. RESULTS: High agreement was found between two raters in terms of subparameters of the ICF core set for activity and participation (r = 0.880, P = 0.000). CONCLUSION: The findings indicate that the raters showed strong agreement in terms of the ICF core set used in this study. This shows that the core set can be used to evaluate activity and participation of children with low vision. PMID- 28081312 TI - The effects of balneotherapy on acute, process-related, and cumulative peripheral cardiac responses and pulmonary functions in patients with musculoskeletal disorders. AB - BACKGROUND/AIM: This study aimed to evaluate the effects of balneotherapy on acute, process-related, and cumulative peripheral cardiac responses and pulmonary functions in patients with musculoskeletal disorders. MATERIALS AND METHODS: Ninety-eight patients with musculoskeletal disorders referred to physiotherapy with balneotherapy were recruited. The patients received balneotherapy for 20 min 5 times per week for 2 weeks. Blood pressure and pulse were measured at the 0th, 5th, 10th, 20th, and 30th minutes during the 1st and 10th sessions. All patients were subjected to pulmonary function testing before balneotherapy and after the 10th session. RESULTS: It was found that systolic blood pressure decreased between the 10th and 20th minutes of the 1st session and between the 10th and 20th minutes and the 20th and 30th minutes of the 10th session (P < 0.05). Diastolic blood pressure (DBP) decreased and pulse increased during balneotherapy (P < 0.05). DBP increase and pulse decrease were observed during recovery time (P < 0.05). The blood pressure decreased and the pulse increased after the 1st session and after the 10th session (P < 0.05). Pulmonary function improved after balneotherapy (P < 0.05). Conclusions: Balneotherapy may be effective for improving peripheral cardiopulmonary responses in patients with musculoskeletal disorders. PMID- 28081313 TI - Clinical and histopathological features of asymptomaticpersistent microscopic hematuria in children. AB - BACKGROUND/AIM: We analyzed the clinical and pathological features and prognosis of 106 children with persistent asymptomatic microscopic hematuria (PAMH) with or without mild proteinuria. MATERIALS AND METHODS: This was a retrospective study of 106 children who were referred to our clinics from 2000 to 2013 for evaluation of PAMH. RESULTS: Among the 106 patients, 69 (65%) were female and 37 (35%) were male. The patients were divided into two groups: 101 patients with isolated microscopic hematuria (IMH) and 5 patients with asymptomatic microscopic hematuria and mild proteinuria (AMHP). Renal biopsy was performed in all 5 children with AHMP: 2 patients had hereditary nephropathy and 2 patients had focal segmental glomerulosclerosis (FSGS). One biopsy specimen revealed nonspecific findings. Renal biopsy was performed in 9 children with IMH: 4 patients had hereditary nephropathy and 5 patients had nonspecific findings. None of the patients received any specific treatment prior to renal biopsy. During the follow-up period, none of the patients developed impaired renal function. Among all the children, only one patient with AMHP developed hypertension and 2 patients with IMH developed proteinuria. CONCLUSION: Long-term follow-up must be done carefully for isolated microscopic hematuria and renal biopsy should be performed in selected cases. PMID- 28081314 TI - Cryptogenic organizing pneumonia: clinical and radiological features, treatment outcomes of 17 patients, and review of the literature. AB - BACKGROUND/AIM: We evaluated patients with cryptogenic organizing pneumonia (COP) who attended our clinic. MATERIALS AND METHODS: We retrospectively investigated the clinical and radiological findings, diagnostic methods, treatment, and follow up outcomes of 17 patients who had been histopathologically diagnosed with COP. RESULTS: The mean age of the patients was 49.8 +/- 10.4 years. The most common symptom was cough (n = 15; 88.2%) and the most common radiological finding (n = 10) was consolidation in the inferior lobes on thoracic computed tomography. The diagnosis of COP was made by open lung biopsy in 11 (64.7%) patients, transbronchial biopsy in 5 (29.4%), and video-assisted thoracoscopic surgery biopsy in 1 (5.9%). The mean follow-up period was 28.7 +/- 25.0 (range: 3-85) months. Twelve patients received oral corticosteroid therapy and seven of them improved without any fibrotic changes. One patient refused treatment; a chest radiography of that patient was found to be normal at the end of the 20-month follow-up period. Three patients received no other therapy, as the lesion had been completely excised. CONCLUSION: Common symptoms included cough and dyspnea, while the main radiological presentation of COP was consolidation. Corticosteroids are a good treatment option in general, but relapse may occur. PMID- 28081315 TI - The association of papillary thyroid cancer with microcalcification in thyroidnodules with indeterminate cytology based on fine-needle aspiration biopsy. AB - BACKGROUND/AIM: Microcalcifications are generally accepted as highly specific for thyroid malignancy, especially for papillary thyroid carcinoma (PTC). The aim of this study was to determine the significance of microcalcification within nodules that were classified as being of “indeterminate cytology” (IC) according to fine-needle aspiration biopsy. MATERIALS AND METHODS: Patients who underwent thyroidectomy between January 2010 and 2013 were included in the study. Nodules identified as “atypia/follicular lesion of undetermined significance", "follicular neoplasm/suspicious for follicular neoplasm", or "suspicious for malignancy" were categorized as IC. Patients were subcategorized depending on the presence of microcalcification (Group 1) or its absence (Group 2). The relationship between microcalcification and PTC was evaluated in the IC group retrospectively. RESULTS: Indeterminate cytology was detected in 135 (28.5%) of 473 patients. Microcalcification was detected in 27 (20%) of 135 nodules and classified as Group 1, while the remaining 108 (80%) patients were classified as Group 2. According to the final pathology results, PTC was diagnosed in 13 of 27 (48.1%) patients in Group 1 and 29 of 108 (26.8%) patients in Group 2. A statistically significant relation between microcalcification and malignancy was determined in the IC group (P < 0.05). CONCLUSION: Surgery might be considered primarily for patients harboring nodule(s) with IC accompanied by microcalcification due to increased risk of PTC. PMID- 28081316 TI - Evaluation of epidemiological characteristics and risk factors affecting mortality in patients with candidemia. AB - BACKGROUND/AIM: The aim of this study was to determine epidemiologic characters of patients with candidemia and to evaluate risk factors that can affect mortality rates among these patients. MATERIALS AND METHODS: Patients admitted to the Istanbul Medeniyet University Goztepe Training Hospital between 2009 and 2011 who had a positive blood culture for Candida spp. during hospitalization were studied retrospectively for demographic characteristics and risk factors. Statistical comparisons were estimated with the Stata 12 package. Independent variables associated with mortality were estimated by Cox regression analyses. RESULTS: A total of 89 patients were identified with a positive blood culture. Of the isolates, 72% (64/89) were C. albicans and 10% (9/89) were non-albicans Candida, while 18% (16/89) were unidentified. C. parapsilosis was the most frequently isolated species among non-albicans Candida. The crude mortality rate among candidemia cases was 30% (27/89). By univariate analysis, being in the ICU and age (>=50 or >=60) were found to be statistically significant, whereas by multivariate analysis only age of >=50 years was independently more associated with mortality (OR, 2.7; CI, 1.05-6.73). CONCLUSION: Candidemia is associated with high mortality rates. Patients older than 50 years are found to be at considerable risk in terms of adverse outcomes. PMID- 28081317 TI - Hormone therapy in hypospadias surgery: a survey on the current practice in Turkey. AB - BACKGROUND/AIM: Nowadays surgical intervention is possible in smaller phalluses and younger children with hypospadias disease. Different hormone treatments with different doses, modalities, indications, and treatment times come along with some disputes. The aim of this study is to evaluate the management approaches in hypospadias surgery of surgeons in regards to hormone preparations. MATERIALS AND METHODS: Questionnaires were sent via e-mail to 110 actively working pediatric surgeons and urologists. The answers of 99 surgeons were evaluated (90%). Two surgeons declared that they did not perform hypospadias surgery. RESULTS: When testosterone usage in penile surgery was questioned, 44.4% of participants (n = 44) answered positively. Small-short penis glans, narrow urethral plate, chordee, disorders of sexual development, buccal mucosa-graft operations, slight tissue, and defective ventral skin were the indications for usage. Forty of forty-four surgeons stated usage in proximal hypospadias, 18 of them in penile hypospadias, and 15 of them in distal hypospadias. The most common form was dihydrotestosterone (62%). According to the respondents, fistulas (83%), infections (78%), and wound dehiscence (77%) were reduced. Fifty-six percent of the surgeons stated that bleeding was increased and 39% stated easier dissection. CONCLUSION: As a result of this questionnaire we can understand that there is no standard usage of testosterone in Turkey. Optimal points of usage can be introduced by increasing prospective randomized trials and education programs can ensure similar effective usage. PMID- 28081318 TI - Clinical characteristics and outcome of Brucella endocarditis. AB - BACKGROUND/AIM: Brucella endocarditis, which is a rare condition, is the most common cause of death in human brucellosis, leading to severe cardiac complications. By collecting and analyzing clinical cases, we analyzed the clinical characteristics and outcome of Brucella endocarditis in endemic areas in China. MATERIALS AND METHODS: Presented here are 5 cases of Brucella endocarditis, all managed uniformly. We present the clinical, serological, and echocardiographic features; the therapeutic approach; and the follow-up of five patients with Brucella endocarditis. RESULTS: There was a predominance of aortic involvement (4 cases) and a high incidence of left ventricular failure (5 cases). Polymerase chain reaction (PCR) testing was positive in all five patients. Diagnostic suspicion was essential in order to test blood cultures correctly, which in this series were positive in 3 patients. In the follow-up postoperative period of a minimum of 24 months, the patients suffered rare relapse in terms of either the infection or the dysfunction in terms of prosthesis after 3-month antibiotic therapy, with only one exception that died within that period. CONCLUSION: We should pay attention to Brucella infections and strengthen public awareness and education. It is necessary to screen for and recognize Brucella endocarditis cases early and to provide adequate antibiotic treatment. PMID- 28081319 TI - Chronic cough: clinical characteristics and etiologies of 510 cases. AB - BACKGROUND/AIM: To investigate the clinical features and underlying etiologies of chronic cough (CC). MATERIALS AND METHODS: Five hundred and ten CC patients were enrolled. The phases, characteristics and associated clinical manifestations of CC among the gastroesophageal reflux cough (GERC), cough-variant asthma (CVA), and upper airway cough syndrome (UACS) groups were compared, and the diagnostic values of each group were evaluated by multiple regression analysis. RESULTS: In the 510 patients, 404 had CC with single etiology-GERC (n = 175), CVA (n = 134), and UACS (n = 95). The characteristic features of GERC included gastric acid backflow symptoms such as sour-tasting regurgitation, heartburn, endoscopic esophagitis, poststimulation cough, frequent throat clearing, daytime mono-cough, and feelings of heaviness and pain in the chest. Patients with CVA typically exhibited sensitivity to smog and other irritants; the cough occurred mostly at night, and was associated with positive bronchodilator and provocation test results. The typical features of UACS included a history and/or symptoms of rhinitis, retropharyngeal postnasal drip, and wet cough occurring mostly during the daytime. The diagnostic specificities of above factors were >70%. CONCLUSION: The most common causes of CC include GERC, CVA, and UACS, and their diagnosis is based on the characteristics of the underlying disease. PMID- 28081320 TI - Pityriasis rosea: a natural history of pediatric cases in theCentral Anatolia Region of Turkey. AB - BACKGROUND/AIM: This study aimed to evaluate the demographic, clinical, and epidemiological features of pityriasis rosea (PR) in a cohort of 46 children in Yozgat, a city in the Central Anatolia Region of Turkey. MATERIALS AND METHODS: Forty-six children with PR were monitored at regular intervals (1, 2, 4, and 12 weeks) for 3 months from the time of diagnosis. A complete evaluation of the patient was performed at each visit. RESULTS: The average age of patients at time of diagnosis was 12 +/- 3.9 years. Cases were most common in the winter (rainy, snowy months; n = 14, 31%). Fifteen patients had a medical history significant for the presence of upper respiratory tract infection, while skin PR manifestations were preceded by drug intake in a second group of 15 patients. The presence of a herald patch was observed in 78.3% of patients, most frequently on the trunk (n = 23). Pruritus occurred in 75% of patients. Median PR duration was 3 weeks (range: 1-20 weeks). CONCLUSION: The course of PR is similar in Turkish children and adults. The high prevalence of pruritus in children with PR in Turkey was also significant. Further evaluation of this finding comparing adults and children is now required. PMID- 28081321 TI - Sleep quality in opioid-naive and opioid-dependent patientson methadone maintenance therapy in Malaysia. AB - BACKGROUND/AIM: Sleep disturbances may contribute to poor treatment outcomes in opioid-dependent patients. The extent to which the sleep profiles of opioid dependent patients differ from those of the general Malaysian population is not documented. This study compared opioid-naive subjects and opioid-dependent patients on methadone maintenance therapy (MMT) in terms of their sleep quality. MATERIALS AND METHODS: Participants comprised Malay male opioid-naive subjects (n = 159) and opioid-dependent patients (n = 160) from MMT clinics in Kelantan, Malaysia, between March and October 2013. Sleep quality was evaluated using the translated and validated Malay version of the Pittsburgh Sleep Quality Index (PSQI). RESULTS: The opioid-dependent patients exhibited higher global PSQI scores [adjusted mean (95% CI) = 5.46 (5.02, 5.90)] than the opioid-naive group [4.71 (4.26, 5.15)] [F (1, 313) = 4.77, P = 0.030]. CONCLUSION: This study confirmed the poorer sleep quality among opioid-dependent patients on MMT, as manifested by their higher global PSQI scores. The sleep complaints in this patient population are a factor to consider and, when necessary, sleep evaluation and treatment should be undertaken to improve MMT patients' quality of sleep and overall treatment outcome. PMID- 28081322 TI - Does CPAP treatment affect the voice? AB - BACKGROUND/AIM: The aim of this study was to investigate alterations in voice parameters among patients using continuous positive airway pressure (CPAP) for the treatment of obstructive sleep apnea syndrome. MATERIALS AND METHODS: Patients with an indication for CPAP treatment without any voice problems and with normal laryngeal findings were included and voice parameters were evaluated before and 1 and 6 months after CPAP. Videolaryngostroboscopic findings, a self rated scale (Voice Handicap Index-10, VHI-10), perceptual voice quality assessment (GRBAS: grade, roughness, breathiness, asthenia, strain), and acoustic parameters were compared. RESULTS: Data from 70 subjects (48 men and 22 women) with a mean age of 44.2 +/- 6.0 years were evaluated. When compared with the pre CPAP treatment period, there was a significant increase in the VHI-10 score after 1 month of treatment and in VHI- 10 and total GRBAS scores, jitter percent (P = 0.01), shimmer percent, noise-to-harmonic ratio, and voice turbulence index after 6 months of treatment. Vague negative effects on voice parameters after the first month of CPAP treatment became more evident after 6 months. CONCLUSION: We demonstrated nonsevere alterations in the voice quality of patients under CPAP treatment. Given that CPAP is a long-term treatment it is important to keep these alterations in mind. PMID- 28081323 TI - Acute exudative tonsillitis in adults: the use of the Centor scoreand some laboratory tests. AB - BACKGROUND/AIM: The aim of our study was to determine the usefulness of the Centor score and some basic laboratory tests (complete blood count and C-reactive protein) for the differential diagnosis of exudative tonsillitis due to Group A β-hemolytic streptococcus (GABHS) or due to non-GABHS agents. MATERIALS AND METHODS: The data of clinical and laboratory characteristics of the patients diagnosed with exudative tonsillitis were collected and statistically compared between those having positive GABHS throat culture result and those who were negative for any bacterial agent. RESULTS: Totally 899 adult patients were included in our study; 56 (6.2%) of them were positive for GABHS, while 34 (3.8%) of the cases had a bacterial cause other than GABHS. The remaining 809 (90%) were accepted as non-GABHS cases. The percentages of patients having Centor score of 3 or greater, neutrophilia, lymphocytopenia, and CRP values of greater than 5-fold normal upper reference range were significantly higher in GABHS patients. CONCLUSION: Centor score of 3 or more together with high CRP, neutrophilia, and lymphocytopenia is predictive for GABHS tonsillopharyngitis. PMID- 28081324 TI - Treatment efficacy and superinfection rates in complicated urinarytract infections treated with ertapenem or piperacillin tazobactam. AB - BACKGROUND/AIM: In this retrospective study, the efficacy of ertapenem and piperacillin tazobactam was compared in the treatment of complicated urinary tract infections (cUTIs). Treatment responses were also evaluated for both antibiotics. MATERIALS AND METHODS: A total of 230 patients were enrolled in the study. Of these, 170 received ertapenem and 60 received piperacillin-tazobactam. RESULTS: In both groups, urine cultures after 48 h were negative for the initial uropathogen. The frequency of superinfection was 29.4% in the ertapenem group and 8.3% in the piperacillin-tazobactam group over the duration of treatment (P < 0.05). Urinary catheterization increased the superinfection risk 2.88-fold in the ertapenem group and diabetes mellitus increased the risk 8.50-fold in the piperacillin-tazobactam group (CI: 1.44-5.76 and 1.16-62.09, respectively, P < 0.05). The main pathogen isolated from superinfection in the ertapenem group after 48 h was Enterococcus spp. (71.4%). CONCLUSION: Both ertapenem and piperacillin-tazobactam were effective in the treatment of cUTIs caused by ESBL producing microorganisms. A high frequency of superinfection in the ertapenem group was the result of Enterococcus and Pseudomonas spp., against which ertapenem is not active. In the presence of urinary catheterization, diabetes mellitus, and urological intervention, patients should be closely monitored for the development of a superinfection, especially patients receiving ertapenem. PMID- 28081325 TI - Plasma levels of serotonin, gastrointestinal symptoms,and sleep problems in children with autism. AB - BACKGROUND/AIM: Autism is a neurodevelopmental disorder identified with higher frequency of serotonin abnormalities and gastrointestinal (GI) and sleep problems. This study aimed to evaluate the plasma levels of serotonin, GI symptoms, and sleep problems, and their relationship with autism severity in children with autism. MATERIALS AND METHODS: Thirty-five children with autism and 31 healthy subjects were studied. GI problems, sleep disorders, and severity of disorder were assessed. Plasma serotonin was determined using ELISA. RESULTS: There was no significant association between GI problems and autism severity, but a significant positive correlation was seen between different indicators of sleep disorder and severity of autism. Plasma levels of serotonin were significantly higher in autistic children and a significant negative correlation was observed between plasma levels of serotonin and autism severity (r = -0.39, P = 0.02). CONCLUSION: Elevated plasma serotonin in autistic children and its negative correlation with disease severity may indicate involvement of the neurotransmitter in the neurophysiologic mechanism of autism. PMID- 28081326 TI - The effect of deep sclerectomy on ocular blood flow: a 6-month clinical trial. AB - BACKGROUND/AIM: To investigate the effect of deep sclerectomy on retrobulbar blood flow. MATERIALS AND METHODS: This prospective study included 20 eyes of 20 patients with open angle glaucoma. Color Doppler imaging (CDI) examinations were performed before and 2, 12, and 24 weeks after deep sclerectomy. Peak systolic velocity (PSV), end diastolic velocity (EDV), and resistance index (RI) were measured for the ophthalmic artery (OA), central retinal artery (CRA), and temporal and nasal short posterior ciliary arteries (SPCAs) at each examination and the results were compared. RESULTS: A significant decrease was determined in intraocular pressure (IOP) (P < 0.001) and a significant increase in ocular perfusion pressure (OPP) (P < 0.001) at all postoperative examinations. The EDV in OA increased significantly (P < 0.001), but the change in RI was not statistically significant (P = 0.67). EDV increased and RI decreased significantly in CRA and SPCA (P < 0.001). CONCLUSION: Deep sclerectomy decreases IOP and increases OPP significantly. Retrobulbar blood flow was seen to improve after deep sclerectomy. PMID- 28081327 TI - Biliary stenting in difficult common bile duct stones: a single tertiary center experience. AB - BACKGROUND/AIM: We aimed to examine the effect of plastic biliary stenting in the treatment of common bile duct (CBD) stones. MATERIALS AND METHODS: The data of 13,034 patients in our unit who had endoscopic retrograde cholangiopancreatography (ERCP) between 2008 and 2015 were scanned retrospectively. RESULTS: A biliary stent was placed in 61 of 74 patients. While the plastic biliary stent was placed in patients, the mean stone size after the 1st ERCP was 20 mm and the bile duct size was 13 mm. At the time of the 2nd ERCP conducted approximately 73.9 days later, the mean stone size was found to be 15 mm and the bile duct size was 12 mm. With recurrent ERCPs, the CBD stone was successfully removed in 53 patients but could not be removed in 8 patients. Among the 53 successful cases, 29 removals were successful in the 2nd ERCP session, 16 were successful in the 3rd session, 2 were successful in the 4th session, 1 was successful in the 5th session, 4 were successful in the 6th session, and 1 was successful in the 7th session. CONCLUSION: For CBD stones that cannot be removed by standard methods, temporary plastic stenting is an alternative method. PMID- 28081328 TI - Cytomegalovirus hepatitis in 49 pediatric patients with normal immunity. AB - BACKGROUND/AIM: Cytomegalovirus (CMV) hepatitis is generally asymptomatic or rarely can lead to severe complications in immunocompetent hosts. This study aims to evaluate CMV hepatitis in immunocompetent young children, which is discussed relatively rarely in the literature. MATERIALS AND METHODS: A retrospective review of 49 pediatric patients with CMV hepatitis from January 2005 to December 2010 was performed. RESULTS: The median age of the patients was 5.81 +/- 6.49 months and 57.1% were female. Complaints were prolonged jaundice, vomiting, diarrhea, and abdominal distension. Seventeen patients (34.6%) had congenital or probable congenital CMV infection, while 32/49 (65.3%) had perinatal CMV infection. CMV hepatitis was accompanied by other system findings in 22 patients (44.9%), and only liver involvement was present in 27/49 (55.1%). Alanine aminotransferase and aspartate aminotransferase were elevated together in all patients. Cholestatic hepatitis was present in 13 patients (26.5%). Four patients (8.16%) were treated with ganciclovir. Complete improvement of hepatitis occurred in 48/49 (97.95%). The recovery time of liver function tests was 7-180 days (mean: 53.92 +/- 40.8). CONCLUSION: CMV hepatitis is usually mild and has a good outcome in immunocompetent individuals. However, cases should be carefully evaluated due to the important role of CMV in the etiology of infantile and neonatal hepatitis. PMID- 28081329 TI - Daily surveillance with early warning scores help predicthospital mortality in medical wards. AB - BACKGROUND/AIM: To analyze the potency of a modified early warning score (EWS) to help predict hospital mortality when used for surveillance in nonacute medical wards. MATERIALS AND METHODS: Patients in internal medicine wards were prospectively recruited. First, highest, and last scores; and mean daily score recordings and values were recorded. Nurses calculated scores for each patient upon admission and every 4 h. The last score was the score before death, discharge, or transfer to another ward. The highest scores in total and for each single parameter were used for analysis. RESULTS: Fifty-nine percent of 182 recruited patients had recordings eligible for data analysis. Patients admitted from the emergency room had higher mortality rates than patients admitted from outpatient clinics (15% vs. 1.5%; P = 0.01) as well as patients whose first (40% vs. 4.9%; P = 0.033) and highest scores (18.8% vs. 1.3%; P = 0.003) were equal to or more than 3. The first recorded EWS was not predictive for mortality while the maximum score during the admission period was. CONCLUSION: This study underlines the fact that each physiological variable of EWS may not have the same weight in determining the outcome. PMID- 28081330 TI - Experiential avoidance, empathy, and anger-related attitudesin antisocial personality disorder. AB - BACKGROUND/AIM: In prevailing opinion, a strong relation exists between lack of empathy and antisocial personality disorder (ASPD). However, recent data fail to wholly clarify this relation, especially in consideration of empathy dimensions. In this study our aim was to address ASPD and social functionality from a contextual behavioral science viewpoint. MATERIALS AND METHODS: The present study was conducted with a sample of 34 individuals with ASPD and 32 healthy individuals as the control group. The participants were assessed with a sociodemographic form, Structured Clinical Interviews for DSM I and II (SCID-I and SCID-II), Social Functioning Scale (SFS), Acceptance and Action Questionnaire II for measuring experiential avoidance, Interpersonal Reactivity Index for measuring empathy dimensions, and the State-Trait Anger Scale for anger-related attitudes. RESULTS: Experiential avoidance, dysfunctional anger regulation patterns, and lack of perspective-taking levels were higher in the ASPD group than in the control group. Experiential avoidance and perspective-taking processes were related with social functioning in ASPD. CONCLUSION: These findings may provide initial data for understanding ASPD clinical features and related social interaction problems. Further relations between scales and social functionality also analyzed and discussed. PMID- 28081331 TI - Segmental epidural anesthesia for percutaneous kyphoplasty:comparison with general anesthesia. AB - BACKGROUND/AIM: This is a feasibility study evaluating whether segmental epidural anesthesia is an alternative anesthetic approach to general anesthesia for percutaneous kyphoplasty. MATERIALS AND METHODS: After ethics committee approval was obtained, 52 ASA class I-III patients scheduled for elective, single-level percutaneous kyphoplasty were recruited. The patients were divided into two equal groups. In Group E (Group Epidural) segmental epidural anesthesia was performed using the loss of resistance technique with saline. In Group G (Group Control) general anesthesia was performed. Hemodynamic parameters, intraoperative and postoperative analgesic requirements, visual analogue scale (VAS) scores, length of stay in the postanesthesia care unit (PACU), and complications were recorded. RESULTS: Hemodynamics were similar between the two groups. Postoperative analgesic requirement was significantly higher in Group G than in Group E (P < 0.004). VAS scores were significantly lower in Group E than in Group G (P < 0.05). Time to first pain experience at the first postoperative 4 h was significantly longer and length of stay in the PACU was significantly shorter in Group E than in Group G (P < 0.001). CONCLUSION: Segmental epidural anesthesia is a safe anesthetic technique for percutaneous kyphoplasty. This technique offered advantages over general anesthesia in terms of postoperative analgesia, analgesic consumption, early recovery, and short PACU stay. Therefore, it should be considered a suitable anesthetic technique in patients undergoing single level percutaneous kyphoplasty. PMID- 28081333 TI - Bone mineral density and growth in children with coeliac disease on a gluten free diet. AB - BACKGROUND/AIM: To evaluate changes in growth and bone metabolism during consumption of a gluten-free diet (GFD) in children with coeliac disease (CD). MATERIALS AND METHODS: Thirty-seven children with CD (mean age of 8.8 +/- 4.6 years, 21 girls) were enrolled. Anthropometric measurements, bone mineral density (BMD) in lumbar 2-4 vertebrae, and serum alkaline phosphatase, calcium, and phosphorus levels at diagnosis and at follow-up were recorded. RESULTS: The mean follow-up period was 3.5 +/- 2.3 years. The BMD of patients was significantly lower than that of control subjects at the time of diagnosis but not after 1 year of the GFD. Incidence of low BMD with respect to z-scores for chronological age (CA) was significantly higher than z-scores for height age (HA) (P = 0.006). At the first year of GFD, BMD, BMD z-score, height-for-age z-scores, and weight-for age z-scores were significantly increased compared with the baseline, but not after 1 year of the GFD. CONCLUSION: In CD, the first year of GFD is important in weight gain, linear growth, and improvement of BMD. A considerable relation of low BMD in children with CD, with respect to z-scores for CA, may be a result of misinterpretation of low BMD due to short stature. PMID- 28081332 TI - Surgical management of large-cell neuroendocrinelung carcinoma: an analysis of 25 cases. AB - BACKGROUND/AIM: Large-cell neuroendocrine carcinoma (LCNEC) of the lung is a relatively uncommon and aggressive subset of pulmonary neuroendocrine tumors, which include typical and atypical carcinoid, and small-cell lung cancer. LCNEC of the lung accounts for no more than 1% of all lung cancers. LCNECs show features of high-grade neuroendocrine tumors and patients with LCNEC have a very poor prognosis. MATERIALS AND METHODS: Twenty-five patients (22 males and 3 females; mean years 60.7; range 48 to 77 years) who underwent pulmonary resection for large-cell neuroendocrine carcinoma between January 2004 and December 2014 were investigated retrospectively. RESULTS: Type of surgery, pathologic TNM stage, adjuvant chemotherapy, time of recurrence, site of recurrence, response to treatment, and long-term results were evaluated. The longest patient follow-up period was 83 months. One-, two-, and three-year survival rates of these patients were, respectively, 80.95%, 76.47%, and 50%. CONCLUSION: Complete surgical resection is the treatment of choice for early-stage LCNEC and chemotherapy after radical surgical treatment improves survival. Follow-up periods after surgery adjuvant chemotherapy will prevent recurrence and patients may survive for many years if complete surgical resection and adjuvant chemotherapy are possible. PMID- 28081334 TI - Comparison of the distinctive pathological features of and p16 and c Kitexpression levels in benign and malignant endometrial polyps. AB - BACKGROUND/AIM: Histopathological examination is crucial for the effective management of endometrial polyps. Immunohistochemical markers such as p16 and c Kit may facilitate the differential diagnoses of benign and malignant polyps. The aim of the present study was to explore the expression levels of c-Kit (CD117) and p16 in endometrial polyps of postmenopausal women. MATERIALS AND METHODS: Twenty-five hysterectomy specimens with malignant endometrial polyps and hysterectomy or polypectomy specimens featuring 55 benign polyps were studied. The polyps were immunohistochemically stained for p16 and c-Kit, and differences in the expression levels of these proteins in the glandular and stromal components of benign polyps and the benign regions of the malignant polyps were assessed by using Fisher's exact test. RESULTS: The glandular components of malignant polyps exhibited significantly more intense p16 immunostaining than did benign polyps. Most immunoreactive cells were glandular cells exhibiting tubal metaplasia. The stromal components of either type of polyp did not differ in terms of p16 immunostaining. The extent of c-Kit immunostaining in benign and malignant polyps was similar. CONCLUSION: The extensive tubal metaplasia in and the p16 immunoreactivity of the glandular components of malignant polyps may be useful to distinguish such polyps from benign polyps. PMID- 28081335 TI - Comparison of wire-guided localization and radio-guided occult lesionlocalization in preoperative localization of nonpalpable breast lesions. AB - BACKGROUND/AIM: Breast lesions that are not palpable on physical examination but considered suspicious for malignancy on mammography or ultrasonography should be marked before surgery. Wire-guided localization (WGL) is the most frequently used method for preoperative marking of nonpalpable breast lesions (NPBLs). An alternative is marking by a radioactive agent (radio-guided occult lesion localization; ROLL). The present study aimed to compare WGL and ROLL for preoperative marking. MATERIALS AND METHODS: The study included 25 patients marked by ROLL and 11 patients marked by WGL. The groups were compared in terms of patient and lesion characteristics, method-related characteristics, hospital stay duration, complications, cosmetic outcomes, and rate of correct marking. RESULTS: Suspicious lesions were marked with a success rate of 95.6% by ROLL and 100% by WGL. Complications and pain sensation rates were found significantly lower in the ROLL group compared to WGL. Although ROLL was considered more advantageous in terms of hospital stay duration, positive surgical margins, cosmetic outcomes, and excision duration, the differences between the groups were not statistically significant. CONCLUSION: ROLL, which is a simple, comfortable, and reliable method, could be used as an alternative to the WGL in preoperative marking of NPBLs. PMID- 28081336 TI - The factors affecting survival in patients with bronchiectasis. AB - BACKGROUND/AIM: There is limited information about the rate and modifiers of mortality in noncystic fibrosis bronchiectasis. MATERIALS AND METHODS: This study enrolled a total of 56 bronchiectasis patients. Patients' body mass index, smoking habit, previous therapies, comorbid disorders, history of vaccination, bronchiectasis type and radiological extent, arterial blood gas analysis, respiratory function tests, and laboratory results were recorded. RESULTS: After a follow-up of 65.38 +/- 18.62 months the overall mortality rate was 35.7%. The mean survival duration was 46.42 +/- 8.25 months. Advanced age significantly increased mortality (HR: 2.031; CI: 0.991-4.072, P = 0.035). A significant correlation was found between mortality rate and the partial oxygen pressure level (HR: 0.886 (CI: 0.817-0.960); P = 0.039). Pulmonary artery pressure was directly proportional to mortality rate (HR: 9.015 (CI: 3.272-94.036); P = 0.03). There was also a significant correlation between Pseudomonas aeruginosa proliferation in sputum and mortality (HR: 7.014 (CI: 2.812-17.962); P = 0.00). Comorbidities increased mortality (HR: 1.984 (CI: 0.972-2.996); P = 0.04). CONCLUSION: Bronchiectasis is a disease with high mortality. Advanced age, comorbid conditions, reduced partial oxygen pressure, pulmonary hypertension, and Pseudomonas aeruginosa proliferation in sputum increase its mortality rate. PMID- 28081337 TI - Do anxiety and depression statuses differ in differentpolycystic ovary syndrome phenotypes? AB - BACKGROUND/AIM: To evaluate psychological parameters and health quality profiles in women with reproductive polycystic ovary syndrome (PCOS) phenotypes and age matched controls. MATERIALS AND METHODS: The study groups included 101 women with PCOS (54 with the National Institutes of Health [NIH] phenotype and 47 with the non-NIH phenotype) and 49 healthy female controls. The participants completed anxiety and depression scales and four quality of life domains. RESULTS: We identified the women with PCOS as having a 3.39 times increased risk for depression (subscale ≥ 7) and a 3.64 times increased risk for anxiety (subscale ≥ 10) compared to the controls. Both NIH and non-NIH phenotypes showed similar rates of depression (46.3% vs. 46.8%, respectively; P = 0.57) and anxiety (31.5% vs. 36.2%, respectively; P = 0.47). Regarding the quality of life scale, the women with NIH PCOS had significantly lower mental health scores compared to those with non-NIH PCOS (P = 0.03). Furthermore, while mental health scores were similar in the women with PCOS and the controls, physical health scores were significantly lower in the women with PCOS (P = 0.007). CONCLUSION: Nearly half of the women with PCOS had higher depression scores and one third had higher anxiety scores. Thus, psychiatric evaluations appear necessary for PCOS patients in order to diagnose and treat clinical depression and anxiety. PMID- 28081338 TI - New immunohistochemical markers in the differential diagnosisof nonsmall cell lung carcinoma. AB - BACKGROUND/AIM: The aim of this study was to investigate Napsin-A, NTRK-1, NTRK 2, Desmoglein-3, and Desmocollin-3 in the differential diagnosis and prognosis of nonsmall cell lung cancer. MATERIALS AND METHODS: The expression of Napsin-A, NTRK-1, NTRK-2, and Desmoglein-3 was examined by immunohistochemistry in 50 squamous cell carcinomas and 50 adenocarcinomas. Desmocollin-3 was investigated in 29 squamous cell carcinoma and 29 adenocarcinoma cases. Associations between expression profiles of Napsin-A, NTRK-1, NTRK-2, Desmoglein-3, and Desmocollin-3 in lung cancers and clinicopathological variables were analyzed. RESULTS: Napsin A staining was statistically significant in detecting adenocarcinomas versus squamous cell carcinomas. The sensitivity of Napsin-A for adenocarcinomas was 96% and the specificity was 100%. NTRK-2 and Desmocollin-3 staining were statistically significant in detecting squamous cell carcinomas versus adenocarcinomas. Desmoglein-3, Napsin-A, and NTRK-2 had no effect on survival. Disease-free survival time was significantly shorter in cases that were moderately positive with NTRK-1. CONCLUSION: Our data suggest that Napsin-A, NTRK 2, and Desmocollin-3 are useful markers in the differentiation of nonsmall cell lung cancer. PMID- 28081339 TI - Management of acute postoperative hypertension for reducing cardiovascular complications in cancer patients: when and how aggressively? AB - BACKGROUND/AIM: We sought to determine what factors cardiovascular complications (CVCs) correlate with in cancer patients with acute postoperative hypertension (APH) and to define when and how aggressively to treat this disorder in the present study. MATERIALS AND METHODS: A retrospective observational study of cancer patients with postoperative hypertension at a single intensive care unit between July 2007 and June 2013 was conducted. The outcome of interest was the incidence of a CVC. RESULTS: There were 1162 patients enrolled, of which 92 (7.9%) experienced one or more CVCs. Preexisting hypertension (OR 38.3, 95% CI 3.2-457.4, P = 0.004) and choice of vasodilator (OR 6.5, 95% CI 2.3-18.6, P = 0.000) were predictors of a CVC. Cardiovascular complications were less likely to occur if pain was relieved efficiently during the postoperative period (OR 15.9, 95% CI 1.9-130.1, P = 0.01). Furthermore, there were increased CVCs among patients with postoperative hypertensive crises compared to those with stage 1 or stage 2 hypertension with the treatment threshold for systolic blood pressure (OR 5.7, 95% CI 2.0-16.5, P = 0.001) or diastolic blood pressure (OR 6.0, 95% CI 1.8 20.3, P = 0.004). CONCLUSION: To reduce CVCs, APH may be defined and managed as a hypertensive crisis in cancer patients. PMID- 28081340 TI - Importance of sonographic paratracheal lymph node evaluationin early autoimmune thyroiditis. AB - BACKGROUND/AIM: To review the sonographic views of paratracheal lymph nodes (PLNs) in the diagnosis and during different stages of autoimmune thyroiditis. MATERIALS AND METHODS: Features of the PLNs (left and right), thyroid sonography, and laboratory data were investigated in 126 cases. Patients were divided into three groups by using thyroid sonographic criteria in the literature (group 1: control, group 2: early-stage/indeterminate, group 3: definite thyroiditis). Indeterminate patients were followed up for 1 year and included as indeterminate/early-stage thyroiditis patients. RESULTS: Percentage of right and left PLN was 13.3% and 46.2% in control cases, 21.2% and 80% in early stage/indeterminate cases, and 41.3% and 88.5% in definite thyroiditis cases. Significant among-group differences were evident in terms of right and left PLNs presence (Pearson chi-squared test, P = 0.011 and P = 0.001). CONCLUSION: Careful and thorough review of the PLNs can ensure diagnosis of autoimmune thyroiditis even in cases of early stage of the disease and prevent false-negative diagnoses. PMID- 28081341 TI - Association of neutrophil/lymphocyte ratio with the degree ofinterstitial lung disease in systemic sclerosis. AB - BACKGROUND/AIM: Determining the severity of systemic sclerosis related interstitial lung disease (SSc-ILD) is based on clinical and radiological findings, inflammation marker levels, and carbon monoxide diffusing capacity of the lung (DLCO). Recently studies are ongoing for objective and easy markers. Neutrophil/lymphocyte ratio (NLR) is shown to be a good marker for inflammation in recent clinical trials. In this study, we aimed to identify the possible relationship between NLR and carbon monoxide transfer coefficient (KCO) of SSc ILD patients. MATERIALS AND METHODS: Fifty-nine patients with systemic sclerosis (SSc) were enrolled in the study. We used high-resolution computed tomography for diagnosis and used DLCO to evaluate degree of lung involvement. Complete blood cell counts and acute phase reactants were included as laboratory assessments. RESULTS: NLR values were significantly higher in the SSc-ILD group (3.66 +/- 1.32 vs. 2.85 +/- 1.12, P = 0.01) and correlated negatively with KCO. The NLR cut-off value was 3.21, its sensitivity was 81%, and its specificity was 81%. CONCLUSION: NLR level may serve as a marker of lung involvement in the presence of ILD in patients with SSc. PMID- 28081342 TI - Exploring CYP2B6 activity by measuring the presence ofnevirapine hydroxy metabolites in plasma. AB - BACKGROUND/AIM: Nevirapine is a reverse-transcriptase inhibitor widely used in combination therapy to treat HIV infection. Nevirapine is extensively metabolized in the liver and CYP2B6 is mainly responsible for oxidation of 3 hydroxynevirapine (3-OH NVP). This study aims to explore CYP2B6 activity by measuring 2-hydroxynevirapine (2-OH NVP) and 3-OH NVP in plasma and to identify factors associated with nevirapine pharmacokinetic parameters. MATERIALS AND METHODS: A total of 112 patients were recruited and treated with nevirapine-based antiretroviral therapy. Plasma nevirapine and metabolite concentrations were assayed using high-performance liquid chromatography via liquid-liquid extraction. RESULTS: Thirty-nine (34.8%) of the patients had no 3-OH NVP detected in their plasma while 2-OH NVP was detected in all patients. Metabolite concentrations were low compared to nevirapine. Positive correlations were observed between nevirapine and its metabolites, 2-OH NVP (P < 0.01) and 3-OH NVP (P = 0.012). Nevirapine concentration was decreased when concomitantly administered with methadone. Univariate analysis showed that ALT level, AST level, and detection of 3-OH NVP were associated with nevirapine pharmacokinetic parameters. CONCLUSION: The variability of nevirapine pharmacokinetic parameters was caused by liver enzymes and the presence of 3-OH NVP metabolites. The presence of 3-OH NVP can probably be used to distinguished CYP2B6 activity and efficacy of nevirapine in patients with HIV infection. PMID- 28081343 TI - The combined effects of proteasome inhibitor bortezomib with topoisomerase I and II inhibitors on topoisomerase enzymes. AB - BACKGROUND/AIM: DNA topoisomerases are ubiquitous enzymes that regulate conformational changes in DNA topology during essential cellular processes, and, for this reason, have been characterized as the cellular targets of a number of anticancer drugs. Bortezomib is a powerful proteasome inhibitor used in the treatment of hematological malignancies. In this study, we investigated the inhibitory effects of bortezomib on human topoisomerase I and II enzymes both alone and in combination modes with camptothecin and etoposide. MATERIALS AND METHODS: The interactions of these drugs with topoisomerase enzymes were evaluated by relaxation assay in cell-free systems. IC50 values of the drugs on topoisomerase enzymes were calculated using the S probit analysis program. RESULTS: Bortezomib showed a very weak inhibition effect on topoisomerase I (IC50 = 87.11 mM). On the other hand, it had a strong inhibitory effect on topoisomerase II (IC50 = 1.41 mM). Our results indicated that bortezomib is effective not only on proteasome but also on topoisomerase II. In addition, bortezomib possesses an increased synergistic effect when used in combination with camptothecin and etoposide than when used alone. CONCLUSION: The results of this study point out that these data may build a framework for combination studies with bortezomib, camptothecin, and etoposide in the treatment of cancer. PMID- 28081344 TI - Peripheral FLT-3 ligand levels as a pathobiological parameter duringthe clinical course of acute myeloid leukemia. AB - BACKGROUND/AIM: FLT-3 ligand is a growth factor affecting the hematopoietic lineage. The aim of this study was to evaluate the variability of peripheral FLT 3 ligand during the clinical course of acute myeloid leukemia (AML) patients. MATERIALS AND METHODS: Twenty-four patients were enrolled in this study in order to assess alterations in the circulating levels of FLT-3 ligand during the clinical course of AML. RESULTS: We studied the association in the diagnostic period between the FLT-3 ligand and peripheral blood cells together with serum electrolytes. FLT-3 ligand levels (pg/mL) during the aplastic period due to remission induction and consolidation were higher than the levels at initial diagnosis. On the other hand, the diagnostic and remission induction values of leukocytes and FLT-3 ligand showed an inverse association. These results indicate to us that higher white cell counts are associated with lower FLT-3 ligand levels. We also found a reversed association between FLT-3 ligand and serum lactate dehydrogenase level. However, there was no association between FLT-3 ligand and other serum electrolyte levels. We also found higher FLT-3 ligand levels in male patients. CONCLUSION: Our study demonstrates the inverse proliferative action of FLT-3 ligand on the early myeloid lineage. In addition, this study showed us that FLT-3 receptor inhibition during chemotherapy-induced aplasia causes a compensative ligand overexpression. PMID- 28081345 TI - Growing OXA-23 type strains among carbapenem-resistant Acinetobacter baumannii and tigecycline as an alternate combination therapy. AB - BACKGROUND/AIM: The increasing prevalence and global spread of difficult-to-treat carbapenem-resistant Acinetobacter baumannii has become a serious problem. The aim of this study is to investigate the resistance patterns and tigecycline sensitivity of carbapenem-resistant A. baumannii strains. MATERIALS AND METHODS: Acinetobacter strains that were carbapenem-resistant and collected mainly from intensive care units were included into this study. The antibiotic sensitivity/resistance of the strains to other antibiotics and tigecycline were noted. Presence of blaOXA-23, blaOXA-48, blaOXA-58, and NDM-1 was investigated by PCR. RESULTS: In total, 44 carbapenem-resistant A. baumannii strains were detected. In addition, 57% (25/44) showed resistance to netilmicin and 2% (1/43) to tigecycline. All of the strains were susceptible to colistin. blaOXA-58 was found only in one (2%) strain while blaOXA-23 was found in 14 (32%) strains. All strains were negative for blaOXA-48 and NDM-1. CONCLUSION: blaOXA-23 was the main resistance pattern in carbapenem-resistant A. baumannii strains. blaOXA-58 was present only in one strain and no blaOXA-48 was found. Tigecycline susceptibility is high and it can be a treatment option for a possible combination therapy of carbapenem-resistant A. baumannii, especially for those for whom colistin is contraindicated because of its toxicity. PMID- 28081346 TI - Neuroprotective effects of bone marrow-derived mesenchymal stem cellsand conditioned medium in mechanically injured neuroblastoma cells. AB - BACKGROUND/AIM: Bone marrow-derived mesenchymal stem cells (BMSCs) possess self renewal characteristics that distinguish them from other cell types. Recent studies have focused on the effects of conditioned medium (CM) that includes the extracellular matrix. Here we examined the neuroprotective effects of BMSCs and CM on damaged neuroblastoma cells. MATERIALS AND METHODS: The cells were divided into five groups: 1) healthy controls, 2) damaged cells alone, 3) damaged cells treated with BMSCs, 4) damaged cells treated with CM, and 5) damaged cells treated with both BMSCs and CM. Neuroprotective effects were then evaluated based upon the levels of oxidative stress, antitransforming growth factor beta1 (anti TGFbeta1) production, and apoptosis. RESULTS: Significant differences were observed between healthy controls and damaged cells (P < 0.001), as well as between damaged cells and those treated with BMSCs alone (P < 0.05), CM alone (P < 0.05), and both BMSCs and CM in combination (P < 0.01). Among the treated groups, the strongest neuroprotective effects were seen in cells treated with both BMSCs and CM. CONCLUSION: These results show that both BMSCs and CM exhibit neuroprotective effects in damaged neuroblastoma cells. The strongest benefits were seen following treatment with both BMSCs and CM. PMID- 28081348 TI - The effect of basolateral amygdala nucleus lesion on memory under acute,mid and chronic stress in male rats. AB - BACKGROUND/AIM: The basolateral amygdala (BLA) modulates memory for emotional events and is involved in both stress and memory. This study investigated different durations of stress and the role of BLA on serum corticosterone level and spatial and cognitive memory. MATERIALS AND METHODS: Different durations of stress (acute, mid, and chronic stress), with and without BLA lesion were induced in rats by 6 h/day restraint stress for 1, 7, and 21 days. Memory functions were evaluated by novel object recognition (NOR) and object location test (OLT). RESULTS: The OLT findings showed locomotor activity and spatial memory slightly decreased with different durations of stress. The NOR findings significantly showed locomotor activity impairment in different durations of stress. Cognitive memory deficit was observed in mid stress. The corticosterone level significantly increased in the mid and chronic stress groups. Moreover, the mid stress was the strongest stress condition. There is a possibility that different stress durations act by different mechanisms. The recognition of a novel location decreased in all lesion groups. It was more severe in the NOR. The BLA lesion significantly decreased corticosterone level in the mid and chronic stress groups compared to similar groups without lesion. CONCLUSION: The BLA lesion caused more damage to cognitive than spatial memory in stressed groups. PMID- 28081347 TI - Virulence factors, biofilm-forming ability, and antimicrobial resistance of urinary Escherichia coli strains isolated from hospitalized patients. AB - BACKGROUND/AIM: Escherichia coli is the most frequent cause of urinary tract infections. We investigated the possible associations between the origin of strains, antimicrobial resistance, the presence of urovirulence factors, and biofilm-forming ability. MATERIALS AND METHODS: Antibiotic susceptibility of E. coli strains was tested by disk diffusion method. Hemagglutination assays were performed for phenotypic characterization of the cell surface. Multiplex PCR was used for detection of virulence genes and for determination of phylogenetic relationships. RESULTS: The resistance to ampicillin (55.5%) and tetracycline (39.3%) was significantly more frequent than to other antimicrobial agents. The fim gene was present in 92.5% of strains. The sfa and pap genes were found in 53.8% and 38.7% of strains, respectively. The pap gene was significantly less frequently detected in strains from dialysis patients. The hly gene was present in 18.5% of strains. The aer gene was detected in 52.6% and cnf in 12.1%, while afa was detected in 4.6% of strains. Most strains belonged to the B2 and D phylogenetic groups. The aer gene was significantly associated with strains producing strong biofilms. CONCLUSION: The E. coli strains causing cystitis in hospitalized patients differed in terms of resistance to antibiotics, virulence genes, and potential for biofilm formation. PMID- 28081350 TI - The effect of systemic isotretinoin treatment on skin biophysicalparameters among patients with acne vulgaris. AB - BACKGROUND/AIM: Systemic isotretinoin has been widely considered an effective and safe medical treatment for severe and refractory acne for nearly 3 decades. However, it also appears to cause undesirable cutaneous side effects. The aim of this study was to prospectively measure biophysical parameters of skin function among patients with acne vulgaris before and after 3 months of isotretinoin therapy, including pH, temperature, sebum content, skin hydration, and transepidermal water loss. MATERIALS AND METHODS: The study cohort consisted of 19 patients with acne vulgaris. Noninvasive methods were used to measure the biophysical characteristics of forehead skin. All measurements were repeated following the completion of 3 months of systemic isotretinoin treatment. RESULTS: Biophysical skin parameter measurements after 3 months of isotretinoin therapy revealed a decrease in the severity of seborrhea. However, the skin was dry, indicting a decrease in stratum corneum hydration. An increase in skin temperature was also determined. CONCLUSION: Treatment with systemic isotretinoin reduces sebum secretion and stratum corneum hydration and increases skin temperature, suggesting that isotretinoin may partially improve the biophysical characteristics of the skin among patients with acne vulgaris. PMID- 28081349 TI - Chrysin prevents brain damage caused by global cerebralischemia/reperfusion in a C57BL/J6 mouse model. AB - BACKGROUND/AIM: The present study investigated the neuroprotective effects of chrysin (CRS) following global cerebral ischemia and reperfusion (I/R) in a C57BL/J6 mouse model. MATERIALS AND METHODS: A total of 40 mice were equally divided into four groups: (1) sham-operated (SH = control), (2) global cerebral I/R (I/R), (3) CRS, and (4) CRS + I/R. In the I/R group, the bilateral carotid arteries were clipped for 15 min and the mice were treated with vehicle (corn oil) for 10 days. In the CRS group, CRS (50 mg/kg) was given for 10 days without carotid occlusion. In the CRS + I/R group bilateral carotid arteries were clipped for 15 min and the mice were also treated with CRS (50 mg/kg) for 10 days. All of the rats were sacrificed under anesthesia on day 10, and neurodegenerative histological changes in the brain and tissue levels of oxidants and antioxidants were evaluated. RESULTS: CRS treatment significantly reversed the oxidative effects of I/R and inhibited the development of neurodegenerative histopathologies. In the CRS + I/R group, the decrease in TBARS levels and increase in GSH levels were similar to those in the SH group. CONCLUSION: Treatment with CRS can positively affect the neural system of mice and it can be used for the treatment of global cerebral I/R. PMID- 28081351 TI - The effect of methylprednisolone treatment on fibrinolysis, thecoagulation system, and blood loss in cardiac surgery. AB - BACKGROUND/AIM: The purpose of this study was to examine steroid pretreatment in order to decrease postoperative coagulopathy disorders and bleeding. MATERIALS AND METHODS: In this randomized double-blinded study, the efficacy of low versus high doses of methylprednisolone on the coagulation system and postoperative bleeding was compared in patients who were undergoing cardiac surgery with cardiopulmonary bypass (CPB). The platelet response to agonists, D-dimer concentration, tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI-1) antigens, and platelet receptors CD42b, CD62P, and CD41a were evaluated. RESULTS: The platelet response to agonists was reduced. The mean concentrations of D-dimer and tPA antigen increased although PAI-1 concentration did not show any significant changes following heparin neutralization. Postoperative expression of CD42b showed no changes in comparison with preoperation values in both groups. There was a significant increase in the expression of CD62P with a methylprednisolone dose of 15 mg/kg, while there was just a slight increase with a dose of 5 mg/kg. CD41a, as a fibrinogen receptor, was increased significantly after CPB in both groups. Significant data were shown in decreasing blood loss with a high dose of methylprednisolone. CONCLUSION: Methylprednisolone at a dose of 15 mg/kg reduced bleeding, probably by increasing CD62P after heparin neutralization, which can activate platelet activation in favor of better hemostasis. PMID- 28081352 TI - Removing the specimen with traction during robotic radical prostatectomy does not cause a positive surgical margin. AB - BACKGROUND/AIM: The aim of this study was to gauge whether removal of a specimen with traction during robot-assisted laparoscopic radical prostatectomy causes a positive surgical margin or not. MATERIALS AND METHODS: One hundred and sixty nine patients with localized prostate cancer who underwent robot-assisted laparoscopic radical prostatectomy from 2009 to 2011 were included in the study. After dividing the patients into two groups, we recorded their characteristics and pre-op/post-op evaluations. RESULTS: There were 111 and 58 patients in groups 1 (with traction) and 2 (without traction), respectively. We evaluated the patients' ages, follow-up time, body mass index (BMI), prostate-specific antigen (PSA) values, pre-op and post-op Gleason score values, pathological stage, positive surgical margin rates, and biochemical PSA recurrence rates. There was no statistically significant difference between the groups for age, pre-op PSA values, BMI, pre-op and post-op Gleason scores, positive surgical margin rates and biochemical recurrence rates. There was a significant difference between prostate weight, tumor volume, and clinical stage. CONCLUSION: Removing the specimen with traction during robot-assisted laparoscopic radical prostatectomy does not cause a positive surgical margin. The incision should be as small as possible for cosmetic appearance. PMID- 28081353 TI - Clinical correlation between the 6-min walk test andcardiopulmonary exercise testing in patients with pulmonary arterial hypertension. AB - BACKGROUND/AIM: The aims of the present study were to assess the relationship between the distance walked during the 6-min walk test (6MWT) and exercise capacity as determined by cardiopulmonary exercise testing (CPET) in patients with pulmonary arterial hypertension (PAH) and to investigate the prognostic value of the 6MWT in comparison to clinical parameters of CPET and echocardiography findings. MATERIALS AND METHODS: Thirty PAH patients participated in the study. Subject characteristics and New York Heart Association (NYHA) classifications were recorded. All subjects completed the 6MWT and CPET. Relationships among the variables were analyzed by the Pearson correlation test. Correlation coefficients between 6MWT distance and other variables were determined by linear regression analysis. RESULTS: Distance walked in the 6MWT was significantly correlated with the following exercise parameters: peak oxygen consumption, work load, and metabolic equivalents. Additionally, cardiac index was correlated with peak oxygen consumption and metabolic equivalents. We also showed that cardiac index and age were two significant determinants for exercise performance, accounting for 35.4% of the variance in the 6MWT. CONCLUSION: The 6MWT provides information that may be a better index for the patient's NYHA functional class determination than maximal exercise testing. PMID- 28081354 TI - Is there a difference between Parkinson disease patients and a control group in terms of urinary symptoms and quality of life? AB - BACKGROUND/AIM: The aim of this study is to research whether urinary symptoms and disruption of quality of life observed in Parkinson disease patients are different than those of their healthy peers. Additionally, whether these complaints were affected by characteristics such as age at onset of Parkinson disease, sex, disease duration, and severity was investigated. MATERIALS AND METHODS: This study comprised a total of 79 individuals, 39 Parkinson patients and a control group of 40 individuals. Parkinson diagnosis was provided by a neurology expert according to the UK Parkinson's Disease Society Brain Bank Criteria. All patients were evaluated by a urologist with the International Prostate Symptom Score (IPSS) and an overactive bladder (OAB) questionnaire. RESULTS: Compared with the control group, the Parkinson patient group had statistically significantly higher rates of urological complaints (P < 0.001), irritative symptoms (P < 0.001), voiding symptoms (P < 0.001), OAB score (P < 0.001), IPSS total score (P = 0.007), and treatment requirements (P < 0.001). CONCLUSION: Urologic complaints were observed more frequently in the Parkinson patient group compared to the control group. Another important result of this study is that in the Parkinson patient group there was no difference found between urologic complaints in terms of sex. PMID- 28081355 TI - Oral Delivery of Probiotics in Poultry Using pH-Sensitive Tablets. AB - As alternatives to antibiotics in livestocks, probiotics have been used, although most of them in the form of liquid or semisolid formulations, which show low cell viability after oral administration. Therefore, suitable dry dosage forms should be developed for livestocks to protect probiotics against the low pH in the stomach such that the products have higher probiotics survivability. Here, in order to develop a dry dosage forms of probiotics for poultry, we used hydroxypropyl methylcellulose phthalate 55 (HPMCP 55) as a tablet-forming matrix to develop probiotics in a tablet form for poultry. Here, we made three different kinds of probiotics-loaded tablet under different compression forces and investigated their characteristics based on their survivability, morphology, disintegration time, and kinetics in simulated gastrointestinal fluid. The results indicated that the probiotics formulated in the tablets displayed higher survival rates in acidic gastric conditions than probiotics in solution. Rapid release of the probiotics from the tablets occurred in simulated intestinal fluid because of fast swelling of the tablets in neutral pH. As a matrix of tablet, HPMCP 55 provided good viability of probiotics after 6 months under refrigeration. Moreover, after oral administration of probiotics-loaded tablets to chicken, more viable probiotics were observed, than with solution type, through several digestive areas of chicken by the tablets. PMID- 28081356 TI - Canna edulis Leaf Extract-Mediated Preparation of Stabilized Silver Nanoparticles: Characterization, Antimicrobial Activity, and Toxicity Studies. AB - A novel approach to synthesize silver nanoparticles (AgNPs) using leaf extract of Canna edulis Ker-Gawl. (CELE) under ambient conditions is reported here. The as prepared AgNPs were analyzed by UV-visible spectroscopy, transmission emission microscopy, X-ray diffraction, Fourier transform-infrared spectroscopy, energy dispersive analysis of X-ray spectroscopy, zeta potential, and dynamic light scattering. The AgNPs showed excellent antimicrobial activity against various pathogens, including bacteria and various fungi. The biocompatibility of the AgNPs was analyzed in the L929 cell line using NRU and MTT assays. Acridine orange/ethidium bromide staining was used to determine whether the AgNPs had necrotic or apoptotic effects on L929 cells. The concentration of AgNPs required for 50% inhibition of growth of mammalian cells is far more than that required for inhibition of pathogenic microorganisms. Thus, CELE is a candidate for the eco-friendly, clean, cost-effective, and nontoxic synthesis of AgNPs. PMID- 28081357 TI - Assessment of Neuronal Cell-Based Cytotoxicity of Neurotoxins from an Estuarine Nemertean in the Han River Estuary. AB - A heteronemertean, Yininemertes pratensis, was collected in Han River Estuary, South Korea. This estuarine nemertean has been known by the local fishermen for harmful effects to the glass eels, juveniles of Japanese eel Anguilla japonica, migrating to fresh water. The present study confirmed the neurotoxic effects of this heteronemertean ribbon worm at the cellular level. Derivative types of neurotoxic tetrodotoxin (TTX), 5,11-dideoxy TTX (m/z 288) and 11-norTTX-6(S)-01 (m/z 305.97), were identified through HPLC and MALDI-TOF MS. However, significant neurotoxicity was confirmed in the fraction containing an undefined molecule corresponding to the 291.1 (m/z) peak, when tested in rat primary astrocytes and dorsal ganglion cells. This study is the first to report neurotoxins of the estuarine nemertean, fairly abundant in the Han River estuary, and suggests the long-term monitoring of population dynamics and surveillance of the toxicity in this river estuary. PMID- 28081358 TI - Microbial Diversity during Fermentation of Sweet Paste, a Chinese Traditional Seasoning, Using PCR-Denaturing Gradient Gel Electrophoresis. AB - The aim of this study was to elucidate the changes in the microbial community and biochemical properties of a traditional sweet paste during fermentation. PCR denaturing gradient gel electrophoresis (DGGE) analysis showed that Aspergillus oryzae was the predominant species in the koji (the fungal mixture), and the majority of the fungi isolated belonged to two Zygosaccharomyces species in the mash. The bacterial DGGE profiles revealed the presence of Bacillus subtilis during fermentation, and Lactobacillus acidipiscis, Lactobacillus pubuzihii, Lactobacillus sp., Staphylococcus kloosi, and several uncultured bacteria were also detected in the mash after 14 days of main fermentation. Additionally, during main fermentation, amino-type nitrogen and total acid increased gradually to a maximum of 6.77 +/- 0.25 g/kg and 19.10 +/- 0.58 g/kg (30 days) respectively, and the concentration of reducing sugar increased to 337.41 +/- 3.99 g/kg (7 days). The 180-day fermented sweet paste contained 261.46 +/- 19.49 g/kg reducing sugar and its pH value remained at around 4.65. This study has used the PCR-DGGE technique to demonstrate the microbial community (including bacteria and fungi) in sweet paste and provides useful information (biochemical properties) about the assessment of the quality of sweet paste throughout fermentation. PMID- 28081359 TI - Benzoic Acid Enhances Embryo Implantation through LIF-Dependent Expression of Integrin alphaVbeta3 and alphaVbeta5. AB - Embryo implantation is the crucial step for a successful pregnancy. Diverse factors, including adhesion molecules, growth factors, and cytokines are important for embryo implantation through improving endometrial receptivity. Benzoic acid (BA), a component of various plants, has been shown to have antifungal and antioxidant effects. However, the effect of BA on embryo implantation remains unknown. Here, we showed the contribution of BA for the enhancement of endometrial receptivity through the leukemia inhibitory factor (LIF)-dependent increase of integrin alphaV, beta3, and beta5 expression. Furthermore, in vivo study using a mifepristone-induced implantation failure model showed that BA definitely improves the numbers of implantation embryos. Taken together, we suggest that BA has a novel function for embryo implantation through the up-regulation of LIF-mediated integrins, and may be a candidate for therapeutic medicine to increase the pregnancy rate. PMID- 28081360 TI - Pinus Densiflora Bark Extract (PineXol) Decreases Adiposity in Mice by Down Regulation of Hepatic De Novo Lipogenesis and Adipogenesis in White Adipose Tissue. AB - PineXol, extracted from Korean red pine bark, has beneficial effects, such as antioxidant, antiinflammatory, and antilipogenic activities in vitro. We tested the hypothesis that PineXol supplementation could have anti-obesity effects on mice fed a high-fat diet (HFD). Four-week-old male C57BL/6 mice were fed normal chow (18% kcal from fat) or a HFD (60% kcal from fat). HFD-fed animals were also subjected to PineXol treatment at a dose of 10 or 50 mg/kg body weight (BW) (PX10 or PX50, respectively) body weight. The body weight and body fat mass in the PX50 group were statistically lower than those in the HFD group (p < 0.05 and p < 0.001, respectively). The concentration of hepatic triglycerides, total cholesterol, and low-density lipoprotein cholesterol were reduced in the PX50 group compared with the HFD group (p < 0.01). Acetyl CoA carboxylase (p < 0.01), elongase of very long chain fatty acids 6 (p < 0.01), stearoyl CoA desaturase 1 (p < 0.05), microsomal triglyceride transfer protein (p < 0.01), and sterol regulatory element-binding protein 1 (p < 0.05) were significantly decreased in the PX50 group compared with that in the HFD group. In white adipose tissue, CCAATenhancer-binding protein alpha (p < 0.05), peroxisome proliferator-activated receptor gamma (p < 0.001), and perilipin (p < 0.01) were decreased in the PX50 group compared with those in the HFD group. Therefore, the current study implies the potential of PineXol for the prevention and/or amelioration of obesity, in part by inhibition of both hepatic lipid synthesis and adipogenesis in white adipose tissue. PMID- 28081361 TI - Microbial Transformation of Multiwalled Carbon Nanotubes by Mycobacterium vanbaalenii PYR-1. AB - Carbonaceous nanomaterials are widely used in industry and consumer products, but concerns have been raised regarding their release into the environment and subsequent impacts on ecosystems and human health. Although many efforts have been devoted to understanding the environmental fate of carbonaceous nanomaterials, information about their microbial transformation is still rare. In this study, we found that within 1 month a polycyclic aromatic hydrocarbon degrading bacterium, Mycobacterium vanbaalenii PYR-1, was able to degrade both pristine and carboxyl-functionalized multiwalled carbon nanotubes (p-MWCNT and c MWCNT), as demonstrated by consistent results from high resolution transmission electron microscopy, Raman spectroscopy, and confocal Raman microspectroscopy. Statistical analysis of Raman spectra identified a significant increase in the density of disordered or amorphous carbon in p-MWCNT and c-MWCNT after biodegradation. Microbial respiration further suggested potential mineralization of MWCNTs within about 1 month. All of our analyses consistently showed higher degradation or mineralization of c-MWCNT compared to p-MWCNT. These results highlight the potential of using bacteria in engineered systems to remove residual carbonaceous nanomaterials and reduce risk of human exposure and environmental impact. Meanwhile, our finding suggests possible transformation of carbonaceous nanomaterials by polycyclic aromatic hydrocarbon-degrading bacteria in the natural environment, which should be accounted for in predicting the environmental fate of these emerging contaminants and in nanotechnology risk regulation. PMID- 28081362 TI - Lithium Carbonate Recovery from Cathode Scrap of Spent Lithium-Ion Battery: A Closed-Loop Process. AB - A closed-loop process to recover lithium carbonate from cathode scrap of lithium ion battery (LIB) is developed. Lithium could be selectively leached into solution using formic acid while aluminum remained as the metallic form, and most of the other metals from the cathode scrap could be precipitated out. This phenomenon clearly demonstrates that formic acid can be used for lithium recovery from cathode scrap, as both leaching and separation reagent. By investigating the effects of different parameters including temperature, formic acid concentration, H2O2 amount, and solid to liquid ratio, the leaching rate of Li can reach 99.93% with minor Al loss into the solution. Subsequently, the leaching kinetics was evaluated and the controlling step as well as the apparent activation energy could be determined. After further separation of the remaining Ni, Co, and Mn from the leachate, Li2CO3 with the purity of 99.90% could be obtained. The final solution after lithium carbonate extraction can be further processed for sodium formate preparation, and Ni, Co, and Mn precipitates are ready for precursor preparation for cathode materials. As a result, the global recovery rates of Al, Li, Ni, Co, and Mn in this process were found to be 95.46%, 98.22%, 99.96%, 99.96%, and 99.95% respectively, achieving effective resources recycling from cathode scrap of spent LIB. PMID- 28081363 TI - Distance-Dependent Measurements of the Conductance of Porphyrin Nanorods Studied with Conductive Probe Atomic Force Microscopy. AB - Protocols for nanopatterning porphyrins on Au(111) were developed based on immersion particle lithography. Porphyrins with and without a central metal ion, 5,10,15,20-tetraphenyl-21H,23H-porphyrin (TPP) and 5,10,15,20-tetraphenyl-21H,23H porphyrin cobalt(II) (CoTPP), were selected for study, which spontaneously formed nanorod geometries depending on concentration parameters. The elongated shapes of the nanorods offers an opportunity for successive distance-dependent conductive probe atomic force microscopy (CP-AFM) measurements along the length of the nanorods. To prepare patterns of TPP and CoTPP nanorods, a mask of silica mesospheres was placed on gold substrates to generate nanoholes within an alkanethiol matrix film. The nanoholes prepared by particle lithography with an immersion step were backfilled with porphyrins by a second immersion step. By controlling the concentration and immersion interval, nanorods of porphyrins were generated with one end of the nanostructure attached to gold within a nanohole. The porphyrin nanorods exhibited slight differences in dimensions at the nanoscale to enable size-dependent measurements of conductive properties. The conductivity along the horizontal direction of the nanorods was evaluated with CP AFM studies. Changes in conductivity were measured along the long axis of TPP and CoTPP nanorods. The TPP nanorods exhibited conductive profiles of an insulating material, and the CoTPP nanorods exhibited profiles of a semiconductor. The experiments demonstrate the applicability of particle lithography for preparing unique and functional surface platforms of porphyrins to measure distance dependent conductive properties on gold. PMID- 28081364 TI - Relative Contributions of Copper Oxide Nanoparticles and Dissolved Copper to Cu Uptake Kinetics of Gulf Killifish (Fundulus grandis) Embryos. AB - The toxicity of soluble metal-based nanomaterials may be due to the uptake of metals in both dissolved and nanoparticulate forms, but the relative contributions of these different forms to overall metal uptake rates under environmental conditions are not quantitatively defined. Here, we investigated the linkage between the dissolution rates of copper(II) oxide (CuO) nanoparticles (NPs) and their bioavailability to Gulf killifish (Fundulus grandis) embryos, with the aim of quantitatively delineating the relative contributions of nanoparticulate and dissolved species for Cu uptake. Gulf killifish embryos were exposed to dissolved Cu and CuO NP mixtures comprising a range of pH values (6.3 7.5) and three types of natural organic matter (NOM) isolates at various concentrations (0.1-10 mg-C L-1), resulting in a wide range of CuO NP dissolution rates that subsequently influenced Cu uptake. First-order dissolution rate constants of CuO NPs increased with increasing NOM concentration and for NOM isolates with higher aromaticity, as indicated by specific ultraviolet absorbance (SUVA), while Cu uptake rate constants of both dissolved Cu and CuO NP decreased with NOM concentration and aromaticity. As a result, the relative contribution of dissolved Cu and nanoparticulate CuO species for the overall Cu uptake rate was insensitive to NOM type or concentration but largely determined by the percentage of CuO that dissolved. These findings highlight SUVA and aromaticity as key NOM properties affecting the dissolution kinetics and bioavailability of soluble metal-based nanomaterials in organic-rich waters. These properties could be used in the incorporation of dissolution kinetics into predictive models for environmental risks of nanomaterials. PMID- 28081365 TI - Visualizing Arsenate Reactions and Encapsulation in a Single Zero-Valent Iron Nanoparticle. AB - A nanostructure-based mechanism is presented on the enrichment, separation, and immobilization of arsenic with nanoscale zero-valent iron (nZVI). The As-Fe reactions are studied with spherical aberration corrected scanning transmission electron microscopy (Cs-STEM). Near-atomic resolution (<1 nm3) electron tomography discovers a thin continuous layer (23 +/- 3 A) of elemental arsenic sandwiched between the iron oxide shell and the zerovalent iron core. This points to a unique mechanism of nanoencapsulation and proves that the outer layer, especially the Fe(0)-oxide interface, is the edge of the As-Fe reactions. Atomic resolution imaging on the grain boundary provides strong evidence that arsenic atoms diffuse preferably along the nonequilibrium, high-energy, and defective polycrystalline grain boundary of iron oxides. Results also offer direct evidence on the surface sorption or surface complex formation of arsenate on ferric hydroxide (FeOOH). The core-shell structure and unique properties of nZVI clearly underline rapid separation, large capacity, and stability for the treatment of toxic heavy metals such as cadmium, chromium, arsenic, and uranium. PMID- 28081367 TI - Ordered Mesoporous Titanium Nitride as a Promising Carbon-Free Cathode for Aprotic Lithium-Oxygen Batteries. AB - Despite the extraordinary gravimetric energy densities, lithium-oxygen (Li-O2) batteries are still facing a technological challenge; limited round trip efficiency leading to insufficient cycle life. Recently, carbonaceous electrode materials were found to be one of the primary origins of the limited cycle life, as they produce irreversible side products during discharge. A few investigations based on noncarbonaceous materials have demonstrated largely suppressed accumulation of irreversible side products, but such studies have focused mainly on the materials themselves rather than delicate morphology control. As such, here, we report the synthesis of mesoporous titanium nitride (m-TiN) with a 2D hexagonal structure and large pores (>30 nm), which was templated by a block copolymer with tunable chain lengths, and introduce it as a stable air-cathode backbone. Due to the well-aligned pore structure and decent electric conductivity of TiN, the battery reaction was quite reversible, resulting in robust cycling performance for over 100 cycles under a potential cutoff condition. Furthermore, by protecting the Li metal with a poreless polyurethane separator and engaging a lithium iodide redox mediator, the original capacity was retained for 280 cycles under a consistent capacity condition (430 mAh g-1). This study reveals that when the appropriate structure and material choice of the air-cathode are coupled with an advanced separator and an effective solution-phase redox mediator, the cycle lives of Li-O2 batteries can be enhanced dramatically. PMID- 28081366 TI - An Estimation of Hybrid Quantum Mechanical Molecular Mechanical Polarization Energies for Small Molecules Using Polarizable Force-Field Approaches. AB - In this work, we report two polarizable molecular mechanics (polMM) force field models for estimating the polarization energy in hybrid quantum mechanical molecular mechanical (QM/MM) calculations. These two models, named the potential of atomic charges (PAC) and potential of atomic dipoles (PAD), are formulated from the ab initio quantum mechanical (QM) response kernels for the prediction of the QM density response to an external molecular mechanical (MM) environment (as described by external point charges). The PAC model is similar to fluctuating charge (FQ) models because the energy depends on external electrostatic potential values at QM atomic sites; the PAD energy depends on external electrostatic field values at QM atomic sites, resembling induced dipole (ID) models. To demonstrate their uses, we apply the PAC and PAD models to 12 small molecules, which are solvated by TIP3P water. The PAC model reproduces the QM/MM polarization energy with a R2 value of 0.71 for aniline (in 10,000 TIP3P water configurations) and 0.87 or higher for other 11 solute molecules, while the PAD model has a much better performance with R2 values of 0.98 or higher. The PAC model reproduces reference QM/MM hydration free energies for 12 solute molecules with a RMSD of 0.59 kcal/mol. The PAD model is even more accurate, with a much smaller RMSD of 0.12 kcal/mol, with respect to the reference. This suggests that polarization effects, including both local charge distortion and intramolecular charge transfer, can be well captured by induced dipole type models with proper parametrization. PMID- 28081368 TI - Smart Metal-Organic Framework Coatings: Triggered Antibiofilm Compound Release. AB - Metal-organic frameworks (MOFs) have a large potential for delivery of active molecules. Here, a MOF coating is investigated as a smart host matrix for triggered release of antibiofilm compounds. In addition to a coating consisting of the regular Fe-terephthalate MIL-88B(Fe), a new hydrophobic MIL-88B(Fe) coating is synthesized in hydrothermal conditions using palmitic acid as a lattice terminating group. These porous materials are used as a host matrix for the antibiofilm compound 5-(4-chlorophenyl)-N-(2-isobutyl)-2-aminoimidazole, which has a specific biofilm-inhibiting effect at concentrations at which no activity against planktonic cells is detected. The stability of MIL-88B(Fe) in distilled water and tryptic soy broth medium is investigated, together with the ability of iron(III) chelators to serve as a trigger for controlled decomposition of MIL-88B(Fe) by metal complexation. Organic iron chelators are used to mimic the iron chelating function of siderophores, which are specific molecules excreted by biofilm-forming bacteria. Trisodium citrate is able to chelate metal ions from the junctions of the framework. By sequestration of these metal ions, the host matrix is partially degraded, resulting in an antibiofilm compound release. Finally, the antibiofilm properties against Salmonella Typhimurium are validated by monitoring biofilm growth on MOF layers either loaded or not with aminoimidazole. A strong proof-of-concept is shown for efficient inhibition of biofilm growth through triggered antibiofilm compound release. PMID- 28081369 TI - Randomized Controlled Ethanol Cookstove Intervention and Blood Pressure in Pregnant Nigerian Women. AB - RATIONALE: Hypertension during pregnancy is a leading cause of maternal mortality. Exposure to household air pollution elevates blood pressure (BP). OBJECTIVES: To investigate the ability of a clean cookstove intervention to lower BP during pregnancy. METHODS: We conducted a randomized controlled trial in Nigeria. Pregnant women cooking with kerosene or firewood were randomly assigned to an ethanol arm (n = 162) or a control arm (n = 162). BP measurements were taken during six antenatal visits. In the primary analysis, we compared ethanol users with control subjects. In subgroup analyses, we compared baseline kerosene users assigned to the intervention with kerosene control subjects and compared baseline firewood users assigned to ethanol with firewood control subjects. MEASUREMENTS AND MAIN RESULTS: The change in diastolic blood pressure (DBP) over time was significantly different between ethanol users and control subjects (P = 0.040); systolic blood pressure (SBP) did not differ (P = 0.86). In subgroup analyses, there was no significant intervention effect for SBP; a significant difference for DBP (P = 0.031) existed among preintervention kerosene users. At the last visit, mean DBP was 2.8 mm Hg higher in control subjects than in ethanol users (3.6 mm Hg greater in control subjects than in ethanol users among preintervention kerosene users), and 6.4% of control subjects were hypertensive (SBP >=140 and/or DBP >=90 mm Hg) versus 1.9% of ethanol users (P = 0.051). Among preintervention kerosene users, 8.8% of control subjects were hypertensive compared with 1.8% of ethanol users (P = 0.029). CONCLUSIONS: To our knowledge, this is the first cookstove randomized controlled trial examining prenatal BP. Ethanol cookstoves have potential to reduce DBP and hypertension during pregnancy. Accordingly, clean cooking fuels may reduce adverse health impacts associated with household air pollution. Clinical trial registered with www.clinicaltrials.gov (NCT02394574). PMID- 28081372 TI - Role of Hyperplasia of Gingival Lymphatics in Periodontal Inflammation. AB - Lymphatic vessels are important for maintenance of tissue fluid homeostasis and afferent antigen transport. In chronic inflammation, lymphangiogenesis takes place and is characterized by lymphatic endothelial cell proliferation and lymphatic hyperplasia. Vascular endothelial growth factor C (VEGFC) is the main known lymphangiogenic growth factor, and its expression is increased in periodontitis, a common chronic infectious disease that results in tissue destruction and alveolar bone loss. The role of lymphangiogenesis during development of periodontitis is unknown. Here, we test if transgenic overexpression of epithelial VEGFC in a murine model is followed by hyperplasia of lymphatic vessels in oral mucosa and if the lymphatic drainage capacity is altered. We also test if lymphatic hyperplasia protects against periodontal disease development. Transgenic keratin 14 (K14)-VEGFC mice had significant hyperplasia of lymphatics in oral mucosa, including gingiva, without changes in blood vessel vasculature. The basal lymph flow was normal but slightly lower than in wild-type mice when oral mucosa was challenged with lipopolysaccharide from Porphyromonas gingivalis. Under normal conditions, K14-VEGFC mice exhibited an increased number of neutrophils in gingiva, demonstrated enhanced phagocyte recruitment in the cervical lymph nodes, and had more alveolar bone when compared with their wild-type littermates. After induction of periodontitis, no strain differences were observed in the periodontal tissues with respect to granulocyte recruitment, bone resorption, angiogenesis, cytokines, and bone-related protein expressions or in draining lymph node immune cell proportions and vascularization. We conclude that overexpression of VEGFC results in hyperplastic lymphatics, which do not enhance lymphatic drainage capacity but facilitate phagocyte transport to draining lymph nodes. Hyperplasia of lymphatics does not protect against development of ligature-induced periodontitis. PMID- 28081373 TI - Loss of Function of Evc2 in Dental Mesenchyme Leads to Hypomorphic Enamel. AB - Ellis-van Creveld (EvC) syndrome is an autosomal-recessive skeletal dysplasia, characterized by short stature and postaxial polydactyly. A series of dental abnormalities, including hypomorphic enamel formation, has been reported in patients with EvC. Despite previous studies that attempted to uncover the mechanism leading to abnormal tooth development, little is known regarding how hypomorphic enamel is formed in patients with EvC. In the current study, using Evc2/ Limbin mutant mice we recently generated, we analyzed enamel formation in the mouse incisor. Consistent with symptoms in human patients, we observed that Evc2 mutant mice had smaller incisors with enamel hypoplasia. Histologic observations coupled with ameloblast marker analyses suggested that Evc2 mutant preameloblasts were capable of differentiating to secretory ameloblasts; this process, however, was apparently delayed, due to delayed odontoblast differentiation, mediated by a limited number of dental mesenchymal stem cells in Evc2 mutant mice. This concept was further supported by the observation that dental mesenchymal-specific deletion of Evc2 phenocopied the tooth abnormalities in Evc2 mutants. Overall, our findings suggest that mutations in Evc2 affect dental mesenchymal stem cell homeostasis, which further leads to hypomorphic enamel formation. PMID- 28081371 TI - GWAS Identifies New Loci for Painful Temporomandibular Disorder: Hispanic Community Health Study/Study of Latinos. AB - Temporomandibular disorder (TMD) is a musculoskeletal condition characterized by pain and reduced function in the temporomandibular joint and/or associated masticatory musculature. Prevalence in the United States is 5% and twice as high among women as men. We conducted a discovery genome-wide association study (GWAS) of TMD in 10,153 participants (769 cases, 9,384 controls) of the US Hispanic Community Health Study/Study of Latinos (HCHS/SOL). The most promising single nucleotide polymorphisms (SNPs) were tested in meta-analysis of 4 independent cohorts. One replication cohort was from the United States, and the others were from Germany, Finland, and Brazil, totaling 1,911 TMD cases and 6,903 controls. A locus near the sarcoglycan alpha ( SGCA), rs4794106, was suggestive in the discovery analysis ( P = 2.6 * 106) and replicated (i.e., 1-tailed P = 0.016) in the Brazilian cohort. In the discovery cohort, sex-stratified analysis identified 2 additional genome-wide significant loci in females. One lying upstream of the relaxin/insulin-like family peptide receptor 2 ( RXP2) (chromosome 13, rs60249166, odds ratio [OR] = 0.65, P = 3.6 * 10-8) was replicated among females in the meta-analysis (1-tailed P = 0.052). The other (chromosome 17, rs1531554, OR = 0.68, P = 2.9 * 10-8) was replicated among females (1-tailed P = 0.002), as well as replicated in meta-analysis of both sexes (1-tailed P = 0.021). A novel locus at genome-wide level of significance (rs73460075, OR = 0.56, P = 3.8 * 10 8) in the intron of the dystrophin gene DMD (X chromosome), and a suggestive locus on chromosome 7 (rs73271865, P = 2.9 * 10-7) upstream of the Sp4 Transcription Factor ( SP4) gene were identified in the discovery cohort, but neither of these was replicated. The SGCA gene encodes SGCA, which is involved in the cellular structure of muscle fibers and, along with DMD, forms part of the dystrophin-glycoprotein complex. Functional annotation suggested that several of these variants reside in loci that regulate processes relevant to TMD pathobiologic processes. PMID- 28081374 TI - Cytokine Profiles in Aqueous Humor and Plasma of HIV-infected Individuals with Ocular Syphilis or Cytomegalovirus Retinitis. AB - PURPOSE: To characterize the immunologic profile in aqueous humor (AqH) of HIV infected individuals with cytomegalovirus retinitis (CMVr) or ocular syphilis and to assess if AqH and plasma represent independent cytokine compartments. METHODS: Concentrations of 27 cytokines in AqH and plasma of HIV-infected individuals with CMVr (n = 23) or ocular syphilis (n = 16) were measured by multiplex assay. Cytokine profiles of both groups were compared. RESULTS: Individuals with CMVr had higher plasma concentrations of interleukin (IL)-7, IL-8, IL-10, interferon (IFN)-gamma, IFN-alpha2, G-CSF, IP-10 and IL-1alpha; as well as higher AqH concentrations of IL-1alpha, IP-10 and GM-CSF than those with ocular syphilis. AqH and plasma levels correlated only for IP-10 in both ocular infections. CONCLUSIONS: Individuals with CMVr had higher plasma cytokine levels than those with ocular syphilis. The immunologic profiles in AqH and plasma are independent. Therefore, AqH cytokine concentrations cannot be inferred from plasma cytokine concentrations in the population studied. PMID- 28081382 TI - Corrigendum. PMID- 28081379 TI - Direct Gingival Fibroblast/Osteoblast Transdifferentiation via Epigenetics. AB - Alveolar bone resorption caused by trauma or periodontal diseases has represented a challenge for both dental clinicians and researchers. In this study, we evaluate the osteogenic potential of human gingival fibroblasts (HGFs) through a direct transdifferentiation from HGFs to functional osteoblasts via epigenetic modification and osteogenic signaling with bone morphogenetic protein 2 (BMP2) in vitro and in vivo. HGF treatment with 5-aza-2'-deoxycytidine (5-aza-dC) induced demethylation in the hypermethylated CpG islands of the osteogenic lineage marker genes RUNX2 and ALP, and subsequent BMP2 treatment successfully drove the fibroblasts to the osteoblasts' lineage. Cell morphological changes viewed under microscopy and alkaline phosphatase (ALP) and alizarin red S (ARS) staining confirmed the osteoblastic change mediated by epigenetic modification as did real time polymerase chain reaction (PCR), methylation-specific PCR (MSP), and chromatin immunoprecipitation (ChIP) assay, which demonstrated the altered methylation patterns in the RUNX2 and ALP promoter regions and their effect on gene expression. Furthermore, micro-computed tomography (CT) analysis of in vivo mouse cell transplantation experiments showed high-density signal in the epigenetically modified HGF group; in addition, a significant amount of bone formation was observed in the transplanted material using hematoxylin and eosin (H&E) staining as well. Collectively, our results indicate that epigenetic modification permits the direct programming of HGFs into functional osteoblasts, suggesting that this approach might open a novel therapeutic avenue in alveolar bone regeneration. PMID- 28081383 TI - Inhibiting Effect of Lithium Chloride on Endotoxin-induced Uveitis in Rats. AB - PURPOSE: To evaluate the anti-inflammatory effect of lithium chloride in endotoxin-induced uveitis. METHODS: A total of 200 Wistar rats were randomly divided into four groups: a control group; EIU group; LiCl-treated control group; and LiCl-treated lipopolysaccharide group. Clinical score, slit-lamp photography, hematoxylin and eosin (H&E) staining were used to determine the degree of inflammatory reaction. Level of glycogen synthase kinase3-beta and nuclear factor kappa B p65 in iris-ciliary body was examined by western blot and RT-PCR. Cytokines in aqueous humor were detected by ELISA. RESULTS: Pretreatment with LiCl produced an anti-inflammatory effect during endotoxin-induced uveitis (EIU). With LiCl treatment, the level of P-GSK3-beta in iris-ciliary body was upregulated and the expression of NF-kappaB p65 was significantly suppressed during EIU. CONCLUSIONS: LiCl pretreatment can suppress intraocular inflammatory responses in EIU rats. Mechanistically, this anti-inflammatory effect may be related to the inhibitory phosphorylation of GSK3-beta. PMID- 28081385 TI - Catheter-Related Bloodstream Infections in Adults Receiving Home Parenteral Nutrition. AB - BACKGROUND: A common complication in patients receiving home parenteral nutrition (HPN) is catheter-related bloodstream infections (CRBSIs). The CRBSI incidence has been advocated as an outcome parameter assessing the quality of care. This study aimed to illustrate how the use of different CRBSI definitions affects the reported incidence. MATERIALS AND METHODS: In an observational study based on the Copenhagen intestinal failure database, all clinically reported CRBSIs from 2002 2013 were compared with data from the affiliated microbiological database according to recommended CRBSI criteria. RESULTS: Clinically, 1034 CRBSIs were observed in 548 adults receiving HPN for 1410 catheter-years. Thus, the clinically assessed CRBSI incidence was 1.95/1000 catheter-days. However, based on the microbiological evaluation, only 47% of our episodes fulfilled the Centers for Disease Control and Prevention (CDC) and European Society for Clinical Nutrition (ESPEN) CRBSI criteria. Employing a catheter-salvaging strategy, 40% of the CRBSI diagnoses were supported by the paired blood culture positivity criteria and only 6% by a positive catheter tip. In 53%, CRBSIs were categorized as a clinical or "probable CRBSI" diagnosis. In 20% of all episodes, missing information/blood cultures hampered a CDC/ESPEN CRBSI diagnosis. Thereby, according to CDC/ESPEN CRBSI definitions, the incidence was 0.92/1000 days or 46% lower than clinically assessed. CONCLUSION: This study illustrates the practical and methodological challenges and great variability in reporting of the CRBSI incidence. Nonetheless, it is recommended as a marker of the quality of care. Consensus regarding CRBSI definitions is a prerequisite for a meaningful comparison of this important outcome parameter between HPN centers. PMID- 28081386 TI - Effects of biodiesel made from swine and chicken fat residues on carbon monoxide, carbon dioxide, and nitrogen oxide emissions. AB - : The effects of two alternative sources of animal fat-derived biodiesel feedstock on CO2, CO, NOx tailpipe emissions as well as fuel consumption were investigated. Biodiesel blends were produced from chicken and swine fat waste (FW 1) or floating fat (FW-2) collected from slaughterhouse wastewater treatment processes. Tests were conducted in an unmodified stationary diesel engine operating under idling conditions in attempt to simulate slow traffic in urban areas. Significant reductions in CO (up to 47% for B100; FW-2) and NOx (up to 20% for B5; FW-2 or B100; FW-1) were attained when using biodiesel fuels at the expense of 5% increase in fuel consumption. Principal component analysis (PCA) was performed to elucidate possible associations among gas (CO2, CO, and NOx) emissions, cetane number and iodine index with different sources of feedstock typically employed in the biodiesel industry. NOx, cetane number and iodine index were inversely proportional to CO2 and biodiesel concentration. High NOx emissions were reported from high iodine index biodiesel derived especially from forestry, fishery and some agriculture feedstocks, while the biodiesel derived from animal sources consistently presented lower iodine index mitigating NOx emissions. The obtained results point out the applicability of biodiesel fuels derived from fat-rich residues originated from animal production on mitigation of greenhouse gas emissions. The information may encourage practitioners from biodiesel industry whilst contributing towards development of sustainable animal production. IMPLICATIONS: Emissions from motor vehicles can contribute considerably to the levels of greenhouse gases in the atmosphere. The use of biodiesel to replace or augment diesel can not only decrease our dependency on fossil fuels but also help decrease air pollution. Thus, different sources of feedstocks are constantly being explored for affordable biodiesel production. However, the amount of carbon monoxide (CO), carbon dioxide (CO2), and/or nitrogen oxide (NOx) emissions can vary largely depending on type of feedstock used to produce biodiesel. In this work, the authors demonstrated animal fat feasibility in replacing petrodiesel with less impact regarding greenhouse gas emissions than other sources. PMID- 28081387 TI - Air Emissions from the Manufacture of Inks. AB - Mass balance data are employed to determine VOC emission factors for ink manufacturing processes. The data represent a broad spectrum of case studies in which inputs to ink mixing vessels are weighed both before and after mixing. The difference between pre-mixing and post-mixing weights represent air emissions. In contrast to EPA's estimate of 30 lb of VOC emissions per ton of manufactured ink (contained in the AP-42 emission factors), this work indicates that 44.7 lb/ton is a more accurate emission factor. The new data are expected to have a significant effect on permitting efforts for ink manufacturers as Title V operating permits are prepared. PMID- 28081388 TI - Maximum Ground-Level Concentrations with Downwash: The Urban Stability Mode. AB - Gaussian model-based equations for critical downwind distance, wind speed, and plume height that result in maximum ground-level concentrations (MGLC) under downwash conditions for the rural stability mode were presented in a previous paper. This paper presents general equations for the critical downwind distance xc for the urban stability mode. Specific examples are presented for Schulman Scire and Huber-Snyder downwash treatments for building-enhanced and regular sigmas. PMID- 28081389 TI - Estimation of Trends in Atmospheric Concentrations of Sulfate in the Northeastern United States. AB - Daily atmospheric concentrations of sulfate collected at six locations in the northeastern United States are regressed against meteorological factors, ozone, seasonal cycles, and time in order to determine if a significant trend in sulfate can be detected. The data used in this analysis were collected during the Sulfate Regional Experiment (SURE, 1977-1978) and the Eulerian Model Evaluation Field Study (EMEFS, 1988-1989). Ozone, specific humidity, and seasonal terms (reflecting the potential of the atmosphere for oxidation of sulfur dioxide) emerged as important explanatory variables. After accounting for the variability explained by environmental factors, the median estimated change in sulfate concentration from the six locations over the 11-year period is -22% (or -28% if ozone is not used as an explanatory variable). Although there are wide variations among locations, these changes are commensurate with an estimated 25% decline in sulfur emissions in the northeastern U.S. during the same period. These analyses provide insight into methods for detecting reductions in sulfate that may be expected to occur as a result of the Clean Air Act Amendments of 1990. Uncertainties in the estimates, with consideration of serial correlation in the data, imply a minimum detectable reduction of 10% using this modeling procedure with similar data availability. PMID- 28081390 TI - Chloroform in Indoor Air and Wastewater: The Role of Residential Washing Machines. AB - A residential washing machine was studied in order to determine the extent of chloroform formation following the application of a laundry bleach containing sodium hypochlorite. A dynamic model was also developed to estimate chloroform formation, mass transfer, and gaseous emissions during a typical wash cycle. A series of 22 experiments was completed to determine model parameters, including chemical reaction and mass transfer rate coefficients, as well as headspace air exchange rates. Three additional experiments were completed to evaluate model performance. Experimental and model results suggest that washing machine environments are very conducive to chloroform formation, with chloroform levels frequently exceeding 1 mg/L in washwater. Chloroform stripping efficiencies were observed to be greater than those previously reported for ethanol, but less than those reported for radon. Mass emissions of chloroform to indoor air during a ten minute wash cycle were predicted to be between 5.3 and 9.8 mg. On a unit activity basis, chloroform emissions associated with hypochlorite-containing bleach addition to washing machines far exceeded emissions from showers. Each source was estimated to emit similar quantities of chloroform on an annual basis. Finally, it was estimated that the use of hypochlorite-containing laundry bleaches may contribute a significant fraction of chloroform mass loadings to municipal wastewater. PMID- 28081391 TI - Determination of the Leaching Dynamics of Metals from Municipal Solid Waste Incinerator Fly Ash Using a Column Test. AB - The objective of this work was to study the dynamic leaching behavior of thirty three elements in municipal solid waste incinerator fly ash using a column test employing double deionized water. Nearly all of the elements initially present in the leachate were found to leach quickly and then decrease to near constant concentrations after five pore volumes of water passed through the column. Of the eight elements subject to toxicity characteristic leaching procedure (TCLP) investigations, all except lead were found in concentrations below regulatory limits. After three pore volumes of water passed through the column, leachate lead concentrations were found to have diminished to TCLP permissible levels. Concerning Resource Conservation and Recovery Act (RCRA) Title D regulations pertaining to permissible landfill leachate production, lead concentrations were still found at levels above allowable limits after as many as 40 pore volumes of leachate production. PMID- 28081392 TI - Modeling the Energy Content of Municipal Solid Waste Using Multiple Regression Analysis. AB - In this research multiple regression analysis was used to develop predictive models of the energy content of municipal solid waste (MSW). The scope of work included collecting waste samples in Kaohsiung City, Taiwan, characterizing the waste, and performing a stepwise forward selection procedure for isolating variables. Two regression models were developed to correlate the energy content with variables derived from physical composition and ultimate analysis. The performance of these models for this particular waste was superior to that of equations developed by other researchers (e.g., Dulong, Steuer) for estimating energy content. Attempts at developing regression models from proximate analysis data were not successful. PMID- 28081393 TI - Models to Estimate Volatile Organic Hazardous Air Pollutant Emissions from Municipal Sewer Systems. AB - Emissions from municipal sewers are usually omitted from hazardous air pollutant (HAP) emission inventories. This omission may result from a lack of appreciation for the potential emission impact and/or from inadequate emission estimation procedures. This paper presents an analysis and comparison of the models available to estimate volatile organic HAP (VOHAP) emissions from sewers. Comparisons were made between the different theoretical foundations of the models, as well as between the emissions predicted by the models for a single sewer component. Sewer gas concentrations predicted by the models were also compared to measured sewer gas concentrations reported in the literature. Two of the models were compared in their ability to estimate sewer VOHAP emissions for a large U. S. city using National Pollution Discharge Effluent System data for the influent wastewater to the city's municipal wastewater treatment facilities. This estimate showed that, regardless of the model used, sewer emissions are a potentially significant source of VOHAP emissions in the urban environment. The choice of model, however, is thought to be less critical to sewer emission estimates than the source of sewer wastewater VOHAP concentration data. PMID- 28081394 TI - Motor Vehicle Emissions Variability. AB - Test-to-test variability has been observed by many current testing methods, including the Federal Test Procedure, the IM240 dynamometer test, the idle test common to many Inspection and Maintenance programs, and on-road remote sensing. The variability is attributable to the vehicle, not to the testing procedure. Because the vehicles are the dominant source of variability, the only way such vehicles can be reliably identified is through the use of multiple tests. The emissions variability increases with increasing average emissions, and it appears to be prevalent among the few newer technology vehicles with defective, but untampered, closed-loop emissions control systems (1981 and newer models). In one fleet the variable emitters constitute 2.2% to 4.8% of the vehicles and contribute 8.5% to 22% of the total carbon monoxide emissions. Scheduled I/M programs that fail to ensure repair of these vehicles allow a significant portion of vehicles with excess emissions to escape reduction measures. PMID- 28081396 TI - Particle Concentrations Inside a Tavern Before and After Prohibition of Smoking: Evaluating the Performance of an Indoor Air Quality Model. AB - Measurements were made of respirable suspended particles (RSP) in a large sports tavern on 26 dates over approximately two years in which smoking was allowed, followed by measurements on 50 dates during the year after smoking was prohibited. The smoking prohibition occurred without warning when the city government passed a regulation restricting smoking in local restaurants and taverns. Two follow-up field surveys, consisting of 24 and 26 visits, respectively, were conducted to measure changes in RSP levels after smoking was prohibited. No decrease in tavern attendance was evident after smoking was prohibited. During the smoking period, the average RSP concentration was 56.8 |ig/m3 above the outdoor concentrations, but the average abruptly dropped to 5.9 ug/m3 above outdoor levels-a 90% decrease- on 24 visits in the first two months immediately after smoking was prohibited (first follow-up study). A second set of 26 follow-up visits (matched by time of day, day of the week, and season to the earlier smoking visits) yielded an average concentration of 12.9 jig/m3 above the outdoor levels, or an overall decrease in the average RSP concentration of 77% compared with the smoking period. During the smoking period, RSP concentrations more than 100 ug/m3 above outdoor levels occurred on 30.7% of the visits. During the 50 nonsmoking visits, 92% of the RSP concentrations were less than 20 u,g/m3 above outdoor levels, and no concentration exceeded 100 ug/m3 on any nonsmoking visit. The data show there was a striking decline in indoor RSP concentrations in the tavern after smoking was prohibited. The indoor concentration observed in the nonsmoking periods (9.1 u.g/m3 average for all nonsmoking visits) was attributed to cooking and resuspended dust. A mathematical model based on the mass balance equation was developed that included smoking, cooking, and resuspended dust. Using cigarette emission rates from the literature, the tavern volume of 521 m3, and the air exchange rate measured in the tavern under conditions regarded by the management as "typical," the model predicted 42.5 ug/m3 for an average smoking count of 1.17 cigarettes, which compared favorably with the average concentration of 43.9 ng/m3 observed in the tavern. A regression analysis indicated that the active smoking count explained over 50% of the variation of the RSP concentrations measured on different dates. The mathematical model can be used to estimate RSP concentrations from smoking in other similar taverns under similar conditions. PMID- 28081397 TI - Research and Evaluation of Organic Hazardous Air Pollutant Source Emission Test Methods. AB - Title III of the Clean Air Act Amendments of 1990 has increased the need for well defined and tested stationary source emission sampling and analysis methods. The Methods Branch of the Air Measurements Research Division of U.S. EPA's Office of Research and Development is responsible for a major methods development and evaluation program intended to help fill that need. This paper summarizes recent developments from several of the component projects of that program. Primary emphasis is placed on status and references for methods for organic hazardous air pollutants, such as phosgene, methanol, chloroform, acetonitrile, isocyanates, aldehydes, halogenated organics, non-halogenated organics, and volatile organic material. PMID- 28081398 TI - Influence of Ethanol-Blended Fuels on the Emissions from Three Pre-1985 Light Duty Passenger Vehicles. AB - Tailpipe and evaporative emissions from three pre-1985 passenger motor vehicles operating on an ethanol oxygenated and on a nonoxygenated (base) fuel were characterized. Emission data were collected for vehicles operating over the Federal Test Procedure at 90 degrees F, 75 degrees F, and 40 degrees F to simulate ambient driving conditions. The two fuels tested were a commercial summer-grade regular gasoline (the nonoxygenated base fuel) and an oxygenated fuel containing 8.8% ethanol, more paraffins and olefins, and less aromatics than the base fuel. The Reid vapor pressure (RVP) was adjusted to correspond to that of the base fuel. The emissions measured were total hydrocarbons (THCs), speciated hydrocarbons, spedated aldehydes, carbon monoxide (CO), and oxides of nitrogen (NOX). This study showed a general reduction in tailpipe emissions of THC, CO, benzene, and 1,3-butadiene when tested with the ethanol fuel. The ethanol fuel significantly reduced these emissions from the high emitting vehicle, MU098, at 90 degrees F, 75 degrees F, and 40 degrees F test temperatures. Additionally, the ethanol fuel reduced CO emissions from vehicle BU950, with and without catalyst, and from vehicle CI415 at 40 degrees F. Both formaldehyde and acetaldehyde emissions generally increased when tested with the oxygenated fuel. The acetaldehyde emissions were about double with this fuel. The limited data indicate that most emissions, including toxics, occur during the first 124 seconds of vehicle start-up. Diurnal evaporative emissions were less from the oxygenated fuel, while hot-soak evaporative emissions were greater from the oxygenated fuel (for all vehicles except MU098). Evaporative emissions were generally greatest at the 90 degrees F test temperature. PMID- 28081399 TI - Modeling of Thermal Treatment of Hazardous Solid Wastes in a DC Arc Melter. AB - Ashley Wenger is a graduate student in the Mechanical Engineering and Mechanics (MEM) Department at Drexel University. Dr. Bakhtier Farouk is a professor in the MEM Department at Drexel University, 32nd and Chestnut Streets, Philadelphia, PA 19104. Dr. J. Kenneth Wittle is the vice president of Electro-Pyrolysis, Inc., Suite 1118, 996 Old Eagle School Road, Wayne, PA 19087. Please address all correspondence to Dr. Bakhtier Farouk. PMID- 28081400 TI - Combustion Modifications of Batch Annealing Furnaces and Ammonia Combustion Ovens for NOX Abatement in Steel Plants. AB - NOX control employing several combustion modification techniques is studied in batch annealing furnaces and ammonia combustion ovens in steel plants. The fuels of the annealing furnace and ammonia oven are by-product fuel gases and ammonia vapor, respectively, which are generated in the same steelworks. Study of the emission characteristics of the annealing furnace show that delayed combustion can effectively reduce NOX emissions. Delayed combustion is accomplished by air staging in burners, off-symmetric mixing of fuel and air, and air-biasing in the furnace, and these modification can operations achieve 60%, 40%, and 26% of NOX reductions, respectively. For the ammonia oven, NOX emission from combustion of ammonia vapor is remarkably reduced by staging the air injected into the oven, adjusting the total air rate, and adding by-product fuel gases to the combustion system. PMID- 28081401 TI - Establishing and Evaluating the Risk Implications of Uniform Soil Remediation Goals. AB - There is growing interest in the establishment of uniform, concentration-based soil remediation goals to accelerate the cleanup of contaminated sites and to provide consistency in the extent of cleanup required for similar sites. If uniform goals are used in a region, post-remediation risk will vary across sites due to regional variability in site properties. Thus far, of the national and state agencies that have established or proposed uniform concentration guidelines, none have quantified the regional variability in risk that is likely to result with their use as remediation goals. This paper describes a methodology for evaluating regional cancer risk variability resulting from use of uniform, concentration-based soil remediation goals, presents an example application of the methodology, and examines its utility for establishing uniform goals for organic contaminants in soil. The methodology is based on the integrated transport, fate, exposure, and risk model SoilRisk. Also addressed is the issue of contaminants for which regional risk variability is expected to be large with use of uniform soil remediation goals. An approach is described for reducing such variability by development of alternative uniform contaminant concentration levels for categories of sites differentiated by site geographic location or physical-chemical properties. PMID- 28081402 TI - Heterogeneous Photocatalysis for Control of Volatile Organic Compounds in Indoor Air. AB - Research results concerning the photocatalytic activity and selectivity of benzene are discussed. This compound, which represents one of an important class of volatile organic compounds found in indoor air, was oxidized in an annular photocatalytic reactor featuring a thin film of titanium dioxide and illuminated by a fluorescent black light. The gas phase products, carbon dioxide and carbon monoxide, were quantified with a Fourier transform infrared spectrometer (FTIR). Adsorbed intermediates were extracted from the surface with water. The extract was analyzed via high performance liquid chromatography and some of the adsorbed species were provisionally identified by retention time matching. The adsorption of reactants on the catalyst surface was studied explicitly, particularly with respect to the effect of near-UV radiation on adsorption processes. Maximum and steady-state rates of the surface reactions are reported here as functions of the operating conditions. Deactivation of the catalyst surface is characterized and methods of regeneration of catalyst activity are explored. This established research methodology provides the framework for a broader outline of research into enhancement of indoor air quality via photocatalytic oxidation. The results of investigations are discussed that pertain to a variety of classes of compounds representative of indoor air pollutants. PMID- 28081403 TI - A Strategy for the Evaluation of Sensory and Pulmonary Irritation Due to Chemical Emissions from Indoor Sources. AB - Sensory and pulmonary irritation are physiological responses to chemical exposure which result in characteristic, measurable changes in respiratory activity in mice. A standard method has been applied to the estimation of sensory irritation associated with a specific chemical exposure. This method has been correlated with human responses to these chemicals. Symptoms associated with chemical irritants are consistent with complaints due to problems with indoor air quality, which may include eye and upper respiratory tract irritation, headaches, and nausea. A stepwise strategy for assessing the contribution of indoor products to sensory and pulmonary irritation is discussed in the current paper. The strategy includes product emissions testing using dynamic environmental chambers, the selection of suspected irritants for respiratory irritation testing, respiratory irritation testing of individual compounds and representative mixtures using synthesized atmospheres, and the evaluation of test data to determine those compounds which may contribute to sensory and pulmonary irritation in humans. The current strategy is being applied to evaluate carpet system materials and their constituent chemicals. PMID- 28081404 TI - Characterization of Volatile Organic Chemical Emissions From Carpet Cushions. AB - The U.S. Consumer Product Safety Commission is investigating chemical emissions from carpet systems in order to determine whether the emissions may be responsible for the numerous health complaints associated with carpet installation. As part of this effort, a study was conducted to identify and quantify volatile organic compounds (VOCs) released into the air by five major product types of new carpet cushions. Cushion samples were tested in small-volume dynamic chambers over a six-hour exposure period. Airborne VOCs collected on multisorbent samplers were identified using sensitive gas chromatography/mass spectrometry. The emissions of selected VOCs were quantitated with the small scale chamber method and further characterized in larger environmental chambers conducted over a 96-hour period under conditions more representative of indoor environments. A separate chamber method was developed to screen polyurethane cushions for emissions of toluene diisocyanates (TDI). Over 100 VOCs, spanning a broad range of chemical classes, were emitted from 17 carpet cushions. The pattern of emitted VOCs varied between and among product types, which reflects probable differences in manufacturing processes and ingredients. No significant quantities of TDI or formaldehyde were released by any cushions. Emission profiles were characterized for total VOCs and for the predominant individual VOCs. As a group, the synthetic fiber cushion samples emitted the lowest quantities of VOCs. Cushion samples purchased from carpet retailers released lesser amounts of VOCs than samples of the same cushion types obtained directly from the manufacturing mills, suggesting that chemical losses from the bulk material may ensue as a result of transport, handling, and storage prior to installation. The data suggest that placement of carpet on top of a carpet cushion, as would occur in a residential installation, reduced the rate of some VOC emissions when compared to the cushion alone. PMID- 28081405 TI - Measurement of Indoor Air Emissions from Dry-Process Photocopy Machines. AB - Presently, no standard test method exists to evaluate the various emissions from office equipment (e.g., ozone, volatile organic compounds, inorganic gases, and particulates) so it is difficult to compare data from different studies.1 As a result, the authors are developing a standardized guidance document for measuring indoor air emissions from office equipment. The ultimate goal is to apply the test method to better understand emissions from office equipment and to develop lower emitting machines. This paper provides background information on indoor air emissions from office equipment with an emphasis on dry-process photocopy machines. The test method is described in detail, along with the results of a study to evaluate the test method using four dry-process photocopy machines. The results from this study indicate that the test method provides acceptable performance for characterizing emissions; that it can adequately identify differences in emissions between machines both in compounds emitted and their emission rates; and that it is capable of measuring both intra- and inter-machine variability in emissions. Challenges and complications were encountered in developing and implementing the test method. These included heat generation, which can cause large increases in chamber temperature; finite paper supplies for photocopy machines, which limit test duration; varying power requirements that may require changes in chamber electrical supply; and remote starting of the machines, which is necessary to maintain chamber integrity. Results show that dry process photocopy machines can produce emissions of ozone and volatile organic compounds that can potentially have a significant impact on indoor air quality. For the four machines tested in this study, the compounds with the highest emission rates overall were ethylbenzene (28,000 ug/hour), m,p-xylenes (29,000 ug/hour), o-xylene (17,000 ug/hour), 2-ethyl-lhexanol (14,000 ug/hour), and styrene (12,000 fig/hour). Although many of the same compounds tended to be detected in emissions from each of the four photocopiers, the relative contribution of individual compounds varied considerably between machines, with differences greater than an order of magnitude for some compounds. PMID- 28081407 TI - A Wind Tunnel Study into the Effects of Raised Intakes and Parapets on Fresh Air Intake Contamination by a Rooftop Stack. AB - A wind tunnel study was completed to determine the effects the presence of a parapet and raised intake configurations have on the dilution of a pollutant between a rooftop stack and building intake. This study was the first to address the effects of building parapets and varying intake configurations. A study of this kind is desirable because it is common practice for architects to attempt to hide stacks with the use of a parapet in order to make industrial buildings more aesthetically pleasing. This is done with no thought to the effect it may have on the intended function of the stacks, which is dispersing gases away from the building to avoid contamination of ventilation air. Three parapet configurations (no parapet and two different parapet heights) and two intake configurations (flush and raised) were investigated. The relative effects of the parapets and the raised intake configurations were also compared and contrasted for five stack heights, two stack locations, and four intake locations. The parapets were found to produce a cavity zone that extends above the building's roof by as much as two times the physical height of the parapet; increasing stack height had little effect on dispersion until the stack extended beyond this cavity region. The independent use of the parapets and raised intake configuration decreased the number of dilutions occurring between stack and intake when compared to the no parapet and flush intake configurations in all cases. Also substantiated in this study is the widely accepted view that the effect of the parapet addition is to decrease the effective stack height by the parapet height itself. The results of this investigation were then compared to existing wind tunnel-derived empirical models. The models tested were not able to predict the effects of varying stack height and of varying the relative distance between stack and intake on the dilution of a pollutant between stack and intake under the tested configurations. PMID- 28081410 TI - Field Assessment of a New Method for Estimating Emission Rates from Volume Sources Using Open-Path FTIR Spectroscopy. AB - An auto-positioning open-path Fourier Transform Infrared (FTIR) spectrometer can be used to directly measure vertical concentration profiles in a plume downwind from an emission source. The multi-component analysis capabilities of FTIR spectroscopy allow simultaneous measurement of diverse downwind pollutant species. Using concentration measurements and meteorological data, it is possible to estimate the emission fluxes across the plume and, thus, the emission rates of pollutants from the source. The field assessment goals were to conduct the first in a series of field tests of a new measurements system developed to perform such emission rate determinations, and to evaluate the system's performance and feasibility. For these purposes, a simple volume source simulator was constructed to emulate process equipment leaks encountered at chemical plants, refineries, and other facilities. By metering the release rates from the volume source simulator, "actual" release rates were compared to the "estimated" release rates calculated using the measurements system. Using simple data screening techniques, over 90% of the field tests conducted produced run-average emission rate estimates within 20% of the actual emission rates. Half of the tests were within 10% of the actual emission rates. PMID- 28081411 TI - Pressure Correction is Not Required for Particulate Matter Sampling. AB - The Environmental Protection Agency's Reference Methods for determining particulate matter as PM10 require pressure corrections before comparison to their National Ambient Air Quality Standards. No chemical, physiological, or toxicological basis exists for correction for particulate sampling when results are expressed in weight per unit volume (fxg/m3). The implications of misapplying pressure corrections are at least twofold: a) exposure assessment comparisons at different elevations, using EPA generated data, do not use equivalent doses; and b) cities at higher elevations are held to a more stringent compliance standard. PMID- 28081412 TI - An Envelope Curve as a 12-Month Rolling Sum Permit Limit. PMID- 28081413 TI - Control of Nitrogen Oxide Emissions by Hydrogen Peroxide-Enhanced Gas-Phase Oxidation Of Nitric Oxide. AB - Nitrogen oxides (NOX) and sulfur oxides (SOX) are criteria air pollutants, emitted in large quantities from fossil-fueled electric power plants. Emissions of SOX are currently being reduced significantly in many places by wet scrubbing of the exhaust or flue gases, but most of the NOX in the flue gases is NO, which is so insoluble that it is virtually impossible to scrub. Consequently, NOX control is mostly achieved by using combustion modifications to limit the formation of NOX, or by using chemical reduction techniques to reduce NOX to N2. Low NOX burners are relatively inexpensive but can only achieve about 50% reduction in NOX emissions; selective catalytic reduction (SCR) can achieve high reductions but is very expensive. The removal of NOX in wet scrubbers could be greatly enhanced by gas-phase oxidation of the NO to NO2, HNO2, and HNO3 (the acid gases are much more soluble in water than NO). This oxidation is accomplished by injecting liquid hydrogen peroxide into the flue gas; the H2O2 vaporizes and dissociates into hydroxyl radicals. The active OH radicals then oxidize the NO and NO2. This NOX control technique might prove economically feasible at power plants with existing SO2 scrubbers. The higher chemical costs for H2O2 would be balanced by the investment cost savings, compared with an alternative such as SCR. The oxidation of NOX by using hydrogen peroxide has been demonstrated in a laboratory quartz tube reactor. NO conversions of 97% and 75% were achieved at hydrogen peroxide/NO mole ratios of 2.6 and 1.6, respectively. The reactor conditions (500 degrees C, a pressure of one atmosphere, and 0.7 seconds residence time) are representative of flue gas conditions for a variety of combustion sources. The oxidized NOX species were removed by caustic water scrubbing. PMID- 28081414 TI - Background Ozone in the Planetary Boundary Layer Over the United States. AB - Reliable estimates of background O3 in the planetary boundary layer are needed as part of the current review by the U.S. EPA of O3 health and welfare criteria and of the National Ambient Air Quality Standards for O3. Such estimates are especially necessary for comparing O3 concentrations at which vegetation effects occur to O3 concentrations reported to represent background levels. Some vegetation researchers have used the seasonal average of the daily 7-h (0900- 1559 h) average as the exposure parameter in exposure-response models. The 7-h (0900-1559 h) seasonal mean reference point for O3 was assumed to be 0.025 ppm. Ozone aerometric data are presented from the monitoring sites in the United States which experience some of the lowest maximum hourly average concentrations, as identified in the U.S. EPA AIRS database. Criteria are enumerated and discussed for determining whether O3 concentrations at a given site can be considered to be "background" O3. The paper also suggests statistical techniques for estimating background O3 concentrations. Linear regression techniques yield valuable information about O3 concentration data from the literature. Coupled with other criteria, such analyses can be used to select sites that represent "background" sites for O3. Selection of such sites thus allows estimations of background O3 in different areas of the country, at different elevations, and for different averaging times. Using several techniques, the current O3 background at inland sites in the United States and Canada for the daylight 7-h (0900-1559 h) seasonal (April-October) average concentrations usually occurred within the range of 35 +/- 10 ppb. For coastal sites, the corresponding O3 concentrations were somewhat lower, occurring within the range of 25 +/- 10 ppb for locations in the northern hemisphere, but with most O3 concentrations at the coastal sites in the range of 30 +/- 5 ppb. The 50th percentile concentrations range from 16 ppb to 45 ppb at inland sites and range from 10 ppb to 33 ppb at coastal sites. The maximum hourly concentrations range from 50 ppb to 98 ppb at inland sites and range from 44 ppb to 80 ppb at coastal sites. We believe that the maximum hourly concentration of 98 ppb experienced in 1988 was influenced by the massive fires in Yellowstone National Park. These ranges suggest that the background O3 is somewhat dependent on a number of conditions such as the nature of upwind flow, lack of pollution sources, and terrain conditions including deposition with respect to forest or agricultural areas. PMID- 28081415 TI - Comparison of Two Ambient Beta Gauge PM10 Samplers. AB - This paper reports on the performance of the Kimoto 180 sampler and the Wedding ambient PM10 beta gauge sampler. Monodisperse ammonium fluorescein test particles were generated in the laboratory and used to determine the penetration curve of the Kimoto 180 cyclonic inlet. It was found that the actual DpaSOof the Kimoto 180 inlet, 3.5 (xm, is much lower than the designated standard value, 10 um. In the field test, the two beta gauge samplers were collocated with an Andersen SA1200 high-volume sampler to compare their measured daily average PM10 concentrations. The low Dpa50 of the Kimoto 180 inlet serves to explain why its daily average PM10 concentrations were much lower than the actual PM10 concentrations found in the field study. In addition, the PM10 concentrations of the Kimoto 180 beta gauge sampler were found to be seriously affected by the water vapor content of the ambient air. In contrast, the daily average PM10 concentrations of the Wedding beta gauge sampler were found to be more accurate, and influences by ambient conditions were insignificant. PMID- 28081416 TI - An Experimental Evaluation of Remote Sensing-Based Hydrocarbon Measurements: A Comparison to FID Measurements. AB - The purpose of this study was to intercompare hydrocarbon (HC) measurements performed by a number of different instruments: a gas chromatograph (GC), a flame ionization detector (FID), a fourier transform infrared spectrometer (FTIR), a commercially produced non-dispersive infrared analyzer (NDIR), and two remote sensors. These instruments were used to measure total HC concentrations in a variety of samples, including (1) ten different individual HC species, (2) 12 different vehicle exhaust samples, and (3) three different volatilized fuel samples. The 12 exhaust samples were generated by operating two different vehicles on a dynamometer. Each vehicle was operated at different times with three different fuels. The vehicles were operated fuel rich, i.e., with low air/fuel ratios to encourage elevated exhaust HC levels. Some of the exhaust samples were obtained while operating each vehicle at a stoichiometric air/fuel ratio with one spark plug wire disconnected. To quantify the degree to which the various instruments agreed with the FID, a parameter called the response factor was used, where the response factor was defined as the HC/CO2 ratio measured by each instrument divided by the HC/CO2 ratio measured by the dynamometer bench. Of the various instruments, only the GC yielded response factors that were consistently at or close to one. The other instruments typically had values at or below one. For the ten individual HC species studied, the NDIR and remote sensors obtained response factors between 0.05 and 1.0, with the highest response factors being obtained for the alkanes and the lowest response factors obtained for toluene and ethylene. For the exhaust samples, the NDIR and remote sensors obtained response factors between 0.23 and 0.68. For raw fuel samples, the response factors were between 0.44 and 0.68. NDIR and remote sensor measurements correlated very poorly with total HC in exhaust. PMID- 28081422 TI - Metals as Catalysts during the Formation and Decomposition of Chlorinated Dioxins and Furans in Incineration Processes. AB - Polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) are found on fly ash and in flue gas of municipal waste incinerators. Municipal waste incinerators seem to be the most important source for PCDDs and PCDFs emitted into the air during the last decades. PCDD/F formation takes place in the cooler zones (250 degrees C-450 degrees C) of a municipal waste incinerator, at the electrostatic precipitator. Copper is an important component of the fly ash that can catalyse the formation of PCDDs and PCDFs. Inhibition of the formation can be done by complexation of the metals (Cu) with EDTA or NTA. PMID- 28081423 TI - Real-World Vehicle Emissions: A Summary of the Seventh Coordinating Research Council On-Road Vehicle Emissions Workshop. AB - The Coordinating Research Council (CRC) has sponsored a series of workshops over the last decade focusing on the most recent research on real-world vehicle emissions. This summary presents findings from the latest workshop by researchers engaged in improving our understanding of the contribution of mobile sources to air quality. Participants in the workshop discussed efforts to evaluate and improve mobile source emission models, field programs designed to understand the contribution of mobile sources to emission inventories, and results from gas- and particle-phase emissions studies from spark-ignition and diesel-powered vehicles, as well as topics for future research. PMID- 28081424 TI - Measurements of Trace Metal (Fe, Cu, Mn, Cr) Oxidation States in Fog and Stratus Clouds. AB - The oxidation state of four transition metals (Fe, Mn, Cu, and Cr) in cloudwater has been investigated during several cloud events at Whiteface Mountain (NY), one cloud event at San Pedro Hill (CA), and one fog event at Bakers-field (CA). Samples were collected and immediately analyzed for the oxidation states of four transition metals: Fe(II) [44 measurements], Cu(I) [30 measurements], Mn(IV) [27 measurements], and Cr(III) [3 measurements]. Extreme care was taken to minimize contamination and interferences when measuring these oxidation states. Par ticulate and dissolved concentrations of these metals were also determined. Other measurements performed-relevant to the redox chemistry of these metals-included pH, total elemental concentrations (Fe, Cu, Mn, Cr, Al, K, Ca, Na, and Mg), organic anions (formate, acetate, glyco-late, oxalate), inorganic anions (chloride, sulfate, nitrate, sulfite), cations (sodium, calcium, magnesium, potassium), peroxides, and formaldehyde. These measurements were then used in thermodynamic-speciation models to understand the speciation of ambient fog and cloudwater. From this analysis, two different cases were found for Fe(III)soluble speciation. Fe(III) was found to exist either as Fe(OH)2+ or Fe(Oxalate)2. However, an unidentified strong chelating ligand with Fe(III) was also suggested by the data. Cu(I) and Cu(II) were calculated to be predominantly Cu+ and Cu2+ (with less than 10% as Cu(II)-oxalate complexes). A chemical kinetic model was also used to investigate the transition-metal chemistry. The model results indicate that Fe(II) should be the predominant chemical form of Fe during daylight conditions. This prediction is in agreement with the field measurements in which the highest ratios of Fe(II)/Fe total were found in samples collected during the day. The model results also indicated that Fe(III) should be the predominant form of Fe during nighttime conditions, which is also in agreement with the field measurements. In the model, Cu(II) and Mn(II) were the predominant oxidation states during daylight and nighttime conditions with Cu(I) and Mn(III) increasing during daylight conditions. Mn(III) concentrations were never high enough to influence the redox chemistry of Cr. Overall, Cr(VI) in cloudwater is predicted to be reduced to Cr(III) if free S(IV) is present. PMID- 28081425 TI - Aqueous Photochemistry of Mercury with Organic Acids. AB - To understand the dynamic chemical changes of mercury taking place in atmospheric water, a more detailed knowledge of the reactions of mercury with organic acids must be obtained. The rate of the above chemical reactions with different Hg(II) species is especially essential for understanding the dominant pathway of mercury transformation in the atmosphere. The objective of this research is to study the rate of photochemical reactions of dissolved divalent mercury with organic acids such as oxalate, acetate, and formate, which are abundant in atmospheric water. Laboratory photochemical experiments with simulated sunlight were conducted to assess the role of homogeneous photochemistry in changing the redox states of mercury in atmospheric water. It is observed that Hg(II) is readily reduced by hydroperoxyl radicals produced by the photolysis of oxalate. The second-order rate constant for the Hg(II)-hydroperoxyl radical reaction was found to be 1.7 x 104 M-1 s-1 when no chloride is present and 1.1 x 104 M-1 s-1 when chloride is present in the system. Modeling of mercury speciation has been performed using MICROQL equilibrium software. PMID- 28081428 TI - Development of a Speciated, Hourly, and Gridded Air Pollutants Emission Modeling System-A Case Study on the Precursors of Photochemical Smog in the Seoul Metropolitan Area, Korea. AB - A speciated, hourly, and gridded air pollutants emission modeling system (SHEMS) was developed and applied in predicting hourly nitrogen dioxide (NO2) and ozone (O3) levels in the Seoul Metropolitan Area (SMA). The primary goal of the SHEMS was to produce a systemized emission inventory for air pollutants including ozone precursors for modeling air quality in urban areas. The SHEMS is principally composed of three parts: (1) a pre-processor to process emission factors, activity levels, and spatial and temporal information using a geographical information system; (2) an emission model for each source type; and (3) a post processor to produce report and input data for air quality models through database modeling. The source categories in SHEMS are point, area, mobile, natural, and other sources such as fugitive emissions. The emission database produced by SHEMS contains 22 inventoried compounds: sulfur dioxide, NO2, carbon monoxide, and 19 speciated volatile organic compounds. To validate SHEMS, the emission data were tested with the Urban Airshed Model to predict NO2 and O3 concentrations in the SMA during selected episode days in 1994. The results turned out to be reliable in describing temporal variation and spatial distribution of those pollutants. PMID- 28081430 TI - Amphibian (Xenopus laevis) tadpoles and adult frogs mount distinct interferon responses to the Frog Virus 3 ranavirus. AB - Infections of amphibians by Frog Virus 3 (FV3) and other ranavirus genus members are significantly contributing to the amphibian declines, yet much remains unknown regarding amphibian antiviral immunity. Notably, amphibians represent an important step in the evolution of antiviral interferon (IFN) cytokines as they are amongst the first vertebrates to possess both type I and type III IFNs. Accordingly, we examined the roles of type I and III IFNs in the skin of FV3 challenged amphibian Xenopus laevis) tadpoles and adult frogs. Interestingly, FV3 infected tadpoles mounted type III IFN responses, whereas adult frogs relied on type I IFN immunity. Subcutaneous administration of type I or type III IFNs offered short-term protection of tadpoles against FV3 and these type I and type III IFNs induced the expression of distinct antiviral genes in the tadpole skin. Moreover, subcutaneous injection of tadpoles with type III IFN significantly extended their survival and reduced FV3 dissemination. PMID- 28081431 TI - Clinical characterization of autoimmune encephalitis and psychosis. AB - BACKGROUND AND PURPOSE: Autoimmune disorders are growing alarmingly high in prevalence across the globe. Autoimmune encephalitis has had a dramatic impact on the medical field, effectually altering diagnostic and treatment paradigms in regard to neuropsychiatric disorders. Our primary goal in conducting this study was to analyze the clinical characteristics of autoimmune encephalitis patients, with special focus on psychiatric presentations, in the West China Hospital and report patient prognoses after immunotherapy. METHODS: Data for patients admitted to the West China Hospital with autoimmune encephalitis diagnoses from 2015 to 2016 were collected and the corresponding clinical features were analyzed. RESULTS: We ultimately included 70 patients with autoimmune encephalitis: 56 (80%) anti-NMDAR encephalitis patients, 8 (11%) LGI1 antibody encephalitis patients, and 6 (9%) GABAbR antibody encephalitis patients. The median age of the 70 patients was 33years, 40% were female, and the initial symptoms in 31 patients (44%) were psychiatric in nature. Psychiatric disturbance appeared in 58 patients (83%) during inpatient treatment, after which 57 patients (81%) recovered. CONCLUSIONS: Many patients with autoimmune encephalitis present psychotic symptoms; psychiatric symptoms typically appear before neurological features emerge. Timely diagnosis and treatment may yield favorable prognosis. PMID- 28081432 TI - Changes in age patterns of suicide in Australia, the United States, Japan and Hong Kong. AB - The patterns of association between age and suicide rate vary by country, subpopulation and gender, and over time. To shed light on factors associated with these differences, we analysed suicide data from four populations, two 'Western' (Australia, the United States [US]) and two Asian (Japan and Hong Kong). We computed suicide rates in five-year age-groups (between 10 and 14 years and 85+ years) for men and women separately, and present graphical representations of the age patterns during selected five-year periods. Rates and age patterns differed markedly, as did gender patterns except in Hong Kong. In 1964-8, male suicide rates in Australia and US were represented by upward-sloping graphs, whereas in Japan the pattern was bimodal. By 1979-83, male patterns in Australia and US were bimodal, but Japan's was trimodal, including a middle-age peak reached in 1994 98. In contrast, female age patterns in the Western countries were shallowly convex or uniform, while in Hong Kong and Japan the upward-sloping graphs became, over time, less steep; by 2009-13, the pattern in Japan was uniform (flat). In recent decades, suicide rates of older men in Australia, US and Japan, and older women in Japan and Hong Kong, have fallen considerably. Suicide rates of men aged 45-64 in Australia and US also fell, though by 2009-13 the US rate had risen again. The suicide rate of Australian men in their twenties halved between 1994 98 and 2009-13, while rates for younger men and women in Japan have risen since 1994-98. In Hong Kong, suicide rates of young men have increased. Age patterns of suicide likely reflect period and cohort effects shaped by socioeconomic stressors, availability of health and welfare services, access to lethal methods of suicide, and other factors. Greater understanding of their impact on age patterns of suicide can result in potential preventive solutions. PMID- 28081433 TI - What's the law got to do with it? Legislation regarding in-vehicle technology use and its impact on driver distraction. AB - Legislation in the road transport domain aims to control safety on the roads. Despite this, a critical issue affecting road safety is that of driver distraction. Although poorly defined, distraction is a significant road safety issue which, in part, is caused by the prevalence of technology within vehicles. Legislation surrounding the use of in-vehicle technologies are explored in this paper from a socio-technical system perspective. This reveals the wider context of the road transport system operating under the current laws using an Accimap analysis. A distinction in the law between the use of hand-held mobile phones, a device that is typically banned for use by drivers worldwide, and the use of other technological devices that are covered by more general laws against 'careless' and/or 'dangerous' driving was found. Historically, individual drivers' have been blamed for distraction, whereas the systems approach shows how current legislation may have created the conditions necessary for driver distraction. PMID- 28081434 TI - Implicit attitudes towards risky driving: Development and validation of an affect misattribution procedure for speeding. AB - The present study aimed to develop and validate an instrument for measuring implicit attitudes towards speeding, based on the Affect Misattribution Procedure (AMP). The data collected from 140 drivers supported the reliability of the AMP (alpha=0.80). Results provided some support for the construct validity of the AMP, through its convergence with explicit attitudes towards speeding (r=0.22). Also, the AMP incrementally predicted driving violations (DeltaR2=0.034) and traffic accidents (DeltaR2=0.022), above and beyond demographic variables and explicit attitudes towards speeding, thus providing initial evidence for its criterion validity. The multiplicative interaction effect between implicit and explicit attitudes (in predicting the same criterion variables) was not supported. Overall, our results provide support for Speeding-AMP's validity and reliability, which can be successfully used in research concerning risky driving behavior. PMID- 28081436 TI - A 3D Sphere Culture System Containing Functional Polymers for Large-Scale Human Pluripotent Stem Cell Production. PMID- 28081435 TI - Heavy episodic drinking and alcohol-related injuries: An open cohort study among college students. AB - AIM: The objective of this study is to assess the effects of Heavy Episodic Drinking (HED) on the incidence of alcohol-related injuries among university students in Spain, taking sex into consideration. METHODS: We carried out an open cohort study among college students in Spain (992 women and 371 men). HED and alcohol-related injuries were measured by question 3rd and 9th of Alcohol Use Disorders Identification Test to every participant at the ages of 18, 20, 22, 24 and 27. For data analysis we used a Multilevel Logistic Regression for repeated measures adjusting for alcohol and cannabis use. RESULTS: The incidence rate of alcohol-related injuries was 0.028year-1 for females and 0.036year-1 for males. The multivariate analysis showed that among females a high frequency of HED and use of cannabis are risk factors for alcohol-related injuries (Odds Ratio [OR]=2.64 and OR=3.68), while being more than 23 is a protective factor (OR=0.34). For males, bivariate analysis also showed HED like risk factor (OR=4.69 and OR=2.51). Finally, the population attributable fraction for HED among females was 37.12%. CONCLUSIONS: HED leads to an increase of alcohol related injuries in both sexes and being over 23 years old acts as a protective factor among women. Our results suggest that about one third of alcohol-related injuries among women could be avoided by removing HED. PMID- 28081437 TI - Defining Differences among Perivascular Cells Derived from Human Pluripotent Stem Cells. PMID- 28081438 TI - TBX3 Directs Cell-Fate Decision toward Mesendoderm. PMID- 28081439 TI - Knotty Zika Virus Blocks Exonuclease to Produce Subgenomic Flaviviral RNAs. AB - In a recent issue of Science, Akiyama et al. (2016) prove the existence of a pseudoknot that stabilizes a nuclease-resistant RNA structure in the 3' untranslated region of Zika virus. This reinforced structure blocks the 5'->3' exonuclease Xrn1 for the production of pathogenic subgenomic flaviviral RNAs. PMID- 28081440 TI - A Knockout Screen of ApiAP2 Genes Reveals Networks of Interacting Transcriptional Regulators Controlling the Plasmodium Life Cycle. AB - A family of apicomplexa-specific proteins containing AP2 DNA-binding domains (ApiAP2s) was identified in malaria parasites. This family includes sequence specific transcription factors that are key regulators of development. However, functions for the majority of ApiAP2 genes remain unknown. Here, a systematic knockout screen in Plasmodium berghei identified ten ApiAP2 genes that were essential for mosquito transmission: four were critical for the formation of infectious ookinetes, and three were required for sporogony. We describe non essential functions for AP2-O and AP2-SP proteins in blood stages, and identify AP2-G2 as a repressor active in both asexual and sexual stages. Comparative transcriptomics across mutants and developmental stages revealed clusters of co regulated genes with shared cis promoter elements, whose expression can be controlled positively or negatively by different ApiAP2 factors. We propose that stage-specific interactions between ApiAP2 proteins on partly overlapping sets of target genes generate the complex transcriptional network that controls the Plasmodium life cycle. PMID- 28081441 TI - Warfare between Host Immunity and Bacterial Weapons. AB - Bacterial pathogens deploy protein secretion systems to facilitate infection and colonization of their hosts. In this issue of Cell Host & Microbe, Chen et al. (2017) report a new role for a type VI secretion effector in promoting bacterial colonization by preventing inflammasome activation induced by a type III secretion system. PMID- 28081442 TI - Mapping and Role of the CD8+ T Cell Response During Primary Zika Virus Infection in Mice. AB - CD8+ T cells may play a dual role in protection against and pathogenesis of flaviviruses, including Zika virus (ZIKV). We evaluated the CD8+ T cell response in ZIKV-infected LysMCre+IFNARfl/fl C57BL/6 (H-2b) mice lacking the type I interferon receptor in a subset of myeloid cells. In total, 26 and 15 CD8+ T cell reactive peptides for ZIKV African (MR766) and Asian (FSS13025) lineage strains, respectively, were identified and validated. CD8+ T cells from infected mice were polyfunctional and mediated cytotoxicity. Adoptive transfer of ZIKV-immune CD8+ T cells reduced viral burdens, whereas their depletion led to higher tissue burdens, and CD8-/- mice displayed higher mortality with ZIKV infection. Collectively, these results demonstrate that CD8+ T cells protect against ZIKV infection. Further, this study provides a T cell competent mouse model for investigating ZIKV-specific T cell responses. PMID- 28081443 TI - The Bacterial T6SS Effector EvpP Prevents NLRP3 Inflammasome Activation by Inhibiting the Ca2+-Dependent MAPK-Jnk Pathway. AB - Inflammasome activation is an important innate immune defense mechanism against bacterial infection, and in return, bacteria express virulence determinants that counteract inflammasome activation. Many such effectors are secreted into host cells via specialized bacterial secretion systems. Here, the intracellular pathogenic bacterium Edwardsiella tarda was demonstrated to activate NLRC4 and NLRP3 inflammasomes via a type III secretion system (T3SS), and to inhibit NLRP3 inflammasome via a type VI secretion system (T6SS), indicating the antagonistic roles of these systems in inflammasome signaling. Furthermore, a non-VgrG T6SS effector, EvpP, was identified that significantly inhibited NLRP3 inflammasome activation. Subsequent studies revealed that EvpP significantly suppressed Jnk activation, thus impairing oligomerization of the inflammasome adaptor ASC. Moreover, EvpP counteracted cytoplasmic Ca2+ increase, which works upstream of Jnk activation to regulate the NLRP3 inflammasome. Finally, EvpP-mediated inflammasome inhibition promoted bacterial colonization in vivo. This work expands our understanding of bacterial T6SS in counteracting host immune responses. PMID- 28081444 TI - Host-to-Host Transmission of the Pneumococcus-New Victims of a Toxic Relationship. AB - Host-to-host transmission is critical for survival of the human-adapted bacterium Streptococcus pneumoniae. In this issue of Cell Host & Microbe, Zafar et al. (2017) show that transmission is dependent on nasopharyngeal inflammation elicited by the toxin pneumolysin, causing increased shedding and enhanced survival of the bacterium in the environment. PMID- 28081445 TI - Bringing the Dynamic Microbiome to Life with Animations. AB - Our bodies and natural environment contain complex microbial communities, colloquially termed microbiomes. We previously created a web-based application, EMPeror, for visualizing ordinations derived from comparisons of these microbiome communities. We have now improved EMPeror to create interactive animations that connect successive samples to highlight patterns over time. PMID- 28081446 TI - Host-to-Host Transmission of Streptococcus pneumoniae Is Driven by Its Inflammatory Toxin, Pneumolysin. AB - Host-to-host transmission is a critical step for infection. Here we studied transmission of the opportunistic pathogen Streptococcus pneumoniae in an infant mouse model. Transmission from nasally colonized pups required high levels of bacterial shedding in nasal secretions and was temporally correlated with, and dependent upon, the acute inflammatory response. Pneumolysin, a pore-forming cytotoxin and major virulence determinant, was both necessary and sufficient to promote inflammation, which increased shedding and allowed for intralitter transmission. Direct contact between pups was not required for transmission indicating the importance of an environmental reservoir. An additional in vivo effect of pneumolysin was to enhance bacterial survival outside of the host. Our findings provide experimental evidence of a microbial strategy for transit to new hosts and explain why an organism expresses a toxin that damages the host upon which it depends. PMID- 28081447 TI - Hepatic transcriptional responses to copper in the three-spined stickleback are affected by their pollution exposure history. AB - Some fish populations inhabiting contaminated environments show evidence of increased chemical tolerance, however the mechanisms contributing to this tolerance, and whether this is heritable, are poorly understood. We investigated the responses of two populations of wild three-spined stickleback (Gasterosteus aculeatus) with different histories of contaminant exposure to an oestrogen and copper, two widespread aquatic pollutants. Male stickleback originating from two sites, the River Aire, with a history of complex pollution discharges, and Siblyback Lake, with a history of metal contamination, were depurated and then exposed to copper (46MUg/L) and the synthetic oestrogen ethinyloestradiol (22ng/L). The hepatic transcriptomic response was compared between the two populations and to a reference population with no known history of exposure (Houghton Springs, Dorset). Gene responses included those typical for both copper and oestrogen, with no discernable difference in response to oestrogen between populations. There was, however, some difference in the magnitude of response to copper between populations. Siblyback fish showed an elevated baseline transcription of genes encoding metallothioneins and a lower level of metallothionein induction following copper exposure, compared to those from the River Aire. Similarly, a further experiment with an F1 generation of Siblyback fish bred in the laboratory found evidence for elevated transcription of genes encoding metallothioneins in unexposed fish, together with an altered transcriptional response to 125MUg/L copper, compared with F1 fish originating from the clean reference population exposed to the same copper concentration. These data suggest that the stickleback from Siblyback Lake have a differential response to copper, which is inherited by the F1 generation in laboratory conditions, and for which the underlying mechanism may include an elevation of baseline transcription of genes encoding metallothioneins. The genetic and/or epigenetic mechanisms contributing to this inherited alteration of metallothionein transcription have yet to be established. PMID- 28081448 TI - The relationships among fear of hypoglycaemia, diabetes-related quality of life and psychological well-being in Norwegian adults with Type 1 diabetes. AB - AIMS: To examine the associations among fear of hypoglycaemia, diabetes-related quality of life and psychological well-being, and determine whether diabetes related quality of life is a mediator of the relationship between fear of hypoglycaemia and psychological well-being in adults with Type 1 diabetes. METHODS: A total of 235 of 319 invited adults (18-69years) with Type 1 diabetes agreed to participate. Hierarchical linear regression was applied to 188 individuals with complete data. Mediation analysis was used to determine whether diabetes-related quality of life mediated the relationship between fear of hypoglycaemia and psychological well-being. RESULTS: Fear of hypoglycaemia was significantly associated with diabetes-related quality of life and psychological well-being. The behaviour and worry components of fear of hypoglycaemia were significantly associated with diabetes-related quality of life (behaviour component: unstandardised coefficient=-0.04, p<0.001, standardised coefficient= 0.40; worry component: unstandardised coefficient=-0.01, p=0.041, standardised coefficient=-0.18). Fear of hypoglycaemia worry had a significant independent association with psychological well-being (unstandardised coefficient=-0.28, p=0.009, standardised coefficient=-0.25), whereas fear of hypoglycaemia behaviour did not. Diabetes-related quality of life mediated approximately half of the association between fear of hypoglycaemia worry and psychological well-being. CONCLUSIONS: Hypoglycaemic episodes can have serious consequences, and assessing fear of hypoglycaemia might help health care providers offer suitable care strategies to individuals with Type 1 diabetes. PMID- 28081449 TI - Diabetes diagnostic thresholds of the glycated hemoglobin A1c and fasting plasma glucose levels considering the 5-year incidence of retinopathy. AB - AIMS: As retinopathy is used as a defining threshold of diabetes, we assessed the glycated hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) values associated with an increased risk of 5-year incidence of retinopathy. METHODS: We studied HbA1c, FPG, and optic fundus findings of 2605 individuals without previously diagnosed diabetes annually during a 5-year period. Retinopathy was examined using non-mydriatic, 45 degrees digital fundus photography. Baseline levels were stratified as <5.3 [34], 5.3-5.6 [34-38], 5.7-6.0 [39-42], 6.1-6.4 [43-47], and ?6.5% [48mmol/mol] for HbA1c and <5.0, 5.0-5.5, 5.6-6.0, 6.1-6.9, and ?7.0mmol/L for FPG. Cox proportional hazard models were used to analyze hazard ratios (HRs) associated with HbA1c or FPG for incident retinopathy. RESULTS: During a total of 11845 person-years, we identified 50 (1.9%) cases of incident retinopathy. The adjusted HRs for incident retinopathy associated with a one-standard deviation increase in HbA1c and FPG were 1.2 (95% confidence intervals: 1.1-1.4) and 1.2 (1.1-1.4), respectively. These HRs were significantly higher for a HbA1c level ?6.5% (48mmol/mol) (3.4 [1.1-10.2]) or FPG level ?7.0mmol/L (3.6 [1.1-11.6]) than for a HbA1c level <5.3% (34mmol/mol) or FPG level <5.0mmol/L. CONCLUSIONS: A HbA1c value of 6.5% (48mmol/mol) and FPG value of 7.0mmol/L might be proper as diabetes diagnostic thresholds that indicate a high risk of future retinopathy. PMID- 28081450 TI - Heparanase-driven inflammation from the AGEs-stimulated macrophages changes the functions of glomerular endothelial cells. AB - AIMS: Amounts of macrophages were infiltrated in glomeruli in diabetic nephropathy. Heparanase has been thought to be closely related to proteinuria. Our aims were to determine the effect of heparanase on the inflammation in AGEs stimulated macrophages and its role on the functions of glomerular endothelial cells (GEnCs). METHODS: The expression of inflammation cytokines in macrophages were assayed by q-RT PCR, western, and ELISA. Then western was used to measure the expression of RAGE and key proteins in NF-kappaB pathway in macrophages. The expression of the adherence molecules and tight junction proteins in GEnCs were assessed by western. The adherence of mononuclear cells to GEnCs were observed by HE staining and transendothelial FITC-BSA were tested for the permeability of GEnCs. RESULTS: HPA siRNA and heparanase inhibitor sulodexide could attenuate the increasing inflammatory factors (TNF-alpha and IL-1beta) in AGEs-stimulated macrophages. NF-kappaB inhibitor PDTC could also decrease the augmented inflammation cytokines through inhibiting the activation of the NF-kappaB pathway induced by AGEs. The phosphorylation of NF-kappaB signaling pathway could be also attenuated by HPA siRNA and sulodexide, the same to the receptor of AGEs RAGE. When the macrophage-conditioned culture medium were added to the glomerular endothelial cells, we found HPA siRNA and sulodexide groups could decrease the increasing adherence and permeability of GEnCs induced by AGEs. CONCLUSIONS: Heparanase increases the inflammation in AGEs-stimulated macrophages through activating the RAGE-NF-kappaB pathway. Heparanase driven inflammation from AGEs stimulated macrophages increases the adherence of GEnCs and augments the permeability of GEnCs. PMID- 28081451 TI - How specialized are writing-specific brain regions? An fMRI study of writing, drawing and oral spelling. AB - Several brain imaging studies identified brain regions that are consistently involved in writing tasks; the left premotor and superior parietal cortices have been associated with the peripheral components of writing performance as opposed to other regions that support the central, orthographic components. Based on a meta-analysis by Planton, Jucla, Roux, and Demonet (2013), we focused on five such writing areas and questioned the task-specificity and hemispheric lateralization profile of the brain response in an functional magnetic resonance imaging (fMRI) experiment where 16 right-handed participants wrote down, spelled out orally object names, and drew shapes from object pictures. All writing related areas were activated by drawing, and some of them by oral spelling, thus questioning their specialization for written production. The graphemic/motor frontal area (GMFA), a subpart of the superior premotor cortex close to Exner's area (Roux et al., 2009), was the only area with a writing-specific lateralization profile, that is, clear left lateralization during handwriting, and bilateral activity during drawing. Furthermore, the relative lateralization and levels of activation in the superior parietal cortex, ventral premotor cortex, ventral occipitotemporal cortex and right cerebellum across the three tasks brought out new evidence regarding their respective contributions to the writing processes. PMID- 28081453 TI - Intertypic recombination of human parechovirus 4 isolated from infants with sepsis-like disease. AB - BACKGROUND: Human parechoviruses (HPeVs) (family Picornaviridae), are common pathogens in young children. Despite their high prevalence, research on their genetic identity, diversity and evolution have remained scarce. OBJECTIVES: Complete coding regions of three previously reported HPeV-4 isolates from Finnish children with sepsis-like disease were sequenced in order to elucidate the phylogenetic relationships and potential recombination events during the evolution of these isolates. STUDY DESIGN: The isolated viruses were sequenced and aligned with all HPeV complete genome sequences available in GenBank. Phylogenetic trees were constructed and similarity plot and bootscanning methods were used for recombination analysis. RESULTS: The three HPeV-4 isolates had 99.8% nucleotide sequence similarity. The phylogenetic analysis indicated that capsid-encoding sequences of these HPeV-4 isolates were closely related to other HPeV-4 strains (80.7-94.7% nucleotide similarity), whereas their non-structural region genes 2A to 3C clustered together with several HPeV-1 and HPeV-3 strains, in addition to the HPeV-4 strain K251176-02 (isolated 2002 in the Netherlands), but not with other HPeV-4 strains. However, in 3D-encoding sequence the Finnish HPeV-4 isolates did not cluster with the strain HPeV-4/K251176-02, but instead, formed a distinct group together with several HPeV-1 and HPeV-3 strains. Similarity plot and Bootscan analyses further confirmed intertypic recombination events in the evolution of the Finnish HPeV-4 isolates. CONCLUSION: Intertypic recombination event(s) have occurred during the evolution of HPeV-4 isolates from children with sepsis-like disease. However, due to the low number of parechovirus complete genomes available, the precise recombination partners could not be detected. The results suggest frequent intratypic recombination among parechoviruses. PMID- 28081454 TI - Study of the adsorption and electroadsorption process of Cu (II) ions within thermally and chemically modified activated carbon. AB - The aim of this work is to modify the porous texture and superficial groups of a commercial activated carbon through chemical and thermal treatment and subsequently study the kinetics of adsorption and electroadsorption of Cu (II) ion for these carbons. Samples of three activated carbons were used. These were a commercial activated carbon, commercial activated carbon modified thermically (C N2-900) and finally commercial activated carbon modified chemically C-SO2-H2S 200. The activated carbons were characterized chemically and texturally and the electrical conductivity of them determined. Different kinetic models were applied. The kinetics of the adsorption and electroadsorption process of the Cu (II) ion fits a pseudo second order model and the most likely mechanism takes place in two stages. A first step through transfer of the metal mass through the boundary layer of the adsorbent and distribution of the Cu (II) on the external surface of the activated carbon and a second step that represents intraparticle diffusion and joining of the Cu (II) with the active centres of the activated carbon. Finally, the kinetics of the adsorption process are faster than the kinetics of the electroadsorption but the percentage of the Cu (II) ion retained is much higher in the electroadsorption process. PMID- 28081452 TI - Differential white matter involvement associated with distinct visuospatial deficits after right hemisphere stroke. AB - Visuospatial attention depends on the integration of multiple processes, and people with right hemisphere lesions after a stroke may exhibit severe or no visuospatial deficits. The anatomy of core components of visuospatial attention is an area of intense interest. Here we examine the relationship between the disruption of core components of attention and lesion distribution in a heterogeneous group (N = 70) of patients with right hemisphere strokes regardless of the presence of clinical neglect. Deficits of lateralized spatial orienting, measured as the difference in reaction times for responding to visual targets in the contralesional or ipsilesional visual field, and deficits in re-orienting attention, as measured by the difference in reaction times for invalidly versus validly cued targets, were measured using a computerized spatial orienting task. Both measures were related through logistic regression and a novel ridge regression method to anatomical damage measured with magnetic resonance imaging. While many regions were common to both deficit maps, a deficit in lateralized spatial orienting was more associated with lesions in the white matter underlying the posterior parietal cortex, and middle and inferior frontal gyri. A deficit in re-orienting of attention toward unattended locations was associated with lesions in the white matter of the posterior parietal cortex, insular cortex and less so with white matter involvement of the anterior frontal lobe. An hodological analysis also supports this partial dissociation between the white matter tracts that are damaged in lateralized spatial biases versus impaired re-orienting. Our results underscore that the integrity of fronto-parietal white matter tracts is crucial for visuospatial attention and that different attention components are mediated by partially distinct neuronal substrates. PMID- 28081455 TI - Correlates of vitamin D in psychotic disorders: A comprehensive systematic review. AB - People with psychosis have high prevalence of low vitamin D levels but the correlates and relevance of this deficiency are unclear. A systematic search of major databases from inception to 03/2016 was undertaken investigating correlates of vitamin D in people with psychosis. Data was summarised with a best evidence synthesis. Across 23 included studies (n=1770 psychosis, n=8171 controls) a mean difference in vitamin D levels between both groups of -11.14ng/ml+/-0.59 was found. 53 unique correlations between vitamin D and outcomes in people with psychosis were identified. The evidence base was broadly equivocal although season of blood sampling (67% of studies found a positive correlation with warmer seasons) and parathyroid hormone (100% of studies found a negative correlation) were associated with vitamin D levels. The most commonly non-correlated variables were: BMI (83% found no correlation), age (73%), gender (86%), smoking (100%), duration of illness (100%) and general assessment of functioning score (100%). In conclusion, whilst many unique correlates have been investigated, there is weak and inconclusive evidence regarding the consistency and meaning of the correlates of vitamin D levels in people with psychosis. Future longitudinal studies should consider the correlates of vitamin D in people with psychosis. PMID- 28081456 TI - Robust, tough and anti-fatigue cationic latex composite hydrogels based on dual physically cross-linked networks. AB - Dual physically cross-linked hydrogels, which are triggered by cationic latexes as hydrophobic association and ionic crosslinking centers, were easily fabricated via a one-pot in situ polymerization method. First, the hydrophobic alkyl chains of hydrophobic monomers are adsorbed on the surface of latex microspheres and stabilized in the presence of surfactants, forming hydrophobic association centers as the first physical crosslinking points. Meanwhile, the anionic sulfate radicals dissociated by persulphate are attracted towards the cationic molecular chains of latex microspheres through ionic interactions, forming the secondary physical crosslinking centers, and initiate the copolymerization between acrylamide and hydrophobic vinyl monomers. The fabricated hydrogel exhibited high tensile strength of 1.32MPa, a remarkable toughness of 4.53MJm-3, excellent self recovery properties and fatigue resistance. Therefore, the current work provides a promising strategy for designing novel hydrogels via multiple physical interactions and devoid of any chemical crosslinking. The novel design of hydrogels can enhance their mechanical properties and expand their biomedical applications. PMID- 28081457 TI - Surface-active ionic liquids in catalysis: Impact of structure and concentration on the aerobic oxidation of octanol in water. AB - We present design and synthesis of surface-active ionic liquids for the application in micellar catalysis. A series of 1-methyl-3-dodecylimidazolium based ionic liquids with variable core structures including dicationic and zwitterionic ones was synthesized and characterized. These surface-active ionic liquids where applied in the aerobic oxidation of aliphatic alcohols to carbonyl compounds. A strong dependence on the ionic liquid concentration and structure was identified, which is in accordance with the concepts of micellar catalysis. Optimum conditions for the oxidation of 1-octanol could be identified, and the use of surface-active ionic liquids strongly improved the reaction performance compared to pure water. Under optimized conditions, it was possible to isolate up to 75% of octanoic acid using only small amounts of surface-active ionic liquid in a 0.05mM solution in water without further ligands. PMID- 28081458 TI - Multistage bioassociation of uranium onto an extremely halophilic archaeon revealed by a unique combination of spectroscopic and microscopic techniques. AB - The interactions of two extremely halophilic archaea with uranium were investigated at high ionic strength as a function of time, pH and uranium concentration. Halobacterium noricense DSM-15987 and Halobacterium sp. putatively noricense, isolated from the Waste Isolation Pilot Plant repository, were used for these investigations. The kinetics of U(VI) bioassociation with both strains showed an atypical multistage behavior, meaning that after an initial phase of U(VI) sorption, an unexpected interim period of U(VI) release was observed, followed by a slow reassociation of uranium with the cells. By applying in situ attenuated total reflection Fourier-transform infrared spectroscopy, the involvement of phosphoryl and carboxylate groups in U(VI) complexation during the first biosorption phase was shown. Differences in cell morphology and uranium localization become visible at different stages of the bioassociation process, as shown with scanning electron microscopy in combination with energy dispersive X ray spectroscopy. Our results demonstrate for the first time that association of uranium with the extremely halophilic archaeon is a multistage process, beginning with sorption and followed by another process, probably biomineralization. PMID- 28081460 TI - Blood-brain barrier dysfunction induced by silica NPs in vitro and in vivo: Involvement of oxidative stress and Rho-kinase/JNK signaling pathways. AB - Silica nanoparticles (SiO2-NPs) has been extensively exploited in biomedical fields and mostly designed to enter the circulatory system, however, few studies focused on the potential adverse effects of SiO2-NPs exposure on the blood-brain barrier (BBB) that serves as a critical barrier between the central nervous system (CNS) and the peripheral circulation. This study attempts to provide an understanding of whether and how SiO2-NPs disrupts the BBB in vitro and in vivo. Through a human BBB model, we found that SiO2-NPs could induce tight junction loss and cytoskeleton arrangement, and increase inflammatory response and the release of vascular endothelial growth factor (VEGF) of brain microvessel endothelial cells (BMECs), which further activates astrocytes to amplify the generation of VEGF and increase the aquaporin-4 expression, and thus causing BBB disruption through a complex immunoregulatory loop between BMECs and astrocytes under SiO2-NPs exposure. Additionally, our data show that inhibition of reactive oxygen species (ROS) and Rho-kinase (ROCK) could effectively protect the SiO2-NPs induced BBB dysfunction. In vivo studies further confirmed that SiO2-NPs could cause the BBB paracellular opening, oxidative stress and astrocyte activation in brains of Sprague-Dawley (SD) rats. These findings demonstrate that SiO2-NPs could disturb BBB structure and function and induce BBB inflammation, and suggest that these effects may occur through ROS and ROCK-mediated pathways, which not only improve neurotoxicity evaluation for SiO2-NPs but also provide useful information in development of SiO2-NPs in neuro-therapeutics and nanodiagnostics. PMID- 28081459 TI - Targeted delivery of in situ PCR-amplified Sleeping Beauty transposon genes to cancer cells with lipid-based nanoparticle-like protocells. AB - A Sleeping Beauty (SB) transposon system is made of a transposon plasmid (containing gene encoding a desired functional or therapeutic protein) and a transposase plasmid (encoding an enzyme capable of cutting and pasting the gene into the host cell genome). It is a kind of natural, nonviral gene delivery vehicle, which can achieve efficient genomic insertion, providing long-term transgenic expression. However, before the SB transposon system could play a role in promoting gene expression, it has to be delivered efficiently first across cell membrane and then into cell nuclei. Towards this end, we used a nanoparticle like lipid-based protocell, a closed bilayer of the neutral lipids with the DNA encapsulated inside, to deliver the SB transposon system to cancer cells. The SB transposon system was amplified in situ inside the protocells by a polymerase chain reaction (PCR) process, realizing more efficient loading and delivery of the target gene. To reach a high transfection efficiency, we introduced two targeting moieties, folic acid (FA) as a cancer cell-targeting motif and Dexamethasone (DEX) as a nuclear localization signaling molecule, into the protocells. As a result, the FA enabled the modified targeting protocells to deliver the DNA into the cancer cells with an increased efficiency and the DEX promoted the DNA to translocate to cell nuclei, eventually leading to the increased chromosome insertion efficiency of the SB transposon. In vivo study strongly suggested that the transfection efficiency of FA-modified protocells in the tumor tissue was much higher than that in other tissues, which was consistent with the in vitro results. Our studies implied that with the targeting ligand modification, the protocells could be utilized as an efficient targeting gene carrier. Since the protocells were made of neutral lipids without cationic charges, the cytotoxicity of protocells was significantly lower than that of traditional cationic gene carriers such as cationic liposomes and polyethylenimine, enabling the protocells to be employed in a wider dosage range in gene therapy. Our work shows that the protocells are a promising gene carrier for future clinical applications. PMID- 28081461 TI - BDNF gene delivery mediated by neuron-targeted nanoparticles is neuroprotective in peripheral nerve injury. AB - Neuron-targeted gene delivery is a promising strategy to treat peripheral neuropathies. Here we propose the use of polymeric nanoparticles based on thiolated trimethyl chitosan (TMCSH) to mediate targeted gene delivery to peripheral neurons upon a peripheral and minimally invasive intramuscular administration. Nanoparticles were grafted with the non-toxic carboxylic fragment of the tetanus neurotoxin (HC) to allow neuron targeting and were explored to deliver a plasmid DNA encoding for the brain-derived neurotrophic factor (BDNF) in a peripheral nerve injury model. The TMCSH-HC/BDNF nanoparticle treatment promoted the release and significant expression of BDNF in neural tissues, which resulted in an enhanced functional recovery after injury as compared to control treatments (vehicle and non-targeted nanoparticles), associated with an improvement in key pro-regenerative events, namely, the increased expression of neurofilament and growth-associated protein GAP-43 in the injured nerves. Moreover, the targeted nanoparticle treatment was correlated with a significantly higher density of myelinated axons in the distal stump of injured nerves, as well as with preservation of unmyelinated axon density as compared with controls and a protective role in injury-denervated muscles, preventing them from denervation. These results highlight the potential of TMCSH-HC nanoparticles as non-viral gene carriers to deliver therapeutic genes into the peripheral neurons and thus, pave the way for their use as an effective therapeutic intervention for peripheral neuropathies. PMID- 28081462 TI - In vitro evaluation of biodegradable lignin-based nanoparticles for drug delivery and enhanced antiproliferation effect in cancer cells. AB - Currently, nanosystems have been developed and applied as promising vehicles for different biomedical applications. We have developed three lignin nanoparticles (LNPs): pure lignin nanoparticles (pLNPs), iron(III)-complexed lignin nanoparticles (Fe-LNPs), and Fe3O4-infused lignin nanoparticles (Fe3O4-LNPs) with round shape, narrow size distribution, reduced polydispersity and good stability at pH 7.4. The LNPs showed low cytotoxicity in all the tested cell lines and hemolytic rates below 12% after 12 h of incubation. Additionally, they induced hydrogen peroxide production in a small extent and time-dependent manner, and the interaction with the cells increased over time, exhibiting a dose-dependent cell uptake. Concerning the drug loading, pLNPs showed the capacity to efficiently load poorly water-soluble drugs and other cytotoxic agents, e.g. sorafenib and benzazulene (BZL), and improve their release profiles at pH 5.5 and 7.4 in a sustained manner. Furthermore, the BZL-pLNPs presented an enhanced antiproliferation effect in different cells compared to the pure BZL and showed a maximal inhibitory concentration ranging from 0.64 to 12.4 MUM after 24 h incubation. Overall, LNPs are promising candidates for drug delivery applications, and the superparamagnetic behavior of Fe3O4-LNPs makes them promising for cancer therapy and diagnosis, such as magnetic targeting and magnetic resonance imaging. PMID- 28081463 TI - Analysis of the results of recurrent intracranial meningiomas treated with re radiosurgery. AB - OBJECTS: Meningioma is the most common intracranial neoplasm, comprising approximately 30% of all primary intracranial tumors (Claus et al., 2005) [1]. Treatment options include observation, microsurgical resection, stereotactic radiosurgery (SRS), and whole brain radiation therapy (WBRT). Gamma knife radiosurgery (GKRS) is a very effective treatment for intracranial meningiomas; previous studies showed the tumor control rate at 5-10 years of follow-up as 84.3%-100% in all cases (Feigl et al., 2005; Linskey et al., 2005; Malik et al., 2005; Aichholzer et al., 2000; Hakim et al., 1998; Chang and Adler 1997; Lunsford, 1994; Ganz et al., 1993) [2-9]. Many studies have discussed issues like optimal dose, conformal configurations, and adverse effects to improve the treatment result with GKRS (Malik et al., 2005; Kenai et al., 2005; Rowe et al., 2004; Shrieve et al., 2004) [4,10-12]. There are some cases in which the radiosurgery result is unfavorable and perhaps further treatment is needed. In these cases, re-radiosurgery can be an option. However, there have not been comprehensive studies discussing the issues of re-radiosurgery. Therefore, we analyzed the result of re-radiosurgery for recurrent meningiomas and their impact on clinical outcomes. METHODS: From 1995 to 2015, we retrospectively reviewed 1163 patients who underwent GKRS for intracranial meningioma at the Asan Medical Center. Patients with multiple meningiomas or a follow-up with a period of less than a year were excluded from this study. Finally, 865 patients were enrolled in this study. Clinical symptoms and brain magnetic resonance imaging (MRI) scans were assessed by neurosurgeons. When tumor size increased together with newly developed neurologic symptoms, further management, such as microsurgical resection or SRS, was considered. Histologic analysis of the resected tumors was performed by neuropathologists. Clinical data, including patient's sex, age, and tumor locations were recorded. Treatment data included tumor volume, tumor grade, radiation dose, and presence of edema. Final outcome data including follow-up period, time to progression, interval between first and second radiosurgery courses and interval between microsurgery and radiosurgery were obtained. RESULTS: Among 865 patients, tumor recurrence was found in 63 patients (7.28%). Seven patients showed transient tumor growth after GKRS. These patients have been under close observation without any further treatments. Fifty-six patients (6.47%) showed permanent tumor growth on follow-up MRI. Thirty-three patients from this group underwent repeated radiosurgery owing to tumor growth, resulting in a re-irradiation rate of 3.82% at our radiosurgery center. The other 23 patients were treated using methods other than re-radiosurgery. Among the 33 patients, 25 underwent microsurgical resection prior to their initial course of GKRS, and the other 8 were treated with re-radiosurgery only. An analysis was performed to determine factors that may have a role in treatment results. Of the many variables, tumor grade (p=0.004, Fisher's exact test) was the only significant factor for progression-free survival (PFS). Thirteen patients with unbiopsied or benign meningioma showed stable tumor size, while there was tumor growth in 8 patients. Among high-grade meningioma patients, 3 and 9 showed stable disease and tumor growth, respectively. As a result of re-radiosurgery, 11 out of 17 patients showed tumor growth and needed further treatments; this involved a third GKRS for 4 patients, microsurgical resection for 6 patients, and cyber knife radiosurgery (CKRS) for 1 patient. Four patients from this group were also treated with WBRT. CONCLUSION: We analyzed the results of re-radiosurgery for recurrent meningiomas and observed that World Health Organization (WHO) grade II and III was significantly associated with a lower PFS rate compared with low grade meningiomas (p=0.004). Conversely, patients with benign meningioma or unbiopsied tumors had much better results. Hence, re-radiosurgery is recommended for patients with unknown or benign meningiomas if their first GKRS result is unsatisfactory. However, re-radiosurgery should be considered carefully for recurrent high-grade tumors. Owing to the small number of recurrent meningioma patients treated with re-radiosurgery, further studies are required to delineate the role of this treatment. PMID- 28081464 TI - Tumor angiogenesis of SCLC inhibited by decreased expression of FMOD via downregulating angiogenic factors of endothelial cells. AB - Fibromodulin (FMOD), an ECM small leucine-rich proteoglycan (SLRP), was reported to promote angiogenesis not only during wound healing, but also in optical and cutaneous angiogenesis-dependent diseases. However, whether it plays important roles in tumor angiogenesis remains unclear. To explore the role of FMOD in tumor angiogenesis of human small cell lung cancer (SCLC), initially the study analyzed the relationship of FMOD expression in cancer tissues of SCLC with clinical characteristics. The analysis revealed that the positive FMOD expression was significantly associated with extensive stage of SCLC and higher vascular density. In mouse models, xenograft tumors developed with FMOD-silenced H446 cells (H446-shFMOD) exhibited slowed growth rate, decreased microvessel density, and reduced blood perfusion related to that of controls (H446-shCON). Additionally, compared with that of controls, the decreased secretion of FMOD in conditioned medium (CM) from H446-shFMOD inhibited proliferation, migration, and invasion of human umbilical vessel endothelial cells (HUVECs). Moreover, the decreased secretion of FMOD downregulated the expression of VEGF, TGF-beta1, FGF 2, and PDGF-B in HUVECs. The findings strongly suggested that the autocrine FMOD of cancer cells may promote tumor angiogenesis of SCLC by upregulating the expression of angiogenic factors that act in concert to facilitate the angiogenic phenotype of endothelial cells as a proangiogenic factor. Therefore, silencing FMOD may be a potentially clinical therapy for repressing tumor angiogenesis. PMID- 28081465 TI - Biological function and mechanism of lncRNA-MEG3 in Tenon's capsule fibroblasts proliferation: By MEG3-Nrf2 protein interaction. AB - OBJECTIVE: The proliferation of Tenon's capsule fibroblasts after glaucoma filtration surgery is a harmful element for operation failure. However, the underlying mechanism remains unclear. In this study, we evaluated the role of long non-coding RNA (lncRNA)-MEG3 in the proliferation of Glaucoma Tenon's capsule fibroblasts (GTFs) with a model of transforming growth factor-beta (TGF beta)-induced proliferation which has been used in previous studies to explore the mechanism underlying glaucoma surgery failure. METHODS: In vitro cell proliferation model was made by TGF-beta2 (5ng/mL)-stimulated GTFs obtained from patients with glaucoma filtration surgery, and cell viability and cell proliferation was assessed by MTT assay and [3H] thymidine incorporation assay respectively. Relative expression of MEG3 and Nrf2 mRNA was determined by quantitative real-time PCR. Nrf2 protein level was detected by western blot. Functional interaction between MEG3 and Nrf2 was examined by RNA pull down and RNA Binding Protein Immunoprecipitation (RIP). RESULTS: As detected in isolated Tenon's capsule fibroblasts, expression level of both MEG3 and Nrf2 is decreased in GTFs compared with control fibroblasts (HTFs). Adenovirus mediated overexpression of MEG3 attenuates cell ability and cell proliferation, as well as contributed to upregulation of Nrf2 protein in TGF-beta2-stimualted GTFs. MEG3 positively affects the expression of Nrf2 protein rather than Nrf2 mRNA. We found that this functional interaction of them depends on MEG3-Nrf2 protein formation by RNA pull down and RIP analysis and also is proved to be involved in TGF-beta2 induced cell proliferation. CONCLUSION: The above data suggested that the functional interaction between lncRNA-MEG3 and Nrf2 constitutes the mechanism by which TGF-beta2 induces Tenon's capsule fibroblasts proliferation after glaucoma filtration surgery via the direct binding of MEG3 to Nrf2. PMID- 28081466 TI - Long non-coding RNA ZFAS1 is an unfavourable prognostic factor and promotes glioma cell progression by activation of the Notch signaling pathway. AB - Survival of patients with glioma remains poor, which is largely attributed to active carcinogenesis. Accumulating evidence indicates that long non-coding RNAs (lncRNAs) play key roles in tumor initiation and progression. However, the function of lncRNA ZFAS1 in glioma is still unclear. In the current study, we found that ZFAS1 was upregulated in glioma tissues and cell lines. High ZFAS1 expression in glioma tissues was significantly correlated with advanced tumor stage and poor overall survival. Furthermore, in vitro assays demonstrated that ZFAS1 inhibition significantly suppressed glioma cell proliferation, migration and invasion. Importantly, we further confirmed that epithelial-mesenchymal transition (EMT) and the Notch signaling pathway was inactivated in the glioma cells after ZFAS1 knockdown. Thus, our findings indicated that ZFAS1 could exhibit a tumor oncogenic role in glioma progression by regulating EMT and Notch signaling pathway. LncRNA ZFAS1 might serve as a therapeutic target for the treatment of glioma patients. PMID- 28081467 TI - Oxidative stress and mRNA expression of acetylcholinesterase in the leukocytes of ischemic patients. AB - BACKGROUND: Pathogenesis of ischemic brain injury is occurred by crucial metabolic reasons. For instance, oxidative stress from free radical generation is causing to the thrombotic cerebrovascular stroke. In this case, the measurement of the oxidative stress is very important for a better understanding of the stroke pathophysiology. Because, the oxidative stress in stroke is generally assumed as one of the mechanisms taking part in neuronal damage. Thus, oxidative stress has a vital role in the cholinergic system. METHODS: We performed on 18 adult patients with stroke and 24 healthy persons as control subjects. First, acetylcholinesterase (AChE) activity and oxidative status were assayed in plasma and subsequently, quantitative gene expression of acetylcholinesterase was determined in leukocytes of patients diagnosed with acute stage of ischemia. RESULT: It was observed an increase in levels of the protein carbonyl content compared to the control (p=0.0011, p<0.01). The amount of the total thiol was lower than in the control groups of the ischemic patients (p=0.023, p<0.05). AChE and GST activities were significantly lower than control (p<0.01) in acute ischemic patients (p<0.01). mRNA expression of AChE was higher in the control groups than in the leukocytes of acute ischemic patients (p<0.05). CONCLUSION: These results suggest that oxidative status, AChE activity and its gene expression were changed significantly at the acute ischemic patients. PMID- 28081468 TI - Role of miR-15a in intervertebral disc degeneration through targeting MAP3K9. AB - BACKGROUND: Accumulating evidence indicates that microRNAs are involved in various cellular processes, including cell proliferation, differentiation, apoptosis and metastasis. miR-15a is an important regulator of immune responses and angiogenesis, endogenous controls as well as potential targets and hallmarks of cancer. However, the role of miR-15a in intervertebral disc degeneration (IDD) has not been elucidated. METHODS: Total RNA was extracted from degenerative nucleus pulposus (NP) tissues of 20 patients with IDD and NP cells, respectively. The expression levels of miR-15a were examined by quantitative real-time PCR. The stable overexpress or silence miR-15a expression cell lines and control cell lines were constructed by lentivirus infection. Subsequently, 3-(4,5-dimethylthia zol-2-yl)-2,5-diphenylte trazolium bromide (MTT) assay, flow cytometry test, TdT mediated dUTP Nick-End Labeling (TUNEL) experiment, colony formation assay and western blot analysis were performed to detect the biological functions of miR 15a. Moreover, a luciferase reporter assay was conducted to confirm its target associations. RESULTS: Herein, the results found that miR-15a was dramatically up regulated in degenerative NP tissues and NP cells compared with the controls. Overexpression of miR-15a promoted NP cells proliferation and induced apoptosis. Moreover, apoptosis-related protein caspase-3 was significantly up-regulated and bcl-2 was observably down-regulated when NP cells were transfected with miR-15a mimics, while bax and caspase-3 were significantly down-regulated as well as bcl 2 was observably up-regulated when NP cells were transfected with miR-15a inhibitors. Further, luciferase reporter assay showed that MAP3K9, an upstream activator of MAPK kinase, was putative target of miR-15a. There was a negatively relationship between miR-15a and MAP3K9 expression in NP cells. In addition, knockdown MAP3K9 inhibited NP cells proliferation and promoted apoptosis, which further inhibited the activation of p38 and ERK MAPK pathway. CONCLUSION: This present study revealed that miR-15a might be considered as a novel therapeutic target for IDD treatment. PMID- 28081469 TI - Anti-osteoporotic effects of an antidepressant tianeptine on ovariectomized rats. AB - In the current investigation, the potential alleviating effects of tianeptine against bone loss induced in ovariectomized (OVX) rats was determined. Two weeks following a bilateral ovariectomy operation, tianeptine treatment (12.5 and 25mg/kg/twice/d) was initiated and continued for twenty-eight consecutive days. Changes in serum and urinary bone turnover biomarkers and osteoclastogenesis inducing factors were estimated. The femoral bone mineral content was estimated using inductively-coupled-plasma mass spectrometry. Morphometric alterations of distal femoral bones were observed in the cortical and trabecular structures using micro-CT. Finally, femur bones were assessed for histopathological changes. The lack of estrogen significantly increased the levels of bone turnover biomarkers and inflammatory mediators. Mineral concentrations in the femoral bones were reduced in the OVX group. Furthermore, the femoral bone micro architecture determined using micro-CT and histopathology were significantly altered by estrogen deficiency. Tianeptine, particularly the higher dose, corrected the elevated levels of bone metabolic products and pro-inflammatory cytokines. Tianeptine also improved mineral concentrations in femoral bones and the disturbed morphometric and histopathological features in OVX rats. In conclusion, tianeptine alleviated the osteoporotic changes in OVX animals, which may be via inhibition of the hypothalamic-pituitary-adrenal axis stress and osteoclastogenesis-provoking factors, suggesting attenuation of bone matrix degradation and osteoclast stimulation. PMID- 28081470 TI - Inhibition viral RNP and anti-inflammatory activity of coumarins against influenza virus. AB - Influenza viruses pose a severe threat to human health and a significant increase in antiviral drug-resistant among influenza viruses worldwide has been observed. Therefore, there is an urgent need to develop the new antiviral drugs, specifically from the natural products. In this study, the anti-viral and anti inflammatory activities of coumarins against influenza A virus in vitro were investigated. One of the derivatives eleutheroside B1 showed a wide spectrum of anti- human influenza virus effect with the IC50 value of 64-125MUg/ml in vitro, but it showed no effects against avian influenza virus. The time of addition was done and the results indicated that it had a potent antiviral effect when added at 0-6h, and also the virus yield was reduced by 60%. The influenza virus ribonucleoprotein was inhibited at 200MUg/ml, and also the NP mRNA expression was inhibited at 50 and 200MUg/ml. The expression level of cytokines and chemokines influenced by eleutheroside B1 was further demonstrated, the IL-6, CXCL-8, CCL-2 expression were all inhibited by the eleuthe roside B1 at concentration 200MUg/ml. The findings of study suggest that eleutheroside B1 can be as potential agent to develop for the prevention and treatment of influenza A virus. PMID- 28081471 TI - In situ morphological assessment of apoptosis induced by Phaleria macrocarpa (Boerl.) fruit ethyl acetate fraction (PMEAF) in MDA-MB-231 cells by microscopy observation. AB - Phaleria macrocarpa (Boerl.) is a well-known medicinal plant and have been extensively used as traditional medicine for ages in treatment of various diseases. The purpose of this study was to determine the in situ cytotoxicity effect P. macrocarpa fruit ethyl acetate fraction (PMEAF) by using various conventional and modern microscopy techniques. The cytotoxicity of PMEAF treated MDA-MB-231 cells was determined through the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) cytotoxicity assay and CyQuant Cell Proliferation Assay after 24h of treatment. Both results were indicated that the PMEAF is a potential anticancer agent with the average IC50 values of 18.10MUg/mL by inhibiting the MDA-MB-231 cell proliferation. Various conventional and modern microscopy techniques such as light microscopy, holographic microscopy, transmission (TEM) and scanning (SEM) electron microscope were used for the observation of morphological changes in PMEAF treated MDA-MB-231cells for 24h. The characteristic of apoptotic cell death includes cell shrinkage, membrane blebs, chromatin condensation and the formation of apoptotic bodies were observed. PMEAF might be the best candidate for developing more potent anticancer drugs or chemo-preventive supplements. PMID- 28081472 TI - Endoplasmic reticulum stress and apoptosis via PERK-eIF2alpha-CHOP signaling in the methamphetamine-induced chronic pulmonary injury. AB - Methamphetamine (MA) leads to multiple organs lesions and apoptosis. The aim of this study is to investigate if endoplasmic reticulum stress (ERS) - initiated apoptosis is involved in the chronic pulmonary injury induced by MA. In this study, rats were divided into a control group, methamphetamine 5mg/kg group and methamphetamine 10mg/kg group. This study found that the protein level of GRP78 is higher in M10 group than in control group. PERK signaling and the relevant apoptosis factors were also activated. Morphological measurements showed that protein BAX and CHOP accumulated in the alveolar epithelium and the alveolar walls with epithelium were damaged and that the number of pulmonary alveoli decreased. The findings showed that ERS and PERK pathway are activated and eventually lead to apoptosis. Severe ERS mediated the apoptosis of alveolar epithelium cells as well as decreasing numbers of pulmonary alveoli. PMID- 28081473 TI - Cortisol extraction through human skin by reverse iontophoresis. AB - Continuous monitoring of cortisol at the surface of the skin would advance the diagnosis and treatment of cortisol-related diseases, or of elevated cortisol levels related to stress in otherwise healthy populations. Reliable and accurate detection of cortisol at the skin surface remains a limiting factor in real-time monitoring of cortisol. To address this limitation, cortisol extraction through excised human skin by reverse iontophoresis was studied in vitro in side-by-side diffusion cells using a radiolabeled probe. The skin was subjected to four direct current regimens (0, 28, 56, 113MUAcm-2) with the anode in the donor chamber and the cumulative cortisol concentrations recorded in the receiver chamber. The 56 and 113MUAcm-2 regimens significantly increased transport of 3H-cortisol through the skin, and current density correlated directly with transcutaneous transport of 3H-cortisol. The threshold of detection of electroosmotic versus passive diffusion of cortisol through the skin was between 28 and 56MUAcm-2. The results of this study are significant in examining how lipophilic analytes found in the bloodstream respond to reverse iontophoresis across the skin. In addition, a device integration technique is presented which illustrates how continuous cortisol extraction and sensing could potentially be achieved in a conventional wearable format. PMID- 28081474 TI - The future excess fraction of occupational cancer among those exposed to carcinogens at work in Australia in 2012. AB - BACKGROUND: Studies in other countries have generally found approximately 4% of current cancers to be attributable to past occupational exposures. This study aimed to estimate the future burden of cancer resulting from current occupational exposures in Australia. METHODS: The future excess fraction method was used to estimate the future burden of occupational cancer (2012-2094) among the proportion of the Australian working population who were exposed to occupational carcinogens in 2012. Calculations were conducted for 19 cancer types and 53 cancer-exposure pairings, assuming historical trends and current patterns continued to 2094. RESULTS: The cohort of 14.6 million Australians of working age in 2012 will develop an estimated 4.8 million cancers during their lifetime, of which 68,500 (1.4%) are attributable to occupational exposure in those exposed in 2012. The majority of these will be lung cancers (n=26,000), leukaemias (n=8000), and malignant mesotheliomas (n=7500). CONCLUSIONS: A significant proportion of future cancers will result from occupational exposures. This estimate is lower than previous estimates in the literature; however, our estimate is not directly comparable to past estimates of the occupational cancer burden because they describe different quantities - future cancers in currently exposed versus current cancers due to past exposures. The results of this study allow us to determine which current occupational exposures are most important, and where to target exposure prevention. PMID- 28081475 TI - Add-on stiripentol elevates serum valproate levels in patients with or without concomitant topiramate therapy. AB - OBJECTIVE: Stiripentol (STP), valproate (VPA) and topiramate (TPM) are reported to have efficacy for Dravet syndrome. In this study, we sought to elucidate the mechanisms underlying the increased serum VPA concentrations following STP adjunctive therapy in patients with Dravet syndrome. METHODS: Twenty-eight patients with Dravet syndrome (age range, 1-35 years) undergoing combination therapy with VPA and STP were included in this study. We evaluated VPA and clobazam (CLB) serum concentrations before and after add-on STP. We also investigated potential factors impacting VPA metabolism during add-on STP therapy, including add-on TPM and CYP2C9 and CYP2C19 gene polymorphisms. The effect of STP on the metabolism of concomitantly administered CLB was also investigated. RESULTS: Add-on STP was significantly associated with the serum concentration-to-dose (CD) ratio of VPA. Two patients, who were concomitantly treated with TPM, developed severe anorexia and thrombocytopenia because of marked increases in serum VPA concentrations. Further analysis revealed that the rate of increase in the VPA CD ratio was positively correlated with TPM dose. In patients not receiving TPM, STP enhanced the rate of increase in the VPA CD ratio to a significantly greater extent in CYP2C19 extensive metabolizers than in CYP2C19 poor metabolizers. Add-on STP was also associated with significant increases in CLB and N-desmethyl-CLB serum concentrations. CONCLUSION: Our findings suggest that serum VPA concentrations should be carefully monitored during STP adjunctive therapy, particularly in patients receiving concomitant TPM therapy. PMID- 28081476 TI - Electron spin relaxation of a boron-containing heterocyclic radical. AB - Preparation of the stable boron-containing heterocyclic phenanthrenedione radical, (C6F5)2B(O2C14H8), by frustrated Lewis pair chemistry has been reported recently. Electron paramagnetic resonance measurements of this radical were made at X-band in toluene:dichloromethane (9:1) from 10 to 293K, in toluene from 180 to 293K and at Q-band at 80K. In well-deoxygenated 0.1mM toluene solution at room temperature hyperfine splittings from 11B, four pairs of 1H, and 5 pairs of 19F contribute to an EPR spectrum with many resolved lines. Observed hyperfine couplings were assigned based on DFT calculations and account for all of the fluorines and protons in the molecule. Rigid lattice g values are gx=2.0053, gy=2.0044, and gz=2.0028. Near the melting point of the solvent 1/Tm is enhanced due to motional averaging of g and A anisotropy. Increasing motion above the melting point enhances 1/T1 due to contributions from tumbling-dependent processes. The overall temperature dependence of 1/T1 from 10 to 293K was modeled with the sum of contributions of a process that is linear in T, a Raman process, spin rotation, and modulation of g anisotropy by molecular tumbling. The EPR measurements are consistent with the description of this compound as a substituted aromatic radical, with relatively small spin density on the boron. PMID- 28081477 TI - Pharmacokinetic studies of active triterpenoid saponins and the total secondary saponin from Anemone raddeana Regel. AB - The rhizome of Anemone raddeana Regel, a Traditional Chinese Medicine (TCM) which has a robust history treating rheumatism and neuralgia. The total secondary saponin (TSS) from it has demonstrated antitumor activity. In this study, a rapid and validated LC-MS/MS method was developed to simultaneously determine the active compounds (Hederacolchiside A1 and Eleutheroside K). Analytes were separated on a reverse-phase C18 column with acetonitrile-water (5mmol/L ammonium acetate) as the mobile phase. This assay showed acceptable linearity (r>0.99) over the concentration range 5-1000 nmol/L for two analytes. The intra- and inter day precision was within 8.06% and accuracy was ranged from -3.16% to 3.34% for two analytes. The mean extraction recoveries of analytes and IS from rat plasma were all more than 76.0%. Under the developed analytical conditions, the obtained values of main pharmacokinetic parameters (Cmax and AUC0-t) indicated that the pure compounds were more efficient than the TSS extract in Hederacolchiside A1 and Eleutheroside K absorption. In addition, pharmacokinetic studies of two individual compounds demonstrated their poor oral absorption in rat (aF%, 0.019 1.521). In the study of absorption and transportation of Hederacolchiside A1 and Eleutheroside K in Caco-2 cell monolayer model, the uptake permeability was in 10 6cm/sec range suggesting poor absorption, which confirmed the previous pharmacokinetic profiles in vivo. Interestingly, the uptake ratio of them declined significantly when treated with phloridzin (SGLT1 inhibitor). It indicated that the absorption of Hederacolchiside A1 in intestine was mainly through positive transport and SGLT1 might participate in its active absorption. PMID- 28081478 TI - Pulmonary Sarcomatoid Carcinoma with ALK Rearrangement: Frequency, Clinical Pathologic Characteristics, and Response to ALK Inhibitor. AB - PURPOSE: The incidence of anaplastic lymphoma kinase (ALK) rearrangement in pulmonary sarcomatoid carcinoma (PSC) is controversial. In this study, we aimed to reveal the reliable frequency and the clinical-pathologic characteristics of pulmonary sarcomatoid carcinoma (PSC) with ALK rearrangement in Chinese population, and to provide insight into the translatability of anti-ALK treatment in this treatment-refractory disease. METHODS: Immunohistochemistry (IHC) using a Ventana anti-ALK (D5F3) rabbit monoclonal antibody was performed in 141 PSC specimens collected from multiple medical centers. IHC-positive cases were then confirmed using ALK fluorescent in situ hybridization (FISH). The incidence rates and clinical-pathologic characteristics of ALK-rearranged PSC were then analyzed. Response to ALK inhibitor crizotinib in a patient with ALK-rearranged PSC was evaluated according to the response evaluation criteria for solid tumors (RECIST) version 1.1. RESULTS: Five of 141 (3.5%) of PSCs showed ALK rearrangement positive by IHC and then were confirmed by FISH. Two were carcinosarcomas and the other three were pulmonary pleomorphic carcinoma (PPC). Strong positive ALK rearrangement was observed in both the epithelioid and sarcomatoid components. The median age of ALK-positive patients was younger than that of ALK-negative patients. PSCs in never-smokers were more likely to harbor ALK rearrangement than those in former or current smokers (P<.05). A 40-year-old woman diagnosed with ALK-rearranged PPC experienced a partial response (-32%) to the ALK inhibitor crizotinib. CONCLUSIONS: The incidence rates of ALK rearrangement in PSC in the Chinese population are similar to those of other subtypes of NSCLC. PSCs in younger never-smokers are more often to harbor ALK rearrangement. ALK inhibitors may serve as an effective treatment for ALK-rearranged PSC. PMID- 28081479 TI - 5-year experience in the diagnosis and treatment of occult urinary incontinence in women with pelvic organ prolapse. AB - OBJECTIVE: Our aim was to analyze our five-year experience in the diagnosis and treatment of occult urinary incontinence in women with pelvic organ prolapse. STUDY DESIGN: The medical records of all patients who were admitted to the Division of Urogynecology of Istanbul Faculty of Medicine between January 2008 and December 2013; in total, 1600 patients were retrospectively evaluated. The study population included 287 patients who had prolapse beyond the hymen and underwent two consecutive urodynamic studies with and without prolapse reduction. Demographic data, medical records, physical examination, full urogynecologic examination, urodynamic investigations, treatment modality, the results of the treatment and King's Health Questionnaire scores before treatment and at one-year follow-up were recorded. RESULTS: Eighty-five of 287 patients (29.6%) were continent, 20 (23.5%) of whom had occult stress urinary incontinence during cystometry. Among these 20 patients, 17 underwent anti-incontinence surgery; 12 were satisfied with their surgery and had no postoperative urinary leakage. Twenty (23.5%) patients had overactive bladder symptoms during urodynamic studies after prolapse reduction. King's Health Questionnaire scores before and after the operation, showed that health status of 12 patients was better, 1 patient was unsatisfied after the treatment, 2 patients' scores did not change and 2 patients were lost to follow up. CONCLUSIONS: In conclusion, the prevalence of occult urinary incontinence was 23.5% when using urodynamics with prolapse reduction. 12 of the 17 patients diagnosed with occult urinary incontinence were satisfied with surgery and had no postoperative urinary leakage. PMID- 28081480 TI - Does the addition of salpingectomy or fimbriectomy to hysterectomy in premenopausal patients compromise ovarian reserve? A prospective study. AB - OBJECTIVE: To evaluate changes in ovarian reserve in patients following hysterectomy, with or without bilateral salpingectomy or fimbriectomy. STUDY DESIGN: Open-label, prospective cohort trial of patients undergoing hysterectomy for benign uterine indications. Levels of follicle-stimulating hormone (FSH), anti-Mullerian hormone (AMH), and ultrasonic measures of peak systolic flow velocity/diastolic velocity (S/D) ratio and resistance index (RI) in the ovarian artery were taken from patients before and 6 weeks after hysterectomy, hysterectomy+salpingectomy or hysterectomy+fimbriectomy. RESULTS: The study period was from November 2011 to May 2014. Sixty patients were included in the final analysis, after two patients were lost to follow-up and one patient underwent bilateral oophorectomy. Of these 60 patients, 16 underwent hysterectomy alone (control group), and 44 were included in the study group (22 patients underwent hysterectomy+fimbriectomy and 22 patients underwent hysterectomy+salpingectomy). The mean age of patients was 46 years (standard deviation 4.07 years). Between-group dfferences in FSH, AMH, ovarian volume, ovarian artery S/D ratio and ovarian artery RI were not significant. CONCLUSION: The addition of salpingectomy or fimbriectomy to routine hysterectomy in premenopausal patients does not diminish ovarian reserve. PMID- 28081481 TI - Fatigue limits of different PEEK materials for dental implants. AB - The increasing use of PEEK (poly-ether-ether-ketone) as a substitute for metal implant components has led to the suggestion that it could also be used as an alternative to titanium in the field of dental implants. A major requirement for dental implant materials is their resistance to cyclic loading due to mastication. A special fatigue test was designed to evaluate the elastic behavior and long-term form stability of cylindrically shaped PEEK specimens of 4, 5 and 6mm in diameter, using 11 different PEEK materials of various grades: unfilled, filled with titanium dioxide or barium sulfate powder, reinforced with short carbon fibers or short glass fibers, and reinforced with continuous carbon fibers. The samples were exposed to cyclic loads of up to 2000N. The elastic limits ranged between 46.57+/-6.44MPa for short carbon fiber reinforced specimens of 6mm diameter and 107.62+/-8.23MPa for samples of a different short carbon fiber reinforced PEEK compound of 4mm diameter. The elastic limits of the two PEEK grades containing continuous carbon fibers could not be observed because they exceeded the limits of the test specification. The elastic moduli ranged between 2.06+/-0.18GPa for barium sulfate powder filled PEEK-specimens of 6 mm diameter and 57.53+/-14.3GPa for continuous carbon fibers reinforced PEEK specimens of 4 mm diameter. In terms of the elastic limit all the PEEK materials in consideration were able to resist the pressure caused by maximum masticatory forces. PMID- 28081482 TI - Following Lives Undergoing Change (Flux) study: Implementation and baseline prevalence of drug use in an online cohort study of gay and bisexual men in Australia. AB - BACKGROUND: Drug use among gay and bisexual men (GBM) is higher than most populations. The use of crystal methamphetamine, erectile dysfunction medication (EDM), and amyl nitrite have been associated with sexual risk behaviour and HIV infection among gay and bisexual men (GBM). OBJECTIVE: This paper describes an online prospective observational study of licit and illicit drug use among GBM and explores baseline prevalence of drug use in this sample. Capturing these data poses challenges as participants are required to disclose potentially illegal behaviours in a geographically dispersed country. To address this issue, an entirely online and study specific methodology was chosen. METHODS: Men living in Australia, aged 16.5 years of age or older, who identified as homosexual or bisexual or had sex with at least one man in the preceding 12 months were eligible to enrol. RESULTS: Between September 2014 and July 2015, a total of 2250 participants completed the baseline questionnaire, of whom, 1710 (76.0%) consented to six-monthly follow-up. The majority (65.7%) were recruited through Facebook targeted advertising. At baseline, over half (50.5%) the men reported the use of any illicit drug in the previous six months, and 28.0% had used party drugs. In the six months prior to enrolment, 12.0% had used crystal methamphetamine, 21.8% had used EDM, and 32.1% had used amyl nitrite. Among the 1710 men enrolled into the cohort, 790 men had used none of these drugs. CONCLUSION: Ease of entry and minimal research burden on participants helped ensure successful recruitment into this online cohort study. Study outcomes will include the initiation and cessation of drug use, associated risk behaviours, and health consequences, over time. Results will provide insights into the role gay community plays in patterns of drug use among GBM. PMID- 28081483 TI - Enhanced visible-light-driven photocatalytic bacteria disinfection by g-C3N4 AgBr. AB - g-C3N4-AgBr was synthesized by depositing AgBr nanoparticles onto g-C3N4. Scanning electron microscopy (SEM), Transmission electron microscope (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), UV-vis diffuse reflectance spectra (DRS) and Photoluminescence (PL) spectra were employed to characterize the as-synthesized photocatalysts. The disinfection activities towards representative Gram-negative strain E. coli and Gram-positive strain S. aureus were examined under visible light irradiation. Complete inactivation of 3*106CFU/mL viable cell density was reached in 60min for E. coli and 150min for S. aureus, respectively. Ag+ released from the photocatalysts did not contribute to the photocatalytic disinfection process. Direct contact of g-C3N4-AgBr composites and bacterial cells, as well as the presence of O2 was indispensable for the cell inactivation. Photo-generated holes, surface bounded OH, and indirect generation of intracellular active species played important roles in disinfection process of g-C3N4-AgBr under visible light irradiation. The disruption of outside structure of cells as well as inner cell injury led to the inactivation. High pH condition led to increasing the cell disinfection due to the generation of surface bounded OH. PMID- 28081484 TI - New insights into antiviral immunity gained through intravital imaging. AB - Viral infections pose an ongoing challenge for mankind. Much of our knowledge of the immune response to viral infections comes from ex vivo analyses of infected animals, which provide important yet static information about events occurring within the host. Recently, a relatively new technique known as intravital microscopy (IVM) has been applied to the study of antiviral immunity. Intravital imaging affords a unique, real-time view of both viral dynamics and the ensuing immune response (along with their interplay) in the living animal. This review details some of the newest observations about the antiviral immune response gained using IVM. PMID- 28081485 TI - The elucidation of non-classical MHC class II antigen processing through the study of viral antigens. AB - By convention, CD4+ T cells are activated predominantly by Major Histocompatibility Complex class II-bound peptides derived from extracellular (exogenous) antigens. It has been known for decades that alternative sources of antigen, particularly those synthesized within the antigen-presenting cell, can also supply peptides but the impact on TCD4+ responses, sometimes considerable, has only recently become appreciated. This review focuses on the contributions that studies of viral antigen have made to this shift in perspective, concluding with discussions of relevance to rational vaccine design, autoimmunity and cancer immunotherapy. PMID- 28081486 TI - Front-line treatment of CLL in the era of novel agents. AB - Although chemoimmunotherapy prolongs survival and as such, is the standard of care for treatment-naive patients, its effectiveness may be reduced by associated toxicity and dose reductions. In addition, it has been associated with the development of myelosuppression and secondary neoplasms; treatments are hence needed which offer greater survival and lowered toxicity. A range of new targeted agents, ibrutinib, idelalisib and venetoclax, have demonstrated such a balance in a second-line setting, offering CLL patients durable remissions and a modest toxicity profile. Ibrutinib has since been given first-line approval, and with news of second-generation targeted agents on the horizon, high-level discussions have taken place concerning their use in elderly or unfit patients; with potential use in younger patients in a first-line setting. This article reviews the potential first-line therapeutic options for treating CLL and their clinical potential and examines whether first-line chemotherapy has a place in the age of targeted agents. PMID- 28081487 TI - Comparative genome-wide phylogenetic and expression analysis of SBP genes from potato (Solanum tuberosum). AB - Flowering time is a very important phase in transition to reproductive stage of life in higher plants. SQUAMOSA promoter-binding protein (SBP) gene family encodes plant-specific transcription factors that are involved in regulation of several developmental processes, especially flowering. Although SBP-box genes have been identified in different plants, there have been no study indicating the regulatory effect of SBP box in potato flowering. Here, we report for the first time the identification and characterization of SBP-box transcription factors as well as determination of expression level of SBP-box genes in Solanum tuberosum L. an important crop worldwide. Fifteen different SBP-box transcription factor genes were identified in potato genome. They were found to be distributed in nine chromosomes and eight of them included miR156 and miRNA157 target sites. Characterization of amino acid sequences were performed and protein interactions were predicted. In addition, expression levels of five S. tuberosum SBP-box genes were analysed by both in silico and qRT-PCR. All these results provide a better understanding of functional role of SBP-box gene family members in flowering time in potato. PMID- 28081488 TI - Chemical and physiological metal bioaccessibility assessment in surface bottom sediments from the Deba River urban catchment: Harmonization of PBET, TCLP and BCR sequential extraction methods. AB - In the present study, the physiologically based extraction test PBET (gastric and intestinal phases) and two chemical based extraction methods, the toxicity characteristic leaching procedure (TCLP) and the sequential extraction procedure BCR 701 (Community Bureau of Reference of the European Commission) have been used to estimate and evaluate the bioaccessibility of metals (Fe, Mn, Zn, Cu, Ni, Cr and Pb) in sediments from the Deba River urban catchment. The statistical analysis of data and comparison among physiological and chemical methods have highlighted the relevance of simulate the gastrointestinal tract environment since metal bioaccessibility seems to depend on water and sediment properties such as pH, redox potential and organic matter content, and, primordially, on the form in which metals are present in the sediment. Indeed, metals distributed among all fractions (Mn, Ni, Zn) were the most bioaccessible, followed by those predominantly bound to oxidizable fraction (Cu, Cr and Pb), especially near major urban areas. Finally, a toxicological risk assessment was also performed by determining the hazard quotient (HQ), which demonstrated that, although sediments from mid- and downstream sampling points presented the highest metal bioaccessibilities, were not enough to have adverse effects on human health, Cr being the most potentially toxic element. PMID- 28081490 TI - Mesoporous activated carbon prepared from NaOH activation of rattan (Lacosperma secundiflorum) hydrochar for methylene blue removal. AB - Hydrothermal carbonization of biomass wastes presents a promising step in the production of cost-effective activated carbon. In the present work, mesoporous activated carbon (HAC) was prepared by the hydrothermal carbonization of rattan furniture wastes followed by NaOH activation. The textural and morphological characteristics, along with adsorption performance of prepared HAC toward methylene blue (MB) dye, were evaluated. The effects of common adsorption variables on performance resulted in a removal efficiency of 96% for the MB sample at initial concentration of 25mg/L, solution pH of 7, 30 degrees C, and 8h. The Langmuir equation showed the best isotherm data correlation, with a maximum uptake of 359mg/g. The adsorbed amount versus time data was well fitted by a pseudo-second order kinetic model. The prepared HAC with a high surface area of 1135m2/g and an average pore size distribution of 35.5A could be an efficient adsorbent for treatment of synthetic dyes in wastewaters. PMID- 28081489 TI - Protective effect of chitosan on photosynthesis and antioxidative defense system in edible rape (Brassica rapa L.) in the presence of cadmium. AB - Chitosan (CTS) induces plant tolerance against several abiotic stresses, including salinity and drought exposure. However, the role of CTS in cadmium (Cd) induced stress amelioration is largely unknown. In the present study, a hydroponic pot experiment was conducted to study the roles of CTS with different molecular weight (Mw) (10kDa,5kDa and 1kDa) in alleviating Cd toxicity in edible rape (Brassica rapa L .). The results showed that Cd stress significantly decreased plant growth, leaf chlorophyll contents and increased the malondialdehyde (MDA) level in rape leaves. Foliar application of CTS promoted the plant growth and leaf chlorophyll contents, and decreased the malondialdehyde (MDA) level in edible rape leaves under Cd stress. The alleviation effect of CTS on toxicity was depended on its Mw and CTS with Mw of 1kDa showed the best activity. Spraying 1kDa CTS onto the leaves of edible rape under Cd-toxicity could decrease shoot Cd2+ concentration and improve photosynthetic characteristics of edible rape. Moreover, 1kDa CTS also significantly enhanced non-enzymatic antioxidants (ascorbic acid) and enzyme activities (superoxide dismutase, catalase and guaiacol peroxidase) under Cd stress. Based on these findings, it can be concluded that application of exogenous CTS could be an effective approach to alleviate the harmful effects of Cd stress and could be explored in an agricultural production system. PMID- 28081491 TI - Effect of humic acid-based amendments with foliar application of Zn and Se on Cd accumulation in tobacco. AB - The smoke of tobacco is a major source of exposure to Cd in humans and therefore it is urgent to find a way to a method to reduce Cd accumulation in tobacco. A four-month tobacco pot experiment was conducted to investigate the effects of two base treatments (humic acid-based amendments) and two foliar treatments (Zn and Se) on Cd uptake by tobacco. The results showed that Cd in tobacco was mainly transferred into leaves, which could be significantly reduced by both applied amendments. The Cd contents in leaves were reduced by up to 67%. Foliar Zn alone significantly decreased Cd contents in leaves while foliar Se slightly increased them. When base and foliar treatments were combined, base treatments had dominant effects but those of foliar treatments were not distinct. The applied amendments did reduce Cd contents in all the parts of tobacco and the translocation into leaves and they were more effective than foliar Zn and Se. PMID- 28081492 TI - Hassle free synthesis of nanodimensional Ni, Cu and Zn sulfides for spectral sensing of Hg, Cd and Pb: A comparative study. AB - A simple room temperature synthesis method of Ni, Cu and Zn sulfide nanoparticles (NPs) in aqueous medium is reported here. The NPs stabilized in aqueous medium by the citrate ions were characterized by UV-vis, zeta potentials, TEM and Raman spectroscopic techniques. The solid NPs could be isolated from the aqueous medium when allowed to stand for a prolonged time (~20h). The solids were also characterized by IR and powder X-ray analysis. The nanoparticles were further used for the development of facile optical sensing and detection of heavy metal ions at trace scale. Alterations in the absorption spectra of the generated NPs were indicative of their interactions with heavy metal ions. Raman spectral measurements further validate the detection technique. It is found that out of the three synthesized nanoparticles, nickel sulfide NP is a specific sensor for mercury ions whereas zinc sulfide and copper sulfide NPs act as sensors for Hg2+, Cd2+ and Pb2+. PMID- 28081493 TI - Optical and vibrational properties of phosphorylcholine-based contact lenses Experimental and theoretical investigations. AB - The Raman, MIR and UV-vis spectroscopy have been used to characterize Omafilcon A material constructing the one of the Proclear family contact lenses. The Omafilcon A is hydrogel material composed of 2-hydroxyethyl methacrylate (HEMA) and 2-methacryloyloxyethyl phosphorylcholine (PC) polymers crosslinked with ethyleneglycol dimethacrylate (EGDMA). Vibrational and electronic properties of the Omafilcon A material were also investigated by quantum chemical calculations. Experimentally obtained Raman, MIR and optical spectra were compared to the theoretical ones calculated applying RHF and DFT methodology. The quantum chemical calculations were performed for isolated monomers of lenses compounds as well as for their dimers and trimers to elucidate the effect of Omafilcon A polymerization and the role of an individual components. PMID- 28081494 TI - A cockspur for the DSS cells: Erythrina crista-galli sensitizers. AB - Dye sensitized solar cells were assembled employing a mixture of anthocyanins extracted from red ceibo's flowers. At the literature different extraction procedures are reported to extract anthocyanins from natural products and sensitize the cells. In order to compare them, different methods were followed to set the cells under the same conditions. Assembled cells showed very interesting conversion efficiency values, reaching a 0.73% value for extracts purified using C18 column, in open cells under illumination using a solar light simulator, 1 sun, 1.5 AM. Data reported herein prove that anthocyanins obtained from ceibo's flower, after simple further purification, might represent an excellent, cheap and clean alternative for the development of DSS cells. PMID- 28081495 TI - Emotional intensity in episodic autobiographical memory and counterfactual thinking. AB - Episodic counterfactual thoughts-imagined alternative ways in which personal past events might have occurred-are frequently accompanied by intense emotions. Here, participants recollected positive and negative autobiographical memories and then generated better and worse episodic counterfactual events from those memories. Our results suggest that the projected emotional intensity during the simulated remembered/imagined event is significantly higher than but typically positively related to the emotional intensity while remembering/imagining the event. Furthermore, repeatedly simulating counterfactual events heightened the emotional intensity felt while simulating the counterfactual event. Finally, for both the emotional intensity accompanying the experience of remembering/imagining and the projected emotional intensity during the simulated remembered/imagined event, the emotional intensity of negative memories was greater than the emotional intensity of upward counterfactuals generated from them but lower than the emotional intensity of downward counterfactuals generated from them. These findings are discussed in relation to clinical work and functional theories of counterfactual thinking. PMID- 28081496 TI - The role of negative parental attributions in the associations between daily stressors, maltreatment history, and harsh and abusive discipline. AB - Negative parental attributions are related to parent and family stressors and are thought to be important predictors of subsequent disciplinary actions and, potentially, abusive parenting. We examined if negative parental attributions mediate the relation between daily stressors (i.e., low SES, parenting stress, partner-related stress) parents' own history of child maltreatment, and harsh and abusive parenting. Mothers (n=53) completed a computerized attribution task and reported on daily stressors, their own history of child maltreatment and their discipline strategies. Mothers' negative parental attributions mediated the association between parenting stress (but not the other stressors) and harsh and abusive discipline. These finding implicate that interventions to decrease (the risk of) child abuse should not only focus on reducing abuse-related stressors, but also target negative parental attributions. PMID- 28081497 TI - Paramedic student exposure to workplace violence during clinical placements - A cross-sectional study. AB - Paramedic students are hesitant to formally report exposure to acts of workplace violence as they feel it may jeopardise their chance of getting a job. The objective of this study was to identify the type and number of workplace violence acts experienced by undergraduate paramedic students whilst on an ambulance clinical placement. This was a cross-sectional study using the Paramedic Workplace Violence Exposure Questionnaire to obtain student exposure to acts of workplace violence which occurred whilst on ambulance clinical placements. The survey response rate was 29.8%. The students' average age was 24.1 years, median age of 23 years, range 18-47 years. There were 32.6% of students who were exposed to at least one act of workplace violence with 56% of these being females. Verbal abuse 18%, and intimidation 17% were the common acts of workplace violence students were exposed to. One female, a nursing/paramedic student, was exposed to sexual harassment on more than one occasion. The findings from this study suggest that paramedic students are exposed to similar rates of workplace violence as full time practising paramedics. Further research is required into workplace violence against students from all professions and what detrimental effect this may have on them. PMID- 28081498 TI - Enhancing analysis throughput, sensitivity and specificity in LC/ESI-MS/MS assay of plasma 25-hydroxyvitamin D3 by derivatization with triplex 4-(4 dimethylaminophenyl)-1,2,4-triazoline-3,5-dione (DAPTAD) isotopologues. AB - The plasma/serum concentration of 25-hydroxyvitamin D3 [25(OH)D3] is a diagnostic index for vitamin D deficiency/insufficiency, which is associated with a wide range of diseases, such as rickets, cancer and diabetes. We have reported that the derivatization with 4-(4-dimethylaminophenyl)-1,2,4-triazoline-3,5-dione (DAPTAD) works well in the liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS) assay of the serum/plasma 25(OH)D3 for enhancing the sensitivity and the separation from a potent interfering metabolite, 3-epi-25 hydroxyvitamin D3 [3-epi-25(OH)D3]. However, enhancing the analysis throughput remains an issue in the LC/ESI-MS/MS assay of 25(OH)D3. The most obvious restriction of the LC/MS/MS throughput is the chromatographic run time. In this study, we developed an enhanced throughput method for the determination of the plasma 25(OH)D3 by LC/ESI-MS/MS combined with the derivatization using the triplex (2H0-, 2H3- and 2H6-) DAPTAD isotopologues. After separate derivatization with 1 of 3 different isotopologues, the 3 samples were combined and injected together into LC/ESI-MS/MS. Based on the mass differences between the isotopologues, the derivatized 25(OH)D3 in the 3 different samples were quantified within a single run. The developed method tripled the hourly analysis throughput without sacrificing assay performance, i.e., ease of pretreatment of plasma sample (only deproteinization), limit of quantification (1.0ng/mL when a 5MUL-plasma was used), precision (intra-assay RSD<=5.9% and inter-assay RSD<=5.5%), accuracy (98.7-102.2%), matrix effects, and capability of separating from an interfering metabolite, 3-epi-25(OH)D3. The multiplexing of samples by the isotopologue derivatization was applied to the analysis of plasma samples of healthy subjects and the developed method was proven to have a satisfactory applicability. PMID- 28081499 TI - Screening active compounds from Corydalis yanhusuo by combining high expression VEGF receptor HEK293 cell membrane chromatography with HPLC - ESI - IT - TOF - MSn method. AB - Corydalis Thizoma,or Yuanhu in China, is a common herbal drug used for thousands of years as analgesic in Chinese medicine that has been reported to have potential anti-angiogenic effects. In this study, a VEGFR/cell membrane chromatography (VEGFR/CMC) coupled with HPLC- ESI-IT-TOF-MSn system was developed and successfully applied for identifying active components from YuanHu extract acting on VEGFR. We identified tetrahydropalmatine and corydaline as bioactive components with VEGFR activity, thus confirming their inhibitory activity on VEGFR engineered HEK293 cell growth by MTT assay. The activity of tetrahydropalmatine and corydaline was compared with the positive control sorafenib in a range of concentration from 6.25 to 50.0MUM, showing a dose dependent inhibitory trend. These results indicate that the VEGFR/CMC coupled with HPLC- ESI-IT-TOF-MSn system can purify and identify specific bioactive components from complex systems, thus representing a promising tool for screening molecules active towards VEGFR from natural herbs. PMID- 28081500 TI - A highly sensitive quantum dots-DNA nanobiosensor based on fluorescence resonance energy transfer for rapid detection of nanomolar amounts of human papillomavirus 18. AB - A very sensitive and convenient nanobiosensor based on fluorescence resonance energy transfer (FRET) was developed for the detection of a 22-mer oligonucleotides sequence in Human Papillomavirus 18 virus (HPV18) gene. For this purpose, water-soluble CdTe quantum dots (QDs) were synthesized and, subsequently, amino-modified 11-mer oligonucleotide as one of the two necessary probes was attached to QDs surface to form functional QDs-DNA conjugates. Right after addition of the QDs-DNA and a second Cyanine5 (Cy5)-labeled 11-mer oligonucleotide probe to the DNA target solution, the sandwiched hybrids were formed. The resulting hybridization brings the Cy5 fluorophore as the acceptor to close proximity of the QDs as donor, so that an effective transfer of energy from the excited QDs to the Cy5 probe would occur via FRET processing. The fluorescence intensity of Cy5 found to linearly enhance by increasing the DNA target concentration from 1.0 to 50.0nM, with a detection limit of 0.2nM. This homogeneous DNA detection method does not require excessive washing and separation steps of un-hybridized DNA, due to the fact that no FRET can be observed when the probes are not ligated. Finally, feasibility and selectivity of the proposed one-spot DNA detection nanobiosensor were investigated by analysis of derived nucleotides from HPV18 and mismatched sequences. PMID- 28081501 TI - Isolation, characterization using LC-ESI-QTOF, NMR and in vitro cytotoxicity assay of niclosamide forced degradation products. AB - The present study describes the isolation, characterization and in vitro cytotoxic effect of all forced degradation products of niclosamide (NCM) an anthelmintic class of drug used specifically to treat tapeworms. NCM was subjected to forced degradation involving hydrolysis (acidic, alkaline and neutral), oxidative, photolysis and thermal stress, as per ICH (Q1A (R2)) suggested conditions. The drug under hydrolytic (acidic and basic) conditions showed extensive degradation, while it was stable under neutral hydrolytic, oxidative, photolytic and thermal stress conditions. A total of four degradation products (DPs) were observed and chromatographic separation of drug and its degradation products were achieved on a reverse phase Fortis diphenyl column (150*4.6mm, 5MUm) using 0.1% formic acid and acetonitrile as mobile phase in gradient mode. All the four degradation products were isolated by semi preparative LC and its structures were characterized and confirmed by high resolution MS and 1H NMR spectroscopic techniques. In view of safety aspects, cytotoxicity assay were carried out for NCM and its four degradation products on human mononuclear cells and cell lines depicting the major organelle: neuronal (Neuro 2a), hepatic (HepG 2) and alveolar (A549). NCM was found to be non toxic on human mononuclear cells and cell lines at tested concentrations. However DP-1, DP-2, DP-3 and DP-4 showed significant increase in LDH release as compared to control at a concentration of 100MUM. DP-1 and DP-3 exhibited toxicity on A549 cells with an IC50 of 92.18+/-4.93MUM and 65.42+/-6.29MUM respectively. DP-2, DP 3 and DP-4 were cytotoxic to Neuro 2a cells with an IC50 of 63.62+/-3.85MUM, 86.09+/-6.19MUM and 42.81+/-8.10MUM respectively. The degradation products were found to be nontoxic on HepG 2 cells. PMID- 28081502 TI - Quantitative determinations using portable Raman spectroscopy. AB - A portable Raman spectrometer was used to develop chemometric models to determine percent (%) drug release and potency for 500mg ciprofloxacin HCl tablets. Parallel dissolution and chromatographic experiments were conducted alongside Raman experiments to assess and compare the performance and capabilities of portable Raman instruments in determining critical drug attributes. All batches tested passed the 30min dissolution specification and the Raman model for drug release was able to essentially reproduce the dissolution profiles obtained by ultraviolet spectroscopy at 276nm for all five batches of the 500mg ciprofloxacin tablets. The five batches of 500mg ciprofloxacin tablets also passed the potency (assay) specification and the % label claim for the entire set of tablets run were nearly identical, 99.4+/-5.1 for the portable Raman method and 99.2+/-1.2 for the chromatographic method. The results indicate that portable Raman spectrometers can be used to perform quantitative analysis of critical product attributes of finished drug products. The findings of this study indicate that portable Raman may have applications in the areas of process analytical technology and rapid pharmaceutical surveillance. PMID- 28081503 TI - In silico identification of alternative oxidase 2 (AOX2) in monocots: A new evolutionary scenario. AB - We identified AOX2 genes in monocot species from Lemnoideae (Spirodela polyrhiza, Lemna gibba and Landoltia punctata), Pothoideae (Anthurium andraeanum and Anthurium amnicola) and Monsteroideae (Epipremnum aureum) subfamilies within the Araceae, an early-diverging monocot family. These findings highlight the presence of AOX2 in the most ancient monocot ancestor and also that at least partial loss of this gene occurred during speciation events within several monocot orders. The presence of AOX2 in monocot species challenges (1) new understanding of the evolutionary history of the AOX gene family in angiosperms and (2) drives experimental and bioinformatics efforts to explore functional relevance of the two AOX gene family members for plant growth and development. Knowledge gain in this field will impact running strategies on AOX-derived functional marker candidate development for plant breeding. PMID- 28081504 TI - The expression and function of the neonatal Fc receptor in thyrocytes of Hashimoto's thyroiditis. AB - OBJECTIVE: Thyroglobulin (Tg) and thyroid peroxidase (TPO) antibodies (TgAb and TPOAb), which are primarily of the immunoglobulin G (IgG) class, can mediate antibody-dependent cell-mediated cytotoxicity in vitro. However, it is unclear whether any thyrocyte molecules can facilitate the transport and elimination of TgAb and TPOAb. The IgG transport receptor neonatal Fc receptor (FcRn) is a candidate mediator of these processes. In this study, we aimed to evaluate FcRn expression and function in normal and Hashimoto's thyroiditis (HT) thyrocytes. METHODS: FcRn expression in primary thyrocyte cultures (four normal and four HT groups) was examined by polymerase chain reaction (PCR) and Western blotting. Localization of FcRn was demonstrated by immunoelectron microscopy. A double immunofluorescence staining method was adopted to detect FcRn and internalized human TgAb IgG. Stimulation experiments were performed to assess the regulation of FcRn expression by T helper cell 1 (Th1) (IFN-gamma and TNF-alpha) and Th2 cytokines (IL-10 and IL-4). RESULTS: FcRn expression was lower in HT thyrocytes than in normal thyrocytes. FcRn was located in the cytoplasm, membranes, mitochondria and transport vesicles of thyrocytes. Both human IgG and TgAb IgG were internalized by thyrocytes in a pH-dependent manner and co-localized with FcRn in thyrocytes. FcRn expression was downregulated by Th1 and Th2 cytokines in both normal and HT thyrocytes in a dose-dependent manner. CONCLUSIONS: Our results suggest that FcRn may be associated with the transport and metabolism of IgG in thyrocytes and that transport is independent of IgG type. FcRn may be involved in HT pathogenesis. PMID- 28081505 TI - Practicability of monitoring soil Cd, Hg, and Pb pollution based on a geochemical survey in China. AB - Repeated visiting, i.e., sampling and analysis at two or more temporal points, is one of the important ways of monitoring soil heavy metal contamination. However, with the concern about the cost, determination of the number of samples and the temporal interval, and their capability to detect a certain change is a key technical problem to be solved. This depends on the spatial variation of the parameters in the monitoring units. The "National Multi-Purpose Regional Geochemical Survey" (NMPRGS) project in China, acquired the spatial distribution of heavy metals using a high density sampling method in the most arable regions in China. Based on soil Cd, Hg, and Pb data and taking administrative regions as the monitoring units, the number of samples and temporal intervals that may be used for monitoring soil heavy metal contamination were determined. It was found that there is a large variety of spatial variation of the elements in each NMPRGS region. This results in the difficulty in the determination of the minimum detectable changes (MDC), the number of samples, and temporal intervals for revisiting. This paper recommends a suitable set of the number of samples (nr) for each region under the balance of cost, practicability, and monitoring precision. Under nr, MDC values are acceptable for all the regions, and the minimum temporal intervals are practical with the range of 3.3-13.3 years. PMID- 28081506 TI - Investigation of ozone and peroxone impacts on natural organic matter character and biofiltration performance using fluorescence spectroscopy. AB - Impacts of ozonation alone as well as an advanced oxidation process of ozone plus hydrogen peroxide (H2O2 + O3) on organic matter prior to and following biofiltration were studied at pilot-scale. Three biofilters were operated in parallel to assess the effects of varying pre-treatment types and dosages. Conventionally treated water (coagulation/flocculation/sedimentation) was fed to one control biofilter, while the remaining two received water with varying applied doses of O3 or H2O2 + O3. Changes in organic matter were characterized using parallel factors analysis (PARAFAC) and fluorescence peak shifts. Intensities of all PARAFAC components were reduced by pre-oxidation, however, individual humic-like components were observed to be impacted to varying degrees upon exposure to O3 or H2O2 + O3. While the control biofilter uniformly reduced fluorescence of all PARAFAC components, three of the humic-like components were produced by biofiltration only when pre-oxidation was applied. A fluorescence red shift, which occurred with the application of O3 or H2O2 + O3, was attributed to a relative increase in carbonyl-containing components based on previously reported results. A subsequent blue shift in fluorescence caused by biofiltration which received pre-oxidized water indicated that biological treatment readily utilized organics produced by pre-oxidation. The results provide an understanding as to the impacts of organic matter character and pre-oxidation on biofiltration efficiency for organic matter removal. PMID- 28081507 TI - Occurrence, fate and environmental risk of linear alkylbenzene sulfonate in the Langat and Selangor River basins, Malaysia. AB - Five homologs (C10-C14) of linear alkylbenzene sulfonate (LAS) were quantitated in surface water collected in the Langat and Selangor River basins using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A geographic information system (GIS) was used to spatially analyze the occurrence of LAS in both river basins, and the LAS contamination associated with the population was elucidated by spatial analysis at a sub-basin level. The LAS concentrations in the dissolved phase (<0.45 MUm) and 4 fractions separated by particle size (<0.1 MUm, 0.1-1 MUm, 1-11 MUm and >11 MUm) were analyzed to elucidate the environmental fate of LAS in the study area. The environmental risks of the observed LAS concentration were assessed based on predicted no effect concentration (PNEC) normalized by a quantitative structure-activity relationship model. The LAS contamination mainly occurred from a few populated sub-basins, and it was correlated with the population density and ammonia nitrogen. The dissolved phase was less than 20% in high contamination sites (>1000 MUg/L), whereas it was more than 60% in less contaminated sites (<100 MUg/L). The environmental fate of LAS in the study area was primarily subject to the adsorption to suspended solids rather than biodegradation because the LAS homologs, particularly in longer alkyl chain lengths, were considerably absorbed to the large size fraction (>11 MUm) that settled in a few hours. The observed LAS concentrations exceeded the normalized PNEC at 3 sites, and environmental risk areas and susceptible areas to the LAS contamination were spatially identified based on their catchment areas. PMID- 28081508 TI - Historical variation in black carbon deposition and sources to Northern China sediments. AB - Black carbon (BC) in fine particulate matter (PM2.5) is an important air pollutant in a large area of China. We have reconstructed a 100-year-long history of BC deposition based on analyses of sediment samples in the coastal area of the Northern China Plain (NCP). During 1900-2010, the sedimentary BC concentrations at three cores increased from 0.2 to 1.3, from 0.2 to 2.3, and from 0.2 to 1.9 mg g-1, and the ranges for the BC deposition fluxes were 0.1-4.7, 0.1-8.2, 0.2-7.4 g m-2 a-1, suggesting the increase of ten times from the pre-industrial era. The BC deposition fluxes showed abrupt variation with two peaks in the 1970s and 2010s. Residential energy consumption and biomass burning (i.e., low-temperature combustion sources; thus, large-scale wildfires with high temperature may not be included) were responsible for the BC increase in the 1970s. Fossil fuel combustion generated by the industrial sectors, including industry, power plants, and transportation, was negligible before 1990 but significantly increased during 1990-2010. The historical increase in the BC deposition was accurately predicted by climate models, specifically the Coupled Model Intercomparison Project Phase 5 (CMIP5). However, the BC fluxes in the NCP sediments were an order of magnitude greater than those of the simulated depositions, suggesting an underestimation of the BC deposition in the severely polluted area in China. PMID- 28081509 TI - In silico prediction of toxicity of phenols to Tetrahymena pyriformis by using genetic algorithm and decision tree-based modeling approach. AB - Risk assessment of chemicals is an important issue in environmental protection; however, there is a huge lack of experimental data for a large number of end points. The experimental determination of toxicity of chemicals involves high costs and time-consuming process. In silico tools such as quantitative structure toxicity relationship (QSTR) models, which are constructed on the basis of computational molecular descriptors, can predict missing data for toxic end points for existing or even not yet synthesized chemicals. Phenol derivatives are known to be aquatic pollutants. With this background, we aimed to develop an accurate and reliable QSTR model for the prediction of toxicity of 206 phenols to Tetrahymena pyriformis. A multiple linear regression (MLR)-based QSTR was obtained using a powerful descriptor selection tool named Memorized_ACO algorithm. Statistical parameters of the model were 0.72 and 0.68 for Rtraining2 and Rtest2, respectively. To develop a high-quality QSTR model, classification and regression tree (CART) was employed. Two approaches were considered: (1) phenols were classified into different modes of action using CART and (2) the phenols in the training set were partitioned to several subsets by a tree in such a manner that in each subset, a high-quality MLR could be developed. For the first approach, the statistical parameters of the resultant QSTR model were improved to 0.83 and 0.75 for Rtraining2 and Rtest2, respectively. Genetic algorithm was employed in the second approach to obtain an optimal tree, and it was shown that the final QSTR model provided excellent prediction accuracy for the training and test sets (Rtraining2 and Rtest2 were 0.91 and 0.93, respectively). The mean absolute error for the test set was computed as 0.1615. PMID- 28081510 TI - Gestational and lactational exposure to di-isobutyl phthalate via diet in maternal mice decreases testosterone levels in male offspring. AB - Phthalates are a large family of ubiquitous environmental chemicals suspected of being endocrine disruptors, with exposure to these chemicals during prenatal and postnatal development possibly resulting in reproductive disorders. Di-isobutyl phthalate (DiBP) is widely used in consumer and industrial products, and although its exposure in the general population has increased in recent years, the mechanisms behind DiBP-induced reproductive disorders in male offspring remain unclear. Here, pregnant mice were exposed to 0 or 450 mg/kg bw/day DiBP via diet from gestation day (GD) 0 to GD21. Until postnatal day 21 (PD21), half of the exposed pups were also exposed to DiBP by lactation (TT), while the rest were not (TC). Half of each group were sacrificed on PD21, with the remaining mice fed a normal diet until PD80 (TCC and TTC, respectively). Reproductive toxicological parameters such as relative organ weights and testosterone levels were determined in male offspring on PD21 and PD80 and sperm quality was tested on PD80. Maternal exposure (pregnancy and lactation) led to decreased serum and testis testosterone concentrations, accompanied by decreased expression of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and cytochrome P450 family 11 subfamily A member 1 (CYP11A1) in PD21 pups and PD80 adults. Furthermore, the TTC group showed decreased epididymis sperm concentration and motility. Taken together, DiBP exposure in early life (prenatal and postnatal) impaired male reproductive function in later life, possibly by interfering with testosterone levels and CYP11A1, which might be a major steroidogenic enzyme targeted by DiBP or other phthalates. PMID- 28081511 TI - Spatiotemporal distributions of butyltin compounds in various intertidal organisms along the Samcheok and Tongyeong coasts of Korea. AB - Thirteen years ago, the Korean Government introduced a regulation prohibiting the use of tributyltin (TBT), which was a component of antifouling paints. A subsequent decline in the concentration of butyltins (BTs) was recorded in seawater and the sediment, however, the current concentration of BTs in biota has not been well documented. The spatiotemporal distribution and concentration of BTs was recorded in biota from 2013 to 2015 along the coasts of Samcheok and Tongyeong using GS/MSD analysis. Crustaceans contained the greatest concentrations of BTs, followed by gastropods, fishes, and bivalves. We found that the concentration of BTs was greater at Tongyeong compared to Samcheok, because of the geographical characteristics of the area. We also confirmed that the regulation has been effective by showing that the TBT concentration decreased over the 3-year study period. The TBT levels of gastropods and bivalves fell within the limits of the guidelines and/or the effective concentration of the toxicological endpoint reported previously. The concentration of BTs also varied among species, being dependent on the weight of the soft tissue. Furthermore, the greater quantities of BTs degradation products compared to TBT confirmed the absence of recent inputs of pollutants during the study periods. However, compared with other Asian countries, biota BTs were greater in Korea, with noticeably greater concentrations along the south coast. Thus, further investigation of the distribution of BTs along the Korean coasts is required in the future. In conclusion, our results provide useful information about the recent trends of BTs in Korea. PMID- 28081512 TI - Association between herpes simplex virus Types 1 and 2 with cardiac myxoma. AB - Most cases of atrial myxoma are sporadic, and the exact etiology is unknown. We examined if herpes simplex virus (HSV)-1 and HSV-2 antigens and/or DNA could be detected in a cohort of Iranian patients with cardiac myxomas. From July 2004 to June 2014, among a total of 36,703 patients undergoing open heart surgeries, consecutive patients with cardiac myxoma who were treated by surgical excision at our center included in this study. Of 73 patients studied, 56% were female with a mean age of 54 years (ranging from 23 to 77 years). Seventy-four myxomas were surgically removed from 73 patients, since one patient had two myxomas which were located on both the right atrium and right ventricle. The materials for this analysis were retrospectively gathered from extracted tumors that stored in a pathology bank of tissue paraffin blocks. The formalin fixed paraffin embedded tissue samples were investigated for HSV genomic DNA by both immunohistochemistry (IHC) and polymerase chain reaction (PCR) analysis. In all 74 cases there was no presence of HSV 1 and HSV 2 infection. This suggests that HSV may not play a role in sporadic cardiac myxomas; however, evidence for such association is currently lacking, and further studies are required to determine such a role. PMID- 28081513 TI - Thrombosis of a mechanical prosthetic aortic valve in early pregnancy: histopathological findings. AB - We present results of the histopathological workup of a prosthetic aortic valve which was explanted from a 31-year-old woman due to valve thrombosis during early pregnancy. Our images demonstrate nicely thrombotic material directly adherent to the pyrolytic carbon surface in a human specimen. PMID- 28081514 TI - Role of miRNA-1 in regulating connexin 43 in ischemia-reperfusion heart injury: a rat model. AB - MiRNA-1 may participate in regulating ischemia-reperfusion injury (IRI) by affecting the expression and distribution of connexin 43 (Cx43). The aim of this study is to investigate miR-1 expression and its potential role in regulating Cx43 during ischemic postconditioning (IPOST) in a rat model. Fifty-five Wistar male rats were randomly divided into five groups: N, IR, IPOST, agomir-1, and antagomir-1 group. The hearts were perfused with the Langendorff system. The reperfusion arrhythmia (RA) and myocardial infarct size were observed and recorded. The miRNA-1 expression and the Cx43 expression and distribution were assessed by RT-PCR, immunoblotting, and immunohistochemistry. First, the RA score in the IR group was higher than that in the control group, whereas there was no difference between the IPOST and antagomir-1 groups. Second, the myocardial infarct size was larger in the agomir-1 than in the IPOST group; there was no difference between the antagomir-1 and the IPOST group. Third, the miRNA-1 expression increased by 78% in the agomir-1 group but decreased by 32% in the antagomir-1 group compared with the IPOST group. Fourth, compared with the Control group, the Cx43 expression in the IR group decreased, the Cx43 expression decreased in the agomir-1 group compared with the IPOST group. Fifth, the distribution of Cx43 was irregular and disorganized in the IR and agomir-1 groups. In the IPOST and antagomir-1 groups, Cx43 was neatly distributed in the intercalated disk area. Our findings suggest that IPOST can inhibit the up regulation of miRNA-1 induced by ischemia-reperfusion and that the down regulation of miRNA-1 can prevent the decrease and redistribution of Cx43, which will protect the heart from IRI. PMID- 28081515 TI - Distinguishing subpopulations of marijuana users with latent profile analysis. AB - BACKGROUND: Although marijuana is the most commonly used illicit drug in the United States, little is known about the effects of typical marijuana use patterns and whether there are distinct subgroups of marijuana users. METHODS: The present study used latent profile analysis to determine the number of distinct subgroups of marijuana users in a large sample of college students (n=2129 past month marijuana users across 11 universities). We also examined how these distinct groups differ on several putative risk/protective factors (e.g., personality traits, perceptions of marijuana, and motives for using marijuana). RESULTS: Using the Lo-Mendell-Rubin Likelihood Ratio Test, we identified four latent classes with the largest class consisting of infrequent marijuana users, and three other classes demonstrating increasingly frequent use and more negative consequences with the most severe class being the smallest class. We found the largest between-class differences (i.e., distinctions across classes) to be on identification with being a marijuana user and use of protective behavioral strategies (PBS), such that the heavier user classes showed higher identification with marijuana users and lower use of PBS. CONCLUSIONS: Our findings demonstrate that college student marijuana users are a heterogeneous group with different profiles of risk/protective factors and that those who use marijuana a few times per month are different from those who are near-daily or daily users. Our findings also serve as a call to action for the field to consider examining identification with being a marijuana user and the use of PBS in future marijuana studies. PMID- 28081516 TI - Autism does not limit strategic thinking in the "beauty contest" game. AB - A popular hypothesis in developmental psychology is that individuals with autism spectrum disorder (ASD) have a specific impairment or developmental delay in their ability to reason about other people's mental processes, especially when this reasoning process is of a higher-order, recursive, or nested variety. One type of interpersonal interaction that involves this sort of complex reasoning about others' minds is an economic game, and because economic games have been extensively modeled in behavioral economics, they provide a unique testbed for a quantitative and precise analysis of cognitive functioning in ASD. This study specifically asked whether ASD is associated with strategic depth in the economic game known as The Beauty Contest, in which all players submit a number from 0 to 100, and the winner is the player who submits the number closest to 2/3 of the mean of all numbers submitted. Unexpectedly, the distribution of responses among adult participants with ASD reflected a level of strategic reasoning at least as deep as that of their neurotypical peers, with the same proportion of participants with ASD being characterized as "higher order" strategic players. Thus, whatever mentalistic reasoning abilities are necessary for typical performance in the context of this economic game appear to be largely intact, and therefore unlikely to be fundamental to persistent social dysfunction in ASD. PMID- 28081517 TI - A path analysis model of factors influencing children's requests for unhealthy foods. AB - Little is known about the complex combination of factors influencing the extent to which children request unhealthy foods from their parents. The aim of this study was to develop a comprehensive model of influencing factors to provide insight into potential methods of reducing these requests. A web panel provider was used to administer a national online survey to a sample of 1302 Australian parent-child dyads (total sample n=2604). Initial univariate analyses identified potential predictors of children's requests for and consumption of unhealthy foods. The identified variables were subsequently incorporated into a path analysis model that included both parents' and children's reports of children's requests for unhealthy foods. The resulting model accounted for a substantial 31% of the variance in parent-reported food request frequency and 27% of the variance in child-reported request frequency. The variable demonstrating the strongest direct association with both parents' and children's reports of request frequency was the frequency of children's current intake of unhealthy foods. Parents' and children's exposure to food advertising and television viewing time were also positively associated with children's unhealthy food requests. The results highlight the need to break the habitual provision of unhealthy foods to avoid a vicious cycle of requests resulting in consumption. PMID- 28081518 TI - Development of a biometric method to estimate age on hand radiographs. AB - Age estimation of living individuals aged less than 13, 18 or 21 years, which are some relevant legal ages in most European countries, is currently problematic in the forensic context. Thus, numerous methods are available for legal authorities, although their efficiency can be discussed. For those reasons, we aimed to propose a new method, based on the biometric analysis of hand bones. 451 hand radiographs of French individuals under the age of 21 were retrospectively analyzed. This total sample was divided into three subgroups bounded by the relevant legal ages previously mentioned: 0-13, 13-18 and 18-21 years. On these radiographs, we numerically applied the osteometric board method used in anthropology, by including each metacarpal and proximal phalange of the five hand rays in the smallest rectangle possible. In that we can access their length and width information thanks to a measurement protocol developed precisely for our treatment with the ORS Visual(r) software. Then, a statistical analysis was performed from these biometric data: a Linear Discriminant Analysis (LDA) evaluated the probability for an individual to belong to one of the age group (0 13, 13-18 or 18-21); and several multivariate regression models were tested for the establishment of age estimation formulas for each of these age groups. The mean Correlation Coefficient between chronological age and both lengths and widths of hand bones is equal to 0.90 for the total sample. Repeatability and reproducibility were assessed. The LDA could more easily predict the belonging to the 0-13 age group. Age can be estimated with a mean standard error which never exceeds 1 year for the 95% confidence interval. Finally, compared to the literature, we can conclude that estimating an age from the biometric information of metacarpals and proximal phalanges is promising. PMID- 28081519 TI - Interoception and psychopathology: A developmental neuroscience perspective. AB - Interoception refers to the perception of the physiological condition of the body, including hunger, temperature, and heart rate. There is a growing appreciation that interoception is integral to higher-order cognition. Indeed, existing research indicates an association between low interoceptive sensitivity and alexithymia (a difficulty identifying one's own emotion), underscoring the link between bodily and emotional awareness. Despite this appreciation, the developmental trajectory of interoception across the lifespan remains under researched, with clear gaps in our understanding. This qualitative review and opinion paper provides a brief overview of interoception, discussing its relevance for developmental psychopathology, and highlighting measurement issues, before surveying the available work on interoception across four stages of development: infancy, childhood, adolescence and late adulthood. Where gaps in the literature addressing the development of interoception exist, we draw upon the association between alexithymia and interoception, using alexithymia as a possible marker of atypical interoception. Evidence indicates that interoceptive ability varies across development, and that this variance correlates with established age-related changes in cognition and with risk periods for the development of psychopathology. We suggest a theory within which atypical interoception underlies the onset of psychopathology and risky behaviour in adolescence, and the decreased socio-emotional competence observed in late adulthood. PMID- 28081520 TI - Mesial temporal lobe epilepsy associated with KCNT1 mutation. PMID- 28081521 TI - Peer victimization in adolescence: The nature, progression, and consequences of being bullied within a developmental context. AB - Since Dan Olweus's seminal work on bullying in the 1970's (Olweus, 1978), there has been a concerted effort by investigators to identify the confluence of factors that contribute to peer victimization and its role in psychosocial development. Although the cause and consequences of peer victimization may include underlying, age-invariant processes, the manifestation of these factors is, in part, driven by the developmental stage being studied. Thus, a comprehensive understanding of peer victimization requires an explicit developmental perspective. This paper examines how peer victimization in adolescence is unique from other developmental periods. Changes in the nature of peer victimization, associated risk factors, the contexts in which victimization is experienced, and the psychosocial outcomes affected are addressed. A primary focus is how maturational processes and interpersonal contexts characteristic of adolescence contribute to changes in victimization, with the objective of informing future research directions and the development of effective interventions. PMID- 28081522 TI - Adrenal giant cystic pheochromocytoma treated by posterior retroperitoneoscopic adrenalectomy. AB - INTRODUCTION: Giant cystic pheochromocytoma (>10cm) is rare with only a few cases described in the literature. Preoperative diagnosis is very difficult because clinical, biochemical and radiologic finds are usually not consistent with a pheochromocytoma. Open surgery is traditionally the gold standard. CASE PRESENTATION: A 51 year-old male patient resorted to surgery department with an adrenal cystic incidentaloma. He was asymptomatic, mild hypertension easily controlled, with increased plasma fractionated metanephrines. MRI and MIBG scans confirmed the presence of a right adrenal giant cystic pheochromocytoma (14cm). A right posterior retroperitoneoscopic adrenalectomy was performed, complicated with an unintended disruption. At follow-up he was asymptomatic and with plasma fractionated metanephrines normalized. DISCUSSION: Although laparoscopic surgery is effective and safe, traditional open surgery is the gold standard in the presence of adrenal tumours with suspicion of malignancy, like masses larger than 8cm (including giant cystic pheochromocytomas). Minimal invasive techniques have the advantages of less postoperative pain and ileus, less morbidity, improved cosmetics, and faster recovery, but with the negative impact in R0 resection and probably a higher risk of cystic rupture. However comparisons between open and minimally invasive surgery are lacking. Additionally posterior retroperitoneoscopic approach has several advantages over laparoscopic transperitoneal method. CONCLUSION: This is the first case report of a giant cystic pheochromocytoma treated by posterior retroperitoneoscopic adrenalectomy, but the occurrence of the unintended rupture may be a factor against this approach. More studies are needed to compare open and minimally invasive techniques in terms of resectability and cystic rupture rate. PMID- 28081523 TI - Enhanced enzymatic hydrolysis and acetone-butanol-ethanol fermentation of sugarcane bagasse by combined diluted acid with oxidate ammonolysis pretreatment. AB - This study aims to propose a biorefinery pretreatment technology for the bioconversion of sugarcane bagasse (SB) into biofuels and N-fertilizers. Performance of diluted acid (DA), aqueous ammonia (AA), oxidate ammonolysis (OA) and the combined DA with AA or OA were compared in SB pretreatment by enzymatic hydrolysis, structural characterization and acetone-butanol-ethanol (ABE) fermentation. Results indicated that DA-OA pretreatment improves the digestibility of SB by sufficiently hydrolyzing hemicellulose into fermentable monosaccharides and oxidating lignin into soluble N-fertilizer with high nitrogen content (11.25%) and low C/N ratio (3.39). The enzymatic hydrolysates from DA-OA pretreated SB mainly composed of glucose was more suitable for the production of ABE solvents than the enzymatic hydrolysates from OA pretreated SB containing high ratio of xylose. The fermentation of enzymatic hydrolysates from DA-OA pretreated SB produced 12.12g/L ABE in 120h. These results suggested that SB could be utilized efficient, economic, and environmental by DA-OA pretreatment. PMID- 28081524 TI - Effects of acidified aqueous glycerol and glycerol carbonate pretreatment of rice husk on the enzymatic digestibility, structural characteristics, and bioethanol production. AB - Rice husk as an abundant biomass was used in this study, and it contained 30.1% glucan and 13.5% xylan, 22.4% lignin. The pretreated rice husk with glycerol carbonate and acidified aqueous glycerol (10% water) at 90 degrees C and 130 degrees C for 60min had the maximum yield of glucan digestibility which was 78.2% and 69.7% respectively, using cellulase for 72h. The simultaneous saccharification and fermentation was conducted anaerobically at 37 degrees C with Saccharomyces cerevisiae, 5% w/v glucan and 10FPU/g glucan of cellulase. 11.58 and 8.84g/L was the highest ethanol concentration after 3days of incubation form pretreated rice husk with glycerol carbonate and acidified aqueous glycerol respectively. PMID- 28081525 TI - Effect of free nitrous acid pre-treatment on primary sludge at low exposure times. AB - The present study was undertaken to investigate the effect of different free nitrous acid (FNA) concentrations at low pre-treatment times (PTs) (1, 2 and 5h) and without pH control with mild agitation on primary sludge (PS) biodegradability and methane production (MP). Increasing PTs resulted in an increase in the solubility of the organic matter (around 25%), but not on cell mortality (>75% in all the cases with FNA) and neither on methane generation. FNA pre-treatment at low PTs improve MP (around 16% at PT of 1h and 650mg N-NO2-/L). However, a similar improvement was found with mild agitation of PS without FNA at 2 and 5h. Taking into account the potential costs associated with the FNA pre treatment, a mild agitation without FNA would be preferred to enhance MP in PS. PMID- 28081526 TI - Phosphomolybdic acid and ferric iron as efficient electron mediators for coupling biomass pretreatment to produce bioethanol and electricity generation from wheat straw. AB - Phosphomolybdic acid (PMo12) was used as an electron mediator and proton carrier to mediate biomass pretreatment for ethanol production and electricity generation from wheat straw. In the pretreatment, lignin was oxidized anaerobically by PMo12 with solubilization of a fraction of hemicelluloses, and the PMo12 was simultaneously reduced. In an external liquid flow cell, the reduced PMo12 was re oxidized with generation of electricity. The effects of several factors on pretreatment were investigated for optimizing the conditions. Enzymatic conversion of cellulose and xylan were about 80% and 45%, respectively, after pretreatment of wheat straw with 0.25M PMo12, at 95 degrees C for 45min. FeCl3 was found to be an effective liquid mediator to transfer electrons to air, the terminal electron acceptor. By investigating the effects of various operation parameters and cell structural factors, the highest output power density of about 11mW/cm2 was obtained for discharging of the reduced PMo12. PMID- 28081527 TI - Enhanced microalgal biomass and lipid production from a consortium of indigenous microalgae and bacteria present in municipal wastewater under gradually mixotrophic culture conditions. AB - The goal of this study was to investigate the influences of gradually mixotrophic culture conditions on microalgal biomass and lipid production by a consortium of indigenous microalgae and bacteria present in raw municipal wastewater. Lab-scale photobioreactors containing the consortium were operated in repeated batch mode. Initial cultivation (phase I) was performed using only the municipal wastewater, then 10% and 25% of the reactor volumes were replaced with the effluent from a sewage sludge fermentation system producing volatile fatty acids (SSFV) at the beginnings of phase II and phase III, respectively. The highest biomass productivity (117.1+/-2.7mg/L/d) was attained during phase II, but the lipid productivity (17.2+/-0.2mg/L/d) was attained during phase III. The increase in the effluent from the SSFV influenced microalgal diversity with a preference for Chlorella sp., but bacterial diversity increased significantly during phase III. PMID- 28081528 TI - Rapid Decrease in Populations of Wild Ring-Tailed Lemurs (Lemur catta) in Madagascar. AB - Lemurs are the most threatened group of mammals on earth. Lemur catta (ring tailed lemur) represents one of the most iconic lemur species and faces numerous anthropogenic threats in the wild. In this study, we present population estimates from 32 sites across the range of L. catta, collected from primary and secondary data sources, to assess the number of ring-tailed lemurs left in the wild. We estimate that there are approximately 2,220 individual L. catta remaining in the 32 sites considered. We note local extinctions of populations of L. catta in at least 12 of the 32 sites examined, and that significantly more extinctions occurred in areas without some form of protection. This decrease in extant populations could represent a decrease of more than 95% of all ring-tailed lemurs in Madagascar since the year 2000. While these results should be considered preliminary, we stress the rapid decline of the species and note that habitat loss, bushmeat hunting and the illegal pet trade are driving populations to local extinction. Based on the data presented here, urgent and immediate funding and conservation action are crucial to ensure the viability of the remaining wild populations of ring-tailed lemurs. PMID- 28081529 TI - Zika Virus-Induced Microcephaly and Its Possible Molecular Mechanism. AB - Zika virus is an arthropod-borne re-emerging pathogen associated with the global pandemic of 2015-2016. The devastating effect of Zika viral infection is reflected by its neurological manifestations such as microcephaly in newborns. This scenario evoked our interest to uncover the neurotropic localization, multiplication of the virus, and the mechanism of microcephaly. The present report provides an overview of a possible molecular mechanism of Zika virus induced microcephaly based on recent publications. Transplacental transmission of Zika viral infection from mother to foetus during the first trimester of pregnancy results in propagation of the virus in human neural progenitor cells (hNPCs), where entry is facilitated by the receptor (AXL protein) leading to the alteration of signalling and immune pathways in host cells. Further modification of the viral-induced TLR3-mediated immune network in the infected hNPCs affects viral replication. Downregulation of neurogenesis and upregulation of apoptosis in hNPCs leads to cell cycle arrest and death of the developing neurons. In addition, it is likely that the environmental, physiological, immunological, and genetic factors that determine in utero transmission of Zika virus are also involved in neurotropism. Despite the global concern regarding the Zika-mediated epidemic, the precise molecular mechanism of neuropathogenesis remains elusive. PMID- 28081530 TI - Antipathy of Trichoderma against Sclerotium rolfsii Sacc.: Evaluation of Cell Wall-Degrading Enzymatic Activities and Molecular Diversity Analysis of Antagonists. AB - The fungus Trichoderma is a teleomorph of the Hypocrea genus and associated with biological control of plant diseases. The microscopic, biochemical, and molecular characterization of Trichoderma was carried out and evaluated for in vitro antagonistic activity against the fungal pathogen Sclerotium rolfsii causing stem rot disease in groundnut. In total, 11 isolates of Trichoderma were examined for antagonism at 6 and 12 days after inoculation (DAI). Out of 11, T. virens NBAII Tvs12 evidenced the highest (87.91%) growth inhibition of the test pathogen followed by T. koningii MTCC 796 (67.03%), T. viride NBAII Tv23 (63.74%), and T. harzianum NBAII Th1 (60.44%). Strong mycoparasitism was observed in the best antagonist Tvs12 strain during 6-12 DAI. The specific activity of cell wall degrading enzymes - chitinase and beta-1,3-glucanase - was positively correlated with growth inhibition of the test pathogen. In total, 18 simple sequence repeat (SSR) polymorphisms were reported to amplify 202 alleles across 11 Trichoderma isolates. The average polymorphism information content for SSR markers was found to be 0.80. The best antagonist Tvs 12 was identified with 7 unique SSR alleles amplified by 5 SSR markers. Clustering patterns of 11 Trichoderma strains showed the best antagonist T. virens NBAII Tvs 12 outgrouped with a minimum 3% similarity from the rest of Trichoderma. PMID- 28081531 TI - Viral Nucleic Acids in the Serum Are Dependent on Blood Sampling Site in Patients with Clinical Suspicion of Myocarditis. AB - BACKGROUND: The meaning of viral nucleic acids in the myocardium in many cases is difficult for clinical interpretation, whereas the presence of viral nucleic acids in the serum is a marker of active infection. We determined the diagnostic value of viral nucleic acids in ventricular serum and peripheral serum samples in comparison with endomyocardial biopsy (EMB) specimens in patients with clinically suspected myocarditis. METHODS: The viral nucleic acid evaluation was performed in serum samples and EMB specimens by real-time PCR in 70 patients (age: 47 +/- 16 years). The biopsy specimens were examined by histo- and immunohistochemistry to detect inflammatory response. RESULTS: The viral nucleic acids were detected in ventricular and peripheral serum, and EMB samples of 10 (14%), 14 (20%), and 32 (46%) patients, respectively. Notably, viral nucleic acids of the same virus as in the EMB sample were present more often in ventricular than in peripheral serum (60 vs. 7%, p = 0.01). A significant concurrence was observed between the positive and the negative results of viral nucleic acids present in EMB and ventricular serum (p = 0.0001). CONCLUSIONS: The detection of the same viral nucleic acid type in the myocardium and in ventricular serum being significantly more frequent than in the peripheral serum may suggest that the site of the blood collection is important for more precise and reliable confirmation of the active viral replication in the heart. PMID- 28081532 TI - Cardiovascular Events in Moderately to Severely Obese Obstructive Sleep Apnea Patients on Positive Airway Pressure Therapy. AB - BACKGROUND: In moderately to severely obese patients with obstructive sleep apnea (OSA), the effects of long-term positive airway pressure (PAP) treatment on cardiovascular risk are poorly defined. PURPOSE: To assess the effect of continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV) on the occurrence of cardiovascular events in obese OSA patients. METHODS: We performed a noninterventional observational study in obese OSA patients recruited between 2007 and 2010 at the Sleep Center, University of Grenoble, treated with CPAP or NIV, and followed for 5.6 years by a single home care provider. Baseline clinical characteristics, blood chemistry, and respiratory and vascular function were assessed. Incident cardiovascular events were investigated by phone interviews. RESULTS: A total of 103 patients (55 men, 48 women; age and body mass index [BMI] at diagnosis 54.1 +/- 10.5 years and 40.3 +/- 5.5, respectively [mean +/- standard deviation]; CPAP: n = 75; NIV: n = 28) agreed to participate in the study. Grade I, II, and III obesity occurred in 17.5, 33.0, and 49.5% of the sample, respectively. In patients using PAP treatment (n = 69), the mean nightly use was 6.3 +/- 2.4 h. Thirty-one patients stopped PAP treatment during follow up. Three patients on NIV died. Nonfatal cardiovascular events (n = 27) occurred in 19 patients, who were older and showed higher number of comorbidities and triglyceride levels than patients without events. In the patients who interrupted treatment, the event rate was high and increased with the number of comorbidities, while BMI at baseline did not predict events. CONCLUSIONS: The study suggests that regular PAP treatment may be associated with protection against cardiovascular risk in obese OSA patients, especially in the presence of multiple comorbidities. PMID- 28081534 TI - Enhanced Auditory Sensitivity to Body Vibrations in Superior Canal Dehiscence Syndrome. AB - A key feature of superior canal dehiscence (SCD) syndrome is supranormal hearing of body sounds. The aim of the present study was to quantify this phenomenon and to ascertain whether auditory sensitivity to body vibrations can distinguish SCD patients. Hearing thresholds in response to vibration at the vertex, at the spinous process of the 7th cervical vertebra, and at the medial malleolus were tested in 10 SCD patients and 10 controls. Both patients and controls had insert earphones in both ears. The insert in the test ear was blocked while masking was presented to the other ear. Vibration in the frequency range of 125-1,000 Hz was presented to each of the 3 stimulation sites. The SCD patients were found to have significantly lower hearing thresholds compared with controls. The two study groups reacted differently with respect to frequency. The SCD patients showed an enhanced sensitivity for the lower stimulus frequencies. The difference was, however, rather independent of stimulus presentation site. The findings suggest that hearing thresholds in response to low-frequency body vibration at sites distant from the ears can distinguish SCD patients. The present findings may also support the idea that auditory sensation to body vibrations is a response related to soft tissue conduction. PMID- 28081533 TI - EEG Monitoring Technique Influences the Management of Hypoxic-Ischemic Seizures in Neonates Undergoing Therapeutic Hypothermia. AB - Electroencephalogram (EEG) monitoring techniques for neonatal hypoxia-ischemia (HI) are evolving over time, and the specific type of EEG utilized could influence seizure diagnosis and management. We examined whether the type of EEG performed affected seizure treatment decisions (e.g., the choice and number of antiseizure drugs [ASDs]) in therapeutic hypothermia-treated neonates with HI from 2007 to 2015 in the Johns Hopkins Hospital Neonatal Intensive Care Unit. During this period, 3 different EEG monitoring protocols were utilized: Period 1 (2007-2009), single, brief conventional EEG (1 h duration) at a variable time during therapeutic hypothermia treatment, i.e., ordered when a seizure was suspected; Period 2 (2009-2013), single, brief conventional EEG followed by amplitude-integrated EEG for the duration of therapeutic hypothermia treatment and another brief conventional EEG after rewarming; and Period 3 (2014-2015), continuous video-EEG (cEEG) for the duration of therapeutic hypothermia treatment (72 h) plus for an additional 12 h during and after rewarming. One hundred and sixty-two newborns were included in this retrospective cohort study. As a function of the type and duration of EEG monitoring, we assessed the risk (likelihood) of receiving no ASD, at least 1 ASD, or >=2 ASDs. We found that the risk of a neonate being prescribed an ASD was 46% less during Period 3 (cEEG) than during Period 1 (brief conventional EEG only) (95% CI 6-69%, p = 0.03). After adjusting for initial EEG and MRI results, compared with Period 1, there was a 38% lower risk of receiving an ASD during Period 2 (95% CI: 9-58%, p = 0.02) and a 67% lower risk during Period 3 (95% CI: 23-86%, p = 0.01). The risk ratio of receiving >=2 ASDs was not significantly different across the 3 periods. In conclusion, in addition to the higher sensitivity and specificity of continuous video-EEG monitoring, fewer infants are prescribed an ASD when undergoing continuous forms of EEG monitoring (aEEG or cEEG) than those receiving conventional EEG. We recommend that use of continuous video-EEG be considered whenever possible, both to treat seizures more specifically and to avoid overtreatment. PMID- 28081535 TI - Efficacy and Safety of Continuous Subcutaneous Infusion of Recombinant Human Gonadotropins for Congenital Micropenis during Early Infancy?. AB - BACKGROUND: Early postnatal administration of gonadotropins to infants with congenital hypogonadotropic hypogonadism (CHH) can mimic minipuberty, thereby increasing penile growth. We assessed the effects of gonadotropin infusion on stretched penile length (SPL) and hormone levels in infants with congenital micropenis. METHODS: Single-center study including 6 males with micropenis in case of isolated CHH (n = 4), panhypopituitarism (n = 1), and partial androgen insensitivity syndrome (PAIS; n = 1). Patients were evaluated at baseline, monthly and at the end of the study through a clinical examination (SPL, testicular position and size), serum hormone assays (testosterone, luteinizing hormone, follicle-stimulating hormone, inhibin B, anti-Mullerian hormone [AMH]), and ultrasound of penis/testes. RESULTS: In CHH, significant increases occurred in serum testosterone (from undetectable level to 3.5 +/- 4.06 ng/mL [12.15 +/- 14.09 nmol/L]), SPL (from 13.8 +/- 4.5 to 42.6 +/- 5 mm; p < 0.0001), inhibin B (from 94.8 +/- 74.9 to 469.4 +/- 282.5 pg/mL, p = 0.04), and AMH (from 49.6 +/- 30.6 to 142 +/- 76.5 ng/mL, p = 0.03). Micropenis was corrected in all patients, except one. On treatment, in the patient with PAIS, SPL was increased from 13 to 38 mm. CONCLUSIONS: Early gonadotropin infusion is a safe, well-tolerated and effective treatment. The effect in PAIS has not been reported previously. Long term follow-up is needed to assess the impact, if any, on future fertility and reproduction.?. PMID- 28081536 TI - WT1 Haploinsufficiency Supports Milder Renal Manifestation in Two Patients with Denys-Drash Syndrome. AB - Denys-Drash syndrome (DDS) is characterized by nephropathy, genital abnormalities, and predisposition to Wilms' tumor. DDS patients usually present heterozygous de novo germline WT1 mutations. The WT1 gene comprises 10 exons encoding the N-terminal transactivation and the C-terminal DNA-binding regions. Two unrelated patients with genital ambiguity and Wilms' tumor were analyzed by sequencing of the WT1 gene, and 3 mutations in exon 1 were identified of which 2 are novel. Patient 1 carried a c.555delC mutation that causes a frameshift and a premature stop codon. Patient 2 carried both c.421A>C and c.424C>T aberrations that lead to the missense p.Lys141Gln and the nonsense p.Lys142* mutation, respectively. As both patients were heterozygous for the mutations, we tested their parents who did not carry any mutation. Therefore, the 3 WT1 mutations occurred de novo in both patients. Heterozygous mutations result in WT1 haploinsufficiency as they impair protein production. They are associated with a milder DDS phenotype as observed in the patients studied here. PMID- 28081537 TI - Impact of disease stage and aetiology on survival in hepatocellular carcinoma: implications for surveillance. AB - BACKGROUND: Variation in survival in hepatocellular carcinoma (HCC) has been attributed to different aetiologies or disease stages at presentation. While international guidelines recommend surveillance of high-risk groups to permit early diagnosis and curative treatment, the evidence that surveillance decreases disease-specific mortality is weak. METHODS: We compared HCC survival figures from Japan (n=1174) and Hong Kong (n=1675) over similar time periods (Japan 2000 2013, Hong Kong, China 2003-2014). The former has an intensive national surveillance programme, while the latter has none. We also analysed changes in survival in Japan over a 50-year period including data from before and after institution of a national HCC surveillance programme. RESULTS: In Japan, over 75% of cases are currently detected by surveillance, whereas in Hong Kong <20% of cases are detected presymptomatically. Median survival was 52 months in Japan and 17.8 months in Hong Kong; this survival advantage persisted after allowance for lead-time bias. Sixty-two per cent of Japanese patients had early disease at diagnosis and 63% received curative treatment. The comparable figures for Hong Kong were 31.7% and 44.1%, respectively. These differences could not be accounted for by disease aetiology, and patients in Hong Kong who were detected at an early stage had a similar survival to the analogous patients in Japan. CONCLUSIONS: The variation in survival is largely accounted for by stage at diagnosis, which in turn relates to the intensity of surveillance programmes and the consequent variation in curative therapeutic options. PMID- 28081538 TI - Testing breast cancer serum biomarkers for early detection and prognosis in pre diagnosis samples. AB - BACKGROUND: Breast cancer is a leading cause of morbidity and mortality worldwide. Although mammography screening is available, there is an ongoing interest in improved early detection and prognosis. Herein, we have analysed a combination of serological biomarkers in a case-control cohort of sera taken before diagnosis. METHODS: This nested case-control study within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) used serum samples from 239 women who subsequently developed breast cancer and 239 matched cancer-free controls. Sera were screened by ELISA for 9 candidate markers. Univariate and multivariate analyses were performed to examine associations with clinico pathological features and between case controls in different time groups before diagnosis. RESULTS: Significant associations with clinico-pathological features related to prognosis were found for several candidates (CA15-3, HSP90A and PAI 1). However, there were no consistent differences between cases and controls for any candidate in the lead up to diagnosis. Whilst combination models outperformed single markers, there was no increase in performance towards diagnosis. CONCLUSIONS: This study using unique pre-diagnosis samples shows that CA15-3, HSP90A and PAI-1 have potential as early prognostic markers and warrant further investigation. However, none of the candidates or combinations would be useful for screening. PMID- 28081539 TI - Regulation of anoikis resistance by NADPH oxidase 4 and epidermal growth factor receptor. AB - BACKGROUND: Normal cells are sensitive to anoikis, which is a cell detachment induced apoptosis. However, cancer cells acquire anoikis resistance that is essential for successful metastasis. This study aimed to demonstrate the function and potential mechanism of NADPH oxidase 4 (NOX4) and EGFR activation in regulating anoikis resistance in lung cancer. METHODS: Cells were cultured either in the attached or suspended condition. Cell viability was measured by cell counting and live and dead cell staining. Expression levels of NOX4 and EGFR were measured by PCR and immunoblotting. Reactive oxygen species (ROS) levels were measured by flow cytometry. Effects of NOX4 overexpression or NOX4 knockdown by si-NOX4 on anoikis sensitivity were explored. Levels of NOX4 and EGFR in lung cancer tissues were evaluated by IHC staining. RESULTS: NOX4 was upregulated but EGFR decreased in suspended cells compared with attached cells. Accordingly, ROS levels were increased in suspended cells, resulting in the activation of Src and EGFR. NOX4 knockdown decreased activation of Src and EGFR, and thus sensitised cells to anoikis. NOX4 overexpression increased EGFR levels and attenuated anoikis. NOX4 expression is upregulated and is positively correlated with EGFR levels in the lung cancer patient tissues. CONCLUSIONS: NOX4 upregulation confers anoikis resistance by ROS-mediated activation of EGFR and Src, and by maintaining EGFR levels, which is critical for cell survival. PMID- 28081540 TI - Efficacy of fluoropyrimidine-based chemotherapy in patients with advanced biliary tract cancer after failure of gemcitabine plus cisplatin: retrospective analysis of 321 patients. AB - BACKGROUND: We aimed to assess the efficacy of second-line fluoropyrimidine-based chemotherapy in patients with advanced biliary tract cancer (BTC) after failure of gemcitabine plus cisplatin (GEMCIS). METHODS: We retrospectively examined patients with histologically documented advanced BTC who received first-line GEMCIS between December 2010 and June 2015. Among 748 patients treated with first line GEMCIS, 321 (43%) subsequently received fluoropyrimidine-based second-line systemic chemotherapy. RESULTS: Fluoropyrimidine monotherapy and fluoropyrimidine platinum combination were used in 255 and 66 patients, respectively. In patients with measurable disease, the overall response rate (ORR) was 3% and disease control rate was 47%. After a median follow-up of 27.6 months (range, 0.9-70.4 months), the median progression-free survival (PFS) and overall survival (OS) were 1.9 months (95% confidence interval (CI), 1.6-2.2) and 6.5 months (95% CI, 5.9-7.0), respectively. The ORR was significantly higher in patients who received fluoropyrimidine-platinum combination compared with those who received fluoropyrimidine alone (8 vs 1%, P=0.009), although the PFS (P=0.43) and OS (P=0.88) did not significantly differ between these groups. CONCLUSIONS: Fluoropyrimidine-based chemotherapy was modestly effective as a second-line chemotherapy for advanced BTC patients after failure of GEMCIS. Fluoropyrimidine platinum combination therapy was not associated with improved survival outcomes, as compared with fluoropyrimidine monotherapy. PMID- 28081542 TI - Galectin-1 has potential prognostic significance and is implicated in clear cell renal cell carcinoma progression through the HIF/mTOR signaling axis. PMID- 28081541 TI - Circular RNA 0000096 affects cell growth and migration in gastric cancer. AB - BACKGROUND: Circular RNAs (circRNAs) are a class of non-coding RNAs broadly expressed in cells of various species. Their role in cancers, especially in gastric cancer, is poorly understood. METHODS: Circular RNA 0000096 (hsa_circ_0000096) levels in 101 paired gastric cancer tissues and adjacent non tumorous tissues from patients with gastric cancer were detected by real-time quantitative reverse transcription-polymerase chain reaction. A receiver operating characteristic curve was generated to evaluate the diagnostic value of hsa_circ_0000096. RNA interference was used to manipulate the expression of hsa_circ_0000096. Its biological effects were evaluated by flow cytometry, real time cell analysis, a wound scratch assay, western blot analysis and xenograft models. RESULTS: Hsa_circ_0000096 was found to be significantly downregulated in gastric cancer tissues and gastric cancer cell lines compared with paired adjacent non-tumorous tissues and normal gastric epithelial cells (P<0.001). Moreover, knockdown of hsa_circ_0000096 significantly inhibited cell proliferation and migration in vitro and in vivo. The results of both immunohistochemical and western blot analyses showed that the protein levels of cyclin D1, cyclin-dependent kinase 6 (CDK6), matrix metalloproteinase-2 and MMP-9 were significantly reduced in vitro and in vivo. A gastric cancer xenograft nude mouse model indicated that Ki67 and VEGF were reduced in a dose-dependent manner following knockdown of hsa_circ_0000096. However, the expression of E-cadherin increased. CONCLUSIONS: Hsa_circ_0000096 may be used as a potential novel biomarker for gastric cancer. It affects gastric cancer cell growth and migration by regulating cyclin D1, CDK6, MMP-2 and MMP-9. PMID- 28081543 TI - Randomised phase II trial of irinotecan plus S-1 in patients with gemcitabine refractory pancreatic cancer. AB - BACKGROUND: We aimed to compare the efficacy and safety of irinotecan/S-1 (IRIS) therapy with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer. METHODS: Patients were treated with oral S-1 (80-120 mg for 14 days every 4 weeks) plus intravenous irinotecan (100 mg m-2 on days 1 and 15 every 4 weeks; IRIS group) or oral S-1 group (80-120 mg daily for 28 days every 6 weeks). The primary endpoint was progression-free survival (PFS). RESULTS: Of 137 patients enrolled, 127 were eligible for efficacy. The median PFS in the IRIS group and S 1 monotherapy group were 3.5 and 1.9 months, respectively (hazard ratio (HR)=0.77; 95% confidence interval (CI), 0.53-1.11; P=0.18), while the median overall survival (OS) were 6.8 and 5.8 months, respectively (HR=0.75; 95% CI, 0.51-1.09; P=0.13). Response rate was significantly higher in the IRIS group than in the S-1 monotherapy group (18.3% vs 6.0%, P=0.03). Grade 3 or higher neutropenia and anorexia occurred more frequently in the IRIS group. CONCLUSIONS: There was a trend for better PFS and OS in the IRIS group that could be a treatment arm in the clinical trials for gemcitabine-refractory pancreatic cancer. PMID- 28081544 TI - Nomogram to predict pathologic complete response in HER2-positive breast cancer treated with neoadjuvant systemic therapy. AB - BACKGROUND: Pathologic complete response (pCR) is associated with improved survival outcomes in patients with HER2-positive primary breast cancer. We developed a nomogram to predict the probability of pCR rates by using oestrogen receptor (ER) expression, progesterone receptor (PR) expression and HER2/CEP17 ratio as continuous variables. METHODS: We retrospectively reviewed patients with stages I-III HER2-positive invasive breast cancer who had definitive surgery in 1999-2015 and received neoadjuvant systemic therapy (NST). Multivariate logistic regression models were applied to assess the effect of variables on pCR. A nomogram was built to estimate the probability of pCR. The discriminative ability was estimated by the concordance index (C-index). The accuracy was assessed graphically with a calibration curve. RESULTS: A total of 793 patients were included in the analysis. Low ER expression (P<0.001), high HER2/CEP12 ratio (P=0.03), and non-inflammatory breast cancer subtype (P=0.003) were associated with increased pCR rates. Regimens containing trastuzumab or trastuzumab and pertuzumab were associated with higher pCR rates than cytotoxic agents alone (P<0.001 and P<0.001, respectively). The C-index was 0.69. The calibration curve showed good agreement. CONCLUSIONS: Our nomogram predicted the pCR rate after NST among patients with HER2-positive primary breast cancer using clinicopathologic factors. PMID- 28081545 TI - Mathematical optimisation of the cisplatin plus etoposide combination for managing extensive-stage small-cell lung cancer patients. AB - BACKGROUND: Small-cell lung cancer (SCLC) represents one of the most aggressive forms of lung cancer. Despite the fair sensitivity of SCLC to chemotherapy and radiotherapy, the current standard treatment regimens have modest survival rates and are associated with potential life-threatening adverse events. Therefore, research into new optimised regimens that increase drug efficacy while respecting toxicity constraints is of primary importance. METHODS: A PK/PD model for the combination of cisplatin and etoposide to treat extensive-stage SCLC patients was generated. The model takes into consideration both the efficacy of the drugs and their haematological toxicity. Using optimisation techniques, the model can be used to propose new regimens. RESULTS: Three new regimens with varying timing for combining cisplatin and etoposide have been generated that respect haematological toxicity constraints and achieve better or similar tumour regression. The proposed regimens are: (1) Protocol OP1: etoposide 80 mg m-2 over 1 h D1, followed by a long infusion 12 h later (over 3 days) of 160 mg m-2 plus cisplatin 80 mg m-2 over 1 h D1, D1-D1 21 days; (2) Protocol OP2: etoposide 80 mg m-2 over 1 h D1, followed by a long infusion 12 h later (over 4 days) of 300 mg m-2 plus cisplatin 100 mg m-2 over 1 h D1, D1-D1 21 days; and (3) Protocol OP3: etoposide 40 mg m-2 over 1 h, followed by a long infusion 6 h later (3 days) of 105 mg m-2 plus cisplatin 50 mg m-2 over 1 h, D1-D1 14 days. CONCLUSIONS: Mathematical modelling can help optimise the design of new cisplatin plus etoposide regimens for managing extensive-stage SCLC patients. PMID- 28081546 TI - Advanced pancreatic adenocarcinoma outcomes with transition from devolved to centralised care in a regional Cancer Centre. AB - BACKGROUND: Previous observations suggest suboptimal 'real world' survival outcomes for advanced pancreatic adenocarcinoma. We hypothesized that centralisation of advanced pancreatic adenocarcinoma management would improve chemotherapy treatment and survival from the disease. METHODS: The data was prospectively collected on all cases of advanced pancreatic adenocarcinoma reviewed through Clatterbridge Cancer Centre according to two groups; 1 October 2009-31st Dec 2010 (devolved care) or 1 January 2013-31 March 2014 (centralised care). Analysis included treatment received, 30-day chemotherapy mortality rate and overall survival (OS). RESULTS: More patients received chemotherapy with central care (67.0% (n=115) vs 43.0% (n=121); P=2.2 * 10-4) with no difference in 30-day mortality (20.8% vs 25%; P=0.573) but reduced time to commencement of chemotherapy (18 vs 28 days, P=1.0 * 10-3). More patients received second-line chemotherapy with central care (23.4% vs 1.9%, P=1.4 * 10-4), while OS was significantly increased with central care (median: Five vs three months, HR 0.785, P=0.045). Exploratory analysis suggested that it was those with a poorer performance status, elderly or with metastatic disease who benefited the most from transition to central care. CONCLUSIONS: A centralised clinic model for advanced pancreatic cancer management resulted in prompt, safe and higher use of chemotherapy compared with devolved care. This was associated with a modest survival benefit. Prospective studies are required to validate the findings reported and the basis for improved survival with centralised care. PMID- 28081547 TI - Diagnosis of pancreaticobiliary malignancy by detection of minichromosome maintenance protein 5 in biliary brush cytology. AB - BACKGROUND: Biliary brush cytology is the standard method of evaluating biliary strictures, but is insensitive at detecting malignancy. In pancreaticobiliary cancer minichromosome maintenance replication proteins (MCM 2-7) are dysregulated in the biliary epithelium and MCM5 levels are elevated in bile samples. This study aimed to validate an immunocolorimetric ELISA assay for MCM5 as a pancreaticobiliary cancer biomarker in biliary brush samples. METHODS: Biliary brush specimens were collected prospectively at ERCP from patients with a biliary stricture. Collected samples were frozen at -80 degrees C. The supernatant was washed and lysed cells incubated with HRP-labelled anti-MCM5 mouse monoclonal antibody. Test positivity was determined by optical density absorbance. Patients underwent biliary brush cytology or additional investigations as per clinical routine. RESULTS: Ninety-seven patients were included in the study; 50 had malignant strictures. Median age was 65 years (range 21-94) and 51 were male. Compared with final diagnosis the MCM5 assay had a sensitivity for malignancy of 65.4% compared with 25.0% for cytology. In the 72 patients with paired MCM5 assay and biliary brush cytology, MCM5 demonstrated an improved sensitivity (55.6% vs 25.0%; P=0.0002) for the detection of malignancy. CONCLUSIONS: Minichromosome maintenance replication protein5 is a more sensitive indicator of pancreaticobiliary malignancy than standard biliary brush cytology. PMID- 28081548 TI - Serum LDH predicts benefit from bevacizumab beyond progression in metastatic colorectal cancer. AB - BACKGROUND: Different antiangiogenics are currently indicated in the second-line treatment of metastatic colorectal cancer (mCRC), following a first-line bevacizumab-containing treatment. The magnitude of benefit is limited, but no predictors of benefit have been identified. METHODS: A total of 184 mCRC patients progressing to a first-line bevacizumab-containing treatment were randomised in the BEBYP study to continue or not the antiangiogenic in combination with a second-line chemotherapy. A subgroup analysis according to baseline serum lactate dehydrogenase (LDH) levels was carried out. RESULTS: A significant interaction effect between LDH levels and treatment was found in terms of progression-free survival (PFS; P=0.002). Although patients with low LDH levels achieved significant PFS benefit from the continuation of bevacizumab (HR: 0.39 (95% CI: 0.23-0.65)), patients with high levels did not (HR: 1.10 (95% CI: 0.74-1.64)). Consistent results were reported in overall survival (OS; P=0.075). CONCLUSIONS: As preclinical evidence suggests that serum LDH may be a marker of tumour angiogenesis activation, low levels may indicate that bevacizumab is still efficacious in inhibiting angiogenesis. Validation of present results in subgroup analyses of other randomised trials of second-line angiogenesis inhibitors is warranted. PMID- 28081549 TI - MicroRNA promoter methylation: a new tool for accurate detection of urothelial carcinoma. AB - BACKGROUND: Urothelial carcinoma (UC) is the most common cancer affecting the urinary system, worldwide. Lack of accurate early detection tools entails delayed diagnosis, precluding more efficient and timely treatment. In a previous study, we found that miR-129-2 and miR-663a were differentially methylated in UC compared with other genitourinary tract malignancies. Here, we evaluated the diagnostic performance of those microRNAs in urine. METHODS: Promoter methylation levels of miR-129-2 and miR-663a were assessed, using real-time quantitative methylation-specific PCR, in UC tissue samples (using normal urothelium as control) and, subsequently, in urine samples from UC and other genitourinary malignancies. Diagnostic and prognostic performances were evaluated by receiver operator characteristics curve and survival analyses, respectively. RESULTS: Promoter methylation levels of both microRNAs were significantly higher in UC tissue samples compared with normal urothelium. In urine, the assay was able to distinguish UC from other genitourinary tract carcinomas with 87.7% sensitivity and 84% specificity, resulting in 85.85% overall accuracy. CONCLUSIONS: This panel of miRNAs promoter methylation accurately detects UC in urine, comparing well with other promising epigenetic-based biomarkers. This may constitute the basis for a non-invasive assay to detect UC. PMID- 28081550 TI - Ninth grade school performance in Danish childhood cancer survivors. AB - BACKGROUND: Childhood cancer survivors can experience learning problems resulting in lower-than-expected attained education as adults. It is unclear whether learning problems manifest already during adolescence. METHODS: We analysed nationwide Danish registries on school grades for Danish children during 2001 2014. Applying a matched design we compared grades of childhood cancer survivors to children without cancer at ninth grade. We estimated grade differences by subject and its correlation to cancer site and age at diagnosis. The available statistical precision allowed for an analysis of more rare cancer sites. RESULTS: The total study population was 793 332 children (mean age 15.24 years and 49.7% girls), of whom 1320 were childhood cancer survivors. Lower rank grades were seen in children with cancer in all school subjects but differed substantially according to cancer site. Most affected were survivors of central nervous system (CNS) tumours, neuroblastoma, lymphoma, leukaemia, other malignant neoplasm and germ-cell tumours. Survivors from other cancer types did not obtain lower grades. Lower rank grades were associated with young age at diagnosis. CONCLUSIONS: The effect of childhood cancer differed substantially between cancer sites. The largest effect was among survivors of CNS tumours and leukaemia diagnosed at a young age, suggesting an association with radiation therapy. However, the majority of cancer survivors fare well. Increasing awareness on children affected by cancer and special accommodations may help maximise the learning potential of those most affected. PMID- 28081551 TI - Time for the New Zealand government to ban alcohol advertising and sponsorship in sport. PMID- 28081552 TI - Demographic and psychological correlates of New Zealanders support for euthanasia. AB - AIMS: To explore the distribution of New Zealanders' support towards the legalisation of euthanasia and examine demographic and psychological factors associated with these attitudes. METHODS: 15,822 participants responded to the 2014/15 New Zealand Attitudes and Values Study (NZAVS) survey. This survey included an item on people's attitudes towards euthanasia, and information on their demographic and psychological characteristics. RESULTS: The majority of New Zealanders expressed support for euthanasia, which was assessed by asking "Suppose a person has a painful incurable disease. Do you think that doctors should be allowed by law to end the patient's life if the patient requests it?" Non-religious, liberal, younger, employed, non-parents and those living in rural areas were more supportive. Those of Pacific or Asian ethnicity, with lower income and higher deprivation, education and socio-economic status were less supportive. Furthermore, those high on extraversion, conscientiousness and neuroticism showed more support, while those high on agreeableness and honesty humility exhibited less support. CONCLUSION: There is strong public support for euthanasia when people are asked whether doctors should be allowed by law to end the life of a patient with a painful incurable disease upon their request. There are reliable demographic and personality differences in support for euthanasia. PMID- 28081553 TI - Changes in the age pattern of New Zealand suicide rates. AB - AIMS: It is timely to examine changes in male and female suicide rates across the age range in New Zealand, comparing them to some of the changes recorded in Australia. METHOD: Data regarding suicide and population figures in New Zealand and Australia were obtained. The suicide rates of different age-groups in the two countries were calculated and compared. Data concerning 'open verdicts' were also obtained. RESULTS: The age patterns of suicide rates in New Zealand and Australia have changed markedly and similarly. Suicide rates of New Zealand males in their twenties increased threefold between the 1960s and 1990s, with a fall since then. Nevertheless, the 2009-13 youth suicide rates in New Zealand were double the corresponding rates in Australia. Since 1979-88 a decrease in suicide rates of men and women aged 60-79 has been even greater than in Australia. The Maori suicide rate is high in young men but almost zero in old age. CONCLUSIONS: The persistently high suicide rate of New Zealand youths (Maori much more than non Maori) remains of concern. The rate is equally high among indigenous young Australians. There has been a welcome decrease in late-life suicide rates in New Zealand and Australia. PMID- 28081554 TI - Alcohol sponsorship of a summer of sport: a frequency analysis of alcohol marketing during major sports events on New Zealand television. AB - AIMS: This research aims to assess the nature and extent of alcohol marketing through sport sponsorship over a summer of televised sport in New Zealand. METHODS: Frequency analysis of New Zealand television broadcasts of five international sporting events during the summer of 2014-2015. Broadcasts were analysed to identify the percentage of time when alcohol brands were visible during game-play. The number of independent alcohol brand exposures was recorded. RESULTS: Alcohol brands were observed during every televised event. Audiences were exposed to between 1.6 and 3.8 alcohol brand exposures per minute. Alcohol brands were visible between 42 and 777 times across the games examined. For three out of the five events alcohol brands were visible for almost half of the game. CONCLUSION: Alcohol sponsorship was prevalent in international sport on New Zealand television. Given the popularity of broadcast sport, especially with children, there is an urgent need for regulation of alcohol sponsorship of sport. There are viable models of alcohol sponsorship replacement but their implementation requires the will of both sporting organisations and politicians. This research adds weight to arguments to implement recommendations to remove all alcohol sponsorship of sport. PMID- 28081555 TI - New Zealand rugby health study: motor cortex excitability in retired elite and community level rugby players. AB - AIMS: Rugby union is a high contact sport in which players frequently experience brain injuries. Acute brain injury is associated with altered corticomotor function. However, it is uncertain if long-term exposure to rugby is associated with any alterations in corticomotor function. The aim of the study was to assess measures of corticomotor excitability and inhibition in retired rugby players in comparison to retired non-contact sport players. METHODS: The design was a cross sectional study with three groups of retired athletes: elite rugby (n=23), community level rugby (n=28) and non-contact sport control (n=22). Assessments of corticomotor excitability were made using transcranial magnetic stimulation. RESULTS: Resting motor threshold was significantly higher and long-interval intracortical inhibition was greater in the elite rugby group compared to the control group. Participants in the two rugby groups had sustained significantly more concussions than the control group. CONCLUSIONS: We provide some evidence of altered corticomotor excitation and inhibition in retired elite rugby players in comparison to retired non-contact sport players. Given the absence of findings in the community rugby group, who had experienced a similar number of concussions, the association with previous brain injury is unclear. PMID- 28081556 TI - Stressful events and circumstances reported by patients prior to being prescribed antidepressants. AB - AIMS: This study investigates the extent to which those who receive a prescription for antidepressants perceive psychosocial stressors to be significant in their difficulties. METHODS: This study draws on a survey of adults prescribed antidepressants. It analyses 1,683 responses to an open-ended question that enquired about difficult events and circumstances participants experienced in the time leading up to receiving an antidepressant prescription. RESULTS: Sixty-five percent of respondents described experiencing one or more stressful events or circumstances, with 19 % reporting two and 20% reporting three or more. The most frequently reported stressors identified by participants were categorised as: relationship difficulties (19%), life transitions (19%), losses (18%), work related difficulties (15%) and participants' own or others' health issues (15%). Other less frequently reported stressors included isolation, academic difficulties, abuse and violence and financial difficulties. CONCLUSIONS: Findings are that stressful life events or circumstances are significant for a large number of who are given a prescription for antidepressants. It is important for GPs to be aware of significance of these psychosocial stressors in their patients' lives and make treatment recommendations that address these difficulties. Conclusions need to be interpreted in the light of limitations arising from the sampling method. PMID- 28081557 TI - Student-led intervention to inNOvate hand hygiene practice in Auckland Region's medical students (the No HHARMS study). AB - BACKGROUND: Hand hygiene is important in reducing healthcare-associated infections. The World Health Organization has defined 'five moments' when hand hygiene compliance is required. During 2013, New Zealand national data showed poor compliance with these moments by medical students. AIM: To improve medical students' compliance with the five moments. METHODS: In this prospective student led quality improvement initiative, student investigators developed, implemented and evaluated a multi-modal intervention comprising a three-month social media campaign, a competition and an entertaining educational video. Data on individual patient-medical student interactions were collected covertly by observers at baseline and at one week, six weeks and three months after initiation of the intervention. RESULTS: During the campaign, compliance improved in moment 2, but not significantly in moments 1, 3, 4 or 5. Statistical analysis of amalgamated data was limited by non-independent data points-a consideration apparently not always addressed in previous studies. CONCLUSIONS: The initiative produced improvements in compliance by medical students with one hand hygiene moment. Statistical analysis of amalgamated data for all five moments should allow for the non-independence of each occasion in which clinicians interact with a patient. More work is needed to ensure excellent hand hygiene practices of future doctors. PMID- 28081558 TI - Should New Zealand introduce nationwide pulse oximetry screening for the detection of critical congenital heart disease in newborn infants? PMID- 28081559 TI - An unusual cause of acute appendicitis in New Zealand. PMID- 28081560 TI - Renal artery embolisation for uncontrolled hypertension in ESRD. PMID- 28081561 TI - A Novel Richardson-Lucy Model with Dictionary Basis and Spatial Regularization for Isolating Isotropic Signals. AB - Diffusion-weighted magnetic resonance imaging is a non-invasive imaging method that has been increasingly used in neuroscience imaging over the last decade. Partial volume effects (PVEs) exist in sampling signal for many physical and actual reasons, which lead to inaccurate fiber imaging. We overcome the influence of PVEs by separating isotropic signal from diffusion-weighted signal, which can provide more accurate estimation of fiber orientations. In this work, we use a novel response function (RF) and the correspondent fiber orientation distribution function (fODF) to construct different signal models, in which case the fODF is represented using dictionary basis function. We then put forward a new index Piso, which is a part of fODF to quantify white and gray matter. The classic Richardson-Lucy (RL) model is usually used in the field of digital image processing to solve the problem of spherical deconvolution caused by highly ill posed least-squares algorithm. In this case, we propose an innovative model integrating RL model with spatial regularization to settle the suggested double models, which improve noise resistance and accuracy of imaging. Experimental results of simulated and real data show that the proposal method, which we call iRL, can robustly reconstruct a more accurate fODF and the quantitative index Piso performs better than fractional anisotropy and general fractional anisotropy. PMID- 28081562 TI - Male Facial Appearance and Offspring Mortality in Two Traditional Societies. AB - It has been hypothesised that facial traits such as masculinity and a healthy appearance may indicate heritable qualities in males (e.g. immunocompetence) and that, consequently, female preferences for such traits may function to increase offspring viability and health. However, the putative link between paternal facial features and offspring health has not previously been tested empirically in humans. Here we present data from two traditional societies with little or no access to modern medicine and family planning technologies. Data on offspring number and offspring survival were analysed for the Agta of the Philippines and the Maya of Belize, and archive facial photographs were assessed by observers for attractiveness and masculinity. While there was no association between attractiveness and offspring survival in either population, a quadratic relationship was observed between masculinity and offspring survival in both populations, such that intermediate levels of masculinity were associated with the lowest offspring mortality, with both high and low levels of masculinity being associated with increased mortality. Neither attractiveness nor masculinity were related to fertility (offspring number) in either population. We consider how these data may or may not reconcile with current theories of female preferences for masculinity in male faces and argue that further research and replication in other traditional societies should be a key priority for the field. PMID- 28081563 TI - Interactions with Astroglia Influence the Shape of the Developing Dendritic Arbor and Restrict Dendrite Growth Independent of Promoting Synaptic Contacts. AB - Astroglia play key roles in the development of neurons, ranging from regulating neuron survival to promoting synapse formation, yet basic questions remain about whether astrocytes might be involved in forming the dendritic arbor. Here, we used cultured hippocampal neurons as a simple in vitro model that allowed dendritic growth and geometry to be analyzed quantitatively under conditions where the extent of interactions between neurons and astrocytes varied. When astroglia were proximal to neurons, dendrites and dendritic filopodia oriented toward them, but the general presence of astroglia significantly reduced overall dendrite growth. Further, dendritic arbors in partial physical contact with astroglia developed a pronounced pattern of asymmetrical growth, because the dendrites in direct contact were significantly smaller than the portion of the arbor not in contact. Notably, thrombospondin, the astroglial factor shown previously to promote synapse formation, did not inhibit dendritic growth. Thus, while astroglia promoted the formation of presynaptic contacts onto dendrites, dendritic growth was constrained locally within a developing arbor at sites where dendrites contacted astroglia. Taken together, these observations reveal influences on spatial orientation of growth as well as influences on morphogenesis of the dendritic arbor that have not been previously identified. PMID- 28081564 TI - African Non-Human Primates Host Diverse Enteroviruses. AB - Enteroviruses (EVs) belong to the family Picornaviridae and are responsible for mild to severe diseases in mammals including humans and non-human primates (NHP). Simian EVs were first discovered in the 1950s in the Old World Monkeys and recently in wild chimpanzee, gorilla and mandrill in Cameroon. In the present study, we screened by PCR EVs in 600 fecal samples of wild apes and monkeys that were collected at four sites in Gabon. A total of 32 samples were positive for EVs (25 from mandrills, 7 from chimpanzees, none from gorillas). The phylogenetic analysis of VP1 and VP2 genes showed that EVs identified in chimpanzees were members of two human EV species, EV-A and EV-B, and those identified in mandrills were members of the human species EV-B and the simian species EV-J. The identification of two novel enterovirus types, EV-B112 in a chimpanzee and EV B113 in a mandrill, suggests these NHPs could be potential sources of new EV types. The identification of EV-B107 and EV90 that were previously found in humans indicates cross-species transfers. Also the identification of chimpanzee derived EV110 in a mandrill demonstrated a wide host range of this EV. Further research of EVs in NHPs would help understanding emergence of new types or variants, and evaluating the real risk of cross-species transmission for humans as well for NHPs populations. PMID- 28081565 TI - Leucine Rich alpha-2 Glycoprotein: A Novel Neutrophil Granule Protein and Modulator of Myelopoiesis. AB - Leucine-rich alpha2 glycoprotein (LRG1), a serum protein produced by hepatocytes, has been implicated in angiogenesis and tumor promotion. Our laboratory previously reported the expression of LRG1 in murine myeloid cell lines undergoing neutrophilic granulocyte differentiation. However, the presence of LRG1 in primary human neutrophils and a role for LRG1 in regulation of hematopoiesis have not been previously described. Here we show that LRG1 is packaged into the granule compartment of human neutrophils and secreted upon neutrophil activation to modulate the microenvironment. Using immunofluorescence microscopy and direct biochemical measurements, we demonstrate that LRG1 is present in the peroxidase-negative granules of human neutrophils. Exocytosis assays indicate that LRG1 is differentially glycosylated in neutrophils, and co released with the secondary granule protein lactoferrin. Like LRG1 purified from human serum, LRG1 secreted from activated neutrophils also binds cytochrome c. We also show that LRG1 antagonizes the inhibitory effects of TGFbeta1 on colony growth of human CD34+ cells and myeloid progenitors. Collectively, these data invoke an additional role for neutrophils in innate immunity that has not previously been reported, and suggest a novel mechanism whereby neutrophils may modulate the microenvironment via extracellular release of LRG1. PMID- 28081566 TI - A Novel Phytophthora sojae Resistance Rps12 Gene Mapped to a Genomic Region That Contains Several Rps Genes. AB - Phytophthora sojae Kaufmann and Gerdemann, which causes Phytophthora root rot, is a widespread pathogen that limits soybean production worldwide. Development of Phytophthora resistant cultivars carrying Phytophthora resistance Rps genes is a cost-effective approach in controlling this disease. For this mapping study of a novel Rps gene, 290 recombinant inbred lines (RILs) (F7 families) were developed by crossing the P. sojae resistant cultivar PI399036 with the P. sojae susceptible AR2 line, and were phenotyped for responses to a mixture of three P. sojae isolates that overcome most of the known Rps genes. Of these 290 RILs, 130 were homozygous resistant, 12 heterzygous and segregating for Phytophthora resistance, and 148 were recessive homozygous and susceptible. From this population, 59 RILs homozygous for Phytophthora sojae resistance and 61 susceptible to a mixture of P. sojae isolates R17 and Val12-11 or P7074 that overcome resistance encoded by known Rps genes mapped to Chromosome 18 were selected for mapping novel Rps gene. A single gene accounted for the 1:1 segregation of resistance and susceptibility among the RILs. The gene encoding the Phytophthora resistance mapped to a 5.8 cM interval between the SSR markers BARCSOYSSR_18_1840 and Sat_064 located in the lower arm of Chromosome 18. The gene is mapped 2.2 cM proximal to the NBSRps4/6-like sequence that was reported to co-segregate with the Phytophthora resistance genes Rps4 and Rps6. The gene is mapped to a highly recombinogenic, gene-rich genomic region carrying several nucleotide binding site-leucine rich repeat (NBS-LRR)-like genes. We named this novel gene as Rps12, which is expected to be an invaluable resource in breeding soybeans for Phytophthora resistance. PMID- 28081567 TI - Risk of Rebleeding and Mortality in Cirrhotic Patients with Peptic Ulcer Bleeding: A 12-Year Nationwide Cohort Study. AB - Although a few studies have investigated the risks of peptic ulcer bleeding (PUB) in cirrhotic patients, large population-based studies on in-hospital and long term reports on recurrent PUB in a cohort of cirrhotic patients are lacking. This 12-year nationwide cohort study aimed to investigate the risks of in-hospital and long-term rebleeding and mortality in cirrhotic patients and to identify possible risk factors. Patient data from 1997 to 2008 were extracted from the National Health Insurance Research Database in Taiwan. A total of 15,575 patients who were discharged with a diagnosis of PUB were identified after strict exclusions (n = 2889). Among them, patients with cirrhosis (n = 737) and those with chronic hepatitis (n = 1044) were compared to propensity-score matched normal controls at a ratio of 1:1. Accumulated in-hospital and long-term follow-up PUB-free survival rates were analyzed in patients with cirrhosis, patients with chronic hepatitis, and matched controls. Cox proportional hazards regression was used to identify each independent risk factor. Compared with matched controls, patients with cirrhosis exhibited a 2.62-fold (95% CI: 1.74-3.92) higher risk of developing in hospital rebleeding, but the risk of long-term rebleeding was comparable between cirrhotic patients and matched controls (hazard ratio: 1.29, 95% CI: 0.8-2.09). On the other hand, no significant difference was observed in in-hospital and long term rebleeding between chronic hepatitis patients and matched controls. We compared the survival rates of cirrhotic and chronic hepatitis patients to that of matched controls. After propensity score matching, both cirrhotic and chronic hepatitis patients showed significantly lower survival than the matched controls (P < 0.0001 and 0.033, respectively) during the 12-year follow-up period. However, in-hospital and long-term rebleeding rates were not significantly different between chronic hepatitis patients and matched controls (P = 0.251 and 0.474, respectively). In conclusion, liver cirrhosis increased health care expenses in patients with PUB and these patients exhibited higher recurrent bleeding rate than non-cirrhotic patients during hospitalization. Cirrhosis and chronic hepatitis are independently associated with an increased long-term mortality when compared with patients without liver disease. PMID- 28081569 TI - Gender Incongruence of Childhood: Clinical Utility and Stakeholder Agreement with the World Health Organization's Proposed ICD-11 Criteria. AB - The World Health Organization (WHO) is revising the tenth version of the International Classification of Diseases and Related Health Problems (ICD-10). This includes a reconceptualization of the definition and positioning of Gender Incongruence of Childhood (GIC). This study aimed to: 1) collect the views of transgender individuals and professionals regarding the retention of the diagnosis; 2) see if the proposed GIC criteria were acceptable to transgender individuals and health care providers; 3) compare results between two countries with two different healthcare systems to see if these differences influence opinions regarding the GIC diagnosis; and 4) determine whether healthcare providers from high-income countries feel that the proposed criteria are clinically useful and easy to use. A total of 628 participants were included in the study: 284 from the Netherlands (NL; 45.2%), 8 from Flanders (Belgium; 1.3%), and 336 (53.5%) from the United Kingdom (UK). Most participants were transgender people (or their partners/relatives; TG) (n = 522), 89 participants were healthcare providers (HCPs) and 17 were both HCP and TG individuals. Participants completed an online survey developed for this study. Overall, the majority response from transgender participants (42.9%) was that if the diagnosis would be removed from the mental health chapter it should also be removed from the ICD-11 completely, while 33.6% thought it should remain in the ICD-11. Participants were generally satisfied with other aspects of the proposed ICD-11 GIC diagnosis: most TG participants (58.4%) thought the term Gender Identity Disorder should change, and most thought Gender Incongruence was an improvement (63.0%). Furthermore, most participants (76.1%) did not consider GIC to be a psychiatric disorder and placement in a separate chapter dealing with Gender and Sexual Health (the majority response in the NL and selected by 37.5% of the TG participants overall) or as a Z-code (the majority response in the UK and selected by 26.7% of the TG participants overall) would be preferable. In the UK, the majority response (35.8%) was that narrowing the GIC diagnosis was an improvement, while the NL majority response (49.5%) was that this was not an improvement. Although generally the results from HCPs were in line with the results from TG participants some differences were found. This study suggests that, although in an ideal world a diagnosis is not welcomed, several participants felt the diagnosis should not be removed. This is likely due to concerns about restricting access to reimbursed healthcare. The choice for positioning of a diagnosis of GIC within the ICD-11 was as a separate chapter dealing with symptoms and/or disorders regarding sexual and gender health. This was the overall first choice for NL participants and second choice for UK participants, after the use of a Z code. The difference reflects that in the UK, Z-codes carry no negative implications for reimbursement of treatment costs. These findings highlight the challenges faced by the WHO in their attempt to integrate research findings from different countries, with different cultures and healthcare systems in their quest to create a manual that is globally applicable. PMID- 28081568 TI - Non-Lethal Endotoxin Injection: A Rat Model of Hypercoagulability. AB - Systemic inflammation co-activates coagulation, which unchecked culminates in a lethal syndrome of multi-organ microvascular thrombosis known as disseminated intravascular coagulation (DIC). We studied an endotoxin-induced inflammatory state in rats to identify biomarkers of hemostatic imbalance favoring hypercoagulability. Intraperitoneal injection of LPS at 15 mg/kg body weight resulted in peripheral leukopenia and widespread neutrophilic sequestration characteristic of an acute systemic inflammatory response. Early indicators of hemostatic pathway activation developed within 4 hours, including increased circulating concentrations of procoagulant extracellular vesicles (EVs), EVs expressing endothelial cell and platelet membrane markers, and high concentration of soluble intercellular adhesion molecule-1 (sICAM-1), plasminogen activator inhibitor-1 (PAI-1), and D-dimers. Inflammation persisted throughout the 48-hour observation period; however, increases were found in a subset of serum microRNA (miRNA) that coincided with gradual resolution of hemostatic protein abnormalities and reduction in EV counts. Dose-adjusted LPS treatment in rats provides a time-course model to develop biomarker profiles reflecting procoagulant imbalance and rebalance under inflammatory conditions. PMID- 28081570 TI - The Population Ecology of Technology: An Empirical Study of US Biotechnology Patents from 1976 to 2003. AB - A detailed understanding of technological change as an evolutionary process is currently not well understood. To increase our understanding, we build upon theory from organizational ecology to develop a model of endogenous technological growth and determine to what extent the pattern of technological growth can be attributed to the structural or systemic characteristics of the technology itself. Through an empirical investigation of patent data in the biotechnology industry from 1976 to 2003, we find that a technology's internal (i.e., density and diversity) ecological characteristics have a positive effect on its growth rate. The niche's external characteristics of crowding and status have a negative effect on its growth rate. Hence, applying theory from organizational ecology increases our understanding of technological change as an evolutionary process. We discuss the implications of our findings for the study of technological growth and evolution, and suggest avenues for further research. PMID- 28081571 TI - Robust Inference from Conditional Logistic Regression Applied to Movement and Habitat Selection Analysis. AB - Conditional logistic regression (CLR) is widely used to analyze habitat selection and movement of animals when resource availability changes over space and time. Observations used for these analyses are typically autocorrelated, which biases model-based variance estimation of CLR parameters. This bias can be corrected using generalized estimating equations (GEE), an approach that requires partitioning the data into independent clusters. Here we establish the link between clustering rules in GEE and their effectiveness to remove statistical biases in variance estimation of CLR parameters. The current lack of guidelines is such that broad variation in clustering rules can be found among studies (e.g., 14-450 clusters) with unknown consequences on the robustness of statistical inference. We simulated datasets reflecting conditions typical of field studies. Longitudinal data were generated based on several parameters of habitat selection with varying strength of autocorrelation and some individuals having more observations than others. We then evaluated how changing the number of clusters impacted the effectiveness of variance estimators. Simulations revealed that 30 clusters were sufficient to get unbiased and relatively precise estimates of variance of parameter estimates. The use of destructive sampling to increase the number of independent clusters was successful at removing statistical bias, but only when observations were temporally autocorrelated and the strength of inter-individual heterogeneity was weak. GEE also provided robust estimates of variance for different magnitudes of unbalanced datasets. Our simulations demonstrate that GEE should be estimated by assigning each individual to a cluster when at least 30 animals are followed, or by using destructive sampling for studies with fewer individuals having intermediate level of behavioural plasticity in selection and temporally autocorrelated observations. The simulations provide valuable information to build reliable habitat selection and movement models that allow for robustness of statistical inference without removing excessive amounts of ecological information. PMID- 28081573 TI - [Prostate Carcinoma Mimics Lung Carcinoma: A Case Report]. AB - A PSA-negative, advanced adenocarcinoma of the prostate is a rare finding. Expression of thyroid transcription factor-1 (TTF-1) in the tumour in combination with a previous medical history of lung adenocarcinoma could complicate the final diagnosis. To the best of our knowledge, we present the second case of a TTF-1 positive, acinar adenocarcinoma of the prostate.We present the case of a 65-year old male with surgically treated lung adenocarcinoma; 3 years later we diagnosed adenocarcinoma of the bladder and prostate. Although our initial assumption was that the patient had metastatic lung carcinoma in the bladder and prostate, a further immune histochemical analysis of the carcinoma with Napsin A, CK7 and CK20, along with the evaluation of the clinical manifestations, led us to the diagnosis of primary adenocarcinoma of the prostate. PMID- 28081572 TI - Exposed Dentin: Influence of Cleaning Procedures and Simulated Pulpal Pressure on Bond Strength of a Universal Adhesive System. AB - PURPOSE: To compare various pre-treatments serving as cleaning procedures of dentin on the bond strength of resin composite promoted by a universal adhesive system applied either in the absence or presence of simulated pulpal pressure. MATERIALS AND METHODS: Prior to application of the adhesive system (Scotchbond Universal) and resin composite (Filtek Z250), ground dentin surfaces were given one of five pre-treatments either without or with simulated pulpal pressure: 1) no pre-treatment, adhesive system in "self-etch" mode, 2) phosphoric acid etching, adhesive system in "total-etch" mode, 3) polishing with pumice on prophylaxis cup, 4) air abrasion with AIR-FLOW PLUS powder, 5) air abrasion with AIR-FLOW PERIO powder; n = 20/group of pre-treatment. After storage (37 degrees C, 100% humidity, 24 h), micro shear bond strength was measured and data analyzed with parametric ANOVA including Bonferroni-Holm correction for multiple testing followed by Student's t tests (significance level: alpha = 0.05). RESULTS: The ANOVA found type of pre-treatment and simulated pulpal pressure to have no significant effect on dentin bond strength. The explorative post-hoc tests showed a negative effect of simulated pulpal pressure for phosphoric acid etching (adhesive system in "total-etch" mode; p = 0.020), but not for the other four pre treatments (all p = 1.000). CONCLUSION: Air abrasion with powders containing either erythritol and chlorhexidine (AIR-FLOW PLUS) or glycine (AIR-FLOW PERIO) yielded dentin bond strengths similar to no pre-treatment, phosphoric acid etching, or polishing with pumice. Simulated pulpal pressure reduced the bond strength only when the self-etch adhesive system was used in total-etch mode. PMID- 28081574 TI - GSTP1 and CYP2B6 Genetic Polymorphisms and the Risk of Bronchopulmonary Dysplasia in Preterm Neonates. AB - Objectives Antioxidant response plays a key role in bronchopulmonary dysplasia (BPD) pathogenesis. The glutathione-S-tranferases pi 1 (GSTP1) and cytochrome P450 (CYP) detoxification enzymes protect cells from oxidative damage. The aim of the study was to investigate whether the A313G GSTP1 and G516T CYP2B6 inactivating polymorphisms could be associated with BPD susceptibility. Study Design To test this hypothesis, we conducted a case-control study enrolled 138 premature neonates <=32 weeks of gestational age; of the 138, 46 developed BPD and 92 did not develop BPD. Genomic deoxyribonucleic acid was extracted from neonates' peripheral blood and was used as template for GSTP1 and CYP2B6 genotyping using the real-time polymerase chain reaction method. Results Our report provides evidence for a possible pathogenetic role of the G516T CYP2B6 polymorphism in BPD susceptibility. Although no differences in the frequencies of the GSTP1 variant genotypes were noticed between premature neonates who developed BPD and neonates who did not develop BPD, a significantly higher frequency of the GSTP1 polymorphism was observed in extremely low birth weight infants. Despite the small sample size, it is very interesting the fact that all neonates <=1,000 g carrying the homozygous mutant GSTP1 genotype developed BPD. Conclusion Our results underscore the significance of both CYP2B6 and GSTP1 polymorphisms in modulating the risk of BPD. PMID- 28081575 TI - What Arthroscopic Skills Need to Be Trained Before Continuing Safe Training in the Operating Room? AB - The purpose of this study was to generate consensus among experienced surgeons on "what skills a resident should possess before continuing safe training in the operating room (OR)." An online survey of 65 questions was developed and distributed to surgeons in the European community. A total of 216 responded. The survey included 15 questions regarding generic and specific skills; 16 on patient and tissue manipulation, 11 on knowledge of pathology and 6 on inspection of e anatomical structures; 5 methods to prepare residents; and 12 on specific skills exercises. The importance of each question (arthroscopic skill) was evaluated ranging from 1 (not important at all) to 6 (very important). Chi-square test, respondent agreement, and a qualitative ranking method were determined to identify the top ranked skills (p < 0.05). The top four of general skills considered important were "anatomical knowledge," "tissue manipulation," "spatial perception," and "triangulation" (all chi-square test > 134, p < 0.001, all excellent agreement > 0.85, and all "high priority" level). The top ranked 2 specific arthroscopic skills were "portal placement" and "triangulating the tip of the probe with a 30-degree scope" (chi-square test > 176, p < 0.001, excellent agreement, and assigned high priority). The online survey identified consensus on skills that are considered important for a trainee to possess before continuing training in the OR. Compared with the Canadian colleagues, the European arthroscopy community demonstrated similar ranking. PMID- 28081576 TI - The Clinical Characteristics of Obese Patients with Acanthosis Nigricans and Its Independent Risk Factors. AB - Objective: This study aimed to investigate the clinical characteristics and risk factors for acanthosis nigricans (AN) in obese patients. Methods: 80 obese patients without AN (OB group) and 128 obese patients with AN (AN group) were included in this study. Clinical data for each patients were collected. Serum levels of leptin were measured by ELISA. Results: Body mass index (BMI), uric acid (UA) levels, fasting insulin, and HOMA-IR were higher in AN than OB (P<0.05). The levels of leptin were significantly higher in AN than OB (P<0.001) after adjustment for BMI and gender. In male patients, AN showed lower serum levels of testosterone than OB (P<0.001). Multiple Logistic-regression analysis demonstrated that UA (OR 4.627, 95%CI 2.443-8.762, P<0.001) and Leptin (OR 4.098, 95%CI 1.237-13.581, P=0.021) were independent risk factors for AN. In addition, low testosterone level was an independent risk factor for AN in male obese patients (OR 39.062, 95%CI 5.523-283.808, P<0.001). Conclusions: AN is associated with more severe hyperinsulinemia and hyperuricemia in obese patients, as well as lower serum testosterone levels in male patients. UA and Leptin were independent risk factors for AN in obese patients. Low testosterone may be a valuable predictor of AN in male obese patients. PMID- 28081577 TI - Can HbA1c be Used to Screen for Glucose Abnormalities Among Adults with Severe Mental Illness? AB - Aim: Prediabetes and type 2 diabetes are highly prevalent among individuals with serious mental illness and increased by antipsychotic medication. Although widely recommended, many obstacles prevent these patients from obtaining a proper screening for dysglycemia. Currently, glycated hemoglobin (HbA1c), fasting glucose, and 2-hour glucose levels from the oral glucose tolerance test are used for screening prediabetes and type 2 diabetes. The objective of this study was to investigate if HbA1c could be used as the only screening test among individuals with serious mental illness. Methods: Cross sectional study comparing the sensitivity of HbA1c, fasting glucose, and 2-h oral glucose tolerance test to detect dysglycemias in serious mental illness participants referred for metabolic complications. Results: A total of 84 participants (43 female; aged: 38.5+/-12.8 years; BMI: 35.0+/-6.8 kg/m2) was included. Regarding prediabetes, 44, 44 and 76% were identified by HbA1c, fasting glucose, and 2 h- oral glucose tolerance test respectively and for type 2 diabetes, 60, 53 and 66% were identified by HbA1c, fasting glucose and 2 h-oral glucose tolerance test. The overlap between the 3 markers was low (8% of participants for prediabetes and 26% for Type 2 diabetes). Sensitivity of HbA1c were moderate (range 40-62.5%), while its specificity was excellent (92-93%). Conclusion: The present study indicates a low agreement between HbA1c, fasting glucose and 2-h oral glucose tolerance test. It appears that these markers do not identify the same participants. Thus, HbA1c may not be used alone to detect all glucose abnormalities among individuals with serious mental illness. PMID- 28081578 TI - Birth Prevalence of Anorectal Malformations for the Western Cape Province, South Africa, 2005 to 2012. AB - Introduction Anorectal malformations (ARMs) are a major birth anomaly worldwide. South Africa has ethnically and geologically diverse populations. A recent publication indicated an increased birth prevalence of ARMs in the Witwatersrand referral area between 2005 and 2010. The purpose of this study was to determine the birth prevalence of ARM and its various subtypes in the Western Cape referral district over an 8-year period. Methods For an 8-year period from January 1, 2005, to December 31, 2012; retrospective data were collected from the Pediatric Surgical Departments of Red Cross War Memorial Children's Hospital, Tygerberg Children's Hospital, as well as the private sector health registries. The number of live births per year for a specific municipal district was obtained from the National Department of Health. The chi-square for trend test was used to determine statistical significance. Results The birth prevalence for ARM in the Western Cape Province (WCP) in 2012 was shown to be 1:5,572 live births (1.79/10,000 live births). The West Coast municipality district had the highest average birth prevalence rate of 1:3,063 (3.26/10,000) live births for years studied. There was a male predominance (1.6:1), the most common ARM was the vestibular fistula (19.2%) and in 26% of the patients, there was an initial delay in the diagnosis. Conclusion This study has provided some recent data for ARMs for the WCP. There was no statistical significant change in the prevalence of ARMs over the 8-year period for the WCP as well as in any of the individual six municipal health districts (chi2 for trend, p = 0.52). The number of delayed diagnosis of ARM is of concern. PMID- 28081579 TI - Predicting Full Enteral Feeding in the Postoperative Period in Infants with Congenital Diaphragmatic Hernia. AB - Introduction The objective of the study is to examine the factors associated with time to achieve full enteral feeding after repair of congenital diaphragmatic hernia. Materials and Methods Demographic, clinical, and therapeutic data were retrospectively assessed, and uni- and multivariate Cox regression were performed to examine factors predictive of achieving full enteral feeding that was defined as time to achieve120 mL/kg/d after surgical repair. Results Of 78 infants, 66 underwent intervention before hospital discharge. All infants who survived had reached full enteral feeding at the time of hospital discharge by a median of 22 days (range: 2-119 days) after surgery and 10 days (range: 1-91) after initiation of postoperative enteral feedings. Independent risk factors associated with a longer time to reach full enteral feeding achievement included gastroesophageal reflux and days of antibiotics in the postoperative period. Daily stool passage preoperatively predicted earlier enteral tolerance. Conclusion Infants who survive congenital diaphragmatic hernia generally are able to achieve full enteral feedings after surgical repair. A longer time to full feeding is needed in the most severe cases, but some specific characteristics can be used to help identify patients at higher risk. Although some of these characteristics are unavoidable, others including rational antibiotic usage and active gastroesophageal reflux prevention and treatment are feasible and may improve enteral tolerance. PMID- 28081580 TI - Biosynthetic Studies on Acetosellin and Structure Elucidation of a New Acetosellin Derivative. AB - Natural products from fungi, especially Ascomycota, play a major role in therapy and drug discovery. Fungal strains originating from marine habitats offer a new avenue for finding unusual molecular skeletons. Here, the marine-derived fungus Epicoccum nigrum (strain 749) was found to produce the azaphilonoid compounds acetosellin and 5',6'-dihydroxyacetosellin. The latter is a new natural product. The biosynthesis of these polyketide-type compounds is intriguing, since two polyketide chains are assembled to the final product. Here we performed 13C labeling studies on solid cultures to prove this hypothesis for acetosellin biosynthesis. PMID- 28081581 TI - Differences in Gene Expression and Gene Associations in Epicardial Fat Compared to Subcutaneous Fat. AB - Epicardial adipose tissue (EAT) plays a role in cardiac physiology and may contribute to the development of coronary artery disease. Our objective was to determine whether there was a significant difference in gene expression in EAT compared to subcutaneous adipose tissue (SAT) and to identify potential relationships. MEDLINE and EMBASE were searched using the key terms "Epicardial Adipose Tissue" or "Epicardial Fat" in combination with "RNA", "mRNA", or "gene". The entry criteria were studies that presented primary data including expression levels of mRNA in human EAT compared with SAT and an expression of variance (SD). Genes identified by 2 or more studies were evaluated. Genes that showed significant change in expression between EAT and SAT were examined using the Gene Functional Classification analytical tool in Database for Annotation, Visualization and Integrated Discovery and cross-validated by ToppGene. Seventeen genes were identified from 25 studies. Meta-analysis showed that 10 genes (ADORA1, adiponectin, AGT, ADM, CATA, IL-1beta, MCP-1, RBP-4, TNF-alpha, UCP-1) were significantly different in EAT. Gene Functional Classification analysis yielded 23 clusters with significant relationships. The top clusters were focused on responses to glucocorticoid stimulus, regulation of apoptosis, cellular ion homeostasis, and responses to hormone stimulus. Genetic analysis shows that EAT is discretely different from SAT. ADORA1, adiponectin, AGT, ADM, CATA, IL-1beta, MCP-1, RBP-4, TNF-alpha, and UCP-1 may play significant roles in the unique physiology of EAT and/or its role in pathophysiology, through mechanisms as diverse as steroid hormone responses and regulation of apoptosis. PMID- 28081582 TI - [Expert Evidence in Whiplash Injury]. AB - The assessment of cervical spine injuries is not a problem - provided full evidence of primary physical damage can be ensured. MRI examinations of the cervical spine carried out soon after the accident provide the best evidence. The assessment is more difficult if only clinical abnormalities are documented by the doctors after the accident in the diagnosis of cervical spine distortion, as functional results of this type are not specific and are also common in the general population. The legal rules of evidence must be taken into account in the summary assessment of the consequences of cervical spine injuries. Testing schemes are available which allow structured assessment of cervical spine injuries and help to avoid incorrect assessments. PMID- 28081583 TI - [Early Results of Adjuvant Topical Treatment of Recurrent Osteomyelitis with Absorbable Antibiotic Carriers]. AB - Background Treatment of musculoskeletal infections principally consists of radical surgical debridement and systemic administration of antibiotics. Additional local antibiotic therapy is not yet generally established, and lacks evidence-based proof of efficacy. Nonetheless, there are a variety of practical approaches, as most specialised departments are unwilling to forego this option. The established polymethylmetacrylate (PMMA) carrier system has a number of practical disadvantages. This has led to the increased use of absorbable carrier systems, and those based on calcium sulphate have given particularly encouraging results. In this article, we present our experience with this procedure in the treatment of osteomyelitis. There is currently no standard procedure or algorithm for the use of local antibiotic carriers in the treatment of recurrent osteomyelitis. Material and Methods Between February 2014 and May 2015, a total of 93 patients were treated with an absorbable carrier of topical antibiotics based on calcium sulphate. These patients had suffered from a recurrence of osteomyelitis that had been unsuccessfully treated by the primary implantation of a PMMA chain and systemic antibiotics. The treatment algorithm consisted of radical debridement, followed by implantation of a commercial PMMA chain. If no remission of the infection was observed, the chains were surgically removed and replaced with an absorbable carrier system and antibiotics chosen in accordance with the resistogram. Pursuant to the classification of Cierny and Mader, 10 patients were classified as type I, 5 as type II, 55 as type III and 23 as type IV. The mean follow-up period was 11 months. Two carrier systems, Osteoset(r) and Herafill(r), were purchased from Wright Medical Technology Inc., Arlington, TN, USA and Heraeus Medical GmbH, Wehrheim, Germany, respectively. These were used as supplied for tobramycin and gentamycin. In the case of Osteoset, it was also possible to add an additional arbitrary, water-soluble antibiotic. Systemic administration of antibiotics was carried out in parallel in accordance with the resistogram. Results The most common clinical entities were femoral (36 %) and tibial (29 %) osteitis. Vancomycin (38 %) and tobramycin (38 %) were the most frequently used topical antibiotics, followed by gentamycin (17 %), ceftriaxone (4 %), fosfomycin (2 %) and colistin (1 %). Systemic administration of antibiotics was carried out in parallel, in accordance with the resistogram. In 85 % of all patients, remission was achieved. Infections with methicillin resistant Staphylococcus aureus (MRSA; 62 %) and Pseudomonas aeruginosa (43 %) showed significantly poorer remission rates. The bacterial spectrum was primarily composed of Staphylococcus aureus (28 %), Staphylococcus epidermidis (22 %), Pseudomonas aeruginosa (7 %) and Enterococcus faecalis (5 %), as well as Escherichia coli and Klebsiella oxytoca (4 %). Conclusion Topical adjuvant antibiotic therapy based on an absorbable carrier system offers an expedient extension of the treatment of osteomyelitis. The remission rate of 85 % for recurrent infections encouraged the use of a therapeutic alternative for many patients. We developed an algorithm for the treatment of osteomyelitis, which includes the application of local antibiotics with different compositions and absorbable carriers. We present early results of successful treatment of patients with recurrent osteomyelitis, after futile topical therapy with non-absorbable antibiotic chains. PMID- 28081584 TI - [Mini-open Approach Shows Good Results in Treatment of Femoroacetabular Impingement]. AB - Background Femoroacetabular impingement (FAI) describes a painful, abnormal (bony) contact between the femoral neck and acetabulum, which, if left untreated, contributes to early osteoarthritis (OA) of the hip. Despite its flat learning curve and long operation times, hip arthroscopy has been used increasingly often in recent years in the surgery of femoroacetabular impingement. The mini-open technique (MOT) offers a possible alternative that addresses the abnormal morphological prominence and allows minimally invasive clearance of hip motion. There is still a lack of information on the influence of the greater degree of soft tissue intrusion inherent to the mini-open approach. Therefore we decided to evaluate the medium-term outcome of the mini-open technique and to compare the results to those of the arthroscopic technique reported in the literature. Patients, Material und Methods 99 patients (105 hips, 40 women, 59 men) underwent mini-open surgical treatment for FAI between 2005 and 2012 and were followed-up for an average of 40.5 months. The evaluation focused on the pre- and postoperative pain intensity (NRS: numeric rating scale), the clinical and functional outcomes such as ROM (range of motion), HOS (Hip Outcome Score) and mHHS (modified Harris Hip Score), changes in athletic behaviour and the satisfaction of the patients. Radiological analysis (alpha-angle, anterior head neck-offset (HNO), head-neck-offset ratio, ossification, grade of OA) was performed using preoperative, immediate postoperative as well as follow-up radiographs. Finally our results were compared to those reported for the arthroscopic technique in the literature. Results The average pain level decreased from 6.5 +/- 2.3 to 2.3 +/- 2.6 (p < 0.001). 80 % (84) confirmed a mean postoperative pain-free period of 29.5 months (2-103 months), and 52.4 % (55) were still almost pain-free by the time of the final follow-up. The mHHS increased from 68.2 +/- 13.5 to 85.2 +/- 18.2 (p < 0.001). The HOS-ADL (ADL: activities of daily life) was 82.2 % +/- 19.7 and the HOS-sport was 69.7 % +/- 27.9 at the final follow-up. At the time of the last follow-up, 93 % of the preoperatively active patients (n = 84) returned to athletic activities (n = 78). In a comparison of athletic behaviour, significantly fewer patients were performing high-impact and more patients were performing low-impact sports after surgery. Flexion (113 degrees +/-16 to 117 degrees +/-16) and internal rotation (12 degrees +/-8 to 25 degrees +/-12) improved significantly. alpha-angle reduction from 62 degrees +/-11 to 42 degrees +/- 9 (p < 0.01) was observed. The HNO increased from 3.8 mm +/- 3.2 to 10.7 mm +/- 3.2. In 17.6 % of the cases, progression of OA was noticed. Patients with initial OA Kellgren >= 2 showed significantly worse outcome than those without OA. Conclusion MOT is a safe and effective alternative for treating FAI. It leads to recovery of pain-free hip function in short- and medium-term follow-up and allows a return to practicing sports in most cases. Patients with preoperative OA >= 2 seem to experience insufficient gains from MO surgery, so surgeons should be reluctant to apply the technique under these circumstances. PMID- 28081585 TI - Drug-eluting stent placement versus coronary artery bypass surgery for unprotected left main coronary artery disease: A meta-analysis of randomized controlled trials. AB - BACKGROUND: Coronary artery bypass grafting (CABG) is the standard of care for treating left main coronary lesions. However, recently published randomized controlled trials (RCT) have shown conflicting results. We sought to compare clinical outcomes of percutaneous coronary intervention (PCI) with drug-eluting stent placement to CABG using a meta-analysis of randomized controlled trials. METHODS: A systemic search of Pubmed, Scopus, Cochrane library, and Clinicaltrials.gov was performed for randomized controlled trials comparing PCI with CABG in patients with left main stenosis. Data were analyzed using random effect models and Mantel-Haenszel methods. The primary outcome was major adverse cardiovascular and cerebral events (MACCE). The secondary outcomes were myocardial infarction, stroke, cardiac, and all-cause mortality. A subgroup analysis based on SYNTAX score was also performed. RESULTS: A total of 4595 patients (2297 in the PCI group and 2298 in the CABG group) from five RCTs were included in the analysis. There were significant differences in MACCE (odds ratio [OR] 1.36, confidence interval [CI] 95%, 1.18-1.58, p-value: < 0.0001) and repeat revascularization (OR 1.85, CI 95%, 1.53-2.23, p-value: < 0.00001) favoring CABG. There were no significant differences in the incidence of myocardial infarction, stroke, or cardiac and all-cause mortality. Based on SYNTAX score, CABG was superior in terms of MACCE only in the subgroup with SYNTAX score of 33 or more. CONCLUSIONS: CABG results in fewer MACCE and need for repeat revascularization than PCI in patients with unprotected left main disease. PMID- 28081586 TI - A case of levocetirizine-induced liver injury. AB - Levocetirizine is a second-generation nonsedative antihistaminic agent that has been demonstrated to be safe and effective for treating allergic disease. There was only one case report of levocetirizine-induced liver toxicity, but a liver biopsy was not performed. In this article, we present the first case of levocetirizine-induced liver injury with histologic findings. A 48-year-old man was hospitalized with jaundice and generalized pruritus that had developed after 2 months of therapy with levocetirizine for prurigo nodularis. Laboratory findings revealed acute hepatitis with cholestasis. A liver biopsy demonstrated portal inflammation and hepatitis with apoptotic hepatocytes. The patient fully recovered 3 weeks after withdrawing levocetirizine. Although levocetirizine is safe and effective, physicians should be aware of its potential hepatotoxicity. PMID- 28081587 TI - Clinical significance and predictive factors of early massive recurrence after radiofrequency ablation in patients with a single small hepatocellular carcinoma. AB - BACKGROUND/AIMS: Radiofrequency ablation (RFA) is one of the most frequently applied curative treatments in patients with a single small hepatocellular carcinoma (HCC). However, the clinical significance of and risk factors for early massive recurrence after RFA-a dreadful event limiting further curative treatment have not been fully evaluated. METHODS: In total, 438 patients with a single HCC of size <=3 cm who underwent percutaneous RFA as an initial treatment between 2006 and 2009 were included. Baseline patient characteristics, overall survival, predictive factors, and recurrence after RFA were evaluated. In addition, the incidence, impact on survival, and predictive factors of early massive recurrence, and initial recurrence beyond the Milan criteria within 2 years were also investigated. RESULTS: During the median follow-up of 68.4 months, recurrent HCC was confirmed in 302 (68.9%) patients, with early massive recurrence in 27 patients (6.2%). The 1-, 3-, and 5-year overall survival rates were 95.4%, 84.7%, and 81.8%, respectively, in patients with no recurrence, 99.6%, 86.4%, and 70.1% in patients with recurrence within the Milan criteria or late recurrence, and 92.6%, 46.5%, and 0.05% in patients with early massive recurrence. Multivariable analysis identified older age, Child-Pugh score B or C, and early massive recurrence as predictive of poor overall survival. A tumor size of >=2 cm and tumor location adjacent to the colon were independent risk factors predictive of early massive recurrence. CONCLUSION: Early massive recurrence is independently predictive of poor overall survival after RFA in patients with a single small HCC. Tumors sized >=2 cm and located adjacent to the colon appear to be independent risk factors for early massive recurrence. PMID- 28081588 TI - Cyanoacrylate injection versus band ligation for bleeding from cardiac varices along the lesser curvature of the stomach. AB - BACKGROUND/AIMS: Practice guidelines recommend endoscopic band ligation (EBL) and endoscopic variceal obturation (EVO) for bleeding from esophageal varices and fundal varices, respectively. However, the optimal treatment for bleeding from cardiac varices along the lesser curvature of the stomach (GOV1) remains undefined. This retrospective study compared the efficacy between EBL and EVO for bleeding from GOV1. METHODS: Patients treated by EBL or EVO via cyanoacrylate injection for bleeding from GOV1 were enrolled. Patients diagnosed with hepatocellular carcinoma or treated with endoscopic injection sclerotherapy were excluded. RESULTS: The study included 91 patients treated for bleeding from GOV1. The mean age was 56.3+/-10.9 years (mean+/-SD), and 78 of them (85.7%) were men. Overall, 51 and 40 patients were treated with EBL and EVO, respectively. A trend for a higher hemostasis rate was noted in the EVO group (100%) than in the EBL group (82.6%, P=0.078). Varices rebled in 15 patients during follow-up. The rebleeding rate was significantly higher in the EBL group than in the EVO group (P=0.004). During follow-up, 13 patients died (11 in the EBL group and 2 in the EVO group); the survival rate was marginally significant between two groups (P=0.050). The rebleeding-free survival rate was significantly higher in the EVO group than in the EBL group (P=0.001). CONCLUSION: Compared to EBL, EVO offered significantly lower rebleeding rates, significantly higher rebleeding-free survival rates, and a trend for higher hemostasis and survival rates. EVO appears to be the better therapeutic option for bleeding from GOV1. PMID- 28081589 TI - Preemptive antiviral therapy with entecavir can reduce acute deterioration of hepatic function following transarterial chemoembolization. AB - BACKGROUND/AIMS: Hepatic damage during transarterial chemoembolization (TACE) is a critical complication in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Apart from its role in preventing HBV reactivation, there is some evidence for the benefits of preemptive antiviral therapy in TACE. This study evaluated the effect of preemptive antiviral therapy on acute hepatic deterioration following TACE. METHODS: This retrospective observational study included a prospectively collected cohort of 108 patients with HBV-related HCC who underwent TACE between January 2007 and January 2013. Acute hepatic deterioration following TACE was evaluated. Treatment-related hepatic decompensation was defined as newly developed encephalopathy, ascites, variceal bleeding, elevation of the bilirubin level, prolongation of prothrombin time, or elevation of the Child-Pugh score by >=2 within 2 weeks following TACE. Univariate and multivariate analyses were conducted to identify factors influencing treatment-related decompensation. Preemptive antiviral therapy involves directing prophylaxis only toward high-risk chronic hepatitis B patients in an attempt to prevent the progression of liver disease. We regarded at least 6 months as a significant duration of preemptive antiviral treatment before diagnosis of HCC. RESULTS: Of the 108 patients, 30 (27.8%) patients received preemptive antiviral therapy. Treatment-related decompensation was observed in 25 (23.1%) patients during the follow-up period. Treatment-related decompensation following TACE was observed more frequently in the nonpreemptive group than in the preemptive group (29.5% vs. 6.7%, P=0.008). In the multivariate analysis, higher serum total bilirubin (Hazard ratio [HR] =3.425, P=0.013), hypoalbuminemia (HR=3.990, P=0.015), and absence of antiviral therapy (HR=7.597, P=0.006) were significantly associated with treatment-related hepatic decompensation. CONCLUSION: Our findings suggest that preemptive antiviral therapy significantly reduces the risk of acute hepatic deterioration. Preventing hepatic deterioration during TACE by applying such a preemptive approach may facilitate the continuation of anticancer therapy and thus improve long-term outcomes. PMID- 28081590 TI - Emergency endoscopic variceal ligation in cirrhotic patients with blood clots in the stomach but no active bleeding or stigmata increases the risk of rebleeding. AB - BACKGROUND/AIMS: This study aimed to evaluate the efficacy and safety of emergency variceal ligation for the prevention of rebleeding in cirrhotic patients who are found on initial endoscopy to have blood clots in the stomach but no actively bleeding esophageal and gastric varices or stigmata. METHODS: This study included 28 cirrhotic patients who underwent emergency prophylactic EVL and 41 who underwent an elective intervention between January 2009 and June 2014. Clinical outcomes were analyzed, including the rebleeding, 6-week mortality, and rebleeding-free survival rates. RESULTS: The rebleeding rate was higher in the emergency than in the elective group (28.6% vs. 7.3%, P=0.041). Multivariate analysis showed that emergency prophylactic EVL (odds ratio [OR] = 7.4, 95% confidence interval [CI]=1.634.8, P=0.012) and Child-Pugh score C (OR=10.6, 95% CI=1.4-80.8, P=0.022) were associated with rebleeding. In the emergency group, the gastric varices were associated with rebleeding (OR=12.0, 95% CI=1.7-83.5, P=0.012). CONCLUSION: Emergency EVL may be associated with variceal rebleeding when blood clots are present in the stomach without active esophageal and gastric variceal bleeding or stigmata. Elective intervention should be considered as a safer strategy for preventing variceal rebleeding in this situation. PMID- 28081592 TI - Primary adenosquamous carcinoma of the liver: a case report. AB - Adenosquamous carcinoma of the liver is a rare variant of cholangiocarcinoma. It is known to be a highly aggressive tumor with a poor prognosis, but its pathogenesis remains unclear owing to limited data in the literature. We report a case of 56-year-old woman who presented with a 1-week history of epigastric pain. Magnetic resonance imaging revealed a 6.5-cm ill-defined mass with low signal intensity in the left lobe of the liver, which was suspicious of cholangiocarcinoma. The patient underwent left hemihepatectomy. Microscopically, the tumor consisted of malignant glandular and squamous components and staged as pT2aN1. Despite postoperative chemoradiation, the patient had recurrence 8 months after surgery. PMID- 28081591 TI - New perspectives of biomarkers for the management of chronic hepatitis B. AB - With recent advances in molecular and genomic investigations, the impact of hepatitis B viral and host factors on the progression of chronic HBV infection has been explored. For viral factors, hepatitis B viral load is a strong predictor for liver disease progression. Hepatitis B viral kinetics appear to be important for successful anti-viral therapy. Serum HBsAg level serves as a complementary marker to viral load for the prediction of HBV-related adverse outcomes in patients with low viral load. In those with low viral load, high serum HBsAg level is associated with higher risks of cirrhosis and HCC. Hepatitis B core-related antigen (HBcrAg) induces host immune responses, and the reduction of the HBcrAg level as well as the increment of total anti-HBc level are significantly associated with favorable outcomes. HBV genotypes (genotype C/D) and mutants (basal core promoter and deletion mutation in pre-S genes) are well known viral genetic markers to predict disease progression. For host factors, serum inflammatory biomarkers have been developed to evaluate the HBV-associated hepatic necroinflammation and fibrosis. Host single nucleotide polymorphism on sodium taurocholate cotransporting polypeptide (NTCP, an HBV entry receptor) may be associated with a decreased risk for cirrhosis and HCC. In conclusion, patients with chronic hepatitis B should be evaluated with relevant viral and host markers to identify those who are at a higher risk of liver disease progression and then receive timely antiviral therapy. PMID- 28081593 TI - Percutaneous cryoablation for hepatocellular carcinoma. AB - Local ablation therapy is considered as a conventional treatment option for patients with early stage hepatocellular carcinoma (HCC). Although radiofrequency (RF) ablation is widely used for HCC, the use of cryoablation has been increasing as newer and safer cryoablation systems have developed. The thermodynamic mechanism of freezing and thawing used in cryoablation is the Joule-Thomson effect. Cryoablation destroys tissue via direct tissue destruction and vascular related injury. A few recent comparative studies have shown that percutaneous cryoablation for HCCs is comparable to percutaneous RF ablation in terms of long term therapeutic outcomes and complications. Cryoablation has several advantages over RF ablation such as well visualization of iceball, no causation of severe pain, and lack of severe damage to great vessels and gallbladder. It is important to know the advantages and disadvantages of cryoablation compared with RF ablation for improvement of therapeutic efficacy and safety. PMID- 28081595 TI - Switch to tenofovir-based therapy or to continue adefovir-based therapy in CHB patients with suboptimal response to adefovir-based combination? PMID- 28081594 TI - Management of direct antiviral agent failures. AB - The current standard of care for patients with chronic hepatitis C virus (HCV) infection is a combination of direct-acting antiviral agents (DAAs). Most HCV patients treated with these drugs achieve viral elimination, but 1% to 15% fail to attain this objective. Treatment failures are usually related to relapse, and less often to on-treatment viral breakthrough. HCV drug resistant associated substitutions are detected in most patients who do not eliminate the virus. The risk of developing these variants depends on host- and virus-related factors, the properties of the drugs used, and the treatment strategies applied. Patients who carry Resistant Associated Substitutions (RASs) may not obtain benefits from treatment, and are at a risk of disease progression. Whether HCV RASs persist depends on their type: NS3-4A variants often disappear gradually after DAA therapy is stopped, whereas NS5A variants tend to persist for more than 2 years. The best way to prevent emergence of resistant variants is to eliminate the virus at the first treatment using highly potent DAAs with genetic barriers to resistance. For those who fail an NS5A inhibitor, deferral of treatment is recommended pending the availability of additional data if they do not have cirrhosis or reasons for urgent re-treatment. If re-treatment is needed, the most commonly used strategy is sofosbuvir as backbone therapy plus a drug from a class other than that previously used, for 24 weeks. Unless it is contraindicated, weight-based ribavirin should also be added. If available, nucleotide-based (eg, sofosbuvir) triple or quadruple DAA regimens may be considered. The optimal treatment for patients who fail an NS5A inhibitor and those with multidrug resistant variants remains to be defined, and research efforts should continue to focus on treatment for these patients. PMID- 28081596 TI - Synthesis and Modular Reactivity of Pyrazole 5-Trifluoroborates: Intermediates for the Preparation of Fully Functionalized Pyrazoles. AB - The regioselective condensation of hydrazines and ynone trifluoroborates provides access to a range of pyrazole 5-trifluoroborates. The stability of the borate unit allows chemoselective halogenation of the heteroaromatic ring, thereby delivering pyrazole scaffolds that allow orthogonal functionalization at C5 and C4. The modular reactivity of these intermediates is exemplified by cross coupling reactions, enabling regiocontrolled synthesis of fully functionalized pyrazole derivatives. PMID- 28081597 TI - New Wide Band Gap Donor for Efficient Fullerene-Free All-Small-Molecule Organic Solar Cells. AB - A new organic small molecule, DRTB-T, that incorporates a two-dimensional trialkylthienyl-substituted benzodithiophene core building block was designed and synthesized. DRTB-T has a band gap (Egopt) of 2.0 eV with a low-lying highest occupied molecular orbital (HOMO) level of -5.51 eV. Nonfullerene small-molecule solar cells consisting of DRTB-T and a nonfullerene acceptor (IC-C6IDT-IC) were constructed, and the morphology of the active layer was fine-tuned by solvent vapor annealing (SVA). The device showed a record 9.08% power conversion efficiency (PCE) with a high open-circuit voltage (Voc = 0.98 V). This is the highest PCE for a nonfullerene small-molecule organic solar cell (NFSM-OSC) reported to date. Our notable results demonstrate that the molecular design of a wide band gap (WBG) donor to create a well-matched donor-acceptor pair with a low band gap (LBG) nonfullerene small-molecule acceptor, as well as subtle morphological control, provides great potential to realize high-performance NFSM OSCs. PMID- 28081598 TI - An AlGaN Core-Shell Tunnel Junction Nanowire Light-Emitting Diode Operating in the Ultraviolet-C Band. AB - To date, semiconductor light emitting diodes (LEDs) operating in the deep ultraviolet (UV) spectral range exhibit very low efficiency due to the presence of large densities of defects and extremely inefficient p-type conduction of conventional AlGaN quantum well heterostructures. We have demonstrated that such critical issues can be potentially addressed by using nearly defect-free AlGaN tunnel junction core-shell nanowire heterostructures. The core-shell nanowire arrays exhibit high photoluminescence efficiency (~80%) in the UV-C band at room temperature. With the incorporation of an epitaxial Al tunnel junction, the p (Al)GaN contact-free nanowire deep UV LEDs showed nearly one order of magnitude reduction in the device resistance, compared to the conventional nanowire p-i-n device. The unpackaged Al tunnel junction deep UV LEDs exhibit an output power >8 mW and a peak external quantum efficiency ~0.4%, which are nearly one to two orders of magnitude higher than previously reported AlGaN nanowire devices. Detailed studies further suggest that the maximum achievable efficiency is limited by electron overflow and poor light extraction efficiency due to the TM polarized emission. PMID- 28081599 TI - Core-Shell Metal-Organic Frameworks/Molecularly Imprinted Nanoparticles as Absorbents for the Detection of Pyrraline in Milk and Milk Powder. AB - A novel core-shell metal-organic framework coated with a dummy template molecularly imprinted polymer (MOF@DMIP) was synthesized by one-pot bulk polymerization for the detection of pyrraline in food samples. The pyrraline analogue pyrrolidine-3-carboxylic acid was used as the template because of its lower cost, and MIL-101 was used as the MOF core owing to its numerous inherent advantages, including high chemical and hydrothermal stabilities. MIL-101@DMIP was used to detect trace pyrraline in foods by solid-phase extraction combined with high-performance liquid chromatography. It exhibited the advantages of faster mass transport, excellent sensitivity, and selectivity. Under optimum conditions, the detection limit of this system was 40.7 MUg L-1, and a linear range was from 5 * 10-7 to 2 * 10-3 mol L-1, within relative standard deviations of 4.46-6.87%. The recoveries ranged from 92.23 to 103.87%, indicating the excellent ability of the prepared MIL-101@DMIP to recognize pyrraline in complex food matrices and its potential for application in pyrraline detection. PMID- 28081600 TI - Isogarcinol Extracted from Garcinia mangostana L. Ameliorates Imiquimod-Induced Psoriasis-like Skin Lesions in Mice. AB - Isogarcinol (YDIS), a natural compound extracted from Garcinia mangostana L., has a significant immunosuppressive effect on systemic lupus erythematosus and rheumatoid arthritis. This paper reports that it reduced imiquimod-induced psoriasis-like skin lesions in mice. It strongly attenuated the aberrant proliferation and differentiation of keratinocytes. Moreover, the expression of genes involving the interleukin-23 (IL-23)/T-helper 17 (Th17) axis was significantly inhibited in the dorsal skin of the YDIS-treated mice, as was that of the other pro-inflammatory factors TNF-alpha, IL-2, and even interferon (IFN) gamma. Furthermore, YDIS prevented the abnormal distribution of T cell types and suppressed the differentiation of CD4+ T cells into Th17 cells in the spleens of mice exposed to imiquimod. Interestingly, it elevated numbers of regulatory T cells (Tregs) in the spleen and boosted IL-10 expression in the skin. In agreement with the above, YDIS increased serum IL-10 and reduced serum IL-17. It also caused less damage to the liver and, especially, kidneys of mice than cyclosporine A (CsA). In vitro, YDIS caused more death of HaCaT keratinocytes than CsA. It also strongly inhibited inflammatory factor expression in lipopolysaccharide (LPS)-stimulated HaCaT cells. These findings suggest that YDIS is a promising immunosuppressive agent for treating psoriasis. PMID- 28081601 TI - Combination Therapy of NSCLC Using Hsp90 Inhibitor and Doxorubicin Carrying Functional Nanoceria. AB - K-RAS driven non-small-cell lung cancer (NSCLC) represents a major cause of death among smokers. Recently, nanotechnology has introduced novel avenues for the diagnosis and personalized treatment options for cancer. Herein, we report a novel, multifunctional nanoceria platform loaded with a unique combination of two therapeutic drugs, doxorubicin (Doxo) and Hsp90 inhibitor ganetespib (GT), for the diagnosis and effective treatment of NSCLC. We hypothesize that the use of ganetespib synergizes and accelerates the therapeutic efficacy of Doxo via ROS production, while minimizing the potential cardiotoxicity of doxorubicin drug. Polyacrylic acid (PAA)-coated cerium oxide nanoparticles (PNC) were fabricated for the targeted combination therapy of lung cancers. Using "click" chemistry, the surface carboxylic acid groups of nanoceria were decorated with folic acid to target folate-receptor-overexpressing NSCLC. As a result of combination therapy, results showed more than 80% of NSCLC death within 48 h of incubation. These synergistic therapeutic effects were assessed via enhanced ROS, cytotoxicity, apoptosis, and migration assays. Overall, these results indicated that the targeted codelivery of Doxo and GT using nanoceria may offer an alternative combination therapy option for the treatment of undruggable NSCLC. PMID- 28081602 TI - Design of Stomach Acid-Stable and Mucin-Binding Enzyme Polymer Conjugates. AB - The reduced immunogenicity and increased stability of protein-polymer conjugates has made their use in therapeutic applications particularly attractive. However, the physicochemical interactions between polymer and protein, as well as the effect of this interaction on protein activity and stability, are still not fully understood. In this work, polymer-based protein engineering was used to examine the role of polymer physicochemical properties on the activity and stability of the chymotrypsin-polymer conjugates and their degree of binding to intestinal mucin. Four different chymotrypsin-polymer conjugates, each with the same polymer density, were synthesized using "grafting-from" atom transfer radical polymerization. The influence of polymer charge on chymotrypsin-polymer conjugate mucin binding, bioactivity, and stability in stomach acid was determined. Cationic polymers covalently attached to chymotrypsin showed high mucin binding, while zwitterionic, uncharged, and anionic polymers showed no mucin binding. Cationic polymers also increased chymotrypsin activity from pH 6-8, while zwitterionic polymers had no effect, and uncharged and anionic polymers decreased enzyme activity. Lastly, cationic polymers decreased the tendency of chymotrypsin to structurally unfold at extremely low pH, while uncharged and anionic polymers induced unfolding more quickly. We hypothesized that when polymers are covalently attached to the surface of a protein, the degree to which those polymers interact with the protein surface is the predominant determinant of whether the polymer will stabilize or inactivate the protein. Preferential interactions between the polymer and the protein lead to removal of water from the surface of the protein, and this, we believe, inactivates the enzyme. PMID- 28081603 TI - Metal Chalcogenide Clusters with Closed Electronic Shells and the Electronic Properties of Alkalis and Halogens. AB - Clusters with filled electronic shells and a large gap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) are generally energetically and chemically stable. Enabling clusters to become electron donors with low ionization energies or electron acceptors with high electron affinities usually requires changing the valence electron count. Here we demonstrate that a metal cluster may be transformed from an electron donor to an acceptor by exchanging ligands while the neutral form of the clusters has closed electronic shells. Our studies on Co6Te8(PEt3)m(CO)n (m + n = 6) clusters show that Co6Te8(PEt3)6 has a closed electronic shell and a low ionization energy of 4.74 eV, and the successive replacement of PEt3 by CO ligands ends with Co6Te8(CO)6 exhibiting halogen-like behavior. Both the low ionization energy Co6Te8(PEt3)6 and high electron affinity Co6Te8(CO)6 have closed electronic shells marked by high HOMO-LUMO gaps of 1.24 and 1.39 eV, respectively. Further, the clusters with an even number of ligands favor a symmetrical placement of ligands around the metal core. PMID- 28081604 TI - Surface State-Dominated Photoconduction and THz Generation in Topological Bi2Te2Se Nanowires. AB - Topological insulators constitute a fascinating class of quantum materials with nontrivial, gapless states on the surface and insulating bulk states. By revealing the optoelectronic dynamics in the whole range from femto- to microseconds, we demonstrate that the long surface lifetime of Bi2Te2Se nanowires allows us to access the surface states by a pulsed photoconduction scheme and that there is a prevailing bolometric response of the surface states. The interplay of the surface and bulk states dynamics on the different time scales gives rise to a surprising physical property of Bi2Te2Se nanowires: their pulsed photoconductance changes polarity as a function of laser power. Moreover, we show that single Bi2Te2Se nanowires can be used as THz generators for on-chip high frequency circuits at room temperature. Our results open the avenue for single Bi2Te2Se nanowires as active modules in optoelectronic high-frequency and THz circuits. PMID- 28081605 TI - Surface Interaction of Water-in-Oil Emulsion Droplets with Interfacially Active Asphaltenes. AB - Adsorption of interfacially active components at the water/oil interface plays critical roles in determining the properties and behaviors of emulsion droplets. In this study, the droplet probe atomic force microscopy (AFM) technique was applied, for the first time, to quantitatively study the interaction mechanism between water-in-oil (W/O) emulsion droplets with interfacially adsorbed asphaltenes. The behaviors and stability of W/O emulsion droplets were demonstrated to be significantly influenced by the asphaltene concentration of organic solution where the emulsions were aged, aging time, force load, contact time, and solvent type. Bare water droplets could readily coalesce with each other in oil (i.e., toluene), while interfacially adsorbed asphaltenes could sterically inhibit droplet coalescence and induce interfacial adhesion during separation of the water droplets. For low asphaltene concentration cases, the adhesion increased with increasing asphaltene concentration (<=100 mg/L), but it significantly decreased at relatively high asphaltene concentration (e.g., 500 mg/L). Experiments in Heptol (i.e., mixture of toluene and heptane) showed that the addition of a poor solvent for asphaltenes (e.g., heptane) could enhance the interfacial adhesion between emulsion droplets at relatively low asphaltene concentration but could weaken the adhesion at relatively high asphaltene concentration. This work has quantified the interactions between W/O emulsion droplets with interfacially adsorbed asphaltenes, and the results provide useful implications into the stabilization mechanisms of W/O emulsions in oil production. The methodology in this work can be readily extended to other W/O emulsion systems with interfacially active components. PMID- 28081606 TI - Orange Carotenoid Protein as a Control Element in an Antenna System Based on a DNA Nanostructure. AB - Taking inspiration from photosynthetic mechanisms in natural systems, we introduced a light-sensitive photo protective quenching element to an artificial light-harvesting antenna model to control the flow of energy as a function of light intensity excitation. The orange carotenoid protein (OCP) is a nonphotochemical quencher in cyanobacteria: under high-light conditions, the protein undergoes a spectral shift, and by binding to the phycobilisome, it absorbs excess light and dissipates it as heat. By the use of DNA as a scaffold, an antenna system made of organic dyes (Cy3 and Cy5) was constructed, and OCP was assembled on it as a modulated quenching element. By controlling the illumination intensity, it is possible to switch the direction of excitation energy transfer from the donor Cy3 to either of two acceptors. Under low-light conditions, energy is transferred from Cy3 to Cy5, and under intense illumination, energy is partially transferred to OCP as well. These results demonstrate the feasibility of controlling the pathway of energy transfer using light intensity in an engineered light-harvesting system. PMID- 28081608 TI - Dynamic Interconversions of HCV Helicase Binding Modes on the Nucleic Acid Substrate. AB - The dynamics involved in the interaction between hepatitis C virus nonstructural protein 3 (NS3) C-terminal helicase and its nucleic acid substrate have been the subject of interest for some time given the key role of this enzyme in viral replication. Here, we employed fluorescence-based techniques and focused on events that precede the unwinding process. Both ensemble Forster resonance energy transfer (FRET) and ensemble protein induced fluorescence enhancement (PIFE) assays show binding on the 3' single-stranded overhang of model DNA substrates (>5 nucleotides) with no preference for the single-stranded/double-stranded (ss/ds) junction. Single-molecule PIFE experiments revealed three enhancement levels that correspond to three discrete binding sites at adjacent bases. The enzyme is able to transition between binding sites in both directions without dissociating from the nucleic acid. In contrast, the NS3 mutant W501A, which is unable to engage in stacking interactions with the DNA, is severely compromised in this switching activity. Altogether our data are consistent with a model for NS3 dynamics that favors ATP-independent random binding and sliding by one and two nucleotides along the overhang of the loading strand. PMID- 28081607 TI - Structure-Activity Relationships of Spectinamide Antituberculosis Agents: A Dissection of Ribosomal Inhibition and Native Efflux Avoidance Contributions. AB - Spectinamides are a novel class of antitubercular agents with the potential to treat drug-resistant tuberculosis infections. Their antitubercular activity is derived from both ribosomal affinity and their ability to overcome intrinsic efflux mediated by the Mycobacterium tuberculosis Rv1258c efflux pump. This study explores the structure-activity relationships through analysis of 50 targeted spectinamides. Compounds are evaluated for ribosomal translational inhibition, MIC activity in Rv1258c efflux pump deficient and wild type tuberculosis strains, and efficacy in an acute model of tuberculosis infection. The results of this study show a narrow structure-activity relationship, consistent with a tight ribosome-binding pocket and strict structural requirements to overcome native efflux. Rationalization of ribosomal inhibition data using molecular dynamics simulations showed stable complex formation for halogenated spectinamides consistent with the long post antibiotic effects observed. The lead spectinamides identified in this study demonstrated potent MIC activity against MDR and XDR tuberculosis and had desirable antitubercular class specific features including low protein binding, low microsomal metabolism, no cytotoxicity, and significant reductions in bacterial burdens in the lungs of mice infected with M. tuberculosis. The structure-activity relationships detailed here emphasize the need to examine efflux-mediated resistance in the design of antituberculosis drugs and demonstrate that it is possible to overcome intrinsic efflux with synthetic modification. The ability to understand the structure requirements for this class has produced a variety of new substituted spectinamides, which may provide useful alternative candidates and promote the further development of this class. PMID- 28081610 TI - The Bare Essentials of Antibiotic Target Validation. AB - The convergence of competitive fitness experiments and phenotypic screening would seem to be an auspicious beginning for validation of an antibacterial target. IMPDH was already identified an essential protein in Mycobacterium tuberculosis when not one, but two, groups discovered inhibitors with promising antitubercular activity. A new target appeared to be born. Surprisingly, the two groups came to completely different conclusions about the vulnerability of IMPDH and its future as a drug target. This viewpoint discusses these papers and how to resolve this conundrum. PMID- 28081611 TI - Endoscopic removal of retained large surgical gauze: a case report. AB - In this paper, a 63-year-old woman was reported with recurrent abdominal pain after cholecystectomy. A retained surgical towel was seen by CT-scan in the peritoneal cavity, where it migrated across duodenum wall toward pre-pyloric region of the stomach. Endoscopic removal of the large retained gauze in size of 40 cm x 40 cm was successfully performed without laparotomy and with no complication. In the last years, the main method for removal of retained foreign objects has been open laparotomy or laparoscopy. We claimed that removal of large retained surgical long gauze is actually possible using upper GI endoscopy by expert endoscopists, and, therefore, there is no need for anesthesia or surgery as well as no occurrence of complication and laceration. PMID- 28081612 TI - Mesenteric schwannoma: an unusual cause of abdominal mass. AB - Schwannomas (or neurilemmomas) are slow-growing mesenchymal neoplasms of the peripheral nerve sheath that may arise at almost any anatomical site. Mesentery schwannoma is extremely rare, with less than ten previously described cases. We present the case of a 38-year-old woman with arterial hypertension and chronic kidney disease with an abdominal painless mass of two years duration and an inconclusive pre-operative clinical diagnosis; she was successfully treated by complete surgical resection of the mass. The aim of this report is to recognize the possibility of schwannomas in the differential diagnosis of abdominal slowly growing tumors. PMID- 28081613 TI - Perceived Patient Preference and Clinical Testing for Chlamydia and Gonorrhea in Females: How Closely Are These Aligned? PMID- 28081614 TI - Stress coping strategies, spirituality, social support and posttraumatic growth in a Polish sample of rheumatoid arthritis patients. AB - The aim of this study was to explore the level of posttraumatic growth (PTG) and its relationship to the level of stress coping strategies, spirituality and social support among rheumatoid arthritis (RA) patients (n = 250). The level of PTG was measured by the Polish adaptation of the Posttraumatic Growth Inventory. Stress coping strategies were evaluated by the Polish adaptation of the Mini-COPE Inventory. Spirituality was measured by the Self-Description Questionnaire. Social support was assessed with the Berlin Social Support Scales. Stress coping strategies (return to religion, acceptance), spirituality and social support (need for support) were significantly related to the level of PTG among participants. Despite evidence of a beneficial relationship between PTG and the course of RA, little empirical attention has been paid to the factors associated with PTG among this patient group. Given the substantial health-related benefits associated with PTG among RA patients, it is important to further explore the phenomena of PTG among RA patients. PMID- 28081615 TI - Assessing Pediatric Food Addiction: Tools for the Clinician. PMID- 28081616 TI - Talking to children about their HIV status: a review of available resources, tools, and models for improving and promoting pediatric disclosure. AB - As children living with HIV (CLHIV) grow into adolescence and adulthood, caregivers and healthcare providers are faced with the sensitive challenge of when to disclose to a CLHIV his or her HIV status. Despite WHO recommendations for CLHIV to know their status, in countries most affected by HIV, effective resources are often limited, and national guidance on disclosure is often lacking. To address the need for effective resources, gray and scientific literature was searched to identify existing tools and resources that can aid in the disclosure process. From peer-reviewed literature, seven disclosure models from six different countries were identified. From the gray literature, 23 resources were identified including children's books (15), job aides to assist healthcare providers (5), and videos (3). While these existing resources can be tailored to reflect local norms and used to aid in the disclosure process, careful consideration must be taken in order to avoid damaging disclosure practices. PMID- 28081617 TI - Pediatric Chest Pain-Low-Probability Referral: A Multi-Institutional Analysis From Standardized Clinical Assessment and Management Plans (SCAMPs(r)), the Pediatric Health Information Systems Database, and the National Ambulatory Medical Care Survey. AB - We conducted a study to assess test characteristics of red-flag criteria for identifying cardiac disease causing chest pain and technical charges of low probability referrals. Accuracy of red-flag criteria was ascertained through study of chest pain Standardized Clinical Assessment and Management Plans (SCAMPs(r)) data. Patients were divided into 2 groups: Group1 (concerning clinical elements) and Group2 (without). We compared incidence of cardiac disease causing chest pain between these 2 groups. Technical charges of Group 2 were analyzed using the Pediatric Health Information System database. Potential savings for the US population was estimated using National Ambulatory Medical Care Survey data. Fifty-two percent of subjects formed Group 1. Cardiac disease causing chest pain was identified in 8/1656 (0.48%). No heart disease was identified in patients in Group 2 ( P = .03). Applying red-flags in determining need for referral identified patients with cardiac disease causing chest pain with 100% sensitivity. Median technical charges for Group 2, over a 4-year period, were US2014$775 559. Eliminating cardiac testing of low-probability referrals would save US2014$3 775 182 in technical charges annually. Red-flag criteria were an effective screen for children with chest pain. Eliminating cardiac testing in children without red-flags for referral has significant technical charge savings. PMID- 28081618 TI - Shifting uncertainties in the pre-diagnostic trajectory of early-onset dementia. AB - This article argues that people with early-onset dementia and their family members experience shifts when it comes to dealing with uncertainty in the pre diagnostic illness trajectory. The empirical data show that these shifts follow three patterns. Upon the appearance of first symptoms, people with early-onset dementia and their family members, in a collaborative effort, maintain uncertainty in order to continue living the lives they know. Following this, various explanations, all with a temporal character, are sought to explain changed behaviour. Finally, when relationships are threatened or health is perceived to be at stake, people seriously start to seek medical advice. This article is based on 41 qualitative interviews with seven people with early-onset dementia and 39 family members in the Netherlands, conducted between 2014 and 2015. Interviews were transcribed, coded and analysed identifying key topics. PMID- 28081619 TI - Fever and a Morbilliform Rash. PMID- 28081620 TI - On-site Mental Health Professionals and Pediatric Residents in Continuity Clinic. AB - The objective of the study was to examine differences in pediatric resident perceptions and practices related to child mental health conditions in continuity clinic settings with versus without on-site mental health professionals (MHPs). A 20-item questionnaire, based on the American Academy of Pediatrics Periodic Survey Number 59, was administered to pediatric residents in a medium-sized program from 2008 to 2011. Of 130 residents surveyed, compared with their peers, those practicing with the on-site MHPs were more likely to report mental health services as very available in their clinic (odds ratio [OR] = 39.7; P = .000). Residents with on-site MHPs inquired more frequently about attention deficit/hyperactivity disorder (ADHD; OR = 2.96; P = .029) and referred more frequently for ADHD (OR = 3.68; P = .006), depression (OR = 2.82; P = .030), and behavioral problems (OR = 3.04; P = .012). On-site MHPs in continuity clinics offer great potential to improve resident education and patient care. Additional research is necessary to further understand their impact. PMID- 28081621 TI - PlA2 Polymorphism in Glycoprotein IIb/IIIa Modulates the Morphology and Nanomechanics of Platelets. AB - Glycoprotein IIb/IIIa (GPIIb/IIIa) is the most abundant platelet surface receptor for fibrinogen and von Willebrand factor. Polymorphism PlA1/A2 in the gene of GPIIb/IIIa is among the risk factors for the development of arterial and venous thrombosis. The aim of this study is to evaluate the effect of the carriage of PlA1/A2 on the size, topographic features, and membrane stiffness of platelets from healthy controls and patients with deep venous thrombosis (DVT). Atomic force microscopy (AFM) imaging and nanoindentation (force-distance curves) were applied to investigate the morphological and nanomechanical properties (Young's modulus) of platelets immobilized on glass surface. The surface roughness ( Ra) and height ( h) of platelets from patients with DVT, carriers of mutant allele PlA2 ( Ra = 30.2 +/- 6 nm; h = 766 +/- 182 nm) and noncarriers ( Ra = 28.6 +/- 6 nm; h = 865 +/- 290 nm), were lower than those of healthy carriers of allele PlA2 ( Ra = 48.1 +/- 12 nm; h = 1072 +/- 338 nm) and healthy noncarriers ( Ra = 49.7 +/- 14 nm; h = 1021 +/- 433 nm), respectively. Platelets isolated from patients with DVT, both carriers and noncarriers, exhibit much higher degree of stiffness at the stage of spreading ( E = 327 +/- 85 kPa and 341 +/- 102 kPa, respectively) compared to healthy noncarriers ( E = 198 +/- 50 kPa). In addition, more pronounced level of platelet activation was found in polymorphism carriers. In conclusion, the carriage of PlA2 allele modulates the activation state, morphology, and membrane elasticity of platelets. PMID- 28081622 TI - Comparison of Effect of Minimally Invasive Percutaneous Nephrolithotomy on Split Renal Function: Single Tract vs Multiple Tracts. AB - OBJECTIVES: To observe serum creatinine (SCr) and treated side glomerular filtration rate (TGFR) variations in patients with upper urinary tract calculi after minimally invasive percutaneous nephrolithotomy (MPCNL). PATIENTS AND METHODS: A total of 178 patients underwent MPCNL in our institute and they were retrospectively evaluated between May 2014 and February 2016. SCr and TGFR variations were observed with renal scintigraphy using 99mTc-diethylene triamine pentaacetic acid (99mTc-DTPA) preoperatively and after at least 6 months of follow-up (FU). The patients were categorized into two groups according to the number of percutaneous access tracts: group I (single tract, n = 122) and group II (multiple tracts, n = 56). RESULTS: At a mean FU of 7.6 months, SCr dropped from 192.9 +/- 151.9/L to 167.6 +/- 113.9 MUM (13.15% decrease, p = 0.008) and TGFR increased from 29.8 +/- 21.2 mL/minute preoperatively to 32.7 +/- 22.5 mL/minute postoperatively (9.79% increase, p = 0.022) in group I. Similarly, SCr dropped from 238.5 +/- 130.1 to 215.8 +/- 128.1MU (9.50% decrease, p = 0.013) and TGFR increased from 29.6 +/- 21.4 mL/minute preoperatively to 32.9 +/- 25.1 mL/minute postoperatively (11.17% increase, p = 0.014) in group II. No statistically significant difference between two groups according to SCr or TGFR variation was observed (p > 0.05). CONCLUSIONS: Stone clearance resulted in improvement of split kidney function after single tract or multiple tract MPCNL. Single tract or multiple tract MPCNL did not show statistically significant difference in split renal function postoperative recovery. PMID- 28081624 TI - What Is Hypospadias? PMID- 28081623 TI - Apocynin derivatives from Iris tectorum. AB - Phytochemical investigation of the rhizomes of Iris tectorum resulted in the isolation and characterization of three new apocynin derivatives, apocynin-4-O beta-D-(6'-O-syringyl)glucopyranoside (1), scrophenoside C-7-ethyl ether (2, 3), together with a new naturally occurring compound but known by synthesis, apocynin 4-O-beta-D-xylopyranoside (4), and five known ones (5-9). Their structures were elucidated on the basis of spectroscopic data interpretation. PMID- 28081625 TI - An unsound AAN Practice Advisory on poststroke etanercept. PMID- 28081627 TI - Fruiting Bodies of Antrodia cinnamomea and Its Active Triterpenoid, Antcin K, Ameliorates N-Nitrosodiethylamine-Induced Hepatic Inflammation, Fibrosis and Carcinogenesis in Rats. AB - Antrodia cinnamomea (A. cinnamomea), a popular medicinal mushroom in Taiwan, is widely used to prevent or treat liver diseases. Systematic studies on the anti inflammatory effect of A. cinnamomea and its molecular mechanisms have not yet been fully investigated. HPLC fingerprint analysis identified seven ergostane type triterpenoids from A. cinnamomea water extract (ACW), including high amounts of Antcin K (AC), Antcin C, Antcin H, Dehydrosulphurenic acid, Antcin B, Antcin A and Dehydroeburicoic acid. Here, we explored the effects and mechanisms of ACW and the highest content AC on N-nitrosodiethylamine (DEN) induced liver inflammation, fibrosis and carcinogenesis in rats. In the in vitro study, we measured how ACW and AC dose-dependently scavenged O[Formula: see text], H2O2 and HOCl by a chemiluminescence analyzer. In the in vivo experiment, oral intake ACW and AC significantly inhibited DEN-enhanced hepatocellular inflammation, fibrosis and carcinoma by pathologic observation, the elevated bile and liver reactive oxygen species (ROS) amounts, plasma [Formula: see text]-glutamyl transpeptidase, and oxidative stress including 3-nitrotyrosine, 4-hydroxynonenal and Kuppfer cell infiltration (ED-1 stains) in the inflammatory livers. DEN enhanced nuclear factor-[Formula: see text]B (NF-[Formula: see text]B) translocation, whereas ACW and AC suppressed DEN-enhanced NF-[Formula: see text]B translocation through the inhibition of its upstream signaling of p85/phosphoinositide-3-kinase, mitogen activated protein kinase and CYP2E1 expression. In conclusion, DEN can induce hepatocellular inflammation, fibrosis and carcinoma by increasing NF-[Formula: see text]B translocation to the nucleus, and oxidative injury. ACW and its active component, Antcin K, counteract DEN-induced hepatic injury and inflammation by the protective and therapeutic mechanisms of a direct scavenging ROS activity and an upregulation of anti-oxidant defense mechanisms. PMID- 28081626 TI - Scutellaria baicalensis Ameliorates Acute Lung Injury by Suppressing Inflammation In Vitro and In Vivo. AB - Scutellaria baicalensis has been widely used as both a dietary ingredient and traditional herbal medicine in Taiwan to treat inflammation, cancer, and bacterial and viral infections of the respiratory tract and gastrointestinal tract. This paper aims to investigate the in vitro and in vivo anti-inflammatory effects of S. baicalensis. In HPLC analysis, the fingerprint chromatogram of the water extract of S. baicalensis (WSB) was established. The anti-inflammatory effects of WSB were inverstigated using lipopolysaccharide (LPS)-stimulated mouse macrophage (RAW264.7) in vitro and LPS-induced lung injury in vivo. WSB attenuated the production of LPS-induced nitric oxide (NO), tumor necrosis factor alpha (TNF-[Formula: see text], interleukin-[Formula: see text] (IL-1[Formula: see text], and IL-6 in vitro and in vivo. Pretreatment with WSB markedly reduced the LPS-induced histological alterations in lung tissues. Furthermore, WSB significantly reduced the number of total cells and the protein concentration levels in the BALF. WSB blocked protein expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), phosphorylation of I[Formula: see text]B [Formula: see text] protein and MAPKs in LPS-stimulated RAW 264.7 cells and LPS induce lung injury was also blocked. This study suggests that WSB possesses anti inflammatory effects in vitro and in vivo, and the results suggested that WSB may be a potential therapeutic candidate for the treatment of inflammatory diseases. PMID- 28081628 TI - Schisandra chinensis and Its Main Constituent Schizandrin Attenuate Allergic Reactions by Down-Regulating Caspase-1 in Ovalbumin-Sensitized Mice. AB - Schisandra chinensis (SC) and its main constituent, schizandrin (SCH) exhibit anti-inflammatory and anti-allergic activities. Allergic and inflammatory reactions are aggravated via caspase-1 signaling pathway. However, the regulatory effects of SC and SCH on caspase-1 activation have not been clarified yet. In this study, we aimed to clarify the anti-allergic effects of SC and SCH using an ovalbumin (OVA)-sensitized mice and anti-CD3 and anti-CD28 antibodies-stimulated splenocytes. SC or SCH significantly inhibited the levels of immunoglobulin (Ig)E, IgG1, or interleukin (IL)-4 in serum of OVA-sensitized mice. SC or SCH significantly inhibited the levels of IL-6, tumor necrosis factor (TNF)-[Formula: see text], and IL-1[Formula: see text] in spleen of the OVA-sensitized mice. SC or SCH significantly suppressed the expression of caspase-1 and receptor interacting protein (RIP)-2 in spleen of the OVA-sensitized mice. In activated splenocytes, SC or SCH significantly decreased the expression of caspase-1 and RIP-2 as well as the production of IL-6 and TNF-[Formula: see text]. We suggest that SC and SCH exert an anti-allergic effect by down-regulating caspase-1 signaling. PMID- 28081629 TI - Punicalagin Pretreatment Attenuates Myocardial Ischemia-Reperfusion Injury via Activation of AMPK. AB - Punicalagin (PUN), a major bioactive component in pomegranate juice, has been proven to exert neuroprotective effects against cerebral ischemia/reperfusion (I/R) insult via anti-oxidant properties. This study aims to investigate whether PUN provides cardioprotection against myocardial I/R (MI/R) injury and the underlying mechanisms. PUN (30[Formula: see text]mg/kg/d) or vehicle was intragastrically administered to Sprague-Dawley rats for one week before the operation. MI/R was induced by ligating the left anterior descending coronary artery for 30[Formula: see text]min and subsequent reperfusion for 3[Formula: see text]h. PUN pretreatment conferred cardioprotective effects against MI/R injury by improving cardiac function, limiting infarct size, reducing serum creatine kinase-MB and lactate dehydrogenase activities, and suppressing cardiomyocyte apoptosis. Moreover, PUN pretreatment inhibited I/R-induced myocardial oxidative stress as evidenced by decreased generation of superoxide content and malonaldialdehyde formation and increased antioxidant capability. Furthermore, PUN pretreatment increased adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation in I/R hearts. AMPK inhibitor compound c inhibited PUN-enhanced AMPK phosphorylation, and blunted PUN mediated anti-oxidative effects and cardioprotection. These results indicate for the first time that PUN pretreatment protect against I/R-induced oxidative stress and myocardial injury via activation of AMPK. PMID- 28081630 TI - Huang Qi Decoction Prevents BDL-Induced Liver Fibrosis Through Inhibition of Notch Signaling Activation. AB - Notch signaling has been demonstrated to be involved in ductular reactions and fibrosis. Previous studies have shown that Huang Qi Decoction (HQD) can prevent the progression of cholestatic liver fibrosis (CLF). However, whether HQD affects the Notch signaling pathway is unclear. In this study, CLF was established by common bile duct ligation (BDL) in rats. At the end of the first week, the rats were randomly divided into a model group (i.e., BDL), an HQD group, and a sorafenib positive control group (SORA) and were treated for 3 weeks. Bile duct proliferation and liver fibrosis were determined by tissue staining. Activation of the Notch signaling pathway was evaluated by analyzing expressions of Notch-1, -2, -3, and -4, Jagged (JAG) 1, and Delta like (DLL)-1, -3, and -4. The results showed that HQD significantly reduced the deposition of collagen and the Hyp content of liver tissue and inhibited the activation of HSCs compared with the BDL group. In addition, HQD significantly decreased the protein and mRNA expressions of TGF-[Formula: see text]1 and [Formula: see text]-SMA. In contrast, HQD significantly enhanced expression of the Smad 7 protein. HQD also reduced biliary epithelial cell proliferation, and reduced the mRNA levels of CK7, CK8, CK18, SRY-related high mobility group-box gene (SOX) 9, epithelial cell adhesion molecule (EpCAM) and the positive areas of CK19 and OV6. In addition, the mRNA and protein expressions of Notch-3, -4, JAG1, and DLL-1, -3 were significantly reduced in the HQD compared to the BDL group. These results demonstrated that HQD may prevent biliary liver fibrosis through inhibition of the Notch signaling pathway, and it may be a potential treatment for cholestatic liver disease. PMID- 28081631 TI - Baicalein Induces Beclin 1- and Extracellular Signal-Regulated Kinase-Dependent Autophagy in Ovarian Cancer Cells. AB - Baicalein (BA), one of the major compounds isolated from the root of Scutellaria baicalensis Gerogi, exhibits various pharmacological effects, such as anti oxidant, anti-inflammatory, and anticancer effects. In this study, we found that BA reduced cell viability and increased apoptosis in ovarian cancer cells. Treatment of cells with BA enhanced microtubule-associated protein light chain 3 II (LC3-II) expression, acidic vesicular organelle and GFP-LC3 fluorescence dot accumulation. Combined treatment with chloroquine and BA apparently reduced cell viability and increased the cleavage of poly (ADPribose) polymerase (PARP) in both HEY and A2780 ovarian cancer cell lines, indicating that BA induces a protective autophagy in these cells. Knockdown of Beclin 1 by siRNA remarkably decreased BA-induced LC3-II lipidation. In addition, we found an increase in the phosphorylation of extracellular signal-regulated kinase (ERK, Thr202/Thr204) and AKT (Ser473) after BA treatment, and inhibition of ERK activation by the pharmacological inhibitor U0126 or ERK siRNA blocked BA-induced autophagy. Taken together, these results suggest that BA induces Beclin 1- and ERK-dependent autophagy in ovarian cancer cells. PMID- 28081632 TI - ERK Signaling Pathway Plays a Key Role in Baicalin Protection Against Acetaminophen-Induced Liver Injury. AB - Acetaminophen (APAP) overdose causes hepatocytes necrosis and acute liver failure. Baicalin (BA), a major flavonoid of Scutellariae radix, has potent hepatoprotective properties in traditional medicine. In the present study, we investigated the protective effects of BA on a APAP-induced liver injury in a mouse model. The mice received an intraperitoneal hepatotoxic dose of APAP (300[Formula: see text]mg/kg) and after 30[Formula: see text]min, were treated with BA at concentrations of 0, 15, 30, or 60[Formula: see text]mg/kg. After 16[Formula: see text]h of treatment, the mice were sacrificed for further analysis. APAP administration significantly elevated the serum alanine transferase (ALT) enzyme levels and hepatic myeloperoxidase (MPO) activity when compared with control animals. Baicalin treatment significantly attenuated the elevation of liver ALT levels, as well as hepatic MPO activity in a dose- dependent manner (15-60[Formula: see text]mg/kg) in APAP-treated mice. The strongest beneficial effects of BA were seen at a dose of 30[Formula: see text]mg/kg. BA treatment at 30[Formula: see text]mg/kg after APAP overdose reduced elevated hepatic cytokine (TNF-[Formula: see text] and IL-6) levels, and macrophage recruitment around the area of hepatotoxicity in immunohistochemical staining. Significantly, BA treatment can also decrease hepatic phosphorylated extracellular signal-regulated kinase (ERK) expression, which is induced by APAP overdose. Our data suggests that baicalin treatment can effectively attenuate APAP-induced liver injury by down-regulating the ERK signaling pathway and its downstream effectors of inflammatory responses. These results support that baicalin is a potential hepatoprotective agent. PMID- 28081633 TI - Activity- vs. structural-oriented treatment approach for frozen shoulder: a randomized controlled trial. AB - OBJECTIVE: To compare the short- and long-term effects of a structural-oriented (convential) with an activity-oriented physiotherapeutic treatment in patients with frozen shoulder. DESIGN: Double-blinded, randomized, experimental study. SETTING: Outpatient clinic. SUBJECTS: We included patients diagnosed with a limited range of motion and pain in the shoulder region, who had received a prescription for physiotherapy treatment, without additional symptoms of dizziness, a case history of headaches, pain and/or limited range of motion in the cervical spine and/or temporomandibular joint. INTERVENTIONS: The study group received treatment during the performance of activities. The comparison group was treated with manual therapy and proprioceptive neuromuscular facilitation (conventional therapy). Both groups received 10 days of therapy, 30 minutes each day. MAIN MEASURES: Range of motion, muscle function tests, McGill pain questionnaire and modified Upper Extremity Motor Activity Log were measured at baseline, after two weeks of intervention and after a three-month follow-up period without therapy. RESULTS: A total of 66 patients were randomized into two groups: The activity-oriented group ( n = 33, mean = 44 years, SD = 16 years) including 20 male (61%) and the structural-oriented group ( n = 33, mean = 47 years, SD = 17 years) including 21 male (64%). The activity-oriented group revealed significantly greater improvements in the performance of daily life activities and functional and structural tests compared with the group treated with conventional therapy after 10 days of therapy and at the three-month follow up ( p < 0.05). CONCLUSIONS: Therapy based on performing activities seems to be more effective for pain reduction and the ability to perform daily life activities than conventional treatment methods. PMID- 28081634 TI - The effect of nitisinone on homogentisic acid and tyrosine: a two-year survey of patients attending the National Alkaptonuria Centre, Liverpool. AB - Background Alkaptonuria is a rare, debilitating autosomal recessive disorder affecting tyrosine metabolism. Deficiency of homogentisate 1,2-dioxygenase leads to increased homogentisic acid which is deposited as ochronotic pigment. Clinical sequelae include severe early onset osteoarthritis, increased renal and prostate stone formation and cardiac complications. Treatment has been largely based on analgaesia and arthroplasty. The National Alkaptonuria Centre in Liverpool has been using 2 mg nitisinone (NTBC) off-license for all patients in the United Kingdom with alkaptonuria and monitoring the tyrosine metabolite profiles. Methods Patients with confirmed alkaptonuria are commenced on 2 mg dose (alternative days) of NTBC for three months with daily dose thereafter. Metabolite measurement by LC-MS/MS is performed at baseline, day 4, three-months, six-months and one-year post-commencing NTBC. Thereafter, monitoring and clinical assessments are performed annually. Results Urine homogentisic acid concentration decreased from a mean baseline 20,557 umol/24 h (95th percentile confidence interval 18,446-22,669 umol/24 h) by on average 95.4% by six months, 94.8% at one year and 94.1% at two year monitoring. A concurrent reduction in serum homogentisic acid concentration of 83.2% compared to baseline was also measured. Serum tyrosine increased from normal adult reference interval to a mean +/- SD of 594 +/- 184 umol /L at year-two monitoring with an increased urinary excretion from 103 +/- 81 umol /24 h at baseline to 1071 +/- 726 umol /24 h two years from therapy. Conclusions The data presented represent the first longitudinal survey of NTBC use in an NHS service setting and demonstrate the sustained effect of NTBC on the tyrosine metabolite profile. PMID- 28081635 TI - Highly sensitive faecal DNA testing of TWIST1 methylation in combination with faecal immunochemical test for haemoglobin is a promising marker for detection of colorectal neoplasia. AB - Background As TWIST1 methylation is specific to colorectal neoplasia, detection of TWIST1 methylation from faeces samples might be useful for colorectal neoplasia screening. However, because the content of human DNA in faeces is very small, it is very difficult to detect TWIST1 methylation by conventional bisulphite-based methylation assays. Therefore, we developed a new methylation assay without bisulphite treatment, the combined restriction digital PCR assay, and evaluated its sensitivity and specificity in combination with and without the faecal immunochemical test for haemoglobin for colorectal neoplasia detection from faeces samples. Methods For the combined restriction digital PCR assay, DNA was treated with three methylation-sensitive restriction enzymes and an exonuclease, followed by measurement of TWIST1 methylation level by droplet digital PCR. Faecal DNA testing and faecal immunochemical test for haemoglobin were performed on 109 patients with colorectal neoplasia and 10 control individuals. Results Basic performance testing showed that the combined restriction digital PCR assay enabled detection of 0.14% of the TWIST1 methylation level for the lymphocyte DNA. The combined restriction digital PCR assay from faeces samples had a sensitivity of 22.2% (95% confidence interval, 2.8-60.0%) for non-advanced adenoma, 47.1% (95% confidence interval, 23.0-72.2%) for advanced adenoma, and 33.7% (95% confidence interval, 23.7-45.0%) for colorectal cancer, and a specificity of 100.0%. Combination of faecal immunochemical test for haemoglobin and faecal combined restriction digital PCR assay increased sensitivity to 82.4% (95% confidence interval, 56.6-96.2%) for the detection of advanced adenoma. Conclusions We developed the combined restriction digital PCR assay, a possible highly sensitive methylation assay. Combination of faecal combined restriction digital PCR assay with faecal immunochemical test for haemoglobin may provide an alternative screening strategy for colorectal neoplasia, especially for potentially precancerous lesions. PMID- 28081636 TI - The serum concentration of soluble interleukin-2 receptor in patients with Kawasaki disease. AB - Kawasaki disease is a febrile disease of childhood that is associated with increased inflammatory cytokines and immunoregulatory abnormalities. While the serum concentrations of soluble IL-2 receptor can change under such pathologies, the relevance of the soluble IL-2 receptor concentration in patients with Kawasaki disease has not been specified. We aimed to summarize the existing studies that reported the soluble IL-2 receptor concentrations in patients with Kawasaki disease. Original articles that were published up to July 2016 were collected using a PubMed/Medline-based search engine. A total of nine articles that reported the serum soluble IL-2 receptor concentrations in acute-phase Kawasaki disease were eligible. All of the articles described a high soluble IL-2 receptor concentration in patients with Kawasaki disease relative to the level of controls or the reference range. Two of five articles on patients with coronary artery aneurysms described a significantly higher soluble IL-2 receptor concentration in patients with coronary artery aneurysms than patients without. Two articles on patients with intravenous immunoglobulin therapy described a significant decrease of the soluble IL-2 receptor concentration after the therapy. Accordingly, the serum soluble IL-2 receptor can be a potent marker of disease activity and therapeutic effects in patients with Kawasaki disease; further studies are thus warranted for its use in the clinical setting. PMID- 28081637 TI - Comparison of method-related reference intervals for thyroid hormones: studies from a prospective reference population and a literature review. AB - Introduction Reference intervals are dependent on the reference population, the analytical methods and the way the data are handled statistically. Individual method-related differences have been studied but the comparative differences in reference intervals have not. Methods We studied a reference population of healthy adult subjects and measured free thyroxine and thyroid-stimulating hormone by the four most commonly used analytical platforms used in the UK. Subjects were excluded if they were > 65 years or had positive thyroid peroxidase antibodies. We also performed a systematic literature review of thyroid hormone reference interval studies in non-pregnant adults. Results In total, 303 subjects were recruited and 42 excluded. The central 95th centile values for thyroid stimulating hormone (mIU/L) were Abbott Architect (0.51-3.67); Beckman Unicel DxI (0.57-3.60); Roche Cobas (0.60-4.31) and Siemens Advia Centaur XP (0.63-4.29). The 95th centile values for thyroxine (pmol/L) were Abbott Architect (10.6-15.5); Beckman Unicel DxI (7.9-13.0); Roche Cobas (12.5-19.6) and Siemens Advia Centaur XP (11.8-19.0). We identified 55 papers describing thyroid reference intervals in male and non-pregnant female adults. The values for upper and lower reference intervals by manufacturer varied but were not significantly different for thyroid stimulating hormone but were for thyroxine. Discussion Our study demonstrates clearly that there are marked variations in the reference intervals for thyroid hormones between analytical platforms. There is an urgent need for standardization of thyroid hormone assays to permit transferability of results. Until then, guidelines will need to reflect this method-related difference. PMID- 28081638 TI - Echocardiography may cause significant pain response in preterm infants. AB - OBJECTIVE: The objective of this study is to evaluate if echocardiographic examination causes any pain response in term and preterm infants. METHODS: Term and preterm neonates who admitted to Neonatal Intensive Care Unit at Gazi University Hospital and Etlik Zubeyde Hanim Training and Research Hospital and were performed echocardiography for any reason were included into the study. Neonates were evaluated before, during and 10 minutes after the examination. Vital signs (heart rate, respiratory rate, blood pressure, transcutaneous oxygen saturation) were recorded. All subjects were also evaluated with Neonatal Infant Pain Scale during the examination. RESULTS: In this study, we evaluated 99 newborn infants. Five infants who received fentanyl treatment were excluded. The heart rate (p = 0.000), respiratory rate (p = 0.000), diastolic blood pressure (p = 0.001) and oxygen saturation (p = 0.000) during the examination were significantly different than the values before and 10 minutes after the examination. Infants whose gestational age <=32 weeks (n:20) have significantly higher NIPS scores (mean +/- SEM = 3.3 +/- 0.4) than the infants whose gestational age is greater than 32 weeks (n:71) (mean +/- SEM = 2.4 +/- 0.2). CONCLUSIONS: Echocardiographic examination which is known as noninvasive and painless causes significant pain in preterm infants. PMID- 28081639 TI - Differential expression of cord blood neurotrophins in gestational diabetes: the impact of fetal growth abnormalities. AB - OBJECTIVE: Gestational diabetes mellitus (GDM) may induce fetal macrosomia or growth restriction and is associated with later offspring neurodevelopmental disorders. We aimed to determine whether neurotrophins brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophin-4 (NT-4) are differentially expressed in cord blood samples at birth in large-for-gestational age (LGA), intrauterine-growth-restricted (IUGR) and appropriate-for-gestational age (AGA) offspring of diabetic mothers, as compared to AGA controls from non diabetic mothers. METHODS: BDNF, NGF and NT-4 concentrations were prospectively determined in 80 cord blood samples from LGA (n = 15), IUGR (n = 12) and AGA (n = 33) diabetic, as well as from AGA normal (controls, n = 20) singleton full-term pregnancies. RESULTS: Fetal BDNF concentrations considerably decreased in GDM, as compared with normal pregnancies [(b = -2.836, 95%CI -5.067 to (-0.604), p = 0.013)] and were higher in females (b = 2.298, 95%CI 0.357-4.238, p = 0.021). Cord blood NGF concentrations were lower in IUGR than AGA infants (p = 0.038). CONCLUSIONS: BDNF is down-regulated in the fetus exposed to GDM, independently of the fetal growth pattern, probably representing a candidate mechanism underlying the association between maternal diabetes and later psychopathology. IUGR fetuses born to diabetic mothers present with NGF deficiency, which may contribute to their long-term neurodevelopmental sequelae. Gender-dependent differences in fetal BDNF may partly explain the higher prevalence of adverse neurodevelopmental outcomes following brain insults in male infants. PMID- 28081640 TI - xCT deficiency aggravates acetaminophen-induced hepatotoxicity under inhibition of the transsulfuration pathway. AB - Cystine, an oxidized form of cysteine (Cys), is imported into cells via the protein xCT, which is also associated with the export of glutamate as the counter amino acid. In the current study, we attempted to rationalize roles of xCT in the livers of male mice. While xCT was not expressed in the livers of ordinary mice, it was induced under conditions of glutathione depletion, caused by the administration of acetaminophen (AAP). To differentiate the role between xCT and the transsulfuration pathway on the supply of Cys, we employed an inhibitor of the enzyme cystathionine gamma-lyase, propargylglycine (PPG). This inhibitor caused a marked aggravation in AAP-induced hepatic damage and the mortality of the xCT-/- mice was increased to a greater extent than that for the xCT+/+ mice. While a PPG pretreatment had no effect on liver condition or Cys levels, the administration of AAP to the PPG-pretreated mice reduced the levels of Cys as well as glutathione to very low levels in both the xCT+/+ and xCT-/- mice. These findings indicate that the transsulfuration pathway plays a major role in replenishing Cys when glutathione levels are low. Moreover, an ascorbic acid insufficiency, induced by Akr1a ablation, further aggravated the AAP-induced liver damage in the case of the xCT deficiency, indicating that glutathione and ascorbic acid function cooperatively in protecting the liver. In conclusion, while the transsulfuration pathway plays a primary role in supplying Cys to the redox system in the liver, xCT is induced in cases of emergencies, by compensating for Cys supply systems. PMID- 28081642 TI - First-trimester placental vascular development in multiparous women differs from that in nulliparous women. AB - OBJECTIVE: Multiparas differ from nulliparas by delivering larger babies with larger placentas and by having a lower risk of developing placental syndromes. We postulate that these differences result from a different initial course of placental vascular development. STUDY DESIGN: We measured placental flow index (FI), vascularization index (VI) and placental volume by 3D power Doppler and obtained blood samples at 8, 10 and 12 weeks pregnancy in 34 healthy nulliparous and 16 multiparous women with an uneventful pregnancy. RESULTS: Between 8 and 12 weeks multiparas differed from nulliparas in a more rapid initial rise in FI, a higher angiopoietin-2 (ang2) level at eight weeks and no decline in the VEGF/sVEGF-R ratio. Nevertheless, at 12 weeks the FI and placental volume were indistinguishable between both study groups. CONCLUSIONS: These results combining serially measured placental vascularization, placental volume and circulating angiogenetic factors show initial differences in placental development, that howeve, did not maintain till the end of first trimester. The results support the concept that early placental vascular development differs between nulliparas and multiparas. Nevertheless, it is unclear whether these differences contribute to the development later on in pregnancy of intergroup differences in birthweight and incidence of placental syndromes. PMID- 28081643 TI - Microemulsion for topical delivery of fenoprofen calcium: in vitro and in vivo evaluation. AB - The aim of this study was to investigate microemulsion (ME) based topical delivery system for fenoprofen calcium (FPCa) to eliminate its oral gastrointestinal adverse effects. ME was prepared by the water titration method using oleic acid as oil phase, tween 80 as a surfactant and propylene glycol as a cosurfactant. Oleic acid was selected as oil phase due to its good solubilizing capacity. ME existence region was determined using pseudo-ternary phase diagrams for preparing different formulations. Six different formulations were selected with various values of oil (25-68%), water (2-3%), and the mixture of surfactant and cosurfactant (1:1) (24-67%). The selected ME formulae were characterized for optical birefringence, transmission electron microscopy (TEM), pH, % transmittance, electronic conductivity, drug content, droplet size, rheological properties and stability evaluation. In vitro release study of FPCa from ME s through the synthetic membrane and hairless rat skin were evaluated. The optimized formula ME5 consisting of 5% w/w FPCa, 60% w/w oleic acid as oil phase, 3% w/w aqueous phase, and 32% w/w of surfactant phase containing Tween 80 and propylene glycol (1: 1) showed the highest transdermal flux and highest skin permeation rate. Finally, the % inhibition of carrageenan-induced rat paw edema of the optimized formula ME5 was highly significant (p < 0.001) as compared to plain gel of FPCa. In conclusion, ME is a promising technique for topical delivery of FPCa. PMID- 28081641 TI - Vessel pruning or healing: endothelial metabolism as a novel target? AB - INTRODUCTION: Antiangiogenic drugs were originally designed to starve tumors by cutting off their vascular supply. Unfortunately, when these agents are used as monotherapy or in combination with chemotherapy, they provide only modest survival benefits in the order of weeks to months in most cancer patients. Strategies normalizing the disorganized tumor vasculature offer the potential to increase tumor perfusion and oxygenation, and to improve the efficacy of radio-, chemo- and immunotherapy, while reducing metastasis. Areas covered: This review discusses tumor vascular normalization (TVN) as an alternative strategy for anti angiogenic cancer treatment. We summarize (pre)-clinical strategies that have been developed to normalize tumor vessels as well as their potential to enhance standard therapy. Notably, we describe how targeting endothelial cell metabolism offers new possibilities for antiangiogenic therapy through evoking TVN. Expert opinion: Several drugs targeting VEGF signaling are now clinically used for antiangiogenic cancer treatment. However, excessive blood vessel pruning impedes perfusion and causes tumor hypoxia, known to promote cancer cell dissemination and impair radio-, chemo- and immunotherapy. Normalized vessels lessen tumor hypoxia, impair cancer cell intravasation and enhance anticancer treatment. New data indicate that targeting endothelial cell metabolism is an alternative strategy of antiangiogenic cancer treatment via promotion of TVN. PMID- 28081644 TI - Reactive nitrogen species as therapeutic targets for autophagy: implication for ischemic stroke. AB - INTRODUCTION: Roles of autophagy/mitophagy activation in ischemic stroke remain controversial. To elucidate potential reasons, we analyze the factors responsible for divergent results in literatures. Reactive nitrogen species (RNS) are important cytotoxic factors in ischemic stroke. Herein, we particularly discuss the roles played by RNS in autophagy/mitophagy and ischemic brain injury. Areas covered: Following factors should be considered in the studies on autophagy/mitophagy in ischemic stroke: (1) Protocols for administration of autophagy regulators including administration time points, routes and doses, etc.; (2) Specificity of autophagy regulators; (3) Animal models of cerebral ischemia with or without reperfusion. In the underlying mechanisms of autophagy/mitophagy, we particularly discuss the potential roles of RNS in mediating excessive autophagy/mitophagy during cerebral ischemia/reperfusion injury. Expert opinion: Emphasis should be given to the following aspects in future studies: (1) Targeting RNS and related cellular signaling pathways in the regulation of autophagy/mitophagy might be a promising strategy for developing novel drugs as well as combined therapy for thrombolytic treatment to reach better outcomes for ischemic stroke; (2) Developing circulating plasma biomarkers linking RNS-mediated autophagy/mitophagy to the magnitude of ischemic brain injury will benefit for stroke treatment. Subsequently, RNS could be dominant therapeutic targets to regulate autophagy/mitophagy for ischemic stroke. PMID- 28081645 TI - Factors related to recurrence of the benign non-functioning thyroid nodules after percutaneous microwave ablation. AB - PURPOSE: To determine the factors affecting the recurrence of the solitary benign thyroid nodules (BTN) after microwave ablation (MWA). MATERIALS AND METHODS: Between January 2013 and January 2015, a total of 110 patients with at least one solid thyroid nodule (solid component >= 80%) were enrolled. MWA was performed under continuous ultrasound (US) guidance. Before and during the follow-up, the thyroid nodule volume, thyroid function and cosmetic complaints were evaluated. Recurrence is defined by the new blood flow in the total ablation area or/and > 50% increase in nodule volume. RESULTS: Almost all thyroid nodules were significantly decreased in size after MWA. After 12 months, the average volume of thyroid nodules was decreased from 12.6 +/- 15.1 to 3.2 +/- 5.7 ml. Of the total 110 patients, 16 cases had recurrence 12 months after MWA, and these patients had a larger initial volume than that of the non-recurrence patients (11.6 +/- 14.9 vs. 23.9 +/- 12.5, p < 0.01). The recurrence group also demonstrated more irregular blood vessels (1.8 8 +/- 1.1 vs. 2.8 5 +/- 1.3, p < 0.05), and a lower energy (1575.5 +/- 674.3 J/ml vs. 1172.3 +/- 454.2 J/ml, p < 0.01). In addition, 81.2% (13/16) of the patients in the recurrence group were adjacent to the vital structures, which is significantly higher than that of the non-recurrence group 28.7% (27/94) (p < 0.01). CONCLUSIONS: The US-guided MWA results in a satisfactory long-term outcome of the patients with a benign solitary thyroid nodule. We identified three risk factors for recurrence: initial volume, vascularity and the energy per 1 ml reduction in nodular volume. PMID- 28081647 TI - Interaction of S-layer proteins of Lactobacillus kefir with model membranes and cells. AB - In previous works, it was shown that S-layer proteins from Lactobacillus kefir were able to recrystallize and stabilize liposomes, this feature reveling a great potential for developing liposomal-based carriers. Despite previous studies on this subject are important milestones, a number of questions remain unanswered. In this context, the feasibility of S-layer proteins as a biomaterial for drug delivery was evaluated in this work. First, S-layer proteins were fully characterized by electron microscopy, 2D-electrophoresis, and anionic exchange chromatography coupled with pulsed amperometric detection (HPAEC-PAD). Afterward, interactions of S-layer proteins with model lipid membranes were evaluated, showing that proteins adsorb to the lipid surface following a non-fickean or anomalous diffusion, when positively charged lipid were employed, suggesting that electrostatic interaction is a key factor in the recrystallization process on these proteins. Finally, the interaction of S-layer coated liposomes with Caco-2 cell line was assessed: First, cytotoxicity of formulations was tested showing no cytotoxic effects in S-layer coated vesicles. Second, by flow cytometry, it was observed an increased ability to transfer cargo molecules into Caco-2 cells from S-layer coated liposomes in comparison to control ones. All data put together, supports the idea that a combination of adhesive properties of S-layer proteins concomitant with higher stability of S-layer coated liposomes represents an exciting starting point in the development of new drug carriers. PMID- 28081648 TI - Chemical pharmacotherapy options for managing adult acne. AB - INTRODUCTION: The incidence of adult acne is increasing worldwide. Despite clinical overlap with conventional acne, it has distinct features. Areas covered: A literature search of English-language review articles, randomized control studies and retrospective studies conducted over the past 30 years was performed using PubMed and Google Scholar. Search terms included acne, adult, topical medication, oral medication and skin of color. We highlight important clinical features and treatment modalities pertinent to the evaluation and management of adult acne. Given the relative dearth of literature detailing treatment options specific to adult acne, we offer expert opinion regarding management of the condition especially in special populations such as skin of color and pregnancy. Expert Opinion: It is unclear whether adult acne represents a distinct entity or a continuum of adolescent disease. Providers may opt to use topical medication as first-line, but should have a low threshold for switching to systemic therapy given the magnitude of psychosocial and emotional burden associated with the condition. PMID- 28081649 TI - Three-dimensional fluoroscopic navigation-assisted surgery for tumors in patients with tumor-induced osteomalacia in the bones. AB - PURPOSE: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome usually caused by phosphaturic mesenchymal tumors. Segmental resection has been recommended for these tumors in the bones because curettage was found to be associated with a high local recurrence rate. Navigation-assisted surgery provides radiological information to guide the surgeon during surgery. No previous study has reported on the efficacy of navigation-assisted surgery for tumors in patients with TIO. Therefore, the present study aimed to evaluate the efficacy of navigation-assisted surgery for tumors in patients with TIO. METHODS: The study included seven patients with TIO who were treated between January 2003 and December 2014 at our hospital. All patients underwent surgical treatment with or without the use of a 3-dimensional (3D) fluoroscopy-based navigation system. The laboratory data and oncological outcomes were evaluated. RESULTS: The follow up period was 8-128 months. The tumors were located at the femur (n = 4), ischium, spine and ilium (n = 1). Of the seven patients, five underwent navigation-assisted surgery and two underwent surgery without navigation assistance. In the two patients who underwent surgery without navigation assistance, a complete cure was not obtained and osteomalacia did not resolve. One of these two patients and the other five patients who underwent navigation assisted surgery, one patient had incomplete resection due to massive invasion of the tumor into the spinal canal, but five patients achieved complete excision and recovered from osteomalacia. CONCLUSIONS: Navigation-assisted surgery using a 3D fluoroscopy-based navigation system is effective for tumors in patients with TIO. PMID- 28081646 TI - Comparison of rapid MMP-8 and interleukin-6 point-of-care tests to identify intra amniotic inflammation/infection and impending preterm delivery in patients with preterm labor and intact membranes. AB - OBJECTIVE: Among patients presenting with preterm labor and intact membranes, those with intra-amniotic inflammation have adverse obstetrical and neonatal outcomes. The diagnosis of intra-amniotic inflammation can easily be made by detecting an elevated concentration of the cytokine interleukin (IL)-6 or the enzyme neutrophil collagenase, also known as matrix metalloproteinase (MMP)-8. The diagnostic performances of MMP-8 and IL-6 enzyme-linked immunosorbent assay tests are similar. Recently, a rapid test has become available for point-of-care determination of either MMP-8 or IL-6. The objectives of this study were to compare the diagnostic indices and predictive values between the rapid MMP-8 and IL-6 tests for the identification of intra-amniotic inflammation in patients with preterm labor and intact membranes. MATERIALS AND METHODS: We performed a retrospective cohort study including 124 women with singleton pregnancies who presented with symptoms of preterm labor and underwent transabdominal amniocentesis for the evaluation of microbial invasion of the amniotic cavity (MIAC). MIAC was defined according to amniotic fluid culture results (aerobic and anaerobic bacteria as well as genital Mycoplasmas). Amniotic fluid white blood cell (WBC) counts were determined using a hemocytometer chamber. An elevated amniotic fluid MMP-8 concentration was assessed using Yoon's MMP-8 Check(r) (cutoff: 10 ng/mL). An elevated amniotic fluid IL-6 concentration was scored when there was a positive result for the lateral flow-based immunoassay (cutoff: >=745 pg/mL and >=1000 pg/mL). In order to objectively compare rapid MMP-8 and rapid IL 6 tests to identify intra-amniotic inflammation, an amniotic fluid WBC count of >=50 cells/mm3 was used to define intra-amniotic inflammation. RESULTS: (1) The rapid tests had the same sensitivity for the detection of intra-amniotic inflammation [85.7% (18/21) for all]; (2) the specificity of the rapid MMP-8 test was higher than that of the rapid IL-6 test (cutoff: 745 pg/mL) for the identification of intra-amniotic inflammation [72.8% (75/103) vs. 64.1% (66/103); p < 0.05]; and (3) there were no differences in the sensitivity and specificity between the rapid MMP-8 test and the rapid IL-6 test (cutoff:1000 pg/mL) in the identification of intra-amniotic inflammation. Of 13 patients with discrepant results between the rapid MMP-8 and rapid IL-6 tests, two had a positive MMP-8 but a negative rapid IL-6 test, and both delivered preterm - one within 24 h, and the other within 10 days - and both had acute histologic chorioamnionitis. On the other hand, there were 11 patients with a positive rapid IL-6 but a negative rapid MMP-8 result: 10 delivered preterm, 3 had acute histologic chorioamnionitis and 1 had subacute chorionitis. CONCLUSION: We conclude that the rapid MMP-8 test has a better specificity than the rapid IL-6 (cutoff: 745 pg/mL) assay for the detection of intra-amniotic infection. Moreover, we observed that among patients who were not identified as having intra-amniotic infection or inflammation by the standard cultivation technique and amniotic fluid WBC count, those who had a positive MMP-8 rapid test delivered preterm and had acute histologic chorioamnionitis. PMID- 28081650 TI - Current and future therapies for the treatment of histamine-induced angioedema. AB - INTRODUCTION: Angioedema, a sudden, self-limited swelling of localized areas of any part of the body that may or may not be associated with urticaria, is thought to be the result of a mast-cell mediated process versus a bradykinin etiology. Understanding the mechanism is key in determining the proper treatment. Areas Covered: Clinical presentation of varying angioedema types may be similar; however, the appropriate treatment algorithm is dependent upon clinicians' knowledge of the underlying pathophysiology and classification of angioedema. Literature review of recent guidelines, available medications, and alternative therapies was completed to provide an overview of options. CONCLUSION: There are no formal guidelines for treatment of acute or chronic histamine-mediated angioedema, and therefore, algorithms for the treatment of acute and chronic urticaria should be followed until such information becomes available. Differentiating histamine-mediated versus bradykinin mediated angioedema is essential, as treatments and treatment responses are quite different. Further research is needed to better understand idiopathic angioedema that is unresponsive to H1/H2 antagonists, LTMAs, or medications designed to treat bradykinin-mediated angioedema. PMID- 28081651 TI - Bridging the gap from values to actions: a family systems framework for family centered AAC services. AB - Despite the growing recognition of the importance of family involvement in augmentative and alternative communication (AAC) intervention, little guidance exists on how professionals can establish successful collaborative relationships with families. In this paper, we discuss family systems theory and ecological systems theory as a framework to guide family-centered AAC practice, review family-focused research in AAC, consider how AAC may impact the family system, and provide examples of the clinical implications of using the proposed family systems framework to improve family-centered AAC practice. PMID- 28081652 TI - A new dimeric stilbene from the lianas of Gnetum parvifolium. AB - A new dimeric stilbene, gnetifolin P (1), was isolated from the lianas of Gnetum parvifolium, together with seven known compounds 2-8. The structure of compound 1 was determined by extensive NMR and HRESIMS data analyses, and quantum chemical calculations. All the compounds were evaluated for their anti-inflammatory activity. Compounds 1 and 6 inhibited the expression of IL-1beta on LPS induced THP-1 cells with the inhibition rate of 35.78 and 64.67%, respectively, at concentration of 25 MUg/mL. PMID- 28081654 TI - Allusive thinking (remote associations) and auditory top-down inhibition skills differentially predict creativity and positive schizotypy. AB - INTRODUCTION: Positive schizotypy and creativity seem to be linked. However, the question still remains why they are related, and what may make the difference? As creative ideation is hypothesised as a dual process (association and inhibition), the propensity for remote associations might be a shared mechanism. However, positive schizotypy and creative thinking might be differentially linked to inhibition. Therefore, this study investigated a potentially overlapping feature of positive schizotypy and creativity (remote associations) as well as a potential dissociative factor (auditory inhibition). METHODS: From a large screening sample, 46 participants covering a broad range of positive schizotypy were selected. Association proneness was assessed via two association tasks, auditory inhibition skill with the forced-left condition of the Dichotic Listening Test, and creative thinking by means of two creative ideation tests. RESULTS: Positive schizotypy and creative thinking were positively associated. Both traits were linked to lower rates of common associations. However, creative thinking was associated with higher and positive schizotypy with lower inhibitory control in the auditory domain. CONCLUSIONS: While creativity and positive schizotypy shared some variance (related to remote associations), profound inhibition skills may be vital for creative performance and may coincide with lower levels of positive schizotypy. PMID- 28081653 TI - Toxicity from automotive screenwashes reported to the United Kingdom National Poisons Information Service (NPIS) from 2012 to 2015. AB - BACKGROUND: Automotive screenwashes commonly contain ethylene glycol, methanol, and/or isopropanol; ethanol is also included in many formulations. The concentrations and combinations of each constituent vary considerably between the products. This study was undertaken to investigate the toxicity of automotive screenwashes as reported by telephone to the United Kingdom National Poisons Information Service (NPIS). METHODS: Enquiries to the NPIS relating to automotive screenwashes were analyzed retrospectively for the period January 2012 to December 2015. RESULTS: There were 295 enquiries involving 255 individual exposures. The majority (n = 241, 94.5%) of exposures involved ingestion and 14 of these also involved other routes. Six cases were due to skin contact alone, three to inhalation alone, three to eye contact alone, one to ear exposure alone and another occurred from inhalation and skin contact. Children below 5 years of age accounted for 26% of all ingestions. The identity (and therefore composition) of the screenwash was known with certainty in 124 of 241 ingestions and included methanol in 106 formulations, isopropanol in 72, ethylene glycol in 38, and ethanol in 104. The World Health Organisation/International Programme on Chemical Safety/European Commission/European Association of Poison Centres and Clinical Toxicologists Poisoning Severity Score was known in 235 of 241 cases of ingestion: most patients were asymptomatic (n = 169, 71.9%), but 59 (25.1%) developed minor (PSS 1), six (2.6%) moderate (PSS 2), and one patient severe (PSS 3) features; this patient later died. Nausea (n = 10), vomiting (n = 11), abdominal pain (n = 10), metabolic acidosis (n = 8) and raised anion gap (n = 8) were reported most commonly after ingestion. CONCLUSIONS: Most patients (71.9%) ingesting automotive screenwash did not develop features. The implication is that the amount of screenwash ingested was very small. Skin and eye exposure produced either no features or only minor toxicity. PMID- 28081655 TI - Marked biochemical difference in amyloid proportion between intra- and extraocular tissues in a liver-transplanted patient with hereditary ATTR amyloidosis. AB - In order to elucidate the pathomechanism of ocular amyloid formation in a liver transplanted patient with hereditary ATTR amyloidosis, we investigated detailed biochemical features of ocular amyloid. The patient was a 49-year-old woman with V30M transthyretin (TTR) variant (p.TTRV50M), who underwent ophthalmectomy due to corneal rupture 10 years after liver transplantation (LT). The amyloid was selectively isolated from several portions in intra- and extraocular tissues using a laser microdissection (LMD) system and analyzed by liquid chromatography tandem mass spectrometry to determine the composition percentage of wild-type and variant TTR in the isolated amyloid. Biochemical analysis revealed that the amyloid consisted mainly of variant TTR in intraocular tissues with a percentage > 80%. On the contrary in the extraocular muscles, wild-type TTR was the main component of the amyloid with a percentage of ~70%. Our data indicate that intraocular amyloid formation strongly depends on locally synthesized variant TTR and the contribution of wild-type TTR to amyloid formation is quite limited. PMID- 28081656 TI - Clinicopathological and biochemical findings of thyroid amyloid in hereditary transthyretin amyloidosis with and without liver transplantation. AB - Hereditary transthyretin (TTR) amyloidosis is a fatal disease causing systemic organ dysfunctions. Histopathological studies revealed that thyroid glands are major target tissues. However, details about thyroid functions remain to be fully elucidated in this disease. For patient treatment, liver transplantation (LT) reportedly prolongs patient survival, but thyroid gland function after LT still remains poorly understood. In this study, we investigated the thyroid functions in 101 patients with hereditary TTR amyloidosis and the effects of LT on thyroid functions in those patients. In addition, we investigated histopathological and biochemical findings of thyroid specimens obtained at autopsy. Disease duration and age at examination inversely correlated with serum levels of free triiodothyronine (fT3) in hereditary TTR amyloidosis. On the contrary, in patients who underwent transplantation, time from disease onset to transplantation and age at transplantation clearly correlated with serum fT3and thyroid stimulating hormone (TSH) levels. In autopsy studies, amounts of thyroid amyloid deposits in patients with transplantation were significantly lower than those in patients without transplantation. Mass spectrometric analyzes also revealed that proportions of wild-type (WT) TTR in thyroid amyloid deposits in patients with hereditary TTR amyloidosis who underwent transplantations were higher than those in patients without transplantation. Thyroid hormone functions may diminish according to the disease progression. LT could prevent thyroid dysfunction in hereditary TTR amyloidosis. PMID- 28081657 TI - Bariatric endoscopy: current state of the art, emerging technologies, and challenges. AB - INTRODUCTION: Over the last few decades obesity has become a major health issue worldwide. Although dietary and lifestyle changes are the cornerstone of obesity management, it still poses a huge challenge for the majority of patients to permanently change their eating habits. Bariatric endoscopy represents an evolving filed of minimally invasive techniques and procedures for weight loss trying to respond to these challenges by developing new methods with the increasing role of endoscopists in the management of obesity. Areas covered: The aim of this article is to review the role and the advantages of bariatric endoscopy in the management of obesity by providing a comprehensive reference source and evaluating the currently available and emerging endoscopic devices and techniques for weight loss. Expert commentary: Endoscopic methods for weight loss represent a useful armamentarium in the management of obesity by providing improved effectiveness compared with medications, with a lower risk profile than traditional bariatric surgery. Although preliminary results of recently introduced methods are encouraging, many questions remain regarding the safety and efficacy of such interventions. Combining scientific background with advancements in technology is the key strategy for the further development of bariatric endoscopy. PMID- 28081658 TI - Breast cancer chemoprevention: A service in need of menopause specialist support. PMID- 28081659 TI - Network of Ethical Relationships model for global North-South population health research. AB - Although a substantial body of literature exists that details how to address ethical issues and provide oversight for traditional research study designs, there currently is very little guidance available to researchers on how to deal with the unique and novel challenges that arise when conducting research that goes outside of these well-defined boundaries. One such example is North-South (N S) team-based global population health (GPH) research. This paper presents a Network of Ethical Relationships (NER) model which can allow GPH researchers better understand and resolve ethical issues that arise in N-S collaborative research efforts. The NER model elucidates some of the core relationships involved in GPH research and sheds light on the complex milieu of moral, institutional, societal and legal processes in which it is embedded. The utility of the NER model is examined by reviewing 14 GPH research teams, looking at two relationships in more detail - Researcher-Ethics Board, and Researcher-Funder relationships. The paper argues that improved dialogue and flexibility in the application of formal ethical rules and procedures can lead to research being conducted in a more ethical manner since it better accounts for the multitude of voices and perspectives influencing researchers' choices and actions. PMID- 28081660 TI - Valsalva maneuver in phlebologic practice. AB - Forced expiration against an airway obstruction was originally described as a method for inflating the Eustachian tubes and is accredited to Antonio Maria Valsalva (1666-1723). The Valsalva maneuver is commonly applied for different diagnostic purposes. Its use for phlebologic diagnosis is the object this review. Venous reflux is the most frequent pathophysiologic mechanism in chronic venous disease. Reflux is easily visualized by duplex ultrasound when properly elicited, in standing position. A simple way to elicit reflux is the so-called "compression release maneuver": by emptying the muscle reservoir, it determines a centrifugal gradient, dependent on hydrostatic pressure, creating an aspiration system from the superficial to the deep system. The same results are obtained with dynamics tests activating calf muscles. The Valsalva maneuver elicits reflux by a different mechanism, increasing the downstream pressure and, thus, highlighting any connection between the source of reflux and the refluxing vessel. The Valsalva maneuver is typically used to investigate the saphenofemoral junction. When the maneuver is performed correctly, it is very useful to analyse several conditions and different hemodynamic behaviours of the valvular system at the saphenofemoral junction. Negative Valsalva maneuver always indicates valvular competence at the saphenofemoral junction. Reverse flow lasting during the whole strain (positive Valsalva maneuver) indicates incompetence or absence of proximal valves. Coupling Valsalva maneuver to compression-release maneuver, with the sample volume in different saphenofemoral junction sections, may reveal different hemodynamic situations at the saphenofemoral junction, which can be analysed in detail. PMID- 28081662 TI - Neuroendocrine, goblet cell and mixed adeno-neuroendocrine tumours of the appendix: updates, clinical applications and the future. AB - INTRODUCTION: Appendiceal neuroendocrine neoplasms are rare, clinically challenging tumours that are typically incidentally diagnosed, have a poorly understood biology and have controversy surrounding their management. Most are adequately treated with appendectomy, and although distant metastases are rare, the threat of disease dissemination remains and current guidelines possess poor accuracy in terms of selecting patients requiring more extensive surgery, i.e. oncological right-hemicolectomy. Areas covered: In this article, we discuss the presentation and diagnostic work-up of patients with appendiceal neuroendocrine neoplasms, and also examine the evidence base for existing management strategies. We highlight controversies within the management of these tumours, and anticipate avenues for further progress. Although no longer classified as neuroendocrine neoplasms, we also discuss two related forms of tumours with neuroendocrine features - goblet cell cancers and mixed adeno-neuroendocrine carcinomas. Expert commentary: Existing guidelines for the treatment of appendiceal neuroendocrine neoplasms are derived from a limited evidence base and are unable to accurately predict which patients require extensive attempts at surgical disease control. Future advances in the field of improved patient selection for more extensive surgery may be possible with multi-factorial tumour assessment integrating morphological and molecular analyses. PMID- 28081661 TI - Patients and physicians agree only partially in symptoms and clinical findings before and after treatment for varicose veins. AB - Objective Quality improvement in surgery has mainly been based on clinical database outcomes. This study compared variables from the patient-reported Aberdeen Varicose Vein Questionnaire with the Danish Clinical Vein Database, in order to reveal agreements and differences in symptoms and clinical findings. Methods In the period January-March 2011, 379 legs in 287 patients treated for varicose veins were registered in the Danish Clinical Vein Database and compared to the Aberdeen Varicose Vein Questionnaire. Results Patients and physicians agreed in reduction of symptoms after intervention with one or more complaints still present in 128 (93%) patients according to Aberdeen Varicose Vein Questionnaire compared to the Danish Clinical Vein Database with only 64 (47%) patients. Patients reported cosmetic complaints and teleangiectasies both before and after treatment (p < 0.001) more often than doctors. Conclusion The Aberdeen Varicose Vein Questionnaire has added valuable information to the dialogue between the doctor and patient on which symptoms expecting to improve and which not. PMID- 28081663 TI - Computational analysis of BACE1-ligand complex crystal structures and linear discriminant analysis for identification of BACE1 inhibitors with anti P glycoprotein binding property. AB - More than 100 years of research on Alzheimer's disease didn't yield a potential cure for this dreadful disease. Poor Blood Brain Barrier (BBB) permeability and P glycoprotein binding of BACE1 inhibitors are the major causes for the failure of these molecules during clinical trials. The design of BACE1 inhibitors with a balance of sufficient affinity to the binding site and little or no interaction with P-glycoproteins is indispensable. Identification and understanding of protein-ligand interactions are essential for ligand optimization process. Structure-based drug design (SBDD) efforts led to a steady accumulation of BACE1 ligand crystal complexes in the PDB. This study focuses on analyses of 153 BACE1 ligand complexes for the direct contacts (hydrogen bonds and weak interactions) observed between protein and ligand and indirect contacts (water-mediated hydrogen bonds), observed in BACE1-ligand complex crystal structures. Intraligand hydrogen bonds were analyzed, with focus on ligand P-glycoprotein efflux. The interactions are dissected specific to subsites in the active site and discussed. The observed protein-ligand and intraligand interactions were used to develop the linear discriminant model for the identification of BACE1 inhibitors with less or no P-glycoprotein binding property. Excellent statistical results and model's ability to correctly predict a new data-set with an accuracy of 92% is achieved. The results are retrospectively analyzed to give input for the design of potential BACE1 inhibitors. PMID- 28081664 TI - Effect of telehealth intervention on breast cancer patients' quality of life and psychological outcomes: A meta-analysis. AB - Introduction Telehealth intervention has been proposed as an innovative intervention approach to breast cancer patients, but there are still conflicting results in the literature about its effect. Methods PubMed, EMBASE, CENTRAL and China National Knowledge Infrastructure (CNKI) were searched from inception to 3 October 2016 for randomized controlled trials (RCTs) which assessed the effect of telehealth intervention versus usual care in breast cancer patients. No language restrictions were used. Standardized mean difference (SMD) with corresponding 95% confidence interval (95% CI) was pooled when needed. Subgroup and sensitivity analyses were conducted if necessary and feasible. Results Twenty RCTs with a total of 2190 participants were included into this meta-analysis. Compared with usual care, telehealth intervention was associated with higher quality of life (SMD = 0.60, 95% CI 0.18-1.01, p = 0.005) and self-efficacy (SMD = 0.59, 95% CI 0.19-0.98, p = 0.003), with less depression (SMD = -1.29, 95% CI -2.28 to -0.30, p = 0.01), distress (SMD = -0.25, 95% CI -0.40 to -0.10, p = 0.001) and perceived stress (SMD = -0.30, 95% CI, -0.59 to -0.02, p = 0.04). However, anxiety score did not differ significantly between the two groups (SMD = -0.09, 95% CI -0.22 to 0.04, p = 0.17). Discussion Telehealth intervention is superior to usual care in breast cancer patients for improved quality of life, higher self-efficacy and less depression, distress, and perceived stress. However, these results should be recognized cautiously due to between-study heterogeneity, indicating that further well-designed RCTs are warranted. PMID- 28081665 TI - PACTRIMS abstracts. PMID- 28081666 TI - Recruitment of ethnic minorities for public health research: An interpretive synthesis of experiences from six interlinked Danish studies. AB - AIMS: This paper examines the importance of recruitment site in relation to the recruitment of ethnic minorities into health research. It presents a synthesis of experiences drawn from six interlinked Danish studies which applied different methods and used healthcare facilities and educational settings as sites for recruitment. METHODS: Inspired by interpretive reviewing, data on recruitment methods from the different studies were synthesized with a focus on the various levels of recruitment success achieved. This involved an iterative process of comparison, analysis and discussion of experiences among the researchers involved. RESULTS: Success in recruitment seemed to depend partly on recruitment site. Using healthcare facilities as the recruitment site and healthcare professionals as gatekeepers was less efficient than using schools and employees from educational institutions. Successful study designs also depended on the possibility of singling out specific locations with a high proportion of the relevant ethnic minority target population. CONCLUSIONS: The findings, though based on a small number of cases, indicate that health professionals and healthcare institutions, despite their interest in high-quality health research into all population groups, fail to facilitate research access to some of the most disadvantaged groups, who need to be included in order to understand the mechanisms behind health disparities. This happens despite the genuine wish of many healthcare professionals to help facilitate such research. In this way, the findings indirectly emphasize the specific challenge of accessing more vulnerable and sick groups in research studies. PMID- 28081667 TI - Contributions of caspase-8 and -9 to liver injury from CYP2E1-produced metabolites of halogenated hydrocarbons. AB - 1. Drug-induced liver injury is difficult to predict at the pre-clinical stage. This study aimed to clarify the roles of caspase-8 and -9 in CYP2E1 metabolite induced liver injury in both rats and cell cultures in vitro treated with carbon tetrachloride (CCl4), halothane or sevoflurane. The human hepatocarcinoma functional liver cell line was maintained in 3-dimensional culture alone or in co culture with human acute monocytic leukemia cells. 2. In vivo, laboratory indices of liver dysfunction and histology were normal after administration of sevoflurane. CCl4 treatment increased blood AST/ALT levels, liver caspase-3 and 9 activities and liver malondialdehyde, accompanied by centrilobular hepatocyte necrosis. Halothane increased AST/ALT levels, caspase-3 and -8 activities (but not malondialdehyde) concomitant with widespread hepatotoxicity. In vitro, CCl4 treatment increased caspase-9 activity and decreased both mitochondrial membrane potential (MMP) and cell viability. In co-culture, halothane increased caspase-8 activity and decreased MMP and cellular viability. There were no toxic responses in CYP2E1 knockdown in monoculture and co-culture. 3. CYP2E1-inducing compounds play a pivotal role in halogenated hydrocarbon toxicity. 4. Changes in hepatocyte caspase-8 and -9 activities could be novel biomarkers of metabolites causing DILI, and in pre-clinical development of new pharmaceuticals can predict nascent DILI in the clinical stage. PMID- 28081668 TI - Synthesis and evaluation of pH-sensitive, self-assembled chitosan-based nanoparticles as efficient doxorubicin carriers. AB - A novel pH-responsive polymer based on amphiphilic N-acetyl histidine and arginine-grafted chitosan was synthesized using N-acetyl histidine as hydrophobic segment and arginine as hydrophilic segment by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide-mediated coupling reactions as anticancer drug delivery system for doxorubicin. The structure of the synthesized polymer was confirmed by Fourier transform infrared and 1H nuclear magnetic resonance analysis. Due to self association behavior, N-acetyl histidine and arginine-grafted chitosan structured nanoparticles with in size range of 204 nm. N-acetyl histidine and arginine grafted chitosan with different substitution degree of N-acetyl histidine were initially prepared and characterized. The critical micelle concentration decreased with increasing substitution degree of N-acetyl histidine. Furthermore, N-acetyl histidine and arginine-grafted chitosan nanoparticles exhibited an acidic pH-triggered aggregation and disassembling nature. The doxorubicin encapsulated nanoparticles based on synthesized conjugate ( N-acetyl histidine and arginine-grafted chitosan/doxorubicin nanoparticles) showed a sustained drug release pattern, which could be hastened under acidic pH conditions but delayed with increasing substitution degree of N-acetyl histidine. Anticancer effects demonstrated that N-acetyl histidine and arginine-grafted chitosan/doxorubicin nanoparticles could suppress both sensitive and resistant human breast tumor cell line (MCF-7) efficiently in a dose- and time-dependent pattern. Confocal microscopy results evidenced increased cellular uptake and enhanced retention of the synthesized nanoparticles in drug-resistant cells demonstrating better efficacy of nanoparticles over native doxorubicin. These results suggest that N acetyl histidine and arginine-grafted chitosan/doxorubicin nanoparticles might be promising carriers for delivery of hydrophobic drug doxorubicin against drug resistant tumors. PMID- 28081669 TI - Graphical timeline software for inpatient medication review. AB - MedHistory is a web-based software module that graphically displays medication usage (y-axis) against time (x-axis). We set out to examine whether MedHistory would improve clinician's interactions with the medical record system. The authors invited house-officers at our institution to complete a survey about inpatient medication administration before and after using MedHistory. Detailed logs were also kept for 1 year after the study period. Compared to the pre intervention survey, the post-intervention survey found that reviewing medication history was easier (pre: 13.2% vs post: 32.4%, p = .008), that medication review now fit within resident workflow (38.9% vs 75.7%, p < .001), and that there was increased satisfaction with the electronic health records software (2.6% vs 29.7%, p = .002). Additionally, determining the timing (29% vs 50.1%, p = .045) and dosing history (21.1% vs. 43.2%, p = .036) of inpatient medication administration was easier with MedHistory. Anti-infective agents and drugs requiring frequent adjustments were the most commonly reviewed. A graphical timeline of inpatient medications (MedHistory) was met with favorable response across multiple areas, including efficiency, speed, safety, and workflow. PMID- 28081670 TI - Oxidation and degradation of polypropylene transvaginal mesh. AB - Polypropylene (PP) transvaginal mesh (TVM) repair for stress urinary incontinence (SUI) has shown promising short-term objective cure rates. However, life-altering complications have been associated with the placement of PP mesh for SUI repair. PP degradation as a result of the foreign body reaction (FBR) has been proposed as a contributing factor to mesh complications. We hypothesized that PP oxidizes under in vitro conditions simulating the FBR, resulting in degradation of the PP. Three PP mid-urethral slings from two commercial manufacturers were evaluated. Test specimens (n = 6) were incubated in oxidative medium for up to 5 weeks. Oxidation was assessed by Fourier Transform Infrared Spectroscopy (FTIR), and degradation was evaluated by scanning electron microscopy (SEM). FTIR spectra of the slings revealed evidence of carbonyl and hydroxyl peaks after 5 weeks of incubation time, providing evidence of oxidation of PP. SEM images at 5 weeks showed evidence of surface degradation, including pitting and flaking. Thus, oxidation and degradation of PP pelvic mesh were evidenced by chemical and physical changes under simulated in vivo conditions. To assess changes in PP surface chemistry in vivo, fibers were recovered from PP mesh explanted from a single patient without formalin fixation, untreated (n = 5) or scraped (n = 5) to remove tissue, and analyzed by X-ray photoelectron spectroscopy. Mechanical scraping removed adherent tissue, revealing an underlying layer of oxidized PP. These findings underscore the need for further research into the relative contribution of oxidative degradation to complications associated with PP-based TVM devices in larger cohorts of patients. PMID- 28081671 TI - Emergence and control of epidemic meningococcal meningitis in sub-Saharan Africa. AB - For more than a century, meningitis epidemics have regularly recurred across sub Saharan Africa, involving 19 contiguous countries that constitute a 'meningitis belt' where historically the causative agent has been serogroup A meningococcus. Attempts to control epidemic meningococcal meningitis in Africa by vaccination with meningococcal polysaccharide (PS) vaccines have not been successful. This is largely because PS vaccines are poorly immunogenic in young children, do not induce immunological memory, and have little or no effect on the pharyngeal carriage. Meningococcal PS-protein conjugate vaccines overcome these deficiencies. Conjugate meningococcal vaccine against serotype A (MenAfriVac) was developed between 2001 and 2009 and deployed in 2010. So far, 262 million individuals have been immunized across the meningitis belt. The public health benefits of MenAfriVac have already been demonstrated by a sharp decline in reported cases of meningococcal disease in the countries where it has been introduced. However, serogroup replacement following mass meningitis vaccination has been noted, and in 2015 an epidemic with a novel strain of serogroup C was recorded in Niger and Nigeria for the first time since 1975. This has posed a serious challenge toward elimination of meningococcal meningitis epidemics in the African. For an effective control of meningococcal meningitis in the African meningitis belt, there is a need for an effective surveillance system, provision of rapid antigen detection kits as well as affordable vaccine that provides protection against the main serogroups causing meningitis in the sub-region. PMID- 28081672 TI - Immunogenicity of modified vaccinia virus Ankara expressing the hemagglutinin stalk domain of pandemic (H1N1) 2009 influenza virus. AB - BACKGROUND: Vaccination offers protection against influenza, although current vaccines need to be reformulated each year. The development of a broadly protective influenza vaccine would guarantee the induction of heterosubtypic immunity also against emerging influenza viruses of a novel subtype. Vaccine candidates based on the stalk region of the hemagglutinin (HA) have the potential to induce broad and persistent protection against diverse influenza A viruses. METHODS: Modified vaccinia virus Ankara (MVA) expressing a headless HA (hlHA) of A/California/4/09 (CA/09) virus was used as a vaccine to immunize C57BL/6 mice. Specific antibody and cell-mediated immune responses were determined, and challenge experiments were performed by infecting vaccinated mice with CA/09 virus. RESULTS: Immunization of mice with CA/09-derived hlHA, vectored by MVA, was able to elicit influenza-specific broad cross-reactive antibodies and cell mediated immune responses, but failed to induce neutralizing antibodies and did not protect mice against virus challenge. CONCLUSION: Although highly immunogenic, our vaccine was unable to induce a protective immunity against influenza. A misfolded and unstable conformation of the hlHA molecule may have affected its capacity of inducing neutralizing antiviral, conformational antibodies. Design of stable hlHA-based immunogens and their delivery by recombinant MVA-based vectors has the potential of improving this promising approach for a universal influenza vaccine. PMID- 28081673 TI - Atherogenic properties of LDL particles after switching from Truvada or Kivexa plus lopinavir/r to lamivudine plus lopinavir/r: OLE-MET substudy. AB - BACKGROUND: The objective of this study was to determine the impact of tenofovir or abacavir discontinuation on low-density lipoprotein (LDL) phenotype and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in HIV-infected patients treated with lopinavir/ritonavir plus 2 nucleos(t)ide reverse transcriptase inhibitors (NRTI). METHODS: Multicenter, open-label study. Patients were randomized to continue with lopinavir/ritonavir plus 2 NRTI (triple therapy) or to switch to lopinavir/ritonavir plus lamivudine (dual therapy). LDL phenotype (by gradient gel electrophoresis) and Lp-PLA2 (by 2-thio-PAF) were determined at baseline and week 48. RESULTS: Forty-four patients included (triple therapy n = 19, dual therapy n = 25): men 63.6%, age 41.5 years (25-61), Framingham score 4.9% (0.2-22). Tenofovir was part of the regimen in 28 (63.6%) patients. Dual therapy patients were younger (p = 0.013) and had lower baseline apolipoprotein A1 (p = 0.029). At week 48, there were no changes in standard lipid measurements, except ApoA1/Apo B, which increased in dual therapy (p = 0.038) with no differences between arms. At week 48, no change in LDL phenotype was found in either arm. No changes in total Lp-PLA2 activity or the relative distribution of LDL and HDL particles were found at week 48 in either arm. CONCLUSIONS: Discontinuing the third nucleos(t)ide, mainly tenofovir and abacavir, in a lopinavir/ritonavir-containing regimen was not associated with a deleterious effect on LDL phenotype nor in Lp-PLA2 activity. PMID- 28081674 TI - In vivo lifetime and anti-cancer efficacy of doxorubicin-loaded nanogels composed of cinnamoyl poly (beta-cyclodextrin) and cinnamoyl Pluronic F127. AB - Nanogel composed of rhodamine B isothiocyanate-labeled cinnamoyl polymeric beta cyclodextrin and cinnamoyl Pluronic F127 was prepared by taking advantage of their self-assembling property in aqueous phase. The in vivo lifetime of the nanogel in the blood circulation system of hairless mouse was determined by fluorescence imaging method using rhodamine B isothiocyanate as a fluorescence probe, and it was more than 192 h. The in vivo clearance of doxorubicin loaded in the nanogel was observed by the same fluorescence imaging method. Doxorubicin loaded in the nanogel was cleared from the blood circulation system more slowly than free drug, indicating that the in vivo lifetime of the anti-cancer drug was prolonged by the nanogel. The fluorescence of doxorubicin was detected from the mouse even 200 h after the doxorubicin-loaded nanogel was intravenously injected into a mouse. According to the histological study of tumor tissue, the in vivo tumor growth-inhibiting efficacy of doxorubicin loaded in the nanogel was higher than that of free drug, possibly because of its longer in vivo lifetime. PMID- 28081675 TI - Three-Dimension-Printed Porous Poly(Propylene Fumarate) Scaffolds with Delayed rhBMP-2 Release for Anterior Cruciate Ligament Graft Fixation. AB - Anterior cruciate ligament (ACL) ruptures reconstructed with tendon grafts are commonly fixed with bioabsorbable implants, which are frequently complicated by incomplete bone filling upon degradation. Bone regeneration after ACL reconstruction could be enhanced by utilizing tissue engineering techniques and three-dimensional (3D) printing to create a porous bioabsorbable scaffold with delayed delivery of recombinant-human bone morphogenetic protein 2 (rhBMP-2). The first aim of this study was to design a 3D poly(propylene fumarate) (PPF) porous scaffold that maintained suitable pullout strength for future testing in a rabbit ACL reconstruction model. Our second aim was to determine the release kinetics of rhBMP-2 from PPF scaffolds that utilized both calcium-phosphate coatings and growth factor delivery on microspheres, both of which have been shown to decrease the initial burst release of rhBMP-2 and increase bone regeneration. To determine the degree of scaffold porosity that maintained suitable pullout strength, tapered scaffolds were fabricated with increasing porosity (0%, 20%, 35%, and 44%) and pullout testing was performed in a cadaveric rabbit ACL reconstruction model. Scaffolds were coated with carbonate hydroxyapatite (synthetic bone mineral [SBM]), and radiolabeled rhBMP-2 was delivered in four different experimental groups as follows: Poly(lactic-co-glycolic acid) microspheres only, microspheres and collagen (50:50), collagen only, and saline solution only. rhBMP 2 release was measured at day 1, 2, 4, 8, 16, and 32. The microsphere delivery groups had a smaller burst release and released a smaller percentage of rhBMP-2 over the 32 days than the collagen and saline only groups. In conclusion, a porous bioabsorbable scaffold with suitable strength for a rabbit ACL reconstruction was developed. Combining a synthetic bone mineral coating with microspheres had an additive effect, decreasing the initial burst release and cumulative release of rhBMP-2. Future studies need to evaluate this scaffold's fixation strength and bone filling capabilities in vivo compared to traditional bioabsorbable implants. PMID- 28081676 TI - Bacterial contamination and stethoscope disinfection practices: a cross-sectional survey of healthcare workers in Karachi, Pakistan. AB - Stethoscopes routinely used for clinical examination of patients may potentially transfer micro-organisms and cause iatrogenic infections. This study was undertaken to detect the presence of microorganisms on stethoscopes used clinically in hospitals of Karachi, Pakistan and to ascertain the infection control practices of healthcare workers (HCWs). In a cross-sectional study, 118 samples were collected from public and private institutions. Samples were tested for the presence and sensitivity of pathogenic microorganisms. Microorganisms were found on diaphragms of 33/64 (51.6%) and 19/57 (33.3%) stethoscopes in public and private sector hospitals, respectively. Methycillin resistance was identified in all staphylococcally contaminated samples. Only 33 (18%) respondents reported cleaning their stethoscopes regularly. We highlight the need for more and better on-the-job routines for decontaminating stethoscopes among HCWs in Karachi. PMID- 28081677 TI - Treatment of oral mucosal manifestations of chronic graft-versus-host disease: dexamethasone vs. budesonide. AB - INTRODUCTION: The oral mucosa is commonly involved in chronic graft-versus-host disease (cGVHD). Oral mucosal cGVHD markedly affect individual's daily function and wellbeing. In some cases, it might become a life threating complication. Areas covered: This article describes the rationale for treatment, method of topical application in the oral cavity, evidence supporting the topical administration of dexamethasone and budesonide for oral cGVHD, and their adverse effects. Expert opinion: Evidence supports the use of topical dexamethasone and budesonide for treatment of oral cGVHD. Topical corticosteroid choice for oral cGVHD, takes into consideration the potency, bioavailability, preferred concentration, and possible adverse effects. Budesonide's pharmacological characteristics mark it as a preferable topical agent for oral cGVHD. PMID- 28081678 TI - Molecular dynamics and MM/GBSA-integrated protocol probing the correlation between biological activities and binding free energies of HIV-1 TAR RNA inhibitors. AB - The interaction of HIV-1 transactivator protein Tat with its cognate transactivation response (TAR) RNA has emerged as a promising target for developing antiviral compounds and treating HIV infection, since it is a crucial step for efficient transcription and replication. In the present study, molecular dynamics (MD) simulations and MM/GBSA calculations have been performed on a series of neamine derivatives in order to estimate appropriate MD simulation time for acceptable correlation between DeltaGbind and experimental pIC50 values. Initially, all inhibitors were docked into the active site of HIV-1 TAR RNA. Later to explore various conformations and examine the docking results, MD simulations were carried out. Finally, binding free energies were calculated using MM/GBSA method and were correlated with experimental pIC50 values at different time scales (0-1 to 0-10 ns). From this study, it is clear that in case of neamine derivatives as simulation time increased the correlation between binding free energy and experimental pIC50 values increased correspondingly. Therefore, the binding energies which can be interpreted at longer simulation times can be used to predict the bioactivity of new neamine derivatives. Moreover, in this work, we have identified some plausible critical nucleotide interactions with neamine derivatives that are responsible for potent inhibitory activity. Furthermore, we also provide some insights into a new class of oxadiazole-based back bone cyclic peptides designed by incorporating the structural features of neamine derivatives. On the whole, this approach can provide a valuable guidance for designing new potent inhibitors and modify the existing compounds targeting HIV-1 TAR RNA. PMID- 28081679 TI - Introduction to microwave tumour ablation special issue. PMID- 28081680 TI - Impact of rectal gonorrhoea and chlamydia on HIV viral load in the rectum: potential significance for onward transmission. AB - The aim of this study was to investigate the effect of asymptomatic rectal bacterial sexually transmitted infections (STIs) on rectal HIV viral load (VL). A prospective cohort study of HIV-positive men who have sex with men attending a tertiary centre in London, UK, for their routine HIV care was performed. Forty two HIV-positive men who have sex with men were recruited between January and August 2014. In participants on antiretroviral therapy (ART), there was no significant difference in rectal VL in those with and without STI ( p = 0.4). All rectal HIV VLs were below the limit of detection (<100 copies/ug of total RNA) whether an STI was present or not. In those not on ART, rectal HIV VL was on average 0.6log10 lower post STI treatment. The presence of asymptomatic rectal chlamydia and gonorrhoea was not associated with increased rectal HIV VL in those fully suppressed on ART. In the context of effective ART, the presence of rectal gonorrhoea or chlamydia does not appear to increase rectal HIV VL and the risk of increased viral infectivity. PMID- 28081681 TI - Contextual, experiential, and behavioral risk factors associated with HIV status: a descriptive analysis of transgender women residing in Atlanta, Georgia. AB - This study assessed the prevalence of self-reported HIV infection among a community sample of transgender women and identified associated contextual, experiential, and behavioral factors. Ninety-two transgender women completed a self-administered interview. Recruitment occurred through an LGBT service organization, a transgender support group, transgender advocates, and informal communications. Eighty-two percent were African American/Black. Of 83 who knew their status, 60% reported being HIV infected. High rates of childhood sexual abuse (52%), rape (53%), intimate partner violence (56%), and incarceration (57%) were reported. Many did not have health insurance (53%), were not employed full time nor in school (63%) and had been recently homeless (49%). HIV-infected transgender women as compared to HIV-uninfected transgender women were more likely to be African American/Black ( P = 0.04), and older than 34 years ( P = 0.01), unemployed/not in school ( P < 0.001). HIV-infected transgender women also experienced less trans-related discrimination ( P = 0.03), perceived less negative psychosocial impact due to trans status ( P = 0.04) and had greater happiness with their physical appearance ( P = 0.01). HIV-infected transgender women may experience relatively less trans-related stress compared to their HIV uninfected counterparts. High rates of HIV, trauma, and social marginalization raise concerns for this population and warrant the development of structural and policy-informed interventions. PMID- 28081682 TI - Genital lichen sclerosus developing around 'ectopic' urethral orifices supports the role of occlusion and urine in its pathogenesis. AB - Several factors such as genetic susceptibility, autoimmunity, hormones, infections, local trauma, urine, and occlusion have been speculated to play a role in the pathogenesis of lichen sclerosus. We report two male patients with lichen sclerosus around 'ectopic' urethral openings and the opposing surfaces of the penile shaft and scrotum, providing further evidence in support of urine and occlusion as contributing factors in the development of lichen sclerosus. PMID- 28081683 TI - High HIV prevalence and associated risk factors among female sex workers in Rwanda. AB - Human immunodeficiency virus (HIV) prevalence is often high among female sex workers (FSWs) in sub-Saharan Africa. Understanding the dynamics of HIV infection in this key population is critical to developing appropriate prevention strategies. We aimed to describe the prevalence and associated risk factors among a sample of FSWs in Rwanda from a survey conducted in 2010. A cross-sectional biological and behavioral survey was conducted among FSWs in Rwanda. Time location sampling was used for participant recruitment from 4 to 18 February 2010. HIV testing was done using HIV rapid diagnostic tests (RDT) as per Rwandan national guidelines at the time of the survey. Elisa tests were simultaneously done on all samples tested HIV-positive on RDT. Proportions were used for sample description; multivariable logistic regression model was performed to analyze factors associated with HIV infection. Of 1338 women included in the study, 1112 consented to HIV testing, and the overall HIV prevalence was 51.0%. Sixty percent had been engaged in sex work for less than five years and 80% were street based. In multivariable logistic regression, HIV prevalence was higher in FSWs 25 years or older (adjusted odds ratio [aOR] = 1.83, 95% [confidence interval (CI): 1.42 2.37]), FSWs with consistent condom use in the last 30 days (aOR = 1.39, [95% CI: 1.05-1.82]), and FSWs experiencing at least one STI symptom in the last 12 months (aOR = 1.74 [95% CI: 1.34-2.26]). There was an inverse relationship between HIV prevalence and comprehensive HIV knowledge (aOR = 0.65, [95% CI: 0.48-0.88]). HIV prevalence was high among a sample of FSWs in Rwanda, and successful prevention strategies should focus on HIV education, treatment of sexually transmitted infections, and proper and consistent condom use using an outreach approach. PMID- 28081685 TI - Tracing partners of patients with syphilis infection remains challenging: experience of Geneva Hospital. AB - Syphilis has been reinstated on the list of notifiable diseases in Switzerland since 2006 and the active management of sexual partners is encouraged to avoid reinfection. However, contact tracing has yielded unsatisfactory results and the incidence of syphilis remains important, especially in high-risk populations. The aim of this study was to compare the proportions of notified sexual partners of patients diagnosed with syphilis by the laboratories of Geneva University Hospitals (HUG) with those diagnosed in private laboratories (non-HUG) and to assess the risk factors for no notification to sexual partners. All syphilis cases notified to the Office of the Surgeon General in Geneva (Switzerland) between 1 January 2011 and 31 December 2013 were analysed. The proportions of partner notification (PN) between HUG and non-HUG laboratories were compared by Chi square test and the main risk factors for no notification to sexual partners were assessed by binomial log-linear regression. Among a total of 720 notifications reported, 244 cases were diagnosed with contagious syphilis stages and 263 with non-contagious stages (i.e. successfully treated patients with or late latent cases). Overall, PN was higher among contagious than non-contagious cases (58.4% versus 31.0%; p = 0.030) and it was significantly higher in the non HUG compared to the HUG group (75.9% versus 50.0%, respectively; p < 0.001). Risk factors independently associated with no notification to sexual partners were the place of diagnosis (risk ratio [RR] 1.66; 95% confidence interval [CI] 1.21-2.27 for HUG versus non-HUG, respectively), age >45 years (RR 1.36; 95% CI: 1.05-1.76) and if the patient had received treatment for syphilis (RR 1.91; 95% CI: 1.38 2.66). Our results illustrate the difficulty of contact tracing in syphilis infection and the necessity to improve this crucial part of sexually transmitted infection management. PMID- 28081684 TI - Implementation and outcomes of a new safeguarding pathway for vulnerable adults presenting to sexual health services. AB - Adult safeguarding is the process of protecting vulnerable adults from harm or exploitation. In 2014, our sexual health clinic implemented a new adult safeguarding pathway, including an adult safeguarding proforma, an electronic database and a monthly adult safeguarding meeting. We conducted a retrospective case note review of patients entered onto the safeguarding database and found that greater numbers of adults were identified as vulnerable following the introduction of this pathway. Many required referral for onward support, highlighting the importance of robust safeguarding procedures in a sexual health setting. PMID- 28081686 TI - 2017 European guideline for the management of chancroid. AB - Chancroid is a sexually acquired infection caused by Haemophilus ducreyi. The infection is characterized by one or more genital ulcers, which are soft and painful, and regional lymphadenitis, which may develop into buboes. The infection may easily be misidentified due to its rare occurrence in Europe and difficulties in detecting the causative pathogen. H. ducreyi is difficult to culture. Nucleic acid amplification tests can demonstrate the bacterium in suspected cases. Antibiotics are usually effective in curing chancroid. PMID- 28081688 TI - Focus Ion Beam/Scanning Electron Microscopy Characterization of Osteoclastic Resorption of Calcium Phosphate Substrates. AB - This article presents the application of dual focused ion beam/scanning electron microscopy (FIB-SEM) imaging for preclinical testing of calcium phosphates with osteoclast precursor cells and how this high-resolution imaging technique is able to reveal microstructural changes at a level of detail previously not possible. Calcium phosphate substrates, having similar compositions but different microstructures, were produced using low- and high-temperature processes (biomimetic calcium-deficient hydroxyapatite [CDHA] and stoichiometric sintered hydroxyapatite, respectively). Human osteoclast precursor cells were cultured for 21 days before evaluating their resorptive potential on varying microstructural features. Alternative to classical morphological evaluation of osteoclasts (OC), FIB-SEM was used to observe the subjacent microstructure by transversally sectioning cells and observing both the cells and the substrates. Resorption pits, indicating OC activity, were visible on the smoother surface of high temperature sintered hydroxyapatite. FIB-SEM analysis revealed signs of acidic degradation on the grain surface under the cells, as well as intergranular dissolution. No resorption pits were evident on the surface of the rough CDHA substrates. However, whereas no degradation was detected by FIB sections in the material underlying some of the cells, early stages of OC-mediated acidic degradation were observed under cells with more spread morphology. Collectively, these results highlight the potential of FIB to evaluate the resorptive activity of OC, even in rough, irregular, or coarse surfaces where degradation pits are otherwise difficult to visualize. PMID- 28081689 TI - Origin and evolutionary dynamics of Hepatitis B virus (HBV) genotype E in Madagascar. AB - Africa is one of the endemic regions of HBV infection. In particular, genotype E is highly endemic in most of sub-Saharan Africa such as West African countries where it represents more than 90% of total infections. Madagascar, which is classified as a high endemic area for HBV and where the most prevalent genotype is E, might play a relevant role in the dispersion of this genotype due to its crucial position in the Indian Ocean. The aim of this study was to investigate the origin, population dynamics, and circulation of HBV-E genotype in Madagascar through high-resolution phylogenetic and phylodynamic approaches. The phylogenetic tree indicated that Malagasy isolates were intermixed and closely related with sequences mostly from West African countries. The Bayesian tree highlighted three statistically supported clusters of Malagasy strains which dated back to the years 1981 (95% HPD: 1971-1992), 1986 (95% HPD: 1974-1996), and 1989 (95% HPD: 1974-2001). Population dynamics analysis showed an exponential increase in the number of HBV-E infections approximately from the year 1975 until 2000s. The migration analysis was also performed and a dynamic pattern of gene flow was identified. In conclusion, this study confirms previous observation of HBV-E circulation in Africa and expands these findings at Madagascar demonstrating its recent introduction, and highlighting the role of the African countries in the spread of HBV-E genotype. Further studies on molecular epidemiology of HBV genotype E are needed to clarify the evolutionary history of this genotype. PMID- 28081690 TI - Immunoglobulin G4-Related Inflammatory Abdominal Aortic Aneurysm Associated With Myasthenia Gravis, With Contained Rupture. AB - Immunoglobulin (Ig) G4-related disease is reportedly among the various causes of inflammatory abdominal aortic aneurysm (IAAA). Many IgG4-related diseases are closely related to allergic constitution and autoimmune disease. We report a case of a 72-year-old man with IgG4-related IAAA associated with myasthenia gravis, with contained rupture. PMID- 28081691 TI - Comparison of Drug-Eluting Balloon and Standard Balloon Angioplasty for Infrapopliteal Arterial Diseases in Diabetic Patients. AB - OBJECTIVE: To consider the clinical outcomes and restenosis rates of drug-eluting balloons (DEBs) and percutaneous transluminal angioplasty (PTA) in diabetic patients with infrapopliteal (IP) arterial disease. MATERIALS AND METHODS: This retrospective, single-center study included 51 patients (37 males; mean age: 63.43 +/- 9.81 years) with diabetes mellitus having IP arterial disease, from October 2012 to September 2014. Twenty-two patients were treated with PTA, and 29 patients were treated with DEBs. After intervention, the patients were evaluated in the first week and every 3 months, clinically and radiologically. Univariate and multivariate analyses were used to evaluate the clinical outcomes of diabetic patients with IP arterial disease who were treated with either DEBs or PTA. RESULTS: There were no statistically significant differences between the groups in terms of age and gender, risk factors, characteristics of lesions, or the diameters or length of the balloons ( P > .05). Primary patency was higher in the DEB group than in the PTA group (97.8% vs 81.1%, P = .020) in the first 3 months. However, there was no statistically significant difference at 1-year follow-up (68.2% vs 48.5%, P = .131). At the 12-month follow-up, there was no difference in clinical improvement between the groups ( P = .193). CONCLUSION: The findings of this study reveal that DEB is a safe alternative treatment method for IP arterial disease in diabetic patients. PMID- 28081692 TI - Percutaneous Removal of a Tiny Needle Fracture From the Right Ventricle of the Heart in a Drug Abuser. AB - PURPOSE: To demonstrate the successful percutaneous removal of a tiny needle fracture from the heart with the use of a guide wire with a magnet at its distal end and two snares through both femoral veins. CASE REPORT: We report a rare case of a tiny needle fracture in the apex of the right ventricle of the heart in a drug abuser after its migration from the neck through the lumen of the right internal jugular vein. The procedure of the percutaneous approach and removal of this tiny foreign body was extremely difficult and dangerous due to its location and tiny size. CONCLUSION: This percutaneous technique for the removal of a tiny foreign body from the heart was proven to be both effective and safe for the patient, and it provides a good therapeutic option for removal of intracardiac foreign bodies. PMID- 28081693 TI - Endovascular Management of Central Retinal Arterial Occlusion. AB - BACKGROUND AND IMPORTANCE: Central retinal artery occlusion (CRAO) is an ophthalmologic emergency due to the sudden cessation of circulation to the inner retinal layer. Without immediate treatment, permanent blindness may ensue. Several treatment options exist, ranging from noninvasive medical management to thrombolysis. Nonetheless, ongoing debate exists regarding the best therapeutic strategy. CASE PRESENTATION: The authors present the case of a 78-year-old woman with a medical history of hypercholesterolemia and rheumatoid arthritis who experienced complete loss of vision in her left eye. Following ophthalmologic evaluation demonstrating left CRAO, anterior chamber paracentesis was performed. Endovascular intervention was performed via local intra-arterial fibrinolysis with alteplase. Her vision returned to 20/20 following the procedure. In general, conventional therapies have not significantly improved patient outcomes. CONCLUSION: Several management options exist for CRAO. In general, conservative measures have not been reported to yield better patient outcomes as compared to the natural history of this medical emergency. Endovascular approaches are another option as observed with this case reported. In cases of CRAO, therapeutic strategies such as intra-arterial fibrinolysis utilize a local infusion of reactive tissue plasminogen activator directly at the site of occlusion via catheterization of the ophthalmic artery. Although several case series do show promising results after treating CRAO with intra-arterial fibrinolysis, further studies are required given the reports of complications. PMID- 28081695 TI - DNA methylation of imprinted loci of autosomal chromosomes and IGF2 is not affected in Parkinson's disease patients' peripheral blood mononuclear cells. AB - OBJECTIVE: Genomic imprinting is an epigenetic phenomenon that results in differential expression of alleles, depending on their parental origin. The functional significance of DNA methylation in genomic imprinting has been widely investigated, and to date, approximately 100 imprinted genes have been identified in humans. METHODS: To investigate whether the methylation status of these 'known' imprinting genes was associated with Parkinson's disease (PD), we analyzed the methylation profiles of all 'known' imprinted genes using the Illumina 450K methylation chip. Samples were derived from mononuclear blood cells of 17 male Parkinson's disease patients vs. 21 healthy male individuals and 12 discordant MZ twin pairs. RESULTS: None of the annotated autosomal genes show changes in DNA methylation between PD individuals and healthy individuals. We further refined our analysis by evaluating the DNA methylation status of the maternally imprinted human gene encoding insulin-like growth factor 2 (IGF2) using bisulfite sequencing PCR (BSP) of DNA derived from 15 PD patients and 9 controls, taking into consideration different dosages of L-dopa. CONCLUSION: Our results demonstrated that methylation of IGF2 in PD patients was neither influenced by the dosage of L-dopa treatment nor by the disease itself. Thus, loss or disruption of imprinting in autosomal chromosomes does not seem to be relevant for the pathogenesis of the disease. PMID- 28081694 TI - International Occupational Therapy Research Priorities. AB - Occupational therapy is a global profession represented by the World Federation of Occupational Therapists (WFOT). International research priorities are needed for strategic guidance on global occupational therapy practice. The objective of this study was to develop international research priorities to reflect global occupational therapy practice. A Delphi study using three rounds of electronic surveys, distributed to WFOT member organizations and WFOT accredited universities, was conducted. Data were analyzed after each round, and priorities were presented for rating and ranking in order of importance. Forty-six (53%) out of 87 WFOT member countries participated in the Delphi process. Eight research priorities were confirmed by the final electronic survey round. Differences were observed in rankings given by member organizations and university respondents. Despite attrition at Round 3, the final research priorities will help to focus research efforts in occupational therapy globally. Follow-up research is needed to determine how the research priorities are being adopted internationally. PMID- 28081696 TI - Effect of Metformin Therapy on Serum Fetuin Levels in Insulin Resistant Type 1 Diabetics. AB - INTRODUCTION: Insulin resistance may develop with Type 1 diabetes. Insulin resistance is currently recognized by the estimated glucose disposal rate. Serum fetuin has been accused as a risk factor for metabolic syndrome. AIM: To determine the relationship between the serum fetuin and insulin resistance in Type 1 diabetes subjects and the effect of short-term Metformin therapy on this relationship. METHODS: 40 T1DM male >= 18 years of age were screened for insulin resistance (defined using estimated glucose disposal rate). 20 subjects (Group I) were insulin resistant with a mean estimated glucose disposal rate of (7.15+/ 0.37 mg/kg/min) while 20 subjects (Group II) were non-insulin resistant with a mean estimated glucose disposal rate of (9.08+/-0.42 mg/kg/min). Fasting blood sugar, 2 hours-post prandial blood sugar, HbA1c%, C-peptide, lipid profile, highly sensitive-C reactive protein, and serum fetuin were assessed. Group I were given 1gm Metformin twice daily for 3 months as an add-on to their insulin regimen. All anthropometric and laboratory parameters were reassessed at the end of the 3 months. RESULTS: Group I had a higher age, BMI and waist/hip ratio, FBS, PPBS, HbA1c%, TC, LDL-C, TG, Hs-CRP and serum fetuin (rho <= 0.001), and a lower C-peptide (rho=0.001). Fetuin showed a positive correlation with age, FBS, HbA1c%, and Hs-CRP. After Metformin therapy, FBS, PPB and HbA1c%, Hs- CRP and fetuin decreased (rho<=0.001) while eGDR and insulin dose in units/kg increased (rho <0.001). Correlation after Metformin therapy within Group I showed that eGDR was inversely related with FBS and PPBS and fetuin showed a positive correlation with Hs-CRP. CONCLUSION: Serum fetuin was elevated in insulin resistant T1DM, yet this was not associated with eGDR. Levels of fetuin-A and HsCRP decreased after Metformin therapy. PMID- 28081698 TI - Treatment Avenues for Type 2 Diabetes and Current Perspectives on Adipokines. AB - BACKGROUND: Diabetes has turned into a pandemic disorder that is affecting millions of people worldwide. Industries are aggressively racing and pursuing research towards the discovery of antidiabetic drug and the current global sale of such drugs are ever on the increase. However, in spite of such massive level of expenditure thereof, WHO projects that by 2030, diabetes will rank as the 7th leading cause of mortality. OBJECTIVE: It is in this context that we have reviewed here the various approaches available and possible towards diabetes management. This review also includes the WHO guidelines for controlling the glycemic levels, which must be known and followed by clinicians for a better diabetes management. CONCLUSION: Despite having a wealth of FDA-approved therapeutic options for type 2 diabetes majorities of the patients are not able to achieve the appropriate glycemic control due to various factors. The development of new options with actions at multiple foci of diabetic manifestation and better efficacy may potentially help in improving the current scenario of T2D management. PMID- 28081697 TI - Cytokine Gene Variants as Predictors of Type 2 Diabetes Mellitus. AB - BACKGROUND: Diabetes is the third widespread after heart disease and cancer. We have investigated genetic polymorphisms in cytokine genes viz. IL-4, IL-1Ra, IL 1beta, IL-18, IL-6, TNF-alpha, IL-10 and ADIPOQ. The aim of study was to investigate the haplotypes, gene-gene interactions and their role in determining individual susceptibility to T2DM of family members with diabetic history. METHODS: Haplotype analysis of 2 SNPs each in IL-6 and adiponectin genes showing Pairwise Linkage disequilibrium (LD) was done by SHEsis software. Logistic regression was used to study various combinations of gene-gene interactions. RESULTS: The TCGT* set of allele combination appeared to increase the disease risk upto 2 times while TATG* upto 51.4 times when four SNPs are taken together viz. IL-1beta-511 C/T, IL-18-607 A/C, ADIPOQ1 +45 G/T and ADIPOQ2 +10211 T/G. Interaction of SNPs in eight genes showed one highly significant combination of alleles, TCGAGCTT* which increased the risk of T2DM upto 7.4 times while CAGAGCGT* allele combination increased the risk upto 4 times. CONCLUSION: During pedigree analysis in six families with four SNPs, it was interesting to note that susceptible 'AC' genotype of IL-18-607 A/C was frequent in diabetic individuals in almost all families. Moreover, when checked for the presence of risk haplotypes it was observed that TCGT* and TATG* sets of allele combinations were present in most of the diabetic individuals. Individuals with certain abnormal biochemical parameters but not yet diagnosed for T2DM carried the risk genotype or haplotype. This suggested that individuals carrying risk genotypes/haplotypes might be susceptible to T2DM and develop the disease in the future. PMID- 28081699 TI - Erratum to: Experiences and attitudes of residents regarding a community-based genome cohort study in Japan: a population-based, cross-sectional study. PMID- 28081700 TI - HHV-6A in vitro infection of thyrocytes and T cells alters the expression of miRNA associated to autoimmune thyroiditis. AB - BACKGROUND: Human herpesviruses have been hypothesized as environmental triggers in the development of autoimmune thyroid diseases (AITD), and in particular active human herpesvirus 6A (HHV-6A) infection was detected in thyrocytes of Hashimoto's thyroiditis (HT) patients, who also show specific anti-viral immune responses. On the other hand, AITD patients display modulation of specific miRNAs in thyroid tissue and blood. We wanted to ascertain whether HHV-6A infection might be correlated to the miRNA dysregulation observed in AITD. METHODS: Human thyroid and T-cell lines were infected in vitro with HHV-6A,-6B or -7, and analysed for miRNAs expression, either by microarray or by specific RT-PCR assays detecting miRNAs associated with AITD in vivo. RESULTS: HHV-6A infection, but not -6B or -7 infections, induced a decrease in miR-155_2 expression and an increase in miR-1238 expression in thyrocytes, as well as an increase in the expression levels of several autoimmunity-associated miRNAs in T lymphocytes, including miR 16_1, miR34a, miR-130a, miR-143_1, miR-202, miR-301b, miR-302c, miR-449b, miR 451_1, and miR-1238_2. CONCLUSIONS: HHV-6A infection modulates miRNAs expression in the cell types involved in the development of AITD. Notably, our in vitro findings correlate with what observed in AITD patients, further supporting the association between HHV-6A infection and AITD development. Moreover, these effects are 6A-specific, emphasizing the differences between the two HHV-6 virus species, and suggesting diverse virus mechanisms of action and therapeutic approaches. PMID- 28081701 TI - Erratum to: Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation. PMID- 28081702 TI - Erratum to: Socioeconomic variation in incidence of primary and secondary major cardiovascular disease events: an Australian population-based prospective cohort study. PMID- 28081703 TI - Identification and validation of differentially expressed transcripts by RNA sequencing of formalin-fixed, paraffin-embedded (FFPE) lung tissue from patients with Idiopathic Pulmonary Fibrosis. AB - BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a lethal lung disease of unknown etiology. A major limitation in transcriptomic profiling of lung tissue in IPF has been a dependence on snap-frozen fresh tissues (FF). In this project we sought to determine whether genome scale transcript profiling using RNA Sequencing (RNA-Seq) could be applied to archived Formalin-Fixed Paraffin Embedded (FFPE) IPF tissues. RESULTS: We isolated total RNA from 7 IPF and 5 control FFPE lung tissues and performed 50 base pair paired-end sequencing on Illumina 2000 HiSeq. TopHat2 was used to map sequencing reads to the human genome. On average ~62 million reads (53.4% of ~116 million reads) were mapped per sample. 4,131 genes were differentially expressed between IPF and controls (1,920 increased and 2,211 decreased (FDR < 0.05). We compared our results to differentially expressed genes calculated from a previously published dataset generated from FF tissues analyzed on Agilent microarrays (GSE47460). The overlap of differentially expressed genes was very high (760 increased and 1,413 decreased, FDR < 0.05). Only 92 differentially expressed genes changed in opposite directions. Pathway enrichment analysis performed using MetaCore confirmed numerous IPF relevant genes and pathways including extracellular remodeling, TGF-beta, and WNT. Gene network analysis of MMP7, a highly differentially expressed gene in both datasets, revealed the same canonical pathways and gene network candidates in RNA-Seq and microarray data. For validation by NanoString nCounter(r) we selected 35 genes that had a fold change of 2 in at least one dataset (10 discordant, 10 significantly differentially expressed in one dataset only and 15 concordant genes). High concordance of fold change and FDR was observed for each type of the samples (FF vs FFPE) with both microarrays (r = 0.92) and RNA-Seq (r = 0.90) and the number of discordant genes was reduced to four. CONCLUSIONS: Our results demonstrate that RNA sequencing of RNA obtained from archived FFPE lung tissues is feasible. The results obtained from FFPE tissue are highly comparable to FF tissues. The ability to perform RNA Seq on archived FFPE IPF tissues should greatly enhance the availability of tissue biopsies for research in IPF. PMID- 28081704 TI - Bilateral benign renal oncocytomas and the role of renal biopsy: single institution review. AB - BACKGROUND: The goal was to assess the natural history and management of patients with pathologically proven bilateral (synchronous) RO after undergoing initial partial nephrectomy (PN). METHODS: All patients underwent either robotic/laparoscopic or open PN by two experienced genitourinary oncologists from 2005-2013. Final pathology was determined by surgical excision, CT-guided percutaneous core biopsy (CT-biopsy) or fine needle aspiration (FNA). Patient demographics, tumor characteristics (pathologic data, location, size) type of surgery, pre/post estimated glomerular filtration rate (eGFR) and surgical complications were recorded. RESULTS: Twelve patients were identified with bilateral RO. Median age at the time of surgery was 68 years (46-77) (Table 1). The median size of the largest tumor(s) resected was 2.75 cm (1.5-5.5 cm) and second largest tumor(s) was 1.75 cm (1.0-4.0 cm). Four patients underwent bilateral staged PN and one patient underwent simultaneous bilateral PN (horseshoe kidney). Two patients underwent RFA at the time of biopsy of the contralateral mass after PN. Five patients underwent CT-bx/FNA (5/5) of the contralateral mass followed by active surveillance. Mean follow up was 34 months. There was no significant change in median creatinine pre- and post-operatively. One patient was lost to follow up and one patient died of unknown causes 5 years post-operatively. eGFR decreased an average of 16.96% post-operatively, including a single patient whose eGFR increased by 7.8% after surgery and a single patient whose eGFR did not change (Table 2). CONCLUSIONS: Patients with bilateral renal masses and pathologically proven RO can be safely managed with active surveillance after biopsy confirmation of the contralateral mass. PMID- 28081705 TI - Development of a microarray for simultaneous detection and differentiation of different tospoviruses that are serologically related to Tomato spotted wilt virus. AB - BACKGROUND: Tospoviruses, the plant-infecting genus in the family Bunyaviridae, are thrips borne and cause severe agricultural losses worldwide. Based on the serological relationships of the structural nucleocapsid protein (NP), the current tospoviruses are divided into six serogroups. The use of NP-antisera is convenient for virus detection, but it is insufficient to identify virus species grouped in a serogroup due to the serological cross-reaction. Alternatively, virus species can be identified by the N gene amplification using specific primers. Tomato spotted wilt virus (TSWV) is the type species of the genus Tospovirus and one of the most destructive plant viruses. Eight known tospoviruses, Alstroemeria necrotic streak virus (ANSV), Chrysanthemum stem necrosis virus (CSNV), Groundnut ringspot virus (GRSV), Impatiens necrotic spot virus (INSV), Melon severe mosaic virus (MeSMV), Pepper necrotic spot virus (PNSV), Tomato chlorotic spot virus (TCSV) and Zucchini lethal chlorosis virus (ZLCV), sharing serological relatedness with TSWV in NP, are grouped in the TSWV serogroup. Most of the TSWV-serogroup viruses prevail in Europe and America. An efficient diagnostic method is necessary for inspecting these tospoviruses in Asia, including Taiwan. METHODS: A microarray platform was developed for simultaneous detection and identification of TSWV-serogroup tospoviruses. Total RNAs extracted from Chenopodium quinoa leaves separately inoculated with ANSV, CSNV, GRSV, INSV, TCSV and TSWV were used for testing purposes. The 5' biotinylated degenerate forward and reverse primers were designed from the consensus sequences of N genes of TSWV-serogroup tospoviruses for reverse transcription-polymerase chain reaction (RT-PCR) amplification. Virus-specific oligonucleotide probes were spotted on the surface of polyvinyl chloride (PVC) chips to hybridize with PCR products. The hybridization signals were visualized by hydrolysis of NBT/BCIP with streptavidine-conjugated alkaline phosphatase. The microarray was further applied to diagnose virus infection in field crop samples. RESULTS: Amplicons of approximately 0.46 kb were amplified from all tested TSWV serogroup tospoviruses by RT-PCR using the degenerate primer pair Pr-dTS-f/Pr-dTS r. Virus species were identified on chips by hybridization of PCR products with respective virus-specific probes. The microarray was successfully used to diagnose TSWV infection in field pepper samples. CONCLUSIONS: In this study, a rapid, sensitive and precise microarray method has been developed to simultaneously detect and identify six TSWV-serogroup tospoviruses. The microarray platform provides a great potential to explore tospoviruses that can help researchers and quarantine staff to prevent invasions of tospoviruses. PMID- 28081706 TI - Berberine inhibits enterovirus 71 replication by downregulating the MEK/ERK signaling pathway and autophagy. AB - BACKGROUND: The MEK-ERK signaling pathway and autophagy play an important role for enterovirus71(EV71) replication. Inhibition of MEK-ERK signaling pathway and autophagy is shown to impair EV71 replication. Berberine (BBR), an isoquinoline alkaloid isolated from Berberis vulgaris L., has been reported to have ability to regulate this signaling pathway and autophagy. Herein, we want to determine whether berberine can inhibit EV71 infection by downregulating the MEK/ERK signaling pathway and autophagy. METHODS: The antiviral effect of berberine was determined by cytopathic effect (CPE) assay, western blotting assay and qRT-PCR assay. The mechanism of BBR anti-virus was determined by western blotting assay and immunofluorescence assay. RESULTS: We showed that berberine does-dependently reduced EV71 RNA and protein synthesis, which was, at least in part, the result of inhibition of activation of MEK/ERK signaling pathway. Furthermore, we found that berberine suppressed the EV71-induced autophagy by activating AKT protein and inhibiting the phosphorylation of JNK and PI3KIII. CONCLUSIONS: BBR inhibited EV71 replication by downregulating autophagy and MEK/ERK signaling pathway. These findings suggest that BBR may be a potential agent or supplement against EV71 infection. PMID- 28081707 TI - Antigen-specific single B cell sorting and expression-cloning from immunoglobulin humanized rats: a rapid and versatile method for the generation of high affinity and discriminative human monoclonal antibodies. AB - BACKGROUND: There is an ever-increasing need of monoclonal antibodies (mAbs) for biomedical applications and fully human binders are particularly desirable due to their reduced immunogenicity in patients. We have applied a strategy for the isolation of antigen-specific B cells using tetramerized proteins and single-cell sorting followed by reconstruction of human mAbs by RT-PCR and expression cloning. RESULTS: This strategy, using human peripheral blood B cells, enabled the production of low affinity human mAbs against major histocompatibility complex molecules loaded with peptides (pMHC). We then implemented this technology using human immunoglobulin transgenic rats, which after immunization with an antigen of interest express high affinity-matured antibodies with human idiotypes. Using rapid immunization, followed by tetramer-based B-cell sorting and expression cloning, we generated several fully humanized mAbs with strong affinities, which could discriminate between highly homologous proteins (eg. different pMHC complexes). CONCLUSIONS: Therefore, we describe a versatile and more effective approach as compared to hybridoma generation or phage or yeast display technologies for the generation of highly specific and discriminative fully human mAbs that could be useful both for basic research and immunotherapeutic purposes. PMID- 28081708 TI - Identifying aggressive prostate cancer foci using a DNA methylation classifier. AB - BACKGROUND: Slow-growing prostate cancer (PC) can be aggressive in a subset of cases. Therefore, prognostic tools to guide clinical decision-making and avoid overtreatment of indolent PC and undertreatment of aggressive disease are urgently needed. PC has a propensity to be multifocal with several different cancerous foci per gland. RESULTS: Here, we have taken advantage of the multifocal propensity of PC and categorized aggressiveness of individual PC foci based on DNA methylation patterns in primary PC foci and matched lymph node metastases. In a set of 14 patients, we demonstrate that over half of the cases have multiple epigenetically distinct subclones and determine the primary subclone from which the metastatic lesion(s) originated. Furthermore, we develop an aggressiveness classifier consisting of 25 DNA methylation probes to determine aggressive and non-aggressive subclones. Upon validation of the classifier in an independent cohort, the predicted aggressive tumors are significantly associated with the presence of lymph node metastases and invasive tumor stages. CONCLUSIONS: Overall, this study provides molecular-based support for determining PC aggressiveness with the potential to impact clinical decision-making, such as targeted biopsy approaches for early diagnosis and active surveillance, in addition to focal therapy. PMID- 28081709 TI - Calprotectin (S100A8/A9) has the strongest association with ultrasound-detected synovitis and predicts response to biologic treatment: results from a longitudinal study of patients with established rheumatoid arthritis. AB - BACKGROUND: Calprotectin (S100A8/A9 or MRP8/14) and S100A12 (leukocyte-derived proteins), interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) are markers of inflammation and angiogenesis. Ultrasound (US) is sensitive for detection of greyscale synovitis and power Doppler (PD) vascularization. The objective of the present study was to explore the associations between calprotectin, S100A12, IL-6, VEGF, erythrocyte sedimentation rate, C-reactive protein and a comprehensive US assessment in patients with rheumatoid arthritis (RA) starting biologic disease-modifying anti-rheumatic drug (bDMARD) treatment. METHODS: A total of 141 patients with RA were assessed by US, clinical examination and biomarker levels at baseline and at 1, 2, 3, 6 and 12 months after initiation of bDMARDs. US assessment of 36 joints and 4 tendon sheaths were scored semi-quantitatively (0-3 scale). European League Against Rheumatism (EULAR) response was calculated. Statistical assessments performed to explore the associations between biomarkers and US sum scores included Spearman's rank correlation analysis as well as linear and linear mixed model regression analyses. RESULTS: Calprotectin showed the overall strongest correlations with both US sum scores (r s = 0.25-0.62) and swollen joint counts (of 32) (r s = 0.24 0.47) (p < 0.05 at all examinations). An association with US sum scores remained after we adjusted for age, sex, disease duration and all the other markers in a regression analysis at baseline. Decreased calprotectin at the first month was predictive of both EULAR response (p <= 0.001) and decreased sum PD scores at 3, 6 and 12 months (p <= 0.05). CONCLUSIONS: Calprotectin had the highest association with US synovitis and predicted treatment response. It may thus be considered as a marker for evaluating inflammation and responsiveness in patients with RA on bDMARD treatment. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) identifier: ACTRN12610000284066 . Registered on 8 April 2010 (retrospectively registered). PMID- 28081712 TI - Erratum to: Perfusion Pressure Cerebral Infarct (PPCI) trial - the importance of mean arterial pressure during cardiopulmonary bypass to prevent cerebral complications after cardiac surgery: study protocol for a randomised controlled trial. PMID- 28081710 TI - The effects of perceived racism on psychological distress mediated by venting and disengagement coping in Native Hawaiians. AB - BACKGROUND: Studies have linked perceived racism to psychological distress via certain coping strategies in several different racial and ethnic groups, but few of these studies included indigenous populations. Elucidating modifiable factors for intervention to reduce the adverse effects of racism on psychological well being is another avenue to addressing health inequities. METHODS: We examined the potential mediating effects of 14 distinct coping strategies on the relationship between perceived racism and psychological distress in a community-based sample of 145 Native Hawaiians using structural equation modeling. RESULTS: Perceived racism had a significant indirect effect on psychological distress, mediated through venting and behavioral disengagement coping strategies, with control for age, gender, educational level, and marital status. DISCUSSION: The findings suggest that certain coping strategies may exacerbate the deleterious effects of racism on a person's psychological well-being. CONCLUSION: Our study adds Native Hawaiians to the list of U.S. racial and ethnic minorities whose psychological well-being is adversely affected by racism. PMID- 28081711 TI - The association between malaria and malnutrition among under-five children in Shashogo District, Southern Ethiopia: a case-control study. AB - BACKGROUND: Recent studies have presented conflicting findings about whether malaria is associated with an increased or decreased risk of malnutrition. Therefore, assessing the relationship between these two disastrous diseases in the most vulnerable groups, such as in children aged below 5 years (under-five children), may lead to the discovery of new low-cost and effective aides to current methods of malnutrition prevention in malaria-endemic areas. Therefore, this study was conducted to assess the relationship between malaria and malnutrition among under five children in an area with a high degree of malaria transmission. METHODS: The study involved comparing malnourished children aged 6 59 months and nourished children of the same age for their past exposure to malaria, in Shashogo District, Southern Ethiopia. A validated structured questionnaire was used to collect home to home socioeconomic data and anthropometric instruments for clinical data. The collected data were analysed using descriptive and inferential statistics by means of EpiData entry software and STATA data analysis software. RESULTS: A total of 356 (89 malnourished and 267 nourished) under-five children participated in the study. Previous exposure to Plasmodium infection was found to be a predictor for the manifestation of malnutrition in under-five children (P = 0.02 [OR = 1.87, CI = 1.115-3.138]). Children from a household with a monthly income of less than USD 15 were 4.5 more likely to be malnourished as compared to the other children (P = 0.001 [OR = 0.422, CI = 0.181-0.978]). CONCLUSION: This study found that exposure to Plasmodium has a significant impact on the nutritional status of children. In addition, socio-demographic factors, such as family income, may play a role in determining whether children are malnourished or not and may lead to increased morbidity due to malnourishment in children living in malaria-endemic areas. Therefore, malnutrition control interventions should be consolidated with malaria prevention strategies particularly in high malaria transmission areas. PMID- 28081713 TI - Genistein protects against Abeta25-35 induced apoptosis of PC12 cells through JNK signaling and modulation of Bcl-2 family messengers. AB - BACKGROUND: Deposition of aggregated amyloid beta (Abeta) protein is hallmark of Alzheimer's disease, leading to dysfunction and apoptosis of neurons. The isoflavone phytoestrogen compound genistein (Gen) exerts a significant protective effect against Abeta25-35 induced neurotoxicity and mitochondrial damage in rat pheochromocytoma (PC12) cells. However, the mechanisms underlying Gen's rescue remain elusive. Therefore we endeavored to research further the molecular mechanisms underlying Gen's inhibition of Abeta25-35 induced apoptosis of neurons. RESULTS: We found that Gen dramatically suppressed the activation by Abeta25-35 of p-c-Jun N-terminal kinase (p-JNK), and also inhibited the JNK dependent decreased of Bcl-w and increased of Bim. Furthermore, Gen significantly reduced the cytoplasmic concentrations of cytochrome c and Smac protein as well as caspase-3 activity. Additionally, pretreatment with JNK inhibitor SP600125 effectively suppressed Abeta25-35 induced PC12 cell cytotoxicity. CONCLUSION: Taken together, the results suggested that Gen protects PC12 cells from Abeta25 35 induced neurotoxicity by interfering with p-JNK activation, thus attenuating the JNK-dependent apoptosis through the mitochondrial pathway. These findings constitute novel insights into the pathway for Abeta25-35 toxicity, and the neuroprotective action of Gen. PMID- 28081715 TI - Erratum to: Mutational landscape of mucinous ovarian carcinoma and its neoplastic precursors. PMID- 28081714 TI - ClinGen Pathogenicity Calculator: a configurable system for assessing pathogenicity of genetic variants. AB - BACKGROUND: The success of the clinical use of sequencing based tests (from single gene to genomes) depends on the accuracy and consistency of variant interpretation. Aiming to improve the interpretation process through practice guidelines, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) have published standards and guidelines for the interpretation of sequence variants. However, manual application of the guidelines is tedious and prone to human error. Web-based tools and software systems may not only address this problem but also document reasoning and supporting evidence, thus enabling transparency of evidence-based reasoning and resolution of discordant interpretations. RESULTS: In this report, we describe the design, implementation, and initial testing of the Clinical Genome Resource (ClinGen) Pathogenicity Calculator, a configurable system and web service for the assessment of pathogenicity of Mendelian germline sequence variants. The system allows users to enter the applicable ACMG/AMP-style evidence tags for a specific allele with links to supporting data for each tag and generate guideline-based pathogenicity assessment for the allele. Through automation and comprehensive documentation of evidence codes, the system facilitates more accurate application of the ACMG/AMP guidelines, improves standardization in variant classification, and facilitates collaborative resolution of discordances. The rules of reasoning are configurable with gene-specific or disease-specific guideline variations (e.g. cardiomyopathy-specific frequency thresholds and functional assays). The software is modular, equipped with robust application program interfaces (APIs), and available under a free open source license and as a cloud-hosted web service, thus facilitating both stand-alone use and integration with existing variant curation and interpretation systems. The Pathogenicity Calculator is accessible at http://calculator.clinicalgenome.org . CONCLUSIONS: By enabling evidence-based reasoning about the pathogenicity of genetic variants and by documenting supporting evidence, the Calculator contributes toward the creation of a knowledge commons and more accurate interpretation of sequence variants in research and clinical care. PMID- 28081716 TI - Heterogeneous pattern of DNA methylation in developmentally important genes correlates with its chromatin conformation. AB - BACKGROUND: DNA methylation is a major epigenetic modification, playing a crucial role in the development and differentiation of higher organisms. DNA methylation is also known to regulate transcription by gene repression. Various developmental genes such as c-mos, HoxB5, Sox11, and Sry show tissue-specific gene expression that was shown to be regulated by promoter DNA methylation. The aim of the present study is to investigate the establishment of chromatin marks (active or repressive) in relation to heterogeneous methylation in the promoter regions of these developmentally important genes. RESULTS: Chromatin-immunoprecipitation (ChIP) assays were performed to immuno-precipitate chromatin by antibodies against both active (H3K4me3) and repressive (H3K9me3) chromatin regions. The analysis of ChIP results showed that both the percentage input and fold enrichment of activated chromatin was higher in tissues expressing the respective genes as compared to the tissues not expressing the same set of genes. This was true for all the genes selected for the study (c-mos, HoxB5, Sox11, and Sry). These findings illustrate that inconsistent DNA methylation patterns (sporadic, mosaic and heterogeneous) may also influence gene regulation, thereby resulting in the modulation of chromatin conformation. CONCLUSIONS: These findings illustrate that various patterns of DNA methylation (asynchronous, mosaic and heterogeneous) correlates with chromatin modification, resulting in the gene regulation. PMID- 28081717 TI - Erratum to: The impact of glutamine supplementation on the symptoms of ataxia telangiectasia: a preclinical assessment. PMID- 28081718 TI - Erratum to: Incidence and risk factor prevalence of community-acquired pneumonia in adults in primary care in Spain (NEUMO-ES-RISK project). PMID- 28081719 TI - The influence of antibiotic prophylaxis on bacterial resistance in urinary tract infections in children with spina bifida. AB - BACKGROUND: Bacterial resistance to antibiotics is an increasingly threatening consequence of antimicrobial exposure for many decades now. In urinary tract infections (UTIs), antibiotic prophylaxis (AP) increases bacterial resistance. We studied the resistance patterns of positive urinary cultures in spina bifida children on clean intermittent catheterization, both continuing and stopping AP. METHODS: In a cohort of 176 spina bifida patients, 88 continued and 88 stopped using AP. During 18 months, a fortnightly catheterized urine sample for bacterial pathogens was cultured. UTIs and significant bacteriuria (SBU) were defined as a positive culture with a single species of bacteria, respectively with and without clinical symptoms and leukocyturia. We compared the percentage of resistance to commonly used antibiotics in the isolated bacteria in both groups. RESULTS: In a total of 4917 cultures, 713 (14.5%) had a positive monoculture, 54.3% of which were Escherichia coli. In the group stopping AP, the resistance percentage to antibiotics in UTI / SBU bacteria was lower than in the group remaining on AP, even when excluding the administered prophylaxis. CONCLUSION: Stopping antibiotic prophylaxis for urinary tract infections is associated with reduced bacterial resistance to antibiotics in children with spina bifida. TRIAL REGISTRATION: ISRCTN ISRCTN56278131 . Registered 20 December 2005. PMID- 28081720 TI - Acute flaccid myelitis associated with enterovirus-D68 infection in an otherwise healthy child. AB - BACKGROUND: Reporting new cases of enterovirus (EV)-D68-associated acute flaccid myelitis (AFM) is essential to understand how the virus causes neurological damage and to characterize EV-D68 strains associated with AFM. CASE PRESENTATION: A previously healthy 4-year-old boy presented with sudden weakness and limited mobility in his left arm. Two days earlier, he had an upper respiratory illness with mild fever. At admission, his physical examination showed that the child was febrile (38.5 degrees C) and alert but had a stiff neck and weakness in his left arm, which was hypotonic and areflexic. Cerebrospinal fluid (CSF) examination showed a mild increase in white blood cell count (80/mm3, 41% neutrophils) and a slightly elevated protein concentration (76 gm/dL). Bacterial culture and molecular biology tests for detecting viral infection in CSF were negative. The patient was then treated with intravenous ceftriaxone and acyclovir. Despite therapy, within 24 h, the muscle weakness extended to all four limbs, which exhibited greatly reduced mobility. Due to his worsening clinical prognosis, the child was transferred to our Pediatric Intensive Care Unit; at admission he was diagnosed with acute flaccid paralysis of all four limbs. Brain magnetic resonance imaging (MRI) was negative, except for a focal signal alteration in the dorsal portion of the medulla oblongata, also involving the pontine tegmentum, whereas spine MRI showed an extensive signal alteration of the cervical and dorsal spinal cord reported as myelitis. Signal alteration was mainly localized in the central grey matter, most likely in the anterior horns. Molecular biology tests performed on nasopharyngeal aspirate and on bronchoalveolar lavage fluid were negative for bacteria but positive for EV-D68 clade B3. Plasmapheresis was performed and corticosteroids and intravenous immunoglobulins were administered. After 4 weeks of treatment, the signs and symptoms of AFM were significantly reduced, although some weakness and tingling remained in the patient's four limbs. MRI acquired after 3 weeks showed that the previously reported alterations were no longer present. CONCLUSION: This case suggests that EV-D68 is a neurotropic agent that can cause AFM and strains are circulating in Europe. EV D68 disease surveillance is required to better understand EV-D68 pathology and to compare various strains that cause AFM. PMID- 28081722 TI - Emerging links between m6A and misregulated mRNA methylation in cancer. AB - N 6-methyladenosine (m6A) in mRNA has emerged as a crucial epitranscriptomic modification that controls cellular differentiation and pluripotency. Recent studies are pointing to a role for the RNA methylation program in cancer self renewal and cell fate, making this a new and promising therapeutic avenue for investigation. PMID- 28081721 TI - Splenic T1-mapping: a novel quantitative method for assessing adenosine stress adequacy for cardiovascular magnetic resonance. AB - BACKGROUND: Perfusion cardiovascular magnetic resonance (CMR) performed with inadequate adenosine stress leads to false-negative results and suboptimal clinical management. The recently proposed marker of adequate stress, the "splenic switch-off" sign, detects splenic blood flow attenuation during stress perfusion (spleen appears dark), but can only be assessed after gadolinium first pass, when it is too late to optimize the stress response. Reduction in splenic blood volume during adenosine stress is expected to shorten native splenic T1, which may predict splenic switch-off without the need for gadolinium. METHODS: Two-hundred and twelve subjects underwent adenosine stress CMR: 1.5 T (n = 104; 75 patients, 29 healthy controls); 3 T (n = 108; 86 patients, 22 healthy controls). Native T1spleen was assessed using heart-rate-independent ShMOLLI prototype sequence at rest and during adenosine stress (140 MUg/kg/min, 4 min, IV) in 3 short-axis slices (basal, mid-ventricular, apical). This was compared with changes in peak splenic perfusion signal intensity (DeltaSIspleen) and the "splenic switch-off" sign on conventional stress/rest gadolinium perfusion imaging. T1spleen values were obtained blinded to perfusion DeltaSIspleen, both were derived using regions of interest carefully placed to avoid artefacts and partial-volume effects. RESULTS: Normal resting splenic T1 values were 1102 +/- 66 ms (1.5 T) and 1352 +/- 114 ms (3 T), slightly higher than in patients (1083 +/- 59 ms, p = 0.04; 1295 +/- 105 ms, p = 0.01, respectively). T1spleen decreased significantly during adenosine stress (mean DeltaT1spleen ~ -40 ms), independent of field strength, age, gender, and cardiovascular diseases. While DeltaT1spleen correlated strongly with DeltaSIspleen (rho = 0.70, p < 0.0001); neither indices showed significant correlations with conventional hemodynamic markers (rate pressure product) during stress. By ROC analysis, a DeltaT1spleen threshold of >= -30 ms during stress predicted the "splenic switch-off" sign (AUC 0.90, p < 0.0001) with sensitivity (90%), specificity (88%), accuracy (90%), PPV (98%), NPV (42%). CONCLUSIONS: Adenosine stress and rest splenic T1-mapping is a novel method for assessing stress responses, independent of conventional hemodynamic parameters. It enables prediction of the visual "splenic switch-off" sign without the need for gadolinium, and correlates well to changes in splenic signal intensity during stress/rest perfusion imaging. DeltaT1spleen holds promise to facilitate optimization of stress responses before gadolinium first-pass perfusion CMR. PMID- 28081723 TI - Kidney dysfunction, systemic inflammation and mental well-being in elderly post myocardial infarction patients. AB - BACKGROUND: The aim was to investigate whether mild kidney dysfunction and low grade inflammation in post-myocardial infarction patients are independently associated with markers of mental well-being (i.e. depressive and apathy symptoms, and dispositional optimism). METHODS: In post-myocardial infarction patients, kidney function was assessed by estimated glomerular filtration rate (eGFR) calculated from the combined CKD-EPI formula based on serum levels of both creatinine and cystatine C. Systemic inflammation was assessed using high sensitivity C-reactive protein (hs-CRP) levels. The 15-item Geriatric Depression Scale (GDS-15), the 3-item apathy subscale and the 4-item optimism questionnaire (4Q) were used to measure mental well-being and were analyzed using linear multivariable regression analysis. RESULTS: Of the 2355 patients, mean age was 72.3 (range 63-84) years and 80.1% were men. After multivariable adjustment, a poorer kidney function was associated with more depressive symptoms (beta = 0.084, p < 0.001), more apathy symptoms (beta = -0.101, p < 0.001), and less dispositional optimism (beta = 0.072, p = 0.002). Moreover, higher levels of hs CRP were associated with more depressive symptoms (beta = 0.051, p = 0.013), more apathy symptoms (beta = 0.083, p < 0.001) and less dispositional optimism (beta = -0.047 p = 0.024). Apathy showed the strongest independent relation with both low eGFR and high hs-CRP. CONCLUSIONS: In post-myocardial infarction patients, impaired kidney function and systemic inflammation showed a stronger association with apathy than with depressive symptoms and dispositional optimism. PMID- 28081724 TI - Health-related quality of life and psychological distress among cancer survivors in Southeast Asia: results from a longitudinal study in eight low- and middle income countries. AB - BACKGROUND: A better understanding of health-related quality of life (HRQoL) and psychological distress in cancer survivors can raise awareness, promote the development of policies in cancer survivorship care, and facilitate better targeted use of limited resources in low- and middle-income countries (LMICs). The main objectives of this paper were therefore to assess HRQoL and the prevalence of psychological distress amongst cancer survivors in Southeast Asia and identify risk factors of these outcomes. METHODS: The ACTION study was a longitudinal study in eight LMICs in Southeast Asia with 5249 first time cancer survivors followed up at 1 year after diagnosis. HRQoL was assessed using the EORTC QLQ-C30 and EQ-5D. Psychological distress (anxiety and depression) was assessed using the Hospital Anxiety and Depression Scale. General linear models and multiple logistic regression were used to identify independent predictors of HRQoL and psychological distress. RESULTS: One year after diagnosis, the mean EORTC QLQ-C30 global health score for survivors was 66.2 out of 100 (SD 22.0), the mean index score on the EQ-5D was 0.74 (SD 0.23), 37% of survivors had at least mild levels of anxiety, and 46% showed at least mild levels of depression. Poorest HRQoL and highest prevalence of anxiety and depression were seen in patients with lung cancer and lymphomas, while highest scores and least psychological distress were seen in female patients with breast and cervical cancer. The most significant predictor of poor HRQoL and psychological distress outcomes was cancer stage at diagnosis. Age, co-morbidities, treatment, and several socioeconomic factors were associated with HRQoL and psychological distress. CONCLUSIONS: Cancer survivors in LMICs in Southeast Asia have impaired HRQoL and substantial proportions have psychological distress. Patients with advanced cancer stages at diagnosis and those in a poor socioeconomic position were most at risk of such poor outcomes. Supportive interventions for cancer patients that address wider aspects of patient wellbeing are needed, as well as policies that address financial and other barriers to timely treatment. PMID- 28081726 TI - Preoperative right ventricle voltage mapping in Ebstein's anomaly: can we make the late arrhythmogenic mortality following the cone procedure zero? AB - A young woman with Epstein's anomaly had a large endocardial scar in the atrialised ventricular myocardium. In patients with significant preoperative ventricular scarring, more information is needed to help appropriately manage the risk of ventricular arrhythmias and sudden death. PMID- 28081727 TI - MicroRNA-200a Suppresses Cell Invasion and Migration by Directly Targeting GAB1 in Hepatocellular Carcinoma. AB - MicroRNA-200a (miR-200a) is frequently downregulated in most cancer types and plays an important role in carcinogenesis and cancer progression. In this study, we determined that miR-200a was downregulated in hepatocellular carcinoma (HCC) tissues and cell lines, consistent with the results of our previous study. Because a previous study suggested that downregulation of miR-200a is correlated with HCC metastasis, we aimed to elucidate the mechanism underlying the role of miR-200a in metastasis in HCC. Here we observed that overexpression of miR-200a resulted in suppression of HCC metastatic ability, including HCC cell migration, invasion, and metastasis, in vitro and in vivo. Furthermore, bioinformatics and luciferase reporter assays indicated that GAB1 is a direct target of miR-200a. Inhibition of GAB1 resulted in substantially decreased cell invasion and migration similar to that observed with overexpression of miR-200a in HCC cell lines, whereas restoration of GAB1 partially rescued the inhibitory effects of miR-200a. Taken together, these data provide novel information for comprehending the tumor-suppressive role of miR-200a in HCC pathogenesis through inhibition of GAB1 translation. PMID- 28081728 TI - Overexpression of Aristaless-Like Homeobox-4 Inhibits Proliferation, Invasion, and EMT in Hepatocellular Carcinoma Cells. AB - Aristaless-like homeobox-4 (ALX4), a member of the Aristaless-like homeobox family, has been found to be involved in tumor cell proliferation, migration, and invasion. However, the role of ALX4 in hepatocellular carcinoma (HCC) remains largely unclear. Therefore, in this study we investigated the effects of ALX4 on HCC. The study results indicated that the expression of ALX4 was downregulated in HCC tissues and cell lines. Furthermore, we demonstrated that overexpression of ALX4 inhibited the proliferation, invasion, and epithelial-mesenchymal transition (EMT) in HCC cells. We also found that ALX4 had an inhibitory effect on the sonic hedgehog (Shh) signaling pathway. Taken together, the results suggest that ALX4 may be a promising target for HCC treatment. PMID- 28081729 TI - Knockdown of Rap2B Inhibits the Proliferation and Invasion in Hepatocellular Carcinoma Cells. AB - Rap2B, a member of the Ras family of small GTP-binding proteins, was found to be highly expressed in various human tumors and plays an important role in the development of tumors. However, the function of Rap2B in hepatocellular carcinoma (HCC) remains unclear. Therefore, in this study, we investigated the biological functions of Rap2B in HCC and the potential underlying mechanisms. Our results indicated that Rap2B was highly expressed in HCC tissues and cell lines. Rap2B silencing obviously inhibited the proliferation, migration, and invasion of HCC cells, as well as attenuated xenografted tumor growth in vivo. Furthermore, Rap2B silencing greatly reduced the expression levels of phosphorylated focal adhesion kinase (p-FAK), matrix metalloproteinase-2 (MMP-2), and MMP-9 in HCC cells. In conclusion, our data suggest that Rap2B silencing inhibits the proliferation and invasion in HCC cells. Thus, Rap2B may have potential as a treatment for HCC. PMID- 28081725 TI - Synthetic and natural antioxidants attenuate cisplatin-induced vomiting. AB - BACKGROUND: Synthetic and natural antioxidants including Bacopa monnieri (L.) Pennell (Scrophulariaceae) which also possess anti-dopaminergic properties, have been proposed to be useful for emetogenic chemotherapy. In this study, synthetic [N-(2-mercaptopropionyl) glycine (MPG), vitamin C (Vit-C)] and natural [grape seed proanthocyanidin (GP), B. monnieri n-butanolic fraction (BM-ButFr)] antioxidants and their combinations were evaluated against cisplatin-induced emesis in pigeons during a 24 h observation period. METHODS: Emesis was induced using cisplatin (7.0 mg/kg, i.v). MPG (10, 20, 30 mg/kg), Vit-C (100, 200, 300 mg/kg), GP (50, 100, 150 mg/kg) and BM-ButFr (5, 10, 20 mg/kg) and their combinations were administered i.m., 15 min before cisplatin administration. The number of vomiting bouts, retching, emetic latency and % weight loss were recorded to assess antiemetic potential. Antioxidant activity was evaluated by the DPPH free radical scavenging assay (FRSA). RESULTS: Significant attenuation of vomiting bouts, retching, % weight loss along with an increase in latency was produced by all the antioxidants and their combinations compared to cisplatin alone and this is the first report of this activity of GP in pigeons. Low EC50 values in the FRSA for MPG (67.66 MUg/mL), Vit-C (69.42 MUg/mL), GP (6.498 MUg/mL) and BM-ButFr (55.61 MUg/mL) compared to BHT standard (98.17 MUg/mL) demonstrated their radical scavenging capacity. Correlation between the antioxidant activity and antiemetic efficacy disclosed a high degree of correlation for the tested antioxidants. CONCLUSION: The selected synthetic and natural antioxidants and their combinations were able to attenuate cisplatin induced vomiting, which correlated with their potent in vitro antioxidant activity. PMID- 28081730 TI - MicroRNA-377 Downregulates Bcl-xL and Increases Apoptosis in Hepatocellular Carcinoma Cells. AB - Aberrantly expressed microRNAs (miRNAs/miRs) and their role in cancer development have recently gained more attention. However, the potential role of miRNAs in hepatocellular carcinoma (HCC) remains largely unknown. In this study, we demonstrated that miR-377 was markedly downregulated in HCC cell lines and primary human HCC tissues. The decreased expression of miR-377 contributes to the upregulation of Bcl-xL expression by targeting its 3'-untranslated region (3' UTR). Functionally, knockdown of miR-377 noticeably increased HCC cell growth and colony formation and inhibited apoptosis. In contrast, overexpression of miR-377 suppressed cell proliferation and increased apoptosis. This study provides new insights for the use of miR-377 as a potential molecular target in HCC therapy. PMID- 28081731 TI - The Biological Effects of Dickkopf1 on Small Cell Lung Cancer Cells and Bone Metastasis. AB - The bone is among the most common sites of metastasis in patients with lung cancer. Over 30%-40% of lung cancers can develop bone metastasis, and no effective therapeutic methods exist in clinic cases. Wnt/beta-catenin signaling and Dickkopf1 (DKK1) play important roles in the progression of lung cancer, which preferentially metastasizes to the skeleton. However, the role of DKK1 in osteotropism of small cell lung cancer (SCLC) remains to be elucidated. This study aimed to define the role of DKK1 in SCLC bone metastasis and investigate the underlying mechanisms. Our results demonstrated that the expression level of DKK1 was dramatically higher in bone metastatic SCLC cells (SBC-5 cell line) compared with that in cells without bone metastatic ability (SBC-3 cell line). Therefore, we hypothesized that DKK1 was involved in the bone metastasis of SCLC. We then suppressed the DKK1 expression in SBC-5 cells by RNAi and found that downregulation of DKK1 can inhibit cell proliferation, colony formation, cell migration, and invasion, but increase the apoptosis rate. Downregulation of DKK1 did not affect the cell cycle progression of SBC-5 cells in vitro. In vivo, downregulated DKK1 in SBC-5 cells resulted in attenuated bone metastasis. These results indicated that DKK1 may be an important regulator in bone metastases of SCLC, and targeting DKK1 may be an effective method to prevent and treat skeleton metastases in SCLC cases. PMID- 28081732 TI - Inhibition of Beclin-1-Mediated Autophagy by MicroRNA-17-5p Enhanced the Radiosensitivity of Glioma Cells. AB - The role of miRNAs in the radiosensitivity of glioma cells and the underlying mechanism is still far from clear. In the present study, we detected six downregulated and seven upregulated miRNAs in the serum after radiotherapy compared with paired serum samples before radiotherapy via miRNA panel PCR. Among these, miR-17-5p was highly reduced (fold change = -4.21). Further, we validated the levels of miR-17-5p in all serum samples with qRT-PCR. In addition, statistical analysis suggested that a reduced miR-17-5P level was positively associated with advanced clinical stage of glioma, incidence of relapse, and tumor differentiation. Moreover, we provided evidence that irradiation markedly activated autophagy and decreased miR-17-5p in the glioma cell line. Further, we demonstrated that irradiation-induced autophagy activation was mediated by beclin 1, and downregulation of beclin-1 via siRNA significantly abolished the irradiation-activated autophagy. Interestingly, we demonstrated that miR-17-5p could directly target beclin-1 via luciferase gene reporter assay. Exotic expression of miRNA-17-5p decreased autophagy activity in vitro. In nude mice, miRNA-17-5p upregulation sensitized the xenograft tumor to irradiation and suppressed irradiation-induced autophagy. Finally, pharmacal inhibition of autophagy markedly enhanced the cytotoxicity of irradiation in RR-U87 cells. PMID- 28081733 TI - Tumor Necrosis Factor (TNF)-alpha-Induced Protein 8-like-2 (TIPE2) Inhibits Proliferation and Tumorigenesis in Breast Cancer Cells. AB - Tumor necrosis factor-alpha (TNF-alpha)-induced protein 8-like-2 (TNFAIP8L2 or TIPE2), a member of the tumor necrosis TNFAIP8 family, was found to be involved in the development and progression of several tumors. However, to date, the role of TIPE2 in breast cancer is still unclear. Thus, the aim of this study is to explore the role of TIPE2 in breast cancer. Our results indicated that TIPE2 expression was significantly decreased in human breast cancer tissue and cell lines. Overexpression of TIPE2 inhibited the proliferation in vitro and tumor xenograft growth in vivo. TIPE2 also inhibited the migration/invasion of breast cancer cells through preventing the epithelial-to-mesenchymal transition (EMT) phenotype. Mechanically, TIPE2 inhibited the expression of beta-catenin, cyclin D1, and c-Myc in breast cancer cells. In conclusion, our findings show that TIPE2 may play an important role in breast cancer cell proliferation, invasion, and tumorigenesis in vivo. Therefore, TIPE2 may be a potential molecular target for the treatment of breast cancer. PMID- 28081734 TI - MicroRNA-142-5p Overexpression Inhibits Cell Growth and Induces Apoptosis by Regulating FOXO in Hepatocellular Carcinoma Cells. AB - Abnormal expression of microRNA (miR)-142-5p has been reported in hepatocellular carcinoma (HCC). However, little information is available regarding the functional role of miR-142-5p in HCC. We aimed to explore the effects of miR-142 5p aberrant expression on HCC cell growth and cell apoptosis, as well as the underlying mechanism. Human HCC cell lines HepG2 and SMMC-7721 cells were transfected with miR-142-5p mimic, inhibitor, or a corresponding negative control. Cell viability, cell cycle distribution, and cell apoptosis were then analyzed. In addition, protein expression of Forkhead box, class O (FOXO) 1 and 3, a Bcl-2-interacting mediator of cell death (Bim), procaspase 3, and activated caspase 3 was measured. After transfection with miR-142-5p inhibitor, FOXO1 and FOXO3 were overexpressed, and then the cell viability and cell apoptosis were determined again. The relative cell viability in both HepG2 and SMMC-7721 cells was significantly reduced by miR-142-5p overexpression (p < 0.05). miR-142-5p overexpression displayed a significant blockage at the G1/S transition and significantly increased the percentages of G0/G1 phase. Moreover, the results showed that miR-142-5p overexpression significantly induced cell apoptosis and statistically elevated the protein expression levels of FOXO1, FOXO3, Bim, procaspase 3, and activated caspase 3. However, the cells transfected with miR 142-5p inhibitor showed contrary results. Additionally, the effects of miR-142-5p inhibitor on cell viability and apoptosis were reversed by overexpression of FOXO. In conclusion, our results suggest that miR-142-5p overexpression shows an important protective role in HCC by inhibiting cell growth and inducing apoptosis. These effects might be by regulating FOXO expression in HCC cells. PMID- 28081735 TI - miR-214-5p Targets ROCK1 and Suppresses Proliferation and Invasion of Human Osteosarcoma Cells. AB - MicroRNAs (miRNAs) are small conserved RNAs regulating specific target genes in posttranscriptional levels. They have been involved in multiple processes of tumor progression, including cell proliferation. miR-214-5p (also miR-214*) is a newly identified miRNA, and its functions are largely unknown. In this study, we explore the role of miR-214-5p in the proliferation and invasion of human osteosarcoma (OS) cells. The results showed that miR-214-5p was sharply reduced in OS tissues and cell lines, compared with normal tissues and cell lines. In addition, the miR-214-5p mimic greatly increased the miR-214-5p level and significantly decreased the proliferation and invasion of HOS and G293 OS cells. In contrast, the miR-214-5p inhibitor had a completely opposite effect on the miR 214-5p level, cell proliferation, and cell invasion. Moreover, bioinformatics and luciferase reporter gene assays confirmed that miR-1908 targeted the mRNA 3'-UTR region of ROCK1, a characterized tumor promoter in OS. In conclusion, miR-214-5p was identified as a new tumor suppressor, which directly targeted ROCK1 and suppressed proliferation of human OS cells. PMID- 28081736 TI - RASSF4 Overexpression Inhibits the Proliferation, Invasion, EMT, and Wnt Signaling Pathway in Osteosarcoma Cells. AB - RASSF4, a member of the RASSF family, is broadly expressed in normal tissues but often inactivated in human cancers. Despite various studies on RASSF4, its role in osteosarcoma remains unclear. Therefore, in this study, we investigated the effects of RASSF4 expression on osteosarcoma cells and explored the underlying mechanism. The results of our study showed that RASSF4 was lowly expressed in osteosarcoma tissues and cells. RASSF4 overexpression significantly inhibited proliferation, migration, and invasion as well as the EMT process in osteosarcoma cells. Meanwhile, we found that RASSF4 overexpression markedly decreased the protein expression of beta-catenin, cyclin D1, and c-Myc in osteosarcoma cells. In conclusion, our findings showed that RASSF4 overexpression inhibits proliferation, invasion, EMT, and Wnt signaling pathway in osteosarcoma cells. Thus, RASSF4 may be considered a novel target for osteosarcoma treatment. PMID- 28081737 TI - Identification of Sensitivity Predictors of Neoadjuvant Chemotherapy for the Treatment of Adenocarcinoma of Gastroesophageal Junction. AB - The identification of reliable predictors of chemotherapy sensitivity and early screening of adenocarcinoma of gastroesophageal junction (AGEJ) patients who are resistant to chemotherapy has become an important area of clinical and translational research. We aimed to investigate the predictive value of seven cancer-associated cellular proteins for neoadjuvant chemotherapy in AGEJ patients. Clinical data of 93 patients who received neoadjuvant chemotherapy for locally advanced AGEJ between June 2010 and December 2014 were reviewed. All patients were administered the combination regimen of S-1 and oxaliplatin (SOX). Expression of P-glycoprotein (P-gp), glutathione S-transferase-pi (GST-pi), topoisomerase II (topo II), multidrug resistance gene-associated protein (MRP), lung resistance-related protein (LRP), Ki-67, and p53 was determined by immunohistochemistry (IHC) in AGEJ tissues before neoadjuvant chemotherapy. Chemotherapeutic efficacy was evaluated according to RECIST 1.0 standards and histopathological results, and the relationship between the expression of the cellular proteins and chemotherapy efficacy was analyzed. The SOX regimen was associated with an overall response rate of 46.2%. The frequency of expression of the seven cancer-associated factors in the AGEJ tissues was as follows: P-gp, 64.5%; GST-pi, 39.8%; topo II, 72.0%; MRP, 33.3%; LRP, 68.8%; Ki-67, 62.4%; and p53, 40.9%. Expression of Ki-67 (p = 0.003) and p53 (p = 0.009) was significantly correlated with chemotherapy sensitivity. Elevated Ki-67 expression and decreased p53 expression predict for SOX insensitivity in AGEJ, and the cellular expression of these respective proteins may provide a useful reference for designing individualized chemotherapy regimens for AGEJ patients in the future. PMID- 28081738 TI - Silencing of Armadillo Repeat-Containing Protein 8 (ARMc8) Inhibits TGF-beta Induced EMT in Bladder Carcinoma UMUC3 Cells. AB - Armadillo repeat-containing protein 8 (ARMc8) is a key factor in regulating cell migration, proliferation, tissue maintenance, and tumorigenesis. However, its role in bladder cancer remains unknown. Thus, in this study we sought to investigate the effect of ARMc8 on the epithelial-to-mesenchymal transition (EMT) progress in bladder cancer cells induced by transforming growth factor-beta1 (TGF beta1). Our results found that ARMc8 was highly expressed in bladder cancer cell lines. ARMc8 silencing inhibited the TGF-beta1-induced migration and invasion and suppressed the EMT progress in bladder cancer cells. Furthermore, ARMc8 silencing inhibited the TGF-beta1-induced expression of beta-catenin, cyclin D1, and c-myc in bladder cancer cells. In conclusion, the present study demonstrates a novel function for ARMc8, which acts as a mediator for TGF-beta1-induced cell migration/invasion through modulation of the Wnt/beta-catenin signaling pathway in bladder cancer cells. This study suggests that ARMc8 may be a potential therapeutic target for the development of therapies for bladder cancer. PMID- 28081739 TI - miR-940 Upregulation Suppresses Cell Proliferation and Induces Apoptosis by Targeting PKC-delta in Ovarian Cancer OVCAR3 Cells. AB - Ovarian cancer remains as one of the most threatening malignancies for females in the world. This study investigated the pivotal role of miR-940 in the progression of ovarian cancer and to reveal the possible molecular mechanism of its action. Ovarian cancer OVCAR3 cells were transfected with the miR-940 vector, miR-940 inhibitor, and/or small interfering RNA (siRNA) targeting PKC-delta (si-PKC delta), respectively. After transfection, cell viability and cell apoptosis were analyzed, as well as cell proliferation and apoptosis-related protein expression. Compared to the control, miR-940 upregulation suppressed cell viability but induced cell apoptosis. miR-940 upregulation increased the expression of p27, Hes1, survivin, and caspase 3, but decreased the expression of PKC-delta. In addition, elevated cell viability induced by the miR-940 inhibitor was significantly decreased by knockdown of PKC-delta, and reduced cell apoptosis induced by the miR-940 inhibitor was increased by knockdown of PKC-delta. Taken together, the results of our study suggest that upregulation of miR-940 may function as a suppressor in the progression of ovarian cancer by inhibiting cell proliferation and inducing apoptosis by targeting PKC-delta. This study may provide a basis for the possible application of miR-940 in illustrating the molecular pathogenic mechanism of ovarian cancer. PMID- 28081740 TI - Knockdown of Tripartite Motif-Containing Protein 37 (TRIM37) Inhibits the Proliferation and Tumorigenesis in Colorectal Cancer Cells. AB - Tripartite motif-containing protein 37 (TRIM37), a new member of the RING-B-box coiled-coil (RBCC) subfamily of zinc finger proteins, was found to be involved in the development and progression of several cancers. However, the expression pattern and biological functions of TRIM37 in colorectal cancer (CRC) remain unknown. Therefore, in the present study, we examined the expression pattern of TRIM37 in CRC and investigated the function of TRIM37 in the progression of CRC. Our results showed that TRIM37 expression was upregulated in CRC cell lines. Knockdown of TRIM37 inhibited CRC cell proliferation and tumor growth in vivo. Furthermore, knockdown of TRIM37 inhibited the migration and invasion in CRC cells. Last, knockdown of TRIM37 inhibited the protein level expression of beta catenin, cyclin D1, and c-Myc in CRC cells. In conclusion, these results demonstrate that TRIM37 may play an important role in the proliferation, invasion, and tumorigenesis of CRC cells. Thus, TRIM37 may be a potential therapeutic target for the treatment of CRC. PMID- 28081741 TI - Depletion of NFBD1/MDC1 Induces Apoptosis in Nasopharyngeal Carcinoma Cells Through the p53-ROS-Mitochondrial Pathway. AB - NFBD1, a signal amplifier of the p53 pathway, is vital for protecting cells from p53-mediated apoptosis and the early phase of DNA damage response under normal culture conditions. Here we investigated its expression in patients with nasopharyngeal carcinoma (NPC), and we describe the biological functions of the NFBD1 gene. We found that NFBD1 mRNA and protein were more highly expressed in NPC tissues than in nontumorous tissues. To investigate the function of NFBD1, we created NFBD1-depleted NPC cell lines that exhibited decreased cellular proliferation and colony formation, an increase in their rate of apoptosis, and an enhanced sensitivity to chemotherapeutic agents compared with in vitro controls. However, N-acetyl cysteine (NAC) and downregulation of p53 expression could partially reverse the apoptosis caused by the loss of NFBD1. Further analysis showed that loss of NFBD1 resulted in increased production of intracellular reactive oxygen species (ROS) depending on p53, which subsequently triggered the mitochondrial apoptotic pathway. Using a xenograft model in nude mice, we showed that silencing NFBD1 also significantly inhibited tumor growth and led to apoptosis. Taken together, our data suggest that inhibition of NFBD1 in NPC could be therapeutically useful. PMID- 28081742 TI - MicroRNA-92a Promotes Cell Proliferation in Cervical Cancer via Inhibiting p21 Expression and Promoting Cell Cycle Progression. AB - MicroRNA-92a (miR-92a) generally plays a promoting role in human cancers, but the underlying mechanism in cervical cancer remains unclear. Here we studied the expression and clinical significance of miR-92a in cervical cancer, as well as the regulatory mechanism in the proliferation of cervical cancer cells. Our data indicated that miR-92a was significantly upregulated in cervical cancer tissues compared to their matched adjacent nontumor tissues (ANTs), and the increased miR 92a levels were significantly associated with a higher grade, lymph node metastasis, and advanced clinical stage in cervical cancer. In vitro study revealed that inhibition of miR-92a led to a significant reduction in the proliferation of HeLa cells via induction of cell cycle arrest at the G1 stage. In contrast, overexpression of miR-92a markedly promoted the proliferation of HeLa cells by promoting cell cycle progression. Further investigation revealed that miR-92a has a negative effect on protein levels, but not the mRNA levels, of p21 in HeLa cells, suggesting that p21 is a direct target of miR-92a. Overexpression of p21 eliminated the promoting effects of miR-92a on the proliferation and cell cycle progression of HeLa cells. However, knockdown of p21 reversed the suppressive effects of miR-92a downregulation on HeLa cell proliferation and cell cycle progression. Moreover, p21 was significantly downregulated in cervical cancer tissues compared to ANTs, suggesting that the increased expression of miR-92a may contribute to the decreased expression of p21, which further promotes cervical cancer growth. In conclusion, our study demonstrates that miR-92a promotes the proliferation of cervical cancer cells via inhibiting p21 expression and promoting cell cycle progression, highlighting the clinical significance of miR-92a in cervical cancer. PMID- 28081743 TI - Overexpression of MicroRNA-27b Inhibits Proliferation, Migration, and Invasion via Suppression of MET Expression. AB - MicroRNA-27b (miR-27b) was recently found to be significantly downregulated in different human cancers. However, evidence of the function of miR-27b in non small cell lung cancer (NSCLC) remains limited. In this study, we aimed to investigate novel miR-27b-mediated targets or signaling pathways associated with the tumorigenesis and metastasis of NSCLC. Real-time (RT) PCR was performed to examine miR-27b expression in NSCLC specimens. MTT assay, wound-healing assay, and Transwell assay were used to determine cell proliferation, migration, and invasion. Our data indicated that the miR-27b levels were significantly decreased in NSCLC specimens and cell lines (SK-MES-1, H358, H460, A549, and H1229) when compared to matched normal adjacent tissues and normal human lung epithelial cell lines, respectively. Restoration of miR-27b significantly inhibited the proliferation, migration, and invasion of A549 cells. We then conducted in silico analysis and luciferase reporter gene assay and identified MET, a receptor tyrosine kinase, as a direct target of miR-27b in NSCLC cells. Moreover, overexpression of MET rescued the suppressive effect of miR-27b on the proliferation, migration, and invasion of A549 cells, suggesting that MET acts as a downstream effecter of miR-27b in NSCLC cells. In summary, our study identified a novel miR-27b/MET signaling pathway involved in the cell proliferation, migration, and invasion of NSCLC, and identification of miR-27b-mediated novel signaling pathways may help reveal the molecular mechanism underlying the development and malignant progression of this disease. PMID- 28081744 TI - ERRATUM. AB - Ovarian cancer (OC) is one of the most common gynecological malignancies. MicroRNAs (miRs) play a crucial role in the development and progression of OC, but the underlying mechanism remains largely unclear. Our study investigated the regulatory role of miR-148a in OC cell proliferation and invasion. We found that miR-148a was significantly downregulated in OC tissues compared to their matched adjacent nontumor tissues. In addition, its expression was also reduced in OC cell lines (SKOV3, ES-2, OVCAR, and A2780) compared to normal ovarian epithelial cells. Overexpression of miR-148a caused a significant decrease in OC cell proliferation and invasion, as well as reduced MMP9 protein levels. Transforming growth factor-beta-induced 2 (TGFI2) was further identified as a target gene of miR-148a, and its protein expression was downregulated in OC cells after miR-148a overexpression. Restoration of TGFI2 attenuated the suppressive effects of miR 148a on OC cell proliferation and invasion. Moreover, we found that TGFI2 was remarkably upregulated in OC tissues when compared with their matched adjacent nontumor tissues, and observed a reverse correlation between miR-148a and TGFI2 expression in OC tissues. On the basis of these findings, we suggest that miR 148a inhibits OC cell proliferation and invasion partly through inhibition of TGFI2. Therefore, our study highlights the importance of the miR-148a/TGFI2 axis in the malignant progression of OC. PMID- 28081745 TI - The Influence of Secular Trends in Body Height and Weight on the Prevalence of Overweight and Obesity among Chinese Children and Adolescents. AB - OBJECTIVE: To explore the influence of secular trends in body height and weight on the prevalence of overweight and obesity among Chinese children and adolescents. METHODS: The data were obtained from five cross-sectional Chinese National Surveys on Students' Constitution and Health. Overweight/obesity was defined as BMI-for-age Z-score of per the Wold Health Organization (WHO) reference values. Body height and weight for each sex and age were standardized to those reported in 1985 (standardized height: SHY; standardized weight: SWY) and for each sex and year at age 7 (standardized height: SHA; standardized weight: SWA) using the Z-score method. RESULTS: The prevalence of overweight/obesity in Chinese children was 20.2% among boys and 10.7% among girls in 2010 and increased continuously from 1985 to 2010. Among boys and girls of normal weight, SHY and SHA were significantly greater than SWY and SWA, respectively (P < 0.001). Among boys and girls with overweight/obesity, SHY was significantly lower than SWY (P < 0.001), and showed an obvious decreasing trend after age 12. SHA was lower than SWA among overweight boys aged 7-8 years and girls aged 7-9 years. SHY/SHW and SHA/SWA among normal-weight groups were greater than among overweight and obese groups (P < 0.001). CONCLUSION: The continuous increase in the prevalence of overweight/obesity among Chinese children may be related to a rapid increase in body weight before age 9 and lack of secular increase in body height after age 12. PMID- 28081746 TI - Effect of Low Level Subchronic Microwave Radiation on Rat Brain. AB - OBJECTIVE: The present study was designed to investigate the effects of subchronic low level microwave radiation (MWR) on cognitive function, heat shock protein 70 (HSP70) level and DNA damage in brain of Fischer rats. METHODS: Experiments were performed on male Fischer rats exposed to microwave radiation for 90 days at three different frequencies: 900, 1800, and 2450 MHz. Animals were divided into 4 groups: Group I: Sham exposed, Group II: animals exposed to microwave radiation at 900 MHz and specific absorption rate (SAR) 5.953 * 10-4 W/kg, Group III: animals exposed to 1800 MHz at SAR 5.835 * 10-4 W/kg and Group IV: animals exposed to 2450 MHz at SAR 6.672 * 10-4 W/kg. All the animals were tested for cognitive function using elevated plus maze and Morris water maze at the end of the exposure period and subsequently sacrificed to collect brain tissues. HSP70 levels were estimated by ELISA and DNA damage was assessed using alkaline comet assay. RESULTS: Microwave exposure at 900-2450 MHz with SAR values as mentioned above lead to decline in cognitive function, increase in HSP70 level and DNA damage in brain. CONCLUSION: The results of the present study suggest that low level microwave exposure at frequencies 900, 1800, and 2450 MHz may lead to hazardous effects on brain. PMID- 28081747 TI - Role of PERK/eIF2alpha/CHOP Endoplasmic Reticulum Stress Pathway in Oxidized Low density Lipoprotein Mediated Induction of Endothelial Apoptosis. AB - OBJECTIVE: PERK/eIF2alpha/CHOP is a major signaling pathway mediating endoplasmic reticulum (ER) stress related with atherosclerosis. Oxidized LDL (ox-LDL) also induces endothelial apoptosis and plays a vital role in the initiation and progression of atherosclerosis. The present study was conducted to explore the regulatory effect of ox-LDL on PERK/eIF2alpha/CHOP signaling pathway in vascular endothelial cells. METHODS: The effects of ox-LDL on PERK and p-eIF2alpha protein expression of primary human umbilical vein endothelial cells (HUVECs) were investigated by Western blot analysis. PERK gene silencing and selective eIF2alpha phosphatase inhibitor, salubrinal were used to inhibit the process of ox-LDL induced endothelial cell apoptosis, caspase-3 activity, and CHOP mRNA level. RESULTS: Ox-LDL treatment significantly increased the expression of PERK, PERK-mediated inactivation of eIF2alpha phosphorylation, and the expression of CHOP, as well as the caspase-3 activity and apoptosis. The effects of ox-LDL were markedly decreased by knocking down PERK with stable transduction of lentiviral shRNA or by selective eIF2alpha phosphatase inhibitor, salubrinal. CONCLUSION: This study provides the first evidence that ox-LDL induces apoptosis in vascular endothelial cells mediated largely via the PERK/eIF2alpha/CHOP ER-stress pathway. It adds new insights into the molecular mechanisms underlying the pathogenesis and progression of atherosclerosis. PMID- 28081748 TI - Inactivated Sendai virus induces apoptosis mediated by reactive oxygen species in murine melanoma cells. AB - OBJECTIVE: This paper aims to investigate the apoptotic effect of inactivated Sendai virus (hemagglutinating virus of Japan-enveloped, HVJ-E) on murine melanoma cells (B16F10) and the possible mechanisms involved in the putative apoptotic reactions. METHODS: B16F10 cells were treated with HVJ-E at various multiplicities of infection (MOI), and the reactive oxygen species (ROS), cell viability, and apoptosis were measured. Next, the roles of ROS in the regulation of Bcl-2/Bax and the activation of mitogen-activated protein kinase (MAPK) pathways in HVJ-E-treated B16F10 cells were analyzed. To further evaluate the cytotoxic effect of HVJ-E-generated ROS on B16F10 cells, HVJ-E was intratumorally injected, both with and without N-acetyl-L-cysteine (NAC), into melanoma tumors on BALB/c mice. Tumor volume was then monitored for 3 weeks, and the tumor proteins were separated for immunoblot assay. RESULTS: Treatment of B16F10 cells with HVJ-E resulted in a dose-dependent inhibition of cell-viability and an induction of apoptosis. The latter effect was associated with the generation of ROS. Inhibition of ROS generation by NAC resulted in a significant reduction of HVJ-E-induced Erk1/2, JNK, and p38 MAPK activation. Additionally, ROS inhibition caused a decrease in the Bcl-2/Bax ratio as well as promoting activation of apoptosis both in vitro and in vivo. CONCLUSION: These results suggest that HVJ-E possesses potential anticancer activity in B16F10 cells through ROS-mediated mitochondrial dysfunction involving the MAPK pathway. PMID- 28081749 TI - Does Periconceptional Fish Consumption by Parents Affect the Incidence of Autism Spectrum Disorder and Intelligence Deficiency? A Case-control Study in Tianjin, China. AB - OBJECTIVE: This study aimed to explore the association between periconceptional fish consumption by parents and autism spectrum disorder (ASD) and intelligence deficiency (ID). METHODS: A case-control study was conducted through a questionnaire with 108 ASD cases, 79 ID cases, and 108 controls. The ASD and ID cases were students from special educational schools in Tianjin from 2012 to 2014. The age- and sex-matched controls were from a high school, three primary schools, and a kindergarten in Tianjin. Multivariate logistic regression was performed. RESULTS: Paternal habit of eating hairtail before fertilization, maternal preference for fruits during pregnancy, and maternal habit of eating grass carp during pregnancy were preventive factors for ASD. Paternal habit of drinking alcohol before fertilization was a risk factor for ID, whereas maternal preference for fruits during pregnancy and maternal habit of eating crucian carp during pregnancy were protective factors for ID. CONCLUSION: Parental fish consumption is beneficial for the prevention of ASD and ID. Meanwhile, the protective effects of fish consumption on ASD and ID differ. More attention should be paid to the combined effect of other food when eating fish. PMID- 28081750 TI - An Epistaxis Emergency Associated with Multiple Pollutants in Elementary Students. AB - Emergencies of epistaxis in students caused by environmental pollution have rarely been reported to date. This study aimed to explore the cause of an emergency of epistaxis in elementary students by using a field epidemiological investigation. Twenty-two epistaxis cases from a single school with differences in gender, age, and classroom, were diagnosed within a period of 7 days. The air concentration of chromic acid mist (Cr6+) in the electroplating factory area, new campus, and residential area exceeded the limit of uncontrolled emissions. The emission of HCL and H2SO4 was also observed. Formaldehyde levels in the classrooms exceeded the limits of indoor air quality. Abnormal nasal mucosa was significantly more frequent in the case group (93.3%) and control group 1 (of the same school) (66.7%) than in control group 2 (from a mountainous area with no industrial zone) (34.8%; P < 0.05 and P < 0.01, respectively). On the basis of the pre-existing local nasal mucosal lesions, excessive chromic acid mist in the school's surrounding areas and formaldehyde in the classrooms were considered to have acutely irritated the nasal mucosa, causing epistaxis. Several lessons regarding factory site selection, eradication of chemical emissions, and indoor air quality in newly decorated classrooms, should be learned from this emergency. PMID- 28081751 TI - Mineral Intake in Urban Pregnant Women from Base Diet, Fortified Foods, and Food Supplements: Focus on Calcium, Iron, and Zinc. AB - In the Chinese national nutrition surveys, fortified foods were not investigated separately from the base diet, and the contribution of fortified foods to micronutrients intake is not very clear. This study investigated the diet, including fortified foods and food supplements, of urban pregnant women and analyzed the intake of calcium, iron, and zinc to assess the corresponding contributions of fortified foods, food supplements, and the base diet. The results demonstrated that the base diet was the major source of calcium, iron, and zinc, and was recommended to be the first choice for micronutrients intake. Furthermore, consumption of fortified foods and food supplements offered effective approaches to improve the dietary intake of calcium, iron, and zinc in Chinese urban pregnant women. PMID- 28081752 TI - A Centralized Report on Pediatric Japanese Encephalitis Cases from Beijing Children's Hospital, 2013. AB - Fifteen pediatric cases of suspected Japanese encephalitis (JE) were reported in Beijing Children's Hospital during the late summer of 2013. The clinical manifestations in most cases included high fever, seizures, and abnormal magnetic resonance imaging findings. Twelve of 15 cases were laboratory-confirmed as JE cases by pathogen identification. Epidemiological investigations showed that five of the 12 laboratory-confirmed patients had an incomplete JE vaccination history. Follow-up investigations after discharge indicated that seven laboratory confirmed JE patients without JE vaccinations had relatively poor prognoses, with an average Modified Rankin Scale (MRS) score of 2.6 when compared with the other five laboratory-confirmed, JE-vaccinated patients with an average MRS score of 0.5. The observation of pediatric JE cases among those with a history of JE vaccination warrants further attention. PMID- 28081753 TI - Early Changes of Peripheral Blood Lymphocyte Subpopulations in Patients with Occupational 2,4-dinitrophenol Poisoning. AB - 2,4-dinitrophenol (DNP), an organic compound which frequently used in industry, is considered to have high toxicity. This study aimed to investigate the early changes of lymphocyte subpopulations in patients with occupational 2,4-DNP poisoning. Totally 9 patients with acute occupational 2,4-DNP poisoning and 30 healthy volunteers as control were enrolled. The patients received immediately comprehensive supportive treatments, including large-dose glucocorticoid and repeated hemoperfusion (HP). The ratio of CD4+/CD8+ T cells were significantly higher in patients upon admission compared to healthy controls (P < 0.01); however, counts of total lymphocytes, CD3+, CD3+CD4+, CD3+CD8+, B (CD19+), and natural killer (NK) cells (CD16+CD56+) were significantly reduced (all P < 0.001). The NK cell count was negatively correlated with initial plasma 2,4-DNP concentration (r = -0.750, P = 0.026). Thus, acute occupational 2,4-DNP poisoning was accompanied by immediate complex immune cell reactions, especially NK cells might play important role in severe 2,4-DNP poisoning. PMID- 28081754 TI - Effectiveness of Adherence to Standardized Hypertension Management by Primary Health Care Workers in China: a Cross-sectional Survey 3 Years after the Healthcare Reform. AB - The standardized hypertension management provided by primary health care workers is an important part of China's recent health care reform efforts. Investigating 5,116 hypertensive patients from a cross-sectional survey conducted by the Chinese Center for Disease Control and Prevention in 2012, this study found that adherence to standardized hypertension management is associated with positive effects on hypertension- related knowledge, healthy lifestyle behavior, antihypertensive medical treatments, and blood pressure control. It will be necessary to provide primary health care workers with sufficient training and reasonable incentives to ensure the implementation and effectiveness of hypertension management. PMID- 28081755 TI - Sibling cell size matters. AB - A motor protein called Klp10A ensures that germline stem cells in male fruit flies divide to produce two sibling cells that are equal in size. PMID- 28081756 TI - ? PMID- 28081757 TI - [Rescue therapy with darunavir for treatment-experienced HIV-infected patients]. PMID- 28081758 TI - [Long-term safety and effectiveness of darunavir]. PMID- 28081759 TI - [Darunavir in special situations]. PMID- 28081760 TI - [Darunavir as initial therapy for human immunodeficiency virus infection and as a strategy for switching regimen not motivated by virological failure]. PMID- 28081761 TI - [Pharmacological aspects of darunavir/cobicistat]. PMID- 28081762 TI - [Present and future of darunavir for the treatment of human immunodeficiency virus infection]. PMID- 28081763 TI - ? PMID- 28081764 TI - Pathogenesis: common pathways between hidradenitis suppurativa and Crohn disease. AB - Both hidradenitis suppurativa and Crohn disease are considered chronic inflammatory diseases due to immune dysregulation. The high prevalence of Crohn disease patients diagnosed with hidradenitis suppurativa suggests the existence of common pathogenic links. The present literature review analyses the similarities and differences in the pathogenesis of the two diseases, in the search for new research and knowledge targets. PMID- 28081765 TI - Therapeutic approach to Crohn disease: possible parallels with hidradenitis suppurativa. AB - The current controversy in the setting of dermatology surrounding the treatment of inflammatory diseases, and specifically hidradenitis suppurativa, bears strong similarities with the debate concerning inflammatory bowel disease (IBD) that took place several years ago. That debate led to new perspectives on this disease and, in particular, its treatment after the development of biological agents. PMID- 28081766 TI - Clinical features of hidradenitis suppurativa and Crohn disease: what do these two entities have in common? AB - Hidradenitis suppurativa (HS) and Crohn disease (CD) are chronic, recurrent inflammatory diseases. They share certain clinical characteristics and flares are common in both. Both entities are usually diagnosed between the second and third decades of life and share risk factors such as smoking and overweight. In CD, as in HS, acute untreated episodes of inflammation can lead to sequels such as abscesses, fistulas and stenosis. Consequently, early management is of the utmost importance. Some patients have both diseases. The estimated prevalence of SH in CD patients is 12.4%-17.9%, while the prevalence of CD in HS patients is around 3%. The presence of HS in patients with inflammatory bowel disease (IBD) is associated with an earlier onset of IBD and with more frequent need for anti-TNF alpha therapy and surgical resection. PMID- 28081767 TI - Hidradenitis suppurativa and perianal Crohn disease: differential diagnosis. AB - The first description of perianal fistulas and complications in Crohn disease was made 75 years ago by Penner and Crohn. Published studies have subsequently confirmed that perianal fistulas are the most common manifestations of fistulising Crohn disease. Hidradenitis suppurativa was described in 1854 by a French surgeon, Aristide Verneuil. It is a chronic, inflammatory, recurrent and debilitating disease of the pilosebaceous follicle, that usually manifests after puberty with deep, painful and inflamed lesions in the areas of the body with apocrine glands, usually the axillary, inguinal and anogenital regions. The differential diagnosis between hidradenitis suppurativa and Crohn disease can be challenging, especially when the disease is primarily perianal. When they occur simultaneously, hidradenitis suppurativa and Crohn disease show severe phenotypes and patients can respond to anti-tumour necrosis factor therapy, although adalimumab is currently the only treatment with demonstrated efficacy in hidradenitis suppurativa and Crohn disease. In addition, there is sometimes a need for different complementary surgical procedures. PMID- 28081769 TI - Clinical experience of the use of adalimumab in the management of hidradenitis suppurativa. Comparison of response rates with Crohn disease. AB - The recent approval of adalimumab as the first treatment to be approved for the management of hidradenitis suppurativa has represented a before and after in the control of this chronic inflammatory disease. Given the inflammatory burden of this cutaneous disease, in the last few years hidradenitis suppurativa has been compared with inflammatory bowel disease, particularly with Crohn disease, to the point of considering hidradenitis suppurativa as "Crohn disease of the skin". These two chronic inflammatory diseases show sufficient similarities to consider whether treatment response based on the inflammatory load could also be similar. The present article aims to analyse the efficacy of adalimumab in hidradenitis suppurativa in comparison with a truly comparable disease, Crohn disease, with a view to evaluating therapeutic response rates and to drawing conclusions on the therapeutic success obtained in this disabling cutaneous disease. PMID- 28081768 TI - Management of patients with hidradenitis suppurativa. AB - Hidradenitis suppurativa (HS) is a chronic inflammatory disease with a high prevalence in the population. Treatment options are both medical and surgical. Medical treatment is based on the use of antibiotics, retinoids, and anti inflammatory drugs, in which anti-TNFalpha agents (infliximab y adalimumab) play a central role in the treatment of moderate-to-severe HS and enjoy the highest level of scientific support. Currently, adalimumab is the only drug approved in the summary of product characteristics for the treatment of this disease. Due to the scarcity of clinical trials in HS, there is still no therapeutic guideline backed by solid evidence and the evidence for most drugs is low. However, early treatment in patients with HS would probably reduce the complications of this disease. This review analyses the distinct treatments used in this dermatological disease and provides a therapeutic algorithm with different treatment options. PMID- 28081770 TI - Epidemiological, clinical and therapeutic aspects in special situations: hidradenitis suppurativa in paediatric patients. AB - Hidradenitis suppurativa usually develops in the third decade of life and is infrequent in children and adolescents. This article reviews the scant epidemiological clinical and therapeutic data that are available for this age group. From the epidemiological point of view, reports have been more numerous in children, which has been related to hormone alterations and with a possibly higher genetic load than when this disease develops in adults. Clinically, it seems that when hidradenitis suppurativa develops in young patients, there is greater disease extension. The therapeutic approach is especially complex, since there is hardly any scientific evidence to serve as a basis for decisions. The challenges posed by this disease are to help patients accept their disease, recommend them healthy lifestyle habits and choose the most appropriate treatment for each patient. PMID- 28081771 TI - Epidemiology of hidradenitis suppurativa and inflammatory bowel disease: are these two disease associated? AB - Hidradenitis suppurativa and inflammatory bowel disease are chronic inflammatory diseases mainly affecting young people. Their aetiology is complex and multifactorial and numerous case series have shown that the two diseases can manifest concurrently, although the strength of this association varies widely among distinct reports. An additional problem is the difficulty of distinguishing between cutaneous Crohn disease and hidradenitis. In the last few years, epidemiological cohort studies have revealed that 1.2%-23% of inflammatory bowel disease patients also have hidradenitis suppurativa. This wide variability is influenced by geographical variables and the biases inherent in the distinct data collection methods, among other factors. There is a clear predominance of Crohn disease over ulcerative colitis. When hidradenitis suppurativa and inflammatory bowel disease manifest concurrently, the bowel disease is more severe and shows a predominance of colon involvement. PMID- 28081772 TI - Metabolic amplification of insulin secretion is differentially desensitized by depolarization in the absence of exogenous fuels. AB - OBJECTIVE: The metabolic amplification of insulin secretion is the sequence of events which enables the secretory response to a fuel secretagogue to exceed the secretory response to a purely depolarizing stimulus. The signals in this pathway are incompletely understood. Here, we have characterized an experimental procedure by which the amplifying response to glucose is reversibly desensitized, while the response to alpha-ketoisocaproic acid (KIC) is unchanged. MATERIALS/METHODS: Insulin secretion, NAD(P)H- and FAD-autofluorescence, Fura-2 fluorescence and oxygen consumption were measured in perifused NMRI mouse islets. The ATP- and ADP-contents were measured in statically incubated mouse islets. All islets were freshly isolated. RESULTS: While the original observation on the dissociation between glucose- and KIC-amplification was obtained with islets that had been exposed to a high concentration of the sulfonylurea glipizide in the absence of glucose, we now show that in the absence of exogenous fuel a moderate depolarization, irrespective of its mechanism, progressively decreased the amplification in response to both glucose and KIC. However, the amplification in response to glucose declined faster, so a time window exists where glucose was already inefficient, whereas KIC was of unimpaired efficiency. Measurements of adenine nucleotides, NAD(P)H- and FAD-autofluorescence, and oxygen consumption point to a central role of the mitochondrial metabolism in this process. The desensitization could be quickly reversed by increasing oxidative deamination of glutamate and consequently anaplerosis of the citrate cycle. CONCLUSION: Depolarization in the absence of exogenous fuel may be a useful model to identify those signals which are indispensable for the generation of metabolic amplification. PMID- 28081773 TI - Mechanisms of marrow adiposity and its implications for skeletal health. AB - The bone marrow niche is composed of cells from hematopoietic and mesenchymal origin. Both require energy to power differentiation and these processes are intimately connected to systemic metabolic homeostasis. Glycolysis is the preferred substrate for mesenchymal stromal cells in the niche, although fatty acid oxidation and glutaminolysis are important during stage specific differentiation. Autophagy and lipophagy, in part triggered by adenosine monophosphate-activated protein kinase (AMPK), may also play an important but temporal specific role in osteoblast differentiation. Enhanced marrow adiposity is caused by clinical factors that are genetically, environmentally, and hormonally mediated. These determinants mediate a switch from the osteogenic to the adipogenic lineage. Preliminary evidence supports an important role for fuel utilization in those cell fate decisions. Although both the origin and function of the marrow adipocyte remain to be determined, and in some genetic mouse models high marrow adiposity may co-exist with greater bone mass, in humans changes in marrow adiposity are closely linked to adverse changes in skeletal metabolism. This supports an intimate relationship between bone and fat in the marrow. Future studies will likely shed more light on the relationship of cellular as well as whole body metabolism on the ultimate fate of bone marrow stromal cells. PMID- 28081774 TI - Nesfatin-1 regulates the lateral hypothalamic area melanin-concentrating hormone responsive gastric distension-sensitive neurons and gastric function via arcuate nucleus innervation. AB - Nesfatin-1, a recently discovered neuropeptide involved in satiety. Recent studies have revealed that central nesfatin-1 inhibits gastric emptying and gastric acid secretion, though the mechanisms involved in these processes are not known. We aim to explore the effects of nesfatin-1 on a population of gastric distension (GD)-sensitive neurons in the lateral hypothalamus (LHA), gastric motility, and gastric secretion and the role for an arcuate nucleus (Arc)-LHA neural pathway in these processes. Single unit extracellular discharge recordings were made in of LHA. Further, gastric motility and gastric secretion in rats were monitored. Retrograde tracing and fluorescent immunohistochemical staining were used to explore nesfatin-1 neuron projection. The results revealed that administration of nesfatin-1 to the LHA or electric stimulation of the Arc could alter the neuronal activity of melanin-concentrating hormone (MCH)-responsive, GD responsive neurons in LHA, which could be blocked by pretreatment with MCH receptor-1 antagonist PMC-3881-PI or weakened by pretreatment of a nesfatin-1 antibody in LHA. Administration of nesfatin-1 into LHA could inhibit gastric motility and gastric secretion, and these effects could be enhanced by administration of PMC-3881-PI. Electrical stimulation of Arc promoted the gastric motility and gastric secretion. Nesfatin-1 antibody or PMC-3881-PI pretreatment to LHA had no effect on Arc stimulation-induced gastric motility, but these pretreatments did alter Arc stimulation-induced effects on gastric secretion. Our findings suggest that nesfatin-1 signaling in LHA participates in the regulation of efferent information from the gastrointestinal tract and gastric secretion which also involve MCH signaling. Further, they show that a nesfatin-1-positive Arc to LHA pathway is critical for these effects. PMID- 28081775 TI - Skeletal muscle extracellular matrix remodeling after short-term overfeeding in healthy humans. AB - BACKGROUND: Skeletal muscle extracellular matrix (ECM) remodeling has been proposed as a feature of the pathogenic milieu associated with obesity and metabolic dysfunction. The aim of the current study was to examine the timeline of this response and determine whether 3 and 28days of overfeeding alters markers of ECM turnover. METHODS: Forty healthy individuals were overfed by 1250kcal/day for 28days. Hyperinsulinemic-euglycemic clamps and abdominal fat distribution were performed at baseline and day 28 of overfeeding and skeletal muscle biopsies taken at baseline, day 3 and day 28. mRNA expression (COL1a1, COL3a1, MMP2, MMP9, TIMP1, CD68, Integrin) was performed in 19 subjects that consented to having all biopsies performed and microarray analysis was performed in 8 participants at baseline and day 28. RESULTS: In the whole cohort, body weight increased by 0.6+/ 0.1 and 2.7+/-0.3kg at days 3 and 28 (both P<0.001), respectively. Glucose infusion rate during the hyperinsulinemic-euglycemic clamp decreased from 54.8+/ 2.8 at baseline to 50.3+/-2.5MUmol/min/kg FFM at day 28 of overfeeding (P=0.03). Muscle COL1 and COL3 and MMP2 mRNA levels were significantly higher 28days after overfeeding (all P<0.05), with no significant changes in MMP9, TIMP1, CD68 and integrin expression. Microarray based gene set tests revealed that pathways related to ECM receptor interaction, focal adhesion and adherens junction were differentially altered. CONCLUSIONS: Skeletal muscle ECM remodeling occurs early in response to over-nutrition with as little as 3% body weight gain. Our findings contribute to the growing evidence linking muscle ECM remodeling and accumulation as another sequela of obesity-related insulin resistance. PMID- 28081776 TI - Factors associated with adipocyte size reduction after weight loss interventions for overweight and obesity: a systematic review and meta-regression. AB - AIMS: Enlarged adipocytes are a prime feature of adipose tissue dysfunction, and may be an appropriate target to decrease disease risk in obesity. We aimed to assess the change in adipocyte size in response to lifestyle and surgical weight loss interventions for overweight or obesity; and to explore whether certain participant and intervention characteristics influence this response. METHODS: We systematically searched MEDLINE, EMBASE, CINAHL and Cochrane electronic databases to identify weight loss studies that quantified adipocyte size before and after the intervention. Using meta-regression analysis, we assessed the independent effects of weight loss, age, sex, adipocyte region, and intervention type (surgical vs. lifestyle) on adipocyte size reduction. We repeated the model as a sensitivity analysis including only the lifestyle interventions. RESULTS: Thirty five studies met our eligibility criteria. In our main model, every 1.0% weight loss was associated with a 0.64% reduction in adipocyte size (p=0.003); and adipocytes from the upper body decreased 5% more in size than those in the lower body (p=0.009). These relationships were no longer significant when focusing only on lifestyle interventions. Moreover, age, sex and intervention type did not independently affect adipocyte size reduction in either model. CONCLUSIONS: Weight loss in obese individuals is consistently associated with a decrease in adipocyte size that is more pronounced in upper-body adipocytes. It remains to be clarified how biological differences and intervention characteristics influence this relationship, and whether it corresponds with reductions in other aspects of adipose tissue dysfunction and disease risk. PMID- 28081777 TI - Research advances in metabolism 2016. PMID- 28081778 TI - An association of metabolic syndrome and chronic kidney disease from a 10-year prospective cohort study. AB - OBJECTIVE: Although metabolic abnormalities have been considered important risk factors of chronic kidney disease (CKD), the impact of metabolic syndrome (MS) and insulin resistance on renal function deterioration is poorly understood. We investigated the association between MS and incident CKD/rapid decline of estimated glomerular filtration rate (eGFR) in a 10-year population-based longitudinal study. MATERIAL AND METHODS: Among 10,030 subjects, 6065 without history of CKD or cardiovascular disease at baseline were analyzed using data generated from the Ansan-Ansung cohort of the Korean Genome Epidemiology Study. Participants were categorized into two groups based on the presence of MS at baseline. Incident CKD was defined as eGFR <60ml/min per 1.73m2, and rapid decline of eGFR was defined as >3ml/min per 1.73m2/yr over 10years. RESULTS: During the 10-year follow-up period, CKD developed in 893 subjects (14.7%). Compared to subjects without MS, the odds ratio (OR; 95% confidence interval, CI) of incident CKD in those with MS was 1.38 (1.16-1.64) after controlling for confounding factors. The risk of rapid decline of eGFR was also higher in subjects with MS than those without MS (OR: 1.20, 95% CI: 1.04-1.39). In addition, we found that higher levels of homeostatic model assessment of insulin resistance (HOMA-IR) were associated with incident CKD and rapid decline of eGFR independently of traditional CKD risk factors (OR: 1.24, 95% CI: 1.04-1.47). CONCLUSION: Both MS and insulin resistance were independent risk factors of incident CKD and rapid decline of eGFR in healthy Korean population. PMID- 28081779 TI - Higher free triiodothyronine is associated with non-alcoholic fatty liver disease in euthyroid subjects: the Lifelines Cohort Study. AB - OBJECTIVE: Overt hypothyroidism confers an increased risk of non-alcoholic fatty liver disease (NAFLD). The liver plays a crucial role in the metabolism of cholesterol and triglycerides; thyroid hormones interact on hepatic lipid homeostasis. Thyroid function within the euthyroid range affects a number of health issues, including atherosclerosis development and biochemical markers of increased cardiovascular risk. However, the association of thyroid hormones with NAFLD in euthyroid subjects has not been unequivocally established. We therefore determined associations of thyroid hormone parameters with NAFLD among euthyroid subjects. METHODS: The study was conducted in the Lifelines Cohort Study, a population-based cohort study of participants living in the North of the Netherlands. Only euthyroid subjects (thyroid-stimulating hormone (TSH) 0.5 4.0mU/L, free thyroxine (FT4) 11-19.5pmol/L and free triiodothyronine (FT3) 4.4 6.7pmol/L) older than 18years were included. Exclusion criteria were participants with excessive alcohol use, known hepatitis or cirrhosis, liver functions >= three times the upper limit, current cancer, non-white ancestry, previous or current use of thyroid medication and current use of lipid or glucose lowering medication. A priori defined liver biochemistry, thyroid function parameters and metabolic syndrome (MetS) were studied. NAFLD was defined by using the validated Fatty Liver Index (FLI); FLI>=60 was categorized as NAFLD. A P<0.01 was considered significant. RESULTS: FLI>=60 was found in 4274 (21.1%) of 20,289 individuals (62.1% male, median age 46years) with increased prevalence of MetS (P<0.0001). In age- and sex-adjusted analysis FLI>=60 was independently associated with a higher FT3 (OR 1.34, 95% CI 1.29-1.39, per SD increment, P<0.0001) and a lower FT4 (OR 0.73, 95% CI 0.70-0.75, P<0.0001) but not by TSH. The strongest association was found for the FT3/FT4 ratio (OR 1.44, 95% CI 1.39 1.49, P<0.0001). These associations remained similar after additional adjustment for the presence of MetS. In subjects with enlarged waist circumference, TSH and FT4 were lower while FT3 was higher, resulting in an increased FT3/FT4 ratio (P<0.0001). CONCLUSIONS: Euthyroid subjects with suspected NAFLD are characterized by higher FT3, lower FT4 and higher FT3/FT4 ratio, probably consequent to central obesity. PMID- 28081780 TI - Association between vascular inflammation and non-alcoholic fatty liver disease: Analysis by 18F-fluorodeoxyglucose positron emission tomography. AB - BACKGROUND: Growing evidence suggests that non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular disease as well as metabolic syndrome. FDG-PET is a novel imaging technique that detects vascular inflammation, which may reflect rupture-prone vulnerable atherosclerotic plaques. METHODS: Vascular inflammation was measured as the maximum target-to-background ratio (maxTBR), along with various cardiometabolic risk factors in 51 subjects with NAFLD, and compared with 100 age- and gender-matched subjects without NAFLD. The liver attenuation index (LAI), which was measured using computed tomography, was used as a parameter for the diagnosis of NAFLD. RESULTS: After adjusting for age and sex, both maxTBR and LAI values were associated with several cardiometabolic risk parameters. Furthermore, there was a significant inter-relationship between LAI and maxTBR values (r=-0.227, P=0.005). Individuals with NAFLD had higher maxTBR values than those without NAFLD (P=0.026), although their carotid intima-media thickness (CIMT) values did not differ. The proportion of subjects with NAFLD showed a step-wise increment following the tertiles of maxTBR values (P for trend=0.015). In multiple logistic regression analysis, maxTBR tertiles were independently associated with NAFLD after adjusting for age, gender, systolic blood pressure, triglycerides, HDL-cholesterol, glucose, BUN, creatinine and homeostasis model assessment of insulin resistance (HOMA-IR) (P=0.030). However, their relationship was attenuated after further adjustment for waist circumference or high sensitive C-reactive protein. CONCLUSION: Patients with NAFLD have an increased risk for vascular inflammation as measured via FDG-PET/CT even without difference in CIMT. (Clinical trials No. NCT01958411, http://www.clinicaltrials.gov/). PMID- 28081781 TI - Effects of visceral adiposity on glycerol pathways in gluconeogenesis. AB - OBJECTIVE: To determine the feasibility of using oral 13C labeled glycerol to assess effects of visceral adiposity on gluconeogenic pathways in obese humans. RESEARCH DESIGN AND METHODS: Obese (BMI >=30kg/m2) participants without type 2 diabetes underwent visceral adipose tissue (VAT) assessment and stratification by median VAT into high VAT-fasting (n=3), low VAT-fasting (n=4), and high VAT-refed (n=2) groups. Participants ingested [U-13C3] glycerol and blood samples were subsequently analyzed at multiple time points over 3h by NMR spectroscopy. The fractions of plasma glucose (enrichment) derived from [U-13C3] glycerol via hepatic gluconeogenesis, pentose phosphate pathway (PPP), and tricarboxylic acid (TCA) cycle were assessed using 13C NMR analysis of glucose. Mixed linear models were used to compare 13C enrichment in glucose between groups. RESULTS: Mean age, BMI, and baseline glucose were 49years, 40.1kg/m2, and 98mg/dl, respectively. Up to 20% of glycerol was metabolized in the TCA cycle prior to gluconeogenesis and PPP activity was minor (<1% of total glucose) in all participants. There was a 21% decrease in 13C enrichment in plasma glucose in the high VAT-fasting compared with low VAT-fasting group (p=0.03), suggesting dilution by endogenous glycerol. High VAT-refed participants had 37% less 13C enrichment in glucose compared with high VAT-fasting (p=0.02). There was a trend toward lower [1,2-13C2] (via PPP) and [5,6-13C2]/[4,5,6-13C3] (via TCA cycle) glucose in high VAT versus low VAT groups. CONCLUSIONS: We applied a simple method to detect gluconeogenesis from glycerol in obese humans. Our findings provide preliminary evidence that excess visceral fat disrupts multiple pathways in hepatic gluconeogenesis from glycerol. PMID- 28081782 TI - Insulin sensitivity and its relation to hormones in adolescent boys and girls. AB - BACKGROUND AND AIMS: A subset of obese individuals lacks cardiometabolic impairment. We aimed to analyze hormonal profiles of insulin-sensitive obese (ISO) and insulin-resistant obese (IRO) adolescents and determine hormonal predictors of homeostasis model of insulin resistance (HOMA-IR). MATERIALS AND METHODS: A threshold of 3.16 of HOMA-IR was used to classify ISO (<3.16) IRO (>=3.16). In 702 individuals aged 13-18years (55.8% girls) anthropometric and laboratory [blood glucose, insulin, thyrotropin (TSH), free thyroxine (fT4), free triiodothyronine (fT3), sex hormone-binding globulin (SHBG), steroid hormones, luteinizing hormone, follicle stimulating hormone, prolactin, ghrelin, glucose dependent insulinotropic polypeptide, glucagon-like-peptide 1glucagon, leptin, resistin, visfatin, leptin, adiponectin and adipsin] assessments were performed. Orthogonal projections to latent structures and Mann-Whitney tests with Bonferroni correction were applied for statistical analysis. RESULTS: 52.6% girls and 42.9% boys were insulin sensitive. In the predictive model of HOMA-IR thyroid function tests, adiponectin, ghrelin and leptin concentrations played an important role in both genders. Prolactin, testosterone and glucagon contributed to the model only in boys, while progesterone and dehydroepiandrosterone sulfate levels only in girls. After Bonferroni correction levels of leptin, adiponectin, leptin/adiponectin ratio, SHBG and fT4/TSH ratio in both genders, testosterone and glucagon levels in boys and levels of TSH and fT3 in girls were related to insulin sensitivity. CONCLUSION: Metabolic health defined by HOMA-IR is partly predicted by various hormones. Some of them are gender specific. Free T4/TSH and leptin/adiponectin ratios are related to insulin sensitivity in both genders. PMID- 28081783 TI - Stress hyperglycemia and acute ischemic stroke in-hospital outcome. AB - BACKGROUND AND AIMS: Stress hyperglycemia is frequent in patients with acute ischemic stroke. However, it is unclear whether stress hyperglycemia only reflects stroke severity or if it is directly associated with adverse outcome. We aimed to evaluate the prognostic significance of stress hyperglycemia in acute ischemic stroke. METHODS: We prospectively studied 790 consecutive patients who were admitted with acute ischemic stroke (41.0% males, age 79.4+/-6.8years). The severity of stroke was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). Stress hyperglycemia was defined as fasting serum glucose levels at the second day after admission >=126mg/dl in patients without type 2 diabetes mellitus (T2DM). The outcome was assessed with adverse outcome rates at discharge (modified Rankin scale between 2 and 6) and with in-hospital mortality. RESULTS: In the total study population, 8.6% had stress hyperglycemia. Patients with stress hyperglycemia had more severe stroke. Independent predictors of adverse outcome at discharge were age, prior ischemic stroke and NIHSS at admission whereas treatment with statins prior to stroke was associated with favorable outcome. When the NIHSS was removed from the multivariate model, independent predictors of adverse outcome were age, heart rate at admission, prior ischemic stroke, log-triglyceride (TG) levels and stress hyperglycemia, whereas treatment with statins prior to stroke was associated with favorable outcome. Independent predictors of in-hospital mortality were atrial fibrillation (AF), diastolic blood pressure (DBP), serum log-TG levels and NIHSS at admission. When the NIHSS was removed from the multivariate model, independent predictors of in-hospital mortality were age, AF, DBP, log-TG levels and stress hyperglycemia. CONCLUSION: Stress hyperglycemia does not appear to be directly associated with the outcome of acute ischemic stroke. However, given that patients with stress hyperglycemia had higher prevalence of cardiovascular risk factors than patients with normoglycemia and that glucose tolerance was not evaluated, more studies are needed to validate our findings. PMID- 28081784 TI - Forensic medical evaluation of deaths resulting from inhalation of cigarette lighter refill fuel in Turkey. AB - Voluntary inhalation/abuse of volatile substances is an important public health problem which especially affects adolescent and young populations worldwide and may be encountered in all socioeconomic and cultural levels. Lighter gas abuse related death is still an important health problem in Turkey. In this study, 25,265 case files and final reports submitted to the Institute of Forensic Medicine of the First Specialization Board between January 2011 and December 2015 were evaluated retrospectively. In 56 of these cases, lighter gas inhalation (n butane, propane, isobutane) was recorded as the cause of death. All subjects were male with a mean age of 16.8years. According to eyewitness and crime scene investigation reports, in 48 (85.7%) of the cases, a lighter refill container was found at the scene. It was determined that 21.4% of the cases used a plastic bag to increase the effects of lighter gas and 76.8% inhaled the lighter gas via their mouth and nose. The toxicological analysis of the samples taken while hospitalized showed no lighter refill components (n-butane, propane, isobutane) in 66% of the cases, n-butane in 32.1% of the cases, and n butane+propane+isobutane in 1.9% of the cases. The importance of lighter gas inhalation-related deaths in Turkey has been increasing. Strict measures against the abuse of these very dangerous substances should be undertaken by the mutual efforts of medical specialists and legislators. PMID- 28081785 TI - Fatal acute intoxication of accidentally ingested nifedipine in an infant - A case report. AB - A fatal case of acute nifedipine intoxication in a two-year-old boy is presented. The boy accidentally orally ingested an unknown amount of his grandfather's nifedipine (40mg/tablet), mistaking it for a ramune confectionery. Despite intensive medical treatment, his death was confirmed at 31h after the accidental ingestion. The forensic autopsy revealed that there were neither pathological alterations or injuries in all of the organs. Toxicologically, nifedipine could be detected at the concentrations of 0.463, 0.669 and 13.0MUg/g in cardiac blood, peripheral blood and stomach contents, respectively. These concentrations were evaluated as fatal levels, and the cause of death was diagnosed as acute nifedipine intoxication. Recently, the number of infants and children who accidentally ingest drugs in the home is increasing. This case report prompts forensic pathologists and toxicologists to emphasize that children are always exposed to the risk of accidental drug ingestion in daily life. PMID- 28081786 TI - Experimental evaluation of freezing preparation for the macroscopic inspection in putrefied brain. AB - PURPOSE: To evaluate the usefulness of freezing preparation for macroscopic investigation in advanced putrefied brain. MATERIALS AND METHODS: After sealing in individual plastic bags, 10 pig heads were stored at 20 degrees C for 5days allow postmortem change (putrefaction) to progress. After an observation period, they were divided into 2 groups to evaluate the usefulness of the freezing effect in macroscopic investigation. The process over the postmortem period and the freezing process were examined. RESULTS: At day-5, the presence of air density was detected between the inner surface of the cranium and the brain parenchyma. Intra-cranial air accumulation presented on CT in all heads. In the control group, the brain parenchyma leaked out from the hole in the meninges, and the gray-white matter difference was clear in 3/72 (4.2%), moderate in 7/72 (9.7%), ambiguous in 17/72 (23.6%), and poor in 45/72 (62.5%). In the freezing group, the brain parenchyma presented homogeneous low density after more than 14h freezing. On opening the cranium, the entire brains were frozen, and the gray-white matter difference was clear in 33/72 (46.0%), moderate in 17/72 (24.0%), ambiguous in 15/72 (21.0%), and poor in 7/72 (10.0%). The freezing group afforded greater clarity in the gray-white matter inspection (p<0.05). CONCLUSION: Freezing preparation was useful for the macroscopic investigation of putrefied brain compared with the ordinary autopsy. PMID- 28081787 TI - Primed neutrophil infiltrations into multiple organs in child physical abuse cases: A preliminary study. AB - Physical abuse of the elderly induces a massive primed neutrophil infiltration into the lung and liver through chemotaxis by interleukin (IL)-8, similar to cases of traumatic or hemorrhagic shock. Here, we used immunohistochemical analyses to investigate this infiltration in cases of physically abused children. In addition, we examined the expression of neutrophil elastase (NE) as the inflammatory mediator and alpha1-antitrypsin (AAT) as the elastase inhibitor. The number of neutrophils in the abuse cases was increased significantly in the heart, lung, liver, and kidney, compared with that of control cases. IL-8 positive cells and NE-positive cells in all organs of abuse cases were significantly greater than those in control cases. Large quantities of oxidized AAT, which fails to inactivate NE and results in tissue damage, was detected in the liver of abuse cases. Neutrophil infiltration showed positive correlation with the degree of systemic accumulation of non-fatal injuries caused by repetitive abusive behavior. Although further investigation using more autopsy samples is necessary, results of our preliminary study indicate that massive neutrophil infiltration induced by IL-8 in multiple organs is a new complementary diagnostic indicator of physical abuse in children. Moreover, the demonstration of NE-positive cells and oxidized AAT provides firm evidence of tissue damage. PMID- 28081788 TI - Autosomal SNPs study of a population sample from Southern Portugal and from a sample of immigrants from Guinea-Bissau residing in Portugal. AB - In recent years, autosomal single nucleotide polymorphisms (SNPs) have been comprehensively investigated in forensic research due to their usefulness in certain circumstances in complementing short tandem repeats (STRs) analysis, or even for use on their own when analysis of STRs fails. However, as with STRs, in order to properly use SNP markers in forensic casuistic we need to understand the population and forensic parameters in question. As a result of Portugal's colonial history during the time of empire, and the subsequent process of decolonization, some African individuals migrated to Portugal, giving rise to large African and African-descendent communities. One of these groups is the community originating from Guinea-Bissau, that in 2014, was enumerated to consist of more than 17,700 individuals with official residency status, more than the third major city of Guinea-Bissau. In order to study the population and forensic parameters mentioned above for the two populations important to our casuistic, a total of 142 unrelated individuals from the South of Portugal and 90 immigrants from Guinea-Bissau (equally non related and all residing in Portugal) were typed with SNaPshotTM assay for all 52 loci included in the SNPforID 52plex. PMID- 28081789 TI - Rapid and highly sensitive analysis of benzodiazepines and tandospirone in human plasma by automated on-line column-switching UFLC-MS/MS. AB - A high-throughput method was developed for the detection of 31 benzodiazepine drugs and tandospirone in human plasma by on-line column-switching ultra-fast liquid chromatography-tandem mass spectrometry. Plasma samples (100MUl) spiked with the 32 drugs and oxazepam-d5 (internal standard) were diluted with 300MUl of 13.3mM ammonium acetate/acetonitrile (33:67, v/v). After centrifugation and filtration, the clear supernatant was injected directly onto the extraction column (Oasis HLB cartridge column). The following procedure was fully automated. The analytes retained on the extraction column were eluted by backflushing of the extraction column and introduced into an analytical column (SUMIPAX ODS D-Swifter column, 30mm*3.0mm i.d.; particle size 2MUm) by column switching. Quantification was performed by multiple reaction monitoring with positive-ion electrospray ionization. Distinct peaks appeared for each drug and the internal standard on each channel within 7min, including the extraction time. All drugs spiked into plasma showed recoveries of 83-95%. The regression equations for the 32 drugs showed excellent linearities in the range of 50-2000pg/ml of plasma and the limits of detection ranged from 20 to 50pg/ml. The lower and upper limits of quantitation were 50-100ng/ml and 2000pg/ml, respectively. Intra- and interday coefficients of variation for none of the drugs were greater than 13.6%. The accuracies of quantitation were 87-112%. The multiple reaction monitoring information-dependent acquisition of enhanced product ions method enabled the quantification and confirmation of diazepam, triazolam, and lorazepam obtained from actual plasma. PMID- 28081790 TI - Non-ionic iodinated contrast media related immediate reactions: A mechanism study of 27 patients. AB - The underlying mechanism of non-ionic iodinated contrast media-related immediate reactions was evaluated in this study. Patients presenting at least grade II immediate reactions after non-ionic iodinated contrast media injection were enrolled. Basophil activation was evaluated by flow cytometry. The plasma concentration of human terminal complement complex SC5b-9, as well as concentrations of serum chymase, tryptase, human mast cell carboxypeptidase A3, human prostaglandin D2, and total IgE were measured by enzyme-linked immunosorbent assay. The basophil activation percentage was significantly higher in the study group than in the control group (17.94+/-21.06% vs 3.45+/-1.49%). The plasma concentration of human terminal complement complex SC5b-9 and concentrations of serum chymase, human mast cell carboxypeptidase A3, prostaglandin D2, tryptase, and total IgE were also significantly increased (236.99+/-318.21 vs 49.70+/-30.41ng/mL, 0.41+/-0.49 vs 0.09+/-0.06ng/mL, 1.17+/ 0.67 vs 0.30+/-0.17ng/mL, 203.52+/-137.27 vs 102.28+/-48.72pg/mL, 3.81+/-0.22 vs 2.70+/-0.16ng/mL, 102.00+/-51.84 vs 19.97+/-2.75ng/mL, respectively). Both mast cells and basophils were activated in non-ionic iodinated contrast media to mediate immediate hypersensitivity, and mast cells may be involved. Different mechanisms, including IgE-dependent, complement-dependent, and direct membrane effects, contributed to mast cell and basophil activation. Individual patients may use a single or combined mechanism involving single or combined mast cells and basophils. Immediate reactions following non-ionic iodinated contrast media injection may be a mechanically heterogenous disease. PMID- 28081791 TI - Traffic accident or dumping? - Striking results of a traffic accident reconstruction. AB - An atypical traffic accident scenario should be investigated directly at the crash site from all concerned professions, especially police men, forensic pathologists and technical experts, to get a personal overview and impression of the situation and the opportunity for interdisciplinary discussion. We present the rare case of a fatal traffic accident on a German motorway which was initially thought to be an accidental discovery of dumping a corpse. Based on autopsy findings, the technical investigation and the accident reconstruction, this case was solved as a spectacular form of a collision between a pedestrian and a bonnet-front car, which was not described elsewhere in scientific literature to the best of our knowledge. The pedestrian was hit in an upright body position, was lifted up by the car, smashed the windscreen and flew over the car with several body rotations. His flight curve ends directly at the roof of the car during brake processing, where the body touched the roof, smashed the rear-window and landed in the trunk. Based on the technical investigation, the driver of the car was not able to hide the accident. However, the pedestrian could have avoided the collision if he did not cross the motorway on foot. PMID- 28081792 TI - Liquid chromatography-tandem mass spectrometry method for the determination of thiosulfate in human blood and urine as an indicator of hydrogen sulfide poisoning. AB - Being a stable metabolite of hydrogen sulfide, thiosulfate has been utilized as an index for hydrogen sulfide poisoning (HSP). Thiosulfate analysis is mainly performed using gas chromatography/mass spectrometry (GC-MS) due to its high sensitivity and specificity. The GC-MS analysis requires two-step derivatizations of thiosulfate, and the derivative is not stable in solution as it has a disulfide moiety. To resolve this stability issue, we developed a novel analytical method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for monitoring the pentafluorobenzyl derivative of thiosulfate (the first reaction product of the GC-MS method) in this study. The established method exhibited high reproducibility despite being a more simplified and rapid procedure compare to the GC-MS method. Phenyl 4-hydroxybenzoate was used as an internal standard because 1,3,5-tribromobenzene which had been used in the GC-MS method was not suitable compound for LC-MS/MS with Electrospray ionization (ESI) negative detection. The linear regression of the peak area ratios versus concentrations was fitted over the concentration ranges of 0.5-250MUM and 0.25 250MUM in blood and urine, respectively. The validation results satisfied the acceptance criteria for intra- and inter-day accuracy and precision. Blood and urine samples from 12 suspected HSP cases were tested using this method. The thiosulfate concentration detected in the sample coincided well with that determined at the scene of each HSP accident. PMID- 28081793 TI - Loss of heterozygosity detected at three short tandem repeat locus commonly used for human DNA identification in a case of paternity testing. AB - Short tandem repeat (STR) is widely used for DNA profiling in forensic sciences for its stable inheritance. Genomic variations in STR loci may affect the results of the genotyping. In this study, using STR profiling and genome-wide chromosomal microarray assay, we detected the incidence of uniparental disomy or copy-neutral loss of heterozygosity (LOH) in a case of a parental testing, which altered the genotype of three commonly used STR markers including D2S1338, D2S441 and D2S1776. To the best of our knowledge, this is the first time found that LOH affect the genotyping of STR markers commonly used for paternity testing. Our findings demonstrated that the incidence of LOH in the genome may dramatically alter the results of DNA identification, and suggested that genomic structure variation need to be taking into consideration in the DNA identification using STR markers. PMID- 28081794 TI - The geographical distribution of fly larvae on corpses in Saitama Prefecture in Japan during the summer season. AB - Identification of fly larvae species may offer valuable information as to the location, or the environment in which corpses were placed, but only if the geographical distribution of larva species is clarified. In this study, we investigated a total of 126 larvae on 42 corpses found in Saitama Prefecture in Japan between July and September. We identified the larva species by analyzing the sequences of mitochondrial DNA cytochrome oxidase gene subunit I. Our results revealed that larvae belonged to 6 different species: Lucilia sericata and Chrysomya pinguis from the Calliphoridae family, and Parasarcophaga crassipalpis, Boettcherisca peregrina, Parasarcophaga harpax, and Parasarcophaga dux from the Sarcophagidae family. Additionally, we investigated if there was a correlation between larvae species and population density. Based on the random sampling and the statistical analysis on the entire larva collection, larvae of Chrysomya pinguis species were more likely to be found in low population density areas, whereas larvae of Lucilia sericata were commonly found in high population density areas. The accumulation of distribution data of larvae may be useful to confirm the environment around the place where corpses were found. PMID- 28081795 TI - Associations of OCA2-HERC2 SNPs and haplotypes with human pigmentation characteristics in the Brazilian population. AB - Panels composed of Single Nucleotide Polymorphisms (SNPs) in genes related to pigmentation, when associated with different phenotypes, may assist in predicting the physical appearance of an individual, being very useful in forensic caseworks. We evaluated the association of seven OCA2-HERC2 SNPs and haplotypes with pigmentation characteristics (eye, skin, hair and freckles) in the highly admixed and phenotypically heterogeneous Brazilian population. All the seven SNPs evaluated presented one allele associated with phenotypes from at least two pigmentation features and the alternative allele associated with the opposite phenotypes from the same trait. The genotypic associations followed the same pattern for all seven SNPs. Nine haplotypes were observed in our sample and eight were associated with at least two pigmentation traits. Such SNPs and haplotypes could be deemed as good predictors for the presence of freckles and for skin, eye and hair pigmentation in the Brazilian population. PMID- 28081796 TI - Helium ion microscopy (HIM): Proof of the applicability on altered human remains (hairs of Holy Maria-Magdalena). PMID- 28081797 TI - Comparison of the cardiothoracic ratio between postmortem and antemortem computed tomography. AB - As postmortem imaging has gained prominence as a supplement to traditional autopsy, it is important to understand the normal postmortem changes to enable the accurate evaluation of postmortem imaging. No studies have evaluated the postmortem changes in cardiothoracic ratio (CTR) compared with antemortem images in the same subjects. We studied 147 consecutive subjects who underwent antemortem and postmortem CT, and autopsy. Postmortem CT was performed <23h after death and was followed by autopsy. The subjects were divided into three groups: normal heart, old myocardial infarction, and CPR-treated hearts. CTR was compared between antemortem and postmortem CT using paired t tests, which revealed that the CTR was greater on postmortem CT than on antemortem CT in all groups (mean CTR: 0.53+/-0.06vs. 0.50+/-0.06, respectively; P<0.01). Sex, age, time elapsed since death, and the causes of death were examined as potential confounding factors for the postmortem changes in CTR, but no significant associations were found. Receiver-operating characteristic (ROC) curves were used to determine CTR values for cardiomegaly, which was defined according to the autopsy weight of the heart. The area under the ROC curve was 0.71 (95% confidence interval 0.63-0.79). The CTR threshold of 0.54 identified cardiomegaly with the greatest accuracy, compared with the general threshold of 0.50. In conclusion, the CT-determined CTR increases after death, irrespective of the heart's condition. We should be cautious of overdiagnosis of cardiomegaly on postmortem CT, and new criteria for interpreting cardiomegaly on postmortem CTR are needed. PMID- 28081798 TI - Post-mortem detection of bacteremia using pairs of blood culture samples. AB - AIM: The objective of this study was to assess the utility of examining pairs of blood culture samples obtained from separate sites (both ventricles or the aorta and vena cava) for detecting bacteremia in the post-mortem setting. METHODS: Autopsy cases in which bacterial species were isolated from blood cultures were identified over a 4-year period. Ante-mortem and post-mortem records and the findings of pathological examinations were reviewed. RESULTS: Overall, 23 bacterial species were detected in 18 autopsy cases. E. coli was the most commonly detected species (5 cases, 27.8%), followed by S. aureus and K. pneumoniae, respectively. Seven of the detected bacterial species (3 cases, 16.7%) were obligate anaerobes (Clostridium spp. and Bacteroides spp.). Among the 3 cases involving obligate anaerobes, multiple bacterial species were detected in 2 cases. Clinically, 2 of the 18 patients in which bacteria were detected were treated for significant infections (urosepsis, pneumonia, and catheter-related bloodstream infection) before their deaths. Seven cases exhibited evidence of significant infection during the post-mortem pathological examination. The differences between the aerobic and anaerobic bacteria positivity rates of the single and paired blood culture samples were significant (aerobic: p=0.013 and anaerobic: p=0.018). CONCLUSION: Analyzing pairs of blood culture samples obtained from separate sites is useful for detecting bacteremia during post mortem examinations. PMID- 28081799 TI - The nicer side of innate immunity: Wound healing and tissue regeneration. PMID- 28081800 TI - Editorial. PMID- 28081801 TI - Management of Descending Thoracic Aorta Disease: Evolving Treatment Paradigms in the TEVAR Era. PMID- 28081802 TI - Editor's Choice - Management of Descending Thoracic Aorta Diseases: Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS). PMID- 28081803 TI - Microalgae as embedded environmental monitors. AB - In marine ecosystems, microalgae are an important component as they transform large quantities of inorganic compounds into biomass and thereby impact environmental chemistry. Of particular relevance is phytoplankton's sequestration of atmospheric CO2, a greenhouse gas, and nitrate, one cause of harmful algae blooms. On the other hand, microalgae sensitively respond to changes in their chemical environment, which initiates an adaptation of their chemical composition. Analytical methodologies were developed in this study that utilize microalgae's adaptation as a novel approach for in-situ environmental monitoring. Longterm applications of these novel methods are investigations of environmental impacts on phytoplankton's sequestration performance and their nutritional value to higher organisms feeding on them. In order to analyze the chemical composition of live microalgae cells (Nannochloropsis oculata), FTIR-ATR spectroscopy has been employed. From time series of IR spectra, the formation of bio-sediment can be monitored and it has been shown that the nutrient availability has a small but observable impact. Since this bio-sediment formation is governed by several biological parameters of the cells such as growth rate, size, buoyancy, number of cells, etc., this enables studies of chemical environment's impact on biomass formation and the cells' physical parameters. Moreover, the spectroscopic signature of these microalgae has been determined from cultures grown under 25 different CO2 and NO3- mixtures (200 ppm-600 ppm CO2, 0.35 mM-0.75 mM NO3-). A novel, nonlinear modeling methodology coined 'Predictor Surfaces' is being presented by means of which the nonlinear responses of the cells to their chemical environment could reliably be described. This approach has been utilized to measure the CO2 concentration in the atmosphere over the phytoplankton culture as well as the nitrate concentration dissolved in their growing environment. The achieved precision of concentration predictions were a few percent of the measurement range. Moreover, the Predictor Surface itself allows for a chemical interpretation of the cells' response to a shift in their chemical environment. This will open new approaches to study the link between concentration levels in an ecosystem and the biological consequences for this ecosystem. PMID- 28081804 TI - Robust l-malate bienzymatic biosensor to enable the on-site monitoring of malolactic fermentation of red wines. AB - Monitoring the malolactic fermentation process is strictly required to guarantee the sensorial quality and freshness of red wines. This could be achieved by in field and real-time continuous measurements of l-malate concentration in the fermentation tanks. The potential of a miniaturized amperometric bienzymatic biosensor as an analytical tool to be applied in such scenario is described in this paper. The biosensor comprises a thin-film gold electrode as transducer, malate dehydrogenase (MDH) and diaphorase (DP) enzymes together with nicotinamide adenine dinucleotide (NAD+) cofactor as the selective receptor and an adequate redox mediator to record the corresponding amperometric signal. Three different biosensor architectures are studied, whose main differences lie in the immobilization of the different chemical components onto the electrode surface. In all cases a fast-electrosynthethized polypyrrole (PPy) membrane is generated for this purpose. The experimental conditions are optimized and the best architecture shows a sensitivity of 1365 +/- 110 mA M-1 cm-2 and a detection limit of 6.3 * 10-8 M in a concentration range of 1 * 10-7 M - 1 * 10-6 M. The biosensor presents an excellent working stability as it retains above 90% of its sensitivity after 37 days, thus enabling the monitoring of the malolactic fermentation of three red wines. The obtained results show excellent agreement with the standard colorimetric method. PMID- 28081805 TI - High-sensitive surface plasmon resonance microRNA biosensor based on streptavidin functionalized gold nanorods-assisted signal amplification. AB - Herein, a facile and sensitive microRNA (miRNA) biosensor was designed by using interfacial biotinylated thiolated DNA molecular beacon (MB) as probe and streptavidin functionalized gold nanorods (Stre-GNRs) as tag for the enhanced surface plasmon resonance (SPR) signal. The MB probe with two terminals labeled with biotin and thiol groups, respectively, was modified on the gold film via thiol-gold interaction. Upon hybridization with the target, the biotinylated group became accessible to the Stre-GNRs. The introduction of the Stre-GNRs tag to the gold film produced strong SPR signal for detection. Our work has illustrated that the plasmonic field extension generated from the gold film to GNRs and the mass increase due to the GNRs have led to drastic sensitivity enhancement. Under optimal conditions, this proposed approach allowed detection of miRNA with the limit of detection (LOD) down to 0.045 pM. The results have shown that the MB probe functionalized sensing film, together with streptavidin conjugated GNRs, was readily served as a plasmonic coupling partner that can be used as a powerful ultrasensitive sandwich assay for miRNA detection, and GNRs were readily served as promising amplification labels in SPR sensing technology. PMID- 28081806 TI - Single nucleotide polymorphism discrimination with and without an ethidium bromide intercalator. AB - Single nucleotide polymorphism (SNP) genotyping is an important aspect in understanding genetic variations. Here, we discriminate SNPs using toe-hold mediated displacement reactions. The biological target is an 80 nucleotide long double-stranded-DNA from the mtDNA HV1 region, associated with maternal ancestry. This target has been specially designed with a pendant toehold and a cationic fluorophore, ATTO 647N, as a reporter, produced in a polymerase chain reaction. Rates of reaction for the toehold-polymerase chain reaction products (TPPs) with their corresponding complementary displacing sequences, labelled with a Black Hole Quencher 1, followed the order TPP-Cytosine > TPP-Thymine > TPP-Adenine >= TPP-Guanine. Non-complementary rates were the slowest with mismatches involving cytosine. These reactions, operating in a static/or contact mode, gave averaged readouts between SNPs within 15 min (with 80-90% quenching), compared to 25-30 min in previous studies involving fluorescence resonance energy transfer. Addition of an intercalating agent, ethidium bromide, retarded the rate of reaction in which cytosine was involved, presumably through stabilization of the base pairing, which resulted in markedly improved discrimination of cytosine containing SNPs. PMID- 28081807 TI - Microwave-assisted grafting polymerization modification of nylon 6 capillary channeled polymer fibers for enhanced weak cation exchange protein separations. AB - A weak cation exchange liquid chromatography stationary phase (nylon-COOH) was prepared by grafting polyacrylic acid on to native nylon 6 capillary-channeled polymer (C-CP) fibers via a microwave-assisted radical polymerization. To the best of our knowledge, this is the first study of applying microwave-assisted grafting polymerization to affect nylon material for protein separation. The C-CP fiber surfaces were characterized by attenuated total reflection (ATR) infrared spectroscopy and scanning electron microscope (SEM). The anticipated carbonyl peak at 1722.9 cm-1 was found on the nylon-COOH fibers, but was not found on the native fiber, indicating the presence of the polyacrylic acid on nylon fibers after grafting. The nylon-COOH phase showed a ~12* increase in lysozyme dynamic binding capacity (~12 mg mL-1) when compared to the native fiber phase (~1 mg mL 1). The loading capacity of the nylon-COOH phase is nearly independent of the lysozyme loading concentration (0.05-1 mg mL-1) and the mobile phase linear velocity (7.3-73 mm s-1). The reproducibility of the lysozyme recovery from the nylon-COOH (RSD = 0.3%, n = 10) and the batch-to-batch variability in the functionalization (RSD = 3%, n = 5) were also investigated, revealing very high levels of consistency. Fast baseline separations of myoglobin, alpha chymotrypsinogen A, cytochrome c and lysozyme were achieved using the nylon-COOH column. It was found that a 5* increase in the mobile phase linear velocity (7.3 to-36.5 mm s-1) had little effect on the separation resolution. The microwave assisted grafting polymerization has great potential as a generalized surface modification methodology across the applications of C-CP fibers. PMID- 28081808 TI - Support vector machine classification trees based on fuzzy entropy of classification. AB - The support vector machine (SVM) is a powerful classifier that has recently been implemented in a classification tree (SVMTreeG). This classifier partitioned the data by finding gaps in the data space. For large and complex datasets, there may be no gaps in the data space confounding this type of classifier. A novel algorithm was devised that uses fuzzy entropy to find optimal partitions for situations when clusters of data are overlapped in the data space. Also, a kernel version of the fuzzy entropy algorithm was devised. A fast support vector machine implementation is used that has no cost C or slack variables to optimize. Statistical comparisons using bootstrapped Latin partitions among the tree classifiers were made using a synthetic XOR data set and validated with ten prediction sets comprised of 50,000 objects and a data set of NMR spectra obtained from 12 tea sample extracts. PMID- 28081809 TI - Off-line mixed-mode liquid chromatography coupled with reversed phase high performance liquid chromatography-high resolution mass spectrometry to improve coverage in lipidomics analysis. AB - The confident identification and in-depth profiling of molecular lipid species remain to be a challenge in lipidomics analysis. In this work, an off-line two dimensional mixed-mode and reversed-phase liquid chromatography (RPLC) method combined with high-field quadrupole orbitrap mass spectrometer (Q Exactive HF) was developed to profile lipids from complex biological samples. In the first dimension, 22 different lipid classes were separated on a monolithic silica column with elution order from neutral to polar lipids. A total of 13 fractions were collected and run on a RPLC C30 column in the second dimension for further separation of the lipid molecular species based on their hydrophobicity, with the elution order being determined by both the length and degree of unsaturation in the fatty-acyl chain. The method was applied to analyze lipids extracted from rat plasma and rat liver. Fatty acid methyl ester analysis by gas chromatography-mass spectrometry was used to identify the fatty acyls from total lipid extracts, which provided a more confident identification of the lipid species present in these samples. More than 800 lipids were identified in each sample and their molecular structures were confidentially confirmed using tandem mass spectrometry (MS/MS). The number of lipid molecular species identified in both rat plasma and rat liver by this off-line two-dimensional method is approximately twice of that by one-dimensional RPLC-MS/MS employing a C30 column. This off-line two dimensional mixed-mode LC-RPLC-MS/MS method is a promising technique for comprehensive lipid profiling in complex biological matrices. PMID- 28081810 TI - Novel assay of antibacterial components in manuka honey using lucigenin chemiluminescence-HPLC. AB - Five components (hydrogen peroxide, methylglyoxal, dihydroxyacetone, fructose and glucose) of New Zealand manuka honey (Leptospermum scoparium) were analyzed using lucigenin chemiluminescence high-performance liquid chromatography (lucigenin-CL HPLC). We focused on active oxygen species produced from the components in order to easily detect these five components contained in manuka honey. H2O2 and O2- generated from these components were identified by lucigenin-CL and electron spin resonance (ESR), and the bactericidal effect of ROS was confirmed using E. coli. The previously reported assays for Manuka honey components have low specificities and require complicated preprocessing methods. As our results, the detection and identification of these components were possible within 30 min in lucigenin-CL HPLC system, without any special treatment. It is considered that lucigenin-CL HPLC is useful for the quality control and the analysis of various honey. PMID- 28081811 TI - Convolutional neural networks for vibrational spectroscopic data analysis. AB - In this work we show that convolutional neural networks (CNNs) can be efficiently used to classify vibrational spectroscopic data and identify important spectral regions. CNNs are the current state-of-the-art in image classification and speech recognition and can learn interpretable representations of the data. These characteristics make CNNs a good candidate for reducing the need for preprocessing and for highlighting important spectral regions, both of which are crucial steps in the analysis of vibrational spectroscopic data. Chemometric analysis of vibrational spectroscopic data often relies on preprocessing methods involving baseline correction, scatter correction and noise removal, which are applied to the spectra prior to model building. Preprocessing is a critical step because even in simple problems using 'reasonable' preprocessing methods may decrease the performance of the final model. We develop a new CNN based method and provide an accompanying publicly available software. It is based on a simple CNN architecture with a single convolutional layer (a so-called shallow CNN). Our method outperforms standard classification algorithms used in chemometrics (e.g. PLS) in terms of accuracy when applied to non-preprocessed test data (86% average accuracy compared to the 62% achieved by PLS), and it achieves better performance even on preprocessed test data (96% average accuracy compared to the 89% achieved by PLS). For interpretability purposes, our method includes a procedure for finding important spectral regions, thereby facilitating qualitative interpretation of results. PMID- 28081812 TI - Standardization from a benchtop to a handheld NIR spectrometer using mathematically mixed NIR spectra to determine fuel quality parameters. AB - The interest in performing in field measures using portable instruments is growing increasingly. Calibration transfer techniques can be used to enable models, predicted values or spectra obtained in a benchtop instrument be used in portable instrument, saving money and time required for a complete recalibration. Most of the calibration transfer methods require a set of transfer samples which spectra have to be acquired in both spectrometers. The present work evaluates the use of virtual standards as transfer samples in the reverse standardization (RS) method in order to standardize very dissimilar spectral responses of fuel samples (gasoline and biodiesel blends) from a high-resolution benchtop Frontier FT-NIR (PerkinElmer) spectrometer and a handheld MicroNIRTM1700 (JDSU). These virtual standards can be created by mathematically mixing spectra from the pure solvents present in gasoline or diesel/biodiesel (D/B) blends, to avoid volatilization and changes in the composition of the compounds during storage and/or transportation of the real transfer fuel samples. Virtual standards were created using ten and five pure solvents for gasoline and D/B blends, respectively. Partial least squares regression (PLS) models were built for five quality parameters of gasoline (distillation temperatures at 10%, 50%, 90% and final boiling point (FBP) volume recovered and density) and one of D/B blends (biodiesel content). The RMSEP values obtained after the standardization approaches were equivalent to the reproducibility of the reference methods, except for density and biodiesel content parameters obtained for the virtual samples standardization approach. RS procedure provided promising results showing that it is possible to transfer gasoline or D/B blend spectra acquired with a high-resolution benchtop instrument to the handheld MicroNIR using virtual standards as transfer samples. PMID- 28081813 TI - Synthesis of palladium@gold nanoalloys/nitrogen and sulphur-functionalized multiple graphene aerogel for electrochemical detection of dopamine. AB - Integration of noble metal nanomaterials on graphene nanosheets potentially paves one way to improve their electronic, chemical and electrochemical properties. The study reported synthesis of palladium@gold nanoalloys/nitrogen and sulphur functionalized multiple graphene aerogel composite (Pd@Au/N,S-MGA). The as prepared composite offers a well-defined three-dimensional architecture with rich of mesopores. The Pd@Au nanoalloys were dispersed on the graphene framework networks and their active sites were fully exposed. The unique structure achieves to ultra high electron/ion conductivity, electrocatalytic activity and structural stability. The sensor based on the Pd@Au/N,S-MGA creates ultrasensitive electrochemical response towards dopamine due to significantly electrochemical synergy between Pd, Au and N,S-MGA. Its differential pulse voltammetric signal linearly increases with the increase of dopamine concentration in the range from 1.0 * 10-9 M to 4.0 * 10-5 M with the detection limit of 3.6 * 10-10 M (S/N = 3). The analytical method provides the advantage of sensitivity, reproducibility, rapidity and long-term stability. It has been successfully applied in the detection of trace dopamine in biological samples. The study also opens a window on the electronic properties of graphene aerogel and metal nanomaterials as well their nanohybrids to meet needs of further applications as nanoelectronics in diagnosis, bioanalysis and catalysis. PMID- 28081814 TI - Surface-coated wooden-tip electrospray ionization mass spectrometry for determination of trace fluoroquinolone and macrolide antibiotics in water. AB - In this study, a surface-coated wooden-tip electrospray ionization mass spectrometry (SCWT-ESI-MS) method was developed for rapid and sensitive analysis of trace fluoroquinolone and macrolide antibiotics in water. First, a SCWT solid phase microextration (SPME) probe was prepared, via silanization and sulfonation for modification of a layer of adsorbent containing both C8-chain and sulfo group on the surface of wooden tips. Then, the SCWT-SPME probe was applied for extraction of trace fluoroquinolone and macrolide antibiotics in water. The specially designed adsorbent gave the probe desirable enrichment capacity towards fluoroquinolone and macrolide antibiotics, with enrichment factors of approximately 100-500 folds for six target analytes. After extraction, the loaded SCWT-SPME probe was directly applied for ambient MS analysis. With the application of a high voltage and some spray solvent on the SCWT-SPME probe, analytes enriched on the probe was desorbed and ionized for mass spectrometric analysis under ambient and open-air conditions. The method was sensitive, with limits of detection and quantification of 1.8-4.5 ng/L and 5.9-15.1 ng/L, respectively. The method also showed good linearity, with correlation coefficient values (r2) of no less than 0.9940 for six target analytes. The developed method was successfully applied for the analysis of six fluoroquinolone and macrolide antibiotics in tap and river water samples, and no antibiotic was found in tap water but some antibiotics were detected in river water with concentrations at dozens to hundreds nanogram-per-liter level. Standard addition experiments were also performed, and the obtained recoveries were 89-102% for tap waters and 82 92% for river waters, respectively. All the experimental results demonstrated that our proposed SCWT-ESI-MS method was rapid, sensitive, and reliable for analyzing trace antibiotics in water. PMID- 28081815 TI - Parts-per-trillion detection of harmala alkaloids in Undaria pinnatifida algae by on-line solid phase extraction capillary electrophoresis mass spectrometry. AB - beta-carboline alkaloids of the harmala group (HAlks)-a family of compounds with pharmacologic effects-can be found at trace levels (<25 MUg kg-1 algae) in the edible invasive algae Undaria pinnatifida, known commonly as wakame. In this study, we present a simple and sensitive method to detect and quantify at low parts-per-trillion levels the six HAlks more frequently found in those plants. The method is based on on-line solid phase extraction capillary electrophoresis mass spectrometry using a C18 sorbent. First, the methodology was optimized and validated with standard solutions through the use of ultraviolet (UV) and mass spectrometry (MS) detection. Second, the optimized method for MS detection was applied to an analysis of the HAlks in U. pinnatifida extracts. The method achieved limits of detection between 2 and 77 pg mL-1 for standards, producing an analyte preconcentration of about 1000-times in comparison to CE-MS. Some matrix effects were observed for the complex wakame extracts, especially for the most polar HAlks (harmol and harmalol), which bear aromatic hydroxyl groups. Harmine, harmaline, and norharmane were not detected in the algal extracts, whereas harmane was found at 70 pg mL-1 (70 ng kg-1 dry algae). The results underscored that C18-SPE-CE-MS may be considered as a powerful method to detect trace levels of alkaloids and other bioactive small molecules in complex plant extracts. PMID- 28081816 TI - Silicon isotope ratio measurements by inductively coupled plasma tandem mass spectrometry for alteration studies of nuclear waste glasses. AB - High-level, long-lived nuclear waste arising from spent fuel reprocessing is vitrified in silicate glasses for final disposal in deep geologic formations. In order to better understand the mechanisms driving glass dissolution, glass alteration studies, based on silicon isotope ratio monitoring of 29Si-doped aqueous solutions, were carried out in laboratories. This work explores the capabilities of the new type of quadrupole-based ICP-MS, the Agilent 8800 tandem quadrupole ICP-MS/MS, for accurate silicon isotope ratio determination for alteration studies of nuclear waste glasses. In order to avoid silicon polyatomic interferences, a new analytical method was developed using O2 as the reaction gas in the Octopole Reaction System (ORS), and silicon isotopes were measured in mass shift mode. A careful analysis of the potential polyatomic interferences on SiO+ and SiO2+ ion species was performed, and we found that SiO+ ion species suffer from important polyatomic interferences coming from the matrix of sample and standard solutions (0.5M HNO3). For SiO2+, no interferences were detected, and thus, these ion species were chosen for silicon isotope ratio determination. A number of key settings for accurate isotope ratio analysis like, detector dead time, integration time, number of sweeps, wait time offset, memory blank and instrumental mass fractionation, were considered and optimized. Particular attention was paid to the optimization of abundance sensitivity of the quadrupole mass filter before the ORS. We showed that poor abundance sensitivity leads to a significant shift of the data away from the Exponential Mass Fractionation Law (EMFL) due to the spectral overlaps of silicon isotopes combined with different oxygen isotopes (i.e. 28Si16O18O+, 30Si16O16O+). The developed method was validated by measuring a series of reference solutions with different 29Si enrichment. Isotope ratio trueness, uncertainty and repeatability were found to be <0.2%, <0.5% and <0.6%, respectively. These performances meet the requirements of the studies of nuclear glasses alteration and open up possibilities to use this method for precise determination of silicon content in natural samples by Isotope Dilution. PMID- 28081817 TI - Highly sensitive quantification for human plasma-targeted metabolomics using an amine derivatization reagent. AB - Amino acids and their related metabolites play important roles in various physiological processes and have consequently become biomarkers for diseases. However, accurate quantification methods have only been established for major compounds, such as amino acids and a limited number of target metabolites. We previously reported a highly sensitive high-throughput method for the simultaneous quantification of amines using 3-aminopyridyl-N-succinimidyl carbamate as a derivatization reagent combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Herein, we report the successful development of a practical and accurate LC-MS/MS method to analyze low concentrations of 40 physiological amines in 19 min. Thirty-five of these amines showed good linearity, limits of quantification, accuracy, precision, and recovery characteristics in plasma, with scheduled selected reaction monitoring acquisitions. Plasma samples from 10 healthy volunteers were evaluated using our newly developed method. The results revealed that 27 amines were detected in one of the samples, and that 24 of these compounds could be quantified. Notably, this new method successfully quantified metabolites with high accuracy across three orders of magnitude, with lowest and highest averaged concentrations of 31.7 nM (for spermine) and 18.3 MUM (for alpha-aminobutyric acid), respectively. PMID- 28081818 TI - Simple approach for the fabrication of screen-printed carbon-based electrode for amperometric detection on microchip electrophoresis. AB - This paper describes a simple method for the fabrication of screen-printed based electrodes for amperometric detection on microchip electrophoresis (ME) devices. The procedure developed is quite simple and does not require expensive instrumentation or sophisticated protocols commonly employed on the production of amperometric sensors, such as photolithography or sputtering steps. The electrodes were fabricated through manual deposition of home-made conductive carbon ink over patterned acrylic substrate. Morphological structure and electrochemical behavior of the carbon electrodes were investigated by scanning electron microscopy and cyclic voltammetry. The produced amperometric sensors were coupled to polydimethylsiloxane (PDMS) microchips at end-channel configuration in order to evaluate their analytical performance. For this purpose, electrophoretic experiments were carried out using nitrite and ascorbic acid as model analytes. Separation of these substances was successfully performed within 50s with good resolution (R = 1.2) and sensitivities (713.5 pA/MUM for nitrite and 255.4 pA/MUM for ascorbate). The reproducibility of the fabrication method was evaluated and revealed good values concerning the peak currents obtained (8.7% for nitrite and 9.3% for ascorbate). The electrodes obtained through this method exhibited satisfactory lifetime (ca. 400 runs) over low fabrication cost (less than $1 per piece). The feasibility of the proposed device for real analysis was demonstrated through the determination of nitrite concentration levels in drinking water samples. Based on the results achieved, the approach proposed here shows itself as an interesting alternative for simple fabrication of carbon-based electrodes. Furthermore, the devices indicate great promise for other kind of analytical applications involving ME devices. PMID- 28081819 TI - A benzothiazole-based fluorescent probe for distinguishing and bioimaging of Hg2+ and Cu2. AB - A new benzothiazole-based fluorescent probe 2-(benzo[d]thiazol-2-yl)-4-(1,3- dithian-2-yl)phenol (BT) with two different reaction sites, a thioacetal group (site 1 for Hg2+), and O and N atoms of the benzothiazole dye (site 2 for Cu2+), was designed and synthesized. The probe BT showed ratiometric fluorescent response to Hg2+ and fluorescence quenching behavior to Cu2+, which induces naked eye fluorescent color changes from green to blue and colorless, respectively. Moreover, it displayed highly sensitivity and selectivity toward Hg2+ and Cu2+ without interference from other metal ions. The sensing mechanisms were also confirmed by 1H NMR titration, mass spectrum and Job's plot analyses. Finally, probe BT was successfully used for fluorescent imaging of Hg2+ and Cu2+ in living cells, demonstrating its potential applications in biological science. PMID- 28081821 TI - Adding CABG to the Dual Antiplatelet Salad. PMID- 28081820 TI - Dual Antiplatelet Therapy Versus Aspirin Monotherapy in Diabetics With Multivessel Disease Undergoing CABG: FREEDOM Insights. AB - BACKGROUND: Clinical practice guidelines recommend post-operative dual antiplatelet therapy (DAPT) in patients who undergo coronary artery bypass grafting (CABG) following acute coronary syndromes (ACS). OBJECTIVES: The authors have evaluated DAPT utilization rates and associated outcomes among post-CABG patients with diabetes. METHODS: In a post hoc, nonrandomized analysis from the FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial, we compared patients receiving DAPT (aspirin plus thienopyridine) and aspirin monotherapy at 30 days post operatively. The primary outcome was the risk adjusted 5-year FREEDOM composite of all-cause mortality, nonfatal myocardial infarction, or stroke. Safety outcomes included major bleeding, blood transfusion, and hospitalization for bleeding. RESULTS: At 30 days post-CABG, 544 (68.4%) patients received DAPT and 251 (31.6%) patients received aspirin alone. The median (25th, 75th percentile) duration of clopidogrel therapy was 0.98 (0.23 to 1.91) years. There was no significant difference in the 5-year primary composite outcome between DAPT- and aspirin-treated patients (12.6% vs. 16.0%; adjusted hazard ratio [HR]: 0.83; 95% confidence interval [CI]: 0.54 to 1.27; p = 0.39). The 5-year primary composite outcomes were similar for patients receiving DAPT versus aspirin monotherapy respectively, in subgroups with pre-CABG ACSs (15.2% vs. 16.5%; HR: 1.06; 95% CI: 0.53 to 2.10; p = 0.88) and those with stable angina (11.6% vs. 15.8%; HR: 0.82; 95% CI: 0.50 to 1.343; p = 0.42). The composite outcomes of both treatment groups were also similar by SYNTAX score, duration of DAPT therapy, completeness of revascularization, and in off-pump CABG. No treatment-related differences in major bleeding (5.6% vs. 5.7%; HR: 1.00; 95% CI: 0.50 to 1.99; p = 0.99), blood transfusions (4.8% vs. 4.5%; HR: 1.09; 95% CI: 0.51 to 2.34; p = 0.82), or hospitalization for bleeding (2.6% vs. 3.3%; HR: 0.85; 95% CI: 0.34 to 2.17; p = 0.74) were observed between aspirin- and DAPT-treated patients, respectively. CONCLUSIONS: The use of DAPT in patients with diabetes post-CABG in our cohort was high. Compared with aspirin monotherapy, no associated differences were observed in cardiovascular or bleeding outcomes, suggesting that routine use of DAPT may not be clinically warranted. (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease [FREEDOM]; NCT00086450). PMID- 28081822 TI - Diabetes Mellitus-Induced Microvascular Destabilization in the Myocardium. AB - BACKGROUND: Diabetes mellitus causes microcirculatory rarefaction and may impair the responsiveness of ischemic myocardium to proangiogenic factors. OBJECTIVES: This study sought to determine whether microvascular destabilization affects organ function and therapeutic neovascularization in diabetes mellitus. METHODS: The authors obtained myocardial samples from patients with end-stage heart failure at time of transplant, with or without diabetes mellitus. Diabetic (db) and wild-type (wt) pigs were used to analyze myocardial vascularization and function. Chronic ischemia was induced percutaneously (day 0) in the circumflex artery. At day 28, recombinant adeno-associated virus (rAAV) (5 * 1012 viral particles encoding vascular endothelial growth factor-A [VEGF-A] or thymosin beta 4 [Tbeta4]) was applied regionally. CD31+ capillaries per high power field (c/hpf) and NG2+ pericyte coverage were analyzed. Global myocardial function (ejection fraction [EF] and left ventricular end-diastolic pressure) was assessed at days 28 and 56. RESULTS: Diabetic human myocardial explants revealed capillary rarefaction and pericyte loss compared to nondiabetic explants. Hyperglycemia in db pigs, even without ischemia, induced capillary rarefaction in the myocardium (163 +/- 14 c/hpf in db vs. 234 +/- 8 c/hpf in wt hearts; p < 0.005), concomitant with a distinct loss of EF (44.9% vs. 53.4% in nondiabetic controls; p < 0.05). Capillary density further decreased in chronic ischemic hearts, as did EF (both p < 0.05). Treatment with rAAV.Tbeta4 enhanced capillary density and maturation in db hearts less efficiently than in wt hearts, similar to collateral growth. rAAV.VEGF-A, though stimulating angiogenesis, induced neither pericyte recruitment nor collateral growth. As a result, rAAV.Tbeta4 but not rAAV.VEGF-A improved EF in db hearts (34.5 +/- 1.4%), but less so than in wt hearts (44.8 +/- 1.5%). CONCLUSIONS: Diabetes mellitus destabilized microvascular vessels of the heart, affecting the amplitude of therapeutic neovascularization via rAAV.Tbeta4 in a translational large animal model of hibernating myocardium. PMID- 28081823 TI - The Transgenic Diabetic Pig Heart: A "Sweet Heart" for Translational Cardiovascular Research. PMID- 28081825 TI - A New Treatable Risk Factor for Stroke and Atherosclerotic Cardiovascular Disease? PMID- 28081824 TI - Oxidized Phospholipids on Apolipoprotein B-100 and Recurrent Ischemic Events Following Stroke or Transient Ischemic Attack. AB - BACKGROUND: Biomarkers to predict recurrent stroke and targets of therapy to prevent stroke are lacking. OBJECTIVES: This study evaluated whether patients with prior cerebrovascular events and elevated levels of oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB), but without prior coronary artery disease (CAD), are at risk for recurrent stroke and CAD events following high-dose statin therapy. METHODS: In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, OxPL-apoB levels were measured in 4,385 patients with stroke or transient ischemic attack at baseline and in 3,106 patients at 5 years following randomization to placebo or 80 mg atorvastatin. The primary endpoint was the time from randomization to a second nonfatal or fatal stroke. Secondary endpoints included first major coronary events and any cardiovascular event. RESULTS: Patients with recurrent stroke had higher baseline median OxPL-apoB levels than patients without (15.5 nmol/l vs. 11.6 nmol/l; p < 0.0001). After multivariable adjustment, elevated baseline OxPL-apoB predicted recurrent stroke (hazard ratio [HR]: 4.3; p < 0.0001), first major coronary events (HR: 4.0; p < 0.0001), and any cardiovascular event (HR: 4.4; p < 0.0001). These comparisons for any endpoint did not differ by treatment, shown as a nonsignificant interaction test. The net reclassification improvement, integrated discrimination improvement, and area under the receiver-operating characteristic curve (AUC) were all significantly improved by adding OxPL-apoB to the models, with DeltaAUC +0.0505 (p < 0.0001) for recurrent stroke, DeltaAUC +0.0409 (p < 0.0001) for first major coronary event, and DeltaAUC +0.0791 (p < 0.0001) for any cardiovascular event. CONCLUSIONS: Elevated OxPL-apoB levels predicted recurrent stroke and first major coronary events in patients with prior stroke or transient ischemic attack. The lack of statin-OxPL-apoB treatment interaction suggested that OxPLs might be statin-independent therapeutic targets to reduce risk of cardiovascular events. (Lipitor in the Prevention of Stroke, for Patients Who Have Had a Previous Stroke [SPARCL]; NCT00147602). PMID- 28081826 TI - Going Polymer Free and Dual Antiplatelet Free Earlier: The Coevolution of Stent and Pharmacotherapy. PMID- 28081828 TI - Cangrelor: The Paradox of Choice. PMID- 28081829 TI - Cardiac Pacemakers: Function, Troubleshooting, and Management: Part 1 of a 2-Part Series. AB - Advances in cardiac surgery toward the mid-20th century created a need for an artificial means of stimulating the heart muscle. Initially developed as large external devices, technological advances resulted in miniaturization of electronic circuitry and eventually the development of totally implantable devices. These advances continue to date, with the recent introduction of leadless pacemakers. In this first part of a 2-part review, we describe indications, implant-related complications, basic function/programming, common pacemaker-related issues, and remote monitoring, which are relevant to the practicing cardiologist. We provide an overview of magnetic resonance imaging and perioperative management among patients with cardiac pacemakers. PMID- 28081830 TI - Advances and Future Directions in Cardiac Pacemakers: Part 2 of a 2-Part Series. AB - In the second part of this 2-part series on pacemakers, we present recent advances in pacemakers and preview future developments. Cardiac resynchronization therapy (CRT) is a potent treatment for heart failure in the setting of ventricular dyssynchrony. Successful CRT using coronary venous pacing depends on appropriate patient selection, lead implantation, and device programming. Despite optimization of these factors, nonresponse to CRT may occur in one-third of patients, which has led to a search for alternative techniques such as multisite pacing, His bundle pacing, and endocardial left ventricular pacing. A paradigm shift in pacemaker technology has been the development of leadless pacemaker devices, and on the horizon is the development of batteryless devices. Remote monitoring has ushered in an era of greater safety and the ability to respond to device malfunction in a timely fashion, improving outcomes. PMID- 28081831 TI - The Relationship Between the Right Ventricle and its Load in Pulmonary Hypertension. AB - In pulmonary hypertension, the right ventricle adapts to the increasing vascular load by enhancing contractility ("coupling") to maintain flow. Ventriculoarterial coupling implies that stroke volume changes little while preserving ventricular efficiency. Ultimately, a phase develops where ventricular dilation occurs in an attempt to limit the reduction in stroke volume, with uncoupling and increased wall stress as a consequence. With pressure-volume analysis, we separately describe the changing properties of the pulmonary vascular system and the right ventricle, as well as their coupling, as important concepts for understanding the changes that occur in pulmonary hypertension. On the basis of the unique properties of the pulmonary circulation, we show how all relevant physiological parameters can be derived using an integrative approach. Because coupling is maintained by hypertrophy until the end stage of the disease, when progressive dilation begins, right ventricular volume is the essential parameter to measure in follow-up of patients with pulmonary hypertension. PMID- 28081832 TI - Medicare Formulary Changes After the 2013 American College of Cardiology/American Heart Association Cholesterol Guideline. PMID- 28081833 TI - HDL Cholesterol Efflux Capacity and Cardiovascular Events in Patients With Chronic Kidney Disease. PMID- 28081834 TI - Reply: Did Mutation Type Affect the Efficacy of Mexiletine Observed in Patients With LQTS Type 3? PMID- 28081835 TI - Did Mutation Type Affect the Efficacy of Mexiletine Observed in Patients With LQTS Type 3? PMID- 28081836 TI - Crushed Prasugrel Tablets in Patients With STEMI Undergoing Primary Percutaneous Coronary Intervention: The CRUSH Study. PMID- 28081837 TI - Reply: Crushed Prasugrel Tablets in Patients With STEMI Undergoing Primary Percutaneous Coronary Intervention: The CRUSH Study. PMID- 28081839 TI - A Cautionary Tone Before Expanded Adoption of the Proposed CHA2DS2-VASc R Score. PMID- 28081838 TI - Reply: A Cautionary Tone Before Expanded Adoption of the Proposed CHA2DS2-VASc R Score. PMID- 28081840 TI - Seventeenth Conference on the Adrenal Cortex (Adrenal 2016) Boston, MA, March 28 31, 2016. PMID- 28081841 TI - Itch: Its perception and involvement in allergy. PMID- 28081842 TI - Corrigendum to "Prevention of food allergy - Early dietary interventions" [Allergol Int 65 (2016) 370-377]. PMID- 28081843 TI - Dissociable effects of stimulus range on perception and action. AB - We have recently reported the discovery that the ability to detect a minimum increment to a stimulus depends on the spread of the other stimuli for which this just noticeable difference (JND) is being measured (Namdar, Ganel, & Algom, 2016). In particular, the JND around a standard stimulus was larger when the other standards tested within the same experimental session spread a larger range. In this study we show that this range of standards effect (RSE) is limited to perceptual estimations and does not extend to action. The JND remained invariant when the participants grasped the objects rather than perceptually estimated their size. This difference supports the hypothesis that visual perception, on the one hand, and visually controlled action, on the other hand, are governed by separate rules and mediated by different mechanisms. PMID- 28081844 TI - Benefits of comanagement with internal medicine on health care and economic outcomes in psychiatric inpatients. PMID- 28081845 TI - Current issues in implementing do-not-resuscitate orders for cardiac patients. AB - Cardiovascular diseases are still the most common cause of death, and heart failure is the most common reason for hospitalization of patients older than 65 years. However, Cardiology attributes low importance to end-of-life care. Cardiac patients' perception of their disease's prognosis and the results of cardiopulmonary resuscitation differ greatly from reality. The "do not resuscitate" order allows patients to pre-emptively express their rejection for cardiopulmonary resuscitation, thereby avoiding its potentially negative consequences. However, these orders are still underused and misinterpreted in cardiac patients. Most of these patients usually have no opportunity to have the necessary conversations with their attending physician on their resuscitation preferences. In this review, we performed an analysis of the causes that could explain this situation. PMID- 28081846 TI - Slow-Growing Keratotic Tumor on the Eyelid. PMID- 28081847 TI - RF- Insufficient Exposure to Sunlight and Global Mortality: Should We Advise Against or Recommend Sun Exposure? PMID- 28081848 TI - Ranolazine and Microvascular Angina by PET in the Emergency Department: Results From a Pilot Randomized Controlled Trial. AB - PURPOSE: Coronary microvascular dysfunction (CMD) is a common but underdiagnosed cause of chest pain. Literature is scant regarding effective treatments. We explored the effect of ranolazine on coronary flow reserve (CFR) among symptomatic patients with CMD. METHODS: This pilot double-blinded randomized controlled trial included emergency department patients with chest pain and CMD admitted to an observation unit between June 2014 and November 2015. Participants were assessed by cardiac Rb-82 positron emission tomography and computed tomography imaging at baseline and 30 days. CMD was defined as CFR <2 corrected for rate pressure product or <2.5 uncorrected, with no evidence of obstructive or nonobstructive coronary artery disease or calcification. Patients with infarction, hypertensive urgency, heart failure, or prescribed QTc-prolonging drugs were excluded. Participants were assigned to ranolazine or placebo in a 2:1 ratio. Primary outcome was change in CFR at 30 days. FINDINGS: We enrolled 31 patients (71% female, mean [SD] age 50 [6] years) with CMD (mean [SD] corrected CFR 1.6 [0.3]). Ranolazine improved CFR at 30 days by 17% (P = 0.005) compared with 0% with placebo (P = 0.67). However, there was no significant difference in the primary outcome as measured by mean change in CFR (0.27 ranolazine compared with 0.06 placebo; 95% CI, -0.08 to 0.62). IMPLICATIONS: The emergency department offers a unique venue to diagnose CMD with acute symptoms. In an exploratory randomized controlled trial of symptomatic patients with CMD and no coronary artery disease, promising results were seem with ranolazine and CFR improving at 30 days. Large robust clinical trials are needed to verify improvement of CMD in a sex-specific model. ClinicalTrials.gov identifier NCT02052011. PMID- 28081849 TI - Constitutive high expression of protein arginine methyltransferase 1 in asthmatic airway smooth muscle cells is caused by reduced microRNA-19a expression and leads to enhanced remodeling. AB - BACKGROUND: In asthma remodeling airway smooth muscle cells (ASMCs) contribute to airway wall thickness through increased proliferation, migration, and extracellular matrix deposition. Previously, we described that protein arginine methyltransferase 1 (PRMT1) participates in airway remodeling in pulmonary inflammation in E3 rats. OBJECTIVE: We sought to define the asthma-specific regulatory mechanism of PRMT1 in human ASMCs. METHODS: ASMCs from healthy subjects and asthmatic patients were activated with platelet-derived growth factor (PDGF)-BB. PRMT1 was localized by means of immunohistochemistry in human lung tissue sections and by means of immunofluorescence in isolated ASMCs. PRMT1 activity was suppressed by the pan-PRMT inhibitor AMI-1, signal transducer and activator of transcription 1 (STAT1) was suppressed by small interfering RNA, and extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein kinase (MAPK) was suppressed by PD98059. MicroRNAs (miRs) were assessed by using real time quantitative PCR and regulated by miR mimics or inhibitors. RESULTS: PRMT1 expression was significantly increased in lung tissue sections and in isolated ASMCs of patients with severe asthma. PDGF-BB significantly increased PRMT1 expression through ERK1/2 MAPK and STAT1 signaling in control ASMCs, whereas in ASMCs from asthmatic patients, these proteins were constitutively expressed. ASMCs from asthmatic patients had reduced miR-19a expression, causing upregulation of ERK1/2 MAPK, STAT1, and PRMT1. Inhibition of PRMT1 abrogated collagen type I and fibronectin deposition, cell proliferation, and migration of ASMCs from asthmatic patients. CONCLUSIONS: PRMT1 is a central regulator of tissue remodeling in ASMCs from asthmatic patients through the pathway: PDGF-BB miR-19a-ERK1/2 MAPK and STAT1. Low miR-19a expression in ASMCs from asthmatic patients is the key event that results in constitutive increased PRMT1 expression and remodeling. Therefore PRMT1 is an attractive target to limit airway wall remodeling in asthmatic patients. PMID- 28081827 TI - Cangrelor With and Without Glycoprotein IIb/IIIa Inhibitors in Patients Undergoing Percutaneous Coronary Intervention. AB - BACKGROUND: Cangrelor, an intravenous, reversible P2Y12 antagonist, is approved for use in patients undergoing percutaneous coronary intervention (PCI). OBJECTIVES: This study sought to evaluate the efficacy and safety of cangrelor compared with clopidogrel in subgroups that did and did not receive glycoprotein IIb/IIIa inhibitors (GPIs). METHODS: This pooled, patient-level analysis of the 3 CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) trials analyzed all randomized patients who underwent PCI and received the study drug (n = 24,902). Only bailout/rescue GPI use was permitted, except in CHAMPION PCI, in which routine or bailout/rescue GPI use was at the site investigator's discretion. The primary efficacy endpoint was the composite of all-cause mortality, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 h after randomization. RESULTS: Overall, 3,173 patients (12.7%) received a GPI, most commonly eptifibatide (69.4%). Despite variation in indications for GPIs, baseline characteristics were well balanced between the cangrelor and clopidogrel arms in subsets receiving and not receiving GPIs. Rates of the primary composite endpoint were lower with cangrelor compared with clopidogrel in patients who did (4.9% vs. 6.5%; odds ratio [OR]: 0.74; 95% confidence interval [CI]: 0.55 to 1.01) or did not receive a GPI (3.6% vs. 4.4%; OR: 0.82; 95% CI: 0.72 to 0.94; Pint = 0.55). Cangrelor did not increase the primary safety endpoint, GUSTO-defined severe/life-threatening bleeding, in patients who did (0.4% vs. 0.5%; OR: 0.71; 95% CI: 0.25 to 1.99) or did not receive GPIs (0.2% vs. 0.1%; OR: 1.56; 95% CI: 0.80 to 3.04; Pint = 0.21). GPI use was associated with increased risk of bleeding in both treatment arms. CONCLUSIONS: Cangrelor's efficacy in reducing ischemic complications in patients undergoing PCI was maintained irrespective of GPI administration. GPI use was associated with substantially higher bleeding rates, regardless of the randomization to cangrelor or clopidogrel. (A Clinical Trial to Demonstrate the Efficacy of Cangrelor [PCI]: NCT00305162; Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition [PLATFORM]: NCT00385138; A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX] [CHAMPION]: NCT01156571). PMID- 28081850 TI - Acid-suppressive medications during pregnancy and risk of asthma and allergy in children: A systematic review and meta-analysis. PMID- 28081851 TI - A new use for maximum deflection index: Detection of intraventricular dyssynchrony. AB - AIM: CRT has been shown to be very beneficial for patients with reduced LVEF, symptomatic HF and increased QRS width. But many patients do not benefit from CRT. Maximum deflection index (MDI) is a quantitive measure of the rapidity of depolarization of the myocardium. In previous studies, high MDI was found to indicate epicardial origin of ventricular tachycardia. We aimed to detect the relationship between echocardiographic intraventricular dyssynchrony and MDI. METHODS: We included 144 patients with HF, QRS>=120ms, LBBB, NYHA II-IV, LVEF<35% and scheduled for CRT (90 male, 54 female; mean age 65.3+/-9.9years). Septal lateral >60ms delay for the beginning of systolic velocity in TDI and septum posterior >130ms delay in M-mode were accepted as intraventricular dyssynchrony. The MDI was calculated by dividing the time from onset of the QRS complex to the earliest point of maximum deflection in V5-V6 by the QRS duration. RESULTS: Septal-lateral delay was associated with MDI and QRS width in bivariate analysis. In logistic regression analysis, MDI (beta=0,264, p=0.001) and QRS width (beta=0,177, p=0.028) were found to be independent parameters for predicting significant septal-lateral delay. MDI was also associated with significant septum posterior delay in bivariate correlations and ROC curve (p<0.05 for all). In bivariate analysis MDI was associated with intraventricular dyssynchrony in both non-strict LBBB (r=0.261, p=0.010) and strict LBBB (r=0.305, p=0.035) groups. CONCLUSION: MDI is closely associated with all echocardiographic intraventricular dyssynchrony parameters. We suggest that MDI may be used as a marker to detect patients with increased intraventricular dyssynchrony. It may be useful to integrate MDI to CRT patient selection procedure in order to minimize nonresponders. PMID- 28081852 TI - Brugada sign in a patient with hyperkalemia due to rhabdomyolysis in hypothermia. AB - The Brugada sign may appear as an indication of severe hyperkalemia. This phenomena has recently been called as the "Brugada phenocopy". Hyperthermia and hypothermia may lead to rhabdomyolysis. Rhabdomyolysis is a syndrome characterized by muscle necrosis and the release of intracellular muscle constituents into the circulation. We present a case where rhabdomyolysis-related delayed hyperkalemia showed Brugada sign on the ECG mimicking ventricular tachycardia. PMID- 28081853 TI - Development of a multi-institutional clinical research consortium for pediatric surgery. AB - BACKGROUND: Multicenter clinical research studies in pediatric surgery have been largely limited to relatively small case-series and retrospective reviews because of the rarity of many of the diseases we treat and difficulty coordinating and executing multi-institutional studies. Creation of a collaborative research network can provide the needed patient population and infrastructure to perform high quality multi-institutional studies. METHODS: In 2013, eleven academic pediatric surgery centers within the United States formed a research consortium to develop and conduct multicenter clinical research projects to advance the practice of pediatric surgery. RESULTS: We present our process for creating, developing, and maintaining this consortium including initial regional geographic limitation, charter development with by-laws and procedures for adopting studies, and research infrastructure including a central website for study monitoring and central reliance institutional review board process. CONCLUSION: Our model could be reproduced or adapted by other institutions to develop or strengthen other research collaboratives. LEVEL OF EVIDENCE: Type of study: retrospective, IV. PMID- 28081855 TI - Same-sex twins are taller and heavier than opposite-sex twins (but only if breastfed): Possible evidence for sex bias in human breast milk. AB - Recent studies show that human and other mammalian breast milk may be tailored for the sex of the offspring. Such sex bias suggests that opposite-sex twins, who receive breast milk that cannot simultaneously be tailored for both sexes, may be at a disadvantage for growth compared with same-sex twins. An analysis of data from the National Longitudinal Study of Adolescent Health (Add Health) shows that, controlling for sex, age, birth weight, and zygosity, breastfed same-sex twins are, on average, about 1 inch taller and 12 pounds heavier than their opposite-sex counterparts through adolescence and early adulthood. In contrast, never-breastfed same-sex twins tend to be shorter and lighter than their opposite sex counterparts. These results may be potential evidence for sex bias in human breast milk and its long-term effects. PMID- 28081854 TI - Deficiency in milk fat globule-epidermal growth factor-factor 8 exacerbates organ injury and mortality in neonatal sepsis. AB - INTRODUCTION: Neonatal sepsis is a systemic inflammation occurring in neonates because of a proven infection within the first 28days of birth. It is the third leading cause of morbidity and mortality in the newborns. The mechanism(s) underlying the systemic inflammation in neonatal sepsis has not been completely understood. We hypothesize that the deficiency of milk fat globule-epidermal growth factor-factor 8 (MFG-E8), a protein commonly found in human milk, could be responsible for the increased inflammatory response leading to morbidity and mortality in neonatal sepsis. METHODS: Male and female newborn mice aged 5-7days were injected intraperitoneally with 0.9mg/g body weight cecal slurry (CS). At 10h after CS injection, they were euthanized, and blood, lungs and gut tissues were obtained for further analyses. Control newborn mice underwent similar procedures with the exception of the CS injection. In duplicate newborn mice after CS injection, they were returned to their respective cages with their mothers and were closely monitored for 7days and survival rate recorded. RESULTS: At 10h after CS injection, serum LDH in the MFG-E8 knockout (KO) newborn mice was significantly increased by 58% and serum IL-6, IL-1beta and TNF-alpha in the MFG E8KO newborn mice were also significantly increased by 56%, 65%, and 105%, respectively, from wild type (WT) newborn mice. There were no significant difference between WT control and MFG-E8 control newborn mice. The lung architecture was severely damaged and a significant 162% increase in injury score was observed in the CS MFG-E8KO newborn mice. The MPO, TUNEL staining, and cytokine levels in the lungs and the intestine in CS MFG-E8KO newborn mice were significantly increased from CS WT newborn mice. Similarly, intestinal integrity was also compromised in the CS MFG-E8KO newborn mice. In a survival study, while the mortality rate within 7days was only 29% in the CS WT newborn mice, 80% of the CS MFG-E8KO newborn mice died during the same time period with the majority of mortality occurring within 48h. CONCLUSION: The deficiency in MFG-E8 caused increases in inflammation, tissue injury, neutrophil infiltration and apoptosis, which led to morbidity and mortality in murine neonatal sepsis. These studies suggest that MFG-E8 has a protective role in fighting against neonatal sepsis. PMID- 28081857 TI - Vaccination against infectious bronchitis virus: A continuous challenge. AB - Infectious bronchitis virus (IBV) is a significant respiratory pathogen of commercial poultry that causes millions of dollars in lost revenue worldwide each year. Even though the poultry industry extensively vaccinates against IBV, emergence of new serotypes and variants continually occur, making control of the disease difficult. Current mass application strategies for IBV vaccines are inefficient and frequently result in vaccination failures. Novel vaccine technology development has been slow, and is hindered by the constraints of large scale poultry production. Further complicating the situation is the lack of knowledge of IBV protein and host cell interactions, making targeted vaccine intervention strategies near impossible. Taken together, it is easy to see why this disease remains significant in poultry production. This review outlines the current situation as it relates to IBV control, including vaccination, vaccines, and development of immunity, and recent developments in vaccine technology that may provide better protection in the future. PMID- 28081856 TI - An angiotensin II type 1 receptor binding molecule has a critical role in hypertension in a chronic kidney disease model. AB - Angiotensin II type 1 receptor-associated protein (ATRAP) promotes AT1R internalization along with suppression of hyperactivation of tissue AT1R signaling. Here, we provide evidence that renal ATRAP plays a critical role in suppressing hypertension in a mouse remnant kidney model of chronic kidney disease. The effect of 5/6 nephrectomy on endogenous ATRAP expression was examined in the kidney of C57BL/6 and 129/Sv mice. While 129/Sv mice with a remnant kidney showed decreased renal ATRAP expression and developed hypertension, C57BL/6 mice exhibited increased renal ATRAP expression and resistance to progressive hypertension. Consequently, we hypothesized that downregulation of renal ATRAP expression is involved in pathogenesis of hypertension in the remnant kidney model of chronic kidney disease. Interestingly, 5/6 nephrectomy in ATRAP-knockout mice on the hypertension resistant C57BL/6 background caused hypertension with increased plasma volume. Moreover, in knockout compared to wild-type C57BL/6 mice after 5/6 nephrectomy, renal expression of the epithelial sodium channel alpha-subunit and tumor necrosis factor-alpha was significantly enhanced, concomitant with increased plasma membrane angiotensin II type 1 receptor in the kidneys. Thus, renal ATRAP downregulation is involved in the onset and progression of blood pressure elevation caused by renal mass reduction, and implicates ATRAP as a therapeutic target for hypertension in chronic kidney disease. PMID- 28081858 TI - Oligo-dT selected spermatozoal transcript profiles differ among higher and lower fertility dairy sires. AB - Spermatozoal messenger RNA (mRNA) has the potential as a molecular marker for sire fertility because this population can reflect gene expression that occurred during spermatogenesis and may have a functional role in early embryonic development. The goal of this study was to compare the oligo-dT selected spermatozoal transcript profiles of higher fertility (Conception Rate (CR) 1.8 3.5) and lower fertility (CR -2.9 to -0.4) sires using Ribonucleic Acid Sequencing (RNA-Seq). A total of 3227 transcripts and 5366 transcripts were identified in the higher and lower fertility populations, respectively. While common transcripts between the two populations were identified (2422 transcripts), several transcripts were also unique to the fertility populations including 805 transcripts that were unique to the higher fertility population and 2944 transcripts that were unique to the lower fertility population. From gene ontological analysis, the transcripts unique to each fertility population differed in Biological Processes (BP), including enrichment of regulatory transcripts for growth and protein kinase activity in the higher fertility bulls. Biological variation in transcript presence among individual sires was also found. Of the candidate fertility spermatozoal transcripts chosen from the RNA Seq population analysis reported here and previous publications, COX7C was negatively correlated with sire fertility. Using high-throughput sequencing, candidate spermatozoal transcripts were identified for further study as potential markers for sire fertility. PMID- 28081859 TI - Hydrostatic pressure effect on PNIPAM cononsolvency in water-methanol solutions. AB - When methanol is added to water at room temperature and 1atm, poly (N isopropylacrylamide), PNIPAM, undergoes a coil-to-globule collapse transition. This intriguing phenomenon is called cononsolvency. Spectroscopic measurements have shown that application of high hydrostatic pressure destroys PNIPAM cononsolvency in water-methanol solutions. We have developed a theoretical approach that identifies the decrease in solvent-excluded volume effect as the driving force of PNIPAM collapse on increasing the temperature. The same approach indicates that cononsolvency, at room temperature and P=1atm, is caused by the inability of PNIPAM to make all the attractive energetic interactions that it could be engaged in, due to competition between water and methanol molecules. The present analysis suggests that high hydrostatic pressure destroys cononsolvency because the coil state becomes more compact, and the quantity measuring PNIPAM solvent attractions increases in magnitude due to the solution density increase, and the ability of small water molecules to substitute methanol molecules on PNIPAM surface. PMID- 28081860 TI - Long-term Outcomes After Bladder-preserving Tri-modality Therapy for Patients with Muscle-invasive Bladder Cancer: An Updated Analysis of the Massachusetts General Hospital Experience. AB - BACKGROUND: Tri-modality therapy (TMT) is a recognized treatment strategy for selected patients with muscle-invasive bladder cancer (MIBC). OBJECTIVE: Report long-term outcomes of patients with MIBC treated by TMT. DESIGN, SETTING, AND PARTICIPANTS: Four hundred and seventy-five patients with cT2-T4a MIBC were enrolled on protocols or treated as per protocol at the Massachusetts General Hospital between 1986 and 2013. INTERVENTION: Patients underwent transurethral resection of bladder tumor followed by concurrent radiation and chemotherapy. Patients with less than a complete response (CR) to chemoradiation or with an invasive recurrence were recommended to undergo salvage radical cystectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Disease-specific survival (DSS) and overall survival (OS) were calculated using the Kaplan-Meier method. RESULTS AND LIMITATIONS: Median follow-up for surviving patients was 7.21 yr. Five- and 10-yr DSS rates were 66% and 59%, respectively. Five- and 10-yr OS rates were 57% and 39%, respectively. The risk of salvage cystectomy at 5 yr was 29%. In multivariate analyses, T2 disease (OS hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.44-0.75, DSS HR: 0.51, 95% CI: 0.36-0.73), CR to chemoradiation (OS HR: 0.61, 95% CI: 0.46-0.81, DSS HR: 0.49, 95% CI: 0.34-0.71), and presence of tumor-associated carcinoma in situ (OS HR: 1.56, 95% CI: 1.17-2.08, DSS HR: 1.50, 95% CI: 1.03-2.17) were significant predictors for OS and DSS. When evaluating our cohort over treatment eras, rates of CR improved from 66% to 88% and 5-yr DSS improved from 60% to 84% during the eras of 1986-1995 to 2005-2013, while the 5-yr risk of salvage radical cystectomy rate decreased from 42% to 16%. CONCLUSIONS: These data demonstrate high rates of CR and bladder preservation in patients receiving TMT, and confirm DSS rates similar to modern cystectomy series. Contemporary results are particularly encouraging, and therefore TMT should be discussed and offered as a treatment option for selected patients. PATIENT SUMMARY: Tri-modality therapy is an alternative to radical cystectomy for patients with muscle-invasive bladder cancer, and is associated with comparable long-term survival and high rates of bladder preservation. PMID- 28081861 TI - An introduction to using Bayesian linear regression with clinical data. AB - Statistical training psychology focuses on frequentist methods. Bayesian methods are an alternative to standard frequentist methods. This article provides researchers with an introduction to fundamental ideas in Bayesian modeling. We use data from an electroencephalogram (EEG) and anxiety study to illustrate Bayesian models. Specifically, the models examine the relationship between error related negativity (ERN), a particular event-related potential, and trait anxiety. Methodological topics covered include: how to set up a regression model in a Bayesian framework, specifying priors, examining convergence of the model, visualizing and interpreting posterior distributions, interval estimates, expected and predicted values, and model comparison tools. We also discuss situations where Bayesian methods can outperform frequentist methods as well has how to specify more complicated regression models. Finally, we conclude with recommendations about reporting guidelines for those using Bayesian methods in their own research. We provide data and R code for replicating our analyses. PMID- 28081862 TI - Getting the Most Out of Liver Biopsy. AB - Histopathologic evaluation of liver biopsy specimens yields information that is not otherwise obtainable and is frequently essential for diagnosing hepatic disease. Percutaneous needle biopsy, laparoscopic biopsy, and surgical biopsy each have their own set of advantages and disadvantages. Care should be taken to ensure an adequate amount of tissue is collected for meaningful histologic evaluation. Because sampling error is a limitation of hepatic biopsy, multiple liver lobes should be biopsied. This article discusses the indications for liver biopsy, associated risks, advantages and disadvantages of different biopsy techniques, and strategies to get the most useful information possible out of this process. PMID- 28081863 TI - Canine Breed-Specific Hepatopathies. AB - Canine hepatopathies, both congenital and acquired, arise from an interaction between genes and environment. Many show increased breed prevalences. This article reviews the current understanding on breed predispositions for congenital portosystemic shunts; microvascular dysplasia and portal vein hypoplasia; ductal plate abnormalities (congenital hepatic fibrosis and Caroli disease); chronic hepatitis (both copper associated and idiopathic); vacuolar hepatopathies; and gallbladder mucocele. Although all these diseases can occur in many breeds and crossbreeds, understanding breed predispositions helps recognition and will guide future research to improve understanding of causes and treatments. PMID- 28081864 TI - Semi-global output consensus of discrete-time multi-agent systems with input saturation and external disturbances. AB - This paper investigates the problem of leader-following output consensus of a linear discrete-time multi-agent system with input saturation and external disturbances. Low-gain state feedback technique and output regulation theory are used to deal with the output consensus of multi-agent systems with input saturation and external disturbances. Both the cases with identical and non identical disturbances are discussed in the multi-agent systems. For the case of identical external disturbance, the output consensus can be attained when the directed graph has no loop and there exists at least one directed path from the leader to every follower agent. For the case of non-identical external disturbances, the output consensus can be achieved if the directed graph is strongly connected and detailed balanced, and at least one follower can have access to the information of the leader. Numerical simulation results are presented to demonstrate the validation of the proposed design. PMID- 28081865 TI - The outcome of super-cutaneous locked plate fixation with percutaneous reduction of displaced intra-articular calcaneal fractures. AB - INTRODUCTION: Supercutaneous (external) fixation with locking plate is utilized for fixation of long bone fractures. One retrospective study for open reduction and supercutaneous fixation of the calcaneus is reported. We prospectively evaluated the use of this method of fixation combined with percutaneous reduction. MATERIALS AND METHODS: Between January 2014 and June 2015, 32 displaced calcaneus fractures in 30 patients were stabilized with percutaneous reduction and super-cutaneous fixation. They were 24 males and six females. The mean age was 37.9+/-5.7 years (21-55). All cases were closed. The time to surgery, complications, radiographic alignment, and time to radiographic union were recorded. Clinical results at the final follow-up were assessed by evaluating Bohler's angles for the radiographic alignment, and the system of the American Orthopedic Foot and Ankle Society (AOFAS) for the functional outcome. RESULTS: According to the Sanders' classification, two cases were type II, 17 cases were type III and 13 cases were type IV. The preoperative average Bohler's angle was 10.57 degrees +/-4.8. The postoperative X-ray films demonstrated that the average Bohler's angle improved to 29.07 degrees +/-5.9 (p<0.001). At the time of radiologic healing (about 3 months), the plates and screws were removed under general anesthesia. The average follow-up was 13.2 months (11-18). Four cases (type IV) showed mal-union and heel pain. According to (AOFAS) rating, the fine score was 87.1+/-17.1 points. CONCLUSION: Super-cutaneous fixation with percutaneous reduction of calcaneal fracture is an effective method in type II and III and can be effective with type IV but with less favorable results. PMID- 28081866 TI - A single nucleotide variant in microRNA-1269a promotes the occurrence and process of hepatocellular carcinoma by targeting to oncogenes SPATS2L and LRP6. AB - Hepatocellular carcinoma (HCC) is one of the malignant and lethal cancers. Single nucleotide polymorphisms (SNPs) in microRNAs(miRNAs) can affect the expression and target identification of miRNAs and lead to the formation of malignant tumors. However, little is known about whether microRNA-1269a (miR-1269a) SNPs affect the susceptibility and progression of HCC or their specific mechanism. The association between microRNA-1269a rs73239138 and the susceptibility to HCC was verified by MassARRAY assay in a large case-control sample. The effect of miR 1269a and the variant on the proliferation and apoptosis of HCC cells was examined by flow cytometry (FCM), CCK8 assay and Western blot. The target of miR 1269a was identified by bioinformatics analysis and qRT-PCR and its role on cell proliferative capacity was examined by CCK8 assay. The expression level of miR 1269a was analyzed by qRT-PCR in HCC cells transfected with wild or variant type pre-miR-1269a plasmid.MiR-1269a produced a tumor suppressor effect by inhibiting cell proliferation and inducing apoptosis of human HCC cells, possibly via inhibiting the expression of its target genes SPATS2L and LRP6, which were tumor promoters. While, rs73239138 (G>A) in miR-1269a reduced the anticancer effect of miR-1269a possibly by attenuating its total amount in HCC cells or its target recognition, reduce its inhibition on target genes and promoted the susceptibility to HCC. Our findings for the first time proved that miR-1269a SNP plays a role in the occurrence and process of HCC and the relevant mechanism, in accompany with the discovery of the novel target genes of miR-1269a. PMID- 28081868 TI - The Rise and Fall of Tuberculosis and Atherosclerosis: First There Is a Mountain.... PMID- 28081867 TI - The central nervous system patterning gene variants associated with clinical symptom severity of autism spectrum disorders. AB - BACKGROUND/PURPOSE: Central nervous system (CNS) patterning genes are recognized as candidate genes for autism spectrum disorders (ASDs) based on neuroimaging and neuropathological evidence. Several genes that regulate CNS development are shown to be associated with ASD. Our previous family-based association study also revealed that a specific haplotype of WNT2 (wingless-type MMTV integration site family member 2) gene was overtransmitted to probands with ASD. Whether the CNS patterning genes moderate the clinical phenotype of ASD is unclear. This study investigated the genetic associations of WNT2, engrailed 2 (EN2), and forkhead box P2 (FOXP2) with the clinical symptom severity. METHODS: The sample included 391 patients (males, 88.3%; mean age+/-standard deviation, 9.5+/-4.4 years) diagnosed with ASDs. Tag single nucleotide polymorphisms (SNPs) of EN2, WNT2, and FOXP2 were genotyped. The single-locus and multilocus markers were tested for association. RESULTS: We found that multilocus markers of WNT2 were associated with stereotyped behaviors whereas the markers of FOXP2 tended to be associated with social deficits. Moreover, an SNP of WNT2 showed a trend to be associated with less inattentive symptoms. CONCLUSION: Our findings that WNT2 and FOXP2 may moderate the clinical phenotypes of ASD provide evidence to support the possible universal effect of WNT2 and FOXP2 on neurodevelopmental symptom dimensions. Such findings warrant further validation in other independent samples. TRIAL REGISTRATION: Clinical trial registration identifier: NCT00494754. PMID- 28081869 TI - Cardiovascular disease risk in patients with schizophrenia. PMID- 28081870 TI - Luteal start vaginal micronized progesterone improves pregnancy success in women with recurrent pregnancy loss. AB - OBJECTIVE: To assess the effectiveness of luteal start vaginal micronized P in a recurrent pregnancy loss (RPL) cohort. DESIGN: Observational cohort study using prospectively collected data. SETTING: Not applicable. PATIENT(S): Women seen between 2004 and 2012 with a history of two or more unexplained pregnancy losses <10 weeks in size; endometrial biopsy (EB) performed 9-11 days after LH surge; and one or more subsequent pregnancy(ies). Women were excluded if concomitant findings, such as endometritis, maturation delay, or glandular-stromal dyssynchrony, were identified on EB. INTERVENTION(S): Vaginal micronized P was prescribed at a dose of 100-200 mg every 12 hours starting 3 days after LH surge (luteal start) if glandular epithelial nuclear cyclin E (nCyclinE) expression was elevated (>20%) in endometrial glands or empirically despite normal nCyclinE (<=20%). Women with normal nCyclinE (<=20%) who did not receive P were used as controls. MAIN OUTCOME MEASURE(S): Pregnancy success was an ongoing pregnancy >10 weeks in size. RESULT(S): One hundred sixteen women met the inclusion criteria, of whom 51% (n = 59) had elevated nCyclinE and 49% (n = 57) had normal nCyclinE. Pregnancy success in the 59 women with elevated nCyclinE significantly improved after intervention: 6% (16/255) in prior pregnancies versus 69% (57/83) in subsequent pregnancies. Pregnancy success in subsequent pregnancies was higher in women prescribed vaginal micronized P compared with controls: 68% (86/126) versus 51% (19/37); odds ratio = 2.1 (95% confidence interval, 1.0-4.4). CONCLUSION(S): In this study, we found that the use of luteal start vaginal micronized P was associated with improved pregnancy success in a strictly defined cohort of women with RPL. PMID- 28081871 TI - Editorial - Will ALLPS pass the test of time? PMID- 28081872 TI - Response to Letter to the Editor. PMID- 28081873 TI - Intraoperative extrinsic left atrial compression due to paraesophageal hiatal hernia. PMID- 28081874 TI - Pneumomediastinum and pneumoperitoneum secondary to cystic intestinal pneumatosis after percutaneous endoscopic gastrostomy placement. PMID- 28081875 TI - Surgery on Twitter. PMID- 28081876 TI - Fluoroquinolone therapy could influence the clinical signs of pulmonary coccidioidomycosis. PMID- 28081877 TI - [Characterisation of Cryptococcus isolates in Uruguay]. PMID- 28081879 TI - Safety and Surgical Outcomes of Same-day Anterior Urethroplasty. AB - OBJECTIVE: To evaluate the safety and feasibility of same-day anterior urethroplasty at our institution and define predictors of postoperative admission and surgical failure. METHODS: We retrospectively reviewed the charts of 118 consecutive anterior urethroplasties performed at a tertiary care center. Data were analyzed to detect predictors of postoperative admission and urethroplasty failure. The 30-day complications and long-term outcomes were compared between same-day and admitted patients. RESULTS: Ninety-two patients (78%) were discharged on the day of surgery. A penile stricture location compared with a bulbar stricture location (odds ratio: 13.4, P = .009) and having undergone more than 3 prior endoscopic stricture interventions (odds ratio: 10.2, P = .001) were significantly associated with postoperative admission. Patients with a ventral onlay approach were more likely to be discharged home (P = .03), whereas patients with combined repairs were more likely to be admitted (P = .04). Same-day urethroplasty did not increase 30-day postoperative complications, patient emergency room visits, unplanned clinic visits, or phone calls. Success rates did not differ between same-day (89%) and admitted (79%) cohorts, and no individual stricture characteristic was predictive of urethroplasty failure. CONCLUSION: Same-day anterior urethroplasty is safe and feasible and could help increase utilization of urethroplasty for urethral stricture disease. PMID- 28081878 TI - [Isolated renal mucormycosis in a critically ill patient]. PMID- 28081880 TI - Prognostic value of endocervical sampling following loop excision of high grade intraepithelial neoplasia. AB - OBJECTIVE: To assess the role of additional biopsies performed with loop electrosurgical excisional procedure (LEEP) in predicting the likelihood of persistent high grade intraepithelial neoplasia. METHODS: Clinicopathologic data were abstracted from women who underwent excision of high grade intraepithelial lesions between 2001 and 2014. Persistent disease was defined as uninterrupted high grade intraepithelial neoplasia, whereas recurrent disease was defined as disease diagnosed >=1year after treatment with intervening normal evaluation. Chi square and Fisher's exact tests were used to examine associations between demographic and histologic parameters and clinical outcomes. RESULTS: A total of 606 women underwent LEEP for high grade intraepithelial neoplasia (HSIL), of whom, 178 (29%) were additionally evaluated by endocervical curettage, 80 (13%), top hat and 99 (16%), both procedures. With mean follow-up of 1.9+/-1.5years, persistent disease was identified in 87 women (14%) while recurrent disease was diagnosed in 20 (3%). After adjusting for age, HIV status and histologic grade of disease, the presence of disease at the endocervical margin (aOR=2.2, 95% CL 1.8 5.5, p<0.0001), with endocervical curettage (aOR=2.39, 95% CL 1.2-9.9, p=0.025) or on top hat (aOR=4.0, 95% CL 1.1-16.2, p=0.04) correlated with the likelihood of persistent but not recurrent disease. Only endocervical margin status remained predictive (p=0.03) of outcome after controlling for pre-procedure likelihood of endocervical disease. Sensitivity of endocervical margin status for persistent disease was 56.9% with specificity of 72.2%. Positive predictive value (PPV) was 24.9% and negative predictive value (NPV) 90.9%. CONCLUSIONS: Despite frequent use of additional procedures to sample the endocervix, these strategies do not improve the ability of endocervical margin status to predict persistent or recurrent dysplasia. PMID- 28081881 TI - The opinions and practices of providers toward the sexual issues of cervical cancer patients undergoing treatment. AB - OBJECTIVES: Cervical cancer and its treatments impair women's sexual function. These complications may or may not be regarded when clinicians develop treatment plans. We aim to investigate the considerations of providers toward the sex life of cervical cancer patients. METHODS: All members of the Society of Gynecologic Oncology received a questionnaire assessing their opinions and practices toward specific questions regarding the sexual functioning of their patients. RESULTS: Of the 124 providers who completed the survey, the majority were Board Certified Gynecologic Oncologists (56%) with an average of 15years in training. Approximately 23% received training about sexual dysfunction. Providers without formal training were more likely to agree that: "Information regarding sexual function in patients undergoing treatment for cervical cancer is lacking" (p=0.02). Providers with over 10years of experience were more likely to agree that "sex is private and discussing it with patients will interfere with our provider-patient relationship" (p=0.03). International clinicians were more likely to agree that: "I feel uncomfortable initiating discussions regarding sexual function with patients" (p=0.03), "Sex is private and discussing it with patients will interfere in our provider-patient relationship" (p=0.02), and "If a patient has a sexual problem, they will raise the subject" (p=0.009). CONCLUSIONS: Years of clinical experience, provider age, a history of training on regarding sexual dysfunction and an international setting of practice affect providers' opinions and practices toward sexual issues of cervical cancer patients. More formal, relevant training regarding sexual dysfunction is warranted for clinicians who treat cervical cancer patients. PMID- 28081882 TI - Colpoplasty by laparoscopic modified Davydov's procedure. AB - OBJECTIVE: To show laparoscopic surgery to treat vaginal shortening, with functional sequelae (sexual disorders), after radiotherapy and brachytherapy for vaginal carcinoma. METHODS: Davydov's procedure was initially described to treat vaginal aplasia (Davydov & Zhvitiashvili, 1974). This surgery was then improved for the upper part of the vagina, performed by laparoscopy (Leblanc, 2010; Adamyan, 1995) [2-3]. We used surgical technique, based on Davydov's procedure, by laparoscopy, to cover the upper neovagina, with two large peritoneal flaps, one anterior with the pre-vesical peritoneum and a second one posterior with the peritoneum of Douglas pouch. This surgery can be performed with no use of intestinal gesture, skin grafting, flap or any foreign material. Leblanc et al. (2016) [4] reported promising results about eight patients with this technique. RESULTS: A 36-years old patient had been treated by chemotherapy, radiotherapy and brachytherapy for a vagina cancer with a para-rectal extension. After four years of remission, she was worried about an important vaginal atrophy related to a significant vaginal shortening (about 5cm), causing major dyspareunia. This situation had caused sexual disorders with a real impact on the quality of life. All non-invasive techniques (dilatators, lubricants...) had led to failures. A colpoplasty by laparoscopic modified Davydov's procedure was performed. The post operative follow-up was simple without complication. The vaginal mandrel was removed after 12days. The clinical examination after 4months demonstrates that size and elasticity of the neovaginal cavity was rewarding. CONCLUSION: This surgical technique requires training and experienced team, but seems to be promising way to restore a normal vaginal length. PMID- 28081883 TI - Comprehensive laparoscopic lymphadenectomy from the deep circumflex iliac vein to the renal veins: Impact on quality of life. AB - OBJECTIVE: Compare quality of life metrics for consecutive patients having total laparoscopic hysterectomy, bilateral salpingo-oophorectomy (TLHBSO) with and without comprehensive pelvic/aortic lymphadenectomy (CPALND) from proximal to the distal circumflex iliac nodes and vessels to the renal vessels. METHODS: Analysis of mailed survey responses with 25 validated questions regarding musculoskeletal/lower extremity, gastro-intestinal, abdominal, urological, and energetic/activities of daily living. Data analyzed with Chi-Square tests of Association, Mann-Whitney U tests and follow up regression analysis. RESULTS: Of 533 surveys mailed, 197 (37%) responded; 57 (28.9%) received CPALND. Age and parity were not different between groups, but the TLHBSO group had a higher BMI (31.4 v. 25.8, p<0.001), and were less likely to receive chemotherapy (CT), radiotherapy (RT), or both (CT+RT). In the CPALND cohort, a mean of 47 nodes were removed, of which 26% were positive: 21% pelvic, 11% inframesenteric, 11% infrarenal. Both groups had similar total quality of life total scores of 86/92. Those having CPALND did not report more swelling but they did report more tingling/numbness (2.8 v. 3.5, p<0.001). A series of hierarchical regressions confirmed that CPALND, per se, did not significantly reduce lower extremity scores apart from CT (p=0.402) and CT+RT (p=0.108). However, CPALND did predict for lower extremity swelling after receipt of CT, RT, or CT+RT. Node count, in total, or from each basin, did not correlate with any QOL decrement. CONCLUSIONS: CPALND did not cause lymphedema or a reduction in overall quality of life. Only after controlling for BMI, and receipt of radiation and/or chemotherapy were QOL scores mildly reduced. Routine omission of the distal circumflex nodes from the dissection may account for the low risk of lymphedema from the dissection. Larger prospective studies are needed to determine the optimal staging protocols that address all the likely sites of metastasis and recurrence, and optimize survival, while maintaining our patients' quality of life. PMID- 28081884 TI - Mortality in Children with Human Immunodeficiency Virus Initiating Treatment: A Six-Cohort Study in Latin America. AB - OBJECTIVES: To assess the risks of and factors associated with mortality, loss to follow-up, and changing regimens after children with HIV infected perinatally initiate combination antiretroviral therapy (cART) in Latin America and the Caribbean. STUDY DESIGN: This 1997-2013 retrospective cohort study included 1174 antiretroviral therapy-naive, perinatally infected children who started cART age when they were younger than 18 years of age (median 4.7 years; IQR 1.7-8.8) at 1 of 6 cohorts from Argentina, Brazil, Haiti, and Honduras, within the Caribbean, Central and South America Network for HIV Epidemiology. Median follow-up was 5.6 years (IQR 2.3-9.3). Study outcomes were all-cause mortality, loss to follow-up, and major changes in cART. We used Cox proportional hazards models stratified by site to examine the association between predictors and times to death or changing regimens. RESULTS: Only 52% started cART at younger than 5 years of age; 19% began a protease inhibitor. At cART initiation, median CD4 count was 472 cells/mm3 (IQR 201-902); median CD4% was 16% (IQR 10-23). Probability of death was high in the first year of cART: 0.06 (95% CI 0.04-0.07). Five years after cART initiation, the cumulative mortality incidence was 0.12 (95% CI 0.10-0.14). Cumulative incidences for loss to follow-up and regimen change after 5 years were 0.16 (95% 0.14-0.18) and 0.30 (95% 0.26-0.34), respectively. Younger children had the greatest risk of mortality, whereas older children had the greatest risk of being lost to follow-up or changing regimens. CONCLUSIONS: Innovative clinical and community approaches are needed for quality improvement in the pediatric care of HIV in the Americas. PMID- 28081886 TI - Breastfeeding, Polyunsaturated Fatty Acid Levels in Colostrum and Child Intelligence Quotient at Age 5-6 Years. AB - OBJECTIVE: To examine the relationship of polyunsaturated fatty acid (PUFA) in breast milk with children's IQ. STUDY DESIGN: In the French Etude des Determinants pre- et postnatals precoces du developpement et de la sante de l'Enfant (EDEN) mother-child cohort, colostrum samples were collected at the maternity unit. Colostrum omega-6 and omega-3 PUFA were analyzed by gas chromatography. At age 5-6 years, the IQs of 1080 children were assessed using the Wechsler Preschool and Primary Scale of Intelligence-III. The relationships of breastfeeding duration and PUFA levels with children's IQs were examined by linear regression. RESULTS: Full scale IQ of ever breastfed children was 4.5 (95% CI: 2.7, 6.2) higher than never breastfed children in the unadjusted model, but this was not statistically significant in the adjusted model (1.3 points higher [ 0.4, 3.0]). Any breastfeeding duration was associated with full scale (0.20 [0.00, 0.41] points/month) and verbal (0.31 [0.09, 0.52]) IQ. Colostrum linoleic acid (LA) levels were negatively associated with Verbal IQ (-0.6 [-1.1, 0.0] points per 1% level increase). Children exposed to colostrum high in LA and low in docosahexaenoic acid (DHA) had lower IQs than those exposed to colostrum high in DHA (3.0 [0.5, 5.5] points) and those exposed to colostrum low in LA and DHA (4.4 [1.6, 7.3] points). Finally, the association between breastfeeding duration and child IQ was stronger when LA levels were high. CONCLUSIONS: Duration of breastfeeding and colostrum PUFA levels were associated with children's IQs in the EDEN cohort. These data support breastfeeding and add evidence for the role of early PUFA exposure on childhood cognition. PMID- 28081885 TI - Health-Related Quality of Life and Lifestyle Behavior Clusters in School-Aged Children from 12 Countries. AB - OBJECTIVE: To evaluate the relationship between children's lifestyles and health related quality of life and to explore whether this relationship varies among children from different world regions. STUDY DESIGN: This study used cross sectional data from the International Study of Childhood Obesity, Lifestyle and the Environment. Children (9-11 years) were recruited from sites in 12 nations (n = 5759). Clustering input variables were 24-hour accelerometry and self-reported diet and screen time. Health-related quality of life was self-reported with KIDSCREEN-10. Cluster analyses (using compositional analysis techniques) were performed on a site-wise basis. Lifestyle behavior cluster characteristics were compared between sites. The relationship between cluster membership and health related quality of life was assessed with the use of linear models. RESULTS: Lifestyle behavior clusters were similar across the 12 sites, with clusters commonly characterized by (1) high physical activity (actives); (2) high sedentary behavior (sitters); (3) high screen time/unhealthy eating pattern (junk food screenies); and (4) low screen time/healthy eating pattern and moderate physical activity/sedentary behavior (all-rounders). Health-related quality of life was greatest in the all-rounders cluster. CONCLUSIONS: Children from different world regions clustered into groups of similar lifestyle behaviors. Cluster membership was related to differing health-related quality of life, with children from the all-rounders cluster consistently reporting greatest health related quality of life at sites around the world. Findings support the importance of a healthy combination of lifestyle behaviors in childhood: low screen time, healthy eating pattern, and balanced daily activity behaviors (physical activity and sedentary behavior). TRIAL REGISTRATION: ClinicalTrials.gov: NCT01722500. PMID- 28081887 TI - Eliminating Disparities in Mother's Milk Feeding in the Neonatal Intensive Care Unit. PMID- 28081888 TI - A Computerized Sexual Health Survey Improves Testing for Sexually Transmitted Infection in a Pediatric Emergency Department. AB - OBJECTIVES: To assess whether clinical decision support, using computerized sexually transmitted infection (STI) risk assessments, results in increased STI testing of adolescents at high risk for STI. STUDY DESIGN: In a 2-arm, randomized, controlled trial conducted at a single, urban, pediatric emergency department, adolescents completed a computerized sexual health survey. For patients assigned to the intervention arm, attending physicians received decision support to guide STI testing based on the sexual health survey-derived STI risk; in the usual care arm, decision support was not provided. We compared STI testing rates between the intervention and usual care groups, adjusting for potential confounding using multivariable logistic regression. RESULTS: Of the 728 enrolled patients, 635 (87.2%) had evaluable data (323 intervention arm; 312 usual care arm). STI testing frequency was higher in the intervention group compared with the usual care group (52.3% vs 42%; aOR 2 [95% CI 1.1, 3.8]). This effect was even more pronounced among the patients who presented asymptomatic for STI (28.6 vs 8.2%; aOR 4.7 [95% CI 1.4-15.5]). CONCLUSIONS: Providing sexual health survey derived decision support to emergency department clinicians led to increased testing rates for STI in adolescents at high risk for infection, particularly in those presenting asymptomatic for infection. Studies to understand potential barriers to decision support adherence should be undertaken to inform larger, multicenter studies that could determine the generalizability of these findings and whether this process leads to increased STI detection. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02509572. PMID- 28081889 TI - The Placebo Response in Pediatric Abdominal Pain-Related Functional Gastrointestinal Disorders: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To investigate the magnitude and determinants of the placebo response in studies with pediatric abdominal pain-related functional gastrointestinal disorders. STUDY DESIGN: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL were searched for systematic reviews and randomized placebo-controlled trials concerning children 4-18 years of age with an abdominal pain-related functional gastrointestinal disorder. The primary outcome was the pooled proportion of subjects assigned to placebo with improvement as defined by the authors. The effect of trial characteristics on the magnitude of the placebo response was investigated using univariate meta regression analysis. RESULTS: Twenty-one trials were identified. The pooled proportion of subjects with improvement was 41% (95% CI, 34%-49%; 17 studies) and with no pain was 17% (95% CI, 8%-32%; 7 studies). The pooled standardized mean difference on the Faces Pain Scales compared with baseline was -0.73 (95% CI, 1.04 to -0.42; 8 studies). There was significant heterogeneity across studies with respect to both outcomes. Lower dosing frequency (P = .04), positive study (P = .03), longer duration of treatment (P < .001), and higher placebo dropout (P < .001) were associated with higher report of no pain. Response on Faces Pain Scales was greater in studies conducted in the Middle East (P = .002), in studies that did not report the randomization schedule (P = .02), and in studies with a higher percentage of females (P = .04). CONCLUSIONS: Approximately 41% of children with abdominal pain-related functional gastrointestinal disorders improve on placebo. Several trial characteristics are correlated significantly with the proportion of patients with no pain on placebo and with the magnitude of the placebo response on Faces Pain Scales. These data could be valuable for the design of future studies. PMID- 28081890 TI - Impact of Latency Duration on the Prognosis of Preterm Infants after Preterm Premature Rupture of Membranes at 24 to 32 Weeks' Gestation: A National Population-Based Cohort Study. AB - OBJECTIVE: To assess the impact of latency duration on survival, survival without severe morbidity, and early-onset sepsis in infants born after preterm premature rupture of membranes (PPROM) at 24-32 weeks' gestation. STUDY DESIGN: This study was based on the prospective national population-based Etude Epidemiologique sur les Petits Ages Gestationnels 2 cohort of preterm births and included 702 singletons delivered in France after PPROM at 24-32 weeks' gestation. Latency duration was defined as the time from spontaneous rupture of membranes to delivery, divided into 4 periods (12 hours to 2 days [reference], 3-7 days, 8-14 days, and >14 days). Multivariable logistic regression was used to assess the relationship between latency duration and survival, survival without severe morbidity at discharge, or early-onset sepsis. RESULTS: Latency duration ranged from 12 hours to 2 days (18%), 3-7 days (38%), 8-14 days (24%), and >14 days (20%). Rates of survival, survival without severe morbidity, and early-onset sepsis were 93.5% (95% CI 91.8-94.8), 85.4% (82.4-87.9), and 3.4% (2.0-5.7), respectively. A crude association found between prolonged latency duration and improved survival disappeared on adjusting for gestational age at birth (aOR 1.0 [reference], 1.6 [95% CI 0.8-3.2], 1.2 [0.5-2.9], and 1.0 [0.3-3.2] for latency durations from 12 hours to 2 days, 3-7 days, 8-14 days, and >14 days, respectively). Prolonged latency duration was not associated with survival without severe morbidity or early-onset sepsis. CONCLUSION: For a given gestational age at birth, prolonged latency duration after PPROM does not worsen neonatal prognosis. PMID- 28081891 TI - Preschool Neurodevelopmental Outcomes in Children with Congenital Heart Disease. AB - OBJECTIVE: To describe preschool neurodevelopmental outcomes of children with complex congenital heart disease (CHD), who were evaluated as part of a longitudinal cardiac neurodevelopmental follow-up program, as recommended by the American Heart Association and the American Academy of Pediatrics, and identify predictors of neurodevelopmental outcomes in these children. STUDY DESIGN: Children with CHD meeting the American Heart Association/American Academy of Pediatrics high-risk criteria for neurodevelopmental delay were evaluated at 4-5 years of age. Testing included standardized neuropsychological measures. Parents completed measures of child functioning. Scores were compared by group (single ventricle [1V]; 2 ventricles [2V]; CHD plus known genetic condition) to test norms and classified as: normal (within 1 SD of mean); at risk (1-2 SD from mean); and impaired (>2 SD from mean). RESULTS: Data on 102 patients were analyzed. Neurodevelopmental scores did not differ based on cardiac anatomy (1V vs 2V); both groups scored lower than norms on fine motor and adaptive behavior skills, but were within 1 SD of norms. Patients with genetic conditions scored significantly worse than 1V and 2V groups and test norms on most measures. CONCLUSIONS: Children with CHD and genetic conditions are at greatest neurodevelopmental risk. Deficits in children with CHD without genetic conditions were mild and may not be detected without formal longitudinal testing. Parents and providers need additional education regarding the importance of developmental follow-up for children with CHD. PMID- 28081893 TI - Advances in spatial epidemiology and geographic information systems. AB - The field of spatial epidemiology has evolved rapidly in the past 2 decades. This study serves as a brief introduction to spatial epidemiology and the use of geographic information systems in applied research in epidemiology. We highlight technical developments and highlight opportunities to apply spatial analytic methods in epidemiologic research, focusing on methodologies involving geocoding, distance estimation, residential mobility, record linkage and data integration, spatial and spatio-temporal clustering, small area estimation, and Bayesian applications to disease mapping. The articles included in this issue incorporate many of these methods into their study designs and analytical frameworks. It is our hope that these studies will spur further development and utilization of spatial analysis and geographic information systems in epidemiologic research. PMID- 28081892 TI - Rapid Resolution of Blended or Composite Multigenic Disease in Infants by Whole Exome Sequencing. AB - Whole-exome sequencing identified multiple genetic causes in 2 infants with heterogeneous disease. Three gene defects in the first patient explained all symptoms, but manifestations were overlapping (blended phenotype). Two gene defects in the second patient explained nonoverlapping symptoms (composite phenotype). Whole-exome sequencing rapidly and comprehensively resolves heterogeneous genetic disease. PMID- 28081894 TI - Prevalence of serious mental illness among parents in the United States: results from the National Survey of Drug Use and Health, 2008-2014. AB - PURPOSE: This brief research report presents findings from a US national household survey on the number and percentage of parents with mental illness. METHODS: Using combined annual data from the 2008-2014 National Survey on Drug Use and Health, parents were defined as having children in the household from birth to 18 years. Prediction models developed in an earlier clinical study using a National Survey on Drug Use and Health subsample were used to estimate serious mental illness (SMI). RESULTS: A total of 2.7 million parents (3.8%) had a SMI in the past year and 12.8 million parents (18.2%) had any mental illness in the past year. Mental illness was more common among mothers than fathers and least common among Asians compared with other races. SMI was less prevalent in parents who were aged 50 years and older compared with younger age groups. CONCLUSIONS: The burden of mental illness in parents is high in the United States, especially among mothers. Physicians who treat parents should routinely screen for mental illness and discuss its implications for parenting. PMID- 28081895 TI - Cyclodextrins as inhibitors of the precipitation of riboflavin-5'-phosphate due to presence of zinc chloride: A NMR investigation. AB - Several cyclodextrins (CDs) were probed in order to counteract the precipitation of riboflavin-5'-phosphate (or flavin mononucleotide, FMN-P) due to the presence of divalent cations, by exploiting Nuclear Magnetic Resonance (NMR) spectroscopy both for quantitative analyses and stereochemical characterizations. Among CDs, beta-cyclodextrin (beta-CD) showed the best solubilizing power in virtue of the formation of a 1-2 FMN-P/beta-CD complex, the stereochemistry of which was ascertained by ROESY (Rotating-frame Overhauser Enhanced SpectroscopY) measurements. PMID- 28081896 TI - [A computerised clinical decision-support system for the management of depression in Primary Care]. AB - Despite its clinical relevance and its importance as a public health problem, there are major gaps in the management of depression. Evidence-based clinical guidelines are useful to improve processes and clinical outcomes. In order to make their implementation easier these guidelines have been transformed into computerised clinical decision support systems. In this article, a description is presented on the basics and characteristics of a new computerised clinical guideline for the management of major depression, developed in the public health system in Catalonia. This tool helps the clinician to establish reliable and accurate diagnoses of depression, to choose the best treatment a priori according to the disease and the patient characteristics. It also emphasises the importance of systematic monitoring to assess the clinical course, and to adjust therapeutic interventions to the patient's needs at all times. PMID- 28081897 TI - The incidence and impact of arthroscopy in the year prior to total knee arthroplasty. AB - BACKGROUND: Prior knee surgery and arthroscopy is known to increase complications and re-operations in subsequent total knee arthroplasty (TKA). We set out to examine the time dependant effect of arthroscopy on Patient Reported Outcome Measures following subsequent TKA. METHODS: A retrospective review of theatre and clinical records identified 186 patients who underwent TKA within a year of arthroscopy (2009-2013). Oxford knee score (OKS) data was compared with a published cohort from the same department (1708 patients). RESULTS: One hundred and eighty six patients were identified who underwent TKA within a year of arthroscopy; 112 females, 74 males; mean age 64 (SD 10); mean BMI 31.4 (SD 4.6). There was no significant difference between groups with respect to sex, age, BMI, or pre-operative OKS. One hundred and three patients underwent TKA within six months of arthroscopy. This group had a significant reduction in OKS compared to the previously published cohort (32.8 vs 36.3, p<0.005). There was no significant difference in OKS when TKA was performed more than six months after arthroscopy (35.3). The re-operation rate was 14% in the arthroscopy group, with a revision rate of 3.8% vs 1.6% in a previously published large cohort from the same institution. CONCLUSIONS: There appears to be a negative impact of arthroscopy in relation to subsequent TKA which seems to be time dependent. TKA should not routinely be performed within six months of arthroscopy. This should inform guidelines on the management knee osteoarthritis. PMID- 28081898 TI - Good functional results following high tibial opening-wedge osteotomy of knees with medial osteoarthritis: A prospective study with a mean of 8.3years of follow up. AB - BACKGROUND: To report time dependent functional improvement and predictive risk factors for failure when the load in varus knees with medial osteoarthritis is shifted from the medial to the lateral knee compartment. METHODS: Forty-nine consecutive patients (52 knees), mean age 47 (31-64) years, underwent a high tibial opening-wedge valgus osteotomy stabilized with a Puddu plate and bone grafting. The patients were evaluated with the Knee Injury and Osteoarthritis Outcome Score (KOOS) preoperatively and at three and six months, one, two, five and 10years postoperatively with a mean follow-up time of 8.3years (2.0-10.6). RESULTS: Mean angular correction was 8.0 degrees (four to 12). The five subscores of KOOS increased significantly during the first year by 40-131% from preoperative values, the good results remaining throughout the 10-year follow-up for those with a surviving osteotomy. The outcome was related to the grade of preoperative osteoarthritis. Seven knees were converted to total knee arthroplasty (TKA) mean 6.2years (two to nine) post-operatively, and had a lower KOOS preoperatively than those of surviving osteotomies. The osteotomy survival rate at five years was 94% and at 10years 83%. Patients with KOOS subscore quality of life (QoL) <44 at the two-year follow-up had a 11.7 times higher risk for later TKA than those with QoL >=44 (P=0.017). CONCLUSION: High tibial opening wedge osteotomy for medial knee osteoarthritis resulted in good functional recovery after one year and favorable mid-term results. It may be a good treatment option for middle-aged patients with varus knees and medial osteoarthritis in order to prevent or postpone TKA. PMID- 28081899 TI - BARCHAN: Blob Alignment for Robust CHromatographic ANalysis. AB - Two-dimensional gas chromatography (GC*GC) plays a central role into the elucidation of complex samples. The automation of the identification of peak areas is of prime interest to obtain a fast and repeatable analysis of chromatograms. To determine the concentration of compounds or pseudo-compounds, templates of blobs are defined and superimposed on a reference chromatogram. The templates then need to be modified when different chromatograms are recorded. In this study, we present a chromatogram and template alignment method based on peak registration called BARCHAN. Peaks are identified using a robust mathematical morphology tool. The alignment is performed by a probabilistic estimation of a rigid transformation along the first dimension, and a non-rigid transformation in the second dimension, taking into account noise, outliers and missing peaks in a fully automated way. Resulting aligned chromatograms and masks are presented on two datasets. The proposed algorithm proves to be fast and reliable. It significantly reduces the time to results for GC*GC analysis. PMID- 28081900 TI - Broadening of analyte streams due to a transverse pressure gradient in free-flow isoelectric focusing. AB - Pressure-driven cross-flows can arise in free-flow isoelectric focusing systems (FFIEF) due to a non-uniform electroosmotic flow velocity along the channel width induced by the pH gradient in this direction. In addition, variations in the channel cross-section as well as unwanted differences in hydrostatic heads at the buffer/sample inlet ports can also lead to such pressure-gradients which besides altering the equilibrium position of the sample zones have a tendency to substantially broaden their widths deteriorating the separations. In this situation, a thorough assessment of stream broadening due to transverse pressure gradients in FFIEF devices is necessary in order to establish accurate design rules for the assay. The present article describes a mathematical framework to estimate the noted zone dispersion in FFIEF separations based on the method-of moments approach under laminar flow conditions. A closed-form expression has been derived for the spatial variance of the analyte streams at their equilibrium positions as a function of the various operating parameters governing the assay performance. This expression predicts the normalized stream variance under the chosen conditions to be determined by two dimensionless Peclet numbers evaluated based on the transverse pressure-driven and electrophoretic solute velocities in the separation chamber, respectively. Moreover, the analysis shows that while the stream width can be expected to increase with an increase in the value of the first Peclet number, the opposite trend will be followed with respect to the latter. The noted results have been validated using Monte Carlo simulations that also establish a time/length scale over which the predicted equilibrium stream width is attained in the system. PMID- 28081901 TI - Development of a multichannel microfluidic system with Schlieren imaging microscopy for online chip-based moving boundary electrophoresis. AB - The concentration gradient detection method based on the Schlieren optics employed for electrophoresis analyses by extending the technology to a multi channel system using a prototyped microfluidic chip (thinXXS Micro-technology, Germany). The results prove that coupling a chip-based microfluidic device with Schlieren detection is an appropriate approach to improve the electrophoretic separations. The effects of channel's geometry and dimension were investigated by conducting the experiments in channels with different cross sectional areas. Fast kinetic data acquisition of the charge-coupled device (CCD) camera facilitated recording of a time sequence of optical images, demonstrating the potential of the CCD camera as a powerful tool for studying dynamic processes such as diffusion. Diffusion coefficients of sample proteins were measured under static and dynamic conditions, where the static mode demonstrated more accurate results. Furthermore, the Fourier transformation was employed to improve the Schlieren images for quantitative analysis of the diffusion coefficient measurement. PMID- 28081902 TI - [Renal abnormalities]. PMID- 28081903 TI - Prevalence of obesity and diabetes in Spanish adults 1987-2012. AB - BACKGROUND AND OBJECTIVE: The prevalence of obesity and diabetes mellitus (DM) has increased worldwide. Our objective was to examine trends in the prevalence of overweight, obesity, morbid obesity and DM in Spain from 1987 to 2012. PARTICIPANTS AND METHODS: Data were obtained from 8 waves of the national health surveys which are cross-sectional studies conducted in representative samples of the Spanish adult population. Self-reported data of 156,440 adults (>=16 years) from 1987 to 2012 were used. Body mass index (BMI) was calculated from self reported weight and height. Overweight was defined as a BMI of 25.0 to 29.9kg/m2, obesity as a BMI>=30kg/m2 and morbid obesity as a BMI>=40kg/m2. DM was considered present if the participant reported having been diagnosed. Age-adjusted prevalence was adjusted by the direct standardisation method to the 2003 survey population. RESULTS: From 1987 to 2012 age-adjusted prevalence of overweight increased from 34.0% (95% confidence interval [95% CI] 33.2-34.8) to 35.8% (95% CI 35.0-36.6), prevalence of obesity from 8.0% (95% CI 7.5-8.5) to 16.5% (95% CI 15.7-17.1%) and DM prevalence from 4.2% (95% CI 3.9-4.5) to 7.1% (95% CI 6.7 7.4%). Morbid obesity increased from 0.20% (95% CI 0.13-0.27) in 1993 to 0.88% (95% CI 0.70-1.05) in 2012. The growth rate was greater among males. CONCLUSIONS: An increasing trend of the prevalence of overweight, obesity, morbid obesity and DM was found in Spain from 1987 to 2012, particularly in males. PMID- 28081904 TI - Screening and treatment of portal vein thrombosis in cirrhosis. PMID- 28081905 TI - [Perioperative stroke following transurethral resection of prostate: high index of suspicion and stabilization of physiological parameters can save lives]. AB - We report a case of a 72 year old hypertensive male who developed severe hypertension followed by neurological deterioration in the immediate postoperative period after transurethral resection of prostate. While arterial blood gas and laboratory tests excluded transurethral resection of prostate syndrome or any other metabolic cause, reduction of blood pressure failed to ameliorate the symptoms. A cranial CT done 4hours after the onset of neurological symptoms revealed bilateral gangliocapsular and right thalamic infarcts. Oral aspirin was advised to prevent early recurrent stroke. Supportive treatment and mechanical ventilation ensured physiological stability and the patient recovered completely over the next few days without any residual neurological deficit. PMID- 28081906 TI - [Neuraxial analgesia in a parturient with the VACTERL association undergoing labor and vaginal delivery]. AB - INTRODUCTION: The term VACTERL is an acronym for an association of congenital malformations: including vertebral, anal, cardiac, tracheo-esophageal, renal and limb anomalies. VACTERL anomalies pose a formidable challenge to anesthesiologists. We describe the anesthetic management of a parturient with VACTERL association, who underwent neuraxial analgesia for labor and vaginal delivery. CASE REPORT: A 23 year old primigravida at 39 weeks gestation presented in labor at 4cm cervical dilatation, completely effaced, requesting labor analgesia. Past medical history included VACTERL association with an imperforate anus and a partial endocardial cushion defect, both repaired in early childhood. She also had significant dorso-lumbar scoliosis with an extra lumbar vertebra. An MRI performed at 14 years age revealed the above findings with no spinal cord abnormalities. With a normal neurologic exam, a combined spinal epidural technique was performed. Despite significant scoliosis, the epidural space was identified at approximately the L3-L4 interspace at a depth of 5cm. Spinal Fentanyl 25mcg was administered followed by continuous patient-controlled epidural analgesia. The patient experienced excellent pain relief throughout her labor, and had an uneventful vaginal delivery 5h after epidural placement. DISCUSSION: The rarity of VACTERL association in the obstetric population with its extensive anomalies mandates a multidisciplinary approach in the prenatal period as it can pose major challenges to all health care providers, including airway, ventilatory, cardiac and neuraxial problems. This is the first reported case of a successful and safe neuraxial technique in a laboring patient with the VACTERL association with albeit limited vertebral and spinal cord anomalies. PMID- 28081907 TI - [Anesthetic management of an infant with giant abdominal neuroblastoma]. AB - Neuroblastoma is the most common, non-central nervous system tumor of childhood. It has the potential to synthesize catecholamines. However, the presences of hypertension are uncommon. We report the perioperative management of a 15-month old infant with giant abdominal neuroblastoma who presented severe hypertension. The pathophysiological alterations of neuroblastoma are reviewed and perioperative management presented. PMID- 28081908 TI - The impact on women's health and the cervical cancer screening budget of primary HPV screening with dual-stain cytology triage in Belgium. AB - Dual stain cytology, or "diagnostic cytology", offers a significant increase in sensitivity compared to cytology, with a slight decrease in specificity. This can reduce additional investigations like colposcopies, biopsies, and follow-up visits. Cervical cancer screening for women between 25 and 65 years of age with diagnostic cytology is estimated to reduce the incidence of cervical cancer by 36% and reduce annual cervical cancer mortalities by 40%. The reduced number of screening visits and the decrease in incidence and mortality will improve quality of life. In this article, a model was created to evaluate the cost-effectiveness of diagnostic cytology for Belgium. In this approach, precancerous cells are more likely to be immediately identified during the first screening visit. This reduces both the number and frequency of follow-up visits required. After two cycles (6 years), the prevalence of CIN and cervical cancer is decreased significantly in the screened population. At a population level, these shifts can reduce the screening budget by 21%, resulting in savings of 5.3 million euro a year in Belgium. Diagnostic cytology benefits all stakeholders involved in cervical cancer screening. PMID- 28081909 TI - Staphylococcus aureus screening and decolonization reduces the risk of surgical site infections in patients undergoing deep brain stimulation surgery. AB - In a controlled before-and-after study in a single centre, it was aimed to determine whether identification of Staphylococcus aureus nasal carriers followed by nasal mupirocin ointment and chlorhexidine soap reduced surgical site infections (SSIs) among 182 patients undergoing deep brain stimulation. In all, 119 patients were included in the control group and 63 in the screening group. There was a significant SSI decrease from 10.9% to 1.6% between the two groups (P<0.04; relative risk: 0.13; 95% confidence interval: 0.003-0.922). There were eight SSIs involving S. aureus in the control group, none in the screening group. No specific risk factors for SSI were identified. PMID- 28081910 TI - The global hand-sanitizing relay: promoting hand hygiene through innovation. AB - On the 10th anniversary of the 'Clean Care is Safer Care' programme, the World Health Organization (WHO) Collaborating Centre on Patient Safety launched the 'Global Hand Sanitizing Relay 2015' (HSRelay). This hospital-wide activity promotes the WHO handrubbing technique to improve hand hygiene (HH) compliance. More than 15,000 healthcare workers (HCWs) from 133 hospitals in 43 countries participated. Between May and September 2015, 14 hospitals submitted pre- and post-event HH compliance data; 57% (8/14) reported a significant increase while others showed minimal or no improvement (average absolute change 9.4%). The HSRelay demonstrated that HCWs were interested in novel strategies to improve HH compliance. PMID- 28081911 TI - Antimicrobial coating innovations to prevent healthcare-associated infection. PMID- 28081912 TI - Veterinary epidemiology: Forging a path toward one health. AB - The One Health concept has been extensively used to describe those practices that support transdisciplinary collaborations involving animal and human health and the environment. During the past International Society of Veterinary Epidemiology and Economics (ISVEE) conference in Merida (Mexico) in November 2015, a panel discussion was held to identify gaps and needs required for success with such approaches. Key messages included further development of dynamic, transdisciplinary collaborations, new mechanisms for obtaining, integrating and interpreting data from diverse sources, the identification of One Health joint priorities and resources for the veterinary and public health professions, and operationalization and institutionalization of One Health. Additionally, all abstracts that were presented at ISVEE containing the term "One Health" were identified. There has been an increase in the use of the term over time. One Health research has been presented at ISVEE since at least as early as 2009 and has been highlighted at the conference for work carried out in at least 41 countries from 69 research centers or institutions, with highly diversified articles, which reveals the richness of this field of research. PMID- 28081913 TI - Checkpoint inhibition: a new beginning for urothelial cancer. PMID- 28081915 TI - FOLFOXIRI plus bevacizumab as conversion-therapy for liver metastases in colorectal cancer: A necessity? PMID- 28081914 TI - Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study. AB - BACKGROUND: PD-1 and its ligands are expressed in urothelial cancer, and findings have shown that inhibition of the PD-1 pathway has clinical benefit. We aimed to assess the safety and activity of an anti-PD-1 antibody pembrolizumab in patients with locally advanced or metastatic urothelial cancer. METHODS: This study was part of the non-randomised, multi-cohort, open-label, phase 1b KEYNOTE-012 basket trial. We enrolled patients aged 18 years and older with a histologically or cytologically confirmed diagnosis of locally advanced or metastatic urothelial cancer, including cancers of the renal pelvis, ureter, bladder, or urethra, from eight hospitals in the USA and Israel. Patients were required to have at least 1% PD-L1 expression detected on the tumour cells or in tumour stroma, as determined by immunohistochemistry. Patients were given 10 mg/kg intravenous pembrolizumab every 2 weeks until disease progression, unacceptable toxic effects, or the end of the study (ie, 24 months of treatment). Primary endpoints were safety and overall response (defined by Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1), as assessed by a masked, independent central review. Safety was assessed in patients who received one or more doses of pembrolizumab (all-patients-as-treated population); activity was assessed in patients who received pembrolizumab, had measurable disease at baseline, and had one or more post-baseline scans, or discontinued because of progressive disease or treatment related adverse events (full analysis set). This study is registered with ClinicalTrials.gov, number NCT01848834, and is no longer enrolling patients; follow-up is ongoing. FINDINGS: Between May 14, 2013, and Dec 10, 2013, 115 patients were tissue pre-screened as part of a two-part consent process. 61 (53%) patients were PD-L1 positive, of whom 33 were enrolled in this study. All enrolled patients received at least one dose of pembrolizumab and were included in the safety analyses. 27 patients comprised the full analysis set and were deemed assessable for activity. Six patients were not assessable: three discontinued study drug because of a non-treatment-related adverse event before the first post-baseline scan, two withdrew before the first post-baseline scan, and one had no measurable disease at baseline. The most common treatment-related adverse events were fatigue (six [18%] of 33 patients) and peripheral oedema (4 [12%]). Five (15%) patients had 11 grade 3 treatment-related adverse events; no single event occurred in more than one patient. Three (9%) patients experienced five serious treatment-related adverse events. After median follow-up of 13 months (range 1-26, IQR 5-23), an overall response was achieved in seven (26% [95% CI 11-46]) of 27 assessable patients, with three (11% [2-29]) complete and four (15% [4-34]) partial responses. Of the four deaths that occurred during the study (cardiac arrest, pneumonia, sepsis, and subarachnoid haemorrhage), none were deemed treatment related. INTERPRETATION: Pembrolizumab showed anti-tumour activity and acceptable safety in patients with advanced urothelial cancer, supporting ongoing phase 2 and 3 studies of pembrolizumab in this population. FUNDING: Merck & Co., Inc. PMID- 28081916 TI - Vocal Characteristics and Laryngoscopic Findings in Future Musical Theater Performers. AB - OBJECTIVE: Musical theater performers are a special group of elite vocal performers with a high vocal load as they combine singing, acting, and physical performance. As they are absolutely depending on their voice quality and vocal capacities for their studies and their future profession, an optimal voice production is very important. The purpose of this study was to determine the voice quality of musical theater students. The voice quality of seven students was then reevaluated 1 year after the first assessment. STUDY DESIGN: Observational study. METHODS: Thirty-one musical students (7 men and 24 women) with a mean age of 20 years participated in the study. To determine the voice quality, objective (aerodynamic measurements, voice range profile, acoustic analysis, and Dysphonia Severity Index) and subjective (videolaryngostroboscopy, Voice Handicap Indexes, and questionnaires regarding voice symptoms and risk factors) voice measurements were performed. RESULTS: The median Dysphonia Severity Index in male and female musical students was respectively 5.3 and 5.7, both corresponding with an overall good voice quality. The questionnaires revealed the presence of vocal fatigue, dryness of the throat, vocal tract discomfort, and harmful vocal habits in the majority of students. In 45% of the subjects, videolaryngostroboscopic evaluation of the vocal folds showed an organic lesion. The majority of these lesions are inflammatory lesions (26%). In 68% of the subjects, a certain degree of supraglottic constriction was observed. CONCLUSION: Despite the overall good voice quality, videolaryngostroboscopy showed a high presence of vocal fold lesions and supraglottic constriction during phonation. PMID- 28081917 TI - [Congenital anomalies of the optic disc: In the differential diagnosis of congenital glaucoma]. PMID- 28081919 TI - [Swept-Source optical coherence tomography angiography of X-linked retinoschisis]. PMID- 28081918 TI - [Selective laser trabeculoplasty: Effect of number of preoperative topical glaucoma medications on pressure lowering and success rate]. AB - PURPOSE: To evaluate the lowering of intraocular pressure (IOP) one year after SLT and to assess if differences are related to number of pre-SLT topical treatments in ocular hypertension (OHT) and primary open angle glaucoma (POAG) patients. METHODS: Retrospective review of 106 eyes of 13 OHT and 93 POAG patients treated by SLT for insufficient IOP control, allergy, discomfort or non compliance to glaucoma medications, excluding patients with less than 1 year of follow-up after SLT. IOP was measured by applanation before and at 1, 6 and 12 months after SLT. RESULTS: Hundred and six eyes untreated (n=13), or treated with one (n=25), two (n=40) or three or more (n=28) glaucoma medications were included. Mean IOP decreased from 19.4+/-3.6mmHg preoperatively to 15.7+/-3.1mmHg at 12 months, which corresponds to an average decrease of 18.8%. At 1 year, 62.2% (n=66) were responders (IOP reduction>=3mmHg): 92.3% without medications (n=12), 68% with one (n=17), 57.5% with two (n=23) and 50% with three or more medications (n=14). Their average IOP decreased from 20.7+/-3.4 to 15.2+/-2.9mmHg (26.6%), respectively from 20.8+/-2.6 to 15.8+/-3.2 (25%) without medications, 20.6+/-3.2 to 14.9+/-3.7 (27.3%) with one, 20.8+/-4.1 to 15.5+/-3.3 (25.1%) with two and 20.7+/-3.2 to 14.4+/-2.4mmHg (29.7%) with three medications. CONCLUSIONS: The number of responders seems to be greater in OHT and POAG patients without or with few glaucoma medications, but the IOP reduction seems to be similar regardless of the number of glaucoma medications. PMID- 28081920 TI - Control of an Acinetobacter baumannii multidrug resistance endemic in the ICU. Recalling the obvious. PMID- 28081921 TI - Urotensinergic system genes in experimental subarachnoid hemorrhage. AB - OBJECTIVE: Cerebral vasospasm, one of the main complications of subarachnoid hemorrhage (SAH), is characterized by arterial constriction and mainly occurs from day 4 until the second week after the event. Urotensin-II (U-II) has been described as the most potent vasoconstrictor peptide in mammals. An analysis is made of the serum U-II concentrations and mRNA expression levels of U-II, urotensin related peptide (URP) and urotensin receptor (UT) genes in an experimental murine model of SAH. DESIGN: An experimental study was carried out. SETTING: Experimental operating room of the Biomedicine Institute of Seville (IBiS), Virgen del Rocio University Hospital (Seville, Spain). PARTICIPANTS: 96 Wistar rats: 74 SAH and 22 sham intervention animals. INTERVENTIONS: Day 1: blood sampling, followed by the percutaneous injection of 100MUl saline (sham) or blood (SAH) into the subarachnoid space. Day 5: blood sampling, followed by sacrifice of the animals. MAIN VARIABLES OF INTEREST: Weight, early mortality, serum U-II levels, mRNA values for U-II, URP and UT. RESULTS: Serum U-II levels increased in the SAH group from day 1 (0.62pg/mL [IQR 0.36-1.08]) to day 5 (0.74pg/mL [IQR 0.39-1.43]) (p<0.05), though not in the sham group (0.56pg/mL [IQR 0.06-0.83] day 1; 0.37pg/mL [IQR 0.23-0.62] day 5; p=0.959). Between-group differences were found on day 5 (p<0.05). The ROC analysis showed that the day 5 serum U-II levels (AUC=0.691), URP mRNA (AUC=0.706) and UT mRNA (AUC=0.713) could discriminate between sham and SAH rats. The normal serum U-II concentration range in rats was 0.56pg/mL (IQR 0.06-0.83). CONCLUSION: The urotensinergic system is upregulated on day 5 in an experimental model of SAH. PMID- 28081922 TI - Application of Nuclear Magnetic Resonance to Detect Toxigenic Clostridium difficile from Stool Specimens: A Proof of Concept. AB - We evaluated the performance of an early prototype core molecular mirroring nuclear magnetic resonance detection platform (Mentor-100) to detect toxigenic Clostridium difficile from stool. This technology uses customized nanoparticles bound to target specific oligonucleotide probes that form binaries in the presence of nucleic acid from the target microorganism. Liquid patient stool specimens were seeded with C. difficile or other Clostridium species to determine the analytical sensitivity and specificity. Samples underwent nucleic acid extraction and target amplification with probes conjugated with iron nanoparticles. Signal from nuclear magnetic resonance spin-spin relaxation time was measured to detect the presence or absence of toxigenic C. difficile. The limit of detection was <180 colony forming units per reaction of toxigenic C. difficile. No cross-reactivity was observed with nontoxigenic C. difficile, Clostridium sordellii, Clostridium perfringens, Bacillus subtilis, or Paenibacillus polymyxa at 108 colony forming units/mL. Correlation studies using frozen stool samples yielded a sensitivity of 88.4% (61 of 69) and a specificity of 87.0% (40 of 46) as compared with a commercial PCR assay for C. difficile. The area under the curve in the receiver operating characteristic curve analysis was 0.922. The prototype molecular mirroring platform showed promising performance for pathogen detection from clinical specimens. The platform design has the potential to offer a novel, low-cost alternative to currently available nucleic acid-based tests. PMID- 28081923 TI - Analysis of rhizobial endosymbionts of Vicia, Lathyrus and Trifolium species used to maintain mountain firewalls in Sierra Nevada National Park (South Spain). AB - Forest fires lead to the annual disappearance of many natural formations that require the creation of firewall areas. They can be maintained by enriching their pastures with attractive plants for grazing livestock, mainly legumes, which have a high protein content and low dependence on N fertilizers due to their ability to establish nitrogen-fixing symbiosis with rhizobia. In this study, the rhizobia isolated from the nodules of six legumes from the genera Vicia, Lathyrus and Trifolium were analysed in a firewall zone established in Lanjaron (Granada) close to the Sierra Nevada National Park (Spain). The results showed a high genetic diversity of the isolated strains that had 3, 16, 14 and 13 different types of rrs, recA, atpD and glnII genes, respectively. All strains were phylogenetically close to the species from the Rhizobium leguminosarum group, although they were not identified as any of them. The isolated strains belonged to the symbiovars viciae and trifolii but high phylogenetic diversity was found within both symbiovars, since there were 16 and 14 nodC gene types, respectively. Some of these strains clustered with strains isolated in other countries and continents, but others formed atpD, recA, glnII and nodC clusters and lineages only found to date in this study. PMID- 28081925 TI - Detection of mcr-1-encoding plasmid-mediated colistin-resistant Salmonella isolates from human infection in Denmark. PMID- 28081924 TI - Physiological and gene expression responses to nitrogen regimes and temperatures in Mastigocladus sp. strain CHP1, a predominant thermotolerant cyanobacterium of hot springs. AB - Cyanobacteria are widely distributed primary producers with significant implications for the global biogeochemical cycles of carbon and nitrogen. Diazotrophic cyanobacteria of subsection V (Order Stigonematales) are particularly ubiquitous in photoautotrophic microbial mats of hot springs. The Stigonematal cyanobacterium strain CHP1 isolated from the Porcelana hot spring (Chile) was one of the major contributors of the new nitrogen through nitrogen fixation. Further morphological and genetic characterization verified that the strain CHP1 belongs to Stigonematales, and it formed a separate clade together with other thermophiles of the genera Fischerella and Mastigocladus. Strain CHP1 fixed maximum N2 in the light, independent of the temperature range. At 50 degrees C nifH gene transcripts showed high expression during the light period, whereas the nifH gene expression at 45 degrees C was arrhythmic. The strain displayed a high affinity for nitrate and a low tolerance for high ammonium concentrations, whereas the narB and glnA genes showed higher expression in light and at the beginning of the dark phase. It is proposed that Mastigocladus sp. strain CHP1 would represent a good model for the study of subsection V thermophilic cyanobacteria, and for understanding the adaptations of these photoautotrophic organisms inhabiting microbial mats in hot springs globally. PMID- 28081927 TI - Florid reactive periostitis of the long bone: A case series of seven patients. AB - BACKGROUND: Florid reactive periostitis (FRP) is a rare benign periosteal lesion, which mostly involves the tubular bones of the extremities. FRP of the long bone is especially rare. We here report a case series of long bone FRP and also discuss the differential diagnosis and clinical outcome of our series. PATIENTS AND METHODS: In total, four female and three male patients with long bone FRP and a mean age of 25.1 years were evaluated for this study, from which four upper extremity and three lower extremity FRP lesions were identified. Patients were classified according to the clinical, radiological and pathological manifestations of the lesion. RESULTS: Periosteal reaction and edema around the lesions were observed in all cases. Calcified mass, bone marrow edema and cortical erosion were observed in six out of seven patients. Moreover, two lesions with peripheral mineralization and zoning appearances were observed. Limb rest and anti-inflammatory therapy proved to be sufficient treatment in all cases. The lesions were spontaneously resolved in all cases, leaving a residual exostosis. CONCLUSION: Our report indicates that short bone and long bone FRP could reveal different characteristics in some aspects, including the choice of the therapeutic approach. In spite of the favorable clinical outcome of long bone FRP, its differentiation from more aggressive lesions, especially osteosarcoma and osteomyelitis, should still be taken into consideration. In addition, according to our evidence, the implication of the zonal pattern in differential diagnosis of FRP and myositis ossificans (MO) could be re-evaluated. PMID- 28081926 TI - Asymmetrical vertebral collapse from spinal metastasis in lower thoracic and lumbar spine. AB - OBJECTIVE: The purpose of this study was to investigate the differences between spinal metastasis and osteoporotic compression fractures on plain X-ray images, focusing on asymmetrical vertebral collapse and fracture level. MATERIALS AND METHODS: This study included 180 patients with pathological collapse from spinal metastasis (188 vertebrae) who were treated at our institution and 70 patients (92 vertebrae) with osteoporotic compression fractures. Anteroposterior X-ray images of the lower thoracic and lumbar spine were evaluated for asymmetrical collapse deformity. RESULTS: Asymmetrical collapse was found in 134 vertebrae (71.3%) with metastasis, and in 20 osteoporotic vertebrae (21.7%); this difference was significant (p < 0.0001). The asymmetrical collapse angle in spinal metastasis patients ranged from 0 to 18 degrees , with a mean of 7.0 and a standard deviation (SD) of 4.5. In contrast, the asymmetrical collapse angle in patients with osteoporotic fractures ranged from 0 to 13 degrees , with a mean of 3.1 and a SD of 2.8. The difference in collapse angle between the two groups was statistically significant (p < 0.001). The cutoff value to suspect spinal metastasis was determined to be 5 degrees or more (sensitivity 0.67, specificity 0.74). Fracture at Th10 or below L3 was found in 20.2% of spinal metastasis patients; only 3% of osteoporotic fractures occurred at these levels. CONCLUSION: Asymmetrical collapse with an angle of 5 degrees or more and fractures at atypical levels on plain radiographs can be useful clues to spinal metastasis. PMID- 28081928 TI - Relationship between clinical symptoms of osteoporotic vertebral fracture with intravertebral cleft and radiographic findings. AB - BACKGROUND: With aging of the population, the numbers of osteoporotic vertebral fractures with intravertebral cleft have been increasing. However, the details of clinical symptoms of osteoporotic vertebral fractures with intravertebral cleft are poorly understood. The purpose of this study was to evaluate the relationship between clinical symptoms of osteoporotic vertebral fractures with intravertebral cleft and radiographic findings. METHODS: Two hundred seventeen patients with single-level osteoporotic vertebral fractures with intravertebral cleft were examined. Clinical symptoms were evaluated using Numerical Rating Scale for back pain and the Oswestry Disability Index for physical disability. The presence of delayed neurologic deficit was also detected. Radiography and computed tomography were used to measure local kyphotic angle and vertebral instability and to detect the presence of posterior wall fracture of the vertebral body. Correlations between clinical symptoms of osteoporotic vertebral fractures with intravertebral cleft and radiographic findings were investigated. RESULTS: Mean Numerical Rating Scale and Oswestry Disability Index were 7.4 and 58.0%, respectively. Delayed neurologic deficit occurred in 41 patients (19%). The mean local kyphotic angle, vertebral instability, and rate of posterior wall fracture of the vertebral body were 19.4 degrees , 7.3 degrees , and 91%, respectively. Numerical Rating Scale and Oswestry Disability Index were statistically correlated with vertebral instability but not with local kyphotic angle and presence of posterior wall fracture. In the patients with delayed neurologic deficit, vertebral instability was significantly higher and posterior wall fractures were significantly more frequent than in the patients without delayed neurologic deficit. Local kyphotic angle was not correlated with delayed neurologic deficit. CONCLUSIONS: Vertebral instability is a factor causing symptoms of osteoporotic vertebral fractures with intravertebral cleft. In addition, vertebral instability may be the predominant cause of delayed neurologic deficit. To manage osteoporotic vertebral fractures with intravertebral cleft and delayed neurologic deficit efficiently, it may be important to control vertebral instability of osteoporotic vertebral fractures. PMID- 28081929 TI - Human knee joint sound during the Lachman test: Comparison between healthy and anterior cruciate ligament-deficient knees. AB - BACKGROUND: The Lachman test is clinically considered to be a reliable physical examination for anterior cruciate ligament (ACL) deficiency. However, the test involves subjective judgement of differences in tibial translation and endpoint quality. An auscultation system has been developed to allow assessment of the Lachman test. The knee joint sound during the Lachman test was analyzed using fast Fourier transformation. The purpose of the present study was to quantitatively evaluate knee joint sounds in healthy and ACL-deficient human knees. METHODS: Sixty healthy volunteers and 24 patients with ACL injury were examined. The Lachman test with joint auscultation was evaluated using a microphone. Knee joint sound during the Lachman test (Lachman sound) was analyzed by fast Fourier transformation. As quantitative indices of the Lachman sound, the peak sound (Lachman peak sound) as the maximum relative amplitude (acoustic pressure) and its frequency were used. RESULTS: In healthy volunteers, the mean Lachman peak sound of intact knees was 100.6 Hz in frequency and -45 dB in acoustic pressure. Moreover, a sex difference was found in the frequency of the Lachman peak sound. In patients with ACL injury, the frequency of the Lachman peak sound of the ACL-deficient knees was widely dispersed. In the ACL-deficient knees, the mean Lachman peak sound was 306.8 Hz in frequency and -63.1 dB in acoustic pressure. If the reference range was set at the frequency of the healthy volunteer Lachman peak sound, the sensitivity, specificity, positive predictive value, and negative predictive value were 83.3%, 95.6%, 95.2%, and 85.2%, respectively. CONCLUSION: Knee joint auscultation during the Lachman test was capable of judging ACL deficiency on the basis of objective data. In particular, the frequency of the Lachman peak sound was able to assess ACL condition. PMID- 28081930 TI - Management of foot deformity in children. AB - This study describes the management of foot deformity in children. Severe congenital clubfeet treated using posteromedial release without talocalcaneal joint release were flexible and functional. Talectomy may be necessary for congenital clubfeet with arthrogryposis multiplex congenita. The diagnosis and severity of vertical talus were defined based on stress radiographs. For the deformity with spina bifida, a combination of talocalcaneal joint fusion and precise correction by soft tissue release and tendon transfer was performed. This combined surgery is effective, particularly in patients with equino-varus feet. PMID- 28081931 TI - Neurogenin-2-transduced human neural progenitor cells attenuate neonatal hypoxic ischemic brain injury. AB - Neonatal hypoxic-ischemic (HI) brain injury leads to high mortality and neurodevelopmental disabilities. Multipotent neural progenitor cells (NPCs) with self-renewing capacity have the potential to reduce neuronal loss and improve the compromised environment in the HI brain injury. However, the therapeutic efficacy of neuronal-committed progenitor cells and the underlying mechanisms of recovery are not yet fully understood. Therefore, this study investigated the regenerative ability and action mechanisms of neuronally committed human NPCs (hNPCs) transduced with neurogenin-2 (NEUROG2) in neonatal HI brain injury. NEUROG2- or green fluorescent protein (GFP)-encoding adenoviral vector-transduced hNPCs (NEUROG2- or GFP-NPCs) were transplanted into neonatal mouse brains with HI injury. Grafted NEUROG2-NPCs showed robust dispersion and engraftment, prolonged survival, and neuronal differentiation in HI brain injury. NEUROG2-NPCs significantly improved neurological behaviors, decreased cellular apoptosis, and increased the neurite outgrowth and axonal sprouting in HI brain injury. In contrast, GFP-NPC grafts moderately enhanced axonal extension with limited behavioral recovery. Notably, NEUROG2-NPCs showed increased secretion of multiple factors, such as nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 (NTF3), fibroblast growth factor 9 (FGF9), ciliary neurotrophic factor (CNTF), and thrombospondins 1 and 2 (THBS 1/2), which promoted SH-SY5Y neuroblastoma cell survival and neurite outgrowth. Thus, we postulate that NEUROG2-expressing human NPCs facilitate functional recovery after neonatal HI brain injury via their ability to secrete multiple factors that enhance neuronal survival and neuroplasticity. PMID- 28081932 TI - Pediatric Traumatic Brain Injury: Families and Healthcare Team Interaction Trajectories During Acute Hospitalization. AB - PURPOSE: To identify common or unique family-healthcare team interactions during acute hospitalization for pediatric patients with a traumatic brain injury (TBI) using a life course trajectory (LCT) theoretical approach. DESIGN AND METHODS: A 3-year prospective observational study of 35 children, ages 5 days to 15 years who were admitted to an urban Level-1 trauma hospital for a TBI. We defined brain injury severity using the admission Glasgow Coma Scale score (mild 13-15, moderate 9-12, and severe 3-8). Using a life course trajectory theoretical approach, we extracted from the patient's electronic health record the first eight-days of hospitalization and plotted the number and type of daily family healthcare team interactions to visualize patterns or phases. RESULTS: A general trajectory for each severity group was determined. When individually compared, family trajectories were similar based on injury severity. Visual interpretations of family-healthcare interactions based on the brain injury severity yielded three phases. The interactions phases included: (1) information seeking, (2) watchful waiting and (3) decision making. CONCLUSION: Using a LCT approach, phases identified based on injury severity and family interactions support the need for proper timing of tailored communication and support. The findings also support the development of future best care practices that facilitate family's needs, decrease caregiver burden to improve functional outcomes. PMID- 28081934 TI - Safety Culture in Neonatal Intensive Care Units in the Gaza Strip, Palestine: A Need for Policy Change. AB - INTRODUCTION: Assessment of the prevailing safety culture within the Gazan health care system can be used to identify problem areas. Specifically, the need for improvements, raising awareness about patient safety, the identification and evaluation of existing safety programs and interventions for improving the safety culture. This study aims to assess the safety culture in the neonatal intensive care units (NICUs) in Gaza Strip hospitals and to assess the safety culture in regards to caregivers' characteristics. METHODS: In a cross-sectional study using a census sample, we surveyed all nurses and physicians working in at all the NICUs in the Gaza Strip, Palestine. The Safety Attitudes Questionnaire (SAQ) which includes six scales was used to assess participants' attitudes towards safety culture. RESULTS: The overall score for SAQ was 63.9. Domains' scores ranged between 55.5 (perception of management) and 71.8 (stress recognition). The scores reported by our participants fell below the 75 out of a possible score of 100, which was considered as a cut-off point for a positive score. Moreover, our results revealed substantial variation in safety culture domain scores among participating NICUs. CONCLUSION: These results should be an indicator to our health care policy makers to modify current or adopt new health care policies to improve safety culture. It should also be a call to design customized programs for improving the safety culture in NICUs in the Gaza Strip. PMID- 28081933 TI - Intention of Mothers in Israel to Vaccinate their Sons against the Human Papilloma Virus. AB - PURPOSE: This study investigated the intention of mothers in Israel to vaccinate their sons against HPV, using the Health Belief Model (HBM) as a framework, while comparing between Arab and Jewish mothers. DESIGN AND METHODS: The study has a quantitative cross-sectional design. A convenience sample of 200 Jewish and Arab mothers of boys aged 5-18 completed a questionnaire based on the HBM. RESULTS: The research findings indicate that only 14% of the mothers, constituting mostly Arab mothers, vaccinated their sons against HPV. Moreover, mothers showed a moderate level of intention to vaccinate their sons. This level was similar among Arab and Jewish mothers. However, the health beliefs of Jewish and Arab mothers differed. The HBM was found to explain 68% of mothers' intention to vaccinate their sons against HPV, and the perceived benefits of the vaccine were the factor most affecting this intention. CONCLUSIONS: Although mothers' health beliefs concerning vaccinating their sons against HPV may vary between sectors, the HBM can be used to explain what motivates mothers to vaccinate their sons. PRACTICE IMPLICATIONS: The research findings can assist in designing a national project among mothers of boys aimed at raising HPV vaccination rates, in both the Jewish and the Arab sector. PMID- 28081935 TI - Chloride on the Move. AB - Chloride (Cl-) is an essential plant nutrient but under saline conditions it can accumulate to toxic levels in leaves; limiting this accumulation improves the salt tolerance of some crops. The rate-limiting step for this process - the transfer of Cl- from root symplast to xylem apoplast, which can antagonize delivery of the macronutrient nitrate (NO3-) to shoots - is regulated by abscisic acid (ABA) and is multigenic. Until recently the molecular mechanisms underpinning this salt-tolerance trait were poorly defined. We discuss here how recent advances highlight the role of newly identified transport proteins, some that directly transfer Cl- into the xylem, and others that act on endomembranes in 'gatekeeper' cell types in the root stele to control root-to-shoot delivery of Cl-. PMID- 28081936 TI - Quadrupolar solid-state NMR and repetitive experiments: Some aspects in the Liouville space. Application to spins I=1. AB - The aim of this work is to generalize the Ernst-Anderson model developed to account of the steady-state regime of isolated spins I=1/2 subject to a train of strictly identical pulse sequences separated by free evolution periods of same duration. We generalize this model to the general case of spins I>=1 and general pulse sequence within the framework of the Liouville space. In particular, it is proved that under reasonable assumptions, a well defined steady-state regime is reached which is independent of the initial conditions. The general formal expressions obeyed by the steady-state density operator are given as a function of pulse propagators and relaxation operator for single and two-pulse sequences. In solid-state NMR where recycle time can be made, at the same time, much longer than typical coherence relaxation times and smaller than typical population relaxation times, further simplification leads to more tractable formula. As an example, the formalism is applied to I=1 spins with hard and soft single pulse sequence, or to the solid echo sequence. In particular, we were able to generalize the Ernst-Anderson formula to spins I=1. The pertinence of the theory is verified by comparing the theoretical and numerical simulations outputs to 2H single crystal experiments performed on nonadecane/urea C19D40/urea-H4 compound. PMID- 28081937 TI - Self-guided interventions for managing psychological distress in people with cancer - A systematic review. AB - OBJECTIVE: People with cancer can experience psychological distress but do not always desire, or engage with, professional support to assist with managing distress. Interventions that are self-directed or guided by patients may hold promise as they allow patients to engage with interventions as they need. The objective of this review is to describe and appraise the evidence for effectiveness of self-guided interventions that aim to manage psychological distress in people with cancer. METHODS: A systematic search of Medline, PsychInfo and CINAHL identified 15 relevant papers, reporting on 14 studies. RESULTS: Of the interventions, three studies comprised hard-copy workbooks, six studies used resource packs, four were online resources and one was a brief multimedia resource. One study was adequately powered and demonstrated a positive effect. Almost all interventions required some level of facilitation. Distressed participants may benefit more from interventions. CONCLUSION: Self-guided interventions represent a potentially efficient way of delivering support for people affected by cancer, however evidence supporting them is lacking. PRACTICE IMPLICATIONS: There is a need to generate evidence to understand the impact of self-guided interventions for: i) the ideal delivery point in the disease trajectory, ii) patient groups, iii) intervention content and iv) type and mode of delivery. PMID- 28081938 TI - Do medical images aid understanding and recall of medical information? An experimental study comparing the experience of viewing no image, a 2D medical image and a 3D medical image alongside a diagnosis. AB - OBJECTIVE: This study compared the experience of viewing 3D medical images, 2D medical images and no image presented alongside a diagnosis. METHODS: We conducted two laboratory experiments, each with 126 healthy participants. Participants heard three diagnoses; one accompanied by 3D medical images, one accompanied by 2D medical images and one with no image. Participants completed a questionnaire after each diagnosis rating their experience. In Experiment 2, half of the participants were informed that image interpretation can be susceptible to errors. RESULTS: Participants preferred to view 3D images alongside a diagnosis (p<0.001) and reported greater understanding (p<0.001), perceived accuracy (p<0.001) and increased trust (p<0.001) when the diagnosis was accompanied by an image compared to no image. There was no significant difference in trust between participants who were informed of errors within image interpretation and those who were not. CONCLUSION: When presented alongside a diagnosis, medical images may aid patient understanding, recall and trust in medical information. PRACTICAL CONSIDERATIONS: Medical images may be a powerful resource for patients that could be utilised by clinicians during consultations. PMID- 28081939 TI - Value of the Definition of Severe Familial Hypercholesterolemia for Stratification of Heterozygous Patients. AB - Familial hypercholesterolemia (FH) is characterized by high low-density lipoprotein (LDL) cholesterol with co-dominant transmission and high risk of cardiovascular disease (CVD), although with high variability among subjects. Currently, CVD stratification tools for heterozygous FH (HeFH) are not available. A definition of severe HeFH has been recently proposed by the International Atherosclerosis Society (IAS), but it has not been validated. Our study aims to see clinical characteristics and prevalence of CVD in subjects defined as severe HeFH by IAS criteria. Probable or definite HeFH introduced in the Dyslipidemia Registry of Spanish Arteriosclerosis Society were analyzed by the IAS criteria. Univariate and multivariate analysis was used to assess the association of CVD with the IAS criteria. About 1,732 HeFH cases were analyzed. Severe HeFH had higher prevalence of familial history of CVD, personal history of tendon xanthomas, LDL cholesterol, and CVD than nonsevere HeFH. A total of 656 (77.1%) and 441 (50.1%) of men and women, respectively, fulfilled the IAS criteria of severe HeFH. In the univariate analysis, subjects defined as severe HeFH showed odds ratio 3.016 (95% CI 3.136 to 4.257, p <0.001) for CVD. However, when traditional risk factors were included in the multivariate analysis, only the presence of cholesterol >400 mg/dl had a statistically significant association with CVD odds ratio 8.76 (95% CI 3.90 to 19.69, p <0.001). In conclusion, the IAS definition of severe HeFH is not significantly associated with CVD when adjusted for classic risk factors. Risk stratification in HeFH is an important issue, but the proposed criteria do not seem to solve this problem. PMID- 28081940 TI - Statins, Ezetimibe, and Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors to Reduce Low-Density Lipoprotein Cholesterol and Cardiovascular Events. AB - Multiple lines of evidence suggest that the physiologically normal levels of low density lipoprotein cholesterol (LDL-C) and the thresholds for development of atherosclerosis and adverse coronary events are in the 30- to 70-mg/dl range. More patients have been studied in randomized controlled trials assessing the effects of statins on outcomes than any other drug class in the history of medicine. This cumulative body of evidence documents that atherosclerosis progression is halted and coronary heart disease events are minimized when statin therapy with or without ezetimibe, and possibly proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors, is used to drive down the LDL-C to a range of about 30 to 50 mg/dl. Thus far, these agents appear to be safe even when LDL-C is lowered to about 50 mg/dl, although more robust outcome and safety data are required, particularly for the PCSK9 inhibitors and very low LDL-C levels (e.g., down to 25 mg/dl). In conclusion, the current national guidelines specifying only the use of a high-potency statin without specific LDL-C goals may lead to substantial undertreatment of high-risk patients, leaving them vulnerable to future adverse cardiovascular events. PMID- 28081941 TI - Comparison of the Incidence of Major Bleeding With Rivaroxaban Use Among Nonvalvular Atrial Fibrillation Patients With Versus Without Diabetes Mellitus. AB - Diabetes mellitus (DM) is a common co-morbidity in those with nonvalvular atrial fibrillation (NVAF). Most patients with DM and NVAF have a CHA2DS2-VASc score of >=1 and should be considered for oral anticoagulation therapy for stroke prevention per treatment guidelines. The most important risk associated with anticoagulation is bleeding, which may be higher in those with NVAF plus DM. Our objective was to evaluate the incidence and characteristics of major bleeding (MB) in rivaroxaban users diagnosed with NVAF, further comparing those with DM versus those without DM, in a real-world clinical setting. Electronic medical records of >10 million patients from the Department of Defense Military Health System were queried to identify rivaroxaban users with NVAF over a 2.5-year period. Major bleeding-related hospitalization was identified by a validated case finding algorithm. Patient characteristics, incidence and management of MB, and fatal outcomes were assessed by DM status. Of 44,793 rivaroxaban users with NVAF, 12,039 (26.9%) had DM, who were more likely men, younger, with more co-morbidity and higher CHA2DS2-VASc scores. Major bleeding incidence was higher among those with DM compared with those without, 3.68 (95% confidence interval [CI] 3.37 to 4.03) versus 2.51 (95% CI 2.34 to 2.69) per 100 person-years, and intracranial bleeding incidence was 0.19 (95% CI 0.13 to 0.28) versus 0.25 (95% CI 0.20 to 0.31) per 100 person-years. Fatal outcomes were rare for both cohorts, 0.09 per 100 person-years. In conclusion, in this post-marketing study of 44,793 rivaroxaban users with NVAF, patients with DM had more co-morbidities and higher incidence of MB compared with those without DM. PMID- 28081942 TI - PTEN: Local and Global Modulation of Neuronal Function in Health and Disease. AB - Phosphatase and tensin homolog deleted on chromosome ten (PTEN) was recently revealed to be a synaptic player during plasticity events in addition to its well established role as a general controlling factor in cell proliferation and neuronal growth during development. Alterations of these direct actions of PTEN at synapses may lead to synaptic dysfunction with behavioral and cognitive consequences. A recent paradigmatic example of this situation, Alzheimer's disease (AD), is associated with excessive recruitment of PTEN into synapses leading to pathological synaptic depression. By contrast, some forms of autism are characterized by failure to weaken synaptic connections, which may be related to insufficient PTEN signaling. Understanding the modulation of synaptic function by PTEN in these pathologies may contribute to the development of new therapies. PMID- 28081943 TI - Capturing the Moment of Fusion Loss in Intermittent Exotropia. AB - PURPOSE: To characterize eye movements made by patients with intermittent exotropia when fusion loss occurs spontaneously and to compare them with those induced by covering 1 eye and with strategies used to recover fusion. DESIGN: Prospective study of a patient cohort referred to our laboratory. PARTICIPANTS: Thirteen patients with typical findings of intermittent exotropia who experienced frequent spontaneous loss of fusion. METHODS: The position of each eye was recorded with a video eye tracker under infrared illumination while fixating on a small central near target. MAIN OUTCOME MEASURES: Eye position and peak velocity measured during spontaneous loss of fusion, shutter-induced loss of fusion, and recovery of fusion. RESULTS: In 10 of 13 subjects, the eye movement made after spontaneous loss of fusion was indistinguishable from that induced by covering 1 eye. It reached 90% of full amplitude in a mean of 1.75 seconds. Peak velocity of the deviating eye's movement was highly correlated for spontaneous and shutter induced events. Peak velocity was also proportional to exotropia amplitude. Recovery of fusion was more rapid than loss of fusion, and often was accompanied by interjection of a disconjugate saccade. CONCLUSIONS: Loss of fusion in intermittent exotropia is not influenced by visual feedback. Excessive divergence tone may be responsible, but breakdown of alignment occurs via a unique, pathological type of eye movement that differs from a normal, physiological divergence eye movement. PMID- 28081944 TI - Early Experience with Technology-Based Eye Care Services (TECS): A Novel Ophthalmologic Telemedicine Initiative. AB - PURPOSE: The aging population is at risk of common eye diseases, and routine eye examinations are recommended to prevent visual impairment. Unfortunately, patients are less likely to seek care as they age, which may be the result of significant travel and time burdens associated with going to an eye clinic in person. A new method of eye-care delivery that mitigates distance barriers and improves access was developed to improve screening for potentially blinding conditions. We present the quality data from the early experience (first 13 months) of Technology-Based Eye Care Services (TECS), a novel ophthalmologic telemedicine program. DESIGN: With TECS, a trained ophthalmology technician is stationed in a primary care clinic away from the main hospital. The ophthalmology technician follows a detailed protocol that collects information about the patient's eyes. The information then is interpreted remotely. Patients with possible abnormal findings are scheduled for a face-to-face examination in the eye clinic. PARTICIPANTS: Any patient with no known ocular disease who desires a routine eye screening examination is eligible. METHODS: Technology-Based Eye Care Services was established in 5 primary care clinics in Georgia surrounding the Atlanta Veterans Affairs hospital. MAIN OUTCOME MEASURES: Four program operation metrics (patient satisfaction, eyeglass remakes, disease detection, and visit length) and 2 access-to-care metrics (appointment wait time and no-show rate) were tracked. RESULTS: Care was rendered to 2690 patients over the first 13 months of TECS. The program has been met with high patient satisfaction (4.95 of 5). Eyeglass remake rate was 0.59%. Abnormal findings were noted in 36.8% of patients and there was >90% agreement between the TECS reading and the face-to face findings of the physician. TECS saved both patient (25% less) and physician time (50% less), and access to care substantially improved with 99% of patients seen within 14 days of contacting the eye clinic, with a TECS no-show rate of 5.2%. CONCLUSIONS: The early experience with TECS has been promising. Tele ophthalmology has the potential to improve operational efficiency, reduce cost, and significantly improve access to care. Although further study is necessary, TECS shows potential to help prevent avoidable vision loss. PMID- 28081945 TI - Long-term Effects of Intravitreal 0.19 mg Fluocinolone Acetonide Implant on Progression and Regression of Diabetic Retinopathy. AB - OBJECTIVE: To investigate the effects of fluocinolone acetonide (FAc) on the progression to proliferative diabetic retinopathy (PDR) and the impact of FAc on changes in Early Treatment Diabetic Retinopathy Study (ETDRS) diabetic retinopathy (DR) severity scale (DRSS) grade during the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) A and B Phase III clinical trials. DESIGN: Post hoc analysis of data from the 36-month prospective, randomized, FAME A and B trials. PARTICIPANTS: Patients with diabetic macular edema (DME) who received sham control or FAc 0.2 or 0.5 MUg/day. METHODS: A masked reading center (University of Wisconsin-Madison) determined DRSS grade and retinal perfusion status using standard 7-field stereo fundus photography and fluorescein angiography, respectively. Retinopathy changes over time were determined by DRSS step differences from baseline to month 36. Pairwise comparisons between the 3 treatment groups were performed using a log-rank test without adjustment for covariates, with the primary comparison between sham control and 0.2 MUg/day FAc. MAIN OUTCOME MEASURES: Study eye progression to PDR based on a composite clinical outcome of (1) progression from nonproliferative diabetic retinopathy (NPDR) to PDR based on graded fundus photographs, (2) panretinal photocoagulation (PRP), or (3) pars plana vitrectomy (PPV) for PDR; and study eye changes on the DRSS. RESULTS: In the integrated FAME data set, compared with sham control-treated subjects, time to first PDR event was significantly delayed in subjects treated with FAc (P < 0.001), and this effect was confirmed in subgroups with more severe DR and chronic DME at baseline. In addition, subjects with retinal nonperfusion at baseline showed greater reduction in progression to PDR with FAc treatment. Both FAc dosages demonstrated statistically significant improvements in mean DR severity compared with sham treatment at months 6, 12, and 18. Numerically more subjects who received FAc experienced 2-or-more- or 3-or-more-step improvements in DR severity compared with subjects who received sham; conversely, fewer subjects treated with FAc experienced 2-or-more- or 3-or-more-step worsening in DR severity. The 3-or-more-step improvement with 0.5 MUg/day FAc was statistically significantly different from sham control. CONCLUSIONS: In subjects with DME, sustained intraocular delivery of FAc slows development of PDR and slows progression of diabetic retinopathy. PMID- 28081946 TI - [Hepatocellular carcinoma surveillance]. AB - Hepatocellular carcinoma related mortality is one of the highest among all cancers. Ninety percent of all hepatocellular carcinoma develop in the context of liver cirrhosis. Liver cirrhosis is not recognized prior to the diagnosis of hepatocellular carcinoma in 25 % of the cases, despite the existence of risk factors. Hepatocellular carcinoma is diagnosed within a surveillance program in less than 25 % of the cases. Ultrasound screening for hepatocellular carcinoma every 6 months increases chances to diagnose HCC at an early stage amenable to curative treatment, and increases survival. Interval greater than 7months between ultrasound imaging has a significant negative impact on survival. All patients diagnosed with cirrhosis have to perform an ultrasound screening for hepatocellular carcinoma and comply with the six months rule. PMID- 28081947 TI - The effects of DPP-4 inhibitor on hypoxia-induced apoptosis in human umbilical vein endothelial cells. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of oral hypoglycemic agents for patients with type 2 diabetes mellitus and have potential antiatherosclerotic properties. Meanwhile, it is unclear how DPP-4 inhibitors have protective effects on atherosclerosis. Our aim was to determine the effects and its mechanisms of DPP-4 inhibitors on cultured endothelial cells. Human umbilical vein endothelial cells (HUVECs) were cultured in hypoxic condition. To evaluate the protective effects of DPP-4 inhibitor on HUVECs, DPP-4 inhibitor was added in the cell culture medium and the cell viability was assessed by TUNEL assay. And we examined the intracellular signaling pathways in relation to the effects of DPP-4 inhibitor. DPP-4 inhibition had beneficial effects by inhibiting the apoptosis under hypoxic conditions in HUVECs. The antiapoptotic effects of DPP-4 inhibitor were abolished by the pretreatment with a CXCR4 antagonist or a Stat3 inhibitor. DPP-4 inhibition has beneficial effects on HUVECs by inhibiting the apoptosis under hypoxic conditions. SDF-1alpha/CXCR4/Stat3 pathways might be involved in the mechanisms of the cytoprotective effects of DPP-4 inhibitor. These results suggested that DPP-4 inhibitor has a potential for protecting vessels. PMID- 28081948 TI - High glucose induces N-linked glycosylation-mediated functional upregulation and overexpression of Cav3.2 T-type calcium channels in neuroendocrine-like differentiated human prostate cancer cells. AB - Given that Cav3.2 T-type Ca2+ channels were functionally regulated by asparagine (N)-linked glycosylation, we examined effects of high glucose on the function of Cav3.2, known to regulate secretory function, in neuroendocrine-like differentiated prostate cancer LNCaP cells. High glucose accelerated the increased channel function and overexpression of Cav3.2 during neuroendocrine differentiation, the former prevented by enzymatic inhibition of N-glycosylation and cleavage of N-glycans. Hyperglycemia thus appears to induce N-linked glycosylation-mediated functional upregulation and overexpression of Cav3.2 in neuroendocrine-like differentiated prostate cancer cells. PMID- 28081949 TI - Myocardial fibrosis detected with Gadolinium Delayed Enhancement in Cardiac Magnetic Resonance Imaging and Ventriculoarterial Coupling alterations in patients with Acute Myocarditis. AB - BACKGROUND: The delayed Gadolinium Myocardium Enhancement (DGE) extent on Cardiac Magnetic Resonance (CMR) correlates with biomarkers of myocardial injury in patients with acute viral myocarditis and is an independent predictor of adverse cardiovascular outcome. Ventriculoarterial Coupling (VAC) is related to both the cardiovascular work output and energy efficiency and can be noninvasively assessed. In this work, we aimed to evaluate alterations in VAC indices in correlation with DGE in patients with acute myocarditis. METHODS: Fifty-seven patients (mean age 42 (18) years old, 58% male, 19% had hypertension, 9% coronary artery disease and 2% diabetes mellitus) with diagnosed acute myocarditis were enrolled. All patients underwent comprehensive echocardiographic evaluation with a VAC value calculation and CMR imaging within a 24-hour period. RESULTS: The mean ejection fraction was 42+/-18%; 49% had preserved systolic function. DGE was noted in 56% of patients. When stratified by EF (preserved or reduced), those with an EF>50% had significantly smaller ventricles and a lower VAC, closer to the values that maximize the stroke work and energy efficiency (p=0.002 for end diastolic diameters, 0.001 for VAC, 0.01 for distance from 0.7 and 0.5 and 0.056 for distance from 1). No difference in DGE prevalence was noted (p=0.34). DGE based stratification did not reveal any difference in the EF or VAC values between groups. Multi-adjusted regression analysis showed that EF was a significant predictor of VAC alterations. CONCLUSION: In acute myocarditis patients, DGE is related to neither EF nor VAC; however, EF significantly affects the VAC status. Further studies are needed to investigate the potential quantitative, rather than qualitative, relationships between these variables. PMID- 28081950 TI - Department of Error. PMID- 28081951 TI - Intracerebral haemorrhage: no good treatment but treatment helps. PMID- 28081952 TI - Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial. AB - BACKGROUND: Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. METHODS: In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0.9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. FINDINGS: Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1.06 [95% CI 0.88-1.28; p=0.554]). A difference of 3.5% (RR 1.08 [95% CI 0.90-1.29], p=0.420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0.60 [95% CI 0.41-0.86], p=0.006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1.99 [95% CI 1.22-3.26], p=0.007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0.55 [95% CI 0.31-0.97], p=0.048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0.76 [95% CI 0.64-0.90], p=0.002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1.21 [95% CI 0.37-3.91], p=0.771) was similar. INTERPRETATION: In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status. FUNDING: National Institute of Neurological Disorders and Stroke. PMID- 28081954 TI - Proton beam radiation as salvage therapy for bilateral colorectal liver metastases not amenable to second-stage hepatectomy. AB - BACKGROUND: Bilobar colorectal liver metastases (CRLM), are now aggressively managed in a multidisciplinary fashion with a two-stage hepatectomy; however, up to 30% of patients are not candidates for second stage hepatectomy. In this report, we describe a novel technique of delivering ablative radiation to the entire right hemiliver by using proton therapy in a series of patients. METHODS: A data base of patients undergoing entire right hemiliver ablative radiation was maintained prospectively. Clinical, pathologic and treatment characteristics were collected for these patients. Survival duration was calculated from end of radiation. Radiation was delivered with proton therapy using deep inspiratory breath hold (DIBH) and a phase contrast simulation CT scan. RESULTS: All five patients tolerated radiation treatment well. All four patients treated with biologic equivalent dose (BED) >89.6 Gy achieved partial or complete radiographic response and in-field local control at last follow up. Two patients are alive and without evidence of disease. Two patients experienced disease progression outside of the liver. CONCLUSION: These results suggest that the use of stereotactic proton therapy as a salvage therapy for patients with CRLM not amenable to second stage hepatectomy may achieve good local control and permit an opportunity for long term survival. PMID- 28081953 TI - Neoadjuvant chemotherapy does not affect future liver remnant growth and outcomes of associating liver partition and portal vein ligation for staged hepatectomy. AB - BACKGROUND: The only potentially curative treatment for patients with colorectal liver metastases is hepatectomy. Associating liver partition and portal vein ligation for staged hepatectomy has emerged as a method of treatment for patients with inadequate future liver remnant. One concern about associating liver partition and portal vein ligation for staged hepatectomy is that preoperative chemotherapy may negatively affect the volume increase of the future liver remnant and outcomes. METHODS: This study from the International Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy Registry (NCT01924741) includes 442 patients with colorectal liver metastases registered from 2012-2016. Future liver remnant hypertrophy (absolute increase, percent increase, and kinetic growth rate) and clinical outcome were analyzed retrospectively in relation to type and amount of chemotherapy. The analyzed groups included patients with no chemotherapy, 1 regimen of chemotherapy, >1 regimen, and a group that received monoclonal antibodies in addition to chemotherapy. RESULTS: Ninety percent of the patients received neoadjuvant oncologic therapy including 42% with 1 regimen of chemotherapy, 44% with monoclonal antibodies, and 4% with >1 regimen. Future liver remnant increased between 74-92% with the largest increase in the group with 1 regimen of chemotherapy. The increase in milliliters was between 241 mL (>1 regimen) and 306 mL (1 regimen). Kinetic growth rate was between 14-18% per week and was greatest for the group with 1 regimen of chemotherapy. No statistical significance was found between the groups with any of the measurements of future liver remnant hypertrophy. CONCLUSION: Neoadjuvant chemotherapy, including monoclonal antibodies, does not negatively affect future liver remnant growth. Patients with colorectal liver metastases who might be potential candidates for associating liver partition and portal vein ligation for staged hepatectomy should be considered for neoadjuvant chemotherapy. PMID- 28081955 TI - Generation of patient-derived xenografts from fine needle aspirates or core needle biopsy. AB - BACKGROUND: Patient-derived xenografts have recently become a powerful tool for cancer research and may be used to guide personalized therapy. Thus far, patient derived xenografts have been grown from tumor tissue obtained after operative resection; however, many cancer patients never undergo operative intervention for a variety of reasons. We hypothesized that xenograft tumors could be grown from smaller volumes of patient tissue, such as those obtained during diagnostic biopsies. METHODS: Surgical specimens were obtained after resection of primary or metastatic lesions of the following cancers: pancreatic carcinoma, non-small cell lung cancer, bladder (urothelial) carcinoma, and melanoma. At least 10 cases of each cancer were included in this study. To mimic clinical biopsies, small fragments of the surgical specimens were biopsied with a 22-gauge needle, and the needle contents were injected subcutaneously in immunocompromised mice. The tumor fragment from which the biopsy was taken was also implanted subcutaneously in the contralateral side of the same mouse as a control. RESULTS: Success rates of the traditional method of xenograft implantation ranged from 27.3%-70%. Success rates of the fine needle aspirate technique ranged from 0%-36.4%. An attempt to engraft a percutaneous core needle liver biopsy of a metastatic pancreatic adenocarcinoma also was successful. CONCLUSION: We have found that it is possible to engraft fine needle aspirates and core biopsies of solid tumors in order to generate patient-derived xenografts. This may open up xenografting to a wider cancer patient population than previously possible. PMID- 28081956 TI - Predatory Bacteria: Moving from Curiosity Towards Curative. AB - In a world where infection-causing, pathogenic bacteria are evolving resistance to conventional antibiotics, new solutions are needed. One proposal is the use of predatory bacteria as living antibiotics. Two new papers show that predators are not harmful and can kill pathogens inside live animals, a very positive step forward. PMID- 28081957 TI - Systematic review of hyperbaric oxygen therapy for the treatment of radiation induced skin necrosis. AB - Every year, 1.2 million cancer patients receive radiation therapy in the United States. Late radiation tissue injury occurs in an estimated 5-15% of these patients. Tissue injury can include skin necrosis, which can lead to chronic nonhealing wounds. Despite many treatments available to help heal skin necrosis such as hyperbaric oxygen therapy, no clinical guidelines exist and evidence is lacking. The purpose of this review is to identify and comprehensively summarize studies published to date to evaluate the effectiveness of hyperbaric oxygen therapy for the treatment of radiation-induced skin necrosis. Adhering to PRISMA guidelines, a systematic review of currently published articles was performed, evaluating the use of hyperbaric oxygen to treat skin necrosis. Eight articles were identified, including one observational cohort, five case series, and two case reports. The articles describe changes in symptoms and alteration in wound healing of radiation-induced skin necrosis after treatment with hyperbaric oxygen therapy. Hyperbaric oxygen therapy is a safe intervention with promising outcomes; however, additional evidence is needed to endorse its application as a relevant therapy in the treatment of radiation-induced skin necrosis. PMID- 28081958 TI - Texas and Louisiana coastal vulnerability and shelf connectivity. AB - A numerical study of connectivity between the continental shelf and coast in the northwestern Gulf of Mexico using a circulation model and surface-limited numerical drifters shows that despite seasonal changes in winds, the overall connectivity of the shelf with the coastline is similar in the winter and summer, though it extends more offshore in Texas in summer. However, there is a spatial pattern to the connectivity: more of the inner shelf is connected with the coast in Texas as compared with Louisiana. Subsets of the coast do have seasonal variability: the coast near both Galveston and Port Aransas has more connectivity from upcoast in the winter and from offshore and downcoast in the summer. In both seasons, we find drifters reach the Port Aransas coast most frequently, with a stronger trend in the summer. These results are important for assessing likely pathways for spilled oil and other potentially hazardous material. PMID- 28081959 TI - Trace element accumulation and elutriate toxicity in surface sediment in northern Tunisia (Tunis Gulf, southern Mediterranean). AB - Metal concentrations in sediments were investigated in the Gulf of Tunis, Tunisia, in relation to anthropic activities along the Mejerda River and Ghar El Melh Lagoon, with effluents discharged into the gulf. Distribution of grain size showed that the silty fraction is dominant with 53%, while sand and clay averages are 34 and 12% respectively. Zn concentration increased in the vicinity of the Mejerda River while Pb was at its highest levels at the outlet of Ghar El Mehl Lagoon. Sediment elutriate toxicity, as measured by oyster embryo bioassays, ranged from 10 to 45% abnormalities after 24h, but no relation was found between metal concentration and sediment toxicity. The AVS fraction that represents monosulfide concentrations in the sediment was higher in the central part of the gulf than in the coastal zone. The results reveal the influence of AVS, TOC and grain size on metal speciation and sediment toxicity. PMID- 28081960 TI - Determination of radioactivity levels and heavy metal concentrations in seawater, sediment and anchovy (Engraulis encrasicolus) from the Black Sea in Rize, Turkey. AB - Seawater, sediment and fish (anchovy) samples consumed in the Rize province of the Eastern Black Sea region of Turkey were collected from five different stations. The radioactivity levels (226Ra, 232Th, 40K and 137Cs) were determined in all the samples using a high-purity germanium detector. While 226Ra, 232Th and 40K radionuclides were detected in all samples, the radionuclide concentration of 137Cs, except for the sediment samples (mean activity is 9+/-1.4Bqkg-1), was not detected for the seawater and fish samples. The total annual effective dose rates from the ingestion of these radionuclides for fish were calculated using the measured activity concentrations in radionuclides and their ingested dose conversion factor. Also, the concentrations of some heavy metals in all the samples were determined. The activity and heavy metal concentration values that were determined for the seawater, sediment and fish samples were compared among the locations themselves and with literature values. PMID- 28081961 TI - Environmental factors in breast cancer invasion: a mathematical modelling review. AB - This review presents a brief overview of breast cancer, focussing on its heterogeneity and the role of mathematical modelling and simulation in teasing apart the underlying biophysical processes. Following a brief overview of the main known pathophysiological features of ductal carcinoma, attention is paid to differential equation-based models (both deterministic and stochastic), agent based modelling, multi-scale modelling, lattice-based models and image-driven modelling. A number of vignettes are presented where these modelling approaches have elucidated novel aspects of breast cancer dynamics, and we conclude by offering some perspectives on the role mathematical modelling can play in understanding breast cancer development, invasion and treatment therapies. PMID- 28081962 TI - Quality of Life Analysis in Patients With RAS Wild-Type Metastatic Colorectal Cancer Treated With First-Line Cetuximab Plus Chemotherapy. AB - BACKGROUND: Adding cetuximab to FOLFIRI (5-fluorouracil, leucovorin, irinotecan) significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in patients with KRAS or RAS (KRAS/NRAS, exons 2-4) wild-type (wt) metastatic colorectal cancer (mCRC) in the first-line CRYSTAL study. The present exploratory and descriptive retrospective analysis assessed the quality of life (QoL) of CRYSTAL study patients with RAS wt mCRC-the labeled indication for cetuximab in many countries. PATIENTS AND METHODS: Patient QoL was investigated using the European Organisation for Research and Treatment of Cancer QoL questionnaire core-30 (EORTC QLQ-C30). QoL assessments were performed at baseline, after every 8 weeks of treatment, and at the final tumor assessment. RAS wt patients were considered evaluable for QoL if they had provided >= 1 evaluable EORTC QLQ-C30. RESULTS: Of the 367 patients with RAS wt tumors, 351 were evaluable for QoL. Global health status (GHS)/QoL and the time to worsening of Eastern Cooperative Oncology Group performance status were similar between the treatment groups. However, the analysis was complicated by a large decrease in the number of evaluable patients in the FOLFIRI arm between weeks 32 and 40. The individual dimensions of interest in mCRC (eg, social functioning, fatigue, nausea/vomiting, pain, appetite loss, constipation, diarrhea, and functional difficulties) were also similar between the treatment arms. Changes in GHS/QoL and social functioning from baseline to week 8 were similar, irrespective of whether patients experienced early skin reactions. CONCLUSION: The findings of the present descriptive retrospective analysis suggest that adding cetuximab to first-line FOLFIRI improves PFS, OS, and ORR without negatively affecting the QoL of CRYSTAL study patients with RAS wt mCRC. PMID- 28081964 TI - Interventions to reduce inappropriate polypharmacy: Implications for research and practice. PMID- 28081963 TI - Rapid neuroinflammatory response localized to injured neurons after diffuse traumatic brain injury in swine. AB - Despite increasing appreciation of the critical role that neuroinflammatory pathways play in brain injury and neurodegeneration, little is known about acute microglial reactivity following diffuse traumatic brain injury (TBI) - the most common clinical presentation that includes all concussions. Therefore, we investigated acute microglial reactivity using a porcine model of closed-head rotational velocity/acceleration-induced TBI that closely mimics the biomechanical etiology of inertial TBI in humans. We observed rapid microglial reactivity within 15min of both mild and severe TBI. Strikingly, microglial activation was restrained to regions proximal to individual injured neurons - as denoted by trauma-induced plasma membrane disruption - which served as epicenters of acute reactivity. Single-cell quantitative analysis showed that in areas free of traumatically permeabilized neurons, microglial density and morphology were similar between sham or following mild or severe TBI. However, microglia density increased and morphology shifted to become more reactive in proximity to injured neurons. Microglial reactivity around injured neurons was exacerbated following repetitive TBI, suggesting further amplification of acute neuroinflammatory responses. These results indicate that neuronal trauma rapidly activates microglia in a highly localized manner, and suggest that activated microglia may rapidly influence neuronal stability and/or pathophysiology after diffuse TBI. PMID- 28081965 TI - 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation: A Report of the American College of Cardiology Clinical Expert Consensus Document Task Force. PMID- 28081966 TI - NPY up-regulation in the tadpole brain of Euphlyctis cyanophlyctis during osmotic stress. AB - Most of the amphibians breed in temporary ponds vulnerable to occasional desiccation, thus, leaving their larvae exposed to stressful fluctuations in various environmental parameters including salinity. These animals possess a well suited central adaptive mechanism to adapt to these alterations. Neuropeptide Y (NPY), a 36 amino acid neurotransmitter, has been reported to antagonize various neuropsychological consequences of stress within the mammalian brain. Osmotic regulation of NPY in the hypothalamo-neurohypophysial pathway of mammalian brain is also known. Although the molecule possesses an extensive distribution in the brain of amphibians, its functional association is not well understood. We have investigated the endogenous response of NPY-ergic system to osmotically stressful conditions in the brain of Indian skipper frog-Euphlyctis cyanophlyctis tadpoles. Using Immunohistochemistry, we observed an up-regulation of NPY immunoreactivity (NPY-ir) in the brain of tadpoles exposed to stressful salt concentrations. A significant increase of NPY-ir occurred in the pallium and septum regions of telencephalon; preoptic area, epithalamic, thalamic and hypothalamic parts of diencephalon. Most of the regions are implicated in the modulation of stress and anxiety related brain functions and have also been shown to respond to the salinity stress in mammals. In addition, NPY producing neurons in pre-optic and hypothalamic parts show a close co-existence with the vasopressin-ergic neurons. Thus, our study suggests a possible role of NPY in stabilizing the neuro endocrinological consequences of osmotic stress in an amphibian brain. PMID- 28081967 TI - [The microRNAs as biomarkers: What prospects?] AB - MicroRNAs are nucleic acids of about twenty nucleotides that regulate about a third of the genome at the post-transcriptional level. Thanks to their different forms of transport, microRNAs are stable and can be detected in biological fluids such as blood, urine, cerebrospinal fluid, or saliva. In addition, the profile of circulating microRNAs is a specific part of the cells in which it is secreted and is modified according to the physiological or pathological conditions of these cells. MicroRNAs therefore appear as biomarkers of interest for many diseases. However, these applications face several challenges because there are currently considerable differences between the sample processing procedures, assay methods, and especially the result standardization strategies. This literature review aims to take stock of the current use of microRNAs as biomarkers mainly in biological fluids and address the perspectives that emerge from the fact that their vesicular circulating forms could be used to assess the state of the cells and the tissues that produce them. PMID- 28081968 TI - The global distribution and diversity of protein vaccine candidate antigens in the highly virulent Streptococcus pnuemoniae serotype 1. AB - Serotype 1 is one of the most common causes of pneumococcal disease worldwide. Pneumococcal protein vaccines are currently being developed as an alternate intervention strategy to pneumococcal conjugate vaccines. Pre-requisites for an efficacious pneumococcal protein vaccine are universal presence and minimal variation of the target antigen in the pneumococcal population, and the capability to induce a robust human immune response. We used in silico analysis to assess the prevalence of seven protein vaccine candidates (CbpA, PcpA, PhtD, PspA, SP0148, SP1912, SP2108) among 445 serotype 1 pneumococci from 26 different countries, across four continents. CbpA (76%), PspA (68%), PhtD (28%), PcpA (11%) were not universally encoded in the study population, and would not provide full coverage against serotype 1. PcpA was widely present in the European (82%), but not in the African (2%) population. A multi-valent vaccine incorporating CbpA, PcpA, PhtD and PspA was predicted to provide coverage against 86% of the global population. SP0148, SP1912 and SP2108 were universally encoded and we further assessed their predicted amino acid, antigenic and structural variation. Multiple allelic variants of these proteins were identified, different allelic variants dominated in different continents; the observed variation was predicted to impact the antigenicity and structure of two SP0148 variants, one SP1912 variant and four SP2108 variants, however these variants were each only present in a small fraction of the global population (<2%). The vast majority of the observed variation was predicted to have no impact on the efficaciousness of a protein vaccine incorporating a single variant of SP0148, SP1912 and/or SP2108 from S. pneumoniae TIGR4. Our findings emphasise the importance of taking geographic differences into account when designing global vaccine interventions and support the continued development of SP0148, SP1912 and SP2108 as protein vaccine candidates against this important pneumococcal serotype. PMID- 28081970 TI - Influenza in the Asia-Pacific region: Findings and recommendations from the Global Influenza Initiative. AB - The fourth roundtable meeting of the Global Influenza Initiative (GII) was held in Hong Kong, China, in July 2015. An objective of this meeting was to gain a broader understanding of the epidemiology, surveillance, vaccination policies and programs, and obstacles to vaccination of influenza in the Asia-Pacific region through presentations of data from Australia, Hong Kong, India, Indonesia, Malaysia, New Zealand, the Philippines, Taiwan, Thailand, and Vietnam. As well as a need for improved levels of surveillance in some areas, a range of factors were identified that act as barriers to vaccination in some countries, including differences in climate and geography, logistical challenges, funding, lack of vaccine awareness and education, safety concerns, perceived lack of vaccine effectiveness, and lack of inclusion in national guidelines. From the presentations at the meeting, the GII discussed a number of recommendations for easing the burden of influenza and overcoming the current challenges in the Asia Pacific region. These recommendations encompass the need to improve surveillance and availability of epidemiological data; the development and publication of national guidelines, where not currently available and/or that are in line with those proposed by the World Health Organization; the requirement for optimal timing of vaccination programs according to local or country-specific epidemiology; and calls for advocacy and government support of vaccination programs in order to improve availability and uptake and coverage. In conclusion, in addition to the varied epidemiology of seasonal influenza across this diverse region, there are a number of logistical and resourcing issues that present a challenge to the development of optimally effective vaccination strategies and that need to be overcome to improve access to and uptake of seasonal influenza vaccines. The GII has developed a number of recommendations to address these challenges and improve the control of influenza. PMID- 28081969 TI - Replacement of in vivo human rabies vaccine potency testing by in vitro glycoprotein quantification using ELISA - Results of an international collaborative study. AB - Three different ELISAs quantifying rabies glycoprotein were evaluated as in vitro alternatives to the National Institutes of Health (NIH) in vivo potency test for batch release of human rabies vaccines. The evaluation was carried out as an international collaborative study supported by the European Partnership for Alternatives to Animal Testing (EPAA). This pre-validation study, the results of which are presented in this paper, compared three different ELISA designs, assessing their within- and between-laboratory precision. One of the ELISA designs was proposed to the European Directorate for the Quality of Medicines & HealthCare (EDQM) and accepted for an international collaborative study under the umbrella of the Biological Standardisation Programme. PMID- 28081972 TI - Methotrexate reduces vaccine-specific immunoglobulin levels but not numbers of circulating antibody-producing B cells in rheumatoid arthritis after vaccination with a conjugate pneumococcal vaccine. AB - BACKGROUND: Treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA) leads to decreased total immunoglobulin (Ig) levels and impairs vaccine-specific IgG antibody levels following pneumococcal vaccination. The mechanisms by which MTX exerts these effects in RA are unknown. We aimed to evaluate whether MTX reduces vaccine-specific serum Ig levels and their functionality in RA patients following vaccination with pneumococcal conjugate vaccine, and if numbers of antigen-specific circulating plasmablasts are affected. METHODS: Ten patients with RA on MTX and 10 RA patients without disease modifying anti-rheumatic drug (DMARD) were immunized with a dose 13-valent pneumococcal conjugate vaccine (Prevenar13). Circulating plasmablasts producing total IgG and IgA as well as specific IgG and IgA against two pneumococcal capsular serotypes (6B and 23F) were enumerated using ELISPOT 6days after vaccination. IgG levels against both these serotypes were determined with ELISA before and 4-6weeks after vaccination. Positive antibody response was defined as ?2-fold increase of pre-vaccination antibody levels. The functionality of vaccine specific antibodies to serotype 23F was evaluated by measuring their ability to opsonize bacteria using opsonophagocytic assay (OPA) in 4 randomly chosen RA patients on MTX and 4 RA patients without DMARD. RESULTS: After vaccination, RA patients on MTX showed significant increase in pre- to postvaccination antibody levels for 6B (p<0.05), while patients without DMARD had significant increases for both 6B and 23F (p<0.05 and p<0.01, respectively). Only 10% of RA on MTX and 40% of RA patients without DMARD showed positive post-vaccination antibody responses for both serotypes. Increased opsonizing ability after vaccination was detected in 1 of 4 RA patients on MTX and 3 of 4 patients on RA without DMARD. However, numbers of circulating total and vaccine-specific IgG- or IgA-producing plasmablasts did not differ between RA patients with or without MTX. CONCLUSIONS: MTX treatment in RA leads to reduced vaccine-specific antibody responses and their functionality compared to untreated RA following pneumococcal vaccination using polysaccharide-protein conjugate vaccine. However, since there was no reduction in numbers of circulating total or vaccine-specific antibody-producing plasmablasts after vaccination this effect is probably not due to reduced activation of B cells in lymphoid tissue. CLINICAL TRIAL REGISTRATION: NCT02240888. PMID- 28081971 TI - Demand- and supply-side determinants of diphtheria-pertussis-tetanus nonvaccination and dropout in rural India. AB - BACKGROUND: Although 93% of 12- to 23-month-old children in India receive at least one vaccine, typically Bacillus Calmette-Guerin, only 75% complete the recommended three doses of diphtheria-pertussis-tetanus (DPT, also referred to as DTP) vaccine. Determinants can be different for nonvaccination and dropout but have not been examined in earlier studies. We use the three-dose DPT series as a proxy for the full sequence of recommended childhood vaccines and examine the determinants of DPT nonvaccination and dropout between doses 1 and 3. METHODS: We analyzed data on 75,728 6- to 23-month-old children in villages across India to study demand- and supply-side factors determining nonvaccination with DPT and dropout between DPT doses 1 and 3, using a multilevel approach. Data come from the District Level Household and Facility Survey 3 (2007-08). RESULTS: Individual and household-level factors were associated with both DPT nonvaccination and dropout between doses 1 and 3. Children whose mothers had no schooling were 2.3 times more likely not to receive any DPT vaccination and 1.5 times more likely to drop out between DPT doses 1 and 3, compared with children whose mothers had 10 or more years of schooling. Although supply-side factors related to availability of public health facilities and immunization-related health workers in villages were not correlated with dropout between DPT doses 1 and 3, children in districts where 46% or more villages had a healthcare subcentre were 1.5 times more likely to receive at least one dose of DPT vaccine compared with children in districts where 30% or fewer villages had subcentres. CONCLUSIONS: Nonvaccination with DPT in India is influenced by village- and district-level contextual factors over and above individuals' background characteristics. Dropout between DPT doses 1 and 3 is associated more strongly with demand-side factors than with village- and district-level supply-side factors. PMID- 28081973 TI - Charles Bonnet syndrome in a young patient with a history of epilepsy. PMID- 28081974 TI - Alice in Wonderland syndrome as the initial and sole manifestation of ischaemic stroke. PMID- 28081975 TI - Pseudotumour cerebri in children: Aetiology, clinical features, and progression. AB - INTRODUCTION: The definition, associated aetiologies, diagnosis, and treatment of idiopathic intracranial hypertension, or pseudotumour cerebri (PTC), are constantly being revised in the paediatric population. OBJECTIVES AND METHODS: Our study included children younger than 15 years old with PTC and attended at a reference hospital in the past 12 years. We analysed the clinical and epidemiological features of our sample and the diagnostic and treatment approaches. PTC was defined as presence of intracranial hypertension (CSF opening pressure>25cmH2O) and absence of space-occupying lesions in brain MR images. RESULTS: A total of 12 children with PTC were included; mean age was 10 years and 90% were girls. Weight was normal in all patients. Eighty-two percent of the patients had symptoms: headache (66%), diplopia (8%), and visual loss (8%). All of them displayed papilloedema (17% unilaterally). Lumbar puncture (LP) provided the diagnosis in all cases and 91% showed no relevant MRI findings. A potential cause of PTC was identified in 5 cases: pharmacological treatment in 2 and infection (Mycoplasma pneumoniae [M. pneumoniae]) in 3. Ninety-one per cent of the patients received treatment: 75% underwent several LPs and 42% received acetazolamide and/or prednisone. Outcomes were favourable in all cases. CONCLUSIONS: The incidence of PTC was estimated at approximately 1 case per 100 000 children/years, in line with data reported by previous studies. Overweight was not found to be a risk factor for PTC in this population. M. pneumoniae infection may trigger PTC and cause recurrences at later stages. The absence of symptoms seems to be independent from the degree of intracranial hypertension. Acetazolamide treatment is effective in most cases, and it represents a viable alternative to repeated LP. PMID- 28081976 TI - Spinal extradural angiolipomas: 7 new cases and review of the literature. AB - INTRODUCTION: We present our experience with the diagnosis and treatment of spinal angiolipomas (SAL). METHODS: We used our database of surgical patients to gather epidemiological, clinical, diagnostic, treatment, and follow-up data from confirmed cases of SAL. Patients' functional status was evaluated using the modified Japanese Orthopaedic Association (mJOA) score for thoracic myelopathy. RESULTS: We included 7 patients with ages ranging between 42 and 63 years; 4 were women. Lesions in all patients were located in the thoracic epidural space; in 2 cases, lesions extended outside the spinal canal. The most frequent form of presentation was pain combined with progressive myelopathy; patients scored 5 to 9 points on the mJOA scale. Radiological findings varied; this variability clearly depended on the proportion of tumour components (cellular variant in one case, predominantly angiomatous in another, and myxoid in yet another case). Four cases displayed radiological signs of bone involvement. Surgery resulted in excellent mJOA scores except in one case (mJOA score of 10); no recurrences were detected during follow-up (periods ranging from 1 to 5 years). CONCLUSIONS: Extradural SAL can present with highly variable radiological and clinical features. Surgery must be tailored to each individual situation according to tumour extension; in some cases, it may include spinal reconstruction. Surgery results in excellent outcomes regardless of preoperative functional status and it is associated with low recurrence rates, even in case of incomplete resection. PMID- 28081977 TI - The combined use of Drug-eluting balloon and Excimer laser for coronary artery Restenosis In-Stent Treatment: The DERIST study. AB - AIM: Stents reduce angiographic restenosis in comparison with balloon angioplasty. The rate of in-stent restenosis (ISR), although less frequent than post-angioplasty restenosis, is becoming increasingly prevalent due to the recent exponential increase in the use of intracoronary stents. The aim of this study is to evaluate angiographic and clinical outcomes of PTCA in combination with the use of excimer laser coronary angioplasty (ELCA) and drug-eluting balloon (DEB) in treatment of in-stent restenosis (ISR). METHODS AND RESULTS: This multi centric case-control study evaluated angiographic and clinical outcomes of PTCA with excimer laser coronary angioplasty (ELCA) and drug-eluting balloon (DEB) in 80 patients with in-stent restenosis (ISR). All patients underwent nine months of clinical and a coronary angiography follow-up. This study showed clinical and angiographic long-term success in the 91% of the patients. The incidence of myocardial infarctions and deaths was lower than the rate after plain balloon angioplasty within the stent. CONCLUSIONS: This study showed that excimer laser coronary angioplasty (ELCA) and drug-eluting balloon (DEB) may be an alternative treatment for in-stent restenosis (ISR). PMID- 28081978 TI - Influence of Genes on the Lifespan of Long- and Short-Lived Families. PMID- 28081980 TI - The lipid accumulation product is a powerful tool to predict metabolic syndrome in undiagnosed Brazilian adults. AB - BACKGROUND & AIMS: Lipid accumulation product (LAP) is emergent predictor of central lipid accumulation linked to diabetes risk and cardiovascular disease. In this study, our aims were (i) to assess the accuracy of the LAP for predicting metabolic syndrome (MS) in subjects without diagnosis of cardiovascular disease (CVD) and type 2 diabetes mellitus compared with other classical anthropometric parameters and (ii) to estimate the optimal LAP cut-off point to predict MS in this population. SUBJECTS/METHODS: We conducted a cross-sectional study with representative undiagnosed subjects aged 20-79 years (n = 201; 37.8% men), selected by simple random sampling. In this study, subjects without previous diagnosis of CVD and type 2 diabetes mellitus, and those who did not make use of continuous medication were included. The independent variables were body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR) and waist-to hip ratio (WHR) and LAP. MS was defined by American Heart Association and the National Heart, Lung, and Blood Institute (AHA/NHLBI); International Diabetes Federation (IDF); and a harmonized criteria between AHA/NHLBI and IDF. RESULTS: The prevalence of MS was 78.9% and 69.6% for men and women, respectively. LAP showed better area under the curve (AUC) for MS in three different criteria than those indexes based on body mass index, waist circumference, waist-to-height ratio and waist-to-hip ratio, even after adjusting for age and sex. In the harmonized criteria, the cut-off point of 34.2 cm.mmol/L for LAP showed the highest accuracy for MS (sensitivity 0.90, specificity 0.61, positive likelihood ratio of 2.31 and negative likelihood ratio of 0.17). CONCLUSIONS: LAP is a simple and accurate predictor tool for MS in undiagnosed adults. Moreover, it has significantly higher predictability than other screening tools commonly used to find subjects at risk of CVD and type 2 diabetes mellitus development, with the best performance at the 34.2 cm.mmol/L cut-off point. PMID- 28081979 TI - Malignant Catarrhal Fever in Brazilian cattle presenting with neurological syndrome. AB - Malignant Catarrhal Fever (MCF) was investigated in the central nervous system of cattle with neurological syndrome. Two-hundred-ninety samples were analyzed by histology, and molecular methods to detect ovine herpesvirus type 2 (OvHV-2) were optimized and validated. The qualitative polymerase chain reaction (qualitative PCR) analytical sensitivity was 101DNA copies/MUL and found 4.8% (14/290) positive for OvHV-2. The quantitative polymerase chain reaction (qPCR) analytical sensitivity was 100DNA copy/MUL and 5.9% (17/290) positivity, with 47.1% (8/17) of the positive samples presenting histological evidence of non-purulent meningo encephalitis. The qualitative PCR products (422bp of the ORF75 region) were sequenced and submitted to phylogenetic analysis. Identity matrices showed 100% similarity in OvHV-2 samples obtained in this study and those recovered from GenBank, corroborating other studies. PMID- 28081981 TI - Impact of treatment modality on quality of life of head and neck cancer patients: Findings from an academic medical institution. AB - PURPOSE: The objective of this pilot study was to determine how different treatment modalities (surgery, radiation, and chemotherapy) impact quality of life (QOL) in a population of head and neck cancer (HNC) survivors. METHODS: Fifty-nine newly diagnosed, biopsy-confirmed HNC patients were recruited between 2007-2012. They completed the EORTC Quality of Life Questionnaire and Head & Neck Module at 5 intervals pre- and post-treatment. Participants were grouped into four categories based on modality: surgery only, surgery/radiation, chemoradiation, or surgery/chemoradiation. Repeated measures ANOVA examined effect of treatment modality on QOL over time. RESULTS: Xerostomia symptoms were significantly associated with chemoradiation (F(2.47, 59.27)=3.57, p=0.03), lowest at pretreatment and highest 6 months post-treatment. Time was significantly associated with head and neck pain, F(2.95,67.89)=3.39, p=0.02. CONCLUSIONS: HNC survivors exhibit different QOL related symptoms depending on combined treatment modalities, and time post-treatment. It is important to understand QOL differences based upon treatment modalities when developing treatment plans for HNC patients. PMID- 28081982 TI - Umbilical cord-derived mesenchymal stromal cell-conditioned medium exerts in vitro antiaging effects in human fibroblasts. AB - BACKGROUND AIMS: Chronic wounds are a common complication of diabetes. Fibroblast myofibroblast differentiation is important for wound repair, which is commonly impaired in non-healing wounds, and the underlying mechanisms need to be further elucidated. METHODS: We used high glucose (HG) to simulated the diabetes microenvironment and explored its effects on the biological features of fibroblasts in vitro. RESULTS: The results showed that prolonged HG induced senescence in fibroblasts through activation of p21 and p16 in a reactive oxygen species (ROS)-dependent manner, further delayed the viability and migration in fibroblasts and also depressed fibroblast differentiation through the TGF beta/Smad signaling pathway. However, mesenchymal stromal cell-conditioned medium (MSC-CM) counteracts the effects of HG. Treatment of fibroblasts with MSC-CM decreased HG-induced ROS overproduction, ameliorated HG-induced senescence in fibroblasts and reversed the defects in myofibroblast formation. Our results may provide clues for the pathogenesis of chronic wounds and a theoretical basis to develop MSC-CM as an alternative therapeutic method to treatment of chronic wounds. PMID- 28081983 TI - Post-partum eosinophilic gastroenteritis: A case report. PMID- 28081984 TI - Updates on a case of Mckittrick-Wheelock syndrome and metabolic coma. PMID- 28081986 TI - Response to Zamponi et al. PMID- 28081985 TI - Repurposing of Potent Drug Candidates for Multiparasite Targeting. AB - Parasite-directed drug discovery efforts require sustained and substantial scientific resources. Many eukaryotic parasites share similarities in metabolic pathways and housekeeping genes, as evident from their underlying protein sequences. Their subsequent structural congruence within enzyme active sites can thus be leveraged for multiparasite targeting using similar or identical drug probes. This bodes well for delivering new anti-infectives. PMID- 28081987 TI - Serum folate, vitamin B12 levels and diabetic peripheral neuropathy in type 2 diabetes: A meta-analysis. AB - The association between serum folate and vitamin B12 levels and the risk of diabetic peripheral neuropathy (DPN) remains unclear. This meta-analysis included 16 studies of serum folate levels (1190 cases and 1501 controls) and 18 studies of serum vitamin B12 levels (1239 cases and 1562 controls) in patients with type 2 diabetes mellitus (T2DM). Reduced serum levels of folate and vitamin B12 were found in patients with T2DM and DPN compared with patients with T2DM but without DPN; weighted mean difference (WMD) = -1.64 (95% confidence interval [CI] = 2.46, -0.81) and WMD = -70.86 (95% CI = -101.55, -40.17), respectively. A subgroup analysis confirmed these associations in the Chinese population, but not in the Caucasian and mixed populations. In conclusion, these findings support the need for further controlled studies in defined patient populations and the importance of monitoring serum folate and vitamin B12 levels in patients with T2DM. PMID- 28081988 TI - Exposure to famine in early life and the risk of obesity in adulthood in Qingdao: Evidence from the 1959-1961 Chinese famine. AB - BACKGROUND AND AIMS: We aimed to evaluate the association between famine exposure during early life and obesity and obesitymax (obese at the highest weight) in adulthood. METHODS AND RESULTS: Data were from two population-based cross sectional surveys conducted in 2006 and 2009 in Qingdao, China. A total of 8185 subjects born between 1/1/1941 and 12/31/1971 were categorized into unexposed (born between 01/01/1962 and 12/31/1971), fetal/infant exposed (born between 01/01/1959 and 12/31/1961), childhood exposed (born between 01/01/1949 and 12/31/1958) and adolescence exposed (born between 01/01/1941 and 12/31/1948) according to their age when exposed to the Chinese famine from 1959 to 1961. Obesity was defined as BMI (body mass index) >=28.0 and obesitymax was defined as BMImax (BMI at the highest weight) >=28.0. We compared fetal/infant exposed, childhood exposed and adolescence exposed to the unexposed using logistic regression models to assess the effect of famine exposure on later obesity and obesitymax. Fetal/infant exposed (OR = 1.59, P < 0.001), childhood exposed (OR = 1.42, P < 0.01) and adolescence exposed (OR = 1.86, P < 0.01) all had higher risks of obesity than the unexposed. Exposure groups were more likely to be obese at their highest weight than the unexposed, and ORs (95%CIs) for obesitymax in the fetal/infant exposed, childhood exposed and adolescence exposed were 1.49(1.20-1.86), 1.24(1.02-1.49) and 1.64 (1.40-1.93), respectively. Similar results were found in both men and women. CONCLUSION: Exposure to famine in early life was associated with increased risks of obesity and obesitymax in adulthood. Preventing undernutrition in early life appears beneficial to reduce the prevalence of later obesity. PMID- 28081989 TI - Dietary glycemic index, glycemic load and metabolic profile in children with phenylketonuria. AB - BACKGROUND AND AIMS: No data exist in the current literature on the glycemic index (GI) and glycemic load (GL) of the diet of phenylketonuric (PKU) children. The aims of this study were to examine the dietary GI and GL in PKU children on a low-phenylalanine (Phe)-diet and to evaluate whether an association may exist between the carbohydrate quality and the metabolic profile. METHODS: Twenty-one PKU children (age 5-11 years) and 21 healthy children, gender and age matched, were enrolled. Dietary (including GI and GL) and blood biochemical assessments were performed. RESULTS: No difference was observed for daily energy intake between PKU and healthy children. Compared to healthy controls, PKU children consumed less protein (p = 0.001) and fat (p = 0.028), and more carbohydrate (% of total energy, p = 0.004) and fiber (p = 0.009). PKU children had higher daily GI than healthy children (mean difference (95% confidence interval), 13.7 (9.3 18.3)) and higher GL (31.7 (10.1-53.2)). PKU children exhibited lower blood total and low density lipoprotein cholesterol (LDL) levels (p < 0.01) and higher triglyceride level (p = 0.014) than healthy children, while glucose and insulin concentrations did not differ. In PKU children the dietary GL was associated with triglyceride glucose index (Spearman's correlation coefficient = 0.515, p = 0.034). CONCLUSION: In PKU children a relationship of the dietary treatment with GI and GL, blood triglycerides and triglyceride glucose index may exist. Improvement towards an optimal diet for PKU children could include additional attention to the management of dietary carbohydrate quality. PMID- 28081990 TI - Can we use lower volume of local anesthetic for infraclavicular brachial plexus nerve block under ultrasound guidance in children? AB - OBJECTIVES: To determine if the infraclavicular brachial plexus block can be applied with lower volume of local anesthetic. DESIGN: Randomised, double-blinded clinical trial. PATIENTS: 60 patients aged 5-15years with ASA I-II who underwent emergent or elective arm, forearm or hand operations were included in the study. INTERVENTIONS: Patients were divided into two groups randomly; standard volume local anesthetic administered group (Group S, n=30) and low volume anesthetic administered group (Group L, n=30). MEASUREMENT: Postoperative pain scores, sensory and motor block durations were noted. MAIN RESULTS: Pain scores (Wong Baker Face Scale) were evaluated and the results were detected to be similar at all times (30min, 1, 2, 4, 8, 12, 24h). Durations of motor block were 168(+/-16) minutes and 268(+/-15) minutes in Group L and Group S respectively and the difference was statistically significant (p<0.001). Durations of sensory block were 385(+/-26) and 402(+/-39) in Group L and Group S respectively and no statistically significant difference was detected (p=0.064). CONCLUSION: Similar block success, postoperative sensory block durations and pain scores could be obtained during infraclavicular brachial plexus in pediatric patients with lower local anesthetic volumes. PMID- 28081991 TI - Obstructive sleep apnoea, type 2 diabetes and cardiovascular risk factors. PMID- 28081992 TI - Corrigendum to "Assessing hazardous risks of indoor airborne polycyclic aromatic hydrocarbons in the kitchen and its association with lung functions and urinary PAH metabolites in kitchen workers" [Clin. Chim. Acta 452 (2016) 204-213.]. PMID- 28081993 TI - Biomethanization of olive mill solid waste after phenols recovery through low temperature thermal pre-treatment. AB - Due to the high polluting potential of Olive Mill Solid Waste (OMSW), it is necessary to develop an economical and environmental-friendly sustainable management method. OMSW anaerobic digestion has been shown to be an interesting management alternative, although it should be optimized to improve its economic viability. In the present study, low-temperature thermal pre-treatment of OMSW is proposed to allow the extraction of high added-value compounds, such as phenols, and to enhance the subsequent biomethanization of the substrate. OMSW low temperature thermal pre-treatment facilitated the separation of a solid phase, where most of organic compounds remained, and a liquid phase, where most of phenolic compounds were concentrated. Hydroxytyrosol presented the highest concentration of the measured individual phenols in the liquid phase, i.e. 1034+/ 22mg/L. Anaerobic digestion of OMSW and the different pre-treated phases and mixtures operated under stable conditions, except the biomethanization of the liquid phase, which was mainly inhibited by the high phenols content. Low temperature thermal pre-treatment allows obtaining an improvement on biodegradability and methane production up to 37% and 34%, respectively. The proposed economic assessment showed that the combination of low-temperature pre treatment, phenols recovery and the subsequent biomethanization of the substrates was the most attractive treatment option. This management option could reach economic benefit of ?0.845/kg OMSW, i.e. twenty times higher than only energy recovery. PMID- 28081994 TI - Sustainable use of tannery sludge in brick manufacturing in Bangladesh. AB - Chromium-rich tannery sludge generated from tanneries has the potential to become a serious environmental burden in Bangladesh and a promising avenue for disposal of this sludge is by stabilizing it in clay brick products. But for sustainable industrial application of such technique it needs to be ensured first that the engineering properties of bricks as a building material are not diminished by addition of sludge, the process becomes energy efficient compared to alternatives and the use of such bricks do not pose any harmful environmental effects in the long run. In this study, clay bricks were prepared with different proportions of sludge (10%, 20%, 30% and 40% by dry weight) in both laboratory-controlled and field conditions and their suitability as a construction material was assessed based on their strength, water absorption, shrinkage, weight-loss on ignition and bulk density. For the sludge incorporated bricks, the compressive strength ranged from 10.98MPa to 29.61MPa and water absorption ranged from 7.2% to 20.9%, which in most cases met both the Bangladesh and ASTM criteria for bricks as a construction material. Volumetric shrinkage, weight loss and efflorescence properties of sludge-amended bricks were found to be favorable and it was estimated that an energy saving of 15-47% could potentially be achieved during firing with 10-40% tannery sludge-amended bricks. The quality of sludge-amended bricks made in the brick kiln was relatively inferior compared to bricks produced in the laboratory due to operating in a less-controlled environment with respect to maintaining adequate compaction and optimum moisture content. The leaching behavior of several heavy metals (Cr, As, Cu, Ni, Cd, Pb and Zn) from sludge amended bricks has been found to be insignificant and far below the Dutch regulations and USEPA regulatory limits. Results from this study indicate that tannery sludge can be sustainably stabilized in clay bricks and large-scale application of this technique can be envisaged in the context of Bangladesh where brick remains a dominant building material. PMID- 28081995 TI - Procedure to describe clavicular motion. AB - BACKGROUND: For many years, researchers have attempted to describe shoulder motions by using different mathematical methods. The aim of this study was to describe a procedure to quantify clavicular motion. METHODS: The procedure proposed for the kinematic analysis consists of 4 main processes: 3 transcortical pins in the clavicle, motion capture, obtaining 3-dimensional bone models, and data processing. RESULTS: Clavicular motion by abduction (30 degrees to 150 degrees ) and flexion (55 degrees to 165 degrees ) were characterized by an increment of retraction of 27 degrees to 33 degrees , elevation of 25 degrees to 28 degrees , and posterior rotation of 14 degrees to 15 degrees , respectively. In circumduction, clavicular movement described an ellipse, which was reflected by retraction and elevation. Kinematic analysis shows that the articular surfaces move by simultaneously rolling and sliding on the convex surface of the sternum for the 3 movements of abduction, flexion, and circumduction. CONCLUSION: The use of 3 body landmarks in the clavicle and the direct measurement of bone allowed description of the osteokinematic and arthrokinematic movement of the clavicle. PMID- 28081996 TI - Tendon vascularity in overhead athletes with subacromial pain syndrome and its correlation with the resting subacromial space. AB - BACKGROUND: Supraspinatus tendinopathy is one of the common causes of subacromial pain syndrome (SAPS) in overhead athletes. Changes in tendon vascularity have been reported in painful tendons; however, the prevalence and distribution have not been investigated in young overhead athletes. METHODS: We conducted a cross sectional study of 47 overhead athletes (male, 31; female, 16) aged 18 to 36 years with SAPS for >3 months. A sonographer graded the severity of the tendinopathy and area of vascularization. Ultrasound imaging was used to measure supraspinatus tendon thickness, vascularity, and resting subacromial space. A self-written program was used to semiquantify the intensity of vascularity, expressed as the vascular index. RESULTS: The majority (87.2%) of the participants had signs of tendinopathy in the supraspinatus tendon, and 40 (85.1%) of the tendinopathic tendons had vascularity. The majority (66.0%) of the vascularized subjects presented with minimal increase in vascularity, and 19.1% had moderate to severe vascularization. Most (79.2%) of the vascularization was observed in the pericortical region. The vascular index was negatively correlated with the resting subacromial space in male athletes with a reduced subacromial space (rho = -0.63; P = .038). CONCLUSION: Of overhead athletes with SAPS, 87.2% had supraspinatus tendinopathy with minimal to moderate vascularization, with the majority of vascularization occurring in the pericortical region. In male athletes with a reduced subacromial space, greater vascularity in the supraspinatus tendon was associated with a smaller resting subacromial space. PMID- 28081997 TI - Persistent motion loss after free joint mobilization in a rat model of post traumatic elbow contracture. AB - BACKGROUND: Post-traumatic joint contracture (PTJC) in the elbow is a challenging clinical problem due to the anatomical and biomechanical complexity of the elbow joint. METHODS: We previously established an animal model to study elbow PTJC, wherein surgically induced soft tissue damage, followed by 6 weeks of unilateral immobilization in Long-Evans rats, led to stiffened and contracted joints that exhibited features similar to the human condition. In this study, after 6 weeks of immobilization, we remobilized the animal (ie, external bandage removed and free cage activity) for an additional 6 weeks, after which the limbs were evaluated mechanically and histologically. The objective of this study was to evaluate whether this decreased joint motion would persist after 6 weeks of free mobilization (FM). RESULTS: After FM, flexion-extension demonstrated decreased total range of motion (ROM) and neutral zone length, and increased ROM midpoint for injured limbs compared with control and contralateral limbs. Specifically, after FM total ROM demonstrated a significant decrease of approximately 22% and 26% compared with control and contralateral limbs for injury I (anterior capsulotomy) and injury II (anterior capsulotomy with lateral collateral ligament transection), respectively. Histologic evaluation showed increased adhesion, fibrosis, and thickness of the capsule tissue in the injured limbs after FM compared with control and contralateral limbs, which is consistent with patterns previously reported in human tissue. CONCLUSION: Even with FM, injured limbs in this model demonstrate persistent joint motion loss and histologic results similar to the human condition. Future work will use this animal model to investigate the mechanisms responsible for PTJC and responses to therapeutic intervention. PMID- 28081999 TI - Influence of the Flavored Cigarette Ban on Adolescent Tobacco Use. AB - INTRODUCTION: This paper estimated the association between the U.S. Food and Drug Administration's 2009 ban on flavored cigarettes (which did not apply to menthol cigarettes or tobacco products besides cigarettes) and adolescents' tobacco use. METHODS: Regression modeling was used to evaluate tobacco use before and after the ban. The analyses controlled for a quadratic time trend, demographic variables, prices of cigarettes and other tobacco products, and teenage unemployment rate. Data from the 1999-2013 National Youth Tobacco Surveys were collected and analyzed in 2016. The sample included 197,834 middle and high schoolers. Outcomes were past 30-day cigarette use; cigarettes smoked in the past 30 days among smokers; rate of menthol cigarette use among smokers; and past 30 day use of cigars, smokeless tobacco, pipes, any tobacco products besides cigarettes, and any tobacco products including cigarettes. RESULTS: Banning flavored cigarettes was associated with reductions in the probability of being a cigarette smoker (17%, p<0.001) and cigarettes smoked by smokers (58%, p=0.005). However, the ban was positively associated with the use by smokers of menthol cigarettes (45%, p<0.001), cigars (34%, p<0.001), and pipes (55%, p<0.001), implying substitution toward the remaining legal flavored tobacco products. Despite increases in some forms of tobacco, overall there was a 6% (p<0.001) reduction in the probability of using any tobacco. CONCLUSIONS: The results suggest the 2009 flavored cigarette ban did achieve its objective of reducing adolescent tobacco use, but effects were likely diminished by the continued availability of menthol cigarettes and other flavored tobacco products. PMID- 28081998 TI - Parent's Physical Activity Associated With Preschooler Activity in Underserved Populations. AB - INTRODUCTION: In the U.S., children from low-income families are more likely to be obese. The impact of parent modeling of physical activity (PA) and sedentary behaviors in low-income American ethnic minorities is unclear, and studies examining objective measures of preschooler and parent PA are sparse. METHODS: This cross-sectional study examined 1,003 parent-child pairs who were of low income, largely Latino and African American, and living in one of two geographically disparate metropolitan areas in the U.S. Parents and children wore GT3X/GT3X+ accelerometers for an average of >12 hours/day (7:00am-9:00pm) for 1 week (September 2012 to May 2014). Analysis occurred in 2015-2016. RESULTS: About 75% of children were Latino and >10% were African American. Mean child age was 3.9 years. The majority of children (60%) were normal weight (BMI >=50th and <85th percentiles), and more than a third were overweight/obese. Children's total PA was 6.03 hours/day, with 1.5 hours spent in moderate to vigorous PA (MVPA). Covariate-adjusted models showed a monotonic, positive association between parent and child minutes of sedentary behavior (beta=0.10, 95% CI=0.06, 0.15) and light PA (beta=0.06; 95% CI=0.03, 0.09). Child and parent MVPA were positively associated up to 40 minutes/day of parent MVPA, but an inverse association was observed when parental MVPA was beyond 40 minutes/day (p=0.002). CONCLUSIONS: Increasing parental PA and reducing sedentary behavior correlate with increased PA-related behaviors in children. However, more work is needed to understand the impact of high levels of parental MVPA on the MVPA levels of their children. PMID- 28082000 TI - Exercise Intensity and Incidence of Metabolic Syndrome: The SUN Project. AB - INTRODUCTION: Emerging evidence suggests that vigorous physical activity may be associated with higher cardioprotective benefits than moderate physical activity. This study aimed to assess the long-term relationship between the intensity of leisure time physical activity (LTPA) and the risk of developing metabolic syndrome (MS) in a prospective cohort study. METHODS: The Seguimiento Universidad de Navarra (SUN) Project comprises Spanish university graduates. Participants (n=10,145) initially free of MS were followed for a minimum of 6 years (2008 2014). Analysis was conducted in 2015. Physical activity was assessed though a validated questionnaire. The intensity of each physical activity was measured in METs. The intensity of LTPA was estimated by the ratio between total METs/week and total hours of LTPA/week, obtaining the mean METs/hour of LTPA. MS was defined according to the harmonizing definition. The association between the intensity of LTPA (METs/hour) and MS was assessed with logistic regression models adjusting for potential confounders. RESULTS: Among 10,145 participants initially free of any MS criteria, 412 new MS cases were observed. Vigorous LTPA was associated with a 37% relatively lower risk (AOR=0.63, 95% CI=0.44, 0.89) compared with light LTPA. For a given total energy expenditure, independent of the time spent on it, participants who performed vigorous LTPA exhibited a higher reduction in the risk of MS than those who performed light to moderate LTPA. CONCLUSIONS: Vigorous LTPA was significantly associated with lower risk of developing MS after a 6-year follow-up period. PMID- 28082002 TI - Identifying adults aging with disability using existing data: The case of the Health and Retirement Study. AB - BACKGROUND: The population of persons aging with disabilities is growing. Being able to segment aging with disability sub-populations within national data sets is becoming increasingly important in order to understand the relationship of aging with disability to a range of outcomes in later life including health and wellness, economic security, and health and long-term service and support need and use. OBJECTIVE: The purpose of this study was to identify viable sub-samples of adults aging with disabilities within the Health and Retirement Study, one of the most used secondary data sets to study aging and older adults. METHOD: Samples used in this research are drawn from wave 11 (2012) of the HRS. Five operationalizations of disability were used: childhood disability (n = 719), childhood chronic condition (n = 3070), adult chronic condition (n = 13,723), functional limitation in adulthood (n = 4448) and work disability (n = 5632). RESULTS: These subsamples are not mutually exclusive. Among respondents that reported having a childhood disability, 87% also report having at least one chronic disease in adulthood, 50% report having functional limitations in adulthood and 38% report interruption in their ability to work due to a disability. Compared to the childhood disability samples, rates of reporting fair/poor health are nearly double among adults with functional limitations or those with work disruptions because of disability. CONCLUSION: Work disability and functional limitation appeared to be the most viable sub-sample options to consider when using the HRS to study experiences of adults aging with disability. Overall, age at onset is unclear. PMID- 28082001 TI - The Built Environment and Cognitive Disorders: Results From the Cognitive Function and Ageing Study II. AB - INTRODUCTION: Built environment features have been related to behavior modification and might stimulate cognitive activity with a potential impact on cognitive health in later life. This study investigated cross-sectional associations between features of land use and cognitive impairment and dementia, and also explored urban and rural differences in these associations. METHODS: Postcodes of the 7,505 community-based participants (aged >=65 years) in the Cognitive Function and Ageing Study II (collected in 2008-2011) were linked to environmental data from government statistics. Multilevel logistic regression investigated associations between cognitive impairment (defined as Mini-Mental State Examination score <=25) and dementia (Geriatric Mental Status and Automatic Geriatric Examination for Computer-Assisted Taxonomy organicity level >=3) and land use features, including natural environment availability and land use mix, fitting interaction terms with three rural/urban categories. Data were analyzed in 2015. RESULTS: Associations between features of land use and cognitive impairment were not linear. After adjusting for individual-level factors and area deprivation, living in areas with high land use mix was associated with a nearly 30% decreased odds of cognitive impairment (OR=0.72, 95% CI=0.58, 0.89). This was similar, yet non-significant, for dementia (OR=0.70, 95% CI=0.46, 1.06). In conurbations, living in areas with high natural environment availability was associated with 30% reduced odds of cognitive impairment (OR=0.70, 95% CI=0.50, 0.97). CONCLUSIONS: Non-linear associations between features of land use and cognitive impairment were confirmed in this new cohort of older people in England. Both lack of and overload of environmental stimulation may be detrimental to cognition in later life. PMID- 28082003 TI - Community integration of people with intellectual and developmental disabilities: A national longitudinal analysis. AB - BACKGROUND: Medicaid Home and Community Based Services (HCBS) 1915(c) waivers are the largest providers of long-term supports and services (LTSS) for people with intellectual and developmental disabilities (IDD) in the United States. National and longitudinal analyses of HCBS 1915(c) waivers for people with IDD are critical because of changes in the fiscal landscape, the variability produced by states ability to flexibly customize their programs, and the significant changes required by the HCBS final settings rule. OBJECTIVE/HYPOTHESIS: The aim of this study was to determine spending allocations and state priorities for LTSS for people with IDD through Medicaid HCBS waivers over a five-year period (fiscal year 2011 to fiscal year 2015). METHODS: Medicaid HCBS 1915(c) waivers for people with IDD from fiscal year (FY) 2011 to FY 2015 were analyzed to determine total projected spending, unduplicated participants, and average spending per participant across fiscal years and states. Over 10,000 services from the five years were also analyzed to determine service priorities. RESULTS: This longitudinal analysis of HCBS IDD waiver allocation revealed large fluctuation across five years in terms of total participants, total spending, and average spending per participant. Trends also revealed a shifting away from residential habilitation settings towards supports for living in one's own home. CONCLUSIONS: When revising waivers to meet the Final Settings Rule, states should utilize our findings to determine areas of need and how to best apply limited funding. PMID- 28082004 TI - On the nature of the speech perception deficits in children with autism spectrum disorders. AB - Previous studies have claimed to show deficits in the perception of speech sounds in autism spectrum disorders (ASD). The aim of the current study was to clarify the nature of such deficits. Children with ASD might only exhibit a lesser amount of precision in the perception of phoneme categories (CPR deficit). However, these children might further present an allophonic mode of speech perception, similar to the one evidenced in dyslexia, characterised by enhanced discrimination of acoustic differences within phoneme categories. Allophonic perception usually gives rise to a categorical perception (CP) deficit, characterised by a weaker coherence between discrimination and identification of speech sounds. The perceptual performance of ASD children was compared to that of control children of the same chronological age. Identification and discrimination data were collected for continua of natural vowels, synthetic vowels, and synthetic consonants. Results confirmed that children with ASD exhibit a CPR deficit for the three stimulus continua. These children further exhibited a trend toward allophonic perception that was, however, not accompanied by the usual CP deficit. These findings confirm that the commonly found CPR deficit is also present in ASD. Whether children with ASD also present allophonic perception requires further investigations. PMID- 28082005 TI - Phylogeographic structure of Canthon cyanellus (Coleoptera: Scarabaeidae), a Neotropical dung beetle in the Mexican Transition Zone: Insights on its origin and the impacts of Pleistocene climatic fluctuations on population dynamics. AB - Canthon cyanellus is a roller dung beetle with a wide distribution range in the tropical forests of the New World. In Mexico, it inhabits the Pacific and the Gulf coasts, the Yucatan Peninsula and the south mainly in the State of Chiapas. This species shows a wide geographical variation in cuticle color, which has been used as defining trait for subspecies. In this study we analyzed the phylogeographic and demographic history of the Mexican populations of C. cyanellus using DNA sequences of the nuclear ITS2, and the mitochondrial COI and 16S genes. We found that not all the current valid subspecies are supported by the molecular analysis. The populations are genetically and geographically structured in five lineages. The diversification events that gave origin to the main lineages within this species complex occurred during the Pleistocine in a time range of 1.63-0.91Myr. The demographic history of these lineages suggests post-glacial expansions toward the middle and the end of the Pleistocene. The combined data of mitochondrial and nuclear DNA suggest that the phylogeographic structure and demographic history of the C. cyanellus populations are the result of: the geological and volcanic activity that occurred from the end of the Pliocene to the Pleistocene; and the contraction and expansion of tropical forests due to the glacial and inter-glacial cycles during the Pleistocene. Landscape changes derived from historical events have affected the demographic history of the populations of this species. The results presented here point to the need to review the taxonomic status and delimitation of the lineages encompassed in the Canthon cyanellus complex. PMID- 28082006 TI - Molecular diversity of Wolbachia in Lepidoptera: Prevalent allelic content and high recombination of MLST genes. AB - Wolbachia are common endosymbiotic bacteria of Arthropoda and Nematoda that are ordinarily transmitted vertically in host lineages through the egg cytoplasm. Despite the great interest in the Wolbachia symbiont, many issues of its biology remain unclear, including its evolutionary history, routes of transfer among species, and the molecular mechanisms underlying the symbiont's effect on its host. In this report, we present data relating to Wolbachia infection in 120 species of 13 Lepidoptera families, mostly butterflies, from West Siberian localities based on Multilocus sequence typing (MLST) and the wsp locus and perform a comprehensive survey of the distribution of Wolbachia and its genetic diversity in Lepidoptera worldwide. We observed a high infection incidence in the studied region; this finding is probably also true for other temperate latitude regions because many studied species have broad Palearctic and even Holarctic distribution. Although 40 new MLST alleles and 31 new STs were described, there was no noticeable difference in the MLST allele content in butterflies and probably also in moths worldwide. A genetic analysis of Wolbachia strains revealed the MLST allele core in lepidopteran hosts worldwide, viz. the ST-41 allele content. The key finding of our study was the detection of rampant recombination among MLST haplotypes. High rates of homologous recombination between Wolbachia strains indicate a substantial contribution of genetic exchanges to the generation of new STs. This finding should be considered when discussing issues related to the reconstruction of Wolbachia evolution, divergence time, and the routes of Wolbachia transmission across arthropod hosts. PMID- 28082008 TI - In reply to: "Meyer CP et al., The association of hypoalbuminemia with early perioperative outcomes - A comprehensive assessment across 16 major procedures". PMID- 28082007 TI - Prognostic performance of coronary computed tomography angiography in asymptomatic individuals as compared to symptomatic patients with an appropriate indication. AB - INTRODUCTION: Current Appropriatene Usa Criteria exclude coronary computed tomography angiography (CTA) in asymptomatic individuals. We compared the prognostic value of coronary CTA in asymptomatic individuals to symptomatic patients with "definitely appropriate" indications for coronary CTA. METHODS: Consecutive patients without previously known CAD referred for a CTA exam were divided into 2 groups. One group consisted ofasymptomatic individuals, the other of symptomatic patients with a "definitely appropriate" indication for coronary CT (unable to exercise and/or with an uninterpretable electrocardiogram and at an intermediate pre-test probability of obstructive coronary artery disease). Patients that did not fit into either groups were excluded. The segment stenosis score (SSS) was calculated based on coronary CTA and patients were followed for a composite endpoint of all-cause death, acute myocardial infarction and late revascularization. RESULTS: A total of 1080 patients (60 +/- 12 years, 65% male) were included in the study (674 "asymptomatic" and 406 "appropriate"). SSS >4 was more frequent in "asymptomatic" than in "appropriate" CT data sets (27% vs 20%, p = 0.02). After a mean follow-up of 4.4 +/- 1.8 yrs, 49 patients reached the composite endpoint. On multivariable analysis adjusting for CAD risk factors and symptoms, only a high-risk CTA study and past smoking were independently predictive of events. CONCLUSIONS: Although currently not regarded as "definitely appropriate", the use of coronary CTA in a selected asymptomatic population had higher yield for identifying high-risk individuals than appropriately indicated studies in symptomatic patients and provided thequal prognostic information. PMID- 28082009 TI - Locally advanced primary recto-sigmoid cancers: Improved survival with multivisceral resection. AB - BACKGROUND: Multivisceral resection (MVR) is considered a radical operation with many surgeons only using it as a last resort. However, when locally advanced colorectal cancers invade adjacent organs, MVR is an important consideration for select patients. The current study addresses the outcomes of MVR in locally advanced recto-sigmoid cancer patients subsequent to these recommendations and hypothesizes that MVR yields improved survival. METHOD: SEER data (1988-2008) was used to identify all eligible patients with MVR. Patients were limited to single primary locally advanced non-metastatic colorectal cancers originating from the sigmoid and rectum. RESULTS: A total of 4111 locally advanced non-metastatic recto sigmoid cancer patients were included in the study. Cox regression analysis showed variables predictive of MVR were female (OR = 1.95) and late year period (OR = 1.90). Kaplan Meier analysis showed that five-year survival was highest for MVR (52.7%, 48 months), followed by standard surgery (SS; 38.9%, 32 months) and no surgery (NS; 16.6%, 12 months, P < 0.001). With radiation treatment, five year survival improved for all groups, with the highest being MVR (57%, 52 months). With no radiation treatment, five year survival decreased for all groups, with the highest being MVR (45.1%, 44 months), followed by SS (27.3%, 19 months), and NS (8.7%, 6 months, P < 0.001). CONCLUSION: The present study supports that MVR offers greater survival advantage in patients with locally advanced colorectal cancer. MVR are extensive surgical procedures with significant associated morbidity that usually require specialized training and sometimes the coordination of multiple surgical specialists. PMID- 28082010 TI - Perioperative feedback in surgical training: A systematic review. AB - BACKGROUND: Changes in surgical training have raised concerns about residents' operative exposure and preparedness for independent practice. One way of addressing this concern is by optimizing teaching and feedback in the operating room (OR). The objective of this study was to perform a systematic review on perioperative teaching and feedback. METHODS: A systematic literature search identified articles from 1994 to 2014 that addressed teaching, feedback, guidance, or debriefing in the perioperative period. Data was extracted according to ENTREQ guidelines, and a qualitative analysis was performed. RESULTS: Thematic analysis of the 26 included studies identified four major topics. Observation of teaching behaviors in the OR described current teaching practices. Identification of effective teaching strategies analyzed teaching behaviors, differentiating positive and negative teaching strategies. Perceptions of teaching behaviors described resident and attending satisfaction with teaching in the OR. Finally models for delivering structured feedback cited examples of feedback strategies and measured their effectiveness. CONCLUSIONS: This study provides an overview of perioperative teaching and feedback for surgical trainees and identifies a need for improved quality and quantity of structured feedback. PMID- 28082011 TI - Quality of sleep in patients undergoing cardiac surgery during the postoperative period in intensive care. AB - OBJECTIVES: To describe the quality of sleep of patients undergoing cardiac surgery during the first two nights following surgery and identify some of the factors conditioning the nightly rest of these patients in the Intensive Care Unit. METHOD: Observational descriptive study based on applying the Richards Campbell Sleep Questionnaire through a consecutive sample of patients undergoing cardiac surgery with Intensive Care Unit admission. Simultaneously, a questionnaire assessing different environmental factors existing in the unit as possible conditioning of the night's rest was applied. The association between consumption of opioid and sleep quality was studied. RESULTS: Sample of 66 patients with a mean age of 65+/-11.57 years, of which 73% were men (N=48). The Richards-Campbell sleep questionnaire garnered average scores of 50.33mm (1.st night) and 53.30mm (2.nd night). The main sleep disturbing factors were discomfort with the different devices, 30.91mm and pain, 30.18mm. The problems caused by environmental noise, 27.5mm or through the voices of the professionals, 26.53mm were also elements of nocturnal discomfort. No statistical association was found between sleep and the distance of the patient with respect to the nursing control area or related to opioid analgesics. CONCLUSIONS: The quality of sleep during the first two nights of Intensive Care Unit admission was "regular". The environmental factors that conditioned the night-time rest of patients were discomfort, pain and ambient noise. PMID- 28082012 TI - Applications of ultrasound in processing of liquid foods: A review. AB - Ultrasonic processing of a variety of liquids, drinks and beverages has generated much interest with published literature papers increasing within this area in recent years. Benefits include enhanced emulsification with improved homogenization and fat globule size reduction being recorded. In dairy systems increased creaming rates are observed on sonication in a process known as fractionation. Whilst fruit juices exhibit retention or enhancement of quality parameters whilst increasing levels of bioactive compounds. Sterilization of liquids is a large feature of ultrasonic treatment with microbial activity of a range of fruit juices being monitored over time as increased stability and reduced spoilage is observed. Progress has also been made towards scale up of ultrasonic processes with several examples of batch and continuous processes being studied with reduced processing times and temperatures being quoted as a result of ultrasonic treatment. This short review covers the effect of sonication on liquids and beverages with a specific focus towards dairy and fruit juices and covers emulsification, fractionation, sterilization and some pilot scale initiatives. PMID- 28082013 TI - Severe methemoglobinemia caused by continuous lidocaine infusion in a term neonate. AB - Neonates and young infants are especially prone to develop drug-induced methemoglobinemia. Therefore, lidocaine is not licensed as local anesthetic in children below the age of 3 months. However, its systemic use is advocated for neonatal seizures. Cardiac arrhythmia has been reported as sole major side effect. Here we report a case of severe methemoglobinemia caused by continuous infusion of lidocaine in a term neonate with neonatal seizures. The increase of methemoglobin up to 13.8% was accompanied by hypoxemia and cyanosis, necessitating additional inspired oxygen and CPAP ventilation. After stopping lidocaine infusion methemoglobin levels fell and the neonate could be weaned from ventilation. Neonates treated with lidocaine for seizures must be monitored for the occurrence of methemoglobinemia. PMID- 28082015 TI - Response shift - The experience of disease progression in Parkinson disease. AB - OBJECTIVE: To investigate response shift, the recalibration of perceived quality of life (QoL) relative to symptomatic changes in Parkinson disease (PD). BACKGROUND: Health-related QoL in PD is influenced by improvement vs. decline in disease severity. However, it is unclear how disease course changes internal standards of QoL over time. METHODS: 124 PD patients were subdivided based on Total UPDRS change over 1 year (stable, improved, declined). The EuroQol Visual Analog Scale assessed QoL at baseline (T1) and 1 year later (T2). At T2, patients rated current QoL (T2-current) and reappraised their T1 QoL (T2-retrospective). Recalibration response shifts were represented by the difference between T1 and T2-retrospective QoL ratings. RESULTS: At follow-up (T2), the total patient sample reported no difference between current (T2 current mean (M) = 76.3) and retrospective (T2-R M = 77.8) QoL ratings. While there was no significant difference between T1 (M = 79.2) and T2-R ratings 1 year later (M = 77.8) for the total sample, there was a change by group interaction (p < 0.005) which showed that retrospectively, decliners reduced ratings (M Delta = -9.0) and improvers increased ratings (M Delta = +6.4) while stable patients did not change. CONCLUSIONS: When PD patients consider their health status one year ago, decliners recalibrate and downgrade last year's health assessment, while improvers upgrade last year's assessment. Changes in internal calibrations cushion periods of decline or improvement in PD such that patients tend to "stabilize" their general disease course when recalling symptom trajectory, providing insight into the process of adaptation to the effects of disease progression and treatment over time. PMID- 28082014 TI - Survey on treatments for primary headaches in 13 specialized juvenile Headache Centers: The first multicenter Italian study. AB - AIM: The purpose of this retrospective multicenter study was to evaluate the use and the self-perceived efficacy and tolerability of pharmacological and non pharmacological treatments in children and adolescents with primary headaches. METHODS: Study of a cohort of children and adolescents diagnosed with primary headache, consecutively referred to 13 juvenile Italian Headache Centers. An ad hoc questionnaire was used for clinical data collection. RESULTS: Among 706 patients with primary headaches included in the study, 637 cases with a single type of headache (migraine 76% - with and without aura in 10% and 67% respectively; tension-type headache 24%) were selected (mean age at clinical interview: 12 years). Acetaminophen and non-steroidal anti-inflammatory drugs (in particular ibuprofen) were commonly used to treat attacks, by 76% and 46% of cases respectively. Triptans were used overall by 6% of migraineurs and by 13% of adolescents with migraine, with better efficacy than acetaminophen and non steroidal anti-inflammatory drugs. Preventive drugs were used by 19% of migraineurs and by 3% of subjects with tension-type headache. In migraineurs, flunarizine was the most frequently used drug (18%), followed by antiepileptic drugs (7%) and pizotifen (6%), while cyproheptadine, propanolol and amitriptyline were rarely used. Pizotifen showed the best perceived efficacy and tolerability. Melatonin and nutraceuticals were used by 10% and 32% of subjects, respectively, both for migraine and tension-type headache, with good results in terms of perceived efficacy and tolerability. Non-pharmacological preventive treatments (i.e. relaxation techniques, biofeedback, cognitive-behavioral therapy, acupuncture) were used only by 10% of cases (migraine 9%, tension-type headache 15%). DISCUSSION: Non-steroidal anti-inflammatory drugs, especially ibuprofen, should be preferred to acetaminophen for acute attacks of migraine or tension type headache, because they were usually more effective and well tolerated. Triptans could be used more frequently as first or almost second choice for treating migraine attack in adolescents. Non-pharmacological preventive treatments are recommended by some pediatric guidelines as first-line interventions for primary headaches and their use should be implemented in clinical practice. Prospective multicenter studies based on larger series are warranted to better understand the best treatment strategies for young people with primary headaches. PMID- 28082016 TI - A Tablet for Healthy Ageing: The Effect of a Tablet Computer Training Intervention on Cognitive Abilities in Older Adults. AB - OBJECTIVE: To test the efficacy of a tablet computer training intervention to improve cognitive abilities of older adults. DESIGN: Prospective randomized controlled trial. SETTING: Community-based aging intervention study, Edinburgh, UK. PARTICIPANTS: Forty-eight healthy older adults aged 65 to 76 years were recruited at baseline with no or minimal tablet experience; 43 completed follow up testing. INTERVENTION: Twenty-two participants attended a weekly 2-hour class for 10 weeks during which they learned how to use a tablet and various applications on it. MEASUREMENTS: A battery of cognitive tests from the WAIS-IV measuring the domains of Verbal Comprehension, Perceptual Processing, Working Memory, and Processing Speed, as well as health, psychological, and well-being measures. RESULTS: A 2 * 2 mixed model ANOVA suggested that the tablet intervention group (N = 22) showed greater improvements in Processing Speed (eta2 = 0.10) compared with controls (N = 21), but did not differ in Verbal Comprehension, Perceptual Processing, or Working Memory (eta2 ranged from -0.03 to 0.04). CONCLUSIONS: Engagement in a new mentally challenging activity (tablet training) was associated with improved processing speed. Acquiring skills in later life, including those related to adopting new technologies, may therefore have the potential to reduce or delay cognitive changes associated with ageing. It is important to understand how the development of these skills might further facilitate everyday activities, and also improve older adults' quality of life. PMID- 28082017 TI - Physical Activity and the Hippocampus in Older Adults. PMID- 28082018 TI - Association Between Exercise Capacity and Late Onset of Dementia, Alzheimer Disease, and Cognitive Impairment. AB - OBJECTIVE: To address the association between exercise capacity and the onset of dementia, Alzheimer disease, and cognitive impairment. PATIENTS AND METHODS: For 6104 consecutive veteran patients (mean +/- SD age: 59.2+/-11.4 years) referred for treadmill exercise testing, the combined end point of dementia, Alzheimer disease, and cognitive impairment was abstracted from the Veterans Affairs computerized patient record system. RESULTS: After mean +/- SD follow-up of 10.3+/-5.5 years, 353 patients (5.8%) developed the composite end point at a mean +/- SD age of 76.7+/-10.3 years. After correction for confounders in multivariate Cox proportional hazards regression, higher age at exercise testing (hazard ratio [HR]=1.08; 95% CI, 1.07-1.09; P<.001), current smoking (HR=1.44; 95% CI, 1.08 1.93; P=.01), and exercise capacity (HR=0.92; 95% CI, 0.89-0.96; P<.001) emerged as predictors of cognitive impairment. Each 1-metabolic equivalent increase in exercise capacity conferred a nearly 8% reduction in the incidence of cognitive impairment. Meeting the recommendations for daily activity was not associated with a delay in onset of cognitive impairment (HR=1.07; 95% CI, 0.86-1.32; P=.55). CONCLUSION: Exercise capacity is strongly associated with cognitive function; the inverse association between fitness and cognitive impairment provides an additional impetus for health care providers to promote physical activity. PMID- 28082019 TI - Mediatory role of NMDA, AMPA/kainate, GABAA and Alpha2 receptors in topiramate neuroprotective effects against methylphenidate induced neurotoxicity in rat. AB - Prolonged abuse of methylphenidate (MPH) often causes neuronal damage. Topiramate (TPM) has neuroprotective properties, but its mechanism of action remains unclear. The current study evaluates in vivo role of various doses of TPM (10, 30, 50, 70 and 100mg/kg) and its possible mechanisms against MPH-induced hippocampal oxidative stress, inflammation and apoptosis, in absence and presence of different receptor agonists and antagonists. Domoic acid (DOM) as AMPA/kainate receptor agonist, bicuculline (BIC) as GABAA receptor antagonist, ketamine (KET) as NMDA receptor antagonist, yohimbine (YOH) as alpha2 adrenergic receptor antagonist and haloperidole (HAL) as D2 dopamine receptor antagonist was used. Open Field Test (OFT) was used to investigate the disturbances in motor activity. Hippocampal oxidative, anti-oxidant and inflammatory parameters and apoptotic factors were studied. Expressions of BDNF at gene and protein levels were also evaluated. Crystal violet staining was performed to determine neuronal cell density. TPM (70 and 100mg/kg) reduced MPH-induced rise in lipid peroxidation, oxidized form of glutathione (GSSG), IL-1beta and TNF-alpha levels, Bax expression and motor activity disturbances. In addition, TPM treatment increased BDNF gene and protein expressions, Bcl-2 expression, the level of reduced form of glutathione (GSH) and activities of enzymes superoxide dismutase, glutathione peroxidase and glutathione reductase.TPM also inhibited MPH-induced hippocampal degeneration. Pretreatment of animals with DOM, BIC, KET and YOH inhibited TPM induced neuroprotection and increased oxidative stress, neuroinflammation, neuroapoptosis and neurodegeneration while reducing BDNF expressions. Thus, TPM by interacting with AMPA/kainate, GABAA, NMDA and alpha2-adrenergic receptors improves BDNF expression and acts as a neuroprotective agent against MPH-induced neurodegeneration. PMID- 28082020 TI - miR424-5p functions as an anti-oncogene in cervical cancer cell growth by targeting KDM5B via the Notch signaling pathway. AB - AIMS: Aberrant expression of miRNAs exert the critical roles in carcinogenesis, including cervical cancer. Recent study corroborated the down-regulation of miR424-5p in uterine cervix adenocarcinoma. This research aimed to investigate the function and underlying mechanisms of miR424-5p in cervical cancer cell growth. MAIN METHODS: Tissues samples were collected from patients with cervical cancer and healthy control. The expression levels of miR424-5p were determined by qRT-PCR. After transfection with miR424-5p mimics or inhibitor, cervical cancer cell proliferation and apoptosis were evaluated by WST-1 and flow cytometry assay, respectively. The underlying mechanism involved in aforementioned processes was also explored. KEY FINDINGS: Expression of miR424-5p was notably decreased in cervical cancer tissues and cells. Overexpression of miR424-5p restrained cell proliferation and promoted cell apoptosis, but with little function in miR424-5p inhibitor-treated groups. Furthermore, KDM5B was identified as a direct target of miR424-5p as the evidence that miR-424-5p inhibited KDM5B expression and luciferase activity of KDM5B 3'-UTR. Here, KDM5B elevation majorly reversed miR424-5p-triggered inhibition in cell proliferation and increase in cell apoptosis. Moreover, silencing KDM5B expression also restrained cell growth. Additionally, miR424-5p overexpression inhibited the expression of Notch1 and Notch2, which was obviously rescued after KDM5B up-regulation. Simultaneously, blocking KDM5B also attenuated the activation of Notch pathway. Importantly, treatment with Notch agonist Jagged1 antagonized miR424-5p-mediated suppression on cell growth. SIGNIFICANCE: This research suggests that miR424-5p may act as a novel anti-oncogene in cervical cancer by blocking cell growth through targeting KDM5B-Notch pathway. Accordingly, our study will support a promising therapeutic strategy against cervical carcinoma. PMID- 28082021 TI - Somatic hypermutation of immunoglobulin genes in Rad18 knockout mice. AB - Somatic hypermutation (SHM) of immunoglobulin (Ig) genes is triggered by the activity of activation-induced cytidine deaminase (AID). AID induces DNA lesions in variable regions of Ig genes, and error-prone DNA repair mechanisms initiated in response to these lesions introduce the mutations that characterize SHM. Error prone DNA repair in SHM is proposed to be mediated by low-fidelity DNA polymerases such as those that mediate trans-lesion synthesis (TLS); however, the mechanism by which these enzymes are recruited to AID-induced lesions remains unclear. Proliferating cell nuclear antigen (PCNA), the sliding clamp for multiple DNA polymerases, undergoes Rad6/Rad18-dependent ubiquitination in response to DNA damage. Ubiquitinated PCNA promotes the replacement of the replicative DNA polymerase stalled at the site of a DNA lesion with a TLS polymerase. To examine the potential role of Rad18-dependent PCNA ubiquitination in SHM, we analyzed Ig gene mutations in Rad18 knockout (KO) mice immunized with T cell-dependent antigens. We found that SHM in Rad18 KO mice was similar to wild type mice, suggesting that Rad18 is dispensable for SHM. However, residual levels of ubiquitinated PCNA were observed in Rad18 KO cells, indicating that Rad18 independent PCNA ubiquitination might play a role in SHM. PMID- 28082022 TI - Cellular cholesterol regulates monocyte deformation. AB - The role of cholesterol content on monocyte biomechanics remains understudied despite the well-established link between cholesterol and monocytes/macrophages in atherosclerosis, and the effect on other cell types. In this work, we have investigated the effect of cholesterol on monocyte deformability and the underlying molecular mechanisms. We altered the baseline cholesterol in human monocytic cell line THP-1, and investigated the changes in monocyte deformability using a custom microfluidic platform and atomic force microscopy. We observed that the cholesterol depletion lowered deformability while enrichment increased deformability compared to untreated cells. As a consequence of altered deformability, cholesterol depleted cells spread more on collagen-coated surfaces with elongated morphology, whereas cholesterol enriched cells had a more rounded morphology. We observed that the decreased deformability in cholesterol depleted cells, despite an increase in the fluidity of the membrane, is due to an increase in phosphorylation of Protein Kinase C (PKC), which translates to a higher degree of actin polymerization. Together, our results highlight the importance of biophysical regulation of monocyte response to cholesterol levels. PMID- 28082023 TI - Oxidative damage and redox in Lysosomal Storage Disorders: Biochemical markers. AB - Lysosomal Storage Disorders (LSD) comprise a heterogeneous group of >50 genetic disorders caused by mutations in genes that encode lysosomal enzymes, transport proteins or other gene products essential for a functional lysosomal system. As a result, abnormal accumulation of substrates within the lysosome leads to a progressive cellular impairment and dysfunction of numerous organs and systems. The exact mechanisms underlying the pathophysiology of LSD remain obscure. Previous studies proposed a relationship between oxidative stress and the pathogenesis of several inborn errors of metabolism, including LSD. Considering these points, in this paper it was reviewed oxidative stress and emerging antioxidant therapy in LSD, emphasizing studies with biological samples from patients affected by this group of conditions. These studies allow presuming that metabolites accumulated in LSD cause an increase of lysosomes' number and size, which may induce excessive production of reactive species and/or deplete the tissue antioxidant capacity, leading to damage in biomolecules. In vitro and in vivo evidence showed that cell oxidative process occurs in LSD and probably contributes to the pathophysiology of these disorders. In this context, it is possible to suggest that, in the future, antioxidants could come to be used as adjuvant therapy for LSD patients. PMID- 28082024 TI - Associations of the fatty liver and hepatic steatosis indices with risk of cardiovascular disease: Interrelationship with age. AB - BACKGROUND: The fatty liver index (FLI) and the hepatic steatosis index (HSI), are biomarker-based algorithms developed as proxies for non-alcoholic fatty liver disease (NAFLD). We assessed associations of FLI and HSI with cardiovascular disease (CVD) risk. MATERIALS AND METHODS: The FLI and HSI were estimated at baseline in the PREVEND cohort involving 6340 participants aged 28-75years without pre-existing CVD. RESULTS: During a median follow-up of 10.5years, 631 CVD events occurred. In age-and sex-adjusted analysis, the hazard ratio (HR) (95% CI) for CVD comparing FLI>=60 versus FLI<30 was 1.53 (1.25-1.88); which was attenuated to 0.89 (0.70-1.13) on adjustment for conventional cardiovascular risk factors. The association remained absent after additional adjustment for potential confounders 0.85 (0.65-1.11). Comparing HSI>36 versus HSI<30, the corresponding adjusted HRs were 1.29 (1.02-1.65), 0.84 (0.65-1.09) and 0.79 (0.55 1.13) respectively. Subgroup analyses suggested a positive association in younger participants (<50years) for FLI and inverse associations in older participants (>=50years) for both indices (P for interaction for all=0.001). CONCLUSION: Current data suggest age interactions in the association of NAFLD (as assessed by FLI or HSI) with CVD risk in a general Caucasian population. PMID- 28082025 TI - Mitral Regurgitation After Orthotopic Lung Transplantation: Natural History and Impact on Outcomes. AB - OBJECTIVE: Progression of mitral regurgitation (MR) after orthotopic lung transplantation (OLT) may be an underrecognized phenomenon due to the overlapping symptomatology of pulmonary and valvular disease. Literature evaluating the progression of MR after OLT currently is limited to case reports. Therefore, the hypothesis that MR progresses after OLT was tested and the association of preprocedure MR with postoperative mortality was assessed. DESIGN: A retrospective cohort. SETTING: A tertiary-care hospital. PARTICIPANTS: Patients who underwent OLT between January 1, 2003 and February 4, 2012. INTERVENTIONS: After receiving institutional review board approval, a preprocedure transesophageal echocardiogram was compared with a postoperative transthoracic echocardiogram (TTE) to determine the progression of MR. Univariate and multivariate association between preprocedure MR grade and 1- and 5-year mortality was assessed. A p value of<0.05 was considered statistically significant. MEASUREMENTS AND MAIN RESULTS: From 715 patients who underwent OLT, 352 had a postoperative TTE and were included in the evaluation of progression of MR. Five patients had progression of MR postoperatively, and the mean change in MR score of -0.04 was found to be nonsignificant (p = 0.25). Mortality data were available for 634 of the 715 patients. After covariate adjustment, there was no significant association between MR grade and 1-year mortality (p = 0.20) or 5 year mortality (p = 0.46). CONCLUSIONS: This study rejected the hypothesis that primary and secondary MR progresses after OLT and found that preprocedure MR was not associated with increased postoperative mortality. Despite the findings that MR does not progress in all patients, there is a subset of patients for whom MR progression is clinically significant. PMID- 28082026 TI - Blood and Anticoagulation Management in Extracorporeal Membrane Oxygenation for Surgical and Nonsurgical Patients: A Single-Center Retrospective Review. AB - OBJECTIVE: To describe blood management and anticoagulation practice for cardiac and respiratory extracorporeal membrane oxygenation (ECMO) with consideration of major surgery at the time of its initiation. DESIGN: A single-center retrospective review over 18 months of blood product usage and anticoagulation in patients treated with veno-venous (VV) ECMO versus veno-arterial (VA) ECMO and after major surgery (Sx) versus no surgery (Nsx). SETTING: Tertiary metropolitan hospital and state ECMO referral and heart and lung transplantation center. PARTICIPANTS: The study comprised 42 patients representing 48 consecutive ECMO runs (16 VV, 32 VA, 26 Sx, 22 Nsx). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thirty-three percent of the total run time of 362 days was with no continuous infusion of heparin. The mean (standard deviation) daily dose of heparin was lower for Sx versus Nsx patients (11,397 [9,297] v 17,324 [10,387] U, p = 0.047). Sx patients also received more fresh frozen plasma (1.1 [1.93] v 0.2 [0.59] U per day, p = 0.049) and platelets (0.5 [0.51] v 0.1 [0.25] U per day, p = 0.003). VV patients received fewer packed red cells (0.7 [0.45] v 2.0 [2.04] U per day, p = 0.016) and platelets (0.1 [0.18] v 0.4 [0.49] U per day, p = 0.008) compared with VA patients. Survival to hospital discharge was 69%. CONCLUSIONS: Heparin doses were low, with frequent interruption of anticoagulation. This was more pronounced in patients with a high bleeding risk recovering from major surgery. The overall usage of blood products was low in VV and Nsx patients, with an overall excellent survival rate. PMID- 28082027 TI - "CAPS" Cardiac Acute Pain Services-A Nationwide Survey From Canada. AB - OBJECTIVES: Acute Pain Services (APS) are well-established worldwide; however, their availability and use in cardiac surgery units are less widespread and, even where present, may be provided less consistently. The authors undertook this survey to assess the current organization of Cardiac Acute Pain Services (CAPS) in Canada. DESIGN: This was a prospectively administered survey. SETTING: This study included all centers in Canada that conducted adult cardiac surgery. PARTICIPANTS: The participants were anesthesiologists. INTERVENTION: A 20-item questionnaire covered the demographics, functioning and APS structure. RESULTS: The authors achieved a response rate of 100% with completed questionnaires from all 31 centers. Ten centers (32.3%) stated that they had a dedicated CAPS, 9 centers (29%) stated that they did not have an APS, and 12 centers (38.7%) had APS but no CAPS. At the time of the survey for the 10 centers with CAPS, 3 of the CAPS had a physician-run model, 4 had a combined physician and nurse service, and 1 used a combination of protocols, intensivists, and nurse practitioners. Nine centers had an anesthesiologist assigned to daily acute pain rounds. Only in 2 of 10 centers with CAPS were more than 50% of their cardiac surgery patients receiving care. In general, postoperative pain management was a protocol-driven activity. CONCLUSIONS: CAPS are varied in both structure and functioning. Further work is required both at the institutional and the national levels to improve the postoperative care and the pain-related outcomes of patients undergoing cardiac surgery. PMID- 28082028 TI - Dealing With the Aftermath of an Atrial Fibrillation Procedure: Another Role for Echocardiography. PMID- 28082029 TI - Chikungunya and Coronary Artery Bypass Graft Surgery. PMID- 28082030 TI - Brain Oxygen Supply Parameters in the Risk Assessment of Cerebral Complications During Carotid Endarterectomy. AB - OBJECTIVE: To determine whether preoperative regional cerebral oxygen saturation (rSO2) and the decrease in rSO2 during carotid clamping were predictive of the risk for neurologic complications in carotid endarterectomy and to determine the cutoff values of the studied parameters. DESIGN: Cohort, prospective, nonrandomized trial. SETTING: Research Institute of Circulation Pathology, Novosibirsk, Russia. PARTICIPANTS: The study comprised 466 adults who underwent carotid endarterectomy since 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient characteristics, postoperative complications, and brain oxygen supply during carotid endarterectomy were analyzed. The primary endpoints were the perioperative and early postoperative neurologic complications. Ischemic stroke was diagnosed in 1.5% of patients, and cognitive disorders were reported in 2.6% of patients. Preoperative rSO2 of 50% was the cutoff value for the prediction of stroke outcome after carotid endarterectomy, with a sensitivity of 90.7% and specificity of 66.7%. A 20% decrease in rSO2 during temporary carotid clamping was the cutoff value for the prediction of stroke, with a sensitivity of 86.0% and specificity of 57.1%, and for the prediction of cognitive disorders, with a sensitivity of 88.1% and specificity of 58.3%. Preoperative rSO2 less than 50% and a decrease in rSO2 of at least 20% during temporary carotid artery clamping caused a significant increase in the hospitalization period. CONCLUSIONS: A 20% or more decrease in rSO2 during temporary internal carotid artery clamping during carotid endarterectomy caused a 10-fold increased risk of ischemic stroke and an 8-fold increased risk of cognitive disorders, whereas preoperative rSO2 less than 50% resulted in a 6-fold increased risk of ischemic stroke in the perioperative and early postoperative periods of carotid endarterectomy. PMID- 28082031 TI - Reliability of Percutaneous Pulmonary Vent and Coronary Sinus Cardioplegia in the Setting of Minimally Invasive Aortic Valve Replacement: A Single-Center Experience. AB - OBJECTIVES: Evaluating the efficacy of 2 new percutaneous devices specifically designed to be placed through the right internal jugular vein, therefore named "necklines," for achieving retrograde cardioplegia and pulmonary venting in the setting of minimally invasive aortic valve replacement (MIAVR). DESIGN: Case series. SETTING: University-affiliated private hospital. PARTICIPANTS: Patients undergoing MIAVR. INTERVENTIONS: Necklines were placed by the anesthesiologist using transesophageal electrocardiography, with pressure guidance before the surgical procedure was initiated. MEASUREMENTS AND MAIN RESULTS: The records of 51 consecutive patients who underwent MIAVR with necklines placement were reviewed retrospectively. The access for MIAVR was through either a J hemisternotomy or a right anterior thoracotomy. The efficacy of the 2 catheters, successful placement rate, time needed to deploy catheters, and perioperative complications were recorded. Necklines were placed successfully in all patients in 23+/-13 minutes. A total of 110 doses of retrograde cardioplegia were delivered at a mean flow rate of 173+/-35 mL/min and a mean pressure of 41+/-6 mmHg. The pulmonary catheter ensured venting of the heart that was graded by surgeons as "excellent" in 33 patients, "sufficient" in 12 patients, and "not adequate" in 2 patients. There were no major adverse events or deaths. CONCLUSIONS: Necklines ensure effective retrograde cardioplegia and venting of the heart, provide optimal surgical vision and access during MIAVR, and allow surgeons to operate in an unobstructed surgical field. Nevertheless, additional studies are required to determine whether the use of necklines is associated with better outcomes than those with conventional methods. PMID- 28082033 TI - Community pharmacy-based point-of-care testing: A case study of pharmacist physician collaborative working relationships. AB - Building collaborative working relationships (CWRs) with physicians or other prescribers is an important step for community pharmacists in establishing a collaborative practice agreement (CPA). This case study describes the individual, context, and exchange factors that drive pharmacist-physician CWR development for community pharmacy-based point-of-care (POC) testing. Two physicians who had entered in a CPA with community pharmacists to provide POC testing were surveyed and interviewed. High scores on the pharmacist-physician collaborative index indicated a high level of collaboration between the physicians and the pharmacist who initiated the relationship. Trust was established through the physicians' personal relationships with the pharmacist or due to the community pharmacy organization's strong reputation. The physicians' individual perceptions of community pharmacy-based POC testing affected their CWRs and willingness to establish a CPA. These findings suggest that exchange characteristics remain significant factors in CWR development. Individual factors may also contribute to physicians' willingness to advance their CWR to include a CPA for POC testing. PMID- 28082032 TI - Recommendations for the use of parenteral methotrexate in rheumatic diseases. AB - OBJECTIVE: To develop recommendations for the use of parenteral methotrexate (MTX) in rheumatic diseases, mainly rheumatoid arthritis, based on best evidence and experience. METHODS: A group of 21 experts on parenteral MTX use was selected. The coordinator formulated 13 questions about parenteral MTX (indications, efficacy, safety and cost-effectiveness). A systematic review was conducted to answer the questions. Using this information, inclusion and exclusion criteria were established, as were the search strategies (involving Medline, EMBASE and the Cochrane Library). Three different reviewers selected the articles. Evidence tables were created. Abstracts from the European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) were evaluated. Based on this evidence, the coordinator proposed preliminary recommendations that the experts discussed and voted in a nominal group meeting. The level of evidence and grade of recommendation were established using the Oxford Center for Evidence-Based Medicine and the level of agreement with the Delphi technique (2 rounds). Agreement was established if at least 80% of the experts voted yes (yes/no). RESULTS: Most of the evidence involved rheumatoid arthritis. A total of 13 preliminary recommendations on the use of parenteral MTX were proposed; 11 of them were accepted. Two of the 13 were not voted and are commented on in the main text. CONCLUSIONS: The manuscript aims to solve frequent questions and help in decision-making strategies when treating patients with parenteral MTX. PMID- 28082034 TI - Enhanced Oral Care and Health Outcomes Among Nursing Facility Residents: Analysis Using the National Long-Term Care Database in Japan. AB - BACKGROUND AND OBJECTIVE: Although oral care may have salutary effects among frail elderly people, access to dental care is often limited in long-term care facilities. In 2009, the Japanese long-term care insurance system introduced an additional reimbursement scheme for enhanced oral care supervised by dentists in nursing facilities. The aim of this study was to examine whether enhanced oral care provided by trained nursing facility staff members is sufficient to improve health outcomes among nursing facility residents. DESIGN, SETTING, AND PARTICIPANTS: This was a quasi-experimental study using a nationwide long-term care database. Using facility-level propensity score matching, we identified 170,874 residents in 742 facilities that provided enhanced oral care and 167,546 residents in 742 control facilities that provided only standard care from 2009 to 2012. We used a resident-level difference-in-differences approach to analyze the impact of enhanced oral care on health outcomes among nursing facility residents. RESULTS: After controlling for resident characteristics and background time trends, no significant differences were found between residents admitted to the facilities with and without enhanced oral care in the incidence of critical illness, transfer to a hospital, mortality, or costs. Yearly change in the odds of discharge to home was significantly increased for residents with enhanced oral care (odds ratio = 1.07; 95% confidence interval: 1.02-1.12; P = .008). CONCLUSION: The results suggest that enhanced oral care provided by trained nursing facility staff members may improve the general condition of elderly residents in nursing facilities and promote their discharge to home. PMID- 28082035 TI - Bifunctional bisphosphonate derivatives and platinum complexes with high affinity for bone hydroxyapatite. AB - A series of ethylenediamine/1,3-propanediamine derivatives containing bifunctional bisphosphonate substituents and their corresponding dichloroplatinum(II) complexes have been synthesized and characterized by elemental analysis, 1H NMR, 13C NMR, 31P NMR, and HRMS spectra. Based on WST-8 assay with CCK-8, in general, the newly synthesized dichloroplatinum complexes 1 6 showed higher in vitro antitumor activity than platinum-free compounds L1-L6 against three tumor cell lines (especially osteosarcoma MG-63). According to hydroxyapatite binding experiment, complexes 2, 3, and 6 showed much higher affinity (K'=3.7, 4.0, and 3.0, respectively) for bone hydroxyapatite than cisplatin (K'<0.1), comparable to zoledronate (K'=2.8). It can be found that representative complex 2 with high cytotoxicity and in vitro antiproliferative activity against osteosarcoma cell line, as well as promising hydroxyapatite binding ability has been screened as a potential bone-targeting antitumor agent for subsequent in vivo study. In addition, flow cytometry experiment was applied to investigate the mode of action of representative complex 2. PMID- 28082037 TI - Sulfonamide-based non-alkyne LpxC inhibitors as Gram-negative antibacterial agents. AB - We attempted to optimize sulfonamide-based non-alkyne LpxC inhibitors by focusing on improvements in enzyme inhibitory and antibacterial activity. It was discovered that inhibitors possessing 2-aryl benzofuran as a hydrophobe exhibited good activity. In particular, compound 21 displayed impressive antibacterial activity (E. coli MIC=0.063MUg/mL, K. pneumoniae MIC=0.5MUg/mL, and P. aeruginosa MIC=0.5MUg/mL), and is a promising lead for further exploration as an antibacterial agent. PMID- 28082036 TI - Structure-based optimization of 1H-imidazole-2-carboxamides as Axl kinase inhibitors utilizing a Mer mutant surrogate. AB - Axl has been a target of interest in the oncology field for several years based on its role in various oncogenic processes. To date, no wild-type Axl crystal structure has been reported. Herein, we describe the structure-based optimization of a novel chemotype of Axl inhibitors, 1H-imidazole-2-carboxamide, using a mutated kinase homolog, Mer(I650M), as a crystallographic surrogate. Iterative optimization of the initial lead compound (1) led to compound (21), a selective and potent inhibitor of wild-type Axl. Compound (21) will serve as a useful compound for further in vivo studies. PMID- 28082038 TI - Design, synthesis and biological activity evaluation of novel 2,6 difluorobenzamide derivatives through FtsZ inhibition. AB - Novel series of 3-substituted 2,6-difluorobenzamide derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their in vitro antibacterial activity against various phenotype of Gram-positive and Gram negative bacteria, and their cell division inhibitory activity against three representative strains. As a result, 3-chloroalkoxy derivative 7, 3-bromoalkoxy derivative 12 and 3-alkyloxy derivative 17 were found to exhibit the best antibacterial activity against Bacillus subtilis with MICs of 0.25-1MUg/mL, and good activity (MIC<10MUg/mL) against both susceptible and resistant Staphylococcus aureus. Additionally, all the three compounds displayed potent cell division inhibitory activity with MIC values of below 1MUg/mL against Bacillus subtilis and Staphylococcus aureus. PMID- 28082039 TI - Synthesis and antioxidant activity of a procyanidin B3 analogue. AB - Proanthocyanidin, an oligomer of catechin, is a natural antioxidant and a potent inhibitor of lectin-like oxidized LDL receptor-1, which is involved in the pathogenesis of arteriosclerosis. We synthesized proanthocyanidin analogue 1, in which the geometry of one catechin molecule in procyanidin B3, a dimer of (+) catechin, is constrained to be planar. The antioxidant activities of the compounds were evaluated in terms of their capacities to scavenge galvinoxyl radicals, and results demonstrate that while procyanidin was 3.8 times more potent than (+)-catechin, the radical scavenging activity of proanthocyanidin analogue 1 was further increased to 1.9 times that of procyanidin B3. This newly designed proanthocyanidin analogue 1 may be a promising lead compound for the treatment of arteriosclerosis and related cerebrovascular diseases. PMID- 28082040 TI - Discovery of medium ring thiophosphorus based heterocycles as antiproliferative agents. AB - Hydrogen sulfide (H2S) has been investigated for its potential in therapy. Recently, we reported novel H2S donor molecules based on a thiophosphorus core, which slowly release H2S and have improved anti-proliferative activity in cancer cell lines compared to the most widely studied H2S donor GYY4137 (1). Herein, we have prepared new thiophosphorus organic H2S donors with different ring sizes and evaluated them in two solid tumor cell lines and one normal cell line. A seven membered ring compound, 17, was found to be the most potent with sub-micromolar IC50s in breast (0.76MUM) and ovarian (0.76MUM) cancer cell lines. No significant H2S release was detected in aqueous solution for this compound. However, confocal imaging showed that H2S was released from 17 inside cells at a similar level to the widely studied H2S donor GYY4137, which was shown to release 10MUM H2S after 12h at a concentration of 400MUM. Comparison of 17 with its non-sulfur oxygen analogue, 26, provided evidence that the sulfur atom is important for its potency. However, the significant potency observed for 26 (5.94-11.0MUM) indicates that the high potency of 17 is not entirely due to release of H2S. Additional mechanism(s) appear to be responsible for the observed activity, hence more detailed studies are required to better understand the role of H2S in cancer with potent thiophosphorus agents. PMID- 28082041 TI - Curculactones A and B induced the differentiation of C3H10T1/2 and MC3T3-E1 cells to osteoblasts. AB - Curculactones A and B are rare gamma-lactone derivatives obtained from yellow, natural curcumin following gamma-irradiation, and are a type of small molecules with a moderate anti-obesity effect. However, the exact role of curculactones A and B in osteoblast differentiation is unknown. In this study, the effects of curculactones A and B on the differentiation of the mesenchymal cell line C3H10T1/2 and pre-osteoblast cell line MC3T3-E1 to osteoblasts were examined. Curculactones A or B could markedly increase the mRNA levels of osteogenic marker genes and alkaline phosphatase (ALP) activity. Collectively, our findings indicate that curculactones A or B induced osteoblast differentiation through osteogenic expression of genes such as distal-less homeobox 5 (Dlx5), runt related transcription factor 2 (Runx2), ALP, and osteocalcin (OC). PMID- 28082042 TI - Cementless vs Cemented Tibial Fixation in Primary Total Knee Arthroplasty. AB - BACKGROUND: The ideal fixation for modern tibial components in total knee arthroplasty (TKA) remains controversial with uncertainty on whether cementless implants can yield equivalent outcomes to cemented fixation in early follow-up. METHODS: A series of 70 consecutive cases with reverse hybrid cementless fixation were matched to 70 cemented cases from 2008 to 2015 based on implant design and patient demographics. RESULTS: Cementless TKA demonstrated greater aseptic loosening (7 vs 0, P = .013) and revision surgery (10 vs 0, P = .001) than cemented fixation within 5 years of follow-up, but with no clinically significant differences in outcome scores. CONCLUSION: It remains unclear whether early aseptic loosening in cementless TKA can be reduced with enhanced adjunct fixation and what proportion of early failure justifies the potential lifelong fixation through biologic ingrowth of cementless tibial components. PMID- 28082043 TI - Superior Survivorship of Cementless vs Cemented Diaphyseal Fixed Modular Rotating Hinged Knee Megaprosthesis at 7 Years' Follow-Up. AB - BACKGROUND: Total knee arthroplasty in the presence of a huge bone and soft tissue defect is always a challenge. A rotating-hinged (RH) megaprosthesis is indicated for extensive soft-tissue loss with a huge bone defect such as a primary or metastatic neoplasm of the bone, repeat periprosthetic joint infection, or extensive trauma of the knee. However, the reported survivorship of RH megaprostheses is unsatisfactory. The aim of this study was to evaluate the survivorship of megaprostheses and the factors that contribute to implant survival. METHODS: A total of 103 RH knee megaprostheses were implanted in 85 patients between January 2001 and June 2013. Each prosthesis was a modular custom made (CM) cemented or cementless fixed total knee system (United USTAR system). Clinical results and prosthesis survivorship were evaluated between the 2 groups. RESULTS: The overall survivorship of this CM knee megaprosthesis was 91% at 2 years, 83% at 5 years, and 68% at 10 years. The cumulative component survivorship was 87% in the cemented group and 96% in the cementless group at 2 years compared with 75% in the cemented group and 94% in the cementless group at 5 years. The failure mechanism included loosening in 5 and breakage in 6 patients in the cemented stem group. The survivorship of the cementless fixed component was significantly superior to that of the cemented fixed component. CONCLUSION: Our data suggest that modular RHCM knee megaprosthesis provides an acceptable clinical result. A diaphyseal long stem with cementless fixation was more reliable and durable than its cemented counterpart. PMID- 28082045 TI - Advantages in Using Cemented Polished Tapered Stems When Performing Total Hip Arthroplasty in Very Young Patients. AB - BACKGROUND: The risk of revision following primary total hip arthroplasty (THA) is increased in young patients who undergo THA for pathologies other than primary osteoarthritis. We report the results of primary THA performed with cemented polished stems in patients aged 40 years and younger for pathologies other than primary osteoarthritis. METHODS: We investigated 52 patients (65 hips) who underwent primary THA for secondary osteoarthritis with a cemented tapered polished stem between 1990 and 2007. Clinical and radiographic outcomes, available in 46 patients (57 hips), included the Harris Hip Scores, Societe Internationale de Chirurgie Orthopedique et de Traumatologie activity, patient satisfaction, stem survival and reoperations, and assessment of prosthesis-cement bone radiolucencies, osteolysis, and femoral bone deficiencies. RESULTS: Median patient age was 34 years (16-40) and follow-up was 14 years (mean 13, range 5 22). Stem survival to the endpoint revision for loosening was 100% and to the endpoint revision for any reason, excluding infection was 88% (95% confidence interval 78-98) at 16 years. No stem was revised for aseptic loosening. Nine stems were revised for other reasons. Radiographically, one stem was definitely loose at 16 years. The median patient Harris pain score improved from marked pain to no pain at latest follow-up. Patient activity level improved, albeit minimally, for 8 years after surgery. At latest follow-up, 98% of the patients remained satisfied with their surgery. CONCLUSION: Primary THA with a cemented polished stem shows excellent results in young patients with pathology other than primary osteoarthritis. In addition, the stem design facilitates cement within cement exchange and therefore preservation of proximal femoral bone stock at revision surgery. PMID- 28082044 TI - The Efficacy of Liposomal Bupivacaine Using Periarticular Injection in Total Knee Arthroplasty: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Total knee arthroplasty (TKA) is gradually emerging as the treatment of choice for end-stage osteoarthritis. In the past, the method of liposomal bupivacaine by periarticular injection (PAI) showed better effects on pain reduction and opioid consumption after surgery. However, some recent studies have reported that liposomal bupivacaine by PAI did not improve pain control and functional recovery in patients undergoing TKA. Therefore, this meta-analysis was conducted to determine whether liposomal bupivacaine provides better pain relief and functional recovery after TKA. METHODS: Web of Science, PubMed, Embase, and the Cochrane Library were comprehensively searched. Randomized controlled trials, controlled clinical trials, and cohort studies were included in our meta analysis. Eleven studies that compared liposomal bupivacaine using the PAI technique with the conventional PAI method were included in our meta-analysis. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines and Cochrane Handbook were applied to assess the quality of the results published in all included studies to ensure that the results of our meta analysis were reliable and veritable. RESULTS: Our pooled data analysis demonstrated that liposomal bupivacaine was as effective as the control group in terms of visual analog scale score at 24 hours (P = .46), 48 hours (P = .43), 72 hours (P = .21), total amount of opioid consumption (P = .25), range of motion (P = .28), length of hospital stay (P = .53), postoperative nausea (P = .34), and ambulation distance (P = .07). CONCLUSION: Compared with the conventional PAI method, liposomal bupivacaine shows similar pain control and functional recovery after TKA. Considering the cost for pain control, liposomal bupivacaine is not worthy of being recommended as a long-acting alternative analgesic agent using the PAI method. PMID- 28082046 TI - A comprehensive evaluation for the treatment of lupus nephritis. AB - Systemic lupus is the prototypic human autoimmune disease. It is a kaleidoscope of autoreactivities, with clear indications of both a genetic and environmental basis. Indeed, it is a disease that can manifest in virtually every tissue and organ and can also be found spontaneously in a number of animal species, including dogs, cats and horses. Moreover, there are multiple murine models of lupus, the first of which, New Zealand Black (NZB) mice, were discovered in 1959. Despite an enormous effort from scientists in multiple disciplines, the etiology of lupus remains elusive and the introduction of new therapies has been disappointing. Fortunately, significant advances have occurred to help patients through the general principles of internal medicine, including antibiotics, dialysis, and of course use of steroids and immunosuppressive agents. However, the magic bullet has yet to be discovered. One of the major causes of morbidity in lupus remains lupus nephritis and there has been significant effort and encouragement in understanding the pathogenesis, renal histologic classification, and use of therapeutic protocols to induce and sustain remission of lupus nephritis. Indeed, the first use of evidence-based clinical trials in lupus was initiated by Dr. Alfred D. Steinberg at NIH in pioneering studies involving either oral or intravenous pulses of cyclophosphamide, azathioprine or corticosteroids alone and/or some combination. Cyclophosphamide intravenously proved to be superior and the use of cyclophosphamide in combination with methylprednisolone remained the standard protocol for the treatment of lupus nephritis for decades. Although alternative therapies have been introduced, including mycophenolate mofetil, the use of therapies first pioneered at NIH may still be considered standard of care in the appropriate indications. More targeted therapies are much desired. In this review we provide a comprehensive overview of lupus nephritis and the evolution of clinical treatments. PMID- 28082047 TI - Smoking activates cytotoxic CD8+ T cells and causes survivin release in rheumatoid arthritis. AB - CD8+ T cells have an emerging role in RA. Resent research indicates a causal relationship between the non-exhausted state of CD8+ T cells, defined by lost function of PD-1, and development of arthritis. We investigated how smoking contributes to the non-exhausted phenotype of CD8+ T cells and cause survivin release to serum. We compared serum survivin levels between smokers and non smokers in 252 RA and 168 healthy subjects. Nicotine effects on CD8+ T cells were studied in peripheral blood of smoking women, bone marrow of nicotine treated mice and in sorted CD8 spleen cells in vitro using flow cytometry and quantitative PCR. Smoking increased the frequency of survivin release in serum of healthy women (OR 3.64, p = 0.025) and in RA patients (OR 1.98, p = 0.039). CD8+ T cells of smokers gained a non-exhausted PD-1 deficient phenotype. Expression of the cytotoxic marker CD107 correlated to survivin levels in serum. In the experimental setting, nicotine exposure led to an accumulation of non-exhausted PD-1-IL-7R+ CD8+ T cells in the bone marrow that is abundant with survivin producing cells. The production of the cytolytic protein perforin in bone marrow correlated to serum survivin levels. In vitro stimulation of nicotinic receptors on murine CD8+ T cells induced repressive transcription factors T-bet and Blimp-1 in support of the non-exhausted phenotype. We conclude that nicotine contributes to autoimmunity by supporting the non-exhausted state of CD8+ T cells resulting in the release of survivin. This presents a new mechanism by which smoking may contribute to the pathogenesis of RA. PMID- 28082048 TI - RET Fusion Lung Carcinoma: Response to Therapy and Clinical Features in a Case Series of 14 Patients. AB - BACKGROUND: RET (rearranged during transfection) fusions have been reported in 1% to 2% of lung adenocarcinoma (LADC) cases. In contrast, KIF5B-RET and CCDC6-RET fusion genes have been identified in 70% to 90% and 10% to 25% of tumors, respectively. The natural history and management of RET-rearranged LADC are still being delineated. MATERIALS AND METHODS: We present a series of 14 patients with RET-rearranged LADC. The response to therapy was assessed by the clinical response and an avatar model in 2 cases. Patients underwent chemotherapy, targeted therapy, and immunotherapy. RESULTS: A total of 14 patients (8 women; 10 never smokers; 4 light smokers; mean age, 57 years) were included. KIF5B-RET and CCDC6-RET variants were diagnosed in 10 and 4 cases, respectively. Eight patients had an early disseminated manifestation, seven with KIF5B-RET rearranged tumor. The features of this subset included bilateral miliary lung metastases, bone metastases, and unusual early visceral abdominal involvement. One such patient demonstrated an early and durable complete response to cabozantinib for 7 months. Another 2 patients treated with cabozantinib experienced a partial response, with rapid significant clinical improvement. Four patients with tumors harboring CCDC6 RET and KIF5B-RET fusions showed pronounced and durable responses to platinum based chemotherapy that lasted for 8 to 15 months. Two patients' tumors showed programmed cell death ligand 1-positive staining but did not respond to pembrolizumab. The median overall survival was 22.8 months. CONCLUSION: RET rearranged LADC in our series tended to occur as bilateral disease with early visceral involvement, especially with KIF5B fusion. Treatment with cabozantinib achieved responses, including 1 complete response. However, further studies are required in this group of patients. PMID- 28082049 TI - Evolution and Increasing Complexity of the Therapeutic Landscape in Advanced Non Small-cell Lung Cancer. AB - The therapeutic landscape in advanced non-small-cell lung cancer (NSCLC) is rapidly changing. Never have so many changes of major importance occurred within so short a time. The present perspective describes this rapid evolution and resultant increasing complexity in the therapeutic decision-making process for the practicing oncologist. PMID- 28082050 TI - Limits of internal fixation in long-bone fracture. AB - Alternatives to internal fixation of long-bone fracture comprise, depending on location, external fixation or joint replacement. Limitations comprise risk of infection and functional outcome quality, which vary according to technique. The present study examines these limitations, based on comparative or large-scale studies from which certain significant results emerge. Four main questions are dealt with: (1) the present role of locking plates; (2) conditions for intramedullary nailing in Gustilo grade IIIb open fracture; (3) the limitations of conversion from external fixation to intramedullary nailing in open lower leg fracture; (4) and the limitations of definitive anterograde femoral nailing in multiple trauma. Locking plate fixation has yet to prove clinical superiority in any of the anatomic sites for which good-quality comparative analyses are available. Infection risk in Gustilo grade IIIb open lower leg fracture is equivalent when treated by intramedullary nailing or external fixation, if wound care and debridement are effective, antibiotherapy is initiated rapidly and skin cover is restored within 7days. Conversion from primary external fixation to intramedullary nailing is possible if the external fixator was fitted less than 28days previously and skin cover was restored within 7days. The pulmonary and systemic impact of peripheral lesions or definitive anterograde intramedullary nailing of femoral fracture in multiple trauma calls for caution and what is known as "damage-control orthopedics" (DCO), a term covering the general consequences of both the initial trauma and its treatment. Femoral intramedullary nailing is thus contraindicated in case of hemorrhagic shock (blood pressure<90mmHg), hypothermia (<33 degrees C), coagulation disorder (platelet count<90,000) or peripheral lesions such as multiple long-bone fractures, crushed limb or primary pulmonary contusion. In such cases, external fixation or retrograde nailing with a small-diameter nail and without reaming are preferable. PMID- 28082051 TI - How does total knee replacement technique influence polyethylene wear? AB - In knee prostheses, wear is inherent to the tribology of the imperfectly congruent surfaces, one in chromium-cobalt alloy, the other in polyethylene. It is a multifactorial phenomenon, involving the properties of the respective materials and implant design, but also implant functioning, as determined by the implantation technique. There are still dark corners in the implantation charge book, especially concerning minimal insert thickness, the adjustment of tibiofemoral alignment and ligament balance. A review of the literature revealed consensus regarding minimal insert thickness (8mm), tibiofemoral alignment (to be kept within 5 degrees on either side of the neutral axis) and ligament balance (identical collateral ligament tension in both extension and flexion spaces). Finer adjustment seems desirable. Tibiofemoral alignment is probably customizable according to individual patient morphology and weight. The rotational alignment of the components should allow harmonious patellar engagement. Classic ligament balance rules underestimate sagittal laxity, which needs checking to prevent paradoxical movement accelerating polymer delamination. Navigation techniques or specific ancillaries can help optimize implant component alignment. Control of sagittal laxity may require specific adaptation, notably in the flexion space. Improved implantation technique could postpone wear onset until beyond the 10th or even 20th postoperative year, barring material failure for other reasons. PMID- 28082052 TI - Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease. AB - Amyloid-beta peptide (Abeta) and tau are major components of senile plaques and neurofibrillary tangles, respectively, deposited in the brains of Alzheimer disease (AD) patients. Abeta is derived from amyloid-beta precursor protein that is sequentially cleaved by two aspartate proteases, beta- and gamma-secretases. Secreted Abeta is then catabolized by several proteases. Several lines of evidence suggest that accumulation of Abeta by increased production or decreased degradation induces the tau-mediated neuronal toxicity and symptomatic manifestations of AD. Thus, the dynamics of cerebral Abeta, called as "Abeta economy", would be the mechanistic basis of AD pathogenesis. Partial loss of gamma-secretase activity leads to the increased generation of toxic Abeta isoforms, indicating that activation of gamma-secretase would provide a beneficial effect for AD. After extensive discovery and development efforts, BACE1, which is a beta-secretase enzyme, has emerged as a prime drug target for lowering brain Abeta levels. Recent studies revealed the decreased clearance of Abeta in sporadic AD patients, suggesting the importance of the catabolic mechanism in the pathogenesis of AD. I will discuss with these proteolytic mechanisms involved in the regulation of Abeta economy, and development of effective treatment and diagnostics for AD. PMID- 28082054 TI - Do small barriers affect the movement of freshwater fish by increasing residency? AB - River fragmentation due to artificial barriers directly impacts fish communities by limiting migratory movements. This work aims to understand how small barriers affect the movements of a potamodromous cyprinid species - the Iberian barbel (Luciobarbus bocagei (Steindachner, 1864)) - in a 5.6km upstream segment of a stream impacted only by the presence of physical barriers. Fish were marked with Visible Implant Elastomer tags (VIE), and barriers were seasonally characterized. A total of 683 fish were tagged, with 104 recaptures, during five sampling seasons (spring 2012 - early summer 2013). Eleven of the recaptured fish moved past a barrier, without any preference in terms of direction of movement. There were no differences in length, either between migrants and residents, or between upstream and downstream migrants. The results show that although barbel are able to negotiate small barriers, part of the population did not move between fragmented reaches - an indication that under such conditions, fish species populations may adjust their life-history strategy to augment residency as it was hypothesized from the results. PMID- 28082053 TI - A description of the "event manager" role in resuscitations: A qualitative study of interviews and focus groups of resuscitation participants. AB - PURPOSE: Communication during resuscitation is essential for the provision of coordinated, effective care. Previously, we observed 44% of resuscitation communication originated from participants other than the physician team leader; 65% of which was directed to the team, exclusive of the team leader. We called this outer-loop communication. METHODS: This institutional review board-approved qualitative study used grounded theory analysis of focus groups and interviews to describe and define outer-loop communication and the role of "event manager" as an additional "leader." Participants were health care staff involved in the medical management of resuscitations in a quaternary pediatric academic hospital. RESULTS: The following 3 domains were identified: the existence and rationale of outer-loop communication; the functions fulfilled by outer-loop communication; and the leadership and learning of event manager skills. The role was recognized by all team members and evolved organically as resuscitation complexity increased. A "good" manager has similar qualities to a "good team leader" with strong nontechnical skills. Event managers were not formally identified and no specific training had occurred. CONCLUSIONS: "Outer-loop" communication supports resuscitation activities. An event manager gives direction to the team, coordinates activities, and supports the team leader. We describe a new role in resuscitation in light of structural organizational theory and cognitive load with a view to incorporating this structure into resuscitation training. PMID- 28082055 TI - Historical record and fluxes of DDTs at the Palos Verdes Shelf Superfund site, California. AB - Marine sediments at many locations in the world are contaminated with a wide range of persistent organic pollutants. The Palos Verdes Shelf (PVS) is located in the ocean off the coast of Los Angeles, California and has been listed as a Superfund site by the US EPA since 1997, because of heavy contamination of DDTs and PCBs. However, little is known about the historical trend in the deposition of DDTs as a result of decades-long discharge of wastewater effluents. In this study, sediment cores were taken from the PVS site and determined for DDT and its metabolites including DDE and DDD (denoted as DDTs). Individual DDTs were found in the majority (95%) of the samples analyzed. The highest ?DDT concentrations were found in three cores along the 60-meter isobath with geometric means of 31300, 7490, and 5010ng/gdw and medians of 82400, 17300, and 5200ng/g dw, respectively. Among DDT congeners, p,p'-DDE, o,p'-DDE and p,p'-DDD were predominant, contributing to approximately 54%, 27%, and 14% of the SigmaDDTs in sediment. The vertical profiles of concentrations of contaminants in the sediment cores were examined. For most of the cores, a steady increase in the concentrations of DDTs during 1940s to 1980s was observed, while the concentrations declined gradually toward the surficial layers. On the basis of the mass flux of DDTs calculated and the area of the PVS Superfund site, we estimated the total deposition amount of DDTs in sediment and the deposition amount of SigmaDDTs in this region during 1947-1971 was 132 tons, which was fairly close to what was reported in earlier studies for industrial wastewater discharge in the PVS site (870-1450tons). Our findings suggest that the elevated levels of DDTs in sediment from the PVS site are linked to the discharge of these contaminants between the 1940s-1980s. PMID- 28082056 TI - Effects of plant-symbiotic relationships on the living soil microbial community and microbial necromass in a long-term agro-ecosystem. AB - We examined the impact of arbuscular mycorrhizal fungi and rhizobia on the living microbial community and microbial necromass under different long-term fertilization treatments at the long-term Static Fertilization Experiment Bad Lauchstadt (Germany). Phospholipid fatty acids (PLFA) and amino sugars plus muramic acid, were used as biomarkers for soil microbial bio- and necromass, respectively, and analyzed from six treatments imposed on two crop rotations, varying only in the inclusion/non-inclusion of a legume. Treatments included: two levels of only farmyard manure (FYM), only mineral fertilizer (NPK), the combined application of both fertilizer types and a non-fertilized control. PLFA profiles differed clearly between the investigated crop rotations and were significantly related to labile C, mineral N, and soil pH. This emphasizes the role of carbon, and of mycorrhizal and rhizobial symbioses, as driver for changes in the microbial community composition due to effects on the living conditions in soil. We found some evidence that legume associated symbiosis with arbuscular mycorrhizal fungi and rhizobia act as a buffer, reducing the impact of varying inputs of mineral nutrients on the decomposer community. While our results support former findings that living microbial populations vary within short-term periods and are reflective of a given crop grown in a given year, soil necromass composition indicates longer term changes across the two crop rotation types, mainly shaped by fertilizer related effects on the community composition and C turnover. However, there was some evidence that specifically the presence of a legume, affects the soil necromass composition not only over the whole crop rotation but even in the short-term. PMID- 28082057 TI - Freshwater ecotoxicity impacts from pesticide use in animal and vegetable foods produced in Sweden. AB - Chemical pesticides are widely used in modern agriculture but their potential negative impacts are seldom considered in environmental assessments of food products. This study aims to assess and compare the potential freshwater ecotoxicity impacts due to pesticide use in the primary production of six food products: chicken fillet, minced pork, minced beef, milk, pea soup, and wheat bread. The assessment is based on a detailed and site-specific inventory of pesticide use in the primary production of the food products, all of which are produced in Sweden. Soybeans, used to produce the animal-based food products, are grown in Brazil. Pesticide emissions to air and surface water were calculated using PestLCI v. 2.0.5. Ecotoxicity impacts were assessed using USEtox v. 2.01, and expressed in relation to five functional units. The results show that the animal-based food products have considerably larger impact potentials than the plant-based food products. In relation to kg pea soup, impact potentials of bread, milk, minced beef, chicken fillet and minced pork are ca. 2, 3, 50, 140 and 170 times larger, respectively. All mass-based functional units yield the same ranking. Notably, chicken fillet and minced pork have larger impacts than minced beef and milk, regardless of functional unit, due to extensive use of pesticides, some with high toxicity, in soybean production. This result stands in sharp contrast to typical carbon footprint and land use results which attribute larger impacts to beef than to chicken and pork. Measures for reducing impacts are discussed. In particular, we show that by substituting soybeans with locally sourced feed crops, the impact potentials of minced pork and chicken fillet are reduced by ca. 70 and 90%, respectively. Brazilian soybean production is heavily reliant on pesticides. We propose that weak legislation, in combination with tropical climate and agronomic practices, explains this situation. PMID- 28082058 TI - The importance of extranodal extension in metastatic head and neck squamous cell carcinoma, in the light of the new AJCC cancer staging system. PMID- 28082059 TI - Corrigendum to "Anti-infective mannose receptor immune mechanism in large yellow croaker (Larimichthys crocea)" [Fish Shellfish Immunol. 54 (2016 Jul) 257-265]. PMID- 28082061 TI - Purification, auto-activation and kinetic characterization of apoptosis signal regulating kinase I. AB - Apoptosis signal-regulating kinase I (ASK1) is a mitogen-activated protein kinase kinase kinase (MAP3K) that activates the downstream MAP kinase kinases (MKKs) from two MAP kinase cascades: c-Jun N-terminal kinase (JNK) and p38. The essential physiological functions of ASK1 have attracted extensive attention. However, our understanding of the molecular mechanisms of ASK1, including the activation mechanism of ASK1 and the catalytic mechanism of ASK1-mediated MKK phosphorylation, remain unclear. The lack of purified ASK1 protein has hindered the elucidation of ASK1-initiated signal transduction mechanisms. Here, we report a one-step chromatography method for the expression and purification of functional full-length ASK1 from Escherichia coli. The purified ASK1 demonstrates auto-phosphorylation activity. The kinase activity of auto-phosphorylated ASK1 (pASK1) was also evaluated on two MKK substrates, MKK4 and 7, from the JNK cascades. Our results show that MKK7 can be phosphorylated by pASK1 more effectively than MKK4. The steady-state kinetic analysis demonstrates that MKK7 is a better ASK1 substrate than MKK4. These observations are further confirmed by direct pull-down assays which shows ASK1 binds MKK7 significantly stronger than MKK4. Furthermore, robust phospho-tyrosine signal is observed in MKK4 phosphorylation by pASK1 in addition to the phospho-serine and phospho-threonine. This study provides novel mechanistic and kinetic insights into the ASK1 initiated MAPK signal transduction via highly controlled reconstructed protein systems. PMID- 28082060 TI - Breastfeeding in Infancy Is Associated with Body Mass Index in Adolescence: A Retrospective Cohort Study Comparing American Indians/Alaska Natives and Non Hispanic Whites. AB - BACKGROUND: American Indians and Alaska Natives have the highest obesity prevalence in the United States, but the influence of early childhood variables on body mass index (BMI; calculated as kg/m2) is not well understood. Previous studies have investigated the association between breastfeeding in infancy and offspring BMI, but rarely included American Indians and Alaska Natives. OBJECTIVE: This study investigated the association between breastfeeding in infancy and BMI in American Indians and Alaska Native and non-Hispanic white adolescents and young adults. DESIGN: Longitudinal analysis based on data from the National Longitudinal Study of Adolescent to Adult Health (1994 to 2008). PARTICIPANTS: Adolescent respondents who self-identified as American Indians and Alaska Native or non-Hispanic white, and whose parents completed the parental questionnaire, reported their height and weight. The final sample included 655 American Indians and Alaska Native and 10,305 non-Hispanic white respondents. STATISTICAL ANALYSES PERFORMED: Generalized estimating equations were used to measure the mean differences, 95% CIs, and P values of the association between breastfeeding in infancy and offspring BMI in adolescence, stratifying by race, and adjusting for demographic and socioeconomic variables. RESULTS: The length of breastfeeding was inversely associated with BMI in both populations. American Indians and Alaska Natives that were breastfed for 6 to 12 months or for more than 12 months had a mean BMI of 2.69 (95% CI -3.46 to -1.92; P<0.01) and 1.54 (95% CI -2.75 to -0.33; P<0.05) units lower than those that were never breastfed. Non-Hispanic whites that were breastfed for 3 to 6 months, 6 to 12 months, or more than 12 months had a mean BMI of 0.71 (95% CI -0.93 to -0.50; P<0.01), 0.68 (95% CI -0.87 to -0.50; P<0.01), and 0.85 (95% CI -1.09 to -0.62; P<0.01) units lower than those that were never breastfed. The association between the length of breastfeeding and offspring BMI varied by race (P<0.01). CONCLUSIONS: Breastfeeding in infancy is associated with lower mean BMI. Future research should investigate causal pathways and whether interventions promoting breastfeeding in American Indians and Alaska Natives can prevent increasing BMI. PMID- 28082062 TI - Five-Strand Hamstring Autograft Versus Quadruple Hamstring Autograft With Graft Diameters 8.0 Millimeters or More in Anterior Cruciate Ligament Reconstruction: Clinical Outcomes With a Minimum 2-Year Follow-Up. AB - PURPOSE: To compare the outcomes of 2 groups of patients undergoing anterior cruciate ligament (ACL) reconstruction: the first with a quadrupled semitendinosus gracilis (ST-G) autograft larger than 8 mm diameter and the second with a 5-strand ST-G autograft larger than 8 mm due to an insufficient diameter graft harvesting. METHODS: This was a retrospective study with 70 patients divided into 2 groups. Inclusion criteria included ACL ruptures of less than 3 months, ST-G ACL reconstructions, and final (4-strand or 5-strand) graft size larger than 8 mm. Exclusion criteria included multiligament knee injuries, meniscal or chondral pathology, ACL re-ruptures, inflammatory joint disease, or other procedures in the knee. RESULTS: Group A comprised 33 patients with a quadruple ST-G graft, and group B comprised 37 patients with an insufficient graft diameter (<8 mm) in which a 5-strand graft was used. Mean age in group A was 29.7 (range 17-52) years and in group B was 30.6 (range 13-53) years (P = .78). Average follow-up in group A was 32.2 (range 24-48) months and in group B was 30.35 (range 24-48) months (P = .75). Average graft diameter in group A was 8.5 mm (range 8-10) and in group B when the graft was measured as quadruple was 7.2 mm (range 6.5-7.5) and 9.2 mm (range 8-10) when it was converted to 5-strand (P = .00596). Group A had 3 (9%) re-ruptures, and group B had 2 (5.4%) (P = .55). The average postoperative Lysholm score in group A was 93.3 (range 71-100) and in group B was 97.1 (range 80-100) (P = .79). Mean postoperative International Knee Documentation Committee in group A was 91 (range 75.9-100) and in group B was 96.8 (range 82-100) (P = .18). CONCLUSIONS: In our study, the 5-strand hamstring autograft in ACL reconstruction was clinically comparable with the quadruple autograft larger than 8 mm. The differences in re-rupture and clinical outcomes were not statistically significant between the 2 groups, suggesting that it is a valid option when we have a graft of insufficient diameter. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 28082063 TI - Arthroscopic Repair of Isolated Subscapularis Tears: A Systematic Review of Technique-Specific Outcomes. AB - PURPOSE: To systematically review the literature to identify all studies reporting outcomes of arthroscopically repaired isolated subscapularis tears, to (1) report outcomes across all repair techniques, (2) compare outcomes by arthroscopic technique, and (3) highlight the frequency and management of associated long head of biceps pathology, and the influence of these concomitant procedures on outcomes following arthroscopic subscapularis repair. METHODS: A systematic literature review was conducted using the MEDLINE, Embase, and Scopus databases with the following term: ("isolated repair" AND "arthroscopic subscapularis tear"). Only studies evaluating the techniques and outcomes of isolated subscapularis repair were included. Data were extracted, including patient characteristics, surgical technique, and outcomes. Descriptive analysis was provided for the available literature. RESULTS: Eight studies were included in this review. Uniformly, improvements in patient-reported outcome scores were substantial after arthroscopic subscapularis repair. Constant Total scores improved in each individual study from preoperative to postoperative (range, Delta18.8-Delta49.8 points), as did Strength (range, Delta1.3-Delta13.7 points), Pain (range, Delta7.6-Delta8.9 points), Range of Motion (range, Delta7.3 Delta13.3 points), and Activities of Daily Living (range, Delta8.7-Delta10.2 points) subscores. Significant improvements were seen in most individual studies for belly-press (Delta21.6 N or Delta1.9 out of 5) and lift-off strength (Delta24.3 N or Delta1.7-Delta1.9 out of 5), range of motion in forward flexion (29.1 degrees -37.0 degrees ), external rotation (10.3 degrees -16.0 degrees ), and internal rotation. Complications were relatively infrequent overall, with 5 studies reporting no complications, and the remaining 3 studies with rerupture rates between 4.8% and 11.8%. Studies that used only double-row repair reported fewer complications (0% vs 5%-10%) and better outcome scores than single-row repair, similar to those studies that uniformly performed biceps tenodesis compared with no biceps intervention. CONCLUSIONS: This descriptive study highlights that arthroscopic subscapularis repair appears to be a reasonable option for the treatment of isolated tears of the subscapularis to obtain successful functional and patient-reported clinical outcomes. Its findings also pose the question of whether future prospective, comparative studies will find double-row surgical fixation and concomitant biceps tenodesis surgery to be superior to single-row fixation and leaving the biceps alone. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies. PMID- 28082064 TI - A case of recombinant coxsackievirus A2 infection with neurological complications in Taiwan. PMID- 28082065 TI - Salvage therapy with intravenous fosfomycin plus ceftriaxone for necrotizing fasciitis caused by penicillin-nonsusceptible Streptococcus pneumoniae. PMID- 28082066 TI - Impact of pneumococcal conjugate vaccine in children on the serotypic epidemiology of adult invasive pneumococcal diseases in Taiwan. AB - BACKGROUND: Invasive pneumococcal disease (IPD) causes significant morbidity and mortality, especially in children and older adults. Pneumococcal 7-valent and 13 valent conjugate vaccines (PCV7 and PCV13) were introduced in Taiwan in 2005 and 2011, respectively, for children. This study was conducted to evaluate the impact of PCV administered in children on adult IPD. METHODS: From the logbooks of microbiology laboratories, we retrospectively retrieved Streptococcus pneumoniae isolates, collected from normally sterile sites in adult patients. One hundred and fifty-seven consecutive, nonduplicated isolates were collected from one hospital during 2001 and 2003 (pre-PCV period) and 150 isolates from three hospitals from July 2011 to June 2015 (post-PCV period). Serotypes were determined by Quellung test. RESULTS: Among the 307 isolates, 31 serotypes/serogroups were identified. PCV7 serotypes, particularly types 14 (31.2%), 23F (19.7%) and 6B (12.7%) dominated in the pre-PCV period (78.3%) but significantly decreased in the post-PCV period (36%) (p < 0.01). PCV13 specific serotypes (PCV13-PCV7) significantly increased from 7% of the isolates in the pre PCV period to 28.7% of the isolates in the post-PCV period (p < 0.001), particularly type 19A (from 0.6% to 10%) and 6A (from 0 to 6.7%). Serotype 15B also increased significantly from 0.6% to 6.7% (p < 0.01). Nonvaccine serotypes increased significantly in the post-PCV period (11.5% to 22.0%, p < 0.05), particularly type 15A (from 0 to 4.4%, p < 0.01). CONCLUSION: Serotype distribution of adult IPD in Taiwan has evolved after the introduction of PCV in children, indicating an indirect impact in adults. Continuous surveillance after the PCV13 vaccination program in children is needed. PMID- 28082067 TI - Clinical predictors of the leading pathogens in human immunodeficiency virus infected adults with community-onset bacteremia in the emergency department: The importance of transmission routes. AB - BACKGROUND/PURPOSE: To investigate the clinical characteristics and pathogens of community-onset bacteremia among human immunodeficiency virus (HIV)-infected adults as well as to establish the clinical predictors of the major microorganisms. METHODS: An observational cohort study was conducted retrospectively between January 2007 and December 2012. Demographic characteristics and pathogens determined from chart records were analyzed. RESULTS: Of the 121 eligible HIV adults with bacteremia, there was a male predominance (106 patients, 87.6%); elderly individuals (age >= 65 years) accounted for only 2.5% of the study population (3 patients). Of the total microorganisms isolated (n=123), Staphylococcus aureus (55, 44.7%) and Salmonella enterica (17, 13.8%) were the common pathogens. In a multivariate analysis, the leading two significant predictors of S. aureus infection were infective endocarditis (odds ratio, 11.49; p=0.001) and transmission risk with injection drug users (IDUs; odds ratio, 6.22; p=0.001). In addition, transmission risk with men who have sex with men (MSM; odds ratio, 37.49; p=0.001) was the leading clinical predictor of S. enterica infection. In further analyses, a strong linear by-linear correlation between S. aureus infection and IDU (gamma=0.94, p=0.02) as well as between S. enterica infection and MSM (gamma=0.96, p=0.01) was evidenced. CONCLUSION: Focusing on the two key pathogens in HIV-infected adults with community-onset bacteremia, IDU was one of independent predictors associated with S. aureus infection, whereas MSM was the leading risk factor of S. enterica infection. Although the proposed predictive model of these pathogens has been not established, a scoring system involving the transmission risk of HIV may be of use for the early identification of these patients for clinicians. PMID- 28082068 TI - Discovery of hepatitis B virus capsid assembly inhibitors leading to a heteroaryldihydropyrimidine based clinical candidate (GLS4). AB - Inhibition of hepatitis B virus (HBV) capsid assembly is a novel strategy for the development of chronic hepatitis B (CHB) therapeutics. Herein we described our lead optimization studies including the synthesis, molecular docking studies and structure-activity relationship (SAR) studies of a series of novel heteroaryldihydropyrimidine (HAP) inhibitors of HBV capsid assembly inhibitors, and the discovery of a potent inhibitor of HBV capsid assembly of GLS4 (ethyl 4 [2-bromo-4-fluorophenyl]-6-[morpholino-methyl]-2-[2-thiazolyl]-1,4-dihydro pyrimidine-5-carboxylate) which is now in clinical phase 2. GLS4 demonstrated potent inhibitory activities in HBV HepG2.2.15 cell assay with an EC50 value of 1nM, and it also exhibited high potency against various drug-resistant HBV viral strains with EC50 values in the range of 10-20nM, more potent than the typical HBV polymerase inhibitors such as lamivudine, telbivudine, and entecavir. Pharmacokinetic profiles of GLS4 were favorable and safety evaluation including acute toxicity and repeated toxicity study indicated that GLS4 was safe enough to support clinical experiments in human. PMID- 28082069 TI - Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer's disease treatment. AB - Alzheimer's disease (AD) is a neurodegenerative disorder associated with an excessive accumulation of amyloid-beta peptide (Abeta). Based on the multifactorial nature of AD, preparation of multi-target-directed ligands presents a viable option to address more pathological events at one time. A novel class of asymmetrical disubstituted indolyl thioureas have been designed and synthesized to interact with monoamine oxidase (MAO) and/or amyloid-binding alcohol dehydrogenase (ABAD). The design combines the features of known MAO inhibitors scaffolds (e.g. rasagiline or ladostigil) and a frentizole moiety with potential to interact with ABAD. Evaluation against MAO identified several compounds that inhibited in the low to moderate micromolar range. The most promising compound (19) inhibited human MAO-A and MAO-B with IC50 values of 6.34MUM and 0.30MUM, respectively. ABAD activity evaluation did not show any highly potent compound, but the compound series allowed identification of structural features to assist the future development of ABAD inhibitors. Finally, several of the compounds were found to be potent inhibitors of horseradish peroxidase (HRP), preventing the use of the AmplexTM Red assay to detect hydrogen peroxide produced by MAO, highlighting the need for serious precautions when using an enzyme-coupled assay. PMID- 28082070 TI - Design, synthesis and biological evaluation of (E)-3,4-dihydroxystyryl 4 acylaminophenethyl sulfone, sulfoxide derivatives as dual inhibitors of HIV-1 CCR5 and integrase. AB - Aiming at the limited effectiveness of current clinical therapeutic effect of AIDS, novel series of compounds bearing (E)-3,4-dihydroxystyryl sulfone (or sulfoxide) and anilide fragments were designed and synthesized as dual inhibitors of HIV-1 CCR5/IN. The biological results indicated that several target compounds showed inhibitory activity against HIV-1 Bal (R5) infection in TZM-bl cells. Besides targeting the chemokine receptor on the host cell surface, they also displayed binding affinities with HIV-1 integrase using the surface plasmon resonance (SPR) binding assays. Molecular docking studies have inferred the possible binding mode of target compounds against integrase. These data demonstrate that the structure of (E)-3,4-dihydroxystyryl sulfone and sulfoxide derivatives have the potential to derive potent dual inhibitors of HIV-1 Integrase and CCR5. PMID- 28082072 TI - Early neurological deterioration in older adults with traumatic brain injury. AB - INTRODUCTION: Traumatic brain injuries (TBIs) and resulting fatalities among older adults increased considerably in recent years. Neurological deterioration often goes unrecognized at the injury scene and patients arrive at emergency departments with near-normal Glasgow Coma Scale (GCS) scores. This study examined the proportion of older adults experiencing early neurological deterioration (prehospital to emergency department), associated factors, and association of the magnitude of neurological deterioration with TBI severity. METHODS: This secondary analysis of National Trauma Data Bank Research Datasets included patients who were age ?65, sustained a TBI, and transported from the injury scene to an emergency department. Data analysis included chi-square analysis, t-tests, and logistic regression. Long-term anticoagulant/antiplatelet therapy was not associated with deterioration. RESULTS: Of the sample of 91,886 patients, 13,913 (15.1%) experienced early neurological deterioration. Adjusting for covariates, age, gender, head AISmax injury severity, and probability of death were associated with early deterioration. Patients with severe and critical head injuries had the highest odds of early neurological deterioration (OR=1.41 [CI=1.22-1.63] and OR=1.98 [CI=1.63-2.40], p<0.001). DISCUSSION/CONCLUSIONS: Prehospital providers, nurses, physicians, and other providers have opportunities to optimize outcomes from older adult TBI through early recognition of neurological deterioration, rapid transport to facilities for definitive treatment, and targeted rehabilitation. PMID- 28082071 TI - Highly predictive and interpretable models for PAMPA permeability. AB - Cell membrane permeability is an important determinant for oral absorption and bioavailability of a drug molecule. An in silico model predicting drug permeability is described, which is built based on a large permeability dataset of 7488 compound entries or 5435 structurally unique molecules measured by the same lab using parallel artificial membrane permeability assay (PAMPA). On the basis of customized molecular descriptors, the support vector regression (SVR) model trained with 4071 compounds with quantitative data is able to predict the remaining 1364 compounds with the qualitative data with an area under the curve of receiver operating characteristic (AUC-ROC) of 0.90. The support vector classification (SVC) model trained with half of the whole dataset comprised of both the quantitative and the qualitative data produced accurate predictions to the remaining data with the AUC-ROC of 0.88. The results suggest that the developed SVR model is highly predictive and provides medicinal chemists a useful in silico tool to facilitate design and synthesis of novel compounds with optimal drug-like properties, and thus accelerate the lead optimization in drug discovery. PMID- 28082073 TI - Specialty-Specific Values Affecting the Management of Symptomatic Uterine Fibroids. AB - PURPOSE: To better understand why interventional radiologists and gynecologists differ in their approaches to symptomatic uterine fibroids. METHODS: Conversational interviews were conducted with 26 interventional radiologists and gynecologists about their professional roles, clinical reasoning, and practice variation within and outside their specialty. Interview transcripts were systematically analyzed using NVivo 10 software (QSR International, Burlington, Massachusetts) according to grounded theory and content analysis to identify key themes and compare themes across specialties and practice environments. Data were supplemented with retrospective analysis of 7,659 patients with symptomatic uterine fibroids treated at a large academic center over 11 years. RESULTS: Interventional radiologists' shares of symptomatic uterine fibroid treatment and endovascular stent treatments have remained constant (P > .05) for 11 y at a large medical center, whereas minimally invasive gynecologic fibroid treatments and the percentage of interventional radiology (IR) procedures reimbursed by Medicaid/Medicare have increased significantly (r > .90, P < .001 and r = .93, P < .001). Interventional radiologists and gynecologists shared a commitment to do "the right thing" for patients, but each group possessed distinct professional values affecting how they viewed medical evidence, outcomes, and their colleagues. When differences were apparent and concerning, physicians tended to suspect ulterior motives not in patients' best interests. CONCLUSIONS: Interventional radiologists and gynecologists demonstrated wide-ranging perspectives regarding their role in caring for patients with symptomatic uterine fibroids. To promote genuine collaboration and adoption of shared goals, stakeholders should seek and promote a deeper understanding of specialty-specific values and culture. PMID- 28082075 TI - Vertebral fractures assessment in children: Evaluation of DXA imaging versus conventional spine radiography. AB - Vertebral fracture assessment (VFA) by DXA is an accepted tool in adults. However, its use in children has not been assessed. The aim of this study was to evaluate DXA VFA and morphometric analysis (MXA) using a GE Lunar iDXA bone densitometer against spinal radiographic assessment (RA) for the identification of vertebral fractures in children. Spine RA and VFA (T3-L5) were acquired on the same day in 80 children. Forty children considered high risk for fracture by their metabolic bone specialist were referred for spinal RA. Another 40 children were recruited as part of a prospective fracture study and were considered low risk for vertebral fracture. Agreement between RA and VFA was assessed by an expert paediatric radiologist and two paediatricians with expertise in bone pathology. Agreement between RA and MXA was assessed by an expert paediatric radiologist, two clinical scientists and an experienced paediatric radiographer. Vertebrae were ranked as normal, mild, moderate or severe if they had <10%, 11 25%, 26-50% and >50% deformity, respectively. Levels of agreement were calculated using the Cohen kappa score. Evaluating the data from all readable vertebrae, 121 mild, 44 moderate and 16 severe vertebral fractures were identified; with 26, 8, and 5 subjects having at least one mild, moderate or severe fracture, respectively. Depending on rater, 92.8-94.8% of the vertebrae were evaluable by RA. In contrast, 98.4% were evaluable by VFA and only 83.6% were evaluable by MXA. Moderate agreement was found between raters for RA [kappa 0.526-0.592], and VFA [kappa 0.601-0.658] and between RA and VFA [kappa 0.630-0.687]. In contrast, only slight agreement was noted between raters for MXA [kappa 0.361-0.406] and between VFA and MXA [kappa 0.137-0.325]. Agreement substantially improved if the deformities were dichotomised as normal or mild versus moderate or severe [kappa 0.826-0.834]. For the detection of moderate and/or severe fractures the sensitivities & specificities were 81.3% & 99.3%, and 62.5% & 99.2% for VFA and MXA, respectively. This study demonstrates that VFA is as good as RA for detecting moderate and severe vertebral fractures. Given the significant radiation dose saving of VFA compared with RA, VFA is recommended as a diagnostic tool for the assessment of moderate or severe vertebral fracture in children. PMID- 28082074 TI - Rescue of Hearing by Gene Delivery to Inner-Ear Hair Cells Using Exosome Associated AAV. AB - Adeno-associated virus (AAV) is a safe and effective vector for gene therapy for retinal disorders. Gene therapy for hearing disorders is not as advanced, in part because gene delivery to sensory hair cells of the inner ear is inefficient. Although AAV transduces the inner hair cells of the mouse cochlea, outer hair cells remain refractory to transduction. Here, we demonstrate that a vector, exosome-associated AAV (exo-AAV), is a potent carrier of transgenes to all inner ear hair cells. Exo-AAV1-GFP is more efficient than conventional AAV1-GFP, both in mouse cochlear explants in vitro and with direct cochlear injection in vivo. Exo-AAV shows no toxicity in vivo, as assayed by tests of auditory and vestibular function. Finally, exo-AAV1 gene therapy partially rescues hearing in a mouse model of hereditary deafness (lipoma HMGIC fusion partner-like 5/tetraspan membrane protein of hair cell stereocilia [Lhfpl5/Tmhs-/-]). Exo-AAV is a powerful gene delivery system for hair cell research and may be useful for gene therapy for deafness. PMID- 28082076 TI - Topical bisphosphonate augments fixation of bone-grafted hydroxyapatite coated implants, BMP-2 causes resorption-based decrease in bone. AB - Bone allograft is used in total joint arthroplasties in order to enhance implant fixation. BMPs are known to stimulate new bone formation within allograft, but also known to accelerate graft resorption. Bisphosphonates are strong inhibitor of bone resorption. The aim of this study was to investigate whether the bisphosphonate zoledronate was able to counteract the accelerated graft resorption without interfering with the BMP induced bone formation. In the present study the two drugs alone and in combination were studied in our canine model of impaction bone grafting. We included 10 dogs in this study. Cancellous allograft bone grafts were soaked in either saline or zoledronate solution (0.005mg/mL) and then vehicle or BMP2 (0.15mg rhBMP2) was added. This produced four treatment groups: A) control, B) BMP2, C) zoledronate and D) BMP2+zoledronate. The allograft treated with A, B, C or D was impacted into a circumferential defect of 2.5mm around HA-coated porous Ti implants. Each dog received all four treatment groups with two implants in the distal part of each femur. The group with allograft soaked in zoledronate (C) showed better biomechanical fixation than all other groups (p<0.05). It had less allograft resorption compared to all other groups (p<0.005) without any statistically significant change in new bone formation. The addition of BMP2 to the allograft did not increase new bone formation significantly, but did accelerate allograft resorption. This was also the case where the allograft was treated with BMP2 and zoledronate in combination (D). This caused a decrease in mechanical implant fixation in both these groups compared to the control group, however only statistically significant for the BMP2 group compared to control. The study shows that topical zoledronate can be a valuable tool for augmenting bone grafts when administered optimally. The use of BMP2 in bone grafting procedures seems associated with a high risk of bone resorption and mechanical weakening. PMID- 28082077 TI - Effects of suppressed bone remodeling by minodronic acid and alendronate on bone mass, microdamage accumulation, collagen crosslinks and bone mechanical properties in the lumbar vertebra of ovariectomized cynomolgus monkeys. AB - Collagen crosslinking is an important determinant of the quality of bone material. We have previously shown that suppressed bone turnover by high doses of minodronic acid and alendronate increases compressive strength of vertebra, but also increases microdamage accumulation, in monkey bone. The aim of this study is to examine the effects of these bisphosphonates on collagen crosslinks and intrinsic material properties, in addition to microdamage accumulation, in vertebral cancellous bone in ovariectomized cynomolgus monkeys. Sixty female monkeys aged 9-17years were divided into five groups: sham and ovariectomized groups were treated daily for 17months with lactose vehicle, and the other three groups were given minodronic acid daily at 0.015 or 0.15mg/kg or alendronate daily at 0.5mg/kg orally. After sacrifice, lumbar vertebrae were subjected to histomorphometry, microdamage measurement, analysis of collagen crosslinking and compressive mechanical tests. Minodronic acid caused dose-dependent suppression of increased bone remodeling due to ovariectomy, and low-dose minodronic acid suppressed remodeling same level as alendronate. However, low-dose minodronic acid did not change microdamage accumulation, collagen maturity and the pentosidine level, whereas high-dose minodronic acid and alendronate increased these parameters. Compressive ultimate load was increased following high-dose minodronic acid and alendronate, but no treatment altered the reduction in intrinsic material properties caused by ovariectomy. These findings suggest that deterioration of bone material and formation of pentosidine and microdamage induced by minodronic acid is less than that expected based on the extent of remodeling suppression, in comparison with alendronate, but this was not reflected in any significant change of mechanical properties. PMID- 28082078 TI - High Bone Mass is associated with bone-forming features of osteoarthritis in non weight bearing joints independent of body mass index. AB - OBJECTIVES: High Bone Mass (HBM) is associated with (a) radiographic knee osteoarthritis (OA), partly mediated by increased BMI, and (b) pelvic enthesophytes and hip osteophytes, suggestive of a bone-forming phenotype. We aimed to establish whether HBM is associated with radiographic features of OA in non-weight-bearing (hand) joints, and whether such OA demonstrates a bone-forming phenotype. METHODS: HBM cases (BMD Z-scores>=+3.2) were compared with family controls. A blinded assessor graded all PA hand radiographs for: osteophytes (0 3), joint space narrowing (JSN) (0-3), subchondral sclerosis (0-1), at the index Distal Interphalangeal Joint (DIPJ) and 1st Carpometacarpal Joint (CMCJ), using an established atlas. Analyses used a random effects logistic regression model, adjusting a priori for age and gender. Mediating roles of BMI and bone turnover markers (BTMs) were explored by further adjustment. RESULTS: 314 HBM cases (mean age 61.1years, 74% female) and 183 controls (54.3years, 46% female) were included. Osteophytes (grade>=1) were more common in HBM (DIPJ: 67% vs. 45%, CMCJ: 69% vs. 50%), with adjusted OR [95% CI] 1.82 [1.11, 2.97], p=0.017 and 1.89 [1.19, 3.01], p=0.007 respectively; no differences were seen in JSN. Further adjustment for BMI failed to attenuate ORs for osteophytes in HBM cases vs. controls; DIPJ 1.72 [1.05, 2.83], p=0.032, CMCJ 1.76 [1.00, 3.06], p=0.049. Adjustment for BTMs (concentrations lower amongst HBM cases) did not attenuate ORs. CONCLUSIONS: HBM is positively associated with OA in non-weight-bearing joints, independent of BMI. HBM-associated OA is characterised by osteophytes, consistent with a bone-forming phenotype, rather than JSN reflecting cartilage loss. Systemic factors (e.g. genetic architecture) which govern HBM may also increase bone-forming OA risk. PMID- 28082079 TI - X-box Binding Protein 1 Regulates Unfolded Protein, Acute-Phase, and DNA Damage Responses During Regeneration of Mouse Liver. AB - BACKGROUND & AIMS: Liver regeneration after partial hepatectomy (PH) increases the protein folding burden at the endoplasmic reticulum of remnant hepatocytes, resulting in induction of the unfolded protein response. We investigated the role of the core unfolded protein response transcription factor X-box binding protein 1 (XBP1) in liver regeneration using genome-wide chromatin immunoprecipitation analysis. METHODS: We performed studies with C57Bl6-J (control) and interleukin 6 knockout mice. Mice underwent PH or sham surgeries. In some mice, hepatic expression of XBP1 was knocked down by injection of adenoviral vectors encoding small hairpin RNAs against Xbp1 messenger RNA. Liver tissues were collected before surgery and at 6 and 48 hours after surgery and analyzed by chromatin immunoprecipitation followed by sequencing. We also performed functional analyses of HepG2 cells. RESULTS: Expression of XBP1 by hepatocytes increased immediately after PH (priming phase of liver regeneration) in control mice, but this effect was delayed in interleukin 6-deficient mice. In mice with knockdown of XBP1, we observed of liver tissue persistent endoplasmic reticulum stress, defects in acute-phase response, and increased hepatocellular damage, compared with control mice. Chromatin immunoprecipitation analyses of liver tissue showed that at 6 hours after PH, liver XBP1 became bound to a large set of genes implicated in proteostasis, the acute-phase response, metabolism, and the DNA damage response (DDR). At this time point, XBP1 bound the promoter of the signal transducer and activator of transcription 3 gene (Stat3). Livers of XBP1-knockdown mice showed reduced expression of STAT3 and had lower levels of STAT3 phosphorylation at Ser727, a modification that promotes cell proliferation and the DDR. Regenerating livers from XBP1-knockdown mice expressed high levels of a marker of DNA double strand breaks, phosphorylated histone 2A, member X (H2AX), compared with control mice. The inhibition of XBP1 expression caused a reduced up-regulation of DDR messenger RNAs in regenerating hepatocytes. CONCLUSION: In livers of mice, we found that PH induces expression of XBP1, and that this activity requires interleukin 6. XBP1 expression regulates the unfolded protein response, acute phase response, and DDR in hepatocytes. In regenerating livers, XBP1 deficiency leads to endoplasmic reticulum stress and DNA damage. PMID- 28082080 TI - Bacteriophage SPP1 pac Cleavage: A Precise Cut without Sequence Specificity Requirement. AB - In many tailed bacteriophages, DNA packaging is initiated by recognition and cleavage of a specific sequence pac by the small (TerS) and large (TerL) terminase subunits. It was previously shown that the SPP1 pac region has two sequences where TerS binds (pacR and pacL), flanking the segment where TerL cleaves the SPP1 DNA (pacC). However, the pac-specific sequences required to achieve this endonucleolytic cut were not established. Their characterization is essential to understand the underlying mechanism. We show that the pacR sequence localized within 35bp downstream of the pac cut can be extensively degenerated, including its c1 and c2 repeats, and that only a disruption of a 5-bp polyadenine tract impairs the pac cleavage. This result together with deletion analysis of pacL shows that the specific DNA sequences required for targeting the terminase for pac cleavage are considerably shorter than the large region bound by TerS. Furthermore, extensive degeneration of the 6-bp target sequence within pacC where pac cleavage occurs reveals that TerL maintains, remarkably, its precise position of cleavage. Studies with SPP1-related phages show the conservation of the cut position, irrespective of the sequence variation in pacC and in pacR or the changes in pacL-pacC distance. Mechanistically, our data are compatible with a model in which TerS interactions with part of the pacL sequence and a poly-A tract in pacR are sufficient to orient very accurately the TerL nuclease to a defined pacC position. They also demonstrate that the resulting precise cut at pacC is independent of the targeted DNA sequence. PMID- 28082083 TI - Adolescents and Contraception: The Updated US Medical Eligibility Criteria for Contraceptive Use. PMID- 28082082 TI - Key European guidelines for the diagnosis and management of patients with phenylketonuria. AB - We developed European guidelines to optimise phenylketonuria (PKU) care. To develop the guidelines, we did a literature search, critical appraisal, and evidence grading according to the Scottish Intercollegiate Guidelines Network method. We used the Delphi method when little or no evidence was available. From the 70 recommendations formulated, in this Review we describe ten that we deem as having the highest priority. Diet is the cornerstone of treatment, although some patients can benefit from tetrahydrobiopterin (BH4). Untreated blood phenylalanine concentrations determine management of people with PKU. No intervention is required if the blood phenylalanine concentration is less than 360 MUmol/L. Treatment is recommended up to the age of 12 years if the phenylalanine blood concentration is between 360 MUmol/L and 600 MUmol/L, and lifelong treatment is recommended if the concentration is more than 600 MUmol/L. For women trying to conceive and during pregnancy (maternal PKU), untreated phenylalanine blood concentrations of more than 360 MUmol/L need to be reduced. Treatment target concentrations are as follows: 120-360 MUmol/L for individuals aged 0-12 years and for maternal PKU, and 120-600 MUmol/L for non-pregnant individuals older than 12 years. Minimum requirements for the management and follow-up of patients with PKU are scheduled according to age, adherence to treatment, and clinical status. Nutritional, clinical, and biochemical follow-up is necessary for all patients, regardless of therapy. PMID- 28082084 TI - The effects of fungal infection and physiological condition on the locomotory behaviour of the ant Myrmica scabrinodis. AB - Parasite infection often results in alterations in host behaviour. These changes vary greatly in their magnitude, from slight shifts in the time spent by the host performing a given activity to the appearance of novel behaviours. The effects of parasites can differ with the age and the physiological condition of the host. Rickia wasmannii is an ectoparasitic fungal symbiont in Myrmica ants that covers the whole body surface of the host and reduces its lifespan. The fungus is present in both young and old individuals, making it an optimal subject for the study of age-related parasitic effects. We tested the effect of fungal infection on the locomotory activity of the Myrmica scabrinodis ant in different age categories. The fat content of workers was measured as a proxy for their physiological status. Based on our findings, old workers bore more thalli and were leaner than young individuals, while they tended to move at higher speeds and with a lower degree of meandering. Young individuals covered smaller distances, at slower speeds and with a higher degree of meandering. Contrary to our expectations, the infection intensity of R. wasmannii affected neither the fat content nor the locomotory activity of ant workers. However, the two age classes seem to have different strategies with regards to the relationship between fat content and distance covered. Our results suggest that characteristics of locomotory activity differ between the age classes in many respects, and are also influenced by their physiological status, but parasitism by R. wasmannii does not seem to have a straightforward effect on any of the variables studied. PMID- 28082085 TI - The E23K variant of the Kir6.2 subunit of the ATP-sensitive potassium channel increases susceptibility to ventricular arrhythmia in response to ischemia in rats. AB - BACKGROUND: The E23K variant of the Kir6.2 subunit of the ATP-sensitive potassium (KATP) channel has been implicated in cardiac remodeling. However, the effects of E23K variant on ventricular electrophysiology and arrhythmogenesis remain unclear. METHODS: Transgenic rats were generated to express human E23K-variant genomic DNA in the heart under the alpha-myosin heavy chain promoter. Electrophysiological parameters including electrocardiograph, ventricular action potential duration (APD), effective refractory period (ERP), electrical alternans and ventricle arrhythmia threshold were examined in wild type (WT) and transgenic rats. The KATP current in cardiomyocytes was recorded using whole-cell patch clamp techniques. RESULTS: No differences in the electrophysiological parameters between the two groups were found at baseline. However, after acute ischemic stress, shortened QT intervals were further aggravated in the E23K-variant rats. Additionally, the E23K variant exacerbated the decrease of APD70, APD90 and ERP. The ventricular arrhythmia and alternans thresholds were significantly attenuated, and the duration of ventricular arrhythmia induced by electrical stimulation was significantly prolonged in the E23K-variant rats. More importantly, the KATP current in cardiomyocytes was significantly increased in the E23K-variant rats after ischemia. CONCLUSION: The E23K variant of the KATP channel increased the susceptibility to ventricular arrhythmia under acute ischemia stress. PMID- 28082086 TI - Effectiveness of subcutaneous implantable cardioverter-defibrillators and determinants of inappropriate shock delivery. AB - AIMS: Assess subcutaneous implantable cardioverter-defibrillator (S-ICD) effectiveness in the prevention of sudden cardiac death and the impact of demographics and the initial detection algorithm in the delivery of inappropriate shocks (safety). METHODS: Real world prospective registry in which we assessed 54 patients (40+/-17years old, 85% males) who underwent S-ICD implantation for primary or secondary prevention of SCD. Safety and efficacy outcomes were defined as the delivery of inappropriate shocks and the prevention of sudden cardiac death, respectively. Tiered-therapy S-ICD had at least two programmed zones, determined by the longest RR interval. RESULTS: During a mean follow-up of 2.6+/ 1.9years, 6 patients (11%) died, none due to sudden cardiac death. Six patients (11%) received appropriate therapies, irrespectively of the established detection algorithm (p=0.59). All ventricular tachycardia and fibrillation episodes were adequately treated. Nine patients (17%) had inappropriate shocks: 6 without tiered-therapy vs 3 with previously programmed tiered-therapy (p=0.001). The yearly rate of inappropriate shocks was 17%/year with single zone detection vs 4%/year with tiered-therapy programming (p=0.007). Single-zone detection programming was an independent predictor of inappropriate shock delivery (HR 1.49, IC 95%: 1.05-18.80, p=0.04). CONCLUSION: In this selected population of patients, the S-ICDs proved effective in preventing sudden cardiac death. Tiered therapy was independently associated with a lower rate of inappropriate shock delivery. PMID- 28082087 TI - Among patients with left bundle branch block, T-wave peak to T-wave end time is prolonged in the presence of acute coronary occlusion. AB - BACKGROUND: Assessing the effect of myocardial ischemia on ventricular repolarization in the setting of left bundle branch block (LBBB) poses a challenge due to secondary prolongation of the QT interval inherent in LBBB. The T-wave peak to T-wave end (TpTe) interval has been noted to prolong during myocardial ischemia and correct after reperfusion in patients with normal conduction. Here we compare the TpTe intervals of patients with LBBB both with and without complete acute coronary occlusion (ACO). METHODS: Retrospectively, emergency department patients with LBBB and symptoms of myocardial ischemia were identified both with angiographically-proven ACO and with No-ACO. The longest QT, JT, and TpTe intervals were analyzed. RESULTS: The ACO and No-ACO groups consisted of 33 and 129 patients, respectively. The mean TpTe was longer in ACO (103.6ms [95%CI 98.5-108.7]) compared to No-ACO patients (88.6ms [95%CI 85.3 91.9]) (P<0.0001) and this held true after correction for heart rate. In ACO versus No-ACO, the TpTe also more frequently exceeded prolongation cutoffs of 85ms (30 [90%] versus 69 [54%]) and 100ms (25 [76%] versus 42 [33%]) (P<0.0001 for all). The mean QT, JT, QTc, and JTc intervals were not significantly different between the groups for either the Bazett's or Rautaharju's correction formulas. CONCLUSIONS: In patients with LBBB on the ECG, the TpTe is longer and more frequently prolonged in patients with ACO compared to patients without ACO. Future studies of ventricular repolarization in patients with LBBB should include analyses of the TpTe interval. PMID- 28082088 TI - Manifestations of Lyme carditis. AB - The first data of Lyme carditis, a relatively rare manifestation of Lyme disease, were published in eighties of the last century. Clinical manifestations include syncope, light-headedness, fainting, shortness of breath, palpitations, and/or chest pain. Atrioventricular (AV) electrical block of varying severity presents the most common conduction disorder in Lyme carditis. Although is usually mild, AV block can fluctuates rapidly and progress from a prolonged P-R interval to a His-Purkinje block within minutes to hours and days. Rarely, Lyme disease may be the cause of endocarditis, while some studies and reports, based on serological and/or molecular investigations, have suggested possible influence of Borrelia burgdorferi on degenerative cardiac valvular disease. Myocarditis, pericarditis, pancarditis, dilated cardiomyopathy, and heart failure have also been described as possible manifestations of Lyme carditis. The clinical course of Lyme carditis is generally mild, short term, and in most cases, completely reversible after adequate antibiotic treatment. PMID- 28082089 TI - Cardiovascular mortality - Comparing risk factor associations within couples and in the total population - The HUNT Study. AB - BACKGROUND: To compare associations of conventional risk factors with cardiovascular death within couples and in the population as a whole. METHODS: We analysed baseline data (1995-97) from the HUNT2 Study in Norway linked to the national Causes of Death Registry. We compared risk within couples using stratified Cox regression. RESULTS: During 914776 person-years, 3964 cardiovascular deaths occurred, and 1658 of the deaths occurred among 1494 couples. There were consistently stronger associations of serum lipids and blood pressure with cardiovascular mortality within couples compared to the population as a whole. For instance, for systolic blood pressure (per 20mmHg), the hazard ratio (HR) within couples was 1.28 (95% confidence interval: 1.17, 1.40) compared to 1.16 (1.12, 1.20) in the total population, and for diastolic pressure (per 10mmHg), the corresponding HRs were 1.16 (1.07, 1.26) and 1.11 (1.08, 1.13). Anthropometric factors (BMI, waist circumference, waist-hip ratio) as well as diabetes, smoking, physical activity, and education, showed nearly identical positive associations within couples and in the total population. CONCLUSIONS: Prospective population studies may tend to slightly underestimate associations of these factors with cardiovascular mortality. PMID- 28082091 TI - Changes in concentrations of circulating fibroblast activation protein alpha are associated with myocardial damage in patients with acute ST-elevation MI. AB - BACKGROUND: Fibroblast activation protein alpha (FAP) is a membrane-bound serine protease expressed by activated fibroblasts after myocardial infarction (MI). Reduced circulating FAP levels were associated with increased mortality in patients with acute coronary syndrome. We hypothesized that FAP concentrations are altered after acute ST-elevation MI (STEMI), and related to myocardial damage. METHODS: We measured circulating FAP concentrations in blood plasma of 60 patients on admission, day 1, day 3 and day 5 after STEMI, and in 25 apparently healthy blood donors as controls. RESULTS: Plasma FAP concentrations were lower in STEMI patients on admission (71ng/mL) than in blood donors (101ng/mL, P<0.0001). FAP concentrations declined in STEMI patients from admission to day 3 (66ng/mL, P<0.05) and day 5 (57ng/mL, P<0.05). FAP concentrations on day 5 were inversely correlated with maximum CK and maximum CRP levels. In a multiple linear regression analysis, maximum CRP was independently associated with low FAP concentrations on day 5 after STEMI. When stratified according to the absolute amount of FAP change from admission to day 5 (DeltaFAP), patients with high DeltaFAP (-22ng/mL) had worse left ventricular function, higher levels of hs cTnT, CK on admission, maximum CK and CRP than patients with low DeltaFAP ( 3ng/mL). CONCLUSIONS: Our study first demonstrates alterations of circulating FAP concentrations acutely after STEMI. A greater decline of circulating FAP concentrations in the first 5days after STEMI is associated with increased myocardial damage and inflammation. Measurement of circulating FAP might help to better understand the relation of myocardial injury and inflammatory response in the individual patient. PMID- 28082090 TI - Endothelial dysfunction and abnormal vascular structure are simultaneously present in patients with heart failure with preserved ejection fraction. AB - BACKGROUND: Endothelial dysfunction and abnormal vascular structure may be involved in the pathogenesis of chronic heart failure (HF). The purpose of this study was to evaluate simultaneously vascular function and vascular structure in patients with heart failure with preserved ejection fraction (HFpEF). METHODS: We measured flow-mediated vasodilatation (FMD) and nitroglycerine-induced vasodilation as indices of vascular function and intima-media thickness (IMT) as an index of vascular structure of the brachial artery in 41 patients with HFpEF (23 men and 18 women; mean age, 66+/-12yr) and 165 patients without HF (95 men and 70 women; mean age, 54+/-16yr). RESULTS: FMD was significantly smaller in patients with HFpEF than in patients without HF (2.9+/-2.1% versus 4.6+/-2.7%, P=0.0002). Nitroglycerine-induced vasodilation was significantly smaller in patients with HFpEF than in patients without HF (9.3+/-4.1% versus 12.9+/-4.9%, P<0.0001). Brachial artery IMT was significantly larger in patients with HFpEF than in patients without HF (0.35+/-0.06mm versus 0.31+/-0.07mm, P=0.0002). After adjustment for age, sex, hypertension, dyslipidemia, and diabetes mellitus, the associations remained significant between HFpEF and FMD (odds ratio, 0.79; 95% confidence interval, 0.66-0.92; P=0.0032), nitroglycerine-induced vasodilation (odds ratio, 0.88; 95% confidence interval, 0.80-0.96; P=0.0039), and brachial artery IMT (odds ratio, 1.08; 95% confidence interval, 1.01-1.17; P=0.033). CONCLUSIONS: These findings suggest that both endothelial dysfunction and abnormal vascular structure may contribute to the pathogenesis and maintenance of HFpEF. Endothelial function and vascular structure may be potential therapeutic targets for HFpEF. PMID- 28082092 TI - Energy utilization of induced pluripotent stem cell-derived cardiomyocyte in Fabry disease. AB - BACKGROUND: Fabry disease (FD) is a lysosomal storage disease in which glycosphingolipids (GB3) accumulate in organs of the human body, leading to idiopathic hypertrophic cardiomyopathy and target organ damage. Its pathophysiology is still poorly understood. OBJECTIVES: We aimed to generate patient-specific induced pluripotent stem cells (iPSC) from FD patients presenting cardiomyopathy to determine whether the model could recapitulate key features of the disease phenotype and to investigate the energy metabolism in Fabry disease. METHODS: Peripheral blood mononuclear cells from a 30-year-old Chinese man with a diagnosis of Fabry disease, GLA gene (IVS4+919G>A) mutation were reprogrammed into iPSCs and differentiated into iPSC-CMs and energy metabolism was analyzed in iPSC-CMs. RESULTS: The FD-iPSC-CMs recapitulated numerous aspects of the FD phenotype including reduced GLA activity, cellular hypertrophy, GB3 accumulation and impaired contractility. Decreased energy metabolism with energy utilization shift to glycolysis was observed, but the decreased energy metabolism was not modified by enzyme rescue replacement (ERT) in FD-iPSCs-CMs. CONCLUSION: This model provided a promising in vitro model for the investigation of the underlying disease mechanism and development of novel therapeutic strategies for FD. This potential remedy for enhancing the energetic network and utility efficiency warrants further study to identify novel therapies for the disease. PMID- 28082093 TI - Long-term prognostic impact of CT-Leaman score in patients with non-obstructive CAD: Results from the COronary CT Angiography EvaluatioN For Clinical Outcomes InteRnational Multicenter (CONFIRM) study. AB - BACKGROUND: Non-obstructive coronary artery disease (CAD) identified by coronary computed tomography angiography (CCTA) demonstrated prognostic value. CT-adapted Leaman score (CT-LeSc) showed to improve the prognostic stratification. Aim of the study was to evaluate the capability of CT-LeSc to assess long-term prognosis of patients with non-obstructive (CAD). METHODS: From 17 centers, we enrolled 2402 patients without prior CAD history who underwent CCTA that showed non obstructive CAD and provided complete information on plaque composition. Patients were divided into a group without CAD and a group with non-obstructive CAD (<50% stenosis). Segment-involvement score (SIS) and CT-LeSc were calculated. Outcomes were non-fatal myocardial infarction (MI) and the combined end-point of MI and all-cause mortality. RESULTS: Patient mean age was 56+/-12years. At follow-up (mean 59.8+/-13.9months), 183 events occurred (53 MI, 99 all-cause deaths and 31 late revascularizations). CT-LeSc was the only multivariate predictor of MI (HRs 2.84 and 2.98 in two models with Framingham and risk factors, respectively) and of MI plus all-cause mortality (HR 2.48 and 1.94 in two models with Framingham and risk factors, respectively). This was confirmed by a net reclassification analysis confirming that the CT-LeSc was able to correctly reclassify a significant proportion of patients (cNRI 0.28 and 0.23 for MI and MI plus all cause mortality, respectively) vs. baseline model, whereas SIS did not. CONCLUSION: CT-LeSc is an independent predictor of major acute cardiac events, improving prognostic stratification of patients with non-obstructive CAD. PMID- 28082094 TI - Effects of acute oxygen supplementation on functional capacity and heart rate recovery in Eisenmenger syndrome. AB - BACKGROUND: Eisenmenger syndrome (ES) precipitates the extreme manifestation of pulmonary hypertension, which leads to severe functional limitation and poor quality of life. The propose of the current study was: 1) examined the acute effects of 40% oxygen supplementation during the 6-minute walk test (6MWT); and 2) evaluate the relation between exercise capacity and clinical cardiac parameters in patients with ES. METHODS: Thirty subjects were prospectively included; all were submitted to a 6MWT with compressed air and with 40% of oxygen. Heart rate recovery at the first minute (HRR1) and perceived effort Borg scale for dyspnea and lower limb fatigue were recorded in both tests scenarios. RESULTS: The 6MWT distance was modestly, negatively associated with pulmonary vascular resistance (PVR) [r=0.46, p=0.02]. Patients improved 6MWT distance (p<0.001) and exhibited a faster HRR1 (p<0.001) with 40% supplemental oxygen compared to compressed air. With 40% supplemental oxygen, subjects revealed lower dyspnea and lower limb fatigue compared to 6MWT without oxygen supplementation (p<0.001). The amount of change in the 6MWT distance from air to oxygen was moderate, positively associated with tricuspid annular plane systolic excursion (TAPSE) and right ventricular fractional area change (RVFAC) [r=0.50, p=0.03; r=0.64, p<0.001, respectively]. CONCLUSION: Acute 40% oxygen supplementation in patients with Eisenmenger syndrome led to an improvement in 6MWT distance, faster HRR1 and lower dyspnea and lower limb fatigue perception. Moreover, functional capacity was positively associated with right ventricular parameters. PMID- 28082095 TI - ATF3, a novel cardiac therapeutic target: Beneficial or harmful? PMID- 28082096 TI - Investigations, findings, and follow-up in patients with chest pain and elevated high-sensitivity cardiac troponin T levels but no myocardial infarction. AB - BACKGROUND: Elevated troponin levels, in patients without myocardial infarction (MI), are associated with increased mortality. In an observational cohort study we aimed to assess how patients with elevated high-sensitivity cardiac troponin T (hs-cTnT) levels, and no MI are investigated and followed up, compared to patients with MI. METHODS: During January 1, 2011 to December 31, 2012, all patients >25years of age, with chest pain and elevated hs-cTnT levels or MI, at the Karolinska University Hospital were included. We calculated risk ratios (RR) with 95% confidence intervals (CI) for echocardiographies, stress tests, and follow-up, and compared medication in patients with and without MI. RESULTS: 1848 patients with elevated hs-cTnT levels but no MI, of whom 871 (47%) had no prior heart disease, and 667 patients with MI were included. Echocardiography was performed in 609 patients (33%) without MI and 580 (87%) with MI (adjusted RR 0.42; 95% CI, 0.37-0.48). Follow-up was planned for 856 (46%) patients without MI and 611 (92%) with MI (adjusted RR 0.54; 95% CI, 0.48-0.60). Among patients without MI and no heart disease who underwent echocardiography 46 (14%) had a left ventricular ejection fraction of <=40%, and on stress tests 27 (37%) had findings associated with ischemia. Platelet inhibitors and statins were started in 266 (25%) and 199 (17%) patients without MI, respectively, compared with 424 (93%), and 416 (86%) patients with MI. CONCLUSIONS: Patients with elevated hs cTnT levels and no MI are rarely investigated for detection of cardiac disease or followed up, or started on cardiovascular medication that potentially could prevent future cardiovascular events and death. PMID- 28082097 TI - Analysis of reperfusion time trends in patients with ST-elevation myocardial infarction across New York State from 2004 to 2012. AB - BACKGROUND: Registry-driven data have shown a significant decrease in door-to balloon (DTB) times in patients with ST-elevation myocardial infarction (STEMI) receiving percutaneous coronary intervention (PCI). We sought to determine the trends in reperfusion times (symptom-onset to door (SOTD) and DTB times) in patients presenting with STEMI across New York State. METHODS: We retrospectively examined 35,613 STEMI patients receiving PCI from 2004 to 2012 and compared median SOTD and DTB times across years. Patients with SOTD time >12h and DTB time >3h were excluded. RESULTS: There was a statistically significant trend towards shorter DTB times (median DTB time of 83min (IQR 53, 116) in 2004 to a median DTB time of 59min (IQR 40, 78) in 2012, P<0.01 for trend) and SOTD times (median SOTD time of 127min (IQR 64, 241) in 2004 to a median SOTD time of 116min (IQR 60, 205) in 2012, P<0.01 for trend). In subgroup analysis, demographics and the presence of co-morbid conditions did not influence the trend in reperfusion times. However, women had longer reperfusion times than men in 2012. After adjusting for confounding variables, DTB was a significant predictor of in hospital mortality (HR=1.04 (per 10minutes), P<0.01). CONCLUSIONS: There was a significant decrease in reperfusion times from 2004 to 2012 in STEMI patients across New York State. This trend was significant regardless of the presence of co-morbid conditions, although a significant gap in reperfusion times persists between men and women. PMID- 28082098 TI - Application of 3D printing technology to left atrial appendage occlusion. AB - BACKGROUND: Three-dimensional printing (3DP) has undergone rapid development in medical applications. However, only a few reports have described its applications in left atrial appendage (LAA) occlusion. We assessed the feasibility and effectiveness of the 3DP technology for left atrial appendage (LAA). METHODS: Forty-two patients with atrial fibrillation (average age: 69.3+/-7.8years) were randomly assigned to two groups equally (3DP and control). The transoesophageal echocardiography (TOE), LAA angiography, and cardiac computed tomography angiography measurements of the LAA orifice size between the groups. The procedure times, radiographic exposure, contrast agent volumes, residual shunt and costs were presented between the two groups. RESULTS: All patients underwent a successful LAA occlusion operation with the Watchman device. TOE, LAA angiography, and cardiac computed tomography angiography measurements of the LAA orifice size between the groups were 20.4+/-2.5 vs. 20.1+/-3.3mm, 19.6+/-2.2 vs. 19.5+/-2.8mm, and 20.8+/-2.1 vs. 20.2+/-3.0mm, respectively (p>0.05). After the occlusion, the immediate TOE examination showed 3 mild residual shunt cases in the control group. The radiation exposure was significantly reduced in the 3DP compared with the control group (p<0.05). The patients were followed for an average of 7.7+/-2.5months. No postoperative complications, device-related thrombosis, or ischemic events occurred. CONCLUSIONS: LAA occlusion guided by 3DP technology is feasible. 3DP increases the working efficiency and ensures the effectiveness of occlusion, making it valuable for clinical application. PMID- 28082099 TI - A beginner's guide to tissue clearing. AB - The last decade has seen a proliferation of tissue clearing methods that render large biological samples transparent and allow unprecedented three-dimensional views of enormous volumes of tissue. For a scientist wondering whether these methods will be useful to address their research problems, it can be bewildering to sort through the ever-increasing number of papers introducing new clearing methods. Here, I provide a concise summary for the novice describing what tissue clearing is, which research problems it can be applied to, how to decide on a clearing method, and where the field is headed in the future. PMID- 28082100 TI - A collaborative study to establish the 3rd WHO International Standard for hepatitis B virus for nucleic acid amplification techniques. AB - Nucleic acid amplification techniques (NAT) are routinely used for clinical diagnostics and monitoring hepatitis B virus (HBV) infections, and are implemented on a voluntary basis for blood screening. A collaborative study was performed to evaluate a replacement WHO International Standard for HBV for the standardization of NAT. Two lyophilised HBV candidates were evaluated by 16 laboratories worldwide, alongside the existing HBV International Standard. The overall mean potency estimates for the candidate samples 1 and 2, relative to sample 3 (2nd HBV International Standard), from quantitative assays, were 5.93 and 5.98 log10 International Units (IU)/mL respectively. The variability in individual laboratory mean estimates for samples 1-3 for quantitative assays was ~0.3 log10 IU/mL. The inter-laboratory variability for qualitative assays was higher. Accelerated thermal degradation studies indicate that both lyophilised candidates are stable and suitable for long-term use. Overall, the results suggested that both candidates were suitable as replacement International Standards. Sample 1 (NIBSC code 10/264) was established as the 3rd WHO International Standard for HBV for NAT with an assigned potency of 850,000 IU/mL (~5.93 log10 IU/mL), when reconstituted in 0.5 mL of nuclease-free water. It is intended for the calibration (in IU) of secondary reference materials used in HBV NAT. PMID- 28082102 TI - Molecular snapshot of an intracellular freezing event in an Antarctic nematode. AB - The Antarctic nematode, Panagrolaimus sp. DAW1 (formerly called Panagrolaimus davidi), is the best documented example of an organism able to survive intracellular ice formation in all of its compartments. Not only is it able to survive such extreme physiological disruption, but it is able to produce progeny once thawed from such a state. In addition, under slower rates, or less extreme degrees, of cooling, its body remains unfrozen and the vapour pressure difference between the supercooled body fluids and the surrounding ice leads to a process termed cryoprotective dehydration. In contrast to a fairly large body of work in building up our molecular understanding of cryoprotective dehydration, no comparable work has been undertaken on intracellular freezing. This paper describes an experiment subjecting cultures of Panagrolaimus sp. DAW1 to a range of temperatures including a rapid descent to -10 degrees C, in a medium just prior to, and after, freezing. Through deep sequencing of RNA libraries we have gained a snapshot of which genes are highly abundant when P. sp. DAW1 is undergoing an intracellular freezing event. The onset of freezing correlated with a high production of genes involved in cuticle formation and subsequently, after 24 h in a frozen state, protease production. In addition to the mapping of RNA sequencing, we have focused on a select set of genes arising both from the expression profiles, as well as implicated from other cold tolerance studies, to undertake qPCR. Among the most abundantly represented transcripts in the RNA mapping is the zinc-metalloenzyme, neprilysin, which also shows a particularly strong upregulated signal through qPCR once the nematodes have frozen. PMID- 28082101 TI - Negative Regulation of Type 2 Immunity. AB - Type 2 immunity encompasses the mechanisms through which the immune system responds to helminths and an array of environmental substances such as allergens. In the developing world, billions of individuals are chronically infected with endemic parasitic helminths. In comparison, in the industrialized world, millions of individuals suffer from dysregulated type 2 immunity, referred to clinically as atopic diseases including asthma, allergic rhinitis, and atopic dermatitis. Thus, type 2 immunity must be carefully regulated to mount protective host responses yet avoid inappropriate activation and immunopathology. In this review, we describe the key players and connections at play in type 2 responses and focus on the emerging mechanisms involved in the negative regulation of type 2 immunity. PMID- 28082103 TI - The Role of Extent of Surgical Resection and Lymph Node Assessment for Clinical Stage I Pulmonary Lepidic Adenocarcinoma: An Analysis of 1991 Patients. AB - BACKGROUND: This study examined the association of extent of lung resection, pathologic nodal evaluation, and survival for patients with clinical stage I (cT1 2N0M0) adenocarcinoma with lepidic histologic features in the National Cancer Data Base. METHODS: The association between extent of surgical resection and long term survival for patients in the National Cancer Data Base with clinical stage I lepidic adenocarcinoma who underwent lobectomy or sublobar resection was evaluated using Kaplan-Meier and Cox proportional hazards regression analyses. RESULTS: Of the 1991 patients with cT1-2N0M0 lepidic adenocarcinoma who met the study criteria, 1544 underwent lobectomy and 447 underwent sublobar resection. Patients treated with sublobar resection were older, more likely to be female, and had higher Charlson/Deyo comorbidity scores, but they had smaller tumors and lower T status. Of the patients treated with lobectomy, 6% (n = 92) were upstaged because of positive nodal disease, with a median of seven lymph nodes sampled (interquartile range 4-10). In an analysis of the entire cohort, lobectomy was associated with a significant survival advantage over sublobar resection in univariate analysis (median survival 9.2 versus 7.5 years, p = 0.022, 5-year survival 70.5% versus 67.8%) and after multivariable adjustment (hazard ratio = 0.81, 95% confidence interval: 0.68-0.95, p = 0.011). However, lobectomy was no longer independently associated with improved survival when compared with sublobar resection (hazard ratio = 0.99, 95% confidence interval: 0.77-1.27, p = 0.905) in a multivariable analysis of a subset of patients in which only those patients who had undergone a sublobar resection including lymph node sampling were compared with patients treated with lobectomy. CONCLUSIONS: Surgeons treating patients with stage I lung adenocarcinoma with lepidic features should cautiously utilize sublobar resection rather than lobectomy, and they must always perform adequate pathologic lymph node evaluation. PMID- 28082104 TI - Transcriptome sequencing analysis of porcine granulosa cells treated with an anti inhibin antibody. AB - Inhibin can regulate granulosa cell proliferation and function via direct action on granulosa cells, or indirectly through stimulation of pituitary follicle stimulating hormone secretion. Thus far, it has not been possible to unravel or formulate the chain of molecular events that lead to enhanced granulosa cell proliferation and function using conventional gene expression analysis. The aim of this study was to examine the biological effects of immuno-neutralization of inhibin bioactivity in porcine granulosa cells using transcriptome profiling by the RNA-seq technology. Treatment of granulosa cells with anti-inhibin alpha subunit antibodies increased both cell proliferation and estradiol secretion. Data revealed by RNA sequencing were subjected to bioinformatic analysis. The results showed that a total of 476 genes, including 27 novel genes, were differentially expressed in anti- inhibin antibody-treated granulosa cells compared to untreated granulosa cells. RNA sequencing data were validated by qRT PCR which confirmed differential expression (upregulation and downregulation) of eighteen of twenty selected genes A total of 476 differentially expressed genes were enriched in processes such as matrix remodeling, chemokine activity, protein binding, and structural molecular activities, and which could be related to granulosa cell proliferation, estradiol synthesis, and ovarian follicle growth. In particular, the data emphasized the importance of extracellular matrix remodeling and the involvement of chemokines in enhanced granulosa cell function, which are important features of ovarian follicle growth, development, maturation, and ovulation. This study provided a new level of understanding of enhanced granulosa cell function and ovarian follicle development achieved through immuno neutralization of endogenous inhibin bioactivity. PMID- 28082105 TI - The relationship between BOLD fMRI response and the underlying white matter as measured by fractional anisotropy (FA): A systematic review. AB - Despite the relationship between brain structure and function being of fundamental interest in cognitive neuroscience, the relationship between the brain's white matter, measured using fractional anisotropy (FA), and the functional magnetic resonance imaging (fMRI) blood oxygen level dependent (BOLD) response is poorly understood. A systematic review of literature investigating the association between FA and fMRI BOLD response was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The PubMed and Web of Knowledge databases were searched up until 22.04.2016 using a predetermined set of search criteria. The search identified 363 papers, 28 of which met the specified inclusion criteria. Positive relationships were mainly observed in studies investigating the primary sensory and motor systems and in resting state data. Both positive and negative relationships were seen in studies using cognitive tasks. This systematic review suggests that there is a relationship between FA and the fMRI BOLD response and that the relationship is task and region dependent. Behavioural and/or clinical variables were shown to be essential in interpreting the relationships between imaging measures. The results highlight the heterogeneity in the methods used across papers in terms of fMRI task, population investigated and data analysis techniques. Further investigation and replication of current findings are required before definitive conclusions can be drawn. PMID- 28082106 TI - Creative constraints: Brain activity and network dynamics underlying semantic interference during idea production. AB - Functional neuroimaging research has recently revealed brain network interactions during performance on creative thinking tasks-particularly among regions of the default and executive control networks-but the cognitive mechanisms related to these interactions remain poorly understood. Here we test the hypothesis that the executive control network can interact with the default network to inhibit salient conceptual knowledge (i.e., pre-potent responses) elicited from memory during creative idea production. Participants studied common noun-verb pairs and were given a cued-recall test with corrective feedback to strengthen the paired association in memory. They then completed a verb generation task that presented either a previously studied noun (high-constraint) or an unstudied noun (low constraint), and were asked to "think creatively" while searching for a novel verb to relate to the presented noun. Latent Semantic Analysis of verbal responses showed decreased semantic distance values in the high-constraint (i.e., interference) condition, which corresponded to increased neural activity within regions of the default (posterior cingulate cortex and bilateral angular gyri), salience (right anterior insula), and executive control (left dorsolateral prefrontal cortex) networks. Independent component analysis of intrinsic functional connectivity networks extended this finding by revealing differential interactions among these large-scale networks across the task conditions. The results suggest that interactions between the default and executive control networks underlie response inhibition during constrained idea production, providing insight into specific neurocognitive mechanisms supporting creative cognition. PMID- 28082107 TI - Sounds facilitate visual motion discrimination via the enhancement of late occipital visual representations. AB - Sensory discriminations, such as judgements about visual motion, often benefit from multisensory evidence. Despite many reports of enhanced brain activity during multisensory conditions, it remains unclear which dynamic processes implement the multisensory benefit for an upcoming decision in the human brain. Specifically, it remains difficult to attribute perceptual benefits to specific processes, such as early sensory encoding, the transformation of sensory representations into a motor response, or to more unspecific processes such as attention. We combined an audio-visual motion discrimination task with the single trial mapping of dynamic sensory representations in EEG activity to localize when and where multisensory congruency facilitates perceptual accuracy. Our results show that a congruent sound facilitates the encoding of motion direction in occipital sensory - as opposed to parieto-frontal - cortices, and facilitates later - as opposed to early (i.e. below 100ms) - sensory activations. This multisensory enhancement was visible as an earlier rise of motion-sensitive activity in middle-occipital regions about 350ms from stimulus onset, which reflected the better discriminability of motion direction from brain activity and correlated with the perceptual benefit provided by congruent multisensory information. This supports a hierarchical model of multisensory integration in which the enhancement of relevant sensory cortical representations is transformed into a more accurate choice. PMID- 28082108 TI - Head-shaft angle changes during internal and external shoulder rotations: 2-D angulation in 3-D space. AB - INTRODUCTION: Restoration of native head-shaft angle (HSA) is critical for treatment of proximal humerus fracture. However, HSA has not been properly investigated according to the humeral rotation. This study was designed to analyze the relationship between the humeral rotation and the HSA at 1 degrees increments, and clarify its serial changing pattern according to the humeral rotation. HYPOTHESIS: The angulation of HSA would be undervalued when the humerus is being rotated externally and it would be overvalued when it is being rotated internally. MATERIALS AND METHODS: Eight dried cadaveric normal humeri were CT scanned. They were analyzed using computer-aided design with a standardized neutral position. HSA was the angle between the humeral shaft axis (SA) and the humeral head axis (HA). SA and HA were the best-fit lines through center of all the best-fitting circles in every cross section along the humeral shaft and within the humeral head, respectively. Each 3D model was rotated 30 degrees internally and 45 degrees externally relatives to the SA at 1 degrees increments with the camera was fixed at antero-posterior view of neutral position. Angulation of HSA in every rotational degree was documented as ratio relatives to the angulation of HSA in neutral position. RESULTS: The average HSA at neutral position was 133+/-1.93 degrees . HSA was underestimated by 8+/-1.9% and it was overestimated by 20+/-5.1% at the maximum external rotation (ER) and internal rotation (IR), respectively. HSA was underestimated by 1% in every 5.8 degrees of ER and overestimated by 1% in every 1.5 degrees of IR. Rotational misalignments within 10 degrees of IR and 18 degrees of ER could be tolerated (P>.05). CONCLUSIONS: HSA was underestimated at ER and was overestimated at IR. This information could be useful for surgeons in restoring the native HSA for treatment of proximal humerus fracture. TYPE OF STUDY: Basic research study. PMID- 28082110 TI - Novel phototoxicity assay using human embryonic stem cell-derived retinal pigment epithelial cells. AB - Some chemicals are harmful in to light-exposed tissues such as skin and eyes. The 3T3 Neutral Red Uptake Phototoxicity Test has been validated and adopted by the Organization of Economic and Community Development (OECD) as a method of evaluating chemical phototoxicity using mouse 3T3 fibroblasts. However, the high rate of false positive results associated with this test eventually led to increased laboratory animal usage. Although the eye is vulnerable to light damage because of constant exposure to environmental radiation, few approaches are available to predict ocular phototoxicity in humans. Here, we propose a tier one test that identifies the potential ocular phototoxicity of chemical substances. Using a three-dimensional culture technique, human embryonic stem cells (hESCs) were differentiated to retinal pigment epithelial cell (RPE) precursors. The precursors after prolonged treatment with FBS formed a uniform hexagonal lattice of cells with well-developed tight junctions and time-dependent elevation of melanin content and RPE maturation marker levels. Hierarchical clustering of gene transcripts revealed that hESC-derived RPEs were very similar to tissue-derived adult RPEs. Interestingly, there were a high percentage of chemicals eliciting a positive response in 3T3 cells and negative in hESC-derived RPEs under the experimental conditions used in the phototoxicity test. The response to treatment of hESC-derived RPEs with these negative chemicals became positive at a higher dose of UVA irradiation; however, the biological responses to these chemicals differed between the two cells. Taken together, we conclude that hESC-derived RPEs are novel tool for future toxicological and mechanistic studies of ocular phototoxicity in humans. PMID- 28082109 TI - 1,3-Butadiene-induced mitochondrial dysfunction is correlated with mitochondrial CYP2E1 activity in Collaborative Cross mice. AB - Cytochrome P450 2E1 (CYP2E1) metabolizes low molecular weight hydrophobic compounds, including 1,3-butadiene, which is converted by CYP2E1 to electrophilic epoxide metabolites that covalently modify cellular proteins and DNA. Previous CYP2E1 studies have mainly focused on the enzyme localized in the endoplasmic reticulum (erCYP2E1); however, active CYP2E1 has also been found in mitochondria (mtCYP2E1) and the distribution of CYP2E1 between organelles can influence an individual's response to exposure. Relatively few studies have focused on the contribution of mtCYP2E1 to activation of chemical toxicants. We hypothesized that CYP2E1 bioactivation of 1,3-butadiene within mitochondria adversely affects mitochondrial respiratory complexes I-IV. A population of Collaborative Cross mice was exposed to air (control) or 200ppm 1,3-butadiene. Subcellular fractions (mitochondria, DNA, and microsomes) were collected from frozen livers and CYP2E1 activity was measured in microsomes and mitochondria. Individual activities of mitochondrial respiratory complexes I-IV were measured using in vitro assays and purified mitochondrial fractions. In air- and 1,3-butadiene-exposed mouse samples, mtDNA copy numbers were assessed by RT-PCR, and mtDNA integrity was assessed through a PCR-based assay. No significant changes in mtDNA copy number or integrity were observed; however, there was a decrease in overall activity of mitochondrial respiratory complexes I, II, and IV after 1,3-butadiene exposure. Additionally, higher mtCYP2E1 (but not erCYP2E1) activity was correlated with decreased mitochondrial respiratory complex activity (in complexes I-IV) in the 1,3-butadiene-exposed (not control) animals. Together, these results represent the first in vivo link between mitochondrial CYP2E1 activity and mitochondrial toxicity. PMID- 28082111 TI - Protective effects of dioscin against doxorubicin-induced nephrotoxicity via adjusting FXR-mediated oxidative stress and inflammation. AB - Dioscin shows active effects against renal ischemia/reperfusion injury and lipopolysaccharide-induced inflammatory kidney injury, however, little is known concerning the role of it on doxorubicin (Dox)-induced nephrotoxicity. In the present study, in vivo test of Dox-induced nephrotoxicity in rats and in vitro model in NRK-52E cells were developed. The results showed that dioscin significantly attenuated cell injury, obviously reduced ROS level in vitro, and markedly decreased the levels of BUN, Cr, MDA, and notably increased the levels of SOD, GSH and GSH-Px in rats. Mechanistic studies showed that dioscin significantly increased the levels of p-AMPKalpha, Nrf2, HO-1 and GST by activation of FXR against oxidative stress. In addition, dioscin suppressed the nuclear translocation of NF-kappaB and HMGB1, and subsequently decreased the mRNA levels of IL-1beta, IL-6, and TNF-alpha against inflammation. These results were further validated by knockdown of FXR using siRNA silencing, and abrogation of FXR using NDB (a FXR inhibitor) in NRK-52E cells, and the results suggested that the protective effect of dioscin against Dox- induced nephrotoxicity via adjusting FXR-mediated signal to suppress oxidative stress and inflammation. In addition, molecular docking assay showed that dioscin directly targeted with FXR through competing with Helix12 (H12) by hydrogen bonding, hydrophobic effect and electrostatic interactions. In a word, our data showed that dioscin is a novel and potent FXR agonist to suppress inflammation and oxidative stress against Dox induced nephrotoxicity. PMID- 28082112 TI - Pleural Effusion in Dasatinib-Treated Patients With Chronic Myeloid Leukemia in Chronic Phase: Identification and Management. AB - Dasatinib has demonstrated durable clinical responses in patients, both as first line and subsequent lines of therapy. Dasatinib use can result in pleural effusion in some patients, occurring any time during treatment and commonly characterized as mild to moderate in severity. Early identification of symptoms is essential in the proper management of pleural effusion. Prompt confirmation of diagnosis and management of pleural effusion can minimize morbidity and maximize the ability to preserve long-term clinical benefits with dasatinib. Here, we provide guidance on early identification and management of dasatinib-related pleural effusion. PMID- 28082113 TI - Effects of Deeper Molecular Responses on Outcomes in Chronic Myeloid Leukemia Patients in Chronic Phase Treated With Imatinib Mesylate. AB - BACKGROUND: The prognostic significance of complete cytogenetic response (CCyR) is well defined in patients with chronic phase chronic myeloid leukemia treated with imatinib as first-line therapy. However, the effect on outcomes of obtaining molecular response itself and the depth of it is not clear. In this study we aimed to determine the frequency of complete molecular response (CMR) during long term follow-up and the clinical significance of CMR on patient outcomes and survival. PATIENTS AND METHODS: We retrospectively evaluated the files of 178 chronic phase chronic myeloid leukemia patients using imatinib therapy. Forty seven patients with missing data were excluded from the study and the assessment was done in 131 patients. CMR was defined as undetectable BCR-ABL transcripts using real-time quantitative polymerase chain reaction with a sensitivity level of >= 104 in 2 consecutive analyses at least 3 months apart. Cytogenetic and molecular monitoring during treatment was performed according to the European LeukemiaNet recommendations criteria. Our primary objective was to analyze the association of deeper molecular response with differences in progression-free survival (PFS). RESULTS: Eighty-eight patients (67%) achieved CMR at any time in a median of 65 months of follow-up. The rate of CMR was higher in patients who achieved CCyR at 12 months and major molecular response (MMR) at 18 months. Fewer events occurred in the CMR group than the MMR group (26.1% vs. 50.0%). Overall survival was not different in both groups. CMR was associated with longer PFS with borderline significance. CONCLUSION: Prolonged imatinib therapy helps to achieve a deeper molecular response in the long-term. Achieving deeper molecular response at any time positively affects maintaining the cytogenetic and molecular responses, and decreases the transformation to accelerated and/or blastic phase. The slight prolongation in PFS did not reach statistical significance. PMID- 28082114 TI - Bioinspired and biocompatible carbon nanotube-Ag nanohybrid coatings for robust antibacterial applications. AB - : The design of self-sterilizing surfaces with favorable biocompatibility is acknowledged as an effective approach to deal with the bacterial infections of biomedical devices. In this study, we report an intriguing protocol for the large scale fabrication of self-sterilizing and biocompatible surface film coatings by using polymer shielded silver nanoparticle loaded oxidized carbon nanotube (AgNPs@oCNT) nano-dispersions. To achieve the antibacterial coatings, the bioinspired positively charged and negatively charged AgNPs@oCNTs were alternately deposited onto substrates by spray-coating assisted layer-by-layer assembly. Then the bacterial inhibitory zones, optical density value monitoring, bacterial killing efficiency and adhesion were investigated; and all the results revealed that the AgNPs@oCNTs thin film coatings exhibited robust and long-term antibacterial activity against both Gram negative and Gram positive bacteria. Moreover, due to the shielding effects of polymer layers, the coatings showed extraordinary blood compatibility and limited toxicity against human umbilical vein endothelial cells. It is believed that the proposed large-scale fabrication of bactericidal, blood and cell compatible AgNPs@oCNT based thin film coatings will have great potential to forward novel operational pathogenic inhibition strategies to avoid undesired bacterial contaminations of biomedical implants or biological devices. STATEMENT OF SIGNIFICANCE: Bacterial infection of medical devices has been considered to be a world-wide clinical threat towards patients' health. In this study, a bioinspired and biocompatible antibacterial coating was prepared via the spray-assisted layer-by-layer (LbL) assembly. The silver nanopartilces loaded oxidized carbon nanotube (AgNPs@oCNT), which were coated by functional polymers (chitosan and synthetic heparin mimicking polymers), were prepared via mussel inspired chemistry; and the spray-assisted assembly process allowed the fast construction on devices. Owing to the antibacterial efficiency of the loaded AgNPs, the coating showed robust bacterial killing activity and resistance towards bacterial adhesion. Moreover, since that the AgNPs were shielded by the polymers, the coating exhibited no clear toxicity at blood or cellular level. Benefiting from the universal and large-scale fabrication advancements of the spray assisted LbL coating; it is believed that the proposed strategy can be applied in designing many other kinds of self-sterilizing biomedical implants and devices. PMID- 28082116 TI - Randomized controlled trial of scleroligation versus band ligation alone for eradication of gastroesophageal varices. AB - BACKGROUND AND AIMS: Gastric varices develop in 5% to 33% of patients with portal hypertension. Their most common form is concomitant gastroesophageal varices. Scleroligation (combined sclerotherapy and band ligation) has been used successfully in management of esophageal varices but has not been evaluated previously in the management of gastroesophageal varices. The aim of this work was evaluation of a new scleroligation technique for management of bleeding gastroesophageal varices regarding efficacy, adverse events, variceal recurrence, and survival. METHODS: This study was conducted on 120 cirrhotic patients with bleeding gastroesophageal varices, whom we divided randomly into 2 groups of 60 patients each-a band ligation group and a scleroligation group. RESULTS: The mean number of sessions was lower in the scleroligation group than in the band ligation group (2.22 +/- 0.92 and 3.43 +/- 0.67, respectively) (P < .001), as were the duration of treatment and total number of bands used. Cost and survival were comparable in the 2 groups. There was no significant difference between the 2 maneuvers regarding adverse events, recurrence rates, or rebleeding rates after obliteration. Recurrence was significantly higher in patients with larger varices, ulceration, and postprocedure pyrexia. Rebleeding was significantly higher among those who experienced postprocedure pyrexia and developed or had worsening of gastric antral vascular ectasia. CONCLUSIONS: Scleroligation appears to achieve a faster rate of eradication with fewer treatment sessions and total number of bands deployed to achieve variceal obliteration than band ligation and is comparable in cost and in adverse event and recurrence rates. (Clinical trial registration number: NCT02646202.). PMID- 28082115 TI - Cap cuff-assisted colonoscopy versus standard colonoscopy for adenoma detection: a randomized back-to-back study. AB - BACKGROUND AND AIMS: EndoCuff is a disposable device applied to standard colonoscopes to improve mucosal visualization. Randomized parallel trials have shown that EndoCuff increases the adenoma detection rate (ADR). The primary aim of this study was to compare the ADR between EndoCuff-assisted colonoscopies (EAC) and standard colonoscopies within a randomized back-to-back trial. METHODS: This was a single-center randomized crossover study (NCT02374515) involving adult patients undergoing screening, surveillance, or diagnostic colonoscopy. Participants received back-to-back standard colonoscopies and EACs in a random order, performed by the same endoscopist. All polyps were excised, but only those proven at histology to be adenomas were considered for analysis. RESULTS: From February 2015 to March 2016, a total of 288 patients were enrolled, and 274 were included in the per-protocol analysis. Compared with standard colonoscopies, EACs increased the ADR (29.6% vs 26.3%; P < .01) and the number of diagnosed adenomas (176 vs 129; P < .01), particularly in the left (73 vs 46; P < .01) and right sides of the colon (83 vs 63; P < .01). EAC increased the detection of adenomas <5 mm (129 vs 84; P < .01), but no difference was found with regard to larger lesions. In 7.3% of patients, findings of EndoCuff shortened the surveillance interval determined by standard colonoscopy findings. EndoCuff caused 7 mucosal erosions (2.5% of patients), requiring a mucosal adrenaline injection in 1 case. CONCLUSIONS: The use of EndoCuff increases the number of identified adenomas, primarily small adenomas in the left and right sides of the colon. This increases the ADR and allows a better definition of the surveillance program. (Clinical trial registration number: NCT02374515.). PMID- 28082117 TI - Targeting endothelial metabolism for anti-angiogenesis therapy: A pharmacological perspective. AB - Current anti-angiogenic therapies in malignant and ocular diseases target growth factor signaling in order to attenuate excessive vascular growth. Although initial responses are promising, overall therapeutic success is limited due to insufficient efficiency, tumor refractoriness and resistance. Emerging evidence suggests that diverse growth factor signaling pathways in endothelial cells (ECs) converge onto cellular metabolism, creating an attractive target for novel alternative anti-angiogenic therapies. Recent studies show that ECs rely on glycolysis for ATP and biomass synthesis, necessary for proliferation and migration, key processes of angiogenesis. In addition, fatty acid beta-oxidation (FAO) is essential for de novo nucleotide synthesis during EC proliferation. Initial proof-of-evidence has been given that administration of pharmacological inhibitors of those metabolic pathways can be used to inhibit pathological angiogenesis in vivo. Deciphering the role of other metabolic pathways and exploring the therapeutic potential of blocking these pathways await further investigation. PMID- 28082119 TI - Periostin Promotes Scar Formation through the Interaction between Pericytes and Infiltrating Monocytes/Macrophages after Spinal Cord Injury. AB - Scar formation is a prominent pathological feature of traumatic central nervous system (CNS) injury, which has long been implicated as a major impediment to the CNS regeneration. However, the factors affecting such scar formation remain to be elucidated. We herein demonstrate that the extracellular matrix protein periostin (POSTN) is a key player in scar formation after traumatic spinal cord injury (SCI). Using high-throughput RNA sequencing data sets, we found that the genes involved in the extracellular region, such as POSTN, were significantly expressed in the injured spinal cord. The expression of POSTN peaked at 7 days after SCI, predominantly in the scar-forming pericytes. Notably, we found that genetic deletion of POSTN in mice reduced scar formation at the lesion site by suppressing the proliferation of the pericytes. Conversely, we found that recombinant POSTN promoted the migration capacity of the monocytes/macrophages and increased the expression of tumor necrosis factor-alpha from the monocytes/macrophages in vitro, which facilitated the proliferation of pericytes. Furthermore, we revealed that the pharmacological blockade of POSTN suppressed scar formation and improved the long-term functional outcome after SCI. Our findings suggest a potential mechanism whereby POSTN regulates the scar formation after SCI and provide significant evidence that POSTN is a promising therapeutic target for CNS injury. PMID- 28082118 TI - Elevated Expression of Moesin in Muscular Dystrophies. AB - Fibrosis is the main complication of muscular dystrophies. We identified moesin, a member of the ezrin-radixin-moesin family, in dystrophic muscles of mice representing Duchenne and congenital muscular dystrophies (DMD and CMD, respectively) and dysferlinopathy, but not in the wild type. High levels of moesin were also observed in muscle biopsy specimens from DMD, Ullrich CMD, and merosin-deficient CMD patients, all of which present high levels of fibrosis. The myofibroblasts, responsible for extracellular matrix protein synthesis, and the macrophages infiltrating the dystrophic muscles were the source of moesin. Moesin positive cells were embedded within the fibrotic areas between the myofibers adjacent to the collagen type I fibers. Radixin was also synthesized by the myofibroblasts, whereas ezrin colocalized with the myofiber membranes. In animal models and patients' muscles, part of the moesin was in its active phosphorylated form. Inhibition of fibrosis by halofuginone, an antifibrotic agent, resulted in a major decrease in moesin levels in the muscles of DMD and CMD mice. In summary, the results of this study may pave the way for exploiting moesin as a novel target for intervention in MDs, and as part of a battery of biomarkers to evaluate treatment success in preclinical studies and clinical trials. PMID- 28082120 TI - Modulation of Antiviral Immunity by Heme Oxygenase-1. AB - Heme oxygenase-1 (HO-1) is a stress-inducible, anti-inflammatory, and cytoprotective enzyme expressed in most cell types in the organism. Under several stress stimuli, HO-1 expression and activity is up-regulated to catalyze the rate limiting enzymatic step of heme degradation into carbon monoxide, free iron, and biliverdin. Besides its effects on cell metabolism, HO-1 is also capable of modulating host innate and adaptive immune responses in response to sepsis, transplantation, and autoimmunity, and preventing oxidative damage associated with inflammation. In addition, recent studies have reported that HO-1 can exert a significant antiviral activity against a wide variety of viruses, including HIV, hepatitis C virus, hepatitis B virus, enterovirus 71, influenza virus, respiratory syncytial virus, dengue virus, and Ebola virus, among others. Herein, we address the current understanding of the functional significance of HO-1 against a variety of viruses and its potential as a therapeutic strategy to prevent and control viral infections. Furthermore, we review the most important features of the immunoregulatory functions for this enzyme. PMID- 28082121 TI - Changes in the Luminal Environment of the Colonic Epithelial Cells and Physiopathological Consequences. AB - Evidence, mostly from experimental models, has accumulated, indicating that modifications of bacterial metabolite concentrations in the large intestine luminal content, notably after changes in the dietary composition, may have important beneficial or deleterious consequences for the colonic epithelial cell metabolism and physiology in terms of mitochondrial energy metabolism, reactive oxygen species production, gene expression, DNA integrity, proliferation, and viability. Recent data suggest that for some bacterial metabolites, like hydrogen sulfide and butyrate, the extent of their oxidation in colonocytes affects their capacity to modulate gene expression in these cells. Modifications of the luminal bacterial metabolite concentrations may, in addition, affect the colonic pH and osmolarity, which are known to affect colonocyte biology per se. Although the colonic epithelium appears able to face, up to some extent, changes in its luminal environment, notably by developing a metabolic adaptive response, some of these modifications may likely affect the homeostatic process of colonic epithelium renewal and the epithelial barrier function. The contribution of major changes in the colonocyte luminal environment in pathological processes, like mucosal inflammation, preneoplasia, and neoplasia, although suggested by several studies, remains to be precisely evaluated, particularly in a long-term perspective. PMID- 28082122 TI - Is There Any Difference Between Questionnaires on Pediatric Lower Urinary Tract Dysfunction? AB - OBJECTIVE: To investigate the diagnostic properties of 3 different scoring systems (Dysfunctional Voiding Symptom Score [DVSS], Dysfunctional Voiding and Incontinence Symptoms Score [DVISS], Incontinence Symptom Index-Pediatric [ISI-P, for children older than 11 years]) that are used to evaluate lower urinary tract symptoms in pediatric population. MATERIALS AND METHODS: Eighty-four participants were evaluated by detailed history, physical examination, 3 different scoring systems (DVSS, DVISS, ISI-P), ultrasonography, and uroflowmetry. Depending on the tests, cases were stratified as healthy or lower urinary tract symptoms (LUTS) by 2 urologists who were blinded to the questionnaires. Patients were reevaluated by the same tests and questionnaires 3 months after treatment. Diagnostic properties of questionnaires were calculated. Additionally, parents were asked to scale the improvement of symptoms subjectively from 0% to 100% to correlate to each of the three scoring systems. RESULTS: The mean ages of the normal and the LUTS groups were 9.1 +/- 2.6 years and 10.1 +/- 2.8 years, respectively (P = .301). Gender (male:female) distribution was 21:21 in the LUTS group and 25:17 in the control group (P = .381). In terms of diagnosis, DVISS has the highest accuracy (sensitivity: 81%, specificity: 97.6%, accuracy: 89%) followed by ISI-P (sensitivity: 55.6%, specificity: 100%, accuracy: 82%) and DVSS (sensitivity: 54.8%, specificity: 97.6%, accuracy: 76%). The similar order was valid for the 23 patients older than 11 years (accuracy for DVISS: 87%, for ISI-P: 82%, and for DVSS: 78%). In terms of response to treatment, all 3 tests showed good correlation with parents' ratings (DVSS: P < .001, DVISS: P = .005, ISI-P: P = .042). CONCLUSION: Although DVISS had the highest accuracy in distinguishing the patients from healthy controls, all 3 questionnaires seem to be equivalent for the evaluation of response to treatment. PMID- 28082123 TI - Nicotine suppresses the neurotoxicity by MPP+/MPTP through activating alpha7nAChR/PI3K/Trx-1 and suppressing ER stress. AB - Parkinson's disease (PD) is a neurodegenerative disease. Nicotine has been reported to have the role in preventing Parkinson's disease. However, its mechanism is still unclear. In present study we found that nicotine suppressed 1 methyl-4-phenylpyridinium ion(MPP+) toxicity in PC12 cells by MTT assay. The expression of thioredoxin-1(Trx-1) was decreased by MPP+, which was restored by nicotine. The nicotine suppressed expressions of Glucose-regulated protein 78(GRP78/Bip) and C/EBP homologous protein (CHOP) induced by MPP+. The methyllycaconitine (MLA), the inhibitor of alpha7nAChR and LY294002, the inhibitor of phosphatidylinositol 3-kinase (PI3K) blocked the suppressions of above molecules, respectively. Consistently, pretreatment with nicotine ameliorated the motor ability, restored the declines of Trx-1 and tyrosine hydroxylase (TH), and suppressed the expressions of Bip and CHOP induced by 1 Methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Our results suggest that nicotine plays role in resisting MPP+/MPTP neurotoxicity through activating the alpha7nAChR/PI3K/Trx-1 pathway and suppressing ER stress. PMID- 28082124 TI - Psychogenic nonepileptic seizures: We know what they are not. But do we know what they are? PMID- 28082125 TI - Oligomeric state of hypoxanthine-guanine phosphoribosyltransferase from Mycobacterium tuberculosis. AB - Sedimentation equilibrium and size-exclusion chromatography experiments on Mycobacterium tuberculosis hypoxanthine-guanine phosphoribosyltransferase (MtHGPRT) have established the existence of this enzyme as a reversibly associating mixture of dimeric and tetrameric species in 0.1 M Tris-HCl-0.012 M MgCl2, pH 7.4. Displacement of the equilibrium position towards the larger oligomer by phosphate signifies the probable existence of MtHGPRT as a tetramer in the biological environment. These data thus add credibility to the relevance of considering enzyme function in the light of a published tetrameric structure deduced from X-ray crystallography. Failure of 5-phospho-alpha-d-ribosyl-1 pyrophosphate (PRib-PP) to perturb the dimer-tetramer equilibrium position indicates the equivalence and independence of binding for this substrate (the first to bind in an ordered sequential mechanism) to the two oligomers. By virtue of the displacement of the equilibrium position towards dimer that is affected by removing MgCl2 from the Tris-HCl buffer, it can be concluded that divalent metal ions, as well as phosphate, can affect the oligomerization. These characteristics of MtHGPRT in solution are correlated with published crystal structures of four enzyme-ligand complexes. PMID- 28082126 TI - Metabolic Syndrome: One Speckled Stone Kills a Flock of Birds? AB - Effectively treating metabolic syndrome and its progression to type 2 diabetes, steatohepatitis and cardiovascular disease remain a major clinical challenge. The use of a novel engineered molecule that combines thyroid hormone and glucagon to target liver and adipose tissue might provide a new 'magic bullet' with exciting future prospects. PMID- 28082127 TI - Beyond dual systems: A genetically-informed, latent factor model of behavioral and self-report measures related to adolescent risk-taking. AB - The dual systems model posits that adolescent risk-taking results from an imbalance between a cognitive control system and an incentive processing system. Researchers interested in understanding the development of adolescent risk-taking use a diverse array of behavioral and self-report measures to index cognitive control and incentive processing. It is currently unclear whether different measures commonly interpreted as indicators of the same psychological construct do, in fact, tap the same underlying dimension of individual differences. In a diverse sample of 810 adolescent twins and triplets (M age=15.9years, SD=1.4years) from the Texas Twin Project, we investigated the factor structure of fifteen self-report and task-based measures relevant to adolescent risk-taking. These measures can be organized into four factors, which we labeled premeditation, fearlessness, cognitive dyscontrol, and reward seeking. Most behavioral measures contained large amounts of task-specific variance; however, most genetic variance in each measure was shared with other measures of the corresponding factor. Behavior genetic analyses further indicated that genetic influences on cognitive dyscontrol overlapped nearly perfectly with genetic influences on IQ (rA=-0.91). These findings underscore the limitations of using single laboratory tasks in isolation, and indicate that the study of adolescent risk taking will benefit from applying multimethod approaches. PMID- 28082128 TI - Individual-based energetic model suggests bottom up mechanisms for the impact of coastal hypoxia on Pacific harbor seal (Phoca vitulina richardii) foraging behavior. AB - Wind-driven coastal hypoxia represents an environmental stressor that has the potential to drive redistribution of gilled marine organisms, and thereby indirectly affect the foraging characteristics of air-breathing upper trophic level predators. We used a conceptual individual-based model to simulate effects of coastal hypoxia on the spatial foraging behavior and efficiency of a marine mammal, the Pacific harbor seal (Phoca vitulina richardii) on the Oregon coast. Habitat compression of fish was simulated at varying intensities of hypoxia. Modeled hypoxia affected up to 80% of the water column and half of prey species' horizontal habitat. Pacific sand lance (Ammodytes hexapterus), Pacific herring (Clupea pallasii), and English sole (Parophrys vetulus) were selected as representative harbor seal prey species. Model outputs most affected by coastal hypoxia were seal travel distance to foraging sites, time spent at depth during foraging dives, and daily energy balance. For larger seals, English sole was the most optimal prey during normoxia, however during moderate to severe hypoxia Pacific sand lance was the most beneficial prey. For smaller seals, Pacific herring was the most efficient prey species during normoxia, but sand lance became more efficient as hypoxia increased. Sand lance represented the highest increase in foraging efficiency during severe hypoxic events for all seals. Results suggest that during increasing hypoxia, smaller adult harbor seals could benefit by shifting from foraging on larger neritic schooling fishes to foraging closer inshore on less energetically-dense forage fish. Larger adult seals may benefit by shifting from foraging on groundfish to smaller, schooling neritic fishes as hypoxia increases. The model suggests a mechanism by which hypoxia may result in increased foraging efficiency of Pacific harbor seals, and therefore increased rates of predation on coastal fishes on the continental shelf during hypoxic events. PMID- 28082129 TI - Effects of stimulus mode and ambient temperature on cerebral responses to local thermal stimulation: An EEG study. AB - The physiological responses to human thermal stimulation have been widely investigated, but most of them are mainly concerned about the whole body thermal stimulation. In this study, we investigated the effects of stimulus mode and ambient temperature on cerebral responses during local thermal stimulation on hand. The left hands were stimulated by metal thermostat based and thermostatic water based stimulators at different stimulated temperatures (38 degrees C, 40 degrees C, 42 degrees C and 44 degrees C) and different ambient temperatures (25 degrees C and 32 degrees C). EEG data were recorded over the whole brain during the experiments. Then the statistical comparisons were conducted on the EEG relative power among different experimental sessions. We observed that EEG activities were alternated between thermal stimulated periods and the baseline in all four frequency bands. And there was a higher percentage of delta band power in the right temporal and parietal regions under the ambient temperature of 32 degrees C while compared to 25 degrees C. In addition, the theta band activity under the metal based stimulation showed significantly higher EEG relative power than that under the water based stimulation over the whole brain. Compared with the water based stimulation, there was a lower EEG relative power of the beta band activity during the metal based stimulation in the bilateral frontal and right temporal regions. The experimental results suggested that the neural physiological responses in different EEG frequency bands were sensitive to different influence factors during the local hand thermal stimulation. PMID- 28082130 TI - Diurnal variations and source apportionment of ozone at the summit of Mount Huang, a rural site in Eastern China. AB - Comprehensive measurements were conducted at the summit of Mount (Mt.) Huang, a rural site located in eastern China during the summer of 2011. They observed that ozone showed pronounced diurnal variations with high concentrations at night and low values during daytime. The Weather Research and Forecasting with Chemistry (WRF-Chem) model was applied to simulate the ozone concentrations at Mt. Huang in June 2011. With processes analysis and online ozone tagging method we coupled into the model system, the causes of this diurnal pattern and the contributions from different source regions were investigated. Our results showed that boundary layer diurnal cycle played an important role in driving the ozone diurnal variation. Further analysis showed that the negative contribution of vertical mixing was significant, resulting in the ozone decrease during the daytime. In contrast, ozone increased at night owing to the significant positive contribution of advection. This shifting of major factor between vertical mixing and advection formed this diurnal variation. Ozone source apportionment results indicated that approximately half was provided by inflow effect of ozone from outside the model domain (O3-INFLOW) and the other half was formed by ozone precursors (O3-PBL) emitted in eastern, central, and southern China. In the O3-PBL, 3.0% of the ozone was from Mt. Huang reflecting the small local contribution (O3-LOC) and the non local contributions (O3-NLOC) accounted for 41.6%, in which ozone from the southerly regions contributed significantly, for example, 9.9% of the ozone originating from Jiangxi, representing the highest geographical contributor. Because the origin and variation of O3-NLOC was highly related to the diurnal movements in boundary layer, the similar diurnal patterns between O3-NLOC and total ozone both indicated the direct influence of O3-NLOC and the importance of boundary layer diurnal variations in the formation of such distinct diurnal ozone variations at Mt. Huang. PMID- 28082131 TI - Dynamic interplay between microbial denitrification and antibiotic resistance under enhanced anoxic denitrification condition in soil. AB - Mixed contamination of nitrate and antibiotics/antibiotic-resistant genes (ARGs) is an emerging environmental risk to farmland soil. This is the first study to explore the role of excessive anthropogenic nitrate input in the anoxic dissipation of soil antibiotic/ARGs. During the initial 10 days of incubation, the presence of soil antibiotics significantly inhibited NO3- dissipation, N2O production rate, and denitrifying genes (DNGs) abundance in soil (p < 0.05). Between days 10 and 30, by contrast, enhanced denitrification clearly prompted the decline in antibiotic contents and ARG abundance. Significantly negative correlations were detected between DNGs and ARGs, suggesting that the higher the DNG activity, the more dramatic is the denitrification and the greater are the antibiotic dissipation and ARG abundance. This study provides crucial knowledge for understanding the mutual interaction between soil DNGs and ARGs in the enhanced anoxic denitrification condition. PMID- 28082132 TI - A laboratory assessment of the potential effect of Cry1Ab/Cry2Aj-containing Bt maize pollen on Folsomia candida by toxicological and biochemical analyses. AB - The common soil arthropod Folsomia candida can survive well when fed only maize pollen and thus may be exposed to insecticidal proteins by ingesting insect resistant genetically engineered maize pollen containing Bacillus thuringiensis (Bt) proteins when being released into the soil. Laboratory experiments were conducted to assess the potential effects of Cry1Ab/Cry2Aj-producing transgenic Bt maize (Shuangkang 12-5) pollen on F. candida fitness. Survival, development, and the reproduction were not significantly reduced when F. candida fed on Bt maize pollen rather than on non-Bt maize pollen, but these parameters were significantly reduced when F. candida fed on non-Bt maize pollen containing the protease inhibitor E-64 at 75 MUg/g pollen. The intrinsic rate of increase (rm) was not significantly reduced when F. candida fed on Bt maize pollen but was significantly reduced when F. candida fed on non-Bt maize pollen containing E-64. The activities of antioxidant-related enzymes in F. candida were not significantly affected when F. candida fed on Bt maize pollen but were significantly increased when F. candida fed on non-Bt pollen containing E-64. The results demonstrate that consumption of Bt maize pollen containing Cry1Ab/Cry2Aj has no lethal or sublethal effects on F. candida. PMID- 28082133 TI - Chemical characterization of submicron aerosol particles during wintertime in a northwest city of China using an Aerodyne aerosol mass spectrometry. AB - An Aerodyne quadrupole aerosol mass spectrometry (Q-AMS) was utilized to measure the size-resolved chemical composition of non-refractory submicron particles (NR PM1) from October 27 to December 3, 2014 at an urban site in Lanzhou, northwest China. The average NR-PM1 mass concentration was 37.3 MUg m-3 (ranging from 2.9 to 128.2 MUg m-3) under an AMS collection efficiency of unity and was composed of organics (48.4%), sulfate (17.8%), nitrate (14.6%), ammonium (13.7%), and chloride (5.7%). Positive matrix factorization (PMF) with the multi-linear engine (ME-2) solver identified six organic aerosol (OA) factors, including hydrocarbon like OA (HOA), coal combustion OA (CCOA), cooking-related OA (COA), biomass burning OA (BBOA) and two oxygenated OA (OOA1 and OOA2), which accounted for 8.5%, 20.2%, 18.6%, 12.4%, 17.8% and 22.5% of the total organics mass on average, respectively. Primary emissions were the major sources of fine particulate matter (PM) and played an important role in causing high chemically resolved PM pollution during wintertime in Lanzhou. Back trajectory analysis indicated that the long-range regional transport air mass from the westerly was the key factor that led to severe submicron aerosol pollution during wintertime in Lanzhou. PMID- 28082134 TI - The dual role of cathelicidins in systemic inflammation. AB - Antimicrobial peptides are key components of the innate immune system. They act as broad-spectrum antimicrobial agents against Gram-positive and -negative bacteria, viruses, and fungi. More recently, antimicrobial peptides have been ascribed immunomodulatory functions, including roles in wound healing, induction of cytokines, and altering host gene expression. Cathelicidins are a class of antimicrobial peptide found in humans, mice, and rats, among others. Known as LL 37 in humans and cathelin-related antimicrobial peptide (CRAMP) in rodents, cathelicidins are produced by many different cells, including macrophages, neutrophils, and epithelial cells. The role of cathelicidins is somewhat confounding, as they exhibit both pro-and anti-inflammatory activity. A major obstacle in the study of cathelicidins is the inability of exogenous LL-37 or CRAMP to mimic the activity of their endogenous counterparts. Nevertheless, studies have shown that LL-37 is recognized by multiple receptors, and may stabilize or modulate Toll-like receptor signaling. In addition, cathelicidins play a role in apoptosis, inflammasome activation, and phagocytosis. However, many studies are revealing the dual effects of cathelicidins. For example, CRAMP appears to be protective in models of group A Streptococcus skin infection, pneumonia, and meningitis, but detrimental in cases of severe bacterial infection, such as septic shock. It is becoming increasingly clear that the activity of cathelicidins is modulated by complex interactions with the microenvironment, as well as the disease background. This article reviews what is currently known about the activity of cathelicidins in an attempt to understand their complex roles in systemic diseases. PMID- 28082135 TI - Routine Postoperative Imaging Is Not Indicated in the Management of Mandibular Fractures. AB - PURPOSE: Prior literature has shown that routine postoperative computed tomography (CT) scans for mandibular fractures have no effect on outcomes and complications; however, past surveys have reported that most clinicians continue to order routine scans. We aimed to determine the current use of routine postoperative CT scans, evaluate what factors contribute to this practice, and identify differences in outcomes and complications among patients with either routine, indicated, or no postoperative CT scans. PATIENTS AND METHODS: We conducted a retrospective review of consecutive patients treated for a mandibular fracture at Vancouver General Hospital from January 1, 2007, to March 1, 2012. RESULTS: We included 167 patients in the study for analysis. No significant differences in outcomes or complications were found between patients who had an indicated postoperative CT scan (27%) and patients with no scans (64%). Only the treating surgeon had a statistically significant effect on whether a patient received a postoperative CT scan (P < .001), and those patients who had an indicated postoperative CT scan (9%) were more likely to have a decreased level of temporomandibular joint function (P = .002) and increased incidence of complications and secondary operations (P < .001 and P < .001, respectively). CONCLUSIONS: Routine postoperative CT scans were found to have no significant effect on outcomes and complications, and a clinician's individual practice was the most significant factor for whether a patient received a routine postoperative CT scan. Future work should aim at providing well-defined indications for postoperative imaging. PMID- 28082136 TI - Diagnostic approach to sudden onset of diffuse isolated oedema of the lips. AB - In the light of a case of sudden onset of diffuse, isolated oedema of the lips, the authors describe the key points of the diagnostic approach and the main epidemiological and clinical data. PMID- 28082137 TI - Sofosbuvir in combination with daclatasvir in liver transplant recipients with HCV infection: A systematic review and meta-analysis. AB - BACKGROUND: Studies focusing on the efficacy of SOF+DCV regimen on liver transplantation recipients with HCV infection are still limited. In the current study, we aimed to perform a systematic review and meta-analysis to evaluate the efficacy and tolerability of SOF+DCV regimen, with or without ribavirin, on post LT setting. METHODS: A systematic literature search of various databases as well as abstracts of major liver diseases conferences was performed. Studies with SVR data in HCV infected liver transplantation recipients treated with daclatasvir/sofosbuvir regimen were included. All statistical analyses were conducted by R version 3.3.1 (The R Foundation for Statistical Computing, Vienna, Austria). RESULTS: Seven studies with a total of 379 LT recipients were included in this study. Most of these LT recipients had genotype 1 HCV infection. The overall rate of SVR12 reached 93.3% (95% CI: 83.3% to 99.4%). After excluding the study of Fontana et al., the SVR12 reached 96.8% and heterogeneity was lowered down (P=0.17). In three studies, patients treated with SOF+DCV (n=146) had a higher SVR12 rate than that of patients treated with SOF+DCV+RBV (n=83) (OR 0.33, 95% CI: 0.12 to 0.87; P=0.02). There was no difference in SVR12 between patients infected with HCV genotype 1 and genotype 3 (P=0.57) and no difference was found in SVR12 rate between 12-week therapy and 24-week therapy (P=0.82). The most common adverse effects (AEs) were: anemia 32% (n=64/202), infections 26% (n=38/149), neutropenia 23% (n=35/149), thrombocytopenia 21% (n=32/149) and renal failure 8% (n=12/149). CONCLUSION: SOF+DCV+/-RBV regimen is of high efficacy and tolerability in LT recipients with HCV infection. PMID- 28082139 TI - Pilot study examining the relationship of childhood trauma, perceived stress, and medication use to serum kynurenic acid and kynurenine levels in schizophrenia. PMID- 28082138 TI - Interhospital transfers of the critically ill: Time spent at referring institutions influences survival. AB - OBJECTIVE: To determine if the length of stay at a referring institution intensive care unit (ICU) before transfer to a tertiary/quaternary care facility is a risk factor for mortality. DESIGN: We performed a retrospective chart review of patients transferred to our ICU from referring institution ICUs over a 3-year period. Logistical regression analysis was performed to determine which factors were independently associated with increased mortality. The primary outcomes were ICU and hospital mortality. MAIN RESULTS: A total of 1248 patients were included in our study. Length of stay at the referring institution was an independent risk factor for both ICU and hospital mortality (P<.0001), with increasing lengths of stay correlating with increased mortality. Each additional day at the referring institution was associated with a 1.04 increase in likelihood of ICU mortality (95% confidence interval, 1.02-1.06; P =0.001) and a 1.029 (95% confidence interval, 1.01-1.05; P .005) increase in likelihood of hospital mortality. CONCLUSIONS: Length of stay at the referring institution before transfer is a risk factor for worse outcomes, with longer stays associated with increased likelihood of mortality. Further studies delineating which factors most affect length of stay at referring institutions, though a difficult task, should be pursued. PMID- 28082140 TI - Shared abnormality of white matter integrity in schizophrenia and bipolar disorder: A comparative voxel-based meta-analysis. AB - Patients with schizophrenia and bipolar disorder (BD) shared a significant overlap in genetic susceptibility, pharmacological treatment responses, neuropsychological deficits, and epidemiological features. However, it remains unknown whether these clinical overlaps are mediated by shared or disorder specific abnormalities of white matter integrity. In this voxel-based meta analytic comparison of whole-brain white matter integrity, we aimed to identify the shared or disorder-specific structural abnormalities between schizophrenia and BD. A comprehensive literature search was conducted up to February 2016 to identify studies that compared between patients and healthy controls (HC) by using whole-brain diffusion approach (schizophrenia: 24 datasets with 754 patients vs. 775 HC; BD: 23 datasets with 705 patients vs. 679 HC). Voxel-wise meta-analyses were conducted and restricted to unified template using seed-based d-Mapping. Abnormal white matter integrity was calculated within each condition and a direct comparison of effect size was performed of alterations between two conditions. Two regions with significant reductions of fractional anisotropy (FA) characterized abnormal water diffusion in both disorders: the genu of the corpus callosum (CC) and posterior cingulum fibers. There was no significant difference found between the two disorders. Our results highlighted shared impairments of FA at genu of the CC and left posterior cingulum fibers, which suggests that, phenotypic overlap between schizophrenia and BD could be related to common brain circuit dysfunction. PMID- 28082141 TI - Regulation of mitochondrial dynamics by DISC1, a putative risk factor for major mental illness. AB - Mitochondria are dynamic organelles that are essential to power the process of neurotransmission. Neurons must therefore ensure that mitochondria maintain their functional integrity and are efficiently transported along the full extent of the axons and dendrites, from soma to synapses. Mitochondrial dynamics (trafficking, fission and fusion) co-ordinately regulate mitochondrial quality control and function. DISC1 is a component of the mitochondrial transport machinery and regulates mitochondrial dynamics. DISC1's role in this is adversely affected by sequence variants connected to brain structure/function and disease risk, and by mutant truncation. The DISC1 interactors NDE1 and GSK3beta are also involved, indicating a convergence of putative risk factors for psychiatric illness upon mitochondrial dynamics. PMID- 28082142 TI - Draft genome sequence of an environmental multidrug-resistant Klebsiella pneumoniae ST340/CC258 harbouring blaCTX-M-15 and blaKPC-2 genes. AB - Anthropogenic activities, including the release of wastewater and sewage from hospitals, have contributed to the contamination of aquatic environments, raising a concern to public health. In this study, we present the first draft genome sequence of a Klebsiella pneumoniae strain (Kp171, TIET-4200) belonging to the high-risk hospital-associated clonal lineage ST340/CC258, which was recovered from a water sample collected in an urban river in Brazil. PMID- 28082143 TI - Draft genome sequence of an aminoglycoside-resistant RmtG-producing Pseudomonas aeruginosa ST235 isolated from a cystic fibrosis patient. AB - Cystic fibrosis (CF) patients are often chronically colonised or infected by non fermenting Gram-negative bacilli, with Pseudomonas aeruginosa being the most prevalent. In this study, we report the draft genome sequence of a multidrug resistant P. aeruginosa strain belonging to sequence type ST235, isolated from the respiratory tract of a CF patient with chronic colonisation. Whole-genome sequencing analysis revealed a 6.7Mb genome size and the presence of 12 antibiotic resistance genes, including the rmtG gene conferring high-level aminoglycoside resistance, located on the chromosome. PMID- 28082144 TI - High-quality genome sequence of human pathogen Enterobacter asburiae type strain 1497-78T. AB - Enterobacter asburiae belongs to the Enterobacter cloacae complex (Ecc), which comprises six heterogenic species. These bacteria can cause nosocomial infections. Moreover, they are well known for antibiotic resistance features based on overproduction of AmpC beta-lactamases. Although Ecc have clinical importance, little is known about their virulence-associated properties, and very few strains from the six species have been sequenced. In this study, the type strain of E. asburiae 1497-78T (ATCC 35953) was sequenced. The genome sequence of the type strain of E. asburiae will help us to understand antibiotic resistance and evolution in Ecc. PMID- 28082145 TI - How resistant is Staphylococcus aureus to the topical antibiotic mupirocin? PMID- 28082146 TI - Reply to: "Histone deacetylase inhibitor for the treatment of hepatocellular carcinoma: Chemoimmunotherapeutic perspective and prospects". PMID- 28082147 TI - Hepatitis C "true" late relapse beyond 48weeks of sustained virologic response after direct acting antiviral therapy. PMID- 28082148 TI - Vps33b is crucial for structural and functional hepatocyte polarity. AB - BACKGROUND & AIMS: In the normal liver, hepatocytes form a uniquely polarised cell layer that enables movement of solutes from sinusoidal blood to canalicular bile. Whilst several cholestatic liver diseases with defects of hepatocyte polarity have been identified, the molecular mechanisms of pathogenesis are not well defined. One example is arthrogryposis, renal dysfunction and cholestasis syndrome, which in most patients is caused by VPS33B mutations. VPS33B is a protein involved in membrane trafficking that interacts with RAB11A at recycling endosomes. To understand the pathways that regulate hepatocyte polarity better, we investigated VPS33B deficiency using a novel mouse model with a liver-specific Vps33b deletion. METHODS: To assess functional polarity, plasma and bile samples were collected from Vps33b liver knockout (Vps33bfl/fl-AlfpCre) and control (Vps33bfl/fl) mice; bile components or injected substrates were quantitated by mass spectrometry or fluorometry. For structural analysis, livers underwent light and transmission electron microscopy. Apical membrane and tight junction protein localisation was assessed by immunostaining. Adeno-associated virus vectors were used for in vivo gene rescue experiments. RESULTS: Like patients, Vps33bfl/fl AlfpCre mice showed mislocalisation of ATP-binding cassette proteins that are specifically trafficked to the apical membrane via Rab11a-positive recycling endosomes. This was associated with retention of bile components in blood. Loss of functional tight junction integrity and depletion of apical microvilli were seen in knockout animals. Gene transfer partially rescued these defects. CONCLUSIONS: Vps33b has a key role in establishing structural and functional aspects of hepatocyte polarity and may be a target for gene replacement therapy. LAY SUMMARY: Hepatocytes are liver cells with tops and bottoms; that is, they are polarised. At their bottoms they absorb substances from blood. They then, at their tops, secrete these substances and their metabolites into bile. When polarity is lost, this directional flow of substances from blood to bile is disrupted and liver disease follows. In this study, using a new mouse model with a liver-specific mutation of Vps33b, the mouse version of a gene that is mutated in most patients with arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome, we investigated how the Vps33b gene product contributes to establishing hepatocyte polarity. We identified in these mice abnormalities similar to those in children with ARC syndrome. Gene transfer could partly reverse the mouse abnormalities. Our work contributes to the understanding of VPS33B disease and hepatocyte polarity in general, and may point towards gene transfer mediated treatment of ARC liver disease. PMID- 28082149 TI - Histone deacetylase inhibitor for the treatment of hepatocellular carcinoma: Chemoimmunotherapeutic perspective and prospects. PMID- 28082150 TI - Searching for proprioceptors in human facial muscles. AB - The human craniofacial muscles innervated by the facial nerve typically lack muscle spindles. However these muscles have proprioception that participates in the coordination of facial movements. A functional substitution of facial proprioceptors by cutaneous mechanoreceptors has been proposed but at present this alternative has not been demonstrated. Here we have investigated whether other kinds of sensory structures are present in two human facial muscles (zygomatic major and buccal). Human checks were removed from Spanish cadavers, and processed for immunohistochemical detection of nerve fibers (neurofilament proteins and S100 protein) and two putative mechanoproteins (acid-sensing ion channel 2 and transient receptor potential vanilloid 4) associated with mechanosensing. Nerves of different calibers were found in the connective septa and within the muscle itself. In all the muscles analysed, capsular corpuscle like structures resembling elongated or round Ruffini-like corpuscles were observed. Moreover the axon profiles within these structures displayed immunoreactivity for both putative mechanoproteins. The present results demonstrate the presence of sensory structures in facial muscles that can substitute for typical muscle spindles as the source of facial proprioception. PMID- 28082151 TI - Antidepressant and anxiolytic-like behavioral effects of erucamide, a bioactive fatty acid amide, involving the hypothalamus-pituitary-adrenal axis in mice. AB - Erucamide (Era) is a bioactive fatty acid amide, which is similar to the classical endocannabinoid analogue oleoylethanolamide (OEA). In the present study, we hypothesized that Era may regulate the central nervous system and may have the potential to antagonize depression and anxiety. Therefore, we investigated the antidepressant and anxiolytic effects of Era in animal models in comparison with fluoxetine (Fxt). Fifty mice were randomly divided into 5 groups, and treated with a vehicle (0.3% methyl cellulose, 20mL/kg, p.o.), Era (5, 10, 20mg/kg, p.o.), or Fxt (20mg/kg, p.o.) for 7days. Immobility was used to evaluate depressive-like behavior in the forced swimming test (FST) and tail suspension test (TST). Animal activity and exploratory behavior as well as anxiety-like behaviors were measured in open field test (OFT) and elevated plus-maze test (EPMT) in mice. Additionally, serum adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) levels were determined using the ELISA method, and the total anti-oxidative capacity (T-AOC) was detected by ultraviolet spectrophotometry. Our data showed that Era (5, 10, or 20mg/kg) induced a significant reduction in mouse immobility time in the TST and FST compared to the normal control group (vehicle group). The positive control, Fxt (20mg/kg group), also induced a significant change in immobility time in the TST and FST compared to the control (vehicle) group. In the OFT, compared with the control group, Fxt (20mg/kg) and Era (5, 10, or 20mg/kg) did not significantly change the locomotive activity (locomotive time, immobility time, or locomotive distance) in mice, but Fxt (20mg/kg) and Era (10, or 20mg/kg) significantly increased the percentage of time spent and squares visited in the OFT central area. In regards to the EPMT, the data showed that Fxt (20mg/kg) and Era (10, 20mg/kg) significantly increased the ratio of time spent and entries in open arms, but did not significantly change the total locomotive distance (including open arms and closed arms) compared to the control group. Biochemical tests found that after 7days of drug treatment, compared with the control group, ACTH and CORT serum levels in mice were significantly decreased, although T-AOC levels did not significantly change. In conclusion, Era (dose range of 5-20mg/kg) administered orally may alleviate depression- and anxiety-like behaviors in mice, and the antidepressant and anti anxiety effects of Era may be related to the regulation of the hypothalamus pituitary-adrenal axis (HPA). PMID- 28082153 TI - Melatonin produces a rapid onset and prolonged efficacy in reducing depression like behaviors in adult rats exposed to chronic unpredictable mild stress. AB - The present study was aimed at evaluating the rapidity and duration of melatonin as an antidepressant in a rat model of depression. The rats were subjected to a six-week period of unpredictable mild stress followed by melatonin treatment. Three groups of rats were included in this study: Controls (CON - no stress exposure), Chronic Unpredictable Mild Stress (CUS) and CUS followed by melatonin (MT). Stressors consisted of exposure to rotation on a shaker, placement in a chamber maintained at 4 degrees C, lights off for 3h, lights on overnight, exposure to an aversive odor, 45 degrees tilted cages, food and water deprivation and crowding and isolated housing. Subsequently, the saline vehicle (CUS) or melatonin was administered at a dose of 10mg/kg for 14days period. Body weight and behavioral tests were used to evaluate depression-like behavior and its recovery following melatonin treatment. While body weight increases were significantly lower in rats exposed to CUS versus CON, body weights of the MT group increased significantly following melatonin treatment as compared with the CUS group. With regard to results obtained with behavioral assays indicative of depression, rapid and long-term functional recoveries in depression were observed in the MT as compared to the CUS group. The results indicate that not only does melatonin induce an antidepressant-like action within this rat model of depression, but does so with a rapid onset and prolonged efficacy. As most current treatments for depression require an extended period of administration, our current results suggest that melatonin may prove to be a particularly effect agent to promote a rapid onset and prolonged behavioral benefits in the treatment of depression. PMID- 28082154 TI - Lead Aprons Are a Lead Exposure Hazard. AB - PURPOSE: To determine whether lead-containing shields have lead dust on the external surface. METHODS: Institutional review board approval was obtained for this descriptive study of a convenience sample of 172 shields. Each shield was tested for external lead dust via a qualitative rapid on-site test and a laboratory-based quantitative dust wipe analysis, flame atomic absorption spectrometry (FAAS). The chi2 test was used to test the association with age, type of shield, lead sheet thickness, storage method, and visual and radiographic appearance. RESULTS: Sixty-three percent (95% confidence interval [CI]: 56%-70%) of the shields had detectable surface lead by FAAS and 50% (95% CI: 43%-57%) by the qualitative method. Lead dust by FAAS ranged from undetectable to 998 MUg/ft2. The quantitative detection of lead was significantly associated with the following: (1) visual appearance of the shield (1 = best, 3 = worst): 88% of shields that scored 3 had detectable dust lead; (2) type of shield: a greater proportion of the pediatric patient, full-body, and thyroid shields were positive than vests and skirts; (3) use of a hanger for storage: 27% of shields on a hanger were positive versus 67% not on hangers. Radiographic determination of shield intactness, thickness of interior lead sheets, and age of shield were unrelated to presence of surface dust lead. CONCLUSIONS: Sixty-three percent of shields had detectable surface lead that was associated with visual appearance, type of shield, and storage method. Lead-containing shields are a newly identified, potentially widespread source of lead exposure in the health industry. PMID- 28082155 TI - Nonresearch Industry Payments to Radiologists: Characteristics and Associations With Regional Medical Imaging Utilization. AB - PURPOSE: To evaluate characteristics of nonresearch industry payments to radiologists and associations with regional diagnostic imaging utilization. METHODS: Using 2014 CMS Open Payment data, all disclosed nonresearch-related industry payments to radiologists were identified. Health Resources and Services Administration Area Health Resources Files were used to identify actual and population-weighted numbers of radiologists by state. Utilizing the 5% random beneficiary sample CMS Research Identifiable Files from 2014, average Medicare imaging spending per beneficiary in each state was calculated. Average frequency and dollar amounts of nonresearch nonroyalty payments to radiologists were calculated at the state level. Using the Pearson correlation coefficient, the relationship between frequency and amounts of nonresearch payments to radiologists versus per-beneficiary Medicare imaging spending was evaluated at the state level. RESULTS: Overall, 2,008 radiologists (1,670 diagnostic, 338 interventional) received nonresearch nonroyalty payments from industry, representing 5.2% of all 38,857 radiologists nationwide. A total of 4,975 individual transfers translated to 2.5 +/- 1.3 discrete payments per receiving radiologist with a mean of $432 +/- $1,976 (median $26; range $1-$34,050). Food and beverage expenses constituted the vast majority of disclosed transfers (4,111; 83%), followed by travel and lodging (444; 9%), consulting fees (279; 6%), and educational expenses (51; 1%). Considerable geographic variation in payments was observed, ranging from 0% of radiologists in Vermont to 12.9% in the District of Columbia. No correlation was identified between average per beneficiary Medicare imaging spending and the proportion of nonresearch-funded radiologists in each state (r = 0.06). Similarly, no correlation was identified between average per-beneficiary Medicare imaging spending and the average nonresearch transfer amount to radiologists in each state (r = -0.08). CONCLUSIONS: In 2014, only a small minority of United States radiologists received nonresearch payments from industry. At the state level, medical imaging utilization does not seem to be influenced by such financial relationships. PMID- 28082152 TI - Pharmacogenomics in epilepsy. AB - There is high variability in the response to antiepileptic treatment across people with epilepsy. Genetic factors significantly contribute to such variability. Recent advances in the genetics and neurobiology of the epilepsies are establishing the basis for a new era in the treatment of epilepsy, focused on each individual and their specific epilepsy. Variation in response to antiepileptic drug treatment may arise from genetic variation in a range of gene categories, including genes affecting drug pharmacokinetics, and drug pharmacodynamics, but also genes held to actually cause the epilepsy itself. From a purely pharmacogenetic perspective, there are few robust genetic findings with established evidence in epilepsy. Many findings are still controversial with anecdotal or less secure evidence and need further validation, e.g. variation in genes for transporter systems and antiepileptic drug targets. The increasing use of genetic sequencing and the results of large-scale collaborative projects may soon expand the established evidence. Precision medicine treatments represent a growing area of interest, focussing on reversing or circumventing the pathophysiological effects of specific gene mutations. This could lead to a dramatic improvement of the effectiveness and safety of epilepsy treatments, by targeting the biological mechanisms responsible for epilepsy in each specific individual. Whilst much has been written about epilepsy pharmacogenetics, there does now seem to be building momentum that promises to deliver results of use in clinic. PMID- 28082156 TI - The Commodity-Proof Radiologist. PMID- 28082157 TI - Improved Image Quality of Low-Dose CT Pulmonary Angiograms. AB - OBJECTIVE: The use of CT pulmonary angiography (CTPA) to evaluate for pulmonary embolism has been increasing, and carries a significant radiation dose. We evaluate image quality of lower-dose images, taking into account patient size as well as the effects of image postprocessing. METHODS: A total of 250 CTPAs were retrospectively reviewed. The following parameters were obtained: kVp, mA, dose length product, Hounsfield units (HU) with standard deviation in the main pulmonary artery, transverse scout measurement, and subjective image quality. RESULTS: Radiation dose decreased 55% by reducing kVp from 120 to 100, and 60% from 100 to 80 kVp. Radiation dose decreased 82% from 120 to 80 kVp. Noise increased 38% from 120 kVp to 100 kVp, and increased 23% from 100 kVp to 80 kVp. Adding an overlapped reconstructed image decreased noise by 16% to 21%. Despite the increase in image noise, diagnostic quality was significantly improved at 80 and 100 kVp, compared with 120 kVp, with an average subjective quality rating of 3.8, 4.0, and 3.2, respectively, and an average pulmonary artery density of 536, 423, and 278 HU. Even in larger patients, qualitative image quality was better at 100 kVp compared with 120 kVp, with an average quality rating of 3.6 versus 2.9, respectively. CONCLUSIONS: Radiation dose exposure can be easily reduced on CTPA by lowering kVp, which at the same time improves image quality. Studies using a lower kVp were of significantly higher diagnostic quality. This held true even in larger patients. PMID- 28082158 TI - Anticipated Impact of the 2016 Federal Election on Federal Health Care Legislation. PMID- 28082159 TI - CT Images Are Noninferior to Anatomic Specimens in Teaching Cardiac Anatomy-A Randomized Quantitative Study. AB - PURPOSE: The new generation's learning habits demand reforms in the methods by which we teach anatomy. Medical imaging techniques such as CT may offer a solution to help the understanding of complex anatomic structures. Our objective was to assess the noninferiority of using radiologic images in teaching anatomy as opposed to prosections or lecture slides. METHODS: Seventy-three first-year medical students were assigned to three experimental groups taught using different approaches: lecture slides (LG), prosections (PG), or radiology images (RG). All three groups received a 2-hour presentation on cardiac anatomy. Three days after the lectures, the participants were subjected to a gross anatomic "pin test" followed by a written theoretical examination to evaluate their knowledge of cardiac anatomy. RESULTS: We found a significant difference between the three groups regarding their gross anatomic examination scores (LG: 8.1 +/- 4.1, PG: 10.6 +/- 3.3, RG: 8.5 +/- 3.4, P = .03; Tukey's honest significant difference: P(LG-PG) = .04, P(PG-RG) = .08, P(LG-RG) = .94), whereas no significant difference was apparent regarding their written theoretical examination scores (LG: 16.6 +/- 4.2, PG: 18.6 +/- 3.5, RG: 18.3 +/- 3.0, P = .13). CONCLUSIONS: Concerning gross anatomic knowledge, groups taught using prosections or radiologic images showed no significant difference. Demonstrative materials do not seem to significantly affect the theoretical knowledge of the students. The use of medical imaging techniques could represent a valuable contribution toward teaching anatomy. PMID- 28082161 TI - Global Registry of Acute Coronary Events risk score predicts mortality and neurological outcome in out-of hospital cardiac arrest. AB - PURPOSE: The aim of this study was to assess the usefulness of the Global Registry of Acute Coronary Events (GRACE) risk score in predicting in-hospital mortality and neurological outcome of patients resuscitated after out-of-hospital cardiac arrest (OHCA). METHODS: We retrospectively analyzed the data of patients admitted to our hospital between October 2009 and October 2015 with OHCA and shockable initial cardiac rhythm who were resuscitated via conventional cardiopulmonary resuscitation. We calculated the GRACE risk score on admission and assessed its usefulness in predicting in-hospital mortality and neurological outcome. RESULTS: Among 91 patients, 42 (46%) had acute myocardial infarction (AMI), 19 (21%) died in-hospital, and 52 (57%) had favorable neurological outcome. Among all the study patients, GRACE risk score was lower in survivors than in non-survivors (median 211 [interquartile range 176-240] vs. 266 [219 301], p<0.001, respectively) and in favorable than in unfavorable neurological outcome group (202 [167-237] vs. 242 [219-275], p<0.001, respectively). Multivariate analysis showed significant association between GRACE risk score and favorable neurological outcome (odds ratio, 0.975; 95% confidence interval, 0.961 0.990). Areas under receiver-operating characteristic curves, that describe the accuracy of GRACE risk score in predicting in-hospital mortality and favorable neurological outcome, were both 0.79. CONCLUSION: GRACE risk score may predict the in-hospital mortality and neurological outcome associated with resuscitated patients with OHCA and shockable initial cardiac rhythm, regardless of the cause of arrest. PMID- 28082160 TI - Derivation of decision rules to predict clinically important outcomes in acute flank pain patients. AB - OBJECTIVE: Routine CT for patients with acute flank pain has not been shown to improve patient outcomes, and it may unnecessarily expose patients to radiation and increased costs. As preliminary steps toward the development of a guideline for selective CT, we sought to determine the prevalence of clinically important outcomes in patients with acute flank pain and derive preliminary decision rules. METHODS: We analyzed data from a randomized trial of CT vs. ultrasonography for patients with acute flank pain from 15 EDs between October 2011 and February 2013. Clinically important outcomes were defined as inpatient admission for ureteral stones and alternative diagnoses. Clinically important stones were defined as stones requiring urologic intervention. We sought to derive highly sensitive decision rules for both outcomes. RESULTS: Of 2759 participants, 236 (8.6%) had a clinically important outcome and 143 (5.2%) had a clinically important stone. A CDR including anemia (hemoglobin <13.2g/dl), WBC count >11000/MUl, age>42years, and the absence of CVAT had a sensitivity of 97.9% (95% CI 94.8-99.2%) and specificity of 18.7% (95% 17.2-20.2%) for clinically important outcome. A CDR including hydronephrosis, prior history of stone, and WBC count <8300/MUl had a sensitivity of 98.6% (95% CI 94.5-99.7%) and specificity of 26.0% (95% 24.2-27.7%) for clinically important stone. CONCLUSIONS: We determined the prevalence of clinically important outcomes in patients with acute flank pain, and derived preliminary high sensitivity CDRs that predict them. Validation of CDRs with similar test characteristics would require prospective enrollment of 2100 patients. PMID- 28082162 TI - Neck anteflexion method for facilitating videolaryngoscopic tracheal intubation while applying cricoid pressure. PMID- 28082163 TI - Identification of the cell binding domain in Nipah virus G glycoprotein using a phage display system. AB - Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus with unusual broad host tropism and is designated as a Category C pathogen by the U.S. National Institute of Allergy and Infectious Diseases. NiV infection is initiated after binding of the viral G glycoprotein to the host cell receptor. The aim of this study was to map the NiV G glycoprotein cell binding domain using a phage display system. The NiV G extracellular domain was truncated and displayed as attachment proteins on M13 phage g3p minor coat protein. The binding efficiency of recombinant phages displaying different regions of NiV G to mammalian cells was evaluated. Results showed that regions of NiV G consisting of amino acids 396 602 (recombinant phage G4) and 498-602 (recombinant phage G5) demonstrated the highest binding to both Vero (5.5*103 cfu/ml and 5.6*103 cfu/ml) and THP-1 cells (3.5*103 cfu/ml and 2.9*103 cfu/ml). However, the binding of both of these recombinant phages to THP-1 cells was significantly lower than to Vero cells, and this could be due to the lack of primary host cell receptor expression on THP-1 cells. Furthermore, the binding between these two recombinant phages was competitive suggesting that there was a common host cell attachment site. This study employed an approach that is suitable for use in a biosafety level 2 containment laboratory without the need to use live virus to show that NiV G amino acids 498-602 play an important role for attachment to host cells. PMID- 28082164 TI - A neutralization assay with a severe fever with thrombocytopenia syndrome virus strain that makes plaques in inoculated cells. AB - Severe fever with thrombocytopenia syndrome (SFTS) is a recently-discovered, potentially fatal infectious disease caused by SFTS virus (SFTSV). Due to the inability of SFTSV to make clear cytopathic effects (CPE) in cell culture, titration and neutralization assays of the virus require immunostaining of inoculated cells; consequently, the assays are time-consuming and expensive. In this report, we demonstrate the use of a highly-passaged SFTSV strain, p50-2, in a neutralization assay, which made clear plaques in inoculated Vero cells under neutral red staining. Furthermore, we performed molecular analyses to determine the characteristics of the strain. The results suggested that a single amino acid mutation within the viral glycoprotein conferred the ability to make clear plaques to SFTSV. PMID- 28082165 TI - An efficient and high fidelity method for amplification, cloning and sequencing of complete tospovirus genomic RNA segments. AB - Tospoviruses (genus Tospovirus, family Bunyaviridae) are responsible for major losses in an extensive range of crops worldwide. New species of these single stranded, ambisense RNA viruses regularly emerge and have been shown to maintain heterogeneous populations with individual isolates having quite variable biological and virulence characteristics. Most tospovirus phylogenetic studies have focused on analysis of a single gene, most often the nucleocapsid protein gene. Complete genomic RNA segment amplification as a single fragment would facilitate more detailed analyses of genome-wide sequence variability, but obtaining such sequences for a large number of tospovirus isolates using traditional methods of amplification and cloning of small overlapping fragments is tedious, time consuming and expensive. In this study, protocols were optimized to amplify, clone and sequence full-length M- and S-RNA genome segments of Tomato spotted wilt virus and Impatiens necrotic spot virus. The strategy presented here is straightforward, scalable and offers several advantages over the previously commonplace and overlapping amplicon-based approach. Use of whole genome segments, instead of individual gene sequences or defined portions of genome segments, will facilitate a better understanding of the underlying molecular diversity of tospoviruses in mixed infections. PMID- 28082166 TI - So Many Possibilities: Lung Nodules in a Transplant Recipient. PMID- 28082167 TI - Continued growth, a new metric, same high quality! PMID- 28082168 TI - Idiopathic REM sleep behavior disorder and neurodegenerative risk: To tell or not to tell to the patient? How to minimize the risk? AB - Most people with idiopathic REM sleep behavior disorder (iRBD) have an underlying synucleinopathy, mainly Parkinson's disease (PD) or dementia with Lewy bodies, with median conversion time of 4-9 y from iRBD diagnosis and of 11-16 y from symptom onset. Subtle signs and imaging tests indicate concomitant neurodegeneration in widespread brain areas. Risk factor studies suggest that iRBD patients may have prior head injury, occupational farming, pesticide exposure, low education level and possibly more frequent family history of dream enactment behavior (but not of PD), plus unexpected risk factors (smoking, ischemic heart disease and inhaled corticosteroid use). Unlike PD, caffeine and smoking appear not to have a protective role. Prior depression and antidepressant use may be early neurodegenerative signs rather than exclusively causative factors. Age, hyposmia, impaired color vision, abnormal dopaminergic imaging, mild cognitive impairment and possibly sleepiness, may identify patients at greater risk of more rapid conversion. The consensus is to generally disclose the neurodegenerative risk to patients (with the caveat that phenoconversion and its temporal course remain uncertain in individuals without "soft neurodegenerative signs" and those under 50 y of age), to suggest a healthy lifestyle and to take part in prospective cohort studies in anticipation of eventual neuroprotective trials. PMID- 28082170 TI - Synergistic antitumor activity of a self-assembling camptothecin and capecitabine hybrid prodrug for improved efficacy. AB - The direct use of anticancer drugs to create their own nanostructures is an emerging concept in the field of drug delivery to obtain nanomedicines of high drug loading and high reproducibility, and the combination use of two or more drugs has been a proven clinical strategy to enhance therapeutic outcomes. We report here the synthesis, assembly and cytotoxicity evaluation of self assembling hybrid prodrugs containing both camptothecin (CPT) and a capecitabine (Cap) analogue. CPT and Cap molecules were conjugated onto a short beta-sheet forming peptide (Sup35) to yield three different self-assembling prodrugs (dCPT Sup35, CPT-Cap-Sup35 and dCap-Sup35). We found that the chemical structure of conjugated drugs could strongly influence their assembled morphology as well as their structural stability in aqueous solution. With a decrease in number of CPT units, the resulting nanostructures exhibited a morphological transformation from nanofibers (dCPT-Sup35) to filaments (CPT-Cap-Sup35) then to spherical particles (dCap-Sup35). Notably, the hybrid CPT-Cap prodrug showed a synergistic effect and significantly enhanced potency against three esophageal adenocarcinoma cell lines compared with the two homo-prodrugs (dCPT-Sup35 and dCap-Sup35) as well as free parent drugs (CPT, 5-Fu and CPT/5-FU mixture (1:1)). We believe this work represents a conceptual advancement in integrating two structurally distinct drugs of different action mechanisms into a single self-assembling hybrid prodrug to construct self-deliverable nanomedicines for more effective combination chemotherapy. PMID- 28082169 TI - Nonmuscle myosin II inhibition disrupts methamphetamine-associated memory in females and adolescents. AB - Memories associated with drug use can trigger strong motivation for the drug, which increases relapse vulnerability in substance use disorder (SUD). Currently there are no treatments for relapse to abuse of psychostimulants, such as methamphetamine (METH). We previously reported that storage of memories associated with METH, but not those for fear or food reward, and the concomitant spine density increase are disrupted in a retrieval-independent manner by depolymerizing actin in the basolateral amygdala complex (BLC) of adult male rats and mice. Similar results are achieved in males through intra-BLC or systemic inhibition of nonmuscle myosin II (NMII), a molecular motor that directly drives actin polymerization. Given the substantial differences in physiology between genders, we sought to determine if this immediate and selective disruption of METH-associated memory extends to adult females. A single intra-BLC infusion of the NMII inhibitor Blebbistatin (Blebb) produced a long-lasting disruption of context-induced drug seeking for at least 30days in female rats that mirrored our prior results in males. Furthermore, a single systemic injection of Blebb prior to testing disrupted METH-associated memory and the concomitant increase in BLC spine density in females. Importantly, as in males, the same manipulation had no effect on an auditory fear memory or associated BLC spine density. In addition, we established that the NMII-based disruption of METH-associated memory extends to both male and female adolescents. These findings provide further support that small molecular inhibitors of NMII have strong therapeutic potential for the prevention of relapse to METH abuse triggered by associative memories. PMID- 28082171 TI - Abdominal muscle activity during breathing in different postures in COPD "Stage 0" and healthy subjects. AB - This study aims to evaluate the effect of different postures on the abdominal muscle activity during breathing in subjects "at risk" for the development of chronic obstructive pulmonary disease (COPD) and healthy. Twenty-nine volunteers, divided in "At Risk" for COPD (n=16; 47.38+/-5.08years) and Healthy (n=13; 47.54+/-6.65years) groups, breathed at the same rhythm in supine, standing, tripod and 4-point-kneeling positions. Surface electromyography was performed to assess the activation intensity of rectus abdominis, external oblique and transversus abdominis/internal oblique (TrA/IO) muscles, during inspiration and expiration. From supine to standing, an increased activation of all abdominal muscles was observed in "At Risk" for COPD group; however, in Healthy group, TrA/IO muscle showed an increased activation. In both groups, the TrA/IO muscle activation in tripod and 4-point kneeling positions was higher than in supine and lower than in standing. Subjects "at risk" for the development of COPD seemed to have a specific recruitment of the superficial layer of ventrolateral abdominal wall for the synchronization of postural function and mechanics of breathing. PMID- 28082172 TI - Barriers and enablers of the prevention of mother-to-child transmission of HIV/AIDS program in China: a systematic review and policy implications. AB - OBJECTIVE: To identify the barriers to and enablers of the prevention of mother to-child transmission (PMTCT) of HIV program in China. METHODS: A systematic review of the existing literature regarding barriers to and enablers of the implementation of the PMTCT program in China was performed. The checklist from the SURE guidelines (Supporting the Use of Research Evidence) was used to synthesize the barriers and enablers (supporting strategies) and to analyze their relationships. The HIV testing rate, vertical transmission rate, and antiretroviral treatment (ART) acceptance rate among HIV-infected women and their infants was also extracted from the included studies to assess the effectiveness of the enablers. RESULTS: Initially 794 publications were identified, and ultimately 14 articles were included. Eighteen types of barrier and nine types of supportive strategy were identified, mainly at the level of social and political issues, healthcare recipients, healthcare providers, and the healthcare system. Based on government-oriented multi-sector cooperation, enablers in China have included community-hospital-family promotion, comprehensive financial support for service recipients, free HIV testing at marriage registration, the opt-out model, and the one-to-one service model. CONCLUSIONS: Experience in China suggests that the government's role in coordination and the acceptability and accessibility of the service should be the primary concerns in regard to the PMTCT project. PMID- 28082173 TI - Balancing thromboembolic and bleeding risk with non-vitamin K antagonist oral anticoagulants (NOACs): A systematic review and meta-analysis on gender differences. AB - Sex and gender differences have been reported in atrial fibrillation (AF), especially in relation to differences in thromboembolic and bleeding risks. More recently, pharmacological treatments have changed following the introduction of non-vitamin K antagonist oral anticoagulants (NOACs) progressively replacing vitamin K antagonists (VKAs). The aims of this systematic review are to summarize the available evidence on NOACs and the relationship to major adverse outcomes according to sex. Moreover, we performed a meta-analysis of data from the phase III clinical trials investigating the sex effect on stroke/systemic embolic events (SEE) and major bleeding. Our literature review found small differences in NOACs efficacy and safety between male and female patients, even if so far available literature is limited to post-hoc ancillary analyses from randomized trials and one cohort study. Meta-analysis from NOAC trials found a differential effect of NOACs, with male patients being more protected from stroke/SEE and female patients more protected from major bleeding events. Further data are needed to fully elucidate sex differences in AF patients treated with NOACs. PMID- 28082174 TI - Isolation and identification methods of Rothia species in oral cavities. AB - Rothia dentocariosa and Rothia mucilaginosa which are Gram-positive bacteria are part of the normal flora in the human oral cavity and pharynx. Furthermore, Rothia aeria, which was first isolated from air samples in the Russian space station Mir, is predicted to be an oral inhabitant. Immunocompromised patients are often infected by these organisms, leading to various systemic diseases. The involvement of these organisms in oral infections has attracted little attention, and their distribution in the oral cavity has not been fully clarified because of difficulties in accurately identifying these organisms. A suitable selective medium for oral Rothia species, including R. aeria, is necessary to assess the veritable prevalence of these organisms in the oral cavity. To examine the bacterial population in the oral cavity, a novel selective medium (ORSM) was developed for isolating oral Rothia species in this study. ORSM consists of tryptone, sodium gluconate, Lab-Lemco powder, sodium fluoride, neutral acriflavin, lincomycin, colistin, and agar. The average growth recovery of oral Rothia species on ORSM was 96.7% compared with that on BHI-Y agar. Growth of other representative oral bacteria, i.e. genera Streptococcus, Actinomyces, Neisseria, and Corynebacterium, was remarkably inhibited on the selective medium. PCR primers were designed based on partial sequences of the 16S rDNA genes of oral Rothia species. These primers reacted to each organism and did not react to other non-oral Rothia species or representative oral bacteria. These results indicated that these primers are useful for identifying oral Rothia species. A simple multiplex PCR procedure using these primers was a reliable method of identifying oral Rothia species. The proportion of oral Rothia species in saliva samples collected from 20 subjects was examined by culture method using ORSM. Rothia dentocariosa, Rothia mucilaginosa, and R. aeria accounted for 1.3%, 5.9%, and 0.8% of the total cultivable bacteria number on BHI-Y agar in the oral cavities of all subjects, respectively. It was indicated that among oral Rothia species, R. mucilaginosa is most predominant in the oral cavity of humans. A novel selective medium, ORSM, was useful for isolating each oral Rothia species. PMID- 28082175 TI - The application of phenotypic microarray analysis to anti-fungal drug development. AB - Candida albicans metabolic activity in the presence and absence of acetylcholine was measured using phenotypic microarray analysis. Acetylcholine inhibited C. albicans biofilm formation by slowing metabolism independent of biofilm forming capabilities. Phenotypic microarray analysis can therefore be used for screening compound libraries for novel anti-fungal drugs and measuring antifungal resistance. PMID- 28082176 TI - Combined Transcranial Direct Current Stimulation and Vision Restoration Training in Subacute Stroke Rehabilitation: A Pilot Study. AB - BACKGROUND: Visual field defects after posterior cerebral artery stroke can be improved by vision restoration training (VRT), but when combined with transcranial direct current stimulation (tDCS), which alters brain excitability, vision recovery can be potentiated in the chronic stage. To date, the combination of VRT and tDCS has not been evaluated in postacute stroke rehabilitation. OBJECTIVES: To determine whether combined tDCS and VRT can be effectively implemented in the early recovery phase following stroke, and to explore the feasibility, safety and efficacy of an early intervention. DESIGN: Open-label pilot study including a case series of 7 tDCS/VRT versus a convenience sample of 7 control patients (ClinicalTrials.gov ID: NCT02935413). SETTING: Rehabilitation center. SUBJECTS: Patients with homonymous visual field defects following a posterior cerebral artery stroke. METHODS: Seven homonymous hemianopia patients were prospectively treated with 10 sessions of combined tDCS (2.mA, 10 daily sessions of 20 minutes) and VRT at 66 (+/-50) days on average poststroke. Visual field recovery was compared with the retrospective data of 7 controls, whose defect sizes and age of lesions were matched to those of the experimental subjects and who had received standard rehabilitation with compensatory eye movement and exploration training. RESULTS: All 7 patients in the treatment group completed the treatment protocol. The safety and acceptance were excellent, and patients reported occasional skin itching beneath the electrodes as the only minor side effect. Irrespective of their treatment, both groups (treatment and control) showed improved visual fields as documented by an increased mean sensitivity threshold in decibels in standard static perimetry. Recovery was significantly greater (P < .05) in the tDCS/VRT patients (36.73% +/- 37.0%) than in the controls (10.74% +/- 8.86%). CONCLUSION: In this open-label pilot study, tDCS/VRT in subacute stroke was demonstrated to be safe, with excellent applicability and acceptance of the treatment. Preliminary effectiveness calculations show that tDCS/VRT may be superior to standard vision training procedures. A confirmatory, larger-sample, controlled, randomized, and double blind trial is now underway to compare real-tDCS- versus sham-tDCS-supported visual field training in the early vision rehabilitation phase. LEVEL OF EVIDENCE: IV. PMID- 28082177 TI - Long-Term Dosing of Intrathecal Baclofen in the Treatment of Spasticity After Acquired Brain Injury. AB - BACKGROUND: Intrathecal baclofen (ITB) often is used to treat severe spasticity of cerebral origin. Although literature exists regarding the efficacy of ITB, there has been minimal investigation related to dosing in the adult-acquired brain injury population, particularly at long-term duration. OBJECTIVE: To investigate long-term dosing of ITB in adult patients with spasticity of cerebral origin due traumatic brain injury (TBI), stroke, and hypoxic-ischemic encephalopathy (HIE). DESIGN: Retrospective cohort study. SETTING: An academic outpatient rehabilitation clinic. PATIENTS: Forty-two adult patients with spasticity secondary to TBI, stroke, or HIE treated with ITB for greater than 3 years. METHODS: Medical records and device manufacturer records of included patients were reviewed to obtain demographic data, dosing information, dates of pump and catheter placements, and revisions. MAIN OUTCOME MEASURE: Average daily ITB doses and mean change in ITB dose over 1, 2, and 3 years. Goal of ITB treatment (active function versus comfort/care/positioning) also was compared. RESULTS: Of 42 total patients, spasticity was attributed to either TBI (n = 19), stroke (n = 11), or HIE (n = 12). The mean (standard deviation) age was 35.21 (10.17), 56.7 (13.1), and 35.1 (12.4) years for the TBI, stroke, and HIE groups, respectively (P < .001). There was a significant difference in the goal of therapy with "improving functional independence," accounting for 27.8%, 72.8%, and 0% in the TBI, stroke, and HIE groups, respectively (P = .002). The mean duration of ITB therapy was 8.5 (5.0), 7.8 (3.4), and 9.1 (4.6) years in the TBI, stroke, and HIE groups, respectively (P = .79). The mean daily ITB dose was 596.9 (322.8) MUg/d, 513.2 (405.7) MUg/d, and 705.2 (271.7) MUg/d for the TBI, stroke, and HIE groups, respectively (P = .39). In the subset of the cohort with ITB therapy for more than 5 years, the mean percent change in daily ITB dose between time of chart review and 1, 2, and 3 years previously was 7.3% (13.6), 12.7% (16), and 24.7% (50.3), respectively. A complex dosing pattern was used more frequently in those with stroke (36.4%) compared with the TBI and HIE (9.7%) groups (P = .04). CONCLUSION: Despite the long-term use of ITB therapy in this cohort, the mean daily dose of ITB continued to require adjustments. There was no significant difference in the mean daily dose between patients with a diagnosis of TBI, stroke, or HIE. A complex dosing pattern was used more frequently in patients with stroke. LEVEL OF EVIDENCE: III. PMID- 28082178 TI - The Course of Concussion Recovery in Children 6-12 Years of Age: Experience From an Interdisciplinary Rehabilitation Clinic. AB - BACKGROUND: Current concussion evidence is derived largely from teenagers and adults. Concussion in younger children occurs within the context of neuromaturation, with differing age-based pathophysiological responses to injury. Therefore, our current understanding of concussion in older children and adults is unlikely to directly apply to younger children. OBJECTIVE: To describe patient variables, clinical course, and factors associated with time to discharge from concussion care in children 6-12 years of age with concussion treated in an interdisciplinary rehabilitation-based concussion clinic. DESIGN: Retrospective chart review. SETTING: Interdisciplinary concussion clinic at an academically affiliated rehabilitation center. PATIENTS: Children aged 6-12 years (n = 105; mean 10.8 years of age, 70% male) seen within 60 days of concussive injury. MAIN OUTCOME MEASUREMENTS: Descriptive statistics explored demographic, injury, and clinical features. The primary outcome measure, time to discharge from concussion care, was estimated with survival-analysis methods based on the date of discharge from the clinic. Multivariate models were used to examine factors associated with longer time to discharge. RESULTS: Median time to discharge was 34 days postinjury (range 5-192 days); 75% of children were discharged within 60 days of injury. A minority reported persisting symptoms at discharge. Younger age and increased symptom burden at initial evaluation predicted longer time to discharge. CONCLUSIONS: Although children 6-12 years old treated in a specialty concussion clinic show variability in time to discharge from concussion care, most were discharged within 2 months after injury. Risk factors for prolonged recovery, such as younger age and greater symptom burden at initial visit, can be used when counseling families and planning interventions. There may be varying contributions, including psychosocial stressors, to ongoing symptoms in children who experience persisting symptoms after other concussion-related concerns have resolved. Future work focused on the subset of children who report persisting symptoms will be useful for developing an evidence base related to their care. LEVEL OF EVIDENCE: II. PMID- 28082179 TI - Strengthening of Quadriceps by Neuromuscular Magnetic Stimulation in Healthy Subjects. AB - BACKGROUND: Quadriceps muscle strengthening is one of the rehabilitation strategies for improving walking in some people with gait impairments, and neuromuscular electrical stimulation (NMES) has been used for that reason. The strengthening effect of neuromuscular magnetic stimulation (NMMS) on the quadriceps has been demonstrated in various conditions, but not specifically for gait training. The purpose of this study was to determine whether the effect of NMMS is clinically applicable. OBJECTIVE: To determine the effect of NMMS on quadriceps muscle strength, cross-sectional area (CSA) and thickness in healthy subjects. DESIGN: Single-blind, prospective, case-control study. SETTING: Tertiary academic hospital setting. PARTICIPANTS: A total of 40 healthy volunteers were randomly assigned to an NMMS (n = 20) or control group (n = 20). INTERVENTIONS: Fifteen minutes of quadriceps NMMS of at maximum tolerable intensity, 3 times per week for 5 weeks. MAIN OUTCOME MEASUREMENTS: At baseline and after the intervention, the CSA and thicknesses of the rectus femoris and vastus intermedius were measured by ultrasound. Isometric and isokinetic maximal and average peak torques of the dominant side knee extensors were also measured at pre- and postintervention. RESULTS: There were no between-group differences in strength, CSA, or muscle thickness at baseline. Isometric maximum and average peak torque of NMMS group were increased significantly after 5 weeks of intervention (P < .001). The isokinetic maximum and average peak torque of NMMS group were increased significantly at both angle velocities of 60 degrees /sec and 120 degrees /sec after 5 weeks of intervention (P < .001). However, neither group showed a significant difference in cross-sectional area or thickness after training. CONCLUSION: NMMS can be a useful strengthening method for large skeletal muscles such as the quadriceps. LEVEL OF EVIDENCE: II. PMID- 28082180 TI - Patient-Centered Goal Setting in a Hospital-Based Outpatient Stroke Rehabilitation Center. AB - BACKGROUND: Goal-setting can have a positive impact on stroke recovery during rehabilitation. Patient participation in goal formulation can ensure that personally relevant goals are set, and can result in greater satisfaction with the rehabilitation experience, along with improved recovery of stroke deficits. This, however, not yet been studied in a stroke outpatient rehabilitation setting. OBJECTIVE: To assess patient satisfaction of meeting self-selected goals during outpatient rehabilitation following a stroke. DESIGN: Retrospective chart review. SETTING: Stroke patients enrolled in a multidisciplinary outpatient rehabilitation program, who set at least 1 goal during rehabilitation. PARTICIPANTS: Patients recovering from a stroke received therapy through the outpatient rehabilitation program between January 2010 and December 2013. METHODS: Upon admission and discharge from rehabilitation, patients rated their satisfaction with their ability to perform goals that they wanted to achieve. Researchers independently sorted and labeled recurrent themes of goals. Goals were further sorted into International Classification of Functioning, Disability and Health (ICF) categories. To compare the perception of patients' goal satisfaction, repeated-measures analysis of variance was conducted across the 3 ICF goal categorizations. MAIN OUTCOME MEASURE: Goal satisfaction scores. RESULTS: A total of 286 patients were included in the analysis. Patient goals concentrated on themes of improving hand function, mobility, and cognition. Goals were also sorted into ICF categories in which impairment-based and activity limitation-based goals were predominant. Compared to activity-based and participation-based goals, patients with impairment-based goals perceived greater satisfaction with meeting their goals at admission and discharge (P < .001). Patient satisfaction in meeting their first-, second-, and third-listed goals each significantly improved by discharge from the rehabilitation program (P < .001). CONCLUSION: Within an outpatient stroke rehabilitation setting, patients set heterogeneous goals that were predominantly impairment based. Satisfaction in achieving goals significantly improved after receiving therapy. The type of goals that patients set were related to their goal satisfaction scores, with impairment based goals being rated significantly higher than activity-based and participation-based goals. LEVEL OF EVIDENCE: III. PMID- 28082181 TI - Return to the Primary Acute Care Service Among Patients With Multiple Myeloma on an Acute Inpatient Rehabilitation Unit. AB - BACKGROUND: Pancytopenia, immunosuppression, and other factors may place patients with multiple myeloma at risk for medical complications. These patients often require inpatient rehabilitation. No previous studies have looked at risk factors for return to the primary acute care service of this patient population. OBJECTIVE: To determine the percentage of and factors associated with return to the primary acute care service of multiple myeloma rehabilitation inpatients. DESIGN: Retrospective review. SETTING: Acute inpatient rehabilitation unit within a National Cancer Institute Comprehensive Cancer Center. PARTICIPANTS: All patients with multiple myeloma admitted to the inpatient rehabilitation unit between March 1, 2004, and February 28, 2015. MAIN OUTCOME MEASURES: Return to the primary acute care service was analyzed with demographic information, multiple myeloma characteristics, medications, laboratory values, and hospital admission characteristics. RESULTS: One hundred forty-three inpatient rehabilitation admissions were found during the study period. After we removed multiple admissions of the same patients and planned transfers to the primary acute care service, 122 admissions were analyzed. Thirty-two (26%) patients transferred back to the primary acute care service for unplanned reasons. Multivariate analysis revealed male gender and thrombocytopenia as significantly associated with return to the primary acute care service. The median survival of patients who transferred back to the inpatient primary acute care service was 180 days versus 550 days for those who did not (P < .001). CONCLUSION: Because of their medical fragility, clinicians caring for rehabilitation inpatients with multiple myeloma should maintain close contact with the primary oncology service. Factors associated with an increased risk of transfer back to the primary acute care service include male gender and thrombocytopenia. LEVEL OF EVIDENCE: IV. PMID- 28082182 TI - Cytosine DNA methylation at promoter of non LTR retrotransposon and heat shock protein gene (HSP70) of Entamoeba histolytica and lack of correlation with transcription status. AB - Non LTR retrotransposons (EhLINEs and EhSINEs) occupy 11% of the Entamoeba histolytica genome. Since promoter DNA methylation at cytosines has been correlated with transcriptional silencing of transposable elements in model organisms we checked whether this was the case in EhLINE1. We located promoter activity in a 841bp fragment at 5'-end of this element by luciferase reporter assay. From RNAseq and RT-PCR analyses we selected a transcriptionally active and silent copy to study cytosine DNA methylation of the promoter region by bisulfite sequencing. None of the cytosines were methylated in either copy. Further, we looked at methylation status of a few selected cytosines in all 5'-intact EhLINE1 copies by single nucleotide incorporation opposite cytosine in bisulfite-treated DNA, where dGTP would be incorporated if the cytosine was methylated. Again we did not find evidence of cytosine methylation, indicating that expression status of this element was not correlated with promoter DNA methylation. To test for any role of cytosine methylation in transcriptional regulation of the E. histolytica Hsp70 gene in which the promoter is fully methylated under normal growth conditions, we checked methylation status and found that the promoter remained fully methylated during heat-shock as well, although transcription was greatly enhanced by heat-shock, showing that cytosine methylation is not a repressive mark for EhHsp70. Our data present direct evidence that promoter methylation, a common mode of transposon silencing, is unlikely to be involved in transcriptional regulation of EhLINE1, and reinforce the conclusion that promoter DNA methylation may not be a major contributor to transcriptional regulation in E. histolytica. PMID- 28082184 TI - Identification and function analysis of an anti-lipopolysaccharide factor from the ridgetail prawn Exopalaemon carinicauda. AB - Anti-lipopolysaccharide factor is a kind of antimicrobial peptide (AMP) with broad-spectrum activities against bacteria, virus, and fungi in crustacean. Different isoforms of ALFs showed different activities to virus or bacteria. Therefore, discovery of more ALFs will provide new insights into drug development and disease control. Here we reported an ALF gene, EcALF1, isolated from the ridgetail prawn Exopalaemon carinicauda. Its transcripts was mainly detected in hemocytes. Silencing of EcALF1 caused a lesion of hepatopancreas and finally led to death of the prawn. In vivo bacteria detection to the hepatopancreas showed that the colonies of thiosulphate citrate bile salts (TCBS) cultured bacteria in EcALF1-silenced prawn increased dramatically. We identified the dominant bacteria cultured in TCBS and found that Vibrio alginolyticus and Vibrio parahaemolyticus were dominant bacteria which were pathogenic species to prawn. We further synthesized the functional domain, LPS binding domain (LBD) of EcALF1, and its antibacterial and antiviral activities were detected. The synthetic EcLBD1 peptide showed very strong antibacterial activity against Micrococcus luteus and V. alginolyticus. Pre-incubation of WSSV with EcLBD1 peptide reduced the pathogenicity of WSSV infection to the prawn. The present data showed the important roles of an ALF gene in modulating the in vivo bacterial proliferation in E. carinicauda and provided new insight in disease control in aquaculture. PMID- 28082183 TI - Effects of P2X7 receptor antagonists on hypoxia-induced neonatal seizures in mice. AB - Neonatal seizures are a common consequence of hypoxic/ischemic encephalopathy (HIE). Phenobarbital remains the frontline treatment for neonatal seizures but is often ineffective. The P2X7 receptor (P2X7R) is a cell surface-expressed ionotropic receptor activated by high amounts of ATP which may be released during seizures or as a consequence of tissue injury. Here, we explored the role of the P2X7R in a mouse model of neonatal seizures induced by hypoxia. Exposure of postnatal day 7 (P7) mouse pups to global hypoxia (5% O2 for 15 min) produced electrographically-defined seizures with behavioural correlates that persisted after restitution of normoxia. Expression of the P2X7R showed age-dependent increases in the hippocampus and neocortex of developing mice and was present in human neonatal brain. P2X7R transcript and protein levels were increased 24 h after neonatal hypoxia-induced seizures in mouse pups. EEG recordings in pups determined that injection of the P2X7R antagonist A-438079 (25 mg/kg-1, intraperitoneal) reduced electrographic seizure number, EEG power and spiking during hypoxia. A-438079 did not reduce post-hypoxia seizures. Caspase-1 processing and molecular markers of inflammation and microglia were reduced in A438079-treated mice. Electrographic seizure-suppressive effects were also observed with a second P2X7R antagonist, JNJ-47965567, in the same model. The present study shows hypoxia-induced seizures alter expression of purinergic and neuroinflammatory signalling components and suggest potential applications but also limitations of the P2X7R as a target for the treatment of HIE and other causes of neonatal seizures. PMID- 28082185 TI - UVA1-Induced Skin Darkening Is Associated with Molecular Changes Even in Highly Pigmented Skin Individuals. PMID- 28082186 TI - The Abnormal Architecture of Healed Diabetic Ulcers Is the Result of FAK Degradation by Calpain 1. AB - Delayed wound healing is a major complication of diabetes occurring in approximately 15% of chronic diabetic patients. It not only significantly affects patients' quality of life but also poses a major economic burden to the health care system. Most efforts have been focused on accelerating wound reepithelialization and closure. However, even after healing the quality of healed tissue in diabetics is abnormal and recurrence is common (50-75%). Thus, understanding how diabetes alters the ultimate mechanical properties of healed wounds will be important to develop more effective approaches for this condition. Focal adhesion kinase is an intracellular protein kinase that plays critical roles in cell migration, focal adhesion formation, and is an important component of cellular mechanotransduction. We have found that focal adhesion kinase expression is downregulated under a high glucose condition both in vitro and in vivo. This is secondary to increased activity of calpain 1, the primary enzyme responsible for focal adhesion kinase degradation, which becomes induced in hyperglycemia. We demonstrate that selective inhibition of calpain 1 activation improves wound healing and normalizes the mechanical properties of diabetic skin, suggesting a new therapeutic approach to prevent diabetic wound recurrence. PMID- 28082187 TI - The MTHFR C677T mutation is not a risk factor recognized for HBV-related HCC in a population with a high prevalence of this genetic marker. AB - BACKGROUND: Polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene can affect disease progression in HBV infection. However, the results from different reports are inconsistent. The aim of this study was to investigate the association between the MTHFR C677T polymorphism and the outcome of HBV infection in a Tianjin Han population. METHODS: TaqMan SNP genotyping was employed to determine the alleles and genotypes of MTHFR C677T in 2511 subjects from various stages of HBV infection and 549 healthy controls. RESULTS: Of the 3060 subjects, the genotypic frequencies were CT 48.9%, TT 29.3% and CC 21.8%; the allelic frequencies were T 53.8% and C 46.2%. There was no significant difference in genotypic or allelic distribution among the different disease groups. When either healthy subjects or self-limited subjects were used as controls, the TT genotype and the T allele conferred protective effects against hepatocellular carcinoma (HCC) (HCC vs healthy subjects: OR=0.588, 95% CI=0.413-0.836, P=0.003; OR=0.768, 95% CI=0.645-0.915, P=0.003, respectively. HCC vs self-limited subjects: OR=0.598, 95% CI=0.404-0.886, P=0.010; OR=0.772, 95% CI=0.635-0.940, P=0.010, respectively). After sub-stratification by gender, the prevalence of the TT genotype or T allele was the lowest in the male HCC group (TT 23.5%, T 49.8%). The protective effects of the TT genotype and the T allele were observed in male HCC and cirrhotic subjects (HCC vs self-limited subjects: OR=0.470, 95% CI=0.288 0.766, P=0.002; OR=0.681, 95% CI=0.535-0.866, P=0.002, respectively. Liver cirrhosis vs self-limited subjects: OR=0.624, 95% CI=0.392-0.992, P=0.046; OR=0.791, 95% CI=0.627-0.998, P=0.048, respectively), but not in female. When the subjects were stratified according to the clinical features, no statistically significant difference in the genotypic distribution was observed (P>0.05). CONCLUSIONS: The TT genotype and T allele of MTHFR C677T may confer a protective effect on disease progression to HCC in HBV-infected individuals, especially among male patients, in a population with a high prevalence of this genetic marker. PMID- 28082189 TI - Immediate rejection of manuscripts without peer review at the CMI. PMID- 28082188 TI - Molecular epidemiology of HIV-1 in Iceland: Early introductions, transmission dynamics and recent outbreaks among injection drug users. AB - The molecular epidemiology of HIV-1 in Iceland has not been described so far. Detailed analyses of the dynamics of HIV-1 can give insights for prevention of virus spread. The objective of the current study was to characterize the genetic diversity and transmission dynamics of HIV-1 in Iceland. Partial HIV-1 pol (1020bp) sequences were generated from 230 Icelandic samples, representing 77% of all HIV-1 infected individuals reported in the country 1985-2012. Maximum likelihood phylogenies were reconstructed for subtype/CRF assignment and determination of transmission clusters. Timing and demographic growth patterns were determined in BEAST. HIV-1 infection in Iceland was dominated by subtype B (63%, n=145) followed by subtype C (10%, n=23), CRF01_AE (10%, n=22), sub-subtype A1 (7%, n=15) and CRF02_AG (7%, n=15). Trend analysis showed an increase in non-B subtypes/CRFs in Iceland over the study period (p=0.003). The highest proportion of phylogenetic clustering was found among injection drug users (IDUs; 89%), followed by heterosexuals (70%) and men who have sex with men (35%). The time to the most recent common ancestor of the oldest subtype B cluster dated back to 1978 (median estimate, 95% highest posterior density interval: 1974-1981) suggesting an early introduction of HIV-1 into Iceland. A previously reported increase in HIV-1 incidence among IDUs 2009-2011 was revealed to be due to two separate outbreaks. Our study showed that a variety of HIV-1 subtypes and CRFs were prevalent in Iceland 1985-2012, with subtype B being the dominant form both in terms of prevalence and domestic spread. The rapid increase of HIV-1 infections among IDUs following a major economic crisis in Iceland raises questions about casual associations between economic factors, drug use and public health. PMID- 28082190 TI - A bioinformatics tool for ensuring the backwards compatibility of Legionella pneumophila typing in the genomic era. AB - OBJECTIVES: Whole genome sequencing (WGS) has revolutionized the subtyping of Legionella pneumophila but calling the traditional sequence-based type from genomic data is hampered by multiple copies of the mompS locus. We propose a novel bioinformatics solution for rectifying that limitation, ensuring the feasibility of WGS for cluster investigation. METHODS: We designed a novel approach based on the alignment of raw reads with a reference sequence. With WGS, reads originating from either of the two mompS copies cannot be differentiated. Therefore, when non-identical copies were present, we applied a read-filtering strategy based on read alignment to a reference sequence via unique 'anchors'. If minimal read coverage was achieved after filtration (>=3X), a consensus sequence was built based on mapped reads followed by calling the sequence-based typing allele. The entire procedure was implemented using a Perl script. RESULTS: The method was validated using a diverse sample of 265 L. pneumophila genomes, consisting of 59 different sequence types (STs) and 23 mompS variants; 57 of the 265 (22%) had non-identical mompS copies. In 237 of the 265 samples (89.4%), mompS calling was successful and no erroneous calling occurred. A 98.1% success was recorded among 109 samples meeting quality requirements. The method was superior to alternative approaches. CONCLUSIONS: As WGS becomes more accessible, technical difficulties in routine clinical and surveillance work will arise. The case of mompS in L. pneumophila serves as an example for such limitations that necessitate the development of novel computational solutions that meet end-user demands. PMID- 28082191 TI - Norwegian patients and retail chicken meat share cephalosporin-resistant Escherichia coli and IncK/blaCMY-2 resistance plasmids. AB - OBJECTIVES: In 2012 and 2014 the Norwegian monitoring programme for antimicrobial resistance in the veterinary and food production sectors (NORM-VET) showed that 124 of a total of 406 samples (31%) of Norwegian retail chicken meat were contaminated with extended-spectrum cephalosporin-resistant Escherichia coli. The aim of this study was to compare selected cephalosporin-resistant E. coli from humans and poultry to determine their genetic relatedness based on whole genome sequencing (WGS). METHODS: Escherichia coli representing three prevalent cephalosporin-resistant multi-locus sequence types (STs) isolated from poultry (n=17) were selected from the NORM-VET strain collections. All strains carried an IncK plasmid with a blaCMY-2 gene. Clinical E. coli isolates (n=284) with AmpC mediated resistance were collected at Norwegian microbiology laboratories from 2010 to 2014. PCR screening showed that 29 of the clinical isolates harboured both IncK and blaCMY-2. All IncK/blaCMY-2-positive isolates were analysed with WGS-based bioinformatics tools. RESULTS: Analysis of single nucleotide polymorphisms (SNP) in 2.5 Mbp of shared genome sequences showed close relationship, with fewer than 15 SNP differences between five clinical isolates from urinary tract infections (UTIs) and the ST38 isolates from poultry. Furthermore, all of the 29 clinical isolates harboured IncK/blaCMY-2 plasmid variants highly similar to the IncK/blaCMY-2 plasmid present in the poultry isolates. CONCLUSIONS: Our results provide support for the hypothesis that clonal transfer of cephalosporin-resistant E. coli from chicken meat to humans may occur, and may cause difficult-to-treat infections. Furthermore, these E. coli can be a source of AmpC-resistance plasmids for opportunistic pathogens in the human microbiota. PMID- 28082192 TI - Glucose homeostasis, nutrition and infections during critical illness. AB - Critical illness is a complex life-threatening disease characterized by profound endocrine and metabolic alterations and by a dysregulated immune response, together contributing to the susceptibility for nosocomial infections and sepsis. Hitherto, two metabolic strategies have been shown to reduce nosocomial infections in the critically ill, namely tight blood glucose control and early macronutrient restriction. Hyperglycaemia, as part of the endocrine-metabolic responses to stress, is present in virtually all critically ill patients and is associated with poor outcome. Maintaining normoglycaemia with intensive insulin therapy has been shown to reduce morbidity and mortality, by prevention of vital organ dysfunction and prevention of new severe infections. The favourable effects of this intervention were attributed to the avoidance of glucose toxicity and mitochondrial damage in cells of vital organs and in immune cells. Hyperglycaemia was shown to impair macrophage phagocytosis and oxidative burst capacity, which could be restored by targeting normoglycaemia. An anti-inflammatory effect of insulin may have contributed to prevention of collateral damage to host tissues. Not using parenteral nutrition during the first week in intensive care units, and so accepting a large macronutrient deficit, also resulted in fewer secondary infections, less weakness and accelerated recovery. This was at least partially explained by a suppressive effect of early parenteral nutrition on autophagic processes, which may have jeopardized crucial antimicrobial defences and cell damage removal. The beneficial impact of these two metabolic strategies has opened a new field of research that will allow us to improve the understanding of the determinants of nosocomial infections, sepsis and organ failure in the critically ill. PMID- 28082193 TI - How common is subsequent central nervous system toxicity in asymptomatic patients with haematologic malignancy and supratherapeutic voriconazole serum levels? AB - OBJECTIVES: We sought to determine the frequency at which patients with elevated voriconazole (VRC) levels but no clinically evident central nervous system (CNS) toxicity subsequently develop CNS toxicity. METHODS: We retrospectively reviewed the records of adult patients with haematolologic malignancy who had a VRC serum level >5.5 MUg/mL at MD Anderson Cancer Center (January 2010 to December 2015). Patients with any documented CNS toxicity at the time the VRC level was obtained or patients whose VRC was discontinued as a response to high VRC level were excluded. Neurologic status was assessed using standard grading scales. Demographic and clinical characteristics, including potentially interacting medications, were correlated with the development of toxicity. RESULTS: We identified 320 such patients (mean age, 57 +/- 15 years; 202 male (63%)). Subsequent CNS toxicity was documented in only 16 patients (5%). The most common CNS toxicities were visual disturbances (9/16, 56%), depressed consciousness (5/16, 31%) and cognitive disturbance (4/16, 19%). Patients with CNS toxicity tended to be older than those without (64 +/- 8 vs 57 +/- 15 y, p 0.08). The use of one or more neurotoxic drugs was common in patients with subsequent CNS toxicity (14/16, 88%). Reduction of VRC dose associated with the high VRC level did not correlate with less subsequent CNS toxicity. CONCLUSIONS: Development of subsequent CNS toxicity is uncommon in haematolologic malignancy patients with elevated VRC levels who had no evidence of toxicity at the time the level was obtained. Automatic reduction of VRC dose out of concern for impending CNS toxicity might not be warranted. PMID- 28082194 TI - Bidirectional relationship of mast cells-neurovascular unit communication in neuroinflammation and its involvement in POCD. AB - Postoperative cognitive dysfunction (POCD) has been hypothesized to be mediated by surgery-induced neuroinflammation, which is also a key element in the pathobiology of neurodegenerative diseases, stroke, and neuropsychiatric disorders. There is extensive communication between the immune system and the central nervous system (CNS). Inflammation resulting from activation of the innate immune system cells in the periphery can impact central nervous system behaviors, such as cognitive performance. Mast cells (MCs), as the"first responders" in the CNS, can initiate, amplify, and prolong other immune and nervous responses upon activation. In addition, MCs and their secreted mediators modulate inflammatory processes in multiple CNS pathologies and can thereby either contribute to neurological damage or confer neuroprotection. Neuroinflammation has been considered to be linked to neurovascular dysfunction in several neurological disorders. This review will provide a brief overview of the bidirectional relationship of MCs-neurovascular unit communication in neuroinflammation and its involvement in POCD, providing a new and unique therapeutic target for the adjuvant treatment of POCD. PMID- 28082195 TI - The influence of calorie and physical activity labelling on snack and beverage choices. AB - BACKGROUND: Much research suggests nutrition labelling does not influence lower energy food choice. This study aimed to assess the impact of physical activity based and kilocalorie (Kcal) based labels on the energy content of snack food and beverage choices made. METHODS: An independent-groups design, utilizing an online questionnaire platform tested 458 UK adults (87 men), aged 18-64 years (mean: 30 years) whose BMI ranged from 16 to 41 kg/m2 (mean: 24 kg/m2). Participants were randomized to one of four label information conditions (no label, Kcal label, physical activity label [duration of walking required to burn the Kcal in the product], Kcal and physical activity label) and were asked to choose from higher and lower energy options for a series of items. RESULTS: Label condition significantly affected low vs. high-energy product selection of snack foods (p < 0.001) and beverages (p < 0.001). The physical activity label condition resulted in significantly lower energy snack and beverage choices than the Kcal label condition (p < 0.001). This effect was found across the full sample and persisted even when participants' dietary restraint, BMI, gender, socioeconomic status, habitual physical activity, calorie and numerical literacy were controlled. CONCLUSION: The provision of physical activity information appeared most effective in influencing the selection of lower Kcal snack food and beverage items, when compared with no information or Kcal information. These findings could inform the debate around potential legislative policies to facilitate healthier nutritional choices at a population level. PMID- 28082196 TI - Multicontextual correlates of energy-dense, nutrient-poor snack food consumption by adolescents. AB - Frequent consumption of energy-dense, nutrient-poor snack foods is an eating behavior of public health concern. This study was designed to inform strategies for reducing adolescent intake of energy-dense snack foods by identifying individual and environmental influences. Surveys were completed in 2009-2010 by 2540 adolescents (54% females, mean age = 14.5 +/- 2.0, 80% nonwhite) in Minneapolis-St. Paul, Minnesota schools. Daily servings of energy-dense snack food was assessed using a food frequency questionnaire that asked about consumption of 21 common snack food items, such as potato chips, cookies, and candy. Data representing characteristics of adolescents' environments were collected from parents/caregivers, friends, school personnel, Geographic Information System sources, and a content analysis of favorite television shows. Linear regression was used to examine relationships between each individual or environmental characteristic and snack food consumption in separate models and also to examine relationships in a model including all of the characteristics simultaneously. The factors found to be significantly associated with higher energy-dense snack food intake represented individual attitudes/behaviors (e.g., snacking while watching television) and characteristics of home/family (e.g., home unhealthy food availability), peer (friends' energy-dense snack food consumption), and school (e.g., student snack consumption norms) environments. In total, 25.5% of the variance in adolescents' energy-dense snack food consumption was explained when factors from within each context were examined together. The results suggest that the design of interventions targeting improvement in the dietary quality of adolescents' snack food choices should address relevant individual factors (e.g., eating while watching television) along with characteristics of their home/family (e.g., limiting the availability of unhealthy foods), peer (e.g., guiding the efforts of a peer leader in making healthy choices), and school environments (e.g., establishing student norms for selecting nutrient-dense snack foods). PMID- 28082197 TI - Dual role of the active-center cysteine in human peroxiredoxin 1: Peroxidase activity and heme binding. AB - HBP23, a 23-kDa heme-binding protein identified in rats, is a member of the peroxiredoxin (Prx) family, the primary peroxidases involved in hydrogen peroxide catabolism. Although HBP23 has a characteristic Cys-Pro heme-binding motif, the significance of heme binding to Prx family proteins remains to be elucidated. Here, we examined the effect of heme binding to human peroxiredoxin-1 (PRX1), which has 97% amino acid identity to HBP23. PRX1 was expressed in Escherichia coli and purified to homogeneity. Spectroscopic titration demonstrated that PRX1 binds heme with a 1:1 stoichiometry and a dissociation constant of 0.17 MUM. UV vis spectra of heme-PRX1 suggested that Cys52 is the axial ligand of ferric heme. PRX1 peroxidase activity was lost upon heme binding, reflecting the fact that Cys52 is not only the heme-binding site but also the active center of peroxidase activity. Interestingly, heme binding to PRX1 caused a decrease in the toxicity and degradation of heme, significantly suppressing H2O2-dependent heme peroxidase activity and degradation of PRX1-bound heme compared with that of free hemin. By virtue of its cytosolic abundance (~20 MUM), PRX1 thus functions as a scavenger of cytosolic hemin (<1 MUM). Collectively, our results indicate that PRX1 has a dual role; Cys-dependent peroxidase activity and cytosolic heme scavenger. PMID- 28082198 TI - Neuroprotectant androst-3beta, 5alpha, 6beta-triol suppresses TNF-alpha-induced endothelial adhesion molecules expression and neutrophil adhesion to endothelial cells by attenuation of CYLD-NF-kappaB pathway. AB - Neuroinflammation is one of key pathologic element in neurological diseases including stroke, traumatic brain injury, Alzheimer' s Disease, Parkinson's Disease, and multiple sclerosis as well. Up-regulation of endothelial adhesion molecules, which facilitate leukocyte adhesion to the endothelium, is the vital process of endothelial cells mediated neuroinflammation. Androst-3beta, 5alpha, 6beta-triol (Triol) is a synthetic steroid which has been reported to have neuroprotective effects in hypoxia/re-oxygenation-induced neuronal injury model. In the present study, we firstly investigated whether Triol inhibited the TNF alpha-induced inflammatory response in rat brain microvascular endothelial cells (RBMECs). Our data showed that Triol decreased TNF-alpha-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) and the adhesion of neutrophil to RBMECs. We also found that Triol inhibited TNF-alpha-induced degradation of IkappaBalpha and phosphorylation of NF kappaBp65 that are required for NF-kappaB activation. Furthermore, Triol significantly reversed TNF-alpha-induced down-expression of CYLD, which is a deubiquitinase that negatively regulates activation of NF-kappaB. These results suggest that Triol displays an anti-inflammatory effect on TNF-alpha-induced RBMECs via downregulating of CYLD-NF-kappaB signaling pathways and might have a potential benefit in therapeutic neuroinflammation related diseases. PMID- 28082199 TI - Ric-8A-mediated stabilization of the trimeric G protein subunit Galphai is inhibited by pertussis toxin-catalyzed ADP-ribosylation. AB - The heterotrimeric G protein subunit Galphai can be activated by G protein coupled receptors and the cytosolic protein Ric-8A, the latter of which is also known to prevent ubiquitin-dependent degradation of Galphai. Here we show that the amounts of the three Galphai-related proteins Galphai1, Galphai2, and Galphai3, but not that of Galphaq, are rapidly decreased by cell treatment with pertussis toxin (PTX). The decrease appears to be due to ADP-ribosylation of Galphai, because PTX treatment does not affect the amount of a mutant Galphai2 carrying alanine substitution for Cys352, the residue that is ADP-ribosylated by the toxin. The presence of endogenous and exogenous Ric-8A increases Galphai stability as shown in cells treated with the protein synthesis inhibitor cycloheximide; however, Ric-8A fails to efficiently stabilize ADP-ribosylated Galphai. The failure agrees with the inability of Ric-8A to bind to ADP ribosylated Galphai both in vitro and in vivo. Thus PTX appears to exert its pathological effects at least in part by converting Galphai to an unstable ADP ribosylated form, in addition to the well-known inability of ADP-ribosylated Galphai to transduce signals triggered by G protein-coupled receptors. PMID- 28082200 TI - mTOR up-regulation of PFKFB3 is essential for acute myeloid leukemia cell survival. AB - Although mTOR (mammalian target of rapamycin) activation is frequently observed in acute myeloid leukemia (AML) patients, the precise function and the downstream targets of mTOR are poorly understood. Here we revealed that PFKFB3, but not PFKFB1, PFKFB2 nor PFKFB4 was a novel downstream substrate of mTOR signaling pathway as PFKFB3 level was augmented after knocking down TSC2 in THP1 and OCI AML3 cells. Importantly, PFKFB3 silencing suppressed glycolysis and cell proliferation of TSC2 silencing OCI-AML3 cells and activated apoptosis pathway. These results suggested that mTOR up-regulation of PFKFB3 was essential for AML cells survival. Mechanistically, Rapamycin treatment or Raptor knockdown reduced the expression of PFKFB3 in TSC2 knockdown cells, while Rictor silencing did not have such effect. Furthermore, we also revealed that mTORC1 up-regulated PFKFB3 was dependent on hypoxia-inducible factor 1alpha (HIF1alpha), a positive regulator of glycolysis. Moreover, PFKFB3 inhibitor PFK15 and rapamycin synergistically blunted the AML cell proliferation. Taken together, PFKFB3 was a promising drug target in AML patients harboring mTOR hyper-activation. PMID- 28082201 TI - Cap-independent protein synthesis is enhanced by betaine under hypertonic conditions. AB - Protein synthesis is one of the main cellular functions inhibited during hypertonic challenge. The subsequent accumulation of the compatible osmolyte betaine during the later adaptive response allows not only recovery of translation but also its stimulation. In this paper, we show that betaine modulates translation by enhancing the formation of cap-independent 48 S pre initiation complexes, leaving cap-dependent 48 S pre-initiation complexes basically unchanged. In the presence of betaine, CrPV IRES- and sodium-dependent neutral amino acid transporter-2 (SNAT2) 5'-UTR-driven translation is 2- and 1.5 fold stimulated in MCF7 cells, respectively. Thus, betaine could provide an advantage in translation of messengers coding for proteins implicated in the response of cells to different stressors, which are often recognized by ribosomal 40 S subunit through simplified cap-independent mechanisms. PMID- 28082202 TI - Hepatitis C virus alters metabolism of biogenic polyamines by affecting expression of key enzymes of their metabolism. AB - Chronic infection with hepatitis C virus (HCV) induces liver fibrosis and cancer. In particular metabolic alterations and associated oxidative stress induced by the virus play a key role in disease progression. Albeit the pivotal role of biogenic polyamines spermine and spermidine in the regulation of liver metabolism and function and cellular control of redox homeostasis, their role in the viral life cycle has not been studied so far. Here we show that in cell lines expressing two viral proteins, capsid and the non-structural protein 5A, expression of the two key enzymes of polyamine biosynthesis and degradation, respectively, ornithine decarboxylase (ODC) and spermidine/spermine-N1-acetyl transferase (SSAT), increases transiently. In addition, both HCV core and NS5A induce sustained expression of spermine oxidase (SMO), an enzyme that catalyzes conversion of spermine into spermidine. Human hepatoma Huh7 cells harboring a full-length HCV replicon exhibited suppressed ODC and SSAT levels and elevated levels of SMO leading to decreased intracellular concentrations of spermine and spermidine. Thus, role of HCV-driven alterations of polyamine metabolism in virus replication and development of HCV-associated liver pathologies should be explored in future. PMID- 28082203 TI - Cell laden hydrogel construct on-a-chip for mimicry of cardiac tissue in-vitro study. AB - Since the leading cause of death are cardiac diseases, engineered heart tissue (EHT) is one of the most appealing topics defined in tissue engineering and regenerative medicine fields. The importance of EHT is not only for heart regeneration but also for in vitro developing of cardiology. Cardiomyocytes could grow and commit more naturally in their microenvironment rather than traditional cultivation. Thus, this research tried to develop a set up on-a-chip to produce EHT based on chitosan hydrogel. Micro-bioreactor was hydrodynamically designed and simulated by COMSOL and produced via soft lithography process. Chitosan hydrogel was also prepared, adjusted, and assessed by XRD, FTIR and also its degradation rate and swelling ratio were determined. Finally, hydrogels in which mice cardiac progenitor cells (CPC) were loaded were injected into the micro device chambers and cultured. Each EHT in every chamber was evaluated separately. Prepared EHTs showed promising results that expanded in them CPCs and work as an integrated syncytium. High cell density culture was the main accomplishment of this study. PMID- 28082205 TI - Blunted respiratory drive response in late onset Pompe disease. PMID- 28082204 TI - Receptor tyrosine kinase inhibition by regorafenib/sorafenib inhibits growth and invasion of meningioma cells. AB - Systemic chemotherapeutic treatment for unresectable and/or aggressive meningiomas is still unsatisfying. PDGF receptor (PDGFR)-mediated activation of mitogenic signalling has been shown to be active in meningiomas. Therefore, we evaluate in vitro and in vivo the effects of inhibiting PDGFR using the clinically well-characterised tyrosine kinase inhibitors sorafenib or regorafenib in meningioma models. IOMM-Lee meningioma cells were used to assess cytotoxic effects, inhibition of proliferation, induction of apoptosis, as well as inhibition of migration and motility by sorafenib and regorafenib. Using an orthotopic mouse xenograft model, growth inhibition as monitored by magnetic resonance imaging, and overall survival of sorafenib- or regorafenib-treated mice compared with control animals was determined. Treatment of malignant IOMM-Lee cells resulted in significantly reduced cell survival and induction of apoptosis following regorafenib and sorafenib treatment. Western blots showed that both drugs target phosphorylation of p44/42 ERK via downregulation of the PDGFR. Both drugs additionally showed significant inhibition of cell motility and invasion. In vivo, mice with orthotopic meningioma xenografts showed a reduced volume (n.s.) of signal enhancement in MRI (mainly tumour) following sorafenib and regorafenib treatment. This was translated in a significantly increased overall survival time (p <= 0.05) for regorafenib-treated mice. Analyses of in vivo-grown tumours demonstrated again reduced PDGFR expression and expression/phosphorylation of p44/42. Sorafenib and regorafenib show antitumour activity in vitro and in vivo by targeting PDGFR and p44/42 ERK signalling. PMID- 28082206 TI - The yield of diagnostic work-up of patients presenting with myalgia, exercise intolerance, or fatigue: A prospective observational study. AB - Myalgia, fatigue, and exercise intolerance are cause for referral to a neurologist. However, the diagnostic value of history, neurological examination, and ancillary investigations in patients with these symptoms is unknown. This study provides a sound footing for deciding which ancillary investigations should be conducted. A prospective observational study of the diagnostic approach in 187 patients with myalgia, exercise intolerance, or fatigue as their predominant symptom was performed. The primary outcomes were independent contribution of referral letter, history, examination, and ancillary investigations to a myopathy diagnosis. The secondary outcome was diagnostic value of combined ancillary investigations. 27% of patients had a myopathy. Positive family history (OR 3.2), progressive symptoms (OR 2.2), atrophy (OR 9.7), weakness (OR 10.9), and hyporeflexia (OR 4.4) were associated with a myopathy. Positive predictive values for myopathy were calculated for CK (0.32), EMG (0.66), ultrasound (0.47), and muscle biopsy (0.78). All contributed significantly in predicting myopathy. Multivariate analysis yielded a diagnostic algorithm facilitating a more efficient work-up in future patients. CK levels, EMG, ultrasound, and muscle biopsy independently contribute to predicting a myopathy. The diagnostic algorithm shows which combination of ancillary investigations should be employed in different subgroups and when to omit invasive techniques. This algorithm may drastically improve diagnostic efficiency. PMID- 28082207 TI - Prevalence of myotonic dystrophy type 1 in adults in western Sweden. AB - Myotonic dystrophy type 1 (DM1) is the most common inherited muscle disorder in adults. The prevalence differs widely between countries, but a figure of 13/100.000 is most frequently cited. It is a multi-organ disorder classified into four categories: congenital, childhood, adult/classical and late-onset/mild. The purpose of this study was to estimate the total and age adjusted prevalence of DM1 in adults in western Sweden (the Vastra Gotaland Region, VGR) as well as in the city of Gothenburg and also in the VGR except Gothenburg. Patients with the diagnosis of DM1 in the VGR were traced by outpatient registers at the Neuromuscular Center, contacted by regular mail and thereafter telephone interviewed about organ manifestations in order to ascertain the age at onset and thus the disease category. Medical records were examined to obtain detail accuracy. We detected 230 adult DM1 patients in the VGR which gives a prevalence of 17.8/100.000. The prevalence of DM1 in Gothenburg was 14.1/100.000, which was significantly lower than in the remaining region which was 19.7/100.000. There was no gender difference. The age adjusted prevalence rates showed that DM1 is most prevalent in the age group 35-44 years (23.9/100.000) and 45-54 years (25.8/100.000). DM1 prevalence in the western Sweden thus seems to be somewhat higher than elsewhere in Europe, and is especially high in the less densely populated areas of the region. The disease burden in the community is larger than what was known previously. PMID- 28082208 TI - Body composition and clinical outcome measures in patients with myotonic dystrophy type 1. AB - Myotonic Dystrophy type 1 (DM1) is the most common form of adult onset muscular dystrophy. In this study we compared body composition in DM1 and matched controls and evaluated the relationship between these parameters and clinical outcome measures in DM1 patients. In addition we established the sensitivity to change of these measures in a prospective 18 month longitudinal study of the DM1 patient cohort. Clinical data, manual muscle testing (MMT), quantitative muscle testing (QMT) of ankle dorsiflexion, bilateral grip dynamometry, 6 minute walk test and a DM1 functional rating scale (DM1-Activ) were collected at baseline (n = 38) and 18 month follow-up (n = 36). The case-control analysis was performed comparing baseline data with 31 anthropometrically matched controls. Dual-energy X-ray absorptiometry (DEXA) was used to obtain regional measurements of fat-free mass index (FFMI) and fat mass index (FMI) and demonstrated significant reduction of FFMI in the legs (left p = 0.004; right p = 0.017) and trunk (p < 0.0001) and increased FMI localised to the trunk (p < 0.0001) in DM1 patients compared to controls. Regional left and right arm FFMI and FMI significantly positively and negatively correlated with grip strength and both total FFMI (p = 0.0009) and FMI (p = 0.02) decreased and increased by 0.38 kg/m2 and 0.31 kg/m2 respectively after 18 month follow-up. DEXA is likely to provide a useful secondary outcome measurement of disease progression in addition to muscle strength and timed functional tasks in clinical trials. PMID- 28082209 TI - Resistant myasthenia gravis and rituximab: A monocentric retrospective study of 28 patients. AB - This retrospective study evaluated the efficiency and tolerance of rituximab in the management of resistant myasthenia gravis (MG). All patients who received rituximab for the treatment of MG between 2004 and 2015 at Pitie-Salpetriere University Hospital (Paris, France) were included. The efficacy of rituximab was evaluated every 6 months by the myasthenic muscle score (MMS), the Myasthenia Gravis Foundation of America - Clinical Classification (MGFA-CC), the MGFA Therapy Status and the Postintervention Status (PIS). All rituximab-related side effects were noted. Twenty-eight patients were included: 21 with anti acetylcholine receptor antibodies, 3 with anti-muscle-specific tyrosine kinase antibodies and 4 seronegatives. The mean age at day 1 of RTX was 50.6 +/- 12.0 years. Patients previously received 1-4 immunosuppressants. The mean follow-up was 27.2 months (range: 6-60 months). The mean total dose of rituximab was 4.8 +/ 2.5 g. The initial median MMS (58.8 points) improved significantly at M6 (74.5 +/- 15.0 points; p < 0.0001) and remained stable thereafter: at M12: 75.9 +/- 14.0 points (p = 0.00014), at M36: 72.5 +/- 13.1 points (p = 0.0013). Among 16 patients with initial severe symptoms (MGFA-CC class IV), 14 improved. The PIS showed efficacy in about 50% of patients: at M6, 12/28 (43%) patients were considered improved. This benefit remained stable thereafter: at M12: 12/24, at M24: 7/17, at M36: 6/12. One patient developed a delayed progressive multifocal leukoencephalopathy. Based on the PIS, rituximab may be efficient in 50% of patients with MG resistant to immunosuppressants. PMID- 28082210 TI - Depression Literacy and Awareness of Psychopathological Symptoms During the Perinatal Period. AB - OBJECTIVE: To characterize women's depression literacy during the perinatal period, including their ability to recognize clinically significant symptoms of depression. DESIGN: A quantitative, cross-sectional, survey design. SETTING: Internet communities and Web sites focused on the topics of pregnancy and motherhood. PARTICIPANTS: A total of 194 women during the perinatal period (32.5% pregnant, 67.5% postnatal) completed the survey; 34.0% had clinically significant psychopathological symptoms. Most women were married/cohabiting (82.0%) and employed (71.8%). METHODS: Women answered self-report questionnaires to assess depression literacy, symptoms of depression, emotional competence, and awareness/recognition of psychopathological symptoms. RESULTS: Women had moderate levels of depression literacy during the perinatal period, with higher literacy levels concerning depression-related characteristics than depression-related treatments. Lower education and lower income were associated with poor depression literacy, whereas prior history of psychiatric problems or treatments was associated with higher levels of depression literacy. An indirect effect through emotional competence in the relationship between depression literacy and awareness/recognition of symptoms was found: women with poor depression literacy tended to have a greater lack of emotional clarity, which negatively affected their symptom awareness and recognition. CONCLUSION: Our results support the need to improve women's mental health literacy during the perinatal period. Education on mental health topics in the context of a trusting relationship with health professionals may contribute to the promotion of women's depression literacy and emotional competence. PMID- 28082211 TI - A Randomized Controlled Trial of Glycerin Suppositories During Phototherapy in Premature Neonates. AB - OBJECTIVE: To determine if glycerin suppositories were effective in reducing total duration of phototherapy in premature neonates. We hypothesized that glycerin suppositories would have no effect on phototherapy duration or total serum bilirubin levels. DESIGN: Prospective randomized controlled double-blinded trial. SETTING: Level IV NICU. PARTICIPANTS: Neonates born between 30 weeks, 0 days and 34 weeks, 6 days gestational age who developed physiologic hyperbilirubinemia needing phototherapy. METHODS: Neonates were randomized to the no-suppository group or to the suppository group. Neonates were randomized to receive glycerin suppositories every 8 hours while under phototherapy or to a sham group. The primary outcome was total hours of phototherapy. Secondary outcomes included peak total serum bilirubin levels, time from start to discontinuation of phototherapy, rate of decline in bilirubin levels, repeat episodes of phototherapy, and number of stools while the neonates received phototherapy. RESULTS: A total of 39 neonates were assigned to the no-suppository group and 40 to the suppository group. Withholding suppositories was not inferior to providing suppositories. The total hours of phototherapy were not longer (i.e., noninferior) among neonates not provided suppositories (61 +/- 53 hours) than among those given suppositories (72 +/- 49 hours). There were no differences in peak bilirubin levels, rate of bilirubin decline, or repeat episodes of phototherapy. CONCLUSION: Routine use of glycerin suppositories among preterm neonates who receive phototherapy does not affect bilirubin levels or phototherapy duration. PMID- 28082212 TI - Improving the sensitivity of immunoassay based on MBA-embedded Au@SiO2 nanoparticles and surface enhanced Raman spectroscopy. AB - Traditional "sandwich" structure immunoassay is mainly based on the self-assembly of "antibody on solid substrate-antigen-antibody with nanotags" architectures, and the sensitivity of this strategy is critically depended on the surface enhanced Raman scattering (SERS) activities and stability of nanotags. Therefore, the rational design and fabrication on the SERS nanotags attracts the common interests to the bio-related detecting and imaging. Herein, silica encapsulated Au with mercaptobenzoic acid (MBA) core-shell nanoparticles (Au-MBA@SiO2) are fabricated instead of the traditional naked Au or Ag nanoparticles for the SERS based immunoassay on human and mouse IgG antigens. The MBA molecules facilitate the formation of continuous pinhole-free silica shell and are also used as SERS labels. The silica shell is employed to protect MBA labels and to isolate Au core from the ambient solution for blocking the aggregation. This shell also played the similar role to BSA in inhibiting the nonspecific bindings, which allowed the procedures for constructing "sandwich" structures to be simplified. All of these merits of the Au-MBA@SiO2 brought the high performance in the related immunoassay. Benefiting from the introduction of silica shell to encapsulate MBA labels, the detection sensitivity was improved by about 1-2 orders of magnitude by comparing with the traditional approach based on naked Au-MBA nanoparticles. This kind of label-embedded core-shell nanoparticles could be developed as the versatile nanotags for the bioanalysis and bioimaging. PMID- 28082213 TI - Deep sequencing analysis reveals a TMV mutant with a poly(A) tract reduces host defense responses in Nicotiana benthamiana. AB - Tobacco mosaic virus (TMV) possesses an upstream pseudoknotted domain (UPD), which is important for replication. After substituting the UPD with an internal poly(A) tract (43 nt), a mutant TMV-43A was constructed. TMV-43A replicated slower than TMV and induced a non-lethal mosaic symptom in Nicotiana benthamiana. In this study, deep sequencing was performed to detect the differences of small RNA profiles between TMV- and TMV-43A-infected N. benthamiana. The results showed that TMV-43A produced lesser amount of virus-derived interfering RNAs (vsiRNAs) than that of TMV. However, the distributions of vsiRNAs generation hotspots between TMV and TMV-43A were similar. Expression of genes related to small RNA biogenesis in TMV-43A-infected N. benthamiana was significantly lower than that of TMV, which leads to generation of lesser vsiRNAs. The expressions of host defense response genes were up-regulated after TMV infection, as compared to TMV 43A-infected plants. Host defense response to TMV-43A infection was lower than that to TMV. The absence of UPD might contribute to the reduced host response to TMV-43A. Our study provides valuable information in the role of the UPD in eliciting host response genes after TMV infection in N. benthamiana. (187 words). PMID- 28082215 TI - Neuropeptides encoded within a neural transcriptome of the giant triton snail Charonia tritonis, a Crown-of-Thorns Starfish predator. AB - Neuropeptides represent a diverse class of signaling molecules originating from neural tissues. These chemical modulators orchestrate complex physiological events including those associated with growth and reproduction. De novo transcriptome sequencing of a cerebral ganglion library of the endangered giant triton snail (Charonia tritonis) was undertaken in an effort to identify key neuropeptides that control or influence its physiology. The giant triton snail is considered a primary predator of the corallivore Acanthaster planci (Crown-of Thorns Starfish) that is responsible for a significant loss in coral cover on reefs in the Indo-Pacific. The transcriptome library was assembled into contigs, and then bioinformatic analysis was used to identify a repertoire of 38 giant triton snail neuropeptide precursor genes, and various isoforms, that encode conserved molluscan neuropeptides. C. tritonis neuropeptides show overall precursor organisation consistent with those of other molluscs. These include those neuropeptides associated with mollusc reproduction such as the APGWamide, buccalin, conopressin, gonadotropin-releasing hormone (GnRH), NKY and egg-laying hormone. These data provide a foundation for further studies targeted towards the functional characterisation of neuropeptides to further understand aspects of the biology of the giant triton snail, such as elucidating its reproductive neuroendocrine pathway to allow the development of knowledge based captive breeding programs. PMID- 28082214 TI - Are perioperative bundles associated with reduced postoperative morbidity in women undergoing benign hysterectomy? Retrospective cohort analysis of 16,286 cases in Michigan. AB - BACKGROUND: Healthcare teams that frequently follow a bundle of evidence-based processes provide care with lower rates of morbidity. Few process bundles to improve surgical outcomes in hysterectomy have been identified. OBJECTIVE: The purpose of this study was to investigate whether a bundle of 4 perioperative care processes is associated with fewer postoperative complications and readmissions for hysterectomies in the Michigan Surgical Quality Collaborative. STUDY DESIGN: A bundle of perioperative care process goals was developed retrospectively with 30-day peri- and postoperative outcome data from the Hysterectomy Initiative in Michigan Surgical Quality Collaborative. All benign hysterectomies that had been performed between January 2013 and January 2015 were included. Based on evidence of lower complication rates after benign hysterectomy, the following processes were considered to be the "bundle": use of guideline-appropriate preoperative antibiotics, a minimally invasive surgical approach, operative duration <120 minutes, and avoidance of intraoperative hemostatic agent use. Each process was considered present or absent, and the number of processes was summed for a bundle score that ranged from 0-4. Cases with a score of zero were excluded. Outcomes measured were rates of complications (any and major) and hospital readmissions, all within 30 days of surgery. Postoperative events that were considered a "major complication" included acute renal failure, cardiac arrest that required cardiopulmonary resuscitation, central line infection, cerebral vascular accident, death, deep vein thrombosis, intestinal obstruction, myocardial infarction, pelvic abscess, pulmonary embolism, rectovaginal fistula, sepsis, surgical site infection (deep and organ-space), unplanned intubation, ureteral obstruction, and ureterovaginal and vesicovaginal fistula. The outcome "any complication" included all those events already described in addition to blood transfusion within 72 hours of surgery, urinary tract infection, and superficial surgical site infection. Outcomes were adjusted for patient demographics, surgical factors, and hospital-level clustering effects. RESULTS: There were 16,286 benign hysterectomies available for analysis. Among all hysterectomies that were reviewed, 33.6% met criteria for all bundle processes; however, there was wide variation in the rate among the 56 hospitals in the study sample with 9.1% of cases at the lowest quartile and 60.4% at the highest quartile of hospitals that met criteria for all bundle processes. Overall, the rate of any complication was 6.8% and of any major complication was 2.3%. The rate of hospital readmissions was 3.6%. After adjustment for confounders, in cases in which all bundle criterion were met compared with cases in which all bundle criterion were not met, the rate of any complications increased from 4.3-7.8% (P<.001); major complications increased from 1.7-2.6% (P<.001), and readmissions increased from 2.6-4.1% (P<.001). After adjustment for confounders, hospitals with greater rates of meeting all 4 criteria were associated significantly with lower hospital-level rates of postoperative complications (P<.001) and readmissions (P<.001). CONCLUSIONS: This multiinstitutional evaluation reveals that reduced morbidity and readmission are associated with rates of bundle compliance. The proposed bundle is a surgical goal, which is not possible in every case, and there is significant variation in the proportion of cases meeting all 4 bundle processes in Michigan hospitals. Implementation of evidence-based process bundles at a healthcare system level are worthy of prospective study to determine whether improvements in patient outcomes are possible. PMID- 28082216 TI - Synthesis and characterization of graphene quantum dots/CoNiAl-layered double hydroxide nanocomposite: Application as a glucose sensor. AB - In the present work, a novel nanocomposite based on the graphene quantum dots and CoNiAl-layered double-hydroxide was successfully synthesized by co-precipitation method. To achieve the morphological, structural and compositional information, the resulted nanocomposite was characterized by scanning electron microscopy X ray diffraction, thermal gravimetric analysis, Fourier transform infrared spectroscopy, and photoluminescence. Then, the nanocomposite was used as a modifier to fabricate a modified carbon paste electrode as a non-enzymatic sensor for glucose determination. Electrochemical behavior and determination of glucose at the nanocomposite modified carbon paste electrode were investigated by cyclic voltammetry and chronoamperometry methods, respectively. The prepared sensor offered good electrocatalytic properties, fast response time, high reproducibility and stability. At the optimum conditions, the constructed sensor exhibits wide linear range; 0.01-14.0 mM with a detection limit of 6 MUM (S/N = 3) and high sensitivity of 48.717 MUAmM-1. Finally, the sensor was successfully applied to determine the glucose in real samples which demonstrated its applicability. PMID- 28082218 TI - A gel-less isolation of untagged plasmid DNA insert from vector backbone in homogeneous format. AB - Agarose gel electrophoresis with subsequent DNA extraction from gel is routinely used for DNA fragment isolation after plasmid DNA digestion. We describe a gel less method for DNA fragment isolation after plasmid DNA digestion which is based on in-solution negative selection through depletion of vector backbone bearing LoxP sites by sorption on solid phase-immobilized mutated Cre recombinase. The method might be especially useful in preparation of DNA fragments for transgenic animal generation where residual agarose presence is a concern, and DNA fragments are frequently large in size and thus might be mechanically damaged during purification with conventional affinity-based gel extraction methods. PMID- 28082217 TI - Imaging based magnetic resonance spectroscopy (MRS) localization for quantitative neurochemical analysis and cerebral metabolism studies. AB - Accurate quantitative metabolic imaging of the brain presents significant challenges due to the complexity and heterogeneity of its structures and compositions with distinct compartmentations of brain tissue types (e.g., gray and white matter). The brain is compartmentalized into various regions based on their unique functions and locations. In vivo magnetic resonance spectroscopy (MRS) techniques allow non-invasive measurements of neurochemicals in either single voxel or multiple voxels, yet the spatial resolution and detection sensitivity of MRS are significantly lower compared with MRI. A fundamentally different approach, namely spectral localization by imaging (SLIM) provides a new framework that overcomes major limitations of conventional MRS techniques. Conventional MRS allows only rectangular voxel shapes that do not conform to the shapes of brain structures or lesions, while SLIM allows compartments with arbitrary shapes. However, the restrictive assumption proposed in the original concept of SLIM, i.e., compartmental homogeneity, led to spectral localization errors, which have limited its broad applications. This review focuses on the recent technical frontiers of image-based MRS localization techniques that overcome the limitations of SLIM through the development and implementation of various new strategies, including incorporation of magnetic field inhomogeneity corrections, the use of multiple receiver coils, and prospective optimization of data acquisition. PMID- 28082219 TI - Characterization and carboplatin loaded chitosan nanoparticles for the chemotherapy against breast cancer in vitro studies. AB - Aim of the studies to synthesized chitosan nanoparticles by an ionic interaction procedure. The nanoparticles were characterized by physicochemical methods like, DLS, TEM, Surface potential measurements, FT-IR and DSC. The average particle size of chitosan and carboplatin nanoparticles was found to be 277.25+/-11.37nm and 289.30+/-8.15nm and zeta potential was found to be 31+/-3.14mV and 33+/ 2.15mV respectively with low polydispersity index. The maximum entrapment of carboplatin in nanoparticles was a spherical shape with a positive charge. The maximum encapsulation and loading efficiencies of carboplatin (5mg/ml) were obtained to be 58.43% and 13.27% respectively. The nanocarboplatin was better blood compatibility as compared to chitosan nanoparticles. Finally, the cytotoxic effects of the carboplatin loaded chitosan nanoparticles were tested in-vitro against breast cancer (MCF-7) cell lines. Our studies showed that the chitosan nanoparticles could be used as a promising candidate for drug delivery for the therapeutic treatment of breast cancer. PMID- 28082220 TI - Structural features and thermal property of propionylated starches with different amylose/amylopectin ratio. AB - This work concerned the effects of amylose/amylopectin ratio on the structure and thermal stability of propionylated starches with high degree of substitution (DS). Four starches with different amylose content were used to obtain propionylated starches. Acylation partly disrupted granule morphology of native starches, and the imperfection and porous structures of starch granule were intensified along with the increased amylose content. It was noted that the crystalline structure of starch was destroyed and thus intense acylation occurred in both amorphous and crystalline regions. The acylated starch with high-amylose content displayed more ordered region compared to low-amylose starch. Acylation enhanced the thermal stability of starch, and this effect became more evident as the amylose content increased. Thus, the amylose/amylopectin ratio has been confirmed capable of affecting the structure and thermal behaviors of hydrophobic propionylated starch, which is of value for the design of starchy materials with tailored thermal stability. PMID- 28082221 TI - Alanine 310 is important for the activity of 1,4-alpha-glucan branching enzyme from Geobacillus thermoglucosidans STB02. AB - 1,4-alpha-Glucan branching enzyme (GBE) catalyzes the formation of alpha-1,6 branch points in starch or glycogen by hydrolyzing alpha-1,4-glucosidic linkages and then synthesizing alpha-1,6-glucosidic linkages. In the GBE from Geobacillus thermoglucosidans STB02, alanine 310 (Ala310) is located in conserved region II. An analysis of the amino acid sequence shows that Ala310 is highly conserved in the prokaryotic GBE subfamily. Site-directed mutagenesis was used to determine the function of Ala310 in GBE. Replacement of Ala310 with glycine, aspartate, asparagine, isoleucine, glutamate, or glutamine resulted in mutant enzymes with less than 10% to 25% of wild-type activity when amylopectin or amylose was used as substrate. Studies using high-performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD) showed that A310G mutant had no effect on the transfer pattern, but the branching activity had been repressed to a large extent. Kinetic analysis also showed that mutations of Ala310 had an effect on the KM value that changed the preferred substrate from amylopectin to amylose. These results show that Ala310 is important for the catalytic activity of the GBE from G. thermoglucosidans STB02. PMID- 28082222 TI - In vitro photodynamic effects of scavenger receptor targeted-photoactivatable nanoagents on activated macrophages. AB - Scavenger receptors (SRs) expressed on the activated macrophages in inflammation sites have been considered as the most interesting and important target biomarker for targeted drug delivery, imaging and therapy. In the present study, we fabricated the scavenger receptor-A (SR-A) targeted-photoactivatable nanoagents (termed as Ce6/DS-DOCA) by entrapping chlorin e6 (Ce6) into the amphiphilic dextran sulfate-deoxycholic acid (DS-DOCA) conjugates via physically hydrophobic interactions. Insoluble Ce6 was easily encapsulated into DS-DOCA nanoparticles by a dialysis method and the loading efficiency was approximately 51.7%. The Ce6/DS DOCA formed nano-sized self-assembled aggregates (28.8+/-5.6nm in diameter), confirmed by transmission electron microscope, UV/Vis and fluorescence spectrophotometer. The Ce6/DS-DOCA nanoagents could generate highly reactive singlet oxygen under laser irradiation. Also, in vitro studies showed that they were more specifically taken up by lipopolysaccharide (LPS)-induced activated macrophages (RAW 264.7) via a SR-A-mediated endocytosis, relative to by non activated macrophages, and notably induced cell death of activated macrophages under laser irradiation. Therefore, SR-A targetable and photoactivatable Ce6/DS DOCA nanoagents with more selective targeting to the activated macrophages will have great potential for treatment of inflammatory diseases. PMID- 28082223 TI - Mechanical, morphological and structural properties of cellulose nanofibers reinforced epoxy composites. AB - Present study, deals about isolation and characterization of cellulose nanofibers (CNFs) from the Northern Bleached Softwood Kraft (NBSK) pulp, fabrication by hand lay-up technique and characterization of fabricated epoxy nanocomposites at different filler loadings (0.5%, 0.75%, 1% by wt.). The effect of CNFs loading on mechanical (tensile, impact and flexural), morphological (scanning electron microscope and transmission electron microscope) and structural (XRD and FTIR) properties of epoxy composites were investigated. FTIR analysis confirms the introduction of CNFs into the epoxy matrix while no considerable change in the crystallinity and diffraction peaks of epoxy composites were observed by the XRD patterns. Additions of CNFs considerably enhance the mechanical properties of epoxy composites but a remarkable improvement is observed for 0.75% CNFs as compared to the rest epoxy nanocomposites. In addition, the electron micrographs revealed the perfect distribution and dispersion of CNFs in the epoxy matrix for the 0.75% CNFs/epoxy nanocomposites, while the existence of voids and agglomerations were observed beyond 0.75% CNFs filler loadings. Overall results analysis clearly revealed that the 0.75% CNFs filler loading is best and effective with respect to rest to enhance the mechanical and structural properties of the epoxy composites. PMID- 28082224 TI - Color reduction of sulfonated eucalyptus kraft lignin. AB - Several eucalyptus lignins named as HSL, SML and BSL were prepared by high temperature sulfonation, sulfomethylation, butane sultone sulfonation respectively. The color properties of samples were investigated. Under optimized conditions the sulfonic group (SO3H) content of HSL, SML and BSL reached 1.52, 1.60 and 1.58mmol/g, respectively. Samples were characterized by UV-vis spectroscopy, FTIR spectroscopy, 1H NMR spectroscopy, GPC and brightness test, respectively. The results revealed that BSL performed a higher molecular weight and lighter color due to the phenolic hydroxyl blocking by 1,4-butane sultone (1,4-BS). The color reduction of sodium borohydride treated BSL (labeled as SBSL) was further enhanced and the brightness value was improved by 76.1% compared with the darkest HSL. SBSL process was much better than HSL and SML process. Hydroxyl blocking effect of 1,4-BS and reducibility of sodium borohydride played important roles in the color reduction of sulfonated eucalyptus kraft lignin. PMID- 28082225 TI - Rigidifying flexible sites: An approach to improve stability of chondroitinase ABC I. AB - The stability of chondroitin ABC lyase I (cABC I) at physiological temperature is one of the current obstacles to its clinical application. In this study, we used a protein engineering approach; rigidify flexible sites, to improve stability of cABC I. B-factor analysis showed a flexible loop at the N-terminal domain of cABC I which may be involved in its thermal instability and five residues in this region were replaced with proline. Thermal inactivation and thermal denaturation analysis revealed that Glu138Pro mutation increased half-life and Tm of enzyme, respectively. The Km values of mutated enzymes were slightly increased compared to the wild type enzyme. The results of limited proteolysis indicated that Glu138Pro mutant was more resistant against trypsinolysis and this variant was less quenched in both acrylamide and KI quenching experiments. Moreover, intrinsic fluorescence intensity of Glu138Pro variant was increased and its ANS fluorescence intensity was decreased, whereas no considerable changes were observed in the far-UV CD spectra. The structural analyses indicated compactness of structure of Glu138Pro enzyme which can be related to moderately enhanced stability of this mutant. This study demonstrated that rigidifying flexible residues can be considered as a possible approach to increase the stability of the protein. PMID- 28082226 TI - Activation of phenoloxidase activity by humoral lectin in hemocytes of freshwater crab Paratelphusa jacquemontii. AB - The lectin, Pjlec isolated from the hemolymph of the freshwater crab Paratelphusa jacquemontii hemagglutinated (HA) with mice, rabbit and rat erythrocytes. However, the lectin failed to agglutinate neraminidase treated asialylated erythrocytes showing its sialic acid specificity. The poyacyrlamide gel electrophoresis of lectin yielded 310kDa proteins, on sodium sulphate dodecyl (SDS) gel appeared as a tetramer with subunits of 76kDa. The observation of in vitro phagocytosis in granular hemocytes of lectin opsonized rabbit erythrocyte by Transmission electron microscopy (TEM) showed the release of lytic vesicles by exocytosis prior to engulfment. The Pjlec lectin also showed an ability to oxidize L-3, 4 dihydroxyphenylalanine (L-DOPA) and in hemocyte lysate preparation (HLS) was enhanced on reduction with SDS and on proteolytic cleavage with trypsin. The lectin appeared to have a regulatory role in activation of enzyme activity associated with phagocytosis and melanin formation. PMID- 28082227 TI - Sulfation of fucogalactan from Agaricus bisporus: Different patterns in the chemical structure and their effects on anticoagulant activity. AB - A fucogalactan from Agaricus bisporus was sulfated by two methodologies based on an optimized sulfation method. The direct action of chlorosulfonic acid and SO3 pyridine complex over the sulfation reaction and its effects on anticoagulant activity were evaluated. The products of chemical sulfations were two sulfated fucogalactans named E100 and ESL respectively. Clotting assays (APTT, PT and TT) showed that both sulfated polysaccharides have anticoagulant activity, and that ESL was more potent compared to E100. The FXa, T and FXIIa activities in the presence of the sulfated polysaccharides were determined. The better anticoagulant activity of ESL could be related to anti-FXIIa activity and also probably to its higher bioavailability. The HPSEC analysis showed similar Mw of 1.08*104gmol-1 and 1.00*104gmol-1 for E100 and ESL respectively. NMR and methylation analyses indicated a heterogeneous sulfation pattern for E100, whereas ESL showed conserved unsulfated (1->6)-linked alpha-d-Galp residues in the main-chain and a more homogeneous sulfation pattern. The DS values of ESL and E100 were 1.0 and 2.8 respectively, indicating that the sulfation pattern is more important for the anticoagulant activity than the amount of sulfate. PMID- 28082228 TI - Multifunctional nanocomposites of chitosan, silver nanoparticles, copper nanoparticles and carbon nanotubes for water treatment: Antimicrobial characteristics. AB - Multifunctional nanocomposites of chitosan with silver nanoparticles, copper nanoparticles and carbon nanotubes either as bi- or multifunctional nanocomposites were prepared. Change in the overall morphology of the prepared nanocomposites was observed; carbon nanotubes, Ag NPs and Cu NPs are distributed homogeneously inside the polymer matrix individually in the case of the bi nanocomposites while a combination of different dimensional shapes; spherical NPs and nanotubes was observed in the multifunctional nanocomposite. Multifunctional nanocomposites has a higher antimicrobial activity, in relative short contact times, against both Gram negative and Gram positive bacteria; E. coli, Staphylococcus aureus; respectively in addition to the fungal strain; Aspergillus flavus isolated from local wastewater sample. The nanocomposites are highly differentiable at the low contact time and low concentration; 1% concentration of the multifunctional nanocomposite is very effective against the tested microbes at contact time of only 10min. PMID- 28082229 TI - Impact of Fusarium mycotoxins on hepatic and intestinal mRNA expression of cytochrome P450 enzymes and drug transporters, and on the pharmacokinetics of oral enrofloxacin in broiler chickens. AB - Cytochrome P450 (CYP450) drug biotransformation enzymes and multidrug resistance (MDR) proteins may influence drug disposition processes. The first part of the study aimed to evaluate the effect of mycotoxins deoxynivalenol (DON) and/or fumonisins (FBs), at contamination levels approaching European Union guidance levels, on intestinal and hepatic CYP450 enzymes and MDR proteins gene expression in broiler chickens. mRNA expression of genes encoding CYP450 enzymes (CYP3A37, CYP1A4 and CYP1A5) and drug transporters (MDR1/ABCB1 and MRP2/ABCC2) was determined using qRT-PCR. A significant up-regulation of CYP1A4 (P = 0.037) and MDR1 (P = 0.036) was observed in the jejunum of chickens fed a diet contaminated with FBs. The second part of this study aimed to investigate the impact of feeding a FBs contaminated diet on the oral absorption of enrofloxacin (10 mg/kg BW), a MDR1 substrate. A significant (P = 0.045), however small, decreased area under the plasma concentration-time curve (AUC0-48 h, mean +/- SD) was observed for enrofloxacin in chickens fed the FBs contaminated diet compared to the control group, 16.28 +/- 1.82 h MUg/mL versus 18.27 +/- 1.79 h MUg/mL. These findings suggest that concurrent administration of drugs with FBs contaminated feed might alter the pharmacokinetic characteristics of CYP1A4 substrate drugs and MDR1 substrates, such as enrofloxacin. PMID- 28082230 TI - Toxicity of hemimethyl-substituted cucurbit[7]uril. AB - Hemimethyl-substituted cucurbit[7]uril (HMeCB[7]), a derivative of cucurbit[7]uril (CB[7]) with nearly identical host-guest complexation properties to that of the parent, has significant potential in biomedical sciences due to its superior solubility in water. Its toxicity profile has been investigated in this work, including its developmental and organ-specific toxicities, with both in vivo zebrafish models and a relevant in vitro cellular model. These results demonstrated that HMeCB[7] has negligible developmental toxicity at concentrations up to 3.2 mM and very moderate cardiotoxicity and hepatotoxicity at concentrations of >=0.8 mM, and is thus generally less toxic than the parent CB[7]. Our results suggest that HMeCB[7] may be a promising candidate of excipient in medicinal and pharmaceutical research fields. PMID- 28082231 TI - Structure elucidation, DNA binding specificity and antiproliferative proficiency of isolated compounds from Garcinia nervosa. AB - Garcinia nervosa is an abundant source of bioactive phytochemicals. The present paper deals with the isolation of a novel isoflavone 5,7-dihydroxy-3-(3'-hydroxy 4',5'-dimethoxyphenyl)-6-methoxy-4H-chromen-4-one (1) along with a known compound DL-Allantoin (2) from the ethanolic extract of the leaves of Garcinia nervosa (Family: Guttiferae). Their structures were elucidated on the basis of chemical and physical evidences viz. elemental analysis, UV, FT-IR, 1H NMR, 13C NMR and mass spectral analysis. Single-crystal X-ray analysis was further used for the authentication of structure of both compounds (1 and 2). Interaction studies of compound (1) and (2) with ctDNA were studied by UV-Visible spectroscopy, fluorescence, KI quenching studies, competitive displacement assay and circular dichroism studies, which showed groove binding interaction (non-intercalation) of both the compounds 1 and 2 with ctDNA. However, compound 1 (K=3.9*104M-1) shows higher binding affinity to the ctDNA than compound 2 (K=1.44*104M-1). The molecular modeling results also illustrated that compound 1 strongly binds to groove of DNA by relative binding energy of docked structure -6.82kcal/mol. In addition the antiproliferative activity also showed high potential of compound 1 against MCF-7 and MDA-MB 231 cell line with IC50 value 8.44+/-3.5MUM and 6.94+/ 2.6MUM, respectively. PMID- 28082232 TI - Ferroptosis and cell death mechanisms in Parkinson's disease. AB - Symptoms of Parkinson's disease arise due to neuronal loss in multiple brain regions, especially dopaminergic neurons in the substantia nigra pars compacta. Current therapies aim to restore dopamine levels in the brain, but while these provide symptomatic benefit, they do not prevent ongoing neurodegeneration. Preventing neuronal death is a major strategy for disease-modifying therapies; however, while many pathogenic factors have been identified, it is currently unknown how neurons die in the disease. Ferroptosis, a recently identified iron dependent cell death pathway, involves several molecular events that have previously been implicated in PD. This review will discuss ferroptosis and other cell death pathways implicated in PD neurodegeneration, with a focus on the potential to therapeutically target these pathways to slow the progression of this disease. PMID- 28082233 TI - Comparison of multiplex platforms for cytokine assessments and their potential use for biomarker profiling in multiple sclerosis. AB - BACKGROUND: The levels of pro and anti-inflammatory cytokines can be altered in different autoimmune pathologies, such as multiple sclerosis (MS). It is likely that cytokines in bodily fluids can provide a good reflection of ongoing disease patho-physiology. In this study we aimed to validate multiplex cytokine platforms and evaluate whether these cytokines are differentially expressed in MS. METHODS: Assay validation for simultaneous quantification of IL-1beta, IL-6, IL-8 and TNF alpha in serum and CSF were performed using both the Luminex-xMAP (Luminex) and Meso Scale Discovery (MSD) platforms. Next, the relation of the pro-inflammatory cytokine 4-plex with disease progression, symptoms and subtypes was studied in paired serum and CSF of MS patients (n=56), and compared with healthy controls (n=203), with the use of the MSD-platform. RESULTS: The MSD-platform showed overall better assay characteristics such as, sensitivity, recovery and linearity compared to the Luminex for the 4-plex cytokines in CSF and serum. IL-6, IL-8 and TNF-alpha (p<0.001) levels were significantly increased in MS serum compared to healthy controls. Moreover, serum IL-1beta levels correlated with expanded disability status scale (EDSS) scores (r=-0.34, p<0.05). Additionally, IL-6 and IL-8 CSF levels were both significantly decreased in MS patients compared to non inflammatory neurological disease controls. Noteworthy, higher IL-8 CSF levels than IL-8 serum levels were observed for MS patients, indicating intrathecal activation of macrophages in MS. CONCLUSION: We have demonstrated that the pro inflammatory 4-plex kit of the MSD-platform shows better assay characteristics in comparison with Luminex kit for quantification of these cytokines in serum and CSF. Overall, the increased levels of IL-6, IL-8 and TNF-alpha in serum of MS patients compared to healthy controls, support the use of multiple cytokines for future MS biomarker and disease progression research. PMID- 28082234 TI - Increased systemic and epidermal levels of IL-17A and IL-1beta promotes progression of non-segmental vitiligo. AB - BACKGROUND: Non-segmental vitiligo (NSV) results from autoimmune destruction of melanocytes. The altered levels of various cytokines have been proposed in the pathogenesis of vitiligo. However, the exact immune mechanisms have not yet been fully elucidated. OBJECTIVES: To investigate the role of epidermal and systemic cytokines in active and stable NSV patients. METHODS: Serum levels of inflammatory cytokines were checked in 42 active and 30 stable NSV patients with 30 controls. The lesional, perilesional and normal skin sections were subjected to H&E staining. The mRNA expression of inflammatory cytokines and their respective receptors were assessed by quantitative PCR in lesional skin of both active and stable NSV skin. The MITF and IL-17A were immunolocalized in lesional, perilesional and normal skin tissue. RESULTS: Significant increase in the expression of inflammatory cytokines, IL-17A, IL-1beta and TGF-beta was observed in active patients, whereas no change was observed in stable patients. A marked reduction in epidermal thickness was observed in lesional skin sections. Significant increase in IL-17A and significant decrease in microphthalmia associated transcription factor (MITF) expression was observed in lesional and perilesional skin sections. Moreover, qPCR analysis showed significant alterations in the mRNA levels of IL-17A, IL-1beta, IFN-gamma, TGF-beta and their respective receptors in active and stable vitiligo patient samples. CONCLUSION: Increased levels of IL-17A and IL-1beta cytokines and decreased expression of MITF suggested a possible role of these cytokines in dysregulation of melanocytic activity in the lesional skin and hence might be responsible for the progression of active vitiligo. PMID- 28082236 TI - Adenosine generated by ectonucleotidases modulates the host immune system during visceral leishmaniasis. AB - Adenosine, an endogenous purine nucleoside is one such extracellular signaling molecule whose role in the regulation of anti-inflammatory cytokines and immune pathogenicity in visceral leishmaniasis is indeterminate. Here, we have evaluated the adenosine in the plasma of 20 visceral leishmaniasis (VL) patients during active disease and after successful treatment. We observed the elevated plasma adenosine during active VL disease (26.73+/-1.95MUM) and the level subsides as the treatment progresses and falls to the normal level after successful treatment (4.32+/-0.45MUM). We demonstrated a direct correlation between changes in the plasma adenosine level and the Th1/Th2 balance in VL patients and it was corroborated with in vitro experiment. Further, we delineated the molecular mechanism involved in the elevation of plasma adenosine during visceral leishmaniasis. Our results reveal that the elevated plasma adenosine level associated with pathogenicity and plays a critical role in skewing immune response from Th1 to Th2 type to influence the outcome of the disease. PMID- 28082235 TI - From stable disease to acute-on-chronic liver failure: Circulating cytokines are related to prognosis in different stages of cirrhosis. AB - INTRODUCTION: Although both pro- and anti-inflammatory circulating cytokines are known to be elevated in liver cirrhosis, its clinical significance is not completely recognized. Our aim was to evaluate the prognostic significance of circulating cytokines interleukin (IL)-6, IL-17 and IL-10 in different stages of cirrhosis. METHODS: This prospective study included two cohorts: (1) stable cirrhosis attended in the Outpatient Clinic (n=118), and (2) subjects hospitalized for acute decompensation (AD) (n=130). Thirty healthy subjects served as control group. RESULTS: Patients with cirrhosis exhibited higher levels of cytokines as compared to controls. In stable cirrhosis, during a median follow up of 17months, liver-related events occurred in 26 patients. Higher IL-10 levels and Child-Pugh B/C were independently associated with reduced event-free survival. In AD cohort, death after 90days of follow-up occurred in 39 patients and was independently associated with ascites, higher IL-6 and model for end stage liver disease. IL-6 levels also showed higher AUROC than CRP for predicting bacterial infection in the AD cohort (0.831+/-0.043vs. 0.763+/-0.048, respectively). IL-17 decreased at third day of hospitalization only in patients who progressed to death. Higher IL-6 levels were observed in acute-on-chronic liver failure (ACLF) patients even in the absence of bacterial infection whereas IL-10 was higher only in subjects with infection-related ACLF. Higher IL-10 and IL-17 levels were associated with progression to death in ACLF. CONCLUSIONS: The pattern of immune response seems to vary according to the phase of cirrhosis and is related to prognosis, from stable disease to ACLF. PMID- 28082237 TI - Follicular fluid cytokine composition and oocyte quality of polycystic ovary syndrome patients with metabolic syndrome undergoing in vitro fertilization. AB - PURPOSE: To provide insights into the correlation among lipid metabolism, cytokine profiles in the follicular fluid (FF) and embryo quality of women with Polycystic Ovary Syndrome (PCOS) with metabolic syndrome (MS). METHODS: Ninety women undergoing in vitro fertilization (IVF) treatment were recruited, including 60 PCOS patients (PCOS non MS and PCOS MS) and 30 age-matched controls. Individual FF samples were analyzed using the cytometric multiplex immunoassay. RESULTS: In the FF, the PCOS MS group was associated with higher, total cholesterol (TC), triglyceride (TG) and lower high-density lipoprotein (HDL) concentrations compared with that in the control group (P<0.05). The FF tumor necrosis factor-alpha (TNF-alpha) level in the PCOS MS group was 3.89+/ 1.18ng/mL, which was significantly higher compared with the control (2.94+/ 1.02ng/mL) and PCOS non-MS groups (3.05+/-1.21ng/mL) (P=0.002), while the granulocyte colony-stimulating factor (G-CSF) level in the PCOS MS group (4.18+/ 1.33ng/mL) was lower compared with the control (5.61+/-1.82ng/mL) and PCOS non-MS groups (5.32+/-1.91ng/mL) (P=0.004). The FF G-CSF showed a trend toward negative relationship with TG and TC; TNF-alpha concentration was positively associated with TG. The percentage of top-quality embryo decreased in the PCOS MS group than in the other two groups (20% vs. 38.4% and 34.6%). CONCLUSIONS: In conclusion, there was an elevated lipolysis condition within the FF of PCOS MS patients and the TNF-alpha and G-CSF levels in FF were associated with top-quality embryo percentage. TNF-alpha and G-CSF may be the key cytokines involved in the mechanism of decreased embryo development potential in PCOS MS patients. PMID- 28082238 TI - Electrochemiluminescent chemodosimeter based on iridium(III) complex for point-of care detection of homocysteine levels. AB - Elevated levels of plasma homocysteine (Hcy) are an independent risk factor for cardiovascular disease. Although a routine, rapid, and simple determination of Hcy levels is highly desired, the existing methods are practically limited because of complicated sample preparation and bulky instrumentation. Herein, we report a chemodosimetric approach for one-step analysis of Hcy levels based on the electrochemiluminescence (ECL). A rationally designed cyclometalated iridium(III) complex possessing a phenylisoquinoline main ligand underwent a selective ring-formation reaction with Hcy to generate a binding adduct, which enabled producing highly luminescent excited states, and yielded strong ECL signals on the surface of electrode without any use of enzymes or antibodies. The level of Hcy was successfully monitored by the ECL increment with a linear correlation between 0 and 40uM in 99.9% aqueous media. The approach required neither sample preparation nor bulky instrument, suggesting the point-of-care testing of Hcy levels, and is potentially useful for routine, cost-effective, and precautionary diagnosis of various cardiovascular diseases. PMID- 28082239 TI - Recent advances in nanomaterial-based biosensors for antibiotics detection. AB - Antibiotics are able to be accumulated in human body by food chain and may induce severe influence to human health and safety. Hence, the development of sensitive and simple methods for rapid evaluation of antibiotic levels is highly desirable. Nanomaterials with excellent electronic, optical, mechanical, and thermal properties have been recognized as one of the most promising materials for opening new gates in the development of next-generation biosensors. This review highlights the current advances in the nanomaterial-based biosensors for antibiotics detection. Different kinds of nanomaterials including carbon nanomaterials, metal nanomaterials, magnetic nanoparticles, up-conversion nanoparticles, and quantum dots have been applied to the construction of biosensors with two main signal-transducing mechanisms, i.e. optical and electrochemical. Furthermore, the current challenges and future prospects in this field are also included to provide an overview for future research directions. PMID- 28082240 TI - Non-invasive, in vitro analysis of islet insulin production enabled by an optical porous silicon biosensor. AB - A label-free porous silicon (pSi) based, optical biosensor, using both an antibody and aptamer bioreceptor motif has been developed for the detection of insulin. Two parallel biosensors were designed and optimised independently, based on each bioreceptor. Both bioreceptors were covalently attached to a thermally hydrosilylated pSi surface though amide coupling, with unreacted surface area rendered stable and low fouling by incorporation of PEG moieties. The insulin detection ability of each biosensor was determined using interferometric reflectance spectroscopy, using a range of different media both with and without serum. Sensing performance was compared in terms of response value, response time and limit of detection (LOD) for each platform. In order to demonstrate the capability of the best performing biosensor to detect insulin from real samples, an in vitro investigation with the aptamer-modified surface was performed. This biosensor was exposed to buffer conditioned by glucose-stimulated human islets, with the result showing a positive response and a high degree of selectivity towards insulin capture. The obtained results correlated well with the ELISA used in the clinic for assaying glucose-stimulated insulin release from donor islets. We anticipate that this type of sensor can be applied as a rapid point-of-use biosensor to assess the quality of donor islets in terms of their insulin production efficiency, prior to transplantation. PMID- 28082241 TI - Bacterial community dynamics in a biodenitrification reactor packed with polylactic acid/poly (3-hydroxybutyrate-co-3-hydroxyvalerate) blend as the carbon source and biofilm carrier. AB - While heterotrophic denitrification has been widely used for treating such nitrogen-rich wastewater, it requires the use of additional carbon sources. With fluctuations in the nitrate concentration in the influent, controlling the C/N ratio to avoid carbon breakthrough becomes difficult. To overcome this obstacle, solid-phase denitrification (SPD) using biodegradable polymers has been used, where denitrification and carbon source biodegradation depend on microorganisms growing within the reactor. However, the microbial community dynamics in continuous-flow SPD reactors have not been fully elucidated yet. Here, we aimed to study bacterial community dynamics in a biodenitrification reactor packed with a polylactic acid/poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PLA/PHBV) blend as the carbon source and biofilm carrier. A lab-scale denitrifying reactor filled with a PLA/PHBV blend was used. With 85 mg/L of influent NO3-N concentration and a hydraulic retention time (HRT) of 2.5 h, more than 92% of the nitrate was removed. The bacterial community of inoculated activated sludge had the highest species richness in all samples. Bacterial species diversity in the reactor first decreased and then increased to a stable level. Diaphorobacter species were predominant in the reactor after day 24. In total, 178 clones were retrieved from the 16S rRNA gene clone library constructed from the biofilm samples in the reactor at 62 days of operation, and 80.9% of the clones were affiliated with Betaproteobacteria. Of these, 97.2% were classified into phylotypes corresponding to Diaphorobacter nitroreducens strain NA10B with 99% sequence similarity. Diaphorobacter, Rhizobium, Acidovorax, Rubrivivax, Azospira, Thermomonas, and Acidaminobacter constituted the biofilm microflora in the stably running reactor. PMID- 28082242 TI - New guidelines, new recommendations! But what is really new? A pragmatic interpretation of the 2016 European guidelines for the management of chronic heart failure. PMID- 28082243 TI - Clinical outcomes in myocardial infarction and multivessel disease after a cardiac rehabilitation programme: Partial versus complete revascularization. AB - BACKGROUND: Current guideline recommendations encourage culprit vessel only percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease. However, recent studies have shown a better clinical outcome in patients who receive multivessel PCI. AIM: To measure and compare clinical outcomes between partial revascularization (PR) versus complete revascularization (CR) in patients with STEMI and multivessel disease who underwent a cardiac rehabilitation programme. METHODS: We retrospectively reviewed the medical records of 282 patients with STEMI and multivessel disease who received PR or CR and were subsequently enrolled in a cardiac rehabilitation programme between July 2006 and November 2013 at La Paz University Hospital. The incidences of cardiovascular events, new PCI, hospital admissions for cardiovascular reasons and mortality were compared between the PR and CR groups. RESULTS: Overall, 143 patients received PR and 139 received CR. Baseline characteristics were similar in both groups, except for mean age (59.3 vs. 56.7 years; P=0.02), diabetes mellitus prevalence (34.3% vs. 20.1%; P=0.01) and number of arteries with stenosis (2.6 vs. 2.3; P=0.001). During the mean follow-up of 48.0+/-25.9 months, a cardiovascular event occurred in 23 (16.1%) PR patients and 20 (14.4%) CR patients, with no statistically significant differences in the early (hazard ratio: 0.61, 95% confidence interval: 0.19-1.89) or late (hazard ratio: 1.40, 95% confidence interval: 0.62-3.14) follow-up periods. Cox regression, adjusted for age, sex, presence of diabetes mellitus and number of affected coronary vessels, showed no difference in new cardiovascular event risk. CONCLUSIONS: There were no statistical differences in clinical outcomes between PR and CR among patients who received cardiac rehabilitation. PMID- 28082244 TI - Isolation of Clostridium perfringens type A from wild bharals (Pseudois nayaur) following sudden death in Tibet, China. AB - Dozens of wild bharals died suddenly in Tibet. Necropsy showed severe congestion and hemorrhage in multiple organs, with large numbers of Gram-positive bacilli. Strains of Clostridium perfringens type A were isolated from the different organs and the intestinal contents. The other possible pathogens were ruled out by PCR. PMID- 28082245 TI - Corticosterone administration after a single-trial contextual fear conditioning does not influence the strength and specificity of recent and remote memory in rats. AB - It is well established that corticosterone (CORT) enhances memory consolidation of emotionally arousing experiences. Despite emotional memories being usually referred to as well remembered for long periods, there are no studies that have investigated the effects of CORT in modulating the duration and specificity of memory. In the present study, we trained Wistar rats in a single-trial contextual fear conditioning protocol and injected CORT (0.3, 1.0 or 3.0mg/kg), immediately after training, to investigate its effects on memory consolidation. Rats were tested 2 and 29days after the training session or only 29days after training to assess recent or remote memory. Our results show that animals tested for recent memory discriminated the training context from a novel one, while those tested only for remote memory generalized the fear response to both contexts. Animals tested for remote memory after being tested for recent memory were able to discriminate both contexts. These results support the literature regarding memory specificity and duration. However, CORT treatment, even at the dose of 1.0mg/kg that effectively enhanced the plasmatic hormone levels, did not affect the strength or the specificity of memory in either recent or remote memory tests. We hypothesize that the lack of effect of CORT treatment could be due to the low arousing training experience of the single-trial protocol which, despite being sufficient to induce significant recent and remote memory consolidation, may not be sufficient to allow the memory-enhancing effect of CORT. PMID- 28082246 TI - Prepubertal ovariectomy modulates paced mating behavior but not sexual preference or conditioned place preference for mating in female rats. AB - The present study investigated whether the presence or absence of peripubertal ovarian hormones affects sexual preference and conditioned place preference for paced mating in adult female rats primed with 10MUg estradiol benzoate and 1mg progesterone. Ovariectomy (OVX) occurred either before or after pubertal development, and 4weeks later rats began a series of behavioral tests. Rats with ovaries removed before the pubertal timeframe (Prepubertal OVX) were more active, more likely to withdrawal from the male compartment, and did not discriminate between mounts and intromissions during paced mating relative to rats with ovaries during puberty (Adult OVX). Both Adult OVX and Prepubertal OVX rats showed a higher preference for the male when hormone primed vs. oil treated and a conditioned place preference for paced mating behavior. The results of the present study demonstrate that some, but not all, aspects of female sexual behavior require ovarian hormones during puberty. PMID- 28082247 TI - The impact of psychological stress on cardiovascular function and health. PMID- 28082248 TI - Pain modulation as a function of hypnotizability: Diffuse noxious inhibitory control induced by cold pressor test vs explicit suggestions of analgesia. AB - The aim of the present study was to compare the effects of explicit suggestions of analgesia and of the activation of the Diffuse Noxious Inhibitory Control (DNIC) by cold pressor test on pain perception and heart rate in healthy participants with high (highs, N=18), low (lows, N=18) and intermediate scores of hypnotizability (mediums, N=15) out of hypnosis. Pain reports and the stimulus locked heart rate changes induced by electrical nociceptive stimulation of the left hand were studied in the absence of concomitant stimuli (Control), during suggestions of analgesia (SUGG, glove analgesia) and during cold pressor test used as a conditioning stimulus to the right hand (DNIC, water temperature=10-12 degrees C) in the REAL session. Participants were submitted also to a SHAM session in which the DNIC water temperature was 30 degrees C and the suggestions for analgesia were substituted with weather forecast information. Both suggestions and DNIC reduced pain significantly in all subjects; however, the percentage of reduction was significantly larger in highs (pain intensity=55% of the control condition) than in mediums (70%) and lows (80%) independently of the REAL/SHAM session and of the specific pain manipulation. Heart rate was not modulated consistently with pain experience. Findings indicate that both suggestions and DNIC influence pain experience as a function of hypnotizability and suggest that both sensory and cognitive mechanisms co-operate in DNIC induced analgesia. PMID- 28082249 TI - Mechanical and chemical properties of composite materials made of dredged sediments in a fly-ash based geopolymer. AB - Dredging activity in harbours and channels produces huge quantities of sediments, generally considered as waste soil (WS) to be disposed: the management of such sediments is a great environmental problem for many countries worldwide. Among the recycling possibilities, the use of dredged sediments for the manufacture of geopolymer-based materials seems to be an interesting alternative to disposal, due to their low cost and easy availability. In order to analyse the possibility to use these geopolymer materials as building materials - for instance as precast construction elements in maritime projects - a multi-disciplinary research activity has been developed at the Federico II University of Napoli (Italy). Some experimental tests have been carried out on different geopolymeric specimens made by mixing sediments from Napoli 'harbour and industrial fly ashes produced by a power plant in the South of Italy. A siliceous sand was used for comparison as an inert reference material. Chemical, morphological and mechanical properties of different specimens have been studied by X-ray diffraction, Scanning Electron Microscopy (SEM), Fourier transformed infrared spectroscopy (FTIR) and finally unconfined compression tests. The experimental results highlight that the use of dredged sediments in combination with fly ash can lead to geopolymeric matrices with interesting mechanical performances. Some differences in the microstructure of the geocomposite built with the siliceous sand or the dredged materials were found. In terms of environmental impacts, on the basis of standard leaching tests and according to Italian thresholds, the adopted dredged mixtures satisfy the prescribed limit for inert or non hazardous waste. PMID- 28082250 TI - Loss of ecosystem services due to chronic pollution of forests and surface waters in the Adirondack region (USA). AB - Sustaining recent progress in mitigating acid pollution could require lower emissions caps that will give rise to real or perceived tradeoffs between healthy ecosystems and inexpensive energy. Because most impacts of acid rain affect ecosystem functions that are poorly understood by policy-makers and the public, an ecosystem services (ES) framework can help to measure how pollution affects human well-being. Focused on the Adirondack region (USA), a global 'hot-spot' of acid pollution, we measured how the chronic acidification of the region's forests, lakes, and streams has affected the potential economic and cultural benefits they provide to society. We estimated that acid-impaired hardwood forests provide roughly half of the potential benefits of forests on moderate to well-buffered soils - an estimated loss of ~ $10,000 ha-1 in net present value of wood products, maple syrup, carbon sequestration, and visual quality. Acidic deposition has had only nominal impact - relative to the effects of surficial geology and till depth - on the capacity of Adirondack lakes and streams to provide water suitable for drinking. However, as pH declines in lakes, the estimated value of recreational fishing decreases significantly due to loss of desirable fish such as trout. Hatchery stocking programs have partially offset the pollution-mediated losses of fishery value, most effectively in the pH range 4.8-5.5, but are costly and limited in scope. Although any estimates of the monetary 'damages' of acid rain have significant uncertainties, our findings highlight some of the more tangible economic and cultural benefits of pollution mitigation efforts, which continue to face litigation and political opposition. PMID- 28082251 TI - Upstream solutions to coral reef conservation: The payoffs of smart and cooperative decision-making. AB - Land-based source pollutants (LBSP) actively threaten coral reef ecosystems globally. To achieve the greatest conservation outcome at the lowest cost, managers could benefit from appropriate tools that evaluate the benefits (in terms of LBSP reduction) and costs of implementing alternative land management strategies. Here we use a spatially explicit predictive model (InVEST-SDR) that quantifies change in sediment reaching the coast for evaluating the costs and benefits of alternative threat-abatement scenarios. We specifically use the model to examine trade-offs among possible agricultural road repair management actions (water bars to divert runoff and gravel to protect the road surface) across the landscape in West Maui, Hawaii, USA. We investigated changes in sediment delivery to coasts and costs incurred from management decision-making that is (1) cooperative or independent among landowners, and focused on (2) minimizing costs, reducing sediment, or both. The results illuminate which management scenarios most effectively minimize sediment while also minimizing the cost of mitigation efforts. We find targeting specific "hotspots" within all individual parcels is more cost-effective than targeting all road segments. The best outcomes are achieved when landowners cooperate and target cost-effective road repairs, however, a cooperative strategy can be counter-productive in some instances when cost-effectiveness is ignored. Simple models, such as the one developed here, have the potential to help managers make better choices about how to use limited resources. PMID- 28082252 TI - Percutaneous management of bile duct stones in children: results of 12 cases. AB - PURPOSE: We aimed to evaluate the effectiveness of percutaneous transhepatic removal of bile duct stones in children. METHODS: The study included 12 pediatric patients (4 males, 8 females; age range, 1-16 years; mean age, 6.6 years) who underwent percutaneous transhepatic removal of bile duct stones between September 2007 and December 2015. Demographic data, patient symptoms, indications for interventions, technical and clinical outcomes of the procedure, and complications were retrospectively evaluated. RESULTS: Of 12 children, five children with cholelithiasis underwent cholecystectomy subsequently. The overall technical and clinical success rate was 100%. One patient had cholangitis as a complication during the follow-up and was treated medically. CONCLUSION: Percutaneous transhepatic removal of bile duct stones is a safe and effective method for the treatment of children with biliary stone disease. It is a feasible alternative when the endoscopic procedure is unavailable or fails. PMID- 28082253 TI - Optimizing care for the obese patient in interventional radiology. AB - With the rising epidemic of obesity, interventional radiologists are treating increasing numbers of obese patients, as comorbidities associated with obesity preclude more invasive treatments. These patients are at heightened risk of vascular and oncologic disease, both of which often require interventional radiology care. Obese patients pose unique challenges in imaging, technical feasibility, and periprocedural monitoring. This review describes the technical and clinical challenges posed by this population, with proposed methods to mitigate these challenges and optimize care. PMID- 28082254 TI - Proton pump inhibitor use for 12 months is not associated with changes in serum magnesium levels: a prospective open label comparative study. AB - BACKGROUND/AIMS: Proton pump inhibitors (PPIs) are a widely used class of drugs because of a generally acceptable safety profile. Among recently raised safety issues of the long-term use of PPIs is the increased risk of developing hypomagnesemia. As there have been very few prospective studies measuring serum magnesium levels before and after PPI therapy, we aimed to prospectively assess the potential association between PPI therapy for 12 months and the risk of hypomagnesemia as well as the incidence of new-onset hypomagnesemia during the study. In addition, the association of PPI therapy with the risk of hypocalcemia was assessed. MATERIALS AND METHODS: The study included 250 patients with normal serum magnesium and total calcium levels, who underwent a long-term PPI treatment. Serum magnesium, total calcium, and parathormone (PTH) levels were measured at baseline and after 12 months. RESULTS: Of the 250 study participants, 209 completed 12 months of treatment and were included in the statistical analysis. The Wilcoxon signed rank test showed no statistically significant differences in serum magnesium levels between measurements at two different time points. However, there were statistically significant differences in serum total calcium and PTH levels in PPI users. CONCLUSION: Stable serum magnesium levels were demonstrated after 12 months and no association between PPI use and risk of hypomagnesemia was shown in the general population. Significant reductions of serum total calcium levels were demonstrated among PPI users; nevertheless, further research is required before recommending any serum calcium and PTH level monitoring in patients initiated on long-term PPI therapy. PMID- 28082255 TI - Pancreatic pseudocyst after measles, mumps, and rubella vaccination. PMID- 28082256 TI - Using Administrative Data to Ascertain True Cases of Muscular Dystrophy: Rare Disease Surveillance. AB - BACKGROUND: Administrative records from insurance and hospital discharge data sources are important public health tools to conduct passive surveillance of disease in populations. Identifying rare but catastrophic conditions is a challenge since approaches for maximizing valid case detection are not firmly established. OBJECTIVE: The purpose of our study was to explore a number of algorithms in which International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes and other administrative variables could be used to identify cases of muscular dystrophy (MD). METHODS: We used active surveillance to identify possible cases of MD in medical practices in neurology, genetics, and orthopedics in 5 urban South Carolina counties and to identify the cases that had diagnostic support (ie, true cases). We then developed an algorithm to identify cases based on a combination of ICD-9-CM codes and administrative variables from a public (Medicaid) and private insurer claims based system and a statewide hospital discharge dataset (passive surveillance). Cases of all types of MD and those with Duchenne or Becker MD (DBMD) that were common to both surveillance systems were examined to identify the most specific administrative variables for ascertainment of true cases. RESULTS: Passive statewide surveillance identified 3235 possible cases with MD in the state, and active surveillance identified 2057 possible cases in 5 actively surveilled counties that included 2 large metropolitan areas where many people seek medical care. There were 537 common cases found in both the active and passive systems, and 260 (48.4%) were confirmed by active surveillance to be true cases. Of the 260 confirmed cases, 70 (26.9%) were recorded as DBMD. CONCLUSIONS: Accuracy of finding a true case in a passive surveillance system was improved substantially when specific diagnosis codes, number of times a code was used, age of the patient, and specialty provider variables were used. PMID- 28082257 TI - Analyzing mHealth Engagement: Joint Models for Intensively Collected User Engagement Data. AB - BACKGROUND: Evaluating engagement with an intervention is a key component of understanding its efficacy. With an increasing interest in developing behavioral interventions in the mobile health (mHealth) space, appropriate methods for evaluating engagement in this context are necessary. Data collected to evaluate mHealth interventions are often collected much more frequently than those for clinic-based interventions. Additionally, missing data on engagement is closely linked to level of engagement resulting in the potential for informative missingness. Thus, models that can accommodate intensively collected data and can account for informative missingness are required for unbiased inference when analyzing engagement with an mHealth intervention. OBJECTIVE: The objectives of this paper are to discuss the utility of the joint modeling approach in the analysis of longitudinal engagement data in mHealth research and to illustrate the application of this approach using data from an mHealth intervention designed to support illness management among people with schizophrenia. METHODS: Engagement data from an evaluation of an mHealth intervention designed to support illness management among people with schizophrenia is analyzed. A joint model is applied to the longitudinal engagement outcome and time-to-dropout to allow unbiased inference on the engagement outcome. Results are compared to a naive model that does not account for the relationship between dropout and engagement. RESULTS: The joint model shows a strong relationship between engagement and reduced risk of dropout. Using the mHealth app 1 day more per week was associated with a 23% decreased risk of dropout (P<.001). The decline in engagement over time was steeper when the joint model was used in comparison with the naive model. CONCLUSIONS: Naive longitudinal models that do not account for informative missingness in mHealth data may produce biased results. Joint models provide a way to model intensively collected engagement outcomes while simultaneously accounting for the relationship between engagement and missing data in mHealth intervention research. PMID- 28082258 TI - EEPD1 Is a Novel LXR Target Gene in Macrophages Which Regulates ABCA1 Abundance and Cholesterol Efflux. AB - OBJECTIVE: The sterol-responsive nuclear receptors, liver X receptors alpha (LXRalpha, NR1H3) and beta (LXRbeta, NR1H2), are key determinants of cellular cholesterol homeostasis. LXRs are activated under conditions of high cellular sterol load and induce expression of the cholesterol efflux transporters ABCA1 and ABCG1 to promote efflux of excess cellular cholesterol. However, the full set of genes that contribute to LXR-stimulated cholesterol efflux is unknown, and their identification is the objective of this study. APPROACH AND RESULTS: We systematically compared the global transcriptional response of macrophages to distinct classes of LXR ligands. This allowed us to identify both common and ligand-specific transcriptional responses in macrophages. Among these, we identified endonuclease-exonuclease-phosphatase family domain containing 1 (EEPD1/KIAA1706) as a direct transcriptional target of LXRs in human and murine macrophages. EEPD1 specifically localizes to the plasma membrane owing to the presence of a myristoylation site in its N terminus. Accordingly, the first 10 amino acids of EEPD1 are sufficient to confer plasma membrane localization in the context of a chimeric protein with GFP. Functionally, we report that silencing expression of EEPD1 blunts maximal LXR-stimulated Apo AI-dependent efflux and demonstrate that this is the result of reduced abundance of ABCA1 protein in human and murine macrophages. CONCLUSIONS: In this study, we identify EEPD1 as a novel LXR-regulated gene in macrophages and propose that it promotes cellular cholesterol efflux by controlling cellular levels and activity of ABCA1. PMID- 28082259 TI - Identification of Genetic Variants Linking Protein C and Lipoprotein Metabolism: The ARIC Study (Atherosclerosis Risk in Communities). AB - OBJECTIVE: Previous studies have identified common genetic variants in 4 chromosomal regions that together account for 14% to 15% of the variance in circulating levels of protein C. To further characterize the genetic architecture of protein C, we obtained denser coverage at some loci, extended investigation of protein C to low-frequency and rare variants, and searched for new associations in genes known to influence protein C. APPROACH AND RESULTS: Genetic associations with protein C antigen level were evaluated in <=10 778 European and 3190 black participants aged 45 to 64 years. Analyses included >26 million autosomal variants available after imputation to the 1000 Genomes reference panel along with additional low-frequency and rare variants directly genotyped using the Illumina ITMAT-Broad-CARe chip and Illumina HumanExome BeadChip. Genome-wide significant associations (P<5*10-8) were found for common variants in the GCKR, PROC, BAZ1B, and PROCR-EDEM2 regions in whites and PROC and PROCR-EDEM2 regions in blacks, confirming earlier findings. In a novel finding, the low-density lipoprotein cholesterol-lowering allele of rs12740374, located in the CELSR2 PSRC1-SORT1 region, was associated with lower protein C level in both whites and blacks, reaching genome-wide significance in a meta-analysis combining results from both groups (P=1.4*10-9). To further investigate a possible link between lipid metabolism and protein C level, we conducted Mendelian randomization analyses using 185 lipid-related genetic variants as instrumental variables. The results indicated that triglycerides, and possibly low-density lipoprotein cholesterol, influence protein C levels. CONCLUSIONS: Discovery of variants influencing circulating protein C levels in the CELSR2-PSRC1-SORT1 region may indicate a novel genetic link between lipoprotein metabolism and hemostasis. PMID- 28082260 TI - Mechanisms of Mas1 Receptor-Mediated Signaling in the Vascular Endothelium. AB - OBJECTIVE: Angiotensin II (AngII) has been shown to regulate angiogenesis and at high pathophysiological doses to cause vasoconstriction through the AngII receptor type 1. Angiotensin 1 to 7 (Ang-(1-7)) acting through the Mas1 receptor can act antagonistically to high pathophysiological levels of AngII by inducing vasodilation, whereas the effects of Ang-(1-7) signaling on angiogenesis are less defined. To complicate the matter, there is growing evidence that a subpressor dose of AngII produces phenotypes similar to Ang-(1-7). APPROACH AND RESULTS: This study shows that low-dose Ang-(1-7), acting through the Mas1 receptor, promotes angiogenesis and vasodilation similar to a low, subpressor dose of AngII acting through AngII receptor type 1. In addition, we show through in vitro tube formation that Ang-(1-7) augments the angiogenic response in rat microvascular endothelial cells. Using proteomic and genomic analyses, downstream components of Mas1 receptor signaling were identified, including Rho family of GTPases, phosphatidylinositol 3-kinase, protein kinase D1, mitogen-activated protein kinase, and extracellular signal-related kinase signaling. Further experimental antagonism of extracellular signal-related kinases 1/2 and p38 mitogen-activated protein kinase signaling inhibited endothelial tube formation and vasodilation when stimulated with equimolar, low doses of either AngII or Ang-(1-7). CONCLUSIONS: These results significantly expand the known Ang-(1-7)/Mas1 receptor signaling pathway and demonstrate an important distinction between the pathological effects of elevated and suppressed AngII compared with the beneficial effects of AngII normalization and Ang-(1-7) administration. The observed convergence of Ang-(1-7)/Mas1 and AngII/AngII receptor type 1 signaling at low ligand concentrations suggests a nuanced regulation in vasculature. These data also reinforce the importance of mitogen-activated protein kinase/extracellular signal-related kinase signaling in maintaining vascular function. PMID- 28082261 TI - Hydrogel versus Bare Platinum Coils in Patients with Large or Recurrent Aneurysms Prone to Recurrence after Endovascular Treatment: A Randomized Controlled Trial. AB - BACKGROUND AND PURPOSE: Some patients are at high risk of aneurysm recurrence after endovascular treatment: patients with large aneurysms (Patients Prone to Recurrence After Endovascular Treatment PRET-1) or with aneurysms that have previously recurred after coiling (PRET-2). We aimed to establish whether the use of hydrogel coils improved efficacy outcomes compared with bare platinum coils. MATERIALS AND METHODS: PRET was an investigator-led, pragmatic, multicenter, parallel, randomized (1:1) trial. Randomized allocation was performed separately for patients in PRET-1 and PRET-2, by using a Web-based platform ensuring concealed allocation. The primary outcome was a composite of a residual/recurrent aneurysm, adjudicated by a blinded core laboratory, or retreatment, intracranial bleeding, or mass effect during the 18-month follow-up. Secondary outcomes included adverse events, mortality, and morbidity (mRS > 2). The hypothesis was that hydrogel would decrease the primary outcome from 50% to 30% at 18 months, necessitating 125 patients per group (500 for PRET-1 and PRET-2). RESULTS: The trial was stopped once 250 patients in PRET-1 and 197 in PRET-2 had been recruited because of slow accrual. A poor primary outcome occurred in 44.4% (95% CI, 35.5%-53.2%) of those in PRET-1 allocated to platinum compared with 52.5% (95% CI, 43.4%-61.6%) of patients allocated to hydrogel (OR, 1.387; 95% CI, 0.838 2.295; P = .20) and in 49.0% (95% CI, 38.8%-59.1%) in PRET-2 allocated to platinum compared with 42.1% (95% CI, 32.0%-52.2%) allocated to hydrogel (OR, 0.959; 95% CI, 0.428-1.342; P = .34). Adverse events and morbidity were similar. There were 3.6% deaths (1.4% platinum, 5.9% hydrogel; P = .011). CONCLUSIONS: Coiling of large and recurrent aneurysms is safe but often poorly effective according to angiographic results. Hydrogel coiling was not shown to be better than platinum. PMID- 28082262 TI - Endovascular Rescue Therapy for Refractory Vasospasm: When and How? PMID- 28082263 TI - Effects of Radiation Exposure on the Cost-Effectiveness of CT Angiography and Perfusion Imaging in Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND AND PURPOSE: CT angiography and perfusion imaging is an important prognostic tool in the management of patients with aneurysmal subarachnoid hemorrhage. The purpose of this study was to perform a cost-effectiveness analysis of advanced imaging in patients with SAH, incorporating the risks of radiation exposure from CT angiography and CT perfusion imaging. MATERIALS AND METHODS: The risks of radiation-induced brain cancer and cataracts were incorporated into our established decision model comparing the cost-effectiveness of CT angiography and CT perfusion imaging and transcranial Doppler sonography in SAH. Cancer risk was calculated by using National Cancer Institute methodology. The remaining input probabilities were based on literature data and a cohort at our institution. Outcomes were expected quality-adjusted life years gained, costs, and incremental cost-effectiveness ratios. One-way, 2-way, and probabilistic sensitivity analyses were performed. RESULTS: CT angiography and CT perfusion imaging were the dominant strategies, resulting in both better health outcomes and lower costs, even when incorporating brain cancer and cataract risks. Our results remained robust in 2-way sensitivity analyses varying the prolonged latency period up to 30 years, with either brain cancer risk up to 50 times higher than the upper 95% CI limit or the probability of cataracts from 0 to 1. Results were consistent for scenarios that considered either symptomatic or asymptomatic patients with SAH. Probabilistic sensitivity analysis confirmed our findings over a broad range of selected input parameters. CONCLUSIONS: While risks of radiation exposure represent an important consideration, CT angiography and CT perfusion imaging remained the preferred imaging compared with transcranial Doppler sonography in both asymptomatic and symptomatic patients with SAH, with improved health outcomes and lower health care costs, even when modeling a significantly higher risk and shorter latency period for both cataract and brain cancer than that currently known. PMID- 28082264 TI - Reply. PMID- 28082265 TI - Regarding "Uremic Encephalopathy: MR Imaging Findings and Clinical Correlation". PMID- 28082267 TI - Use of X-rays to study acupuncture points of the hand: implications for education. PMID- 28082266 TI - Reporting characteristics and risk of bias in randomised controlled trials of acupuncture analgesia published in PubMed-listed journals. AB - BACKGROUND: Acupuncture analgesia has been evaluated by a number of randomised controlled trials (RCTs); however, a systematic summary of reporting quality of RCTs in this specific field is lacking. OBJECTIVE: To examine the reporting characteristics and risk of bias of RCTs of acupuncture analgesia indexed in the PubMed database. METHODS: A PubMed search of RCTs of acupuncture analgesia was conducted through November 2015. The Cochrane Collaboration Risk of Bias Tool was used to assess the risk of bias of each trial. RESULTS: 206 articles were identified across 59 journals (impact factor 0.4-20), of which 56% of articles and 86% of journals were Science Citation Index (SCI)-indexed. Nearly half of the articles were published in China. The next most represented countries of origin were the UK (22%) and USA (21%). Of the included trials, postoperative pain was the most prevalent phenotype, and manual acupuncture was the most frequently applied type of stimulation (46%). A total of 12% of articles reported on analgesic mechanisms. The most frequently used acupuncture points were LI4, ST36, PC6, SP6 and Shenmen. The overwhelming majority of trials were considered to be at high risk of bias (84%). Furthermore, 79% of trials enrolled <50 participants per treatment arm. CONCLUSIONS: RCTs of acupuncture analgesia indexed in PubMed journals generally exhibited poor reporting of methodological and treatment details. Future studies should provide more information regarding clinical trial registration, blinding of participants (including sham procedures where applicable) and outcome assessors, as well as the training and qualification of acupuncturists. PMID- 28082268 TI - New onset facial swelling. PMID- 28082269 TI - Commentary: It's not all doom and gloom...but the crunch is coming. PMID- 28082270 TI - Modern Healthcare Versus Nontuberculous Mycobacteria: Who Will Have the Upper Hand? PMID- 28082271 TI - A painful swollen knee after a fall. PMID- 28082272 TI - Let's hear it for the case report. PMID- 28082273 TI - Infographic: The training-injury prevention paradox: should athletes be training smarter and harder? PMID- 28082274 TI - NHS chief warns of more financial challenges. PMID- 28082275 TI - Validity and Reliability of the Positive Aspects of Caregiving (PAC) Scale and Development of Its Shorter Version (S-PAC) Among Family Caregivers of Older Adults. AB - Purpose of the Study: To (a) assess the validity and reliability of the 9-item Positive Aspects of Caregiving (PAC) scale among a national sample of caregivers for older adults with functional limitations, (b) develop a shorter version (short-PAC [S-PAC] scale) and assess its psychometric properties, and (c) investigate both scales' measurement equivalence/invariance (ME/I) across language of administration (Chinese/English/Malay). Design and Methods: Scale/item measurement property assessment, confirmatory factor analysis (CFA), testing the "original" 2-factor model (6 items: first factor; 3 items: second factor), and exploratory FA (EFA) of the 9-item PAC scale was done. Consequently, alternate CFA models were tested. The S-PAC was developed and subjected to CFA. For both scales, convergent (correlation with caregiver esteem) and divergent (correlation with caregiver depressive symptoms) validity, and language ME/I was assessed. Results: For the 9-item PAC scale, the "original" 2-factor CFA model had a poor fit; its EFA and scale/item measurement properties supported a single factor. Among alternate CFA models, a bi-factor model (all nine items: first factor [overall PAC]; six items: second factor [self-affirmation]; three items: third factor [outlook-on-life]) had the best fit. The bi-factor CFA model also had a good fit for the S-PAC scale, developed after eliminating 2 items from the 9-item PAC scale. Both scales demonstrated convergent and divergent validity, and partial ME/I across language of administration. Implications: Both the 9-item PAC and 7-item S-PAC scales can be used to assess positive feelings resulting from care provision among family caregivers of older adults with functional limitations. PMID- 28082276 TI - Balancing Eating With Breathing: Community-Dwelling Older Adults' Experiences of Dysphagia and Texture-Modified Diets. AB - Purpose: Although many older adults suffer from dysphagia and are required to eat texture-modified diets, little is known about the experiences and challenges faced in doing so at home. In this study, we explored the perspectives of community-dwelling older adults as they struggled to balance dysphagia symptoms and recommended diet modifications with their preferred lifestyles. Design and Methods: Using an interpretive descriptive design, we conducted 37 in-home semi structured interviews and 5 member-checking interviews, participant observations during a meal, and reviewed the medical charts of 20 participants recruited through maximum variation purposeful sampling. Meaning units and codes were identified and synthesized into 4 themes. Results: Participants faced a frightening choice between eating and breathing. Hiding dysphagia symptoms from the public eye was important to preserve self-identity. Following the recommended diet created a feeling that life was "falling apart." We also found that adhering to the diet was not an "all or none" phenomenon. Implications: Given that correct adherence to the restrictive diet is rare, to effectively manage dysphagia symptoms, clinicians must appreciate the full range of impact of dysphagia and texture-modified diets on the lives of older adults. PMID- 28082278 TI - Ageism and the Older Worker: A Scoping Review. AB - Purpose of the Study: Given the policy shifts toward extended work lives, it is critically important to address barriers that older workers may face in attaining and maintaining satisfactory work. This article presents a scoping review of research addressing ageism and its implications for the employment experiences and opportunities of older workers. Design and Methods: The five-step scoping review process outlined by Arksey and O'Malley was followed. The data set included 43 research articles. Results: The majority of articles were cross sectional quantitative surveys, and various types of study participants (older workers, human resource personnel/manager, employers, younger workers, undergraduate students) were included. Four main themes, representing key research emphases, were identified: stereotypes and perceptions of older workers; intended behavior toward older workers; reported behavior toward older workers; and older workers' negotiation of ageism. Implications: Existing research provides a foundational evidence base for the existence of ageist stereotypes and perceptions about older workers and has begun to demonstrate implications in relation to intended behaviors and, to a lesser extent, actual behaviors toward older workers. A few studies have explored how aging workers attempt to negotiate ageism. Further research that extends beyond cross-sectional surveys is required to achieve more complex understandings of the implications of ageism and inform policies and practices that work against ageism. PMID- 28082277 TI - Interdisciplinary Practice Models for Older Adults With Back Pain: A Qualitative Evaluation. AB - Purpose: Older adults seek health care for low back pain from multiple providers who may not coordinate their treatments. This study evaluated the perceived feasibility of a patient-centered practice model for back pain, including facilitators for interprofessional collaboration between family medicine physicians and doctors of chiropractic. Design and Methods: This qualitative evaluation was a component of a randomized controlled trial of 3 interdisciplinary models for back pain management: usual medical care; concurrent medical and chiropractic care; and collaborative medical and chiropractic care with interprofessional education, clinical record exchange, and team-based case management. Data collection included clinician interviews, chart abstractions, and fieldnotes analyzed with qualitative content analysis. An organizational level framework for dissemination of health care interventions identified norms/attitudes, organizational structures and processes, resources, networks linkages, and change agents that supported model implementation. Results: Clinicians interviewed included 13 family medicine residents and 6 chiropractors. Clinicians were receptive to interprofessional education, noting the experience introduced them to new colleagues and the treatment approaches of the cooperating profession. Clinicians exchanged high volumes of clinical records, but found the logistics cumbersome. Team-based case management enhanced information flow, social support, and interaction between individual patients and the collaborating providers. Older patients were viewed positively as change agents for interprofessional collaboration between these provider groups. Implications: Family medicine residents and doctors of chiropractic viewed collaborative care as a useful practice model for older adults with back pain. Health care organizations adopting medical and chiropractic collaboration can tailor this general model to their specific setting to support implementation. PMID- 28082279 TI - Perceived Neighborhood Safety, Social Cohesion, and Psychological Health of Older Adults. AB - Purpose of the Study: We aimed to investigate the interactive effects of perceived neighborhood safety and social cohesion on the psychological health of older adults with and without functional impairments. Design and Methods: This cross-sectional study included 13,897 community-dwelling older adults (aged 65 years and older) from the 2011-2012 California Health Interview Survey (CHIS). Hypotheses were tested using weighted moderated ordinary least squared regression analysis. Results: Perceived neighborhood safety was significantly associated with psychological health regardless of respondents' physical functioning, although the effect was greater among older adults with functional limitations. Perceived social cohesion, however, was only significantly related to psychological health among those with functional limitations. Among physically impaired respondents, social cohesion buffered the ill-effect of an unsafe neighborhood on psychological health. Implications: Findings suggest that efforts to promote perceived neighborhood safety and social cohesion are essential to the well-being of older adults. Special attention should be paid to older adults with functional limitations, who appear to be more vulnerable to the negative effects of neighborhood environments. PMID- 28082281 TI - The American Journal of Botany in 2017: Let's work together! PMID- 28082280 TI - Serum Metabolomic Profiles Identify ER-Positive Early Breast Cancer Patients at Increased Risk of Disease Recurrence in a Multicenter Population. AB - Purpose: Detecting signals of micrometastatic disease in patients with early breast cancer (EBC) could improve risk stratification and allow better tailoring of adjuvant therapies. We previously showed that postoperative serum metabolomic profiles were predictive of relapse in a single-center cohort of estrogen receptor (ER)-negative EBC patients. Here, we investigated this further using preoperative serum samples from ER-positive, premenopausal women with EBC who were enrolled in an international phase III trial.Experimental Design: Proton nuclear magnetic resonance (NMR) spectroscopy of 590 EBC samples (319 with relapse or >=6 years clinical follow-up) and 109 metastatic breast cancer (MBC) samples was performed. A Random Forest (RF) classification model was built using a training set of 85 EBC and all MBC samples. The model was then applied to a test set of 234 EBC samples, and a risk of recurrence score was generated on the basis of the likelihood of the sample being misclassified as metastatic.Results: In the training set, the RF model separated EBC from MBC with a discrimination accuracy of 84.9%. In the test set, the RF recurrence risk score correlated with relapse, with an AUC of 0.747 in ROC analysis. Accuracy was maximized at 71.3% (sensitivity, 70.8%; specificity, 71.4%). The model performed independently of age, tumor size, grade, HER2 status and nodal status, and also of Adjuvant! Online risk of relapse score.Conclusions: In a multicenter group of EBC patients, we developed a model based on preoperative serum metabolomic profiles that was prognostic for disease recurrence, independent of traditional clinicopathologic risk factors. Clin Cancer Res; 23(6); 1422-31. (c)2017 AACR. PMID- 28082282 TI - A wild origin of the loss-of-function lycopene beta cyclase (CYC-b) allele in cultivated, red-fleshed papaya (Carica papaya). AB - PREMISE OF THE STUDY: The red flesh of some papaya cultivars is caused by a recessive loss-of-function mutation in the coding region of the chromoplast specific lycopene beta cyclase gene (CYC-b). We performed an evolutionary genetic analysis of the CYC-b locus in wild and cultivated papaya to uncover the origin of this loss-of-function allele in cultivated papaya. METHODS: We analyzed the levels and patterns of genetic diversity at the CYC-b locus and six loci in a 100 kb region flanking CYC-b and compared these to genetic diversity levels at neutral autosomal loci. The evolutionary relationships of CYC-b haplotypes were assessed using haplotype network analysis of the CYC-b locus and the 100-kb CYC-b region. KEY RESULTS: Genetic diversity at the recessive CYC-b allele (y) was much lower relative to the dominant Y allele found in yellow-fleshed wild and cultivated papaya due to a strong selective sweep. Haplotype network analyses suggest the y allele most likely arose in the wild and was introduced into domesticated varieties after the first papaya domestication event. The shared haplotype structure between some wild, feral, and cultivated haplotypes around the y allele supports subsequent escape of this allele from red cultivars back into wild populations through feral intermediates. CONCLUSIONS: Our study supports a protracted domestication process of papaya through the introgression of wild-derived traits and gene flow from cultivars to wild populations. Evidence of gene flow from cultivars to wild populations through feral intermediates has implications for the introduction of transgenic papaya into Central American countries. PMID- 28082283 TI - Five species, many genotypes, broad phenotypic diversity: When agronomy meets functional ecology. AB - PREMISE OF THE STUDY: Current ecological theory can provide insight into the causes and impacts of plant domestication. However, just how domestication has impacted intraspecific genetic variability (ITV) is unknown. We used 50 ecotypes and 35 cultivars from five grassland species to explore how selection drives functional trait coordination and genetic differentiation. METHODS: We quantified the extent of genetic diversity among different sets of functional traits and determined how much genetic diversity has been generated within populations of natural ecotypes and selected cultivars. KEY RESULTS: In general, the cultivars were larger (e.g., greater height, faster growth rates) and had larger and thinner leaves (greater SLA). We found large (average 63%) and trait-dependent (ranging from 14% for LNC to 95.8% for growth rate) genetic variability. The relative extent of genetic variability was greater for whole-plant than for organ level traits. This pattern was consistent within ecotypes and within cultivars. However, ecotypes presented greater ITV variability. CONCLUSIONS: The results indicated that genetic diversity is large in domesticated species with contrasting levels of heritability among functional traits and that selection for high yield has led to indirect selection of some associated leaf traits. These findings open the way to define which target traits should be the focus in selection programs, especially in the context of community-level selection. PMID- 28082285 TI - Plasticity of neuroeffector transmission during bowel inflammation1. AB - Altered gastrointestinal (GI) function contributes to the debilitating symptoms of inflammatory bowel diseases (IBD). Nerve circuits contained within the gut wall and outside of the gut play important roles in modulating motility, mucosal fluid transport, and blood flow. The structure and function of these neuronal populations change during IBD. Superimposed on this plasticity is a diminished responsiveness of effector cells - smooth muscle cells, enterocytes, and vascular endothelial cells - to neurotransmitters. The net result is a breakdown in the precisely orchestrated coordination of motility, fluid secretion, and GI blood flow required for health. In this review, we consider how inflammation-induced changes to the effector innervation of these tissues, and changes to the tissues themselves, contribute to defective GI function in models of IBD. We also explore the evidence that reversing neuronal plasticity is sufficient to normalize function during IBD. PMID- 28082284 TI - Hepatocyte-specific PPARA expression exclusively promotes agonist-induced cell proliferation without influence from nonparenchymal cells. AB - Peroxisome proliferator-activated receptor-alpha (PPARA) is a nuclear transcription factor and key mediator of systemic lipid metabolism. Prolonged activation in rodents causes hepatocyte proliferation and hepatocellular carcinoma. Little is known about the contribution of nonparenchymal cells (NPCs) to PPARA-mediated cell proliferation. NPC contribution to PPARA agonist-induced hepatomegaly was assessed in hepatocyte (Ppara?Hep)- and macrophage (Ppara?Mac) specific Ppara null mice. Mice were treated with the agonist Wy-14643 for 14 days, and response of conditional null mice was compared with conventional knockout mice (Ppara-/- ). Wy-14643 treatment caused weight loss and severe hepatomegaly in wild-type and Ppara?Mac mice, and histological analysis revealed characteristic hepatocyte swelling; Ppara?Hep and Ppara-/- mice were protected from these effects. Ppara?Mac serum chemistries, as well as aspartate aminotransferase and alanine aminotransferase levels, matched wild-type mice. Agonist-treated Ppara?Hep mice had elevated serum cholesterol, phospholipids, and triglycerides when compared with Ppara-/- mice, indicating a possible role for extrahepatic PPARA in regulating circulating lipid levels. BrdU labeling confirmed increased cell proliferation only in wild-type and Ppara?Mac mice. Macrophage PPARA disruption did not impact agonist-induced upregulation of lipid metabolism, cell proliferation, or DNA damage and repair-related gene expression, whereas gene expression was repressed in Ppara?Hep mice. Interestingly, downregulation of inflammatory cytokines IL-15 and IL-18 was dependent on macrophage PPARA. Cell type-specific regulation of target genes was confirmed in primary hepatocytes and Kupffer cells. These studies conclusively show that cell proliferation is mediated exclusively by PPARA activation in hepatocytes and that Kupffer cell PPARA has an important role in mediating the anti-inflammatory effects of PPARA agonists. PMID- 28082286 TI - Enteric glia cells are critical to limiting the intestinal inflammatory response after injury. AB - Vagal nerve stimulation (VNS) has been shown to limit intestinal inflammation following injury; however, a direct connection between vagal terminals and resident intestinal immune cells has yet to be identified. We have previously shown that enteric glia cell (EGC) expression is increased after injury through a vagal-mediated pathway to help restore gut barrier function. We hypothesize that EGCs modulate immune cell recruitment following injury and relay vagal anti inflammatory signals to resident immune cells in the gut. EGCs were selectively ablated from an isolated segment of distal bowel with topical application of benzalkonium chloride (BAC) in male mice. Three days following BAC application, mice were subjected to an ischemia-reperfusion injury (I/R) by superior mesenteric artery occlusion for 30 min. VNS was performed in a separate cohort of animals. EGC+ and EGC- segments were compared utilizing histology, flow cytometry, immunohistochemistry, and intestinal permeability. VNS significantly reduced immune cell recruitment after I/R injury in EGC+ segments with cell percentages similar to sham. VNS failed to limit immune cell recruitment in EGC- segments. Histologic evidence of gut injury was diminished with VNS application in EGC+ segments, whereas EGC- segments showed features of more severe injury. Intestinal permeability increased following I/R injury in both EGC+ and EGC- segments. Permeability was significantly lower after VNS application compared with injury alone in EGC+ segments only (95.1 +/- 30.0 vs. 217.6 +/- 21.7 MUg/ml, P < 0.05). Therefore, EGC ablation uncouples the protective effects of VNS, suggesting that vagal-mediated signals are translated to effector cells through EGCs.NEW & NOTEWORTHY Intestinal inflammation is initiated by local immune cell activation and epithelial barrier breakdown, resulting in the production of proinflammatory mediators with subsequent leukocyte recruitment. Vagal nerve stimulation (VNS) has been shown to limit intestinal inflammation following injury; however, direct connection between vagal terminals and resident intestinal immune cells has yet to be identified. Here, we demonstrate that intact enteric glia cells are required to transmit the gut anti-inflammatory effects of VNS. PMID- 28082287 TI - Ups and downs of the ADP phosphoproteome. PMID- 28082288 TI - Making a case for more sickle cell initiatives in Africa. PMID- 28082289 TI - Transplant biomarkers ready for the clinic? PMID- 28082290 TI - Microbes prevent HSPCs from "NOD"-ing off. PMID- 28082291 TI - One size doesn't fit all in Ph-like ALL. PMID- 28082292 TI - CML stem cells: evasion for better invasion. PMID- 28082293 TI - Driving the hemophilia tolerance CAR. PMID- 28082294 TI - Zika virus in the blood supply. PMID- 28082295 TI - Near-triploid B lymphoblastic leukemia with Burkitt-like morphology. PMID- 28082296 TI - Nerves in bone marrow of newly diagnosed therapy-related acute myeloid leukemia. PMID- 28082297 TI - Varied effects of age-related neuropathologies on the trajectory of late life cognitive decline. AB - The objective of this study was to examine whether the effects of age-related neuropathologies on cognition change over time. Participants were 1096 deceased persons from two clinical-pathologic studies. All were without dementia at baseline, completed a detailed battery of cognitive tests annually over up to 21 years, died, and underwent detailed neuropathologic examinations to identify Alzheimer's disease pathology, vascular pathologies (i.e. macro- and microscopic infarcts, atherosclerosis, arteriolar sclerosis, and cerebral amyloid angiopathy), Lewy bodies, transactive response DNA-binding protein 43 (TDP-43) pathology, and hippocampal sclerosis. A time-varying effects model was used to flexibly characterize the trajectory of global cognition and assess whether the effects of demographics and each neuropathologic index on cognition changed over time. Results indicated that the mean trajectory of global cognition was characterized by gradual cognitive decline beginning ~15 years before death and accelerated decline in the last few years. With the exception of microinfarcts and arteriolar sclerosis, all neuropathologies were associated with the cognitive trajectory. However, the nature of their associations varied. Alzheimer's disease pathology, macroscopic infarcts, Lewy bodies, TDP-43 pathology, and hippocampal sclerosis were associated with progressive cognitive decline, with their deleterious effects increasing over time. By contrast, atherosclerosis and cerebral amyloid angiopathy pathology were associated with a lower level of cognition but their effects were relatively stable over time. These results suggest that age-related neuropathologies are differentially related to late life cognitive trajectories. Whereas some contribute to progressive cognitive deterioration, others lower the level of cognition but exert relatively stable effects over time. PMID- 28082298 TI - Finding the imposter: brain connectivity of lesions causing delusional misidentifications. AB - SEE MCKAY AND FURL DOI101093/AWW323 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Focal brain injury can sometimes lead to bizarre symptoms, such as the delusion that a family member has been replaced by an imposter (Capgras syndrome). How a single brain lesion could cause such a complex disorder is unclear, leading many to speculate that concurrent delirium, psychiatric disease, dementia, or a second lesion is required. Here we instead propose that Capgras and other delusional misidentification syndromes arise from single lesions at unique locations within the human brain connectome. This hypothesis is motivated by evidence that symptoms emerge from sites functionally connected to a lesion location, not just the lesion location itself. First, 17 cases of lesion-induced delusional misidentifications were identified and lesion locations were mapped to a common brain atlas. Second, lesion network mapping was used to identify brain regions functionally connected to the lesion locations. Third, regions involved in familiarity perception and belief evaluation, two processes thought to be abnormal in delusional misidentifications, were identified using meta-analyses of previous functional magnetic resonance imaging studies. We found that all 17 lesion locations were functionally connected to the left retrosplenial cortex, the region most activated in functional magnetic resonance imaging studies of familiarity. Similarly, 16 of 17 lesion locations were functionally connected to the right frontal cortex, the region most activated in functional magnetic resonance imaging studies of expectation violation, a component of belief evaluation. This connectivity pattern was highly specific for delusional misidentifications compared to four other lesion-induced neurological syndromes (P < 0.0001). Finally, 15 lesions causing other types of delusions were connected to expectation violation (P < 0.0001) but not familiarity regions, demonstrating specificity for delusion content. Our results provide potential neuroanatomical correlates for impaired familiarity perception and belief evaluation in patients with delusional misidentifications. More generally, we demonstrate a mechanism by which a single lesion can cause a complex neuropsychiatric syndrome based on that lesion's unique pattern of functional connectivity, without the need for pre existing or hidden pathology. PMID- 28082301 TI - Coca-Cola is sued over claims of misleading advertising. PMID- 28082300 TI - Trajectories of prediagnostic functioning in Parkinson's disease. AB - SEE BREEN AND LANG DOI101093/AWW321 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: At the time of clinical diagnosis, patients with Parkinson's disease already have a wide range of motor and non-motor features that affect their daily functioning. However, the temporal sequence of occurrence of these features remains largely unknown. We studied trajectories of daily functioning and motor and non-motor features in the 23 years preceding Parkinson's disease diagnosis by performing a nested case-control study within the prospective Rotterdam study. Between 1990 and 2013, we repeatedly performed standardized assessments of daily functioning (Stanford Health Assessment Questionnaire, Lawton Instrumental Activities of Daily Living Scale), potential prediagnostic motor (hypo- and bradykinesia, tremor, rigidity, postural imbalance, postural abnormalities) and non-motor features of Parkinson's disease, including cognition (Mini-Mental State Examination, Stroop Test, Letter-Digit-Substitution Test, Word Fluency Test), mood (Center for Epidemiological Studies-Depression Scale, Hamilton Anxiety and Depression Scale), and autonomic function (blood pressure, laxative use). In addition, the cohort was followed-up for the onset of clinical Parkinson's disease using several overlapping modalities, including repeated in-person examinations, as well as complete access to medical records and specialist letters of study participants. During follow-up, 109 individuals were diagnosed with Parkinson's disease, and each case was matched to 10 controls based on age and sex (total n = 1199). Subsequently, we compared prediagnostic trajectories of daily functioning and other features between Parkinson's disease cases and controls. From 7 years before diagnosis onwards, prediagnostic Parkinson's disease cases more commonly had problems in instrumental activities of daily functioning, and more frequently showed signs of movement poverty and slowness, tremor and subtle cognitive deficits. In the past 5 years, Parkinson's disease cases developed additional motor features (postural imbalance, rigidity, and postural abnormalities) and increasingly reported problems in basic daily activities. Parkinson's disease cases also increasingly reported anxiety symptoms, depressive symptoms, and use of laxatives throughout study follow-up, although differences with controls only became statistically significant in the last years before diagnosis. In conclusion, in patients with prediagnostic Parkinson's disease, impairments in instrumental daily activities, which require both motor and non-motor skills, pre-date difficulties in more physically oriented daily activities.media 1vid110.1093/brain/aww291_video_abstractaww291_video_abstract. PMID- 28082302 TI - Impact of a national antimicrobial stewardship mentoring program: Insights and lessons learned. AB - PURPOSE: The impact of an interprofessional mentoring program to advance antimicrobial stewardship programs (ASPs) in selected U.S. hospitals and lessons learned are described. SUMMARY: A seven-step mentoring process with self assessment, telephone calls, continuing education, a one-day onsite visit, action plan, and outcome data collection and analysis was provided to ASP teams at nine hospitals. Six hospitals completed the program. A significant improvement in the timeliness and appropriateness of i.v. antibiotic therapy (defined as a hang time within one hour after prescriber order entry and broad-spectrum coverage for gram negative pathogens administered first when combination therapy was used) was observed in patients with sepsis over the 12-month period after implementation of the mentoring program. As a result of requiring hospital administration's participation in the mentoring program, increased funding became available at three hospitals for the microbiology laboratory to provide new rapid diagnostic tests and for pharmacist and physician time to devote to ASP activities. The collaboration and engagement of ASP team members, inclusion of hospital administrators and pharmacy directors in the onsite mentoring visits, and an experienced mentor team with an infectious diseases (ID) physician and ID pharmacist contributed to ASP success. Challenges included insufficient time to collect outcome metrics due to competing hospital priorities and loss of momentum over time. CONCLUSION: A mentoring program for antimicrobial stewardship provided the perspective that comes from experience. Engagement of hospital administration was a key factor for both developing and sustaining a stewardship program. PMID- 28082303 TI - Significant publications on infectious diseases pharmacotherapy in 2015. AB - PURPOSE: The most important articles on infectious diseases (ID) pharmacotherapy published in the peer-reviewed literature in 2015, as nominated and selected by panels of pharmacists and others with ID expertise, are summarized. SUMMARY: Members of the Houston Infectious Diseases Network were asked to nominate articles published in prominent peer-reviewed journals in 2015 that were thought to have a major impact in the field of ID pharmacotherapy. A list of 55 nominated articles on general ID-related topics and 10 articles specifically related to human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) was compiled. In a national online survey, members of the Society of Infectious Diseases Pharmacists (SIDP) were asked to select from the list 10 general ID articles believed to have made a significant contribution to the field of ID pharmacotherapy and 1 article contributing to HIV/AIDS pharmacotherapy. Of the 361 SIDP members surveyed, 153 (42%) and 76 (21%) participated in the selection of general ID-related articles and HIV/AIDS-related articles, respectively. The 11 highest-ranked publications (10 general ID-related articles and 1 HIV/AIDS-related article) are summarized here. CONCLUSION: With the growing number of significant ID-related publications each year, it can be challenging to stay current with the literature. This review of important ID pharmacotherapy publications in 2015 may be helpful in identifying key articles and lessening this burden. PMID- 28082304 TI - Protein Kinase C Activation Promotes alpha1B-Adrenoceptor Internalization and Late Endosome Trafficking through Rab9 Interaction. Role in Heterologous Desensitization. AB - Upon agonist stimulation, alpha1B-adrenergic receptors couple to Gq proteins, calcium signaling and protein kinase C activation; subsequently, the receptors are phosphorylated, desensitized, and internalized. Internalization seems to involve scaffolding proteins, such as beta-arrestin and clathrin. However, the fine mechanisms that participate remain unsolved. The roles of protein kinase C and the small GTPase, Rab9, in alpha1B-AR vesicular traffic were investigated by studying alpha1B-adrenergic receptor-Rab protein interactions, using Forster resonance energy transfer (FRET), confocal microscopy, and intracellular calcium quantitation. In human embryonic kidney 293 cells overexpressing Discosoma spp. red fluorescent protein (DsRed)-tagged alpha1B-ARs and enhanced green fluorescent protein--tagged Rab proteins, pharmacological protein kinase C activation mimicked alpha1B-AR traffic elicited by nonrelated agents, such as sphingosine 1 phosphate (i.e., transient alpha1B-AR-Rab5 FRET signal followed by a sustained alpha1B-AR-Rab9 interaction), suggesting brief receptor localization in early endosomes and transfer to late endosomes. This latter interaction was abrogated by blocking protein kinase C activity, resulting in receptor retention at the plasma membrane. Similar effects were observed when a dominant-negative Rab9 mutant (Rab9-GDP) was employed. When alpha1B-adrenergic receptors that had been mutated at protein kinase C phosphorylation sites (S396A, S402A) were used, phorbol ester-induced desensitization of the calcium response was markedly decreased; however, interaction with Rab9 was only partially decreased and internalization was observed in response to phorbol esters and sphingosine 1 phosphate. Finally, Rab9-GDP expression did not affect adrenergic-mediated calcium response but abolished receptor traffic and altered desensitization. Data suggest that protein kinase C modulates alpha1B-adrenergic receptor transfer to late endosomes and that Rab9 regulates this process and participates in G protein mediated signaling turn-off. PMID- 28082299 TI - Neuromodulation interventions for addictive disorders: challenges, promise, and roadmap for future research. AB - Addictive disorders are a major public health concern, associated with high relapse rates, significant disability and substantial mortality. Unfortunately, current interventions are only modestly effective. Preclinical studies as well as human neuroimaging studies have provided strong evidence that the observable behaviours that characterize the addiction phenotype, such as compulsive drug consumption, impaired self-control, and behavioural inflexibility, reflect underlying dysregulation and malfunction in specific neural circuits. These developments have been accompanied by advances in neuromodulation interventions, both invasive as deep brain stimulation, and non-invasive such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation. These interventions appear particularly promising as they may not only allow us to probe affected brain circuits in addictive disorders, but also seem to have unique therapeutic applications to directly target and remodel impaired circuits. However, the available literature is still relatively small and sparse, and the long-term safety and efficacy of these interventions need to be confirmed. Here we review the literature on the use of neuromodulation in addictive disorders to highlight progress limitations with the aim to suggest future directions for this field. PMID- 28082305 TI - Modulation of Chemokine Receptor Function by Cholesterol: New Prospects for Pharmacological Intervention. AB - Chemokine receptors are seven transmembrane-domain receptors belonging to class A of G-protein-coupled receptors (GPCRs). The receptors together with their chemokine ligands constitute the chemokine system, which is essential for directing cell migration and plays a crucial role in a variety of physiologic and pathologic processes. Given the importance of orchestrating cell migration, it is vital that chemokine receptor signaling is tightly regulated to ensure appropriate responses. Recent studies highlight a key role for cholesterol in modulating chemokine receptor activities. The steroid influences the spatial organization of GPCRs within the membrane bilayer, and consequently can tune chemokine receptor signaling. The effects of cholesterol on the organization and function of chemokine receptors and GPCRs in general include direct and indirect effects (Fig. 1). Here, we review how cholesterol and some key metabolites modulate functions of the chemokine system in multiple ways. We emphasize the role of cholesterol in chemokine receptor oligomerization, thereby promoting the formation of a signaling hub enabling integration of distinct signaling pathways at the receptor-membrane interface. Moreover, we discuss the role of cholesterol in stabilizing particular receptor conformations and its consequence for chemokine binding. Finally, we highlight how cholesterol accumulation, its deprivation, or cholesterol metabolites contribute to modulating cell orchestration during inflammation, induction of an adaptive immune response, as well as to dampening an anti-tumor immune response. PMID- 28082306 TI - Spontaneous retroperitoneal haematoma resulting in bowel ischaemia. AB - A 69-year-old man presented to the emergency department with sudden onset abdominal pain. He was hypotensive and tachycardic with a peritonitic abdomen. On admission, the patient had been taking clopidogrel, a known cause of spontaneous retroperitoneal haematoma. An initial computed tomography of the abdomen showed a mass in the pelvis, which was thought to most likely be a gastrointestinal stromal tumour arising from the sigmoid colon. Explorative surgery identified a retroperitoneal haematoma of the rectosigmoid region. There was no evidence of bowel perforation. Hence a washout and closure was performed. Five days following an initial improvement, the patient developed symptoms of peritonitis. A second operation revealed that the rectum had become necrotic and perforated with free faeces. The ischaemia was caused by the retroperitoneal haematoma restricting the blood supply to this part of the upper rectum. PMID- 28082307 TI - Intracranial infection caused by minor skin contusion associated with previous craniotomy. AB - Minor damage to the scalp may lead to intracranial infection. Moreover, the postoperative state of the scalp, skull and meninges is especially noteworthy with respect to invasion of pathogens into the skull. Therefore, a detailed medical history should be obtained from patients with even minor scalp injuries to avoid intracranial infection. We herein report a case of intracranial infection caused by a minor scalp injury associated with previous craniotomy, which was missed at first. PMID- 28082308 TI - Concomitant orbital cavernous haemangioma and schwannoma in a patient. AB - A woman aged 39 years presented with right eye painless proptosis and decreased vision since 5 months. Right fundus examination revealed optic disc oedema. CT of the orbit revealed a well-defined homogeneous mass in the intraconal space in both orbits. Surgical excisional biopsy of the orbital lesions was performed. Histopathological examination of the right orbital lesion was suggestive of cavernous haemangioma and the left orbital lesion revealed schwannoma. The patient had an unremarkable postoperative course with improved visual acuity. This case illustrates benign orbital masses of 2 different tissues of origin in a single patient, which has not been described in the literature. PMID- 28082309 TI - Graphics and statistics for cardiology: survival analysis. AB - Reports of data in the medical literature frequently lack information needed to assess the validity and generalisability of study results. Some recommendations and standards for reporting have been developed over the last two decades, but few are available specifically for survival data. We provide recommendations for tabular and graphical representations of survival data. We argue that data and analytic software should be made available to promote reproducible research. PMID- 28082310 TI - Very Early Onset IBD: How Very Different 'on Average'? PMID- 28082311 TI - Science, modernity, and the Muslim world: To improve scientific research in Muslim countries requires profound social and economic liberalization of their societies. PMID- 28082313 TI - Regulating phage therapy: The biological master file concept could help to overcome regulatory challenge of personalized medicines. PMID- 28082312 TI - A single MIU motif of MINDY-1 recognizes K48-linked polyubiquitin chains. AB - The eight different types of ubiquitin (Ub) chains that can be formed play important roles in diverse cellular processes. Linkage-selective recognition of Ub chains by Ub-binding domain (UBD)-containing proteins is central to coupling different Ub signals to specific cellular responses. The motif interacting with ubiquitin (MIU) is a small UBD that has been characterized for its binding to monoUb. The recently discovered deubiquitinase MINDY-1/FAM63A contains a tandem MIU repeat (tMIU) that is highly selective at binding to K48-linked polyUb. We here identify that this linkage-selective binding is mediated by a single MIU motif (MIU2) in MINDY-1. The crystal structure of MIU2 in complex with K48-linked polyubiquitin chains reveals that MIU2 on its own binds to all three Ub moieties in an open conformation that can only be accommodated by K48-linked triUb. The weak Ub binder MIU1 increases overall affinity of the tMIU for polyUb chains without affecting its linkage selectivity. Our analyses reveal new concepts for linkage selectivity and polyUb recognition by UBDs. PMID- 28082314 TI - A CMC1-knockout reveals translation-independent control of human mitochondrial complex IV biogenesis. AB - Defects in mitochondrial respiratory chain complex IV (CIV) frequently cause encephalocardiomyopathies. Human CIV assembly involves 14 subunits of dual genetic origin and multiple nucleus-encoded ancillary factors. Biogenesis of the mitochondrion-encoded copper/heme-containing COX1 subunit initiates the CIV assembly process. Here, we show that the intermembrane space twin CX9C protein CMC1 forms an early CIV assembly intermediate with COX1 and two assembly factors, the cardiomyopathy proteins COA3 and COX14. A TALEN-mediated CMC1 knockout HEK293T cell line displayed normal COX1 synthesis but decreased CIV activity owing to the instability of newly synthetized COX1. We demonstrate that CMC1 stabilizes a COX1-COA3-COX14 complex before the incorporation of COX4 and COX5a subunits. Additionally, we show that CMC1 acts independently of CIV assembly factors relevant to COX1 metallation (COX10, COX11, and SURF1) or late stability (MITRAC7). Furthermore, whereas human COX14 and COA3 have been proposed to affect COX1 mRNA translation, our data indicate that CMC1 regulates turnover of newly synthesized COX1 prior to and during COX1 maturation, without affecting the rate of COX1 synthesis. PMID- 28082317 TI - Colorectal cancer cells use the negative feedback regulators of WNT signalling to activate epithelial-mesenchymal transition pathways. PMID- 28082318 TI - Response to letter to the editor. PMID- 28082316 TI - miR-16 and miR-125b are involved in barrier function dysregulation through the modulation of claudin-2 and cingulin expression in the jejunum in IBS with diarrhoea. AB - OBJECTIVE: Micro-RNAs (miRNAs) play a crucial role in controlling intestinal epithelial barrier function partly by modulating the expression of tight junction (TJ) proteins. We have previously shown differential messenger RNA (mRNA) expression correlated with ultrastructural abnormalities of the epithelial barrier in patients with diarrhoea-predominant IBS (IBS-D). However, the participation of miRNAs in these differential mRNA-associated findings remains to be established. Our aims were (1) to identify miRNAs differentially expressed in the small bowel mucosa of patients with IBS-D and (2) to explore putative target genes specifically involved in epithelial barrier function that are controlled by specific dysregulated IBS-D miRNAs. DESIGN: Healthy controls and patients meeting Rome III IBS-D criteria were studied. Intestinal tissue samples were analysed to identify potential candidates by: (a) miRNA-mRNA profiling; (b) miRNA-mRNA pairing analysis to assess the co-expression profile of miRNA-mRNA pairs; (c) pathway analysis and upstream regulator identification; (d) miRNA and target mRNA validation. Candidate miRNA-mRNA pairs were functionally assessed in intestinal epithelial cells. RESULTS: IBS-D samples showed distinct miRNA and mRNA profiles compared with healthy controls. TJ signalling was associated with the IBS-D transcriptional profile. Further validation of selected genes showed consistent upregulation in 75% of genes involved in epithelial barrier function. Bioinformatic analysis of putative miRNA binding sites identified hsa-miR-125b-5p and hsa-miR-16 as regulating expression of the TJ genes CGN (cingulin) and CLDN2 (claudin-2), respectively. Consistently, protein expression of CGN and CLDN2 was upregulated in IBS-D, while the respective targeting miRNAs were downregulated. In addition, bowel dysfunction, perceived stress and depression and number of mast cells correlated with the expression of hsa-miR-125b-5p and hsa-miR-16 and their respective target proteins. CONCLUSIONS: Modulation of the intestinal epithelial barrier function in IBS-D involves both transcriptional and post transcriptional mechanisms. These molecular mechanisms include miRNAs as master regulators in controlling the expression of TJ proteins and are associated with major clinical symptoms. PMID- 28082319 TI - Delayed severe bleeding complications after treatment of pancreatic fluid collections with lumen-apposing metal stents. PMID- 28082320 TI - Red palms associated with adenovirus gastroenteritis. PMID- 28082322 TI - Headache, Chiari malformation type 1 and treatment options. PMID- 28082321 TI - Female genital mutilation in children presenting to Australian paediatricians. AB - OBJECTIVE: The WHO reports that female genital mutilation/cutting (FGM/C) is an ancient cultural practice prevalent in many countries. FGM/C has been reported among women resident in Australia. Our paper provides the first description of FGM/C in Australian children. DESIGN: Cross-sectional survey conducted in April June 2014. SETTING: Paediatricians and other child health specialists recruited through the Australian Paediatric Surveillance Unit were asked to report children aged <18 years with FGM/C seen in the last 5 years, and to provide data for demographics, FGM/C type, complications and referral for each case. PARTICIPANTS: Of 1311 eligible paediatricians/child health specialists, 1003 (76.5%) responded. RESULTS: Twenty-three (2.3%) respondents had seen 59 children with FGM/C and provided detailed data for 31. Most (89.7%) were identified during refugee screening and were born in Africa. Three (10.3%) were born in Australia: two had FGM/C in Australia and one in Indonesia. All parents were born overseas, mainly Africa (98.1%). Ten children had WHO FGM/C type I, five type II, five type III and six type IV. Complications in eight children included recurrent genitourinary infections, menstrual, sexual, fertility and psychological problems. Nineteen children (82.6%) were referred to obstetrics/gynaecology: 16 (69.9%) to social work and 13 (56.5%) to child protection. CONCLUSIONS: This study confirms that FGM/C is seen in paediatric clinical practice within Australia. Paediatricians need cultural awareness, education and resources to help them identify children with FGM/C and/or at risk of FGM/C, to enable appropriate referral and counselling of children, families and communities to assist in the prevention of this practice. PMID- 28082323 TI - Second Generation Electronic Nicotine Delivery System Vape Pen Exposure Generalizes as a Smoking Cue. AB - Introduction: Second generation electronic nicotine delivery systems (ENDS; also known as e-cigarettes, vaporizers or vape pens) are designed for a customized nicotine delivery experience and have less resemblance to regular cigarettes than first generation "cigalikes." The present study examined whether they generalize as a conditioned cue and evoke smoking urges or behavior in persons exposed to their use. Methods: Data were analyzed in N = 108 young adult smokers (>=5 cigarettes per week) randomized to either a traditional combustible cigarette smoking cue or a second generation ENDS vaping cue in a controlled laboratory setting. Cigarette and e-cigarette urge and desire were assessed pre- and post cue exposure. Smoking behavior was also explored in a subsample undergoing a smoking latency phase after cue exposure (N = 26). Results: The ENDS vape pen cue evoked both urge and desire for a regular cigarette to a similar extent as that produced by the combustible cigarette cue. Both cues produced similar time to initiate smoking during the smoking latency phase. The ENDS vape pen cue elicited smoking urge and desire regardless of ENDS use history, that is, across ENDS naive, lifetime or current users. Inclusion of past ENDS or cigarette use as covariates did not significantly alter the results. Conclusions: These findings demonstrate that observation of vape pen ENDS use generalizes as a conditioned cue to produce smoking urge, desire, and behavior in young adult smokers. As the popularity of these devices may eventually overtake those of first generation ENDS cigalikes, exposure effects will be of increasing importance. Implications: This study shows that passive exposure to a second generation ENDS vape pen cue evoked smoking urge, desire, and behavior across a range of daily and non-daily young adult smokers. Smoking urge and desire increases after vape pen exposure were similar to those produced by exposure to a first generation ENDS cigalike and a combustible cigarette, a known potent cue. Given the increasing popularity of ENDS tank system products, passive exposures to these devices will no doubt increase, and may contribute to tobacco use in young adult smokers. PMID- 28082324 TI - Genetic Dissection of a QTL Affecting Bone Geometry. AB - Parameters of bone geometry such as width, length, and cross-sectional area are major determinants of bone strength. Although these traits are highly heritable, few genes influencing bone geometry have been identified. Here, we dissect a major quantitative trait locus (QTL) influencing femur size. This QTL was originally identified in an F2 cross between the C57BL/6J-hg/hg (HG) and CAST/EiJ strains and was referred to as femur length in high growth mice 2 (Feml2). Feml2 was located on chromosome (Chr.) 9 at ~20 cM. Here, we show that the HG.CAST (D9Mit249-D9Mit133)/Ucd congenic strain captures Feml2 In an F2 congenic cross, we fine-mapped the location of Feml2 to an ~6 Mbp region extending from 57.3 to 63.3 Mbp on Chr. 9. We have identified candidates by mining the complete genome sequence of CAST/EiJ and through allele-specific expression (ASE) analysis of growth plates in C57BL/6J * CAST/EiJ F1 hybrids. Interestingly, we also find that the refined location of Feml2 overlaps a cluster of six independent genome-wide associations for human height. This work provides the foundation for the identification of novel genes affecting bone geometry. PMID- 28082325 TI - Adapting Genotyping-by-Sequencing for Rice F2 Populations. AB - Rapid and cost-effective genotyping of large mapping populations can be achieved by sequencing a reduced representation of the genome of every individual in a given population, and using that information to generate genetic markers. A customized genotyping-by-sequencing (GBS) pipeline was developed to genotype a rice F2 population from a cross of Oryza sativa ssp. japonica cv. Nipponbare and the African wild rice species O. longistaminata While most GBS pipelines aim to analyze mainly homozygous populations, we attempted to genotype a highly heterozygous F2 population. We show how species- and population-specific improvements of established protocols can drastically increase sample throughput and genotype quality. Using as few as 50,000 reads for some individuals (134,000 reads on average), we were able to generate up to 8154 informative SNP markers in 1081 F2 individuals. Additionally, the effects of enzyme choice, read coverage, and data postprocessing are evaluated. Using GBS-derived markers, we were able to assemble a genetic map of 1536 cM. To demonstrate the usefulness of our GBS pipeline, we determined quantitative trait loci (QTL) for the number of tillers. We were able to map four QTL to chromosomes 1, 3, 4, and 8, and partially confirm their effects using introgression lines. We provide an example of how to successfully use GBS with heterozygous F2 populations. By using the comparatively low-cost MiSeq platform, we show that the GBS method is flexible and cost effective, even for smaller laboratories. PMID- 28082326 TI - Friedreich Ataxia: Hypoplasia of Spinal Cord and Dorsal Root Ganglia. AB - After Friedreich's description in 1877, depletion of myelinated fibers in the dorsal columns, dorsal spinocerebellar and lateral corticospinal tracts, and neuronal loss in the dorsal nuclei of Clarke columns were considered unique and essential neuropathological features of Friedreich ataxia (FA). Lack of large neurons in dorsal root ganglia (DRG), thinning of dorsal roots (DR), and poor myelination in sensory nerves are now recognized as key components of FA. Here, we measured cross-sectional areas of the mid-thoracic spinal cord (SC) and neuronal sizes in lumbosacral DRG of 24 genetically confirmed FA cases. Mean thoracic SC areas in FA (24.17 mm2) were significantly smaller than those in 12 normal controls (37.5 mm2); DRG neuron perikarya in FA (1362 um2) were also significantly smaller than normal (2004 um2). DRG neuron sizes were not correlated with SC areas. The FA patients included a wide range of disease onset and duration suggesting that the SC undergoes growth arrest early and remains abnormally small throughout life. Immunohistochemistry for phosphorylated neurofilament protein, peripheral myelin protein 22, and myelin proteolipid protein confirmed chaotic transition of axons into the SC in DR entry zones. We conclude that smaller SC areas and lack of large DRG neurons indicate hypoplasia rather than atrophy in FA. PMID- 28082327 TI - A Functional and Neuropathological Testing Paradigm Reveals New Disability-Based Parameters and Histological Features for P0180-190-Induced Experimental Autoimmune Neuritis in C57BL/6 Mice. AB - We assessed novel disability-based parameters and neuropathological features of the P0180-190 peptide-induced model of experimental autoimmune neuritis (EAN) in C57BL/6 mice. We show that functional assessments such as running capacity provide a more sensitive method for detecting alterations in disease severity than a classical clinical scoring paradigm. We performed detailed ultrastructural analysis and show for the first time that tomaculous neuropathy is a neuropathological feature of this disease model. In addition, we demonstrate that ultrastructural assessments of myelin pathology are sufficiently sensitive to detect significant differences in both mean G-ratio and mean axon diameter between mice with EAN induced with different doses of pertussis toxin. In summary, we have established a comprehensive assessment paradigm for discriminating variations in disease severity and the extent of myelin pathology in this model. Our findings indicate that this model is a powerful tool to study the pathogenesis of human peripheral demyelinating neuropathies and that this assessment paradigm could be used to determine the efficacy of potential therapies that aim to promote myelin repair and protect against nerve damage in autoimmune neuritides. PMID- 28082328 TI - Response to Selection in Finite Locus Models with Nonadditive Effects. AB - Under the finite-locus model in the absence of mutation, the additive genetic variation is expected to decrease when directional selection is acting on a population, according to quantitative-genetic theory. However, some theoretical studies of selection suggest that the level of additive variance can be sustained or even increased when nonadditive genetic effects are present. We tested the hypothesis that finite-locus models with both additive and nonadditive genetic effects maintain more additive genetic variance (VA) and realize larger medium- to long-term genetic gains than models with only additive effects when the trait under selection is subject to truncation selection. Four genetic models that included additive, dominance, and additive-by-additive epistatic effects were simulated. The simulated genome for individuals consisted of 25 chromosomes, each with a length of 1 M. One hundred bi-allelic QTL, 4 on each chromosome, were considered. In each generation, 100 sires and 100 dams were mated, producing 5 progeny per mating. The population was selected for a single trait (h2 = 0.1) for 100 discrete generations with selection on phenotype or BLUP-EBV. VA decreased with directional truncation selection even in presence of nonadditive genetic effects. Nonadditive effects influenced long-term response to selection and among genetic models additive gene action had highest response to selection. In addition, in all genetic models, BLUP-EBV resulted in a greater fixation of favorable and unfavorable alleles and higher response than phenotypic selection. In conclusion, for the schemes we simulated, the presence of nonadditive genetic effects had little effect in changes of additive variance and VA decreased by directional selection. PMID- 28082329 TI - Tortuous great artery in association with partial anomalous pulmonary venous connection in an infant. PMID- 28082330 TI - Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes. AB - Aim: Hypertrophic cardiomyopathy (HCM) exhibits genetic heterogeneity that is dominated by variation in eight sarcomeric genes. Genetic variation in a large number of non-sarcomeric genes has also been implicated in HCM but not formally assessed. Here we used very large case and control cohorts to determine the extent to which variation in non-sarcomeric genes contributes to HCM. Methods and results: We sequenced known and putative HCM genes in a new large prospective HCM cohort (n = 804) and analysed data alongside the largest published series of clinically genotyped HCM patients (n = 6179), previously published HCM cohorts and reference population samples from the exome aggregation consortium (ExAC, n = 60 706) to assess variation in 31 genes implicated in HCM. We found no significant excess of rare (minor allele frequency < 1:10 000 in ExAC) protein altering variants over controls for most genes tested and conclude that novel variants in these genes are rarely interpretable, even for genes with previous evidence of co-segregation (e.g. ACTN2). To provide an aid for variant interpretation, we integrated HCM gene sequence data with aggregated pedigree and functional data and suggest a means of assessing gene pathogenicity in HCM using this evidence. Conclusion: We show that genetic variation in the majority of non sarcomeric genes implicated in HCM is not associated with the condition, reinforce the fact that the sarcomeric gene variation is the primary cause of HCM known to date and underscore that the aetiology of HCM is unknown in the majority of patients. PMID- 28082331 TI - Sleep during an Antarctic summer expedition: new light on "polar insomnia". AB - Sleep complaints are consistently cited as the most prominent health and well being problem in Arctic and Antarctic expeditions, without clear evidence to identify the causal mechanisms. The present investigation aimed at studying sleep and determining circadian regulation and mood during a 4-mo Antarctic summer expedition. All data collection was performed during the continuous illumination of the Antarctic summer. After an habituation night and acclimatization to the environment (3 wk), ambulatory polysomnography (PSG) was performed in 21 healthy male subjects, free of medication. An 18-h profile (saliva sampling every 2 h) of cortisol and melatonin was assessed. Mood, sleepiness, and subjective sleep quality were assessed, and the psychomotor vigilance task was administered. PSG showed, in addition to high sleep fragmentation, a major decrease in slow-wave sleep (SWS) and an increase in stage R sleep. Furthermore, the ultradian rhythmicity of sleep was altered, with SWS occurring mainly at the end of the night and stage R sleep at the beginning. Cortisol secretion profiles were normal; melatonin secretion, however, showed a severe phase delay. There were no mood alterations according to the Profile of Mood States scores, but the psychomotor vigilance test showed an impaired vigilance performance. These results confirm previous reports on "polar insomnia", the decrease in SWS, and present novel insight, the disturbed ultradian sleep structure. A hypothesis is formulated linking the prolonged SWS latency to the phase delay in melatonin.NEW & NOTEWORTHY The present paper presents a rare body of work on sleep and sleep wake regulation in the extreme environment of an Antarctic expedition, documenting the effects of constant illumination on sleep, mood, and chronobiology. For applied research, these results suggest the potential efficiency of melatonin supplementation in similar deployments. For fundamental research, these results warrant further investigation of the potential link between melatonin secretion and the onset of slow-wave sleep. PMID- 28082332 TI - Losartan reduces the immediate and sustained increases in muscle sympathetic nerve activity after hyperacute intermittent hypoxia. AB - Obstructive sleep apnea (OSA) is characterized by intermittent hypoxemia, which produces elevations in sympathetic nerve activity (SNA) and associated hypertension in experimental models that persist beyond the initial exposure. We tested the hypotheses that angiotensin receptor blockade in humans using losartan attenuates the immediate and immediately persistent increases in 1) SNA discharge and 2) mean arterial pressure (MAP) after hyperacute intermittent hypoxia training (IHT) using a randomized, placebo-controlled, repeated-measures experimental design. We measured ECG and photoplethysmographic arterial pressure in nine healthy human subjects, while muscle SNA (MSNA) was recorded in seven subjects using microneurography. Subjects were exposed to a series of hypoxic apneas in which they inhaled two to three breaths of nitrogen, followed by a 20-s apnea and 40 s of room air breathing every minute for 20 min. Hyperacute IHT produced substantial and persistent elevations in MSNA burst frequency (baseline: 15.3 +/- 1.8, IHT: 24 +/- 1.5, post-IHT 20.0 +/- 1.3 bursts/min, all P < 0.01) and MAP (baseline: 89.2 +/- 3.3, IHT: 92.62 +/- 3.1, post-IHT: 93.83 +/- 3.1 mmHg, all P < 0.02). Losartan attenuated the immediate and sustained increases in MSNA (baseline: 17.3 +/- 2.5, IHT: 18.6 +/- 2.2, post-IHT 20.0 +/- 1.3 bursts/min, all P < 0.001) and MAP (baseline: 81.9 +/- 2.6, IHT: 81.1 +/- 2.8, post-IHT: 81.3 +/- 3.0 mmHg, all P > 0.70). This investigation confirms the role of angiotensin II type 1a receptors in the immediate and persistent sympathoexcitatory and pressor responses to IHT.NEW & NOTEWORTHY This study demonstrates for the first time in humans that losartan, an angiotensin receptor blocker (ARB), abrogates the acute and immediately persistent increases in muscle sympathetic nerve activity and arterial pressure in response to acute intermittent hypoxia. This investigation, along with others, provides important beginning translational evidence for using ARBs in treatment of the intermittent hypoxia observed in obstructive sleep apnea patients. PMID- 28082333 TI - The cerebrovascular response to lower-body negative pressure vs. head-up tilt. AB - Lower-body negative pressure (LBNP) has been proposed as a MRI-compatible surrogate for orthostatic stress. Although the effects of LBNP on cerebral hemodynamic behavior have been considered to reflect those of orthostatic stress, a direct comparison with actual orthostasis is lacking. We assessed the effects of LBNP (-50 mmHg) vs. head-up tilt (HUT; at 70 degrees ) in 10 healthy subjects (5 female) on transcranial Doppler-determined cerebral blood flow velocity (CBFv) in the middle cerebral artery and cerebral perfusion pressure (CPP) as estimated from the blood pressure signal (finger plethysmography). CPP was maintained during LBNP but decreased after 2 min in response to HUT, leading to an ~15% difference in CPP between LBNP and HUT (P <= 0.020). Mean CBFv initially decreased similarly in response to LBNP and for HUT, but, from minute 3 on, the decline became ~50% smaller (P <= 0.029) during LBNP. The reduction in end-tidal Pco2 partial pressure (PetCO2 ) was comparable but with an earlier return toward baseline values in response to LBNP but not during HUT (P = 0.008). We consider the larger decrease in CBFv during HUT vs. LBNP attributable to the pronounced reduction in PetCO2 and to gravitational influences on CPP, and this should be taken into account when applying LBNP as an MRI-compatible orthostatic stress modality.NEW & NOTEWORTHY Lower-body negative pressure (LBNP) has the potential to serve as a MRI-compatible surrogate of orthostatic stress but a comparison with actual orthostasis was lacking. This study showed that the pronounced reduction in end-tidal Pco2 together with gravitational effects on the brain circulation lead to a larger decline in cerebral blood flow velocity in response to head-up tilt than during lower-body negative pressure. This should be taken into account when employing lower-body negative pressure as MRI-compatible alternative to orthostatic stress. PMID- 28082334 TI - Moderate-intensity resistance exercise alters skeletal muscle molecular and cellular structure and function in inactive older adults with knee osteoarthritis. AB - High-intensity resistance exercise (REX) training increases physical capacity, in part, by improving muscle cell size and function. Moderate-intensity REX, which is more feasible for many older adults with disease and/or disability, also increases physical function, but the mechanisms underlying such improvements are not understood. Therefore, we measured skeletal muscle structure and function from the molecular to the tissue level in response to 14 wk of moderate-intensity REX in physically inactive older adults with knee osteoarthritis (n = 17; 70 +/- 1 yr). Although REX training increased quadriceps muscle cross-sectional area (CSA), average single-fiber CSA was unchanged because of reciprocal changes in myosin heavy chain (MHC) I and IIA fibers. Intermyofibrillar mitochondrial content increased with training because of increases in mitochondrial size in men, but not women, with no changes in subsarcolemmal mitochondria in either sex. REX increased whole muscle contractile performance similarly in men and women. In contrast, adaptations in single-muscle fiber force production per CSA (i.e., tension) and contractile velocity varied between men and women in a fiber type dependent manner, with adaptations being explained at the molecular level by differential changes in myosin-actin cross-bridge kinetics and mechanics and single-fiber MHC protein expression. Our results are notable compared with studies of high-intensity REX because they show that the effects of moderate intensity REX in older adults on muscle fiber size/structure and myofilament function are absent or modest. Moreover, our data highlight unique sex-specific adaptations due to differential cellular and subcellular structural and functional changes.NEW & NOTEWORTHY Moderate-intensity resistance training causes sex-specific adaptations in skeletal muscle structure and function at the cellular and molecular levels in inactive older adult men and women with knee osteoarthritis. However, these responses were minimal compared with high intensity resistance training. Thus adjuncts to moderate-intensity training need to be developed to correct underlying cellular and molecular structural and functional deficits that are at the root of impaired physical function in this mobility-limited population. PMID- 28082336 TI - Kinetics of circulating progenitor cell mobilization during submaximal exercise. AB - Circulating progenitor cells (CPCs) are a heterogeneous population of stem/progenitor cells in peripheral blood that includes hematopoietic stem and progenitor cells (HSPCs and HSCs), endothelial progenitor cells (EPCs), and mesenchymal stem cells (MSCs) that are involved in tissue repair and adaptation. CPC mobilization during exercise remains uncharacterized in young adults. The purpose of this study was to investigate the kinetics of CPC mobilization during and after submaximal treadmill running and their relationship to mobilization factors. Seven men [age = 25.3 +/- 2.4 yr, body mass index = 23.5 +/- 1.0 kg/m2, peak O2 uptake (Vo2peak) = 60.9 +/- 2.74 ml.kg-1.min-1] ran on a treadmill for 60 min at 70% Vo2peak Blood sampling occurred before (Pre), during [20 min (20e), 40 min (40e), 60 min (60e)], and after exercise [15 min (15p), 60 min (60p), 120 min (120p)] for quantification of CPCs (CD34+), HSPCs (CD34+/CD45low), HSCs (CD34+/CD45low/CD38-), CD34+ MSCs (CD45-/CD34+/CD31-/CD105+), CD34- MSCs (CD45 /CD34-/CD31-/CD105+), and EPCs (CD45-/CD34+/CD31+) via flow cytometry. CPC concentration increased compared with Pre at 20e and 40e (2.7- and 2.4-fold, respectively, P < 0.05). HSPCs and HSCs increased at 20e compared with 60p (2.7- and 2.8-fold, respectively, P < 0.05), whereas EPCs and both MSC populations did not change. CXC chemokine ligand (CXCL) 12 (1.5-fold; P < 0.05) and stem cell factor (1.3-fold; P < 0.05) were increased at 40e and remained elevated postexercise. The peak increase in CPCs was positively correlated to concentration of endothelial cells during exercise with no relationship to CXCL12 and SCF. Our data show the kinetics of progenitor cell mobilization during exercise that could provide insight into cellular mediators of exercise-induced adaptations, and have implication for the use of exercise as an adjuvant therapy for CPC collection in hematopoietic stem cell transplant.NEW & NOTEWORTHY Using a comprehensive evaluation of circulating progenitor cells (CPCs), we show that CPC mobilization during exercise is related to tissue damage, and not plasma concentrations of CXC chemokine ligand 12 and stem cell factor. These data have implications for the use of exercise interventions as adjuvant therapy for CPC mobilization in the context of hematopoietic stem cell transplant and also support the role of mobilized progenitor cells as cellular mediators of systemic adaptations to exercise. PMID- 28082335 TI - Adenosine receptor-dependent signaling is not obligatory for normobaric and hypobaric hypoxia-induced cerebral vasodilation in humans. AB - Hypoxia increases cerebral blood flow (CBF) with the underlying signaling processes potentially including adenosine. A randomized, double-blinded, and placebo-controlled design, was implemented to determine if adenosine receptor antagonism (theophylline, 3.75 mg/Kg) would reduce the CBF response to normobaric and hypobaric hypoxia. In 12 participants the partial pressures of end-tidal oxygen ([Formula: see text]) and carbon dioxide ([Formula: see text]), ventilation (pneumotachography), blood pressure (finger photoplethysmography), heart rate (electrocardiogram), CBF (duplex ultrasound), and intracranial blood velocities (transcranial Doppler ultrasound) were measured during 5-min stages of isocapnic hypoxia at sea level (98, 90, 80, and 70% [Formula: see text]). Ventilation, [Formula: see text] and [Formula: see text], blood pressure, heart rate, and CBF were also measured upon exposure (128 +/- 31 min following arrival) to high altitude (3,800 m) and 6 h following theophylline administration. At sea level, although the CBF response to hypoxia was unaltered pre- and postplacebo, it was reduced following theophylline (P < 0.01), a finding explained by a lower [Formula: see text] (P < 0.01). Upon mathematical correction for [Formula: see text], the CBF response to hypoxia was unaltered following theophylline. Cerebrovascular reactivity to hypoxia (i.e., response slope) was not different between trials, irrespective of [Formula: see text] At high altitude, theophylline (n = 6) had no effect on CBF compared with placebo (n = 6) when end tidal gases were comparable (P > 0.05). We conclude that adenosine receptor dependent signaling is not obligatory for cerebral hypoxic vasodilation in humans.NEW & NOTEWORTHY The signaling pathways that regulate human cerebral blood flow in hypoxia remain poorly understood. Using a randomized, double-blinded, and placebo-controlled study design, we determined that adenosine receptor-dependent signaling is not obligatory for the regulation of human cerebral blood flow at sea level; these findings also extend to high altitude. PMID- 28082338 TI - New diagnosis of polycystic ovary syndrome. PMID- 28082337 TI - Contribution of rostral fluid shift to intrathoracic airway narrowing in asthma. AB - In asthma, supine posture and sleep increase intrathoracic airway narrowing. When humans are supine, because of gravity fluid moves out of the legs and accumulates in the thorax. We hypothesized that fluid shifting out of the legs into the thorax contributes to the intrathoracic airway narrowing in asthma. Healthy and asthmatic subjects sat for 30 min and then lay supine for 30 min. To simulate overnight fluid shift, supine subjects were randomized to receive increased fluid shift out of the legs with lower body positive pressure (LBPP, 10-30 min) or none (control) and crossed over. With forced oscillation at 5 Hz, respiratory resistance (R5) and reactance (X5, reflecting respiratory stiffness) and with bioelectrical impedance, leg and thoracic fluid volumes (LFV, TFV) were measured while subjects were seated and supine (0 min, 30 min). In 17 healthy subjects (age: 51.8 +/- 10.9 yr, FEV1/FVC z score: -0.4 +/- 1.1), changes in R5 and X5 were similar in both study arms (P > 0.05). In 15 asthmatic subjects (58.5 +/- 9.8 yr, -2.1 +/- 1.3), R5 and X5 increased in both arms (DeltaR5: 0.6 +/- 0.9 vs. 1.4 +/- 0.8 cmH2O.l-1.s-1, DeltaX5: 0.3 +/- 0.7 vs. 1.1 +/- 0.9 cmH2O.l-1.s-1). The increases in R5 and X5 were 2.3 and 3.7 times larger with LBPP than control, however (P = 0.008, P = 0.006). The main predictor of increases in R5 with LBPP was increases in TFV (r = 0.73, P = 0.002). In asthmatic subjects, the magnitude of increases in X5 with LBPP was comparable to that with posture change from sitting to supine (1.1 +/- 0.9 vs. 1.4 +/- 0.9 cmH2O.l-1.s-1, P = 0.32). We conclude that in asthmatic subjects fluid shifting from the legs to the thorax while supine contributed to increases in the respiratory resistance and stiffness.NEW & NOTEWORTHY In supine asthmatic subjects, application of positive pressure to the lower body caused appreciable increases in respiratory system resistance and stiffness. Moreover, these changes in respiratory mechanics correlated positively with increase in thoracic fluid volume. These findings suggest that fluid shifts from the lower body to the thorax may contribute to overnight intrathoracic airway narrowing and worsening of asthma symptoms. PMID- 28082339 TI - BCR-ABL translocation as a favorable prognostic factor in elderly patients with acute lymphoblastic leukemia in the era of potent tyrosine kinase inhibitors. PMID- 28082340 TI - Long-term relapse-free survival in a phase 2 study of blinatumomab for the treatment of patients with minimal residual disease in B-lineage acute lymphoblastic leukemia. PMID- 28082341 TI - The transcription factor GATA1 regulates NBEAL2 expression through a long distance enhancer. AB - Gray platelet syndrome is named after the gray appearance of platelets due to the absence of alpha-granules. It is caused by recessive mutations in NBEAL2, resulting in macrothrombocytopenia and myelofibrosis. Though using the term gray platelets for GATA1 deficiency has been debated, a reduced number of alpha granules has been described for macrothrombocytopenia due to GATA1 mutations. We compared platelet size and number of alpha-granules for two NBEAL2 and two GATA1 deficient patients and found reduced numbers of alpha-granules for all, with the defect being more pronounced for NBEAL2 deficiency. We further hypothesized that the granule defect for GATA1 is due to a defective control of NBEAL2 expression. Remarkably, platelets from two patients, and Gata1-deficient mice, expressed almost no NBEAL2. The differentiation of GATA1 patient-derived CD34+ stem cells to megakaryocytes showed defective proplatelet and alpha-granule formation with strongly reduced NBEAL2 protein and ribonucleic acid expression. Chromatin immunoprecipitation sequencing revealed 5 GATA binding sites in a regulatory region 31 kb upstream of NBEAL2 covered by a H3K4Me1 mark indicative of an enhancer locus. Luciferase reporter constructs containing this region confirmed its enhancer activity in K562 cells, and mutagenesis of the GATA1 binding sites resulted in significantly reduced enhancer activity. Moreover, DNA binding studies showed that GATA1 and GATA2 physically interact with this enhancer region. GATA1 depletion using small interfering ribonucleic acid in K562 cells also resulted in reduced NBEAL2 expression. In conclusion, we herein show a long distance regulatory region with GATA1 binding sites as being a strong enhancer for NBEAL2 expression. PMID- 28082342 TI - Second-line rituximab, lenalidomide, and bendamustine in mantle cell lymphoma: a phase II clinical trial of the Fondazione Italiana Linfomi. PMID- 28082343 TI - Integrative clinicopathological and molecular analyses of angioimmunoblastic T cell lymphoma and other nodal lymphomas of follicular helper T-cell origin. PMID- 28082344 TI - Is immunotherapy here to stay in multiple myeloma? AB - Immune escape and impaired immune surveillance have been identified as emerging hallmarks of cancer.1 Multiple myeloma represents a genuine example of disrupted immune surveillance characterized by: impaired antibody production, deregulation of the T and natural killer cell compartment, disruption of antigen presentation machinery, upregulation of inhibitory surface ligands, and recruitment of immunosuppressive cells. Although the potential value of immunotherapeutic interventions had a clear antecedent in the graft-versus-myeloma effect induced by allogeneic stem cell transplant and donor lymphocyte infusions, it is only recently that this field has faced a real revolution. In this review we discuss the current results obtained with immune approaches in patients with multiple myeloma that have placed this disease under the scope of immuno-oncology, bringing new therapeutic opportunities for the treatment of multiple myeloma patients. PMID- 28082345 TI - Gfi1b controls integrin signaling-dependent cytoskeleton dynamics and organization in megakaryocytes. AB - Mutations in GFI1B are associated with inherited bleeding disorders called GFI1B related thrombocytopenias. We show here that mice with a megakaryocyte-specific Gfi1b deletion exhibit a macrothrombocytopenic phenotype along a megakaryocytic dysplasia reminiscent of GFI1B-related thrombocytopenia. GFI1B deficiency increases megakaryocyte proliferation and affects their ploidy, but also abrogates their responsiveness towards integrin signaling and their ability to spread and reorganize their cytoskeleton. Gfi1b-null megakaryocytes are also unable to form proplatelets, a process independent of integrin signaling. GFI1B deficient megakaryocytes exhibit aberrant expression of several components of both the actin and microtubule cytoskeleton, with a dramatic reduction of alpha tubulin. Inhibition of FAK or ROCK, both important for actin cytoskeleton organization and integrin signaling, only partially restored their response to integrin ligands, but the inhibition of PAK, a regulator of the actin cytoskeleton, completely rescued the responsiveness of Gfi1b-null megakaryocytes to ligands, but not their ability to form proplatelets. We conclude that Gfi1b controls major functions of megakaryocytes such as integrin-dependent cytoskeleton organization, spreading and migration through the regulation of PAK activity whereas the proplatelet formation defect in GFI1B-deficient megakaryocytes is due, at least partially, to an insufficient alpha-tubulin content. PMID- 28082346 TI - Initiation, Progression, and Sustained Waterpipe Use: A Nationally Representative Longitudinal Study of U.S. Young Adults. AB - Background: Waterpipe tobacco smoking (WTS) is increasing in popularity despite evidence of harm and potential for dependence. Intervention development has been hampered by a lack of longitudinal, nationally representative data on usage patterns and factors independently associated with WTS initiation. Therefore, we aimed to characterize key transitions between WTS states in a nationally representative group of young adults, with particular attention to factors independently associated with initiation.Methods: Participants were randomly selected from a national probability-based panel representing 97% of the United States. A total of 1,785 adults ages 18 to 30 at baseline completed two Web-based surveys 18 months apart in 2013 and 2014. Assessments included knowledge of waterpipe tobacco smoke composition, positive and negative attitudes toward WTS, normative beliefs, intention to use waterpipe, and WTS behavior. We used multivariable logistic regression to assess the association between predictive factors and subsequent WTS initiation.Results: In fully adjusted models, overall knowledge about toxicants associated with WTS was not associated with subsequent WTS initiation. Similarly, negative attitudes and normative beliefs were not associated with WTS uptake. However, baseline positive attitudes were strongly and significantly associated with WTS initiation [adjusted OR (AOR) = 1.7; 95% confidence interval (CI), 1.2-2.3]. Similarly, baseline intention to use WTS was strongly associated with subsequent initiation (AOR = 7.0; 95% CI, 3.5 13.7).Conclusions: Prevention efforts may be most successful if they target individuals with clear intentions to use WTS and challenge positive attitudes surrounding WTS.Impact: Surveillance of WTS trajectories will help inform health care and policy surrounding this emerging risk behavior among U.S. young adults. Cancer Epidemiol Biomarkers Prev; 26(5); 748-55. (c)2017 AACR. PMID- 28082347 TI - Cytokeratin 7 in Oropharyngeal Squamous Cell Carcinoma: A Junctional Biomarker for Human Papillomavirus-Related Tumors. AB - Background: Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (SCC) represents a distinct subgroup of head and neck tumors. We analyze the expression of cytokeratin 7, a junctional biomarker with a SEQIKA fragment, which stabilizes HPV-16 E7 transcripts, in oropharyngeal SCCs.Methods: Archived tumor specimens and epidemiologic data were collected from patients with oropharyngeal SCCs over 10 years. Briefly, DNA was extracted from tissue blocks, and HPV testing was carried out using SPF10 HPV PCR and INNO-LiPA HPV Genotyping. Immunohistochemical staining for CK7 and p16ink4a was performed on the Ventana BenchMark Ultra Immunostainer. Analysis was by light microscopy using the H score. CK7 expression was correlated with epidemiologic data, p16ink4a positivity, and HPV status using SPSS.Results: CK7 expression was observed specifically and uniformly in the tonsillar crypt epithelium of normal tonsils and tumor specimens. There were 226 cases of oropharyngeal SCCs, with 70 demonstrating both HPV and p16 positivity. Of 216 cases evaluated for CK7, 106 demonstrated some positivity, whereas H-score > 60 was seen in 55 of these. CK7 H score > 60 was significantly associated with tonsillar subsite and HPV and p16 positivity.Conclusions: An association between CK7 and HPV has been demonstrated. CK7-expressing tonsillar crypt cells potentially represent an oropharyngeal subsite susceptible to HPV-related SCC.Impact: Along with the cervix and anorectum, specific oropharyngeal expression of CK7 in a site predisposed to HPV related tumors may suggest a role for CK7 in the pathogenesis of this subgroup of tumors. Further research is warranted to characterize the association between CK7 and HPV-related head and neck SCC. Cancer Epidemiol Biomarkers Prev; 26(5); 702 10. (c)2017 AACR. PMID- 28082349 TI - Seasonality of the Mediterranean Fruit Fly (Diptera: Tephritidae) on Terceira and Sao Jorge Islands, Azores, Portugal. AB - Population dynamics studies are very important for any area-wide control program as they provide detailed knowledge about the relationship of Medfly [Ceratitis capitata (Wiedemann)] life cycle with host availability and abundance. The main goal of this study is to analyse seasonality of C. capitata in Terceira and Sao Jorge Islands (Azores archipelago) using field and laboratory data collected during (2010-2014) CABMEDMAC (MAC/3/A163) project. The results from Sao Jorge Island indicate significantly lower male/female ratio than on Terceira Island. This is an important finding specially regarding when stablishing the scenario parameters for a sterile insect technique application in each island. The population dynamics of C. capitata are generally linked with host fruit availability and abundance. However, on Terceira Island fruit infestation levels are not synchronized with the trap counts. For example, there was Medfly infestations in some fruits [e.g., Solanum mauritianum (Scop.)] while in the nearby traps there were no captures at the same time. From this perspective, it is important to denote the importance of wild invasive plants, on the population dynamics of C. capitata, as well important to consider the possibility of having different densities of traps according to the characteristics of each area in order to improve the network of traps surveillance's sensitivity on Terceira Island. PMID- 28082348 TI - Interactome disassembly during apoptosis occurs independent of caspase cleavage. AB - Protein-protein interaction networks (interactomes) define the functionality of all biological systems. In apoptosis, proteolysis by caspases is thought to initiate disassembly of protein complexes and cell death. Here we used a quantitative proteomics approach, protein correlation profiling (PCP), to explore changes in cytoplasmic and mitochondrial interactomes in response to apoptosis initiation as a function of caspase activity. We measured the response to initiation of Fas-mediated apoptosis in 17,991 interactions among 2,779 proteins, comprising the largest dynamic interactome to date. The majority of interactions were unaffected early in apoptosis, but multiple complexes containing known caspase targets were disassembled. Nonetheless, proteome-wide analysis of proteolytic processing by terminal amine isotopic labeling of substrates (TAILS) revealed little correlation between proteolytic and interactome changes. Our findings show that, in apoptosis, significant interactome alterations occur before and independently of caspase activity. Thus, apoptosis initiation includes a tight program of interactome rearrangement, leading to disassembly of relatively few, select complexes. These early interactome alterations occur independently of cleavage of these protein by caspases. PMID- 28082350 TI - Secretin is involved in sodium conservation through the renin-angiotensin aldosterone system. AB - Secretin (SCT) and its receptor (SCTR) are important in fluid regulation at multiple levels via the modulation of expression and translocation of renal aquaporin 2 and functions of central angiotensin II (ANGII). The functional interaction of SCT with peripheral ANGII, however, remains unknown. As the ANGII aldosterone axis dominates the regulation of renal epithelial sodium channel (ENaC) function, we therefore tested whether SCT/SCTR can regulate sodium homeostasis via the renin-angiotensin-aldosterone system. SCTR-knockout (SCTR-/-) mice showed impaired aldosterone synthase (CYP11B2) expression and, consequently, aldosterone release upon intraperitoneal injection of ANGII. Endogenous ANGII production induced by dietary sodium restriction was higher in SCTR-/- than in C57BL/6N [wild-type (WT)] mice, but CYP11B2 and aldosterone synthesis were not elevated. Reduced accumulation of cholesteryl ester-the precursor of aldosterone was observed in adrenal glands of SCTR-/- mice that were fed a low-sodium diet. Absence of SCTR resulted in elevated basal transcript levels of adrenal CYP11B2 and renal ENaCs. Although transcript and protein levels of ENaCs were similar in WT and SCTR-/- mice under sodium restriction, ENaCs in SCTR-/- mice were less sensitive to amiloride hydrochloride. In summary, the SCT/SCTR axis is involved in aldosterone precursor uptake, and the knockout of SCTR results in defective aldosterone biosynthesis/release and altered sensitivity of ENaCs to amiloride. Bai, J., Chow, B. K. C. Secretin is involved in sodium conservation through the renin-angiotensin-aldosterone system. PMID- 28082351 TI - FTY720/fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann-Pick type C mutant fibroblasts. AB - Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder caused by mutations in NPC1 or NPC2 with decreased functions leading to lysosomal accumulation of cholesterol and sphingolipids. FTY720/fingolimod, used for treatment of multiple sclerosis, is phosphorylated by nuclear sphingosine kinase 2, and its active phosphorylated form (FTY720-P) is an inhibitor of class I histone deacetylases. In this study, administration of clinically relevant doses of FTY720 to mice increased expression of NPC1 and -2 in brain and liver and decreased cholesterol in an SphK2-dependent manner. FTY720 greatly increased expression of NPC1 and -2 in human NPC1 mutant fibroblasts that correlated with formation of FTY720-P and significantly reduced the accumulation of cholesterol and glycosphingolipids. In agreement with this finding, FTY720 pretreatment of human NPC1 mutant fibroblasts restored transport of the cholera toxin B subunit, which binds ganglioside GM1, to the Golgi apparatus. Together, these findings suggest that FTY720 administration can ameliorate cholesterol and sphingolipid storage and trafficking defects in NPC1 mutant fibroblasts. Because neurodegeneration is the main clinical feature of NPC disease, and FTY720 accumulates in the CNS and has several advantages over available histone deacetylase inhibitors now in clinical trials, our work provides a potential opportunity for treatment of this incurable disease.-Newton, J., Hait, N. C., Maceyka, M., Colaco, A., Maczis, M., Wassif, C. A., Cougnoux, A., Porter, F. D., Milstien, S., Platt, N., Platt, F. M., Spiegel, S. FTY720/fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann-Pick type C mutant fibroblasts. PMID- 28082352 TI - Estrogen receptor alpha is required for oviductal transport of embryos. AB - Newly fertilized embryos spend the first few days within the oviduct and are transported to the uterus, where they implant onto the uterine wall. An implantation of the embryo before reaching the uterus could result in ectopic pregnancy and lead to maternal death. Estrogen is necessary for embryo transport in mammals; however, the mechanism involved in estrogen-mediated cellular function within the oviduct remains unclear. In this study, we show in mouse models that ciliary length and beat frequency of the oviductal epithelial cells are regulated through estrogen receptor alpha (ESR1) but not estrogen receptor beta (ESR2). Gene profiling indicated that transcripts in the WNT/beta-catenin (WNT/CTNNB1) signaling pathway were regulated by estrogen in mouse oviduct, and inhibition of this pathway in a whole oviduct culture system resulted in a decreased embryo transport distance. However, selective ablation of CTNNB1 from the oviductal ciliated cells did not affect embryo transport, possibly because of a compensatory mechanism via intact CTNNB1 in the adjacent secretory cells. In summary, we demonstrated that disruption of estrogen signaling in oviductal epithelial cells alters ciliary function and impairs embryo transport. Therefore, our findings may provide a better understanding of etiology of the ectopic pregnancy that is associated with alteration of estrogen signals.-Li, S., O'Neill, S. R. S., Zhang, Y., Holtzman, M. J., Takemaru, K.-I., Korach, K. S., Winuthayanon, W. Estrogen receptor alpha is required for oviductal transport of embryos. PMID- 28082353 TI - Gestational disruptions in metabolic rhythmicity of the liver, muscle, and placenta affect fetal size. AB - Maternal metabolic adaptations are essential for successful pregnancy outcomes. We investigated how metabolic gestational processes are coordinated, whether there is a functional link with internal clocks, and whether disruptions are related to metabolic abnormalities in pregnancy, by studying day/night metabolic pathways in murine models and samples from pregnant women with normally grown and large-for-gestational age infants. In early mouse pregnancy, expression of hepatic lipogenic genes was up-regulated and uncoupled from the hepatic clock. In late mouse pregnancy, rhythmicity of energy metabolism-related genes in the muscle followed the patterns of internal clock genes in this tissue, and coincided with enhanced lipid transporter expression in the fetoplacental unit. Diurnal triglyceride patterns were disrupted in human placentas from pregnancies with large-for-gestational age infants and this overlapped with an increase in BMAL1 expression. Metabolic adaptations in early pregnancy are uncoupled from the circadian clock, whereas in late pregnancy, energy availability is mediated by coordinated muscle-placenta metabolic adjustments linked to internal clocks. Placental triglyceride oscillations in the third trimester of human pregnancy are lost in large-for-gestational age infants and may be regulated by BMAL1. In summary, disruptions in metabolic and circadian rhythmicity are associated with increased fetal size, with implications for the pathogenesis of macrosomia. Papacleovoulou, G., Nikolova, V., Oduwole, O., Chambers, J., Vazquez-Lopez, M., Jansen, E., Nicolaides, K., Parker, M., Williamson, C. Gestational disruptions in metabolic rhythmicity of the liver, muscle, and placenta affect fetal size. PMID- 28082354 TI - Combination therapy with liposomal neuroprotectants and tissue plasminogen activator for treatment of ischemic stroke. AB - For ischemic stroke treatment, extension of the therapeutic time window (TTW) of thrombolytic therapy with tissue plasminogen activator (tPA) and amelioration of secondary ischemia/reperfusion (I/R) injury are most desirable. Our previous studies have indicated that liposomal delivery of neuroprotectants into an ischemic region is effective for stroke treatment. In the present study, for solving the above problems in the clinical setting, the usefulness of combination therapy with tPA and liposomal fasudil (fasudil-Lip) was investigated in ischemic stroke model rats with photochemically induced thrombosis, with clots that were dissolved by tPA. Treatment with tPA 3 h after occlusion markedly increased blood brain barrier permeability and activated matrix metalloproteinase (MMP)-2 and -9, which are involved in cerebral hemorrhage. However, an intravenous administration of fasudil-Lip before tPA markedly suppressed the increase in permeability and the MMP activation stemming from tPA. The combination treatment showed significantly larger neuroprotective effects, even in the case of delayed tPA administration compared with each treatment alone or the tPA/fasudil-treated group. These findings suggest that treatment with fasudil-Lip before tPA could decrease the risk of tPA-derived cerebral hemorrhage and extend the TTW of tPA and that the combination therapy could be a useful therapeutic option for ischemic stroke.-Fukuta, T., Asai, T., Yanagida, Y., Namba, M., Koide, H., Shimizu, K., Oku, N. Combination therapy with liposomal neuroprotectants and tissue plasminogen activator for treatment of ischemic stroke. PMID- 28082355 TI - Under pressure. PMID- 28082356 TI - IKKalpha controls ATG16L1 degradation to prevent ER stress during inflammation. AB - Inhibition of the IkappaB kinase complex (IKK) has been implicated in the therapy of several chronic inflammatory diseases including inflammatory bowel diseases. In this study, using mice with an inactivatable IKKalpha kinase (IkkalphaAA/AA), we show that loss of IKKalpha function markedly impairs epithelial regeneration in a model of acute colitis. Mechanistically, this is caused by compromised secretion of cytoprotective IL-18 from IKKalpha-mutant intestinal epithelial cells because of elevated caspase 12 activation during an enhanced unfolded protein response (UPR). Induction of the UPR is linked to decreased ATG16L1 stabilization in IkkalphaAA/AA mice. We demonstrate that both TNF-R and nucleotide-binding oligomerization domain stimulation promote ATG16L1 stabilization via IKKalpha-dependent phosphorylation of ATG16L1 at Ser278. Thus, we propose IKKalpha as a central mediator sensing both cytokine and microbial stimulation to suppress endoplasmic reticulum stress, thereby assuring antiinflammatory function during acute intestinal inflammation. PMID- 28082357 TI - Defective ATG16L1-mediated removal of IRE1alpha drives Crohn's disease-like ileitis. AB - ATG16L1T300A, a major risk polymorphism in Crohn's disease (CD), causes impaired autophagy, but it has remained unclear how this predisposes to CD. In this study, we report that mice with Atg16l1 deletion in intestinal epithelial cells (IECs) spontaneously develop transmural ileitis phenocopying ileal CD in an age dependent manner, driven by the endoplasmic reticulum (ER) stress sensor IRE1alpha. IRE1alpha accumulates in Paneth cells of Atg16l1DeltaIEC mice, and humans homozygous for ATG16L1T300A exhibit a corresponding increase of IRE1alpha in intestinal epithelial crypts. In contrast to a protective role of the IRE1beta isoform, hyperactivated IRE1alpha also drives a similar ileitis developing earlier in life in Atg16l1;Xbp1DeltaIEC mice, in which ER stress is induced by deletion of the unfolded protein response transcription factor XBP1. The selective autophagy receptor optineurin interacts with IRE1alpha, and optineurin deficiency amplifies IRE1alpha levels during ER stress. Furthermore, although dysbiosis of the ileal microbiota is present in Atg16l1;Xbp1DeltaIEC mice as predicted from impaired Paneth cell antimicrobial function, such structural alteration of the microbiota does not trigger ileitis but, rather, aggravates dextran sodium sulfate-induced colitis. Hence, we conclude that defective autophagy in IECs may predispose to CD ileitis via impaired clearance of IRE1alpha aggregates during ER stress at this site. PMID- 28082360 TI - Comment on: Pneumocystis jirovecii pneumonia: still a concern in patients with haematological malignancies and stem cell transplant recipients. PMID- 28082359 TI - Class II MHC-independent suppressive adhesion of dendritic cells by regulatory T cells in vivo. AB - Regulatory T (T reg) cells are essential for peripheral homeostasis and known to target and suppress dendritic cells (DCs). One important mechanism is through prolonged interaction between antigen-specific T reg cells and DCs that down regulates the co-stimulatory capacity of DCs. However, the dynamics and TCR specificities of such T reg cell-DC interaction and its relevance to the suppressive outcomes for individual DCs have not been clarified. To gain insights into the underlying cellular events in vivo, we analyzed individual T reg cell-DC interaction events in lymph nodes by intravital microscopy. Our results show that, upon exposure to interleukin-2, T reg cells formed prolonged adhesive contact with DCs, independent of antigen or MHC recognition, which significantly suppressed the contemporaneous interaction of the same DCs with antigen-specific conventional T cells and impaired T cell priming. Therefore, T reg cells may function in part as feedback regulators in inflammatory milieu, by suppressing local DCs and interrupting immune activation in a contact-dependent and class II MHC-independent manner. PMID- 28082358 TI - Strong adhesion by regulatory T cells induces dendritic cell cytoskeletal polarization and contact-dependent lethargy. AB - Dendritic cells are targeted by regulatory T (T reg) cells, in a manner that operates as an indirect mode of T cell suppression. In this study, using a combination of single-cell force spectroscopy and structured illumination microscopy, we analyze individual T reg cell-DC interaction events and show that T reg cells exhibit strong intrinsic adhesiveness to DCs. This increased DC adhesion reduces the ability of contacted DCs to engage other antigen-specific cells. We show that this unusually strong LFA-1-dependent adhesiveness of T reg cells is caused in part by their low calpain activities, which normally release integrin-cytoskeleton linkage, and thereby reduce adhesion. Super resolution imaging reveals that such T reg cell adhesion causes sequestration of Fascin-1, an actin-bundling protein essential for immunological synapse formation, and skews Fascin-1-dependent actin polarization in DCs toward the T reg cell adhesion zone. Although it is reversible upon T reg cell disengagement, this sequestration of essential cytoskeletal components causes a lethargic state of DCs, leading to reduced T cell priming. Our results reveal a dynamic cytoskeletal component underlying T reg cell-mediated DC suppression in a contact-dependent manner. PMID- 28082361 TI - Extensive Ca2+ leak through K4750Q cardiac ryanodine receptors caused by cytosolic and luminal Ca2+ hypersensitivity. AB - Various ryanodine receptor 2 (RyR2) point mutations cause catecholamine-induced polymorphic ventricular tachycardia (CPVT), a life-threatening arrhythmia evoked by diastolic intracellular Ca2+ release dysfunction. These mutations occur in essential regions of RyR2 that regulate Ca2+ release. The molecular dysfunction caused by CPVT-associated RyR2 mutations as well as the functional consequences remain unresolved. Here, we study the most severe CPVT-associated RyR2 mutation (K4750Q) known to date. We define the molecular and cellular dysfunction generated by this mutation and detail how it alters RyR2 function, using Ca2+ imaging, ryanodine binding, and single-channel recordings. HEK293 cells and cardiac HL-1 cells expressing RyR2-K4750Q show greatly enhanced spontaneous Ca2+ oscillations. An endoplasmic reticulum-targeted Ca2+ sensor, R-CEPIA1er, revealed that RyR2-K4750Q mediates excessive diastolic Ca2+ leak, which dramatically reduces luminal [Ca2+]. We further show that the K4750Q mutation causes three RyR2 defects: hypersensitization to activation by cytosolic Ca2+, loss of cytosolic Ca2+/Mg2+-mediated inactivation, and hypersensitization to luminal Ca2+ activation. These defects combine to kinetically stabilize RyR2-K4750Q openings, thus explaining the extensive diastolic Ca2+ leak from the sarcoplasmic reticulum, frequent Ca2+ waves, and severe CPVT phenotype. As the multiple concurrent defects are induced by a single point mutation, the K4750 residue likely resides at a critical structural point at which cytosolic and luminal RyR2 control input converge. PMID- 28082362 TI - Case characteristics among Middle East respiratory syndrome coronavirus outbreak and non-outbreak cases in Saudi Arabia from 2012 to 2015. AB - OBJECTIVES: As of 1 November 2015, the Saudi Ministry of Health had reported 1273 cases of Middle East respiratory syndrome (MERS); among these cases, which included 9 outbreaks at several hospitals, 717 (56%) patients recovered, 14 (1%) remain hospitalised and 543 (43%) died. This study aimed to determine the epidemiological, demographic and clinical characteristics that distinguished cases of MERS contracted during outbreaks from those contracted sporadically (ie, non-outbreak) between 2012 and 2015 in Saudi Arabia. DESIGN: Data from the Saudi Ministry of Health of confirmed outbreak and non-outbreak cases of MERS coronavirus (CoV) infections from September 2012 through October 2015 were abstracted and analysed. Univariate and descriptive statistical analyses were conducted, and the time between disease onset and confirmation, onset and notification and onset and death were examined. RESULTS: A total of 1250 patients (aged 0-109 years; mean, 50.825 years) were reported infected with MERS-CoV. Approximately two-thirds of all MERS cases were diagnosed in men for outbreak and non-outbreak cases. Healthcare workers comprised 22% of all MERS cases for outbreak and non-outbreak cases. Nosocomial infections comprised one-third of all Saudi MERS cases; however, nosocomial infections occurred more frequently in outbreak than non-outbreak cases (p<0.001). Patients contracting MERS during an outbreak were significantly more likely to die of MERS (p<0.001). CONCLUSIONS: To date, nosocomial infections have fuelled MERS outbreaks. Given that the Kingdom of Saudi Arabia is a worldwide religious travel destination, localised outbreaks may have massive global implications and effective outbreak preventive measures are needed. PMID- 28082363 TI - Direct-to-consumer advertising of success rates for medically assisted reproduction: a review of national clinic websites. AB - OBJECTIVES: To establish how medically assisted reproduction (MAR) clinics report success rates on their websites. SETTING: Websites of private and NHS clinics offering in vitro fertilisation (IVF) in the UK. PARTICIPANTS: We identified clinics offering IVF using the Choose a Fertility Clinic facility on the website of the Human Fertilisation and Embryology Authority (HFEA). Of 81 clinics identified, a website could not be found for 2, leaving 79 for inclusion in the analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: Outcome measures reported by clinic websites. The numerator and denominator included in the outcome measure were of interest. RESULTS: 53 (67%) websites reported their performance using 51 different outcome measures. It was most common to report pregnancy (83% of these clinics) or live birth rates (51%). 31 different ways of reporting pregnancy and 9 different ways of reporting live birth were identified. 11 (21%) reported multiple birth or pregnancy rates. 1 clinic provided information on adverse events. It was usual for clinics to present results without relevant contextual information such as sample size, reporting period, the characteristics of patients and particular details of treatments. CONCLUSIONS: Many combinations of numerator and denominator are available for the purpose of reporting success rates for MAR. The range of reporting options available to clinics is further increased by the possibility of presenting results for subgroups of patients and for different time periods. Given the status of these websites as advertisements to patients, the risk of selective reporting is considerable. Binding guidance is required to ensure consistent, informative reporting. PMID- 28082364 TI - Rethinking clinical governance: healthcare professionals' views: a Delphi study. AB - OBJECTIVE: Although the guiding principle of clinical governance states that healthcare professionals are the leading contributors to quality and safety in healthcare, little is known about what healthcare professionals perceive as important for clinical governance. The aim of this study is to clarify this by exploring healthcare professionals' views on clinical governance. DESIGN: Based on a literature search, a list of 99 elements related to clinical governance was constructed. This list was refined, extended and restricted during a three-round Delphi study. SETTING AND PARTICIPANTS: The panel of experts was formed of 24 healthcare professionals from an academic hospital that is seen as a leader in terms of its clinical governance expertise in the Netherlands. MAIN OUTCOME MEASURES: Rated importance of each element on a four-point scale. RESULTS: The 50 elements that the panel perceived as most important related to adopting a bottom up approach to clinical governance, ownership, teamwork, learning from mistakes and feedback. The panel did not reach a consensus concerning elements that referred to patient involvement. Elements that referred to a managerial approach to clinical governance and standardisation of work were rejected by the panel. CONCLUSIONS: In the views of the panel of experts, clinical governance is a practice-based, value-driven approach that has the goal of delivering the highest possible quality care and ensuring the safety of patients. Bottom-up approaches and effective teamwork are seen as crucial for high quality and safe healthcare. Striving for high quality and safe healthcare is underpinned by continuous learning, shared responsibility and good relationships and collaboration between healthcare professionals, managers and patients. PMID- 28082365 TI - Effectiveness of diagnostic screening tests in mass screening for COPD using a cooperative regional system in a region with heavy air pollution: a cross sectional study. AB - OBJECTIVES: This study aimed to evaluate the effectiveness of a cooperative healthcare model for early detection and diagnosis of chronic obstructive pulmonary disease (COPD). METHODS: This was a cross-sectional observational study. We performed diagnosis of COPD at 4 public health centres in Omuta, Japan from March 2015 to March 2016, by adding screening for COPD at the time of routine medical evaluations. All patients aged over 40 years were eligible to participate. Among 397 eligible patients, 293 agreed to participate in the study. RESULTS: The estimated prevalence of COPD in Omuta was 10% among patients aged over 40 years and was 17% among smokers. Among those who were screened, over half of them had questionnaire scores over the cut-off of 17 points and decreased FEV1/FVC%, indicating COPD (p>0.05). 30 patients with suspected COPD were referred for further investigation at a local central hospital, but only 6 underwent further medical examinations. CONCLUSIONS: The combination of a COPD questionnaire and medical examination is effective as a COPD screening tool. Future research should investigate behavioural interventions for smoking cessation that can be offered in a cooperative model, as well as for improving participation in COPD screening and for encouraging early presentation for treatment in those suspected of having COPD. PMID- 28082366 TI - Psychosocial well-being and health-related quality of life in a UK population with Usher syndrome. AB - OBJECTIVES: To determine whether psychosocial well-being is associated with the health-related quality of life (HRQOL) of people with Usher syndrome. SETTING: The survey was advertised online and through deafblind-related charities, support groups and social groups throughout the UK. PARTICIPANTS: 90 people with Usher syndrome took part in the survey. Inclusion criteria are having a diagnosis of Usher syndrome, being 18 or older and being a UK resident. PRIMARY AND SECONDARY OUTCOME MEASURES: All participants took part in a survey that measured depressive symptoms, loneliness and social support (predictors) and their physical and mental HRQOL (outcomes). Measured confounders included age-related, sex-related and health-related characteristics. Hierarchical multiple linear regression analyses examined the association of each psychosocial well-being predictor with the physical and mental HRQOL outcomes while controlling for confounders in a stepwise manner. RESULTS: After adjusting for all confounders, psychosocial well being was shown to predict physical and mental HRQOL in our population with Usher syndrome. Increasing depressive symptoms were predictive of poorer physical (beta=-0.36, p<0.01) and mental (beta=-0.60, p<0.001) HRQOL. Higher levels of loneliness predicted poorer mental HRQOL (beta=-0.20, p<0.05). Finally, increasing levels of social support predicted better mental HRQOL (beta=0.19, p<0.05). CONCLUSIONS: Depression, loneliness and social support all represent important issues that are linked with HRQOL in a UK population with Usher syndrome. Our results add to the growing body of evidence that psychosocial well being is an important factor to consider in people with Usher syndrome alongside functional and physical impairment within research and clinical practice. PMID- 28082367 TI - Antidepressant use during pregnancy and the risk of major congenital malformations in a cohort of depressed pregnant women: an updated analysis of the Quebec Pregnancy Cohort. AB - OBJECTIVE: Antidepressant use during gestation has been associated with risk of major congenital malformations but estimates can lack statistical power or be confounded by maternal depression. We aimed to determine the association between first-trimester exposure to antidepressants and the risk of major congenital malformations in a cohort of depressed/anxious women. SETTING AND PARTICIPANTS: Data were obtained from the Quebec Pregnancy Cohort (QPC). All pregnancies with a diagnosis of depression or anxiety, or exposed to antidepressants in the 12 months before pregnancy, and ending with a live-born singleton were included. OUTCOME MEASURES: Antidepressant classes (selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA) and other antidepressants) and types were individually compared with non-exposure during the first trimester (depressed untreated). Major congenital malformations overall and organ-specific malformations in the first year of life were identified. RESULTS: 18 487 pregnant women were included. When looking at the specific types of antidepressant used during the first trimester, only citalopram was increasing the risk of major congenital malformations (adjusted OR, (aOR) 1.36, 95% CI 1.08 to 1.73; 88 exposed cases), although there was a trend towards increased risk for the most frequently used antidepressants. Antidepressants with serotonin reuptake inhibition effect (SSRI, SNRI, amitriptyline (the most used TCA)) increased the risk of certain organ specific defects: paroxetine increased the risk of cardiac defects (aOR 1.45, 95% CI 1.12 to 1.88), and ventricular/atrial septal defects (aOR 1.39, 95% CI 1.00 to 1.93); citalopram increased the risk of musculoskeletal defects (aOR 1.92, 95% CI 1.40 to 2.62), and craniosynostosis (aOR 3.95, 95% CI 2.08 to 7.52); TCA was associated with eye, ear, face and neck defects (aOR 2.45, 95% CI 1.05 to 5.72), and digestive defects (aOR 2.55, 95% CI 1.40 to 4.66); and venlafaxine was associated with respiratory defects (aOR 2.17, 95% CI 1.07 to 4.38). CONCLUSIONS: Antidepressants with effects on serotonin reuptake during embryogenesis increased the risk of some organ-specific malformations in a cohort of pregnant women with depression. PMID- 28082368 TI - Efficacy of combined conservative therapies on clinical outcomes in patients with thumb base osteoarthritis: protocol for a randomised, controlled trial (COMBO). AB - INTRODUCTION: Management of thumb base osteoarthritis (OA) using a combination of therapies is common in clinical practice; however, evidence for the efficacy of this approach is lacking. The aim of this study is to determine the effect of a combination of conservative therapies for the treatment of thumb base OA compared with an education control group. METHODS AND ANALYSIS: This is a randomised, controlled, single-centre, two-arm superiority trial with 1:1 allocation ratio; with assessor and statistician blinded. Participants are blinded to the trial's hypothesis and to the interventions received by the opposite group. A total of 204 participants will be recruited from the community and randomised using a computer-generated schedule. The intervention group will receive education for joint protection and OA, a splint for the base of the thumb, hand exercises and topical diclofenac sodium 1% gel over 6 weeks. The control group will receive education for joint protection and OA alone. Main inclusion criteria are pain >=40 mm (Visual Analogue Scale, 0-100) at the base of the thumb, impairment in hand function >=6 (Functional Index for Hand Osteoarthritis, 0-30) and radiographic thumb base OA (Kellgren Lawrence grade >=2). Participants currently receiving any of the intervention components will be excluded. Outcomes will be measured at 2, 6 and 12 weeks. The primary outcome is change in pain and hand function from baseline to 6 weeks. Other outcomes include changes in grip and pinch strength, quality of life, presence of joint swelling and tenderness, duration of joint stiffness, patient's global assessment and use of rescue medication. Analysis will be performed according to the intention-to-treat principle. Adverse events will be monitored throughout the study. ETHICS AND DISSEMINATION: This protocol is approved by the local ethics committee (HREC/15/HAWKE/479). Dissemination will occur through presentations at international conferences and publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12616000353493; Pre-results. PMID- 28082370 TI - An approach to hypopigmentation. PMID- 28082372 TI - Structural developmental psychology and health promotion in the third age. AB - In response to the ever-increasing longevity in Western societies, old age has been divided into two different periods, labelled the third and fourth age. Where the third age, with its onset at retirement, mostly involves positive aspects of growing old, the fourth age involves functional decline and increased morbidity. This article focuses on the entry to the third age and its potential for health promotion initiatives. Well-being is an important factor to emphasize in such health promotion, and this article views the lifestyle of third agers as essential for their well-being. The structural developmental theory of Robert Kegan delineates how a person's way of knowing develops throughout the life course. This theory is an untapped and salient perspective for health promotion initiatives in the third age. This article outlines Kegan's approach as a tool for developing psychologically spacious health promotion, and suggests future directions for research on the topic. PMID- 28082373 TI - Nutrition labelling is a trade policy issue: lessons from an analysis of specific trade concerns at the World Trade Organization. AB - Interpretive nutrition labels provide simplified nutrient-specific text and/or symbols on the front of pre-packaged foods, to encourage and enable consumers to make healthier choices. This type of labelling has been proposed as part of a comprehensive policy response to the global epidemic of non-communicable diseases. However, regulation of nutrition labelling falls under the remit of not just the health sector but also trade. Specific Trade Concerns have been raised at the World Trade Organization's Technical Barriers to Trade Committee regarding interpretive nutrition labelling initiatives in Thailand, Chile, Indonesia, Peru and Ecuador. This paper presents an analysis of the discussions of these concerns. Although nutrition labelling was identified as a legitimate policy objective, queries were raised regarding the justification of the specific labelling measures proposed, and the scientific evidence for effectiveness of such measures. Concerns were also raised regarding the consistency of the measures with international standards. Drawing on policy learning theory, we identified four lessons for public health policy makers, including: strategic framing of nutrition labelling policy objectives; pro-active policy engagement between trade and health to identify potential trade issues; identifying ways to minimize potential 'practical' trade concerns; and engagement with the Codex Alimentarius Commission to develop international guidance on interpretative labelling. This analysis indicates that while there is potential for trade sector concerns to stifle innovation in nutrition labelling policy, care in how interpretive nutrition labelling measures are crafted in light of trade commitments can minimize such a risk and help ensure that trade policy is coherent with nutrition action. PMID- 28082369 TI - Regulation of PI3K effector signalling in cancer by the phosphoinositide phosphatases. AB - Class I phosphoinositide 3-kinase (PI3K) generates phosphatidylinositol 3,4,5 trisphosphate (PtdIns(3,4,5)P3) at the plasma membrane in response to growth factors, activating a signalling cascade that regulates many cellular functions including cell growth, proliferation, survival, migration and metabolism. The PI3K pathway is commonly dysregulated in human cancer, and drives tumorigenesis by promoting aberrant cell growth and transformation. PtdIns(3,4,5)P3 facilitates the activation of many pleckstrin homology (PH) domain-containing proteins including the serine/threonine kinase AKT. There are three AKT isoforms that are frequently hyperactivated in cancer through mutation, amplification or dysregulation of upstream regulatory proteins. AKT isoforms have converging and opposing functions in tumorigenesis. PtdIns(3,4,5)P3 signalling is degraded and terminated by phosphoinositide phosphatases such as phosphatase and tensin homologue (PTEN), proline-rich inositol polyphosphate 5-phosphatase (PIPP) (INPP5J) and inositol polyphosphate 4-phosphatase type II (INPP4B). PtdIns(3,4,5)P3 is rapidly hydrolysed by PIPP to generate phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2), which is further hydrolysed by INPP4B to form phosphatidylinositol 3-phosphate (PtdIns3P). PtdIns(3,4)P2 and PtdIns3P are also important signalling molecules; PtdIns(3,4)P2 together with PtdIns(3,4,5)P3 are required for maximal AKT activation and PtdIns3P activates PI3K-dependent serum and glucocorticoid-regulated kinase (SGK3) signalling. Loss of Pten, Pipp or Inpp4b expression or function promotes tumour growth in murine cancer models through enhanced AKT isoform-specific signalling. INPP4B inhibits PtdIns(3,4)P2 mediated AKT activation in breast and prostate cancer; however, INPP4B expression is increased in acute myeloid leukaemia (AML), melanoma and colon cancer where it paradoxically promotes cell proliferation, transformation and/or drug resistance. This review will discuss how PTEN, PIPP and INPP4B distinctly regulate PtdIns(3,4,5)P3 signalling downstream of PI3K and how dysregulation of these phosphatases affects cancer outcomes. PMID- 28082374 TI - Cohort Profile: The Nijmegen Biomedical Study (NBS). PMID- 28082377 TI - A creeping hand eruption. PMID- 28082375 TI - Evidence for large-scale gene-by-smoking interaction effects on pulmonary function. AB - Background: Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV 1 (forced expiratory volume in 1 second) or FEV 1 /FVC (FEV 1 /forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking. Methods: We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV 1 or FEV 1 /FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia. Results: We identified an interaction ( betaint = -0.036, 95% confidence interval, -0.040 to -0.032, P = 0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV 1 /FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV /FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect. Conclusions: This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV 1 /FVC may be more susceptible to the deleterious effects of smoking. PMID- 28082378 TI - Cancer, Oxidative Stress, and Metastasis. AB - Reactive oxygen species (ROS) are highly reactive molecules that arise from a number of cellular sources, including oxidative metabolism in mitochondria. At low levels they can be advantageous to cells, activating signaling pathways that promote proliferation or survival. At higher levels, ROS can damage or kill cells by oxidizing proteins, lipids, and nucleic acids. It was hypothesized that antioxidants might benefit high-risk patients by reducing the rate of ROS-induced mutations and delaying cancer initiation. However, dietary supplementation with antioxidants has generally proven ineffective or detrimental in clinical trials. High ROS levels limit cancer cell survival during certain windows of cancer initiation and progression. During these periods, dietary supplementation with antioxidants may promote cancer cell survival and cancer progression. This raises the possibility that rather than treating cancer patients with antioxidants, they should be treated with pro-oxidants that exacerbate oxidative stress or block metabolic adaptations that confer oxidative stress resistance. PMID- 28082376 TI - Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains. AB - Local mRNA translation in growing axons allows for rapid and precise regulation of protein expression in response to extrinsic stimuli. However, the role of local translation in mature CNS axons is unknown. Such a mechanism requires the presence of translational machinery and associated mRNAs in circuit-integrated brain axons. Here we use a combination of genetic, quantitative imaging and super resolution microscopy approaches to show that mature axons in the mammalian brain contain ribosomes, the translational regulator FMRP and a subset of FMRP mRNA targets. This axonal translational machinery is associated with Fragile X granules (FXGs), which are restricted to axons in a stereotyped subset of brain circuits. FXGs and associated axonal translational machinery are present in hippocampus in humans as old as 57 years. This FXG-associated axonal translational machinery is present in adult rats, even when adult neurogenesis is blocked. In contrast, in mouse this machinery is only observed in juvenile hippocampal axons. This differential developmental expression was specific to the hippocampus, as both mice and rats exhibit FXGs in mature axons in the adult olfactory system. Experiments in Fmr1 null mice show that FMRP regulates axonal protein expression but is not required for axonal transport of ribosomes or its target mRNAs. Axonal translational machinery is thus a feature of adult CNS neurons. Regulation of this machinery by FMRP could support complex behaviours in humans throughout life. PMID- 28082381 TI - Pneumopericardium and colo-pericardial fistula. PMID- 28082379 TI - Five years of specialised early intervention versus two years of specialised early intervention followed by three years of standard treatment for patients with a first episode psychosis: randomised, superiority, parallel group trial in Denmark (OPUS II). AB - OBJECTIVE: To compare the effects of five years of specialised early intervention (SEI) treatment for first episode schizophrenia spectrum disorder with the standard two years of SEI plus three years of treatment as usual. DESIGN: Randomised, superiority, parallel group trial with blinded outcome assessment. Randomisation was centralised and computerised with concealed randomisation sequence carried out at an external site. SETTING: Participants were recruited from six OPUS teams in Denmark between 2009 and 2012. OPUS teams provide SEI treatment to all patients diagnosed with a schizophrenia spectrum disorder in Denmark. PARTICIPANTS: 400 participants (51% women) with a mean age of 25.6 (standard deviation 4.3) were randomised to five years of SEI (experimental intervention; n=197) or to two years of SEI plus three years of treatment as usual (control; n=203). INTERVENTIONS: OPUS treatment consists of three core elements-modified assertive community treatment, family involvement, and social skill training-with a patient-case manager ratio of no more than 12:1. For participants randomised to five years of OPUS treatment, the treatment was largely unchanged. Participants randomised to the control group were mostly referred to community health centres after two years of SEI treatment. MAIN OUTCOMES: Follow-up assessments were conducted five years after start of OPUS treatment. Primary outcome was negative symptoms measured on the scale for assessment of negative symptoms (avolition-apathy, anhedonia, alogia, and affective blunting). Secondary outcomes were remission of both negative and psychotic symptoms, psychotic symptoms, suicidal ideation, substance abuse, compliance with medical treatment, adherence with treatment, client satisfaction, days in hospital care, and labour market affiliation. RESULTS: Levels of negative symptoms did not differ between the intervention group and control group (1.72 v 1.81 points; estimated mean difference -0.10 (95% confidence interval -0.33 to 0.13), P=0.39). Participants receiving five years of OPUS treatment were more likely to remain in contact with specialised mental health services (90.4% v 55.6%, P<0.001), had higher client satisfaction (estimated mean difference 2.57 points (95% confidence interval 1.36 to 3.79), P<0.001), and had a stronger working alliance (estimated mean difference 5.56 points (95% confidence interval 2.30 to 8.82), P=0.001) than the control group. CONCLUSIONS: This trial tests SEI treatment for up to five years for patients with first episode schizophrenia spectrum disorder; previous trials have found treatment effects for programmes lasting from one to three years. The prolonged SEI treatment had few effects, which could be due to the high level of treatment provided to control participants and the late start of specialised treatment.Trial registration Clinicaltrial.gov NCT00914238. PMID- 28082382 TI - Monocytes primed with GTS-21/alpha7 nAChR (nicotinic acetylcholine receptor) agonist develop anti-inflammatory memory. AB - Background: The neural system can finely tune immune system, especially pro- or anti-inflammatory responses of monocytes/macrophages. To maintain immune homeostasis, monocytes/macrophages are supposed to be primed by alpha7 nAChR agonist to establish anti-inflammatory memory. Aim: To study whether activation of alpha7 nAChR would elicit anti-inflammatory memory in splenic monocytes in vivo and J774 monocytes in vitro . Design: Laboratory study. Methods: The wildtype mice were sacrificed 4 or 12 h after receiving intravenous injection of GTS-21. The splenocytes were isolated and stimulated with LPS for 4 h to detect Ly6C hi TNF-alpha + monocytes by flow cytometry. In the in vitro study, J774 monocytes received priming with GTS-21, washing GTS-21 out and resting, and thereafter stimulating with TLR ligands. The TNF-alpha protein and Tnfalpha , Il1beta and il6 mRNAs were measured to evaluate anti-inflammatory responses. The H3K9ac, H4K5ac, H4K8ac, Acetyl-CBP, CBP (CREB-binding protein), PCAF (P300/CBP associated factor) and Acetyl-NF-kB levels were measured in GTS-21-primed monocytes. Results: Activation of alpha7 nAChR by GTS-21 suppressed TNF-alpha production in splenic Ly6C hi monocytes. In vivo -GTS-21-primed splenic Ly6C hi monocytes passed on anti-inflammatory feature if stimulated with LPS in vitro . J774 monocytes primed with GTS-21 developed anti-inflammatory trait in response to LPS (TLR4), Poly:IC (TLR3) and R848 (TLR7/8) ligands. In GTS-21-primed monocytes, H3K9ac, H4K5ac, H4K8ac, Acetyl-CBP, CBP, PCAF and Acetyl-NF-kB were reduced 4 h after washing and resting. In the nuclear extract, PCAF, Acetyl-NF kB, p-NF-kB and p-STAT3 were decreased in LPS-stimulated GTS-21 primed J774 monocytes 4 h after washing and resting. Conclusions: Monocytes primed by alpha7 nAChR agonist developed anti-inflammatory memory. PMID- 28082383 TI - More Than Window Dressing: Revealing 5-Methylcytocine Patterns That Decorate Arabidopsis RNA. PMID- 28082385 TI - Management of Pregnancy in Patients With Complex Congenital Heart Disease: A Scientific Statement for Healthcare Professionals From the American Heart Association. AB - Today, most female children born with congenital heart disease will reach childbearing age. For many women with complex congenital heart disease, carrying a pregnancy carries a moderate to high risk for both the mother and her fetus. Many such women, however, do not have access to adult congenital heart disease tertiary centers with experienced reproductive programs. Therefore, it is important that all practitioners who will be managing these women have current information not only on preconception counseling and diagnostic evaluation to determine maternal and fetal risk but also on how to manage them once they are pregnant and when to refer them to a regional center with expertise in pregnancy management. PMID- 28082384 TI - The Rice Receptor-Like Kinases DWARF AND RUNTISH SPIKELET1 and 2 Repress Cell Death and Affect Sugar Utilization during Reproductive Development. AB - Cell-to-cell communication precisely controls the creation of new organs during reproductive growth. However, the sensor molecules that mediate developmental signals in monocot plants are poorly understood. Here, we report that DWARF AND RUNTISH SPIKELET1 (DRUS1) and DRUS2, two closely related receptor-like kinases (RLKs), redundantly control reproductive growth and development in rice (Oryza sativa). A drus1-1 drus2 double knockout mutant, but not either single mutant, showed extreme dwarfism and barren inflorescences that harbored sterile spikelets. The gibberellin pathway was not impaired in this mutant. A phenotypic comparison of mutants expressing different amounts of DRUS1 and 2 revealed that reproductive growth requires a threshold level of DRUS1/2 proteins. DRUS1 and 2 maintain cell viability by repressing protease-mediated cell degradation and likely by affecting sugar utilization or conversion. In the later stages of anther development, survival of the endothecium requires DRUS1/2, which may stimulate expression of the UDP-glucose pyrophosphorylase gene UGP2 and starch biosynthesis in pollen. Unlike their Arabidopsis thaliana ortholog FERONIA, DRUS1 and 2 mediate a fundamental signaling process that is essential for cell survival and represents a novel biological function for the CrRLK1L RLK subfamily. PMID- 28082386 TI - Population-Based Long-Term Cardiac-Specific Mortality Among 34 489 Five-Year Survivors of Childhood Cancer in Great Britain. AB - BACKGROUND: Increased risks of cardiac morbidity and mortality among childhood cancer survivors have been described previously. However, little is known about the very long-term risks of cardiac mortality and whether the risk has decreased among those more recently diagnosed. We investigated the risk of long-term cardiac mortality among survivors within the recently extended British Childhood Cancer Survivor Study. METHODS: The British Childhood Cancer Survivor Study is a population-based cohort of 34 489 five-year survivors of childhood cancer diagnosed from 1940 to 2006 and followed up until February 28, 2014, and is the largest cohort to date to assess late cardiac mortality. Standardized mortality ratios and absolute excess risks were used to quantify cardiac mortality excess risk. Multivariable Poisson regression models were used to evaluate the simultaneous effect of risk factors. Likelihood ratio tests were used to test for heterogeneity and trends. RESULTS: Overall, 181 cardiac deaths were observed, which was 3.4 times that expected. Survivors were 2.5 times and 5.9 times more at risk of ischemic heart disease and cardiomyopathy/heart failure death, respectively, than expected. Among those >60 years of age, subsequent primary neoplasms, cardiac disease, and other circulatory conditions accounted for 31%, 22%, and 15% of all excess deaths, respectively, providing clear focus for preventive interventions. The risk of both overall cardiac and cardiomyopathy/heart failure mortality was greatest among those diagnosed from 1980 to 1989. Specifically, for cardiomyopathy/heart failure deaths, survivors diagnosed from 1980 to 1989 had 28.9 times the excess number of deaths observed for survivors diagnosed either before 1970 or from 1990 on. CONCLUSIONS: Excess cardiac mortality among 5-year survivors of childhood cancer remains increased beyond 50 years of age and has clear messages in terms of prevention strategies. However, the fact that the risk was greatest in those diagnosed from 1980 to 1989 suggests that initiatives to reduce cardiotoxicity among those treated more recently may be having a measurable impact. PMID- 28082387 TI - High-Intensity Interval Training in Patients With Heart Failure With Reduced Ejection Fraction. AB - BACKGROUND: Small studies have suggested that high-intensity interval training (HIIT) is superior to moderate continuous training (MCT) in reversing cardiac remodeling and increasing aerobic capacity in patients with heart failure with reduced ejection fraction. The present multicenter trial compared 12 weeks of supervised interventions of HIIT, MCT, or a recommendation of regular exercise (RRE). METHODS: Two hundred sixty-one patients with left ventricular ejection fraction <=35% and New York Heart Association class II to III were randomly assigned to HIIT at 90% to 95% of maximal heart rate, MCT at 60% to 70% of maximal heart rate, or RRE. Thereafter, patients were encouraged to continue exercising on their own. Clinical assessments were performed at baseline, after the intervention, and at follow-up after 52 weeks. Primary end point was a between-group comparison of change in left ventricular end-diastolic diameter from baseline to 12 weeks. RESULTS: Groups did not differ in age (median, 60 years), sex (19% women), ischemic pathogenesis (59%), or medication. Change in left ventricular end-diastolic diameter from baseline to 12 weeks was not different between HIIT and MCT (P=0.45); left ventricular end-diastolic diameter changes compared with RRE were -2.8 mm (-5.2 to -0.4 mm; P=0.02) in HIIT and -1.2 mm (-3.6 to 1.2 mm; P=0.34) in MCT. There was also no difference between HIIT and MCT in peak oxygen uptake (P=0.70), but both were superior to RRE. However, none of these changes was maintained at follow-up after 52 weeks. Serious adverse events were not statistically different during supervised intervention or at follow-up at 52 weeks (HIIT, 39%; MCT, 25%; RRE, 34%; P=0.16). Training records showed that 51% of patients exercised below prescribed target during supervised HIIT and 80% above target in MCT. CONCLUSIONS: HIIT was not superior to MCT in changing left ventricular remodeling or aerobic capacity, and its feasibility remains unresolved in patients with heart failure. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00917046. PMID- 28082389 TI - An optimized, broadly applicable piggyBac transposon induction system. AB - The piggyBac (PB) transposon has been used in a number of biological applications. The insertion of PB transposons into the genome can disrupt genes or regulatory regions, impacting cellular function, so for many experiments it is important that PB transposition is tightly controlled. Here, we systematically characterize three methods for the post-translational control of the PB transposon in four cell lines. We investigated fusions of the PB transposase with ERT2 and two degradation domains (FKBP-DD, DHFR-DD), in multiple orientations, and determined (i) the fold-induction achieved, (ii) the absolute transposition efficiency of the activated construct and (iii) the effects of two inducer molecules on cellular transcription and function. We found that the FKBP-DD confers the PB transposase with a higher transposition activity and better dynamic range than can be achieved with the other systems. In addition, we found that the FKBP-DD regulates transposon activity in a reversible and dose-dependent manner. Finally, we showed that Shld1, the chemical inducer of FKBP-DD, does not interfere with stem cell differentiation, whereas tamoxifen has significant effects. We believe the FKBP-based PB transposon induction will be useful for transposon-mediated genome engineering, insertional mutagenesis and the genome wide mapping of transcription factor binding. PMID- 28082388 TI - Imaging chromatin nanostructure with binding-activated localization microscopy based on DNA structure fluctuations. AB - Advanced light microscopy is an important tool for nanostructure analysis of chromatin. In this report we present a general concept for Single Molecule localization Microscopy (SMLM) super-resolved imaging of DNA-binding dyes based on modifying the properties of DNA and the dye. By careful adjustment of the chemical environment leading to local, reversible DNA melting and hybridization control over the fluorescence signal of the DNA-binding dye molecules can be introduced. We postulate a transient binding as the basis for our variation of binding-activated localization microscopy (BALM). We demonstrate that several intercalating and minor-groove binding DNA dyes can be used to register (optically isolate) only a few DNA-binding dye signals at a time. To highlight this DNA structure fluctuation-assisted BALM (fBALM), we applied it to measure, for the first time, nanoscale differences in nuclear architecture in model ischemia with an anticipated structural resolution of approximately 50 nm. Our data suggest that this approach may open an avenue for the enhanced microscopic analysis of chromatin nano-architecture and hence the microscopic analysis of nuclear structure aberrations occurring in various pathological conditions. It may also become possible to analyse nuclear nanostructure differences in different cell types, stages of development or environmental stress conditions. PMID- 28082390 TI - Identification of endoribonuclease specific cleavage positions reveals novel targets of RNase III in Streptococcus pyogenes. AB - A better understanding of transcriptional and post-transcriptional regulation of gene expression in bacteria relies on studying their transcriptome. RNA sequencing methods are used not only to assess RNA abundance but also the exact boundaries of primary and processed transcripts. Here, we developed a method, called identification of specific cleavage position (ISCP), which enables the identification of direct endoribonuclease targets in vivo by comparing the 5? and 3? ends of processed transcripts between wild type and RNase deficient strains. To demonstrate the ISCP method, we used as a model the double-stranded specific RNase III in the human pathogen Streptococcus pyogenes. We mapped 92 specific cleavage positions (SCPs) among which, 48 were previously described and 44 are new, with the characteristic 2 nucleotides 3? overhang of RNase III. Most SCPs were located in untranslated regions of RNAs. We screened for RNase III targets using transcriptomic differential expression analysis (DEA) and compared those with the RNase III targets identified using the ISCP method. Our study shows that in S. pyogenes, under standard growth conditions, RNase III has a limited impact both on antisense transcripts and on global gene expression with the expression of most of the affected genes being downregulated in an RNase III deletion mutant. PMID- 28082391 TI - FACT is a sensor of DNA torsional stress in eukaryotic cells. AB - Transitions of B-DNA to alternative DNA structures (ADS) can be triggered by negative torsional strain, which occurs during replication and transcription, and may lead to genomic instability. However, how ADS are recognized in cells is unclear. We found that the binding of candidate anticancer drug, curaxin, to cellular DNA results in uncoiling of nucleosomal DNA, accumulation of negative supercoiling and conversion of multiple regions of genomic DNA into left-handed Z form. Histone chaperone FACT binds rapidly to the same regions via the SSRP1 subunit in curaxin-treated cells. In vitro binding of purified SSRP1 or its isolated CID domain to a methylated DNA fragment containing alternating purine/pyrimidines, which is prone to Z-DNA transition, is much stronger than to other types of DNA. We propose that FACT can recognize and bind Z-DNA or DNA in transition from a B to Z form. Binding of FACT to these genomic regions triggers a p53 response. Furthermore, FACT has been shown to bind to other types of ADS through a different structural domain, which also leads to p53 activation. Thus, we propose that FACT acts as a sensor of ADS formation in cells. Recognition of ADS by FACT followed by a p53 response may explain the role of FACT in DNA damage prevention. PMID- 28082392 TI - The ribosome biogenesis factor yUtp23/hUTP23 coordinates key interactions in the yeast and human pre-40S particle and hUTP23 contains an essential PIN domain. AB - Two proteins with PIN endonuclease domains, yUtp24(Fcf1)/hUTP24 and yUtp23/hUTP23 are essential for early pre-ribosomal (r)RNA cleavages at sites A0, A1/1 and A2/2a in yeast and humans. The yUtp24/hUTP24 PIN endonuclease is proposed to cleave at sites A1/1 and A2/2a, but the enzyme cleaving at site A0 is not known. Yeast yUtp23 contains a degenerate, non-essential PIN domain and functions together with the snR30 snoRNA, while human hUTP23 is associated with U17, the human snR30 counterpart. Using in vivo RNA-protein crosslinking and gel shift experiments, we reveal that yUtp23/hUTP23 makes direct contacts with expansion sequence 6 (ES6) in the 18S rRNA sequence and that yUtp23 interacts with the 3? half of the snR30 snoRNA. Protein-protein interaction studies further demonstrated that yeast yUtp23 and human hUTP23 directly interact with the H/ACA snoRNP protein yNhp2/hNHP2, the RNA helicase yRok1/hROK1(DDX52), the ribosome biogenesis factor yRrp7/hRRP7 and yUtp24/hUTP24. yUtp23/hUTP23 could therefore be central to the coordinated integration and release of ES6 binding factors and likely plays a pivotal role in remodeling this pre-rRNA region in both yeast and humans. Finally, studies using RNAi-rescue systems in human cells revealed that intact PIN domain and Zinc finger motifs in human hUTP23 are essential for 18S rRNA maturation. PMID- 28082393 TI - Alternative lengthening of telomeres can be maintained by preferential elongation of lagging strands. AB - Alternative lengthening of telomeres (ALT) is a telomerase independent telomere maintenance mechanism that occurs in ~15% of cancers. The potential mechanism of ALT is homology-directed telomere synthesis, but molecular mechanisms of how ALT maintains telomere length in human cancer is poorly understood. Here, we generated TERC (telomerase RNA) gene knockouts in telomerase positive cell lines that resulted in long-term surviving clones acquiring the ALT pathway but at a very low frequency. By comparing these ALT cells with parental telomerase positive cells, we observed that ALT cells possess excessively long telomeric overhangs derived from telomere elongation processes that mostly occur during S phase. ALT cells exhibited preferential elongation of the telomeric lagging strands, whereas telomerase positive cells exhibited similar elongation between leading and lagging strands. We propose that the ALT pathway preferentially occurs at telomeric lagging strands leading to heterogeneous telomere lengths observed in most ALT cancers. PMID- 28082394 TI - TSSPlant: a new tool for prediction of plant Pol II promoters. AB - Our current knowledge of eukaryotic promoters indicates their complex architecture that is often composed of numerous functional motifs. Most of known promoters include multiple and in some cases mutually exclusive transcription start sites (TSSs). Moreover, TSS selection depends on cell/tissue, development stage and environmental conditions. Such complex promoter structures make their computational identification notoriously difficult. Here, we present TSSPlant, a novel tool that predicts both TATA and TATA-less promoters in sequences of a wide spectrum of plant genomes. The tool was developed by using large promoter collections from ppdb and PlantProm DB. It utilizes eighteen significant compositional and signal features of plant promoter sequences selected in this study, that feed the artificial neural network-based model trained by the backpropagation algorithm. TSSPlant achieves significantly higher accuracy compared to the next best promoter prediction program for both TATA promoters (MCC?0.84 and F1-score?0.91 versus MCC?0.51 and F1-score?0.71) and TATA-less promoters (MCC?0.80, F1-score?0.89 versus MCC?0.29 and F1-score?0.50). TSSPlant is available to download as a standalone program at http://www.cbrc.kaust.edu.sa/download/. PMID- 28082395 TI - The crystal structure of the 5? functional domain of the transcription riboregulator 7SK. AB - In vertebrates, the 7SK RNA forms the scaffold of a complex, which regulates transcription pausing of RNA-polymerase II. By binding to the HEXIM protein, the complex comprising proteins LARP7 and MePCE captures the positive transcription elongation factor P-TEFb and prevents phosphorylation of pausing factors. The HEXIM-binding site embedded in the 5?-hairpin of 7SK (HP1) encompasses a short signature sequence, a GAUC repeat framed by single-stranded uridines. The present crystal structure of HP1 shows a remarkably straight helical stack involving several unexpected triples formed at a central region. Surprisingly, two uridines of the signature sequence make triple interactions in the major groove of the (GAUC)2. The third uridine is turned outwards or inward, wedging between the other uridines, thus filling the major groove. A molecular dynamics simulation indicates that these two conformations of the signature sequence represent stable alternatives. Analyses of the interaction with the HEXIM protein confirm the importance of the triple interactions at the signature sequence. Altogether, the present structural analysis of 7SK HP1 highlights an original mechanism of swapping bases, which could represent a possible '7SK signature' and provides new insight into the functional importance of the plasticity of RNA. PMID- 28082396 TI - PHF1 Tudor and N-terminal domains synergistically target partially unwrapped nucleosomes to increase DNA accessibility. AB - The Tudor domain of human PHF1 recognizes trimethylated lysine 36 on histone H3 (H3K36me3). PHF1 relies on this interaction to regulate PRC2 methyltransferase activity, localize to DNA double strand breaks and mediate nucleosome accessibility. Here, we investigate the impact of the PHF1 N-terminal domain (NTD) on the Tudor domain interaction with the nucleosome. We show that the NTD is partially ordered when it is natively attached to the Tudor domain. Through a combination of FRET and single molecule studies, we find that the increase of DNA accessibility within the H3K36me3-containing nucleosome, instigated by the Tudor binding to H3K36me3, is dramatically enhanced by the NTD. We demonstrate that this nearly order of magnitude increase is due to preferential binding of PHF1 to partially unwrapped nucleosomes, and that PHF1 alters DNA-protein binding within the nucleosome by decreasing dissociation rates. These results highlight the potency of a PTM-binding protein to regulate DNA accessibility and underscores the role of the novel mechanism by which nucleosomes control DNA-protein binding through increasing protein dissociation rates. PMID- 28082397 TI - Differential hepatitis C virus RNA target site selection and host factor activities of naturally occurring miR-122 3? variants. AB - In addition to suppressing cellular gene expression, certain miRNAs potently facilitate replication of specific positive-strand RNA viruses. miR-122, a pro viral hepatitis C virus (HCV) host factor, binds and recruits Ago2 to tandem sites (S1 and S2) near the 5? end of the HCV genome, stabilizing it and promoting its synthesis. HCV target site selection follows canonical miRNA rules, but how non-templated 3? miR-122 modifications impact this unconventional miRNA action is unknown. High-throughput sequencing revealed that a 22 nt miRNA with 3?G ('22 3?G') comprised <63% of total miR-122 in human liver, whereas other variants (23 3?A, 23-3?U, 21-3?U) represented 11-17%. All loaded equivalently into Ago2, and when tested individually functioned comparably in suppressing gene expression. In contrast, 23-3?A and 23-3?U were more active than 22-3?G in stabilizing HCV RNA and promoting its replication, whereas 21-3?U was almost completely inactive. This lack of 21-3?U HCV host factor activity correlated with reduced recruitment of Ago2 to the HCV S1 site. Additional experiments demonstrated strong preference for guanosine at nt 22 of miR-122. Our findings reveal the importance of non templated 3? miR-122 modifications to its HCV host factor activity, and identify unexpected differences in miRNA requirements for host gene suppression versus RNA virus replication. PMID- 28082398 TI - The large terminase DNA packaging motor grips DNA with its ATPase domain for cleavage by the flexible nuclease domain. AB - Many viruses use a powerful terminase motor to pump their genome inside an empty procapsid shell during virus maturation. The large terminase (TerL) protein contains both enzymatic activities necessary for packaging in such viruses: the adenosine triphosphatase (ATPase) that powers DNA translocation and an endonuclease that cleaves the concatemeric genome at both initiation and completion of genome packaging. However, how TerL binds DNA during translocation and cleavage remains mysterious. Here we investigate DNA binding and cleavage using TerL from the thermophilic phage P74-26. We report the structure of the P74 26 TerL nuclease domain, which allows us to model DNA binding in the nuclease active site. We screened a large panel of TerL variants for defects in binding and DNA cleavage, revealing that the ATPase domain is the primary site for DNA binding, and is required for nuclease activity. The nuclease domain is dispensable for DNA binding but residues lining the active site guide DNA for cleavage. Kinetic analysis of DNA cleavage suggests flexible tethering of the nuclease domains during DNA cleavage. We propose that interactions with the procapsid during DNA translocation conformationally restrict the nuclease domain, inhibiting cleavage; TerL release from the capsid upon completion of packaging unlocks the nuclease domains to cleave DNA. PMID- 28082399 TI - Radiation-Induced Enhancement of Antitumor T-cell Immunity by VEGF-Targeted 4-1BB Costimulation. AB - Radiotherapy can elicit systemic immune control of local tumors and distant nonirradiated tumor lesions, known as the abscopal effect. Although this effect is enhanced using checkpoint blockade or costimulatory antibodies, objective responses remain suboptimal. As radiotherapy can induce secretion of VEGF and other stress products in the tumor microenvironment, we hypothesized that targeting immunomodulatory drugs to such products will not only reduce toxicity but also broaden the scope of tumor-targeted immunotherapy. Using an oligonucleotide aptamer platform, we show that radiation-induced VEGF-targeted 4 1BB costimulation potentiated both local tumor control and abscopal responses with equal or greater efficiency than 4-1BB, CTLA-4, or PD1 antibodies alone. Although 4-1BB and CTLA-4 antibodies elicited organ-wide inflammatory responses and tissue damage, VEGF-targeted 4-1BB costimulation produced no observable toxicity. These findings suggest that radiation-induced tumor-targeted immunotherapy can improve the therapeutic index and extend the reach of immunomodulatory agents. Cancer Res; 77(6); 1310-21. (c)2017 AACR. PMID- 28082401 TI - A Multifunctional Role for Adjuvant Anti-4-1BB Therapy in Augmenting Antitumor Response by Chimeric Antigen Receptor T Cells. AB - Adoptive immunotherapy utilizing chimeric antigen receptor (CAR) T cells has demonstrated high success rates in hematologic cancers, but results against solid malignancies have been limited to date, due in part to the immunosuppressive tumor microenvironment. Activation of the 4-1BB (CD137) pathway using an agonistic alpha-4-1BB antibody is known to provide strong costimulatory signals for augmenting and diversifying T-cell responses. We therefore hypothesized that a combination of alpha-4-1BB and CAR T-cell therapy would result in improved antitumor responses. Using a human-Her2 self-antigen mouse model, we report here that alpha-4-1BB significantly enhanced CAR T-cell efficacy directed against the Her2 antigen in two different established solid tumor settings. Treatment also increased the expression of IFNgamma and the proliferation marker Ki67 in tumor infiltrating CAR T cells when combined with alpha-4-1BB. Strikingly, alpha-4-1BB significantly reduced host immunosuppressive cells at the tumor site, including regulatory T cells and myeloid-derived suppressor cells, correlating with an increased therapeutic response. We conclude that alpha-4-1BB has a multifunctional role for enhancing CAR T-cell responses and that this combination therapy has high translational potential, given current phase I/II clinical trials with alpha-4-1BB against various types of cancer. Cancer Res; 77(6); 1296 309. (c)2017 AACR. PMID- 28082400 TI - ARF Confers a Context-Dependent Response to Chemotherapy in Muscle-Invasive Bladder Cancer. AB - Muscle-invasive bladder cancer (MIBC) generally responds poorly to treatment and tends to exhibit significant mortality. Here we show that expression of the tumor suppressor p14ARF (ARF) is upregulated in aggressive subtypes of MIBC. Accumulation of ARF in the nucleolus is associated with poor outcome and attenuated response to chemotherapy. In both genetically engineered mouse models and murine xenograft models of human MIBC, we demonstrate that tumors expressing ARF failed to respond to treatment with the platinum-based chemotherapy agent cisplatin. Resistance was mediated in part by the integrin-binding protein ITGB3BP (CENPR) and reflected ARF-dependent impairment of protein translation, which was exaggerated by drug treatment. Overall, our results highlight a context dependent role for ARF in modulating the drug response of bladder cancer. Cancer Res; 77(4); 1035-46. (c)2017 AACR. PMID- 28082402 TI - Enriching the Housing Environment for Mice Enhances Their NK Cell Antitumor Immunity via Sympathetic Nerve-Dependent Regulation of NKG2D and CCR5. AB - Mice housed in an enriched environment display a tumor-resistant phenotype due to eustress stimulation. However, the mechanisms underlying enriched environment induced protection against cancers remain largely unexplained. In this study, we observed a significant antitumor effect induced by enriched environment in murine pancreatic cancer and lung cancer models. This effect remained intact in T/B lymphocyte-deficient Rag1-/- mice, but was nearly eliminated in natural killer (NK) cell-deficient Beige mice or in antibody-mediated NK-cell-depleted mice, suggesting a predominant role of NK cells in enriched environment-induced tumor inhibition. Exposure to enriched environment enhanced NK-cell activity against tumors and promoted tumoral infiltration of NK cells. Enriched environment increased the expression levels of CCR5 and NKG2D (KLRK1) in NK cells; blocking their function effectively blunted the enriched environment-induced enhancement of tumoral infiltration and cytotoxic activity of NK cells. Moreover, blockade of beta-adrenergic signaling or chemical sympathectomy abolished the effects of enriched environment on NK cells and attenuated the antitumor effect of enriched environment. Taken together, our results provide new insight into the mechanism by which eustress exerts a beneficial effect against cancer. Cancer Res; 77(7); 1611-22. (c)2017 AACR. PMID- 28082403 TI - RORgammat+ Innate Lymphoid Cells Promote Lymph Node Metastasis of Breast Cancers. AB - Cancer cells tend to metastasize first to tumor-draining lymph nodes, but the mechanisms mediating cancer cell invasion into the lymphatic vasculature remain little understood. Here, we show that in the human breast tumor microenvironment (TME), the presence of increased numbers of RORgammat+ group 3 innate lymphoid cells (ILC3) correlates with an increased likelihood of lymph node metastasis. In a preclinical mouse model of breast cancer, CCL21-mediated recruitment of ILC3 to tumors stimulated the production of the CXCL13 by TME stromal cells, which in turn promoted ILC3-stromal interactions and production of the cancer cell motile factor RANKL. Depleting ILC3 or neutralizing CCL21, CXCL13, or RANKL was sufficient to decrease lymph node metastasis. Our findings establish a role for RORgammat+ILC3 in promoting lymphatic metastasis by modulating the local chemokine milieu of cancer cells in the TME. Cancer Res; 77(5); 1083-96. (c)2017 AACR. PMID- 28082404 TI - SRSF2 Regulates Alternative Splicing to Drive Hepatocellular Carcinoma Development. AB - Aberrant RNA splicing is recognized to contribute to cancer pathogenesis, but the underlying mechanisms remain mainly obscure. Here, we report that the splicing factor SRSF2 is upregulated frequently in human hepatocellular carcinoma (HCC), where this event is associated with poor prognosis in patients. RNA-seq and other molecular analyses were used to identify SRSF2-regulated alternative splicing events. SRSF2 binding within an alternative exon was associated with its inclusion in the RNA, whereas SRSF2 binding in a flanking constitutive exon was associated with exclusion of the alternative exon. Notably, cancer-associated splice variants upregulated by SRSF2 in clinical specimens of HCC were found to be crucial for pathogenesis and progression in hepatoma cells, where SRSF2 expression increased cell proliferation and tumorigenic potential by controlling expression of these variants. Our findings identify SRSF2 as a key regulator of RNA splicing dysregulation in cancer, with possible clinical implications as a candidate prognostic factor in patients with HCC. Cancer Res; 77(5); 1168-78. (c)2017 AACR. PMID- 28082406 TI - Ataxia Telangiectasia and Juvenile Idiopathic Arthritis. AB - We report, to the best of our knowledge, the first case of a child with typical ataxia telangiectasia (A-T) who developed juvenile idiopathic arthritis (JIA). The patient was a 15-year-old boy with A-T who presented with noninfectious polyarthritis. A-T is a rare, autosomal recessive disorder characterized by cerebellar atrophy, oculocutaneous telangiectasia, immunodeficiency, radiosensitivity, and predisposition to cancer. The gene responsible for A-T is the A-T mutated (ATM) gene. Clinical manifestations of the disorder are the result of lacking ATM protein, which is involved in DNA repair, apoptosis, various checkpoints in the cell cycle, gene regulation, translation, initiation, and telomere maintenance. There are a few articles that describe deficiency of the DNA repair enzyme, ATM, in rheumatoid arthritis, but the connection between the absence of ATM protein and JIA has not been presented or studied yet. JIA is a heterogeneous group of diseases characterized by arthritis of unknown origin with onset before the age of 16 years. It is the most common childhood chronic rheumatic disease and causes significant disability. Because immunodeficiency can be part of A-T, infectious arthritis can occur, but chronic autoimmune arthritis in these patients is rare. We report a rare case of a 15-year-old boy with A-T and JIA. This case shows a possible relationship between altered function of ATM protein and the pathogenesis of JIA. PMID- 28082407 TI - Improving Early Identification and Intervention for Children at Risk for Autism Spectrum Disorder. AB - OBJECTIVES: To provide an example of a successful, novel statewide effort to increase early identification of young children at risk for autism spectrum disorder (ASD) using a 2-tiered screening process with enhanced quality assessment, interagency policy collaboration and coordination. METHODS: The South Carolina Act Early Team (SCAET) provided focused collaboration among leaders representing state agencies, universities, health care systems, private organizations, and families to improve quality of life for children with ASD. Specific focus was on implementing policy changes and training to result in earlier identification and home-based behavioral intervention for young children at risk for ASD. RESULTS: Policy changes, training, and modified state agency practices were accomplished. Presumptive eligibility, on the basis of a 2-tiered screening process was implemented by BabyNet (South Carolina's Early Intervention Program) in collaboration with the lead agency for developmental disability services. There was a fivefold increase in children eligible for early intensive behavioral intervention without waiting for a diagnosis of ASD, avoiding long waits for diagnostic evaluations. Only 16 children (2.5%) were later found not to have ASD from a comprehensive evaluation. CONCLUSIONS: Improvements in early identification and intervention are feasible through collaborative policy change. The South Carolina Act Early Team and its key stakeholders committed to improving outcomes for this population used existing tools and methods in new ways to improve early identification of children with ASD and to make available evidence based intervention services. This example should be replicable in other states with key stakeholders working collaboratively for the benefit of young children with ASD. PMID- 28082405 TI - Superior Efficacy and Selectivity of Novel Small-Molecule Kinase Inhibitors of T790M-Mutant EGFR in Preclinical Models of Lung Cancer. AB - The clinical utility of approved EGFR small-molecule kinase inhibitors is plagued both by toxicity against wild-type EGFR and by metastatic progression in the central nervous system, a disease sanctuary site. Here, we report the discovery and preclinical efficacy of GNS-1486 and GNS-1481, two novel small-molecule EGFR kinase inhibitors that are selective for T790M-mutant isoforms of EGFR. Both agents were effective in multiple mouse xenograft models of human lung adenocarcinoma (T790M-positive or -negative), exhibiting less activity against wild-type EGFR than existing approved EGFR kinase inhibitors (including osimertinib). In addition, GNS-1486 showed superior potency against intracranial metastasis of EGFR-mutant lung adenocarcinoma. Our results offer a preclinical proof of concept for new EGFR kinase inhibitors with the potential to improve therapeutic index and efficacy against brain metastases in patients. Cancer Res; 77(5); 1200-11. (c)2017 AACR. PMID- 28082408 TI - julius seizure, a Drosophila Mutant, Defines a Neuronal Population Underlying Epileptogenesis. AB - Epilepsy is a neural disorder characterized by recurrent seizures. Bang-sensitive Drosophila represent an important model for studying epilepsy and neuronal excitability. Previous work identified the bang-sensitive gene slamdance (sda) as an allele of the aminopeptidase N gene. Here we show through extensive genetic analysis, including recombination frequency, deficiency mapping, transposon insertion complementation testing, RNA interference (RNAi), and genetic rescue that the gene responsible for the seizure sensitivity is julius seizure (jus), formerly CG14509, which encodes a novel transmembrane domain protein. We also describe more severe genetic alleles of jus RNAi-mediated knockdown of jus revealed that it is required only in neurons and not glia, and that partial bang sensitivity is caused by knockdown in GABAergic or cholinergic but not glutamatergic neurons. RNAi knockdown of jus at the early pupal stages leads to strong seizures in adult animals, implicating that stage as critical for epileptogenesis. A C-terminal-tagged version of Jus was generated from a fosmid genomic clone. This fosmid fusion rescued the bang-sensitive phenotype and was expressed in the optic lobes and the subesophageal and thoracic abdominal ganglia. The protein was primarily localized in axons, especially in the neck connectives, extending into the thoracic abdominal ganglion. PMID- 28082409 TI - Unbound free fatty acid profiles in human plasma and the unexpected absence of unbound palmitoleate. AB - We determined for the first time the profiles of the nine most abundant unbound FFAs (FFAus) in human plasma. Profiles were determined for a standard reference plasma of pooled healthy adults for which the Lipid MAPSMAPS Consortium had determined the total FFA profiles. Measurements were performed by using 20 different acrylodan-labeled fatty acid binding protein mutants (probes), which have complementary specificities for the nine FFAs that comprise more than 96% of long-chain plasma FFA. The acrylodan fluorescence emission for each probe changes upon binding a FFAu. The plasma concentrations of each of the nine FFAus were determined by combining the measured fluorescence ratios of the 20 probes. The total molar FFAu concentration accounted for <10-5 of the total FFA concentration, and the mole fractions of the FFAu profiles were substantially different than the total FFA profiles. Myristic acid, for example, comprises 22% of the unbound versus 2.8% of the total. The most surprising difference is our finding of zero unbound cis-9-palmitoleic acid (POA), whereas the total POA was 7.2%. An unidentified plasma component appears to specifically prevent the release of POA. FFAus are the physiologically active FFAs, and plasma FFAu profiles may provide novel information about human health. PMID- 28082410 TI - Sphingomyelins and ceramides with VLCPUFAs are excluded from low-density raft like domains in differentiating spermatogenic cells. AB - Rat spermatogenic cells contain sphingomyelins (SMs) and ceramides (Cers) with very long-chain PUFAs (VLCPUFAs) in nonhydroxylated (n-V) and 2-hydroxylated (h V) forms. How these atypical species distribute among membrane fractions during differentiation was investigated here using a detergent-free procedure to isolate a small light raft-like low-density fraction and a large heavy fraction, mostly derived from the plasma membrane of spermatocytes, round spermatids, and late spermatids. The light fraction contained cholesterol, glycerophospholipids (GPLs), and SM with the same saturated fatty acids in all three stages. In the heavy fraction, as PUFA increased in the GPL and VLCPUFA in SM from spermatocytes to spermatids, the concentration of cholesterol was also augmented. The heavy fraction had mostly n-V SM in spermatocytes, but accumulated h-V SM and h-V Cer in spermatids. A fraction containing intracellular membranes had less SM and more Cer than the latter, but in both fractions SM and Cer species with h-V increased over species with n-V with differentiation. This accretion of h-V was consistent with the differentiation-dependent expression of fatty acid 2-hydroxylase (Fa2h), as it increased significantly from spermatocytes to spermatids. The non-raft region of the plasma membrane is thus the main target of the dynamic lipid synthesis and remodeling that is involved in germ cell differentiation. PMID- 28082411 TI - TZAP: A telomere-associated protein involved in telomere length control. AB - Telomeres are found at the end of chromosomes and are important for chromosome stability. Here we describe a specific telomere-associated protein: TZAP (telomeric zinc finger-associated protein). TZAP binds preferentially to long telomeres that have a low concentration of shelterin complex, competing with the telomeric-repeat binding factors TRF1 and TRF2. When localized at telomeres, TZAP triggers a process known as telomere trimming, which results in the rapid deletion of telomeric repeats. On the basis of these results, we propose a model for telomere length regulation in mammalian cells: The reduced concentration of the shelterin complex at long telomeres results in TZAP binding and initiation of telomere trimming. Binding of TZAP to long telomeres represents the switch that triggers telomere trimming, setting the upper limit of telomere length. PMID- 28082413 TI - A paralogous decoy protects Phytophthora sojae apoplastic effector PsXEG1 from a host inhibitor. AB - The extracellular space (apoplast) of plant tissue represents a critical battleground between plants and attacking microbes. Here we show that a pathogen secreted apoplastic xyloglucan-specific endoglucanase, PsXEG1, is a focus of this struggle in the Phytophthora sojae-soybean interaction. We show that soybean produces an apoplastic glucanase inhibitor protein, GmGIP1, that binds to PsXEG1 to block its contribution to virulence. P. sojae, however, secretes a paralogous PsXEG1-like protein, PsXLP1, that has lost enzyme activity but binds to GmGIP1 more tightly than does PsXEG1, thus freeing PsXEG1 to support P. sojae infection. The gene pair encoding PsXEG1 and PsXLP1 is conserved in many Phytophthora species, and the P. parasitica orthologs PpXEG1 and PpXLP1 have similar functions. Thus, this apoplastic decoy strategy may be widely used in Phytophthora pathosystems. PMID- 28082412 TI - Deficiency of microRNA miR-34a expands cell fate potential in pluripotent stem cells. AB - Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) efficiently generate all embryonic cell lineages but rarely generate extraembryonic cell types. We found that microRNA miR-34a deficiency expands the developmental potential of mouse pluripotent stem cells, yielding both embryonic and extraembryonic lineages and strongly inducing MuERV-L (MERVL) endogenous retroviruses, similar to what is seen with features of totipotent two-cell blastomeres. miR-34a restricts the acquisition of expanded cell fate potential in pluripotent stem cells, and it represses MERVL expression through transcriptional regulation, at least in part by targeting the transcription factor Gata2. Our studies reveal a complex molecular network that defines and restricts pluripotent developmental potential in cultured ESCs and iPSCs. PMID- 28082414 TI - Thyroid cytology-histology correlation using the RCPath terminology for thyroid cytology reporting. AB - AIMS: The Royal College of Pathologists Thy1-5 thyroid cytology guidance, 2009, second edition 2016, invites audits of its use. This report documents the experience of one department, assessing percentage usage of each Thy category, correlation with subsequent histology and comparison with other published studies. METHODS: Thyroid cytology and subsequent histology reports for 7 years (1 January 2008-31 December 2014) were reviewed, excluding referrals. Years 2008 2010 were compared with 2011-2014. RESULTS: There were 1090 specimens in 2008 2010, 1239 in 2011-2014. Thy usage for 2008-2010/2011-2014, respectively was: Thy1 16.1%/9.8%; Thy1c 10.6%/10.7%; Thy2/2c 52.4%/45.2%; Thy3a 9.6%/14.4%; Thy3f 5.8%/10.9%; Thy4 2.3%/3.6%; Thy5 1.8%/5.4%. 772 specimens had subsequent histology: 415 non-neoplastic lesions; 357 neoplasms (110 benign, 247 malignant). Risk of malignancy (ROM) (including non-histology cases) for 2008-2010/2011-2014: Thy1/1c 5.2%/4.0%; Thy2/2c 1.4%/1.4%; Thy3a 10.0%/14.5%; Thy3f 25.4%/26.7%. Positive predictive values (PPVs) for neoplasia (histology cases only): Thy3a 20.3%/56.9%; Thy3f 60.0%/64.8%; Thy4 58.3%/90.9%; Thy5 100%/100%. PPVs for malignancy (histology cases only): Thy3a 10.2%/36.1%; Thy3f 35.4%/33.3%; Thy4 50.0%/81.8%; Thy5 100%/100%. The Thy3a/Thy5 ratio for 2011-2014 was 2.7. CONCLUSIONS: Numerical reporting categories facilitate audit and comparison with other published results. Technique-related inadequates (Thy1) have reduced but cystic lesions (Thy1c) are stable, in keeping with increased use of ultrasound scanning (USS). Thy2/2c has reduced, probably reflecting increased USS selection of non-benign nodules for sampling. ROMs for Thy1/1c/2/2c are low. Usage of all positive categories, Thy3a, Thy3f, Thy4 and Thy5, has increased. As others have reported for atypia of undetermined significance or follicular lesion of undetermined significance, Thy3a is followed by malignancy more frequently than expected. There is stable prediction of malignancy by Thy3f and Thy5, the latter being 100% throughout. PMID- 28082415 TI - SMO mutation status defines a distinct and frequent molecular subgroup in olfactory groove meningiomas. AB - Background: Meningiomas are the most common primary intracranial tumors in adults. Identification of SMO and AKT1 mutations in meningiomas has raised the hope for targeted therapies. It would be useful to know the precise frequency of these mutations in anatomical subgroups and clarify their prognostic value. Methods: We used the Sanger sequencing technique to characterize 79 samples of olfactory groove meningiomas for SMO (L412F and W535L) and AKT1E17K mutations. We reviewed clinical data to assess the prognostic value of these mutations in this anatomical subgroup. Results: Out of the 79 patients with olfactory groove meningiomas, we identified targetable mutations in 34 patients (43%) (22 patients [28%] with SMO mutation-L412F almost exclusively-and 12 patients [15%] with AKT1 mutation). Meningiomas in the SMO-mutant group had an overall 36% recurrence rate, significantly higher than in the AKT1-mutant group (16%) and in the "SMO and AKT1 wildtype" group (11%) (chi2 test, P = .04). All late recurrences (after 5 y) occurred in the SMO-mutant group. Among grade I meningiomas, the SMO-mutant group was identified as having a significantly poorer prognosis. World Health Organization histological grade II (P = .006) and incomplete resection (P = .001) were independently associated with shorter recurrence-free survival. Conclusion: Molecular diagnosis of SMOL412F/W535L and AKT1E17K mutations improves prognostic evaluation in olfactory groove meningiomas and opens new therapeutic perspectives with SMO or AKT inhibitors for recurrent cases. PMID- 28082417 TI - Impact of Enterovirus Testing on Resource Use in Febrile Young Infants: A Systematic Review. AB - CONTEXT: Enterovirus infection commonly causes fever in infants aged 0 to 90 days and, without testing, is difficult to differentiate from serious bacterial infection. OBJECTIVE: To determine the cost savings of routine enterovirus testing and identify subgroups of infants with greater potential impact from testing among infants 0 to 90 days old with fever. DATA SOURCES: Studies were identified systematically from published and unpublished literature by using Embase, Medline, the Cochrane database, and conference proceedings. STUDY SELECTION: Inclusion criteria were original studies, in any language, of enterovirus infection including the outcomes of interest in infants aged 0 to 90 days. DATA EXTRACTION: Standardized instruments were used to appraise each study. The evidence quality was evaluated using Grading of Recommendations Assessment, Development, and Evaluation criteria. Two investigators independently searched the literature, screened and critically appraised the studies, extracted the data, and applied the Grading of Recommendations Assessment, Development, and Evaluation criteria. RESULTS: Of the 257 unique studies identified and screened, 32 were completely reviewed and 8 were included. Routine enterovirus testing was associated with reduced hospital length of stay and cost savings during peak enterovirus season. Cerebrospinal fluid pleocytosis was a poor predictor of enterovirus meningitis. The studies were all observational and the evidence was of low quality. CONCLUSIONS: Enterovirus polymerase chain reaction testing, independent of cerebrospinal fluid pleocytosis, can reduce length of stay and achieve cost savings, especially during times of high enterovirus prevalence. Additional study is needed to identify subgroups that may achieve greater cost savings from testing to additionally enhance the efficiency of testing. PMID- 28082416 TI - A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas. AB - Background: Activating mutations or structural rearrangements in BRAF are identified in roughly 75% of all pediatric low-grade astrocytomas (PLGAs). However, first-generation RAF inhibitors approved for adult melanoma have poor blood-brain penetrance and are only effective on tumors that express the canonical BRAFV600E oncoprotein, which functions as a monomer. These drugs (type I antagonists that target the "DFG-in" conformation of the kinase) fail to block signaling via KIAA1549:BRAF, a truncation/fusion BRAF oncoprotein which functions as a dimer and is found in the most common form of PLGA. Methods: A panel of small molecule RAF inhibitors (including type II inhibitors, targeting the "DFG out" conformation of the kinase) was screened for drugs showing efficacy on murine models of PLGA and on authentic human PLGA cells expressing KIAA1549:BRAF. Results: We identify a type II RAF inhibitor that serves as an equipotent antagonist of BRAFV600E, KIAA1549:BRAF, and other noncanonical BRAF oncoproteins that function as dimers. This drug (MLN2480, also known as TAK-580) has good brain penetrance and is active on authentic human PLGA cells in brain organotypic cultures. Conclusion: MLN2480 may be an effective therapeutic for BRAF mutant pediatric astrocytomas. PMID- 28082418 TI - Heterogeneous distribution of substrates between the endocardium and epicardium promotes ventricular fibrillation in arrhythmogenic right ventricular dysplasia/cardiomyopathy. AB - Aims: Whether the distribution of scar in arrhythmogenic right ventricular cardiomyopathy (ARVC) plays a role in predicting different types of ventricular arrhythmias is unknown. This study aimed to investigate the prognostic value of scar distribution in patients with ARVC. Methods and results: We studied 80 consecutive ARVC patients (46 men, mean age 47 +/- 15 years) who underwent an electrophysiological study with ablation. Thirty-four patients receive both endocardial and epicardial mapping. Abnormal endocardial substrates and epicardial substrates were characterized. Three groups were defined according to the epicardial and endocardial scar gradient (<10%: transmural, 10-20%: intermediate, >20%: horizontal, as groups 1, 2, and 3, respectively). Sinus rhythm electrograms underwent a Hilbert-Huang spectral analysis and were displayed as 3D Simultaneous Amplitude Frequency Electrogram Transformation (SAFE T) maps, which represented the arrhythmogenic potentials. The baseline characteristics were similar between the three groups. Group 3 patients had a higher incidence of fatal ventricular arrhythmias requiring defibrillation and cardiac arrest during the initial presentation despite having fewer premature ventricular complexes. A larger area of arrhythmogenic potentials in the epicardium was observed in patients with horizontal scar. The epicardial endocardial scar gradient was independently associated with the occurrence of fatal ventricular arrhythmias after a multivariate adjustment. The total, ventricular tachycardia, and VF recurrent rates were higher in Group 3 during 38 +/- 21 months of follow-up. Conclusion: For ARVC, the epicardial substrate that extended in the horizontal plane rather than transmurally provided the arrhythmogenic substrate for a fatal ventricular arrhythmia circuit. PMID- 28082419 TI - Implantable cardioverter-defibrillator therapy among patients with non-ischaemic vs. ischaemic cardiomyopathy for primary prevention of sudden cardiac death. AB - Aim: The magnitude of benefit related to implantable cardioverter defibrillator (ICD) therapy for primary prevention of sudden cardiac death (SCD) in non ischaemic cardiomyopathy (NICM) and ischaemic cardiomyopathy (ICM) has not been evaluated extensively in clinical practice. Methods and results: Of the 5539 consecutive patients enrolled in the multicentre Defibrillateur Automatique Implantable-Prevention Primaire (DAI-PP) study (2002-12), 5485 patients (with information on underlying heart disease) were included in the present analysis: 2181 (39.8%) had NICM and 3304 (60.2%) had ICM. ICM patients were older (63.7 +/ 10.3 vs. 60.6 +/- 12.2 years, P < 0.0001), with a higher ejection fraction [27% (25-30) vs. 25% (20-30), P < 0.0001], narrower QRS (37.3% vs. 21.4% with QRS <120, P < 0.0001), and higher prevalence of sinus rhythm (77.3% vs. 74.0%, P = 0.009). During a mean follow-up of 3.1 +/- 2.2 years, 814 patients died, giving a mortality incidence of 48.6 per 1000 person-years [95% confidence interval (CI) 45.2-51.9], higher among ICM patients (52.3, 95% CI 47.8-56.7) than in NICM patients (42.4, 95% CI 37.3-47.6; P = 0.008) (adjusted hazard ratio 1.31, 95% CI 1.06-1.61, P = 0.01). The increase in mortality among ICM patients was mainly due to non-cardiovascular mortality (P = 0.0002), whereas incidences of cardiovascular mortality (including ICD-unresponsive SCD) were similar in the two groups. Incidences of appropriate ICD interventions (anti-tachycardia pacing, shocks) were similar, but inappropriate therapies were more frequent in NICM (7.94 vs. 5.96%; P = 0.005). Conclusion: NICM and ICM patients had a same rate of ICD therapy for primary prevention of SCD in everyday practice. But, ICM patients more often died of a non- cardiovascular cause of death. Clinical Trial Registration: NCT 01992458. PMID- 28082420 TI - Actin visualization at a glance. AB - Actin functions in a multitude of cellular processes owing to its ability to polymerize into filaments, which can be further organized into higher-order structures by an array of actin-binding and regulatory proteins. Therefore, research on actin and actin-related functions relies on the visualization of actin structures without interfering with the cycles of actin polymerization and depolymerization that underlie cellular actin dynamics. In this Cell Science at a Glance and the accompanying poster, we briefly evaluate the different techniques and approaches currently applied to analyze and visualize cellular actin structures, including in the nuclear compartment. Referring to the gold standard F-actin marker phalloidin to stain actin in fixed samples and tissues, we highlight methods for visualization of actin in living cells, which mostly apply the principle of genetically fusing fluorescent proteins to different actin binding domains, such as LifeAct, utrophin and F-tractin, as well as anti-actin nanobody technology. In addition, the compound SiR-actin and the expression of GFP-actin are also applicable for various types of live-cell analyses. Overall, the visualization of actin within a physiological context requires a careful choice of method, as well as a tight control of the amount or the expression level of a given detection probe in order to minimize its influence on endogenous actin dynamics. PMID- 28082421 TI - Role of the phagosomal redox-sensitive TRP channel TRPM2 in regulating bactericidal activity of macrophages. AB - Acidification of macrophage phagosomes serves an important bactericidal function. We show here that the redox-sensitive transient receptor potential (TRP) cation channel TRPM2 is expressed in the phagosomal membrane and regulates macrophage bactericidal activity through the activation of phagosomal acidification. Measurement of the TRPM2 current in phagosomes identified TRPM2 as a functional redox-sensitive cation channel localized in the phagosomal membrane. Simultaneous measurements of phagosomal Ca2+ changes and phagosome acidification in macrophages undergoing phagocytosis demonstrated that TRPM2 was required to mediate the efflux of cations and for phagosomal acidification during the process of phagosome maturation. Acidification in phagosomes was significantly reduced in macrophages isolated from Trpm2-/- mice as compared to wild type, and acidification was coupled to reduced bacterial clearance in Trpm2-/- mice. Trpm2+/+ macrophages treated with the vacuolar H+-ATPase inhibitor bafilomycin showed reduced bacterial clearance, similar to that in Trpm2-/- macrophages. Direct activation of TRPM2 using adenosine diphosphate ribose (ADPR) induced both phagosomal acidification and bacterial killing. These data collectively demonstrate that TRPM2 regulates phagosomal acidification, and is essential for the bacterial killing function of macrophages. PMID- 28082423 TI - Facile manipulation of protein localization in fission yeast through binding of GFP-binding protein to GFP. AB - GFP-binding protein (or GBP) has been recently developed in various systems and organisms as an efficient tool to purify GFP-fusion proteins. Due to the high affinity between GBP and GFP or GFP variants, this GBP-based approach is also ideally suited to alter the localization of functional proteins in live cells. In order to facilitate the wide use of the GBP-targeting approach in the fission yeast Schizosaccharomyces pombe, we developed a set of pFA6a-, pJK148- and pUC119 based vectors containing GBP- or GBP-mCherry-coding sequences and variants of inducible nmt1 or constitutive adh1 promoters that result in different levels of expression. The GBP or GBP-mCherry fragments can serve as cassettes for N- or C terminal genomic tagging of genes of interest. We illustrated the application of these vectors in the construction of yeast strains with Dma1 or Cdc7 tagged with GBP-mCherry and efficient targeting of Dma1- or Cdc7-GBP-mCherry to the spindle pole body by Sid4-GFP. This series of vectors should help to facilitate the application of the GBP-targeting approach in manipulating protein localization and the analysis of gene function in fission yeast, at the level of single genes, as well as at a systematic scale. PMID- 28082422 TI - Suppression of intestinal tumorigenesis in Apc mutant mice upon Musashi-1 deletion. AB - Therapeutic strategies based on a specific oncogenic target are better justified when elimination of that particular oncogene reduces tumorigenesis in a model organism. One such oncogene, Musashi-1 (Msi-1), regulates translation of target mRNAs and is implicated in promoting tumorigenesis in the colon and other tissues. Msi-1 targets include the tumor suppressor adenomatous polyposis coli (Apc), a Wnt pathway antagonist lost in ~80% of all colorectal cancers. Cell culture experiments have established that Msi-1 is a Wnt target, thus positioning Msi-1 and Apc as mutual antagonists in a mutually repressive feedback loop. Here, we report that intestines from mice lacking Msi-1 display aberrant Apc and Msi-1 mutually repressive feedback, reduced Wnt and Notch signaling, decreased proliferation, and changes in stem cell populations, features predicted to suppress tumorigenesis. Indeed, mice with germline Apc mutations (ApcMin ) or with the Apc1322T truncation mutation have a dramatic reduction in intestinal polyp number when Msi-1 is deleted. Taken together, these results provide genetic evidence that Msi-1 contributes to intestinal tumorigenesis driven by Apc loss, and validate the pursuit of Msi-1 inhibitors as chemo-prevention agents to reduce tumor burden. PMID- 28082424 TI - Accumulation of nuclear ADAR2 regulates adenosine-to-inosine RNA editing during neuronal development. AB - Adenosine to inosine (A-to-I) RNA editing is important for a functional brain, and most known sites that are subject to selective RNA editing have been found to result in diversified protein isoforms that are involved in neurotransmission. In the absence of the active editing enzymes ADAR1 or ADAR2 (also known as ADAR and ADARB1, respectively), mice fail to survive until adulthood. Nuclear A-to-I editing of neuronal transcripts is regulated during brain development, with low levels of editing in the embryo and a dramatic increase after birth. Yet, little is known about the mechanisms that regulate editing during development. Here, we demonstrate lower levels of ADAR2 in the nucleus of immature neurons than in mature neurons. We show that importin-alpha4 (encoded by Kpna3), which increases during neuronal maturation, interacts with ADAR2 and contributes to the editing efficiency by bringing it into the nucleus. Moreover, we detect an increased number of interactions between ADAR2 and the nuclear isomerase Pin1 as neurons mature, which contribute to ADAR2 protein stability. Together, these findings explain how the nuclear editing of substrates that are important for neuronal function can increase as the brain develops. PMID- 28082425 TI - Cullin neddylation may allosterically tune polyubiquitin chain length and topology. AB - Conjugation of Nedd8 (neddylation) to Cullins (Cul) in Cul-RING E3 ligases (CRLs) stimulates ubiquitination and polyubiquitination of protein substrates. CRL is made up of two Cul-flanked arms: one consists of the substrate-binding and adaptor proteins and the other consists of E2 and Ring-box protein (Rbx). Polyubiquitin chain length and topology determine the substrate fate. Here, we ask how polyubiquitin chains are accommodated in the limited space available between the two arms and what determines the polyubiquitin linkage topology. We focus on Cul5 and Rbx1 in three states: before Cul5 neddylation (closed state), after neddylation (open state), and after deneddylation, exploiting molecular dynamics simulations and the Gaussian Network Model. We observe that regulation of substrate ubiquitination and polyubiquitination takes place through Rbx1 rotations, which are controlled by Nedd8-Rbx1 allosteric communication. Allosteric propagation proceeds from Nedd8 via Cul5 dynamic hinges and hydrogen bonds between the C-terminal domain of Cul5 (Cul5CTD) and Rbx1 (Cul5CTD residues R538/R569 and Rbx1 residue E67, or Cul5CTD E474/E478/N491 and Rbx1 K105). Importantly, at each ubiquitination step (homogeneous or heterogeneous, linear or branched), the polyubiquitin linkages fit into the distances between the two arms, and these match the inherent CRL conformational tendencies. Hinge sites may constitute drug targets. PMID- 28082426 TI - Metabolic profiling reveals reprogramming of lipid metabolic pathways in treatment of polycystic ovary syndrome with 3-iodothyronamine. AB - Complex diseases such as polycystic ovary syndrome (PCOS) are associated with intricate pathophysiological, hormonal, and metabolic feedbacks that make their early diagnosis challenging, thus increasing the prevalence risks for obesity, cardiovascular, and fatty liver diseases. To explore the crosstalk between endocrine and lipid metabolic pathways, we administered 3-iodothyronamine (T1AM), a natural analog of thyroid hormone, in a mouse model of PCOS and analyzed plasma and tissue extracts using multidisciplinary omics and biochemical approaches. T1AM administration induces a profound tissue-specific antilipogenic effect in liver and muscle by lowering gene expression of key regulators of lipid metabolism, PTP1B and PLIN2, significantly increasing metabolites (glucogenic, amino acids, carnitine, and citrate) levels, while enhancing protection against oxidative stress. In contrast, T1AM has an opposing effect on the regulation of estrogenic pathways in the ovary by upregulating STAR, CYP11A1, and CYP17A1. Biochemical measurements provide further evidence of significant reduction in liver cholesterol and triglycerides in post-T1AM treatment. Our results shed light onto tissue-specific metabolic vs. hormonal pathway interactions, thus illuminating the intricacies within the pathophysiology of PCOS This study opens up new avenues to design drugs for targeted therapeutics to improve quality of life in complex metabolic diseases. PMID- 28082427 TI - Respiratory gas exchange as a new aid to monitor acidosis in endotoxemic rats: relationship to metabolic fuel substrates and thermometabolic responses. AB - This study introduces the respiratory exchange ratio (RER; the ratio of whole body CO2 production to O2 consumption) as an aid to monitor metabolic acidosis during the early phase of endotoxic shock in unanesthetized, freely moving rats. Two serotypes of lipopolysaccharide (lipopolysaccharide [LPS] O55:B5 and O127:B8) were tested at shock-inducing doses (0.5-2 mg/kg). Phasic rises in RER were observed consistently across LPS serotypes and doses. The RER rise often exceeded the ceiling of the quotient for oxidative metabolism, and was mirrored by depletion of arterial bicarbonate and decreases in pH It occurred independently of ventilatory adjustments. These data indicate that the rise in RER results from a nonmetabolic CO2 load produced via an acid-induced equilibrium shift in the bicarbonate buffer. Having validated this new experimental aid, we asked whether acidosis was interconnected with the metabolic and thermal responses that accompany endotoxic shock in unanesthetized rats. Contrary to this hypothesis, however, acidosis persisted regardless of whether the ambient temperature favored or prevented downregulation of mitochondrial oxidation and regulated hypothermia. We then asked whether the substrate that fuels aerobic metabolism could be a relevant factor in LPS-induced acidosis. Food deprivation was employed to divert metabolism away from glucose oxidation and toward fatty acid oxidation. Interestingly, this intervention attenuated the RER response to LPS by 58%, without suppressing other key aspects of systemic inflammation. We conclude that acid production in unanesthetized rats with endotoxic shock results from a phasic activation of glycolysis, which occurs independently of physiological changes in mitochondrial oxidation and body temperature. PMID- 28082428 TI - A comparison of substrate oxidation during prolonged exercise in men at terrestrial altitude and normobaric normoxia following the coingestion of 13C glucose and 13C fructose. AB - This study compared the effects of coingesting glucose and fructose on exogenous and endogenous substrate oxidation during prolonged exercise at altitude and sea level, in men. Seven male British military personnel completed two bouts of cycling at the same relative workload (55% Wmax) for 120 min on acute exposure to altitude (3375 m) and at sea level (~113 m). In each trial, participants ingested 1.2 g.min-1 of glucose (enriched with 13C glucose) and 0.6 g.min-1 of fructose (enriched with 13C fructose) directly before and every 15 min during exercise. Indirect calorimetry and isotope ratio mass spectrometry were used to calculate fat oxidation, total and exogenous carbohydrate oxidation, plasma glucose oxidation, and endogenous glucose oxidation derived from liver and muscle glycogen. Total carbohydrate oxidation during the exercise period was lower at altitude (157.7 +/- 56.3 g) than sea level (286.5 +/- 56.2 g, P = 0.006, ES = 2.28), whereas fat oxidation was higher at altitude (75.5 +/- 26.8 g) than sea level (42.5 +/- 21.3 g, P = 0.024, ES = 1.23). Peak exogenous carbohydrate oxidation was lower at altitude (1.13 +/- 0.2 g.min-1) than sea level (1.42 +/- 0.16 g.min-1, P = 0.034, ES = 1.33). There were no differences in rates, or absolute and relative contributions of plasma or liver glucose oxidation between conditions during the second hour of exercise. However, absolute and relative contributions of muscle glycogen during the second hour were lower at altitude (29.3 +/- 28.9 g, 16.6 +/- 15.2%) than sea level (78.7 +/- 5.2 g (P = 0.008, ES = 1.71), 37.7 +/- 13.0% (P = 0.016, ES = 1.45). Acute exposure to altitude reduces the reliance on muscle glycogen and increases fat oxidation during prolonged cycling in men compared with sea level. PMID- 28082429 TI - Chronic TrkB agonist treatment in old age does not mitigate diaphragm neuromuscular dysfunction. AB - Previously, we found that brain-derived neurotrophic factor (BDNF) signaling through the high-affinity tropomyosin-related kinase receptor subtype B (TrkB) enhances neuromuscular transmission in the diaphragm muscle. However, there is an age-related loss of this effect of BDNF/TrkB signaling that may contribute to diaphragm muscle sarcopenia (atrophy and force loss). We hypothesized that chronic treatment with 7,8-dihydroxyflavone (7,8-DHF), a small molecule BDNF analog and TrkB agonist, will mitigate age-related diaphragm neuromuscular transmission failure and sarcopenia in old mice. Adult male TrkBF616A mice (n = 32) were randomized to the following 6-month treatment groups: vehicle-control, 7,8-DHF, and 7,8-DHF and 1NMPP1 (an inhibitor of TrkB kinase activity in TrkBF616A mice) cotreatment, beginning at 18 months of age. At 24 months of age, diaphragm neuromuscular transmission failure, muscle-specific force, and fiber cross-sectional areas were compared across treatment groups. The results did not support our hypothesis in that chronic 7,8-DHF treatment did not improve diaphragm neuromuscular transmission or mitigate diaphragm muscle sarcopenia. Taken together, these results do not exclude a role for BDNF/TrkB signaling in aging-related changes in the diaphragm muscle, but they do not support the use of 7,8-DHF as a therapeutic agent to mitigate age-related neuromuscular dysfunction. PMID- 28082430 TI - Increased cardiac work provides a link between systemic hypertension and heart failure. AB - The spontaneously hypertensive rat (SHR) is an established model of human hypertensive heart disease transitioning into heart failure. The study of the progression to heart failure in these animals has been limited by the lack of longitudinal data. We used MRI to quantify left ventricular mass, volume, and cardiac work in SHRs at age 3 to 21 month and compared these indices to data from Wistar-Kyoto (WKY) controls. SHR had lower ejection fraction compared with WKY at all ages, but there was no difference in cardiac output at any age. At 21 month the SHR had significantly elevated stroke work (51 +/- 3 mL.mmHg SHR vs. 24 +/- 2 mL.mmHg WKY; n = 8, 4; P < 0.001) and cardiac minute work (14.2 +/- 1.2 L.mmHg/min SHR vs. 6.2 +/- 0.8 L.mmHg/min WKY; n = 8, 4; P < 0.001) compared to control, in addition to significantly larger left ventricular mass to body mass ratio (3.61 +/- 0.15 mg/g SHR vs. 2.11 +/- 0.008 mg/g WKY; n = 8, 6; P < 0.001). SHRs showed impaired systolic function, but developed hypertrophy to compensate and successfully maintained cardiac output. However, this was associated with an increase in cardiac work at age 21 month, which has previously demonstrated fibrosis and cell death. The interplay between these factors may be the mechanism for progression to failure in this animal model. PMID- 28082431 TI - Underlying mechanism of the cyclic migrating motor complex in Suncus murinus: a change in gastrointestinal pH is the key regulator. AB - In the fasted gastrointestinal (GI) tract, a characteristic cyclical rhythmic migrating motor complex (MMC) occurs in an ultradian rhythm, at 90-120 min time intervals, in many species. However, the underlying mechanism directing this ultradian rhythmic MMC pattern is yet to be completely elucidated. Therefore, this study aimed to identify the possible causes or factors that involve in the occurrence of the fasting gastric contractions by using Suncus murinus a small model animal featuring almost the same rhythmic MMC as that found in humans and dogs. We observed that either intraduodenal infusion of saline at pH 8 evoked the strong gastric contraction or continuously lowering duodenal pH to 3-evoked gastric phase II-like and phase III-like contractions, and both strong contractions were essentially abolished by the intravenous administration of MA 2029 (motilin receptor antagonist) and D-Lys3-GHRP6 (ghrelin receptor antagonist) in a vagus-independent manner. Moreover, we observed that the prostaglandin E2 alpha (PGE2-alpha) and serotonin type 4 (5HT4) receptors play important roles as intermediate molecules in changes in GI pH and motilin release. These results suggest a clear insight mechanism that change in the duodenal pH to alkaline condition is an essential factor for stimulating the endogenous release of motilin and governs the fasting MMC in a vagus-independent manner. Finally, we believe that the changes in duodenal pH triggered by flowing gastric acid and the release of duodenal bicarbonate through the involvement of PGE2-alpha and 5HT4 receptor are the key events in the occurrence of the MMC. PMID- 28082433 TI - Optimization of Labeling PSMAHBED with Ethanol-Postprocessed 68Ga and Its Quality Control Systems. AB - Radiolabeling of the prostate-specific membrane antigen (PSMA) inhibitor Glu-NH CO-NH-Lys(Ahx) using the 68Ga chelator HBED-CC (PSMAHBED) allows imaging of prostate cancer lesions because of high expression of PSMA in prostate carcinoma cells and in bone metastases and lymph nodes related to the disease. The aim of this work was to optimize labeling of 68Ga-PSMAHBED using the efficient cation exchange postprocessing of 68Ga as well as the development of a thin-layer chromatography (TLC)-based quality control system. Methods: Labeling was optimized for online ethanol-postprocessed 68Ga eluate investigating various parameters, such as buffer molarity (0.1-1 M), temperature (25 degrees C-90 degrees C), tracer amount (0.11-0.74 nmol), and labeling time. In addition, purification of the crude product was tested. For radio-TLC quality control, various mobile phases were analyzed using silica gel 60 plates and the results were validated using high-performance liquid chromatography. The most superior mobile phases were also applied on instant thin-layer chromatography (ITLC) silica gel plates. Results: Using optimized conditions, labeling yields of more than 95% were obtained within 10 min when ethanol-based postprocessing was applied using PSMAHBED amounts as low as 0.1 nmol. A higher precursor concentration (0.7 nmol) further increased labeling and quantitative yields to more than 98% within 5 min. In clinical routine, patient batches (>200 applications) with radiochemical purity greater than 98% and specific activities of 326 +/- 20 MBq/nmol are obtained reproducibly. When TLC quality control was performed on silica gel 60 plates, 4 mobile phases with suitable separation properties and complementary Rf values were identified. Two systems showed equivalent separation on ITLC silica gel plates, with ITLC analysis finished within 5 min, in contrast to 20 min for the TLC system. Labeling of PSMAHBED was optimized for cation-exchange postprocessing methods, ensuring almost quantitative labeling and high nuclide purity of final 68Ga-PSMAHBED, making subsequent purification steps unnecessary. Conclusion: The new radio-TLC method allows quality control in a short time using a fast, reliable, low-cost method with little equipment complexity. Using this approach, the synthesis is easily adopted by automated synthesis modules. PMID- 28082432 TI - Quantification of Lung PET Images: Challenges and Opportunities. AB - Millions of people are affected by respiratory diseases, leading to a significant health burden globally. Because of the current insufficient knowledge of the underlying mechanisms that lead to the development and progression of respiratory diseases, treatment options remain limited. To overcome this limitation and understand the associated molecular changes, noninvasive imaging techniques such as PET and SPECT have been explored for biomarker development, with 18F-FDG PET imaging being the most studied. The quantification of pulmonary molecular imaging data remains challenging because of variations in tissue, air, blood, and water fractions within the lungs. The proportions of these components further differ depending on the lung disease. Therefore, different quantification approaches have been proposed to address these variabilities. However, no standardized approach has been developed to date. This article reviews the data evaluating 18F FDG PET quantification approaches in lung diseases, focusing on methods to account for variations in lung components and the interpretation of the derived parameters. The diseases reviewed include acute respiratory distress syndrome, chronic obstructive pulmonary disease, and interstitial lung diseases such as idiopathic pulmonary fibrosis. Based on review of prior literature, ongoing research, and discussions among the authors, suggested considerations are presented to assist with the interpretation of the derived parameters from these approaches and the design of future studies. PMID- 28082434 TI - 89Zr-Bevacizumab PET: Potential Early Indicator of Everolimus Efficacy in Patients with Metastatic Renal Cell Carcinoma. AB - Currently, biomarkers that predict the efficacy of everolimus in metastatic renal cell carcinoma (mRCC) patients are lacking. Everolimus inhibits vascular endothelial growth factor A (VEGF-A) expression. We performed PET scans on mRCC patients with 89Zr-bevacizumab, a VEGF-A-binding antibody tracer. The aims were to determine a change in tumor tracer uptake after the start of everolimus and to explore whether 89Zr-bevacizumab PET can identify patients with early disease progression. Methods:89Zr-bevacizumab PET was done before and 2 and 6 wk after the start of everolimus, 10 mg/d, in mRCC patients. Routine CT scans were performed at baseline and every 3 mo thereafter. Tumor tracer uptake was quantified using SUVmax The endpoints were a change in tumor tracer uptake and treatment response on CT after 3 mo. Results: Thirteen patients participated. The median SUVmax of 94 tumor lesions was 7.3 (range, 1.6-59.5). Between patients, median tumor SUVmax varied up to 8-fold. After 2 wk, median SUVmax was 6.3 (1.7 62.3), corresponding to a mean decrease of 9.1% (P < 0.0001). Three patients discontinued everolimus early. At 6 wk, a mean decrease in SUVmax of 23.4% compared with baseline was found in 70 evaluable lesions of 10 patients, with a median SUVmax of 5.4 (1.1-49.4, P < 0.0001). All 10 patients who continued treatment had stable disease at 3 mo. Conclusion: Everolimus decreases 89Zr bevacizumab tumor uptake. Further studies are warranted to evaluate the predictive value of 89Zr-bevacizumab PET for everolimus antitumor efficacy. PMID- 28082435 TI - Cumulated Activity Comparison of 64Cu-/177Lu-Labeled Anti-Epidermal Growth Factor Receptor Antibody in Esophageal Squamous Cell Carcinoma Model. AB - This work aimed at estimating the kinetic parameters, and hence cumulated activity (AC), of a diagnostic/therapeutic convergence radiopharmaceutical, namely 64Cu-/177Lu-labeled antibody (64Cu-/177Lu-cetuximab), that acts as anti epidermal growth factor receptor. Methods: In mice bearing esophageal squamous cell carcinoma tumors, to estimate uptake (K), release rate constant (kR), and hence AC, a kinetic model analysis was applied to recently published biodistribution data of immuno-PET imaging with 64Cu-cetuximab and of small animal SPECT/CT imaging with 177Lu-cetuximab, including blood and TE-8 tumor. Results: K, kR, and AC were estimated to be 0.0566/0.0593 g?h-1?g-1, 0.0150/0.0030 h-1, and 2.3 * 1010/4.1 * 1012 disintegrations (per gram of TE-8 tumor), with an injected activity of 3.70/12.95 MBq, for 64Cu-/177Lu-cetuximab, respectively. Conclusion: A model is available for comparing kinetic parameters and AC of the companion diagnostic/therapeutic 64Cu-/177Lu-cetuximab that may be considered as a step for determining whether one can really use the former to predict dosimetry of the latter. PMID- 28082436 TI - Resin Versus Glass Microspheres for 90Y Transarterial Radioembolization: Comparing Survival in Unresectable Hepatocellular Carcinoma Using Pretreatment Partition Model Dosimetry. AB - The aim of this study was to compare survival of patients treated for unresectable hepatocellular carcinoma (uHCC) with 90Y transarterial radioembolization (TARE) using pretreatment partition model dosimetry (PMD). Methods: We performed a retrospective analysis of prospectively collected data on 77 patients consecutively treated (mean age +/- SD, 66.4 +/- 12.2 y) for uHCC (36 uninodular, 5 multinodular, 36 diffuse) with 90Y TARE (41 resin, 36 glass) using pretreatment PMD. Study endpoints were progression-free survival (PFS) and overall survival (OS) assessed by Kaplan-Meier estimates. Several variables including Barcelona Clinic Liver Cancer (BCLC) staging system, tumor size, and serum alpha-fetoprotein (AFP) level were investigated using Cox proportional hazards regression. Results: The characteristics of 2 groups were comparable with regard to demographic data, comorbidities, Child-Pugh score, BCLC, serum AFP level, and 90Y global administered activity. The median follow-up time was 7.7 mo (range, 0.4-50.1 mo). Relapse occurred in 44 patients (57%) at a median of 6 mo (range, 0.4-27.9 mo) after 90Y TARE, and 41 patients (53%) died from tumor progression. Comparison between resin and glass microspheres revealed higher but not statistically significantly PFS and OS rates in the 90Y resin group than the 90Y glass group (resin PFS 6.1 mo [95% confidence interval CI, 4.7-7.4] and glass PFS 5 mo [95% CI, 0.9-9.2], P = 0.53; resin OS 7.7 mo [95% CI, 7.2-8.2] and glass OS 7 mo [95% CI 1.6-12.4], P = 0.77). No significant survival difference between both types of 90Y microspheres was observed in any subgroups of patients with early/intermediate or advanced BCLC stages. Among the variables investigated, Cox analyses showed that only in the glass group, the BCLC staging system and the serum AFP level were associated with PFS (P = 0.04) and OS (P = 0.04). Tumor size was a prognostic factor without significant influence on PFS and OS after 90Y TARE. Conclusion: Comparison between resin and glass microspheres revealed no significant survival difference in patients treated for uHCC with 90Y TARE using pretreatment PMD. Further, larger prospective studies are warranted to confirm these findings. PMID- 28082437 TI - Whole-Body 18F-FDG PET/CT Is Superior to CT as First-Line Diagnostic Imaging in Patients Referred with Serious Nonspecific Symptoms or Signs of Cancer: A Randomized Prospective Study of 200 Patients. AB - A fast-track pathway has been established in Denmark to investigate patients with serious nonspecific symptoms and signs of cancer (NSSC), who are not eligible to enter an organ-specific cancer program. The prevalence of cancer in this cohort is approximately 20%. The optimal screening strategy in patients with NSSC remains unknown. The aim of the study was to investigate whether 18F-FDG PET/CT was superior to CT as an initial imaging modality in patients with NSSC. In a randomized prospective trial, the imaging modalities were compared with regard to diagnostic performance. Methods: Two hundred patients were randomized 1:1 to whole-body 18F-FDG PET/CT or CT of the thorax and abdomen as the imaging modality. A tentative diagnosis was established after first-line imaging. The final referral diagnosis was adjudicated by the physician, when sufficient data were available. Results: One hundred ninety-seven patients were available for analysis because 3 patients withdrew consent before scanning. Thirty-nine (20%) patients were diagnosed with cancer, 10 (5%) with an infection, 15 (8%) with an autoimmune disease, and 76 (39%) with other diseases. In the remaining 57 patients (28%), no specific disease was found. 18F-FDG PET/CT had a higher specificity (96% vs. 85%; P = 0.028) and a higher accuracy (94% vs. 82%; P = 0.017) than CT. However, there were no statistically significant differences in sensitivity (83% vs. 70%) or negative predictive values (96% vs. 92%). No difference in days to final referral diagnosis according to randomization group could be shown (7.2 vs. 7.6 d). However, for the subgroups in which the imaging modality showed a suggestion of malignancy, there was a significant delay to final diagnosis in the CT group compared with the 18F-FDG PET/CT group (11.6 vs. 5.7 d; P = 0.02). Conclusion: Compared with CT, we found a higher diagnostic specificity and accuracy of 18F-FDG PET/CT for detecting cancer in patients with NSSC. 18F-FDG PET/CT should therefore be considered as first-line imaging in this group of patients. PMID- 28082438 TI - The Impact of Somatostatin Receptor-Directed PET/CT on the Management of Patients with Neuroendocrine Tumor: A Systematic Review and Meta-Analysis. AB - Somatostatin receptor (SSTR) imaging is widely used for guiding the management of neuroendocrine tumor (NET) patients. 68Ga-DOTATATE approval by the U.S. Food and Drug Administration has triggered widespread clinical interest in SSTR PET/CT throughout the United States. Here, we performed a systematic review and meta analysis to evaluate the impact of SSTR PET/CT on the management of patients with NETs. Methods: A comprehensive literature search was performed using The National Center for Biotechnology Information PubMed online database, applying the following key words: "management" AND "PET" AND "neuroendocrine". Fourteen of 190 studies were deemed suitable based on the following inclusion criteria: original research, cohort study, number of patients 10 or more, and reported change in management after SSTR PET/CT. Change in management across studies was determined by a random-effects model. Results: A total of 1,561 patients were included. Overall, change in management occurred in 44% (range, 16%-71%) of NET patients after SSTR PET/CT. In 4 of 14 studies, SSTR PET/CT was performed after an 111In Octreotide scan. In this subgroup, additional information by SSTR PET/CT led to a change in management in 39% (range, 16%-71%) of patients. Seven of 14 studies differentiated between inter- and intramodality changes, with most changes being intermodality (77%; intramodality, 23%). Conclusion: The management was changed in more than one third of patients undergoing SSTR PET/CT even when performed after an 111In-Octreotide scan. Intermodality changes were 3 times more likely than intramodality changes, underlining the clinical impact of SSTR PET/CT. PMID- 28082440 TI - A Common Mistake in Assessing the Diagnostic Value of a Test: Failure to Account for Statistical and Methodologic Issues. PMID- 28082439 TI - Dissociation Between Brown Adipose Tissue 18F-FDG Uptake and Thermogenesis in Uncoupling Protein 1-Deficient Mice. AB - 18F-FDG PET imaging is routinely used to investigate brown adipose tissue (BAT) thermogenesis, which requires mitochondrial uncoupling protein 1 (UCP1). It remains uncertain, however, whether BAT 18F-FDG uptake is a reliable surrogate measure of UCP1-mediated heat production. Methods: UCP1 knockout (KO) and wild type (WT) mice housed at thermoneutrality were treated with the selective beta3 adrenergic receptor agonist CL 316, 243 and underwent metabolic cage, infrared thermal imaging and 18F-FDG PET/MRI experiments. Primary brown adipocytes were additionally examined for their bioenergetics by extracellular flux analysis as well as their uptake of 2-deoxy-3H-glucose. Results: In response to CL 316, 243 treatments, oxygen consumption, and BAT thermogenesis were diminished in UCP1 KO mice, but BAT 18F-FDG uptake was fully retained. Isolated UCP1 KO brown adipocytes exhibited defective induction of uncoupled respiration whereas their glycolytic flux and 2-deoxy-3H-glucose uptake rates were largely unaffected. Conclusion: Adrenergic stimulation can increase BAT 18F-FDG uptake independently of UCP1 thermogenic function. PMID- 28082441 TI - Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era. AB - Acute promyelocytic leukemia (APL) is commonly complicated by a complex coagulopathy. Uncertainty remains as to which markers of bleeding risk are independent predictors. Drawing from 5 large clinical trials that included all trans retinoic acid (ATRA) as part of induction, we assessed known determinants of bleeding at baseline and evaluated them as potential predictors of hemorrhagic death (HD) in the first 30 days of treatment. The studies included were ALLG APML3 (single arm of ATRA + idarubicin +/- prednisone), ALLG APML4 (single arm of ATRA + idarubicin + arsenic trioxide + prednisone), CALGB C9710 (single arm of ATRA + cytarabine + daunorubicin), Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) E2491 (intergroup I0129, consisting of daunorubicin + cytarabine vs ATRA), and SWOG S0521 (single-arm induction of ATRA + cytarabine + daunorubicin). A total of 1009 patients were included in the original trials, of which 995 had sufficient data to be included in our multivariate analysis. In this final cohort, there were 37 HD cases during the first 30 days following induction, for an estimated cumulative incidence of 3.7% (95% confidence interval [CI], 2.6% to 5.0%). Using multivariate Cox proportional hazards regression, the hazard ratio of HD in the first 30 days was 2.17 (95% CI, 0.84-5.62) for an ECOG performance status of 3-4 vs 0-2 and 5.20 (95% CI, 2.70-10.02) for a white blood cell count of >=20 000/MUL vs <20 000/MUL. In this large cohort of APL patients, high white blood cell count emerged as an independent predictor of early HD. PMID- 28082442 TI - RhIg-prophylaxis is not influenced by FCGR2/3 polymorphisms involved in red blood cell clearance. PMID- 28082443 TI - A novel PTPN1 splice variant upregulates JAK/STAT activity in classical Hodgkin lymphoma cells. AB - Chronic activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways is a hallmark of a variety of B-cell lymphomas, including classical Hodgkin lymphoma (cHL). Constitutive JAK/STAT signaling is crucial for survival and proliferation of Hodgkin/Reed-Sternberg (HRS) cells, the malignant cells of cHL. Although the molecular basis of this constitutive JAK/STAT signaling in cHL has not been completely understood, accumulating reports highlight the role of an inactivation or reduced expression of negative JAK/STAT regulators such as silencer of cell signaling 1 (SOCS1) or protein-tyrosine phosphatase 1B (PTP1B) in this process. Here, we report the expression of truncated PTP1B mRNA variants identified in cHL cell lines and primary cHL tumor samples lacking either 1 or several exon sequences. One of these novel PTP1B variants, a splice variant lacking exon 6 (PTP1BDelta6), was found expressed at low levels in cHL cell lines. However, serum stimulation of cHL augmented the expression of PTP1BDelta6 significantly. Functional characterization of PTP1BDelta6 revealed a positive effect on interferon-gamma- and interleukin-4-induced JAK/STAT activity in HEK293 or HEK293-STAT6 cells, and on the basal STAT activity in stably transfected L-428 and U-HO1 cHL cell lines. Furthermore, PTP1BDelta6 expression increased the proliferation of L-428 and U HO1 cells and reduced cytotoxic effects of the chemotherapeutical agents gemcitabine and etoposide distinctively. Collectively, these data indicate that PTP1BDelta6 is a positive regulator of JAK/STAT signaling in cHL. PMID- 28082444 TI - Mutational landscape and response are conserved in peripheral blood of AML and MDS patients during decitabine therapy. PMID- 28082445 TI - p53-related protein kinase confers poor prognosis and represents a novel therapeutic target in multiple myeloma. AB - p53-related protein kinase (TP53RK, also known as PRPK) is an upstream kinase that phosphorylates (serine residue Ser15) and mediates p53 activity. Here we show that TP53RK confers poor prognosis in multiple myeloma (MM) patients, and, conversely, that TP53RK knockdown inhibits p53 phosphorylation and triggers MM cell apoptosis, associated with downregulation of c-Myc and E2F-1-mediated upregulation of pro-apoptotic Bim. We further demonstrate that TP53RK downregulation also triggers growth inhibition in p53-deficient and p53-mutant MM cell lines and identify novel downstream targets of TP53RK including ribonucleotide reductase-1, telomerase reverse transcriptase, and cyclin dependent kinase inhibitor 2C. Our previous studies showed that immunomodulatory drugs (IMiDs) downregulate p21 and trigger apoptosis in wild-type-p53 MM.1S cells, Importantly, we demonstrate by pull-down, nuclear magnetic resonance spectroscopy, differential scanning fluorimetry, and isothermal titration calorimetry that IMiDs bind and inhibit TP53RK, with biologic sequelae similar to TP53RK knockdown. Our studies therefore demonstrate that either genetic or pharmacological inhibition of TP53RK triggers MM cell apoptosis via both p53-Myc axis-dependent and axis-independent pathways, validating TP53RK as a novel therapeutic target in patients with poor-prognosis MM. PMID- 28082446 TI - Elevated mean platelet volume is associated with poor outcome after mechanical thrombectomy. AB - BACKGROUND: Elevated mean platelet volume (MPV), indicating higher platelet activity, could be a predictor of prognosis in patients with acute ischemic stroke receiving medical therapy. OBJECTIVE: To investigate the relationship between MPV and functional outcome in patients with acute anterior circulation stroke 3 months after undergoing mechanical thrombectomy (MT). METHODS: A total of 153 consecutive patients with acute stroke following MT, in two separate stroke centers, were enrolled between May 2013 and March 2016. MPV was measured on admission. Subjects were divided into two groups according to average MPV level. Univariate and multivariate analyses were performed. MPV was also incorporated into the Houston IA Therapy (HIAT) score, which was developed as a scoring system to predict poor prognosis, and the prediction capability was compared with the HIAT score alone. RESULTS: The average MPV was 10.4 fL. Patients with high MPV had a significantly lower rate of functional independence (28.9% vs 57.1%, p=0.000). After multivariable analysis, elevated MPV remained an independent predictor of unfavorable outcome (OR=3.93, 95% CI 1.73 to 8.94, p=0.001). When the MPV cut-off value was set at 10.4 fL using the receiver operating characteristic (ROC) analysis, MPV >=10.4 fL predicted unfavorable outcome with 62.1% sensitivity and 66.7% specificity, respectively. Addition of MPV to the HIAT score did not improve predictive power compared with the HIAT score system alone by a comparison of the areas under the two ROC curves (0.70 vs 0.62, p=0.174). CONCLUSIONS: Elevated MPV is an independent predictor of poor outcome in patients with acute anterior circulation stroke undergoing MT at 3 months. PMID- 28082447 TI - A pilot study and novel angiographic classification for superior sagittal sinus stenting in patients with non-thrombotic intracranial venous occlusive disease. AB - OBJECTIVE: Safety and efficacy of superior sagittal sinus (SSS) stenting for non thrombotic intracranial venous occlusive disease (VOD) is unknown. The aim of this retrospective cohort study is to evaluate outcomes after SSS stenting. METHODS: We evaluated an institutional database to identify patients who underwent SSS stenting. Radiographic and clinical outcomes were analyzed and a novel angiographic classification of the SSS was proposed. RESULTS: We identified 19 patients; 42% developed SSS stenosis after transverse sinus stenting. Pre stent maximum mean venous pressure (MVP) in the SSS of 16.2 mm Hg decreased to 13.1 mm Hg after stenting (p=0.037). Preoperative trans-stenosis pressure gradient of 4.2 mm Hg decreased to 1.5 mm Hg after stenting (p<0.001). No intraprocedural complication or junctional SSS stenosis distal to the stent construct was noted. Improvement in headache, tinnitus, and visual obscurations was reported by 66.7%, 63.6%, and 50% of affected patients, respectively, at mean follow-up of 5.2 months. We divided the SSS into four anatomically equal segments, numbered S1-S4, from the torcula to frontal pole. SSS stenosis typically occurs in the S1 segment, and the anterior extent of SSS stents was deployed at the S1-S2 junction in all but one case. CONCLUSIONS: SSS stenting is reasonably safe, may improve clinical symptoms, and significantly reduces maximum MVP and trans-stenosis pressure gradients in patients with VOD with SSS stenosis. The S1 segment is most commonly stenotic, and minimum pressure gradients for symptomatic SSS stenosis may be lower than for transverse or sigmoid stenosis. Additional studies and follow-up are necessary to better elucidate appropriate clinical indications and long-term efficacy of SSS stenting. PMID- 28082448 TI - Congenital anomaly of the posterior arch of the atlas: a rare risk factor for posterior circulation stroke. AB - We report an extremely rare case involving a posterior arch anomaly of the atlas, causing a vertebral artery dissection (VAD) induced posterior circulation stroke. A 16-year-old girl was admitted to hospital because of new onset dizziness. VAD related multiple infarction in the posterior circulation was revealed. The congenital posterior arch anomaly of the atlas, along with instability of the atlantoaxial joint, were discovered accidentally during follow-up. This is the first case of ischemic stroke related to atlantal posterior arch aplasia and atlantoaxial instability. Although rare, it reminds us that investigation of the craniovertebral junction should be considered when stroke occurs in young patients. PMID- 28082449 TI - A novel protective role for activating transcription factor 3 in the cardiac response to metabolic stress. PMID- 28082450 TI - A landscape of circular RNA expression in the human heart. AB - Aims: Circular RNA (circRNA) is a newly validated class of single-stranded RNA, ubiquitously expressed in mammalian tissues and possessing key functions including acting as microRNA sponges and as transcriptional regulators by binding to RNA-binding proteins. While independent studies confirm the expression of circRNA in various tissue types, genome-wide circRNA expression in the heart has yet to be described in detail. Methods and results: We performed deep RNA sequencing on ribosomal-depleted RNA isolated from 12 human hearts, 25 mouse hearts and across a 28-day differentiation time-course of human embryonic stem cell-derived cardiomyocytes. Using purpose-designed bioinformatics tools, we uncovered a total of 15 318 and 3017 cardiac circRNA within human and mouse, respectively. Their abundance generally correlates with the abundance of their cognate linear RNA, but selected circRNAs exist at disproportionately higher abundance. Top highly expressed circRNA corresponded to key cardiac genes including Titin (TTN), RYR2, and DMD. The most abundant cardiac-expressed circRNA is a cytoplasmic localized single-exon circSLC8A1-1. The longest human transcript TTN alone generates up to 415 different exonic circRNA isoforms, the majority (83%) of which originates from the I-band domain. Finally, we confirmed the expression of selected cardiac circRNA by RT-PCR, Sanger sequencing and single molecule RNA-fluorescence in situ hybridization. Conclusions: Our data provide a detailed circRNA expression landscape in hearts. There is a high-abundance of specific cardiac-expressed circRNA. These findings open up a new avenue for future investigation into this emerging class of RNA. PMID- 28082451 TI - The neuronal transcription factor NPAS4 is a strong inducer of sprouting angiogenesis and tip cell formation. AB - RATIONALE: Regarding branching morphogenesis, neurogenesis and angiogenesis share common principle mechanisms and make use of the same molecules. Therefore, the investigation of neuronal molecules involved in vascular morphogenesis provides new possibilities for pro-angiogenic approaches in cardiovascular diseases. OBJECTIVE: In this study, we investigated the role of the neuronal transcription factor NPAS4 in angiogenesis. METHODS AND RESULTS: Here, we demonstrate that the neuronal transcription factor NPAS4 is expressed in endothelial cells of different origin using reverse transcription PCR and western blot analysis. To investigate how NPAS4 affects endothelial cell function, NPAS4 was overexpressed by plasmid transfection or depleted from human umbilical vein endothelial cells (HUVECs) by specific siRNAs. In vitro HUVEC sprouting assays showed that sprouting and branching of endothelial cells was enhanced by NPAS4 overexpression. Consistently, silencing of NPAS4 resulted in reduced HUVEC sprouting and branching. Mechanistically, we identified as target gene vascular endothelial adhesion molecule VE-cadherin to be involved in the pro-angiogenic function of NPAS4. In endothelial cell mosaic spheroid sprouting assays, NPAS4 was involved in tip cell formation. In vivo experiments in mouse and zebrafish confirmed our in vitro findings. NPAS4-deficient mice displayed reduced ingrowth of endothelial cells in the Matrigel plug assay. Consistent with a regulatory role of NPAS4 in endothelial cell function silencing of NPAS4 in zebrafish by specific morpholinos resulted in perturbed intersegmental vessels growth. CONCLUSIONS: NPAS4 is expressed in endothelial cells, regulates VE-cadherin expression and regulates sprouting angiogenesis. PMID- 28082452 TI - Sphingosine-1-phosphate signalling-a key player in the pathogenesis of Angiotensin II-induced hypertension. AB - AIMS: Hypertension is a complex condition involving functional and structural alterations of the microvasculature and an activation of the immune system. T lymphocytes play a crucial role during the development of hypertension in experimental models, yet the underlying mechanisms remain elusive. Lymphocyte egress from lymph nodes is controlled by sphingosine-1-phosphate (S1P), a natural lipid mediator regulating immune cell and vascular function in health and disease. We therefore investigated the involvement of S1P signalling in the pathogenesis of hypertension. METHODS AND RESULTS: Angiotensin-II (AngII) treatment resulted in high blood pressure (BP) associated to increased plasma S1P and circulating T-cell counts. T-cell egress from lymph nodes was found to be a critical initial step for the onset of hypertension as fingolimod, a S1P-receptor agonist sequestering lymphocytes in the lymph nodes and inducing lymphopenia, blunted BP responses to AngII. Furthermore, activity of S1P-generating enzyme type 2 (SphK2) in haematopoietic cells critically contributed to AngII-induced lymphocyte mobilization from the lymph nodes as SphK2-/- mice and mice where SphK2 was ablated only in the haematopoietic system presented an accumulation of T-cells in mesenteric lymph nodes and a blunted BP response. In addition, deregulation of vascular SphK2 expression associated to a thrombo-inflammatory phenotype of the microvasculature, and to functional alterations of small resistance arteries. CONCLUSION: The presented results point to a critical involvement of S1P and its signalling axis in the pathogenesis of hypertension. Specifically, SphK2 evolves as key player in immune cell trafficking and vascular dysfunction contributing to the development of overt hypertension. PMID- 28082453 TI - ATF3 expression in cardiomyocytes preserves homeostasis in the heart and controls peripheral glucose tolerance. AB - AIMS: Obesity and type 2 diabetes (T2D) trigger a harmful stress-induced cardiac remodeling process known as cardiomyopathy. These diseases represent a serious and widespread health problem in the Western world; however the underlying molecular basis is not clear. ATF3 is an 'immediate early' gene whose expression is highly and transiently induced in response to multiple stressors such as metabolic, oxidative, endoplasmic reticulum and inflammation, stressors that are involved in T2D cardiomyopathy. The role of ATF3 in diabetic cardiomyopathy is currently unknown. Our research has aimed to study the effect of ATF3 expression on cardiomyocytes, heart function and glucose homeostasis in an obesity-induced T2D mouse model. METHODS AND RESULTS: We used wild type mice (WT) as well as mutant mice with a cardiac-specific ATF3 deficiency (ATF3-cKO). Mice were fed a high-fat diet (HFD) for 15 weeks. HFD induced high ATF3 expression in cardiomyocytes. Mice were examined for cardiac remodeling processes and the diabetic state was assessed. HFD-fed ATF3-cKO mice exhibited severe cardiac fibrosis, higher levels of heart hypertrophic markers, increased inflammation and worse cardiac function, as compared to WT mice. Interestingly, HFD-fed ATF3-cKO mice display increased hyperglycemia and reduced glucose tolerance, despite higher blood insulin levels, as compared to HFD-fed WT mice. Elevated levels of the cardiac inflammatory cytokines IL-6 and TNFalpha leading to impaired insulin signalling may partially explain the peripheral glucose intolerance. CONCLUSIONS: Cardiac ATF3 has a protective role in dampening the HFD-induced cardiac remodeling processes. ATF3 exerts both local and systemic effects related to T2D induced cardiomyopathy. This study provides a strong relationship between heart remodeling processes and blood glucose homeostasis. PMID- 28082454 TI - Modifying head nurse messages during daily conversations as leverage for safety climate improvement: a randomised field experiment. AB - BACKGROUND: Recent literature reviews lament the paucity of high-quality intervention studies designed to test safety culture improvement in hospitals. The current study adapts an empirically supported strategy developed for manufacturing companies by focusing on patient care and safety messages head nurses communicate during daily conversations with nurses. METHODS: The study was designed as randomised control trial coupled with before-after measurement of outcome variables. We randomly assigned 445 nurses working in 27 inpatient departments in a midsize hospital in Israel to experimental and control groups. Ten randomly chosen nurses in both groups filled a brief questionnaire referring to last conversation with head nurse. One month later, head nurses in the experimental group received individual feedback, comparing individual with mean hospital scores, coupled with self-set goals for the following feedback session. Head nurses in the control group received no feedback, except for a summary report by the end of intervention. RESULTS: Patient care messages increased by 16% and professional development messages by 12%, accompanied by 17% decline in nurse-blaming messages in the experimental group, remaining unchanged in the control group. Such changes led to statistically significant increase in patient care behaviours (17%), safety climate (13%), teamwork (9%) and supervisory leadership quality (18%). Rule-compliance messages and workaround behaviours remained unchanged in experimental and control departments. CONCLUSIONS: These data support the utility of our intervention strategy for improving patient safety climate and resultant caring behaviours in healthcare organisations. The fact that our intervention used easy-to-deliver feedback requiring only two sessions minimised its organisational costs. PMID- 28082456 TI - Obesity-Associated Alterations in Glucose Metabolism Are Reversed by Chronic Bilateral Stimulation of the Abdominal Vagus Nerve. AB - Acute vagal stimulation modifies glucose and insulin metabolism, but the effect of chronic bilateral vagal stimulation is not known. Our aim was to quantify the changes in whole-body and organ-specific insulin sensitivities 12 weeks after permanent, bilateral, vagal stimulation performed at the abdominal level in adult mini-pigs. In 15 adult mini-pigs, stimulating electrodes were placed around the dorsal and ventral vagi using laparoscopy and connected to a dual-channel stimulator placed subcutaneously. Animals were divided into three groups based on stimulation and body weight (i.e., lean nonstimulated, obese nonstimulated, and obese stimulated). Twelve weeks after surgery, glucose uptake and insulin sensitivity were measured using positron emission tomography during an isoglycemic clamp. Mean whole-body insulin sensitivity was lower by 34% (P < 0.01) and the hepatic glucose uptake rate was lower by 33% (P < 0.01) in obese nonstimulated mini-pigs but was no different in obese-stimulated compared with lean mini-pigs. An improvement in skeletal glucose uptake rate was also observed in obese-stimulated compared with obese-nonstimulated groups (P < 0.01). Vagal stimulation was associated with increased glucose metabolism in the cingulate and prefrontal brain areas. We conclude that chronic vagal stimulation improves insulin sensitivity substantially in diet-induced obesity by both peripheral and central mechanisms. PMID- 28082455 TI - Modeling gene-wise dependencies improves the identification of drug response biomarkers in cancer studies. AB - Motivation: In recent years, vast advances in biomedical technologies and comprehensive sequencing have revealed the genomic landscape of common forms of human cancer in unprecedented detail. The broad heterogeneity of the disease calls for rapid development of personalized therapies. Translating the readily available genomic data into useful knowledge that can be applied in the clinic remains a challenge. Computational methods are needed to aid these efforts by robustly analyzing genome-scale data from distinct experimental platforms for prioritization of targets and treatments. Results: We propose a novel, biologically motivated, Bayesian multitask approach, which explicitly models gene centric dependencies across multiple and distinct genomic platforms. We introduce a gene-wise prior and present a fully Bayesian formulation of a group factor analysis model. In supervised prediction applications, our multitask approach leverages similarities in response profiles of groups of drugs that are more likely to be related to true biological signal, which leads to more robust performance and improved generalization ability. We evaluate the performance of our method on molecularly characterized collections of cell lines profiled against two compound panels, namely the Cancer Cell Line Encyclopedia and the Cancer Therapeutics Response Portal. We demonstrate that accounting for the gene centric dependencies enables leveraging information from multi-omic input data and improves prediction and feature selection performance. We further demonstrate the applicability of our method in an unsupervised dimensionality reduction application by inferring genes essential to tumorigenesis in the pancreatic ductal adenocarcinoma and lung adenocarcinoma patient cohorts from The Cancer Genome Atlas. Availability and Implementation: : The code for this work is available at https://github.com/olganikolova/gbgfa. Contact: : nikolova@ohsu.edu or margolin@ohsu.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28082457 TI - Neu5Gc and alpha1-3 GAL Xenoantigen Knockout Does Not Affect Glycemia Homeostasis and Insulin Secretion in Pigs. AB - Xenocell therapy from neonate or adult pig pancreatic islets is one of the most promising alternatives to allograft in type 1 diabetes for addressing organ shortage. In humans, however, natural and elicited antibodies specific for pig xenoantigens, alpha-(1,3)-galactose (GAL) and N-glycolylneuraminic acid (Neu5Gc), are likely to significantly contribute to xenoislet rejection. We obtained double knockout (DKO) pigs lacking GAL and Neu5Gc. Because Neu5Gc-/- mice exhibit glycemic dysregulations and pancreatic beta-cell dysfunctions, we evaluated islet function and glucose metabolism regulation in DKO pigs. Isolation of islets from neonate piglets yielded identical islet equivalent quantities to quantities obtained from control wild-type pigs. In contrast to wild-type islets, DKO islets did not induce anti-Neu5Gc antibody when grafted in cytidine monophosphate-N acetylneuraminic acid hydroxylase KO mice and exhibited in vitro normal insulin secretion stimulated by glucose and theophylline. Adult DKO pancreata showed no histological abnormalities, and immunostaining of insulin and glucagon was similar to that from wild-type pancreata. Blood glucose, insulin, C-peptide, the insulin-to-glucagon ratio, and HOMA-insulin resistance in fasted adult DKO pigs and blood glucose and C-peptide changes after intravenous glucose or insulin administration were similar to wild-type pigs. This first evaluation of glucose homeostasis in DKO pigs for two major xenoantigens paves the way to their use in (pre)clinical studies. PMID- 28082459 TI - Deletion of CD1d in Adipocytes Aggravates Adipose Tissue Inflammation and Insulin Resistance in Obesity. AB - Adipose tissue inflammation is an important factor in obesity that promotes insulin resistance. Among various cell types in adipose tissue, immune cells actively regulate inflammatory responses and affect whole-body energy metabolism. In particular, invariant natural killer T (iNKT) cells contribute to mitigating dysregulation of systemic energy homeostasis by counteracting obesity-induced inflammation in adipose tissue. However, the molecular mechanisms by which adipose iNKT cells become activated and mediate anti-inflammatory roles in obese adipose tissue have not been thoroughly understood yet. In the current study, we demonstrate that adipocyte CD1d plays a key role in the stimulation of adipose iNKT cells, leading to anti-inflammatory responses in high-fat diet (HFD)-fed mice. Accordingly, adipocyte-specific CD1d-knockout (CD1dADKO) mice showed reduced numbers of iNKT cells in adipose tissues and decreased responses to alpha galactosylceramide-induced iNKT cell activation. Additionally, HFD-fed CD1dADKO mice revealed reduced interleukin-4 expression in adipose iNKT cells and aggravated adipose tissue inflammation and insulin resistance. Collectively, these data suggest that adipocytes could selectively stimulate adipose iNKT cells to mediate anti-inflammatory responses and attenuate excess proinflammatory responses in obese adipose tissue. PMID- 28082460 TI - First Evidence of Thaumastocoris peregrinus (Heteroptera: Thaumastocoridae) Feeding From Mesophyll of Eucalyptus Leaves. AB - The bronze bug, Thaumastocoris peregrinus Carpintero & Dellape, 2006 (Heteroptera: Thaumastocoridae) originally restricted to Australia, is an important emerging pest of Eucalyptus plantations in the Southern Hemisphere. It feeds on mature leaves, causing the loss of photosynthetic surface area and defoliation and, according to some studies, even tree death. In this work, feeding activities of T. peregrinus on Eucalyptus camaldulensis Dehn leaves and its primary food resources were identified. In cross sections of leaves, solid salivary deposits on epidermal cells and in the vicinity of stomata cells were detected. In subepidermal cells of the palisade parenchyma near the stylet penetration point, disorganization and removal of chloroplasts were also observed. The presence of chlorophyll in guts of adults and nymphs was analyzed using spectrophotometry and confocal laser scanning to obtain in situ fluorescent spectra. Both spectra showed chlorophyll absorbance peaks. In addition, the presence of chlorophyll in guts of T. peregrinus using fluorescence microscopy was identified. These results provide the first evidence that T. peregrinus feeds from the palisade parenchyma (chlorenchyma) of Eucalyptus leaves. PMID- 28082458 TI - Developmental Role of Macrophage Cannabinoid-1 Receptor Signaling in Type 2 Diabetes. AB - Islet inflammation promotes beta-cell loss and type 2 diabetes (T2D), a process replicated in Zucker Diabetic Fatty (ZDF) rats in which beta-cell loss has been linked to cannabinoid-1 receptor (CB1R)-induced proinflammatory signaling in macrophages infiltrating pancreatic islets. Here, we analyzed CB1R signaling in macrophages and its developmental role in T2D. ZDF rats with global deletion of CB1R are protected from beta-cell loss, hyperglycemia, and nephropathy that are present in ZDF littermates. Adoptive transfer of CB1R-/- bone marrow to ZDF rats also prevents beta-cell loss and hyperglycemia but not nephropathy. ZDF islets contain elevated levels of CB1R, interleukin-1beta, tumor necrosis factor-alpha, the chemokine CCL2, and interferon regulatory factor-5 (IRF5), a marker of inflammatory macrophage polarization. In primary cultured rodent and human macrophages, CB1R activation increased Irf5 expression, whereas knockdown of Irf5 blunted CB1R-induced secretion of inflammatory cytokines without affecting CCL2 expression, which was p38MAPKalpha dependent. Macrophage-specific in vivo knockdown of Irf5 protected ZDF rats from beta-cell loss and hyperglycemia. Thus, IRF5 is a crucial downstream mediator of diabetogenic CB1R signaling in macrophages and a potential therapeutic target. PMID- 28082461 TI - Temporal and Directional Patterns of Nymphal Halyomorpha halys (Hemiptera: Pentatomidae) Movement on the Trunk of Selected Wild and Fruit Tree Hosts in the Mid-Atlantic Region. AB - Halyomorpha halys (Stal) (Hemiptera: Pentatomidae) is an invasive and polyphagous herbivore that has been problematic in Mid-Atlantic fruit orchards, many of which are adjacent to woodlands containing its wild hosts. Our tree census in woodlands bordering 15 Mid-Atlantic apple orchards revealed 47 species of deciduous trees and shrubs, 76.6% of which were recorded hosts of H. halys. Tree of heaven was most common and abundant overall. Halyomorpha halys nymphs have a substantial walking dispersal capacity, and their fitness is enhanced by feeding on multiple hosts. Directional and temporal patterns of nymphal H. halys movement on selected wild hosts and apple and peach trees at the orchard-woodland interface were monitored in 2014 and 2015 using passive traps to capture nymphs walking up and down tree trunks. Weekly captures from mid-May to late September or mid-October were compared among hosts across both seasons. Despite higher total nymphal captures in 2014 than 2015, the seasonal trends for both years were similar and indicated bivoltine H. halys populations. In both years, more nymphs were intercepted while walking up than down and captures of upward- and downward walking nymphs varied significantly among the hosts. All instars were captured, but captures of second instars predominated. Captures reflected seasonal changes in instar distribution and consisted predominantly of younger and older nymphs, early and later in the season, respectively. Results are discussed in relation to host and seasonal effects on the movement of nymphs at the orchard-woodland interface, and the implications for H. halys management. PMID- 28082463 TI - The Ubiquitous Existence of MicroRNA in Body Fluids. PMID- 28082464 TI - Conversion after off-pump coronary artery bypass grafting: the CORONARY trial experience. AB - Objectives: Emergent and late conversions form OFF-to-ON pump coronary artery bypass grafting (CABG) have been associated with worse outcomes, however, it remains unclear as to which risk factors are associated with conversion and how to prevent them. Methods: Among 4718 patients who randomly underwent off- or on pump CABG, the incidence of off-pump to on-pump cross-over, or 'OFF-to-ON conversion', was 7.9% (186/2356). The primary outcome was a composite of death, stroke, myocardial infarction, or new renal failure requiring dialysis. We assessed the risk factors and outcomes of converted patients. Results: Emergent OFF-to-ON conversions, defined as conversions for hypotension or ischaemia, were required for 3.2% of patients ( n = 75), while most elective conversions were due to small or intramuscular coronaries ( n = 83). OFF-to-ON converted patients required increased surgery time, blood transfusions, intensive care unit stay, and presented a higher incidence at 1 year of the composite outcome compared with non-converted off-pump patients (all P < 0.01), especially if the conversion was emergent. Conversely, elective conversions outcomes were no different compared with non-converted off-pump patients ( P = 0.35). Independent predictors of emergent conversions included higher heart rate or chronic atrial fibrillation, urgent surgery, more grafts planned and surgeon experience with off-pump CABG. Conclusions: Emergent OFF-to-ON conversion is associated with worse outcomes compared with elective conversion or no conversion. In the presence of risk factors for emergent conversion, an early and elective conversion approach is a judicious strategy. PMID- 28082465 TI - Pacing induced recurrent ventricular fibrillation following cardiac surgery. PMID- 28082466 TI - Can total bronchopleural fistulas from complete stump dehiscence be endoscopically treated? AB - Objectives: Bronchopleural fistula (BPF) is an uncommon complication following a lung resection to address various conditions. BPFs are associated with high morbidity and mortality rates. This study evaluated the endoscopic treatment of 'total' BPFs using the Occlutech-Figulla(r) cardiac device at a single centre. Methods: We selected nine patients with chronic and complete BPFs. Under direct bronchoscopic visualization, the BPFs were treated using the Occlutech-Figulla device. The patients were followed up for 12 months to determine the treatment level and complications. Results: The procedure had a favourable outcome in three patients, resulting in complete fistula closure. Two patients had partial closure and showed improvements in their clinical conditions. In two other cases, closure of the bronchial stump was unsuccessful using this method. Two patients died from causes unrelated to the procedure or the device. During the follow-up period, no complications related to infection or device-related injuries were reported. Conclusions: In patients without clinical conditions that require surgical treatment, the Occlutech-Figulla cardiac device can be a safe and effective method for the endoscopic treatment of large BPFs resulting from complete dehiscence of a bronchial stump. No severe events were reported. PMID- 28082467 TI - Dilated cardiomyopathy associated with elephant trunk in Loeys-Dietz syndrome. AB - A 14-year-old boy presented to our institution with a diagnosis of acute type A dissection. He was diagnosed with Loeys-Dietz syndrome and underwent aortic valve sparing repair at the age of 9 years. Emergency total arch repair with elephant trunk (ET) was performed successfully; echocardiogram before discharge showed normal left ventricular function and size. However, he was readmitted 1 month after discharge with significant left ventricular dysfunction and dilatation. The small folded ET caused a pressure gradient between the upper and lower body, which might deteriorate left ventricular function. Urgent balloon arterioplasty was performed to unfold the ET graft, resulting in no improvement of left ventricular function. ET removal and descending aorta replacement with an 18-mm graft was performed eventually. Left ventricular function and brain natriuretic peptide gradually improved after approximately 2 years of follow-up. PMID- 28082468 TI - Is experience the best teacher? PMID- 28082469 TI - Acquired Von Willebrand syndrome in patients on long-term support with HeartMate II. AB - Objectives: Impaired binding of Von Willebrand factor (VWF) to platelets and to collagen due to acquired Von Willebrand syndrome (AVWS) is associated with support from a ventricular assist device (VAD) and can contribute to bleeding tendencies in patients with VADs. The onset of AVWS has been shown to occur immediately after VAD implantation. Our aim was to determine long-term data on AVWS in VAD patients. Methods: We analysed 278 data sets of 74 patients on HeartMate II (HMII) support for 3-80 months after implantation (11.2 +/- 12.1, median 6.3 months.). Ristocetin cofactor activity (VWF:RCo), collagen binding capacity (VWF:CB), VWF antigen (VWF:Ag) and the ratios of VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag were determined. Further, the presence of high molecular weight (HMW) multimers of VWF was investigated. Results: Abnormally low values of VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag were found in 69% and 97% of blood samples, respectively. Only ten of 181 multimer analyses showed a normal pattern, and HMW multimers were present in both specimens in only one of the 74 patients. No significant changes in these parameters were observed over time. The VWF:CB/VWF:Ag ratio correlated with the multimer patterns, whereas the VWF:RCo/VWF:Ag ratio seemed to be less sensitive for AVWS. Conclusions: Our data indicate that AVWS is a typical phenomenon in patients with VAD support and that there are no time-dependent changes in these parameters apparent in most patients on long-term support with HMII. PMID- 28082470 TI - Refraining from smoking shortly before lobectomy has no influence on the risk of pulmonary complications: a case-control study on a matched population. AB - Objectives: Whether or not smoking increases the risk of postoperative pulmonary complications (PPCs) in lung resection patients remains controversial. The objective of this study was to evaluate whether active smoking at the time of surgery increases the risk of PPCs compared to abstention shortly before the procedure. Methods: We conducted a case-control study on 378 patients who underwent non-extended lobectomy in our institution. Cases were active smokers at the time of surgery, and controls were patients who quit smoking at any time up to 16 weeks before surgery. All patients received the same perioperative care, including chest physiotherapy. The occurrence of PPCs was the considered outcome. PPCs were defined as pneumonia (American Thoracic Society criteria, 2004) or atelectasis requiring bronchoscopy. Cases and controls were matched according to age, body mass index, forced expiratory volume in the first second of expiration (FEV1%), FEV1/forced vital capacity, type of approach and diagnosis of non-small cell lung cancer. We calculated the odds ratio (OR) with 95% confidence interval (CI) for PPCs. Results: The overall prevalence of PPCs was 4.7% (18/378); 5.3% (13 out of 244) in the active smokers group and 3.7% (5 out of 134) in the ex smokers group. After matching, two sets of 134 patients each were compared. The prevalence was 4.5% (6/134) in active and 3.7% (5/134) in ex-smokers (OR 1.21 95% CI: 0.29-5.13, P = 0.76). Conclusions: In this population of patients strictly matched according to risk criteria for PPCs, smoking at the time of surgery was not identified as a risk variable. Therefore, the practice of postponing surgery until tobacco abstention has been achieved does not seem to be justified. PMID- 28082471 TI - Profiling inflammation and tissue injury markers in perfusate and bronchoalveolar lavage fluid during human ex vivo lung perfusion. AB - Objectives: Availability of donor lungs suitable for transplant falls short of current demand and contributes to waiting list mortality. Ex vivo lung perfusion (EVLP) offers the opportunity to objectively assess and recondition organs unsuitable for immediate transplant. Identifying robust biomarkers that can stratify donor lungs during EVLP to use or non-use or for specific interventions could further improve its clinical impact. Methods: In this pilot study, 16 consecutive donor lungs unsuitable for immediate transplant were assessed by EVLP. Key inflammatory mediators and tissue injury markers were measured in serial perfusate samples collected hourly and in bronchoalveolar lavage fluid (BALF) collected before and after EVLP. Levels were compared between donor lungs that met criteria for transplant and those that did not. Results: Seven of the 16 donor lungs (44%) improved during EVLP and were transplanted with uniformly good outcomes. Tissue and vascular injury markers lactate dehydrogenase, HMGB-1 and Syndecan-1 were significantly lower in perfusate from transplanted lungs. A model combining IL-1beta and IL-8 concentrations in perfusate could predict final EVLP outcome after 2 h assessment. In addition, perfusate IL-1beta concentrations showed an inverse correlation to recipient oxygenation 24 h post-transplant. Conclusions: This study confirms the feasibility of using inflammation and tissue injury markers in perfusate and BALF to identify donor lungs most likely to improve for successful transplant during clinical EVLP. These results support examining this issue in a larger study. PMID- 28082472 TI - Long-term experience with the E-vita Open hybrid graft in complex thoracic aortic disease?. AB - OBJECTIVES: The E-vita Open hybrid stent graft is intended to achieve one-stage treatment of the proximal and distal thoracic aorta down to the mid-thoracic level in cases of acute (AAD) or chronic (CAD) type I aortic dissection and complex thoracic aortic aneurysm (TAA). We report our long-term results up to 10 year experience. METHODS: From February 2005 until March 2015, 178 consecutive patients (mean age 59 +/- 11 years) underwent surgery using the E-vita Open hybrid graft for AAD ( n = 96), CAD ( n = 43) or TAA ( n = 39). Pre-, intra- and postoperative variables, influential procedural improvements and follow-up data including aortic remodelling analyses are presented. RESULTS: Overall 30-day mortality was 10%, 10% for AAD, 7% for CAD and 13% for TAA. Univariable analysis identified low left ventricular ejection fraction, peripheral arterial disease, chronic obstructive pulmonary disease and severely compromised haemodynamics as risk factors for in-hospital death. Logistic regression analysis defined compromised haemodynamics and duration of cardiopulmonary bypass as significant. After 7 years, estimated survival was 55% for AAD, 74% for CAD and 73% for TAA patients. Freedom from aorta-related late death was 94%, 91% in AAD, 100% in CAD and 97% in TAA. Positive or stable aortic remodelling down to the stent graft end was achieved in 92% AAD, 82% in CAD and full aneurysmal exclusion in 88%. Further downstream, negative remodelling was observed in 27% of the AAD, 41% of the CAD and 22% of the TAA patients. Freedom from endovascular intervention downstream was 96% in AAD, 75% in CAD and 74% in TAA patients. Freedom from thoraco abdominal surgery was 97%, 65% and 93%, respectively. CONCLUSIONS: The E-vita Open hybrid stent graft renders durable long-term performance without any proximal endoleakage or graft failure over time and represents the ideal landing or docking zone for either thoracic endovascular thoracic repair or thoraco abdominal surgery, if required. No reinterventions were necessary down to the end of the stent graft, proving that the disease is overcome along the hybrid graft down to mid-thoracic level. PMID- 28082473 TI - Poor preoperative patient-reported quality of life is associated with complications following pulmonary lobectomy for lung cancer. AB - Objectives: To assess whether quality of life (QOL) was associated with cardiopulmonary complications following pulmonary lobectomy for lung cancer. Methods: Retrospective analysis of 200 consecutive patients who had pulmonary lobectomy for lung cancer (September 2014-October 2015). QOL was assessed by the self-administration of the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire within 2 weeks before the operation. The individual QOL scales were tested for a possible association with cardiopulmonary complications along with other objective baseline and surgical parameters by univariable and multivariable analyses. Results: Forty-three patients (21.5%) developed postoperative cardiopulmonary complications; 4 of them died within 30 days (2%). Univariable analysis showed that, compared to patients without complications, those with complications reported a lower global health status (GHS) [59.1; standard deviation (SD) 27.2 vs 69.6; SD 20.6, P = 0.02], were older (71.2; SD 8.4 vs 67.7; SD 9.4, P = 0.03), had lower values of forced expiratory volume in one second (FEV1) (83.9; SD 27.2 vs 91.4; SD 20.9), P = 0.06) and carbon monoxide lung diffusion capacity (DLCO) (67.9; SD 20.9 vs 74.2; SD 17.6, P = 0.02) and higher performance score (0.76; SD 0.63 vs 0.53; SD 0.64, P = 0.02). Stepwise logistic regression analysis showed that factors independently associated with cardiopulmonary complications were age [odds ratio (OR) 1.04, 95% CI 1.0-1.09, P = 0.02] and patient-reported GHS [OR 0.98, 95% confidence interval (CI) 0.96-0.99, P = 0.006], whereas other objective parameters (i.e. FEV1, DLCO) were not. The best cut-off value for GHS to discriminate patients with complications after surgery was 50 (c-index 0.65, 95% CI 0.58-0.72). Conclusions: A poor GHS perceived by the patient was associated with postoperative cardiopulmonary morbidity. Patient perceptions and values should be included in the risk stratification process to tailor cancer treatment. PMID- 28082474 TI - Perventricular device closure of perimembranous ventricular septal defect: effectiveness of symmetric and asymmetric occluders. AB - Objectives: To assess safety and effectiveness of symmetric and asymmetric occluders in perventricular device closure without cardiopulmonary bypass of perimembranous ventricular septal defects (pmVSDs). Methods: The present retrospective study enrolled 581 patients who underwent perventricular device closure of pmVSDs under transoesophageal echocardiography guidance from May 2011 to April 2016, and outpatient electrocardiography and transthoracic echocardiography assessments at 1, 3, 6 and 12 months, and yearly thereafter. Results: The overall success rate of device implantation was 92.6% (43 surgical conversions immediately). Between patients receiving symmetric ( n = 353) and asymmetric ( n = 185) occluders, there were no significant differences in age, weight and defect diameter distributions; however, both before discharge and at mean 28.6 +/- 21.2 (range, 1-60)-month follow-up, the symmetric group had lower rates of trivial residual shunt (5.7% vs 11.4%, P = 0.018; and 0.8% vs 5.9%, P = 0.001) and bundle branch block (0.8% vs 5.4%, P = 0.002; and 0.6% vs 3.8%, P = 0.009); and at follow-up, the asymmetric group had lower residual shunt (47.6% vs 85.0%, P = 0.020) and similar branch block (30.0% vs 33.3%, P = 1.000) disappearance rates. There were no severe complications, i.e. aortic regurgitation, malignant arrhythmias, haemolysis or device dislocation. Conclusions: Perventricular device closure of pmVSDs appears safe and effective with symmetric and asymmetric occluders. However, the lower residual shunt disappearance and higher branch block incidence rates for asymmetric occluders would favour more proactive conversion to surgical repair immediately when residual shunt is present intraoperatively. PMID- 28082475 TI - Locoregional recurrence after segmentectomy for clinical-T1aN0M0 radiologically solid non-small-cell lung carcinoma. AB - Objectives: We aimed to identify the clinicopathological features of loco regional recurrence after segmentectomy for clinical-T1aN0M0 radiologically invasive non-small-cell lung carcinoma (NSCLC). Methods: Between 2008 and 2014, 353 patients underwent pulmonary lobectomy or segmentectomy with nodal dissection for clinical-T1aN0M0 radiologically invasive NSCLC showing 0.5 <= consolidation tumour ratio (CTR)<=1.0 on thin-section computed tomography (CT). Radiological invasive NSCLC was divided into two groups, i.e. part-solid (0.5 <= CTR < 1.0) and pure-solid (CTR = 1.0). Significant prognostic factors for oncological outcomes were evaluated by multivariate analysis. Results: Lobectomy was performed in 270 (76.5%) patients and segmentectomy in 83 (23.5%). Locoregional recurrence-free survival (LRFS) of clinical-T1a radiologically invasive NSCLC on the whole showed no significant differences between the lobectomy and segmentectomy arms (3-year LRFS, 93.0 vs 90.1%, P = 0.2725). In contrast, the multivariate analysis revealed that radiologically pure-solid appearance and tumour size were significant predictors of loco-regional recurrence ( P = 0.0106, 0.0408). Among 212 clinical-T1a radiologically pure-solid NSCLCs, frequency of loco-regional recurrence was high in the segmentectomy arm (20.7%) compared with that of lobectomy arm (8.2%). Furthermore, segmentectomy and larger tumour size were independent significant clinical factors of loco-regional recurrence based on the multivariate analysis ( P = 0.0292, 0.0402). The 3-year LRFS of the segmentectomy arm was significantly worse than that of the lobectomy arm in the c-T1a disease (82.2 vs 90.6%, P = 0.0488) provided the tumour showed a pure-solid appearance. Conclusions: Even in cases of small-sized lung carcinoma, segmentectomy should be applied with great caution especially for a radiological pure-solid NSCLC on thin-section CT due to their high incidence of loco-regional recurrence. PMID- 28082476 TI - Need for Examination of Broader Range of Risks When Predicting the Effects of New Tobacco Products. PMID- 28082477 TI - Developing Consistent and Transparent Models of E-cigarette Use: Reply to Glantz and Soneji et al. PMID- 28082482 TI - Genome Sequence of Phytomonas francai, a Cassava (Manihot esculenta) Latex Parasite. AB - Here, we report the genome sequence of the cassava (Manihot esculenta) latex parasite Phytomonas francai P. francai infection is linked with the yield-loss disease "chochamento de raizes" (empty roots) in the Unha variety of cassava, a disease characterized by poor root development and chlorosis of the leaves. PMID- 28082483 TI - Draft Genome Sequence of Aeromonas sobria Strain 08005, Isolated from Sick Rana catesbeiana. AB - Aeromonas sobria is a Gram-negative, rod-shaped, and ubiquitous bacterium. We present here the draft genome sequence of A. sobria strain 08005, isolated from an infected bullfrog. It is composed of 66 contigs totaling 4,678,951 bp, contains 4,252 coding DNA sequences (CDSs), four rRNAs, and 88 tRNA sequences, and shows the presence of various putative virulence-related genes. PMID- 28082484 TI - Draft Genome Sequence of Micromonospora sp. Strain WMMB235, a Marine Ascidian Associated Bacterium. AB - Micromonospora sp. strain WMMB235 was isolated in 2011 off the coast of the Florida Keys, USA, from a marine ascidian as part of an ongoing drug discovery project. Analysis of the ~7.1-Mb genome provides insight into this strain's biosynthetic potential, means of regulation, and response to coculturing conditions. PMID- 28082485 TI - Whole-Genome Sequence of Streptococcus parauberis Strain SP-llh, Isolated from Cows with Mastitis in Western China. AB - Streptococcus parauberis strain SP-llh was isolated from cows with mastitis in western China in 2015. The 2,522,235-bp genome sequence consists of 46 large contigs in 14 scaffolds and contains 2,620 predicted protein-coding genes, with a G+C content of 35.3%. PMID- 28082486 TI - Whole-Genome Sequences of Mycobacterium tuberculosis TB282 and TB284, a Widespread and a Unique Strain, Respectively, Identified in a Previous Study of Tuberculosis Transmission in Central Los Angeles, California, USA. AB - We report here the genome sequences of two Mycobacterium tuberculosis clinical isolates previously identified in central Los Angeles, CA, in the 1990s using a PacBio platform. Isolate TB282 represents a large-cluster strain that caused 27% of the tuberculosis cases, while TB284 represents a strain that caused disease in only one patient. PMID- 28082487 TI - Complete Genome Sequence of Lleida Bat Lyssavirus. AB - All lyssaviruses (family Rhabdoviridae) cause the disease rabies, an acute progressive encephalitis for which, once symptoms occur, there is no effective cure. Using next-generation sequencing, the full-genome sequence for a novel lyssavirus, Lleida bat lyssavirus (LLEBV), from the original brain of a common bent-winged bat has been confirmed. PMID- 28082488 TI - Complete Genome Sequence of Mumps Virus Isolated from Karnataka State, India. AB - We report the first whole-genome sequence of mumps virus isolated from a two-year old girl with bilateral parotitis from a Chikkahallivana village in the Davangere district of Karnataka State, India. The genome of the Davangere mumps isolate was 15,384 bp in length and identical to previously published mumps virus (MuV) genomes from India. BLAST results show 99.1% identity with previously sequenced genotype C viruses isolated from the states of Maharashtra, Tamil Nadu, and Uttar Pradesh. PMID- 28082489 TI - First Complete Genome Sequence of Papaya ringspot virus-W Isolated from a Gourd in the United States. AB - In the United States, the Papaya ringspot virus was first reported from papaya in Florida in 1949. Here, we determined the first complete genome sequence (10,302 nucleotides) of a Papaya ringspot virus-W isolate, which was collected from a commercial field of gourd in Tulsa, OK. PMID- 28082490 TI - Draft Genome Sequence of the Plant Growth-Promoting Pseudomonas punonensis Strain D1-6 Isolated from the Desert Plant Erodium hirtum in Jordan. AB - Pseudomonas punonensis strain D1-6 was isolated from roots of the desert plant Erodium hirtum, near the Dead Sea in Jordan. The genome of strain D1-6 reveals several key plant growth-promoting and herbicide-resistance genes, indicating a possible specialized role for this endophyte. PMID- 28082491 TI - Genome Sequence of Uric Acid-Fermenting Eubacterium angustum DSM 1989T (MK-1). AB - Eubacterium angustum DSM 1989T (MK-1) is a strictly anaerobic and uric acid-, xanthine-, and guanine-fermenting organism isolated from sewage sludge. The draft genome consists of one circular chromosome (2.4 Mb) and harbors 2,397 predicted protein-encoding genes. PMID- 28082492 TI - Metagenomic Analysis of Cucumber RNA from East Timor Reveals an Aphid lethal paralysis virus Genome. AB - We present here the first complete genomic Aphid lethal paralysis virus (ALPV) sequence isolated from cucumber plant RNA from East Timor. We compare it with two complete ALPV genome sequences from China, and one each from Israel, South Africa, and the United States. It most closely resembled the Chinese isolate LGH genome. PMID- 28082493 TI - Sequence of Reston Virus Isolate AZ-1435, an Ebolavirus Isolate Obtained during the 1989-1990 Reston Virus Epizootic in the United States. AB - Reston virus (RESTV) was discovered in 1989-1990 during three connected epizootics of highly lethal viral hemorrhagic fever among captive macaques in primate housing facilities in the United States and Philippines. Currently, only one RESTV isolate from that outbreak (named Pennsylvania) has been sequenced. Here, we report the sequence of a second isolate, Reston virus/M.fascicularis tc/USA/1990/Philippines89-AZ1435. PMID- 28082494 TI - Metagenome Sequencing of Prokaryotic Microbiota Collected from Rivers in the Upper Amazon Basin. AB - Tropical freshwater environments, like rivers, are important reservoirs of microbial life. This study employed metagenomic sequencing to survey prokaryotic microbiota in the Solimoes, Purus, and Urucu Rivers of the Amazon Basin in Brazil. We report a rich and diverse microbial community. PMID- 28082495 TI - Genome Sequence of Christensenella minuta DSM 22607T. AB - Obesity influences and is influenced by the human gut microbiome. Here, we present the genome of Christensenella minuta, a highly heritable bacterial species which has been found to be strongly associated with obesity through an unknown biological mechanism. This novel genome provides a valuable resource for future obesity therapeutic studies. PMID- 28082496 TI - Complete Genome Sequence of a Novel WU Polyomavirus Isolate from Arkansas, USA, Associated with Acute Respiratory Infection. AB - We report here the complete genome sequence of a WU polyomavirus (WUPyV) isolate, also known as human polyomavirus 4, collected in 2016 from a patient in Arkansas with an acute respiratory infection. Isolate hPyV4/USA/AR001/2016 has a double stranded DNA genome of 5,229 bp in length. PMID- 28082497 TI - Complete Genome Sequence of Streptococcus iniae UEL-Si1, Isolated in Diseased Nile Tilapia (Oreochromis niloticus) from Northern Parana, Southern Brazil. AB - The Streptococcus iniae UEL-Si1 strain was isolated from diseased Nile tilapia within the Paranapanema River Basin, Northern Parana, Brazil. This is an emerging infectious disease agent of fish from Brazil, and sequencing of the complete genome is fundamental to understanding aspects relative to pathogenesis, infection, epidemiology, and immunity. PMID- 28082498 TI - Whole-Genome Sequence of Escherichia coli Serotype O157:H7 Strain PA20. AB - Escherichia coli serotype O157:H7 strain PA20 is a Pennsylvania Department of Health clinical isolate. It has been used to study biofilm formation in O157:H7 clinical isolates, where the high incidence of prophage insertions in the mlrA transcription factor disrupts traditional csgD biofilm regulation. Here, we report the complete PA20 genome sequence. PMID- 28082499 TI - Draft Genome Sequences of 15 Staphylococcus aureus Isolates Recovered from Raw Milk and Associated Milk Filters from Victoria, Australia. AB - This study describes draft whole genomes of 15 Staphylococcus aureus isolates from dairy farms located in Victoria, Australia. Two novel sequence types (ST3183 and ST3184) were identified among these isolates. PMID- 28082500 TI - Complete Genome Sequence of Spiroplasma sp. TU-14. AB - Spiroplasma sp. TU-14 was isolated from a contaminated sample of Entomoplasma lucivorax PIPN-2T obtained from the International Organization for Mycoplasmology collection. Here, we report the complete genome sequence of this bacterium to facilitate the investigation of its biology and the comparative genomics among Spiroplasma spp. PMID- 28082502 TI - Draft Genome Sequence of an Anicemycin Producer, Streptomyces sp. TP-A0648. AB - We report the draft genome sequence of Streptomyces sp. TP-A0648 isolated from a leaf of Aucuba japonica This strain produces a new tumor cell growth inhibitor designated anicemycin. The genome harbors at least 12 biosynthetic gene clusters for polyketides and nonribosomal peptides, suggesting the potential to produce diverse secondary metabolites. PMID- 28082503 TI - Metaviromes of Extracellular Soil Viruses along a Namib Desert Aridity Gradient. AB - The Namib Desert in southwest Africa is hyperarid and composed of distinct microbial communities affected by a longitudinal aridity gradient. Here, we report four soil metaviromes from the Namib Desert, assessed using deep sequencing of metavirome libraries prepared from DNA extracted from gravel plain surface soils. PMID- 28082501 TI - Genome Sequence of Porphyromonas gingivalis Strain 381. AB - Porphyromonas gingivalis is associated with both oral and systemic diseases. Strain-specific P. gingivalis invasion phenotypes do not reliably predict disease presentation during in vivo studies. Here, we present the genome sequence of 381, a common laboratory strain, with a single contig of 2,378,872 bp and a G+C content of 48.36%. PMID- 28082504 TI - Draft Genome Sequence of Pseudomonas aeruginosa Strain Hex1T Isolated from Soils Contaminated with Used Lubricating Oil in Argentina. AB - Pseudomonas aeruginosa Hex1T was isolated from soils contaminated with used lubricating oil from a garage in Cordoba, Argentina. This strain is capable of utilizing this pollutant as the sole carbon and energy source. Here, we present the 6.9-Mb draft genome sequence of Hex1T, which contains many heavy metal resistance genes. PMID- 28082505 TI - Annotation of Fusarium graminearum (PH-1) Version 5.0. AB - Fusarium graminearum floral infections are a major risk to the global supply of safe cereal grains. We report updates to the PH-1 reference genome and significant improvements to the annotation. Changes include introduction of legacy annotation identifiers, new gene models, secretome and effectorP predictions, and inclusion of extensive untranslated region (UTR) annotations. PMID- 28082506 TI - Draft Genome Sequence of JVAP01T, the Type Strain of the Novel Species Acinetobacter dijkshoorniae. AB - Here, we report the draft genome sequence of the type strain of Acinetobacter dijkshoorniae, a novel human pathogen within the Acinetobacter calcoaceticus Acinetobacter baumannii (ACB) complex. Strain JVAP01T has an estimated genome size of 3.9 Mb, exhibits a 38.8% G+C content, and carries a plasmid with the blaNDM-1 carbapenemase gene. PMID- 28082507 TI - Genome Sequence of Lactobacillus sunkii Strain CG_D. AB - Lactobacillus sunkii CG_D is a rod-shaped, Gram-positive, and heterofermentative lactic acid bacterium. The draft genome of L. sunkii strain CG_D comprises 2,794,637 bp with an average G+C content of 42.03%. The genome harbors 2,662 predicted protein-encoding, and 71 RNA genes. PMID- 28082508 TI - Genome Sequence of Enterococcus faecalis Strain CG_E. AB - Enterococcus faecalis CG_E is a Gram-positive, lactic acid-producing coccus. The draft genome of E. faecalis strain CG_E comprises 2,969,881 bp and exhibits a G+C content of 37.34%. The genome encodes 2,848 predicted protein-encoding and 97 RNA genes. PMID- 28082509 TI - Draft Genome Sequence of Flavobacterium succinicans Strain DD5b. AB - We present the first 3.315-Mbp assembled draft genome sequence of Flavobacterium succinicans strain DD5b. This bacterium is a phosphite-assimilating representative of the genus Flavobacterium isolated from guts of the zooplankton Daphnia magna. PMID- 28082510 TI - Discharge of surplus phloem water may be required for normal grape ripening. AB - At the onset of ripening, some fleshy fruits shift the dominant water import pathway from the xylem to the phloem, but the cause for the decline in xylem inflow remains obscure. This study found that xylem-mobile dye movement into grape berries decreased despite transient increases in berry growth and transpiration during early ripening, whereas outward dye movement continued unless the roots were pressurized. Modeling berry vascular flows using measurements of pedicel phloem sap sugar concentration, berry growth, solute accumulation, and transpiration showed that a fraction of phloem-derived water was used for berry growth and transpiration; the surplus was recirculated via the xylem. Changing phloem sap sugar concentration to a much higher published value led to model simulations predicting xylem inflow or backflow depending on the developmental stage and genotype. Mathematically preventing net xylem flow resulted in large variations in phloem sap sugar concentration in pedicels serving neighboring berries on the same fruit cluster. Moreover, restricting water discharge via the xylem and/or across the skin impaired berry solute accumulation and color change. Collectively, these results indicate that discharge of surplus phloem water via berry transpiration and/or xylem backflow may be necessary to facilitate normal grape ripening. PMID- 28082512 TI - Mathematical model of T-cell lymphoblastic lymphoma: disease, treatment, cure or relapse of a virtual cohort of patients. AB - T lymphoblastic lymphoma (T-LBL) is a rare type of lymphoma with a good prognosis with a remission rate of 85%. Patients can be completely cured or can relapse during or after a 2-year treatment. Relapses usually occur early after the remission of the acute phase. The median time of relapse is equal to 1 year, after the occurrence of complete remission (range 0.2-5.9 years) (Uyttebroeck et al., 2008). It can be assumed that patients may be treated longer than necessary with undue toxicity.The aim of our model was to investigate whether the duration of the maintenance therapy could be reduced without increasing the risk of relapses and to determine the minimum treatment duration that could be tested in a future clinical trial.We developed a mathematical model of virtual patients with T-LBL in order to obtain a proportion of virtual relapses close to the one observed in the real population of patients from the EuroLB database. Our simulations reproduced a 2-year follow-up required to study the onset of the disease, the treatment of the acute phase and the maintenance treatment phase. PMID- 28082513 TI - The Glutamate Model of Schizophrenia: It's All About Signal Muscarinic Connections. PMID- 28082511 TI - Glycerol-3-Phosphate Acyltransferase 3 (OsGPAT3) is required for anther development and male fertility in rice. AB - Lipid molecules are key structural components of plant male reproductive organs, such as the anther and pollen. Although advances have been made in the understanding of acyl lipids in plant reproduction, the metabolic pathways of other lipid compounds, particularly glycerolipids, are not fully understood. Here we report that an endoplasmic reticulum-localized enzyme, Glycerol-3-Phosphate Acyltransferase 3 (OsGPAT3), plays an indispensable role in anther development and pollen formation in rice. OsGPAT3 is preferentially expressed in the tapetum and microspores of the anther. Compared with wild-type plants, the osgpat3 mutant displays smaller, pale yellow anthers with defective anther cuticle, degenerated pollen with defective exine, and abnormal tapetum development and degeneration. Anthers of the osgpat3 mutant have dramatic reductions of all aliphatic lipid contents. The defective cuticle and pollen phenotype coincide well with the down regulation of sets of genes involved in lipid metabolism and regulation of anther development. Taking these findings together, this work reveals the indispensable role of a monocot-specific glycerol-3-phosphate acyltransferase in male reproduction in rice. PMID- 28082514 TI - Engineered Context-Sensitive Agonism: Tissue-Selective Drug Signaling through a G Protein-Coupled Receptor. AB - Drug discovery strives for selective ligands to achieve targeted modulation of tissue function. Here we introduce engineered context-sensitive agonism as a postreceptor mechanism for tissue-selective drug action through a G protein coupled receptor. Acetylcholine M2-receptor activation is known to mediate, among other actions, potentially dangerous slowing of the heart rate. This unwanted side effect is one of the main reasons that limit clinical application of muscarinic agonists. Herein we show that dualsteric (orthosteric/allosteric) agonists induce less cardiac depression ex vivo and in vivo than conventional full agonists. Exploration of the underlying mechanism in living cells employing cellular dynamic mass redistribution identified context-sensitive agonism of these dualsteric agonists. They translate elevation of intracellular cAMP into a switch from full to partial agonism. Designed context-sensitive agonism opens an avenue toward postreceptor pharmacologic selectivity, which even works in target tissues operated by the same subtype of pharmacologic receptor. PMID- 28082515 TI - Impact of Cystinosin Glycosylation on Protein Stability by Differential Dynamic Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC). AB - Cystinosis is a rare autosomal recessive lysosomal storage disorder characterized by intralysosomal accumulation of cystine. The causative gene for cystinosis is CTNS, which encodes the protein cystinosin, a lysosomal proton-driven cystine transporter. Over 100 mutations have been reported, leading to varying disease severity, often in correlation with residual cystinosin activity as a transporter and with maintenance of its protein-protein interactions. In this study, we focus on the DeltaITILELP mutation, the only mutation reported that sometimes leads to severe forms, inconsistent with its residual transported activity. DeltaITILELP is a deletion that eliminates a consensus site on N66, one of the protein's seven glycosylation sites. Our hypothesis was that the DeltaITILELP mutant is less stable and undergoes faster degradation. Our dynamic stable isotope labeling by amino acids in cell culture (SILAC) study clearly showed that wild-type cystinosin is very stable, whereas DeltaITILELP is degraded three times more rapidly. Additional lysosome inhibition experiments confirmed DeltaITILELP instability and showed that the degradation was mainly lysosomal. We observed that in the lysosome, DeltaITILELP is still capable of interacting with the V ATPase complex and some members of the mTOR pathway, similar to the wild-type protein. Intriguingly, our interactomic and immunofluorescence studies showed that DeltaITILELP is partially retained at the endoplasmic reticulum (ER). We proposed that the DeltaITILELP mutation causes protein misfolding, ER retention and inability to be processed in the Golgi apparatus, and we demonstrated that DeltaITILELP carries high-mannose glycans on all six of its remaining glycosylation sites. We found that the high turnover of DeltaITILELP, because of its immature glycosylation state in combination with low transport activity, might be responsible for the phenotype observed in some patients. PMID- 28082516 TI - HMGB1-induced autophagy: a new pathway to maintain Treg function during chronic hepatitis B virus infection. AB - High-mobility group box-1 (HMGB1) protein, as one of the well-known damage associated molecular pattern molecules (DAMPs), is enriched in chronic hepatitis B virus (HBV) infection and has a context-dependent role in autophagy, a highly conserved self-digestive process in response to environmental stress. Recent mouse studies indicate that autophagy is highly active in regulatory T (Treg) cells. In the present study, we evaluated spontaneous and induced autophagy of peripheral Treg cells from 98 patients with chronic hepatitis B (CHB), by measuring levels of lipidated form of microtubule-associated light chain 3 (LC3 II, marker for closed autophagosomes) and observing autophagic vacuoles (AV) with transmission electron microscope. No significant difference was found in spontaneous autophagy of either Treg or CD4+ naive cells when comparing CHB patients with healthy subjects, apart from CHB-Treg showed significantly higher autophagic activity after activation by anti-CD3-CD28 beads. Besides, incubation of CHB-Treg cells with CHB-serum greatly maintained their autophagic behaviour, which could be significantly diminished by blocking HMGB1 with the neutralizing antibody. Further, we characterized time- and dose-dependent effects by recombinant HMGB1 protein on autophagy of CHB-Treg cells. We also documented a significant up-regulation of HMGB1 and its receptors [toll-like receptor (TLR4), receptor for advanced glycation end-product (RAGE)] in both peripheral and intra hepatic microenvironments of CHB patients. Moreover, the RAGE-extracellular regulated protein kinases (ERK) axis and rapamycin-sensitive components of mammalian target of rapamycin (mTOR) pathways were demonstrated in vitro to be involved in HMGB1-induced autophagy of Treg cells. Additionally, HMGB1-induced autophagy could maintain cell survival and functional stability of CHB-Treg cells. Our findings could open new perspectives in developing therapeutic strategies to activate specific anti-HBV immunity by diminishing Treg autophagy. PMID- 28082517 TI - SEXUAL STERILITY is Essential for Both Male and Female Gametogenesis in Tomato. AB - Gametogenesis is a key step in the production of ovules or pollen in higher plants. The molecular aspects of gametogenesis are well characterized in the model plant Arabidopsis; however, little information is known in tomato, which is a model plant for fleshy fruit development. In this study, we characterized a tomato (Solanum lycopersicum L.) gamma-ray mutant, sexual sterility (Slses), that exhibited both male and female sterility. Morphological analysis revealed that the Slses mutant forms incomplete ovules and wilted anthers devoid of pollen grains at the anthesis stage. Genetic and next-generation sequencing analyses revealed that the Slses mutant carried a 13 bp deletion within the first exon of a homolog of SPOROCYTELESS/NOZZLE (SPL/NZZ), which plays an important role in gametogenesis in Arabidopsis. Complementation analysis in which the complete SlSES genomic region was introduced into the Slses mutant fully restored normal phenotypes, demonstrating that Solyc07g063670 is responsible for the Slses mutation. SlSES probably act as a transcriptional repressor because of an EAR motif at the C-terminal region. Gene expression levels of WUSCHEL (SlWUS) and INNER NO OUTER (SlINO), both of which are required for ovule development, were dramatically reduced in the early stages of pistil development in the Slses mutant, suggesting a positive regulatory role for SlSES in the transcription of gametogenesis genes and differences in the regulation of INO (SlINO) and integument development by SPL/NZZ (SLSES) between Arabidopsis and tomato. Taken together, our results indicate that SlSES is a novel tomato gametogenesis gene essential for both male and female gametogenesis. PMID- 28082518 TI - Vancomycin-Associated Cast Nephropathy. AB - Vancomycin is a widely prescribed antibiotic, but the exact nature of vancomycin associated nephrotoxicity is unclear, in particular when considering the frequent coadministration of aminoglycosides. We describe here the initial case of a 56 year-old woman with normal renal function developing unexplained ARF without hypovolemia after administration of vancomycin without coadministration of aminoglycosides. Studying the patient's renal biopsy specimen, we ascertained that obstructive tubular casts composed of noncrystal nanospheric vancomycin aggregates entangled with uromodulin explained the vancomycin-associated ARF. We developed in parallel a new immunohistologic staining technique to detect vancomycin in renal tissue and confirmed retrospectively that deleterious vancomycin-associated casts existed in eight additional patients with acute tubular necrosis in the absence of hypovolemia. Concomitant high vancomycin trough plasma levels had been observed in each patient. We also reproduced experimentally the toxic and obstructive nature of vancomycin-associated cast nephropathy in mice, which we detected using different in vivo imaging techniques. In conclusion, the interaction of uromodulin with nanospheric vancomycin aggregates represents a new mode of tubular cast formation, revealing the hitherto unsuspected mechanism of vancomycin-associated renal injury. PMID- 28082519 TI - Effects of Ferric Citrate in Patients with Nondialysis-Dependent CKD and Iron Deficiency Anemia. AB - Iron deficiency anemia is common and consequential in nondialysis-dependent CKD (NDD-CKD). Efficacy and tolerability of conventional oral iron supplements are mixed; intravenous iron administration associates with finite but important risks. We conducted a randomized double-blind clinical trial in adults with NDD CKD and iron deficiency anemia to compare the safety and efficacy of oral ferric citrate (n=117) and placebo (n=115). The primary end point was the proportion of patients who achieved a >=1.0 g/dl increase in hemoglobin at any time during a 16 week randomized period. Patients who completed the 16-week period could also participate in an 8-week open-label extension period. Significantly more patients randomized to ferric citrate achieved the primary end point (61 [52.1%] versus 22 [19.1%] with placebo; P<0.001). All secondary end points reached statistical significance in the ferric citrate group, including the mean relative change in hemoglobin (0.84 g/dl; 95% confidence interval, 0.58 to 1.10 g/dl; P<0.001) and the proportion of patients who achieved a sustained increase in hemoglobin (>=0.75 g/dl over any 4-week period during the randomized trial; 57 [48.7%] versus 17 [14.8%] with placebo; P<0.001). Rates of serious adverse events were similar in the ferric citrate (12.0%) and placebo groups (11.2%). Gastrointestinal disorders were the most common adverse events, with diarrhea reported in 24 (20.5%) and 19 (16.4%) and constipation in 22 (18.8%) and 15 (12.9%) patients treated with ferric citrate and placebo, respectively. Overall, in patients with NDD-CKD, we found oral ferric citrate to be a safe and efficacious treatment for iron deficiency anemia. PMID- 28082522 TI - Correction for An mDia1-INF2 formin activation cascade facilitated by IQGAP1 regulates stable microtubules in migrating cells. PMID- 28082520 TI - The secretory pathway at 50: a golden anniversary for some momentous grains of silver. AB - The secretory pathway along which newly synthesized secretory and membrane proteins traffic through the cell was revealed in two articles published 50 years ago. This discovery was the culmination of decades of effort to unite the power of biochemical and morphological methodologies in order to elucidate the dynamic nature of the cell's biosynthetic machinery. The secretory pathway remains a central paradigm of modern cell biology. Its elucidation 50 years ago inspired tremendous multidisciplinary and on-going efforts to understand the machinery that makes it run, the adaptations that permit it to serve the needs of specialized cell types, and the pathological consequences that arise when it is perturbed. PMID- 28082521 TI - Trafficking to the primary cilium membrane. AB - The primary cilium has been found to be associated with a number of cellular signaling pathways, such as vertebrate hedgehog signaling, and implicated in the pathogenesis of diseases affecting multiple organs, including the neural tube, kidney, and brain. The primary cilium is the site where a subset of the cell's membrane proteins is enriched. However, pathways that target and concentrate membrane proteins in cilia are not well understood. Processes determining the level of proteins in the ciliary membrane include entry into the compartment, removal, and retention by diffusion barriers such as the transition zone. Proteins that are concentrated in the ciliary membrane are also localized to other cellular sites. Thus it is critical to determine the particular role for ciliary compartmentalization in sensory reception and signaling pathways. Here we provide a brief overview of our current understanding of compartmentalization of proteins in the ciliary membrane and the dynamics of trafficking into and out of the cilium. We also discuss major unanswered questions regarding the role that defects in ciliary compartmentalization might play in disease pathogenesis. Understanding the trafficking mechanisms that underlie the role of ciliary compartmentalization in signaling might provide unique approaches for intervention in progressive ciliopathies. PMID- 28082523 TI - Predictors of Cold and Pressure Pain Tolerance in Healthy South African Adults. AB - Background: Studies on relationships between sex, ethnicity, and pain have largely emanated from the United States and Europe. We compared cold (CPT) and pressure pain tolerance (PPT) in male and female South Africans of African and European ancestry and assessed whether psychosocial factors (including pain beliefs) predicted differences in pain tolerance. Methods: We recruited 106 (62 female) students of African ancestry and 106 (55 female) of European ancestry and subjected them to a cold-pressor test and pressure algometry. Socioeconomic status (SES), pain catastrophizing, depression, anxiety, and pain beliefs were assessed as predictors of pain tolerance. Results: CPT was lower in students of African compared with European ancestry (for both sexes), and PPT was lower in female than male students (for both ethnicities). Females were very accepting of men expressing pain and males less so. Males of African ancestry were least accepting but still tolerant. Multivariate analysis identified African ancestry, and particularly being a female of African ancestry, as strong predictors of lower CPT. Anxiety was a weak predict or of CPT. Sex was the only strong predictor of PPT on multivariate analysis (PPT females < males), and catastrophizing was a weak predictor. Female sex and African ancestry were strong predictors of acceptance of expression of pain in males. SES was a weak predictor of the Appropriate Pain Behavior Questionnaire-Malescore. Conclusions: Despite different cultural and social backgrounds from US and European cohorts, we saw similar patterns of sex and ethnic differences in CPT and PPT in an African cohort. Traditional psychosocial predictors of pain sensitivity predicted variation in the outcome variables but were not strong predictors. PMID- 28082524 TI - Rates and Correlates of Pain Specialty Clinic Use Nationally in the Veterans Health Administration. AB - Objective: Chronic pain management is a growing focus of attention, in part because of concern over excessive use of opioids for treatment of chronic noncancer pain. In the Veterans Health Administration (VHA), pain specialty clinics have been established to address the needs of patients with challenging pain issues. The current study identified characteristics of such patients in a national sample of VHA service users in fiscal year 2012. Design: Bivariate analyses compared patients diagnosed with pain who visited a pain specialty clinic with those who did not on sociodemographic characteristics, medical, pain, and psychiatric diagnoses, health service use, and opioid and psychotropic drug use. Logistic regression identified variables that independently differentiated pain clinic users from nonusers. Results: Altogether, 122,240 of 2,025,765 patients with pain diagnoses (5.79%) attended pain specialty clinics. Pain clinic users had higher rates of muscle spasms, neuralgia, neuritis, radiculitis, and fibromyalgia, as well as major depression and personality disorders. Further, a fibromyalgia diagnosis was the strongest independent correlate of pain clinic attendance, along with the number of medical-surgical clinic visits. Veterans attending a pain clinic also received more opioids than those not attending (10.4 vs 6.7 prescriptions, respectively), but there were no substantial differences in other factors. Conclusions: Patients attending pain specialty clinics have more difficult-to-treat pain conditions and comorbid psychiatric disorders that are independent of major medical diagnoses, use more outpatient services, and receive a greater number of opioid prescriptions. These data support the inclusion of mental health care in the specialized treatment of chronic pain. PMID- 28082526 TI - Is the Pain Medicine Community Reluctant to Discuss Limb Amputation in Patients with Intractable Complex Regional Pain Syndrome? PMID- 28082525 TI - Are We Speaking the Same Language? Finding Theoretical Coherence and Precision in "Mindfulness-Based Mechanisms" in Chronic Pain. AB - Objective: Over the past 50 years, the field of chronic pain has witnessed an evolution of psychological approaches with some notable success. Some of this evolution has included "mindfulness-based interventions" (MBIs), now regarded as having encouraging partial support for their effectiveness. However, several theoretical challenges remain that may inhibit the progress of MBIs. These challenges include a lack of clarity surrounding the mindfulness construct itself, the proliferation of purported underlying mechanisms arising from different theories, and limited evidence for the mechanisms through which MBIs work. The current conceptual review provides a critique of existing theoretical models of mindfulness that have been applied to understanding and treating chronic pain. Design: A conceptual narrative review was conducted. Setting: Treatment programs for people with chronic pain. Patients: Individuals with any type of chronic pain. Interventions: MBIs for chronic pain. Outcome Measures: Mindfulness-based mechanisms explored in relation to several domains of functioning. Results and Conclusions: Based on this assessment, a summary of available evidence for a particular contextual behavioral theory of "mindfulness" psychological flexibility-is outlined. Findings show the need for further integration of existing mindfulness constructs to better guide development and evaluation of mindfulness-based treatment methods in the future. PMID- 28082527 TI - Ventricular Tachycardia Ablation in Severe Heart Failure: An International Ventricular Tachycardia Ablation Center Collaboration Analysis. AB - BACKGROUND: Ventricular tachycardia (VT) radiofrequency ablation has been associated with reduced VT recurrence and mortality, although it is typically not considered among New York Heart Association class IV (NYHA IV) heart failure patients. We compared characteristics and VT radiofrequency ablation outcomes of those with and without NYHA IV in the International VT Ablation Center Collaboration. METHODS AND RESULTS: NYHA II-IV patients undergoing VT radiofrequency ablation at 12 international centers were included. Clinical variables, VT recurrence, and mortality were analyzed by NYHA IV status using Kaplan-Meier analysis and Cox proportional hazard models. There were significant differences between NYHA IV (n=111) and NYHA II and III (n=1254) patients: NYHA IV had lower left ventricular ejection fraction; more had diabetes mellitus, kidney disease, cardiac resynchronization implantable cardioverter-defibrillator, and VT storm despite greater antiarrhythmic drug use (P<0.01). NYHA IV subjects required more hemodynamic support, were inducible for more and slower VTs, and were less likely to undergo final programmed stimulation. There was no significant difference in acute complications. In-hospital deaths, recurrent VT, and 1-year mortality were higher in the NYHA IV group, in the context of greater baseline comorbidities. Importantly, NYHA IV patients without recurrent VT had similar survival compared with NYHA II and III patients with recurrent VT (68% versus 73%). Early VT recurrence (<=30 days) was significantly associated with mortality, especially in NYHA IV patients. CONCLUSIONS: Despite greater baseline comorbidities, VT radiofrequency ablation can be safely performed among NYHA IV patients. Early VT recurrence is significantly associated with subsequent mortality regardless of NYHA status. Elimination of recurrent VT in NYHA IV patients may reduce mortality to a level comparable to NYHA II and III with arrhythmia recurrence. PMID- 28082528 TI - Right Ventricular Structure and Function Are Associated With Incident Atrial Fibrillation: MESA-RV Study (Multi-Ethnic Study of Atherosclerosis-Right Ventricle). AB - BACKGROUND: Right ventricular (RV) morphology has been associated with drivers of atrial fibrillation (AF) risk, including left ventricular and pulmonary pathology, systemic inflammation, and neurohormonal activation. The aim of this study was to investigate the association between RV morphology and risk of incident AF. METHODS AND RESULTS: We interpreted cardiac magnetic resonance imaging in 4204 participants free of clinical cardiovascular disease in the MESA (Multi-Ethnic Study of Atherosclerosis). Incident AF was determined using hospital discharge records, study electrocardiograms, and Medicare claims data. The study sample (n=3819) was 61+/-10 years old and 47% male with 47.2% current/former smokers. After adjustment for demographics and clinical factors, including incident heart failure, higher RV ejection fraction (hazard ratio, 1.16 per SD; 95% confidence interval, 1.03-1.32; P=0.02) and greater RV mass (hazard ratio, 1.25 per SD; 95% confidence interval, 1.08-1.44; P=0.002) were significantly associated with incident AF. After additional adjustment for the respective left ventricular parameter, higher RV ejection fraction remained significantly associated with incident AF (hazard ratio, 1.15 per SD; 95% confidence interval, 1.01-1.32; P=0.04), whereas the association was attenuated for RV mass (hazard ratio, 1.16 per SD; 95% confidence interval, 0.99-1.35; P=0.07). In a subset of patients with available spirometry (n=2540), higher RV ejection fraction and mass remained significantly associated with incident AF after additional adjustment for lung function (P=0.02 for both). CONCLUSIONS: Higher RV ejection fraction and greater RV mass were associated with an increased risk of AF in a multiethnic population free of clinical cardiovascular disease at baseline. PMID- 28082530 TI - The use of pretest probability increases the value of high-resolution CT in diagnosing usual interstitial pneumonia. AB - BACKGROUND: Recent studies have suggested that non-definitive patterns on high resolution CT (HRCT) scan provide sufficient diagnostic specificity to forgo surgical lung biopsy in the diagnosis of idiopathic pulmonary fibrosis (IPF). The objective of this study was to determine test characteristics of non-definitive HRCT patterns for identifying histopathological usual interstitial pneumonia (UIP). METHODS: Patients with biopsy-proven interstitial lung disease (ILD) and non-definitive HRCT scans were identified from two academic ILD centres. Test characteristics for HRCT patterns as predictors of UIP on surgical lung biopsy were derived and validated in independent cohorts. RESULTS: In the derivation cohort, 64/385 (17%) had possible UIP pattern on HRCT; 321/385 (83%) had inconsistent with UIP pattern. 113/385 (29%) patients had histopathological UIP pattern in the derivation cohort. Possible UIP pattern had a specificity of 91.2% (95% CI 87.2% to 94.3%) and a positive predictive value (PPV) of 62.5% (95% CI 49.5% to 74.3%) for UIP pattern on surgical lung biopsy. The addition of age, sex and total traction bronchiectasis score improved the PPV. Inconsistent with UIP pattern demonstrated poor PPV (22.7%, 95% CI 18.3% to 27.7%). HRCT pattern specificity was nearly identical in the validation cohort (92.7%, 95% CI 82.4% to 98.0%). The substantially higher prevalence of UIP pattern in the validation cohort improved the PPV of HRCT patterns. CONCLUSIONS: A possible UIP pattern on HRCT has high specificity for UIP on surgical lung biopsy, but PPV is highly dependent on underlying prevalence. Adding clinical and radiographic features to possible UIP pattern on HRCT may provide sufficient probability of histopathological UIP across prevalence ranges to change clinical decision making. PMID- 28082529 TI - Analysis of nocturnal actigraphic sleep measures in patients with COPD and their association with daytime physical activity. AB - BACKGROUND: Sleep disturbances are common in patients with chronic obstructive pulmonary disease (COPD) with a considerable negative impact on their quality of life. However, factors associated with measures of sleep in daily life have not been investigated before nor has the association between sleep and the ability to engage in physical activity on a day-to-day basis been studied. AIMS: To provide insight into the relationship between actigraphic sleep measures and disease severity, exertional dyspnoea, gender and parts of the week; and to investigate the association between sleep measures and next day physical activity. METHODS: Data were analysed from 932 patients with COPD (66% male, 66.4+/-8.3 years, FEV1% predicted=50.8+/-20.5). Participants had sleep and physical activity continuously monitored using a multisensor activity monitor for a median of 6 days. Linear mixed effects models were applied to investigate the factors associated with sleep impairment and the association between nocturnal sleep and patients' subsequent daytime physical activity. RESULTS: Actigraphic estimates of sleep impairment were greater in patients with worse airflow limitation and worse exertional dyspnoea. Patients with better sleep measures (ie, non-fragmented sleep, sleeping bouts >=225 min, sleep efficiency >=91% and time spent awake after sleep onset <57 min) spent significantly more time in light (p<0.01) and moderate-to-vigorous physical activity (p<0.01). CONCLUSIONS: There is a relationship between measures of sleep in patients with COPD and the amount of activity they undertake during the waking day. Identifying groups with specific sleep characteristics may be useful information when designing physical activity enhancing interventions. PMID- 28082532 TI - Combining theory and experiment in electrocatalysis: Insights into materials design. AB - Electrocatalysis plays a central role in clean energy conversion, enabling a number of sustainable processes for future technologies. This review discusses design strategies for state-of-the-art heterogeneous electrocatalysts and associated materials for several different electrochemical transformations involving water, hydrogen, and oxygen, using theory as a means to rationalize catalyst performance. By examining the common principles that govern catalysis for different electrochemical reactions, we describe a systematic framework that clarifies trends in catalyzing these reactions, serving as a guide to new catalyst development while highlighting key gaps that need to be addressed. We conclude by extending this framework to emerging clean energy reactions such as hydrogen peroxide production, carbon dioxide reduction, and nitrogen reduction, where the development of improved catalysts could allow for the sustainable production of a broad range of fuels and chemicals. PMID- 28082533 TI - Erratum for the Letter "Response to 'Forest value: More than commercial'" by C. B. Barrett, M. Zhou, P. B. Reich, T. W. Crowther, J. Liang. PMID- 28082531 TI - Aspirin reduces lipopolysaccharide-induced pulmonary inflammation in human models of ARDS. AB - RATIONALE: Platelets play an active role in the pathogenesis of acute respiratory distress syndrome (ARDS). Animal and observational studies have shown aspirin's antiplatelet and immunomodulatory effects may be beneficial in ARDS. OBJECTIVE: To test the hypothesis that aspirin reduces inflammation in clinically relevant human models that recapitulate pathophysiological mechanisms implicated in the development of ARDS. METHODS: Healthy volunteers were randomised to receive placebo or aspirin 75 or 1200 mg (1:1:1) for seven days prior to lipopolysaccharide (LPS) inhalation, in a double-blind, placebo-controlled, allocation-concealed study. Bronchoalveolar lavage (BAL) was performed 6 hours after inhaling 50 ug of LPS. The primary outcome measure was BAL IL-8. Secondary outcome measures included markers of alveolar inflammation (BAL neutrophils, cytokines, neutrophil proteases), alveolar epithelial cell injury, systemic inflammation (neutrophils and plasma C-reactive protein (CRP)) and platelet activation (thromboxane B2, TXB2). Human lungs, perfused and ventilated ex vivo (EVLP) were randomised to placebo or 24 mg aspirin and injured with LPS. BAL was carried out 4 hours later. Inflammation was assessed by BAL differential cell counts and histological changes. RESULTS: In the healthy volunteer (n=33) model, data for the aspirin groups were combined. Aspirin did not reduce BAL IL-8. However, aspirin reduced pulmonary neutrophilia and tissue damaging neutrophil proteases (Matrix Metalloproteinase (MMP)-8/-9), reduced BAL concentrations of tumour necrosis factor alpha and reduced systemic and pulmonary TXB2. There was no difference between high-dose and low-dose aspirin. In the EVLP model, aspirin reduced BAL neutrophilia and alveolar injury as measured by histological damage. CONCLUSIONS: These are the first prospective human data indicating that aspirin inhibits pulmonary neutrophilic inflammation, at both low and high doses. Further clinical studies are indicated to assess the role of aspirin in the prevention and treatment of ARDS. TRIAL REGISTRATION NUMBER: NCT01659307 Results. PMID- 28082534 TI - Strong peak in Tc of Sr2RuO4 under uniaxial pressure. AB - Sr2RuO4 is an unconventional superconductor that has attracted widespread study because of its high purity and the possibility that its superconducting order parameter has odd parity. We study the dependence of its superconductivity on anisotropic strain. Applying uniaxial pressures of up to ~1 gigapascals along a <100> direction (a axis) of the crystal lattice results in the transition temperature (Tc) increasing from 1.5 kelvin in the unstrained material to 3.4 kelvin at compression by ~0.6%, and then falling steeply. Calculations give evidence that the observed maximum Tc occurs at or near a Lifshitz transition when the Fermi level passes through a Van Hove singularity, and open the possibility that the highly strained, Tc = 3.4 K Sr2RuO4 has an even-parity, rather than an odd-parity, order parameter. PMID- 28082536 TI - News at a glance. PMID- 28082535 TI - Global clean energy in 2017. PMID- 28082537 TI - Expedition probes ocean trench's deepest secrets. PMID- 28082539 TI - NASA missions aim at asteroid oddballs. PMID- 28082538 TI - Jilted again, Venus scientists pine for their neglected planet. PMID- 28082540 TI - Pioneering study images activity in fetal brains. PMID- 28082541 TI - Life-saving diphtheria drug is running out. PMID- 28082542 TI - Observations hint at a new recipe for giant black holes. PMID- 28082543 TI - Birds don't need exercise to stay fit for epic flights. PMID- 28082544 TI - Fateful imprints. PMID- 28082545 TI - A matter of tree longevity. PMID- 28082546 TI - Multiple mechanisms for memory replay? PMID- 28082547 TI - Putting the squeeze on superconductivity. PMID- 28082548 TI - Belowground drivers of plant diversity. PMID- 28082549 TI - Electron diffraction and the hydrogen atom. PMID- 28082550 TI - Life in the age of the algorithm. PMID- 28082551 TI - Travels through time. PMID- 28082552 TI - Europe's biodiversity avoids fatal setback. PMID- 28082553 TI - Pipelines imperil Canada's ecosystem. PMID- 28082554 TI - Comment on "Ribose and related sugars from ultraviolet irradiation of interstellar ice analogs". AB - Meinert et al (Reports, 8 April 2016, p. 208) reported the formation of prebiotic molecules, including ribose, in an interstellar ice analog experiment. We show that if their experimental procedure is accurately described, much or most of their products may have been formed during their analysis process, not in the parent ice. PMID- 28082555 TI - Response to Comment on "Ribose and related sugars from ultraviolet irradiation of interstellar ice analogs". AB - We detected ribose and related sugars in the organic residues of simulated interstellar ices using multidimensional gas chromatography. Kawai questions the formation of sugar compounds in the ices and suggests that they arise from a classical formose reaction during sample workup for analysis. We disagree with this hypothesis and present additional data to argue that Kawai's criticism does not apply. PMID- 28082556 TI - A big, bug science party. PMID- 28082557 TI - Are you aware how well you remember? PMID- 28082558 TI - Designing proteins with cavities. PMID- 28082559 TI - Initiating an antitumor attack. PMID- 28082561 TI - Inducing strong coupling. PMID- 28082560 TI - Poised for the second step of splicing. PMID- 28082562 TI - Phages build themselves a wall. PMID- 28082563 TI - Prions enter another domain of life. PMID- 28082564 TI - Channeling pain through GPCRs. PMID- 28082565 TI - Better living through water-splitting. PMID- 28082567 TI - Squeezing out the oddness. PMID- 28082566 TI - A machine for building ribosomes. PMID- 28082568 TI - A cyclic catalyst to pair up sugars. PMID- 28082570 TI - Redox metabolite role in biofilms. PMID- 28082569 TI - Pin the tail on the hydrogens. PMID- 28082571 TI - Soil biota and plant diversity. PMID- 28082572 TI - How to get to place B. PMID- 28082573 TI - Parallel computation in memory-making. PMID- 28082575 TI - More light on dopamine receptors. PMID- 28082574 TI - Faster tree growth is no panacea. PMID- 28082576 TI - TAMpering with tumors. PMID- 28082578 TI - Effects of drought on tree performance. PMID- 28082577 TI - Three strands ironed closely together. PMID- 28082579 TI - Observing peculiar vortices. PMID- 28082580 TI - Fast point-of-care detection of biomarkers. PMID- 28082581 TI - Cancer and nerves: A tuf(t) partnership. PMID- 28082582 TI - Did Phaethon father the Geminids? PMID- 28082584 TI - Speedy sperm. PMID- 28082583 TI - Gut communities form a history of connection. PMID- 28082585 TI - Braiding a molecular knot with eight crossings. AB - Knots may ultimately prove just as versatile and useful at the nanoscale as at the macroscale. However, the lack of synthetic routes to all but the simplest molecular knots currently prevents systematic investigation of the influence of knotting at the molecular level. We found that it is possible to assemble four building blocks into three braided ligand strands. Octahedral iron(II) ions control the relative positions of the three strands at each crossing point in a circular triple helicate, while structural constraints on the ligands determine the braiding connections. This approach enables two-step assembly of a molecular 819 knot featuring eight nonalternating crossings in a 192-atom closed loop ~20 nanometers in length. The resolved metal-free 819 knot enantiomers have pronounced features in their circular dichroism spectra resulting solely from topological chirality. PMID- 28082586 TI - Macrocyclic bis-thioureas catalyze stereospecific glycosylation reactions. AB - Carbohydrates are involved in nearly all aspects of biochemistry, but their complex chemical structures present long-standing practical challenges to their synthesis. In particular, stereochemical outcomes in glycosylation reactions are highly dependent on the steric and electronic properties of coupling partners; thus, carbohydrate synthesis is not easily predictable. Here we report the discovery of a macrocyclic bis-thiourea derivative that catalyzes stereospecific invertive substitution pathways of glycosyl chlorides. The utility of the catalyst is demonstrated in the synthesis of trans-1,2-, cis-1,2-, and 2-deoxy beta-glycosides. Mechanistic studies are consistent with a cooperative mechanism in which an electrophile and a nucleophile are simultaneously activated to effect a stereospecific substitution reaction. PMID- 28082587 TI - Hydrogen positions in single nanocrystals revealed by electron diffraction. AB - The localization of hydrogen atoms is an essential part of crystal structure analysis, but it is difficult because of their small scattering power. We report the direct localization of hydrogen atoms in nanocrystalline materials, achieved using the recently developed approach of dynamical refinement of precession electron diffraction tomography data. We used this method to locate hydrogen atoms in both an organic (paracetamol) and an inorganic (framework cobalt aluminophosphate) material. The results demonstrate that the technique can reliably reveal fine structural details, including the positions of hydrogen atoms in single crystals with micro- to nanosized dimensions. PMID- 28082589 TI - Vectorial representation of spatial goals in the hippocampus of bats. AB - To navigate, animals need to represent not only their own position and orientation, but also the location of their goal. Neural representations of an animal's own position and orientation have been extensively studied. However, it is unknown how navigational goals are encoded in the brain. We recorded from hippocampal CA1 neurons of bats flying in complex trajectories toward a spatial goal. We discovered a subpopulation of neurons with angular tuning to the goal direction. Many of these neurons were tuned to an occluded goal, suggesting that goal-direction representation is memory-based. We also found cells that encoded the distance to the goal, often in conjunction with goal direction. The goal direction and goal-distance signals make up a vectorial representation of spatial goals, suggesting a previously unrecognized neuronal mechanism for goal-directed navigation. PMID- 28082588 TI - Plant-soil feedback and the maintenance of diversity in Mediterranean-climate shrublands. AB - Soil biota influence plant performance through plant-soil feedback, but it is unclear whether the strength of such feedback depends on plant traits and whether plant-soil feedback drives local plant diversity. We grew 16 co-occurring plant species with contrasting nutrient-acquisition strategies from hyperdiverse Australian shrublands and exposed them to soil biota from under their own or other plant species. Plant responses to soil biota varied according to their nutrient-acquisition strategy, including positive feedback for ectomycorrhizal plants and negative feedback for nitrogen-fixing and nonmycorrhizal plants. Simulations revealed that such strategy-dependent feedback is sufficient to maintain the high taxonomic and functional diversity characterizing these Mediterranean-climate shrublands. Our study identifies nutrient-acquisition strategy as a key trait explaining how different plant responses to soil biota promote local plant diversity. PMID- 28082590 TI - Plant-soil feedbacks and mycorrhizal type influence temperate forest population dynamics. AB - Feedback with soil biota is an important determinant of terrestrial plant diversity. However, the factors regulating plant-soil feedback, which varies from positive to negative among plant species, remain uncertain. In a large-scale study involving 55 species and 550 populations of North American trees, the type of mycorrhizal association explained much of the variation in plant-soil feedbacks. In soil collected beneath conspecifics, arbuscular mycorrhizal trees experienced negative feedback, whereas ectomycorrhizal trees displayed positive feedback. Additionally, arbuscular mycorrhizal trees exhibited strong conspecific inhibition at multiple spatial scales, whereas ectomycorrhizal trees exhibited conspecific facilitation locally and less severe conspecific inhibition regionally. These results suggest that mycorrhizal type, through effects on plant soil feedbacks, could be an important contributor to population regulation and community structure in temperate forests. PMID- 28082591 TI - Superficial layers of the medial entorhinal cortex replay independently of the hippocampus. AB - The hippocampus is thought to initiate systems-wide mnemonic processes through the reactivation of previously acquired spatial and episodic memory traces, which can recruit the entorhinal cortex as a first stage of memory redistribution to other brain areas. Hippocampal reactivation occurs during sharp wave-ripples, in which synchronous network firing encodes sequences of places. We investigated the coordination of this replay by recording assembly activity simultaneously in the CA1 region of the hippocampus and superficial layers of the medial entorhinal cortex. We found that entorhinal cell assemblies can replay trajectories independently of the hippocampus and sharp wave-ripples. This suggests that the hippocampus is not the sole initiator of spatial and episodic memory trace reactivation. Memory systems involved in these processes may include nonhierarchical, parallel components. PMID- 28082592 TI - Causal neural network of metamemory for retrospection in primates. AB - We know how confidently we know: Metacognitive self-monitoring of memory states, so-called "metamemory," enables strategic and efficient information collection based on past experiences. However, it is unknown how metamemory is implemented in the brain. We explored causal neural mechanism of metamemory in macaque monkeys performing metacognitive confidence judgments on memory. By whole-brain searches via functional magnetic resonance imaging, we discovered a neural correlate of metamemory for temporally remote events in prefrontal area 9 (or 9/46d), along with that for recent events within area 6. Reversible inactivation of each of these identified loci induced doubly dissociated selective impairments in metacognitive judgment performance on remote or recent memory, without impairing recognition performance itself. The findings reveal that parallel metamemory streams supervise recognition networks for remote and recent memory, without contributing to recognition itself. PMID- 28082593 TI - Assembly of a nucleus-like structure during viral replication in bacteria. AB - We observed the assembly of a nucleus-like structure in bacteria during viral infection. Using fluorescence microscopy and cryo-electron tomography, we showed that Pseudomonas chlororaphis phage 201phi2-1 assembled a compartment that separated viral DNA from the cytoplasm. The phage compartment was centered by a bipolar tubulin-based spindle, and it segregated phage and bacterial proteins according to function. Proteins involved in DNA replication and transcription localized inside the compartment, whereas proteins involved in translation and nucleotide synthesis localized outside. Later during infection, viral capsids assembled on the cytoplasmic membrane and moved to the surface of the compartment for DNA packaging. Ultimately, viral particles were released from the compartment and the cell lysed. These results demonstrate that phages have evolved a specialized structure to compartmentalize viral replication. PMID- 28082594 TI - A bacterial global regulator forms a prion. AB - Prions are self-propagating protein aggregates that act as protein-based elements of inheritance in fungi. Although prevalent in eukaryotes, prions have not been identified in bacteria. Here we found that a bacterial protein, transcription terminator Rho of Clostridium botulinum (Cb-Rho), could form a prion. We identified a candidate prion-forming domain (cPrD) in Cb-Rho and showed that it conferred amyloidogenicity on Cb-Rho and could functionally replace the PrD of a yeast prion-forming protein. Furthermore, its cPrD enabled Cb-Rho to access alternative conformations in Escherichia coli-a soluble form that terminated transcription efficiently and an aggregated, self-propagating prion form that was functionally compromised. The prion form caused genome-wide changes in the transcriptome. Thus, Cb-Rho functions as a protein-based element of inheritance in bacteria, suggesting that the emergence of prions predates the evolutionary split between eukaryotes and bacteria. PMID- 28082597 TI - Choosing the hard road. PMID- 28082595 TI - Principles for designing proteins with cavities formed by curved beta sheets. AB - Active sites and ligand-binding cavities in native proteins are often formed by curved beta sheets, and the ability to control beta-sheet curvature would allow design of binding proteins with cavities customized to specific ligands. Toward this end, we investigated the mechanisms controlling beta-sheet curvature by studying the geometry of beta sheets in naturally occurring protein structures and folding simulations. The principles emerging from this analysis were used to design, de novo, a series of proteins with curved beta sheets topped with alpha helices. Nuclear magnetic resonance and crystal structures of the designs closely match the computational models, showing that beta-sheet curvature can be controlled with atomic-level accuracy. Our approach enables the design of proteins with cavities and provides a route to custom design ligand-binding and catalytic sites. PMID- 28082598 TI - Prenatal Exposure to DEHP Induces Premature Reproductive Senescence in Male Mice. AB - Di-(2-ethylhexyl) phthalate (DEHP) is the most commonly used phthalate, and it is an endocrine-disrupting chemical. This study tested a hypothesis that prenatal exposure to DEHP lays the foundation for premature gonadal dysfunction and subsequent reproductive senescence in male mice. Pregnant female CD-1 mice were orally dosed with vehicle control (tocopherol-stripped corn oil) or with 20 MUg/kg/day, 200 MUg/kg/day, 500 mg/kg/day, or 750 mg/kg/day of DEHP from gestational day 11 to birth. Overall, the prenatal DEHP exposure did not cause any overt physical health problems in male offspring, as no significant differences in their body nor gonadal weight were seen up to the age of 23 months. However, an age- and dose-dependent gonadal dysfunction was observed. As early as 7 months of age, the 750 mg/kg/day group of mice exhibited significantly reduced fertility. At 19 months of age, 86% of the 750 mg/kg/day mice became infertile, whereas only 25% of the control mice were infertile. At this age, all of the DEHP-exposed mice had lower serum testosterone levels, higher serum estradiol levels, and higher LH levels compared with control mice. Histological evaluations showed that mice prenatally exposed to DEHP displayed a wide array of gonadal and epididymal abnormalities such as increased germ cell apoptosis, degenerative seminiferous tubules, oligozoospermia, asthenozoospermia, and teratozoospermia in comparison to age-matching control mice. In summary, this study shows that prenatal exposure to DEHP induces premature reproductive senescence in male mice. PMID- 28082599 TI - Hsp90 and Physiological Stress Are Linked to Autonomous Transposon Mobility and Heritable Genetic Change in Nematodes. AB - Transposable elements (TEs) have been recognized as potentially powerful drivers of genomic evolutionary change, but factors affecting their mobility and regulation remain poorly understood. Chaperones such as Hsp90 buffer environmental perturbations by regulating protein conformation, but are also part of the PIWI-interacting RNA pathway, which regulates genomic instability arising from mobile TEs in the germline. Stress-induced mutagenesis from TE movement could thus arise from functional trade-offs in the dual roles of Hsp90. We examined the functional constraints of Hsp90 and its role as a regulator of TE mobility by exposing nematodes (Caenorhabditis elegans and Caenorhabditis briggsae) to environmental stress, with and without RNAi-induced silencing of Hsp90. TE excision frequency increased with environmental stress intensity at multiple loci in several strains of each species. These effects were compounded by RNAi-induced knockdown of Hsp90. Mutation frequencies at the unc-22 marker gene in the offspring of animals exposed to environmental stress and Hsp90 RNAi mirrored excision frequency in response to these treatments. Our results support a role for Hsp90 in the suppression of TE mobility, and demonstrate that that the Hsp90 regulatory pathway can be overwhelmed with moderate environmental stress. By compromising genomic stability in germline cells, environmentally induced mutations arising from TE mobility and insertion can have permanent and heritable effects on both the phenotype and the genotype of subsequent generations. PMID- 28082600 TI - Evolution of Chaperonin Gene Duplication in Stigonematalean Cyanobacteria (Subsection V). AB - Chaperonins promote protein folding and are known to play a role in the maintenance of cellular stability under stress conditions. The group I bacterial chaperonin complex comprises GroEL, that forms a barrel-like oligomer, and GroES that forms the lid. In most eubacteria the GroES/GroEL chaperonin is encoded by a single-copy bicistronic operon, whereas in cyanobacteria up to three groES/groEL paralogs have been documented. Here we study the evolution and functional diversification of chaperonin paralogs in the heterocystous, multi-seriate filament forming cyanobacterium Chlorogloeopsis fritschii PCC 6912. The genome of C. fritschii encodes two groES/groEL operons (groESL1, groESL1.2) and a monocistronic groEL gene (groEL2). A phylogenetic reconstruction reveals that the groEL2 duplication is as ancient as cyanobacteria, whereas the groESL1.2 duplication occurred at the ancestor of heterocystous cyanobacteria. A comparison of the groEL paralogs transcription levels under different growth conditions shows that they have adapted distinct transcriptional regulation. Our results reveal that groEL1 and groEL1.2 are upregulated during diazotrophic conditions and the localization of their promoter activity points towards a role in heterocyst differentiation. Furthermore, protein-protein interaction assays suggest that paralogs encoded in the two operons assemble into hybrid complexes. The monocistronic encoded GroEL2 is not forming oligomers nor does it interact with the co-chaperonins. Interaction between GroES1.2 and GroEL1.2 could not be documented, suggesting that the groESL1.2 operon does not encode a functional chaperonin complex. Functional complementation experiments in Escherichia coli show that only GroES1/GroEL1 and GroES1/GroEL1.2 can substitute the native operon. In summary, the evolutionary consequences of chaperonin duplication in cyanobacteria include the retention of groESL1 as a housekeeping gene, subfunctionalization of groESL1.2 and neofunctionalization of the monocistronic groEL2 paralog. PMID- 28082601 TI - Genomic Characterization of the Evolutionary Potential of the Sea Urchin Strongylocentrotus droebachiensis Facing Ocean Acidification. AB - Ocean acidification (OA) is increasing due to anthropogenic CO2 emissions and poses a threat to marine species and communities worldwide. To better project the effects of acidification on organisms' health and persistence, an understanding is needed of the 1) mechanisms underlying developmental and physiological tolerance and 2) potential populations have for rapid evolutionary adaptation. This is especially challenging in nonmodel species where targeted assays of metabolism and stress physiology may not be available or economical for large scale assessments of genetic constraints. We used mRNA sequencing and a quantitative genetics breeding design to study mechanisms underlying genetic variability and tolerance to decreased seawater pH (-0.4 pH units) in larvae of the sea urchin Strongylocentrotus droebachiensis. We used a gene ontology-based approach to integrate expression profiles into indirect measures of cellular and biochemical traits underlying variation in larval performance (i.e., growth rates). Molecular responses to OA were complex, involving changes to several functions such as growth rates, cell division, metabolism, and immune activities. Surprisingly, the magnitude of pH effects on molecular traits tended to be small relative to variation attributable to segregating functional genetic variation in this species. We discuss how the application of transcriptomics and quantitative genetics approaches across diverse species can enrich our understanding of the biological impacts of climate change. PMID- 28082602 TI - A SNP-Enabled Assessment of Genetic Diversity, Evolutionary Relationships and the Identification of Candidate Genes in Chrysanthemum. AB - Varieties of the economically important ornamental species chrysanthemum have been bred to fit a number of market niches, but the genetic basis and evolutionary relationships among various cultivated types are poorly understood. Here, a DNA marker-based analysis of 199 chrysanthemum entries representing each of the five cultivated types is presented. A set of >90,000 single nucleotide polymorphisms (SNPs) associated with a minor allele frequency of at least 5% was defined, and used to perform a phylogenetic analysis which corresponded well with the phenotypic classification. The analysis revealed that the small-flowered types, spray cut chrysanthemum (SCC) and potted and ground chrysanthemum (PGC), are more closely related to the wild progenitor species (WC) than are the large flowered ones, disbud cut chrysanthemum (DCC) and traditional chrysanthemum (TC); and the PGC type was closest. Some 550 genetic regions appeared to have experienced selection in the separation of potted and ground-cover types from disbud cut types, and that between potted and ground-cover types from traditional types. A genome-wide association analysis revealed that seven SNPs lying within six genes were predictive of three important traits (ray floret type, cultivated type and flower shape), but no association with flower color was detected. The study has provided a number of novel insights into evolutionary relationships, the population structure and the genetic basis of some key ornamental traits. PMID- 28082603 TI - Analysis of Three Sugarcane Homo/Homeologous Regions Suggests Independent Polyploidization Events of Saccharum officinarum and Saccharum spontaneum. AB - Whole genome duplication has played an important role in plant evolution and diversification. Sugarcane is an important crop with a complex hybrid polyploid genome, for which the process of adaptation to polyploidy is still poorly understood. In order to improve our knowledge about sugarcane genome evolution and the homo/homeologous gene expression balance, we sequenced and analyzed 27 BACs (Bacterial Artificial Chromosome) of sugarcane R570 cultivar, containing the putative single-copy genes LFY (seven haplotypes), PHYC (four haplotypes), and TOR (seven haplotypes). Comparative genomic approaches showed that these sugarcane loci presented a high degree of conservation of gene content and collinearity (synteny) with sorghum and rice orthologous regions, but were invaded by transposable elements (TE). All the homo/homeologous haplotypes of LFY, PHYC, and TOR are likely to be functional, because they are all under purifying selection (dN/dS ? 1). However, they were found to participate in a nonequivalently manner to the overall expression of the corresponding gene. SNPs, indels, and amino acid substitutions allowed inferring the S. officinarum or S. spontaneum origin of the TOR haplotypes, which further led to the estimation that these two sugarcane ancestral species diverged between 2.5 and 3.5 Ma. In addition, analysis of shared TE insertions in TOR haplotypes suggested that two autopolyploidization may have occurred in the lineage that gave rise to S. officinarum, after its divergence from S. spontaneum. PMID- 28082604 TI - Landscape of Fluid Sets of Hairpin-Derived 21-/24-nt-Long Small RNAs at Seed Set Uncovers Special Epigenetic Features in Picea glauca. AB - Conifers' exceptionally large genome (20-30 Gb) is scattered with 60% retrotransposon (RT) components and we have little knowledge on their origin and evolutionary implications. RTs may impede the expression of flanking genes and provide sources of the formation of novel small RNA (sRNAs) populations to constrain events of transposon (TE) proliferation/transposition. Here we show a declining expression of 24-nt-long sRNAs and low expression levels of their key processing gene, pgRTL2 (RNASE THREE LIKE 2) at seed set in Picea glauca. The sRNAs in 24-nt size class are significantly less enriched in type and read number than 21-nt sRNAs and have not been documented in other species. The architecture of MIR loci generating highly expressed 24-/21-nt sRNAs is featured by long terminal repeat-retrotransposons (LTR-RTs) in families of Ty3/Gypsy and Ty1/Copia elements. This implies that the production of sRNAs may be predominantly originated from TE fragments on chromosomes. Furthermore, a large proportion of highly expressed 24-nt sRNAs does not have predictable targets against unique genes in Picea, suggestive of their potential pathway in DNA methylation modifications on, for instance, TEs. Additionally, the classification of computationally predicted sRNAs suggests that 24-nt sRNA targets may bear particular functions in metabolic processes while 21-nt sRNAs target genes involved in many different biological processes. This study, therefore, directs our attention to a possible extrapolation that lacking of 24-nt sRNAs at the late conifer seed developmental phase may result in less constraints in TE activities, thus contributing to the massive expansion of genome size. PMID- 28082605 TI - Molecular Evolution of piggyBac Superfamily: From Selfishness to Domestication. AB - The piggyBac transposable element was originally isolated from the cabbage looper moth, Trichoplusia ni, in the 1980s. Despite its early discovery and specificity compared to the other Class II elements, the diversity and evolution of this superfamily have been only partially analyzed. Two main types of elements can be distinguished: the piggyBac-like elements (PBLE) with terminal inverted repeats, untranslated region, and an open reading frame encoding a transposase, and the piggyBac-derived sequences (PGBD), containing a sequence derived from a piggyBac transposase, and which correspond to domesticated elements. To define the distribution, their structural diversity and phylogenetic relationships, analyses were conducted using known PBLE and PGBD sequences to scan databases. From this data mining, numerous new sequences were characterized (50 for PBLE and 396 for PGBD). Structural analyses suggest that four groups of PBLE can be defined according to the presence/absence of sub-terminal repeats. The transposase is characterized by highly variable catalytic domain and C-terminal region. There is no relationship between the structural groups and the phylogeny of these PBLE elements. The PGBD are clearly structured into nine main groups. A new group of domesticated elements is suspected in Neopterygii and the remaining eight previously described elements have been investigated in more detail. In all cases, these sequences are no longer transposable elements, the catalytic domain of the ancestral transposase is not always conserved, but they are under strong purifying selection. The phylogeny of both PBLE and PGBD suggests multiple and independent domestication events of PGBD from different PBLE ancestors. PMID- 28082606 TI - Support for Lungfish as the Closest Relative of Tetrapods by Using Slowly Evolving Ray-Finned Fish as the Outgroup. AB - In a previous analysis of the phylogenetic relationships of coelacanths, lungfishes and tetrapods, using cartilaginous fish (CF) as the outgroup, the sister relationship of lungfishes and tetrapods was constructed with high statistical support. However, using as the outgroup ray-finned fish (RF), which are more taxonomically closely related to the three lineages than CF, the sister relationship of coelacanths and tetrapods was most often constructed depending on the methods and the data sets, but the statistical support was generally low except in the cases in which the data set including a small number of species was analyzed. In this study, instead of the fast evolving ray-finned fish, teleost fish (TF), in the previous data sets, by using two slowly evolving RF, gar and bowfin, as the outgroup, we showed that the sister relationship of lungfishes and tetrapods was reconstructed with high statistical support. In our analysis the evolutionary rates of gar and bowfin were similar to each other and one third to one half of TF. The difference of the amino acid frequencies of the two species with other lineages was larger than those of TF. This study provides a strong support for lungfishes as the closest relative of tetrapods and indicates the importance of using an appropriate outgroup with small divergence in phylogenetic construction. PMID- 28082607 TI - Proteome Evolution of Deep-Sea Hydrothermal Vent Alvinellid Polychaetes Supports the Ancestry of Thermophily and Subsequent Adaptation to Cold in Some Lineages. AB - Temperature, perhaps more than any other environmental factor, is likely to influence the evolution of all organisms. It is also a very interesting factor to understand how genomes are shaped by selection over evolutionary timescales, as it potentially affects the whole genome. Among thermophilic prokaryotes, temperature affects both codon usage and protein composition to increase the stability of the transcriptional/translational machinery, and the resulting proteins need to be functional at high temperatures. Among eukaryotes less is known about genome evolution, and the tube-dwelling worms of the family Alvinellidae represent an excellent opportunity to test hypotheses about the emergence of thermophily in ectothermic metazoans. The Alvinellidae are a group of worms that experience varying thermal regimes, presumably having evolved into these niches over evolutionary times. Here we analyzed 423 putative orthologous loci derived from 6 alvinellid species including the thermophilic Alvinella pompejana and Paralvinella sulfincola. This comparative approach allowed us to assess amino acid composition, codon usage, divergence, direction of residue changes and the strength of selection along the alvinellid phylogeny, and to design a new eukaryotic thermophilic criterion based on significant differences in the residue composition of proteins. Contrary to expectations, the alvinellid ancestor of all present-day species seems to have been thermophilic, a trait subsequently maintained by purifying selection in lineages that still inhabit higher temperature environments. In contrast, lineages currently living in colder habitats likely evolved under selective relaxation, with some degree of positive selection for low-temperature adaptation at the protein level. PMID- 28082610 TI - The Social Life of Abortion Law: on Personal and Political Pedagogy. AB - The current contribution seeks to start a conversation around our pedagogical practice in respect of abortion law. Centralising the traditional portrayal of abortion law within the medical law curriculum, this essay highlights the privileging of a very particular storyline about abortion. Exploring the terrain in evaluating medical law methodologies, this essay highlights the illusion of 'balance', 'objectivity', and 'neutrality' that emerges from current pedagogy in light of how abortion law is framed and in particular what is excluded: women's own voices. Focusing on a number of 'exclusions' and 'silences' and noting how closely these mirror dominant discourse in the public sphere, this essay highlights the irony of a curriculum that reflects, rather than challenges, these discursive gaps. Arguing that the setting of a curriculum is inevitably political, ambitions for delivering a programme around abortion that is 'neutral', 'objective', or 'balanced' are dismissed. Instead, highlighting the problems of what is currently excluded, how materials are ordered, and the tacit hierarchies that lend legitimacy and authority to a particular way of 'knowing' abortion, this essay argues for a new curriculum and a new storyline-one which is supported by prior learning in feminist legal scholarship and a medical law curriculum in which the social, historical, geographical, and above all, personal is ever-present and central. PMID- 28082609 TI - Variation in the Intensity of Selection on Codon Bias over Time Causes Contrasting Patterns of Base Composition Evolution in Drosophila. AB - Four-fold degenerate coding sites form a major component of the genome, and are often used to make inferences about selection and demography, so that understanding their evolution is important. Despite previous efforts, many questions regarding the causes of base composition changes at these sites in Drosophila remain unanswered. To shed further light on this issue, we obtained a new whole-genome polymorphism data set from D. simulans. We analyzed samples from the putatively ancestral range of D. simulans, as well as an existing polymorphism data set from an African population of D. melanogaster. By using D. yakuba as an outgroup, we found clear evidence for selection on 4-fold sites along both lineages over a substantial period, with the intensity of selection increasing with GC content. Based on an explicit model of base composition evolution, we suggest that the observed AT-biased substitution pattern in both lineages is probably due to an ancestral reduction in selection intensity, and is unlikely to be the result of an increase in mutational bias towards AT alone. By using two polymorphism-based methods for estimating selection coefficients over different timescales, we show that the selection intensity on codon usage has been rather stable in D. simulans in the recent past, but the long-term estimates in D. melanogaster are much higher than the short-term ones, indicating a continuing decline in selection intensity, to such an extent that the short-term estimates suggest that selection is only active in the most GC-rich parts of the genome. Finally, we provide evidence for complex evolutionary patterns in the putatively neutral short introns, which cannot be explained by the standard GC biased gene conversion model. These results reveal a dynamic picture of base composition evolution. PMID- 28082608 TI - The Conservation of the Germline Multipotency Program, from Sponges to Vertebrates: A Stepping Stone to Understanding the Somatic and Germline Origins. AB - The germline definition in metazoans was first based on few bilaterian models. As a result, gene function interpretations were often based on phenotypes observed in those models and led to the definition of a set of genes, considered as specific of the germline, named the "germline core". However, some of these genes were shown to also be involved in somatic stem cells, thus leading to the notion of germline multipotency program (GMP). Because Porifera and Ctenophora are currently the best candidates to be the sister-group to all other animals, the comparative analysis of gene contents and functions between these phyla, Cnidaria and Bilateria is expected to provide clues on early animal evolution and on the links between somatic and germ lineages. Our present bioinformatic analyses at the metazoan scale show that a set of 18 GMP genes was already present in the last common ancestor of metazoans and indicate more precisely the evolution of some of them in the animal lineage. The expression patterns and levels of 11 of these genes in the homoscleromorph sponge Oscarella lobularis show that they are expressed throughout their life cycle, in pluri/multipotent progenitors, during gametogenesis, embryogenesis and during wound healing. This new study in a nonbilaterian species reinforces the hypothesis of an ancestral multipotency program. PMID- 28082611 TI - Protecting Patients from their Bad Decisions: Rebalancing Rights, Relationships, and Risk. AB - Patients have a right to autonomy that encompasses making medical decisions that others consider 'bad'. The ambits of this right in law and clinical practice are explored in this article, which describes an expansion of welfare protections across different aspects of medical law and explores their justifications and implications. In England and Wales, the Mental Capacity Act 2005 sets out protections for those who fall within its definition of incapacity. Those who retain capacity are ostensibly free to make decisions others consider unwise. But the decisions of those with borderline capacity; those whose decisions conflict with the public interest in protecting the patient from harm; and those considered 'vulnerable' are, in circumstances explored in this article, susceptible to override. The article explores the effects of these developments on the relationship between patients' autonomy rights and clinicians' responsibilities. PMID- 28082612 TI - Development of a vortex generator to perturb fish locomotion. AB - Knowledge about the stiffness of fish fins, and whether stiffness is modulated during swimming, is important for understanding the mechanics of a fin's force production. However, the mechanical properties of fins have not been studied during natural swimming, in part because of a lack of instrumentation. To remedy this, a vortex generator was developed that produces traveling vortices of adjustable strength which can be used to perturb the fins of swimming fish. Experiments were conducted to understand how the generator's settings affected the resulting vortex rings. A variety of vortices (14-32 mm diameter traveling at 371-2155 mm s-1) were produced that elicited adequate responses from the fish fins to help us to understand the fin's mechanical properties at various swimming speeds (0-350 mm s-1). PMID- 28082613 TI - A novel technique for the precise measurement of CO2 production rate in small aquatic organisms as validated on aeshnid dragonfly nymphs. AB - The present study describes and validates a novel yet simple system for simultaneous in vivo measurements of rates of aquatic CO2 production (MCO2 ) and oxygen consumption (MO2 ), thus allowing the calculation of respiratory exchange ratios (RER). Diffusion of CO2 from the aquatic phase into a gas phase, across a hollow fibre membrane, enabled aquatic MCO2 measurements with a high-precision infrared gas CO2 analyser. MO2 was measured with a PO2 optode using a stop-flow approach. Injections of known amounts of CO2 into the apparatus yielded accurate and highly reproducible measurements of CO2 content (R2=0.997, P<0.001). The viability of in vivo measurements was demonstrated on aquatic dragonfly nymphs (Aeshnidae; wet mass 2.17 mg-1.46 g, n=15) and the apparatus produced precise MCO2 (R2=0.967, P<0.001) and MO2 (R2=0.957, P<0.001) measurements; average RER was 0.73+/-0.06. The described system is scalable, offering great potential for the study of a wide range of aquatic species, including fish. PMID- 28082614 TI - Archerfish use their shooting technique to produce adaptive underwater jets. AB - Archerfish are renowned for dislodging aerial prey using well-aimed shots of water. Recently it has been shown that these fish can shape their aerial jets by adjusting the dynamics of their mouth opening and closing. This allows the fish to adjust their jet to target distance so that they can forcefully hit prey over considerable distances. Here, we suggest that archerfish use the same technique to also actively control jets under water. Fired from close range, the underwater jets are powerful enough to lift up buried food particles, which the fish then can pick up. We trained fish so that we could monitor their mouth opening and closing maneuvers during underwater shooting and compare them with those employed in aerial shooting. Our analysis suggests that the fish use the same dynamic mechanism to produce aerial and underwater jets and that they employ the same basic technique to adjust their jets in both conditions. When food is buried in substrate that consists of large particles, the fish use a brief pulse, but they use a longer one when the substrate is more fine-grained. These findings extend the notion that archerfish can flexibly shape their jets to be appropriate in different contexts and suggest that archerfish shooting might have been shaped both by constraints in aerial and underwater shooting. PMID- 28082615 TI - Temperature and photoperiod as environmental cues affect body mass and thermoregulation in Chinese bulbuls, Pycnonotus sinensis. AB - Seasonal changes in temperature and photoperiod are important environmental cues used by small birds to adjust their body mass (Mb) and thermogenesis. However, the relative importance of these cues with respect to seasonal adjustments in Mb and thermogenesis is difficult to distinguish. In particular, the effects of temperature and photoperiod on energy metabolism and thermoregulation are not well known in many passerines. To address this problem, we measured the effects of temperature and photoperiod on Mb, energy intake, resting metabolic rate (RMR), organ mass and physiological and biochemical markers of metabolic activity in the Chinese bulbul (Pycnonotus sinensis). Groups of Chinese bulbuls were acclimated in a laboratory to the following conditions: (1) warm and long photoperiod, (2) warm and short photoperiod, (3) cold and long photoperiod, and (4) cold and short photoperiod, for 4 weeks. The results indicate that Chinese bulbuls exhibit adaptive physiological regulation when exposed to different temperatures and photoperiods. Mb, RMR, gross energy intake and digestible energy intake were higher in cold-acclimated than in warm-acclimated bulbuls, and in the short photoperiod than in the long photoperiod. The resultant flexibility in energy intake and RMR allows Chinese bulbuls exposed to different temperatures and photoperiods to adjust their energy balance and thermogenesis accordingly. Cold-acclimated birds had heightened state-4 respiration and cytochrome c oxidase activity in their liver and muscle tissue compared with warm-acclimated birds indicating the cellular mechanisms underlying their adaptive thermogenesis. Temperature appears to be a primary cue for adjusting energy budget and thermogenic ability in Chinese bulbuls; photoperiod appears to intensify temperature-induced changes in energy metabolism and thermoregulation. PMID- 28082616 TI - Economic thermoregulatory response explains mismatch between thermal physiology and behaviour in newts. AB - Temperature is an important factor determining distribution and abundance of organisms. Predicting the impact of warming climate on ectotherm populations requires information about species' thermal requirements, i.e. their so-called 'thermal niche'. The characterization of thermal niche remains a complicated task. We compared the applicability of two indirect approaches, based on reaction norm (aerobic scope curve) and optimality (preferred body temperature) concepts, for indirect estimation of thermal niche while using newts, Ichthyosaura alpestris, as a study system. If the two approaches are linked, then digesting newts should keep their body temperatures close to values maximizing aerobic scope for digestion. After feeding, newts maintained their body temperatures within a narrower range than did hungry individuals. The range of preferred body temperatures was well below the temperature maximizing aerobic scope for digestion. Optimal temperatures for factorial aerobic scope fell within the preferred body temperature range of digesting individuals. We conclude that digesting newts prefer body temperatures that are optimal for the maximum aerobic performance but relative to the maintenance costs. What might be termed the 'economic' thermoregulatory response explains the mismatch between thermal physiology and behaviour in this system. PMID- 28082617 TI - Appropriate rearing density in domesticated zebrafish to avoid masculinization: links with the stress response. AB - The zebrafish (Danio rerio) has become a well-established experimental model in many research fields but the loss of the primary sex-determining region during the process of domestication renders laboratory strains of zebrafish susceptible to the effects of environmental factors on sex ratios. Further, an essential husbandry aspect - the optimal rearing density to avoid stress-induced masculinization - is not known. We carried out two experiments: the first focusing on the effects of density on survival, growth and sex ratio by rearing zebrafish at different initial densities (9, 19, 37 and 74 fish per litre) for 3 months (6-90 days post-fertilization, dpf), and the second focusing on the effects of cortisol during the sex differentiation period (15-45 dpf) for zebrafish reared at low density. The results showed an increase in the number of males in groups subjected to the two highest initial rearing densities; we also observed a reduction of survival and growth in a density-dependent manner. Furthermore, zebrafish treated with cortisol during the sex differentiation period showed a complete masculinization of the population; treatment with the cortisol synthesis inhibitor metyrapone negated the effects of exogenous cortisol. Our results indicate that the process of sex differentiation in domesticated zebrafish can be perturbed by elevated stocking density and that this effect is likely to be mediated by an increase in cortisol through the stress response. However, the underlying mechanism needs further study. PMID- 28082618 TI - Metabolic plasticity for subcutaneous fat accumulation in a long-distance migratory bird traced by 2H2O. AB - The migrant black-tailed godwit (Limosa limosa) traditionally used natural wetlands in the Iberian Peninsula to prepare for migratory flights by feeding mainly in estuaries. In recent decades, this species has become increasingly dependent on rice fields, thereby relying on a plant-based diet for fuelling. Dietary fatty acids (FA) seem to be determinant to the composition of accumulated subcutaneous fat in migratory birds. It is still unclear whether metabolic plasticity allows for modification and/or synthesis of FA, contributing to a lipid profile that enables a successful migratory performance. Deuterated water was administered to captive black-tailed godwits submitted to two diets (fly larvae versus rice) and the incorporation of deuterium (2H) into subcutaneous triglycerides was analyzed by NMR. A recently developed localized biopsy method for sampling subcutaneous fat was employed with later successful release of all birds into the wild. The average chemical structure reflected mostly a mixture of saturated and monounsaturated 16- and 18-carbon FA, a profile frequently found in migrant birds. Significantly higher levels of polyunsaturated FA, as well as detectable levels of n-3 FA, were observed in fly-larvae-fed birds. Excess 2H enrichments in FA revealed significantly higher rates of fractional de novo lipogenesis and FA desaturation capacity in rice-fed birds. This novel and non lethal tracer method revealed the capacity of this species to alter its lipid metabolism to compensate for a poorer dietary lipid contribution. Because of its versatility, adapting this method to other scenarios and/or other migratory species is considered feasible and cost-effective. PMID- 28082619 TI - Functional morphology of tegmina-based stridulation in the relict species Cyphoderris monstrosa (Orthoptera: Ensifera: Prophalangopsidae). AB - Male grigs, bush crickets and crickets produce mating calls by tegminal stridulation: the scraping together of modified forewings functioning as sound generators. Bush crickets (Tettigoniidae) and crickets (Gryllinae) diverged some 240 million years ago, with each lineage developing unique characteristics in wing morphology and the associated mechanics of stridulation. The grigs (Prophalangopsidae), a relict lineage more closely related to bush crickets than to crickets, are believed to retain plesiomorphic features of wing morphology. The wing cells widely involved in sound production, such as the harp and mirror, are comparatively small, poorly delimited and/or partially filled with cross veins. Such morphology is similarly observed in the earliest stridulating ensiferans, for which stridulatory mechanics remains poorly understood. The grigs, therefore, are of major importance to investigate the early evolutionary stages of tegminal stridulation, a critical innovation in the evolution of the Orthoptera. The aim of this study is to appreciate the degree of specialization on grig forewings, through identification of sound radiating areas and their properties. For well-grounded comparisons, homologies in wing venation (and associated areas) of grigs and bush crickets are re-evaluated. Then, using direct evidence, this study confirms the mirror cell, in association with two other areas (termed 'neck' and 'pre-mirror'), as the acoustic resonator in the grig Cyphoderris monstrosa Despite the use of largely symmetrical resonators, as found in field crickets, analogous features of stridulatory mechanics are observed between C. monstrosa and bush crickets. Both morphology and function in grigs represents transitional stages between unspecialized forewings and derived conditions observed in modern species. PMID- 28082620 TI - Long-term persistence and adherence on urate-lowering treatment can be maintained in primary care-5-year follow-up of a proof-of-concept study. AB - Objectives: To evaluate the persistence and adherence on urate-lowering treatment (ULT) in primary care 5 years after an initial nurse-led treatment of gout. Methods: One hundred gout patients initiated on up-titrated ULT between March and July 2010 were sent a questionnaire that elicited information on current ULT, reasons for discontinuation of ULT if applicable, medication adherence and generic and disease-specific quality-of-life measures in 2015. They were invited for one visit at which height and weight were measured and blood was collected for serum uric acid measurement. Results: Seventy-five patients, mean age 68.13 years ( s . d . 10.07) and disease duration 19.44 years ( s . d . 13), returned completed questionnaires. The 5-year persistence on ULT was 90.7% (95% CI 81.4, 91.6) and 85.3% of responders self-reported taking ULT ?6 days/week. Of the 65 patients who attended the study visit, the mean serum uric acid was 292.8 MUmol/l ( s . d . 97.2). Conclusion: An initial treatment that includes individualized patient education and involvement in treatment decisions results in excellent adherence and persistence on ULT >4 years after the responsibility of treatment is taken over by the patient's general practitioner, suggesting that this model of gout management should be widely adopted. PMID- 28082621 TI - CCR5Delta32 and the genetic susceptibility to rheumatoid arthritis in admixed populations: a multicentre study. PMID- 28082622 TI - Myositis-associated usual interstitial pneumonia has a better survival than idiopathic pulmonary fibrosis. AB - Objective: To compare the survival outcomes between myositis-associated usual interstitial pneumonia (MA-UIP) and idiopathic pulmonary fibrosis (IPF-UIP). Methods: Adult MA-UIP and IPF-UIP patients were identified using CTD and IPF registries. The MA-UIP cohort included myositis or anti-synthetase syndrome patients with interstitial lung disease while manifesting UIP on high-resolution CT chest and/or a lung biopsy revealing UIP histology. IPF subjects met American Thoracic Society criteria and similarly had UIP histopathology. Kaplan-Meier survival curves compared cumulative and pulmonary event-free survival (event = transplant or death) between (i) all MA-UIP and IPF-UIP subjects, (ii) MA-UIP with biopsy proven UIP (n = 25) vs IPF-UIP subjects matched for age, gender and baseline forced vital capacity (+/-10%). Cox proportional hazards ratios compared the survival controlling for co-variates. Results: Eighty-one IPF-UIP and 43 MA UIP subjects were identified. The median cumulative and event-free survival time in IPF vs MA-UIP was 5.25/1.8 years vs 16.2/10.8 years, respectively. Cumulative and event-free survival was significantly worse in IPF-UIP vs MA-UIP [hazards ratio of IPF-UIP was 2.9 (95% CI: 1.5, 5.6) and 5.0 (95% CI: 2.8, 8.7) (P < 0.001), respectively]. IPF-UIP event-free survival (but not cumulative) remained significantly worse than MA-UIP with a hazards ratio of 6.4 (95% CI: 3.0, 13.8) after controlling for age at interstitial lung disease diagnosis, gender, ethnicity and baseline forced vital capacity%. Respiratory failure was the most common cause of death in both groups. A sub-analysis of 25 biopsy-proven MA-UIP subjects showed similar results. Conclusion: MA-UIP patients demonstrated a significant survival advantage over a matched IPF cohort, suggesting that despite similar histological and radiographic findings at presentation, the prognosis of MA-UIP is superior to that of IPF-UIP. PMID- 28082623 TI - Comment on Qu et al. 2016. PMID- 28082624 TI - Response to Dr. Robertson's Letter to the Editor. PMID- 28082625 TI - Limited Evidence for Rickettsia felis as a Cause of Zoonotic Flea-Borne Rickettsiosis in Southern California. AB - Over 90% of human flea-borne rickettsioses cases in California are reported from suburban communities of Los Angeles and Orange counties and are presumed to be associated with either Rickettsia typhi or Rickettsia felis infection. Ctenocephalides felis (Bouche) is considered the principal vector for both rickettsiae, and R. felis has largely replaced R. typhi as the presumptive etiologic agent based on the widespread incidence of R. felis in cat flea populations. However, with no evidence to confirm R. felis as the cause of human illness in southern California, coupled with recent findings that showed R. felis to be widespread in cat fleas statewide, we propose that this hypothesis should be reconsidered. Evidence of only limited numbers of R. typhi-infected cat fleas in the environment may indicate a very rare infection and explain why so few cases of flea-borne rickettsioses are reported each year in southern California relative to the population. PMID- 28082626 TI - How Zoophilic Japanese Encephalitis Vector Mosquitoes Feed on Humans. AB - Japanese encephalitis virus (JEV) is the most frequent cause of mosquito-borne encephalitis in Asian countries. Several culicine species are potential vectors. The primary JEV vectors feed mainly on cows (a dead-end host for JEV), pigs (an amplifying host), and, occasionally, humans (a dead-end host). It is essential to determine blood-feeding patterns to understand the transmission cycle of the disease. Here we review blood-feeding characteristics of the primary JEV vectors Culex tritaeniorhynchus, Culex vishnui, and Culex gelidus based on experimental works and field surveys conducted in Asian countries. Several studies showed that these JEV vectors have an innate preference for cows; however, the former two species often showed higher rates of blood-feeding on pigs than on cows, probably because pigs are more abundant than cows. On the other hand, the latter species Cx. gelidus fed mostly on cows. Thus, the first two species showed higher plasticity to compromise host availability than the last. By reviewing the available articles and based on our relevant studies, it may be deduced that JEV transmission cannot be reduced by zooprophylaxis. We emphasize the need of keeping cows away from the human residences to dampen the human risk of JEV. These primary JEV vector species exhibit pre-biting resting. The adaptive significance of this behavior remains to be unexplored, but it may have a function to avoid defensive attack of host animals. Application of recent quantitative analysis of gene expression in this phase may enable us to come up with novel vector control strategies. PMID- 28082628 TI - Comparison of Intrinsic Rate of Different House Fly Densities in a Simulated Condition: A Prediction for House Fly Population and Control Threshold. AB - Determining the control threshold for a pest is common prior to initiating a pest control program; however, previous studies related to the house fly control threshold for a poultry farm are insufficient for determining such a threshold. This study aimed to predict the population changes of house fly population by comparing the intrinsic rate of increase (rm) for different house fly densities in a simulated system. This study first defined the knee points of a known population growth curve as a control threshold by comparing the rm of five densities of house flies in a simulated condition. Later, to understand the interactions between the larval and adult populations, the correlation between larval and adult capacity rate (rc) was studied. The rm values of 300- and 500 fly densities were significantly higher compared with the rm values at densities of 50 and 100 flies. This result indicated their representative indices as candidates for a control threshold. The rc of larval and adult populations were negatively correlated with densities of fewer than 300 flies; this implicated adult populations with fewer than 300 flies as declining while the larval population was growing; therefore, control approaches should focus on the immature stages. The results in the present study suggest a control threshold for house fly populations. Future works should focus on calibrating the threshold indices in field conditions. PMID- 28082627 TI - Chemotaxonomic Profile and Intraspecific Variation in the Blow Fly of Forensic Interest Chrysomya megacephala (Diptera: Calliphoridae). AB - Necrophagous insects such as blow flies (Diptera: Calliphoridae) are considered crucial in forensic entomology. Identification at species level and determination of larval stage are the basis for estimation of postmortem interval (PMI). Insect evidence can also be used in the determination of crime scenes, since body displacement is common. The aim of this study was to determine the chemotaxonomic profile and intraspecific variability of the forensically important blow fly Chrysomya megacephala (F. 1794). Adults were collected in the municipalities of Dourados-MS (Brazil) and Rio Claro-SP (Brazil), and then transferred to the laboratory for oviposition and development of the immature stages. Chemical analysis of cuticular compounds was performed by gas chromatography. Cuticular chemical profiles varied significantly between the two populations, as well as between developmental stages, supporting the use of these compounds as a complementary tool to help identify the species and its stages, along with geographical variability. This could greatly accelerate forensic investigations, eliminating the need to allow the fly larvae to develop until adult stage in order to confirm the species identity and sample origin. PMID- 28082629 TI - Volume of Larvae Is the Most Important Single Predictor of Mass Temperatures in the Forensically Important Calliphorid, Chrysomya megacephala (Diptera: Calliphoridae). AB - Calliphorid species form larval aggregations that are capable of generating heat above ambient temperature. We wanted to determine the relationship between volume, number of larvae, and different combinations of instars on larval mass heat generation. We compared different numbers of Chrysomya megacephala (F.) larvae (40, 100, 250, 600, and 2,000), and different combinations of instars (~50/50 first and second instars, 100% second instars, ~50/50 second and third instars, and 100% third instars) at two different ambient temperatures (20 and 30 degrees C). We compared 13 candidate multiple regression models that were fitted to the data; the models were then scored and ranked with Akaike information criterion and Bayesian information criterion. The results indicate that although instar, age, treatment temperature, elapsed time, and number of larvae in a mass were significant, larval volume was the best predictor of larval mass temperatures. The volume of a larval mass may need to be taken into consideration for determination of a postmortem interval. PMID- 28082630 TI - Spatial Distribution of Phlebotomine Sand Fly Species (Diptera: Psychodidae) in Qom Province, Central Iran. AB - Zoonotic cutaneous leishmaniasis (ZCL) is transmitted to humans by phlebotomine sand fly bites. ZCL is a major health problem in Iran, where basic knowledge gaps about sand fly species diversity persist in some ZCL-endemic areas. This paper describes the richness and spatial distribution of sand fly species, collected with sticky traps, in Qom province, a ZCL-endemic area in central Iran, where sand fly fauna has been poorly studied. Collected species were mapped on urban and rural digital maps based on a scale of 1/50,000. All analyses were undertaken with rural- and urban-level precision, i.e., rural and urban levels were our basic units of analysis. After identifying the sand flies, high-risk foci were determined. For spatial analysis of vector species population, the entomological sampling sites were geo-referenced using GPS. Arc GIS 9.3 software was used to determine the foci with leishmaniasis vector species. Following the analyses, two genera (Phlebotomus and Sergentomyia) and 14 species were identified. Based on the mapping and sand fly dispersion analysis, the rural districts were categorized into three groups-infection reported, without infection, and no report. Based on Geographical Information System analyses, Kahak and Markazi districts were identified as high-risk foci with leishmaniasis vector species. These findings can act as a help guide to direct active control measures to the identified high-risk foci and, eventually, lead to reduction in incidence of the disease. PMID- 28082631 TI - Chromosome Painting in Triatomine Insects Reveals Shared Sequences Between X Chromosomes and Autosomes. AB - In order to provide a broad picture on the origin and evolution of holocentric X chromosomes in heteropteran species, we prepared a sex chromosome painting probe by microdissection of the X1 and X2 chromosomes from a kissing bug Mepraia spinolai (Hemiptera: Reduviidae: Triatominae). Fluorescence in situ hybridization on four species of the Triatomini having different amounts of autosomal heterochromatin and sex chromosome systems show that the Xs probe hybridizes on the euchromatin, located both on autosomes and X chromosomes. The heterochromatic Y chromosome and autosomal heterochromatic regions always appear free of hybridization signals. The hybridization results of the Xs probe on Rhodnius prolixus (Rhodniini) is completely different to that observed in Triatomini species. The hybridization signals are small and scattered on all euchromatin, without specific regions including the X chromosome. These results are in accordance with previous data obtained by genomic in situ hybridization and fluorescent banding, suggesting a clear differentiation in the repeat sequence composition of both sex chromosomes between Triatomini and Rhodniini tribes. These results also support that each sex chromosome in Triatomini has evolved independently from different autosomal pairs of a common ancestor, as described in other insect orders. PMID- 28082632 TI - Taxonomic Revision of Lipoptilocnema (Diptera: Sarcophagidae), With Notes on Natural History and Forensic Importance of Its Species. AB - Lipoptilocnema Townsend is a small genus of Neotropical Sarcophaginae with a distinctive genitalic morphology. This genus is revised based on the examination of the type series and large numbers of specimens of the seven previously known species, plus three new ones herein described, one from Argentina (L. delfinado Mulieri and Mello-Patiu, sp. nov.), and two from Brazil (L. savana Mulieri and Mello-Patiu, sp. nov. and L. tibanae Mulieri and Mello-Patiu, sp. nov.). All species are described or redescribed and illustrated. Distribution maps and a key for male identification are provided. The taxonomic position of this genus is reviewed and the interpretation of phallic structures is discussed. Notes on the natural history of Lipoptilocnema species are provided, and their potential importance as PMI indicators is highlighted, including the first record of Lipoptilocnema reared from a dead human body. PMID- 28082633 TI - A New Species of Sand Fly, Psathyromyia elizabethdorvalae sp. n. (Diptera: Psychodidae: Phlebotominae), From Brazil. AB - A new species of phlebotomine sand fly, Psathyromyia elizabethdorvalae sp. n. Brilhante, Sabio & Galati from Xapuri, Acre state, Brazil, is described, with illustrations of male and female adults. PMID- 28082635 TI - Simulium maleewongae, a New Species of Simulium (Gomphostilbia) (Diptera: Simuliidae) From Thailand. AB - Simulium (Gomphostilbia) maleewongae sp. nov. is described based on the adult males and females, their pupal exuviae, and larvae from Thailand. This new species is placed in the Simulium gombakense species-group of Simulium (Gomphostilbia). It is characterized by the female cibarium with a cup-like appendage, male ventral plate deeply depressed ventromedially, pupal gill composed of an inflated structure and eight slender filaments, cone-shaped pupal terminal hooks, and cocoon with an anterodorsal projection. Taxonomic notes are given to separate this new species from 10 other species of the same species group known from China, India, Malaysia, Thailand, Nepal, and Vietnam. Keys to identify all 11 species of the S. gombakense species-group are provided for females, males, pupae, and larvae. PMID- 28082634 TI - Description of Blankaartia shatrovi n. sp. (Acari: Trombiculidae) From Brazil. AB - The chigger mite genus Blankaartia includes 28 known species, of which 10 are distributed in the Nearctic and Neotropical regions. These species preferentially parasitize birds, but occasionally they can also be found on rodents, bats, and reptiles, showing low host selectivity. In the present study, we report the presence of this genus in Brazil for the first time, including the first report of Blankaartia sinnamaryi (Floch and Fauran) and the description of a new species of Blankaartia collected from birds (Order Passeriformes). PMID- 28082636 TI - Photoperiod Differences in Sand Fly (Diptera: Psychodidae) Species Richness and Abundance in Caves in Minas Gerais State, Brazil. AB - Caves are unique habitats that are inhabited by a diverse and singular biota. Among these inhabitants are sand flies, which are of great epidemiological interest in the Neotropical region because they are vectors of Leishmania The period of activity of these insects is usually crepuscular and nocturnal, but there are reports of diurnal activity of sand flies in caves. Thus, the aim of this study was to evaluate the periodicity of daily activity of sand flies in cave environments in the municipality of Pains, Minas Gerais. Sand flies were collected with light traps, which were operated for 5 consecutive days in the rainy season and in the dry season. Samples were collected every 12 h and separated between photophase and scotophase periods. In total, 1,777 sand flies of 23 species were collected. The most abundant species was Lutzomyia renei (Martins, Falcao, and Silva) (44%), followed by Lutzomyia longipalpis (Lutz and Neiva) (15%), Evandromyia edwardsi (Mangabeira) (11%), and Micropygomyia quinquefer (Costa Lima) (6%). The richness and abundance of total sand flies and the abundance of male and female sand flies in the aphotic zone of the caves did not differ between the photophase and scotophase, but differed between photoperiods at the entrance and at sites surrounding the caves. From our study of the daily activity of these insects in this ecotope, it will be possible to know which period of the day is of greatest risk of exposure of vertebrates who visit or live in these environments, including the human population. PMID- 28082637 TI - Egg Hatching and Survival of Immature Stages of Aedes aegypti (Diptera: Culicidae) Under Natural Temperature Conditions During the Cold Season in Buenos Aires, Argentina. AB - In temperate regions, the seasonal dynamics of Aedes aegypti (L.) (Diptera: Culicidae) is mainly influenced by temperature. It is assumed that, during the winter season, the population remains as eggs and that the development and population growth of surviving eggs begin during the following spring. The aim of the current study was to assess egg hatching of Ae. aegypti during the winter in Buenos Aires city (Argentina), and analyze the survival of immature stages. The experiments consisted of immersing eggs and studying the development of immature stages of cohorts from June and September under natural temperature conditions. The proportion of hatched eggs was compared between weeks of immersion and related to environmental variables. Survival was compared among cohorts and the development rate was related to the mean temperature during development. The results showed that, with few exceptions, egg hatching was over 45% during the winter period. The proportion of hatched eggs was positively associated with immersion temperature, pre-immersion temperature and photoperiod. The immature stages completed the development during the cold season, with a trend toward increased survival of late-hatching cohorts. Survival was 30% at 13.2 degrees C and above 90% at 20 degrees C, whereas the development time at low temperatures was 49.4 d at 13.2 degrees C and 17.7 d at 20 degrees C. The high hatching and survival compared with other studies suggest that the local population might be adapting to winter conditions. The anticipated emergence of adults would be adaptive if they are able to reproduce successfully in the early spring. PMID- 28082638 TI - Nycthemeral Rhythm of Phlebotominae (Diptera: Psychodidae) in a Craggy Region, Transitioning Between the Wetland and the Plateau, Brazil. AB - Recording the nycthemeral rhythm of sand flies allows the evaluation of the daily activity in different ecotypes, the period of greatest activity, and their degree of anthropophily. We investigated the fauna and the rhythm of sand fly activity in an ecotourism region in Mato Grosso do Sul (MS) state, Brazil. Sand flies were captured monthly, using a Shannon trap for 24 h periods between July 2012 and June 2014. We collected 1,815 sand flies, in which Lutzomyia whitmani (=Nyssomyia whitmani, sensu Galati) and Lutzomyia longipalpis were the most abundant species during the dry season, with activity from 5 p.m.-7 a.m. and 6 p.m.-5 a.m., respectively. Both species require particular attention as vectors of Leishmania (Viannia) braziliensis and Leishmania (Leishmania) infantum in several regions of Brazil, including MS. However, Lutzomyia dispar was more anthropophilic, and was most active between January and March, from 5 p.m. to 5 a.m. Lutzomyia misionensis (=Pintomyia misionensis, sensu Galati) was present throughout both years, active from 4 p.m. to 5 a.m. Other species were active from 5 p.m. to 6 a.m. Due to intense tourism in the months that coincide with a high number of vectors for leishmaniases in Piraputanga, it is essential to determine vector monitoring strategies in the area by investigating sand fly rhythm while not neglecting other periods of the year when the insects are present. PMID- 28082639 TI - Host-Seeking Phenology of Ixodes pacificus (Acari: Ixodidae) Nymphs in Northwestern California in Relation to Calendar Week, Woodland Type, and Weather Conditions. AB - Local knowledge of when humans are at elevated risk for exposure to tick vectors of human disease agents is required both for the effective use of personal protection measures to avoid tick bites and for implementation of control measures to suppress host-seeking ticks. Here, we used previously published data on the seasonal density of host-seeking Ixodes pacificus Cooley and Kohls nymphs, the primary vectors of Lyme disease spirochetes in the far western USA, collected across a broad habitat and climate gradient in northwestern California to identify predictors of periods of time within the year when questing nymphal density is elevated. Models based on calendar week alone performed similarly to models based on calendar week and woodland type, or meteorological variables. The most suitable model for a given application will depend on user objectives, timescale of interest, and the geographic extent of predictions. Our models sought not only to identify when seasonal host-seeking activity commences, but also when it diminishes to low levels. Overall, we report a roughly 5-7 month period in Mendocino County during which host-seeking nymphal densities exceed a low threshold value. PMID- 28082640 TI - Amblyomma auricularium (Ixodida: Ixodidae) in Florida: New Hosts and Distribution Records. AB - Previous published evidence for the occurrence of an exotic armadillo tick, Amblyomma auricularium (Conil), in Florida is scant, but we found it is fully established and integrated into the state's tick fauna. We collected 11,192 specimens of this tick from naturalized nine-banded armadillos, Dasypus novemcinctus L., and 14 other species of wild native mammals and birds in Florida, while sampling statewide during 2004 through 2007. In all, we document its specific presence only in 14 contiguous South Florida counties. Moreover, we report the first collections of A. auricularium from the Virginia opossum (Didelphis virginiana Kerr), common raccoon [Procyon lotor (L.)], cotton deermouse [Peromyscus gossypinus (Le Conte)], gray fox [Urocyon cinereoargenteus (Schreber)], eastern spotted skunk [Spilogale putorius (L.)], and white-tailed deer [Odocoileus virginianus (Zimmerman)]. For the first time on birds, we report the collection of this tick from the broad-winged hawk [Buteo platypterus (Vieillot)], northern cardinal [Cardinalis cardinalis (L.)], Carolina wren [Thryothorus ludovicianus (Latham)], gray catbird [Dumetella carolinensis (L.)], and yellow-rumped warbler [Setophaga coronata (L.)]. In addition, we report unattached A. auricularium collected from humans for the first time, and additional new collections from domestic dogs, Canis lupus familiaris L. PMID- 28082641 TI - Development of Aedes albopictus (Diptera: Culicidae) Larvae Under Different Laboratory Conditions. AB - Critical to successful application of the sterile insect technique against Aedes albopictus (Skuse) is the development of an efficient and standardized rearing protocol to be employed in the mass production system. In this study, several life history traits of Ae. albopictus were analyzed to identify upper and lower thresholds of larval density and diet concentration. Survival to pupation, time to pupation, and sex ratio were evaluated under a range of larval densities (0.5 5 larvae/ml) and food levels (0.05-1.6 mg/larva/d) using two larval diets (one locally developed; one developed by the FAO/IAEA). The larvae reared at 28 degrees C, at a density of 2 larvae/ml and receiving a food dose equal to 0.6 mg/larva/d of a diet consisting of 50% tuna meal, 50% bovine liver powder (the FAO/IAEA diet), and, as an additive, 0.2 g of Vitamin Mix per 100 ml of diet solution, developed in 5 d and had 90% survival to the pupal stage. With this rearing regime male pupae production 24 h after the onset of pupation was the highest; these pupae were ~94% male. PMID- 28082642 TI - Evaluation of Clove Oil, Icaridin, and Transfluthrin for Spatial Repellent Effects in Three Tests Systems Against the Aedes aegypti (Diptera: Culicidae). AB - One essential oil (clove oil), one skin repellent (icaridin), and one insecticide (transfluthrin) were tested for spatial repellent effects against non-blood-fed female Aedes aegypti (L.) mosquitoes. The compounds were tested in acetone dilution series using a Y-olfactometer, a double cage system, and a double room system. All compounds exhibited spatial repellent effects at certain concentrations. Clove oil required relative high dosages to cause high effects (Y olfactometer 6 mg, double cage 60 mg, and double room 1,200 mg). The dosages to achieve comparable results with icaridin were lower (Y-olfactometer and double cage 1 mg, and double room 150 mg). For transfluthrin, the equivalent dosages were lower again (Y-olfactometer 0.003 mg, double cage 0.03 mg, and double room 0.1 mg). Furthermore, these results reveal a correlation between the size of the test system and the effective dosage. Averaged for the three compounds, the quantity for the double room was 21-fold higher than for the double cage, which required again a 9-fold higher dosage than the Y-olfactometer. An establishment of a screening cascade is discussed starting with the Y-olfactometer (high throughput rate), followed by the double cage system and ending with the double room system as the most nearest to practical conditions. Furthermore, the testing of existing repellent products to validate the double room test, the role of sublethal dosages concerning insecticides including possible upcoming of resistance after exposure, the delayed action and impact on blood feeding and oviposition are exemplified. PMID- 28082643 TI - Toxicity and Larvicidal Activity of Podophyllum-Based Lignans Against Aedes aegypti (Diptera: Culicidae). AB - Aedes aegypti L. (Diptera: Culicidae) is a mosquito species that has adapted to urban environments and is the main vector of dengue viruses. Because of the increasing incidence of dengue, a more environmentally acceptable insecticide needs to be found. Natural products have been and continue to be an important source of leading compounds that can be modified in order to develop new drugs. The lignan family of natural products includes compounds with a diverse spectrum of biological activity. Podophyllotoxin and its related lignans represent an exciting class of natural products that can be targeted at different types of biological activity and are therefore worth exploring further. This study had the aim of evaluating the larvicidal activity of an ethanolic extract from the rhizomes and roots of Podophyllum hexandrum (PM-3) and its isolated lignans, podophyllotoxone (1) and desoxypodophyllotoxin (2), on the larvae of the mosquito vector Ae. aegypti. The PM-3 extract and the compounds (1) and (2) were dissolved in a mixture of acetone and dimethylsulfoxide at final concentrations of 1, 10, 30, 50, 100, and 200 MUg/ml. After dilution, the solutions were applied (MUg/ml) to the larvae-rearing medium. Overall, the ethanolic extract from the rhizomes and roots of P. hexandrum and the compounds (1) and (2) showed larvicidal activity against the larvae of Ae. aegypti According to the results from this study, it can be concluded that podophyllotoxone (1) and desoxypodophyllotoxin (2) exhibited significant toxicity toward Ae. aegypti larvae. PMID- 28082644 TI - Ovicidal Efficacy of Abametapir Against Eggs of Human Head and Body Lice (Anoplura: Pediculidae). AB - Studies were undertaken to determine the ovicidal efficacy of 5,5'-dimethyl-2,2' bipyridyl (abametapir) against eggs of both human head and body lice. Head lice eggs of different ages (0-2, 3-5, and 6-8-d-old eggs) were exposed to varying concentrations of abametapir in isopropanol and concentration-dependent response relationships established based on egg hatch. One hundred percent of all abametapir-treated eggs failed to hatch at the 0.74 and 0.55% concentrations, whereas 100% of 6-8-d-old head louse eggs failed to hatch only at the 0.74% concentration. The LC50 value for abametapir varied, depending on the age of the head lice eggs, from ~0.10% recorded for 0-2-d-old eggs and increasing to ~0.15% for 6-8-d-old eggs. Abametapir was also evaluated once formulated into a lotion referred to as Xeglyze (0.74% abametapir) and serial dilutions made. Ovicidal efficacies were determined against head lice eggs 0-8-d-old. Results indicated 100% ovicidal activity at the 0.74, 0.55, 0.37, and 0.18% concentrations. Additional studies undertaken using body lice eggs also demonstrated that abametapir was 100% ovicidal against eggs of all ages when evaluated at a concentration of 0.37 and 0.55%. Given that ovicidal activity is a critical component of any effective treatment regime for louse control, the data presented in this study clearly demonstrate the ability of abametapir to inhibit hatching of both head and body louse eggs as assessed in vitro. PMID- 28082645 TI - Selected Insecticide Delivery Devices for Management of Horn Flies (Haematobia irritans) (Diptera: Muscidae) on Beef Cattle. AB - The horn fly, Haematobia irritans (L.) (Diptera: Muscidae), is one of the most important pests of the beef cattle industry. Horn fly adults are blood feeders that remain in constant contact with cattle, providing management opportunities via insecticide-impregnated ear tags. Controlling horn flies in the United States is time consuming and costly, but failure to implement management can lead to weight loss and decreased weight gain of calves and yearlings. In the past decade, new chemical combinations have been impregnated into ear tags for pest management. The objectives of this project were to 1) evaluate the efficacy of ear tags against horn fly populations and 2) determine if reduced fly density results in economic return. During 2013, data were compiled by insecticide class; treated cows averaged fly reductions of 198 (s = 38.91; n = 3) for macrocyclic lactone treatments, 175 (s = 62.74; n = 4) for pyrethroid treatments, and 174 (s = 35.28; n = 8) for organophosphate treatments compared with untreated animals (214; s = 50.38; n = 9). During 2014, mean fly reductions were 187 (s = 14.15; n = 4) for macrocyclic lactone, 147 (s = 61.41; n = 13) for pyrethroid, and 143 (s = 77.16; n = 8) for organophosphate treatments relative to the untreated (200; s = 99.83; n = 14). A novel technology, the VetGun application system, tested in 2014, resulted in fly reductions (121 +/-, n = 4), but means were not statistically significant from the control (200; s = 99.83; n = 14). Treatment of cattle with ear tags significantly reduced horn fly numbers compared with untreated cattle. PMID- 28082646 TI - Excito-Repellency of Citrus hystrix DC Leaf and Peel Essential Oils Against Aedes aegypti and Anopheles minimus (Diptera: Culicidae), Vectors of Human Pathogens. AB - The essential oils of kaffir lime (Citrus hystrix DC.) at four different concentrations (0.5, 1.0, 2.5, and 5.0% v/v) were studied for their repellency, excitation, and knockdown properties against laboratory strains of Aedes aegypti (L.) and Anopheles minimus Theobald using an excito-repellency test system. Both contact and noncontact escape responses to leaf- and peel-derived kaffir lime oils were observed. Comparing unadjusted escape responses for An. minimus, leaf oil had strong combined irritant and repellent activity responses at 1-5% concentrations (90.0-96.4% escape) and the strongest spatial repellent activity at 1% and 2% (85.9% and 87.2% escape, respectively). The peel oil exhibited good excitation with repellency at concentrations of 2.5% (89.8% escape) and 5% (96.28% escape), while concentrations 1-5% showed more moderate repellent activity against An. minimus. For Ae. aegypti, 2.5% leaf oil produced the greatest response for both contact (56.1% escape) and noncontact (63.3% escape) trials, while 2.5% produced the strongest response among all concentrations of peel oil, with 46.5% escape. However, after adjusting the contact trial escape (a measure of combined excitation and repellency), the estimated escape due to contact alone was a much weaker response than spatial repellency for both species. Knockdown responses above 50% were only observed in Ae. aegypti exposed to 5% leaf oil. Kaffir lime oils were more active against An. minimus than Ae. aegypti mosquitoes. There were statistically significant differences between leaf (more active) and peel oils at each concentration against An. minimus in contact and noncontact trials, except at the highest (5%) concentration. PMID- 28082647 TI - Molecular Detection of Leishmania DNA in Wild-Caught Phlebotomine Sand Flies (Diptera: Psychodidae) From a Cave in the State of Minas Gerais, Brazil. AB - Leishmania spp. are distributed throughout the world, and different species are associated with varying degrees of disease severity. In Brazil, Leishmania transmission involves several species of phlebotomine sand flies that are closely associated with different parasites and reservoirs, and thereby giving rise to different transmission cycles. Infection occurs during the bloodmeals of sand flies obtained from a variety of wild and domestic animals, and sometimes from humans. The present study focused on detection of Leishmania DNA in phlebotomine sand flies from a cave in the state of Minas Gerais. Detection of Leishmania in female sand flies was performed with ITS1 PCR-RFLP (internal transcribed spacer 1) using HaeIII enzyme and genetic sequencing for SSUrRNA target. The survey of Leishmania DNA was carried out on 232 pools and the parasite DNA was detected in four: one pool of Lutzomyia cavernicola (Costa Lima, 1932), infected with Le. infantum (ITS1 PCR-RFLP), two pools of Evandromyia sallesi (Galvao & Coutinho, 1939), both infected with Leishmania braziliensis complex (SSUrRNA genetic sequencing analysis), and one pool of Sciopemyia sordellii (Shannon & Del Ponte, 1927), infected with subgenus Leishmania (SSUrRNA genetic sequencing analysis). The present study identified the species for Leishmania DNA detected in four pools of sand flies, all of which were captured inside the cave. These results represent the first molecular detection of Lu cavernicola with Le infantum DNA, Sc sordellii with subgenus Leishmania DNA, and Ev sallesi with Leishmania braziliensis complex DNA. The infection rate in females captured for this study was 0.17%. PMID- 28082648 TI - Aedes aegypti (Diptera: Culicidae) Longevity and Differential Emergence of Dengue Fever in Two Cities in Sonora, Mexico. AB - Dengue virus, primarily transmitted by the Aedes aegypti (L.) mosquito, has rapidly expanded in geographic extent over the past several decades. In some areas, however, dengue fever has not emerged despite established Ae. aegypti populations. The reasons for this are unclear and have sometimes been attributed to socio-economic differences. In 2013 we compared Ae. aegypti adult density and population age structure between two cities in Sonora, Mexico: Hermosillo, which has regular seasonal dengue virus transmission, and Nogales, which has minimal transmission. Larval and pupal abundance was greater in Nogales, and adult density was only higher in Hermosillo during September. Population age structure, however, was consistently older in Hermosillo. This difference in longevity may have been one factor that limited dengue virus transmission in Nogales in 2013, as a smaller proportion of Ae. aegypti females survived past the extrinsic incubation period. PMID- 28082649 TI - Molecular and Parasitological Survey of Ovine Piroplasmosis, Including the First Report of Theileria annulata (Apicomplexa: Theileridae) in Sheep and Goats from Turkey. AB - Blood and tick samples were collected from 333 apparently healthy sheep and 257 goats as well as 10 sheep exhibiting clinical signs of babesiosis in Adana, Gaziantep, and Adiyaman Provinces in southern Turkey. Fully engorged female ticks were selected and maintained in an incubator until they oviposited. The tick carcasses and their egg masses were examined. Piroplasms compatible with Babesia spp. and Theileria spp. were observed in both symptomatic and asymptomatic small ruminants. Genomic DNA isolates from blood of ovine, tick samples, and egg masses were screened for piroplasms by utilizing 18S rRNA polymerase chain reaction and reverse line blotting (RLB) assays. Parasitemia ranged from 0.01% to 5.6% of erythrocytes in clinical cases. RLB showed positivity in 239 (40.5%) of the sampled apparently healthy sheep and goats and revealed the presence of three Theileria and one Babesia species. Theileria ovis was the most prevalent (35.4%), followed by Babesia ovis (5.4%), Theileria annulata (3.9%), and Theileria sp. MK (0.3%). Thirty-two small ruminants infected with T. ovis were also infected with B. ovis One animal infected with T. ovis was also infected with Theileria sp. MK. Ticks were identified as Rhipicephalus bursa, Rhipicephalus turanicus, Hyalomma excavatum, Haemaphysalis parva, and Hyalomma anatolicum Egg masses of two female R. bursa carcasses were infected with B. ovis This is the first report of theileriosis caused by T. annulata in sheep and goats in Turkey. PMID- 28082650 TI - Comparison of Adult Mosquito Black-Light and Light-Emitting Diode Traps at Three Cowsheds Located in Malaria-Endemic Areas of the Republic of Korea. AB - Adult mosquito surveillance and field trials evaluated selected commercially available ultraviolet black-light (BL) and light-emitting diode (LED) traps at three sites where vivax malaria is endemic from May to October 2015 in northwestern Republic of Korea. Collections totaled 283,929 adult mosquitoes (280,355 [98.74%] females and 3,574 [1.26%] males) comprising 17 species (including six members of the Anopheles Hyrcanus Group) belonging to six genera. The four most predominant female species collected were Aedes vexans nipponii (Theobald) (83.84%), followed by Anopheles Hyrcanus Group (13.66%), Culex pipiens Group (1.67%), and Culex tritaeniorhynchus Giles (0.54%). Overall, LED traps (188,125) collected significantly more female mosquitoes compared with BL traps (92,230; P = 0.0001, P < 0.05). Results from these field evaluations significantly enhance vector and disease surveillance efforts, especially for the primary vectors of malaria (Anopheles Hyrcanus Group) and Japanese encephalitis (Cx. tritaeniorhynchus). PMID- 28082651 TI - Aspects on the Ecology of Phlebotomine Sand Flies (Diptera: Psychodidae) From Guarai, State of Tocantins, Brazil, Endemic Area for American Cutaneous Leishmaniasis. AB - In Brazil, American cutaneous leishmaniasis (ACL) ecology involves a diversity of Leishmania species transmitted by different sand fly species. Workers involved in agricultural activities are those mainly affected by ACL in some regions from Tocantins State (TO), Brazil, where the disease can be established in new settlements. The objective of this study was to examine the seasonal and hourly frequency of sand fly species, focusing on the potential vectors of ACL, in a settlement in Guarai (TO), an ACL transmission area. Sand flies were captured in forested area close to Pedra Branca Agricultural Project settlement, from March 2006 until December 2007, using Shannon trap. Monthly captures were made from 06:00 p.m. to 10:00 p.m., and 24-h captures were done twice per semester, from 06:00 a.m. to 06:00 a.m. A total of 10,089 specimens from 30 species were identified. Psychodopygus complexus Mangabeira, Psychodopygus llanosmartinsi Fraiha & Ward, and Nyssomyia antunesi Coutinho were the most abundant species. Nyssomyia antunesi was more frequent during the dry period, whereas Ps. complexus and Ps. llanosmartinsi had high frequencies during the rainy season. Precipitation was positively correlated with Ps. complexus and Ps. llanosmartinsi abundance, and negatively correlated with Ny. antunesi During 24-h captures, the majority of specimens were captured during the night followed by a decrease at dawn. The behavior and previous finding of natural infection by Leishmania (Viannia) braziliensis of Ps. complexus led us to the conclusion that this species can be a potential vector of L. (V.) braziliensis during the rainy season in Guarai. PMID- 28082652 TI - Attractive Toxic Sugar Bait (ATSB) Mixed With Pyriproxyfen for Control of Larval Aedes albopictus (Diptera: Culicidae) Through Fecal Deposits of Adult Mosquitoes. AB - Studies were conducted to determine if pyriproxyfen, an insect growth regulator (IGR) added to attractive toxic sugar baits (ATSBs) and ingested by adult Aedes albopictus (Skuse), could be fecally disseminated into water to inhibit emergence of mosquitoes (EI). Experimental treatments consisted of four dilutions of pyriproxyfen (0.5, 1, 5, and 10 ppb) in ATSB, with attractive sugar bait (ASB) serving as the negative control. To ensure no tarsal transfer of the IGR, the experimental treatments were dispensed in collagen sausages. Mosquito excrement was collected on card stock at the bottom of the mosquito cages at 1, 4, 6, and 8 h during the study. There were no differences between the EI times at which the fecal cards were collected (F19,88 = 1.8, P = 0.1592). The highest dilution of pyriproxyfen in ATSB (10 ppb) inhibited mosquito emergence in the most amounts (57%), as compared with the EI of other pyriproxyfen dilutions: 0.5 ppb = 42%, 1 ppb = 34%, and 5 ppb = 46% (F19,88 = 1.8, P = 0.1592). This study demonstrates that pyriproxyfen can be fecally disseminated into water and control larvae through adult mosquito ingestion and excretion of pyriproxyfen in ASB. PMID- 28082654 TI - Presence of Borrelia turdi and Borrelia valaisiana (Spirochaetales: Spirochaetaceae) in Ticks Removed From Birds in the North of Spain, 2009-2011. AB - The genus Borrelia includes species responsible for severe human diseases such as Lyme disease. Birds are involved in their epidemiology as dispersers of infected ticks (Ixodida: Ixodidae) and as reservoirs or amplifiers of the bacterium. Herein, the presence of Borrelia burgdorferi sensu lato (s.l.) Johnson, Schmid, Hyde, Steigerwalt & Brenner in 336 ticks collected from birds in the north of Spain from 2009 to 2011 was investigated. Nucleic acid extracts from 174 Ixodes frontalis (Panzer), 108 Haemaphysalis punctata Canestrini & Fanzango, 34 Hyalomma marginatum Koch, 17 Ixodes ricinus (L.), and 3 Ixodes spp. were screened for the presence of B. burgdorferi s.l. by PCR. Borrelia turdi was detected in 22 I. frontalis, 2 H. punctata, and 2 I. ricinus Additionally, 1 I. frontalis and 1 H. punctata were found to be infected with the human pathogen Borrelia valaisiana Moreover, 3 I. frontalis showed coinfection with both Borrelia species. This study corroborates the presence of B. turdi and B. valaisiana in ticks from birds in the north of Spain. The presence of these bacteria in larval specimens could suggest the role of birds as their reservoirs, or the occurrence of the cofeeding phenomenon. In addition, the detection of B. turdi and B. valaisiana in H. punctata and I. frontalis ticks, respectively, is reported for the first time. PMID- 28082653 TI - Comparison of Vector Efficiency of Ixodes scapularis (Acari: Ixodidae) From the Northeast and Upper Midwest of the United States for the Lyme Disease Spirochete Borrelia mayonii. AB - Borrelia mayonii, a recently recognized species within the Borrelia burgdorferi sensu lato complex, has been detected in host-seeking Ixodes scapularis Say ticks and found to be associated with Lyme disease in the Upper Midwest. This spirochete has, to date, not been documented from the Northeast, but we previously demonstrated that I. scapularis ticks originating from Connecticut are capable of serving as a vector of B. mayonii In this follow-up study, we compared the vector efficiency for B. mayonii (strain MN14-1420) of I. scapularis ticks originating from Minnesota in the Upper Midwest and Connecticut in the Northeast. CD-1 outbred white mice previously infected with B. mayonii via tick bite were exposed to simultaneous feeding by Minnesota and Connecticut larvae contained within separate feeding capsules. We found no difference in the ability of Minnesota and Connecticut larvae to acquire B. mayonii from infected mice and pass spirochetes to the nymphal stage (overall nymphal infection rates of 11.6 and 13.3%, respectively). Moreover, the efficiency of transmission of B. mayonii by single infected nymphs was similar for the Minnesota and Connecticut ticks (33 and 44%, respectively). We conclude that the examined I. scapularis ticks from the Upper Midwest and Northeast did not differ in their efficiency as vectors for B. mayonii. PMID- 28082655 TI - Erratum. PMID- 28082656 TI - Retraction. PMID- 28082661 TI - RHDV2 overcoming RHDV immunity in wild rabbits (Oryctolagus cuniculus) in Australia. PMID- 28082662 TI - Sustained effect of couples' HIV counselling and testing on risk reduction among Zambian HIV serodiscordant couples. AB - BACKGROUND: We present temporal trends in self-reported and biological markers of unprotected sex and sex with concurrent partners in discordant couples receiving couples' voluntary HIV counselling and testing (CVCT). METHODS: Heterosexual Zambian HIV-serodiscordant couples were enrolled into longitudinal follow-up in an open cohort (1994-2012). Multivariable Anderson-Gill models explored predictors of self-report and biological indicators of unprotected sex within (including sperm on a vaginal swab, incident pregnancy or incident linked HIV infection) and outside (including self-report, STI and unlinked HIV infection) the union. Measures of secular trends in baseline measures were also examined. RESULTS: At enrolment of 3049 couples, men were 35 years old on average, women were 29 years, and couples had been together for an average of 7 years. M+F- couples reported an average of 16.6 unprotected sex acts in the 3 months prior to enrolment (pre-CVCT), dropping to 5.3 in the >0-3 month interval, and 2.0 in >6 month intervals (p-trend <0.001). Corresponding values for M-F+ couples were 22.4 unprotected sex acts in the 3 months prior enrolment, dropping to 5.2 in the >0-3 month interval, and 3.1 in >6 month intervals (p-trend <0.001). Significant reductions in self-report and biological markers of outside partners were also noted. Predictors of unprotected sex between study partners after CVCT included prevalent pregnancy (adjusted HR, aHR=1.6-1.9); HIV+ men being circumcised (aHR=1.2); and HIV- women reporting sex with outside partners (aHR=1.3), alcohol (aHR=1.2), injectable (aHR=1.4) or oral (aHR=1.4) contraception use. Fertility intentions were also predictive of unprotected sex (aHR=1.2-1.4). Secular trends indicated steady declines in reported outside partners and STIs. CONCLUSION: Reductions in self-reported unprotected sex after CVCT were substantial and sustained. Reinforced risk-reduction counselling in pregnant couples, couples desiring children and couples with HIV- women having outside partners or using alcohol or injectable or oral contraception are indicated. PMID- 28082663 TI - Clinical and Epidemiological Characteristics of Burkitt Lymphomas in Pediatric Patients from Two Defined Socioeconomic Regions in Mexico. AB - We analyzed clinical and epidemiological characteristics of Burkitt lymphoma (BL) in two defined socioeconomic regions in Mexico: high socioeconomic region (HSER; with two political jurisdictions) and low socioeconomic region (LSER; with three jurisdictions). Of the 63 cases registered in the Childhood Cancer Registry (1996 2013), 45 (71.4%) were from HSER and 18 (28.6%) from LSER. The incidence was higher in the LSER (3.1 vs. 1.4 cases per million children/year). The sporadic form and Stages III/IV predominated in both regions. Only one post-renal transplant (HSER) was found. The male/female ratio was higher in the LSER (5.0 vs. 1.4). The peak incidence was in the 1-4 age group for LSER, and in the 5-9 age group for HSER. This difference in the sporadic BL by socioeconomic regions may be related to different exposure factors. PMID- 28082664 TI - Prevalence of Hypertension in Nigerian Children and Adolescents: A Systematic Review and Trend Analysis of Data from the Past Four Decades. AB - Despite four decades of research, there is no systematic review and trend analysis on paediatric (pre)hypertension in Nigeria. This article reviewed data from cross-sectional studies on the subject. From the initial 9334 articles identified, 30 studies that met the inclusion criteria were systematically reviewed. Data from studies that defined hypertension as blood pressure (BP) greater than the 95th percentile for age, height and sex gave a prevalence of 8.2% [95% confidence interval (CI): 3.6-28.2%] for prehypertension and 5.1% (95% CI: 2.9-8.6%) for hypertension. For studies that defined hypertension as BP greater than 2 SD points from the mean of the population, the prevalence of hypertension was found to be 4.0% (95% CI: 2.8-5.7%). A significant negative trend (Z = -0.89; alpha < 0.01) with small magnitude (Q = -0.019; 95% CI: -0.070 to 0.028) was found for hypertension in the reviewed population. The prevalence of (pre)hypertension in Nigerian children and adolescents is moderate but has slightly declined over time. PMID- 28082665 TI - Chronic Pruritus in an 18-Month-Old Male Infant Due to Anicteric Cholestasis. AB - An 18-month-old male infant was referred to us with pruritus from 6 months of age. He was being managed as atopic eczema with emollients and antihistamines without any response to treatment. On examination, he was found to have extensive scratch marks, mild hepatomegaly and no icterus. Blood investigations were suggestive of anicteric cholestatic liver disease. Liver biopsy was suggestive of progressive familial intrahepatic cholestasis type 3. He showed symptomatic improvement after starting ursodeoxycholic acid and fat-soluble vitamins and is under follow up. PMID- 28082666 TI - Isoniazid Preventive Therapy among Children Living with Tuberculosis Patients: Is It Working? A Mixed-Method Study from Bhopal, India. AB - Objective: We assessed uptake of isoniazid preventive therapy (IPT) among child contacts of smear-positive tuberculosis (TB) patients and its implementation challenges from healthcare providers' and parents' perspectives in Bhopal, India. Methods: A mixed-method study design: quantitative phase (review of programme records and house-to-house survey of smear-positive TB patients) followed by qualitative phase (interviews of healthcare providers and parents). Results: Of 59 child contacts (<6 years) of 129 index patients, 51 were contacted. Among them, 19 of 51 (37%) were screened for TB and one had TB. Only 11 of 50 (22%) children were started and 10 of 50 (20%) completed IPT. Content analysis of interviews revealed lack of awareness, risk perception among parents, cumbersome screening process, isoniazid stock-outs, inadequate knowledge among healthcare providers and poor programmatic monitoring as main barriers to IPT implementation. Conclusion: National TB programme should counsel parents, train healthcare providers, simplify screening procedures, ensure regular drug supply and introduce an indicator to strengthen monitoring and uptake of IPT. PMID- 28082667 TI - Weight-for-Height Z Score and Mid-Upper Arm Circumference as Predictors of Mortality in Children with Severe Acute Malnutrition. AB - Background: Mortality associated with severe acute malnutrition (SAM) could be reduced by screening malnourished children for those most vulnerable to death. We compared the weight-for-height Z score (WHZ) and mid-upper arm circumference (MUAC) as predictors of mortality in children with SAM. Methods: We conducted a retrospective study spanning over 8 years, using records of children aged 6-59 months, hospitalized for SAM and discharged alive or who died during hospitalization. Results: Area under the curve was greater for MUAC [0.809 (95% CI, 0.709-0.911, p = 0.001)] than WHZ [0.649 (95% CI, 0.524-0.774, p = 0.032)]. MUAC predicted death better [sensitivity: 95.5%, specificity: 25.0%, positive likelihood ratio (PLR): 1.27, negative likelihood ratio (NLR): 0.18] than WHZ (sensitivity: 86.4%, specificity: 21.4%, PLR: 1.10, NLR: 0.64). Best MUAC and WHZ cut-offs for predicting death (10.3 cm and -4, respectively) were most accurate in infants aged <12 months, the former being more accurate. Conclusion: MUAC predicts death better than WHZ in children with SAM. PMID- 28082668 TI - BE-FAST (Balance, Eyes, Face, Arm, Speech, Time): Reducing the Proportion of Strokes Missed Using the FAST Mnemonic. AB - BACKGROUND AND PURPOSE: The FAST algorithm (Face, Arm, Speech, Time) helps identify persons having an acute stroke. We determined the proportion of patients with acute ischemic stroke not captured by FAST and evaluated a revised mnemonic. METHODS: Records of all patients admitted to the University of Kentucky Stroke Center between January and December 2014 with a discharge International Classification of Diseases, Ninth Revision, Clinical Modification code for acute ischemic stroke were reviewed. Those misclassified, having missing National Institutes of Health Stroke Scale data, or were comatose or intubated were excluded. Presenting symptoms, demographics, and examination findings based on the National Institutes of Health Stroke Scale data were abstracted. RESULTS: Of 858 consecutive records identified, 736 met inclusion criteria; 14.1% did not have any FAST symptoms at presentation. Of these, 42% had gait imbalance or leg weakness, 40% visual symptoms, and 70% either symptom. With their addition, the proportion of stroke patients not identified was reduced to 4.4% (P<0.0001). In a sensitivity analysis, if face weakness, arm weakness, or speech impairment on admission examination were considered in addition to a history of FAST symptoms, the proportion missed was reduced to 9.9% (P=0.0010). The proportion of stroke patients not identified was also reduced (2.6%) with the addition of a history of gait imbalance/leg weakness or visual symptoms (P<0.0001). CONCLUSIONS: Of patients with ischemic stroke with deficits potentially amenable to acute intervention, 14% are not identified using FAST. The inclusion of gait/leg and visual symptoms leads to a reduction in missed strokes. If validated in a prospective study, a revision of public educational programs may be warranted. PMID- 28082669 TI - Stroke as the Initial Manifestation of Atrial Fibrillation: The Framingham Heart Study. AB - BACKGROUND AND PURPOSE: To prevent strokes that may occur as the first manifestation of atrial fibrillation (AF), screening programs have been proposed to identify patients with undiagnosed AF who may be eligible for treatment with anticoagulation. However, the frequency with which patients with AF present with stroke as the initial manifestation of the arrhythmia is unknown. METHODS: We estimated the frequency with which AF may present as a stroke in 1809 community based Framingham Heart Study participants with first-detected AF and without previous strokes, by tabulating the frequencies of strokes occurring on the same day, within 30 days before, 90 days before, and 365 days before first-detected AF. Using previously reported AF incidence rates, we estimated the incidence of strokes that may represent the initial manifestation of AF. RESULTS: We observed 87 strokes that occurred <=1 year before AF detection, corresponding to 1.7% on the same day, 3.4% within 30 days before, 3.7% within 90 days before, and 4.8% <=1 year before AF detection. We estimated that strokes may present as the initial manifestation of AF at a rate of 2 to 5 per 10 000 person-years, in both men and women. CONCLUSIONS: We observed that stroke is an uncommon but measureable presenting feature of AF. Our data imply that emphasizing cost effectiveness of population-wide AF-screening efforts will be important given the relative infrequency with which stroke represents the initial manifestation of AF. PMID- 28082670 TI - New Insight Into the Pathogenesis of Cerebral Small-Vessel Diseases. PMID- 28082671 TI - Telemedicine Can Replace the Neurologist on a Mobile Stroke Unit. AB - BACKGROUND AND PURPOSE: The BEST-MSU study (Benefits of Stroke Treatment Delivered Using a Mobile Stroke Unit) is a comparative effectiveness trial in patients randomized to mobile stroke unit or standard management. A substudy tested interrater agreement for tissue-type plasminogen activator eligibility between a telemedicine vascular neurologist and onboard vascular neurologist. METHODS: On scene, both the telemedicine vascular neurologist and onboard vascular neurologist independently evaluated the patient, documenting their tissue-type plasminogen activator treatment decision, National Institutes of Health Stroke Scale score, and computed tomographic interpretation. Agreement was determined using Cohen kappa statistic. Telemedicine-related technical failures that impeded remote assessment were recorded. RESULTS: Simultaneous and independent telemedicine vascular neurologist and onboard vascular neurologist assessment was attempted in 174 patients. In 4 patients (2%), the telemedicine vascular neurologist could not make a decision because of technical problems. The telemedicine vascular neurologist agreed with the onboard vascular neurologist on 88% of evaluations (kappa=0.73). CONCLUSIONS: Remote telemedicine vascular neurologist assessment is reliable and accurate, supporting either telemedicine vascular neurologist or onboard vascular neurologist assessment on our mobile stroke unit. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02190500. PMID- 28082672 TI - NF-kappaB Signaling Activation Induced by Chloroquine Requires Autophagosome, p62 Protein, and c-Jun N-terminal Kinase (JNK) Signaling and Promotes Tumor Cell Resistance. AB - Macroautophagy (hereafter autophagy) is a catabolic cellular self-eating process by which unwanted organelles or proteins are delivered to lysosomes for degradation through autophagosomes. Although the role of autophagy in cancer has been shown to be context-dependent, the role of autophagy in tumor cell survival has attracted great interest in targeting autophagy for cancer therapy. One family of potential autophagy blockers is the quinoline-derived antimalarial family, including chloroquine (CQ). However, the molecular basis for tumor cell response to CQ remains poorly understood. We show here that in both squamous cell carcinoma cells and melanoma tumor cells, CQ induced NF-kappaB activation and the expression of its target genes HIF-1alpha, IL-8, BCL-2, and BCL-XL through the accumulation of autophagosomes, p62, and JNK signaling. The activation of NF kappaB further increased p62 gene expression. Either genetic knockdown of p62 or inhibition of NF-kappaB sensitized tumor cells to CQ, resulting in increased apoptotic cell death following treatment. Our findings provide new molecular insights into the CQ response in tumor cells and CQ resistance in cancer therapy. These findings may facilitate development of improved therapeutic strategies by targeting the p62/NF-kappaB pathway. PMID- 28082673 TI - Omecamtiv Mecarbil Enhances the Duty Ratio of Human beta-Cardiac Myosin Resulting in Increased Calcium Sensitivity and Slowed Force Development in Cardiac Muscle. AB - The small molecule drug omecamtiv mecarbil (OM) specifically targets cardiac muscle myosin and is known to enhance cardiac muscle performance, yet its impact on human cardiac myosin motor function is unclear. We expressed and purified human beta-cardiac myosin subfragment 1 (M2beta-S1) containing a C-terminal Avi tag. We demonstrate that the maximum actin-activated ATPase activity of M2beta-S1 is slowed more than 4-fold in the presence of OM, whereas the actin concentration required for half-maximal ATPase was reduced dramatically (30-fold). We find OM does not change the overall actin affinity. Transient kinetic experiments suggest that there are two kinetic pathways in the presence of OM. The dominant pathway results in a slow transition between actomyosin.ADP states and increases the time myosin is strongly bound to actin. However, OM also traps a population of myosin heads in a weak actin affinity state with slow product release. We demonstrate that OM can reduce the actin sliding velocity more than 100-fold in the in vitro motility assay. The ionic strength dependence of in vitro motility suggests the inhibition may be at least partially due to drag forces from weakly attached myosin heads. OM causes an increase in duty ratio examined in the motility assay. Experiments with permeabilized human myocardium demonstrate that OM increases calcium sensitivity and slows force development (ktr) in a concentration dependent manner, whereas the maximally activated force is unchanged. We propose that OM increases the myosin duty ratio, which results in enhanced calcium sensitivity but slower force development in human myocardium. PMID- 28082674 TI - Cdx2 Regulates Gene Expression through Recruitment of Brg1-associated Switch Sucrose Non-fermentable (SWI-SNF) Chromatin Remodeling Activity. AB - The packaging of genomic DNA into nucleosomes creates a barrier to transcription that can be relieved through ATP-dependent chromatin remodeling via complexes such as the switch-sucrose non-fermentable (SWI-SNF) chromatin remodeling complex. The SWI-SNF complex remodels chromatin via conformational or positional changes of nucleosomes, thereby altering the access of transcriptional machinery to target genes. The SWI-SNF complex has limited ability to bind to sequence specific elements, and, therefore, its recruitment to target loci is believed to require interaction with DNA-associated transcription factors. The Cdx family of homeodomain transcript ion factors (Cdx1, Cdx2, and Cdx4) are essential for a number of developmental programs in the mouse. Cdx1 and Cdx2 also regulate intestinal homeostasis throughout life. Although a number of Cdx target genes have been identified, the basis by which Cdx members impact their transcription is poorly understood. We have found that Cdx members interact with the SWI-SNF complex and make direct contact with Brg1, a catalytic member of SWI-SNF. Both Cdx2 and Brg1 co-occupy a number of Cdx target genes, and both factors are necessary for transcriptional regulation of such targets. Finally, Cdx2 and Brg1 occupancy occurs coincident with chromatin remodeling at some of these loci. Taken together, our findings suggest that Cdx transcription factors regulate target gene expression, in part, through recruitment of Brg1-associated SWI-SNF chromatin remodeling activity. PMID- 28082675 TI - A Single Point Mutation Resulting in Cadherin Mislocalization Underpins Resistance against Bacillus thuringiensis Toxin in Cotton Bollworm. AB - Transgenic plants that produce Bacillus thuringiensis (Bt) crystalline (Cry) toxins are cultivated worldwide to control insect pests. Resistance to B. thuringiensis toxins threatens this technology, and although different resistance mechanisms have been identified, some have not been completely elucidated. To gain new insights into these mechanisms, we performed multiple back-crossing from a 3000-fold Cry1Ac-resistant BtR strain from cotton bollworm (Helicoverpa armigera), isolating a 516-fold Cry1Ac-resistant strain (96CAD). Cry1Ac resistance in 96CAD was tightly linked to a mutant cadherin allele (mHaCad) that contained 35 amino acid substitutions compared with HaCad from a susceptible strain (96S). We observed significantly reduced levels of the mHaCad protein on the surface of the midgut epithelium in 96CAD as compared with 96S. Expression of both cadherin alleles from 96CAD and 96S in insect cells and immunofluorescence localization in insect midgut tissue sections showed that the HaCAD protein from 96S localizes on the cell membrane, whereas the mutant 96CAD-mHaCad was retained in the endoplasmic reticulum (ER). Mapping of the mutations identified a D172G substitution mainly responsible for cadherin mislocalization. Our finding of a mutation affecting membrane receptor trafficking represents an unusual and previously unrecognized B. thuringiensis resistance mechanism. PMID- 28082676 TI - Binding of Nitric Oxide in CDGSH-type [2Fe-2S] Clusters of the Human Mitochondrial Protein Miner2. AB - Iron-sulfur proteins are among the primary targets of nitric oxide in cells. Previous studies have shown that iron-sulfur clusters hosted by cysteine residues in proteins are readily disrupted by nitric oxide forming a protein-bound dinitrosyl iron complex, thiolate-bridged di-iron tetranitrosyl complex, or octanitrosyl cluster. Here we report that human mitochondrial protein Miner2 [2Fe 2S] clusters can bind nitric oxide without disruption of the clusters. Miner2 is a member of a new CDGSH iron-sulfur protein family that also includes two mitochondrial proteins: the type II diabetes-related mitoNEET and the Wolfram syndrome 2-linked Miner1. Miner2 contains two CDGSH motifs, and each CDGSH motif hosts a [2Fe-2S] cluster via three cysteine and one histidine residues. Binding of nitric oxide in the reduced Miner2 [2Fe-2S] clusters produces a major absorption peak at 422 nm without releasing iron or sulfide from the clusters. The EPR measurements and mass spectrometry analyses further reveal that nitric oxide binds to the reduced [2Fe-2S] clusters in Miner2, with each cluster binding one nitric oxide. Although the [2Fe-2S] cluster in purified human mitoNEET and Miner1 fails to bind nitric oxide, a single mutation of Asp-96 to Val in mitoNEET or Asp-123 to Val in Miner1 facilitates nitric oxide binding in the [2Fe-2S] cluster, indicating that a subtle change of protein structure may switch mitoNEET and Miner1 to bind nitric oxide. The results suggest that binding of nitric oxide in the CDGSH-type [2Fe-2S] clusters in mitochondrial protein Miner2 may represent a new nitric oxide signaling mode in cells. PMID- 28082677 TI - The Pseudouridine Synthase RPUSD4 Is an Essential Component of Mitochondrial RNA Granules. AB - Mitochondrial gene expression is a fundamental process that is largely dependent on nuclear-encoded proteins. Several steps of mitochondrial RNA processing and maturation, including RNA post-transcriptional modification, appear to be spatially organized into distinct foci, which we have previously termed mitochondrial RNA granules (MRGs). Although an increasing number of proteins have been localized to MRGs, a comprehensive analysis of the proteome of these structures is still lacking. Here, we have applied a microscopy-based approach that has allowed us to identify novel components of the MRG proteome. Among these, we have focused our attention on RPUSD4, an uncharacterized mitochondrial putative pseudouridine synthase. We show that RPUSD4 depletion leads to a severe reduction of the steady-state level of the 16S mitochondrial (mt) rRNA with defects in the biogenesis of the mitoribosome large subunit and consequently in mitochondrial translation. We report that RPUSD4 binds 16S mt-rRNA, mt-tRNAMet, and mt-tRNAPhe, and we demonstrate that it is responsible for pseudouridylation of the latter. These data provide new insights into the relevance of RNA pseudouridylation in mitochondrial gene expression. PMID- 28082678 TI - The Activating C-type Lectin-like Receptor NKp65 Signals through a Hemi immunoreceptor Tyrosine-based Activation Motif (hemITAM) and Spleen Tyrosine Kinase (Syk). AB - NKp65 is an activating human C-type lectin-like receptor (CTLR) triggering cellular cytotoxicity and cytokine secretion upon high-affinity interaction with the cognate CTLR keratinocyte-associated C-type lectin (KACL) selectively expressed by human keratinocytes. Previously, we demonstrated that NKp65-mediated cellular cytotoxicity depends on tyrosine 7, located in a cytoplasmic sequence motif of NKp65 resembling a hemi-immunoreceptor tyrosine-based activation motif (hemITAM). HemITAMs have been reported for a few activating myeloid-specific CTLRs, including Dectin-1 and CLEC-2, and consist of a single tyrosine signaling unit preceded by a triacidic motif. Upon receptor engagement, the hemITAM undergoes phosphotyrosinylation and specifically recruits spleen tyrosine kinase (Syk), initiating cellular activation. In this study, we addressed the functionality of the putative hemITAM of NKp65. We show that NKp65 forms homodimers and is phosphorylated at the hemITAM-embedded tyrosine 7 upon engagement by antibodies or KACL homodimers. HemITAM phosphotyrosinylation initiates a signaling pathway involving and depending on Syk, leading to cellular activation and natural killer (NK) cell degranulation. However, although NKp65 utilizes Syk for NK cell activation, a physical association of Syk with the NKp65 hemITAM could not be detected, unlike shown previously for the hemITAM of myeloid CTLR. Failure of NKp65 to recruit Syk is not due to an alteration of the triacidic motif, which rather affects the efficiency of hemITAM phosphotyrosinylation. In summary, NKp65 utilizes a hemITAM-like motif for cellular activation that requires Syk, although Syk appears not to be recruited to NKp65. PMID- 28082679 TI - Vesicular Polyamine Transporter Mediates Vesicular Storage and Release of Polyamine from Mast Cells. AB - Mast cells are secretory cells that play an important role in host defense by discharging various intragranular contents, such as histamine and serotonin, upon stimulation of Fc receptors. The granules also contain spermine and spermidine, which can act as modulators of mast cell function, although the mechanism underlying vesicular storage remains unknown. Vesicular polyamine transporter (VPAT), the fourth member of the SLC18 transporter family, is an active transporter responsible for vesicular storage of spermine and spermidine in neurons. In the present study, we investigated whether VPAT functions in mast cells. RT-PCR and Western blotting indicated VPAT expression in murine bone marrow-derived mast cells (BMMCs). Immunohistochemical analysis indicated that VPAT is colocalized with VAMP3 but not with histamine, serotonin, cathepsin D, VAMP2, or VAMP7. Membrane vesicles from BMMCs accumulated spermidine upon the addition of ATP in a reserpine- and bafilomycin A1-sensitive manner. BMMCs secreted spermine and spermidine upon the addition of either antigen or A23187 in the presence of Ca2+, and the antigen-mediated release, which was shown to be temperature-dependent and sensitive to bafilomycin A1 and tetanus toxin, was significantly suppressed by VPAT gene RNA interference. Under these conditions, expression of vesicular monoamine transporter 2 was unaffected, but antigen dependent histamine release was significantly suppressed, which was recovered by the addition of 1 mm spermine. These results strongly suggest that VPAT is expressed and is responsible for vesicular storage of spermine and spermidine in novel secretory granules that differ from histamine- and serotonin-containing granules and is involved in vesicular release of these polyamines from mast cells. PMID- 28082681 TI - A Positive Amplification Mechanism Involving a Kinase and Replication Initiation Factor Helps Assemble the Replication Fork Helicase. AB - The assembly of the replication fork helicase during S phase is key to the initiation of DNA replication in eukaryotic cells. One step in this assembly in budding yeast is the association of Cdc45 with the Mcm2-7 heterohexameric ATPase, and a second step is the assembly of the tetrameric GINS (GG-Ichi-Nii-San) complex with Mcm2-7. Dbf4-dependent kinase (DDK) and S-phase cyclin-dependent kinase (S-CDK) are two S phase-specific kinases that phosphorylate replication proteins during S phase, and Dpb11, Sld2, Sld3, Pol epsilon, and Mcm10 are factors that are also required for replication initiation. However, the exact roles of these initiation factors in assembly of the replication fork helicase remain unclear. We show here that Dpb11 stimulates DDK phosphorylation of the minichromosome maintenance complex protein Mcm4 alone and also of the Mcm2-7 complex and the dsDNA-loaded Mcm2-7 complex. We further demonstrate that Dpb11 can directly recruit DDK to Mcm4. A DDK phosphomimetic mutant of Mcm4 bound Dpb11 with substantially higher affinity than wild-type Mcm4, suggesting a mechanism to recruit Dpb11 to DDK-phosphorylated Mcm2-7. Furthermore, dsDNA-loaded Mcm2-7 harboring the DDK phosphomimetic Mcm4 mutant bound GINS in the presence of Dpb11, suggesting a mechanism for how GINS is recruited to Mcm2-7. We isolated a mutant of Dpb11 that is specifically defective for binding to Mcm4. This mutant, when expressed in budding yeast, diminished cell growth and DNA replication, substantially decreased Mcm4 phosphorylation, and decreased association of GINS with replication origins. We conclude that Dpb11 functions with DDK and Mcm4 in a positive amplification mechanism to trigger the assembly of the replication fork helicase. PMID- 28082682 TI - TBP-like Protein (TLP) Disrupts the p53-MDM2 Interaction and Induces Long-lasting p53 Activation. AB - Stress-induced activation of p53 is an essential cellular response to prevent aberrant cell proliferation and cancer development. The ubiquitin ligase MDM2 promotes p53 degradation and limits the duration of p53 activation. It remains unclear, however, how p53 persistently escapes MDM2-mediated negative control for making appropriate cell fate decisions. Here we report that TBP-like protein (TLP), a member of the TBP family, is a new regulatory factor for the p53-MDM2 interplay and thus for p53 activation. We found that TLP acts to stabilize p53 protein to ensure long-lasting p53 activation, leading to potentiation of p53 induced apoptosis and senescence after genotoxic stress. Mechanistically, TLP interferes with MDM2 binding and ubiquitination of p53. Moreover, single cell imaging analysis shows that TLP depletion accelerates MDM2-mediated nuclear export of p53. We further show that a cervical cancer-derived TLP mutant has less p53 binding ability and lacks a proliferation-repressive function. Our findings uncover a role of TLP as a competitive MDM2 blocker, proposing a novel mechanism by which p53 escapes the p53-MDM2 negative feedback loop to modulate cell fate decisions. PMID- 28082680 TI - Structural Determinants of the Gain-of-Function Phenotype of Human Leukemia associated Mutant CBL Oncogene. AB - Mutations of the tyrosine kinase-directed ubiquitin ligase CBL cause myeloid leukemias, but the molecular determinants of the dominant leukemogenic activity of mutant CBL oncogenes are unclear. Here, we first define a gain-of-function attribute of the most common leukemia-associated CBL mutant, Y371H, by demonstrating its ability to increase proliferation of hematopoietic stem/progenitor cells (HSPCs) derived from CBL-null and CBL/CBL-B-null mice. Next, we express second-site point/deletion mutants of CBL-Y371H in CBL/CBL-B null HSPCs or the cytokine-dependent human leukemic cell line TF-1 to show that individual or combined Tyr -> Phe mutations of established phosphotyrosine residues (Tyr-700, Tyr-731, and Tyr-774) had little impact on the activity of the CBL-Y371H mutant in HSPCs, and the triple Tyr -> Phe mutant was only modestly impaired in TF-1 cells. In contrast, intact tyrosine kinase-binding (TKB) domain and proline-rich region (PRR) were critical in both cell models. PRR deletion reduced the stem cell factor (SCF)-induced hyper-phosphorylation of the CBL-Y371H mutant and the c-KIT receptor and eliminated the sustained p-ERK1/2 and p-AKT induction by SCF. GST fusion protein pulldowns followed by phospho-specific antibody array analysis identified distinct CBL TKB domains or PRR-binding proteins that are phosphorylated in CBL-Y371H-expressing TF-1 cells. Our results support a model of mutant CBL gain-of-function in which mutant CBL proteins effectively compete with the remaining wild type CBL-B and juxtapose TKB domain associated PTKs with PRR-associated signaling proteins to hyper-activate signaling downstream of hematopoietic growth factor receptors. Elucidation of mutant CBL domains required for leukemogenesis should facilitate targeted therapy approaches for patients with mutant CBL-driven leukemias. PMID- 28082683 TI - Autoinhibition of the Nuclease ARTEMIS Is Mediated by a Physical Interaction between Its Catalytic and C-terminal Domains. AB - The nuclease ARTEMIS is essential for the development of B and T lymphocytes. It is required for opening DNA hairpins generated during antigen receptor gene assembly from variable (V), diversity (D), and joining (J) subgenic elements (V(D)J recombination). As a member of the non-homologous end-joining pathway, it is also involved in repairing a subset of pathological DNA double strand breaks. Loss of ARTEMIS function therefore results in radiosensitive severe combined immunodeficiency (RS-SCID). The hairpin opening activity is dependent on the DNA dependent protein kinase catalytic subunit (DNA-PKcs), which can bind to and phosphorylate ARTEMIS. The ARTEMIS C terminus is dispensable for cellular V(D)J recombination and in vitro nuclease assays with C-terminally truncated ARTEMIS showing DNA-PKcs-independent hairpin opening activity. Therefore, it has been postulated that ARTEMIS is regulated via autoinhibition by its C terminus. To obtain evidence for the autoinhibition model, we performed co-immunoprecipitation experiments with combinations of ARTEMIS mutants. We show that an N-terminal fragment comprising the catalytic domain can interact both with itself and with a C-terminal fragment. Amino acid exchanges N456A+S457A+E458Q in the C terminus of full-length ARTEMIS resulted in unmasking of the N terminus and in increased ARTEMIS activity in cellular V(D)J recombination assays. Mutations in ARTEMIS deficient patients impaired the interaction with the C terminus and also affected protein stability. The interaction between the N- and C-terminal domains was not DNA-PKcs-dependent, and phosphomimetic mutations in the C-terminal domain did not result in unmasking of the catalytic domain. Our experiments provide strong evidence that a physical interaction between the C-terminal and catalytic domains mediates ARTEMIS autoinhibition. PMID- 28082687 TI - Advice for backyard poultry keepers as further case of HPAI confirmed. PMID- 28082691 TI - Time to #DoSomethingForNothing in 2017? PMID- 28082684 TI - Absence of IQGAP1 Protein Leads to Insulin Resistance. AB - Insulin binds to the insulin receptor (IR) and induces tyrosine phosphorylation of the receptor and insulin receptor substrate-1 (IRS-1), leading to activation of the PKB/Akt and MAPK/ERK pathways. IQGAP1 is a scaffold protein that interacts with multiple binding partners and integrates diverse signaling cascades. Here we show that IQGAP1 associates with both IR and IRS-1 and influences insulin action. In vitro analysis with pure proteins revealed that the IQ region of IQGAP1 binds directly to the intracellular domain of IR. Similarly, the phosphotyrosine binding domain of IRS-1 mediates a direct interaction with the C-terminal tail of IQGAP1. Consistent with these observations, both IR and IRS-1 co immunoprecipitated with IQGAP1 from cells. Investigation of the functional effects of the interactions revealed that in the absence of IQGAP1, insulin stimulated phosphorylation of Akt and ERK, as well as the association of phosphatidylinositol 3-kinase with IRS-1, were significantly decreased. Importantly, loss of IQGAP1 results in impaired insulin signaling and glucose homeostasis in vivo Collectively, these data reveal that IQGAP1 is a scaffold for IR and IRS-1 and implicate IQGAP1 as a participant in insulin signaling. PMID- 28082694 TI - Do dogs bite without warning, or should we see it coming? AB - When dog bites occur, many owners will report the incident as being 'out of character' for the dog and as happening 'out of the blue'. But do dogs provide warning signs before biting and should owners and vets be able to see it coming? This question was explored in a session during the London Vet Show. Laura Honey reports. PMID- 28082698 TI - Disease surveillance in England and Wales, December 2016. AB - Current and emerging issues: avian influenza and Schmallenberg virusHighlights from the scanning surveillance networkUpdate on international disease threatsCongenital tremor associated with atypical porcine pestivirus These are among matters discussed in the Animal and Plant Health Agency's (APHA's) disease surveillance report for December 2016. PMID- 28082699 TI - Congenital tremor associated with atypical porcine pestivirus. AB - This article has been prepared by Susanna Williamson and colleagues from the Pig Expert Group at the APHA. PMID- 28082700 TI - Managing the spread of canine leishmaniosis in Europe. PMID- 28082706 TI - Blood cholesterol concentrations in dairy calves. PMID- 28082712 TI - My week: Francesco Cian. AB - Francesco Cian is a veterinary clinical pathologist and co-manager at BattLab, a veterinary diagnostic laboratory based in Coventry. PMID- 28082713 TI - Third-year student diary. AB - Rosie Perrett enjoyed Christmas, especially her Secret Santa gift, which was inspired by her enjoyment of Planet Earth II. When she returns to Liverpool vet school, she will be getting to grips with pathology. PMID- 28082714 TI - Association of Rapid Care Process Implementation on Reperfusion Times Across Multiple ST-Segment-Elevation Myocardial Infarction Networks. AB - BACKGROUND: The Mission: Lifeline STEMI Systems Accelerator program, implemented in 16 US metropolitan regions, resulted in more patients receiving timely reperfusion. We assessed whether implementing key care processes was associated with system performance improvement. METHODS AND RESULTS: Hospitals (n=167 with 23 498 ST-segment-elevation myocardial infarction patients) were surveyed before (March 2012) and after (July 2014) program intervention. Data were merged with patient-level clinical data over the same period. For reperfusion, hospitals were grouped by whether a specific process of care was implemented, preexisting, or never implemented. Uptake of 4 key care processes increased after intervention: prehospital catheterization laboratory activation (62%-91%; P<0.001), single call transfer protocol from an outside facility (45%-70%; P<0.001), and emergency department bypass for emergency medical services direct presenters (48%-59%; P=0.002) and transfers (56%-79%; P=0.001). There were significant differences in median first medical contact-to-device times among groups implementing prehospital activation (88 minutes implementers versus 89 minutes preexisting versus 98 minutes nonimplementers; P<0.001 for comparisons). Similarly, patients treated at hospitals implementing single call transfer protocols had shorter median first medical contact-to-device times (112 versus 128 versus 152 minutes; P<0.001). Emergency department bypass was also associated with shorter median first medical contact-to-device times for emergency medical services direct presenters (84 versus 88 versus 94 minutes; P<0.001) and transfers (123 versus 127 versus 167 minutes; P<0.001). CONCLUSIONS: The Accelerator program increased uptake of key care processes, which were associated with improved system performance. These findings support efforts to implement regional ST-segment elevation myocardial infarction networks focused on prehospital catheterization laboratory activation, single call transfer protocols, and emergency department bypass. PMID- 28082715 TI - Modest Improvement of Reperfusion Times Across Multiple ST-Segment-Elevation Myocardial Infarction Networks With Rapid Care Process Implementation but no Effect on Mortality. PMID- 28082716 TI - Three Pectin Methylesterase Inhibitors Protect Cell Wall Integrity for Arabidopsis Immunity to Botrytis. AB - Infection by necrotrophs is a complex process that starts with the breakdown of the cell wall (CW) matrix initiated by CW-degrading enzymes and results in an extensive tissue maceration. Plants exploit induced defense mechanisms based on biochemical modification of the CW components to protect themselves from enzymatic degradation. The pectin matrix is the main CW target of Botrytis cinerea, and pectin methylesterification status is strongly altered in response to infection. The methylesterification of pectin is controlled mainly by pectin methylesterases (PMEs), whose activity is posttranscriptionally regulated by endogenous protein inhibitors (PMEIs). Here, AtPMEI10, AtPMEI11, and AtPMEI12 are identified as functional PMEIs induced in Arabidopsis (Arabidopsis thaliana) during B. cinerea infection. AtPMEI expression is strictly regulated by jasmonic acid and ethylene signaling, while only AtPMEI11 expression is controlled by PME related damage-associated molecular patterns, such as oligogalacturonides and methanol. The decrease of pectin methylesterification during infection is higher and the immunity to B. cinerea is compromised in pmei10, pmei11, and pmei12 mutants with respect to the control plants. A higher stimulation of the fungal oxalic acid biosynthetic pathway also can contribute to the higher susceptibility of pmei mutants. The lack of PMEI expression does not affect hemicellulose strengthening, callose deposition, and the synthesis of structural defense proteins, proposed as CW-remodeling mechanisms exploited by Arabidopsis to resist CW degradation upon B. cinerea infection. We show that PME activity and pectin methylesterification are dynamically modulated by PMEIs during B. cinerea infection. Our findings point to AtPMEI10, AtPMEI11, and AtPMEI12 as mediators of CW integrity maintenance in plant immunity. PMID- 28082717 TI - Jasmonate Regulates Plant Responses to Postsubmergence Reoxygenation through Transcriptional Activation of Antioxidant Synthesis. AB - Submergence induces hypoxia in plants; exposure to oxygen following submergence, termed reoxygenation, produces a burst of reactive oxygen species. The mechanisms of hypoxia sensing and signaling in plants have been well studied, but how plants respond to reoxygenation remains unclear. Here, we show that reoxygenation in Arabidopsis (Arabidopsis thaliana) involves rapid accumulation of jasmonates (JAs) and increased transcript levels of JA biosynthesis genes. Application of exogenous methyl jasmonate improved tolerance to reoxygenation in wild-type Arabidopsis; also, mutants deficient in JA biosynthesis and signaling were very sensitive to reoxygenation. Moreover, overexpression of the transcription factor gene MYC2 enhanced tolerance to posthypoxic stress, and myc2 knockout mutants showed increased sensitivity to reoxygenation, indicating that MYC2 functions as a key regulator in the JA-mediated reoxygenation response. MYC2 transcriptionally activates members of the VITAMIN C DEFECTIVE (VTC) and GLUTATHIONE SYNTHETASE (GSH) gene families, which encode rate-limiting enzymes in the ascorbate and glutathione synthesis pathways. Overexpression of VTC1 and GSH1 in the myc2-2 mutant suppressed the posthypoxic hypersensitive phenotype. The JA-inducible accumulation of antioxidants may alleviate oxidative damage caused by reoxygenation, improving plant survival after submergence. Taken together, our findings demonstrate that JA signaling interacts with the antioxidant pathway to regulate reoxygenation responses in Arabidopsis. PMID- 28082720 TI - Enzymatic kinetics of the quinol peroxidase of an aggressive periodontopathic bacterium. AB - Aggregatibacter actinomycetemcomitans is an oral pathogen for aggressive periodontitis, and encodes a triheme c-containing membrane-bound enzyme, quinol peroxidase (QPO) that catalyzes peroxidase activity using quinol in the respiratory chain. In the previous work, we have characterized recombinant QPO purified from the membrane fraction of Escherichia coli harboring a plasmid containing QPO gene. Irreversible inactivation of QPO by high concentration of H2O2 exhibited pseudo-first order kinetics. Analysis of initial-rate kinetics of QPO may suggest that enzyme catalytic mechanism is explained by a Ping Pong Bi Bi system rather than sequential systems. In addition, the redox reactions of cytochrome c in the presence of several values of [Q1H2]/[Q1] were at equilibrium, and only about 2/3 of the cytochrome c of QPO is reduced at high ratios of [Q1H2]/[Q1]. These results indicated that one of the three heme c moieties of QPO is maintained in an oxidized form even at increased ratios of [Q1H2]/[Q1], suggesting that QPO is reduced in the absence of H2O2 and only two of the three heme c moieties are reduced in the presence of high concentration of the Q1H2. Product inhibition of QPO accorded with our theoretical model for the reaction mechanism. Considered together, the enzymatic kinetics data for QPO confirm the Ping Pong Bi Bi system. PMID- 28082718 TI - Analysis of Exocyst Subunit EXO70 Family Reveals Distinct Membrane Polar Domains in Tobacco Pollen Tubes. AB - The vesicle-tethering complex exocyst is one of the crucial cell polarity regulators. The EXO70 subunit is required for the targeting of the complex and is represented by many isoforms in angiosperm plant cells. This diversity could be partly responsible for the establishment and maintenance of membrane domains with different composition. To address this hypothesis, we employed the growing pollen tube, a well-established cell polarity model system, and performed large-scale expression, localization, and functional analysis of tobacco (Nicotiana tabacum) EXO70 isoforms. Various isoforms localized to different regions of the pollen tube plasma membrane, apical vesicle-rich inverted cone region, nucleus, and cytoplasm. The overexpression of major pollen-expressed EXO70 isoforms resulted in growth arrest and characteristic phenotypic deviations of tip swelling and apical invaginations. NtEXO70A1a and NtEXO70B1 occupied two distinct and mutually exclusive plasma membrane domains. Both isoforms partly colocalized with the exocyst subunit NtSEC3a at the plasma membrane, possibly forming different exocyst complex subpopulations. NtEXO70A1a localized to the small area previously characterized as the site of exocytosis in the tobacco pollen tube, while NtEXO70B1 surprisingly colocalized with the zone of clathrin-mediated endocytosis. Both NtEXO70A1a and NtEXO70B1 colocalized to different degrees with markers for the anionic signaling phospholipids phosphatidylinositol 4,5 bisphosphate and phosphatidic acid. In contrast, members of the EXO70 C class, which are specifically expressed in tip-growing cells, exhibited exocytosis related functional effects in pollen tubes despite the absence of apparent plasma membrane localization. Taken together, our data support the existence of multiple membrane-trafficking domains regulated by different EXO70-containing exocyst complexes within a single cell. PMID- 28082719 TI - Heteroblastic Development of Transfer Cells Is Controlled by the microRNA miR156/SPL Module. AB - We report that wall ingrowth deposition in phloem parenchyma (PP) transfer cells (TCs) in leaf veins of Arabidopsis (Arabidopsis thaliana) represents a novel trait of heteroblasty. Development of PP TCs involves extensive deposition of wall ingrowths adjacent to cells of the sieve element/companion cell complex. These PP TCs potentially facilitate phloem loading by enhancing efflux of symplasmic Suc for subsequent active uptake into cells of the sieve element/companion cell complex. PP TCs with extensive wall ingrowths are ubiquitous in mature cotyledons and juvenile leaves, but dramatically less so in mature adult leaves, an observation consistent with PP TC development reflecting vegetative phase change (VPC) in Arabidopsis. Consistent with this conclusion, the abundance of PP TCs with extensive wall ingrowths varied across rosette development in three ecotypes displaying differing durations of juvenile phase, and extensive deposition of wall ingrowths was observed in rejuvenated leaves following prolonged defoliation. PP TC development across juvenile, transition, and adult leaves correlated positively with levels of miR156, a major regulator of VPC in plants, and corresponding changes in wall ingrowth deposition were observed when miR156 was overexpressed or its activity suppressed by target mimicry. Analysis of plants carrying miR156-resistant forms of SQUAMOSA PROMOTER BINDING PROTEIN LIKE (SPL) genes showed that wall ingrowth deposition was increased in SPL9-group but not SPL3-group genes, indicating that SPL9-group genes may function as negative regulators of wall ingrowth deposition in PP TCs. Collectively, our results point to wall ingrowth deposition in PP TCs being under control of the genetic program regulating VPC. PMID- 28082721 TI - Roles of the cytoskeleton, cell adhesion and rho signalling in mechanosensing and mechanotransduction. AB - All cells sense and respond to various mechanical forces in and mechanical properties of their environment. To respond appropriately, cells must be able to sense the location, direction, strength and duration of these forces. Recent progress in mechanobiology has provided a better understanding of the mechanisms of mechanoresponses underlying many cellular and developmental processes. Various roles of mechanoresponses in development and tissue homeostasis have been elucidated, and many molecules involved in mechanotransduction have been identified. However, the whole picture of the functions and molecular mechanisms of mechanotransduction remains to be understood. Recently, novel mechanisms for sensing and transducing mechanical stresses via the cytoskeleton, cell-substrate and cell-cell adhesions and related proteins have been identified. In this review, we outline the roles of the cytoskeleton, cell-substrate and cell-cell adhesions, and related proteins in mechanosensing and mechanotransduction. We also describe the roles and regulation of Rho-family GTPases in mechanoresponses. PMID- 28082722 TI - Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL /- clear cell renal carcinoma. AB - Most clear cell renal carcinomas (ccRCCs) are initiated by somatic inactivation of the VHL tumor suppressor gene. The VHL gene product, pVHL, is the substrate recognition unit of an ubiquitin ligase that targets the HIF transcription factor for proteasomal degradation; inappropriate expression of HIF target genes drives renal carcinogenesis. Loss of pVHL is not sufficient, however, to cause ccRCC. Additional cooperating genetic events, including intragenic mutations and copy number alterations, are required. Common examples of the former are loss-of function mutations of the PBRM1 and BAP1 tumor suppressor genes, which occur in a mutually exclusive manner in ccRCC and define biologically distinct subsets of ccRCC. PBRM1 encodes the Polybromo- and BRG1-associated factors-containing complex (PBAF) chromatin remodeling complex component BRG1-associated factor 180 (BAF180). Here we identified ccRCC lines whose ability to proliferate in vitro and in vivo is sensitive to wild-type BAF180, but not a tumor-associated BAF180 mutant. Biochemical and functional studies linked growth suppression by BAF180 to its ability to form a canonical PBAF complex containing BRG1 that dampens the HIF transcriptional signature. PMID- 28082723 TI - Presenilin-1 mutations and Alzheimer's disease. PMID- 28082724 TI - Unplanned ecological engineering. PMID- 28082725 TI - Tumor suppression by p53 involves inhibiting an enabler, FGF13. PMID- 28082727 TI - Correction: A novel small molecule agent displays potent anti-myeloma activity by inhibiting the JAK2-STAT3 signaling pathway. PMID- 28082728 TI - Correction: Infiltrating mast cells enhance prostate cancer invasion via altering LncRNA-HOTAIR/PRC2-androgen receptor (AR)-MMP9 signals and increased stem/progenitor cell population. PMID- 28082726 TI - Multi-modality imaging to assess metabolic response to dichloroacetate treatment in tumor models. AB - Reverting glycolytic metabolism is an attractive strategy for cancer therapy as upregulated glycolysis is a hallmark in various cancers. Dichloroacetate (DCA), long used to treat lactic acidosis in various pathologies, has emerged as a promising anti-cancer drug. By inhibiting the pyruvate dehydrogenase kinase, DCA reactivates the mitochondrial function and decreases the glycolytic flux in tumor cells resulting in cell cycle arrest and apoptosis. We recently documented that DCA was able to induce a metabolic switch preferentially in glycolytic cancer cells, leading to a more oxidative phenotype and decreasing proliferation, while oxidative cells remained less sensitive to DCA treatment. To evaluate the relevance of this observation in vivo, the aim of the present study was to characterize the effect of DCA in glycolytic MDA-MB-231 tumors and in oxidative SiHa tumors using advanced pharmacodynamic metabolic biomarkers. Oxygen consumption, studied by 17O magnetic resonance spectroscopy, glucose uptake, evaluated by 18F-FDG PET and pyruvate transformation into lactate, measured using hyperpolarized 13C-magnetic resonance spectroscopy, were monitored before and 24 hours after DCA treatment in tumor bearing mice. In both tumor models, no clear metabolic shift was observed. Surprisingly, all these imaging parameters concur to the conclusion that both glycolytic tumors and oxidative tumors presented a similar response to DCA. These results highlight a major discordance in metabolic cancer cell bioenergetics between in vitro and in vivo setups, indicating critical role of the local microenvironment in tumor metabolic behaviors. PMID- 28082729 TI - Correction: Infiltrated pre-adipocytes increase prostate cancer metastasis via modulation of the miR-301a/androgen receptor (AR)/TGF-beta1/Smad/MMP9 signals. PMID- 28082730 TI - A proximal retarding field analyzer for scanning probe energy loss spectroscopy. AB - A compact proximal retarding field analyzer for scanning probe energy loss spectroscopy measurements is described. Using the scanning tunneling microscope (STM) tip as a field emission (FE) electron source in conjunction with this analyzer, which is placed at a glancing angle to the surface plane, FE sample current and electron reflectivity imaging may be performed simultaneously. This is demonstrated in measurements of Ag nanostructures prepared on graphite by electron-beam lithography, where a material contrast of 13% is observed, with a lateral resolution of 25 nm, between the silver and graphite in electron reflectivity images. Topological contrast mechanisms such as edge enhancement and shadowing are also observed, giving rise to additional features in the electron reflectivity images. The same instrument configuration has been used to measure electron energy loss spectra on bare graphite, where the zero loss peak, pi band plasmon loss peak and secondary electron peaks are observed. Using this simple and compact analyzer an STM, with sufficient open access to the tip-sample junction, may easily be augmented to provide simultaneous elemental and topographic mapping, supplementing STM image measurements with FE sample current and electron reflectivity images, as well as electron energy loss spectroscopy measurements, in the same instrument. PMID- 28082731 TI - Conversion efficiency of an energy harvester based on resonant tunneling through quantum dots with heat leakage. AB - We study the conversion efficiency of an energy harvester based on resonant tunneling through quantum dots with heat leakage. Heat leakage current from a hot electrode to a cold electrode is taken into account in the analysis of the harvester operation. Modeling of electrical output indicates that a maximum heat leakage current is not negligible because it is larger than that of the heat current harvested into electrical power. A reduction of heat leakage is required in this energy harvester in order to obtain efficient heat-to-electrical conversion. Multiple energy levels of a quantum dot can increase the output power of the harvester. Heavily doped colloidal semiconductor quantum dots are a possible candidate for a quantum-dot monolayer in the energy harvester to reduce heat leakage, scaling down device size, and increasing electrical output via multiple discrete energy levels. PMID- 28082732 TI - Electrocardiograms: diagnostic problems and clinical interpretations. PMID- 28082733 TI - A Case of Chronic Total Occlusion of the Left Anterior Descending Artery Successfully Treated with Side Branch Technique Using the Soutenir CV. AB - BACKGROUND Success rates for treatment of chronic total occlusion (CTO) have dramatically improved in recent years with the development of new CTO guidewires and development of new techniques such as the retrograde approach. In the antegrade approach, a guidewire is occasionally passed through a side branch despite successful wire crossing of the CTO lesion. In order to pass a wire through the main artery, there are a few side branch techniques such as a reverse wire technique. CASE REPORT A 54-year-old man with symptoms of heart failure was admitted to our hospital. Coronary angiography showed CTO of the proximal left anterior descending artery. Percutaneous coronary intervention with an antegrade approach was started. We succeeded in passing the wire through a side branch but not the main artery. Unfortunately, a reverse wire technique failed in this case. Next, the wire passed through a side branch was exchanged with the Soutenir CV, and a retrograde approach was started. The wire crossing from retrograde was entwined around the Soutenir CV. After that, the retrograde wire was snared and guided to the antegrade guiding catheter, which resulted in successful wiring into the main artery easily. CONCLUSIONS The side branch technique using the Soutenir CV may be an effective strategy in some cases. PMID- 28082734 TI - Environmental Enrichment Improves Spatial Learning and Memory in Vascular Dementia Rats with Activation of Wnt/beta-Catenin Signal Pathway. AB - BACKGROUND Environmental enrichment (EE) has a beneficial effect on some neuropsychiatric disorders. In this study, we aimed to investigate whether environmental enrichment could improve the spatial learning and memory in rats with vascular dementia (VaD) and the mechanism underpinning it. MATERIAL AND METHODS Bilateral common carotid occlusion (2-vessel occlusion [2VO]) was used to develop the animal model of vascular dementia. Adult male Sprague-Dawley (SD) rats were used in the experiment and were randomly divided into 4 groups: sham group, 2VO group, sham+EE group, and 2VO+EE group (n=19/group). The 2VO group and 2VO+EE group underwent bilateral common carotid occlusion. Two different housing conditions were used in this experiment: standard environment (SE) and enriched environment (EE). Rats in the sham group and 2VO group were put into SE cages for 4 weeks, while rats in the sham+EE group and 2VO+EE group were put in EE cages for 4 weeks. The Morris water maze and Y-maze were used to assess spatial learning and memory. Apoptosis was detected by TUNEL. The damage of neurons in the hippocampus was assessed by Nissl staining. The level of wnt pathway proteins were detected by Western blot. RESULTS Compared with the 2VO group, the rats in the 2VO+EE group had better behavioral performance, fewer apoptotic neurons, and more surviving neurons. Western blot analysis showed that the levels of wnt pathway proteins were higher in 2VO+EE rats than in the 2VO group. CONCLUSIONS Environmental enrichment can improve the spatial learning and memory in rats with vascular dementia, and the mechanism may be related to activation of the wnt/beta catenin signal pathway. PMID- 28082735 TI - Hydrogenation of iron in the early stage of Earth's evolution. AB - Density of the Earth's core is lower than that of pure iron and the light element(s) in the core is a long-standing problem. Hydrogen is the most abundant element in the solar system and thus one of the important candidates. However, the dissolution process of hydrogen into iron remained unclear. Here we carry out high-pressure and high-temperature in situ neutron diffraction experiments and clarify that when the mixture of iron and hydrous minerals are heated, iron is hydrogenized soon after the hydrous mineral is dehydrated. This implies that early in the Earth's evolution, as the accumulated primordial material became hotter, the dissolution of hydrogen into iron occurred before any other materials melted. This suggests that hydrogen is likely the first light element dissolved into iron during the Earth's evolution and it may affect the behaviour of the other light elements in the later processes. PMID- 28082736 TI - Expeditious diastereoselective synthesis of elaborated ketones via remote Csp3-H functionalization. AB - The quest for selective C-H functionalization reactions, able to provide new strategic opportunities for the rapid assembly of molecular complexity, represents a major focus of the chemical community. Examples of non-directed, remote Csp3-H activation to forge complex carbon frameworks remain scarce due to the kinetic stability and thus intrinsic challenge associated to the chemo-, regio- and stereoselective functionalization of aliphatic C-H bonds. Here we describe a radical-mediated, directing-group-free regioselective 1,5-hydrogen transfer of unactivated Csp3-H bonds followed by a second Csp2-H functionalization to produce, with exquisite stereoselectivity, a variety of elaborated fused ketones. This study demonstrates that aliphatic acids can be strategically harnessed as 1,2-diradical synthons and that secondary aliphatic C H bonds can be engaged in stereoselective C-C bond-forming reactions, highlighting the potential of this protocol for target-oriented natural product and pharmaceutical synthesis. PMID- 28082737 TI - Phosphoproteomic analysis reveals hyperactivation of mTOR/STAT3 and LCK/Calcineurin axes in pediatric early T-cell precursor ALL. PMID- 28082738 TI - Heterogeneity in mantle carbon content from CO2-undersaturated basalts. AB - The amount of carbon present in Earth's mantle affects the dynamics of melting, volcanic eruption style and the evolution of Earth's atmosphere via planetary outgassing. Mantle carbon concentrations are difficult to quantify because most magmas are strongly degassed upon eruption. Here we report undegassed carbon concentrations from a new set of olivine-hosted melt inclusions from the Mid Atlantic Ridge. We use the correlations of CO2 with trace elements to define an average carbon abundance for the upper mantle. Our results indicate that the upper mantle carbon content is highly heterogeneous, varying by almost two orders of magnitude globally, with the potential to produce large geographic variations in melt fraction below the volatile-free solidus. Such heterogeneity will manifest as variations in the depths at which melt becomes interconnected and detectable, the CO2 fluxes at mid-ocean ridges, the depth of the lithosphere asthenosphere boundary, and mantle conductivity. PMID- 28082739 TI - Resilient cooperators stabilize long-run cooperation in the finitely repeated Prisoner's Dilemma. AB - Learning in finitely repeated games of cooperation remains poorly understood in part because their dynamics play out over a timescale exceeding that of traditional lab experiments. Here, we report results of a virtual lab experiment in which 94 subjects play up to 400 ten-round games of Prisoner's Dilemma over the course of twenty consecutive weekdays. Consistent with previous work, the typical round of first defection moves earlier for several days; however, this unravelling process stabilizes after roughly one week. Analysing individual strategies, we find that approximately 40% of players behave as resilient cooperators who avoid unravelling even at significant cost to themselves. Finally, using a standard learning model we predict that a sufficiently large minority of resilient cooperators can permanently stabilize unravelling among a majority of rational players. These results shed hopeful light on the long-term dynamics of cooperation, and demonstrate the importance of long-run experiments. PMID- 28082740 TI - Epigenetic regulation and chromatin remodeling in learning and memory. AB - Understanding the underlying mechanisms of memory formation and maintenance has been a major goal in the field of neuroscience. Memory formation and maintenance are tightly controlled complex processes. Among the various processes occurring at different levels, gene expression regulation is especially crucial for proper memory processing, as some genes need to be activated while some genes must be suppressed. Epigenetic regulation of the genome involves processes such as DNA methylation and histone post-translational modifications. These processes edit genomic properties or the interactions between the genome and histone cores. They then induce structural changes in the chromatin and lead to transcriptional changes of different genes. Recent studies have focused on the concept of chromatin remodeling, which consists of 3D structural changes in chromatin in relation to gene regulation, and is an important process in learning and memory. In this review, we will introduce three major epigenetic processes involved in memory regulation: DNA methylation, histone methylation and histone acetylation. We will also discuss general mechanisms of long-term memory storage and relate the epigenetic control of learning and memory to chromatin remodeling. Finally, we will discuss how epigenetic mechanisms can contribute to the pathologies of neurological disorders and cause memory-related symptoms. PMID- 28082741 TI - Bioinformatic identification of prognostic signature defined by copy number alteration and expression of CCNE1 in non-muscle invasive bladder cancer. AB - Non-muscle invasive bladder cancer (NMIBC) patients frequently fail to respond to treatment and experience disease progression because of their clinical and biological diversity. In this study, we identify a prognostic molecular signature for predicting the heterogeneity of NMIBC by using an integrative analysis of copy number and gene expression data. We analyzed the copy number and gene expression profiles of 404 patients with bladder cancer obtained from The Cancer Genome Atlas (TCGA) consortium. Of the 14 molecules with significant copy number alterations that were previously reported, 13 were significantly correlated with copy number and expression changes. Prognostic gene sets based on the 13 genes were developed, and their prognostic values were verified in three independent patient cohorts (n=501). Among them, a signature of CCNE1 and its coexpressed genes was significantly associated with disease progression and validated in the independent cohorts. The CCNE1 signature was an independent risk factor based on the result of a multivariate analysis (hazard ratio=6.849, 95% confidence interval=1.613-29.092, P=0.009). Finally, gene network and upstream regulator analyses revealed that NMIBC progression is potentially mediated by CCND1-CCNE1 SP1 pathways. The prognostic molecular signature defined by copy number and expression changes of CCNE1 suggests a novel diagnostic tool for predicting the likelihood of NMIBC progression. PMID- 28082742 TI - Gene-metabolite network analysis in different nonalcoholic fatty liver disease phenotypes. AB - We sought to identify common key regulators and build a gene-metabolite network in different nonalcoholic fatty liver disease (NAFLD) phenotypes. We used a high fat diet (HFD), a methionine-choline-deficient diet (MCDD) and streptozocin (STZ) to establish nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH) and NAFL+type 2 diabetes mellitus (T2DM) in rat models, respectively. Transcriptomics and metabolomics analyses were performed in rat livers and serum. A functional network-based regulation model was constructed using Cytoscape with information derived from transcriptomics and metabolomics. The results revealed that 96 genes, 17 liver metabolites and 4 serum metabolites consistently changed in different NAFLD phenotypes (>2-fold, P<0.05). Gene-metabolite network analysis identified ccl2 and jun as hubs with the largest connections to other genes, which were mainly involved in tumor necrosis factor, P53, nuclear factor-kappa B, chemokine, peroxisome proliferator activated receptor and Toll-like receptor signaling pathways. The specifically regulated genes and metabolites in different NAFLD phenotypes constructed their own networks, which were mainly involved in the lipid and fatty acid metabolism in HFD models, the inflammatory and immune response in MCDD models, and the AMPK signaling pathway and response to insulin in HFD+STZ models. Our study identified networks showing the general and specific characteristics in different NAFLD phenotypes, complementing the genetic and metabolic features in NAFLD with hepatic and extra-hepatic manifestations. PMID- 28082744 TI - Strategies for delivering value from digital technology transformation. PMID- 28082745 TI - The SCCHN drug market. PMID- 28082743 TI - Adipose stem cell-derived nanovesicles inhibit emphysema primarily via an FGF2 dependent pathway. AB - Cell therapy using stem cells has produced therapeutic benefits in animal models of COPD. Secretory mediators are proposed as one mechanism for stem cell effects because very few stem cells engraft after injection into recipient animals. Recently, nanovesicles that overcome the disadvantages of natural exosomes have been generated artificially from cells. We generated artificial nanovesicles from adipose-derived stem cells (ASCs) using sequential penetration through polycarbonate membranes. ASC-derived artificial nanovesicles displayed a 100 nm sized spherical shape similar to ASC-derived natural exosomes and expressed both exosomal and stem cell markers. The proliferation rate of lung epithelial cells was increased in cells treated with ASC-derived artificial nanovesicles compared with cells treated with ASC-derived natural exosomes. The lower dose of ASC derived artificial nanovesicles had similar regenerative capacity compared with a higher dose of ASCs and ASC-derived natural exosomes. In addition, FGF2 levels in the lungs of mice treated with ASC-derived artificial nanovesicles were increased. The uptake of ASC-derived artificial nanovesicles was inhibited by heparin, which is a competitive inhibitor of heparan sulfate proteoglycan that is associated with FGF2 signaling. Taken together, the data indicate that lower doses of ASC-derived artificial nanovesicles may have beneficial effects similar to higher doses of ASCs or ASC-derived natural exosomes in an animal model with emphysema, suggesting that artificial nanovesicles may have economic advantages that warrant future clinical studies. PMID- 28082746 TI - Signature of type-II Weyl semimetal phase in MoTe2. AB - Topological Weyl semimetal (TWS), a new state of quantum matter, has sparked enormous research interest recently. Possessing unique Weyl fermions in the bulk and Fermi arcs on the surface, TWSs offer a rare platform for realizing many exotic physical phenomena. TWSs can be classified into type-I that respect Lorentz symmetry and type-II that do not. Here, we directly visualize the electronic structure of MoTe2, a recently proposed type-II TWS. Using angle resolved photoemission spectroscopy (ARPES), we unravel the unique surface Fermi arcs, in good agreement with our ab initio calculations that have nontrivial topological nature. Our work not only leads to new understandings of the unusual properties discovered in this family of compounds, but also allows for the further exploration of exotic properties and practical applications of type-II TWSs, as well as the interplay between superconductivity (MoTe2 was discovered to be superconducting recently) and their topological order. PMID- 28082748 TI - Correction to 117th Annual Meeting of the American Association of Colleges of Pharmacy, Anaheim, California, July 23-27, 2016. AB - [This corrects the article DOI: 10.5688/ajpe805S2.]. PMID- 28082749 TI - Parenthood and Happiness: Effects of Work-Family Reconciliation Policies in 22 OECD Countries. AB - The recent proliferation of studies examining cross-national variation in the association between parenthood and happiness reveal accumulating evidence of lower levels of happiness among parents than nonparents in most advanced industrialized societies. Conceptualizing parenting as a stressor buffered by institutional support, we hypothesize that parental status differences in happiness are smaller in countries providing more resources and support to families. Our analyses of the European Social Surveys (ESS) and International Social Survey Programme (ISSP) reveal considerable variation in the parenthood gap in happiness across countries, with the U.S. showing the largest disadvantage of parenthood. We also find that more generous family policies, particularly paid time off and childcare subsidies, are associated with smaller disparities in happiness between parents and non-parents. Moreover, the policies that augment parental happiness do not reduce the happiness of nonparents. Our results shed light on macro-level causes of emotional processes, with important implications for public policy. PMID- 28082747 TI - A RuBisCO-mediated carbon metabolic pathway in methanogenic archaea. AB - Two enzymes are considered to be unique to the photosynthetic Calvin-Benson cycle: ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO), responsible for CO2 fixation, and phosphoribulokinase (PRK). Some archaea possess bona fide RuBisCOs, despite not being photosynthetic organisms, but are thought to lack PRK. Here we demonstrate the existence in methanogenic archaea of a carbon metabolic pathway involving RuBisCO and PRK, which we term 'reductive hexulose phosphate' (RHP) pathway. These archaea possess both RuBisCO and a catalytically active PRK whose crystal structure resembles that of photosynthetic bacterial PRK. Capillary electrophoresis-mass spectrometric analysis of metabolites reveals that the RHP pathway, which differs from the Calvin-Benson cycle only in a few steps, is active in vivo. Our work highlights evolutionary and functional links between RuBisCO-mediated carbon metabolic pathways in methanogenic archaea and photosynthetic organisms. Whether the RHP pathway allows for autotrophy (that is, growth exclusively with CO2 as carbon source) remains unknown. PMID- 28082750 TI - Equity Dynamics in the Perceived Fairness of Infant Care. AB - How is the perceived fairness of infant care affected by spouses' relative contributions to it as well as to other domains of their relationship? Longitudinal data on 178 couples expecting the birth of their first child were collected over a period spanning approximately the first year of the child's life. Overall, wives were more likely than husbands to see infant care as fair to the wife. Net of fathers' contributions to infant care, spouses were more likely to see infant care as fair to wives the more the father worked in paid labor and did housework and the more wives benefited in the sexual relationship. Fathers' contributions to infant care had a stronger effect on fairness when the child was a son. The findings are consistent with equity predictions, in that fathers' compensatory contributions to other domains of marriage counterbalance an unequal workload in the arena of family work. PMID- 28082751 TI - Local dispersal of Puccinia striiformis f. sp. tritici from isolated source lesions. AB - Understanding how disease foci arise from single source lesions has not been well studied. Here, single wheat leaves were inoculated with Puccinia striiformis f. sp. tritici urediniospores, and all wheat leaves within two intersecting 0.3 * 3.0 m transects were sampled in eight replicates over three years. The lesions observed on each of the top three leaves on plants within 1.5 m from the source lesion were three-dimensionally mapped. The total number of lesions within a 1.5 m radius was estimated by dividing the number of lesions observed within each 0.025 m-wide annulus by the fraction of the annulus sampled. The estimated total number of lesions produced within 1.5 m of a single source lesion ranged from 27 to 776, with a mean of 288 lesions. Eighty percent of the lesions were recorded within 0.69 m of the source infection. The proportion of total lesions observed at a given distance from the source was fitted well by the Lomax and Weibull distributions, reflecting the large proportion of lesions arising close to the source, and when fitted to an inverse-power distribution had a slope (b) of 2.5. There were more lesions produced on leaves higher in the canopy than on lower leaves, with more lesions being detected above than below the point of inoculation. Simultaneous measurement of lesion gradients and spore dispersal in the final year of the study suggests that this pattern is due to greater susceptibility of upper leaves, rather than increased dispersal to upper leaves. PMID- 28082752 TI - Rural Agricultural Change and Individual Out-migration. PMID- 28082753 TI - PRODUCTION AND ECONOMIC OPTIMIZATION OF DIETARY PROTEIN AND CARBOHYDRATE IN THE CULTURE OF JUVENILE SEA URCHIN Lytechinus variegatus. AB - Juvenile Lytechinus variegatus (ca. 3.95+/- 0.54 g) were fed one of 10 formulated diets with different protein (ranging from 11- 43%) and carbohydrate (12 or 18%; brackets determined from previous studies) levels. Urchins (n= 16 per treatment) were fed a daily sub-satiation ration equivalent to 2.0% of average body weight for 10 weeks. Our objective was (1) to create predictive models of growth, production and efficiency outcomes and (2) to generate economic analysis models in relation to these dietary outcomes for juvenile L. variegatus held in culture. At dietary protein levels below ca. 30%, models for most growth and production outcomes predicted increased rates of growth and production among urchins fed diets containing 18% dietary carbohydrate levels as compared to urchins fed diets containing 12% dietary carbohydrate. For most outcomes, growth and production was predicted to increase with increasing level of dietary protein up to ca. 30%, after which, no further increase in growth and production were predicted. Likewise, dry matter production efficiency was predicted to increase with increasing protein level up to ca. 30%, with urchins fed diets with 18% carbohydrate exhibiting greater efficiency than those fed diets with 12% carbohydrate. The energetic cost of dry matter production was optimal at protein levels less than those required for maximal weight gain and gonad production, suggesting an increased energetic cost (decreased energy efficiency) is required to increase gonad production relative to somatic growth. Economic analysis models predict when cost of feed ingredients are low, the lowest cost per gram of wet weight gain will occur at 18% dietary carbohydrate and ca. 25- 30% dietary protein. In contrast, lowest cost per gram of wet weight gain will occur at 12% dietary carbohydrate and ca. 35- 40% dietary protein when feed ingredient costs are high or average. For both 18 and 12% levels of dietary carbohydrate, cost per gram of wet weight gain is predicted to be maximized at low dietary protein levels, regardless of feed ingredient costs. These models will compare dietary requirements and growth outcomes in relation to economic costs and provide insight for future commercialization of sea urchin aquaculture. PMID- 28082754 TI - Race, Adolescent Binge Drinking, and the Context of Neighborhood Exposure. AB - Drawing on theories of social structure and normative exposure, we examine how the neighborhood context of socioeconomic advantage and racial composition affects race/ethnic differences in youth binge drinking. Using data from Waves 1 and 2 of the National Longitudinal Study of Adolescent to Adult Health, logistic regressions reveal significant racial differences, with whites having higher odds of binge drinking than other groups. We also find that neighborhood advantage and racial composition have moderating effects on binge drinking; black youths' odds of binge drinking are significantly lower than whites' odds in highly advantaged neighborhoods, and Hispanics living in racially integrated neighborhoods have significantly lower odds of binge drinking than Hispanics living in white neighborhoods. PMID- 28082755 TI - The Self-Fulfilling Prophecy of Adolescent Social Expectations. AB - Adolescents' negative social expectations of their peers were examined as long term predictors of problematic self-reported social functioning. Early adolescent negative expectations were hypothesized to predict risk-averse functioning in late adolescence that would ultimately contribute to confirmation of those expectations. Utilizing observational data and friend- and self-reports from a community sample of 184 adolescents followed from ages 13 to 25, adolescents with more negative expectations were found to have become increasingly submissive with friends over time and were rated as less romantically appealing by late adolescence (after controlling for baseline levels of these variables, baseline friend-rated social competence and self-reported depressive symptoms). In turn, submissiveness and romantic appeal predicted problematic self-reported social functioning well into adulthood and mediated the relationship between adolescent negative expectations and problematic self-reported adult social functioning. These findings support the possibility of a self-fulfilling social process unfolding from early adolescence to adulthood. PMID- 28082756 TI - Executive Function as a Mediator Between SES and Academic Achievement Throughout Childhood. AB - Childhood socioeconomic status (SES), as measured by parental education and family income, is highly predictive of academic achievement, but little is known about how specific cognitive systems shape SES disparities in achievement outcomes. This study investigated the extent to which executive function (EF) mediated associations between parental education and family income and changes in reading and math achievement in a sample of 336 children between the ages of 6 and 15 years from the NIH MRI Study of Normal Brain Development. Verbal memory was simultaneously modeled as a comparison candidate mediator. SES predicted significant changes in reading and math achievement over a two-year time period. Furthermore, executive function, but not verbal memory, was found to partially mediate the relationship between SES variables and change in math achievement. Collectively, these results suggest that executive function may be an important link between childhood SES and academic achievement. PMID- 28082757 TI - Diversity and taxonomy of Chaetomium and chaetomium-like fungi from indoor environments. AB - During a study of indoor fungi, 145 isolates belonging to Chaetomiaceae were cultured from air, swab and dust samples from 19 countries. Based on the phylogenetic analyses of DNA-directed RNA polymerase II second largest subunit (rpb2), beta-tubulin (tub2), ITS and 28S large subunit (LSU) nrDNA sequences, together with morphological comparisons with related genera and species, 30 indoor taxa are recognised, of which 22 represent known species, seven are described as new, and one remains to be identified to species level. In our collection, 69 % of the indoor isolates with six species cluster with members of the Chaetomium globosum species complex, representing Chaetomium sensu stricto. The other indoor species fall into nine lineages that are separated from each other with several known chaetomiaceous genera occurring among them. No generic names are available for five of those lineages, and the following new genera are introduced here: Amesia with three indoor species, Arcopilus with one indoor species, Collariella with four indoor species, Dichotomopilus with seven indoor species and Ovatospora with two indoor species. The generic concept of Botryotrichum is expanded to include Emilmuelleria and the chaetomium-like species B. muromum (= Ch. murorum) in which two indoor species are included. The generic concept of Subramaniula is expanded to include several chaetomium-like taxa as well as one indoor species. Humicola is recognised as a distinct genus including two indoor taxa. According to this study, Ch. globosum is the most abundant Chaetomiaceae indoor species (74/145), followed by Ch. cochliodes (17/145), Ch. elatum (6/145) and B. piluliferum (5/145). The morphological diversity of indoor Chaetomiaceae as well as the morphological characteristics of the new genera are described and illustrated. This taxonomic study redefines the generic concept of Chaetomium and provides new insight into the phylogenetic relationships among different genera within Chaetomiaceae. PMID- 28082759 TI - The forgotten Calonectria collection: Pouring old wine into new bags. AB - The genus Calonectria with its Cylindrocladium asexual morphs has been subject to several taxonomic revisions in the past. These have resulted in the recognition of 116 species, of which all but two species (C. hederae and C. pyrochroa) are supported by ex-type cultures and supplemented with DNA barcodes. The present study is based on a large collection of unidentified Calonectria isolates that have been collected over a period of 20 years from various substrates worldwide, which has remained unstudied in the basement of the CBS-KNAW Fungal Biodiversity Centre. Employing a polyphasic approach, the identities of these isolates were resolved and shown to represent many new phylogenetic species. Of these, 24 are newly described, while C. uniseptata is reinstated at species level. We now recognise 141 species that include some of the most important plant pathogens globally. PMID- 28082761 TI - Marital Adjustment and Psychological Distress in Japan. AB - This study was conducted to examine the association between marital adjustment and psychological distress in a large, probability sample of married adults in Japan (N = 710) from the Midlife Development in Japan (MIDJA) study. Results indicate that positive and negative dimensions of marital adjustment were significantly associated with dimensional and categorical measures of psychological distress. Furthermore, the associations between marital adjustment and psychological distress remained significant when statistically controlling for neuroticism, quality of friend and family relationships, and demographic variables. These results demonstrate that the well-established association between marital adjustment and psychological distress found in European-American countries is also found in Japan. Findings support continued research on marital functioning and psychological distress in East Asian countries. PMID- 28082760 TI - Aspergillus is monophyletic: Evidence from multiple gene phylogenies and extrolites profiles. AB - Aspergillus is one of the economically most important fungal genera. Recently, the ICN adopted the single name nomenclature which has forced mycologists to choose one name for fungi (e.g. Aspergillus, Fusarium, Penicillium, etc.). Previously two proposals for the single name nomenclature in Aspergillus were presented: one attributes the name "Aspergillus" to clades comprising seven different teleomorphic names, by supporting the monophyly of this genus; the other proposes that Aspergillus is a non-monophyletic genus, by preserving the Aspergillus name only to species belonging to subgenus Circumdati and maintaining the sexual names in the other clades. The aim of our study was to test the monophyly of Aspergilli by two independent phylogenetic analyses using a multilocus phylogenetic approach. One test was run on the publicly available coding regions of six genes (RPB1, RPB2, Tsr1, Cct8, BenA, CaM), using 96 species of Penicillium, Aspergillus and related taxa. Bayesian (MrBayes) and Ultrafast Maximum Likelihood (IQ-Tree) and Rapid Maximum Likelihood (RaxML) analyses gave the same conclusion highly supporting the monophyly of Aspergillus. The other analyses were also performed by using publicly available data of the coding sequences of nine loci (18S rRNA, 5,8S rRNA, 28S rRNA (D1-D2), RPB1, RPB2, CaM, BenA, Tsr1, Cct8) of 204 different species. Both Bayesian (MrBayes) and Maximum Likelihood (RAxML) trees obtained by this second round of independent analyses strongly supported the monophyly of the genus Aspergillus. The stability test also confirmed the robustness of the results obtained. In conclusion, statistical analyses have rejected the hypothesis that the Aspergilli are non-monophyletic, and provided robust arguments that the genus is monophyletic and clearly separated from the monophyletic genus Penicillium. There is no phylogenetic evidence to split Aspergillus into several genera and the name Aspergillus can be used for all the species belonging to Aspergillus i.e. the clade comprising the subgenera Aspergillus, Circumdati, Fumigati, Nidulantes, section Cremei and certain species which were formerly part of the genera Phialosimplex and Polypaecilum. Section Cremei and the clade containing Polypaecilum and Phialosimplex are proposed as new subgenera of Aspergillus. The phylogenetic analysis also clearly shows that Aspergillus clavatoflavus and A. zonatus do not belong to the genus Aspergillus. Aspergillus clavatoflavus is therefore transferred to a new genus Aspergillago as Aspergillago clavatoflavus and A. zonatus was transferred to Penicilliopsis as P. zonata. The subgenera of Aspergillus share similar extrolite profiles indicating that the genus is one large genus from a chemotaxonomical point of view. Morphological and ecophysiological characteristics of the species also strongly indicate that Aspergillus is a polythetic class in phenotypic characters. PMID- 28082762 TI - Lognormal Distributions and Geometric Averages of Symmetric Positive Definite Matrices. AB - This article gives a formal definition of a lognormal family of probability distributions on the set of symmetric positive definite (SPD) matrices, seen as a matrix-variate extension of the univariate lognormal family of distributions. Two forms of this distribution are obtained as the large sample limiting distribution via the central limit theorem of two types of geometric averages of i.i.d. SPD matrices: the log-Euclidean average and the canonical geometric average. These averages correspond to two different geometries imposed on the set of SPD matrices. The limiting distributions of these averages are used to provide large sample confidence regions and two-sample tests for the corresponding population means. The methods are illustrated on a voxelwise analysis of diffusion tensor imaging data, permitting a comparison between the various average types from the point of view of their sampling variability. PMID- 28082763 TI - Trophic ecology of introduced populations of Alaska blackfish (Dallia pectoralis) in the Cook Inlet Basin, Alaska. AB - Introduced non-native fishes have the potential to substantially alter aquatic ecology in the introduced range through competition and predation. The Alaska blackfish (Dallia pectoralis) is a freshwater fish endemic to Chukotka and Alaska north of the Alaska Range (Beringia); the species was introduced outside of its native range to the Cook Inlet Basin of Alaska in the 1950s, where it has since become widespread. Here we characterize the diet of Alaska blackfish at three Cook Inlet Basin sites, including a lake, a stream, and a wetland. We analyze stomach plus esophageal contents to assess potential impacts on native species via competition or predation. Alaska blackfish in the Cook Inlet Basin consume a wide range of prey, with major prey consisting of epiphytic/benthic dipteran larvae, gastropods, and ostracods. Diets of the introduced populations of Alaska blackfish are similar in composition to those of native juvenile salmonids and stickleback. Thus, Alaska blackfish may affect native fish populations via competition. Fish ranked third in prey importance for both lake and stream blackfish diets but were of minor importance for wetland blackfish. PMID- 28082758 TI - The good, the bad and the tasty: The many roles of mushrooms. AB - Fungi are often inconspicuous in nature and this means it is all too easy to overlook their importance. Often referred to as the "Forgotten Kingdom", fungi are key components of life on this planet. The phylum Basidiomycota, considered to contain the most complex and evolutionarily advanced members of this Kingdom, includes some of the most iconic fungal species such as the gilled mushrooms, puffballs and bracket fungi. Basidiomycetes inhabit a wide range of ecological niches, carrying out vital ecosystem roles, particularly in carbon cycling and as symbiotic partners with a range of other organisms. Specifically in the context of human use, the basidiomycetes are a highly valuable food source and are increasingly medicinally important. In this review, seven main categories, or 'roles', for basidiomycetes have been suggested by the authors: as model species, edible species, toxic species, medicinal basidiomycetes, symbionts, decomposers and pathogens, and two species have been chosen as representatives of each category. Although this is in no way an exhaustive discussion of the importance of basidiomycetes, this review aims to give a broad overview of the importance of these organisms, exploring the various ways they can be exploited to the benefit of human society. PMID- 28082764 TI - Learning metathesis: Evidence for syllable structure constraints. AB - One of the major questions in the cognitive science of language is whether the perceptual and phonological motivations for the rules and patterns that govern the sounds of language are a part of the psychological reality of grammatical representations. This question is particularly important in the study of phonological patterns - systematic constraints on the representation of sounds, because phonological patterns tend to be grounded in phonetic constraints. This paper focuses on phonological metathesis, which occurs when two adjacent sounds switch positions (e.g., cast pronounced as cats ). While many cases of phonological metathesis appear to be motivated by constraints on syllable structure, it is possible that these metathesis patterns are merely artifacts of historical change, and do not represent the linguistic knowledge of the speaker (Blevins & Garrett, 1998). Participants who were exposed to a metathesis pattern that can be explained in terms of structural or perceptual improvement were less likely to generalize to metathesis patterns that did not show the same improvements. These results support a substantively biased theory in which phonological patterns are encoded in terms of structurally motivated constraints. PMID- 28082765 TI - Individual differences in the bilingual brain: The role of language background and DRD2 genotype in verbal and non-verbal cognitive control. AB - Bilingual language control may involve cognitive control, including inhibition and switching. These types of control have been previously associated with neural activity in the inferior frontal gyrus (IFG) and the anterior cingulate cortex (ACC). In previous studies, the DRD2 gene, related to dopamine availability in the striatum, has been found to play a role in neural activity during cognitive control tasks, with carriers of the gene's A1 allele showing different patterns of activity in inferior frontal regions during cognitive control tasks than non carriers. The current study sought to extend these findings to the domain of bilingual language control. Forty-nine Spanish-English bilinguals participated in this study by providing DNA samples through saliva, completing background questionnaires, and performing a language production task (picture-naming), a non verbal inhibition task (Simon task), and a non-verbal switching task (shape-color task) in the fMRI scanner. The fMRI data were analyzed to determine whether variation in the genetic background or bilingual language background predicts neural activity in the IFG and ACC during these three tasks. Results indicate that genetic and language background variables predicted neural activity in the IFG during English picture naming. Variation in only the genetic background predicted neural activity in the ACC during the shape-color switching task; variation in only the language background predicted neural activity in the ACC and IFG during the Simon task. These results suggest that variation in the DRD2 gene should not be ignored when drawing conclusions about bilingual verbal and non-verbal cognitive control. PMID- 28082767 TI - Presidential Address at 42nd Annual Conference of the Indian Association of Pediatric Surgeons (IAPSCON 2016) Agra September 29-October 2, 2016. PMID- 28082766 TI - Vestibular Migraine: Clinical Challenges and Opportunities for Multidisciplinarity. AB - Migraine and vertigo are two very prevalent conditions in general population. The coexistence of both in the same subject is a significant clinical challenge, since it is not always possible to understand whether they are causally related or associated by chance, requiring different diagnostic and therapeutic approaches. In this review we analyze and summarize the actual knowledge about vestibular migraine (VM), focusing on the new concepts proposed by the International Classification of Headache Disorders 3-beta and by the Barany Society and also addressing the former concepts, which are still present in clinical practice. We conclude that clinical studies using a multidisciplinary approach are crucial in this field, since different specialists observe the same pathology with different eyes. Clinical presentation of VM is variable in what concerns vestibular symptoms temporal relation with migraine headache, as well as in their accompanying manifestations. Biomarkers, either genomics or functional, and molecular imaging techniques will be helpful to clarify many aspects of the complexity of this entity, helping to define to what extent can VM be considered a separate and independent clinical entity. PMID- 28082768 TI - Association of Levels of Serum Inhibin B and Follicle-stimulating Hormone with Testicular Vascularity, Volume, and Echotexture in Children with Undescended Testes. AB - AIMS: The aim of our study was to assess the association between reproductive hormones (inhibin B [inh B], follicle-stimulating hormone [FSH]) with testicular volume, echogenicity, and blood flow (resistive index [RI]) in children with undescended testis (UDT). SETTINGS AND DESIGN: This was a prospective study of 1 year study duration. MATERIALS AND METHODS: A total of 33 patients (16 unilateral and 17 bilateral) UDTs aged 5-12 years with palpable UDT were included in the study. Morning fasting blood samples were taken for estimation of serum inh B and FSH as well as inh B/FSH ratio. Testicular ultrasound was done to compute testicular volume, testicular echogenicity, and testicular vascularity in terms of RI. RESULTS: The mean age of patients enrolled in the study was 8.29 years for unilateral UDT and 7.97 years in bilateral UDT and it was comparable. The study groups were further subdivided into two age-wise subgroups school goers (5-8 years) and prepubertal (9-12 years). The values of inh B, FSH, and inh B/FSH ratios as well as mean testicular volume were comparable between both groups and subgroups. Overall mean testicular volume had a positive correlation with FSH, inh B, and inh B/FSH, but statistical significance was reached only for inh B (P < 0.001) in children with both unilateral and bilateral UDT. Apart from five patients with hypoechogenicity within the testis, all remaining testes were of homogenous echotexture with no instances of irregular echogenicity or tumor. Children with RI >0.6 were separately studied. The incidence of high RI (>0.6) was also comparable in unilateral or bilateral disease. These subjects had unfavorable biochemical parameters in terms of low inh B levels and high FSH levels. CONCLUSIONS: Our findings hint to the fact that palpable UDT forms a homogenous group, whether unilateral or bilateral, whereas impalpable testes may form a separate category and need further studies to substantiate this hypothesis. PMID- 28082769 TI - Pediatric Penile and Glans Anthropometry Nomograms: An Aid in Hypospadias Management. AB - OBJECTIVE: To establish pediatric penile and glans anthropometry nomograms. This may be used as a reference model for penile assessment while managing hypospadias. PATIENTS AND METHODS: Between October 2012 and September 2013, 263 boys of varying ages (0-16 years) were included in the study. Those with genetic, endocrine disorders, having genital anomaly, undescended testis, neonates, and infants with a nonretractile prepuce, with multiple congenital anomalies and refusal to take part in the study were excluded. Evaluated outcome variables were stretched penile length, glans circumference (GC) at coronal sulcus, glans diameter at coronal sulcus (Gdcl), mid glans diameter, and ventral glans length. Glans ratios were generated by dividing Gdcl by GC. Data were expressed as mean, median, and standard deviation. Correlation between age and variables was evaluated using nonparametric Spearman's rank correlation coefficient. RESULTS: The patients were divided in six age groups, namely 0-1 (n = 61), 1-3 (n = 37), 3 5 (n = 36), 5-7 (n = 36), 7-12 (n = 45), and >12 years (n = 48). Gdcl was the maximum transverse glans diameter and based on it small glans size varied widely from 8.9 to 35.04 mm for various age groups. Although glans anthropometry showed age-related changes, glans ratio remained relatively constant between 0.49 and 0.53 (mean: 0.5 +/- 0.051, r = 0.29). All the variables except glans ratio showed a significant positive correlation with age (r = 0.954-0.98, P < 0.01). CONCLUSION: Penile anthropometry nomograms provide a reference model for hypospadias. This may aid in (a) objective preoperative assessment of glans size (b) patient selection for preoperative hormonal stimulation (c) provides a yardstick for postoperative cosmesis. PMID- 28082770 TI - Assessment of Nutritional Status of Patients of Congenital Pouch Colon Following Definitive Surgery. AB - PURPOSE: To assess the nutritional status in 31 patients of congenital pouch colon (CPC) who had undergone definitive surgery and closure of a protective stoma, if any, at least 1 year earlier and were below 14 years age. MATERIALS AND METHODS: The clinical history, demographic details, anthropometric measurements, and results of hematological and biochemical tests were recorded. In addition to collective data, analysis was also performed after grouping by age, subtype of CPC (Types I/II and Types III/IV CPC), and in Types I/II CPC patients, by whether the colonic pouch had been completely excised or else a segment preserved by tubular colorraphy (TC). RESULTS: Severe fecal incontinence (FI) was common (64.52%). Anthropometry showed a significant malnutrition in 53.85-95.45% patients, especially stunting which was most prevalent in the 0-5 years age group. Serum Vitamin B12, folate, and Vitamin D were lower than normal in 38.71%, 22.58%, and 74.19% patients, respectively, without statistically significant difference among the various groups studied. Patients with Types I/II CPC had a statistically significant higher incidence of anemia, low serum ferritin, and severe FI than patients with Types III/IV CPC. Patients with Types I/II CPC, managed by excision of the colonic pouch, had a higher incidence of severe FI, wasting, and thinness than those undergoing TC. CONCLUSIONS: On follow-up of the patients of CPC, anthropometry shows a high incidence of malnutrition, especially stunting in the 0-5 years age-group. There is an adequate adaptation of fluid electrolyte homeostasis. Although Types I/II CPC patients have a significantly higher incidence of anemia and severe FI than Types III/IV CPC patients, long term anthropometric parameters are similar. In Types I/II CPC, preservation of the colonic pouch by TC offers long-term benefit. PMID- 28082771 TI - Quality of Life of Indian Pediatric Surgeons: Results of a Survey (of Indian Association of Pediatric Surgeons Members). AB - INTRODUCTION: Much is debated on the quality of life of pediatric surgeons practicing in India, all based on anecdotal and personal experiences. There is no systematic study on this. This study addresses this and attempts to glean a clearer picture of the life as a pediatric surgeon in India. METHODOLOGY: This questionnaire-based study was administered via an online survey to all Indian Association of Pediatric Surgeons members. The responses were anonymous and investigators blinded. Data were collated and analyzed using STAT11.1. RESULTS: A total of 173 pediatric surgeons responded. Eighty-six percent were men. About 73.7% of the surgeons were between 31 and 50 years of age. Almost 63.4% practiced in urban areas, whereas 36% in other smaller towns. About 0.6% reported that their practice was rural. Almost 26.4% were in private/solo practices, whereas 53.4% were in institution-based practice. Almost 80% felt that they were adequately trained while starting their practice. About 78% are professionally satisfied with their work. Only 44.5% of surgeons felt that they were compensated adequately financially. Reading was the favorite pass time. Almost 40% of the surgeons felt that they were either overweight or obese. About 41% of the surgeons exercise more than 3 times a week. Only 11.4% smoke, whereas 36% drink. Fifty-three percent of surgeons felt that their personal savings were adequate. Seventy-six percent use Facebook. Sixty-eight percent were satisfied with their quality of life. Age was significantly associated with professional satisfaction, financial satisfaction, and quality of life and all improve as one's age progresses. None were affected with one's gender, type of practice, and the place of practice. Age, weight, exercise, and one's savings significantly affected ones quality of life. CONCLUSION: This is the first study which objectively highlights that most surgeons are happy professionally and financially in due course of time and demolishes the common belief that pediatric surgeons are unsatisfied. It also acts as a point of reference and encouragement to newer aspirants in pediatric surgery. PMID- 28082772 TI - Progressive Perineal Urethroplasty for Pelvic Fracture Urethral Distraction Defect in Prepubertal Children: The Outcome. AB - BACKGROUND: Urethroplasty in pediatric patients is a challenging task. In this study, we have tried to assess the complexity and evaluate the outcome of progressive perineal anastomotic urethroplasty in prepubertal children. MATERIALS AND METHODS: Retrospective data of all the prepubertal children who underwent progressive perineal urethroplasty between March 2009 and April 2014 were analyzed. Patients were evaluated with history, examination, essential laboratory investigations, retrograde urethrogram, and voiding cystourethrogram. Before subjecting the patients for definitive surgery, antegrade and retrograde endoscopic assessment was done. The surgery was performed by the transperineal route with the help of *2.5 magnification. Patients were followed up with uroflowmetry for every 3 months in the 1st year and for every 6 months in the subsequent years. RESULTS: Mean age of the patients was 7.3 (range 5-11) years. Mean urethral distraction defect was 1.7 (range 1-2.5) cm. All the patients were successfully managed by the perineal approach. Crural separation was performed in all the patients while additional inferior pubectomy was required in six patients. Mean operating time was 298 (range 180-400) min. Mean blood loss was 174 (range 100-500) ml. One patient had the left calf hematoma in the immediate postoperative period. Seven out of nine (77.7%) patients had successful urethroplasty. Two patients had failed urethroplasty who were successfully managed by redo-urethroplasty. Transient incontinence was observed in one patient. Erectile function could not be assessed in these patients. CONCLUSION: This study shows the feasibility of progressive perineal urethroplasty by the perineal route in prepubertal children. An endoscopic assessment should be performed before the definitive surgery. Use of loupe helps in performing better anastomosis and hence yielding a better result. PMID- 28082773 TI - Determination of Normal Anal Position Index Using a Modified Technique in Turkish Neonates. AB - AIM: This study was aimed to determine the normal position of the anus using the anal position index (API) in an attempt to develop a more sensitive method for measuring API. To investigate API in a wide range of neonates, both term and preterm infants were included in the present study. MATERIALS AND METHODS: API was determined by measuring the anus-fourchette (FA) and anus-coccyx (AC) distance in female neonates and the anus-scrotum and AC distance in male neonates. API is defined as the ratio of the FA (scrotum) distance to the AC distance. A digital caliper was used for all measurements. The FA or scrotum and coccyx-fourchette or -scrotum distances were measured using digital calipers. RESULTS: A total of 267 neonates (females, 143; males 124) were included in this study. Of these, 36 were borderline premature infants (birth at 35-37 weeks gestation) and 231 were term infants (birth at 38-42 weeks gestation). The mean API was 1.06 +/- 0.04 in female and 0.90 +/- 0.08 in male neonates. When premature infants were analyzed separately, the mean API was 1.12 +/- 0.08 in female and 0.99 +/- 0.09 in male neonates. No significant difference in API values was observed between term and preterm neonates (P < 0.05). CONCLUSIONS: API values that differ from the previous studies were identified in the present study. We believe our modified method allows for more accurate measurements of the API in newborns. According to our method, the anus should be considered as anteriorly located if API is <1 in female and < 0.9 in male neonates. In addition, the present study is the first to measure API using digital calipers. Digital calipers were found to be convenient and are useful in determining the API with high accuracy (to within 0.01 cm). PMID- 28082774 TI - Epidemiology of Pediatric Trauma and its Pattern in Urban India: A Tertiary Care Hospital-Based Experience. AB - AIM: To assess the epidemiology, pattern, and outcome of trauma in pediatric population. MATERIALS AND METHODS: A total of 1148 pediatric patients below 15 years of age presenting in the emergency department of our hospital were studied over a period of 3 years. The patients were categorized into four age groups of <1 year, 1-5 years, 6-10 years, and 11-15 years. The data were compared regarding mode of trauma, type of injury, place of injury among different age groups and both sexes. RESULTS: The majority of the pediatric trauma cases were seen in males 69.86%, (n = 802) and females comprised only 30.13% (n = 346). Road traffic accident (RTA) was the most common mode of trauma in male children, i.e. 59.47% (n = 477) followed by fall injuries, i.e. 29.42% (n = 236). In females, fall was the most common mode of trauma, i.e. 52.31% (n = 181) followed by RTA (36.70%, n = 127). Fall injuries occurred mostly at homes. Among RTA, hit by vehicle on road while playing was most common followed by passenger accidents on two wheelers, followed by hit by vehicle while walking to school. Among fall, fall while playing at home was the most common. Out of total 1148 patients, 304 (26.48%) comprised the polytrauma cases (involvement of more than two organ systems), followed by abdominal/pelvic trauma (20.99%, n = 241), followed by head/face trauma (19.86%, n = 228). Out of total 1148 patients admitted over a period of 36 months, 64 died (5.57%). 75 (6.5%) patients had some kind of residual deformity or disability. CONCLUSION: The high incidence of pediatric trauma on roads and falls indicate the need for more supervision during playing and identification of specific risk factors for these injuries in our setting. This study shows that these epidemiological parameters could be a useful tool to identify burden and research priorities for specific type of injuries. A comprehensive trauma registry in our set up seems to be important for formulating policies to reduce pediatric trauma burden. PMID- 28082775 TI - Male Gender Assignment of a Child with Aphallia and Associated Complex Urological Anomaly. AB - A 2-year-old male child presented to us with aphallia. At birth, he was passing urine from the anus and had undergone emergency colostomy and pyelostomy for urinary sepsis at 1 week of life. After a complete evaluation, the child underwent perineal urethrostomy and scrotal phalloplasty followed by buccal mucosal tube urethroplasty in the second stage, which was completed before the child started schooling. PMID- 28082776 TI - Protean Presentations of Parathyroid Adenoma in Childhood. AB - Parathyroid adenoma is a rare disease which is known to present with protean manifestations, leading to misdiagnosis in the initial stage of the disease. It is known to pose a diagnostic dilemma to the clinician, in which a high index of suspicion alone often leads to a proper diagnosis and timely management. We encountered two such cases who presented to us with varied presentation, in which nuclear scintigraphy along with intraoperative parathyroid hormone assay played a major role in diagnosis and management. PMID- 28082777 TI - Extensive Chest Wall Tissue Loss and its Management by Vertical Rectus Abdominis Myocutaneous Flap. AB - Extensive electric burn around the chest in children is rare and this type of injury always poses a great challenge for its management. A 12-year-old male child with extensive electric burn of the chest wall was admitted to hospital. It was a neglected case of 9 days old burn; the young boy was in critical condition having systemic features of toxemia with widespread necrosis of the skin, subcutaneous tissues, and muscles along with exposed bones (ribs and sternum) with the risk of impending rupture of pleura through the exposed intercostal spaces. After initial resuscitation, a thorough debridement of all necrotic tissues was done. Thereafter, a superiorly based vertical rectus abdominis myocutaneous flap was harvested to cover the exposed bones and intercostal spaces. The remaining raw areas were skin grafted. The child made an excellent recovery with good outcome. PMID- 28082778 TI - Tessier 30 Facial Cleft with Duplication of Tongue. AB - A case of midline cleft of the lower lip, mandible, and the neck with complete duplication of the tongue repaired at neonatal period is reported here. Median cleft of the lower lip, mandible, and bifid tongue with ankyloglossia is reported in the literature, but cleft of the neck with complete duplication of the tongue as a part of the Tessier 30 cleft is very rare. We could not find such report in the available English literature. PMID- 28082779 TI - Laparoscopic Treatment of Median Arcuate Ligament Syndrome: A Rare Cause of Chronic Severe Abdominal Pain. AB - Median arcuate ligament syndrome is a rare disorder characterized by chronic postprandial abdominal pain and weight loss caused by compression on celiac artery. A 17-year-old girl with chronic severe abdominal pain and weight loss was referred to our clinic. Other causes of chronic abdominal pain were investigated and excluded. The compression on celiac artery was detected on Doppler ultrasound and diagnosis was confirmed by computed tomography angiography. The patient underwent laparoscopic release of median arcuate ligament. There were no intraoperative complications; however, partial pain response was observed postoperatively that necessitated para-spinal ganglion blockage. The patient is symptom-free in 1-year follow-up period. PMID- 28082780 TI - Intrauterine Arrow Injury. AB - Injury of a pregnant lady risks both mother and fetus. Various modes of injuries are possible. But arrow injury is not usually heard of in today's world. We have reported a male child delivered with a cut injury on the face. It was caused by a penetrating arrow hitting his mother in her lower abdomen at term. The injury of the baby was repaired successfully. PMID- 28082781 TI - Obstructive Jaundice Caused by Hepatic Torsion in an Infant with Congenital Diaphragmatic Hernia. AB - Right sided congenital diaphragmatic hernia may cause biliary obstruction. We present a 2 months female infant who had respiratory distress and persistent jaundice since birth. Investigations suggested direct hyperbilirubinemia, right sided diaphragmatic hernia with liver herniation in the thorax, and intra- and extrahepatic biliary dilatation. Laparotomy showed herniation of liver in the chest with hepatic torsion of about 180 degrees causing obstruction of bile ducts. Liver torsion was corrected and liver relocated in the abdomen. An operative cholangiogram confirmed free passage of contrast to the intestine after correction of hepatic torsion. Repair of the diaphragmatic hernia was performed. Only skin closure was performed leaving a ventral hernia to avoid abdominal compartment syndrome. Postoperatively, the baby was kept on ventilator for 2 days and then extubated. She showed rapid recovery and was discharged in a stable condition. The ventral hernia was repaired at the age of 6 months. Her total bilirubin levels dropped gradually from 12.50 mg/dl into its normal values within 3 months. PMID- 28082782 TI - Torsion of Accessory Hepatic Lobe. AB - An accessory hepatic lobe is a rare congenital anomaly that can undergo torsion and present as an acute surgical emergency. A 5-year-old child admitted as acute abdomen, on laparotomy found to have torsion of accessory lobe of liver, is being reported. PMID- 28082783 TI - Primary Pulmonary Rhabdomyosarcoma in a Child. AB - A 9-year-old female presented with fever, cough, and hemoptysis for a week. The chest skiagram and contrast-enhanced computerized tomography delineated a well defined solid lesion localized to the superior segment of the right lower lobe with features of a congenital pulmonary airway malformation. The lesion was surgically managed with a segmentectomy and histopathology confirmed a contained pulmonary rhabdomyosarcoma (RMS). No other primary site of origin was evident, and a final diagnosis of "primary" pulmonary RMS was made. She received adjuvant chemotherapy and was disease free after 6 years of surveillance. The unique clinicoradiological features of the case are discussed and the sparse literature is reviewed. PMID- 28082785 TI - Laparoscopic Pyloromyotomy. PMID- 28082784 TI - Fetal Cyst Reveling Retroperitoneal Enteric Duplication. AB - Retroperitoneum is a very uncommon site of enteric duplication (ED). We report a new case of retroperitoneal ED cyst suspected in utero. Prenatal ultrasound showed an abdominal cystic mass. Noncommunicating retroperitoneal ED cyst measuring 70 mm * 30 mm was resected. Histopathologic examination confirmed the diagnosis. PMID- 28082786 TI - Use of WhatsApp in Pediatric Surgery Division of General Surgery Department: Is it Worthwhile? PMID- 28082787 TI - Pancreatoblastoma Masquerading as a Retroperitoneal Germ Cell Tumor. PMID- 28082788 TI - Exploration of Phytochemicals Found in Terminalia sp. and their Antiretroviral Activities. AB - The human immunodeficiency virus (HIV) infects cells of the immune system and destroys their function. Approximately, 2 million people die every year from HIV as reported by the World Health Organization. HIV/AIDS is difficult to treat as the virus continuously develops resistance to drugs being developed. Approach is now turning toward natural products for the development of anti-HIV drugs. Although HIV/AIDS is not a new disease, but research based on plant-derived products is still under clinical trials. Experimentally, it has been proven that plants have the potential for HIV treatment. The process involves identification of the active ingredients responsible for the reported anti-HIV activities, testing of the extract, and development of appropriate bioassays. Further development would require optimization of the formulation and manufacturing in compliance with preclinical safety and efficacy testing. The most challenging task for the natural product scientists is to separate these highly complex extracts containing several compounds into its individual components that are biologically active. Recently developed direct binding assay with mass spectrometry (MS) technology (viz., real-time time-of-flight-MS) is helpful in this respect but needs extensive optimization. At present, we have compiled all the information for the various phytochemicals present in Terminalia catappa having anti-HIV properties. These include tannins, gallotannins, ellagitannins, cyanidin, and flavonoids. Further, we have also discussed their pharmacological as well as pharmacokinetics studies. PMID- 28082789 TI - Overviews of Biological Importance of Quercetin: A Bioactive Flavonoid. AB - Antioxidants are substances that may protect cells from the damage caused by unstable molecules such as free radicals. Flavonoids are phenolic substances widely found in fruits and vegetables. The previous studies showed that the ingestion of flavonoids reduces the risk of cardiovascular diseases, metabolic disorders, and certain types of cancer. These effects are due to the physiological activity of flavonoids in the reduction of oxidative stress, inhibiting low-density lipoproteins oxidation and platelet aggregation, and acting as vasodilators in blood vessels. Free radicals are constantly generated resulting in extensive damage to tissues leading to various disease conditions such as cancer, Alzheimer's, renal diseases, cardiac abnormalities, etc., Medicinal plants with antioxidant properties play a vital functions in exhibiting beneficial effects and employed as an alternative source of medicine to mitigate the disease associated with oxidative stress. Flavonoids have existed over one billion years and possess wide spectrum of biological activities that might be able to influence processes which are dysregulated in a disease. Quercetin, a plant pigment is a potent antioxidant flavonoid and more specifically a flavonol, found mostly in onions, grapes, berries, cherries, broccoli, and citrus fruits. It is a versatile antioxidant known to possess protective abilities against tissue injury induced by various drug toxicities. PMID- 28082791 TI - The Unexplored Anticaries Potential of Shiitake Mushroom. AB - Keeping an eye the escalating costs of dental services, the treatment cost of the consequences of dental caries can be reduced to manageable proportions by preventive measures aimed at decreasing the prevalence. One such measure is by increasing the consumption of caries preventive foods. Recently, there has been an upsurge of interest in mushrooms not only as a healthy food but also as a caries preventive food. The most common type of mushroom, Lentinula edodes also called as shiitake, is studied in-depth for its oral health benefits. The cultivation of shiitake dates way back to 1100 A.D. during the rule of Sung dynasty which is replaced by more modern and efficient sawdust substrate log cultures lately. Shiitake mushroom extract can be isolated in various forms such as freeze dried, oil, and ethyl acetate extracts. Various biologically active compounds such as erythritol, copalic acid, adenosine, carvacrol, and many more are responsible for this mushroom's antimicrobial activity. Anticariogenicity can be attributed to the induction of the detachment of cariogenic microorganisms from hydroxyapatite, changes in cell surface hydrophobicity, bactericidal activity, and disruption of signal transduction in Streptococcus mutans as proved through various in vivo and in vitro studies. Apart from these benefits, it has tremendous potential to be used as an antioxidant, anticancer, antigingivitis, antifungal, and antiviral agent. The one and only known adverse reaction due to shiitake mushroom consumption is the eruption of pruritic erythematous papules termed as shiitake dermatitis. This review highlights the unexplored anticaries potential of one such useful bioactive metabolite-shiitake mushroom. PMID- 28082790 TI - Anticancer Alkaloids from Trees: Development into Drugs. AB - Trees have made an enormous phytochemical contribution in anticancer drugs' development more than any other life form. The contributions include alkaloids that are biosynthesized in various ways and yield. Lead alkaloids isolated from the trees are taxol and camptothecins that currently have annual sales in billion dollars. Other important alkaloids isolated from these life forms include rohitukine, harringtonine, acronycine, thalicarpine, usambarensine, ellipticine, and matrines. Studies on their mechanism of action and target on the DNA and protein of cancerous cells aided the development of potent hemisynthesized congeners. The molecules and their congeners passed/are passing a long period of historical development before approved as antineoplastic drugs for cancer chemotherapy. Some of them did not find the application as anticancer drugs due to ineffectiveness in clinical trials; others are generating research interest in the antineoplastic activity at the present and have reached clinical trial stages. Potentials in antineoplastic molecules from trees are high and are hoped to be commensurate with cancer types afflicting human society in the future. PMID- 28082792 TI - Review of Neuro-nutrition Used as Anti-Alzheimer Plant, Spinach, Spinacia oleracea. AB - Neuro-nutrition is the nutrition needed to achieve health brain and neurocognitive function. Diets rich in antioxidants, vitamins, flavonoids, and polyphenolic compounds will help suppress the onset of Alzheimer's disease. Spinacia oleracea (Family: Amaranthaceae) commonly known as spinach or Buai Leng (in Thai), one of the traditional medicinal plants with high in those mention nutrients. The micronutrients in spinach include a range of vitamins and minerals, which can prevent deficiency diseases and are essential for normal physiological function. Its phytochemicals are carotenoids, flavonoids, and phenolic compounds, which can prevent chronic health problems, as well as other diseases associated with aging. The objective of this article was to conduct a review on various ethnomedicinal uses of the spinach and its influences on the pathophysiology of Alzheimer's disease based on a literature review. PMID- 28082793 TI - An Updated Review on the Phytochemistry, Pharmacology, and Clinical Trials of Salacia oblonga. AB - Salacia oblonga (S. oblonga), a perennial herb, has been used for thousands of years in ayurvedic medicine and is closely associated with prevention, treatment, and cure of various human ailments such as obesity and diabetes. A vast and wide range of chemical compounds such as polyphenols, friedelane-type triterpenes, norfriedelane-type triterpenes, eudesmane-type sesquiterpenes including various glycosides had been isolated from this plant. This review is aimed to survey the literature covering the phytochemistry and pharmacology of S. oblonga and to review the scientific data including active components and their multi-targeted mechanisms of action against various metabolic syndromes. We also included clinical trials related to this plant in this review. The overview would assist researchers to gather scientific information related to S. oblonga in future. PMID- 28082794 TI - An Updated Review on Phytochemical Properties of "Golden Dewdrop" Duranta erecta. AB - Duranta erecta (family: Verbenaceae) commonly referred to golden dewdrop, pigeon berry, angel whisper, or skyflower is one of the traditional medicinal plants. It has been shown to possess antimicrobial, antioxidant, and insecticide properties. Its phytoconstituents such as alkaloids, flavonoids, glycosides, phenolics, saponins, steroids, tannins, and terpenoids are reported as the basis of its efficacious therapeutic properties. The other important constituents which contribute to the remedial properties are durantol, pectolinaringenin, repennoside, repenins, and scutellarein. Published information on the phytochemical property of D. erecta was gathered by the use of different database platforms, including Google Scholar, ScienceDirect, PubMed, SciFinder, and Scopus, that provided an up-to-date review on its importance. PMID- 28082795 TI - Anticancer Activity of Key Lime, Citrus aurantifolia. AB - Citrus aurantifolia (family: Rutaceae) is mainly used in daily consumption, in many cultural cuisines, and in juice production. It is widely used because of its antibacterial, anticancer, antidiabetic, antifungal, anti-hypertensive, anti inflammation, anti-lipidemia, and antioxidant properties; moreover, it can protect heart, liver, bone, and prevent urinary diseases. Its secondary metabolites are alkaloids, carotenoids, coumarins, essential oils, flavonoids, phenolic acids, and triterpenoids. The other important constituents are apigenin, hesperetin, kaempferol, limonoids, quercetin, naringenin, nobiletin, and rutin, all of these contribute to its remedial properties. The scientific searching platforms were used for publications from 1990 to present. The abstracts and titles were screened, and the full-text articles were selected. The present review is up-to-date of the phytochemical property of C. aurantifolia to provide a reference for further study. PMID- 28082796 TI - A Complete Profile on Blind-your-eye Mangrove Excoecaria Agallocha L. (Euphorbiaceae): Ethnobotany, Phytochemistry, and Pharmacological Aspects. AB - Traditional system of medicine consists of large number of plants with various medicinal and pharmacological importances. This article provides a comprehensive review of the complete profile of an important mangrove plant Excoecaria agallocha L. (Euphorbiaceae) and elaborately describing the ethnobotany, phytochemistry, and pharmacological properties. It is used traditionally in the treatment of various diseases such as epilepsy, ulcers, leprosy, rheumatism, and paralysis. The latex obtained from the bark is poisonous in nature and may cause temporary blindness, thus it is also known as the blind-your-eye mangrove plant. Many phytoconstituents were isolated from the plant, which were mainly diterpenoids, triterpenoids, flavonoids, sterols, and few other compounds. The plant also showed many pharmacological activities such as antioxidant, antimicrobial, anti-inflammatory, analgesic, antiulcer, anticancer, antireverse transcriptase, antihistamine-release, antifilarial, DNA damage protective, antidiabetic, and antitumor protecting activities. Hence, this review could help guide researchers anticipating to undertake further investigations in these directions. PMID- 28082797 TI - Review Ergogenic Effect of Long Jack, Eurycoma Longifolia. AB - Eurycoma longifolia (family: Simaroubaceae) is commonly distributed in the Southeast Asia and Indo-China. In particular, the aqueous extract and decoction of its root are a well-known folk medicine which enhances sexuality, fertility, and antiaging. Furthermore, it has been shown to possess anti-inflammatory, antimalarial, antimicrobial, and antioxidant properties. Its common phytochemical components include alkaloids, flavonoids, phenolics, saponins, tannins, and triterpenes. This plant is rich in various quassinoids including eurycolactone, eurycomalactone, eurycomanol, eurycomanone, and eurycomaoside all of which has been reported to contribute to its remedial properties including increased muscle strength, endurance in cycling time, and reduced anxiety and stress. Based on established literature on the health benefits of E. longifolia, this review article has attempted to compile E. longifolia to be one of the choices of ergogenic plants. PMID- 28082798 TI - Is Myrtol(r) Standardized a New Alternative toward Antibiotics? AB - GeloMyrtol(r) and GeloMyrtol(r) forte, also known as Myrtol(r) standardized, is an herbal medical product (phytomedicine) obtained by a multistep distillation procedure from essential oils. The major biological marker of in vivo and ex vivo activity of Myrtol(r) standardized is the monoterpenes, d-limonene, 1,8-cineole, and alpha-pinene. Myrtol(r) standardized is estimated to have antioxidative, anti inflammatory, and antibacterial potential while many studies confirmed its secretolytic and bronchospasmolytic effects. As such, the medication is proposed to be initiated in several acute and chronic infections of the upper and lower airway system as acute and chronic rhinosinusitis, acute and chronic bronchitis, and chronic obstructive pulmonary disease. This review intends to give an insight into several prescription indications of Myrtol(r) standardized, all involved mechanisms, and potential advantages toward antibiotic therapy, especially in cases when bacterial infection is uncertain. PMID- 28082799 TI - Retraction: Oleandrin: A Cardiac Glycosides with Potent Cytotoxicity. AB - [This retracts the article on p. 131 in vol. 7, PMID: 24347921.]. PMID- 28082800 TI - Protons pump inhibitor treatment and lower gastrointestinal bleeding: Balancing risks and benefits. AB - Proton pump inhibitors (PPIs) represent a milestone in the treatment of acid related diseases, and are the mainstay in preventing upper gastrointestinal bleeding in high-risk patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin. However, this beneficial effect does not extend to the lower gastrointestinal tract. PPIs do not prevent NSAID or aspirin-associated lower gastrointestinal bleeding (LGB). PPIs may increase both small bowel injury related to NSAIDs and low-dose aspirin treatment and the risk of LGB. Recent studies suggested that altering intestinal microbiota by PPIs may be involved in the pathogenesis of NSAID-enteropathy. An increase in LGB hospitalization rates may occur more frequently in older patients with more comorbidities and are associated with high hospital resource utilization, longer hospitalization, and increased mortality. Preventive strategies for NSAID and aspirin-associated gastrointestinal bleeding should be directed toward preventing both upper and lower gastrointestinal damage. Future research should be directed toward identifying patients at low-risk for gastrointestinal events associated with the use of NSAIDs or aspirin to avoid inappropriate PPI prescribing. Alternatively, the efficacy of new pharmacologic strategies should be evaluated in high-risk groups, with the aim of reducing the risk of both upper and lower gastrointestinal bleeding in these patients. PMID- 28082801 TI - Does pressure cause liver cirrhosis? The sinusoidal pressure hypothesis. AB - Independent of their etiology, all chronic liver diseases ultimately lead to liver cirrhosis, which is a major health problem worldwide. The underlying molecular mechanisms are still poorly understood and no efficient treatment strategies are available. This paper introduces the sinusoidal pressure hypothesis (SPH), which identifies an elevated sinusoidal pressure (SP) as cause of fibrosis. SPH has been mainly derived from recent studies on liver stiffness. So far, pressure changes have been exclusively seen as a consequence of cirrhosis. According to the SPH, however, an elevated SP is the major upstream event that initiates fibrosis via biomechanic signaling by stretching of perisinusoidal cells such as hepatic stellate cells or fibroblasts (SPH part I: initiation). Fibrosis progression is determined by the degree and time of elevated SP. The SPH predicts that the degree of extracellular matrix eventually matches SP with critical thresholds > 12 mmHg and > 4 wk. Elevated arterial flow and final arterialization of the cirrhotic liver represents the self-perpetuating key event exposing the low-pressure-organ to pathologically high pressures (SPH part II: perpetuation). It also defines the "point of no return" where fibrosis progression becomes irreversible. The SPH is able to explain the macroscopic changes of cirrhotic livers and the uniform fibrotic response to various etiologies. It also opens up new views on the role of fat and disease mechanisms in other organs. The novel concept will hopefully stimulate the search for new treatment strategies. PMID- 28082802 TI - Updated therapeutic outcome for patients with periampullary and pancreatic cancer related to recent translational research. AB - Chemotherapy with improved effect in patients with metastatic pancreatic cancer has recently been established, launching a new era for patients with this very aggressive disease. FOLFIRINOX and gemcitabine plus nab-paclitaxel are different regimens, both capable of stabilizing the disease, thus increasing the number of patients who can reach second line and even third line of treatment. Concurrently, new windows of opportunity open for nutritional support and other therapeutic interventions, improving quality of life. Also pancreatic surgery has changed significantly during the latest years. Extended operations, including vascular/multivisceral resections are frequently performed in specialized centers, pushing borders of resectability. Potentially curative treatment including neoadjuvant and adjuvant chemotherapy is offered new patient groups. Translational research is the basis for the essential understanding of the ongoing development. Even thou biomarkers for clinical management of patients with periampullary tumors have almost been lacking, biomarker driven trials are now in progress. New insight is constantly made available for clinicians; one recent example is selection of patients for gemcitabine treatment based on the expression level of the human equilibrium nucleoside transporter 1. An example of new diagnostic tools is identification of early pancreatic cancer patients by a three-biomarker panel in urine: The proteins lymphatic vessel endothelial hyaluronan receptor 1, regenerating gene 1 alpha and translation elongation factor 1 alpha. Requirement of treatment guideline revisions is intensifying, as combined chemotherapy regimens result in unexpected advantages. The European Study Group for Pancreatic Cancer 4 trial outcome is an illustration: Addition of capecitabine in the adjuvant setting improved overall survival more than expected from the effect in advanced disease. Rapid implementation of new treatment options is mandatory when progress finally extends to patients with this serious disease. PMID- 28082804 TI - Gastric adenocarcinoma of the fundic gland (chief cell-predominant type): A review of endoscopic and clinicopathological features. AB - Gastric adenocarcinoma of the fundic gland (chief cell-predominant type, GA-FG CCP) is a rare variant of well-differentiated adenocarcinoma, and has been proposed to be a novel disease entity. GA-FG-CCP originates from the gastric mucosa of the fundic gland region without chronic gastritis or intestinal metaplasia. The majority of GA-FG-CCPs exhibit either a submucosal tumor-like superficial elevated shape or a flat shape on macroscopic examination. Narrow band imaging with endoscopic magnification may reveal a regular or an irregular microvascular pattern, depending on the degree of tumor exposure to the mucosal surface. Pathological analysis of GA-FG-CCPs is characterized by a high frequency of submucosal invasion, rare occurrences of lymphatic and venous invasion, and low-grade malignancy. Detection of diffuse positivity for pepsinogen-I by immunohistochemistry is specific for GA-FG-CCP. Careful endoscopic examination and detailed pathological evaluation are essential for early and accurate diagnosis of GA-FG-CCP. Nearly all GA-FG-CCPs are treated by endoscopic resection due to their small tumor size and low risk of recurrence or metastasis. PMID- 28082803 TI - Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets. AB - Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the absence of liver transplantation. Fibrosis generally results from chronic hepatic injury caused by various factors, mainly viral infection, schistosomiasis, and alcoholism; however, the exact pathological mechanisms are still unknown. Although numerous drugs have been shown to have antifibrotic activity in vitro and in animal models, none of these drugs have been shown to be efficacious in the clinic. Importantly, hepatic stellate cells (HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis. These cells are subject to intricate cross-talk with adjacent cells, resulting in scarring and subsequent liver damage. Thus, an understanding of the molecular mechanisms of liver fibrosis and their relationships with HSCs is essential for the discovery of new therapeutic targets. This comprehensive review outlines the role of HSCs in liver fibrosis and details novel strategies to suppress HSC activity, thereby providing new insights into potential treatments for liver fibrosis. PMID- 28082805 TI - Effects of Saccharomyces cerevisiae or boulardii yeasts on acute stress induced intestinal dysmotility. AB - AIM: To investigate the capacity of Saccharomyces cerevisiae (S. cerevisiae) and Saccharomyces boulardii (S. boulardii) yeasts to reverse or to treat acute stress related intestinal dysmotility. METHODS: Adult Swiss Webster mice were stressed for 1 h in a wire-mesh restraint to induce symptoms of intestinal dysmotility and were subsequently killed by cervical dislocation. Jejunal and colon tissue were excised and placed within a tissue perfusion bath in which S. cerevisiae, S. boulardii, or their supernatants were administered into the lumen. Video recordings of contractility and gut diameter changes were converted to spatiotemporal maps and the velocity, frequency, and amplitude of propagating contractile clusters (PCC) were measured. Motility pre- and post-treatment was compared between stressed animals and unstressed controls. RESULTS: S. boulardii and S. cerevisiae helped to mediate the effects of stress on the small and large intestine. Restraint stress reduced jejunal transit velocity (mm/s) from 2.635 +/ 0.316 to 1.644 +/- 0.238, P < 0.001 and jejunal transit frequency (Hz) from 0.032 +/- 0.008 to 0.016 +/- 0.005, P < 0.001. Restraint stress increased colonic transit velocity (mm/s) from 0.864 +/- 0.183 to 1.432 +/- 0.329, P < 0.001 and frequency to a lesser degree. Luminal application of S. boulardii helped to restore jejunal and colonic velocity towards the unstressed controls; 1.833 +/- 0.688 to 2.627 +/- 0.664, P < 0.001 and 1.516 +/- 0.263 to 1.036 +/- 0.21, P < 0.001, respectively. S. cerevisiae also had therapeutic effects on the stressed gut, but was most apparent in the jejunum. S. cerevisiae increased PCC velocity in the stressed jejunum from 1.763 +/- 0.397 to 2.017 +/- 0.48, P = 0.0031 and PCC frequency from 0.016 +/- 0.009 to 0.027 +/- 0.007, P < 0.001. S. cerevisiae decreased colon PCC velocity from 1.647 +/- 0.187 to 1.038 +/- 0.222, P < 0.001. Addition of S. boulardii or S. cerevisiae supernatants also helped to restore motility to unstressed values in similar capacity. CONCLUSION: There is a potential therapeutic role for S. cerevisiae and S. boulardii yeasts and their supernatants in the treatment of acute stress-related gut dysmotility. PMID- 28082806 TI - Effects of asymmetric dimethylarginine on renal arteries in portal hypertension and cirrhosis. AB - AIM: To evaluate the effects of asymmetric dimethylarginine (ADMA) in renal arteries from portal hypertensive and cirrhotic rats. METHODS: Rat renal arteries from Sham (n = 15), pre-hepatic portal hypertension (PPVL; n = 15) and bile duct ligation and excision-induced cirrhosis (BDL; n = 15) were precontracted with norepinephrine, and additional contractions were induced with ADMA (10-6-10-3 mol/L), an endogenous inhibitor of nitric oxide (NO) synthase. Concentration response curves to acetylcholine (1 * 10-9-3 * 10-6 mol/L) were determined in precontracted renal artery segments with norepinephrine in the absence and in the presence of ADMA. Kidneys were collected to determine the protein expression and activity of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that catabolizes ADMA. RESULTS: In renal arteries precontracted with norepinephrine, ADMA caused endothelium-dependent contractions. The pD2 values to ADMA were similar in the Sham and PPVL groups (4.20 +/- 0.08 and 4.11 +/- 0.09, P > 0.05, respectively), but were lower than those of the BDL group (4.79 +/- 0.16, P < 0.05). Acetylcholine-induced endothelium-dependent relaxation that did not differ, in terms of pD2 and maximal relaxation, among the 3 groups studied. Treatment with ADMA (3 * 10-4 mol/L) inhibited acetylcholine-induced relaxation in the 3 groups, but the inhibition was higher (P < 0.05) in the BDL group compared with that for the Sham and PPVL groups. The mRNA and protein expression of DDAH-1 were similar in kidneys from the three groups. Conversely, DDAH-2 expression was increased (P < 0.05) in PPVL and further enhanced (P < 0.05) in the BDL group. However, renal DDAH activity was significantly decreased in the BDL group. CONCLUSION: Cirrhosis increased the inhibitory effect of ADMA on basal and induced-release of NO in renal arteries, and decreased DDAH activity in the kidney. PMID- 28082807 TI - Clinical and epidemiological characteristics of norovirus gastroenteritis among hospitalized children in Lebanon. AB - AIM: To assess the burden of norovirus (NoV) and to determine the diversity of circulating strains among hospitalized children in Lebanon. METHODS: Stool samples were collected from children presenting with acute gastroenteritis to six major hospitals in Lebanon. A total of 739 eligible stool samples, testing negative for diarrhea caused by rotavirus as a possible viral pathogen, were collected between January 2011 and June 2013. A standardized questionnaire including demographic, epidemiological and clinical observations was used at the time of hospitalization of children presenting with diarrhea. Viral RNA was extracted from stool samples followed by reverse transcription polymerase chain reaction and nucleotide sequencing of a fragment of the viral protein 1 capsid gene. Multiple sequence alignments were carried out and phylogenetic trees were constructed using the MEGA 6 software. RESULTS: Overall, 11.2% of stool samples collected from children aged < 5 years tested positive for NoV genogroups I (GI) and II (GII). GII accounted for 10.6% of the gastroenteritis cases with only five samples being positive for GI (0.7%). The majority of hospitalized children showed symptoms of diarrhea, dehydration, vomiting and fever. Upon sequencing of positive samples and based on their clustering in the phylogenetic tree, 4/5 of GI gastroenteritis cases were designated GI.3 and one case as GI.4. GII.4 was predominantly detected in stool of our study participants (68%). We report a JB 15/KOR/2008 GII.4 Apeldoorn 2008-like variant strain circulating in 2011; this strain was replaced between 2012 and 2013 by a variant sharing homology with the Sydney/NSW0514/2012/AUS GII.4 Sydney 2012 and Sydney 2012/FRA GII.4 strains. We also report the co-circulation of non-GII.4 genotypes among hospitalized children. Our data show that NoV gastroenteritis can occur throughout the year with the highest number of cases detected during the hot months. CONCLUSION: The majority of NoV-associated viral gastroenteritis cases among our participants are attributable to GII.4, which is compatible with results reported worldwide. PMID- 28082808 TI - Helicobacter pylori inhibits the cleavage of TRAF1 via a CagA-dependent mechanism. AB - AIM: To study the impact on cleavage of tumor necrosis factor receptor-associated factor 1 (TRAF1) regulated by Helicobacter pylori (H. pylori). METHODS: Cleavage of TRAF1 was detected by western blotting in the human gastric cancer cell line AGS following treatment with an apoptosis inducer. Cleavage of TRAF1 mediated by caspase was examined in vitro using specific caspase inhibitors. The effect of the COOH-terminal TRAF1 fragment on gastric cell apoptosis during H. pylori infection was measured using flow cytometry. The impact of H. pylori infection on TRAF1 cleavage was detected in the presence of apoptosis inducer. The roles of H. pylori virulence factors that may regulate TRAF1 cleavage were analyzed using isogenic cagA-, vacA- and cagE-null mutants. RESULTS: TRAF1 was found to be cleaved in AGS cells treated with the apoptosis inducer, and caspase-8 was the major caspase involved in the cleavage of TRAF1. The COOH-terminal TRAF1 fragment significantly induced cell apoptosis (P < 0.05) as well as promoted H. pylori induced cell apoptosis (P < 0.05). H. pylori infection was found to significantly inhibit the cleavage of TRAF1 and to inhibit the activation of caspase-8 in the presence of the apoptosis inducer at specific infection times and different cell/bacteria ratios. We also found that the effects of cagE- and cagA-null mutants on the inhibition of TRAF1 cleavage and activation of caspase-8 were significantly attenuated, compared with wild-type H. pylori, in the presence of the apoptosis inducer, showing that the virulence factor CagA was mainly involved in the inhibition of TRAF1 cleavage. CONCLUSION: H. pylori infection significantly inhibits the cleavage of TRAF1 via a CagA-dependent mechanism, which would increase the relative amounts of full-length TRAF1 and exert an antiapoptotic effect on H. pylori-infected cells. PMID- 28082809 TI - Repair of a common bile duct defect with a decellularized ureteral graft. AB - AIM: To evaluate the feasibility of repairing a common bile duct defect with a decellularized ureteral graft in a porcine model. METHODS: Eighteen pigs were randomly divided into three groups. An approximately 1 cm segment of the common bile duct was excised from all the pigs. The defect was repaired using a 2 cm long decellularized ureteral graft over a T-tube (T-tube group, n = 6) or a silicone stent (stent group, n = 6). Six pigs underwent bile duct reconstruction with a graft alone (stentless group). The surviving animals were euthanized at 3 mo. Specimens of the common bile ducts were obtained for histological analysis. RESULTS: The animals in the T-tube and stent groups survived until sacrifice. The blood test results were normal in both groups. The histology results showed a biliary epithelial layer covering the neo-bile duct. In contrast, all the animals in the stentless group died due to biliary peritonitis and cholangitis within two months post-surgery. Neither biliary epithelial cells nor accessory glands were observed at the graft sites in the stentless group. CONCLUSION: Repair of a common bile duct defect with a decellularized ureteral graft appears to be feasible. A T-tube or intraluminal stent was necessary to reduce postoperative complications. PMID- 28082810 TI - Regulating effect of TongXie-YaoFang on colonic epithelial secretion via Cl- and HCO3- channel. AB - AIM: To investigate the pharmacological effect of TongXie-YaoFang (TXYF) formula, a Chinese herbal formula, on Diarrhea-predominant irritable bowel syndrome (D IBS) rats. METHODS: In a neonatal maternal separation plus restraint stress (NMS + RS) model of D-IBS, male Sprague Dawley rats were randomly divided into two groups (NMS + RS group and TXYF-formula group) with no handlings were used as controls (NH group). Starting from postnatal day 60, rats in TXYF-formula group were administered TXYF-formula (4.92 g/100 g bodyweight) orally twice a day for 14 consecutive days while NH group and NMS + RS group were given distilled water. Using short-circuit current technology, we observed 5-HT-induced changes of current across ion channels, such as cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel, epithelial Na+ channel (ENaC), Ca2+-dependent Cl- channel (CACC), Na+-K+-2Cl- co-transporter (NKCC), and Na+-HCO3- co-transporter (NBC), in the colonic epithelium of three groups after exposure to drugs and specific blockers with a Power Lab System (AD Instruments International). RESULTS: Under basal conditions, the changes of short-circuit current (?Isc, uA/cm2) induced by 5-HT were similar in NH group and TXYF-formula group, and both higher than NMS + RS group (70.86 uA/cm2 +/- 12.32 uA/cm2, 67.67 uA/cm2 +/- 11.68 uA/cm2vs 38.8 uA/cm2 +/- 7.25 uA/cm2, P < 0.01, respectively). When CACC was blocked by 4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid, 5-HT-induced ?Isc was smaller in NMS + RS group than in NH group and TXYF-formula group, respectively (48.41 uA/cm2 +/- 13.15 uA/cm2vs 74.62 uA/cm2 +/- 10.73 uA/cm2, 69.22 uA/cm2 +/- 11.7 uA/cm2, P < 0.05, respectively). The similar result could be obtained when ENaC was blocked by Amiloride (44.69 uA/cm2 +/- 12.58 uA/cm2vs 62.05 uA/cm2 +/- 11.26 uA/cm2, 62.11 uA/cm2 +/- 12.01 uA/cm2, P < 0.05, respectively). However, when CFTR Cl- channel was blocked by 1,1-dimethyl piperidinium chloride (DPC), 5-HT-induced ?Isc did not significantly differ in three groups (42.28 uA/cm2 +/- 10.61 uA/cm2vs 51.48 uA/cm2 +/- 6.56 uA/cm2vs 47.75 uA/cm2 +/- 7.99 uA/cm2, P > 0.05, respectively). The similar results could also be obtained in three groups when NBC and NKCC were respectively blocked by their blockers. CONCLUSION: TXYF-formula can regulate the Cl- and HCO3- secretion of colonic mucosa via CFTR Cl- channel, Cl-/HCO3- exchanger, NBC and NKCC co transporters. PMID- 28082812 TI - Clinical significance of mesenteric panniculitis-like abnormalities on abdominal computerized tomography in patients with malignant neoplasms. AB - AIM: To clarify the association of malignancy with mesenteric panniculitis-like changes on computed tomography (CT). METHODS: All abdominal CT scans performed at NorthShore University HealthSystem showing mesenteric panniculitis from January 2005 to August 2010 were identified in the Radnet (RadNet Corporation, Los Angeles, CA) database. Patients with a new or known diagnosis of a malignancy were included for this analysis. Longitudinal clinical histories were obtained from electronic medical records. RESULTS: In total, 147794 abdominal CT scans were performed during the study period. Three hundred and fifty-nine patients had mesenteric panniculitis (MP)-like abnormalities on their abdominal CT. Of these patients, 81 patients (22.6%) had a known history of cancer at the time of their CT scan. Nineteen (5.3%) had a new diagnosis of cancer in concurrence with their CT, but the majority of these (14/19, 74%) were undergoing CT as part of a malignancy evaluation. Lymphomas were the most common cancers associated with MP like findings on CT (36 cases, 36%), with follicular lymphoma being the most frequent subtype (17/36). A variety of solid tumors, most commonly prostate (7) and renal cell cancers (6) also were seen. CT follow up was obtained in 56 patients. Findings in the mesentery were unchanged in 45 (80%), worsened in 6 (11%), and improved in 5 patients (9%). Positron emission tomography (PET) scans performed in 44 patients only showed a positive uptake in the mesenteric mass in 2 patients (5%). CONCLUSION: A new diagnosis of cancer is uncommon in patients with CT findings suggestive of MP. MP-like mesenteric abnormalities on CT generally remain stable in patients with associated malignancies. PET scanning is not recommended in the evaluation of patients with mesenteric panniculitis-like findings on CT. PMID- 28082811 TI - Risk stratification for malignant progression in Barrett's esophagus: Gender, age, duration and year of surveillance. AB - AIM: To clarify risk based upon segment length, diagnostic histological findings, patient age and year of surveillance, duration of surveillance and gender. METHODS: Patients registered with the United Kingdom Barrett's Oesophagus Registry from 9 United Kingdom centers were included. The outcome measures were (1) development of all grades of dysplasia; (2) development of high-grade of dysplasia or adenocarcinoma; and (3) development of adenocarcinoma. Prevalent cases and subjects with < 1 year of follow-up were excluded. The covariates examined were segment length, previous biopsy findings, age at surveillance, duration of surveillance, year of surveillance and gender. RESULTS: One thousand and one hundred thirty six patients were included (total 6474 patient-years). Fifty-four patients developed adenocarcinoma (0.83% per annum), 70 developed high grade dysplasia/adenocarcinoma (1.1% per annum) and 190 developed any grade of dysplasia (3.5% per annum). High grade dysplasia and adenocarcinoma increased with age and duration of surveillance. The risk of low-grade dysplasia development was not dependent on age at surveillance. Segment length and previous biopsy findings were also significant factors for development of dysplasia and adenocarcinoma. CONCLUSION: The risk of development of low-grade dysplasia is independent of age at surveillance, but high-grade dysplasia and adenocarcinoma were more commonly found at older age. Segment length and previous biopsy findings are also markers of risk. This study did not demonstrate stabilisation of the metaplastic segment with prolonged surveillance. PMID- 28082813 TI - Non-variceal upper gastrointestinal bleeding: Rescue treatment with a modified cyanoacrylate. AB - AIM: To evaluate the safety and efficacy of a modified cyanoacrylate [N-butyl-2 cyanoacrylate associated with methacryloxysulfolane (NBCA + MS)] to treat non variceal upper gastrointestinal bleeding (NV-UGIB). METHODS: In our retrospective study we took into account 579 out of 1177 patients receiving endoscopic treatment for NV-UGIB admitted to our institution from 2008 to 2015; the remaining 598 patients were treated with other treatments. Initial hemostasis was not achieved in 45 of 579 patients; early rebleeding occurred in 12 of 579 patients. Thirty-three patients were treated with modified cyanoacrylate: 27 patients had duodenal, gastric or anastomotic ulcers, 3 had post-mucosectomy bleeding, 2 had Dieulafoy's lesions, and 1 had duodenal diverticular bleeding. RESULTS: Of the 45 patients treated endoscopically without initial hemostasis or with early rebleeding, 33 (76.7%) were treated with modified cyanoacrylate glue, 16 (37.2%) underwent surgery, and 3 (7.0%) were treated with selective transarterial embolization. The mean age of patients treated with NBCA + MS (23 males and 10 females) was 74.5 years. Modified cyanoacrylate was used in 24 patients during the first endoscopy and in 9 patients experiencing rebleeding. Overall, hemostasis was achieved in 26 of 33 patients (78.8%): 19 out of 24 (79.2%) during the first endoscopy and in 7 out of 9 (77.8%) among early rebleeders. Two patients (22.2%) not responding to cyanoacrylate treatment were treated with surgery or transarterial embolization. One patient had early rebleeding after treatment with cyanoacrylate. No late rebleeding during the follow-up or complications related to the glue injection were recorded. CONCLUSION: Modified cyanoacrylate solved definitively NV-UGIB after failure of conventional treatment. Some reported life-threatening adverse events with other formulations, advise to use it as last option. PMID- 28082814 TI - Assessment of disease activity by fecal immunochemical test in ulcerative colitis. AB - AIM: To evaluate the efficacy of quantitative fecal immunochemical test (FIT) as biomarker of disease activity in ulcerative colitis (UC). METHODS: Between February 2013 and November 2014, a total of 82 FIT results, obtained in conjunction with colonoscopies, were retrospectivelyevaluated for 63 patients with UC. The efficacy of FIT for evaluation of disease activity was compared to colonoscopic findings. Quantitative fecal blood with automated equipment examined from collected feces. Endoscopic disease severity were assessed using the Mayo endoscopic subscore (MES) classification. The extent of disease were classified by proctitis (E1), left sided colitis (E2), and extensive colitis (E3). Clinical activity were subgrouped by remission or active. RESULTS: All of 21 patients with MES 0 had negative FIT (< 7 ng/mL), but 22 patients with MES 2 or 3 had a mean FIT of > 134.89 ng/mL. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of negative FIT about mucosal healing were 73.33%, 81.82%, 91.49%, 51.43% and 73.17%, respectively. The sensitivity, specificity, PPV, NPV and accuracy of predictive value of positive FIT (cutoff value > 100 ng/mL) about active disease status were 45.45%, 93.33%, 71.43%, 82.35% and 26.83%, respectively. Among patients with clinical remission, FIT was negative in 31 (81.6%) of 38 cases, with a mean fecal hemoglobin concentration of 6.12 ng/mL (range, negative to 80.9 ng/mL) for this group of patients. Among patients with clinical active disease, FIT was negative in 16 (36.4%) out of 44 cases, with a mean fecal hemoglobin concentration > 167.4 ng/mL for this group of patients. FIT was positively correlated with endoscopic activity (r = 0.626, P < 0.01) and clinical activity (r = 0.496, P < 0.01). But, FIT did not correlate with the extent of disease (r = -0.047, P = 0.676). CONCLUSION: Quantitative FIT can be a non-invasive and effective biomarker for evaluation of clinical and endoscopic activity in UC, but not predict the extent of disease. PMID- 28082815 TI - Capsule endoscopy and single-balloon enteroscopy in small bowel diseases: Competing or complementary? AB - AIM: To evaluate diagnostic yields of capsule endoscopy (CE) and/or single balloon enteroscopy (SBE) in patients with suspected small bowel diseases. METHODS: We retrospectively analyzed 700 patients with suspected small bowel diseases from September 2010 to March 2016. CE, SBE, or SBE with prior CE was performed in 401, 353, and 47 patients, respectively. Data from clinical and endoscopy records were collected for analysis. Indications, procedure times, diagnostic yields, and complications were summarized and evaluated. RESULTS: The overall diagnostic yield for the CE group was 57.6%. The diagnostic yield of CE in patients with obscure gastrointestinal bleeding (OGIB) was significantly greater than that in patients with no bleeding (70.5% vs 43.8%, P < 0.01). The overall diagnostic yield of SBE was 69.7%. There was no difference in the diagnostic yield of SBE between patients with OGIB and those with no bleeding (72.5% vs 68.9%, P = 0.534). Forty-seven patients underwent CE prior to SBE. Among them, the diagnostic yield of SBE with positive findings on prior CE was 93.3%. In addition, SBE detected two cases with superficial ulcer and erosive lesions in the small bowel, which were missed by CE. However, one case with lymphoma and two with Crohn's disease were not confirmed by SBE. The rate of capsule retention was 2.0%. There were no significant complications during or after SBE examinations. CONCLUSION: SBE is a safe and effective technique for diagnosing small bowel diseases. SBE with prior CE seemed to improve the diagnostic yield of small bowel diseases. PMID- 28082816 TI - Irritable bowel syndrome symptom severity improves equally with probiotic and placebo. AB - AIM: To determine the effects of Lactobacillus acidophilus NCFM on irritable bowel syndrome (IBS) symptoms and quality of life (QoL). METHODS: In this randomized triple-blind trial, adult IBS volunteers who were recruited according to Rome III criteria received 109 or 1010 colony-forming units of NCFM or placebo daily for 12 wk. IBS Symptom Severity Score (IBS-SSS), which constituted the primary outcome, and secondary outcomes, including individual IBS symptoms, IBS related QoL questionnaire, anxiety and depression, defecation frequency, and stool consistency, were assessed at baseline at the end of the 8-wk run-in period, after 4 and 12 wk of intervention, and after a 4-wk washout. RESULTS: A total of 340 of 391 randomized volunteers completed the trial. IBS-SSS improved over 12 wk of treatment in all treatment groups, decreasing by a mean +/- SD of 44.0 +/- 80.2, 50.8 +/- 82.4, and 48.3 +/- 72.2 in the placebo, active low-dose, and active high-dose groups, respectively. Similarly, secondary outcomes did not differ between treatment groups. However, in a post hoc analysis of volunteers with moderate to severe abdominal pain at baseline (VAS > 35/100), the treatment significantly reduced the sensation of abdominal pain. Pain scores fell by 20.8 +/- 22.8, 29.4 +/- 17.9, and 31.2 +/- 21.9 in the placebo, active low-dose, and active high-dose groups, respectively (P value for placebo vs combined active doses = 0.0460). CONCLUSION: NCFM alleviates moderate to severe abdominal pain, consistent with earlier observations of this strain mitigating visceral pain through increased analgesic receptor expression. PMID- 28082817 TI - Prevalence of upper gastrointestinal bleeding risk factors among the general population and osteoarthritis patients. AB - AIM: To assess the prevalence of possible risk factors of upper gastrointestinal bleeding (UGIB) and their age-group specific trend among the general population and osteoarthritis patients. METHODS: We utilized data from the National Health Insurance Service that included claims data and results of the national health check-up program. Comorbid conditions (peptic ulcer, diabetes, liver disease, chronic renal failure, and gastroesophageal reflux disease), concomitant drugs (aspirin, clopidogrel, cilostazol, non-steroidal anti-inflammatory drugs, steroid, anticoagulants, and SSRI), personal habits (smoking, and alcohol consumption) were considered as possible UGIB risk factors. We randomly imputed the prevalence of infection in the data considering the age-specific prevalence of Helicobacter pylori (H. pylori) infection in Korea. The prevalence of various UGIB risk factors and the age-group specific trend of the prevalence were identified. Prevalence was compared between osteoarthritis patients and others. RESULTS: A total of 801926 subjects (93855 osteoarthritis patients) aged 20 and above were included. The prevalence of individual and concurrent multiple risk factors became higher as the age increased. The prevalence of each comorbid condition and concomitant drug were higher in osteoarthritis patients. Thirty five point zero two percent of the overall population and 68.50% of osteoarthritis patients had at least one or more risk factors of UGIB. The prevalence of individual and concurrent multiple risk factors in younger age groups were also substantial. Furthermore, when personal habits (smoking, and alcohol consumption) and H. pylori infection were included, the prevalence of concurrent multiple risk factors increased greatly even in younger age groups. CONCLUSION: Prevalence of UGIB risk factors was high in elderly population, but was also considerable in younger population. Patient with osteoarthritis was at higher UGIB risk than those without osteoarthritis. Physicians should consider individualized risk assessment regardless of age when prescribing drugs or performing procedures that may increase the risk of UGIB, and take necessary measures to reduce modifiable risk factors such as H. pylori eradication or lifestyle counseling. PMID- 28082818 TI - Variable outcome in infantile-onset inflammatory bowel disease in an Asian cohort. AB - AIM: Infantile-onset inflammatory bowel disease (IO-IBD) with the onset of disease before 12 mo of age, is a different disease entity from childhood IBD. We aimed to describe the clinical features, outcome and role of mutation in interleukin-10 (IL-10) and interleukin-10 receptors (IL-10R) in Asian children with IO-IBD. METHODS: All cases of IO-IBD, defined as onset of disease before 12 mo of age, seen at University Malaya Medical Center, Malaysia were reviewed. We performed mutational analysis for IL10 and IL10R genes in patients with presenting clinical features of Crohn's disease (CD). RESULTS: Six [13%; CD = 3, ulcerative colitis (UC) = 2, IBD-unclassified (IBD-U) = 1] of the 48 children (CD = 25; UC = 23) with IBD have IO-IBD. At final review [median (range) duration of follow-up: 6.5 (3.0-20) years], three patients were in remission without immunosuppression [one each for post-colostomy (IBD-U), after standard immunosuppression (CD), and after total colectomy (UC)]. Three patients were on immunosuppression: one (UC) was in remission while two (both CD) had persistent disease. As compared with later-onset disease, IO-IBD were more likely to present with bloody diarrhea (100% vs 55%, P = 0.039) but were similar in terms of an associated autoimmune liver disease (0% vs 19%, P = 0.31), requiring biologics therapy (50% vs 36%, P = 0.40), surgery (50% vs 29%, P = 0.27), or achieving remission (50% vs 64%, P = 0.40). No mutations in either IL10 or IL10R in the three patients with CD and the only patient with IBD-U were identified. CONCLUSION: The clinical features of IO-IBD in this Asian cohort of children who were negative for IL-10 or IL-10R mutations were variable. As compared to childhood IBD with onset of disease after 12 mo of age, IO-IBD achieved remission at a similar rate. PMID- 28082819 TI - Risk factors of admission for acute colonic diverticulitis in a population-based cohort study: The North Trondelag Health Study, Norway. AB - AIM: To assess risk factors of hospital admission for acute colonic diverticulitis. METHODS: The study was conducted as part of the second wave of the population-based North Trondelag Health Study (HUNT2), performed in North Trondelag County, Norway, 1995 to 1997. The study consisted of 42570 participants (65.1% from HUNT2) who were followed up from 1998 to 2012. Of these, 22436 (52.7%) were females. The cases were defined as those 358 participants admitted with acute colonic diverticulitis during follow-up. The remaining participants were used as controls. Univariable and multivariable Cox regression analyses was used for each sex separately after multiple imputation to calculate HR. RESULTS: Multivariable Cox regression analyses showed that increasing age increased the risk of admission for acute colonic diverticulitis: Comparing with ages < 50 years, females with age 50-70 years had HR = 3.42, P < 0.001 and age > 70 years, HR = 6.19, P < 0.001. In males the corresponding values were HR = 1.85, P = 0.004 and 2.56, P < 0.001. In patients with obesity (body mass index >= 30) the HR = 2.06, P < 0.001 in females and HR = 2.58, P < 0.001 in males. In females, present (HR = 2.11, P < 0.001) or previous (HR = 1.65, P = 0.007) cigarette smoking increased the risk of admission. In males, breathlessness (HR = 2.57, P < 0.001) and living in rural areas (HR = 1.74, P = 0.007) increased the risk. Level of education, physical activity, constipation and type of bread eaten showed no association with admission for acute colonic diverticulitis. CONCLUSION: The risk of hospital admission for acute colonic diverticulitis increased with increasing age, in obese individuals, in ever cigarette smoking females and in males living in rural areas. PMID- 28082820 TI - Effects of premedication with Pronase for endoscopic ultrasound of the stomach: A randomized controlled trial. AB - AIM: To analyze the effects of premedication with Pronase for endoscopic ultrasound (EUS) examination of the stomach. METHODS: This was a prospective, randomized and controlled clinical study. All patients were randomly assigned to either the Pronase group or placebo group. The pretreatment solution was a mixed solution of 20000 U of Pronase and 60 mL sodium bicarbonate solution in the Pronase group, while an equal amount of sodium bicarbonate solution was administered to the placebo group. All operators, image evaluators and experimental recorders in EUS did not participate in the preparation and allocation of pretreatment solution. Two blinded investigators assessed the obscurity scores for the EUS images according to the size of artifacts (including ultrasound images of the gastric cavity and the gastric wall). Differences in imaging quality, the duration of examination and the usage of physiological saline during the examination process between the Pronase group and the control group were compared. RESULTS: No differences existed in patient demographics between the two groups. For the gastric cavity, the Pronase group had significantly lower mean obscurity scores than the placebo group (1.0476 +/- 0.77 vs 1.6129 +/- 0.96, respectively, P = 0.000). The mean obscurity scores for the gastric mucosal surface were significantly lower in the Pronase group than the placebo group (1.2063 +/- 0.90 vs 1.7581 +/- 0.84, respectively, P = 0.001). The average EUS procedure duration for the Pronase group was 11.60 +/- 3.32 min, which was significantly shorter than that of the placebo group (13.13 +/- 3.81 min, P = 0.007). Less saline was used in the Pronase group than the placebo group, and the difference was significant (417.94 +/- 121.38 mL vs 467.42 +/- 104.52 mL, respectively, P = 0.016). CONCLUSION: The group that had Pronase premedication prior to the EUS examination had clearer images than the placebo group. With Pronase premedication, the examination time was shorter, and the amount of saline used during the EUS examination was less. PMID- 28082822 TI - Measuring The Influence of Pearlite Dissolution on the Transient Dynamic Strength of Rapidly-Heated Plain Carbon Steels. AB - Carbon steels containing ferrite-pearlite microstructures weaken dramatically when pearlite dissolves into austenite on heating. The kinetics of this phase transformation, while fast, can play a role during dynamic, high temperature manufacturing processes, including high speed machining, when the time scale of this transformation is on the order of the manufacturing process itself. In such a regime, the mechanical strength of carbon steel can become time-dependent. The present work uses a rapidly-heated, high strain rate mechanical test to study the effect of temperature and time on the amount of pearlite dissolved and on the resulting transient effect on dynamic strength of a low and a high carbon (eutectoid) steel. Measurements indicate that the transient effect occurs for heating times less than about three seconds. The 1075 steel loses about twice the strength compared to the 1018 steel (85 MPa to 45 MPa) owing to its higher initial pearlite volume fraction. Pearlite dissolution is confirmed by metallographic examination of tested samples. Despite the different starting pearlite fractions, the kinetics of dissolution are comparable for the two steels, owing to the similarity in their initial pearlite morphology. PMID- 28082821 TI - Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein. AB - Precision medicine is defined by the administration of drugs based on the tumor's particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer (CRC). Besides for these well-known mutations, the purpose of performing larger genetic testing in this pathology is unknown. Recent reports have shown that using the poly ADP ribose polymerase (PARP) inhibitor olaparib in patients with homologous repair enzyme deficiency gave positive clinical results in breast, ovarian and prostate cancers. We have reported here the cases of 2 patients with multi-treated metastatic CRC who underwent somatic and constitutional exome analyses. The analyses revealed a loss of function mutation in a homologous repair enzyme resulting in the loss of heterozygosity for both patients (Check2 for the first patient and RAD51C for the second one). Both patients were treated with off-label usage of olaparib. While the first patient showed clinical benefit, reduction of carcinoembryonic antigen tumor marker and radiologic response, the second patient quickly presented a progression of the tumor. Additional genetic analyses revealed a frameshift truncating mutation of the TP53BP1 gene in the patient who progressed. Interestingly, deficiency in TP53BP1 was previously described to confer resistance to olaparib in mice breast cancer models. Our findings suggest that exome analysis may be a helpful tool to highlight targetable mutations in CRC and that olaparib may be efficient in patients with a homologous repair deficiency. PMID- 28082823 TI - Atlas-Based Ventricular Shape Analysis for Understanding Congenital Heart Disease. AB - Congenital heart disease is associated with abnormal ventricular shape that can affect wall mechanics and may be predictive of long-term adverse outcomes. Atlas based parametric shape analysis was used to analyze ventricular geometries of eight adolescent or adult single-ventricle CHD patients with tricuspid atresia and Fontans. These patients were compared with an "atlas" of non-congenital asymptomatic volunteers, resulting in a set of z-scores which quantify deviations from the control population distribution on a patient-by-patient basis. We examined the potential of these scores to: (1) quantify abnormalities of ventricular geometry in single ventricle physiologies relative to the normal population; (2) comprehensively quantify wall motion in CHD patients; and (3) identify possible relationships between ventricular shape and wall motion that may reflect underlying functional defects or remodeling in CHD patients. CHD ventricular geometries at end-diastole and end-systole were individually compared with statistical shape properties of an asymptomatic population from the Cardiac Atlas Project. Shape analysis-derived model properties, and myocardial wall motions between end-diastole and end-systole, were compared with physician observations of clinical functional parameters. Relationships between altered shape and altered function were evaluated via correlations between atlas-based shape and wall motion scores. Atlas-based shape analysis identified a diverse set of specific quantifiable abnormalities in ventricular geometry or myocardial wall motion in all subjects. Moreover, this initial cohort displayed significant relationships between specific shape abnormalities such as increased ventricular sphericity and functional defects in myocardial deformation, such as decreased long-axis wall motion. These findings suggest that atlas-based ventricular shape analysis may be a useful new tool in the management of patients with CHD who are at risk of impaired ventricular wall mechanics and chamber remodeling. PMID- 28082824 TI - Anticorrosive influence of Acetobacter aceti biofilms on carbon steel. AB - Microbiologically influenced corrosion (MIC) of carbon steel infrastructure is an emerging environmental and cost issue for the ethanol fuel industry, yet its examination lacks rigorous quantification of microbiological parameters that could reveal effective intervention strategies. To quantitatively characterize the effect of cell concentration on MIC of carbon steel, numbers of bacteria exposed to test coupons were systematically controlled to span four orders of magnitude throughout a seven-day test. The bacterium studied, Acetobacter aceti, has been found in ethanol fuel environments, and can convert ethanol to the corrosive species acetic acid. A. aceti biofilms formed during the test were qualitatively evaluated with fluorescence microscopy, and steel surfaces were characterized by scanning electron microscopy. During exposure, biofilms developed more quickly, and test reactor pH decreased at a faster rate, when cell exposure was higher. Resulting corrosion rates, however, were inversely proportional to cell exposure, indicating that A. aceti biofilms are able to protect carbon steel surfaces from corrosion. This is a novel demonstration of corrosion inhibition by an acid-producing bacterium that occurs naturally in corrosive environments. Mitigation techniques for MIC that harness the power of microbial communities have the potential to be scalable, inexpensive, and green solutions to industrial problems. PMID- 28082825 TI - Bayesian Variable Selection on Model Spaces Constrained by Heredity Conditions. AB - This paper investigates Bayesian variable selection when there is a hierarchical dependence structure on the inclusion of predictors in the model. In particular, we study the type of dependence found in polynomial response surfaces of orders two and higher, whose model spaces are required to satisfy weak or strong heredity conditions. These conditions restrict the inclusion of higher-order terms depending upon the inclusion of lower-order parent terms. We develop classes of priors on the model space, investigate their theoretical and finite sample properties, and provide a Metropolis-Hastings algorithm for searching the space of models. The tools proposed allow fast and thorough exploration of model spaces that account for hierarchical polynomial structure in the predictors and provide control of the inclusion of false positives in high posterior probability models. PMID- 28082826 TI - Parent-Child Aggression Risk in Expectant Mothers and Fathers: A Multimethod Theoretical Approach. AB - The current investigation evaluated whether cognitive processes characteristic of the Social Information Processing model predicted parent-child aggression (PCA) risk independent of personal vulnerabilities and resiliencies. This study utilized a multimethod approach, including analog tasks, with a diverse sample of 203 primiparous expectant mothers and 151 of their partners. Factors considered in this study included PCA approval attitudes, empathy, reactivity, negative child attributions, compliance expectations, and knowledge of non-physical discipline alternatives; additionally, vulnerabilities included psychopathology symptoms, domestic violence victimization, and substance use, whereas resiliencies included perceived social support, partner relationship satisfaction, and coping efficacy. For both mothers and fathers, findings supported the role of greater approval of PCA attitudes, lower empathy, more overreactivity, more negative attributions, and higher compliance expectations in relation to elevated risk of PCA. Moreover, personal vulnerabilities and resiliencies related to PCA risk for mothers; however, fathers and mothers differed on the nature of these relationships with respect to vulnerabilities as well as aspects of empathy and PCA approval attitudes. Findings provide evidence for commonalities in many of the factors investigated between mothers and fathers with some notable distinctions. Results are discussed in terms of how findings could inform prevention programs. PMID- 28082827 TI - Impaired fear recognition and social anxiety symptoms in adolescence. AB - This study represents the first examination of adolescent anxiety in relation to peer emotion recognition, rather than adult emotion recognition. Additionally, we examine potential mechanisms for the development of Social Anxiety in females. Facial emotion recognition (FER) is important for accurate social cognition, which is impaired in individuals with various disorders, including anxiety disorders. Social anxiety often onsets during adolescence, is observed more commonly in females, and is often associated with FER difficulties. Given the importance of peer interaction during adolescence, and some evidence that FER may differ as a function of the stimuli (adolescent or adult faces), we sought to study FER in relation to social anxiety symptoms using stimuli portraying adolescent faces. Male and female adolescents (N=64) completed an online survey in which they rated 257 child and adolescent emotional faces and completed a self report measure of social anxiety symptoms. We examined differences in emotion recognition (e.g., fear, anger, sadness) between individuals with high and low levels of social anxiety symptoms. Adolescents with high social anxiety symptoms were more likely to have problems correctly identifying fearful expressions (90.55% accuracy) compared to adolescents with low social anxiety symptoms (96.00% accuracy; t = 2.375, p = .021, d = 0.594), and this effect was observed exclusively in female adolescents. The observed sex difference in accurate identification of fearful faces in relation to social anxiety could suggest a potential mechanism for social anxiety development in adolescent females. PMID- 28082829 TI - Proactive Parent Engagement in Public Schools: Using a Brief Strengths and Needs Assessment in a Multiple-Gating Risk Management Strategy. AB - This study examined the viability of a brief, parent-reported strengths and needs assessment as the first step in a multiple-gating approach to proactive positive behavior support for families. The Positive Family Support-Strengths and Needs Assessment (PFS-SaNA) was designed to collaboratively engage parents early in the school year in a home-school coordinated Positive Family Support (PFS) system. In this study, we evaluated the reliability and validity of the PFS-SaNA in the context of public middle schools. Findings suggest that the 14-item, unidimensional PFS-SaNA shows convergent validity with teacher ratings of risk. It can be easily and cost-effectively used by school personnel when parents register their children for school at the beginning of each school year. PMID- 28082828 TI - Pharmacotherapy for Substance Use Disorders in Youths. AB - Despite recent advances in psychosocial treatments targeting adolescent substance use disorders (SUD), effect sizes generally remain small to modest, and few treatment-enrolled youth achieve sustained abstinence. Among adults, SUD-targeted pharmacotherapies have emerged as viable options to complement psychosocial treatments and enhance outcomes. Developmental differences exist in pharmacodynamics and treatment-response, and comparatively little research has focused on SUD-targeted pharmacotherapies for youth. This article provides a review and synthesis of relevant published clinical trials focusing on youth SUDs and co-occurring/comorbid psychiatric and substance use disorders. It offers recommendations for clinical practice and further research based on the limited findings to date. PMID- 28082830 TI - Numerical Simulation of the Freeze-Thaw Behavior of Mortar Containing Deicing Salt Solution. AB - This paper presents a one-dimensional finite difference model that is developed to describe the freeze-thaw behavior of an air-entrained mortar containing deicing salt solution. A phenomenological model is used to predict the temperature and the heat flow for mortar specimens during cooling and heating. Phase transformations associated with the freezing/melting of water/ice or transition of the eutectic solution from liquid to solid are included in this phenomenological model. The lever rule is used to calculate the quantity of solution that undergoes the phase transformation, thereby simulating the energy released/absorbed during phase transformation. Undercooling and pore size effects are considered in the numerical model. To investigate the effect of pore size distribution, this distribution is considered using the Gibbs-Thomson equation in a saturated mortar specimen. For an air-entrained mortar, the impact of considering pore size (and curvature) on freezing was relatively insignificant; however the impact of pore size is much more significant during melting. The fluid inside pores smaller than 5 nm (i.e., gel pores) has a relatively small contribution in the macroscopic freeze-thaw behavior of mortar specimens within the temperature range used in this study (i.e., +24 degrees C to -35 degrees C), and can therefore be neglected for the macroscopic freeze-thaw simulations. A heat sink term is utilized to simulate the heat dissipation during phase transformations. Data from experiments performed using a low-temperature longitudinal guarded comparative calorimeter (LGCC) on mortar specimens fully saturated with various concentration NaCl solutions or partially saturated with water is compared to the numerical results and a promising agreement is generally obtained. PMID- 28082832 TI - Asymmetric Dearomatization/Cyclization Enables Access to Polycyclic Chemotypes. AB - Enantioenriched, polycyclic compounds were obtained from a simple acylphloroglucinol scaffold. Highly enantioselective dearomatization was accomplished using a Trost ligand-palladium(0) complex. A computational DFT model was developed to rationalize observed enantioselectivities and revealed a key reactant-ligand hydrogen bonding interaction. Dearomatized products were used in visible light-mediated photocycloadditions and oxidative free radical cyclizations to obtain novel polycyclic chemotypes including tricyclo[4.3.1.01,4]decan-10-ones, bicyclo[3.2.1]octan-8-ones and highly substituted cycloheptanones. PMID- 28082831 TI - A Positive Psychology Intervention for Patients with an Acute Coronary Syndrome: Treatment Development and Proof-of-Concept Trial. AB - Positive psychological constructs are associated with superior outcomes in cardiac patients, but there has been minimal study of positive psychology (PP) interventions in this population. Our objective was to describe the intervention development and pilot testing of an 8-week phone-based PP intervention for patients following an acute coronary syndrome (ACS). Initial intervention development and single-arm proof-of-concept trial, plus comparison of the PP intervention to a subsequently-recruited treatment as usual (TAU) cohort. PP development utilized existing literature, expert input, and qualitative interview data in ACS patients. In the proof-of-concept trial, the primary outcomes were feasibility and acceptability, measured by rates of exercise completion and participant ratings of exercise ease/utility. Secondary outcomes were pre-post changes in psychological outcomes and TAU comparisons, measured using effect sizes (Cohen's d). The PP intervention and treatment manual were successfully created. In the proof-of-concept trial, 17/23 PP participants (74 %) completed at least 5 of 8 exercises. Participants rated the ease (M = 7.4/10; SD = 2.1) and utility (M = 8.1/10, SD = 1.6) of PP exercises highly. There were moderate pre post improvements (ds = .46-.69) in positive affect, anxiety, and depression, but minimal effects on dispositional optimism (d = .08). Compared to TAU participants (n = 22), PP participants demonstrated greater improvements in positive affect, anxiety, and depression (ds = . 47-.71), but not optimism. A PP intervention was feasible, well-accepted, and associated with improvements in most psychological measures among cardiac patients. These results provide support for a larger trial focusing on behavioral outcomes. PMID- 28082833 TI - Success in School for Justice-Involved Girls: Do Specific Aspects of Developmental Immaturity Matter? AB - Developmental immaturity (DI) may help explain some of the variability in aspects of academic achievement among girls in the juvenile justice system, a population with high rates of truancy, dropout, and school failure. This study examined the relationships among the decision making and independent functioning components of DI, verbal intelligence, and academic achievement within this population. Using data from 60 girls in residential juvenile justice facilities, multiple regression analyses indicated that verbal IQ moderated the relationship between the DI construct of decision making and academic achievement. Self-reported school attendance and number of previous arrests did not significantly mediate the relationship between DI and academic achievement. These results may indicate that the decision-making factor of DI may be particularly important, and, if results are replicated, future intervention efforts could focus more on improving this skill within this juvenile justice population. Additionally, the overall importance of the full DI construct is an important area of future study. PMID- 28082834 TI - Give Me a Hand: Adult Involvement During Object Exploration Affects Object Individuation in Infancy. AB - The development of object individuation, a fundamental ability that supports identification and discrimination of objects across discrete encounters, has been examined extensively by researchers. There are significant advancements in infants' ability to individuate objects during the first year-and-a-half. Experimental work has established a timeline of object individuation abilities and revealed some mechanisms underlying this ability, however, the influence of adult assistance during object exploration has not yet been explored. The current study investigates the effect of adult involvement during object exploration on infants' object individuation abilities. In Experiment 1a and 1b, we examined 9.5 month-old infants' colour-based object individuation following adult-assisted multisensory object exploration. Two components of adult interaction were of particular interest: facilitation of object manipulation (grasping, rotating, and attention-getting behaviours) and social engagement (smiling, pointing, attention getting verbalizations, and object-directed gaze). Experiment 2a and 2b assessed these components with 4.5-month-olds to examine their impact across development. The results showed that after adult-guided object exploration, both 9.5- and 4.5 month-old infants successfully individuated previously undifferentiated objects. Results of Experiments 1b and 2b provide implications for the mechanisms underlying the scaffolding influence of adult interaction during infant behaviours. PMID- 28082835 TI - Mothers' and Fathers' Reports of their Supportive Responses to their Children's Negative Emotions over Time. AB - OBJECTIVE: Parents' emotion socialization practices are thought to be moderately stable over time; however, a partner's socialization practices could initiate change. DESIGN: We examined mothers' and fathers' reports of their supportive responses to their children's negative emotions when the target child was 7 years old and again at age 10. We tested a dyadic, longitudinal path model with 111 mother-father pairs. RESULTS: Significant actor and partner effects emerged. Parents' age 7 responses predicted their own age 10 responses and their partners' later responses. CONCLUSIONS: Parents' reported responses to children's negative emotions during middle childhood are predicted by their own earlier responses and by their partners' responses. PMID- 28082836 TI - Incorporating Human-like Walking Variability in an HZD-Based Bipedal Model. AB - Predictive simulations of human walking could be used to investigate a wide range of questions. Promising moderately complex models have been developed using the robotics control technique hybrid zero dynamics (HZD). Existing simulations of human walking only consider the mean motion, so they cannot be used to investigate fall risk, which is correlated with variability. This work determines how to incorporate human-like variability into an HZD-based healthy human model to generate a more realistic gait. The key challenge is determining how to combine the existing mathematical description of variability with the dynamic model so that the biped is still able to walk without falling. To do so, the commanded motion is augmented with a sinusoidal variability function and a polynomial correction function. The variability function captures the variation in joint angles while the correction function prevents the variability function from growing uncontrollably. The necessity of the correction function and the improvements with a reduction of stance ankle variability are demonstrated via simulations. The variability in temporal measures is shown to be similar to experimental values. PMID- 28082837 TI - Trends in the Treatment of Dupuytren Disease in the United States Between 2007 and 2014. AB - Background: Dupuytren disease is a common fibroproliferative disorder. Multiple procedural treatment options are available, with Collagenase Clostridium Histolyticum (CCH) injection being introduced in 2010. The purpose of this study was to investigate trends in the treatment of Dupuytren disease in the United States between 2007 and 2014. Methods: The PearlDiver Humana database was queried using International Classification of Diseases, Ninth Revision (ICD-9) and Current Procedural Terminology (CPT) codes for patients with Dupuytren disease that received percutaneous needle aponeurotomy (PNA), fasciotomy, fasciectomy, and CCH injection. Patients were filtered by age, number of comorbidities, and gender. Change in composition of treatments over time was analyzed for each demographic group between 2007 and 2014. Results: Patients presenting to clinic for Dupuytren disease increased from 1118 to 3280, with unchanging treatment percentage of 41. Percent fasciotomies and fasciectomies decreased from 5% to 3% and 33% to 21%, while CCH injection increased to 11% by 2012 to 2014. Percent fasciotomies decreased (P < .05) in younger healthier (age <65, 0-1 comorbidities) and older less healthy (age 65-74, 4+ comorbidities) populations. Percent fasciectomies decreased significantly in nearly all age and comorbidity groups, but by greater amounts in patients with 2+ comorbidities with increasing age. Percent CCH injections increased in all groups, at rates similar to the losses seen in open procedures. Conclusions: CCH injections have risen to substantial levels, with corresponding decreases in the percentage of patients receiving fasciotomies and fasciectomies. Patient age, comorbidities, and gender appear to have influence on the treatment chosen, likely due to their effects on surgical risk and the importance of timely return to activity. PMID- 28082839 TI - Long-Term Outcomes of Scaphoid Malunion. AB - Background: The optimal treatment of patients with a scaphoid malunion remains controversial. The long-term outcomes of operative and nonoperative management have not been established. Methods: We conducted a retrospective review of the outcomes of all scaphoid malunions treated at single institution over a 30-year period. This included patients who underwent corrective osteotomy, salvage procedures (ie, dorsal cheilectomy, radial styloidectomy, and scaphoidectomy with midcarpal fusion), and those who refused operative intervention. The Mayo Wrist Score was determined at the time of surgical evaluation. Patient-Rated Wrist Evaluation (PRWE) and Disabilities of the Arm, Shoulder and Hand (QuickDASH) surveys were sent to all patients for long-term follow-up. Results: Seventeen patients had follow-up at a mean 21.4 years (range, 12-30 years). The mean initial lateral intrascaphoid angle was 58 degrees . Of the 17 patients, 11 proceeded with surgery and 6 opted for nonoperative management. A corrective osteotomy was performed in 4 patients. Of the remaining 7 surgical patients, 5 patients underwent procedures such as cheilectomy and radial styloidectomy, whereas 2 patients had a scaphoidectomy with midcarpal fusion. The final mean PRWE and QuickDASH scores for corrective osteotomy, salvage procedures, and nonoperative treatment were 23 and 6, 18 and 10, and 33 and 22, respectively. Conclusion: Long-term outcomes were similar between operative and nonoperative management. PMID- 28082838 TI - Hand Surgery and Fluoroscopic Eye Radiation Dosage: A Prospective Pilot Comparison of Large Versus Mini C-Arm Fluoroscopy Use. AB - Background: The purpose of this study is to (1) perform a prospective pilot comparison of the impact of large versus mini C-arm fluoroscopy on resultant eye radiation exposure and (2) test the hypothesis that the use of either modality during routine hand surgery does not exceed the current recommended limits to critical eye radiation dosage. Methods: Over a 12-month period, eye radiation exposure was prospectively measured by a board-certified hand surgeon using both large and mini C-arm fluoroscopy. For each modality, accumulated eye radiation dosage was measured monthly, while fluoroscopic radiation output was recorded, including total exposure time and dose rate. Results: A total of 58 cases were recorded using large C-arm and 25 cases using mini C-arm. Between the 2 groups, there was not a significant difference with total exposure time (P = .88) and average dose rate per case (P = .10). With the use of either modality, average monthly eye radiation exposure fell within the undetectable range (<30 mrem), significantly less than the current recommended limit of critical eye radiation (167 mrem/month). Conclusions: The impact of various fluoroscopic sources on eye radiation exposure remains relatively unexplored. In this study, the minimal detectable eye radiation dosages observed in both groups were reliably consistent. Our findings suggest that accumulated eye radiation dosage, from the use of either fluoroscopic modality, does not approach previously reported levels of critical radiation loads. PMID- 28082840 TI - A Survey of the Use of Ultrasound by Upper Extremity Surgeons. AB - Background: Ultrasound is a versatile imaging modality that can be used by upper extremity surgeons for diagnostic purposes and guided injections. The perceptions of ultrasound for diagnosis and treatment among upper extremity surgeons and its barriers for adoption have not been formally surveyed. The purpose of this study is to determine the current usage of musculoskeletal ultrasound for diagnostic purposes and guided injections by upper extremity surgeons and their reasons for using it or not using it in practice. Methods: A 22-question survey was distributed to the American Society for Surgery of the Hand (ASSH). The survey questions consisted of respondent characteristic questions and questions pertaining to the use of ultrasound. Chi-square analysis was performed to assess for a difference in ultrasound usage across respondent characteristics. Results: Three hundred four (43%) answered that they have an ultrasound machine in their office; Fifty-one percent (362) of the respondents use ultrasound for diagnostic purposes. Fifty-five (8%) of the survey respondents use ultrasound to diagnose carpal tunnel syndrome; 168 (23.5%) respondents reported that they use ultrasound for guided injections. There was a statistically significant difference between access to an ultrasound machine in the office by practice setting and use of ultrasound for diagnostic purposes by practice setting. Conclusions: The use of ultrasound by upper extremity surgeons is split for diagnostic purposes, with fewer surgeons using ultrasound to diagnose carpal tunnel syndrome and guided injections. Ultrasound machine availability and the use of ultrasound for diagnosis appear to be influenced by practice setting. PMID- 28082841 TI - Prospective Evaluation of Opioid Consumption Following Carpal Tunnel Release Surgery. AB - Background: Postoperative pain management and opioid consumption following carpal tunnel release (CTR) surgery may be influenced by many variables. To understand factors affecting opioid consumption, a prospective study was undertaken with the hypothesis that CTR performed under local anesthesia (wide awake local anesthesia with no tourniquet [WALANT]) would result in increased opioid consumption postoperatively compared with cases performed under sedation. Methods: All patients undergoing open CTR surgery were consecutively enrolled over a 6-month period. Information collected included patient demographics, surgical technique, amount and type of narcotic prescribed, number of pills taken, and type of anesthesia. Results: 277 patients were enrolled (56% women, 44% men). On average, 21 pills were prescribed, and 4.3 pills (median = 2) were consumed. There was no difference in consumption between patients who received WALANT (78 cases) versus (198 cases) sedation (4.9 vs 3.9 pills, respectively) (P = .22). There was no difference in opioid consumption based on insurance type (P = .47) or type of narcotic (P = .85). However, more men consumed no opioids (47%) compared with women (36%) (P < .05) and older patients consumed less than younger patients (P < .05). Conclusions: Opioid consumption following CTR is more influenced by age and gender, and less influenced by anesthesia type, insurance type, or the type of opioid prescribed. Many more opioids were prescribed than needed, on an average of 5:1. Many patients, particularly older patients, do not require any opioid analgesia after CTR. PMID- 28082842 TI - A Clinical Scoring System for Distinguishing Patients With Coincident Cubital Tunnel Syndrome Among Patients With Carpal Tunnel Syndrome. AB - Background: Coincident carpal and cubital tunnel syndromes present a diagnostic challenge, exacerbated by the limitations of nerve conduction study (NCS) for confirming cubital tunnel syndrome. This study develops a diagnostic scoring system, the Koh-Benhaim (KB) score, to identify patients with coincident compression neuropathies. Methods: A retrospective review of 515 patients was performed from patients surgically treated for carpal and/or cubital tunnel release. These patients were divided as patients with isolated carpal tunnel syndrome (n = 337) or coincident carpal and cubital tunnel syndromes (n = 178), then characterized according to demographics, medical history, physical examination, and NCS results. Univariate and multivariate logistic regression identified predictors of coincident neuropathy. A clinical score was constructed by integerizing regression coefficients of predictive factors. Receiver operating characteristic (ROC) curves were generated for each iteration of the score. Sensitivities, specificities, and positive and negative predictive values were calculated to identify the best cutoff value. Results: Decreased intrinsic muscle strength, decreased ulnar sensation, positive elbow flexion test, positive cubital tunnel Tinel's sign, and abnormal NCS result were selected. The cutoff value for high risk of coincident compression was 3 points: positive predictive value, 82.9% and specificity, 93.4%. Model performance was very good-ROC area under the curve of 0.917. Conclusions: A KB score of 3 or greater represents high risk of coincident cubital tunnel compression. The variables involved are routinely used to assess the cubital tunnel, and all component factors of the KB score were of equivalent clinical weight in assessing patients with potential coincident compression neuropathy. PMID- 28082843 TI - Brachial Plexus Blockade Causes Subclinical Neuropathy: A Prospective Observational Study. AB - Background: The objective of this study is to determine subclinical changes in hand sensation after brachial plexus blocks used for hand surgery procedures. We used Semmes-Weinstein monofilament testing to detect these changes. We hypothesized that patients undergoing brachial plexus nerve blocks would have postoperative subclinical neuropathy detected by monofilament testing when compared with controls. Methods: In total, 115 hand surgery adult patients were prospectively enrolled in this study. All patients undergoing nerve-related procedures were excluded as well as any patients with preoperative clinically apparent nerve deficits. Eighty-four patients underwent brachial plexus blockade preoperatively, and 31 patients underwent general anesthesia (GA). Semmes Weinstein monofilament testing of the hand was performed preoperatively on both the operative and nonoperative extremities and postoperatively at a mean of 11 days on both hands. Preoperative and postoperative monofilament testing scores were compared between the block hand and the nonoperated hand of the same patient, as well as between the block hands and the GA-operated hands. Results: There were no recorded clinically relevant neurologic complications in the block group or GA group. A statistically significant decrease in sensation in postoperative testing in the operated block hand compared with the nonoperated hand was noted. When comparing the operated block hand with the operated GA hand, there was a decrease in postoperative sensation in the operated block hand that did not reach statistical significance. Conclusions: Brachial plexus blockade causes subtle subclinical decreases in sensibility at short-term follow-up, without any clinically relevant manifestations. PMID- 28082844 TI - A Preliminary Assessment of the Utility of Large-Caliber Processed Nerve Allografts for the Repair of Upper Extremity Nerve Injuries. AB - Background: Cabled sensory nerve autografts are the historical gold standard for overcoming gaps in larger diameter nerves as repair utilizing large-diameter autograft risks central graft necrosis. Commercially available processed nerve allograft (PNA) is available in diameters up to 5 mm but represents an acellular 3-dimensional matrix as opposed to viable tissue. The purpose of this study is to specifically evaluate whether similar concerns regarding the use of large-caliber PNA are warranted. Methods: The RANGER Registry is an active database designed to collect injury, repair, safety, and outcomes data for PNAs (Avance(r) Nerve Graft; AxoGen, Inc, Alachua, Florida) according to an institutional review board approved protocol. The database was queried for patients presenting with large caliber nerve allograft repairs in the upper extremity. Identified patients reporting quantitative outcomes with a minimum of 9-month follow-up were included in the data set. Results: The large-caliber PNA subgroup included 13 patients with 15 injuries. The mean +/- SD age was 36 +/- 22 years. Large-caliber single stranded repairs included twelve 4- to 5-mm-diameter grafts. Large-caliber cabled repairs included the combined use of 3- to 4-mm and 4- to 5-mm-diameter nerve allografts in 3 repairs. The mean nerve gap was 33 +/- 10 mm with a mean follow up time of 13 months. Available quantitative data reported meaningful recovery of sensory and motor function in 67% and 85% of the repairs, respectively. Conclusion: Although based on a small subset of patients, PNAs of up to 5 mm in diameter appear capable of supporting successful nerve regeneration. PMID- 28082845 TI - Frequency of Incidental Median Thenar Motor Nerve Branch Visualization During Mini-Open and Endoscopic Carpal Tunnel Release. AB - Background: Clinical studies using extensile approaches for carpal tunnel release (CTR) report a fairly high incidence of thenar motor branch (TMB) variants. As mini-open and endoscopic CTRs have become commonplace, the likelihood of encountering one of these variants in current practice is unknown. The purpose of the present study was to assess prospectively the frequency with which TMB variants are encountered during routine surgery. Methods: All patients who underwent a primary CTR between August 2014 and April 2015 by 11 hand fellowship trained, orthopedic surgeons were prospectively evaluated. All surgeons performed releases in their usual technique and notified the lead investigator of any median nerve variations encountered. A total of 890 primary CTRs in 795 patients were performed during the study period. Results: Four TMBs seen were transligamentous variants (4/890 of procedures = 0.45%; 4/795 of patients = 0.50%). Three were identified during open CTR, and 1 during endoscopic CTR. In 2 cases, the transligamentous TMB originated from the volar aspect of the median nerve and penetrated the midportion of the transverse carpal ligament. One TMB originated from the volar and ulnar aspect of the median nerve. One TMB originated from the ulnar aspect of the median nerve proximal to the carpal tunnel. There were no cases of TMB injury during the course of the study. Conclusions: TMB variations are encountered infrequently during routine CTR. The most commonly encountered variant during routine mini-open or endoscopic CTR in our study was a transligamentous branch. PMID- 28082846 TI - Muscle Atrophy at Presentation of Cubital Tunnel Syndrome: Demographics and Duration of Symptoms. AB - Background: The purpose of this study is to describe the demographics and duration of symptoms of patients with cubital tunnel syndrome who present with muscle atrophy. Methods: We identified 146 patients who presented to the hand surgery clinic at a single institution over a 5-year period with an initial diagnosis of cubital tunnel syndrome based on history and physical examination. Medical records were retrospectively reviewed to determine if there was a difference in demographic data, physical examination findings, and duration of symptoms in patients who presented with muscle atrophy from those with sensory complaints alone. Results: A total of 17/146 (11.6%) of patients presented with muscle atrophy, all of which were men. In all, 17.2% of men presented with atrophy. Age by itself was not a predictor of presentation with atrophy; however, younger patients with atrophy presented with significantly shorter duration of symptoms. Patients under the age of 29 years presenting with muscle atrophy on average had symptoms for 2.4 months compared with 16.2 months of symptoms for those over 55 years of age. Conclusions: Men with cubital tunnel syndrome are more likely to present with muscle atrophy than women. Age is not necessarily a predictor of presentation with atrophy. There is a subset population of younger patients who presents with extremely short duration of symptoms that rapidly develops muscle atrophy. PMID- 28082847 TI - Optimized Repopulation of Tendon Hydrogel: Synergistic Effects of Growth Factor Combinations and Adipose-Derived Stem Cells. AB - Background: Tendon-derived extracellular matrix (ECM) hydrogel has been shown to augment tendon healing in vivo. We hypothesized that reseeding of the gel with adipose-derived stem cells (ASCs) could further assist repopulation of the gel and that combinations of growth factors (GFs) would improve the survival of these cells after reseeding. Methods: A tendon-specific ECM solution was supplemented with varying concentrations of basic fibroblast growth factor (bFGF), insulin like growth factor-1 (IGF-1), and platelet-derived growth factor-BB (PDGF-BB). Gels were then seeded with ASCs transfected with a green fluorescent protein/luciferin construct. Cell proliferation was determined using the MTT assay and histology, and GF and ASC augmented gels were injected into the back of Sprague Dawley rats. Bioluminescence of seeded gels was continuously followed after reseeding, and cell counts were performed after the gels were explanted at 14 days. Results: Synergistic effects of the GFs were seen, and an optimal combination was determined to be 10 ng/mL bFGF, 100 ng/mL IGF-1, and 100 ng/mL PDGF-BB (2.8-fold increase; P < .05). In vivo bioluminescence showed an improved initial survival of cells in gels supplemented with the optimal concentration of GF compared with the control group (10.6-fold increase at 8 days; P < .05). Cell counts of explants showed a dramatic endogenous repopulation of gels supplemented by GF + ASCs compared with both gels with GF but no ASCs (7.6-fold increase) and gels with ASCs but no GF (1.6-fold increase). Conclusion: Synergistic effects of GFs can be used to improve cellular proliferation of ASCs seeded to a tendon ECM gel. Reseeding with ASCs stimulates endogenous repopulation of the gel in vivo and may be used to further augment tendon healing. PMID- 28082848 TI - Biomechanical and Dimensional Measurements of the Pulvertaft Weave Versus the Cow Hitch Technique. AB - Background: In this study, biomechanical strength and bulkiness of the cow-hitch technique and Pulvertaft weave were compared. Our goal was to investigate whether the cow hitch can withstand equal strength in comparison with the Pulvertaft and to see if there is a difference in bulk, which could enhance gliding function and reduce friction and adhesion formation. Methods: Sheep tendons were used to perform 10 cow-hitch and 10 Pulvertaft repairs. Tensile strength was obtained with a cyclic loading tensile testing machine and tendon width and height measurements were obtained through digital analysis by photographs of the repairs. Results: The cow hitch showed significantly better ultimate strength and had less bulk. There was no statistical difference in displacement, defined as gain in total length of the tendon. Conclusions: The results in this study show that the cow hitch outperforms the Pulvertaft weave in both ultimate strength and bulk. PMID- 28082849 TI - Biceps to Triceps Transfer in Tetraplegic Patients: Our Experience and Review of the Literature. AB - Background: Management and indications for surgery in the tetraplegic patient are highly complex because of the substantial functional deficits that they present and their effect on their daily activity. Our purpose was to evaluate the functional outcome in tetraplegic patients who underwent biceps-to-triceps transfer surgery according to Zancolli's modified technique. Methods: This is a retrospective study of 6 biceps-to-triceps transfers using Zancolli's modified technique in 4 patients. Mean follow-up was 45 months. We evaluated each patient's DASH (Disabilities of the Arm, Shoulder and Hand) score before surgery and 12 months later. Results: In the 6 arms that underwent surgery, full and active elbow extension against gravity at 12 months after surgery was achieved. The mean DASH score was 73.2 preoperatively and 20.8 twelve months postoperatively. One complication occurred. One patient reported loss of elbow flexion preventing thigh lift for transfers. This was resolved with a program of rehabilitation and specific muscle strengthening Conclusions: Zancolli's modified technique is simple and effective, with few complications, whereby we can provide more autonomy for the tetraplegic patient. PMID- 28082850 TI - The Lateral Proximal Phalanx Flap for Contractures and Soft Tissue Defects in the Proximal Interphalangeal Joint: An Anatomical and Clinical Study. AB - Background: The management of contractures and soft tissue defects in the proximal interphalangeal (PIP) finger joint remains a challenge. We report a transposition flap from the lateral skin of the proximal phalanx that is based on perforating branches of the digital arteries and can be used safely for both palmar and dorsal cover defects. Methods: We first completed an anatomic study, dissecting 20 fingers in fresh cadavers with arterial injections and made the new flap in patients with dorsal or palmar defects in PIP joints. Results: In cadavers, we can reveal 4 constant branches from each digital artery in the proximal phalanx, with the more distal just in the PIP joint constituting the flap pedicle. Between February 2010 and February 2015, we designed 33 flaps in 29 patients, 7 for dorsal and 26 for palmar defects, with no instances of flap necrosis and 4 distal epidermolysis. The patients were between 4 and 69 years with no major complications, and all of the skin defects in the PIP joint were resolved satisfactorily without any relevant sequelae at the donor site. Conclusions: This flap procedure is an easy, reliable, versatile, and safe technique, and could be an important tool for the management of difficult skin defects and contractures at the PIP joint level. PMID- 28082851 TI - Comments on the article "Non-Surgical Treatment of Lateral Epicondylitis: A Systematic Review of Randomized Controlled Trials". PMID- 28082852 TI - Pediatric Trigger Finger due to Osteochondroma: A Report of Two Cases. AB - Background: The trigger finger is characterized by the painful blocking of finger flexor tendons of the hand, while crossing the A1 pulley. It is a rare disease in children and, when present, is usually located in the thumb, and does not have any defined cause. Methods: We report 2 pediatric trigger finger cases affecting the long digits of the hand that were caused by an osteochondroma located at the proximal phalanx. Both children held the diagnosis of juvenile multiple osteochondromatosis. They had presented at the initial visit with a painful finger blocking. Surgical approach was decided with wide regional exposure, as compared with the trigger finger traditional surgical techniques, with the opening of the A1 pulley and the initial portion of the A2 pulley, along with bone tumor resection. Results: Patients evolved uneventfully, and recovered the affected finger motion. Conclusion: It is important to highlight that pediatric trigger finger is a distinct ailment from the adult trigger finger, and also in children is important to differentiate whenever the disease either affects the thumb or the long fingers. A secondary cause shall be sought whenever the long fingers are affected by a trigger finger. PMID- 28082853 TI - Gouty Tenosynovitis of the Distal Biceps Tendon Insertion Complicated by Partial Rupture: First Case and Review of the Literature. AB - Background: Given the appreciable prevalence of gout, gout-induced tendon ruptures in the upper extremity are extremely rare. Although these events have been reported only 5 times in the literature, all in patients with a risk factor for or history of gout, they have conspicuously never been diagnosed in the shoulder or elbow. Methods: A 45-year-old, right-hand-dominant man with a history of gout presented with pain in his right anterior elbow and weakness in his forearm after a trivial injury. Results: Here, we report the first case of gouty tenosynovitis of the distal biceps tendon insertion complicated by partial rupture, a composite diagnosis supported by both intraoperative and histological observations. Conclusions: In patients who are clinically diagnosed with biceps tendon rupture and have a history of gout, it is important to consider the possibility of a gout-related pathological manifestation causing or simulating tendon rupture. PMID- 28082854 TI - Iatrogenic Injury to the Median Nerve During Palmaris Longus Harvest: An Overview of Safe Harvesting Techniques. AB - Background: A rare and disastrous complication of harvesting a tendon graft is the misidentification of the median nerve for the palmaris longus. Methods: The authors report a referred case in which the median nerve was harvested as a free tendon graft. Results: Few reports of this complication are found in the literature despite the frequency of palmaris longus tendon grafting and the proximity of the palmaris tendon to the median nerve. Given the obvious medicolegal implications, the true incidence of this complication is difficult to assess. Discussion: Safe harvesting of the palmaris longus mandates a thorough understanding of the relevant anatomy, in particular the proper differentiation between nerve and tendon and recognition of when the palmaris longus tendon is absent. Techniques to facilitate proper identification of the palmaris longus are outlined. PMID- 28082855 TI - Morel-Lavallee Lesion in the Upper Extremity. AB - Background: The Morel-Lavallee lesion (MLL) is a closed internal degloving injury that results from shearing of the skin and subcutaneous tissue from the underlying fascia. Disruption of the perforating blood vessels and lymphatics results in a lesion filled with serosanguinous fluid and necrotized fat. MLLs are most commonly described in association with pelvic and lower extremity trauma, and there are limited reports of these lesions in other locations. Methods: This case report describes a 58-year-old male referred from his primary care physician with a soft tissue mass in the upper arm. Careful history discovered prior trauma with extensive bruising and MRI revealed a large encapsulated mass consistent with MLL. Results: An open debridement with excision of pseudocapsule was performed. Meticulous closure over a drain was performed and the patient healed without complication or recurrence. Intra-operative cultures were negative and pathology was consistent with MLL. Conclusion: MLL should always be considered in the setting of previous trauma regardless the location. In the chronic setting an open approach with excision of pseudocapsule can have an acceptable result. PMID- 28082856 TI - Chemical diversity and pharmacological significance of the secondary metabolites of nutmeg (Myristica fragrans Houtt.). AB - Nutmeg is a valued kitchen spice that has been used for centuries all over the world. In addition to its use in flavoring foods and beverages, nutmeg has been used in traditional remedies for stomach and kidney disorders. The antioxidant, antimicrobial and central nervous system effects of nutmeg have also been reported in literature. Nutmeg is a rich source of fixed and essential oil, triterpenes, and various types of phenolic compounds. Many of the secondary metabolites of nutmeg exhibit biological activities that may support its use in traditional medicine. This article provides an overview of the chemistry of secondary metabolites isolated from nutmeg kernel and mace including common methods for analysis of extracts and pure compounds as well as recent approaches towards total synthesis of some of the major constituents. A summary of the most significant pharmacological investigations of potential drug leads isolated from nutmeg and reported in the last decade is also included. PMID- 28082857 TI - Mind the Noise When Identifying Computational Models of Cognition from Brain Activity. AB - The aim of this study was to analyze how measurement error affects the validity of modeling studies in computational neuroscience. A synthetic validity test was created using simulated P300 event-related potentials as an example. The model space comprised four computational models of single-trial P300 amplitude fluctuations which differed in terms of complexity and dependency. The single trial fluctuation of simulated P300 amplitudes was computed on the basis of one of the models, at various levels of measurement error and at various numbers of data points. Bayesian model selection was performed based on exceedance probabilities. At very low numbers of data points, the least complex model generally outperformed the data-generating model. Invalid model identification also occurred at low levels of data quality and under low numbers of data points if the winning model's predictors were closely correlated with the predictors from the data-generating model. Given sufficient data quality and numbers of data points, the data-generating model could be correctly identified, even against models which were very similar to the data-generating model. Thus, a number of variables affects the validity of computational modeling studies, and data quality and numbers of data points are among the main factors relevant to the issue. Further, the nature of the model space (i.e., model complexity, model dependency) should not be neglected. This study provided quantitative results which show the importance of ensuring the validity of computational modeling via adequately prepared studies. The accomplishment of synthetic validity tests is recommended for future applications. Beyond that, we propose to render the demonstration of sufficient validity via adequate simulations mandatory to computational modeling studies. PMID- 28082859 TI - Comparison of Local Information Indices Applied in Resting State Functional Brain Network Connectivity Prediction. AB - Anatomical distance has been widely used to predict functional connectivity because of the potential relationship between structural connectivity and functional connectivity. The basic implicit assumption of this method is "distance penalization." But studies have shown that one-parameter model (anatomical distance) cannot account for the small-worldness, modularity, and degree distribution of normal human brain functional networks. Two local information indices-common neighbor (CN) and preferential attachment index (PA), are introduced into the prediction model as another parameter to emulate many key topological of brain functional networks in the previous study. In addition to these two indices, many other local information indices can be chosen for investigation. Different indices evaluate local similarity from different perspectives. Currently, we still have no idea about how to select local information indices to achieve higher predicted accuracy of functional connectivity. Here, seven local information indices are chosen, including CN, hub depressed index (HDI), hub promoted index (HPI), Leicht-Holme-Newman index (LHN I), Sorensen index (SI), PA, and resource allocation index (RA). Statistical analyses were performed on eight network topological properties to evaluate the predictions. Analysis shows that different prediction models have different performances in terms of simulating topological properties and most of the predicted network properties are close to the real data. There are four topological properties whose average relative error is less than 5%, including characteristic path length, clustering coefficient, global efficiency, and local efficiency. CN model shows the most accurate predictions. Statistical analysis reveals that five properties within the CN-predicted network do not differ significantly from the real data (P > 0.05, false-discovery rate method corrected for seven comparisons). PA model shows the worst prediction performance which was first applied in models of growth networks. Our results suggest that PA is not suitable for predicting connectivity in a small-world network. Furthermore, in order to evaluate the predictions rapidly, prediction power was proposed as an evaluation metric. The current study compares the predictions of functional connectivity with seven local information indices and provides a reference of method selection for construction of prediction models. PMID- 28082860 TI - Evaluating the Influence of Spatial Resampling for Motion Correction in Resting State Functional MRI. AB - Head motion is one of major concerns in current resting-state functional MRI studies. Image realignment including motion estimation and spatial resampling is often applied to achieve rigid-body motion correction. While the accurate estimation of motion parameters has been addressed in most studies, spatial resampling could also produce spurious variance, and lead to unexpected errors on the amplitude of BOLD signal. In this study, two simulation experiments were designed to characterize these variance related with spatial resampling. The fluctuation amplitude of spurious variance was first investigated using a set of simulated images with estimated motion parameters from a real dataset, and regions more likely to be affected by spatial resampling were found around the peripheral regions of the cortex. The other simulation was designed with three typical types of motion parameters to represent different extents of motion. It was found that areas with significant correlation between spurious variance and head motion scattered all over the brain and varied greatly from one motion type to another. In the last part of this study, four popular motion regression approaches were applied respectively and their performance in reducing spurious variance was compared. Among them, Friston 24 and Voxel-specific 12 model (Friston et al., 1996), were found to have the best outcomes. By separating related effects during fMRI analysis, this study provides a better understanding of the characteristics of spatial resampling and the interpretation of motion BOLD relationship. PMID- 28082861 TI - Stochastic Resonance Controlled Upregulation of Internal Noise after Hearing Loss as a Putative Cause of Tinnitus-Related Neuronal Hyperactivity. AB - Subjective tinnitus is generally assumed to be a consequence of hearing loss. In animal studies it has been demonstrated that acoustic trauma induced cochlear damage can lead to behavioral signs of tinnitus. In addition it was shown that noise trauma may lead to deafferentation of cochlear inner hair cells (IHC) even in the absence of elevated hearing thresholds, and it seems conceivable that such hidden hearing loss may be sufficient to cause tinnitus. Numerous studies have indicated that tinnitus is correlated with pathologically increased spontaneous firing rates and hyperactivity of neurons along the auditory pathway. It has been proposed that this hyperactivity is the consequence of a mechanism aiming to compensate for reduced input to the auditory system by increasing central neuronal gain, a mechanism referred to as homeostatic plasticity (HP), thereby maintaining mean firing rates over longer timescales for stabilization of neuronal processing. Here we propose an alternative, new interpretation of tinnitus-related development of neuronal hyperactivity in terms of information theory. In particular, we suggest that stochastic resonance (SR) plays a key role in both short- and long-term plasticity within the auditory system and that SR is the primary cause of neuronal hyperactivity and tinnitus. We argue that following hearing loss, SR serves to lift signals above the increased neuronal thresholds, thereby partly compensating for the hearing loss. In our model, the increased amount of internal noise-which is crucial for SR to work-corresponds to neuronal hyperactivity which subsequently causes neuronal plasticity along the auditory pathway and finally may lead to the development of a phantom percept, i.e., subjective tinnitus. We demonstrate the plausibility of our hypothesis using a computational model and provide exemplary findings in human patients that are consistent with that model. Finally we discuss the observed asymmetry in human tinnitus pitch distribution as a consequence of asymmetry of the distribution of auditory nerve type I fibers along the cochlea in the context of our model. PMID- 28082858 TI - Enhancing Nervous System Recovery through Neurobiologics, Neural Interface Training, and Neurorehabilitation. AB - After an initial period of recovery, human neurological injury has long been thought to be static. In order to improve quality of life for those suffering from stroke, spinal cord injury, or traumatic brain injury, researchers have been working to restore the nervous system and reduce neurological deficits through a number of mechanisms. For example, neurobiologists have been identifying and manipulating components of the intra- and extracellular milieu to alter the regenerative potential of neurons, neuro-engineers have been producing brain machine and neural interfaces that circumvent lesions to restore functionality, and neurorehabilitation experts have been developing new ways to revitalize the nervous system even in chronic disease. While each of these areas holds promise, their individual paths to clinical relevance remain difficult. Nonetheless, these methods are now able to synergistically enhance recovery of native motor function to levels which were previously believed to be impossible. Furthermore, such recovery can even persist after training, and for the first time there is evidence of functional axonal regrowth and rewiring in the central nervous system of animal models. To attain this type of regeneration, rehabilitation paradigms that pair cortically-based intent with activation of affected circuits and positive neurofeedback appear to be required-a phenomenon which raises new and far reaching questions about the underlying relationship between conscious action and neural repair. For this reason, we argue that multi-modal therapy will be necessary to facilitate a truly robust recovery, and that the success of investigational microscopic techniques may depend on their integration into macroscopic frameworks that include task-based neurorehabilitation. We further identify critical components of future neural repair strategies and explore the most updated knowledge, progress, and challenges in the fields of cellular neuronal repair, neural interfacing, and neurorehabilitation, all with the goal of better understanding neurological injury and how to improve recovery. PMID- 28082862 TI - The Pursuit of Chronically Reliable Neural Interfaces: A Materials Perspective. AB - Brain-computer interfaces represent one of the most astonishing technologies in our era. However, the grand challenge of chronic instability and limited throughput of the electrode-tissue interface has significantly hindered the further development and ultimate deployment of such exciting technologies. A multidisciplinary research workforce has been called upon to respond to this engineering need. In this paper, I briefly review this multidisciplinary pursuit of chronically reliable neural interfaces from a materials perspective by analyzing the problem, abstracting the engineering principles, and summarizing the corresponding engineering strategies. I further draw my future perspectives by extending the proposed engineering principles. PMID- 28082863 TI - Menstrual Cycle Phase Modulates Auditory-Motor Integration for Vocal Pitch Regulation. AB - In adult females, previous work has demonstrated that changes in auditory function and vocal motor behaviors may accompany changes in gonadal steroids. Less is known, however, about the influence of gonadal steroids on auditory-motor integration for voice control in humans. The present event-related potential (ERP) study sought to examine the interaction between gonadal steroids and auditory feedback-based vocal pitch regulation across the menstrual cycle. Participants produced sustained vowels while hearing their voice unexpectedly pitch-shifted during the menstrual, follicular, and luteal phases of the menstrual cycle. Measurement of vocal and cortical responses to pitch feedback perturbations and assessment of estradiol and progesterone levels were performed in all three phases. The behavioral results showed that the menstrual phase (when estradiol levels are low) as associated with larger magnitudes of vocal responses than the follicular and luteal phases (when estradiol levels are high). Furthermore, there was a significant negative correlation between the magnitudes of vocal responses and estradiol levels. At the cortical level, ERP P2 responses were smaller during the luteal phase (when progesterone levels were high) than the menstrual and follicular phases (when progesterone levels were low). These findings show neurobehavioral evidence for the modulation of auditory-motor integration for vocal pitch regulation across the menstrual cycle, and provide important insights into the neural mechanisms and functional outcomes of gonadal steroids' influence on speech motor control in adult women. PMID- 28082864 TI - Vsx1 Transiently Defines an Early Intermediate V2 Interneuron Precursor Compartment in the Mouse Developing Spinal Cord. AB - Spinal ventral interneurons regulate the activity of motor neurons, thereby controlling motor activities. Interneurons arise during embryonic development from distinct progenitor domains distributed orderly along the dorso-ventral axis of the neural tube. A single ventral progenitor population named p2 generates at least five V2 interneuron subsets. Whether the diversification of V2 precursors into multiple subsets occurs within the p2 progenitor domain or involves a later compartment of early-born V2 interneurons remains unsolved. Here, we provide evidence that the p2 domain produces an intermediate V2 precursor compartment characterized by the transient expression of the transcriptional repressor Vsx1. These cells display an original repertoire of cellular markers distinct from that of any V2 interneuron population. They have exited the cell cycle but have not initiated neuronal differentiation. They coexpress Vsx1 and Foxn4, suggesting that they can generate the known V2 interneuron populations as well as possible additional V2 subsets. Unlike V2 interneurons, the generation of Vsx1-positive precursors does not depend on the Notch signaling pathway but expression of Vsx1 in these cells requires Pax6. Hence, the p2 progenitor domain generates an intermediate V2 precursor compartment, characterized by the presence of the transcriptional repressor Vsx1, that contributes to V2 interneuron development. PMID- 28082865 TI - Habit Formation after Random Interval Training Is Associated with Increased Adenosine A2A Receptor and Dopamine D2 Receptor Heterodimers in the Striatum. AB - Striatal adenosine A2A receptors (A2ARs) modulate striatal synaptic plasticity and instrumental learning, possibly by functional interaction with the dopamine D2 receptors (D2Rs) and metabotropic glutamate receptors 5 (mGluR5) through receptor-receptor heterodimers, but in vivo evidence for these interactions is lacking. Using in situ proximity ligation assay (PLA), we studied the subregional distribution of the A2AR-D2R and A2AR-mGluR5 heterodimer complexes in the striatum and their adaptive changes over the random interval and random ratio training of instrumental learning. After confirming the specificity of the PLA detection of the A2AR-D2R heterodimers with the A2AR knockout and D2R knockout mice, we detected a heterogeneous distribution of the A2AR-D2R heterodimer complexes in the striatum, being more abundant in the dorsolateral than the dorsomedial striatum. Importantly, habit formation after the random interval training was associated with the increased formation of the A2AR-D2R heterodimer complexes, with prominant increase in the dorsomedial striatum. Conversely, goal directed behavior after the random ratio schedule was not associated with the adaptive change in the A2AR-D2R heterodimer complexes. In contrast to the A2AR D2R heterodimers, the A2AR-mGluR5 heterodimers showed neither subregional variation in the striatum nor adaptive changes over either the random ratio (RR) or random interval (RI) training of instrumental learning. These findings suggest that development of habit formation is associated with increased formation of the A2AR-D2R heterodimer protein complexes which may lead to reduced dependence on D2R signaling in the striatum. PMID- 28082866 TI - Changes in C57BL6 Mouse Hippocampal Transcriptome Induced by Hypergravity Mimic Acute Corticosterone-Induced Stress. AB - Centrifugation is a widely used procedure to study the impact of altered gravity on Earth, as observed during spaceflights, allowing us to understand how a long term physical constraint can condition the mammalian physiology. It is known that mice, placed in classical cages and maintained during 21 days in a centrifuge at 3G gravity level, undergo physiological adaptations due to hypergravity, and/or stress. Indeed, an increase of corticosterone levels has been previously measured in the plasma of 3G-exposed mice. Corticosterone is known to modify neuronal activity during memory processes. Although learning and memory performances cannot be assessed during the centrifugation, literature largely described a large panel of proteins (channels, second messengers, transcription factors, structural proteins) which expressions are modified during memory processing. Thus, we used the Illumina technology to compare the whole hippocampal transcriptome of three groups of C57Bl6/J mice, in order to gain insights into the effects of hypergravity on cerebral functions. Namely, a group of 21 days 3G centrifuged mice was compared to (1) a group subjected to an acute corticosterone injection, (2) a group receiving a transdermal chronic administration of corticosterone during 21 days, and (3) aged mice because aging could be characterized by a decrease of hippocampus functions and memory impairment. Our results suggest that hypergravity stress induced by corticosterone administration and aging modulate the expression of genes in the hippocampus. However, the modulations of the transcriptome observed in these conditions are not identical. Hypergravity affects per-se the hippocampus transcriptome and probably modifies its activity. Hypergravity induced changes in hippocampal transcriptome were more similar to acute injection than chronic diffusion of corticosterone or aging. PMID- 28082867 TI - The Role of the Carboxyl-Terminal Sequence of Tau and MAP2 in the Pathogenesis of Dementia. AB - Dementia includes several diseases characterized by acquired and irreversible brain dysfunctions that interfere with daily life. According to the etiology, dementia can be induced by poisoning or metabolic disorders, and other cases of dementia have a clear pathogenesis. However, half of neurodegenerative diseases have an unclear pathogenesis and etiology. Alzheimer's disease (AD), Lewy body dementia and frontal-temporal dementia are the three most common types of dementia. These neurodegenerative diseases are characterized by the appearance of the following specific protein inclusions: amyloid beta and tau in AD; alpha synuclein in Lewy body dementia; and tau, TDP-43, or FUS in frontal-temporal dementia. Thus far, studies on the pathogenesis of dementia mainly focus aberrant inclusions formed by the aforementioned proteins. As a historically heavily studied protein tau is likely to be associated with the pathogenesis of several neurodegenerative diseases that cause dementia. The role of tau in neurodegeneration has been unknown for many years. However, both pathological and genetic analyses have helped tau become gradually recognized as an important factor in the pathogenesis of tauopathy. Currently, especially in the field of AD, tau is attracting more attention and is being considered a potential target for drug development. In this review article, previously discovered biochemical and pathological features of tau are highlighted, and current opinions regarding the neurotoxicity of tau are summarized. Additionally, we introduce key amino acid sequences responsible for tau neurotoxicity from our studies using transgenic Caenorhabditis elegans. Finally, a new hypothesis regarding the roles of microtubule-associated protein 2 (MAP2) and tau in the pathogenesis of tauopathy is discussed. PMID- 28082868 TI - Neuromuscular Junction Impairment in Amyotrophic Lateral Sclerosis: Reassessing the Role of Acetylcholinesterase. AB - Amyotrophic Lateral Sclerosis (ALS) is a highly debilitating disease caused by progressive degeneration of motorneurons (MNs). Due to the wide variety of genes and mutations identified in ALS, a highly varied etiology could ultimately converge to produce similar clinical symptoms. A major hypothesis in ALS research is the "distal axonopathy" with pathological changes occurring at the neuromuscular junction (NMJ), at very early stages of the disease, prior to MNs degeneration and onset of clinical symptoms. The NMJ is a highly specialized cholinergic synapse, allowing signaling between muscle and nerve necessary for skeletal muscle function. This nerve-muscle contact is characterized by the clustering of the collagen-tailed form of acetylcholinesterase (ColQ-AChE), together with other components of the extracellular matrix (ECM) and specific key molecules in the NMJ formation. Interestingly, in addition to their cholinergic role AChE is thought to play several "non-classical" roles that do not require catalytic function, most prominent among these is the facilitation of neurite growth, NMJ formation and survival. In all this context, abnormalities of AChE content have been found in plasma of ALS patients, in which AChE changes may reflect the neuromuscular disruption. We review these findings and particularly the evidences of changes of AChE at neuromuscular synapse in the pre-symptomatic stages of ALS. PMID- 28082869 TI - Proteostasis and Diseases of the Motor Unit. AB - The accumulation in neurons of aberrant protein species, the pathological hallmark of many neurodegenerative diseases, results from a global impairment of key cellular processes governing protein synthesis/degradation and repair mechanisms, also known as the proteostasis network (PN). The growing number of connections between dysfunction of this intricate network of pathways and diseases of the motor unit, where both motor neurons and muscle are primarily affected, has provided momentum to investigate the muscle- and motor neuron specific response to physiological and pathological stressors and to explore the therapeutic opportunities that manipulation of this process may offer. Furthermore, these diseases offer an unparalleled opportunity to deepen our understanding of the molecular mechanisms behind the intertissue communication and transfer of signals of proteostasis. The most compelling aspect of these investigations is their immediate potential for therapeutic impact: targeting muscle to stem degeneration of the motor unit would represent a dramatic paradigm therapeutic shift for treating these devastating diseases. Here we will review the current state of the art of the research on the alterations of the PN in diseases of the motor unit and its potential to result in effective treatments for these devastating neuromuscular disorders. PMID- 28082870 TI - FUS Mislocalization and Vulnerability to DNA Damage in ALS Patients Derived hiPSCs and Aging Motoneurons. AB - Mutations within the FUS gene (Fused in Sarcoma) are known to cause Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease affecting upper and lower motoneurons. The FUS gene codes for a multifunctional RNA/DNA-binding protein that is primarily localized in the nucleus and is involved in cellular processes such as splicing, translation, mRNA transport and DNA damage response. In this study, we analyzed pathophysiological alterations associated with ALS related FUS mutations (mFUS) in human induced pluripotent stem cells (hiPSCs) and hiPSC derived motoneurons. To that end, we compared cells carrying a mild or severe mFUS in physiological- and/or stress conditions as well as after induced DNA damage. Following hyperosmolar stress or irradiation, mFUS hiPS cells recruited significantly more cytoplasmatic FUS into stress granules accompanied by impaired DNA-damage repair. In motoneurons wild-type FUS was localized in the nucleus but also deposited as small punctae within neurites. In motoneurons expressing mFUS the protein was additionally detected in the cytoplasm and a significantly increased number of large, densely packed FUS positive stress granules were seen along neurites. The amount of FUS mislocalization correlated positively with both the onset of the human disease (the earlier the onset the higher the FUS mislocalization) and the maturation status of the motoneurons. Moreover, even in non-stressed post-mitotic mFUS motoneurons clear signs of DNA-damage could be detected. In summary, we found that the susceptibility to cell stress was higher in mFUS hiPSCs and hiPSC derived motoneurons than in controls and the degree of FUS mislocalization correlated well with the clinical severity of the underlying ALS related mFUS. The accumulation of DNA damage and the cellular response to DNA damage stressors was more pronounced in post-mitotic mFUS motoneurons than in dividing hiPSCs suggesting that mFUS motoneurons accumulate foci of DNA damage, which in turn might be directly linked to neurodegeneration. PMID- 28082872 TI - Reboxetine Improves Auditory Attention and Increases Norepinephrine Levels in the Auditory Cortex of Chronically Stressed Rats. AB - Chronic stress impairs auditory attention in rats and monoamines regulate neurotransmission in the primary auditory cortex (A1), a brain area that modulates auditory attention. In this context, we hypothesized that norepinephrine (NE) levels in A1 correlate with the auditory attention performance of chronically stressed rats. The first objective of this research was to evaluate whether chronic stress affects monoamines levels in A1. Male Sprague-Dawley rats were subjected to chronic stress (restraint stress) and monoamines levels were measured by high performance liquid chromatographer (HPLC) electrochemical detection. Chronically stressed rats had lower levels of NE in A1 than did controls, while chronic stress did not affect serotonin (5-HT) and dopamine (DA) levels. The second aim was to determine the effects of reboxetine (a selective inhibitor of NE reuptake) on auditory attention and NE levels in A1. Rats were trained to discriminate between two tones of different frequencies in a two-alternative choice task (2-ACT), a behavioral paradigm to study auditory attention in rats. Trained animals that reached a performance of >=80% correct trials in the 2-ACT were randomly assigned to control and stress experimental groups. To analyze the effects of chronic stress on the auditory task, trained rats of both groups were subjected to 50 2-ACT trials 1 day before and 1 day after of the chronic stress period. A difference score (DS) was determined by subtracting the number of correct trials after the chronic stress protocol from those before. An unexpected result was that vehicle-treated control rats and vehicle-treated chronically stressed rats had similar performances in the attentional task, suggesting that repeated injections with vehicle were stressful for control animals and deteriorated their auditory attention. In this regard, both auditory attention and NE levels in A1 were higher in chronically stressed rats treated with reboxetine than in vehicle-treated animals. These results indicate that NE has a key role in A1 and attention of stressed rats during tone discrimination. PMID- 28082871 TI - Sevoflurane Alters Spatiotemporal Functional Connectivity Motifs That Link Resting-State Networks during Wakefulness. AB - Background: The spatiotemporal patterns of correlated neural activity during the transition from wakefulness to general anesthesia have not been fully characterized. Correlation analysis of blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI) allows segmentation of the brain into resting-state networks (RSNs), with functional connectivity referring to the covarying activity that suggests shared functional specialization. We quantified the persistence of these correlations following the induction of general anesthesia in healthy volunteers and assessed for a dynamic nature over time. Methods: We analyzed human fMRI data acquired at 0 and 1.2% vol sevoflurane. The covariance in the correlated activity among different brain regions was calculated over time using bounded Kalman filtering. These time series were then clustered into eight orthogonal motifs using a K-means algorithm, where the structure of correlated activity throughout the brain at any time is the weighted sum of all motifs. Results: Across time scales and under anesthesia, the reorganization of interactions between RSNs is related to the strength of dynamic connections between member pairs. The covariance of correlated activity between RSNs persists compared to that linking individual member pairs of different RSNs. Conclusions: Accounting for the spatiotemporal structure of correlated BOLD signals, anesthetic-induced loss of consciousness is mainly associated with the disruption of motifs with intermediate strength within and between members of different RSNs. In contrast, motifs with higher strength of connections, predominantly with regions-pairs from within-RSN interactions, are conserved among states of wakefulness and sevoflurane general anesthesia. PMID- 28082873 TI - Interhemispheric Connections between the Primary Visual Cortical Areas via the Anterior Commissure in Human Callosal Agenesis. AB - Aim: In humans, images in the median plane of the head either fall on both nasal hemi-retinas or on both temporal hemi-retinas. Interhemispheric connections allow cortical cells to have receptive fields on opposite sides. The major interhemispheric connection, the corpus callosum, is implicated in central stereopsis and disparity detection in front of the fixation plane. Yet individuals with agenesis of the corpus callosum may show normal stereopsis and disparity vergence. We set out to study a possible interhemispheric connection between primary visual cortical areas via the anterior commissure to explain this inconsistency because of the major role of these cortical areas in elaborating 3D visual perception. Methods: MRI, DTI and tractography of the brain of a 53-year old man with complete callosal agenesis and normal binocular single vision was undertaken. Tractography seed points were placed in both the right and the left V1 and V2. Nine individuals with both an intact corpus callosum and normal binocularity served as controls. Results: Interhemispheric tracts through the anterior commissure linking both V1 and V2 visual cortical areas bilaterally were indeed shown in the subject with callosal agenesis. All other individuals showed interhemispheric visual connections through the corpus callosum only. Conclusion: Callosal agenesis may result in anomalous interhemispheric connections of the primary visual areas via the anterior commissure. It is proposed here that these connections form as alternative to the normal callosal pathway and may participate in binocularity. PMID- 28082875 TI - Differential Functionality of Right and Left Parietal Activity in Controlling a Motor Vehicle. AB - Driving a motor vehicle is an inherently complex task that requires robust control to avoid catastrophic accidents. Drivers must maintain their vehicle in the middle of the travel lane to avoid high speed collisions with other traffic. Interestingly, while a vehicle's lane deviation (LD) is critical, studies have demonstrated that heading error (HE) is one of the primary variables drivers use to determine a steering response, which directly controls the position of the vehicle in the lane. In this study, we examined how the brain represents the dichotomy between control/response parameters (heading, reaction time (RT), and steering wheel corrections) and task-critical parameters (LD). Specifically, we examined electroencephalography (EEG) alpha band power (8-13 Hz) from estimated sources in right and left parietal regions, and related this activity to four metrics of driving performance. Our results demonstrate differential task involvement between the two hemispheres: right parietal activity was most closely related to LD, whereas left parietal activity was most closely related to HE, RT and steering responses. Furthermore, HE, RT and steering wheel corrections increased over the duration of the experiment while LD did not. Collectively, our results suggest that the brain uses differential monitoring and control strategies in the right and left parietal regions to control a motor vehicle. Our results suggest that the regulation of this control changes over time while maintaining critical task performance. These results are interpreted in two complementary theoretical frameworks: the uncontrolled manifold and compensatory control theories. The central tenet of these frameworks permits performance variability in parameters (i.e., HE, RT and steering) so far as it does not interfere with critical task execution (i.e., LD). Our results extend the existing research by demonstrating potential neural substrates for this phenomenon which may serve as potential targets for brain-computer interfaces that predict poor driving performance. PMID- 28082874 TI - Cortico-Striatal-Thalamic Loop Circuits of the Salience Network: A Central Pathway in Psychiatric Disease and Treatment. AB - The salience network (SN) plays a central role in cognitive control by integrating sensory input to guide attention, attend to motivationally salient stimuli and recruit appropriate functional brain-behavior networks to modulate behavior. Mounting evidence suggests that disturbances in SN function underlie abnormalities in cognitive control and may be a common etiology underlying many psychiatric disorders. Such functional and anatomical abnormalities have been recently apparent in studies and meta-analyses of psychiatric illness using functional magnetic resonance imaging (fMRI) and voxel-based morphometry (VBM). Of particular importance, abnormal structure and function in major cortical nodes of the SN, the dorsal anterior cingulate cortex (dACC) and anterior insula (AI), have been observed as a common neurobiological substrate across a broad spectrum of psychiatric disorders. In addition to cortical nodes of the SN, the network's associated subcortical structures, including the dorsal striatum, mediodorsal thalamus and dopaminergic brainstem nuclei, comprise a discrete regulatory loop circuit. The SN's cortico-striato-thalamo-cortical loop increasingly appears to be central to mechanisms of cognitive control, as well as to a broad spectrum of psychiatric illnesses and their available treatments. Functional imbalances within the SN loop appear to impair cognitive control, and specifically may impair self-regulation of cognition, behavior and emotion, thereby leading to symptoms of psychiatric illness. Furthermore, treating such psychiatric illnesses using invasive or non-invasive brain stimulation techniques appears to modulate SN cortical-subcortical loop integrity, and these effects may be central to the therapeutic mechanisms of brain stimulation treatments in many psychiatric illnesses. Here, we review clinical and experimental evidence for abnormalities in SN cortico-striatal-thalamic loop circuits in major depression, substance use disorders (SUD), anxiety disorders, schizophrenia and eating disorders (ED). We also review emergent therapeutic evidence that novel invasive and non-invasive brain stimulation treatments may exert therapeutic effects by normalizing abnormalities in the SN loop, thereby restoring the capacity for cognitive control. Finally, we consider a series of promising directions for future investigations on the role of SN cortico-striatal-thalamic loop circuits in the pathophysiology and treatment of psychiatric disorders. PMID- 28082876 TI - Rehabilitation Approaches in Macular Degeneration Patients. AB - Age related macular degeneration (AMD) is a visual disease that affects elderly population. It entails a progressive loss of central vision whose consequences are dramatic for the patient's quality of life. Current rehabilitation programs are restricted to technical aids based on visual devices. They only temporarily improve specific visual functions such as reading skills. Considering the rapid increase of the aging population worldwide, it is crucial to intensify clinical research on AMD in order to develop simple and efficient methods that improve the patient's visual performances in many different contexts. One very promising approach to face this challenge is based on perceptual learning (PL). Through intensive practice, PL can induce neural plasticity in sensory cortices and result in long-lasting enhancements for various perceptual tasks in both normal and visually impaired populations. A growing number of studies showed how appropriate PL protocols improve visual functions in visual disorders, namely amblyopia, presbyopia or myopia. In order to successfully apply these approaches to more severe conditions such as AMD, numerous challenges have to be overcome. Indeed, the overall elderly age of patients and the reduced cortical surface that is devoted to peripheral vision potentially limit neural plasticity in this population. In addition, ocular fixation becomes much less stable because patients have to rely on peripheral fixation spots outside the scotoma whose size keeps on evolving. The aim of this review article is to discuss the recent literature on this topic and to offer a unified approach for developing new rehabilitation programs of AMD using PL. We argue that with an appropriate experimental and training protocol that is adapted to each patient needs, PL can offer fascinating opportunities for the development of simple, non-expensive rehabilitation approaches a large spectrum of visual functions in AMD patients. PMID- 28082877 TI - Individual Differences in the Attribution of Incentive Salience to a Pavlovian Alcohol Cue. AB - Individual differences exist in the attribution of incentive salience to conditioned stimuli associated with food. Here, we investigated whether individual differences also manifested with a Pavlovian alcohol conditioned stimulus (CS). We compiled data from five experiments that used a Pavlovian autoshaping paradigm and tests of conditioned reinforcement. In all experiments, male, Long-Evans rats with unrestricted access to food and water were acclimated to 15% ethanol. Next, rats received Pavlovian autoshaping training, in which a 10 s presentation of a retractable lever served as the CS and 0.2 mL of 15% ethanol served as the unconditioned stimulus (US). Finally, rats underwent conditioned reinforcement tests in which nose-pokes to an active aperture led to brief presentations of the lever-CS, but nose-pokes to an inactive aperture had no consequence. Rats were categorized as sign-trackers, goal-trackers and intermediates based on a response bias score that reflected their tendencies to sign-track or goal-track at different times during training. We found that distinct groups of rats either consistently interacted with the lever-CS ("sign trackers") or routinely approached the port during the lever-CS ("goal-trackers") across a majority of the training sessions. However, some individuals ("shifted sign-trackers") with an early tendency to goal-track later shifted to comparable asymptotic levels of sign-tracking as the group identified as sign-trackers. The lever-CS functioned as a conditioned reinforcer for sign-trackers and shifted sign-trackers, but not for goal-trackers. These results provide evidence of robust individual differences in the extent to which a Pavlovian alcohol cue gains incentive salience and functions as a conditioned reinforcer. PMID- 28082879 TI - Editorial: Prosocial and Antisocial Behavior in Economic Games. PMID- 28082878 TI - Long-Term Effects of Prenatal Exposure to Undernutrition on Cannabinoid Receptor Related Behaviors: Sex and Tissue-Specific Alterations in the mRNA Expression of Cannabinoid Receptors and Lipid Metabolic Regulators. AB - Maternal malnutrition causes long-lasting alterations in feeding behavior and energy homeostasis in offspring. It is still unknown whether both, the endocannabinoid (eCB) machinery and the lipid metabolism are implicated in long term adaptive responses to fetal reprogramming caused by maternal undernutrition. We investigated the long-term effects of maternal exposure to a 20% standard diet restriction during preconceptional and gestational periods on the metabolically relevant tissues hypothalamus, liver, and perirenal fat (PAT) of male and female offspring at adulthood. The adult male offspring from calorie-restricted dams (RC males) exhibited a differential response to the CB1 antagonist AM251 in a chocolate preference test as well as increased body weight, perirenal adiposity, and plasma levels of triglycerides, LDL, VLDL, bilirubin, and leptin. The gene expression of the cannabinoid receptors Cnr1 and Cnr2 was increased in RC male hypothalamus, but a down-expression of most eCBs-metabolizing enzymes (Faah, Daglalpha, Daglbeta, Mgll) and several key regulators of fatty-acid beta oxidation (Cpt1b, Acox1), mitochondrial respiration (Cox4i1), and lipid flux (Ppargamma) was found in their PAT. The female offspring from calorie-restricted dams exhibited higher plasma levels of LDL and glucose as well as a reduction in chocolate and caloric intake at post-weaning periods in the feeding tests. Their liver showed a decreased gene expression of Cnr1, Pparalpha, Ppargamma, the eCBs degrading enzymes Faah and Mgll, the de novo lipogenic enzymes Acaca and Fasn, and the liver-specific cholesterol biosynthesis regulators Insig1 and Hmgcr. Our results suggest that the long-lasting adaptive responses to maternal caloric restriction affected cannabinoid-regulated mechanisms involved in feeding behavior, adipose beta-oxidation, and hepatic lipid and cholesterol biosynthesis in a sex-dependent manner. PMID- 28082880 TI - Attachment Representations and Brain Asymmetry during the Processing of Autobiographical Emotional Memories in Late Adolescence. AB - Frontal and parietal asymmetries have repeatedly been shown to be related to specific functional mechanisms involved in emotion regulation. From a developmental perspective, attachment representations based on experiences with the caregiver are theorized to serve regulatory functions and influence how individuals deal with emotionally challenging situations throughout the life span. This study aimed to investigate neural substrates of emotion regulation by assessing state- and trait dependent EEG asymmetries in secure, insecure dismissing and insecure-preoccupied subjects. The sample consisted of 40 late adolescents. The Adult Attachment Interview was administered and they were asked to report upon personally highly salient emotional memories related to anger, happiness and sadness. EEG was recorded at rest and during the retrieval of each of these emotional memories, and frontal and parietal hemispheric asymmetry were analyzed. We found attachment representations to differentially affect both the frontal and parietal organization of hemispheric asymmetry at rest and (for parietal region only) during the retrieval of emotional memories. During rest, insecure-dismissing subjects showed an elevated right-frontal brain activity and a reduced right-parietal brain activity. We interpret this finding in light of a disposition to use withdrawal strategies and low trait arousal in insecure dismissing subjects. Emotional memory retrieval did not affect frontal asymmetry. However, both insecure groups showed an increase in right-sided parietal activity indicating increased arousal during the emotional task as compared to the resting state suggesting that their emotion regulation capability was especially challenged by the retrieval of emotional memories while securely attached subjects maintained a state of moderate arousal. The specific neurophysiological pattern of insecure-dismissing subjects is discussed with regard to a vulnerability to affective disorders. PMID- 28082881 TI - Association between Attention and Heart Rate Fluctuations in Pathological Worriers. AB - Recent data suggests that several psychopathological conditions are associated with alterations in the variability of behavioral and physiological responses. Pathological worry, defined as the cognitive representation of a potential threat, has been associated with reduced variability of heart beat oscillations (i.e., decreased heart rate variability; HRV) and lapses of attention indexed by reaction times (RTs). Clinical populations with attention deficit show RTs oscillation around 0.05 and 0.01 Hz when performing a sustained attention task. We tested the hypothesis that people who are prone to worry do it in a predictable oscillating pattern revealed through recurrent lapses in attention and concomitant oscillating HRV. Sixty healthy young adults (50% women) were recruited: 30 exceeded the clinical cut-off on the Penn State Worry Questionnaire (PSWQ; High-Worry, HW); the remaining 30 constituted the Low-Worry (LW) group. After a diagnostic assessment, participants performed two 15-min sustained attention tasks, interspersed by a standardized worry-induction procedure. RTs, HRV and moods were assessed. The analyses of the frequency spectrum showed that the HW group presents a significant higher and constant peak of RTs oscillation around 0.01 Hz (period 100 s) after the induction of worry, in comparison with their baseline and with the LW group that was not responsive to the induction procedure. Physiologically, the induction significantly reduced high-frequency HRV and such reduction was associated with levels of self-reported worry. Results are coherent with the oscillatory nature of the default mode network (DMN) and further confirm an association between cognitive rigidity and autonomic nervous system inflexibility. PMID- 28082883 TI - Older Adults with Mild Cognitive Impairments Show Less Driving Errors after a Multiple Sessions Simulator Training Program but Do Not Exhibit Long Term Retention. AB - The driving performance of individuals with mild cognitive impairment (MCI) is suboptimal when compared to healthy older adults. It is expected that the driving will worsen with the progression of the cognitive decline and thus, whether or not these individuals should continue to drive is a matter of debate. The aim of the study was to provide support to the claim that individuals with MCI can benefit from a training program and improve their overall driving performance in a driving simulator. Fifteen older drivers with MCI participated in five training sessions in a simulator (over a 21-day period) and in a 6-month recall session. During training, they received automated auditory feedback on their performance when an error was noted about various maneuvers known to be suboptimal in MCI individuals (for instance, weaving, omitting to indicate a lane change, to verify a blind spot, or to engage in a visual search before crossing an intersection). The number of errors was compiled for eight different maneuvers for all sessions. For the initial five sessions, a gradual and significant decrease in the number of errors was observed, indicating learning and safer driving. The level of performance, however, was not maintained at the 6-month recall session. Nevertheless, the initial learning observed opens up possibilities to undertake more regular interventions to maintain driving skills and safe driving in MCI individuals. PMID- 28082882 TI - Dominance of the Unaffected Hemisphere Motor Network and Its Role in the Behavior of Chronic Stroke Survivors. AB - Balance of motor network activity between the two brain hemispheres after stroke is crucial for functional recovery. Several studies have extensively studied the role of the affected brain hemisphere to better understand changes in motor network activity following stroke. Very few studies have examined the role of the unaffected brain hemisphere and confirmed the test-retest reliability of connectivity measures on unaffected hemisphere. We recorded blood oxygenation level dependent functional magnetic resonance imaging (fMRI) signals from nine stroke survivors with hemiparesis of the left or right hand. Participants performed a motor execution task with affected hand, unaffected hand, and both hands simultaneously. Participants returned for a repeat fMRI scan 1 week later. Using dynamic causal modeling (DCM), we evaluated effective connectivity among three motor areas: the primary motor area (M1), the premotor cortex (PMC) and the supplementary motor area for the affected and unaffected hemispheres separately. Five participants' manual motor ability was assessed by Fugl-Meyer Motor Assessment scores and root-mean square error of participants' tracking ability during a robot-assisted game. We found (i) that the task performance with the affected hand resulted in strengthening of the connectivity pattern for unaffected hemisphere, (ii) an identical network of the unaffected hemisphere when participants performed the task with their unaffected hand, and (iii) the pattern of directional connectivity observed in the affected hemisphere was identical for tasks using the affected hand only or both hands. Furthermore, paired t-test comparison found no significant differences in connectivity strength for any path when compared with one-week follow-up. Brain-behavior linear correlation analysis showed that the connectivity patterns in the unaffected hemisphere more accurately reflected the behavioral conditions than the connectivity patterns in the affected hemisphere. Above findings enrich our knowledge of unaffected brain hemisphere following stroke, which further strengthens our neurobiological understanding of stroke-affected brain and can help to effectively identify and apply stroke-treatments. PMID- 28082884 TI - Interaction between Perceived Action and Music Sequences in the Left Prefrontal Area. AB - Observing another person's piano play and listening to a melody interact with the observer's execution of piano play. This interaction is thought to occur because the execution of musical-action and the perception of both musical-action and musical-sound share a common representation in which the frontoparietal network is involved. However, it is unclear whether the perceptions of observed piano play and listened musical sound use a common neural resource. The present study used near-infrared spectroscopy to determine whether the interaction between the perception of musical-action and musical-sound sequences appear in the left prefrontal area. Measurements were obtained while participants watched videos that featured hands playing familiar melodies on a piano keyboard. Hand movements were paired with either a congruent or an incongruent melody. Two groups of participants (nine well-trained and nine less-trained) were instructed to identify the melody according to hand movements and to ignore the accompanying auditory track. Increased cortical activation was detected in the well-trained participants when hand movements were paired with incongruent melodies. Therefore, an interference effect was detected regarding the processing of action and sound sequences, indicating that musical-action sequences may be perceived with a representation that is also used for the perception of musical-sound sequences. However, in less-trained participants, such a contrast was not detected between conditions despite both groups featuring comparable key-touch reading abilities. Therefore, the current results imply that the left prefrontal area is involved in translating temporally structured sequences between domains. Additionally, expertise may be a crucial factor underlying this translation. PMID- 28082885 TI - A Supervoxel-Based Method for Groupwise Whole Brain Parcellation with Resting State fMRI Data. AB - Node definition is a very important issue in human brain network analysis and functional connectivity studies. Typically, the atlases generated from meta analysis, random criteria, and structural criteria are utilized as nodes in related applications. However, these atlases are not originally designed for such purposes and may not be suitable. In this study, we combined normalized cut (Ncut) and a supervoxel method called simple linear iterative clustering (SLIC) to parcellate whole brain resting-state fMRI data in order to generate appropriate brain atlases. Specifically, Ncut was employed to extract features from connectivity matrices, and then SLIC was applied on the extracted features to generate parcellations. To obtain group level parcellations, two approaches named mean SLIC and two-level SLIC were proposed. The cluster number varied in a wide range in order to generate parcellations with multiple granularities. The two SLIC approaches were compared with three state-of-the-art approaches under different evaluation metrics, which include spatial contiguity, functional homogeneity, and reproducibility. Both the group-to-group reproducibility and the group-to-subject reproducibility were evaluated in our study. The experimental results showed that the proposed approaches obtained relatively good overall clustering performances in different conditions that included different weighting functions, different sparsifying schemes, and several confounding factors. Therefore, the generated atlases are appropriate to be utilized as nodes for network analysis. The generated atlases and major source codes of this study have been made publicly available at http://www.nitrc.org/projects/slic/. PMID- 28082886 TI - Mapping the Parameter Space of tDCS and Cognitive Control via Manipulation of Current Polarity and Intensity. AB - In the cognitive domain, enormous variation in methodological approach prompts questions about the generalizability of behavioral findings obtained from studies of transcranial direct current stimulation (tDCS). To determine the impact of common variations in approach, we systematically manipulated two key stimulation parameters-current polarity and intensity-and assessed their impact on a task of inhibitory control (the Eriksen Flanker). Ninety participants were randomly assigned to one of nine experimental groups: three stimulation conditions (anode, sham, cathode) crossed with three intensity levels (1.0, 1.5, 2.0 mA). As participants performed the Flanker task, stimulation was applied over left dorsolateral prefrontal cortex (DLPFC; electrode montage: F3-RSO). The behavioral impact of these manipulations was examined using mixed effects linear regression. Results indicate a significant effect of stimulation condition (current polarity) on the magnitude of the interference effect during the Flanker; however, this effect was specific to the comparison between anodal and sham stimulation. Inhibitory control was therefore improved by anodal stimulation over the DLPFC. In the present experimental context, no reliable effect of stimulation intensity was observed, and we found no evidence that inhibitory control was impeded by cathodal stimulation. Continued exploration of the stimulation parameter space, particularly with more robustly powered sample sizes, is essential to facilitating cross-study comparison and ultimately working toward a reliable model of tDCS effects. PMID- 28082887 TI - Comparison of Three Non-Invasive Transcranial Electrical Stimulation Methods for Increasing Cortical Excitability. AB - Transcranial direct current stimulation (tDCS) is a representative non-invasive brain stimulation method (NIBS). tDCS increases cortical excitability not only in healthy individuals, but also in stroke patients where it contributes to motor function improvement. Recently, two additional types of transcranial electrical stimulation (tES) methods have been introduced that may also prove beneficial for stimulating cortical excitability; these are transcranial random noise stimulation (tRNS) and transcranial alternating current stimulation (tACS). However, comparison of tDCS with tRNS and tACS, in terms of efficacy in cortical excitability alteration, has not been reported thus far. We compared the efficacy of the three different tES methods for increasing cortical excitability using the same subject population and same current intensity. Fifteen healthy subjects participated in this study. Similar stimulation patterns (1.0 mA and 10 min) were used for the three conditions of stimulation (tDCS, tRNS, and tACS). Cortical excitability was explored via single-pulse TMS elicited motor evoked potentials (MEPs). Compared with pre-measurements, MEPs significantly increased with tDCS, tACS, and tRNS (p < 0.05). Compared with sham measurements, significant increases in MEPs were also observed with tRNS and tACS (p < 0.05), but not with tDCS. In addition, a significant correlation of the mean stimulation effect was observed between tRNS and tACS (p = 0.019, r = 0.598). tRNS induced a significant increase in MEP compared with the Pre or Sham at all time points. tRNS resulted in the largest significant increase in MEPs. These findings suggest that tRNS is the most effective tES method and should be considered as part of a treatment plan for improving motor function in stroke patients. PMID- 28082888 TI - Nonlinear Origin of SSVEP Spectra-A Combined Experimental and Modeling Study. AB - Steady state visual evoked potentials (SSVEPs) are steady state oscillatory potentials elicited in the electroencephalogram (EEG) by flicker stimulation. The frequency of these responses maches the frequency of the stimulation and of its harmonics and subharmonics. In this study, we investigated the origin of the harmonic and subharmonic components of SSVEPs, which are not well understood. We applied both sine and square wave visual stimulation at 5 and 15 Hz to human subjects and analyzed the properties of the fundamental responses and harmonically related components. In order to interpret the results, we used the well-established neural mass model that consists of interacting populations of excitatory and inhibitory cortical neurons. In our study, this model provided a simple explanation for the origin of SSVEP spectra, and showed that their harmonic and subharmonic components are a natural consequence of the nonlinear properties of neuronal populations and the resonant properties of the modeled network. The model also predicted multiples of subharmonic responses, which were subsequently confirmed using experimental data. PMID- 28082889 TI - Representational Distance Learning for Deep Neural Networks. AB - Deep neural networks (DNNs) provide useful models of visual representational transformations. We present a method that enables a DNN (student) to learn from the internal representational spaces of a reference model (teacher), which could be another DNN or, in the future, a biological brain. Representational spaces of the student and the teacher are characterized by representational distance matrices (RDMs). We propose representational distance learning (RDL), a stochastic gradient descent method that drives the RDMs of the student to approximate the RDMs of the teacher. We demonstrate that RDL is competitive with other transfer learning techniques for two publicly available benchmark computer vision datasets (MNIST and CIFAR-100), while allowing for architectural differences between student and teacher. By pulling the student's RDMs toward those of the teacher, RDL significantly improved visual classification performance when compared to baseline networks that did not use transfer learning. In the future, RDL may enable combined supervised training of deep neural networks using task constraints (e.g., images and category labels) and constraints from brain-activity measurements, so as to build models that replicate the internal representational spaces of biological brains. PMID- 28082890 TI - Bursting Neurons in the Hippocampal Formation Encode Features of LFP Rhythms. AB - Burst spike patterns are common in regions of the hippocampal formation such as the subiculum and medial entorhinal cortex (MEC). Neurons in these areas are immersed in extracellular electrical potential fluctuations often recorded as the local field potential (LFP). LFP rhythms within different frequency bands are linked to different behavioral states. For example, delta rhythms are often associated with slow-wave sleep, inactivity and anesthesia; whereas theta rhythms are prominent during awake exploratory behavior and REM sleep. Recent evidence suggests that bursting neurons in the hippocampal formation can encode LFP features. We explored this hypothesis using a two-compartment model of a bursting pyramidal neuron driven by time-varying input signals containing spectral peaks at either delta or theta rhythms. The model predicted a neural code in which bursts represented the instantaneous value, phase, slope and amplitude of the driving signal both in their timing and size (spike number). To verify whether this code is employed in vivo, we examined electrophysiological recordings from the subiculum of anesthetized rats and the MEC of a behaving rat containing prevalent delta or theta rhythms, respectively. In both areas, we found bursting cells that encoded information about the instantaneous voltage, phase, slope and/or amplitude of the dominant LFP rhythm with essentially the same neural code as the simulated neurons. A fraction of the cells encoded part of the information in burst size, in agreement with model predictions. These results provide in-vivo evidence that the output of bursting neurons in the mammalian brain is tuned to features of the LFP. PMID- 28082891 TI - On the Phase Relationship between Excitatory and Inhibitory Neurons in Oscillation. AB - Characteristic phase shifts between discharges of pyramidal cells and interneurons in oscillation have been widely observed in experiments, and they have been suggested to play important roles in neural computation. Previous studies mainly explored two independent mechanisms to generate neural oscillation, one is based on the interaction loop between pyramidal cells and interneurons, referred to as the E-I loop, and the other is based on the interaction loop between interneurons, referred to as the I-I loop. In the present study, we consider neural networks consisting of both the E-I and I-I loops, and the network oscillation can operate under either E-I loop dominating mode or I-I loop dominating mode, depending on the network structure, and neuronal connection patterns. We found that the phase shift between pyramidal cells and interneurons displays different characteristics in different oscillation modes, and its amplitude varies with the network parameters. We expect that this study helps us to understand the structural characteristics of neural circuits underlying various oscillation behaviors observed in experiments. PMID- 28082892 TI - Neurons in Primate Visual Cortex Alternate between Responses to Multiple Stimuli in Their Receptive Field. AB - A fundamental question concerning representation of the visual world in our brain is how a cortical cell responds when presented with more than a single stimulus. We find supportive evidence that most cells presented with a pair of stimuli respond predominantly to one stimulus at a time, rather than a weighted average response. Traditionally, the firing rate is assumed to be a weighted average of the firing rates to the individual stimuli (response-averaging model) (Bundesen et al., 2005). Here, we also evaluate a probability-mixing model (Bundesen et al., 2005), where neurons temporally multiplex the responses to the individual stimuli. This provides a mechanism by which the representational identity of multiple stimuli in complex visual scenes can be maintained despite the large receptive fields in higher extrastriate visual cortex in primates. We compare the two models through analysis of data from single cells in the middle temporal visual area (MT) of rhesus monkeys when presented with two separate stimuli inside their receptive field with attention directed to one of the two stimuli or outside the receptive field. The spike trains were modeled by stochastic point processes, including memory effects of past spikes and attentional effects, and statistical model selection between the two models was performed by information theoretic measures as well as the predictive accuracy of the models. As an auxiliary measure, we also tested for uni- or multimodality in interspike interval distributions, and performed a correlation analysis of simultaneously recorded pairs of neurons, to evaluate population behavior. PMID- 28082893 TI - Editorial: Modeling of Visual Cognition, Body Sense, Motor Control and Their Integrations. PMID- 28082895 TI - Editorial: Muscle-Tendon-Innervation Unit: Degeneration and Aging Pathophysiological and Regeneration Mechanisms. PMID- 28082894 TI - Aerobic Activity in the Healthy Elderly Is Associated with Larger Plasticity in Memory Related Brain Structures and Lower Systemic Inflammation. AB - Cognitive abilities decline over the time course of our life, a process, which may be mediated by brain atrophy and enhanced inflammatory processes. Lifestyle factors, such as regular physical activities have been shown to counteract those noxious processes and are assumed to delay or possibly even prevent pathological states, such as dementing disorders. Whereas the impact of lifestyle and immunological factors and their interactions on cognitive aging have been frequently studied, their effects on neural parameters as brain activation and functional connectivity are less well studied. Therefore, we investigated 32 healthy elderly individuals (60.4 +/- 5.0 SD; range 52-71 years) with low or high level of self-reported aerobic physical activity at the time of testing. A higher compared to a lower level in aerobic physical activity was associated with an increased encoding related functional connectivity in an episodic memory network comprising mPFC, thalamus, hippocampus precuneus, and insula. Moreover, encoding related functional connectivity of this network was associated with decreased systemic inflammation, as measured by systemic levels of interleukin 6. PMID- 28082896 TI - Effect of Aging on Motor Inhibition during Action Preparation under Sensory Conflict. AB - Motor behaviors often require refraining from selecting options that may be part of the repertoire of natural response tendencies but that are in conflict with ongoing goals. The presence of sensory conflict has a behavioral cost but the latter can be attenuated in contexts where control processes are recruited because conflict is expected in advance, producing a behavioral gain compared to contexts where conflict occurs in a less predictable way. In the present study, we investigated the corticospinal correlates of these behavioral effects (both conflict-driven cost and context-related gain). To do so, we measured motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) of young and healthy older adults performing the Eriksen Flanker Task. Subjects performed button-presses according to a central arrow, flanked by irrelevant arrows pointing in the same (congruent trial) or opposite direction (incongruent trial). Conflict expectation was manipulated by changing the probability of congruent and incongruent trials in a given block. It was either high (mostly incongruent blocks, MIB, 80% incongruent trials) or low (mostly congruent blocks, MCB, 80% congruent). The MEP data indicate that the conflict-driven behavioral cost is associated with a strong increase in inappropriate motor activity regardless of the age of individuals, as revealed by larger MEPs in the non-responding muscle in incongruent than in congruent trials. However, this aberrant facilitation disappeared in both groups of subjects when conflict could be anticipated (i.e., in the MIBs) compared to when it occurred in a less predictably way (MCBs), probably allowing the behavioral gain observed in both the young and the older individuals. Hence, the ability to overcome and anticipate conflict was surprisingly preserved in the older adults. Nevertheless, some control processes are likely to evolve with age because the behavioral gain observed in the MIB context was associated with an attenuated suppression of MEPs at the time of the imperative signal (i.e., before conflict is actually detected) in older individuals, suggesting altered motor inhibition, compared to young individuals. In addition, the behavioral analysis suggests that young and older adults rely on different strategies to cope with conflict, including a change in speed-accuracy tradeoff. PMID- 28082897 TI - The Role of Neuropeptide Y mRNA Expression Level in Distinguishing Different Types of Depression. AB - Previous studies demonstrate that the protein of neuropeptide Y (NPY) is abnormal in depression patients, but the changes of NPY in different types of depression are unclear. This study was aimed to examine protein and mRNA expression levels of NPY in 159 cases with four groups including post-stroke depression (PSD) group, stroke without depression (Non-PSD) group, major depressive disorder (MDD) group and normal control (NC) group. The protein and gene expression analysis were performed by enzyme-linked immunosorbent assay (ELISA) and quantitative polymerase chain reaction-based methods. One way analysis of variance (ANOVA), chi-square tests and nonparametric test were used to evaluate general characteristics, clinical and biological materials. In order to explore the role of NPY in different types of depression, the partial correlations, binary logistic regression analysis and receiver operating characteristic (ROC) curve were calculated for PSD and MDD groups. There are significant differences of NPY protein (Fdf(3) = 5.167, P = 0.002) and mRNA expression levels ([Formula: see text] = 20.541, P < 0.001) among four groups. Bonferroni multiple comparisons found that the NPY protein was significantly decreased in PSD (FBonferroni = 7.133, P = 0.002) and Non-PSD group (FBonferroni = -5.612, P = 0.018) compared with NC group. However, contrasted with MDD group, the mRNA expression was increased in PSD and Non-PSD group by nonparametric test (all P < 0.05). In binary logistic analyses, NPY mRNA expression was independent predictors of PSD (odds ratio: 1.452, 95% CI, 1.081-1.951, P = 0.013). The ROC curve showed NPY mRNA had a general prognostic accuracy (area under the curve: 0.766, 95% CI, 0.656-0.876, P < 0.001). This is the first study to explore the distinguishing function of NPY in different types of depression. It will provide help in the identification of different subtypes of depression. PMID- 28082898 TI - Comparison of Different Risk Classification Systems in 558 Patients with Gastrointestinal Stromal Tumors after R0-Resection. AB - Background: Due to adjuvant treatment concepts for patients with R0-resected gastrointestinal stromal tumors (GIST), a reproducible and reliable risk classification system proved of utmost importance for optimal treatment of patients and prediction of prognosis. The aim of this study was to reevaluate the impact of five widely-applied and well-established GIST risk classification systems (i.e., scores by Fletcher, Miettinen, Huang, Joensuu, and TNM classification) on a series of 558 GIST patients with long-term follow-up after R0 resection. Methods: Tumor size, mitotic count and site were used in variable combination to predict high- and low risk patients by the use of the five risk classification models. For survival analyses disease-specific survival, disease free survival and overall-survival were investigated. Patients with initial metastatic disease or incompletely resectable tumors were excluded. Results: All GIST classification models distinguished well between patients with high-risk and low-risk tumors and none of the five risk systems was superior to predict patient outcome. The models showed significant heterogeneity. There was no significant difference between the different risk-groups regarding overall-survival. Subdivision of GIST patients with very low- and low-risk appeared to be negligible. Conclusions: Currently applied GIST risk classification systems are comparable to predict high- or low-risk patients with initial non-metastatic and completely resected GIST. However, the heterogeneity of the high-risk group and the absence of differences in overall survival indicate the need for more precise tumor- and patient-related criteria for better stratification of GIST and identification of patients who would benefit best from adjuvant tyrosine kinase inhibitor therapy. PMID- 28082899 TI - BNN27, a 17-Spiroepoxy Steroid Derivative, Interacts With and Activates p75 Neurotrophin Receptor, Rescuing Cerebellar Granule Neurons from Apoptosis. AB - Neurotrophin receptors mediate a plethora of signals affecting neuronal survival. The p75 pan-neurotrophin receptor controls neuronal cell fate after its selective activation by immature and mature isoforms of all neurotrophins. It also exerts pleiotropic effects interacting with a variety of ligands in different neuronal or non-neuronal cells. In the present study, we explored the biophysical and functional interactions of a blood-brain-barrier (BBB) permeable, C17-spiroepoxy steroid derivative, BNN27, with p75NTR receptor. BNN27 was recently shown to bind to NGF high-affinity receptor, TrkA. We now tested the p75NTR-mediated effects of BNN27 in mouse Cerebellar Granule Neurons (CGNs), expressing p75NTR, but not TrkA receptors. Our findings show that BNN27 physically interacts with p75NTR receptors in specific amino-residues of its extracellular domain, inducing the recruitment of p75NTR receptor to its effector protein RIP2 and the simultaneous release of RhoGDI in primary neuronal cells. Activation of the p75NTR receptor by BNN27 reverses serum deprivation-induced apoptosis of CGNs resulting in the decrease of the phosphorylation of pro-apoptotic JNK kinase and of the cleavage of Caspase-3, effects completely abolished in CGNs, isolated from p75NTR null mice. In conclusion, BNN27 represents a lead molecule for the development of novel p75NTR ligands, controlling specific p75NTR-mediated signaling of neuronal cell fate, with potential applications in therapeutics of neurodegenerative diseases and brain trauma. PMID- 28082900 TI - Blockade of Serotonin 5-HT2A Receptors Suppresses Behavioral Sensitization and Naloxone-Precipitated Withdrawal Symptoms in Morphine-Treated Mice. AB - : The increasing prescription of opioids is fueling an epidemic of addiction and overdose deaths. Morphine is a highly addictive drug characterized by a high relapse rate - even after a long period of abstinence. Serotonin (5-HT) neurotransmission participates in the development of morphine dependence, as well as the expression of morphine withdrawal. In this study, we examined the effect of blockade of 5-HT2A receptors (5-HT2ARs) on morphine-induced behavioral sensitization and withdrawal in male mice. 5-HT2AR antagonist MDL 11,939 (0.5 mg/kg, i.p.) suppressed acute morphine (5.0 mg/kg, s.c.)-induced increase in locomotor activity. Mice received morphine (10 mg/kg, s.c.) twice a day for 3 days and then drug treatment was suspended for 5 days. On day 9, a challenge dose of morphine (10 mg/kg) was administered to induce the expression of behavioral sensitization. MDL 11,939 (0.5 mg/kg, i.p.) pretreatment suppressed the expression of morphine-induced behavioral sensitization. Another cohort of mice received increasing doses of morphine over a 7-day period to induce morphine dependence. MDL 11,939 (0.5 mg/kg, i.p.) prevented naloxone-precipitated withdrawal in morphine-dependent mice on day 7. Moreover, chronic morphine treatment increased 5-HT2AR protein level and decreased the phosphorylation of extracellular signal-regulated kinases in the prefrontal cortex. Together, these results by the first time demonstrate that 5-HT2ARs modulate opioid dependence and blockade of 5-HT2AR may represent a novel strategy for the treatment of morphine use disorders. HIGHLIGHTS: (i)Blockade of 5-HT2A receptors suppresses the expression of morphine-induced behavioral sensitization.(ii)Blockade of 5 HT2A receptors suppresses naloxone-precipitated withdrawal in morphine-treated mice.(iii)Chronic morphine exposure induces an increase in 5-HT2A receptor protein level and a decrease in ERK protein phosphorylation in prefrontal cortex. PMID- 28082901 TI - Sustained Contraction in Vascular Smooth Muscle by Activation of L-type Ca2+ Channels Does Not Involve Ca2+ Sensitization or Caldesmon. AB - Vascular smooth muscle (VSM) is unique in its ability to maintain an intrinsic level of contractile force, known as tone. Vascular tone is believed to arise from the constitutive activity of membrane-bound L-type Ca2+ channels (LTCC). This study used a pharmacological agonist of LTCC, Bay K8644, to elicit a sustained, sub-maximal contraction in VSM that mimics tone. Downstream signaling was investigated in order to determine what molecules are responsible for tone. Medial strips of swine carotid artery were stimulated with 100 nM Bay K8644 to induce a sustained level of force. Force and phosphorylation levels of myosin light chain (MLC), MAP kinase, MYPT1, CPI-17, and caldesmon were measured during Bay K8644 stimulation in the presence and absence of nifedipine, ML-7, U0126, bisindolylmaleimide (Bis), and H-1152. Nifedipine and ML-7 inhibited force and MLC phosphorylation in response to Bay K8644. Inhibition of Rho kinase (H-1152) but not PKC (Bis) inhibited Bay K8644 induced force. U0126 significantly increased Bay K8644-dependent force with no effect on MLC phosphorylation. Neither CPI-17 nor caldesmon phosphorylation were increased during the maintenance of sustained force. Our results suggest that force due to the influx of calcium through LTCCs is partially MLC phosphorylation-dependent but does not involve PKC or caldesmon. Interestingly, inhibition of MLC kinase (MLCK) and PKC significantly increased MAP kinase phosphorylation suggesting that MLCK and PKC may directly or indirectly inhibit MAP kinase activity during prolonged contractions induced by Bay K8544. PMID- 28082902 TI - Optimized Cocktail Phenotyping Study Protocol Using Physiological Based Pharmacokinetic Modeling and In silico Assessment of Metabolic Drug-Drug Interactions Involving Modafinil. AB - In vivo cocktail pathway phenotyping (ICPP) is routinely used to assess the metabolic drug-drug interaction (mDDI) potential of new drug candidates (NDC) during drug development. However, there are a number of potential limitations to this approach and the use of validated drug cocktails and study protocols is essential. Typically ICPP mDDI studies assess only the impact of interactions following multiple postulated perpetrator doses and hence the emphasis in terms of validation of these studies has been ensuring that there are no interactions between probe substrates. Studies assessing the comparative impact of single and multiple doses of the postulated perpetrator have the potential to provide richer information regarding both the clinical impact and mechanism of mDDIs. Using modafinil as a model compound, we sought to develop an optimized ICPP mDDI study protocol to evaluate the potential magnitude and clinical relevance of mDDIs using a physiologically based pharmacokinetic modeling approach. PMID- 28082903 TI - Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations. AB - ATP-binding cassette transporter G2 (ABCG2) is a plasma membrane protein that regulates the pharmacokinetics of a variety of drugs and serum uric acid (SUA) levels in humans. Despite the pharmacological and physiological importance of this transporter, there is no clinically available drug that modulates ABCG2 function. Therefore, to identify such drugs, we investigated the effect of drugs that affect SUA levels on ABCG2 function. This strategy was based on the hypothesis that the changes of SUA levels might caused by interaction with ABCG2 since it is a physiologically important urate transporter. The results of the in vitro screening showed that 10 of 25 drugs investigated strongly inhibited the urate transport activity of ABCG2. Moreover, febuxostat was revealed to be the most promising candidate of all the potential ABCG2 inhibitors based on its potent inhibition at clinical concentrations; the half-maximal inhibitory concentration of febuxostat was lower than its maximum plasma unbound concentrations reported. Indeed, our in vivo study demonstrated that orally administered febuxostat inhibited the intestinal Abcg2 and, thereby, increased the intestinal absorption of an ABCG2 substrate sulfasalazine in wild-type mice, but not in Abcg2 knockout mice. These results suggest that febuxostat might inhibit human ABCG2 at a clinical dose. Furthermore, the results of this study lead to a proposed new application of febuxostat for enhancing the bioavailability of ABCG2 substrate drugs, named febuxostat-boosted therapy, and also imply the potential risk of adverse effects by drug-drug interactions that could occur between febuxostat and ABCG2 substrate drugs. PMID- 28082904 TI - Effect of Different Formulations of Magnesium Chloride Used As Anesthetic Agents on the Performance of the Isolated Heart of Octopus vulgaris. AB - Magnesium chloride (MgCl2) is commonly used as a general anesthetic in cephalopods, but its physiological effects including those at cardiac level are not well-characterized. We used an in vitro isolated perfused systemic heart preparation from the common octopus, Octopus vulgaris, to investigate: (a) if in vivo exposure to MgCl2 formulations had an effect on cardiac function in vitro and, if so, could this impact recovery and (b) direct effects of MgCl2 formulations on cardiac function. In vitro hearts removed from animals exposed in vivo to 3.5% MgCl2 in sea water (20 min) or to a mixture of MgCl2+ ethanol (1.12/1%; 20 min) showed cardiac function (heart rate, stroke volume, cardiac output) comparable to hearts removed from animals killed under hypothermia. However, 3.5% MgCl2 (1:1, sea water: distilled water, 20 min) produced a significant impairment of the Frank-Starling response as did 45 min exposure to the MgCl2+ ethanol mixture. Perfusion of the isolated heart with MgCl2+/- ethanol formulations produced a concentration-related bradycardia (and arrest), a decreased stroke volume and cardiac output indicating a direct effect on the heart. The cardiac effects of MgCl2 are discussed in relation to the involvement of magnesium, sodium, chloride, and calcium ions, exposure time and osmolality of the formulations and the implications for the use of various formulations of MgCl2 as anesthetics in octopus. Overall, provided that the in vivo exposure to 3.5% MgCl2 in sea water or to a mixture of MgCl2+ ethanol is limited to ~20 min, residual effects on cardiac function are unlikely to impact post-anesthetic recovery. PMID- 28082905 TI - Treatment of Acidified Blood Using Reduced Osmolarity Mixed-Base Solutions. AB - We hypothesize that reduced osmolarity mixed-base (ROMB) solutions can potentially serve as customizable treatments for acidoses, going beyond standard solutions in clinical use, such as 1.0 M sodium bicarbonate. Through in silico quantitative modeling, by treating acidified canine blood using ROMB solutions, and by performing blood-gas and optical microscopy measurements in vitro, we demonstrate that ROMB solutions having a high proportion of a strong base, such as disodium carbonate or sodium hydroxide, can be effective in reducing carbon dioxide pressure PCO2 while raising pH and bicarbonate ion concentration without causing significant osmotic damage to red blood cells, which can occur during rapid administration of hypertonic solutions of weak bases. These results suggest that a ROMB solution, which is composed mostly of a strong base, could be administered in a safe and effective manner, when compared to a hypertonic solution of sodium bicarbonate. Because of the reduced osmolarity and the customizable content of strong base in ROMB solutions, this approach differs from prior approaches involving hypertonic solutions that only considered a single molar ratio of strong to weak base. Our calculations and measurements suggest that custom-tailored ROMB solutions merit consideration as potentially efficacious treatments for specific types of acidosis, particularly acute metabolic acidosis and acute respiratory acidosis. PMID- 28082906 TI - Spatiotemporal Dynamics of Insulitis in Human Type 1 Diabetes. AB - Type 1 diabetes (T1D) is an auto-immune disease characterized by the selective destruction of the insulin secreting beta cells in the pancreas during an inflammatory phase known as insulitis. Patients with T1D are typically dependent on the administration of externally provided insulin in order to manage blood glucose levels. Whilst technological developments have significantly improved both the life expectancy and quality of life of these patients, an understanding of the mechanisms of the disease remains elusive. Animal models, such as the NOD mouse model, have been widely used to probe the process of insulitis, but there exist very few data from humans studied at disease onset. In this manuscript, we employ data from human pancreases collected close to the onset of T1D and propose a spatio-temporal computational model for the progression of insulitis in human T1D, with particular focus on the mechanisms underlying the development of insulitis in pancreatic islets. This framework allows us to investigate how the time-course of insulitis progression is affected by altering key parameters, such as the number of the CD20+ B cells present in the inflammatory infiltrate, which has recently been proposed to influence the aggressiveness of the disease. Through the analysis of repeated simulations of our stochastic model, which track the number of beta cells within an islet, we find that increased numbers of B cells in the peri-islet space lead to faster destruction of the beta cells. We also find that the balance between the degradation and repair of the basement membrane surrounding the islet is a critical component in governing the overall destruction rate of the beta cells and their remaining number. Our model provides a framework for continued and improved spatio-temporal modeling of human T1D. PMID- 28082907 TI - High-Intensity Exercise in Hypoxia: Is Increased Reliance on Anaerobic Metabolism Important? PMID- 28082908 TI - Exogenous Cortisol Administration; Effects on Risk Taking Behavior, Exercise Performance, and Physiological and Neurophysiological Responses. AB - Rationale: Exogenous cortisol is a modulator of behavior related to increased motivated decision making (Putman et al., 2010), where risky choices yield potentially big reward. Making risk based judgments has been shown to be important to athletes in optimizing pacing during endurance events (Renfree et al., 2014; Micklewright et al., 2015). Objectives: Therefore, the aims of this study were to examine the effect of 50 mg exogenous cortisol on neurophysiological responses and risk taking behavior in nine healthy men. Further to this, to examine the effect of exogenous cortisol on exercise performance. Methods: Using a double blind counterbalanced design, cyclists completed a placebo (PLA), and a cortisol (COR) trial (50 mg cortisol), with drug ingestion at 0 min. Each trial consisted of a rest period from 0 to 60 min, followed by a risk taking behavior task, a 30 min time trial (TT) with 5 * 30 s sprints at the following time intervals; 5, 11, 17, 23, and 29 min. Salivary cortisol (SaCOR), Electroencephalography (EEG) and Near Infrared Spectroscopy (NIRs) were measured at 15, 30, 45, and 60 min post-ingestion. Glucose and lactate samples were taken at 0 and 60 min post-ingestion. During exercise, power output (PO), heart rate (HR), EEG, and NIRS were measured. SaCOR was measured 10 min post-exercise. Results: Cortisol increased risk taking behavior from baseline testing. This was in line with significant neurophysiological changes at rest and during exercise. At rest, SaCOR levels were higher (P < 0.01) in COR compared to PLA (29.7 +/- 22.7 and 3.27 +/- 0.7 nmol/l, respectively). At 60 min alpha slow EEG response was higher in COR than PLA in the PFC (5.5 +/- 6.4 vs. -0.02 +/- 8.7% change; P < 0.01). During the TT there was no difference in total km, average power or average sprint power, although Peak power (PP) achieved was lower in COR than PLA (465.3 +/- 83.4 and 499.8 +/- 104.3; P < 0.05) and cerebral oxygenation was lower in COR (P < 0.05). Conclusion: This is the first study to examine the effect of exogenous cortisol on exercise performance. These results are in line with previous research showing altered risk taking behavior following exogenous cortisol, however the altered behavior did not translate into changes in exercise performance. PMID- 28082909 TI - Training Intensity Distribution and Changes in Performance and Physiology of a 2nd Place Finisher Team of the Race across America Over a 6 Month Preparation Period. AB - Aim: To monitor the training intensity distribution (TID) and the development of physiological and performance parameters. Methods: During their preparation period for the RAAM, 4 athletes (plus 1 additional backup racer) performed 3 testing sessions; one before, one after 3, and one after 6 months of training. VO2max, maximal rate of lactate accumulation (dLa/dtmax), critical power, power output at lactate minimum (MLSSP), peak and mean power output during a sprint test, heart rate recovery, isometric strength, jumping height, and body composition were determined. All training sessions were recorded with a power meter. The endurance TID was analyzed based on the time in zone approach, according to a classical 3-zone model, including all power data of training sessions, and a power specific 3-zone model, where time with power output below 50% of MLSSP was not considered. Results: The TID using the classical 3-zone model reflected a pyramidal TID (zone 1: 63 +/- 16, zone 2: 28 +/- 13 and zone 3: 9 +/- 4%). The power specific 3-zone model resulted in a threshold-based TID (zone 1: 48 +/- 13, zone 2: 39 +/- 10, zone 3: 13 +/- 4%). VO2max increased by 7.1 +/- 5.3% (P = 0.06). dLa/dtmax decreased by 16.3 +/- 8.1% (P = 0.03). Power output at lactate minimum and critical power increased by 10.3 +/- 4.1 and 16.8 +/- 6.2% (P = 0.01), respectively. No changes were found for strength parameters and jumps. Conclusion: The present study underlines that a threshold oriented TID results in only moderate increases in physiological parameters. The amount of training below 50% of MLSSp (~28% of total training time) is remarkably high. Researchers, trainers, and athletes should pay attention to the different ways of interpreting training power data, to gain realistic insights into the TID and the corresponding improvements in performance and physiological parameters. PMID- 28082910 TI - Acute Effects of Different Exercise Protocols on the Circulating Vascular microRNAs -16, -21, and -126 in Trained Subjects. AB - Aim: mircoRNAs (miRNAs), small non-coding RNAs regulating gene expression, are stably secreted into the blood and circulating miRNAs (c-miRNAs) may play an important role in cell-cell communication. Furthermore, c-miRNAs might serve as novel biomarkers of the current vascular cell status. Here, we examined how the levels of three vascular c-miRNAs (c-miR-16, c-miR-21, c-miR-126) are acutely affected by different exercise intensities and volumes. Methods: 12 subjects performed 3 different endurance exercise protocols: 1. High-Volume Training (HVT; 130 min at 55% peak power output (PPO); 2. High-Intensity Training (HIT; 4 * 4 min at 95% PPO); 3. Sprint-Interval Training (SIT; 4 * 30 s all-out). c-miRNAs were quantified using quantitative real-time PCR with TaqMan probes at time points pre, 0', 30', 60', and 180' after each intervention. The expression of miR 126 and miR-21 was analyzed in vitro, in human coronary artery endothelial cells, human THP-1 monocytes, human platelets, human endothelial microparticles (EMPs) and human vascular smooth muscle cells (VSMCs). To investigate the transfer of miRNAs via EMPs, VSMCs were incubated with EMPs. Results: HVT and SIT revealed large increases on c-miR-21 [1.9-fold by HVT (cohen's d = 0.85); 1.5-fold by SIT (cohen's d = 0.85)] and c-miR-126 [2.2-fold by SIT (cohen's d = 1.06); 1.9-fold by HVT (cohen's d = 0.85)] post-exercise compared to pre-values, while HIT revealed only small to moderate changes on c-miRs-21 (cohen's d = -0.28) and c miR-126 (cohen's d = 0.53). c-miR-16 was only slightly affected by SIT (1.4-fold; cohen's d = 0.57), HVT (1.3-fold; cohen's d = 0.61) or HIT (1.1-fold; cohen's d = 0.2). Further in vitro experiments revealed that miR-126 and miR-21 are mainly of endothelial origin. Importantly, under conditions of endothelial apoptosis, miR 126 and miR-21 are packed from endothelial cells into endothelial microparticles, which were shown to transfer miR-126 into target vascular smooth muscle cells. Conclusion: Taken together, we found that HVT and SIT are associated with the release of endothelial miRNAs into the circulation, which can function as intercellular communication devices regulating vascular biology. PMID- 28082911 TI - Personalized Prediction of Proliferation Rates and Metabolic Liabilities in Cancer Biopsies. AB - Cancer is a heterogeneous disease and its genetic and metabolic mechanism may manifest differently in each patient. This creates a demand for studies that can characterize phenotypic traits of cancer on a per-sample basis. Combining two large data sets, the NCI60 cancer cell line panel, and The Cancer Genome Atlas, we used a linear interaction model to predict proliferation rates for more than 12,000 cancer samples across 33 different cancers from The Cancer Genome Atlas. The predicted proliferation rates are associated with patient survival and cancer stage and show a strong heterogeneity in proliferative capacity within and across different cancer panels. We also show how the obtained proliferation rates can be incorporated into genome-scale metabolic reconstructions to obtain the metabolic fluxes for more than 3000 cancer samples that identified specific metabolic liabilities for nine cancer panels. Here we found that affected pathways coincided with the literature, with pentose phosphate pathway, retinol, and branched-chain amino acid metabolism being the most panel-specific alterations and fatty acid metabolism and ROS detoxification showing homogeneous metabolic activities across all cancer panels. The presented strategy has potential applications in personalized medicine since it can leverage gene expression signatures for cell line based prediction of additional metabolic properties which might help in constraining personalized metabolic models and improve the identification of metabolic alterations in cancer for individual patients. PMID- 28082912 TI - The Rate of Concentration Change and How It Determines the Resolving Power of Olfactory Receptor Neurons. AB - The response characteristics of olfactory receptor neurons (ORNs) and their corollary, the differential sensitivity and the resolving power, are fundamental to understand olfactory coding and the information extracted from a fluctuating olfactory signal. Previous work has focused on the temporal resolution of odor pulses presented for very brief periods at varying concentrations. The time course of the odor pulses as a stimulus parameter has not been considered. The present study investigated the precision of the ON and OFF ORNs on the antennae of the cockroach to discriminate increments and decrements of continuously rising and falling odor concentrations. Stimulation consisted of ramp-like upward and downward concentration changes in a trapezoid fashion. By varying ramp steepness, we examined the effect of the rate of concentration change. Both ORNs were clearly dependent on continuously rising and falling odor concentrations. As the rate of upward and downward concentration changes increases, differential sensitivity improves. Since the scatter of responses around the stimulus-response functions also increases, the resolving power for concentration increments and decrements deteriorates. Thus, the slower the rate of concentration change, the higher the precision in differentiating small concentration changes. Intuitively, the inverse relationship between the rate of concentration change and the resolving power is not surprising because accuracy requires time. A high degree of precision at slow concentration rates enables the cockroach to use information about the onset and offset slopes of odor pulses in addition to the pulse height to encode the spatial-temporal structure of turbulent odor plumes. PMID- 28082913 TI - TGR5, Not Only a Metabolic Regulator. AB - G-protein-coupled bile acid receptor, Gpbar1 (TGR5), is a member of G-protein coupled receptor (GPCR) superfamily. High levels of TGR5 mRNA were detected in several tissues such as small intestine, stomach, liver, lung, especially in placenta and spleen. TGR5 is not only the receptor for bile acids, but also the receptor for multiple selective synthetic agonists such as 6alpha-ethyl-23(S) methyl-cholic acid (6-EMCA, INT-777) and a series of 4-benzofuranyloxynicotinamde derivatives to regulate different signaling pathways such as nuclear factor kappaB (NF-kappaB), AKT, and extracellular signal-regulated kinases (ERK). TGR5, as a metabolic regulator, is involved in energy homeostasis, bile acid homeostasis, as well as glucose metabolism. More recently, our group and others have extended the functions of TGR5 to more than metabolic regulation, which include inflammatory response, cancer and liver regeneration. These findings highlight TGR5 as a potential drug target for different diseases. This review summarizes the basic information of TGR5 and its new functions. PMID- 28082914 TI - Heart Rate and Cardiovascular Responses to Commercial Flights: Relationships with Physical Fitness. AB - The aim of this study was to examine the influence of physical fitness on cardiac autonomic control in passengers prior to, during and following commercial flights. Twenty-two, physically active men (36.4 +/- 6.4 years) undertook assessments of physical fitness followed by recordings of 24-h heart rate (HR), heart rate variability (HRV), and blood pressure (BP) on a Control (no flight) and Experimental (flight) day. Recordings were analyzed using a two-way analysis of variance for repeated measures with relationships between variables examined via Pearson product-moment correlation coefficients. Compared to the Control day, 24-h HR was significantly greater (>7%) and HRV measures (5-39%) significantly lower on the Experimental day. During the 1-h flight, HR (24%), and BP (6%) were increased while measures of HRV (26-45%) were reduced. Absolute values of HRV during the Experimental day and relative changes in HRV measures (Control Experimental) were significantly correlated with measures of aerobic fitness (r = 0.43 to 0.51; -0.53 to -0.52) and body composition (r = -0.63 to -0.43; 0.48 0.61). The current results demonstrated that short-term commercial flying significantly altered cardiovascular function including the reduction of parasympathetic modulations. Further, greater physical fitness and lower body fat composition were associated with greater cardiac autonomic control for passengers during flights. Enhanced physical fitness and leaner body composition may enable passengers to cope better with the cardiovascular stress and high allostatic load associated with air travel for enhanced passenger well-being. PMID- 28082915 TI - Is Maximum Food Intake in Endotherms Constrained by Net or Factorial Aerobic Scope? Lessons from the Leaf-Eared Mouse. AB - Food availability varies substantially throughout animals' lifespans, thus the ability to profit from high food levels may directly influence animal fitness. Studies exploring the link between basal metabolic rate (BMR), growth, reproduction, and other fitness traits have shown varying relationships in terms of both magnitude and direction. The diversity of results has led to the hypothesis that these relationships are modulated by environmental conditions (e.g., food availability), suggesting that the fitness consequences of a given BMR may be context-dependent. In turn, there is indirect evidence that individuals with an increased capacity for aerobic work also have a high capacity for acquiring energy from food. Surprisingly, very few studies have explored the correlation between maximum rates of energy acquisition and BMR in endotherms, and to the best of our knowledge, none have attempted to elucidate relationships between the former and aerobic capacity [e.g., maximum metabolic rate (MMR), aerobic scope (Factorial aerobic scope, FAS; Net aerobic scope, NAS)]. In this study, we measured BMR, MMR, maximum food intake (recorded under low ambient temperature and ad libitum food conditions; MFI), and estimated aerobic scope in the leaf-eared mouse (Phyllotis darwini). We, then, examined correlations among these variables to determine whether metabolic rates and aerobic scope are functionally correlated, and whether an increased aerobic capacity is related to a higher MFI. We found that aerobic capacity measured as NAS is positively correlated with MFI in endotherms, but with neither FAS nor BMR. Therefore, it appears plausible that the capacity for assimilating energy under conditions of abundant resources is determined adaptively by NAS, as animals with higher NAS would be promoted by selection. In theory, FAS is an invariant measurement of the extreme capacity for energy turnover in relation to resting expenditure, whereas NAS represents the maximum capacity for simultaneous aerobic processes above maintenance levels. Accordingly, in our study, FAS and NAS represent different biological variables; FAS, in contrast to NAS, may not constrain food intake. The explanations for these differences are discussed in biological and mathematical terms; further, we encourage the use of NAS rather than FAS when analyzing the aerobic capacity of animals. PMID- 28082916 TI - Electrophysiological Characteristics of the LQT2 Syndrome Mutation KCNH2-G572S and Regulation by Accessory Protein KCNE2. AB - Mutations in hERG cause long QT syndrome type 2 which is characterized by a prolonged QT interval on electrocardiogram and predisposition to life-threatening ventricular tachyarrhythmia, syncope, and sudden death. hERG-G572S induces trafficking defects of hERG channel protein from Golgi to the plasma membrane and results in a dominant negative suppression of hERG current density. As an accessory beta subunit, KCNE2 promotes hERG migration from Golgi to cellular membrane. In this study, we investigated the rescue effect of KCNE2 in a G572S mutation of hERG. Transfection was performed into HEK293 cells. Patch clamp technique, western blotting analyses and confocal microscopic examination were used. Results showed that KCNE2 had a significantly enhanced effect on G572S mutation current. The increase of current was largest at KCNH2:KCNE2 of 1:3. Confocal images showed co-expressing G572S and KCNE2 could cause a substantial up regulated membrane protein (155 kDa) expression. Expression of membrane protein accumulated markedly with increasing ratio of KCNH2:KCNE2. G572S defective mutant could be restored by both KCNE2 and lower temperature (27 degrees C), which suggested that the lower temperature could be the favorable circumstances for the rescue function of KCNE2. In this study, we successfully set up "the action potential" on the HEK 293 cells by genetically engineered to express Kir2.1, Nav1.5, and Kv11.1, wherein on reaching over an excitation threshold by current injection. The results suggested that KCNE2 could shorten action potential duration which was prolonged by G572S. These findings described electrophysiological characteristics of the LQT2 syndrome mutation KCNH2-G572S and regulation by accessory protein KCNE2, and provided a clue about LQT2 and relative rescue mechanism. PMID- 28082917 TI - Transfer Function Analysis of the Longitudinal Motion of the Common Carotid Artery Wall. AB - The longitudinal motion of the carotid wall is a potential new measure of arterial stiffness. Despite the over decade long research on the subject, the driving force and the specific longitudinal kinetics of the carotid wall has remained unclear. In this study, a transfer function analysis with 20 healthy subjects is presented to derive how the energy from the blood pressure moves the innermost arterial wall longitudinally and how the kinetic energy is then transferred to the outermost arterial layer. The power spectrums display that the main kinetic energy of the longitudinal motion is on band 0-3 Hz with a peak on the 1.1 Hz frequency. There is a large variation among the individuals, how the energy from the blood pressure transfers into the longitudinal motion of the arterial wall since the main direction of the longitudinal motion varies individually and because early arterial stiffening potentially has an effect on the time characteristics of the energy transfer. The energy transfer from the innermost to the outermost wall layer is more straightforward: on average, a 17% of the longitudinal amplitude is lost and an 18.9 ms delay is visible on the 1.0 Hz frequency. PMID- 28082918 TI - Spectroscopic and Mechanical Properties of a New Generation of Bulk Fill Composites. AB - Objectives: The aims of this study were to in vitro evaluate the degree of conversion and the microhardness properties of five bulk fill resin composites; in addition, the performance of two curing lamps, used for composites polymerization, was also analyzed. Materials and Methods: The following five resin-based bulk fill composites were tested: SureFil SDR(r), Fill Up!TM, FiltekTM, SonicFillTM, and SonicFill2TM. Samples of 4 mm in thickness were prepared using Teflon molds filled in one increment and light-polymerized using two LED power units. Ten samples for each composite were cured using Elipar S10 and 10 using Demi Ultra. Additional samples of SonicFill2, (3 and 5 mm-thick) were also tested. The degree of conversion (DC) was determined by Raman spectroscopy, while the Vickers microhardness (VMH) was evaluated using a microhardness tester. The experimental evaluation was carried out on top and bottom sides, immediately after curing (t0), and, on bottom, after 24 h (t24). Two-ways analysis of variance was applied to evaluate DC and VMH-values. In all analyses, the level of significance was set at p < 0.05. Results: All bulk fill resin composites recorded satisfactory DCs on top and bottom sides. At t0, the top of SDR and SonicFill2 showed the highest DCs-values (85.56 +/- 9.52 and 85.47 +/- 1.90, respectively), when cured using Elipar S10; using Demi Ultra, SonicFill2 showed the highest DCs-values (90.53 +/- 2.18). At t0, the highest DCs values of bottom sides were recorded by SDR (84.64 +/- 11.68), when cured using Elipar S10, and Filtek (81.52 +/- 4.14), using Demi Ultra. On top sides, Demi Ultra lamp showed significant higher DCs compared to the Elipar S10 (p < 0.05). SonicFill2 reached suitable DCs also on bottom of 5 mm-thick samples. At t0, VMH values ranged between 24.4 and 69.18 for Elipar S10, and between 26.5 and 67.3 for Demi Ultra. Using both lamps, the lowest VMH-values were shown by SDR, while the highest values by SonicFill2. At t24, all DC and VMH values significantly increased. Conclusions: Differences in DC and VMH among materials are suggested to be material and curing lamp dependent. Even at t0, the three high viscosity bulk composites showed higher VMH than the flowable or dual curing composites. PMID- 28082919 TI - QRS Fragmentation Patterns Representing Myocardial Scar Need to Be Separated from Benign Normal Variants: Hypotheses and Proposal for Morphology based Classification. AB - The presence of a fragmented QRS complex (fQRS) in two contiguous leads of a standard 12-lead electrocardiogram (ECG) has been shown to be an indicator of myocardial scar in multiple different populations of cardiac patients. QRS fragmentation is also a predictor of adverse prognosis in acute myocardial infarction, coronary artery disease, and ischemic cardiomyopathy and a prognostic tool in structural heart diseases. An increased risk of sudden cardiac death associated with fQRS has been documented in patients with ischemic cardiomyopathy and hypertrophic cardiomyopathy. However, fQRS is also frequently observed in apparently healthy subjects. Thus, a more detailed classification of different QRS fragmentations is needed to identify the pathological fragmentation patterns and refine the role of fQRS as a risk marker of adverse cardiac events and sudden cardiac death. In most studies fQRS has been defined by the presence of an additional R wave (R'), or notching in the nadir of the S wave, or the presence of >1 R' in two contiguous leads corresponding to a major coronary territory. However, this approach does not discriminate between minor and major fragmentations and the location of the fQRS is also neglected. In addition to this, the method is susceptible to large interobserver variability. We suppose that some fQRS subtypes result from conduction delays in the His-Purkinje system, which is a benign finding and thus can weaken the prognostic values of fQRS. The classification of fQRSs to subtypes with unambiguous definitions is needed to overcome the interobserver variability related issues and to separate fQRSs caused by myocardial scarring from benign normal variants. In this paper, we review the anatomic correlates of fQRS and the current knowledge of prognostic significance of fQRS. We also propose a detailed fQRS classification for research purposes which can later be simplified after the truly pathological morphologies have been identified. The research material of our study consist of 15,245 ECGs from the random general population and approximately six thousands (n = 6,241) ECGs from subjects with a known cardiac disease. PMID- 28082920 TI - Tissue Specific Impacts of a Ketogenic Diet on Mitochondrial Dynamics in the BTBRT+tf/j Mouse. AB - The ketogenic diet (KD) has been utilized as a dietary therapeutic for nearly a century. One experimental model particularly responsive to the KD is the BTBRT+tf/j (BTBR) mouse, which displays phenotypic characteristics of autism spectrum disorder (ASD) and insulin resistance. Recently, the study of impaired mitochondrial function has become a focal point of research investigating the pathophysiology of ASD. As highly dynamic organelles, mitochondria undergo constant fluctuations in morphology, biogenesis, and quality control in order to maintain cellular homeostasis. An important modifier of mitochondrial dynamics is energy availability. Therefore, the aim of this study was to examine the impact of a KD on mitochondrial dynamics in the liver and brain (prefrontal cortex) of the BTBR mouse model of ASD. Juvenile male C57Bl/6 (B6) and BTBR mice were age matched to 5 weeks of age before being fed standard chow (CD, 13% kcal fat) or a KD (75% kcal fat) for 10-14 days. Analysis of brain tissue identified differences in mitochondrial gene expression but no correlation with protein levels. Unlike in the brain, KD led to decreased levels of mitochondrial proteins in the liver, despite increased gene expression. Consistent with decreased mitochondrial proteins, we also observed decreased mtDNA for all mice on the KD, demonstrating that the KD reduces the total amount of mitochondria in the liver. In order to explain the discrepancy between protein levels and gene expression, we investigated whether mitochondrial turnover via mitophagy was increased. To this end, we examined expression levels of the mitophagy regulator BNIP3 (BCL2/adenovirus E1B 19 kd-interacting protein 3). BNIP3 gene and protein expression were significantly elevated in liver of KD animals (p < 0.05), indicating the potential activation of mitophagy. Therefore, consumption of a KD exerts highly tissue-specific effects, ultimately increasing mitochondrial turnover in the liver, while gene and protein expression in the brain remaining tightly regulated. PMID- 28082921 TI - Social Phobia Is Associated with Delayed Onset of Chickenpox, Measles, and Mumps Infections. AB - OBJECTIVE: Evidence showing that infectious diseases in childhood play an important role in the etiopathogenesis of neurodevelopmental and other mental disorders is growing. The aim of this study was to explore the timing of common childhood diseases in early-onset anxiety disorders. MATERIALS AND METHODS: We analyzed data from PsyCoLaus, a large Swiss Population Cohort Study (N = 3720). In this study, we regressed overanxious disorder, separation anxiety disorder, social phobia, and specific phobias on the age of onset of several childhood diseases, always adjusting for the other anxiety disorders listed above and for sex. RESULTS: The timing of viral childhood diseases (chickenpox, measles, and mumps) was consistently delayed in social phobia, notably both in men and women. We found no evidence for a reversed sequence of onset of phobia symptoms before that of the infections included. CONCLUSION: Social phobia was the only early anxiety disorder to show an association with a delayed onset of common viral childhood diseases. PMID- 28082922 TI - The Contributions of Memory and Vocabulary to Non-Verbal Ability Scores in Adolescents with Intellectual Disability. AB - It is usually assumed that performance on non-verbal intelligence tests reflects visual cognitive processing and that aspects of working memory (WM) will be involved. However, the unique contribution of memory to non-verbal scores is not clear, nor is the unique contribution of vocabulary. Thus, we aimed to investigate these contributions. Non-verbal test scores for 17 individuals with intellectual disability (ID) and 39 children with typical development (TD) of similar mental age were compared to determine the unique contribution of visual and verbal short-term memory (STM) and WM and the additional variance contributed by vocabulary scores. No significant group differences were found in the non verbal test scores or receptive vocabulary scores, but there was a significant difference in expressive vocabulary. Regression analyses indicate that for the TD group STM and WM (both visual and verbal) contributed similar variance to the non verbal scores. For the ID group, visual STM and verbal WM contributed most of the variance to the non-verbal test scores. The addition of vocabulary scores to the model contributed greater variance for both groups. More unique variance was contributed by vocabulary than memory for the TD group, whereas for the ID group memory contributed more than vocabulary. Visual and auditory memory and vocabulary contributed significantly to solving visual non-verbal problems for both the TD group and the ID group. However, for each group, there were different weightings of these variables. Our findings indicate that for individuals with TD, vocabulary is the major factor in solving non-verbal problems, not memory, whereas for adolescents with ID, visual STM, and verbal WM are more influential than vocabulary, suggesting different pathways to achieve solutions to non-verbal problems. PMID- 28082924 TI - Perceived Organizational Support for Enhancing Welfare at Work: A Regression Tree Model. AB - When trying to examine outcomes such as welfare and well-being, research tends to focus on main effects and take into account limited numbers of variables at a time. There are a number of techniques that may help address this problem. For example, many statistical packages available in R provide easy-to-use methods of modeling complicated analysis such as classification and tree regression (i.e., recursive partitioning). The present research illustrates the value of recursive partitioning in the prediction of perceived organizational support in a sample of more than 6000 Italian bankers. Utilizing the tree function party package in R, we estimated a regression tree model predicting perceived organizational support from a multitude of job characteristics including job demand, lack of job control, lack of supervisor support, training, etc. The resulting model appears particularly helpful in pointing out several interactions in the prediction of perceived organizational support. In particular, training is the dominant factor. Another dimension that seems to influence organizational support is reporting (perceived communication about safety and stress concerns). Results are discussed from a theoretical and methodological point of view. PMID- 28082923 TI - Therapeutic Perspective on Tardive Syndrome with Special Reference to Deep Brain Stimulation. AB - Tardive syndrome (TDS) is a potentially permanent and irreversible hyperkinetic movement disorder caused by exposure to dopamine receptor blocking agents. Guidelines published by the American Academy of Neurology recommend pharmacological first-line treatment for TDS with clonazepam (level B), ginkgo biloba (level B), amantadine (level C), and tetrabenazine (level C). Recently, a class II study provided level C evidence for use of deep brain stimulation (DBS) of the globus pallidus internus (GPi) in patients with TDS. Although the precise pathogenesis of TDS remains to be elucidated, the beneficial effects of GPi-DBS in patients with TDS suggest that the disease may be a basal ganglia disorder. In addition to recent advances in understanding the pathophysiology of TDS, this article introduces the current use of DBS in the treatment of medically intractable TDS. PMID- 28082925 TI - Semantically Transparent and Opaque Compounds in German Noun-Phrase Production: Evidence for Morphemes in Speaking. AB - This study examines the lexical representation and processing of noun-noun compounds and their grammatical gender during speech production in German, a language that codes for grammatical gender (masculine, feminine, and neuter). Using a picture-word interference paradigm, participants produced determiner compound noun phrases in response to pictures, while ignoring written distractor words. Compound targets were either semantically transparent (e.g., birdhouse) or opaque (e.g., hotdog), and their constituent nouns either had the same or a different gender (internal gender match). Effects of gender-congruent but otherwise unrelated distractor nouns, and of two morphologically related distractors corresponding to the first or second constituent were assessed relative to a completely unrelated, gender-incongruent distractor baseline. Both constituent distractors strongly facilitated compound naming, and these effects were independent of the targets' semantic transparency. This supports retrieval of constituent morphemes for semantically transparent and opaque compounds during speech production. Furthermore, gender congruency between compounds and distractors did not speed up naming in general, but interacted with gender match of the compounds' constituent nouns, and their semantic transparency. A significant gender-congruency effect was obtained with semantically transparent compounds, consisting of two constituent nouns of the same gender, only. In principle, this pattern is compatible with a multiple lemma representation account for semantically transparent, but not for opaque compounds. The data also fit with a more parsimonious, holistic representation for all compounds at the lemma level, when differences in co-activation patterns for semantically transparent and opaque compounds are considered. PMID- 28082926 TI - Bridge Over Troubled Water: Perspective Connections between Coping and Play in Children. AB - We propose that children's play and coping strategies are connected. However, this connection has often been overlooked in the literature. To prove our hypothesis, the principal developmental functions of play are reviewed and compared with the different stages of the coping process. Our results show that coping and play are essential elements in child development, and indicate the presence of several overlapping areas where play and coping intersect. In spite of this, their interrelationship has seldom been examined. We explore the possible reasons for this omission with reference to the different natures of play and coping constructs, and also to the definitive psychometric and cognitive characteristics of most common coping measurement instruments. We conclude by proposing that play should be considered an elective form of coping in most aspects of children's lives. We also propose that methods to measure coping in children should be improved and a more analogical approach should be adopted toward play to enable accurate recognition of coping. PMID- 28082928 TI - Can Contraries Prompt Intuition in Insight Problem Solving? AB - This paper aims to test whether the use of contraries can facilitate spatial problem solving. Specifically, we examined whether a training session which included explicit guidance on thinking in contraries would improve problem solving abilities. In our study, the participants in the experimental condition were exposed to a brief training session before being presented with seven visuo spatial problems to solve. During training it was suggested that it would help them to find the solution to the problems if they systematically transformed the spatial features of each problem into their contraries. Their performance was compared to that of a control group (who had no training). Two participation conditions were considered: small groups and individuals. Higher success rates were found in the groups exposed to training as compared to the individuals (in both the training and no training conditions), even though the time required to find a solution was longer. In general, participants made more attempts (i.e., drawings) when participating in groups than individually. The number of drawings done while the participants were trying to solve the problems did not increase after training. In order to explore if the quality (if not the number) of drawings was modified, we sampled one problem out of the seven we had used in the experiment (the "pigs in a pen" problem) and examined the drawings in detail. Differences between the training and no training conditions emerged in terms of properties focused on and transformed in the drawings. Based on these results, in the final discussion possible explanations are suggested as to why training had positive effects specifically in the group condition. PMID- 28082927 TI - Cerebral versus Ocular Visual Impairment: The Impact on Developmental Neuroplasticity. AB - Cortical/cerebral visual impairment (CVI) is clinically defined as significant visual dysfunction caused by injury to visual pathways and structures occurring during early perinatal development. Depending on the location and extent of damage, children with CVI often present with a myriad of visual deficits including decreased visual acuity and impaired visual field function. Most striking, however, are impairments in visual processing and attention which have a significant impact on learning, development, and independence. Within the educational arena, current evidence suggests that strategies designed for individuals with ocular visual impairment are not effective in the case of CVI. We propose that this variance may be related to differences in compensatory neuroplasticity related to the type of visual impairment, as well as underlying alterations in brain structural connectivity. We discuss the etiology and nature of visual impairments related to CVI, and how advanced neuroimaging techniques (i.e., diffusion-based imaging) may help uncover differences between ocular and cerebral causes of visual dysfunction. Revealing these differences may help in developing future strategies for the education and rehabilitation of individuals living with visual impairment. PMID- 28082929 TI - Practical Person-Fit Assessment with the Linear FA Model: New Developments and a Comparative Study. AB - Linear factor analysis (FA) is, possibly, the most widely used model in psychometric applications based on graded-response or more continuous items. However, in these applications consistency at the individual level (person fit) is virtually never assessed. The aim of the present study is to propose a simple and workable approach to routinely assess person fit in FA-based studies. To do so, we first consider five potentially appropriate indices, of which one is a new proposal and the other is a modification of an existing index. Next, the effectiveness of these indices is assessed by using (a) a thorough simulation study that attempts to mimic realistic conditions, and (b) an illustrative example based on real data. Results suggest that the mean-squared lico index and the personal correlation work well in conjunction and can function effectively for detecting different types of inconsistency. Finally future directions and lines of research are discussed. PMID- 28082930 TI - The Testing Effect and Far Transfer: The Role of Exposure to Key Information. AB - Butler (2010: Experiment 3) showed that retrieval practice enhanced transfer to a new knowledge domain compared to rereading. The first experiment of the present study was a direct replication of Butler's third experiment. Participants studied text passages and then either reread them three times or went through three cycles of cued recall questions (i.e., retrieval practice) with feedback. As in Butler's (2010) experiment, an advantage of retrieval practice on the final far transfer test emerged after 1 week. Additionally, we observed an advantage of retrieval practice on the final test administered after 5 min. However, these advantages might have been due to participants in the retrieval practice condition receiving focused exposure to the key information (i.e., the feedback) that was needed to answer the final test questions. We therefore conducted a second experiment in which we included the retrieval practice condition and the reread condition from our first experiment, as well as a new reread-plus statements condition. In the reread-plus-statements condition, participants received focused exposure to the key information after they had reread a text. As in Experiment 1, we found a large effect on far transfer when retrieval practice was compared to rereading. However, this effect was substantially reduced when retrieval practice was compared to the reread-plus-statements condition. Taken together, the results of the present experiments demonstrate that Butler's (2010) testing effect in far transfer is robust. Moreover, focused exposure to key information appears to be a significant factor in this far transfer testing effect. PMID- 28082931 TI - Pain Interference Mediates the Relationship between Pain and Functioning in Pediatric Chronic Pain. AB - Pediatric chronic pain is a major health problem commonly associated with impaired functioning. There is a great need for more knowledge regarding the complex interplay between demographic variables such as age and gender, pain, and functioning in pediatric chronic pain. Objective: The objective of the study was to investigate if; (1) pediatric chronic pain patients with high and low levels of functioning differ in demographic variables, pain, and pain interference; (2) explore the mediating function of pain interference in the relationship between pain and functioning (i.e., depression and functional disability). Method: The study includes a consecutive sample of children and adolescents referred to a tertiary pain clinic due to chronic pain (n = 163). Cross-sectional data was analyzed to investigate the interrelationships between variables. Analyses of indirect effects were used to assess the impact of pain interference on the relation between pain and depression. Results: Findings illustrate high levels of depression, school absence and pain interference in this sample. Furthermore, pain interference mediated the relationship between pain and depression. Conclusion: Thus, this study adds to the growing support of findings suggesting that functioning and pain interference should be routinely assessed in pediatric chronic pain and a central target in treatment. Particularly, these findings imply a need for interventions specifically aimed at improved functioning for patients with chronic debilitating pain. PMID- 28082932 TI - American Sign Language Syntax and Analogical Reasoning Skills Are Influenced by Early Acquisition and Age of Entry to Signing Schools for the Deaf. AB - Failing to acquire language in early childhood because of language deprivation is a rare and exceptional event, except in one population. Deaf children who grow up without access to indirect language through listening, speech-reading, or sign language experience language deprivation. Studies of Deaf adults have revealed that late acquisition of sign language is associated with lasting deficits. However, much remains unknown about language deprivation in Deaf children, allowing myths and misunderstandings regarding sign language to flourish. To fill this gap, we examined signing ability in a large naturalistic sample of Deaf children attending schools for the Deaf where American Sign Language (ASL) is used by peers and teachers. Ability in ASL was measured using a syntactic judgment test and language-based analogical reasoning test, which are two sub tests of the ASL Assessment Inventory. The influence of two age-related variables were examined: whether or not ASL was acquired from birth in the home from one or more Deaf parents, and the age of entry to the school for the Deaf. Note that for non-native signers, this latter variable is often the age of first systematic exposure to ASL. Both of these types of age-dependent language experiences influenced subsequent signing ability. Scores on the two tasks declined with increasing age of school entry. The influence of age of starting school was not linear. Test scores were generally lower for Deaf children who entered the school of assessment after the age of 12. The positive influence of signing from birth was found for students at all ages tested (7;6-18;5 years old) and for children of all age-of-entry groupings. Our results reflect a continuum of outcomes which show that experience with language is a continuous variable that is sensitive to maturational age. PMID- 28082933 TI - Exploring Changes in Valued Action in the Presence of Chronic Debilitating Pain in Acceptance and Commitment Therapy for Youth - A Single-Subject Design Study. AB - Objective: The objective of the study was to improve the understanding of processes of change in Acceptance and Commitment Therapy for youth with chronic debilitating pain by exploring the relation between individual change patterns in pain intensity and valued activities. Method: A single-subject design across three adolescents suffering from longstanding debilitating pain was utilized. Pain intensity and participation in valued activities were rated daily. Visual analysis of the graphed data was performed to evaluate the effects of the intervention, and the relationship between pain intensity and values-based activity. Results: The graphed data illustrated that pain levels did not decrease from the baseline period to the follow-up period. In contrast, compared to baseline ratings values oriented behaviors increased from the start of treatment to the follow-up period. Conclusion: Results illustrate that increases in values based behavior may occur without corresponding decreases in pain, and warrant further research on change processes in ACT for youth suffering from chronic pain. PMID- 28082934 TI - Risk Factors for School Dropout in a Sample of Juvenile Offenders. AB - Backgrounds: The high rates of school dropout worldwide and their relevance highlight the need for a close study of its causes and consequences. Literature has suggested that school dropout might be explained by multiple causes at different levels (individual, family, school, and neighborhood). The aim of the current study is to examine the relation between individual (defiant attitude, irresponsibility, alcohol abuse, and illegal drugs use), family (educational figure absent and parental monitoring), school factors (truancy and school conflict) and school dropout. Method: Judicial files of all juvenile offenders (218 males and 46 females) with a judicial penal measure in Asturias (Spain) in the year 2012 were examined. Multivariate logistic regression analyses were performed to estimate the relationships between school dropout and individual, family and school variables. Results: As for the individual characteristics, results showed that school dropouts were more irresponsible than non-dropouts. Also they had higher rates of illegal drug use and alcohol abuse. Moreover, lack of parental monitoring emerged as a key predictive factor of school dropout, beyond the type of family structure in terms of the presence of both or only one educational figure. Finally, school factors did not show a significant relationship to school dropout. Conclusions: These findings indicate that school dropout is a multidimensional process. School and family policies that emphasize the role of parental monitoring and prevent alcohol and substance abuse are recommended. PMID- 28082935 TI - Web-Based Psychoeducation Program for Caregivers of First-Episode of Psychosis: An Experience of Chinese Population in Hong Kong. AB - Caregivers of patients with first-episode psychosis are often with little knowledge about the illness and experience more burden of care. Psychoeducation to caregivers has shown to be effective in improving outcomes of patients and possibly reduce stress of the caregivers. This has been recommended as one of the key psychosocial interventions for specific early intervention for psychosis service. However, the accessibility of the service, high case load of the health care professionals and self-stigma of caregivers are often the barriers of implementation of these programs in the real world. Incorporating the convenience of information access via internet and the concept of self-management approach, an interactive internet-based self-help psychoeducation program (iPEP) (www.ipep.hk) for the caregivers of patients with psychosis was established targeting the caregivers of patients with psychosis at early stage in Hong Kong. It provides a comprehensive online resource center in both written and video format on knowledge about psychosis, skills of care, and information of local resources. It also has a forum facilitate information exchange between healthcare professionals and the caregivers, allowing for self-management. Over 800 caregivers have joined the program as members. The evaluation of the subset of the members/users of the iPEP suggested that the iPEP program has been well received and appreciated by the caregivers of patients with first episode psychosis locally. It can potentially serve as a platform for future development of specific manual-based psychoeducation program for caregivers targeting at the needs of different groups. PMID- 28082936 TI - The Information and Communication Technology User Role: Implications for the Work Role and Inter-Role Spillover. AB - Management and organization research has traditionally focused on employees' work role and the interface between their work and family roles. We suggest that persons assume a third role in modern society that is relevant to work and organizations, namely the Information and Communication Technology User (ICTU) role. Based on role theory and boundary theory, we develop propositions about the characteristics of this role, as well as how ICTU role characteristics are related to boundary spanning activity, inter-role spillover with the work role, and work role performance. To this end, we first conceptualize the ICTU role and its associations with work and family roles. We then apply identity theory and boundary management theory to advance our understanding of how the ICTU role is related to criteria that are important to individuals and to organizations, namely self-selection into certain types of work roles and positive and negative inter-role spillover. The implications of this role for theory, research, and practice in management and organizations are discussed. PMID- 28082937 TI - It Pays to Go Off-Track: Practicing with Error-Augmenting Haptic Feedback Facilitates Learning of a Curve-Tracing Task. AB - Researchers in the domain of haptic training are now entering the long-standing debate regarding whether or not it is best to learn a skill by experiencing errors. Haptic training paradigms provide fertile ground for exploring how various theories about feedback, errors and physical guidance intersect during motor learning. Our objective was to determine how error minimizing, error augmenting and no haptic feedback while learning a self-paced curve-tracing task impact performance on delayed (1 day) retention and transfer tests, which indicate learning. We assessed performance using movement time and tracing error to calculate a measure of overall performance - the speed accuracy cost function. Our results showed that despite exhibiting the worst performance during skill acquisition, the error augmentation group had significantly better accuracy (but not overall performance) than the error minimization group on delayed retention and transfer tests. The control group's performance fell between that of the two experimental groups but was not significantly different from either on the delayed retention test. We propose that the nature of the task (requiring online feedback to guide performance) coupled with the error augmentation group's frequent off-target experience and rich experience of error-correction promoted information processing related to error-detection and error-correction that are essential for motor learning. PMID- 28082938 TI - School Refusal Assessment Scale-Revised: Factorial Invariance and Latent Means Differences across Gender and Age in Spanish Children. AB - The aim of this study was to analyze the factorial invariance and latent means differences of the Spanish version of the School Refusal Assessment Scale-Revised for Children (SRAS-R-C) in a sample of 1,078 students (50.8% boys) aged 8-11 years (M = 9.63, SD = 1.12). The results revealed that the proposed model in this study, with a structure of 18 items divided into four factors (Negative Affective, Social Aversion and/or Evaluation, To Pursue Attention and Tangible Reinforcements), was the best-fit model with a tetra-factorial structure, remaining invariant across gender and age. Analysis of latent means differences indicated that boys and 11-year-old students scored highest on the Tangible Reinforcements subscale compared with their 8- and 9-year-old peers. On the contrary, for the subscales of Social Aversion and/or Evaluation and to Pursue Attention, the differences were significant and higher in younger age groups compared to 11-year-olds. Appropriate indexes of reliability were obtained for SRAS-R-C subscales (0.70, 0.79, 0.87, and 0.72). Finally, the founded correlation coefficients of scores of the SRAS-R-C revealed a predictable pattern between school refusal and positive/negative affect and optimism/pessimism. PMID- 28082939 TI - Dynamics of Social Interaction: Kinematic Analysis of a Joint Action. AB - Non-verbal social interaction between humans requires accurate understanding of the others' actions. The cognitivist approach suggests that successful interaction depends on the creation of a shared representation of the task, where the pairing of perceptive and motor systems of partners allows inclusion of the other's goal into the overarching representation. Activity of the Mirror Neurons System (MNS) is thought to be a crucial mechanism linking two individuals during a joint action through action observation. The construction of a shared representation of an interaction (i.e., joint action) depends upon sensorimotor cognitive processes that modulate the ability to adapt in time and space. We attempted to detect individuals' behavioral/kinematic change resulting in a global amelioration of performance for both subjects when a common representation of the action is built using a repetitive joint action. We asked pairs of subjects to carry out a simple task where one puts a base in the middle of a table and the other places a parallelepiped fitting into the base, the crucial manipulation being that participants switched roles during the experiment. We aimed to show that a full comprehension of a joint action is not an automatic process. We found that, before switching the interactional role, the participant initially placing the base orientated it in a way that led to an uncomfortable action for participants placing the parallelepiped. However, after switching roles, the action's kinematics by the participant who places the base changed in order to facilitate the action of the other. More precisely, our data shows significant modulation of the base angle in order to ease the completion of the joint action, highlighting the fact that a shared knowledge of the complete action facilitates the generation of a common representation. This evidence suggests the ability to establish an efficient shared representation of a joint action benefits from physically taking our partner's perspective because simply observing the actions of others may not be enough. PMID- 28082940 TI - Culture and Unmerited Authorship Credit: Who Wants It and Why? AB - Unmerited authorship is a practice common to many countries around the world, but are there systematic cultural differences in the practice? We tested whether scientists from collectivistic countries are more likely to add unmerited coauthors than scientists from individualistic countries. We analyzed archival data from top scientific journals (Study 1) and found that national collectivism predicted the number of authors, which might suggest more unmerited authors. Next, we found that collectivistic scientists were more likely to add unmerited coauthors than individualistic scientists, both between cultures (Studies 2-3) and within cultures (Study 4). Finally, we found that priming people with collectivistic self-construal primes made them more likely to endorse questionable authorship attitudes (Study 5). These findings show that culture collectivism is related to unmerited authorship. PMID- 28082941 TI - A Bayesian Framework for False Belief Reasoning in Children: A Rational Integration of Theory-Theory and Simulation Theory. AB - Two apparently contrasting theories have been proposed to account for the development of children's theory of mind (ToM): theory-theory and simulation theory. We present a Bayesian framework that rationally integrates both theories for false belief reasoning. This framework exploits two internal models for predicting the belief states of others: one of self and one of others. These internal models are responsible for simulation-based and theory-based reasoning, respectively. The framework further takes into account empirical studies of a developmental ToM scale (e.g., Wellman and Liu, 2004): developmental progressions of various mental state understandings leading up to false belief understanding. By representing the internal models and their interactions as a causal Bayesian network, we formalize the model of children's false belief reasoning as probabilistic computations on the Bayesian network. This model probabilistically weighs and combines the two internal models and predicts children's false belief ability as a multiplicative effect of their early-developed abilities to understand the mental concepts of diverse beliefs and knowledge access. Specifically, the model predicts that children's proportion of correct responses on a false belief task can be closely approximated as the product of their proportions correct on the diverse belief and knowledge access tasks. To validate this prediction, we illustrate that our model provides good fits to a variety of ToM scale data for preschool children. We discuss the implications and extensions of our model for a deeper understanding of developmental progressions of children's ToM abilities. PMID- 28082942 TI - Replication Requires Psychological Rather than Statistical Hypotheses: The Case of Eye Movements Enhancing Word Recollection. AB - Can an experiment be replicated in a mechanical fashion without considering the processes underlying the initial results? Here I will consider a non-replication of Saccade Induced Retrieval Enhancement (SIRE) and argue that it results from focusing on statistical instead of on substantive process hypotheses. Particularly the theoretical integration of SIRE with Eye-Movement Desensitization and Reprocessing (EMDR) therapy, provides clues about when the memory enhancement should occur. A relatively large memory enhancement effect in participants with a consistent (i.e., extreme right or left) handedness should be observed, (a) when explicitly instructed to retrieve and imagine the memories during the eye manipulation, and (b) for emotionally negative material. A finer theoretical analysis may thus well explain the contrast between the original SIRE studies and the non-replication. Also the findings from preregistered confirmatory research (i.e., focusing solely on statistical hypotheses) should be considered preliminary, representing shifts on a gradual scale of evidence, and awaiting interpretation in terms of theoretical hypotheses. Stronger, but still not definitive, conclusions can better be postponed until after multi-study meta analyses with theoretically motivated moderator variables have been performed. PMID- 28082944 TI - Verbal Synchrony and Action Dynamics in Large Groups. AB - While synchronized movement has been shown to increase liking and feelings of togetherness between people, we investigated whether collective speaking in time would change the way that larger groups played a video game together. Anthropologists have speculated that the function of interpersonal coordination in dance, chants, and singing is not just to produce warm, affiliative feelings, but also to improve group action. The group that chants and dances together hunts well together. Direct evidence for this is sparse, as research so far has mainly studied pairs, the effects of coordinated physical movement, and measured cooperation and affiliative decisions. In our experiment, large groups of people were given response handsets to play a computer game together, in which only joint coordinative efforts lead to success. Before playing, the synchrony of their verbal behavior was manipulated. After the game, we measured group members' affiliation toward their group, their performance on a memory task, and the way in which they played the group action task. We found that verbal synchrony in large groups produced affiliation, enhanced memory performance, and increased group members' coordinative efforts. Our evidence suggests that the effects of synchrony are stable across modalities, can be generalized to larger groups and have consequences for action coordination. PMID- 28082943 TI - Three Ways That Non-associative Knowledge May Affect Associative Learning Processes. AB - Associative learning theories offer one account of the way animals and humans assess the relationship between events and adapt their behavior according to resulting expectations. They assume knowledge about event relations is represented in associative networks, which consist of mental representations of cues and outcomes and the associative links that connect them. However, in human causal and contingency learning, many researchers have found that variance in standard learning effects is controlled by "non-associative" factors that are not easily captured by associative models. This has given rise to accounts of learning based on higher-order cognitive processes, some of which reject altogether the notion that humans learn in the manner described by associative networks. Despite the renewed focus on this debate in recent years, few efforts have been made to consider how the operations of associative networks and other cognitive operations could potentially interact in the course of learning. This paper thus explores possible ways in which non-associative knowledge may affect associative learning processes: (1) via changes to stimulus representations, (2) via changes to the translation of the associative expectation into behavior (3) via a shared source of expectation of the outcome that is sensitive to both the strength of associative retrieval and evaluation from non-associative influences. PMID- 28082945 TI - Trustworthy Tricksters: Violating a Negative Social Expectation Affects Source Memory and Person Perception When Fear of Exploitation Is High. AB - People who are high in victim-sensitivity-a personality trait characterized by a strong fear of being exploited by others-are more likely to attend to social cues associated with untrustworthiness rather than to cues associated with trustworthiness compared with people who are low in victim-sensitivity. But how do these people react when an initial expectation regarding a target's trustworthiness turns out to be false? Results from two studies show that victim sensitive compared with victim-insensitive individuals show enhanced source memory and greater change in person perception for negatively labeled targets that violated rather than confirmed negative expectations (the "trustworthy trickster"). These findings are in line with recent theorizing on schema inconsistency and expectancy violation effects in social cognition and with research on the different facets of justice sensitivity in personality psychology. PMID- 28082946 TI - Distress and Psychosocial Needs in Patients Accessing a Cancer Day Surgery Division: Implications for Clinical Decision Making. AB - : Introduction: The Distress Thermometer (DT) was built and validated for screening cancer patients for distress, as suggested by the National Comprehensive Cancer Network. The current work was designed to measure the rates of distress in a sample of patients being hospitalized in a multidisciplinary outpatient surgery clinic. OBJECTIVE: To measure the rates of distress in a sample of patients referring to a multidisciplinary day surgery division in a comprehensive cancer center based in Northern Italy. Methods: A total of 177 patients were asked to fill in the (DT) before surgery. Results: Out of 177 patients, 154 (87%) patients completed the DT. While 13% of the patients indicated a total absence of distress, more than half of the sample declared a moderate or high distress. A total of 55% of patients presented at least three difficulties in the Problem List Checklist. Distress was not correlated with age or other medical and clinical variables. Number of emotional problems was the best predictor of distress at admission (beta = 0.655, p = 0.000). Conclusion: Screening for distress in a day surgery multidisciplinary oncology division is feasible and a relevant percentage of patients can be identified as clinically distressed. Outcomes also highlight the impact of age and precise physical and psycho-social signs as prognostic indicators of clinically significant distress. Measurement of distress and associated problems list represent the preliminary endpoint toward adequate recommendations that contribute to taking care of distress in cancer patients in cost-effective clinical setting. PMID- 28082948 TI - Thyrotropin Stimulates Differentiation Not Proliferation of Normal Human Thyrocytes in Culture. AB - Although TSH has been suggested to be a proliferative agent for thyrocytes, the effect of TSH on human thyroid cells remains controversial. In particular, most of the reported studies relied primarily on changes in DNA synthesis but have not included measurement of the number of cells. We argue that only a direct count of cell number, demonstrating classical exponential expansion, serves as a valid measurement of proliferation. Thus, although some data support TSH as a proliferative agent, most do not provide conclusive evidence. To generate conclusive evidence with regard to a proliferative effect of TSH in human thyrocytes, we performed various experiments using primary cultures of human thyrocytes. In contrast to previous reports, TSH [+/-insulin-like growth factor 1 (IGF-1)] did not induce proliferation of thyrocytes under a variety of different conditions. However, TSH/IGF-1 cotreatment did upregulate thyroid-specific gene expression including thyroglobulin (TG) and TSHR in a manner consistent with cellular differentiation. Evidence for a proliferative effect of TSH has been used to inform the American Thyroid Association's guidelines for the management of thyroid cancer patients, which include TSH suppression. While these recommendations are admittedly based on low- to moderate-quality evidence, TSH suppression is still widely used. We present data that question the consensus view that TSH promotes proliferation of human thyrocytes (upon which the American Thyroid Association's guidelines are based) and suggest that additional studies, including randomized controlled trials, are warranted to address this important clinical question. PMID- 28082947 TI - Understanding the Relationship between Trauma Exposure and Depression among Adolescents after Earthquake: The Roles of Fear and Resilience. AB - Middle school students (N = 1435) were assessed 18 months after the Wenchuan earthquake using measures of trauma exposure, fear, resilience, and depression, to examine the effects of fear and resilience on the relationship between trauma exposure and depression. Fear mediated the relationship between trauma exposure and depression, whereas resilience moderated the relationship between fear and depression. These findings suggest that trauma exposure has a direct positive impact on depression, but also indirectly affects depression through fear. Moreover, fear positively predicted depression under conditions of low resilience, whereas this effect was not significant when resilience was high. These results are discussed in terms of their implications for adolescents after trauma. PMID- 28082950 TI - Expanding the Repertoire of Carbapenem-Hydrolyzing Metallo-beta-Lactamases by Functional Metagenomic Analysis of Soil Microbiota. AB - Carbapenemases are bacterial enzymes that hydrolyze carbapenems, a group of last resort beta-lactam antibiotics used for treatment of severe bacterial infections. They belong to three beta-lactamase classes based amino acid sequence (A, B, and D). The aim of this study was to elucidate occurrence, diversity and functionality of carbapenemase-encoding genes in soil microbiota by functional metagenomics. Ten plasmid libraries were generated by cloning metagenomic DNA from agricultural (n = 6) and grassland (n = 4) soil into Escherichia coli. The libraries were cultured on amoxicillin-containing agar and up to 100 colonies per library were screened for carbapenemase production by CarbaNP test. Presumptive carbapenemases were characterized with regard to DNA sequence, minimum inhibitory concentration (MIC) of beta-lactams, and imipenem hydrolysis. Nine distinct class B carbapenemases, also known as metallo-beta-lactamases (MBLs), were identified in six soil samples, including two subclass B1 (GRD23-1 and SPN79-1) and seven subclass B3 (CRD3-1, PEDO-1, GRD33-1, ESP-2, ALG6-1, ALG11-1, and DHT2-1). Except PEDO-1 and ESP-2, these enzymes were distantly related to any previously described MBLs (33 to 59% identity). RAIphy analysis indicated that six enzymes (CRD3-1, GRD23-1, DHT2-1, SPN79-1, ALG6-1, and ALG11-1) originated from Proteobacteria, two (PEDO-1 and ESP-2) from Bacteroidetes and one (GRD33-1) from Gemmatimonadetes. All MBLs detected in soil microbiota were functional when expressed in E. coli, resulting in detectable imipenem-hydrolyzing activity and significantly increased MICs of clinically relevant beta-lactams. Interestingly, the MBLs yielded by functional metagenomics generally differed from those detected in the same soil samples by antibiotic selective culture, showing that the two approaches targeted different subpopulations in soil microbiota. PMID- 28082951 TI - Isotopic Analysis of Sporocarp Protein and Structural Material Improves Resolution of Fungal Carbon Sources. AB - Fungal acquisition of resources is difficult to assess in the field. To determine whether fungi received carbon from recent plant photosynthate, litter or soil derived organic (C:N bonded) nitrogen, we examined differences in delta13C among bulk tissue, structural carbon, and protein extracts of sporocarps of three fungal types: saprotrophic fungi, fungi with hydrophobic ectomycorrhizae, or fungi with hydrophilic ectomycorrhizae. Sporocarps were collected from experimental plots of the Duke Free-air CO2 enrichment experiment during and after CO2 enrichment. The differential 13C labeling of ecosystem pools in CO2 enrichment experiments was tracked into fungi and provided novel insights into organic nitrogen use. Specifically, sporocarp delta13C as well as delta15N of protein and structural material indicated that fungi with hydrophobic ectomycorrhizae used soil-derived organic nitrogen sources for protein carbon, fungi with hydrophilic ectomycorrhizae used recent plant photosynthates for protein carbon and both fungal groups used photosynthates for structural carbon. Saprotrophic fungi depended on litter produced during fumigation for both protein and structural material. PMID- 28082949 TI - GnIH Control of Feeding and Reproductive Behaviors. AB - In 2000, Tsutsui and colleagues discovered a neuropeptide gonadotropin-inhibitory hormone (GnIH) that inhibits gonadotropin release in birds. Subsequently, extensive studies during the last 15 years have demonstrated that GnIH is a key neurohormone that regulates reproduction in vertebrates, acting in the brain and on the pituitary to modulate reproduction and reproductive behavior. On the other hand, deprivation of food and other metabolic challenges inhibit the reproductive axis as well as sexual motivation. Interestingly, recent studies have further indicated that GnIH controls feeding behavior in vertebrates, such as in birds and mammals. This review summarizes the discovery of GnIH and its conservation in vertebrates and the neuroendocrine control of feeding behavior and reproductive behavior by GnIH. PMID- 28082952 TI - Evolution of Variable Number Tandem Repeats and Its Relationship with Genomic Diversity in Salmonella Typhimurium. AB - Salmonella enterica serovar Typhimurium is the most common Salmonella serovar causing human infections in Australia and many other countries. A total of 12,112 S. Typhimurium isolates from New South Wales were analyzed by multi-locus variable number of tandem repeat (VNTR) analysis (MLVA) using five VNTRs from 2007 to 2014. We found that mid ranges of repeat units of 8-14 in VNTR locus STTR5, 6-13 in STTR6, and 9-12 in STTR10 were always predominant in the population (>50%). In vitro passaging experiments using MLVA type carrying extreme length alleles found that the majority of long length alleles mutated to short ones and short length alleles mutated to longer ones. Both data suggest directional mutability of VNTRs toward mid-range repeats. Sequencing of 28 isolates from a newly emerged MLVA type and its five single locus variants revealed that single nucleotide variation between isolates with up to two MLVA differences ranged from 0 to 12 single nucleotide polymorphisms (SNPs). However, there was no relationship between SNP and VNTR differences. A population genetic model of the joint distribution of VNTRs and SNPs variations was used to estimate the mutation rates of the two markers, yielding a ratio of 1 VNTR change to 6.9 SNP changes. When only one VNTR repeat difference was considered, the majority of pairwise SNP difference between isolates were 4 SNPs or fewer. Based on this observation and our previous findings of SNP differences of outbreak isolates, we suggest that investigation of S. Typhimurium community outbreaks should include cases of 1 repeat difference to increase sensitivity. This study offers new insights into the short-term VNTR evolution of S. Typhimurium and its application for epidemiological typing. PMID- 28082953 TI - Bioinformatic Analyses of Unique (Orphan) Core Genes of the Genus Acidithiobacillus: Functional Inferences and Use As Molecular Probes for Genomic and Metagenomic/Transcriptomic Interrogation. AB - Using phylogenomic and gene compositional analyses, five highly conserved gene families have been detected in the core genome of the phylogenetically coherent genus Acidithiobacillus of the class Acidithiobacillia. These core gene families are absent in the closest extant genus Thermithiobacillus tepidarius that subtends the Acidithiobacillus genus and roots the deepest in this class. The predicted proteins encoded by these core gene families are not detected by a BLAST search in the NCBI non-redundant database of more than 90 million proteins using a relaxed cut-off of 1.0e-5. None of the five families has a clear functional prediction. However, bioinformatic scrutiny, using pI prediction, motif/domain searches, cellular location predictions, genomic context analyses, and chromosome topology studies together with previously published transcriptomic and proteomic data, suggests that some may have functions associated with membrane remodeling during cell division perhaps in response to pH stress. Despite the high level of amino acid sequence conservation within each family, there is sufficient nucleotide variation of the respective genes to permit the use of the DNA sequences to distinguish different species of Acidithiobacillus, making them useful additions to the armamentarium of tools for phylogenetic analysis. Since the protein families are unique to the Acidithiobacillus genus, they can also be leveraged as probes to detect the genus in environmental metagenomes and metatranscriptomes, including industrial biomining operations, and acid mine drainage (AMD). PMID- 28082954 TI - Commentary: Changes in Bacillus Spore Small Molecules, rRNA, Germination, and Outgrowth after Extended Sublethal Exposure to Various Temperatures: Evidence that Protein Synthesis Is Not Essential for Spore Germination. PMID- 28082955 TI - Eradication of Enterococcus faecalis Biofilms on Human Dentin. AB - Objectives: This work assesses different methods to interfere with Enterococcus faecalis biofilms formed on human dentin slabs. Methods: First, methods are presented that select for small molecule inhibitors of biofilm targets using multi-well polystyrene biofilm plates. Next, we establish methodologies to study and interfere with biofilm formation on a medically relevant model, whereby biofilms are grown on human root dentin slabs. Results: Non-conventional D-amino acid (D-Leucine) can efficiently disperse biofilms formed on dentin slabs without disturbing planktonic growth. Cation chelators interfere with biofilm formation on dentin slabs and polystyrene surfaces, and modestly impact planktonic growth. Strikingly, sodium hypochlorite, the treatment conventionally used to decontaminate infected root canal systems, was extremely toxic to planktonic bacteria, but did not eradicate biofilm cells. Instead, it induced a viable but non-culturable state in biofilm cells when grown on dentin slabs. Conclusion: Sodium hypochlorite may contribute to bacterial persistence. A combination of the methods described here can greatly contribute to the development of biofilm inhibitors and therapies to treat Enterococcus faecalis infections formed in the root canal system. PMID- 28082956 TI - Genome Analysis of Two Pseudonocardia Phylotypes Associated with Acromyrmex Leafcutter Ants Reveals Their Biosynthetic Potential. AB - The attine ants of South and Central America are ancient farmers, having evolved a symbiosis with a fungal food crop >50 million years ago. The most evolutionarily derived attines are the Atta and Acromyrmex leafcutter ants, which harvest fresh leaves to feed their fungus. Acromyrmex and many other attines vertically transmit a mutualistic strain of Pseudonocardia and use antifungal compounds made by these bacteria to protect their fungal partner against co evolved fungal pathogens of the genus Escovopsis. Pseudonocardia mutualists associated with the attines Apterostigma dentigerum and Trachymyrmex cornetzi make novel cyclic depsipeptide compounds called gerumycins, while a mutualist strain isolated from derived Acromyrmex octospinosus makes an unusual polyene antifungal called nystatin P1. The novelty of these antimicrobials suggests there is merit in exploring secondary metabolites of Pseudonocardia on a genome-wide scale. Here, we report a genomic analysis of the Pseudonocardia phylotypes Ps1 and Ps2 that are consistently associated with Acromyrmex ants collected in Gamboa, Panama. These were previously distinguished solely on the basis of 16S rRNA gene sequencing but genome sequencing of five Ps1 and five Ps2 strains revealed that the phylotypes are distinct species and each encodes between 11 and 15 secondary metabolite biosynthetic gene clusters (BGCs). There are signature BGCs for Ps1 and Ps2 strains and some that are conserved in both. Ps1 strains all contain BGCs encoding nystatin P1-like antifungals, while the Ps2 strains encode novel nystatin-like molecules. Strains show variations in the arrangement of these BGCs that resemble those seen in gerumycin gene clusters. Genome analyses and invasion assays support our hypothesis that vertically transmitted Ps1 and Ps2 strains have antibacterial activity that could help shape the cuticular microbiome. Thus, our work defines the Pseudonocardia species associated with Acromyrmex ants and supports the hypothesis that Pseudonocardia species could provide a valuable source of new antimicrobials. PMID- 28082957 TI - Carbon Availability Modifies Temperature Responses of Heterotrophic Microbial Respiration, Carbon Uptake Affinity, and Stable Carbon Isotope Discrimination. AB - Microbial transformations of organic carbon (OC) generate a large flux of CO2 into the atmosphere and influence the C balance of terrestrial and aquatic ecosystems. Yet, inherent heterogeneity in natural environments precludes direct quantification of multiple microbial C fluxes that underlie CO2 production. Here we used a continuous flow bioreactor coupled with a stable C isotope analyzer to determine the effects of temperature and C availability (cellobiose concentration) on C fluxes and 13C discrimination of a microbial population growing at steady-state in a homogeneous, well-mixed environment. We estimated C uptake affinity and C use efficiency (CUE) to characterize the physiological responses of microbes to changing environmental conditions. Temperature increased biomass-C specific respiration rate and C uptake affinity at lower C availability, but did not influence those parameters at higher C availability. CUE decreased non-linearly with increasing temperature. The non-linear, negative relationship between CUE and temperature was more pronounced under lower C availability than under relatively high C availability. We observed stable isotope fractionation between C substrate and microbial biomass C (7~120/00 depletion), and between microbial biomass and respired CO2 (4~100/00 depletion). Microbial discrimination against 13C-containing cellobiose during C uptake was influenced by temperature and C availability, while discrimination during respiration was only influenced by C availability. Shifts in C uptake affinity with temperature and C availability may have modified uptake-induced 13C fractionation. By stressing the importance of C availability on temperature responses of microbial C fluxes, C uptake affinity, CUE, and isotopic fractionation, this study contributes to a fundamental understanding of C flow through microbes. This will help guide parameterization of microbial responses to varying temperature and C availability within Earth-system models. PMID- 28082958 TI - Use of Random T-DNA Mutagenesis in Identification of Gene UvPRO1, A Regulator of Conidiation, Stress Response, and Virulence in Ustilaginoidea virens. AB - False smut of rice, caused by Ustilaginoidea virens (Cooke) Takahashi (teleomorph: Villosiclava virens), is one of the most important diseases affecting rice worldwide. Agrobacterium tumefaciens-mediated transformation was used to identify functional genes in U. virens. In this study, we selected a single-copy insertion mutant T133 with deficiency in producing conidia by screening the T-DNA insertion mutant library of U. virens. The UvPRO1-deletion mutant was successfully obtained after cloning the targeted gene by analysis of the T-DNA insert site of mutant T133. Further research showed that the UvPRO1 mutant was reduced in growth rate and could not produce conidia in PSB medium, while sensitivities to sodium dodecyl sulfate, Congo red, and hyperosmotic stress increased. Moreover, the UvPRO1 deletion mutant hyphae could extend along the surface of spikelets at 1-3 dpi, but mycelia became shriveled and completely lost the ability to infect spikelets at 4 dpi. The relative expression level of UvPRO1 at 8 dpi was more than twice as high as that at 1-2 dpi. These results suggest that UvPRO1 plays a critical role in hyphal growth and conidiation, as well as in stress response and pathogenesis. These findings provide a novel mode of action for the PRO1 protein in fungi and improve the understanding of the function of UvPRO1 in the life cycle of U. virens. PMID- 28082959 TI - Editorial: Emerging Approaches for Typing, Detection, Characterization, and Traceback of Escherichia coli. PMID- 28082961 TI - Generation of Germ-Free Ciona intestinalis for Studies of Gut-Microbe Interactions. AB - Microbes associate with animal hosts, often providing shelter in a nutrient-rich environment. The gut, however, can be a harsh environment with members of the microbiome settling in distinct niches resulting in more stable, adherent biofilms. These diverse communities can provide orders of magnitude more gene products than the host genome; selection and maintenance of a functionally relevant and useful microbiome is now recognized to be an essential component of homeostasis. Germ-free (GF) model systems allow dissection of host-microbe interactions in a simple and direct way where each member of the symbiosis can be studied in isolation. In addition, because immune defenses in the gut are often naive in GF animals, host immune recognition and responses during the process of colonization can be studied. Ciona intestinalis, a basal chordate, is a well characterized developmental model system and holds promise for addressing some of these important questions. With transparent juveniles, Ciona can be exposed to distinct bacterial isolates by inoculating GF artificial seawater; concentrated bacteria can subsequently be visualized in vivo if fluorescent stains are utilized. Rearing GF Ciona is a first step in untangling the complex dialogue between bacteria and innate immunity during colonization. PMID- 28082960 TI - In vitro Determination of Extracellular Proteins from Xylella fastidiosa. AB - The phytopathogen Xylella fastidiosa causes economic losses in important agricultural crops. Xylem vessel occlusion caused by biofilm formation is the major mechanism underlying the pathogenicity of distinct strains of X. fastidiosa. Here, we provide a detailed in vitro characterization of the extracellular proteins of X. fastidiosa. Based on the results, we performed a comparison with a strain J1a12, which cannot induce citrus variegated chlorosis symptoms when inoculated into citrus plants. We then extend this approach to analyze the extracellular proteins of X. fastidiosa in media supplemented with calcium. We verified increases in extracellular proteins concomitant with the days of growth and, consequently, biofilm development (3-30 days). Outer membrane vesicles carrying toxins were identified beginning at 10 days of growth in the 9a5c strain. In addition, a decrease in extracellular proteins in media supplemented with calcium was observed in both strains. Using mass spectrometry, 71 different proteins were identified during 30 days of X. fastidiosa biofilm development, including proteases, quorum-sensing proteins, biofilm formation proteins, hypothetical proteins, phage-related proteins, chaperones, toxins, antitoxins, and extracellular vesicle membrane components. PMID- 28082962 TI - Effect of Different Lignocellulosic Diets on Bacterial Microbiota and Hydrolytic Enzyme Activities in the Gut of the Cotton Boll Weevil (Anthonomus grandis). AB - Cotton boll weevils, Anthonomus grandis, are omnivorous coleopteran that can feed on diets with different compositions, including recalcitrant lignocellulosic materials. We characterized the changes in the prokaryotic community structure and the hydrolytic activities of A. grandis larvae fed on different lignocellulosic diets. A. grandis larvae were fed on three different artificial diets: cottonseed meal (CM), Napier grass (NG) and corn stover (CS). Total DNA was extracted from the gut samples for amplification and sequencing of the V3-V4 hypervariable region of the 16S rRNA gene. Proteobacteria and Firmicutes dominated the gut microbiota followed by Actinobacteria, Spirochaetes and a small number of unclassified phyla in CM and NG microbiomes. In the CS feeding group, members of Spirochaetes were the most prevalent, followed by Proteobacteria and Firmicutes. Bray-Curtis distances showed that the samples from the CS community were clearly separated from those samples of the CM and NG diets. Gut extracts from all three diets exhibited endoglucanase, xylanase, beta-glucosidase and pectinase activities. These activities were significantly affected by pH and temperature across different diets. We observed that the larvae reared on a CM showed significantly higher activities than larvae reared on NG and CS. We demonstrated that the intestinal bacterial community structure varies depending on diet composition. Diets with more variable and complex compositions, such as CS, showed higher bacterial diversity and richness than the two other diets. In spite of the detected changes in composition and diversity, we identified a core microbiome shared between the three different lignocellulosic diets. These results suggest that feeding with diets of different lignocellulosic composition could be a viable strategy to discover variants of hemicellulose and cellulose breakdown systems. PMID- 28082963 TI - Sub-optimal Specificity of Modified Ziehl-Neelsen Staining for Quick Identification of Tuberculous Meningitis. AB - Background: Microbiological confirmation of tuberculous meningitis (TBM) remains problematic. We assessed the diagnostic performance of a modified Ziehl-Neelsen (MZN) staining method that showed promise in earlier studies. Methods: Patients evaluated for TBM in Shaanxi province, China, were prospectively enrolled from May, 2011 to April, 2013. Cerebrospinal fluid (CSF) specimens were evaluated using the Xpert MTB/RIF(r) assay, MZN staining, and standard biochemical and microbiological tests, together with detailed clinical and radiological assessment. Results: Among 316 patients included in the study, 38 had definite TBM, 66 probable TBM, 163 possible TBM and 49 "no TBM," using consensus uniform research case definition criteria. Comparing "definite or probable TBM" to "no TBM" MZN staining had higher sensitivity than Xpert MTB/RIF(r) (88.5 vs. 36.5%), but greatly reduced specificity (71.4 vs. 100.0%); 14/49 (28.6%) cases with "no TBM" tested positive on MZN. Mycobacterium tuberculosis culture was performed in 104/179 (58.1%) of MZN positive samples; 12.5% (13/104) were positive. Using Xpert MTB/RIF(r) as the reference standard, MZN had a sensitivity of 92.1% (95% CI 79.2-97.3) and specificity of 71.4% (95% CI 57.6-82.2). Conclusion: Xpert MTB/RIF(r) offered a rapid and specific TBM diagnosis, but sensitivity was poor. MZN was mainly hampered by false positives. Strategies to enhance the sensitivity of Xpert MTB/RIF(r) or improve the diagnostic accuracy of MZN should be explored. PMID- 28082964 TI - Mycobacterium kansasii Subtype I Is Associated With Clarithromycin Resistance in China. AB - Mycobacterium kansasii is the second most common cause of slowly growing non tuberculous mycobacteria diseases in China. The aim of the present study was to analyze M. kansasii subtypes isolated from patients in China, and to explore the antimicrobial susceptibility of the differentiation among these diverse subtypes. A total of 78 M. kansasii strains from 16 provinces of China were enrolled in this study. Amikacin (AMK) was the most highly active against M. kansasii strains, and only 4 isolates (5.1%) exhibited in vitro resistance to AMK. The percentage of levofloxacin (LFX) resistant strains among the 78 M. kansasii isolates was 39.7% (31/78), which was significantly higher than that of moxifloxacin (16.7%, P = 0.001) and gatifloxacin (19.2%, P = 0.005). By using PCR restriction fragment analysis of the hsp65 gene (PRA), all the isolates were classified as four different subtypes. Of these four subtypes, M. kansasii subtype I was the most frequent genotype in China, accounting for 71.8% (56/78) of M. kansasii isolates. Resistance to clarithromycin (CLA) was noted in 26.8% (15/56) of subtype I isolates, which was significant higher than that of other subtypes (4.5%, P = 0.031). DNA sequencing revealed that the presence of mutations in 23S rRNA was associated with 56.2% (9/16) of CLA-resistant M. kansasii isolates. In conclusion, our data demonstrate that AMK is the most active agent against M. kansasii in vitro, while the high proportion of CLA resistance is noted in M. kansasii isolates. In addition, the predominant subtype I is associated with CLA resistance in China. PMID- 28082965 TI - Whole-genome Sequencing for Surveillance of Invasive Pneumococcal Diseases in Ontario, Canada: Rapid Prediction of Genotype, Antibiotic Resistance and Characterization of Emerging Serotype 22F. AB - Background: Molecular typing is essential for inferring genetic relatedness between bacterial pathogens. In this study, we applied whole genome sequencing (WGS) for rapid prediction of sequence type and antibiotic resistance for invasive pneumococcal isolates. Methods: 240 isolates from adults (>=50 years old) in Ontario, Canada during 2009 to 2013 were subjected to WGS. Sequence type, antibiotic susceptibility and resistance were predicted directly from short reads. Emerging non-vaccine serotype 22F was further characterized by WGS. Results: Sequence type was successfully determined for 98.3% of isolates. The overall sensitivity and specificity for antibiotic resistance prediction were 95 and 100% respectively, compared to standard susceptibility testing methods. WGS based phylogeny divided emerging 22F (ST433) strains into two distinct clades: clade A harboring a 23 kb-prophage and anti-phage PhD/Doc system and clade B with virulence-related proteases. Five isolates in clade A developed macrolide resistance via 5.1 kb mega element recombination (encoding mefE and msrD), while one isolate in clade B displayed quinolone resistance via a gyrA mutation. Conclusions: WGS is valuable for routine surveillance of pneumococcal clinical isolates and facilitates prediction of genotype and antibiotic resistance. The emergence of 22F in Ontario in the post-vaccine era and evidence of evolution and divergence of the 22F population warrants heightened pneumococcal molecular surveillance. PMID- 28082966 TI - Iron Uptake Analysis in a Set of Clinical Isolates of Pseudomonas putida. AB - Pseudomonas putida strains are frequent inhabitants of soil and aquatic niches and they are occasionally isolated from hospital environments. As the available iron sources in human tissues, edaphic, and aquatic niches are different, we have analyzed iron-uptake related genes in different P. putida strains that were isolated from all these environments. We found that these isolates can be grouped into different clades according to the genetics of siderophore biosynthesis and recycling. The pyoverdine locus of the six P. putida clinical isolates that have so far been completely sequenced, are not closely related; three strains (P. putida HB13667, HB3267, and NBRC14164T) are grouped in Clade I and the other three in Clade II, suggesting possible different origins and evolution. In one clinical strain, P. putida HB4184, the production of siderophores is induced under high osmolarity conditions. The pyoverdine locus in this strain is closely related to that of strain P. putida HB001 which was isolated from sandy shore soil of the Yellow Sea in Korean marine sand, suggesting their possible origin, and evolution. The acquisition of two unique TonB-dependent transporters for xenosiderophore acquisition, similar to those existing in the opportunistic pathogen P. aeruginosa PAO, is an interesting adaptation trait of the clinical strain P. putida H8234 that may confer adaptive advantages under low iron availability conditions. PMID- 28082967 TI - Stable and Variable Parts of Microbial Community in Siberian Deep Subsurface Thermal Aquifer System Revealed in a Long-Term Monitoring Study. AB - The goal of this work was to study the diversity of microorganisms inhabiting a deep subsurface aquifer system in order to understand their functional roles and interspecies relations formed in the course of buried organic matter degradation. A microbial community of a deep subsurface thermal aquifer in the Tomsk Region, Western Siberia was monitored over the course of 5 years via a 2.7 km deep borehole 3P, drilled down to a Palaeozoic basement. The borehole water discharges with a temperature of ca. 50 degrees C. Its chemical composition varies, but it steadily contains acetate, propionate, and traces of hydrocarbons and gives rise to microbial mats along the surface flow. Community analysis by PCR-DGGE 16S rRNA genes profiling, repeatedly performed within 5 years, revealed several dominating phylotypes consistently found in the borehole water, and highly variable diversity of prokaryotes, brought to the surface with the borehole outflow. The major planktonic components of the microbial community were Desulfovirgula thermocuniculi and Methanothermobacter spp. The composition of the minor part of the community was unstable, and molecular analysis did not reveal any regularity in its variations, except some predominance of uncultured Firmicutes. Batch cultures with complex organic substrates inoculated with water samples were set in order to enrich prokaryotes from the variable part of the community. PCR-DGGE analysis of these enrichments yielded uncultured Firmicutes, Chloroflexi, and Ignavibacteriae. A continuous-flow microaerophilic enrichment culture with a water sample amended with acetate contained Hydrogenophilus thermoluteolus, which was previously detected in the microbial mat developing at the outflow of the borehole. Cultivation results allowed us to assume that variable components of the 3P well community are hydrolytic organotrophs, degrading buried biopolymers, while the constant planktonic components of the community degrade dissolved fermentation products to methane and CO2, possibly via interspecies hydrogen transfer. Occasional washout of minor community components capable of oxygen respiration leads to the development of microbial mats at the outflow of the borehole where residual dissolved fermentation products are aerobically oxidized. Long-term community analysis with the combination of molecular and cultivation techniques allowed us to characterize stable and variable parts of the community and propose their environmental roles. PMID- 28082968 TI - Early Recovery of Salmonella from Food Using a 6-Hour Non-selective Pre enrichment and Reformulation of Tetrathionate Broth. AB - Culture based methods are commonly employed to detect pathogens in food and environmental samples. These methods are time consuming and complex, requiring multiple non-selective and selective enrichment broths, and usually take at least 1 week to recover and identify pathogens. Improving pathogen detection in foods is a primary goal for regulatory agencies and industry. Salmonella detection in food relies on a series of culture steps in broth formulations optimized to resuscitate Salmonella and reduce the abundance of competitive bacteria. Examples of non-selective pre-enrichment broths used to isolate Salmonella from food include Lactose, Universal Pre-enrichment, BPW, and Trypticase Soy broths. Tetrathionate (TT) and Rappaport-Vassiliadis (RV) broths are employed after a 24 h non-selective enrichment to select for Salmonella and hamper the growth of competitive bacteria. In this study, we tested a new formulation of TT broth that lacks brilliant green dye and has lower levels of TT . We employed this TT broth formulation in conjunction with a 6-h non-selective pre-enrichment period and determined that Salmonella recovery was possible one day earlier than standard food culture methods. We tested the shortened culture method in different non selective enrichment broths, enumerated Salmonella in the non-selective enrichments, and used 16S rRNA gene sequencing to determine the proportional abundances of Salmonella in the TT and RV selective enrichments. Together these data revealed that a 6-h non-selective pre-enrichment reduces the levels of competitive bacteria inoculated into the selective TT and RV broths, enabling the recovery of Salmonella 1 day earlier than standard culture enrichment methods. PMID- 28082970 TI - The Campylobacter jejuni Oxidative Stress Regulator RrpB Is Associated with a Genomic Hypervariable Region and Altered Oxidative Stress Resistance. AB - Campylobacter jejuni is the leading cause of bacterial foodborne diarrhoeal disease worldwide. Despite the microaerophilic nature of the bacterium, C. jejuni can survive the atmospheric oxygen conditions in the environment. Bacteria that can survive either within a host or in the environment like C. jejuni require variable responses to survive the stresses associated with exposure to different levels of reactive oxygen species. The MarR-type transcriptional regulators RrpA and RrpB have recently been shown to play a role in controlling both the C. jejuni oxidative and aerobic stress responses. Analysis of 3,746 C. jejuni and 486 C. coli genome sequences showed that whilst rrpA is present in over 99% of C. jejuni strains, the presence of rrpB is restricted and appears to correlate with specific MLST clonal complexes (predominantly ST-21 and ST-61). C. coli strains in contrast lack both rrpA and rrpB. In C. jejuni rrpB+ strains, the rrpB gene is located within a variable genomic region containing the IF subtype of the type I Restriction-Modification (hsd) system, whilst this variable genomic region in C. jejuni rrpB- strains contains the IAB subtype hsd system and not the rrpB gene. C. jejuni rrpB- strains exhibit greater resistance to peroxide and aerobic stress than C. jejuni rrpB+ strains. Inactivation of rrpA resulted in increased sensitivity to peroxide stress in rrpB+ strains, but not in rrpB- strains. Mutation of rrpA resulted in reduced killing of Galleria mellonella larvae and enhanced biofilm formation independent of rrpB status. The oxidative and aerobic stress responses of rrpB- and rrpB+ strains suggest adaptation of C. jejuni within different hosts and niches that can be linked to specific MLST clonal complexes. PMID- 28082969 TI - Mechanisms Underlying T Cell Immunosenescence: Aging and Cytomegalovirus Infection. AB - The ability of the human immune system to protect against infectious disease declines with age and efficacy of vaccination reduces significantly in the elderly. Aging of the immune system, also termed as immunosenescence, involves many changes in human T cell immunity that is characterized by a loss in naive T cell population and an increase in highly differentiated CD28- memory T cell subset. There is extensive data showing that latent persistent human cytomegalovirus (HCMV) infection is also associated with age-related immune dysfunction in the T cells, which might enhance immunosenescence. Understanding the molecular mechanisms underlying age-related and HCMV-related immunosenescence is critical for the development of effective age-targeted vaccines and immunotherapies. In this review, we will address the role of both aging and HCMV infection that contribute to the T cell senescence and discuss the potential molecular mechanisms in aged T cells. PMID- 28082971 TI - Tracking the Evolution of Polymerase Genes of Influenza A Viruses during Interspecies Transmission between Avian and Swine Hosts. AB - Human influenza pandemics have historically been caused by reassortant influenza A viruses using genes from human and avian viruses. This genetic reassortment between human and avian viruses has been known to occur in swine during viral circulation, as swine are capable of circulating both avian and human viruses. Therefore, avian-to-swine transmission of viruses plays an important role in the emergence of new pandemic strains. The amino acids at several positions on PB2, PB1, and PA are known to determine the host range of influenza A viruses. In this paper, we track viral transmission between avian and swine to investigate the evolution on polymerase genes associated with their hosts. We traced viral transmissions between avian and swine hosts by using nucleotide sequences of avian viruses and swine viruses registered in the NCBI GenBank. Using BLAST and the reciprocal best hits technique, we found 32, 33, and 30 pairs of avian and swine nucleotide sequences that may be associated with avian-to-swine transmissions for PB2, PB1, and PA genes, respectively. Then, we examined the amino acid substitutions involved in these sporadic transmissions. On average, avian-to-swine transmission pairs had 5.47, 3.73, and 5.13 amino acid substitutions on PB2, PB1, and PA, respectively. However, amino acid substitutions were distributed over the positions, and few positions showed common substitutions in the multiple transmission events. Statistical tests on the number of repeated amino acid substitutions suggested that no specific positions on PB2 and PA may be required for avian viruses to infect swine. We also found that avian viruses that transmitted to swine tend to process I478V substitutions on PB2 before interspecies transmission events. Furthermore, most mutations occurred after the interspecies transmissions, possibly due to selective viral adaptation to swine. PMID- 28082972 TI - Bovine Adenovirus-3 pVIII Suppresses Cap-Dependent mRNA Translation Possibly by Interfering with the Recruitment of DDX3 and Translation Initiation Factors to the mRNA Cap. AB - Earlier, targeting of DDX3 by few viral proteins has defined its role in mRNA transport and induction of interferon production. This study was conducted to investigate the function of bovine adenovirus (BAdV)-3 pVIII during virus infection. Here, we provided evidence regarding involvement of DDX3 in cap dependent cellular mRNA translation and demonstrated that targeting of DDX3 by adenovirus protein VIII interfered with cap-dependent mRNA translation function of DDX3 in virus infected cells. Adenovirus late protein pVIII interacted with DDX3 in transfected and BAdV-3 infected cells. pVIII inhibited capped mRNA translation in vitro and in vivo by limiting the amount of DDX3 and eIF3. Diminished amount of DDX3 and eIFs including eIF3, eIF4E, eIF4G, and PABP were present in cap binding complex in BAdV-3 infected or pVIII transfected cells with no trace of pVIII in cap binding complex. The total amount of eIFs appeared similar in uninfected or infected cells as BAdV-3 did not appear to degrade eIFs. The co-immunoprecipitation experiments indicated the absence of direct interaction between pVIII and eIF3, eIF4E, or PABP. These data indicate that interaction of pVIII with DDX3 interferes with the binding of eIF3, eIF4E and PABP to the 5' Cap. We conclude that DDX3 promotes cap-dependent cellular mRNA translation and BAdV-3 pVIII inhibits translation of capped cellular mRNA possibly by interfering with the recruitment of eIFs to the capped cellular mRNA. PMID- 28082974 TI - Persistent Persister Misperceptions. AB - Persister cells survive antibiotic treatment due to their lack of metabolism, rather than through genetic change, as shown via four seminal experiments conducted by the discoverers of the phenotype (Hobby et al., 1942; Bigger, 1944). Unfortunately, over seven decades of persister cell research, the literature has been populated by misperceptions that do not withstand scrutiny. This opinion piece examines some of those misunderstandings in the literature with the hope that by shining some light on these inaccuracies, the field may be advanced and subsequent manuscripts may be reviewed more critically. PMID- 28082973 TI - An Overview of Trypanosoma brucei Infections: An Intense Host-Parasite Interaction. AB - Trypanosoma brucei rhodesiense and T. brucei gambiense, the causative agents of Human African Trypanosomiasis, are transmitted by tsetse flies. Within the vector, the parasite undergoes through transformations that prepares it to infect the human host. Sequentially these developmental stages are the replicative procyclic (in which the parasite surface is covered by procyclins) and trypo epimastigote forms, as well as the non-replicative, infective, metacyclic form that develops in the vector salivary glands. As a pre-adaptation to their life in humans, metacyclic parasites begin to express and be densely covered by the Variant Surface Glycoprotein (VSG). Once the metacyclic form invades the human host the parasite develops into the bloodstream form. Herein the VSG triggers a humoral immune response. To avoid this humoral response, and essential for survival while in the bloodstream, the parasite changes its cover periodically and sheds into the surroundings the expressed VSG, thus evading the consequences of the immune system activation. Additionally, tools comparable to quorum sensing are used by the parasite for the successful parasite transmission from human to insect. On the other hand, the human host promotes clearance of the parasite triggering innate and adaptive immune responses and stimulating cytokine and chemokine secretion. All in all, the host-parasite interaction is extremely active and leads to responses that need multiple control sites to develop appropriately. PMID- 28082975 TI - The Importance of an In-depth Study of Immunoglobulin Gene Rearrangements When Ascertaining the Clonal Relationship between Concomitant Chronic Lymphocytic Leukemia and Multiple Myeloma. AB - Chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are hematological disorders that occur at different stages of B-cell development. It has been shown that CLL B-cells can differentiate into plasma cells in vitro and in vivo. CLL is the most frequent adult leukemia in the western world. It is a heterogeneous disease, characterized by clonal proliferation and the accumulation of mature CD5+ B lymphocytes (1). MM is a clonal plasma cell malignancy that accounts for more than 10% of all hematologic cancers (2). Although secondary cancers [particularly solid tumors (3-5)] can occur with CLL and MM, the concomitant occurrence of these two disorders in the same patient is rare [for a review of the few reported cases, see Ref. (6)]. The clonal relationship between these diseases has not always been clarified but is important in terms of understanding the pathogenesis and optimizing treatment. The clonal relationship between CLL and MM can be evaluated by (i) analyzing immunoglobulin (Ig) heavy chain and light chain (Ig kappa light chain and Ig lambda light chain) gene rearrangement, (ii) identifying and comparing somatic mutations, and (iii) studying chromosomic aberrations. Nevertheless, Ig rearrangements must always be interpreted in the light of specific phenomena such as allelic exclusion, B-cell receptor (BCR) revision (VH and DH gene replacement), BCR editing, and somatic mutations-events that were not considered in previous studies. These issues can be addressed by sequencing the rearranged Ig genes from sorted populations and interpreting the generated data. In the present study, we evaluated the putative clonal relationship between the two diseases by combining DNA copy number analysis with an assessment of Ig gene rearrangements [clonality assessment, V(D)J sequencing, and somatic hypermutation analysis] in highly enriched CD19+ CD5+ (CLL) and CD38+ CD138+ (MM) cell populations. Array comparative genomic hybridization data suggested a possible phylogenic progression from CLL to MM. Moreover, V(D)J sequencing indicated that both CLL and MM cells used the same VH and JH genes but different DH genes. However, in-depth analysis and interpretation of Ig gene rearrangements ultimately suggested that the two diseases had distinct clonal origins. PMID- 28082978 TI - Editorial: HSPs-Ambiguous Mediators of Immunity. PMID- 28082976 TI - The Wnt Blows: On the Functional Role of Wnt Signaling in Mycobacterium tuberculosis Infection and Beyond. AB - In recent years, it has become apparent that the Wnt signaling pathway, known for its essential functions in embryonic development and tissue homeostasis, exerts immunomodulatory functions during inflammation and infection. Most functional studies indicate that Wnt5a exerts pro-inflammatory functions on its cellular targets, which include various types of immune and non-immune cells. Wnt5a expression has also been linked to the pathogenesis of chronic inflammatory diseases. Activation of beta-catenin-dependent Wnt signaling, e.g., by Wnt3a, has however been shown to limit inflammation by interfering with the nuclear factor kappa-light chain-enhancer of activated B-cells (NF-kappaB) pathway. This review focuses on the regulation of Wnt5a, Wnt3a, and the recently identified Wnt6 and their functional role in bacterial infections with a primary focus on pulmonary tuberculosis, a leading infectious cause of morbidity and mortality worldwide. PMID- 28082977 TI - Differential Modulation of IgT and IgM upon Parasitic, Bacterial, Viral, and Dietary Challenges in a Perciform Fish. AB - Three different immunoglobulin (Ig) isotypes can be found in teleost fish, IgM, IgD, and the teleost-specific IgT. IgM is considered to have a systemic activity, and IgT is attributed a mucosal role, similar to mammalian IgA. In this study, the complete sequence of gilthead sea bream IgM and IgT in their membrane (m) and soluble (s) forms are described for the first time in a perciform fish. Their constitutive gene expression is analyzed in different tissues, and their regulation upon viral, bacterial, parasitic, mucosal vaccination and dietary challenges are studied. GCB IgM and IgT have the prototypical structure when compared to other fish Igs. The constitutive expression of sIgM was the highest overall in all tissues, whereas mIgT expression was highest in mucosal tissues, such as gills and intestine. IgM and IgT were differentially regulated upon infection. IgT was highly upregulated locally upon infection with the intestinal parasite Enteromyxum leei or systemically after Nodavirus infection. Long-term intestinal parasitic infections increased the serum titer of both isotypes. Mucosal vaccination against Photobacterium damselae subsp. piscicida finely regulated the Ig response inducing a systemic increase of IgM titers in serum and a local IgT response in skin mucus when animals were exposed to the pathogen by bath challenge. Interestingly, plant-based diets inhibit IgT upregulation upon intestinal parasitic challenge, which was related to a worse disease outcome. All these results corroborate the mucosal role of IgT and emphasize the importance of a finely tuned regulation of Ig isotypes upon infection, which could be of special interest in vaccination studies. PMID- 28082979 TI - Nasal Immunization Confers High Avidity Neutralizing Antibody Response and Immunity to Primary and Recurrent Genital Herpes in Guinea Pigs. AB - Genital herpes is one of the most prevalent sexually transmitted infections in both the developing and developed world. Following infection, individuals experience life-long latency associated with sporadic ulcerative outbreaks. Despite many efforts, no vaccine has yet been licensed for human use. Herein, we demonstrated that nasal immunization with an adjuvanted HSV-2 gD envelope protein mounts significant protection to primary infection as well as the establishment of latency and recurrent genital herpes in guinea pigs. Nasal immunization was shown to elicit specific T cell proliferative and IFN-gamma responses as well as systemic and vaginal gD-specific IgG antibody (Ab) responses. Furthermore, systemic IgG Abs displayed potent HSV-2 neutralizing properties and high avidity. By employing a competitive surface plasmon resonance (SPR) analysis combined with a battery of known gD-specific neutralizing monoclonal Abs (MAbs), we showed that nasal immunization generated IgG Abs directed to two major discontinuous neutralizing epitopes of gD. These results highlight the potential of nasal immunization with an adjuvanted HSV-2 envelope protein for induction of protective immunity to primary and recurrent genital herpes. PMID- 28082980 TI - A Universal Influenza Vaccine Can Lead to Disease Exacerbation or Viral Control Depending on Delivery Strategies. AB - The development of influenza A virus (IAV) vaccines, which elicits cross-strain immunity against seasonal and pandemic viruses is a major public health goal. As pigs are susceptible to human, avian, and swine-adapted IAV, they would be key targets of so called universal IAV vaccines, for reducing both the zoonotic risk and the economic burden in the swine industry. They also are relevant preclinical models. However, vaccination with conserved IAV antigens (AGs) in pigs was reported to elicit disease exacerbation. In this study, we assessed whether delivery strategies, i.e., dendritic cell (DC) targeting by the intradermal (ID) or intramuscular (IM) routes, impact on the outcome of the vaccination with three conserved IAV AGs (M2e, NP, and HA2) in pigs. The AGs were addressed to CD11c by non-covalent binding to biotinylated anti-CD11c monoclonal antibody. The CD11c targeted AGs given by the ID route exacerbated disease. Conversely, CD11c targeted NP injected by the IM route promoted T cell response compared to non targeted NP. Furthermore, the conserved IAV AGs injected by the IM route, independently of DC targeting, induced both a reduction of viral shedding and a broader IgG response as compared to the ID route. Our findings highlight in a relevant animal species that the route of vaccine delivery impacts on the protection induced by conserved IAV AGs and on vaccine adverse effects. Finally, our results indicate that HA2 stands as the most promising conserved IAV AG for universal vaccine development. PMID- 28082981 TI - Lymphoid Neogenesis and Tertiary Lymphoid Organs in Transplanted Organs. AB - The progressive organization of immune effectors into functional ectopic lymphoid structures, named tertiary lymphoid organs (TLO), has been observed in many conditions in which target antigens fail to be eliminated by the immune system. Not surprisingly, TLO have been recurrently identified in chronically rejected allografts. Although significant progress has been made over the last decades in understanding the molecular mechanisms involved in TLO development (a process named lymphoid neogenesis), the role of intragraft TLO (if any) in chronic rejection remains elusive. The prevailing dogma is that TLO contribute to graft rejection by generating and propagating local humoral and cellular alloimmune responses. However, TLO have been recently observed in long-term accepting allografts, suggesting that they might also be able to regulate alloimmune responses. In this review, we discuss our current understanding of how TLO are induced and propose a unified model in which TLO can play deleterious or regulatory roles and therefore actively modulate the kinetics of chronic rejection. PMID- 28082983 TI - T Cell Maturation Stage Prior to and During GMP Processing Informs on CAR T Cell Expansion in Patients. AB - Autologous T cells were genetically modified to express a chimeric antigen receptor (CAR) directed toward carboxy-anhydrase-IX (CAIX) and used to treat patients with CAIX-positive metastatic renal cell carcinoma. In this study, we questioned whether the T cell maturation stage in the pre-infusion product affected CAIX CAR expression and function in vitro as well as in vivo CAR T cell numbers and expansion. During the 14 days expansion of CAR T cells prior to administration, we observed shifts from a predominant CD4 to a CD8 T cell phenotype and from a significant fraction of naive to central effector T cells. Surface expression of the CAR was equally distributed among different T cell subsets and T cell maturation stages. During T cell culture days 14-18 (which covered patient treatment days 1-5), T cells demonstrated a decline in CAR expression level per cell irrespective of T cell maturation stage, although the proportion of CAR-positive T cells and CAR-mediated T cell effector functions remained similar for both CD4 and CD8 T cell populations. Notably, patients with a higher fraction of naive CD8 T cells at baseline (prior to genetic modification) or central effector CD8 T cells at 2 weeks of CAR T cell culture demonstrated a higher fold expansion and absolute numbers of circulating CAR T cells at 1 month after start of therapy. We conclude that the T cell maturation stage prior to and during CAR T cell expansion culture is related to in vivo CAR T cell expansion. PMID- 28082982 TI - C1q Deficiency and Neuropsychiatric Systemic Lupus Erythematosus. AB - C1q deficiency is a rare immunodeficiency, which is strongly associated with the development of systemic lupus erythematosus (SLE). A mutation in one of the C1q genes can either lead to complete deficiency or to low C1q levels with C1q polypeptide in the form of low-molecular weight (LMW) C1q. Patients with C1q deficiency mainly present with cutaneous and renal involvement. Although less frequent, neuropsychiatric (NP) involvement has also been reported in 20% of the C1q-deficient patients. This involvement appears to be absent in other deficiencies of early components of the complement classical pathway (CP) (C1r/C1s, C2, or C4 deficiencies). We describe a new case with C1q deficiency with a homozygous G34R mutation in C1qC-producing LMW-C1q presenting with a severe SLE flare with NP involvement. The serum of this patient contained very low levels of a LMW variant of C1q polypeptides. Cell lysates contained the three chains of C1q, but no intact C1q was detected, consistent with the hypothesis of the existence of a LMW-C1q. Furthermore, we provide a literature overview of NP SLE in C1q deficiency and hypothesize about the potential role of C1q in the pathogenesis of NP involvement in these patients. The onset of NP-SLE in C1q deficient individuals is more severe when compared with complement competent NP SLE patients. An important number of cases present with seizures and the most frequent findings in neuroimaging are changes in basal ganglia and cerebral vasculitis. A defective CP, because of non-functional C1q, does not protect against NP involvement in SLE. The absence of C1q and, subsequently, some of its biological functions may be associated with more severe NP-SLE. PMID- 28082985 TI - Local Treatment with Lactate Prevents Intestinal Inflammation in the TNBS-Induced Colitis Model. AB - Lactate has long been considered as a metabolic by-product of cells. Recently, this view has been changed by the observation that lactate can act as a signaling molecule and regulates critical functions of the immune system. We previously identified lactate as the component responsible for the modulation of innate immune epithelial response of fermented milk supernatants in vitro. We have also shown that lactate downregulates proinflammatory responses of macrophages and dendritic cells. So far, in vivo effects of lactate on intestinal inflammation have not been reported. We evaluated the effect of intrarectal administration of lactate in a murine model of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). The increase in lactate concentration in colon promoted protective effects against TNBS-induced colitis preventing histopathological damage, as well as bacterial translocation and rise of IL-6 levels in serum. Using intestinal epithelial reporter cells, we found that flagellin treatment induced reporter gene expression, which was abrogated by lactate treatment as well as by glycolysis inhibitors. Furthermore, lactate treatment modulated glucose uptake, indicating that high levels of extracellular lactate can impair metabolic reprograming induced by proinflammatory activation. These results suggest that lactate could be a potential beneficial microbiota metabolite and may constitute an overlooked effector with modulatory properties. PMID- 28082984 TI - The Fab Fragment of a Human Anti-Siglec-9 Monoclonal Antibody Suppresses LPS Induced Inflammatory Responses in Human Macrophages. AB - Sepsis is a major cause of death for hospitalized patients and is characterized by massive overreaction of immune responses to invading pathogens which is mediated by cytokines. For decades, there has been no effective treatment for sepsis. Sialic acid-binding, Ig-like lectin-9 (Siglec-9), is an immunomodulatory receptor expressed primarily on hematopoietic cells which is involved in various aspects of inflammatory responses and is a potential target for treatment of sepsis. The aim of the present study was to develop a human anti-Siglec-9 Fab fragment, which was named hS9-Fab03 and investigate its immune activity in human macrophages. We began by constructing the hS9-Fab03 prokaryotic expression vector from human antibody library and phage display. Then, we utilized a multitude of assays, including SDS-PAGE, Western blotting, ELISA, affinity, and kinetics assay to evaluate the binding affinity and specificity of hS9-Fab03. Results demonstrated that hS9-Fab03 specifically bind to Siglec-9 antigen with high affinity, and pretreatment with hS9-Fab03 could attenuate lipopolysaccharide (LPS)-induced TNF-alpha, IL-6, IL-1beta, IL-8, and IFN-beta production in human PBMC-derived macrophages, but slightly increased IL-10 production in an early time point. We also observed similar results in human THP-1-differentiated macrophages. Collectively, we prepared the hS9-Fab03 with efficient activity for blocking LPS-induced pro-inflammatory cytokines production in human macrophages. These results indicated that ligation of Siglec-9 with hS9-Fab03 might be a novel anti-inflammatory therapeutic strategy for sepsis. PMID- 28082987 TI - Editorial: HLA-G-Mediated Immune Tolerance: Past and New Outlooks. PMID- 28082986 TI - Type I Interferons in Bacterial Infections: A Balancing Act. AB - Defense against bacterial infections requires activation of the immune response as well as timely reestablishment of tissue and immune homeostasis. Instauration of homeostasis is critical for tissue regeneration, wound healing, and host recovery. Recent studies revealed that severe infectious diseases frequently result from failures in homeostatic processes rather than from inefficient pathogen eradication. Type I interferons (IFN) appear to play a key role in such processes. Remarkably, the involvement of type I IFNs in the regulation of immune and tissue homeostasis upon bacterial insult may have beneficial or detrimental consequences for the host. The reasons for such ambivalent function of type I IFNs are not understood. The disparate effects of type I IFNs on bacterial infections are in marked contrast to their well-established protective roles in most viral infections. In this review, we will focus on type I IFN effector mechanisms which balance processes involved in immune and tissue homeostasis during specific bacterial infections and highlight the most important missing links in our understanding of type I IFN functions. PMID- 28082988 TI - Investigating Factors Associated with Thymic Regeneration after Chemotherapy in Patients with Lymphoma. AB - The factors involved in thymus regeneration after chemotherapy has not been sufficiently explored. This study was aimed to identify the clinical characteristics and single-nucleotide polymorphisms in the gene (IL7R) encoding IL-7Ralpha associated with thymus renewal after chemotherapy in Chinese Han individuals with lymphoma. The dynamics of thymic activity in 134 adults with Hodgkin lymphoma (HL) and B cell lymphoma from baseline to 12 months post chemotherapy were analyzed by assessing thymic structural changes using serial computed tomography scans and correlating these with measurements of thymic output by concurrent analysis of single-joint T-cell receptor excision circles (sjTREC) and CD31+ recent thymic emigrants (RTE) in peripheral blood. The association of clinical variables and IL7R polymorphisms with the occurrence of rebound thymic hyperplasia (TH) and the recovery of thymic output following chemotherapy were evaluated. Thymic regeneration was observed, with the evidence that TH occurred in 38/134 (28.4%) cases, and thymic output, assessed by CD31+ RTE numbers and sjTREC content, recovered to baseline levels within 1 year after the end of therapy. The frequencies of the T allele and TT + GT genotype of rs7718919 located in the promoter of IL7R were significantly higher in patients with TH compared with those without TH (P = 0.031 and 0.027, respectively). In contrast, no significant difference was found between two groups with respect to the distribution of allele and genotype frequencies of rs6897932. By general linear models repeated-measure analysis, rs7718919 and rs6897932 were determined to exert no significant effects on the recovery of thymic output after therapy. Univariate analysis revealed host age under 30, the diagnosis of HL, baseline thymic index and CD31+ RTE counts, and rs7718919 genotype as potential predictors for TH after chemotherapy (P < 0.05); after multivariate adjustment, only host age was independently associated with the occurrence of TH (odds ratios = 4.710, 95% confidence intervals: 1.727-12.845, P = 0.002). These findings indicate that patient age is an independent predictor for thymic regrowth after chemotherapy, which should promote awareness among physicians to make a timely diagnosis of TH in young adults and help physicians to prioritize intervention strategies for thymus rejuvenation in this population. PMID- 28082989 TI - Neuroimmune Interface in the Comorbidity between Alcohol Use Disorder and Major Depression. AB - Bidirectional communication links operate between the brain and the body. Afferent immune-to-brain signals are capable of inducing changes in mood and behavior. Chronic heavy alcohol drinking, typical of alcohol use disorder (AUD), is one such factor that provokes an immune response in the periphery that, by means of circulatory cytokines and other neuroimmune mediators, ultimately causes alterations in the brain function. Alcohol can also directly impact the immune functions of microglia, the resident immune cells of the central nervous system (CNS). Several lines of research have established the contribution of specific inflammatory mediators in the development and progression of depressive illness. Much of the available evidence in this field stems from cross-sectional data on the immune interactions between isolated AUD and major depression (MD). Given their heterogeneity as disease entities with overlapping symptoms and shared neuroimmune correlates, it is no surprise that systemic and CNS inflammation could be a critical determinant of the frequent comorbidity between AUD and MD. This review presents a summary and analysis of the extant literature on neuroimmune interface in the AUD-MD comorbidity. PMID- 28082990 TI - Human NK Cell Subsets in Pregnancy and Disease: Toward a New Biological Complexity. AB - In humans, NK cells are mainly identified by the surface expression levels of CD56 and CD16, which differentiate between five functionally different NK cell subsets. However, nowadays NK cells are considered as a more heterogeneous population formed by various subsets differing in function, surface phenotype, and anatomic localization. In human CMV- and hantaviruses-infected subjects, an increased frequency of a NKG2A-CD57+NKG2C+ NK cell subset has been observed, while the phenotype of the NK cell subpopulation associated with cancer may vary according to the specific kind of tumor and its anatomical location. The healthy human lymph nodes contain mainly the CD56bright NK cell subset while in melanoma metastatic lymph nodes the CD56dimCD57+KIR+CCR7+ NK cell subpopulation prevails. The five NK cell subpopulations are found in breast cancer patients, where they differ for expression pattern of chemokine receptors, maturation stage, functional capabilities. In pregnancy, uterine NK cells show a prevalence of the CD56brightCD16- NK cell compartment, whose activity is influenced by KIRs repertoire. This NK cell subset's super specialization could be explained by (i) the expansion of single mature CD56dim clones, (ii) the recruitment and maturation of CD56bright NK cells through specific stimuli, and (iii) the in situ development of tumor-resident NK cells from tissue-resident CD56bright NK cells independently of the circulating NK cell compartment. This new and unexpected biological feature of the NK cell compartment could be an important source of new biomarkers to improve patients' diagnosis. PMID- 28082991 TI - Editorial: Immune Cells in the Mucosa. PMID- 28082993 TI - COTIP: Cotton TILLING Platform, a Resource for Plant Improvement and Reverse Genetic Studies. AB - Cotton is cultivated worldwide for its white fiber, of which around 90% is tetraploid upland cotton (Gossypium hirsutum L.) carrying both A and D genome. Since centuries, yield increasing efforts for the cotton crop by conventional breeding approaches have caused an extensive erosion of natural genetic variability. Mutation based improvement strategies provide an effective way of creating new allelic variations. Targeting Induced Local Lesions IN Genomes (TILLING) provides a mutation based reverse genetic strategy to create and evaluate induced genetic variability at DNA level. Here, we report development and testing of TILLING populations of allotetraploid cotton (G. hirsutum) for functional genomic studies and mutation based enrichment of cotton genetic resources. Seed of two cotton cultivars "PB-899 and PB-900" were mutagenized with 0.3 and 0.2% (v/v) ethyl methanesulfonate, respectively. The phenotyping of M1 and M2 populations presented numerous mutants regarding the branching pattern, leaf morphology, disease resistance, photosynthetic lesions and flower sterility. Molecular screening for point mutations was performed by TILLING PCR aided CEL1 mismatch cleavage. To estimate the mutation frequency in the mutant genomes, five gene classes were TILLed in 8000 M2 plants of each var. "PB-899" and "PB-900." These include actin (GhACT), Pectin Methyl Esterase (GhPME), sucrose synthase (GhSUS), resistance gene analog, and defense response gene (DRGs). The var. PB 899 was harboring 47% higher mutation induction rate than PB-900. The highest rate of mutation frequency was identified for NAC-TF5 (EU706348) of DRGs class, ranging from 1/58 kb in PB-899 to 1/105 kb in PB-900. The mutation screening assay revealed the presence of significant proportion of induced mutations in cotton TILLING populations such as 1/153 kb and 1/326 kb in var. "PB-899" and "PB 900," respectively. The establishment of a cotton TILLING platform (COTIP) and data obtained from the resource TILLING population suggest its effectiveness in widening the genetic bases of cotton for improvement and utilizing it for subsequent reverse genetic studies of various genes. PMID- 28082992 TI - CD4 T Follicular Helper and Regulatory Cell Dynamics and Function in HIV Infection. AB - T follicular helper cells (TFH) are a specialized subset of CD4 T cells that reside in B cell follicles and promote B cell maturation into plasma cells and long-lived memory B cells. During chronic infection prior to the development of AIDS, HIV-1 (HIV) replication is largely concentrated in TFH. Paradoxically, TFH numbers are increased in early and midstages of disease, thereby promoting HIV replication and disease progression. Despite increased TFH numbers, numerous defects in humoral immunity are detected in HIV-infected individuals, including dysregulation of B cell maturation, impaired somatic hypermutation, and low quality of antibody production despite hypergammaglobulinemia. Clinically, these defects are manifested by increased vulnerability to bacterial infections and impaired vaccine responses, neither of which is fully reversed by antiretroviral therapy (ART). Deficits in TFH function, including reduced HIV-specific IL-21 production and low levels of co-stimulatory receptor expression, have been linked to these immune impairments. Impairments in TFH likely contribute as well to the ability of HIV to persist and evade humoral immunity, particularly the inability to develop broadly neutralizing antibodies. In addition to direct infection of TFH, other mechanisms that have been linked to TFH deficits in HIV infection include upregulation of PD-L1 on germinal center B cells and augmented follicular regulatory T cell responses. Challenges to development of strategies to enhance TFH function in HIV infection include lack of an established phenotype for memory TFH as well as limited understanding of the relationship between peripheral TFH and lymphoid tissue TFH. Interventions to augment TFH function in HIV-infected individuals could enhance immune reconstitution during ART and potentially augment cure strategies. PMID- 28082994 TI - Annual Cambial Rhythm in Pinus halepensis and Pinus sylvestris as Indicator for Climate Adaptation. AB - To understand better the adaptation strategies of intra-annual radial growth in Pinus halepensis and Pinus sylvestris to local environmental conditions, we examined the seasonal rhythm of cambial activity and cell differentiation at tissue and cellular levels. Two contrasting sites differing in temperature and amount of precipitation were selected for each species, one typical for their growth and the other represented border climatic conditions, where the two species coexisted. Mature P. halepensis trees from Mediterranean (Spain) and sub Mediterranean (Slovenia) sites, and P. sylvestris from sub-Mediterranean (Slovenia) and temperate (Slovenia) sites were selected. Repeated sampling was performed throughout the year and samples were prepared for examination with light and transmission electron microscopes. We hypothesized that cambial rhythm in trees growing at the sub-Mediterranean site where the two species co-exist will be similar as at typical sites for their growth. Cambium in P. halepensis at the Mediterranean site was active throughout the year and was never truly dormant, whereas at the sub-Mediterranean site it appeared to be dormant during the winter months. In contrast, cambium in P. sylvestris was clearly dormant at both sub-Mediterranean and temperate sites, although the dormant period seemed to be significantly longer at the temperate site. Thus, the hypothesis was only partly confirmed. Different cambial and cell differentiation rhythms of the two species at the site where both species co-exist and typical sites for their growth indicate their high but different adaptation strategies in terms of adjustment of radial growth to environmental heterogeneity, crucial for long-term tree performance and survival. PMID- 28082995 TI - Bcl-2?21 and Ac-DEVD-CHO Inhibit Death of Wheat Microspores. AB - Microspore cell death and low green plant production efficiency are an integral obstacle in the development of doubled haploid production in wheat. The aim of the current study was to determine the effect of anti-apoptotic recombinant human B-cell lymphoma-2 (Bcl-2?21) and caspase-3-inhibitor (Ac-DEVD-CHO) in microspore cell death in bread wheat cultivars AC Fielder and AC Andrew. Induction medium containing Bcl-2?21 and Ac-DEVD-CHO yielded a significantly higher number of viable microspores, embryo-like structures and total green plants in wheat cultivars AC Fielder and AC Andrew. Total peroxidase activity was lower in Bcl 2?21 treated microspore cultures at 96 h of treatment compared to control and Ac DEVD-CHO. Electron paramagnetic resonance study of total microspore protein showed a different scavenging activity for Bcl-2?21 and Ac-DEVD-CHO. Bcl-2?21 scavenged approximately 50% hydroxyl radical (HO*) formed, whereas Ac-DEVD-CHO scavenged approximately 20% of HO*. Conversely, reduced caspase-3-like activities were detected in the presence of Bcl-2?21 and Ac-DEVD-CHO, supporting the involvement of Bcl-2?21 and Ac-DEVD-CHO in increasing microspore viability by reducing oxidative stress and caspase-3-like activity. Our results indicate that Bcl-2?21 and Ac-DEVD-CHO protects cells from cell death following different pathways. Bcl-2?21 prevents cell damage by detoxifying HO* and suppressing caspase-3-like activity, while Ac-DEVD-CHO inhibits the cell death pathways by modulating caspase-like activity. PMID- 28082996 TI - Major Contribution of Flowering Time and Vegetative Growth to Plant Production in Common Bean As Deduced from a Comparative Genetic Mapping. AB - Determinacy growth habit and accelerated flowering traits were selected during or after domestication in common bean. Both processes affect several presumed adaptive traits such as the rate of plant production. There is a close association between flowering initiation and vegetative growth; however, interactions among these two crucial developmental processes and their genetic bases remain unexplored. In this study, with the aim to establish the genetic relationships between these complex processes, a multi-environment quantitative trait locus (QTL) mapping approach was performed in two recombinant inbred line populations derived from inter-gene pool crosses between determinate and indeterminate genotypes. Additive and epistatic QTLs were found to regulate flowering time, vegetative growth, and rate of plant production. Moreover, the pleiotropic patterns of the identified QTLs evidenced that regions controlling time to flowering traits, directly or indirectly, are also involved in the regulation of plant production traits. Further QTL analysis highlighted one QTL, on the lower arm of the linkage group Pv01, harboring the Phvul.001G189200 gene, homologous to the Arabidopsis thaliana TERMINAL FLOWER1 (TFL1) gene, which explained up to 32% of phenotypic variation for time to flowering, 66% for vegetative growth, and 19% for rate of plant production. This finding was consistent with previous results, which have also suggested Phvul.001G189200 (PvTFL1y) as a candidate gene for determinacy locus. The information here reported can also be applied in breeding programs seeking to optimize key agronomic traits, such as time to flowering, plant height and an improved reproductive biomass, pods, and seed size, as well as yield. PMID- 28082997 TI - Detection of Invertebrate Suppressive Soils, and Identification of a Possible Biological Control Agent for Meloidogyne Nematodes Using High Resolution Rhizosphere Microbial Community Analysis. AB - White clover (Trifolium repens) is the key legume component of New Zealand pastoral agriculture due to the high quality feed and nitrogen inputs it provides. Invertebrate pests constrain white clover growth and this study investigated rhizosphere-associated fungal controls for two of these pests and attempts to disentangle the underpinning mechanisms. The degree of suppressiveness of 10 soils, in a latitudinal gradient down New Zealand, to added Meloidogyne hapla and Costelytra zealandica scarab larvae was measured in untreated soil. Most of the soils showed no suppressive activity against these pests but two showed activity against M. hapla and two against C. zealandica. Rhizosphere fungi responsible for pest suppressive responses were elucidated via next-generation sequencing. In the M. hapla-suppressive soils nematode-trapping Orbiliomycetes fungi were present in significantly greater abundance than non suppressive soils and their abundance increased further with addition of M. hapla. A comparison of plant growth and the rhizosphere fungal community between untreated and irradiated soil was carried out on 5 of the 10 soils using Pyronota as the scarab larvae. Soil irradiation either: reduced (by 60-70%); increased (16*) or made no difference to white clover growth across the five soils tested, illustrating the range of microbial impacts on plant production. In one of the M. hapla suppressive soils irradiation resulted in a significant increase in nematode galling suggesting that Orbiliomycetes fungi were indeed responsible for the suppressive effect. Lack of consistent changes in soil macronutrients and pH post-irradiation suggest these were not responsible for plant or invertebrate responses. The use of next generation sequencing in controlled pot trials has allowed identification of a potential biological control organism and bioindicator for M. hapla suppression. PMID- 28082998 TI - Production of Reactive Oxygen Species by Photosystem II as a Response to Light and Temperature Stress. AB - The effect of various abiotic stresses on photosynthetic apparatus is inevitably associated with formation of harmful reactive oxygen species (ROS). In this review, recent progress on ROS production by photosystem II (PSII) as a response to high light and high temperature is overviewed. Under high light, ROS production is unavoidably associated with energy transfer and electron transport in PSII. Singlet oxygen is produced by the energy transfer form triplet chlorophyll to molecular oxygen formed by the intersystem crossing from singlet chlorophyll in the PSII antennae complex or the recombination of the charge separated radical pair in the PSII reaction center. Apart to triplet chlorophyll, triplet carbonyl formed by lipid peroxidation transfers energy to molecular oxygen forming singlet oxygen. On the PSII electron acceptor side, electron leakage to molecular oxygen forms superoxide anion radical which dismutes to hydrogen peroxide which is reduced by the non-heme iron to hydroxyl radical. On the PSII electron donor side, incomplete water oxidation forms hydrogen peroxide which is reduced by manganese to hydroxyl radical. Under high temperature, dark production of singlet oxygen results from lipid peroxidation initiated by lipoxygenase, whereas incomplete water oxidation forms hydrogen peroxide which is reduced by manganese to hydroxyl radical. The understanding of molecular basis for ROS production by PSII provides new insight into how plants survive under adverse environmental conditions. PMID- 28082999 TI - Loop-Mediated Isothermal Amplification (LAMP): Emergence As an Alternative Technology for Herbal Medicine Identification. AB - Correct identification of medicinal plant ingredients is essential for their safe use and for the regulation of herbal drug supply chain. Loop-mediated isothermal amplification (LAMP) is a recently developed approach to identify herbal medicine species. This novel molecular biology technique enables timely and accurate testing, especially in settings where infrastructures to support polymerase chain reaction facilities are lacking. Studies that used this method have altered our view on the extent and complexity of herbal medicine identification. In this review, we give an introduction into LAMP analysis, covers the basic principles and important aspects in the development of LAMP analysis method. Then we presented a critical review of the application of LAMP-based methods in detecting and identifying raw medicinal plant materials and their processed products. We also provide a practical standard operating procedure (SOP) for the utilization of the LAMP protocol in herbal authentication, and consider the prospects of LAMP technology in the future developments of herbal medicine identification and the challenges associated with its application. PMID- 28083000 TI - The Promoter of AtUSP Is Co-regulated by Phytohormones and Abiotic Stresses in Arabidopsis thaliana. AB - Universal stress proteins (USPs) are known to be expressed in response to various abiotic stresses in a wide variety of organisms, such as bacteria, archaebacteria, protists, algae, fungi, plants, and animals. However, in plants, biological function of most of the USPs still remains obscure. In the present study, Arabidopsis USP gene (AtUSP) showed induction in response to abscisic acid (ABA) and various abiotic stresses viz. heat, dehydration, salt, osmotic, and cold stresses. Additionally, in silico analysis of AtUSP promoter identified several cis-elements responsive to phytohormones and abiotic stresses such as ABRE, ERE, DRE, and HSE, etc. To functionally validate the AtUSP promoter, the 1115 bp region of promoter was characterized under phytohormone and abiotic stress treatments. Deletion analysis of promoter was carried out by cloning the full length promoter (D0) and its three 5' deletion derivatives, D1 (964 bp), D2 (660 bp), and D3 (503 bp) upstream of the beta-glucuronidase (GUS) reporter gene, which were then stably transformed in Arabidopsis plants. The AtUSP promoter (D0) showed minimal activity under non-stress conditions which was enhanced in response to phytohormone treatments (ABA and ACC) and abiotic stresses such as dehydration, heat, cold, salt, and osmotic stresses. The seedlings harboring D1 and D2 deletion fragments showed constitutive GUS expression even under control condition with increased activity almost under all the treatments. However, D3 seedlings exhibited complete loss of activity under control condition with induction under ACC treatment, dehydration, heat, oxidative, salt, and osmotic stresses. Thus, present study clearly showed that AtUSP promoter is highly inducible by phytohormones and multiple abiotic stresses and it can be exploited as stress inducible promoter to generate multi-stress tolerant crops with minimal effects on their other important traits. PMID- 28083002 TI - Differential Responses of Arctic Vegetation to Nutrient Enrichment by Plankton- and Fish-Eating Colonial Seabirds in Spitsbergen. AB - The role of seabirds as sea-land biovectors of nutrients is well documented. However, no studies have examined whether and how colonial seabirds that differ in diet may influence terrestrial vegetation. Therefore, the purpose of the study was to describe and compare plant communities located in the vicinity of the two most common types of seabird colonies in Arctic, occupied by piscivorous or planktivorous species. Within 46 plots arranged in four transects in the vicinity of planktivorous (little auk, Alle alle) and piscivorous colonies (mixed colony of Brunnich's guillemot, Uria lomvia, and black-legged kittiwake, Rissa tridactyla) we measured the following: guano deposition, physical and chemical characteristics of soil, total nitrogen and its stable isotope signatures in soil and plants, ground vegetation cover of vascular plants and mosses, and the occurrence of lichens, algae and cyanobacteria. Using LINKTREE analysis, we distinguished five plant communities, which reflected declining influence along a birds fertilization gradient measured as guano deposition. SIMPROOF test revealed that these communities differed significantly in species composition, with the differences related to total soil nitrogen content and delta15N, distinctive levels of phosphates, potassium and nitrates, and physical soil properties, i.e., pH, conductivity and moisture. The communities were also clearly distinguished by distance from the bird colony. The two colony types promoted development of specific plant communities: the immediate vicinity of the planktivorous colony characterized by a Deschampsia alpina-Cerastium arcticum community while under the piscivorous colony a Cochlearia groenlandica-Poa alpina community was present. Despite the similar size of the colonies and similar magnitude of guano input, differences between ornithogenic communities were connected mostly to phosphate content in the soil. Our results show that the guano input from seabirds which have different diets can affect High Arctic vegetation in specific and more complex ways than previously realized. PMID- 28083001 TI - Global Scale Transcriptional Profiling of Two Contrasting Barley Genotypes Exposed to Moderate Drought Conditions: Contribution of Leaves and Crowns to Water Shortage Coping Strategies. AB - Drought is a serious threat for sustainable agriculture. Barley represents a species well adapted to environmental stresses including drought. To elucidate the adaptive mechanism of barley on transcriptional level we evaluated transcriptomic changes of two contrasting barley cultivars upon drought using the microarray technique on the level of leaves and crowns. Using bioinformatic tools, differentially expressed genes in treated vs. non-treated plants were identified. Both genotypes revealed tissue dehydration under drought conditions as shown at water saturation deficit and osmotic potential data; however, dehydration was more severe in Amulet than in drought-resistant Tadmor under the same ambient conditions. Performed analysis showed that Amulet enhanced expression of genes related to active plant growth and development, while Tadmor regarding the stimulated genes revealed conservative, water saving strategy. Common reactions of both genotypes and tissues included an induction of genes encoding several stress-responsive signaling proteins, transcription factors as well as effector genes encoding proteins directly involved in stress acclimation. In leaf, tolerant cultivar effectively stimulated mainly the expression of genes encoding proteins and enzymes involved in protein folding, sulfur metabolism, ROS detoxification or lipid biosynthesis and transport. The crown specific reaction of tolerant cultivar was an enhanced expression of genes encoding proteins and enzymes involved in cell wall lignification, ABRE-dependent abscisic acid (ABA) signaling, nucleosome remodeling, along with genes for numerous jasmonate induced proteins. PMID- 28083003 TI - Phytochrome B Negatively Affects Cold Tolerance by Regulating OsDREB1 Gene Expression through Phytochrome Interacting Factor-Like Protein OsPIL16 in Rice. AB - Cross talk between light signaling and cold signaling has been elucidated in the model plant Arabidopsis and tomato, but little is known about their relationship in rice. Here, we report that phytochrome B (phyB) mutants exhibit improved cold tolerance compared with wild type (WT) rice (Oryza sativa L. cv. Nipponbare). The phyB mutants had a lower electrolyte leakage index and malondialdehyde concentration than the WT, suggesting that they had greater cell membrane integrity and less lipid peroxidation. Real-time PCR analysis revealed that the expression levels of dehydration-responsive element binding protein 1 (OsDREB1) family genes, which functions in the cold stress response in rice, were increased in the phyB mutant under normal and cold stress conditions. PIFs are central players in phytochrome-mediated light signaling networks. To explore the relationship between rice PIFs and OsDREB1 gene expression, we produced overexpression lines of rice PIF genes. OsDREB1 family genes were up-regulated in OsPIL16-overexpression lines, which had improved cold tolerance relative to the WT. Chromatin immunoprecipitation (ChIP)-qPCR assay revealed that OsPIL16 can bind to the N-box region of OsDREB1B promoter. Expression pattern analyses revealed that OsPIL16 transcripts were induced by cold stress and was significantly higher in the phyB mutant than in the WT. Moreover, yeast two hybrid assay showed that OsPIL16 can bind to rice PHYB. Based on these results, we propose that phyB deficiency positively regulates OsDREB1 expression through OsPIL16 to enhance cell membrane integrity and to reduce the malondialdehyde concentration, resulting in the improved cold tolerance of the phyB mutants. PMID- 28083005 TI - Varying Response of the Concentration and Yield of Soybean Seed Mineral Elements, Carbohydrates, Organic Acids, Amino Acids, Protein, and Oil to Phosphorus Starvation and CO2 Enrichment. AB - A detailed investigation of the concentration (e.g., mg g-1 seed) and total yield (e.g., g plant-1) of seed mineral elements and metabolic profile under phosphorus (P) starvation at ambient (aCO2) and elevated carbon dioxide (eCO2) in soybean is limited. Soybean plants were grown in a controlled environment at either sufficient (0.50 mM P, control) or deficient (0.10 and 0.01 mM, P-stress) levels of P under aCO2 and eCO2 (400 and 800 MUmol mol-1, respectively). Both the concentration and yield of 36 out of 38 seed components responded to P treatment and on average 25 and 11 components increased and decreased, respectively, in response to P starvation. Concentrations of carbohydrates (e.g., glucose, sugar alcohols), organic acids (e.g., succinate, glycerate) and amino acids increased while oil, and several minerals declined under P deficiency. However, the yield of the majority of seed components declined except several amino acids (e.g., phenylalanine, serine) under P deficiency. The concentration-based relationship between seed protein and oil was negative (r2 = 0.96), whereas yield-based relationship was positive (r2 = 0.99) across treatments. The CO2 treatment also altered the concentration of 28 out of 38 seed components, of which 23 showed decreasing (e.g., sucrose, glucose, citrate, aconitate, several minerals, and amino acids) while C, iron, Mn, glycerate, and oil showed increasing trends at eCO2. Despite a decreased concentration, yields of the majority of seed components were increased in response to eCO2, which was attributable to the increased seed production especially near sufficient P nutrition. The P * CO2 interactions for the concentration of amino acids and the yield of several components were due to the lack of their response to eCO2 under control or the severe P starvation, respectively. Thus, P deficiency primarily reduced the concentration of oil and mineral elements but enhanced a majority of other components. However, seed components yield consistently declined under P starvation except for several amino acids. The study highlighted a P nutritional status dependent response of soybean seed components to eCO2 suggesting the requirement of an adequate P supply to obtain the beneficial effects of eCO2 on the overall yield of various seed components. PMID- 28083004 TI - Tomato SlERF.A1, SlERF.B4, SlERF.C3 and SlERF.A3, Members of B3 Group of ERF Family, Are Required for Resistance to Botrytis cinerea. AB - The Ethylene-Responsive Factors (ERFs) comprise a large family of transcriptional factors that play critical roles in plant immunity. Gray mold disease caused by Botrytis cinerea, a typical necrotrophic fungal pathogen, is the serious disease that threatens tomato production worldwide. However, littler is known about the molecular mechanism regulating the immunity to B. cinerea in tomato. In the present study, virus-induced gene silencing (VIGS)-based functional analyses of 18 members of B3 group (also called Group IX) in tomato ERF family were performed to identify putative ERFs that are involved in disease resistance against B. cinerea. VIGS-based silencing of either SlERF.B1 or SlERF.C2 had lethal effect while silencing of SlERF.A3 (Pit4) significantly suppressed vegetative growth of tomato plants. Importantly, silencing of SlERF.A1, SlERF.A3, SlERF.B4, or SlERF.C3 resulted in increased susceptibility to B. cinerea, attenuated the B. cinerea-induced expression of jasmonic acid/ethylene-mediated signaling responsive defense genes and promoted the B. cinerea-induced H2O2 accumulation. However, silencing of SlERF.A3 also decreased the resistance against Pseudomonas syringae pv. tomato (Pst) DC3000 but silencing of SlERF.A1, SlERF.B4 or SlERF.C3 did not affect the resistance to this bacterial pathogen. Expression of SlERF.A1, SlERF.A3, SlERF.B4, or SlERF.C3 was induced by B. cinerea and by defense signaling hormones such as salicylic acid, methyl jasmonate, and 1 aminocyclopropane-1-carboxylic acid (an ethylene precursor). SlERF.A1, SlERF.B4, SlERF.C3, and SlERF.A3 proteins were found to localize in nucleus of cells and possess transactivation activity in yeasts. These data suggest that SlERF.A1, SlERF.B4, and SlERF.C3, three previously uncharacterized ERFs in B3 group, and SlERF.A3, a previously identified ERF with function in immunity to Pst DC3000, play important roles in resistance against B. cinerea in tomato. PMID- 28083006 TI - Diaphorina citri Induces Huanglongbing-Infected Citrus Plant Volatiles to Repel and Reduce the Performance of Propylaea japonica. AB - Transmission of plant pathogens through insect vectors is a complex biological process involving interactions between the host plants, insects, and pathogens. Simultaneous impact of the insect damage and pathogenic bacteria in infected host plants induce volatiles that modify not only the behavior of its insect vector but also of their natural enemies, such as parasitoid wasps. Therefore, it is essential to understand how insects such as the predator ladybird beetle responds to volatiles emitted from a host plant and how the disease transmission alters the interactions between predators, vector, pathogens, and plants. In this study, we investigated the response of Propylaea japonica to volatiles from citrus plants damaged by Diaphorina citri and Candidatus Liberibacter asiaticus through olfactometer bioassays. Synthetic chemical blends were also used to determine the active compounds in the plant volatile. The results showed that volatiles emitted by healthy plants attracted more P. japonica than other treatments, due to the presence of high quantities of D-limonene and beta-ocimene, and the lack of methyl salicylate. When using synthetic chemicals in the olfactory tests, we found that D-limonene attracted P. japonica while methyl salicylate repelled the predator. However, beta-ocimene attracted the insects at lower concentrations but repelled them at higher concentrations. These results indicate that P. japonica could not efficiently search for its host by using volatile cues emitted from psyllids- and Las bacteria-infected citrus plants. PMID- 28083007 TI - Bensulfuron-Methyl Treatment of Soil Affects the Infestation of Whitefly, Aphid, and Tobacco Mosaic Virus on Nicotiana tabacum. AB - Bensulfuron-methyl (BSM) is widely used in paddy soil for weed control. BSM residue in the soil has been known to inhibit the growth of sensitive crop plants. However, it is unknown whether BSM residue can affect the agrosystem in general. In this study, we have found significant effects of BSM on the infestation of Bemisia tabaci, Myzus persicae, and Tobacco mosaic virus (TMV) in Nicotiana tabacum. The soil was treated with BSM before the pest inoculation. The herbicide-treated tobaccos showed resistance to B. tabaci, but this resistance could not be detected until 15-day post-infestation when smaller number of adults B. tabaci appeared. In M. persicae assay, the longevity of all development stages of insects, and the fecundity of insects were not significantly affected when feeding on BSM-treated plants. In TMV assay, the BSM treatment also reduced virus induced lesions in early infection time. However, the titer of TMV in BSM treated plants increased greatly over time and was over 40-fold higher than the mock infected control plants after 20 days. Further studies showed that BSM treatment increased both jasmonic acid (JA) and salicylic acid (SA) levels in tobacco, as well as the expression of target genes in the JA and SA signaling pathways, such as NtWIPK, NtPR1a, and NtPAL. NtPR1a and NtPAL were initially suppressed after virus-inoculation, while NtRDR1 and NtRDR6, which play a key role in fighting virus infection, only showed up- or were down-regulated 20 days post virus inoculation. Taken together, our results suggested that BSM residue in the soil may affect the metabolism of important phytohormones such as JA and SA in sensitive plants and consequently affect the plant immune response against infections such as whitefly, aphids, and viruses. PMID- 28083008 TI - Comparative Transcriptomics Atlases Reveals Different Gene Expression Pattern Related to Fusarium Wilt Disease Resistance and Susceptibility in Two Vernicia Species. AB - Vernicia fordii (tung oil tree) is a promising industrial crop. Unfortunately, the devastating Fusarium wilt disease has caused its great losses, while its sister species (Vernicia montana) is remarkably resistant to this pathogen. However, the genetic mechanisms underlying this difference remain largely unknown. We here generated comparative transcriptomic atlases for different stages of Fusarium oxysporum infected Vernicia root. The transcriptomes of V. fordii and V. montana were assembled de novo and contained 258,430 and 245,240 non-redundant transcripts with N50 values of 1776 and 2452, respectively. A total of 44,310 pairs of putative one-to-one orthologous genes were identified in Vernicia species. Overall, the vast majority of orthologous genes shared a remarkably similar expression mode. The expression patterns of a small set of genes were further validated by quantitative real-time PCR. Moreover, 157 unigenes whose expression significantly correlated between the two species were defined, and gene set enrichment analysis indicated roles in increased defense response and in jasmonic and salicylic acid signaling responses during pathogen attack. Co-expression network analysis further identified the 17 hub unigenes, such as the serine/threonine protein kinase D6PK, leucine-rich repeat receptor like kinase (LRR-RLK), and EREBP transcription factor, which play essential roles in plant pathogen resistance. Intriguingly, the expression of most hub genes differed significantly between V. montana and V. fordii. Based on our results, we propose a model to describe the major molecular reactions that underlie the defense responses of resistant V. montana to F. oxysporum. These data represent a crucial step toward breeding more pathogen-resistant V. fordii. PMID- 28083009 TI - Increased Sucrose in the Hypocotyls of Radish Sprouts Contributes to Nitrogen Deficiency-Induced Anthocyanin Accumulation. AB - Effects of nitrogen (N) deficiency and sucrose (Suc) addition on regulation of anthocyanin biosynthesis and their relationship were investigated in this study. Radish sprouts subjected to N deficiency had 50% higher anthocyanin accumulation than when grown in Hoagland solution (a nutrient medium with all macronutrients). The contents of endogenous soluble sugars (Suc, fructose, and glucose) in the hypocotyls were also markedly increased by N limitation, with Suc showing the highest increase. Inhibition of carbohydrate biosynthesis by addition of 3-(3,4 dichlorophenyl)-1,1-dimethylurea (DCMU) also eliminated N deficiency-induced anthocyanin accumulation. The latter was further supported by the expression of anthocyanin biosynthesis related genes and decreased activities of nitrate reductase in the presence of Suc. Together our results indicate that N deficiency induced anthocyanin accumulation was, at least partly, dependent on the increase of the soluble sugar, especially Suc. This work is the first comprehensive study on relationship between N deficiency and sugar content on anthocyanin accumulation in the hypocotyls of radish sprouts. PMID- 28083010 TI - Molecular Cloning and Functional Analysis of a Na+-Insensitive K+ Transporter of Capsicum chinense Jacq. AB - High-affinity K+ (HAK) transporters are encoded by a large family of genes and are ubiquitous in the plant kingdom. These HAK-type transporters participate in low- and high-affinity potassium (K+) uptake and are crucial for the maintenance of K+ homeostasis under hostile conditions. In this study, the full-length cDNA of CcHAK1 gene was isolated from roots of the habanero pepper (Capsicum chinense). CcHAK1 expression was positively regulated by K+ starvation in roots and was not inhibited in the presence of NaCl. Phylogenetic analysis placed the CcHAK1 transporter in group I of the HAK K+ transporters, showing that it is closely related to Capsicum annuum CaHAK1 and Solanum lycopersicum LeHAK5. Characterization of the protein in a yeast mutant deficient in high-affinity K+ uptake (WDelta3) suggested that CcHAK1 function is associated with high-affinity K+ uptake, with Km and Vmax for Rb of 50 MUM and 0.52 nmol mg-1 min-1, respectively. K+ uptake in yeast expressing the CcHAK1 transporter was inhibited by millimolar concentrations of the cations ammonium ([Formula: see text]) and cesium (Cs+) but not by sodium (Na+). The results presented in this study suggest that the CcHAK1 transporter may contribute to the maintenance of K+ homeostasis in root cells in C. chinense plants undergoing K+-deficiency and salt stress. PMID- 28083011 TI - Non-destructive Phenotyping of Lettuce Plants in Early Stages of Development with Optical Sensors. AB - Rapid development of plants is important for the production of 'baby-leaf' lettuce that is harvested when plants reach the four- to eight-leaf stage of growth. However, environmental factors, such as high or low temperature, or elevated concentrations of salt, inhibit lettuce growth. Therefore, non destructive evaluations of plants can provide valuable information to breeders and growers. The objective of the present study was to test the feasibility of using non-destructive phenotyping with optical sensors for the evaluations of lettuce plants in early stages of development. We performed the series of experiments to determine if hyperspectral imaging and chlorophyll fluorescence imaging can determine phenotypic changes manifested on lettuce plants subjected to the extreme temperature and salinity stress treatments. Our results indicate that top view optical sensors alone can accurately determine plant size to approximately 7 g fresh weight. Hyperspectral imaging analysis was able to detect changes in the total chlorophyll (RCC) and anthocyanin (RAC) content, while chlorophyll fluorescence imaging revealed photoinhibition and reduction of plant growth caused by the extreme growing temperatures (3 and 39 degrees C) and salinity (100 mM NaCl). Though no significant correlation was found between Fv/Fm and decrease in plant growth due to stress when comparisons were made across multiple accessions, our results indicate that lettuce plants have a high adaptability to both low (3 degrees C) and high (39 degrees C) temperatures, with no permanent damage to photosynthetic apparatus and fast recovery of plants after moving them to the optimal (21 degrees C) temperature. We have also detected a strong relationship between visual rating of the green- and red-leaf color intensity and RCC and RAC, respectively. Differences in RAC among accessions suggest that the selection for intense red color may be easier to perform at somewhat lower than the optimal temperature. This study serves as a proof of concept that optical sensors can be successfully used as tools for breeders when evaluating young lettuce plants. Moreover, we were able to identify the locus for light green leaf color (qLG4), and position this locus on the molecular linkage map of lettuce, which shows that these techniques have sufficient resolution to be used in a genetic context in lettuce. PMID- 28083012 TI - Phylogenomics and Plastome Evolution of Tropical Forest Grasses (Leptaspis, Streptochaeta: Poaceae). AB - Studies of complete plastomes have proven informative for our understanding of the molecular evolution and phylogenomics of grasses. In this study, a plastome phylogenomic analysis sampled species from lineages of deeply diverging grasses including Streptochaeta spicata (Anomochlooideae), Leptaspis banksii, and L. zeylanica (both Pharoideae). Plastomes from next generation sequences for three species were assembled by de novo methods. The unambiguously aligned coding and non-coding sequences of the entire plastomes were aligned with those from 43 other grasses and the outgroup Joinvillea ascendens. Outgroup sampling of grasses has previously posed a challenge for plastome phylogenomic studies because of major rearrangements of the plastome. Here, over 81,000 bases of homologous sequence were aligned for phylogenomic and divergence estimation analyses. Rare genomic changes, including persistently long psiycf1 and psiycf2 loci, the loss of the rpoC1 intron, and a 21 base tandem repeat insert in the coding sequence for rps19 defined branch points in the grass phylogeny. Marked differences were seen in the topologies inferred from the complete plastome and two gene matrices, and mean maximum likelihood support values for the former were 10% higher. In the full plastome phylogenomic analyses, the two species of Anomochlooideae were monophyletic. Leptaspis and Pharus were found to be reciprocally monophyletic, with the estimated divergence of two Leptaspis species preceding those of Pharus by over 14 Ma, consistent with historical biogeography. Our estimates for deep divergences among grasses were older than previous such estimates, likely influenced by more complete taxonomic and molecular sampling and the use of recently available or previously unused fossil calibration points. PMID- 28083013 TI - OsSGL, a Novel DUF1645 Domain-Containing Protein, Confers Enhanced Drought Tolerance in Transgenic Rice and Arabidopsis. AB - Drought is a major environmental factor that limits plant growth and crop productivity. Genetic engineering is an effective approach to improve drought tolerance in various crops, including rice (Oryza sativa). Functional characterization of relevant genes is a prerequisite when identifying candidates for such improvements. We investigated OsSGL (Oryza sativa Stress tolerance and Grain Length), a novel DUF1645 domain-containing protein from rice. OsSGL was up regulated by multiple stresses and localized to the nucleus. Transgenic plants over-expressing or hetero-expressing OsSGL conferred significantly improved drought tolerance in transgenic rice and Arabidopsis thaliana, respectively. The overexpressing plants accumulated higher levels of proline and soluble sugars but lower malondialdehyde (MDA) contents under osmotic stress. Our RNA-sequencing data demonstrated that several stress-responsive genes were significantly altered in transgenic rice plants. We unexpectedly observed that those overexpressing rice plants also had extensive root systems, perhaps due to the altered transcript levels of auxin- and cytokinin-associated genes. These results suggest that the mechanism by which OsSGL confers enhanced drought tolerance is due to the modulated expression of stress-responsive genes, higher accumulations of osmolytes, and enlarged root systems. PMID- 28083014 TI - Genotyping-by-Sequencing Uncovers the Introgression Alien Segments Associated with Sclerotinia Basal Stalk Rot Resistance from Wild Species-I. Helianthus argophyllus and H. petiolaris. AB - Basal stalk rot (BSR), caused by Sclerotinia sclerotiorum, is a devastating disease in sunflower worldwide. The progress of breeding for Sclerotinia BSR resistance has been hampered due to the lack of effective sources of resistance for cultivated sunflower. Our objective was to transfer BSR resistance from wild annual Helianthus species into cultivated sunflower and identify the introgressed alien segments associated with BSR resistance using a genotyping-by-sequencing (GBS) approach. The initial crosses were made between the nuclear male sterile HA 89 with the BSR resistant plants selected from wild Helianthus argophyllus and H. petiolaris populations in 2009. The selected resistant F1 plants were backcrossed to HA 458 and HA 89, respectively. Early generation evaluations of BSR resistance were conducted in the greenhouse, while the BC2F3 and subsequent generations were evaluated in the inoculated field nurseries. Eight introgression lines; six from H. argophyllus (H.arg 1 to H.arg 6), and two from H. petiolaris (H.pet 1 and H.pet 2), were selected. These lines consistently showed high levels of BSR resistance across seven environments from 2012 to 2015 in North Dakota and Minnesota, USA. The mean BSR disease incidence (DI) for H.arg 1 to H.arg 6, H.pet 1, and H.pet 2 was 3.0, 3.2, 0.8, 7.2, 7.7, 1.9, 2.5, and 4.4%, compared to a mean DI of 36.1% for Cargill 270 (susceptible hybrid), 31.0% for HA 89 (recurrent parent), 19.5% for HA 441 (resistant inbred), and 11.6% for Croplan 305 (resistant hybrid). Genotyping of the highly BSR resistant introgression lines using GBS revealed the presence of the H. argophyllus segments in linkage groups (LGs) 3, 8, 9, 10, and 11 of the sunflower genome, and the H. petiolaris segments only in LG8. The shared polymorphic SNP loci in the introgression lines were detected in LGs 8, 9, 10, and 11, indicating the common introgression regions potentially associated with BSR resistance. Additionally, a downy mildew resistance gene, Pl17 , derived from one of the parents, HA 458, was integrated into five introgression lines. Germplasms combining resistance to Sclerotinia BSR and downy mildew represent a valuable genetic source for sunflower breeding to combat these two destructive diseases. PMID- 28083015 TI - Comparison of Multiple Methods for Determination of FCGR3A/B Genomic Copy Numbers in HapMap Asian Populations with Two Public Databases. AB - Low FCGR3 copy numbers (CNs) has been associated with susceptibility to several systemic autoimmune diseases. However, inconsistent associations were reported and errors caused by shaky methods were suggested to be the major causes. In large scale case control association studies, robust copy number determination method is thus warranted, which was the main focus of the current study. In the present study, FCGR3 CNs of 90 HapMap Asians were firstly checked using four assays including paralog ratio test combined with restriction enzyme digest variant ratio (PRT-REDVR), real-time quantitative (qPCR) using TaqMan assay, real time qPCR using SYBR Green dye and short tenden repeat (STR). To improve the comparison precision reproductively, the results were compared with those from recently released sequencing data from 1000 genomes project as well as whole genome tiling BAC array data. The tendencies of inconsistent samples by these methods were also characterized. Refined in-home TaqMan qPCR assay showed the highest correlation with array-CGH results (r = 0.726, p < 0.001) and the highest concordant rate with 1000 genome sequencing data (FCGR3A 91.76%, FCGR3B 85.88%, and FCGR3 81.18%). For samples with copy number variations, comprehensive analysis of multiple methods was required in order to improve detection accuracy. All these method were prone to detect copy number to be higher than that from direct sequencing. All the four PCR based CN determination methods (qPCR using TaqMan probes or SYBR Green, PRT, STR) were prone to higher estimation errors and thus may lead to artificial associations in large-scale case-control association studies. But different to previous reports, we observed that properly refined TaqMan qPCR assay was not inferior to or even more accurate than PRT when using sequencing data as the reference. PMID- 28083016 TI - Genomic Selection in the Era of Next Generation Sequencing for Complex Traits in Plant Breeding. AB - Genomic selection (GS) is a promising approach exploiting molecular genetic markers to design novel breeding programs and to develop new markers-based models for genetic evaluation. In plant breeding, it provides opportunities to increase genetic gain of complex traits per unit time and cost. The cost-benefit balance was an important consideration for GS to work in crop plants. Availability of genome-wide high-throughput, cost-effective and flexible markers, having low ascertainment bias, suitable for large population size as well for both model and non-model crop species with or without the reference genome sequence was the most important factor for its successful and effective implementation in crop species. These factors were the major limitations to earlier marker systems viz., SSR and array-based, and was unimaginable before the availability of next-generation sequencing (NGS) technologies which have provided novel SNP genotyping platforms especially the genotyping by sequencing. These marker technologies have changed the entire scenario of marker applications and made the use of GS a routine work for crop improvement in both model and non-model crop species. The NGS-based genotyping have increased genomic-estimated breeding value prediction accuracies over other established marker platform in cereals and other crop species, and made the dream of GS true in crop breeding. But to harness the true benefits from GS, these marker technologies will be combined with high-throughput phenotyping for achieving the valuable genetic gain from complex traits. Moreover, the continuous decline in sequencing cost will make the WGS feasible and cost effective for GS in near future. Till that time matures the targeted sequencing seems to be more cost-effective option for large scale marker discovery and GS, particularly in case of large and un-decoded genomes. PMID- 28083018 TI - Causes of short stature in Pakistani children found at an Endocrine Center. AB - BACKGROUND AND OBJECTIVE: Short stature is defined as height below 3rd centile. Causes of short stature can range from familial, endocrine disorders, chronic diseases to chromosomal disorders. Most common cause in literature being idiopathic short stature. Early detection and management of remedial disorders like malnutrition and vitamin D deficiency, Endocrine disorders like growth hormone deficiency & hypothyroidism can lead to attainment of expected height. Pakistani data shows idiopathic short stature as the most common cause of short stature. Our study aimed at detecting causes of short stature in children/adolescents at an Endocrine referral center. METHODS: A retrospective study was conducted at WILCARE Center for Diabetes, Endocrinology & Metabolism, Lahore on 70 well-nourished children/adolescents. The patients had been evaluated clinically, biochemically and radiologically as needed. Biochemical testing included hormonal testing as well to detect endocrine causes. Data was entered and analyzed in SPSS 20.0. RESULTS: Leading cause of short stature in our population was Growth Hormone (GH) deficiency seen in 48 out of 70 (69%) patients. Second most common endocrine abnormality seen in these patients was Vitamin D deficiency [44 out of 70 patients (63%)]. Primary hypothyroidism; pan hypopituitarism & adrenal insufficiency were other endocrine causes. The weight for age was below 3rd percentile in 57 (81%) patients, with no association with other major causes. CONCLUSION: Growth hormone and Vitamin D deficiency constitute one of the major causes of short stature among well-nourished children with short stature in Pakistan. PMID- 28083019 TI - Clinical values of the early detection of serum procalcitonin, C-reactive protein and white blood cells for neonates with infectious diseases. AB - OBJECTIVE: To discuss application values of serum procalcitonin (PCT), C-reactive protein (CRP) and white blood cells (WBC) count in early diagnosis and treatment of neonatal bacterial infectious diseases. METHODS: Clinical data of one hundred and thirty-six newborns with infectious diseases who were admitted into the hospital were retrospectively analyzed. They were divided into bacterial infection group (N=70) and non-bacterial infection group (N=66). Additionally, sixty-six healthy newborns who underwent physical examination in our hospital in the same period were selected as controls. Subjects in the three groups were all detected for serum PCT, CRP and WBC levels. RESULTS: The levels of PCT, CRP and WBC in the bacterial infection group were much higher than those of the non bacterial infection group and the healthy control group, and the differences had statistical significance (P<0.05). The positive rates of PCT, CRP and WBC of the bacterial infection group were higher than those of the non-bacterial infection group (P<0.05); the specificity and sensitivity of the PCT level were obviously higher than those of the CRP and WBC levels in diagnosing bacterial infectious diseases (P<0.05). CONCLUSION: Serum PCR, CRP and WBC levels are of high diagnostic values to neonatal infectious diseases. Compared to WBC and CRP, PCT is more sensitive index in the diagnosis of neonatal infectious diseases. PMID- 28083017 TI - Distribution of Hydrogenases in Cyanobacteria: A Phylum-Wide Genomic Survey. AB - Microbial Molecular hydrogen (H2) cycling plays an important role in several ecological niches. Hydrogenases (H2ases), enzymes involved in H2 metabolism, are of great interest for investigating microbial communities, and producing BioH2. To obtain an overall picture of the genetic ability of Cyanobacteria to produce H2ases, we conducted a phylum wide analysis of the distribution of the genes encoding these enzymes in 130 cyanobacterial genomes. The concomitant presence of the H2ase and genes involved in the maturation process, and that of well conserved catalytic sites in the enzymes were the three minimal criteria used to classify a strain as being able to produce a functional H2ase. The [NiFe] H2ases were found to be the only enzymes present in this phylum. Fifty-five strains were found to be potentially able produce the bidirectional Hox enzyme and 33 to produce the uptake (Hup) enzyme. H2 metabolism in Cyanobacteria has a broad ecological distribution, since only the genomes of strains collected from the open ocean do not possess hox genes. In addition, the presence of H2ase was found to increase in the late branching clades of the phylogenetic tree of the species. Surprisingly, five cyanobacterial genomes were found to possess homologs of oxygen tolerant H2ases belonging to groups 1, 3b, and 3d. Overall, these data show that H2ases are widely distributed, and are therefore probably of great functional importance in Cyanobacteria. The present finding that homologs to oxygen-tolerant H2ases are present in this phylum opens new perspectives for applying the process of photosynthesis in the field of H2 production. PMID- 28083020 TI - Analysis of liver function test abnormalities in kidney transplant recipients: 7 year experience. AB - OBJECTIVE: Immunosuppressive drugs, antimicrobial agents and infectious complications may cause liver function test abnormalities (LFTA) in kidney transplant recipients (KTR). The objectives of this study were to identify the outcome of (LFTA). To identify the risk factors affecting development and severity of hepatotoxicity in KTR. METHODS: We retrospectively evaluated the medical records of KTR. Hepatotoxicity attacks were defined as impairment in liver function tests that was responsive to drug dose reduction or discontinuation, or treatment of specific causes such as infectious complications. RESULTS: One hundred-fifty-six episodes of hepatotoxicity occurred in 107 patients in 281 KTR, with an incidence of 38%. Patients with hepatotoxicity episodes had a high total mortality rate, higher incidence of positive pre-transplant cytomegalovirus (CMV) IgM test, higher creatinine values during the first month post-transplant, underwent additional acute rejection episodes, and received fewer cyclosporin A based ID. Only positive CMV IgM testing was identified as a significant independent risk factor for hepatotoxicity in our multiple analysis. Mycophenolatemofetil (MMF) related hepatotoxicity was the most common cause of drug related LFTA. CONCLUSIONS: Patients with LFTA can have significant complications. Pre-transplant positive CMV IgM tests predispose transplant recipients to the development of LFTA during the post-transplant period. MMF can be a serious hepatotoxic drug. PMID- 28083021 TI - Use of Aspirin and Statin as primary prevention for cardiovascular diseases. AB - OBJECTIVE: To ascertain whether recommendations for the use of Statins and Aspirin as primary prevention in diabetic patients are correctly implemented at our institution. METHODS: This cross-sectional study was conducted between February 2014 and April 2014 at the General Practice Department of King Abdulaziz University Hospital. Three hundred twelve patients were included in the study. Data were collected from the electronic patient medical records for the characteristics of the patients, existing co-morbidities, and results of laboratory investigations. Descriptive statistics were performed for all variables. RESULTS: Of 312 patients, aspirin was indicated for 17.0% but it was not prescribed. It was both indicated and prescribed in 36.2% of the cases. Statin treatment was indicated in 27.2% of the patients but it was not prescribed, while in 63.1% of cases it was indicated and prescribed. CONCLUSION: The proportion of patients who achieved treatment targets at our institution is greater than that reported by other studies, albeit treatment targets are not being met in a significant number of cases. PMID- 28083022 TI - Depression, anxiety and stress among female patients of infertility; A case control study. AB - OBJECTIVES: Infertility, in many ways, is a very distressing condition that can have its impact on social and marital life of a couple. Depression, anxiety and stress associated with infertility may affect treatment and outcomes for such couples. The purpose of this study was to find out prevalence of depression, anxiety and stress among females suffering from infertility. METHODS: One hundred females suffering from infertility as study subjects and 100 females accompanying them as controls were randomly selected from infertility clinic at Arif Memorial Teaching Hospital, Lahore, Pakistan. Females with diagnosed mental health issues and those from couples having male factor infertility were not included. Validated Urdu version of Depression, anxiety, stress scale (DASS) was used for assessment of depression, anxiety and stress scores. Results from both groups were compared and independent sample t-test was used to analyze the results. RESULTS: There was high prevalence of depression, anxiety and stress among females suffering from infertility compared to females in control group (p < 0.05). Level of education did not appear to have any positive effect on these scores. Similarly, results did not appear to change when occupations of infertile females were used for stratified analysis. CONCLUSION: Depression, anxiety and stress are very common among females suffering from infertility. Healthcare professionals should consider psychological counseling, and psychiatric help if required, when they offer fertility treatment for such females. PMID- 28083023 TI - Clinical characteristics and epidermal barrier function of papulopustular rosacea: A comparison study with acne vulgaris. AB - OBJECTIVE: To evaluate the clinical characteristics and epidermal barrier function of papulopustular rosacea by comparing with acne vulgaris. METHODS: Four hundred and sixty-three papulopustular rosacea patients and four hundred and twelve acne vulgaris patients were selected for the study in Xiangya Hospital of Central South University from March 2015 to May 2016. They were analyzed for major facial lesions, self-conscious symptoms and epidermal barrier function. RESULTS: Erythema, burning, dryness and itching presented in papulopustular rosacea patients were significantly higher than that in acne vulgaris patients (P<0.001). The clinical scores of erythema, burning, dryness and itching in papulopustular rosacea patients were significantly higher than those in acne vulgaris patients (P<0.001). The water content of the stratum cornuem and skin surface lipid level were both significantly lower in papulopustular rosacea patients than that of the acne vulgaris patients (P<0.001) and healthy subjects (P<0.001); Water content of the stratum cornuem and skin surface lipid level were higher in acne vulgaris patients in comparison with that of healthy subjects (P>0.05, P<0.001; respectively). Transepidermal water loss was significantly higher in papulopustular rosacea patients than that of acne vulgaris patients and healthy subjects (P<0.001); transepidermal water loss was lower in skin of acne vulgaris patients than that of healthy subjects (P<0.001). CONCLUSION: Erythema, burning, dryness and itching are the characteristics of papulopustular rosacea, which makes it different from acne vulgaris. The epidermal barrier function was damaged in papulopustular rosacea patients while not impaired in that of acne vulgaris patients. PMID- 28083024 TI - Comparison of serum lipid profile in Type-2 Diabetics with and without retinopathy in Pakistani population. AB - OBJECTIVE: To compare serum cholesterol, TG, HDL-C and LDL-C concentrations between type-2 Diabetes mellitus (DM) patients with retinopathy and without retinopathy and to study association between various modifiable risk factors of Diabetic retinopathy (DR). METHODS: The study included 300 patients with type 2 DM; 140 of them were without DR (Group-I) and 160 were with DR (Group-II). Serum total cholesterol, LDL-C, HDL-C, and TG levels were determined. SPSS 17.0 for windows was used for statistical analysis. RESULTS: Overall, mean age of study population was 48.86 +/- 5.62 years. Subjects with DR were older (P < 0.018), had higher fasting plasma glucose (P < 0.01) and higher HbA1c (P <0.01) concentrations compared with those without DR. Analysis of serum cholesterol, LDL C, HDL-C and TG among subgroups of patients with no DR, with NPDR and PDR showed statistically significant difference (p <0.01). There was strong positive correlation of severity of DR with BSF, HbA1c, serum LDL-C, total cholesterol and TG. CONCLUSION: The serum cholesterol, TG, HDL-C and LDL-C concentrations were found to be significantly deranged in patients with DR as compared to those without DR. PMID- 28083025 TI - Can anemia predict perinatal outcomes in different stages of pregnancy? AB - OBJECTIVE: To investigate the effect of anemia on perinatal outcomes as preterm delivery (PTD) and low birth weight (LBW) in the different stages of pregnancy. METHODS: Medical records of 39,587 Turkish pregnant women who delivered between January 2011 and September 2014 were reviewed. Anemia during pregnancy was defined as hemoglobin (Hb)< 11 g/dl, low birth weight was defined as birth weight <2500 gr and PTD was defined as <37 weeks. The pregnant women were divided into three groups (Hb<10 gr/dl, Hb 10-11 gr/dl, Hb>11 gr/dl). Perinatal outcomes were compared between these anemic and non-anemic groups. RESULTS: The anemia prevalence in our study was 25.1%. In the first and second trimester of Hb<10g/dl group LBW ratio was significantly higher (respectively 13.5%, 9.8%, p=0.03; 22.7%, 14.7%, p=0.01). In the second and third trimesters of Hb<10 g/dl group PTD ratio was significantly higher (respectively 29.1%, 19%, p=0.00; 17.7%, 15.4% p=0.02). In the first trimester Hb<10 g/dl group cesarean section rate was significantly higher (respectively 65.2%, 57.6%, p = 0.01). CONCLUSIONS: LBW infants and preterm birth rate was higher in Hb <10 gr/dl group than non-anemic in the first, second and third trimester. Hb <10 gr/dl group had higher cesarean rate in first trimester. The mean birth weight was significantly lower in anemic pregnant women in the second trimester. Preterm birth and cesarean section rate, in the group of anemic throughout pregnancy was higher than those of non-anemic in the whole pregnancy period. PMID- 28083026 TI - Frequency of early remodeling of left ventricle and its comparison between patients with stroke volume >=97 Ml versus patients with stroke volume <97 Ml after aortic valve replacement for severe aortic regurgitation. AB - OBJECTIVES: To evaluate the frequency of early remodeling in patients of severe aortic regurgitation after aortic valve replacement and to see the incidence of early remodeling in patients with stroke volume >97 ml versus < 97 ml before aortic valve replacement. METHOD: This was a prospective comparative study conducted from August 2013 to December 2014 in a tertiary care hospital. Fifty seven (57) patients of isolated chronic aortic regurgitation were included in this study. SPSS v23 was used for data analysis. Independent sample t-test was used for analysis of continuous variables and chi-square test for qualitative variables. RESULTS: Out of fifty seven patients, early remodeling occurred in 34 (59.64%) patients after surgery. The mean pre-operative stroke volume of patient in whom remodeling occurred was 110.3+9.66 ml while mean pre-operative stroke volume of patients who did not undergo remodeling was 86.65+7.63 ml. There were 28 (82.4%) patients with stroke volume >97 ml in whom Remodeling occurred where as in patients with stroke volume <97 ml remodeling occurred only in 6 (17.6%) patients (p value 0.004). There was no in-hospital mortality. CONCLUSION: There is an association between stroke volume and early LV remodeling after Aortic valve replacement. Stroke volume >97 ml is a good predictor of early LV remodeling. PMID- 28083027 TI - Relationship of coping ways and anxiety with Pregnancy Specific-stress. AB - OBJECTIVES: To explore whether coping strategies and general anxiety are associated with pregnancy-specific stress (PSS) and how much of variance of PSS is explained with these variables. METHODS: A cross sectional study was conducted at two teaching hospitals between November 2013 and December 2015. Total 190 pregnant women (60 women at 6-13-weeks of gestation, 60 at 13-26 weeks, and 70 at 27-40 weeks of gestation) completed the study. The participants completed three questionnaires including; Pregnancy experience scale (PES-41), Ways of Coping Questionnaire (WCQ), and State-Trait anxiety inventory (SATI). Pearson coefficients and analysis of regression was done to assess the correlations between variables. RESULTS: Pregnant women who experienced higher mean level of pregnancy specific-stress had significantly higher mean level of occult anxiety, overt anxiety, and total anxiety than women who did not experience PSS. Although there was a positive and significant relationship between intensity of hassles and uplifts and ways of coping, the correlation between PSS and ways of coping was not significant. The results of analysis regression showed that general anxiety during pregnancy predicted 25% of the variance of PSS (F=4.480, beta=0.159). Also, ways of coping predicted 38% of the variance in pregnancy Hassles (F=7.033, beta=0.194). CONCLUSION: The ways of coping predicted the variance of pregnancy hassles, but does not evaluate pregnancy specific-stress. To think about PSS in terms of general anxiety may help to clarify past findings and to guide future research and interventions. PMID- 28083028 TI - 1, 25-dihydroxyvitamin D3, a potential role player in the development of thyroid disorders in schizophrenics. AB - OBJECTIVE: The present study was designed to assess the role of vitamin-D, in the development of autoimmune thyroid dysfunction in newly diagnosed schizophrenics. METHODS: For the present study 100 patients and 100 controls were screened out and studied for their thyroid antibodies, GSH, homocysteine, NOS and vitamin D levels by appropriate protocols to assess the underlying mechanism involved in the schizophrenics susceptible to autoimmune thyroid diseases. RESULTS: The results of the present study depicted that in schizophrenics, levels of cytokines like IL-6 (7.98+/-0.67 pg/ml), TNF-alpha, (40.76+/-6.98 pg/ml), homocysteine (16.98+/-1.09 umol/L), Tg-Ab (30.93+/-3.87 IU/L), TPO-Ab (10.33+/-1.78 IU/L) and TSHr-Ab (3.76+/-0.055 IU/L) increased whereas, those of Vit-D (12.76+/-0.99 pmol/L), NOS (5.99+/-0.87 IU/L), GSH (4.48+/-.965 ug/dl) and NO (16.87+/-3.98 ng/ml) were decreased in the patients as compared to healthy control subjects. CONCLUSION: Vitamin-D in schizophrenia is involved in augmentation of hyperhomocysteinemia, inflammation, oxidative stress and thyroid antibodies, thereby playing a significant role not only in induction of schizophrenic symptoms but may also result in autoimmune thyroid diseases. Thus, earlier detection and rectification of its levels are helpful to limit the miseries of schizophrenia. PMID- 28083029 TI - A prospective randomized comparison of early embryo cleavage kinetics between two media culture systems. AB - OBJECTIVE: To investigate whether early embryo cleavage kinetics were affected by type of culture media. METHODS: In this prospective sibling-split study, 620 oocytes from 37 patients were randomly allocated into two groups: Cook group and Vitrolife group. Oocytes/embryos in Cook group, would be cultured with Cook sequential culture medium, while oocytes/embryos in Vitrolife group, would be cultured with Vitrolife sequential culture medium. Time-lapse imaging technology was used to calculate exact timing of early embryo cleavage events which included time to 2PN breakdown, cleavage to 2-, 3-, 4-, 5- cell and the time duration in the 2-,3-cell stage. Then these timing of early embryo cleavage events were compared between Cook group and Vitrolife group. Moreover, fertilization rate, cleavage rate, high quality embryo rate, usable blastocyst rate, pregnancy rate and implantation rate of these two groups were also analyzed. RESULTS: The results showed there were no differences in all timing of early embryo cleavage events between the two groups. In addition, the two groups were similar in fertilization rate (Cook 71.0% vs. Vitrolife 71.3%, P>0.05), cleavage rate (Cook 98.1% vs. Vitrolife 98.2%, P>0.05), high quality embryo rate (Cook 52.1% vs. Vitrolife 52.7%, P>0.05), usable blastocyst rate (Cook 29.7% vs. Vitrolife 28.0%, P>0.05), pregnancy rate (Cook 46.7% VS. Vitrolife 50.0%, P>0.05) and implantation rate (Cook 30.3% VS. Vitrolife 29.0%, P>0.05). CONCLUSIONS: Morphokinetics used for embryo selection are not affected by the two different culture media. PMID- 28083030 TI - KCNQ1 rs2237895 polymorphism is associated with Gestational Diabetes in Pakistani Women. AB - BACKGROUND AND OBJECTIVE: Genetic studies on gestational diabetes (GDM) are relatively scarce; moreover, limited data is available for KCNQ1 polymorphism in Pakistani pregnant women. We aimed to determine the frequency of KCNQ1 rs2237895 in GDM and normal pregnant controls and its association with GDM-related phenotypes. METHODS: A total of 637 pregnant females (429 controls and 208 cases) in their second trimester were classified according to the International Association of the Diabetes and Pregnancy Study criteria in this study. Their blood samples were genotyped for KCNQ1 SNP rs2237895 using PCR-RFLP method and sequencing. Fasting and two hour-post glucose load blood levels, serum HbA1c, insulin, and anthropometric assessment was performed.: Pearson's Chi Square test, Mann- Whitney U test, and regression analyses were performed. A p-value of <0.05 was considered significant. RESULTS: The variant genotyped was in Hardy-Weinberg equilibrium (p>0.05). The rs2237895 showed an association with GDM (OR 2.281; 1.388-3.746: p <0.001) and remained significant after multiple adjustments for age and body mass index (OR 2.068; 1.430-2.997: p=0.005). The C allele showed positive association with insulin level, and HOMA-IR in study subjects. CONCLUSIONS: This study identifies that KCNQ1 rs2237895 polymorphisms might be associated with risk of GDM in Pakistani population and that it is related to higher glucose levels and insulin resistance. Further large scale studies are required to consolidate on the functional aspect of this polymorphism. PMID- 28083031 TI - Outcome after surgical repair of partial anomalous pulmonary venous connection. AB - OBJECTIVE: To review the operative results of 55 cases of partial anomalous pulmonary venous connection (PAPVC). METHODS: This retrospective case series of 55 cases of PAPVC operated from January 2011 to June 2016 at CPE Institute of cardiology, Multan. Baseline characteristics of patients, their operative findings and results were retrieved from the hospital record. RESULTS: Operation for PAPVC was performed in 55 patients. Patient's age varied from 3-28 years (mean 12.56+/-7.49), their weight was 9-62 kg mean (25.61+/-16.28). There were 41(74.5%) males and 14(25.5%) females. 49(89.0%) patients had right sided PAPVC associated with ASD moreover 3(5.4%) cases had right pulmonary vein draining into right atrium. While there was only one case having left sided PAPVC (1.8%) and two cases (3.6%) of bilateral PAPVC (4%). Reassuringly, there was not a single mortality. However, one patient developed junctional rhythum, which was successfully controlled on amiodarone. SVC obstruction having 6mmHg gradient was observed in one case however patient is doing well and is on follow up since 9 months. CONCLUSION: Surgical correction of PAPVC generally carries highly reproducible results with low morbidity. PMID- 28083032 TI - Similarities and variances in perception of professionalism among Saudi and Egyptian Medical Students. AB - BACKGROUND & OBJECTIVE: Professionalism has a number of culturally specific elements, therefore, it is imperative to identify areas of congruence and variations in the behaviors in which professionalism is understood in different countries. This study aimed to explore and compare the recommendation of sanctions by medical students of College of Medicine, King Saud University (KSU), Riyadh, Saudi Arabia and students from three medical colleges in Egypt. METHODS: The responses were recorded using an anonymous, self-administered survey " Dundee Polyprofessionalism Inventory I: Academic Integrity". In the study 750 medical students of College of Medicine, KSU, Riyadh were invited and a questionnaire was electronically sent. They rated the importance of professionalism lapses by choosing from a hierarchical menu of sanctions for first time lapses with no justifying circumstances. These responses were compared with published data from 219 students from three medical schools in Egypt. RESULTS: We found variance for 23 (76.66%) behaviors such as "physically assaulting a university employee or student" and "plagiarizing work from a fellow student or publications/internet". We also found similarities for 7 (23.33%) behaviors including "lack of punctuality for classes" and drinking alcohol over lunch and interviewing a patient in the afternoon", when comparing the median recommended sanctions from medical students in Saudi Arabia and Egypt. CONCLUSION: There are more variances than congruence regarding perceptions of professionalism between the two cohorts. The students at KSU were also found to recommend the sanction of "ignore" for a behavior, a response, which otherwise was absent from Egyptian cohort. PMID- 28083033 TI - Vildagliptin ameliorates biochemical, metabolic and fatty changes associated with non alcoholic fatty liver disease. AB - OBJECTIVE: To determine the effect of Vildagliptin in non-alcoholic, fatty liver disease patients with dyslipidemia. METHODS: A randomized placebo controlled trial was conducted at outpatient clinic of Medical Unit-I of Sheikh Zayed Medical College/Hospital, Rahim Yar Khan, in which fifty eight patients of NAFLD with dyslipidemia were divided in to two, case and control groups. The case group was given tablet Vildagliptin 50mg twice a day for twelve weeks and control group was given placebo in same way. Body weight, body mass index (BMI), lipid profile, liver enzymes and ultrasound finding of fatty liver were assayed before and after treatment. RESULTS: After 12 weeks treatment of vildagliptin there was significant improvement in following parameters. Body weight and BMI decreased significantly from 88 +/- 11 to79 +/- 12 kg (p0.036) and 30+/-4to 27+/-5 kg/m2 (p 0.005) respectively. Notable reduction in the value of TC, TG and LDL-C (TC:252+/ 24 to 220+/-20mg/dl (p 0.031); TG: 190+/-24 to115+/-22 mg/dl (p 0.005); LDL-C 160+/-15 to 145+/-13mg/dl (p 0.004). HDL-C level increased significantly from 29+/-5to45+/-4 mg/dl (p 0.001). There was remarkable reduction in aminotransferases level (ALT: 78+/- 17 to 48+/-14IU/L (p 0.036). AST: 63.3+/-13 to41+/-11IU/L (p 0.002). There was overall 65.5% improvement in fatty liver grading on ultrasound with vildagliptin while non significant effects were seen in placebo group in all of the above parameters. CONCLUSION: Vildagliptin exhibited beneficial effects in non-alcoholic fatty liver disease, Non-diabetic patients with dyslipidemia. PMID- 28083034 TI - Increased heart rate on first day in Intensive Care Unit is associated with increased mortality. AB - OBJECTIVE: To investigate the association of maximum HR during the first day of intensive care unit (ICU) and mortality. METHODS: Data of 850 patients over 45 years of age, who were hospitalized in ICU, was retrospectively analyzed. They were divided into two groups; Group-I, patients with maximum HR<100/min Group-II, patients with maximum HR>=100/min on first day. The groups were compared regarding age, sex, use of beta-blockers, use of inotropic and vasopressor drugs, hemodynamic parameters, anemia, mechanical ventilation, length of hospitalization (ICU and total), mortality (ICU and total), and CHARLSON & APACHE-II scores. RESULTS: The mean age of patients was 63+/-12 years and 86% were after non cardiac surgery. Maximum HR was 83+/-11 in Group-I and 115+/-14/min in Group-II (p=0.002). Group-II patients had more frequent vasopressor and inotropic drugs usage, (p<0.001), anemia, mechanical ventilation (p<0.005), higher CHARLSON & APACHE-II scores, stayed longer in ICU and hospital, and had higher ICU and hospital mortality compared to group-I (p<0.05). APACHE-II scores and maximum HR<100/min were independent variables predicting ICU mortality in multivariate logistic regression analysis whereas usage of beta-blockers was not. CONCLUSIONS: Our study showed that maximum HR less than100/minute during the first day of ICU is associated with decreased mortality in Intensive Care Unit. PMID- 28083036 TI - Clinical value of color doppler ultrasound in prenatal diagnosis of umbilical cord entry abnormity. AB - OBJECTIVE: To study the clinical value of prenatal diagnosis of umbilical cord entry abnormity (UCEA) by means of color Doppler ultrasound (CDUS). METHODS: Clinical data of sixty-four cases with confirmed umbilical cord entry abnormity were reviewed and the specific UCEA conditions and the outcomes of perinatal infants were analyzed. RESULTS: Detection rates of marginal umbilical cord entry abnormity and velamentous umbilical cord entry abnormity by means of CDUS at second trimester were 94.1% and 93.8% respecdtively much higher than 80.0% and 68.8% which were those of third trimester. Discrepancy had statistical significance (P<0.05). True positive rate of prenatal diagnosis of UCEA by means of CDUS was 85.9% (55/64), and false negative rate was 14.1% (9/64). Among sixty four patients with UCEA, seventeen patients (26.6%) underwent selective caesarean delivery; twenty-six patients (35.9%) underwent emergency caesarean delivery and twenty-four patients (37.5%) had normal delivery. CONCLUSION: Prenatal diagnosis of UCEA by means of CDUS is intuitive and accurate. It provides an evidence for determination of the best time to diagnose UCEA, and also offers a proper advice for pregnant women about delivery mode to ensure the fetus survival rate, which is clinically valuable. PMID- 28083035 TI - Chemotherapy alone or combined chemotherapy and involved field radiotherapy in favorable risk early-stage classical Hodgkin lymphoma-a 10 years experience. AB - OBJECTIVE: To determine the outcome of patients with early-stage (stage I-II) favorable risk classical Hodgkin lymphoma treated with chemotherapy alone or combined modality treatment (CMT) utilizing chemotherapy and involved field radiotherapy. METHODS: This retrospective study was done at Department of Medical oncology, Shaukat Khanum Memorial Cancer Hospital & Research Centre, Lahore, Pakistan from January 2004 to December 2013. RESULTS: There were 101 patients, with male predominance (71.3%). Mean age was 34 years. Sixty three (62.4%) patients received CMT and 38 (37.6%) patients had chemotherapy alone. Ninety eight percent patients had ABVD chemotherapy. Dose of radiotherapy ranged from 20 to 36 gray. Difference between baseline characteristics and major toxicities among the two groups was insignificant. Patients treated with CMT had better overall survival compared to chemotherapy alone: 100% versus 91% at five years and 96% versus 81% at 10 years, respectively (p=0.03). Progression free survival was also better with CMT against chemotherapy alone at five years (98% versus 81%) and 10 years (82% versus 71%) (p=0.01). CONCLUSION: Favorable risk classical Hodgkin lymphoma patients had better overall survival and progression free survival when treated with CMT against chemotherapy alone. PMID- 28083037 TI - Adipokine Serum visfatin level in pregnancy induced hypertension and uncomplicated pregnancy. AB - BACKGROUND AND OBJECTIVES: Hypertensive disorder in pregnancy is the significant disease that badly affects the maternal and fetal prognosis and lead to higher mortality and morbidity in the prenatal period. Visfatin, potentially a new adipokine has emerged having high contribution in pathogenesis of pre-eclampsia. The objective of the study was to find the level of Visfatin in pregnancy induced hypertension and normal pregnant women. METHODS: This study was carried out in tertiary care hospitals, Peshawar from March-October 2014. A total of 234 pregnant women (gestational age >20 weeks) were included in the study with distribution as Preeclampsia (PE=86), Eclampsia (E=74) and control (N=74). Blood was taken for measuring Visfatin level by Enzyme Linked Immunosorbent Assay (ELISA) technique. SPSS version 19 was used for statistical analysis. Student's t test was performed to evaluate the mean differences in patients and control. RESULTS: Serum level of visfatin was significantly higher in pregnancy induced hypertension when compared with control (P value<0.001).: Comparisons of mean value of visfatin with age group of 21-40 years, body mass index (BMI), primary parous and parity 2-4, gestational age of >36 weeks and both systolic and diastolic blood pressure were highly significant in pregnancy induced hypertension when compared with control (p value<0.001). CONCLUSION: Pregnancy induced hypertensive women showed increased level of serum Visfatin than normal pregnant women. PMID- 28083038 TI - Analyzing musculoskeletal system discomforts and risk factors in computer-using office workers. AB - OBJECTIVE: This study analyzed the prevalence of work-related computer-user musculoskeletal discomforts, personal and computer-related risk factors. METHODS: A cross-sectional survey on 395 office workers was made between July-September 2015. Musculoskeletal symptoms and risk factors were evaluated for participants' demographics and job attributes on the 21-item questionnaire and the Turkish Cornell Musculoskeletal Discomfort Questionnaire. RESULTS: Participants reported musculoskeletal symptoms in the neck (67.85%), back (66.33%), lower back (59.49%), right shoulder (45.32%) and left shoulder (43.54%) during the past week and work interference was 33.6%, 28.5%, 30.6%, 31.3% and 31.9%, respectively. Musculoskeletal discomfort risks were being male, increasing daily computer usage, feeling computer-usage discomfort, hours working at desk and having knowledge about ergonomic exercises. CONCLUSION: Musculoskeletal symptoms are common in Turkish office workers and indicated the need for more attention to musculoskeletal disorders and designing effective preventive interventions. PMID- 28083039 TI - Effects of Vitamin D supplementation on physical activity of patients with Heart Failure. AB - OBJECTIVE: To see the role of Vitamin D supplementation on physical status of patients suffering from Congestive Heart Failure (dilated cardiomyopathy). METHODS: In this nonrandomized clinical trial, Forty three Patients with dilated cardiomyopathy who were not showing any significant improvements in physical performance on optimal treatment of heart failure were included. Vitamin D (200,000 IU) supplementation on weekly basis for a period of 12 weeks was added to heart failure treatment. And its effect was seen on 6 minutes' walk distance and Pro-BNP levels. SPSS version 19 was used for data analysis. Dependent sample t-test was used to see the significant effect of vitamin D supplementation on pre intervention vitamin D levels, 6MWD and Pro-BNP. Taking p-value <0.05 as significant. RESULTS: On clinical assessment most of the patients were in NYHA class II (65%), the percentages of NYHA Class I, III and IV was 19%, 9% and 7% respectively. The baseline mean vitamin D level of the study group was 16.59+/ 3.54ng/ml and it raised to 31.97+/-3.64ng/ml after 12 weeks of supplementation with vitamin D, p value<0.0005. The mean distance travelled by the study group before the intervention was 806+/-380ft while it increased to 945+/-393ft after the intervention, p value of 0.008. The mean of pro-BNP level of the study group before the intervention was 1024+/-635 while it improved to 159+/-80 after the intervention with a significant p value<0.0005. CONCLUSION: Vitamin D supplementation decreases the severity of HF as reflected by reduction in serum pro-BNP levels and significant increase in six minutes' walk distance. PMID- 28083040 TI - Effects of letrozole in combination with low-dose intramuscular injection of human menopausal gonadotropin on ovulation and pregnancy of 156 patients with polycystic ovary syndrome. AB - OBJECTIVE: To explore the effects of letrozole (LE) in combination with low-dose intramuscular injection of human menopausal gonadotropin (HMG) on the ovulation induction and pregnancy of patients with polycystic ovary syndrome (PCOS). METHODS: A total of 156 patients with PCOS infertility were randomly divided into an LE group, a clomiphene citrate (CC) group and an LE + HMG group (n= 52). LE and CC were orally taken according to the prescribed dosage on the 3rd-5th days of menstruation respectively, and 75 IU HMG was given through intramuscular injection. The ovulation induction parameters and pregnancy outcomes were observed. RESULTS: The number of ovulation cycle of LE + HMG group was significantly higher than that of LE group (chi2=8.451, P<0.001). After injection of human chorionic gonadotropin, both endometrial thickness and number of mature follicles of LE + HMG group were significantly higher than those of other two groups (P<0.001), and the daily estradiol (E2) level was also higher (q=4.531, P<0.05). The pregnancy rate of LE + HMG group was 55.7%, which exceeded those of other two groups (compared to LE group, chi2=4.012, P<0.05). In LE + HMG group, the average medication cycle of clinically pregnant patients was (2.9 +/- 0.3) weeks, which was significantly shorter than those of CC and LE groups (F=17.241, P<0.001). CONCLUSION: The regimen using LE in combination with low-dose intramuscular injection of HMG has satisfactory therapeutic effects on ovulation induction, short medication cycle and high clinical pregnancy rate, which is promising for treating patients with PCOS infertility. PMID- 28083041 TI - Management of Cerebrospinal Fluid Leak following Posterior Cranial Fossa Surgery. AB - OBJECTIVE: Cerebrospinal fluid leakage remains a significant cause of morbidity following posterior fossa surgery, and its treatment remains a difficult problem. The aim of the study was to propose a treatment algorithm for its management. METHODS: A retrospective, single-center study was conducted on 147 patients who underwent elective posterior fossa surgery for a variety of diseases . Patients with post operative CSF leakage had either been treated initially with conservative measures including re-suturing of the wound, with CSF lumbar drainage to be employed in case the CSF leakage didn't stop, or the initial intervention was the institution of CSF lumbar drainage simultaneously with conservative measures. VP (ventriculo-peritoneal) shunt was done in patients with gross hydrocephalus on postoperative CT brain. RESULTS: There were 25 (17%) cases of CSF leakage, including 24 incisional CSF leaks and one case of CSF otorrhea. In eight patients with incisional CSF leakage treated initially with conservative measures including re-suturing of the wound, CSF leakage stopped in only two cases. CSF lumbar drainage instituted later on in six cases with persistent leakage stopped the CSF leakage. In fourteen patients managed initially with re suturing of the wound and concomitant CSF lumbar drainage, CSF leakage settled in all the cases. Two patients with gross hydrocephalus on post operative CT were managed successfully with VP shunt. Re-suturing of the wound with concomitant CSF lumbar drainage was found to be significantly associated (p=0.003) with the stoppage of CSF leakage, and the settlement of meningitis (p= 0.014). CONCLUSION: Incisional CSF leaks after posterior fossa surgery should be managed with re suturing of the wound and concomitant CSF lumbar drainage, instead of an initial trial of conservative therapy alone. PMID- 28083042 TI - Reducing computed tomography radiation dose in diagnosing pulmonary embolism. AB - BACKGROUND AND OBJECTIVE: Computed tomography angiography plays a major role in the diagnosis of pulmonary embolism. Radiation dose associated with it is a major concern; therefore it is important to optimize protocols and techniques to ensure minimum radiation dose. METHODS: The study compares two protocols i. Conventional Timing Bolus CT protocol and Delayed Timing Bolus protocol used to assist suspected pulmonary embolism patients. RESULTS: A significant reduction in the average effective dose (39%) was noticed when using the delayed timing bolus protocol. CONCLUSION: Delayed timing bolus protocol has a good impact on radiation dose without affecting the value of the computed tomography angiography study. PMID- 28083043 TI - Hypocalcemia in jaundiced neonates receiving phototherapy. AB - OBJECTIVE: To determine the frequency of hypocalcemia in term neonates with jaundice receiving phototherapy. METHODS: This was a cross sectional study conducted at Neonatal intensive care unit, National Institute of Child Health, Karachi from 1st January 2014 to 30th December 2014. A total of 123 term neonates with jaundice of either gender managed by phototherapy were enrolled in the study. Gestational age was assessed through modified Ballard scoring. Duration of phototherapy was recorded. A sample of 3 ml of blood was sent to the laboratory for serum calcium level before initiating phototherapy and after 24 hours of continued phototherapy. All the data were recorded in the preformed proforma. Data was analyzed using SPSS version 19. P value <0.05 was taken as significant. RESULTS: The mean age of the neonates was 8.35+/-6.74 days. Mean gestational age at the time of birth was 39.08+/-1.37 weeks. Mean duration of jaundice was 2.4+/ 1.20 days. Mean duration of phototherapy was 1.74+/-0.98 days. Serum calcium level before and after 24 hours of initiating phototherapy was 8.73+/-0.68 mg/dl and 7.47+/-0.82mg/dl respectively Frequency of hypocalcemia in term jaundiced neonates receiving phototherapy were observed in 22.76% (28/123). CONCLUSIONS: The frequency of hypocalcemia is significant in the jaundiced neonates treated with phototherapy. One needs to be vigilant in dealing neonates in this context while serial monitoring for hypocalcemia and its complications should be considered in institutional policy and research priority. PMID- 28083044 TI - Serum C-reactive protein level in COPD patients stratified according to GOLD 2011 grading classification. AB - BACKGROUND AND OBJECTIVE: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 grading classification has been used to evaluate the severity of patients with chronic obstructive pulmonary disease (COPD). However, little is known about the relationship between the systemic inflammation and this classification. We aimed to study the relationship between serum CRP and the components of the GOLD 2011 grading classification. METHODS: C-reactive protein (CRP) levels were measured in 391 clinically stable COPD patients and in 50 controls from June 2, 2015 to October 31, 2015 in the First Affiliated Hospital of Xiamen University. The association between CRP levels and the components of the GOLD 2011 grading classification were assessed. RESULTS: Correlation was found with the following variables: GOLD 2011 group (0.240), age (0.227), pack year (0.136), forced expiratory volume in one second % predicted (FEV1%; -0.267), forced vital capacity % predicted (-0.210), number of acute exacerbations in the past year (0.265), number of hospitalized exacerbations in the past year (0.165), British medical Research Council dyspnoea scale (0.121), COPD assessment test score (CAT, 0.233). Using multivariate analysis, FEV1% and CAT score manifested the strongest negative association with CRP levels. CONCLUSIONS: CRP levels differ in COPD patients among groups A-D based on GOLD 2011 grading classification. CRP levels are associated with several important clinical variables, of which FEV1% and CAT score manifested the strongest negative correlation. PMID- 28083045 TI - Exploring the usefulness of interviewers' training before and after Multiple Mini Interviews (MMI) for undergraduate medical students' selection: Was it really helpful? AB - OBJECTIVE: To compare the change in interviewers' perception of Multiple Mini Interviews (MMI) after MMI training and after actual MMI experience. METHODS: Six sessions were conducted during two weeks (October 26, 2015- to November 6, 2015) to a total of 87 faculty members. The evaluation dealt with 13 items questionnaire for representation of assessors' perception on 5 point rating scale. Assessors rated their perceptions to complete an anonymised questionnaire about rationale behind MMI, the process of MMI, and the use of scoring criteria (rubrics). In addition, assessors were also asked to rate their level of satisfaction on MMI process after training and after interviews. Wilcoxon Signed Ranks Test (two-tailed) was used to compare participant's pre- and post-interview ratings. RESULTS: With 81.6% response rate, the positive views of assessors about the MMI selection process and the use of scoring criteria (Rubric) to assess the candidate are not altered after experiencing a MMI selection day (p> 0.001). Assessors (87%) would prefer to be involved in the process of MMI in future. CONCLUSION: The outstanding consistency of assessors' ratings before and after interview concluded that MMI training sessions were helpful in improving knowledge and skills about MMI process and candidates' assessment criteria (rubrics). PMID- 28083046 TI - The effects of serum leptin levels on thrombocyte aggregation in peritoneal dialysis patients. AB - OBJECTIVE: Serum leptin levels of chronic kidney disease patients have been detected higher than normal population. The aim of this study was to investigate the effects of serum leptin levels on thrombocyte aggregation in peritoneal dialysis patients. METHODS: Fourty three peritoneal dialysis patients were included in the study. Thrombocyte aggregation was calculated from the whole blood subsequently the effects of different concentrations of human recombinant leptin on thrombocyte aggregations were investigated. Four test cells were used for this process. While leptin was not added into the first test cell, increasing amounts of leptin was added into the second, third and fourth test cells to attain the concentrations of 25, 50 and 100 ng/ml respectively. RESULTS: Thrombocyte aggregation was inhibited by recombinant leptin in peritoneal dialysis patients. Thrombocyte aggregation mean values were found statistically significantly higher in first test cell when compared to leptin groups in peritoneal dialysis patients. For leptin groups we could not find any statistically significant differences for thrombocyte aggregation mean values between any of the groups. CONCLUSION: Further studies with larger number of peritoneal dialysis patients are required to prove the action of leptin on thrombocyte aggregation. PMID- 28083047 TI - A way forward for teaching and learning of Physiology: Students' perception of the effectiveness of teaching methodologies. AB - OBJECTIVE: To compare the perception of medical students on the usefulness of the interactive lectures, case-based lectures, and structured interactive sessions (SIS) in teaching and learning of Physiology. METHODS: A cross-sectional study was carried out from January to December 2012 at Bahria University Medical & Dental College, Karachi, which had qualitative and quantitative aspects, assessed by self- reported questionnaire and focused group discussion (FGD). The questionnaire was distributed to 100 medical students after completion of first year of teaching of MBBS Physiology. The data was analyzed using SPSS version 15. Differences were considered significant at p-values <0.05 after application of Friedman test. Responses of FGD were analyzed. RESULTS: All the teaching methodologies helped in understanding of precise learning objectives. The comprehension of structure and functions with understanding of difficult concepts was made best possible by SIS (p=0.04, p<0.01). SIS enabled adult learning, self directed learning, peer learning and critical reasoning more than the other teaching strategies (p< 0.01). CONCLUSION: SIS involved students who used reasoning skills and power of discussion in a group to comprehend difficult concepts for better understanding of Physiology as compared to interactive and case-based lectures. PMID- 28083048 TI - Fracture resistance of endodontically treated teeth restored with Zirconia filler containing composite core material and fiber posts. AB - OBJECTIVES: To assess the fracture resistance of endodontically treated teeth with a novel Zirconia (Zr) nano-particle filler containing bulk fill resin composite. METHODS: Forty-five freshly extracted maxillary central incisors were endodontically treated using conventional step back preparation and warm lateral condensation filling. Post space preparation was performed using drills compatible for fiber posts (Rely X Fiber Post) on all teeth (n=45), and posts were cemented using self etch resin cement (Rely X Unicem). Samples were equally divided into three groups (n=15) based on the type of core materials, ZirconCore (ZC) MulticCore Flow (MC) and Luxacore Dual (LC). All specimens were mounted in acrylic resin and loads were applied (Universal testing machine) at 130 degrees to the long axis of teeth, at a crosshead speed of 0.5 mm/min until failure. The loads and the site at which the failures occurred were recorded. Data obtained was tabulated and analyzed using a statistical program. The means and standard deviations were compared using ANOVA and Multiple comparisons test. RESULTS: The lowest and highest failure loads were shown by groups LC (18.741+/-3.02) and MC (25.16+/-3.30) respectively. Group LC (18.741+/-3.02) showed significantly lower failure loads compared to groups ZC (23.02+/-4.21) and MC (25.16+/-3.30) (p<0.01). However groups ZC (23.02+/-4.21) and MC (25.16+/-3.30) showed comparable failure loads (p=0.23). CONCLUSIONS: Fracture resistance of endodontically treated teeth restored with Zr filler containing bulk fill composite cores was comparable to teeth restored with conventional Zr free bulk fill composites. Zr filled bulk fill composites are recommended for restoration of endodontically treated teeth as they show comparable fracture resistance to conventional composite materials with less catastrophic failures. PMID- 28083049 TI - Urdu translation of the Hamilton Rating Scale for Depression: Results of a validation study. AB - OBJECTIVE: To develop a standardized validated version of the Hamilton Rating Scale for Depression (HAM-D) in Urdu. METHODS: After translation of the HAM-D into the Urdu language following standard guidelines, the final Urdu version (HAM D-U) was administered to 160 depressed outpatients. Inter-item correlation was assessed by calculating Cronbach alpha. Correlation between HAM-D-U scores at baseline and after a 2-week interval was evaluated for test-retest reliability. Moreover, scores of two clinicians on HAM-D-U were compared for inter-rater reliability. For establishing concurrent validity, scores of HAM-D-U and BDI-U were compared by using Spearman correlation coefficient. The study was conducted at Mayo Hospital, Lahore, from May to December 2014. RESULTS: The Cronbach alpha for HAM-D-U was 0.71. Composite scores for HAM-D-U at baseline and after a 2-week interval were also highly correlated with each other (Spearman correlation coefficient 0.83, p-value < 0.01) indicating good test-retest reliability. Composite scores for HAM-D-U and BDI-U were positively correlated with each other (Spearman correlation coefficient 0.85, p < 0.01) indicating good concurrent validity. Scores of two clinicians for HAM-D-U were also positively correlated (Spearman correlation coefficient 0.82, p-value < 0.01) indicated good inter rater reliability. CONCLUSION: The HAM-D-U is a valid and reliable instrument for the assessment of Depression. It shows good inter-rater and test-retest reliability. The HAM-D-U can be a tool either for clinical management or research. PMID- 28083050 TI - The role of serum procalcitonin and C-reactive protein levels in predicting spontaneous bacterial peritonitis in patients with advanced liver cirrhosis. AB - OBJECTIVE: To determine the role of serum procalcitonin (PCT) and C-reactive protein (CRP) in predicting spontaneous bacterial peritonitis (SBP) in patients with advanced liver cirrhosis. METHODS: A total of 88 patients with advanced liver cirrhosis were enrolled for this study, which included 40 cases with SBP and 48 cases with CNNA. Bacterial cultures, ascitic fluid (AF) leukocyte, C reactive protein (CRP) and serum PCT measurements were carried out prior to the use of antibiotics. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic performance of procalcitonin levels. RESULTS: Serum PCT levels in advanced liver cirrhotic patients with SBP were significantly higher than those with CNNA. We used PCT 0.78 ng/mL as optimal cutoff value to diagnose SBP, for which the sensitivity and specificity was 77.5% and 60.4%. The area under the curve (AUC) was 0.706 (95% confidence interval: 0.576-0.798). The PCT level was significantly correlated with the AF WBC count (rs=0.404, P<0.01). However, there was no significant difference between SBP and CNNA patients in serum CRP levels. CONCLUSION: According to our findings, serum PCT levels seem to provide an early diagnostic accuracy in advanced liver cirrhotic patients with SBP. PMID- 28083051 TI - Students' views of mentoring at Bahria University Medical and Dental College. AB - OBJECTIVE: To explore the mentoring program on a subset of Pakistani medical students in a private medical college. METHOD: Total students targeted were 300 MBBS students of 1st Year (group B), 2nd Year (group C) and 3rd Year (group D), of these 256 students filled the self-reported questionnaire. The questionnaire was based on Likert Scale. The statements in the questionnaire are designed in a positive manner so that if the students agree to them the level of satisfaction with the mentoring program was considered significantly good. Open-ended questionnaires were also given so as to have a clearer concept of the students' perception. This study is a mixed method study catering to both quantitative and qualitative domains. RESULTS: The overall results reported that the junior students of group B and group C showed higher satisfaction in being mentored as compared group D (p-value=0.001). All three groups were compared with each other to check the response of every statement by applying Tukey's test. Analysis of the result showed that majority of the students considered mentoring program a beneficial tool for their academic and non-academic lives. The students of all three years have reported that the mentor is mostly available and helps to reconcile internal conflicts. They also confirmed that their mentor keeps records but most of the students have reported that communication via email is limited. CONCLUSION: Majority of students of Bahria University Medical and Dental College are able to carry on with their academic and non-academic routine due to the presence of mentoring. The medical students appreciated the presence of a mentor during thick and thin; they have also accepted that it is due to the presence of this guide that they are able to continue with their difficult studies in these difficult times. PMID- 28083052 TI - Thrombotic thrombocytopenic purpura - analysis of clinical features, laboratory characteristics and therapeutic outcome of 24 patients treated at a Tertiary Care Center in Saudi Arabia. AB - OBJECTIVE: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease. The primary aim was overall response rate (ORR) assessment in the treated patients. METHODS: This retrospective study included 24 patients treated during 2006-2015. TTP patients with microangiopathic hemolysis (MAHA) and thrombocytopenia were included. We analyzed clinical features, laboratory characteristics and treatment outcomes of 24 TTP patients treated at our tertiary care center (KFMC). RESULTS: Twenty-four TTP patients (18 females; 6 males) had a mean age of 33.5+/-13.9 years; 22(91%) had neurologic features, 7(29%) fever, 10(42%) renal impairment; 4(20.83%) cardiac manifestations; 22(91.7%) had triad with additional neurologic abnormalities; only 2(8.2%) had pentad of TTP. Majority (54.16%) had idiopathic TTP. All patients received therapeutic plasma exchange (TPE); 23(95.8%) received adjunctive corticosteroids and 13(54.2%) received rituximab either due to refractoriness to TPE on ~day7, or earlier. Twenty-one out of 24 (87.5%) achieved complete remission (CR) without any subsequent relapse. At 22 months (median, range 1-113), 20 patients (83.3%) are alive at the time of report. Three patients died during acute episode because of sever disease or delayed treatment and one died in CR. CONCLUSION: TPE, steroids and or rituximab was very effective in preventing high risk of mortality and achieving durable CR in 87.5% of patients. More awareness is needed for early diagnosis and early referral to centers with appropriate tertiary care facilities.. PMID- 28083053 TI - Effective role of lady health workers in immunization of children in Pakistan. AB - OBJECTIVE: To determine the association of Lady Health Worker's role with immunization of children in Pakistan. METHODS: Secondary analysis was conducted on data obtained from Pakistan's Demographic and Health Survey. Children who did not receive all doses of vaccines were considered incompletely immunized or vice versa. The association between determinants was assessed by simple and multivariable binary logistic regression. RESULTS: The mothers and fathers had a mean age of 32.7 (SD+8.6) years and 37.9 (SD +10.1) years, respectively. Age of mother greater than 35 (OR=0.93; 95% CI:0.70-1.25); born in Baluchistan (OR=3.47,95% CI:2.21-5.49); rural area dwellers (OR=2.04; 95% CI:1.65-2.51); female gender (OR=1.06; 95% CI:0.87-1.29); birth order (of last born child) greater than 7 (OR=2.21, 95% CI:1.60-3.06); delivered at home (OR=2.20, 95% CI:1.76-2.74); long distance to health care facility (OR=2.66, 95% CI:2.16-3.28); and no LHW visit in last 12 months (OR=1.91, CI:1.48-2.47) were significantly associated with incomplete immunization in bivariate analysis. In final model of multinomial regression analysis the absence of visit by LHW in last 12 months was the most significant factor when all risk factors were analyzed in last model. CONCLUSIONS: This study has concluded that visit of LHW in last 12 months was significantly associated with immunization. PMID- 28083054 TI - Does periodic lung screening of films meets standards? AB - OBJECTIVE: To determine whether the workers' periodic chest x-ray screening techniques in accordance with the quality standards is the responsibility of physicians. Evaluation of differences of interpretations by physicians in different levels of education and the importance of standardization of interpretation. METHODS: Previously taken chest radiographs of 400 workers who are working in a factory producing the glass run channels were evaluated according to technical and quality standards by three observers (pulmonologist, radiologist, pulmonologist assistant). There was a perfect concordance between radiologist and pulmonologist for the underpenetrated films. Whereas there was perfect concordance between pulmonologist and pulmonologist assistant for over penetrated films. RESULTS: Pulmonologist (52%) has interpreted the dose of the films as regular more than other observers (radiologist; 44.3%, pulmonologist assistant; 30.4%). The frequency of interpretation of the films as taken in inspiratory phase by the pulmonologist (81.7%) was less than other observers (radiologist; 92.1%, pulmonologist assistant; 92.6%). The rate of the pulmonologist (53.5%) was higher than the other observers (radiologist; 44.6%, pulmonologist assistant; 41.8%) for the assessment of the positioning of the patients as symmetrical. Pulmonologist assistant (15.3%) was the one who most commonly reported the parenchymal findings (radiologist; 2.2%, pulmonologist; 12.9%). CONCLUSION: It is necessary to reorganize the technical standards and exposure procedures for improving the quality of the chest radiographs. The reappraisal of all interpreters and continuous training of technicians is required. PMID- 28083055 TI - Detection of AmpC beta-lactamase producing bacteria isolated in neonatal sepsis. AB - OBJECTIVE: The objective of this study was to determine the occurrence and antimicrobial profile of AmpC beta-lactamase producing bacteria. METHODS: The study was conducted at The Children's Hospital and The Institute of Child Health Lahore, Pakistan, during September 2011 to June 2012. A total number of 1,914 blood samples of suspected neonatal septicemia were processed. Isolates were identified using Gram's staining, API 20E and API 20NE tests. Gram negative isolates were screened for AmpC beta-lactamase production against ceftazidime, cefotaxime and cefoxitin resistance and confirmed by inhibitor based method. RESULTS: Total number of 54 (8.49%) Gram positive and 582 (91.5%) Gram negative bacteria were identified. Among Gram negative isolates 141 (22%) were AmpC producers and found to be 100% resistant to co-amoxiclav, cefoxitin, ceftazidime, cefotaxime, cefuroxime, cefixime, ceftriaxone, cefpodoxime, gentamicin, amikacin and aztreonam. Less resistance was observed against cefepime (30.4%), sulbactam cefoperazone (24.8%), piperacillin-tazobactam (10.6%), ciprofloxacin (20.5%) and meropenem (2.1%). All the isolates were found sensitive to imipenem. The patients harbored AmpC beta-lactamases were on various interventions in which intravenous line was noted among (51.1%), naso-gastric tube (37.6%), ambu bag (8.5%), endotracheal tube (3.5%), ventilator (2.1%) and surgery (0.7%). CONCLUSION: Extensive use of invasive procedures and third generation cephalosporins should be restricted to avoid the emergence of AmpC beta-lactamases in neonates. PMID- 28083056 TI - Early nasogastric feeding versus parenteral nutrition in severe acute pancreatitis: A retrospective study. AB - OBJECTIVE: To compare the efficacy and safety of early nasogastric enteral nutrition (EN) with total parenteral nutrition (TPN) in patients with severe acute pancreatitis (SAP). METHODS: From July 2008 to July 2014,185 patients with SAP admitted to our centre were enrolled in this retrospective study. They were divided into EN group (n=89) and TPN group (n=96) based on the nutrition support modes. Patients in EN group received nasogastric EN support, while patients in TPN group received TPN support within 72 hours of disease onset. The medical records were reviewed and clinical factors were retrospectively analyzed. RESULTS: There were no significant differences in baseline characteristics between two groups. EN group had significantly lower incidence of pancreatic infections (P=0.0333) and extrapancreatic infections (P=0.0431). Significantly shorter hospital stay (P=0.0355) and intensive-care stay (P=0.0313) were found in EN group. TPN group was found to have significantly greater incidence of multiple organ dysfunction syndrome (MODS) (P=0.0338) and mortality (P=0.0382). Moreover, the incidence of hyperglycemia was significantly higher in TPN group (P=0.0454). CONCLUSIONS: Early nasogastric EN was feasible and significantly decreased the incidence of infectious complications as well as the frequency of MODS and mortality caused by SAP. PMID- 28083057 TI - Effects of Diet and Metformin on placental morphology in Gestational Diabetes Mellitus. AB - OBJECTIVE: To evaluate the effects of diet control and Metformin on placental morphology in gestational diabetes mellitus (GDM). METHODS: After written informed consent 62 GDMs were enrolled. According to WHO criteria, 30 cases of GDMs with blood sugar level <130 mg/dl, were assigned Group B (2000-2500Kcal/day and 30 minute walk thrice weekly were kept on diet control and 32 cases of GDM with blood sugar level >130 mg/dl, assigned Group C were kept on diet with tablet Metformin,(500mg TDS) Finally 25 normal pregnant females were kept in Group A as control. After delivery placentae were preserved and evaluated for morphology. RESULTS: Heavy placentae with abundant villous immaturity, chorangiosis and syncytial knots in group B and fibrinoid necrosis and calcification in group C were seen. In group B versus A placental and cord width while in Group C versus A only cord width in gross morphology showed significant results. In group B versus A villous immaturity, chorangiosis, infarction and syncytial knots in light microscopy were present; similarly in B versus C placental width, chorangiosis and syncytial knots showed significant results, while in C versus A results were non-significant. CONCLUSION: Metformin produced beneficial effects on placental morphology being comparable to normal control in contrast to diet group. PMID- 28083058 TI - Frequency of obesity and comorbidities in medical students. AB - OBJECTIVES: To determine the frequency of obesity disorders and their co morbidities in medical students. METHODS: This cross-sectional study was conducted in Faculty of Medicine, Northern Border University, Ar'ar, Saudi Arabia. All medical students who consented to participate were included in the study. Their relevant information was recorded on a structured proforma. Weight and height of the participants were measured using calibrated manual weighing scale and Body mass index (BMI) was calculated. The obtained results were interpreted according to classification of body weight disorders. The participants who turned out to be over-weight and obese were further assessed for hypertension, diabetes mellitus and gallstones. The collected data was analyzed using the Statistical Package for Social Science (SPSS) version 20. RESULTS: A total of 405 students participated in study, age range was 19-25 years. Male were 169 (41.7%) and female students were 236(58.3%). Family history of obesity was present in 34.3%. Out of 405 students, 126 were having BMI between 25 and 45.6, among them 34(8.4%) students were obese and 88 (21.7%) were overweight. Sixty two (15.3%) among them were male and 64 (15.8%) female. Fourteen (11.1%) were hypertensive and 9(7.1%) were having gall stones. CONCLUSION: The frequency of obesity among medical students was 8.4%. Increasing frequency of obesity associated with unhealthy life style needs to be controlled at national level to raise a healthy generation and to reduce burden on health economy. PMID- 28083059 TI - Comparison of retinal nerve fiber layer thickness in patients having pseudo exfoliation syndrome with healthy adults. AB - OBJECTIVE: To compare mean retinal nerve fiber layer (RNFL) thickness in patients having pseudo exfoliation (PXF) with normal age matched controls using spectral domain optical coherence tomography (SD-OCT). METHODS: This was a case control study conducted at Armed Forces Institute of Ophthalmology (AFIO) Rawalpindi from 12 June 2013 to 12 January 2014. Seventy eyes (Group A - 35 patients with PXF and Group B - 35 healthy age matched subjects) of more than 40 years of age were included in the study. Intraocular pressure (IOP) was measured with Goldmann applanation tonometer (GAT) and peripapillary RNFL thickness was measured in four quadrants with SD-OCT (Topcon 3D OCT-1000 Mark II) in all subjects. Data was analyzed using the SPSS version 14. RESULTS: Mean age of group A (PXF patients) was 65.63 +/- 8.47 years and of group B (Healthy subjects) was 64.31 +/- 6.51 years (p = 0.470). Both groups were gender matched with male preponderance (p = 0.673). Mean IOP in each group was 13.80 +/- 2.59 mm Hg, and 13.49 +/- 2.07 mm Hg respectively (p= 0.578). Mean average peripapillary RNFL thickness was 77.46 +/- 12.17 um in group A and 83.96 +/- 10.58 um in group B. Statistically significant differences were detected between two groups for mean average RNFL thickness (p= 0.020) and mean RNFL thickness in inferior quadrant (p=0.014). CONCLUSION: PXF patients with normal IOP and visual fields have thin RNFL as compared to healthy age matched controls. Therefore routine assessment and follow up of PXF patients with OCT may help in early diagnosis of PXF glaucoma. PMID- 28083060 TI - Assessment of Risk Factors of Obesity and Diet on Breast Cancer in Ankara, Turkey. AB - OBJECTIVE: To determine the risk factors of obesity and diet on breast cancer in Ankara, Turkey. METHODS: A case-controlled study was carried out on newly diagnosed 40 breast cancer patients [patient group (PC)] and 40 volunteer individuals [control group (CG)] with no diagnosis of cancer and history of cancer in the family with similar characteristics to the age and gender-matched patient group between March and July 2016. All the individuals were administered a questionnaire by face-to-face interview method. RESULTS: The mean menarche age, age at first birth and menopause age were 13.0+/-1.17, 22.6+/-3.78 and 44.33+/ 2.39 years in PG and 12.3+/-0.95, 21.6+/-2.99, 46.71+/-2.41 years in CG, respectively. The mean BMI values were determined as 28.1+/-6.75 kg/m2 in PG and 30.1+/-6.18 kg/m2 in CG (p>0.05). It was determined that intake of vitamin C and fiber decreases the risk of breast cancer. Also, eating quickly and smoking were risk factors for breast cancer (p<0.05). CONCLUSION: This study indicated that there are relationships between menarche age, menopause age, and age at first birth, eating quickly, smoking and breast cancer. Conversely, there are significant negative relationships between dietary fiber, vitamin C intake and breast cancer. As a result, it can be said that there is a link between breast cancer and lifestyle factors and a reduction in the risk of developing breast cancer can be achieved through changes in diet, one of the lifestyle factors. PMID- 28083061 TI - Etiology and severity of various forms of ocular war injuries in patients presenting at an Army Hospital in Pakistan. AB - OBJECTIVE: To determine the etiology and severity of various forms of ocular war injuries in patients presenting at an Army Hospital in Pakistan. METHODS: This cross sectional study was conducted at the Department of Ophthalmology, Combined Military Hospital, Peshawar over four years period from June 2012 through March 2016, Two hundred ten consecutive soldiers who presented with ocular war injuries were included for analysis after taking written informed consent. A predesigned proforma was used to record patient's demographic details along with the cause, side, type and severity of injury, ocular trauma score was also recorded at presentation. RESULTS: The mean age of the patients was 29.34+/-5.35 years. All of them were males. Left side was more frequently involved (n=126, 60.0%) and the most frequent underlying cause was IED blast injury (n=114, 54.3%). Closed globe injuries were more frequent and were recorded in 120 (57.1%) patients. Upon assigning Ocular Trauma Score, Grade-V (28.6%) injuries were the most frequent followed by Grade-I (25.7%), Grade III (25.7%), Grade II (11.4%) and Grade IV (8.6%). When stratified for the type of injury, OTS Grade I injuries were highest (60.0%) among patients with open globe injuries, hence poorer prognosis, while OTS Grade V injuries were highest (50.0%) among patients with closed globe injuries (p=0.000). CONCLUSION: IED blast injuries are most frequently encountered ocular war injuries often involving soldiers in the age group 20-30 years. These open globe injuries had worst clinical presentation to begin with and poorer prognosis than closed globe injuries. PMID- 28083062 TI - Correlation between bone marrow dose volumes and acute hematological toxicity in postoperative gynecological cancer patients. AB - OBJECTIVE: To identify the association between radiation dose volume and acute hematological toxicity (HT) in postoperative gynecological cancer patients receiving whole pelvic radiotherapy (RT) or intensity-modulated RT (IMRT), a principal component regression model was used to calculate HT. METHODS: Women (n=100) receiving with or without chemotherapy RT were retrospectively analyzed, 52 of whom received chemotherapy (paclitaxel and nedaplatin). The pelvis and lumbar vertebrae, defined as the prolong-pelvic bone marrow, were divided into the (1) combined ilium, ischium and pubis and the (2) lumbar vertebrae and the sacrum. The V5-V40 of subsides was calculated. The complete blood counts were recorded weekly. The principal component analysis was performed on volumes which generated the principal components (PCs), followed by using a logistic regression model. RESULTS: Forty-seven patients presented with grade 2-3 HT during RT. Chemotherapy increased the incidence of HT compared with RT alone (70.21% vs. 29.79%; p=0.001). Fifty-three patients with persistent HT developed more serious HT at an earlier stage of RT. The chemotherapy cycles and three PCs associated with grade 2-3 HT was identified to form the resulting principal logistic regression model. CONCLUSION: A new method to calculate the NTCP was achieved by PCs logistic regression. PMID- 28083063 TI - Prognostic factors of recurrence and neck metastasis in oral carcinomas. AB - OBJECTIVE: To assess the effects of tumor size, proximity to midline and invasion depth of oral cancer of the tongue (TC) on neck metastasis and recurrence. METHODS: In this retrospective observational study, was conducted through a chart review of the 11 male and 9 female patients who underwent surgeries with the diagnosis of tongue squamous cell carcinoma and at least one side neck dissection. We wanted to assess effects of tumor size, proximity to midline, and invasion depth of TC, according to the surgical specimens and pre-operative magnetic resonance imaging, on neck metastasis and recurrence between 2007 and 2014. The study was conducted in a training hospital-based otorhinolaryngology clinic. Statistical analyses were performed to determine possible relationship between such tumor features and tumor recurrence and neck metastasis. RESULTS: Statistically significant relationship were detected between recurrence and the proximity of tumor to midline (p=0.031) and between invasion depth and neck metastasis (p=0.017). No relationship was found between tumor size and recurrence and neck metastasis (p=0.721 and p=0.827, respectively). CONCLUSIONS: Parameters like invasion depth and tumor proximity to midline might provide useful information about prognosis and may help to determine a treatment schedule in patients suffering fdrom cancer of the tongue. The present TNM classification might not be sufficient to provide enough information to determine prognosis and staging adequately in these patients. PMID- 28083064 TI - Knowledge, Attitude and Practice of mothers on acute respiratory infection in children under five years. AB - OBJECTIVE: To assess Knowledge, Attitude and Practices of mothers on ARI (Acute Respiratory Tract Infection) in children less than five years of age. METHODS: This cross-sectional survey was conducted in the Department of Pediatrics, Darul Sehat hospital from 1st December 2014 to 28th February 2015. Mothers(n=335) who were local residents, had at least one child below the age of five years and coming to the hospital for any medical problem along with accompanying women were included. Foreign mothers and/or those having difficulty in perceiving questions were excluded. Language used in the Questionnaire was English which was translated to Urdu for better understanding. Questionnaire was interviewer administered. Researchers and two house physicians took part in questioning the mothers. RESULTS: Total 335 children were studied. Out of 335 children 228(68%) had ARI. Mean age of the children was 20 months +/-17 SD while mean Birth weight was 2.7 kg +/- 1.8 SD. The most common symptom perceived was cough (n=303, 40%), mostly worsening during winter season (n=255,87%), commonest aggravating factor was dust (n=174,81%), most common complication was Pneumonia (n=135, 83%), and most mothers opted for medical practitioner (n=268,89%) for treatment. Self medication was practiced by 192(58%) and paracetamol was frequently used medication (n=117,42%). CONCLUSION: The study reveals good knowledge of mothers on ARI symptoms, worsening environmental conditions, aggravating factors and complications. Their attitude towards ARI was appropriate with early consultation with qualified medical practitioner. Better literacy rate, has a positive influence on the Knowledge, Attitude and Practices of mothers. PMID- 28083065 TI - Publish or Perish mantra in the medical field: A systematic review of the reasons, consequences and remedies. AB - OBJECTIVES: Generally, academic promotions, job retention, job mobility, and professional development of a medical faculty members are judged primarily by the growth in publication outputs. Universities and research institutions are more likely to recruit and promote those academics carrying voluminous resumes with larger number of published articles. This review elaborates the causes and consequences of the pressure to publish and the ways and means to cope with this paradigm. METHODS: In 2015, database of Abstracts of Reviews of Effects, LISTA (EBSCO), Medline and Oxford University Library were searched for the English language full-text articles published during 2000-2015, by using MeSH terms "pressure to publish", "urge to publish", "research ethics", "plagiarism", "article retraction", "medical field". This search was further refined by selecting the articles in terms of relevancy and contents. RESULTS: This research showed that some universities offer generous grants to researchers with a high h index and with more publications in elite journals, which promise an enhanced prospect of citations and elevation in the scientific rankings of the funding institutions. This generates an involuntary obsession to publish with the primary intention to obtain promotions, high scientific rankings, and improved job security. This compelling pressure to publish results in widespread publication of non-significant research with a high index of plagiarism that eventually leads to an increased frequency of retractions. CONCLUSION: Research centers and academic institutions have an obligation to train their academics in sound scientific writing and to apprise them of the publication ethics and the grave consequences of plagiarism and research misconduct. PMID- 28083066 TI - Prognostic significance of B7-H3 expression in patients with colorectal cancer: A meta-analysis. AB - OBJECTIVE: The co-stimulatory molecule B7-H3 plays an important role in prognosis of several malignancies. However, its prognostic value in clinic in patient with colorectal cancer (CRC) is still controversial. This meta-analysis evaluated the relationship between B7-H3 expression and the outcomes of CRC patients. METHODS: PubMed, Google Scholar, Embase, CNKI and Wanfang database were searched for the studies on the relationship between the expression of B7-H3 and prognosis of CRC patients. Pooled odds ratios (ORs) analysis with 95% confidence interval (95% CIs) for lymph node metastasis, 24-month overall survival and 72-month overall survival were performed mainly using Review Manager 5.0. RESULTS: Six articles including 1,202 total CRC cases were included for the meta-analysis. Pooled analysis with fixed-effects model showed that B7-H3 expression had no relationship with lymphatic metastasis in CRC patients (Fixed-effects, OR= 1.18; 95 % CI:0.87-1.61, P=0.28). However, B7-H3 expression was associated with 24 month overall survival (Fixed-effects, OR=0.48, 95% CI:0.32-0.74, P<0.001) and 72 month overall survival (Fixed-effects, OR = 0.61, 95% CI: 0.43-0.85, P< 0.01) in CRC patients. CONCLUSION: The co-stimulatory molecule B7-H3 expression is negatively associated with lymph node metastasis in CRC. However, B7-H3 detection might be a feasible and effective means to predict the prognosis in CRC patients. PMID- 28083067 TI - Clinical Analysis of Five Cases of AIDS-related Non-Hodgkin Lymphoma. AB - OBJECTIVE: Secondary malignancy is a major life-threatening complication facing patients afflicted with acquired immunodeficiency syndrome (AIDS). This study aimed to retrospectively review clinical features and treatment course of five patients with AIDS-associated non-Hodgkin lymphoma (A-NHL) in Jilin Tumor Hospital. METHODS: Five A-NHL patients were retrospectively and consecutively hospitalized at our oncological unit between January 2012 and June 2014. All patients received pre-emptive highly active antiretroviral therapy (HAART) and chemotherapy, and were subsequently followed up at the outpatient clinic. All five patients were male, aged 27-53 years, and afflicted with A-NHL involving upper jaw, right inguinal region, right-side gingiva, mediastinum, or right-side neck. Histology showed diffuse large B-cell lymphoma (n = 3) or plasmablastic lymphoma (n = 2). RESULTS: Two patients achieved complete remission after HAART and chemotherapy, whereas other three patients required a second-line treatment, with two achieving stable disease and one dying within a follow-up period of 0.5 2 years. CONCLUSION: The findings of the present study showed that A-NHL is a disease often diagnosed in the middle-to-late stages, with diverse clinical manifestations and short overall survival. In the cases reviewed in this study, HAART in combination with standard dose or high-dose chemotherapy, HAART and molecular targeted chemotherapy was administered, and these treatments proved to be effective for improving the prognosis of these patients. Moreover, the CD4+ cell count was important for determining the prognosis of patients. PMID- 28083068 TI - Unusual presentation; seeding of tumor after biopsy for hepatocellular carcinoma. AB - Hepatocellular cancer is one of the most common and fatal cancer tumor worldwide. However, the obtained results are questionable in terms of medical treatment of hepatocellular cancer. The muscle, soft tissue and cutaneous metastases of hepatocellular cancer, for instance, are rare and may result from interventional procedures. Seeding of tumor along the biopsy needle upon percutaneous biopsy is a very rare phenomenon. We report a very rare case of a 79 -year- old man, known to be hepatitis C virus carrier with a metastatic tumor in abdominal wall caused by seeding of tumor after three years following a percutaneous biopsy procedure. Even years later, after a biopsy procedure for diagnostic purposes and may be soft tissue metastases. This complication is a very rare condition that should not be ignored but can be observed. The biopsy requirement should be questioned closely and avoided unnecessary biopsy procedures. PMID- 28083069 TI - Oral Hemorrhage in a 3-year-old Boy Caused by Self-Mutilating Behavior. AB - A 3-year-old boy referred for persistent tongue bleeding was diagnosed with a rare self-mutilating disease that had also affected his lip and fingers. He underwent multiple odontectomy and partial glossectomy and continues to undergo behavior therapy and on-demand splints and restraints. He has stopped self-biting and has gained appetite and weight. Lesch-Nyhan Syndrome can cause significant morbidity including self-inflicted oral hemorrhage and emergent measures are not easily decided. The long-term management of its neurobehavioral symptoms is problematic and multidisciplinary, and health providers remain challenged to find the best treatment, prolong lifespan and improve quality of life within their respective contexts. PMID- 28083071 TI - "Gauze Technique" in the Treatment of the Fungus Ball of the Maxillary Sinus: A Technique as Simple as It Is Effective. AB - Fungus ball of maxillary sinus generally affects immunocompetent and nonatopic subjects. Although endoscopic removal is the current gold standard treatment, removal is at times difficult due to an accumulation of fungal elements in the anterior ad inferior recesses. Aim. To present our experience of maxillary fungus ball treated by the "gauze technique" that avoids these removal difficulties. Materials and Methods. A retrospective, cross-sectional, and descriptive study of 25 patients affected by maxillary fungus ball was carried out: 19 were treated by the "gauze technique" and 6 were treated without "gauze technique." Results. A comparison was made between the two groups for surgery procedure time, length of hospitalization, time from surgery to nasal unpacking, complications, and postsurgical patient satisfaction. The only statistically significant difference observed was a shorter surgical procedure time (p < 0.05) for the "gauze technique." Conclusions. The data obtained in this study demonstrated that the "gauze technique" is a safe, simple, and quick technique, able to reduce surgery procedure time whilst providing excellent functional outcomes and patient satisfaction. PMID- 28083072 TI - The avian influenza H9N2 at avian-human interface: A possible risk for the future pandemics. AB - The avian influenza subtype H9N2 is considered a low pathogenic virus which is endemic in domestic poultry of a majority of Asian countries. Many reports of seropositivity in occupationally poultry-exposed workers and a number of confirmed human infections with an H9N2 subtype of avian influenza have been documented up to now. Recently, the human infections with both H7N9 and H10N8 viruses highlighted that H9N2 has a great potential for taking a part in the emergence of new human-infecting viruses. This review aimed at discussing the great potential of H9N2 virus which is circulating at avian-human interface, for cross-species transmission, contribution in the production of new reassortants and emergence of new pandemic subtypes. An intensified surveillance is needed for controlling the future risks which would be created by H9N2 circulation at avian human interfaces. PMID- 28083070 TI - Biologics for Targeting Inflammatory Cytokines, Clinical Uses, and Limitations. AB - Proinflammatory cytokines are potent mediators of numerous biological processes and are tightly regulated in the body. Chronic uncontrolled levels of such cytokines can initiate and derive many pathologies, including incidences of autoimmunity and cancer. Therefore, therapies that regulate the activity of inflammatory cytokines, either by supplementation of anti-inflammatory recombinant cytokines or by neutralizing them by using blocking antibodies, have been extensively used over the past decades. Over the past few years, new innovative biological agents for blocking and regulating cytokine activities have emerged. Here, we review some of the most recent approaches of cytokine targeting, focusing on anti-TNF antibodies or recombinant TNF decoy receptor, recombinant IL-1 receptor antagonist (IL-1Ra) and anti-IL-1 antibodies, anti-IL-6 receptor antibodies, and TH17 targeting antibodies. We discuss their effects as biologic drugs, as evaluated in numerous clinical trials, and highlight their therapeutic potential as well as emphasize their inherent limitations and clinical risks. We suggest that while systemic blocking of proinflammatory cytokines using biological agents can ameliorate disease pathogenesis and progression, it may also abrogate the hosts defense against infections. Moreover, we outline the rational need to develop new therapies, which block inflammatory cytokines only at sites of inflammation, while enabling their function systemically. PMID- 28083073 TI - Experience Sampling of Positive Affect in Adolescents with Autism: Feasibility and Preliminary Findings. AB - BACKGROUND: Experience sampling is a powerful method for obtaining ecologically valid data from research participants in real-world contexts. Given the urgent need for innovative and sensitive outcome measures in autism spectrum disorder (ASD) research, the present study sought to examine the feasibility of using experience sampling of positive affect and behavior in adolescents with ASD. METHOD: Nineteen high functioning adolescents with ASD and 20 sex and age matched controls completed smartphone- and Qualtrics(r) -based experience sampling of positive affect and behavior six times over four days. RESULTS: Adherence was excellent: adolescents with ASD completed 85% of the assessments, compared to 93% in controls, and response rates were not impacted by age or IQ. Groups did not differ in positive affect overall or as a function of activities, nor did groups differ in the proportion of assessments completed during social or nonsocial activities. However, groups did differ in the proportion of assessments completed during preferred activities. CONCLUSIONS: Results suggest that smartphone- and Qualtrics(r) -based experience sampling with high functioning adolescents with ASD is feasible and captures real-world behaviors that would not be possible using laboratory-based measures. PMID- 28083074 TI - Zoosporic parasites infecting marine diatoms - A black box that needs to be opened. AB - Living organisms in aquatic ecosystems are almost constantly confronted by pathogens. Nevertheless, very little is known about diseases of marine diatoms, the main primary producers of the oceans. Only a few examples of marine diatoms infected by zoosporic parasites are published, yet these studies suggest that diseases may have significant impacts on the ecology of individual diatom hosts and the composition of communities at both the producer and consumer trophic levels of food webs. Here we summarize available ecological and morphological data on chytrids, aphelids, stramenopiles (including oomycetes, labyrinthuloids, and hyphochytrids), parasitic dinoflagellates, cercozoans and phytomyxids, all of which are known zoosporic parasites of marine diatoms. Difficulties in identification of host and pathogen species and possible effects of environmental parameters on the prevalence of zoosporic parasites are discussed. Based on published data, we conclude that zoosporic parasites are much more abundant in marine ecosystems than the available literature reports, and that, at present, both the diversity and the prevalence of such pathogens are underestimated. PMID- 28083075 TI - Biorheology of platelet activation in the bloodstream distal to thrombus formation. AB - Thrombus growth at the site of vascular injury is mediated by the sequential events of platelet recruitment, activation and aggregation concomitant with the initiation of the coagulation cascade, resulting in local thrombin generation and fibrin formation. While the biorheology of a localized thrombus formation has been well studied, it is unclear whether local sites of thrombin generation propagate platelet activation within the bloodstream. In order to study the physical biology of platelet activation downstream of sites of thrombus formation, we developed a platform to measure platelet activation and microaggregate formation in the bloodstream. Our results show that thrombi formed on collagen and tissue factor promote activation and aggregation of platelets in the bloodstream in a convection-dependent manner. Pharmacological inhibition of the coagulation factors (F) X, XI or thrombin dramatically reduced the degree of distal platelet activation and microaggregate formation in the bloodstream without affecting the degree of local platelet deposition and aggregation on a surface of immobilized collagen. Herein we describe the development and an example of the utility of a platform to study platelet activation and microaggregate formation in the bloodstream (convection-limited regime) relative to the local site of thrombus formation. PMID- 28083076 TI - Facets of Mindfulness Mediate the Relationship between Depressive Symptoms and Smoking Behavior. AB - The relationship between cigarette smoking and depressive symptoms is well established. Dispositional mindfulness has been associated with lower depressive symptoms, lower smoking dependence, and higher odds of smoking cessation. Given that mindfulness is multi-faceted, the current study examined which facets of mindfulness might mediate the relationship between depressive symptoms and smoking behavior. Participants (n = 72) completed the Smoking Consequences Questionnaire (SCQ), Center for Epidemiologic Studies Depression Scale (CESD), and Kentucky Inventory of Mindfulness Skills (KIMS; subscales-Observe, Describe, Acting with Awareness, Accepting without Judgment), and indicated number of cigarettes smoked per day (CPD). Simple mediation models (followed by multiple mediation when more than one facet was significant) tested whether mindfulness facets mediated the relationship between CESD and smoking behavior (CPD and SCQ subscales). Results indicated that 1) lower depressive symptoms were associated with higher Accepting without Judgment, which was related to lower Negative Reinforcement expectancies, 2) lower depressive symptoms were associated with increased Describe, which was associated with greater perceived Negative Consequences, 3) lower depressive symptoms were associated with higher Accepting without Judgment, which was associated with lower Negative Consequences expectancies, and 4) higher depressive symptoms were associated with higher scores on Observe, which related to both greater Positive Reinforcement and Negative Consequences expectancies. Greater Accepting without Judgment and Describe aspects of mindfulness may serve as protective factors in the relationship of depressive symptoms and smoking. PMID- 28083077 TI - Spatial and Temporal Distribution of Polycyclic Aromatic Hydrocarbons and Elemental Carbon in Bakersfield, California. AB - Despite increasing evidence that airborne polycyclic aromatic hydrocarbon (PAH) exposures contribute to adverse health outcomes for sensitive populations, limited data are available on short-term intraurban spatial distributions for use in epidemiologic research. Exposure assessments for airborne PAHs are uncommon because air sampling for PAHs is a labor-, equipment-, and time-intensive task. To address this gap we measured wintertime PAH concentrations during 2010-2011 in Bakersfield, California, USA, a major city in the Southern San Joaquin Valley. Specifically, 58 96-hour integrated PAH samples were collected during 4 time periods at 14 locations from November 2010 to January 2011; duplicates were collected at two sites. We also collected elemental carbon (EC) at the same 14 sites and analyzed the two time periods with the highest ambient PAH pollution. We used linear regression models to quantify the relationship between potential spatial and temporal predictors of PAH concentrations. We found that wintertime PAH concentrations in Bakersfield, CA, are best predicted by meteorological variables and traffic proximity. Our model explains a moderate amount of the variability in the data (R2=0.58), likely reflecting the major sources of PAHs in Bakersfield. We also observed that PAH concentrations were more spatially variable than EC concentrations. Comparing our data to historical monitoring data at one location in Bakersfield showed that the relatively low PAH concentrations during the 2010-2011 winter in Bakersfield is part of a long-term trend in decreasing PAH concentrations. PMID- 28083078 TI - A Summary of a Cochrane Review: Ganoderma lucidum (Reishi mushroom) for the treatment of cancer. PMID- 28083079 TI - Inkjet printed silver electrodes on macroporous paper for a paper-based isoelectric focusing device. AB - We demonstrate a combined printing process utilizing inkjet printing of silver electrodes and solid-ink technology for printing hydrophobic wax barriers for fabricating paper microfluidic devices with integrated electrodes. Optimized printing parameters are given for achieving conducting silver lines on the top of macroporous chromatography paper down to 250 MUm-300 MUm resolution. Electrical characterization and wicking experiments demonstrate that the printed silver patterns are simultaneously conductive and porous enough to allow reliable capillary wicking across the electrodes. The combined wax and silver printing method is used for fabrication of paper microfluidic isoelectric focusing devices for separation and concentration of proteins. PMID- 28083080 TI - Chronic Oral Capsaicin Exposure During Development Leads to Adult Rats with Reduced Taste Bud Volumes. AB - INTRODUCTION: Cross-sensory interaction between gustatory and trigeminal nerves occurs in the anterior tongue. Surgical manipulations have demonstrated that the strength of this relationship varies across development. Capsaicin is a neurotoxin that affects fibers of the somatosensory lingual nerve surrounding taste buds, but not fibers of the gustatory chorda tympani nerve which synapse with taste receptor cells. Since capsaicin is commonly consumed by many species, including humans, experimental use of this neurotoxin provides a naturalistic perturbation of the lingual trigeminal system. Neonatal or adults rats consumed oral capsaicin for 40 days and we examined the cross-sensory effect on the morphology of taste buds across development. METHODS: Rats received moderate doses of oral capsaicin, with chronic treatments occurring either before or after taste system maturation. Tongue morphology was examined either 2 or 50 days after treatment cessation. Edema, which has been previously suggested as a cause of changes in capsaicin-related gustatory function, was also assessed. RESULTS: Reductions in taste bud volume occurred 50 days, but not 2 days post-treatment for rats treated as neonates. Adult rats at either time post-treatment were unaffected. Edema was not found to occur with the 5 ppm concentration of capsaicin we used. CONCLUSIONS: Results further elucidate the cooperative relationship between these discrete sensory systems and highlight the developmentally mediated aspect of this interaction. IMPLICATIONS: Chronic exposure to even moderate levels of noxious stimuli during development has the ability to impact the orosensory environment, and these changes may not be evident until long after exposure has ceased. PMID- 28083082 TI - Restructuring of the vascular bed in response to hemodynamic disturbances in portal hypertension. AB - In recent years, defined progress has been made in understanding the mechanisms of hemodynamic disturbances occurring in liver cirrhosis, which are based on portal hypertension. In addition to pathophysiological disorders related to endothelial dysfunction, it was revealed: There is the restructuring of the vasculature, which includes vascular remodeling and angiogenesis. In spite of the fact that these changes are the compensatory-adaptive response to the deteriorating conditions of blood circulation, taken together, they contribute to the development and progression of portal hypertension causing severe complications such as bleeding from esophageal varices. Disruption of systemic and organ hemodynamics and the formation of portosystemic collaterals in portal hypertension commence with neovascularization and splanchnic vasodilation due to the hypoxia of the small intestine mucosa. In this regard, the goal of comprehensive treatment may be to influence on the chemokines, proinflammatory cytokines, and angiogenic factors (vascular endothelial growth factor, placental growth factor, platelet-derived growth factor and others) that lead to the development of these disorders. This review is to describe the mechanisms of restructuring of the vascular bed in response to hemodynamic disturbances in portal hypertension. Development of pathogenetic methods, which allow correcting portal hypertension, will improve the efficiency of conservative therapy aimed at prevention and treatment of its inherent complications. PMID- 28083083 TI - Fractionation of gamma-glutamyltransferase in patients with nonalcoholic fatty liver disease and alcoholic liver disease. AB - AIM: To assess how serum gamma-glutamyltransferase (GGT) fractions vary in patients with alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). METHODS: Serum samples were obtained from 14 patients with biopsy-proven alcoholic liver diseases and 9 patients with biopsy proven non-alcoholic fatty liver disease. In addition to these biopsy-proven cases, 16 obese (body mass index > 25) patients without any history of alcohol consumption but with a fatty liver on ultrasound examination and with elevated GGT were included for an additional analysis. Serum GGT fractionation was conducted by high-performance gel filtration liquid chromatography and was separated into the four fractions, big-GGT, medium-GGT, small-GGT (s-GGT), and free-GGT (f-GGT). RESULTS: The results were expressed as a ratio of each fraction including the total GGT (t GGT). The s-GGT/t-GGT ratios were lowest for the control group and highest for the ALD group. The differences between the control and NAFLD groups and also between the NAFLD and ALD groups were statistically significant. In contrast, the f-GGT/t-GGT ratios were highest in the control group and lowest in the ALD group, with the differences being statistically significant. As a result, the s-GGT/f GGT ratios were markedly increased in the NAFLD group as compared with the control group. The increase of the s-GGT/t-GGT ratios, the decrease of the f GGT/t-GGT ratios, and the increase of s-GGT/F-GGT ratios as compared with the control group subjects were also found in obese patients with clinically diagnosed fatty change of the liver. CONCLUSION: Serum GGT fractionation by high performance gel filtration liquid chromatography is potentially useful for the differential diagnosis of ALD and NAFLD. PMID- 28083081 TI - Biliary atresia: Where do we stand now? AB - The pathway from clinical suspicion to establishing the diagnosis of biliary atresia in a child with jaundice is a daunting task. However, investigations available help to point towards the correct diagnosis in reasonable time frame. Imaging by Sonography has identified several parameters which can be of utility in the diagnostic work up. Comparison of Sonography with imaging by Nuclear medicine can bring out the significant differences and also help in appropriate imaging. The battery of Biochemical tests, available currently, enable better understanding of the line-up of investigations in a given child with neonatal cholestasis. Management protocols enable standardized care with optimal outcome. The place of surgical management in biliary atresia is undisputed, although Kasai procedure and primary liver transplantation have been pitted against each other. This article functions as a platform to bring forth the various dimensions of biliary atresia. PMID- 28083084 TI - Spontaneous bacterial peritonitis prevalence in pre-transplant patients and its effect on survival and graft loss post-transplant. AB - AIM: To investigate the incidence of spontaneous bacterial peritonitis (SBP) in pre-transplant patients and its effect on post transplant mortality and graft failure. METHODS: We conducted a retrospective cohort study of patient records from the organ procurement and transplant network data set. Patients were identified by the presence of SBP pre-transplant. Univariate post-transplant survival models were constructed using the Kaplan-Meier technique and multivariate models were constructed using the Cox proportional hazards model. Variables that affected post-transplant graft survival were identified in the SBP population. RESULTS: Forty-seven thousand eight hundred and eighty patient records were included in the analysis for both groups, and 1966 (4.11%) patients were identified in the data set as having pre-transplant SBP. Patients that had pre-transplant SBP had higher rates of graft loss from recurrent hepatitis C virus (HCV) (3.6% vs 2.0%, P < 0.0001), infections leading to graft loss (1.9% vs 1.3%, P = 0.02), primary non-function (4.3% vs 3.0%, P < 0.0001) and chronic rejection (1.1% vs 0.7%, P = 0.04). Kaplan-Meier survival analysis showed a statistically significant difference in all-cause survival in patients with a history of SBP vs those without (P < 0.0001). Pre-transplant history of SBP was independently predictive of mortality due to recurrent HCV (HR = 1.11, 95%CI: 1.02-1.21, P < 0.017) after liver transplantation. CONCLUSION: HCV patients prior to the advent of directing acting anti-viral agents had a higher incidence of pre transplant SBP than other patients on the liver transplant wait list. SBP history pre-transplant resulted in a higher rate of graft loss due to recurrent HCV infection and chronic rejection. PMID- 28083085 TI - Prevalence of significant liver disease in human immunodeficiency virus-infected patients exposed to Didanosine: A cross sectional study. AB - AIM: To identify significant liver disease [including nodular regenerative hyperplasia (NRH)] in asymptomatic Didanosine (DDI) exposed human immunodeficiency virus (HIV) positive patients. METHODS: Patients without known liver disease and with > 6 mo previous DDI use had liver stiffness assessed by transient elastography (TE). Those with alanine transaminase (ALT) above upper limit normal and/or TE > 7.65 kPa underwent ultrasound scan (U/S). Patients with: (1) abnormal U/S; or (2) elevated ALT plus TE > 7.65 kPa; or (3) TE > 9.4 kPa were offered trans-jugular liver biopsy (TJLB) with hepatic venous pressure gradient (HVPG) assessment. RESULTS: Ninety-nine patients were recruited, median age 50 years (range 31-70), 81% male and 70% men who have sex with men. Ninety five percent with VL < 50 copies on antiretroviral therapy with median CD4 count 639 IU/L. Median DDI exposure was 3.4 years (range 0.5-14.6). Eighty-one had a valid TE readings (interquartile range/score ratio < 0.3): 71 (88%) < 7.65 kPa, 6 (7%) 7.65-9.4 kPa and 4 (6%) > 9.4 kPa. Seventeen (17%) met criteria for TJLB, of whom 12 accepted. All had HVPG < 6 mmHg. Commonest histological findings were steatosis (n = 6), normal architecture (n = 4) and NRH (n = 2), giving a prevalence of previously undiagnosed NRH of 2% (95%CI: 0.55%, 7.0%). CONCLUSION: A screening strategy based on TE, liver enzymes and U/S scan found a low prevalence of previously undiagnosed NRH in DDI exposed, asymptomatic HIV positive patients. Patients were more likely to have steatosis highlighting the increased risk of multifactorial liver disease in this population. PMID- 28083086 TI - Enzyme pattern of biliary colic: A counterintuitive picture. AB - AIM: To evaluate the diagnostic value of serial biochemical blood tests in the diagnosis of biliary colic. METHODS: Files were reviewed of 1039 patients who were admitted to the Share'e Zedek Medical Center emergency department between the years 2012-2013, and received the coding of acute biliary disease. Of these, the first 100 cases were selected that met the following criteria: (1) a diagnosis of biliary colic or symptomatic cholelithiasis; (2) at least two biochemical blood tests performed; and (3) 18 years of age or older. Patients with other acute biliary diseases were excluded. The biochemical profile of the patients was analyzed as were their clinical and radiological findings. RESULTS: Three-quarters of the patients were women, whose average age of 37 years was younger than the average of the men, at 50 years. According to their histories, 47% of the patients had previously known cholelithiasis. Pain in either the right upper quadrant or the epigastrium was the presenting symptom in 93% cases. The greatest change in serum biochemical results was seen during the first day of the patients' admissions. Alanine aminotransferase (ALT) showed the highest initial rise above the reference range, followed by aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), bilirubin and alkaline phosphatase (ALKP) - all these increases were statistically significant (P < 0.05). AST showed the sharpest decline followed by bilirubin and ALT. GGT and ALKP did not fall. A sharp rise and fall in liver enzymes, especially during the first day, most prominently in AST and ALT, was seen in 70% percent of cases. In 65% of cases trans-abdominal sonography did not give diagnostic findings. CONCLUSION: Serial serum liver enzyme measurements are helpful in the initial diagnosis of acute biliary colic. PMID- 28083087 TI - Isolated bilateral Tapia's syndrome after liver transplantation: A case report and review of the literature. AB - AIM: To describe one case of bilateral Tapia's syndrome in a liver transplanted patient and to review the literature. METHODS: We report a case of bilateral Tapia's syndrome in a 50-year-old man with a history of human immunodeficiency virus and hepatitis C virus child. A liver cirrhosis and a bi-nodular hepatocellular carcinoma, who underwent liver transplantation after general anesthesia under orotracheal intubation. Uneventful extubation was performed in the intensive care unit during the following hours. On postoperative day (POD) 3, he required urgent re-laparotomy due to perihepatic hematoma complicated with respiratory gram negative bacilli infection. On POD 13, patient was extubated, but required immediate re-intubation due to severe respiratory failure. At the following day a third weaning failure occurred, requiring the performance of a percutaneous tracheostomy. Five days later, the patient was taken off mechanical ventilation and severe dysphagia, sialorrea and aphonia revealed. A computerized tomography and a magnetic resonance imaging of the head and neck excluded central nervous injury. A stroboscopy showed bilateral paralysis of vocal cords and tongue and a diagnosis of bilateral Tapia's syndrome was performed. With conservative management, including a prompt establishment of a speech and swallowing rehabilitation program, the patient achieved full recovery within four months after liver transplantation. We carried out MEDLINE search for the term Tapia's syndrome. The inclusion criteria had no restriction by language or year but must provide sufficient available data to exclude duplicity. We described the clinical evolution of the patients, focusing on author, year of publication, age, sex, preceding problem, history of endotracheal intubation, unilateral or bilateral presentation, diagnostic procedures, type of treatment, follow-up, and outcome. RESULTS: Several authors mentioned the existence of around 70 cases, however only 54 fulfilled our inclusion criteria. We found only five published studies of bilateral Tapia's syndrome. However this is the first case reported in the literature in a liver transplanted patient. Most patients were male and young and the majority of cases appeared as a complication of airway manipulation after any type of surgery, closely related to the positioning of the head during the procedure. The diagnosis was founded on a rapid suspicion, a complete head and neck neurological examination and a computed tomography and or a magnetic resonance imaging of the brain and neck to establish the origin of central or peripheral type of Tapia's syndrome and also the nature of the lesion, ischemia, abscess formation, tumor or hemorrhage. Apart from corticosteroids and anti- inflammatory therapy, the key of the treatment was an intensive and multidisciplinary speech and swallowing rehabilitation. Most studies have emphasized that the recovery is usually completed within four to six months. CONCLUSION: Tapia's syndrome is almost always a transient complication after airway manipulation. Although bilateral Tapia's syndrome after general anesthesia is exceptionally rare, this complication should be recognized in patients reporting respiratory obstruction with complete dysphagia and dysarthria after prolonged intubation. Both anesthesiologists and surgeons should be aware of the importance of its preventing measurements, prompt diagnosis and intensive speech and swallowing rehabilitation program. PMID- 28083088 TI - Dust evolution, a global view I. Nanoparticles, nascence, nitrogen and natural selection ... joining the dots. AB - The role and importance of nanoparticles for interstellar chemistry and beyond is explored within the framework of The Heterogeneous dust Evolution Model for Interstellar Solids (THEMIS), focusing on their active surface chemistry, the effects of nitrogen doping and the natural selection of interesting nanoparticle sub-structures. Nanoparticle-driven chemistry, and in particular the role of intrinsic epoxide-type structures, could provide a viable route to the observed gas phase OH in tenuous interstellar clouds en route to becoming molecular clouds. The aromatic-rich moieties present in asphaltenes probably provide a viable model for the structures present within aromatic-rich interstellar carbonaceous grains. The observed doping of such nanoparticle structures with nitrogen, if also prevalent in interstellar dust, could perhaps have important and observable consequences for surface chemistry and the formation of precursor pre-biotic species. PMID- 28083089 TI - Dust evolution, a global view: II. Top-down branching, nanoparticle fragmentation and the mystery of the diffuse interstellar band carriers. AB - The origin of the diffuse interstellar bands (DIBs), one of the longest-standing mysteries of the interstellar medium (ISM), is explored within the framework of The Heterogeneous dust Evolution Model for Interstellar Solids (THEMIS). The likely nature of the DIB carriers and their evolution is here explored within the framework of the structures and sub-structures inherent to doped hydrogenated amorphous carbon grains in the ISM. Based on the natural aromatic-rich moieties (asphaltenes) recovered from coal and oil, the likely structure of their interstellar analogues is investigated within the context of the diffuse band problem. It is here proposed that the top-down evolution of interstellar carbonaceous grains, and, in particular, a-C(:H) nanoparticles, is at the heart of the formation and evolution of the DIB carriers and their associations with small molecules and radicals, such as C2, C3, CH and CN. It is most probable that the DIBs are carried by dehydrogenated, ionized, hetero-cyclic, olefinic and aromatic-rich moieties that form an integral part of the contiguous structure of hetero-atom-doped hydrogenated amorphous carbon nanoparticles and their daughter fragmentation products. Within this framework, it is proposed that polyene structures in all their variants could be viable DIB carrier candidates. PMID- 28083090 TI - Dust evolution, a global view: III. Core/mantle grains, organic nano-globules, comets and surface chemistry. AB - Within the framework of The Heterogeneous dust Evolution Model for Interstellar Solids (THEMIS), this work explores the surface processes and chemistry relating to core/mantle interstellar and cometary grain structures and their influence on the nature of these fascinating particles. It appears that a realistic consideration of the nature and chemical reactivity of interstellar grain surfaces could self-consistently and within a coherent framework explain: the anomalous oxygen depletion, the nature of the CO dark gas, the formation of 'polar ice' mantles, the red wing on the 3 MUm water ice band, the basis for the O-rich chemistry observed in hot cores, the origin of organic nano-globules and the 3.2 MUm 'carbonyl' absorption band observed in comet reflectance spectra. It is proposed that the reaction of gas phase species with carbonaceous a-C(:H) grain surfaces in the interstellar medium, in particular the incorporation of atomic oxygen into grain surfaces in epoxide functional groups, is the key to explaining these observations. Thus, the chemistry of cosmic dust is much more intimately related with that of the interstellar gas than has previously been considered. The current models for interstellar gas and dust chemistry will therefore most likely need to be fundamentally modified to include these new grain surface processes. PMID- 28083091 TI - Language as a coordination tool evolves slowly. AB - Social living ultimately depends on coordination between group members, and communication is necessary to make this possible. We suggest that this might have been the key selection pressure acting on the evolution of language in humans and use a behavioural coordination model to explore the impact of communication efficiency on social group coordination. We show that when language production is expensive but there is an individual benefit to the efficiency with which individuals coordinate their behaviour, the evolution of efficient communication is selected for. Contrary to some views of language evolution, the speed of evolution is necessarily slow because there is no advantage in some individuals evolving communication abilities that much exceed those of the community at large. However, once a threshold competence has been achieved, evolution of higher order language skills may indeed be precipitate. PMID- 28083092 TI - Age-related environmental gradients influence invertebrate distribution in the Prince Charles Mountains, East Antarctica. AB - The potential impact of environmental change on terrestrial Antarctic ecosystems can be explored by inspecting biodiversity patterns across large-scale gradients. Unfortunately, morphology-based surveys of Antarctic invertebrates are time consuming and limited by the cryptic nature of many taxa. We used biodiversity information derived from high-throughput sequencing (HTS) to elucidate the relationship between soil properties and invertebrate biodiversity in the Prince Charles Mountains, East Antarctica. Across 136 analysed soil samples collected from Mount Menzies, Mawson Escarpment and Lake Terrasovoje, we found invertebrate distribution in the Prince Charles Mountains significantly influenced by soil salinity and/or sulfur content. Phyla Tardigrada and Arachnida occurred predominantly in low-salinity substrates with abundant nutrients, whereas Bdelloidea (Rotifera) and Chromadorea (Nematoda) were more common in highly saline substrates. A significant correlation between invertebrate occurrence, soil salinity and time since deglaciation indicates that terrain age indirectly influences Antarctic terrestrial biodiversity, with more recently deglaciated areas supporting greater diversity. Our study demonstrates the value of HTS metabarcoding to investigate environmental constraints on inconspicuous soil biodiversity across large spatial scales. PMID- 28083093 TI - Intraspecific variation in body size does not alter the effects of mesopredators on prey. AB - As humans continue to alter the species composition and size structure of marine food webs, it is critical to understand size-dependent effects of predators on prey. Yet, how shifts in predator body size mediate the effect of predators is understudied in tropical marine ecosystems, where anthropogenic harvest has indirectly increased the density and size of small-bodied predators. Here, we combine field surveys and a laboratory feeding experiment in coral reef fish communities to show that small and large predators of the same species can have similar effects. Specifically, surveys show that the presence of a small predator (Paracirrhites arcatus) was correlated with lower chances of prey fish presence, but these correlations were independent of predator size. Experimental trials corroborated the size-independent effect of the predator; attack rates were indistinguishable between small and large predators, suggesting relatively even effects of hawkfish in various size classes on the same type of prey. Our results indicate that the effects of small predators on coral reefs can be size independent, suggesting that variation in predator size-structure alone may not always affect the functional role of these predators. PMID- 28083094 TI - Accurate recapture identification for genetic mark-recapture studies with error tolerant likelihood-based match calling and sample clustering. AB - Error-tolerant likelihood-based match calling presents a promising technique to accurately identify recapture events in genetic mark-recapture studies by combining probabilities of latent genotypes and probabilities of observed genotypes, which may contain genotyping errors. Combined with clustering algorithms to group samples into sets of recaptures based upon pairwise match calls, these tools can be used to reconstruct accurate capture histories for mark recapture modelling. Here, we assess the performance of a recently introduced error-tolerant likelihood-based match-calling model and sample clustering algorithm for genetic mark-recapture studies. We assessed both biallelic (i.e. single nucleotide polymorphisms; SNP) and multiallelic (i.e. microsatellite; MSAT) markers using a combination of simulation analyses and case study data on Pacific walrus (Odobenus rosmarus divergens) and fishers (Pekania pennanti). A novel two-stage clustering approach is demonstrated for genetic mark-recapture applications. First, repeat captures within a sampling occasion are identified. Subsequently, recaptures across sampling occasions are identified. The likelihood based matching protocol performed well in simulation trials, demonstrating utility for use in a wide range of genetic mark-recapture studies. Moderately sized SNP (64+) and MSAT (10-15) panels produced accurate match calls for recaptures and accurate non-match calls for samples from closely related individuals in the face of low to moderate genotyping error. Furthermore, matching performance remained stable or increased as the number of genetic markers increased, genotyping error notwithstanding. PMID- 28083095 TI - Knowing your neighbourhood: local ecology and personal experience predict neighbourhood perceptions in Belfast, Northern Ireland. AB - Evolutionary theory predicts that humans should adjust their life-history strategies in response to local ecological threats and opportunities in order to maximize their reproductive success. Cues representing threats to individuals' lives and health in modern, Western societies may come in the form of local ages at death, morbidity rate and crime rate in their local area, whereas the adult sex ratio represents a measure of the competition for reproductive partners. These characteristics are believed to have a strong influence over a wide range of behaviours, but whether they are accurately perceived has not been robustly tested. Here, we investigate whether perceptions of four neighbourhood characteristics are accurate across eight neighbourhoods in Belfast, Northern Ireland. We find that median age at death and morbidity rates are accurately perceived, whereas adult sex ratios and crime rates are not. We suggest that both neighbourhood characteristics and personal experiences contribute to the formation of perceptions. This should be considered by researchers looking for associations between area-level factors. PMID- 28083096 TI - Sperm allocation in relation to female size in a semelparous salmonid. AB - To maximize reproductive success, males have to adaptively tailor their sperm expenditure in relation to the quality of potential mates because they require time to replenish their sperm supply for subsequent mating opportunities. Therefore, in mating contexts where males must choose among females in a short period of time, as is the case with semelparous species (which die after one intensely competitive short duration breeding season), selection on sperm allocation can be expected to be a powerful selective agent that shapes the male reproductive success. We quantitatively investigated sperm allocation patterns in chum salmon in relation to perceived female quality by developing a novel method for determining the amount of sperm allocated per ejaculate during spawning bouts. We examined the relationship between sperm expenditure and the body size of paired females (a proxy of egg number and egg quality) in the absence of male male competition in an experimental channel. The estimated amount of sperm released per spawning event was positively correlated with the size of paired females. However, the number of spawning events a female participated in, which reduces the number of eggs she spawns in each subsequent bout, did not affect this relationship. These results provide support for predictions arising from the sperm allocation hypothesis, male salmon do economize their sperm expenditure in accordance with paired female body size as predicted for their first spawning event, but males overestimate or are unable to assess the quality of females beyond size and provide more sperm than they should in theory when paired with a female that spawned previously. Overall, the observed sperm allocation pattern in chum salmon appears to be adapted to maximize reproductive success assuming female size is an honest indicator of quality, although temporal changes in a female's quality during a reproductive season should be considered when examining sperm allocation strategies. PMID- 28083097 TI - Calcium interacts with temperature to influence Daphnia movement rates. AB - Predicting the ecological responses to climate change is particularly challenging, because organisms might be affected simultaneously by the synergistic effects of multiple environmental stressors. Global warming is often accompanied by declining calcium concentration in many freshwater ecosystems. Although there is growing evidence that these changes in water chemistry and thermal conditions can influence ecosystem dynamics, little information is currently available about how these synergistic environmental stressors could influence the behaviour of aquatic organisms. Here, we tested whether the combined effects of calcium and temperature affect movement parameters (average speed, mean turning frequency and mean-squared displacement) of the planktonic Daphnia magna, using a full factorial design and exposing Daphnia individuals to a range of realistic levels of temperature and calcium concentration. We found that movement increased with both temperature and calcium concentration, but temperature effects became considerably weaker when individuals were exposed to calcium levels close to survival limits documented for several Daphnia species, signalling a strong interaction effect. These results support the notion that changes in water chemistry might have as strong an effect as projected changes in temperature on movement rates of Daphnia, suggesting that even sublethal levels of calcium decline could have a considerable impact on the dynamics of freshwater ecosystems. PMID- 28083098 TI - Halloysite nanotube-based electrospun ceramic nanofibre mat: a novel support for zeolite membranes. AB - Some key parameters of supports such as porosity, pore shape and size are of great importance for fabrication and performance of zeolite membranes. In this study, we fabricated millimetre-thick, self-standing electrospun ceramic nanofibre mats and employed them as a novel support for zeolite membranes. The nanofibre mats were prepared by electrospinning a halloysite nanotubes/polyvinyl pyrrolidone composite followed by a programmed sintering process. The interwoven nanofibre mats possess up to 80% porosity, narrow pore size distribution, low pore tortuosity and highly interconnected pore structure. Compared with the commercial alpha-Al2O3 supports prepared by powder compaction and sintering, the halloysite nanotube-based mats (HNMs) show higher flux, better adsorption of zeolite seeds, adhesion of zeolite membranes and lower Al leaching. Four types of zeolite membranes supported on HNMs have been successfully synthesized with either in situ crystallization or a secondary growth method, demonstrating good universality of HNMs for supporting zeolite membranes. PMID- 28083099 TI - Invasive mutualisms between a plant pathogen and insect vectors in the Middle East and Brazil. AB - Complex multi-trophic interactions in vectorborne diseases limit our understanding and ability to predict outbreaks. Arthropod-vectored pathogens are especially problematic, with the potential for novel interspecific interactions during invasions. Variations and novelties in plant-arthropod-pathogen triumvirates present significant threats to global food security. We examined aspects of a phytoplasma pathogen of citrus across two continents. 'Candidatus Phytoplasma aurantifolia' causes Witches' Broom Disease of Lime (WBDL) and has devastated citrus production in the Middle East. A variant of this phytoplasma currently displays asymptomatic or 'silent' infections in Brazil. We first studied vector capacity and fitness impacts of the pathogen on its vectors. The potential for co-occurring weed species to act as pathogen reservoirs was analysed and key transmission periods in the year were also studied. We demonstrate that two invasive hemipteran insects-Diaphorina citri and Hishimonus phycitis-can vector the phytoplasma. Feeding on phytoplasma-infected hosts greatly increased reproduction of its invasive vector D. citri both in Oman and Brazil; suggesting that increased fitness of invasive insect vectors thereby further increases the pathogen's capacity to spread. Based on our findings, this is a robust system for studying the effects of invasions on vectorborne diseases and highlights concerns about its spread to warmer, drier regions of Brazil. PMID- 28083100 TI - Automatic prediction of tumour malignancy in breast cancer with fractal dimension. AB - Breast cancer is one of the most prevalent types of cancer today in women. The main avenue of diagnosis is through manual examination of histopathology tissue slides. Such a process is often subjective and error-ridden, suffering from both inter- and intraobserver variability. Our objective is to develop an automatic algorithm for analysing histopathology slides free of human subjectivity. Here, we calculate the fractal dimension of images of numerous breast cancer slides, at magnifications of 40*, 100*, 200* and 400*. Using machine learning, specifically, the support vector machine (SVM) method, the F1 score for classification accuracy of the 40* slides was found to be 0.979. Multiclass classification on the 40* slides yielded an accuracy of 0.556. A reduction of the size and scope of the SVM training set gave an average F1 score of 0.964. Taken together, these results show great promise in the use of fractal dimension to predict tumour malignancy. PMID- 28083101 TI - Food provisioning increases the risk of injury in a long-lived marine top predator. AB - Food provisioning of wildlife is a major concern for management and conservation agencies worldwide because it encourages unnatural behaviours in wild animals and increases each individual's risk for injury and death. Here we investigate the contributing factors and potential fitness consequences of a recent increase in the frequency of human interactions with common bottlenose dolphins (Tursiops truncatus) in Sarasota Bay, Florida. A rising proportion of the local long-term resident dolphin community is becoming conditioned to human interactions through direct and indirect food provisioning. We investigate variables that are affecting conditioning and if the presence of human-induced injuries is higher for conditioned versus unconditioned dolphins. Using the most comprehensive long term dataset available for a free-ranging bottlenose dolphin population (more than 45 years; more than 32 000 dolphin group sightings; more than 1100 individuals), we found that the association with already conditioned animals strongly affected the probability of dolphins becoming conditioned to human interactions, confirming earlier findings that conditioning is partly a learned behaviour. More importantly, we found that conditioned dolphins were more likely to be injured by human interactions when compared with unconditioned animals. This is alarming, as conditioning could lead to a decrease in survival, which could have population-level consequences. We did not find a significant relationship between human exposure or natural prey availability and the probability of dolphins becoming conditioned. This could be due to low sample size or insufficient spatio-temporal resolution in the available data. Our findings show that wildlife provisioning may lead to a decrease in survival, which could ultimately affect population dynamics. PMID- 28083103 TI - Convergence between a mosquito-eating predator's natural diet and its prey-choice behaviour. AB - On the basis of 1115 records of Evarcha culicivora feeding in the field, we can characterize this East African jumping spider (Salticidae) as being distinctively stenophagic. We can also, on the basis of laboratory prey-choice experiments, characterize E. culicivora as having a specialized prey-classification system and a hierarchy of innate preferences for various categories of mosquitoes and other arthropods. Prey from the field belonged to 10 arthropod orders, but 94.5% of the prey records were dipterans. Mosquitoes were the dominant prey (80.2% of the records), with the majority (82.9%) of the mosquitoes being females, and thereafter midges were the most common prey (9.2% of the records). Preference profiles that were determined from experiments showed strong convergence with natural diet in some, but not all, instances. In experiments, E. culicivora adults appeared to distinguish between six prey categories and juveniles between seven, with blood-carrying anopheline female mosquitoes being ranked highest in preference. For adults, this was followed by blood-carrying culicine female mosquitoes and then anopheline female mosquitoes not carrying blood, but these two preferences were reversed for juveniles. Moreover, for juveniles, but not for adults, anopheline male mosquitoes seem to be a distinct prey category ranked in preference after blood-carrying culicine females and, for both adults and juveniles, preference for midges is evident when the alternatives are not mosquitoes. These findings illustrate the importance of going beyond simply specifying preferred prey categories when characterizing predators as 'specialized' and a need to make clear conceptual distinctions between a predator's natural diet, the prey categories that are relevant to the predator, and the predator's prey-choicebehaviour. PMID- 28083102 TI - Effects of cell-cycle-dependent expression on random fluctuations in protein levels. AB - Expression of many genes varies as a cell transitions through different cell cycle stages. How coupling between stochastic expression and cell cycle impacts cell-to-cell variability (noise) in the level of protein is not well understood. We analyse a model where a stable protein is synthesized in random bursts, and the frequency with which bursts occur varies within the cell cycle. Formulae quantifying the extent of fluctuations in the protein copy number are derived and decomposed into components arising from the cell cycle and stochastic processes. The latter stochastic component represents contributions from bursty expression and errors incurred during partitioning of molecules between daughter cells. These formulae reveal an interesting trade-off: cell-cycle dependencies that amplify the noise contribution from bursty expression also attenuate the contribution from partitioning errors. We investigate the existence of optimum strategies for coupling expression to the cell cycle that minimize the stochastic component. Intriguingly, results show that a zero production rate throughout the cell cycle, with expression only occurring just before cell division, minimizes noise from bursty expression for a fixed mean protein level. By contrast, the optimal strategy in the case of partitioning errors is to make the protein just after cell division. We provide examples of regulatory proteins that are expressed only towards the end of the cell cycle, and argue that such strategies enhance robustness of cell-cycle decisions to the intrinsic stochasticity of gene expression. PMID- 28083104 TI - Influence of environmental parameters on movements and habitat utilization of humpback whales (Megaptera novaeangliae) in the Madagascar breeding ground. AB - Assessing the movement patterns and key habitat features of breeding humpback whales is a prerequisite for the conservation management of this philopatric species. To investigate the interactions between humpback whale movements and environmental conditions off Madagascar, we deployed 25 satellite tags in the northeast and southwest coast of Madagascar. For each recorded position, we collated estimates of environmental variables and computed two behavioural metrics: behavioural state of 'transiting' (consistent/directional) versus 'localized' (variable/non-directional), and active swimming speed (i.e. speed relative to the current). On coastal habitats (i.e. bathymetry < 200 m and in adjacent areas), females showed localized behaviour in deep waters (191 +/- 20 m) and at large distances (14 +/- 0.6 km) from shore, suggesting that their breeding habitat extends beyond the shallowest waters available close to the coastline. Males' active swimming speed decreased in shallow waters, but environmental parameters did not influence their likelihood to exhibit localized movements, which was probably dominated by social factors instead. In oceanic habitats, both males and females showed localized behaviours in shallow waters and favoured high chlorophyll-a concentrations. Active swimming speed accounts for a large proportion of observed movement speed; however, breeding humpback whales probably exploit prevailing ocean currents to maximize displacement. This study provides evidence that coastal areas, generally subject to strong human pressure, remain the core habitat of humpback whales off Madagascar. Our results expand the knowledge of humpback whale habitat use in oceanic habitat and response to variability of environmental factors such as oceanic current and chlorophyll level. PMID- 28083105 TI - Endocranial volume is heritable and is associated with longevity and fitness in a wild mammal. AB - Research on relative brain size in mammals suggests that increases in brain size may generate benefits to survival and costs to fecundity: comparative studies of mammals have shown that interspecific differences in relative brain size are positively correlated with longevity and negatively with fecundity. However, as yet, no studies of mammals have investigated whether similar relationships exist within species, nor whether individual differences in brain size within a wild population are heritable. Here we show that, in a wild population of red deer (Cervus elaphus), relative endocranial volume was heritable (h2 = 63%; 95% credible intervals (CI) = 50-76%). In females, it was positively correlated with longevity and lifetime reproductive success, though there was no evidence that it was associated with fecundity. In males, endocranial volume was not related to longevity, lifetime breeding success or fecundity. PMID- 28083106 TI - A finite-element approach to evaluating the size effects of complex nanostructures. AB - The size effects that reveal the dramatic changes of mechanical behaviour at nanoscales have traditionally been analysed for regular beam systems. Here, the method of using finite-element analysis is explored with the intention of evaluating the size effects for complex nanostructures. The surface elasticity theory and generalized Young-Laplace equation are integrated into a beam element to account for the size effects in classical Euler-Bernoulli and Timoshenko beam theories. Computational results match well with the theoretical predictions on the size effect for a cantilever beam and a cubic unit cell containing 24 horizontal/vertical ligaments. For a simply supported nanowire, it is found that the results are very close to the experimental data. With the assumption that nanoporous gold is composed of many randomly connected beams, for the first time, the size effect of such a complex structure is numerically determined. PMID- 28083107 TI - Next Gen Pop Gen: implementing a high-throughput approach to population genetics in boarfish (Capros aper). AB - The recently developed approach for microsatellite genotyping by sequencing (GBS) using individual combinatorial barcoding was further improved and used to assess the genetic population structure of boarfish (Capros aper) across the species' range. Microsatellite loci were developed de novo and genotyped by next generation sequencing. Genetic analyses of the samples indicated that boarfish can be subdivided into at least seven biological units (populations) across the species' range. Furthermore, the recent apparent increase in abundance in the northeast Atlantic is better explained by demographic changes within this area than by influx from southern or insular populations. This study clearly shows that the microsatellite GBS approach is a generic, cost-effective, rapid and powerful method suitable for full-scale population genetic studies-a crucial element for assessment, sustainable management and conservation of valuable biological resources. PMID- 28083108 TI - It is lonely at the front: contrasting evolutionary trajectories in male and female invaders. AB - Invasive species often exhibit rapid evolutionary changes, and can provide powerful insights into the selective forces shaping phenotypic traits that influence dispersal rates and/or sexual interactions. Invasions also may modify sexual dimorphism. We measured relative lengths of forelimbs and hindlimbs of more than 3000 field-caught adult cane toads (Rhinella marina) from 67 sites in Hawai'i and Australia (1-80 years post-colonization), along with 489 captive-bred individuals from multiple Australian sites raised in a 'common garden' (to examine heritability and reduce environmental influences on morphology). As cane toads spread from east to west across Australia, the ancestral condition (long limbs, especially in males) was modified. Limb length relative to body size was first reduced (perhaps owing to natural selection on locomotor ability), but then increased again (perhaps owing to spatial sorting) in the invasion vanguard. In contrast, the sex disparity in relative limb length has progressively decreased during the toads' Australian invasion. Offspring reared in a common environment exhibited similar geographical divergences in morphology as did wild-caught animals, suggesting a genetic basis to the changes. Limb dimensions showed significant heritability (2-17%), consistent with the possibility of an evolved response. Cane toad populations thus have undergone a major shift in sexual dimorphism in relative limb lengths during their brief (81 years) spread through tropical Australia. PMID- 28083109 TI - Thermally moderated firefly activity is delayed by precipitation extremes. AB - The timing of events in the life history of temperate insects is most typically primarily cued by one of two drivers: photoperiod or temperature accumulation over the growing season. However, an insect's phenology can also be moderated by other drivers like rainfall or the phenology of its host plants. When multiple drivers of phenology interact, there is greater potential for phenological asynchronies to arise between an organism and those with which it interacts. We examined the phenological patterns of a highly seasonal group of fireflies (Photinus spp., predominantly P. pyralis) over a 12-year period (2004-2015) across 10 plant communities to determine whether interacting drivers could explain the variability observed in the adult flight activity density (i.e. mating season) of this species. We found that temperature accumulation was the primary driver of phenology, with activity peaks usually occurring at a temperature accumulation of approximately 800 degree days (base 10 degrees C); however, our model found this peak varied by nearly 180 degree-day units among years. This variation could be explained by a quadratic relationship with the accumulation of precipitation in the growing season; in years with either high or low precipitation extremes at our study site, flight activity was delayed. More fireflies were captured in general in herbaceous plant communities with minimal soil disturbance (alfalfa and no-till field crop rotations), but only weak interactions occurred between within-season responses to climatic variables and plant community. The interaction we observed between temperature and precipitation accumulation suggests that, although climate warming has the potential to disrupt phenology of many organisms, changes to regional precipitation patterns can magnify these disruptions. PMID- 28083110 TI - An approximate solution for a penny-shaped hydraulic fracture that accounts for fracture toughness, fluid viscosity and leak-off. AB - This paper develops a closed-form approximate solution for a penny-shaped hydraulic fracture whose behaviour is determined by an interplay of three competing physical processes that are associated with fluid viscosity, fracture toughness and fluid leak-off. The primary assumption that permits one to construct the solution is that the fracture behaviour is mainly determined by the three-process multiscale tip asymptotics and the global fluid volume balance. First, the developed approximation is compared with the existing solutions for all limiting regimes of propagation. Then, a solution map, which indicates applicability regions of the limiting solutions, is constructed. It is also shown that the constructed approximation accurately captures the scaling that is associated with the transition from any one limiting solution to another. The developed approximation is tested against a reference numerical solution, showing that accuracy of the fracture width and radius predictions lie within a fraction of a per cent for a wide range of parameters. As a result, the constructed approximation provides a rapid solution for a penny-shaped hydraulic fracture, which can be used for quick fracture design calculations or as a reference solution to evaluate accuracy of various hydraulic fracture simulators. PMID- 28083111 TI - Strategic adjustment of parental care in tree swallows: life-history trade-offs and the role of glucocorticoids. AB - Life-history theory predicts that optimal strategies of parental investment will depend on ecological and social factors, such as current brood value and offspring need. Parental care strategies are also likely to be mediated in part by the hypothalamic-pituitary-adrenal axis and glucocorticoid hormones. Here, we present an experiment in tree swallows (Tachycineta bicolor), a biparental songbird with wide geographical distribution, asking whether parental care is strategically adjusted in response to signals of offspring need and brood value and if so, whether glucocorticoids are involved in these adjustments. Using an automated playback system, we carried out playbacks of nestling begging calls specifically to females in two populations differing in their brood value: a northern population in Ontario, Canada (relatively higher brood value) and a southern population in North Carolina, USA (relatively lower brood value). We quantified female offspring provisioning rates before and during playbacks and plasma corticosterone levels (cort) once during late incubation and once immediately after playbacks. Females in both populations increased feeding rates temporarily during the first 2 h of playback but the increase was not sustained for the entire duration of playback (6 h). Cort levels from samples at the end of the playback did not differ between control females and females that received playbacks. However, females that had higher increases in cort between the incubation and nestling period had greater fledging success. These results suggest that females are able to strategically respond to offspring need, although the role of glucocorticoids in this strategic adjustment remains unclear. PMID- 28083112 TI - Clap-and-fling mechanism in a hovering insect-like two-winged flapping-wing micro air vehicle. AB - This study used numerical and experimental approaches to investigate the role played by the clap-and-fling mechanism in enhancing force generation in hovering insect-like two-winged flapping-wing micro air vehicle (FW-MAV). The flapping mechanism was designed to symmetrically flap wings at a high flapping amplitude of approximately 192 degrees . The clap-and-fling mechanisms were thereby implemented at both dorsal and ventral stroke reversals. A computational fluid dynamic (CFD) model was constructed based on three-dimensional wing kinematics to estimate the force generation, which was validated by the measured forces using a 6-axis load cell. The computed forces proved that the CFD model provided reasonable estimation with differences less than 8%, when compared with the measured forces. The measurement indicated that the clap and flings at both the stroke reversals augmented the average vertical force by 16.2% when compared with the force without the clap-and-fling effect. In the CFD simulation, the clap and flings enhanced the vertical force by 11.5% and horizontal drag force by 18.4%. The observations indicated that both the fling and the clap contributed to the augmented vertical force by 62.6% and 37.4%, respectively, and to the augmented horizontal drag force by 71.7% and 28.3%, respectively. The flow structures suggested that a strong downwash was expelled from the opening gap between the trailing edges during the fling as well as the clap at each stroke reversal. In addition to the fling phases, the influx of air into the low-pressure region between the wings from the leading edges also significantly contributed to augmentation of the vertical force. The study conducted for high Reynolds numbers also confirmed that the effect of the clap and fling was insignificant when the minimum distance between the two wings exceeded 1.2c (c = wing chord). Thus, the clap and flings were successfully implemented in the FW-MAV, and there was a significant improvement in the vertical force. PMID- 28083113 TI - Paradigm shifts and the interplay between state, business and civil sectors. AB - The recent rise of the civil sector as a main player of socio-political actions, next to public and private sectors, has largely increased the complexity underlying the interplay between different sectors of our society. From urban planning to global governance, analysis of these complex interactions requires new mathematical and computational approaches. Here, we develop a novel framework, grounded on evolutionary game theory, to envisage situations in which each of these sectors is confronted with the dilemma of deciding between maintaining a status quo scenario or shifting towards a new paradigm. We consider multisector conflicts regarding environmentally friendly policies as an example of application, but the framework developed here has a considerably broader scope. We show that the public sector is crucial in initiating the shift, and determine explicitly under which conditions the civil sector-reflecting the emergent reality of civil society organizations playing an active role in modern societies-may influence the decision-making processes accruing to other sectors, while fostering new routes towards a paradigm shift of the society as a whole. Our results are shown to be robust to a wide variety of assumptions and model parametrizations. PMID- 28083114 TI - Gait control in a soft robot by sensing interactions with the environment using self-deformation. AB - All animals use mechanosensors to help them move in complex and changing environments. With few exceptions, these sensors are embedded in soft tissues that deform in normal use such that sensory feedback results from the interaction of an animal with its environment. Useful information about the environment is expected to be embedded in the mechanical responses of the tissues during movements. To explore how such sensory information can be used to control movements, we have developed a soft-bodied crawling robot inspired by a highly tractable animal model, the tobacco hornworm Manduca sexta. This robot uses deformations of its body to detect changes in friction force on a substrate. This information is used to provide local sensory feedback for coupled oscillators that control the robot's locomotion. The validity of the control strategy is demonstrated with both simulation and a highly deformable three-dimensionally printed soft robot. The results show that very simple oscillators are able to generate propagating waves and crawling/inching locomotion through the interplay of deformation in different body parts in a fully decentralized manner. Additionally, we confirmed numerically and experimentally that the gait pattern can switch depending on the surface contact points. These results are expected to help in the design of adaptable, robust locomotion control systems for soft robots and also suggest testable hypotheses about how soft animals use sensory feedback. PMID- 28083115 TI - Morbillivirus-associated unusual mortality event in South Australian bottlenose dolphins is largest reported for the Southern Hemisphere. AB - Cases of morbillivirus have been recorded in the Southern Hemisphere but have not been linked to significant marine mammal mortality. Post-mortems were conducted on 58 carcasses (44 Indo-Pacific bottlenose dolphins, two common bottlenose dolphins, 12 short-beaked common dolphins) from South Australia during 2005-2013, including an unusual mortality event (UME) in St Vincent Gulf Bioregion (SVG) during 2013. Diagnostic pathology, circumstance of death, body condition, age and stomach contents were documented for Indo-Pacific bottlenose dolphins. At least 50 dolphins died during the UME, 41 were Indo-Pacific bottlenose dolphins and most were young. The UME lasted about seven months and had two peaks, the first being the largest. Effect on the population is unknown. Diagnostic testing for morbillivirus was conducted on 57 carcasses, with evidence for infection in all species during 2011-2013. All tested UME bottlenose dolphins were positive for cetacean morbillivirus (CeMV), and the pathology included interstitial pneumonia, lymphoid depletion and syncytia. Concurrent pathologies, including lung parasite and fungal infections, and severe cutaneous bruising were observed in many dolphins. The event coincided with elevated water temperatures, a diatom bloom and significant fish die-offs. We conclude that the cause for the UME was multifactorial and that CeMV was a major contributor. PMID- 28083116 TI - Evolving interactions between diazotrophic cyanobacterium and phage mediate nitrogen release and host competitive ability. AB - Interactions between nitrogen-fixing (i.e. diazotrophic) cyanobacteria and their viruses, cyanophages, can have large-scale ecosystem effects. These effects are mediated by temporal alterations in nutrient availability in aquatic systems owing to the release of nitrogen and carbon sources from cells lysed by phages, as well as by ecologically important changes in the diversity and fitness of cyanobacterial populations that evolve in the presence of phages. However, ecological and evolutionary feedbacks between phages and nitrogen-fixing cyanobacteria are still relative poorly understood. Here, we used an experimental evolution approach to test the effect of interactions between a common filamentous, nitrogen-fixing cyanobacterium (Nodularia sp.) and its phage on cellular nitrogen release and host properties. Ecological, community-level effects of phage-mediated nitrogen release were tested with a phytoplankton bioassay. We found that cyanobacterial nitrogen release increased significantly as a result of viral lysis, which was associated with enhanced growth of phytoplankton species in cell-free filtrates compared with phage-resistant host controls in which lysis and subsequent nutrient release did not occur after phage exposure. We also observed an ecologically important change among phage-evolved cyanobacteria with phage-resistant phenotypes, a short-filamentous morphotype with reduced buoyancy compared with the ancestral long-filamentous morphotype. Reduced buoyancy might decrease the ability of these morphotypes to compete for light compared with longer, more buoyant filaments. Together, these findings demonstrate the potential of cyanobacteria-phage interactions to affect ecosystem biogeochemical cycles and planktonic community dynamics. PMID- 28083117 TI - Does the stress response predict the ability of wild birds to adjust to short term captivity? A study of the rock pigeon (Columbia livia). AB - Although the transfer of wild animals to captivity is crucial for conservation purposes, this process is often challenging because some species or individuals do not adjust well to captive conditions. Chronic stress has been identified as a major concern for animals held on long-term captivity. Surprisingly, the first hours or days of captivity have been relatively overlooked. However, they are certainly very stressful, because individuals are being transferred to a totally novel and confined environment. To ensure the success of conservation programmes, it appears crucial to better understand the proximate causes of interspecific and interindividual variability in the sensitivity to these first hours of captivity. In that respect, the study of stress hormones is relevant, because the hormonal stress response may help to assess whether specific individuals or species adjust, or not, to such captive conditions ('the stress response-adjustment to captivity hypothesis'). We tested this hypothesis in rock pigeons by measuring their corticosterone stress response and their ability to adjust to short-term captivity (body mass loss and circulating corticosterone levels after a day of captivity). We showed that an increased corticosterone stress response is associated with a lower ability to adjust to short-term captivity (i.e. higher body mass loss and circulating corticosterone levels). Our study suggests, therefore, that a low physiological sensitivity to stress may be beneficial for adjusting to captivity. Future studies should now explore whether the stress response can be useful to predict the ability of individuals from different populations or species to not only adjust to short-term but also long-term captivity. PMID- 28083118 TI - Correction to 'Evolutionary diversification of retinoic acid receptor ligand binding pocket structure by molecular tinkering'. AB - [This corrects the article DOI: 10.1098/rsos.150484.]. PMID- 28083119 TI - Correction to 'Hypoxia increases the risk of egg predation in a nest-guarding fish'. AB - [This corrects the article DOI: 10.1098/rsos.160326.]. PMID- 28083120 TI - On balance: lifestyle, mental health and wellbeing. AB - Given the supremacy of the biomedical model in defining our understanding and treatment of a wide range of physcial and psychological disorders, it is perhaps curious that simultaneously, scientists, clinicians, governments and patients routinely employ the concepts of "lifestyle" and "balance" to try to explain the causes of bodily disease and psychological disorder. Concurrently, the health advantages that are assumed to be inherent in a "balanced life" have been exploited by a rapidly expanding consumer market in "wellbeing"-by companies and individuals promoting food supplements, "wearable fitness", diet trends and the self-help material. Exploring the tension between the biomedical doctrine and the parallel preoccupation with balance and lifestyle has provided the impetus for this special issue. Emerging originally from papers presented at an interdisciplinary conference held at the University of Exeter in June 2015, and augmented by two further comment pieces, the collection of articles aims to explore the ways in which changing notions of "balance" have been used to understand the causes of mental illness; to rationalise new approaches to its treatment; and to validate advice relating to balance in work and family life. PMID- 28083121 TI - Crystal structure of N-(7-di-bromo-methyl-5-methyl-1,8-naphthyridin-2 yl)benzamide-pyrrolidine-2,5-dione (1/1). AB - The title compound, C17H13Br2N3O.C4H5NO2, is a co-crystal of N-(7-di-bromo-methyl 5-methyl-1,8-naphthyridin-2-yl)benzamide and pyrrolidine-2,5-dione (succinimide). The benzamide mol-ecule exhibits pseudo-mirror symmetry, with an r.m.s. deviation of the non-H atoms of 0.09 A (except for the two Br atoms). The angle between the least-squares planes of the two mol-ecules is 26.2 (2) degrees . In the crystal, the two mol-ecules are mutually linked by N-H?O and N-H?N hydrogen bonds. The packing is consolidated by C-H?(O,N) hydrogen bonds and pi-pi stacking inter actions. PMID- 28083122 TI - Crystal structure of bis-{MU-(E)-2-[(2-oxido-phenyl-imino)-meth-yl]quinolin-8 olato-kappa4O,N,N',O'}bis-[di-butyl-tin(IV)]. AB - Condensation of 8-hy-droxy-quinoline-2-carbaldehyde with 2-amino-phenol gave the (E)-2-[(2-hy-droxy-phenyl-imino)-meth-yl]quinolin-8-ol derivative that reacted with di-n-butyl-tin oxide with release of H2O to yield the chelate title complex, [Sn2(C4H9)4(C16H10N2O2)2]. The compound crystallizes in the triclinic space group P-1, with two independent centrosymmetric dimers in the unit cell. Each features a typical pincer-type structure where the dianionic ligand is tetra-dentate, coordinating to the central tin atom through both phenolate oxygen atoms, as well as through the quinoline and imine N atoms. Each metal atom adopts a distorted penta-gonal-bipyramidal SnC2N2O3 coordination arising from the N,N',O,O'-tetra dentate deprotonated Schiff base, one bridging phenolate O atom of the neighbouring ligand and two butyl groups in the axial sites. PMID- 28083123 TI - Disorder of the dimeric TCNQ-TCNQ unit in the crystal structure of [Ni(bpy)3]2(TCNQ-TCNQ)(TCNQ)2.6H2O (TCNQ is 7,7,8,8-tetra-cyano-quinodi-methane). AB - Crystallization from an aqueous methanol system composed of Ni(NO3)2, 2,2' bipyridine (bpy) and LiTCNQ (TCNQ is 7,7,8,8-tetra-cyano-quinodi-methane) in a 1:3:2 molar ratio yielded single crystals of bis-[tris-(2,2'-bi-pyridine kappa2N,N')nickel(II)] bis-(7,7,8,8-tetra-cyano-quinodi-methane radical anion) bi[7,7,8,8-tetra-cyano-quino-dimethanide] hexa-hydrate, [Ni(C10H8N2)3]2(C24H8N8)(C12H4N4)2.6H2O or [Ni(bpy)3]2(TCNQ-TCNQ)(TCNQ)2.6H2O. The crystal structure comprises [Ni(bpy)3]2+ complex cations, two centrosymmetric crystallographically independent TCNQ .- anion radicals with pi-stacked exo groups, and an additional dimeric TCNQ-TCNQ unit which comprises 75.3 (9)% of a sigma-dimerized (TCNQ-TCNQ)2- dianion and 24.7 (9)% of two TCNQ.- anion radicals with tightly pi-stacked exo groups. The title complex represents the first example of an NiII complex containing a sigma-dimerized (TCNQ-TCNQ)2- dianion. Disordered solvent water mol-ecules present in the crystal structure participate in hydrogen-bonding inter-actions. PMID- 28083124 TI - Crystal structure of (6E,20E)-3,24-di-fluoro-13,14,28,29-tetra-hydro-5H,22H-tetra benzo[e,j,p,u][1,4,12,15]tetra-oxa-cyclo-docosine-5,22-dione. AB - The conformation of the title compound, C34H26F2O6, is cone-shaped, partially determined by intra-molecular C-H?O short contacts. The benzene rings at the top of the cone are inclined to one another by 73.10 (7) degrees , while the benzene rings at the bottom of the cone are inclined to one another by 35.49 (8) degrees . In the crystal, mol-ecules are linked by C-H?O and C-H?F hydrogen bonds, forming a three-dimensional supra-molecular structure. There are also C-H?pi contacts present within the framework structure. PMID- 28083125 TI - Crystal structure of {(S)-1-phenyl-N,N-bis-[(pyridin-2-yl)meth-yl]ethanamine kappa3N,N',N''}bis-(thio-cyanato-kappaN)zinc from synchrotron data. AB - The title ZnII complex, [Zn(NCS)2(C20H21N3)], has been characterized by synchrotron single-crystal diffraction and FT-IR spectroscopy. The central ZnII ion has a distorted square-pyramidal coordination geometry, with three N atoms of the chiral (S) 1-phenyl-N,N-bis-[(pyridin-2-yl)meth-yl]ethanamine (S-ppme) ligand and one N atom of a thio-cyanate anion in the equatorial plane, and one N atom of another thio-cyanate anion at the apical position. The average Zn-N S-ppme and Zn NNCS bond lengths are 2.183 (2) and 1.986 (2) A, respectively. In the crystal, inter-molecular C-H?S hydrogen bonds and a face-to-face pi-pi inter-action [centroid-centroid distance = 3.482 (1) A] link the mol-ecules and give rise to a supra-molecular sheet structure parallel to the ac plane. PMID- 28083126 TI - Crystal structures of (E)-4-[1-(2-carbamo-thio-yl-hydrazinyl-idene)eth-yl]phenyl acetate and (E)-4-[1-(2-carbamo-thio-ylhydrazinyl-idene)eth-yl]phenyl benzoate. AB - In the title compounds, C11H13N3O2S, (I), and C16H15N3O2S, (II), the thio semicarbazone group adopts an extended conformation. The acetate ester (I) crystallizes with two independent mol-ecules in the asymmetric unit. In the benzoate ester (II), the planes of the two aryl rings are inclined to one another by 46.70 (7) degrees . In both compounds, there is a short intra-molecular N-H?N contact present, forming an S(5) ring motif. In the crystals of both compounds, mol-ecules are linked via pairs of N-H?S hydrogen bonds, forming dimers with R22(8) ring motifs. The dimers are linked by N-H?S and N-H?O hydrogen bonds, forming slabs parallel to (01-1). In (I), there are N-H?pi and C-H?pi inter actions present within the slabs, while in (II), there are only N-H?pi inter actions present. PMID- 28083127 TI - Crystal structure of bis-(MU-N-hy-droxy-picolin-amid-ato)bis-[bis-(N-hy-droxy picolinamide)-sodium]. AB - The title compound, [Na2(C6H5N2O2)2(C6H6N2O2)4], is a centrosymmetric coordination dimer based on the sodium(I) salt of N-hy-droxy-picolinamide. The mol-ecule has an {Na2O6(MU-O)2} core with two bridging carbonyl O atoms and two hydroxamate O atoms of two mono-deprotonated residues of N-hy-droxy-picolinamide, while two neutral N-hy-droxy-picolinamide mol-ecules are coordinated in a monodentate manner to each sodium ion via the carbonyl O atoms [the Na-O distances range from 2.3044 (2) to 2.3716 (2) A]. The penta-coordinated sodium ion exhibits a distorted trigonal-pyramidal coordination polyhedron. In the crystal, the coordination dimers are linked into chains along the c axis via N H?O and N-H?N hydrogen bonds; the chains are linked into a two-dimensional framework parallel to (100) via weak C-H?O and pi-pi stacking inter-actions. PMID- 28083128 TI - Crystal structure of bis-{N'-[(E)-4-hy-droxy-benzyl-idene]pyridine-4 carbohydrazide-kappaN1}di-iodidocadmium methanol disolvate. AB - In the title compound, [Cd(C13H11IN3O2)2].2CH3OH, which crystallizes with Z = 4 in the space group Pbcn, the CdII atom is located on a twofold rotation axis and coordinated by two I- anions and two N atoms from the pyridine rings of the two N'-[(E)-4-hy-droxy-benzyl-idene]pyridine-4-carbohydrazide ligands. The geometry around the CdII atom is distorted tetra-hedral, with bond angles in the range 94.92 (11)-124.29 (2) degrees . The iodide anions undergo inter-molecular hydrogen-bonding contacts with the C-H groups of the organic ligands of an adjacent complex mol-ecule, generating a chain structure along the b axis. Furthermore, an extensive series of O-H?O, N-H?O and C-H?O hydrogen-bonding inter actions involving both the complex mol-ecules and the ethanol solvate mol-ecules generate a three-dimensional network. PMID- 28083129 TI - Crystal structure of (perchlorato-kappaO)(1,4,7,10-tetra-aza-cyclo-dodecane kappa4N)copper(II) perchlorate. AB - The crystal structure of the title salt, [Cu(ClO4)(C8H20N4)]ClO4, is reported. The CuII ion exhibits a square-pyramidal geometry and is coordinated by the four N atoms of the neutral 1,4,7,10-tetra-aza-cyclo-dodecane (cyclen) ligand and an O atom from one perchlorate anion, with the second perchlorate ion hydrogen-bonded to one of the amine N atoms of the cyclen ligand. Additional N-H?O hydrogen bonds between the amine H atoms and the coordinating and non-coordinating perchlorate groups create a three-dimensional network structure. Crystals were grown from a concentrated methanol solution at ambient temperature, resulting in no co crystallization of solvent. PMID- 28083130 TI - Synthesis and crystal structure of N-(4-chloro-phen-yl)-5,7-dimethyl-1,2,4 triazolo[1,5-a]pyrimidin-2-amine. AB - The title compound, C13H12ClN5, was synthesized by the cyclization of 1-(4,6-di methyl-pyrimidin-2-yl)-4-phenyl-thio-semicarbazide in the presence of Ni(NO3)2. The mol-ecular structure of the compound is essentially planar. In the crystal, mol-ecules form dimers via pairs of N-H?N hydrogen bonds between the H atom of the exocyclic amino group and the N atom at the 4-position of the triazole ring. The resulting dimers are packed into layers which are connected by pi-stacking inter-actions between the aromatic systems of the pyrimidine and benzene nuclei, and between the triazole cores. PMID- 28083131 TI - Crystal structure of (E)-9-({[4-(di-ethyl-amino)-phen-yl]imino}-meth-yl)-2,3,6,7 tetra-hydro-1H,5H-pyrido[3,2,1-ij]quinolin-8-ol. AB - The title compound, C23H29N3O, was synthesized from the condensation reaction of 8-hy-droxy-julolidine-9-carbaldehyde and N,N-diethyl-p-phenyl-enedi-amine. The hy droxy group forms a intra-molecular hydrogen bond to the imine N atom and generates an S(6) ring motif. The conformation about the C=N bond is E, and the aromatic ring of the julolidine moiety is inclined to the benzene ring by 3.74 (14) degrees . One of the fused non-aromatic rings of the julolidine moiety adopts an envelope conformation and the other has a screw-boat conformation. In the crystal, mol-ecules are linked by C-H?pi inter-actions involving the aromatic julolidine ring, forming slabs parallel to the bc plane. The tricyclic fragment of the julolidine ring and the azomethine C=N bond are disordered over two sets of sites with a refined occupancy ratio of 0.773 (3):0.227 (3). PMID- 28083132 TI - Crystal structure of chlorido-[1-(4-nitro-phen-yl)thio-urea-kappaS]bis-(tri phenyl-phosphane-kappaP)copper(I). AB - The mononuclear mixed-ligand title complex, [CuCl(C7H7N3O2S)(C18H15P)2], displays a distorted tetra-hedral coordination sphere around the CuI atom, with two P atoms from two tri-phenyl-phosphane mol-ecules, one terminal S atom from a 1-(4 nitro-phen-yl)thio-urea mol-ecule and a chloride ion as ligands. An intra molecular N-H?Cl hydrogen bond stabilizes the mol-ecular conformation [graph-set motif R22(6)]. In the crystal, further N-H?Cl hydrogen bonds connect individual mol-ecules into zigzag chains parallel to [001]. The chains are linked by weak C H?O hydrogen-bonding inter-actions into a three-dimensional network. PMID- 28083133 TI - Crystal structure of 2-oxo-2H-chromen-3-yl 4-chloro-benzoate and Hirshfeld surface analysis. AB - In the title compound, C16H9ClO4 the dihedral angle between the coumarin ring system [maximum deviation = 0.023 (1) A] and the benzene ring is 73.95 (8) degrees . In the crystal, pi-pi inter-actions link the dimers into a three dimensional framework. A quantum chemical calculation is in generally good agreement with the observed structure, although the calculated dihedral angle between the ring systems (85.7%) is somewhat larger than the observed value [73.95 (8) degrees ]. Hirshfeld surface analysis has been used to confirm and qu antify the supra-molecular inter-actions. PMID- 28083134 TI - Crystal structure of meso-di-MU-chlorido-bis-[bis-(2,2'-bi-pyridine)-cadmium] bis (1,1,3,3-tetra-cyano-2-ethoxy-propenide) 0.81-hydrate. AB - The hydrated title salt, [Cd2Cl2(C10H8N2)4](C9H5N4O)2.0.81H2O, was obtained from the hydro-thermal reaction between 2,2'-bi-pyridine, cadmium(II) chloride and potassium 1,1,3,3-tetra-cyano-2-eth-oxy-propenide. The binuclear cation lies across a centre of inversion in the space group P21/c, with the other components in general positions. The cation has approximate, but non-crystallographic 2/m symmetry and each of the CdII atoms is a stereogenic centre, one having the Delta configuration and the other the Lambda configuration. In the anion, one of the C(CN)2 units is disordered over two sets of atomic sites having occupancies 0.75 (2) and 0.25 (2). The cations are linked by two independent C-H?Cl hydrogen bonds to form a sheet of R22(14) and R42(24) rings. PMID- 28083135 TI - Crystal structure of catena-poly[[bis-(N-acethyl-thio-morpholine kappaS)copper(I)]-MU-iodido]. AB - The reaction of copper(I) iodide with N-acetyl-thio-morpholine (L, C6H11NOS) in aceto-nitrile results in a coordination polymer with composition [CuI(L)2] n . The CuI atom is coordinated by two S atoms and two I atoms, adopting a distorted tetra-hedral environment. The MU2-bridging mode of the I atoms gives rise to chains extending parallel to [010]. C-H?O hydrogen-bonding inter-actions between the chains lead to a three-dimensional network. PMID- 28083136 TI - Crystal structure of 4-(4b,8a-di-hydro-9H-pyrido[3,4-b]indol-1-yl)-7-methyl-2H chromen-2-one. AB - The title compound, C21H14N2O2, was prepared by Pictet-Spengler cyclization of tryptamine and 4-formyl coumarin. In the mol-ecule, the dihedral angle between the mean planes of the coumarin and beta-carboline ring systems is 63.8 (2) degrees . In the crystal, mol-ecules are linked via N-H?N hydrogen bonds, forming chains along the b-axis direction. Within the chains, there are a number of offset pi-pi inter-actions present [shortest inter-centroid distance = 3.457 (2) A]. PMID- 28083137 TI - Crystal structure of 1-[2-(4-chloro-phen-yl)-4,5-diphenyl-1H-imidazol-1-yl]propan 2-ol. AB - The title compound, C24H21ClN2O, crystallizes with two unique mol-ecules in the asymmetric unit. In each mol-ecule, the central imidazole ring is substituted at the 2-, 4- and 5-positions by benzene rings. The 2-substituted ring carries a Cl atom at the 4-position. One of the imidazole N atoms in each mol-ecule has a propan-2-ol substituent. In the crystal, a series of O-H?N, C-H?O and C-H?Cl hydrogen bonds, augmented by several C-H?pi(ring) inter-actions, generate a three dimensional network of mol-ecules stacked along the a-axis direction. PMID- 28083138 TI - Crystal structures of bis-[(9S,13S,14S)-3-meth-oxy-17-methyl-morphinanium] tetra chlorido-cobaltate and tetra-chlorido-cuprate. AB - (9S,13S,14S)-3-Meth-oxy-17-methyl-morphinan (dextromethorphan) forms two isostructural salts with (a) tetra-chlorido-cobaltate, namely bis-[(9S,13S,14S)-3 meth-oxy-17-methyl-morphinanium] tetra-chlorido-cobaltate, (C18H26NO)2[CoCl4], and (b) tetra-chlorido-cuprate, namely bis-[(9S,13S,14S)-3-meth-oxy-17-methyl morphinanium] tetra-chlorido-cuprate, (C18H26NO)2[CuCl4]. The distorted tetra hedral anions are located on twofold rotational axes. The dextromethorphan cation can be described as being composed of two ring systems, a tetra-hydro-naphthalene system A+B and a deca-hydro-isoquinolinium subunit C+D, that are nearly perpendicular to one another: the angle between mean planes of the A+B and C+D moieties is 78.8 (1) degrees for (a) and 79.0 (1) degrees for (b). Two symmetry related cations of protonated dextromethorphan are connected to the tetra chlorido-cobaltate (or tetra-chlorido-cuprate) anions via strong N-H?Cl hydrogen bonds, forming neutral ion associates. These associates are packed in the (001) plane with no strong attractive bonding between them. Both compounds are attractive crystalline forms for unambiguous identification of the dextromethorphan and, presumably, of its optical isomer, levomethorphan. PMID- 28083139 TI - Crystal structure of MU-carbonyl-1:2kappa2C:C-carbonyl-1kappaC-(1eta5-cyclo-penta dien-yl)iodido-2kappaI-[MU-2-(pyridin-2-yl)ethene-1,1-diyl 1kappaC1:2kappa2N,C1]ironpalladium(Fe-Pd) benzene monosolvate. AB - The reaction of Cp(CO)2FeI with 2-ethynyl-pyridine under Sonogashira conditions [5% PdCl2(PPh3)2, 10% CuI, THF-NEt3 (2:1)] afforded the title binuclear MU pyridyl-vinyl-idene FePd complex (FePd1) as a benzene solvate, [FePd(C5H5)(C7H5N)I(CO)2].C6H6, in a very low yield rather than the expected iron o-pyridyl-ethynyl complex Cp(CO)2Fe-C=C-(2-C5H4N). The Fe and Pd atoms in FePd1 are bridged by carbonyl and pyridyl-vinyl-idene ligands, the pyridyl N atom being bonded to the palladium atom. The use of equimolar amounts of PdCl2 increases the yield of FePd1 to 12%. The reaction pathway leading to FePd1 is proposed. PMID- 28083140 TI - Crystal structure of bis-[cis-(1,4,8,11-tetra-aza-cyclo-tetra-deca-ne kappa4N)bis(thio-cyanato-kappaN)chrom-ium(III)] dichromate monohydrate from synchrotron X-ray diffraction data. AB - The structure of the complex salt, cis-[Cr(NCS)2(cyclam)]2[Cr2O7].H2O (cyclam = 1,4,8,11-tetra-aza-cyclo-tetra-decane, C10H24N4), has been determined from synchrotron data. The asymmetric unit comprises of one [Cr(NCS)2(cyclam)]+ cation, one half of a Cr2O72- anion (completed by inversion symmetry) and one half of a water mol-ecule (completed by twofold rotation symmetry). The CrIII ion is coordinated by the four cyclam N atoms and by two N atoms of cis-arranged thio cyanate anions, displaying a distorted octa-hedral coordination sphere. The Cr N(cyclam) bond lengths are in the range 2.080 (2) to 2.097 (2) A while the average Cr-N(NCS) bond length is 1.985 (4) A. The macrocyclic cyclam moiety adopts the cis-V conformation. The bridging O atom of the dichromate anion is disordered around an inversion centre, leading to a bending of the Cr-O-Cr bridging angle [157.7 (3) degrees ]; the anion has a staggered conformation. The crystal structure is stabilized by inter-molecular hydrogen bonds involving the cyclam N-H groups and water O-H groups as donor groups, and the O atoms of the Cr2O72- anion and water mol-ecules as acceptor groups, giving rise to a three dimensional network. PMID- 28083141 TI - Hydrogen bonds and van der Waals forces as tools for the construction of a herringbone pattern in the crystal structure of hexane-1,6-diaminium hexane-1,6 diyl bis-(hydrogen phospho-nate). AB - The asymmetric unit of the title salt, [H3N(CH2)6NH3][(HO)O2P(CH2)6PO2(OH)], consists of one half of a hexane-1,6-diaminium dication and one half of a hexane 1,6-diyl bis-(hydrogen phospho-nate) dianion. Both are located around different centres of inversion (Wyckoff sites: 2a and 2d) of the space group P21/c. The shape of the hexane-1,6-diaminium cation is best described as a double hook. Both aminium groups as well as the two attached CH2 groups are turned out from the plane of the central four C atoms. In contrast, all six C atoms of the dianion are almost in a plane. The hydrogen phospho-nate (-PO3H) groups of the anions and the aminium groups of the cations form two-dimensional O-H? and O-H?N hydrogen bonded networks parallel to the ac plane, built up from ten-membered and twelve membered ring motifs with graph-set descriptors R33(10) and R54(12), respectively. These networks are linked by the alkyl-ene chains of the anions and cations. The resulting three-dimensional network shows a herringbone pattern, which resembles the parent structures 1,6-di-amino-hexane and hexane-1,6-di phospho-nic acid. PMID- 28083142 TI - Crystal structure and absolute configuration of (3aR,3'aR,7aS,7'aS)-2,2,2',2' tetra-methyl-3a,6,7,7a,3'a,6',7',7'a-octa-hydro-4,4'-bi[1,3-benzodioxol-yl], obtained from a Pd-catalyzed homocoupling reaction. AB - The absolute configuration, i.e. (3aR,3'aR,7aS,7'aS), of the title compound, C18H26O4, synthesized via a palladium-catalyzed homocoupling reaction, was determined on the basis of the synthetic pathway and was confirmed by X-ray diffraction. The homocoupled mol-ecule is formed by two chemically identical moieties built up from two five- and six-membered fused rings. The supra molecular assembly is controlled mainly by C-H?O inter-actions that lead to the formation of hydrogen-bonded chains of mol-ecules along the [001] direction, while weak dipolar inter-actions and van der Waals forces hold the chains together in the crystal structure. PMID- 28083143 TI - Crystal structure of (2R*,3aR*)-2-phenyl-sulfonyl-2,3,3a,4,5,6-hexa-hydro-pyrrolo [1,2-b]isoxazole. AB - The title compound, C12H15NO3S, was prepared by 1,3-dipolar cyclo-addition of 3,4 di-hydro-2H-pyrrole 1-oxide and phenyl vinyl sulfone. In the mol-ecule, both fused five-membered rings display a twisted conformation. In the crystal, C-H?O hydrogen bonds link neighbouring mol-ecules, forming chains running parallel to the b axis. PMID- 28083144 TI - Crystal structure of a rare trigonal bipyramidal titanium(IV) coordination complex: tri-chlorido-(3,3'-di-tert-butyl-2'-hy-droxy-5,5',6,6'-tetra-methyl-1,1' biphenyl-2-olato-kappaO2)(tetra-hydro-furan-kappaO)-titanium(IV). AB - The title compound, [Ti(C24H33O2)Cl3(C4H8O)], is a rare example of a trigonal bipyramidal titanium coordination complex with three chloride and two oxygen donor ligands. The asymmetric unit contains two independent mol-ecules having essentially the same conformation. The mol-ecules feature the titanium(IV) metal cation complexed with three chloride ligands, a tetra-hydro-furan mol-ecule, and one oxygen atom from the resolved ligand precursor (R)-(+)-5,5',6,6'-tetra-methyl 3,3'-di-t-butyl-1,1'-biphenyl-2,2'-diol, where the remaining phenolic hydrogen atom engages in inter-molecular O-H?Cl hydrogen bonding. In one mol-ecule, the THF ligand is disordered over two orientations with refined site occupancies of 0.50 (3). PMID- 28083145 TI - Crystal structure of dirubidium hydrogen citrate from laboratory X-ray powder diffraction data and DFT comparison. AB - The crystal structure of dirubidium hydrogen citrate, 2Rb+.HC6H5O72-, has been solved and refined using laboratory X-ray powder diffraction data, and optimized using density functional techniques. The un-ionized carb-oxy-lic acid group forms helical chains of very strong hydrogen bonds (O?O ~ 2.42 A) along the b axis. The hy-droxy group participates in a chain of intra- and inter-molecular hydrogen bonds along the c axis. These hydrogen bonds result in corrugated hydrogen-bonded layers in the bc plane. The Rb+ cations are six-coordinate, and share edges and corners to form layers in the ab plane. The inter-layer contacts are composed of the hydro-phobic methyl-ene groups. PMID- 28083146 TI - The minimotif synthesis hypothesis for the origin of life. AB - Several theories for the origin of life have gained widespread acceptance, led by primordial soup, chemical evolution, metabolism first, and the RNA world. However, while new and existing theories often address a key step, there is less focus on a comprehensive abiogenic continuum leading to the last universal common ancestor. Herein, I present the "minimotif synthesis" hypothesis unifying select origin of life theories with new and revised steps. The hypothesis is based on first principles, on the concept of selection over long time scales, and on a stepwise progression toward complexity. The major steps are the thermodynamically driven origination of extant molecular specificity emerging from primordial soup leading to the rise of peptide catalysts, and a cyclic feed-forward catalytic diversification of compound and peptides in the primordial soup. This is followed by degenerate, semi-partially conservative peptide replication to pass on catalytic knowledge to progeny protocells. At some point during this progression, the emergence of RNA and selection could drive the separation of catalytic and genetic functions, allowing peptides and proteins to permeate the catalytic space, and RNA to encode higher fidelity information transfer. Translation may have emerged from RNA template driven organization and successive ligation of activated amino acids as a predecessor to translation. PMID- 28083148 TI - Effects of Exercise Training under Hyperbaric Oxygen on Oxidative Stress Markers and Endurance Performance in Young Soccer Players: A Pilot Study. AB - The aim of the present study was to determine the effects of three weeks of hyperbaric oxygen (HBO2) training on oxidative stress markers and endurance performance in young soccer players. Participants (18.6 +/- 1.6 years) were randomized into hyperbaric-hyperoxic (HH) training (n = 6) and normobaric normoxic (NN) training (n = 6) groups. Immediately before and after the 5th, 10th, and 15th training sessions, plasma oxidative stress markers (lipid hydroperoxides and uric acid), plasma antioxidant capacity (6-hydroxy-2,5,7,8 tetramethylchroman-2-carboxylic acid [TROLOX]), arterial blood gases, acid-base balance, bases excess (BE), and blood lactate analyses were performed. Before and after intervention, maximal oxygen uptake (VO2max) and peak power output (PPO) were determined. Neither HH nor NN experienced significant changes on oxidative stress markers or antioxidant capacity during intervention. VO2max and PPO were improved (moderate effect size) after HH training. The results suggest that HBO2 endurance training does not increase oxidative stress markers and improves endurance performance in young soccer players. Our findings warrant future investigation to corroborate that HBO2 endurance training could be a potential training approach for highly competitive young soccer players. PMID- 28083149 TI - Attitudes Regarding Participation in a Diabetes Screening Test among an Assyrian Immigrant Population in Sweden. AB - Immigrants from the Middle East have higher prevalence and incidence of type 2 diabetes (T2D) compared with native Swedes. The aim of the study was to describe and understand health beliefs in relation to T2D as well as attitudes regarding participation in a screening process in a local group of Assyrian immigrants living in Sweden. A qualitative and quantitative method was chosen in which 43 individuals participated in a health check-up and 13 agreed to be interviewed. Interviews were conducted, anthropometric measurements and blood tests were collected, and an oral glucose tolerance test was performed. In total, 13 of the 43 participants were diagnosed with impaired glucose metabolism, 4 of these 13 had TD2. The interviewed participants perceived that screening was an opportunity to discover more about their health and to care for themselves and their families. Nevertheless, they were not necessarily committed to taking action as a consequence of the screening. Instead, they professed that their health was not solely in their own hands and that they felt safe that God would provide for them. Assyrians' background and religion affect their health beliefs and willingness to participate in screening for TD2. PMID- 28083150 TI - Serum Endocan Levels Associated with Hypertension and Loss of Renal Function in Pediatric Patients after Two Years from Renal Transplant. AB - Endocan is an important biomarker of inflammation and endothelial dysfunction that increases in association with several chronic diseases. Few published data have described the role of endocan in pediatric renal transplant (RT) patients. We evaluated the endocan concentrations in 62 children who underwent renal transplantation and assessed their relationships with the patients' blood pressure and loss of renal function. The endocan levels were significantly elevated in the pediatric RT patients who had hypertension and a loss of renal function. We determined positive correlations between the endocan concentrations and the hemodynamic variables (systolic blood pressure: r = 0.416; P = 0.001; pulse pressure: r = 0.412; P = 0.003). The endocan levels were inversely correlated with the estimated glomerular filtration rate (r = -0.388; P = 0.003). An endocan cutoff concentration of 7.0 ng/mL identified pediatric RT patients who had hypertension and a loss of renal function with 100% sensitivity and 75% specificity. In conclusion, the endocan concentrations were significantly elevated in pediatric RT patients who had both hypertension and a loss of renal function. The correlations between the endocan levels and the hemodynamic variables and the markers of renal function strengthen the hypothesis that it is an important marker of cardiorenal risk. PMID- 28083151 TI - Treatment of Light Chain Deposition Disease Using Bortezomib-Based Regimen Followed by Thalidomide-Based Regimen in a Saudi Male. AB - Light chain deposition disease (LCDD) is a rare illness with, as yet, no clear evidence-based guidelines for its treatment. To the best of our knowledge, LCDD has not been previously reported from Saudi Arabia. We present in this report, a 38-year-old Saudi male who presented with clinical features suggestive of hypertensive nephropathy but kidney biopsy later revealed the diagnosis of LCDD. His serum creatinine at presentation was 297 MUmol/L which came down to 194 MUmol/L on treatment with Bortezomib, Cyclophosphamide and Dexamethasone. His 24 hour protein excretion at presentation was 6 g/L which also came down to less than 1 g/day. He was later placed on Cyclophosphamide, Thalidomide, and Dexamethasone regimen because of persistent high titres of serum free light chains. He went into remission with undetectable serum free light chains and remained so for three years at the time of writing this report. We conclude that LCDD, though rare, does occur in Saudi population. The treatment of LCDD is challenging but the use of Bortezomib, a proteosome inhibitor, is promising. However, suboptimal response may require further treatment with other therapeutic options such as chemotherapy with alkylating agents or high-dose Melphalan with autologous stem cell transplant. PMID- 28083152 TI - Giant Anterior Chest Wall Basal Cell Carcinoma: An Approach to Palliative Reconstruction. AB - Anterior chest wall giant basal cell carcinoma (GBCC) is a rare skin malignancy that requires a multidisciplinary treatment approach. This case report demonstrates the challenges of anterior chest wall GBCC reconstruction for the purpose of palliative therapy in a 72-year-old female. Surgical resection of the lesion included the manubrium and upper four ribs. The defect was closed with bilateral pectoral advancement flaps, FlexHD, and pedicled VRAM. The palliative nature of this case made hybrid reconstruction more appropriate than rigid sternal reconstruction. In advanced metastatic cancers, the ultimate goals should be to avoid risk for infection and provide adequate coverage for the defect. PMID- 28083147 TI - Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression. AB - Protein synthesis can be segmented into distinct phases comprising mRNA translation initiation, elongation, and termination. Translation initiation is a highly regulated and rate-limiting step of protein synthesis that requires more than 12 eukaryotic initiation factors (eIFs). Extensive evidence shows that the transcriptome and corresponding proteome do not invariably correlate with each other in a variety of contexts. In particular, translation of mRNAs specific to angiogenesis, tumor development, and apoptosis is altered during physiological and pathophysiological stress conditions. In cancer cells, the expression and functions of eIFs are hampered, resulting in the inhibition of global translation and enhancement of translation of subsets of mRNAs by alternative mechanisms. A precise understanding of mechanisms involving eukaryotic initiation factors leading to differential protein expression can help us to design better strategies to diagnose and treat cancer. The high spatial and temporal resolution of translation control can have an immediate effect on the microenvironment of the cell in comparison with changes in transcription. The dysregulation of mRNA translation mechanisms is increasingly being exploited as a target to treat cancer. In this review, we will focus on this context by describing both canonical and noncanonical roles of eIFs, which alter mRNA translation. PMID- 28083153 TI - A Retroperitoneal Isolated Enteric Duplication Cyst Mimicking a Teratoma: A Case Report and Literature Review. AB - Enteric duplication cysts lacking anatomic association with the gastrointestinal tract are called isolated enteric duplication cysts (IEDCs). We present an atypical case of a retroperitoneal IEDC with a tortuous tubular complex shape that enfolded the surrounding retroperitoneal fat and mimicked a retroperitoneal teratoma. Multiplanar reconstruction images should be used to evaluate such a lesion correctly. A tortuous tubular complex shape could be a key finding to differentiate from other retroperitoneal cysts. PMID- 28083154 TI - Assessment of Health-Related Quality of Life for Caregivers of Alzheimer's Disease Patients. AB - Background. Alzheimer's disease (AD) dementia is a chronic neurodegenerative disorder that results in total cognitive impairment and functional decline. Family members are the most usual caregivers worldwide, resulting in a subsequent degradation of their quality of life. Methods. During November 2013-March 2014 in Athens, Greece, 155 AD patients' family caregivers' Health-Related Quality of Life and existence of depressive symptomatology were assessed. Results. A strong negative correlation between the dimensions of HRQoL and the scores of the depression scale was revealed. AD patients' caregivers have a lower HRQoL almost in all dimensions compared to the Greek urban general population. The caregivers' social role, the existence of emotional problems, and their mental health status led to this result. Furthermore significantly important differences in caregivers' total HRQoL and depressive symptomatology were indicated in relation to their gender, hypertension existence, patient care frequency, cohabitation with the patient, disease aggravation, and economic status. Conclusions. Caring for relatives with AD strongly correlates with negative caregivers' HRQoL scores and adversely affects their depressive symptomatology. This negative correlation is enhanced in the later stages of the disease, in greater frequency of care, through living with a patient, in poor financial status, and with the existence of a chronic illness. PMID- 28083155 TI - Impact of Auxins on Vegetative Propagation through Stem Cuttings of Couroupita guianensis Aubl.: A Conservation Approach. AB - The present study explores the potential of exogenous auxins in the development of adventitious shoots and roots from shoot cuttings of Couroupita guianensis (Nagalingam), a threatened tree. Experiments were conducted to assess the effect of various concentrations of auxins on shoot and root morphological traits of stem cuttings in the greenhouse. Amongst the auxins tested, significant effects on number of shoot buds' induction and their growth were observed with alpha Naphthalene Acetic Acid (NAA) treated nodal cuttings. Cent percentage of the stem cuttings of C. guianensis were rooted and shoots were induced when pretreated with 400 mg L-1 NAA for 5 min. Maximum 79% of stem cuttings responded to pretreatment of 300 mg L-1indole-3-butyric acid (IBA) for 5 min, and 75% of stem cuttings induced shoots with 400 mg L-1indole-3-acetic acid (IAA). Presence of at least 5 nodes on stem cuttings was found to be prerequisite for root and shoot induction. About 92% of plants were survived under natural soil conditions raised from the stem cuttings. This is the first report of vegetative propagation of C. guianensis through stem cuttings which could be used for conservation strategy and sustainable utilization of this threatened medicinal tree. PMID- 28083157 TI - Is Better Patient Safety Associated with Less Malpractice Activity?: Evidence from California. AB - In principle, efforts to improve patient safety, if they are successful, should lead to reductions in claims of medical malpractice. In practice, however, this has not yet been systematically demonstrated to be so. The authors examined the relationship between safety outcomes in hospitals and malpractice claiming against providers, using administrative data and measures for California from 2001 to 2005. They found that decreases in the county-level frequency of adverse safety outcomes were positively and significantly associated with decreases in the volume of malpractice claims, as captured by records from four of the largest malpractice insurers in the state. This result suggests that policy options that improve patient safety may offer a new avenue for reducing malpractice pressure on physicians, at the same time that they improve clinical outcomes. PMID- 28083156 TI - Primary Care Providers Knowledge, Attitude and Practices Related to Hepatitis C Screening and Treatment in the Oral Direct Acting Antiviral Agents Era. AB - BACKGROUND: There are over 3 million Americans infected with hepatitis C virus (HCV). Despite recent advances in HCV treatment, a major barrier to care remains a limited number of treaters. HCV therapy provision by primary care providers (PCPs) could expand access by increasing the pool of HCV treating clinicians. OBJECTIVE: To characterize current HCV care practices, willingness and self efficacy of PCPs to become HCV treaters. DESIGN PARTICIPANTS AND MAIN MEASURES: Two hundred and seventy one PCPs were identified from community clinics affiliated with a large academic center and 4 large federally qualified health centers in Baltimore, MD. An internet-based survey was administered to assess provider demographics, clinical practice site and willingness to provide HCV care. Factors associated with willingness to provide HCV care were examined using odds ratios (OR). KEY RESULTS: Among 129 (48%) PCPs who responded, the majority (70%) had an MD/DO degree and were white (60%). Only a few PCPs, 12 (10%), had treated at least 1 patient for HCV in the prior year. Although only 22% agreed that HCV treatment should be provided by PCPs, 84% were interested in more HCV training. Willingness to provide treatment was strongly linked to having a high proportion of HCV-infected patients (>20% versus <20%; OR 3.9; 95% confidence interval [CI] 1.5-10) and availability of other services at the primary care site including HIV treatment (OR 6.5; 95% CI 2.5-16.5), substance abuse treatment (OR 3.3; 95% CI 1.3-8.4) and mental health services (OR 4.9; 95% CI 2.0-12.1). CONCLUSION: These data suggest that efforts to expand HCV medical provider capacity will be most impactful if they initially focus HCV training on PCPs with a high prevalence of HCV among their patients and existing systems to support HCV care. PMID- 28083158 TI - The War Within: Preventing Suicide in the U.S. Military. AB - Since late 2001, U.S. military forces have been engaged in conflicts around the globe, most notably in Iraq and Afghanistan. These conflicts have exacted a substantial toll on soldiers, marines, sailors, and airmen, and this toll goes beyond the well-publicized casualty figures. It extends to the stress that repetitive deployments can have on the individual servicemember and his or her family. This stress can manifest itself in different ways-increased divorce rates, spouse and child abuse, mental distress, substance abuse-but one of the most troubling manifestations is suicide, which is increasing across the U.S. Department of Defense (DoD). The increase in suicides among members of the military has raised concern among policymakers, military leaders, and the population at large. While DoD and the military services have had a number of efforts under way to deal with the increase in suicides among their members, the Assistant Secretary of Defense for Health Affairs asked RAND to review the current evidence detailing suicide epidemiology in the military, identify "state of-the-art" suicide-prevention programs, describe and catalog suicide-prevention activities in DoD and across each service, and recommend ways to ensure that the activities in DoD and across each service reflect state-of-the-art prevention science. PMID- 28083159 TI - Payment Reform: Analysis of Models and Performance Measurement Implications. AB - Insurers and purchasers of health care in the United States are on the verge of potentially revolutionary changes in the approaches they use to pay for health care. Recently, purchasers and insurers have been experimenting with payment approaches that include incentives to improve quality and reduce the use of unnecessary and costly services. The Patient Protection and Affordable Care Act of 2010 is likely to accelerate payment reform based on performance measurement. This article provides details of the results of a technical report that catalogues nearly 100 implemented and proposed payment reform programs, classifies each of these programs into one of 11 payment reform models, and identifies the performance measurement needs associated with each model. A synthesis of the results suggests near-term priorities for performance measure development and identifies pertinent challenges related to the use of performance measures as a basis for payment reform. The report is also intended to create a shared framework for analysis of future performance measurement opportunities. This report is intended for the many stakeholders tasked with outlining a national quality strategy in the wake of health care reform legislation. PMID- 28083160 TI - International Variation in the Usage of Medicines: A Review of the Literature. AB - This article describes a review of the published and grey literature on international variation in the use of medicines in six areas (osteoporosis, atypical anti-psychotics, dementia, rheumatoid arthritis, cardiovascular disease/lipid-regulating drugs (statins), and hepatitis C). We identify three broad groups of determinants of international variation in medicines use: (1) Macro- or system level factors: Differences in reimbursement policies, and the role of health technology assessment, were highlighted as a likely driving force of international variation in almost all areas of medicines use reviewed. A related aspect is patient co-payment, which is likely to play an important role in the United States in particular. The extent to which cost-sharing policies impact on overall use of medicines in international comparison remains unclear. (2) Service organisation and delivery: Differences in access to specialists are a likely driver of international variation in areas such as atypical anti psychotics, dementia, and rheumatic arthritis, with for example access to and availability of relevant specialists identified as acting as a crucial bottleneck for accessing treatment for dementia and rheumatoid arthritis. (3) Clinical practice: Studies highlighted the role of variation in the use and ascertainment methods for mental disorders; differences in the use of clinical or practice guidelines; differences in prescribing patterns; and reluctance among clinicians in some countries to take up newer medicines. Each of these factors is likely to play a role in explaining international variation in medicines use, but their relative importance will vary depending on the disease area in question and the system context. PMID- 28083161 TI - The Role of Faith-Based Organizations in HIV Prevention and Care in Central America. AB - Faith-based organizations (FBOs) have historically played an important role in delivering health and social services in developing countries; however, little research has been done on their role in HIV prevention and care, particularly in Latin America. This article summarizes a study that describes FBO involvement in HIV/AIDS in three Central American countries hard hit by this epidemic: Belize, Guatemala, and Honduras. Summarizing the results of key informant and stakeholder interviews with health and FBO leaders and site visits to FBO-sponsored HIV/AIDS clinics, hospices, programs, and other activities, the authors describe the range of FBO activities and assess the advantages of FBO involvement in addressing HIV/AIDS, such as churches' diverse presence and extensive reach, and the challenges to such involvement, such as the unwillingness of some FBOs to discuss condom use and their lack of experience in evaluating the impact of programs. The authors conclude with a discussion of possible ways that FBOs can address the HIV epidemic, both independently and in collaboration with other organizations, such as government ministries of health. PMID- 28083162 TI - Building Community Resilience to Disasters: A Way Forward to Enhance National Health Security. AB - Community resilience, or the sustained ability of a community to withstand and recover from adversity, has become a key policy issue at federal, state, and local levels, including in the National Health Security Strategy. Because resources are limited in the wake of an emergency, it is increasingly recognized that resilience is critical to a community's ability to reduce long recovery periods after an emergency. This article shares details of a report that provides a roadmap for federal, state, and local leaders who are developing plans to enhance community resilience for health security threats and describes options for building community resilience in key areas. Based on findings from a literature review and a series of community and regional focus groups, the authors provide a definition of community resilience in the context of national health security and a set of eight levers and five core components for building resilience. They then describe suggested activities that communities are pursuing and may want to strengthen for community resilience, and they identify challenges to implementation. PMID- 28083163 TI - Disease Management Evaluation: A Comprehensive Review of Current State of the Art. AB - Many countries across Europe and elsewhere have been experimenting with various structured approaches to manage patients with chronic illness as a way to improve quality of care, reduce costs and lead to better population health outcomes in the long run. Despite a body of studies of disease management interventions, uncertainty about the effects of these remains not least because current guidance on evaluation methods and metrics require further development to enhance scientific rigour while also being practical in routine operations. This article provides details from a report that reviews the academic and grey literature to help advance the task of improving the science of assessing disease management initiatives in Europe. Challenges identified are methodological, analytical and conceptual in nature, with a key issue being the establishment of the counterfactual. An array of sophisticated statistical techniques and analytical frameworks can assist in the construction of a sound comparison strategy when a randomised controlled trial is not possible. Issues to consider include: a clear framework of the mechanisms of action and expected effects of disease management; an understanding of the characteristics of disease management (scope, content, dose, context), and of the intervention and target populations (disease type, severity, case-mix); a period of observation over multiple years; and a logical link between performance measures and the intervention's aims and underlying theory of behaviour change. PMID- 28083164 TI - Developing Military Health Care Leaders: Insights from the Military, Civilian, and Government Sectors. AB - The U.S. Department of Defense has highlighted the importance of preparing health care leaders to succeed in joint, performance-based environments. The current wartime environment, rising health care costs, and an increased focus on joint operations have led to recommendations for Military Health System (MHS) transformation. Part of that transformation will involve improving the identification and development of potential MHS leaders. An examination of how candidates are identified for leadership positions, the training and education opportunities offered to them, and the competencies they are expected to achieve revealed both a range of approaches and several commonalities in the military, civilian, and government sectors. A conceptual framework guided a series of interviews with senior health care executives from a wide range of organizations and military health care leaders from the Army, Navy, and Air Force, as well as a case study of the leader development approaches used by the Veterans Health Administration. Several themes emerged in terms of how leaders are developed in each sector, including the importance of mentoring, career counseling, 360-degree feedback, self-development, and formal education and training programs. Lessons learned in the civilian and government sectors hold importance for transforming the way in which MHS identifies and develops health care officers with high leadership potential for senior executive positions. PMID- 28083165 TI - Chronic Kidney Disease-A Quiet Revolution in Nephrology: Six Case Studies. AB - This article describes a study that examines changes in nephrology as it evolves from a focus on end-stage renal disease (ESRD) to the treatment of earlier stages of chronic kidney disease (CKD). Once patients reach ESRD, treatments are limited to kidney transplantation and dialysis. However, the progression of earlier stages of CKD can be slowed, halted, or reversed when treated. Data from 15 clinics focusing on CKD were examined, with the focus on six case studies. Clinics are still establishing best-practice models, and reimbursement remains a challenge. Recommendations also include widespread education for primary care physicians on how to interpret levels of kidney function and on referral of patients with decreased kidney function to nephrologists before ESRD is reached. PMID- 28083166 TI - Feasibility and Design Options for a Potential Entity to Research the Comparative Effectiveness of Medical Treatments. AB - In 2008, the Massachusetts state legislature mandated an examination of the feasibility of the state's participation in establishing a comparative effectiveness center (CEC) and requested recommendations for the entity's design. "Comparative effectiveness" research involves the direct comparative assessment of the efficacy and cost-effectiveness of health care interventions and strategies. The center's findings would guide purchasing and payment decisions related to medical procedures, devices, drugs, and biologics by public- and private-sector organizations. The state has several options in terms of its approach to comparative effectiveness research. It could establish an interstate CEC that synthesizes existing findings for regional decisionmakers, it could establish an interstate CEC that supports new research, it could join an existing CEC, it could join the Drug Effectiveness Review Project and the Medicare Evidence-Based Decisions Project and also establish a regional center, or it could elect not to establish a CEC at all. An exploration of the options and the types of research that could be sponsored reveals that all of the options are potentially feasible, but the legislature's decision with regard to design must consider the level of prioritization of comparative effectiveness research relative to other approaches to improving health care quality and reducing spending growth. PMID- 28083167 TI - How Health Systems Make Available Information on Service Providers: Experience in Seven Countries. AB - This article provides details on a report that reviews and discusses information systems reporting on the quality or performance of providers of healthcare ("quality information systems") in seven countries: Denmark, England, Germany, Italy, the Netherlands, Sweden and the United States. Data collection involves a review of the published and grey literature and is complemented by information provided by key informants in the selected countries using a detailed questionnaire. Quality information systems typically address a number of audiences, including patients (or respectively the general public before receiving services and becoming patients), commissioners, purchasers and regulators. We observe that as the policy context for quality reporting in countries varies, so also does the nature and scope of quality information systems within and between countries. Systems often pursue multiple aims and objectives, which typically are (a) to support patient choice (b) to influence provider behaviour to enhance the quality of care (c) to strengthen transparency of the provider-commissioner relationship and the healthcare system as a whole and (d) to hold healthcare providers and commissioners to account for the quality of care they provide and the purchasing decisions they make. We emphasise that the main users of information systems are the providers themselves as the publication of information provides an incentive for improving the quality of care. Finally, based on the evidence reviewed, we identify a number of considerations for the design of successful quality information systems, such as the clear definition of objectives, ensuring users' accessibility and stakeholder involvement, as well as the need to provide valid, reliable and consistent data. PMID- 28083168 TI - Views from the Homefront: The Experiences of Youth and Spouses from Military Families. AB - As the United States continues deployments of service members to support operations in Iraq and Afghanistan, it is increasingly important to understand the effects of this military involvement, not only on service members but also on the health and well-being of their spouses and youth. This article shares highlights from a study that examined the functioning of a sample of youth in military families who applied to a free camp for children of military personnel and to specifically assess how these youth are coping with parental deployment. It addresses the general well-being of military youth during and after parental deployment, with attention to their emotional, social, and academic functioning. It also examines the challenges that their nondeployed caregivers face. The study included quantitative and qualitative components: three waves of phone surveys with youth and nondeployed caregivers, and in-depth interviews with a subsample of caregivers. The researchers found that children and caregivers who had applied to attend the camp confronted significant challenges to their emotional well being and functioning. Four factors in particular-(1) caregiver emotional well being, (2) more cumulative months of deployment, (3) National Guard or Reserve status, and (4) quality of caregiver-youth communication-were strongly associated with greater youth or caregiver difficulties. PMID- 28083169 TI - Assessing the Impacts of Revising the Tobacco Products Directive: Study to Support a DG SANCO Impact Assessment. AB - Tobacco use is one of the largest avoidable causes of morbidity and premature death in the EU. Whilst smoking prevalence in the EU has been declining over the past 30 years, smoking has remained more prevalent among men than women in the EU 27, with some of the new Member States reporting the widest gaps between male and female smokers. For young smokers (13 to 15 years old) this situation is somewhat reversed, with slightly more girls than boys smoking. Against this background, the European Commission Directorate-General for Health and Consumer Protection (DG SANCO) considered a revision of the Tobacco Products Directive 2001/37/EC across five general areas: scope of the directive, labelling requirements, registration and market control fees, ingredients, and sales arrangements. More specifically, the types of policy options under consideration included (but were not limited to): an increase of warning label sizes on the back of packaging to 100%, a restriction for the display of products at retail outlets and an introduction of additional measurement method for TNCO (the modified ISO method) with maximum limits set accordingly. DG SANCO commissioned RAND Europe to provide support in assessing the potential health, macroeconomic, and compliance cost and administrative burden impacts of revising the Tobacco Products Directive. In addition to assessing impacts, the study provides an up-to-date overview of the evidence and basis for current tobacco product regulation that may be of interest to a wider audience interested in tobacco control policies. PMID- 28083170 TI - A Needs Assessment of New York State Veterans: Final Report to the New York State Health Foundation. AB - Mental health disorders and other types of impairments resulting from deployment experiences are beginning to emerge, but fundamental gaps remain in our knowledge about the needs of veterans returning from Iraq and Afghanistan, the services available to meet those needs, and the experiences of veterans who have tried to use these services. This article highlights the findings of a study focused directly on the veterans living in New York state. The study included veterans who currently use U.S. Department of Veterans Affairs (VA) services as well as those who do not; and it looked at needs across a broad range of domains. The authors collected information and advice from a series of qualitative interviews with veterans of Operation Iraqi Freedom (OIF)/Operation Enduring Freedom (OEF) residing in New York, as well as their family members. In addition, they conducted a quantitative assessment of the needs of veterans and their spouses from a sample that is broadly representative of OEF/OIF veterans in New York state. Finally, they conducted a review the services currently available in New York state for veterans. The study found substantially elevated rates of post traumatic stress disorder (PTSD) and major depression among veterans. It also found that both VA and non-VA services are critically important for addressing veterans' needs, and that the health care systems that serve veterans are extremely complicated. Addressing veterans' mental health needs will require a multipronged approach: reducing barriers to seeking treatment; improving the sustainment of, or adherence to, treatment; and improving the quality of the services being delivered. Finally, veterans have other serious needs besides mental health care and would benefit from a broad range of services. PMID- 28083171 TI - A Prototype Interactive Mapping Tool to Target Low Health Literacy in Missouri. AB - An estimated 36 percent of American adults have health literacy levels rated at "basic or below," indicating that they have difficulty obtaining, processing, and understanding basic health information and services. To help healthcare decisionmakers in Missouri identify neighborhood-level "hotspots" of suboptimal health or healthcare that may be due to low health literacy, RAND developed a prototype interactive web-based mapping tool. This builds on earlier RAND work to develop a predictive model of health literacy and estimate levels of health literacy in small geographic areas (e.g., census tracts). The interactive mapping tool allows stakeholders to select the level of geography (e.g., census tract, county), obtain information for and map specific regions of interest, select the characteristics to be mapped (i.e., estimates of community-level health literacy, health outcomes and care quality, neighborhood sociodemographic characteristics, and neighborhood health services data), and generate tables and reports on the regions and characteristics of interest. Housed on a dedicated RAND website (http://www.rand.org/health/projects/missouri-health-literacy.html), the mapping tool makes it possible for a range of stakeholders, from health plans to community organizations, to access and use the tool to help address healthcare disparities in their communities. PMID- 28083172 TI - Project Retrosight: Understanding the Returns from Cardiovascular and Stroke Research: The Policy Report. AB - This project explores the impacts arising from cardiovascular and stroke research funded 15-20 years ago and attempts to draw out aspects of the research, researcher or environment that are associated with high or low impact. The project is a case study-based review of 29 cardiovascular and stroke research grants, funded in Australia, Canada and UK between 1989 and 1993. The case studies focused on the individual grants but considered the development of the investigators and ideas involved in the research projects from initiation to the present day. Grants were selected through a stratified random selection approach that aimed to include both high- and low-impact grants. The key messages are as follows: 1) The cases reveal that a large and diverse range of impacts arose from the 29 grants studied. 2) There are variations between the impacts derived from basic biomedical and clinical research. 3) There is no correlation between knowledge production and wider impacts 4) The majority of economic impacts identified come from a minority of projects. 5) We identified factors that appear to be associated with high and low impact. This article presents the key observations of the study and an overview of the methods involved. It has been written for funders of biomedical and health research and health services, health researchers, and policy makers in those fields. It will also be of interest to those involved in research and impact evaluation. PMID- 28083173 TI - Building Bridges: Lessons from a Pittsburgh Partnership to Strengthen Systems of Care for Maternal Depression. AB - Between January 2007 and June 2010, members of the Allegheny County Maternal and Child Health Care Collaborative designed, implemented, and evaluated the Allegheny County Maternal Depression Initiative, a local system-change effort focused on increasing identification, referrals, and engagement in treatment as needed and appropriate for women at high risk for maternal depression. The collaborative was successful in improving key organizational and clinical processes related to the achievement of its aims. This article describes how and why the initiative was created, the processes through which it was implemented and evaluated, and the results and lessons learned. It concludes with recommendations in four areas for practice and policy change designed to expand and sustain the initiative's achievements: improve identification of maternal depression, enhance access to available resources and services, increase engagement in behavioral health treatment, and improve overall system performance. PMID- 28083174 TI - Navigating the Road to Recovery: Assessment of the Coordination, Communication, and Financing of the Disaster Case Management Pilot in Louisiana. AB - In 2009, individuals heavily affected by Hurricanes Katrina and Rita were still in need of social services. The Federal Emergency Management Agency (FEMA) provided funding to the Louisiana Recovery Authority to implement the Disaster Case Management Pilot (DCMP) in order to help people still living in FEMA temporary housing units in April 2009 move to permanent and secure housing and access services. Despite concerted effort by participating agencies, the implementation of the DCMP was fraught with challenges. As a result, the pilot could not be implemented as intended, leaving the needs of many clients not fully met. This article shares details of a study that documents some of the key challenges in coordination, communication, and financing of the program and offers recommendations for future state and FEMA implementation of disaster case management. In light of these challenges, the authors recommend that federal and state governments review the systems used to identify and locate residents in need of disaster case management; these systems performed poorly in the DCMP, making it difficult to appropriately plan services. The stop and start of recovery initiatives led to serious discontinuities in client recovery, so the authors also recommend that federal and state governments consider a single, longer-term recovery initiative that seamlessly acknowledges the stages of human recovery. Improvements in how federal and state governments identify and locate affected residents, consider needs and vulnerabilities in planning, and ensure continuity of services are critical to ensure high-quality disaster case management. PMID- 28083175 TI - The Impact of the Coverage-Related Provisions of the Patient Protection and Affordable Care Act on Insurance Coverage and State Health Care Expenditures in California: An Analysis from RAND COMPARE. AB - The Patient Protection and Affordable Care Act (ACA) contains substantial new requirements aimed at increasing rates of health insurance coverage. Because many of these provisions impose additional costs on the states, officials need reliable estimates of the likely impact of the ACA in their state. To demonstrate the usefulness of modeling for state-level decisionmaking, RAND undertook a preliminary analysis of the impact of the ACA on five states-California, Connecticut, Illinois, Montana, and Texas-using the RAND COMPARE microsimulation model. For California, the model predicts that, in 2016 (the year that all of the provisions in the ACA related to coverage expansion will be fully implemented), the uninsured rate in California will fall to 4 percent; without the law, it would remain at 20 percent. The model projects that total state government spending on health care will be 7 percent higher for the combined 2011-2020 period because of the ACA. PMID- 28083176 TI - Promoting Psychological Resilience in the U.S. Military. AB - As U.S. service members deploy for extended periods on a repeated basis, their ability to cope with the stress of deployment may be challenged. A growing number of programs and strategies provided by the military and civilian sectors are available to encourage and support psychological resilience to stress for service members and families. Though previous research from the field of psychology delineating the factors that foster psychological resilience is available, there has been no assessment of whether and how well the current military resilience programs are addressing these factors in their activities. Further, little is known about the effectiveness of these programs on developing resilience. To assist the Department of Defense in understanding methodologies that could be useful in promoting resilience among service members and their families, the research team conducted a focused literature review to identify evidence-informed factors for promoting psychological resilience. The team also reviewed a subset of military resilience programs to determine the extent to which they included those evidence-informed factors. This article describes the context, approach, and findings from these research activities. PMID- 28083177 TI - Source Materials for the Healthy Communities Toolkit: A Resource Guide for Community and Faith-Based Organizations. AB - The Patient Protection and Affordable Care Act places significant emphasis on the role of community-based health promotion initiatives; within this focus, community and faith-based organizations (CFBOs) are seen as critical partners for improving community well-being. This article describes a report that provides the content for a toolkit that will prepare community and faith-based organizations to take advantage of opportunities presented in the Patient Protection and Affordable Care Act and engage faith and community leaders in promoting health in their communities. This includes key facts and figures about health topics, handouts for community groups, and web links for resources and other information in the following areas: healthcare reform; community health centers and development of the community health workforce; promotion of healthy families; mental health; violence and trauma; prevention of teen and unintended pregnancy and HIV/AIDS; and chronic disease prevention. The report also includes recommendations for testing the content of the toolkit with communities and considerations for its implementation. PMID- 28083178 TI - Recovery Under the Medicare Secondary Payer Act: Impact of Reporting Thresholds. AB - Effective January 1, 2012, Medicare will require insurers and self-insured companies to report settlements, awards, and judgments that involve a Medicare beneficiary to the Centers for Medicare and Medicaid Services (CMS). In the first year of the law's implementation, claims resolved for less than $5,000 will be exempt from the reporting requirement. In the second year, the threshold for reporting will fall to $2,000 and then $600. In the third year, all claims will have to be reported regardless of payment size. As a first step toward informing the policy debate about the costs of compliance, the amounts likely to be available for recovery under the Medicare Secondary Payer (MSP) Act, and the effects of different thresholds on these quantities, the researchers analyzed the effects of the eventual phaseout of the $5,000 threshold. The results of the analysis suggest that collecting on low-value claims provides Medicare with relatively little revenue and that such claims represent a substantial fraction of the reporting burden. PMID- 28083179 TI - A Prize Worth Paying?: Non-Standard Ways to Support and Reward Excellence in Health Research and Development in the UK NHS. AB - This article describes a study scoping the issues involved in considering the merits of using prizes to support the objectives of the Department of Health Research and Development Directorate (DH R&D). The paper concludes that there is indeed merit in developing incentives to support excellence in health research in addition to "standard" performance management and routine inspection. These could act either to reinforce the signals created by standard metrics (for example, awards recognising the best performers as measured by standard metrics) or they could "fill the gaps" to encourage behaviour not influenced by conventional incentives. This would create an ecosystem to more effectively link reward with motivation, which could deliver benefits for patients and the health care system more widely. Prizes, it is argued, should play a more significant role in the UK health R&D system than in the past, but it is not suggested that they replace existing systems to support high-quality research and development. PMID- 28083180 TI - How Is Deployment to Iraq and Afghanistan Affecting U.S. Service Members and Their Families?: An Overview of Early RAND Research on the Topic. AB - The conflicts in Iraq and Afghanistan, which have extended over the past decade, have put America's all-volunteer force to its most severe test since its inception in 1973. In this environment of ongoing demand for battle-ready soldiers, sailors, airmen, and marines, there is concern about the effects and consequences of prolonged stress on the force as a whole and on individual service members and their families. The well-being of troops and the people close to them is an issue of much importance, both because it affects military readiness and the ability of the U.S. armed forces to carry out their mission and because the nation is committed to acting on its appreciation of the sacrifices made by military families. To devise policies effective for facilitating the well being of this community, there must first be a comprehensive understanding of the myriad issues and consequences that service members and their families may face because of deployment. Yet for much of the 2000s, this understanding was largely lacking. Recognizing the need for analysis, RAND launched a program of research around 2005, its goal being to investigate this topic and, where possible, offer policymakers informed recommendations. This article introduces this body of work still being added to today-through descriptions of six of RAND's earliest studies on various aspects of the topic. It calls attention to the pressing policy questions; summarizes the key findings, insights into the issues, and policy implications; and, where applicable, lays out recommendations. PMID- 28083181 TI - Employer Self-Insurance Decisions and the Implications of the Patient Protection and Affordable Care Act as Modified by the Health Care and Education Reconciliation Act of 2010 (ACA). AB - The Patient Protection and Affordable Care Act as amended by the Health Care and Education Reconciliation Act of 2010 (ACA) changes the regulatory environment within which health insurance policies on the small-group market are bought and sold. New regulations include rate bands that limit premium price variation, risk adjustment policies that will transfer funds from low-actuarial-risk to high actuarial-risk plans, and requirements that plans include "essential health benefits." While the new regulations will be applied to all non-grandfathered fully insured policies purchased by businesses with 100 or fewer workers, self insured plans are exempt from these regulations. As a result, some firms may have a stronger incentive to offer self-insured plans after the ACA takes full effect. In this article we identify factors that influence employers' decisions to self insure and estimate how the ACA will influence self-insurance rates. We also consider the implications of higher self-insurance rates for adverse selection in the non-self-insured small-group market and whether enrollees in self-insured plans receive different benefits than enrollees in fully-insured plans. Results are based on data analysis, literature review, findings from discussions with stakeholders, and microsimulation analysis using the COMPARE model. Overall, we find little evidence that self-insured plans differ systematically from fully insured plans in terms of benefit generosity, price, or claims denial rates. Stakeholders expressed significant concern about adverse selection in the health insurance exchanges due to regulatory exemptions for self-insured plans. However, our microsimulation analysis predicts a sizable increase in self-insurance only if comprehensive stop-loss policies become widely available after the ACA takes full effect and the expected cost of self-insuring with stop-loss is comparable to the cost of being fully insured in a market without rating regulations. PMID- 28083182 TI - Establishing a Research and Evaluation Capability for the Joint Medical Education and Training Campus. AB - In calling for the transformation of military medical education and training, the 2005 Base Realignment and Closure Commission recommended relocating basic and specialty enlisted medical training to a single site to take advantage of economies of scale and the opportunity for joint training. As a result, a joint medical education and training campus (METC) has been established at Fort Sam Houston, Texas. Two of METC's primary long-term goals are to become a high performing learning organization and to seek accreditation as a community college. Such goals require a clear model of organizational improvement with well defined metrics for measuring its performance and using research and evaluation to assess and improve that performance. Lessons learned from a review of practices at institutions with similar missions-such as community colleges, corporate universities, the UK's Defence Medical Education and Training Agency, and other federal agencies, such as the Veterans Health Administration-establish a clear need for an office of institutional research to help METC attain its organizational goals. They also provide useful recommendations regarding the METC office's structure, scope, and governance. PMID- 28083183 TI - Healthcare Technology Co-Operatives: Filling a Niche in the English R&D Landscape. AB - The Department of Health (England) commissioned this evaluation of the pilot Health Technology Cooperatives (HTCs), which are part of its research infrastructure. Its purpose is to explore how this initiative has affected relationships between clinical, industrial and academic partners; how the HTCs fit into the current health innovation landscape; and the alignment of HTC activities to the goals set out in the NIHR strategy. Since the HTC scheme was intended to focus on medical devices, this review investigated how medical device development is being pursued by other similar entities in England, Australia and the USA. The key question was whether the institutional relationships initiated by the HTCs are contributing to the health research system in England and if this scheme is the most effective way of pursuing these relationships. This review had no specific theory or hypothesis to test, so information was gathered so as to allow key conclusions to be drawn and linked to existing theories. This review used documented evidence from the institutions involved as well as interviews. The pilot HTCs have shown that there are different, but equally legitimate, management approaches to the clinician-industry-patient relationship. These different approaches are reflections both of the disease field and the host institution culture. Neither HTC has concluded how best to sustain activities in the long term, particularly core management facilities such as supporting initial meetings with potential partners and early development of technologies from non commercial sources. Recommendations focused on how best to support core HTC activities in the future. PMID- 28083184 TI - The Impact of the Coverage-Related Provisions of the Patient Protection and Affordable Care Act on Insurance Coverage and State Health Care Expenditures in Connecticut: An Analysis from RAND COMPARE. AB - The Patient Protection and Affordable Care Act (ACA) contains substantial new requirements aimed at increasing rates of health insurance coverage. Because many of these provisions impose additional costs on the states, officials need reliable estimates of the likely impact of the ACA in their state. To demonstrate the usefulness of modeling for state-level decisionmaking, RAND undertook a preliminary analysis of the impact of the ACA on five states-California, Connecticut, Illinois, Montana, and Texas-using the RAND COMPARE microsimulation model. For Connecticut, the model predicts that, in 2016 (the year that all of the provisions in the ACA related to coverage expansion will be fully implemented), the uninsured rate in Connecticut will fall to 5 percent; without the law, it would remain at 11 percent. The model projects that total state government spending on health care will be 10 percent lower for the combined 2011 2020 period than it would be without the ACA, mostly because of federal subsidies for residents who would have been covered by Connecticut's state-run health insurance program (State-Administered General Assistance). PMID- 28083185 TI - The Impact of the Coverage-Related Provisions of the Patient Protection and Affordable Care Act on Insurance Coverage and State Health Care Expenditures in Montana: An Analysis from RAND COMPARE. AB - The Patient Protection and Affordable Care Act (ACA) contains substantial new requirements aimed at increasing rates of health insurance coverage. Because many of these provisions impose additional costs on the states, officials need reliable estimates of the likely impact of the ACA in their state. To demonstrate the usefulness of modeling for state-level decisionmaking, RAND undertook a preliminary analysis of the impact of the ACA on five states-California, Connecticut, Illinois, Montana, and Texas-using the RAND COMPARE microsimulation model. For Montana, the model predicts that, in 2016 (the year that all of the provisions in the ACA related to coverage expansion will be fully implemented), the uninsured rate in Montana will fall to 3 percent; without the law, it would remain at 18 percent. The model projects that total state government spending on health care will be 3 percent higher for the combined 2011-2020 period because of the ACA. PMID- 28083186 TI - The Impact of the Coverage-Related Provisions of the Patient Protection and Affordable Care Act on Insurance Coverage and State Health Care Expenditures in Texas: An Analysis from RAND COMPARE. AB - The Patient Protection and Affordable Care Act (ACA) contains substantial new requirements aimed at increasing rates of health insurance coverage. Because many of these provisions impose additional costs on the states, officials need reliable estimates of the likely impact of the ACA in their state. To demonstrate the usefulness of modeling for state-level decisionmaking, RAND undertook a preliminary analysis of the impact of the ACA on five states-California, Connecticut, Illinois, Montana, and Texas-using the RAND COMPARE microsimulation model. For Texas, the model predicts that, in 2016 (the year that all of the provisions in the ACA related to coverage expansion will be fully implemented), the uninsured rate in Texas will fall to 6 percent; without the law, it would remain at 28 percent, the highest in the nation. The model projects that total state government spending on health care will be 10 percent higher for the combined 2011-2020 period because of the ACA. PMID- 28083187 TI - The Impact of the Coverage-Related Provisions of the Patient Protection and Affordable Care Act on Insurance Coverage and State Health Care Expenditures in Illinois: An Analysis from RAND COMPARE. AB - The Patient Protection and Affordable Care Act (ACA) contains substantial new requirements aimed at increasing rates of health insurance coverage. Because many of these provisions impose additional costs on the states, officials need reliable estimates of the likely impact of the ACA in their state. To demonstrate the usefulness of modeling for state-level decisionmaking, RAND undertook a preliminary analysis of the impact of the ACA on five states-California, Connecticut, Illinois, Montana, and Texas-using the RAND COMPARE microsimulation model. For Illinois, the model predicts that, in 2016 (the year that all of the provisions in the ACA related to coverage expansion will be fully implemented), the uninsured rate in Illinois will fall to 3 percent; without the law, it would remain near 15 percent. The model projects that total state government spending on health care will be 10 percent higher for the combined 2011-2020 period because of the ACA. PMID- 28083188 TI - Improving Access to Medicines for Non-Communicable Diseases in the Developing World. AB - Non-communicable diseases (NCDs) now account for the majority of global morbidity and mortality and are increasingly affecting developing countries whose under resourced health care systems also have to handle a high burden of infectious disease. To counter the global devastation caused by NCDs, the United Nations General Assembly decided to "set a new global agenda" and convened a high-level meeting on NCDs in September 2011. In connection with this meeting, the authors of this article took a first step toward developing a policy research agenda for improving access to NCD medicines in developing countries, a step that the research-based pharmaceutical industry, in particular, can carry forward as part of broader global efforts to combat NCD. The authors provide a framework for understanding the obstacles to access for NCD medicines, review specific issues to be confronted within each obstacle in the developing world, identify promising ideas for improving access to NCD medicines, and point to several highly promising areas for the research-based pharmaceutical industry to focus on as it develops its NCD policy research program in close collaboration with other key stakeholders. PMID- 28083189 TI - The Role of Consumer-Controlled Personal Health Management Systems in the Evolution of Employer-Based Health Care Benefits. AB - The passage of the Patient Protection and Affordable Care Act has piqued employers' interest in new benefit designs because it includes numerous provisions that favor cost-reducing strategies, such as workplace wellness programs, value-based insurance design (VBID), and consumer-directed health plans (CDHPs). Consumer-controlled personal health management systems (HMSs) are a class of tools that provide encouragement, data, and decision support to individuals. Their functionalities fall into the following three categories: health information management, promotion of wellness and healthy lifestyles, and decision support. In this study, we review the evidence for many of the possible components of an HMS, including personal health records, web-based health risk assessments, integrated remote monitoring data, personalized health education and messaging, nutrition solutions and physical activity monitoring, diabetes management solutions, medication reminders, vaccination and preventive-care applications, integrated incentive programs, social-networking tools, comparative data on price and value of providers, telehealth consultations, virtual coaching, and an integrated nurse hotline. The value of the HMS will be borne out as employers begin to adopt and implement these emerging technologies, enabling further assessment as their benefits and costs become better understood. PMID- 28083190 TI - National Evaluation of Safe Start Promising Approaches. AB - Safe Start Promising Approaches (SSPA) is the second phase of a community-based initiative focused on developing and fielding interventions to prevent and reduce the impact of children's exposure to violence (CEV). This article shares the results of SSPA, which was intended to implement and evaluate promising and evidence-based programs in community settings. Fifteen program sites across the country were selected to implement a range of interventions for helping children and families cope with the effects of CEV. The settings, populations served, intervention types, types of violence addressed, community partners, and program goals differed across the 15 sites. PMID- 28083191 TI - Medical Care Provided Under California's Workers' Compensation Program: Effects of the Reforms and Additional Opportunities to Improve the Quality and Efficiency of Care. AB - Since 2004, significant changes have been made to the California workers' compensation (WC) system. The Commission on Health and Safety and Workers' Compensation (CHSWC) asked the RAND Corporation to examine the impact that these changes have on the medical care provided to injured workers. This study synthesizes findings from interviews and available information regarding the implementation of the changes affecting WC medical care and identifies areas in which additional changes might increase the quality and efficiency of care delivered under the WC system. To improve incentives for efficiently providing medically appropriate care, California should revise its fee schedule allowances for services provided by hospitals to inpatients, freestanding ambulatory surgery centers, and physicians, create nonmonetary incentives for providing medically appropriate care in the medical provider network (MPN) context through more selective contracting with providers and reducing medical review requirements for high-performing physicians; reduce incentives for inappropriate prescribing practices by curtailing in-office physician dispensing; and implement pharmacy benefit network regulations. To increase accountability for performance, California should revise the MPN certification process to place accountability for meeting MPN standards on the entity contracting with the physician network; strengthen Division of Workers' Compensation (DWC) authorities to provide intermediate sanctions for failure to comply with MPN requirements; and modify the Labor Code to remove payers and MPNs from the definition of individually identifiable data so that performance on key measures can be publicly available. To facilitate monitoring and oversight, California should provide DWC with more flexibility to add needed data elements to medical data reporting and provide penalties for a claim administrator failing to comply with the data-reporting requirements; require that medical cost-containment expenses be reported by category of cost; compile information on the types of medical services that are subject to UR denials and expedited hearings; and expand ongoing monitoring of system performance. Finally, to increase administrative efficiency, California should use an external medical review organization to review medical-necessity determinations, and it should explore best practices of other WC programs and health programs in carrying out medical cost-containment activities. PMID- 28083192 TI - Assessing the Performance of Military Treatment Facilities. AB - The U.S. Department of Defense (DoD) has increasingly confronted financial, managerial, and operational challenges in sustaining health benefits for service members and their families: For example, medical costs are projected to increase to 12 percent of DoD's total budget in 2015, from a level of 8 percent in 2007. To address these challenges, DoD is working to transform business practices within the Military Health System. As part of this effort, DoD has considered setting targets for health care utilization in its military treatment facilities (MTFs) and rewarding or penalizing MTFs according to their performance. In this article, the authors discuss the potential and limitations of using MTF utilization and costs as measures of MTF leaders' performance. Nicosia, Wynn, and Romley report the findings of (1) their qualitative review of performance assessment in the nonmilitary health care sector and (2) their quantitative analysis of how MTF utilization and cost metrics are limited by random variation in the data, and how MTF size and resource-intensive catastrophic cases affect this variation. PMID- 28083193 TI - Policy Options for Addressing Medicare Payment Differentials Across Ambulatory Settings. AB - Under Medicare, many health care services can be provided in a range of ambulatory settings, and improvements in technology and delivery mean that many services no longer require an inpatient hospital stay. Medicare's payment for physician work and malpractice liability expenses is the same regardless of where a service is provided. However, payment differentials exist between settings for the facility-related components of care, such as nursing and other staff salaries, equipment, buildings, and supplies. A three-phase RAND study examined the available data on various procedure costs and payment differentials and the bundling or packaging of services offered to Medicare beneficiaries in physician offices, ambulatory surgical centers, and hospital outpatient departments. Building on exploratory analyses conducted in the first two phases of the study, this article documents findings from the third phase, which sought to identify options for modifying Medicare payment policies to improve the value of services and address the differential in the amount that Medicare pays for similar facility-related services in various settings. The findings confirm that payments tend to be highest for services provided in hospitals, but they also indicate that payment differentials generally exceed cost differentials and vary by procedure. The proposed policy options offer solutions to standardize these differentials and potentially reduce Medicare spending. PMID- 28083194 TI - RAND/UCLA Quality-of-Care Measures for Carpal Tunnel Syndrome: Tools for Assessing Quality of Care and Appropriateness of Surgery. AB - Claims relating to carpal tunnel syndrome (CTS) are common in workers' compensation systems. Given that the human and economic costs related to CTS are considerable, healthcare organizations must be able to offer high-quality care to people affected by this condition. The study on which this article is based is a step toward improving care for CTS. It has produced two unique tools for institutions to use, one for assessing the quality of care received by a population of patients who have or may have CTS, and the other for identifying the appropriateness of surgery for individual patients. Tools that assist in measuring quality of care are fundamental to efforts to improve healthcare quality. Tools that assess the appropriateness of surgery ensure that people who need surgery receive it and, conversely, that people are not subjected to inappropriate operations. Applied in this way, these two tools are likely to improve clinical circumstances and economic outcomes for people with CTS. Together, they can be useful to provider organizations, medical groups, medical certification boards, and other associated decisionmakers attempting to assess, monitor, and provide appropriate care for people with CTS. PMID- 28083195 TI - Evaluation of RxNorm in Ambulatory Electronic Prescribing. AB - Drug prescriptions need to accurately identify the medications that prescribers intend for pharmacists to dispense. However, the set of computer-interpretable identifiers currently used in electronic prescribing (e-prescribing) does not support the specific needs of the prescribers and pharmacists who conduct e prescribing transactions. RxNorm, a drug nomenclature from the National Library of Medicine, assigns a rigorously derived, centrally maintained, and publicly available unique identifier to each clinically distinct drug. It therefore has the potential to greatly improve drug identification in e-prescribing transactions. Through laboratory research and pilot testing, the authors evaluated RxNorm's potential to improve how medications are represented in e prescribing transactions. They found that RxNorm is highly complete for prescription drugs used in ambulatory practice that are within its scope and that it offers substantial efficiency and parsimony gains for communicating health plan formulary information to prescribers. The errors that arose during use were of low clinical significance. In live pilot testing, RxNorm identifiers were successfully added to prescription transactions sent between participating prescribers and pharmacies, and the pharmacies were able to use this information to check for dispensing errors or to disambiguate prescriptions. The authors found that RxNorm appears to provide drug identifiers that more accurately reflect the prescriber's intent than the drug identifier set currently used. PMID- 28083196 TI - Policy Implications of the Use of Retail Clinics. AB - Retail clinics, located within larger retail stores, treat a limited number of acute conditions and offer a small set of preventive services. Although there are nearly 1,200 such clinics in the United States, a great deal about their utilization, relationships with other parts of the health care system, and quality of care remains unknown. The federal government has taken only limited action regarding retail clinics, and little evidence exists about the potential costs and benefits of integrating retail clinics into federal programs and initiatives. Through a literature review, semistructured interviews, and a panel of experts, the authors show that retail clinics have established a niche in the health care system based on their convenience and customer service. Levels of patient satisfaction and of the quality and appropriateness of care appear comparable to those of other provider types. However, we know little about the effects of retail clinic use on preventive services, care coordination, and care continuity. As clinics begin to expand into other areas of care, including chronic disease management, and as the number of patients with insurance increases and the shortage of primary care physicians continues, answering outstanding questions about retail clinics' role in the health care system will become even more important. These changes will create new opportunities for health policy to influence both how retail clinics function and the ways in which their care is integrated with that of other providers. PMID- 28083197 TI - The Effect of the Assessment of Recruit Motivation and Strength (ARMS) Program on Army Accessions and Attrition. AB - The fraction of American youth meeting U.S. Army enlistment standards for weight and body fat has decreased markedly over the past three decades. In response to this adverse trend, in 2005, the Army allowed six Military Entrance Processing Stations (MEPS) to grant an enlistment waiver to applicants who exceeded weight and body fat standards as long as they passed a physical endurance, motivation, and strength test known as the Assessment of Recruit Motivation and Strength (ARMS) test. The test was developed by Army medical scientists who believed that it complements existing physical tests used to identify potential enlistees who would and would not fare well in the military. The Army implemented ARMS at eight additional MEPS in February 2006 and then at the remaining 51 MEPS in April 2006. The authors find that ARMS increased male and female accessions of overweight applicants in the six ARMS study sites by 35 and 62 percent, respectively, between 2004 and 2005. They also report that this substantial increase in overweight accessions had no effect on 6- and 18-month attrition rates. Given the low cost of implementing the program, the authors conclude that ARMS is a highly cost-effective means of screening overweight applicants for military service. PMID- 28083198 TI - Evaluation of DG SANCO Data Management Practices. AB - The European Commission Health and Consumer Protection Directorate-General (DG SANCO) commissioned RAND Europe to provide support in developing a comprehensive data strategy for DG SANCO that meets the needs of increasingly evidence-based policymaking in the future. This work builds on previous work by RAND Europe conducted for DG SANCO, mapping out international good practice of data management. The work described in this study had two aims: to assess the current data management practices within DG SANCO that relate to the four specific issues identified by DG SANCO: data needs, DG SANCO data sources, key partnerships on data, and data quality; and to develop, on the basis of this review, recommendations for improving DG SANCO's current data management and the definition of DG SANCO's Good Practice Model for Data Strategy. This article presents the findings of RAND Europe's analysis. PMID- 28083199 TI - Establishing State Health Insurance Exchanges: Implications for Health Insurance Enrollment, Spending, and Small Businesses. AB - The RAND Corporation's Comprehensive Assessment of Reform Efforts microsimulation model was used to analyze the effects of the Patient Protection and Affordable Care Act (PPACA) on employers and enrollees in employer-sponsored health insurance, with a focus on small businesses and businesses offering coverage through health insurance exchanges. Outcomes assessed include the proportion of nonelderly Americans with insurance coverage, the number of employers offering health insurance, premium prices, total employer spending, and total government spending relative to what would have been observed without the policy change. The microsimulation predicts that PPACA will increase insurance offer rates among small businesses from 53 to 77 percent for firms with ten or fewer workers, from 71 to 90 percent for firms with 11 to 25 workers, and from 90 percent to nearly 100 percent for firms with 26 to 100 workers. Simultaneously, the uninsurance rate in the United States would fall from 19 to 6 percent of the nonelderly population. The increase in employer offer rates is driven by workers' demand for insurance, which increases due to an individual mandate requiring all people to obtain insurance policies. Employer penalties incentivizing businesses to offer coverage do not have a meaningful impact on outcomes. The model further predicts that approximately 60 percent of businesses will offer coverage through the health insurance exchanges after the reform. Under baseline assumptions, a total of 68 million people will enroll in the exchanges, of whom 35 million will receive exchange-based coverage from an employer. PMID- 28083200 TI - Require Individuals to Obtain Coverage. AB - This article explores how requiring individuals to obtain health insurance (an individual mandate) would affect health system performance along nine dimensions. An individual mandate would increase the number of people with coverage by 9 to 34 million, depending on the policy's design. Newly insured individuals would have improved patient experience and increased life expectancy. There is little evidence about how an individual mandate would affect waste; it would have no effect on spending, consumer financial risk, the reliability of receiving recommended care, or system capacity. Implementing an individual mandate would be challenging because it is difficult to determine compliance and enforce penalties for noncompliance. PMID- 28083201 TI - Require Employers to Offer Coverage. AB - This article explores how requiring employers to offer health insurance (an employer mandate) would affect health system performance along nine dimensions. An employer mandate would increase the number of people with coverage by 1.8 to 3.4 million; the newly insured would have better health, as measured by life expectancy. No studies directly analyze how an employer mandate would affect patient experience; it would have no effect on spending, consumer financial risk, waste, the reliability of receiving recommended care, or system capacity. An employer mandate would be moderately challenging to implement primarily because of the need to monitor and enforce compliance. PMID- 28083202 TI - Increase the Use of "Bundled" Payment Approaches. AB - This article explores how increased use of bundled payment approaches would affect health system performance along seven dimensions. Bundled payment approaches have the potential to reduce spending, consumer financial risk, and waste. Evidence is mixed regarding how these approaches would affect health. There is no good evidence about the effects of bundled payments on reliability of care or patient experience. Bundled payment approaches are not applicable to coverage or health system capacity. Implementing bundled payment approaches would require fundamental changes in the way that health care providers bill and are paid for services. PMID- 28083203 TI - Grandfathering in the Small Group Market Under the Patient Protection and Affordable Care Act: Effects on Offer Rates, Premiums, and Coverage. AB - The Patient Protection and Affordable Care Act (PPACA), signed into law by President Barack Obama on March 23, 2010, will introduce new health insurance options for many Americans. While PPACA will alter the health insurance options available to many people, one of the goals of the law is to enable Americans to keep the coverage they currently have if they choose to do so. In an effort to ensure that current coverage options do not change, PPACA exempts existing health insurance plans from certain regulations, a policy known as "grandfathering." Newly offered plans, including plans available through state health insurance exchanges, are not eligible for grandfathering. This paper uses the Comprehensive Assessment of Reform Efforts (COMPARE) microsimulation model to analyze the effects that grandfathering in the small group market will have on outcomes, including the percentage of small firms (with 100 or fewer workers) offering coverage, premium prices in the grandfathered market and in the exchanges, the total number of people enrolled in health insurance coverage, and the number of people enrolled in exchange-based health insurance plans. Results suggest that, while grandfathering may lead to slightly higher exchange premiums, grandfathering is also associated with higher employer-sponsored insurance enrollment and lower government spending. Therefore, grandfathering may be an effective policy if the goal is to maximize the number of people enrolled in employment-based coverage. PMID- 28083204 TI - Modify Federal Tax Code to Create Incentives for Individuals to Obtain Coverage. AB - This article explores how a refundable tax credit to offset the cost of health insurance premiums would affect health system performance along nine dimensions. A refundable tax credit would produce a slight gain in health as measured by life expectancy; 2.3 to 10 million people would become newly insured under this policy change. It is uncertain how the policy would affect waste or patient experience. Refundable tax credits would have no discernable effect on total health care spending, overall consumer financial risk, reliability of care, or health system capacity. Implementing refundable tax credits would be relatively easy. PMID- 28083205 TI - An Analysis of the Labor Markets for Anesthesiology. AB - The roughly 40,000 anesthesiologists (ANs) and anesthesiology residents and 39,000 licensed certified registered nurse anesthetists (CRNAs) and student CRNAs in the United States provide most anesthesiology services. Shortages in this critical area of health care can lead to problems in the provision of health services. The authors' surveys of ANs, CRNAs, and anesthesiology directors included questions about employer types, work hours, earnings, types of anesthesia provision, and technology adoption and preferences. They found a great deal of heterogeneity in work arrangements, clear urban/rural differences in the labor markets for anesthesiology, and even more-pronounced regional differences. In addition to the survey, demand-based and econometric analyses were conducted. The authors conclude that shortage of ANs and CRNAs is highly likely at the national level, with the survey approach providing hints of such a shortage and the economic analysis providing stronger confirmation. Finally, the authors examine the evolution of AN and CRNA labor markets up to 2020 under various scenarios. PMID- 28083206 TI - Enhancing Public Health Emergency Preparedness for Special Needs Populations: A Toolkit for State and Local Planning and Response. AB - Experiences from recent emergencies, such as Hurricanes Katrina and Rita, have shown that current emergency preparedness plans are inadequate to address the unique issues of special needs populations. This article shares details about a toolkit meant to assist state and local public health agencies improve their emergency preparedness activities. It distills the most relevant strategies, practices, and resources from a variety of sources, including peer-reviewed research, government reports, the trade literature, and public health leaders, to identify priority populations and critical strategies. The contents include potential strategies for addressing special needs, summaries of promising practices implemented in communities across the country, information on how to select one or more practices that will work in a specific community, information on how to determine whether a practice is working, and a Web-based Geographic Information Systems (GIS) tool to identify and enumerate those with special needs in communities across the United States. Used together, the toolkit and the GIS tool are intended to provide a comprehensive resource to enable public health planners to account for special needs populations in their emergency preparedness efforts. PMID- 28083207 TI - Seasonal Influenza Vaccine Use by Adults in the U.S.: A Snapshot from the End of the 2009-2010 Vaccination Season. AB - In March 2010, the RAND Corporation surveyed a nationally representative sample of noninstitutionalized adults age 18 and over (n=4,040) to collect data on the receipt of seasonal influenza vaccine in the United States. This overview of the survey results will inform public health officials and other stakeholders about seasonal influenza vaccination of adults shortly following the end of the vaccination season. The information on flu vaccine uptake among population groups should be of interest to those working to increase uptake among different segments of the population, including those specifically recommended for the vaccine by the Advisory Committee on Immunization Practices (ACIP) to the Centers for Disease Control and Prevention. Survey findings indicate that during the 2009 2010 vaccination season, 39 percent of all U.S. adults were vaccinated against seasonal influenza, 45 percent of adults specifically recommended for vaccination were vaccinated, and 48 percent of vaccinated adults received the vaccine at a doctor's office or medical clinic. PMID- 28083208 TI - Living Longer in Mexico: Income Security and Health. AB - This analysis of aging and income security in Mexico establishes that the older population in Mexico is increasing quickly and that this population is especially vulnerable to poverty. Mexican citizens are living longer and overall have experienced an improvement in the quality of life compared to that of prior generations. However, this study demonstrates that social improvements are not affecting the daily lives of all persons equally. The authors attempt to uncover and highlight those differences. One of the primary challenges facing Mexico is a growing older population. The demographic transition in Mexico combined with the lack of formal sources of income in retirement place many older persons in a state of financial insecurity. The information contained in this study and the proposed policy research areas are intended to enlarge the portfolio of options for older Mexicans. The authors analyze wealth and sources of income during retirement, the relationship between health and wealth, urban and rural disparities, and the impact of migration spells to the United States on wealth accumulation and health insurance in Mexico. PMID- 28083209 TI - Value for Money in Donor HIV Funding. AB - Countries with the highest burden of human immunodeficiency virus (HIV) disease are heavily reliant on donor funding from such sources as the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) and the Global Fund to Fight AIDS, Tuberculosis and Malaria for their HIV programs. In recent years, commitments from these organizations have flattened while demand for HIV/AIDS care continues to rise. To meet the continued need for more HIV services in developing countries, existing resources need to be better leveraged, i.e., to provide improved value for the money. This article examines options for improving value for money in HIV funding by using a case study that focuses on the two largest funders, PEPFAR and the Global Fund, with funding for antiretroviral therapy (ART) as its leading example. The authors' assessment of available input and output data suggests that current spending allocations across direct and indirect services are not based on increasing value for money. The authors recommend that expenditure data for PEPFAR be made available to the public in a transparent fashion on an annual basis in a usable format and that the Global Fund make its data accessible for each program funded. They find that program output indicators to track indirect services are incomplete and need to be further developed. The trade-off between providing current services and providing future ones needs to be stated clearly, and funding decisions made accordingly. Finally, given projections that funding for HIV will likely not increase, particularly for low income countries facing the highest HIV burden, an explicit emphasis on improving value for money by finding ways to better leverage existing monies is imperative. PMID- 28083210 TI - An Evaluation of the Use of Performance Measures in Health Care. AB - The National Quality Forum (NQF), a private, nonprofit membership organization committed to improving health care quality performance measurement and reporting, was awarded a contract with the U.S. Department of Health and Human Services (HHS) to establish a portfolio of quality and efficiency measures. The portfolio of measures would allow the federal government to examine how and whether health care spending is achieving the best results for patients and taxpayers. As part of the scope of work under the HHS contract, NQF was required to conduct an independent evaluation of the uses of NQF-endorsed measures for the purposes of accountability (e.g., public reporting, payment, accreditation, certification) and quality improvement. In September 2010, NQF entered into a contract with the RAND Corporation for RAND to serve as the independent evaluator. This article presents the results of the evaluation study. It describes how performance measures are being used by a wide array of organizations and the types of measures being used for different purposes, summarizes key barriers and facilitators to the use of measures, and identifies opportunities for easing the use of performance measures moving forward. PMID- 28083211 TI - Challenges to Value-Enhancing Innovation in Health Care Delivery: Commonalities and Contrasts with Innovation in Drugs and Devices. AB - Limiting the growth of health care costs while improving population health is perhaps the most important and difficult challenge facing U.S. health policymakers. The role of innovation in advancing these social goals is controversial, with many seeing innovation as a major cause of cost growth and many others viewing innovation as crucial for improving the quality of care and health outcomes. The authors argue that mitigating the tension between improving health and controlling costs requires more-nuanced perspectives on innovation. More specifically, they argue that policymakers should carefully distinguish between innovative activities that are worth their social costs and activities that are not worth their social costs and try to encourage the former and discourage the latter. The article considers innovation in drugs, devices, and methods of delivering health care, with particular attention to delivery. PMID- 28083212 TI - Policy Options for Radio Frequency Identification (RFID) Application in Healthcare; a Prospective View: Final Report (D5). AB - This article reviews the state of play of European markets and applications of Radio Frequency Identification (RFID) technology in healthcare in Europe. Based on the current situation the study presents three scenarios for 2020, to describe futures in which the technology and health care sectors develop in different ways. The scenarios were discussed in expert workshops to derive issues that need to be addressed by future policies of the European Union and other stakeholders. The market assessment is based on a review of literature and an analysis of proprietary market data. The information on the state of RFID applications in Health in Europe summarises the results of a literature review, an online Delphi survey, expert interviews and seven cases studies in Europe and the US. The policy analysis is based on the outcomes of a scenario gaming workshop with experts from academia, industry, healthcare providers, policymakers and representatives of patient organisations. PMID- 28083213 TI - International Benchmarking of Healthcare Quality: A Review of the Literature. AB - There is growing interest in the systematic assessment and international benchmarking of quality of care provided in different healthcare systems, and major work is under way to support this process through the development and validation of quality indicators that can be used internationally. Recognising that cross-national data comparison remains a challenge, there is now a considerable body of data that allow for comparisons of healthcare quality in selected areas of care. The study includes a description of existing indicators that could be used to compare healthcare quality in different countries, along with a discussion of specific problems in making comparisons at this level of detail. This is illustrated with case studies of two measures widely used for international comparisons: avoidable mortality and cancer survival. These show both the potential power of cross-national comparisons and some of the difficulties in drawing valid interpretations from the data. The study focuses on the three quality domains identified as important by the NHS Next Stage Review High Quality Care for All, namely effectiveness of care, patient safety and patient experience. It is however important to recognise that access is an important additional component of quality which may be a key determinant of differences in outcome between different countries. Thus comparing quality across countries is only a first step to then assess the causes underlying those differences and determining what actions may be appropriate to take to improve health outcomes. PMID- 28083214 TI - Funding Intensive Care - Approaches in Systems Using Diagnosis-Related Groups. AB - This article summarizes a review of approaches to funding intensive care in health systems that use activity-based payment mechanisms based on diagnosis related groups (DRGs) to reimburse hospital care in Australia (Victoria), Denmark, France, Germany, Italy, Spain, Sweden and the United States (Medicare). The study aims to inform the current debate about options for funding intensive care services for adults, children and newborns in England. Mechanisms of funding intensive care services tend to fall into three broad categories: (1) those that fund intensive care through DRGs as part of one episode of hospital care only (US Medicare, Germany, selected regions in Sweden and Italy; (2) those that use DRGs in combination with co-payments (Victoria, France); and (3) those that exclude intensive care from DRG funding and use an alternative form of payment, for example global budgets (Spain) or per diems (South Australia). The review suggests that there is no obvious example of "best practice" or dominant approach used by a majority of systems. Each approach has advantages and disadvantages, particularly in relation to the financial risk involved in providing intensive care. While the risk of underfunding intensive care may be highest in systems that apply DRGs to the entire episode of hospital care, including intensive care, concerns about potential underfunding were voiced in all systems reviewed here. Arrangements for additional funding in the form of co-payments or surcharges may reduce the risk of underfunding. However, these approaches also face the difficulty of determining the appropriate level of (additional) payment and balancing the incentive effect arising from higher payment. PMID- 28083215 TI - Programs Addressing Psychological Health and Traumatic Brain Injury Among U.S. Military Servicemembers and Their Families. AB - Over the last decade, U.S. military forces have been engaged in extended conflicts that are characterized by increased operational tempo, most notably in Iraq and Afghanistan. While most military personnel cope well across the deployment cycle, many will experience difficulties handling stress at some point; will face psychological health challenges, such as post-traumatic stress disorder or major depression; or will be affected by the short- and long-term psychological and cognitive consequences of a traumatic brain injury (TBI). Over the past several years, the Department of Defense (DoD) has implemented numerous programs that address various components of psychological health along the resilience, prevention, and treatment continuum and focus on a variety of clinical and nonclinical concerns. This article provides detail from an evaluation of 211 programs currently sponsored or funded by DoD to address psychological health and TBI, along with descriptions of how programs relate to other available resources and care settings. It also provides recommendations for clarifying the role of programs, examining gaps in routine service delivery that could be filled by programs, and reducing implementation barriers. Barriers include inadequate funding and resources, concerns about the stigma associated with receiving psychological health services, and inability to have servicemembers spend adequate time in programs. The authors found that there is significant duplication of effort, both within and across branches of service. As each program develops its methods independently, it is difficult to determine which approaches work and which are ineffective. Recommendations include strategic planning, centralized coordination, and information-sharing across branches of service, combined with rigorous evaluation. Programs should be evaluated and tracked in a database, and evidence-based interventions should be used to support program efforts. PMID- 28083216 TI - Tackling Problem Drug Use. AB - The National Audit Office (NAO) is conducting a value-for-money study on the UK Government's 2008 drug strategy, Drugs: Protecting Families and Communities ("the Strategy"). The NAO study, Tackling Problem Drug Use, focuses in particular on local delivery authorities' capacity and capability to effectively tackle problem drug use (PDU) through delivery of local services. To inform the NAO's value-for money study, RAND Europe performed a literature review on problem drug use and reviewed the evidence base, both literature and data, underpinning the Strategy. One of the key findings is that the narrower focus in the UK on most significant harms may be useful, but also carries risks and drawbacks. In addition, we find that the Strategy draws on robust evidence in the area of drug treatment and drug related crime; however, other topics would benefit from further context or detail, and in places it is difficult to relate the evidence base to implications for intervention and delivery of services. PMID- 28083217 TI - The European Alcohol and Health Forum: First Monitoring Progress Report. AB - The European Alcohol and Health Forum was launched in June 2007 following the adoption by the European Commission in October 2006 of the EU strategy to reduce alcohol-related harm. It began as a stakeholder platform of 50 founding members from production and sales organisations, media and advertising organisations, NGOs that work to limit alcohol-related harm, research organisations, professional bodies and others. Membership of the Forum is voluntary and members are expected to commit formally and publicly to concrete actions to reduce alcohol-related harm. These concrete actions are referred to as "commitments." Each commitment must be put in writing in a standardised commitment form, which also includes monitoring information. Such information includes details of the objectives of the commitments, resources allocated to them and outputs produced, as well as dissemination of the results of the commitments alongside other information. PMID- 28083218 TI - Bibliometrics as a Tool for Supporting Prospective R&D Decision-Making in the Health Sciences: Strengths, Weaknesses and Options for Future Development. AB - Bibliometric analysis is an increasingly important part of a broader "toolbox" of evaluation methods available to research and development (R&D) policymakers to support decision-making. In the US, UK and Australia, for example, there is evidence of gradual convergence over the past ten years towards a model of university research assessment and ranking incorporating the use of bibliometric measures. In Britain, the Department of Health (England) has shown growing interest in using bibliometric analysis to support prospective R&D decision making, and has engaged RAND Europe's expertise in this area through a number of exercises since 2005. These range from the macro-level selection of potentially high impact institutions, to micro-level selection of high impact individuals for the National Institute for Health Research's faculty of researchers. The aim of this study is to create an accessible, "beginner's guide" to bibliometric theory and application in the area of health R&D decision-making. The study also aims to identify future directions and possible next steps in this area, based on RAND Europe's work with the Department of Health to date. It is targeted at a range of audiences, and will be of interest to health and biomedical researchers, as well as R&D decision-makers in the UK and elsewhere. The study was completed with funding support from RAND Europe's Health R&D Policy Research Unit with the Department of Health. PMID- 28083219 TI - Changing the Translational Research Landscape: A Review of the Impacts of Biomedical Research Units in England. AB - This article describes a review of the Biomedical Research Units (BRU) scheme, undertaken for the Department of Health. This review was a perceptions audit of senior executives involved in the scheme, and explored what impact they felt the scheme is having on the translational research landscape. More specifically, we investigated whether and how institutional relationships between NHS and academic partners, industry and other health research system players are changing because of the scheme; how the scheme is helping build critical mass in specific priority disease areas; and the effects of any changes on efforts to deliver the broader goals set out in Best Research for Best Health. The views presented are those of study informants only. The information obtained through our interviews suggests that the BRU scheme is significantly helping shape the health research system to pursue translational research and innovation, with the clear goal of realising patient benefit. The BRUs are already contributing to observable changes in institutional relationships between the NHS and academic partners: trusts and medical schools are collaborating more closely than in the past, have signed up to the same vision of translational research from bench to bedside, and are managing and governing targeted research resources more professionally and transparently than in the past. There is also a stronger emphasis on engaging industry and more strategic thinking about strengthening regional and national collaboration with other hospital trusts, PCTs, research organisations, networks and development agencies. The scheme is also transforming capacity building in the health research system. This includes (i) developing and modernising facilities and equipment for translation; (ii) building a critical mass of human resources through recruitment and training, as well as improving retention of existing expertise; and (iii) helping ensure a steady flow of funds needed to sustain research activity and accelerate movement through the innovation pipeline. A number of centres are also trying to recreate the BRU model in new disease areas, with their own resources. PMID- 28083220 TI - Enabling Long-Term Access to Scientific, Technical and Medical Data Collections. AB - In recent decades, online access to large, high quality data collections has led to a new, deeper level of sharing and analysis, potentially accelerating and improving the quality of scientific research. These online datasets are becoming imperative at all stages of the research process, particularly in scientific, technical and medical (STM) disciplines. Since libraries have a traditional responsibility to guarantee the availability of the output of scholarly research, they have a potentially important role to play in facilitating long-term access to these resources. Yet, the role of a national library in the realm of STM data remains unclear. This article presents the results of a scoping study that addresses the potential role of the British Library (BL) in facilitating access to relevant datasets in the biosciences and environmental science. The aim of this study is to assist the BL in developing an appropriate strategy that would enable it to establish a role for itself in the intake, curation, archiving, and preservation of STM reference datasets, in order to provide access to these datasets for research purposes. The focus of this study is to explore a range of alternative strategies for the BL, which might be different for different types of databases or for data supporting different research fields or disciplines. PMID- 28083221 TI - In Search of the Holy Grail: Understanding Research Success. AB - This article considers the continuing challenges facing research funders when trying to allocate research money. It focuses on the area of research policy in mental health research funding, with a particular emphasis on funding for schizophrenia research, and provides an overview of research policy in the last 20-25 years. It then goes on to consider what approaches funders could take to build an evidence base to support future decisions about funding. PMID- 28083222 TI - Strengthening Research Portfolio Evaluation at the Medical Research Council: Developing a Survey for the Collection of Information About Research Outputs. AB - The Medical Research Council (MRC) wished to better understand the wider impact of MRC research output on society and the economy. The MRC wanted to compare the strengths of different types of funding and areas of research and identify the good news stories and successes it can learn from. As an initial step in this process RAND Europe: (1) examined the range of output and outcome information MRC already collected; and (2) used that analysis to suggest how data collection could be improved. This article outlines the approach taken to the second part of this exercise and focuses on the development of a new survey instrument to support the MRC's data collection approach. Readers should bear in mind that some later stages of survey development and implementation were conducted exclusively by the MRC and are not reported here. PMID- 28083223 TI - Ease Medicaid/SCHIP Eligibility Rules. AB - This article explores how expanding Medicaid/State Children's Health Insurance Program (SCHIP) eligibility would affect health system performance along nine dimensions. Expansion would substantially reduce consumer financial risk for those newly insured and would increase coverage by 6 to 26 percent. Expanded coverage should improve the health of some groups, as measured by life expectancy. The effect of Medicaid/SCHIP expansion on waste or patient experience is uncertain. Expansion would have no discernible effect on overall health care spending but would increase government spending. Expansion is unlikely to affect the reliability of care or health system capacity. Expanding Medicaid/SCHIP eligibility would be relatively simple because the administrative infrastructure already exists. PMID- 28083224 TI - The Effect of the Affordable Care Act on Enrollment and Premiums, With and Without the Individual Mandate. AB - This article describes the results of an analysis using RAND's COMPARE (Comprehensive Assessment of Reform Efforts) microsimulation model to predict the effects of a possible Supreme Court decision invalidating the individual mandate provision in the Patient Protection and Affordable Care Act of 2010 while keeping the other parts of the law intact. The authors predict the effects of such a decision on health insurance coverage overall and for subgroups based on income. They also estimate where people will obtain insurance in scenarios with and without the mandate and how the elimination of the individual mandate will affect insurance premiums. The analysis predicted that, if the individual mandate were to be eliminated: (1) 12.5 million people who would have otherwise signed up for coverage will be uninsured. (2) Premium prices in the non-group market will increase by 2.4 percent. (3) Total government spending will increase modestly, from $394 billion to $404 billion in 2016. (4) The amount of government spending per newly insured individual will more than double, from $3,659 to $7,468. The study estimates a smaller effect on premiums than comparable studies because the RAND team uses a method that accounts for the difference in the age composition of enrollees with and without the mandate. PMID- 28083225 TI - Physician Cost Profiling-Reliability and Risk of Misclassification: Detailed Methodology and Sensitivity Analyses. AB - This article describes the methods and sensitivity analyses used by the authors in an article published in the New England Journal of Medicine. Purchasers are experimenting with a variety of approaches to control health care costs, including limiting network contracts to lower-cost physicians and offering patients differential copayments to encourage them to visit "high-performance" (i.e., higher-quality, lower-cost) physicians. These approaches require a method for analyzing physicians' costs and a classification system for determining which physicians have lower relative costs. There has been little analysis of the reliability of such methods. Reliability is determined by three factors: the number of observations, the variation between physicians in their use of resources, and random variation in the scores. A study of claims data from four Massachusetts health plans demonstrates that, according to the current methods of physician cost profiling, the majority of physicians did not have cost profiles that met common reliability thresholds and, importantly, reliability varied significantly by specialty. Low reliability results in a substantial chance that a given physician will be misclassified as lower-cost when he or she is not, or vice versa. Such findings raise concerns about the use of cost profiling tools and the utility of their results. It also explains the relationship between reliability measurement and misclassification for physician quality and cost measures in health care. It provides details and a practical method to calculate reliability and misclassification from the data typically available to health plans. This article builds on other RAND work on reliability and misclassification and has two main goals. First, it can serve as a tutorial for measuring reliability and misclassification. Second, it will describe the likelihood of misclassification in a situation not addressed in our prior work in which physicians are categorized using statistical testing. For any newly proposed system, the methods presented here should enable an evaluator to calculate the reliabilities and, consequently, the misclassification probabilities. It is our hope that knowing these misclassification probabilities will increase transparency about profiling methods and stimulate an informed debate about the costs and benefits of alternative profiling systems. PMID- 28083226 TI - An Outcome Evaluation of the Success for Kids Program. AB - This article presents results from a multisite, quantitative evaluation of the international Success for Kids (SFK) after-school program. The program seeks to build resilience in children by teaching them to access inner resources and build positive connections with others. The SFK program is unlike most after-school programs both in its focus on spiritual development and in its emphasis on outcomes related to resilience rather than academics. The authors found that the program had beneficial effects on adaptive skills, behavioral problems, overexternalization of problems, and school problems, and the effects persisted at 12-week follow-up. Interestingly, the program positively affected school related outcomes, even though SFK is not an academic intervention. Specifically, it improved reported study skills and reduced reported learning problems and attention problems. Overall, a major strength of the program appears to be its careful attention to uniformity of program delivery-in particular, its standardized curriculum, use of experienced teachers, and formal teacher-training program. PMID- 28083227 TI - Toward a Culture of Consequences: Performance-Based Accountability Systems for Public Services. AB - Performance-based accountability systems (PBASs), which link incentives to measured performance as a means of improving services to the public, have gained popularity. While PBASs can vary widely across sectors, they share three main components: goals, incentives, and measures. Research suggests that PBASs influence provider behaviors, but little is known about PBAS effectiveness at achieving performance goals or about government and agency experiences. This study examines nine PBASs that are drawn from five sectors: child care, education, health care, public health emergency preparedness, and transportation. In the right circumstances, a PBAS can be an effective strategy for improving service delivery. Optimum circumstances include having a widely shared goal, unambiguous observable measures, meaningful incentives for those with control over the relevant inputs and processes, few competing interests, and adequate resources to design, implement, and operate the PBAS. However, these conditions are rarely fully realized, so it is difficult to design and implement PBASs that are uniformly effective. PBASs represent a promising policy option for improving the quality of service-delivery activities in many contexts. The evidence supports continued experimentation with and adoption of this approach in appropriate circumstances. Even so, PBAS design and its prospects for success depend on the context in which it will operate. Also, ongoing system evaluation and monitoring are integral components of a PBAS; they inform refinements that improve system functioning over time. Empirical evidence of the effects of performance-based public management is scarce. This article also describes a framework used to evaluate a PBAS. Such a system identifies individuals or organizations that must change their behavior for the performance of an activity to improve, chooses an implicit or explicit incentive structure to motivate these organizations or individuals to change, and then chooses performance measures tailored to inform the incentive structure appropriately. The study focused on systems in the child care, education, health care, public health emergency preparedness, and transportation sectors, mainly in the United States. Analysts could use this framework to seek empirical information in other sectors and other parts of the world. Additional empirical information could help refine existing PBASs and, more broadly, improve decisions on where to initiate new PBASs, how to implement them, and then how to design, manage, and refine them over time. PMID- 28083228 TI - Funding and Performance on Clinical Guidelines: The Cases of Dementia and Chronic Obstructive Pulmonary Disease. AB - In September 2009, the United Kingdom (UK) Medical Research Council, the Wellcome Trust and the Department of Health (England) commissioned RAND Europe to investigate the characteristics of research cited in two UK clinical guidelines: Dementia and Chronic Obstructive Pulmonary Disease (COPD). The exploratory work is part of an overall drive among funders to understand better how research reaches policy and practice. The objectives of our exploratory study were to understand the following questions.What are the characteristics of publications cited in these clinical guidelines?On those papers with a UK affiliation, who funded the research cited in these clinical guidelines? PMID- 28083229 TI - National Evaluation of Safe Start Promising Approaches: Assessing Program Implementation. AB - Children's exposure to violence (CEV)-including direct child maltreatment, witnessing domestic violence, and witnessing community and school violence-can have serious consequences, including a variety of psychiatric disorders and behavioral problems, such as posttraumatic stress disorder, depression, and anxiety. Fortunately, research has shown that interventions for CEV can substantially improve children's chances of future social and psychological well being. Safe Start Promising Approaches (SSPA) was the second phase of a planned four-phase initiative focusing on preventing and reducing the impact of CEV, sponsored by the U.S. Department of Justice's Office of Juvenile Justice and Delinquency Prevention (OJJDP). OJJDP selected 15 program sites across the country that proposed a range of intervention approaches, focused on multiple types of violence, included variations in ages and age-appropriate practices, and would be implemented in different settings. Each site participated in a national evaluation, conducted by the RAND Corporation. The evaluation design involved three components: a process evaluation, an evaluation of training, and an outcomes evaluation. This article presents the results of the first two evaluations. It describes the program and community settings, interventions, and implementations of the 15 SSPA programs for the first two years of implementation (through March 2009), as well as the training evaluation results. PMID- 28083230 TI - National Evaluation of the DH Integrated Care Pilots. AB - This article provides detail on the final output of a two-year, real-time evaluation of the Department of Health (DH) integrated care pilots (ICPs). It is intended to provide information about the evaluation activities conducted, the data collected and the analyses completed, in addition to evaluators' conclusions about the processes and outcomes seen within the pilot period. It will be of interest to the DH and other policymakers, staff involved in supporting the implementation of the pilots, and other organisations looking to develop similar initiatives designed to integrate care. PMID- 28083231 TI - The National Institute for Health Research Leadership Programme: An Evaluation of Programme Progress and Delivery. AB - RAND Europe evaluated the National Institute for Health Research (NIHR) Leadership Programme in an effort to help the English Department of Health consider the extent to which the programme has helped to foster NIHR's aims, extract lessons for the future, and develop plans for the next phase of the leadership programme. Successful delivery of high-quality health research requires not only an effective research base, but also a system of leadership supporting it. However, research leaders are not often given the opportunity, nor do they have the time, to attend formal leadership or management training programmes. This is unfortunate because research has shown that leadership training can have a hugely beneficial effect on an organisation. Therefore, the evaluation has a particular interest in understanding the role of the programme as a science policy intervention and will use its expertise in science policy analysis to consider this element alongside other, more traditional, measures of evaluation. PMID- 28083232 TI - Preventing Emergency Readmissions to Hospital: A Scoping Review. AB - This article reviews the evidence and potential for use of "emergency readmissions within 28 days of discharge from hospital" as an indicator within the NHS Outcomes Framework. It draws on a rapid review of systematic reviews, complemented by a synopsis of work in four countries designed to better understand current patterns of readmissions and the interpretation of observed patterns. Reviewed studies suggest that between 5 percent and 59 percent of readmissions may be avoidable. Studies are highly heterogeneous, but based on the evidence reviewed, about 15 percent up to 20 percent may be considered reasonable although previous authors have advised against producing a benchmark figure for the percentage of readmissions that can be avoided. The majority of published studies focus on clinical factors associated with readmission. Studies are needed of NHS organisational factors which are associated with readmission or might be altered to prevent readmission. The introduction of new performance indicators always has the potential to produce gaming. Observers from the USA cite experience which suggests hospitals might increase income by admitting less serious cases, thus simultaneously increasing their income and reducing their rate of readmission. There is also the possibility that there may be some shift in coding of admissions between "emergency" and "elective" depending on the incentives. If hospitals are performance managed on the basis of readmission rates, it would be reasonable to expect that some behaviour of this type would occur. PMID- 28083233 TI - Priorities for Investments in Children and Families in Caddo and Bossier Parishes: Application of a Unique Framework for Identifying Priorities. AB - In Louisiana, the Community Foundation of Shreveport-Bossier pools funds from sources in Caddo and Bossier Parishes, manages the funds, and allocates the funding within the two-parish region. (The City of Shreveport is in Caddo Parish; the city of Bossier City is in Bossier Parish.) In 2008, the foundation selected education, health, and poverty as priority areas for its investments in children and families, and it asked the RAND Corporation to assist the community in identifying priority strategies within these three focus areas. RAND researchers developed a unique framework based on the intersection of needs, assets, and best practices. Applying this framework to the Shreveport-Bossier community, they identified health care providers, public school teachers, and Barksdale Air Force Base as strong assets that can help the community address three high-need areas: infant health, child maltreatment, and educational attainment. The "Needs-Assets Best Practices" framework developed to assist the Shreveport-Bossier community can be applied in many other settings; this article can be viewed as a case study of the application of the framework. PMID- 28083234 TI - Sustainable Development in the National Health Service (NHS): The Views and Values of NHS Leaders. AB - This article presents National Health Service (NHS) leaders' views of priorities and approaches regarding sustainable development in the NHS. It was produced in close collaboration with the United Kingdom (UK) NHS Sustainable Development Unit (SDU), and it represents the first systematic picture of leadership views in the NHS. It also provides a commentary on ways forward. Analysis draws on results of a survey of 172 leaders of NHS organisations (primarily chief executives), 12 follow-up interviews, interviews with the SDU, and additional data and literature searches. A major conclusion is that almost all leaders consider sustainable development to be important for the NHS and that a focus on sustainability can most likely be aligned with delivering other corporate goals. Aligned incentives at all organisational levels and support for diversity are considered necessary to achieve sustainability, as well as relevant performance metrics. The main barrier is organisational culture. PMID- 28083235 TI - Toolkit for Adapting Cognitive Behavioral Intervention for Trauma in Schools (CBITS) or Supporting Students Exposed to Trauma (SSET) for Implementation with Youth in Foster Care. AB - Cognitive Behavioral Intervention for Trauma in Schools (CBITS) was developed for use by school-based mental health professionals for any student with symptoms of distress following exposure to trauma. Supporting Students Exposed to Trauma (SSET) was adapted from CBITS for use by any school personnel with the time and interest to work with students affected by trauma. The purpose of this toolkit is to assist school-based mental health professionals, school personnel, and child welfare social workers in adapting these interventions for use with youth aged 10 15 who are in foster care. The authors note that delivering a school-based mental health program to youth in foster care has many challenges, including collaboration between the child welfare and education systems, confidentiality and information sharing policies regarding youth in foster care, and identification of these youth. The toolkit was designed to help understand these challenges and provide strategies for addressing them. PMID- 28083236 TI - Behavioral Health in the District of Columbia: Assessing Need and Evaluating the Public System of Care. AB - This article shares findings from a study of the public behavioral health care system in the District of Columbia, including the prevalence of mental health disorders and substance use, the organization and financing of public behavioral health services, utilization of public behavioral health services, and priorities for improvement. The authors' analyses found that prevalence of mental health conditions resembles patterns nationally, among both adults and youth. Substance use disorders are more prevalent among adults and comparatively lower for the youth population, compared to national patterns. Potentially 60 percent of adults and 72 percent of adolescents enrolled in Medicaid managed care may have unmet need for depression services. Based on claims data, 45 percent of children and 41 percent of adults enrolled in Mental Health Rehabilitation Services programs have gaps in care that exceed six months during a 12-month period. Participants in focus groups and stakeholder interviews highlighted such challenges as gaps in care and difficulties in coordination of care for particular populations and services. High-level priorities include reducing unmet need for public mental health care, tracking and coordinating care, improving the availability and accessibility of substance use treatment services, and upgrading the data infrastructure. PMID- 28083237 TI - A Blueprint for Improving the Promotion and Delivery of Adult Vaccination in the United States. AB - Vaccine-preventable disease continues to take a heavy toll on adults despite the widespread availability of effective vaccines. This article identifies where efforts to improve the delivery of adult vaccination have stalled and recommends targeted strategies that are supported by available evidence and build on existing infrastructure. The authors conducted a comprehensive review of the published literature on adult immunization, a stakeholder workshop, and follow-up interviews with meeting participants and additional experts. They also partnered with an organization represented at the workshop to conduct a telephone survey of adults to learn about the relationship between influenza vaccination and beliefs about the safety of influenza vaccine. Findings include that office-based providers remain the primary source of vaccination, though a substantial proportion of physicians who treat adults appear not to vaccinate at all and adult vaccination is infrequently discussed at health care encounters. Adult practices also lack a strong business case to offer vaccination, as it entails substantial fixed costs. In addition, achieving substantial increases in adult vaccination will require persuading large numbers of individuals disinclined to be vaccinated. Vaccination stakeholders need to engage in a collaborative fashion to promote adult vaccination and the integration of advice about vaccination into routine office-based practice. Recommendations include strengthening evidence surrounding practice gaps and the economic value of promoting vaccination in office-based settings, improving guidance to providers about vaccinating adults, and formalizing procedures for referring patients to complementary vaccinators. PMID- 28083238 TI - An Evaluation of the California Injury and Illness Prevention Program. AB - The Injury and Illness Prevention Program (IIPP) requirement has been the most frequently cited standard in California workplace health and safety inspections almost every year since it became effective in July 1991. Every workplace safety inspection must assess compliance with the IIPP. This article presents the results of an evaluation of the IIPP's effects on worker injuries in California and should inform policy both in California and in the federal Occupational Safety and Health Administration (OSHA) program, which has made the adoption of a similar national requirement a top priority. Using data from the Workers' Compensation Information System, OSHA Data Initiative statistics, and Workers' Compensation Insurance Rating Bureau of California reports on medical and indemnity claims from single-establishment firms, the evaluation team analyzed the impact of citations for violations of the IIPP on safety performance by (1) using the number of citations as a measure of effectiveness and (2) assessing the number of establishments that were cited for noncompliance and then came into compliance. They found that enforcement of the IIPP appears to prevent injuries only when inspectors cite firms for violations of specific subsections of that standard. Eighty percent of the citations of the IIPP by the California Division of Occupational Safety and Health program are for only a different section, the one that requires employers to have a written IIPP. The specific subsections refer to the provisions that mandate surveying and fixing hazards, investigating the causes of injuries, and training employees to work safely. Because about 25 percent of all inspections cite the IIPP, citations of the specific subsections occur in about 5 percent of all inspections. In those inspections, the total recordable injury rate falls by more than 20 percent in the two years following the inspection. PMID- 28083239 TI - Analysis of the Cities Readiness Initiative. AB - The Centers for Disease Control and Prevention's (CDC's) Cities Readiness Initiative (CRI) provides funding, program guidance, and technical assistance to improve communities' ability to rapidly provide life-saving medications in response to a large-scale bioterrorist attack, naturally occurring disease outbreak, or other public health emergency. Focusing on both capacities and operational capabilities, the authors examine (1) the current status of communities' operational capability to meet CRI program goals related to delivering medical countermeasures within 48 hours of a federal decision to deploy assets and (2) whether there is evidence that CRI has improved communities' capability to meet the 48-hour goal. Analysis shows that, overall, state capacity appears to be strong; CRI appears to have improved state capacity, but the data are not conclusive. Performance across Metropolitan Statistical Areas varies considerably, as does performance in particular functional areas. The authors also note that testing of operational capabilities has not been conducted at a large enough scale to measure readiness for the 48-hour scenario, recommending that jurisdictions be required to conduct drills at a larger scale. Other proposed recommendations include improving CDC feedback to jurisdictions, attempting to leverage assessments of non-CRI sites as a comparison group, and assessing program cost-effectiveness. PMID- 28083240 TI - The Modified Kalman Filter Macro: User's Guide. AB - The Modified Kalman Filter approach for pooling information across time and across outcomes is shown to improve accuracy in national estimates of health outcomes, including cancer, diabetes, and hypertension, especially in small racial/ethnic subgroups. The developed SAS macro models true health states in each subgroup assuming a linear time evolution and an autoregressive deviation around such trend. The macro provides multiple options for users. PMID- 28083241 TI - Letter from the Editor. PMID- 28083242 TI - The Economics of Air Force Medical Service Readiness. AB - The prime mission of the Air Force Medical Service (AFMS), like those of the medical departments of its sister services, is to provide medical care during wartime. AFMS currently runs three successful in-theater hospitals that treat severely injured or wounded U.S. personnel from all four services. But this wartime mission depends on capabilities built at home, as critical-care specialists maintain their technical proficiency, as much as peacetime opportunities allow, by meeting health-care needs of Department of Defense beneficiaries at home. These patients have ranged from young, healthy active-duty personnel to aging retirees, historically presenting a broad range of injuries and illnesses for treatment. However, between the demands of deployments creating gaps in staff at home and changes in care plans, some beneficiaries now seek care in the civilian sector. In addition, several AFMS hospitals stateside have been closed, converted to clinics, or combined with those of other services for various reasons. All is problematic for two reasons: First, inpatient workloads in particular represent the best opportunities for critical care providers to prepare for their wartime missions. AFMS will need to increase these opportunities, perhaps working with other services, the Department of Veterans Affairs, or civilian hospitals. Second, AFMS's funding depends, in part, on the workload performed, but current measurement methods do not necessarily do a good job of accounting for the work AFMS practitioners accomplish outside their home stations. Some imminent changes may help resolve this situation, but AFMS should pursue opportunities to create additional workload for its medical personnel and to increase its budgets. PMID- 28083243 TI - New Equipping Strategies for Combat Support Hospitals. AB - The U.S. Army uses Combat Support Hospitals (CSHs)-mobile, deployable hospitals housed in tents and expandable containers-to provide surgical and trauma care close to combat action. CSHs typically operate as hospitals only when deployed, and deployments occur only once every three to five years under the Army's rotational cycle. When not deployed, CSHs keep a partial set of equipment at home station for training or possible local emergency medical missions, while the remainder of the unit's equipment is in long-term storage at a site in the high desert of Northern California. This strategy of providing equipment for CSHs has created maintenance and obsolescence challenges. Nondeployed CSHs have old, poorly maintained equipment that is seldom or never used. Further, the Army has not programmed sufficient funds to keep all its CSH sets technologically current; in practice, deploying units do not deploy with their own equipment, but instead receive new medical equipment when deploying or take ownership of existing, upgraded equipment that is already deployed. RAND Arroyo Center researchers developed a new equipping strategy for the Army's CSHs, proposing three options for home station equipment sets: an "Expanded" design that provides more surgical and trauma capability and capacity; an "Enhanced" design that provides roughly the same amount of equipment but improved medical capabilities; and a "Lean" design that provides only enough equipment for some individual and team training. The research team also proposed changing the equipping strategy of deploying CSHs to eliminate much of the unit-owned equipment now residing in long-term storage. Deploying units would instead draw on a shared pool of up-to-date and well maintained equipment. The proposed strategy would reduce total equipment costs from $1 billion to less than $700 million, leaving the Army with sufficient funds to continually upgrade and maintain both home-station and shared equipment. PMID- 28083244 TI - Harnessing Full Value from the DoD Serum Repository and the Defense Medical Surveillance System. AB - The Army manages the Department of Defense Serum Repository (DoDSR) of over 43 million serum samples and the associated Defense Medical Surveillance System (DMSS) database that links individual service member characteristics to these biological samples. The main mission and use of these resources has been for military health surveillance. The Army turned to RAND Arroyo Center to systematically examine current requirements and capabilities of the DoDSR and DMSS, identify gaps, and suggest strategies to improve their ability to meet current and potential future military health needs, including surveillance, outbreak investigation, research, and clinical support, particularly as these relate to influenza and other infectious disease threats. The research drew information from written documents and interviews with military and civilian experts. The study identified a number of opportunities to improve the management, content, and use of the serum repository and associated database. There were six main recommendations: (1) clarify and communicate the missions of the DoDSR and DMSS both within and beyond the Department of Defense; (2) empower, structure, and resource the organizational oversight of DoDSR and DMSS so that they can fulfill the full range of their missions; (3) create an integrative data plan for comprehensive health surveillance; (4) enhance the utility of specimens; (5) plan for the next repository facility; and (6) raise awareness of and expand access to DoDSR and DMSS. PMID- 28083245 TI - Assessment of the USCENTCOM Medical Distribution Structure. AB - This study examined whether there might be a medical supply and distribution structure for U.S. Central Command (USCENTCOM) that would maintain or improve performance while reducing costs. The authors evaluated the likely performance and cost implications of the range of possibilities, considering both the medical and nonmedical logistics structures, for providing medical supplies to support medical activities in USCENTCOM. They found that three options would preserve or improve performance while either lowering or not increasing costs. Additionally, they considered how the value of these solutions would likely change with future shifts in USCENTCOM operations. PMID- 28083247 TI - An Analysis of the Populations of the Air Force's Medical and Professional Officer Corps. AB - Since the advent of the all-volunteer force, one of the foremost personnel challenges of the U.S. Air Force has been recruiting and retaining an adequate number of medical and professional officers in the Air Force's seven medical and professional officer corps: the Biomedical Sciences Corps (BSC), the Chaplain Corps, the Dental Corps, the Judge Advocate General (JAG) Corps (attorneys), the Medical Corps (physicians), the Medical Service Corps (MSC), and the Nurse Corps. For each of these corps, there are highly similar jobs in the private sector, so attracting and retaining these corps' officers is a constant challenge. This article analyzes all seven Air Force medical and professional officer corps and their relative statuses with regard to end strengths, accession levels, promotion flow, and attrition since the late 1970s. The authors find that recent accession and retention trends have been most adverse in the Air Force's Nurse Corps, while the MSC and the JAG Corps appear to have the most stable populations. PMID- 28083246 TI - Bridging the Gap: Developing a Tool to Support Local Civilian and Military Disaster Preparedness. AB - U.S. policymakers have stepped up systematic disaster preparedness efforts sharply since the terrorist attacks of September 11, 2001, including the creation of the U.S. Department of Homeland Security and a plethora of federal initiatives. Against a backdrop of natural disasters that occur each year in the United States and heightened concern about pandemic influenza, there is an emerging national consensus that the best path is an all-hazards approach to disaster preparedness planning and that effective local planning is critical. Military installations and their civilian counterparts-local government and local health-care providers, especially the U.S. Department of Veterans Affairs-can strengthen local-level disaster preparedness planning. This is an interim report for the first phase of a larger study aiming to develop a planning support tool for local military and civilian planners. It describes current policies and programs-especially those with nationwide application-for domestic emergency preparedness, risk analysis, and capabilities-based planning. It also describes results from interviews with local military and civilian planners at five selected sites to help understand how local preparedness planning currently operates and identify the needs of local planners. Collectively, these form the basis for a proposed tool, for which the framework is described in this article. The next phase of the study will include development and field testing of a proof of-concept prototype of the tool. PMID- 28083248 TI - Medical Readiness of the Reserve Component. AB - The reserve components (RCs) of the U.S. military must ensure that reservists are not only properly equipped and trained, but also medically ready to serve. Medical readiness means that service members are free from health-related conditions, including dental conditions, that could limit their ability to carry out their duties. Medically ready reservists require less medical and dental support in theater and fewer medical evacuations from theater, both of which save money and free assets for other purposes. This article identifies existing medical readiness requirements, quantifies the current status of RC medical readiness, identifies obstacles to achieving compliance, and suggests options for improving medical readiness in a cost-effective manner. The authors find that time and expense are the major barriers to the RCs achieving their overall goals for medical readiness. Recommendations include standardizing medical readiness criteria across services, improving data reporting and archiving processes, providing incentives to individuals and units to achieve medical readiness, and continuing to extend TRICARE coverage to reservists prior to deployment. PMID- 28083249 TI - Healthcare Coverage and Disability Evaluation for Reserve Component Personnel: Research for the 11th Quadrennial Review of Military Compensation. AB - Because Reserve Component (RC) members have been increasingly used in an operational capacity, among the policy issues being addressed by the 11th Quadrennial Review of Military Compensation (QRMC) is compensation and benefits for the National Guard and Reserve. As part of the review, RAND was asked to analyze healthcare coverage and disability benefits for RC members, including participation in the TRICARE Reserve Select (TRS) program, the potential effects of national health reform on coverage rates, and disability evaluation outcomes for RC members. This article summarizes the results of RAND's analysis. The author finds that 30 percent of RC members lack health insurance to cover care for non-service-related conditions. The TRS program offers the option of purchasing health insurance through the military on terms that are superior to typical employer benefits. Although program participation has increased, it remains low and TRS does not appear to be effectively targeting those most likely to be uninsured. TRS premiums are also lower than the premiums for the new options that will be available under health reform and the same as the penalty for not being insured. So health reform is likely to increase TRS enrollment. Finally, previously deployed RC members are referred to the Disability Evaluation System at a much lower rate than Active Component (AC) members, even for deployment-related conditions, but those who are referred receive dispositions (and thus benefits) similar to those for AC members. These findings suggest that the Department of Defense may want to consider ways to better coordinate TRS with other insurance options that will be available to RC members and that the identification of RC members who experience health consequences from deployment leading to disability merits further investigation. PMID- 28083250 TI - Improving Joint Expeditionary Medical Planning Tools Based on a Patient Flow Approach. AB - The U.S. military's current concept of operations for expeditionary medical care emphasizes quickly moving patients to a series of successively more sophisticated medical facilities that provide the patients with the care necessary to treat their injury or condition. Balancing the deployment of treatment and evacuation resources is therefore necessary to ensure that the right mix of resources is available in a timely fashion. The authors propose a planning concept that, by promoting patient flow rate as the common unit of measurement, will help integrate medical planning across treatment and evacuation functions, across the increasing levels of care, and across the different military services. The primary medical planning tool approved for use by combatant commands for developing their operational plans-the Joint Medical Analysis Tool (JMAT)-already operates in a manner consistent with this concept. However, modifications and enhancements to JMAT are necessary to ensure that the concept can be fully implemented. PMID- 28083251 TI - Understanding and Reducing Off-Duty Vehicle Crashes Among Military Personnel. AB - The authors review traffic safety in the United States, with specific reference to military personnel, focusing on safety interventions and attempts to change driver behavior and decisions. Overall, driving has become safer over the last 20 years: A variety of factors seem to have contributed to this increased safety better vehicle safety features, better road safety features, decreases in teenage drunk driving, more seat belt use, and at least recently, fewer vehicle miles traveled. In contrast, motorcycle riding, a topic of particular interest to the military, is becoming more dangerous. The main difference between the military and civilian population is the proportion of military crash fatalities on motorcycles-the U.S. rate is currently about 15 percent of fatalities, while in some military branches the rate is on average 35-40 percent. This review shows that the following safety interventions tend to help in the reduction of vehicle crashes and that some in particular may be useful in the military setting: (1) better enforcement of underage drinking laws and continuation of alcohol deglamorization campaigns (Department of Defense regulations exist, but underage drinking seems to be relatively common); (2) high-visibility enforcement techniques for sobriety checkpoints; (3) high-visibility enforcement techniques for seat belt use; (4) adoption of a lower blood alcohol concentration level (such as 0.05) for motorcyclists, since the evidence shows that motorcyclists' ability to drive safely begins declining at lower levels than those for car drivers; (5) screening-perhaps as part of military medical assessment-and brief intervention with a trained counselor for at-risk drinkers, since they are at higher risk for drinking and driving; (6) media campaigns that are paired with community activities that also emphasize driver safety, such as workshops or fairs and with enforcement of driving regulations, and targeted at the drivers at highest risk (men in their teens and early 20s); (7) requirements that motorcyclists be licensed and own their vehicles. PMID- 28083252 TI - A Prototype Knowledge-Sharing Service for Clinical Decision Support Artifacts. AB - This article, by researchers from Partners HealthCare and the RAND Corporation, primarily describes the work associated with Task 4.8 of the Advancing Clinical Decision Support (ACDS) effort, a project intended to accelerate the effective use of computer-based clinical decision support (CDS) interventions to facilitate evidence-based clinical practice and the meaningful use of health information technology. The key objectives of Task 4.8 were to develop CDS artifacts for at least 20 interventions of different types, targeted toward guidelines and clinical conditions called for in the 2011 meaningful use criteria, and to disseminate the tools, content, and materials through a knowledge-sharing service (KSS) that could potentially be deployed on a national scale. The ACDS interventions or artifacts were built utilizing the extensible markup language (XML) schema developed by the Clinical Decision Support Consortium (CDSC) project and were published on the CDSC portal (http://cdsportal.partners.org/), which functions as the ACDS KSS. While the original CDSC Level 3 XML schema adequately supported the development of the ACDS artifacts, the authors worked with the CDSC team to expand the schema to support additional intervention types (order sets, documentation templates, infobuttons, relevant data display, and value sets). Twenty-two CDS artifacts and 16 value sets were developed that cover the five CDS intervention types. Three custom style sheets were developed to render the XML files in human-readable form. The authors recommend investment in the foundational building blocks for shareable CDS, such as dictionaries and value sets, as these will be essential. The CDS content on the portal will need to be expanded and maintained in order for it to remain a viable resource for CDS implementers. PMID- 28083253 TI - The Impact of Health Care Reform on Workers' Compensation Medical Care: Evidence from Massachusetts. AB - Although it is widely recognized that health care reform has the potential to affect the volume and cost of medical care received through the workers' compensation (WC) system, to date there is little empirical evidence of this effect. This study used the experience of Massachusetts, which implemented a health care reform package with several provisions similar to those in the Patient Protection and Affordable Care Act of 2010, to empirically estimate how health reform impacts WC hospital care. It was found that WC billing frequency for both emergency room visits and inpatient hospitalizations fell by 5 to 10 percent as a result of reform, but that billed charges and treatment volume were not measurably affected. These impacts were observable among patients with more costly injuries and persisted even after various approaches were used to account for the effects of the economic downturn that began at the end of 2007. While many outstanding questions about the impacts of health reform on WC remain, this early quantitative, empirical evidence suggests that reform may reduce medical costs borne by the WC system. PMID- 28083254 TI - Medicines as a Service: A New Commercial Model for Big Pharma in the Postblockbuster World. AB - The past decade has not been kind to large pharmaceutical companies. Their share prices have been lagging the market after many years of outperforming it. Many had to undergo painful restructuring and workforce reductions because their traditional blockbuster model is becoming extinct. More and more top-selling drugs are being replaced by cheap generics, and developing new drugs is more difficult because fewer opportunities exist and more-costly research and development (R&D) productivity has declined. Although this diagnosis is not disputed, the best course of treatment is not clear. Companies have tried to stop the bleeding with the help of mergers and reorganizations and infused new blood by acquiring biotech companies or their innovative products or by diversifying into products other than prescription drugs. In this article, the authors propose that the pharmaceutical industry can reconfigure its considerable resources to develop innovative and meaningful business models that are based on services that improve access and adherence to prescription drugs for chronic conditions. They argue that such innovation beyond drug development is consistent with the core capabilities of large pharmaceutical companies and has the potential to achieve profit levels similar to those of its traditional models. Their argument is based on the fact that, although effective medicines for most chronic conditions exist, access and adherence to medicines is far from what would be needed to achieve full treatment efficacy. Therefore, value can be created by getting and keeping more patients on their drugs, and innovative business models would allow pharmaceutical companies to capture that value. PMID- 28083255 TI - Measuring Health System Progress in Reducing Mortality from Noncommunicable Diseases. AB - Noncommunicable diseases (NCDs) place a heavy burden on developing countries, whose relatively recent adoption of Western-style health behaviors and lifestyle choices has led to increased prevalence of risk factors for NCDs over the past decade. NCDs are compounding the burden of infectious disease on health systems in those countries. In response, the World Health Organization (WHO) has launched several risk reduction initiatives. WHO is drafting a monitoring framework and voluntary targets as the basis for a consultation process with member states. However, the indicators and targets that a global consultation process will produce will inevitably provide high-level, aggregated information, such as progress toward reducing premature NCD mortality. Regional and national decisionmakers and planners, on the other hand, will need more proximal and granular information to track progress toward high-level goals and will be constrained by the resources and demands in their respective jurisdictions. The relative importance of different risk factors and manifest NCDs differs across countries, and so do health systems' capabilities and resources. Thus, national and regional decisionmakers will need: (1) a comprehensive set of indicators to guide on-the-ground prioritization decisions and track progress toward high-level targets and (2) actionable data to predict the impact of changes in proximal indicators on high-level targets. As a first step, this article outlines a roadmap toward a comprehensive system for national and regional decisionmakers to (1) track progress toward the key WHO goal of reducing NCD mortality by 25 percent by 2025 and (2) prioritize resources and interventions to achieve that goal. PMID- 28083256 TI - Assessment of the implementation of the EU Drugs Strategy 2005-2012 and its Action Plans. AB - Illicit drug use continues to be an important public health and safety concern in Europe. Production, trafficking and dealing in illicit drugs constitute important criminal justice challenges in themselves, and are associated with other criminal activities. The 2005-2012 EU Drugs Strategy (as with previous strategies) was developed to complement and add value to national strategies and approaches while respecting the principles of subsidiarity and proportionality set out in the EU Treaties. The main rationale for its development was that while drugs problems vary across Member States, and are experienced at the local and national level, they are "a global issue that needs to be addressed in a transnational context." RAND Europe undertook an independent evaluation of the current Strategy and its Action Plans, addressing four research objectives: (1) to assess barriers and facilitators to the implementation of objectives and priorities at EU and Member State level, (2) to assess the relevance and influence of the Strategy with respect to national drugs policy and legislation, (3) to assess possible impact on the drugs situation in the EU, and (4) to identify key aspects and recommendations for future EU Drugs Strategies. PMID- 28083257 TI - Postmenopausal Osteoporosis Management: A Review of the Evidence to Inform the Development of Quality Indicators. AB - This article aims to inform the development of quality indicators for postmenopausal osteoporosis management through (a) assessing the evidence for screening and diagnosis of osteoporosis and related risk factors, and for prevention and treatment of osteoporosis and osteoporosis-related fractures; (b) describing current practice for managing postmenopausal osteoporosis in Europe; and (c) highlighting existing gaps in the evidence base and management practices in Europe. Analyses involved a comprehensive review of reviews regarding the screening and diagnosis of osteoporosis and related risk factors and the prevention and treatment of osteoporosis and osteoporosis-related fractures. While this identified a well-developed evidence base on the effects of selected treatments on clinical outcomes of postmenopausal osteoporosis and associated fractures, and on the usefulness of selected simple risk factor assessment tools to identify postmenopausal women who would benefit from further diagnostic assessment, uncertainties remain regarding for example the optimal use of pharmacological interventions for preventive purposes and the effectiveness of population-based screening. We also carried out case study reviews of current practices for managing postmenopausal osteoporosis in England, France, Germany and Spain. We identify a need for the establishment of routine monitoring systems to enable better understanding of contemporary patterns and trends and identify care gaps in the management of postmenopausal osteoporosis and associated fractures. Such analyses are crucial to inform targeted strategies and policies to effectively address the burden of osteoporosis and associated fractures, which is sizable and set to increase across Europe. We set out considerations as a starting point for the further development of quality measures for postmenopausal osteoporosis in Europe. PMID- 28083258 TI - Further Study on the Affordability of Alcoholic Beverages in the EU: A Focus on Excise Duty Pass-Through, On- and Off-Trade Sales, Price Promotions and Statutory Regulations. AB - Policies related to alcohol pricing, promotion and discounts provide opportunities to address harms associated with alcohol misuse. However, there are important gaps in information and knowledge about the regulations in place across parts of Europe and their impacts on consumer prices and locations of purchase. Using market data, we explored the overall scale and trend of price promotions and discounts in the off-premise (e.g. supermarket) and on-premise (e.g. restaurants, pubs) across five EU Member States. To better understand the factors that may influence sales in the on- vs. off-premises, we performed regression analysis for four EU Member States with relevant data. This found that increases in broadband penetration and population density were associated with relatively higher levels of off-premise alcohol purchases and that increases in income were associated with relatively higher levels of on-premise purchases of alcohol. There was no statistically significant relationship for female higher education. We further used time-series methods, drawing on data for Ireland, Latvia, Slovenia and Finland, to estimate the impact of changes in excise duty on price ("pass-through"). This showed that a ?1 increase in excise duty increased beer prices by ?0.50-?2.50 in the off-premise, and increased spirits prices by ?0.70 ?1.40 in the off-premise. These findings suggest that, depending on the price sensitivity of consumers and other strategies employed by suppliers (e.g. advertising), changes in excise duty may be an effective instrument to reduce harmful alcohol consumption. PMID- 28083259 TI - Letter from the Editor. PMID- 28083260 TI - Evaluation of the Arkansas Tobacco Settlement Program: Progress During 2008 and 2009. AB - The Tobacco Settlement Proceeds Act, a referendum passed by Arkansans in the November 2000 election, invests Arkansas' share of the tobacco Master Settlement Agreement funds in seven health-related programs. RAND was contracted to perform a comprehensive evaluation of the progress of the seven programs in fulfilling their missions, as well as the effects of the programs on smoking and other health-related outcomes. This article discusses the Arkansas Tobacco Settlement Commission's activities and its responses to recommendations by RAND in the earlier evaluation reports and documents continued activity and progress by the seven funded programs for 2008 and 2009. The article evaluates the progress of each of the funded programs, including assessing progress in achieving programmatic goals and tracking the programs' activities and indicators. It also updates trends in outcome measures developed to monitor the effects of the funded programs on smoking and other health-related outcomes. Finally, it provides both program-specific and statewide recommendations for future program activities and funding, including ongoing strategic planning, developing evaluation measures, collaboration with other programs, and sustaining funding and growth. PMID- 28083261 TI - The U.S. Drug Policy Landscape: Insights and Opportunities for Improving the View. AB - Discussions about reducing the harms associated with drug use and antidrug policies are often politicized, infused with questionable data, and unproductive. This article provides an overview of a nonpartisan primer that should be of interest to those who are new to the field of drug policy, as well as those who have been working in the trenches. It begins with an overview of problems and policies related to illegal drugs in the United States, including the nonmedical use of prescription drugs. It then discusses the efficacy of U.S. drug policies and programs, including long-standing issues that deserve additional attention. Next, the article lists the major funders of research and analysis in the area and describes their priorities. By highlighting the issues that receive most of the funding, this discussion identifies where gaps remain. Comparing these needs, old and new, to the current funding patterns suggests eight opportunities to improve understanding of drug problems and drug policies in the United States: (1) sponsor young scholars and strengthen the infrastructure of the field, (2) accelerate the diffusion of good ideas and reliable information to decisionmakers, (3) replicate and evaluate cutting-edge programs in an expedited fashion, (4) support nonpartisan research on marijuana policy, (5) investigate ways to reduce drug-related violence in Mexico and Central America, (6) improve understanding of the markets for diverted pharmaceuticals, (7) help build and sustain comprehensive community prevention efforts, and (8) develop more sensible sentencing policies that reduce the excessive levels of incarceration for drug offenses and address the extreme racial disparities. PMID- 28083262 TI - Nurse Practitioners and Sexual and Reproductive Health Services: An Analysis of Supply and Demand. AB - Use of Sexual and Reproductive Health (SRH) services is projected to grow between 10 and 20 percent from 2006 to 2020. This growth is driven largely by changes in the racial/ethnic make-up of the population of women of reproductive age and an increase in the number of people with insurance coverage because of new health care legislation. Trends in supply and demand for SRH services, particularly for low-income individuals, suggest demand will outstrip supply in the next decade. Nurse Practitioners (NPs) with a women's health focus are key providers of SRH care in Title X-funded clinics, which deliver a significant proportion of U.S. family planning and SRH services to low-income populations. This article looks at why numbers of women's health NPs (WHNPs) have been declining, and are projected to continue to decline, despite significant growth in total numbers of NPs. Barriers to increasing the supply of NPs competent in SRH care-such as reduced funding for WHNP training, increased funding for primary care and geriatric NP training, and a shrinking proportion of WHNPs choosing to work in public health, clinics, and family planning-are identified. From the standpoint that the evolution of the health care delivery system may serve as an opportunity to optimize the delivery of SRH services in the United States, a comprehensive set of options spanning education, federal and state regulations, and emerging models of care delivery are explored to reverse this trend of too few WHNPs, particularly for servicing Title X facilities and their patients. PMID- 28083263 TI - The Frequency, Severity, and Economic Consequences of Musculoskeletal Injuries to Firefighters in California. AB - The most common work-related injuries among firefighters are musculoskeletal disorders (MSDs). The strict physical demands of the job and limited modified work opportunities suggest that MSDs are potentially more disruptive and costly to firefighters than to others. The importance of understanding the frequency and severity of firefighter MSDs has become heightened due to changes to the California workers' compensation landscape since 2004, including the reduction of permanent-disability ratings that occurred due to the adoption of a new disability rating system and new rules for apportioning disability with respect to job-related causation, the adoption of treatment guidelines to provide utilization review in workers' compensation medical care, and the imposition of caps on the number of times injured workers can be reimbursed for use of chiropractic care and physical therapy. Each of these could have a potentially disadvantageous and disproportionate impact on firefighters with MSDs. This article describes the average frequency and severity of work-related MSDs experienced by California firefighters; examines the impact of work-related MSDs on the firefighters' earnings and employment several years after injury; evaluates the reforms' impact on the ratings of firefighters with permanently disabling MSDs; and assesses whether reforms to the medical delivery system affected the employment outcomes of firefighters with MSDs. PMID- 28083264 TI - Extending U.S. Medicare to Mexico: Why It's Important to Consider and What Can Be Done. AB - There is a lack of hard data on the exact number of Medicare-eligible retirees residing in Mexico, but it is at least in the tens of thousands and is certainly rising as the baby boom generation reaches retirement. Because Medicare does not cover health services received outside the United States, these retirees must travel to the United States for health care or purchase alternative coverage for health services received in Mexico. There are several arguments for extending Medicare to Mexico-that is, allowing Medicare-eligible beneficiaries to receive their Medicare benefits in Mexico. Medicare-eligible retirees living in Mexico would certainly benefit, and Mexico might benefit from improved quality of care and an expanded health economy. Moreover, American taxpayers might benefit from a reduced total cost of Medicare: To the extent that extending Medicare to Mexico induces Medicare beneficiaries to substitute higher-cost U.S. health care services with lower-cost Mexican services, overall Medicare expenditures might be reduced. The authors outline four options for how this policy change might be implemented and describe a conceptual model that could be used to assess the effects of each option. PMID- 28083265 TI - The Impact of Air Quality on Hospital Spending. AB - Air pollution is harmful to human health, but little is known about the costs of pollution-related health care. If such care imposes a significant burden on insurance companies and employers, they would have substantial stakes in improving air quality. Reduced medical spending could also benefit public programs such as Medicare and Medicaid. This study estimated the amount of medical spending by private health insurers and public purchasers, such as Medicare, that is related to air pollution. Specifically, the authors determined how much failing to meet air quality standards cost various purchasers of hospital care in California over 2005-2007. The results indicate that substantial reductions in hospital spending can be achieved through reductions in air pollution. PMID- 28083266 TI - Negotiation Strategies for Antiretroviral Drug Purchasers in the United States. AB - Antiretroviral treatment has transformed HIV from a death sentence to a chronic condition, allowing people with HIV to live longer and healthier lives. However, they face significant barriers to accessing and affording life-saving-but expensive-antiretroviral (ARV) medications. These barriers are particularly severe for low-income patients, and they disproportionately affect racial and ethnic minorities. High ARV prices create pressure for government insurers to contain costs either by rationing care or by restricting eligibility for public programs. Limited funding, coupled with a growing demand for HIV care and treatment, is likely to make programmatic decisions about who is covered become more difficult over time. Therefore, it is important to identify options for reducing the cost of providing ARVs to allow more people to receive treatment. This study examines a variety of options for negotiating lower ARV procurement costs in U.S. markets. A case-study approach is used to assess options that different stakeholders could use in negotiating ARV price discounts with drug manufacturers given the regulatory and market constraints that exist in the United States. PMID- 28083267 TI - Evaluating the Reliability of Emergency Response Systems for Large-Scale Incident Operations. AB - The ability to measure emergency preparedness-to predict the likely performance of emergency response systems in future events-is critical for policy analysis in homeland security. Yet it remains difficult to know how prepared a response system is to deal with large-scale incidents, whether it be a natural disaster, terrorist attack, or industrial or transportation accident. This research draws on the fields of systems analysis and engineering to apply the concept of system reliability to the evaluation of emergency response systems. The authors describe a method for modeling an emergency response system; identifying how individual parts of the system might fail; and assessing the likelihood of each failure and the severity of its effects on the overall response effort. The authors walk the reader through two applications of this method: a simplified example in which responders must deliver medical treatment to a certain number of people in a specified time window, and a more complex scenario involving the release of chlorine gas. The authors also describe an exploratory analysis in which they parsed a set of after-action reports describing real-world incidents, to demonstrate how this method can be used to quantitatively analyze data on past response performance. The authors conclude with a discussion of how this method of measuring emergency response system reliability could inform policy discussion of emergency preparedness, how system reliability might be improved, and the costs of doing so. PMID- 28083268 TI - Is Military Disability Compensation Adequate to Offset Civilian Earnings Losses from Service-Connected Disabilities? AB - The Departments of Defense and Veterans' Affairs (DoD and VA) pay about $35 billion in disability compensation to about 3.2 million veterans each year. Their disabilities range from battlefield injuries to health conditions like diabetes and asthma. This research examines the adequacy of disability compensation to offset the reduction in civilian earnings opportunities that are associated with service-connected disabilities (SCDs). The authors focus on cohorts of veterans who left active military service between fiscal year (FY) 1993 and FY 2004. They track these veterans' civilian earnings and labor force participation for up to 12 years, from 1994 through 2005, compare the labor-market success of veterans with and without SCDs, and recommend changes to disability compensation. PMID- 28083269 TI - Health and Economic Outcomes in the Alumni of the Wounded Warrior Project. AB - : Since 2002, the not-for-profit Wounded Warrior Project (WWP) has sought to offer support for and raise public awareness of those injured during service on or after September 11, 2001. WWP gives members (alumni) access to programs that ensure that wounded warriors are well-adjusted in mind, spirit, and body and that they are economically empowered. Here the authors report a detailed analysis of how individuals with different marital statuses, genders, pay grades, and employment statuses were meeting these goals and how outcomes of its alumni compared with the outcomes of other veteran and nonveteran U.S. POPULATIONS: The organization's decisionmakers can use the information from this report to determine the degree to which strategic objectives are met for each subgroup and to set new goals and the means by which the organization and its alumni and may reach those goals. PMID- 28083270 TI - Assessing Operation Purple: A Program Evaluation of a Summer Camp for Military Youth. AB - Parental military deployments pose a host of challenges for child and family well being. Military family support programs have proliferated since the start of the wars in Afghanistan and Iraq a decade ago to address these emotional, social, and academic issues, but there has been little evaluation of whether these programs are meeting their key objectives. To help fill this gap, a RAND study team explored the curriculum, themes, and outcomes of Operation Purple, a free weeklong summer camp program for youth with a deployed parent. Using a quasi experimental approach, the study incorporated youth and parent survey data (from both camp attendees and a control group of non-attendees) and camp after-action reports and visitor observation logs to determine whether there were differences between attendees and non-attendees in the four camp theme areas: comfort and skill in communicating about feelings, understanding and appreciation of military life, sense of service/stewardship, and outdoor education. The study also sought to determine how and to what extent the program's curriculum was implemented by participating camps in the summer of 2011. Despite limitations in the data (e.g., a non-random study sample, some variation in curriculum implementation across camps), the study found some positive effects from camp participation, particularly in communicating about feelings, as well as valuable youth and parent perspectives about camp, reflected in responses to open-ended questions. As such, it helps lay the groundwork for future investigation of similar support programs for military youth and their families. PMID- 28083271 TI - Building Partner Health Capacity with U.S. Military Forces: Enhancing AFSOC Health Engagement Missions. AB - The U.S. Air Force Special Operations Command (AFSOC) has developed an approach to planning for, assessing, and enhancing the effectiveness of missions to build partner capacity in health. These missions are systematic, long-term efforts to enhance the ability of governments in developing states that are important to U.S. interests to deliver essential medical, dental, and veterinary services to vulnerable populations. Helping to improve local public health and providing health services is expected to support the extension of good governance and counter insurgent and terrorist infiltration, recruitment, and exploitation. AFSOC believes that its health assets can be more effectively and systematically used by combatant commanders in achieving their theater security cooperation objectives, in conjunction with other organizations. This article documents the results of three research tasks undertaken to assist AFSOC in executing its mission: (1) placing health security in the context of U.S. strategy and security cooperation efforts; (2) drawing lessons from outside organizations on ways U.S. military forces can maximize their effectiveness in helping build partner health capacity; (3) developing a framework for planning and executing partner health capacity missions. Key findings are presented, along with recommendations for maximizing the effectiveness of efforts to build partner health capacity. PMID- 28083272 TI - Letter from the Editor. PMID- 28083273 TI - Evaluating the Impact of Prevention and Early Intervention Activities on the Mental Health of California's Population. AB - In 2004, California voters passed the Mental Health Services Act, which was intended to transform California's community mental health system from a crisis driven system to one that included a focus on prevention and wellness. The vision was that prevention and early intervention (PEI) services comprised the first step in a continuum of services designed to identify early symptoms and prevent mental illness from becoming severe and disabling. Twenty percent of the act's funding was dedicated to PEI services. The act identified seven negative outcomes that PEI programs were intended to reduce: suicide, mental health-related incarcerations, school failure, unemployment, prolonged suffering, homelessness, and removal of children from the home. The Mental Health Services Oversight and Accountability Commission (MHSOAC) coordinated with the California Mental Health Services Authority (CalMHSA), an independent administrative and fiscal intergovernmental agency, to seek development of a statewide framework for evaluating and monitoring the short- and long-term impact of PEI funding on the population. CalMHSA selected the RAND Corporation to develop a framework for the statewide evaluation. This article describes the approach, the data sources, and the frameworks developed: an overall approach framework and outcome-specific frameworks. PMID- 28083274 TI - Interventions to Prevent Suicide: A Literature Review to Guide Evaluation of California's Mental Health Prevention and Early Intervention Initiative. AB - To help inform the evaluation design for CalMHSA's suicide prevention (SP) and early intervention initiatives, a review of program evaluation literature was done to assess program effectiveness and identify previously used evaluation methodologies. Using evidence from the literature review, the authors provide an overview of the epidemiology of suicides and of non-fatal self-inflicted injuries in California and present a framework for evaluating SP programs, including candidate evaluation measures. The review identified three methodological considerations that can inform the evaluation of SP programs: (1) identifying whether a SP program was effective at reducing suicide deaths is challenging because suicide is such a rare event; (2) SP programs may have differential effects on population subgroups, because suicide rates differ by age, race, and sex; and (3) SP programs may show immediate reductions in suicide attempts but their long-term effects are uncertain. The review also identified two critical gaps in the literature. First, SP evaluation research explores the effects of programs on such outcomes as reduced access to lethal means, provision of care, and crisis response; however, we need to learn more about how these programs influence suicide rates. Second, more research must address the differential effectiveness of SP programs for population subgroups vulnerable to suicide. PMID- 28083275 TI - Interventions to Reduce Mental Health Stigma and Discrimination: A Literature Review to Guide Evaluation of California's Mental Health Prevention and Early Intervention Initiative. AB - A number of programs aim to reduce the stigma and discrimination associated with mental illness, and they can include a variety of components such as training, education, media campaigns, and contact with people with mental illness. Stigma and discrimination reduction activities are evaluated in this article, using evidence from an extensive literature review. Specific areas reviewed include relevant theories of stigma and prejudice reduction, what is and is not known about the effectiveness of various approaches to reducing the stigma of mental illness, the kinds of methodologies previously used in evaluating these approaches, and the methodologies that should be employed in the future. The authors also introduce a conceptual model of mental health stigma reduction based on a variety of existing theories and evidence. PMID- 28083276 TI - Interventions to Improve Student Mental Health: A Literature Review to Guide Evaluation of California's Mental Health Prevention and Early Intervention Initiative. AB - The authors review data on the prevalence of youth mental health disorders and schools' use of student mental health (SMH) programs. They also describe the role of schools in addressing SMH concerns and outline a conceptual model for guiding evaluation of SMH programs. Finally, they touch on issues related to evaluation of cross-system collaborations that can influence students' access to resources and services and then review some of the challenges associated with evaluating SMH programs. They determine that SMH programs can be effective and can improve staff, faculty, and student knowledge of mental health problems; provide skills for identifying and referring students with mental health and social and emotional difficulties; and change attitudes toward mental health problems. PMID- 28083277 TI - Dissemination and Adoption of Comparative Effectiveness Research Findings When Findings Challenge Current Practices. AB - Insufficient evidence regarding the effectiveness of medical treatments has been identified as a key source of inefficiency in the U.S. healthcare system. Variation in the use of diagnostic tests and treatments for patients with similar symptoms or conditions has been attributed to clinical uncertainty, since the published scientific evidence base does not provide adequate information to determine which treatments are most effective for patients with specific clinical needs. The federal government has made a dramatic investment in comparative effectiveness research (CER), with the expectation that CER will influence clinical practice and improve the efficiency of healthcare delivery. To do this, CER must provide information that supports fundamental changes in healthcare delivery and informs the choice of diagnostic and treatment strategies. This article summarizes findings from a qualitative analysis of the factors that impede the translation of CER into clinical practice and those that facilitate it. A case-study methodology is used to explore the extent to which these factors led to changes in clinical practice following five recent key CER studies. The enabling factors and barriers to translation for each study are discussed, the root causes for the failure of translation common to the studies are synthesized, and policy options that may optimize the impact of future CER-particularly CER funded through the American Recovery and Reinvestment Act of 2009-are proposed. PMID- 28083278 TI - Monitoring Cancer Outcomes Across the Continuum: Data Synthesis and Analysis for the District of Columbia. AB - This article synthesizes and analyzes available data regarding cancer-related outcomes among District of Columbia residents, highlighting key findings and data gaps across the continuum of cancer prevention, treatment, and outcomes and noting variability across subgroups of District residents. Data sources used in this report include the Behavioral Risk Factor Surveillance System, the National Cancer Database, the Centers for Disease Control and Prevention and National Cancer Institute Wide-Ranging Online Data for Epidemiologic Research database, and the American Community Survey. The findings reveal disparities in cancer related outcomes between black and white District residents across the continuum. First, black District residents are more likely than white residents to be uninsured. Lack of insurance is associated with lower rates of routine cancer screening among asymptomatic patients and may delay care for patients experiencing early symptoms of cancer. In addition, the rate of smoking is significantly higher, and the rate of exercise is significantly lower, among black District residents than among white residents, placing black residents at higher risk of the most common cancers. Limitations in general access to health care, in primary and secondary prevention, and in access to cancer-related treatment all likely contribute to dramatically higher cancer incidence and mortality among black residents of the District than among white residents. PMID- 28083280 TI - Letter from the Editor. PMID- 28083279 TI - A Review of the U.S. Workplace Wellness Market. AB - This article describes the current state of workplace wellness programs in the United States, including typical program components; assesses current uptake among U.S. employers; reviews the evidence for program impact; and evaluates the current use and the impact of incentives to promote employee engagement. Wellness programs have become very common, as 92 percent of employers with 200 or more employees reported offering them in 2009. Survey data indicate that the most frequently targeted behaviors are exercise (addressed by 63 percent of employers with programs), smoking (60 percent), and weight loss (53 percent). In spite of widespread availability, the actual participation of employees in such programs remains limited. A 2010 survey suggests that typically less than 20 percent of eligible employees participate in wellness interventions. At this time, it is difficult to definitively assess the impact of workplace wellness on health outcomes and cost. While employer sponsors are mostly satisfied with the results, more than half stated in a recent survey that they did not know their program's return on investment. The peer-reviewed literature, while predominately positive, covers only a tiny percentage of the universe of programs. Evaluating such complex interventions is difficult and poses substantial methodological challenges that can invalidate findings. The use of incentives, such as cash, cash equivalents, and variances in health plan costs, to promote employee engagement, while increasingly popular, remains poorly understood. Future research should focus on finding out which wellness approaches deliver which results under which conditions to give much-needed guidance on best practices. PMID- 28083281 TI - The Economic Impact of the Affordable Care Act on Arkansas. AB - The Affordable Care Act (ACA) will increase coverage through the expansion of Medicaid and the creation of a Health Insurance Exchange with subsidies. RAND researchers analyzed the ACA's economic impact on the state of Arkansas and found that by 2016, about 400,000 people will be newly insured, net federal payments to the state will amount to $430 million annually, and the total gross domestic product will see a net increase of $550 million. PMID- 28083282 TI - Exploring the Addition of Physician Identifiers to the California Hospital Discharge Data Set. AB - To advance consideration of whether California should collect and release physician-identified data, RAND conducted a study to explore issues associated with requiring the inclusion of physician identifiers in the California hospital discharge data set and the potential use of physician-identified data by the state and/or release to others. RAND researchers conducted interviews with a broad set of California stakeholders, reviewed the legal and regulatory authority of the Office of Statewide Health Planning and Development to collect and release physician identifiers, and interviewed representatives from other states to understand any issues encountered by the states in their collection and use of physician-identified data. The authors found that physician-identified data could be useful to a variety of stakeholders. Of the 48 states that have hospital discharge reporting programs, all but California collect physician identifiers and do so without substantial burden to hospitals. States vary in their release policies, but those who do release the data have not reported problems. California stakeholders expressed concerns related to who would have access to the data, how the data would be analyzed, and how consumers would interpret the information, which should be carefully considered in efforts to advance the collection of physician identifiers in the California hospital discharge data. PMID- 28083283 TI - Military Caregivers: Cornerstones of Support for Our Nation's Wounded, Ill, and Injured Veterans. AB - Military caregivers are an essential part of our nation's ability to care for returning wounded warriors. Far too often, their own needs are neglected. The RAND Corporation and the Elizabeth Dole Foundation collaborated on a first, exploratory phase of a larger research effort regarding this demographic and its needs. The research explores what is known about the number and characteristics of military caregivers, describes the roles and functions they perform, and highlights the effect of caregiving on their own well-being. Most existing literature on family caregivers is heavily focused on an older population caring for persons with chronic conditions or dementia. By comparison, research on military caregivers is scant, and there are notable differences that make this population unique: Military caregivers are spouses with young children, parents with full- and part-time jobs, and sometimes even young children helping shoulder some of the burden. Government services available to this population are in their infancy; community service organizations offer diverse services but they are generally uncoordinated. This article lays the groundwork to inform policy and program development relative to the unique needs of military caregivers. PMID- 28083284 TI - Exploring the Association Between Military Base Neighborhood Characteristics and Soldiers' and Airmen's Outcomes. AB - Current extended military engagements in foreign nations have taken their toll on U.S. service members and their families. As a result, the services have made renewed commitments to support the needs of these families of military personnel. Quality-of-life and family programs across the services continue to grow. But no service has applied neighborhood theory and methods to better understand these military issues. Installations, and the communities where they are located, vary in terms of the quality of life they provide inhabitants. Similarly, the families who live in these communities and who are assigned to these installations vary in terms of their needs. A one-size-fits-all approach to base resource allocation and the provision of services may not be the most effective in fostering health and well-being among service members and their families. Thus, the services may want to use this approach as part of their efforts to identify gaps in support to service members and families so that they can make the necessary adjustments and better compensate where communities are lacking. This article explores the applicability of neighborhood theory and social indicators research to understanding the quality of life in and around military bases. It also highlights gaps in neighborhood study methodology that need to be addressed in future research. Finally, it outlines how a more in-depth neighborhood analysis of military installations could be conducted. PMID- 28083285 TI - Regulatory Cultures and Research Governance. AB - This research is intended to help improve understanding of health research governance in the UK by exploring the regulatory practices and cultures in other countries and sectors. It is a comparative study of the practice of those who are subject to regulatory requirements in the health research, medical drugs, environmental and financial sectors. The research is informed by a review of a small subset of literature which is particularly relevant to this question, and focuses on different elements of regulation and regulatory governance for each of the different sectors. PMID- 28083286 TI - Hepatitis C: A Projection of the Healthcare and Economic Burden in the UK. AB - Work presented in this article sought to assess the healthcare and economic burden of the hepatitis C virus (HCV) infection in the United Kingdom. It used a cohort simulation model to estimate the prevalence of HCV infection in the UK, including the number of persons who live with HCV infection at different disease stages, and the number of deaths that can be attributed to HCV infection through to 2035. It further assessed the healthcare and societal costs that are associated with HCV infection under different scenarios of diagnosis and treatment rates. PMID- 28083287 TI - Cataract Blindness and Simulation-Based Training for Cataract Surgeons: An Assessment of the HelpMeSee Approach. AB - Cataracts account for about half of all cases of blindness worldwide, with the vast majority in developing countries, where blindness and visual impairment can reduce life expectancy and economic productivity. Most of these cases can be cured by quick, inexpensive surgical procedures, but a shortage of trained surgeons makes it unlikely that the need for such surgeries-estimated to reach 32 million cases globally by 2020-can be met under current practices. HelpMeSee Inc. (HMS) is developing an approach to surgery training and delivery that includes use of high-fidelity simulator technology and associated curricula for high volume training, development of a system of independent private practitioners, and training where necessary of individuals without medical degrees. RAND researchers determined that the program has the potential to scale up surgical capacity rapidly and that under optimistic assumptions, the HMS program could largely close the backlog of surgical cases in the four major regions studied, resulting in 21 million cases of cataract-caused visual impairment in 2030, compared with 134 million cases under the status quo. The program also promises to have large impacts on health and productivity, and the estimated costs per year of disability averted suggest that the intervention would be highly cost effective in each of the regions researched. However, a number of significant challenges need to be met, particularly in the areas of outreach, remote monitoring of independent practitioners (especially non-doctors), and public and legal acceptance of non-doctors as surgeons. It is important to carefully pilot and monitor the approach before fully scaling up. PMID- 28083288 TI - Building the Future: Summary of Four Studies to Develop the Private Sector, Education, Health Care, and Data for Decisionmaking for the Kurdistan Region - Iraq (with Arabic-language version). AB - In 2010, the Kurdistan Regional Government (KRG) asked the RAND Corporation to undertake four studies aimed at improving the economic and social development of the Kurdistan Region of Iraq. RAND's work was intended to help the KRG expand access to high-quality education and health care, increase private-sector development and employment for the expanding labor force, and design a data collection system to support high-priority policies. The studies were carried out over the year beginning February 2010. The RAND teams worked closely with the Ministries of Planning, Education, and Health to develop targeted solutions to the critical issues faced by the KRG. This article summarizes the health care study. It is intended to provide a high-level overview of the approaches, followed by the studies, key findings, and major recommendations. PMID- 28083289 TI - Analysis of Research and Education Indicators to Support Designation of Academic Health Science Centres in England. AB - In April 2013, the Department of Health (DH) announced an open competition to designate Academic Health Science Centres (AHSCs) in England. To support the current competition, the DH commissioned RAND Europe to compile and analyse various types of publicly available data and quality assessments in the domains of medical research and health education. This article presents the results of this analysis in the form of summary "tables of excellence," focusing on medical schools/academic partners likely to seek AHSC status. A detailed bibliometric analysis of health-related research publications has also been carried out and is presented. In addition, the article provides an overview of the publicly available data and outlines the significant caveats to using the data to produce education and research rankings for institutions. Given the various caveats and the requirements to balance two domains of activity (research and education), the ranking methodology presented in this article can be used in an "advisory" capacity to provide a general indication of the quality of the candidate AHSC institutions. The analysis is intended to assist potential applicants in deciding whether to submit a pre-qualifying questionnaire as part of the procurement process, and subsequently to inform the deliberations of the selection panel for the AHSCs. PMID- 28083290 TI - The Evolving Role of Emergency Departments in the United States. AB - The research described in this article was performed to develop a more complete picture of how hospital emergency departments (EDs) contribute to the U.S. health care system, which is currently evolving in response to economic, clinical, and political pressures. Using a mix of quantitative and qualitative methods, it explores the evolving role that EDs and the personnel who staff them play in evaluating and managing complex and high-acuity patients, serving as the key decisionmaker for roughly half of all inpatient hospital admissions, and serving as "the safety net of the safety net" for patients who cannot get care elsewhere. The report also examines the role that EDs may soon play in either contributing to or helping to control the rising costs of health care. PMID- 28083291 TI - Oral Health in the District of Columbia: Parental and Provider Perspectives. AB - Research suggests that there are significant barriers to oral health care for many children in Washington, D.C. This article assesses the perspectives of Washington, D.C., stakeholders, including parents and providers, about the oral health of children, particularly those insured by Medicaid. The authors present qualitative data from focus groups with parents and providers, from an oral health forum with primary care medical and oral health clinicians and representatives from the D.C. government, and from a provider survey. The opinions captured here provide a snapshot of the challenges to improving access to oral care for D.C. children and suggest recommendations for doing so. PMID- 28083292 TI - The Economic Impact of Medicaid Expansion on Pennsylvania. AB - The Affordable Care Act is a substantial reform of the U.S. health care insurance system. Using the RAND COMPARE model, researchers assessed the act's potential economic effects on Pennsylvania, factoring in an optional expansion of Medicaid, and found the state would enjoy significant net benefits. With or without the expansion of Medicaid, the act will increase insurance coverage to hundreds of thousands of Pennsylvanians, but the COMPARE model estimates that the expansion of Medicaid eligibility would cover an additional 350,000 people and bring more than $2 billion in federal spending into the state annually than if the state did not expand. Should the state expand Medicaid, the additional spending will add more than $3 billion a year to the state's GDP and support 35,000 jobs. But Medicaid expansion is not without cost for the state; the estimated cumulative effect on Pennsylvania's Medicaid spending will be $180 million higher with the expansion than without between 2014 and 2020. Substantial reductions in uncompensated care costs for hospitals are possible even without expansion, but savings to hospitals for uncompensated care funding are even larger with the Medicaid expansion, amounting to $550 million or more each year. PMID- 28083293 TI - Pharmaceutical Pricing: The Use of External Reference Pricing. AB - External reference pricing, or international price comparison, is a common strategy to control prices of pharmaceuticals that are protected by intellectual property rights and benefit from a legal monopoly (in-patent drugs). In the UK negotiations are under way that seek to define new arrangements for the pricing of branded (new) medicines from 2014. The pharmaceutical market in the UK only accounts for a small proportion of global sales; however, UK prices are important as many countries reference their prices against those in the UK. This article seeks to contribute to our understanding of approaches to pharmaceutical pricing in high-income countries and the role of reference pricing as a means to determining pharmaceutical prices. Reviewing experiences in Canada, France, Germany, Italy, the Netherlands and Spain, we find high variability of external reference pricing across different settings and of the relative importance of this approach in comparison with other pricing strategies. There was also considerable variation in the terminology and practices used, and understanding the complexities of countries included in reference baskets for external pricing requires considerable semantic clarification. There was considerable overlap between countries that cross-reference, and it remains challenging to estimate the direct, immediate impact on external reference baskets. This review suggests that the international impact of pricing changes in the UK is likely to be minimal or indirect, largely because of the diverse ways in which reference pricing is implemented in the countries examined. PMID- 28083294 TI - Workplace Wellness Programs Study: Final Report. AB - This article investigates the characteristics of workplace wellness programs, their prevalence, their impact on employee health and medical cost, facilitators of their success, and the role of incentives in such programs. The authors employ four data collection and analysis streams: a review of the scientific and trade literature, a national survey of employers, a longitudinal analysis of medical claims and wellness program data from a sample of employers, and five case studies of existing wellness programs in a diverse set of employers to gauge the effectiveness of wellness programs and employees' and employers' experiences. PMID- 28083295 TI - An Assessment of the Army's Tactical Human Optimization, Rapid Rehabilitation and Reconditioning Program. AB - In 2009, U.S. Special Operations Command provided U.S. Army Special Operations Command with funds to establish the Tactical Human Optimization, Rapid Rehabilitation and Reconditioning (THOR3) program, an investment reflecting "truth number 1" of special operations forces: "Humans are more important than hardware." The goals of THOR3 are to increase the physical and mental capabilities of Army special forces, help these soldiers recover more rapidly from injuries sustained in combat or training, and help them stay healthy and able to contribute longer. The program differs from other Army fitness programs in several important ways, including its holistic approach to improving physical and mental performance, its focus on individual and unit needs, and its reliance on a professional staff of program coordinators, strength and conditioning coaches, physical therapists, dietitians, and cognitive enhancement specialists to deliver training and rehabilitation services that are on par with those provided to professional sports teams. U.S. Army Special Operations Command asked RAND Arroyo Center to determine whether THOR3 is effectively utilizing the resources provided and to identify opportunities for improvement in the program's planning and implementation, staffing (including hiring and retention), leader development and education, facility and equipment requirements, and ability to support participating personnel. PMID- 28083296 TI - Patient Privacy, Consent, and Identity Management in Health Information Exchange: Issues for the Military Health System. AB - The Military Health System (MHS) and the Veterans Health Administration (VHA) have been among the nation's leaders in health information technology (IT), including the development of health IT systems and electronic health records that summarize patients' care from multiple providers. Health IT interoperability within MHS and across MHS partners, including VHA, is one of ten goals in the current MHS Strategic Plan. As a step toward achieving improved interoperability, the MHS is seeking to develop a research roadmap to better coordinate health IT research efforts, address IT capability gaps, and reduce programmatic risk for its enterprise projects. This article contributes to that effort by identifying gaps in research, policy, and practice involving patient privacy, consent, and identity management that need to be addressed to bring about improved quality and efficiency of care through health information exchange. Major challenges include (1) designing a meaningful patient consent procedure, (2) recording patients' consent preferences and designing procedures to implement restrictions on disclosures of protected health information, and (3) advancing knowledge regarding the best technical approaches to performing patient identity matches and how best to monitor results over time. Using a sociotechnical framework, this article suggests steps for overcoming these challenges and topics for future research. PMID- 28083297 TI - CMS Innovation Center Health Care Innovation Awards: Evaluation Plan. AB - The Center for Medicare and Medicaid Innovation within the Centers for Medicare & Medicaid Services (CMS) has funded 108 Health Care Innovation Awards, funded through the Affordable Care Act, for applicants who proposed compelling new models of service delivery or payment improvements that promise to deliver better health, better health care, and lower costs through improved quality of care for Medicare, Medicaid, and Children's Health Insurance Program enrollees. CMS is also interested in learning how new models would affect subpopulations of beneficiaries (e.g., those eligible for Medicare and Medicaid and complex patients) who have unique characteristics or health care needs that could be related to poor outcomes. In addition, the initiative seeks to identify new models of workforce development and deployment, as well as models that can be rapidly deployed and have the promise of sustainability. This article describes a strategy for evaluating the results. The goal for the evaluation design process is to create standardized approaches for answering key questions that can be customized to similar groups of awardees and that allow for rapid and comparable assessment across awardees. The evaluation plan envisions that data collection and analysis will be carried out on three levels: at the level of the individual awardee, at the level of the awardee grouping, and as a summary evaluation that includes all awardees. Key dimensions for the evaluation framework include implementation effectiveness, program effectiveness, workforce issues, impact on priority populations, and context. The ultimate goal is to identify strategies that can be employed widely to lower cost while improving care. PMID- 28083298 TI - The Role and Importance of the 'D' in PTSD. AB - Recently, the American Psychiatric Association (APA) board of trustees voted on changes to the new edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM). Among the decisions was one to retain the word "disorder" in the term "posttraumatic stress disorder." U.S. Army leadership initially requested a change in terminology, stating that the word "disorder" is stigmatizing and that removing it would encourage more individuals suffering from symptoms to access care. Although the APA has issued its ruling, the term "posttraumatic stress" is being used informally by some individuals within military communities. It is unclear whether informal use of the term will continue, or whether military leaders will continue to advocate future changes to the DSM. RAND explored the rationales for not changing the diagnostic terminology, and to the extent possible, anticipated what the effects of widespread informal use of new terminology might be. PMID- 28083299 TI - Post-Traumatic Stress Disorder and the Earnings of Military Reservists. AB - This study investigates the effects of having symptoms of post-traumatic stress disorder (PTSD) on the labor market earnings of reservists in the years following deployment. Data on more than 315,000 reservists returning from deployments between 2003 and 2006, combined with longitudinal labor market earnings data, indicate that reservists who have symptoms of PTSD do earn substantially less than those who do not experience PTSD, but much of that gap in earnings was apparent prior to deployment. This suggests that characteristics of individuals reporting symptoms of PTSD that typically are not controlled for in empirical studies are responsible for much of the observed difference in earnings. Controlling for such characteristics, the study finds that reservists reporting symptoms of PTSD on average earn up to 6 percent less than they would have earned if they had not had such symptoms in the first four years following deployment. These lower earnings are attributable to higher military separation rates, a concomitant decline in military earnings, and no compensating increase in civilian labor market earnings. PMID- 28083300 TI - The Defense and Veterans Brain Injury Center Care Coordination Program: Assessment of Program Structure, Activities, and Implementation. AB - Improvised explosive devices have been used extensively against U.S. forces during Operation Enduring Freedom and Operation Iraqi Freedom and have been one of the leading causes of death. Injuries among survivors often include traumatic brain injuries (TBIs). Those recovering from TBIs often find they must coordinate services across multiple systems of care to meet all their medical and psychological health needs. This task is difficult even for those without the cognitive challenges associated with TBI and may prove overwhelming or even impossible, particularly during periods of transition from inpatient to outpatient services or from active duty to veteran status, for example. Although case management and care coordination are readily available for those who have experienced a severe TBI, fewer resources are available for those with symptomatic mild and moderate TBI. This article focuses on a program designed to facilitate care coordination for individuals with mild and moderate TBI, the Defense and Veterans Brain Injury Center Care Coordination Program. It summarizes RAND's assessment of the program's structure, activities, and implementation. To address the goals above, the authors conducted semistructured interviews in person with program administrators and via telephone with regional care coordinators. The subsequent analysis identified innovative practices, continuing challenges, and lessons learned. The recommendations provided here suggest strategies for meeting these challenges while maintaining the benefits possible through this novel approach to care. PMID- 28083301 TI - The Affordable Care Act and Health Insurance Markets: Simulating the Effects of Regulation. AB - The Affordable Care Act changes the rating regulations governing the nongroup and small group markets while simultaneously encouraging enrollment through a combination of subsidies, tax credits, and tax penalties. In this study, the authors estimate the effects of the Affordable Care Act on health insurance enrollment and premiums for ten states (Florida, Kansas, Louisiana, Minnesota, New Mexico, North Dakota, Ohio, Pennsylvania, South Carolina, and Texas) and for the nation overall, with a focus on outcomes in the nongroup and small group markets. The authors also consider the implications of two decisions confronting states: whether to expand their Medicaid programs to cover all adults with incomes below 138 percent of the federal poverty level and whether to merge or combine their small group and nongroup risk pools. The authors conclude that the Affordable Care Act will lead to an increase in insurance coverage and higher enrollment in the nongroup market. However, data limitations and uncertainties about insurer behavior make estimates uncertain, particularly when considering outcomes for the nongroup market. They find that the law has little effect on small group premiums and find large variation in the effects for nongroup premiums across states. The analysis suggests that comparisons of average premiums with and without the Affordable Care Act may overstate the potential for premium increases. PMID- 28083302 TI - Delaying the Employer Mandate: Small Change in the Short Term, Big Cost in the Long Run. AB - In July 2013, the Obama administration announced a one-year delay in enforcement of the Affordable Care Act's (ACA) penalty on large employers that do not offer affordable health insurance coverage. To help policymakers understand the implications of this decision, RAND analysts employed the COMPARE microsimulation model to gauge the impact of the one-year delay of the so-called employer mandate. They found that the delay will not have a large impact on insurance coverage: Because relatively few firms and employees are affected, only 300,000 fewer people, or 0.2% of the population, will have access to insurance from their employer, and nearly all of these will get insurance from another source. However, a one-year delay in implementation of the mandate will result in $11 billion dollars less in federal inflows from employer penalties for that year. A full repeal of the employer mandate would cause revenue to fall by $149 billion over the next ten years (10% of the ACA's spending offsets), providing substantially less money to pay for other components of the law. The bottom line: The one-year delay in the employer mandate will have relatively few consequences, primarily resulting in a relatively small one-year drop in revenue; however, a complete elimination of the mandate would have a large cumulative net cost, potentially removing a nontrivial revenue source that in turn funds the coverage provisions in the ACA. PMID- 28083303 TI - Does It Cost More to Train Residents or to Replace Them?: A Look at the Costs and Benefits of Operating Graduate Medical Education Programs. AB - The policy issue underlying this study is whether Medicare support for graduate medical education (GME) should be restructured to differentiate between programs that are less costly or are self-sustaining and those that are more costly to the sponsoring institution and its educational partners. The authors used available literature, interviews with individuals involved in operating GME programs, and analysis of administrative data to explore how the financial impact of operating residency training programs might differ by specialty. The study does not quantify the variation in financial impact, but it provides a framework for examining both the costs and benefits of operating GME programs to the sponsoring institution and its educational partners. It also identifies the major factors that are likely to affect financial performance and influence program offerings and size. Marginal financial impacts are more likely to influence sponsor decisions on changes in GME program size and offerings and help explain why GME program expansions are occurring without additional Medicare funding. If the hospital has service needs, there is a marginal benefit to adding a resident, particularly in the more-lucrative specialty and subspecialty programs, before considering the additional benefits of any Medicare GME-related revenues. PMID- 28083304 TI - Barking, Havering and Redbridge University Hospitals NHS Trust Fellowships in Clinical Leadership Programme: An Evaluation. AB - Leadership is seen to be central to improving the quality of healthcare and existing research suggests that absence of leadership is related to poor quality and safety performance. Leadership training might therefore provide an important means through which to promote quality improvement and, more widely, performance within the healthcare environment. This article presents an evaluation of the Fellowships in Clinical Leadership Programme, which combines leadership training and quality improvement initiatives with the placement of temporary external clinical champions in Barking, Havering and Redbridge University Hospitals NHS Trust. We assessed impacts of the Programme on individual and organisational change, alongside core enablers and barriers for Programme success. Analyses drew on the principles of a theory-of-change-led realist evaluation, using logic modelling to specify the underlying causal mechanisms of the Programme. Data collection involved a stakeholder workshop, online questionnaires of programme participants, senior managers and support staff (n=114), and follow-up in-depth semi-structured interviews with a subsample of survey participants (n=15). We observed that the Programme had notable impacts at individual and organisational levels. Examples of individual impact included enhanced communication and negotiation skills or increased confidence as a result of multi-modal leadership training. At the organisational level, participants reported indications of behaviour change among staff, with evidence of spill-over effects to non participants towards a greater focus on patient-centred care. Our findings suggest that there is potential for combined leadership training and quality improvement programmes to contribute to strengthening a culture of care quality in healthcare organisations. Our study provides useful insights into strategies seeking to achieve sustainable improvement in NHS organisations. PMID- 28083305 TI - District of Columbia Community Health Needs Assessment. AB - The District of Columbia Healthy Communities Collaborative (DCHCC) represents a unique collaboration among D.C.-area hospitals and federally qualified health centers. In response to its community commitment and Affordable Care Act requirements, DCHCC set forth to conduct a community health needs assessment (CHNA) that can guide decisions about where and how to allocate resources and implement appropriate health interventions for the population it serves. The CHNA described in this article includes analysis of existing demographic, health status, and hospital service use data, as well as hospital and emergency department discharge data. The analysis of this quantitative data is complemented by an analysis of current stakeholder perspectives regarding health needs, as well as health policy and investment priorities. This CHNA demonstrates the persistence of many issues identified in prior CHNAs: asthma, obesity, mental health, and sexual health. Despite high insurance rates, health care services are not evenly distributed by ward, creating significant challenges to access. There is a need to expand these services, as well as improve care coordination between health and social services to help residents navigate the system and obtain the services they need. In addition to these intervention pathways by priority health condition, we identified emerging issues that require further investigation, including declines in coronary atherosclerosis discharges and a spike in stress related diagnoses (headaches and back pain) and associated alcohol-related issues. This may be related to a host of factors, including economic downturn and demographic transitions in the District. PMID- 28083306 TI - Factors Affecting Physician Professional Satisfaction and Their Implications for Patient Care, Health Systems, and Health Policy. AB - The American Medical Association asked RAND Health to characterize the factors that affect physician professional satisfaction. RAND researchers sought to identify high-priority determinants of professional satisfaction by gathering data from 30 physician practices in six states, using a combination of surveys and semistructured interviews. This article presents the results of the subsequent analysis. PMID- 28083307 TI - Development of a Framework to Estimate the Cost of Opioid Dependence. AB - Opioid dependence imposes a range of costs on individuals, families, communities and society, and understanding these costs is important to inform policy and decision making in this area, especially when budgets for services to address challenges such as substance misuse are under pressure. This article sets out the findings of a targeted review of the harms of opioid dependence, and an assessment of existing estimates of the costs of opioid dependence. A proposed framework for developing new, more comprehensive estimates of the costs of opioid dependence is outlined. PMID- 28083308 TI - Effects of the Affordable Care Act on Consumer Health Care Spending and Risk of Catastrophic Health Costs. AB - This study examines the likely effects of the Affordable Care Act (ACA) on average annual consumer health care spending and the risk of catastrophic medical costs for the United States overall and in two large states that have decided not to expand their Medicaid programs (Texas and Florida). The ACA will have varied impacts on individuals' and families' spending on health care, depending on income level and on estimated 2016 insurance status without the ACA. The authors find that average out-of-pocket spending is expected to decrease for all groups considered in the analysis, although decreases in out-of-pocket spending will be largest for those who would otherwise be uninsured. People who would otherwise be uninsured who transition to the individual market under the ACA will have higher total health care spending on average after implementation of the ACA because they will now incur the cost of health insurance premiums. The authors also find that risk of catastrophic health care spending will decrease for individuals of all income levels for the insurance transitions considered; decreases will be greatest for those at the lowest income levels. Case studies found that in Texas and Florida, Medicaid expansion would substantially reduce out-of-pocket and total health care spending for those with incomes below 100 percent of the federal poverty level, compared with a scenario in which the ACA is implemented without Medicaid expansion. Expansion would reduce the risk of high medical spending for those covered under Medicaid who would remain uninsured without expansion. PMID- 28083309 TI - Medical Fitness and Resilience: A Review of Relevant Constructs, Measures, and Links to Well-Being. AB - This study is one of a series designed to support Air Force leaders in promoting resilience among its Airmen, civilian employees, and Air Force family members. It examines the relationship between medical fitness and resilience, using key constructs found in the scientific literature, which address preventive care, the presence and management of injuries and chronic conditions, and facilitators and barriers to access of appropriate health care. Supporting or increasing the levels of the key measures of medical fitness identified in this study may facilitate resilience and can protect Airmen, civilian employees, and Air Force families from the negative effects of stress. The study also reviews interventions designed to promote those constructs, focusing generally on preventive care as one of the most promising ways to reduce the prevalence and burden associated with medical conditions and injuries. PMID- 28083310 TI - Out of the Shadows: The Health and Well-Being of Private Contractors Working in Conflict Environments. AB - Over the past decade, private contractors have been deployed extensively around the globe. In addition to supporting U.S. and allied forces in Iraq and Afghanistan, contractors have assisted foreign governments, nongovernmental organizations, and private businesses by providing a wide range of services, including base support and maintenance, logistical support, transportation, intelligence, communications, construction, and security. At the height of the conflicts in Iraq and Afghanistan, contractors outnumbered U.S. troops deployed to both theaters. Although these contractors are not supposed to engage in offensive combat, they may nonetheless be exposed to many of the stressors that are known to have physical and mental health implications for military personnel. RAND conducted an online survey of a sample of contractors who had deployed on contract to a theater of conflict at least once between early 2011 and early 2013. The survey collected demographic and employment information, along with details about respondents' deployment experience (including level of preparation for deployment, combat exposure, and living conditions), mental health (including probable posttraumatic stress disorder, depression, and alcohol misuse), physical health, and access to and use of health care. The goal was to describe the contractors' health and well-being and to explore differences across the sample by such factors as country of citizenship, job specialty, and length and frequency of contract deployment. The findings provide a foundation for future studies of contractor populations and serve to inform policy decisions affecting contractors, including efforts to reduce barriers to mental health treatment for this population. PMID- 28083311 TI - Physical Fitness and Resilience: A Review of Relevant Constructs, Measures, and Links to Well-Being. AB - This study is one of a series designed to support Air Force leaders in promoting resilience among its Airmen, civilian employees, and Air Force family members. It examines the relationship between physical fitness and resilience, using key constructs found in the scientific literature that address work-related physical fitness and health-related physical fitness. Supporting or increasing the levels of physical fitness identified in this study may facilitate resilience and can protect Airmen, civilian employees, and Air Force families from the negative effects of stress. The study also reviews interventions designed to promote physical fitness applicable at the individual, unit, family, and community levels. PMID- 28083312 TI - Social Fitness and Resilience: A Review of Relevant Constructs, Measures, and Links to Well-Being. AB - This study is one of a series designed to support Air Force leadership in promoting resilience among Airmen, its civilian employees, and Air Force family members. One key component to resilience is social fitness, or the combined resources a person gets from his or her social world. This concept encompasses the availability and maintenance of social relationships, and the ability to utilize those ties to manage stressors and successfully perform tasks. Social fitness resources are the aspects of those relationships that strengthen a person's ability to withstand and rebound from challenges and even grow from them. U.S. Airmen and their families face several unique challenges that can strain the strength and accessibility of these resources, particularly geographic movement. This study identifies several scales and indexes used in social science research to measure three primary social fitness resources, emotional support, instrumental support, and informational support, and proposes that interventions aimed at increasing the quantity and quality of social support should focus on (1) sociodemographic characteristics and dispositional traits; (2) dynamics that strengthen social groups, support networks, and teams; (3) practices that improve social skills and promote more frequent and constructive interactions; and (4) activities that reduce conflict and group division. Particular attention is given to interventions that utilize cyber or virtual communities as an effective means of increasing social connectedness and social support among U.S. Airmen and their families. PMID- 28083313 TI - Spiritual Fitness and Resilience: A Review of Relevant Constructs, Measures, and Links to Well-Being. AB - This study is one of a series designed to support Air Force leaders in promoting resilience among its Airmen, civilian employees, and Air Force families. It examines the relationship between spiritual fitness and resilience, using key constructs found in the scientific literature: a spiritual worldview, personal religious or spiritual practices, support from a spiritual community, and spiritual coping. The literature shows that possessing a sense of meaning and purpose in life is strongly positively related to quality of life and improved health and functioning. The authors find that diverse types of spiritual interventions are linked to improved resilience and well-being. These interventions focus mainly on the individual, but some address the military unit, the family, and the community. PMID- 28083314 TI - Toward Integrated DoD Biosurveillance: Assessment and Opportunities. AB - In the context of the 2012 National Strategy for Biosurveillance, the Office of Management and Budget (OMB) asked the Department of Defense (DoD) to review its biosurveillance programs, prioritize missions and desired outcomes, evaluate how DoD programs contribute to these, and assess the appropriateness and stability of the department's funding system for biosurveillance. DoD sought external analytic support through the RAND Arroyo Center. In response to the questions posed by OMB request, this study finds the following: (1) Current DoD biosurveillance supports three strategic missions. Based mostly on existing statute, the highest-priority mission is force health protection, followed by biological weapons defense and global health security. (2) Guidance issued by the White House on June 27, 2013, specified priorities for planning fiscal year 2015 budgets; it includes an explicit global health security priority, which strengthens the case for this as a key DoD biosurveillance strategic mission. (3) DoD biosurveillance also supports four desired outcomes: early warning and early detection, situational awareness, better decision making at all levels, and forecast of impacts. (4) Programs and measures that address priority missions-force health protection in particular-and desired outcomes should be prioritized over those that do not do so. (5) More near-real-time analysis and better internal and external integration could enhance the performance and value of the biosurveillance enterprise. (6) Improvements are needed in key enablers, including explicit doctrine/policy, efficient organization and governance, and increased staffing and improved facilities for the Armed Forces Health Surveillance Center (AFHSC). (7) AFHSC has requested additional funding to fully implement its current responsibilities under the 2012 Memorandum of Understanding between the Assistant Secretaries of Defense for Health Affairs and for Nuclear, Chemical, and Biological Defense Programs. Additional responsibilities for coordinating the entire DoD biosurveillance enterprise would need concomitant resourcing. (8) There is not a single, unified funding system for the DoD biosurveillance enterprise; the multiple current funding systems would likely benefit from an organizing mechanism with the authority to manage and control funds to meet enterprise goals. Interim guidance issued by the Deputy Secretary of Defense on June 13, 2013, is significant because it is the first policy to explicitly address biosurveillance; it adopts the definition from the National Strategy for Biosurveillance, calls for development of a DoD Directive for biosurveillance, and specifies tasks for DoD's implementation of the Strategy. PMID- 28083315 TI - Regulating Quality and Safety of Health and Social Care: International Experiences. AB - This study is concerned with "standards of quality and safety" within health and social care systems. Care standards are intended to support efforts in maintaining and improving the quality of care; they have been developed across countries, although the ways in which they are implemented and applied differs between nations. Taking a range of six countries, we review the regulatory mechanisms that have been implemented to ensure that essential standards of care are applied and are being adhered to, and consider the range of policy instruments used to encourage and ensure continuous quality improvement. We report on Australia, England, Finland, Germany, the Netherlands and the USA. The study is intended to inform policy thinking for the Department of Health and others in developing the regulation of safety and quality of health and social care in England. It was prepared as part of the project "An 'On-call' Facility for International Healthcare Comparisons" funded by the Department of Health in England through its Policy Research Programme. PMID- 28083316 TI - Evaluating the "Keep Your Health Plan Fix": Implications for the Affordable Care Act Compared to Legislative Alternatives. AB - President Obama's promise that Americans could keep their existing health care plans under the Affordable Care Act (ACA) has received increased scrutiny in the wake of millions of Americans having their plans cancelled. These cancellations primarily occurred in the individual or nongroup market, where individuals purchase health care plans directly from an insurer instead of through an employer. Many such plans do not meet the minimum coverage requirements of the ACA, leading insurers to send plan-cancellation notices to their enrollees. This study describes a comparative analysis of three proposals to remedy the situation: one by the White House, another by Senator Mary Landrieu (D-LA), and a third by Representative Fred Upton (R-MI). The proposals are evaluated based on their potential impact on the ACA-compliant market and the cost and coverage of health insurance. The possibility of each proposal causing a "death spiral," in which rising premiums and decreasing enrollment undermine the viability of the ACA-compliant market, is also addressed. The authors find that the three proposals vary from slight to moderate impact on ACA premiums, enrollment, and federal spending, but none of them would result in the unraveling of the ACA compliant market. PMID- 28083317 TI - Redirecting Innovation in U.S. Health Care: Options to Decrease Spending and Increase Value. AB - New medical technologies are a leading driver of U.S. health care spending. This article identifies promising policy options to change which medical technologies are created, with two related policy goals: (1) Reduce total health care spending with the smallest possible loss of health benefits, and (2) ensure that new medical products that increase spending are accompanied by health benefits that are worth the spending increases. The analysis synthesized information from peer reviewed and other literature, a panel of technical advisors convened for the project, and 50 one-on-one expert interviews. The authors also conducted case studies of eight medical products. The following features of the U.S. health care environment tend to increase spending without also conferring major health benefits: lack of basic scientific knowledge about some disease processes, costs and risks of U.S. Food and Drug Administration (FDA) approval, limited rewards for medical products that could lower spending, treatment creep, and the medical arms race. The authors identified ten policy options that would help advance the two policy goals. Five would do so by reducing the costs and/or risks of invention and obtaining FDA approval: (1) Enable more creativity in funding basic science, (2) offer prizes for inventions, (3) buy out patents, (4) establish a public-interest investment fund, and (5) expedite FDA reviews and approvals. The other five options would do so by increasing market rewards for products: (1) Reform Medicare payment policies, (2) reform Medicare coverage policies, (3) coordinate FDA approval and Centers for Medicare & Medicaid Services coverage processes, (4) increase demand for technologies that decrease spending, and (5) produce more and more-timely technology assessments. PMID- 28083318 TI - Small Ideas for Saving Big Health Care Dollars. AB - A focused review of recent RAND Health research identified small ideas that could save the U.S. health care system $13 to $22 billion per year, in the aggregate, if successfully implemented. In the substituting lower-cost treatments category, ideas are to reduce use of anesthesia providers in routine gastroenterology procedures for low-risk patients, change payment policy for emergency transport, increase use of lower-cost antibiotics for treatment of acute otitis media, shift care from emergency departments to retail clinics when appropriate, eliminate co payments for higher-risk patients taking cholesterol-lowering drugs, increase use of $4 generic drugs, and reduce Medicare Part D use of brand-name prescription drugs by patients with diabetes. In the patient safety category, ideas are to prevent three types of health care-associated infections: (1) central line associated bloodstream infections, (2) ventilator-associated pneumonia, and (3) catheter-associated urinary tract infections; use preoperative and anesthesia checklists to prevent operative and postoperative events; prevent in-facility pressure ulcers; use ultrasound guidance for central line placement; and prevent recurrent falls. Small ideas do not require systemic change; thus, they may be both more feasible to operationalize and less likely to encounter stiff political and organizational resistance. PMID- 28083319 TI - Mapping Gender Differences in Cardiovascular Disease and Diabetes Care: A Pilot Assessment of LDL Cholesterol Testing Rates in a California Health Plan. AB - Despite improvements over recent decades in care for cardiovascular disease (CVD) and diabetes, which is a major CVD risk factor, evidence suggests that the care women receive-and their health outcomes-continue to lag behind those of men, even for routine care, such as monitoring and control of cholesterol. Awareness of and action to address gender gaps in women's CVD care are limited, in part, because quality of care is not routinely measured and reported by gender. This pilot project describes and maps gender differences in CVD and diabetes care using data from a large health plan. The study aims to identify gender gaps in care in California and, where they are found, to increase awareness of potential gender disparities and begin to inform approaches to address gaps in care. The study assesses gender differences in one key aspect of routine CVD care and related prevention among patients with diabetes: low-density lipoprotein (LDL) cholesterol screening. The results from this study are intended to provide the basis for further work to learn and document what it will take to rapidly spread mapping approaches that prove to be helpful in understanding and addressing disparities in health and health care, particularly with regard to improving women's health outcomes. Key findings include that men had higher rates of LDL screening than did women in both the CVD and diabetes populations. These gaps varied by age and insurance type. In addition, mapping gender gaps revealed larger gaps at local levels than were apparent at the state or regional level. PMID- 28083320 TI - Psychological Fitness and Resilience: A Review of Relevant Constructs, Measures, and Links to Well-Being. AB - This study is one of a series designed to support Air Force leaders in promoting resilience among its Airmen, civilian employees, and Air Force family members. It examines the relationship between psychological fitness and resilience, using key constructs found in the scientific literature that address self-regulation, positive affect, perceived control, self-efficacy, self-esteem, and optimism. Supporting or increasing the levels of the key measures of psychological fitness identified in this study may facilitate resilience and can protect Airmen, civilian employees, and Air Force families from the negative effects of stress. The study also reviews construct measures, well-being, and resilience outcomes as well as interventions designed to promote the psychological fitness constructs. PMID- 28083321 TI - Evaluation of the California Mental Health Services Authority's Prevention and Early Intervention Initiatives: Executive Summary and Commentary. AB - In 2004, California voters passed Proposition 63, the Mental Health Services Act (MHSA), which includes a mandate that the state provide prevention and early intervention (PEI) services and education for people who experience mental illness in the state of California. The California Mental Health Services Authority (CalMHSA), a coalition of California counties formed to provide economic and administrative support to mental health service delivery, formed the Statewide PEI Implementation Program based on extensive recommendations from a large number of stakeholders statewide. The Statewide PEI program is made up of three strategic initiatives: (1) reduction of stigma and discrimination towards those with mental illness, (2) prevention of suicide, and (3) improvement in student mental health. This article provides a summary and commentary on a more detailed interim RAND evaluation of the CalMHSA Statewide PEI Program. PMID- 28083322 TI - Mental Health Retrosight: Understanding the Returns From Research (Lessons From Schizophrenia): Policy Report. AB - This study examines the impacts arising from neuroscience and mental health research going back 20-25 years, and identifies attributes of the research, researchers or research setting that are associated with translation into patient benefit, in the particular case of schizophrenia. The study combined two methods: forward-tracing case studies to examine where scientific advances of 20 years ago have led to impact today; and backward-tracing perspectives to identify the research antecedents of today's interventions in schizophrenia. These research and impact trails are followed principally in Canada, the UK and the USA. The headline findings are as follows: The case studies and perspectives support the view that mental health research has led to a diverse and beneficial range of academic, health, social and economic impacts over the 20 years since the research was undertaken.Clinical research has had a larger impact on patient care than basic research has over the 20 years since the research was undertaken.Those involved in mental health research who work across boundaries are associated with wider health and social benefits.Committed individuals, motivated by patient need, who effectively champion research agendas and/or translation into practice are key in driving the development and implementation of interventions.This study provides an overview of the methods and presents the full set of findings, with the policy provocations they raise, and an emerging research agenda. It has been written for funders of biomedical and health research and health services, health researchers, and policymakers in those fields. It will also be of interest to those involved in research and impact evaluation. PMID- 28083323 TI - Psychological Wellbeing and Work: Improving Service Provision and Outcomes. AB - This study explores proposals to improve employment and health outcomes for people with common mental health problems and makes a number of recommendations. These include: using evidence-based models to provide services that combine employment and mental health support; increasing integration between existing treatment and employment services to improve outcomes in both areas; applying evidence-based models in new ways or a using combination of approaches; and providing timely access to coordinated treatment and employment support for a greater number of people with common mental health problems. PMID- 28083324 TI - The Development and Application of the RAND Program Classification Tool. AB - As a result of extended military engagements in Iraq and Afghanistan during the past decade, the U.S. Department of Defense (DoD) has implemented numerous programs to support servicemembers and family members who experience difficulty handling stress, face mental health challenges, or are affected by a traumatic brain injury (TBI). As these efforts have proliferated, it has become more challenging to monitor these programs and to avoid duplication. To support DoD in this area, RAND compiled a comprehensive catalog of DoD-funded programs that address psychological health and TBI. In creating the catalog of programs, RAND recognized the need to consistently describe and compare multiple programs according to a set of core program characteristics, driven largely by the lack of a single, clear, widely accepted operational definition of what constitutes a program. To do this, RAND developed the RAND Program Classification Tool (R-PCT) to allow users to describe and compare programs, particularly those related to psychological health and TBI, along eight key dimensions that that define a program. The tool consists of a set of questions and responses for consistently describing various aspects of programs, along with detailed guidance regarding how to select the appropriate responses. The purpose of this article is to describe the R-PCT, to help potential users understand how it was developed, and to explain how the tool can be used. PMID- 28083325 TI - The RAND Online Measure Repository for Evaluating Psychological Health and Traumatic Brain Injury Programs. AB - Since 2001, U.S. military forces have been engaged in extended conflicts in Iraq and Afghanistan. While most military personnel cope well across the deployment cycle, the operational tempo may raise the risk of mental health problems, such as post-traumatic stress disorder (PTSD) and major depression, and consequences from traumatic brain injury (TBI). To support servicemembers and their families as they cope with these challenges, the U.S. Department of Defense has implemented numerous programs addressing biological, social, spiritual, and holistic influences on psychological health along the resilience, prevention, and treatment continuum that focus on a variety of clinical and nonclinical concerns. As these efforts have proliferated, evaluating their effectiveness has become increasingly important. To support the design and implementation of program evaluation, RAND developed the RAND Online Measure Repository (ROMR) which indexes and describes measures related to psychological health and TBI. The ROMR is a publicly accessible, online, searchable database containing 171 measures related to psychological health and TBI. This article describes the rationale for developing the ROMR, the content included in the ROMR, and its potential in both civilian and military populations. The ROMR includes information about measure domains, psychometrics, number of items, and costs, which can inform the selection of measures for program evaluations. Included measures address domains of primary importance to psychological health (PTSD, depression, anxiety, suicidal ideation, and resiliency) and TBI (cognition, executive functioning, and memory). Also identified are measures relevant to military units, such as unit cohesion and force readiness. PMID- 28083326 TI - A Systematic Process to Facilitate Evidence-Informed Decisionmaking Regarding Program Expansion. AB - While the Department of Defense supports more than 200 psychological health and traumatic brain injury programs, it lacks an approach and process to systematically develop, track, and assess the performance of this portfolio of programs. Further, there is not yet a uniform approach to decisionmaking around program support and expansion of particularly promising, evidence-based programs. This lack of centralized oversight may result in the proliferation of untested programs that are developed without an evidence base; an inefficient use of resources; and added cost and administrative inefficiencies. RAND researchers developed a potential model and tools to support a centralized, systematic, and ongoing process to help in making decisions around continued program support, and by which expansion can be facilitated. This study includes two tools. The first is a Program Abstraction Form, which collects relevant background information from programs and asks explicitly about program effectiveness and the design of the program evaluation used to assess program effectiveness, as a poor evaluation design may lead to incorrect conclusions about the effectiveness of the program. The second is the RAND Program Expansion Tool, which provides a standardized summary of the quality and outcome of a program evaluation. The focus of these tools is on decisionmaking around program expansion, and does not preclude or address initial funding decisions of particularly promising new programs that may not yet have a solid evidence base. PMID- 28083327 TI - A Program Manager's Guide for Program Improvement in Ongoing Psychological Health and Traumatic Brain Injury Programs. AB - Between 2001 and 2011, the U.S. Department of Defense has implemented numerous programs to support service members and their families in coping with the stressors from a decade of the longstanding conflicts in Iraq and Afghanistan. These programs, which address both psychological health and traumatic brain injury (TBI), number in the hundreds and vary in their size, scope, and target population. To ensure that resources are wisely invested and maximize the benefits of such programs, RAND developed a tool to help assess program performance, consider options for improvement, implement solutions, then assess whether the changes worked, with the intention of helping those responsible for managing or implementing programs to conduct assessments of how well the program is performing and to implement solutions for improving performance. Specifically, the tool is intended to provide practical guidance in program improvement and continuous quality improvement for all programs. PMID- 28083328 TI - Development and Pilot Test of the RAND Suicide Prevention Program Evaluation Toolkit. AB - Evaluations are critical for assessing the impact of U.S. Department of Defense investments in suicide prevention and can be used as the basis for decisions about whether to sustain or scale up existing efforts. The Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury asked RAND to draw from the scientific literature and create a toolkit to guide future evaluations of suicide prevention programs. The resulting toolkit is designed to help program staff determine whether their programs produce beneficial effects and, ultimately, to guide the responsible allocation of scarce resources. This article summarizes the three complementary methods used to develop the RAND Suicide Prevention Program Evaluation Toolkit: an examination of the peer-reviewed evaluation literature and clinical trials, a review of other evaluation toolkits, and feedback from staff responsible for implementing suicide prevention programs in the Department of Defense. It is intended to serve as both a companion and supplement to the toolkit and offers additional background on its development and testing. PMID- 28083329 TI - Health and Economic Outcomes in the Alumni of the Wounded Warrior Project: 2010 2012. AB - The Wounded Warrior Project (WWP) has developed programs to help care for injured service members and veterans. In order to assess the mental, physical, and economic health of its member population, as well as to gain an understanding of WWP participation, WWP is engaged in a five-year survey effort. The RAND Corporation was asked to analyze the first three survey waves in order to take a more in-depth look at survey responses to explore whether outcomes differ across various subsets of WWP's database of members and, where possible, compare the experiences and outcomes of alumni with those of other ill and injured populations. This study describes specifically how WWP alumni who responded to the surveys are faring in domains related to mental health and resiliency, physical health, and employment and finances. The study finds that WWP goals are being met across a wide range of outcomes of interest but that individuals who have never been married, who are male, who are employed, and who are in higher ranks enjoy better mental health outcomes. On the other hand, women and those in junior ranks report more favorably on their physical health. Finally, married respondents and officers are more likely to have higher levels of education, be employed, and own homes. These outcomes enable WWP to target its programming and messaging to the alumni in need of support in these areas. PMID- 28083330 TI - The Future of Health Care in the Kurdistan Region - Iraq: Toward an Effective, High-Quality System with an Emphasis on Primary Care. AB - At the request of the Kurdistan Regional Government (KRG), RAND researchers undertook a yearlong analysis of the health care system in the Kurdistan Region of Iraq, with a focus on primary care. RAND staff reviewed available literature on the Kurdistan Region and information relevant to primary care; interviewed a wide range of policy leaders, health practitioners, patients, and government officials to gather information and understand their priorities; collected and studied all available data related to health resources, services, and conditions; and projected future supply and demand for health services in the Kurdistan Region; and laid out the health financing challenges and questions. In this volume, the authors describe the strengths of the health care system in the Kurdistan Region as well as the challenges it faces. The authors suggest that a primary care-oriented health care system could help the KRG address many of these challenges. The authors discuss how such a system might be implemented and financed, and they make recommendations for better utilizing resources to improve the quality, access, effectiveness, and efficiency of primary care. PMID- 28083331 TI - Improving Dementia Long-Term Care: A Policy Blueprint. AB - In 2010, 15 percent of Americans older than age 70 had dementia, and the number of new dementia cases among those 65 and older is expected to double by the year 2050. As the baby boomer generation ages, many older adults will require dementia related long-term services and supports (LTSS). This blueprint is the only national document to date that engages local, state, and national stakeholders to specifically focus on policy options at the intersection of dementia and LTSS. The authors undertook five major tasks that resulted in a prioritized list of policy options and research directions to help decisionmakers improve the dementia LTSS delivery system, workforce, and financing. These were to (1) identify weaknesses in the LTSS system that may be particularly severe for persons with dementia; (2) review national and state strategies addressing dementia or LTSS policy; (3) identify policy options from the perspective of a diverse group of stakeholders; (4) evaluate the policy options; and (5) prioritize policy options by impact and feasibility. Stakeholders identified 38 policy options. RAND researchers independently evaluated these options against prespecified criteria, settling on 25 priority options. These policy options can be summarized into five objectives for the dementia LTSS system: (1) increase public awareness of dementia to reduce stigma and promote earlier detection; (2) improve access to and use of LTSS; (3) promote high-quality, person- and caregiver-centered care; (4) provide better support for family caregivers of people with dementia; and (5) reduce the burden of dementia LTSS costs on individuals and families. This policy blueprint provides a foundation upon which to build consensus among a larger set of stakeholders to set priorities and the sequencing of policy recommendations. PMID- 28083332 TI - Substance Use Treatment and Reentry (STAR) Program: Final Evaluation Report. AB - Substance use disorders are common among juvenile justice populations, and few resources exist to address this problem as young offenders transition into the community upon release. To address this need, in October 2010, the Substance Abuse and Mental Health Services Administration (SAMHSA), Center for Substance Abuse Treatment (CSAT), awarded three-year grants to community-based organizations to expand and/or enhance substance abuse treatment and recovery and reentry services to sentenced offenders returning to the community. Homeboy Industries, Inc., in collaboration with Behavioral Health Services, Inc., and the RAND Corporation, was awarded a grant to serve up to 220 16- to 25-year-olds recently released from juvenile detention to receive substance use treatment and recovery services at Homeboy Industries in downtown Los Angeles. This study represents the evaluation of that Substance Use Treatment and Reentry (STAR) Program. Ninety-four percent of the proposed population was enrolled into the program. Ninety percent of participants received at least one substance use treatment session, and 73 percent successfully completed the five-session treatment in six months. Analysis of the client outcome data following participation showed improvements or stability over time in housing and social connectedness. Over 70 percent of participants who completed a 12-month interview reported continued employment, and self-reported arrests were below 15 percent. Abstinence rates did not change much throughout the project (about 30 percent); however, those reporting use at intake showed reductions in use over time. These findings reveal a continued need among the population for substance use treatment and recovery support. PMID- 28083333 TI - Ambulatory Surgical Services Provided Under California Workers' Compensation: An Assessment of the Feasibility and Advisability of Expanding Coverage. AB - The California Department of Industrial Relations asked RAND to examine the feasibility and appropriateness of including procedures that are typically performed only in an inpatient setting on the workers' compensation Official Medical Fee Schedule for ambulatory surgical center facility fees. The authors used interviews, literature review, and data analysis to assemble information on the requirements applicable to ASCs, assess how the criteria that Medicare uses to assess whether procedures can be safely performed in an outpatient setting apply to the workers' compensation patient population, and to examine alternative methods for establishing fee schedule amounts. The study focused on 23 high volume workers' compensation inpatient procedures with relatively short average lengths of stay. The study finds that most ASCs that are currently eligible for facility fees are equipped to provide services that do not require a one-night stay. However, the data analyses and literature review did not provide strong support for adding any procedures to the fee schedule with the possible exception of procedures related to cervical spinal fusions. Other than instrumentation used in conjunction with spinal fusions, relatively few of the study procedures are being performed in an ambulatory setting on either WC or privately insured patients ages 18-64. The literature suggests that two-level anterior cervical fusions and the use of instrumentation for one- or two-level fusions can be performed safely on an outpatient basis but does not include evidenced-based selection criteria to suggest which patients are appropriate candidates for having the procedures in an outpatient setting. PMID- 28083334 TI - Final Report: Evaluation of Tools and Metrics to Support Employer Selection of Health Plans. AB - The Patient Protection and Affordable Care Act (ACA) places strong emphasis on quality of care as a means to improve outcomes for Americans and promote the financial sustainability of our health care system. Included in the ACA are new disclosure requirements that require health plans to provide a summary of benefits and coverage that accurately describes the benefits under the plan or coverage. These requirements are intended to support employers' procurement of high-value health coverage for their employees. This study attempts to help employers understand the structural differences between health plans and the performance dimensions along which plans can differ, as well as to educate employers about available tools that can be used to evaluate plan options. The study also discusses the extent to which these and other tools or resources are used by employers to inform choices between health plans. PMID- 28083335 TI - How Will the Patient Protection and Affordable Care Act Affect Liability Insurance Costs? AB - The Patient Protection and Affordable Care Act (ACA) will greatly expand private coverage and Medicaid while making major changes to payment rates and the health care delivery system. These changes will affect traditional health insurers, individuals, and government payers. In addition, a considerable amount of health care is paid for directly by or is indirectly paid for via legal settlements after the care occurs, by liability insurers. This study identifies potential mechanisms through which the ACA might affect claim costs for several major types of liability coverage, especially auto insurance, workers' compensation coverage, and medical malpractice. The authors discuss the conceptual basis for each mechanism, review existing scholarly evidence regarding its importance, and, where possible, develop rough estimates of the size and direction of expected impacts as of 2016. They examine how each mechanism might operate across different liability lines and discuss how variation across states in legal rules, demographics, and other factors might moderate each mechanism's operation. Overall, expected short-term effects of the ACA appear likely to be small relative to aggregate liability insurer payouts in the markets in question. However, under reasonable assumptions, some mechanisms can generate potential cost changes as high as 5 percent or more in particular states and insurance lines. The authors also discuss longer-run changes that could be fostered by the ACA that might exert more significant effects on insurance claim costs, including shifts in tort law, changes in physician supply, new pricing approaches under the accountable care organization model, and changes in population health. PMID- 28083336 TI - Implementing a Resource-Based Relative Value Scale Fee Schedule for Physician Services: An Assessment of Policy Options for the California Workers' Compensation Program. AB - A RAND study used 2011 medical data to examine the impact of implementing a resource-based relative value scale to pay for physician services under the California workers' compensation system. Current allowances under the Official Medical Fee Schedule are approximately 116 percent of Medicare-allowed amounts and, by law, will transition to 120 percent of Medicare over four years. Using Medicare policies to establish the fee-schedule amounts, aggregate allowances are estimated to decrease for four types of service by the end of the transition in 2017: anesthesia (-16.5 percent), surgery (-19.9 percent), radiology (-16.5 percent), and pathology (-29.0 percent). Aggregate allowances for evaluation and management visits are estimated to increase by 39.5 percent. Allowances for services classified as "medicine" in the Current Procedural Terminology codebook will increase by 17.3 percent. In the aggregate, across all services, allowances are projected to increase 11.9 percent. Because most specialties furnish different types of services, the impacts by specialty are generally less than the impacts by type of service. PMID- 28083337 TI - California K-12 Schools and Communities Collaborate to Support Student Mental Health. AB - This article evaluates the development, quality, and effectiveness of collaboration activities among California K-12 Student Mental Health program partners. PMID- 28083338 TI - Findings from the School-Based Theatrical Performance Walk In Our Shoes. AB - This article examines the effects of a school-based theatrical performance, Walk In Our Shoes, designed to educate youth about and reduce stigma and discrimination toward mental illness. PMID- 28083339 TI - Racial and Ethnic Differences in Exposure to Suicide Prevention Messaging, Confidence in One's Ability to Intervene with Someone at Risk, and Resource Preferences. AB - This article assesses differences in racial and ethnic groups' exposure to suicide prevention messaging, preferences for suicide crisis services, and confidence in their ability to intervene with persons at risk of suicide. PMID- 28083340 TI - Where Would California Adults Prefer to Get Help If They Were Feeling Suicidal? AB - This article assesses the types of resources, ranging from face-to-face interactions with mental health professionals to texting a crisis line, that adults in California prefer to utilize for suicidal thoughts or feelings. PMID- 28083341 TI - An Evaluation of the Implementation and Perceived Utility of the Airman Resilience Training Program. AB - Since 2001, the U.S. Military has been functioning at an operational tempo that is historically high for the all-volunteer force in which service members are deploying for extended periods on a repeated basis. Even with the drawdown of troops from Iraq in 2011, some service members are returning from deployment experiencing difficulties handling stress, mental health problems, or deficits caused by a traumatic brain injury (TBI). In response to these challenges, the U.S. Department of Defense (DoD) has implemented numerous programs to support service members and their families in these areas. In 2009, the Assistant Secretary of Defense for Health Affairs asked the RAND National Defense Research Institute to develop a comprehensive catalog of existing programs sponsored or funded by DoD to support psychological health and care for TBI, to create tools to support ongoing assessment and evaluation of the DoD portfolio of programs, and to conduct evaluations of a subset of these programs. This article describes RAND's assessment of an Air Force program, Airman Resilience Training (ART), which is a psychoeducational program designed to improve airmen's reactions to stress during and after deployment and to increase the use of mental health services when needed. ART was initiated in November 2010, replacing a previous program named Landing Gear, which had been in place since April 2008. The RAND study took place from August 2011 through November 2011. This study will be of particular interest to officials within the Air Force who are responsible for the psychological health and well-being of airmen, as well as to others within the military who are developing programs for service members to help them cope with stress while in combat situations and after returning from deployment. PMID- 28083342 TI - Health and Economic Outcomes Among the Alumni of the Wounded Warrior Project: 2013. AB - The Wounded Warrior Project (WWP) offers support and raises public awareness of service members who have experienced physical or mental health conditions associated with their service on or after September 11, 2001. In this study, the authors use WWP's 2013 survey of its members (alumni) to understand the physical, mental, and economic challenges that Wounded Warriors face. The researchers find that at least half of alumni reported dealing with mental health conditions such as depression and posttraumatic stress disorder, and many of these alumni reported difficulties or delays in seeking mental health care, or not doing so at all. Alcohol misuse also poses a problem. A large proportion of alumni are overweight or obese, conditions that negatively affect their daily lives, exercise routines, and overall health. Almost half of alumni are not working, and there is low participation in veteran-specific employment and education programs. This information can be used to better understand the needs of WWP alumni and the ways that WWP can serve and support this constituency. PMID- 28083343 TI - Hidden Heroes: America's Military Caregivers - Executive Summary. AB - While much has been written about the role of caregiving for the elderly and chronically ill and for children with special needs, little is known about "military caregivers"-the population of those who care for wounded, ill, and injured military personnel and veterans. These caregivers play an essential role in caring for injured or wounded service members and veterans. This enables those for whom they are caring to live better quality lives, and can result in faster and improved rehabilitation and recovery. Yet playing this role can impose a substantial physical, emotional, and financial toll on caregivers. This article distills a longer report, Hidden Heroes: America's Military Caregivers, which describes the results of a study designed to describe the magnitude of military caregiving in the United States today, as well as to identify gaps in the array of programs, policies, and initiatives designed to support military caregivers. Improving military caregivers' well-being and ensuring their continued ability to provide care will require multifaceted approaches to reducing the current burdens caregiving may impose, and bolstering their ability to serve as caregivers more effectively. Given the systematic differences among military caregiver groups, it is also important that tailored approaches meet the unique needs and characteristics of post-9/11 caregivers. PMID- 28083344 TI - Health and Healthcare: Assessing the Real World Data Policy Landscape in Europe. AB - Real-world data (RWD) is an umbrella term for different types of data that are not collected in conventional randomised controlled trials. RWD in the healthcare sector comes from various sources and includes patient data, data from clinicians, hospital data, data from payers and social data. There are already examples of ways in which research has contributed to the provision, construction and capture of RWD to improve health outcomes. However, to maximise the potential of these new pools of data in the healthcare sector, stakeholders need to identify pathways and processes which will allow them to efficiently access and use RWD in order to achieve better research outcomes and improved healthcare delivery. Current efforts to improve access to RWD and facilitate its use take place in a context of resource scarcity. Based on a literature review, case studies, a small set of interviews of experts from public and private organisations and a scenario based workshop, the study outlined possible strategies to illustrate how RWD standards development could facilitate RWD-based research. By investigating the current forms and uses of RWD in Europe, this study has highlighted their significant potential for assessing the (short- or long-term) impact of different drugs or medical treatments and for informing and improving healthcare service delivery. Although the potential of RWD use seems quite clear, this research reveals barriers that restrict further development towards its full exploitation: the absence of common standards for defining the content and quality of RWD, methodological barriers that may limit the potential benefits of RWD analysis, governance issues underlying the absence of standards for collaboration between stakeholders, and privacy concerns and binding data protection legislation which can be seen to restrict access and use of data. PMID- 28083345 TI - Investigating Time Lags and Attribution in the Translation of Cancer Research: A Case Study Approach. AB - In 2012, RAND Europe and the Health Economics Research Group (Brunel University) were commissioned by the Wellcome Trust, Cancer Research UK, the National Institute for Health Research and the Academy of Medical Science to conduct a study of the returns to the public/charitable investment in cancer-related research. This study built on previous work published in the 2008 "What's it worth?" report that estimated the economic returns to medical research in terms of spillover benefits and health gain. The 2008 study was extensively quoted and cited as a clear justification for the economic importance of medical research and appears to have played a role in achieving the protection of the medical science budget in the recent public expenditure cuts. This cancer study used a similar approach to that used in the previous study, but with some methodological developments. One of the methodological developments was the inclusion of case studies to examine the validity and variability of the estimates on elapsed time between funding and health gains, and the amount of health gains that can be attributed to UK research. This study provides the full text of the five case studies conducted as well as some discussion of observations emerging across the case study set. PMID- 28083346 TI - Supporting the Development of a New Health R&D Strategy: A Rapid Review of International Theory and Practice for Norway's HelseOmsorg21. AB - The HelseOmsorg21 initiative was set up by the Ministry of Health and Care Services to develop a new research and innovation strategy for health and care services in Norway. The HelseOmsorg21 Strategy Group, through the Research Council of Norway which is providing the secretariat for the strategy development, asked RAND Europe to support the strategic review process. RAND Europe's role was to conduct a series of rapid evidence reviews around the recommendations arising from the five working groups that comprise the initiative. The reviews were conducted around networks and collaboration, data linkage and exchange, culture, values and leadership, and incentives for innovation, while capacity building was a recurrent theme throughout. This study presents the rapid evidence reviews, summarising relevant literature and highlighting international examples of particularly relevant or innovative approaches. The issues and ideas identified around each theme are then pulled together in a suggested conceptual representation of the Norwegian health and care research system. PMID- 28083348 TI - International Variation in Drug Usage: An Exploratory Analysis of the "Causes" of Variation. AB - This article explores the range of possible causes that might explain observed international variations in the usage of medicines for selected disease areas: dementia, osteoporosis, cancer, diabetes and hepatitis C. Commissioned by the UK Department of Health, through its Policy Research Programme, it complements a quantitative analysis of medicines uptake carried out by the Office for Health Economics (OHE) of medicines uptake across 16 classes of medicines in 13 high income countries in 2012/13. Both studies build on an earlier study led by Professor Sir Mike Richards (UK) into the extent and causes of international variations in drug usage, published in 2010. Drawing on a rapid evidence assessment, we explore, for each of the five disease areas, epidemiological factors such as the disease burden and aspects of health system and service organisation that were shown to have a direct or indirect impact on drug usage, such as reimbursement mechanisms, access to diagnosis and treatment more broadly. We also provide a summary overview of key features of the health systems and of the principles of drug assessment or approval processes across the countries included in the OHE analysis. We find that a range of factors are likely to play a role in explaining international variation in medicines use, but their relative importance will vary depending on the disease area in question and the system context. Any given level of use of a given medicine in one country is likely determined by a set of factors the combination and the relative weight of which will be different in another country. PMID- 28083347 TI - Measuring Success in Health Care Value-Based Purchasing Programs: Findings from an Environmental Scan, Literature Review, and Expert Panel Discussions. AB - Value-based purchasing (VBP) refers to a broad set of performance-based payment strategies that link financial incentives to health care providers' performance on a set of defined measures in an effort to achieve better value. The U.S. Department of Health and Human Services is advancing the implementation of VBP across an array of health care settings in the Medicare program in response to requirements in the 2010 Patient Protection and Affordable Care Act, and policymakers are grappling with many decisions about how best to design and implement VBP programs so that they are successful in achieving stated goals. This article summarizes the current state of knowledge about VBP based on a review of the published literature, a review of publicly available documentation from VBP programs, and discussions with an expert panel composed of VBP program sponsors, health care providers and health systems, and academic researchers with VBP evaluation expertise. Three types of VBP models were the focus of the review: (1) pay-for-performance programs, (2) accountable care organizations, and (3) bundled payment programs. The authors report on VBP program goals and what constitutes success; the evidence on the impact of these programs; factors that characterize high- and low-performing providers in VBP programs; the measures, incentive structures, and benchmarks used by VBP programs; evidence on spillover effects and unintended consequences; and gaps in the knowledge base. PMID- 28083349 TI - Barriers to Enrollment in Health Coverage in Colorado. AB - As part of the implementation of the Affordable Care Act, Colorado has expanded Medicaid and also now operates its own health insurance exchange for individuals (called Connect for Health Colorado). As of early 2014, more than 300,000 Coloradans have newly enrolled in Medicaid or health insurance through Connect for Health Colorado, but there also continues to be a diverse mix of individuals in Colorado who remain eligible for but not enrolled in either private insurance or Medicaid. The Colorado Health Foundation commissioned the RAND Corporation to conduct a study to better understand why these individuals are not enrolled in health insurance coverage and to develop recommendations for how Colorado can strengthen its outreach and enrollment efforts during the next open enrollment period, which starts in November 2014. RAND conducted focus groups with uninsured and newly insured individuals across the state and interviews with local stakeholders responsible for enrollment efforts in their regions. The authors identified 11 commonly cited barriers, as well as several that were specific to certain regions or populations (such as young adults and seasonal workers). Collectively, these barriers point to a set of four priority recommendations that stakeholders in Colorado may wish to consider: (1) Support and expand localized outreach and tailored messaging; (2) Strengthen marketing and messaging to be clear, focused on health benefits of insurance (rather than politics and mandates), and actionable; (3) Improve the clarity and transparency of insurance and health care costs and enrollment procedures; and (4) Revisit the two-stage enrollment process and improve Connect for Health Colorado website navigation and technical support. PMID- 28083350 TI - Quantitative Evaluation of the Impact of the Healthy Communities Initiative in Cincinnati. AB - Metropolitan Cincinnati residents have traditionally had among the highest health care costs in the United States, yet little evidence exists that residents are getting their money's worth, especially in terms of preventive and primary care. Recently, large employers, health plans, and health care providers in the Cincinnati area joined with community organizations in an effort to improve health care and population health, as well as reduce health care costs by focusing on five priority areas: coordinated primary care, health information exchange, quality improvement, public reporting and consumer engagement, and payment innovations. Spearheaded by General Electric (GE) Cincinnati, the resulting Healthy Communities Initiative in Cincinnati was implemented in 2009. In 2012, GE asked RAND Health Advisory Services to assess progress over the first three years of the initiative. Overall, the findings were largely inconclusive because of a concomitant marketwide shift to high-deductible health policies (which are known to have profound effects on care-seeking behavior) and the early stage of the intervention. However, there were some encouraging signs that better care coordination bears fruit, such as less illness-related work loss and fewer avoidable hospital admissions and readmissions. These early impacts suggest that the initiative may succeed in improving care, lowering cost, and improving health status if given sufficient time. PMID- 28083351 TI - Assessing Alternative Modifications to the Affordable Care Act: Impact on Individual Market Premiums and Insurance Coverage. AB - The goals of the Affordable Care Act (ACA) are to enable all legal U.S. residents to have access to affordable health insurance and to prevent sicker individuals (such as those with preexisting conditions) from being priced out of the market. The ACA also instituted several policies to stabilize premiums and to encourage enrollment among healthy individuals of all ages. The law's tax credits and cost sharing subsidies offer a "carrot" that may encourage enrollment among some young and healthy individuals who would otherwise remain uninsured, while the individual mandate acts as a "stick" by imposing penalties on individuals who choose not to enroll. In this article, the authors use the COMPARE microsimulation model, an analytic tool that uses economic theory and data to predict the effects of health policy reforms, to estimate how eliminating the ACA's individual mandate, eliminating the law's tax credits, and combined scenarios that change these and other provisions of the act might affect 2015 individual market premiums and overall insurance coverage. Underlying these estimates is a COMPARE-based analysis of how premiums and insurance coverage outcomes depend on young adults' propensity to enroll in insurance coverage. The authors find that eliminating the ACA's tax credits and eliminating the individual mandate both increase premiums and reduce enrollment on the individual market. They also find that these key features of the ACA help to protect against adverse selection and stabilize the market by encouraging healthy people to enroll and, in the case of the tax credit, shielding subsidized enrollees from premium increases. Further, they find that individual market premiums are only modestly sensitive to young adults' propensity to enroll in insurance coverage, and ensuring market stability does not require that young adults make up a particular share of enrollees. PMID- 28083352 TI - The Health Risks of Bathing in Recreational Waters: A Rapid Evidence Assessment of Water Quality and Gastrointestinal Illness. AB - The European Bathing Directive (2006/7/EC) stipulates water quality standards for recreational bathing waters based on specified limits of faecal indicator organisms (FIOs). Presence of FIOs above the limits is considered to be indicative of poor water quality and to present a risk to bathers' health. The European Bathing Directive (2006) is to be reviewed in 2020. We conducted a rapid evidence assessment on recreational bathing waters and gastrointestinal illness (GI) to identify the extent of the literature published since the previous review period in 2003 and to determine whether there is any new evidence which may indicate that a revision to the Directive would be justified. Overall, 21 papers (from 16 studies), including two RCTs, met the inclusion criteria; 12 were conducted in marine waters and four were conducted in freshwater. Considerable heterogeneity existed between study protocols and the majority had significant methodological limitations, including self-selection and misclassification biases. Moreover, there was limited variation in water quality among studies, providing a limited evidence base on which to assess the classification standards. Overall, there appears to be a consistent significant relationship between faecal indicator organisms and GI in freshwater, but not marine water studies. Given the apparent lack of relationship between GI and water quality, it is unclear whether the boundaries of the Bathing Waters Directive are supported by studies published in the post-2003 period. We suggest that more epidemiological evidence is needed to disprove or confirm the original work that was used to derive these boundaries for marine waters. PMID- 28083353 TI - Targeting Alcohol Misuse: A Promising Strategy for Reducing Military Sexual Assaults? AB - On the 2012 Workplace and Gender Relations Survey on Active Duty Service Members, 23 percent of female and 4 percent of male service members indicated that they had experienced a completed or attempted sexual assault during their military service. In addition, official numbers show no decline in sexual assaults, despite the implementation of sexual assault prevention programs across the U.S. Department of Defense (DoD). Alcohol misuse is also a problem in the military: One-third of active-duty service members reported binge drinking, a rate that compares unfavorably with that of their civilian counterparts. DoD has invested considerable resources in universal sexual assault prevention programs and social media campaigns, but evaluation results are not yet available, and the effectiveness of these programs is unclear. Research on civilian populations particularly college students, who share some characteristics with junior enlisted personnel-could provide insights for DoD. For example, the research indicates a connection between alcohol and aggression, including sexual aggression. Alcohol can also have a range of effects on the risk of victimization from a reduced awareness of risk indicators to incapacitation or unconsciousness. An extensive review of the existing research provides some guidance for how DoD can implement and evaluate efforts to reduce alcohol misuse as part of a larger strategy to reduce the incidence of sexual assault among members of the armed forces. PMID- 28083354 TI - Population Health Management and the Second Golden Age of Arab Medicine: Promoting Health, Localizing Knowledge Industries, and Diversifying Economies in the GCC Countries. AB - Over the past half-century, the Gulf Cooperation Council (GCC) countries-Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates-have experienced rapid economic growth and, with it, dramatic lifestyle changes. Low levels of physical activity and calorie-dense diets have led to an increase in the prevalence of chronic disease, most prominently diabetes. After having successfully controlled communicable diseases and made advanced acute care accessible locally, the GCC countries now face the challenge of orienting their health care systems toward prevention and treatment of chronic diseases. In this study, Dr. Mattke and his colleagues argue that this challenge presents GCC countries with a historic opportunity to reestablish the thought leadership role that Arab medicine had in the Islamic Golden Age. They propose that GCC countries could apply their considerable wealth to design and implement innovative health care systems based on population health management principles and sophisticated health information technology. Taking this path would not only improve prevention and management of chronic disease in the GCC countries but also contribute to the diversification of their economies and localization of knowledge industries. PMID- 28083355 TI - Best Practice: Medical Training From an International Perspective. AB - This study seeks to help inform the further development of medical education and training for primary care in Germany. It explores approaches to medical education and training in a small number of high-income countries and how these seek to address shortages of doctors practising in primary or ambulatory care through reforming their education and training systems. It does so by means of an exploratory analysis of the experiences of three countries: England, France and the Netherlands, with Germany included for comparison. Data collection involved a review of the published and grey literature, using a structured template, complemented by information provided by key informants in the selected countries. The study sets out the general context within which the medical education and training systems in the four countries operate, and describe the education and training pathways for general practice for each. We highlight options for medical education and training in Germany that arise from this study by placing our observations in the context of ongoing reform activity. This study will be of relevance for decisionmakers and practitioners concerned with ensuring a medical workforce that is prepared for the demands in a changing healthcare environment. PMID- 28083356 TI - The DNP by 2015: A Study of the Institutional, Political, and Professional Issues that Facilitate or Impede Establishing a Post-Baccalaureate Doctor of Nursing Practice Program. AB - In 2004, members of the American Association of Colleges of Nursing (AACN) voted to endorse a position statement identifying the doctor of nursing practice (DNP) degree as the most appropriate degree for advanced-practice registered nurses (APRNs) to enter practice. At the same time, AACN members voted to approve the position that all master's programs that educate APRNs to enter practice should transition to the DNP by 2015. While the number of DNP programs for APRNs has grown significantly and steadily over this period, at this time, not all nursing schools have made this transition. To better understand why, the AACN contracted with RAND to investigate schools' progress toward this goal and the factors that facilitate or impede this transition. This article describes the results of a mixed-method RAND study undertaken between October 2013 and April 2014 that sought to understand schools' program offerings to prepare APRNs to enter practice and the reasons for those offerings, as well as the barriers or facilitators to nursing schools' full adoption of the DNP. PMID- 28083357 TI - Medicare Imaging Demonstration Final Evaluation: Report to Congress. AB - Increasing use of advanced medical imaging is often cited as a key driver of cost growth in medical spending. In 2011, the Medicare Imaging Demonstration from the Centers for Medicare & Medicaid Services began testing whether exposing ordering clinicians to appropriateness guidelines for advanced imaging would reduce ordering inappropriate images. The evaluation examined trends in advanced diagnostic imaging utilization starting January 1, 2009-more than two years before the beginning of the demonstration-to November 30, 2013-two months after the close of the demonstration. Small changes in ordering patterns were noted, but decision support systems were unable to assign appropriateness ratings to many orders, thus limiting the potential effectiveness of decision support. Many opportunities to refine decision support systems have been identified. PMID- 28083358 TI - Development of a Model for the Validation of Work Relative Value Units for the Medicare Physician Fee Schedule. AB - The Centers for Medicare & Medicaid Services (CMS) uses the resource-based relative value scale to pay physicians and other practitioners for professional services. The work values measure the relative levels of professional time and intensity (physical effort, skills, and stress) associated with providing services. CMS asked RAND to develop a model to validate the work values using external data sources. RAND's goal was to test the feasibility of using external data and regression analysis to create prediction models to validate work values. Data availability limited the models to surgical procedures and selected medical procedures typically performed in an operating room. Key findings from the study include the following: RAND estimates of intra-service time using external data are typically shorter than the current CMS estimates. Model assumptions about how shorter intra-service times affect procedure intensity have implications for the work estimates. RAND estimates for work on average were similar to current work values if shorter intra-service time is assumed to increase procedure intensity and were on average up to 10 percent lower than current work values if shorter intra-service time is assumed to not impact on procedure intensity. The RAND estimates could be used for two key applications: CMS could flag codes as potentially misvalued if the RAND estimates are notably different from the current CMS values. CMS could also use the RAND estimates as an independent estimate of the work values. In some cases, further review will identify a clinical rationale for why a code is valued differently than the RAND model predictions. PMID- 28083359 TI - The Economic Incidence of Health Care Spending in Vermont. AB - In 2015, Vermont legislators may consider financing plans to implement Act 48, a law that aims to provide universal health care coverage to all Vermont residents starting in 2017. In this analysis, we estimate the economic incidence of payments for health care by Vermont residents and the value of health care benefits received by Vermont residents in 2012 and 2017, without the implementation of Act 48 reforms. The goal of the analysis was to understand how health care is currently paid for in Vermont, and to provide a baseline for understanding the possible effects of Act 48. We use data from the 2012 Vermont Household Health Interview Survey, the Vermont Health Care Uniform Evaluation and Reporting System, and administrative data on taxes to estimate payments in 2012. We then project these estimates forward to 2017, using the RAND COMPARE microsimulation to account for how health care coverage in Vermont will change as a result of the Affordable Care Act (ACA). We find that most Vermont residents receive more in health benefits than they pay for directly or through taxes. While lower-income individuals, on average, pay less than higher-income individuals, there is considerable variation across individuals in the level of payment for health care. Much of the current variation stems from the fractured nature of the health system, with some individuals receiving coverage through employers, some through the Exchange (i.e., the health insurance marketplace created by the ACA), and some through other sources. As Vermont considers health care reform, legislators may wish to consider options to reduce the degree of variation in payments made by individuals with similar income levels. PMID- 28083360 TI - The Effect of Eliminating the Affordable Care Act's Tax Credits in Federally Facilitated Marketplaces. AB - In this study, RAND Corporation researchers assess the expected change in enrollment and premiums in the Patient Protection and Affordable Care Act (ACA) compliant individual market in federally facilitated marketplace (FFM) states if the U.S. Supreme Court decides to eliminate subsidies in FFM states. The analysis used the Comprehensive Assessment of Reform Efforts (COMPARE) microsimulation model, an economic model developed by RAND researchers, to assess the impact of proposed health reforms. The authors found that enrollment in the ACA-compliant individual market, including plans sold in the marketplaces and those sold outside of the marketplaces that comply with ACA regulations, would decline by 9.6 million, or 70 percent, in FFM states if subsidies were eliminated. They also found that unsubsidized premiums in the ACA-compliant individual market would increase 47 percent in FFM states. This corresponds to a $1,610 annual increase for a 40-year-old nonsmoker purchasing a silver plan. PMID- 28083361 TI - Effects of Health Care Payment Models on Physician Practice in the United States. AB - The project reported here, sponsored by the American Medical Association (AMA), aimed to describe the effects that alternative health care payment models (i.e., models other than fee-for-service payment) have on physicians and physician practices in the United States. These payment models included capitation, episode based and bundled payment, shared savings, pay for performance, and retainer based practice. Accountable care organizations and medical homes, which are two recently expanding practice and organizational models that frequently participate in one or more of these alternative payment models, were also included. Project findings are intended to help guide efforts by the AMA and other stakeholders to make improvements to current and future alternative payment programs and help physician practices succeed in these new payment models-i.e., to help practices simultaneously improve patient care, preserve or enhance physician professional satisfaction, satisfy multiple external stakeholders, and maintain economic viability as businesses. The article provides both findings and recommendations. PMID- 28083362 TI - Home Health Care for California's Injured Workers: Options for Implementing a Fee Schedule. AB - The California Department of Industrial Relations/Division of Worker's Compensation asked RAND to provide technical assistance in developing a fee schedule for home health services provided to injured workers. The fee schedule needs to address the full spectrum of home health services ranging from skilled nursing and therapy services to unskilled personal care or chore services that may be provided by family members. RAND researchers consulted with stakeholders in the California workers' compensation system to outline issues the fee schedule should address, reviewed home health fee schedules used by other payers, and conducted interviews with WC administrators from other jurisdictions to elicit their experiences. California stakeholders identified unskilled attendant services as most problematic in determining need and payment rates, particularly services furnished by family members. RAND researchers concentrated on fee schedule options that would result in a single fee schedule covering the full range of home health care services furnished to injured workers and made three sets of recommendations. The first set pertains to obtaining additional information that would highlight the policy issues likely to occur with the implementation of the fee schedule and alternatives for assessing an injured worker's home health care needs. Another approach conforms most closely with the Labor Code requirements. It would integrate the fee schedules used by Medicare, In-Home Health Supportive Services, and the federal Office of Workers' Compensation. The third approach would base the home health fee schedule on rules used by the federal Office of Workers' Compensation. PMID- 28083363 TI - Specialty Payment Model Opportunities and Assessment: Gastroenterology and Cardiology Model Design Report. AB - Gastroenterology and cardiology services are common and costly among Medicare beneficiaries. Episode-based payment, which aims to create incentives for high quality, low-cost care, has been identified as a promising alternative payment model. This article describes research related to the design of episode-based payment models for ambulatory gastroenterology and cardiology services for possible testing by the Center for Medicare and Medicaid Innovation at the Centers for Medicare and Medicaid Services (CMS). The authors analyzed Medicare claims data to describe the frequency and characteristics of gastroenterology and cardiology index procedures, the practices that delivered index procedures, and the patients that received index procedures. The results of these analyses can help inform CMS decisions about the definition of episodes in an episode-based payment model; payment adjustments for service setting, multiple procedures, or other factors; and eligibility for the payment model. PMID- 28083364 TI - Specialty Payment Model Opportunities and Assessment: Oncology Model Design Report. AB - This article describes research related to the design of a payment model for specialty oncology services for possible testing by the Center for Medicare and Medicaid Innovation at the Centers for Medicare & Medicaid Services (CMS). Cancer is a common and costly condition. Episode-based payment, which aims to create incentives for high-quality, low-cost care, has been identified as a promising alternative payment model for oncology care. Episode-based payment systems can provide flexibility to health care providers to select among the most effective and efficient treatment alternatives, including activities that are not currently reimbursed under Medicare payment policies. However, the model design also needs to ensure that high-quality care is delivered and that beneficial treatments are not withheld from patients. CMS asked MITRE and RAND to conduct analyses to inform design decisions related to an episode-based oncology model for Medicare beneficiaries undergoing chemotherapy treatment for cancer. In particular, this study focuses on analyses of Medicare claims data related to the definition of the initiation of an episode of chemotherapy, patterns of spending during and surrounding episodes of chemotherapy, and attribution of episodes of chemotherapy to physician practices. We found that the time between the primary cancer diagnosis and chemotherapy initiation varied widely across patients, ranging from one day to over seven years, with a median of 2.4 months. The average level of total monthly payments varied considerably across cancers, with the highest spending peak of $9,972 for lymphoma, and peaks of $3,109 for breast cancer and $2,135 for prostate cancer. PMID- 28083365 TI - Specialty Payment Model Opportunities and Assessment: Oncology Simulation Report. AB - This article describes the results of a simulation analysis of a payment model for specialty oncology services that is being developed for possible testing by the Center for Medicare and Medicaid Innovation at the Centers for Medicare & Medicaid Services (CMS). CMS asked MITRE and RAND to conduct simulation analyses to preview some of the possible impacts of the payment model and to inform design decisions related to the model. The simulation analysis used an episode-level dataset based on Medicare fee-for-service (FFS) claims for historical oncology episodes provided to Medicare FFS beneficiaries in 2010. Under the proposed model, participating practices would continue to receive FFS payments, would also receive per-beneficiary per-month care management payments for episodes lasting up to six months, and would be eligible for performance-based payments based on per-episode spending for attributed episodes relative to a per-episode spending target. The simulation offers several insights into the proposed payment model for oncology: (1) The care management payments used in the simulation analysis $960 total per six-month episode-represent only 4 percent of projected average total spending per episode (around $27,000 in 2016), but they are large relative to the FFS revenues of participating oncology practices, which are projected to be around $2,000 per oncology episode. By themselves, the care management payments would increase physician practices' Medicare revenues by roughly 50 percent on average. This represents a substantial new outlay for the Medicare program and a substantial new source of revenues for oncology practices. (2) For the Medicare program to break even, participating oncology practices would have to reduce utilization and intensity by roughly 4 percent. (3) The break-even point can be reduced if the care management payments are reduced or if the performance-based payments are reduced. PMID- 28083366 TI - California College and University Collaborations: Facilitators, Challenges, and Impact on Student Mental Health. AB - This article reports on an evaluation of student mental health collaboration activities among California higher education systems, community agencies, and county mental health. PMID- 28083367 TI - California K-12 and Community Collaborations: Facilitators, Challenges, and Impact on Student Mental Health. AB - This article reports on an evaluation of student mental health collaboration activities among California K-12 school districts, counties, and regions. PMID- 28083368 TI - Evaluation of California's Statewide Mental Health Prevention and Early Intervention Programs: Summary of Key Year 2 Findings. AB - This article summarizes key findings from the second year of an evaluation of the California Mental Health Services Authority's statewide prevention and early intervention programs. PMID- 28083370 TI - Mental Health Trainings in California's Higher Education System Are Associated with Increased Confidence and Likelihood to Intervene with and Refer Students. AB - This article reports on an evaluation of California mental health trainings offered to staff and students in California's higher education system. PMID- 28083369 TI - Gatekeeper Training for Suicide Prevention: A Theoretical Model and Review of the Empirical Literature. AB - In recent years, the rising rate of suicides by military personnel has generated concern among policymakers, military leaders, and the public at large. Based on a recommendation from an earlier RAND report on preventing suicide among military personnel, this study reviews the literature on gatekeeper models of suicide prevention to better understand what is known about the effectiveness of gatekeepers and gatekeeper training. The study presents a theoretical model describing how gatekeeper training may influence individual knowledge, beliefs, and attitudes that may, in turn, result in intervention behaviors. It then reviews the evidence supporting each of the relationships presented in this model, and concludes with recommendations for advancing research in this field. PMID- 28083371 TI - Mental Health Trainings in California's K-12 System Are Associated with Increased Confidence and Likelihood to Intervene with and Refer Students. AB - This article reports on an evaluation of California mental health trainings offered to staff in California's K-12 system. PMID- 28083372 TI - Reviewing the Evidence Base for Mental Health First Aid: Is There Support for Its Use with Key Target Populations in California? AB - This article reviews the current state of evidence for Mental Health First Aid's effectiveness in key target populations, to help the California Mental Health Services Authority's planning for future prevention and early intervention activities. PMID- 28083373 TI - A Review of Research on Problematic Internet Use and Well-Being: With Recommendations for the U.S. Air Force. AB - This article reviews the scientific literature on the epidemiology, prevention, and treatment of problematic Internet use (PIU) with the goal of informing Air Force policies aimed at mitigating PIU's negative impact on operations and the mental health of Airmen. The study is motivated by a recent RAND study estimating that 6 percent of Airmen have PIU. Individuals with PIU, similar to people with substance addictions, suffer from excessive and compulsive online activities, symptoms of tolerance and withdrawal, and functional impairment. PIU is also strongly associated with other mental health problems including major depression. However, at present there is no single accepted definition of PIU, and no up-to date estimates of the prevalence of PIU in the general U.S. population are available. A range of prevention and treatment approaches have been developed, but none has been rigorously tested in clinical trials. Prevention programs rely on workplace Internet policies and strategies to help individuals self-regulate their Internet use. Treatment approaches that have proven feasible and acceptable to patients with PIU include adaptations of cognitive-behavioral therapy, an evidence-based treatment for depression and anxiety, to the specific symptoms of PIU. Based on our findings, we recommend: (1) increasing awareness of PIU among organizational leadership and mental health professionals, (2) incorporating content related to PIU into existing trainings related to mental health, (3) providing support for self-regulation of Internet use on the job by incorporating PIU management principles into Internet use policies, and (4) continuing monitoring of the emerging scientific literature on PIU. PMID- 28083374 TI - Access to Behavioral Health Care for Geographically Remote Service Members and Dependents in the U.S. AB - With many service members now returning to the United States from the recent conflicts in Iraq and Afghanistan, concern over adequate access to behavioral health care (treatment for mental, behavioral, or addictive disorders) has risen. Yet data remain very sparse regarding how many service members (and their dependents) reside in locations remote from behavioral health providers, as well as the resulting effect on their access to and utilization of care. Little is also known about the effectiveness of existing policies and other efforts to improve access to services among this population. To help fill these gaps, a team of RAND researchers conducted a geospatial analysis using TRICARE and other data, finding that roughly 300,000 military service members and 1 million dependents are geographically distant from behavioral health care, and an analysis of claims data indicated that remoteness is associated with lower use of specialty behavioral health care. A review of existing policies and programs discovered guidelines for access to care, but no systematic monitoring of adherence to those guidelines, limiting their value. RAND researchers recommend implementing a geospatial data portal and monitoring system to track access to care in the military population and mark progress toward improvements in access to care. In addition, the RAND team highlighted two promising pathways for improving access to care among remote military populations: telehealth and collaborative care that integrates primary care with specialty behavioral care. PMID- 28083375 TI - Behavioral Fitness and Resilience: A Review of Relevant Constructs, Measures, and Links to Well-Being. AB - This study is one of a series designed to support Air Force leaders in promoting resilience among its Airmen, civilian employees, and Air Force family members. It examines the relationship between behavioral fitness and resilience, using key constructs found in the scientific literature that relate to sleep, alcohol use, and tobacco use. Supporting or increasing the levels of the key measures of behavioral fitness identified in this study may facilitate resilience and can protect Airmen, civilian employees, and Air Force families from the negative effects of conduct, routines, and habits that are detrimental to fitness. The study also reviews behavioral fitness construct measures and resilience outcomes as well as interventions designed to promote behavioral fitness. PMID- 28083376 TI - Pre-Deployment Stress, Mental Health, and Help-Seeking Behaviors Among Marines. AB - The Marine Corps Operational Stress Control and Readiness (OSCAR) program is designed to provide mental health support to marines by embedding mental health personnel within Marine Corps units and increasing the capability of officers and senior noncommissioned officers to improve the early recognition and intervention of marines exhibiting signs of stress. The Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury have asked RAND to evaluate the OSCAR program. As part of this evaluation, RAND conducted a large survey of marines who were preparing for a deployment to Iraq or Afghanistan in 2010 or 2011. This article describes the methods and findings from this survey. The results are among the first to shed light on the pre-deployment mental health status of marines, as well as the social resources they draw on when coping with stress and their attitudes about seeking help for stress-related problems. The 2,620 marines in the survey sample had high rates of positive screens for current major depressive disorder (12.5 percent) and high-risk drinking (25.7 percent) and reported having experienced more potentially traumatic events over their lifetime than adult males in the general population. Marines in the sample also reported relying on peers for support with stress and perceiving moderate levels of support from the Marine Corps for addressing stress problems. PMID- 28083377 TI - From Coverage to Care: Strengthening and Facilitating Consumer Connections to the Health System. AB - To date, most Affordable Care Act implementation efforts have focused on getting individuals enrolled in health insurance coverage; indeed, millions of Americans, many of whom had never been insured, have since obtained health coverage, either through the health insurance marketplaces or through expanded Medicaid eligibility, if available in their state. Yet reducing the number of uninsured is only part of the law's goal. It also aims to improve population health and lower health care costs. Less attention has been paid to confirming that the newly insured obtain appropriate health care and maintain long-term relationships with their health care providers, which are critical steps to help achieve these latter goals. This article describes lessons learned from conversations with a variety of stakeholders in the health care industry. These conversations covered the gamut of steps consumers must undergo to become fully engaged with their health care, from applying for coverage and selecting a plan to finding a provider, accessing care, and engaging in care over time. In each phase of the process, consumers must take specific actions and overcome new challenges. Stakeholder efforts to help consumers often focus on just one of these phases, at the expense of the bigger picture, and often occur in isolation, with little coordination across stakeholder groups. Thinking more strategically and holistically can help provide the "connective tissue" that can help prevent consumers from becoming disengaged and falling through the system's cracks. PMID- 28083378 TI - The future of anticoagulation management in atrial fibrillation in Europe: An assessment of today's challenges with recommendations for the future. AB - Atrial fibrillation (AF) is the most common type of cardiac arrhythmia, affecting approximately 1-2 per cent of the population worldwide. Those who suffer from AF have a five times higher risk of stroke. AF prevalence increases with age and it affects roughly 18 per cent of the population over 85. Consequently, as populations age, AF is becoming an increasingly significant public health issue. Over recent years there have been developments in treatment and management options, both for treating the arrhythmia directly, and assessing and reducing the risk of AF-related stroke, but there is a need to ensure that available knowledge is applied optimally to benefit patients so that opportunities to prevent AF-related stroke are not missed. The aims of this project were to assess the current landscape and explore the direction of future developments in AF management in Europe, with a focus on the use of anticoagulants in the prevention of AF-related stroke. Through rapid evidence assessment, key informant interviews, PESTLE analysis and the development and exploration of future scenarios, we have developed sets of shorter- and longer-term recommendations for improving AF-related patient outcomes. The short-term recommendations are: i) improve AF awareness among the public and policymakers; ii) support education about AF management for healthcare professionals and patients; and iii) maintain engagement in AF-related research across the health services. PMID- 28083379 TI - Improving Care for Chronic Conditions: Current Practices and Future Trends in Health Plan Programs. AB - The need for better management of chronic conditions is urgent. About 141 million people in the United States were living with one or more chronic conditions in 2010, and this number is projected to increase to 171 million by 2030. To address this challenge, many health plans have piloted and rolled out innovative approaches to improving care for their members with chronic conditions. This article documents the current range of chronic care management services, identifies best practices and industry trends, and examines factors in the plans' operating environment that limit their ability to optimize chronic care programs. The authors conducted telephone surveys with a representative sample of health plans and made in-depth case studies of six plans. All plans in the sample provide a wide range of products and services around chronic care, including wellness/lifestyle management programs for healthy members, disease management for members with common chronic conditions, and case management for high-risk members regardless of their underlying condition. Health plans view these programs as a "win-win" situation and believe that they improve care for their most vulnerable members and reduce cost of coverage. Plans are making their existing programs more patient-centric and are integrating disease and case management, and sometimes lifestyle management and behavioral health, into a consolidated chronic care management program, believing that this will increase patient engagement and prevent duplication of services and missed opportunities. PMID- 28083380 TI - The NIHR Invention for Innovation (i4i) Programme: A Review of Progress and Contributions to Innovation in Healthcare Technologies. AB - The National Institute for Health Research (NIHR) Invention for Innovation (i4i) programme supports the development of innovative medical technologies for patient benefit. The i4i product development stream involves collaborative projects between at least two partners from academia, the NHS and industry. Medical technology innovators apply for funding for one to three years, through a peer review-based process that includes presentation to a selection panel. The funding and business advice provided by i4i support the development of early-stage innovations, generally at proof of concept and prototype stages. Since its inception the product development stream has identified and supported 170 projects, led by 146 principal investigators (PIs). RAND Europe evaluated the programme, with the aim of identifying its outputs and impacts and examining the factors influencing performance. The evaluation findings should help inform the future of the programme. The evaluation used a multi-method approach, including a focused review of background information from i4i, scoping interviews with key informants, a survey of programme participants and case studies of projects representing diverse technologies and health needs. PMID- 28083381 TI - Paths to Sustainability for Innovative Delivery System Programs. AB - Innovative health care delivery organizations are developing programs that aim to improve quality and demonstrate reductions in unnecessary use of acute care and costs. RAND researchers sought to identify paths to sustainability for these innovative care delivery programs. Using a sample of health plans and ACOs in Massachusetts, researchers sought to identify the methods in use to reimburse new care delivery models, criteria that health plans use to determine eligibility for these models, and criteria that accountable care organizations apply for their investments in delivery innovations. Researchers identified a highly uncertain environment for the sustainability of care delivery innovations despite a high degree of interest in these programs. Dynamics in the current environment suggest that innovation will likely be concentrated in health care delivery systems that are able to manage financial risk and that have experience and capacity in delivery innovation. For providers seeking to innovate, the central challenge will be building the capacity to manage financial risk in global payment arrangements and to support improvements in care. This will be particularly challenging for smaller organizations. Payers interested in innovation should seek ways to provide support and build the capacity of smaller and less experienced providers so that they, too, can innovate and improve how they provide care. PMID- 28083382 TI - Insurance Transitions Following the First ACA Open Enrollment Period. AB - While most of the Affordable Care Act's (ACA's) coverage-related provisions took effect in January 2014, there is limited information on insurance transitions that occurred in the period before and after these changes became operational. In Insurance Transitions Following the First ACA Open Enrollment Period, the authors examine insurance transitions between September 2013 and November 2014 using longitudinal data from the RAND Health Reform Opinion Study, a part of the RAND American Life Panel (ALP). The ALP includes 2,953 respondents-ages 18 to 64, in a population-based sample-who were approached to participate in this data collection. Out of the 2,953 individuals, 2,329 (79 percent) responded in September 2013, and 1,972 (67 percent) responded in November 2014; 1,636 (55 percent) responded in both months, and 1,628 (55 percent) provided clear information about their source of insurance. The authors report the type of coverage people had before the law's major provisions took effect (September 2013) and at the end of the Marketplace enrollment year (November 2014). They estimate that 20.4 million nonelderly adults became newly insured and 7.4 million lost coverage, for a net increase of 12.9 million between September 2013 and November 2014. Among those previously uninsured, most (7.5 million) enrolled in Medicaid, followed by employer plans (7.3 million), the Marketplaces (3.1 million), and other insurance sources. Among those losing coverage, most (3.4 million) lost employer coverage, with the remaining insurance losses spread across a variety of coverage sources. The authors estimate that 7.6 million people enrolled in Marketplace plans; this includes the 3.1 million people who became newly insured in Marketplace plans and another 4.5 million people who transitioned to Marketplace plans from another coverage source. The majority of those insured at baseline (81 percent) experienced no change in source of coverage during the study period, suggesting that disruption from the law has been limited. The majority of Americans continue to be enrolled in employer coverage, and more gained coverage in employer plans than through the ACA's Marketplaces. These findings suggest that the ACA is expanding coverage through a variety of insurance sources, perhaps because the individual mandate is encouraging people to take up insurance offers that they might otherwise have declined. PMID- 28083383 TI - Workplace Wellness Programs: Services Offered, Participation, and Incentives. AB - This article leverages existing data on wellness programs to explore patterns of wellness program availability, employers' use of incentives, and program participation and utilization among employees. Researchers used two sets of data for this project: The first included data from the 2012 RAND Employer Survey, which used a nationally representative sample of U.S. employers that had detailed information on wellness program offerings, program uptake, incentive use, and employer characteristics. These data were used to answer questions on program availability, configuration, uptake, and incentive use. The second dataset included health care claims and wellness program information for a large employer. These data were analyzed to predict program participation and changes in utilization and health. The findings underscore the increasing prevalence of worksite wellness programs. About four-fifths of all U.S. employers with more than 1,000 employees are estimated to offer such programs. For those larger employers, program offerings cover a range of screening activities, interventions to encourage healthy lifestyles, and support for employees with manifest chronic conditions. Smaller employers, especially those with fewer than 100 employees, appear more reserved in their implementation of wellness programs. The use of financial incentives appears to increase employee participation in wellness programs, but only modestly. Employee participation in lifestyle management aspects of workplace wellness programs does not reduce healthcare utilization or cost regardless of whether we focus on higher-risk employees or those who are more engaged in the program. PMID- 28083384 TI - Adults Newly Exposed to "Know the Signs" Campaign Report Greater Gains in Confidence to Intervene with Those Who Might Be at Risk for Suicide Than Those Unexposed to the Campaign. AB - Presents results of a one-year follow-up to a survey on "Know the Signs," a California mass media suicide prevention campaign, and examines the effect of campaign exposure on respondents' confidence to intervene with someone at risk for suicide. PMID- 28083385 TI - Analysis of the Benefits and Costs of CalMHSA's Investment in Applied Suicide Intervention Skills Training (ASIST). AB - Estimates the possible reductions in suicide attempts resulting from investment in ASIST and estimates the financial return to Californians from reduced medical costs associated with suicide attempts and increased earnings from each life saved. PMID- 28083386 TI - Changes in Mental Illness Stigma in California During the Statewide Stigma and Discrimination Reduction Initiative. AB - Presents results of a one-year follow-up to the 2014 California Statewide Survey, which was developed to track attitudes, beliefs, and behaviors related to mental illness. This article focuses on items measuring stigma. PMID- 28083387 TI - Stigma, Discrimination, and Well-Being Among California Adults Experiencing Mental Health Challenges. AB - Presents results of the 2014 California Well-Being Survey, which tracks mental illness stigma and discrimination, well-being, and exposure to prevention and early intervention activities among Californians experiencing psychological distress. PMID- 28083388 TI - Care Transitions to and from the National Intrepid Center of Excellence (NICoE) for Service Members with Traumatic Brain Injury. AB - Improvised explosive devices (IEDs) have been one of the leading causes of death and injury among U.S. troops. Those who survive an IED blast or other injuries may be left with a traumatic brain injury (TBI) and attendant or co-occurring psychological symptoms. In response to the need for specialized services for these populations, the U.S. Department of Defense (DoD) established the National Intrepid Center of Excellence (NICoE) in Bethesda, Maryland, in 2010. The NICoE's success in fulfilling its mission is impacted by its relationships with home station providers, patients, and their families. The RAND Corporation was asked to evaluate these relationships and provide recommendations for strengthening the NICoE's efforts to communicate with these groups to improve patients' TBI care. Through surveys, site visits, and interviews with NICoE staff, home station providers, service members who have received care at the NICoE, and the families of these patients, RAND's evaluation examined the interactions between the NICoE and the providers responsible for referring patients and implementing treatment plans. PMID- 28083389 TI - Evaluating the Implementation of the Re-Engineering Systems of Primary Care Treatment in the Military (RESPECT-Mil). AB - A RAND team conducted an independent implementation evaluation of the Re Engineering Systems of Primary Care Treatment in the Military (RESPECT-Mil) Program, a system of care designed to screen, assess, and treat posttraumatic stress disorder and depression among active duty service members in the Army's primary care settings. Evaluating the Implementation of the Re-Engineering Systems of Primary Care Treatment in the Military (RESPECT-Mil) presents the results from RAND's assessment of the implementation of RESPECT-Mil in military treatment facilities and makes recommendations to improve the delivery of mental health care in these settings. Analyses were based on existing program data used to monitor fidelity to RESPECT-Mil across the Army's primary care clinics, as well as discussions with key stakeholders. During the time of the evaluation, efforts were under way to implement the Patient Centered Medical Home, and uncertainties remained about the implications for the RESPECT-Mil program. Consideration of this transition was made in designing the evaluation and applying its findings more broadly to the implementation of collaborative care within military primary care settings. PMID- 28083390 TI - Evaluation of the Operational Stress Control and Readiness (OSCAR) Program. AB - The Marine Corps Operational Stress Control and Readiness (OSCAR) program embeds mental health personnel within Marine Corps units and extends their reach by training officers and noncommissioned officers to recognize Marines showing signs of stress and intervene early. RAND Corporation researchers conducted an outcome evaluation of the OSCAR program that included four components: (1) a quasi experimental study that compared Marines in OSCAR-trained and non-OSCAR-trained battalions on a wide array of stress-related outcomes before and after deployment, (2) a longitudinal pre- and postdeployment survey of perceptions of OSCAR among Marines who attended OSCAR training, (3) focus groups with Marines, and (4) semistructured interviews with commanding officers of battalions that had received OSCAR training. Results indicated that, after the authors adjust for a wide array of baseline characteristics and deployment experiences, Marines in OSCAR-trained battalions were more likely than those in non-OSCAR-trained battalions to report having sought help with stress problems from a peer, leader, or corpsman-behavior that is consistent with OSCAR goals. In addition, Marines considered OSCAR a valuable tool for enhancing combat and operational stress response and recovery efforts in the Marine Corps. However, this evaluation did not find evidence that OSCAR affected the key mental health outcomes it was designed to address. Thus, the results of this evaluation do not support the continuation of OSCAR in its current form. Based on lessons learned about OSCAR from this evaluation, other research, and best practices for program improvement and implementation, recommendations for improving combat and operational stress training in the Marine Corps are offered. PMID- 28083391 TI - Faith-Based Organizations and Veteran Reintegration: Enriching the Web of Support. AB - Faith-based organizations (FBOs) are an important community-based resource for veterans as they readjust to civilian life. Through interviews with both national level and smaller, local FBOs, the authors sought to understand better the current and potential roles for FBOs in veteran reintegration. Interviewees suggested that veterans may look to FBOs for support because they offer privacy and confidentiality, two features that may be especially critical when a potential stigma is involved. Some FBOs have also developed a reputation as safe places for veterans, providing supportive, judgment-free environments. FBOs not only help veterans with spiritual matters but address diverse areas of veteran health and wellness, including vocation, education, financial and legal stability, shelter, access to goods and services, mental health, access to health care, physical health, family, and social networks. In some cases, the support is offered to veterans directly; in other instances, the support is indirect, via training individuals to help veterans or educating the public about them. In the process of providing support, FBOs interact with varied organizations, including government entities, private nonprofits, and one another, for training, outreach, referrals, information exchange, obtaining donations, and collaboration. Yet challenges exist, including insufficient connections with chaplains working in different settings and others in the web of support, resource and capacity constraints, lack of awareness of experience with veterans, issues related to religious philosophy or orientation, and characteristics of veterans themselves. To move forward, the authors offer recommendations for policymakers, organizations that interact with FBOs, and FBOs themselves to help FBOs engage fully in the web of reintegration support. PMID- 28083393 TI - Navigating the Road to Reintegration: Status and Continuing Support of the U.S. Air Force's Wounded Warriors. AB - The U.S. Air Force, wanting to gain greater insight into the well-being of its members who have sustained mental or physical injuries in combat or combat related situations, including their quality of life and the challenges they will confront in their reintegration following separation or retirement, asked the RAND Corporation for assistance in gauging the current status of the Air Force's wounded warriors, including their use of and satisfaction with Air Force programs designed to serve them. This article presents the baseline findings from a longitudinal analysis of enrollees in the Air Force Wounded Warrior (AFW2) program who were receiving benefits or undergoing evaluation to receive benefits, the majority of whom had a primary administrative diagnosis of post-traumatic stress disorder (PTSD). A high proportion of the Airmen in the sample screened positive for PTSD (roughly 78 percent) and major depressive disorder (MDD) (roughly 75 percent); 69 percent screened positive for both. Although more than 90 percent of those in the sample who screened positive for PTSD or MDD were receiving treatment, about half indicated that there was at least one instance during the past year in which they desired mental health treatment but did not receive it. Participants reported concerns about stigma, confidentiality, and the quality of available treatment as barriers to receiving mental health care, though the current data do not link these concerns to a particular treatment setting. About 10 percent of Airmen reported a financial situation that could be considered as living in poverty based on U.S. Department of Health and Human Services' poverty guidelines. Similarly, close to 15 percent of those in the labor force could be considered unemployed. Reserve and National Guard Airmen evidenced heightened challenges across examined domains. Respondents were overall satisfied with the services they received from the AFW2 and Air Force Recovery Care Coordinator programs. PMID- 28083392 TI - Measuring the Quality of Care for Psychological Health Conditions in the Military Health System: Candidate Quality Measures for Posttraumatic Stress Disorder and Major Depressive Disorder. AB - In recent years, the number of U.S. service members treated for psychological health conditions has increased substantially. In particular, at least two psychological health conditions-posttraumatic stress disorder (PTSD) and major depressive disorder (MDD)-have become more common, with prevalence estimates up to 20 percent for PTSD and 37 percent for MDD. Delivering quality care to service members with these conditions is a high-priority goal for the military health system (MHS). Meeting this goal requires understanding the extent to which the care the MHS provides is consistent with evidence-based clinical practice guidelines and its own standards for quality. To better understand these issues, RAND Corporation researchers developed a framework to identify and classify a set of measures for monitoring the quality of care provided by the MHS for PTSD and MDD. The goal of this project was to identify, develop, and describe a set of candidate quality measures to assess care for PTSD and MDD. To accomplish this goal, the authors performed two tasks: (1) developed a conceptual framework for assessing the quality of care for psychological health conditions and (2) identified a candidate set of measures for monitoring, assessing, and improving the quality of care for PTSD and MDD. This article describes their research approach and the candidate measure sets for PTSD and MDD that they identified. The current task did not include implementation planning but provides the foundation for future RAND work to pilot a subset of these measures. PMID- 28083394 TI - Public-Private Partnerships for Providing Behavioral Health Care to Veterans and Their Families: What Do We Know, What Do We Need to Learn, and What Do We Need to Do? AB - American veterans and their family members struggle with behavioral health problems, yet few engage in treatment to address these problems. Barriers to care include trouble accessing treatment and limited communication between civilian and military health care systems, which treat veterans and their family members separately. Even though the Department of Veterans Affairs (VA) is making efforts to address barriers to care, more work is needed to effectively serve veterans and their families. Public-private partnerships have been discussed as a potential solution and could include collaborations between a public agency, such as the VA, and a private organization, such as a veteran service organization, private industry, or private hospital. Despite the call for such partnerships, not much is known about what a public-private partnership would entail for addressing behavioral health concerns for veterans and their families. The health care literature is sparse in this area, and published examples and recommendations are limited. Thus, the authors wrote this article to inform the creation of public-private partnerships to better serve veterans and their families. The article outlines nine key components for public-private partnerships addressing veteran behavioral health care. These components are supported by qualitative interview data from five successful public-private partnerships that serve veterans and their families. This study will assist policymakers in the VA and other federal agencies in developing and fostering public-private partnerships to address the behavioral health care needs of veterans and their families. The article also discusses next steps for research and policymaking efforts with regard to these partnerships. PMID- 28083396 TI - Suicide Postvention in the Department of Defense: Evidence, Policies and Procedures, and Perspectives of Loss Survivors. AB - The U.S. Department of Defense (DoD) has been struggling with increasing rates of suicide among military personnel for the past decade. As DoD continues to implement new programs and examine its policies in an effort to prevent military personnel from taking their own lives, it is important to assess its current responses to suicide and to identify opportunities to enhance these programs and policies. Unfortunately, there is little scientific evidence on how best to respond to suicides, how to ensure that surveillance activities are managed appropriately and that loss survivors are given sufficient support to grieve, how additional suicides can be prevented, and how to honor and respect the decedent and his or her loved ones. At the same time, there are many resource guides intended to provide recommendations for organizations (mostly schools) in responding to suicides. A review of the existing scientific evidence on postvention (responses to prevent additional suicides in the aftermath of a suicide) and guidance for other types of organizations provides potential insights for DoD, however. Complemented by the perspectives of those most intimately touched by military suicide-the family and friends of those who have died-these sources may help DoD formulate its guidance in a practical and sensitive way. PMID- 28083397 TI - Methodology of the RAND Health Reform Opinion Study. AB - The Affordable Care Act has already and will continue to lead to significant changes in health insurance coverage. Understanding insurance transitions is critical to evaluating the success of the reform and to identifying opportunities for improvement. The RAND Health Reform Opinion Study uses the American Life Panel to study transitions in health insurance enrollment from 2013 through 2015. Methodology of the RAND Health Reform Opinion Study provides a description of the methodology the authors use to track health insurance choices between November 2014 and December 2015. PMID- 28083395 TI - Sleep in the Military: Promoting Healthy Sleep Among U.S. Servicemembers. AB - Sleep disturbances are a common reaction to stress and are linked to a host of physical and mental health problems. Given the unprecedented demands placed on U.S. military forces since 2001, there has been growing concern about the prevalence and consequences of sleep problems for servicemembers. Sleep problems often follow a chronic course, persisting long after servicemembers return home from combat deployments, with consequences for their reintegration and the readiness and resiliency of the force. Therefore, it is critical to understand the role of sleep problems in servicemembers' health and functioning and the policies and programs available to promote healthy sleep. This study provides the first comprehensive review of sleep-related policies and programs across the U.S. Department of Defense (DoD), along with a set of actionable recommendations for DoD, commanders, researchers, and medical professionals who treat U.S. servicemembers. The two-year multimethod study also examined the rates and correlates of sleep problems among post-deployed servicemembers, finding negative effects on mental health, daytime impairment, and perceived operational readiness. The research reviewed evidence-based interventions to treat sleep disturbances among servicemembers and veterans and exposed several individual- and system-level barriers to achieving healthy sleep. Implementing evidence-based treatments is just one step toward improving sleep across the force; as the research recommendations highlight, it is equally important that policies and programs also focus on preventing sleep problems and their consequences. PMID- 28083398 TI - Leadership as a Health Research Policy Intervention: An Evaluation of the NIHR Leadership Programme (Phase 2). AB - In early 2012, the National Institute for Health Research (NIHR) leadership programme was re-commissioned for a further three years following an evaluation by RAND Europe. During this new phase of the programme, we conducted a real-time evaluation, the aim of which was to allow for reflection on and adjustment of the programme on an on-going basis as events unfold. This approach also allowed for participants on the programme to contribute to and positively engage in the evaluation. The study aimed to understand the outputs and impacts from the programme, and to test the underlying assumptions behind the NIHR Leadership Programme as a science policy intervention. Evidence on outputs and impacts of the programme were collected around the motivations and expectations of participants, programme design and individual-, institutional- and system-level impacts. PMID- 28083400 TI - The International AIDS Vaccine Initiative's Capacity Building Activities in East Africa: Evaluating Progress and Impacts in Kenya, Uganda and Rwanda. AB - The International AIDS Vaccine Initiative (IAVI) is one of a number of Product Development Partnerships created to bridge the gap between scientific and technological potential and the needs of low income populations in low and middle income countries. Specifically IAVI is focused on creating a preventative vaccine for HIV/AIDS. Whilst the remit of IAVI is to create new science, technology and products, its work necessarily involves a wide range of stakeholders and different constituencies in industrially developing and developed countries. Its capacity building activities relate to strengthening the ability to conduct clinical trials and are broad based, spanning scientific and technological capacity through to organisational, advocacy and broader development capabilities. The aim of this study was to deepen IAVI's understanding of how it contributes to capacity building activities in East Africa (Uganda, Kenya and Rwanda), spanning scientific and technological capacity through to organisational, advocacy and broader development capabilities. IAVI's mission to develop an HIV vaccine has become increasingly connected to wider health systems strengthening, through its clinical research activities in East Africa. Since it began its operations in the region, IAVI has made a significant contribution to training interventions to support scientific excellence and good clinical practice and invested in infrastructure and laboratories at Clinical Research Centres in East Africa. Although clear challenges still exist with ensuring sustained investment, accessing marginalized populations and demonstrating progress in capacity building, the experiences of IAVI to date suggest that substantial progress is being made towards wider health systems strengthening in the region. PMID- 28083399 TI - Antimicrobial Stewardship: The Effectiveness of Educational Interventions to Change Risk-Related Behaviours in the General Population: A Systematic Review. AB - RAND Europe undertook a systematic review of the evidence of effectiveness and cost effectiveness on changing the public's risk related behaviour pertaining to antimicrobial use to inform the development of a NICE public health guideline aimed at delaying antimicrobial resistance (AMR). The review considered educational interventions targeting individuals, communities or the general public delivered via any mode. Specifically, it aimed to address: 1. Which educational interventions are effective and cost-effective in changing the public's behaviour to ensure they only ask for antimicrobials when appropriate and use them correctly? 2. Which educational interventions are effective and cost effective in changing the public's behaviour to prevent infection and reduce the spread of antimicrobial resistance? Overall, 60 studies met the inclusion criteria; 29 related to research question 1, and 36 related to research question 2 (five studies were applicable to both). The key findings are summarised in "Evidence Statements" in accordance with NICE guidelines. Evidence Statements provide a high level overview of the key features of the evidence including: the number of studies, the quality of evidence, and the direction of the estimated effect followed by a brief summary of each of the supporting studies. Studies are grouped into Evidence Statements by setting and intervention. PMID- 28083401 TI - CalMHSA Stigma and Discrimination Reduction Online Resources: Highlights from an Evaluation of Web Analytic Data. AB - Reports on an evaluation of online resources developed by the California Mental Health Services Authority's stigma and discrimination reduction initiative program partners and provides an overview of these resources and the use of partner websites. PMID- 28083402 TI - Effects of Stigma and Discrimination Reduction Trainings Conducted Under the California Mental Health Services Authority: An Evaluation of Disability Rights California and Mental Health America of California Trainings. AB - Describes the methods and results of a RAND evaluation of stigma and discrimination reduction trainings delivered by two program partners, Disability Rights California and Mental Health America of California. PMID- 28083403 TI - Effects of Stigma and Discrimination Reduction Trainings Conducted Under the California Mental Health Services Authority: An Evaluation of NAMI's Ending the Silence. AB - This article evaluates the short-term outcomes of students attending the National Alliance on Mental Illness' Ending the Silence presentations, delivered across three high schools in a Northern California school district. PMID- 28083404 TI - The Mental Health Association of San Francisco Partner Organizations Meet Their Goals in Stigma Reduction Efforts: Results of a Qualitative Evaluation of the Technical Assistance Process. AB - This article describes the results of RAND's evaluation of the San Francisco based Center for Dignity, Recovery, and Empowerment's technical assistance program for stigma-reduction programs through interviews with community-partner participants. PMID- 28083405 TI - RAND's Silent Monitoring Protocol for Assessing Suicide Crisis Line Call Content and Quality. AB - This article describes the methods for developing and testing a silent monitoring protocol for California suicide crisis call centers to evaluate call content and quality, document staff strengths and weaknesses, and identify areas for further training. PMID- 28083406 TI - Student Mental Health in California's K-12 Schools: School Principal Reports of Common Problems and Activities to Address Them. AB - Reports results of a survey of K-12 principals to take inventory of student mental health and wellness needs and the types of programs schools are most often implementing to help students in California's public schools. PMID- 28083407 TI - Airman and Family Resilience: Lessons from the Scientific Literature. AB - This final overarching study in a series documents research and recommendations RAND offered to the Air Force to help strengthen the development of a new office responsible for monitoring and promoting resilience among Air Force Airmen, civilian employees, and Air Force families. Efforts to boost resilience have become an important military response to suicide and other markers of distress and poor health. The study reviews the concepts and measures of resilience, resilience factors, hardiness and flourishing. It describes how resilience and the military's Total Force Fitness concepts are related. The study brings together highlights from the eight companion studies on each Total Force Fitness domain and characterizes types of Air Force data that could be used to track resilience. PMID- 28083408 TI - Behavioral Health and Service Use Among Civilian Wives of Service Members and Veterans: Evidence from the National Survey of Drug Use and Health. AB - In recent years, policymakers and members of the media have raised concerns regarding access to behavioral health care for service members and veterans of the U.S. military and their families. Particular concern has been raised regarding the availability and accessibility of care to individuals covered by the U.S. Department of Defense Military Health System and the Veterans Health Administration. In this study, researchers analyzed the National Study of Drug Use and Health to examine utilization of behavioral health care among current or former wives of service members and veterans who are covered by either TRICARE or CHAMP-VA. Three findings of interest emerged from the analysis. First, relative to the comparison group, military wives were more likely to receive behavioral health services, but this pattern was exclusively due to use of prescription psychiatric medications. No difference was found for specialty behavioral health treatment. Second, residing in rural areas was negatively associated with behavioral health care service use for both groups. Third, contrary to expectations, military wives who live more than 30 minutes from a military treatment facility were more likely than military wives who lived closer to receive prescription psychiatric mediations but not other types of behavioral health services. PMID- 28083409 TI - Family Resilience in the Military: Definitions, Models, and Policies. AB - Military life presents a variety of challenges to military families, including frequent separations and relocations as well as the risks that service members face during deployment; however, many families successfully navigate these challenges. Despite a recent emphasis on family resilience, the U.S. Department of Defense (DoD) does not have a standard and universally accepted definition of family resilience. A standard definition is a necessary for DoD to more effectively assess its efforts to sustain and improve family resilience. RAND authors reviewed the literature on family resilience and, in this study, recommend a definition that could be used DoD-wide. The authors also reviewed DoD policies related to family resilience, reviewed models that describe family resilience and identified key family resilience factors, and developed several recommendations for how family-resilience programs and policies could be managed across DoD. PMID- 28083410 TI - SimCoach Evaluation: A Virtual Human Intervention to Encourage Service-Member Help-Seeking for Posttraumatic Stress Disorder and Depression. AB - This article describes RAND Corporation researchers' assessment of SimCoach, a computer program featuring a virtual human that speaks and gestures in a video game-like interface, designed to encourage service members, especially those with signs or symptoms of posttraumatic stress disorder (PTSD) or depression, to seek help to improve their psychological health. The assessment included a formative component assessing SimCoach's design, development, and implementation approaches and a summative component assessing outcomes among participants in a user experience survey and a randomized controlled trial (RCT). Results of the formative evaluation identified both strengths and opportunities for improvement. For example, although SimCoach development processes were well-aligned with best practices for software engineering, SimCoach content development and evaluation processes could have been more tightly coupled to best practices in psychological health. The summative evaluation RCT did not show any SimCoach-related benefit in intent to seek help compared with that of control users not exposed to any intervention. However, secondary outcomes indicated that SimCoach users had satisfying experiences without distress. If SimCoach development is continued, greater attention to clinical processes and outcomes is needed so that the program can have its intended impact on help-seeking for PTSD and depression. PMID- 28083411 TI - A Methodological Critique of the ProPublica Surgeon Scorecard. AB - On July 14, 2015, ProPublica published its Surgeon Scorecard, which displays "Adjusted Complication Rates" for individual, named surgeons for eight surgical procedures performed in hospitals. Public reports of provider performance have the potential to improve the quality of health care that patients receive. A valid performance report can drive quality improvement and usefully inform patients' choices of providers. However, performance reports with poor validity and reliability are potentially damaging to all involved. This article critiques the methods underlying the Scorecard and identifies opportunities for improvement. Until these opportunities are addressed, the authors advise users of the Scorecard-most notably, patients who might be choosing their surgeons-not to consider the Scorecard a valid or reliable predictor of the health outcomes any individual surgeon is likely to provide. The authors hope that this methodological critique will contribute to the development of more-valid and more reliable performance reports in the future. PMID- 28083412 TI - Improving Hospital Efficiency Through Data-Driven Management: A Case Study of Health First, Florida. AB - This article presents a case study of how one health system-Health First, in Brevard County, Florida-addressed resource challenges by using Lean thinking enabled by information technology. Examining Health First provides an opportunity to learn about how one hospital system addressed these challenges by making fundamental changes in their operations, in advance of the shift toward accountable care. Three years after Health First embarked on an effort to streamline patient flow and improve throughput, adult transfers within the system have increased by more than 300 percent and emergency department times between admission and inpatient bed occupancy decreased by 37 percent. PMID- 28083413 TI - Alternatives to the ACA's Affordability Firewall. AB - The Affordable Care Act (ACA) was designed to increase health insurance coverage while limiting the disruption to individuals with existing sources of insurance coverage, particularly those with employer-sponsored insurance (ESI). To limit disruption to those with coverage, the ACA implements the employer mandate, which requires firms with more than 50 employees to offer health insurance or face penalties, and the individual "affordability firewall," which limits subsidies to individuals lacking access to alternative sources of coverage that are "affordable." This article examines the policy impacts of the affordability firewall and investigates two potential modifications. Option 1, which is the "entire family" scenario, involves allowing an exception to the firewall for anyone in a family where the family ESI premium contribution exceeds 9.5 percent of the worker's household income. In Option 2, the "dependents only" scenario, only dependents (and not the worker) become eligible for Marketplace subsidies when the ESI premium contribution exceeds 9.5 percent of the worker's household income. Relative to the ACA, RAND researchers estimate that nongroup enrollment will increase by 4.1 million for Option 1 and by 1.4 million for Option 2. However, the number without insurance only declines by 1.5 million in Option 1 and 0.7 million in Option 2. The difference between the increase in nongroup enrollment and the decrease in uninsurance is primarily due to ESI crowd-out, which is more pronounced for Option 1. Researchers also estimated that about 1.3 million families who have ESI and unsubsidized nongroup coverage under current ACA policy would receive Marketplace subsidies under the alternative affordability firewall scenarios. For these families, health insurance coverage would become substantially more affordable; these families' risk of spending at least 20 percent of income on health care would drop by more than two thirds. We additionally estimated that federal spending will increase by $8.9 billion and $3.9 billion for Options 1 and 2, respectively, relative to the ACA. PMID- 28083414 TI - Harnessing Private-Sector Innovation to Improve Health Insurance Exchanges. AB - Overhauling the individual health insurance market-including through the creation of health insurance exchanges-was a key component of the Patient Protection and Affordable Care Act's multidimensional approach to addressing the long-standing problem of the uninsured in the United States. Despite succeeding in enrolling millions of Americans, the exchanges still face several challenges, including poor consumer experience, high operational and development costs, and incomplete market penetration. In light of these challenges, analysts considered a different model for the exchanges-privately facilitated exchanges-which could address these challenges and deepen the Affordable Care Act's impact. In this model, the government retains control over sovereign exchange functions but allows the private sector to assume responsibility for more-peripheral exchange functions, such as developing and sustaining exchange websites. Although private-sector entities have already undertaken exchange-related functions on a limited basis, privately facilitated exchanges could conceivably relieve the government of its responsibility for front-end website operations and consumer decision-support functions entirely. A shift to privately facilitated exchanges could improve the consumer experience, increase enrollment, and lower costs for state and federal governments. A move to such a model requires, nonetheless, managing its risks, such as reduced consumer protection, increased consumer confusion, and the possible lack of a viable revenue base for privately facilitated exchanges, especially in less populous states. On net, the benefits are large enough and the risks sufficiently manageable to seriously consider such a shift. This paper provides background information and more detail on the analysts' assessment. PMID- 28083415 TI - Returns on Research Funded Under the NIHR Health Technology Assessment (HTA) Programme: Economic Analysis and Case Studies. AB - The Department of Health (England) requested that RAND Europe conduct an economic analysis of the impact of the HTA Programme. This article describes the results of that work, which consisted of analysis of the potential economic benefits of a sample of HTA funded studies and comparison to programme costs, supplemented by a set of short case studies exploring the impacts of the HTA Programme on policy and practice. Based on our analysis, if 12 per cent of the potential net benefit of implementing the findings of this sample of 10 studies for one year was realised, it would cover the cost of the HTA Programme from 1993 to 2012. Drawing on the case studies and the economic analysis, we have also made a number of observations that could help ensure that the HTA Programme maximises the likelihood of findings being adopted. PMID- 28083416 TI - Evaluating the Impact of Whole-Body Vibration (WBV) on Fatigue and the Implications for Driver Safety. AB - Driver fatigue is a significant contributor to motor vehicle accidents and fatalities, although the exact share of those events attributable to fatigue is still uncertain. In 2013, accidents involving heavy trucks killed more than 3,944 people in the United States, with over 80 percent of those killed not in the truck. Numerous factors contribute to driver fatigue among commercial drivers, including shiftwork schedules; high prevalence of alcohol and substance use; extended hours; comorbid medical conditions, such as pain; and high prevalence of sleep disorders. Many of these factors have been studied extensively in the trucking industry. Whole-body vibration (WBV) is another potential factor that may contribute to driver fatigue, but it has received little attention. Beginning in January 2015, Bose Corporation and AIG commissioned the RAND Corporation to study the link between WBV and driver fatigue. This article summarizes the findings from RAND's systematic review of the literature on WBV and fatigue as well as considers appropriate study designs and methodology that will inform new areas of research focused on improving the safety of truckers and those who share the road with them. The literature review identified 24 studies examining the impact of WBV on fatigue or sleepiness. The majority of studies (n = 18) found a significant association between WBV and fatigue or sleepiness; however, there are several limitations of the existing literature that preclude definitive conclusions regarding the impact of WBV on these outcomes. This research concludes with recommendations for future studies to strengthen the evidence base. PMID- 28083417 TI - Acupuncture for Major Depressive Disorder: A Systematic Review. AB - Major depressive disorder (MDD) is a prevalent condition associated with significant burden in terms of reduced quality of life, lower productivity, increased prevalence of other conditions and increased health care costs. We conducted a systematic review and qualitative summary of randomized controlled trials (RCTs) that assessed the effectiveness and safety of acupuncture for the treatment of MDD. We searched the databases PubMed, CINAHL, PsycINFO, Web of Science, Embase, CDSR, CENTRAL, clinicaltrials.gov, DARE, and PILOTS for English language RCTs published through January 2015. Two independent reviewers screened the identified literature against inclusion and exclusion criteria, abstracted study level data, and assessed the risk of bias and methodological quality of included studies. The quality of the evidence was assessed using GRADE. Eighteen studies met inclusion criteria. Eleven assessed acupuncture as monotherapy, seven as adjunct depression treatment. Intervention approaches and comparators varied. Evidence on the effectiveness and comparative effectiveness of acupuncture to treat MDD for the outcomes depression improvement, measured as scale score differences and the number of responders, is very weak. Acupuncture may be superior to waitlist (low quality of evidence) but findings for effect estimates compared to other comparators are inconclusive. Few studies reported on patients achieving remission. The effect of acupuncture on relapse rates could not be determined. Too few studies assessed quality of life to estimate treatment effects. Reported adverse events were typically mild in nature, but the assessment lacked rigor and studies were not designed to detect rare events. PMID- 28083418 TI - Effects of Stigma and Discrimination Reduction Programs Conducted Under the California Mental Health Services Authority: An Evaluation of Runyon Saltzman Einhorn, Inc., Documentary Screening Events. AB - Describes the methods and results of a RAND evaluation of stigma and discrimination reduction efforts by Runyon Saltzman Einhorn, Inc., involving screenings of a documentary film called "A New State of Mind: Ending the Stigma of Mental Illness." PMID- 28083419 TI - Effects of Stigma and Discrimination Reduction Trainings Conducted Under the California Mental Health Services Authority: An Evaluation of the National Alliance on Mental Illness Adult Programs. AB - This study evaluated three National Alliance on Mental Illness (NAMI) programs aimed at reducing mental illness stigma and discrimination among adult audiences. PMID- 28083420 TI - Effects of the Integrated Behavioral Health Project's Efforts to Promote Integrated Care Under Funding from the California Mental Health Services Authority. AB - Describes the methods and results of a RAND evaluation of the Integrated Behavioral Health Project's efforts to promote the integration of mental and physical health care among various health care stakeholders in California. PMID- 28083421 TI - Payoffs for California College Students and Taxpayers from Investing in Student Mental Health. AB - Reports results of a survey to assess the impact of CalMHSA's investments in mental health programs at California public colleges and estimates the return on investment in terms of student use of treatment, graduation rates, and lifetime earnings. PMID- 28083422 TI - St. John's Wort for Major Depressive Disorder: A Systematic Review. AB - RAND researchers conducted a systematic review that synthesized evidence from randomized controlled trials of St. John's wort (SJW)-used adjunctively or as monotherapy-to provide estimates of its efficacy and safety in treating adults with major depressive disorder. Outcomes of interest included changes in depressive symptomatology, quality of life, and adverse effects. Efficacy meta analyses used the Hartung-Knapp-Sidik-Jonkman method for random-effects models. Quality of evidence was assessed using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. In total, 35 studies met inclusion criteria. There is moderate evidence, due to unexplained heterogeneity between studies, that depression improvement based on the number of treatment responders and depression scale scores favors SJW over placebo, and results are comparable to antidepressants. The existing evidence is based on studies testing SJW as monotherapy; there is a lack of evidence for SJW given as adjunct therapy to standard antidepressant therapy. We found no systematic difference between SJW extracts, but head-to-head trials are missing; LI 160 (0.3% hypericin, 1-4% hyperforin) was the extract with the greatest number of studies. Only two trials assessed quality of life. SJW adverse events reported in included trials were comparable to placebo, and were fewer compared with antidepressant medication; however, adverse event assessments were limited, and thus we have limited confidence in this conclusion. PMID- 28083423 TI - Current and Projected Characteristics and Unique Health Care Needs of the Patient Population Served by the Department of Veterans Affairs. AB - The Veterans Access, Choice, and Accountability Act of 2014 addressed the need for access to timely, high-quality health care for veterans. Section 201 of the legislation called for an independent assessment of various aspects of veterans' health care. The RAND Corporation was tasked with an assessment of the current and projected demographics and health care needs of patients served by the Department of Veterans Affairs (VA). The number of U.S. veterans will continue to decline over the next decade, and the demographic mix and geographic locations of these veterans will change. While the number of veterans using VA health care has increased over time, demand will level off in the coming years. Veterans have more favorable economic circumstances than non-veterans, but they are also older and more likely to be diagnosed with many health conditions. Not all veterans are eligible for or use VA health care. Whether and to what extent an eligible veteran uses VA health care depends on a number of factors, including access to other sources of health care. Veterans who rely on VA health care are older and less healthy than veterans who do not, and the prevalence of costly conditions in this population is projected to increase. Potential changes to VA policy and the context for VA health care, including effects of the Affordable Care Act, could affect demand. Analysis of a range of data sources provided insight into how the veteran population is likely to change in the next decade. PMID- 28083424 TI - Resources and Capabilities of the Department of Veterans Affairs to Provide Timely and Accessible Care to Veterans. AB - The Veterans Access, Choice, and Accountability Act of 2014 addressed the need for access to timely, high-quality health care for veterans. Section 201 of the legislation called for an independent assessment of various aspects of veterans' health care. The RAND Corporation was tasked with an assessment of the Department of Veterans Affairs (VA) current and projected health care capabilities and resources. An examination of data from a variety of sources, along with a survey of VA medical facility leaders, revealed the breadth and depth of VA resources and capabilities: fiscal resources, workforce and human resources, physical infrastructure, interorganizational relationships, and information resources. The assessment identified barriers to the effective use of these resources and capabilities. Analysis of data on access to VA care and the quality of that care showed that almost all veterans live within 40 miles of a VA health facility, but fewer have access to VA specialty care. Veterans usually receive care within 14 days of their desired appointment date, but wait times vary considerably across VA facilities. VA has long played a national leadership role in measuring the quality of health care. The assessment showed that VA health care quality was as good or better on most measures compared with other health systems, but quality performance lagged at some VA facilities. VA will require more resources and capabilities to meet a projected increase in veterans' demand for VA care over the next five years. Options for increasing capacity include accelerated hiring, full nurse practice authority, and expanded use of telehealth. PMID- 28083425 TI - Authorities and Mechanisms for Purchased Care at the Department of Veterans Affairs. AB - The Veterans Access, Choice, and Accountability Act of 2014 addressed the need for access to timely, high-quality health care for veterans. Section 201 of the legislation called for an independent assessment of various aspects of veterans' health care. The RAND Corporation was tasked with an assessment of the authorities and mechanisms by which the Department of Veterans Affairs (VA) pays for health care services from non-VA providers. Purchased care accounted for 10 percent, or around $5.6 billion, of VA's health care budget in fiscal year 2014, and the amount of care purchased from outside VA is growing rapidly. VA purchases non-VA care through an array of programs, each with different payment processes and eligibility requirements for veterans and outside providers. A review and analysis of statutes, regulations, legislation, and literature on VA purchased care, along with interviews with expert stakeholders, a survey of VA medical facilities, and an evaluation of local-level policy documents revealed that VA's purchased care system is complex and decentralized. Inconsistencies in procedures, unclear goals, and a lack of cohesive strategy for purchased care could have ramifications for veterans' access to care. Adding to the complexity of VA's purchased care system is a lack of systematic data collection on access to and quality of care provided through VA's purchased care programs. The analysis also explored concepts of "episodes of care" and their implications for purchased care by VA. PMID- 28083426 TI - Assessing the Quality and Value of Psychological Health Care in Civilian Health Plans: Lessons and Implications for the Military Health System. AB - The Military Health System (MHS) strives to provide high-quality care and improve outcomes for individuals with psychological health conditions. Over the last decade, the MHS has provided care to a growing number of individuals with psychological health conditions, such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). However, little is known about the extent to which the MHS delivers care that is consistent with evidence-based clinical practice guidelines or if it is achieving positive outcomes for its service members. To better understand these issues, the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury (DCoE) asked the RAND Corporation to describe civilian health plansa; approaches to systematically measuring the quality of psychological health care delivered by providers in their networks. This work was part of a larger effort by RAND to develop a framework and identify a set of measures for monitoring the quality of care provided by the MHS for psychological health conditions. PMID- 28083427 TI - Information and Communication Technologies in Behavioral Health: A Literature Review with Recommendations for the Air Force. AB - The dramatic evolution in information and communication technologies (ICTs) online and on smartphones has led to rapid innovations in behavioral health care. To assist the U.S. Air Force in developing a strategy for use of ICTs, the authors reviewed the scientific literature on their use to prevent and treat behavioral health conditions, such as major depression, posttraumatic stress disorder, and alcohol misuse. There is currently little scientific evidence supporting additional investment in ICT-based psychosocial programs for resilience or prevention of posttraumatic stress symptoms, depression, or anxiety. Instead, preventive interventions might prioritize problems of alcohol misuse and intimate partner violence. ICT applications that play a role in the treatment process may be used for patient education and activation, to improve decisionmaking by clinicians, to provide a therapy, to improve adherence to treatment, or to maintain treatment gains over time. However, partly due to the rapid pace of development of the technology, there is little or no evidence in the literature regarding the efficacy of the most recently developed types of ICTs, in particular those using smartphones. Despite the lack of solid research evidence to date, ICTs hold promise in addressing the challenges of mental health care. One promising avenue is development of reliable methods for patient clinician communication between therapy sessions; another is Internet-based cognitive behavioral therapy. The authors recommend that the Air Force should take an incremental approach to adopting the use of ICTs-one that involves a program of measurement-based implementation and process and outcome monitoring rather than urgent dissemination. PMID- 28083428 TI - Strategic Analysis of the 2014 Wounded Warrior Project Annual Alumni Survey: A Way Forward. AB - Wounded Warrior Project(r) (WWP) provides support and raises public awareness for service members and veterans who incurred physical or mental injury, illness, or wound coincident to their military service on or after September 11, 2001, as well as their families and caregivers. Through WWP, members (Alumni) have access to programs that support four main areas of recovery-engagement, mind, body, and economic empowerment. Using 2014 WWP Annual Alumni Survey data, RAND researchers offer a detailed analysis of how Alumni of different genders, races and ethnicities, military service histories, and service-related health conditions fare in terms of mental health, physical health, and economic well-being. The study also offers recommendations for the organization's decisionmakers to consider in setting goals and creating programs to support WWP Alumni. PMID- 28083429 TI - Access to Dental Providers in Pennsylvania: Exploration of the County-Level Distribution of Dental Providers and Populations in 2013. AB - Ensuring access to dental care, particularly for children, is a significant policy concern in the United States. Many factors affect access on both the provider and patient sides. This study examines an important factor in the ability to access dental care: the distribution and availability of dental health providers. The authors assess providers across the counties of Pennsylvania, primarily using data from the 2013 Survey of Dentists and Dental Hygienists administered by the Pennsylvania Department of Health. To identify possible dental provider shortages in Pennsylvania counties, the authors assessed ten indicators of access to dental providers. They find significant variation in the indicators across Pennsylvania counties. PMID- 28083430 TI - Developing a Strategic Program for Chilean Health Information Technology: Environmental Scan and Key Informant Interviews. AB - As part of an effort to assist Chile in developing a strategic program to foster the development of the health information technology (health IT) sector over the next five to ten years, this study assesses the current state of health IT adoption and implementation in Chile, as well as the challenges and opportunities facing the sector over the coming years. The authors conducted an environmental scan and ten key informant interviews and found that there are a number of successful health IT projects and strategies for further development currently underway in Chile, but that the successful projects are generally localized within specific health care providers and lack integration. These and other challenges suggest significant potential for the Ministry of Economy and other stakeholders to take specific actions designed to encourage further development of the health IT sector in Chile over the coming years. The next phase of this effort will use the results from this study to develop a roadmap for the Ministry of Economy to encourage health IT development in Chile over the short, medium, and long terms. PMID- 28083431 TI - Employer, Insurer, and Industry Perspectives on Patient-Centered Comparative Effectiveness Research: Final Report. AB - The Patient-Centered Outcomes Research Institute (PCORI) is an independent, nonprofit, nongovernmental organization authorized under the Affordable Care Act of 2010 and funded by Congress to help close the gaps in research needed to improve key health outcomes. To do this, PCORI identifies critical research questions, funds patient-centered comparative effectiveness research (CER), and strives to disseminate the results in ways that stakeholders, including patients, providers, health insurance purchasers, payers, and industry, will find useful. PCORI commissioned RAND and the National Pharmaceutical Council to conduct an independent study of the health-related decisions, information needs, understanding and use of CER, and opportunities for involvement of these three stakeholder communities in CER. RAND conducted ten telephone and Web-enabled focus groups involving representatives from all three communities. This article describes the key themes emerging from those discussions and presents implications for PCORI's work. PMID- 28083432 TI - Response to ProPublica's Rebuttal of Our Critique of the Surgeon Scorecard. AB - In the summer of 2015, ProPublica published its Surgeon Scorecard, which displays "Adjusted Complication Rates" for individual, named surgeons for eight surgical procedures performed in hospitals. Public reports of provider performance have the potential to improve the quality of health care that patients receive. A valid performance report can drive quality improvement and usefully inform patients' choices of providers. However, performance reports with poor validity and reliability are potentially damaging to all involved. In September 2015, RAND released a critique of the Scorecard authored by a group of health policy researchers from RAND and other institutions, and on October 7, 2015 ProPublica published a rebuttal of our critique. In this follow-on Perspective, we revisit the main points in our initial critique, summarize ProPublica's rebuttal, explain why this rebuttal fails to address our methodological concerns, provide suggestions on how to validate and improve the Scorecard, and explain why we continue to advise potential users of the Scorecard, as it is currently constructed, not to consider it a valid or reliable predictor of the health outcomes any individual surgeon is likely to provide. PMID- 28083433 TI - Treatment for Dementia: Learning from Breakthroughs for Other Conditions. AB - The past few decades have seen a number of medical breakthroughs that enabled the effective treatment of a range of conditions, transforming them from fatal into manageable ones. Examples include certain cancers and HIV. Conversely, progress on dementia has been limited. There are currently no treatments that will cure or even alter the progressive course of dementia, despite ongoing research investigating new therapies and care options. The UK Department of Health is interested in the potential to learn from other disease areas to better understand the particular social, economic, political, legislative and scientific contexts that have contributed to accelerating progress and breakthroughs in treatment. Such learning could helpfully inform dementia research and innovation efforts, and help identify levers for supportive policy development. This project analysed breakthroughs in the treatment of four selected conditions of ill health and seeks to identify potentially transferable lessons for the dementia context. Using evidence review and key informant interviews we sought to identify the series of "events" that eventually led to a given breakthrough, and the key milestones in the process that have helped improve understanding and potential for treatment. We also aimed to capture the temporal and causal relationships between "notable" events looking at a variety of factors implicated in the breakthrough pathway. The focus of this work was on political, economic, social, scientific and technological, and legal, regulatory and environmental factors. PMID- 28083434 TI - A 'DECISIVE' Approach to Research Funding: Lessons from Three Retrosight Studies. AB - The Retrosight approach consists of looking at research that was conducted in the past and, using Payback case studies, tracing that research through to the present day to understand both the extent to which the research has had impacts, within academia and more widely, and how these impacts came about. RAND Europe has conducted three studies based on this approach in different research fields: arthritis research, cardiovascular research and mental health research. Each drew out a set of observations and recommendations for policymakers and research funders in those research fields. By reviewing and comparing the findings of the three studies, we have identified eight lessons which combine to provide a "DECISIVE" approach to biomedical and health research funding: Different skills: Fund researchers with more than just research skills-individuals are key when it comes to translation of research into wider impact. Engaged: Support your researchers to engage with non-academic stakeholders to help their work have a wider impact. Clinical: For greater impact on patient care within 10-20 years, fund clinical rather than basic research. Impact on society: If you want to have a wider impact, don't just fund for academic excellence. Size: Bigger isn't necessarily better when it comes to the size of a research grant. International: For high academic impact, fund researchers who collaborate internationally and support them to do so. Variety: Simple metrics will only capture some of the impact of your research. Expectations: Most broader social and economic impact will come from just a few projects. PMID- 28083435 TI - Evaluating the Role and Contribution of Innovation to Health and Wealth in the UK: A Review of Innovation, Health and Wealth: Phase 1 Final Report. AB - The Department of Health's Innovation, Health and Wealth (IHW) strategy aimed to introduce a more strategic approach to the spread of innovation across the NHS. This study represents the first phase of a three-year evaluation and aims to map progress towards the IHW strategy and its component actions. This evaluation used a combination of quantitative and qualitative methods: document review, key informant interviews and stakeholder survey. This study also forms the basis for selecting case studies for phase two of the evaluation. Our findings from the interviews and survey suggest broad stakeholder support for the overarching ambitions of the IHW strategy. However, we found variable progress towards the overarching objectives of the eight IHW themes and an ambiguous relationship between many of the themes' objectives and their actions. It was difficult to assess progress on IHW's actions as commitment to the actions, implementation guidance and expected outcomes of the actions were not clearly articulated. The Academic Health Science Networks (AHSNs) and the Small Business Research Initiative (SBRI) were reported to be working well, which may be attributed to their clear structures of accountability and earmarked budgets. However, survey respondents and interviewees raised concerns that budgetary pressures may limit the impact of both AHSNs and the SBRI. The main challenges identified for ongoing action were the resources available for their implementation (e.g. Medtech Briefings), lack of awareness of the initiative (e.g. the NICE Implementation Collaborative) and the design of the actions (e.g. the Innovation Scorecard, web portal and High Impact Innovations). PMID- 28083436 TI - Galvanising the NHS to Adopt Innovation: The Feasibility and Practicality of Recommendations from the Interim Report of the Accelerated Access Review. AB - The Department of Health and the Wellcome Trust, in co-operation with NHS England, asked RAND Europe to conduct a limited consultation with key stakeholders about the practicality of measures and incentives proposed as part of the NHS Accelerated Access Review (AAR), which aims to assess the pathways for the development, assessment, and adoption of innovative medicines and medical technology. Through a focused engagement exercise with key healthcare stakeholders this project explored the implications of selected interim AAR propositions and feasibility of implementation for key actors, in primary and secondary care as well as commissioners and academia. Specifically, the project investigated the feasibility of implementation of three specific propositions including: a new earmarked fund to encourage AHSNs and other key innovation actors to re-design systems to embrace innovation; mobilising the influence of clinical system leaders to champion change; and encouraging secondary care organisations to take on "innovation champion" roles linked to financial incentives and a new emphasis on accountable care organisations. Data was collected on the feasibility of the three AAR propositions from a workshop with AHSN CEOs and Commercial Directors and interviews with senior NHS staff in three AHSN regions (South West, University College London Partners, and North East, North Cumbria). The study concludes with reflections on the feasibility of each recommendation and identifies factors expected to facilitate or challenge their implementation, as well as considering the wider cross cutting issues that may influence the adoption and diffusion of innovation in the NHS. PMID- 28083437 TI - Medical Device Innovation in the Era of the Affordable Care Act: The End of Sexy. AB - In this article, the authors explore why medical device innovation has traditionally been geared so thoroughly toward improving performance, with little regard to cost. They argue that the changing incentives in the health care sector and the move to value-based payment models, accelerated by the implementation of the Affordable Care Act, will force device manufacturers to redirect investments from the spectacular toward the prudent, which they dub "the end of sexy." The authors explore consequences for manufacturers, investors, and policymakers. PMID- 28083438 TI - Evaluation of CalMHSA Student Mental Health Online Resources. AB - Analysis of visitors to CalMHSA-funded student mental health websites shows that visitors at educational institutions comprised the largest audience segment and promotional campaigns likely increased traffic. PMID- 28083439 TI - Mapping the Global Mental Health Research Funding System. AB - This study maps the global funding of mental health research between 2009 and 2014. It builds from the bottom up a picture of who the major funders are, what kinds of research they support and how their strategies relate to one another. It uses the funding acknowledgements on journal papers as a starting point for this. The study also looks to the future, considering some of the areas of focus, challenges and opportunities which may shape the field in the coming few years. PMID- 28083440 TI - Balancing Demand and Supply for Veterans' Health Care: A Summary of Three RAND Assessments Conducted Under the Veterans Choice Act. AB - In response to concerns that the Department of Veterans Affairs (VA) has faced about veterans' access to care and the quality of care delivered, Congress enacted the Veterans Access, Choice, and Accountability Act of 2014 ("Veterans Choice Act") in August 2014. The law was passed to help address access issues by expanding the criteria through which veterans can seek care from civilian providers. In addition, the law called for a series of independent assessments of the VA health care system across a broad array of topics related to the delivery of health care services to veterans in VA-owned and -operated facilities, as well as those under contract to VA. RAND conducted three of these assessments: Veteran demographics and health care needs (A), VA health care capabilities (B), and VA authorities and mechanisms for purchasing care (C). This article summarizes the findings of our assessments and includes recommendations from the reports for improving the match between veterans' needs and VA's capabilities, including VA's ability to purchase necessary care from the private sector. PMID- 28083441 TI - Can Access to Data Prevent Army Suicides?: Identifying Optimal Response Strategies for Army Leaders. AB - Over the past decade, the U.S. Army has invested significant resources in its efforts to prevent suicide and respond to a well-documented increase in suicides among active-duty soldiers. Among the efforts under way is a program to develop an information system that provides leaders with data on individual- and unit level suicide risk factors and could serve as the basis for prevention and intervention activities. One shortfall of this approach is the lack of guidance on how Army leaders should interpret and use this information. To address this gap, RAND Arroyo Center convened a group of experts to reach consensus on recommended actions for leaders who are informed that an individual soldier exhibits a risk factor for suicide or that their unit exhibits an atypically high prevalence of suicide risk factors or a concerning trend of suicidality. The experts generally agreed that information on suicide risk indicators could be useful to unit leaders if they also received guidance on appropriate actions from behavioral health providers-and central to any response is the need to keep information about individual soldiers confidential. At the unit level, data on atypically high-risk behaviors should prompt a "root cause" analysis to discern whether the heightened prevalence is a reflection of actual behaviors or can be explained by other factors. The experts concluded that unit-level suicide trend data have limited utility for leader action because suicide is a relatively rare event and because individuals assigned to a unit change over time. The results of the exercise led to several recommendations on the use of data in response planning for Army leaders and directions for future research. PMID- 28083442 TI - Quality of Care for PTSD and Depression in the Military Health System: Phase I Report. AB - The U.S. Department of Defense (DoD) strives to maintain a physically and psychologically healthy, mission-ready force, and the care provided by the Military Health System (MHS) is critical to meeting this goal. Given the rates of posttraumatic stress disorder (PTSD) and depression among U.S. service members, attention has been directed to ensuring the quality and availability of programs and services targeting these and other psychological health (PH) conditions. Understanding the current quality of care for PTSD and depression is an important step toward improving care across the MHS. To help determine whether service members with PTSD or depression are receiving evidence-based care and whether there are disparities in care quality by branch of service, geographic region, and service member characteristics (e.g., gender, age, pay grade, race/ethnicity, deployment history), DoD's Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury (DCoE) asked the RAND Corporation to conduct a review of the administrative data of service members diagnosed with PTSD or depression and to recommend areas on which the MHS could focus its efforts to continuously improve the quality of care provided to all service members. This study characterizes care for service members seen by MHS for diagnoses of PTSD and/or depression and finds that while the MHS performs well in ensuring outpatient follow-up following psychiatric hospitalization, providing sufficient psychotherapy and medication management needs to be improved. Further, quality of care for PTSD and depression varied by service branch, TRICARE region, and service member characteristics, suggesting the need to ensure that all service members receive high-quality care. PMID- 28083443 TI - Supporting the Mental Health Needs of Veterans in the Metro Detroit Area. AB - Supporting the mental health needs of veterans is a national priority. Over the past decade, there have been several studies describing the needs of the veteran population, particularly those who served in the post-9/11 era, calling for improved access to high-quality mental health services. In response, the federal government has expanded funding and services to meet increasing demand. At the same time, there has also been a proliferation of nongovernmental support to improve services for veterans in local communities. Often, in an attempt to deploy resources quickly, new programs and services are implemented without a full understanding of the specific needs of the population. This article discusses findings and recommendations from a study designed to gather information on the mental health-related needs facing veterans in the Detroit metropolitan area to identify gaps in the support landscape and inform future investments for community-level resources to fill the identified gaps. PMID- 28083444 TI - When Race/Ethnicity Data Are Lacking: Using Advanced Indirect Estimation Methods to Measure Disparities. AB - A key aim of U.S. health care reforms is to ensure equitable care while improving quality for all Americans. Limited race/ethnicity data in health care records hamper efforts to meet this goal. Despite improvements in access and quality, gaps persist, particularly among persons belonging to racial/ethnic minority and low-income groups. This study describes the use of indirect estimation methods to produce probabilistic estimates of racial/ethnic populations to monitor health care utilization and improvement. One method described, called Bayesian Indirect Surname Geocoding, uses a person's Census surname and the racial/ethnic composition of their neighborhood to produce a set of probabilities that a given person belongs to one of a set of mutually exclusive racial/ethnic groups. Advances in methods for estimating race/ethnicity are enabling health plans and other health care organizations to overcome a long-standing barrier to routine monitoring and actions to reduce disparities in care. Though these new estimation methods are promising, practical knowledge and guidance on how to most effectively apply newly available race/ethnicity data to address disparities can be greatly extended. PMID- 28083445 TI - Development of Absorbable, Antibiotic-Eluting Sutures for Ophthalmic Surgery. AB - PURPOSE: To develop and evaluate an antibiotic-eluting suture for ophthalmic surgery. METHODS: Wet electrospinning was used to manufacture sutures composed of poly(L-lactide), polyethylene glycol (PEG), and levofloxacin. Size, morphology, and mechanical strength were evaluated via scanning electron microscopy and tensile strength, respectively. In vitro drug release was quantified using high performance liquid chromatography. In vitro suture activity against Staphylococcus epidermidis was investigated through bacterial inhibition studies. Biocompatibility was determined via histological analysis of tissue sections surrounding sutures implanted into Sprague-Dawley rat corneas. RESULTS: Sutures manufactured via wet electrospinning were 45.1 +/- 7.7 MUm in diameter and 0.099 +/- 0.007 newtons (N) in breaking strength. The antibiotic release profile demonstrated a burst followed by sustained release for greater than 60 days. Increasing PEG in the polymer formulation, from 1% to 4% by weight, improved drug release without negatively affecting tensile strength. Sutures maintained a bacterial zone of inhibition for at least 1 week in vitro and elicited an in vivo tissue reaction comparable to a nylon suture. CONCLUSIONS: There is a need for local, postoperative delivery of antibiotics following ophthalmic procedures. Wet electrospinning provides a suitable platform for the development of sutures that meet size requirements for ophthalmic surgery and are capable of sustained drug release; however, tensile strength must be improved prior to clinical use. TRANSLATIONAL RELEVANCE: No antibiotic-eluting suture exists for ophthalmic surgery. A biocompatible, high strength suture capable of sustained antibiotic release could prevent ocular infection and preclude compliance issues with topical eye drops. PMID- 28083446 TI - Erratum. AB - [This corrects the article on p. 4 in vol. 5.]. PMID- 28083447 TI - Sex Differences in Virtual Network Characteristics and Sexual Risk Behavior among Emerging Adults. AB - Emerging adults (EAs)ages 18 to 24 account for a large proportion of all sexually transmitted infections (STIs), HIV infections, and unintended pregnancies in the United States. Given the increased influence of online media on decision-making, we examined how EA online networks were associated with sexual risk behaviors. We used egocentric network data collected from EAs aged 18 to 24 years old across the United States (N=1,687) to examine how online norms (e.g., acceptance of HIV infections, other STIs, and pregnancy) and network characteristics (i.e., network size and density; ties' closeness, race, age, and sex similarities) were associated with participants' unprotected vaginal intercourse (UVI) in the last 30 days. Findings suggested that in male EAs, there was a strong association between sexual norms, structural characteristics, and sexual risk behavior compared to females. Researchers and practitioners may wish to address online peer norms and EAs' online network composition when developing online sexual risk prevention tools. PMID- 28083448 TI - A network analysis of developmental change in ADHD symptom structure from preschool to adulthood. AB - Although there is substantial support for the validity of the diagnosis of ADHD, there is considerable disagreement about how to best capture developmental changes in the expression of ADHD symptomatology. The current paper examines the associations among the 18 individual ADHD symptoms using a novel network analysis approach, from preschool to adulthood. The 1,420 participants were grouped into four age brackets: Preschool (age 3-6, n = 109), childhood (age 6-12, n = 548), adolescence (age 13-17, n = 357), and young adulthood (age 18-36, n = 406). All participants completed a multi-stage, multi-informant diagnostic process, and self and informant symptom ratings were obtained. Network analysis indicated ADHD symptom structure became more differentiated over development. Two symptoms Often easily distracted and Difficulty sustaining attention appeared as central, or core, symptoms across all age groups. Thus, a small number of core symptoms may warrant extra weighting in future diagnostic systems. PMID- 28083449 TI - Acute Abdominal Aorta Thrombosis and Ischemic Rhabdomyolysis Secondary to Severe Alcohol Intoxication. AB - Acute alcohol intoxication is a common cause of emergency visits worldwide. Although moderate alcohol consumption is protective against coronary artery disease, binge drinking is associated with adverse cardiovascular and neurological outcomes and may even cause sudden death. Although, few past accounts of venous thrombosis with alcohol binge drinking are available, arterial thrombosis with the condition has never been reported in the literature. We present the unusual case of a young Afghan male, who presented to us with painful, tender and swollen legs three days after a heavy alcohol binge on a Saturday night. He was diagnosed as a case of acute limb ischemia secondary to massive abdominal aorta and bilateral femoral artery thrombosis. He also had acute renal failure secondary to rhabdomyolysis. Cardiac workup revealed new onset paroxysmal atrial fibrillation and a large thrombus in the left ventricular cavity. His blood ethanol level was high. He was treated by a multidisciplinary team; urgent surgical thrombectomy for thrombotic complications, intravenous fluid hydration and later renal replacement therapy for acute renal failure. To the best of our knowledge, such a constellation of clinical features in association with severe acute alcohol intoxication has not been reported in the literature. We believe, the procoagulant nature of high blood ethanol levels and the onset of atrial fibrillation after the heavy alcohol binge, known as the holiday heart syndrome, precipitated the thrombotic events leading to rhabdomyolysis and acute renal failure. Through this case, we conclude that a very heavy alcohol binge may cause thrombotic occlusion of the abdominal aorta and femoral arteries resulting in ischemic rhabdomyolysis and acute renal failure. A high index of suspicion must be kept, especially for a patient presenting with tender, swollen lower limbs and acute renal failure after an alcohol binge. PMID- 28083450 TI - Mixed Connective Tissue Disorder Complicated by Polymyositis, Sjogren's Syndrome, Pleural Effusion and Pericarditis. AB - We report a case of a 24-year-old female with a history of asthma and gastroesophageal reflux disease (GERD). She presented to the emergency room with severe chest pain, chest tightness, and shortness of breath following an upper respiratory tract infection. The patient reported that she had a cough and runny nose one week prior to this presentation, followed by a sudden sharp pain in the center of the chest 8/10 in intensity on the visual analog scale and pleuritic in nature, which aggravated by deep breathing and lying down flat. It was relieved by sitting up straight and did not radiate to her left arm or jaw. Computed tomography (CT) scan of the chest, posteroanterior and lateral views, showed a mild left pleural effusion with adjacent left basilar atelectasis/infiltrate. CT angiography of the chest with axial contrast showed mild left pleural effusion as well as a small pericardial effusion with bilateral lower lobe interstitial infiltrates. There was no evidence of pulmonary embolism. Electrocardiogram (EKG) showed no apparent ST segment elevation or depression that would be consistent with pericarditis, or acute ischemia or infarct. There was non-specific T wave abnormality. The patient was prescribed prednisone on a tapering dose. On follow up visit, her condition significantly improved. PMID- 28083451 TI - IgG4-Related Hypophysitis: Case Report and Literature Review. AB - IgG4-related hypophysitis is a rare, inflammatory process of the pituitary that mimics more commonly seen pituitary tumors. We report a case of IgG4-related hypophysitis in a 16-year-old female with diabetes insipidus who was found to have IgG4-related hypophysitis based on tissue diagnosis. This entity has not been previously described in a pediatric patient. Recognition of certain inflammatory processes of the pituitary may lead to alternative means of diagnosis and medical management without a biopsy. PMID- 28083452 TI - A Non-invasive 24 Hours Stabilization of Duodenal Ulcer Perforation by a Combination Regimen. AB - Surgical repair of perforated gastroduodenal ulcer has been extensively practiced in emergency clinical situations. Non-invasive conservation treatment is regaining the attention towards management of such ulcers. We report the case of a 50-year-old male smoker who presented in the emergency unit with acute generalized abdominal pain and guarding in the epigastric and right upper quadrant region. He is a known regular user of over-the-counter nonsteroidal anti inflammatory drugs (NSAIDS) for more than 10 years for his osteoarthiritis and myalgias. A differential diagnosis of gastritis and duodenal perforation was made owing to the symptoms and long usage of NSAIDs. He was managed with an intravenous proton pump inhibitor and intravenous antibiotics. This therapy lead to stabilization of the clinical symptoms as well as laboratory and imaging studies. PMID- 28083453 TI - A Comparison of Magnetic Resonance Angiography Techniques for the Evaluation of Intracranial Aneurysms Treated With Stent-assisted Coil Embolization. AB - AIM: To identify the effective magnetic resonance angiography (MRA) technique to monitor intracranial aneurysms treated with stent-assisted coiling. MATERIALS AND METHODS: Retrospective analysis of various MRA techniques was performed in 42 patients. Three neuroradiologists independently compared non-contrast time of flight (ncTOF) MRA of the head, contrast-enhanced time of flight (cTOF) MRA of the head and dynamic contrast-enhanced MRA (CEMRA) of the head and neck or of the head. Digital subtraction angiography (DSA) was available for comparison in 32 cases. Inter-rater agreement (kappa statistic) was assessed. RESULTS: Artifactual in-stent severe stenosis or flow gap was identified by ncTOF MRA in 23 of 42 cases (55%) and by cTOF MRA in 23 of 38 cases (60%). DSA excluded in-stent stenosis or occlusion in all 32 cases. No difference was noted between ncTOF and cTOF in the demonstration of neck remnants or residual aneurysms in three cases each. CEMRA of the head and neck or of the head was rated superior to ncTOF and cTOF MRA by all three investigators in seven out of eight cases. In one case, all three techniques demonstrated signifcant artifacts due to double stent placement during coiling. The kappa statistic revealed 0.8 agreement between investigators. CONCLUSIONS: In the assessment of stent-assisted coiling of intracranial aneurysm, both ncTOF and cTOF MRA show similar results. CEMRA tends to show better flow signals in stent and residual aneurysm. PMID- 28083454 TI - Treatment of Angio-Seal(r) Vascular Closure Device-Induced Acute Femoral Artery Occlusion with SilverHawk(r) Directional Atherectomy. AB - Vascular closure devices provide a safe and cost-effective method to achieve rapid hemostasis and early ambulation after angiographic procedures. Rarely, they can result in arterial injury with resultant stenosis or acute arterial closure requiring open surgical intervention. We report an Angio-Seal(r) vascular closure device-induced acute arterial closure successfully treated percutaneously with the SilverHawk(r) plaque excision system. This report discusses the possible mechanisms of Angio-Seal(r) induced arterial occlusion and various percutaneous options for treatment. PMID- 28083455 TI - Multicenter Study of Pin Site Infections and Skin Complications Following Pinning of Pediatric Supracondylar Humerus Fractures. AB - INTRODUCTION: Pediatric supracondylar humerus fractures are the most common elbow fractures in pediatric patients. Surgical fixation using pins is the primary treatment for displaced fractures. Pin site infections may follow supracondylar humerus fracture fixation; the previously reported incidence rate in the literature is 2.34%, but there is significant variability in reported incidence rates of pin site infection. This study aims to define the incidence rate and determine pre-, peri-, and postoperative factors that may contribute to pin site infection following operative reduction, pinning, and casting. METHODS: A retrospective chart analysis was performed over a one-year period on patients that developed pin site infection. A cast care form was added to Nemours' electronic medical records (EMR) system (Epic Systems Corp., Verona, WI) to identify pin site infections for retrospective review. The cast care form noted any inflamed or infected pins. Patients with inflamed or infected pin sites underwent a detailed chart review. Preoperative antibiotic use, number and size of pins used, method of postoperative immobilization, pin dressings, whether postoperative immobilization was changed prior to pin removal, and length of time pins were in place was recorded. RESULTS: A total of 369 patients underwent operative reduction, pinning, and casting. Three patients developed a pin site infection. The pin site infection incidence rate was 3/369=0.81%. Descriptive statistics were reported for the three patients that developed pin site infections and three patients that developed pin site complications. CONCLUSION: Pin site infection development is low. Factors that may contribute to the development of pin site infection include preoperative antibiotic use, length of time pins are left in, and changing the cast prior to pin removal. PMID- 28083456 TI - Myxedema Ascites: A Rare Presentation of Uncontrolled Hypothyroidism. AB - Less than four percent of patients with hypothyroidism develop ascites. Ascites as the presenting feature of hypothyroidism is uncommon, hence diagnosis is often delayed. Once it is diagnosed, treatment of hypothyroidism leads to quick clinical improvement in ascites. We report a case of a female patient who presented with ascites secondary to severe hypothyroidism and discuss the diagnostic characteristics of the ascitic fluid in myxedema ascites on the basis of literature review. PMID- 28083457 TI - Novel and Conservative Approaches Towards Effective Management of Plantar Fasciitis. AB - We assessed the effectiveness of the different treatments for plantar fasciitis (PF) based on the changes in functional outcomes. A systematic literature search was carried out and studies from 2010 to 2016 were included in this review. The databases from Google Scholar, PubMed and Cochrane were used for the various treatment modalities of plantar fasciitis. The objectives measured included visual analog scale (VAS), Roles and Maudsley scale, foot function index (FFI), plantar fascia thickness and American Orthopedic Foot and Ankle Society (AOFAS) ankle-hind foot scale as the tools to predict the improvement in symptoms of pain and discomfort. Eight randomized controlled trails that met the selection criteria were included in this review. Extracorporeal shock wave lithotripsy (ESWL) with botulinum toxin type A, corticosteroid injections, autologous whole blood and plasma treatment, novel treatments like cryopreserved human amniotic membrane, effect of placebo, platelet rich plasma injections and corticosteroid injections, physiotherapy and high strength training were analyzed. All the treatment modalities applied did lead to the reduction in pain scores, but for long term management autologous condition plasma and platelet rich plasma are the preferred treatment options. Impact of physiotherapy and high strength training is equivalent to corticosteroid injections and hence is suited for patients avoiding invasive forms of treatment. PMID- 28083458 TI - Bilateral Breast Irradiation Using Hybrid Volumetric Modulated Arc Therapy (h VMAT) Technique: A Planning Case Report. AB - The purpose of this planning case report is to share the perceived dosimetric benefits of innovative hybrid volumetric modulated arc therapy (h-VMAT) for bilateral breast cancer radiotherapy in two patients with synchronous bilateral breast cancer. Two patients with early bilateral breast cancer after breast conservation surgery and adjuvant chemotherapy were planned for bilateral breast radiotherapy. On the planning computed tomography (CT) dataset, bilateral breast planning treatment volume (PTV) and organs at risk (OARs) were delineated using standard guidelines. Using the same structure set, volumetric modulated arc therapy (VMAT) and h-VMAT plans were generated and compared dosimetrically. The h VMAT showed comparable target coverage, conformity and homogeneity while sparing of both lungs and heart were better. The dose to heart was reduced with h-VMAT, with a V25Gy and V5Gy of 3.2 & 22.3% for h-VMAT versus 11.6 & 84.9% for the VMAT plan. Similarly, the dose to the total lung was better in h-VMAT with a V20Gy and V5Gy of 12.1 & 46.2 versus 19.9 & 83.3% for VMAT. Overall the results indicate a better sparing of lung and heart at low doses with h-VMAT. Long-term clinical follow-up will give us more insight about the dosimetric benefits of these innovative techniques. PMID- 28083459 TI - A Case of Koch's Spine Treated with Modified Transpedicular Vertebral Curettage and Posterior Fixation: A Novel Technique. AB - Tuberculosis (TB) is a chronic granulomatous infection caused by acid-fast mycobacterium tuberculosis bacilli. Spinal involvement occurs in less than one percent of TB. Spinal TB (Pott's disease) accounts for 50% of skeletal TB. Though it most commonly affects the thoracolumbar junction, it can occur at any level of the spine. Early diagnosis and treatment is mandatory in order to avoid neurological complications and spinal deformity. We report a case of a young female with tuberculosis of D12-L1 who was treated with posterior decompression using a modified transpedicular approach and posterior instrumentation with a successful outcome. PMID- 28083460 TI - First Reported Case of 'Epidermal Nevus Syndrome' with a Triad of Central Nervous System Deformities. AB - Epidermal nevus syndrome (ENS) is a term used to describe the occurrence of an epidermal nevus in association with other extra-cutaneous developmental anomalies, most commonly involving the nervous and musculoskeletal systems. The nevus is classified on the basis of the main component which may be keratinocytic, sebaceous, follicular, apocrine, or eccrine. Most patients who present with ENS is at the time of birth, though some become apparent later in life. This case describes a young female who presented with seizures and cognitive impairment along with a linear epidermal nevus on the midline of her face. The presence of the nevus prompted brain imaging which showed cortical dysplasia, multiple hamartomas in the temporal lobe, thalamus, and periventricular regions along with cerebellar atrophy and Dandy-Walker variant. To our knowledge, this is the first case in which three different types of brain lesions were found in the same patient. PMID- 28083461 TI - Instillation Therapy for the Treatment of Necrotizing Fasciitis: A Case Study. AB - A 57-year-old obese female with uncontrolled diabetes mellitus type I presented to the emergency department (ED) with the main complaint of worsening pain and redness in her right groin and inguinal regions. In the ED, a CT scan confirmed the likely presence of necrotizing fasciitis in the right groin and thigh. She was also found to be febrile and septic on admission. She was urgently taken to the OR for extensive debridement then admitted to the ICU for medical stabilization. She was subsequently taken back for serial debridements, and a negative pressure wound therapy with instillation (NPWTi-d) Veraflo device was placed once the wound was successfully debrided down to viable tissue. This is a case study on the wound progression of this patient. PMID- 28083462 TI - Hydration Status as a Predictor of High-altitude Mountaineering Performance. AB - BACKGROUND: Hydration status is a controversial determinant of athletic performance. This relationship has not been examined with mountaineering performance. METHODS: This was a prospective observational study of mountaineers who attempted to climb Denali in Alaska. Participants' urine specific gravity (SG), and ultrasound measurements of the inferior vena cava size and collapsibility index (IVC-CI) were measured at rest prior to ascent. Upon descent, climbers reported maximum elevation gained for determination of summit success. RESULTS: One hundred twenty-one participants enrolled in the study. Data were collected on 111 participants (92% response rate); of those, 105 (87%) had complete hydration data. Fifty-seven percent of study participants were found to be dehydrated by IVC-CI on ultrasound, and 55% by urine SG. No significant association was found with summit success and quantitative measurements of hydration: IVC-CI (50.4% +/- 15.6 vs. 52.9% +/- 15.4, p = 0.91), IVC size (0.96 cm +/- 0.3 vs. 0.99 cm +/- 0.3, p = 0.81), and average SG (1.02 +/- 0.008 vs. 1.02 +/- 0.008, p = 0.87). Categorical measurements of urine SG found 24% more successful summiters were hydrated at 14 Camp, but this was not found to be statistically significant (p = 0.56). Summit success was associated with greater water-carrying capacity on univariate analysis only: 2.3 L, 95% confidence interval (2.1 - 2.5) vs. 2.1 L, 95% confidence interval (2 - 2.2); p < 0.01. CONCLUSIONS: Intravascular dehydration was found in approximately half of technical high-altitude mountaineers. Hydration status was not significantly associated with summit success, but increased water-carrying capacity may be an easy and inexpensive educational intervention to improve performance. PMID- 28083463 TI - Magnetic Resonance-Guided Laser-Induced Thermal Therapy for Recurrent Brain Metastases in the Motor Strip After Stereotactic Radiosurgery. AB - The authors report a challenging case of a brain metastasis located in the motor cortex, which was not responsive to radiosurgery. Use of a novel technique, magnetic resonance-guided laser-induced thermotherapy (MRgLITT), resulted in the complete obliteration of the lesion without adverse effects or evidence of tumor recurrence at follow-up. This case illustrates that MRgLITT may provide a viable alternative for patients with brain metastases refractory to radiosurgery or in deep locations, where both stereotactic radiosurgery (SRS) and surgical resection may be ineffective. PMID- 28083464 TI - The Use of NPWT-i Technology in Complex Surgical Wounds. AB - Advanced wound management of complex surgical wounds remains a significant challenge as more patients are being hospitalized with infected wounds. Reducing recurrent infections and promoting granulation tissue formation is essential to overall wound healing. Wounds with acute infection and critical colonization require advanced multimodal approaches including systemic antibiotics, surgical debridement, and primary wound care. The goal in surgical wound management is to optimize clinical outcomes such as time to wound closure and functional recovery. A review of current literature suggests that negative pressure wound therapy with instillation (NPWT-i) is a viable adjunct therapy in the management of infected wounds especially in patients with medical comorbidities. The aim of this case series is to highlight the ability of NPWT-i as adjunct to prepare the wound bed for closure on infected surgical wounds that would normally require multiple operations to obtain source control. PMID- 28083465 TI - Emergence Delirium With Post-traumatic Stress Disorder Among Military Veterans. AB - The clinical characteristics of emergence delirium (ED) associated with post traumatic stress disorder (PTSD) among military veterans encompass transient agitation, restlessness, disorientation, and violent verbal and physical behaviors due to re-experiencing of PTSD-related incidents. Two cases of ED after general anesthesia associated with PTSD are presented. Different anesthesia methods were applied for the two cases. A traditional medical approach appeared not to prevent the incidence of ED. In the second case, dexmedetomidine infusion along with verbal coaching was effective in preventing ED for a veteran known to have "wild wake-ups" with prior anesthetics. Further clinical studies in effectively utilizing dexmedetomidine in this population with PTSD at high risk for ED are warranted. PMID- 28083466 TI - Evaluation of an Ecologically Valid Group Intervention to Address Sleep Health in Families of Children With Allergic Diseases. AB - Sleep issues in children with allergic diseases may be a result of illness related factors (e.g., itching, wheezing) and/or poor sleep habits due to disrupted routines and parental permissiveness. However, the ability of parents to attend a multi-session sleep intervention may be limited. Thus we examined the validity of a one-time sleep health group intervention for parents of children with allergic diseases. Ninety-three parents of children who were admitted to a two-week intensive day hospital treatment program completed measures of child sleep habits (Children's Report of Sleep Patterns), parent sleep habits (Sleep Hygiene Inventory), parent sleep quality (Pittsburgh Sleep Quality Index), and parental insomnia symptoms (Insomnia Severity Index) before the group intervention and one-month after program discharge; 54 parents attended the sleep health group. Sleep habits and sleep quality improved for both parents and children at the one-month follow-up. However, improvements were seen regardless of group attendance. Potential reasons for the lack of difference between those who did and did not participate in group are presented, and implications of this study for pediatric psychologist in practice are discussed. PMID- 28083467 TI - Diagnosis and Management of Congenital Sensorineural Hearing Loss. AB - Hearing loss is the most common sensory disorder in the USA. The diagnosis of congenital hearing loss starts with newborn hearing screening, which is best performed with auditory brainstem evoked responses in order to avoid the risk of missing auditory neuropathy spectrum disorder. A careful history and physical exam can occasionally help reveal the etiology for congenital hearing loss. Imaging studies, either CT temporal bones or MRI of the internal auditory canals without gadolinium, and genetic testing, in particular for connexin 26, connexin 30, and Pendred syndrome, are the most useful diagnostic tests. Management of congenital hearing loss involves early fitting of amplification. Early cochlear implantation, preferably before 2 years of age, should be strongly considered for children with bilateral severe hearing loss. PMID- 28083468 TI - Increased body weight affects academic performance in university students. AB - For K-12 students, obesity has been linked to student educational achievements. The study objective was to determine whether academic performance in university students is correlated with BMI. Students from two consecutive academic years (Jan-May 2013 and Jan-May 2014) were given an optional class survey in May, as extra credit. Of the 452 students that completed the survey, 204 females and 75 males (N = 279; 73% female and 27% male) consented to participate in the study. The number of correct answers to problem-solving questions (PSQs) and the overall final grade for the class were compared to the calculated BMI using linear regression with a Pearson's R correlation and unpaired t-tests. BMI was significantly negatively correlated with student's final grades (P = 0.001 Pearson's r = - 0.190) and PSQs were positively correlated with final grades (P < 0.001; Pearson's r = 0.357). Our findings show a correlation between healthy body weight and improved academic performance. Further, the data suggest that future research in the area of body weight, diet, and exercise and any correlations of these with academic performance in college students are warranted. PMID- 28083469 TI - Leisure-time, occupational, household physical activity and insulin resistance (HOMAIR) in the Midlife in the United States (MIDUS) national study of adults. AB - Physical activity is a critical cornerstone of successful diabetes prevention and management. Current U.S. physical activity guidelines do not differentiate among physical activity for leisure, work, or other purposes, effectively implying that physical activity in any domain confers the same health benefits. It is currently unknown whether physical activity performed in different domains (leisure-time physical activity = LTPA, occupational physical activity = OPA, and household physical activity = HPA) is associated with insulin resistance. The associations between LTPA, OPA, HPA, and insulin resistance (indexed by homeostatic model assessment of insulin resistance = HOMAIR) were determined in the MIDUS (Midlife in the U.S.; 1995-2006) national study (N = 1229, ages 34-84). Not meeting physical activity guidelines with LTPA was associated with a 34% higher HOMAIR among participants with diabetes, 42% higher HOMAIR among participants with prediabetes, and 17% higher HOMAIR among participants with normal glucoregulation. These associations were slightly attenuated but remained significant after further adjusting for obesity status, education, smoking, and alcohol intake. There was no evidence that engaging in OPA or HPA was significantly associated with HOMAIR. These results confirm the health-promoting role of LTPA and suggest that LTPA may provide unique glucoregulatory benefits, as opposed to HPA and OPA. Physical activity domain is an important dimension that potentially belongs in the guidelines, similarly to intensity, frequency, duration, and type. PMID- 28083470 TI - Analysis of the Surface, Secreted, and Intracellular Proteome of Propionibacterium acnes. AB - Propionibacterium acnes , plays an important role in acne vulgaris and other diseases. However, understanding of the exact mechanisms of P. acnes pathogenesis is limited. Few studies have investigated its proteome, which is essential for vaccine development. Here, we comprehensively investigate the proteome of P. acnes strain ATCC 6919, including secreted, cell wall, membrane, and cytosolic fractions in three types of growth media. A total of 531 proteins were quantified using an Orbitrap mass spectrometer and bioinformatically categorized for localization and function. Several, including PPA1939, a highly expressed surface and secreted protein, were identified as potential vaccine candidates. PMID- 28083471 TI - Communicating Fistula Between Colocutan and Nephrocutan With Renal Stones and Renal Replacement Lipomatosis. A Case Report. AB - Colocutaneous fistula with nephrocutaneous fistula is a rare condition. Renal replacement lipomatosis is the result of the atrophy and destruction of renal parenchyma. We report a 60-year-old male with intermittent drainage mucus and fluid from ulcer of his right lumbar region. Renal ultrasound and plain abdominal X-ray revealed a chronic parenchymal disease with stone of the right kidney. Fistulography showed a fistula tract connecting the skin and the right pelvicalyceal system and the colon. Computerized tomography demonstrated a renal calculus with a massive fatty proliferation. The patient was planned for right nephrectomy and excision of the sinus tract. PMID- 28083472 TI - Renal Pseudoaneurysm Mimicking Local Cancer Recurrence After Partial Nephrectomy. AB - The development of an iatrogenic vascular lesion, such a renal pseudoaneurysm or arteriovenous fistula, is a rare complication of partial nephrectomy. These lesions should be considered in patients presenting with an enhancing mass in the resection bed shortly following partial nephrectomy. Early timing following surgery, large relative size, and the presence of recurrent hematuria suggest the diagnosis of an iatrogenic vascular lesion. Duplex ultrasound is a useful non invasive imaging modality for differentiating these lesions from a local tumor recurrence. PMID- 28083473 TI - Tuberculous Granuloma in the Scrotal Skin After Intravesical Bacillus Calmette Guerin Therapy for Bladder Cancer: A Case Report. AB - Rare cases of tuberculous urinary tract or genital infection caused by intravesical Intravesical Bacillus Calmette-Guerin (BCG) instillation therapy have been reported. We encountered a patient with tuberculous granuloma in the scrotal skin after intravesical BCG therapy for bladder cancer. There was evidence of infection in the scrotal skin, but not in the epididymis. To the best of our knowledge, this is the first report of tuberculous granuloma in the scrotal skin without epididymitis after intravesical BCG therapy. In our case, lower urinary tract symptoms such as the terminal dribbling of urine appear to support the theory of direct BCG inoculation. PMID- 28083474 TI - Metastatic Prostate Cancer Diagnosed by Bone Marrow Aspiration in an Elderly Man Not Undergoing PSA Screening. AB - Prostate cancer screening by PSA testing remains controversial, particularly in the elderly. Practice guidelines from most clinical societies suggest discontinuing PSA screening at age 70 while the USPSTF recommends against screening at any age. Recent reports have demonstrated an increased incidence of metastatic prostate cancer, with men aged 75 or older accounting for roughly half of those newly diagnosed at an incurable stage. We herein describe the case of an elderly gentleman with no history of prostate cancer screening who presented with anorexia and back pain of unclear etiology. Evaluation with bone marrow aspiration revealed a diagnosis of metastatic prostate cancer. PMID- 28083475 TI - Urinary Retention as the Only Symptom of Retained Surgical Sponge (Gossypiboma), 29 Years After Cesarean Procedure. AB - A 68 year old lady presented to urology department suffering from acute urinary retention. The U/S revealed hydronephrosis in left kidney and a mass at the left side of the small pelvis which pushed forward the uterus and the bladder. The CT scan confirmed a mixed (solid and cystic) mass, with diameter of 12 cm with interpretation of the left ovary. The patient underwent laparotomy and the mass was excised after a difficult dissection due to severe adhesion with the bowel. The well-capsulated mass was a retained surgical sponge. The patient had undergone cesarean procedure 29 years ago. PMID- 28083476 TI - Efficacy of Everolimus for Treating Renal Angiomyolipoma with Inferior Vena Cava Thrombus Associated with Tuberous Sclerosis: A Case Report. AB - Here we report a case of 57-year-old woman with renal angiomyolipoma associated with tuberous sclerosis complex involving inferior vena cava thrombus. We could perform less invasive nephrectomy with thrombectomy because everolimus administration reduced the inferior vena cava thrombus. To the best of our knowledge, this is the first report the use of everolimus before performing surgery to treat renal angiomyolipoma with inferior vena cava thrombus. PMID- 28083477 TI - Clinical Treatment of Penile Fibrosis After Penoscrotal Lymphedema. AB - Genital lymphedema in men can affect the penis and/or scrotum, causing deformity and causing sexual limitations, social isolation, poor quality of life and recurrent subcutaneous infections due to difficulties in hygiene. There are few studies in the literature emphasizing the treatment of penile fibrosis after penoscrotal lymphedema. The purpose of this report is to describe a case of penile fibrosis treated using a new compression method. PMID- 28083478 TI - Transitional Bladder Cell Carcinoma Spreading to the Skin. AB - Cutaneous metastases from bladder malignancies are rare. We report the case of a 74 year old man who underwent cysto-prostatectomy and adjuvant chemotherapy for a pT3b N+ bladder transitional cell carcinoma. Four months later, he presented with skin disseminated pigmented lesions. Skin biopsy confirmed cutaneous metastasis from urothelial carcinoma. PMID- 28083479 TI - Successful Preservation of the Bladder in a Case of Inflammatory Myofibroblastic Tumor with the Diagnostic Efficacy of ALK/p80 Immunohistochemistry and FISH Analysis: Case Report and Review of the Literature. AB - Inflammatory myofibroblastic tumor is a rare benign entity of unclear etiology. It can present with histological features that include a mixture of spindle cells, myofibroblasts and inflammatory cells. Positive immunohistochemical staining for ALK/p80 is often observed, and this marker has been considered diagnostically effective. Despite having these histological features, a previous case was incorrectly diagnosed as malignant disease and was treated with extensive surgical resection. Here we present a case of inflammatory myofibroblastic tumor in the bladder, diagnosed in part based on immunohistochemical and fluorescence in situ hybridization analysis of ALK/p80. The patient was successfully treated with bladder-preserving partial cystectomy. PMID- 28083480 TI - Urinary Tract Infection Caused by Citrobacter koseri in a Patient With Spina Bifida, an Ileal Conduit and Renal Caluli Progressing to Peri-nephric Abscess and Empyema. AB - Urological problems are common in spina bifida and are often treated with urinary diversions. Spina bifida and ileal conduits put patients at increased risk for ascending urinary tract infections. Here we present a novel case of a Citrobacter koseri urinary tract infection complicated by a perinephric abscess with pleural extension. To our knowledge, no case of an ascending C. koseri UTI progressing to peri-nephric abscess and empyema by direct extension exists in the literature. PMID- 28083481 TI - Robot-assisted Partial Cystectomy for Treatment of Inflammatory Myofibroblastic Tumor of the Bladder. AB - Inflammatory myofibroblastic tumors rarely occur in the urinary bladder. These masses follow an indolent course, but due to their histologic similarities to more malignant types of bladder masses, they must be differentiated with immunohistochemical staining. Once diagnosed, the mainstay of treatment for these masses is surgical resection. Due to advancements in robotic surgery, new surgical techniques can be employed to treat these masses with fewer perioperative complications. We report a case of inflammatory myofibroblastic tumor of the urinary bladder in a 29-year-old male treated with robot-assisted partial cystectomy. PMID- 28083482 TI - Novel Management of Anastomotic Disruption and Persistent Hematuria Following Robotic Prostatectomy: Case Report and Review of the Literature. AB - Vesicourethral anastomosis leaks are not uncommon following radical prostatectomy. We present a case of a 59-year-old male who presented to our ED with hematuria, abdominal pain, and clot retention 17 days after a robotic assisted laparoscopic prostatectomy. A 50% vesicourethral disruption was ultimately managed endoscopically and with hemostatic agents. At 9-month follow up he is fully continent with normal erectile function. Vesicourethral leaks can typically be managed conservatively with gentle traction and prolonged catheterization. Persistent hematuria can complicate management, and hemostatic agents may allow for completely endoscopic management with minimal morbidity as seen in this case. PMID- 28083483 TI - Paratesticular Leiomyosarcoma: A Case Report and Review of the Literature. AB - Paratesticular sarcomas are rare. Most cases reported in the literature are depending on retrospective analysis of case reports, small series, literature reviews, and expert opinion and they show different outcomes depending on several variables. The majority indicate that this may be an indolent tumor with a potential for cure if treated early. We present a case of a 58 year old man with a history of painless enlargement of the right testis. The ultrasound showed an extratesticular lesion and a right excisional of the mass was performed. The pathological examination revealed a leiomyosarcoma, and was then completed with a right radical inguinal orchiectomy. A review of the literature regarding paratesticular sarcomas presentation, diagnosis and treatment is presented in this article. PMID- 28083484 TI - Metastatic Melanoma to the Bladder: Case Report and Review of the Literature. AB - A 49-year-old Caucasian woman presented to the dermatology clinic for follow-up of malignant melanoma with a complaint of painless gross hematuria. Two years prior she was diagnosed with malignant melanoma from a skin lesion on her left flank treated with wide excision, negative axillary sentinel lymph node biopsy, and adjuvant radiotherapy. Subsequently, she had no evidence of disease until urologic evaluation of her hematuria revealed two lesions in her bladder and cytopathology demonstrated findings consistent with malignant melanoma. We review literature on melanoma metastatic to the bladder and discuss the potential role of metastasectomy and other treatment strategies in such rare cases. PMID- 28083485 TI - Chronic Colovesical Fistula Leading to Chronic Urinary Tract Infection Resulting in End-Stage Renal Disease in a Chronic Granulomatous Disease Patient. AB - A 46-year old man with X-linked chronic granulomatous disease (CGD) being followed at the National Institute of Health with uncontrolled CGD colitis who developed chronic colovesical fistula, and end-stage renal disease (ESRD). Despite aggressive medical management of symptoms with immunomodulators and antibiotic prophylaxis, the chronic colovesical fistula led to chronic pyelonephritis, recurrent urinary tract infections, persistent air in the collecting system and bladder, and post-renal obstruction resulting in renal failure. Patient is now hemodialysis dependent and required diverting loop ileostomy placement. This report highlights multiple potential etiologies of rising serum creatinine in patients with CGD. PMID- 28083486 TI - Metastatic Mucinous Adenocarcinoma and Carcinoid Tumor Arising From a Mature Cystic Teratoma of a Horseshoe Kidney. AB - Concurrent primary carcinoid tumor and primary mucinous adenocarcinoma arising within a mature cystic teratoma of a horseshoe kidney is a rare event and has been reported once in the literature. We present the first case where this tumor subtype has metastasized to lymph nodes. Treatment included open partial nephrectomy, lymph node dissection, and adjuvant chemotherapy with temozolomide and capecitabine. Due to the rare combination of tumor histologies, it is unlikely that this cohort will ever be able to be adequately studied to determine a standard of care. Thus extrapolation of treatment methods of similar tumors will continue to guide treatment. PMID- 28083487 TI - JNS Turns Five; Toddler No More. PMID- 28083488 TI - Atropine: A Cure for Persistent Post Laparoscopic Pyloromyotomy Emesis? AB - BACKGROUND: Atropine has been used as a successful primary medical treatment for hypertrophic pyloric stenosis. Several authors have reported a higher rate of incomplete pyloromyotomy with the laparoscopic approach compared to open. In this study, we evaluated the use of atropine as a medical treatment for infants with emesis persisting greater than 48 hours after a laparoscopic pyloromyotomy. MATERIALS AND METHODS: We performed a retrospective chart review of infants receiving a laparoscopic pyloromyotomy between November 1998 and November 2012. Infants with emesis that persisted beyond 48 hours postoperatively were given 0.01mg/kg of oral atropine 10 minutes prior to feeding. Infants remained inpatient until they tolerated two consecutive feedings without emesis. RESULTS: 965 patients underwent laparoscopic pyloromyotomy; 816 (84.6%) male and 149 (15.4%) female. Twenty-four (2.5%) received oral atropine. The mean length of stay for patients who received atropine was 5.6 +/- 2.6 days, an average of 3 additional days. They were discharged home with a one-month supply of oral atropine. Follow up evaluation did not reveal any complications from receiving atropine. The median follow up was 21 days. None returned to the operating room for incomplete pyloromyotomy. There were 17 (1.8%) operative complications in our series; 9 mucosal perforations, 2 duodenal perforations, and 6 conversions to open for equipment failure or poor exposure. There were 4 (0.4%) post-operative complications: 2 episodes of apnea requiring reintubation and 2 incisional hernias that required a second operation. There were no deaths. CONCLUSION: Oral atropine is a viable treatment for persistent emesis after a pyloromyotomy and reduces the need for a second operation due to incomplete pyloromyotomy. PMID- 28083489 TI - Management of Complex Ovarian Cysts in Newborns - Our Experience. AB - AIMS: To analyse the clinical presentation, clinicopathological correlation and management of complex ovarian cysts in newborn and infants. MATERIALS AND METHODS: Over a period of 6 years (2009-2015), 25 newborns who were diagnosed to have ovarian cyst on antenatal ultrasound, were followed up. We collected data in the form of clinical features, radiological findings, pathology and mode of treatment. RESULTS: Of the 25 fetuses who were diagnosed to have ovarian cysts, fourteen (56%) underwent spontaneous regression by 6-8 months. Eight were operated in newborn period while 3 were operated in early infancy. Seven had ovarian cyst on right side, 4 had on left side. Eight babies underwent laparoscopy while 3 underwent laparotomy. Histopathology showed varied features of hemorrhagic cyst with necrosis and calcification, serous cystadenoma with hemorrhage, benign serous cyst with hemorrhage and simple serous cyst. Post operative recovery was uneventful in all. CONCLUSION: All the ovarian cysts detected antenatally in female fetuses need close follow-up after birth. Since spontaneous regression is known, only complex or larger cysts need surgical intervention, preferably by laparoscopy. Majority of the complex cysts show atrophic ovarian tissue hence end up in oophorectomy but simple cysts can be removed preserving normal ovarian tissue whenever possible. PMID- 28083490 TI - Ileostomy Complications in Infants less than 1500 grams - Frequent but Manageable. AB - BACKGROUND: In very low birth weight infants abdominal emergency surgery may result in ileostomy formation. We observed a frequent stoma complications in these patients. This retrospective analysis put light on ileostomy-related problems and complications in very low birth weight (VLBW) infants. MATERIALS AND METHODS: In a seven-year retrospective chart review (2008 - 2014) infants with ileostomy formation weighing less than 1500 grams at time of operation were identified and reviewed. Data analysis included demographic data, complications and short term outcomes. RESULTS: Thirty patients were included. Ileostomy was formed for spontaneous intestinal perforation (SIP) (n=17), meconium obstruction of prematurity (MOP) (n=6), midgut volvulus (MV) (n=5), necrotizing enterocolitis (NEC) (n=1) and Hirschsprung's disease (HD) (n=1). Three patients died before ileostomy reversal was considered. In seven patients planned ileostomy reversal was done. Twenty infants had stoma related complications (stoma prolapse, prestomal obstruction, stoma retraction, high output stoma, peristomal skin excoriation, and stomal ischemia). Complications did not correlate with underlying diseases. Stomal complications necessitated earlier stoma reversal (mean 62 days). Postoperative complications after stoma reversal occurred in three children (wound dehiscence, adhesion ileus, anastomotic stricture). CONCLUSIONS: Although ileostomy related complications are frequent in very low birth weight infants, mortality is low. Morbidity is manageable. PMID- 28083491 TI - Gastrointestinal Duplication Presenting as Neonatal Intestinal Obstruction: An Experience of 15 Years at Tertiary Care Centre. AB - BACKGROUND: Gastrointestinal tract (GIT) duplications are one of the rare congenital anomalies and can occur in any portion of the gastrointestinal tract but are more commonly encountered in small intestine. The duplication cysts cause symptoms like abdominal mass and intestinal obstruction requiring surgery or may remain asymptomatic. We are reporting our 15 years' experience duplication cysts presenting in neonates. METHODS: It is a retrospective study undertaken in the department of pediatric surgery between 2001 and 2015 for GIT duplications in neonates. Patients were analyzed for their antenatal diagnosis, age, sex, clinical diagnosis, investigatory approach, operative management and surgical outcomes. RESULTS: Total number of neonates, diagnosed with gastrointestinal duplication in the last 15 years, was 17. Male to female ratio was 3.3:1. The most common location was found to be the ileum occurring in 71% of cases. Apart from ileum, 2 cases of duodenal and 1 case each of gastric, colonic and cecal duplication cyst were encountered. Majority cases presented with sub-acute intestinal obstruction and were managed successfully by resection and end to end anastomosis. Associated gut atresia was found in 4 cases while 1 case was found to be associated with perforation of gut. CONCLUSION: Gastrointestinal tract duplications often present with typical symptoms of gastrointestinal tract obstruction. Early diagnosis and management is required to prevent postoperative morbidity and mortality. PMID- 28083492 TI - Abdominal Plain Radiograph in Neonatal Intestinal Obstruction. AB - A comprehensive all-inclusive resource on plain radiograph in neonatal intestinal obstruction is presented. This is an attempt to develop a protocol and to regain expertise in evaluating a plain radiograph that most often yields more than enough clues to diagnose and to decide a plan of action. PMID- 28083493 TI - Is there a Place for Prebiotics in the Management of Neonatal Inguinal Hernia? A Preliminary Study. AB - The objective of this study was to assess the place of prebiotics in the management of neonatal inguinal hernia. Boys with a diagnosis of unilateral non complicated inguinal hernia, aged less than 40 days, were prospectively followed from January 2012 to December 2014. Clinical and psychiatric data and outcomes were collected before and after prebiotics (Primalac AC) administration. Ninety eight patients were included. There were 75 inguinal hernias and 23 inguino scrotal hernias. Before prebiotics administration 72.2% of infants had abdominal distention and 98% had colic. After prebiotics, abdominal distention and colic regressed in 85.2% and 73.2% of patients, respectively. Hernias disappeared clinically in 66.3% of cases. The factors associated with the disappearance of hernias were the type of the hernia (p<0.001), colic (p<0.001), and abdominal distention (p<0.001). Prebiotics would be a new adjunct in the management of neonatal inguinal hernia. They decrease colic and abdominal distention, which seems helpful to prevent strangulation and probably get spontaneous resolution of small hernias. PMID- 28083494 TI - Newborn with Gastroschisis associated with Limb Anomalies. AB - Gastroschisis is often found together with other extra intestinal conditions such as limb, spine, cardiac, central nervous system and genitourinary abnormalities. There are reports of its association with young maternal age. The cases presented here highlight the association of gastroschisis with limbs anomalies and young maternal age. PMID- 28083495 TI - New Variant of Esophageal Atresia. AB - Esophageal atresia with tracheoesophageal fistula (EA/TEF) associated with distal congenital esophageal stenosis (CES) is a well-known entity. We encountered three patients of EA/TEF associated with long and unusual CES. PMID- 28083496 TI - Neonatal Sleeve Gastrectomy for Multiple Gastric Perforations: A Case Report. AB - Neonatal gastric perforation (NGP) may be spontaneous, secondary to necrotizing enterocolitis (NEC), or due to distal obstruction. A 27-week old premature male newborn presented with pneumoperitoneum. A single perforation of stomach was found at surgery. Primary repair and gastrostomy were performed. On fifth postoperative day, pneumoperitoneum was again detected. At reoperation, multiple gastric perforations of the greater curvature were found. Sleeve gastrectomy was performed. The patient responded well to the treatment. PMID- 28083497 TI - Priapism in the Newborn: Shall We Intervene? AB - Idiopathic neonatal priapism is rarely published. We report the case of a newborn presenting with priapism on the first day of life and reviewed the published data on the management and the follow up of this condition. PMID- 28083498 TI - Congenital Syngnathia; Turmoils and Tragedy. AB - Congenital syngnathia is an extremely rare condition with no standardized treatment. We hereby report a case highlighting the difficulties faced in its management and the postoperative complications. PMID- 28083499 TI - Intussusception in Premature Baby: Unusual Cause of Bowel Obstruction and Perforation. AB - Intussusception in a premature baby is a rare condition. We report a male preterm infant, who developed abdominal distension and abdominal wall erythema. He was operated with suspicion of NEC but an ileo-ileal intussusception and intestinal perforation were encountered at operation. PMID- 28083500 TI - Ineffective Ventilation in A Neonate with A Large Pre-Carinal Tracheoesophageal Fistula and Bilateral Pneumonitis-Microcuff Endotracheal Tube to Our Rescue! AB - Tracheoesophageal fistula (TEF) is one of the most common congenital anomaly requiring surgical correction in neonatal period. The important goal of airway management is to avoid excessive gastric distension and ensure adequate ventilation prior to surgical ligation of the fistula. If a large fistula is present close to carina, excessive loss of delivered tidal volume may lead to ineffective ventilation. In addition, gastric distension elevates diaphragm and diminishes the lung compliance. If lung compliance is already impaired due to pre existing lung pathology, situation becomes much more demanding. We report the successful airway management of a patient with large precarinal fistula and bilateral pneumonitis using the novel Microcuff tube. The unique design of microcuff makes it suitable to be used for this purpose. To the best of our knowledge, the use of microcuff ETT for perioperative airway management in case of a large precarinal fistula in a neonate with respiratory pathology has not been reported in the past. PMID- 28083501 TI - Congenital Giant Dysplastic Kidney Presenting as Respiratory Distress: A Case Report. AB - Multicystic dysplastic kidney (MCDK) is the most common form of renal cystic disease in children and is one of the most common causes of abdominal mass in infancy. Here in we are reporting a rare case of a large MCKD that caused respiratory compromise and the infant presented with respiratory distress. PMID- 28083502 TI - Chylous Ascites in a Newborn with Gastroschisis. Case Report. AB - Chylous ascites is a rare disease, only two cases associated with gastroschisis have been published. We report a case treated conservatively with total parenteral nutrition (TPN) and octreotide. We reviewed the literature about management options for the chylous ascites. PMID- 28083503 TI - Mesenteric Cyst in Association with Type-II Jejunoileal Atresia. AB - A rare case of type-II jejunoileal atresia with mesenteric cyst in a neonate is being reported here with a brief review of literature. PMID- 28083504 TI - In-Utero Limb Amputation. PMID- 28083505 TI - Gollop-Wolfgang Complex. PMID- 28083506 TI - Riga Fede Disease. PMID- 28083507 TI - Giant Macrocystic Lymphatic Malformation in a Neonate. PMID- 28083508 TI - Giant Choledochal Cyst in A Neonate. PMID- 28083509 TI - A Rare Case of Split Notochord Syndrome. PMID- 28083510 TI - Malpositioned Central Line in A Neonate Presenting as Superficial Abdominal Abscess. PMID- 28083511 TI - A Retrospective Cohort Study of Total Colonic Aganglionosis: Is the Appendix a Reliable Diagnostic Tool? PMID- 28083512 TI - Targeting Phospholipid Metabolism in Cancer. AB - All cancers tested so far display abnormal choline and ethanolamine phospholipid metabolism, which has been detected with numerous magnetic resonance spectroscopy (MRS) approaches in cells, animal models of cancer, as well as the tumors of cancer patients. Since the discovery of this metabolic hallmark of cancer, many studies have been performed to elucidate the molecular origins of deregulated choline metabolism, to identify targets for cancer treatment, and to develop MRS approaches that detect choline and ethanolamine compounds for clinical use in diagnosis and treatment monitoring. Several enzymes in choline, and recently also ethanolamine, phospholipid metabolism have been identified, and their evaluation has shown that they are involved in carcinogenesis and tumor progression. Several already established enzymes as well as a number of emerging enzymes in phospholipid metabolism can be used as treatment targets for anticancer therapy, either alone or in combination with other chemotherapeutic approaches. This review summarizes the current knowledge of established and relatively novel targets in phospholipid metabolism of cancer, covering choline kinase alpha, phosphatidylcholine-specific phospholipase D1, phosphatidylcholine-specific phospholipase C, sphingomyelinases, choline transporters, glycerophosphodiesterases, phosphatidylethanolamine N-methyltransferase, and ethanolamine kinase. These enzymes are discussed in terms of their roles in oncogenic transformation, tumor progression, and crucial cancer cell properties such as fast proliferation, migration, and invasion. Their potential as treatment targets are evaluated based on the current literature. PMID- 28083514 TI - Reduced Innate Immune Response to a Staphylococcus aureus Small Colony Variant Compared to Its Wild-Type Parent Strain. AB - Background:Staphylococcus aureus (S. aureus) small colony variants (SCVs) can survive within the host intracellular milieu and are associated with chronic relapsing infections. However, it is unknown whether host invasion rates and immune responses differ between SCVs and their wild-type counterparts. This study used a stable S. aureus SCV (WCH-SK2SCV) developed from a clinical isolate (WCH SK2WT) in inflammation-relevant conditions. Intracellular infection rates as well as host immune responses to WCH-SK2WT and WCH-SK2SCV infections were investigated. Method: NuLi-1 cells were infected with either WCH-SK2WT or WCH SK2SCV, and the intracellular infection rate was determined over time. mRNA expression of cells infected with each strain intra- and extra-cellularly was analyzed using a microfluidic qPCR array to generate an expression profile of thirty-nine genes involved in the host immune response. Results: No difference was found in the intracellular infection rate between WCH-SK2WT and WCH-SK2SCV. Whereas, extracellular infection induced a robust pro-inflammatory response, intracellular infection elicited a modest response. Intracellular WCH-SK2WT infection induced mRNA expression of TLR2, pro-inflammatory cytokines (IL1B, IL6, and IL12) and tissue remodeling factors (MMP9). In contrast, intracellular WCH SK2SCV infection induced up regulation of only TLR2. Conclusions: Whereas, host intracellular infection rates of WCH-SK2SCV and WCH-SK2WT were similar, WCH SK2SCV intracellular infection induced a less widespread up regulation of pro inflammatory and tissue remodeling factors in comparison to intracellular WCH SK2WT infection. These findings support the current view that SCVs are able to evade host immune detection to allow their own survival. PMID- 28083513 TI - Dissecting the Biology of Menstrual Cycle-Associated Breast Cancer Risk. AB - Fluctuations in circulating estrogen and progesterone across the menstrual cycle lead to increased breast cancer susceptibility in women; however, the biological basis for this increased risk is not well understood. Estrogen and progesterone have important roles in normal mammary gland development, where they direct dynamic interactions among the hormonally regulated mammary epithelial, stromal, and immune cell compartments. The continuous fluctuations of estrogen and progesterone over a woman's reproductive lifetime affect the turnover of mammary epithelium, stem cells, and the extracellular matrix, as well as regulate the phenotype and function of mammary stromal and immune cells, including macrophages and regulatory T cells. Collectively, these events may result in genome instability, increase the chance of random genetic mutations, dampen immune surveillance, and promote tolerance in the mammary gland, and thereby increase the risk of breast cancer initiation. This article reviews the current status of our understanding of the molecular and the cellular changes that occur in the mammary gland across the menstrual cycle and how continuous menstrual cycling may increase breast cancer susceptibility in women. PMID- 28083515 TI - Genome-Wide Transcriptional and Post-transcriptional Regulation of Innate Immune and Defense Responses of Bovine Mammary Gland to Staphylococcus aureus. AB - Staphylococcus aureus (S. aureus) is problematic for lactating mammals and public health. Understanding of mechanisms by which the hosts respond to severe invasion of S. aureus remains elusive. In this study, the genome-wide expression of mRNAs and miRNAs in bovine mammary gland cells were interrogated at 24 h after intra mammary infection (IMI) with high or low concentrations of S. aureus. Compared to the negative control quarters, 194 highly-confident responsive genes were identified in the quarters with high concentration (109 cfu/mL) of S. aureus, which were predominantly implicated in pathways and biological processes pertaining to innate immune system, such as cytokine-cytokine receptor interaction and inflammatory response. In contrast, only 21 highly-confident genes were significantly differentially expressed in face of low concentration (106 cfu/mL) of S. aureus, which slightly perturbed the cell signaling and invoked corresponding responses like vasoconstriction, indicating limited perturbations and immunological evading. Additionally, the significant up regulations of bta-mir-223 and bta-mir-21-3p were observed in the quarters infected by high concentration of S. aureus. Network analysis suggested that the two miRNAs' pivotal roles in defending hosts against bacterial infection probably through inhibiting CXCL14 and KIT. The significant down-regulation of CXCL14 was also observed in bovine mammary epithelial cells at 24 h post-infection of S. aureus (108 cfu/mL) in vitro. Integrated analysis with QTL database further suggested 28 genes (e.g., CXCL14, KIT, and SLC4A11) as candidates of bovine mastitis. This study first systematically revealed transcriptional and post transcriptional responses of bovine mammary gland cells to invading S. aureus in a dosage-dependent pattern, and highlighted a complicated responsive mechanism in a network of miRNA-gene-pathway interplay. PMID- 28083516 TI - Antimicrobial Peptides: An Emerging Category of Therapeutic Agents. AB - Antimicrobial peptides (AMPs), also known as host defense peptides, are short and generally positively charged peptides found in a wide variety of life forms from microorganisms to humans. Most AMPs have the ability to kill microbial pathogens directly, whereas others act indirectly by modulating the host defense systems. Against a background of rapidly increasing resistance development to conventional antibiotics all over the world, efforts to bring AMPs into clinical use are accelerating. Several AMPs are currently being evaluated in clinical trials as novel anti-infectives, but also as new pharmacological agents to modulate the immune response, promote wound healing, and prevent post-surgical adhesions. In this review, we provide an overview of the biological role, classification, and mode of action of AMPs, discuss the opportunities and challenges to develop these peptides for clinical applications, and review the innovative formulation strategies for application of AMPs. PMID- 28083517 TI - Sterol Regulatory Element-Binding Protein-1c Regulates Inflammasome Activation in Gingival Fibroblasts Infected with High-Glucose-Treated Porphyromonas gingivalis. AB - Background:Porphyromonas gingivalis is a major bacterial species implicated in the progression of periodontal disease, which is recognized as a common complication of diabetes. The interleukin (IL)-1beta, processed by the NLR family pyrin domain containing 3 (NLRP3) inflammasome, has been identified as a target for pathogenic infection of the inflammatory response. However, the effect of P. gingivalis in a high-glucose situation in the modulation of inflammasome activation in human gingival fibroblasts (HGFs) is not well-understood. Methods:P. gingivalis strain CCUG25226 was used to study the mechanisms underlying the regulation of HGF NLRP3 expression by the infection of high glucose-treated P. gingivalis (HGPg). Results: HGF infection with HGPg increases the expression of IL-1beta and NLRP3. We further demonstrated that the upregulation of sterol regulatory element-binding protein (SREBP)-1c by activation of the Akt and p70S6K pathways is critical for HGPg-induced NLRP3 expression. We showed that the inhibition of Janus kinase 2 (JAK2) blocks the Akt and p70S6K-mediated SREBP-1c, NLRP3, and IL-1beta expression. The effect of HGPg on HGF signaling and NLRP3 expression is mediated by beta1 integrin. In addition, gingival tissues from diabetic patients with periodontal disease exhibited higher NLRP3 and SREBP-1c expression. Conclusions: Our findings identify the molecular pathways underlying HGPg-dependent NLRP3 inflammasome expression in HGFs, providing insight into the effect of P. gingivalis invasion in HGFs. PMID- 28083518 TI - Identification of Aeromonas hydrophila Genes Preferentially Expressed after Phagocytosis by Tetrahymena and Involvement of Methionine Sulfoxide Reductases. AB - Free-living protozoa affect the survival and virulence evolution of pathogens in the environment. In this study, we explored the fate of Aeromonas hydrophila when co-cultured with the bacteriovorous ciliate Tetrahymena thermophila and investigated bacterial gene expression associated with the co-culture. Virulent A. hydrophila strains were found to have ability to evade digestion in the vacuoles of this protozoan. In A. hydrophila, a total of 116 genes were identified as up-regulated following co-culture with T. thermophila by selective capture of transcribed sequences (SCOTS) and comparative dot-blot analysis. A large proportion of these genes (42/116) play a role in metabolism, and some of the genes have previously been characterized as required for bacterial survival and replication within macrophages. Then, we inactivated the genes encoding methionine sulfoxide reductases, msrA, and msrB, in A. hydrophila. Compared to the wild-type, the mutants DeltamsrA and DeltamsrAB displayed significantly reduced resistance to predation by T. thermophila, and 50% lethal dose (LD50) determinations in zebrafish demonstrated that both mutants were highly attenuated. This study forms a solid foundation for the study of mechanisms and implications of bacterial defenses. PMID- 28083519 TI - Staphylococcus aureus Lpl Lipoproteins Delay G2/M Phase Transition in HeLa Cells. AB - The cell cycle is an ordered set of events, leading to cell growth and division into two daughter cells. The eukaryotic cell cycle consists of interphase (G1, S, and G2 phases), followed by the mitotic phase and G0 phase. Many bacterial pathogens secrete cyclomodulins that interfere with the host cell cycle. In Staphylococcus aureus four cyclomodulins have been described so far that all represent toxins and are secreted into the culture supernatant. Here we show that the membrane-anchored lipoprotein-like proteins (Lpl), encoded on a genomic island called nuSaalpha, interact with the cell cycle of HeLa cells. By comparing wild type and lpl deletion mutant it turned out that the lpl cluster is causative for the G2/M phase transition delay and also contributes to increased invasion frequency. The lipoprotein Lpl1, a representative of the lpl cluster, also caused G2/M phase transition delay. Interestingly, the lipid modification, which is essential for TLR2 signaling and activation of the immune system, is not necessary for cyclomodulin activity. Unlike the other staphylococcal cyclomodulins Lpl1 shows no cytotoxicity even at high concentrations. As all Lpl proteins are highly conserved there might be a common function that is accentuated by their multiplicity in a tandem gene cluster. The cell surface localized Lpls' suggests a correlation between G2/M phase transition delay and host cell invasion. PMID- 28083521 TI - Participatory Action Research in the Field of Neonatal Intensive Care: Developing an Intervention to Meet the Fathers' Needs. A Case Study. AB - BACKGROUND: In neonatal intensive care units (NICUs) health care professionals typically give most of their attention to the infants and the mothers while many fathers feel uncertain and have an unmet need for support and guidance. This paper describes and discusses participatory action research (PAR) as a method to improve NICUs' service for fathers. Our goal is to develop a father-friendly NICU where both the needs of fathers and mothers are met using an approach based on PAR that involves fathers, mothers, interdisciplinary healthcare professionals, and managers. DESIGN AND METHODS: This PAR process was carried out from August 2011 to July 2013 and included participant observations, semi-structured interviews, multi sequential interviews, workshops, focus groups, group discussion, and a seminar. The theoretical framework of validity described by Herr and Anderson's three criteria; process-, democratic-, and catalytic validity were used to discuss this PAR. RESULTS: Twelve fathers, 11 mothers, 48 health professionals and managers participated in the PAR process. The collaboration ensured the engagement for viable and constructive local changes to be used in designing the concept of the father friendly NICU. CONCLUSIONS: This paper contributed new knowledge of how PAR can be used to ensure that participants engaged in the field are involved in the entire process; consequently, this will ensure that the changes are feasible and sustainable. PMID- 28083520 TI - Prevalence of Diabetes in the 2009 Influenza A (H1N1) and the Middle East Respiratory Syndrome Coronavirus: A Systematic Review and Meta-Analysis. AB - Over the past two decades a number of severe acute respiratory infection outbreaks such as the 2009 influenza A (H1N1) and the Middle East respiratory syndrome coronavirus (MERS-CoV) have emerged and presented a considerable global public health threat. Epidemiologic evidence suggests that diabetic subjects are more susceptible to these conditions. However, the prevalence of diabetes in H1N1 and MERS-CoV has not been systematically described. The aim of this study is to conduct a systematic review and meta-analysis of published reports documenting the prevalence of diabetes in H1N1 and MERS-CoV and compare its frequency in the two viral conditions. Meta-analysis for the proportions of subjects with diabetes was carried out in 29 studies for H1N1 (n=92,948) and 9 for MERS-CoV (n=308). Average age of H1N1 patients (36.2+/-6.0 years) was significantly younger than that of subjects with MERS-CoV (54.3+/-7.4 years, P<0.05). Compared to MERS-CoV patients, subjects with H1N1 exhibited 3-fold lower frequency of cardiovascular diseases and 2- and 4-fold higher prevalence of obesity and immunosuppression, respectively. The overall prevalence of diabetes in H1N1 was 14.6% (95% CI: 12.3 17.0%; P<0.001), a 3.6-fold lower than in MERS-CoV (54.4%; 95% CI: 29.4-79.5; P<0.001). The prevalence of diabetes among H1N1 cases from Asia and North America was ~two-fold higher than those from South America and Europe. The prevalence of diabetes in MERS-CoV cases is higher than in H1N1. Regional comparisons suggest that an etiologic role of diabetes in MERS-CoV may exist distinctive from that in H1N1. PMID- 28083522 TI - Monitoring Polypharmacy in Healthcare Systems Through a Multi-Setting Survey: Should We Put More Attention on Long Term Care Facilities? AB - BACKGROUND: Polypharmacy is a main issue of patient safety in all healthcare settings (i.e. increase adverse drug reactions and incidence of drug-drug interactions, etc.). The main object of the study was to evaluate the prevalence of polypharmacy and the appropriateness of drugs prescriptions in the regional health system (RHS) of Friuli Venezia-Giulia Region, Italy. DESIGN AND METHODS: We carried out a point prevalence study in May 2014; 1582 patients >=65 years were included from: 14 acute hospitals, 46 Long Term Care Facilities (LTCFs) and 42 general practitioners' (GPs) clinics. Data analysis included the evaluation of potentially inappropriate prescriptions (PIPs) taking Beers criteria as a reference. RESULTS: Patients in therapy with 10 drugs or more were 13.5%: 15.2% in hospitals, 9.7% in GPs' clinics and 15.6% in LTCFs. According to Beers criteria we identified 1152 PIPs that involved globally almost half of patients (46.0%): 41.9% in hospitals, 59.6% in LTCFs and 37.0% in GP's clinics. The 53.9% of patients received at least one mainly kidney excreted drug; for these patients the evaluation of serum creatinine was overall present in the 87.7% (747/852): 96.4% in hospital ones, 87.5% in GPs' clinics and 77.8% in LTCFs. LTCFs residents were significantly (P<0.05) more exposed to PIPs and less monitored for the renal function. CONCLUSIONS: A reliable estimation of the phenomenon in all the main healthcare settings is a necessary prerequisite to set tailored policies for facing polypharmacy within a RHS; the results showed the necessity to put a special attention on LTCFs. PMID- 28083524 TI - Are Food Labels Effective as a Means of Health Prevention? AB - Chronic diseases related to unbalanced and unhealthy eating habits have definitely become one of the major issues of modern age, not only in western countries but also in those ones where rapid economic growth has increased global prosperity levels. In order to avoid medical systems to collapse under excessive costs, International and Public Organizations strongly support health policies that aim to make people shift towards wholesome dietary patterns, also encouraging the use of food-labels to choose healthier products. To evaluate the consumers' knowledge and perception about food-labels a brief questionnaire was developed and shared on Facebook between January-March 2016. Most of the participants were young adults with higher education. They declared to do their shopping at least once a week, reading the food-labels quite often. Despite owing limited knowledge in basic nutrition principles and food-labelling they were generally able to recognize healthier products looking over their nutritional fact tables. Anyway, on average, what they care the most about the products they purchase is the global quality level rather than the nutritional values. In order to induce the whole population to use food label as an effective self-protection tool, more efforts should be done to improve their knowledge on nutrition fundamentals and basics about food labelling, because that would make them able to take safer and more conscious choices as regards their own health. PMID- 28083523 TI - Intentional and Unintentional Medication Non-Adherence in Hypertension: The Role of Health Literacy, Empowerment and Medication Beliefs. AB - BACKGROUND: Medication non-adherence is a major public health issue, creating obstacles to effective treatment of hypertension. Examining the underlying factors of deliberate and non-deliberate non-adherence is crucial to address this problem. Thus, the goal of the present study is to assess the socio-demographic, clinical and psychological determinants of intentional and unintentional non adherence. DESIGN AND METHODS: A cross-sectional survey was conducted between March, 2015 and April, 2016. The sample consisted of hypertension patients holding at least one medical prescription (N=109). Measurements assessed patients' medication adherence, health literacy, empowerment, self-efficacy, medication beliefs, and patients' acceptance of their doctor's advice, socio demographic and clinical characteristics. RESULTS: Patients who occasionally engaged in either intentional or unintentional non-adherence reported to have lower adherence selfefficacy, higher medication concern beliefs, lower meaningfulness scores and were less likely to accept the doctor's treatment recommendations. Patients who occasionally engaged in unintentional nonadherence were younger and had experienced more side effects compared to completely adherent patients. Adherence self-efficacy was a mediator of the effect of health literacy on patients' medication adherence and acceptance of the doctor's advice was a covariate. CONCLUSIONS: Regarding the research implications, health literacy and adherence self-efficacy should be assessed simultaneously when investigating the factors of non-adherence. Regarding the practical implications, adherence could be increased if physicians i) doublecheck whether their patients accept the treatment advice given and ii) if they address patients' concerns about medications. These steps could be especially important for patients characterized with lower self-efficacy, as they are more likely to engage in occasional nonadherence. PMID- 28083525 TI - Occurrence and Control of Genotoxins in Drinking Water: A Monitoring Proposal. AB - Many studies have shown the presence of numerous organic genotoxins and carcinogens in drinking water. These toxic substances derive not only from pollution, but also from the disinfection treatments, particularly when water is obtained from surface sources and then chlorinated. Most of the chlorinated compounds in drinking water are nonvolatile and are difficult to characterize. Thus, it has been proposed to study such complex mixtures using short-term genotoxicity tests predictive of carcinogenic activity. Mutagenicity of water before and after disinfection has mainly been studied by the Salmonella/microsome (Ames test); in vitro genotoxicity tests have also been performed in yeasts and mammalian cells; in situ monitoring of genotoxins has also been performed using complete organisms such as aquatic animals or plants (in vivo). The combination of bioassay data together with results of chemical analyses would give us a more firm basis for the assessment of human health risks related to the consumption of drinking water. Tests with different genetic end-points complement each other with regard to sensitivity toward environmental genotoxins and are useful in detecting low genotoxicity levels which are expected in drinking water samples. PMID- 28083526 TI - Intestinal Bacterial Colonization in the First 2 Weeks of Life of Nigerian Neonates Using Standard Culture Methods. AB - OBJECTIVE: The pattern and timing of development of intestinal microflora in Nigerian infants have been scarcely researched. This study was carried out to investigate the bacteria flora in the rectum of healthy neonates in Ibadan, Nigeria. PATIENTS AND METHODS: In this hospital-based longitudinal study, rectal swabs of 70 neonates were taken within 6-12 h of birth (day 1) and subsequently on days 3, 9, and 14. Information collected included maternal sociodemographic characteristics, antibiotic use for the neonates, and type of feeding during the first 14 days of life. Identification and speciation of gram-negative isolates were done using the Analytical Profile Index 20E(r) and 20NE(r) as appropriate. Gram-positive bacteria were identified biochemically using the catalase and coagulase tests. Data were analyzed using descriptive statistics and Chi-square at p = 0.05. RESULTS: Majority (92.9%) of the neonates were delivered vaginally with a median gestational age of 38 weeks (range = 34-42). On the first day of life, Escherichia coli was isolated more frequently from the rectal swabs of preterm (50.0%) than term (23.1%) neonates (p = 0.031). On day 3 of life, coagulase-negative staphylococcus was the most frequently isolated bacteria from the rectal swabs of nonasphyxiated (64.4%) compared with asphyxiated (27.3%) neonates' rectal swabs (p = 0.042). Staphylococcus aureus was the most frequently isolated bacteria from the rectal swabs of nonexclusively breastfed (66.7%) than exclusively breastfed (21.3%) neonates on day 14 (p = 0.004). CONCLUSION: Staphylococcus aureus and Escherichia coli were the predominant isolates from the rectum of Nigerian neonates, and these isolates were influenced by breastfeeding and mild-moderate asphyxia. In all, bacterial diversity in the rectum increased as the neonates got older. PMID- 28083528 TI - Managers' Compensation in a Mixed Ownership Industry: Evidence from Nursing Homes. AB - An extensive literature is devoted to differences between for-profit and non profit health-care providers' prices, utilization, and quality. Less is known about for-profit and non-profit managers' compensation and its relationship with financial and quality performance. The aim of this study is to examine whether for-profit and non-profit nursing homes place differential weights on financial and quality performance in determining managers' compensation. Using a unique 8 year dataset on Ohio nursing homes, fixed-effect regression models of managers' compensation include financial and quality performance as well as other explanatory variables concerning firm and market characteristics and manager qualifications. Among for-profit nursing homes, compensation of owner-managers and non-owner managers are compared. Compensation of for-profit managers is significantly positively associated with profit margin and return-on-assets, while compensation of non-profit managers does not exhibit any consistent relationship with financial measures. Compensation of neither for-profit nor non profit managers is significantly related to quality measures. Nursing home size and managers' years of experience are the only consistent determinants of compensation. Owner-managers earn significantly higher compensation than non owner managers and their compensation is less related to nursing home performance. Finding that home size and experience are strong determinants of compensation, and the association with ownership and financial performance for for-profit nursing homes are as expected. The insignificant relationship between compensation and quality performance is potentially troublesome. PMID- 28083529 TI - Editorial: Public Mental Health Policy, Mental Health Promotion, and Interventions Which Focus on the Social Determinants of Mental Health. PMID- 28083527 TI - Mechanotransduction as an Adaptation to Gravity. AB - Gravity has played a critical role in the development of terrestrial life. A key event in evolution has been the development of mechanisms to sense and transduce gravitational force into biological signals. The objective of this manuscript is to review how living organisms on Earth use mechanotransduction as an adaptation to gravity. Certain cells have evolved specialized structures, such as otoliths in hair cells of the inner ear and statoliths in plants, to respond directly to the force of gravity. By conducting studies in the reduced gravity of spaceflight (microgravity) or simulating microgravity in the laboratory, we have gained insights into how gravity might have changed life on Earth. We review how microgravity affects prokaryotic and eukaryotic cells at the cellular and molecular levels. Genomic studies in yeast have identified changes in genes involved in budding, cell polarity, and cell separation regulated by Ras, PI3K, and TOR signaling pathways. Moreover, transcriptomic analysis of late pregnant rats have revealed that microgravity affects genes that regulate circadian clocks, activate mechanotransduction pathways, and induce changes in immune response, metabolism, and cells proliferation. Importantly, these studies identified genes that modify chromatin structure and methylation, suggesting that long-term adaptation to gravity may be mediated by epigenetic modifications. Given that gravity represents a modification in mechanical stresses encounter by the cells, the tensegrity model of cytoskeletal architecture provides an excellent paradigm to explain how changes in the balance of forces, which are transmitted across transmembrane receptors and cytoskeleton, can influence intracellular signaling pathways and gene expression. PMID- 28083531 TI - Pulse Shape and Timing Dependence on the Spike-Timing Dependent Plasticity Response of Ion-Conducting Memristors as Synapses. AB - Ion-conducting memristors comprised of the layered materials Ge2Se3/SnSe/Ag are promising candidates for neuromorphic computing applications. Here, the spike timing dependent plasticity (STDP) application is demonstrated for the first time with a single memristor type operating as a synapse over a timescale of 10 orders of magnitude, from nanoseconds through seconds. This large dynamic range allows the memristors to be useful in applications that require slow biological times, as well as fast times such as needed in neuromorphic computing, thus allowing multiple functions in one design for one memristor type-a "one size fits all" approach. This work also investigated the effects of varying the spike pulse shapes on the STDP response of the memristors. These results showed that small changes in the pre- and postsynaptic pulse shape can have a significant impact on the STDP. These results may provide circuit designers with insights into how pulse shape affects the actual memristor STDP response and aid them in the design of neuromorphic circuits and systems that can take advantage of certain features in the memristor STDP response that are programmable via the pre- and postsynaptic pulse shapes. In addition, the energy requirement per memristor is approximated based on the pulse shape and timing responses. The energy requirement estimated per memristor operating on slower biological timescales (milliseconds to seconds) is larger (nanojoules range), as expected, than the faster (nanoseconds) operating times (~0.1 pJ in some cases). Lastly, the memristors responded in a similar manner under normal STDP conditions (pre- and post-spikes applied to opposite memristor terminals) as they did to the case where a waveform corresponding to the difference between pre- and post-spikes was applied to only one electrode, with the other electrode held at ground potential. By applying the difference signal to only one terminal, testing of the memristor in various applications can be achieved with a simplified test set-up, and thus be easier to accomplish in most laboratories. PMID- 28083530 TI - Toward Multiscale Models of Cyanobacterial Growth: A Modular Approach. AB - Oxygenic photosynthesis dominates global primary productivity ever since its evolution more than three billion years ago. While many aspects of phototrophic growth are well understood, it remains a considerable challenge to elucidate the manifold dependencies and interconnections between the diverse cellular processes that together facilitate the synthesis of new cells. Phototrophic growth involves the coordinated action of several layers of cellular functioning, ranging from the photosynthetic light reactions and the electron transport chain, to carbon concentrating mechanisms and the assimilation of inorganic carbon. It requires the synthesis of new building blocks by cellular metabolism, protection against excessive light, as well as diurnal regulation by a circadian clock and the orchestration of gene expression and cell division. Computational modeling allows us to quantitatively describe these cellular functions and processes relevant for phototrophic growth. As yet, however, computational models are mostly confined to the inner workings of individual cellular processes, rather than describing the manifold interactions between them in the context of a living cell. Using cyanobacteria as model organisms, this contribution seeks to summarize existing computational models that are relevant to describe phototrophic growth and seeks to outline their interactions and dependencies. Our ultimate aim is to understand cellular functioning and growth as the outcome of a coordinated operation of diverse yet interconnected cellular processes. PMID- 28083532 TI - CD24: A Rheostat That Modulates Cell Surface Receptor Signaling of Diverse Receptors. PMID- 28083533 TI - Inactivation of Sonic Hedgehog Signaling and Polydactyly in Limbs of Hereditary Multiple Malformation, a Novel Type of Talpid Mutant. AB - Hereditary Multiple Malformation (HMM) is a naturally occurring, autosomal recessive, homozygous lethal mutation found in Japanese quail. Homozygote embryos (hmm-/-) show polydactyly similar to talpid2 and talpid3 mutants. Here we characterize the molecular profile of the hmm-/- limb bud and identify the cellular mechanisms that cause its polydactyly. The hmm-/- limb bud shows a severe lack of sonic hedgehog (SHH) signaling, and the autopod has 4 to 11 unidentifiable digits with syn-, poly-, and brachydactyly. The Zone of Polarizing Activity (ZPA) of the hmm-/- limb bud does not show polarizing activity regardless of the presence of SHH protein, indicating that either the secretion pathway of SHH is defective or the SHH protein is dysfunctional. Furthermore, mesenchymal cells in the hmm-/- limb bud do not respond to ZPA transplanted from the normal limb bud, suggesting that signal transduction downstream of SHH is also defective. Since primary cilia are present in the hmm-/- limb bud, the causal gene must be different from talpid2 and talpid3. In the hmm-/- limb bud, a high amount of GLI3A protein is expressed and GLI3 protein is localized to the nucleus. Our results suggest that the regulatory mechanism of GLI3 is disorganized in the hmm-/- limb bud. PMID- 28083534 TI - The Efficacy of Triamcinolone Acetonide in Keloid Treatment: A Systematic Review and Meta-analysis. AB - Keloid is a cutaneous dermal outgrowth resulting from uncontrolled deposition of collagen and glycosaminoglycan around the wound. The uncontrolled and persistent growth of keloids scar will result in cosmetic disfigurement, functional impairment, and affect the quality of life. Triamcinolone acetonide (TAC) is traditionally employed in treating keloid scars. In this study, we aim to evaluate the effectiveness of TAC and compare it with other common therapy employed in keloid treatment. Only randomized controlled trial (RCT) and controlled trial were included. Inverse variance risk ratio, weighted mean difference, and corresponding 95% confidence intervals were calculated to evaluate the effect of intervention. Meta-analysis indicated that TAC treatment significantly reduced the size of keloid compared to untreated control. Reduction in size was statistically different in favor of TAC compared to silicone gel sheet. Significant difference in favor of TAC was observed compared with verapamil in term of vascularity and scar pliability. TAC treatment was more effective in reducing scar thickness in comparison with cryotherapy. However, the current meta-analysis has several limitations. Only a limited number of trials with the same comparison are available. Most trials recruited a small number of patients and used inconsistent outcome assessment. Most trials did not provide detail information on allocation concealment and blinding. Therefore, further evaluation in multi-center RCTs with consistent comparisons and outcome measurements are warrant to reach a consensus on the selection between TAC and different treatment modalities. PMID- 28083535 TI - Sundowning in Dementia: Clinical Relevance, Pathophysiological Determinants, and Therapeutic Approaches. AB - Sundowning means the emergence or worsening of neuropsychiatric symptoms (NPS) in the late afternoon or early evening. This syndrome has been recognized since a long time in the field of dementing illnesses and is well known among most of health-care providers involved in the assistance of people with dementia. Indeed, it represents a common manifestation among persons with dementia and is associated with several adverse outcomes (such as institutionalization, faster cognitive worsening, and greater caregiver burden). Its occurrence and phenotypic characteristics may be influenced by diverse neurobiological, psychosocial, and environmental determinants. Moreover, it may pose diagnostic challenges in relation to other common causes of behavioral disruptions. Beside these considerations, this phenomenon has so far drawn limited clinical and scientific interest compared to other specific NPS occurring in dementias, as indicated by the lack of commonly agreed definitions, specific screening/assessment tools, and robust estimates on its prevalence. Accordingly, no randomized controlled trial specifically investigating the effectiveness of pharmacological and non pharmacological strategies in managing this condition among demented patients has been yet conducted. In the present narrative review, we present and discuss available evidence concerning sundowning occurring in people with dementia. A special focus is given to its definitions, pathophysiological determinants, and clinical relevance, as well as to the clinical and therapeutic approaches required for its management in the daily practice. PMID- 28083536 TI - Conformational Rigidity within Plasticity Promotes Differential Target Recognition of Nerve Growth Factor. AB - Nerve Growth Factor (NGF), the prototype of the neurotrophin family, is essential for maintenance and growth of different neuronal populations. The X-ray crystal structure of NGF has been known since the early '90s and shows a beta-sandwich fold with extensive loops that are involved in the interaction with its binding partners. Understanding the dynamical properties of these loops is thus important for molecular recognition. We present here a combined solution NMR/molecular dynamics study which addresses the question of whether and how much the long loops of NGF are flexible and describes the N-terminal intrinsic conformational tendency of the unbound NGF molecule. NMR titration experiments allowed identification of a previously undetected epitope of the anti-NGF antagonist antibody alphaD11 which will be of crucial importance for future drug lead discovery. The present study thus recapitulates all the available structural information and unveils the conformational versatility of the relatively rigid NGF loops upon functional ligand binding. PMID- 28083538 TI - Educational Possibilities of Keeping Goats in Elementary Schools in Japan. AB - Many Japanese elementary schools keep small animals for educational purposes, and the effects and challenges have been investigated. Although goats are medium sized animals that are familiar to Japanese, few practical studies have been conducted on keeping goats in schools. This study investigated the effects and challenges of keeping goats in elementary schools and discussed its educational possibilities. A semi-structured interview survey was conducted with 11 personnel that were responsible for keeping goats in 6 elementary schools in urban areas. They described benefits, problems, and tips related to keeping goats. Participant observation was also conducted on daily human-goat interactions in these schools. The results indicated that children in all six grades were able to care for goats. Goats were used for various school subjects and activities. As a result of keeping goats, children developed affection for them, attitude of respect for living things, greater sense of responsibility, and enhanced interpersonal interactional skills. Stronger ties between the schools and parents and community were developed through cooperation in goat-keeping. Some anxieties existed about the risk of injury to children when interacting with goats. Other challenges included the burden of taking care of the goats on holidays and insufficient knowledge about treatment in case of their illness or injury. The results suggested similarities to the benefits and challenges associated with keeping small animals in elementary schools, although the responsibility and the burden on the schools were greater for keeping goats than small animals because of their larger size and the need for children to consider the goats' inner state and to cooperate with others when providing care. At the same time, goats greatly stimulated interest, cooperation, and empathy in children. Goats can expand educational opportunities and bring about many positive effects on child development. PMID- 28083537 TI - Comparative Normal Mode Analysis of the Dynamics of DENV and ZIKV Capsids. AB - Key steps in the life cycle of a virus, such as the fusion event as the virus infects a host cell and its maturation process, relate to an intricate interplay between the structure and the dynamics of its constituent proteins, especially those that define its capsid, much akin to an envelope that protects its genomic material. We present a comprehensive, comparative analysis of such interplay for the capsids of two viruses from the flaviviridae family, Dengue (DENV) and Zika (ZIKV). We use for that purpose our own software suite, DD-NMA, which is based on normal mode analysis. We describe the elements of DD-NMA that are relevant to the analysis of large systems, such as virus capsids. In particular, we introduce our implementation of simplified elastic networks and justify their parametrization. Using DD-NMA, we illustrate the importance of packing interactions within the virus capsids on the dynamics of the E proteins of DENV and ZIKV. We identify differences between the computed atomic fluctuations of the E proteins in DENV and ZIKV and relate those differences to changes observed in their high resolution structures. We conclude with a discussion on additional analyses that are needed to fully characterize the dynamics of the two viruses. PMID- 28083539 TI - Antiproliferative Effects of Oxytocin and Desmopressin on Canine Mammary Cancer Cells. AB - Neoplasms of the mammary gland represent the most frequent tumor type in the female dog, and according to the histologic criteria, approximately 50% of them are malignant. In the most aggressive cases of mammary cancer, surgery is not enough to warrant a favorable outcome, and adjuvant therapies are needed to improve the patient's overall survival. The aim of the present study was to evaluate the effects of two peptides on proliferation of a canine mammary cancer cell line derived from a simple carcinoma. The cell line CMT-U27 was grown in 96 well plates, at two cell densities (4 * 103 and 8 * 103 cells/well). Cultures were treated with oxytocin (OT) or desmopressin at five concentrations (10, 50, 100, 500, and 1000 nM). After 72 h of incubation, cell proliferation was determined by the MTT assay. Results showed that with 4 * 103 cells/well, OT at 50, 500, and 1000 nM was growth inhibitory for the cells, being statistically significant at 1000 nM. On the contrary, no antiproliferative effect was observed with 10 or 100 nM. At 8 * 103 cells/well, OT showed a significant antiproliferative effect only with the highest concentration (1000 nM). Desmopressin at 4 * 103 cells/well decreased cell viability at concentrations of 50, 100, 500, and 1000 nM (statistically significant with the highest concentration), while no effect was observed with 10 nM. With 8 * 103 cells/well, this peptide reduced cell growth at 100, 500, and 1000 nM. In conclusion, we suggest that these peptides may be potential and promising compounds for the treatment of dogs with simple carcinomas of the mammary gland. In vivo studies are required to confirm this hypothesis. PMID- 28083540 TI - Identification of Alternative Variants and Insertion of the Novel Polymorphic AluYl17 in TSEN54 Gene during Primate Evolution. AB - TSEN54 encodes a subunit of the tRNA-splicing endonuclease complex, which catalyzes the identification and cleavage of introns from precursor tRNAs. Previously, we identified an AluSx-derived alternative transcript in TSEN54 of cynomolgus monkey. Reverse transcription-polymerase chain reaction (RT-PCR) amplification and TSEN54 sequence analysis of primate and human samples identified five novel alternative transcripts, including the AluSx exonized transcript. Additionally, we performed comparative expression analysis via RT qPCR in various cynomolgus, rhesus monkey, and human tissues. RT-qPCR amplification revealed differential expression patterns. Furthermore, genomic PCR amplification and sequencing of primate and human DNA samples revealed that AluSx elements were integrated in human and all of the primate samples tested. Intriguingly, in langur genomic DNA, an additional AluY element was inserted into AluSx of intron eight of TSEN54. The new AluY element showed polymorphic insertion. Using standardized nomenclature for Alu repeats, the polymorphic AluY of the langur TSEN54 was designated as being of the AluYl17 subfamily. Our results suggest that integration of the AluSx element in TSEN54 contributed to diversity in transcripts and induced lineage- or species-specific evolutionary events such as alternative splicing and polymorphic insertion during primate evolution. PMID- 28083541 TI - Localized holes and delocalized electrons in photoexcited inorganic perovskites: Watching each atomic actor by picosecond X-ray absorption spectroscopy. AB - We report on an element-selective study of the fate of charge carriers in photoexcited inorganic CsPbBr3 and CsPb(ClBr)3 perovskite nanocrystals in toluene solutions using time-resolved X-ray absorption spectroscopy with 80 ps time resolution. Probing the Br K-edge, the Pb L3-edge, and the Cs L2-edge, we find that holes in the valence band are localized at Br atoms, forming small polarons, while electrons appear as delocalized in the conduction band. No signature of either electronic or structural changes is observed at the Cs L2-edge. The results at the Br and Pb edges suggest the existence of a weakly localized exciton, while the absence of signatures at the Cs edge indicates that the Cs+ cation plays no role in the charge transport, at least beyond 80 ps. This first, time-resolved element-specific study of perovskites helps understand the rather modest charge carrier mobilities in these materials. PMID- 28083543 TI - A general method for baseline-removal in ultrafast electron powder diffraction data using the dual-tree complex wavelet transform. AB - The general problem of background subtraction in ultrafast electron powder diffraction (UEPD) is presented with a focus on the diffraction patterns obtained from materials of moderately complex structure which contain many overlapping peaks and effectively no scattering vector regions that can be considered exclusively background. We compare the performance of background subtraction algorithms based on discrete and dual-tree complex (DTCWT) wavelet transforms when applied to simulated UEPD data on the M1-R phase transition in VO2 with a time-varying background. We find that the DTCWT approach is capable of extracting intensities that are accurate to better than 2% across the whole range of scattering vector simulated, effectively independent of delay time. A Python package is available. PMID- 28083542 TI - Structural enzymology using X-ray free electron lasers. AB - Mix-and-inject serial crystallography (MISC) is a technique designed to image enzyme catalyzed reactions in which small protein crystals are mixed with a substrate just prior to being probed by an X-ray pulse. This approach offers several advantages over flow cell studies. It provides (i) room temperature structures at near atomic resolution, (ii) time resolution ranging from microseconds to seconds, and (iii) convenient reaction initiation. It outruns radiation damage by using femtosecond X-ray pulses allowing damage and chemistry to be separated. Here, we demonstrate that MISC is feasible at an X-ray free electron laser by studying the reaction of M. tuberculosis beta-lactamase microcrystals with ceftriaxone antibiotic solution. Electron density maps of the apo-beta-lactamase and of the ceftriaxone bound form were obtained at 2.8 A and 2.4 A resolution, respectively. These results pave the way to study cyclic and non-cyclic reactions and represent a new field of time-resolved structural dynamics for numerous substrate-triggered biological reactions. PMID- 28083544 TI - Adolescents' Internalizing Symptoms as Predictors of the Content of Their Facebook Communication and Responses Received from Peers. AB - This research examined how adolescents' internalizing symptoms, such as depression, anxiety, and loneliness, relate to the content of their Facebook communication and the responses they receive from peers on Facebook. Participants (n = 125, 56 female, age 18) reported on their internalizing symptoms in the summer following 12th grade, and downloaded an application to their Facebook account that stored the content of all of their Facebook communication to secure, online archive. Two months of participants' status updates and comments and peers' comments were coded for content. Relations between internalizing symptoms and Facebook communication differed for girls and boys. For girls, internalizing symptoms predicted several types of Facebook content: negative affect, somatic complaints and eliciting support. In contrast, internalizing symptoms were not related to boys' Facebook posts. Relations between internalizing symptoms and peers' responses on Facebook also differed by gender. For girls, internalizing symptoms positively predicted receiving more peer comments expressing negative affect, and peer responses offering support. For boys, internalizing symptoms did not predict any of the measured peer responses. These findings suggest that girls prone to internalizing symptoms use Facebook in ways that appear similar to co rumination, by expressing problems to friends and receive possibly reinforcing feedback in return. PMID- 28083545 TI - Youth-Targeted E-cigarette Marketing in the US. AB - OBJECTIVES: The purpose of this project was to explore the extent to which e cigarette advertisements use youth-appealing content. METHODS: A sample of e cigarette video ads (N = 154) were coded by 3 independent coders using the content appealing to youth (CAY) index, which measures over 40 youth-appealing features. To calculate a total CAY score for each ad, scores were normalized and summed such that a higher score represented the presence of more youth-appealing elements. RESULTS: All ads included some youth-appealing content, with frequent use of emotional appeals, including happiness (68%), friendship (41%), sex (24%), and success (24%). Over half featured animation. However, product appeals, known to be disliked by youth, were also prevalent. Eighty-seven percent used a direct appeal to e-cigarettes' value over tobacco cigarettes; 66% mentioned product composition; and 40% mentioned health. CONCLUSIONS: Given the unregulated context in the US, e-cigarette marketing currently contains many features that may be particularly appealing to youth. PMID- 28083546 TI - Special Issue on Global Health Disparities Focus on Cancer. AB - Haeok Lee, PhD, RN, FAAN who is a Korean-American nurse scientist, received her doctor al degree from the Nursing Physiology Department, College of Nursing, University of California, San Francisco (UCSF), in 1993, and her post doctor al training from College of Medicine, UCSF. Dr. Lee worked at Case Western Reserve University and University of Colorado Health Sciences Center. She has worked at the UMass Boston since 2008. Dr. Lee has established a long-term commitment to minority health, especially Asian American Pacific Islanders, as a community leader, community health educator, and community researcher, and all these services have become a foundation for her community-based participatory research. Dr. Lee's research addresses current health problems framed in the context of social, political, and economic settings, and her studies have improved racial and ethnic data and developed national health policies to address health disparities in hepatitis B virus (HBV) infections and liver cancer among minorities. Dr. Lee's research, which is noteworthy for its theoretical base, is clearly filling the gap. Especially, Dr. Lee's research is beginning to have a favorable impact on national and international health policies and continuing education programs directed toward the global elimination of cervical and liver cancer-related health disparities in underserved and understudied populations. PMID- 28083547 TI - Independent Clinical Research May Alleviate Disparities in Cancer Treatment. AB - Disparities in cancer care are a reality of the modern world. Unfortunately, current clinical research is in the hands of for-profit pharmaceutical companies and of researchers from the developed world. Problems specific to cancer care in developing countries and among deprivileged populations are ignored. Independent clinical research can offer new valuable knowledge and identify affordable and cost-effective treatments. As such, research not depending on commercial sponsors should become one of the important avenues to alleviate the problem of cancer disparities. PMID- 28083548 TI - Global Perspectives on Cancer Health Disparities: Impact, Utility, and Implications for Cancer Nursing. AB - This paper examines cancer health disparities and contributing factors at national, regional, and international levels. The authors all live in different countries and regions with different health-care systems and practices. Despite the shared cancer nursing perspective, each country or global region approaches cancer disparities differently. With globalization the world is becoming smaller, and in turn becoming interconnected and interdependent. This article focuses on cancer health disparities and global cancer nursing, exemplifying these concepts about the impact and implications of person-centered care. PMID- 28083549 TI - Correlates of Hepatitis B Virus-related Stigmatization Experienced by Asians: A Scoping Review of Literature. AB - OBJECTIVE: Although remarkable progress in the pharmacological components of the prevention and treatment of hepatitis B virus (HBV) and liver cancer has been achieved, HBV-related stigma is recognized as a major barrier to HBV management. The purpose of this Revised Social Network Model (rSNM)-guided review was to examine the existing research literature about HBV-related stigma among Asians and Asian immigrants residing in other countries. METHODS: A scoping review of literature was conducted to determine the depth and breadth of literature. Totally, 21 publications were identified. The review findings were linked with the concepts of rSNM to demonstrate how individual factors and sociocultural contexts shape and affect the experience of HBV-related stigma. RESULTS: Most studies were quantitative cross-sectional surveys or qualitative methods research that had been conducted among Chinese in China and in the USA. The three concepts in rSNM that have been identified as important to stigma experience are individual factors, sociocultural factors, and health behaviors. The major factors of most studies were on knowledge and attitudes toward HBV; only three studies focused on stigma as the primary purpose of the research. Few studies focused on the measurement of stigma, conceptual aspects of stigma, or interventions to alleviate the experience of being stigmatized. CONCLUSIONS: The scoping review revealed the existing depth and breadth of literature about HBV related stigma. Gaps in the literature include lack of research address group specific HBV-related stigma instruments and linkages between stigma and stigma related factors. PMID- 28083550 TI - Health Disparity and Cancer Health Disparity in China. AB - China is one of the largest and most populated countries in the world. It has undergone rapid economic growth in recent years. However, the development is not equitable, and the distribution of wealth significantly varies among the regions in China. Geographical and socioeconomic inequalities, together with the lack of an equitable national social support system, cause the high variance of health outcomes among the regions. Furthermore, the fast growth of the economy has evoked many environmental challenges and puts much pressure on the population. The severe environmental deterioration, especially of the atmosphere and water bodies, has affected the health of the people living in China. As a result, cancer has become a major public health issue, and an alarming increase in incidence and mortality has been reported. However, cancer incidence and mortality vary in different areas in China. Cancer and cancer treatment disparities have existed for years. This article will discuss the existing health and cancer disparities associated with the risk factors and how these disparities are managed in China. PMID- 28083551 TI - Knowledge and Attitudes toward HIV, Hepatitis B Virus, and Hepatitis C Virus Infection among Health-care Workers in Malawi. AB - OBJECTIVE: The highest prevalence of HIV infection occurs in Sub-Saharan Africa and hepatitis B virus (HBV), and hepatitis C virus (HCV) prevalence are the second highest in Sub-Saharan Africa including Malawi. Health-care workers (HCWs) play an important role in the prevention of, response to, and management of these infectious diseases. There is, however, no published research about the level of knowledge and attitudes toward HIV, HBV, and HCV infection among Malawian HCWs. The purpose of this study was to explore and determine the knowledge of and attitudes toward HIV, HBV, and HCV among a targeted population of Malawian HCWs. METHODS: A cross-sectional community-based participatory research with 194 HCWs was completed employing health survey method. The project was a collaborative effort between nursing faculties in the USA and Malawian. A one-way analysis of variance (ANOVA) with the Bonferroni adjustment for multiple comparisons was used to assess the differences in knowledge and attitude among three subgroups of HCWs. RESULTS: Of 194 of Malawian HCWs surveyed, 41% were support staff, 37% were nursing students, and 22% were health-care professionals. Both health-care professionals and support staff had high knowledge scores related to HIV/AIDS, and their attitudes were mainly positive. However, a series of one-way ANOVAs revealed significant differences in knowledge and attitude toward HIV/AIDs, HBV, and HCV among HCWs (P < 0.01). The majority had less knowledge about HBV and HCV and more negative attitudes toward hepatitis. CONCLUSIONS: This study highlights the ongoing need for reducing negative attitudes toward HIV, HBV, and HCV; and providing health education among HCWs, especially focusing on HBV and HCV prevention. The findings of the research project can be used to develop interventions addressing low HBV- and HCV-related knowledge and attitudes. PMID- 28083552 TI - How Quality of Oncology Care and Services be Improved through Leadership and Collaborations: Cross-clusters CQI Program in Hong Kong. PMID- 28083553 TI - Venous Access Devices: Clinical Rounds. AB - Nursing management of venous access devices (VADs) requires knowledge of current evidence, as well as knowledge of when evidence is limited. Do you know which practices we do based on evidence and those that we do based on institutional history or preference? This article will present complex VAD infection and occlusion complications and some of the controversies associated with them. Important strategies for identifying these complications, troubleshooting, and evaluating the evidence related to lack of blood return, malposition, infection, access and maintenance protocols, and scope of practice issues are presented. PMID- 28083554 TI - Genotoxic Monitoring of Nurses Handling Cytotoxic Drugs. AB - OBJECTIVE: Several biomarkers may be used to detect harmful exposure and individual susceptibility to cancer. Monitoring of biomarkers related to exposure may have a significant effect on early detection of cell transformation, thereby aiding the primary prevention of various chronic and malignant diseases. Nurses who handle cytotoxic drugs are exposed to carcinogenic agents, which have the potential to interrupt the cell cycle and to induce chromosomal aberrations. The presence of high chromosomal aberrations indicates the need for intervention even when exposure to these carcinogens is low. METHODS: Nationally representative samples of 552 nurses were investigated by a follow-up monitoring system. The measured biomarkers were clinical laboratory routine tests, completed with genotoxicological (chromosome aberrations [CAs] and sister chromatid exchanges [SCEs]) and immunotoxicological monitoring (ratio of lymphocyte subpopulations and lymphocyte activation markers) measured on peripheral blood lymphocytes. Results were compared to the data of 140 healthy, age-matched controls. RESULTS: In nurses exposed to cytostatics, we observed a significantly increased frequency of CAs and SCEs compared with those in the controls. Cytostatic drug exposure also manifested itself in an increased frequency of helper T lymphocytes. Genotoxicological and immunotoxicological changes, as well as negative health effects (i.e., iron deficiency, anemia, and thyroid diseases), increased among cytostatic exposed subjects. CONCLUSIONS: These results raised concerns about the protection of nursing staff from chemical carcinogens in the working environment. PMID- 28083555 TI - Impact of Symptom Clusters on Quality of Life Outcomes in Patients from Japan with Advanced Nonsmall Cell Lung Cancers. AB - OBJECTIVE: Identify symptom clusters based on symptoms experienced by patients with advanced nonsmall cell lung cancers (NSCLCs), and examine the relationship between the symptom clusters and impairment in everyday life and quality of life (QOL). METHODS: Using the M.D. Anderson Symptom Inventory, 9 symptom items and the QOL Questionnaire (QLQ-C-30) evaluation apparatus from the European Organization for Research and Treatment of Cancer, we evaluated symptom severity, interference in daily life, and QOL. Factor analysis and multiple regression analysis techniques were used. RESULTS: Sixty patients with advanced NSCLCs seen in pulmonary medicine departments were included in the study. The average age of patients was 64.33 (standard deviation = 11.40). Thirty-six were male and 24 were female. Three symptom clusters were identified as fatigue/anorexia cluster (dry mouth, altered the sense of taste, drowsiness, fatigue/tiredness, and lack of appetite), pain cluster (anxiety, sadness, and pain), numbness cluster (numbness, leg weakness, and distress). The pain cluster had the strongest influence (adjusted R2 = 0.355) on daily life (emotions) while the numbness cluster most strongly affected walking. The fatigue/anorexia cluster explained 22.7% of role function variance. This symptom clustering may be unique among patients with advanced NSCLCs. CONCLUSIONS: Each of these clusters affected QOL and everyday life with varying degrees of influence. In clinical screening assessments, focusing on symptom clusters could provide tailored management strategies for patients with advanced NSCLCs. These care strategies may improve outcomes specifically for advanced NSCLCs patients. PMID- 28083556 TI - Development of Booklet on Male Sexual Dysfunction, its Measures and Assessing its Impact on Knowledge of Patients with Urological Cancers. AB - OBJECTIVE: Urological cancer and its surgeries have great impact on male sexuality which could have physical or emotional consequences. In India, speaking openly about the sexual matter is a taboo and an aspect considered forbidden. Therefore, the aim of the present study is to develop an information booklet about male sexual dysfunction and assess its impact on knowledge of patients with urological cancers. METHODS: Information booklet was developed after literature review, and its content validity was established. Reliability of the questionnaire was 0.95. A randomized control trail using pre- and post-test design was used for 30 male urological cancer patients and was assigned to experimental group (15) who received information booklet and control group (15) who received standard treatment. Subjects in the experimental group were provided with opinionnaire during posttest. Data were analyzed using descriptive and inferential statistics. RESULTS: In experimental group, 40% of the subjects were <= 40 years, whereas 27% in the control group (P = 0.699). The pre- and post-mean difference score was significantly higher in experimental group (mean difference 5) than control group (mean difference - 0.4). All subjects (100%) opined that the information booklet was useful, adequate, self-explanatory, sequential, and clear. CONCLUSIONS: Information in the booklet will help subjects to understand the common sexual problems after urological surgeries and help them to cope with the problems, thereby improving their quality of life. PMID- 28083557 TI - Nutritional Issues and Self-care Measures Adopted by Cancer Patients Attending a University Hospital in Turkey. AB - OBJECTIVE: This study aimed to assess the nutritional status of cancer patients and the self-care measures they adopted as a response to nutritional problems. METHODS: This descriptive study included seventy cancer patients staying in the oncology and internal disease clinics of a university hospital in Turkey. Data were collected using a questionnaire with 29 questions. RESULTS: The mean age of participants was 40.2 +/- 1.82 years. Approximately, 62.9% of the patients ate only half of the meals offered to them, 65.7% experienced weight loss, and 45.7% had difficulty eating their meals on their own. Moreover, 47.1% of the patients received nutritional support and nutritional problems were observed in 71.4% of the patients; 80% were unable to eat hospital food, 54.3% had an eating disorder related to a special diet, 30% suffered from loss of appetite, 27% had nausea, and 14.3% had difficulty swallowing. Furthermore, 48.5% of patients responded that they ate home-cooked food or ordered food from outside when questioned about the self-care measures taken to avoid the aforementioned nutritional problems. CONCLUSIONS: Most of the cancer patients had serious nutritional problems and ate home-cooked food and used nutritional supplements to overcome these problems. Oncology nurses are responsible for evaluating the nutritional status of cancer patients and eliminating nutritional problems. PMID- 28083558 TI - Erratum to Happy Birthday: We are Two Years Old. AB - [This corrects the article on p. 211 in vol. 3, PMID: 27981161.]. PMID- 28083559 TI - Culture and Consumer Behavior: The Role of Horizontal and Vertical Cultural Factors. AB - We examine the influence of culture on consumer behavior with a particular focus on horizontal and vertical individualism and collectivism. Cultures vary in their propensity to emphasize hierarchy, a distinction captured by examining horizontal/vertical cultural orientations or contexts. These cultural factors pattern personal values and goals, power concepts, and normative expectations applied to the exercise of power. We review implications for how consumers respond to brands in the marketplace, service providers, and each others' needs. PMID- 28083560 TI - Altered Sensory Code Drives Juvenile-to-Adult Behavioral Maturation in Caenorhabditis elegans. AB - Adults perform better than juveniles in food-seeking tasks. Using the nematode Caenorhabditis elegans to probe the neural mechanisms underlying behavioral maturation, we found that adults and juveniles require different combinations of sensory neurons to generate age-specific food-seeking behavior. We first show that adults and juveniles differ in their response to and preference for food associated odors, and we analyze genetic mutants to map the neuronal circuits required for those behavioral responses. We developed a novel device to trap juveniles and record their neuronal activity. Activity measurements revealed that adult and juvenile AWA sensory neurons respond to the addition of diacetyl stimulus, whereas AWB, ASK, and AWC sensory neurons encode its removal specifically in adults. Further, we show that reducing neurotransmission from the additional AWB, ASK, and AWC sensory neurons transforms odor preferences from an adult to a juvenile-like state. We also show that AWB and ASK neurons drive behavioral changes exclusively in adults, providing more evidence that age specific circuits drive age-specific behavior. Collectively, our results show that an odor-evoked sensory code is modified during the juvenile-to-adult transition in animal development to drive age-appropriate behavior. We suggest that this altered sensory code specifically enables adults to extract additional stimulus features and generate robust behavior. PMID- 28083562 TI - Beyond the Dichotomy: Modernizing Stigma Categorization. AB - Even though our knowledge of the cause of disease and disability has grown, stigma still exists. Weiner, Perry, and Magnusson's seminal study on attributions of stigma has been cited over 500 times since its publication in 1988. The current research sought to replicate and expand this literature in two studies. We used the 10 stigmas from the original study and we added six more (representing common psychological and physical stigmas). In the first study, we examined the classification of stigmas using cluster analysis. We found that instead of dichotomizing stigmas into either psychological or physical, attributions of controllability and stability together resulted in four distinct clusters. Although these were mostly consistent with past literature, the fourth cluster included both psychological and physical stigmas and was rated as moderately controllable and moderately stable. In the second study, we examined how information about responsibility shifts causal attributions, emotional responses, and helping behaviors. Information that an individual was responsible for their stigma led to greater attributions of controllability, less positive emotions, and less help compared to information that an individual was not responsible. More interestingly, the no-information control condition was similar to the responsibility information condition for stigmas that fell into the controllable clusters whereas the control condition was similar to the not responsible information condition for stigmas that fell into the uncontrollable clusters. While parsimony is valued, the psychological/physical dichotomy is not nuanced enough to fully capture the variation in stigmas, which in turn has implications for future research on stigma reduction. PMID- 28083563 TI - The Quantitative Imaging Network in Precision Medicine. AB - Precision medicine is a healthcare model that seeks to incorporate a wealth of patient information to identify and classify disease progression and to provide tailored therapeutic solutions for individual patients. Interventions are based on knowledge of molecular and mechanistic causes, pathogenesis and pathology of disease. Individual characteristics of the patients are then used to select appropriate healthcare options. Imaging is playing an increasingly important role in identifying relevant characteristics that help to stratify patients for different interventions. However, lack of standards, limitations in image processing interoperability, and errors in data collection can limit the applicability of imaging in clinical decision support. Quantitative imaging is the attempt to extract reliable, numerical information from images to eliminate qualitative judgments and errors for providing accurate measures of tumor response to therapy or for predicting future response. This issue of Tomography reports quantitative imaging developments made by several members of the National Cancer Institute Quantitative Imaging Network, a program dedicated to the promotion of quantitative imaging methods for clinical decision support. PMID- 28083561 TI - Medial Preoptic Regulation of the Ventral Tegmental Area Related to the Control of Sociosexual Behaviors. AB - During sociosexual encounters, different brain mechanisms interact to orchestrate information about the salience of external stimuli along with the current physiological and environmental conditions in order to process these in an optimal manner. One candidate neural system involves the potential interplay between the medial preoptic nucleus (POM) and mesolimbic reward circuitry. We present here evidence indicating that projections originating from the POM play a modulatory role on the mesolimbic reward circuitry related to male sexual behavior in Japanese quail (Coturnix japonica). First, we used an asymmetrical inactivation strategy where POM and ventral tegmental area (VTA) were unilaterally inactivated via the GABAA agonist muscimol, either in an ipsilateral or contralateral fashion. Ipsilateral injections of muscimol had negligible effects on both appetitive and consummatory sexual behaviors. In contrast, contralateral injections significantly impaired appetitive sexual behaviors but had no clear effect on consummatory sexual behaviors. Next, we labeled cells projecting from the POM to the VTA by stereotaxic injection into VTA of the retrograde tracer biotinylated dextran amine (BDA). Two weeks later, brains from males who had been allowed to interact freely with a female (15 min) or kept as controls were collected and fixed for double immunohistochemical labeling of BDA and the immediate early gene Fos. More retrogradely labeled BDA cells in POM expressed Fos after sociosexual interactions than in control conditions. Overall, these findings provide novel evidence for the interplay between POM and VTA in the modulation of appetitive but not consummatory sexual behaviors. Schematic representation of the putative role of the projection from the medial POM to the VTA in the regulation of appetitive and consummatory sexual behaviors. Unilateral inactivation of POM and VTA on (1) ipsilateral sides has negligible effects on both aspects of sexual behaviors, whereas (2) contralateral inactivation disrupts appetitive sexual behaviors. PMID- 28083564 TI - Direct Heme Uptake by Phytoplankton-Associated Roseobacter Bacteria. AB - Iron is an essential micronutrient and can limit the growth of both marine phytoplankton and heterotrophic bacterioplankton. In this study, we investigated the molecular basis of heme transport, an organic iron acquisition pathway, in phytoplankton-associated Roseobacter bacteria and explored the potential role of bacterial heme uptake in the marine environment. We searched 153 Roseobacter genomes and found that nearly half contained putative complete heme transport systems with nearly the same synteny. We also examined a publicly available coculture transcriptome and found that Roseobacter strain Sulfitobacter sp. strain SA11 strongly downregulated a putative heme transport gene cluster during mutualistic growth with a marine diatom, suggesting that the regulation of heme transport might be influenced by host cues. We generated a mutant of phytoplankton-associated Roseobacter strain Ruegeria sp. strain TM1040 by insertionally inactivating its homolog of the TonB-dependent heme transporter hmuR and confirmed the role of this gene in the uptake of heme and hemoproteins. We performed competition experiments between iron-limited wild-type and mutant TM1040 strains and found that the wild type maintains a growth advantage when competing with the mutant for iron compounds derived solely from lysed diatom cells. Heme transport systems were largely absent from public marine metagenomes and metatranscriptomes, suggesting that marine bacteria with the potential for heme transport likely have small standing populations in the free-living bacterioplankton. Heme transport is likely a useful strategy for phytoplankton associated bacteria because it provides direct access to components of the host intracellular iron pool after lysis. IMPORTANCE Ecosystem productivity in large regions of the surface ocean is fueled by iron that has been microbially regenerated from biomass. Currently, the specific microbes and molecules that mediate the transfer of recycled iron between microbial trophic levels remain largely unknown. We characterized a marine bacterial heme transporter and verified its role in acquiring heme, an abundant iron-containing enzyme cofactor. We present evidence that after host cell lysis, phytoplankton-associated bacteria directly extract heme and hemoproteins from algal cellular debris in order to fulfill their iron requirements and that the regulation of this process may be modulated by host cues. Direct heme transport, in contrast to multistep extracellular processing of hemoproteins, may allow certain phytoplankton associated bacteria to rapidly extract iron from decaying phytoplankton, thus efficiently recycling cellular iron into the wider microbial loop. PMID- 28083566 TI - Within- and Between-Session Changes in Neural Activity During Emotion Processing in Unipolar and Bipolar Depression. AB - BACKGROUND: Bipolar disorder (BD) and unipolar depression (UD) can be difficult to distinguish clinically, particularly during episodes of depression. In this study we test for differences between BD, UD, and healthy control (HC) adults regarding within- and between-session changes in BOLD response during implicit emotional processing. METHODS: During fMRI, HC adults (N=19) and depressed adults with UD (N=19) and BD (N=16) performed an implicit emotion-processing task. Each participant was scanned twice, separated by 6-months, resulting in 108 scans. BOLD response and linear change in BOLD response were examined within and between sessions. RESULTS: We observed within-session linear decreases in BOLD signal (irrespective of group, condition, or session) in the left amygdala, a right sided temporo-parietal region, and a right-sided fronto-insular region. Furthermore, we observed group differences in within-session BOLD signal change (p<0.05, FWE corrected) in a left-sided striatal-insular-thalamic region. Individuals with BD demonstrated a linear decrease in BOLD signal compared to HC (p<0.008, FWE corrected) across this region and compared to UD in the posterior insula portion of the region (p<0.008, FWE corrected). Finally, we observed main effects of emotional valence in bilateral visuo-spatial processing regions as well as in the left and right amygdala. CONCLUSIONS: Individuals with BD demonstrated linear attenuation of BOLD response to emotional stimuli within left sided striatal-insular-thalamic regions. Individuals with BD may either have experienced abnormal habituation in this region or disengaged quickly from processing the emotional stimuli, despite comparable task performance. This pattern may represent an underlying pathophysiological process associated with BD that differs from UD. PMID- 28083565 TI - The Disrupted Connectivity Hypothesis of Autism Spectrum Disorders: Time for the Next Phase in Research. AB - During the past decade, the disrupted connectivity theory has generated considerable interest as a pathophysiological model for autism spectrum disorders (ASD). This theory postulates that deficiencies in the way the brain coordinates and synchronizes activity amongst different regions may account for the clinical symptoms of ASD. This review critically examines the current structural and functional connectivity data in ASD and evaluates unresolved assumptions and gaps in knowledge that limit the interpretation of these data. Collectively, studies very often show group alterations in what are thought of as measures of cerebral connectivity, though the patterns of findings vary considerably. We argue that there are three principle needs in this research agenda. First, further basic research is needed to understand the links between measures commonly used (DTI, fMRI, EEG) and other (histological, computational) levels of analysis. Second, speculated causes of inconsistencies in the literature (age, clinical heterogeneity) demand studies that directly evaluate these interpretations. Finally, the field needs well-specified mechanistic models of altered cerebral communication in ASD whose predictions can be tested on multiple levels of analyses. PMID- 28083567 TI - Deep Voting: A Robust Approach Toward Nucleus Localization in Microscopy Images. AB - Robust and accurate nuclei localization in microscopy image can provide crucial clues for accurate computer-aid diagnosis. In this paper, we propose a convolutional neural network (CNN) based hough voting method to localize nucleus centroids with heavy cluttering and morphologic variations in microscopy images. Our method, which we name as deep voting, mainly consists of two steps. (1) Given an input image, our method assigns each local patch several pairs of voting offset vectors which indicate the positions it votes to, and the corresponding voting confidence (used to weight each votes), our model can be viewed as an implicit hough-voting codebook. (2) We collect the weighted votes from all the testing patches and compute the final voting density map in a way similar to Parzen-window estimation. The final nucleus positions are identified by searching the local maxima of the density map. Our method only requires a few annotation efforts (just one click near the nucleus center). Experiment results on Neuroendocrine Tumor (NET) microscopy images proves the proposed method to be state-of-the-art. PMID- 28083568 TI - A Hybrid Multishape Learning Framework for Longitudinal Prediction of Cortical Surfaces and Fiber Tracts Using Neonatal Data. AB - Dramatic changes of the human brain during the first year of postnatal development are poorly understood due to their multifold complexity. In this paper, we present the first attempt to jointly predict, using neonatal data, the dynamic growth pattern of brain cortical surfaces (collection of 3D triangular faces) and fiber tracts (collection of 3D lines). These two entities are modeled jointly as a multishape (a set of interlinked shapes). We propose a hybrid learning-based multishape prediction framework that captures both the diffeomorphic evolution of the cortical surfaces and the non-diffeomorphic growth of fiber tracts. In particular, we learn a set of geometric and dynamic cortical features and fiber connectivity features that characterize the relationships between cortical surfaces and fibers at different timepoints (0, 3, 6, and 9 months of age). Given a new neonatal multishape at 0 month of age, we hierarchically predict, at 3, 6 and 9 months, the postnatal cortical surfaces vertex-by-vertex along with fibers connected to adjacent faces to these vertices. This is achieved using a new fiber-to-face metric that quantifies the similarity between multishapes. For validation, we propose several evaluation metrics to thoroughly assess the performance of our framework. The results confirm that our framework yields good prediction accuracy of complex neonatal multishape development within a few seconds. PMID- 28083569 TI - Riemannian Metric Optimization for Connectivity-driven Surface Mapping. AB - With the advance of human connectome research, there are great interests in computing diffeomorphic maps of brain surfaces with rich connectivity features. In this paper, we propose a novel framework for connectivity-driven surface mapping based on Riemannian metric optimization on surfaces (RMOS) in the Laplace Beltrami (LB) embedding space. The mathematical foundation of our method is that we can use the pullback metric to define an isometry between surfaces for an arbitrary diffeomorphism, which in turn results in identical LB embeddings from the two surfaces. For connectivity-driven surface mapping, our goal is to compute a diffeomorphism that can match a set of connectivity features defined over anatomical surfaces. The proposed RMOS approach achieves this goal by iteratively optimizing the Riemannian metric on surfaces to match the connectivity features in the LB embedding space. At the core of our framework is an optimization approach that converts the cost function of connectivity features into a distance measure in the LB embedding space, and optimizes it using gradients of the LB eigen-system with respect to the Riemannian metric. We demonstrate our method on the mapping of thalamic surfaces according to connectivity to ten cortical regions, which we compute with the multi-shell diffusion imaging data from the Human Connectome Project (HCP). Comparisons with a state-of-the-art method show that the RMOS method can more effectively match anatomical features and detect thalamic atrophy due to normal aging. PMID- 28083571 TI - Gaussian fluctuations of spatially inhomogeneous polymers. AB - Inhomogeneous polymers, such as partially cofilin-bound actin filaments, play an important role in various natural and biotechnological systems. At finite temperatures, inhomogeneous polymers exhibit non-trivial thermal fluctuations. More broadly, these are relatively simple examples of fluctuations in spatially inhomogeneous systems, which are less understood compared to their homogeneous counterparts. Here we develop a statistical theory of torsional, extensional and bending Gaussian fluctuations of inhomogeneous polymers (chains), where the inhomogeneity is an inclusion of variable size and stiffness, using both continuum and discrete approaches. First, we analytically calculate the complete eigenvalue and eigenmode spectra within a continuum field theory. In particular, we show that the wavenumber inside and outside of the inclusion is nearly linear in the eigenvalue index, with a nontrivial coefficient. Second, we solve the corresponding discrete problem and highlight fundamental differences between the continuum and discrete spectra. In particular, we demonstrate that above a certain wavenumber the discrete spectrum changes qualitatively and discrete evanescent eigenmodes, which do not have continuum counterparts, emerge. The implications of these differences are explored by calculating fluctuation-induced forces associated with free-energy variations with either the inclusion properties (e.g. inhomogeneity formed by adsorbing molecules) or with an external geometric constraint. The former, which is the fluctuation-induced contribution to the adsorbing molecule binding force, is shown to be affected by short wavelengths and thus cannot be calculated using the continuum approach. The latter, on the other hand, is shown to be dominated by long wavelength shape fluctuations and hence is properly described by the continuum theory. PMID- 28083570 TI - Pancreas Segmentation in MRI using Graph-Based Decision Fusion on Convolutional Neural Networks. AB - Automated pancreas segmentation in medical images is a prerequisite for many clinical applications, such as diabetes inspection, pancreatic cancer diagnosis, and surgical planing. In this paper, we formulate pancreas segmentation in magnetic resonance imaging (MRI) scans as a graph based decision fusion process combined with deep convolutional neural networks (CNN). Our approach conducts pancreatic detection and boundary segmentation with two types of CNN models respectively: 1) the tissue detection step to differentiate pancreas and non pancreas tissue with spatial intensity context; 2) the boundary detection step to allocate the semantic boundaries of pancreas. Both detection results of the two networks are fused together as the initialization of a conditional random field (CRF) framework to obtain the final segmentation output. Our approach achieves the mean dice similarity coefficient (DSC) 76.1% with the standard deviation of 8.7% in a dataset containing 78 abdominal MRI scans. The proposed algorithm achieves the best results compared with other state of the arts. PMID- 28083572 TI - Exciton valley dynamics in monolayer WSe2 probed by the two-color ultrafast Kerr rotation. AB - The newly developed two-dimensional layered materials provide a perfect platform for valley-spintronics exploration. To determine the prospect of utilizing the valley degree of freedom, it is of great importance to directly detect and understand the valley dynamics in these materials. Here, the exciton valley dynamics in monolayer WSe2 is investigated by the two-color pump-probe magneto optical Kerr technique. By tuning the probe photon energy in resonance with the free excitons and trions, the valley relaxation time of different excitonic states in monolayer WSe2 is determined. Valley relaxation time of the free exciton in monolayer WSe2 is confirmed to be several picoseconds. A slow valley polarization relaxation process is observed to be associated with the trions, showing that the valley lifetime for trions is one order of magnitude longer than that of free excitons. This finding suggests that trion can be a good candidate for valleytronics applications. PMID- 28083573 TI - Water vapour effects on secondary organic aerosol formation in isoprene ozonolysis. AB - Secondary organic aerosol (SOA) formation from isoprene ozonolysis was investigated using a Teflon bag reactor under dry and humid conditions. Both the number and volume concentrations of SOA were found to be decreased by the addition of water vapour. Gas- and particle-phase product analyses with a negative ion chemical ionization mass spectrometer show that oligomers composed of stabilized Criegee intermediates as the chain units contribute to the SOA formation and that water vapour inhibits stabilized Criegee intermediates from forming the oligomers, resulting in the suppression of SOA formation. Additionally, it is suggested that a portion of stabilized Criegee intermediates other than CH2OO have low reactivity toward H2O, and thus can be involved in the oligomer and SOA formation even under humid conditions. Volatility estimation predicts that the oligomers containing even one or two stabilized Criegee intermediates can be partitioned into the aerosol phase. PMID- 28083574 TI - Shock wave studies of the pyrolysis of fluorocarbon oxygenates. I. The thermal dissociation of C3F6O and CF3COF. AB - The thermal decomposition of hexafluoropropylene oxide, C3F6O, to perfluoroacetyl fluoride, CF3COF, and CF2 has been studied in shock waves highly diluted in Ar between 630 and 1000 K. The measured rate constant k1 = 1.1 * 1014 exp(-162(+/-4) kJ mol-1/RT) s-1 agrees well with literature data and modelling results. Using the reaction as a precursor, equimolar mixtures of CF3COF and CF2 were further heated. Combining experimental observations with theoretical modelling (on the CBS-QB3 and G4MP2 ab initio composite levels), CF3COF is shown to dissociate on two channels, either leading to CF2 + COF2 or to CF3 + FCO. By monitoring the CF2 signals, the branching ratio was determined between 1400 and 1900 K. The high pressure rate constants for the two channels were obtained from theoretical modelling as k5,infinity(CF3COF -> CF2 + COF2) = 7.1 * 1014 exp(-320 kJ mol-1/RT) s-1 and k6,infinity(CF3COF -> CF3 + FCO) = 3.9 * 1015 exp(-355 kJ mol-1/RT) s-1. The experimental results obtained at [Ar] ~ 5 * 10-6 mol cm-3 were consistent with modelling results, showing that the reaction is in the falloff range of the unimolecular dissociation. The mechanism of secondary reactions following CF3COF dissociation has been analysed as well. PMID- 28083575 TI - Slow magnetic relaxation in a mononuclear 8-coordinate Fe(ii) complex. AB - The synthesis and structure of an 8-coordinate Fe(ii) compound [FeII(L1)2](ClO4)2 (1) with a [FeN4O4] core are reported. 1 exhibits uni-axial anisotropy for which a slow magnetic relaxation is observed under 1.4 kOe dc field. It is the first example of an 8-coordinate Fe(ii) complex exhibiting field-induced single molecule magnet (SMM) behaviour. PMID- 28083576 TI - Two-liquid wetting properties as a surface polarity probe for hydrophobic coatings. AB - A model for the spreading of a non-polar liquid on a surface within a polar medium is described theoretically, according to Fowkes, Good and Girifalco approximations on interfacial tension. We demonstrate both theoretically and experimentally that surface polarity measurements using the contact angle of two immiscible liquids minimize drastically the measurement error. The present method has been successfully applied to various substrates of variable polarity and overall surface energy. We also demonstrate that this method allows a direct measurement of surface sensitivity to pH. PMID- 28083577 TI - Bright metal coatings from sustainable electrolytes: the effect of molecular additives on electrodeposition of nickel from a deep eutectic solvent. AB - Organic and inorganic additives are often added to nickel electroplating solutions to improve surface finish, reduce roughness and promote uniform surface morphology of the coatings. Such additives are usually small molecules and often referred to as brighteners or levellers. However, there have been limited investigations into the effect of such additives on electrodeposition from ionic liquids (ILs) and deep eutectic solvents (DESs). Here we study the effect of four additives on electrolytic nickel plating from an ethyleneglycol based DES; these are nicotinic acid (NA), methylnicotinate (MN), 5,5-dimethylhydantoin (DMH) and boric acid (BA). The additives show limited influence on the bulk Ni(ii) speciation but have significant influence on the electrochemical behaviour of Ni deposition. Small concentrations (ca. 15 mM) of NA and MN show inhibition of Ni(ii) reduction whereas high concentrations of DMH and BA are required for a modest difference in behaviour from the additive free system. NA and MN also show that they significantly alter the nucleation and growth mechanism when compared to the additive free system and those with DMH and BA. Each of the additive systems had the effect of producing brighter and flatter bulk electrodeposits with increased coating hardness but XRD shows that NA and MN direct crystal growth to the [111] orientation whereas DMH and BA direct crystal growth to the [220] orientation. PMID- 28083578 TI - Electrocatalysis for the oxygen evolution reaction: recent development and future perspectives. AB - There is still an ongoing effort to search for sustainable, clean and highly efficient energy generation to satisfy the energy needs of modern society. Among various advanced technologies, electrocatalysis for the oxygen evolution reaction (OER) plays a key role and numerous new electrocatalysts have been developed to improve the efficiency of gas evolution. Along the way, enormous effort has been devoted to finding high-performance electrocatalysts, which has also stimulated the invention of new techniques to investigate the properties of materials or the fundamental mechanism of the OER. This accumulated knowledge not only establishes the foundation of the mechanism of the OER, but also points out the important criteria for a good electrocatalyst based on a variety of studies. Even though it may be difficult to include all cases, the aim of this review is to inspect the current progress and offer a comprehensive insight toward the OER. This review begins with examining the theoretical principles of electrode kinetics and some measurement criteria for achieving a fair evaluation among the catalysts. The second part of this review acquaints some materials for performing OER activity, in which the metal oxide materials build the basis of OER mechanism while non oxide materials exhibit greatly promising performance toward overall water splitting. Attention of this review is also paid to in situ approaches to electrocatalytic behavior during OER, and this information is crucial and can provide efficient strategies to design perfect electrocatalysts for OER. Finally, the OER mechanism from the perspective of both recent experimental and theoretical investigations is discussed, as well as probable strategies for improving OER performance with regards to future developments. PMID- 28083579 TI - Metal complexes with oxygen-functionalized NHC ligands: synthesis and applications. AB - Ligand design has met with considerable success with both categories of hybrid ligands, which are characterized by chemically different donor groups, and of N heterocyclic carbenes (NHCs). Their spectacular development and diversity are attracting worldwide interest and offers almost unlimited diversity and potential in e.g. coordination/organometallic main group and transition metal chemistry, catalysis, medicinal chemistry and materials science. This review aims at providing a comprehensive update on a specific class of ligands that has enjoyed much attention in the past few years, at the intersection between the two categories mentioned above, that of hybrid NHC ligands in which the functionality associated with the carbene donor is of the oxygen-donor type. For each type of oxygen-donor present in such chelating (Section 1) or bridging (Section 2) hybrid ligands, we will examine the synthesis, structures and reactivity of their metal complexes and their applications, with a special focus on homogeneous catalysis (Section 3). Thus, hydrogenation, C-H bond activation, C-C, C-N, C-O bond formation, hydrolysis of silanes, oligomerization, polymerization, metathesis, hydrosilylation, C-C bond cleavage, acceptorless dehydrogenation, dehalogenation/hydrogen transfer, oxidation and reduction reactions will be successively presented in a tabular manner, to facilitate an overview and a rapid identification of the relevant publications describing which metals associated with a given oxygen functionality are most suitable. The literature coverage includes the year 2015. PMID- 28083580 TI - Facile synthesis of N-acyl 2-aminobenzothiazoles by NHC-catalyzed direct oxidative amidation of aldehydes. AB - A mild, general, and high yielding synthesis of N-acyl 2-aminobenzothiazoles has been demonstrated by N-heterocyclic carbene (NHC)-organocatalyzed direct amidation of aldehydes with 2-aminobenzothiazoles proceeding via acyl azolium intermediates. The carbene generated from the triazolium salt under oxidative conditions was the key for the success of this reaction. The method was subsequently applied to the synthesis of various biologically important N-acyl 2 aminobenzothiazoles. PMID- 28083581 TI - Thermal annealing behaviour and gel to crystal transition of a low molecular weight hydrogelator. AB - The thermal annealing behaviour of an electrolyte-triggered calixarene hydrogelator is found to depend strongly on the specific metal chloride used. While the lithium chloride gel showed typical gel-sol transitions as a function of temperature, the magnesium chloride gel was found to repeatedly strengthen with heat-cool cycles. Structural investigations using small-angle neutron scattering, and scanning probe microscopy, suggest that the annealing behaviour is associated with a change in morphology of the fibrous structures supporting the gel. On prolonged standing at room temperature, the magnesium chloride gel underwent a gel-crystal transition, with the collapsing gel accompanied by the deposition of crystals of a magnesium complex of the proline-functionalised calix[4]arene gelator. PMID- 28083582 TI - Influence of NO and (NO)2 adsorption on the properties of Fe-N4 porphyrin-like graphene sheets. AB - Detection of NO in biological systems and removing or reducing NO for environment protection is paramount. Herein, we investigate the influence of NO and (NO)2 adsorption on the properties of Fe-N4 porphyrin-like graphene (G-Fe-N4) sheets using periodic DFT calculations with the dispersion correction. The results show that NO can be converted into N2O through adsorbed (NO)2 with a total energy barrier of 0.92 eV. The adsorption of N2O and of two NO on O/G-Fe-N4 sheets can proceed through (N2)gas + (O2)ads and (N2O)gas + (O2)ads, respectively. Both paths have a rate-determining step with a high (~1.80 eV) energy barrier. Nevertheless, the formation of (O2)ads on the G-Fe-N4 can be regarded as an oxygen reduction reaction (ORR) precursor. Detailed analyses of the electronic properties of the various systems involved in this reaction reveal the increased spin filter characteristics for some structures. Hence, the obtained spin filter parameters of the NO@G-Fe-N4 and (NO)2@G-Fe-N4 structures are 72.53% and 47.96%, respectively. Also, it is found that the adsorption of NO gas molecules induces different energy antiresonant dips not found in G-Fe-N4, which are induced by quasi-bound states related to the adsorbate and Fe-N4 defect. PMID- 28083583 TI - Kinetic analysis of overlapping multistep thermal decomposition comprising exothermic and endothermic processes: thermolysis of ammonium dinitramide. AB - This study focused on kinetic modeling of a specific type of multistep heterogeneous reaction comprising exothermic and endothermic reaction steps, as exemplified by the practical kinetic analysis of the experimental kinetic curves for the thermal decomposition of molten ammonium dinitramide (ADN). It is known that the thermal decomposition of ADN occurs as a consecutive two step mass-loss process comprising the decomposition of ADN and subsequent evaporation/decomposition of in situ generated ammonium nitrate. These reaction steps provide exothermic and endothermic contributions, respectively, to the overall thermal effect. The overall reaction process was deconvoluted into two reaction steps using simultaneously recorded thermogravimetry and differential scanning calorimetry (TG-DSC) curves by considering the different physical meanings of the kinetic data derived from TG and DSC by P value analysis. The kinetic data thus separated into exothermic and endothermic reaction steps were kinetically characterized using kinetic computation methods including isoconversional method, combined kinetic analysis, and master plot method. The overall kinetic behavior was reproduced as the sum of the kinetic equations for each reaction step considering the contributions to the rate data derived from TG and DSC. During reproduction of the kinetic behavior, the kinetic parameters and contributions of each reaction step were optimized using kinetic deconvolution analysis. As a result, the thermal decomposition of ADN was successfully modeled as partially overlapping exothermic and endothermic reaction steps. The logic of the kinetic modeling was critically examined, and the practical usefulness of phenomenological modeling for the thermal decomposition of ADN was illustrated to demonstrate the validity of the methodology and its applicability to similar complex reaction processes. PMID- 28083584 TI - Influence of metal coordination and co-ligands on the magnetic properties of 1D Co(NCS)2 coordination polymers. AB - Two new transition metal thiocyanate coordination polymers with the composition [Co(NCS)2(4-vinylpyridine)2]n (1) and [Co(NCS)2(4-benzoylpyridine)2]n (2) were synthesized and their crystal structures were determined. In both compounds the Co cations are octahedrally coordinated by two trans-coordinating 4-vinyl- or 4 benzoylpyridine co-ligands and four MU-1,3-bridging thiocyanato anions and linked into chains by the anionic ligands. While in 1 the N and the S atoms of the thiocyanate anions are also in trans-configuration, in 2 they are in cis configuration. A detailed magnetic study showed that the intra-chain ferromagnetic coupling is slightly stronger for 2 than for 1, and that the chains in both compounds are weekly antiferromagnetically coupled. Both compounds show a long range magnetic ordering transition at Tc = 3.9 K for 1 and Tc = 3.7 K for 2, which is confirmed by specific heat measurements. They also show a metamagnetic transition at a critical field of 450 Oe (1) and 350 Oe (2), respectively. Below Tc1 and 2 exhibit magnetic relaxations resembling relaxations of single chains. The exchange constants obtained from magnetic and specific heat data are in good accordance with those obtained from constrained DFT calculations carried out on isolated model systems. The ab initio calculations allowed us to find the principal directions of anisotropy. PMID- 28083585 TI - Metal ion mediated electron transfer at dye-semiconductor interfaces. AB - Here we demonstrate that the incorporation of Cu2+ linking ions into self assembled bilayer films significantly perturbs the electron transfer rate at dye semiconductor interfaces. Despite near unity quenching of the excited state of the dye by the Cu2+ ions, a charge separated state with slowed recombination is observed. PMID- 28083586 TI - Shock wave studies of the pyrolysis of fluorocarbon oxygenates. II. The thermal dissociation of C4F8O. AB - The thermal decomposition of octafluorooxalane, C4F8O, to C2F4 + CF2 + COF2 has been studied in shock waves highly diluted in Ar between 1300 and 2200 K. The primary dissociation was shown to be followed by secondary dissociation of C2F4 and dimerization of CF2. The primary dissociation was found to be in its falloff range and falloff curves were constructed. The limiting low and high pressure rate constants were estimated and compared with modelling results. Quantum chemical calculations identified possible reaction pathways, either leading directly to the final products of the reaction or passing through an open-chain CF2CF2CF2 intermediate which dissociates in a second step. PMID- 28083587 TI - Thermal transport across nanoparticle-fluid interfaces: the interplay of interfacial curvature and nanoparticle-fluid interactions. AB - We investigate the general dependence of the thermal transport across nanoparticle-fluid interfaces using molecular dynamics computations. We show that the thermal conductance depends strongly both on the wetting characteristics of the nanoparticle-fluid interface and on the nanoparticle size. Strong nanoparticle-fluid interactions, leading to full wetting states in the host fluid, result in high thermal conductances and efficient interfacial transport of heat. Weak interactions result in partial drying or full drying states, and low thermal conductances. The variation of the thermal conductance with particle size is found to depend on the fluid-nanoparticle interactions. Strong interactions coupled with large interfacial curvatures lead to optimum interfacial heat transport. This complex dependence can be modelled using an equation that includes the interfacial curvature as a parameter. In this way, we rationalise the existing experimental and computer simulation results and show that the thermal transport across nanoscale interfaces is determined by the correlations of both interfacial curvature and nanoparticle-fluid interactions. PMID- 28083588 TI - Halogen bonding versus hydrogen bonding induced 2D self-assembled nanostructures at the liquid-solid interface revealed by STM. AB - We design a bifunctional molecule (5-bromo-2-hexadecyloxy-benzoic acid, 5-BHBA) with a bromine atom and a carboxyl group and its two-dimensional self-assembly is experimentally and theoretically investigated by using scanning tunneling microscopy (STM) and density functional theory (DFT) calculations. The supramolecular self-organization of 5-BHBA in two different solvents (1-octanoic acid and n-hexadecane) at the liquid-solid interface at different solution concentrations is obviously different due to the cooperative and competitive intermolecular halogen and hydrogen bonds. Three kinds of nanoarchitectures composed of dimers, trimers and tetramers are formed at the 1-octanoic acid/graphite interface based on -COOHHOOC-, triangular C[double bond, length as m-dash]OBrH-C, -BrO(H), BrBr, and OH interactions. Furthermore, by using n hexadecane as the solvent, two kinds of self-assembled linear patterns can be observed due to the coadsorption, in which the dimers are formed by intermolecular -COOHHOOC- hydrogen bonds. The molecule-solvent and solvent solvent van der Waals force and intermolecular hydrogen bonds dominate the formation of coadsorbed patterns. We propose that the cooperative and competitive halogen and hydrogen bonds are related to the polarity of the solvent and the type of molecule-solvent interaction. The intermolecular binding energy of different dimers and their stability are supported by theoretical calculations. The result provides a new and innovative insight to induce the 2D self-assembled nanostructures by halogen and hydrogen bonds at the liquid-solid interface. PMID- 28083589 TI - Polarization loss in the organic ferroelectric trialkylbenzene-1,3,5 tricarboxamide (BTA). AB - We investigate the polarization loss in the archetypical molecular organic ferroelectric trialkylbenzene-1,3,5-tricarboxamide (BTA). We prove that the polarization loss is due to thermally activated R-relaxation, which is a collective reversal of the amide dipole moments in ferroelectric domains. By applying a weak electrostatic field both the polarization loss and the R relaxation are suppressed, leading to an enhancement of the retention time by at least several orders of magnitude. Alternative loss mechanisms are discussed and ruled out. By operating the thin-film devices slightly above the crystalline to liquid crystalline phase transition temperature the retention time of one compound becomes more than 12 hours even in absence of supportive bias, which is among the longest reported so far for organic ferroelectric materials. PMID- 28083590 TI - Liberation of three dihydrogens from two ethene molecules as mediated by the tantalum nitride anion cluster Ta3N2- at room temperature. AB - The reactivity of gas-phase cluster anions Ta3N2- with C2H4 under thermal collision conditions was studied by mass spectrometry in conjunction with density functional theory calculations. The full dehydrogenation of the C2H4 molecule was observed, with the formation of two dihydrogen molecules. Interestingly, the two carbon atoms originating from the first C2H4 molecule are used to construct another cluster Ta3N2C2-, which can activate one more C2H4 releasing one H2 molecule. Therefore, three dihydrogen molecules are liberated from two ethene molecules in the overall reaction. The full dehydrogenation of C2H4 by gas-phase anions as well as the structure and reactivity of M-N-C (M: transition metal) cluster is reported for the first time. The properties of Ta3N2- and Ta3N2C2- elucidated herein are of use in providing fundamental information that is necessary to tailor the design of new and effective catalysts by applying the related materials. PMID- 28083591 TI - Structural evolution of reduced GeOx nanoparticles. AB - GeOx nanoparticles (NPs) are of growing interest in lithium storage and optoelectronics. GeOx NPs prepared by chemical reduction, exposed to air or retained under N2, then annealed under H2 at various temperatures are studied herein using soft X-ray spectroscopy. We find that fresh and air-exposed GeOx NPs evolve rather differently under annealing. The fresh GeOx NPs start as a very amorphous heterogeneous mixture of GeOx and Ge, and during annealing both the valence band and conduction band edges evolve. In contrast, the air-exposed GeOx NPs initially contain quartz-phase GeO2, and during annealing only the conduction band edge evolves due to increased oxygen vacancies forming unoccupied defect states (the valence band does not change until annealing at high temperture, at which point almost all of the GeO2 is removed). These findings suggest a preparation and annealing strategy that could be used to tailor GeOx NPs for their intended use in lithium storage or optoelectronic applications. PMID- 28083593 TI - Phase behavior of active Brownian disks, spheres, and dimers. AB - In this paper we provide high precision estimates of the phase diagram of active Brownian particles. We extract coexisting densities from simulations of phase separated states in an elongated box (slab geometry) which minimizes finite-size effects and allows for precise determination of points on the binodal lines. Using this method, we study the influence of both shape and dimensionality on the two-phase region. Active spheres and dimers of active particles are compared to the known phase diagram of active Brownian disks. In the case of dimers, both correlated and uncorrelated propulsion of the two beads are studied. The influence of correlations is discussed through a simple mapping. PMID- 28083592 TI - Single, Janus, and Cerberus emulsions from the vibrational emulsification of oils with significant mutual solubility. AB - Single, Janus, and Cerberus emulsions are prepared in one system consisting of three oils: silicone (SO), fluorocarbon (FO) and ethoxylated trimethylolpropane triacrylate (ETPTA) with mutual solubility. An aqueous solution of Pluronic F127, which is an poly(ethylene oxide)/poly(propylene oxide) co-polymer of average composition EO97PO68EO97, was employed as the continuous phase. The three dimensional phase diagram of the oils was determined, and different oil compositions within the various regions of the phase diagram were emulsified by one-step vortex mixing with an F127 aqueous solution. The result showed single, Janus, and Cerberus emulsions within the different regions of the phase diagram; i.e. the emulsions reflected the equilibrium system. The topology of the Cerberus droplets is to an overwhelming extent linear-singlet and exclusively lobe order of EF/FO/SF. Since the results indicate a significant effect of the equilibrium interfacial tensions on the drop topology, thermodynamic calculations were made using the experimentally determined interfacial tensions. The results, as expected, show that the Cerberus emulsions are thermodynamically preferred over separate drops of the individual oils. In addition, the calculations demonstrate that the order of lobes within a drop is thermodynamically favored. PMID- 28083594 TI - Pyrene based D-pi-A architectures: synthesis, density functional theory, photophysics and electron transfer dynamics. AB - Pyrene derivatives show immense potential as sensitizers for dye-sensitized solar cells (DSCs). Therefore, this work focuses on the impact of pi-spacers on the photophysical, electrochemical and photovoltaic properties of pyrene based D-pi-A dyes, since the insertion of pi-spacers is one of the doable strategies to improve the light harvesting properties of the dye. In this respect, three new pyrene based D-pi-A dyes have been synthesized and characterized by 1H, 13C NMR, and elemental analyses and EI-MS spectrometry. The selected pi-spacers are benzene, thiophene and furan. Compared with a benzene spacer, the introduction of a heterocyclic ring spacer reduces the band gap of the dye and brings about the broadening of the absorption spectra to the longer wavelength region through intramolecular charge-transfer (ICT). Combined experimental and theoretical studies were performed to investigate the ICT process involved in the pyrene derivatives. The profound solvatochromism with increased nonradiative rate constants (knr) has been construed in terms of ICT from the pyrene core to rhodanine-3-acetic acid via conjugated pi-spacers. Electrochemical data also reveal that the HOMO and LUMO energy levels are fine-tuned by incorporating different pi-spacers between pyrene and rhodanine-3-acetic acid. On the basis of the optimized DSC test conditions, the best performance was found for PBRA, in which a benzene group is the conjugated pi-spacer. The divergence in the photovoltaic behaviors of these dyes was further explicated by femtosecond fluorescence and electrochemical impedance spectroscopy. PMID- 28083596 TI - Cytochrome P450 2U1, a very peculiar member of the human P450s family. AB - Cytochrome P450 2U1 (CYP2U1) exhibits several distinctive characteristics among the 57 human CYPs, such as its presence in almost all living organisms with a highly conserved sequence, its particular gene organization with only five exons, its major location in thymus and brain, and its protein sequence involving an unusually long N-terminal region containing 8 proline residues and an insert of about 20 amino acids containing 5 arginine residues after the transmembrane helix. Few substrates, including fatty acids, N-arachidonoylserotonin (AS), and some drugs, have been reported so far. However, its biological roles remain largely unknown, even though CYP2U1 mutations have been involved in some pathological situations, such as complicated forms of hereditary spastic paraplegia. These data together with its ability to hydroxylate some fatty acids and AS suggest its possible role in lipid metabolism. PMID- 28083595 TI - Mitochondrial dynamics as regulators of cancer biology. AB - Mitochondria are dynamic organelles that supply energy required to drive key cellular processes, such as survival, proliferation, and migration. Critical to all of these processes are changes in mitochondrial architecture, a mechanical mechanism encompassing both fusion and fragmentation (fission) of the mitochondrial network. Changes to mitochondrial shape, size, and localization occur in a regulated manner to maintain energy and metabolic homeostasis, while deregulation of mitochondrial dynamics is associated with the onset of metabolic dysfunction and disease. In cancers, oncogenic signals that drive excessive proliferation, increase intracellular stress, and limit nutrient supply are all able to alter the bioenergetic and biosynthetic requirements of cancer cells. Consequently, mitochondrial function and shape rapidly adapt to these hostile conditions to support cancer cell proliferation and evade activation of cell death programs. In this review, we will discuss the molecular mechanisms governing mitochondrial dynamics and integrate recent insights into how changes in mitochondrial shape affect cellular migration, differentiation, apoptosis, and opportunities for the development of novel targeted cancer therapies. PMID- 28083597 TI - [Psoriatic arthritis : Overview of drug therapy options and administration characteristics]. AB - Psoriatic arthritis is a chronic inflammatory disease of the musculoskeletal system with association to skin psoriasis and is characterized by variable clinical symptoms with very heterogeneous degrees of disease suffering for patients. Clinical manifestations essentially include alterations to the skin and nails, peripheral arthritis, enthesitis, dactylitis and/or spinal involvement. This variability necessitates an individualized therapy of patients with different therapy targets. Apart from international guidelines no therapy recommendations are available in Germany for treatment of psoriatic arthritis. For this reason this article summarizes the established points, characteristics and aspects to be considered in the therapy of psoriatic arthritis in Germany, taking the various main forms of the disease into consideration. PMID- 28083598 TI - [Drug treatment of dementia]. AB - The number of patients with dementia continues to increase worldwide, mainly due to the demographic developments. Early diagnosis and individualized therapy offers the chance of healing in secondary dementias. The therapy of the more common primary neurodegenerative forms is able to improve the course of the disease. As part of a multimodal management the therapy of dementias includes pharmacological treatment, nondrug treatment strategies, and psychosocial interventions. The treatment is administered depending on dementia form and stage. Antidementive medication and differentiated pharmacological therapy of frequent mental and behavioral symptoms corresponding to current guidelines contribute decisively to stabilize quality of life and activities of daily living, delaying the progression, and thus improving the care situation of patients and caregivers. PMID- 28083599 TI - [PCSK9 inhibitors : Current clinical relevance]. AB - BACKGROUND: Hypercholesterolemias are known risk factors for cardiovascular diseases. Although statins have reduced the cardiovascular morbidity and mortality and further therapeutic measures are available, treatment goals are often not achieved. In cases of very high levels of low-density lipoprotein (LDL) cholesterol or of intolerability, the established therapies are often not sufficiently effective or cannot be used in adequate doses. For these high-risk patients further treatment options are required. OBJECTIVES: The current clinical relevance of the new substance class of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for the treatment of hypercholesterolemias is presented on the basis of the available data and the German regulations. CURRENT DATA: The two PCSK9 inhibitors, evolocumab and alirocumab, were approved in 2015. Data from many different patient groups are available for both substances. The significant reduction of LDL cholesterol of 50-60% and the very good tolerability and safety profile (at placebo level) are shown for both substances. The PCSK9 inhibitors are not as effective only in homozygous familial hypercholesterolemia. The first long-term data and one imaging study raise hope that the endpoint trials will show the expected reduction in cardiovascular events. Long-term trials have to show the long-term safety. In Germany it is legally regulated which patients can be treated by PCSK9 inhibitors and these prerequisites are largely in accordance with clinical practice. CONCLUSION: The body of evidence is rapidly increasing thereby facilitating the decision making when PCSK9 inhibitors could be used. The PCSK9 inhibitors will considerably improve the options for optimal treatment of high-risk patients. PMID- 28083600 TI - [Radiotherapeutic management of lymphatic fistulas : An effective but disregarded therapy option]. AB - BACKGROUND: Lymphatic fistulas and lymphoceles are known complications after vascular surgery of the groin and after extended surgical interventions in the pelvic region. Unfortunately, conservative standard therapies are not always successful. OBJECTIVES: Evaluation of the therapeutic efficacy and related side effects of percutaneous low-dose irradiation in patients with lymphorrhea and definition of its importance. MATERIAL AND METHODS: Current presentation of previously published case series, reviews and guidelines. RESULTS: The use of low dose irradiation therapy with single doses of 0.3-0.5 Gy leads to a cessation of the lymphatic flow in a high percentage of patients when standard therapies do not show a sufficient effect. With cessation of lymphorrhea irradiation should be terminated. Acute side effects have not been reported and the risk of tumor induction is almost negligible. CONCLUSION: Low-dose irradiation is an effective and very well-tolerated therapeutic alternative in the treatment of lymphatic fistulas and lymphorrhea when conservative therapies are unsuccessful. PMID- 28083601 TI - [Intraoperative pitfalls and complications in defecation disorders and rectal prolapse]. AB - BACKGROUND: No generally accepted gold standard exists for the operative therapy of rectal prolapse in its variety of manifestations. Existing evidence suggests that an individualized choice of procedure provides the best result for each single patient. Knowledge of possible pitfalls and intraoperative management of complications in frequently applied procedures are important prerequisites for reliable treatment of affected patients. MATERIAL AND METHODS: A consecutive series of 233 patients (June 2011-May 2016) with individualized choice of operative procedure in patients with rectal prolapse and rectocele based on an algorithm for a clinical treatment pathway and stapled hemorrhoidopexy were included. Intraoperative pitfalls and complications and their management (iPCM) were prospectively documented and analyzed. RESULTS: The iPCM could be classified into three different categories: group I: iPCM was immediately noted and intraoperatively treated with no impact on the further clinical course (n = 20), group II: iPCM was successfully treated conservatively within a short time after the procedure (n = 9) and group III: iPCM required surgical revision (n = 5). CONCLUSION: Individualized treatment of rectal prolapse and rectocele requires a broad spectrum of methods in specialized coloproctology units. A clinical treatment pathway facilitates the optimal choice of procedure. Overall the complication rates during surgical treatment of transanal rectal prolapse are low; however, available operative procedures hold specific risks and knowledge of these risks helps to avoid them. Once complications occur, measures demonstrated in this study lead to normal clinical courses in the majority of cases. PMID- 28083603 TI - Genetic Structure of the Armenian Population. AB - Located at the crossroads of Europe and the Middle East, the Armenian Highland served as a transition corridor for major waves of prehistoric and historic migrations. The genetic history of Armenians as an indigenous population of the region attracts keen scientific interest to resolve the puzzle of ancient Middle Eastern populations' expansion and the spread of Indo-European languages. Here, we review the current state of studies on the genetic structure of both modern and ancient inhabitants of the Armenian Highland and outline further steps to be fulfilled in this regard. PMID- 28083602 TI - [Isolated limb perfusion for liposarcoma : Histopathological response and subgroup analysis after TNF melphalan-based ILP]. AB - BACKGROUND: Tumor necrosis factor alpha (TNF) and melphalan-based isolated limb perfusion (TM-ILP) is one of the most effective treatment modalities for unresectable soft tissue sarcoma (STS) of the extremities. Liposarcomas (LS) are a large and heterogeneous subgroup of STS with different biological behavior and prognoses. The aim of this study was to evaluate LS and the different subentities with respect to their responsiveness towards TM-ILP. METHODS: We matched our ILP database with our pathology database to identify patients who received TM-ILP due to STS followed by resection of the residual tumor. We identified 126 patients who matched these inclusion criteria. In this patient group we identified 24 patients with a LS. Histopathological regression was assessed from all resection specimens and was compared between groups: LS vs. non-LS and for myxoid and non myxoid LS subgroups. RESULTS: There were no significant differences in the overall tumor regression comparing non-LS (median 95%, mean 77%) and LS (median 90%, mean 74%). For the subgroup analysis, a higher grade of regression after TM ILP was found in myxoid-LS (median 95%, mean 79% +/- 31.5) compared to the non myxoid LS (median 75%, mean 72% +/- 24.6). Atypical lipomatous tumors (ALT) were less responsive to TM-ILP treatment (median 40%, mean 40%). CONCLUSION: The histopathological response of LS toward TM-ILP is equally good compared to non lipomatous STS. Myxoid LS seem to have a tendency towards a better response to TM ILP compared to non-myxoid LS and ALT showed the lowest response rate in the liposarcoma subgroup. Furthermore, we found that TM-ILP seems to facilitate successful R0 resection. Due to the low number of cases in the subgroups we advocate further research on this topic. PMID- 28083604 TI - The Frequency of CCR5del32 Mutation in Populations of Russians, Tatars and Bashkirs of Chelyabinsk Region, Russia. AB - The distribution of genetic variants associated with natural resistance to viral infections can vary among human ethnic groups due to evolutionary factors, defining the different epidemiologic background of world populations. The polymorphisms, defining the natural resistance to HIV-infection and the rate of progression up to AIDS, are very important since epidemic is still on rise. We have studied the distribution of allele and genotype frequencies of CCR5delta32 mutation in major populations inhabiting Chelyabinsk region of the Russian Federation. Genetic survey included the population of 509 potential blood marrow donors: Russians (N = 300), Bashkirs (N = 118) and Tatars (N = 91). The genotyping assay was performed using real-time polymerase chain reaction (real time PCR). The genotypes were defined by melting curve analysis. The CCR5delta32 allele and CCR5delta32/delta32 genotype are presented in population of Russians in Chelyabinsk region with the frequencies of F x = 10.83% and P x = 1.67, for the CCR5delta32 allele and its homozygosity, respectively. In populations of Bashkirs and Tatars CCR5delta32 allele and CCR5delta32/delta32 genotype are presented at lower frequencies of F x = 6.36%/P x = 0.85 and F x = 7.14%/P x = 1.10, respectively. These data are consistent with the theory of northern origin of the CCR5delta32 mutation. PMID- 28083605 TI - Genetic Factors of Diabetes. AB - Monogenic diabetes is a rare genetic type of diabetes caused by pancreatic beta cells dysfunction. All subtypes of monogenic diabetes are recognized in the pediatric population. They include maturity onset diabetes of the young, permanent neonatal diabetes mellitus and rare syndromic forms of diabetes. An early and proper diagnosis allows to implement an optimal treatment, leads to improved metabolic control and amelioration of related disabilities as well as increases the quality of life of the patients. PMID- 28083606 TI - The Influence of HLA and KIR Genes on Malignant Melanoma Development and Progression. AB - Many studies have described the role of killer immunoglobulin-like receptors (KIRs) and their cognate human leukocyte antigen (HLA) class I ligands in the immune protection against melanoma, but the effect of these markers on intra individual variations in tumor development and progression has remained less clear. We performed KIR, HLA, and KIR/ligand analysis in 283 patients with malignant melanoma in order to evaluate their integrated influence on disease stage and progression. The patients were grouped according to AJCC staging, histological type of the primary tumor, progression, and survival rate. Analysis of HLA class I alleles revealed positive association of HLA-C*14 (Pc = 0.026, OR = 5.99) and negative association of HLA-C*02 (Pc = 0.026, OR = 0.43) with the disease. Decreased frequency of KIR2DS5 was observed in patients with rapid progression, as compared to those with slow progression. KIR BB genotype was prevalent in patients with metastasis (p = 0.004, OR = 0.025). KIR AA genotype was nearly twice as frequent in rapidly progressive cases, but without statistical relevance (p = 0.055, OR = 2.6). Significantly increased frequency of KIR2DL2 in the presence of C1 ligand (strong inhibition) was found in patients with AJCC III and IV, as compared to individuals with AJCC I stage (p = 0.045, OR = 1.93). In summary, our data imply that KIR/ligand gene content in patients could modulate the disease course towards unfavorable tumor behavior. PMID- 28083607 TI - The Expression of Toll-Like Receptors in Patients with B-Cell Chronic Lymphocytic Leukemia. AB - B-cell chronic lymphocytic leukemia (B-CLL) presents with progressive accumulation of monoclonal B cells in the peripheral blood, bone marrow and lymphoid organs. B-CLL is characterized by heterogeneous clinical outcome. The expression of Toll-like receptors (TLRs) and their association with other prognostic factors in B-CLL patients remain unclear. The aim of our study was to evaluate the expression of TLR2, TLR4 and TLR9 genes and their significance as biological markers in patients with B-CLL. Sixty patients with newly diagnosed B CLL were evaluated. The healthy control group included 20 age-matched individuals. Using quantitative reverse transcriptase PCR, the mRNA expression of genes TLR2, TLR4 and TLR9 was measured. TLR4 gene expression was lower in B-CLL patients as compared to the control group and TLR2 gene expression was higher in B-CLL patients than in healthy individuals. TLR9 gene expression was higher in the control group than in patients with B-CLL. TLR4 mRNA expression was lower in patients with advanced-stage CLL (Rai stages III and IV) than in patients with early stage disease (Rai stages 0-II). TLR2 gene expression was higher in patients with advanced-stage CLL (Rai stages III and IV) than in patients with early stage disease (Rai stages 0-II; p < 0.05). Our results suggest that TLRs could become potential biological markers for the clinical outcome in patients with B-CLL. PMID- 28083608 TI - Soluble BAFF Cytokine Levels and Antibody-Mediated Rejection of the Kidney Allograft. AB - The B-cell activating factor (BAFF) cytokine has important functions for the survival and maturation of B lymphocytes, which implies that this cytokine might play a role in the development of antibody-mediated rejection (AMR) after kidney transplantation. In our study, we compared the concentrations of the soluble BAFF cytokine in kidney graft recipients with AMR and patients without rejection with the goal of testing the hypothesis whether BAFF level measurement might be useful as a diagnostic marker of AMR. The study included a cohort of 19 high-risk patients with diagnosed AMR and 17 control patients free of rejection. BAFF was measured in all patients before transplantation, during the rejection episodes, and three months after transplantation in patients free of rejection using the Luminex technique. Before transplantation, the serum concentrations of BAFF in patients with AMR and kidney recipients without rejection did not significantly differ. After transplantation, however, BAFF levels were significantly lower in patients with AMR and also in patients with concurrent humoral and cellular rejection compared with patients without rejection (p < 0.05 and p < 0.01, respectively). No correlation was found between BAFF and the production of donor specific antibodies (DSA) before and after transplantation. Patients experiencing AMR and simultaneous cellular and AMR had significantly lower concentrations of BAFF in comparison with patients free of rejection. PMID- 28083609 TI - An Association Between Functional Polymorphisms of the Interleukin 1 Gene Complex and Schizophrenia Using Transmission Disequilibrium Test. AB - IL1 gene complex has been implicated in the etiology of schizophrenia. To assess whether IL1 gene complex is associated with susceptibility to schizophrenia in Polish population we conducted family-based study. Functional polymorphisms from IL1A (rs1800587, rs17561, rs11677416), IL1B (rs1143634, rs1143643, rs16944, rs4848306, rs1143623, rs1143633, rs1143627) and IL1RN (rs419598, rs315952, rs9005, rs4251961) genes were genotyped in 143 trio with schizophrenia. Statistical analysis was performed using transmission disequilibrium test. We have found a trend toward an association of rs1143627, rs16944, rs1143623 in IL1B gene with the risk of schizophrenia. Our results show a protective effect of allele T of rs4251961 in IL1RN against schizophrenia. We also performed haplotype analysis of IL1 gene complex and found a trend toward an association with schizophrenia of GAGG haplotype (rs1143627, rs16944, rs1143623, rs4848306) in IL1B gene, haplotypes: TG (rs315952, rs9005) and TT (rs4251961, rs419598) in IL1RN. Haplotype CT (rs4251961, rs419598) in IL1RN was found to be associated with schizophrenia. After correction for multiple testing associations did not reach significance level. Our results might support theory that polymorphisms of interleukin 1 complex genes (rs1143627, rs16944, rs1143623, rs4848306 in IL1B gene and rs4251961, rs419598, rs315952, rs9005 in IL1RN gene) are involved in the pathogenesis of schizophrenia, however, none of the results reach significance level after correction for multiple testing. PMID- 28083610 TI - Characterization of Three CYP2C19 Gene Variants by MassARRAY and Point of Care Techniques: Experience from a Czech Centre. AB - Distribution of cytochrome P450 2C19 enzyme gene (CYP2C19) variants affecting metabolism of clopidogrel was determined in 526 Czech patients after percutaneous coronary intervention using MassARRAY genotyping and compared to distribution in other populations of European descent. Fifty-three (10%) patients underwent parallel determination of CYP2C19 genotypes from buccal swabs by a point of care technique with 100% concordance to the main genotyping platform. Observed CYP2C19 genotypes were related to clopidogrel metabolism phenotypes and discussed in population context. Hereby, presented methodologies provide accurate CYP2C19 genotyping results in a relatively short time of one up to 12 h and may, therefore, find the relevant place in the field of genotype-guided antiplatelet therapy. PMID- 28083611 TI - Distribution of HLA-DQB1 in Czech Patients with Central Hypersomnias. AB - The aim of our study was to analyze the distribution of HLA-DQB1 in Czech patients with central hypersomnias and differences between diagnostic groups of narcolepsy type 1 (NT1), type 2 (NT2), idiopathic hypersomnia (IH) and no central hypersomnia subjects (no-CH). Statistical analysis of DQB1 genotyping was performed on the cohort of 716 patients (375 men, 341 women) with reported excessive daytime sleepiness. DQB1*06:02 allele was present in 94% of the NT1 patients. The decrease of DQB1*06:03 allele was also confirmed. No other DQB1*06 allele nor any other DQB1 allele group was differently distributed in the NT1. In the cohort of NT2 patients DQB1*06:02 allele was present in 43%. Allele group DQB*05 was detected with a significantly higher frequency in this diagnostic unit. Any differences in presence of DQB1*05 alleles in NT2 patients were not reported so far. The cohort of patients with IH did not show any difference in allele distribution of DQB1 alleles/allele groups comparing to healthy controls. DQB1*06:02 allele was significantly increased in the no hypersomnia group. No other DQB1 allele/allele group had any difference in distribution in patients comparing to healthy controls. The different distribution of DQB1*06:02 and other DQB1 alleles/allele groups was detected in analyzed diagnostic groups. These results indicate that DQB1 contributes to the genetic predisposition to NT1, NT2, IH and no-CH in different manners. PMID- 28083612 TI - Transplantology: Challenges for Today. AB - Clinical transplantology in Poland had its 50th anniversary this year. With the early and long results comparable to the best achieved in the world leading centers, we face old and completely new challenges for this medical speciality. Main and growing challenge is insufficient number of available organs. With less than 15 donors/mln population/year Poland stay in the lower row of European countries in this measurement of transplant activity. Donation system is not efficient enough and we lose a big number of potential donors still. Living donation (with the exception for the fragments of the liver) remains low despite of different initiatives made so far on the national and local levels. Donation after cardiac death is possible from the point of Polish juridical regulations, but since last 3 years had not showed real impact on country donation rates (only three procedures done). Methods of tissue typing remain slow and cause relatively long times of cold ischemia for kidney programs. Second main challenge is chronic rejection causing loss of organs in the long-term follow-up and no efficient treatment employed. The emerging possibility of tolerance induction despite of plenty of new protocols proposition in the publications does not show up a clinical everyday practice in work. The same is with xenotransplantation promises; even we were informed recently that till 2030 such genetically modified porcine organs will be available. The next challenge is production of organs and tissues from own recipients cells installed on the different scaffolds or 3D printed. Other challenge is the personnel working in this field. We observe like in the other European countries lack of new candidates for work in this field together with serious problems of nursing staff, being a catastrophic perspective in country medical service in general, not only in transplant centers. The last but not least challenge is financial side of transplant programs. PMID- 28083614 TI - Significance of Polymorphism and Expression of miR-146a and NFkB1 Genetic Variants in Patients with Rheumatoid Arthritis. AB - MicroRNA-146a (miR-146a) has been shown to play an important role in the regulation of inflammatory innate immune responses, and found to be differentially expressed in rheumatoid arthritis (RA). Through NF-kappaB pathway, this molecule is able to stimulate the release of pro-inflammatory cytokines such as TNF-alpha, IL-1beta, and IL-17. It has been also suggested that single nucleotide polymorphisms (SNPs) in miRNA sequences may alter miRNA expression and that miR-146a rs2910164 SNP may contribute to RA development. These observations prompted us to analyze the potential associations between the miR-146a-3p (rs2910164, G > C) and NFkB1 (rs28362491, ins/del ATTG) polymorphisms and miR 146a-5p expression in patients' sera in relation to clinical outcome of the treatment as well as predisposition to RA. Genotyping was performed in 111 patients and 130 healthy individuals while 16 controls and 13 RA patients (before and after three months of therapy with TNF-alpha inhibitors (TNFi)) were studied for the circulating miR-146a-5p serum expression level. Patients carrying the NFkB1 ins/ins genotype were characterized by worse response to TNFi treatment (p = 0.023). In patients, before TNFi therapy, expression levels of miR-146a-5p were less (0.422 +/- 0.171) as compared to those detected after three months of treatment (1.809 +/- 0.658, p = 0.033) and observed for healthy controls (5.302 +/- 2.112, p = 0.048). Moreover, patients with higher circulating miR-146a-5p levels after three months of TNFi administration were more frequently carrying the rs2910164-C allele (p = 0.032). These results support the hypothesis that miR 146a might be involved in pathogenesis of RA and imply that miR-146a-3p polymorphism may be associated with miR-146a-5p levels in serum after anti-TNF alpha treatment. PMID- 28083613 TI - Single Nucleotide Polymorphisms of the ERAP1 Gene and Risk of NSCLC: A Comparison of Genetically Distant Populations, Chinese and Caucasian. AB - An effective cytotoxic immune response to neoplastic cells requires efficient presentation of antigenic peptides to T lymphocytes by HLA class I (HLA-I) molecules. The HLA-I-bound peptide repertoire depends on antigen-processing machinery molecules. Aminopeptidase residing in endoplasmic reticulum 1 (ERAP1) trims peptides to the optimal length for HLA-I binding. Single nucleotide polymorphisms (SNPs) in the ERAP1 gene result in changes in aminopeptidase activity and specificity. This may affect susceptibility to cancer. However, non small cell lung carcinoma (NSCLC) has not been studied in this respect. We compared genotype and haplotype frequencies of four coding, nonsynonymous ERAP1 SNPs, rs26653G > C, rs26618T > C, rs30187C > T, and rs27044C > G, in NSCLC occurring in two genetically distant populations, Chinese and Poles. We found associations of all four SNPs with NSCLC in Chinese but not in Poles. The differences in ERAP1-NSCLC associations might be explained by highly significant differences in SNP genotype frequencies between Chinese and Poles (except for rs26618). In accordance with this, the most frequent ERAP1 haplotypes were distributed differently in cases versus controls in Chinese, but not in Poles. Our findings add to the differences between Orientals and Caucasians in genetics of disease susceptibility. PMID- 28083615 TI - Functional Polymorphism in the Interleukin 6 (IL6) Gene with Respect to Depression Induced in the Course of Interferon-alpha and Ribavirin Treatment in Chronic Hepatitis Patients. AB - Interleukin (IL)-6 is a multifactorial cytokine known to be increased in patients with chronic hepatitis C (CHC) and to be predictive of depression incidence. The aim of the study was to explore the association between IL6 gene C-174G polymorphism and depressive symptom severity in the longitudinal study design following the course of pegylated interferon/ribavirin treatment in CHC patients. In our study, we included 62 CHC subjects. They were assessed using present state examination, Beck Depression Inventory (BDI) and Montgomery Asberg Depression Rating Scale (MADRS) at weeks 0, 3, 5, 9, 13, 24 and 24 weeks after the end of treatment. The risk of depression was associated with higher baseline MADRS score and BDI score. Interestingly, when stratified by IL6 C-174G polymorphism, higher baseline depressive symptom severity measured by MADRS and BDI predicted higher risk of depression in the course of antiviral treatment only in high IL-6 producers-G allele carriers (patients with GG and CG genotypes) (p = 0.004, p = 0.00008, respectively). There is interaction between severity of baseline depressive symptoms at the beginning of antiviral therapy and IL6 gene C-174G polymorphism leading to increased risk for the development of depressive episode in CHC patients in the course of antiviral treatment. PMID- 28083616 TI - ERAP1 and ERAP2 Gene Variations Influence the Risk of Psoriatic Arthritis in Romanian Population. AB - Psoriatic arthritis (PsA) is a chronic inflammatory disorder that belongs to the group of spondyloarthritis (SpA). It was found that single nucleotide polymorphisms (SNPs) of endoplasmic reticulum aminopeptidase (ERAP1 and ERAP2) genes influence the risk of ankylosing spondylitis, the most common form of SpA and the risk of psoriasis. Our purpose was to investigate the possible association of ERAP1 and ERAP2 gene SNPs with psoriatic arthritis susceptibility in Romanian population. Subsequent analyses included patients' subgroups according to HLA-B27 status. Psoriatic arthritis patients (N = 98) and random healthy controls (N = 139) were genotyped for ERAP1/2 genes SNPs rs30187, rs27044, rs2910686, and rs2248374 by TaqMan Allelic Discrimination Assays. An additional control group (N = 108; 100% HLA-B27 positive) was used for subsequent analyses. The results showed the association of rs2248374 SNP of ERAP2 gene with the risk of PsA, especially for HLA-B27 negative disease (p = 0.02; OR 1.59). ERAP2 haplotype GT (rs2248374/rs2910686) was significantly under-represented in PsA patients than in controls (43 vs. 55%; p = 0.02). The analysis of ERAP1 SNPs in HLA-B27 positive controls and PsA subgroup showed strong evidence of association for rs30187 (p = 0.005; OR 2.73) and for CC rs30187/rs27044 haplotype (47% in patients vs. 70.5% in controls; p = 0.006). In conclusion, we found a significant association of ERAP2 with PsA and HLA-B27 negative PsA, while ERAP1 association was restricted only to HLA-B27 positive disease. To our knowledge, this is the first study that investigated ERAP2 polymorphisms in relation to PsA susceptibility. PMID- 28083617 TI - Profile of Inflammation-Associated Proteins in Early Post-Transplant Samples of Patients After Allogeneic Hematopoietic Stem Cell Transplantation: a Preliminary Study. AB - Allogeneic hematopoietic stem cell transplantation (aHSCT) is used as a curative treatment in severe hematological and immunological disorders. Despite clear improvement of the aHSCT outcome, substantial proportion of patients still suffers from severe complications, including graft-versus-host disease (GvHD). The aim of this study was, therefore, to identify inflammation-associated molecules deregulated in the early serum samples of the patients after aHSCT and nominate markers associated with particular aHSCT parameters/complications. Serum concentrations of 92 inflammation-associated proteins were measured in samples obtained from 80 aHSCT patients 14 days after transplantation and from 23 healthy control subjects by a novel sensitive proximity extension assay technology using Proseek Multiplex Inflammation I kit. Serum profiles of inflammatory proteins in patients after aHSCT were substantially different from those observed in control subjects and related to underlying disease status before transplantation. Particularly, the difference between aHSCT patients and controls reached significance level for 57 analytes (40 upregulated, 17 downregulated in aHSCT patients). The concentration of several markers was associated with the level of donor/recipient HLA match (TGF-alpha: p corr = 0.025, HGF: p corr = 0.036) and with complete donor chimerism at day +30 after allografting (DNER: p corr = 0.042). None of the markers was significantly associated with acute and chronic GvHD after correction. More than half of investigated proteins significantly differed between the samples from aHSCT patients and healthy control subjects as a consequence of the "cytokine storm" after aHSCT. Comparisons of patient's subgroups based on specific biological/clinical parameters revealed much less evident differences; nevertheless, we nominated several markers associated with the level of donor/recipient HLA match and post-transplant chimerism. PMID- 28083618 TI - Cereblon and IRF4 Variants Affect Risk and Response to Treatment in Multiple Myeloma. AB - Multiple myeloma (MM) is a plasma-cell malignancy derived from an early precursor of the B-cell lineage characterised by bone-marrow infiltration, lytic bone lesions, and the presence of a monoclonal protein in serum and/or urine. Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator in B-cell development and function that is required during immune response for lymphocyte activation and the generation of immunoglobulin-secreting plasma cells. Immunomodulatory drugs, derivatives of thalidomide, are commonly used in therapy against MM. They are known to target a protein called cereblon (CRBN); however, the exact mechanism remains unknown. The present study aimed to assess the association of two (rs12203592 and rs872071) polymorphisms within the IRF4 gene and two (rs711613 and rs1045433) in the CRBN gene with MM susceptibility, progression, and response to treatment. For this purpose, 144 MM patients and 126 healthy individuals were genotyped for the IRF4 and CRBN alleles. The presence of the IRF4 (rs872071) G allele was more frequently detected in patients than healthy individuals (OR 1.78; P = 0.034), and this relationship was especially pronounced in women (OR 2.83; P = 0.012). The CRBN (rs711613) A allele-carriers were better responders to the treatment (P = 0.012), in particular to thalidomide including therapy (P = 0.023). These results underline the prognostic significance of the IRF4 and CRBN polymorphisms in patients with MM. PMID- 28083619 TI - Determination of HLA-A, -B, and -DRB1 Allele and Haplotype Frequencies in the Croatian Population Based on a Family Study. AB - In the present study, HLA allele and haplotype frequencies among Croatian families were investigated to evaluate valuable information about HLA genotypes and to compare them with data from the Croatian Bone Marrow Donor Registry (CBMDR). A total of 350 families which have been typed for the purpose of HSCT were included. All individuals were tested using PCR-SSO or PCR-SSP methods for HLA-A, -B, and -DRB1 alleles. The HLA-A-B-DRB1 haplotypes were determined by segregation and directly counted. A total of 30 HLA-A, 54 HLA-B, and 38 HLA-DRB1 alleles and 716 different HLA-A-B-DRB1 haplotypes were identified. Of these, the three most frequent alleles at HLA-A, -B, and -DRB1 loci, respectively, were A*02:01 (30.39%), A*11:01 (13.37%), A*24:02 (10.91%); B*51:01 (12.48%), B*18:01 (8.35%), B*08:01 (8.06%); DRB1*03:01 (11.20%), DRB1*01:01 (9.84%), DRB1*16:01 (9.63%). The following HLA alleles were detected only once: A*02:09, A*24:03, A*24:04, A*24:07; B*07:04, B*15:07, B*15:08, B*39:04, B*39:10, B*39:24, B*40:04; DRB1*08:03, DRB1*11:06, DRB1*13:32, DRB1*14:05. Five most frequent haplotypes were: A*01:01-B*08:01-DRB1*03:01 (5.34%), A*02:01-B*18:01-DRB1*11:04 (1.57%), A*02:01-B*27:02-DRB1*16:01 (1.50%), A*02:01-B*27:05-DRB1*01:01 (1.42%) and A*02:01-B*44:02:01G-DRB1*16:01 (1.28%). The haplotype frequencies based on the family study were compared with the frequencies from CBMDR, and similar results were obtained for all except for the HLA-A*26:01-B*38:01-DRB1*04:02 haplotype. A significantly higher frequency (P = 0.0017) of this haplotype was observed among family individuals. Nine haplotypes were unique and data about their frequencies do not exist in current databases. The data obtained in this study could be useful for anthropology, transplantation and disease association studies. PMID- 28083620 TI - Apportioning Blame: Autoreactive CD4+ and CD8+ T Cells in Type 1 Diabetes. AB - Type 1 diabetes (T1D) is one of the most studied archetypal organ-specific autoimmune diseases. Although many clinical, epidemiological, and pathological characteristics have been described, there are still important issues which need to be resolved as these will have a major impact on the development of future antigen-specific immunotherapies. An important question relates to T lymphocytes in the development of the disease, in particular their role in the destruction of insulin-producing beta cells. Since the discovery that certain class II histocompatibility complex molecules (HLA) are linked to the development of T1D, much research has focused on CD4+ helper T lymphocytes; however, recent studies highlight class I HLA molecules as an independent risk factor; hence, research into the role played by CD8+ cytotoxic T lymphocytes has gained momentum. In this review, we summarize recent studies clarifying the role played by both sets of autoreactive T lymphocytes in T1D, discuss the targets recognized by these cells and their phenotype in T1D patients. Finally, we will examine the possible generation of regulatory CD8+ T lymphocytes upon different immuno-intervention strategies. PMID- 28083621 TI - Mutation c.256_257delAA in RAG1 Gene in Polish Children with Severe Combined Immunodeficiency: Diversity of Clinical Manifestations. AB - Mutations in RAG1 gene may result in different types of severe combined immunodeficiencies. In this study, we compare clinical symptoms and laboratory findings in four children with identical mutation in RAG1 gene. All of analyzed patients presented symptoms of severe combined immunodeficiencies associated or not with Omenn syndrome (OS) features. In our patients two different types of variants in RAG1 gene were detected. The first of the mutation was the deletion of AA dinucleotide at position c.256_257 (p.Lys86ValfsTer33), the second gene variant was substitution c.2867T>C (p.Ile956Thr). In Patient 1 we detected that compound heterozygous mutations involved both of the mentioned variants. Whereas, in Patients 2, 3 and 4, we confirmed the presence of the dinucleotide deletion but in a homozygous state. In all described patients, sequence analysis of RAG2 gene did not reveal any nucleotide changes. Our data show that mutation c.256_257delAA in RAG1 gene seems to occur quite frequently in the polish patients with severe combined immunodeficiency and may result in classical OS as well as in severe combined immunodeficiency without clinical and laboratory features of OS when occurred in homozygous state. The same mutation but in heterozygous state, in combination with other mutation in RAG1 gene, may result in incomplete OS. PMID- 28083622 TI - Aspiration thrombectomy in clinical routine interventional stroke treatment : Is this the end of the stent retriever era? AB - PURPOSE: The aim of our study was the technical evaluation of a first pass approach of primary thrombus aspiration (AST) in patients with emergency large intracerebral vessel occlusions (ELVO) under routine clinical conditions. MATERIALS AND METHODS: We collected procedural and clinical data of 104 patients who underwent mechanical thrombectomy due to ELVO between June 2014 and January 2016 with intentional first-line thrombus aspiration. Procedures were conducted due to occlusions of the distal internal carotid artery, middle cerebral artery, anterior cerebral artery, basilar artery and posterior cerebral artery and were performed with the patient under either conscious sedation or general anesthesia. If the AST technique failed completely or to some extent, stent retriever-based thrombectomy (SRT) was performed. RESULTS: As a stand-alone method AST was successful in achieving TICI (Thrombolysis in Cerebral Infarction) score 2b or 3 results in 29 cases (27.8%). After additional use of SRT successful recanalization was achieved in a total of 95 cases (91.3%, p = 0.048). If AST was performed exclusively, median procedure time until TICI 2b/3 was 15 min, in cases of combined procedures 35 min (p = 0.001). Subarachnoid hemorrhage (SAH) after thrombectomy appeared only if additional SRT was performed (12.0%) and not in cases of AST maneuvers alone (p = 0.09). CONCLUSION: When used as a first pass attempt AST is a fast and safe approach for patients suffering from stroke due to ELVO. Nonetheless, early conversion to SRT is needed in most cases and leads to overall excellent procedural results with low complication rates. PMID- 28083624 TI - [Perioperative management of patients on NOACs]. AB - Regarding thromboembolic events, non-vitamin K antagonists, so-called new oral anticoagulative agents (NOACs), have widely enlarged prophylaxis and therapy. In contrast to vitamin K antagonists they can be administered in a definite dose and do not need any regular control of coagulation parameters. Thus being simple in handling, these drugs have become enormously attractive for both patient and physician.In spite of all their advantages NOACs have to be considered carefully. They have a significant disadvantage: the plasma concentration is not detectable by a simple blood test, nor is there any antidote available. As a consequence the bleeding risk remains unknown.In this review we focus on two different settings in routine surgical work: the preoperative management of patients undergoing elective surgery differs significantly from that needed in urgent surgery. PMID- 28083623 TI - Sulforaphane promotes ER stress, autophagy, and cell death: implications for cataract surgery. AB - : Posterior capsule opacification (PCO) commonly develops following cataract surgery and is a wound-healing response that can ultimately lead to secondary visual loss. Improved management of this problem is required. The isothiocyanate, sulforaphane (SFN), is reported to exert cytoprotective and cytotoxic actions, and the latter may be exploited to treat/prevent PCO. SFN concentrations of 10 MUM and above significantly impaired wound-healing in a human lens capsular bag model. A similar pattern of response was also seen with a human lens cell line, FHL124. SFN treatment promoted increased expression of endoplasmic reticulum (ER) stress genes, which also corresponded with protein expression. Evidence of autophagy was observed in response to SFN as determined by increased microtubule associated protein 1A/1B-light chain 3 (LC3)-II levels and detection of autophagic vesicles. This response was disrupted by established autophagy inhibitors chloroquine and 3-MA. SFN was found to promote MAPK signaling, and inhibition of ERK activation using U0126 prevented SFN-induced LC3-II elevation and vesicle formation. SFN also significantly increased levels of reactive oxygen species. Taken together, our findings suggest that SFN is capable of reducing lens cell growth and viability and thus could serve as a putative therapeutic agent for PCO. KEY MESSAGE: SFN reduces lens epithelial cell growth, migration, and viability. SFN can promote ER stress and autophagy in lens cells. SFN promotes MAPK signaling, and inhibition of MEK can suppress SFN-induced autophagy. ER stress and autophagy in lens cells are likely promoted by ROS production. SFN may help prevent posterior capsule opacification after cataract surgery. PMID- 28083626 TI - [Urine sample during and after biliary obstruction in cholangitis]. PMID- 28083625 TI - [Monitoring of NOAC]. AB - BACKGROUND: Monitoring non-vitamin K antagonist oral anticoagulants (NOAC) is usually not necessary; however, in some patients it may prove beneficial. OBJECTIVES: Patient subgroups who may profit from monitoring were identified, and methods of monitoring (including assessment of which coagulation parameters are affected by NOAC) are described. MATERIALS AND METHODS: We searched the PubMed database for each of the search terms, "NOAC", "DOAC", "rivaroxaban", "dabigatran", and "apixaban", in combination with one of the terms, "monitoring", "measurement", "measuring", or "assessment". The results were compiled and reviewed. RESULTS: Monitoring is most advantageous in emergency cases with severe bleeding where drug activity needs to be assessed. It can also help in deciding for or against lysis therapy after acute stroke in patients taking NOAC. Furthermore, it can also identify compliance problems and help in planning periprocedural management. There are quantitative measurement methods which measure plasma concentrations exactly and qualitative methods which only allow for a rough estimate or a general confirmation of drug activity. Recommended quantitative measurement methods are diluted thrombin time for dabigatran, and anti-factor Xa activity (calibrated) for rivaroxaban and apixaban. CONCLUSIONS: Several patient subgroups may profit from monitoring of NOAC plasma concentration. One should, however, take several issues into consideration before measurements, such as the objective of each individual measurement, possible consequences (e. g., dose adjustment), and which measurement method to pick. PMID- 28083627 TI - [Triceps tendon rupture : Double-row repair and overview of alternative techniques]. AB - Triceps tendon rupture is a rare injury. While partial tendon ruptures can be treated non-operatively, complete ruptures are an indication for surgical treatment in order to restore strength and a full range of motion. Although many different methods have been published, there is no consensus on the optimal surgical technique.We report the case of a patient who suffered from a complete triceps rupture after a fall. The injury was treated by open reduction and refixation of the tendon using the double-row technique. The following article describes the technique and highlights its advantages and disadvantages in comparison to other procedures. PMID- 28083628 TI - [Basic research in traumatology and its contribution to routine operation]. AB - Basic research in traumatology supports the clinical outcome of patients in trauma care and tries to find science-based solutions for clinical problems. Furthermore, institutions for basic research in traumatology usually offer training in different skills, such as how to write a scientific paper, or practice in microsurgery or intubation. Two examples of clinically significant research topics are presented. PMID- 28083629 TI - [Salmonella osteomyelitis - a rare differential diagnosis of bone tumors]. AB - This case describes a rare salmonella infection suspected to be an osseous lymphoma. A 27-year-old female presented herself with painful swelling of her knee, with prednisolone-treated Crohn's disease as her only pre-existing condition. Salmonella species group C were detected in the osseous material derived from an extraction. The disease was treated with intravenous ceftriaxone, oral cotrimoxazole as well as multiple debridements. The working diagnosis should thus always be questioned and bone pain in patients who are immunosuppressed should be further investigated. PMID- 28083630 TI - [Teaching medical students informed consent]. AB - BACKGROUND AND OBJECTIVES: Teaching competencies in communication are important for medical education, but implementation in the surgical curriculum is still deficient. Communication during informed consent is one main issue. The aim of the study was to implement a reproducible teaching module for informed consent, which closely represents reality. MATERIAL AND METHODS: In the existing practical surgical course we implemented a module for practising communication during surgical informed consent with the help of standardized patients and feedback rounds. The outcome was assessed during a clinical examination and the students evaluated the module. RESULTS: The module was evaluated by the students positively and deemed helpful for their later work as a doctor. The outcome at clinical examination was 63% (mean) for content and structure of the informed consent and 92% for competency in communication. CONCLUSION: For improving the quality of informed consent, teaching competencies in communication during informed consent should be implemented in the curriculum of medical studies, but legal and content-based aspects should not be ignored. PMID- 28083631 TI - [The complicated course of a femoral shaft fracture in childhood]. AB - We report a difficult healing process after a femoral shaft fracture in childhood. We present surgical correction options of femoral shortening due to pseudarthrosis after elastic stable intramedullary nailing. First, we tried to establish distraction using an external fixator, followed by plate osteosynthesis. After material failure of plate osteosynthesis, we treated the refracture with intramedullary nailing, after which bone healing occurred. PMID- 28083632 TI - Do horses with poor welfare show 'pessimistic' cognitive biases? AB - This field study tested the hypothesis that domestic horses living under putatively challenging-to-welfare conditions (for example involving social, spatial, feeding constraints) would present signs of poor welfare and co occurring pessimistic judgement biases. Our subjects were 34 horses who had been housed for over 3 years in either restricted riding school situations (e.g. kept in single boxes, with limited roughage, ridden by inexperienced riders; N = 25) or under more naturalistic conditions (e.g. access to free-range, kept in stable social groups, leisure riding; N = 9). The horses' welfare was assessed by recording health-related, behavioural and postural indicators. Additionally, after learning a location task to discriminate a bucket containing either edible food ('positive' location) or unpalatable food ('negative' location), the horses were presented with a bucket located near the positive position, near the negative position and halfway between the positive and negative positions to assess their judgement biases. The riding school horses displayed the highest levels of behavioural and health-related problems and a pessimistic judgment bias, whereas the horses living under more naturalistic conditions displayed indications of good welfare and an optimistic bias. Moreover, pessimistic bias data strongly correlated with poor welfare data. This suggests that a lowered mood impacts a non-human species' perception of its environment and highlights cognitive biases as an appropriate tool to assess the impact of chronic living conditions on horse welfare. PMID- 28083633 TI - [Systematic errors in clinical studies : A comprehensive survey]. AB - Systematic errors and related phenomena represent an intrinsic challenge to the quality of clinical research. As a consequence even otherwise methodologically demanding studies may produce results that systematically differ from the true values. Systematic errors relating to investigative medicine are divided into six groups according to their affiliation with the consecutive chronological sections of the study. Bias can occur in preliminary literature research in the field, specifying the study design and selecting the study sample, measuring exposure and outcome, analyzing the data, interpreting the analyses and publishing the results. The most important systematic errors that concern diagnostic and interventional studies are created by access to the data of previous tests, calculated study design, preselection of the participants, comparison with non contemporaneous controls, antedating the time of diagnosis and overdiagnosis of slowly progressive forms of diseases examined. Checking the measured values often leads to a mosaic of several biases with one being more or less dominant. Even by exercising due care in the preparation and performance of the study, the majority of distortions cannot be eliminated but only diminished. It is essential to consider each detected bias as a potential full or partial argument in support of an observed correlation. The control of systematic errors and related phenomena is both a significant element of the discussion of the study report and a key element for assessment of its scientific value. PMID- 28083634 TI - Tau interactome mapping based identification of Otub1 as Tau deubiquitinase involved in accumulation of pathological Tau forms in vitro and in vivo. AB - Dysregulated proteostasis is a key feature of a variety of neurodegenerative disorders. In Alzheimer's disease (AD), progression of symptoms closely correlates with spatiotemporal progression of Tau aggregation, with "early" oligomeric Tau forms rather than mature neurofibrillary tangles (NFTs) considered to be pathogenetic culprits. The ubiquitin-proteasome system (UPS) controls degradation of soluble normal and abnormally folded cytosolic proteins. The UPS is affected in AD and is identified by genomewide association study (GWAS) as a risk pathway for AD. The UPS is determined by balanced regulation of ubiquitination and deubiquitination. In this work, we performed isobaric tags for relative and absolute quantitation (iTRAQ)-based Tau interactome mapping to gain unbiased insight into Tau pathophysiology and to identify novel Tau-directed therapeutic targets. Focusing on Tau deubiquitination, we here identify Otub1 as a Tau-deubiquitinating enzyme. Otub1 directly affected Lys48-linked Tau deubiquitination, impairing Tau degradation, dependent on its catalytically active cysteine, but independent of its noncanonical pathway modulated by its N terminal domain in primary neurons. Otub1 strongly increased AT8-positive Tau and oligomeric Tau forms and increased Tau-seeded Tau aggregation in primary neurons. Finally, we demonstrated that expression of Otub1 but not its catalytically inactive form induced pathological Tau forms after 2 months in Tau transgenic mice in vivo, including AT8-positive Tau and oligomeric Tau forms. Taken together, we here identified Otub1 as a Tau deubiquitinase in vitro and in vivo, involved in formation of pathological Tau forms, including small soluble oligomeric forms. Otub1 and particularly Otub1 inhibitors, currently under development for cancer therapies, may therefore yield interesting novel therapeutic avenues for Tauopathies and AD. PMID- 28083636 TI - Content Validity of a Short Calcium Intake List to Estimate Daily Dietary Calcium Intake of Patients with Osteoporosis. AB - PURPOSE: Calcium supplements are prescribed for prevention of osteoporotic fractures, but there is controversy whether excess of calcium intake is associated with cardiovascular events. While an accurate estimation of dietary calcium intake is a prerequisite to prescribe the adequate amount of supplementation, the most adequate tools for estimating intake are time consuming. The aim of this study is to validate a short calcium intake list (SCaIL) that is feasible in daily clinical practice. METHODS: Based on the food groups contributing most to daily dietary calcium intake and portion sizes determined in an earlier study, a three-item, 1-min SCaIL was designed. As a reference method, an extensive dietary history (DH) with specific focus on calcium-rich foods and extra attention for portion sizes was performed. Beforehand, a difference of >=250 mg calcium between both methods was considered clinically relevant. RESULTS: Sixty-six patients with either primary (n = 40) or secondary (n = 26) osteoporosis were included. On average, the SCaIL showed a small and clinically non-relevant difference in calcium intake with the DH: 24 +/ 350 mg/day (1146 +/- 440 vs. 1170 +/- 485 mg, respectively; p = 0.568). Sensitivity and specificity of the SCaIL, compared to the DH, were 73 and 80%, respectively. However, in 50% of the individuals, a clinically relevant difference of >=250 mg calcium was observed between both methods, while in 17% this was even >=500 mg. CONCLUSIONS: The SCaIL is a quick and easy questionnaire to estimate dietary calcium intake at a group level, but is not sufficiently reliable for use in individual patients. Remarkably, the mean dietary calcium intake estimated by the DH of 1170 mg/day indicates that a large proportion of osteoporosis patients might not even need calcium supplementation, although more data are needed to confirm this finding. PMID- 28083635 TI - Inflammation and N-formyl peptide receptors mediate the angiogenic activity of human vitreous humour in proliferative diabetic retinopathy. AB - AIMS/HYPOTHESIS: Angiogenesis and inflammation characterise proliferative diabetic retinopathy (PDR), a major complication of diabetes mellitus. However, the impact of inflammation on the pathogenesis of PDR neovascularisation has not been elucidated. Here, we assessed the capacity of PDR vitreous fluid to induce pro-angiogenic/proinflammatory responses in endothelium and the contribution of the inflammation-related pattern recognition N-formyl peptide receptors (FPRs) in mediating these responses. METHODS: Pooled and individual pars plana vitrectomy derived PDR vitreous fluid ('PDR vitreous') samples were assessed in endothelial cell proliferation, motility, sprouting and morphogenesis assays, and for the capacity to induce proinflammatory transcription factor activation, reactive oxygen species production, intercellular junction disruption and leucocyte adhesion molecule upregulation in these cells. In vivo, the pro angiogenic/proinflammatory activity of PDR vitreous was tested in murine Matrigel plug and chick embryo chorioallantoic membrane (CAM) assays. Finally, the FPR inhibitors Boc-Phe-Leu-Phe-Leu-Phe (Boc-FLFLF) and Ac-L-Arg-Aib-L-Arg-L Calpha(Me)Phe-NH2 tetrapeptide (UPARANT) were evaluated for their capacity to affect the biological responses elicited by PDR vitreous. RESULTS: PDR vitreous activates a pro-angiogenic/proinflammatory phenotype in endothelial cells. Accordingly, PDR vitreous triggers a potent angiogenic/inflammatory response in vivo. Notably, the different capacity of individual PDR vitreous samples to induce neovessel formation in the CAM correlates with their ability to recruit infiltrating CD45+ cells. Finally, the FPR inhibitor Boc-FLFLF and the novel FPR antagonist UPARANT inhibit neovessel formation and inflammatory responses triggered by PDR vitreous in the CAM assay. CONCLUSIONS/INTERPRETATION: This study provides evidence that inflammation mediates the angiogenic activity of PDR vitreous and paves the way for the development of FPR-targeting anti inflammatory/anti-angiogenic approaches for PDR therapy. PMID- 28083637 TI - Restoring independency with an osteochondral graft of the navicular for coronoid process reconstruction. AB - INTRODUCTION: The coronoid is a crucial element for elbow stability. In case of posttraumatic instability or reduced range of motion, a complex reconstruction might be necessary. CASE: We present the case of a polytraumatized patient with complex upper extremity injury and initial poor outcome. Subluxation after initial surgery was treated by sublime tubercle reconstruction with a corticocancellous iliac crest graft. Due to massive ossification, the elbow remained stiff and the paraplegic patient was unable to use a manually propelled wheelchair. After arthrolysis, the unstable elbow was treated with an osteocartilaginous graft from the navicular of the foot as well as ulnar and radial collateral ligamentoplasties. At the time of follow-up, the patient had a stable joint and was able to independently perform activities of daily living. CONCLUSION: An autologous navicular graft seems to be an excellent option for our paraplegic patient as the shape matches the sublime tubercle of the ulna. PMID- 28083638 TI - A New Deep-Sea Suctorian-Nematode Epibiosis (Loricophrya-Tricoma) from the Blanes Submarine Canyon (NW Mediterranean). AB - During a pluri-disciplinary study carried out within the frame of the Spanish research project DOS MARES, multicore samples were collected along the Blanes submarine canyon and its adjacent open slope to study the structure and dynamics of the meiofaunal organisms, mainly nematodes. Among the 5808 nematode individuals identified, only 190 of them belonged to the genus Tricoma (Desmoscolecidae), and only two harboured epibiont suctorian ciliates. The three specimens were located near the tail of the basibionts. A careful examination of the ciliates revealed that they were suctorians, which are here described as a new species of Loricophrya, namely L. mediterranea sp. nov. The new species is characterized by having a conical, slightly elongated lorica, narrowing towards posterior end; an anterior end inward curved, surrounding the lorica opening; a body placed near the lorica opening, occupying 1/3 of the lorica length, 4-8 capitate tentacles, and a peripheral, oval to sausage-shaped macronucleus. Our findings represent the first known report of an association with a deep-sea species of Tricoma, and the first record in the Mediterranean Sea, for a species of Loricophrya. The significance of the relationships between suctorian ciliates and their host in extreme environments such as deep-sea submarine canyons is discussed. PMID- 28083639 TI - Traumatic extracranial vasculopathies. PMID- 28083640 TI - Primary angiitis of the central nervous system in a 7-month-old infant. PMID- 28083642 TI - ? PMID- 28083641 TI - Notomelia and related neural tube defects in a baby born in Niger: case report and literature review. AB - INTRODUCTION: Notomelia associated with neural tube defects are rare diseases. CASE REPORT: A baby was born in Niger with multiple congenital embryonic malformations on the posterior midline. The most rostral malformation was an accessory limb (polymelia) at the level of the lumbar vertebrae composed of two long bones, a foot and three toes. Accessory male genitalia were present at the base of this malformed accessory limb which had no apparent motor or sensory innervation. The second malformation was a sacral vestigial appendage with an adjacent dermal sinus opening onto the posterior midline and extending internally to the dura through a defect of the vertebral arches. From the published literature and this particular case, we conclude that notomelia is a rare clinical sequela of a neural tube defect (NTD) and is correctly classified as a dysraphic appendage. CONCLUSION: The recent occurrence of three similar cases in the same ethnic group from Niger, three from consanguineous parents, suggests that genetic factors are likely to contribute significantly to the genesis of this syndrome, consistent with a recent report that mutation of the bovine NHLRC2 gene resulting in a V311A substitution at a highly conserved locus in the NHLRC2 protein is, when homozygous, causally associated with several forms of polymelia including notomelia, with heteropagus conjoined twinning and with other NTD related embryonic malformations. Detailed genome-wide studies of children with dysraphic appendages are indicated. PMID- 28083643 TI - ? PMID- 28083644 TI - Evaluation of deep gray matter volume, cortical thickness and white matter integrity in patients with typical absence epilepsy: a study using voxelwise based techniques. AB - INTRODUCTION: The objective of this study was to evaluate the cortical thickness and the volume of deep gray matter structures, measured from 3D T1-weighted gradient echo imaging, and white matter integrity, by diffusion tensor imaging (DTI) in patients with typical absence epilepsy (AE). METHODS: Patients (n = 19) with typical childhood AE and juvenile AE, currently taking antiepileptic medication, were compared with control subjects (n = 19), matched for gender and age. 3D T1 magnetization-prepared rapid gradient echo-weighted imaging and DTI along 30 noncolinear directions were performed using a 1.5-T MR scanner. FreeSurfer was used to perform cortical volumetric reconstruction and segmentation of deep gray matter structures. For tract-based spatial statistics analysis of DTI, a white matter skeleton was created, along with a permutation based inference with 5000 permutations. A threshold of p < 0.05 was used to identify abnormalities in fractional anisotropy (FA). The mean, radial, and axial diffusivities were also projected onto the mean FA skeleton. RESULTS: Patients with AE presented decreased FA and increased mean diffusivity and radial diffusivity values in the genu and the body of the corpus callosum and right anterior corona radiata, as well as decreased axial diffusivity in the left posterior thalamic radiation, inferior cerebellar peduncle, right cerebral peduncle, and right corticospinal tract. However, there were no significant differences in cortical thickness or deep gray matter structure volumes between patients with AE and controls. CONCLUSION: Abnormalities found in white matter integrity may help to better understand the pathophysiology of AE and optimize diagnosis and treatment strategies. PMID- 28083645 TI - Extrahepatic Arteries Originating from Hepatic Arteries: Analysis Using CT During Hepatic Arteriography and Visualization on Digital Subtraction Angiography. AB - PURPOSE: To investigate the prevalence and site of origin of extrahepatic arteries originating from hepatic arteries on early phase CT during hepatic arteriography (CTHA) was accessed. Visualization of these elements on digital subtraction hepatic angiography (DSHA) was assessed using CTHA images as a gold standard. MATERIALS AND METHODS: A total of 943 patients (mean age 66.9 +/- 10.3 years; male/female, 619/324) underwent CTHA and DSHA. The prevalence and site of origin of extrahepatic arteries were accessed using CTHA and visualized using DSHA. RESULTS: In 924 (98.0%) patients, a total of 1555 extrahepatic branches, representing eight types, were found to originate from hepatic arteries on CTHA. CTHA indicated the following extrahepatic branch prevalence rates: right gastric artery, 890 (94.4%); falciform artery, 386 (40.9%); accessory left gastric artery, 161 (17.1%); left inferior phrenic artery (IPA), 43 (4.6%); posterior superior pancreaticoduodenal artery, 33 (3.5%); dorsal pancreatic artery, 26 (2.8%); duodenal artery, 12 (1.3%); and right IPA, 4 (0.4%). In addition, 383 patients (40.6%) had at least one undetectable branch on DSHA. The sensitivity, specificity, and accuracy of visualization on DSHA were as follows: RGA, 80.0, 86.8, and 80.4%; falciform artery, 53.9, 97.7, and 80.0%; accessory LGA, 64.6, 98.6, and 92.3%; left IPA, 76.7, 99.8, and 98.7%; PSPDA, 100, 99.7, and 99.9%; dorsal pancreatic artery, 57.7, 100, and 98.8%; duodenal artery, 8.3, 99.9, and 98.7%; and right IPA, 0, 100, and 99.6%, respectively. CONCLUSION: Extrahepatic arteries originating from hepatic arteries were frequently identified on CTHA images. These arteries were frequently overlooked on DSHA. PMID- 28083647 TI - Phenytoin: 80 years young, from epilepsy to breast cancer, a remarkable molecule with multiple modes of action. AB - In 1908 phenytoin (5,5-diphenylhydantoin) was first synthesized as a barbiturate derivative in Germany by professor Heinrich Biltz (1865-1943) and subsequently resynthesized by an American chemist of the pharmaceutical company Parke-Davis in 1923 in Detroit. Screening phenytoin did not reveal comparable sedative side effects as barbiturates and, thus, Parke-Davis discarded this compound as a useful drug. In 1936, phenytoin's anticonvulsive properties were identified via a new animal model for convulsive disorders, developed by Putnam and Merritt, who also evaluated its clinical value in a number of patients in the period 1937 1940. For many diseases, mechanism of action of phenytoin remains obscure. The voltage-gated sodium channel was and is generally regarded as the main target to explain phenytoin's activity as an anticonvulsant and an anti-arrhythmic drug. This target, however, does not explain many of the other clinical properties of phenytoin. We will explore a number of original articles on phenytoin published in its 80 years history and give extra attention to the various hypothesis and experiments done to elucidate its mechanisms of action. Phenytoin has been explored in over 100 different disorders; the last two promising indications tested in the clinic are breast cancer and optic neuritis. Most probably, there are multiple targets active for these various disorders, and the insight into which targets are relevant is still very incomplete. It is remarkable that many pharmacological studies tested one dose only, mostly 50 or 100 MUM, doses which most probably are higher than the non-plasma bound phenytoin plasma levels obtained during treatment. PMID- 28083648 TI - Single-center comparison of multiple chemotherapy regimens for concurrent chemoradiotherapy in unresectable stage III non-small-cell lung cancer. AB - PURPOSE: To date, the best chemotherapy regimen to combine with concurrent radiotherapy in stage III non-small-cell lung cancer remains undetermined. We compared the survival outcomes and toxicities in patients who were treated with etoposide-cisplatin (EP), paclitaxel-carboplatin (PC), or vinblastine-cisplatin (VP) in one large cancer referral center. METHODS: We enrolled patients who received concurrent chemoradiotherapy at our university-affiliated hospital between January 1, 2009 and December 31, 2013. Demographic and clinical characteristics were identified. Progression-free survival (PFS) and overall survival (OS) between the different treatment groups were compared using Kaplan Meier and Cox proportional hazards regression models. Treatment-related toxicities were also compared. RESULTS: A total of 107 patients were treated with EP (31.8%), PC (32.7%) or VP (35.5%). Treatment with VP was significantly superior to PC, both in terms of median PFS [29.2 vs. 10.5 months; hazard ratio (HR) 0.43; 95% CI 0.21-0.85; p = 0.01] and in terms of median OS [40.7 vs. 17.8 months; (HR) 0.42; (0.21-0.84); p = 0.01]. However, there was no survival difference between EP and either one of the other regimens, but there was significantly more toxicities reported with the use of EP (73.5%) compared to PC (44.7%) or VP (37.1%); (p = 0.001). The most frequent non-hematologic toxicities for the entire cohort were esophagitis (28%), fatigue (22.4%), pneumonitis (14%), and nephrotoxicity (9.3%). CONCLUSION: Although the present study is limited by its small cohort and its retrospective nature, the results suggest that VP might be superior to PC and is less toxic than EP. PMID- 28083646 TI - Potential importance of B cells in aging and aging-associated neurodegenerative diseases. AB - Our understanding of B cells as merely antibody producers is slowly changing. Alone or in concert with antibody, they control outcomes of seemingly different diseases such as cancer, rheumatoid arthritis, diabetes, and multiple sclerosis. While their role in activation of effector immune cells is beneficial in cancer but bad in autoimmune diseases, their immunosuppressive and regulatory subsets (Bregs) inhibit autoimmune and anticancer responses. These pathogenic and suppressive functions are not static and appear to be regulated by the nature and strength of inflammation. Although aging increases inflammation and changes the composition and function of B cells, surprisingly, little is known whether the change affects aging-associated neurodegenerative disease, such as Alzheimer's disease (AD). Here, by analyzing B cells in cancer and autoimmune and neuroinflammatory diseases, we elucidate their potential importance in AD and other aging-associated neuroinflammatory diseases. PMID- 28083651 TI - Cyanobacteria: photosynthetic factories combining biodiversity, radiation resistance, and genetics to facilitate drug discovery. AB - Cyanobacteria are ancient, abundant, and widely diverse photosynthetic prokaryotes, which are viewed as promising cell factories for the ecologically responsible production of chemicals. Natural cyanobacteria synthesize a vast array of biologically active (secondary) metabolites with great potential for human health, while a few genetic models can be engineered for the (low level) production of biofuels. Recently, genome sequencing and mining has revealed that natural cyanobacteria have the capacity to produce many more secondary metabolites than have been characterized. The corresponding panoply of enzymes (polyketide synthases and non-ribosomal peptide synthases) of interest for synthetic biology can still be increased through gene manipulations with the tools available for the few genetically manipulable strains. In this review, we propose to exploit the metabolic diversity and radiation resistance of cyanobacteria, and when required the genetics of model strains, for the production and radioactive (14C) labeling of bioactive products, in order to facilitate the screening for new drugs. PMID- 28083649 TI - Reassessment of GLUT7 and GLUT9 as Putative Fructose and Glucose Transporters. AB - Although increased dietary fructose consumption is associated with metabolic impairments, the mechanisms and regulation of intestinal fructose absorption are poorly understood. GLUT5 is considered to be the main intestinal fructose transporter. Other GLUT family members, such as GLUT7 and GLUT9 are also expressed in the intestine and were shown to transport fructose and glucose. A conserved isoleucine-containing motif (NXI) was proposed to be essential for fructose transport capacity of GLUT7 and GLUT9 but also of GLUT2 and GLUT5. In assessing whether human GLUT2, GLUT5, GLUT7, and GLUT9 are indeed fructose transporters, we expressed these proteins in Xenopus laevis oocytes. Stably transfected NIH-3T3 fibroblasts were used as second expression system. In proving the role of the NXI motif, variants p.I322V of GLUT2 and p.I296V of GLUT5 were tested as well. Sugar transport was measured by radiotracer flux assays or by metabolomics analysis of cell extracts by GC-MS. Fructose and glucose uptakes by GLUT7 were not increased in both expression systems. In search for the physiological substrate of GLUT7, cells overexpressing the protein were exposed to various metabolite mixtures, but we failed to identify a substrate. Although urate transport by GLUT9 could be shown, neither fructose nor glucose transport was detectable. Fructose uptake was decreased by the GLUT2 p.I322V variant, but remained unaffected in the p.I296V GLUT5 variant. Thus, our work does not find evidence that GLUT7 or GLUT9 transport fructose or glucose or that the isoleucine residue determines fructose specificity. Rather, the physiological substrate of GLUT7 awaits to be discovered. PMID- 28083650 TI - Association between N-desethylamiodarone/amiodarone ratio and amiodarone-induced thyroid dysfunction. AB - PURPOSE: We used a retrospective data mining approach to explore the association between serum amiodarone (AMD) and N-desethylamiodarone (DEA) concentrations and thyroid-related hormone levels. METHODS: Laboratory data sets from January 2012 to April 2016 were extracted from the computerized hospital information system database at the National Cerebral and Cardiovascular Center (NCVC). Data sets that contained serum AMD and DEA concentrations and thyroid function tests, including thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3), were analyzed. RESULTS: A total of 1831 clinical laboratory data sets from 330 patients were analyzed. Data sets were classified into five groups (euthyroidism, hyperthyroidism, subclinical hyperthyroidism, hypothyroidism, and subclinical hypothyroidism) based on the definition of thyroid function in our hospital. Most abnormal levels of thyroid hormones were observed within the therapeutic range of serum AMD and DEA concentrations. The mean DEA/AMD ratio in the hyperthyroidism group was significantly higher than that in the euthyroidism group (0.95 +/- 0.42 vs. 0.87 +/- 0.28, p = 0.0209), and the mean DEA/AMD ratio in the hypothyroidism group was significantly lower than that in the euthyroidism group (0.77 +/- 0.26 vs. 0.87 +/- 0.28, p = 0.0038). The suppressed TSH group (0.98 +/- 0.41 vs. 0.87 +/- 0.28, p < 0.001) and the elevated FT4 level group (0.90 +/- 0.33 vs. 0.84 +/- 0.27, p = 0.0037) showed significantly higher DEA/AMD ratios compared with normal level groups. The elevated TSH group showed a significantly lower DEA/AMD ratio compared with the normal group (0.81 +/- 0.25 vs. 0.87 +/- 0.28, p < 0.0001). CONCLUSIONS: High and low DEA/AMD ratios were associated with AMD-induced hyperthyroidism and hypothyroidism, respectively. The DEA/AMD ratio may be a predictive marker for AMD-induced thyroid dysfunction. PMID- 28083652 TI - Improved eicosapentaenoic acid production in Pythium splendens RBB-5 based on metabolic regulation analysis. AB - Eicosapentaenoic acid (EPA) is an essential polyunsaturated fatty acid for human beings. At present, the production of commercially available long-chain polyunsaturated fatty acids, mainly from wild-caught ocean fish, is struggling to meet the increasing demand for EPA. Production of EPA by microorganisms may be an alternative, effective and economical method. The oleaginous fungus Pythium splendens RBB-5 is a potential source of EPA, and thanks to the simple culture conditions required, high yields can be achieved in a facile manner. In the study, lipid metabolomics was performed in an attempt to enhance EPA biosynthesis in Pythium splendens. Synthetic, metabolic regulation and gene expression analyses were conducted to clarify the mechanism of EPA biosynthesis, and guide optimization of EPA production. The results showed that the Delta6 desaturase pathway is the main EPA biosynthetic route in this organism, and ?6, ?12 and Delta17 desaturases are the rate-limiting enzymes. All the three desaturase genes were separately introduced into the parent strain to increase the flow of fatty acids into the Delta6 desaturase pathway. Enhanced expression of these key enzymes, in combination with improved regulation of metabolism, resulted in a maximum yield of 1.43 g/L in the D12 transgenic strain, which represents a tenfold increase over the parent strain before optimization. This is the higher EPA production yield yet reported for a microbial system. Our findings may allow the production of EPA at an industrial scale, and the strategy employed could be used to increase the production of EPA or other lipids in oleaginous microorganisms. PMID- 28083654 TI - Vorstand und Ausschuss der OGIM mit 1. Janner 2017. PMID- 28083653 TI - Developmental and ultrastructural characters of the pollen grains and tapetum in species of Nymphaea subgenus Hydrocallis. AB - Variations in pollen characters and tapetum behavior were recently acknowledged in the early-divergent family Nymphaeaceae and even within the genus Nymphaea, which probably is not monophyletic; some traits such as infratectum and tapetum type are also a matter of different interpretations. In this study, developmental characters of the pollen grains and tapetum in Nymphaea subgenus Hydrocallis are provided for the first time. Observations were made in N. amazonum, N. gardneriana, and N. prolifera using light, scanning, and transmission electron microscopy. Tapetum is of the secretory type and produces orbicules. At microspore and pollen grain stages, the distal and proximal walls differ considerably. This result supports the operculate condition of the aperture in Hydrocallis, and such aperture might be plesiomorphic for Nymphaeoideae. The infratectum is intermediate, composed of inter-columellae granular elements, robust columellae consisting of agglomerated granules, complete columellae, and fused columellae. Narrow microchannels are present and persist until the mature pollen grain stage. The membranous granular layer is often present in the pollen grains of Nymphaeaceae. In N. gardneriana, this layer is most probably a component of the intine because it is lost after acetolysis. Orbicules in the Nymphaeaceae are characterized as spherical or subspherical, with a smooth sporopolleninic wall that surrounds an electron-lucent core and with individual orbicules that usually merge to give irregular aggregations. The aperture, pollen wall ultrastructure, and the tapetum of the studied species are discussed in an evolutionary and systematic context, and these characters are also compared with those of other angiosperm lineages. PMID- 28083656 TI - Syntheses and CO2 reduction activities of pi-expanded/extended iron porphyrin complexes. AB - The construction of molecular catalysts that are active toward CO2 reduction is of great significance for designing sustainable energy conversion systems. In this study, we aimed to develop catalysts for CO2 reduction by introducing aromatic substituents to the meso-positions of iron porphyrin complexes. Three novel iron porphyrin complexes with pi-expanded substituents (5,10,15,20 tetrakis(pyren-1-yl)porphyrinato iron(III) chloride (Fe-Py)), pi-extended substituents (5,10,15,20-tetrakis((1,1'-biphenyl)-4-yl)porphyrinato iron(III) chloride (Fe-PPh)) and pi-expanded and extended substituents (5,10,15,20 tetrakis(4-(pyren-1-yl)phenyl)porphyrinato iron(III) chloride (Fe-PPy)) were successfully synthesized, and their physical properties were investigated by UV vis absorption spectroscopy and electrochemical measurements under Ar in comparison with an iron complex with a basic framework, 5,10,15,20 tetrakis(phenyl)porphyrinato iron(III) chloride (Fe-Ph). Moreover, the catalytic activity of the complexes was studied by electrochemical measurements under CO2, and it is found that the complex with the pi-expanded substituents exhibits the highest activity among these complexes. PMID- 28083657 TI - Peripheral blood CD4+/CD25+ regulatory T cells in alcoholic patients with Strongyloides stercoralis infection. AB - An increased number of regulatory T (Treg) cells has been reported in patients with HTLV-1 and Strongyloides stercoralis co-infection, suggesting the contribution of these cells to worm survival. As Strongyloides infections have been found to be highly prevalent in chronic alcoholics, we investigated the effect of abusive ethanol ingestion on the induction of Treg cells in alcoholic patients with Strongyloides infection. Treg cells were assessed by flow cytometry in the peripheral blood of 12 healthy non-alcoholic (control) and 14 alcoholic patients (alcoholic) without Strongyloides infection and five non-alcoholics (controlSs) and five chronic alcoholics (alcoholSs) with Strongyloides infection. The results showed significantly higher frequencies of Treg cells in the alcoholic, controlSs and alcoholSs group patients than in the control group patients. However, the frequencies of Treg cells did not differ between the alcoholSs and controlSs groups. In conclusion, our results demonstrate that ethanol consumption induced an increase in the number of circulating Treg cells in chronic alcoholics in this study but was unable to potentiate the induction of these cells in alcoholics with Strongyloides infection. PMID- 28083655 TI - Photostable and photoswitching fluorescent dyes for super-resolution imaging. AB - Super-resolution fluorescence microscopy is a recently developed imaging tool for biological researches. Several methods have been developed for detection of fluorescence signals from molecules in a subdiffraction-limited area, breaking the diffraction limit of the conventional optical microscopies and allowing visualization of detailed macromolecular structures in cells. As objectives are exposed to intense laser in the optical systems, fluorophores for super resolution microscopy must be tolerated even under severe light irradiation conditions. The fluorophores must also be photoactivatable and photoswitchable for single-molecule localization-based super-resolution microscopy, because the number of active fluorophores must be controlled by light irradiation. This has led to growing interest in these properties in the development of fluorophores. In this mini-review, we focus on the development of photostable and photoswitching fluorescent dyes for super-resolution microscopy. We introduce recent efforts, including improvement of fluorophore photostability and control of photoswitching behaviors of fluorophores based on photochemical and photophysical processes. Understanding and manipulation of chemical reactions in excited fluorophores can develop highly photostable and efficiently photoswitchable fluorophores that are suitable for super-resolution imaging applications. PMID- 28083658 TI - Left atrial phasic function and heart rate variability in asymptomatic diabetic patients. AB - AIMS: We evaluated left atrial (LA) phasic function and heart rate variability (HRV) in asymptomatic diabetic patients, and the relationship between HRV indices and LA phasic function assessed by volumes and speckle tracking imaging. METHOD: This cross-sectional study included 55 asymptomatic patients with type 2 diabetes and 50 healthy controls without cardiovascular risk factors. All study subjects underwent laboratory analyses, complete two-dimensional echocardiography examination (2DE) and 24-h Holter monitoring. RESULTS: Maximum, minimum LA and pre-A LA volumes and volume indexes are significantly higher in diabetic patients. Total and passive LA emptying fractions (EF), representing the LA reservoir and conduit function, are significantly lower in diabetic subjects. Active LA EF, the parameter of the LA booster pump function, is compensatory increased in diabetic patients. Similar results were obtained by 2DE strain analysis. Cardiac autonomic function, assessed by HRV, is significantly deteriorated in diabetic patients. Time and frequency-domain HRV measures are significantly lower in diabetic subjects than in controls. HbA1c, LV mass index and HRV are associated with total LA EF and longitudinal LA strain independently of age, body mass index and LV diastolic function in the whole study population. CONCLUSIONS: LA phasic function and cardiac autonomic nervous system assessed by HRV are impacted by diabetes. HbA1c and HRV are independently associated with LA reservoir function evaluated by volumetric and strain methods in the whole study population. This study emphasizes the importance of determination of LA function and HRV as important markers of preclinical cardiac damage and autonomic function impairment in diabetic patients. PMID- 28083659 TI - Diagnostic accuracy of demarcation of undifferentiated-type early gastric cancer after Helicobacter pylori eradication. AB - BACKGROUND: It is unknown whether Helicobacter pylori (H. pylori) eradication is beneficial when demarcating undifferentiated-type early gastric cancers (UD-type EGCs). This study aimed to determine whether H. pylori eradication is beneficial, and also when benefits become detectable. METHODS: Sixty lesions that were detected as a <=20-mm lesion without metastasis or ulceration on routine examination, diagnosed as UD-type EGC on biopsy, and treated with endoscopic submucosal dissection between January 2010 and January 2015 were studied. Magnifying endoscopy with narrow-band imaging (ME-NBI) was performed to demarcate the lesions. The most oral and most anal sites were marked. After endoscopic therapy, the markings were compared with the pathological examination results to calculate accurate diagnosis rates, which were compared between 27 patients with H. pylori eradication and 33 patients without. Mean intercrypt distance ratio and inflammatory cell infiltration were also compared, as were seven patients who underwent the procedure 1 month after H. pylori eradication and 20 patients who underwent the procedure more than 1 month after H. pylori eradication. RESULTS: Accurate diagnosis rates were 92.2% with eradication and 60.6% without. Mean intercrypt distance ratios were 1.95 and 1.59, respectively. Neutrophil infiltration was mild in the eradication group. Significant differences were observed in each parameter (p < 0.05). No significant difference was observed between the 1-month eradication and >1-month eradication subgroups in terms of accurate diagnosis rate, mean intercrypt distance ratio, or histological grade of any item. CONCLUSIONS: This study suggests that H. pylori eradication therapy aids the accurate delineation of UD-type EGC in ME-NBI. PMID- 28083660 TI - Life history plasticity does not confer resilience to environmental change in the mole salamander (Ambystoma talpoideum). AB - Plasticity in life history strategies can be advantageous for species that occupy spatially or temporally variable environments. We examined how phenotypic plasticity influences responses of the mole salamander, Ambystoma talpoideum, to disturbance events at the St. Marks National Wildlife Refuge (SMNWR), FL, USA from 2009 to 2014. We observed periods of extensive drought early in the study, in contrast to high rainfall and expansive flooding events in later years. Flooding facilitated colonization of predatory fishes to isolated wetlands across the refuge. We employed multistate occupancy models to determine how this natural experiment influenced the occurrence of aquatic larvae and paedomorphic adults and what implications this may have for the population. We found that, in terms of occurrence, responses to environmental variation differed between larvae and paedomorphs, but plasticity (i.e. the ability to metamorphose rather than remain in aquatic environment) was not sufficient to buffer populations from declining as a result of environmental perturbations. Drought and fish presence negatively influenced occurrence dynamics of larval and paedomorphic mole salamanders and, consequently, contributed to observed short-term declines of this species. Overall occurrence of larval salamanders decreased from 0.611 in 2009 to 0.075 in 2014 and paedomorph occurrence decreased from 0.311 in 2009 to 0.121 in 2014. Although variation in selection pressures has likely maintained this polyphenism previously, our results suggest that continued changes in environmental variability and the persistence of fish in isolated wetlands could lead to a loss of paedomorphosis in the SMNWR population and, ultimately, impact regional persistence in the future. PMID- 28083661 TI - Error analysis in newborn screening: can quotients support the absolute values? AB - Newborn screening is performed using modern tandem mass spectrometry, which can simultaneously detect a variety of analytes, including several amino acids and fatty acids. Tandem mass spectrometry measures the diagnostic parameters as absolute concentrations and produces fragments which are used as markers of specific substances. Several prominent quotients can also be derived, which are quotients of two absolute measured concentrations. In this study, we determined the precision of both the absolute concentrations and the derived quotients. First, the measurement error of the absolute concentrations and the measurement error of the ratios were practically determined. Then, the Gaussian theory of error calculation was used. Finally, these errors were compared with one another. The practical analytical accuracies of the quotients were significantly higher (e.g., coefficient of variation (CV) = 5.1% for the phenylalanine to tyrosine (Phe/Tyr) quotient and CV = 5.6% for the Fisher quotient) than the accuracies of the absolute measured concentrations (mean CVs = 12%). According to our results, the ratios are analytically correct and, from an analytical point of view, can support the absolute values in finding the correct diagnosis. PMID- 28083662 TI - Metabolic profiling of human plasma and urine in chronic kidney disease by hydrophilic interaction liquid chromatography coupled with time-of-flight mass spectrometry: a pilot study. AB - A typical characteristic of chronic kidney disease (CKD) is the progressive loss in renal function over a period of months or years with the concomitant accumulation of uremic retention solutes in the body. Known biomarkers for the kidney deterioration, such as serum creatinine or urinary albumin, do not allow effective early detection of CKD, which is essential towards disease management. In this work, a hydrophilic interaction liquid chromatography time-of-flight mass spectrometric (HILIC-TOF MS) platform was optimized allowing the search for novel uremic retention solutes and/or biomarkers of CKD. The HILIC-ESI-MS approach was used for the comparison of urine and plasma samples from CKD patients at stage 3 (n = 20), at stage 5 not yet receiving dialysis (n = 20) and from healthy controls (n = 20). Quality control samples were used to control and ensure the validity of the metabolomics approach. Subsequently the data were treated with the XCMS software for multivariate statistical analysis. In this way, differentiation could be achieved between the measured metabolite profile of the CKD patients versus the healthy controls. The approach allowed the elucidation of a number of metabolites that showed a significant up- and downregulation throughout the different stages of CKD. These compounds are cinnamoylglycine, glycoursodeoxycholic acid, 2-hydroxyethane sulfonate, and pregnenolone sulfate of which the identity was unambiguously confirmed via the use of authentic standards. The latter three are newly identified uremic retention solutes. PMID- 28083663 TI - A metaproteomic approach dissecting major bacterial functions in the rhizosphere of plants living in serpentine soil. AB - A metaproteomic approach, based on liquid chromatography-high resolution mass spectrometry (LC-HRMS) analysis, was followed to map the major bacterial metabolic functions associated with the rhizosphere of metal-tolerant and metal hyperaccumulator plants, growing in a serpentine soil naturally contaminated by heavy metals such as Ni, Co and Cr. In particular, an "in-house" bacterial protein database was built based on the genera recognised by 16S rDNA profiling, then it was used for protein identification from LC-MS data. The combination of the information arising from three different extraction protocols, applied to each soil sample, permitted the identification of almost 800 proteins, corresponding to functions assigned to proper Gene Ontology categories. Mainly proteins involved in response to stimulus or in transport of metals and nutrients revealed variability of bacteria responses to microenvironment conditions. As for taxonomy, Phyllobacterium, Microbacterium oxidans, Pseudomonas oryzihabitans, Stenotrophomonas rhizophila and Bacillus methylotrophicus bacterial species were more represented in the rhizosphere samples of the metal-tolerant Biscutella laevigata and of the Ni hyperaccumulator Noccaea caerulescens with respect to bulk soil. Combining 16S rRNA gene-based sequencing and metaproteomic analysis, we get insights into microbial community functions and their interaction with plants colonising the stressful environment of serpentine soils. PMID- 28083664 TI - Improved single-step enrichment methods of cross-linked products for protein structure analysis and protein interaction mapping. AB - Chemical cross-linking/mass spectrometry (MS) is gradually developing into a routine method to investigate protein conformation and to decipher protein interaction networks. To increase identification rates of the frequently low abundant cross-linked products in LC/MS/MS experiments, fast and reliable sample preparation protocols are indispensable. We present simplified solid phase extraction methods using C18/SCX StageTips and mixed-mode OASIS MCX cartridges for a single-step enrichment of cross-linked products prior to LC/MS/MS analysis. Our improved protocols result in 3.5 to 4.6 times higher numbers of cross-link identifications for the model protein bovine serum albumin compared to non processed samples. PMID- 28083665 TI - The prevalence of osteoporosis and the rate of bone loss in Korean adults: the Chungju metabolic disease cohort (CMC) study. AB - : Because the rate of bone loss is an important risk factor for fracture, we studied longitudinal changes in bone mineral density (BMD). Although the BMD of the hip decreased over time, spine BMD remained largely stable or increased. Therefore, spine BMD may not be appropriate for assessing BMD change. INTRODUCTION: The rate of age-dependent bone loss has been shown to be an important risk factor for fracture. However, longitudinal rates of BMD loss in Korea have not yet been reported. The objective of this study was to evaluate longitudinal changes in BMD in Korea. METHODS: This cohort study was performed in a population of individuals 40 years of age or older living in the rural area of Chungju City, Korea. A second BMD examination was conducted approximately 4 years after a baseline examination. A total of 3755 of the 6007 subjects completed the follow-up visit, corresponding to a follow-up rate of 62.51%. RESULTS: The age standardized osteoporosis prevalence was 12.81% in males and 44.35% in females. In males, the average annual BMD loss at the total hip increased from -0.25% per year in their 40s to -1.12% per year in their 80s. In females, the average annual BMD loss at the total hip increased from -0.69% per year in their 40s to -1.51% per year in their 80s. However, the average annual percentage change in spine BMD in females increased from -0.91% per year in their 40s to +1.39% per year in their 80s. CONCLUSIONS: A substantial number of subjects had osteoporosis, even though we standardized the prevalence of osteoporosis. In total hip, the mean BMD was decreased during the follow-up period; in addition, the annual percentage loss increased with age. However, spine BMD remained approximately stable or increased over time and therefore may not be appropriate for assessing BMD change. PMID- 28083666 TI - The relationship between vitamin D status and muscle strength in young healthy adults from sunny climate countries currently living in the northeast of Scotland. AB - : The current study examined the relationship between vitamin D status and muscle strength in young healthy adults: residents (>6 months) and newcomers (0-3 months), originally from sunny climate countries but currently living in the northeast of Scotland. Our longitudinal data found a positive, albeit small, relationship between vitamin D status and knee extensor isometric strength. INTRODUCTION: Vitamin D has been suggested to play a role in muscle health and function, but studies so far have been primarily in older populations for falls prevention and subsequent risk of fractures. METHODS: Vitamin D status was assessed in a healthy young adults from sunny climate countries (n = 71, aged 19 42 years) with 56% seen within 3 months of arriving in Aberdeen [newcomers; median (range) time living in the UK = 2 months (9-105 days)] and the remainder resident for >6 months [residents; 23 months (6-121 months)]. Participants attended visits every 3 months for 15 months. At each visit, fasted blood samples were collected for analysis of serum 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), carboxy-terminal collagen crosslinks (CTX) and N-terminal propeptide of type I collagen (P1NP). Maximal voluntary contractions (MVC) were performed for grip strength (both arms) and for maximal isometric strength of the knee extensors (right knee). RESULTS: There were small seasonal variations in 25(OH)D concentrations within the newcomers and residents, but no seasonal variation in bone turnover markers. There was a positive, albeit small, association between 25(OH)D and knee extensor maximal isometric strength. Mixed modelling predicted that for each 1 nmol/L increase in 25(OH)D, peak torque would increase by 1 Nm (p = 0.04). CONCLUSIONS: This study suggests that vitamin D may be important for muscle health in young adults migrating from sunnier climates to high latitudes, yet the potential effect is small. PMID- 28083667 TI - Use of proton pump inhibitors and mortality after hip fracture in a nationwide study. AB - : We analyzed the association of proton pump inhibitors (PPIs) with mortality after osteoporosis-related hip fracture in Austria. PPIs were associated with reduced 90-day mortality but elevated mortality after half a year when initiated pre-fracture. Inpatients and discharged patients on PPIs showed lowered in hospital and 90-day mortality, respectively. INTRODUCTION: We herein investigated use of proton pump inhibitors (PPIs) and mortality among hip fracture patients in a nationwide study in Austria. METHODS: In this retrospective cohort study, data on use of PPIs were obtained from 31,668 Austrian patients >=50 years with a hip fracture between July 2008 and December 2010. All-cause mortality in patients without anti-osteoporotic drug treatment who had received their first recorded PPI prescription in the study period either before or after fracture was compared with hip fracture patients on neither PPIs nor anti-osteoporotic medication using logistic and Cox regression analysis. RESULTS: With PPI use, 90-day mortality was significantly reduced, both at initiation before (OR 0.66; p < 0.0001) and after hip fracture (OR 0.23; p < 0.0001). 90-day mortality was also reduced when PPIs were prescribed not until after discharge from the last recorded hip fracture related hospital stay (OR 0.49; p < 0.0001) except for patients aged <70 years. In a sub-cohort of patients beginning PPIs during hospital stay, in-hospital mortality (0.2%) was substantially reduced relative to matched control patients (3.5%) (p < 0.0001). Longer-term mortality significantly increased after half a year post-fracture only among those who started PPI prescription before fracture. CONCLUSIONS: PPI use during and after hospital stay due to hip fracture is associated with a considerable decrease in mortality. These findings could have implications for hip fracture treatment. PMID- 28083668 TI - Long-term effect of aromatase inhibitors on bone microarchitecture and macroarchitecture in non-osteoporotic postmenopausal women with breast cancer. AB - : In non-osteoporotic postmenopausal women with breast cancer, aromatase inhibitors (AIs) negatively affected bone mineral density (BMD), lumbar spine trabecular bone score (TBS) as a bone microarchitecture index, and hip geometry as a bone macroarchitecture index. INTRODUCTION: AIs increase the risk of fracture in patients with breast cancer. Therefore, we aimed to evaluate the long term skeletal effects of AIs in postmenopausal women with primary breast cancer. METHODS: We performed a retrospective longitudinal observational study in non osteoporotic patients with breast cancer who were treated with AIs for >=3 years (T-score >-2.5). Patients with previous anti-osteoporosis treatment or those who were given bisphosphonate during AI treatment were excluded from the analysis. We serially assessed BMD, lumbar spine TBS, and hip geometry using dual-energy X-ray absorptiometry. RESULTS: BMD significantly decreased from baseline to 5 years at the lumbar spine (-6.15%), femur neck (-7.12%), and total hip (-6.35%). Lumbar spine TBS also significantly decreased from baseline to 5 years (-2.12%); this change remained significant after adjusting for lumbar spine BMD. The annual loss of lumbar spine BMD and TBS slowed after 3 and 1 year of treatment, respectively, although there was a relatively constant loss of BMD at the femur neck and total hip for up to 4 years. The cross-sectional area, cross-sectional moment of inertia, minimal neck width, femur strength index, and section modulus significantly decreased, although the buckling ratio increased over the treatment period (all P < 0.001); these changes were independent of total hip BMD. CONCLUSIONS: Long-term adjuvant AI treatment negatively influenced bone quality in addition to BMD in patients with breast cancer. This study suggests that early monitoring and management are needed in non-osteoporotic patients with breast cancer who are starting AIs. PMID- 28083669 TI - Use of antipsychotics increases the risk of fracture: a systematic review and meta-analysis. AB - : Our systematic review and meta-analysis of observational studies indicated that the use of antipsychotics was associated with a nearly 1.5-fold increase in the risk of fracture. First-generation antipsychotics (FGAs) appeared to carry a higher risk of fracture than second-generation antipsychotics (SGAs). INTRODUCTION: The risk of fractures associated with the use of antipsychotic medications has inconsistent evidence between different drug classes. A systematic review and meta-analysis was conducted to evaluate whether there is an association between the use of antipsychotic drugs and fractures. METHODS: Searches were conducted through the PubMed and EMBASE databases to identify observational studies that had reported a quantitative estimate of the association between use of antipsychotics and fractures. The summary risk was derived from random effects meta-analysis. RESULTS: The search yielded 19 observational studies (n = 544,811 participants) with 80,835 fracture cases. Compared with nonuse, use of FGAs was associated with a significantly higher risk for hip fractures (OR 1.67, 95% CI, 1.45-1.93), and use of second generation antipsychotics (SGAs) was associated with an attenuated but still significant risk for hip fractures (OR 1.33, 95% CI, 1.11-1.58). The risk of fractures associated with individual classes of antipsychotic users was heterogeneous, and odds ratios ranged from 1.24 to 2.01. Chlorpromazine was associated with the highest risk (OR 2.01, 95% CI 1.43-2.83), while Risperidone was associated with the lowest risk of fracture (OR 1.24, 95% CI 0.95-1.83). CONCLUSIONS: FGA users were at a higher risk of hip fracture than SGA users. Both FGAs and SGAs were associated with an increased risk of fractures, especially among the older population. Therefore, the benefit of the off-label use of antipsychotics in elderly patients should be weighed against any risks for fracture. PMID- 28083670 TI - Results and outcome predictors after open release of complete ankylosis of the elbow caused by heterotopic ossification. AB - BACKGROUND: Heterotopic ossification (HO) may lead to complete elbow ankylosis, resulting in severe disability. The prognostic factors that may be valuable in guiding treatment of this condition have not yet been evaluated. The goals of this study were to describe the outcomes of open release for ankylosed elbow caused by HO and to analyse factors associated with clinical outcomes. METHOD: This retrospective study assessed 41 patients with ankylosed elbows treated by open release surgery. We report final clinical outcomes and analyses of the association between outcomes and clinical variables. RESULTS: Mean patient age was 36.4 years; follow-up was 36.1 months. Mean arc of motion increased from 0 to 112 degrees post-operatively, mean pronation from 34 to 52 degrees , supination from a mean of 51 to 76 degrees , and Mean Mayo Elbow Performance Score (MEPS) from 42.8 to 84.2. Eight patients experienced recurrence, two of whom underwent a second operation: one for elbow instability and one for revision surgery. Linear regression analysis demonstrated that initial injury type (p = 0.020), articular surface damage (p = 0.001), coma iduringthe initial injury (p = 0.001) and concomitant radial head replacement (p = 0.029) were independent factors affecting the final MEPS. CONCLUSIONS: Satisfactory outcomes were achieved, indicating that open release is effective for ankylosed elbows. Our findings demonstrated that initial injury type, articular surface damage, coma and radial head replacement are outcome predictors affecting final outcomes. PMID- 28083671 TI - Role of platelet gel embedded within gelatin scaffold on healing of experimentally induced critical-sized radial bone defects in rats. AB - PURPOSE: We investigated the role of human platelet gel (PG) embedded within gelatin (Gel) scaffold on healing of critical-sized radial bone defects in rats. METHODS: Twenty-five Sprague-Dawley rats were randomly divided into five equal groups. In each animal, critical-sized 5-mm bone defects were created in the radial bones of both forelimbs (n = 10/group). The defects were then either left untreated or filled with autograft, Gel, PG or Gel-PG. Before euthanasia, the healing defects were evaluated radiologically and clinically. The animals were euthanized after eight weeks and their radial bones evaluated by radiography, computed tomography (CT) scan, histology, biomechanical testing and ultrastructural evaluations. RESULTS: PG implantation significantly increased cellular differentiation, osteoblastic proliferation and consequently new bone formation so that those defects treated with PG showed superior structural and biomechanical properties to the Gel and PG-Gel-treated defects. The PG-treated defects had radiological, morphological and mechanical properties closely comparable with those of the autograft group. In contrast, in the PG-Gel group, Gel significantly reduced the beneficial effects of PG on bone healing. CONCLUSIONS: Human PG had beneficial effects on bone regeneration, while combination of PG and Gel had no remarkable beneficial effect. Therefore, PG when used alone can be regarded as a promising osteoinductive and osteoconductive option in bone tissue engineering applications. PMID- 28083673 TI - Erratum to: Abstracts : XXXI International Congress of the IAP and 28th Congress of the ESP. PMID- 28083672 TI - Minimally invasive plate osteosynthesis technique for displaced midshaft clavicular fracture using the clavicle reductor. AB - OBJECTIVE: This study aims to introduce a self-designed clavicle reductor and to test the effectivity of a alternative minimally invasive plate osteosynthesis technique (MIPO) for displaced midshaft clavicular fractures (DMCFs) with the application of our self-designed clavicle reductor. METHOD: From October 2012 to February 2013, 27 male patients who suffered with unilateral displaced midshaft clavicular fracture (DMCFs) were included into our study. Patients were treated by minimally invasive plate osteosynthesis (MIPO) technique with the application of our self-designed clavicle reductor and followed up regularly. Constant-Murley score was employed to test the functional outcomes at one year's follow up. RESULT: The average follow-up time for the 27 patients was 15.8 months (range, 13 18 months). The average age of all patients was 32.6 (range, 21 to 48). According to OTC system, 12 cases were simple fractures (15-B1), ten cases were wedge fractures (15-B2) and five cases were comminuted fractures (15-B3). With the application of the clavicle reductor, minimally invasive plate osteosynthesis technique can be performed without any barrier in all of the 27 cases. Operative duration was 48.1 minutes (range, 35-65 minutes) and average fluoroscopy time was 12.8 seconds (range, from 7 to 22 seconds). All of the 27 cases healed from four to six months post-operatively. The average Constant-Murley-score of the 27 patients was 92.7 +/- 5.88 (range, 80 to 100). No complications were noted. CONCLUSION: The self-designed clavicle reductor can effectively pave the way for the application of MIPO technique in the treatment of DMCFs. MIPO technique with locking reconstruction plate is a feasible and worthwhile alternative for displaced midshaft clavicular fractures (DMCFs). PMID- 28083674 TI - Clinical practices among healthcare professionals concerning neonatal jaundice and pale stools. AB - : Jaundice and pale stools are major indicators of neonatal liver disease. Prognosis depends on timely diagnosis and management. We evaluated the clinical practices among healthcare professionals concerning jaundiced newborns and their ability to recognize pale stools. We supplied a questionnaire and a panel with eight photographs of stools, both locally validated, to physicians and nurses of the National Healthcare Service. Analysis was conducted according to professional status, specialization and years of experience of professionals and level of healthcare. Questionnaires were administered to 266 participants (100 physicians, 166 nurses). The decision to send patients to medical observation depended on the intensity of jaundice for a significant percentage of nurses. Concerning jaundiced newborns breastfed and otherwise healthy, 28.9% of physicians would never request a conjugated bilirubin assay, and only 43.3% would request it after 14 days old; for those with other signs/symptoms of disease, only 69.1% of physicians would request it immediately. Multiple linear regression analysis identified specialization as an independent variable significantly associated with the ability to recognize pale stools. CONCLUSION: A significant percentage of healthcare professionals assumed clinical practices that preclude the timely recognition of cholestasis/pale stools, reinforcing the idea of educational needs. Specialization, rather than years of experience of professionals, was associated with better skills and practices. What is Known: * Neonatal cholestasis is a condition with some rare underlying entities having high mortality and morbidity. Early diagnosis is crucial to improve prognosis. Yet, many cases remain late recognized and referred. * Studies evaluating the ability of healthcare professionals to recognize neonatal cholestasis are scarce. What is New: * In this study, a significant percentage of professionals assumed clinical practices that preclude timely recognition of neonatal cholestasis and pale stools, reinforcing the idea of educational needs. * Specialization of professionals was associated with better skills and practices. PMID- 28083676 TI - In Memory of Athina Markou (1961-2016): Obituary. PMID- 28083675 TI - Assessment of a glycine uptake inhibitor in animal models of effort-related choice behavior: implications for motivational dysfunctions. AB - RATIONALE: Motivated behavior can be characterized by a substantial exertion of effort, and organisms often make effort-related decisions based upon analyses of work-related response costs and reinforcement preference. Moreover, alterations in effort-based choice can be seen in people with major depression and schizophrenia. Effort-related decision making is studied using tasks offering choices between high effort options leading to highly valued reinforces vs low effort/low reward options. Interference with dopamine (DA) transmission by administration of the DA D2 family antagonist haloperidol biases behavior towards the lower effort option that can be obtained with minimal work, and previous research has shown that DA interacts with other transmitters, including adenosine and GABA, to regulate effort-based choice. OBJECTIVES: The present studies focused upon the ability of the glycine transport inhibitor bitopertin to attenuate haloperidol-induced shifts in effort-related choice behavior. METHODS: Effort-based choice in rats was assessed using the concurrent fixed ratio (FR) 5/chow feeding choice task and the T-maze barrier choice procedure. RESULTS: Haloperidol shifted effort-based choice, biasing animals towards the low effort option in each task. Co-administration of bitopertin (1.0-10.0 mg/kg) significantly attenuated haloperidol-induced shifts in choice behavior, but the same doses of bitopertin had no effect when administered alone. CONCLUSIONS: These results indicated that elevation of extracellular glycine via inhibition of glycine uptake was able to reverse the effects of D2 antagonism. Increases in extracellular glycine, possibly through actions on the glycine allosteric site on the NMDA receptor, may be a useful strategy for treating motivational dysfunctions in humans. PMID- 28083677 TI - Results and complications of percutaneous pelvic osteotomy and intertrochanteric varus shortening osteotomy in 54 consecutively operated GMFCS level IV and V cerebral palsy patients. AB - PURPOSE: This retrospective study evaluated mid-to-long-term outcome of a minimally invasive percutaneous pelvic osteotomy (PPO) approach combined with varus derotational shortening osteotomy (VDRSO) and soft tissue release in children with severe CP. METHODS: A retrospective review was performed of all patients presenting with a diagnosis of CP with hip subluxation or dislocation treated surgically by simultaneous soft tissue release, VDRSO, and PPO between 2002 and 2015. Eligible patients included those with a diagnosis of spastic quadriplegia or CP GMFCS level IV or V with unilateral or bilateral hip subluxation or dislocation and surgical treatment of the deformity by simultaneous soft tissue release, VDRSO and PPO. All anterior-posterior (AP) radiographs of the pelvis were reviewed and Reimers migration percentage (MP) and acetabular angle (AA) were measured. RESULTS: In total, 54 children and adolescents (34 boys, 20 girls) with CP GMFCS level IV and V were treated during study period: 38 (70.4%) classified GMFCS level IV and 16 (29.6%) classified GMFCS level V. A total of 64 consecutive hips underwent simultaneous PPO associated with VDRSO. Overall, at the time of chart and radiograph review, mean age was 9.1 +/- 3.3 years (range 4-16.5) and mean follow-up was 43.9 +/- 19.5 months (range 3-72). Mean migration percentage improved from 66.8 +/- 19.8% (range 33-100) preoperatively to 8.1 +/- 16.5% (range 0-70) at last follow-up. Mean acetabular angle improved from 32.7 degrees +/- 7.1 degrees (range 20-50) preoperatively to 14 degrees +/- 6.7 degrees (range 0-27) at last follow-up. Only one case of bone graft dislodgment was observed. We did not observe any cases of avascular necrosis of the femoral head. All operated hips were pain free at the time of last follow-up. CONCLUSION: PPO through a less invasive surgical approach offers a valuable alternative to standard techniques as it gives similar outcome but with less muscle stripping and less time in surgery. LEVEL OF EVIDENCE: III. PMID- 28083678 TI - Intraocular use of acid violet 17 at a concentration of 1.5 mg/ml is not safe. PMID- 28083679 TI - The effects of pleiotrophin in proliferative vitreoretinopathy. AB - PURPOSE: The purpose of our study was to investigate the effects of pleiotrophin (PTN) in proliferative vitreoretinopathy (PVR) both in vitro and in vivo. METHODS: Immunofluorescence was used to observe the PTN expression in periretinal membrane samples from patients with PVR and controls. ARPE-19 cells were exposed to TGF-beta1. The epithelial-to-mesenchymal transition (EMT) of the ARPE-19 cells was confirmed by observed morphological changes and the increased expression of alpha-SMA and fibronectin at both the mRNA and protein levels. We used specific small interfering (si)RNA to knock down the expression of PTN. The subsequent effects of PTN inhibition were assessed with regard to the EMT, migration, proliferation, cytoskeletal arrangement, TGF-beta signaling, PTN signaling, integral tight junction protein expression (e.g., claudin-1 and occludin), and p38 MAPK and p-p38 MAPK levels. Additionally, a PVR rat model was established by the intravitreal injection of ARPE-19 cells transfected with PTN-siRNA and was evaluated accordingly. RESULTS: PTN was highly expressed in PVR membranes compared to controls. PTN knockdown attenuated the TGF-beta1-induced migration, proliferation, cytoskeletal rearrangement, and expression of EMT markers such as alpha-SMA and fibronectin in the ARPE-19 cells, and these effects may have been mediated through p38 MAPK signaling pathway activation. PTN silencing inhibited the up-regulation of claudin-1 and occludin stimulated by TGF-beta1, and PTN knockdown inhibited the proliferative aspects of severe PVR in vivo. CONCLUSIONS: PTN is involved in the process of EMT induced by TGF-beta1 in human ARPE-19 cells in vitro, and PTN knockdown attenuated the progression of experimental PVR in vivo. These findings provide new insights into the pathogenesis of PVR. PMID- 28083680 TI - Hybrid minimally invasive esophagectomy vs. open esophagectomy: a matched case analysis in 120 patients. AB - PURPOSE: In esophageal surgery, total minimally invasive techniques compete with hybrid and robot-assisted procedures. The benefit of the individual techniques for the patient remains vague. At our institution, the hybrid minimally invasive laparoscopic-thoracotomic esophagectomy (HMIE) has been routinely applied since 2013. We conducted this retrospective study to analyze the perioperative outcome. METHODS: Since 2013, 60 patients were operated in HMIE technique for esophageal cancer. Each of these patients was paired according to the criteria of gender, BMI, age, tumor histology, pulmonary preexisting conditions, and a history of smoking with a patient treated by open esophagectomy (OE). Perioperative parameters were extracted from our prospectively maintained database and compared among the groups. RESULTS: The HMIE and OE groups were homogeneous in terms of patient- and tumor-related data. There was no difference in lymph nodes harvested (22 vs. 20, p = 0.459) and R0-resection rate (95 vs. 93%, p = 0.500). The operation time for the HMIE was significantly shorter (329 vs. 407 min, p < 0.001). There was no difference between the groups with respect to surgical complications (37 vs. 37%, p = 0.575), but the patients undergoing hybrid technique showed more delayed gastric emptying (23 vs. 10%, p = 0.042). Pulmonary morbidity was significantly reduced after HMIE (20 vs. 42%, p = 0.009). This affected both the occurrence of pneumonia and pleural effusions. The difference in the overall complication rate was not significant (50 vs. 60%, p = 0.179), but life-threatening complications (Clavien/Dindo 4/5) were less frequent (2 vs. 12%, p = 0.031). Overall, there was significantly less need for transfusion after HMIE (18 vs. 50%, p < 0.001), and hospital (and IMC) stay was significantly shorter (14 (6) vs. 18 (7) days, p = 0.002 (0.003)). The multivariate analysis confirms the surgical procedure as an independent risk factor for the development of pulmonary complications (OR 3.2, p = 0.011). Furthermore, preexisting pulmonary conditions were identified as a risk factor (OR 3.6, p = 0.006). CONCLUSION: Our retrospective analysis shows that reduction of postoperative pulmonary morbidity, perioperative blood loss, and shortening of hospital stay can be achieved by HMIE. The procedure is safe, and the rate of surgical complications and oncological radicality is comparable to the conventional procedure. PMID- 28083681 TI - [Treatment of acetabular defects with the trabecular metal revision system]. AB - BACKGROUND: The results after acetabular component revision are very heterogeneous, irrespective of the use of established or new components. This could be due to a lack of treatment standards for new revision components. The Trabecular MetalTM (TM) revision system, through its modularity, allows for an individual intraoperative reconstruction of the acetabular defect with a single implant system. It was the aim of this study to investigate the results of acetabular revision with the TMT system taking into consideration the utilized components and the acetabular defect. METHODS: A total of 200 consecutive isolated revisions of the acetabular component from 2010 until 2012 were retrospectively analyzed from our institutional database. Of the 200 cases, 114 revisions were performed with a combination of different TMT components (wedge and cup, cup and cage). Aseptic cup failure and revision for any reason were the defined endpoints of this study. The acetabular defects were graded according to the Paprosky classification. RESULTS: The average patient age was 63.6 +/- 14.8 years (range 32-85 years) and the average follow-up was 5.3 +/- 0.7 years. The overall revision rate, independent of the utilized components, was 4.4% and the revision rate for aseptic failure of the acetabular component was 2.6%. The revision rate for aseptic loosening for Paprosky type I and II defects was 0% and Paprosky type III and IV defects was 12%. CONCLUSIONS: The modular TMT system shows low revision rates. The modularity of the system allows for a safe and intraoperative adaptation to the individual acetabular defect without the need for extensive preoperative imaging or custom-made implants. PMID- 28083682 TI - [Revision arthroplasty of the hip : Direct anterior approach]. AB - The direct anterior approach to the hip allows good exposure of acetabulum and periacetabular bones. For simple acetabular revisions it can be chosen to be small (minimally invasive); in the case of extensive periacetabular bone loss exposure of the entire ilium cranial of the acetabulum may be achieved, and the pubic bone as well as inner-pelvic structures adjacent to the acetabulum can be exposed. The internerval plane of the approach between muscles innervated by the femoral nerve and the gluteal nerves allows exposure of the ilium without endangering the nerve supply of gluteal muscles. PMID- 28083684 TI - [Mission (im)possible : Setting up a neurological center 12,000 km away with telemedicine]. AB - BACKGROUND: Specialized neurological treatment decreases the mortality and morbidity of stroke patients. In many regions of the world an extensive coverage is not available. The cooperation between the Krankenhaus Nordwest (KHNW, Frankfurt, Germany) and the Government of Brunei Darussalam describes the set-up process of a specialized neurological center, including stroke unit, science and rehabilitation center. AIM: The aim of this project called to teach to treat - to treat to teach was to set up a center of excellence in neurology in Brunei Darussalam over a distance of 12,000 km. Treatment options were elucidated by teaching and taught by case examples. MATERIAL AND METHODS: The construction of the Brunei Neuroscience Stroke and Rehabilitation Center (BNSRC) began in July 2010. To overcome the large distance between the department of neurology and neuroradiology at the KHNW and the BNSRC, a telemedical network was established. We provided daily teleteaching for all professions involved in patient care as well as 24/7 availability of teleneurological services from Germany to support the local team on site. RESULTS: In the BNSRC unit over 1000 patients with ischemic and hemorrhagic stroke and all the various acute neurological conditions were treated from July 2010 until July 2016 as inpatients and over 5000 were treated as outpatients. Since 2010, a total of 52 patients with stroke were treated by thrombolysis within the thrombolytic window and 81 hemicraniectomies were performed. CONCLUSION: The project has shown that it is possible to convey specialized neurological knowledge over large distances to provide significant benefits for patients and caregivers. PMID- 28083683 TI - [Partial exchange in total hip arthroplasty : What can we combine?] AB - BACKGROUND: In case of hip revision arthroplasty, one component (cup/stem) is often well fixed and does not need to be exchanged. The newly implanted component needs to be compatible with the well-fixed implant. The combination of implants from different companies leads to "mix and match" or even mismatch between the implants. OBJECTIVES AND METHODS: The objective of this work was to describe possible combinations including their specifications that need to be considered in partial exchange of hip prostheses. For this purpose the literature, surgical techniques of companies and judgements concerning this topic were analysed and our own results and experiences were included. RESULTS AND CONCLUSIONS: Partial revision arthroplasty can be challenging and needs to be planned in detail. In case of isolated cup or inlay revision with exchange of a modular head the cone of the stem needs to be identified. A ceramic head may be used in revision with a titanium sleeve even from a different company as long as they are compatible. Patients however need to give their informed consent for this mix and match procedure. This procedure is done frequently and good study results support this, however from a juristic point of view a definite recommendation cannot be given. If the inlay of a cup is replaced, the original inlay should be used. If this is not available anymore, it can be manufactured as a special product in many cases. If this is also not possible, an inlay can also be cemented into a well-fixed cup. Biomechanical and clinical studies support this off-label technique. In case of an isolated exchange of the stem with a ceramic inlay that is retained in a well-fixed cup, the revision stem and ceramic head need to be from the same company as the cup. In case of ceramic fracture, a ceramic head with a titanium sleeve should be combined with a PE or ceramic inlay, a metal head or inlay should never be used. PMID- 28083685 TI - [Telemedicine: Comprehensive coverage and quality - Not a contradiction : Practical experience from the stroke network with telemedicine in northern Bavaria (STENO)]. AB - Telemedicine is widely used in the field of stroke treatment. Following the pioneering and implementation phase, the quality of the whole stroke treatment process needs to be ensured in telemedically connected hospitals. This is particular important for telestroke hospitals without neurological expertise and can be achieved by integrating telemedicine into the stroke unit concept and stroke networks. The Stroke Network with Telemedicine in Northern Bavaria (STENO) provides an example of how quality management can be practically implemented. The implementation of STENO has established a network-wide quality management system which has been certified according to DIN EN ISO 9001:2008 since 2011. PMID- 28083686 TI - [Telescience : Feasibility studies, definition and a fair answer to the scientific brain drain]. AB - BACKGROUND: What is telescience? Is it feasible to transfer academic information with the help of telematics to educate and teach young scientists over large distances? The term telescience has so far not been defined but covers a variety of possibilities, which could be successfully implemented worldwide. This article gives examples and highlights the feasibility analysis of telescience. METHODS: We have carried out feasibility analyses for neurological functional diagnostics, an epidemiological cross-sectional study as well as a laboratory study for detection of thrombocyte function during dengue fever with the help of telemedicine. The basis for all these projects was a telemedical transcontinental cooperation over a distance of 12,000 km. RESULTS: All performed studies demonstrated the feasibility. With the help of telematics the laboratory techniques, planning, conduction and interpretation of results as well as publication skills can be transferred. DISCUSSION: Telescience is feasible. Our studies showed that telescience is a very promising option to transfer knowledge, which will help to enable professional expertise to be transferred directly to the region/country without a brain drain. All too often young motivated scientists are enticed to move to well-known institutions, which involves the danger of a brain drain. Brain drain can be avoided in favor of local implementation of scientific projects. Our results illustrate that it is feasible to educate and guide scientists with the help of telematics infrastructures. PMID- 28083687 TI - [The career of the psychiatrist Dietfried Muller-Hegemann (1910-1989) : Example of a politically motivated rise and fall in the German Democratic Republic]. AB - Dietfried Muller-Hegemann was one of the prominent figures in East German psychiatry and psychotherapy of the 1950s and 1960s. Having been a communist prior to 1933, a resistance fighter during the National Socialist regime and having gone through political training during his exile in Soviet Russia, he proved to be a committed member of the new ruling SED socialist party in Eastern Germany. As such both governmental and party organs regarded him as a promising and reliable party member to be supported and implemented as executive staff within the new, socialist scientific system. Also, due to the fact that he supported the Pavlovian school of thought for modern psychiatry, Muller-Hegemann was installed as the new head of the Department of Neurology and Psychiatry at Leipzig University by the state secretary for higher education, notably against the clear opposition of the university medical faculty. Soon thereafter however Muller-Hegemann fell from favor due to the fact that he supported views that did not follow the strict ideological guidelines, e. g. with regard to the emergence of fascism. Moreover, he strongly opposed the separation of neurology from psychiatry as ruled by the ministry. An attempt in 1963 by junior party members and ministerial staff to remove him from office failed, but still managed to make Muller-Hegemann resign from his Leipzig post and take over that of director of the Griesinger hospital for the mentally ill in East Berlin. In May 1971, after new conflicts with party officials, he did not return from a business trip to Essen in West Germany. This study does not review the scientific and medical merits of Muller-Hegemann, but concentrates on how his career as a leading psychiatrist was manipulated, both supported and sabotaged, and ideologically controlled by the German Democratic Republic (GDR) system. His development is documented proof that party officials did not tolerate opposition, neither in ideological nor in professional questions, even if the opponent was a committed Marxist. The example of his career shows that political and ideological dissent soon melted into personal animosity and drives, as a result of which Muller Hegemann's promising career as professor in Leipzig was terminated. PMID- 28083688 TI - [Idiopathic intracranial hypertension]. AB - This review describes the clinical findings as well as thes diagnostic and therapeutic options for idiopathic intracranial hypertension (pseudotumor cerebri). Furthermore, the pathophysiological concepts are discussed. Idiopathic intracranial hypertension is characterized by signs and symptoms of raised intracranial pressure with no established pathogenesis. Common symptoms include headaches, visual loss and pulsatile tinnitus. Treatment has two major goals: the alleviation of headaches and the preservation of vision. Weight loss and acetazolamide are the cornerstones in the treatment of the disorder. Drainage of cerebrospinal fluid, optic nerve sheath fenestration and stent angioplasty of a sinus stenosis can be employed in severe cases. PMID- 28083689 TI - Neural correlates of the popular music phenomenon: evidence from functional MRI and PET imaging. AB - PURPOSE: Music can induce different emotions. However, its neural mechanism remains unknown. The aim of this study was to use functional magnetic resonance imaging (fMRI) and position emission tomography (PET) imaging for mapping of neural changes under the most popular music in healthy volunteers. METHODS: Blood oxygen-level-dependent (BOLD) fMRI and monoamine receptor PET imaging with 11C-N methylspiperone (11C-NMSP) were conducted under the popular music Gangnam Style and light music A Comme Amour in healthy subjects. PET and fMRI images were analyzed by using the Statistical Parametric Mapping software (SPM). RESULTS: Significantly increased fMRI BOLD signals were found in the bilateral superior temporal cortices, left cerebellum, left putamen and right thalamus cortex. Monoamine receptor availability was increased significantly in the left superior temporal gyrus and left putamen, but decreased in the bilateral superior occipital cortices under the Gangnam Style compared with the light music condition. Significant positive correlation was found between 11C-NMSP binding and fMRI BOLD signals in the left temporal cortex. Furthermore, increased 11C NMSP binding in the left putamen was positively correlated with the mood arousal level score under the Gangnam Style condition. CONCLUSION: Popular music Gangnam Style can arouse pleasure experience and strong emotional response. The left putamen is positively correlated with the mood arousal level score under the Gangnam Style condition. Our results revealed characteristic patterns of brain activity associated with Gangnam Style, and may also provide more general insights into the music-induced emotional processing. PMID- 28083690 TI - The 68Ga/177Lu theragnostic concept in PSMA targeting of castration-resistant prostate cancer: correlation of SUVmax values and absorbed dose estimates. AB - INTRODUCTION: A targeted theragnostic approach based on increased expression of prostate-specific membrane antigen (PSMA) on PC cells is an attractive treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: Ten consecutive mCRPC patients were selected for 177Lu-PSMA617 therapy on the basis of PSMA-targeted 68Ga-PSMA-HBED-CC PET/CT diagnosis showing extensive and progressive tumour load. Following dosimetry along with the first therapy cycle restaging (68Ga-PSMA-HBED-CC and 18F-NaF PET/CT) was performed after 2 and 3 therapy cycles (each 6.1 +/- 0.3 GBq, range 5.4-6.5 GBq) given intravenously over 30 minutes, 9 +/- 1 weeks apart. PET/CT scans were compared to 177Lu-PSMA617 24-hour whole-body scans and contrast-enhanced dual-phase CT. Detailed comparison of SUVmax values and absorbed tumour doses was performed. RESULTS: 177Lu-PSMA617 dosimetry indicated high tumour doses for skeletal (3.4 +/ 1.9 Gy/GBq; range 1.1-7.2 Gy/GBq), lymph node (2.6 +/- 0.4 Gy/GBq; range 2.3-2.9 Gy/GBq) as well as liver (2.4 +/- 0.8 Gy/GBq; range 1.7-3.3 Gy/GBq) metastases whereas the dose for tissues/organs was acceptable in all patients for an intention-to-treat activity of 18 +/- 0.3 GBq. Three patients showed partial remission, three mixed response, one stable and three progressive disease. Decreased 177Lu-PSMA617 and 68Ga-PSMA-HBED-CC uptake (mean SUVmax values 20.2 before and 15.0 after 2 cycles and 11.5 after 3 cycles, p < 0.05) was found in 41/54 skeletal lesions, 12/13 lymph node metastases, 3/5 visceral metastases and 4/4 primary PC lesions. CONCLUSION: Due to substantial individual variance, dosimetry is mandatory for a patient-specific approach following 177Lu-PSMA617 therapy. Higher activities and/or shorter treatment intervals should be applied in a larger prospective study. PMID- 28083691 TI - Personalized medicine: a new option for nuclear medicine and molecular imaging in the third millennium. PMID- 28083692 TI - Correlation of ultra-low dose chest CT findings with physiologic measures of asbestosis. AB - OBJECTIVES: The correlation between ultra low dose computed tomography (ULDCT) detected parenchymal lung changes and pulmonary function abnormalities is not well described. This study aimed to determine the relationship between ULDCT detected interstitial lung disease (ILD) and measures of pulmonary function in an asbestos-exposed population. METHODS: Two thoracic radiologists independently categorised prone ULDCT scans from 143 participants for ILD appearances as absent (score 0), probable (1) or definite (2) without knowledge of asbestos exposure or lung function. Pulmonary function measures included spirometry and diffusing capacity to carbon monoxide (DLCO). RESULTS: Participants were 92% male with a median age of 73.0 years. CT dose index volume was between 0.6 and 1.8 mGy. Probable or definite ILD was reported in 63 (44.1%) participants. Inter-observer agreement was good (k = 0.613, p < 0.001). There was a statistically significant correlation between the ILD score and both forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) (r = -0.17, p = 0.04 and r = -0.20, p = 0.02). There was a strong correlation between ILD score and DLCO (r = -0.34, p < 0.0001). CONCLUSION: Changes consistent with ILD on ULDCT correlate well with corresponding reductions in gas transfer, similar to standard CT. In asbestos exposed populations, ULDCT may be adequate to detect radiological changes consistent with asbestosis. KEY POINTS: * Interobserver agreement for the ILD score using prone ULDCT is good. * Prone ULDCT appearances of ILD correlate with changes in spirometric observations. * Prone ULDCT appearances of ILD correlate strongly with changes in gas transfer. * Prone ULDCT may provide sufficient radiological evidence to inform the diagnosis of asbestosis. PMID- 28083693 TI - Management for BI-RADS category 3 lesions detected in preoperative breast MR imaging of breast cancer patients. AB - OBJECTIVE: To retrospectively evaluate characteristics of and determine appropriate follow-up recommendations for BI-RADS category 3 lesions detected in preoperative MRI of breast cancer patients. METHODS: BI-RADS category 3 assessments were identified from the breast MRI database for 5,110 consecutive breast cancer patients who had undergone preoperative MRI and surgery. Patient and lesion characteristics, malignancy rate, and interval between lesion detection and cancer diagnosis were analysed. Histopathological results or imaging at or after 2-year follow-up were used as reference standards. RESULTS: Of the 626 lesions, morphological features included a single focus in 26.5% (n = 166), multiple foci in 47.1% (n = 295), mass in 21.7% (n = 136) and non-mass enhancement in 4.6% (n = 29). Cancer was found in 0.8% (5/626) at a median interval of 50 months (range, 29-66 months). Malignancy rate according to morphological feature was: 1.8% (3/166) in a single focus, 0.7% (1/136) in mass and 3.4% (1/29) in non-mass enhancement. All detected cancers were stage 0 or IA. CONCLUSIONS: Annual follow-up might be adequate for BI-RADS category 3 lesions detected at preoperative MRI because of the 0.8% (5/626) malignancy rate, long interval between lesion detection and cancer diagnosis, and early stage of diagnosed cancers. KEY POINTS: * BI-RADS category 3 lesions on preoperative MRI had 0.8% malignancy rate. * All cancer diagnoses from BI-RADS 3 occurred after 24 month follow-up. * Annual follow-up might be adequate for BI-RADS 3 detected on preoperative MRI. PMID- 28083694 TI - Liver stiffness measurements with supersonic shear wave elastography in the diagnosis of biliary atresia: a comparative study with grey-scale US. AB - OBJECTIVES: To prospectively assess the diagnostic performance of supersonic shear wave elastography (SSWE) in identifying biliary atresia (BA) among infants with conjugated hyperbilirubinaemia by comparing this approach with grey-scale ultrasonography (US). METHODS: Forty infants were analysed as the control group to determine normal liver stiffness values. The use of SSWE values for identifying BA was investigated in 172 infants suspected of having BA, and results were compared with the results obtained by grey-scale US. The Mann Whitney U test, unpaired t-test, Spearman correlation and linear regression were also performed. RESULTS: The success rates of SSWE measurements in the control and study group were 100% (40/40) and 96.4% (244/253), respectively. Age, direct bilirubin, and indirect bilirubin all significantly correlated with SSWE in the liver (all P < 0.001). Linear regression showed that age had a greater effect on SSWE values than direct or indirect bilirubin. The diagnostic performance of liver stiffness values in identifying BA was lower than that of grey-scale US (area under the receiver operating characteristic curve [AUC], 0.790 vs 0.893, P < 0.001). CONCLUSIONS: SSWE is feasible and valuable in differentiating BA from non-BA. However, its diagnostic performance does not exceed that of grey-scale US. KEY POINTS: * SSWE could be successfully performed in an infant population. * For infants, the liver stiffness will increase as age increases. * SSWE is potentially useful in assessing infants suspected of biliary atresia. * SSWE is inferior to grey-scale US in identifying biliary atresia. PMID- 28083695 TI - Serial assessment of pulmonary lesion volume by computed tomography allows survival prediction in invasive pulmonary aspergillosis. AB - BACKGROUND: Serial chest CT is the standard of care to establish treatment success in invasive pulmonary aspergillosis (IPA). Data are lacking how response should be defined. METHODS: Digital CT images from a clinical trial on treatment of IPA were re-evaluated and compared with available biomarkers. Total volume of pneumonia was added up after manual measurement of each lesion, followed by statistical analysis. RESULTS: One-hundred and ninety CT scans and 309 follow-up datasets from 40 patients were available for analysis. Thirty-one were neutropenic. Baseline galactomannan (OR 4.06, 95%CI: 1.08-15.31) and lesion volume (OR 3.14, 95%CI: 0.73-13.52) were predictive of death. Lesion volume at d7 and trend between d7 and d14 were strong predictors of death (OR 20.01, 95%CI: 1.42-282.00 and OR 15.97, 95%CI: 1.62-157.32) and treatment being rated as unsuccessful (OR 4.75, 95%CI: 0.94-24.05 and OR 40.69, 95%CI: 2.55-649.03), which was confirmed by a Cox proportional hazards model using time-dependent covariates. CONCLUSION: Any increase in CT lesion volume between day 7 and day 14 was a sensitive marker of a lethal outcome (>50%), supporting a CT rescan each one and 2 weeks after initial detection of IPA. The predictive value exceeded all other biomarkers. Further CT follow-up after response at day 14 was of low additional value. KEY POINTS: * CT evaluation offers good prediction of outcome for invasive pulmonary aspergillosis. * Predictive capability exceeds galactomannan, blood counts, and lesion count. * Any progression between day 7 and day 14 constitutes a high-risk scenario. PMID- 28083696 TI - Gadolinium deposition in the brain: association with various GBCAs using a generalized additive model. AB - OBJECTIVES: To determine the relationship between the number of administrations of various gadolinium-based contrast agents (GBCAs) and increased T1 signal intensity in the globus pallidus (GP) and dentate nucleus (DN). METHODS: This retrospective study included 122 patients who underwent double-dose GBCA-enhanced magnetic resonance imaging. Two radiologists calculated GP-to-thalamus (TH) signal intensity ratio, DN-to-pons signal intensity ratio and relative change (Rchange) between the baseline and final examinations. Interobserver agreement was evaluated. The relationships between Rchange and several factors, including number of each GBCA administrations, were analysed using a generalized additive model. RESULTS: Six patients (4.9%) received linear GBCAs (mean 20.8 number of administration; range 15-30), 44 patients (36.1%) received macrocyclic GBCAs (mean 26.1; range 14-51) and 72 patients (59.0%) received both types of GBCAs (mean 31.5; range 12-65). Interobserver agreement was almost perfect (0.99; 95% CI: 0.99-0.99). Rchange (DN:pons) was associated with gadodiamide (p = 0.006) and gadopentetate dimeglumine (p < 0.001), but not with other GBCAs. Rchange (GP:TH) was not associated with GBCA administration. CONCLUSIONS: Previous administration of linear agents gadoiamide and gadopentetate dimeglumine is associated with increased T1 signal intensity in the DN, whereas macrocyclic GBCAs do not show an association. KEY POINTS: * Certain linear GBCAs are associated with T1 signal change in the dentate nucleus. * The signal change is related to the administration number of certain linear GBCAs. * Difference in signal change may reflect differences in stability of agents. PMID- 28083697 TI - Practical use of visual medial temporal lobe atrophy cut-off scores in Alzheimer's disease: Validation in a large memory clinic population. AB - OBJECTIVE: To provide age-specific medial temporal lobe atrophy (MTA) cut-off scores for routine clinical practice as marker for Alzheimer's disease (AD). METHODS: Patients with AD (n = 832, mean age 81.8 years) were compared with patients with subjective cognitive impairment (n = 333, mean age 71.8 years) in a large single-centre memory clinic. Mean of right and left MTA scores was determined with visual rating (Scheltens scale) using CT (0, no atrophy to 4, severe atrophy). Relationships between age and MTA scores were analysed with regression analysis. For various MTA cut-off scores, decade-specific sensitivity and specificity and area under the curve (AUC) values, computed with receiver operator characteristic curves, were determined. RESULTS: MTA strongly increased with age in both groups to a similar degree. Optimal MTA cut-off values for the age ranges <65, 65-74, 75-84 and >=85 were: >=1.0, >=1.5, >= 2.0 and >=2.0. Corresponding values of sensitivity and specificity were 83.3% and 86.4%; 73.7% and 84.6%; 73.7% and 76.2%; and 84.0% and 62.5%. CONCLUSION: From this large unique memory clinic cohort we suggest decade-specific MTA cut-off scores for clinical use. After age 85 years, however, the practical usefulness of the MTA cut-off is limited. KEY POINTS: * We suggest decade-specific MTA cut-off scores for AD. * MTA cut-off after the age of 85 years has limited use. * CT is feasible and accurate for visual MTA rating. PMID- 28083698 TI - Emergency assessment of patients with acute abdominal pain using low-dose CT with iterative reconstruction: a comparative study. AB - OBJECTIVES: To determine if radiation dose delivered by contrast-enhanced CT (CECT) for acute abdominal pain can be reduced to the dose administered in abdominal radiography (<2.5 mSv) using low-dose CT (LDCT) with iterative reconstruction algorithms. METHODS: One hundred and fifty-one consecutive patients requiring CECT for acute abdominal pain were included, and their body mass index (BMI) was calculated. CECT was immediately followed by LDCT. LDCT series was processed using 1) 40% iterative reconstruction algorithm blended with filtered back projection (LDCT-IR-FBP) and 2) model-based iterative reconstruction algorithm (LDCT-MBIR). LDCT-IR-FBP and LDCT-MBIR images were reviewed independently by two board-certified radiologists (Raters 1 and 2). RESULTS: Abdominal pathology was revealed on CECT in 120 (79%) patients. In those with BMI <30, accuracies for correct diagnosis by Rater 1 with LDCT-IR-FBP and LDCT-MBIR, when compared to CECT, were 95.4% (104/109) and 99% (108/109), respectively, and 92.7% (101/109) and 100% (109/109) for Rater 2. In patients with BMI >=30, accuracies with LDCT-IR-FBP and LDCT-MBIR were 88.1% (37/42) and 90.5% (38/42) for Rater 1 and 78.6% (33/42) and 92.9% (39/42) for Rater 2. CONCLUSIONS: The radiation dose delivered by CT to non-obese patients with acute abdominal pain can be safely reduced to levels close to standard radiography using LDCT-MBIR. KEY POINTS: * LDCT-MBIR (<2.5 mSv) can be used to assess acute abdominal pain. * LDCT-MBIR (<2.5 mSv) cannot safely assess acute abdominal pain in obese patients. * LDCT-IR-FBP (<2.5 mSv) cannot safely assess patients with acute abdominal pain. PMID- 28083699 TI - Extremely high intracellular concentration of glucose-6-phosphate and NAD(H) in Deinococcus radiodurans. AB - Deinococcus radiodurans is highly resistant to ionizing radiation and UV radiation, and oxidative stress caused by such radiations. NADP(H) seems to be important for this resistance (Slade and Radman, Microbiol Mol Biol Rev 75:133 191; Slade, Radman, Microbiol Mol Biol Rev 75:133-191, 2011), but the mechanism underlying the generation of NADP(H) or NAD(H) in D. radiodurans has not fully been addressed. Intracellular concentrations of NAD+, NADH, NADP+, and NADPH in D. radiodurans are also not determined yet. We found that cell extracts of D. radiodurans catalyzed reduction of NAD(P)+ in vitro, indicating that D. radiodurans cells contain both enzymes and a high concentration of substrates for this activity. The enzyme and the substrate were attributed to glucose-6 phosphate dehydrogenase and glucose-6-phosphate of which intracellular concentration was extremely high. Unexpectedly, the intracellular concentration of NAD(H) was also much greater than that of NADP(H), suggesting some significant roles of NADH. These unusual features of this bacterium would shed light on a new aspect of physiology of this bacterium. PMID- 28083700 TI - MRI usage in a pediatric emergency department: an analysis of usage and usage trends over 5 years. AB - BACKGROUND: Magnetic resonance imaging (MRI) usage has anecdotally increased due to the principles of ALARA and the desire to Image Gently. Aside from a single abstract in the emergency medicine literature, pediatric emergency department MRI usage has not been described. OBJECIVE: Our objective was to determine whether MRI use is indeed increasing at a high-volume urban pediatric emergency department with 24/7 MRI availability. Also, we sought to determine which exams, time periods and demographics influenced the trend. MATERIALS AND METHODS: Institutional Review Board exemption was obtained. Emergency department patient visit and exam data were obtained from the hospital database for the 2011-2015 time period. MRI usage data were normalized using emergency department patient visit data to determine usage rates. The z-test was used to compare MRI use by gender. The chi-square test was used to test for trends in MRI usage during the study period and in patient age. MRI usage for each hour and each weekday were tabulated to determine peak and trough usage times. RESULTS: MRI usage rate per emergency department patient visit was 0.36%. Headache, pain and rule-out appendicitis were the most common indications for neuroradiology, musculoskeletal and trunk exams, respectively. Usage in female patients was significantly greater than in males (0.42% vs. 0.29%, respectively, P<0.001). Usage significantly increased during the 5-year period (P<0.001). Use significantly increased from age 3 to 17 (0.011% to 1.1%, respectively, P<0.001). Sixty percent of exams were performed after-hours, the highest volume during the 10 p.m. hour and lowest between 4 a.m. and 9 a.m. MRI use was highest on Thursdays and lowest on Sundays (MRI on 0.45% and 0.22% of patients, respectively). CONCLUSION: MRI use in children increased during the study period, most notably in females, on weekdays and after-hours. PMID- 28083701 TI - Disorders of fatty acid oxidation and autosomal recessive polycystic kidney disease-different clinical entities and comparable perinatal renal abnormalities. AB - BACKGROUND: Differential diagnosis of prenatally detected hyperechogenic and enlarged kidneys can be challenging as there is a broad phenotypic overlap between several rare genetic and non-genetic disorders. Metabolic diseases are among the rarest underlying disorders, but they demand particular attention as their prognosis and postnatal management differ from those of other diseases. METHODS: We report two cases of cystic, hyperechogenic and enlarged kidneys detected on prenatal ultrasound images, resulting in the suspected diagnosis of autosomal recessive polycystic kidney disease (ARPKD). Postnatal clinical course and work-up, however, revealed early, neonatal forms of disorders of fatty acid oxidation (DFAO) in both cases, namely, glutaric acidemia type II, based on identification of the novel, homozygous splice-site mutation c.1117-2A > G in the ETFDH gene, in one case and carnitine palmitoyltransferase II deficiency in the other case. RESULTS: Review of pre- and postnatal sonographic findings resulted in the identification of some important differences that might help to differentiate DFAO from ARPKD. In DFAO, kidneys are enlarged to a milder degree than in ARPKD, and the cysts are located ubiquitously, including also in the cortex and the subcapsular area. Interestingly, recent studies have pointed to a switch in metabolic homeostasis, referred to as the Warburg effect (aerobic glycolysis), as one of the underlying mechanisms of cell proliferation and cyst formation in cystic kidney disease. DFAO are characterized by the inhibition of oxidative phosphorylation, resulting in aerobic glycolysis, and thus they do resemble the Warburg effect. We therefore speculate that this inhibition might be one of the pathomechanisms of renal hyperproliferation and cyst formation in DFAO analogous to the reported findings in ARPKD. CONCLUSIONS: Neonatal forms of DFAO can be differentially diagnosed in neonates with cystic or hyperechogenic kidneys and necessitate immediate biochemical work-up to provide early metabolic management. PMID- 28083702 TI - Increased urinary neutrophil gelatinase-associated lipocalin in very-low-birth weight infants with oliguria and normal serum creatinine. AB - BACKGROUND: In infants, oliguria is defined as a urine output of <1.5 mL/kg/h. The aim of our study was to assess the impact of oliguria on urinary neutrophil gelatinase-associated lipocalin (NGAL) and serum cystatin C (CysC) levels in very low-birth-weight infants (VLBWIs) with a normal serum creatinine (Cr) level. METHODS: Fifty-seven VLBWIs were enrolled in the study. Urinary NGAL, serum CysC and Cr levels and urinary NGAL/Cr ratios were measured. Infants with Apgar scores of >5 at 5 min and/or a serum Cr level of >1.5 mg/dL or those treated for patent ductus arteriosus were excluded. In case of antibiotic treatment, blood and urine samples were collected at >=48 h after discontinuation of antibiotic treatment. RESULTS: There was a significant difference in gestational age between infants with oliguric episodes during hospitalization and those without, but not in birth weight, perinatal or postnatal factors. Gestational age was negatively correlated with urinary NGAL and serum CysC levels and urinary NGAL/Cr ratio (p < 0.05), whereas postnatal age was negatively correlated with serum Cr level and urinary NGAL/Cr ratio (p < 0.05). Of the 117 urine and blood samples collected, 25 (21.4%) were obtained from neonates with oliguric episodes. After adjusting for gestational age and postnatal age, comparison of samples collected in infants with and without oliguric episodes revealed significant differences in the mean level of urinary NGAL and in the urinary NGAL/Cr ratio, but not in mean serum CysC or serum Cr levels. The urinary NGAL level [area under the curve (AUC) 0.886, 95% confidence interval (CI) 0.814-0.937] and urinary NGAL/Cr ratio (AUC 0.853, 95% CI 0.775-0.911) showed significantly greater discrimination for oliguria than serum CysC (AUC 0.610, 95% CI: 0.515-0.699) or serum Cr (AUC 0.747, 95%CI 0.659-0.823) levels. CONCLUSIONS: Urinary NGAL level and urinary NGAL/Cr ratio were more sensitive markers for the presence of oliguria in VLBWIs with normal serum Cr levels than serum CysC level. PMID- 28083703 TI - Effect of soil moisture on root-associated fungal communities of Erica dominans in Drakensberg mountains in South Africa. AB - Ericoid mycorrhiza represents a key adaptation of the Ericaceae plants to facilitate their establishment in harsh conditions. The Ericaceae are a large family of flowering plants, with global distribution. However, our current knowledge about the ericoid mycorrhizal fungal diversity and ecology largely relates to the Northern Hemisphere. Our study focused on the assembly of root associated fungal (RAF) communities of Erica dominans in two types of microhabitats of contrasting moisture along an elevation gradient in Drakensberg mountains in South Africa. RAF communities were determined by 454-sequencing of the internal transcribed spacer (ITS) region of ribosomal DNA. The majority of RAF showed affinity to the orders Helotiales, Pezizales, and Pleosporales. Microhabitat type as well as elevation had significant but weak effect on RAF community composition. We identified two putative ericoid mycorrhizal fungi, the ecological niches of which were differentiated between the studied microhabitats. Our study also provides one of the first comprehensive data about RAF communities of Ericaceae on African continent and shows the occurrence of the most studied ericoid mycorrhizal fungus Pezoloma ericae (belonging to P. ericae aggregate) in roots of Ericaceae host plant in Africa. PMID- 28083704 TI - MDM2 gene polymorphisms and risk of classic Kaposi's sarcoma among Iranian patients. AB - A single-nucleotide polymorphism (SNP) in the promoter region of MDM2 (SNP309T>G, rs2279744) has been shown to increase the expression of the MDM2 protein in various cancer types. However, only one study has analyzed the role of the MDM2 polymorphism in the development of Kaposi's sarcoma (KS). The association of MDM2 SNP309 with classic KS risk was evaluated in 79 Iranian patients with classic KS and 123 healthy controls. The MDM2 SNP309 was genotyped using PCR and restriction fragment length polymorphism methods. No significant correlation was found between the SNP309 polymorphism in MDM2 promoter and classic KS risk. There was no significant correlation between gender and disease stage. However, a significant association was found between SNP309 GG genotype and younger age (<=50 years) (odds ratio 9.5, 95% confidence intervals 1.5-60, p = 0.03). Our findings support no major role for the MDM2 SNP309 in KS development although it might influence the clinical outcome of KS in younger patients. PMID- 28083705 TI - Oral appliance therapy versus nasal continuous positive airway pressure in obstructive sleep apnea: a randomized, placebo-controlled trial on psychological distress. AB - OBJECTIVES: The aim of this randomized placebo-controlled trail was to compare the effects of an objectively titrated mandibular advancement device (MAD) with those of nasal continuous positive airway pressure (nCPAP) and an intraoral placebo device on symptoms of psychological distress in OSA patients. MATERIALS AND METHODS: In a parallel design, 64 mild/moderate OSA patients (52.0 +/- 9.6 years) were randomly assigned to an objectively titrated MAD, nCPAP, or an intraoral placebo appliance. All patients filled out the Symptom Checklist-90 Revised twice: one before treatment and one after 6 months of treatment. The Symptom Checklist-90-Revised is a multidimensional symptom inventory designed to measure symptomatic psychological distress over the past week. Linear mixed model analyses were performed to study differences between the therapy groups for the different dimensions of the Symptom Checklist-90-Revised over time. RESULTS: The MAD group showed significant improvements over time in the dimensions "somatization," "insufficiency of thinking and acting," "agoraphobia," "anxiety," "sleeping problems," and "global severity index" (F = 4.14-16.73, P = 0.048 0.000). These improvements in symptoms of psychological distress were, however, not significantly different from those observed in the nCPAP and placebo groups (P = 0.374-0.953). CONCLUSION: There is no significant difference between MAD, nCPAP, and an intraoral placebo appliance in their beneficial effects on symptoms of psychological distress. CLINICAL RELEVANCE: The improvement in psychological distress symptoms in mild/moderate OSA patients under MAD or nCPAP treatment may be explained by a placebo effect. PMID- 28083706 TI - Gao et al. (2016): Change of urinary cadmium and renal tubular protein in female works after cessation of cadmium exposure : Response to the Letter to the Editor by Kawada (2016). PMID- 28083708 TI - ? PMID- 28083707 TI - Effect of repeated forearm muscle cooling on the adaptation of skeletal muscle metabolism in humans. AB - This study aimed to investigate the effect of repeated cooling of forearm muscle on adaptation in skeletal muscle metabolism. It is hypothesized that repeated decreases of muscle temperature would increase the oxygen consumption in hypothermic skeletal muscle. Sixteen healthy males participated in this study. Their right forearm muscles were locally cooled to 25 degrees C by cooling pads attached to the skin. This local cooling was repeated eight times on separate days for eight participants (experimental group), whereas eight controls received no cold exposure. To evaluate adaptation in skeletal muscle metabolism, a local cooling test was conducted before and after the repeated cooling period. Change in oxy-hemoglobin content in the flexor digitorum at rest and during a 25-s isometric handgrip (10% maximal voluntary construction) was measured using near infrared spectroscopy at every 2 degrees C reduction in forearm muscle temperature. The arterial blood flow was occluded for 15 s by upper arm cuff inflation at rest and during the isometric handgrip. The oxygen consumption in the flexor digitorum muscle was evaluated by a slope of the oxy-hemoglobin change during the arterial occlusion. In the experimental group, resting oxygen consumption in skeletal muscle did not show any difference between pre- and post intervention, whereas muscle oxygen consumption during the isometric handgrip was significantly higher in post-intervention than in pre-test from thermoneutral baseline to 31 degrees C muscle temperature (P < 0.05). This result indicated that repeated local muscle cooling might facilitate oxidative metabolism in the skeletal muscle. In summary, skeletal muscle metabolism during submaximal isometric handgrip was facilitated after repeated local muscle cooling. PMID- 28083709 TI - Tissue and cell-type co-expression networks of transcription factors and wood component genes in Populus trichocarpa. AB - MAIN CONCLUSION: Co-expression networks based on transcriptomes of Populus trichocarpa major tissues and specific cell types suggest redundant control of cell wall component biosynthetic genes by transcription factors in wood formation. We analyzed the transcriptomes of five tissues (xylem, phloem, shoot, leaf, and root) and two wood forming cell types (fiber and vessel) of Populus trichocarpa to assemble gene co-expression subnetworks associated with wood formation. We identified 165 transcription factors (TFs) that showed xylem-, fiber-, and vessel-specific expression. Of these 165 TFs, 101 co-expressed (correlation coefficient, r > 0.7) with the 45 secondary cell wall cellulose, hemicellulose, and lignin biosynthetic genes. Each cell wall component gene co expressed on average with 34 TFs, suggesting redundant control of the cell wall component gene expression. Co-expression analysis showed that the 101 TFs and the 45 cell wall component genes each has two distinct groups (groups 1 and 2), based on their co-expression patterns. The group 1 TFs (44 members) are predominantly xylem and fiber specific, and are all highly positively co-expressed with the group 1 cell wall component genes (30 members), suggesting their roles as major wood formation regulators. Group 1 TFs include a lateral organ boundary domain gene (LBD) that has the highest number of positively correlated cell wall component genes (36) and TFs (47). The group 2 TFs have 57 members, including 14 vessel-specific TFs, and are generally less correlated with the cell wall component genes. An exception is a vessel-specific basic helix-loop-helix (bHLH) gene that negatively correlates with 20 cell wall component genes, and may function as a key transcriptional suppressor. The co-expression networks revealed here suggest a well-structured transcriptional homeostasis for cell wall component biosynthesis during wood formation. PMID- 28083710 TI - Is 3-years duration of adjuvant imatinib mesylate treatment sufficient for patients with high-risk gastrointestinal stromal tumor? A study based on long term follow-up. AB - BACKGROUND: The therapy for gastrointestinal stromal tumors (GIST) has changed significantly since the use of imatinib mesylate (IM). However, the appropriate duration of receiving adjuvant IM for patients with high-risk GIST who underwent R0 resection is still controversial. METHODS: From January 2005 to December 2014, 234 patients who underwent R0 resection and were treated with adjuvant imatinib at our institution were identified from a prospectively collected database. The effect of the medication duration on the long-term outcomes was analyzed. RESULTS: In this study, 140 cases were male and 94 cases were female, and the mean age was 57.5 +/- 11.4 years. The most common site was the stomach (103 cases, 44%), followed by the small intestine (81 cases, 34.6%). The 5 year recurrence-free survival (RFS) rate and overall survival (OS) rate in the whole groups were 76.2 and 83.4%, respectively. The patient's prognosis was improved due to the prolongation of the time of receiving the imatinib treatment (P < 0.05). According to the results of the risk stratification analysis, the outcomes of the moderate-risk patients who received IM adjuvant therapy for 1-year group, 1-3 years group and more than 3 years group showed improvement, but the difference was not statistically significant (P > 0.05). However, in the high risk patients, the RFS rates of the 1-year group, 1-3-years group, 3-5-years group and more than 5 years group were 36.5, 68.7, 71.2 and 90.8%, respectively, and the OS rates were 36.7, 76.6, 84.0 and 97.4%, respectively (P < 0.001). In addition, linear regression analysis showed that the long-term outcomes of patients with high-risk GIST significantly improved due to prolonged adjuvant IM treatment durations (P < 0.05). The RFS rate of patients receiving IM for more than 5 years was significantly better than those receiving it for less than 5 years. Multivariate COX regression analysis in the patients with high-risk GIST showed that tumor located in small intestine was an independent risk factor, while receiving IM treatment was an independent protective factor for prognosis. CONCLUSIONS: The long-term outcomes of patients with high risk GIST improved due to the prolongation of the IM treatment. To reduce the recurrence and improve the long-term survival, we suggest that patients with high-risk GIST receive imatinib treatment for at least 5 years. PMID- 28083711 TI - No influence of BCR-ABL1 transcript types e13a2 and e14a2 on long-term survival: results in 1494 patients with chronic myeloid leukemia treated with imatinib. AB - PURPOSE: The genomic break on the major breakpoint cluster region of chromosome 22 results in two BCR-ABL1 transcripts of different sizes, e14a2 and e13a2. Favorable survival probabilities of patients with chronic myeloid leukemia (CML) in combination with too small patient samples may yet have obstructed the observation of differences in overall survival of patients according to transcript type. To overcome potential power problems, overall survival (OS) probabilities and probabilities of CML-related death were analyzed in 1494 patients randomized to first-line imatinib treatment. METHODS: OS probabilities and probabilities of dying of CML were compared using the log-rank or Gray test whichever was appropriate. Both tests were stratified for the EUTOS long-term survival score. RESULTS: Between the groups with a single transcript, neither OS probabilities (stratified log-rank test: p = 0.106) nor probabilities of CML related death were significantly different (stratified Gray test: p = 0.256). Regarding OS, the Cox hazard ratio (HR) of transcript type e13a2 (n = 565) to type e14a2 (n = 738) was 1.332 (95% CI 0.940-1.887). Considering probabilities of leukemia-related death, the corresponding subdistribution HR resulted in 1.284 (95% CI 0.758-2.176). Outcome did not change if patients with both transcripts (n = 191) were added to the 738 with type e14a2 only. CONCLUSIONS: The prognostic association of transcript type and long-term survival outcome was weak and without clinical relevance. However, earlier reported differences in the rate and the depth of molecular response could be relevant for the chance of successfully discontinuing TKI treatment. The effect of transcript type on molecular relapse after discontinuation is unknown, yet. PMID- 28083712 TI - Pelvic floor morphometry: a predictor of success of pelvic floor muscle training for women with stress and mixed urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to determine if pelvic floor muscle (PFM) morphometry at baseline, as measured by MRI, can predict response to PFM training in women with stress or mixed urinary incontinence (UI). METHODS: This study was a prospective quasi-experimental pre-test, post-test cohort study of women with UI, aged 60 years and older. All participants completed a baseline assessment of UI severity and impact, using the 72-h bladder diary and the Incontinence Impact Questionnaire. They underwent a pelvic MRI examination to assess the PFM anatomy. Women then participated in a 12-week PFM training program. Finally, they attended a post intervention assessment of UI severity and impact. The association between morphometry and PFM training response was assessed by univariate analysis, multivariate analysis, and receiver operating characteristic (ROC) curve analysis. RESULTS: The urethro-vesical junction height at rest, as measured by MRI before treatment, was associated with response to PFM training both on univariate (p <= 0.005) and multivariate analyses (p = 0.007). The area under the ROC curve was 0.82 (95% confidence interval [CI]: 0.67-0.96). Using a cut-off point of 11.4 mm, participants' response to PFM training was predicted with a sensitivity of 77% and a specificity of 83%. Incontinent women with a urethro-vesical junction height above this threshold were 35% more likely to respond to PFM training (OR 1.35; 95% CI: 1.08-1.67). CONCLUSION: In older women with UI, a urethro-vesical junction height at rest of at least 11.4 mm appears to be predictive of PFM training response. PMID- 28083713 TI - Is levator hiatus distension associated with peripheral ligamentous laxity during pregnancy? AB - INTRODUCTION AND HYPOTHESIS: The impact of pregnancy on pelvic floor disorders remains poorly understood. During pregnancy, an increase in ligamentous laxity and pelvic organ mobility is often reported. Our main objective was to investigate a possible association between peripheral ligamentous laxity and levator hiatus (LH) distension during pregnancy. METHODS: This was a prospective longitudinal study of 26 pregnant women followed up from the first to the third trimester. We collected the following information: occurrence of pelvic organ prolapse (POP) symptoms (score higher than 0 for the POP section of the Pelvic Floor Distress Inventory 20 questions score), 4D perineal ultrasound scan results with LH distension assessment and measurement of metacarpophalangeal joint mobility (MCP laxity). The association between MCP laxity and LH distension was estimated by mixed multilevel linear regression. The associations between MCP laxity and categorical parameters were estimated in a multivariate analysis using a generalized estimating equation model. RESULTS: MCP laxity and LH distension were correlated with a correlation coefficient of 0.26 (p = 0.02), and 6.8% of the LH distension variance was explained by MCP laxity. In the multivariate analysis, MCP laxity was associated with POP symptoms with an odds ratio at 1.05 (95% CI 1.01-1.11) for an increase of 1 degrees in MCP laxity. CONCLUSION: LH distension and peripheral ligamentous laxity are significantly associated during pregnancy. However, the relationship is weak, and the results need to be confirmed in larger populations and with more specific techniques such as elastography to directly assess the elastic properties of the pelvic floor muscles. PMID- 28083714 TI - Effectiveness of BTX-A and neuromodulation in treating OAB with or without detrusor overactivity: a systematic review. AB - INTRODUCTION AND HYPOTHESIS: Patients with refractory overactive bladder (OAB) pose a therapeutic challenge. Guidelines such as those from the National Institute for Health and Care Excellence recommend invasive treatments such as botulinum toxin-A ((BTX-A), sacral neural stimulation (SNS) etc. only if there is detrusor overactivity (DO) on urodynamics. METHODS: Our aim was to systematically evaluate evidence based on the presence or absence of DO in relation to differences in effectiveness and complications related to invasive treatment in patients with refractory OAB. We carried out a systematic search of Cochrane, MEDLINE, Embase, CINAHL, LILACS, meta-Register of Controlled Trials (mRCT), CENTRAL, and Google Scholar databases from inception until April 2016. Abstracts presented at IUGA, ICS and EAU conferences (until April 2016) were included and journals that were hand searched. RESULTS: We found five studies (two prospective cohort studies and subgroup analyses of two randomized controlled trials (RCTs) and one cohort study for BTX-A, one multicenter prospective cohort study for percutaneous tibial nerve stimulation (PTNS) and three (one RCT and two cohort studies) for SNS. The outcomes in patients without (n = 77) or with (n = 135) DO were similar in the context of urodynamic findings, bladder diaries, quality of life (QoL) questionnaires, etc. when treated with BTX-A [odds ratio (OR) 1.52, 95% confidence interval (CI) 0.40-5.77] or SNS (50 patients without and 81 with DO; OR1.37, CI 0.76-2.48). Outcomes for PTNS (based on a single study) seem to be better in patients without DO. CONCLUSION: The limited evidence suggests that urodynamic diagnosis of DO does not alter patient reported outcomes for invasive treatments such as BTX-A and SNS. Noninferiority RCTs powered to evaluate the role of DO in predicting treatment response are required. PMID- 28083715 TI - Characterization of LuxI and LuxR Protein Homologs of N-Acylhomoserine Lactone Dependent Quorum Sensing System in Pseudoalteromonas sp. 520P1. AB - Pseudoalteromonas sp. 520P1 (hereafter referred to as strain 520P1) produces N acylhomoserine lactones (AHLs), which serve as signaling molecules in Gram negative bacterial quorum sensing. In a previous genomic analysis of the 5.25-Mb genome of strain 520P1, we detected the presence of at least one homolog of the AHL synthase gene (luxI) and five homologs of the transcriptional regulator protein gene (luxR). The LuxI homolog of strain 520P1 (PalI) contained the conserved amino acid motifs shared by all the LuxI family proteins of the different species examined here. The palI gene expressed in Escherichia coli produced two types of AHLs. In the thin-layer chromatography analysis, these AHLs showed identical mobility to the AHLs produced by strain 520P1. The five LuxR homologs of strain 520P1 (PalR1-PalR5) shared only 17-34% amino acid sequence identity, although higher identities were observed in the C-terminal DNA-binding domain. Among the five PalRs, only PalR5 displayed close homology with LuxR family proteins from other Pseudoalteromonas strains. Notably, the palR3 and palI genes were located close together and only 1021 bases apart in the genome. No cognate luxI homolog associated with the four other palR genes was detected. These characteristics of PalI and the PalRs suggest that AHL autoinducers generated by the PalI enzyme might regulate cellular metabolism in cooperation with five transcriptional regulator PalRs, each of which is presumed to play a distinctive role in bacterial signaling. PMID- 28083717 TI - Physiology of the Vc-NhaP paralogous group of cation-proton antiporters in Vibrio cholerae. AB - The genome of Vibrio cholerae encodes three cation-proton antiporters of NhaP type, Vc-NhaP1, 2, and 3. To examine physiological roles of Vc-NhaP antiporters, triple DeltanhaP1DeltanhaP2DeltanhaP3 and single DeltanhaP3 deletion mutants of V. cholerae were constructed and characterized. Vc-NhaP3 was, for the first time, cloned and biochemically characterized. Activity measurements on the inside-out membrane vesicle experimental model defined Vc-NhaP3 as a potassium-specific cation-proton antiporter. While elimination of functional Vc-NhaP3 resulted in only minor growth defect in potassium-rich medium at pH 6.0, the triple Vc-NhaP mutant demonstrated severe growth defects at both low and high [K+] at pH 6.0 and failed to grow at high [K+] in mildly alkaline (pH 8.0 and 8.5) media, as well. Expressed from a plasmid, neither of the Vc-NhaP paralogues was able to complement the severe potassium-sensitive phenotype of the triple deletion mutant completely. Vc-NhaP1 provided much better complementation at acidic pH compared to Vc-NhaP2, despite the fact that Vc-NhaP2 showed much higher antiport activity in sub-bacterial vesicles. In mildly alkaline pH only Vc-NhaP2 complemented the potassium-sensitive phenotype of the triple deletion mutant. Taken together, these data suggest that in vivo all three isoforms operate in concert, contributing to K+ resistance of V. cholerae. We suggest that the Vc-NhaP paralogue group might play a role in passing gastric acid barrier by ingested V. cholerae cells. PMID- 28083716 TI - Manganese supplementation increases adiponectin and lowers ICAM-1 and creatinine blood levels in Zucker type 2 diabetic rats, and downregulates ICAM-1 by upregulating adiponectin multimerization protein (DsbA-L) in endothelial cells. AB - Blood and tissue levels of manganese (Mn) are lower in type 2 diabetic and atherosclerosis patients compared with healthy subjects. Adiponectin has anti diabetic and anti-atherogenic properties. Impairment in Disulfide bond A-like protein (DsbA-L) is associated with low adiponectin levels and diabetes. This study investigates the hypothesis that the beneficial effects of Mn supplementation are mediated by adiponectin and DsbA-L. At 6 weeks of age, Male Zucker diabetic fatty rats (ZDF) were randomly divided into two groups: diabetic controls and Mn-supplemented diabetic rats. Each rat was supplemented with Mn (D+Mn, 16 mg/kg BW) or water (placebo, D+P) daily for 7 weeks by oral gavage. For cell culture studies, Human Umbilical Vein Endothelial Cells (HUVEC) or 3T3L1 adipocytes were pretreated with Mn (0-10 uM MnCl2) for 24 h, followed by high glucose (HG, 25 mM) or normal glucose (5 mM) exposure for another 24 h. Mn supplementation resulted in higher adiponectin (p = 0.01), and lower ICAM-1 (p = 0.04) and lower creatinine (p = 0.04) blood levels compared to those in control ZDF rats. Mn-supplemented rats also caused reduced oxidative stress (ROS) and NADPH oxidase, and higher DsbA-L expression in the liver (p = 0.03) of ZDF rats compared to those in livers of control rats; however, Fe levels in liver were lower but not significant (p = 0.08). Similarly, treatment with high glucose (25 mM) caused a decrease in DsbA-L, which was prevented by Mn supplementation in HUVEC and adipocytes. Mechanistic studies with DsbA-L siRNA showed that the beneficial effects of Mn supplementation on ROS, NOX4, and ICAM-1 expression were abolished in DsbA-L knock-down HUVEC. These studies demonstrate that DsbA-L linked adiponectin mediates the beneficial effects observed with Mn supplementation and provides evidence for a novel mechanism by which Mn supplementation can increase adiponectin and reduce the biomarkers of endothelial dysfunction in diabetes. PMID- 28083719 TI - A critical assessment of the association between postnatal toxoplasmosis and epilepsy in immune-competent patients. AB - While postnatal toxoplasmosis in immune-competent patients is generally considered a self-limiting and mild illness, it has been associated with a variety of more severe clinical manifestations. The causal relation with some manifestations, e.g. myocarditis, has been microbiologically proven, but this is not unequivocally so for other reported associations, such as with epilepsy. We aimed to systematically assess causality between postnatal toxoplasmosis and epilepsy in immune-competent patients. A literature search was performed. The Bradford Hill criteria for causality were used to score selected articles for each component of causality. Using an arbitrary but defined scoring system, the maximal score was 15 points (13 for case reports). Of 704 articles, five case reports or series and five case-control studies were selected. The strongest evidence for a causal relation was provided by two case reports and one case control study, with a maximal causality score of, respectively, 9/13, 10/13 and 10/15. The remaining studies had a median causality score of 7 (range 5-9). No selection bias was identified, but 6/10 studies contained potential confounders (it was unsure whether the infection was pre- or postnatal acquired, or immunodeficiency was not specifically excluded). Based on the evaluation of the available literature, although scanty and of limited quality, a causal relationship between postnatal toxoplasmosis and epilepsy seems possible. More definite proof requires further research, e.g. by performing Toxoplasma serology in all de novo epilepsy cases. PMID- 28083718 TI - Ledipasvir/sofosbuvir without ribavirin is effective in the treatment of recurrent hepatitis C virus infection post-liver transplant. AB - BACKGROUND/AIM: Recurrent hepatitis C virus infection is a challenging complication post-liver transplant. Current guidelines recommend the combination of ribavirin and ledipasvir/sofosbuvir for 12 weeks for the treatment of recurrent HCV genotype 1 post-liver transplant. Data are limited on the use of ledipasvir/sofosbuvir without ribavirin. The aim of this study was to evaluate the use of ledipasvir/sofosbuvir without ribavirin for the treatment of recurrent hepatitis C virus post-liver transplant. METHODS: This is a retrospective study of liver transplant patients who received ledipasvir/sofosbuvir without ribavirin for the treatment of recurrent hepatitis C virus in our liver center from 2014 to 2016. RESULTS: A total of 60 patients were enrolled of which 70% were male, 88% Caucasian, age 60 +/- 7 years, 15% cirrhotic, and 45% treatment-experienced with recurrent hepatitis C virus infection genotype 1 post-liver transplant. Treatment duration varied from 8 to 24 weeks. There were no serious adverse events and no discontinuation of treatment. A total of 71% of patients had undetectable serum hepatitis C virus at 4 weeks. However, irrespective of treatment duration, 100% of patients had undetectable serum hepatitis C virus at the end of treatment and 100% of patients achieved sustained viral response at 12 weeks. CONCLUSION: Ledipasvir/sofosbuvir without ribavirin is an effective treatment of recurrent hepatitis C virus infection post-liver transplant. The entire group achieved sustained viral response at 12 weeks irrespective of the length of treatment. The combination of ledipasvir/sofosbuvir was well tolerated without serious adverse effects or discontinuation. PMID- 28083720 TI - Effects of Acute Stress on Decision Making. AB - The study examined the effects of a social stressor (Trier Social Stress Test) on 24 male and 32 female college students' affective and physiological reactivity and their subsequent performance on a decision-making task (Iowa Gambling Task). The 56 participants were randomly assigned to a social stressor or a control condition. Compared to controls, participants in the stress condition responded with higher heart rates and skin conductance responses, reported more negative affect, and on the decision-making task made less advantageous choices. An exploratory regression analysis revealed that among men higher levels of heart rate were positively correlated with riskier choices on the Iowa Gambling Task, whereas for women this relationship was curvilinear. Exploratory correlational analyses showed that lower levels of skin conductance within the stress condition were associated with greater levels of substance use and gambling. The results suggest that the presence of a stressor may generally result in failure to attend to the full range of possible consequences of a decision. The relationship pattern between the degree of stress responding and successful decision making may be different for men and women. PMID- 28083721 TI - Caspase dependent and independent mechanisms of apoptosis across gestation in a sheep model of placental insufficiency and intrauterine growth restriction. AB - Increased placental apoptosis is a hallmark of intrauterine growth restricted (IUGR). Several molecules have been shown to be involved in the control of apoptosis during this disease. Our objective was to determine the expression of Bcl2, Bax, phospho XIAP, AIF, caspase 3 and 9, and telomerase activity across gestation in an ovine hyperthermia-induced model of IUGR. Pregnant sheep were placed in hyperthermic (HT) conditions to induce IUGR along with age-matched controls. Placental tissues were collected at 55 (early), 95 (mid-gestation) and 130 (near-term) days of gestational age (dGA) to determine the expression of apoptotic molecules during the development of IUGR. Compared to the control placenta, IGUR pregnancies showed: significantly reduced placental Bcl2 in early gestation (55 dGA) with a significant increase observed at mid gestation (95 dGA); decreased placental pXIAP at both mid and near term gestational days (95 and 130 dGA); placental AIF increased only at 55 dGA (early gestation); active caspase 3 increased at both mid and near term gestational days (95 and 130 dGA); caspase 9 only increased at mid gestation (95 dGA) and decreased Telomerase activity near term. Placental apoptosis, mediated in part by the apoptosis related molecule, participates in the development of IUGR. Findings from this study suggest a caspase-independent apoptotic pathway during early gestation and caspase-dependent apoptosis at mid and near term gestation. The data also implicate decreased activation of XIAP as a plausible factor involved in the control of placental apoptosis during IUGR. PMID- 28083722 TI - Will cancer cells be defeated by sodium bicarbonate? PMID- 28083723 TI - Genetic and Environmental Sources of Implicit and Explicit Self-Esteem and Affect: Results from a Genetically Sensitive Multi-group Design. AB - In today's world, researchers frequently utilize indirect measures of implicit (i.e., automatic, spontaneous) evaluations. The results of several studies have supported the usefulness of these measures in predicting behavior, as compared to utilizing direct measures of explicit (i.e., purposeful, deliberate) evaluations. A current, under-debate issue concerns the origin of these implicit evaluations. The present genetically sensitive multi-group study analyzed data from 223 twin pairs and 222 biological core families to estimate possible genetic and environmental sources of individual differences in implicit and explicit self esteem and affect. The results show that implicit self-esteem and affect maintain a substantial genetic basis, but demonstrate little influence from the shared environment by siblings (e.g., shared familial socialization in childhood). A bivariate analysis found that implicit and explicit evaluations of the same construct share a common genetic core which aligns with the motivation and opportunity as determinants (MODE) model. PMID- 28083724 TI - Negotiating Discourses of Shame, Secrecy, and Silence: Migrant and Refugee Women's Experiences of Sexual Embodiment. AB - In Australia and Canada, the sexual health needs of migrant and refugee women have been of increasing concern, because of their underutilization of sexual health services and higher rate of sexual health problems. Previous research on migrant women's sexual health has focused on their higher risk of difficulties, or barriers to service use, rather than their construction or understanding of sexuality and sexual health, which may influence service use and outcomes. Further, few studies of migrant and refugee women pay attention to the overlapping role of culture, gender, class, and ethnicity in women's understanding of sexual health. This qualitative study used an intersectional framework to explore experiences and constructions of sexual embodiment among 169 migrant and refugee women recently resettled in Sydney, Australia and Vancouver, Canada, from Afghanistan, Iraq, Somalia, South Sudan, Sudan, Sri Lanka, India, and South America, utilizing a combination of individual interviews and focus groups. Across all of the cultural groups, participants described a discourse of shame, associated with silence and secrecy, as the dominant cultural and religious construction of women's sexual embodiment. This was evident in constructions of menarche and menstruation, the embodied experience that signifies the transformation of a girl into a sexual woman; constructions of sexuality, including sexual knowledge and communication, premarital virginity, sexual pain, desire, and consent; and absence of agency in fertility control and sexual health. Women were not passive in relation to a discourse of sexual shame; a number demonstrated active resistance and negotiation in order to achieve a degree of sexual agency, yet also maintain cultural and religious identity. Identifying migrant and refugee women's experiences and constructions of sexual embodiment are essential for understanding sexual subjectivity, and provision of culturally safe sexual health information in order to improve well-being and facilitate sexual agency. PMID- 28083725 TI - Return of the JITAI: Applying a Just-in-Time Adaptive Intervention Framework to the Development of m-Health Solutions for Addictive Behaviors. AB - PURPOSE: Lapses are strong indicators of later relapse among individuals with addictive disorders, and thus are an important intervention target. However, lapse behavior has proven resistant to change due to the complex interplay of lapse triggers that are present in everyday life. It could be possible to prevent lapses before they occur by using m-Health solutions to deliver interventions in real-time. METHOD: Just-in-time adaptive intervention (JITAI) is an intervention design framework that could be delivered via mobile app to facilitate in-the moment monitoring of triggers for lapsing, and deliver personalized coping strategies to the user to prevent lapses from occurring. An organized framework is key for successful development of a JITAI. RESULTS: Nahum-Shani and colleagues (2014) set forth six core elements of a JITAI and guidelines for designing each: distal outcomes, proximal outcomes, tailoring variables, decision points, decision rules, and intervention options. The primary aim of this paper is to illustrate the use of this framework as it pertains to developing a JITAI that targets lapse behavior among individuals following a weight control diet. CONCLUSION: We will detail our approach to various decision points during the development phases, report on preliminary findings where applicable, identify problems that arose during development, and provide recommendations for researchers who are currently undertaking their own JITAI development efforts. Issues such as missing data, the rarity of lapses, advantages/disadvantages of machine learning, and user engagement are discussed. PMID- 28083726 TI - Developmental Patterns of Adolescent Marijuana and Alcohol Use and Their Joint Association with Sexual Risk Behavior and Outcomes in Young Adulthood. AB - Urban populations disproportionately experience poor sexual outcomes, including high rates of teenage pregnancy and sexually transmitted infections. However, the contribution of substance use across adolescence to poor sexual outcomes in young adulthood has not been investigated in depth, despite offering opportunities for more targeted prevention. This study aimed to estimate joint trajectories of adolescent alcohol and marijuana use to determine if they relate differently to four sexual outcomes: multiple sexual partners, sex without a condom, teenage pregnancy, and contraction of a sexually transmitted infection in young adulthood (by age 25). Data came from a longitudinal study of urban youth followed from age 6 to age 25, with annual assessments during adolescence and young adulthood (n = 608). The sample showed high levels of sexual risk, with young adults on average having sex without a condom once in the past month, 28.5% having multiple sexual partners in the past month, one quarter having contracted a sexually transmitted infection, and over 60% of the women being pregnant as a teenager and 36% of the men having gotten a partner pregnant. Applying longitudinal latent profile analysis to estimate joint trajectories of alcohol and marijuana use from grades 8-12, we identified four classes representing high dual use, moderate alcohol use, moderate alcohol use with increasing marijuana use, and non-use. Class membership differently predicted all four outcomes investigated with high dual users having the highest level of teenage pregnancy and the increasing marijuana trajectory having the highest risk of engaging with multiple sexual partners in the past month. Results suggest implications for both sexual risk and substance use prevention for urban youth. PMID- 28083727 TI - The Impact of Introducing Centering Pregnancy in a Community Health Setting: A Qualitative Study of Experiences and Perspectives of Health Center Clinical and Support Staff. AB - Objectives Introducing new programming into an existing setting may be challenging. Understanding how staff and clinicians who are not directly involved in program delivery view the program can help support program implementation. This study aimed to understand how peripheral staff and clinicians perceived a newly implemented Centering Pregnancy group prenatal care program in a community based health center and its impact on clinic operations. Methods Semi-structured interviews were conducted with a purposive sample of 12 staff members at a community-based health center. The interview guide covered topics such as perceptions of Centering Pregnancy and how the program impacted their work. An interpretive description approach was used to analyze the interview data. A coding framework was developed iteratively and all interview data were analyzed independently by multiple researchers. Results Staff had overall positive perceptions of Centering Pregnancy, but the level of understanding about the program varied widely. Most respondents viewed the Centering Pregnancy program as separate from other programs offered by the clinic, which created both opportunities and challenges. Opportunities included increased cross-referrals between established services and Centering Pregnancy. Challenges included a lack of communication about responsibilities of staff in relation to Centering Pregnancy patients. Impact on staff and overall clinic operations was perceived to be minimal to moderate, and most tensions related to roles and expectations were resolved. Conclusions for Practice Clear communication regarding fit within clinic structures and processes and expectations of staff in relation to the program was critical to the integration of Centering Pregnancy program into an established health center. PMID- 28083728 TI - Challenges and Progress in Building a Comprehensive Statewide System for Fetal Alcohol Spectrum Disorders Prevention in Hawai'i. AB - Introduction Fetal Alcohol Spectrum Disorders (FASD) has been a maternal and child public health concern in Hawai'i for over the past decade. Methods A historical assessment of FASD related activities was conducted to map the challenges and progress made in building a comprehensive statewide system for FASD prevention and intervention in an island state. Results Progress has primarily been reflected in increasing the number of individuals receiving FASD education and training, as well as some initiatives in public awareness. The creation of a State FASD Coordinator position was significant in catalyzing support for FASD initiatives and extending collaborative networks with national experts/teams, community-based organizations, and other local agencies to leverage resources in a time of economic strain. Major challenges and barriers included loss of the FASD Coordinator position, reliance on external resources and lack of local capacity for training and education integration into existing practice systems, and inadequate surveillance infrastructure. Discussion Lack of funding and resources were a common factor overall, and impeded the development of a state strategic plan which was needed to guide overall efforts and policies into a more coordinated system to reduce and prevent FASDs in Hawai'i. PMID- 28083729 TI - Higher Pre-pregnancy BMI and Excessive Gestational Weight Gain are Risk Factors for Rapid Weight Gain in Infants. AB - Objective To describe the effects of maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) on infant anthropometrics at birth and 3 months and infant growth rates between birth and 3 months. Methods Body weight prior to and during pregnancy and infant weight and length at birth and 3 months were collected from 600 mother-infant pairs. Adherence to GWG was based on IOM recommendations. Age and sex specific z-scores were calculated for infant weight and length at birth and 3 months. Rapid postnatal growth was defined as a difference of >0.67 in weight-for-age z-score between birth and 3 months. Relationships between maternal and infant characteristics were analysed using multilinear regression. Results Most women (65%) had a normal pre-pregnancy BMI and 57% gained above GWG recommendations. Infants were 39.3 +/- 1.2 weeks and 3431 +/- 447.9 g at birth. At 3 months postpartum 60% were exclusively breast fed while 38% received breast milk and formula. Having a pre-pregnancy BMI >25 kg/m2 was associated with higher z-scores for birth weight and weight-for-age at 3 months. Gaining above recommendations was associated with higher z-scores for birth weight, weight-for-age and BMI. Infants who experienced rapid postnatal growth had higher odds of being born to women who gained above recommendations. Conclusion for Practice Excessive GWG is associated with higher birth weight and rapid weight gain in infants. Interventions that optimize GWG should explore effects on total and rates of early infant growth. PMID- 28083731 TI - Prenatal Predictors of Maternal Attachment and Their Association with Postpartum Depressive Symptoms in Mexican Women at Risk of Depression. AB - Objectives Although maternal attachment is an important predictor of infant developmental outcomes, little is known about its pre- and postnatal predictors. The purpose of this secondary data analysis is to assess several risk factors for maternal attachment at 6 months postpartum in a sample of Mexican women at risk of depression. The predictors included were prenatal depressive symptoms, pregnancy intendedness, partner relationship, social support, maternal history of childhood sexual abuse, and postpartum depressive symptoms. Methods A total of 156 pregnant women seeking antenatal care at three health centers were selected because they displayed depressive symptoms (CES-D >= 16) or had previously suffered depression. Women were interviewed during pregnancy and at 6 months postpartum. A step-wise multivariate logistic regression was conducted to evaluate the pre- and postpartum risk factors for postpartum depression related to low maternal attachment. Results Pre- and postpartum depressive symptoms increased the risk of low maternal attachment by factors of 3.00 and 3.97, respectively, compared with women who did not present these symptoms; low level of adjustment with the partner increased the risk by a factor of 3.11, low social support by a factor of 2.90, and CSA by a factor of 2.77. Conclusions for practice Prevention programs during pregnancy to reduce depressive symptoms should strengthen strategies to promote maternal attachment by improving partner relations and increasing social support. However, evidence shows that such programs alone are insufficient, so direct interventions should also be implemented. Women with a history of childhood sexual abuse should be given additional attention during prenatal care. PMID- 28083730 TI - Sleep Trajectories Among Pregnant Women and the Impact on Outcomes: A Population Based Cohort Study. AB - Objectives Sleep problems and deprivation are common during pregnancy, particularly in the third trimester. Previous studies are mostly descriptive or focused on specific clinical groups and late pregnancy. We aimed to identify sleep duration trajectories during the pregnancy period, their associated factors, and impact on pregnancy and birth outcomes. Methods We studied 200 women from a mother-child cohort recruited in 2009-2011 from the French general population. We used semi-parametric models to analyze data collected through questionnaires. Results We detected three sleep duration trajectories during pregnancy: short-decreasing (<6.5h/night, 10.8% of the sample), medium-decreasing (6.5-8h/night, 57.6%), and long-increasing (>8h/night, 31.6%) trajectories. Factors associated with the short-decreasing trajectory relative to the medium decreasing trajectory were older age (odds-ratio/year = 1.13 [95%Confidence Interval 1.00-1.29]) and working > 28 weeks of gestational age (odds-ratio = 0.30 [0.10-0.90]). Sleep duration during pregnancy in this trajectory group was modified by insomniac symptoms (regression coefficient/trimester = -0.74 [Standard-Error 0.12]) and naps (regression coefficient/trimester = 0.58 [0.25]). Restless legs syndrome was the only factor associated with the long-increasing trajectory and decreased sleep duration (regression coefficient/trimester = -0.88 [0.25]). Assisted delivery (i.e. cesarean section and/or instrumental delivery) and post-partum depression were more frequent among women with the short decreasing and long-increasing trajectories whereas cesarean section alone was more prevalent among those with the short-decreasing trajectory. Proportion of premature births was higher in the short-decreasing trajectory group. Birth weight-z-score was lower in the long-increasing trajectory group. Conclusion We identified sleep trajectories among pregnant women with specific risk factors that could affect both pregnancy and birth outcomes. Taking these into consideration could improve both maternal and child health. PMID- 28083732 TI - Association Between Fruit and Vegetable Consumption and Sleep Quantity in Pregnant Women. AB - Introduction To determine the association of fruit and vegetable consumption with overall sleep duration among pregnant women. Methods Data from the 2011 and 2012 Behavioral Risk Factors Surveillance System (BRFSS) were used. All women (n = 2951) of childbearing age (18-44 years) who were pregnant and responded to all fruit and vegetable consumption and sleep duration questions were included. Covariates included age, race, education level, exercise, and marital status. Data were analyzed using linear and ordinal logistic regression. Results Total daily fruit and vegetable consumption was not associated with sleep duration among pregnant women, controlling for confounders [beta = -0.03, (-0.07, 0.00)]. Orange and green vegetable consumption were both inversely associated with sleep duration [beta = -0.19, (-0.38, -0.01) and beta = -0.20, (-0.33, -0.08) respectively]. Ordinal logistic regression found that the odds of meeting or exceeding sleep time recommendations increased slightly with each unit increase in total fruit and vegetable consumption [OR = 1.05 (1.003, 1.092)] and for every unit increase in fruit consumption [OR = 1.12 (1.038, 1.208)]. Women who exercised within the past 30 days reported approximately 20 min of additional sleep compared to those who did not [beta = 0.32 (0.16, 0.49)]. Age, employment status, and marital status were also independently associated with sleep duration. Discussion Sleep duration in pregnant women was associated with exercise and other demographic factors, but only mildly associated with fruit and vegetable consumption. Future research should investigate the effects of additional factors including sleep quality, gestational age, family status and other medications as potential confounders. PMID- 28083733 TI - Smartphone-based colorimetric ELISA implementation for determination of women's reproductive steroid hormone profiles. AB - Biologists frequently collect and analyze biospecimens in naturalistic (i.e., field) conditions to ascertain information regarding the physiological status of their study participants. Generally, field-collected biospecimens need to be stored frozen in the field and then transported frozen to laboratory facilities where traditional biomarker assays, such as enzyme-linked immunosorbent assays (ELISAs), are conducted. As proper storage and transport of frozen specimens is often logistically difficult and expensive, particularly in nonurban field settings, methods that reduce the need for specimen storage and transport would benefit field-research dependent disciplines such as biology, ecology and epidemiology. One limiting factor to running assays in the field is the use of large and expensive equipment to visualize and quantify the assays, such as microplate readers. Here, we describe an implementation of colorimetric ELISA visualization and quantification using two novel and portable imaging instrumentation systems and data processing techniques for the determination of women's reproductive steroid hormone profiles. Using the light absorbance and transmittance properties of the chemical compounds that make up the hormone assay, we were able to estimate unknown hormone concentrations using a smartphone system and a webcam system. These estimates were comparable to those from a standard laboratory multiple reader (smartphone: accuracy = 82.20%, R 2 > 0.910; webcam: accuracy = 87.59%, R 2 > 0.942). This line of applied research, in the long run, is expected to provide necessary information for examining the extent to which reproductive function varies within and between populations and how it is influenced by psychosocial, energetic and environmental challenges. Our validation of these novel, portable visualization and quantification systems allows for the eventual development of a compact and economical closed system which can be used to quantify biomarker concentrations in remote areas. PMID- 28083734 TI - Effects of beta-hydroxy-beta-methylbutyrate (HMB) on the expression of ubiquitin ligases, protein synthesis pathways and contractile function in extensor digitorum longus (EDL) of fed and fasting rats. AB - Beta-hydroxy-beta-methylbutyrate (HMB), a leucine metabolite, enhances the gain of skeletal muscle mass by increasing protein synthesis or attenuating protein degradation or both. The aims of this study were to investigate the effect of HMB on molecular factors controlling skeletal muscle protein synthesis and degradation, as well as muscle contractile function, in fed and fasted conditions. Wistar rats were supplied daily with HMB (320 mg/kg body weight diluted in NaCl-0.9%) or vehicle only (control) by gavage for 28 days. After this period, some of the animals were subjected to a 24-h fasting, while others remained in the fed condition. The EDL muscle was then removed, weighed and used to evaluate the genes and proteins involved in protein synthesis (AKT/4E-BP1/S6) and degradation (Fbxo32 and Trim63). A sub-set of rats were used to measure in vivo muscle contractile function. HMB supplementation increased AKT phosphorylation during fasting (three-fold). In the fed condition, no differences were detected in atrogenes expression between control and HMB supplemented group; however, HMB supplementation did attenuate the fasting-induced increase in their expression levels. Fasting animals receiving HMB showed improved sustained tetanic contraction times (one-fold) and an increased muscle to tibia length ratio (1.3-fold), without any cross-sectional area changes. These results suggest that HMB supplementation under fasting conditions increases AKT phosphorylation and attenuates the increased of atrogenes expression, followed by a functional improvement and gain of skeletal muscle weight, suggesting that HMB protects skeletal muscle against the deleterious effects of fasting. PMID- 28083735 TI - Toxicological effects of aflatoxin B1 on the earthworm Eisenia fetida as determined in a contact paper test. AB - In this study, aflatoxin B1 (AFB1) toxicity toward the earthworm Eisenia fetida (Savigny 1826) was evaluated in contact paper test systems containing distilled water and ethanol or 20 to 400 MUg/ml of AFB1 over 72 h of exposure. The results indicated that AFB1 could induce significant damage to earthworms (coiling, curling, excessive mucus secretion, clitellum swelling) at greater than 75 MUg/ml. Moreover, AFB1 had harmful effects on E. fetida (degenerative changes such as bulging of the clitella regions) at levels higher than 150 MUg/ml. The calculated LD50 was 168.5 MUg/ml. These findings confirm that E. fetida and standardized methods based on this organism (OECD 207 1984) are applicable and useful in mycotoxin related toxicity studies. PMID- 28083736 TI - Curcuma longa as additive in the diet for Astyanax aff. bimaculatus. AB - The aim of the present study was to evaluate the effect of turmeric (Curcuma longa) as additive in the diet for Astyanax aff. bimaculatus. Fish (0.83 +/- 0.04 g) were fed, for 60 days, with six diets containing 0.0, 20.0, 40.0, 60.0, 80.0, and 100.0 g turmeric kg-1 feed. There was an increasing linear effect of turmeric on the thickness of the muscular layer, and height and width of the folds of the intestine. In the liver, a quadratic effect was observed of turmeric on the percentage of hepatocyte cytoplasm and a decreasing linear effect on the percentage of sinusoid capillaries. A quadratic effect was also observed of turmeric on the liver glycogen. There was no effect of turmeric on the antioxidant activity in the liver, carcass composition or productive performance of the fish. Thus, we concluded that Curcuma longa has trophic effects on the epithelium and the muscular layer of the intestine of A. aff. bimaculatus. Additionally, low levels of Curcuma longa cause increased deposition of liver glycogen and high levels cause reduction. PMID- 28083737 TI - Histologic grade and peritoneal cytology as prognostic factors in type 1 endometrial cancer. AB - BACKGROUND: Prognostic clinicopathological factors for type 1 endometrial cancer are unknown and the purpose of the current study was to determine the independent prognostic variables for type 1 endometrial cancer. METHODS: We performed a retrospective study of 168 patients with type 1 endometrial cancer primarily treated with comprehensive staging surgery. The median follow-up time was 68 (12 100) months. Independent risk factors for disease-free survival (DFS) and overall survival (OS) were determined using multivariate Cox regression models. Sub-group analysis of stage I was also performed. We also assessed the patterns of failure among patients with recurrences and investigated the associations with the prognostic variables determined by multivariate analysis. RESULTS: Twenty patients (11.9%) had recurrence and 13 patients (7.7%) died of the disease overall. Multivariate analysis revealed that grade 2 (G2) histology (p = 0.008) and positive peritoneal cytology (p = 0.001) predicted the recurrent event in type 1 endometrial cancer. G2 histology (p = 0.007) and positive peritoneal cytology (p = 0.003) were also found to be independent risk factors for tumor related deaths. Among stage I patients, G2 histology and positive peritoneal cytology were also independent prognostic variables for DFS and OS. Patients with G2 histology and/or positive peritoneal cytology were more likely to have recurrence at distant sites. CONCLUSIONS: G2 histology and positive peritoneal cytology were independent prognostic factors for DFS and OS in type 1 endometrial cancer. PMID- 28083738 TI - Differences in the accumulation and tissue distribution of Pb, Cd, and Cu in Mediterranean mussels (Mytilus galloprovincialis) exposed to single, binary, and ternary metal mixtures. AB - Heavy metals often accumulate in complex mixtures in the environment and are currently a source of concern in many marine ecosystems. Pb, Cd, and Cu are regarded as priority hazardous metals due to their great persistence, bioaccumulation, and toxicity. The aim of the present study was to investigate the tissue accumulation and distribution of these heavy metals in Mediterranean mussels (Mytilus galloprovincialis) exposed to binary and ternary mixtures of metals as opposed to only single exposures. Heavy metal concentrations in the digestive gland, gills, and the other soft tissues were determined by inductively coupled plasma optical emission spectrometry (ICP-OES), and the distribution of each metal was analyzed according to compartments. The concentrations of Pb, Cd, and Cu increased significantly in the group exposed to the ternary mixture; however, there was no common response pattern to exposure in single and binary mixtures. Above all, the metals concentrated in the digestive gland, although the percentages of each element varied between compartments and varied between tissues according to the treatment. PMID- 28083739 TI - Bioconcentration pattern and induced apoptosis of bisphenol A in zebrafish embryos at environmentally relevant concentrations. AB - Bisphenol A (BPA) is a well-known endocrine-disrupting chemical that is ubiquitously present in the environment. In the present study, 4-h post fertilization (hpf) zebrafish embryos were exposed to various environmentally relevant concentrations of BPA (0.1, 1, 10, 100, and 1000 MUg/L) until 72 and 168 hpf, and the accumulation pattern of BPA and its potential to induce toxicity through apoptosis were determined. Compared to BPA concentrations in larvae at 168 hpf, BPA concentrations in embryos exposed until 72 hpf were at relatively higher levels (p < 0.05) with higher bioconcentration factor (BCF) values. The nonlinear fitting analysis indicated that the BCF values of BPA in fish embryos/larvae were significantly correlated to the log10-transformed BPA exposure concentrations in water in an inverse concentration-dependent manner. Fish accumulated more BPA as the exposure concentrations increased; however, their accumulation capacity of BPA declined and tended to be saturated in the high exposure groups of BPA. Moreover, caspase-3 activity was significantly induced upon BPA exposure at 0.1, 1, 10, and 100 MUg/L BPA at 72 hpf, and also at 10 and 100 MUg/L BPA at 168 hpf. Correspondingly, exposure to 10 and 100 MUg/L of BPA significantly increased the DNA fragmentation in the extracted DNA at 168 hpf as determined by DNA ladder analysis. In addition, the expression patterns of four genes related to apoptosis including caspase-3, bax, p53, and c-jun were significantly up-regulated (p < 0.05) in fish embryos/larvae upon BPA exposure at 72 and 168 hpf. Our results revealed that low and environmentally relevant concentrations of BPA could be significantly accumulated in zebrafish and induced apoptosis with involvement of the regulation of caspase-3 and other apoptosis related genes. PMID- 28083740 TI - The impact of energy, agriculture, macroeconomic and human-induced indicators on environmental pollution: evidence from Ghana. AB - In this study, the impact of energy, agriculture, macroeconomic and human-induced indicators on environmental pollution from 1971 to 2011 is investigated using the statistically inspired modification of partial least squares (SIMPLS) regression model. There was evidence of a linear relationship between energy, agriculture, macroeconomic and human-induced indicators and carbon dioxide emissions. Evidence from the SIMPLS regression shows that a 1% increase in crop production index will reduce carbon dioxide emissions by 0.71%. Economic growth increased by 1% will reduce carbon dioxide emissions by 0.46%, which means that an increase in Ghana's economic growth may lead to a reduction in environmental pollution. The increase in electricity production from hydroelectric sources by 1% will reduce carbon dioxide emissions by 0.30%; thus, increasing renewable energy sources in Ghana's energy portfolio will help mitigate carbon dioxide emissions. Increasing enteric emissions by 1% will increase carbon dioxide emissions by 4.22%, and a 1% increase in the nitrogen content of manure management will increase carbon dioxide emissions by 6.69%. The SIMPLS regression forecasting exhibited a 5% MAPE from the prediction of carbon dioxide emissions. PMID- 28083741 TI - Stem and crown growth of Japanese larch and its hybrid F1 grown in two soils and exposed to two free-air O3 regimes. AB - Ozone (O3) pollution and soil infertility may negatively affect boreal forests across the Northern Hemisphere. Impacts to economically and ecologically important larches (Larix sp., Pinacaeae) are particularly concerning. Using a free air O3 enrichment (FACE) system, we investigated the effect of 2-year elevated O3 exposure (~66 nmol mol-1) on Japanese larch (L. kaempferi) and its hybrid larch F1 (L. gmelinii var. japonica * L. kaempferi) planted directly into either fertile brown forest soil (BF) or BF mixed with infertile volcanic ash soil (VA). Overall, photosynthetic pigmentation and the growth performance of the stem and crown were reduced in both taxa exposed to elevated O3. Furthermore, hybrid larch, in both O3 treatments, performed better than Japanese larch. This finding contradicts findings of prior experiments with potential experimental artifacts of O3 exposure facilities and root restrictions. Elevated O3 also disproportionately inhibited stem diameter growth and caused an imbalance in chlorophylls a/b and chlorophyll/carotenoid ratios. Hybrid and Japanese larches grown in BF and VA had a significantly lower drop of stem diameter over the run of stem height (from base to top) when exposed to elevated O3, compared to ambient O3. This finding indicates altered stem shape under elevated O3. Among 11 response variables, there were no significant interactions between O3 treatment and taxa. There was also no significant interaction of soil condition and taxa, suggesting that the two larches shared a similar response to O3 and soil type. Understanding the performance of hybrid larch in relation to its parent species has ramifications for breeding success in a soil-degraded and O3-polluted environment. PMID- 28083742 TI - The endophytic bacterium Serratia sp. PW7 degrades pyrene in wheat. AB - This research was conducted to isolate polycyclic aromatic hydrocarbon-degrading (PAH-degrading) endophytic bacteria and investigate their potential in protecting plants against PAH contamination. Pyrene-degrading endophytic bacteria were isolated from plants grown in PAH-contaminated soil. Among these endophytic bacteria, strain PW7 (Serratia sp.) isolated from Plantago asiatica was selected to investigate the suppression of pyrene accumulation in Triticum aestivum L. In the in vitro tests, strain PW7 degraded 51.2% of the pyrene in the media within 14 days. The optimal biodegradation conditions were pH 7.0, 30 degrees C, and MS medium supplemented with additional glucose, maltose, sucrose, and peptones. In the in vivo tests, strain PW7 successfully colonized the roots and shoots of inoculated (E+) wheat plants, and its colonization decreased pyrene accumulation and pyrene transportation from roots to shoots. Remarkably, the concentration of pyrene in shoots decreased much more than that in roots, suggesting that strain PW7 has the potential for protecting wheat against pyrene contamination and mitigating the threat of pyrene to human health via food consumption. PMID- 28083743 TI - Synergistic effect of aluminum and ionizing radiation upon ultrastructure, oxidative stress and apoptotic alterations in Paneth cells of rat intestine. AB - Environmental and occupational exposure to aluminum along with ionizing radiation results in serious health problems. This study was planned to investigate the impact of oxidative stress provoked by exposure to ionizing radiation with aluminum administration upon cellular ultra structure and apoptotic changes in Paneth cells of rat small intestine . Animals received daily aluminum chloride by gastric gavage at a dose 0.5 mg/Kg BW for 4 weeks. Whole body gamma irradiation was applied at a dose 2 Gy/week up to 8 Gy. Ileum malondialdehyde, advanced oxidative protein products, protein carbonyl and tumor necrosis factor-alpha were assessed as biomarkers of lipid peroxidation, protein oxidation and inflammation respectively along with superoxide dismutase, catalase, and glutathione peroxidase activities as enzymatic antioxidants. Moreover, analyses of cell cycle division and apoptotic changes were evaluated by flow cytometry. Intestinal cellular ultra structure was investigated using transmission electron microscope.Oxidative and inflammatory stresses assessment in the ileum of rats revealed that aluminum and ionizing radiation exposures exhibited a significant effect upon the increase in oxidative stress biomarkers along with the inflammatory marker tumor necrosis factor-alpha accompanied by a significant decreases in the antioxidant enzyme activities. Flow cytometric analyses showed significant alterations in the percentage of cells during cell cycle division phases along with significant increase in apoptotic cells. Ultra structurally, intestinal cellular alterations with marked injury in Paneth cells at the sites of bacterial translocation in the crypt of lumens were recorded. The results of this study have clearly showed that aluminum and ionizing radiation exposures induced apoptosis with oxidative and inflammatory disturbance in the Paneth cells of rat intestine, which appeared to play a major role in the pathogenesis of cellular damage. Furthermore, the interaction of these two intestinal toxic routes was found to be synergistic. PMID- 28083744 TI - Relay cropping as a sustainable approach: problems and opportunities for sustainable crop production. AB - Climate change, soil degradation, and depletion of natural resources are becoming the most prominent challenges for crop productivity and environmental sustainability in modern agriculture. In the scenario of conventional farming system, limited chances are available to cope with these issues. Relay cropping is a method of multiple cropping where one crop is seeded into standing second crop well before harvesting of second crop. Relay cropping may solve a number of conflicts such as inefficient use of available resources, controversies in sowing time, fertilizer application, and soil degradation. Relay cropping is a complex suite of different resource-efficient technologies, which possesses the capability to improve soil quality, to increase net return, to increase land equivalent ratio, and to control the weeds and pest infestation. The current review emphasized relay cropping as a tool for crop diversification and environmental sustainability with special focus on soil. Briefly, benefits, constraints, and opportunities of relay cropping keeping the goals of higher crop productivity and sustainability have also been discussed in this review. The research and knowledge gap in relay cropping was also highlighted in order to guide the further studies in future. PMID- 28083745 TI - Personal exposure to PM2.5 associated with heavy metals in four travel modes of Tianjin during the summer season. AB - Personal exposure to PM2.5 associated with heavy metals were investigated at and around the same road by cycling, walking, taxi and bus in Tianjin, China. One trip on each mode was undertaken during 4 h of both morning and evening peak hours. Results of one-way analysis of variance (ANOVA) to compare mean concentrations of PM2.5 and each metal measured by four modes, the enrichment level of heavy metals in four modes and the carcinogenic, non-carcinogenic risk and probabilistic estimation of health risks of metals (Cr, Ni, Cu, Zn and Pb). Arithmetic means of PM2.5 personal exposure were 323.66, 313.37, 214.84 and 160.71 MUg/m3 for cycling, walking, bus and taxi, which resulted from the difference of source (vehicle exhaust and road dust) of exposure to PM2.5. Na has the highest concentration, followed by Al, Ca, K, Fe, Mg, Zn, Ni, Pb, Cu and Cr. The higher Na concentrations were observed in Tianjin in light of its major sea salt influence. The concentrations of Ca, Mg, Fe and Zn in four modes followed different orders, while other metals have no significant difference between four modes. Enrichment factors of metals in PM2.5 showed that some metals are enriched, ranging from contaminated to extremely contaminated, for example, Ni, Cu, Zn, Pb, Na and Cr. Others are barely enriched such as Ca, K, Mg and Fe. It illustrated the former is mainly effected by anthropogenic activates and the source of latter comes from crust. From the results of non-carcinogenic and carcinogenic risks of metals, the intake of metals with inhalation for 4 h by four modes did not pose a significant potential chronic-toxic risk and was an acceptable or tolerable risk at present. But uncertainty analysis of health risks showed there were 4.05 and 6.87% probability that make carcinogenic risk values to exceed 10-4 when male choose walking/cycling to work. Commuters' rush hour exposures were significantly influenced by mode of transport. We suggest that future work should focus on further research between heavy metals in PM2.5 exposure and its specific epidemiology effects. PMID- 28083746 TI - Low-cost magnetic herbal biochar: characterization and application for antibiotic removal. AB - Magnetic biochar (M-BC) was derived from herbal medicine waste, Astragalus membranaceus residue, and was used as an adsorbent for ciprofloxacin removal from aqueous solutions. The M-BC was characterized by Brunauer-Emmett-Teller surface area analyses, Fourier transform infrared spectrometry, X-ray diffraction analysis, hysteresis loops, scanning electron microscopy energy-dispersive spectrometry, and X-ray photoelectron spectroscopy. The BET surface area increased from 4.40 to 203.70 m2/g after pyrolysis/magnetic modification. Batch experiments were performed at different dosages, initial concentrations, contact times, and solution pHs. Adsorption performances were evaluated using Langmuir and Freundlich isotherm models, and the results indicated that the Langmuir model appropriately described the adsorption process. The kinetic data were better fitted by a pseudo-second-order kinetic model. The maximum ciprofloxacin removal was observed at pH 6 (adsorption capacity of 68.9 +/- 3.23 mg/g). Studies demonstrated that magnetically modified biochar might be an attractive, cost effective, and easily separated adsorbent for contaminated water. Graphical abstract. PMID- 28083747 TI - Erratum to: Effect of the pollution level on the functional bacterial groups aiming at degrading bisphenol A and nonylphenol in natural biofilms of an urban river. PMID- 28083748 TI - Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-kappaB signaling. AB - Zinc is a nutritionally fundamental trace element, essential to the structure and function of numerous macromolecules, including enzymes regulating cellular processes and cellular signaling pathways. The mineral modulates immune response and exhibits antioxidant and anti-inflammatory activity. Zinc retards oxidative processes on a long-term basis by inducing the expression of metallothioneins. These metal-binding cysteine-rich proteins are responsible for maintaining zinc related cell homeostasis and act as potent electrophilic scavengers and cytoprotective agents. Furthermore, zinc increases the activation of antioxidant proteins and enzymes, such as glutathione and catalase. On the other hand, zinc exerts its antioxidant effect via two acute mechanisms, one of which is the stabilization of protein sulfhydryls against oxidation. The second mechanism consists in antagonizing transition metal-catalyzed reactions. Zinc can exchange redox active metals, such as copper and iron, in certain binding sites and attenuate cellular site-specific oxidative injury. Studies have demonstrated that physiological reconstitution of zinc restrains immune activation, whereas zinc deficiency, in the setting of severe infection, provokes a systemic increase in NF-kappaB activation. In vitro studies have shown that zinc decreases NF-kappaB activation and its target genes, such as TNF-alpha and IL-1beta, and increases the gene expression of A20 and PPAR-alpha, the two zinc finger proteins with anti inflammatory properties. Alternative NF-kappaB inhibitory mechanism is initiated by the inhibition of cyclic nucleotide phosphodiesterase, whereas another presumed mechanism consists in inhibition of IkappaB kinase in response to infection by zinc ions that have been imported into cells by ZIP8. PMID- 28083749 TI - Micromolar Levels of Sodium Fluoride Promote Osteoblast Differentiation Through Runx2 Signaling. AB - Bone remodeling is a vital physiological process of healthy bone tissue in humans. Imbalances in this vital process lead to pathological conditions, including periodontal diseases. In this study, we characterized the effects of micromolar levels of NaF on the proliferation and osteogenic differentiation of MC3T3-E1 osteoblastic cells. NaF significantly enhanced the proliferation, alkaline phosphatase (ALP) activity, and mineralization of MC3T3-E1 cells. Quantitative real-time PCR analysis revealed that the expression of mRNAs encoding runt-related transcription factor 2 (Runx2), Osterix, Osteopontin and Osteocalcin was up-regulated in NaF-treated MC3T3-E1 cells compared with untreated controls. Western blot analysis demonstrated that Runx2 and Osterix were inhibited by Runx2 siRNA but were re-activated by treatment with NaF. Furthermore, in vivo evidence indicated that NaF protects against Porphyromonas gingivalis-induced periodontal inflammation and alveolar bone loss in a P. gingivalis-challenged experimental periodontitis animal model. These data suggest that NaF promotes the osteoblastic differentiation of MC3T3-E1 cells through the Runx2/Osterix pathway and may be effective for the treatment of bone-related disorders. PMID- 28083750 TI - Shame, Blame, and Status Incongruity: Health and Stigma in Rural Brazil and the Urban United Arab Emirates. AB - Stigma is a powerful determinant of physical and mental health around the world, a perennial public health concern that is particularly resistant to change. This article builds from sociologist Erving Goffman's classic conception of stigma as a unitary social phenomenon to explore the stigma attached to two seemingly dissimilar conditions: food insecurity in rural Brazil, and obesity in the urban United Arab Emirates. Our analyses underscore that both conditions are stigmatized because they represent a departure from a deeply-held social norm, and in both cases, self-stigma plays an important role. Furthermore, in both cases, the stigma associated with food insecurity and obesity is likely at least as harmful to personal wellbeing as are the biological consequences of these conditions. Finally, evidence increasingly links obesity and food insecurity causally. Our analyses suggest that these forms of stigma transcend individuals and are largely structural in their origins, and therefore that they are most likely to be improved through structural change. PMID- 28083751 TI - Clinical presentation, diagnosis and treatment of vulvovaginitis in girls: a current approach and review of the literature. AB - BACKGROUND: Vulvovaginitis is the most common cause of gynecological complaints in children and young girls. Some of the factors which cause vulvovaginitis include hypoestrogenism, the anatomical proximity of rectum and delicate vulvar skin and vaginal mucosa. DATA SOURCES: We made a literature search with Pubmed, Medline and Cochrane database from January 2002 to May 2015 in English language using the key words vulvovaginitis, children, clinical, diagnosis and treatment. RESULTS: Vulvovaginitis in girls is usually caused by non-specific factors and hygiene measures, bioyoghurt and avoidance of chemical irritants are generally useful. Weight control if necessary and prevention of voiding dysfunction are effective. Vaginal flora is important in girls and results should be interpreted with clinical features to decide whether an isolated microorganism is part of the normal microflora or is the cause of symptomatic vulvovaginitis. Specific treatment is generally considered in case of a detected pathogen microorganism. Isolation of a sexually transmitted organism requires further investigation. Persistent disease may not always indicate a foreign body but it must be taken into account. Girls and parents are encouraged psychologically in all steps of evaluation, diagnosis and treatment. Probiotics, nanotechnology and petroleum jelly are other important treatment options used in vulvovaginitis. CONCLUSIONS: In this review, we present current approach to the presentation and management of vulvovaginitis in childhood. This disorder requires a comprehensive evaluation in all steps of diagnosis, differential diagnosis and treatment. PMID- 28083752 TI - Can Multistate Modeling of Local Recurrence, Distant Metastasis, and Death Improve the Prediction of Outcome in Patients With Soft Tissue Sarcomas? AB - BACKGROUND: Exploration of the complex relationship between prognostic indicators such as tumor grade and size and clinical outcomes such as local recurrence and distant metastasis in patients with cancer is crucial to guide treatment decisions. However, in patients with soft tissue sarcoma, there are many gaps in our understanding of this relationship. Multistate analysis may help us in gaining a comprehensive understanding of risk factor-outcome relationships in soft tissue sarcoma, because this methodology can integrate multiple risk factors and clinical endpoints into a single statistical model. To our knowledge, no study of this kind has been performed before in patients with soft tissue sarcoma. QUESTIONS/PURPOSES: We implemented a multistate model of localized soft tissue sarcoma to statistically evaluate the relationship among baseline risk factors, recurrence, and death in patients with localized soft tissue sarcoma undergoing curative surgery. METHODS: Between 1998 and 2015, our center treated 539 patients for localized soft tissue sarcoma with surgery as curative intent. Of those, 96 patients (18%) were not included in this single-center retrospective study owing to missing baseline histopathology data (n = 3), not yet observed followup (n = 80), or because a neoadjuvant treatment approach in the presence of synchronous distant metastasis was used (n = 13), leaving 443 patients (82%) for the current analysis, of which 40 were lost to followup during the first year after surgery. All patients had tumors of the stages I to III according to the American Joint Committee on Cancer Stages. The median age of the patients was 62 years (range, 16-96 years), and 217 patients (49%) were female. Three hundred forty-six patients (78%) had tumors of high grade (Grades 2 and 3), and 310 (70%) tumors were greater than 5 cm in maximum diameter. Patients who had died during the first year of followup were included in this analysis. Median followup for the 443 study patients was 6 years, with 84%, 52%, and 23% of patients being followed for more than 1, 5, and 10 years, respectively. The 15-year cumulative incidences of local recurrence, distant metastasis, and death from any cause, using a competing risk analysis, were 16% (95% CI, 11%-22%), 21% (95% CI, 17% 26%), and 55% (95% CI, 44%-67%), respectively. Wide resection with a margin of 1 mm was the preferred treatment for all patients, except for those with Grade 1 liposarcoma where a marginal resection was considered adequate. Multistate models were implemented with the mstate library in R. RESULTS: In multistate analysis, patients who experienced a local recurrence were more likely to have distant metastasis develop (hazard ratio [HR] = 8.4; 95% CI, 4.3-16.5; p < 0.001), and to die (HR = 3.4; 95% CI, 2.1-5.6; p < 0.001). The occurrence of distant metastasis was associated with a strong increase in the risk of death (HR = 12.6; 95% CI, 8.7-18.3; p < 0.001). Distant metastasis occurring after a long tumor-free interval was not associated with a more-favorable prognosis with respect to mortality than distant metastasis occurring early after surgery (estimated relative decrease in the adverse effect of distant metastasis on mortality for 1 year delay in the occurrence of distant metastasis = 0.9; 95% CI, 0.7-1.1; p = 0.28). High-grade histology (Grades 2 and 3) was associated with a higher risk of overall recurrence (defined as a composite of local recurrence and distant metastasis, HR = 3.8; 95% CI, 1.8-7.8; p = 0.0003) and a higher risk of death after recurrence developed (HR = 4.4; 95% CI, 1.1-18.2; p = 0.04). Finally, the multistate model predicted distinct outcome patterns depending on baseline covariates and how long a patient has remained free from recurrence after surgery. CONCLUSIONS: In patients with localized soft tissue sarcoma undergoing resection, the occurrence of local recurrence and distant metastasis contributes to a dramatically impaired long-term survival outcome. Local recurrences are a substantial risk factor for distant metastasis. Multistate modeling is a very powerful approach for analysis of sarcoma cohorts, and may be used in the future to obtain highly personalized, dynamic predictions of outcomes in patients with localized soft tissue sarcoma. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 28083753 TI - Definitional Differences of 'Outpatient' Versus 'Inpatient' THA and TKA Can Affect Study Outcomes. AB - BACKGROUND: There has been great interest in performing outpatient THA and TKA. Studies have compared such procedures done as outpatients versus inpatients. However, stated "outpatient" status as defined by large national databases such as the National Surgical Quality Improvement Program (NSQIP) may not be a consistent entity, and the actual lengths of stay of those patients categorized as outpatients in NSQIP have not been specifically ascertained and may in fact include some patients who are "observed" for one or more nights. Current regulations in the United States allow these "observed" patients to stay more than one night at the hospital under observation status despite being coded as outpatients. Determining the degree to which this is the case, and what, exactly, "outpatient" means in the NSQIP, may influence the way clinicians read studies from that source and the way hospital systems and policymakers use those data. QUESTIONS/PURPOSES: The purposes of this study were (1) to utilize the NSQIP database to characterize the differences in definition of "inpatient" and "outpatient" (stated status versus actual length of stay [LOS], measured in days) for THA and TKA; and (2) to study the effect of defining populations using different definitions. METHODS: Patients who underwent THA and TKA in the 2005 to 2014 NSQIP database were identified. Outpatient procedures were defined as either hospital LOS = 0 days in NSQIP or being termed "outpatient" by the hospital. The actual hospital LOS of "outpatients" was characterized. "Outpatients" were considered to have stayed overnight if they had a LOS of 1 day or longer. The effects of the different definitions on 30-day outcomes were evaluated using multivariate analysis while controlling for potential confounding factors. RESULTS: Of 72,651 patients undergoing THA, 529 were identified as "outpatients" but only 63 of these (12%) had a LOS = 0. Of 117,454 patients undergoing TKA, 890 were identified as "outpatients" but only 95 of these (11%) had a LOS = 0. After controlling for potential confounding factors such as gender, body mass index, functional status before surgery, comorbidities, and smoking status, we found "inpatient" THA to be associated with increased risk of any adverse event (relative risk, 2.643, p = 0.002), serious adverse event (relative risk, 2.455, p = 0.011), and readmission (relative risk, 2.775, p = 0.010) compared with "outpatient" THA. However, for the same procedure and controlling for the same factors, patients who had LOS > 0 were not associated with any increased risk compared with patients who had LOS = 0. A similar trend was also found in the TKA cohort. CONCLUSIONS: Future THA, TKA, or other investigations on this topic should consistently quantify the term "outpatient" because different definitions, stated status or actual LOS, may lead to different assignments of risk factors for postoperative complications. Accurate data regarding risk factors for complications after total joint arthroplasty are crucial for efforts to reduce length of hospital stay and minimize complications. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 28083754 TI - CORR Insights(r): Phosphatidylcholine Coatings Deliver Local Antimicrobials and Reduce Infection in a Murine Model: A Preliminary Study. PMID- 28083756 TI - The oncology day hospital in Spain: an updated analysis of Spanish Society of Medical Oncology (SEOM) looking forward. PMID- 28083755 TI - High Risk of Readmission in Octogenarians Undergoing Primary Hip Arthroplasty. AB - BACKGROUND: As life expectancy increases, more elderly patients with end-stage hip arthritis are electing to undergo primary THA. Octogenarians undergoing THA have more comorbidities than younger patients, but this is not reflected in risk adjustment models for bundled care programs. The burden of care associated with THA in octogenarians has not been well characterized, and doing so may help these value-based programs make adjustments so that this vulnerable patient population does not risk losing access under accountable care models. QUESTIONS/PURPOSES: The purpose of this study was to describe care use, comorbidities, and complications among octogenarians undergoing primary THA. METHODS: Five percent of the Medicare national administrative claims data was queried to identify patients diagnosed with hip osteoarthritis between January 1, 1998, and December 31, 2013. Patients who underwent primary THA were identified and followed longitudinally during the study period using their unique, encrypted Medicare beneficiary identifiers. We compared risk factors and complications between the octogenarian group versus those aged 65 to 69 years. Multivariate Cox regression was used to evaluate the effect of patient/hospital factors on risk of revision, periprosthetic joint infection, dislocation, venous thromboembolism (VTE), and mortality. Patient factors in the model included age, sex, race, region, socioeconomic status, and health status based on Charlson comorbidity score 12 months before replacement surgery. RESULTS: There were 11,960 THAs in the octogenarians in 1998, which increased to 21,620 in 2013, an 81% increase during this study period. Octogenarians were more likely to have a Charlson score of 3 or higher than those patients aged 65 to 69 years (30% versus 17%, odds ratio [OR] 2.07 [1.98-2.20]; p < 0.001), and they were more likely to have coronary artery disease or congestive heart failure (47% versus 29%, OR 2.16 [2.06-2.26]; p < 0.001). The octogenarian group had a greater risk of dislocation (+12%, p = 0.01), VTE (+14%, p < 0.001), and mortality (+150%, p < 0.001) compared with the younger age cohort. A total of 21% of the octogenarians were readmitted after surgery compared with 12% for patients in the younger group (OR=1.64, 95% confidence interval 1.54-1.75; p < 0.001). CONCLUSIONS: Because octogenarians are at increased risk of dislocation, VTE, medical complications, and mortality after THA, value-based care models that penalize hospitals for readmissions and complications may inadvertently result in loss of access to care for this group of patients as a result of the financial makeup of these bundled care models. Value-based care models were developed to improve care and decrease healthcare costs but may have unintended consequences in the octogenarian with higher complication and readmission risks. Financial losses may lead to institutions from withdrawing from the Bundled Payments for Care Improvement program. To try to prevent this from happening to this vulnerable patient population, bundled care programs should evolve and be modified to allow for risk stratification in the overall payment formula to account for increased age and comorbid conditions to ensure continued successful participation in the program among all the stakeholders. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 28083757 TI - Finding Biomass Degrading Enzymes Through an Activity-Correlated Quantitative Proteomics Platform (ACPP). AB - The microbial secretome, known as a pool of biomass (i.e., plant-based materials) degrading enzymes, can be utilized to discover industrial enzyme candidates for biofuel production. Proteomics approaches have been applied to discover novel enzyme candidates through comparing protein expression profiles with enzyme activity of the whole secretome under different growth conditions. However, the activity measurement of each enzyme candidate is needed for confident "active" enzyme assignments, which remains to be elucidated. To address this challenge, we have developed an Activity-Correlated Quantitative Proteomics Platform (ACPP) that systematically correlates protein-level enzymatic activity patterns and protein elution profiles using a label-free quantitative proteomics approach. The ACPP optimized a high performance anion exchange separation for efficiently fractionating complex protein samples while preserving enzymatic activities. The detected enzymatic activity patterns in sequential fractions using microplate based assays were cross-correlated with protein elution profiles using a customized pattern-matching algorithm with a correlation R-score. The ACPP has been successfully applied to the identification of two types of "active" biomass degrading enzymes (i.e., starch hydrolysis enzymes and cellulose hydrolysis enzymes) from Aspergillus niger secretome in a multiplexed fashion. By determining protein elution profiles of 156 proteins in A. niger secretome, we confidently identified the 1,4-alpha-glucosidase as the major "active" starch hydrolysis enzyme (R = 0.96) and the endoglucanase as the major "active" cellulose hydrolysis enzyme (R = 0.97). The results demonstrated that the ACPP facilitated the discovery of bioactive enzymes from complex protein samples in a high-throughput, multiplexing, and untargeted fashion. Graphical Abstract ?. PMID- 28083758 TI - Spontaneous Mass and Charge Losses from Single Multi-Megadalton Ions Studied by Charge Detection Mass Spectrometry. AB - Spontaneous mass and charge losses from individual multi-megadalton ions have been observed with charge detection mass spectrometry (CDMS) by trapping single hepatitis B virus (HBV) capsids for 3 s. Gradual increases in the oscillation frequency of single ions in the ion trap are attributed mainly to mass loss (probably solvent, water, and/or salt). The total mass lost during the 3 s trapping period peaks at around 20 kDa for 4 MDa HBV T = 4 capsids. Discrete frequency drops punctuate the gradual increases in the oscillation frequencies. The drops are attributed to a sudden loss of charge. In most cases a single positive charge is lost along with some mass (on average around 1000 Da). Charge loss occurs for over 40% of the trapped ions. It usually occurs near the beginning of the trapping event, and it occurs preferentially in regions of the trap with strong electric fields, indicating that external electric fields promote charge loss. This process may contribute to the decrease in m/z resolution that often occurs with megadalton ions. Graphical Abstract ?. PMID- 28083759 TI - Effect of hand volume and other anthropometric measurements on carpal tunnel syndrome. AB - Carpal tunnel syndrome (CTS), majority of cases are considered to be idiopathic, is the most commonly encountered peripheral neuropathy causing disability. We asserted that thick and big hands may more prone to idiopathic CTS (ICTS) than others. The study included 165 subjects admitted to our electrophysiology lab with pre-diagnosis of CTS between May 2014 and April 2015. Eighty-five of the subjects were diagnosed as ICTS. The parameters analyzed were: age, gender, occupation, BMI, hand dominance, grade of ICTS, wrist circumference, proximal/distal width of palm, hand/palm length, hand volume and palm length/proximal palm width. Female gender was significantly higher in both groups. The mean age of study group was 44.02 +/- 9.11 years, and control group was 41.25 +/- 9.94 years. BMI, wrist circumference and hand volume were significantly higher in the study group (p < 0.05). However, palm length/prox.palm width ratio was higher in the control group (p = 0.00). There were also significant differences among CTS groups in terms of age (p = 0.001). Mean age was higher in severe CTS group. Female gender, older age and high BMI are risk factors for ICTS. Higher hand volume, wrist circumference and lower palm length/prox. palm width ratio can also be anthropometric risk factors. Large hand volumes, big and coarse hands are more prone to ICTS. PMID- 28083760 TI - A case of thalamo-mesencephalon infarct presenting as transient global amnesia: do we overlook the diagnosis? PMID- 28083761 TI - Migraine as a risk factor for young patients with ischemic stroke: a case-control study. AB - Studies have suggested a possible association of migraine and increased risk of ischemic stroke in young adults, particularly in smokers and in women who use oral contraceptive drugs. We aimed to analyze the association between migraine and ischemic stroke in young population in a hospital-based cohort. We included 202 consecutive patients with the diagnosis of ischemic stroke who were between 15 and 50 years and age- and gender-matched 250 volunteers with no history of stroke. All participants were interviewed using a questionnaire for migraine. Localization of ischemic lesion was classified as anterior and posterior circulation according to neuroimaging findings. The cause of ischemic lesion and all risk factors were recorded. Undetermined etiology was the most frequent (43.1%) and the most common determined cause was cardioembolism (22.3%) in young stroke patients. Frequency of migraine was 30.2% among patients with stroke whereas 16.8% of healthy subjects had migraine (p = 0.001). Migraine with aura was significantly more common among patients with stroke compared to healthy subjects (18.3 vs 4.4%; p = 0.000) whereas the frequency of migraine without aura was similar in both groups (11.9 vs 12.4%). Using logistic regression, migraine with aura was shown to be an independent risk factor for ischemic stroke in young population (p = 0.000) and separate analysis for gender demonstrated that it was only a risk factor for women (p = 0.009) but not for men (p = 0.107). Migraine with aura was found to be more common in ischemic stroke in young patients. It was an independent risk factor in women. PMID- 28083762 TI - Protein sequence-similarity search acceleration using a heuristic algorithm with a sensitive matrix. AB - Protein database search for public databases is a fundamental step in the target selection of proteins in structural and functional genomics and also for inferring protein structure, function, and evolution. Most database search methods employ amino acid substitution matrices to score amino acid pairs. The choice of substitution matrix strongly affects homology detection performance. We earlier proposed a substitution matrix named MIQS that was optimized for distant protein homology search. Herein we further evaluate MIQS in combination with LAST, a heuristic and fast database search tool with a tunable sensitivity parameter m, where larger m denotes higher sensitivity. Results show that MIQS substantially improves the homology detection and alignment quality performance of LAST across diverse m parameters. Against a protein database consisting of approximately 15 million sequences, LAST with m = 105 achieves better homology detection performance than BLASTP, and completes the search 20 times faster. Compared to the most sensitive existing methods being used today, CS-BLAST and SSEARCH, LAST with MIQS and m = 106 shows comparable homology detection performance at 2.0 and 3.9 times greater speed, respectively. Results demonstrate that MIQS-powered LAST is a time-efficient method for sensitive and accurate homology search. PMID- 28083763 TI - Suicide Risk Assessment by Residents: Deficiencies of Documentation. AB - OBJECTIVE: The authors sought to assess the documentation of suicide risk assessments performed by psychiatry residents in a psychiatric emergency service (PES) and to identify differences in documentation between previously used paper charts and a new electronic medical record (EMR) system based on the Columbia Suicide Severity Rating Scale (C-SSRS)-risk assessment version. METHODS: This study is a retrospective chart review of psychiatric evaluations performed by psychiatry residents during a 1-year period in the PES of a large, urban, academic medical center. The sample was selected by a systematic random sampling technique from a total of 3931 evaluations performed on adult patients during the study period. The suicide risk assessments were evaluated using data regarding demographics, process indicators identified from the C-SSRS, and diagnoses. RESULTS: A total of 300 charts were reviewed. Only 91% of the evaluations contained documentation of suicidal ideations (either admitted or denied); 5 other variables were documented in more than 50% of the evaluations: treatment status (95.3%), presence/absence of previous suicide attempts (84.6%), recent event-denies (56%), history of recent negative events (55%), and suicidal behavior-denies (53%). Additionally, 2 risk factors and 3 protective factors were documented in over 25% of the evaluations. CONCLUSION: Documentation was deficient in multiple areas, with even the presence/absence of suicidal ideations not being documented in all evaluations. Use of an EMR with built-in "clickable" options selectively improved documentation especially regarding risk and protective factors adapted from the C-SSRS. Emphasis on documentation of assessments is paramount while training residents in suicide risk assessment. PMID- 28083764 TI - Treatment of HCV in renal transplant patients with peginterferon and ribavirin: long-term follow-up. AB - BACKGROUND: In addition to the observation of an increased viremia among patients with chronic hepatitis C virus (HCV) infection who undergo renal transplantation, fibrosis and necroinflammatory activity have been noted to worsen comparing pre- and post-renal transplantation liver biopsies in some of these patients. Apart from the reported reduced patient and allograft survival rates, post-transplant diabetes mellitus, de novo glomerulonephritis, and an increased overall risk of infection have been observed. However, antiviral therapy for HCV is generally considered contraindicated among patients with solid organ transplants, with the main worry being the risk of acute rejection in relation to the use of interferon. We reported the long-term outcome of four renal transplant patients with chronic HCV infection who received peginterferon-based therapy. METHODS: We collected the long-term follow-up data of four patients who completed the therapy with peginterferon in combination with ribavirin. Two of them had renal impairment at baseline. RESULTS: With treatment, they had a significant improvement in terms of serum liver transaminase level, and two patients achieved the early virological response and the other two rapid virological response. All four patients achieved sustained virological response, with neither HCV flare up nor renal dysfunction during follow-up for a mean duration of 74.3 months after therapy. CONCLUSIONS: These results suggest that sustained HCV virological response may be achieved without allograft dysfunction, in selected renal transplant patients using a peginterferon-based therapy. PMID- 28083765 TI - An introduction to CKD-MBD research: restart for the future. PMID- 28083766 TI - Role of IL-13 Genetic Variants in Signalling of Asthma. AB - Asthma is a chronic inflammatory disease of the lower airways characterised by intermittent airway narrowing and airflow obstruction. The aim of this study was to examine the association of IL-13 Arg 130 Gln (A/G) and -1112C/T cytokine gene polymorphisms and to know the secretion of IL-13 cytokine levels and the interactions between the IL-13 130A/G and IL-13Ralpha1/IL-4Ralpha complex cytokine genes. The study population comprised of atopic and non-atopic asthma patients and healthy controls (HC) (N = 120). Single nucleotide polymorphisms (SNPs) were determined by restriction fragment length polymorphism (RFLP). IL-13 cytokine serum levels were measured by enzyme-linked immunosorbent assay (ELISA), and homology modelling of IL-13 A/G cytokine gene was performed through in silico analysis. In IL-13 130A/G cytokine gene AG, GG genotypes (p < 0.0042, OR = 2.87, CI 1.46-5.65; OR = 1.92, CI 1.06-3.48) were found to be significant in atopic asthma patients vs HC. The mean IL-13 serum cytokine levels were found to be significantly high in atopic (38.48 +/- 36.54) and non-atopic (36.05 +/- 34.54) asthma patients whereas total serum IgE levels were significantly high at p < 0.0001 in atopic and low in non-atopic asthma patients at p < 0.003 compared to HC. In silico analysis indicated that residue IL-13 130 with charge modifying variants was crucial in ligand-receptor interactions. IL-13 cytokine serum levels were significantly high in atopic and non-atopic asthma patients compared to HC. The GG genotype of IL-13 130A/G cytokine gene might be involved in the induced production of total IgE and IL-13 cytokine serum levels suggesting IL-13 may be important in the signalling of asthma. PMID- 28083767 TI - A green one-pot three-component cascade reaction: the synthesis of 2-amino-5,8 dihydro-3H-pyrido[2,3-D]pyrimidin-4-ones in aqueous medium. AB - A one-pot three-component cascade reaction for the green synthesis of a new class of 2-amino-5,8-dihydro-3H-pyrido[2,3-d]pyrimidin-4-ones was developed from the condensation of aromatic aldehydes with 2,6-diaminopyrimidin-4(3H)-one and acetophenone derivatives or various cyclic ketones in the presence of a catalytic amount of sodium carbonate in a mixture of water and ethanol at 60 [Formula: see text]. This reaction led to the construction of two carbon-carbon bonds and one carbon-nitrogen bond in a single synthetic step. PMID- 28083768 TI - Invasive fungal tracheobronchitis in mechanically ventilated critically ill patients: underlying conditions, diagnosis, and outcomes. AB - BACKGROUND: Invasive fungal tracheobronchitis (IFT) is a severe form of pulmonary fungal infection that is not limited to immunocompromised patients. Although respiratory failure is a crucial predictor of death, information regarding IFT in critically ill patients is limited. METHODS: In this retrospective, multicenter, observational study, we enrolled adults diagnosed as having IFT who had been admitted to the intensive care unit between January 2007 and December 2015. Their demographics, clinical imaging data, bronchoscopic and histopathological findings, and outcomes were recorded. RESULTS: This study included 31 patients who had been diagnosed as having IFT, comprising 24 men and 7 women with a mean age of 64.7 +/- 13.7 years. All patients developed respiratory failure and received mechanical ventilation before diagnosis. Eighteen (58.1%) patients had diabetes mellitus, and 12 (38.7%) had chronic lung disease. Four (12.9%) patients had hematologic disease, and none of the patients had neutropenia. Twenty-five (80.6%) patients were diagnosed as having proven IFT, and the remaining patients had probable IFT. Aspergillus spp. (61.3%) were the most common pathogenic species, followed by Mucorales (25.8%) and Candida spp. (6.5%). The diagnoses in six (19.4%) patients were confirmed only through bronchial biopsy and histopathological examination, whereas their cultures of bronchoalveolar lavage fluid were negative for fungi. The overall in-hospital mortality rate was 93.5%. CONCLUSIONS: IFT in critically ill patients results in a high mortality rate. Diabetes mellitus is the most prevalent underlying disease, followed by chronic lung disease. In addition to Aspergillus spp., Mucorales is another crucial pathogenic species. Bronchial lesion biopsy is the key diagnostic strategy. PMID- 28083769 TI - Identification of Caveolin-1 as an Invasion-Associated Gene in Liver Cancer Cells Using Dendron-Coated DNA Microarrays. AB - The conventional gene expression profiling approaches have been replaced with DNA microarrays with exhibiting a powerful high-throughput capacity. Most solid surfaces of DNA microarrays contain such a high area density of functional groups to immobilize capture DNAs to the surface that the hybridization of capture DNAs with cDNA can be hindered, resulting in low intensity and reproducibility. Since our previous works showed that the 9-acid dendron was able to increase the hybridization efficiency, we aimed to demonstrate the feasibility of 9-acid dendron-coated glass slides as an advanced microarray platform for gene expression profiling. The 9-acid dendron-coated DNA microarray could reproducibly obtain the expression levels of 2800 human cancer-associated genes in the two liver cancer lines: Hep3B and SK-Hep1. Among the differentially expressed genes, Caveolin-1 (Cav-1) was identified as the most highly up-regulated gene in invasive SK-Hep1 in comparison to non-motile Hep3B. The overexpression of Cav-1 in Hep3B promoted the cell invasion, whereas its knockdown in SK-Hep1 suppressed the invasive feature, which confirms that the overexpression of Cav-1 is closely associated with cell invasion of liver carcinoma. Collectively, the 9-acid dendron-coated surface could successfully detect the transcript levels of cells, demonstrating its feasible potential to identify the candidate genes for further functional studies or diagnosis of diseases. PMID- 28083770 TI - Structure Characterization and Lead Detoxification Effect of Carboxymethylated Melanin Derived from Lachnum Sp. AB - In the present study, an intracellular melanin, named LIM205, was separated from Lachnum YM205 mycelia and was purified on a Sephadex G-15 column. The molecular weight of LIM205 was determined as 522 Da, and its molecular formula was speculated as C28H14N2O7S. The possible chemical structure of LIM205 was determined according to the results of Fourier transform infrared (FT-IR), 1H NMR, 13C NMR, and pyrolysis/GC-MS analysis. With the aim to increase its water solubility, its carboxymethylated derivative, named CLIM205, was formed by the substitution of hydrogen atoms in LIM205 with one, two, and three carboxymethylate groups. FT-IR, UV, and ESI-MS analysis demonstrated that the carboxymethylate groups were conjugated onto LIM205. The lead detoxification activities of LIM205 and CLIM205 had also been investigated. In vivo test showed that both LIM205 and CLIM205 reduced the tissue lead concentration, enhanced lead excretion, and reversed lead-induced alterations in superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) concentrations in mice, with CLIM205 showed better efficacy. The study indicates that LIM205 and CLIM205 have significant lead detoxification effect which will contribute to solve related problems. PMID- 28083771 TI - Sorting Carbon Nanotubes. AB - Sorting of single-wall carbon nanotubes by their electronic and atomic structures in liquid phases is reviewed in this chapter. We first introduce the sorting problem, and then provide an overview of several sorting methodologies, following roughly the chronological order of their development over the past 15 years or so. Major methods discussed include ion-exchange chromatography, density-gradient ultracentrifugation, selective extraction in organic solvents, gel chromatography, and aqueous two-phase extraction. A main focus of the review is on the common mechanisms underlining all sorting processes. We propose that differences in solvation among different nanotube species are the ultimate driving force of sorting, and we corroborate this proposal by presenting analysis on how the differences are realized in electronic-structure-based sorting and atomic-structure-based sorting. In the end, we offer some suggestions on future directions that may grow out of carbon nanotube sorting. In particular, the prospect of expanding the function of DNA/carbon nanotube hybrid to control inter particle interactions both inside and outside the nanotube is discussed. PMID- 28083772 TI - Pupillary correlates of covert shifts of attention during working memory maintenance. AB - The pupillary light reflex (PLR) was used to track covert shifts of attention to items maintained in visual working memory (VWM). In three experiments, participants performed a change detection task in which rectangles appeared on either side of fixation and at test participants indicated if the cued rectangle changed its orientation. Prior to presentation or during the delay, participants were cued to the light or dark side of the screen. When cued to the light side, the pupil constricted, and when cued to the dark side, the pupil dilated, suggesting that the PLR tracked covert shifts of attention. Similar covert shifts of attention were seen when the target stimuli remained onscreen and during a blank delay period, suggesting similar effects for attention to perceptual stimuli and attention to stimuli maintained in VWM. Furthermore, similar effects were demonstrated when participants were pre-cued or retro-cued to the prioritized location, suggesting that shifts of covert attention can occur both before and after target presentation. These results are consistent with prior research, suggesting an important role of covert shifts of attention during VWM maintenance and that the PLR can be used to track these covert shifts of attention. PMID- 28083773 TI - Assessment of cytotoxicity, genotoxicity and 7-ethoxyresorufin-O-deethylase (EROD) induction in sediment extracts from New Zealand urban estuaries. AB - Sediments represent a major sink for contaminants resulting from industrial and agricultural activities - especially lipophilic substances. This study exclusively used in vitro methodologies to characterize specific toxicity effects of contaminants in sediment extracts from two urban New Zealand estuaries. Sediment extracts were prepared and tested for a range of biological endpoints. The micronucleus and comet assays in V79 cells were used to assess genotoxicity. Induction of 7-ethoxyresorufin-O-deethylase in piscine RTL-W1 cells was determined to estimate dioxin-like toxicity. Cytotoxic potentials were analyzed by neutral red uptake and MTT reduction. There was evidence of strong dioxin-like toxicity and moderate cytotoxicity. Genotoxicity was distinct in the micronucleus assay, but low in the comet assay. The results indicate the presence of chemicals in the sediments with the potential to pose a risk through multiple mechanisms of toxicity, the identities and amounts of which will be disclosed in a parallel study alongside with in vivo toxicity data. PMID- 28083774 TI - Does seed size and surface anatomy play role in combating phytotoxicity of nanoparticles? AB - Rapid utilization of nano-based products will inevitably release nanoparticles into the environment with unidentified consequences. Plants, being an integral part of ecosystem play a vital role in the incorporation of nanoparticles in food chain and thus, need to be critically assessed. The present study assesses the comparative phytotoxicity of nanoparticle, bulk and ionic forms of zinc at different concentrations on selected plant species with varying seed size and surface anatomy. ZnO nanoparticles were chosen in view of their wide spread use in cosmetics and health care products, which allow their direct release in the environment. The impact on germination rate, shoot & root length and vigour index were evaluated. A concentration dependent inhibition of seed germination as well as seedling length was observed in all the tested plants. Due to the presence of thick cuticle on testa and root, pearl millet (xerophytic plant) was found to be relatively less sensitive to ZnO nanoparticles as compared to wheat and tomato (mesophytic plants) with normal cuticle layer. No correlation was observed between nanoparticles toxicity and seed size. The results indicated that variations in surface anatomy of seeds play a crucial role in determining the phytotoxicity of nanoparticles. The present findings significantly contribute to assess potential consequences of nanoparticle release in environment particularly with major emphasis on plant systems. It is the first report which suggests that variations observed in phytotoxicity of nanoparticles is mainly due to the predominant differences in size and surface anatomy of tested plant seeds and root architecture. Effect of various concentrations of nano ZnO, bulk ZnO and zinc sulphate on the growth of pearl millet (A), tomato (B) and wheat (C) seedlings. PMID- 28083775 TI - The effect of sediment characteristics on bioturbation-mediated transfer of lead, in freshwater laboratory microcosms with Lumbriculus variegatus. AB - While it has been well established that sediment bioturbators can affect the fate of metals in aquatic systems and that the fate of metals there can depend on sediment characteristics, the interaction between these influences is not well known. The present study therefore investigated whether the influence of a sediment bioturbator on the fate of metals is affected by sediment characteristics. This was investigated using two laboratory microcosm experiments with lead-contaminated sediment and the oligochaete Lumbriculus variegatus. The first experiment used sediment collected from five Toledo Bend reservoir sites that differed in sediment characteristics, and analyses looked at the influence of sediment organic matter, sediment silt/clay content, sediment pH, and pore water pH. In the second experiment, organic matter and silt/clay content of Toledo Bend reservoir sediment were varied experimentally using alpha-cellulose and clay, and Pb transfer to the water column and bioaccumulation were again quantified. Both experiments were conducted with sediment spiked with Pb to a concentration of 100 ug/g, at an oligochaete density of 6279 ind./m2. In the first experiment, the Pb concentrations in the water column and those in the worms at the end of the 14-day experiment differed among sediment-collection sites. Silt/clay content and sediment pH were the two most important variables influencing Pb transfer from sediment to the water column. A multiple regression model with these variables explained 58% of the variability in this lead transfer. For Pb accumulation by the worms, sediment organic matter and pore water pH were the two most important variables. This regression model explained 85% of the variability in tissue Pb levels. In the second experiment, where the individual effects of the organic matter and silt/clay content on Pb transport and distribution were assessed, the use of sediment with more organic matter resulted in a reduction in both the Pb transfer to the water column and the accumulation in worms. The increase in the sediment's silt/clay content resulted in a reduction in Pb bioaccumulation only. Overall, the results of the present study demonstrate that sediment pH, pore-water pH, organic matter, and silt/clay content influence the bioturbation-mediated transfer and the environmental distribution of Pb. PMID- 28083776 TI - Serum progesterone trend after day of transfer predicts live birth in fresh IVF cycles. AB - PURPOSE: Our objective was to determine if a change in serum P4 from day of transfer (defined as day 19) to day 28 could predict live birth outcome in patients undergoing IVF. METHODS: This study was a retrospective analysis of fresh IVF cycles from 2010 to 2013 at a single center. Primary outcomes include raw and percent change in serum P4, live birth rate, missed abortion, and biochemical pregnancies. RESULTS: Our results showed an association between live birth rate and percent change in P4. Patients with a 10% or greater drop in serum P4 from day 19 to day 28 had a lower live birth rate, at 26 versus 63%. Interestingly, both groups had "normal" serum P4 levels on day 19, but patients with a 10% or greater drop had lower P4 levels than their counterparts. There was no association between percent P4 change and spontaneous abortion or biochemical pregnancy. CONCLUSIONS: This is the first study to show that percent drop in serum P4 from day of transfer to day 28 is associated with decreased rates of live birth and ongoing pregnancy in fresh IVF cycles, even despite "high or normal" P4 levels on day of transfer. PMID- 28083777 TI - Working Memory Impairments in Chromosome 22q11.2 Deletion Syndrome: The Roles of Anxiety and Stress Physiology. AB - Stress and anxiety have a negative impact on working memory systems by competing for executive resources and attention. Broad memory deficits, anxiety, and elevated stress have been reported in individuals with chromosome 22q11.2 deletion syndrome (22q11.2DS). We investigated anxiety and physiological stress reactivity in relation to visuospatial working memory impairments in 20 children with 22q11.2DS and 32 typically developing (TD) children ages 7 to 16. Children with 22q11.2DS demonstrated poorer working memory, reduced post-stress respiratory sinus arrhythmia recovery, and overall increased levels of cortisol in comparison to TD children. Anxiety, but not physiological stress responsivity, mediated the relationship between 22q11.2DS diagnosis and visuospatial working memory impairment. Findings indicate that anxiety exacerbates impaired working memory in children with 22q11.2DS. PMID- 28083778 TI - Linguistic and Non-Linguistic Semantic Processing in Individuals with Autism Spectrum Disorders: An ERP Study. AB - Individuals with autism spectrum disorders (ASD) experience difficulties with language, particularly higher-level functions like semantic integration. Yet some studies indicate that semantic processing of non-linguistic stimuli is not impaired, suggesting a language-specific deficit in semantic processing. Using a semantic priming task, we compared event-related potentials (ERPs) in response to lexico-semantic processing (written words) and visuo-semantic processing (pictures) in adults with ASD and adults with typical development (TD). The ASD group showed successful lexico-semantic and visuo-semantic processing, indicated by similar N400 effects between groups for word and picture stimuli. However, differences in N400 latency and topography in word conditions suggested different lexico-semantic processing mechanisms: an expectancy-based strategy for the TD group but a controlled post-lexical integration strategy for the ASD group. PMID- 28083779 TI - Do Handwriting Difficulties Correlate with Core Symptomology, Motor Proficiency and Attentional Behaviours? AB - Handwriting is commonly identified as an area of weakness in children with autism spectrum disorder (ASD), but precise deficits have not been fully characterised. Boys with ASD (n = 23) and matched controls (n = 20) aged 8-12 years completed a simple, digitised task to objectively assess handwriting performance using advanced descriptive measures. Moderate to large associations were identified between handwriting performance and attention, ASD symptoms and motor proficiency. The ASD group demonstrated significantly less smooth movements and significantly greater sizing variability and peak velocity relative to controls. These findings provide a clearer indication of the specific nature of handwriting impairments in children with ASD, and suggest a relationship with core clinical symptom severity, attention and motor behaviours. PMID- 28083780 TI - What Difference Does It Make? Implicit, Explicit and Complex Social Cognition in Autism Spectrum Disorders. AB - We tested social cognition abilities of adolescents with autism spectrum disorders (ASD) and neurotypically developed peers (NTD). A multi-faceted test battery including facial emotion categorization (FEC), classical false belief tasks (FBT), and complex social cognition (SC), yielded significantly lower accuracy rates for FEC and complex SC tasks in ASD, but no significant differences in performance concerning FBT. A significant correlation between age and performance in a FEC task and in a complex task was found only in ASD. We propose that dynamic and/or fragmented FEC tasks can elicit deficits in implicit processing of facial emotion more efficiently. The difficulties of ASD in solving complex SC tasks can be ascribed to deficits in the acquisition and application of social schemata. PMID- 28083781 TI - Dietary fatty acids influence the growth and fatty acid composition of the yellow mealworm Tenebrio molitor (Coleoptera: Tenebrionidae). AB - Fat is the second most abundant component of the nutrient composition of the mealworm Tenebrio molitor (Coleoptera: Tenebrionidae) that represents also an interesting source of PUFA, especially n-6 and n-3 fatty acids, involved in prevention of cardiovascular diseases. This study investigated the possibility of modifying the fat content and the FA composition of yellow mealworms through feeding and how this would be influenced by developmental stages, pupal sex, and generation with the future aim of applying this coleopteran as a diet supplement for human health. Growth rate and cumulative mortality percentage on the different feeding substrates were also evaluated to select the optimal conditions for a mass-raising of this insect species. Despite the different fat content in the six different breeding substrates used, T. molitor larvae and pupae contained a constant fat percentage (>34% in larvae and >30% in pupae). A similar total fat content was found comparing larvae and male and female pupae of the second generation to those of the first generation. On the contrary, FA composition differed both in larvae and pupae reared on the different feeding substrates. However, the exemplars reared on the diets based on 100% bread and 100% oat flour showed SFA, PUFA percentages, and an n-6/n-3 ratio more suitable for human consumption; the diet based on beer yeast, wheat flour, and oat flour resulted in a contemporary diet that most satisfied the balance between a fat composition of high quality and favorable growth conditions. PMID- 28083782 TI - Current issues in postmortem imaging of perinatal and forensic childhood deaths. AB - Perinatal autopsy practice is undergoing a state of change with the introduction of evidence-based cross-sectional imaging, driven primarily by parental choice. In particular, the introduction of post mortem magnetic resonance imaging (PMMR) has helped to advance less-invasive perinatal autopsy in the United Kingdom (UK) and Europe. However, there are limitations to PMMR and other imaging techniques which need to be overcome, particularly with regard to imaging very small fetuses. Imaging is also now increasingly used to investigate particular deaths in childhood, such as suspected non-accidental injury (NAI) and sudden unexpected death in infancy (SUDI). Here we focus on current topical developments the field, with particular emphasis on the application of imaging to perinatal autopsy, and pediatric forensic deaths. Different imaging modalities and their relative advantages and disadvantages are discussed, together with other benefits of more advanced cross-sectional imaging which currently lie in the research domain. Whilst variations in local imaging service provision and need may determine different practice patterns, and access to machines and professionals with appropriate expertise and experience to correctly interpret the findings may limit current practices, we propose that gold standard perinatal and pediatric autopsy services would include complete PMMR imaging prior to autopsy, with PMCT in suspicious childhood deaths. This approach would provide maximal diagnostic yield to the pathologist, forensic investigator and most importantly, the parents. PMID- 28083783 TI - Flower structure and developmental stages of the capitulum of Smallanthus sonchifolius (Asteraceae): reproductive implications. AB - Yacon (Smallanthus sonchifolius, Asteraceae) is an ancient andean crop that has numerous dietary and medicinal properties. Morphological and anatomical features and developmental changes of the capitulum were studied. A ray floret is a pistillate, female flower, while a disc floret is a staminate male flower, and the former opens before the latter, being pseudanthium protogynous. The capitulum presents interesting attributes for pollinators such as flower structure, nectaries and pollenkitt. Gynoecial nectaries were found on undeveloped ovary in the disc floret, but not in the ray floret. Glandular trichomes were observed on the abaxial epidermis of corolla in the ray floret, but not in the disc floret. Capitulum development was divided into eight stages. Stigma receptivity varied with these stages. Pollen viability was low (15%). In accordance with low viability, pollen grains exhibit diverse sizes and shapes, reduction in length of spines, and abnormal protoplasm. Examination of ovary development in the ray floret showed that a mature ovule was formed, but fertilization did not occur. In advanced developmental stages, the capitulum showed proliferation of the endothelium, degeneration of the embryo sac, and all harvested cypselae had aborted seeds. Problems found in pollen viability and aborted cypselae could be the result of a history of vegetative propagation in the domestication process. PMID- 28083785 TI - Erratum to: Association Between Statin Use and Bell's Palsy: A Population-Based Study. PMID- 28083784 TI - Understanding Parkinson's Disease through the Use of Cell Reprogramming. AB - Recent progress in the field of somatic cell reprogramming offers exciting new possibilities for the study and treatment of Parkinson's disease (PD). Reprogramming technology offers the ability to untangle the diverse contributing risk factors for PD, such as ageing, genetics and environmental toxins. In order to gain novel insights into such a complex disease, cell-based models of PD should represent, as closely as possible, aged human dopaminergic neurons of the substantia nigra. However, the generation of high yields of functionally mature, authentic ventral midbrain dopamine (vmDA) neurons has not been easy to achieve. Furthermore, ensuring cells represent aged rather than embryonic neurons has presented a significant challenge. To date, induced pluripotent stem (iPS) cells have received much attention for modelling PD. Nonetheless, direct reprogramming strategies (either to a neuronal or neural stem/progenitor fate) represent a valid alternative that are yet to be extensively explored. Direct reprogramming is faster and more efficient than iPS cell reprogramming, and appears to conserve age-related markers. At present, however, protocols aiming to derive authentic, mature vmDA neurons by direct reprogramming of adult human somatic cells are sorely lacking. This review will discuss the strategies that have been employed to generate vmDA neurons and their potential for the study and treatment of PD. PMID- 28083787 TI - Two cases of serious rhabdomyolysis during linezolid treatment. AB - Linezolid is an oxazolidinone antibiotic with activity against gram-positive organisms, particularly methicillin-resistant Staphylococcus aureus (MRSA). To the best of our knowledge, there are only two case reports on rhabdomyolysis in patients treated with linezolid. Here, we describe two cases of serious rhabdomyolysis: one in a patient with septic community-acquired (CA)-MRSA pneumonia and a second case in a patient with suspected catheter-related blood stream infection. PMID- 28083786 TI - Effects of the functional HOTAIR rs920778 and rs12826786 genetic variants in glioma susceptibility and patient prognosis. AB - Abnormal expression of the long non-coding RNA HOX transcript antisense intergenic RNA (HOTAIR) is oncogenic in several human cancers, including gliomas. The HOTAIR single nucleotide polymorphisms (SNPs) rs920778 (C > T) and rs12826786 (C > T) present in the intronic enhancer and promoter regions of HOTAIR, respectively, are associated with expression, cancer susceptibility, and patient prognosis in some tumor types. However, the relevance of these HOTAIR SNPs has not been studied in glioma. Here, we report a case-control study comprising 177 Portuguese glioma patients and 199 cancer-free controls. All subjects were genotyped by PCR and restriction fragment length polymorphism (RFLP). No statistically significant differences were found in the genotype or allele distributions of either rs920778 or rs12826786 between glioma patients and controls, suggesting these SNPs are not associated with glioma risk. No significant associations were found between rs920778 variants and HOTAIR expression levels, while rs12826786 CT genotype was associated with increased intratumoral HOTAIR RNA levels when compared to TT genotype (p-value = 0.04). Univariate (Log-rank) and multivariate (Cox proportional) analyses showed both rs920778 CT and rs12826786 CT genotypes were significantly associated with longer overall survival of WHO grade III anaplastic oligodendroglioma patients. Our results suggest that HOTAIR SNPs rs920778 and rs12826786 do not play a significant role in glioma susceptibility, but may be important prognostic factors in anaplastic oligodendroglioma patients. Future studies are warranted to validate and expand these findings, and to further dissect the importance of these SNPs in glioma. PMID- 28083788 TI - Erratum to: HIV and Aging Research in Women: An Overview. PMID- 28083790 TI - Role of the Orexin/Hypocretin System in Stress-Related Psychiatric Disorders. AB - Orexins (hypocretins) are critically involved in coordinating appropriate physiological and behavioral responses to aversive and threatening stimuli. Acute stressors engage orexin neurons via direct projections from stress-sensitive brain regions. Orexin neurons, in turn, facilitate adaptive behavior via reciprocal connections as well as via direct projections to the hypophysiotropic neurons that coordinate the hypothalamic-pituitary-adrenal (HPA) axis response to stress. Consequently, hyperactivity of the orexin system is associated with increased motivated arousal and anxiety, and is emerging as a key feature of panic disorder. Accordingly, there has been significant interest in the therapeutic potential of pharmacological agents that antagonize orexin signaling at their receptors for the treatment of anxiety disorders. In contrast, disorders characterized by inappropriately low levels of motivated arousal, such as depression, generally appear to be associated with hypoactivity of the orexin system. This includes narcolepsy with cataplexy, a disorder characterized by the progressive loss of orexin neurons and increased rates of moderate/severe depression symptomology. Here, we provide a comprehensive overview of both clinical and preclinical evidence highlighting the role of orexin signaling in stress reactivity, as well as how perturbations to this system can result in dysregulated behavioral phenotypes. PMID- 28083789 TI - Co-Expression of Putative Cancer Stem Cell Markers CD44 and CD133 in Prostate Carcinomas. AB - Cancer stem cells (CSCs) are the main players of prostate tumorigenesis thus; characterization of CSCs can pave the way for understanding the early detection, drug resistance, metastasis and relapse. The current study was conducted to evaluate the expression level and clinical significance of the potential CSC markers CD44 and CD133 in a series of prostate tissues. One hundred and forty eight prostate tissues composed of prostate cancer (PCa), high-grade prostatic intraepithelial neoplasia (HGPIN), and benign prostate hyperplasia (BPH) were immunostained for the putative CSC markers CD44 and CD133. Subsequently, the correlation between the expression of these markers and the clinicopathological variables was examined. A higher level of CD44 expression was observed in 42% of PCa, 57% of HGPIN, and 42% BPH tissues. In the case of CD133 expression PCa, HGPIN, and BPH samples demonstrated high immunoreactivity in 46%, 43%, and 42% of cells, respectively. Statistical analysis showed an inverse significant correlation between CD44 expression with Gleason score of PCa (P = 0.02), while no significant correlation was observed between CD133 expression and clinicopathological parameters. A significant reciprocal correlation was observed between the expression of two putative CSC markers CD44 and CD133 in PCa specimens while not indicating clinical significance. Further clinical investigation is required to consider these markers as targets of new therapeutic strategies for PCa. PMID- 28083791 TI - Vertex stability and topological transitions in vertex models of foams and epithelia. AB - In computer simulations of dry foams and of epithelial tissues, vertex models are often used to describe the shape and motion of individual cells. Although these models have been widely adopted, relatively little is known about their basic theoretical properties. For example, while fourfold vertices in real foams are always unstable, it remains unclear whether a simplified vertex model description has the same behavior. Here, we study vertex stability and the dynamics of T1 topological transitions in vertex models. We show that, when all edges have the same tension, stationary fourfold vertices in these models do indeed always break up. In contrast, when tensions are allowed to depend on edge orientation, fourfold vertices can become stable, as is observed in some biological systems. More generally, our formulation of vertex stability leads to an improved treatment of T1 transitions in simulations and paves the way for studies of more biologically realistic models that couple topological transitions to the dynamics of regulatory proteins. PMID- 28083792 TI - Three-body potential for simulating bond swaps in molecular dynamics. AB - Novel soft matter materials join the resistance of a permanent mesh of strong inter-particle bonds with the self-healing and restructuring properties allowed by bond-swapping processes. Theoretical and numerical studies of the dynamics of coarse-grained models of covalent adaptable networks and vitrimers require effective algorithms for modelling the corresponding evolution of the network topology. Here I propose a simple trick for performing molecular dynamics simulations of bond-swapping network systems with particle-level description. The method is based on the addition of a computationally non-expensive three-body repulsive potential that encodes for the single-bond per particle condition and establishes a flat potential energy surface for the bond swap. PMID- 28083793 TI - Role and significance of wetting pressures during droplet impact on structured superhydrophobic surfaces. AB - The impact dynamics and spreading behavior of droplets impinging on structured superhydrophobic surfaces are dependent on both the droplet initial conditions and the surface texture. The equivalence of wetting and dewetting pressures is classically known to be a critical factor in determining the state of a droplet during the contact and spreading phases. The present study extensively examines the underlying physics behind this pressure balance during the impact process and its direct role in determining the wetting process. Extensive three-dimensional simulations employing droplet impact on a structured superhydrophobic surface has been performed to reveal the intricacies of the interactivities of the fluid with the microstructure. Insight onto the acute role of wetting pressures and the implications of the same on determining the wetting dynamics, with internal fluidics of the droplet during the impact process, has been discussed. The phenomenon of state transition from the Cassie-Baxter to the Wenzel up on impact is also investigated and the intricate flow mechanics at play within the posts has been presented. Knowledge of pressure distribution and internal flow structures within the droplet during its interaction with the surface at different instances of time reveals the root mechanism behind the impalement of the droplet to a fully wetting state. Analysis of the internal pressure and flow distribution also presents necessary justification for the existence of a partially impaled state. The time evolution of spread for different scenarios is in agreement with experimental results and the article provides insight onto the role of wetting pressure in determining fluidic interactions on such surfaces. PMID- 28083794 TI - A Case Report of Widespread Majocchi's Granuloma in a Patient with Systemic Lupus Erythematosus. AB - Majocchi's granuloma is an intracutaneous or subcutaneous granulomatous inflammation caused by invasion of dermatophytic fungus, especially Trichophyton rubrum. This type of lesion is misdiagnosed frequently without proper auxiliary examination. Here, we report a case of widespread Majocchi's granuloma caused by T. rubrum in a 35-year-old woman with systemic lupus erythematosus for 9 years. The patient was initially misdiagnosed as SLE-associated skin lesions, which delayed her treatment and resulted in severe multiple disseminated lesions. After confirmed as Majocchi's granuloma, the patient was cured after 11-month treatment with terbinafine. PMID- 28083795 TI - Characterization and toxicity of hospital wastewaters in Turkey. AB - The aim of the study was to present first preliminary characterization of Turkish hospital wastewaters, their environmental risk, and a method for toxicity assessment. The hospital wastewater samples were collected from two of the largest medical faculty hospitals and a training and research hospital in Istanbul, Turkey. The samples from the selected hospitals were taken as grab samples on March 2014. Overall, 55 substances including pharmaceuticals and their metabolites, pesticides, and corrosion inhibitors were analyzed in all hospital wastewaters. Analysis of toxicity and the antibiotic resistance bacteria were investigated in addition to the chemical analysis in the wastewater of one hospital. Hazard quotients (HQs) and toxic units (TUs) were calculated as basis of the environmental risk assessment. Fourteen pharmaceuticals in hospital wastewater (HWW) were classified as "high risk" with HQ > 10. HQHWW values higher than 100 were determined for five antibiotics and one analgesic, namely, ofloxacin, clarithromycin, ciprofloxacin, sulfapyridine, trimethoprim, and diclofenac. Ofloxacin with an HQHWW of 9090 was observed to be the most hazardous compound. HQ and TU values of the wastewater treatment plant (WWTP) effluent dropped significantly due to dilution in the sewer. Further elimination by biological degradation or adsorption was observed only in some cases. However, the decreased HQWWTPeffluent values do not the change environmental load significantly. Therefore, advanced treatment processes should be applied to remove the persistent compounds. In combination with the results on antibiotic resistance, we would prefer on-site treatment of hospital wastewater. Toxicological assessment was performed using cytotoxic and mutagenic screening tests. The results of the Ames assay showed that the native hospital wastewaters had strongly mutagenic activity with a <=10-fold increase relative to negative controls. The mutagenic potentials of the samples were generally concentration and metabolic activation dependent. Multiple antibiotic resistances were demonstrated with the tested isolates to ciprofloxacin, trimethoprim, and ceftazidime. This study demonstrates that the hospital wastewaters in Istanbul exhibit strong environmental and toxicological risks, as well as high multiple drug resistance to commonly used antibiotics. PMID- 28083797 TI - Population Pharmacokinetic-Pharmacodynamic Model of Oral Fludrocortisone and Intravenous Hydrocortisone in Healthy Volunteers. AB - This study aimed at describing the pharmacokinetics and the concentration-effect relationships of fludrocortisone and hydrocortisone on urinary sodium/potassium excretion in healthy volunteers. This was a placebo-controlled, randomized, double blind, crossover study, of oral fludrocortisone and intravenous hydrocortisone, given alone or in combination, in 12 healthy male volunteers. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics and pharmacokinetic-pharmacodynamic relationships on urinary sodium/potassium ratio for each drug. A one-compartment model was used to describe fludrocortisone and hydrocortisone pharmacokinetics. Mean plasma half-life was 1.40 h (95%CI [0.80;2.10]) for fludrocortisone and 2.10 h (95%CI [1.78;2.40]) for hydrocortisone. Clearance was 40.8 L/h (95%CI [33.6;48]) for fludrocortisone and 30 L/h (95%CI [25.3;34.7]) for hydrocortisone. An indirect response model was used to describe effects on urinary sodium/potassium ratio. Fludrocortisone plasma concentrations showed a wider inter-individual dispersion than hydrocortisone plasma concentrations. Urinary sodium/potassium ratio variability was also higher with fludrocortisone as compared to hydrocortisone. The plasma concentration of drug producing 50% of maximal inhibition of urinary sodium/potassium (IC50) was about 200 times lower for fludrocortisone (0.08 MUg/L, 95%CI [0.035;0.125]) than for hydrocortisone (16.7 MUg/L, 95%CI [10.5;22.9]). Simulations showed that a 4-time per day administration regimen allow to achieve steady fludrocortisone plasma concentrations with stable decrease in urinary sodium/potassium ratio after the second administration of fludrocortisone. Fludrocortisone and hydrocortisone have short and similar plasma elimination half-lives in healthy subjects. Fludrocortisone plasma concentrations and effect on urinary sodium/potassium ratio had a higher inter-individual variability as compared to hydrocortisone. The administration regimen of fludrocortisone should be reconsidered. PMID- 28083796 TI - Approaches to Mitigate the Unwanted Immunogenicity of Therapeutic Proteins during Drug Development. AB - All biotherapeutics have the potential to induce an immune response. This immunological response is complex and, in addition to antibody formation, involves T cell activation and innate immune responses that could contribute to adverse effects. Integrated immunogenicity data analysis is crucial to understanding the possible clinical consequences of anti-drug antibody (ADA) responses. Because patient- and product-related factors can influence the immunogenicity of a therapeutic protein, a risk-based approach is recommended and followed by most drug developers to provide insight over the potential harm of unwanted ADA responses. This paper examines mitigation strategies currently implemented and novel under investigation approaches used by drug developers. The review describes immunomodulatory regimens used in the clinic to mitigate deleterious ADA responses to replacement therapies for deficiency syndromes, such as hemophilia A and B, and high risk classical infantile Pompe patients (e.g., cyclophosphamide, methotrexate, rituximab); novel in silico and in vitro prediction tools used to select candidates based on their immunogenicity potential (e.g., anti-CD52 antibody primary sequence and IFN beta-1a formulation); in vitro generation of tolerogenic antigen-presenting cells (APCs) to reduce ADA responses to factor VIII and IX in murine models of hemophilia; and selection of novel delivery systems to reduce in vivo ADA responses to highly immunogenic biotherapeutics (e.g., asparaginase). We conclude that mitigation strategies should be considered early in development for biotherapeutics based on our knowledge of existing clinical data for biotherapeutics and the immune response involved in the generation of these ADAs. PMID- 28083798 TI - Reliability of orthostatic beat-to-beat blood pressure tests: implications for population and clinical studies. AB - OBJECTIVE: To assess the test-retest reliability of orthostatic beat-to-beat blood pressure responses to active standing and related clinical definitions of orthostatic hypotension. METHODS: A random sample of community-dwelling older adults from the pan-European Survey of Health, Ageing and Retirement in Europe, Ireland underwent a health assessment that mimicked that of the Irish Longitudinal Study on Ageing. An active stand test was performed using continuous blood pressure measurements. Participants attended a repeat assessment 4-12 weeks after the initial measurement. A mixed-effects regression model estimated the reliability and minimum detectable change while controlling for fixed observer and time of day effects. RESULTS: A total of 125 individuals underwent repeat assessment (mean age 66.2 +/- 7.5 years; 55.6% female). Mean time between visits was 84.3 +/- 23.3 days. There was no significant mean difference in heart rate or blood pressure recovery variables between the first and repeat assessments. Minimum detectable change was noted for changes from resting values in systolic blood pressure (26.4 mmHg) and diastolic blood pressure (13.7 mmHg) at 110 s and for changes in heart rate (10.9 bpm) from resting values at 30 s after standing. Intra-class correlation values ranged from 0.47 for nadir values to 0.80 for heart rate and systolic blood pressure values measured 110 s after standing. CONCLUSION: Continuous orthostatic beat-to-beat blood pressure and related clinical definitions show low to moderate reliability and substantial natural variation over a 4-12-week period. Understanding variation in measures is essential for study design or estimating the effects of orthostatic hypotension, while clinically it can be used when evaluating longer term treatment effects. PMID- 28083799 TI - Flow of essential elements in subcellular fractions during oxidative stress. AB - Essential trace elements are commonly found in altered concentrations in the brains of patients with neurodegenerative diseases. Many studies in trace metal determination and quantification are conducted in tissue, cell culture or whole brain. In the present investigation, we determined by ICP-MS Fe, Cu, Zn, Ca, Se, Co, Cr, Mg, and Mn in organelles (mitochondria, nuclei) and whole motor neuron cell cultured in vitro. We performed experiments using two ways to access oxidative stress: cell treatments with H2O2 or Abeta-42 peptide in its oligomeric form. Both treatments caused accumulation of markers of oxidative stress, such as oxidized proteins and lipids, and alteration in DNA. Regarding trace elements, cells treated with H2O2 showed higher levels of Zn and lower levels of Ca in nuclei when compared to control cells with no oxidative treatments. On the other hand, cells treated with Abeta-42 peptide in its oligomeric form showed higher levels of Mg, Ca, Fe and Zn in nuclei when compared to control cells. These differences showed that metal flux in cell organelles during an intrinsic external oxidative condition (H2O2 treatment) are different from an intrinsic external neurodegenerative treatment. PMID- 28083800 TI - Assessing disparities in colorectal cancer mortality by socioeconomic status using new tools: health disparities calculator and socioeconomic quintiles. AB - PURPOSE: Colorectal cancer mortality rates dropped by half in the past three decades, but these gains were accompanied by striking differences in colorectal cancer mortality by socioeconomic status (SES). Our research objective is to examine disparities in colorectal cancer mortality by SES, using a scientifically rigorous and reproducible approach with publicly available online tools, HD*Calc and NCI SES Quintiles. METHODS: All reported colorectal cancer deaths in the United States from 1980 to 2010 were categorized into NCI SES quintiles and assessed at the county level. Joinpoint was used to test for significant changes in trends. Absolute and relative concentration indices (CI) were computed with HD*Calc to graph change in disparity over time. RESULTS: Disparities by SES significantly declined until 1993-1995, and then increased until 2010, due to a mortality drop in populations living in high SES areas that exceeded the mortality drop in lower SES areas. HD*Calc results were consistent for both absolute and relative concentration indices. Inequality aversion parameter weights of 2, 4, 6 and 8 were compared to explore how much colorectal cancer mortality was concentrated in the poorest quintile compared to the richest quintile. Weights larger than 4 did not increase the slope of the disparities trend. CONCLUSIONS: There is consistent evidence for a significant crossover in colorectal cancer disparity from 1980 to 2010. Trends in disparity can be accurately and readily summarized using the HD*Calc tool. The disparity trend, combined with published information on the timing of screening and treatment uptake, is concordant with the idea that introduction of medical screening and treatment leads to lower uptake in lower compared to higher SES populations and that differential uptake yields disparity in population mortality. PMID- 28083803 TI - Reducing Out-of-Pocket Costs to Coordinate Prescription Medication Benefit Design with Chronic Disease Outreach and Clinical Care. PMID- 28083801 TI - Unravelling the Lesser Known Facets of Angiotensin II Type 1 Receptor. AB - PURPOSE OF REVIEW: Hypertension is an important risk factor in various pathologies. Despite enormous advancements in health sciences, the number of hypertensive individuals is increasing worldwide. The complex interplay between genetic and epigenetic factors seems to be a promising pathway to exploring the pathophysiology of hypertension. RECENT FINDINGS: Various single gene and genome wide association studies have generated huge but non-reproducible data that highlights the role of some additional but as yet unidentified factor(s) in disease outcome. Dietary pattern and epigenetic mechanism (mainly DNA methylation) have shown a profound effect on blood pressure regulation. Angiotensin II and its receptors are known to play an important role in maintaining blood pressure; hence, a larger section of antihypertensive drugs targets the renin-angiotensin system (RAS). Angiotensin II type 1 receptor (AT1R), besides maintaining blood pressure, also has a role in cancer progression. Besides other pathways, RAS still remains the main player in blood pressure regulation. Additionally, AT1R has recently emerged as a molecule with diverse roles ranging from physiologic to cancer progression. PMID- 28083804 TI - Improved surgical procedure using intraoperative navigation for the implantation of the SPG microstimulator in patients with chronic cluster headache. AB - INTRODUCTION: The ATI SPG microstimulator is designed to be fixed on the posterior maxilla, with the integrated lead extending into the pterygopalatine fossa to electrically stimulate the sphenopalatine ganglion (SPG) as a treatment for cluster headache. Preoperative surgical planning to ensure the placement of the microstimulator in close proximity (within 5 mm) to the SPG is critical for treatment efficacy. The aim of this study was to improve the surgical procedure by navigating the initial dissection prior to implantation using a passive optical navigation system and to match the post-operative CBCT images with the preoperative treatment plan to verify the accuracy of the intraoperative placement of the microstimulator. METHODS: Custom methods and software were used that result in a 3D rotatable digitally reconstructed fluoroscopic image illustrating the patient-specific placement with the ATI SPG microstimulator. Those software tools were preoperatively integrated with the planning software of the navigation system to be used intraoperatively for navigated placement. Intraoperatively, the SPG microstimulator was implanted by completing the initial dissection with CT navigation, while the final position of the stimulator was verified by 3D CBCT. Those reconstructed images were then immediately matched with the preoperative CT scans with the digitally inserted SPG microstimulator. This method allowed for visual comparison of both CT scans and verified correct positioning of the SPG microstimulator. RESULTS: Twenty-four surgeries were performed using this new method of CT navigated assistance during SPG microstimulator implantation. Those results were compared to results of 21 patients previously implanted without the assistance of CT navigation. Using CT navigation during the initial dissection, an average distance reduction of 1.2 mm between the target point and electrode tip of the SPG microstimulator was achieved. Using the navigation software for navigated implantation and matching the preoperative planned scans with those performed post-operatively, the average distance was 2.17 mm with navigation, compared to 3.37 mm in the 28 surgeries without navigation. CONCLUSION: Results from this new procedure showed a significant reduction (p = 0.009) in the average distance from the SPG microstimulator to the desired target point. Therefore, a distinct improvement could be achieved in positioning of the SPG microstimulator through the use of intraoperative navigation during the initial dissection and by post-operative matching of pre- and post-operatively performed CBCT scans. PMID- 28083805 TI - Early Minocycline and Late FK506 Treatment Improves Survival and Alleviates Neuroinflammation, Neurodegeneration, and Behavioral Deficits in Prion-Infected Hamsters. AB - Prion infections of the central nervous system (CNS) are characterized by initial reactive gliosis followed by overt neuronal death. Gliosis is likely to be caused initially by the deposition of misfolded, proteinase K-resistant, isoforms (termed PrPSc) of the normal cellular prion protein (PrPc) in the brain. Proinflammatory cytokines and chemokines released by PrPSc-activated glia and stressed neurons may also contribute directly or indirectly to the disease development by enhancing gliosis and inducing neurotoxicity. Recent studies have illustrated that early neuroinflammation activates nuclear factor of activated T cells (NFAT) in the calcineurin signaling cascade, resulting in nuclear translocation of nuclear factor kappa B (NF-kappaB) to promote apoptosis. Hence, useful therapeutic approaches to slow down the course of prion disease development should control early inflammatory responses to suppress NFAT signaling. Here we used a hamster model of prion diseases to test, for the first time, the neuroprotective and NFAT-suppressive effect of a second-generation semisynthetic tetracycline derivative, minocycline, versus a calcineurin inhibitor, FK506, with known NFAT suppressive activity. Our results indicate that prolonged treatment with minocycline, starting from the presymptomatic stage of prion disease was more effective than FK506 given either during the presymptomatic or symptomatic stage of prion disease. Specifically, minocycline treatment reduced the expression of the astrocyte activation marker glial fibrillary acidic protein and of the microglial activation marker ionized calcium binding adapter molecule-1, subsequently reducing the level of proinflammatory cytokines interleukin 1beta and tumor necrosis factor-alpha. We further found that minocycline and FK506 treatment inhibited mitogen-activated protein kinase p38 phosphorylation and NF-kappaB nuclear translocation in a caspase-dependent manner, and enhanced phosphorylated cyclic adenosine monophosphate response element-binding protein and phosphorylated Bcl2-associated death promoter levels to reduce cognitive impairment and apoptosis. Taken together, our results indicate that minocycline is a better choice for prolonged use in prion diseases and encourage its further clinical development as a possible treatment for this disease. PMID- 28083807 TI - Redox-Switchable New Phthalocyanines Containing Hydrazono-Thiazole-Carboxylate Fragments: Synthesis, Electrochemical, Spectroelectrochemical and Electrocolorimetric Investigation. AB - New phthalonitrile compound with Schiff base, carbothioamide and thiazole moieties as substituents and its corresponding metal-free and metallophthalocyanines (Zn(II), Ni(II), Co(II), and Cu(II)) were synthesized and characterized for the first time. The solubilities of these novel phthalocyanines were high in organic solvents. The redox properties of the compounds have been researched by cyclic voltammetry, square wave voltammetry, controlled-potential coulometry and in situ spectroelectrochemistry in dimethylsulfoxide. The compounds displayed metal and/or phthalocyanine ring-based, generally reversible or quasi-reversible reduction and oxidation processes. The effect of aggregation on the redox behavior of these complexes was also discussed. In general, decreased intensity and broadening in the main Q absorption band and the appearance of a new blue-shifted band confirmed the presence of H-type aggregates in the solutions of the complexes 4, 6 and 8 in DMSO/TBAP. The color changes associated with the redox processes and electrogenerated anionic and cationic redox species were also recorded with in situ electrocolorimetric measurements. In situ UV-vis spectral and associated color changes monitored during the reduction processes of the complexes suggested their applicability in the fields of the electrochemical technologies. PMID- 28083806 TI - New Directions in Anti-Angiogenic Therapy for Glioblastoma. AB - Anti-angiogenic therapy has become an important component in the treatment of many solid tumors given the importance of adequate blood supply for tumor growth and metastasis. Despite promising preclinical data and early clinical trials, anti-angiogenic agents have failed to show a survival benefit in randomized controlled trials of patients with glioblastoma. In particular, agents targeting vascular endothelial growth factor (VEGF) appear to prolong progression free survival, possibly improve quality of life, and decrease steroid usage, yet the trials to date have demonstrated no extension of overall survival. In order to improve duration of response and convey a survival benefit, additional research is still needed to explore alternative pro-angiogenic pathways, mechanisms of resistance, combination strategies, and biomarkers to predict therapeutic response. PMID- 28083808 TI - Heat Acclimation of Bifidobacterium longum and Proteomic Changes Behind It. AB - Bifidobacterium is an important probiotic bacterium and extensively applied to functional food. Its survival is strongly affected by the heat-shock process during manufacture. Acclimation is thought to be able to enhance Bifidobacterium's resistance to heat stress; however, so far little is known about the protein expression changes underlying the adaptation process. In this study, the appropriate acclimation temperature for Bifidobacterium longum was determined as 43 degrees C, and 2-dimensional gel electrophoresis-based proteomic analysis was performed to reveal the protein changes in expression levels behind heat acclimation. Twenty proteins displayed significantly expression changes after heat acclimation, including general stress response proteins, metabolic enzymes, components of ABC transporters, transcriptional regulators, and hypothetical proteins. Two important chaperones GroEL and IbpA were found to be induced during heat acclimation, implying that they might play key roles in the heat resistance of acclimation. Although many further studies are needed to explore the complex mechanisms, this study enhances the understanding of protein changes underlying the heat acclimation of Bifidobacterium and provides important molecular clues for its future research. PMID- 28083809 TI - Effects of Dietary Bacillus licheniformis on Gut Physical Barrier, Immunity, and Reproductive Hormones of Laying Hens. AB - Previous study showed that dietary Bacillus licheniformis (B. licheniformis) administration contributes to the improvement of laying performance and egg quality in laying hens. In this study, we aimed to further evaluate its underlying mechanisms. Three hundred sixty Hy-Line Variety W-36 hens (28 weeks of age) were randomized into four groups, each group with six replications (n = 15). The control group received the basal diet and the treatment groups received the same basal diets supplemented with 0.01, 0.03, and 0.06% B. licheniformis powder (2 * 1010 cfu/g) for an 8-week trial. The results demonstrate that B. licheniformis significantly enhance the intestinal barrier functions via decreasing gut permeability, promoting mucin-2 transcription, and regulating inflammatory cytokines. The systemic immunity of layers in B. licheniformis treatment groups is improved through modulating the specific and non-specific immunity. In addition, gene expressions of hormone receptors, including estrogen receptor alpha, estrogen receptor beta, and follicle-stimulating hormone receptor, are also regulated by B. licheniformis. Meanwhile, compared with the control, B. licheniformis significantly increase gonadotropin-releasing hormone level, but markedly reduce ghrelin and inhibin secretions. Overall, our data suggest that dietary inclusion of B. licheniformis can improve the intestinal barrier function and systemic immunity and regulate reproductive hormone secretions, which contribute to better laying performance and egg quality of hens. PMID- 28083811 TI - Abstracts from HSG 2016: Discovering Our Future, the 23rd Annual Meeting of the Huntington Study Group (HSG). PMID- 28083812 TI - Effect of Dendrobium officinale on D-galactose-induced aging mice. AB - OBJECTIVE: To examine the effect of Dendrobium officinale (DO) on D-galactose induced aging mice. METHODS: Aging mice was induced by D-galactose at 0.125 g/kg for 10 weeks through subcutaneous injection except for the negative control group. After 10 days, according to complete random design, the aging modeling mice were randomized into 4 groups: aging control group (10 ML.kg-1.d-1) of distilled water), positive control group (vitamin B6 and ganodema lucidum tablets with a dose of 1 tablet/kg), DO-1 treatment group (DO juice with a dose of 1 g/kg), DO-2 treatment group (DO Polysaccharide with a dose of 0.32 g/kg), 14 mice in each group. All the animals were orally medicated daily for 9 weeks. Cognitive function assessment was performed using the maze test and step-down test. At the end of experiment, the superoxide dismutase (SOD), glutathione peroxidase (GSH Px), and total antioxidant capacity (T-AOC) levels in the serum, the SOD, GSH-Px and nitric oxide (NO) levels in the cerebrum, the SOD and catalase (CAT) levels in the liver, the SOD and NO levels in the heart, and the SOD level in the kidney, were determined using commercial kits. The spleen, liver, heart, cerebrum and kidney were excised for histological study. RESULTS: Compared to aging control group, DO shortened the time of passing through the maze and prolong the step-down latency of aging mice (P <0.05 or P<0.01). DO markedly up-regulated serum levels of SOD, GSH-Px and T-AOC, and restored SOD levels in the heart, liver, kidney and cerebrum to normal status (P<0.05 or P<0.01). DO at the dose of 1 g/kg also signififi cantly improved the degree of spleen lesions (P<0.01). CONCLUSIONS: DO had marked anti-aging effect on D-galactose-induced model of aging. The underlying mechanism could be related to modulation on antioxidation system and immune system. The results indicated that DO could potentially be used as natural drugs or functional foods for preventing aging. PMID- 28083810 TI - Comparative microarray analyses of mono(2-ethylhexyl)phthalate impacts on fat cell bioenergetics and adipokine network. AB - Cellular accumulation of mono(2-ethylhexyl)phthalate (MEHP) has been recently demonstrated to disturb fat cell energy metabolism; however, the underlying mechanism remained unclear. The study aimed to determine how MEHP influenced fat cell transcriptome and how the changes might contribute to bioenergetics. Because of the pivotal role of PPARgamma in energy metabolism of fat cells, comparative microarray analysis of gene expression in 3T3-L1 adipocytes treated with both MEHP and rosiglitazone was performed. Pathway enrichment analysis and gene ontology (GO) enrichment analysis revealed that both treatments caused up regulation of genes involved in PPAR signaling/energy metabolism-related pathways and down-regulation of genes related to adipokine/inflammation signals. MEHP/rosiglitazone-treated adipocytes exhibited increased levels of lipolysis, glucose uptake, and glycolysis; the gene expression profiles provided molecular basis for the functional changes. Moreover, MEHP was shown to induce nuclear translocation and activation of PPARgamma. The similarity in gene expression and functional changes in response to MEHP and rosiglitazone suggested that MEHP influenced bioenergetics and adipokine network mainly via PPARgamma. Importantly, adipokine levels in C57BL/6J mice with di(2-ethylhexyl)phthalate (DEHP) treatments provided in vivo evidence for microarray results. On the basis of correlation between gene expression and functional assays, possible involvements of genes in bioenergetics of MEHP-treated adipocytes were proposed. PMID- 28083813 TI - Serum Calcium Concentration in Ethylene Glycol Poisoning. AB - INTRODUCTION: The diagnosis of ethylene glycol intoxication can be challenging. Definitive testing for ethylene glycol is not readily available and clinical decisions are often based on clinical suspicion and the results of more readily available tests. One of these findings is hypocalcemia, presumable through complexation with the ethylene glycol metabolite oxalate. METHODS: We performed a retrospective review of all patients admitted to a tertiary care hospital between 2005 and 2013 with laboratory confirmed ethylene glycol intoxication. Serum calcium on presentation was compared to blood gas pH on presentation as well as presentation serum bicarbonate. RESULTS: We did not find any relationship between calcium and serum pH either by linear regression or when dichotomized by pH >= or <7.3. We did observe an inverse relationship between serum calcium and bicarbonate. CONCLUSIONS: Hypocalcemia is not commonly observed following ethylene glycol poisoning, even in acidotic patients. PMID- 28083814 TI - Use of fictional medical television in health sciences education: a systematic review. AB - While medical television programs are popular among health profession trainees, it is not clear to what extent these programs affect their knowledge, perceptions, and/or behaviors. Therefore, we conducted a systematic review of research evaluating associations between program exposure and outcomes. We conducted systematic literature searches in Pubmed, CINAHL, and PsycINFO. Selected studies were required to be scholarly research, involve exposure to fictionalized medical television programming by health professional students, and assess associations between exposure and outcomes. Studies were classified according to quality and factors related to population, exposure, and outcomes. Of 3541 studies identified, 13 met selection criteria. Six studies involved undergraduate medical students, one involved nursing students, two involved both medical and nursing students, two involved medical residents, one involved medical students, residents and attending physicians, and one involved graduate epidemiology students. Mean study quality according to the MERSQI was 8.27. The most commonly assessed television programs were ER and Grey's Anatomy (six each). Five studies assessed regular viewing habits, and found that fictional medical programs are popular among students and that students recall health topics from episodes. The eight studies that assessed the association with outcomes when using clips as educational tools reported high satisfaction and increased knowledge of the presented health topics. While relatively few published studies have explored influences of fictional medical television on health professional students, those conducted suggest that students often view these television programs independently and that integration of this programming into medical education is feasible and acceptable. PMID- 28083815 TI - Optimizing the Use of Linaclotide in Patients with Constipation-Predominant Irritable Bowel Syndrome: An Expert Consensus Report. AB - INTRODUCTION: Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by chronic or recurrent abdominal pain in association with defecation or a change in bowel habits. A predominant disorder of bowel habits, IBS is classified into three main subtypes: constipation-predominant IBS (IBS-C), diarrhea-predominant IBS (IBS-D) and IBS alternating between constipation and diarrhea (IBS-M). Linaclotide is a first-in-class, oral, once-daily guanylate cyclase-C receptor agonist (GC-CA) that is licensed for the symptomatic treatment of moderate-to-severe IBS-C in adults. This review aims to facilitate and optimize clinical practices, establishing common guidelines to monitor patients with IBS-C that are treated with linaclotide. METHODS: A group of experts in functional digestive disorders was convened to review the efficacy and safety of linaclotide and to develop an updated consensus report for the treatment of patients with IBS-C. A search was performed for English, French and Spanish language articles in PubMed. On the basis of the articles identified, an initial document was drafted addressing different issues frequently raised by general practitioners and GI specialists that are related to the prescription, efficacy and safety of linaclotide. This document was then reviewed and modified by the expert panel until a final text was agreed upon and validated. RESULTS: Based on the evidence, the panel addressed the following recommendations: (1) Linaclotide is indicated for the treatment of moderate to severe IBS-C in adults; (2) it is recommended that patients take linaclotide continuously and not sporadically; (3) patients should be warned about the risk of diarrhea and given choices concerning how to deal with this possible side effect; (4) the absence of tachyphylaxis or potential risks implies that linaclotide treatment can be maintained for long periods of time. CONCLUSIONS: This document seeks to lay down a set of recommendations and to identify key issues that may be useful for the clinical management of IBS-C patients treated with linaclotide. PMID- 28083816 TI - HAP1 Is Required for Endocytosis and Signalling of BDNF and Its Receptors in Neurons. AB - When BDNF binds to its receptors, TrkB and p75NTR, the BDNF-receptor complex is endocytosed and trafficked to the cell body for downstream signal transduction, which plays a critical role in neuronal functions. Huntingtin-associated protein 1 (HAP1) is involved in trafficking of vesicles intracellularly and also interacts with several membrane proteins including TrkB. Although it has been known that HAP1 has functions in vesicular trafficking and receptor stabilisation, it is not yet established whether HAP1 has a role in BDNF and its receptor endocytosis. In the present study, we found that HAP1 is in an interacting complex with p75NTR, TrkB and BDNF, especially newly endocytosed BDNF. BDNF and TrkB internalisation is abolished in HAP1 knock-out (KO) cortical neurons. TrkB downstream signalling pathways such as ERK, Akt and PLCgamma-1 are also impaired in HAP1 KO cortical neurons upon BDNF stimulation. Proliferation of cerebellar granule cells is also impaired in cell culture and cerebellum of HAP1 KO mice. Our findings suggest that HAP1 may play a key role in BDNF and its receptor endocytosis and may promote neuronal survival and proliferation. PMID- 28083817 TI - Carnosic Acid Induces Anti-Inflammatory Effects in Paraquat-Treated SH-SY5Y Cells Through a Mechanism Involving a Crosstalk Between the Nrf2/HO-1 Axis and NF kappaB. AB - Carnosic acid (CA) is a phenolic diterpene obtained from Rosmarinus officinalis L. and has demonstrated cytoprotective properties in several experimental models. CA exerts antioxidant effects by upregulating the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which controls the expression of antioxidant and phase II detoxification enzymes. Heme oxygenase-1 (HO-1) expression is modulated by Nrf2 and has been demonstrated as part of the mechanism underlying the CA-induced cytoprotection. Nonetheless, it remains to be studied whether and how HO-1 would mediate CA-elicited anti-inflammatory effects. Therefore, we have investigated here whether and how CA would prevent paraquat (PQ)-induced inflammation-related alterations in human neuroblastoma SH-SY5Y cells. SH-SY5Y cells were pretreated for 12 h with CA at 1 MUM before exposure to PQ for further 24 h. CA suppressed the PQ-induced alterations on the levels of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and cyclooxygenase-2 (COX-2) through a mechanism involving the activation of the Nrf2/HO-1 axis. Furthermore, we observed a crosstalk between the Nrf2/HO-1 signaling pathway and the activation of the nuclear factor-kappaB (NF-kappaB) transcription factor, since administration of ZnPP IX (specific inhibitor of HO 1) or Nrf2 knockdown using small interfering RNA (siRNA) abolished the anti inflammatory effects induced by CA. Moreover, administration of SN50 (specific inhibitor of NF-kappaB) inhibited the PQ-induced inflammation-related effects in SH-SY5Y cells. Therefore, CA exerted anti-inflammatory effects in SH-SY5Y cells through an Nrf2/HO-1 axis-dependent manner associated with downregulation of NF kappaB. PMID- 28083818 TI - Ferulic Acid Improves Cognitive Skills Through the Activation of the Heme Oxygenase System in the Rat. AB - Over the last years, many studies reported on the antioxidant effects of ferulic acid (FA) in preclinical models of dementia through the activation of the heme oxygenase/biliverdin reductase (HO/BVR) system. However, only a few studies evaluated whether FA could improve neurological function under milder conditions, such as psychological stress. The aim of this study was to investigate the effects of FA (150 mg/kg intraperitoneal route) on cognitive function in male Wistar rats exposed to emotional arousal. Animals were randomly assigned to two experimental groups, namely not habituated or habituated to the experimental context, and the novel object recognition test was used to evaluate their cognitive performance. The administration of FA significantly increased long-term retention memory in not habituated rats. Ferulic acid increased the expression of HO-1 in the hippocampus and frontal cortex of not habituated rats only, whereas HO-2 resulted differently modulated in these cognitive brain areas. No significant effects on either HO-1 or HO-2 or BVR were observed in the cerebellum of both habituated and not habituated rats. Ferulic acid activated the stress axis in not habituated rats, as shown by the increase in hypothalamic corticotrophin-releasing hormone levels. Pre-treatment with Sn-protoporphyrin-IX [0.25 MUmol/kg, intracerebroventricular route (i.c.v.)], a well-known inhibitor of HO activity through which carbon monoxide (CO) and biliverdin (BV) are generated, abolished the FA-induced improvement of cognitive performance only in not habituated rats, suggesting a role for HO-derived by-products. The CO-donor tricarbonyldichlororuthenium (II) (30 nmol/kg i.c.v.) mimicked the FA-related improvement of cognitive skills only in not habituated rats, whereas BV did not have any effect in any group. In conclusion, these results set the stage for subsequent studies on the neuropharmacological action of FA under conditions of psychological stress. PMID- 28083819 TI - Abnormal Expression of MicroRNAs Induced by Chronic Unpredictable Mild Stress in Rat Hippocampal Tissues. AB - Previous research has demonstrated that the behaviors observed in chronic unpredictable mild stressed (CUMS) rats are similar to the symptoms of depressed patients and that the abnormal expression of cerebral microRNAs is associated with depressive disorder. However, little is known regarding the expression profile of microRNAs induced by CUMS. In this study, we aimed to examine the hippocampal microRNA expression profile in CUMS rats. Forty adolescent male Sprague-Dawley rats were randomly divided into normal and model groups. The rats in the model group were stimulated daily with randomly applied mild stressors from among 14 different mild stressors. The stressors were changed every day and were applied for 35 consecutive days. On the 28th and 35th days after treatment, the weights, physical condition, sucrose preference, and open-field test scores of the rats of the two groups were evaluated. Successful induction of CUMS was considered if the differences of the above metrics between the two groups were statistically significant on the 28th and 35th days after treatment. Cerebral sucrose metabolism images of rats were obtained by 18F-FDG PET/CT. The rats were euthanized under anesthesia, and hippocampal tissues were collected for hematoxylin-eosin (HE) staining. In addition, the samples were used for microRNA array chip and qRT-PCR analysis. The target genes of different microRNAs were predicted using bioinformatic analysis, and the functions and signal pathways of these target genes were investigated by GO and KEGG analyses. Sixteen rats exhibited successful induction of CUMS. Cerebral 18F-FDG PET/CT imaging showed that the glucose metabolism rate of CUMS rats were significantly lower than normal rats in the central nucleus of the inferior colliculus (CIC, p = 0.022), the retrosplenial agranular area (RSA, p = 0.002), the second sensory cortex (S2, p = 0.028), the first auditory cortex (Au1, p = 0.012), the primary somatosensory cortex, barrel field (SIBF, p = 0.001), and the ventral posteromedial nucleus (VPM) of the right thalamus (p = 0.048). HE staining showed that hippocampal pyramidal cells CUMS rats were thinner, disordered, and exhibited irregular shapes, with many pyknotic cells. The microarray chip and qRT-PCR analysis revealed that five microRNAs were significantly up-regulated [miR-382-3p (p = 0.026), miR-183-5p (p = 0.018), miR-3573-5p (p = 0.042), miR-202-3p (p = 0.016), miR-493-3p (p = 0.009)], and only miR-370-3p was significantly down-regulated (p = 0.036). miRNA target gene prediction and functional annotation analysis showed significant enrichment in several GO terms and pathways associated with depression. Our findings provide supportive evidence for the abnormal expression of multiple CUMS-induced hippocampal microRNAs in rats as well as the involvement of these microRNAs in depressive disorder. PMID- 28083820 TI - Recurrence outcomes after omission of postoperative radiotherapy following breast conserving surgery for ductal carcinoma in situ of the breast: a multicenter, retrospective study in Korea (KROG 16-02). AB - PURPOSE: To evaluate the loco-regional recurrence (LRR) rate after breast conserving surgery without postoperative radiotherapy (RT) for ductal carcinoma in situ (DCIS) of the breast. METHODS: Between 2000 and 2010, 311 DCIS patients from 9 institutions were analyzed retrospectively. The median age was 47 (range, 20-82). The median tumor size was 7 mm (range, 0.01-76). Margin width was <1 cm in 85 patients (27.3%), and nuclear grade was high in 37 patients (11.9%). Two hundred and three patients (65.3%) received tamoxifen. RESULTS: With a median follow-up of 74 months (range, 5-189), there were 11 local recurrences (invasive carcinoma in 6 and DCIS in 5) and 1 regional recurrence. The 7-year LRR rate was 3.8%. On univariate analysis, age and margin width were significant risk factors influencing LRR (p = 0.017 and 0.014, respectively). When age and margin width were combined among 211 patients whose margin width were available, the 7-year LRR rates were as follows (p < 0.001): (1) 0% in patients with age >50 years and any margin width status (n = 64), (2) 1.2% in age <=50 years and margin width >=1 cm (n = 93), (3) 13.1% in age <=50 years and margin width <1 cm (n = 54). CONCLUSIONS: The LRR rate was very low in selected DCIS patients treated with breast-conserving surgery without postoperative RT. However, adjuvant RT should be considered for those with age <=50 years and margin width <1 cm. PMID- 28083821 TI - Surgical treatment of secondary lymphedema of the upper limb by stepped microsurgical lymphaticovenous anastomoses. AB - OBJECTIVE: The incidence of lymphedema following treatment for breast cancer ranges between 10 and 50% after complete axillary dissection and gives rise to severe functional discomfort in patients. Results of lymphaticovenous anastomoses (LVA) in surgical treatment of lymphedema appear to be favorable. However, the available literature on this topic is scarce, often with short follow-up times. The aim of this study is to analyze the results of LVA on 31 patients and to review the existing literature. PATIENTS AND METHODS: This study comprised 31 female patients presenting lymphedema of the upper limb following treatment for breast cancer for which surgical treatment was given by microsurgery consisting of three stepped LVA performed in an outpatient setting. RESULTS: The post-LVA arm circumference was measured at three levels (wrist, forearm, and arm) in 31 female patients. Mean follow-up time was 12.8 months. Reduction in the circumference was 22.5, 21.32, and 30.2%, respectively, in the wrist, forearm, and arm. Functional improvement was observed in the majority (84%) of patients ranging from moderate to substantial. Only 2 patients had no result. The only patients to experience recurrence were those with a high level of lymphedema. CONCLUSION: The review of the current literature and the present study revealed modest results in terms of decreased excess volume, although a major improvement in function points to LVA as a useful technique in this indication. Progress in imaging techniques has enhanced the results achieved with this procedure, although further studies on recurrence rates are needed with a follow-up greater than 1 year. PMID- 28083822 TI - Diagnostic performance of tomosynthesis and breast ultrasonography in women with dense breasts: a prospective comparison study. AB - PURPOSE: To compare the diagnostic performances of tomosynthesis and ultrasonography as adjunctives to digital mammography in women with dense breasts. METHODS: A total of 778 women with dense breasts underwent digital mammography with tomosynthesis and ultrasonography for screening and diagnostic purposes. The findings of tomosynthesis and ultrasonography were evaluated independently. The primary endpoint was overall diagnostic accuracy determined by area under the receiver operating characteristic curve (AUC). Secondary endpoints included sensitivity, specificity, and predictive values. RESULTS: Of the 778 participants, 698 women (140 breast cancers) were included in the analysis. Based on the AUC findings, the non-inferiority of tomosynthesis to ultrasonography was established in the overall group as well as in all subgroups except for that comprising women with extremely dense breast composition. There were no significant differences in AUC between tomosynthesis and ultrasonography among asymptomatic participants and participants who underwent imaging for screening (0.912 vs. 0.934 [P = 0.403] and 0.987 vs. 0.950 [P = 0.270], respectively). Tomosynthesis exhibited lower sensitivity (91.4 vs. 96.4%; P = 0.039), and higher specificity (83.9 vs. 70.4%; P < 0.001) and positive predictive value (58.7 vs. 45.0%; P < 0.001) than ultrasonography. CONCLUSIONS: Tomosynthesis exhibits comparable performance to ultrasonography as an adjunct to mammography for diagnosis of breast cancer, except among women with extremely dense breasts. PMID- 28083823 TI - Fluoride: changes in knowledge and prescription habits of paediatricians for 11 years in Brittany, France. AB - AIMS: To assess via a questionnaire the changes in knowledge and prescription habits for systemic fluoride of physicians at maternal and infant protection centres (MIP) and paediatricians in private practice (PPP) in the Brittany region between 2003 and 2014. METHODS: In both 2003 and 2014, the same seven-question survey was mailed to PPP (110 in 2003 and 101 in 2014) and MIP (61 in 2003 and 71 in 2014). An eighth question was added in 2014 about French guidelines published in 2008 (AFSSAPS guidelines). RESULTS: The overall response rate was significantly higher in 2003 (69.0%) than in 2014 (54.7%). In 2014 systemic fluoride was still considered an effective means of caries prevention (79.8% vs. 98.7% in 2003) and systematic prescription of fluoride supplements was less common (39.4 vs. 87.0% in 2003). When prescribed, systemic fluoride was given after the first 6 months of a child's life in 2014 (79.8%) instead of within the first month of life (73.5%) in 2003. CONCLUSIONS: Paediatricians and MIP physicians in Brittany were significantly less prone to routinely prescribe systemic fluoride in 2014. Certain sources of fluoride were still not well known in 2014. Collaboration and information sharing between dentists and physicians is necessary. PMID- 28083824 TI - Impact of food craving and calorie intake on body mass index (BMI) changes during an 18-month behavioral weight loss trial. AB - The purpose of this study was to explore relations between food craving, caloric intake, and body mass index (BMI) changes over the course of an 18-month weight loss trial. Two-hundred two obese adults (mean BMI = 34.9 kg/m2; mean age = 51.30 years, 92.2% White; 57.8% female) who participated in a behavioral weight loss trial completed measures of food craving, caloric intake, and BMI at baseline, 6 and 18 months. From baseline to 6 months, higher initial food cravings were associated with more gradual and less steep reductions in BMI. Additionally, the relation between changes in food craving and BMI changes varied by levels of change in caloric intake, such that BMI change and change in food cravings were positively associated at low levels of change in caloric intake, but were unrelated at average and high levels of change in caloric intake. Similarly, from baseline to 6 months and from 6 to 18 months, the relation between changes in food craving and BMI changes also varied by initial levels of caloric intake. Explicit clinical targeting of food craving management may be beneficial for individuals beginning weight loss programs, especially for those who report higher levels of food craving at baseline. Baseline caloric intake and change in calorie intake over time may serve as moderators of the relation between food cravings and BMI. PMID- 28083825 TI - Radiosynthesis and Preclinical Evaluation of [18F]F-DPA, A Novel Pyrazolo[1,5a]pyrimidine Acetamide TSPO Radioligand, in Healthy Sprague Dawley Rats. AB - PURPOSE: Many neurological conditions result in the overexpression of the translocator protein 18 kDa (TSPO), today recognized as a biomarker for microglial activation and neuroinflammation imaging. The pyrazolo[1,5 a]pyrimidine acetamides are a particularly attractive class of TSPO-specific ligands, prompting the development of several positron emission tomography (PET) radiotracers. This includes F-DPA, a recently reported fluorinated ligand (K i = 1.7 nM), wherein the fluorine atom is directly linked to the phenyl moiety without the presence of an alkyl or alkoxy spacer chain. Reported here is the preparation of [18F]F-DPA using [18F]Selectfluor bis(triflate) and the preliminary evaluation of [18F]F-DPA in healthy rats. Its metabolic profile and biodistribution in rats are compared with that of [18F]DPA-714, a closely related structure. PROCEDURES: [18F]F-DPA was synthesized by electrophilic fluorination using [18F]Selectfluor bis(triflate), [18F]DPA-714 was synthesized by conventional nucleophilic fluorination. The biodistribution of both radiotracers was compared in Sprague Dawley rats. Radiometabolites of both radiotracers in plasma and brain homogenates were analyzed by radioTLC. RESULTS: The radiochemical yield of [18F]F-DPA was 15 +/- 3 % and the specific activity was 7.8 +/- 0.4 GBq/MUmol. The radiochemical purity exceeded 99 %. The in vivo time activity curves of [18F]F-DPA demonstrate rapid entry into the brain and a concentration equilibrium at 20-30 min after injection. The metabolic profiles at 90 min after radiotracer injection in the plasma show that unchanged [18F]F-DPA and [18F]DPA-714 account for 28.3 +/- 6.4 and 11.1 +/- 2.6 % of the remaining radioactivity, respectively. In the brain, unchanged [18F]F-DPA accounts for 93.5 +/- 2.8 % of the radioactivity; whereas for [18F]DPA-714, this value is 53.6 +/- 1.6 %. CONCLUSIONS: [18F]Selectfluor bis(triflate) was successfully used to label F-DPA with fluorine-18. The labeling position on the aromatic moiety imparts a higher stability compared to [18F]DPA-714 with regard to in vivo metabolism. [18F]F-DPA is a promising new radiotracer and warrants further investigation in animal models of disease. PMID- 28083826 TI - Development of a Reference Image Collection Library for Histopathology Image Processing, Analysis and Decision Support Systems Research. AB - Histopathology image processing, analysis and computer-aided diagnosis have been shown as effective assisting tools towards reliable and intra-/inter-observer invariant decisions in traditional pathology. Especially for cancer patients, decisions need to be as accurate as possible in order to increase the probability of optimal treatment planning. In this study, we propose a new image collection library (HICL-Histology Image Collection Library) comprising 3831 histological images of three different diseases, for fostering research in histopathology image processing, analysis and computer-aided diagnosis. Raw data comprised 93, 116 and 55 cases of brain, breast and laryngeal cancer respectively collected from the archives of the University Hospital of Patras, Greece. The 3831 images were generated from the most representative regions of the pathology, specified by an experienced histopathologist. The HICL Image Collection is free for access under an academic license at http://medisp.bme.teiath.gr/hicl/ . Potential exploitations of the proposed library may span over a board spectrum, such as in image processing to improve visualization, in segmentation for nuclei detection, in decision support systems for second opinion consultations, in statistical analysis for investigation of potential correlations between clinical annotations and imaging findings and, generally, in fostering research on histopathology image processing and analysis. To the best of our knowledge, the HICL constitutes the first attempt towards creation of a reference image collection library in the field of traditional histopathology, publicly and freely available to the scientific community. PMID- 28083827 TI - Detection and Labeling of Vertebrae in MR Images Using Deep Learning with Clinical Annotations as Training Data. AB - The purpose of this study was to investigate the potential of using clinically provided spine label annotations stored in a single institution image archive as training data for deep learning-based vertebral detection and labeling pipelines. Lumbar and cervical magnetic resonance imaging cases with annotated spine labels were identified and exported from an image archive. Two separate pipelines were configured and trained for lumbar and cervical cases respectively, using the same setup with convolutional neural networks for detection and parts-based graphical models to label the vertebrae. The detection sensitivity, precision and accuracy rates ranged between 99.1-99.8, 99.6-100, and 98.8-99.8% respectively, the average localization error ranges were 1.18-1.24 and 2.38-2.60 mm for cervical and lumbar cases respectively, and with a labeling accuracy of 96.0-97.0%. Failed labeling results typically involved failed S1 detections or missed vertebrae that were not fully visible on the image. These results show that clinically annotated image data from one image archive is sufficient to train a deep learning-based pipeline for accurate detection and labeling of MR images depicting the spine. Further, these results support using deep learning to assist radiologists in their work by providing highly accurate labels that only require rapid confirmation. PMID- 28083828 TI - Educational Material for 3D Visualization of Spine Procedures: Methods for Creation and Dissemination. AB - Spine anatomy can be difficult to master and is essential for performing spine procedures. We sought to utilize the rapidly expanding field of 3D technology to create freely available, interactive educational materials for spine procedures. Our secondary goal was to convey lessons learned about 3D modeling and printing. This project involved two parallel processes: the creation of 3D-printed physical models and interactive digital models. We segmented illustrative CT studies of the lumbar and cervical spine to create 3D models and then printed them using a consumer 3D printer and a professional 3D printing service. We also included downloadable versions of the models in an interactive eBook and platform independent web viewer. We then provided these educational materials to residents with a pretest and posttest to assess efficacy. The "Spine Procedures in 3D" eBook has been downloaded 71 times as of October 5, 2016. All models used in the book are available for download and printing. Regarding test results, the mean exam score improved from 70 to 86%, with the most dramatic improvement seen in the least experienced trainees. Participants reported increased confidence in performing lumbar punctures after exposure to the material. We demonstrate the value of 3D models, both digital and printed, in learning spine procedures. Moreover, 3D printing and modeling is a rapidly expanding field with a large potential role for radiologists. We have detailed our process for creating and sharing 3D educational materials in the hopes of motivating and enabling similar projects. PMID- 28083829 TI - Inpatient Complexity in Radiology-a Practical Application of the Case Mix Index Metric. AB - With ongoing healthcare payment reforms in the USA, radiology is moving from its current state of a revenue generating department to a new reality of a cost center. Under bundled payment methods, radiology does not get reimbursed for each and every inpatient procedure, but rather, the hospital gets reimbursed for the entire hospital stay under an applicable diagnosis-related group code. The hospital case mix index (CMI) metric, as defined by the Centers for Medicare and Medicaid Services, has a significant impact on how much hospitals get reimbursed for an inpatient stay. Oftentimes, patients with the highest disease acuity are treated in tertiary care radiology departments. Therefore, the average hospital CMI based on the entire inpatient population may not be adequate to determine department-level resource utilization, such as the number of technologists and nurses, as case length and staffing intensity gets quite high for sicker patients. In this study, we determine CMI for the overall radiology department in a tertiary care setting based on inpatients undergoing radiology procedures. Between April and September 2015, CMI for radiology was 1.93. With an average of 2.81, interventional neuroradiology had the highest CMI out of the ten radiology sections. CMI was consistently higher across seven of the radiology sections than the average hospital CMI of 1.81. Our results suggest that inpatients undergoing radiology procedures were on average more complex in this hospital setting during the time period considered. This finding is relevant for accurate calculation of labor analytics and other predictive resource utilization tools. PMID- 28083830 TI - Comparative efficiency of exercise stress testing with and without stress-only myocardial perfusion imaging in patients with low-risk chest pain. AB - OBJECTIVES: To compare major adverse cardiac event (MACE), downstream resource utilization, and direct cost of care for low-risk chest pain patients observed in the clinical decision unit (CDU) with exercise treadmill testing (ETT) and with stress-only myocardial perfusion imaging (sMPI). BACKGROUND: CDUs are poised to increase efficiency and resource utilization. However, the optimal testing strategy that would assure favorable outcomes while decreasing cost is not defined. METHODS: 1016 subjects from 2 locations were propensity score-matched (PSM) by age, gender, pre-test likelihood, Duke treadmill score, and test results. Outcomes were length of stay >24 hours, MACE (acute coronary syndrome, revascularization, cardiac death), downstream resource use (admission for chest pain, repeat testing, angiography), and mean direct cost per patient. RESULTS: PSM yielded 680 patients (340 matches). 98% of all tests were normal. 96.6% of patients were discharged from the CDU within 24 hours but twice as many exceeded 24 hours in the sMPI group. There were no cardiac deaths. MACE rate was 1.47% at 72 hours and 1% at 1 year. Downstream resource use was 4.82% at 72 hours, and 7.69% at 1 year. The sMPI group was event-free longer than the ETT group reflecting less repeat testing. The mean direct cost was 30% higher for sMPI ($3168.70) vs. ETT ($2226.96). CONCLUSION: Low-risk chest pain patients in the observation unit had low MACE rate, not different for ETT vs. sMPI. The majority of ETT and sMPI tests were normal. The sMPI reduced additional testing, but resulted in greater expense and longer stay. PMID- 28083831 TI - Left ventricular eccentricity index measured with SPECT myocardial perfusion imaging: An additional parameter of adverse cardiac remodeling. AB - BACKGROUND: Single-photon emission computed-tomography (SPECT) allows the quantification of LV eccentricity index (EI), a measure of cardiac remodeling. We sought to evaluate the feasibility of EI measurement with SPECT myocardial perfusion imaging and its interactions with relevant LV functional and structural parameters. METHODS AND RESULTS: Four-hundred and fifty-six patients underwent myocardial perfusion imaging on a Cadmium-Zinc-Telluride (CZT) camera. The summed rest, stress, and difference scores were calculated. From rest images, the LV end diastolic (EDV) and end-systolic volumes, ejection fraction (EF), and peak filling rate (PFR) were calculated. In every patient, the EI, ranging from 0 (sphere) to 1 (line), was computed using a dedicated software (QGS/QPS; Cedars Sinai Medical Center). Three-hundred and thirty-eight/456 (74%) patients showed a normal EF (>50%), while 26% had LV systolic dysfunction. The EI was computed from CZT images with excellent reproducibility (interclass correlation coefficient: 0.99, 95% CI 0.98-0.99). More impaired EI values correlated with the presence of a more abnormal LV perfusion (P < .001), function (EF and PFR, P < .001), and structure (EDV, P < .001). On multivariate analysis, higher EDV (P < .001) and depressed EF (P = .014) values were independent predictors of abnormal EI. CONCLUSIONS: The evaluation of LV eccentricity is feasible on gated CZT images. Abnormal EI associates with significant cardiac structural and functional abnormalities. PMID- 28083832 TI - Identification of Key Beliefs Explaining Male Circumcision Motivation Among Adolescent Boys in Zimbabwe: Targets for Behavior Change Communication. AB - Male circumcision (MC) significantly reduces HIV acquisition among men, leading WHO/UNAIDS to recommend high HIV and low MC prevalence countries circumcise 80% of adolescents and men age 15-49. Despite significant investment to increase MC capacity only 27% of the goal has been achieved in Zimbabwe. To increase adoption, research to create evidence-based messages is greatly needed. The Integrated Behavioral Model (IBM) was used to investigate factors affecting MC motivation among adolescents. Based on qualitative elicitation study results a survey was designed and administered to a representative sample of 802 adolescent boys aged 13-17 in two urban and two rural areas in Zimbabwe. Multiple regression analysis found all six IBM constructs (2 attitude, 2 social influence, 2 personal agency) significantly explained MC intention (R2 = 0.55). Stepwise regression analysis of beliefs underlying each IBM belief-based construct found 9 behavioral, 6 injunctive norm, 2 descriptive norm, 5 efficacy, and 8 control beliefs significantly explained MC intention. A final stepwise regression of all the significant IBM construct beliefs identified 12 key beliefs best explaining intention. Similar analyses were carried out with subgroups of adolescents by urban-rural and age. Different sets of behavioral, normative, efficacy, and control beliefs were significant for each sub-group. This study demonstrates the application of theory-driven research to identify evidence-based targets for the design of effective MC messages for interventions to increase adolescents' motivation. Incorporating these findings into communication campaigns is likely to improve demand for MC. PMID- 28083833 TI - Integrating HIV Prevention and Relationship Education for Young Same-Sex Male Couples: A Pilot Trial of the 2GETHER Intervention. AB - Young men who have sex with men are at high risk for HIV, and most new HIV infections occur in serious relationships. This pilot study assessed the feasibility, acceptability and preliminary efficacy of the 2GETHER couples-based HIV prevention and relationship education intervention for young same-sex male couples. We enrolled 57 young male couples (N = 114) into a four-session hybrid group and individual intervention. We assessed acceptability via post-session surveys and exit interviews, and we examined preliminary efficacy at a two week posttest. The vast majority of participants (93%) reported exclusively positive impressions of 2GETHER, and all components received high mean ratings. We observed decreases in HIV risk behavior, increases in information, motivation and behavioral skills related to HIV prevention, and improvement in relationship investment between pretest and posttest. Integrating relationship education and sexual health programming may be an effective way to reduce HIV transmissions in young male couples. PMID- 28083834 TI - Generation and characterization of a potentially applicable Vero cell line constitutively expressing the Schmallenberg virus nucleocapsid protein. AB - Schmallenberg virus (SBV) is a Culicoides-transmitted orthobunyavirus that poses a threat to susceptible livestock species such as cattle, sheep and goats. The nucleocapsid (N) protein of SBV is an ideal diagnostic antigen for the detection of viral infection. In this study, a stable Vero cell line, Vero-EGFP-SBV-N, constitutively expressing the SBV-N protein was established using a lentivirus system combined with puromycin selection. This cell line spontaneously emitted green fluorescent signals distributed throughout the cytoplasm, in which the expression of SBV-N fusion protein was confirmed by western blot analysis. The expression of SBV-N protein in Vero-EGFP-SBV-N cells was stable for more than fifty passages without puromycin pressure. The SBV-N fusion protein contained both an N-terminal enhanced green fluorescent protein (EGFP) tag and a C-terminal hexa-histidine (6 * His) tag, by which the N protein was successfully purified using Ni-NTA affinity chromatography. The cell line was further demonstrated to be reactive with SBV antisera and an anti-SBV monoclonal antibody in indirect immunofluorescence assays. Taken together, our results demonstrate that the Vero EGFP-SBV-N cell line has potential for application in the serological diagnosis of SBV infection. PMID- 28083835 TI - Which Abdominal Symptoms are Associated with Clinical Events in a Population Unaware of Their Gallstones? a Cohort Study. AB - BACKGROUND: High rates of persistent symptoms are found following cholecystectomy in patients with gallstones. The aim of this population based cohort study was to determine which symptoms were associated with the development of clinical gallstone events in a population unaware of their gallstones. MATERIAL AND METHODS: Three random population samples from Copenhagen (N = 6037) were examined with ultrasound during 1982-1994. Participants were not informed about gallstone status. Abdominal symptoms were assessed at baseline through a questionnaire. Follow-up for clinical events was performed through central registers until 2011. Multivariable Cox regression analyses were performed. RESULTS: Participants unaware of their gallstones (N = 595) were followed for median 17.5 years. A total of 16.6% participants developed clinical events. Both uncomplicated and complicated events were associated with high pain intensity at baseline. Complicated events were also associated with pain at night. Uncomplicated events were associated with pain localized in the epigastrium, of longer duration, and in need of pain medication. No associations were identified for dyspepsia or irritable bowel syndrome. CONCLUSIONS: In a population of unaware gallstone carriers, it was possible to identify abdominal symptoms associated with later clinical detection of the gallstones. These finding may contribute to a better selection of patients for surgery. PMID- 28083836 TI - Hand-Assisted Laparoscopic Colectomy Improves Perioperative Outcomes Without Increasing Operative Time Compared to the Open Approach: a National Analysis of 8791 Patients. AB - INTRODUCTION: Hand-assisted laparoscopic surgery (HALS) is often used in procedures too complex for completely minimally invasive approaches. However, there are concerns for whether this hybrid approach abrogates perioperative benefits of the completely minimally invasive technique. METHODS: We queried the 2012-2013 National Surgery Quality Improvement Program for adults undergoing elective HALS or open colectomy (OC). After propensity matching, short-term outcomes were compared. Subset analysis was performed for segmental resections. Multivariate analysis was used to determine predictors of utilizing either approach. RESULTS: This query included 8791 patients (OC 2707, HALS 6084). Predictors of HALS included male sex (OR 1.17, p = 0.006), increasing BMI (OR 1.01, p = 0.02), benign indication (OR 1.48, p < 0.001), and total abdominal colectomy (OR 10.39, p < 0.001). Younger age, black race, ASA class >=3, inflammatory bowel disease, and low pelvic anastomosis were predictive of OC (all p < 0.05). HALS demonstrated reduced overall complications (p < 0.001), wound complications (p < 0.001), anastomotic leak (p = 0.014), transfusion (p < 0.001), postoperative ileus (p < 0.001), length of stay (p < 0.001), and readmission (p < 0.001) without increased operative time. For segmental resection, HALS demonstrated reduced overall complications, wound complications, respiratory complications, postoperative ileus, anastomotic leak, transfusion, length of stay, and readmissions (all p < 0.05). CONCLUSIONS: Compared to OC, HALS demonstrates improved perioperative outcomes without increased operative time. PMID- 28083837 TI - Kinetic Changes in Liver Parenchyma After Preoperative Chemotherapy for Patients with Colorectal Liver Metastases. AB - BACKGROUND: Total liver volume (TLV) empirically changes after aggressive preoperative chemotherapy for colorectal liver metastases (CLM). However, the actual degree of changes in normal liver parenchyma and its clinical relevance remain unclear. METHODS: Morphometric data of 110 patients who underwent initial hepatectomy after preoperative chemotherapy were reviewed. TLVs before and after chemotherapy were measured using a computer-based volumetry software and their relevance to clinical factors was investigated. RESULTS: More than 10% of decrease in TLV was observed in 42 (38.2%) patients, and more than 10% of increase was observed in 11 (10.0%) patients. Change in TLV was within 10% in the remaining 57 (51.8%) patients. Indocyanine green retention rate at 15 min (ICG R15) value was significantly higher in patients with TLV decrease more than 10% (13.4 vs. 9.3 vs. 8.5%; p = 0.004). Steatosis in the underlying liver was significantly frequent in patients with TLV increase more than 10% (p < 0.001). Multivariate logistic regression analysis revealed that more than 10% of shrinkage in TLV after chemotherapy was independently associated with ICG-R15 >15% (odds ratio 8.8; p = 0.0001). Tendency of correlation was confirmed in the kinetic changes in TLV and ICG-R15 during chemotherapy even though there was no statistical significance (r = -0.33, p = 0.080). CONCLUSION: Perichemotherapy kinetic changes in TLV may predict histopathologic changes or changes in hepatic functional reserve in the underlying liver. More than 10% of shrinkage in TLV is associated with impaired hepatic functional reserve, and it can be a new supplemental finding in the prediction of surgical risk of major hepatectomy for CLM. PMID- 28083838 TI - Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios can Predict Treatment Response to Neoadjuvant Therapy in Esophageal Cancer. AB - INTRODUCTION: We hypothesized that serum neutrophil-to-lymphocyte and platelet-to lymphocyte ratios may predict pathologic complete response to neoadjuvant chemoradiotherapy in esophageal cancer patients. The ability to predict favorable treatment response to therapy may aid in determining optimal treatment regimens. MATERIALS AND METHODS: A retrospective review of a prospective esophageal disease registry was conducted. Neutrophil-to-lymphocyte ratio was defined as the pre chemoradiotherapy serum neutrophil count divided by lymphocyte count. Platelet-to lymphocyte ratio was similarly defined. Logistic regression was applied to analyze these ratios and their effect on pathologic complete response. A Cox proportional-hazards model was used to analyze survival. RESULTS: Sixty patients were included. Elevated neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio were both negative predictors of pathologic complete response (odds ratio: 0.62; 95% confidence interval: 0.37-0.89, P = 0.037 and odds ratio: 0.91; 95% confidence interval: 0.82-0.98, P = 0.028, respectively). Only platelet-to lymphocyte ratio was predictive of decreased overall survival (hazard ratio: 1.05, 95% confidence interval: 0.94-1.16, P = 0.40). CONCLUSION: Elevated neutrophil and platelet-to-lymphocyte ratios were significant predictors of a poor treatment response to neoadjuvant therapy. Only elevated platelet-to lymphocyte ratio was predictive of worse overall survival. Neutrophil-to lymphocyte and platelet-to-lymphocyte ratios may offer a simple serum test to assess the likelihood of a pathologic complete response after neoadjuvant therapy in esophageal cancer. PMID- 28083839 TI - Chronic Gastrointestinal Dysmotility and Pain Following Total Pancreatectomy with Islet Autotransplantation for Chronic Pancreatitis. AB - BACKGROUND: The prevalence and impact of chronic gastrointestinal dysmotility following total pancreactectomy with islet autotransplantation (TP-IAT) for chronic pancreatitis is not known. METHODS: A cross-sectional study of all patients who underwent TP-IAT at our institution from August 2011 to November 2015 was undertaken. The GCSI (Gastroparesis Cardinal Symptom Index), PAGI-SYM (Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index), PAC-SYM (Patient Assessment of Constipation Symptoms), Bristol stool chart, 12 item Short Form Health Survey (SF-12), and visual analog scale for pain were administered >=4 weeks following TP-IAT. KEY RESULTS: The prevalence of any dysmotility symptoms in patients who completed the survey (33/45, 73%) post-TP IAT was 45%. Post-TP-IAT, the mean reduction in opioid dosing was 77.6 oral morphine equivalents (OMEs) (95% CI 32.1-123.0, p = 0.002) with 42% of patients requiring no opioids. There was significant negative correlation between dysmotility scores and SF-12 physical scores (r = -0.46, p = 0.008, 95% CI -0.70 to -0.13). Self-reported abdominal pain had significant negative correlation with both physical and mental SF-12 scores (r = -0.67, p < 0.001, 95% CI -0.83 to 0.41 and r = -0.39, p = 0.03, 95% CI -0.65 to -0.04). There was no correlation between gastrointestinal dysmotility and self-reported pain. CONCLUSIONS AND INFERENCES: Symptoms of chronic gastrointestinal dysmotility and chronic abdominal pain are common post-TP-IAT and will need to be better recognized and differentiated to improve the management of these patients. PMID- 28083840 TI - Effect of Age (over 75 Years) on Postoperative Complications and Survival in Patients Undergoing Hepatic Resection for Hepatocellular Carcinoma. AB - BACKGROUND: Thanks to technical advancement in surgery for hepatocellular carcinoma (HCC), hepatic resection (HR) for elderly HCC patients has become safer. However, elderly patients may have shorter long-term survival after surgery if compared with younger patients because of their expected life span. The aim of the present study was to evaluate clinical outcomes and safety after HR in HCC patients aged >75 years (older) compared with HCC patients aged <75 years (younger). METHOD: One hundred sixty-eight patients who underwent HR for HCC from 1998 to 2015 in our Center were analyzed using a prospective database. Complications, disease-free survival rates, and cumulative survival rates were compared between the two groups. RESULTS: During the immediate postoperative period, no differences were found about liver-related complications, hospital stay and 90-day mortality. However, older patients had more complications in class II or higher (Clavien classification) (p = 0.017). Although disease-free survival in both groups was similar (p = 0.099), overall survival was worse in the elderly group (p = 0.024). On multivariate analysis, only age >=75 years was significantly related to overall survival. CONCLUSION: If elderly patients with liver cirrhosis and HCC are appropriately selected and evaluated, they might have favorable prognoses after HR. PMID- 28083841 TI - Emergent Colectomy Is Independently Associated with Decreased Long-Term Overall Survival in Colon Cancer Patients. AB - BACKGROUND: The purpose of this study was to examine the long-term overall survival (OS) of colon cancer patients who underwent emergent resection versus patients who were resected electively. METHODS: The 2006-2012 National Cancer Data Base was queried for colon cancer patients who underwent surgical resection. Emergent resection was defined as resection within 24 h of diagnosis. A mixed effects logistic regression was used to estimate the effect of emergent resection on 30- and 90-day mortality. A propensity score-matched mixed-effects Cox proportional-hazards model was used to estimate the effect of emergent resection on 5-year OS. RESULTS: Two hundred fourteen thousand one hundred seventy-four patients met inclusion criteria, 30% of the cohort had an emergent resection. After controlling for patient and hospital factors, pathological stage, lymph node yield, margin status, and adjuvant chemotherapy, emergent resection was associated with increased odds of 30-day mortality (OR = 1.69, 95% CI = 1.60, 1.78) and hazard of death at 5 years (HR = 1.13, 95% CI = 1.09, 1.15) compared to elective resections. CONCLUSION: Emergent resection for colon cancer is independently associated with poor short-term outcomes and decreased 5-year OS compared to elective resection. With 30% of cases in this study emergent, these findings underlie the importance of adherence to colon cancer screening guidelines to limit the need for emergent resections. PMID- 28083843 TI - MicroRNA-19b Expression in Human Biliary Atresia Specimens and Its Role in BA Related Fibrosis. AB - BACKGROUND AND AIM: Biliary atresia (BA) is a pediatric liver disease with unknown underlying etiology. MicroRNAs (miRNAs) represent a family of small noncoding RNAs. Among them, miR-19b has been suggested to function in the diseased liver. We therefore decided to investigate its potential role in BA. METHODS: We used infant-derived specimens to analyze miR-19b expression in a tissue- and cell-specific fashion, predicted interaction with genes, and finally performed a functional study in vitro. RESULTS: Patients with BA showed significantly lower miR-19b level in liver compared with controls, and pediatric end-stage liver disease (PELD) score was inversely correlated with miR-19b level. In vitro, miR-19b was significantly downregulated in activated hepatic stellate cells (HSCs) and exerted inhibitory effects on HSC activation, as confirmed by decreased alpha-smooth muscle actin (alpha-SMA) and type I collagen expression. Moreover, one mRNA target gene (TGFbetaR2) was identified. Computational prediction of miR-19b binding to the 3'-untranslated region (UTR) of TGFbetaR2 was validated by luciferase reporter assay. Furthermore, miR-19b mimic negatively regulated transforming growth factor-beta (TGF-beta) signaling components, as demonstrated by decreased drosophila mothers against decapentaplegic homolog 3 (SMAD3) expression and blocking of TGF-beta-induced expression of a1(I) and a2(I) procollagen miRNAs. CONCLUSIONS: Our data indicate that miR-19b may be involved in BA-related fibrosis. PMID- 28083842 TI - Effect of Vonoprazan, a Potassium-Competitive Acid Blocker, on the 13C-Urea Breath Test in Helicobacter pylori-Positive Patients. AB - BACKGROUND AND AIM: Vonoprazan (VPZ) is a new oral potassium-competitive acid blocker that has recently become available. The aim of this study was to investigate the effects of VPZ on the urease activity of H. pylori as measured by the 13C-urea breath test (13C-UBT). PATIENTS AND METHODS: A total of 60 patients (26 men, 34 women; mean age 53.2 +/- 13.6 years) who were diagnosed as H. pylori positive were recruited. The patients were randomly allocated to three treatment groups: lansoprazole (LPZ) 30 mg (n = 20), VPZ 20 mg (n = 20) once daily for 3 weeks, or the control group (n = 20). The 13C-UBT was carried out at baseline and after 3 weeks of treatment, and the baseline and after treatment results then compared. Delta13C0/00 >= 2.50/00 was considered H. pylori-positive. RESULTS: Four patients failed to complete the medication and were omitted from the analysis; data from the LPZ group (n = 18), VPZ group (n = 18), and control group (n = 20) were analyzed. The control group showed no significant change in 13C-UBT data between baseline and the completion of 3-week treatment (baseline: 26.6 +/- 23.00/00, completion: 21.1 +/- 13.10/00). The 13C-UBT data at week 3 were significantly decreased in both the VPZ group (baseline: 32.8 +/- 22.70/00, completion: 7.6 +/- 9.20/00, p = 0.0002) and the LPZ group (baseline: 41.8 +/- 33.40/00; completion: 9.6 +/- 8.80/00, p = 0.0006) compared to baseline. CONCLUSIONS: VPZ treatment reduced the value of UBT, warning that UBT for patients with VPZ treatment should be evaluated carefully. PMID- 28083844 TI - Attention and processing speed performance in multiple sclerosis is mostly related to thalamic volume. AB - Cognitive impairment (CI), mainly involving attention and processing speed (A PS), is a common and disabling symptom in multiple sclerosis (MS). Symbol Digit Modalities Test (SDMT) is one of the more sensitive and reliable tests to assess A-PS deficits in MS. Structural MRI correlates of A-PS in MS still need to be clarified. This study aimed to investigate, in a large group of MS patients, the relationship between regional gray matter (GM) atrophy and SDMT performance. 125 relapsing remitting MS patients and 52 healthy controls (HC) underwent a 3 T-MRI protocol including high-resolution 3D-T1 imaging. All subjects underwent a neurological evaluation and SDMT. A Voxel Based Morphometry analysis was performed to assess: 1) correlations between regional GM volume and SDMT performance in MS patients; 2) regional differences in GM volume between MS patients and HC. Thalamic, putamen and cerebellar volumes were also calculated using FIRST tool from the FMRIB Software Library. A linear regression analysis was performed to assess the contribution of each one of these structures to A-PS performance. A significant negative correlation was found between regional GM volume and SDMT score at the level of the thalamus, cerebellum, putamen, and occipital cortex in MS patients. Thalamus, cerebellum and putamen also showed significant GM atrophy in MS patients compared to HC. Thalamic atrophy is also an independent and additional contributor to A-PS deficits in MS patients. These findings support the role of thalamus as the most relevant GM structure subtending A-PS performance in MS, as measured by SDMT. PMID- 28083845 TI - Breast cancer genetic counseling among Dutch patients from Turkish and Moroccan descent: participation determinants and perspectives of patients and healthcare professionals. AB - Lower participation rates in cancer genetic counseling are observed among different ethnic minorities. The goal of our study is to gain insight into determinants of Turkish and Moroccan patients' participation in breast cancer genetic counseling and DNA testing, from the point of view of healthcare professionals and patients. Questionnaire-based telephone interviews about awareness, perceptions, and reasons for (non-) participation in cancer genetic counseling were conducted with 78 Dutch breast cancer patients from Turkish and Moroccan descent. The interviews were held in Arabic, Berber, Turkish, or Dutch by bilingual research assistants. Additionally, 14 breast cancer patients participated in one of two focus group meetings, and two focus groups were held with 11 healthcare professionals. SPSS and QSR Nvivo were used to examine the quantitative and qualitative data, respectively. Half of the total group of patients (N = 78) and 79% of patients eligible for genetic counseling and testing (N = 33) were aware of the possibility of genetic counseling. The most important determinants for nonparticipation in genetic counseling were experienced difficulties in patient-doctor communication, cultural factors (e.g., social norms), limited health literacy, limited knowledge of the family cancer history, and anxiety about cancer. Religious beliefs and knowing personal and family members' breast cancer risks were motives to obtain genetic counseling. Despite the fact that our study showed that Moroccan and Turkish women reported several personal motives to obtain genetic counseling and testing (GCT), patients and healthcare professionals experience significant language and health literacy difficulties, which make it harder to fully access health care such as genetic counseling and testing. PMID- 28083846 TI - Laparoscopic Adjustable Gastric Banding in Australian Adolescents: Should It Be Done? AB - OBJECTIVE: There are very few studies on laparoscopic adjustable gastric banding (LAGB) in obese adolescents with follow up for more than 36 months, let alone good prospective data beyond 24 months in Australian adolescents. We aimed to evaluate medium term (>36 months) safety and efficacy of LAGB in adolescents with severe obesity. METHODS: This is a prospective cohort study (March 2009-December 2015) in one tertiary referral hospital including obese adolescents (14-18 years) with a body mass index (BMI) >40 (or >=35 with comorbidities) who consented to have LAGB. Exclusion criteria were syndromal causes of obesity, depression and oesophageal motility disorders. Main outcome measures include change in weight and BMI at 6, 12, 24, 36 and 48 months post LAGB; postoperative complications; and admissions. RESULTS: Twenty-one adolescents (median [interquartile range (IQR)] 17.4 [16.5-17.7] years, 9 males, mean +/- SD BMI 47.3 +/- 8.4 kg/m2) had a median follow up of 45.5 [32-50] months post LAGB. Follow up data were available for 16 adolescents. Weight and BMI improved significantly at all follow up times (all p < 0.01). The median maximum BMI loss was 10 [7.1-14.7] kg/m2. There were four minor early complications. Seven bands were removed due to weight loss failure/regain (two had also obstructive symptoms). CONCLUSIONS: We have shown in the longest prospective LAGB postoperative follow up study of Australian adolescents that LAGB improves BMI in the majority of adolescents without significant comorbidities. LAGB is still a reasonable option to be considered as a temporary procedure to manage severe obesity during adolescence. PMID- 28083847 TI - Influence of Ivabradine on the Anticonvulsant Action of Four Classical Antiepileptic Drugs Against Maximal Electroshock-Induced Seizures in Mice. AB - Although the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in neuronal excitability and synaptic transmission is still unclear, it is postulated that the HCN channels may be involved in seizure activity. The aim of this study was to assess the effects of ivabradine (an HCN channel inhibitor) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) against maximal electroshock-induced seizures in mice. Tonic seizures (maximal electroconvulsions) were evoked in adult male albino Swiss mice by an electric current (sine-wave, 25 mA, 0.2 s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles of the combinations of ivabradine with classical antiepileptic drugs were measured in mice along with total brain antiepileptic drug concentrations. Results indicate that ivabradine (10 mg/kg, i.p.) significantly enhanced the anticonvulsant activity of valproate and considerably reduced that of phenytoin in the mouse maximal electroshock-induced seizure model. Ivabradine (10 mg/kg) had no impact on the anticonvulsant potency of carbamazepine and phenobarbital in the maximal electroshock-induced seizure test in mice. Ivabradine (10 mg/kg) significantly diminished total brain concentration of phenytoin and had no effect on total brain valproate concentration in mice. In conclusion, the enhanced anticonvulsant action of valproate by ivabradine in the mouse maximal electroshock-induced seizure model was pharmacodynamic in nature. A special attention is required when combining ivabradine with phenytoin due to a pharmacokinetic interaction and reduction of the anticonvulsant action of phenytoin in mice. The combinations of ivabradine with carbamazepine and phenobarbital were neutral from a preclinical viewpoint. PMID- 28083849 TI - Erythropoietin Rescues Primary Rat Cortical Neurons by Altering the Nrf2:Bach1 Ratio: Roles of Extracellular Signal-Regulated Kinase 1/2. AB - While inhalation anesthetics are indispensable, and generally considered safe and effective, there is growing concern about the selective neurotoxicity of these agents, especially sevoflurane. Erythropoetin (EPO)-induced protection against sevoflurane-induced neuronal death is an effective intervention, but the underlying mechanism is poorly understood. Extracellular signal-related kinases (Erk) 1/2 plays a pivotal role in cell growth and proliferation. Alteration of the nuclear factor erythroid 2-related factor (Nrf2)/BTB-to-CNC homology 1 (Bach1) ratio by Erk1/2 ameliorates the oxidative stress which occurs in human macrophages. Primary cortical neuron cultures exposed to sevoflurane were assessed for Nrf2, Bach1, total Erk1/2, and phosphorylated Erk1/2 with the following: 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; propidium iodide uptake; lactate dehydrogenase; malondialdehyde (MDA); superoxide dismutase (SOD); and Western blot. Sevoflurane exposure increased cell death, injury, and MDA (n = 9, P < 0.05), but decreased cell viability and the Nrf2:Bach1 ratio (n = 9, P < 0.05) and down-regulated SOD (n = 9, P < 0.05), while EPO partially rescued the neurotoxicity induced by sevoflurane (n = 9, P < 0.05). Inhibition of Erk1/2 phosphorylation via PD98059 reversed the protective effect of EPO (n = 9, P < 0.05). Thus, protection of EPO markedly attenuated death of neurons exposed to sevoflurane by altering the Nrf2:Bach1 ratio mediated by phosphorylation and activation of Erk1/2. PMID- 28083848 TI - Effect of Physical and Social Components of Enriched Environment on Astrocytes Proliferation in Rats After Cerebral Ischemia/Reperfusion Injury. AB - Treatment of enriched environment (EE) exerts neuroprotective effect in cerebral ischemia/reperfusion (I/R) injury. However, how the component of EE contributes to the functional recovery after brain ischemia remains unclear. Here we examined the effect of physical and social components of EE on poststroke astrocytes proliferation using an animal model of middle cerebral artery occlusion (MCAO) followed by reperfusion. Rats were divided into five groups: physical enrichment group (PE), social enrichment group (SE), physical and social enrichment group (PSE), ischemia + standard group (IS) and sham-operated + standard group (SS). In a set of behavioral tests, we demonstrated that animals in the enriched groups exhibited improved functional outcomes compared with those in standard group. Reduced infarct volume was only observed in PSE and PE groups. Double immunofluorescent labeling and western blot analysis revealed that rats in PSE and PE groups showed significantly more proliferated astrocytes and higher expression levels of brain-derived neurotrophic factor (BDNF) in the periinfarct cortex, compared with those in SE group. Astrocytes proliferation and BDNF expression were significantly correlated with functional outcomes. Collectively, this study suggests that physical activity is a more important component of EE regarding the effect on astrocytes proliferation and BDNF expression, which may contribute to the improved neurological function of stroke animals. PMID- 28083850 TI - Glycogen Supercompensation in the Rat Brain After Acute Hypoglycemia is Independent of Glucose Levels During Recovery. AB - Patients with diabetes display a progressive decay in the physiological counter regulatory response to hypoglycemia, resulting in hypoglycemia unawareness. The mechanism through which the brain adapts to hypoglycemia may involve brain glycogen. We tested the hypothesis that brain glycogen supercompensation following hypoglycemia depends on blood glucose levels during recovery. Conscious rats were submitted to hypoglycemia of 2 mmol/L for 90 min and allowed to recover at different glycemia, controlled by means of i.v. glucose infusion. Brain glycogen concentration was elevated above control levels after 24 h of recovery in the cortex, hippocampus and striatum. This glycogen supercompensation was independent of blood glucose levels in the post-hypoglycemia period. In the absence of a preceding hypoglycemia insult, brain glycogen concentrations were unaltered after 24 h under hyperglycemia. In the hypothalamus, which controls peripheral glucose homeostasis, glycogen levels were unaltered. Overall, we conclude that post-hypoglycemia glycogen supercompensation occurs in several brain areas and its magnitude is independent of plasma glucose levels. By supporting brain metabolism during recurrent hypoglycemia periods, glycogen may have a role in the development of hypoglycemia unawareness. PMID- 28083851 TI - The influence of the dose calculation resolution of VMAT plans on the calculated dose for eye lens and optic pathway. AB - To investigate the effect of dose calculation grid on calculated dose-volumetric parameters for eye lenses and optic pathways. A total of 30 patients treated using the volumetric modulated arc therapy (VMAT) technique, were retrospectively selected. For each patient, dose distributions were calculated with calculation grids ranging from 1 to 5 mm at 1 mm intervals. Identical structures were used for VMAT planning. The changes in dose-volumetric parameters according to the size of the calculation grid were investigated. Compared to dose calculation with 1 mm grid, the maximum doses to the eye lens with calculation grids of 2, 3, 4 and 5 mm increased by 0.2 +/- 0.2 Gy, 0.5 +/- 0.5 Gy, 0.9 +/- 0.8 Gy and 1.7 +/- 1.5 Gy on average, respectively. The Spearman's correlation coefficient between dose gradients near structures vs. the differences between the calculated doses with 1 mm grid and those with 5 mm grid, were 0.380 (p < 0.001). For the accurate calculation of dose distributions, as well as efficiency, using a grid size of 2 mm appears to be the most appropriate choice. PMID- 28083852 TI - DNA sensors to assess the effect of VKORC1 and CYP2C9 gene polymorphisms on warfarin dose requirement in Chinese patients with atrial fibrillation. AB - The optimal dose of warfarin depends on polymorphisms in the VKORC1 (the vitamin K epoxide reductase complex subunit (1) and CYP2C9 (cytochrome P450 2C9) genes. To minimize the risk of adverse reactions, warfarin dosages should be adjusted according to results from rapid and simple monitoring methods. However, there are few pharmacogenetic-guided warfarin dosing algorithms that are based on large cohorts from the Chinese population, especially patients with atrial fibrillation. This study aimed to validate a pharmacogenetic-guided warfarin dosing algorithm based on results from a new rapid electrochemical detection method used in a multicenter study. Three SNPs (CYP2C9 *2, *3 and VKORC1 c.-1639G > A) were genotyped by electrochemical detection using a sandwich-type format that included a 3' short thiol capture probe and a 5' ferrocene-labeled signal probe. A total of 1285 samples from four clinical hospitals were evaluated. Concordance rates between the results from the electrochemical DNA biosensor and the sequencing test were 99.8%. The results for gene distribution showed that most Chinese patients had higher warfarin susceptibility because mutant-type and heterozygotes were present in the majority of subjects (99.4%) at locus c.-1639G > A. When the International Warfarin Pharmacogenetics Consortium algorithm was used to estimate therapeutic dosages for 362 patients with AF and the values were compared with their actual dosages, the results revealed that 56.9% were similar to actual dosages (within the 20% range). A novel electrochemical detection method of CYP2C9 *2, *3and VKORC1 c.-1639G > A alleles was evaluated. The warfarin dosing algorithm based on data gathered from a large patient cohort can facilitate the reasonable and effective use of warfarin in Chinese patients with AF. PMID- 28083853 TI - Design, synthesis and pharmacological analysis of 5-[4'-(substituted-methyl)[1,1' biphenyl]-2-yl]-1H-tetrazoles. AB - In the present paper 5-[4'-({4-[(4-aryloxy)methyl]-1H-1,2,3-triazol-1 yl}methyl)[1,1'-biphenyl]-2-yl]-1H-tetrazoles (5a-g) and [2'-(1H-tetrazol-5 yl)[1,1'-biphenyl]-4-yl]methyl-substituted-1-carbodithioates (11h-q) have been designed and synthesized. These compounds were subjected to docking (against AT1 receptor protein enzyme in complex with Lisinopril), in vitro angiotensin converting enzyme inhibition, anti-proliferative, anti-inflammatory screening (through egg albumin denaturation inhibition and red blood cell membrane stabilization assay) and finally anti-fungal activity analyses. Some of the compounds have shown significant pharmacological properties. PMID- 28083854 TI - Analysis of prognostic value of complete response by PET-CT and further stratification by clinical and biological markers in DLBCL patients. AB - Positron emission tomography-computed tomography (PET-CT) is performed as the standard method for response assessment of diffuse large B cell lymphoma (DLBCL) patients. However, a substantial proportion of patients experience relapse even if they have achieved complete response (CR) defined by PET-CT. We validated the prognostic value of CR by PET-CT and applied the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) and cell of origin (COO) to patients with CR by PET-CT to evaluate their additional predictive ability for survival outcomes. We retrospectively analyzed DLBCL patients who were treated with R-CHOP or an R-CHOP-like regimen and who achieved CR by PET-CT or CT only. A total of 185 patients were analyzed: 114 patients achieved CR by PET-CT and 71 patients by CT only. Patients with CR by PET-CT had significantly better overall survival (OS) than those with CR by CT (5-year OS, 87.5 vs. 62.4%, P = 0.003). Patients with high risk according to the NCCN-IPI had a dismal outcome despite achieving CR by PET-CT (5-year OS, 61.8%). In contrast, low-, low-intermediate-, and high-intermediate-risk patients had excellent outcomes (5-year OS, 100, 89.7, and 93.5%, respectively). Among patients with CR by PET-CT, patients with germinal center B cell (GCB) DLBCL (n = 40) had significantly better survival than those with non-GCB DLBCL (n = 57) (5-year OS, 96.9 vs. 75.5%, P = 0.039). We demonstrated that CR by PET-CT was a better predictor of survival outcomes than CR by CT only. The NCCN-IPI and COO subtypes could identify a subpopulation of poor-risk patients among those who achieved CR by PET-CT. PMID- 28083855 TI - Obstructive sleep apnea risk and leukocyte telomere length in African Americans from the MH-GRID study. AB - PURPOSE: Shorter telomere length and obstructive sleep apnea are associated with increased oxidative stress and chronic inflammation, which are both considered leading causes of age-related diseases. Different forms of sleep disordered breathing have been linked to telomere length although their relationship remains uncertain. The purpose of this study was to explore the associations between the risk of obstructive sleep apnea and telomere length in African Americans. METHODS: The analysis included 184 women and 122 men aged 30-55 years from the Morehouse School of Medicine Study. Relative TL (T/S ratio) was measured from peripheral blood leukocytes using quantitative real-time polymerase chain reaction. The Berlin questionnaire was used for OSA risk assessments. Multivariable linear regression models were used to examine the associations between OSA risk and LTL. RESULTS: We observed that LTL varied by OSA risk in women (0.532 +/- 0.006 vs. 0.569 +/- 0.008) (p = 0.04). Multiple linear regression analysis confirmed that women at higher risk for OSA presented shorter LTL compared to those at lower risk, independent of age, income, education, obesity, smoking, alcohol consumption, and hypertension. These differences were not observed in men. CONCLUSIONS: Our findings suggest that OSA risk may contribute to the acceleration of cellular aging processes through telomere shortening. PMID- 28083856 TI - Micafungin: A Review in the Prophylaxis and Treatment of Invasive Candida Infections in Paediatric Patients. AB - Intravenous micafungin (Mycamine(r); Funguard(r)), an echinocandin, is approved in the EU for the treatment of invasive candidiasis in children (including neonates) and adolescents (<16 years of age) and as prophylaxis against Candida infections in patients undergoing haematopoietic stem cell transplantation (HSCT) or who are expected to have neutropenia for >=10 days. This narrative review focuses on the use of micafungin in paediatric indications approved in the EU, which may vary from those approved elsewhere in the world. Micafungin has a broad spectrum of in vitro activity against clinically relevant isolates of Candida spp. (including fluconazole-resistant Candida glabrata isolates), a low propensity for emergence of resistant isolates and a convenient once-daily regimen. In paediatric substudies and a small multinational, phase 3 trial in neonates with proven invasive candidiasis, intravenous micafungin was effective and generally well tolerated in the treatment of candidaemia and other types of invasive candidiasis and as prophylaxis against fungal infections in patients undergoing HSCT. Hence, micafungin remains an important option for the prophylaxis and treatment of invasive Candida infections in paediatric and adult patients. PMID- 28083857 TI - Structural and congenital heart disease interventions: the role of three dimensional printing. AB - Advances in catheter-based interventions in structural and congenital heart disease have mandated an increased demand for three-dimensional (3D) visualisation of complex cardiac anatomy. Despite progress in 3D imaging modalities, the pre- and periprocedural visualisation of spatial anatomy is relegated to two-dimensional flat screen representations. 3D printing is an evolving technology based on the concept of additive manufacturing, where computerised digital surface renders are converted into physical models. Printed models replicate complex structures in tangible forms that cardiovascular physicians and surgeons can use for education, preprocedural planning and device testing. In this review we discuss the different steps of the 3D printing process, which include image acquisition, segmentation, printing methods and materials. We also examine the expanded applications of 3D printing in the catheter-based treatment of adult patients with structural and congenital heart disease while highlighting the current limitations of this technology in terms of segmentation, model accuracy and dynamic capabilities. Furthermore, we provide information on the resources needed to establish a hospital-based 3D printing laboratory. PMID- 28083858 TI - Effect of View, Scan Orientation and Analysis Volume on Digital Tomosynthesis (DTS) Based Textural Analysis of Bone. AB - Digital tomosynthesis (DTS) derived textural parameters of human vertebral cancellous bone have been previously correlated to the finite element (FE) stiffness and 3D microstructure. The objective of this study was to optimize scanning configuration and use of multiple image slices in the analysis, so that FE stiffness prediction using DTS could be maximized. Forty vertebrae (T6, T8, T11, and L3) from ten cadavers (63-90 years) were scanned using microCT to obtain trabecular bone volume fraction (BV/TV) and FE stiffness. The vertebrae were then scanned using DTS anteroposteriorly (AP) and laterally (LM) while aligned axially (0 degrees ), transversely (90 degrees ) or obliquely (23 degrees ) to the superior-inferior axis of the vertebrae. From the serial DTS images, fractal dimension (FD), mean intercept length (MIL) and line fraction deviation (LFD) parameters were obtained from a 2D-single mid-stack location and 3D-multi-image stack. The DTS derived textural parameters were then correlated with FE stiffness using linear regression models within each scanning orientation. 3D-multi-image stack models obtained from Transverse-LM scanning orientation (90 degrees ) were most explanatory regardless of accounting for the effects of BV/TV. Therefore, DTS scanning perpendicular to the axis of the spine in an LM view is the preferred configuration for prediction of vertebral cancellous bone stiffness. PMID- 28083859 TI - An unusual complication of ureterorenoscopy: a liver abscess. PMID- 28083860 TI - Prostate cancer outcomes and delays in care. AB - OBJECTIVES: To examine the survival effect of treatment delays from the time of confirmed diagnosis of prostate cancer to first treatment in an Australian population. METHODS: Three thousand one hundred and forty patients were identified from the South Australian Prostate Cancer Clinical Outcomes Collaborative database for analysis. Selected patients had dates recorded for both diagnosis and treatment. We examined the effect of treatment delay (the time from diagnosis to date of first treatment) on survival using Cox and competing risks regression and compared quartiles of delay across the cohort. Adjustment was made for age, PSA levels, treatment modality and Gleason score. Outcomes included overall survival (OS) and prostate cancer-specific mortality (PCSM). RESULTS: Quartiles of delay were as follows (days)-Q1: 35, Q2: 86, Q3: 138.0, Q4: 264. Shorter delays were associated with hormonal treatment, high Gleason score and high PSA values. Measuring PCSM with Q2 as reference, age-adjusted associations were-Q1: sHR 4.37 (2.75-6.94), Q3: sHR 1.29 (0.73-2.28), Q4: sHR 1.55 (0.91-2.63). After additional adjustment for treatment type, Gleason score and PSA, Q1 remained at increased risk [sHR 2.46 (1.10-5.54)]. A similar trend was observed for OS. In analysis stratified by Gleason score, delays were not significantly associated with OS. CONCLUSIONS: Factors associated with shorter delay in treatment include high Gleason score, high PSA and hormonal treatment. After adjustment for these variables, increased delays were not associated with OS or PCSM in this cohort. The nonlinear association of delay with risk may explain conflicting reports in the literature. PMID- 28083861 TI - Multimodal imaging analyses of hyperreflective dot-like lesions in acute syphilitic posterior placoid chorioretinopathy. AB - BACKGROUND: Retrospective review of one acute syphilitic posterior placoid chorioretinitis (ASPPC) case with serological evidence of syphilis who had ocular signs and symptoms not attributable to other diseases. Enface and spectral-domain optical coherence tomographySD-OCT were analyzed at the time of presentation and at 1-month visit following initiation of treatment. The study patient underwent standard treatment for neurosyphilis. RESULTS: Ophthalmic examination and imaging studies were consistent with the diagnosis of ASPPC. The patient age was 33 year old and the baseline visual acuity was 20/400 and 20/80 in the right and left eyes, respectively. At presentation, SD-OCT scans showed disruption and loss of the ellipsoid zone (EZ), small nodular elevations on retinal pigment epithelium (RPE) and punctate hyperreflectivity in the choroid. Enface OCT at the level of RPE and EZ demonstrated multiple hyperreflective dot-like lesions simmetrically distributed within the macular area. These dot-like lesions corresponded to the small nodular elevations on RPE and to disruption/loss of EZ observed with SD OCT. One month after neurosyphilis therapy, the visual acuity improved and the outer retinal changes partially reversed in both eyes. CONCLUSIONS: We report the outer retinal findings and its correlation using both en-face and SD-OCT in a patient with ASPPC. En-face OCT imaging provides a more precise outer retinal layers analyses allowing a better understanding of the ASPPC pathophysiology. PMID- 28083862 TI - Pathogenicity assessment of wild-type and mouse-adapted influenza A(H1N1) pdm09 viruses in comparison with highly pathogenic influenza A(H5N1) virus. AB - Here we compare the results of pathological and virological examinations of mice experimentally infected with either wild-type or mouse-adapted pandemic A(H1N1) pdm09 viruses and highly pathogenic avian influenza (HPAI) virus A(H5N1). Mice were sacrificed on days 1, 3, 6, and 10 post infection or whenever morbidity was severe enough to justify euthanasia. Morbidity rates were calculated on the basis of clinical signs (weight loss, poor hair coat, hunched posture and paresis); virus-induced disease was characterised by the histopathology of lung; virus dissemination was determined by virus isolation on organ samples of lung, brain, liver, kidney and spleen. All mice infected with mouse-adapted A(H1N1) pdm09 died in the course of the experiment, whereas 20% of animals survived the infection with A(H5N1). Echinocyte formation changed the rheological properties of blood in animals infected with either mouse-adapted A(H1N1) pdm09 or A(H5N1). To sum up, the adaptation of pandemic A(H1N1) pdm09 virus can confer an enhanced virulence similar to or even exceeding that of HPAI A(H5N1) virus. PMID- 28083863 TI - Treatment of patients with chronic hepatitis C infection in Lombardia: a report by the Lombardia Hepatitis Network. AB - The arrival of potent directly acting antivirals (DAAs) for the treatment of chronic Hepatitis C virus (HCV) infection was a challenge for the regional health system of the Lombardia Region. Lombardia represents roughly 8% of the Italian territory but includes nearly 16% of the Italian population. In 2014, nearly 37,600 HCV patients were routinely followed-up in liver centers across the region; nearly 16,000 were classified as having advanced fibrosis or cirrhosis (Metavir F3-F4). The creation of a regional network was necessary to ensure uniformity in treatment access and treatment management. The first database analysis of the Lombardia Hepatitis Network was conducted in January 2016, and included data on 2432 patients who had received treatment from December 2014 to December 2015. The most prevalent HCV genotypes were HCV-1 found in 63% and HCV-3 found in 17%. Overall 90.4% patients achieved an SVR, SVR rates were 92.9% in HCV 1, 89.3% in HCV-2, 81.1% in HCV-3 and 88.9% in HCV-4. PMID- 28083864 TI - The HCV Sicily Network: a web-based model for the management of HCV chronic liver diseases. AB - OBJECTIVE: Epidemiological studies report that in Sicily reside about 30,000 citizens with a diagnosis of chronic hepatitis due to HCV. The availability of direct antiviral action (DAA) is a real therapeutic breakthrough, but the high cost of the therapeutic regimes limits their use and forced the National Health System to establish clinical priority for the treatment. MATERIALS AND METHODS: The HCV Sicily Network is a web-based model of best medical practice, which was designed to improve the management and the treatment of HCV chronic hepatitis and cirrhosis. The network includes 41 centers and 84 gastroenterologists or infectivologists connected by a web platform that recorder the diagnosis and the clinic priority for the therapy. RESULTS: From March 2015 to September 2016, 9,965 patients (57% male, mean age 61 years, 34% with age over 70 years) have been recorded in the web platform, 3,319 patients completed the treatment, and 1,754 completed the 12 weeks of follow-up. The Sustained Virological Response (SVR) was achieved in 1,541 patients (87.8%), while 136 patients (7.7%) 77 patients (4.5%) experienced a virological relapse during the 12 weeks of follow up. CONCLUSIONS: The HCV Sicily Network is an excellent system for the Regional Department of Health that can have a real estimation of patients that received an efficacy, but high-cost therapy. PMID- 28083865 TI - HCV - Estimation of the number of diagnosed patients eligible to the new anti-HCV therapies in Italy. AB - OBJECTIVE: The present research wants to take a picture of the current epidemiological scenario regarding HCV infection in Italy. Studies used to estimate HCV burden of illness in Italy were so far local and performed a number of years ago, not mirroring the state of the art. EpaC wanted to provide a real number of diagnosed patients, eligible to new anti-HCV therapies. PATIENTS AND METHODS: EpaC is the most important Italian NGO for hepatopathic patients. A number of sources were cross-checked. Starting from all regional data regarding HCV-related exemptions, a correction/integration was performed with online questionnaire to associated patients (from which we derived patients cured and also other/no exemptions); survey to all prescribing centers in Italy (from which we derived the percentage of ineligible patients); prevalence of particular subpopulations was also collected (prisoners and HIV/HCV coinfected); calculations of new diagnosed, dead and cured patients in 2015. Excluded patients were illegal immigrants and active drug addicts (subpopulations currently rarely cured). RESULTS: A total of 221,549 patients were derived from regional exemptions databases and the mean national prevalence was 0.364%. Adding patients without exemptions/other exemptions, total was 308,624. We deducted the yearly deaths, cured and not eligible patients and, last, integrated with coinfected and prisoner special groups. Prevalence was also estimated at regional level, highlighting a reduction of the typical North-to-South prevalence gradient. Applying the above-mentioned corrections/integrations, total diagnosed and eligible HCV patients in Italy who can be immediately cured are supposed to range 163,148-187,756. CONCLUSIONS: This is a research aimed at filling an informative gap able to provide useful actual information in terms of HCV patients real-life management and future resource allocation. These data may be considered the basis for policy- and decision-makers to plan and manage patients ready to be cured. The research does not provide information on patients not yet diagnosed. PMID- 28083866 TI - HCV - Treatment ratio and governance footprints: analysis of regional differentiation in Italy. AB - Due to the strongly fragmented reality of HCV treatment in the various Regions of Italy, effectiveness of access to treatment is difficult to gather. The aim of this paper was to analyze regional differences in healthcare governance models regarding HCV, in order to understand the ability of each Region to give access to HCV diagnosed patients. The analysis was performed by comparing treatment ratios (TR) across all Regions (treated patients/diagnosed patients). Furthermore, the study provides insight to regional regulatory environment and to all HCV treatments entering the market in each Region. Sicily has the highest TR value (73%), whereas Friuli Venezia Giulia has the lowest (5%). Overall, Regions where a technical document on HCV clinical pathways has been implemented, result in a higher number of treated patients. PMID- 28083867 TI - The healthcare service in Italy: regional variability. AB - The Italian health system is highly decentralized, with most administrative and organizational powers governed by Regions and rather limited powers at national level. The state has full control over the definition of the core benefit package (LEA) but there is evidence that the actual provision of these services varies greatly across Regions. PMID- 28083868 TI - Motor impairment in children born preterm: assessment with the Movement ABC-2. PMID- 28083871 TI - An exploratory study using framework analysis to investigate health-seeking behaviour in patients with psoriasis. AB - BACKGROUND: Psoriasis is a long-term inflammatory skin disorder, with negative effects on employment, relationships and social function, frequently causing reduced quality of life. People with psoriasis often present to secondary care late into their condition but the reasons for this are unknown. OBJECTIVES: To examine the patient pathway, health-seeking behaviour and drivers for referral to secondary care in patients with psoriasis. METHODS: Sixteen patients with mild-to severe psoriasis, newly referred to secondary care participated in a semi structured interview. Scripts were analysed by a thematic framework. RESULTS: The median duration of time living with psoriasis was 15 years at referral. Drivers of secondary care referral included rapid deterioration or extremis, development of comorbidities, knowledge of treatment options, and influence of partners and friends. Reasons for late presentation to secondary care include familial experience of psoriasis, lack of follow-up after the initiation of treatments, beliefs that psoriasis is incurable and must be tolerated, and that psoriasis is not life threatening and therefore not worthy of medical help and difficulty in obtaining a secondary care referral. A common pathway from seeking help at psoriasis onset, evolving into the development of delayed health seeking later in the pathway, was identified. CONCLUSIONS: Identifying the causes of delay in presentation to secondary care and effective treatment ascertains key areas to target. Health seeking early in the disease pathway provides a 'window of opportunity' for intervention, which may enable people with psoriasis to obtain early, effective treatment and achieve their full life potential. PMID- 28083870 TI - The ethnic profile of patients with birthmarks reveals interaction of germline and postzygotic genetics. PMID- 28083872 TI - A space-time skew-t model for threshold exceedances. AB - To assess the compliance of air quality regulations, the Environmental Protection Agency (EPA) must know if a site exceeds a pre-specified level. In the case of ozone, the level for compliance is fixed at 75 parts per billion, which is high, but not extreme at all locations. We present a new space-time model for threshold exceedances based on the skew-t process. Our method incorporates a random partition to permit long-distance asymptotic independence while allowing for sites that are near one another to be asymptotically dependent, and we incorporate thresholding to allow the tails of the data to speak for themselves. We also introduce a transformed AR(1) time-series to allow for temporal dependence. Finally, our model allows for high-dimensional Bayesian inference that is comparable in computation time to traditional geostatistical methods for large data sets. We apply our method to an ozone analysis for July 2005, and find that our model improves over both Gaussian and max-stable methods in terms of predicting exceedances of a high level. PMID- 28083869 TI - Bayesian genome- and epigenome-wide association studies with gene level dependence. AB - High-throughput genetic and epigenetic data are often screened for associations with an observed phenotype. For example, one may wish to test hundreds of thousands of genetic variants, or DNA methylation sites, for an association with disease status. These genomic variables can naturally be grouped by the gene they encode, among other criteria. However, standard practice in such applications is independent screening with a universal correction for multiplicity. We propose a Bayesian approach in which the prior probability of an association for a given genomic variable depends on its gene, and the gene-specific probabilities are modeled nonparametrically. This hierarchical model allows for appropriate gene and genome-wide multiplicity adjustments, and can be incorporated into a variety of Bayesian association screening methodologies with negligible increase in computational complexity. We describe an application to screening for differences in DNA methylation between lower grade glioma and glioblastoma multiforme tumor samples from The Cancer Genome Atlas. Software is available via the package BayesianScreening for R: github.com/lockEF/BayesianScreening. PMID- 28083873 TI - Follow-up assessment of problem-based learning in dental alveolar surgery education: a pilot trial. AB - BACKGROUND: Limited information exists on the effects of an oral and maxillofacial surgery integrated problem-based learning (PBL) course for dental undergraduates and the performance of these students after graduation. Therefore, we designed a PBL-implemented course with integrated dental alveolar surgery to evaluate its effects on the preparedness of graduates for clinical practice, their lifelong learning habits and their ability to collaborate, compared with the results of traditional courses. METHODS: A randomised controlled trial was performed with 90 undergraduate students. The undergraduates were asked to perform a theoretical examination and to complete a clinical case analysis at the end of the course. Three years later, a follow-up survey was administered via a telephone interview and a questionnaire that measured self-perceived and supervisor-rated preparedness for clinical practice related to professional knowledge of dental alveolar surgery, lifelong learning habits, attitude and collaboration ability. All results were analysed using one-way analysis of variance (ANOVA) and a t-test. RESULTS: At the 3-year post-graduation time point, both PBL graduates and their supervisors rated their preparation for clinical practice as higher than those who received traditional lecture-based courses. In addition, the respondents in the PBL group believed that they were more likely than their counterparts in the traditional group to consult with professionals and other health-care staff members. No significant between-group differences were observed in the graduates' habits or lifelong learning attitudes. CONCLUSIONS: The PBL mode of teaching integrated dental alveolar surgery may improve preparedness for clinical practice and help undergraduates to develop the desire to collaborate. PMID- 28083874 TI - Barriers to oral health across selected European countries and the USA. AB - In this review we consider oral-health access among older adults within and between the USA and various European countries with regard to possible primary financial and modifiable secondary non-financial factors. For older adults, the likelihood of using dental services has been associated, in the health literature, with a multiplicity of factors. These factors are traditionally classified into predisposing, enabling and need categories, and can be further classified into modifiable and non-modifiable subcategories. This raises the question of which single factor or group of factors has the most influence in keeping older adults from seeking care, and how these influences might differ between the USA and various other (European) countries. As it turns out, there is variation in the magnitude of effects across certain measurable potential barriers, but generally it takes a combination of characteristics associated with non-use to have a substantial impact. PMID- 28083875 TI - The role of oncoplastic breast reduction in the conservative management of breast cancer: Complications, survival, and quality of life. AB - BACKGROUND AND OBJECTIVES: Reduction Mammaplasty (RM) in breast cancer allows mammary remodeling after wide excisions. We aimed to analyze the complications, survival, and quality of life after RM. METHODS: Retrospective study of women who underwent a surgical intervention for breast cancer between 2000 and 2016. Patients were divided into two groups: RM and tumorectomy. Postoperative complications, survival and quality of life were assessed using the Breast-Q questionnaire. RESULTS: A total of 801 patients were evaluated, with a mean follow up of 84 months. RM patients experienced a longer operating time and hospital stay, and a higher proportion of tissue necrosis compared to tumorectomy patients (P < 0.001). No significant differences were observed regarding rate of re-excision or rate of mastectomy, but the recurrence rate at 10 years was higher for RM patients (P < 0.03). Patients who underwent RM reported optimal satisfaction with the breast and a good quality of life. CONCLUSIONS: RM is a useful approach in breast cancer surgery, with a low rate of re-excision and mastectomy. Overall survival at 10 years is similar to that associated with tumorectomy, though with a higher rate of local recurrence. Patient satisfaction and quality of life appears to be good one year after radiotherapy. PMID- 28083876 TI - Dynamic changes in absolute immature platelet count suggest the presence of a coexisting immune process in the setting of thrombotic thrombocytopenic purpura. AB - BACKGROUND: Previous studies have indicated the usefulness of absolute immature platelet counts (A-IPCs) in the management and diagnostic algorithm of thrombotic thrombocytopenic purpura (TTP). Specifically a threefold increase in A-IPC from baseline may be diagnostic of TTP. Here, A-IPC was used to understand a coexisting immune dysregulation complicating TTP treatment. CASE REPORT: A 17 year-old previously healthy female was admitted with altered mental status, petechiae, anemia, thrombocytopenia, and schistocytes on peripheral smear. Daily therapeutic plasma exchange (TPE) and corticosteroids were started for suspected TTP supported by ADAMTS13 activity of less than 5%, inhibitor more than 8, and more than threefold A-IPC increase from baseline post-TPE initiation. Despite daily TPE, the patient had significant and unexpected decreases in platelet (PLT) counts and A-IPCs during her hospital course. After each PLT count decline, response to TPE and immunosuppression led to increasingly prolonged count recovery with subsequent episodes. Decreases in both PLTs and A-IPCs indicated that both mature and immature PLTs were being cleared from circulation. Recovery occurred once A-IPC dynamics indicated restored negative feedback in relation to PLT count. CONCLUSION: Serial monitoring of A-IPC dynamics was indicative of coexisting processes in the setting of ADAMTS13 deficiency. Uncoupling of the expected A-IPC and PLT count seen in TTP suggested the presence of such an immune process in addition to TTP with high ADAMTS13 inhibitor. Monitoring of A-IPC is a clinically valuable, rapid, and noninvasive thrombopoietic measurement when TTP is suspected. PMID- 28083877 TI - Proximal onycholysis as a complication of hand, foot, and mouth disease. PMID- 28083878 TI - The B6 -vitamer Pyridoxal is a Sensitizer of UVA-induced Genotoxic Stress in Human Primary Keratinocytes and Reconstructed Epidermis. AB - UVA-driven photooxidative stress in human skin may originate from excitation of specific endogenous chromophores acting as photosensitizers. Previously, we have demonstrated that 3-hydroxypyridine-derived chromophores including B6 -vitamers (pyridoxine, pyridoxamine and pyridoxal) are endogenous photosensitizers that enhance UVA-induced photooxidative stress in human skin cells. Here, we report that the B6 -vitamer pyridoxal is a sensitizer of genotoxic stress in human adult primary keratinocytes (HEKa) and reconstructed epidermis. Comparative array analysis indicated that exposure to the combined action of pyridoxal and UVA caused upregulation of heat shock (HSPA6, HSPA1A, HSPA1L, HSPA2), redox (GSTM3, EGR1, MT2A, HMOX1, SOD1) and genotoxic (GADD45A, DDIT3, CDKN1A) stress response gene expression. Together with potentiation of UVA-induced photooxidative stress and glutathione depletion, induction of HEKa cell death occurred only in response to the combined action of pyridoxal and UVA. In addition to activational phosphorylation indicative of genotoxic stress [p53 (Ser15) and gamma-H2AX (Ser139)], comet analysis indicated the formation of Fpg-sensitive oxidative DNA lesions, observable only after combined exposure to pyridoxal and UVA. In human reconstructed epidermis, pyridoxal preincubation followed by UVA exposure caused genomic oxidative base damage, procaspase 3 cleavage and TUNEL positivity, consistent with UVA-driven photooxidative damage that may be relevant to human skin exposed to high concentrations of B6 -vitamers. PMID- 28083879 TI - Health Services Utilization in Older Adults with Dementia Receiving Care Coordination: The MIND at Home Trial. AB - OBJECTIVE: To investigate effects of a novel dementia care coordination program on health services utilization. DATA SOURCES/STUDY SETTING: A total of 303 community-dwelling adults aged >=70 with a cognitive disorder in Baltimore, Maryland (2008-2011). STUDY DESIGN: Single-blind RCT evaluating efficacy of an 18 month care coordination intervention delivered through community-based nonclinical care coordinators, supported by an interdisciplinary clinical team. DATA COLLECTION/EXTRACTION METHODS: Study partners reported acute care/inpatient, outpatient, and home- and community-based service utilization at baseline, 9, and 18 months. PRINCIPAL FINDINGS: From baseline to 18 months, there were no significant group differences in acute care/inpatient or total outpatient services use, although intervention participants had significantly increased outpatient dementia/mental health visits from 9 to 18 months (p = .04) relative to controls. Home and community-based support service use significantly increased from baseline to 18 months in the intervention compared to control (p = .005). CONCLUSIONS: While this dementia care coordination program did not impact acute care/inpatient services utilization, it increased use of dementia-related outpatient medical care and nonmedical supportive community services, a combination that may have helped participants remain at home longer. Future care model modifications that emphasize delirium, falls prevention, and behavior management may be needed to influence inpatient service use. PMID- 28083881 TI - The use of sonoelastography to assess the recovery of stiffness after equine superficial digital flexor tendon injuries: A preliminary prospective longitudinal study of the healing process. AB - BACKGROUND: The objective assessment of the mechanical properties of the superficial digital flexor tendon (SDFT) could provide useful information for the rehabilitation of horses with SDFT injuries. Assessment of strain ratio (the strain of a standard reference divided by that of lesions) is a quantitative method in sonoelastography for evaluating tissue stiffness in vivo. As yet, no longitudinal studies have used strain ratio to evaluate the progression of stiffness in SDFT injuries. OBJECTIVES: To test the hypothesis that strain ratio can evaluate the recovery of stiffness during the healing of SDFT injuries. STUDY DESIGN: Prospective and longitudinal study with observer-blinded evaluation. METHODS: Ultrasonography, including sonoelastography, was performed in seven Thoroughbred horses with naturally occurring SDFT injuries at five time points: within 20 days of the injury, and at 2, 3, 6 and 9 months after the injury. Blinded sonoelastographic images were independently evaluated by two veterinarians to assess interobserver agreement. The recovery of stiffness and echogenicity in lesions were evaluated using the strain ratio and grey-scale ratio (echogenicity of lesions divided by that of the surrounding area), respectively. RESULTS: Interobserver agreement was assessed as 'almost perfect'. Strain ratios were significantly higher at 9 months after injury than at the other time points (all P<0.05). Strain ratios at 6 months after injury were significantly higher than those at earlier time points (P<0.05). Grey-scale ratios within 20 days of injury were significantly lower than those at the other time points (all P<0.05). MAIN LIMITATIONS: Validations of SDFT status were evaluated only by recovery of the echogenicity in lesions and not by histopathological examination. CONCLUSIONS: Although further studies are needed to validate the relationships between injured SDFT status and sonoelastographic findings, this preliminary study shows that strain ratio may provide a means to monitor the recovery of stiffness in lesions during rehabilitation, even when the grey-scale ratio remains unchanged from a few months after SDFT injury. The Summary is available in Chinese - see Supporting Information. PMID- 28083880 TI - Oral health-related quality-of-life scores differ by socioeconomic status and caries experience. AB - OBJECTIVES: (i) Quantify the relative association between child dental caries experience and maternal-reported child oral health-related quality of life (OHRQoL); (ii) examine whether that association differed according to family socioeconomic status (SES); and (iii) explore whether absolute OHRQoL varied by family SES at similar levels of child caries experience. METHODS: This study was a cross-sectional analysis of children in southern Brazil (n=456, mean age: 38 months) participating in an existing health centre-based intervention study. OHRQoL impact was quantified as mean score on the Brazilian Early Childhood Oral Health Impact Scale (ECOHIS) and compared over categories of caries experience (dmft: 0, dmft: 1-4, dmft: >=5). Adjusted ECOHIS ratios between caries categories were calculated using regression modelling, overall and within socioeconomic strata defined by maternal education, social class and household income. RESULTS: Caries prevalence (dmft >0) was 39.7%, mean ECOHIS score was 2.0 (SD: 3.5), and 44.3% of mothers reported OHRQoL impact (ECOHIS score >0). Increasing child caries experience was associated with worsening child and family quality of life: ECOHIS scores were 3.0 times greater (95% CI: 2.0, 4.4) for children with dmft >=5 vs dmft=0, a pattern that persisted regardless of family socioeconomic status (P for interaction: all >0.3). However, adjusted for dental status and sociodemographic characteristics, mean ECOHIS scores were lower when reported by mothers of less educational attainment (ratio: 0.7; 95% CI: 0.5, 1.0), lower social class (ratio: 0.7; 95% CI: 0.5, 1.0) or in lower income households (ratio: 0.8; 95% CI: 0.6, 1.3). CONCLUSION: Dental caries was associated with negative child and family experiences and lower OHRQoL across all social groups; yet, families facing greater disadvantage may report lesser quality-of-life impact at the same level of disease experience. Thus, subjective quality-of-life measures may differ under varying social contexts, with possible implications for service utilization, evaluating oral health interventions, or quantifying disease morbidity in low-SES groups. PMID- 28083882 TI - Reflectance confocal microscopy for the characterization of primary cutaneous amyloidosis: a pilot study. PMID- 28083883 TI - A Comparison of Dose Metrics to Predict Local Tumor Control for Photofrin mediated Photodynamic Therapy. AB - This preclinical study examines light fluence, photodynamic therapy (PDT) dose and "apparent reacted singlet oxygen," [1 O2 ]rx , to predict local control rate (LCR) for Photofrin-mediated PDT of radiation-induced fibrosarcoma (RIF) tumors. Mice bearing RIF tumors were treated with in-air fluences (50-250 J cm-2 ) and in air fluence rates (50-150 mW cm-2 ) at Photofrin dosages of 5 and 15 mg kg-1 and a drug-light interval of 24 h using a 630-nm, 1-cm-diameter collimated laser. A macroscopic model was used to calculate [1 O2 ]rx and PDT dose based on in vivo explicit dosimetry of the drug concentration, light fluence and tissue optical properties. PDT dose and [1 O2 ]rx were defined as a temporal integral of drug concentration and fluence rate, and singlet oxygen concentration consumed divided by the singlet oxygen lifetime, respectively. LCR was stratified for different dose metrics for 74 mice (66 + 8 control). Complete tumor control at 14 days was observed for [1 O2 ]rx >= 1.1 mm or PDT dose >=1200 MUm J cm-2 but cannot be predicted with fluence alone. LCR increases with increasing [1 O2 ]rx and PDT dose but is not well correlated with fluence. Comparing dosimetric quantities, [1 O2 ]rx outperformed both PDT dose and fluence in predicting tumor response and correlating with LCR. PMID- 28083885 TI - Preparation of diclofenac-imprinted polymer beads for selective molecular separation in water. AB - Molecular imprinting technique is an attractive strategy to prepare materials for target recognition and rapid separation. In this work, a new type of diclofenac (DFC)-imprinted polymer beads was synthesized by Pickering emulsion polymerization using 2-(dimethylamino)ethyl methacrylate as the functional monomer. The selectivity and capacity of the molecularly imprinted polymers (MIPs) were investigated in aqueous solution. Equilibrium binding results show that the MIPs have a high selectivity to bind DFC in a wide range of pH values. Moreover, in liquid chromatography experiment, the imprinted polymer beads were packed into column to investigate the binding selectivity under nonequilibrium conditions. The retention time of DFC on the MIP column is significantly longer than its structural analogues. Also, retention of DFC on the MIP column was significantly longer than on the nonimprinted polymer column under aqueous condition. As the new MIP beads can be used to achieve direct separation of DFC from water, the synthetic method and the affinity beads developed in this work opened new possibilities for removing toxic chemicals from environmental and drinking water. PMID- 28083884 TI - Disabled-1 dorsal horn spinal cord neurons co-express Lmx1b and function in nociceptive circuits. AB - The Reelin-signaling pathway is essential for correct neuronal positioning within the central nervous system. Mutant mice with a deletion of Reelin, its lipoprotein receptors, or its intracellular adaptor protein Disabled-1 (Dab1), exhibit nociceptive abnormalities: thermal (heat) hyperalgesia and reduced mechanical sensitivity. To determine dorsal horn alterations associated with these nociceptive abnormalities, we first characterized the correctly positioned Dab1 neurons in wild-type and mispositioned neurons in Reelin-signaling pathway mutant lumbar spinal cord. Using immunofluorescence, we found that 70% of the numerous Dab1 neurons in Reln+/+ laminae I-II and 67% of those in the lateral reticulated area and lateral spinal nucleus (LSN) co-express the LIM-homeobox transcription factor 1 beta (Lmx1b), an excitatory glutamatergic neuron marker. Evidence of Dab1- and Dab1-Lmx1b neuronal positioning errors was found within the isolectin B4 terminal region of Reln-/- lamina IIinner and in the lateral reticulated area and LSN, where about 50% of the Dab1-Lmx1b neurons are missing. Importantly, Dab1-Lmx1b neurons in laminae I-II and the lateral reticulated area express Fos after noxious thermal or mechanical stimulation and thus participate in these circuits. In another pain relevant locus - the lateral cervical nucleus (LCN), we also found about a 50% loss of Dab1-Lmx1b neurons in Reln-/- mice. We suggest that extensively mispositioned Dab1 projection neurons in the lateral reticulated area, LSN, and LCN and the more subtle positioning errors of Dab1 interneurons in laminae I-II contribute to the abnormalities in pain responses found in Reelin-signaling pathway mutants. PMID- 28083886 TI - Incidence and risk estimate of drug-induced agranulocytosis in Hong Kong Chinese. A population-based case-control study. AB - PURPOSE: Drug-induced agranulocytosis is a rare but life-threatening adverse drug reaction. Its epidemiology in Chinese is largely unknown. This study aimed to estimate the incidence, mortality, and risk of the drugs associated with agranulocytosis in Hong Kong Chinese. METHODS: A population-based case-control study was conducted using the Clinical Data Analysis and Reporting System, a database managed by the Hong Kong Hospital Authority. Patients with drug-induced agranulocytosis from 1 January 2004 to 31 December 2013 were identified. World Health Organization causality assessment was used to evaluate the possible drug aetiology of each case. Odd ratios (ORs) of the drug exposure were calculated using exact conditional logistic regression. RESULTS: A total of 155 cases of drug-induced agranulocytosis were identified. Mean age was 51.4 years, and 95 cases were female. Incidence rate was estimated to be 2.2 cases per million person-years, and the all-cause mortality of patients with drug-induced agranulocytosis was 3.9%. Among the cases, the most common associated drug groups were antithyroid drugs (41.9%), antimicrobials (20%), anticonvulsants (10.3%), and antipsychotics (6.5%). Carbimazole had the highest risk of agranulocytosis (adjusted OR 416.7, 95% confidence interval (CI) 51.5-3372.9) with an incidence of 9.2 (95%CI 6.9-12.1) per 10 000 users and 3.6 (95%CI 2.7-4.8) per 10 000 user years. Other drugs with significant risk included cephalosporins, clozapine, penicillins, phenytoin, and propyl thiouracil. CONCLUSIONS: The incidence and mortality in Hong Kong Chinese were relatively low compared to Caucasians. Antithyroid drugs were the most common implicated drug class, and carbimazole had the highest risk of agranulocytosis. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28083887 TI - Stability of the Gross Motor Function Classification System in children and adolescents with cerebral palsy: a retrospective cohort registry study. AB - AIM: To investigate the stability and to determine factors that affect change in the Gross Motor Function Classification System (GMFCS) in a sample from the total population with cerebral palsy (CP) in two regions of Sweden. METHOD: Retrospective cohort registry study based on the follow-up programme for CP. Children with CP and a minimum of two GMFCS ratings were included. Subtype, sex, ages at GMFCS ratings, time between ratings, number of ratings, assessor change, and birth cohort were analysed in relation to initial GMFCS levels, with descriptive statistics and logistic regression models. RESULTS: Ninety-three per cent (n=736) of children with CP born between 1990 and 2007 were included, resulting in 7922 assessments between 1995 and 2014. Fifty-six per cent of the children received the same GMFCS rating at all assessments, with a median of 11 individual GMFCS ratings (range 2-21) and a median of three different assessors (range 1-10). Changes were often transient; downward change (higher performance) was more likely in GMFCS levels II and III than in the other levels. The probability of upward change (lower performance) was lowest in unilateral spastic CP. INTERPRETATION: The results support the stability of the GMFCS shown previously and add new information on the properties of the classification. PMID- 28083888 TI - Rechargeable or Nonrechargeable Deep Brain Stimulation in Dystonia: A Cost Analysis. AB - OBJECTIVE: Deep brain stimulation of the internal Globus Pallidus (GPi DBS) delivered by an implantable neurostimulator (INS) is an established, effective, and safe treatment option for patients with medically refractory primary dystonia. Compared to other DBS targets, the battery life of the INS is substantially shorter due to the higher energy demands required to penetrate the GPi resulting in faster battery depletion and more frequent hospitalizations for INS replacement. We, therefore, performed a cost analysis to compare a rechargeable DBS system, Activa(r)RC, with nonrechargeable systems, from the perspective of the French public health insurer. MATERIALS AND METHODS: To estimate the cost of INS replacement in the nonrechargeable cohort, and costs potentially avoided in the hypothetical Activa(r) RC cohort, the medical records of patients who had undergone GPi DBS with a nonrechargeable INS between 1996 and 2010 at a center in France were accessed. Replacement rates were estimated for up to nine years. RESULTS: With Activa(r) RC, a total of 315 hospitalizations for replacement procedures would have been avoided over nine years compared with a nonrechargeable INS, resulting in a discounted mean direct medical cost per patient over nine years of ?50,119 with a nonrechargeable INS and ?33,306 with Activa(r) RC, a reduction of 34%. CONCLUSIONS: The adoption of a rechargeable instead of a nonrechargeable INS for eligible patients with dystonia may provide substantial savings to the public health insurer in France. PMID- 28083889 TI - A prospective clinical assessment of anatomic variability of the submental vascularized lymph node flap. AB - INTRODUCTION: The vascularized submental lymph node (VSLN) flap has become a popular choice for the treatment of lymphedema. Despite its favorable characteristics, anatomic variability exists, making the harvest of this flap challenging. Knowledge and characterization of anatomic variability can aid the surgeon in safe and effective flap harvest. METHODS: A prospective analysis of all patients who underwent VSLN flap transfer for lymphedema was performed. Demographics, operative details, and post-operative recovery were analyzed for included patients. Intraoperative videography and detailed anatomic drawings of each case were reviewed to accurately account for anatomic variability and details. RESULTS: Forty-two patients were identified during the study period. Arteriovenous anatomic variability (A1-A2 and V1-V4) existed, with most patients having the artery and vein present superior to the submandibular gland (A1V1; 31%), with other combinations occurring less frequently. Flap harvest time was found to be significantly increased with an intraglandular arterial course (P < 0.01). CONCLUSIONS: The VSLN flap can be safely and effectively harvested with knowledge of arteriovenous anatomic variability. Most commonly, the artery and vein travel together superior to the submandibular gland, but other variations exist, which may add time to surgical flap harvest and increased need for dissection. J. Surg. Oncol. 2017;115:43-47. (c) 2017 Wiley Periodicals, Inc. PMID- 28083890 TI - Amhezole, A Novel Fungal Secondary Metabolite from Aspergillus terreus for Treatment of Microbial Mouth Infection. AB - Bio-guided fractionation of Aspergillus terreus extract leads to isolation of a novel terpenoidal secondary metabolite. The isolated compound and the total alcoholic extract of Aspergillus terreus showed a remarkable activity against microbial mouth infections; namely, Candida albicans, Lactobacillus acidophilus, Streptococcus gordonii, and S. mutan. Moreover, the Minimum Inhibitory Concentration of the isolated compound was determined and showed low values. The combination of each of the alcoholic extract of A. terreus and the isolated compound Coe-Comfort tissue conditioner inhibited the growth of Candida albicans at concentrations of 500 and 7.81 ug/mL, respectively, Lactobacillus acidophilus at concentrations of 250 and 7.81 ug/mL, respectively, Streptococcus gordonii at concentrations of 1000 and 62.50 ug/mL, respectively, and S. mutans at concentrations of 1000 and 125 ug/mL, respectively. The oral dosing of the extract and the isolated compound did not show any significant effect on the activity of alanine aminotransferase, aspirate aminotransferase, and the levels of blood urea and serum creatinine. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28083891 TI - Functional activation independently contributes to naming ability and relates to lesion site in post-stroke aphasia. AB - Language network reorganization in aphasia may depend on the degree of damage in critical language areas, making it difficult to determine how reorganization impacts performance. Prior studies on remapping of function in aphasia have not accounted for the location of the lesion relative to critical language areas. They rectified this problem by using a multimodal approach, combining multivariate lesion-symptom mapping and fMRI in chronic aphasia to understand the independent contributions to naming performance of the lesion and the activity in both hemispheres. Activity was examined during two stages of naming: covert retrieval, and overt articulation. Regions of interest were drawn based on over- and under-activation, and in areas where activity had a bivariate relationship with naming. Regressions then tested whether activation of these regions predicted naming ability, while controlling for lesion size and damage in critical left hemisphere naming areas, as determined by lesion-symptom mapping. Engagement of the right superior temporal sulcus (STS) and disengagement of the left dorsal pars opercularis (dPOp) during overt naming was associated with better than predicted naming performance. Lesions in the left STS prevented right STS engagement and resulted in persistent left dPOp activation. In summary, changes in activity during overt articulation independently relate to naming outcomes, controlling for stroke severity. Successful remapping relates to network disruptions that depend on the location of the lesion in the left hemisphere. Hum Brain Mapp 38:2051-2066, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28083892 TI - Evidence of regulatory myeloid dendritic cells and circulating inflammatory epidermal dendritic cells-like modulated by Toll-like receptors 2 and 7/8 in adults with atopic dermatitis. AB - BACKGROUD: Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by intense pruritus and xerosis. Dendritic cells (DC) play an essential role in tissue inflammation in atopic dermatitis (AD) skin, especially the inflammatory epidermal dendritic cells (IDEC), a particular subset of myeloid dendritic cells (mDC). The aim of the present study was to assess the phenotype and function of mDC and circulating IDEC-like in peripheral blood mononuclear cells (PBMC) of adults with AD. METHODS: We selected 21 AD patients and 21 non-AD controls, age and gender matched. Expressions of FcepsilonRI, CD36, TNF, IFN- gamma, and IL-10 in mDC were analyzed by flow cytometry under various stimuli, such as staphylococcal enterotoxin B (SEB), TLR2 (Pam3CSK4), TLR4 (LPS), and TLR7/8 (CL097) agonists. RESULTS: The most prominent findings in AD patients were: (i) enhanced frequency of IL-10 under TLR4 (LPS), and decreased frequency of IFN-gamma and TNF under TLR2 (Pam3CSK4) and 7/8 (CL097) stimulation in classic mDC; (ii) elevation of circulating IDEC-like frequency with TLR2 (Pam3CSK4) stimuli, augmented frequency of IFN-gamma in nonstimulated condition, and of IL 10 under TLR7/8 (CL097) stimuli in IDEC-like population. CONCLUSIONS: In AD individuals, classic mDC showed an immunomodulatory profile, favoring tolerance in a combined action with IDEC-like, and inducing Th1 polarization. Our findings indicate a potential role of IDEC-like in the maintenance of inflammation in atopic dermatitis patients; moreover, IDEC-like may exert a regulatory impact on T cells of AD individuals through IL-10, often induced by agonist mimicking single stranded RNA virus. PMID- 28083893 TI - Malocclusion traits and oral health-related quality of life in Finnish adults. AB - AIM: The aim of this study was to examine the association of increased overjet, cross-bite/scissor-bite and increased overbite/open bite with oral health-related quality of life (OHRQoL) among Finnish adults using nationally representative data. METHODS: Part of the data from the Health 2000 Survey, Finland, was used in this study. A total of 4711 people were included, representing adults aged >=30 years. The outcome variable was OHRQoL severity which was measured using the 14 item Oral Health Impact Profile (OHIP-14). Three malocclusion traits (increased overjet, cross-bite/scissor-bite and increased overbite/open bite) were used as explanatory variables. Age group, marital status, education level, income, employment status, having at least one decayed tooth or periodontal pocket >=6 mm, the number of contacting pairs of teeth, denture status and self-reported general health status were controlled for. A series of multivariable zero Inflated Poisson (ZIP) models were used to calculate incidence rate ratios (IRR) for the nonzero scores and odds ratios (OR) of having no event. RESULTS: The weighted prevalence of increased overjet was 8.4%, while it was 23.6% for cross bite/scissor-bite and 6.7% for increased overbite/open bite. The mean (SE) OHIP 14 (OHRQoL severity) was 2.8 (0.92); the mean score was highest in the pain domain and lowest in the physical and social disability domains. The mean OHIP-14 score was higher in people with increased overjet but not significantly different in people with cross-bite/scissor-bite or with increased overbite/open bite. In multivariate ZIP models, people with increased overjet had a 10% higher OHIP-14 score than people with normal overjet. Increased overjet was associated only with the physical disability domain. Cross-bite/scissor-bite was associated only with the social disability domain, and psychological disability was associated with increased overbite/open bite. CONCLUSION: People with increased overjet had significantly poorer OHRQoL than people with normal overjet in a nationally representative population of Finnish adults >=30 years. Other malocclusion traits were not associated with OHRQoL. However, all three malocclusion traits were associated with either physical or psychological or social disability domains of the OHRQoL. PMID- 28083894 TI - The amino acid transporter SLC36A4 regulates the amino acid pool in retinal pigmented epithelial cells and mediates the mechanistic target of rapamycin, complex 1 signaling. AB - The dry (nonneovascular) form of age-related macular degeneration (AMD), a leading cause of blindness in the elderly, has few, if any, treatment options at present. It is characterized by early accumulation of cellular waste products in the retinal pigmented epithelium (RPE); rejuvenating impaired lysosome function in RPE is a well-justified target for treatment. It is now clear that amino acids and vacuolar-type H+ -ATPase (V-ATPase) regulate the mechanistic target of rapamycin, complex 1 (mTORC1) signaling in lysosomes. Here, we provide evidence for the first time that the amino acid transporter SLC36A4/proton-dependent amino acid transporter (PAT4) regulates the amino acid pool in the lysosomes of RPE. In Cryba1 (gene encoding betaA3/A1-crystallin) KO (knockout) mice, where PAT4 and amino acid levels are increased in the RPE, the transcription factors EB (TFEB) and E3 (TFE3) are retained in the cytoplasm, even after 24 h of fasting. Consequently, genes in the coordinated lysosomal expression and regulation (CLEAR) network are not activated, and lysosomal function remains low. As these mice age, expression of RPE65 and lecithin retinol acyltransferase (LRAT), two vital visual cycle proteins, decreases in the RPE. A defective visual cycle would possibly slow down the regeneration of new photoreceptor outer segments (POS). Further, photoreceptor degeneration also becomes obvious during aging, reminiscent of human dry AMD disease. Electron microscopy shows basal laminar deposits in Bruch's membrane, a hallmark of development of AMD. For dry AMD patients, targeting PAT4/V-ATPase in the lysosomes of RPE cells may be an effective means of preventing or delaying disease progression. PMID- 28083895 TI - Surface-based vertexwise analysis of morphometry and microstructural integrity for white matter tracts in diffusion tensor imaging: With application to the corpus callosum in Alzheimer's disease. AB - In this article, we present a unified statistical pipeline for analyzing the white matter (WM) tracts morphometry and microstructural integrity, both globally and locally within the same WM tract, from diffusion tensor imaging. Morphometry is quantified globally by the volumetric measurement and locally by the vertexwise surface areas. Meanwhile, microstructural integrity is quantified globally by the mean fractional anisotropy (FA) and trace values within the specific WM tract and locally by the FA and trace values defined at each vertex of its bounding surface. The proposed pipeline consists of four steps: (1) fully automated segmentation of WM tracts in a multi-contrast multi-atlas framework; (2) generation of the smooth surface representations for the WM tracts of interest; (3) common template surface generation on which the localized morphometric and microstructural statistics are defined and a variety of statistical analyses can be conducted; (4) multiple comparison correction to determine the significance of the statistical analysis results. Detailed herein, this pipeline has been applied to the corpus callosum in Alzheimer's disease (AD) with significantly decreased FA values and increased trace values, both globally and locally, being detected in patients with AD when compared to normal aging populations. A subdivision of the corpus callosum in both hemispheres revealed that the AD pathology primarily affects the body and splenium of the corpus callosum. Validation analyses and two multiple comparison correction strategies are provided. Hum Brain Mapp 38:1875-1893, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28083896 TI - Loss of protohaem IX farnesyltransferase in mature dentate granule cells impairs short-term facilitation at mossy fibre to CA3 pyramidal cell synapses. AB - KEY POINTS: Neurodegenerative disorders can exhibit dysfunctional mitochondrial respiratory chain complex IV activity. Conditional deletion of cytochrome c oxidase, the terminal enzyme in the respiratory electron transport chain of mitochondria, from hippocampal dentate granule cells in mice does not affect low frequency dentate to CA3 glutamatergic synaptic transmission. High-frequency dentate to CA3 glutamatergic synaptic transmission and feedforward inhibition are significantly attenuated in cytochrome c oxidase-deficient mice. Intact presynaptic mitochondrial function is critical for the short-term dynamics of mossy fibre to CA3 synaptic function. ABSTRACT: Neurodegenerative disorders are characterized by peripheral and central symptoms including cognitive impairments which have been associated with reduced mitochondrial function, in particular mitochondrial respiratory chain complex IV or cytochrome c oxidase activity. In the present study we conditionally removed a key component of complex IV, protohaem IX farnesyltransferase encoded by the COX10 gene, in granule cells of the adult dentate gyrus. Utilizing whole-cell patch-clamp recordings from morphologically identified CA3 pyramidal cells from control and complex IV deficient mice, we found that reduced mitochondrial function did not result in overt deficits in basal glutamatergic synaptic transmission at the mossy-fibre synapse because the amplitude, input-output relationship and 50 ms paired-pulse facilitation were unchanged following COX10 removal from dentate granule cells. However, trains of stimuli given at high frequency (> 20 Hz) resulted in dramatic reductions in short-term facilitation and, at the highest frequencies (> 50 Hz), also reduced paired-pulse facilitation, suggesting a requirement for adequate mitochondrial function to maintain glutamate release during physiologically relevant activity patterns. Interestingly, local inhibition was reduced, suggesting the effect observed was not restricted to synapses with CA3 pyramidal cells via large mossy-fibre boutons, but rather to all synapses formed by dentate granule cells. Therefore, presynaptic mitochondrial function is critical for the short-term dynamics of synapse function, which may contribute to the cognitive deficits observed in pathological mitochondrial dysfunction. PMID- 28083897 TI - Objective measurements of skin surface roughness after microdermabrasion treatment. AB - BACKGROUND: The aim of this article is to present a new methodology for assessment of skin topology using a three-dimensional image (3D). METHODS: The measurement of the skin surface roughness is based on 3D scanning of silicone replicas by chromatic aberration length technique in a contactless manner, i.e. by a polychromatic light beam. Analysis of the skin surface reprints was performed using Talymap, Gold version. Results were analysed by fractal geometry, which allows to evaluate changes of the skin surface before and after application of cosmetics and instrumental cosmetological techniques. The methodology was applied for objective assessment of the effects of diamond microdermabrasion on the skin surface roughness. Measurements were performed on 23 volunteers in the age group of 31-67 years. RESULTS: Based on the results of skin surface scanning after the treatment with diamond microdermabrasion it may be concluded that inequalities of the skin surface are reduced immediately after exfoliation. However, this effect mostly diminishes within 14 days after treatment. The entire study ultimately suggests that the instrumental method used only leads to improvement of the skin surface immediately after its application. Thermo vision images of the skin surface temperature were obtained during the application of the abrasive method. The experimental results showed that the skin is rather cooled than heated by the treatment. CONCLUSION: This study is focused on the development of a methodology for objective measurement of changes in treated skin relief using 3D scanning. The results are evaluated using fractal dimension. The output may also include also an enlarged model of the skin surface made by 3D printer, which can serve for illustrative communication with the client. PMID- 28083898 TI - Engineering the production of conjugated fatty acids in Arabidopsis thaliana leaves. AB - The seeds of many nondomesticated plant species synthesize oils containing high amounts of a single unusual fatty acid, many of which have potential usage in industry. Despite the identification of enzymes for unusual oxidized fatty acid synthesis, the production of these fatty acids in engineered seeds remains low and is often hampered by their inefficient exclusion from phospholipids. Recent studies have established the feasibility of increasing triacylglycerol content in plant leaves, which provides a novel approach for increasing energy density of biomass crops. Here, we determined whether the fatty acid composition of leaf oil could be engineered to accumulate unusual fatty acids. Eleostearic acid (ESA) is a conjugated fatty acid produced in seeds of the tung tree (Vernicia fordii) and has both industrial and nutritional end-uses. Arabidopsis thaliana lines with elevated leaf oil were first generated by transforming wild-type, cgi-58 or pxa1 mutants (the latter two of which contain mutations disrupting fatty acid breakdown) with the diacylglycerol acyltransferases (DGAT1 or DGAT2) and/or oleosin genes from tung. High-leaf-oil plant lines were then transformed with tung FADX, which encodes the fatty acid desaturase/conjugase responsible for ESA synthesis. Analysis of lipids in leaves revealed that ESA was efficiently excluded from phospholipids, and co-expression of tung FADX and DGAT2 promoted a synergistic increase in leaf oil content and ESA accumulation. Taken together, these results provide a new approach for increasing leaf oil content that is coupled with accumulation of unusual fatty acids. Implications for production of biofuels, bioproducts, and plant-pest interactions are discussed. PMID- 28083899 TI - Canaloplasty with Stegmann Canal Expander for primary open-angle glaucoma: two year clinical results. AB - PURPOSE: To examine longer-term postsurgical safety and efficacy of a new expander for Schlemm's canal. METHODS: In a non-comparative, prospective study, 42 White patients with medically uncontrolled primary open-angle glaucoma (POAG) underwent primary canaloplasty with >2-year follow-up. The bleb-independent procedure comprised catheter-assisted canaloplasty and implantation of two Stegmann Canal Expanders to maintain trabecular distension and canal patency over 180 degrees . Intraocular pressure (IOP), glaucoma medication use and complications were assessed. RESULTS: Mean IOP was 26.8 +/- 5.6 mmHg presurgery, 12.8 +/- 1.5 mmHg at 6 months, 13.2 +/- 1.2 mmHg at 12 months and 13.3 +/- 2.5 mmHg at 24 months (p < 0.001). Rate of complete success, defined as IOP <=21, <=18 and <=16 mmHg and a >= 30% IOP reduction, was 85% (95% CI: 0.76-0.95), 85% (0.76-0.95) and 82% (0.70-0.96) at 12 months and 83% (0.73-0.94), 80% (0.70-0.92) and 80% (0.70-0.92) at 24 months. Preoperative factors were not significant predictors of <=16 mmHg IOP reduction: IOP (hazard ratio [HR]: 0.68; 95% CI: 0.44 1.04; p = 0.08), mean visual defect (1.06; 0.90-1.20; p = 0.47), number of medications (0.59; 0.17-2.14; p = 0.42) and age (0.96; 0.87-1.13; p = 0.41). Number of medications dropped from 2.8 +/- 0.4 presurgery to 0.2 +/- 0.5 postsurgery (p < 0.001). Mean preoperative best-corrected visual acuity was 0.19 +/- SD 0.21 (range: 0-1.6), and logMAR was similar to 0.23 +/- 0.16 (range: 0 1.6; p = 0.42) after a mean follow-up of 27.4 months. Complications included peripheral Descemet's membrane detachment (7.2%) and trimming of the expander (4.7%) during surgery, and transient microhyphaema (23.8%) and IOP elevation (7.2%) postsurgery. CONCLUSION: Canaloplasty with the Stegmann Canal Expander was a safe and effective procedure to reduce IOP in White patients with moderate to advanced POAG. PMID- 28083900 TI - Penile amebiasis mimicking penile squamous cell carcinoma. PMID- 28083901 TI - Combining randomized and non-randomized evidence in network meta-analysis. AB - Non-randomized studies aim to reveal whether or not interventions are effective in real-life clinical practice, and there is a growing interest in including such evidence in the decision-making process. We evaluate existing methodologies and present new approaches to using non-randomized evidence in a network meta analysis of randomized controlled trials (RCTs) when the aim is to assess relative treatment effects. We first discuss how to assess compatibility between the two types of evidence. We then present and compare an array of alternative methods that allow the inclusion of non-randomized studies in a network meta analysis of RCTs: the naive data synthesis, the design-adjusted synthesis, the use of non-randomized evidence as prior information and the use of three-level hierarchical models. We apply some of the methods in two previously published clinical examples comparing percutaneous interventions for the treatment of coronary in-stent restenosis and antipsychotics in patients with schizophrenia. We discuss in depth the advantages and limitations of each method, and we conclude that the inclusion of real-world evidence from non-randomized studies has the potential to corroborate findings from RCTs, increase precision and enhance the decision-making process. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28083903 TI - Editor's Note. PMID- 28083902 TI - Liver imaging reporting and data system category 4 observations in MRI: Risk factors predicting upgrade to category 5. AB - PURPOSE: To identify demographic and imaging features in magnetic resonance imaging (MRI) that are associated with upgrade of Liver Imaging Reporting and Data System (LI-RADS) category 4 (LR-4) observations to category 5 (LR-5), and to assess their effects on risk of upgrade and time to upgrade. MATERIALS AND METHODS: Institutional Review Board approval was obtained for this retrospective, dual-institution Health Insurance Portability and Accountability Act (HIPAA) compliant study. Radiologists reviewed 1.5T and 3T MRI examinations for 181 LR-4 observations in 139 patients, as well as follow-up computed tomography (CT) and MRI examinations and treatment. A stepwise multivariate Cox proportional hazards model analysis was performed to identify predictive risk factors for upgrade to LR-5, including patient demographics and LI-RADS imaging features. Overall cumulative risk of upgrade was calculated by using the Kaplan-Meier method. The cumulative risks were compared in the presence/absence of significant predictive risk factors using the log-rank test. RESULTS: The independent significant predictive risk factors in the 56 LR-4 observations that upgraded to LR-5 were mild-moderate T2 hyperintensity (P < 0.001; hazard ratio = 1.84), growth (P < 0.001; hazard ratio = 3.71), and hepatitis C infection (P = 0.02; hazard ratio = 1.69). The overall 6-month cumulative risk of upgrade was 32.7%. The 6-month cumulative risk rate was significantly higher in the presence of T2 hyperintensity (P = 0.03; 48.1% vs. 25.4%). CONCLUSION: For LR-4 observations, mild-moderate T2 hyperintensity, threshold growth, and hepatitis C infection are associated with significantly higher risk of upgrade to LR-5. Although mild moderate T2 hyperintensity was the most useful risk factor for predicting upgrade, actual risk level was only mildly elevated, and the risk of upgrade associated with LR-4 observations is similar across subtypes. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 5 J. MAGN. RESON. IMAGING 2017;46:783-792. PMID- 28083904 TI - Exposure to subthreshold dose of UVR-B induces apoptosis in the lens epithelial cells and does not in the lens cortical fibre cells. AB - PURPOSE: The aim of this study was to investigate in which part of the lens in vivo exposure to subthreshold dose of UVR-B radiation induces apoptosis. METHODS: Twenty 6-week-old female albino Sprague-Dawley rats were exposed to subthreshold dose (1 kJ/m2 ) of UVR-B unilaterally and killed at 120 hr after exposure. Lenses were enucleated and dissected on three regions: the lens epithelium, the cortex and the nucleus. The lens nucleus then was removed. Apoptosis markers p53 and caspase 3 were used to study apoptosis in the lens regions. qRT-PCR and Western blot were utilized to analyse the lenses. RESULTS: TP53 and CASP3 mRNA expressions are increased in exposed lenses, both in the lens epithelium and in the cortex regions, in relation to non-exposed lenses. Expression of p53 protein is increased in exposed lens epithelium in relation to non-exposed lens epithelium. Caspase 3 protein is expressed in exposed lens epithelial cells, while it is not expressed in non-exposed lens epithelial cells. p53 and caspase 3 proteins are not expressed in either exposed nor non-exposed lens fibre cells. CONCLUSION: Exposure to UVR-B increases mRNA transcription of apoptosis marker p53 in vivo in both regions of the lens and of apoptosis marker caspase 3 in the lens cortex. Exposure to UVR-B increases p53 and caspase 3 proteins expression just in the lens epithelium. In vivo exposure to subthreshold dose of UVR-B induces apoptosis in the lens epithelial cells and does not in the lens fibre cells. PMID- 28083905 TI - Can parents provide hand function training for their child with cerebral palsy? PMID- 28083906 TI - Diverging lesion and connectivity patterns influence early and late swallowing recovery after hemispheric stroke. AB - Knowledge about the recovery of oral intake after hemispheric stroke is important to guide therapeutic decisions, including the administration of enteral tube feeding and the choice of the appropriate feeding route. They aimed to determine the localization and connectivity of lesions in impaired recovery versus recovered swallowing after initially dysphagic stroke. Sixty-two acute ischemic hemispheric stroke patients with impaired oral intake were included in a prospective observational cohort study. Voxel-based lesion-symptom mapping and probabilistic tractography were used to determine the association of lesion location and connectivity with impaired recovery of oral intake >=7 days (indication for early tube feeding) and >=4 weeks (indication for percutaneous endoscopic gastrostomy feeding) after stroke. Two distinct patterns influencing recovery of swallowing were recognized. Firstly, impaired recovery of oral intake after >=7 days was significantly associated with lesions of the superior corona radiata (65% of statistical map, P < 0.05). The affected fibers were connected with the thalamus, primary motor, and supplemental motor areas and the basal ganglia. Secondly, impaired recovery of oral intake after >=4 weeks significantly correlated with lesions of the anterior insula (54% of statistical map, P < 0.05), which was connected to adjacent operculo-insular areas of deglutition. These findings indicate that early swallowing recovery is influenced by white matter lesions disrupting thalamic and corticobulbar projection fibers. Late recovery is determined by specific cortical lesions affecting association fibers. This knowledge may help clinicians to identify patients at risk of prolonged swallowing problems that would benefit from enteral tube feeding. Hum Brain Mapp 38:2165-2176, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28083907 TI - Pectoral nerve blocks are useful for axillary sentinel lymph node biopsy in malignant tumors on the upper extremities. PMID- 28083908 TI - Latitude as a co-driver of human gut microbial diversity? AB - The human gut microbial diversity has been reported to be lower in industrialized populations as compared to non-industrialized ones. Since it is also reduced in individuals with some metabolic and inflammatory diseases as compared to healthy ones, this "loss" of diversity in industrialized populations is currently considered to be a public health issue. However, little is known on the mechanisms that are causing this pattern. Is it due to differences in diet, sanitation, medication, host genetics, and/or other unidentified factors? In this review, we propose that part of this decrease in diversity is driven by latitude, as all studied industrialized countries are in higher latitudes than non industrialized ones, and latitude is known to correlate with species diversity. Reanalyzing available data, we find that part of the gut microbial diversity is significantly correlated with latitude, which might therefore exacerbate the effect of lifestyle. Intriguingly, the observation of a higher diversity in industrialized countries has not been replicated in other human microbiomes. PMID- 28083909 TI - Increased PLEKHO1 within osteoblasts suppresses Smad-dependent BMP signaling to inhibit bone formation during aging. AB - Emerging evidence indicates that the dysregulation of protein ubiquitination plays a crucial role in aging-associated diseases. Smad-dependent canonical BMP signaling pathway is indispensable for osteoblastic bone formation, which could be disrupted by the ubiquitination and subsequent proteasomal degradation of Smad1/5, the key molecules for BMP signaling transduction. However, whether the dysregulation of Smad1/5 ubiquitination and disrupted BMP signaling pathway is responsible for the age-related bone formation reduction is still underexplored. Pleckstrin homology domain-containing family O member 1 (PLEKHO1) is a previously identified ubiquitination-related molecule that could specifically target the linker region between the WW domains of Smurf1 to promote the ubiquitination of Smad1/5. Here, we found an age-related increase in the expression of PLEKHO1 in bone specimens from either fractured patients or aging rodents, which was associated with the age-related reduction in Smad-dependent BMP signaling and bone formation. By genetic approach, we demonstrated that loss of Plekho1 in osteoblasts could promote the Smad-dependent BMP signaling and alleviated the age related bone formation reduction. In addition, osteoblast-specific Smad1 overexpression had beneficial effect on bone formation during aging, which could be counteracted after overexpressing Plekho1 within osteoblasts. By pharmacological approach, we showed that osteoblast-targeted Plekho1 siRNA treatment could enhance Smad-dependent BMP signaling and promote bone formation in aging rodents. Taken together, it suggests that the increased PLEKHO1 could suppress Smad-dependent BMP signaling to inhibit bone formation during aging, indicating the translational potential of targeting PLEKHO1 in osteoblast as a novel bone anabolic strategy for reversing established osteoporosis during aging. PMID- 28083910 TI - Post-mastectomy radiation therapy and overall survival after neoadjuvant chemotherapy. AB - BACKGROUND: The role of postmastectomy radiation therapy (PMRT) after neoadjuvant chemotherapy (NAC) and mastectomy is unclear, especially in patients that have post-treatment tumor negative axillary nodes (ypN0). METHODS: The National Cancer Data Base was used to identify women that had PMRT after NAC and mastectomy for clinically node positive (cN1-2) disease from 2004 to 2008. Median follow-up time was 69 months. RESULTS: 8,321 patients were included for analysis, and 6140 (65.6%) had cN1 disease and 2181 (23.3%) had cN2 disease. On adjusted survival analysis, PMRT was associated with an overall survival (OS) benefit in both patients with cN1 (5-yr OS 75.8% vs. 71.9%, P < 0.01) and cN2 (5-yr OS 69.2% vs. 58.6%, P < 0.01) disease. In the subgroup of patients that were ypN0 after NAC, there was no significant survival difference (P > 0.11) for PMRT compared to those patients who were not ypN0, except for patients with hormone-receptor negative tumors, who had improved OS with PMRT (HR 0.65, P < 0.01). CONCLUSIONS: PMRT is associated with improved OS in patients with cN1 and cN2 disease after NAC and mastectomy. However, in the subgroup of patients that were ypN0 after NAC, PMRT improved OS for hormone-receptor negative patients but not hormone receptor positive patients. PMID- 28083911 TI - Degradation of methomyl by the combination of Aminobacter sp. MDW-2 and Afipia sp. MDW-3. AB - : Methomyl (S-methyl N-(methylcarbamoyloxy) thioacetimidate) is a kind of oxime carbamate insecticide. It is considered to be extremely toxic to nontarget organism. To date, no pure culture or consortium has been reported to have the ability to degrade methomyl completely. In this study, a methomyl-degrading enrichment E1 was obtained by using the sludge from the wastewater-treating system of a pesticide manufacturer as the original inoculant. Two bacterial strains named MDW-2 and MDW-3 were isolated from this enrichment, and they were preliminarily identified as Aminobacter sp. and Afipia sp. respectively. Strains MDW-2 and MDW-3 could coexist and degrade 50 mg l-1 methomyl completely within 3 days by the cooperative metabolism. Methomyl was first converted to methomyl oxime and methylcarbamic acid by strain MDW-2, and the latter could be used as the carbon source for the growth of strain MDW-2. But methomyl oxime could not be sequentially degraded by strain MDW-2. However, it could be degraded and used as the carbon source by strain MDW-3. SIGNIFICANCE AND IMPACT OF THE STUDY: This study presents a bacterial combination of Aminobacter sp. MDW-2 and Afipia sp. MDW-3, which could degrade methomyl completely by biochemical cooperation. This study also proposes the biodegradation pathway of methomyl for the first time and highlights the application potential of a bacterial combination in the remediation of methomyl-contaminated environments. PMID- 28083912 TI - Targeting stroma in pancreatic cancer: Promises and failures of targeted therapies. AB - Desmoplasia or abundant fibrotic stroma is a typical property of most malignancies, which has a great effect on tumorigenesis, angiogenesis, and resistance to therapy. The activated stroma cells comprises several cell types including endothelial cells, nerve cells, inflammatory/macrophages cells, stellate cells, and extracellular matrix. In other word, the interactions of cancer-stroma modulate tumorigenesis, therapy resistance, and poor delivery of drugs. Therefore, targeting the tumor stroma in combination with conventional chemotherapeutic agents could provide a promising approach in the treatment of pancreatic cancer. This review summarizes the current knowledge about pancreatic stellate cells, targeting stroma compartments with particular emphasis on preclinical, and clinical trials on targeting of stroma as an option in pancreatic cancer treatment. PMID- 28083914 TI - Synthesis and biological evaluation of 1,2,4-triazole-3-thione and 1,3,4 oxadiazole-2-thione as antimycobacterial agents. AB - Resistance among dormant mycobacteria leading to multidrug-resistant and extremely drug-resistant tuberculosis is one of the major threats. Hence, a series of 1,2,4-triazole-3-thione and 1,3,4-oxadiazole-2-thione derivatives (4a 5c) have been synthesized and screened for their antitubercular activity against Mycobacterium tuberculosis H37Ra (H37Ra). The triazolethiones 4b and 4v showed high antitubercular activity (both MIC and IC50 ) against the dormant H37Ra by in vitro and ex vivo. They were shown to have more specificity toward mycobacteria than other Gram-negative and Gram-positive pathogenic bacteria. The cytotoxicity was almost insignificant up to 100 MUg/ml against THP-1, A549, and PANC-1 human cancer cell lines, and solubility was high in aqueous solution, indicating the potential of developing these compounds further as novel therapeutics against tuberculosis infection. PMID- 28083913 TI - Gadolinium-based contrast agents: A comprehensive risk assessment. AB - : Gadolinium-based contrast agents (GBCAs) have been used in magnetic resonance imaging (MRI) since the 1980s and are now administered in up to 35% of all MRI examinations. While GBCAs were initially felt to carry minimal risk, the subsequent identification of GBCAs as the key etiologic factor in the development of nephrogenic systemic fibrosis (NSF) has raised concerns about the broader health impacts of gadolinium exposure. Clinicians, radiologists, and patients should be aware of the most up-to-date data pertaining to the risks of GBCA administration. Specific issues covered in this review article include immediate adverse reactions; pregnancy and lactation; and gadolinium deposition and toxicity, with a special focus on NSF. Practice recommendations based on the presented data, as well as current professional society guidelines, are provided for each section. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 5 J. MAGN. RESON. IMAGING 2017;46:338-353. PMID- 28083915 TI - Effect of postprocedural full-dose infusion of bivalirudin on acute stent thrombosis in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: Outcomes in a large real-world population. AB - AIM: This study aimed to evaluate the effect of prolonged full-dose bivalirudin infusion in real-world population with ST-elevation myocardial infarction (STEMI). BACKGROUND: Subgroup data as well as meta-analysis from randomized clinical trials have shown the potency of postprocedural full-dose infusion (1.75 mg/kg/h) of bivalirudin on attenuating acute stent thrombosis (ST) after primary percutaneous coronary intervention (PCI). METHODS: In this multicenter retrospective observational study, 2047 consecutive STEMI patients treated with bivalirudin during primary PCI were enrolled in 65 Chinese centers between July 2013 and May 2016. The primary outcome was acute ST defined as ARC definite/probable within 24 hours after the index procedure, and the secondary endpoints included total ST, major adverse cardiac or cerebral events (MACCE, defined as death, reinfarction, stroke, and target vessel revascularization), and any bleeding at 30 days. RESULTS: Among 2047 STEMI patients, 1123 (54.9%) were treated with postprocedural bivalirudin full-dose infusion (median 120 minutes) while the other 924 (45.1%) received low-dose (0.25 mg/kg/h) or null postprocedural infusion. A total of three acute ST (0.3%) occurred in STEMI patients with none or low-dose prolonged infusion of bivalirudin, but none was observed in those treated with post-PCI full-dose infusion (0.3% vs 0.0%, P=.092). Outcomes on MACCE (2.1% vs 2.7%, P=.402) and total bleeding (2.1% vs 1.4%, P=.217) at 30 days showed no significant difference between the two groups, and no subacute ST was observed. CONCLUSION: Post-PCI full-dose bivalirudin infusion is safe and has a trend to protect against acute ST in STEMI patients undergoing primary PCI in real-world settings. PMID- 28083917 TI - Target-based Anemia Management with Erythropoiesis Stimulating Agents (Risks and Benefits Relearned) and Iron (Still More to Learn). AB - The FDA first licensed erythropoiesis stimulating agents (ESA) for use in patients with ESRD in 1989. Hemoglobin targets for treatment with ESAs were established at the outset on the basis of descriptive pre-ESA literature and Phase I-III data in patients with ESRD. Postrelease literature in ESA-treated patients accumulating over time initially supported improvement in indices of both cardiovascular and other organ function as well as quality of life with therapy. Recommended treatment targets for hemoglobin would evolve further in the United States from four iterations of evidence- and opinion-based practice guidelines appearing between 1997 and 2007. Several randomized, controlled trials published from 1998 to 2009 examined normalization and near-normalization of hemoglobin in patients with both ESRD and CKD; they raised fundamental questions as to the safety of robust correction of anemia. These findings, taken together with subsequent actions of the FDA in ESA labeling and CMS's quality expectations for hemoglobin in payment for dialysis treatments, would result in a comprehensive reassessment of the hemoglobin targets in ESA therapy. A marked decrease in both national ESA utilization and hemoglobin attainment has ensued as a result. This discussion addresses the history of the striking changes in enthusiasm for hemoglobin-targeted anemia therapy from 1989 to the present, and similarly examines the evolution of ferritin-targeted iron administration, which has followed different-and markedly slower-historical development. PMID- 28083918 TI - Mentoring: what matters most? PMID- 28083919 TI - New approach for studying mobile genes using metagenomic analysis. PMID- 28083916 TI - Acetylated tau in Alzheimer's disease: An instigator of synaptic dysfunction underlying memory loss: Increased levels of acetylated tau blocks the postsynaptic signaling required for plasticity and promotes memory deficits associated with tauopathy. AB - Pathogenesis in tauopathies involves the accumulation of tau in the brain and progressive synapse loss accompanied by cognitive decline. Pathological tau is found at synapses, and it promotes synaptic dysfunction and memory deficits. The specific role of toxic tau in disrupting the molecular networks that regulate synaptic strength has been elusive. A novel mechanistic link between tau toxicity and synaptic plasticity involves the acetylation of two lysines on tau, K274, and K281, which are associated with dementia in Alzheimer's disease (AD). We propose that an increase in tau acetylated on these lysines blocks the expression of long term potentiation at hippocampal synapses leading to impaired memory in AD. Acetylated tau could inhibit the activity-dependent recruitment of postsynaptic AMPA-type glutamate receptors required for plasticity by interfering with the postsynaptic localization of KIBRA, a memory-associated protein. Strategies that reduce the acetylation of tau may lead to effective treatments for cognitive decline in AD. PMID- 28083920 TI - Introduction to the Issue on Computational Models of Memory: Selected Papers From the International Conference on Cognitive Modeling. PMID- 28083921 TI - Unstable bodyweight and incident type 2 diabetes mellitus: A meta-analysis. AB - AIMS/INTRODUCTION: The present meta-analysis aimed to clarify the association of unstable bodyweight with the risk of type 2 diabetes mellitus, an association that has been controversial among longitudinal studies. MATERIALS AND METHODS: An electronic literature search using EMBASE and MEDLINE was followed up to 31 August 2016. The relative risks (RRs) of type 2 diabetes mellitus in individuals with unstable bodyweight were pooled using the inverse variance method. RESULTS: Eight studies were eligible for the meta-analysis. The median duration of measurements of weight change and follow-up years for ascertaining type 2 diabetes mellitus were 13.5 and 9.4 years, respectively. The pooled RR for the least vs most stable category was 1.33 (95% confidence interval 1.12-1.57). Between-study heterogeneity was statistically significant (P = 0.048). Whether type 2 diabetes mellitus was ascertained by blood testing explained 66.0% of the variance in the logarithm of RR (P = 0.02). In three studies in which blood testing was carried out, type 2 diabetes mellitus risk was not significant (RR 1.06, 95% confidence interval 0.91-1.25). Furthermore, publication bias that inflated type 2 diabetes mellitus risk was statistically detected by Egger's test (P = 0.09). CONCLUSIONS: Unstable bodyweight might be modestly associated with the elevated risk of type 2 diabetes mellitus; although serious biases, such as diagnostic suspicion bias and publication bias, made it difficult to assess this association. PMID- 28083922 TI - Neoagarotetraose protects mice against intense exercise-induced fatigue damage by modulating gut microbial composition and function. AB - SCOPE: Exhaustive exercise stress has emerged as an important health issue, and gastrointestinal problems are a common concern during intense exercise. In this study, we investigated the potential antifatigue effects of neoagarotetraose (NAT) in mice under intense exercise stress. MATERIALS AND METHODS: Exhaustive exercise stress significantly weakened several physiological and physical parameters of the mice, including decreased food intake, reduced body weight, and impaired integrity of the intestinal epithelial barrier. Our data showed that a 16-day NAT treatment resulted in a profound change in microbiome composition, which subsequently led to widespread shifts in the functional potential of the gut microbiome. Furthermore, NAT administration significantly increased the fecal concentration of total short-chain fatty acids (p < 0.01). CONCLUSION: Together, our findings suggest that NAT may protect mice against intense exercise-induced fatigue and provide insights into the mechanisms of NAT as a potential prebiotic. PMID- 28083923 TI - Comments regarding "Hair regrowth during chemotherapy after scalp cooling technique". PMID- 28083924 TI - Differential association between affect and somatic symptoms at the between- and within-individual level. AB - OBJECTIVES: The established between-subjects associations between affect and somatic symptoms have often been interpreted as indicating a causal effect of affect on somatic symptoms, but it is doubtful whether this is valid. In this study, we evaluate the association between positive affect (PA), negative affect (NA), and somatic symptoms at both the between- and within-subject level. DESIGN AND METHODS: Diary data were collected in the context of an online study called 'HowNutsAreTheDutch'. Participants filled out an online questionnaire, three times a day for 30 consecutive days. A mixed linear model was used to test the contemporaneous and lagged associations between affect and somatic symptoms. RESULTS: Five hundred and eighty-six participants (481 females, median age 39.6 years [range 18.1-71.4]) were included with a total number of 28,264 completed questionnaires. At the between-subjects level, a positive association between NA and somatic symptoms was found (B = .60, p < .001), whereas the negative association between PA and somatic symptoms was much smaller (B = -.14, p = .062). At the within-subject level, PA (B = -.33, p < .001) was more strongly associated with somatic symptoms than NA (B = .13, p < .001). The lagged analyses showed a negative association between previous-day PA and somatic symptoms (B = .05, p = .001). CONCLUSIONS: The results suggest that NA is more important for differences in symptom levels between subjects, whereas PA is more important for variations in symptom levels within subjects. Moreover, our results suggest that an increase in PA is followed by a decrease in somatic symptoms after 24 hr, which suggests a causal effect. Statement of contribution What is already known on this subject? Affect and somatic processes are closely linked. Cross-sectional studies show, for example, that people with higher levels of negative affect tend to report more somatic symptoms. Findings between individuals, though, might camouflage processes at within-individual level, and it might not always be possible to translate findings at the population level to the individual. However, diary studies are upcoming and show more about processes on individual level. What does this study add? Highlights the difference between processes at the within-individual and the between-individual level. Shows the importance of positive affect at individual level in relation to somatic symptoms. Shows the benefits of the use of new techniques in diary studies. PMID- 28083925 TI - Controlled gas exchange in whole lung bioreactors. AB - In cellular, tissue-level or whole organ bioreactors, the level of dissolved oxygen is one of the most important factors requiring control. Hypoxic environments may lead to cellular apoptosis, while hyperoxic environments may lead to cellular damage or dedifferentiation, both resulting in loss of overall tissue function. This manuscript describes the creation, characterization and validation of a bioreactor system that can control oxygen delivery based on real time metabolic demand of cultured whole lung tissue. A mathematical model describing and predicting gas exchange within the tunable bioreactor system is developed. In addition, the inherent gas exchange properties of the bioreactor and the inherent oxygen consumption rates of native rat lungs are determined, thereby providing a quantitative relationship between system parameters and levels of dissolved oxygen. Finally, the mathematical model is validated during whole lung culture under a range of system parameters. The system presented here provides a quantitative relationship between the concentration of dissolved oxygen, tissue oxygen consumption rates, and controllable system parameters that introduce gasses into the bioreactor. This relationship not only enables the maintenance of constant levels of dissolved oxygen throughout a culture period during which cells are replicating, but also provides noninvasive and real-time estimation of the metabolic and proliferative states of native or engineered lung tissue simply through dissolved oxygen measurements. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28083926 TI - The place and willingness of professional tattooists for melanoma screening. PMID- 28083927 TI - Program changes are effective and cost-effective in increasing the amount of oil used in preparing corn soy blend porridge for treatment of moderate acute malnutrition in Malawi. AB - Corn Soy Blend (CSB) porridge is commonly prepared with oil for treatment of moderate acute malnutrition (MAM). A recent review recommended that 30 g of oil be used with 100 g of CSB to increase energy density and micronutrient absorption. This study assessed the effectiveness and cost-effectiveness of program changes aimed at achieving that target oil:CSB ratio in prepared porridge. Caregivers of children in MAM supplementary feeding programs were assigned to three groups: a control group received monthly rations of 1 L oil, 8 kg CSB in bulk, and social and behavior change communication (SBCC); intervention groups received 2.6 L oil, 8 kg CSB provided either in bulk (Group 1) or four 2 kg packages with printed messages (Group 2), and enhanced SBCC emphasizing the target oil:CSB ratio. Compared to the control, both intervention groups had higher mean added oil per 100 g CSB (18 g, p < 0.01, and 13 g, p= 0.04, higher in groups 1 and 2, respectively), and greater odds of meeting or exceeding the target ratio (28.4, p< 0.01, and 12.7, p= 0.02, in groups 1 and 2, respectively). Cost per caregiver reaching the target ratio was most favorable in Group 1 ($391 in Group 1, $527 in Group 2, and $1,666 in the control). Enhanced SBCC combined with increased oil ration resulted in increased use of oil in CSB porridge in a supplementary feeding program. Modified packaging did not improve effectiveness. However, both interventions were more cost-effective than standard programming. PMID- 28083929 TI - The risk predictive values of UK-PBC and GLOBE scoring system in Chinese patients with primary biliary cholangitis: the additional effect of anti-gp210. AB - BACKGROUND: Adequate risk stratification is critical for the management of the patients with primary biliary cholangitis (PBC). The UK-PBC and GLOBE scoring systems for prognosis of PBC have been proposed recently, but have not been validated in Asian population. AIM: To validate the UK-PBC and GLOBE scoring systems in Chinese patients for prognosis of PBC. To clarify the role of anti gp210 as a biomarker, and to investigate whether anti-gp210 could affect the prognostic values of UK-PBC and GLOBE scoring systems. METHODS: We retrospectively analysed 276 patients with PBC evaluated between September 2004 and May 2016, including 133 anti-gp210+ and 143 anti-gp210- patients. RESULTS: The 5-year adverse outcome-free survivals of anti-gp210+ vs. anti-gp210- patients were 70% and 85%, respectively (P = 0.005). Cirrhosis (P = 0.001), albumin level <=40 g/L (P = 0.011) and platelet count <=153 * 109 (P < 0.001) had a superimposition effect on anti-gp210 antibody as a risk factor. Furthermore, long term prognoses were evaluated using the UK-PBC and GLOBE scores. For UK-PBC scoring system, the area under receiver operating characteristic curve (AUROC) was 0.924 for all patients with PBC (n = 223), 0.940 for anti-gp210+ patients (n = 110) and 0.888 for anti-gp210- patients (n = 113). For GLOBE scoring system, the area under receiver operating characteristic curve was 0.901 for all patients with PBC (n = 223), 0.924 for anti-gp210+ patients (n = 110) and 0.848 for anti gp210- patients (n = 113). UK-PBC score >0.0578 (P < 0.001, HR: 32.736, 95% CI: 11.368-94.267) and GLOBE score <0.850 (P < 0.001, HR: 18.763, 95% CI: 7.968 44.180) were associated with poorer outcomes in the whole cohort. CONCLUSIONS: The UK-PBC and GLOBE scoring systems were good 5-year prognostic predictors in Chinese patients with PBC, especially in anti-gp210+ patients. As a biomarker, anti-gp210 antibody was associated with a more severe cholestatic manifestation and a worse long-term prognosis. The anti-gp210 antibody could be added to further optimise the UK-PBC and GLOBE scoring systems. PMID- 28083928 TI - Effect of reproductive ageing on pregnant mouse uterus and cervix. AB - KEY POINTS: Older pregnant women have a greater risk of operative delivery, still birth and post-term induction. This suggests that maternal age can influence the timing of birth and processes of parturition. We have found that increasing maternal age in C57BL/6J mice is associated with prolongation of gestation and length of labour. Older pregnant mice also had delayed progesterone withdrawal and impaired myometrial function. Uterine ageing and labour dysfunction should be investigated further in older primigravid women. ABSTRACT: Advanced maternal age (>=35 years) is associated with increased rates of operative delivery, stillbirth and post-term labour induction. The physiological causes remain uncertain, although impaired myometrial function has been implicated. To investigate the hypothesis that maternal age directly influences successful parturition, we assessed the timing of birth and fetal outcome in pregnant C57BL/6J mice at 3 months (young) and 5 months (intermediate) vs. 8 months (older) of age using infrared video recording. Serum progesterone profiles, myometrium and cervix function, and mitochondrial electron transport chain complex enzymatic activities were also examined. Older pregnant mice had a longer mean gestation and labour duration (P < 0.001), as well as reduced litter size (P < 0.01) vs. 3-month-old mice. Older mice did not exhibit the same decline in serum progesterone concentrations as younger mice. Cervical tissues from older mice were more distensible than younger mice (P < 0.05). Oxytocin receptor and connexin-43 mRNA expression were reduced in the myometrium from 8-month-old vs. 3-month-old mice (P < 0.05 and P < 0.01 respectively) in tandem with more frequent but shorter duration spontaneous myometrial contractions (P < 0.05) and an attenuated contractile response to oxytocin. Myometrial mitochondrial copy number was reduced in older mice, although there were no age-induced changes to the enzymatic activities of the mitochondrial electron transport chain complexes. In conclusion, 8-month-old mice provide a useful model of reproductive ageing. The present study has identified potential causes of labour dysfunction amenable to investigation in older primigravid women. PMID- 28083930 TI - Functional and structural characterization of four mouse monoclonal antibodies to complement C3 with potential therapeutic and diagnostic applications. AB - C3 is the central component of the complement system. Upon activation, C3 sequentially generates various proteolytic fragments, C3a, C3b, iC3b, C3dg, each of them exposing novel surfaces, which are sites of interaction with other proteins. C3 and its fragments are therapeutic targets and markers of complement activation. We report the structural and functional characterization of four monoclonal antibodies (mAbs) generated by immunizing C3-deficient mice with a mixture of human C3b, iC3b and C3dg fragments, and discuss their potential applications. This collection includes three mAbs interacting with native C3 and inhibiting AP complement activation; two of them by blocking the cleavage of C3 by the AP C3-converase and one by impeding formation of the AP C3-convertase. The interaction sites of these mAbs in the target molecules were determined by resolving the structures of Fab fragments bound to C3b and/or iC3b using electron microscopy. A fourth mAb specifically recognizes the iC3b, C3dg, and C3d fragments. It binds to an evolutionary-conserved neoepitope generated after C3b cleavage by FI, detecting iC3b/C3dg deposition over opsonized surfaces by flow cytometry and immunohistochemistry in human and other species. Because well characterized anti-complement mAbs are uncommon, the mAbs reported here may offer interesting therapeutic and diagnostic opportunities. PMID- 28083931 TI - Radiation exposure to female plastic surgeons of childbearing age during reverse lymphatic mapping. PMID- 28083932 TI - Randomised clinical trial of comparing effects of acupuncture and varicocelectomy on sperm parameters in infertile varicocele patients. PMID- 28083933 TI - "Breastfeeding" but not at the breast: Mothers' descriptions of providing pumped human milk to their infants via other containers and caregivers. AB - As pumping has become more prevalent among American women, pumped human milk (HM) is on the rise in their infants' diets in place of some or all feeding at the breast. We aimed to fill a gap in knowledge about mothers' motivations, practices and perceptions related to pumping, and about mothers' and other caregivers' motivations, practices, and perceptions related to feeding pumped HM. Results related to providing pumped HM are reported here, and results related to pumping are reported elsewhere. We conducted in-depth, semi-structured interviews among a diverse sample of mothers whose infants were fed pumped HM (n = 20), following each up to 1 year postpartum. Data were analyzed using thematic analysis with Atlas.ti. Nearly all mothers felt bottles were necessary to meet infant HM feeding goals. Nearly all pumped HM was fed by other caregivers because mothers typically preferred and prioritized feeding at the breast for convenience and maintaining their milk supply. Infants were bottle-fed HM for several reasons that changed over time, such as mother's absence, latch difficulty, or desire to share the burden and bonding of feeding. Feeding practices differed between feeds from bottles versus at the breast; some infants were bottle-fed on schedules but fed at the breast on demand. Mothers' methods for storing, transporting, and preparing HM varied substantially and included practices associated with loss of nutrients and microbial contamination. Mothers' reasons for bottle-feeding HM may affect how much their infants are bottle-fed. Consumption of pumped HM may not provide the same benefits to infants as feeding at the breast. These findings highlight important avenues for future research into the relationships between bottle-feeding HM and infant health, growth, and developmental outcomes. PMID- 28083934 TI - Roughness preserving filter design to remove spatial noise from stereoscopic skin images for stable haptic rendering. AB - BACKGROUND/PURPOSE: A problem in skin rendering with haptic feedback is the reconstruction of accurate 3D skin surfaces from stereo skin images to be used for touch interactions. This problem also encompasses the issue of how to accurately remove haptic spatial noise caused by the construction of disparity maps from stereo skin images, while minimizing the loss of the original skin roughness for cloning real tough textures without errors. Since the haptic device is very sensitive to high frequencies, even small amounts of noise can cause serious system errors including mechanical oscillations and unexpected exerting forces. Therefore, there is a need to develop a noise removal algorithm that preserves haptic roughness. METHODS: A new algorithm for a roughness preserving filter (RPF) that adaptively removes spatial noise, is proposed. The algorithm uses the disparity control parameter (lambda) and noise control parameter (k), obtained from singular value decomposition of a disparity map. The parameter k determines the amount of noise to be removed, and the optimum value of k is automatically chosen based on a threshold of gradient angles of roughness (Ra ). RESULTS: The RPF algorithm was implemented and verified with three real skin images. Evaluation criteria include preserved roughness quality and removed noise. Mean squared error (MSE), peak signal to noise ratio (PSNR), and objective roughness measures Ra and Rq were used for evaluation, and the results were compared against a median filter. The results show that the proposed RPF algorithm is a promising technology for removing noise and retaining maximized roughness, which guarantees stable haptic rendering for skin roughness. CONCLUSION: The proposed RPF is a promising technology because it allows for any stereo image to be filtered without the risk of losing the original roughness. In addition, the algorithm runs automatically for any given stereo skin image with relation to the disparity parameter lambda, and the roughness parameters Ra or Rq are given priority. Although this method has been optimized by graph-cut disparity map building, it can be extended to other disparity map building methods because the parameter k is determined by actual roughness Ra data that can be obtained by simple measurement. PMID- 28083935 TI - Propacetamol poses a potential harm of adverse hypotension in male and older patients. AB - PURPOSE: Researchers recently suggested intravenous paracetamol as a potential cause of hypotension. We aimed to investigate risk factors of paracetamol- and propacetamol-associated adverse drug reactions (ADRs) in Korean individuals. METHODS: All adverse hypotension cases, regardless of suspected drug, and all ADRs associated with paracetamol and propacetamol use were collected from the Korea Adverse Event Reporting System database between 2011 and 2014. The seriousness, causality, and type of ADR were classified. RESULTS: Of 4,771 cases of adverse hypotension, 403 (8.4%) were reported to be related to propacetamol. This was comparable to the rate of hypotension associated with fentanyl (454, 9.5%), the major suspected drug of hypotension. Paracetamol-associated hypotension accounted for merely 1.2% (55 cases) of all hypotension cases. Among ADRs associated with propacetamol use, hypotension was the most common (37.1%), whereas cutaneous reactions were the primary paracetamol-associated ADR. Propacetamol/paracetamol-associated hypotension was frequently recorded in older patients (>=54 years) (53.9 +/- 25.8 vs. 42.8 +/- 21.7, P < 0.001) and taking more concomitant drugs (1.9 +/- 5.0 vs. 1.1 +/- 3.2, P < 0.001). Also, compared with other ADRs associated by propacetamol/paracetamol, hypotension was more commonly assessed as a serious outcome (27.3% vs. 11.4%, P < 0.001). Regarding concomitant medications, the risk for hypotension associated with propacetamol was significantly increased in patients simultaneously taking antibacterials (J01), cold preparations (R05), drugs for acid related disorders (A02), blood substitutes (B05), or antithrombotics (B01). CONCLUSIONS: Propacetamol was found to be a major suspected drug of pharmacologically associated hypotension in Korea. Older and male patients taking medications in combination with propacetamol/paracetamol should undergo monitoring of their blood pressure. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28083936 TI - ADHD medications and cardiovascular adverse events in children and adolescents: cross-national comparison of risk communication in drug labeling. AB - PURPOSE: Regulators approve written medical information for healthcare professionals and consumers, but the consistency of these sources has not been studied. We investigated the consistency of information regarding four cardiovascular risks of attention-deficit/hyperactivity disorder (ADHD) medications approved in four countries. METHODS: Professional and consumer product labeling for five ADHD medications approved in Australia, Canada, the UK, and the USA were obtained in March/April 2016. Language describing the relationship between medication and elevated blood pressure and/or heart rate, myocardial infarction, stroke, and sudden death was extracted verbatim and classified into one of four categories based on the described relationship between medication and adverse event: "confirmed," "unconfirmed," "mixed," and "not mentioned." We judged the consistency of messages delivered to healthcare professionals and consumers as either "consistent" or "inconsistent." RESULTS: We obtained 20 healthcare professional labels and 20 corresponding consumer labels for the five ADHD medications registered in all four countries. Not all professional and consumer labeling contained language regarding all four adverse events. Of the 80 theoretically evaluable drug-risk pairs, 38 (48%) were not evaluable because of absence of mention of the adverse event in the consumer label. For the remaining 42, the potential causal relationship was expressed consistently in professional and consumer labeling in 25 (60%) cases. The cardiovascular risk profile was not described consistently across all four countries for any of the five drugs. CONCLUSIONS: Product labeling provides healthcare professionals and consumers with inconsistent messages regarding the potential causal relationship between stimulant use and specific cardiovascular risks in children and adolescents. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28083937 TI - Type 1 diabetes pathogenesis is modulated by spontaneous autoimmune responses to endogenous retrovirus antigens in NOD mice. AB - Secreted microvesicles (MVs) are potent inflammatory triggers that stimulate autoreactive B and T cells, causing Type 1 Diabetes in non-obese diabetic (NOD) mice. Proteomic analysis of purified MVs released from islet cells detected the presence of endogenous retrovirus (ERV) antigens, including Env and Gag sequences similar to the well-characterized murine leukemia retroviruses. This raises the possibility that ERV antigens may be expressed in the pancreatic islets via MV secretion. Using virus-like particles produced by co-expressing ERV Env and Gag antigens, and a recombinant gp70 Env protein, we demonstrated that NOD but not diabetes-resistant mice developed anti-Env autoantibodies that increase in titer as disease progresses. A lentiviral-based RNA interference knockdown of Gag revealed that Gag contributes to the MV-induced T-cell response, whose diabetogenic function can be demonstrated via cell-transfer into immune-deficient mice. Finally, we observed that Gag and Env are expressed in NOD islet-derived primary mesenchymal stem cells (MSCs). However, MSCs derived from the islets of diabetes-resistant mice do not express the antigens. Taken together, abnormal ERV activation and secretion of MVs may induce anti-retroviral responses to trigger autoimmunity. PMID- 28083938 TI - Yeast's balancing act between ethanol and glycerol production in low-alcohol wines. AB - Alcohol is fundamental to the character of wine, yet too much can put a wine off balance. A wine is regarded to be well balanced if its alcoholic strength, acidity, sweetness, fruitiness and tannin structure complement each other so that no single component dominates on the palate. Balancing a wine's positive fruit flavours with the optimal absolute and relative concentration of alcohol can be surprisingly difficult. Over the past three decades, consumers have increasingly demanded wine with richer and riper fruit flavour profiles. In response, grape and wine producers have extended harvest times to increase grape maturity and enhance the degree of fruit flavours and colour intensity. However, a higher degree of grape maturity results in increased grape sugar concentration, which in turn results in wines with elevated alcohol concentration. On average, the alcohol strength of red wines from many warm wine-producing regions globally rose by about 2% (v/v) during this period. Notwithstanding that many of these 'full bodied, fruit-forward' wines are well balanced and sought after, there is also a significant consumer market segment that seeks lighter styles with less ethanol derived 'hotness' on the palate. Consumer-focussed wine producers are developing and implementing several strategies in the vineyard and winery to reduce the alcohol concentration in wines produced from well-ripened grapes. In this context, Saccharomyces cerevisiae wine yeasts have proven to be a pivotal strategy to reduce ethanol formation during the fermentation of grape musts with high sugar content (> 240 g l-1 ). One of the approaches has been to develop 'low alcohol' yeast strains which work by redirecting their carbon metabolism away from ethanol production to other metabolites, such as glycerol. This article reviews the current challenges of producing glycerol at the expense of ethanol. It also casts new light on yeast strain development programmes which, bolstered by synthetic genomics, could potentially overcome these challenges. PMID- 28083940 TI - Personalized Medicine in Europe. PMID- 28083939 TI - Linear nonpalpable purpura in a young male: a unique presentation of leukemia cutis in T-cell prolymphocytic leukemia. PMID- 28083941 TI - Influence of the microbiota on host physiology - moving beyond the gut. PMID- 28083942 TI - Decoding host-microbiota communication in the gut - now we're flying! PMID- 28083944 TI - Progress in the biology and analysis of short chain fatty acids. PMID- 28083943 TI - Insights into the pathophysiology of ulcerative colitis: interleukin-13 modulates STAT6 and p38 MAPK activity in the colon epithelial sodium channel. PMID- 28083945 TI - Associations between pathologic tumor features and preadjuvant therapy cognitive performance in women diagnosed with breast cancer. AB - Intertumor heterogeneity has been proposed as a potential mechanism to account for variability in cognitive performance in women diagnosed with breast cancer. The purpose of this study was to explore associations between variation in pathologic tumor features (PTFs) and variability in preadjuvant therapy cognitive performance in postmenopausal women newly diagnosed with early-stage breast cancer. Participants (N = 329) completed a comprehensive battery of neuropsychological tests to evaluate cognitive performance after primary surgery but prior to initiation of adjuvant anastrozole+/-chemotherapy. PTF data were abstracted from medical records. Robust multiple linear regression models were fit to estimate associations between individual PTFs and the cognitive function composite domain scores. All models controlled for age, estimated intelligence, and levels of depressive symptoms, anxiety, fatigue, and pain. Diagnosis of a HER2-positive tumor contributed to poorer verbal (b = -0.287, P = 0.018), visual (b = -0.270, P = 0.001), and visual working (b = -0.490, P < 0.001) memory performance compared to diagnosis of a HER2-negative tumor. Similarly, as HER2 immunohistochemistry classification score increased, verbal (b = -0.072, P = 0.093), visual (b = -0.081, P = 0.003), and visual working (b = -0.170, P < 0.001) memory performance score decreased. Associations with performance were also noted between location, focality/centricity, hormone receptor expression, cellular proliferation (i.e., Ki67), and Oncotype DX(r) Breast Cancer Assay Recurrence Score(r) .) Our results suggest that certain PTFs related to more aggressive tumor phenotypes or inferior breast cancer prognosis may be implicated in poorer preadjuvant therapy cognitive performance. Follow-up studies that include a cognitive assessment before primary surgery should be conducted to further delineate the role of intertumor heterogeneity on cognitive performance. PMID- 28083946 TI - Expiratory muscle strength training evaluated with simultaneous high-resolution manometry and electromyography. AB - OBJECTIVE: To examine feasibility of a simultaneous high-resolution pharyngeal manometry (HRM) and electromyography (EMG) experimental paradigm to detect swallowing-related patterns of palatal, laryngeal, and pharyngeal muscle activity during expiratory training. STUDY DESIGN: Technical report. METHODS: Simultaneous HRM, surface submental, and intramuscular EMG were acquired in two healthy participants during five tasks: 10-cc water swallow, maximum expiratory pressure (MEP) testing, and expiratory muscle strength training (EMST) at three pressure levels (sham, 50%, and 75% MEP). RESULTS: Experimental conditions were feasible. Velopharyngeal closing pressure, palate EMG activity, and pharyngeal EMG activity increased as expiratory load increased. In contrast, thyroarytenoid EMG activity was low during the expiratory task, consistent with glottic opening during exhalation. Submental EMG patterns were more variable during expiratory tasks. Intraluminal air pressures recorded with HRM were correlated with measured expiratory pressures and target valve-opening pressures of the EMST device. CONCLUSION: Results suggest that a simultaneous HRM/EMG/EMST paradigm may be used to detect previously unquantified swallowing-related muscle activity during EMST, particularly in the palate and pharynx. Our approach and initial findings will be helpful to guide future hypothesis-driven studies and may enable investigators to evaluate other muscle groups active during these tasks. Defining mechanisms of action is a critical next step toward refining therapeutic algorithms using EMST and other targeted treatments for populations with dysphagia and airway disorders. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:797-804, 2017. PMID- 28083947 TI - Cross-sectional study of fetal long-bone length in an Iranian population at 17-25 weeks of gestation. AB - OBJECTIVE: To construct improved reference charts for fetal long bones in an Iranian setting and to compare them with previous studies. METHODS: The present prospective cross-sectional study included singleton fetuses assessed by ultrasonography at 17-25 weeks of gestation at the Comprehensive Medical Genetics Center, Shahid Soltani, Shiraz, Iran between May 1, 2012, and February 28, 2014. Exclusion criteria included conditions that could affect fetal growth. Fetal long bones (femur, humerus, tibia, fibula, ulna, and radius) were measured with ultrasonography and biometric charts were produced. Regression models were fitted to estimate bone lengths. The models produced were compared with those from previous studies in other populations. RESULTS: There were 660 singleton fetuses included and 660 femur, 633 humerus, 512 tibia, 498 fibula, 505 ulna, and 498 radius biometric measurements were recorded. The models generated to predict the length of the tibia, fibula, ulna, and radius from the length of the femur and humerus demonstrated a high goodness of fit when the predicted lengths were plotted against the actual lengths. Comparisons of mean lengths with previous studies suggested that long-bone length was affected by maternal ethnicity. CONCLUSION: The equations generated could be used to predict long-bone length in an Iranian population and ethnicity should be considered when using fetal long bone length as a prenatal diagnostic tool. PMID- 28083948 TI - Gain of CD26 expression on the malignant T-cells in relapsed erythrodermic leukemic mycosis fungoides. AB - Loss of CD26 surface expression on the circulating malignant T-cell is the most widely accepted diagnostic marker in patients with leukemic cutaneous T-cell lymphoma (CTCL). CTCL cases with reemergence of CD7 and/or CD26 surface expression are unusual and of uncertain prognosis. We report the case of an erythrodermic leukemic mycosis fungoides patient who had achieved temporary remission after several months on multimodality immunotherapy and extracorporeal photopheresis, but who relapsed with aggressive disease phenotypically characterized by CD4+ T-cells with high CD26 expression. Polymerase chain reaction studies and high-throughput sequencing analyses from peripheral blood mononuclear cells at presentation and relapse consistently showed an identical clonal T-cell receptor suggesting evolution of her original malignant clone which lacked CD26 expression. Interestingly, quantitative expression of the sialomucin, CD164, mirrored her clinical picture, thus favoring its reliability as a novel biomarker in CTCL. PMID- 28083949 TI - Big biology meets microclimatology: defining thermal niches of ectotherms at landscape scales for conservation planning. AB - Temperature profoundly affects ecology, a fact ever more evident as the ability to measure thermal environments increases and global changes alter these environments. The spatial structure of thermalscapes is especially relevant to the distribution and abundance of ectothermic organisms, but the ability to describe biothermal relationships at extents and grains relevant to conservation planning has been limited by small or sparse data sets. Here, we combine a large occurrence database of >23 000 aquatic species surveys with stream microclimate scenarios supported by an equally large temperature database for a 149 000-km mountain stream network to describe thermal relationships for 14 fish and amphibian species. Species occurrence probabilities peaked across a wide range of temperatures (7.0-18.8 degrees C) but distinct warm- or cold-edge distribution boundaries were apparent for all species and represented environments where populations may be most sensitive to thermal changes. Warm-edge boundary temperatures for a native species of conservation concern were used with geospatial data sets and a habitat occupancy model to highlight subsets of the network where conservation measures could benefit local populations by maintaining cool temperatures. Linking that strategic approach to local estimates of habitat impairment remains a key challenge but is also an opportunity to build relationships and develop synergies between the research, management, and regulatory communities. As with any data mining or species distribution modeling exercise, care is required in analysis and interpretation of results, but the use of large biological data sets with accurate microclimate scenarios can provide valuable information about the thermal ecology of many ectotherms and a spatially explicit way of guiding conservation investments. PMID- 28083950 TI - Is it safe to use N-acetylcysteine in the treatment of bilateral ectropion on collodion baby? PMID- 28083951 TI - Enantioselectivity in the Metabolism of Cyclophosphamide in Patients With Multiple or Systemic Sclerosis. AB - The aim of this study was to evaluate the enantioselective pharmacokinetics of cyclophosphamide and its metabolites 4-hydroxycyclophosphamide and carboxyethylphosphoramide mustard in patients with systemic or multiple sclerosis. Patients with systemic sclerosis (n = 10) or multiple sclerosis (n = 10), genotyped for the allelic variants of CYP2C9*2 and CYP2C9*3 and of the CYP2B6 G516T polymorphism, were treated with 50 mg cyclophosphamide/kg daily for 4 days. Serial blood samples were collected up to 24 hours after administration of the last cyclophosphamide dose. Cyclophosphamide, 4-hydroxycyclophosphamide, and carboxyethylphosphoramide enantiomers were analyzed in plasma samples using liquid chromatography-tandem mass spectrometry coupled to chiral column Chiralcel OD-R or Chiralpak AD-RH. Cytokines IL-2, IL-4, IL-6, IL-8, IL-10, IL- 12p70, IL 17, TNF-alpha, and INT-delta in the plasma samples collected before cyclophosphamide infusion were analyzed by Milliplex MAP human cytokine/chemokine. Pharmacokinetic parameters showed higher plasma concentrations of (S)-(-)-cyclophosphamide (AUC 215.0 vs 186.2 MUg.h/mL for multiple sclerosis patients and 219.1 vs 179.2 MUg.h/mL for systemic sclerosis patients) and (R)-4-hydroxycyclophosphamide (AUC 5.6 vs 3.7 MUg.h/mL for multiple sclerosis patients and 6.3 vs 5.6 MUg.h/mL for systemic sclerosis patients) when compared to their enantiomers in both groups of patients, whereas the pharmacokinetics of the carboxyethylphosphoramide metabolite was not enantioselective. Cytokines' plasma concentrations were similar between multiple and systemic sclerosis groups. The pharmacokinetics of cyclophosphamide is enantioselective in patients with systemic sclerosis and multiple sclerosis, with higher plasma concentrations of the (S)-(-)-cyclophosphamide enantiomer due to the preferential formation of the (R)-4-hydroxycyclophosphamide metabolite. PMID- 28083952 TI - Family-oriented services in pediatric rehabilitation: a scoping review and framework to promote parent and family wellness. AB - Family-oriented services are not as common as one would expect, given the widespread endorsement of family-centred care, the role of parents in supporting optimal child outcomes, and legislation and literature indicating that parent outcomes are important in their own right. There are no published service delivery frameworks describing the scope of services that could be delivered to promote parent and family wellness. A scoping review was conducted to identify types of family-oriented services for parents of children with physical disabilities and/or intellectual impairments. This information was then synthesized into a conceptual framework of services to inform service selection and design. A scoping review of the recent literature was performed to capture descriptions of services targeting parents/families of children with physical disabilities and/or intellectual impairments, published in a six-year period (2009 to 2014). Six databases were searched and 557 retrieved articles were screened using inclusion and exclusion criteria. Thirty six relevant articles were identified. Based on descriptions of services in these articles, along with seminal articles describing the nature of desirable services, we propose a needs based and capacity-enhancing framework outlining a continuum of family-oriented services for parents of children with disabilities. The framework includes six types of services to meet parent/family needs, organized as a continuum from fundamental information/education services, to those supporting parents to deliver services to meet their child's needs, to a variety of services addressing parents' own needs (support groups, psychosocial services and service coordination). The framework provides pediatric rehabilitation service organizations with a way to consider different possible family-oriented services. Implications include the particular importance of providing information resources, support groups and psychosocial services to meet parents' needs, enhance capacity and promote family wellness. There is also an opportunity to provide composite parent-child services to address the needs of both parents and children. PMID- 28083953 TI - Anatomical distribution and outcome of surgical excision of fibrokeratoma - a clinical analysis of 124 cases. AB - BACKGROUND: Fibrokeratoma is a benign, cutaneous, fibrous tumor usually occurring on the digits. There is little data about their occurrence on nondigital areas and their surgical outcomes. OBJECTIVES: We sought to retrospectively characterize the distribution and surgical outcome of fibrokeratoma. METHODS: We retrospectively reviewed the clinical information of patients with a histopathological diagnosis of fibrokeratoma, including age, gender, lesion site, number of lesions, symptoms and signs, history of trauma, and any recurrence. RESULTS: We identified 124 patients diagnosed with fibrokeratoma in a 13-year period. The mean age was 42 years. There was a male predilection (2 : 1), and all lesions were solitary. Twenty patients (16%) had symptoms, and 13 patients (10%) had a history of trauma. Thirty patients (24%) had lesions on nondigital areas, including the upper and lower extremities and buttocks. The overall recurrence rate was 4% (five cases). Among them, three recurrent lesions were located on the periungual area of the toe. Nine patients (7%) had giant fibrokeratoma (>1 cm) but none recurred. CONCLUSION: Although most fibrokeratomas appeared on the digits, a certain number of cases (24%) were located on nondigital areas. The periungual area of the toe was the most common local recurrent site. PMID- 28083954 TI - Donating blood on a regular basis appears to reduce blood pressure, but appearances can be deceiving. AB - BACKGROUND: Previous studies have reported a relationship between blood donation and decreased risk for cardiovascular events, and it has been proposed that this may be due to a lowering of blood pressure among hypertensive individuals who donate on a regular basis. STUDY DESIGN AND METHODS: With the use of a retrospective longitudinal analysis, predonation blood pressure readings were examined across consecutive whole blood donations for New York Blood Center donors. With blood pressure levels recorded at the first, second, third, and fourth donations, the sample was divided into three subgroups including high (>=140 mmHg), intermediate (>100 and <40 mmHg), and low (<=100 mmHg) systolic blood pressure (SBP). In addition, a computational approach was used to estimate regression to the mean effects for donors with high SBP or high diastolic blood pressure (DBP) at their first, second, or third donation. RESULTS: Visual examination of SBP and DBP patterns across donations revealed that, on average, donors with extreme values at one donation had relatively normal values at the other donations. Further, comparison of computed expected versus observed blood pressure decreases supported the notion of a subsequent regression to the mean among donors with elevated SBP or DBP at Donation 1, 2, or 3. CONCLUSION: Among individuals who are hypertensive at initial donation, reductions in blood pressure at subsequent donations appear to result from regression to the mean as opposed to a salutary physiologic process. PMID- 28083955 TI - Cryptococcus laurentii diarrhea post hematopoietic stem cell transplant. AB - We report the recent isolation of Cryptococcus laurentii from the feces of a patient with Hodgkin's lymphoma who underwent autologous hematopoietic stem cell transplant (HSCT). The organism was identified using microscopic morphology, cultural characteristics, and biochemical tests including sugar assimilation. Minimum inhibitory concentration of various antifungals was determined by microbroth dilution method. The recovery of pure culture of C. laurentii from stool culture, and the patient's response to treatment with voriconazole support its potential etiological role. To the best of our knowledge, we report the first case of diarrhea caused by C. laurentii in an HSCT recipient. PMID- 28083956 TI - Introduction to E. Pichon Riviere's 'The link and the theory of the three Ds (depositant, depositary and deposited): Role and status' by E. Pichon Riviere. PMID- 28083957 TI - Synthesis and Oxidation of a Paddlewheel-Shaped Rhodium/Antimony Complex Featuring Pyridine-2-Thiolate Ligands. AB - The paddlewheel-shaped complex [Sb(MU-pyS)4 Rh]2 (1) (pyS- = 2-S-C5 H4 N- ) was synthesized from [Rh(pyS)(cod)]2 (cod=1,5-cyclooctadiene) and Sb(pyS)3 . Upon oxidation with ONMe3 , the complex [(MU-O)Sb(MU-pyS)3 Rh(kappa2 -pyS)]2 (2) is formed. Both 1 and 2 form dimers and feature short Rh-Sb bonds and bridging pyS ligands. 121 Sb Mossbauer spectro- scopy and computational studies were employed to elucidate the Rh-Sb bonding in 1 and 2. Both covalent (Rh-Sb, X-type Sb ligand) and dative (Rh->Sb, Z-type; Rh<-Sb L-type Sb ligand) interactions have to be considered for the description of their bonding situations. PMID- 28083958 TI - Methods for the detection and serum depletion of porcine galectin-3. AB - BACKGROUND: Circulating galectin-3 (Gal-3) is elevated in systemic inflammatory disorders, fibrotic diseases, and in cancers. Gal-3 is a promising cancer target where it promotes tumorigenesis and metastasis, as well as in renal, pulmonary, hepatic, and cardiovascular diseases, because of its role as a driver of fibrotic remodeling. This reports goal was to establish methods for the detection and removal of porcine Gal-3 that will enable further studies of the therapeutic potential of Gal-3 depletion by apheresis in porcine disease models. The long term aim is to develop a safe, effective method of removing Gal-3 via apheresis as a standalone therapeutic tool and as an adjuvant to other therapies. METHODS: Purified recombinant porcine Gal-3 was prepared and used as the standard for development of a porcine Gal-3 enzyme-linked immunosorbent assay (ELISA). Different affinity column matrices that incorporated either a rat IgG2a anti-Gal 3 monoclonal antibody or carbohydrate ligand were assessed for depletion of Gal-3 from porcine serum. RESULTS: A porcine Gal-3 ELISA with a linear range from 0.3 to 20 ng/mL was able to detect native porcine Gal-3 in both fetal (~150-200 ng/mL) and juvenile (~5-15 ng/mL) porcine serum samples. Use of an anti-Gal-3 monoclonal antibody affinity column depleted Gal-3 from porcine serum to at least 313 pg/mL, the limit of ELISA detection. CONCLUSIONS: Methods have been developed for the detection and depletion of porcine Gal-3. These methods will be used to study the specific effects of Gal-3 depletion via apheresis in porcine models of disease. PMID- 28083959 TI - The hippocampus facilitates integration within a symbolic field. AB - This paper attempts to elaborate a fundamental brain mechanism involved in the creation and maintenance of symbolic fields of thought. It will integrate theories of psychic spaces as explored by Donald Winnicott and Wilfred Bion with the neuroscientific examinations of those with bilateral hippocampal injury to show how evidence from both disciplines sheds important light on this aspect of mind. Possibly originating as a way of maintaining an oriented, first person psychic map, this capacity allows individuals a dynamic narrative access to a realm of layered elements and their connections. If the proposed hypothesis is correct, the hippocampus facilitates the integration of this symbolic field of mind, where narrative forms of thinking, creativity, memory, and dreaming are intertwined. Without the hippocampus, there is an inability to engage many typical forms of thought itself. Also, noting the ways these individuals are not impaired supports theories about other faculties of mind, providing insight into their possible roles within human thought. The evidence of different systems working in conjunction with the symbolic field provides tantalizing clues about these fundamental mechanisms of brain and mind that are normally seamlessly integrated, and hints at future areas of clinical and laboratory research, both within neuroscience and psychoanalysis. PMID- 28083960 TI - Quality-of-life perception by Parkinson's disease patients and caregivers. AB - BACKGROUND: The quality-of-life (QoL) perception by Parkinson's disease (PD) patients and their caregivers (CG) has not been studied in depth. OBJECTIVE: To examine patient/proxy agreements on the PD QoL Questionnaire (PDQ-39), the Scale of Quality of Life of Care-Givers (SQLC) and the Multidimensional Caregiver Strain Index (MCSI). METHODS: Patients with PD and their CG completed the above mentioned questionnaires about themselves and each other. The intraclass correlations between their scores (paired t test) were compared. RESULTS: Twelve patient-CG pairs were studied. Agreements for QoL items were strong and comparable for the total scores of the PDQ-39, SQLC and MCSI questionnaires (75.4% +/- 14%; 78.1% +/- 14.1% and 78.2% +/- 14.3%, respectively). Agreements ranged from moderate to strong (0.57-0.88, P<=.05) for the patients' physical condition (PDQ-39 items 3, 5, 6, 8, 12-15, 23, 24, 35), mental concentration (item 31) and depression (item 17). Disagreements were apparent in 20%-25% of the pairs and were particularly significant for PDQ-39 items #33 and #25 (embarrassment of patients in public and distressing dreams or hallucinations), in which the CG gave higher scores than the patients. CONCLUSIONS: Agreements between patients with PD and CG were generally good for most, but not all, of the PDQ-39, SQLC and MCSI domains. PMID- 28083961 TI - Disruption of comA homolog in Ralstonia solanacearum does not impair its twitching motility. AB - Ralstonia solanacearum is an important phyto-pathogenic bacterium. The bacterium exhibits type IV pili meditated twitching motility that has been implicated in the process of natural transformation in it. A comA gene homolog, alike in several other naturally competent bacteria, has been already reported in this bacterium. However, there are no report of direct link between comA and twitching motility during the natural transformation process in this pathogen. In order to figure out any connection between comA and twitching motility, we created an insertion mutation in comA gene homolog of R. solanacearum F1C1 strain. As anticipated, the insertion mutant (CBRS01 strain) was inefficient for natural transformation. CBRS01 strain was found to be proficient for twitching motility alike the wild-type F1C1. This is interesting since recent findings of Salzer et al. (2016;Environ Microbiol;18:65-74) showed deficiency of twitching motility due to comEC gene (comA homolog) mutation in another naturally competent Gram negative bacterium Thermus thermophilus. Additionally, we also found CBRS01 strain to be proficient for extracellular cellulase activity and virulence on tomato seedlings. Our findings in this work indicate that an R. solanacearum strain inefficient in undergoing natural transformation can, however, be proficient in exhibiting twitching motility. PMID- 28083962 TI - Case report of fatal post-coital bleeding with systemic bleeding diathesis. PMID- 28083963 TI - Differences in anatomical connections across distinct areas in the rodent prefrontal cortex. AB - Prefrontal cortex (PFC) network structure is implicated in a number of complex higher-order functions and with a range of neurological disorders. It is therefore vital to our understanding of PFC function to gain an understanding of its underlying anatomical connectivity. Here, we injected Fluoro-Gold and Fluoro Ruby into the same sites throughout rat PFC. Tracer injections were applied to two coronal levels within the PFC (anterior +4.7 mm to bregma and posterior +3.7 mm to bregma). Within each coronal level, tracers were deposited at sites separated by approximately 1 mm and located parallel to the medial and orbital surface of the cortex. We found that both Fluoro-Gold and Fluoro-Ruby injections produced prominent labelling in temporal and sensory-motor cortex. Fluoro-Gold produced retrograde labelling and Fluoro-Ruby largely produced anterograde labelling. Analysis of the location of these connections within temporal and sensory-motor cortex revealed a consistent topology (as the sequence of injections was followed mediolaterally along the orbital surface of each coronal level). At the anterior coronal level, injections produced a similar topology to that seen in central PFC in earlier studies from our laboratory (i.e. comparing equivalently located injections employing the same tracer), this was particularly prominent within temporal cortex. However, at the posterior coronal level this pattern of connections differed significantly, revealing higher levels of reciprocity, in both temporal cortex and sensory-motor cortex. Our findings indicate changes in the relative organization of connections arising from posterior in comparison to anterior regions of PFC, which may provide a basis to determine how complex processes are organized. PMID- 28083964 TI - Stimulation of neurotrophic factors and inhibition of proinflammatory cytokines by exogenous application of triiodothyronine in the rat model of ischemic stroke. AB - There is a positive relation between decreases of triiodothyronine (T3) amounts and severity of stroke. The aim of this study was to evaluate the effect of exogenous T3 application on levels of neurogenesis markers in the subventricular zone. Cerebral ischemia was induced by middle cerebral artery occlusion in male Wistar rats. There were 4 experimental groups: sham, ischemic, vehicle, and treatment. Rats were injected with T3 (25 MUg/kg, IV injection) at 24 hours after ischemia. Animals were sacrificed at day 7 after ischemia. There were high levels of brain-derived neurotrophic factor, nestin, and Sox2 expressions in gene and protein levels in the T3 treatment group (P <= .05 vs ischemic group). Treatment group showed high levels of sera T3 and thyroxine (T4) but low levels of thyrotropin (TSH), tumor necrosis factor-alpha, and interleukin-6 (P <= .05 vs ischemic group) at day 4 after ischemia induction. Findings of this study revealed the effectiveness of exogenous T3 application in the improvement of neurogenesis possibly via regulation of proinflammatory cytokines. PMID- 28083965 TI - Mechanistic insight into nuclear receptor-mediated regulation of bile acid metabolism and lipid homeostasis by grape seed procyanidin extract (GSPE). AB - Dietary procyanidins have emerged as important bioactive components that regulate various metabolic pathways to maintain homeostasis. Grape seed procyanidin extract (GSPE), in particular, has demonstrated regulatory effects on bile acid and lipid metabolism in vivo. While numerous studies in rodent models have shown the potent hypolipidemic action of grape seed extracts, human studies have shown inconsistent results. This review will focus on the molecular mechanisms underlying the hypolipidemic actions of GSPE identified to date, specifically highlighting the effects exerted via nuclear receptors. Such evidence may provide avenues for future research in human subjects with GSPE as a therapeutic treatment for the prevention and amelioration of the metabolic syndrome and cardiovascular disease. PMID- 28083966 TI - Small animal models to understand pathogenesis of osteoarthritis and use of stem cell in cartilage regeneration. AB - Osteoarthritis (OA) is one of the most common diseases, which affect the correct functionality of synovial joints and is characterized by articular cartilage degradation. Limitation in the treatment of OA is mostly due to the very limited regenerative characteristic of articular cartilage once is damaged. Small animal models are of particular importance for mechanistic analysis to understand the processes that affect cartilage degradation. Combination of joint injury techniques with the use of stem cells has been shown to be an important tool for understanding the processes of cartilage degradation and regeneration. Implementation of stem cells and small animal models are important tools to help researchers to find a solution that could ameliorate and prevent the symptoms of OA. PMID- 28083968 TI - First case of neonatal diabetes with KCNJ11 Q52R mutation successfully switched from insulin to sulphonylurea treatment. AB - In this report, we present the first known case of intermediate developmental delay, epilepsy and permanent neonatal diabetes (DEND) syndrome caused by a Q52R mutation in the KCNJ11 gene who was successfully switched (at age 1.3 years) to sulphonylurea monotherapy, namely glibenclamide. The most recent evaluation, after 2 years, showed a glycated hemoglobin level of 6.0% (42 mmol/mol). This mutation is so severe that none of the previously reported four cases were able to switch from insulin to sulphonylurea monotherapy. The Q52R mutation seems to have a chance of positive response to glibenclamide administered every 3-6 h instead of the classical 8-12 h, in doses around or above 2.5 mg/kg/day. PMID- 28083967 TI - Strain uses gap junctions to reverse stimulation of osteoblast proliferation by osteocytes. AB - Identifying mechanisms by which cells of the osteoblastic lineage communicate in vivo is complicated by the mineralised matrix that encases osteocytes, and thus, vital mechanoadaptive processes used to achieve load-bearing integrity remain unresolved. We have used the coculture of immunomagnetically purified osteocytes and primary osteoblasts from both embryonic chick long bone and calvariae to examine these mechanisms. We exploited the fact that purified osteocytes are postmitotic to examine both their effect on proliferation of primary osteoblasts and the role of gap junctions in such communication. We found that chick long bone osteocytes significantly increased basal proliferation of primary osteoblasts derived from an identical source (tibiotarsi). Using a gap junction inhibitor, 18beta-glycyrrhetinic acid, we also demonstrated that this osteocyte related increase in osteoblast proliferation was not reliant on functional gap junctions. In contrast, osteocytes purified from calvarial bone failed to modify basal proliferation of primary osteoblast, but long bone osteocytes preserved their proproliferative action upon calvarial-derived primary osteoblasts. We also showed that coincubated purified osteocytes exerted a marked inhibitory action on mechanical strain-related increases in proliferation of primary osteoblasts and that this action was abrogated in the presence of a gap junction inhibitor. These data reveal regulatory differences between purified osteocytes derived from functionally distinct bones and provide evidence for 2 mechanisms by which purified osteocytes communicate with primary osteoblasts to coordinate their activity. PMID- 28083969 TI - Predictors and Clinical Outcomes of Transient Responders to Cardiac Resynchronization Therapy. AB - BACKGROUND: Left ventricular end-systolic volume (LVESV) changes at 6 months and clinical status are useful for assessing responses to cardiac resynchronization therapy (CRT). Regression of the LVESV following CRT has not been described beyond 6 months. This study aimed to assess the proportion, predictors, and clinical outcomes of responders whose LVESVs had regressed. METHODS: We retrospectively analyzed 104 consecutive CRT patients. A responder was defined as a patient with a relative reduction in the LVESV >=15% at 6 months after CRT. Fifty-six responders participated in this study. A transient responder was defined as a responder without a relative reduction in the LVESV >=15% at 2 years after CRT or who died of cardiac events during the 24-month follow-up period. RESULTS: Of the 56 responders, 16 (29%) were transient responders. Multivariable logistic regression analysis showed that chronic atrial fibrillation (odds ratio [OR] = 19.2, 95% confidence interval [CI] [1.93, 190], P = 0.012) and amiodarone usage (OR = 60.9, 95% CI [4.18, 886], P = 0.003) were independent predictors of transient responses. Hospitalizations for heart failure were significantly higher among the transient responders than among the lasting responders during a mean follow-up period of 7.6 years (log-rank P < 0.001), and all-cause mortality tended to be higher among the transient responders (log-rank P = 0.093). CONCLUSIONS: One-third of the responders were transient responders at 2 years after CRT, and their long-term prognoses were poor. Careful attention should be paid to maintain the reduction in LVESV especially in patients with chronic AF. PMID- 28083970 TI - Molecular subtypes of colorectal cancers determined by PCR-based analysis. AB - Tumor tissue consists of a heterogeneous cell population. The allelic imbalance (AI) ratio, determined in isolated tumor glands, is a good index of tumor heterogeneity. However, associations of the patterns of AI and microsatellite instability (MSI) development, observed in most cases of colorectal cancer (CRC), with tumor progression have not been reported previously. In this study, we examined whether CRC genetic profiles stratified by a combination of the AI ratio and MSI facilitate categorization of CRC, and whether these genetic profiles are associated with specific molecular alterations in CRC. A crypt isolation method was used to isolate DNA from tumors and normal glands obtained from 147 sporadic CRCs. AI and MSI statuses were determined using PCR-based microsatellite analysis and stratified based on AI ratio and MSI status. DNA methylation status (high methylation, intermediate methylation and low methylation status and mutations in KRAS, BRAF, and TP53 were examined. In addition, mucin markers were immunostained. Based on this analysis, four subgroups were categorized. Subgroup 1 was characterized by a high MSI status and BRAF mutation; subgroup 2 was closely associated with a high AI ratio, which accumulated during the early phases of colorectal carcinogenesis, and TP53 mutation; subgroup 3 was associated with a low AI ratio, seen during the later phases of colorectal carcinogenesis, and KRAS mutation; and subgroup 4 was defined as a minor subgroup. These results confirmed that classification of distinct molecular profiles provides important insights into colorectal carcinogenesis. PMID- 28083971 TI - Lipoblastoma in children: Review of 12 cases. AB - BACKGROUND: Lipoblastoma is a rare benign mesenchymal tumor of infancy and early childhood. Symptoms vary depending on localization, and signs of compression of adjacent organs may be seen. METHODS: A total of 12 children with pathologically proven lipoblastoma from 2000 to 2014 were reviewed retrospectively for their clinical features, treatment and follow up. RESULTS: There were seven boys and five girls between 7.5 months and 7.5 years of age. The most common symptom was painless rapid-growing mass. The tumors were located in the neck, the abdomen, the groin, pelvis, axilla, glutea, labium majus, thigh and trunk. The largest tumor was in a retroperitoneal location and was 13 * 10 cm in size. Complete resection was performed in 10 patients. All of these patients were followed without any evidence of recurrence. Subtotal excision was performed in two patients. At a median follow up of 38 months (range, 1.8 months-10 years), all patients were disease free. CONCLUSIONS: Lipoblastoma should be considered in the differential diagnosis of rapidly growing mass in patients <3 years of age. Total excision is the treatment of choice with preservation of vital organs. The prognosis is excellent despite large tumor size and local invasion. Recurrence rate is high in incompletely resected tumors. Regular follow up is important for early detection of recurrence. PMID- 28083973 TI - Corrigendum. PMID- 28083972 TI - Renal safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus. AB - The incidence of renal-related adverse events (AEs) with canagliflozin in patients with type 2 diabetes mellitus from a pooled population of patients in 7 active- and placebo-controlled trials (N = 5598) and in a 104-week study vs glimepiride (N = 1450) was low and similar in canagliflozin and non-canagliflozin groups. In the study vs glimepiride, canagliflozin was associated with an initial acute decrease in estimated glomerular filtration rate (eGFR) that attenuated over time, while eGFR declined progressively over 104 weeks with glimepiride. The incidence of renal-related AEs with canagliflozin was generally stable over time, while the incidence with glimepiride increased over 104 weeks. In the present analysis, based on postmarketing reports from the US Food and Drug Administration Adverse Event Reporting System, a potential signal was identified for acute kidney injury with all approved sodium glucose co-transporter 2 (SGLT2) inhibitors (ie, canagliflozin, dapagliflozin and empagliflozin). The early onset of acute kidney injury events with SGLT2 inhibitors in postmarketing reports probably reflects the acute changes in eGFR attibutable to the known renal haemodynamic effects of SGLT2 inhibition. PMID- 28083974 TI - Parental knowledge, attitude, and behavior toward children with atopic dermatitis. AB - BACKGROUND: Successful control of atopic dermatitis (AD) in children depends on parents' knowledge on the disease and attitude toward ill child, but there is a lack studies exploring parental knowledge, attitude, and behaviors. The aim of this study was to investigate parents' knowledge, attitude, and behavior toward AD. METHODS: A cross-sectional study was conducted at the Clinic of Dermatovenereology, Clinical Center of Serbia, Belgrade, between February 2015 and March 2016. Parents of children with AD were invited to complete the questionnaire, which was comprised of five parts: parental sociodemographic characteristics, demographic and clinical characteristics of children, knowledge, attitude, and behavior. To assess factors associated with a higher knowledge level on AD, stronger positive attitude, and more supportive behavior, we performed two multiple linear regression models. RESULTS: The average parental knowledge score was 9.5 +/- 1.9 out of 12. The level of knowledge did not correlate with parental conviction that they were well-informed on AD (rho = 0.121; P = 0.319). Older (beta = 0.08, 95% confidence interval [CI] 0.00-0.16, P = 0.040), married/partnered parents (beta = -2.14, 95% CI -3.55 to 0.72, P = 0.004), and those who have had AD themselves were more likely to be more knowledgeable on AD. Older (beta = 0.18, 95% CI 0.01-0.34, P = 0.036) and employed (beta = 3.99, 95% CI 1.59-6.38, P = 0.002) parents had stronger positive attitudes toward their children with AD. More supportive behavior of parents of children with AD was associated with being older (beta = 0.24, 95% CI 0.04-0.45, P = 0.020) and less educated (beta = -0.76, 95% CI -1.24 to 0.28, P = 0.003). CONCLUSION: The importance of understanding AD and accounting for attitudes by family members is obvious for successful control of the disease. PMID- 28083975 TI - Hay fever, asthma, and eczema and early infectious diseases among children in Kilimanjaro, Tanzania. AB - OBJECTIVES: To investigate the hygiene (or "old friends") hypothesis in a high infectious disease (ID) environment, rural Kilimanjaro, Tanzania. METHODS: Among a cross-sectional sample of 2- to 7-year-old children, we collected physician diagnosed hay fever, asthma, and eczema, history of hospitalization, family size, and household environment information via questionnaire; performed active and passive surveillance for ID; and, evaluated total immunoglobulin E (IgE) and biomarkers of inflammation in dried blood spot specimens. We used regression models to describe patterns in allergic diseases. RESULTS: Complete information was available for 280 children: 12.5% had been diagnosed with hay fever; 18.9% with eczema; 2.1% with asthma. There was a positive association between hay fever and eczema diagnoses (pi2 : 4.07; P = 0.044); total IgE was positively associated with eczema (beta: 0.24; P = 0.100) and allergic diseases together (beta: 0.26; P = 0.042). ID were common: the incidence of any ID diagnosis was 28 per 100 children per month. Hay fever was inversely associated with household animals (OR: 0.27; P = 0.006), and positively associated with earth housing materials (OR: 1.93; P = 0.079) and hospitalization in infancy with an ID (3.16; P = 0.066); patterns were similar when allergic disease outcomes were considered together. Few associations between these predictors and eczema or asthma alone were apparent. CONCLUSIONS: Allergic diseases were common among children in Kilimanjaro. The inverse association between household animals and allergy is consistent with the hygiene/old friends hypothesis; however, positive associations between allergic diseases and earth housing materials and early hospitalization with ID bear further explanation. PMID- 28083976 TI - Serial in-office laser treatment of vocal fold leukoplakia: Disease control and voice outcomes. AB - OBJECTIVE: Although vocal fold (VF) leukoplakia is commonly treated with in office laser, there is no data on its long-term effectiveness. This study hypothesizes that VF leukoplakia treated by serial in-office laser results in long-term disease control with maintenance of voice and minimal morbidity. STUDY DESIGN: Retrospective review (2008-2015). METHODS: Forty-six patients with VF leukoplakia treated by in-office KTP (potassium titanyl phosphate) or PDL (pulsed dye laser) were included. Median follow-up from final laser treatment was 19.6 months. Main outcomes included: 1) rate of disease control, 2) percentage of disease regression using ImageJ analysis. Secondary outcomes included vocal assessment using the Voice Handicap Index-10 (VHI-10). RESULTS: Patients underwent a median of 2 (range: 1-6) in-office laser treatments. Time between treatments was median 7.6 months. After final treatment, 19 patients (41.3%) had no disease; two patients (4.3%) progressed to invasive cancer; overall disease regression was median 77.1% (P < 0.001); and VHI-10 score decreased by median 5 (P = 0.037). Thirty-one patients (67.4%) were responders (controlled with in office treatment only); failures were 13 patients (28.3%) who required operative intervention and two patients (4%) who underwent radiation. Compared to responders, failures demonstrated significantly shorter duration between treatments (median 2.3 vs. 8.9 months, P = 0.038) and significantly less regression (median 49.3% vs. 100%, P = 0.006). CONCLUSION: Serial outpatient KTP or PDL treatment of VF leukoplakia is effective for disease control with minimal morbidity and preservation of voice quality. We suggest that patients requiring repeated in-office treatment every 6 months may benefit from earlier operative intervention; other factors associated with in-office success remain unclear. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:1644-1651, 2017. PMID- 28083977 TI - Nephrectomy-induced reduced renal function and the health-related quality of life of living kidney donors. AB - OBJECTIVE: To evaluate the health impact of nephrectomy on living kidney donors (LKDs) by comparing the health-related quality of life (HrQOL) scores measured by Short Form-36 (SF36) between those with and without postdonation renal function impairment (PRFI). METHODS: Eighty-two LKDs (47 females, mean age=50.2+/-11.2 years) were prospectively recruited to participate in a SF-36 HrQOL survey. Chart review, individual baseline, and postoperative renal function (eGFR) was determined using the Modification of Diet in Renal Disease formula. PRFI was defined as eGFR<60 mL/min/1.73 m2 or proteinuria. Mean SF-36 domain scores were compared between those with and without PRFI. RESULTS: After a median follow-up of 5.7 years, the prevalence of postdonation comorbidities was 29.3% (n=24) PRFI, 25.6% (n=21) hypertension, 6.1% (n=5) diabetes, and 3.7% (n=3) heart disease, and no LKDs developed end-stage renal disease. Mean eGFR before and after donor nephrectomy was 95.5+/-23.4 and 71.0+/-17.3 mL/min/1.73 m2 (P<.01). Mean SF-36 scores of LKDs were not significantly different between those with and without PRFI in all the domains (all P>.05). Similarly, the proportion of LKDs with PRFI did not differ significantly between the patients with SF-36 domain scores above and below the published reference values. CONCLUSION: Nephrectomy-induced PRFI may not have a significant impact on the HrQOL of the LKD population with a low proportion of other major comorbidities such as diabetes and ischemic heart disease. PMID- 28083979 TI - Regular mailing of personalized feedback reports improves glycemic control in diabetes: A randomized controlled trial. PMID- 28083978 TI - Factors enhancing the migration and the homing of mesenchymal stem cells in experimentally induced cardiotoxicity in rats. AB - Doxorubicin is an effective anti-neoplastic drug but its use is limited by its cardiotoxicity. Administration of mesenchymal stem cells (MSCs) for the management of cardiotoxicity was with poor myocardial homing capacity. With the aim of developing novel techniques to improve the migration of MSCs, we tested whether valproate and electric fields (EFs) direct the migration of MSCs towards the damaged myocardium. The study included five groups of female albino rats. The first group included 10 healthy rats as normal control group. The remaining 40 female rats received doxorubicin for induction of acute cardiotoxicity. Four rats were sacrificed for histopathological confirmation of cardiotoxicity. The remaining rats were equally divided into subsequent four groups. The second group included nine rats that did not receive further treatment (positive control group). The third group included nine rats which received intravenous bone marrow derived mesenchymal stem cells (BM-MSCs) after cardiotoxicity induction. The fourth group included nine rats which received BM-MSCs plus sodium valporate after cardiotoxicity induction. The fifth group included nine rats which received BM-MSCs plus sodium valporate after cardiotoxicity induction and were exposed to an electrical stimulation (ES). Blood samples were taken from all groups at the end of the study to estimate creatine kinase-MB (CK-MB), aspartate transaminase (AST) and lactate dehydrogenase (LDH). Heart tissues from all rats were used for RNA extraction for assessment of sry gene expression. Homing was tested by PKH26 fluorescence in myocardial tissue sections and by sry gene expression. The best biochemical and histopathological improvement in cardiotoxicity was demonstrated in group 5 (rats that received ES and valporate with MSCs). We concluded that EFs and sodium valproate enhance homing ability of MSCs towards the damaged myocardium in doxorubicin induced carditoxicity model. (c) 2017 IUBMB Life, 69(3):162-169, 2017. PMID- 28083980 TI - Increased availability of paracetamol in Sweden and incidence of paracetamol poisoning: using laboratory data to increase validity of a population-based registry study. AB - PURPOSE: To estimate the incidence trend and outcome of paracetamol poisoning, in relation to increased availability of paracetamol from non-pharmacy outlets in 2009. METHOD: Patients' serum paracetamol results over 14 years (2000-2013) from 20 (out of 21) regions in Sweden were linked to national registers of hospital care, cause of death, and prescriptions. Paracetamol poisonings were defined by serum paracetamol levels, hospital diagnoses, or cause of death. The change in incidence of poisonings following increased availability of paracetamol was analysed by using segmental regression of time series. RESULTS: Of the 12 068 paracetamol poisonings, 85% were classified as intentional self-harm. Following increased availability from non-pharmacy outlets, there was a 40.5% increase in the incidence of paracetamol poisoning, from 11.5/100 000 in 2009 to 16.2/100 000 in 2013. Regression analyses indicated a change in the trend (p < 0.0001) but not an immediate jump in the incidence (p = 0.5991) following the increased availability. Adjusting for trends in hospital episodes for self-harm, suicides, and the sales volume of paracetamol did not influence the result. All-cause mortality at 30 days (3.2%) did not change over time. CONCLUSIONS: The incidence of paracetamol poisoning in Sweden has increased since 2009, contrasting the decreased incidence in the period of 2007-2009. The change in trend was temporally associated with the introduction of availability of paracetamol from non-pharmacy outlets but did not appear to be related to sales volume of paracetamol or general trends in self-harm or suicides. (c) 2017 Commonwealth of Australia. Pharmacoepidemiology and Drug Safety (c) 2017 John Wiley & Sons, Ltd. PMID- 28083981 TI - The statistics of the vestibular input experienced during natural self-motion differ between rodents and primates. AB - KEY POINTS: In order to understand how the brain's coding strategies are adapted to the statistics of the sensory stimuli experienced during everyday life, the use of animal models is essential. Mice and non-human primates have become common models for furthering our knowledge of the neuronal coding of natural stimuli, but differences in their natural environments and behavioural repertoire may impact optimal coding strategies. Here we investigated the structure and statistics of the vestibular input experienced by mice versus non-human primates during natural behaviours, and found important differences. Our data establish that the structure and statistics of natural signals in non-human primates more closely resemble those observed previously in humans, suggesting similar coding strategies for incoming vestibular input. These results help us understand how the effects of active sensing and biomechanics will differentially shape the statistics of vestibular stimuli across species, and have important implications for sensory coding in other systems. ABSTRACT: It is widely believed that sensory systems are adapted to the statistical structure of natural stimuli, thereby optimizing coding. Recent evidence suggests that this is also the case for the vestibular system, which senses self-motion and in turn contributes to essential brain functions ranging from the most automatic reflexes to spatial perception and motor coordination. However, little is known about the statistics of self motion stimuli actually experienced by freely moving animals in their natural environments. Accordingly, here we examined the natural self-motion signals experienced by mice and monkeys: two species commonly used to study vestibular neural coding. First, we found that probability distributions for all six dimensions of motion (three rotations, three translations) in both species deviated from normality due to long tails. Interestingly, the power spectra of natural rotational stimuli displayed similar structure for both species and were not well fitted by power laws. This result contrasts with reports that the natural spectra of other sensory modalities (i.e. vision, auditory and tactile) instead show a power-law relationship with frequency, which indicates scale invariance. Analysis of natural translational stimuli revealed important species differences as power spectra deviated from scale invariance for monkeys but not for mice. By comparing our results to previously published data for humans, we found the statistical structure of natural self-motion stimuli in monkeys and humans more closely resemble one another. Our results thus predict that, overall, neural coding strategies used by vestibular pathways to encode natural self motion stimuli are fundamentally different in rodents and primates. PMID- 28083982 TI - Novel reuterin-related compounds suppress odour by periodontopathic bacteria. AB - OBJECTIVE: Halitosis is caused by volatile sulphur compounds including methyl mercaptan (CH3 SH) in the oral cavity and is a serious problem that limits interpersonal social communication. The aim of study was to evaluate the effects of reuterin-related compounds (RRCs) on halitosis-related periodontopathic bacteria in vitro. MATERIALS AND METHODS: RRC-01, RRC-02 and RRC-03 (32 and 64 MUg ml-1 ) in culture media containing Fusobacterium nucleatum JCM8523 and Porphyromonas gingivalis ATCC33277 were used. The effects of RRCs on CH3 SH production and detectable odour by F. nucleatum and P. gingivalis were examined by CH3 SH production assay and organoleptic test, respectively. The number of bacterial cells was also measured using an ATP assay. In P. gingivalis treated with RRCs, the expression of mgl gene, which is responsible for CH3 SH production, was examined by qRT-PCR. RESULTS: CH3 SH production and the score of detectable odour from F. nucleatum and P. gingivalis culture media containing RRCs were significantly lower than that without RRCs (P < 0.05). The expression of mgl gene in P. gingivalis was significantly downregulated by RRC-01 (P < 0.01), but not by RRC-02 or RRC-03. CONCLUSIONS: RRCs are potent oral care products for preventing halitosis via reducing CH3 SH production. PMID- 28083983 TI - Local and landscape drivers of predation services in urban gardens. AB - In agroecosystems, local and landscape features, as well as natural enemy abundance and richness, are significant predictors of predation services that may result in biological control of pests. Despite the increasing importance of urban gardening for provisioning of food to urban populations, most urban gardeners suffer from high pest problems, and have little knowledge about how to manage their plots to increase biological control services. We examined the influence of local, garden scale (i.e., herbaceous and arboreal vegetation abundance and diversity, ground cover) and landscape (i.e., landscape diversity and surrounding land use types) characteristics on predation services provided by naturally occurring predators in 19 urban gardens in the California central coast. We introduced sentinel pests (moth eggs and larvae and pea aphids) onto greenhouse raised plants taken to gardens and assigned to open or bagged (predator exclosure) treatments. We found high predation rates with between 40% and 90% of prey items removed in open treatments. Predation services varied with local and landscape factors, but significant predictors differed by prey species. Predation of eggs and aphids increased with vegetation complexity in gardens, but larvae predation declined with vegetation complexity. Smaller gardens experienced higher predation services, likely due to increases in predator abundance in smaller gardens. Several ground cover features influenced predation services. In contrast to patterns in rural agricultural landscapes, predation on aphids declined with increases in landscape diversity. In sum, we report the relationships between several local management factors, as well as landscape surroundings, and implications for garden management. PMID- 28083984 TI - Whole genome sequencing analysis of lung adenocarcinoma in Xuanwei, China. AB - BACKGROUND: The lung cancer mortality rate in Xuanwei city is among the highest in China and adenocarcinoma is the major histological type. Lung cancer has been associated with exposure to indoor smoky coal emissions that contain high levels of polycyclic aromatic hydrocarbons; however, the pathogenesis of lung cancer has not yet been fully elucidated. METHODS: We performed whole genome sequencing with lung adenocarcinoma and corresponding non-tumor tissue to explore the genomic features of Xuanwei lung cancer. We used the Molecule Annotation System to determine and plot alterations in genes and signaling pathways. RESULTS: A total of 3 428 060 and 3 416 989 single nucleotide variants were detected in tumor and normal genomes, respectively. After comparison of these two genomes, 977 high confidence somatic single nucleotide variants were identified. We observed a remarkably high proportion of C.G-A.T transversions. HECTD4, RCBTB2, KLF15, and CACNA1C may be cancer-related genes. Nine copy number variations increased in chromosome 5 and one in chromosome 7. The novel junctions were detected via clustered discordant paired ends and 1955 structural variants were discovered. Among these, we found 44 novel chromosome structural variations. In addition, EGFR and CACNA1C in the mitogen-activated protein kinase signaling pathway were mutated or amplified in lung adenocarcinoma tumor tissue. CONCLUSION: We obtained a comprehensive view of somatic alterations of Xuanwei lung adenocarcinoma. These findings provide insight into the genomic landscape in order to further learn about the progress and development of Xuanwei lung adenocarcinoma. PMID- 28083985 TI - HLA-G regulatory polymorphisms are associated with susceptibility to HCV infection. AB - BACKGROUND: Hepatitis C virus (HCV) is able to bypass the immune system modulating innate and adaptive immune response and blocking T helper 1 (Th1) cell production. Because the human leukocyte antigen (HLA)-G molecule has immunomodulatory properties inhibiting the function and production of natural killer and cytotoxic lymphocyte T cells, as well as promoting shift from Th1 toward Th2 response, we hypothesized its involvement in susceptibility to HCV infection. MATERIALS AND METHODS: Considering that HLA-G mRNA expression has been reported to be under genetic control, an association study was conducted analyzing 800 base pairs upstream the ATG at the 5'upstream regulator region (URR) and 850 base pairs from ATG to exon 3 and the 3'untranslated region (UTR) of HLA-G gene in Italian HCV-positive patients and uninfected controls. RESULTS: Four 5'URR polymorphisms (-725C>G>T, -509C>G, -400G>A and -398G>A), 7 polymorphisms at coding region (+15G>A, +36G>A, +243G>A, insC506, 531G>C, delA615 and 685G>A), the +644G>T polymorphism, and 1 haplotype (TTGTTCCIGAC) showed different frequency distributions between HCV patients and uninfected controls. CONCLUSION: The results from our study suggest a possible involvement of HLA-G in the risk modulation toward HCV infection. PMID- 28083987 TI - VWF collagen (types III and VI)-binding defects in a cohort of type 2M VWD patients - a strategy for improvement of a challenging diagnosis. PMID- 28083986 TI - The PacC transcription factor regulates secondary metabolite production and stress response, but has only minor effects on virulence in the insect pathogenic fungus Beauveria bassiana. AB - The PacC transcription factor is an important component of the fungal ambient pH responsive regulatory system. Loss of pacC in the insect pathogenic fungus Beauveria bassiana resulted in an alkaline pH-dependent decrease in growth and pH dependent increased susceptibility to osmotic (salt, sorbitol) stress and SDS. Extreme susceptibility to Congo Red was noted irrespective of pH, and DeltaBbpacC conidia showed subtle increases in UV susceptibility. The DeltaBbPacC mutant showed a reduced ability to acidify media during growth due to failure to produce oxalic acid. The DeltaBbPacC mutant also did not produce the insecticidal compound dipicolinic acid, however, production of a yellow-colored compound was noted. The compound, named bassianolone B, was purified and its structure determined. Despite defects in growth, stress resistance, and oxalate/insecticidal compound production, only a small decrease in virulence was seen for the DeltaBbpacC strain in topical insect bioassays using larvae from the greater waxmoth, Galleria mellonella or adults of the beetle, Tenebrio molitor. However, slightly more pronounced decreases were seen in virulence via intrahemcoel injection assays (G. mellonella) and in assays using T. molitor larvae. These data suggest important roles for BbpacC in mediating growth at alkaline pH, regulating secondary metabolite production, and in targeting specific insect stages. PMID- 28083988 TI - Breaking the Gordian Knot in the Structural Chemistry of Polyoxometalates: Copper(II)-Oxo/Hydroxo Clusters. AB - This Concept article provides insights into the molecular design and construction aspects of polyoxocuprates (POCus), an emerging class of polyoxometalate (POM) like architectures featuring low-to-high nuclearity copper(II)-oxo/hydroxo skeletons. POCus have been identified to adopt the structural principles of classical POMs consisting of early transition metals. Their potential to afford motifs of the noble-metal-based POMs is exploited. "Cross-structural topological transformation" is introduced to generalize skeletal relationships between POCus and POMs. The study opens up strategies toward the brand-new structural chemistry of POCus with relevance to homogeneous photocatalysis, medicinal chemistry, molecular magnetism, and quantum computing. PMID- 28083989 TI - Final NIH Policy on the Use of a Single Institutional Review Board for Multisite Research. PMID- 28083991 TI - Reporting Characteristics and Quality of Systematic Reviews of Acupuncture Analgesia. AB - BACKGROUND: Evaluating the clinical efficacy of acupuncture analgesia with systematic reviews (SRs) has attracted wide interest. OBJECTIVE: To collect a sample of published SRs on acupuncture analgesia in PubMed and examine them in terms of reporting characteristics and quality. METHODS: A search in PubMed was performed in January 2016. All SRs on acupuncture analgesia were included. To assess the quality of the SRs, AMSTAR tool and PRISMA Statements were used. RESULTS: One hundred and nine SRs were included in our analysis, the yearly number of publications ranging from 1 in 1997 to 15 in 2015. Only 17% of these publications were Cochrane Systematic Reviews, and 94% were published in Science Citation Index journals. The United Kingdom was the country with the higher number of publications. Low back pain, headache, cancer pain, and labor pain were the most reported diseases or phenotypes. Nearly 73% of these SRs conducted a meta-analysis, 58% revealed positive results, 53% used RevMan software to analyze data, and 44% used the Cochrane Risk of Bias Tool for quality assessment. Only a few SRs assessed the likelihood of publication bias, reported details about the protocol and the registration information, and performed additional analyses. CONCLUSIONS: The quantity and the quality of SRs regarding acupuncture analgesia have been promoted in recent years. More effort should be expended on the assessment of publication bias, the provision of detailed information about the protocol and the registration process, and the implementation of additional analyses to improve the validity of the SRs. PMID- 28083990 TI - BKV-specific T cells in the treatment of severe refractory haemorrhagic cystitis after HLA-haploidentical haematopoietic cell transplantation. AB - BACKGROUND: Haemorrhagic cystitis caused by BK virus (BKV) is a known complication of allogeneic haematopoietic cell transplantation (HCT) and is relatively common following HLA-haploidentical transplantation. Adoptive immunotransfer of virus-specific T cells from the donor is a promising therapeutic approach, although production of these cells is challenging, particularly when dealing with low-frequency T cells such as BKV-specific T cells. CASE REPORT: Here, we present a patient who, following haploidentical HCT, developed severe BKV haemorrhagic cystitis, resistant to standard therapy. He responded well to adoptive transfer of donor cells enriched in BKV-specific T cells using the new second-generation CliniMACS Prodigy and the Cytokine Capture System from Miltenyi Biotec. Treatment led to full resolution of both the symptoms and viraemia without unwanted complications. CONCLUSION: Our observations suggest that use of products enriched with BKV-specific T cells generated using this system is safe and efficient in HLA-haploidentical HCT where BKV cystitis can be a serious complication. PMID- 28083992 TI - Peptide-functionalized starPEG/heparin hydrogels direct mitogenicity, cell morphology and cartilage matrix distribution in vitro and in vivo. AB - Cell-based tissue engineering is a promising approach for treating cartilage lesions, but available strategies still provide a distinct composition of the extracellular matrix and an inferior mechanical property compared to native cartilage. To achieve fully functional tissue replacement more rationally designed biomaterials may be needed, introducing bioactive molecules which modulate cell behavior and guide tissue regeneration. This study aimed at exploring the impact of cell-instructive, adhesion-binding (GCWGGRGDSP called RGD) and collagen-binding (CKLER/CWYRGRL) peptides, incorporated in a tunable, matrixmetalloprotease (MMP)-responsive multi-arm poly(ethylene glycol) (starPEG)/heparin hydrogel on cartilage regeneration parameters in vitro and in vivo. MMP-responsive-starPEG-conjugates with cysteine termini and heparin maleimide, optionally pre-functionalized with RGD, CKLER, CWYRGRL or control peptides, were cross-linked by Michael type addition to embed and grow mesenchymal stromal cells (MSC) or chondrocytes. While starPEG/heparin-hydrogel strongly supported chondrogenesis of MSC according to COL2A1, BGN and ACAN induction, MMP-degradability enhanced cell viability and proliferation. RGD modification of the gels promoted cell spreading with intense cell network formation without negative effects on chondrogenesis. However, CKLER and CWYRGRL were unable to enhance the collagen content of constructs. RGD-modification allowed more even collagen type II distribution by chondrocytes throughout the MMP-responsive constructs, especially in vivo. Collectively, peptide-instruction via heparin-enriched MMP-degradable starPEG allowed adjustment of self-renewal, cell morphology and cartilage matrix distribution in order to guide MSC and chondrocyte-based cartilage regeneration towards an improved outcome. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28083993 TI - Algae through the looking glass. AB - Microalgae are one of the most suitable subjects for testing the potentiality of light microscopy and image analysis, because of the size of single cells, their endogenous chromaticity, and their metabolic and physiological characteristics. Microscope observations and image analysis can use microalgal cells from lab cultures or collected from water bodies as model to investigate metabolic processes, behavior/reaction of cells under chemical or photic stimuli, and dynamics of population in the natural environment in response to changing conditions. In this paper we will describe the original microscope we set up together with the image processing techniques we improved to deal with these topics. Our system detects and recognizes in-focus cells, extracts their features, measures cell concentration in multi-algal samples, reconstructs swimming cell tracks, monitors metabolic processes, and measure absorption and fluorescent spectra of subcellular compartments. It can be used as digital microscopy station for algal cell biology and behavioral studies, and field analysis applications. PMID- 28083994 TI - On paranoid parents. PMID- 28083996 TI - Pulmonary lesion characterization using diffusion weighted imaging: Attention should be paid to patient inclusion criteria and scanning parameters. PMID- 28083995 TI - BEX3 contributes to cisplatin chemoresistance in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) can develop cisplatin-resistant phenotype. Research has revealed that enriched in cancer stem cell population is involved in developing cisplatin-resistant phenotype. CD271 is a candidate stem cell maker in head and neck cancers. The CD receptor does not possess any enzymatic property. Signal transduction function of CD271 is mediated by the cellular receptor associated protein. Our data showed that Brain-expressed X-linked 3 (BEX3), a CD271 receptor-associated protein, was overexpressed in NPC. BEX3 overexpression was a unique event in cancer developed in the head and neck regions, especially NPC. BEX3 expression was inducible by cisplatin in NPC. In cisplatin-resistant NPC xenograft, treatment with nontoxic level of cisplatin led to a remarkable increase in BEX3 level. High BEX3 expression was accompanied with high octamer binding transcription factor 4 (OCT4) expression in cisplatin-resistant NPC. To confirm the inducing role of BEX3 on OCT4 expression, we knockdown BEX3 using siRNA and compared the expression of OCT4 with mock transfectants. Suppressing BEX3 transcripts led to a significant reduction in OCT4. In addition, targeting BEX3 using shRNA could increase the sensitivity of NPC cells to cisplatin. In summary, our results indicated a unique functional role of BEX3 in mediating the sensitivity of NPC cells to cisplatin. Targeting or blocking BEX3 activity might be useful in reversing the cisplatin-resistant phenotype in NPC. PMID- 28083997 TI - Dysregulation of cell-cell interactions in brain arteriovenous malformations: A quantitative proteomic study. AB - PURPOSE: Detailed and exact mechanisms underlying brain arteriovenous malformations (bAVM) are still clinically confusing. Understanding the quantitative changes in proteins and signaling pathways would provide useful information for clinicians to understand the formation and development of bAVM, guiding individualized treatment strategies. This study was performed to establish a large human bAVM proteome database using tandem mass tag labeling and to detect changes of protein expression and pathways in human bAVM. EXPERIMENTAL DESIGN: This study used quantitative 6-plex tandem mass tag labeling to profile protein changes in bAVM lesions. Integrated bioinformatics analysis was used to classify and identify the altered proteins and relating signaling pathways. Western blot analyzes were used to validate the proteomic data. RESULTS: Our work established the first human bAVM proteome databases to date. A total of 1264 proteins were identified, and the expression of 316 proteins was significantly differentially expressed, with 249 upregulated proteins. Bioinformatics analysis demonstrated that the altered proteins had close functional correlations, including integrin cell surface interactions, extracellular matrix organization, and smooth muscle contraction. Three signaling pathways (focal adhesions, tight junctions, and gap junctions), which represent an important arena of cell-cell interactions, were found to be activated in bAVM. The proteomics data are available via ProteomeXchange with identifier PXD003289. CONCLUSION AND CLINICAL RELEVANCE: Cell-cell interactions, including focal adhesions, tight junctions, and gap junctions, were significantly influenced in human bAVM. Understanding the molecular mechanisms that underlie bAVM would provide useful information for the development of future therapeutic approaches, guiding possible precise and individual treatment strategies. PMID- 28083998 TI - Late surgical correction of hypospadias increases the risk of complications: a series of 501 consecutive patients. AB - OBJECTIVES: To evaluate the outcomes of hypospadias surgery according to age and to determine if some complications are age-related. PATIENTS AND METHODS: This retrospective study was based on 722 boys with hypospadias undergoing primary repair. A total of 501 boys underwent urethroplasty and were included in the study. Complications requiring an additional procedure (stenosis, fistula, dehiscence, relapse of curvature, urethrocele) were included in the analysis, as well as healing problems, infections, haematomas and detrusor-sphincter dyssynergy. Logistic regression analysis was performed. RESULTS: Hypospadias was anterior in 63.1%, mid-penile in 20.5%, posterior in 8.4% and scrotal in 7.9% of the boys. The median (range) age was 4 (1-16) years. The overall rates of re intervention and complications were 22.8% and 36.2%, respectively. Age >2 years was a significant predictor of complications (P = 0.002, odds ratio 1.98 [95% confidence interval 1.26-3.13]). Some periods of time appeared to be associated with a specific complication: dyssynergy was more common between the ages of 24 and 36 months (12.5 vs 3.6%; P = 0.01) and healing problems were more common in boys aged >13 years (1.5 vs 28.5%; P = 0.06). CONCLUSION: Delayed surgery may be detrimental for patients. Factors related to age may influence the rate of complications. After the age of 2 years, urethral surgery may interfere with the normal toilet-training process. During puberty, endogenous testosterone may alter healing. Even if no specific data exist for severe hypospadias, it may be prudent to continue to advocate early surgery in patients with disorders of sex development. PMID- 28083999 TI - Determinants of Patient Satisfaction in a Private Practice Pain Management Clinic. AB - BACKGROUND: Patient satisfaction is used to measure physician performance in hospital and governmental practice settings. There is limited understanding about factors affecting satisfaction in a chronic pain management setting for patients prescribed chronic opioids. OBJECTIVE: To identify the determinants of patient satisfaction and correlation with recommended outcome measures in a private practice pain management clinic. METHODS: We performed a 4-week quality assessment survey to define the determinants of patient satisfaction among pain management patients who were prescribed opioids. The data obtained from the survey were analyzed with descriptive and multiple regression analysis. RESULTS: Overall provider satisfaction was 96% and clinic satisfaction was 94% for a chronic pain population prescribed opioids for over 1 year. There was no correlation between provider satisfaction and functional outcomes. Only "level of stress" correlated with positive clinic satisfaction. The remainder of the functional outcomes were not correlated with satisfaction. "Listened to you carefully about your questions and concerns," "Treated you with courtesy and respect," and "Helped you with your problem" were found to be significant predictors of provider satisfaction. CONCLUSIONS: These results indicate that a patient's perception of a provider's engagement and concern more heavily impacts perceived satisfaction than the patient's progress. A patient's perception of his or her clinic experience is heavily influenced by the attentiveness and coordination of the entire clinic care team. Staff attentiveness and coordination may affect a patient's level of stress. Adherence to current opioid prescription guidelines did not appear to have an overall negative effect on patient satisfaction. PMID- 28084000 TI - Injectable chitosan-platelet-rich plasma implants to promote tissue regeneration: in vitro properties, in vivo residence, degradation, cell recruitment and vascularization. AB - The purpose of this study was to develop freeze-dried chitosan formulations that can be solubilized in platelet-rich plasma (PRP) to form injectable implants for tissue repair. A systematic approach to adjust formulation parameters, including chitosan number average molar mass (Mn ), chitosan concentration and lyoprotectant concentration, was undertaken to identify compositions that would rapidly (< 1 min) and completely solubilize in PRP, would have paste-like handling properties upon solubilization and coagulate rapidly (< 5 min) to form solid chitosan-PRP hybrid implants that are stable and homogenous. Freeze-dried cakes containing calcium chloride, as well as distinct chitosan Mn , chitosan concentration and lyoprotectant concentration, were prepared. PRP was used to solubilize the freeze-dried cakes and assess in vitro and in vivo performance, the latter as dorsal subcutaneous injections into New Zealand White rabbits. Freeze-dried polymer formulations containing low and medium chitosan Mn and concentrations were rapidly and completely solubilized in PRP. The paste-like chitosan-PRP mixtures coagulated quickly to form solid chitosan-PRP hybrids, which retracted much less than PRP-only controls. Homogeneous dispersion of chitosan within the hybrid clots was strongly dependent on chitosan Mn , and occurred only with medium Mn chitosan. Chitosan-PRP hybrid clots were resident subcutaneously in vivo until at least 2 weeks while PRP controls were quickly degraded in one day. Compared to PRP alone, chitosan-PRP hybrids had much greater capacity to induce local cell recruitment accompanied by angiogenesis, suggesting a strong potential for their use in regenerative medicine. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28084001 TI - No Evidence for Association of beta-Defensin Genomic Copy Number with HIV Susceptibility, HIV Load during Clinical Latency, or Progression to AIDS. AB - Common single-nucleotide variation in the host accounts for 25% of the variability in the plasma levels of HIV during the clinical latency stage (viral load set point). However, the role of rare variants and copy number variants remains relatively unexplored. Previous work has suggested copy number variation of a cluster of beta-defensin genes affects HIV load in treatment-naive sub Saharan Africans and rate of response to antiretroviral treatment. Here we analyse a total of 1827 individuals from two cohorts of HIV-infected individuals from Europe and sub-Saharan Africa to investigate the role of beta-defensin copy number variation on HIV load at set point. We find no evidence for association of copy number with viral load. We also compare distribution of beta-defensin copy number between European cases and controls and find no differences, arguing against a role of beta-defensin copy number in HIV acquisition. Taken together, our data argue against an effect of copy number variation of the beta-defensin region in the spontaneous control of HIV infection. PMID- 28084002 TI - Identification of potential protein quality markers in pathogen inactivated and gamma-irradiated red cell concentrates. AB - PURPOSE: Post-collection manipulations (PCMs) aim to increase blood product safety. However, PCMs improve safety at a cost to quality, causing elevated hemolysis. As hemolysis is linked to red blood cell membrane integrity, a quantitative proteomics approach was employed to assess membrane proteome alterations induced by PCMs. EXPERIMENTAL DESIGN: Three ABO-matched whole blood (WB) units were pooled-and-split into three identical units. One WB unit was treated with riboflavin/ultraviolet illumination prior to red cell concentrate (RCC) production (RCCWB* ). Two WB units were produced into RCC; one was gamma irradiated (RCCgamma ) and the other was left untreated as control (RCCO ). In vitro quality parameters were measured during storage. Membrane protein profiles of RCCO , RCCgamma , and RCCWB* were assessed on selected hemoglobin-depleted membrane fractions using a quantitative proteomics approach based on iTRAQ. RESULTS: Quantitative proteomic analysis identified 100 proteins at the membrane, with seven unique proteins exhibiting significant changes in RCCWB* at day 28 of storage. Membrane peroxiredoxin-2, catalase, and proteasome levels demonstrated robust negative correlation with percentage hemolysis. CONCLUSION: Overall, the in vitro parameters and alterations of membrane protein profiles indicated that pathogen inactivation treatment impacts RCC quality more severely than gamma irradiation and that it may induce damage through a predominately oxidative mechanism. PMID- 28084003 TI - Comparison between the short-term outcomes of bevacizumab and ziv-aflibercept in the treatment of primary diabetic macular oedema. PMID- 28084004 TI - Body fat composition in hidradenitis suppurativa: a hospital-based cross sectional study. PMID- 28084006 TI - Genetic and phenotypic intraspecific variability of non-Saccharomyces yeasts populations from La Rioja winegrowing region (Spain). AB - AIMS: To determine the intraspecific genetic diversity within five non Saccharomyces yeast species and the diversity in phenotypic characteristic related to their technological properties. METHODS AND RESULTS: Seventy-one non Saccharomyces yeasts isolated from different fermentations and facilities of the DOCa Rioja (Spain) belonging to five different wine species (Torulaspora delbrueckii, Lachancea thermotolerans, Metschnikowia pulcherrima, Zygosaccharomyces bailii and Williopsis pratensis) were subjected to clonal characterization by RAPD-PCR, which evidenced wide diversity between them. They were also submitted to a screening for some oenological traits related to the improvement of the aroma of the wine and yeast development in musts. Strains within the same species showed different enzyme activities, tolerated different levels of SO2 and possessed different killer phenotypes. These characteristics made them adjust better or worse to specific vinification processes or wine quality criteria. CONCLUSIONS: A significant genetic and phenotypic variation within the non-Saccharomyces species studied was found, which makes necessary to carry out a selection process in each one. SIGNIFICANCE AND IMPACT OF THE STUDY: Williopsis pratensis, a species that has not been thoroughly explored, may deserve further consideration for oenological applications. Due to the wide range of variation within species, the strains adaptation to the SO2 levels in musts has to be taken into account in selection processes. PMID- 28084005 TI - Oral mucous membrane pemphigoid and pemphigus vulgaris-a retrospective two-center cohort study. AB - OBJECTIVES: Few studies have compared oral mucous membrane pemphigoid (MMP) and pemphigus vulgaris (PV). Descriptive analysis of oral features, extent of extra oral involvement, and management outcomes were performed. SUBJECTS AND METHODS: Patients with PV and MMP, the latter with exclusive oral involvement at first presentation, were included. RESULTS: There were 26 MMP (46%) and 31 PV (54%) patients. Desquamative gingivitis was evident in 84% of MMP cases compared to 28% of PV cases (P < 0.05). Non-gingival lesions were noted in 6% of MMP cases compared to 55% of PV cases (P < 0.01). Management of MMP consisted of only topical corticosteroids in 88% of cases while 12% of cases required concomitant systemic therapy. All PV cases (100%) required systemic therapy. No patients with MMP developed scarring or ocular lesions, and one patient (4%) developed cutaneous lesions. Five PV cases (16%) had oral cavity involvement only with three (60%) developing pharyngeal involvement and two (40%) developing cutaneous lesions on follow-up. CONCLUSION: Oral MMP presents primarily as desquamative gingivitis, infrequently involving extragingival sites, and is highly amenable to topical therapy, while PV is a systemic mucocutaneous disease with extensive non gingival oral lesions that almost always requires systemic therapy. PMID- 28084007 TI - Are Australian medical students being taught to teach? AB - BACKGROUND: The current global trend of growth in medical training is increasing the demand for the teaching and supervision of medical students and junior doctors. If well trained and supported, junior doctors and medical students represent an important teaching resource. Unfortunately, there is limited evidence available on whether Australian medical students are equipped with teaching skills. This study aimed to gain insight into the type and amount of teaching-skills training and peer-to-peer teaching present in Australian medical schools. METHODS: A survey of Australian medical schools was conducted between May and December 2014. An online 22-item questionnaire was sent to all 19 Australian medical schools. RESULTS: The response rate to the questionnaire was 100 per cent. Eleven Australian medical schools reported offering a teaching skills programme, of which five were described as compulsory formal programmes. Eight schools did not offer such a programme, citing time restraints and other subjects taking higher priority. Formal peer-to-peer teaching opportunities were described by 17 schools, with 13 offering this electively. Two schools reported that they did not offer such opportunities because of time restraints, the belief that the quality of expert teaching is superior and because of a lack of staffing. The demand for the teaching and supervision of medical students and junior doctors is increasing CONCLUSIONS: Despite the increasing number of medical students and subsequently junior doctors in Australia, a minority of Australian medical schools report including a formal, compulsory teaching-skills programme. These results may imply a lost opportunity to use the positive effects of teaching-skills programmes, and are in line with studies from other countries. PMID- 28084008 TI - Pulsed xenon flash treatment inactivates bacteria in apheresis platelet concentrates while preserving in vitro quality and functionality. AB - BACKGROUND: Pulsed xenon (Xe) flash without any photoreactive compounds has been shown to inactivate a type of bacteria spiked into platelet (PLT) suspension in plasma, but enhanced the PLT storage lesion (PSL). Predicting reduction of PSL with increasing bactericidal ability, pulsed Xe flash was filtered through a band stop filter, which excluded ultraviolet (UV)A, UVB, and visible light. STUDY DESIGN AND METHODS: Apheresis PLT concentrates (PCs) inoculated with bacteria were irradiated with filtered Xe flash (fXe treatment). For in vitro functional quality assessment, PLT aggregation and thrombin generation together with other assays that monitor the PSL were investigated. RESULTS: Staphylococcus aureus and Streptococcus dysgalactiae could be inactivated without regrowth during 6 days of storage. PC variables, such as PLT count, concentrations of soluble CD40 ligand, and ratio of aggregated PLTs, were not significantly different between fXe treated and untreated PCs after 6 days of storage, while PAC-1 binding increased in the fXe-treated PLTs. Responsiveness of fXe-treated PLTs to ADP was maintained over a 6-day storage period as shown by the up regulation of P-selectin expression and induction of both integrin alphaIIbbeta3 conformational change and PLT aggregation. The fXe-treated PLTs showed a sustained aggregation curve in response to ADP, whereas untreated PLTs transiently aggregated and then subsequently dissociated. Thrombin-generating kinetics of fXe-treated PLTs via PLT membrane surface were equivalent to those of untreated PLTs. CONCLUSIONS: The fXe treatment inactivated bacteria in apheresis PCs in plasma without additional chemical compounds. The fXe-treated PCs retained acceptable in vitro properties of PC quality and PLT functionality. PMID- 28084009 TI - Aspirin for acute treatment of episodic tension-type headache in adults. AB - BACKGROUND: Tension-type headache (TTH) affects about 1 person in 5 worldwide. It is divided into infrequent episodic TTH (fewer than one headache per month), frequent episodic TTH (two to 14 headache days per month), and chronic TTH (15 headache days per month or more). Aspirin is one of a number of analgesics suggested for acute treatment of episodic TTH. OBJECTIVES: To assess the efficacy and safety of aspirin for acute treatment of episodic tension-type headache (TTH) in adults compared with placebo or any active comparator. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and the Oxford Pain Relief Database from inception to September 2016, and also reference lists of relevant published studies and reviews. We sought unpublished studies by asking personal contacts and searching online clinical trial registers and manufacturers' websites. SELECTION CRITERIA: We included randomised, double-blind, placebo-controlled studies (parallel-group or cross over) using oral aspirin for symptomatic relief of an acute episode of TTH. Studies had to be prospective, with participants aged 18 years or over, and include at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and extracted data. For various outcomes (predominantly those recommended by the International Headache Society (IHS)), we calculated the risk ratio (RR) and number needed to treat for one additional beneficial outcome (NNT), one additional harmful outcome (NNH), or to prevent one event (NNTp) for oral aspirin compared to placebo or an active intervention.We assessed the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We included five studies enrolling adults with frequent episodic TTH; 1812 participants took medication, of which 767 were included in comparisons of aspirin 1000 mg with placebo, and 405 in comparisons of aspirin 500 mg or 650 mg with placebo. Not all of these participants provided data for outcomes of interest in this review. Four studies specified using IHS diagnostic criteria; one predated commonly recognised criteria, but described comparable characteristics and excluded migraine. All participants treated headaches of at least moderate pain intensity.None of the included studies were at low risk of bias across all domains considered, although for most studies and domains this was likely to be due to inadequate reporting rather than poor methods. We judged one study to be at high risk of bias due to small size.There were no data for aspirin at any dose for the IHS preferred outcome of being pain free at two hours, or for being pain free at any other time, and only one study provided data equivalent to having no or mild pain at two hours (very low quality evidence). Use of rescue medication was lower with aspirin 1000 mg than with placebo (2 studies, 397 participants); 14% of participants used rescue medication with aspirin 1000 mg compared with 31% with placebo (NNTp 6.0, 95% confidence interval (CI) 4.1 to 12) (low quality evidence). Two studies (397 participants) reported a Patient Global Evaluation at the end of the study; we combined the top two categories for both studies to determine the number of participants who were 'satisfied' with treatment. Aspirin 1000 mg produced more satisfied participants (55%) than did placebo (37%) (NNT 5.7, 95% CI 3.7 to 12) (very low quality evidence).Adverse events were not different between aspirin 1000 mg and placebo (RR 1.1, 95% CI 0.8 to 1.5), or aspirin 500 mg or 650 mg and placebo (RR 1.3, 95% CI 0.8 to 2.0) (low quality evidence). Studies reported no serious adverse events.The quality of the evidence using GRADE comparing aspirin doses between 500 mg and 1000 mg with placebo was low or very low. Evidence was downgraded because of the small number of studies and events, and because the most important measures of efficacy were not reported.There were insufficient data to compare aspirin with any active comparator (paracetamol alone, paracetamol plus codeine, peppermint oil, or metamizole) at any of the doses tested. AUTHORS' CONCLUSIONS: A single dose of aspirin between 500 mg and 1000 mg provided some benefit in terms of less frequent use of rescue medication and more participants satisfied with treatment compared with placebo in adults with frequent episodic TTH who have an acute headache of moderate or severe intensity. There was no difference between a single dose of aspirin and placebo for the number of people experiencing adverse events. The amount and quality of the evidence was very limited and should be interpreted with caution. PMID- 28084010 TI - Effect of the degree of magnetic resonance-guided high-intensity focused ultrasound ablation of uterine fibroid tissue on 6-month volume reduction. PMID- 28084011 TI - Sorafenib analogue SC-60 induces apoptosis through the SHP-1/STAT3 pathway and enhances docetaxel cytotoxicity in triple-negative breast cancer cells. AB - Recurrent triple-negative breast cancer (TNBC) needs new therapeutic targets. Src homology region 2 domain-containing phosphatase-1 (SHP-1) can act as a tumor suppressor by dephosphorylating oncogenic kinases. One major target of SHP-1 is STAT3, which is highly activated in TNBC. In this study, we tested a sorafenib analogue SC-60, which lacks angiokinase inhibition activity, but acts as a SHP-1 agonist, in TNBC cells. SC-60 inhibited proliferation and induced apoptosis by dephosphorylating STAT3 in both a dose- and time-dependent manner in TNBC cells (MDA-MB-231, MDA-MB-468, and HCC1937). By contrast, ectopic expression of STAT3 rescued the anticancer effect induced by SC-60. SC-60 also increased the SHP-1 activity, but this effect was inhibited when the N-SH2 domain (DN1) was deleted or with SHP-1 point mutation (D61A), implying that SHP-1 is the major target of SC-60 in TNBC. The use of SC-60 in combination with docetaxel synergized the anticancer effect induced by SC-60 through the SHP-1/STAT3 pathway in TNBC cells. Importantly, SC-60 also displayed a significant antitumor effect in an MDA-MB-468 xenograft model by modulating the SHP-1/STAT3 axis, indicating the anticancer potential of SC-60 in TNBC treatment. Targeting SHP-1/p-STAT3 and the potential combination of SHP-1 agonist with chemotherapeutic docetaxel is a feasible therapeutic strategy for TNBC. PMID- 28084012 TI - UVA Light-mediated Ascorbate Oxidation in Human Lenses. AB - Whether ascorbate oxidation is promoted by UVA light in human lenses and whether this process is influenced by age and GSH levels are not known. In this study, we used paired lenses from human donors. One lens of each pair was exposed to UVA light, whereas the other lens was kept in the dark for the same period of time as the control. Using LC-MS/MS analyses, we found that older lenses (41-73 years) were more susceptible to UVA-induced ascorbate oxidation than younger lenses (18 40 years). Approximately 36% of the ascorbate (relative to control) was oxidized in older lenses compared to ~16% in younger lenses. Furthermore, lenses with higher levels of GSH were less susceptible to UVA-induced ascorbate oxidation compared to those with lower levels, and this effect was not dependent on age. The oxidation of ascorbate led to elevated levels of reactive alpha-dicarbonyl compounds. In summary, our study showed that UVA light exposure leads to ascorbate oxidation in human lenses and that such oxidation is more pronounced in aged lenses and is inversely related to GSH levels. Our findings suggest that UVA light exposure could lead to protein aggregation through ascorbate oxidation in human lenses. PMID- 28084013 TI - The Role of SNAP in Home Food Availability and Dietary Intake among WIC Participants Facing Unstable Housing. AB - OBJECTIVE: Little nutrition research has been conducted among families with unstable housing. The objective of this study was to examine the role of food stamps (i.e., Supplemental Nutrition Assistance Program; SNAP) in home food availability and dietary intake among WIC families who experienced unstable housing. DESIGN AND SAMPLE: Cross-sectional study among vulnerable families. Low income, multiethnic families with children participating in WIC (n = 54). MEASURES: Dietary intake was assessed with 24-hr recalls. Home food availability was assessed with an adapted home food inventory for low-income, multiethnic families. Validation results from adapted home food inventory for these families are also reported. RESULTS: SNAP households had more foods than non-SNAP households; few significant associations were observed between food availability and child dietary intake. CONCLUSIONS: With few exceptions, the home food environment was not related to children's dietary intake among these vulnerable families. More research is needed on food access for families facing unstable housing. PMID- 28084014 TI - Primary and Secondary Stroke Prevention Using Left Atrial Appendage Closure with Watchman Devices in Atrial Fibrillation Patients: A Single Center Experience from Mainland China. AB - BACKGROUND: Atrial fibrillation (AF) is associated with increased stroke risk resulting from cardiac embolism of the left atrial appendage (LAA). Stroke tends to recur in NVAF patients. Yet safety and feasibility of secondary stroke preventions with LAA closure (LAAC) have not been assessed in detail. This retrospective study was designed to compare the feasibility and safety of LAAC in primary and secondary stroke preventions, in a real-world setting of Chinese patients. METHODS: From 2014 to 2015, non-valvular AF patients with CHA2DS2-VASc >=1 were selected for percutaneous LAAC operations. Outcome observations of primary and secondary stroke preventions with Watchman devices were analyzed and compared. RESULTS: Overall, 122 patients were included. LAAC with Watchman devices were attempted in 115 patients, of whom 68 were for primary stroke prevention and 47 were for secondary prevention. Both the CHA2DS2-VASc score and the HASBLED score were significantly higher in the secondary prevention group (4.09 +/- 1.06 vs. 1.93 +/- 1.09 for CHA2DS2-VASc and 1.83 +/- 1.03 vs. 1.26 +/- 0.87 for HASBLED, P < 0.01). In both groups LAAC were achieved with high successful rate (98.53% in the primary prevention group and 100% in the secondary prevention group, P > 0.05) and low complication rates. The stroke rates were at a low level in both groups (1.47% in primary prevention group vs. 2.13% in secondary prevention group, P > 0.05). CONCLUSIONS: In our initial single-center experience, percutaneous LAA closure was a feasible and safe procedure for both primary and secondary stroke preventions in Chinese patients with nonvalvular AF. PMID- 28084016 TI - Digital mucous cyst: surgical closure technique based on self-grafting using skin overlying the lesion. AB - BACKGROUND: Digital mucous cysts or myxoid cysts are relatively common, benign pseudocysts of the digits typically located at the distal interphalangeal joints or in the proximal nail fold. There are several therapeutic modalities for its treatment ranging from conservative to surgical procedures; however, there is no consensus about the best approach. MATERIAL AND METHODS: We describe a surgical technique based on the excision of the digital mucous cyst and reconstruction using a self-grafting from the overlying skin lesion. RESULTS: The use of the cyst's overlying skin as a partial cutaneous graft followed by a long-term Brown's dressing, in this case, provided a satisfactory functional and esthetic result. CONCLUSIONS: This technique is a new option for the reconstruction of digital mucous cyst defects that decreases the surgical time and avoids a graft removal of healthy skin and consequently a new scar. PMID- 28084015 TI - Plasma mannose level, a putative indicator of glycogenolysis, and glucose tolerance in Japanese individuals. AB - AIMS/INTRODUCTION: Mannose is a monosaccharide constituent of glycoproteins and glycolipids. Experiments in rats have shown previously that the plasma mannose level decreases after glucose load, but does not decrease in diabetic rats, and that hepatic glycogenolysis is a source of this plasma mannose; however, these results are not fully elucidated in humans. Plasma mannose levels before/after glucose loading in humans with various degrees of glucose intolerance were examined to analyze their association with clinical factors. MATERIALS AND METHODS: The 75-g oral glucose tolerance test was carried out in Japanese individuals not taking diabetes medications. Participants were classified into normal glucose tolerance, impaired glucose metabolism and diabetes mellitus groups. Insulinogenic index as an index of insulin secretion, and Matsuda Index as an index of insulin sensitivity were calculated. Mannose was assayed by the established method using high-performance liquid chromatography after labeling. RESULTS: After glucose load, the plasma mannose level decreased gradually in the normal glucose tolerance group, but did not decrease in the diabetes mellitus group. Plasma mannose changes during 120 min from baseline (M120 -M0 ) were significantly different among the three groups (normal glucose tolerance: -16.7 +/- 1.7; impaired glucose metabolism: -9.0 +/- 1.9; diabetes mellitus: -1.4 +/- 1.8 MUmol/L [n = 25 in each group], P < 0.0001). Plasma glucose 120 min after glucose loading (R2 = 0.412) or loge -insulinogenic index, loge -Matsuda Index and age (R2 = 0.230) were determinants of M120 -M0 in multiple regression analyses. CONCLUSIONS: We clarified the relationship between plasma mannose level and glucose tolerance in humans. The present results are compatible with those using rats, in which mannose derived from glycogenolysis plays an important role in the alteration of mannose levels after glucose loading. PMID- 28084017 TI - Estimation of the relatedness coefficients from biallelic markers, application in plant mating designs. AB - The problem of inferring the relatedness distribution between two individuals from biallelic marker data is considered. This problem can be cast as an estimation task in a mixture model: at each marker the latent variable is the relatedness state, and the observed variable is the genotype of the two individuals. In this model, only the prior proportions are unknown, and can be obtained via ML estimation using the EM algorithm. When the markers are biallelic and the data unphased, the identifiability of the model is known not to be guaranteed. In this article, model identifiability is investigated in the case of phased data generated from a crossing design, a classical situation in plant genetics. It is shown that identifiability can be guaranteed under some conditions on the crossing design. The adapted ML estimator is implemented in an R package called Relatedness. The performance of the ML estimator is evaluated and compared to that of the benchmark moment estimator, both on simulated and real data. Compared to its competitor, the ML estimator is shown to be more robust and to provide more realistic estimates. PMID- 28084018 TI - Ultrasound-responsive gene-activated matrices for osteogenic gene therapy using matrix-assisted sonoporation. AB - Gene-activated matrix (GAM)-based therapeutics for tissue regeneration are limited by efficacy, the lack of spatiotemporal control and availability of target cells, all of which impact negatively on their translation to the clinic. Here, an advanced ultrasound-responsive GAM is described containing target cells that facilitates matrix-assisted sonoporation (MAS) to induce osteogenic differentiation. Ultrasound-responsive GAMs consisting of fibrin/collagen hybrid matrices containing microbubbles, bone morphogenetic protein BMP2/7 coexpression plasmids together with C2C12 cells were treated with ultrasound either in vitro or following parenteral intramuscular implantation in vivo. Using direct measurement for alkaline phosphatase activity, von Kossa staining and immunohistochemical analysis for osteocalcin expression, MAS-stimulated osteogenic differentiation was confirmed in the GAMs in vitro 7 days after treatment with ultrasound. At day 30 post-treatment with ultrasound, ectopic osteogenic differentiation was confirmed in vivo using X-ray microcomputed tomography and histological analysis. Osteogenic differentiation was indicated by the presence of ectopic bone structures in all animals treated with MAS. In addition, bone volumes in this group were statistically greater than those in the control groups. This novel approach of incorporating a MAS capability into GAMs could be exploited to facilitate ex vivo gene transfer with subsequent surgical implantation or alternatively provide a minimally invasive means of stimulating in situ transgene delivery for osteoinductive gene-based therapies. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28084019 TI - Is being a medical educator a lonely business? The essence of social support. AB - CONTEXT: Social support helps prevent burnout and promotes its positive opposite, work engagement. With higher work engagement performance increases. The context specific aspects of social support for medical educators, in their educator role, are unknown. To help facilitate social support our study describes the essential elements of social support and their meaning for medical educators. METHODS: We held interviews with medical educators purposefully sampled for diverse backgrounds and working circumstances and who spent a considerable amount of time on education. Both clinicians and basic scientists participated. The Pictor technique guided the interviews. Participants were invited to talk about the breadth of social support and elaborate on meaningful experiences. Template analysis was used for a descriptive phenomenological approach. RESULTS: Thirteen medical educators were interviewed. We identified four themes: (i) sources of support and their intent (e.g. a superior with the intent to stimulate personal growth); (ii) the materialisation of support (e.g. sought or offered); (iii) its manifestation (e.g. the act of providing protected time); and (iv) the overarching effect of social support, both in terms of practical effects and the meaning of support. We identified three sorts of meanings of social support for educators. Receiving support could lead to (i) feeling reassured and confident; (ii) feeling encouraged and determined and (iii) a sense of relatedness and acknowledgement of the educator role. CONCLUSION: Support for education comes from a wide range of sources because it is both sought and offered beyond the boundaries of the educational role. The resulting differences in support provided necessitate that educational leaders and policymakers consider the sources available to each educator, connecting educators where necessary. When facilitating or designing social support it is important that the need to feel reassured, encouraged or related is met. PMID- 28084020 TI - Successful treatment of type B insulin resistance with mixed connective tissue disease by pulse glucocorticoids and cyclophosphamide. AB - Type B insulin resistance syndrome is a very rare condition caused by autoantibodies against the insulin receptor. We report the successful treatment of a patient with refractory type B insulin resistance with pulse glucocorticoids and cyclophosphamide. The medical record of a patient with type B insulin resistance was reviewed. A 36-year-old Chinese woman presented with menopause, weight loss and refractory hyperglycemia for 3 months, which could not be controlled by up to 972 of insulin units per day. Mixed connective tissue disease was diagnosed with high titers of antinuclear antibody, ribonucleoprotein antibody and interstitial lung disease. Type B insulin resistance was diagnosed with positive immunoprecipitation assay of anti-insulin-receptor antibodies in serum. We started one cycle of pulse methylprednisolone (1,000 mg/day for 3 days) then tapered to prednisone 1 mg/kg/day, and cyclophosphamide 0.4 g/week was added on. Three weeks after pulse glucocorticoid therapy, fasting glucose returned to 4.4 mmol/L. Fasting insulin decreased from 647.27 to 12.95 uIU/mL 6 weeks later. The patient had gained 15 kg during 20 months of uneventful following up, and glycated hemoglobin decreased from 10.1 to 5.1%.In this patient with type B insulin resistance, a combination of pulse glucocorticoids and cyclophosphamide was successful in inducing a complete remission. Close cooperation between endocrinologists and rheumatologists will ensure an individualized regimen for this rare condition. PMID- 28084021 TI - Concurrent external and intraluminal vacuum-assisted closure in head and neck necrotizing fasciitis. PMID- 28084022 TI - Acute generalized exanthematous pustulosis: clinical characteristics, etiologic associations, treatments, and outcomes in a series of 28 patients at Mayo Clinic, 1996-2013. AB - BACKGROUND: Acute generalized exanthematous pustulosis (AGEP) is a rare skin condition typically caused by medications. The objective of this study was to examine the clinical features, causes, and outcomes of AGEP at a sole tertiary care center. METHODS: A retrospective review of patients with AGEP (European Study of Severe Cutaneous Adverse Reactions score of >= 5) seen at Mayo Clinic (Rochester, MN, USA) between January 1, 1996, and December 31, 2013, was conducted. RESULTS: Of 28 patients (mean age at onset: 56 years), 17 (61%) were women. The development of AGEP was attributed to medications in 25 patients (89%), with clindamycin the most common culprit (six patients). Three patients (11%) had mucous membrane involvement, and 21 (75%) showed systemic involvement. Ten patients (36%) received systemic corticosteroids for treatment of AGEP. Skin findings resolved within 15 days in 26 patients (93%) (mean time to resolution: 7.6 days). In three patients (11%), generalized skin eruptions or dermatitis developed weeks to months after the resolution of AGEP. Twenty-four patients (86%) had a personal history of drug reactions before the development of AGEP. CONCLUSIONS: A previous history of drug reactions and clindamycin causation were more common in the present cohort than in prior reports. A small subset of patients experienced new-onset non-AGEP skin eruptions within a few months of the resolution of AGEP. PMID- 28084023 TI - Crystal structure of a family 80 chitosanase from Mitsuaria chitosanitabida. AB - Chitosanases belong to glycoside hydrolase families 5, 7, 8, 46, 75 and 80 and hydrolyse glucosamine polymers produced by partial or full deacetylation of chitin. Herein, we determined the crystal structure of chitosanase from the beta proteobacterium, Mitsuaria chitosanitabida, (McChoA) at 1.75 A resolution; the first structure of a family 80 chitosanase. McChoA is a 34 kDa extracellular protein of 301 amino acids that fold into two (upper and lower) globular domains with an active site cleft between them. Key substrate-binding features are conserved with family 24 lysozymes and family 46 chitosanases. The distance between catalytic residues E41 and E61 (10.8 A) indicates an inverting type mechanism. Uniquely, three disulphide bridges and the C terminus might contribute to enzyme activity. PMID- 28084024 TI - Characterization of the cathelicidin cluster in the Japanese quail (Coturnix japonica). AB - The Japanese quail has several advantages as a low-fat meat bird with high immunity against diseases. Cathelicidins (CATHs) are antimicrobial peptides that play an important role in innate immunity. The aim of this study was to characterize the CATH cluster in the Japanese quail (Coturnix japonica). The Japanese quail CATH (CjCATH) cluster, contains four CATH genes, as in the chicken. The coding sequences of CjCATHs exhibited >85.3% identity to chicken CATHs. The predicted amino acid sequences of the four CjCATH genes contained the cathelin-like domain characteristic of CATH proteins. Polymorphisms were detected in the open reading frames (ORFs) of all CjCATH sequences. Two amino acid substitutions were observed in the antimicrobial region of the mature peptide of CjCATH2, and predicted to influence peptide function. CjCATH1 is expressed in lung, heart, bone marrow and bursa of Fabricius (BF). CjCATH2 is expressed in bone marrow. CjCATH3 is expressed in lung, heart, bone marrow, BF, tongue and duodenum. CjCATHB1 is expressed in bone marrow and BF. This study is the first to characterize CATH genes in the Japanese quail, and identifies novel antimicrobial peptide sequences belonging to the cathelicidin family, which may play a role in immunity in this species. PMID- 28084026 TI - Blood pressure is blood pressure is blood pressure: Or is it? PMID- 28084025 TI - Comparative pharmacokinetic study of the main components of cortex fraxini after oral administration in normal and hyperuricemic rats. AB - Cortex Fraxini is an important traditional Chinese herbal medicine used for the treatment of gout and hyperuricemia. An efficient and rapid ultra-performance liquid chromatography mass spectrometry method was developed and validated for simultaneous quantitation of six coumarins (aesculin, fraxin, aesculetin, fraxetin, sopoletin and 7-hydroxycoumarin) in normal and hyperuricemic rats plasma after oral administration of Cortex Fraxini. The method could successfully be applied for pharmacokinetics studies. The pharmacokinetic behavior of six coumarins in normal and hyperuricemia rats plasma was determined. Results showed that, for some of analytes, the pharmacokinetic parameters (AUC0-t , AUC0 infinity , Cmax , Tmax and CL) were significantly different between normal and hyperuricemic rats. The different pharmacokinetic parameters might result from renal impairment or a change of metabolic enzymes in the pathological state. The pharmacokinetic study in pathological state could provide more useful information to guide the clinical use of traditional Chinese herbal medicine. PMID- 28084027 TI - Assessing factors associated with infertility using a couple-based approach. PMID- 28084028 TI - Clinical Study of the 3D-Master Color System among the Spanish Population. AB - PURPOSE: To study whether the shades of the 3D-Master System were grouped and represented in the chromatic space according to the three-color coordinates of value, chroma, and hue. MATERIALS AND METHODS: Maxillary central incisor color was measured on tooth surfaces through the Easyshade Compact spectrophotometer using 1361 participants aged between 16 and 89. The natural (not bleached teeth) color of the middle thirds was registered in the 3D-Master System nomenclature and in the CIELCh system. Principal component analysis and cluster analysis were applied. RESULTS: 75 colors of the 3D-Master System were found. The statistical analysis revealed the existence of 5 cluster groups. The centroid, the average of the 75 samples, in relation to lightness (L*) was 74.64, 22.87 for chroma (C*), and 88.85 for hue (h*). All of the clusters, except cluster 3, showed significant statistical differences with the centroid for the three-color coordinates (p <0.001). CONCLUSIONS: The results of this study indicated that 75 shades in the 3D-Master System were grouped into 5 clusters following coordinates L*, C*, and h* resulting from the dental spectrophotometer Vita Easyshade compact. The shades that composed each cluster did not belong to the same lightness color dimension groups. There was no special uniform chromatic distribution among the colors of the 3D-Master System. PMID- 28084030 TI - Use of a fluoride channel as a new selection marker for fission yeast plasmids and application to fast genome editing with CRISPR/Cas9. PMID- 28084029 TI - Bioluminescence Imaging of Spheroids for High-throughput Longitudinal Studies on 3D Cell Culture Models. AB - Bioluminescent (BL) cell-based assays based on two-dimensional (2D) monolayer cell cultures represent well-established bioanalytical tools for preclinical screening of drugs. However, cells in 2D cultures do not often reflect the morphology and functionality of living organisms, thus limiting the predictive value of 2D cell-based assays. Conversely, 3D cell models have the capability to generate the extracellular matrix and restore cell-to-cell communications; thus, they are the most suitable model to mimic in vivo physiology. In this work, we developed a nondestructive real-time BL imaging assay of spheroids for longitudinal studies on 3D cell models. A high-throughput BL 3D cell-based assay in micropatterned 96-well plate format is reported. The assay performance was assessed using the transcriptional regulation of nuclear factor K beta response element in human embryonic kidney (HEK293) cells. We compared concentration response curves for tumor necrosis factor-alpha with those obtained using conventional 2D cell cultures. One of the main advantages of this approach is the nonlysing nature of the assay, which allows for repetitive measurements on the same sample. The assay can be implemented in any laboratory equipped with basic cell culture facilities and paves the way to the development of new 3D bioluminescent cell-based assays. PMID- 28084031 TI - Direct and Autocatalytic Reductive Elimination from Gold Complexes ([(Ph3 P)Au(Ar)(CF3 )(X)], X=F, Cl, Br, I): The Key Role of Halide Ligands. AB - Kinetic and thermodynamic preferences for the reductive elimination of Caryl -CF3 , Caryl -X, Caryl -P, and CF3 -X bonds and competitive phosphine dissociation from a series of AuIII complexes [(Ph3 P)Au(Ar)(CF3 )(X)] (1 X ; Ar=4-Me-C6 H4 ; X=F, Cl, Br, I) are studied computationally. Kinetically, the most favorable pathways were found to consist of an initial phosphine dissociation from complex 1 X , which furnished the respective three-coordinate AuIII complexes [Au(Ar)(CF3 )(X)] (2 X ). The computed enthalpy barriers for various reductive elimination reactions from complex 2 X by a direct (or uncatalyzed) mechanism showed that Caryl -CF3 bond formation was the most favorable fate for any X group. When the direct elimination was compared with an autocatalytic mechanism that proceeded through the formation of a mixed-valent binuclear AuIII -AuI intermediate, the preference for the formation of a Caryl -CF3 bond is dependent on the nature of the bridging halide atom and follows the order F>Cl>Br>I. Concomitantly, the selectivity for the formation of Caryl -X bonds for various X atoms follows the opposite trend. The preference for the direct and autocatalytic processes is controlled entirely by the nature of the halide ligand. The predicted mechanisms and product selectivity trends for various halides show excellent agreement with recent experimental observation. The selectivity of various reductive elimination pathways was rationalized by using molecular orbital theory and distortion interaction model analyses. Attractive interactions between the AuI complex and complex 2X were found to reduce the activation barrier for Caryl -X elimination and critically control the selectivity of the product formation. PMID- 28084033 TI - Low performing students have insightfulness when they reflect-in-action. AB - CONTEXT: Measuring appropriateness of certainty of responses in a progress test using descriptors authentic to practice as reflection-in-action builds on existing theories of self-monitoring. Clinicians making decisions require the ability to accurately self-monitor, including certainty of being correct. Inappropriate certainty could lead to medical error. Self-assessment and certainty of assessment performance have been measured in a variety of ways. Previous work has shown that those with less experience are less accurate in self assessment, but such studies looked at self-assessment using methods less authentic to clinical practice. This study investigates how correctness varies with certainty, allowing for experience and performance. METHODS: Students in Years 2-5 were certain of their responses to two iterations of a progress test during one calendar year. Analyses compared correctness for certainty of response, test number, student year cohort and performance level, defined by criterion scores. RESULTS: The odds of a correct response increased with student certainty for all subsets allowing for year group and ability, including student subsets with less experience and subsets in lower-performance groups. CONCLUSION: Unlike previous work showing poorer accuracy of self-assessment for those with less experience or ability, we postulate that our finding of similar increases in correctness with increasing certainty even in the less experienced and lower performance groups, relates to certainty descriptors being worded in a way that is authentic to clinical practice, and in turn related to reflection-in-action. PMID- 28084032 TI - Cocatalyst-Free Hybrid Ionic Liquid (IL)-Based Porous Materials for Efficient Synthesis of Cyclic Carbonates through a Cooperative Activation Pathway. AB - Cocatalyst-free ionic liquid (IL)-based porous polymers (Px -Vy -OHz R) functionalized with an intermolecular hydroxyl group were prepared by means of radical copolymerization of 1-butyl-3-vinylimidazolium bromide, (4 vinylphenyl)methanol (VBzOH), and divinylbenzene (DVB) under solvothermal conditions. As the ratio of 4-vinylphenylmethanol in the initial mixture increased, the content of the hydroxyl groups in the polymer increased from 3.35 to 5.35 mmol g-1 and the Brunauer-Emmett-Teller (BET) surface area of the polymer decreased sharply from 365 to 2.5 m2 g-1 . In the carbonation of CO2 and epoxides, the turnover frequency (TOF) of Px -Vy -OHz R increased gradually from 25 to 67 h-1 as the OH ratio increased irrespective of the sharp decrease in BET surface area, which suggests the existence of a cooperative activation effect between OH and ILs. To obtain a high OH content while still maintaining a high BET surface area, hybrid porous materials (SBA-[Vx OHy ]R-n) were prepared by means of copolymerization of 1-ethyl-3-vinylimidazolium bromide and 4 vinylphenylmethanol in the mesopores of SBA-15. SBA-[Vx OHy ]R-n was more active than its polymer counterpart (TOF: 188 versus 71 h-1 ) in the cycloaddition of CO2 with propyl oxide owing to the combined effect of the high BET surface area and the high OH content. The hybridization of mesoporous materials with polymers represents an efficient strategy for the preparation of high-performance solid catalysts for chemical transformations. PMID- 28084034 TI - Prediction of liver volume - a population-based approach to meta-analysis of paediatric, adult and geriatric populations - an update. AB - Liver volume is a critical scaling factor for predicting drug clearance in physiologically based pharmacokinetic modelling and for both donor/recipient graft size estimation in liver transplantation. The accurate and precise estimation of liver volume is therefore essential. The objective here was to extend an existing meta-analysis using a non-linear mixed effects modelling approach for the estimation of liver volume to other race groups and paediatric and geriatric populations. Interrogation of the PubMed(r) database was undertaken using a text string query to ensure as objective a retrieval of liver volume data for the modelling exercise as possible. Missing body size parameters were estimated using simulations from the Simcyp Simulator V13R1 for an age and ethnically appropriate population. Non-linear mixed effect modelling was undertaken in Phoenix 1.3 (Certara) utilizing backward deletion and forward inclusion of covariates from fully parameterized models. Existing liver volume models based on body surface area (BSA) and body weight and height were implemented for comparison. The extension of a structural model using a BSA equation and incorporating the Japanese race and age as covariates and exponents on LV0 (thetaBaseline ) and body surface area (thetaBSA ), respectively, delivered a comparatively low objective function value. Bootstrapping of the original dataset revealed that the confidence intervals (2.5-97.5%) for the fitted (theta) parameter estimates were bounded by the bootstrapped estimates of the same. In conclusion, extension and re-parameterization of the existing Johnson model adequately describes changes in liver volume using the body surface area in all investigated populations. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28084035 TI - Conservative approach to rectosigmoid endometriosis: a cohort study. AB - INTRODUCTION: The aim of the study was to assess the risk of surgery after initial conservative treatment of rectosigmoid endometriosis in relation to demographic data. MATERIAL AND METHODS: The study was conducted on the tertiary endometriosis referral unit, Aarhus University Hospital. Medical records, from patients seen from January 2009 onwards with a diagnosis of rectosigmoid endometriosis and more than 6 months' follow up were audited. Demographic data, results of magnetic resonance imaging and time to secondary surgery for rectosigmoid endometriosis were registered. RESULTS: Data on 238 patients diagnosed with rectosigmoid endometriosis were included. In all, 78 (32.8%) patients had primary surgery, 27 (11.3%) had secondary surgery and 133 (55.9%) continued conservative treatment throughout the observation period. Patients who underwent primary or secondary surgery were younger than patients continuing conservative treatment. CONCLUSIONS: In a tertiary referral center where about half of patients with rectosigmoid endometriosis were scheduled for conservative treatment, more than 80% of these avoided surgery. PMID- 28084036 TI - EDITORIAL: ACKNOWLEDGMENT OF 2016 REVIEWERS AND EDITORIAL BOARD MEMBERS. PMID- 28084037 TI - EDITORIAL: AN INTRODUCTION TO THE NEW RADIATION REPORTING GUIDELINES. PMID- 28084038 TI - Response of vascular pigment epithelium detachment due to age-related macular degeneration to monthly treatment with ranibizumab: the prospective, multicentre RECOVER study. AB - PURPOSE: To assess the effects of monthly intravitreal ranibizumab injections in patients with vascularized pigment epithelium detachment (vPED) secondary to age related macular degeneration (AMD). METHODS: A total of 40 patients were prospectively observed and treated monthly with 0.5 mg ranibizumab injections (ClinicalTrials.gov Ident. NCT00976222). Inclusion criterion was a treatment naive vPED lesion with a minimum height of >=200 MUm. Best-corrected visual acuity (BCVA) and spectral-domain optical coherence tomography (SD-OCT) were evaluated at all visits. Fluorescein angiography and indocyanine green angiography were performed at baseline and quarterly. Lesions were differentiated between serous vascular PED (svPED, group A, 29 patients) and fibrovascular PED (fPED, group B, 11 patients). Primary outcome was the effectivity of continuous monthly treatment during a 12-month period as measured in change in BCVA. Secondary outcomes were change in PED height and PED greatest linear diameter (GLD). Further secondary outcomes were the presence of subretinal fluid and prognostic markers of an impending retinal pigment epithelium (RPE) tear: PED lesion height and diameter, ratio of choroidal neovascularization (CNV) size to PED size, hyperreflective lines in near-infrared images, microrips and subretinal cleft. RESULTS: Mean BCVA was 56.9 +/- 11.5 letters (A: 55.4 +/- 10.8; B: 59.1 +/ 13.4) at baseline and 55.1 +/- 15.9 (A: 53.7 +/- 17.0; B: 58.9 +/- 12.7) at 12 month follow-up. Excluding the RPE tear patients, the svPED group showed an increase in BCVA from 56.1 +/- 10.3 at baseline to 62.4 +/- 10.2 at 12-month follow-up (p = 0.048). Best-corrected visual acuity in patient who developed a RPE tear was 55.8 +/- 12.5 at baseline and 37.1 +/- 14.9 at 12-month follow-up. The mean change in PED height was -242.1 MUm +/- 285.5 (A: -427.3 MUm +/- 299.7; B: -51.6 MUm +/- 99.5). The mean decrease in PED GLD was -471.8 MUm +/- 727.6 (A: -738.9 MUm +/- 788.2; B: -10.4 MUm +/- 185.6). In group A, 10 patients developed a RPE tear (25%) after a mean of 3.6 injections. No tear was documented in group B. Lesion height, ratio of CNV size to PED size and presence of hyperreflective lines differed significantly between patients with and without RPE tear development. CONCLUSION: Serous vascular PED lesions showed an improvement regarding BCVA and morphologic characteristics unless an RPE tear occurred. In fPED lesions, a functional and morphological stabilization was observed. Monthly ranibizumab injections are an effective treatment regarding the resorption of subretinal fluid in vPED due to AMD. Patients should be screened for the presence of morphologic risk factors for RPE tear development before and during treatment. PMID- 28084039 TI - Experimental and Clinical Pharmacology of Ziziphus jujuba Mills. AB - Ziziphus jujuba Mills, 'annab' in Iran, 'ber' in India or 'pomme sourette' in France, is a species whose fruit (known warmly as 'the fruits of life' in China) has been consumed for centuries for its nutritional value. The food industry used it as a food additive and flavoring. The dry seeds, the crude leaves and the stem bark are still used in ethnopharmacology to treat digestive disorders and gastric ulcers as antitussive, laxative and hypotensive drugs; even now, it is used in China to treat children who suffer from typhoid fever, furuncle and ecthyma. In Taiwan, the dry seeds for the variety spinosa (Suan Zao Ren) are the second most commonly prescribed and used phytomedicine for insomnia. Its popularity and production have increased worldwide in recent years, especially in Europe. The European Pharmacopoeia Commission has been unable to elaborate upon the EP monograph on Ziziphi spinosae semen as was planned. The EMA has not made its recommendations yet. Is it still a gap in the scientific knowledge? Or is difficult for traditional Chinese medicinal herbs to fulfill the style and quality parameters that are required? Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28084040 TI - Type I and Type II Photosensitized Oxidation Reactions: Guidelines and Mechanistic Pathways. AB - Here, 10 guidelines are presented for a standardized definition of type I and type II photosensitized oxidation reactions. Because of varied notions of reactions mediated by photosensitizers, a checklist of recommendations is provided for their definitions. Type I and type II photoreactions are oxygen dependent and involve unstable species such as the initial formation of radical cation or neutral radicals from the substrates and/or singlet oxygen (1 O21 ?g ) by energy transfer to molecular oxygen. In addition, superoxide anion radical (O2.-) can be generated by a charge-transfer reaction involving O2 or more likely indirectly as the result of O2 -mediated oxidation of the radical anion of type I photosensitizers. In subsequent reactions, O2.- may add and/or reduce a few highly oxidizing radicals that arise from the deprotonation of the radical cations of key biological targets. O2.- can also undergo dismutation into H2 O2 , the precursor of the highly reactive hydroxyl radical (.OH) that may induce delayed oxidation reactions in cells. In the second part, several examples of type I and type II photosensitized oxidation reactions are provided to illustrate the complexity and the diversity of the degradation pathways of mostly relevant biomolecules upon one-electron oxidation and singlet oxygen reactions. PMID- 28084041 TI - Salvage therapy for children with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia. AB - BACKGROUND: In the tyrosine kinase inhibitor (TKI) era, outcomes after salvage therapy for relapsed or refractory Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) remain unclear. PROCEDURE: The clinical courses of 19 patients with relapse (n = 13) or induction failure (n = 6) in the Japanese Pediatric Leukemia/Lymphoma Study Group Ph+ ALL04 study were retrospectively reviewed. RESULTS: Fifteen male and four female patients had a median age of 8 (range 4-15) years at relapse or induction failure. Patients received imatinib in combination with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) and methotrexate and cytarabine (MTX/Ara-C) (n = 9), imatinib in combination with other chemotherapy (n = 5), chemotherapy without imatinib (n = 2), imatinib alone (n = 2), or no additional chemotherapy (n = 1). Two patients underwent hematopoietic stem cell transplantation (HSCT) without achieving complete remission (CR) and died of leukemia. The remaining 17 patients achieved CR with salvage therapies and underwent HSCT whilst in CR: 10 patients remain alive in CR, five died of transplantation-related complications, and two died of relapse. In six of seven patients with available data on minimal residual disease (MRD), imatinib in combination with the first course of hyper-CVAD was more effective in achieving a favorable MRD response compared with the Ph+ ALL04 induction regimen. CONCLUSION: This study suggested that cross-resistance to imatinib failed to develop after conventional chemotherapy. Imatinib in combination with chemotherapy including hyper-CVAD+MTX/Ara-C was effective and safe for relapsed or refractory Ph+ ALL patients who received frontline therapy without imatinib. PMID- 28084042 TI - Differentiation between optic disc drusen and optic disc oedema using fundus photography. AB - PURPOSE: To describe a funduscopic sign that can be used to differentiate between optic disc drusen (ODD) and optic disc oedema (ODE). METHODS: A total of 73 eyes from 73 consecutive subjects with disc margin blurring who had been evaluated using spectral-domain optical coherence tomography (SD-OCT) were included. Final diagnosis was made by SD-OCT; ODD was defined by direct visualization of ODD, while ODE was defined by documentation of retinal nerve fibre layer oedema (nasal retinal nerve fibre layer thickness >78.0 MUm). Peripapillary retina was selected as a two-disc-diameter-sized square image from the fundus photograph. Using MATLAB software, colour photographs were converted to indexed image of eight colours. Presence of a smooth contour strip between the nasal disc margin and juxtapapillary retina was defined as a halo. Whether the halo could predict the ODD was analysed retrospectively. RESULTS: The halo sign was detected in 45 eyes (100%) with ODD including one eye with both ODD and ODE. No eyes with ODE alone showed the halo sign. The halo sign implied the presence of ODD (Cohen's kappa = 1.000, p < 0.001) and the absence of ODE (Cohen's kappa = 0.971, p < 0.001). The halo sign showed a good interobserver reliability [ICC (2, 1) = 0.944, 95% confidence interval 0.912-0.964]. SD-OCT images showed that halos represented retinal elevations above ODD. CONCLUSIONS: In the patients with blurred disc margin, the presence of a halo strongly suggested underlying ODD rather than ODE. PMID- 28084043 TI - Emergent climate and CO2 sensitivities of net primary productivity in ecosystem models do not agree with empirical data in temperate forests of eastern North America. AB - Ecosystem models show divergent responses of the terrestrial carbon cycle to global change over the next century. Individual model evaluation and multimodel comparisons with data have largely focused on individual processes at subannual to decadal scales. Thus far, data-based evaluations of emergent ecosystem responses to climate and CO2 at multidecadal and centennial timescales have been rare. We compared the sensitivity of net primary productivity (NPP) to temperature, precipitation, and CO2 in ten ecosystem models with the sensitivities found in tree-ring reconstructions of NPP and raw ring-width series at six temperate forest sites. These model-data comparisons were evaluated at three temporal extents to determine whether the rapid, directional changes in temperature and CO2 in the recent past skew our observed responses to multiple drivers of change. All models tested here were more sensitive to low growing season precipitation than tree-ring NPP and ring widths in the past 30 years, although some model precipitation responses were more consistent with tree rings when evaluated over a full century. Similarly, all models had negative or no response to warm-growing season temperatures, while tree-ring data showed consistently positive effects of temperature. Although precipitation responses were least consistent among models, differences among models to CO2 drive divergence and ensemble uncertainty in relative change in NPP over the past century. Changes in forest composition within models had no effect on climate or CO2 sensitivity. Fire in model simulations reduced model sensitivity to climate and CO2 , but only over the course of multiple centuries. Formal evaluation of emergent model behavior at multidecadal and multicentennial timescales is essential to reconciling model projections with observed ecosystem responses to past climate change. Future evaluation should focus on improved representation of disturbance and biomass change as well as the feedbacks with moisture balance and CO2 in individual models. PMID- 28084045 TI - Tapentadol for Cancer Pain Management: A Narrative Review. AB - BACKGROUND AND OBJECTIVE: Pain is one of the most common symptoms in patients with cancer. The aim of this review is to summarize the most recent literature regarding tapentadol use in oncology patients and moderate or severe pain. DATABASES AND DATA TREATMENT: We have conducted a review of the literature using PubMed, The Cochrane Library, EMBASE, and Google Scholar for all manuscripts published between 2008 and 2016, using the key words "tapentadol," "cancer," "pain," "tumor," and "malignant." RESULTS: Nine studies met the inclusion criteria (four randomized clinical trials and five prospective cohort studies). The scope of the literature was diverse, with 15 instruments used to measure different aspects of pain (intensity, health status, quality of life, psychometric and well-being, perception of change, and neuropathic pain). All these studies concluded that tapentadol is seemingly a well-tolerated and efficacious agent for moderate-severe cancer pain, with few typically mild adverse reactions. However, the most significant detected weaknesses of research were that (1) existing studies do not clearly show a superiority of tapentadol with respect to previous generation opioids, (2) low-to-moderate sample sizes prevent obtaining robust conclusions about effectiveness, (3) there was an absence of noninferiority trials comparing tapentadol vs. fentanyl or oxycodone naloxone, and (4) there was scarce generalizability of prospective observational studies. CONCLUSION: Tapentadol is seemingly an effective, well-tolerated alternative for moderate or severe cancer pain. Most prospective cohort studies have relatively small samples, are restricted to few research centers, and lack detailed subgroup information. More experience is required to draw valid generalizable conclusions. PMID- 28084044 TI - Bi-layer silk fibroin grafts support functional tissue regeneration in a porcine model of onlay esophagoplasty. AB - Partial circumferential, full thickness defects of the esophagus can occur as a result of organ perforation or tumour resection, or during surgical reconstruction of strictured segments. Complications associated with autologous tissue flaps conventionally utilized for defect repair necessitate the development of new graft options. In this study, bi-layer silk fibroin (BLSF) scaffolds were investigated for their potential to support functional restoration of partial circumferential defects in a porcine model of esophageal repair. Onlay thoracic esophagoplasty with BLSF matrices (~3 x 1.5 cm) was performed in adult swine (N = 6) for 3 months of implantation. All animals receiving BLSF grafts survived with no complications and were capable of solid food consumption. Radiographic esophagrams revealed preservation of organ continuity with no evidence of contrast extravasation or strictures. Fluoroscopic analysis demonstrated peristaltic contractions. Ex vivo tissue bath studies displayed contractile responses to carbachol, electric field stimulation, and KCl while isoproterenol produced tissue relaxation. Histological and immunohistochemical evaluations of neotissues showed a stratified, squamous epithelium, a muscularis mucosa composed of smooth muscle bundles, and a muscularis externa organized into circular and longitudinal layers, with a mix of striated skeletal muscle fascicles interspersed with smooth muscle. De novo innervation and vascularization were observed throughout the graft sites and consisted of synaptophysin-positive neuronal boutons and vessels lined with CD31-positive endothelial cells. The results of this study demonstrate that BLSF scaffolds can facilitate constructive remodeling of partial circumferential, full thickness esophageal defects in a large animal model. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28084046 TI - The role of hypertension in retinal blood flow alterations in open-angle glaucoma patients. PMID- 28084047 TI - Response to: Why fat suits do not advance the scientific study of weight stigma. PMID- 28084049 TI - Towards more systematic and better theorised research on simulations. PMID- 28084050 TI - Evaluating evaluations: an ouroboros for medical education. PMID- 28084051 TI - Supervisor expertise to optimise learner : preceptor ratios. PMID- 28084052 TI - Contexts, concepts and cognition: principles for the transfer of basic science knowledge. AB - CONTEXT: Transfer of basic science aids novices in the development of clinical reasoning. The literature suggests that although transfer is often difficult for novices, it can be optimised by two complementary strategies: (i) focusing learners on conceptual knowledge of basic science or (ii) exposing learners to multiple contexts in which the basic science concepts may apply. The relative efficacy of each strategy as well as the mechanisms that facilitate transfer are unknown. In two sequential experiments, we compared both strategies and explored mechanistic changes in how learners address new transfer problems. METHODS: Experiment 1 was a 2 * 3 design in which participants were randomised to learn three physiology concepts with or without emphasis on the conceptual structure of basic science via illustrative analogies and by means of one, two or three contexts during practice (operationalised as organ systems). Transfer of these concepts to explain pathologies in familiar organ systems (near transfer) and unfamiliar organ systems (far transfer) was evaluated during immediate and delayed testing. Experiment 2 examined whether exposure to conceptual analogies and multiple contexts changed how learners classified new problems. RESULTS: Experiment 1 showed that increasing context variation significantly improved far transfer performance but there was no difference between two and three contexts during practice. Similarly, the increased conceptual analogies led to higher performance for far transfer. Both interventions had independent but additive effects on overall performance. Experiment 2 showed that such analogies and context variation caused learners to shift to using structural characteristics to classify new problems even when there was superficial similarity to previous examples. CONCLUSIONS: Understanding problems based on conceptual structural characteristics is necessary for successful transfer. Transfer of basic science can be optimised by using multiple strategies that collectively emphasise conceptual structure. This means teaching must focus on conserved basic science knowledge and de-emphasise superficial features. PMID- 28084053 TI - Six fallacies that hinder development of the medical humanities in medical education. PMID- 28084055 TI - Small Molecule Activation with N,NR-MIC Platinum Complexes. AB - The reaction of platinum complex trans-[1] bearing an N,NEt-imidazolide ligand with bis(diphenylphosphino)ethane (dppe) or bis(dicyclohexylphosphino)ethane (dchpe) yields the dinuclear MIC complexes [2]I2 or the mononuclear MIC complex [3]I, respectively. Whereas dinuclear [2]I2 does not react with elemental hydrogen, the mononuclear complex [3]I splits elemental hydrogen under mild reaction conditions with formation of hydride complex [4]I and N-ethylimidazole. Dinuclear complex [3]I activates CS2 with formation of complex [5]I featuring the CS2 molecule bound through the carbon atom to the MIC nitrogen atom and one sulfur atom coordinating to the platinum center. PMID- 28084056 TI - Genetic Influences of OPRM1, OPRD1 and COMT on Morphine Analgesia in a Multi Modal, Multi-Tissue Human Experimental Pain Model. AB - Human studies on experimentally induced pain are of value to elucidate the genetic influence on morphine analgesia under controlled conditions. The aim of this study was to investigate whether genetic variants of mu-, kappa- and delta opioid receptor genes (OPRM1, OPRK1 and OPRD1) and catechol-O-methyltransferase gene (COMT) are associated with the morphine analgesia. The study was a randomized, double-blind, two-way, crossover, single-dose study conducted in 40 healthy participants, where morphine was compared with placebo. Pain was induced by contact heat, muscle pressure, bone pressure, rectal stimulations (mechanical, electrical and thermal) and cold pressor test (immersion of the hand into ice water). Sixteen genetic polymorphisms of four candidate genes were explored. Variability in morphine analgesia to contact heat stimulation was associated with COMT rs4680 (p = 0.04), and rectal thermal stimulation was associated with OPRM1 rs9479757 (p = 0.03). Moreover, in males, variability in morphine analgesia to rectal thermal stimulation was associated with OPRD1 polymorphisms: rs2234918 (p = 0.01) and rs533123 (p = 0.046). The study was explorative and hypothesis generating due to the relatively small study size. However, results suggest that genetic variants in the COMT and OPRM1 irrespective of gender, and OPRD1 in males may contribute to the variability in morphine analgesia in experimental pain models. PMID- 28084057 TI - Clinical and Radiological Outcomes of Implants in Osteotome Sinus Floor Elevation with and without Grafting: A Systematic Review and a Meta-Analysis. AB - PURPOSE: To systematically appraise the clinical and radiological outcomes after osteotome sinus floor elevation (OSFE) with or without grafting in the published dental literature. METHODS: An electronic search was conducted using PubMed, Web of Science, and the Cochrane Central Register of Controlled Trial to identify studies after OSFE from January 1, 1994 to August 30, 2015. The primary outcome was the implant survival rates after OSFE with and without grafting materials. RESULTS: After search and evaluation of the literature according to the inclusion criteria, 7 studies were included in the review. The random-effect model meta analysis based on 463 implants in patients without grafting and 415 implants in patients with grafting showed that the risk ratio difference of survival rates was 1.010 (95%CI 0.910, 1.120), which did not reach statistical significance (p = 0.99). The membrane perforation rates ranged from 0% to 10.80%. No significant difference of crestal bone loss was reported between graft and nongraft groups. CONCLUSIONS: Based on currently available evidence, OSFE techniques with and without grafting were both predictable in the short term. In addition, survival rates of dental implants in OSFE with or without grafting did not show any significant difference in the short term. PMID- 28084058 TI - Selective peroxisome proliferator-activated receptor-alpha modulator K-877 efficiently activates the peroxisome proliferator-activated receptor-alpha pathway and improves lipid metabolism in mice. AB - AIMS/INTRODUCTION: Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a therapeutic target for hyperlipidemia. K-877 is a new selective PPARalpha modulator (SPPARMalpha) that activates PPARalpha transcriptional activity. The aim of the present study was to assess the effects of K-877 on lipid metabolism in vitro and in vivo compared with those of classical PPARalpha agonists. MATERIALS AND METHODS: To compare the effects of K-877 on PPARalpha transcriptional activity with those of the classical PPARalpha agonists Wy14643 (Wy) and fenofibrate (Feno), the cell-based PPARalpha transactivation luciferase assay was carried out. WT and Ppara-/- mice were fed with a moderate-fat (MF) diet for 6 days, and methionine-choline-deficient (MCD) diet for 4 weeks containing Feno or K-877. RESULTS: In luciferase assays, K-877 activated PPARalpha transcriptional activity more efficiently than the classical PPARalpha agonists Feno and Wy. After being fed MF diet containing 0.001% K-877 or 0.2% Feno for 6 days, mice in the K-877 group showed significant increases in the expression of Ppara and its target genes, leading to marked reductions in plasma triglyceride levels compared with those observed in Feno-treated animals. These K 877 effects were blunted in Ppara-/- mice, confirming that K-877 activates PPARalpha. In further experiments, K-877 (0.00025%) and Feno (0.1%) equally improved the pathology of MCD diet-induced non-alcoholic fatty liver disease, with increased expression of hepatic fatty acid oxidation genes. CONCLUSIONS: The present data show that K-877 is an attractive PPARalpha-modulating drug and can efficiently reduce plasma triglyceride levels, thereby alleviating the dysregulation of lipid metabolism. PMID- 28084059 TI - Robot-assisted retinal vein cannulation in an in vivo porcine retinal vein occlusion model. AB - PURPOSE: To evaluate the feasibility of robot-assisted retinal vein cannulation for retinal vein occlusion. METHODS: Prospective experimental study performed in in vivo porcine eyes. A standard three port pars plana vitrectomy was followed by laser-induced branch retinal vein occlusion. Consequently, a retinal vein cannulation with the help of a surgical robot and a microneedle was performed. Complete success was defined as a stable intravenous position of the needle tip confirmed by blood washout for at least 3 min. Secondary outcomes were the occurrence of intra-operative complications and technical failures. RESULTS: Cannulation was successful in 15 of 18 eyes with a complete success rate (duration of infusion of more than 3 min) of 73% after exclusion of two eyes from analysis due to failure in establishing a blood clot. There were no technical failures regarding the robotic device. The intravessel injections of ocriplasmin in two of two eyes led to a clot dissolution. In a subset of five eyes, a second cannulation attempt at the border of the optic disc resulted in a stable intravessel position and infusion during 362 (+/-138) seconds. CONCLUSION: Robot assisted retinal vein cannulation with prolonged infusion time is technically feasible. Human experiments are required to analyse the clinical benefit of this new therapy. PMID- 28084061 TI - A comparison of two comorbidity indices for predicting inpatient rehabilitation outcomes. AB - BACKGROUND: Comorbid conditions are important in health care. The best comorbidity index for predicting the impact of comorbidities on rehabilitation outcomes has not been determined. AIM: Compare the associations of comorbidity measured using the Charlson Comorbidity Index (CCI) and the Cumulative Index Rating Scale (CIRS) with key rehabilitation outcomes. Aim was to determine whether either of these comorbidity indices helped explain the variation in key rehabilitation outcomes. DESIGN: Prospective open-cohort study. SETTING: Inpatient rehabilitation ward, Melbourne, Australia. POPULATION: Adults admitted for inpatient rehabilitation (N.=280). METHODS: The main outcomes were demographic (e.g. age, gender, discharge destination) and clinical outcomes (reason for rehabilitation, length of stay, LOS, Functional Independence Measure, CCI and CIRS). A series of regression analyses were performed to determine the influence of comorbidity on three dependent variables: 1) LOS in rehabilitation; 2) the change in Functional Independence Measure-motor score between rehabilitation discharge and admission; 3) the discharge destination (home vs. other). RESULTS: The mean age was 57.7 years, there were slightly more females (51%), most (95%) patients previously lived at home with family or other relatives (63%). The most common reason for rehabilitation was orthopedic or other conditions (52%) and most (80%) people were discharged home. The median LOS was 27 days. There were 100 (35.7%) patients who had no comorbidity recorded using the CCI, 112 (40.0%) had one comorbidity and 26 (9.3%) who had three or more. All patients had at least one comorbidity recorded with the CIRS, and 264 (94.3%) had 3 or more comorbidities. There was little or no difference between the CCI or CIRS in terms of their ability to explain the variance in LOS (adjusted R2=0.38 with and without comorbidities), change in disability during rehabilitation (adjusted R2=0.31-0.33 with and without comorbidities) or the discharge destination (AUC=0.72 without comorbidities; 0.73-0.74 with comorbidities) beyond that accounted for by demographic and clinical information. CONCLUSIONS: Neither the CIRS nor the CCI in our patient sample provide additional information that explains the impact of comorbidities on key rehabilitation outcomes. CLINICAL REHABILITATION IMPACT: Further research is needed to determine the most appropriate measure of comorbidity of relevance to inpatient rehabilitation outcomes. PMID- 28084060 TI - What do spinal cord injury patients think of their improvement? A study of the minimal clinically important difference of the Spinal Cord Independence Measure III. AB - BACKGROUND: The Spinal Cord Independence Measure (SCIM III) is a scale of independence in the activities of daily life, specifically designed for spinal cord injury subjects. AIM: The aim of this study was to calculate the minimal clinically important difference (MCID) of the SCIM III according to distribution and anchor based approach. DESIGN: Prospective study. SETTING: Four Spinal Cord Units in Italy. POPULATION: Patients with acute/subacute spinal cord injury/lesion. METHODS: The scores of the total SCIM and of the four subscale was recorded at admission and discharge. Clinical significance was calculated according to anchor based methodology using a global rating of change questionnaire. The accuracy of MCID values in predicting a judgment of small improvement by the patients has been assessed by means of the area under the receiving operating curves (aROC). RESULTS: Total SCIM MCID values varied from 12 for patients with complete tetraplegia to 45.3 for those with incomplete thoracic lesions. The MCID of self-care varied from 3.3 to 8.5 and from 10 to 18 for respiration and sphincter management, depending on the level and severity of the lesion. With regard to mobility (room and toilet), the MCID varied from 1 to 3 and from 2.5 to 7.26 for mobility (indoors and outdoors). The aROC was between good and excellent for all these values. CONCLUSIONS: The results provide benchmarks for clinicians and researchers to interpret whether patients' change score on the SCIM III can be interpreted as true or clinically meaningful and to make clinical judgments about the patients' progress. CLINICAL REHABILITATION IMPACT: Our data could be useful for both clinicians and researchers. At the beginning of rehabilitation clinicians may have an idea of the minimal improvement of the patient (based on his neurological status) that could have an impact on patient's life. At the end of rehabilitation process, it is possible to control if the patient achieved an improvement that is true and significant. Researchers could also use these criteria to evaluate the clinical significance of an intervention by calculating the number of subjects in the treatment and control groups (or in two different treatment groups) who achieved a change calculated as the natural recovery plus the MCID. PMID- 28084062 TI - Body composition influenced by progressive elastic band resistance exercise of sarcopenic obesity elderly women: a pilot randomized controlled trial. AB - BACKGROUND: Sarcopenia involves age-related decreases in muscle strength and muscle mass, leading to frailty and disability in elderly people. When combined with obesity, it is defined as sarcopenic obesity (SO), which can result in more functional limitations and metabolic disorders than either disorder alone. AIM: The aim of this study was to investigate body composition changes after elastic band resistance training in elderly women with SO. DESIGN: Randomized single blinded (assessor blinded) controlled pilot trial. SETTING: Academic medical center. POPULATION: Thirty-five elderly (>60 years old) women with SO. METHODS: This pilot randomized controlled trial focused on elderly women with SO. The study group underwent progressive elastic band resistance training for 12 weeks (3 times per week). The control group received only a 40-minute lesson about the exercise concept. Dual-energy X-ray absorptiometry was performed before and after intervention to evaluate body composition. Mann-Whitney U and Wilcoxon signed rank tests were used to analyze the differences within and between these groups. RESULTS: In total, 35 elderly women with SO were enrolled and divided into study (N.=18) and control groups (N.=17). No difference was observed in age, biochemical parameters, or Body Mass Index between both groups. After the intervention, the fat proportion of body composition in the right upper extremity (P=0.03), left upper extremity (P=0.04), total fat (P=0.035), and fat percentage (P=0.012) had decreased, and bone mineral density (BMD) (P=0.026), T-score (P=0.028), and Z-score (P=0.021) had increased in the study group. Besides, statistical difference was observed in outcome measurements of right upper extremity (P=0.013), total fat (P=0.023), and fat percentage (P=0.012) between the groups. CONCLUSIONS: Our study demonstrated that progressive elastic band resistance exercise can reduce fat mass and increase BMD in elderly women with SO, and that this exercise program is feasible for this demographic. Additional studies with larger sample sizes and longer intervention periods should be conducted. CLINICAL REHABILITATION IMPACT: Twelve weeks of progressive elastic band resistance exercise program is safe and effective for SO elder women. PMID- 28084063 TI - Test-retest reliability and minimal detectable change of two simplified 3-point balance measures in patients with stroke. AB - BACKGROUND: The 3-point Berg Balance Scale (BBS-3P) and 3-point Postural Assessment Scale for Stroke Patients (PASS-3P) were simplified from the BBS and PASS to overcome the complex scoring systems. The BBS-3P and PASS-3P were more feasible in busy clinical practice and showed similarly sound validity and responsiveness to the original measures. However, the reliability of the BBS-3P and PASS-3P is unknown limiting their utility and the interpretability of scores. AIM: We aimed to examine the test-retest reliability and minimal detectable change (MDC) of the BBS-3P and PASS-3P in patients with stroke. DESIGN: Cross sectional study. SETTING: The rehabilitation departments of a medical center and a community hospital. POPULATION: A total of 51 chronic stroke patients (64.7% male). METHODS: Both balance measures were administered twice 7 days apart. The test-retest reliability of both the BBS-3P and PASS-3P were examined by intraclass correlation coefficients (ICC). The MDC and its percentage over the total score (MDC%) of each measure was calculated for examining the random measurement errors. RESULTS: The ICC values of the BBS-3P and PASS-3P were 0.99 and 0.97, respectively. The MDC% (MDC) of the BBS-3P and PASS-3P were 9.1% (5.1 points) and 8.4% (3.0 points), respectively, indicating that both measures had small and acceptable random measurement errors. CONCLUSIONS: Our results showed that both the BBS-3P and the PASS-3P had good test-retest reliability, with small and acceptable random measurement error. These two simplified 3-level balance measures can provide reliable results over time. CLINICAL REHABILITATION IMPACT: Our findings support the repeated administration of the BBS-3P and PASS-3P to monitor the balance of patients with stroke. The MDC values can help clinicians and researchers interpret the change scores more precisely. PMID- 28084064 TI - Feasibility and safety of early lower limb robot-assisted training in sub-acute stroke patients: a pilot study. AB - BACKGROUND: So far, the development of robotic devices for the early lower limb mobilization in the sub-acute phase after stroke has received limited attention. AIM: To explore the feasibility of a newly robotic-stationary gait training in sub-acute stroke patients. To report the training effects on lower limb function and muscle activation. DESIGN: A pilot study. SETTING: Rehabilitation ward. POPULATION: Two sub-acute stroke inpatients and ten age-matched healthy controls were enrolled. Healthy controls served as normative data. METHODS: Patients underwent 10 robot-assisted training sessions (20 minutes, 5 days/week) in alternating stepping movements (500 repetitions/session) on a hospital bed in addition to conventional rehabilitation. Feasibility outcome measures were compliance, physiotherapist time, and responses to self-report questionnaires. Efficacy outcomes were bilateral lower limb muscle activation pattern as measured by surface electromyography (sEMG), Motricity Index (MI), Medical Research Council (MRC) grade, and Ashworth Scale (AS) scores before and after training. RESULTS: No adverse events occurred. No significant differences in sEMG activity between patients and healthy controls were observed. Post-training improvement in MI and MRC scores, but no significant changes in AS scores, were recorded. Post treatment sEMG analysis of muscle activation patterns showed a significant delay in rectus femoris offset (P=0.02) and prolonged duration of biceps femoris (P=0.04) compared to pretreatment. CONCLUSIONS: The robot-assisted training with our device was feasible and safe. It induced physiological muscle activations pattern in both stroke patients and healthy controls. Full-scale studies are needed to explore its potential role in post-stroke recovery. CLINICAL REHABILITATION IMPACT: This robotic device may enrich early rehabilitation in subacute stroke patients by inducing physiological muscle activation patterns. Future studies are warranted to evaluate its effects on promoting restorative mechanisms involved in lower limb recovery after stroke. PMID- 28084065 TI - Global Advisory Committee on Vaccine Safety, 30 November - 1 December 2016. PMID- 28084070 TI - Carrier Step-by-Step Transport Initiated by Precise Defect Distribution Engineering for Efficient Photocatalytic Hydrogen Generation. AB - Semiconductor photocatalysts have been widely used for solar-to-hydrogen conversion; however, efficient photocatalytic hydrogen generation still remains a challenge. To improve the photocatalytic activity, the critical step is the transport of photogenerated carriers from bulk to surface. Here, we report the carrier step-by-step transport (CST) for semiconductor photocatalysts through precise defect engineering. In CST, carriers can fast transport from bulk to shallow traps in the defective subsurface first, and then transfer to the surface active acceptors. The key challenge of initiating CST lies in fine controlling defect distribution in semiconductor photocatalysts to introduce the special band matching between the crystalline bulk and defect-controllable surface, moderate bridgelike shallow traps induced by subsurface defects, and abundant surface active sites induced by surface defects. In our proof-of-concept demonstration, the CST was introduced into typical semiconductor TiO2 assisted by the fluorine assisted kinetic hydrolysis method, and the designed TiO2 can exhibit the state of-the-art photocatalytic hydrogen generation rate among anatase TiO2 up to 13.21 mmol h-1 g-1, which is 120 times enhanced compared with crystalline anatase TiO2 under sunlight. The CST initiated by precise defect distribution engineering provides a new sight on greatly improving photocatalytic hydrogen generation performance of semiconductor catalysts. PMID- 28084071 TI - Highly Enhanced Thermoelectric Properties of Bi/Bi2S3 Nanocomposites. AB - Bismuth sulfide (Bi2S3) has been of high interest for thermoelectric applications due to the high abundance of sulfur on Earth. However, the low electrical conductivity of pristine Bi2S3 results in a low figure of merit (ZT). In this work, Bi2S3@Bi core-shell nanowires with different Bi shell thicknesses were prepared by a hydrothermal method. The core-shell nanowires were densified to Bi/Bi2S3 nanocomposite by spark plasma sintering (SPS), and the structure of the nanowire was maintained as the nanocomposite due to rapid SPS processing and low sintering temperature. The thermoelectric properties of bulk samples were investigated. The electrical conductivity of a bulk sample after sintering at 673 K for 5 min using Bi2S3@Bi nanowire powders prepared by treating Bi2S3 nanowires in a hydrazine solution for 3 h is 3 orders of magnitude greater than that of a pristine Bi2S3 sample. The nanocomposite possessed the highest ZT value of 0.36 at 623 K. This represents a new strategy for densifying core-shell powders to enhance their thermoelectric properties. PMID- 28084072 TI - Reactions of Lithiated Diphosphanes R2P-P(SiMe3)Li (R = tBu and iPr) with [MeNacnacTiCl2.THF] and [MeNacnacTiCl3]. Formation and Structure of TitaniumIII and TitaniumIV beta-Diketiminato Complexes Bearing the Side-on Phosphanylphosphido and Phosphanylphosphinidene Functionalities. AB - beta-Diketiminate complexes of TiIII-containing phosphanylphosphido ligands [MeNacnacTi(Cl){eta2-P(SiMe3)-PR2}] (MeNacnac- = [Ar]NC(Me)CHC(Me)N[Ar]; Ar = 2,6 iPr2C6H3) were prepared by reactions of [MeNacnacTiCl2.THF] with lithium derivatives of diphosphanes R2P-P(SiMe3)Li (R = tBu, iPr) in toluene solutions. Surprisingly, reactions of [MeNacnacTiCl2.THF] with R2P-P(SiMe3)Li in THF solutions led to TiIV complexes containing phosphanylphosphinidene ligands [MeNacnacTi(Cl)(eta2-P-PtBu2)] via an autoredox path involving a migration of a nitrene NAr from the Nacnac skeleton to the Ti centers. Solid-state structures of [MeNacnacTi(Cl){eta2-P(SiMe3)-PtBu2}] (1a) and [MeNacnacTi(Cl)(eta2-P-PtBu2)] (two isomers 2a1, 2a2) together with [MeNacnacTi(Cl){eta2-P(SiMe3)-PiPr2}] (1b) and [MeNacnacTi(Cl)(eta2-P-PiPr2)] (2b) were established by the single-crystal X ray diffraction and display clearly side-on geometry of the (Me3Si)P-PR2 and P PR2 moieties in the solid state. Phosphanylphosphinidene complexes [MeNacnacTi(Cl)(eta2-P-PR2)] indicate that the 31P NMR resonances of phosphinidene P atoms appear at a very low field in solution and in the solid state. PMID- 28084073 TI - Biobased and Sustainable Alternative Route to Long-Chain Cellulose Esters. AB - Fatty acid cellulose esters (FACEs), which have been identified recently as sustainable film materials, are conventionally synthesized by the use of the reaction with acyl chloride/anhydride pyridine in the presence of LiCl/N,N dimethylacetamide. In this study, we have developed a new synthetic route to FACEs using a vinyl ester of long chain fatty acid, which is an excellent biobased and highly reactive reagent, for the functionalization of cellulose. The developed method involves the synthesis of the long aliphatic fatty acid vinyl ester via a transition-metal-catalyzed transvinylation reaction between vinyl acetate and the fatty acid, followed by its subsequent reaction with cellulose to yield FACEs. In this work, we have used vinyl oleate as a model precursor to introduce the fatty acid chain to cellulose. The covalent grafting of the fatty acid chain to the free hydroxyl groups of cellulose was achieved through potassium carbonate (K2CO3)-catalyzed transesterification of vinyl oleate in the presence of N-methyl pyrrolidone as solvent with low toxicity. Successful functionalization of cellulose was confirmed by FTIR, 13C CP-MAS NMR, X-ray diffraction, and the thermogravimetric analysis. The results obtained showed that the functionalization efficiency of the cellulose increased with higher temperature and prolonged reaction times. The strategy proposed in the present work is an important step onward in terms of sustainability because the long chain vinyl ester can be synthesized from a renewable and biobased source, and the toxic and corrosive chemicals commonly employed for cellulose esterification are avoided. PMID- 28084074 TI - Isoindolinones via Copper-Catalyzed Intramolecular Benzylic C-H Sulfamidation. AB - 2-Benzyl-N-tosylbenzamides and related substrates undergo copper-catalyzed intramolecular sulfamidation at the benzylic methylene to give N-arylsuflonyl-1 arylisoindolinones, which can be N-deprotected using samarium iodide to generate the free 1-arylisoindolinones. Preliminary mechanistic studies indicate that the rate-determining step is not C-H bond cleavage but are instead consistent with slow oxidation of a copper pi-arene intermediate. PMID- 28084075 TI - A Two-Dimensional Polymer Synthesized through Topochemical [2 + 2]-Cycloaddition on the Multigram Scale. AB - The single-crystal-to-single-crystal (scsc) synthesis of a 2D polymer based on photochemically triggered [2 + 2]-cycloaddition is reported. Both monomer and polymer single crystals are analyzed by X-ray diffraction, which is the first case of a scsc two-dimensional polymerization based on this cycloaddition and the third ever case for a scsc synthesis of a 2D polymer. The product crystals at quantitative conversion are wet-exfoliated under mild conditions and afford countless features that are single and double layers as judged by their AFM heights of hAFM ~ 1.2 +/- 0.5 and 2.2 +/- 0.5 nm, respectively. The X-ray structure-based molecular weight of the 2D polymers and their degree of polymerization per MUm2 are M = 360 MDa and Pn = 464 900, respectively. The sheet size is on the order of 5 * 5 MUm2. PMID- 28084076 TI - Partitioning of Alkali Metal Salts and Boric Acid from Aqueous Phase into the Polyamide Active Layers of Reverse Osmosis Membranes. AB - The partition coefficient of solutes into the polyamide active layer of reverse osmosis (RO) membranes is one of the three membrane properties (together with solute diffusion coefficient and active layer thickness) that determine solute permeation. However, no well-established method exists to measure solute partition coefficients into polyamide active layers. Further, the few studies that measured partition coefficients for inorganic salts report values significantly higher than one (~3-8), which is contrary to expectations from Donnan theory and the observed high rejection of salts. As such, we developed a benchtop method to determine solute partition coefficients into the polyamide active layers of RO membranes. The method uses a quartz crystal microbalance (QCM) to measure the change in the mass of the active layer caused by the uptake of the partitioned solutes. The method was evaluated using several inorganic salts (alkali metal salts of chloride) and a weak acid of common concern in water desalination (boric acid). All partition coefficients were found to be lower than 1, in general agreement with expectations from Donnan theory. Results reported in this study advance the fundamental understanding of contaminant transport through RO membranes, and can be used in future studies to decouple the contributions of contaminant partitioning and diffusion to contaminant permeation. PMID- 28084077 TI - Growing Up on an Appalachian Farm: A Centenarian Perspective. AB - Background Research on centenarians to date has focused on areas with a high population of centenarians. However, there is limited literature on centenarians' perspectives about growing up on farms from the heartland of Appalachia in Eastern Tennessee. Purpose This qualitative descriptive study was designed to characterize the role of a farming childhood by exploring the viewpoints of community-dwelling centenarians who grew up on farms in south central Appalachia. Methods A qualitative descriptive design was used with a convenience sample ( n = 16). Cognitive status was determined with the Short Portable Mental Status Questionnaire. Demographic data were collected. Interviews were transcribed and analyzed with the Neuendorf method of content analysis. Results Main emerging themes were the farm, the family, and the environment. Conclusion The farm was at the center of these centenarians' childhood, influencing their family, community relations, and social interactions, which provided lessons that they utilized throughout their long lives. PMID- 28084078 TI - Association of GWAS Top Genes With Late-Onset Alzheimer's Disease in Colombian Population. AB - OBJECTIVE: The association of variants in CLU, CR1, PICALM, BIN1, ABCA7, and CD33 genes with late-onset Alzheimer's disease (LOAD) was evaluated and confirmed through genome-wide association study. However, it is unknown whether these associations can be replicated in admixed populations. METHODS: The association of 14 single-nucleotide polymorphisms in those genes was evaluated in 280 LOAD cases and 357 controls from the Colombian population. RESULTS: In a multivariate analysis using age, gender, APOE?4 status, and admixture covariates, significant associations were obtained ( P < .05) for variants in BIN1 (rs744373, odds ratio [OR]: 1.42), CLU (rs11136000, OR: 0.66), PICALM (rs541458, OR: 0.69), ABCA7 (rs3764650, OR: 1.7), and CD33 (rs3865444, OR: 1.12). Likewise, a significant interaction effect was observed between CLU and CR1 variants with APOE. CONCLUSION: This study replicated the associations previously reported in populations of European ancestry and shows that APOE variants have a regulatory role on the effect that variants in other loci have on LOAD, reflecting the importance of gene-gene interactions in the etiology of neurodegenerative diseases. PMID- 28084079 TI - Fast assessment and management of chest pain patients without ST-elevation in the pre-hospital gateway (FamouS Triage): ruling out a myocardial infarction at home with the modified HEART score. AB - BACKGROUND: The first study of the FamouS Triage project investigates the feasibility of ruling out a myocardial infarction in pre-hospital chest pain patients without electrocardiographic ST-segment elevation by using the modified HEART score at the patient's home, incorporating only a single highly sensitive troponin T measurement. METHODS: A venous blood sample was drawn in the ambulance from 1127 consecutive chest pain patients for measurement of the pre-hospital highly sensitive troponin T levels, in order to establish a pre-hospital HEART score (i.e. the modified HEART score) and evaluate the possibility of triage at the patient's home. The primary endpoint was the occurrence of a major adverse cardiac event (MACE) i.e. acute myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting or death within 30 days after initial presentation. RESULTS: Two hundred and six patients (18%) developed a MACE during 30 days of follow-up. Thirty-six per cent of the patients ( n=403) had a low modified HEART score (0-3 points) and none of them developed a MACE during follow-up. Forty-four per cent of the patients ( n=494) had an intermediate modified HEART score (4-6 points) and 18% of them developed a MACE. Twenty per cent of the patients ( n=230) had a high modified HEART score (7-10 points) of which 52% developed a MACE during follow-up. CONCLUSION: It seems feasible to rule out a myocardial infarction at home in chest pain patients without ST-segment elevation by using the modified HEART score. TRIAL ID: NTR4205. Dutch Trial Register [ http://www.trialregister.nl ]: trial number 4205. PMID- 28084081 TI - Unusual Mucus Impaction in an Adolescent Patient With Severe Asthma. PMID- 28084080 TI - Visual encoding, consolidation, and retrieval in amyotrophic lateral sclerosis: executive function as a mediator, and predictor of performance. AB - OBJECTIVE: This study aimed to illustrate the variation of non-executive cognitive processes, i.e. visual memory, considering executive dysfunction in amyotrophic lateral sclerosis (ALS). METHODS: Patients with ALS (n = 203), and matched healthy controls (n = 117) completed a battery of neuropsychological tests. Sub-stratification was based on whether cognitive assessment detected no cognitive abnormalities (NCA: n = 117), multiple executive cognitive deficits (ALS-Exec; n = 56), or a comorbid frontotemporal dementia process (ALS-FTD; n = 30). The Rey-Osterrieth Complex Figure Test (ROCFT) was the main dependent variable for visual memory in this study. RESULTS: Patients and controls significantly differed on the Copy trial (p < 0.0001: omega2 = 0.317) immediate recall (p < 0.0001: omega2 = 0.272) and delayed recall (p < 0.0001: omega2 = 0.308) of the ROCFT. Sub-stratification based on executive dysfunction revealed an association with greater executive dysfunction and lower ROCFT performance. Regression analysis predicted that premorbid IQ, executive function, and demographics predict performance on the ROCFT delayed recall trial (R2 = 0.833). CONCLUSIONS: These findings illustrate that patients without executive dysfunction do not show visual memory impairments within this cohort; that patients with executive dysfunction have poorer performance on visual memory tasks; and that the severity of executive dysfunction, as per cognitive categorisation, is related to increased visual memory impairment as tested with the ROCFT. PMID- 28084082 TI - An Infant With Tachypnea. PMID- 28084083 TI - Off-pump grafting does not reduce postoperative pulmonary dysfunction. AB - Objectives Pulmonary dysfunction is a recognized postoperative complication that may be linked to use of cardiopulmonary bypass. The off-pump technique of coronary artery bypass aims to avoid some of the complications that may be related to cardiopulmonary bypass. In this study, we compared the influence of on pump or off-pump coronary artery bypass on pulmonary gas exchange following routine surgery. Methods Fifty patients (mean age 60.4 +/- 8.4 years) with no preexisting lung disease and good left ventricular function undergoing primary coronary artery bypass grafting were prospectively randomized to undergo surgery with or without cardiopulmonary bypass. Alveolar/arterial oxygen pressure gradients were calculated prior to induction of anesthesia while the patients were breathing room air, and repeated postoperatively during mechanical ventilation and after extubation while inspiring 3 specific fractions of oxygen. Results Baseline preoperative arterial blood gases and alveolar/arterial oxygen pressure gradients were similar in both groups. At both postoperative stages, the partial pressure of arterial oxygen and alveolar/arterial oxygen pressure gradients increased with increasing fraction of inspired oxygen, but there were no statistically significant differences between patients who underwent surgery with or without cardiopulmonary bypass, either during ventilation or after extubation. Conclusions Off-pump surgery is not associated with superior pulmonary gas exchange in the early postoperative period following routine coronary artery bypass grafting in patients with good left ventricular function and no preexisting lung disease. PMID- 28084084 TI - The existence of renal dysfunction in diabetics undergoing coronary artery bypass. PMID- 28084086 TI - Toddler With Hemoptysis. PMID- 28084085 TI - Bridge to transplant or recovery in cardiogenic shock in a developing country. AB - Background Durable mechanical support devices are prohibitively expensive in our health system and may be unsuitable for critically ill patients. CentriMag is an alternative bridge to transplantation or recovery. Methods We retrospectively reviewed 28 patients (23 males) aged 13-60 years who received CentriMag support. The etiology was ischemic in 13 (46%), dilated cardiomyopathy in 8 (29%), and others in 7 (25%). All patients were in Interagency Registry for Mechanically Assisted Circulatory Support class I, and 27 (96%) had multiorgan failure; 2 (7%) were post-cardiotomy and 12 (43%) had a previous cardiac arrest (mean arrest time 21 +/- 17 min). Results Thirty-day post-implant survival was 79% (22 patients). Twenty (71%) patients were successfully bridged to transplantation or recovery. The mean support time was 40 days; 12 (43%) patients had >4-weeks' support (longest was 292 days). Eight (29%) patients died on support. Complications included bleeding in 10 (36%) cases, immediate stroke in 4 (14%), and dialysis in 8 (29%). There was no stroke during subsequent support. Eighteen (64%) patients underwent transplantation, and 17 of them were discharged. Two (7%) patients recovered and were discharged. Two-year survival was 62% +/- 10%. Mean follow-up was 21 months (total follow-up 579 months). Two (7%) patients died during follow up. All survivors were in New York Heart Association class I. Conclusions CentriMag is useful for medium-term support for cardiogenic shock in a developing country. Support for >4 weeks is feasible. The stroke rate is low during support. The major drawback is prolonged intensive care unit stay. PMID- 28084087 TI - In Vivo Effect of a 5-HT7 Receptor Agonist on 5-HT Neurons and GABA Interneurons in the Dorsal Raphe Nuclei of Sham and PD Rats. AB - The 5-hydroxytryptamine (5-HT; serotonin) neurotransmission is severely affected by the degeneration of nigrostriatal dopaminergic neurons. Here, we report the effects of the systemic administration of the 5-HT7 receptor agonist AS-19. In sham rats, the mean response of the 5-HT neurons in the dorsal raphe nucleus (DRN) to systemic AS-19 was excitatory and the mean response of the gamma aminobutyric acid (GABA) interneurons was inhibitory. In Parkinson disease (PD) rats, the same dose did not affect the 5-HT neurons and only high doses (640 MUg/kg intravenous) were able to the increase GABA interneuron activity. These results indicate that DRN 5-HT neurons and GABA interneurons are regulated by the activation of 5-HT7 receptors and that the degeneration of the nigrostriatal pathway leads to decreased responses of these neurons to AS-19, which in turn suggests that the 5-HT7 receptors on 5-HT neurons and GABA interneurons in PD rats are dysfunctional and downregulated. PMID- 28084088 TI - The IJA system for systematic reviews: "the whys and hows". PMID- 28084089 TI - Metabolic changes in rat serum after administration of suberoylanilide hydroxamic acid and discriminated by SVM. AB - Suberoylanilide hydroxamic acid (SAHA) exerts marked anticancer effects via promotion of apoptosis, cell cycle arrest, and prevention of oncogene expression. In this study, serum metabolomics and artificial intelligence recognition were used to investigate SAHA toxicity. Forty rats (220 +/- 20 g) were randomly divided into control and three SAHA groups (low, medium, and high); the experimental groups were treated with 12.3, 24.5, or 49.0 mg kg-1 SAHA once a day via intragastric administration. After 7 days, blood samples from the four groups were collected and analyzed by gas chromatography-mass spectrometry, and pathological changes in the liver were examined using microscopy. The results showed that increased levels of urea, oleic acid, and glutaconic acid were the most significant indicators of toxicity. Octadecanoic acid, pentadecanoic acid, glycerol, propanoic acid, and uric acid levels were lower in the high SAHA group. Microscopic observation revealed no obvious damage to the liver. Based on these data, a support vector machine (SVM) discrimination model was established that recognized the metabolic changes in the three SAHA groups and the control group with 100% accuracy. In conclusion, the main toxicity caused by SAHA was due to excessive metabolism of saturated fatty acids, which could be recognized by an SVM model. PMID- 28084091 TI - CORRIGENDUM to Projected age- and sex-specific prevalence of cardiovascular diseases in Western Australian adults from 2005-2045. PMID- 28084090 TI - Protective effects of salidroside against isoflurane-induced cognitive impairment in rats. AB - Postoperative cognitive dysfunction, which is associated with a wide range of cognitive functions including working memory, long-term memory, information processing, attention, and cognitive flexibility, is a major clinical issue in geriatric surgical patients. The aim of the current study was to determine the protective role and possible mechanisms of salidroside against isoflurane-induced cognitive impairment. Sprague Dawley rats were randomly assigned to five groups and were treated with or without salidroside before isoflurane exposure. Open field and fear conditioning tests were conducted to evaluate the cognitive function of the rats. Moreover, the hippocampus tissues were obtained for biochemical analysis. The results showed that the isoflurane anesthesia decreased the freezing time to context significantly at 48 h after the isoflurane exposure in the fear conditioning test. Salidroside could ameliorate isoflurane-induced cognitive dysfunction. Further analysis demonstrated salidroside markedly suppressed the release of tumor necrosis factor-alpha and interleukin-1beta. Moreover, salidroside reversed the decreased activity of choline acetyltransferase, superoxide dismutase, glutathione peroxidase, and content of acetylcholine, as well as the increased activity of acetylcholine esterase and content of malondialdehyde in hippocampal tissue of isoflurane-exposed rats. According to the results, we concluded that that salidroside has a protective effect against isoflurane-induced cognitive dysfunction by inhibiting excessive inflammatory responses, decreasing oxidative stress, and regulating the cholinergic system. PMID- 28084092 TI - Mortality and extent of coronary artery disease in 2776 patients with type 1 diabetes undergoing coronary angiography: A nationwide study. AB - Background In a modern perspective there is limited information on mortality by affected coronary vessels assessed by coronary angiography in patients with type 1 diabetes. The aim of the present study was to characterise distribution of coronary artery disease and impact on long-term mortality in patients with type 1 diabetes undergoing coronary angiography. Design The design of this research was a nationwide population-based cohort study. Methods Individuals ( n = 2776) with type 1 diabetes undergoing coronary angiography 2001-2013 included in the Swedish National Diabetes Registry and Swedish Coronary Angiography and Angioplasty Registry were followed for mortality until 31 December 2013 (mean 7.1 years). In 79% the indication was stable or acute coronary artery disease. Coronary artery disease was categorised into normal (21%), one- (23%), two- (18%), three- (29%) and left main-vessel disease (8%). Results Mean age was 57 years and 58% were male. Mean diabetes duration was 35 years, glycated haemoglobin was 67 mmol/mol and 44% had normal or one-vessel disease. In multivariate Cox proportional analyses hazard ratio for mortality compared with normal findings was 1.09 (95% confidence interval 0.80-1.48) for one, 1.43 (1.05-1.94) for two, 1.47 (1.10 1.96) for three and 1.90 (1.35-2.68) for left main-vessel disease. Renal failure 2.29 (1.77-2.96) and previous heart failure 1.76 (1.46-2.13) were highly associated with mortality. Standard mortality ratio the first year was 5.55 (4.65 6.56) and decreased to 2.80 (2.18-3.54) after five years. Conclusions In patients with type 1 diabetes referred for coronary angiography mortality is influenced by numbers of affected coronary vessels. The overall mortality rate was higher compared with the general population. These results support early intensive prevention of coronary artery disease in this population. PMID- 28084093 TI - Time and temperature affect glycolysis in blood samples regardless of fluoride based preservatives: a potential underestimation of diabetes. AB - Background The inhibition of glycolysis prior to glucose measurement is an important consideration when interpreting glucose tolerance tests. This is particularly important in gestational diabetes mellitus where prompt diagnosis and treatment is essential. A study was planned to investigate the effect of preservatives and temperature on glycolysis. Methods Blood samples for glucose were obtained from consented females. Lithium heparin and fluoride-EDTA samples transported rapidly in ice slurry to the laboratory were analysed for glucose concentration and then held either in ice slurry or at room temperature for varying time intervals. Paired fluoride-citrate samples were received at room temperature and held at room temperature, with analysis at similar time intervals. Results No significant difference was noted between mean glucose concentrations when comparing different sample types received in ice slurry. The mean glucose concentrations decreased significantly for both sets of samples when held at room temperature (0.4 mmol/L) and in ice slurry (0.2 mmol/L). A review of patient glucose tolerance tests reported in our hospital indicated that 17.8% exceeded the recommended diagnostic criteria for gestational diabetes mellitus. It was predicted that if the results of fasting samples were revised to reflect the effect of glycolysis at room temperature, the adjusted diagnostic rate could increase to 35.3%. Conclusion Preanalytical handling of blood samples for glucose analysis is vital. Fluoride-EDTA is an imperfect antiglycolytic, even when the samples are transported and analysed rapidly provides such optimal conditions. The use of fluoride-citrate tubes may offer a viable alternative in the diagnosis of diabetes mellitus. PMID- 28084094 TI - Existence of a squamous cell carcinoma antigen-immunoglobulin complex causes a deviation between squamous cell carcinoma antigen concentrations determined using two different immunoassays: first report of squamous cell carcinoma antigen coupling with immunoglobulin A. AB - Background Squamous cell carcinoma antigen is used as a tumour marker and is routinely measured in clinical laboratories. We validated two different immunoassays and found three cases in which the squamous cell carcinoma antigen concentrations deviated greatly between the two immunoassays. Here, we aimed to elucidate the mechanisms responsible for these deviations. Methods The squamous cell carcinoma antigen concentrations were determined using the ARCHITECT SCC (CLIA method) and the ST AIA-PACK SCC (FEIA method). We performed polyethylene glycol precipitation and size exclusion chromatography to assess the molecular weight and spike recovery and absorption tests to examine the presence of an autoantibody. Results Both methods exhibited good performances for the measurement of squamous cell carcinoma antigen, although a correlation test showed large differences in the squamous cell carcinoma antigen concentrations measured using the two methods in three cases. The results of polyethylene glycol treatment and size exclusion chromatography indicated the existence of a large molecular weight squamous cell carcinoma antigen in these three cases. The spike recovery tests suggested the possible presence of an autoantibody against squamous cell carcinoma antigen. Moreover, the absorption test revealed that large squamous cell carcinoma antigen complexes were formed by the association of squamous cell carcinoma antigen with IgG in two cases and with both IgG and IgA in one case. Conclusions This study describes the existence of large molecular weight squamous cell carcinoma antigen that has complexed with immunoglobulin in the serum samples. The reason for the deviations between the two immunoassays might be due to differences of their reactivities against the squamous cell carcinoma antigen immune complexes with their autoantibody. To our knowledge, this is the first report to describe the coupling of squamous cell carcinoma antigen with IgA. PMID- 28084096 TI - Marital Status and Persons With Dementia in Assisted Living. AB - Despite the prevalence of dementia among residents in assisted living (AL), few researchers have focused on the length of stay (LOS) in AL among this population. Little is known about the factors that may contribute to LOS in these settings, particularly for residents with dementia. In the current study, a sub-set of AL residents with dementia (n = 112) was utilized to examine whether marital status was associated with LOS in AL as this has received sparse attention in previous research despite studies suggesting that marital status influences LOS in other health-care and long-term care settings. The Andersen-Newman behavioral model was used as a conceptual framework for the basis of this study of LOS, marital status, and dementia in AL. We hypothesized that persons with dementia who were married would have longer LOS than unmarried persons with dementia in AL. Cox regression was used to examine the association between marital status and LOS in AL of residents with dementia and whether activities of daily living were related to discharge from AL settings among married and unmarried residents with dementia. Main effects for marital status and the interaction between marital status and mobility with LOS were examined. Study findings provide information related to the psychosocial needs of AL residents with dementia and offer implications for assessing the on-going needs of vulnerable AL residents. PMID- 28084097 TI - The Reality of Recovery in Personality Disorder, By Heather Castillo. PMID- 28084099 TI - Motivational Interviewing: a Guide for Medical Trainees. PMID- 28084098 TI - MTNR1A and MTNR1B gene polymorphisms in women with gestational diabetes. AB - Gestational diabetes mellitus (GDM) is glucose intolerance detected during pregnancy. The MTNR1B gene is the genetic locus associated with type 2 diabetes, that may affect insulin secretion and pancreatic glucose sensing. In this study, we examined the association between MTNR1A (rs2119882) and MTNR1B (rs10830963, rs4753426) gene polymorphisms and the risk of GDM. According to the results of their oral glucose tolerance test (OGTT), the women were divided into two groups: 204 pregnant women with GDM and 207 pregnant women with normal glucose tolerance (NGT). There were no statistically significant differences in the distribution of MTNR1A rs2119882 and MTNR1B rs4753426 genotypes and alleles between women with GDM and healthy pregnant women. With regard to the MTNR1B rs10830963 polymorphism, we observed a statistically significant prevalence of GG and CG genotypes and the G allele among pregnant women with GDM (GG + CG vs CC, OR 1.50, 95% CI 1.02-2.22, p = 0.04; G vs C, OR 1.43, 95% CI 1.07-1.90, p = 0.016). In a multivariate logistic regression analysis, a higher number of MTNR1B rs10830963 G alleles was an independent significant predictor of a higher risk of GDM. The results of our study indicate that MTNR1B rs10830963 polymorphism is associated with GDM susceptibility, and women with a higher number of G alleles have an increased risk of GDM development. PMID- 28084100 TI - Intervention research: Appraising study designs, interpreting findings and creating research in clinical practice. AB - Speech-language pathologists (SLPs) are increasingly required to read, interpret and create evidence regarding the effectiveness of interventions. This requires a good understanding of the strengths and weaknesses of different intervention study designs. This paper aims to take readers through a range of designs commonly used in speech-language pathology, working from those with the least to most experimental control, with a particular focus on how the more robust designs avoid some of the limitations of weaker designs. It then discusses the factors other than research design which need to be considered when deciding whether or not to implement an intervention in clinical practice. The final section offers some tips and advice on carrying out research in clinical practice, with the hope that more SLPs will become actively involved in creating intervention research. PMID- 28084101 TI - Retrograde venography during balloon-occluded retrograde transvenous obliteration of gastric varices. AB - PURPOSE: The purpose of this study was to evaluate changes in thrombosis in gastric varices. MATERIAL AND METHODS: Fourteen patients were studied who underwent balloon-occluded retrograde transvenous obliteration (B-RTO) for gastric varices with a gastrorenal shunt. The B-RTO catheter was retained overnight in all patients. Balloon-occluded retrograde venography (B-RTV) was performed to evaluate the degree of thrombus formation. This evaluation was done twice during the overnight B-RTO procedure: A few hours after the procedure and on the following day. Investigated were the degree of thrombus formation observed by the first and second B-RTV, change in the degree of thrombus between the first and second B-RTV, and whether and how much sclerosing agent was administered on the second day. RESULTS: The first B-RTV showed entire or partial enhancement of the gastric varix in seven (50%) cases and complete or almost complete lack of enhancement in the remaining seven cases. In four of the former seven cases, the second B-RTV showed entire or partial enhancement of the gastric varix, and the sclerosing agent was added. However, in the remaining ten cases, enhancement was almost or completely lacking. CONCLUSION: When complete thrombosis is shown on B RTV obtained a few hours after B-RTO, the addition of a sclerotic agent would be unnecessary. PMID- 28084102 TI - Relationship between caregiving burden and depression in caregivers of individuals with intellectual disabilities in Korea. AB - BACKGROUND: Individuals with intellectual disabilities (IWID) need intensive long term care. Consequently, caregivers experience not only economic burdens but also tension, depression, insecurity, etc. AIM: This study aimed to provide basic data and materials for preparing policy alternatives to improve caregiver quality of life of by examining relationships between IWID caregiving burden and depression. METHODS: This study involved secondary analysis of data from the 2011 Survey on the Actual Conditions of Individuals with Developmental Disabilities, conducted by the Ministry of Health and Welfare of Korea. Effects of caregivers' characteristics, caregiving time and cost, and perceptions of time and cost, on depression were analyzed. RESULTS: All components of caregiving burden and depression were significantly higher in the 1st grade, designating the most severe disabilities. Overall, caregiving burden tended to be higher in female caregivers, the unemployed, parents, co-residents, and people with health problems. Caregivers' characteristics such as spouse relationship, having health problems, and perception of caregiving time and cost were associated with depression. CONCLUSION: Caregiving burden and depression vary depending on the characteristics of IWID and their caregivers. Services for decreasing caregiving burden may be optimized by focusing on these characteristics. PMID- 28084103 TI - Mental health problems among survivors in hard-hit areas of the 5.12 Wenchuan and 4.20 Lushan earthquakes. AB - BACKGROUND: Earthquake exposure has often been associated with psychological distress. However, little is known about the cumulative effect of exposure to two earthquakes on psychological distress and in particular, the effect on the development of post-traumatic stress disorder (PTSD), anxiety and depression disorders. AIMS: This study explored the effect of exposure on mental health outcomes after a first earthquake and again after a second earthquake. METHODS: A population-based mental health survey using self-report questionnaires was conducted on 278 people in the hard-hit areas of Lushan and Baoxing Counties 13 16 months after the Wenchuan earthquake (Sample 1). 191 of these respondents were evaluated again 8-9 months after the Lushan earthquake (Sample 2), which struck almost 5 years after the Wenchuan earthquake. RESULTS: In Sample 1, the prevalence rates for PTSD, anxiety and depression disorders were 44.53, 54.25 and 51.82%, respectively, and in Sample 2 the corresponding rates were 27.27, 38.63 and 36.93%. Females, the middle-aged, those of Tibetan nationality, and people who reported fear during the earthquake were at an increased risk of experiencing post-traumatic symptoms. CONCLUSIONS: Although the incidence of PTSD, anxiety and depression disorders decreased from Sample 1 to Sample 2, the cumulative effect of exposure to two earthquakes on mental health problems was serious in the hard hit areas. Therefore, it is important that psychological counseling be provided for earthquake victims, and especially those exposed to multiple earthquakes. PMID- 28084105 TI - Elizabeth Usher Memorial Lecture: Rethinking the clinical pathway for autism spectrum disorder and challenging the status quo. AB - Autism spectrum disorder (ASD) is typically diagnosed between 2 and 5 years of age, which is currently thought to be the earliest that the behavioural symptoms are able to be identified without ambiguity. A significant problem with this relatively "late" age of diagnosis is that by the time a child has been identified and diagnosed with ASD, many of the best opportunities for therapies to capitalise upon brain plasticity very early in development are not realised. This paper provides an overview of the benefits and drawbacks of the current clinical pathway that places primacy on a diagnostic assessment for triggering the commencement of therapy. The paper then presents an alternative clinical pathway - the identification and provision of therapy to infants at risk of ASD - and provides a critical review of current evidence supporting this model. The aim of the paper is to outline a vision for the future of early identification and intervention of individuals with ASD, and the research goals that need to be addressed to achieve this vision. PMID- 28084106 TI - Severe antiphospholipid antibody syndrome - response to plasmapheresis and rituximab. AB - Antiphospholipid antibody syndrome (APS) is a systemic autoimmune disease characterized by arterial and/or venous thrombosis, recurrent abortions and detection of antiphospholipid antibodies. In fulminant cases, involvement of multiple organs can lead to significant morbidity and even fatal outcomes, so that a rapid, interdisciplinary treatment is needed. Here, we describe the case of a 39-year-old woman with a severe hard-to-treat APS with arterial occlusion and progressive skin necrosis, who was successfully treated with a combination therapy with plasmapheresis and rituximab. The treatment led to complete remission of the skin lesions for over a year. Clinical response correlated with a long-lasting reduction of antiphospholipid antibodies and B-cell depletion. This case demonstrates the use of antiphospholipid antibodies for monitoring APS activity and shows that this severe vascular disease requires rigorous therapeutic approaches. PMID- 28084107 TI - The risk of gastrointestinal bleeding in patients receiving dabigatran etexilate: a systematic review and meta-analysis of the literature. AB - BACKGROUND: Evidence on the risk of gastrointestinal (GI) bleeding associated with dabigatran etexilate (DE) is contrasting. We performed a meta-analysis of literature to address this issue. METHODS AND RESULTS: Studies on GI bleeding risk in patients receiving DE or vitamin-K antagonists (VKA) were systematically searched. Twenty-three studies (26 datasets) showed no difference in the GI bleeding risk between the 250,871 patients treated with DE and the 460,386 receiving VKA (OR: 1.052, 95% CI: 0.815, 1.359). Similar results were obtained when pooling together adjusted ORs/HRs, obtained by means of multivariate analysis (OR: 1.06, 95% CI: 0.914, 1.222). Compared with VKA, DE use was associated with a significantly lower risk of upper GI (OR: 0.742, 95% CI: 0.569, 0.968), but not of lower GI bleedings (OR: 1.208, 95% CI: 0.902, 1.619). Furthermore, no significant difference in the GI bleeding risk was found when data on DE 110 mg and DE 150 mg twice-daily were separately compared with VKA. CONCLUSIONS: No difference in GI bleeding risk was found between DE and VKA. These results were confirmed for both dosages of DE and when specifically analyzing lower GI bleeding. In contrast, the risk of upper GI bleeding was lower with DE than with VKA. KEY MESSAGES No difference in the risk of gastrointestinal (GI) bleeding can be found between dabigatran etexilate (DE) and vitamin K antagonists (VKA). These results are confirmed for both dosages of DE. The risk of upper GI bleeding is lower with DE than with VKA. PMID- 28084108 TI - Enhanced hepatic insulin signaling in the livers of high altitude native rats under basal conditions and in the livers of low altitude native rats under insulin stimulation: a mechanistic study. AB - This study was designed to investigate the role of the liver in lowering fasting blood glucose levels (FBG) in rats native to high (HA) and low altitude (LA) areas. As compared with LA natives, besides the improved insulin and glucose tolerance, HA native rats had lower FBG, at least mediated by inhibition of hepatic gluconeogenesis and activation of glycogen synthesis. An effect that is mediated by the enhancement of hepatic insulin signaling mediated by the decreased phosphorylation of TSC induced inhibition of mTOR function. Such effect was independent of activation of AMPK nor stabilization of HIF1alpha, but most probably due to oxidative stress induced REDD1 expression. However, under insulin stimulation, and in spite of the less activated mTOR function in HA native rats, LA native rats had higher glycogen content and reduced levels of gluconeogenic enzymes with a more enhanced insulin signaling, mainly due to higher levels of p IRS1 (tyr612). PMID- 28084109 TI - How to treat recurrent/metastatic head and neck cancer: the economic issue in real-world practice. PMID- 28084110 TI - A novel method for electronic measurement and recording of surgical drain output. AB - Surgical drains are used to collect and measure fluids (e.g. serous fluid, lymph, blood, etc.). The volume of fluid in the container is measured using graded markings on the container and then recorded manually on a "drain chart" allowing for manual rate calculations. This method is dependant on regularly checking the volume of the drain and recording the value accurately; unfortunately, this is often not feasible due to staffing levels and time constraints. This results in inaccurate "drain charts" making clinical decisions based on these figures unreliable. Often the lack of confidence in these measurements leads to delayed drain removal with consequent increased infection risks and potential delayed discharge. Accurate digital measurement of drain content would have a significant impact on clinical care. This paper describes a digital technology to measure volume, making use of a positive terminal at the lowest point of the vessel and negative (sensor) terminals placed at accurate intervals along an axis of the vessel. A proof-of-concept prototype was developed using commercially available electronic components to test the feasibility of a technology for electronic measurement and recording of surgical drain content. In a simulated environment, the proposed technology was shown to be effective and accurate. The proposed electronic drain has a number of advantages over currently used devices in saving time and easing pressure on nursing staff, reduce disturbance of patients, and allows for preset alarms. PMID- 28084111 TI - Day hospital treatment for people with severe mental illness according to users' perspectives: what helps and what hinders recovery? AB - BACKGROUND: Scarce information is available about how users experience treatment at mental health day hospitals, particularly in South America. AIMS: To explore users' perspectives about elements of day hospital treatment that facilitate or hinder the recovery process in a mental health facility in Buenos Aires, Argentina. METHODS: Semi-structured individual interviews (n = 8) and focus groups (n = 4) were carried out with a convenience sample of users of a mental health day hospital program based on a formulation, testing and redevelopment of propositions approach. Results were analyzed through grounded theory techniques. RESULTS: Categories indicating recovery were: starting to do things, being able to see themselves from a new perspective, mood improvement and changes in interpersonal relationships. Aspects facilitating recovery were: activities organized by the facility, the group approach, the care provided by facility workers and the physical environment. Hindering aspects were: heterogeneity of users in terms of age, severity, diagnosis and being underestimated by staff. CONCLUSIONS: Being active again was considered to be the main recovery indicator in this cultural context and participating in activities led by skilled facilitators was the most beneficial factor of the program according to the users. PMID- 28084112 TI - Changes in semantic fluency across childhood: Normative data from Australian English speakers. AB - PURPOSE: Verbal fluency tests are often used as part of an assessment battery to investigate children's lexical knowledge as well as executive function skills. To date, however, issues surrounding consistency of measurement cloud comparisons across studies, with the developmental performance of Australian-English speaking children also currently lacking. This study tracked verbal fluency development as measured by two semantic fluency tasks that included coding of fluency, clustering and switching type responses. METHOD: Participants included 355 typically developing Australian-English speaking children (4-10 years) and 46 young adults. Total fluency was determined by the number of words produced for each category (Animals or Food), minus repetitions and rule violations. Semantic clusters (words generated within a subcategory) were coded while switches between single words or subcategories were differentiated and coded as either hard or cluster switches. RESULT: Fluency showed consistent improvement over age. Cluster Switches and Hard Switches showed some evidence of a plateau in performance relative to fluency, but in opposite direction. Other measures showed no strong trends over age. Results were similar for both semantic categories. CONCLUSION: Our results highlight the rich information available within a semantic fluency task and the importance of differentiating hard and cluster switches in paediatric samples. PMID- 28084113 TI - Risk factors leading to mucoperiosteal flap necrosis after primary palatoplasty in patents with cleft palate. AB - BACKGROUND: Few studies have been published reporting risk factors for flap necrosis after primary palatoplasty in patients with cleft palate. This complication is rare, and the event is a disaster for both the patient and the surgeon. This study was performed to explore the associations between different risk factors and the development of flap necrosis after primary palatoplasty in patients with cleft palate. METHODS: This is a case-control study. A 20 years retrospective analysis (1994-2015) of patients with nonsyndromic cleft palate was identified from medical records and screening day registries). Demographical and risk factor data were collected using a patient's report, including information about age at surgery, gender, cleft palate type, and degree of severity. Odds ratios and 95% confident intervals were derived from logistic regression analysis. RESULTS: All cases with diagnoses of flap necrosis after primary palatoplasty were included in the study (48 patients) and 156 controls were considered. In multivariate analysis, female sex, age (older than 15 years), cleft type (bilateral and incomplete), and severe cleft palate index were associated with significantly increased risk for flap necrosis. CONCLUSIONS: The findings suggest that female sex, older age, cleft type (bilateral and incomplete), and severe cleft palatal index may be associated with the development of flap necrosis after primary palatoplasty in patients with cleft palate. PMID- 28084114 TI - Results of a 5-year contraceptive trial in parous and nulliparous women with a new LNG-IUS. AB - OBJECTIVE: To report on the contraceptive performance and continuation of a new T shaped LNG-IUS, releasing 20 MUg of levonorgestrel/day, in both parous and nulliparous nulliparous women after 5 years of use. MATERIALS AND METHODS: An observational prospective contraceptive study conducted in parous and nulliparous women up to 48 years of age. RESULTS: The study was conducted in a sample size of 356 women of whom 67.1% were parous and 32.9% were nulliparous with mean age of 35.1 (range 15-48). The total cumulative observation period was 27 269 woman months. Only one accidental pregnancy was observed and two expulsions were reported with no partial expulsions. There were 12.7% medical removals for abnormal bleeding, pain and other medical reasons, mostly not related to the use of the LNG-IUS, and 13.3% removals in women wishing to become pregnant. The discontinuation rate at 5 years amounts to 25.7% including women with pregnancy wish, who used the LNG-IUS for an average of 44 months. There were no serious adverse events (e.g. perforation, pelvic inflammatory disease). CONCLUSION: The LNG-IUS used in this study is highly effective and well tolerated resulting in a high continuation of use. The only two expulsions that occurred during the study is remarkable. The ease and safety of insertion together with optimal retention is considered an advance in intrauterine contraceptive device technology. PMID- 28084115 TI - Insomnia and PTSD one month after wildfires: evidence for an independent role of the "fear of imminent death". AB - OBJECTIVE: The relationship of insomnia with Post-Traumatic Stress Disorder (PTSD) one month after wildfires and more specifically with the experience of 'fear of imminent death' were investigated. METHODS: Ninety-two randomly chosen victims of wildfires in the Greek province of Ilia, were assessed through a specifically designed semi-structured psychiatric interview comprising of questionnaires and scales to measure psychopathology, as well as psychosocial and environmental parameters. PTSD was set according to ICD-10 research diagnostic criteria, while insomnia was assessed with the Athens Insomnia Scale (AIS). RESULTS: The presence of insomnia was identified in 63.0% of the victims. 46.7% of the participants were diagnosed with PTSD in the first post-disaster month, while 51.1% of the total sample experienced 'fear of imminent death'. The majority of sleep complaints were significantly more frequent in subjects with PTSD. Female gender, PTSD, older age, and 'fear of imminent death' were independently associated with insomnia. CONCLUSIONS: The findings of the present study indicate that the diagnosis of insomnia, as well as, certain specific insomnia complaints were more frequent in female victims of wildfires who have experienced 'fear of imminent death' and have developed PTSD. PMID- 28084116 TI - Does personality influence job acquisition and tenure in people with severe mental illness enrolled in supported employment programs? AB - BACKGROUND: When employment difficulties in people with severe mental illness (SMI) occur, it could be partly linked to issues not specific to SMI, such as personality traits or problems. Despite the fact that personality has a marked influence on almost every aspect of work behavior, it has scarcely been investigated in the context of employment for people with SMI. AIMS: We aimed to evaluate if personality was more predictive than clinical variables of different competitive work outcomes, namely acquisition of competitive employment, delay to acquisition and job tenure. METHOD: A sample of 82 people with a SMI enrolled in supported employment programs (SEP) was recruited and asked to complete various questionnaires and interviews. Statistical analyses included logistic regressions and survival analyses (Cox regressions). RESULTS: Prior employment, personality problems and negative symptoms are significantly related to acquisition of a competitive employment and to delay to acquisition whereas the conscientiousness personality trait was predictive of job tenure. CONCLUSION: Our results point out the relevance of personality traits and problems as predictors of work outcomes in people with SMI registered in SEP. Future studies should recruit larger samples and also investigate these links with other factors related to work outcomes. PMID- 28084118 TI - The Wiley handbook of art therapy, edited by David E. Gussak and Marcia L. Rosal. PMID- 28084117 TI - Making sound waves: selected papers from the 2016 annual conference of the National Hearing Conservation Association. PMID- 28084119 TI - Quantitative assessment of the effects of 6 months of adapted physical activity on gait in people with multiple sclerosis: a randomized controlled trial. AB - PURPOSE: The purpose of this study is to quantitatively assess the effect of 6 months of supervised adapted physical activity (APA i.e. physical activity designed for people with special needs) on spatio-temporal and kinematic parameters of gait in persons with Multiple Sclerosis (pwMS). METHODS: Twenty-two pwMS with Expanded Disability Status Scale scores ranging from 1.5 to 5.5 were randomly assigned either to the intervention group (APA, n = 11) or the control group (CG, n = 11). The former underwent 6 months of APA consisting of 3 weekly 60-min sessions of aerobic and strength training, while CG participants were engaged in no structured PA program. Gait patterns were analyzed before and after the training using three-dimensional gait analysis by calculating spatio-temporal parameters and concise indexes of gait kinematics (Gait Profile Score - GPS and Gait Variable Score - GVS) as well as dynamic Range of Motion (ROM) of hip, knee, and ankle joints. RESULTS: The training originated significant improvements in stride length, gait speed and cadence in the APA group, while GPS and GVS scores remained practically unchanged. A trend of improvement was also observed as regard the dynamic ROM of hip, knee, and ankle joints. No significant changes were observed in the CG for any of the parameters considered. CONCLUSIONS: The quantitative analysis of gait supplied mixed evidence about the actual impact of 6 months of APA on pwMS. Although some improvements have been observed, the substantial constancy of kinematic patterns of gait suggests that the full transferability of the administered training on the ambulation function may require more specific exercises. Implications for rehabilitation Adapted Physical Activity (APA) is effective in improving spatio-temporal parameters of gait, but not kinematics, in people with multiple sclerosis. Dynamic range of motion during gait is increased after APA. The full transferability of APA on the ambulation function may require specific exercises rather than generic lower limbs strength/flexibility training. PMID- 28084120 TI - Inflammatory arthritis and systemic bone loss are attenuated by gastrointestinal helminth parasites. AB - Infections with different helminth species have been observed to ameliorate a variety of chronic inflammatory diseases. Herein, we show that the natural murine helminth species, Heligmosomoides polygyrus bakeri (Hp) is capable of attenuating disease severity in two different inflammatory arthritis models. Furthermore, we show that excretory-secretory (ES) products from Hp directly suppress osteoclast differentiation in vitro. Taken together, these results demonstrate that helminth infections can dampen autoimmune diseases and highlight a previously unrecognized and important role for ES products, by directly impacting on bone destruction. PMID- 28084121 TI - Predictors of emotional exhaustion, disengagement and burnout among improving access to psychological therapies (IAPT) practitioners. AB - BACKGROUND: Among mental health staff, burnout has been associated with undesirable outcomes, such as physical and mental ill-health, high levels of staff turnover and poorer patient care. AIMS: To estimate the prevalence and predictors of burnout amongst Improving Access to Psychological Therapist (IAPT) practitioners. METHODS: IAPT practitioners (N = 201) completed an on-line survey measuring time spent per week on different types of work related activity. These were investigated as predictors of burnout (measured using the Oldenburg Burnout Inventory). RESULTS: The prevalence of burnout was 68.6% (95% confidence interval (CI) 58.8-77.3%) among psychological wellbeing practitioners (PWP) and 50.0% (95% CI 39.6-60.4%) among high intensity (HI) therapists. Among PWPs hours of overtime predicted higher odds of burnout and hours of clinical supervision predicted lower odds of burnout. The odds of burnout increased with telephone hours of patient contact among PWPs who had worked in the service for two or more years. None of the job characteristics significantly predicted burnout among HI therapists. CONCLUSIONS: Our results suggest a high prevalence of burnout among IAPT practitioners. Strategies to reduce burnout among PWPs involving reductions in workload, particularly telephone contact and increases in clinical supervision need to be evaluated. PMID- 28084123 TI - Benedict J. Marafino (1947-2011). PMID- 28084122 TI - Plasma endothelin-1 levels in patients with resistant hypertension: effects of renal sympathetic denervation. AB - INTRODUCTION: Resistant arterial hypertension (RHT) is defined as poor controlled blood pressure (BP) despite optimal doses of three or more antihypertensive agents, including a diuretic. In the development of RHT, hyperactivity of sympathetic (SNS) and renin-angiotensin-aldosterone (SRAA) systems are involved, and SNS is a potent stimulator of vasoactive endothelin-1 (ET-1) peptide. Renal sympathetic denervation (RSD) through disrupting renal afferent and efferent nerves attenuates SNS activity. MATERIAL AND METHODS: We carried out pilot study investigating the effect of RSD on BP and plasma ET-1 levels in consecutive 9 RHT patients (7 male and 2 female, mean age of 56 +/- 13.3). RESULTS: After 12 months of the RSD, we observed a significant reduction of BP office, 24-h ambulatory BP monitoring (ABPM) (p < 0.05, respectively), and "non-dipping" pattern (from 55% to 35%) (p < 0.05). Moreover, RSD significantly decreased plasma ET-1 levels in both renal artery (at right from 21.8 +/- 4.1 to 16.8 +/- 2.9 pg/ml; p = 0.004; at left from 22.1 +/- 3.7 to 18.9 +/- 3.3 pg/ml; p = 0.02). We observed positive correlations between plasma renal arteries ET-1 levels and systolic BP values at ABPM [Global-SBP (r = 0.58; p < 0.01), Diurnal-SBP (r = 0.51; p < 0.03) and Nocturnal-SBP (r = 0.58; p < 0.01), respectively]. DISCUSSION: Our data confirmed the positive effects of RSD on BP values in patients with RHT, and showed a possible physio-pathological role of ET-1. KEY MESSAGES RSD is associated to a significant reduction of plasma ET-1 levels, representing an useful tool into reduction of BP in RHT patients. PMID- 28084125 TI - Antioxidant and antimicrobial activities of ethanol and aqueous extracts from Urtica urens. AB - CONTEXT: Urtica urens L. (Urticaceae) is an important and commonly used plant for its medicinal and pharmacological properties. OBJECTIVE: We analyzed the antioxidant and antimicrobial activities of the leaves of Urtica urens in ethanol (EtOH) and water (WA) solvents, employing standard analytical methods. MATERIALS AND METHODS: Polyphenol, flavonoid and tannin content of Urtica urens leaves were determined, after their extraction, using EtOH (70%) and WA extracts as well as the antioxidant (DPPH, ABTS, beta-carotene and FRAP) and the antibacterial (via the method of dilution tests) activities of EtOH and WA extracts. RESULTS: The 70% EtOH of Urtica urens showed the highest values of total phenolic (31.41 mg GAE/g DW), flavonoids (6.81 mg quercetin/g DW), tannin (8.29 mg GAE/g DW) and TEAC (560 mmol Trolox/g DW), compared to the WA. The results of DPPH for EtOH (95.56%) were higher than that of WA (64.56%) at a concentration of 40 mg/L. The extracts displayed a FRAP 106.23 for EtOH and 30.55 MUmol Fe(II)/g DW for WA. The results clearly indicated that EtOH was the strongest radical scavenger (IC50 = 245.65 +/- 10.2 MUg/mL). Ethanol was the most effective with minimum inhibitory concentration (MIC) < 250 MUg/mL. WA has no antibacterial activity. DISCUSSION AND CONCLUSION: The results indicate that leaves of Urtica urens could be used as natural antioxidant and antimicrobial agents. PMID- 28084126 TI - Eating Disorder Examination Questionnaire (EDE-Q) and Clinical Impairment Assessment (CIA): clinical norms and functional impairment in male and female adults with eating disorders. AB - AIM: The aim of the current study was to collect clinical normative data for the Clinical Impairment Assessment questionnaire (CIA) and the Eating Disorder Examination Questionnaire (EDE-Q) from adult patients with eating disorders (EDs). This study also examined unique contributions of eating disorder (ED) symptoms on levels of ED-related impairment. METHODS: A sample of 667 patients, 620 females and 47 males, was recruited from six specialist centres across Norway. The majority of the sample (40.3%) was diagnosed with eating disorder not otherwise specified (EDNOS), 34.5% had bulimia nervosa (BN), and 25.2% were diagnosed with anorexia nervosa (AN). RESULTS: There were significant differences for global EDE-Q and CIA scores between females and males. In the female sample, significant differences were found on several EDE-Q sub-scales between the AN and BN group, and between the AN and EDNOS group. No significant differences were found between the diagnostic groups on the CIA. In the male sample, no significant differences were found between diagnostic groups on the EDE-Q or CIA. A multiple regression analysis revealed that 46.8% of the variance in impairment as measured by the CIA was accounted for by ED symptoms. CONCLUSIONS: Body mass index, Eating Concern, Shape/Weight Concern, and binge eating served as significant, unique predictors of impairment. The results from the present study contribute to the interpretation of EDE-Q and CIA scores in ED samples. PMID- 28084129 TI - Order Form (August 2013). PMID- 28084127 TI - Vincristine and E-viniferine-loaded PLGA-b-PEG nanoparticles: pharmaceutical characteristics, cellular uptake and cytotoxicity. AB - The objective of this study was to prepare the E-viniferine and vincristine loaded PLGA-b-PEG nanoparticle and to investigate advantages of these formulations on the cytotoxicity of HepG2 cells. Prepared nanoparticle has shown a homogeneous distribution with 113 +/- 0.43 nm particle size and 0.323 +/- 0.01 polydispersity index. Zeta potential was determined as -35.03 +/- 1.0 mV. The drug-loading percentages were 6.01 +/- 0.23 and 2.01 +/- 0.07 for E-viniferine and vincristine, respectively. The cellular uptake efficiency of coumarin-6 loaded nanoparticles was increased up to 87.8% after 4 h. Nanoparticles loaded with high concentrations of both drugs showed a cytotoxic effect on HepG2 cells, having the percentage of cell viability of between 43.23% and 47.37%. Unfortunately, the percentage of apoptotic cells after treated with drugs-loaded nanaoparticles (10.93%) was similar to free forms of drugs (12.1%) that might be due to low E-viniferine release in biological pH at 24 h. PMID- 28084130 TI - Membership Renewal. PMID- 28084131 TI - Association News from the ILCA Board of Directors. PMID- 28084132 TI - Independent Study Module for Lactation Consultants. PMID- 28084133 TI - Use of geriatric assessment and screening tools of frailty in elderly patients with prostate cancer. Review. AB - The management of prostate cancer in the elderly is a major public health concern in most countries. Currently, most prostate cancers are diagnosed in elderly males. The elderly population is very heterogeneous. Thus, the current challenge is to identify better those individuals for whom specific screening tools and a Comprehensive Geriatric Assessment (CGA) would be beneficial. On the basis of the recommendations of the Prostate Cancer Working Group in the International Society of Geriatric Oncology, older patients with prostate cancer should be managed according to their individual health status and not by their age. CGA is the best tool for determining the health status of an older patient. In this article, we sought to assemble all available evidence on the models of CGA and the prevalence of geriatric conditions in older patients with prostate cancer. We also discuss the feasibility of the most used screening tools in elderly patients, that is, the Vulnerable Elders Survey-13 (VES-13) and G-8 as screening tools in this group of patients. PMID- 28084134 TI - Psychometric properties of the Finnish version of the Young Person's Clinical Outcomes in Routine Evaluation (YP-CORE) questionnaire. AB - BACKGROUND: An increasing need exists for suitable measures to evaluate treatment outcome in adolescents. YP-CORE is a pan-theoretical brief questionnaire developed for this purpose, but it lacks studies in different cultures or languages. AIMS: To explore the acceptability, factor structure, reliability, validity, and sensitivity to change of the Finnish translation of YP-CORE. METHODS: The study was conducted at the Department of Adolescent Psychiatry, Helsinki University Central Hospital. A Finnish translation was prepared by a team of professionals and adolescents. A clinical sample of 104 patients was asked to complete the form together with BDI-21 and BAI, and 92 of them filled the forms again after a 3-month treatment. Analysis included acceptability, confirmatory factor analysis, internal and test-re-test reliability, concurrent validity, influence of gender and age, and criteria for reliable change. RESULTS: YP-CORE was well accepted, and the rate of missing values was low. Internal consistency (alpha = 0.83-.92) and test-re-test reliability were good (r = 0.69), and the results of CFA supported a one-factor model. YP-CORE showed good concurrent validity against two widely used symptom-specific measures (r = 0.62 0.87). Gender had a moderately strong effect on the scores (d = 0.67), but the effect of age was not as evident. The measure was sensitive to change, showing a larger effect size (d = 0.55) than in the BDI-21 and BAI (d = 0.31-0.50). CONCLUSIONS: The results show that the translation of YP-CORE into Finnish has been successful, the YP-CORE has good psychometric properties, and the measure could be taken into wider use in clinical settings for outcome measurement in adolescents. PMID- 28084135 TI - Calcium gluconate as cross-linker improves survival and shelf life of encapsulated and dried Metarhizium brunneum and Saccharomyces cerevisiae for the application as biological control agents. AB - Calcium chloride (CC) is the most common cross-linker for the encapsulation of biocontrol microorganisms in alginate beads. The aim of this study was to evaluate if calcium gluconate (CG) can replace CC as cross-linker and at the same time improve viability after drying and rehydration, hygroscopic properties, shelf life and nutrient supply. Hence, the biocontrol fungi Metarhizium brunneum and Saccharomyces cerevisiae were encapsulated in Ca-alginate beads supplemented with starch. Beads were dried and maximum survival was found in beads cross linked with CG. Beads prepared with CG showed lower hygroscopic properties, but a higher shelf life for encapsulated fungi. Moreover, we demonstrated that gluconate has a nutritive effect on encapsulated fungi, leading to increased mycelium growth of M. brunneum and to enhanced CO2 release from beads containing Saccharomyces cerevisiae. The application of CG as cross-linker will pave the way towards increasing drying survival and shelf life of various, especially drying sensitive microbes. PMID- 28084136 TI - Evidence-based cross validation for acoustic power transmission for a novel treatment system. AB - INTRODUCTION: The novel Trans-Fusimo Treatment System (TTS) is designed to control Magnetic Resonance guided Focused Ultrasound (MRgFUS) therapy to ablate liver tumours under respiratory motion. It is crucial to deliver the acoustic power within tolerance limits for effective liver tumour treatment via MRgFUS. Before application in a clinical setting, evidence of reproducibility and reliability is a must for safe practice. MATERIALS AND METHODS: The TTS software delivers the acoustic power via ExAblate-2100 Conformal Bone System (CBS) transducer. A built-in quality assurance application was developed to measure the force values, using a novel protocol to measure the efficiency for the electrical power values of 100 and 150W for 6s of sonication. This procedure was repeated 30 times by two independent users against the clinically approved ExAblate-2100 CBS for cross-validation. RESULTS: Both systems proved to deliver the power within the accepted efficiency levels (70-90%). Two sample t-tests were used to assess the differences in force values between the ExAblate-2100 CBS and the TTS (p > 0.05). Bland-Altman plots were used to demonstrate the limits of agreement between the two systems falling within the 10% limits of agreement. Two sample t tests indicated that TTS does not have user dependency (p > 0.05). CONCLUSIONS: The TTS software proved to deliver the acoustic power without exceeding the safety levels. Results provide evidence as a part of ISO13485 regulations for CE marking purposes. The developed methodology could be utilised as a part of quality assurance system in clinical settings; when the TTS is used in clinical practice. PMID- 28084137 TI - Preservation of deep-layer fat of lateral zones prevents postoperative seroma after TRAM-flap harvesting for breast reconstruction: a retrospective study. AB - OBJECTIVE: The present study elucidates whether or not preserving fat tissues deeper than the Scarpa's fascia in zone 3 and zone 4 reduces postoperative fluid collection after harvesting the transverse rectus-abdominis muscle (TRAM) flap. METHODS: Thirty-one patients for whom breast reconstruction with free TRAM flaps had been performed were included in the study. Fat tissues deeper than the Scarpa's fascia in zone 3 and zone 4 were addressed in two ways. With 17 patients, these tissues were preserved on the abdominal wall; with 14 patients, these fat tissues were harvested as part of the TRAM flap. The former and latter groups were named the Preservation Group and Non-Preservation Group, respectively. Drainage tubes were placed at the donor site until daily drainage became less than 20 ml, at which time the tubes were removed. The total amount of postoperative fluid drained from the donor site and the days required before tube removal were compared between the two groups. RESULTS: The total volume of drained fluid was significantly greater for the Non-Preservation Group (444 +/- 48.2 ml) than for the Preservation Group (230 +/- 21.9 ml); the period before removal of drainage tubes was significantly longer for the Non-Preservation Group (12.4 +/- 0.84 days) than for the Preservation Group (7.6 +/- 0.55 days). CONCLUSION: Preservation of deep-fat tissues in zone 3 and zone 4 reduces postoperative fluid exuded from the donor site, and enables earlier removal of drainage tubes. For cases where optimal breast shape can be achieved without these fat tissues, the fat tissues should be preserved. PMID- 28084138 TI - Intraoperative vasopressors and thrombotic complications in free flap breast reconstruction. AB - OBJECTIVE: The purpose of this study was to critically examine intraoperative vasopressor usage as it relates to free flap perfusion and its effect on perioperative complications in autologous breast reconstruction. METHODS: A retrospective cohort study was performed involving all free autologous breast reconstructions at a single institution over a 5 year period. Data collection focused on perioperative care, specifically fluid administration, urine output (UOP), use of vasopressors, and case duration. Outcomes included major intraoperative and postoperative complications. Patients who received intraoperative vasopressors were compared to all patients who did not. The use, type, and timing of the vasopressor agent were assessed with standard statistical analyses and regression modelling. RESULTS: Six hundred and eighty-two patients reconstructed with 1039 flaps were included. Of these, 475 (69.6%) patients received vasopressors. The vasopressor cohort was older (p = 0.001), with higher rates of hypertension (p = 0.02). They had a greater number of hypotensive episodes (2.3 vs 0.8, p < 0.0001) and received a greater volume of fluid (4653.0 vs 4291.7 ml, p = 0.004). Examining complications, no increase in intraoperative thrombotic events (arterial or venous) or flap loss was noted with vasopressor administration. A higher rate of minor complications was, however, noted (53.1% vs 43.0%, p = 0.016). CONCLUSIONS: This study demonstrates that the use of intraoperative vasopressor agents in the anaesthetic care of free flap breast reconstruction patients is common, but likely does not impact thrombotic events or flap loss. Minor complications may, however, be more common in these patients. PMID- 28084139 TI - A high frequency missense SULT1B1 allelic variant (L145V) selectively expressed in African descendants exhibits altered kinetic properties. AB - 1. Human cytosolic sulfotransferase 1B1 (SULT1B1) sulfates small phenolic compounds and bioactivates polycyclic aromatic hydrocarbons. To date, no SULT1B1 allelic variants have been well-characterized. 2. While cloning SULT1B1 from human endometrial specimens, an allelic variant resulting in valine instead of leucine at the 145th amino acid position (L145V) was detected. NCBI reported this alteration as the highest frequency SULT1B1 allelic variant. 3. L145V frequency comprised 9% of 37 mixed-population human patients and was specific to African Americans with an allelic frequency of 25%. Structurally, replacement of leucine with valine potentially destabilizes a conserved helix (alpha8) that forms the "floor" of both the substrate and PAPS binding domains. This destabilization results in altered kinetic properties including a four-fold decrease in affinity for PAP (3', 5'-diphosphoadenosine). Kms for 3'-phosphoadenosine- 5' phosphosulfate (PAPS) are similar; however, maximal turnover rate of the variant isoform (0.86 pmol/(min*MUg)) is slower than wild-type (WT) SULT1B1 (1.26 pmol/(min*MUg)). The L145V variant also displays altered kinetics toward small phenolic substrates, including a diminished p-nitrophenol Km and increased susceptibility to 1-naphthol substrate inhibition. 4. No significant correlation between genotype and prostate or colorectal cancer was observed in patients; however, the variant isoform could underlie specific pathologies in sub-Saharan African carriers. PMID- 28084140 TI - The impact of cancer survivorship care plans on patient and health care provider outcomes: a current perspective. AB - BACKGROUND: To help the growing number of cancer survivors deal with the challenges of cancer survivorship, survivorship care plans (SCPs) were recommended by the Institute of Medicine (IOM) in 2006. The SCP is a formal document that contains both a tailored treatment summary and a follow-up care plan. Since the IOM recommendation 10 years ago, the implementation in daily clinical practice is minimal. Several studies have investigated the effects of SCPs on patient-reported outcomes and oncology and primary care providers (PCPs), but the quantity and quality of these studies are limited. RESULTS: The first four randomized trials comparing SCP delivery with usual care failed to show a positive effect on satisfaction with information provision, satisfaction with care, distress or quality of life. SCPs did improve the amount of information provided and communication of PCPs with medical specialists and patients. A recent small trial that changed the focus from SCP as primarily an information delivery intervention to a behavioral intervention did observe positive effects on self-reported health, lower social role limitations and a trend towards greater self-efficacy. Gaps in knowledge about SCPs include uncertainty about content and length of the SCP; whether it should be delivered online or on paper; the timing and frequency of delivery; which health care provide should deliver SCP care. Finally, cost-effectiveness of SCP interventions has received limited attention. CONCLUSION: Currently, there is not enough evidence to warrant large scale implementation of SCPs, or to abandon SCPs altogether. Emphasis on the SCP process and survivor engagement, supporting self-management may be an important way forward in SCP delivery. Whether this is beneficial and cost-effective on the long term and among different groups of cancer survivors needs further investigation. PMID- 28084141 TI - Routine clinical application of virtual reality in abdominal surgery. AB - BACKGROUND: The advantages of 3D reconstruction, immersive virtual reality (VR) and 3D printing in abdominal surgery have been enunciated for many years, but still today their application in routine clinical practice is almost nil. We investigate their feasibility, user appreciation and clinical impact. MATERIAL AND METHODS: Fifteen patients undergoing pancreatic, hepatic or renal surgery were studied realizing a 3D reconstruction of target anatomy. Then, an immersive VR environment was developed to import 3D models, and some details of the 3D scene were printed. All the phases of our workflow employed open-source software and low-cost hardware, easily implementable by other surgical services. A qualitative evaluation of the three approaches was performed by 20 surgeons, who filled in a specific questionnaire regarding a clinical case for each organ considered. RESULTS: Preoperative surgical planning and intraoperative guidance was feasible for all patients included in the study. The vast majority of surgeons interviewed scored their quality and usefulness as very good. CONCLUSIONS: Despite extra time, costs and efforts necessary to implement these systems, the benefits shown by the analysis of questionnaires recommend to invest more resources to train physicians to adopt these technologies routinely, even if further and larger studies are still mandatory. PMID- 28084142 TI - The role of sex steroid hormones in benign prostatic hyperplasia. AB - INTRODUCTION: The etiology of benign prostatic hyperplasia (BPH) remains a mystery to scientists; estrogen/androgen imbalance in aged men has been implicated. METHODS: Thirty (30) apparently healthy men and newly diagnosed BPH patients were recruited from the Ghana Police Hospital. Lower urinary tract syndrome (LUTS) and prostate volume were assessed via the prostate symptom score sheet (IPSS) and abdominopelvic scan, respectively. Laboratory assays for total prostate specific antigen (tPSA) and hormones [androstenedione (AED), testosterone (T), dihydrotestosterone (DHT), androstanedioladiol (3alpha-adiol), androstanediol (3beta-diol), estrone (E1) and estradiol (E2)] were performed via ELISA techniques. Non-parametric analyses were employed. p < 0.05 was considered significant. RESULTS: AED was significantly higher in controls compared to the BPH patients. AKRIC2 (3alpha-diol/DHT) was significantly higher in the BPH group (p < 0.001) whiles AKRIC1 (3beta-diol/DHT) was significantly lower. Estradiol was significantly higher in BPH (p= 0.029). Age correlated negatively with T, while a negative correlation was observed between TIPSS and 3beta-diol and AKRIC1. Also, prostate volume correlated negatively with fT.tPSA correlated positively with E2 and aromatase activity (E2/T) and negatively with fT. On multiple linear regression, DHT and 3beta-diol remained independent predictors for TIPSS and fT for tPSA. CONCLUSION: Estrogens and androstanediols seem to play a role in BPH development. PMID- 28084143 TI - A portable surgical navigation device to display resection planes for bone tumor surgery. AB - INTRODUCTION: Surgical navigation has been used in musculoskeletal tumor surgical procedures to improve the precision of tumor resection. Despite the favorable attributes of navigation-assisted surgery, conventional systems do not display the resection margin in real time, and preoperative manual input is required. In addition, navigation systems are often expensive and complex, and this has limited their widespread use. In this study, we propose an augmented reality surgical navigation system that uses a tablet personal computer with no external tracking system. MATERIAL AND METHODS: We realized a real-time safety margin display based on three-dimensional dilation. The resection plane induced by the safety margin is updated in real time according to the direction of sawing. The minimum separation between the saw and the resection plane is also calculated and displayed. The surgeon can resect bone tumors accurately by referring to the resection plane and the minimum separation updated in real time. RESULTS: The effectiveness of the system was demonstrated with experiments on pig pelvises. When the desired resection margin was 10 mm, the measured resection margin was 9.85 +/- 1.02 mm. CONCLUSIONS: The proposed method exhibits sufficient accuracy and convenience for use in bone tumor resection. It also has favorable practical applicability due to its low cost and portability. PMID- 28084144 TI - Investigation and improvement of a novel double-working-electrode electrochemical system for organic matter treatment from high-salinity wastewater. AB - The novel double-working-electrode electrochemical system with air diffusion cathode (ADC) and Ti/SnO2-Sb anode (TSSA) has shown higher efficiency and lower energy consumption for the degradation of organic pollutant from high-salinity wastewater, compared to the traditional single anode system. To further investigate and improve this system, in this work, firstly the effect of vital factors of the double-working-electrode electrochemical system including initial methyl orange (MO) concentration, NaCl concentration and initial pH value of organic solution were investigated, using MO as the targeted organic pollutant, carbon black ADC (CBAC) as cathode and stainless steel mesh electrode (SSME) as control. Besides, for the further improvement of removal performance, a novel home-made activated carbon-ADC (ACAC) was studied as cathode with the same investigation process. The results showed that, in the experiments studying the effect of both initial MO and NaCl concentrations, the removal performance was in the order of TSSA-ACAC > TSSA-CBAC > TSSA-SSME in all conditions of initial MO and NaCl concentrations. However, with the pH value reduced from 6.0 to 3.0, the performances of three systems turned to be much closer to each other. Besides, ACAC played a synergistic role in MO removal by greatly improving the MO removal performance and enhancing its adaptability to the reactor parametric variation. ACAC created a weak acidic environment for accelerating the indirect electro oxidation of MO on TSSA. The MO degradation pathways in the three systems were the same but the TSSA-ACAC system gave a higher degradation kinetics order. PMID- 28084145 TI - Multimodal ultrasonographic algorithm in the differentiation of submandibular masses. AB - CONCLUSION: The multimodal diagnostic algorithm is a simple diagnostic tool in the pre-operative assessment of submandibular masses that enables one-stage surgical concepts. BACKGROUND: The pre-operative assessment of submandibular masses is of major clinical impact. This study assesses the diagnostic utility of a newly introduced diagnostic algorithm in the differentiation of submandibular masses based on epidemiological and B-mode ultrasonographic data. METHODS: One hundred and eighty-eight patients with submandibular triangle masses were included. Epidemiological and ultrasonographic data of 128 consecutively included patients were assessed and structured in a multimodal algorithm. The diagnostic algorithm was prospectively validated in a further 60 patients. RESULTS: Single epidemiological and ultrasonographic data do not reliably predict the lesional entity. The multimodal diagnostic algorithm achieved a diagnostic sensitivity/specificity of 100%/100% in sialolithiasis, 44%/100% in benign submandibular gland diseases (BSD), 94%/96% in nodal lymphoma/unspecific lymphadenitis, and 91%/84% in carcinomas. Reduced sensitivity in BSD or specificity in carcinomas increased after intra-operative fresh frozen section in patients suspected for BSD. PMID- 28084146 TI - Lip carcinoma: clinical presentation, surgical treatment, and outcome: a series of 108 cases from Denmark. AB - OBJECTIVE: Lip carcinomas are among the most common malignant tumours of the head and neck region but reports on the course and outcome of this disease are mainly based on Mediterranean, South American, and Oceanian populations. The aim of the study was to describe the treatment and outcome of patients with lip carcinoma at a Danish department of plastic surgery. METHOD: We conducted a single institution retrospective cohort study including patients with primary cancer of the lips including squamous cell (SCC), basal cell (BCC), and basosquamous carcinomas (BSC) in a 5-year period. RESULTS: We included 108 consecutive patients. Median age was 72 years (range 28 -98) and 58% were male. Seventy patients (65%) were diagnosed with SCC, 36 (33%) BCC, and 2 (2%) BSC. The majority of lesions were stage T1 (84%) and T2 (11%). An unexpected total of 35 (32%) patients experienced wound healing problems; whereof 19 (54%) classified as mild (not demanding treatment), 10 (29%) as moderate (non-functional surgical corrections or medical treatment of infection needed) and 6 (17%) experienced severe dehiscence (requiring surgical intervention for functional improvement). Total defect size >=20 mm and full thickness excision was directly correlated to the risk of early postoperative complications (p-value: 0.03 and 0.04). Three patients (2/36 with BCC; 6% and 1/70 with SCC; 1%) developed local recurrence and five patients with SCC (5/70; 7%) developed regional lymph node metastases. One patient (1%) died from metastatic SCC. CONCLUSION: This study confirms that lip carcinoma is associated with a risk of recurrence and mortality. However, the risk of wound complications is notable compared to other series. PMID- 28084147 TI - Early weight loss predicts the reduction of obesity in men with erectile dysfunction and hypogonadism undergoing long-term testosterone replacement therapy. AB - We and others have previously shown that testosterone replacement therapy (TRT) results in sustained weight loss in the majority of middle-aged hypogonadal men. Previously, however, a small proportion failed to lose at least 5% of their baseline weight. The reason for this is not yet understood. In the present study, we sought to identify early indicators that may predict successful long-term weight loss, defined as a reduction of at least 5% of total body weight relative to baseline weight (T0), in men with hypogonadism undergoing TRT. Eight parameters measured were assessed as potential predictors of sustained weight loss: loss of 3% or more of baseline weight after 1 year of TU treatment, severe hypogonadism, BMI, waist circumference, International Prostate Symptom Score (IPSS), glycated hemoglobin (HbA1C), age and use of vardenafil. Among the eight measured parameters, three factors were significantly associated with sustained weight loss over the entire period of TU treatment: (1) a loss of 3% of the baseline body weight after 1 year of TRT; (2) baseline BMI over 30; and (3) a waist circumference >102 cm. Age was not a predictor of weight loss. PMID- 28084149 TI - CORLAS group photo 2016. PMID- 28084148 TI - Does Body Mass Index Predict Premature Cardiomyopathy Onset for Duchenne Muscular Dystrophy? AB - Duchenne muscular dystrophy leads to cardiomyopathy. The objective of this study was to estimate the association of body mass index with cardiomyopathy onset. Cardiomyopathy was defined as left ventricular ejection fraction <55% or left ventricular fractional shortening <28%. Overall, 48% met the criteria for cardiomyopathy. We were unable to demonstrate an association between body mass index Z score and age of cardiomyopathy onset (hazard ratio 0.79, 95% confidence interval 0.57-1.11, P = .17) after adjusting for covariates. Duration of corticosteroid use ( P = .01), but not loss of ambulatory ability ( P = .47), was associated with age of cardiomyopathy onset. We were unable to detect a significant difference in median body mass index Z scores in corticosteroid treated boys compared with corticosteroid-naive boys (1.11, 95% confidence interval 0.25-1.95, vs 1.05, 95% confidence interval 0.01-1.86, P = .69). No association was detected between the body mass index Z scores of Duchenne muscular dystrophy subjects and age of cardiomyopathy onset. PMID- 28084150 TI - Progressive strength training to prevent LYmphoedema in the first year after breast CAncer - the LYCA feasibility study. AB - BACKGROUND: Lymphoedema is a common late effect after breast cancer (BC) that has no effective cure once chronic. Accumulating evidence supports progressive strength training (PRT) as a safe exercise modality in relation to the onset and exacerbation of lymphoedema. In the 'preventive intervention against LYmphoedema after breast CAncer' (LYCA) feasibility study we examined the feasibility of a program of PRT in the first year after BC to inform a planned randomised controlled trial (RCT). MATERIAL AND METHODS: LYCA was a one-group prospective pilot trial inviting women operated with axillary lymph node dissection for unilateral primary BC. Participants exercised three times a week for 50 weeks (20 weeks supervised followed by 30 weeks home-based exercise). The program ensured slow individualised progression during the exercise program. The primary outcome was feasibility measured by eligibility and recruitment rates, as well as questionnaire-assessed satisfaction and adherence to exercise. Furthermore, we assessed arm interlimb volume difference by water displacement, muscle strength by dynamic and isometric muscle testing and range of movement in the shoulder by goniometry. RESULTS: In August 2015, eight of 11 eligible patients accepted participation. Two of them dropped out early due to other health issues. The remaining six participants had high exercise adherence through the supervised period, but only three maintained this through the home exercise period. Program satisfaction was high and no serious adverse events from testing or exercising were reported. One participant presented with lymphoedema at 50-week follow-up. Muscle strength markedly increased with supervised exercise, but was not fully maintained through the home exercise period. Range of shoulder movement was not negatively affected by the program. CONCLUSION: Recruitment, testing, and exercise in LYCA was safe and feasible. At the 50-week follow-up, there was one case of lymphoedema. The LYCA program will be further tested in a full-scale RCT. PMID- 28084151 TI - Study of behavioural disorders in children with primary enuresis. AB - BACKGROUND: Enuresis results in behavioural disorder in children. This study investigated the behavioural disorders in children possessing primary enuresis. MATERIALS AND METHODS: In this cross-sectional study, 100 children with primary enuresis were referred to children's hospital Khorramabad; the census method was used in this study. Data were collected using a short screening instrument for enuresis psychological problems, the reliability and validity of which have been confirmed in previous studies. First, a questionnaire was used to assess academic failure, anxiety, behavioural disorders, sleep, and psychological disorders. Results obtained were compared in terms of gender and age. Statistical analyses using inferential and descriptive statistics including Chi-square and Fisher test were employed. RESULTS: The average age of children was 8.46 years. Sixty-six per cent of participants were male and the rest of them were female. Ninety per cent of subjects were between the age range of 1-9 years, and 10% were over 10 years old. Forty-three per cent of children suffered from anxiety disorders and 34% had sleep disorders, 4% also suffered from academic failure. Among behavioural disorders, hyperactivity and restlessness were the most common disorders, and they were significantly higher in nine boys. Headache, obsessive, and sleep disorders were more common in children above 10. There was a significant correlation between eating disorders, headache, sleep disorders, and strange movements in males, while feelings of sadness were more common in females. CONCLUSION: Social personality development in children with enuresis can be improved by informing parents of enuresis. PMID- 28084152 TI - Southern Pediatric Neurology Society Annual Meeting. PMID- 28084153 TI - Case-control study of risk factors for suicide attempts in Isfahan, Iran. AB - BACKGROUND: Suicide is an important, preventable, public health problem worldwide, caused by the interaction of numerous environmental, biological and psychosocial factors. AIMS: This study aimed to identify the factors associated with suicidal attempts in Isfahan, Iran, in 2015. METHODS: In this case-control study, 175 cases who committed suicide and were admitted to emergency services were compared with 175 controls selected among outpatients from the same hospital without any history of suicide attempt. Demographic, psychosocial, personality traits, religiosity, coping skills, stressful life events, socioeconomic status and psychiatric distress were compared between groups. Multivariable logistic regression was used to identify independent risk factors for suicide. RESULTS: Marital status, education, socioeconomic status, psychological distress, perceived social support, stress coping strategies, personality, religious beliefs, stress life events and general health condition were significantly different between groups. The regression analysis revealed that perceived social support (odds ratio (OR) = 0.962, 95% confidence interval (CI): 0.94-0.984), religious beliefs (OR = 0.923, 95% CI: 0.867-0.984) and stressful life event (OR = 1.524, 95% CI: 1.251-1.856) were significantly associated with suicide attempts. CONCLUSION: Our finding showed that religious beliefs, perceived social support and stressful life events are the main factors associated with suicide attempts. So, positive strategies such as improvements in life skills to control stressful life events, religiosity and perceived social support can be used to control suicide attempts. PMID- 28084154 TI - The impact of a TV report in schizophrenia stigma reduction: A quasi-experimental study. AB - BACKGROUND: Stigma is a major problem in schizophrenia, and the most effective way to reduce it is to provide information. But literature lacks studies evaluating long-term efficacy of mass communication. AIMS: This is a pilot study to assess if a brief intervention (TV report) may have long-term effects. METHOD: Assessing stigma scores from subjects before and after seeing a vignette. RESULTS: We found that the social distance and restriction to patients not only fell after a brief intervention but also kept lower after 1 and 3 months. CONCLUSION: We conclude that even brief intervention may create persistent impact in reducing discrimination. PMID- 28084155 TI - Three-year postoperative outcomes between MIS and conventional TLIF in1-segment lumbar disc herniation. AB - AIM: The aim of this study is to assess the long-term clinical and radiological outcomes between minimally invasive (MIS) and conventional transforaminal lumbar interbody fusion (TLIF) in treating one-segment lumbar disc herniation (LDH). MATERIAL AND METHODS: One-hundred and six patients treated by MIS-TLIF (50 cases) or conventional TLIF (56 cases) were included. Perioperative results were evaluated. Clinical outcomes were compared preoperatively and postoperatively. Radiologic parameters were based on a comparison of preoperative and three-year postoperative lumbar lordosis, segmental lordosis, sacral slope, the cross sectional area of the paraspinal muscle and fusion rates. RESULTS: MIS TILF had significantly less blood, shorter operation time, mean return to work time and lower intramuscular pressure compared with the conventional group during the operation. VAS scores for lower back pain and ODI in MIS-TLIF were significantly decreased. The mean cross-sectional area of the paraspinal muscle was significantly decreased after surgery in the conventional TLIF group and no significant intragroup differences were established in the MIS-TLIF group. No significant differences were found in fusion rate, lumbar lordosis, segmental lordosis and sacral slope. CONCLUSIONS: Both MIS and conventional TLIF were beneficial for patients with LDH. However, MIS-TLIF manifests a great improvement in perioperative outcomes, low back pain, disability and preventing paraspinal muscle atrophy during the follow-up period observation. PMID- 28084157 TI - Cholesterol-lowering drugs: science and marketing. AB - Long-term use of statin therapy is essential to obtain clinical benefits, but adherence is often suboptimal and some patients are also reported to fail because of 'statin resistance'. The identification of PCSK9 as a key factor in the LDL clearance pathway has led to the development of new monoclonal antibodies. Here we critically review the economic evaluations published in Europe and focused on statins. We searched the PubMed database to select the studies published from July 2006 to June 2016 and finally selected 19 articles. Overall, the majority of studies were conducted from a third-party payer's viewpoint and recurred to modelling. Most studies were sponsored by industry and funding seemed to play a pivotal role in the study design. Patients resistant to LDL-C level reduction were considered only in a few studies. The place in therapy of the new class of biologic should be considered a kind of 'third line' for cholesterol-lowering, after patients have failed with restricted dietary regimens and then with current drug therapies. Otherwise they could result in hardly sustainable expenses even for developed countries. PMID- 28084158 TI - Atrial fibrillation in beta thalassemia major: how to perform effective screening and early detection. PMID- 28084159 TI - Tailoring the properties of a zero-valent iron-based composite by mechanochemistry for nitrophenols degradation in wastewaters. AB - Zero-valent iron (ZVI) is a valuable material for environmental remediation, because of its safeness, large availability, and inexpensiveness. Moreover, its reactivity can be improved by addition of (nano-) particles of other elements such as noble metals. However, common preparation methods for this kind of iron based composites involve wet precipitation of noble metal salt precursors, so they are often expensive and not green. Mechanochemical procedures can provide a solvent-free alternative, even at a large scale. The present study demonstrates that it is possible to tailor functional properties of ZVI-based materials, utilizing high-energy ball milling. All main preparation parameters are investigated and discussed. Specifically, a copper-carbon-iron ternary composite was prepared for fast degradation of 4-nitrophenol (utilized as model pollutant) to 4-aminophenol and other phenolic compounds. Copper and carbon are purposely chosen to insert specific properties to the composite: Copper acts as efficient nano-cathode that enhances electron transfer from iron to 4-nitrophenol, while carbon protects the iron surface from fast oxidation in open air. In this way, the reactive material can rapidly reduce high concentration of nitrophenols in water, it does not require acid washing to be activated, and can be stored in open air for one week without any significant activity loss. PMID- 28084160 TI - Population segmentation: an approach to reducing childhood obesity inequalities. AB - AIMS: The aims of this study are threefold: (1) to investigate the relationship between socio-economic status (inequality) and childhood obesity prevalence within Birmingham local authority, (2) to identify any change in childhood obesity prevalence between deprivation quintiles and (3) to analyse individualised Birmingham National Child Measurement Programme (NCMP) data using a population segmentation tool to better inform obesity prevention strategies. METHODS: Data from the NCMP for Birmingham (2010/2011 and 2014/2015) were analysed using the deprivation scores from the Income Domain Affecting Children Index (IDACI 2010). The percentage of children with excess weight was calculated for each local deprivation quintile. Population segmentation was carried out using the Experian's Mosaic Public Sector 6 (MPS6) segmentation tool. RESULTS: Childhood obesity levels have remained static at the national and Birmingham level. For Year 6 pupils, obesity levels have increased in the most deprived deprivation quintiles for boys and girls. The most affluent quintile shows a decreasing trend of obesity prevalence for boys and girls in both year groups. For the middle quintiles, the results show fluctuating trends. CONCLUSION: This research highlighted the link in Birmingham between obesity and socio-economic factors with the gap increasing between deprivation quintiles. Obesity is a complex problem that cannot simply be addressed through targeting most deprived populations, rather through a range of effective interventions tailored for the various population segments that reside within communities. Using population segmentation enables a more nuanced understanding of the potential barriers and levers within populations on their readiness for change. The segmentation of childhood obesity data will allow utilisation of social marketing methodology that will facilitate identification of suitable methods for interventions and motivate individuals to sustain behavioural change. Sequentially, it will also inform policy makers to commission the most appropriate interventions. PMID- 28084161 TI - A Message From the Editor-in-Chief. PMID- 28084165 TI - Tyramine and beta-phenylethylamine, from fermented food products, as agonists for the human trace amine-associated receptor 1 (hTAAR1) in the stomach. AB - The aromatic amines tyramine and beta-phenylethylamine are abundant in fermented foods. Recently, a family of human trace amine-associated receptors (hTAARs) was discovered that responds to these compounds. This study examined the expression of hTAAR genes in five human organs. Among them, the stomach expressed hTAAR1 and hTAAR9. Interestingly, more hTAAR1 was expressed in the pylorus than in the other stomach regions. The CRE-SEAP reporter assay revealed that only hTAAR1 functioned as a Gs-coupled receptor in response to tyramine and beta-phenylethylamine stimulation. The beta-phenylethylamine-mediated hTAAR1 activity could be potentiated using 3-isobutyl-1-methylxanthine. These data suggest that tyramine and beta-phenylethylamine in fermented foods act at hTAAR1 as agonists in the pylorus of stomach. PMID- 28084166 TI - Implementing medical revalidation in the United Kingdom: Findings about organisational changes and impacts from a survey of Responsible Officers. AB - Objective To describe the implementation of medical revalidation in healthcare organisations in the United Kingdom and to examine reported changes and impacts on the quality of care. Design A cross-sectional online survey gathering both quantitative and qualitative data about structures and processes for medical revalidation and wider quality management in the organisations which employ or contract with doctors (termed 'designated bodies') from the senior doctor in each organisation with statutory responsibility for medical revalidation (termed the 'Responsible Officer'). Setting United Kingdom Participants Responsible Officers in designated bodies in the United Kingdom. Five hundred and ninety-five survey invitations were sent and 374 completed surveys were returned (63%). Main outcome measures The role of Responsible Officers, the development of organisational mechanisms for quality assurance or improvement, decision-making on revalidation recommendations, impact of revalidation and mechanisms for quality assurance or improvement on clinical practice and suggested improvements to revalidation arrangements. Results Responsible Officers report that revalidation has had some impacts on the way medical performance is assured and improved, particularly strengthening appraisal and oversight of quality within organisations and having some impact on clinical practice. They suggest changes to make revalidation less 'one size fits all' and more responsive to individual, organisational and professional contexts. Conclusions Revalidation appears primarily to have improved systems for quality improvement and the management of poor performance to date. There is more to be done to ensure it produces wider benefits, particularly in relation to doctors who already perform well. PMID- 28084167 TI - The definition of stroke. PMID- 28084168 TI - Forthcoming events. PMID- 28084171 TI - What can clinicians learn from therapeutic studies about the treatment of acute oral methotrexate poisoning? AB - CONTEXT: Methotrexate (MTX) is an anti-folate drug that has been utilized in both malignant and chronic inflammatory conditions. Doctors are often concerned with a potential adverse outcome when managing patients with acute oral MTX poisoning given its potential for serious adverse reactions at therapeutic doses. However, there is surprisingly little data from acute poisoning cases and more data from the therapeutic use of high-dose MTX. OBJECTIVES: To review pharmacokinetic and pharmacological properties of MTX and systematically review series of acute MTX poisonings and therapeutic studies on high-dose MTX that provide pharmacokinetic or clinical data. METHODS: An Embase (1974-October 2016) and Medline (1946 October 2016) search was performed by combining "MTX" and "overdose/poison" or "MTX" and "toxicity" or "MTX" and "high-dose MTX" or "MTX" and "bioavailability" or "pharmacokinetics"; 25, 135, 109 and 365 articles were found, respectively, after duplicates were removed. There were 15 papers that provided clinical data on acute ingestion and toxicity that occurred with low-dose administration. Eighteen papers were on high-dose MTX (>1 g per m2 body surface area) used as a single chemotherapy agent which provided pharmacokinetic or clinical data on MTX toxicity. Thirty papers were reviewed to determine the toxic dose, pharmacokinetics, risk factors, clinical symptoms and management of acute MTX toxicity. Given the limited acute poisoning data, a retrospective audit was performed through the consultant records of the New South Wales Poisons Information Centre from April 2004 to July 2015 to examine the clinical syndrome and toxicity of acute oral MTX poisoning. Pharmacokinetics: Reduced MTX bioavailability is a result of saturable absorption. Although maximal bioavailable absorption occurs at a dose of ~15 mg m-2, splitting the dose increases bioavailability. MTX clearance is proportional to renal function. Acute toxicity: Oncologists prescribe doses up to 12 g m-2 of MTX. Patients treated with an intravenous dose of MTX <1g m-2 do not require folinic acid rescue. MTX toxicity correlates better with duration and extent of exposure than peak serum concentration. Acute oral poisoning: Acute oral MTX poisoning in 177 patients did not report any severe toxicity. In the New South Wales Poisons Information Centre audit data (2004-2015), 51 cases of acute MTX poisoning were reported, of which 15 were accidental paediatric ingestions. The median reported paediatric ingestion was 50 mg (IQR: 10-100; range: 10-150) with a median age of 2 years (IQR: 2-2; range: 1-4). Of the 36 patients with acute deliberate MTX poisoning, median age and dose were 47 years (IQR: 31-62; range: 10-85) and 325 mg (IQR: 85 500; range: 40-1000), respectively. Of the 19 patients who had serum MTX concentrations measured, all were significantly below the concentrations used in oncology and the folinic acid rescue nomogram line and no patient reported adverse sequelae. Management of acute oral poisoning: Due to the low bioavailability of MTX, treatment is not necessary for single ingestions. Oral folinic acid may be used to lower the bioavailability further with large ingestions >1 g m-2. Oral followed by intravenous folinic acid may be used in patients with staggered ingestion >36 h or patients with acute overdose and renal impairment (eGFR <45 mL/min/1.73 m2). CONCLUSIONS: As a consequence of saturable absorption MTXs bioavailability is so low that neither accidental paediatric MTX ingestion nor acute deliberate MTX overdose causes toxicity. An acute oral overdose will not provide a bioavailable dose even close to 1 g m-2 of parenteral MTX. Hence, no treatment is required in acute ingestion unless the patient has renal failure or staggered ingestion. There is also no need to monitor MTX concentrations in acute oral MTX poisoning. PMID- 28084172 TI - Erratum. PMID- 28084173 TI - Characterization of chicken interferon-inducible transmembrane protein-10. AB - Interferon-inducible transmembrane protein (IFITM) family proteins are antivirus factors. In the present study, we examined the expression pattern of chicken IFITM10 using quantitative reverse transcription-polymerase chain reaction. In adult chickens, IFITM10 levels were markedly lower than those of IFITM3, which exhibits antivirus activity. On the other hand, IFITM10 was expressed in levels similar to those of IFITM3 in embryonic organs. Primordial germ cells in 2.5-d embryos expressed high levels of IFITM10, which gradually decreased with time. The interferon-alpha stimulation of embryonic fibroblast cells did not enhance the expression of IFITM10. The forced expression of IFITM10 slightly inhibited the infectivity of the VSV-G-pseudotyped lentiviral vector. Furthermore, cell fusion was inhibited by IFITM10 when HeLa cells transfected with the VSV-G expression vector were treated with low pH buffer. Although it remains unclear whether IFITM10 inhibits viral infections under physiological conditions, these results suggest that chicken IFITM10 exhibits antivirus activity. PMID- 28084174 TI - Erratum. PMID- 28084175 TI - Antidiabetic drug use and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer. AB - OBJECTIVE: Diabetic men have lowered overall prostate cancer (PCa) risk, while their risk of high-grade disease may be elevated. The antidiabetic drug metformin may reduce the risk. This study evaluated PCa incidence among users of metformin and other antidiabetic drugs in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). METHODS: The study population (78,615 men) was linked to the national prescription database. Hazard ratios (HRs) and 95% confidence intervals (CIs) for PCa were estimated using Cox regression, with medication use as a time-dependent variable. The effect of diabetes was estimated by comparing antidiabetic drug users to non-users, while drug-specific effects were evaluated within antidiabetic drug users. Analyses were performed in both study arms of FinRSPC. RESULTS: Compared to non-users, men using antidiabetic drugs had lowered overall PCa risk (HR 0.85, 95% CI 0.79-0.92), and this association was not affected by PCa screening. However, the risk of metastatic PCa was increased (HR 1.44, 95% CI 1.09-1.91). Among antidiabetic drug users, metformin decreased overall PCa risk (HR 0.81, 95% CI 0.69-0.95) in a dose-dependent manner. When stratified by FinRSPC study arm, the risk reduction was observed only in the screening arm. Sulphonylureas increased the risk of metastatic PCa (HR 2.04, 95% CI 1.11-3.77). Use of thiazoledenediones or insulin was not associated with PCa risk. CONCLUSION: Among antidiabetic drug users, metformin lowered the overall PCa risk, while the risk of metastatic disease was elevated in sulphonylurea users. As sulphonylureas stimulate insulin secretion, the results suggest that hyperinsulinemia may be a risk factor for PCa. PMID- 28084176 TI - Obesity is associated with a higher prevalence of musculoskeletal pain in middle aged women. AB - Musculoskeletal pain (MSP) has been recently linked with high plasma leptin levels. Our objective was to study if obese women, who have higher leptin levels, could have a higher frequency of MSP. We studied 6079 Latin-American women, 40-59 years old. Their epidemiological data were recorded and the Menopause Rating Scale (MRS), Golberg Anxiety and Depression Scale and Insomnia Scale were applied. MSP was defined as a score >=2 on MRS11. Women with MSP were slightly older, had fewer years of schooling and were more sedentary. They also complained of more severe menopausal symptoms (29.2% versus. 4.4%, p < 0.0001). Furthermore, they had a higher abdominal perimeter (87.2 +/- 12.0 cm versus 84.6 +/- 11.6 cm, p < 0.0001) and a higher prevalence of obesity (23.1% versus 15.2%, p < 0.0001). Compared to normal weight women, those with low body weight (IMC <18.5) showed a lower risk of MSP (OR 0.71; 95%CI, 0.42-1.17), overweight women had a higher risk (OR 1.64; 95%CI, 1.44-1.87) and obese women the highest risk (OR 2.06; 95%CI, 1.76-2.40). Logistic regression analysis showed that obesity is independently associated to MSP (OR 1.34; 95%CI, 1.16-1.55). We conclude that obesity is one identifiable risk factor for MSP in middle-aged women. PMID- 28084178 TI - Collegium Oto-Rhino-Laryngologicum Amicitiae Sacrum. PMID- 28084177 TI - Non-invasive vagus nerve stimulation reduces sympathetic preponderance in patients with tinnitus. AB - CONCLUSION: Transcutaneous vagal nerve stimulation (tVNS) might offer a targeted, patient-friendly, and low-cost therapeutic tool for tinnitus patients with sympathovagal imbalance. OBJECTIVES: Conventionally, VNS has been performed to treat severe epilepsy and depression with an electrode implanted to the cervical trunk of vagus nerve. This study investigated the acute effects of tVNS on autonomic nervous system (ANS) imbalance, which often occurs in patients with tinnitus-triggered stress. METHODS: This study retrospectively analysed records of 97 patients who had undergone ANS function testing by heart rate variability (HRV) measurement immediately before and after a 15-60 min tVNS stimulation. RESULTS: The pre-treatment HRV recording showed sympathetic preponderance/reduced parasympathetic activity in about three quarters (73%) of patients. Active tVNS significantly increased variability of R-R intervals in 75% of patients and HRV age was decreased in 70% of patients. Either the variability of R-R intervals was increased or the HRV age decreased in 90% of the patients. These results indicate that tVNS can induce a shift in ANS function from sympathetic preponderance towards parasympathetic predominance. tVNS caused no major morbidity, and heart rate monitoring during the tVNS treatment showed no cardiac or circulatory effects (e.g. bradycardia) in any of the patients. PMID- 28084179 TI - PKCalpha promotes local advancement via its dual roles in nasopharyngeal carcinoma. AB - CONCLUSION: In patients with nasopharyngeal carcinoma (NPC), PKCalpha is linked to local advancement and plays dual roles in tumorigenesis. Moreover, positive PKCalpha is associated with 2-year overall survival of NPC. OBJECTIVE: This study seeks to investigate the role of PKCalpha to identify different sub-types in NPC. METHODS: PKCalpha expression levels were detected in a collection of NPC samples. CT and MRI scans of the corresponding patients were used to assess adjacent tissue invasion and lymph node metastasis. The correlation of tumour invasion and PKCalpha levels was evaluated by statistical analysis. The correlation between expression level of PKCalpha and 2-year overall survival was analysed by the Kaplan-Meier curves. Moreover, a multivariate Cox proportional hazard regression analysis was used to identify the independent prognostic factors for NPC. RESULTS: PKCalpha is linked to the invasion of adjacent tissues, especially in the skull base. However, down-regulation of PKCalpha is a risk factor for regional lymph node metastasis. The 2-year overall survival of the PKCalpha negative group is better than that of the PKCalpha positive group (PKCalpha negative group 100%, PKCalpha positive group 88.5%, p = 0.034). Based on the multivariate Cox proportional hazard regression analysis, age was identified as a risk factor. PMID- 28084180 TI - Processing Information After a Child's Cancer Diagnosis-How Parents Learn. AB - Parents of a child newly diagnosed with cancer must receive an extensive amount of information before their child's initial hospital discharge; however, little is known about best practices for providing this education. An interpretive descriptive study design was used to describe actual and preferred educational content, timing, and methods among parents of children newly diagnosed with cancer prior to their child's first hospital discharge. Twenty parents of children diagnosed with various malignancies participated in individual interviews 2 to 12 months after their child's diagnosis. Data were analyzed using constant comparative analysis. Education delivery occurred in a telling manner at diagnosis transitioning to a reciprocal process of teaching during the inpatient stay, then primarily back to telling immediately before discharge. Parents expressed a variety of preferred learning styles but noted that their preferences were rarely assessed by health care providers. Multiple factors influenced parents' ability to process educational information received during their child's initial hospitalization. Findings suggest that nursing practices should include assessing for influencing factors, providing anticipatory guidance, and incorporating parents' preferred learning style into the educational plan. PMID- 28084181 TI - Corrigendum. AB - Conte, T., & Cantrell, M. A. (2016). From chemo to college: The college experience of childhood cancer survivors. Journal of Pediatric Oncology Nursing, 33(5), 329-338. doi: 10.1177/1043454215604816. PMID- 28084182 TI - Corrigendum. AB - Mahon, P., Holsti, L., Siden, H., Strahlendorf, C., Turnham, L, & Giaschi, D. (2015). Using colors to assess pain in toddlers: Validation of "the Rainbow Pain Scale"-A proof-of-principle study. Journal of Pediatric Oncology Nursing, 32(1), 40-46. doi: 10.1177/1043454214555197. PMID- 28084184 TI - The Miriam Labbok New Investigator Award. PMID- 28084183 TI - Research and Project Abstracts Presented at the 2016 ILCA Conference. PMID- 28084187 TI - Association News from the ILCA Board of Directors. PMID- 28084186 TI - Changes in Pasteurized Donor Human Milk during Refrigeration. PMID- 28084188 TI - [Formula: see text]Associations among parent-child relationships and cognitive and language outcomes in a clinical sample of preschool children. AB - OBJECTIVE: To examine associations among parent-child relationship characteristics and child cognitive and language outcomes. METHODS: Preschool children (n = 72) with early neurological insult completed assessments of cognitive and language functioning and participated in a parent-child semi structured interaction. RESULTS: Quality of the parent-child relationship accounted for a significant amount of unique variance (12%) in predicting children's overall cognitive and language functioning. Impact of neurological insult was a significant predictor. CONCLUSIONS: Caregiver-child interactions that are harmonious and reciprocal as evidenced by affective and/or verbal exchanges support children's cognitive and language development. Observations of interactions can guide providers in facilitating child- and family-centered interventions. PMID- 28084191 TI - Application of Multivariate Classification Protocols in Research Focusing on Food, Environmental Samples, and Wastewater Technological Processes. AB - Analysis and quantification of multiple analytes in complex samples originating from food and environmental matrixes generate large data sets that can be difficult to analyze and interpret. Multivariate analysis and related computation protocols provide an effective platform and enable such problems to be dealt with. This review illustrates the effective application of chemometrics protocols used to improve quantification techniques and the interpretation of raw data from complex samples. PMID- 28084190 TI - Depression at Treatment Initiation Predicts HIV Antiretroviral Adherence in Uganda. AB - We examined the relationship between depression (symptom type, diagnostic severity, and change over time) and adherence to HIV antiretroviral therapy (ART) with data from 3 longitudinal studies (N = 1021) of patients starting ART in Uganda. The Patient Health Questionnaire was used to assess depressive symptoms (total score; somatic and cognitive subscales) and categorize severity level. At baseline, 9% had major depression and 30% had minor depression; 82% were adherent (reported no missed ART doses in the past 7 days) at month 6 and 85% at month 12. Controlling for demographic and medical covariates, multivariate random-effects logistic regression models revealed that change in depression was not related to adherence; however, baseline total depression symptoms and cognitive symptoms in particular as well as major and minor depression were significant predictors of adherence. These findings highlight the need for early identification and aggressive treatment of depression to optimize ART adherence. PMID- 28084189 TI - Impact of Unplanned Care Interruption on CD4 Response Early After ART Initiation in a Nigerian Cohort. AB - The authors conducted a retrospective cohort study of unplanned care interruption (UCI) among adults initiating antiretroviral therapy (ART) from 2009 to 2011 in a Nigerian clinic. The authors used repeated measures regression to model the impact of UCI on CD4 count upon return to care and rate of CD4 change on ART. Among 2496 patients, 83% had 0, 15% had 1, and 2% had >=2 UCIs. Mean baseline CD4 for those with 0, 1, or >=2 UCIs was 228/cells/mm3, 355/cells/mm3, and 392/cells/mm3 ( P < .0001), respectively. The UCI was associated with a 62 CD4 cells/mm3 decrease (95% confidence interval [CI]: -78 to -45) at next measurement. In months 1 to 6 on ART, patients with 0 UCI gained 10 cells/uL/mo (95% CI: 7-4). Those with 1 and >=2 UCIs lost 2 and 5 cells/uL/mo (95% CI: -18 to 13 and -26 to 16). Patients with UCI did not recover from early CD4 losses associated with UCI. Preventing UCI is critical to maximize benefits of ART. PMID- 28084192 TI - The Immune Interaction between HIV-1 Infection and Mycobacterium tuberculosis. AB - The modulation of tuberculosis (TB)-induced immunopathology caused by human immunodeficiency virus (HIV)-1 coinfection remains incompletely understood but underlies the change seen in the natural history, presentation, and prognosis of TB in such patients. The deleterious combination of these two pathogens has been dubbed a "deadly syndemic," with each favoring the replication of the other and thereby contributing to accelerated disease morbidity and mortality. HIV-1 is the best-recognized risk factor for the development of active TB and accounts for 13% of cases globally. The advent of combination antiretroviral therapy (ART) has considerably mitigated this risk. Rapid roll-out of ART globally and the recent recommendation by the World Health Organization (WHO) to initiate ART for everyone living with HIV at any CD4 cell count should lead to further reductions in HIV-1-associated TB incidence because susceptibility to TB is inversely proportional to CD4 count. However, it is important to note that even after successful ART, patients with HIV-1 are still at increased risk for TB. Indeed, in settings of high TB incidence, the occurrence of TB often remains the first presentation of, and thereby the entry into, HIV care. As advantageous as ART induced immune recovery is, it may also give rise to immunopathology, especially in the lower-CD4-count strata in the form of the immune reconstitution inflammatory syndrome. TB-immune reconstitution inflammatory syndrome will continue to impact the HIV-TB syndemic. PMID- 28084193 TI - Type I Protein Secretion-Deceptively Simple yet with a Wide Range of Mechanistic Variability across the Family. AB - A very large type I polypeptide begins to reel out from a ribosome; minutes later, the still unidentifiable polypeptide, largely lacking secondary structure, is now in some cases a thousand or more residues longer. Synthesis of the final hundred C-terminal residues commences. This includes the identity code, the secretion signal within the last 50 amino acids, designed to dock with a waiting ATP binding cassette (ABC) transporter. What happens next is the subject of this review, with the main, but not the only focus on hemolysin HlyA, an RTX protein toxin secreted by the type I system. Transport substrates range from small peptides to giant proteins produced by many pathogens. These molecules, without detectable cellular chaperones, overcome enormous barriers, crossing two membranes before final folding on the cell surface, involving a unique autocatalytic process.Unfolded HlyA is extruded posttranslationally, C-terminal first. The transenvelope "tunnel" is formed by HlyB (ABC transporter), HlyD (membrane fusion protein) straddling the inner membrane and periplasm and TolC (outer membrane). We present a new evaluation of the C-terminal secretion code, and the structure function of HlyD and HlyB at the heart of this nanomachine. Surprisingly, key details of the secretion mechanism are remarkably variable in the many type I secretion system subtypes. These include alternative folding processes, an apparently distinctive secretion code for each type I subfamily, and alternative forms of the ABC transporter; most remarkably, the ABC protein probably transports peptides or polypeptides by quite different mechanisms. Finally, we suggest a putative structure for the Hly-translocon, HlyB, the multijointed HlyD, and the TolC exit. PMID- 28084194 TI - Evaluation of Method-Specific Extraction Variability for the Measurement of Fatty Acids in a Candidate Infant/Adult Nutritional Formula Reference Material. AB - To address community needs, the National Institute of Standards and Technology has developed a candidate Standard Reference Material (SRM) for infant/adult nutritional formula based on milk and whey protein concentrates with isolated soy protein called SRM 1869 Infant/Adult Nutritional Formula. One major component of this candidate SRM is the fatty acid content. In this study, multiple extraction techniques were evaluated to quantify the fatty acids in this new material. Extraction methods that were based on lipid extraction followed by transesterification resulted in lower mass fraction values for all fatty acids than the values measured by methods utilizing in situ transesterification followed by fatty acid methyl ester extraction (ISTE). An ISTE method, based on the identified optimal parameters, was used to determine the fatty acid content of the new infant/adult nutritional formula reference material. PMID- 28084195 TI - Intravital Imaging of Myeloid Cells: Inflammatory Migration and Resident Patrolling. AB - Myeloid cell recruitment to sites of infection and injury started out as a simple model that has been referred to as the universal concept of leukocyte recruitment. However, as we gain more insight into the different mechanisms, it is becoming clear that each organ and perhaps even each cell has its own unique mechanism of recruitment. Moreover, as the ability to visualize specific cell types in specific organs becomes more accessible, it is also becoming clear that there are resident populations of leukocytes, some within the tissues and others attached to the vasculature of tissues, the latter poised to affect the local environment. In this review, we will first highlight the imaging approaches that have allowed us to gain spectacular insight into locale and function of specific cell types, and then we will discuss what we have learned from this approach as far as myeloid cells are concerned. We will also highlight some of the gaps in our knowledge, which exist almost certainly because of the challenges of being able to visualize certain compartments of the body. PMID- 28084196 TI - Age-Associated Differences in Hematopoietic Stem and Progenitor Cells of Mice. AB - Establishing the appropriate yet minimal number of control mice for experiments is a critical step in experimental design. Thisdecision is particularly important regarding the study of the hematopoietic system over time, given various age associated changes in murine hematopoietic cell populations. Here we used flow cytometry to serially monitor the frequencies of hematopoietic stem cells, common lymphoid progenitor cells, and common myeloid progenitor cells and RT-PCR assays to study the levels of Ly6a(Sca1), Slamf1, Ikzf1, and Cebpa-4 genes that control the hematopoietic process-in wildtype male and female mice with a B6SJL genetic background. These analyses revealed many differences, both at the cellular and mRNA levels, between immature and mature mice at various developmental stages. In conclusion, although it is necessary to minimize the number of mice possible insofar as possible to reduce animal use and meet animal welfare requirements, the numerous differences shown by our findings highlight the need to establish controls for every time point selected for the study of the hematopoietic system cells. This need is especially crucial when comparing immature and mature stages of mouse development. PMID- 28084197 TI - Macrophages in Endocrine Glands, with Emphasis on Pancreatic Islets. AB - We review here the macrophages found in endocrine tissues, placing emphasis on those residing in the islets of Langerhans of the pancreas. The islets represent the endocrine organ where macrophages have been examined in great detail and where our own studies and experience have been directed. PMID- 28084198 TI - Determination of Organophosphorous Pesticides in Environmental Water Samples Using Surface-Engineered C18 Functionalized Silica-Coated Core-Shell Magnetic Nanoparticles-Based Extraction Coupled with GC-MS/MS Analysis. AB - The present paper depicts a novel method based on magnetic SPE (MSPE) for the determination of organophosphorus pesticides (OPs) such as phorate, malathion, and chlorpyrifos in environmental water samples. In this study, C18 functionalized silica-coated core-shell iron oxide magnetic nanoparticles (MNPs) were used as a surface-engineered magnetic sorbent for the selective extraction of pesticides from aqueous samples, followed by GC-MS and GC-tandem MS analysis for confirmative determination of the analytes. Various important method parameters, including quantity of MNP adsorbent, volume of sample, effective time for extraction, nature of the desorbing solvent, and pH of the aqueous sample, were investigated and optimized to obtain maximum method performance. Under the optimized instrumental analysis conditions, good linearity (r2 value >=0.994) was achieved at the concentration range of 0.5-500 MUg/L. Recoveries were in the range of 79.2-96.3 and 80.4-97.5% in selective-ion monitoring and multiple reaction monitoring (MRM) modes, respectively, at the spiking concentrations of 1, 5, and 10 MUg/L. MRM mode showed better sensitivity, selectivity, and low level detection (0.5 MUg/L) of analytes. The novel MSPE method is a simple, cheap, rapid, and eco-friendly method for the determination of OPs in environmental water samples. PMID- 28084199 TI - Epidemiology and Host Factors. AB - In 2014, WHO reported approximately 9.6 million new cases of tuberculosis (TB) in the world, more than half of which are contributed by developing countries in Asia and Africa. Lack of modern diagnostic tools, underreporting of the new cases and underutilization of directly observed therapy (DOT) remain a concern in developing countries. Transient resurgence of TB during the HIV epidemic has subsided and the annual decline has resumed in developed countries including the USA. In 2014 though, the rate of decline has slowed down resulting in leveling of TB incidence in the USA. In developed countries like the USA, the incidence of TB remains high in those with certain risk factors for TB. This group includes immunocompromised patients, particularly those with positive HIV infection. Others at high risk include those with diabetes, cancer, those taking immunosuppressive drugs, and those with other medical conditions that reduce host immunity. If we look at age and ethnicity, elderly patients are at higher risk of developing TB. African-American, foreign-born, and homeless populations are also at higher risk of developing tuberculosis. Virulence of the mycobacteria, and immunological and genetically mediated factors are also mentioned, but these topics are not the primary goal of this article. This review, thus discusses the epidemiology, host factors, and those at high risk for developing active TB. A brief review of the current trends in drug resistance of mycobacteria is also presented. PMID- 28084201 TI - Gastrointestinal Tuberculosis. AB - Gastrointestinal tuberculosis (TB) is a fascinating disease which can be observed both in the clinical context of active pulmonary disease and as a primary infection with no pulmonary involvement. It represents a significant clinical challenge because of the resurgence of TB as well as the diagnostic challenges it poses. A high clinical suspicion remains the most powerful tool in an era of medicine when reliance on diagnostic technology increases. Antimicrobial therapy is the mainstay of therapy, but surgical and endoscopic interventions are frequently required for intestinal TB. Gastrointestinal TB is truly the "great mimic" and continues to require the astute clinical acumen of skillful clinicians to diagnose and treat. PMID- 28084200 TI - Innate Immune Responses to Bladder Infection. AB - Urinary tract infections are one of the most frequent bacterial infections of mankind. In spite of this frequency, the study of the immune system in the urinary tract has not attracted much attention. This could, in part, be attributable to the widespread use of antibiotics and similar antimicrobial agents, which for many decades have been both highly effective and relatively inexpensive to administer. In light of the emergence of multidrug-resistant bacteria among urinary tract infection isolates, interest in understanding the immune system in the urinary tract has grown. Several recent studies have revealed the existence of a powerful and highly coordinated innate immune system in the urinary tract designed to rapidly clear infecting pathogens; however, it also evokes harmful side effects. PMID- 28084202 TI - Mycobacterium bovis and Other Uncommon Members of the Mycobacterium tuberculosis Complex. AB - Since its discovery by Theobald Smith, Mycobacterium bovis has been a human pathogen closely related to animal disease. At present, M. bovis tuberculosis is still a problem of importance in many countries and is considered the main cause of zoonotic tuberculosis throughout the world. Recent development of molecular epidemiological tools has helped us to improve our knowledge about transmission patterns of this organism, which causes a disease indistinguishable from that caused by Mycobacterium tuberculosis. Diagnosis and treatment of this mycobacterium are similar to those for conventional tuberculosis, with the important exceptions of constitutive resistance to pyrazinamide and the fact that multidrug-resistant and extremely drug-resistant M. bovis strains have been described. Among other members of this complex, Mycobacterium africanum is the cause of many cases of tuberculosis in West Africa and can be found in other areas mainly in association with immigration. M. bovis BCG is the currently available vaccine for tuberculosis, but it can cause disease in some patients. Other members of the M. tuberculosis complex are mainly animal pathogens with only exceptional cases of human disease, and there are even some strains, like "Mycobacterium canettii," which is a rare human pathogen that could have an important role in the knowledge of the evolution of tuberculosis in the history. PMID- 28084203 TI - Tuberculous Otomastoiditis. AB - Tuberculous otitis media and mastoiditis, or tuberculous otomastoiditis, is a rare but well-described infectious process occasionally affecting individuals in the United States but more frequently seen in countries where tuberculosis is endemic. Infection may be primary and occur through mucus aspirated through the Eustachian tube. Alternatively, organisms may secondarily infect the nasopharynx when expectorated from the lungs and, less frequently, may be hematogenously spread. Chronic otorrhea and hearing loss are common symptoms, and extensive perforation of the tympanic membranes and facial nerve paralysis are routinely described. Diagnosis is made by direct culture of Mycobacterium tuberculosis, although more recently, molecular techniques have been used. Successful treatment of tuberculous otomastoiditis routinely involves surgical intervention combined with prolonged antituberculosis therapy. PMID- 28084205 TI - Tuberculous Lymphadenitis and Parotitis. AB - Tuberculous lymphadenitis is the most common extrapulmonary manifestation of disseminated tuberculosis (TB). It is considered to be the local manifestation of the systemic disease that has disseminated to local lymph nodes, but a high index of suspicion is needed for the diagnosis, because there are several infectious and noninfectious diseases that can mimic the same clinical picture. In recent years, different diagnostic methods have been introduced, including fine-needle aspiration cytology, which has emerged as a simple outpatient diagnostic procedure that replaced the complete excisional node biopsy, and a number of molecular methods which have greatly improved diagnostic accuracy. This chapter covers the most actual knowledge in terms of epidemiology, clinical manifestations, pathogenesis, and treatment and emphasizes current trends in diagnosis of tuberculous lymphadenitis. TB parotid gland involvement is extremely rare, even in countries in which TB is endemic. Because of the clinical similarity, parotid malignancy and other forms of parotid inflammatory disease always take priority over the rarely encountered TB parotitis when it comes to differential diagnosis. As a result, clinicians often fail to make a timely diagnosis of TB parotitis when facing a patient with a slowly growing parotid lump. This chapter highlights the most important features of this uncommon disease. PMID- 28084207 TI - Tuberculosis and Pregnancy-Maternal, Fetal, and Neonatal Considerations. AB - The issue of tuberculosis during pregnancy is not simply a historical inquiry but rather an increasingly familiar clinical problem facing industrial nations as well as the developing countries of the world. This review focuses on the maternal aspects of tuberculous infection, as well as transmission to the fetus and newborn. PMID- 28084206 TI - Diabetes and Tuberculosis. AB - The increase in type 2 diabetes mellitus (DM) patients in countries where tuberculosis (TB) is also endemic has led to the reemerging importance of DM as a risk factor for TB. DM causes a 3-fold increase in TB risk and a 2-fold increase in adverse TB treatment outcomes. Given the sheer numbers of DM patients worldwide, there are now more TB patients with TB-DM comorbidity than TB-HIV coinfection. There is an urgent need to implement strategies for TB prevention and control among the millions of DM patients exposed to Mycobacterium tuberculosis. This chapter summarizes the current epidemiological, clinical, and immunological knowledge on TB and DM and their clinical and public health implications. These include the underlying mechanisms for TB risk in DM patients and their clinical and sociodemographic characteristics that distinguish them from TB patients without DM. TB-DM comorbidity is posing a new challenge for integrating the short-term care for TB with the long-term care for DM, particularly in low- and middle-income countries. PMID- 28084208 TI - Biologic Agents and Tuberculosis. AB - Treatment with biologic agents, in particular tumor necrosis factor alpha (TNF alpha) inhibitors, is associated with an increased risk of tuberculosis (TB), and screening and treatment for latent TB infection (LTBI) in patients undergoing such treatment is therefore indicated. The risk of TB associated with different biologics varies significantly, with the highest relative risks, 29.3 and 18.6, associated with adalimumab and infliximab, respectively. The risk of TB with newer TNF-alpha inhibitors and other biologics appears to be lower. Performance of LTBI screening tests is affected by immune-mediated inflammatory diseases and immunosuppressive therapy in patients due to commence TNF-alpha inhibitor treatment. Interferon gamma release assays (IGRAs) have a higher specificity than the tuberculin skin test (TST) in patients with Bacillus Calmette-Guerin (BCG) vaccination and have probably a better sensitivity than TST in immunosuppressed patients. LTBI screening programs prior to commencement of anti-TNF-alpha treatment significantly reduce the incidence of TB, but the optimal screening algorithm, in particular the question of whether a combination of IGRA and TST or a single test only should be used, is a matter of ongoing debate. Use of TST in combination with IGRA is justified to increase sensitivity. Repeat testing for LTBI should be limited to patients at increased risk of TB. If TB develops during anti-TNF-alpha treatment, it is more likely to be disseminated and extrapulmonary than are other TB cases. Discontinuation of anti-TNF-alpha treatment in patients diagnosed with TB is associated with an increased risk of immune reconstitution inflammatory syndrome, which is probably best managed by reintroduction of anti TNF-alpha treatment. PMID- 28084209 TI - The Role of Therapeutic Drug Monitoring in Mycobacterial Infections. AB - Tuberculosis (TB) is a leading cause of infectious death. Nontuberculous mycobacteria (NTM) cause a wide variety of difficult-to-treat infections in various human hosts. Therapeutic drug monitoring (TDM) remains a standard clinical technique that uses plasma drug concentrations to determine dose. The reason to do this is simple: drug exposure (that is, the free drug area under the plasma concentration-time curve) relative to the MIC and not the dose per se largely determines the outcome of the infections. TDM provides objective information that clinician can use to make informed dosing decisions. The normal plasma concentration ranges provide reasonable guidance for initial target concentrations. Clinicians then combine concentration data with knowledge about the patients, in order to decide how aggressive to be with dosing. With sicker patients, who are closer to a poor outcome, one may be willing to accept an increased risk of potential toxicity in order to secure patient survival. In the clinic, time and resources are limited, so typically only two samples are collected postdose. The 2-h postdose concentrations approach the peak for most TB and NTM drugs. A 6-h sample allows the clinician to distinguish between delayed absorption and malabsorption, because patients with the latter need higher doses in order to gain the benefit associated with standard doses. Plasma concentrations do not account for all of the variability in patient responses to TB or NTM treatment, and concentrations cannot guarantee patient outcomes. However, combined with clinical and bacteriological data, TDM can be a decisive tool, allowing clinicians to look inside of their patients and adjust doses based on objective data. Knowing the dose, rather than guessing at the dose, is the path to shorter and more successful treatment regimens. PMID- 28084210 TI - Hematologic Complications of Tuberculosis. AB - Tuberculosis (TB) affects the production and life span of all hematologic cellular components. In addition, plasma coagulation factors may be affected, resulting in sometimes life-threatening complications. Iron, folate, and vitamin B12 metabolism is derailed. The pharmacological agents used for TB therapy may also cause hematologic changes. There are some uncommon manifestations of TB in nontuberculous hematologic patients. There have been some exciting developments in the field of imaging to screen for TB, TB pathophysiology at the cellular level, and our understanding of immune response in TB. Advances have been made in pharmacologic therapeutic options, including discovery of new drugs in the fight against drug-resistant TB, bearing in mind their hematologic effects. This chapter reviews and updates known hematologic effects of TB and its therapy and some lesser known effects of TB in patients with nontuberculous hematologic conditions. PMID- 28084211 TI - Rapidly Growing Mycobacteria. AB - Rapidly growing mycobacteria (RGM) compose approximately one-half of the currently validated mycobacterial species and are divided into six major groups, including the Mycobacterium fortuitum group, M. chelonae/M. abscessus complex, M. smegmatis group, M. mucogenicum group, M. mageritense/M. wolinskyi, and the pigmented RGM. This review discusses each group and highlights the major types of infections associated with each group. Additionally, phenotypic and molecular laboratory identification methods, including gene sequencing, mass spectrometry, and the newly emerging whole-genome sequencing, are detailed, along with a discussion of the current antimicrobial susceptibility methods and patterns of the most common pathogenic species. PMID- 28084212 TI - Toll-Like Receptor Signaling and Its Inducible Proteins. AB - Studies that bridge innate immunity and various diseases are making rapid advances. Macrophages and dendritic cells play a leading role in innate immunity, using pattern recognition receptors (PRRs) to sense both pathogen invasion and danger signals. Among these PRRs, the Toll-like receptors (TLRs) play a central role in the immune response by recognizing not only pathogen-associated molecular patterns from bacteria and viruses but also damage-associated molecular patterns from dying or injured cells. These TLR family molecules facilitate not only the elimination of pathogens but also the development of various disorders, including arteriosclerosis, cancer, and metabolic syndrome. TLRs activate signaling pathways that result in the production of cytokines, chemokines, and various inducible molecules associated with the immune response. Although most components of the innate immune signaling pathways, such as the TLR family and its downstream signaling, have been identified, the physiological roles of many TLR signal-inducible proteins remain unclear. Recent studies have shown that some TLR inducible proteins are critical in the immune response and the development of various disorders. In this review, we focus on the TLR signaling pathways and the roles of some TLR-inducible proteins. PMID- 28084214 TI - Novel real-time PCR-based patho- and phylotyping of potentially zoonotic avian influenza A subtype H5 viruses at risk of incursion into Europe in 2017. PMID- 28084213 TI - The Minimal Unit of Infection: Mycobacterium tuberculosis in the Macrophage. AB - The interaction between Mycobacterium tuberculosis and its host cell is highly complex and extremely intimate. Were it not for the disease, one might regard this interaction at the cellular level as an almost symbiotic one. The metabolic activity and physiology of both cells are shaped by this coexistence. We believe that where this appreciation has greatest significance is in the field of drug discovery. Evolution rewards efficiency, and recent data from many groups discussed in this review indicate that M. tuberculosis has evolved to utilize the environmental cues within its host to control large genetic programs or regulons. But these regulons may represent chinks in the bacterium's armor because they include off-target effects, such as the constraint of the metabolic plasticity of M. tuberculosis. A prime example is how the presence of cholesterol within the host cell appears to limit the ability of M. tuberculosis to fully utilize or assimilate other carbon sources. And that is the reason for the title of this review. We believe firmly that, to understand the physiology of M. tuberculosis and to identify new drug targets, it is imperative that the bacterium be interrogated within the context of its host cell. The constraints induced by the environmental cues present within the host cell need to be preserved and exploited. The M. tuberculosis-infected macrophage truly is the "minimal unit of infection." PMID- 28084215 TI - Dialysis Arteriovenous Fistula Failure and Angioplasty: Intimal Hyperplasia and Other Causes of Access Failure. AB - The arteriovenous fistula (AVF) is the preferred hemodialysis access type because it has better patency rates and fewer complications than other access types. However, primary failure remains a common problem impeding AVF maturation and adding to patients' morbidity and mortality. Juxta-anastomotic (or inflow) stenosis is the most common reason leading to primary failure, and percutaneous transluminal angioplasty continues to be the gold-standard treatment with excellent success rates. Intimal hyperplasia (IH) has been traditionally blamed as the main pathophysiologic culprit, but new evidence raises doubts regarding the contribution of IH alone to primary failure. We report a 64-year-old man with a 2-stage brachiobasilic AVF that was complicated by failure 4 months after creation. An angiogram showed multiple juxta-anastomotic and midfistula stenotic lesions. Percutaneous transluminal angioplasty was successful in assisting maturation and subsequently cannulating the AVF for hemodialysis treatment. We failed to identify the underlying cause of stenosis because biopsy specimens from fistula tissue obtained at the time of transposition revealed no occlusive IH. This case emphasizes the need for additional research on factors contributing to AVF failure besides IH and highlights the need for more therapeutic options to reduce AVF failure rate. PMID- 28084218 TI - Nucleation and growth of single layer graphene on electrodeposited Cu by cold wall chemical vapor deposition. AB - The nucleation density and average size of graphene crystallites grown using cold wall chemical vapor deposition (CVD) on 4 MUm thick Cu films electrodeposited on W substrates can be tuned by varying growth parameters. Growth at a fixed substrate temperature of 1000 degrees C and total pressure of 700 Torr using Ar, H2 and CH4 mixtures enabled the contribution of total flow rate, CH4:H2 ratio and dilution of the CH4/H2 mixture by Ar to be identified. The largest variation in nucleation density was obtained by varying the CH4:H2 ratio. The observed morphological changes are analogous to those that would be expected if the deposition rate were varied at fixed substrate temperature for physical deposition using thermal evaporation. The graphene crystallite boundary morphology progresses from irregular/jagged through convex hexagonal to regular hexagonal as the effective C deposition rate decreases. This observation suggests that edge diffusion of C atoms along the crystallite boundaries, in addition to H2 etching, may contribute to shape evolution of the graphene crystallites. These results demonstrate that graphene grown using cold wall CVD follows a nucleation and growth mechanism similar to hot wall CVD. As a consequence, the vast knowledge base relevant to hot wall CVD may be exploited for graphene synthesis by the industrially preferable cold wall method. PMID- 28084217 TI - Neuromorphic meets neuromechanics, part I: the methodology and implementation. AB - OBJECTIVE: One goal of neuromorphic engineering is to create 'realistic' robotic systems that interact with the physical world by adopting neuromechanical principles from biology. Critical to this is the methodology to implement the spinal circuitry responsible for the behavior of afferented muscles. At its core, muscle afferentation is the closed-loop behavior arising from the interactions among populations of muscle spindle afferents, alpha and gamma motoneurons, and muscle fibers to enable useful behaviors. APPROACH: We used programmable very- large-scale-circuit (VLSI) hardware to implement simple models of spiking neurons, skeletal muscles, muscle spindle proprioceptors, alpha-motoneuron recruitment, gamma motoneuron control of spindle sensitivity, and the monosynaptic circuitry connecting them. This multi-scale system of populations of spiking neurons emulated the physiological properties of a pair of antagonistic afferented mammalian muscles (each simulated by 1024 alpha- and gamma motoneurones) acting on a joint via long tendons. MAIN RESULTS: This integrated system was able to maintain a joint angle, and reproduced stretch reflex responses even when driving the nonlinear biomechanics of an actual cadaveric finger. Moreover, this system allowed us to explore numerous values and combinations of gamma-static and gamma-dynamic gains when driving a robotic finger, some of which replicated some human pathological conditions. Lastly, we explored the behavioral consequences of adopting three alternative models of isometric muscle force production. We found that the dynamic responses to rate coded spike trains produce force ramps that can be very sensitive to tendon elasticity, especially at high force output. SIGNIFICANCE: Our methodology produced, to our knowledge, the first example of an autonomous, multi-scale, neuromorphic, neuromechanical system capable of creating realistic reflex behavior in cadaveric fingers. This research platform allows us to explore the mechanisms behind healthy and pathological sensorimotor function in the physical world by building them from first principles, and it is a precursor to neuromorphic robotic systems. PMID- 28084216 TI - DNA Damage Signaling Instructs Polyploid Macrophage Fate in Granulomas. AB - Granulomas are immune cell aggregates formed in response to persistent inflammatory stimuli. Granuloma macrophage subsets are diverse and carry varying copy numbers of their genomic information. The molecular programs that control the differentiation of such macrophage populations in response to a chronic stimulus, though critical for disease outcome, have not been defined. Here, we delineate a macrophage differentiation pathway by which a persistent Toll-like receptor (TLR) 2 signal instructs polyploid macrophage fate by inducing replication stress and activating the DNA damage response. Polyploid granuloma resident macrophages formed via modified cell divisions and mitotic defects and not, as previously thought, by cell-to-cell fusion. TLR2 signaling promoted macrophage polyploidy and suppressed genomic instability by regulating Myc and ATR. We propose that, in the presence of persistent inflammatory stimuli, pathways previously linked to oncogene-initiated carcinogenesis instruct a long lived granuloma-resident macrophage differentiation program that regulates granulomatous tissue remodeling. PMID- 28084219 TI - Flow separation on flapping and rotating profiles with spanwise gradients. AB - The growth of leading-edge vortices (LEV) on analogous flapping and rotating profiles has been investigated experimentally. Three time-varying cases were considered: a two-dimensional reference case with a spanwise-uniform angle-of attack variation alpha; a case with increasing alpha towards the profile tip (similar to flapping flyers); and a case with increasing alpha towards the profile root (similar to rotor blades experiencing an axial gust). It has been shown that the time-varying spanwise angle-of-attack gradient produces a vorticity gradient, which, in combination with spanwise flow, results in a redistribution of circulation along the profile. Specifically, when replicating the angle-of-attack gradient characteristic of a rotor experiencing an axial gust, the spanwise-vorticity gradient is aligned such that circulation increases within the measurement domain. This in turn increases the local LEV growth rate, which is suggestive of force augmentation on the blade. Reversing the relative alignment of the spanwise-vorticity gradient and spanwise flow, thereby replicating that arrangement found in a flapping flyer, was found to reduce local circulation. From this, we can conclude that spanwise flow can be arranged to vary LEV growth to prolong lift augmentation and reduce the unsteadiness of cyclic loads. PMID- 28084220 TI - Motions of leaves and stems, from growth to potential use. AB - The study on aerial plant organs (leaves and stems) motions is reviewed. The history of observations and studies is put in the perspective of the ideas surrounding them, leading to a presentation of the current classification of these motions. After showing the shortcomings of such a classification, we present, following an idea of Darwin's, the various movements in a renewed and observation-based perspective of the plant development. With this perspective, the different movements fit together logically, and in particular we point out that the mature reversible movements, such as the sensitive or circadian movements, are just partial regressions of the developmental ones. PMID- 28084221 TI - Enhancement of output performance through post-poling technique on BaTiO3/PDMS based triboelectric nanogenerator. AB - In the modern era, the invention of new energy sources is important in order to make advances possible in electronic media. A triboelectric nanogenerator (TENG) is considered to be strong design that converts mechanical power into electrical power, using organic (polymer) or inorganic (lead, ceramic etc) materials to initiate the triboelectrification process, followed by charge separation. In this study, a lead-free BaTiO3/PDMS-Al-based TENG was fabricated by mixing tetragonal ferroelectric BaTiO3 nanocrystals in a PDMS matrix to make a composite for a working electrode film. It is worth noting that a new post- poling process has been introduced to align the dipole structures in the BaTiO3 nanocrystals, and to attain a high electron density on the surface of the working electrode film. The output was recorded up to 375 V and 6 MUA of close circuit voltage and short circuit current, respectively, at a current density of 0.3 MUA cm-2 and an effective power equal to 2.25 mW at a load resistance of 100 MOmega, and is four times higher than a PDMS-Al-based TENG. This study also reveals the hidden locks that will enable other inorganic materials with a dipole structure to enhance their output using the post-poling technique. The TENG has a vast field of applications due to its stability, the flexibility of its thin films and its biocompatibility. It is also an aid for exploring new TENG devices with enhanced output performance. PMID- 28084222 TI - Symmetric transparent and flexible supercapacitor based on bio-inspired graphene wrapped Fe2O3 nanowire networks. AB - Transition metal oxides with high specific capacitance materials are ideal for a new generation of high-performance transparent supercapacitors but are rarely reported. Commonly, the synthesis of the required nanostructured materials is a crucial step required to achieve the transparency of the device. In this study, a Fe2O3 nanowire network transparent film is developed simply through air-solution interface reactions and wrapped in graphene shells for use as transparent electrodes. The Fe2O3 nanowire networks surrounded by the graphene layer exhibit an effective encapsulation structure, providing rapid three-dimensional electron and ion transport pathways. The specific areal capacitance (3.3 mF cm-2 at a scan rate of 10 mV s-1) was greatly improved, which is at least one hundred times higher than that for transparent devices based on planar chemical vapor deposition graphene. Furthermore, the films have a power density of 191.3 W cm-3, which is higher than that of electrolytic capacitors, an energy density of 8 mWh cm-3, which is comparable to that of lithium thin-film batteries, and superior cycling stability. PMID- 28084223 TI - Role of limited hydrogen and flow interval on the growth of single crystal to continuous graphene by low-pressure chemical vapor deposition. AB - A method for defect-free large crystallite graphene growth remains unknown despite much research effort. In this work, we discuss the role of flow duration of H2 gas for the production of graphene as per requirement and production at a minimum flow rate considering the safety issue of hydrogen utilization. The copper substrate used for growth was treated for different time intervals (0 to 35 min) in H2 flow prior to growth. Structural and chemical changes occurring in the copper substrate surface were probed by grazing incidence x-ray diffraction and x-ray photoelectron spectroscopy. The results were correlated with the Raman spectroscopy data, which can quantify the quality of graphene. With increasing H2 flow interval, secondary nucleation sites were observed and growth favored few layer graphene structures. The surface-adsorbed oxygen molecules and its conversion to an OH terminated surface with increasing hydrogen flow interval was found to be a key factor in enhancing nucleation density. The Stranski-Krastanov type of nucleation was observed for samples grown with different time intervals of H2 treatment, except 5 min of H2 flow prior to growth for which the Volmer Weber type of growth favored monolayer graphene crystallite growth. PMID- 28084224 TI - Films fabricated from partially fluorinated graphene suspension: structural, electronic properties and negative differential resistance. AB - The band structure and electric properties of films created from a partially fluorinated graphene suspension are analyzed in this paper. As may be inferred from the structural study, graphene islands (quantum dots) are formed in these films. Various types of negative differential resistance (NDR) and a step-like increase in the current are found for films created from the fluorinated graphene suspension. NDR resulting from the formation of the potential barrier system in the film and corresponding to the theoretical prediction is observed for a relatively low fluorination degree. The origin of the NDR varies with an increase in the fluorination degree of the suspension. The observation of NDR in the fluorinated films widens the range of application of such films, including as active device layers fabricated using 2D printed technologies on rigid and flexible substrates. PMID- 28084225 TI - Evolution of hollow nanostructures in hybrid Ce1-x Cu x O2 under droplet confinement leading to synergetic effects on the physical properties. AB - The paper discusses a successful strategy for tuning the hollow, porous or even solid morphologies of pure and Cu2+-doped CeO2 nanostructures. The reaction of nanodroplets at the interface in miniemulsions is significantly affected by the concentration of dopants. The growth mechanism is both reaction- as well as diffusion-controlled, which finally determines the particular morphology. With a varying degree of dopant concentration and quantum confinement, the concentration of Ce3+ available on the surface of the nano-droplets and -particles is found to change quite appreciably. This immediately leads to modulation in the physical properties, such as ferromagnetism or absorption. The significant red shift in the absorption spectra and associated broadband visible photoluminescence opens newer applications for the present material in visible optoelectronic devices. PMID- 28084226 TI - The cover page. PMID- 28084227 TI - Clinicopathological conference: A strong educational tool. PMID- 28084228 TI - Two patriarchs of Indian Neurosciences: Professor Baldev Singh and Professor Jacob Chandy. PMID- 28084229 TI - An early description of monomelic amyotrophy: An excerpt from the diaries of Dr. Charles I Smith (1830-1880) in Bangalore, Southern India. AB - An early description of paralysis confined to an upper limb can be found in the casebook of Dr. Charles I Smith, who was a doctor in Bangalore in the 19th century. The historical and clinical aspects, as well as the current importance of this entity are described briefly. PMID- 28084230 TI - The death wish and motor neuron disease! The chameleons and new research optimism. PMID- 28084231 TI - Death wish in patients with amyotrophic lateral sclerosis. PMID- 28084232 TI - Sonothrombolysis in acute large vessel ischemic stroke. PMID- 28084233 TI - Sonothrombolysis: An effective adjunct to intravenous tissue plasminogen activator therapy in acute ischemic stroke. PMID- 28084234 TI - Association between endothelial nitric oxide synthase gene polymorphisms and risk of ischemic stroke: A meta-analysis. AB - Previously published studies that have examined whether the three polymorphisms, G894T, T786C, and 4b/a in the endothelial nitric oxide synthase (eNOS) gene, are associated with ischemic stroke (IS) have reported conflicting results. Thus, we performed a meta-analysis to examine the potential association between these three single nucleotide polymorphisms (SNPs) of the eNOS gene and IS risk. A literature search was carried out for eligible candidate gene studies published before August 05, 2015 in the PubMed, Embase, and Google Scholar databases. The following combinations of main keywords were used in our study: ('endothelial nitric oxide synthase') or ('eNOS') and ('G894T, 4b/a, and T786C') and ('polymorphism') or ('polymorphisms') and ('Ischemic Stroke' or 'IS') and ('Cerebral Infarction' or 'CI') and ('genetic polymorphism' or 'single nucleotide polymorphisms' or 'SNP'). Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by using fixed or random effects model. Meta-regression analysis was used to investigate the potential sources of heterogeneity. Begg's funnel plots were used to explore the publication bias, and heterogeneity was assessed by I2 test. Twenty seven case-control studies involving 6733 cases and 7305 controls were analyzed in our meta-analysis. Significant association was observed for G894T (OR = 1.17; 95% CI: 1.08 to 1.28; P< 0.001) and 4b/a (OR = 1.25; 95% CI: 1.13 to 1.39; P < 0.001) whereas a non-significant association was observed for T786C (OR = 1.11; 95% CI: 0.98 to 1.26; P =0.109) eNOS gene polymorphisms and IS. Our meta-analysis establishes that the G894T and 4b/a polymorphisms of eNOS gene are significantly associated with the risk of IS. However, a non-significant association was found between T786C polymorphism of the eNOS gene and IS risk. Further prospective large epidemiological studies need to be done to confirm these findings. PMID- 28084235 TI - A systematic review of pipeline embolization device for giant intracranial aneurysms. AB - The experience with respect to the treatment of giant intracranial aneurysms with flow-diversion devices is limited. The aim of the present systematic review was to evaluate the effect of the pipeline embolization device (PED) on giant intracranial aneurysms. Eligible related articles were identified by searching the PubMed, Web of Science, Springer, ScienceDirect, and OVID databases using "giant aneurysm" and "pipeline" as the search items. The date of the last search was November 20, 2015. This systematic review adopted the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. In a total of 9 eligible studies with 200 patients and 215 aneurysms, 40 (18.6%) giant (aneurysm diameter >25mm) intracranial aneurysms treated with PED were analyzed. During a 6 to 34 month follow-up, complete occlusion was achieved in 23 (57.5%) cases. Seven patients (17.5%) developed intracranial hemorrhage, 5 developed ischemic attack (12.5%), and 13 (32.5%) developed a mass effect after PED treatment. The complication rate was 77.8% in PED for giant vertebrobasilar artery aneurysms. The cumulative mortality rate for giant paraclinoid carotid artery and middle cerebral artery aneurysms was 13.3% and increased up to 50% for giant vertebrobasilar artery aneurysms. The complete obliteration rate of PED for giant intracranial aneurysms was approximately 60%. Mass effect is the most mechanism of complications. Complication and mortality rates associated with PED for giant vertebrobasilar artery aneurysms are still extremely high. PMID- 28084236 TI - Intensive care unit models: Do you want them to be open or closed? A critical review. AB - Intensive care is a specialized branch of medicine dealing with the diagnosis, management, and follow up of critically ill or critically injured patients. It requires input from other branches of medicine on various issues. A critical care specialist has expertise in managing such patients round the clock. Based on his freedom to take decisions in the intensive care unit (ICU), different types of ICUs - open, closed, or semi-closed - have been defined. There is no doubt that all critical patients should be evaluated by an intensivist. Therefore, it is argued that a closed ICU model would be the ideal model. However, this may not always be feasible and other models may be more useful in resource-limited countries. In this review, we compare the different formats of ICU functioning and their suitability in different hospitals. PMID- 28084237 TI - An insight into death wish among patients with amyotrophic lateral sclerosis in India using "Wish-to-Die Questionnaire". AB - AIMS: In amyotrophic lateral sclerosis (ALS), death wish is expressed in a varying proportion of patients in different countries. In this first study from India, influence of belief system of religion/spirituality and attitude towards death, widely prevalent in the country, in decision making, was evaluated. MATERIAL AND METHODS: Twenty ALS patients were assessed using 'Wish-to-Die Questionnaire' (WDQ) developed to reflect seven domains, namely religion/spirituality, belief in karma, meaning of life, hope, family support, financial support and death wish. Functional impairment, depression, hopelessness and suicidal ideation were assessed by ALS Functional Rating Scale, Beck's Depression Inventory, Beck Hopelessness Scale and The Scale of Suicidal Ideation, respectively. RESULTS: On WDQ, all the 20 patients had belief in religion/spirituality, had hope and family support. Nineteen patients (95%) believed in karma, 16 (80%) still found life meaningful and 15 (75%) had financial support. Six patients (30%) had mild to moderate depression; hopelessness was present in 6 (30%) and suicidal ideation was present in one (5%). The 5 (25%) patients who expressed death wish did not significantly differ from others in 6 domains (religion/spirituality, belief in karma, meaning of life, hope, family support, financial support) of WDQ. The main reason in 3 patients who expressed death wish was lack of financial support. The fourth patient could not find meaning of life after the onset of illness, and the fifth wished to end his life since he had satisfactorily fulfilled all his responsibilities. CONCLUSION: Smaller proportion of patients of ALS expressed death wish in India compared to the Western countries. This may be attributed to belief in religion/spirituality and karma, having meaning of life and family support. As this is the first report from India, useful information may be obtained if similar studies are done on a larger sample. PMID- 28084238 TI - Sonothrombolysis for acute ischemic stroke - Break on through to the other side. AB - BACKGROUND: Intravenous (IV) tissue plasminogen activator (tPA) infusion combined with transcranial low-frequency ultrasound waves targeted on the occluded arterial segment (sonothrombolysis) can increase recanalization in large artery acute ischemic stroke (LA-AIS). AIMS: To evaluate the benefits of sonothrombolysis in LA-AIS. SETTINGS AND DESIGNS: An open-labeled observational study done in a quaternary care teaching hospital. METHODOLOGY: Patients with LA AIS within the window period (<4.5 h) with no contraindications for IV recombinant tPA were sonothrombolysed. Recanalization was monitored and graded using the transcranial Doppler thrombolysis in brain ischemia (TIBI) flow criteria and also by time of flight magnetic resonance angiography using a modified thrombolysis in myocardial infarction score. Parenchymal changes were assessed using computed tomography (CT) or diffusion-weighted imaging-Alberta Stroke Programme Early CT Score. National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) were used to assess the outcome. RESULTS: Eighteen patients underwent sonothrombolysis and the mean onset to needle time was 138 min (range 65-256). TIBI residual flow grade of >=2 was seen in 15 of 18 patients (83%). Immediate dramatic improvement (NIHSS score <=3 points or improvement by >=10 points) was seen in 6 of 18 patients (30%) and in 9 of 18 patients (50%) within the next 24 h. Two patients (one with TIBI 0, another with re-occlusion) underwent mechanical thrombectomy post-sonothrombolysis. Symptomatic hemorrhage occurred in 5.5% of the patients. At 6 months, 2 of 18 patients (11%) died and 10 of 16 patients (63%) achieved mRS <=2. CONCLUSIONS: Sonothrombolysis appears to be a safe way to augment the effect of tPA without increasing the door to needle time with the added advantage of observing flow through the occluded artery in real time. PMID- 28084239 TI - Robotic thymectomy for myasthenia gravis with or without thymoma-surgical and neurological outcomes. AB - : Context (Background): We report our experience with robotic thymectomy in patients with myasthenia gravis (MG)and provide data on the surgical results and neurologic outcomes, as per the Myasthenia Gravis Foundation of America (MGFA) recommendations for MG clinical research standards. OBJECTIVE: The study aims at reporting the surgical and neurological outcomes of patients of Myasthenia gravis treated by robotic thymectomy. MATERIALS AND METHODS: Prospective data was collected from 71 patients with myasthenia gravis (in the age range 15-67 years) with or without thymoma, who had completed a minimum follow up of one year. All patients were treated with robotic radical thymectomy. The clinical classification, status of preoperative and postoperative therapy, evaluation of post-interventional clinical status, and descriptions of morbidity/mortality were done as per the MGFA recommendations. Univariate and multivariate analysis was done to assess the factors associated with achievement of complete stable remission(CSR). RESULTS: A total of 71 patients were included in this study. Twenty-one out of 71 patients (29.6%) with myasthenia gravis had thymoma. At the last follow up, 70 patients were alive. No evidence of tumour recurrence was found in patients with thymoma. The overall CSR rate was 38% with the median time to CSR of 17.5 months (range 11-48 months). The CSR rate for patient of MG with thymoma was 19 % (n=4/21). Factor found to be significantly predicting CSR were young age, lesser severity of MG and non-thymomatous histology. CONCLUSIONS: Robotic thymectomy is a technically feasible and safe operation with a low morbidity and short hospitalization. It is associated with good neurological long term results in terms of both CSR and clinical improvement. PMID- 28084240 TI - Neurological manifestations of HIV-AIDS at a tertiary care institute in North Eastern India. AB - BACKGROUND: The nervous system is among the most frequent and serious targets of human immunodeficiency virus (HIV) infection. The infection usually occurs in patients with profound immunosuppression. In 10 - 20% of the patients, the presence of a neurological disease is the first manifestation of symptomatic HIV infection. AIMS AND OBJECTIVE: Despite the wide prevalence of neurological manifestations in HIV, there is no study examining the clinical manifestations of this disease in the resource- limited communities from north-eastern parts of India. To characterize the neurological involvement in patients with HIV infection at a tertiary care institute in northeast India, we studied various neurological presentations of HIV. SETTING AND DESIGN: This was a retrospective observational study done at a tertiary care institute in northeast India over a period of 6 years from August 2008 to September 2014. MATERIAL AND METHODS: A total of 91 HIV seropositive patients of both genders, aged >18 years, showing clinical evidence of central nervous system (CNS) involvement, and admitted in a tertiary care institute were included. Their clinical manifestations, laboratory investigations, and imaging were studied. RESULT: Tuberculous meningitis was the most common presentation as secondary CNS illness (43.9%), followed by cryptococcal meningitis (14.2%) and cerebrovascular accidents (5.49%). Furthermore, 6.59% had neurosyphilis, 6.59% had acquired immune deficiency syndrome (AIDS) - associated dementia, and peripheral neuropathy occurred in 16.4% of the patients. Headache was the most common neurological symptom seen in 25% of the patients. Seizures were noted in 25% of the pateints. CD4 was significantly low in most of the patients with progressive multifocal leukoencephalopathy, HIV associated encephalopathy (HAD) and cryptococcal meningitis compared with other neurological manifestations. CD4 counts in tuberculous meningitis and HAD were 110.3/MUl and 95/MUl, respectively. CONCLUSION: CNS tuberculosis was the most common secondary infection seen in HIV patients followed by cryptococcal meningitis. A high index of clinical suspicion of neurological involvement in HIV patients helps in the early diagnosis and early institution of specific treatment, which in turn decreases the morbidity and mortality considerably. PMID- 28084241 TI - The "11 O'clock Heel First" technique for microvascular end-to-side anastomosis. AB - BACKGROUND: The heel of a microvascular end-to-side anastomosis is a common site for technical imperfections. We describe a simple technique to overcome this challenge. The aim of the technique is to insert all the sutures in an inside-to outside manner at the heel area on the donor side of the anastomosis. This technique has first been tested in a laboratory setting and then was further elaborated in a clinical setting. MATERIALS AND METHODS: One hundred and twenty adult albino Wistar rats of both genders were randomized into the following two groups: (A) Control, 48 rats, representing approximately 40% of the total sample, underwent the usual two anchoring stitch technique; (B) Study group, 72 rats, representing approximately 60% of the total sample, underwent the technique described. Patency was confirmed both clinically and by the use of fluorescein angiography. Rat weight, diameter of both the donor and recipient vessels, type of anastomosis (arterio-arterial or arterio-venous) and angiographic findings were used as variables. A P value of less than 0.05 was considered significant. RESULTS: The proposed technique had increased patency rates as compared to the standard technique, which was statistically significant (P = 0.021). However, there was no difference between the patency rates of arterio-arterial and arterio venous atastomoses. CONCLUSION: The proposed technique is useful for perfecting the heel area of a microvascular end-to-side anastomosis in both laboratory and clinical settings. PMID- 28084242 TI - The quest to revascularize brain in ischemic stroke. PMID- 28084243 TI - Multimodal intraoperative neuromonitoring in scoliosis surgery: A two-year prospective analysis in a single centre. AB - AIM: The present study is a prospective analysis of neuromonitoring [somatosensory evoked potentials (SSEP) and transcranial motor evoked potentials (TcMEP)] in consecutive scoliosis surgeries done at a tertiary care spine centre. MATERIALS AND METHODS: Prospective analysis was performed on 52 consecutive patients undergoing scoliosis correction from 2013 to 2015. SSEPs were obtained by stimulating the median and tibial nerves with stimulus intensity level 20-25 mA. TcMEPs were recorded bilaterally from abductor pollicis brevis, biceps, and deltoid for the upper limb, and from tibialis anterior, quadriceps, gastrocnemius, and abductor hallucis for the lower limb. Stimulation was given in the form of a high voltage (300-400 V) stimulus. An "alert" was defined as reduction in the amplitude of at least 50% for SSEP and at least 65% for TcMEP compared to the baseline recordings and an increase in the latency by more than 10%. RESULTS: The mean age of the patients was 14.6 years (7-33 years). Thirty nine of the patients were females and 13 were males. Baseline values in neuromuscular scoliosis were low compared to adolescent idiopathic scoliosis (AIS). There were no false negative incidents. False positive cases were due to low blood pressure and malfunctioning of the leads. CONCLUSION: Use of upper limb leads could help in identifying malposition or malfunctioning of leads to eliminate false positive results. Combined multimodal intraoperative monitoring helps in increasing the safety in scoliosis corrective surgeries with a high sensitivity and specificity. Baseline values in neuromuscular scoliosis patients are possibly lower than idiopathic scoliosis patients. Intraoperative variations must be interpreted with caution. PMID- 28084244 TI - Multimodal intraoperative neuromonitoring during surgery for correction of spinal deformity: Standard of care or luxury? PMID- 28084245 TI - Predictive validity of disability rating scale in determining functional outcome in patients with severe traumatic brain injury. AB - BACKGROUND: Most patients with severe traumatic brain injury (TBI) are discharged when they have still not recovered completely. Many such patients are not available for follow up. AIMS: We conducted this study to determine whether the condition at discharge from acute care setting, as assessed with disability rating scale (DRS), correlates with functional outcome at follow up. SETTINGS AND DESIGN: This study was conducted at a Neurosurgical intensive care unit (ICU) of a tertiary care referral center. This was a prospective observational study. MATERIALS AND METHODS: Patients admitted to ICU with a diagnosis of severe TBI were enrolled for the study. On the day of discharge, all patients underwent DRS assessment. A final assessment was performed using Glasgow outcome scale extended (GOSE) at 6 months after discharge from the hospital. STATISTICAL ANALYSIS: The correlation between the DRS scores at the time of discharge with DRS scores and GOSE categories at 6 months after discharge was determined using Spearman's rho correlation coefficient. RESULTS: A total of 88 patients were recruited for the study. The correlation coefficient of DRS at discharge for DRS at 6 months was 0.536 and for GOSE was -0.553. The area under the curve of DRS score at discharge for predicting unfavorable outcome and mortality at 6 months was 0.770 and 0.820, respectively. CONCLUSION: The predictive validity of DRS is fair to good in determining GOSE at follow-up. Pending availability of a more accurate outcome assessment tool, DRS at discharge can be used as a surrogate outcome for GOSE at follow up. PMID- 28084246 TI - Outcome prediction in traumatic brain injury: Is it a "Holy Grail?" PMID- 28084247 TI - Segmental polymethylmethacrylate-augmented fenestrated pedicle screw fixation for lumbar spondylolisthesis in patients with osteoporosis - A case series and review of literature. AB - BACKGROUND: Instrumentation in patients with osteoporosis is challenging. Bone cement-augmented fenestrated pedicle screw fixation is a new procedure for fixation in osteoporotic bone. Very few studies related to this procedure are published in literature. AIMS: To evaluate the clinical and radiological outcome of polymethylmethacrylate (PMMA)-augmented fenestrated pedicle screw fixation in patients with spondylolisthesis having significant osteoporosis. SETTINGS AND DESIGN: This was a prospective, observational, single centre study. MATERIALS AND METHODS: All the patients with lumbar spondylolisthesis and osteoporosis with symptomatic neural compression, managed surgically with PMMA-augmented fenestrated pedicle screws, were included in the study. Patients were evaluated preoperatively and postoperatively by means of Oswestry disability index (ODI), visual analog score (VAS); and, radiologically by plain radiography and computed tomography. STATISTICAL ANALYSIS: Wilcoxon nonparametric test for paired samples with a level of significance of 0.05 was performed. RESULTS: A total of 25 patients of spondylolisthesis with osteoporosis (average T score of -3.0) were included in the study. The average age at presentation was 56.5 years. Females predominated with a female:male ratio of 3.16:1.Most of the patients had spondylolisthesis at the L4/L5 level followed by the L5/SI level. All the patients underwent spinal fusion with instrumentation and bone cement (PMMA) augmentation through fenestrated cannulated pedicle screws. Preoperative and postoperative functional assessment done with VAS and ODI showed statistically significant improvement. All the patients had an evidence of bone fusion at follow-up. CONCLUSION: Fenestrated pedicle screw fixation with bone cement augmentation in patients with lumbar spondylolisthesis and osteoporosis provided effective and lasting screw purchase. PMID- 28084248 TI - Spinal surgery in patients with significant osteoporosis: The therapeutic advances and research perspectives. PMID- 28084250 TI - Neuromodulation in Tourette's syndrome. PMID- 28084251 TI - Diagnostic dilemma-dengue or Japanese encephalitis? AB - Dengue and Japanese encephalitis (JE) are arboviral diseases that are common in the tropical countries. JE virus is a classical neurotropic virus. The dengue virus, however, is usually not considered to be neurotropic, even though in recent years, reports of direct central nervous system involvement in dengue has been described. Here, we report a case wherein the patient had magnetic resonance imaging evidence of bilateral thalamic and brainstem involvement with positive serologies for both dengue and JE. We also discuss the diagnostic challenge in these cases. PMID- 28084249 TI - "I swear, I can't stop it!" - A case of severe Tourette's syndrome treated with deep brain stimulation of anteromedial globus pallidus interna. AB - INTRODUCTION: Tourette's syndrome (TS) is a complex neuropsychiatric disorder characterized by the presence of multiple motor and vocal tics. Here, we report the case of a young man with severe TS refractory to multiple medications who underwent deep brain stimulation (DBS), which was successful in substantially ameliorating his tics. To our knowledge, this is the first such report from India and South Asia. CASE REPORT: An 18-year-old right-handed male patient was diagnosed with TS at the age of 10 years. He had facial and ocular tics. He was also hitting his fist against his chest and shouting obscenities. The manifestations would be present in every waking hour with a maximum tic free interval of 15-20 minutes. They would often result in self-injury or damage to objects. He would have frequent crying spells, anger outbursts, and death wishes. As tics became highly conspicuous and socially inappropriate, he dropped out of school and remained almost completely house-bound for the preceding year. On evaluation, he scored 96 (46 on tic-severity subscale and 50 on impairment subscale) of a maximum of 100 on the Yale Global Tic Severity Scale. (YGTSS). MANAGEMENT: After failure of multiple combinations of medicines, repetitive transcranial magnetic stimulation, and behavioural therapies, he successfully underwent DBS to bilateral anteromedial globus pallidus interna. CONCLUSION: Tic severity reduced substantially post-surgery, with the YGTSS score improving by more than 72%. These improvements were sustained on follow-up visits with the patient successfully returning to join college. To our knowledge, this is the first such report from India and South Asia. PMID- 28084252 TI - Dual infection with Japanese encephalitis and dengue fever: Issues with diagnosis. PMID- 28084253 TI - Coexistent intracerebral metastatic melanoma and meningioma. AB - Coexistence of multifocal neural crest tumors, namely meningioma, melanoma, and nerve sheath tumors, is termed as neurocristopathy. Neurofibromatosis is the commonest form of neurocristopathy. We report a rare case of frontal lobe metastatic melanoma coexistent with a parietal lobe meningioma, in the absence of any stigmata of neurofibromatosis. PMID- 28084255 TI - Histological spectrum of oligodendroglial tumors: Only a subset shows 1p/19q codeletion. PMID- 28084254 TI - Histological spectrum of oligodendroglial tumors: Only a subset shows 1p/19q codeletion. AB - BACKGROUND: Canonical oligodendroglial tumors (ODGs) are characterized genetically by chromosomes 1p/19q codeletion. AIMS: This study was essentially aimed at the detection of frequency of 1p/19q codeletion in the different histological spectrum of ODG tumors in a large cohort of Indian patients. MATERIALS AND METHODS: All the ODG tumors evaluated for 1p/19q by fluorescence in situ hybridization (FISH) during 2009-2015 were correlated with histology, immunohistochemical expression for p53 protein and clinical features. RESULTS: A total of 676 cases included both pediatric (n = 18) and adult (n = 658) patients. Histologically, 346 pure ODGs [oligodendroglioma (OD) and anaplastic oligodendroglioma (AOD)] and 330 mixed ODGs [oligoastrocytomas (OA), anaplastic oligoastrocytomas (AOA) and glioblastoma with oligodendroglioma component (GBM O)] were included. 1p/19q co-deletion was noted in 69% (60/87), 55.9% (145/259), 18.2% (18/99), 10.5% (18/172), and in 5.1% (3/59) cases of OD, AOD, OA, AOA, and GBM-O, respectively. In the pediatric age-group, 1p/19q codeletion was seen in 25% (2/8) of pure ODGs and in 10% (1/10) of mixed ODGs. In adults, it was observed in 60% (203/338) cases of pure ODGs and in 11.9% (38/320) cases of mixed ODGs. In adults, pure ODG histology (P = 0.00), frontal location (P = 0.004), calcification [in pure ODGs] (P = 0.03), and lack of p53 protein overexpression (P = 0.00) showed significant statistical correlation with 1p/19q codeletion. CONCLUSIONS: This study is unique in being one of the largest on ODGs for 1p/19q co-deletion including both pediatric and adult age groups of Indian patients. The results showed co-deletion in 60% of adult ODGs and 25% of pediatric pure ODGs. This reemphasizes the occurrence of 1p/19q codeletion, even though rare, in the pediatric age group. PMID- 28084256 TI - How to recognize and treat metabolic encephalopathy in Neurology intensive care unit. AB - Metabolic encephalopathy (ME) represents a syndrome of temporary or permanent disturbance of brain functions that occurs in different diseases and varies in clinical presentation. It can be manifested in a range from very mild mental disorders to deep coma and death. Clinically, it is characterized by a variety of psychiatric and neurological symptoms and signs. The most common causes of ME are: hypoxia, ischemia, systemic diseases and toxic agents. ME is the most frequent in elderly people who have previously been exhausted by chronic illnesses and prolonged stay in bed. ME is a very common complication in patients treated in intensive care units. Treatment and prognosis of the disease are varied and depend on aetiology, as well as on the type and severity of clinical presentation. Mortality of patients with septic encephalopathy ranges from 16 65%, while the one-year survival of patients with encephalopathy and liver cirrhosis is less than 50%. PMID- 28084257 TI - A novel nasoseptal flap harvesting technique in revision expanded endoscopic transsphenoidal approaches. AB - OBJECTIVES: To describe the technique of harvesting the nasoseptal flap (NSF) in revision-expanded endoscopic approaches (EEA). STUDY DESIGN: We retrospectively analyzed four cases of endoscopic skull base reconstruction (ESBR) following revision EEA done for pituitary adenoma recurrence. The presence of an intact mucoperiosteum between the nasal septum and the roof of the choana as judged on a preoperative endoscopic and radiological assessment was considered to be sufficient for the presence of a viable pedicle. By strategic placement of the incisions, the entire bilateral posterior nasal septal mucoperiosteum was raised in the NSF containing the remnant vascular pedicle. ESBR was performed with multilayer grafting of the dural defect, and the NSF was placed onto the bony margins of the defect. RESULTS: All patients had successful skull base reconstruction with the NSF raised by this technique as none of them developed postoperative cerebrospinal fluid leak. CONCLUSION: Though the number of patients in this study is small, we would like to present the concept of harvesting the NSF in revision surgery, wherein neither measuring the surface area of the pedicle nor the acoustic Doppler assessment of the pedicle is required. PMID- 28084258 TI - History of Neurosurgery at Postgraduate Institute of Medical Education and Research, Chandigarh. AB - The Department of Neurosurgery started functioning at the Postgraduate Institute of Medical Education and Research, Chandigarh in 1962 with the joining of Dr. Gulati. The department provides neurosurgical services primarily to the people of Chandigarh, Punjab, Haryana, Himachal Pradesh, Jammu and Kashmir as well as the neighbouring areas of Rajasthan, Uttar Pradesh and Uttarakhand. The infrastructure and subspecialties have been developed over the last 5 decades by the dedicated and tireless efforts of the faculty and residents. We attempt to chronicle the contributions of those who have served the department in the past. PMID- 28084259 TI - A summary of some of the recently published, seminal papers in neuroscience. PMID- 28084260 TI - Ipilimumab-induced hypophysitis and ileocolitis: Serial pituitary MRI findings. PMID- 28084261 TI - Dural venous sinus thrombosis following intravitreal bevacizumab. PMID- 28084262 TI - Proximal ulnar artery thrombosis after cysticidal therapy: A rare complication of neurocysticercosis. PMID- 28084263 TI - Refractory status dystonicus in ataxia telangiectasia. PMID- 28084264 TI - Drug-induced Parkinsonism on the rise: Beware of levosulpiride and its combinations with proton pump inhibitors. PMID- 28084265 TI - "Hot-cross bun" and "inverse trident sign' in neurosarcoidosis: An important finding. PMID- 28084266 TI - Multiple Acyl CoA dehydrogenase deficiency: Uncommon yet treatable disorder. PMID- 28084267 TI - Guillain-Barre syndrome: A rare manifestation of Hansen's disease. PMID- 28084268 TI - Novel SCN8A mutation in a girl with refractory seizures and autistic features. PMID- 28084269 TI - Newly described additional sites of extrapontine myelinolysis along with typical pontine and extrapontine myelinolysis. PMID- 28084270 TI - Trunk proprioceptive neuromuscular facilitation influences pulmonary function and respiratory muscle strength in a patient with pontine bleed. PMID- 28084271 TI - Bartter's syndrome: A rare cause of seizures and quadriparesis. PMID- 28084272 TI - Chronic encephalopathy with ataxia, myoclonus, and auditory neuropathy: A case of bismuth poisoning. PMID- 28084273 TI - An unusual cause of bilateral tongue wasting and weakness. PMID- 28084274 TI - Paroxysmal sympathetic hyperactivity after symptomatic hypoglycemia. PMID- 28084275 TI - Reversal of angiographic findings of moyamoya syndrome after congenital cyanotic heart disease repair. PMID- 28084276 TI - Intracranial fibrous xanthoma mimicking a falcine meningioma. PMID- 28084277 TI - Treatment challenges in neurogenic stress cardiomyopathy following aneurysmal subarachnoid hemorrhage. PMID- 28084278 TI - Unilateral moyamoya disease with co-existing arteriovenous malformation. PMID- 28084279 TI - A rare association of dysphagia and cervical compressive myelopathy in diffuse idiopathic skeletal hyperostosis. PMID- 28084280 TI - Recurrent meningitis with unusually delayed cerebrospinal fluid leak detected by magnetic resonance cisternography. PMID- 28084281 TI - Extraventricular neurocytoma: An uncommon tumor in a young boy. A review of literature. PMID- 28084282 TI - "Stroke by pencil": A friend turned fiend. PMID- 28084283 TI - Unusual presentation of an intracranial hemangiopericytoma as a cystic intraparenchymal mass lesion closely mimicking a glioma. PMID- 28084284 TI - A case of traumatic C2-3 listhesis without pars fracture: Insights from this possible variant of hangman's fracture. PMID- 28084285 TI - Surgical considerations for intramedullary conus medullaris metastatic tumors with origin from primary lung lesions: A review of the literature. PMID- 28084286 TI - Spinal dysraphism with tripedus: A child with three legs. PMID- 28084287 TI - Intradural sacral mature teratoma associated with a low-lying conus. PMID- 28084288 TI - Incidentally detected bilateral petrous apex cephaloceles: CT and MRI features. PMID- 28084289 TI - Posterior reversible encephalopathy syndrome after high-dose cytarabine in acute myelogenous leukemia. PMID- 28084290 TI - Unilateral lateral rectus cysticercosis presenting as Duane retraction syndrome type IIb. PMID- 28084291 TI - Choroid plexus involvement in Rosai-Dorfman disease. PMID- 28084292 TI - Type 1 neurofibromatosis with intracanalicular rib head dislocation. PMID- 28084293 TI - Early-onset pure absence epilepsy with eyebrow myoclonia. PMID- 28084294 TI - Traumatic retropharyngeal pseudomeningocele following C5-C6 subluxation. PMID- 28084295 TI - "Going home the same day" - Is day care neurosurgery a measure of surgical skill and technical advancement? PMID- 28084296 TI - Author's Reply: Resurgence of day care surgery in Neurosurgery. PMID- 28084297 TI - Concern and utilization of smart phone based telemedical health-care in allied neurological speciality: Real health-care model of future India. PMID- 28084298 TI - Author's Reply: Smartphone-based telemedical healthcare: The HP telestroke model. PMID- 28084300 TI - Facile synthesis, microstructure and photophysical properties of core-shell nanostructured (SiCN)/BN nanocomposites. AB - Increasing structural complexity at nanoscale can permit superior control over photophysical properties in the precursor-derived semiconductors. We demonstrate here the synthesis of silicon carbonitride (SiCN)/boron nitride (BN) nanocomposites via a polymer precursor route wherein the cobalt polyamine complexes used as the catalyst, exhibiting novel composite structures and photophysical properties. High Resolution Transmission Electron Microscopy (HRTEM) analysis shows that the diameters of SiCN-BN core-shell nanocomposites and BN shells are 50-400 nm and 5-25 nm, respectively. BN nanosheets (BNNSs) are also observed with an average sheet size of 5-15 nm. The photophysical properties of these nanocomposites are characterized using the UV-Vis and photoluminescence (PL) analyses. The as-produced composites have emission behavior including an emission lifetime of 2.5 ns (+/-20 ps) longer observed in BN doped SiCN than that seen for SiC nanoparticles. Our results suggest that the SiCN/BN nanocomposites act as semiconductor displaying superior width photoluminescence at wavelengths spanning the visible to near-infrared (NIR) spectral range (400-700 nm), owing to the heterojunction of the interface between the SiC(N) nanowire core and the BN nanosheet shell. PMID- 28084299 TI - Contractile forces at tricellular contacts modulate epithelial organization and monolayer integrity. AB - Monolayered epithelia are composed of tight cell assemblies that ensure polarized exchanges. EpCAM, an unconventional epithelial-specific cell adhesion molecule, is assumed to modulate epithelial morphogenesis in animal models, but little is known regarding its cellular functions. Inspired by the characterization of cellular defects in a rare EpCAM-related human intestinal disease, we find that the absence of EpCAM in enterocytes results in an aberrant apical domain. In the course of this pathological state, apical translocation towards tricellular contacts (TCs) occurs with striking tight junction belt displacement. These unusual cell organization and intestinal tissue defects are driven by the loss of actomyosin network homoeostasis and contractile activity clustering at TCs, yet is reversed by myosin-II inhibitor treatment. This study reveals that adequate distribution of cortical tension is crucial for individual cell organization, but also for epithelial monolayer maintenance. Our data suggest that EpCAM modulation protects against epithelial dysplasia and stabilizes human tissue architecture. PMID- 28084301 TI - Glutamate Water Gates in the Ion Binding Pocket of Na+ Bound Na+, K+-ATPase. AB - The dynamically changing protonation states of the six acidic amino acid residues in the ion binding pocket of the Na+, K+ -ATPase (NKA) during the ion transport cycle are proposed to drive ion binding, release and possibly determine Na+ or K+ selectivity. We use molecular dynamics (MD) and density functional theory (DFT) simulations to determine the protonation scheme of the Na+ bound conformation of NKA. MD simulations of all possible protonation schemes show that the bound Na+ ions are most stably bound when three or four protons reside in the binding sites, and that Glu954 in site III is always protonated. Glutamic acid residues in the three binding sites act as water gates, and their deprotonation triggers water entry to the binding sites. From DFT calculations of Na+ binding energies, we conclude that three protons in the binding site are needed to effectively bind Na+ from water and four are needed to release them in the next step. Protonation of Asp926 in site III will induce Na+ release, and Glu327, Glu954 and Glu779 are all likely to be protonated in the Na+ bound occluded conformation. Our data provides key insights into the role of protons in the Na+ binding and release mechanism of NKA. PMID- 28084302 TI - K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression. AB - T-cell proliferation is regulated by ubiquitination but the underlying molecular mechanism remains obscure. Here we report that Lys-48-linked ubiquitination of the transcription factor KLF4 mediated by the E3 ligase Mule promotes T-cell entry into S phase. Mule is elevated in T cells upon TCR engagement, and Mule deficiency in T cells blocks proliferation because KLF4 accumulates and drives upregulation of its transcriptional targets E2F2 and the cyclin-dependent kinase inhibitors p21 and p27. T-cell-specific Mule knockout (TMKO) mice develop exacerbated experimental autoimmune encephalomyelitis (EAE), show impaired generation of antigen-specific CD8+ T cells with reduced cytokine production, and fail to clear LCMV infections. Thus, Mule-mediated ubiquitination of the novel substrate KLF4 regulates T-cell proliferation, autoimmunity and antiviral immune responses in vivo. PMID- 28084304 TI - Significantly improved photovoltaic performance in polymer bulk heterojunction solar cells with graphene oxide /PEDOT:PSS double decked hole transport layer. AB - This work demonstrates the high performance graphene oxide (GO)/PEDOT:PSS doubled decked hole transport layer (HTL) in the PCDTBT:PC71BM based bulk heterojunction organic photovoltaic device. The devices were tested on merits of their power conversion efficiency (PCE), reproducibility, stability and further compared with the devices with individual GO or PEDOT:PSS HTLs. Solar cells employing GO/PEDOT:PSS HTL yielded a PCE of 4.28% as compared to either of individual GO or PEDOT:PSS HTLs where they demonstrated PCEs of 2.77 and 3.57%, respectively. In case of single GO HTL, an inhomogeneous coating of ITO caused the poor performance whereas PEDOT:PSS is known to be hygroscopic and acidic which upon direct contact with ITO reduced the device performance. The improvement in the photovoltaic performance is mainly ascribed to the increased charge carriers mobility, short circuit current, open circuit voltage, fill factor, and decreased series resistance. The well matched work function of GO and PEDOT:PSS is likely to facilitate the charge transportation and an overall reduction in the series resistance. Moreover, GO could effectively block the electrons due to its large band-gap of ~3.6 eV, leading to an increased shunt resistance. In addition, we also observed the improvement in the reproducibility and stability. PMID- 28084303 TI - Soluble Uric Acid Activates the NLRP3 Inflammasome. AB - Uric acid is a damage-associated molecular pattern (DAMP), released from ischemic tissues and dying cells which, when crystalized, is able to activate the NLRP3 inflammasome. Soluble uric acid (sUA) is found in high concentrations in the serum of great apes, and even higher in some diseases, before the appearance of crystals. In the present study, we sought to investigate whether uric acid, in the soluble form, could also activate the NLRP3 inflammasome and induce the production of IL-1beta. We monitored ROS, mitochondrial area and respiratory parameters from macrophages following sUA stimulus. We observed that sUA is released in a hypoxic environment and is able to induce IL-1beta release. This process is followed by production of mitochondrial ROS, ASC speck formation and caspase-1 activation. Nlrp3-/- macrophages presented a protected redox state, increased maximum and reserve oxygen consumption ratio (OCR) and higher VDAC protein levels when compared to WT and Myd88-/- cells. Using a disease model characterized by increased sUA levels, we observed a correlation between sUA, inflammasome activation and fibrosis. These findings suggest sUA activates the NLRP3 inflammasome. We propose that future therapeutic strategies for renal fibrosis should include strategies that block sUA or inhibit its recognition by phagocytes. PMID- 28084306 TI - In vivo response of AZ31 alloy as biliary stents: a 6 months evaluation in rabbits. AB - Mg-based metallic materials have been making continuing progress as vascular stents. However, the research of Mg-based materials as non-vascular stents is still at its primary stage. AZ31 stents hereby were implanted into the common bile duct of rabbits for 6 months. The results revealed an existence of 93.82 +/- 1.36% and 30.89 +/- 2.46% of the original volume after 1 and 3 month, respectively. Whole blood tests indicated an inflammation decreasing to normal level after 3 month implantation. A benign host response was observed via H&E staining. Nonuniform corrosion at the two ends of the stents was observed and considered the results of flow or local inflammation. Moreover, the application of Mg-based materials for different stenting treatment were reviewed and compared. Esophagus was hypothesized most destructive, whilst blood vessel and bile duct considered similar and less destructive. Trachea and nasal cavity were thought to be mildest. PMID- 28084305 TI - Very Early Colorectal Anastomotic Leakage within 5 Post-operative Days: a More Severe Subtype Needs Relaparatomy. AB - Early anastomotic leakage (AL), usually defined as leakage within 30 post operative days, represents a severe entity. However, mounting evidence has indicated that majorities of leakage occur within one week after surgery, making late AL rarity. Here we analyzed 101 consecutive colorectal AL, all of which occurred within 30 post-operative days, during Jan 2013 and Dec 2015 in cancer hospital of Fudan University. AL occurring within 5 post-operative days was defined as very early AL (vE-AL). We evaluated risk factors of vE-AL compared with non-vEAL and correlated with post-leakage peritonitis and need of relaparatomy. We found that AL occurred at median time of 7 days after surgery. 23 cases were vE-AL. Reconstruction of post-peritoneum for mid-low rectal carcinoma significantly reduced incidence of vE-AL compared with non-vE-AL (p = 0.042). Patients with vE-AL was associated with presence of peritonitis (p = 0.031), the latter significantly correlated with increased re-operation rate (p = 6.8E-13). Besides, patients with vE-AL trended to correlate with increased re operation rate after leakage (p = 0.088). In concludsion, vE-AL occurring within 5 post-operative days represents a severe subtype associated with general peritonitis and need of relaparatomy. PMID- 28084307 TI - Regulation of sleep plasticity by a thermo-sensitive circuit in Drosophila. AB - Sleep is a highly conserved and essential behaviour in many species, including the fruit fly Drosophila melanogaster. In the wild, sensory signalling encoding environmental information must be integrated with sleep drive to ensure that sleep is not initiated during detrimental conditions. However, the molecular and circuit mechanisms by which sleep timing is modulated by the environment are unclear. Here we introduce a novel behavioural paradigm to study this issue. We show that in male fruit flies, onset of the daytime siesta is delayed by ambient temperatures above 29 degrees C. We term this effect Prolonged Morning Wakefulness (PMW). We show that signalling through the TrpA1 thermo-sensor is required for PMW, and that TrpA1 specifically impacts siesta onset, but not night sleep onset, in response to elevated temperatures. We identify two critical TrpA1 expressing circuits and show that both contact DN1p clock neurons, the output of which is also required for PMW. Finally, we identify the circadian blue-light photoreceptor CRYPTOCHROME as a molecular regulator of PMW, and propose a model in which the Drosophila nervous system integrates information encoding temperature, light, and time to dynamically control when sleep is initiated. Our results provide a platform to investigate how environmental inputs co-ordinately regulate sleep plasticity. PMID- 28084308 TI - Hole Transport in A-form DNA/RNA Hybrid Duplexes. AB - DNA/RNA hybrid duplexes are prevalent in many cellular functions and are an attractive target form for electrochemical biosensing and electric nanodevice. However the electronic conductivities of DNA/RNA hybrid duplex remain relatively unexplored and limited further technological applications. Here cyclopropyl modified deoxyribose- and ribose-adenosines were developed to explore hole transport (HT) in both DNA duplex and DNA/RNA hybrids by probing the transient hole occupancies on adenine tracts. HT yields through both B-form and A-form double helixes displayed similar shallow distance dependence, although the HT yields of DNA/RNA hybrid duplexes were lower than those of DNA duplexes. The lack of oscillatory periods and direction dependence in HT through both helixes implied efficient hole propagation can be achieved via the hole delocalization and coherent HT over adenine tracts, regardless of the structural variations. PMID- 28084309 TI - A label-retaining but unipotent cell population resides in biliary compartment of mammalian liver. AB - Cells with slow proliferation kinetics that retain the nuclear label over long time periods-the label-retaining cells (LRCs)-represent multipotent stem cells in a number of adult tissues. Since the identity of liver LRCs (LLRCs) had remained elusive we utilized a genetic approach to reveal LLRCs in normal non-injured livers and characterized their regenerative properties in vivo and in culture. We found that LLRCs were located in biliary vessels and participated in the regeneration of biliary but not hepatocyte injury. In culture experiments the sorted LLRCs displayed an enhanced self-renewal capacity but a unipotent biliary differentiation potential. Transcriptome analysis revealed a unique set of tumorigenesis- and nervous system-related genes upregulated in LLRCs when compared to non-LRC cholangiocytes. We conclude that the LLRCs established during the normal morphogenesis of the liver do not represent a multipotent primitive somatic stem cell population but act as unipotent biliary progenitor cells. PMID- 28084310 TI - Continental drift and plateau uplift control origination and evolution of Asian and Australian monsoons. AB - Evolutions of Asian and Australian monsoons have important significance for understanding the past global change but are still a controversial subject. Here, we explore systematically the effects of plate movement and plateau uplift on the formation and evolution of the Asian and Australian monsoons by numerical simulations based on land-sea distributions and topographic conditions for five typical geological periods during the Cenozoic. Our results suggest that the timings and causes of formation of the monsoons in South Asia, East Asia and northern Australia are different. The Indian Subcontinent, which was located in the tropical Southern Hemisphere in the Paleocene, was influenced by the austral monsoon system simulated at that time. Once it moved to the tropical Northern Hemisphere in the Eocene, the South Asian monsoon established and remained persistently thereafter. However, the monsoons of East Asia and northern Australia did not appear until the Miocene. The establishment of the simulated low-latitude South Asian (northern Australian) monsoon appeared to have strongly depended on the location of mainland India (Australia), associated with northward plate motion, without much relation to the plateau uplift. On the contrary, the establishment of the mid-latitude East Asian monsoon was mainly controlled by the uplift of Tibetan plateau. PMID- 28084311 TI - A Case-control Study on Risk Factors for Severe Hand, Foot and Mouth Disease. AB - The objective of this study was to identify potential risk factors for severe hand, foot and mouth disease (HFMD). In this case-control study, 459 severe HFMD patients and 246 mild HFMD patients from Guangdong province and Henan province, China were included. Data comprising demographic characteristics, clinical symptoms and signs, laboratory findings and other factors were collected. Univariate analysis revealed 30 factors associated with severe cases. Further multivariate analysis indicated four independent risk factors: fatigue (p < 0.01, odd ratio [OR] = 204.7), the use of glucocorticoids (p = 0.03, OR = 10.44), the use of dehydrant drugs (p < 0.01, OR = 73.7) and maculopapular rash (p < 0.01, OR = 84.4); and one independent protective factor: herpes or ulcers in mouth (p = 0.01, OR = 0.02). However, more systematic research and validation are needed to understand the underlying risk factors for severe HFMD. PMID- 28084313 TI - Substrate-dependent electronic structure and film formation of MAPbI3 perovskites. AB - We present investigations on the interface formation between the hybrid perovskite MAPbI3 and various substrates, covering a wide range of work functions. The perovskite films are incrementally evaporated in situ while the electronic structure is evaluated using photoelectron spectroscopy. Our results show that there is an induction period in the growth of the perovskite during which volatile compounds are formed, catalyzed by the substrate. The duration of the induction period depends strongly on the nature of the substrate material, and it can take up to 20-30 nm of formal precursor deposition before the surface is passivated and the perovskite film starts forming. The stoichiometry of the 2 3 nm thin passivation layer deviates from the expected perovskite stoichiometry, being rich in decomposition products of the organic cation. During the regular growth of the perovskite, our measurements show a deviation from the commonly assumed flat band condition, i.e., dipole formation and band bending dominate the interface. Overall, the nature of the substrate not only changes the energetic alignment of the perovskite, it can introduce gap states and influence the film formation and morphology. The possible impact on device performance is discussed. PMID- 28084312 TI - Perturbed CD8+ T cell TIGIT/CD226/PVR axis despite early initiation of antiretroviral treatment in HIV infected individuals. AB - HIV-specific CD8+ T cells demonstrate an exhausted phenotype associated with increased expression of inhibitory receptors, decreased functional capacity, and a skewed transcriptional profile, which are only partially restored by antiretroviral treatment (ART). Expression levels of the inhibitory receptor, T cell immunoglobulin and ITIM domain (TIGIT), the co-stimulatory receptor CD226 and their ligand PVR are altered in viral infections and cancer. However, the extent to which the TIGIT/CD226/PVR-axis is affected by HIV-infection has not been characterized. Here, we report that TIGIT expression increased over time despite early initiation of ART. HIV-specific CD8+ T cells were almost exclusively TIGIT+, had an inverse expression of the transcription factors T-bet and Eomes and co-expressed PD-1, CD160 and 2B4. HIV-specific TIGIThi cells were negatively correlated with polyfunctionality and displayed a diminished expression of CD226. Furthermore, expression of PVR was increased on CD4+ T cells, especially T follicular helper (Tfh) cells, in HIV-infected lymph nodes. These results depict a skewing of the TIGIT/CD226 axis from CD226 co-stimulation towards TIGIT-mediated inhibition of CD8+ T cells, despite early ART. These findings highlight the importance of the TIGIT/CD226/PVR axis as an immune checkpoint barrier that could hinder future "cure" strategies requiring potent HIV-specific CD8+ T cells. PMID- 28084314 TI - Topological frustration of artificial spin ice. AB - Frustrated systems, typically characterized by competing interactions that cannot all be simultaneously satisfied, display rich behaviours not found elsewhere in nature. Artificial spin ice takes a materials-by-design approach to studying frustration, where lithographically patterned bar magnets mimic the frustrated interactions in real materials but are also amenable to direct characterization. Here, we introduce controlled topological defects into square artificial spin ice lattices in the form of lattice edge dislocations and directly observe the resulting spin configurations. We find the presence of a topological defect produces extended frustration within the system caused by a domain wall with indeterminate configuration. Away from the dislocation, the magnets are locally unfrustrated, but frustration of the lattice persists due to its topology. Our results demonstrate the non-trivial nature of topological defects in a new context, with implications for many real systems in which a typical density of dislocations could fully frustrate a canonically unfrustrated system. PMID- 28084315 TI - A minimal length rigid helical peptide motif allows rational design of modular surfactants. AB - Extensive work has been invested in the design of bio-inspired peptide emulsifiers. Yet, none of the formulated surfactants were based on the utilization of the robust conformation and self-assembly tendencies presented by the hydrophobins, which exhibited highest surface activity among all known proteins. Here we show that a minimalist design scheme could be employed to fabricate rigid helical peptides to mimic the rigid conformation and the helical amphipathic organization. These designer building blocks, containing natural non coded alpha-aminoisobutyric acid (Aib), form superhelical assemblies as confirmed by crystallography and microscopy. The peptide sequence is amenable to structural modularity and provides the highest stable emulsions reported so far for peptide and protein emulsifiers. Moreover, we establish the ability of short peptides to perform the dual functions of emulsifiers and thickeners, a feature that typically requires synergistic effects of surfactants and polysaccharides. This work provides a different paradigm for the molecular engineering of bioemulsifiers. PMID- 28084316 TI - TNFalpha drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling. AB - Heterozygous germ-line mutations in the bone morphogenetic protein type-II receptor (BMPR-II) gene underlie heritable pulmonary arterial hypertension (HPAH). Although inflammation promotes PAH, the mechanisms by which inflammation and BMPR-II dysfunction conspire to cause disease remain unknown. Here we identify that tumour necrosis factor-alpha (TNFalpha) selectively reduces BMPR-II transcription and mediates post-translational BMPR-II cleavage via the sheddases, ADAM10 and ADAM17 in pulmonary artery smooth muscle cells (PASMCs). TNFalpha mediated suppression of BMPR-II subverts BMP signalling, leading to BMP6-mediated PASMC proliferation via preferential activation of an ALK2/ACTR-IIA signalling axis. Furthermore, TNFalpha, via SRC family kinases, increases pro-proliferative NOTCH2 signalling in HPAH PASMCs with reduced BMPR-II expression. We confirm this signalling switch in rodent models of PAH and demonstrate that anti-TNFalpha immunotherapy reverses disease progression, restoring normal BMP/NOTCH signalling. Collectively, these findings identify mechanisms by which BMP and TNFalpha signalling contribute to disease, and suggest a tractable approach for therapeutic intervention in PAH. PMID- 28084317 TI - Therapeutic vaccination based on side population cells transduced by the granulocyte-macrophage colony-stimulating factor gene elicits potent antitumor immunity. AB - Among cancer immunotherapies, granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced tumor cell vaccine (GVAX) therapies appear promising and have been shown to be safe and effective in multiple clinical trials. However, the antitumor efficacies of GVAX therapy alone are in some cases limited. Here we showed that GVAX therapy targeting cancer stem cells (CSCs) substantially suppressed tumor development in syngeneic immunocompetent mice recapitulating normal immune systems. CSCs were isolated as side population (SP) cells from 4T1 murine breast carcinoma cell line and transduced with GM-CSF gene delivered by non-transmissible Sendai virus (4T1-SP/GM). Impaired tumorigenicity of subcutaneously injected 4T1-SP/GM depended on CD8+ T cells in concert with CD4+ T cells and natural killer cells. Mice therapeutically vaccinated with irradiated 4T1-SP/GM cells had markedly suppressed tumor development of subcutaneously transplanted 4T1-SP cells compared with those treated with irradiated cells of non-transduced 4T1-SP cells or non-SP (4T1-NSP/GM) cells. Tumor suppression was accompanied by the robust accumulation of mature dendritic cells at vaccination sites and T-helper type 1-skewed systemic cellular immunity. Our results suggested that CSC cell-based GVAX immunotherapy might be clinically useful for inducing potent tumor-specific antitumor immunity. PMID- 28084318 TI - Apoptosis-inducing and antiproliferative effect by inhibition of miR-182-5p through the regulation of CASP9 expression in human breast cancer. AB - Recent advances in molecular medicine and gene therapy have offered new effective achievements in the treatment of cancers. One of the molecular research lines for the diagnosis and treatment of cancer is the use of microRNAs (miRNAs), which are single-stranded noncoding RNAs. miRNAs are involved in the post-transcriptional regulation of gene expression and have a role in the growth, differentiation, cell death and cancer development. One of the miRNAs that showed upregulation in breast cancer is miR-182-5p. Oncogenic features of miR-182-5p in some cancers were confirmed. In the present study, blockage of miR-182-5p was performed in human breast cancer cell line (MCF-7) using locked nucleic acid (LNA)-anti-miR. MTT (3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay and annexin/propidium iodide staining at different time points after LNA-anti-miR-182 5p transfection were accomplished. Our results showed that miR-182-5p inhibition can reduce the viability of MCF-7 cells because of apoptosis induction, probably through the upregulation of CASP9. A western blot analysis revealed that the expression of CASP9 protein is associated with miR-182-5p inhibition. The CASP9 protein acts as an initiator caspase of apoptosis in the mitochondrial cell death pathway. Our results can be used in translational medicine for future investigation in breast cancer and approach treatment based on antisense therapy. PMID- 28084319 TI - Tumor-associated immune factors are associated with recurrence and metastasis in non-small cell lung cancer. AB - Dynamic interaction between tumor cells and the microenvironment is critical for tumorigenesis, and cancer immunosurveillance plays an important role in the tumor evolution. In some tumors (such as esophageal cancer, pancreatic cancer and colorectal cancer), studies have shown that the number of tumor-infiltrating lymphocytes (TILs) has a significant relationship with the prognosis, but there is little research on the prognosis of TILs and non-small cell lung cancer (NSCLC) has been performed. Therefore, it is necessary to discover the relationship between the TILs and cytokines with NSCLC prognosis and metastasis in patients. Tumor samples were carefully examined for tissue preservation and complete follow-up. A total of 107 tumor samples from NSCLC patients with radical surgical resection were enrolled for the analysis. All samples were subjected to immunohistochemistry for detection of CD3, CD4, CD8, CD28, forkhead box protein P3 (Foxp3), cytotoxic T lymphocyte-associated protein-4, cyclooxygenase2 (COX-2), transforming growth factor beta 1, interleukin-2 (IL-2), interleukin-6, interleukin-10, interleukin-12 receptor and hypoxia inducible factor 1a (HIF-1a). The number, function and location of the targets were analyzed to determine their correlation with disease-free survival (DFS) and overall survival (OS). Immunhistochemical results from 107 samples indicated that the FoxP3+ regulatory TIL (HR=1.336, P=0.031), IL-2 (HR=0.595, P=0.007) and HIF-1a (HR=1.510, P=0.002) levels in tumor cells closely correlated with DFS in a COX analysis model. FoxP3+ regulatory TILs (HR=1.566, P=0.002) significantly correlated with OS and tumor node metastasis staging. The patients were divided into two groups due to the coexpression pattern of the IL-2, FoxP3+ and HIF-1a. The high-risk group had an overall worse survival than those at low risk. We confirmed that Foxp3 expression in lymphocyte and IL-2 expression in tumor cells were associated with recurrence or transfer. Furthermore, we also observed that HIF-1a expression significantly correlated with DFS and OS. PMID- 28084323 TI - Movement disorders in 2016: Progress in Parkinson disease and other movement disorders. PMID- 28084321 TI - Soluble ectodomain CD163 and extracellular vesicle-associated CD163 are two differently regulated forms of 'soluble CD163' in plasma. AB - CD163 is the macrophage receptor for uptake of hemoglobin-haptoglobin complexes. The human receptor can be shed from the macrophage surface owing to a cleavage site for the inflammation-inducible TACE/ADAM17 enzyme. Accordingly, plasma 'soluble CD163' (sCD163) has become a biomarker for macrophage activity and inflammation. The present study disclosed that 10% of sCD163 in healthy persons is actually extracellular vesicle (EV)-associated CD163 not being cleaved and shed. Endotoxin injection of human volunteers caused a selective increase in the ectodomain CD163, while septic patients exhibited high levels of both soluble ectodomain CD163 and extracellular vesicle (EV) CD163, the latter representing up 60% of total plasma CD163. A poor prognosis of septic patients measured as the sequential organ failure assessment (SOFA) score correlated with the increase in membrane-associated CD163. Our results show that soluble ectodomain CD163 and EV CD163 in plasma are part of separate macrophage response in the context of systemic inflammation. While that soluble ectodomain CD163 is released during the acute systemic inflammatory response, this is not the case for EV CD163 that instead may be released during a later phase of the inflammatory response. A separate measurement of the two forms of CD163 constituting 'soluble CD163' in plasma may therefore add to the diagnostic and prognostic value. PMID- 28084322 TI - Temperature shapes coral-algal symbiosis in the South China Sea. AB - With the increase in sea surface temperature (SST), scleractinian corals are exposed to bleaching threats but may possess certain flexibilities in terms of their associations with symbiotic algae. Previous studies have shown a close symbiosis between coral the and Symbiodinium; however, the spatial variation of the symbiosis and the attribution underlying are not well understood. In the present study, we examined coral-algal symbiosis in Galaxea fascicularis and Montipora spp. from three biogeographic regions across ~10 degrees of latitude in the South China Sea. Analysis of similarities (ANOSIM) indicated a highly flexible coral-algal symbiosis in both G. fascicularis and Montipora spp. and canonical correspondence analysis (CCA) showed that temperature explained 83.2% and 60.1% of the explanatory subclade variations in G. fascicularis and Montipora spp., respectively, which suggested that temperature was the main environmental factor contributing to the diversity of Symbiodinium across the three regions. The geographic specificity of the Symbiodinium phylogeny was identified, revealing possible environmental selection across the three regions. These results suggest that scleractinian corals may have the ability to regulate Symbiodinium community structures under different temperatures and thus be able to adapt to gradual climate change. PMID- 28084320 TI - Structural basis for the recognition and degradation of host TRIM proteins by Salmonella effector SopA. AB - The hallmark of Salmonella Typhimurium infection is an acute intestinal inflammatory response, which is mediated through the action of secreted bacterial effector proteins. The pro-inflammatory Salmonella effector SopA is a HECT-like E3 ligase, which was previously proposed to activate host RING ligases TRIM56 and TRIM65. Here we elucidate an inhibitory mechanism of TRIM56 and TRIM65 targeting by SopA. We present the crystal structure of SopA in complex with the RING domain of human TRIM56, revealing the atomic details of their interaction and the basis for SopA selectivity towards TRIM56 and TRIM65. Structure-guided biochemical analysis shows that SopA inhibits TRIM56 E3 ligase activity by occluding the E2 interacting surface of TRIM56. We further demonstrate that SopA ubiquitinates TRIM56 and TRIM65, resulting in their proteasomal degradation during infection. Our results provide the basis for how a bacterial HECT ligase blocks host RING ligases and exemplifies the multivalent power of bacterial effectors during infection. PMID- 28084324 TI - CNS Infections in 2016: 2016, the year of Zika virus. PMID- 28084325 TI - Alzheimer disease: Soluble TREM2 in CSF sheds light on microglial activation in AD. PMID- 28084326 TI - Alzheimer disease in 2016: Putting AD treatments and biomarkers to the test. PMID- 28084328 TI - Painting a specific chromosome with CRISPR/Cas9 for live-cell imaging. PMID- 28084327 TI - Treatment decisions in multiple sclerosis - insights from real-world observational studies. AB - The complexity of multiple sclerosis (MS) treatment means that doctors and decision-makers need the best available evidence to make the best decisions for patient care. Randomized controlled trials (RCTs) are accepted as the gold standard for assessing the efficacy and safety of any new drug, but conclusions of these trials do not always aid in daily decision-making processes. Indeed, RCTs are usually conducted in ideal conditions, so can measure efficacy only in restricted and unrepresentative populations. In the past decade, a growing number of MS databases and registries have started to produce long-term outcome data from large cohorts of patients with MS treated with disease-modifying therapies in real-world settings. Such observational studies are addressing issues that are otherwise difficult or impossible to study. In this Review, we focus on the most recently published observational studies designed to identify predictors of poor outcome and treatment response or failure, and to evaluate the relative and long term effectiveness of currently used MS treatments. We also outline the statistical approaches that are most commonly used to reduce bias and limitations in these studies, and the challenges associated with the use of 'big MS data' to facilitate the implementation of personalized medicine in MS. PMID- 28084330 TI - CRISPR control of virulence in Pseudomonas aeruginosa. AB - Clustered regularly interspaced short palindromic repeats (CRISPR) and their associated genes (cas) are essential components of an adaptive immune system that protects bacteria and archaea from viral infection. Now a recent paper published in Cell Research suggests that the Type I-F immune system in Pseudomonas aeruginosa may also be involved in post-transcriptional regulation of virulence. PMID- 28084329 TI - SPSB1-mediated HnRNP A1 ubiquitylation regulates alternative splicing and cell migration in EGF signaling. AB - Extracellular signals have been shown to impact on alternative pre-mRNA splicing; however, the molecular mechanisms and biological significance of signal-induced splicing regulation remain largely unknown. Here, we report that epidermal growth factor (EGF) induces splicing changes through ubiquitylation of a well-known splicing regulator, hnRNP A1. EGF signaling upregulates an E3 ubiquitin (Ub) ligase adaptor, SPRY domain-containing SOCS box protein 1 (SPSB1), which recruits Elongin B/C-Cullin complexes to conjugate lysine 29-linked polyUb chains onto hnRNP A1. Importantly, SPSB1 and ubiquitylation of hnRNP A1 have a critical role in EGF-driven cell migration. Mechanistically, EGF-induced ubiquitylation of hnRNP A1 together with the activation of SR protein kinases (SRPKs) results in the upregulation of a Rac1 splicing isoform, Rac1b, to promote cell motility. These findings unravel a novel crosstalk between protein ubiquitylation and alternative splicing in EGF/EGF receptor signaling, and identify a new EGF/SPSB1/hnRNP A1/Rac1 axis in modulating cell migration, which may have important implications for cancer treatment. PMID- 28084331 TI - Cryo-EM structure of Nma111p, a unique HtrA protease composed of two protease domains and four PDZ domains. PMID- 28084332 TI - Macrophagic CD146 promotes foam cell formation and retention during atherosclerosis. AB - The persistence of cholesterol-engorged macrophages (foam cells) in the artery wall fuels the development of atherosclerosis. However, the mechanism that regulates the formation of macrophage foam cells and impedes their emigration out of inflamed plaques is still elusive. Here, we report that adhesion receptor CD146 controls the formation of macrophage foam cells and their retention within the plaque during atherosclerosis exacerbation. CD146 is expressed on the macrophages in human and mouse atheroma and can be upregulated by oxidized low density lipoprotein (oxLDL). CD146 triggers macrophage activation by driving the internalization of scavenger receptor CD36 during lipid uptake. In response to oxLDL, macrophages show reduced migratory capacity toward chemokines CCL19 and CCL21; this capacity can be restored by blocking CD146. Genetic deletion of macrophagic CD146 or targeting of CD146 with an antibody result in much less complex plaques in high-fat diet-fed ApoE-/- mice by causing lipid-loaded macrophages to leave plaques. Collectively, our findings identify CD146 as a novel retention signal that traps macrophages within the artery wall, and a promising therapeutic target in atherosclerosis treatment. PMID- 28084333 TI - Male breast cancer precursor lesions: analysis of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program. AB - In men, data regarding breast cancer carcinogenesis are limited. The aim of our study was to describe the presence of precursor lesions adjacent to invasive male breast cancer, in order to increase our understanding of carcinogenesis in these patients. Central pathology review was performed for 1328 male breast cancer patients, registered in the retrospective joint analysis of the International Male Breast Cancer Program, which included the presence and type of breast cancer precursor lesions. In a subset, invasive breast cancer was compared with the adjacent precursor lesion by immunohistochemistry (n=83) or targeted next generation sequencing (n=7). Additionally, we correlated the presence of ductal carcinoma in situ with outcome. A substantial proportion (46.2%) of patients with invasive breast cancer also had an adjacent precursor lesion, mainly ductal carcinoma in situ (97.9%). The presence of lobular carcinoma in situ and columnar cell-like lesions were very low (<1%). In the subset of invasive breast cancer cases with adjacent ductal carcinoma in situ (n=83), a complete concordance was observed between the estrogen receptor, progesterone receptor, and HER2 status of both components. Next generation sequencing on a subset of cases with invasive breast cancer and adjacent ductal carcinoma in situ (n=4) showed identical genomic aberrations, including PIK3CA, GATA3, TP53, and MAP2K4 mutations. Next generation sequencing on a subset of cases with invasive breast cancer and an adjacent columnar cell-like lesion showed genomic concordance in two out of three patients. A multivariate Cox model for survival showed a trend that the presence of ductal carcinoma in situ was associated with a better overall survival, in particular in the Luminal B HER2+ subgroup. In conclusion, ductal carcinoma in situ is the most commonly observed precursor lesion in male breast cancer and its presence seems to be associated with a better outcome, in particular in Luminal B HER2+ cases. The rate of lobular carcinoma in situ and columnar cell-like lesions adjacent to male breast cancer is very low, but our findings support the role of columnar cell-like lesions as a precursor of male breast cancer. PMID- 28084334 TI - Langerhans cell histiocytosis associated with lymphoma: an incidental finding that is not associated with BRAF or MAP2K1 mutations. AB - Langerhans cell histiocytosis is characterized by a localized or systemic proliferation of Langerhans cells. BRAF mutations have been reported in 40-70% of cases and MAP2K1 mutations have been found in BRAF-negative cases, supporting that Langerhans cell histiocytosis is a true neoplasm, at least in mutated cases. In a small subset of patients, Langerhans cell histiocytosis is detected incidentally in a biopsy involved by lymphoma. These lesions are usually minute and rarely have been assessed for mutations. We assessed for BRAF and MAP2K1 mutations in seven cases of Langerhans cell histiocytosis detected incidentally in biopsies involved by lymphoma. We performed immunohistochemical analysis for phosphorylated (p)-ERK. There were four men and three women (median age, 54 years; range, 28-84). The biopsies included lymph nodes (n=6) and chest wall (n=1). The lymphomas included five classical Hodgkin lymphoma, one mantle cell lymphoma, and one angioimmunoblastic T-cell lymphoma. All cases were negative for BRAF V600E and MAP2K1 mutations. Nevertheless, three of seven cases showed ERK activation as shown by expression of p-ERK. We performed mutation analysis using a panel of 134 commonly mutated genes (including BRAF and MAP2K1) by next generation sequencing on three cases, including two cases positive for p-ERK by immunohistochemistry. No mutations were detected in any of the three cases assessed. Six patients received therapy appropriate for their lymphoma. With a median follow-up of 21 months (range, 6-89), no patients developed disseminated or recurrent Langerhans cell histiocytosis. We conclude that lymphoma-associated Langerhans cell histiocytosis is a clinically benign process that is not associated with BRAF V600E or MAP2K1 mutations and, as suggested by others, the designation Langerhans cell hyperplasia may be more appropriate. Nevertheless, the expression of p-ERK in three cases suggests that the RAS-RAF-MAP2K-ERK pathway is activated, perhaps by non-mutational mechanisms induced by the presence of lymphoma or lymphoma-microenvironment interactions. PMID- 28084335 TI - HHV8-related lymphoid proliferations: a broad spectrum of lesions from reactive lymphoid hyperplasia to overt lymphoma. AB - Human herpesvirus 8 (HHV8)-associated lymphoid proliferations are uncommon and poorly characterized disorders mainly affecting immunosuppressed patients, especially with HIV infection. They encompass different diseases with overlapping features that complicate their classification. In addition, the role of HHV8 in reactive lymphoid hyperplasia is not well known. To analyze the clinicopathological spectrum of these lesions, we have reviewed 66 biopsies of 61 patients with HHV8 infection. All cases were also investigated for Epstein-Barr virus (EBV) and HIV infection. We identified 13 (20%) cases of HHV8-related reactive lymphoid hyperplasia, 2 (3%) HHV8 plasmablastic proliferations of the splenic red pulp, 28 (42%) multicentric Castleman disease, 6 (9%) germinotropic lymphoproliferative disorders, and 17 (26%) HHV8-related lymphomas. As expected, the pathologic subtype was predictive of overall survival (P<0.05). Forty-seven of our cases were HIV positive (77%). In addition to the classical presentation of the different entities, we identified novel and overlapping features. Reactive HHV8 proliferations were frequently associated with systemic symptoms but never progressed to overt HHV8-positive lymphoma. Two cases had a plasmablastic proliferation limited to spleen. Eight cases of multicentric Castleman disease had a previously unrecognized presentation shortly after the diagnosis of HIV infection, six cases had cavity effusions, and three showed plasmablast enriched proliferations. One germinotropic lymphoproliferative disorder was EBV negative and three occurred in HIV-positive patients, who had distinctive clinical and morphological features. Two of the HHV8-related lymphomas did not fulfill the criteria for previously recognized entities. All these findings expand the clinical and pathological spectrum of HHV8-related lymphoid proliferations, which is broader than current recognized. PMID- 28084336 TI - Giant cell tumor of soft tissue is genetically distinct from its bone counterpart. AB - Giant cell tumors of bone are locally aggressive bone neoplasms with a predilection for young adults. Histologically, they are composed of histiocytoid to spindled mononuclear cells, admixed with numerous large osteoclastic giant cells. Giant cell tumors of soft tissue are rare tumors that bear striking histological resemblance to giant cell tumors of bone and might be regarded as a soft tissue analog thereof. Point mutations of the H3F3A gene (coding for a histone H3.3 protein) at the Gly34 codon, mostly G34W resulting from a GGG>TGG nucleotide change, have recently been identified in a vast majority of giant cell tumors of bone. To delineate the possible pathogenic linkage between both tumor types, we analyzed the H3F3A genotypes in a series of 15 giant cell tumors of soft tissue by Sanger sequencing and found no mutation in any case. We then sequenced cognate histone H3 genes with an identical nucleotide sequence ('GGG') at the codon Gly34, including the H3F3B, H3F3C, HIST2H3A, HIST2H3C, and HIST2H3D genes, and no somatic mutation was detected. These results reveal that giant cell tumors of soft tissue are probably genetically distinct from their bone counterparts and suggest that they might be pathogenically unrelated. Given the prominence of non-neoplastic cells in these tumors and the limitations of the current study, however, analyses using more sensitive techniques might be required to solve the issue. PMID- 28084337 TI - Tumoral PD-L1 expression in desmoplastic melanoma is associated with depth of invasion, tumor-infiltrating CD8 cytotoxic lymphocytes and the mixed cytomorphological variant. AB - Recently, patients with metastatic desmoplastic melanoma (DM) have been shown to respond more favorably to anti-PD1/PD-L1 therapy than other melanoma subtypes. Given this, we evaluated PD-L1/2 expression in primary DM samples and correlated these with subtype, CD8+ lymphocyte status, histopathological prognosticators, and select genetic alterations. Eighty-six (36 mixed DM, 50 pure DM) archival annotated samples met inclusion criteria and were immunohistochemically semiquantitatively evaluated. Per established criteria, for PD-L1/L2, cases with ?5% tumoral expression, and for CD8, cases with a predominantly peri/intratumoral CD8+ infiltrate were scored positive. Univariate analysis (chi-square and Wilcoxon) identified potential confounders and a nested case-control study was accomplished using multiple logistic regression. For PD-L1, 49% of cases were positive and 71% of cases with thickness >4 mm were positive; PD-L1 expression differed by median depth (3.29 mm, interquartile range=3.58 mm for PD-L1 positives vs 1.75 mm, interquartile range=2.04 mm for PD-L1 negatives, P=0.0002) and was linearly associated with increasing depth of invasion (P=0.0003). PD-L1 positive cases were more likely to display CD8+ lymphocytes (60 vs 28% P=0.0047).The presence of CD8+ lymphocytes correlated significantly with depth of invasion >1 mm (P=0.022). On multivariate analysis, PD-L1 was 6.14 * more likely to be expressed in mixed DM than pure DM (P=0.0131), CD8+ staining was 6.22 * more likely in PD-L1 positive cases than in PD-L1 negative (P=0.0118), and tumor depth was associated with greater odds of PD-L1 expression (OR=1.61, P=0.0181). PD-L2 expression was observed in 48% of cases but did not correlate with any variables. Correlation of tumoral PD-L1 with increased depth and CD8+ lymphocytes implicates the tumoral immune microenvironment with advancing disease in DM. Enhanced tumoral PD-L1 expression in the mixed cytomorphological variant provides an insight into the differential pathogenesis of the subtypes and suggests that these patients are likely better candidates for anti-PD/PD-L1 therapy. PMID- 28084338 TI - P-cadherin: a useful biomarker for axillary-based breast cancer decisions in the clinical practice. AB - Axillary lymph node metastases represent the most powerful breast cancer prognostic factor, dictating disease staging and clinical therapeutic decisions. Nonetheless, breast cancer patients with positive lymph nodes still exhibit a heterogeneous behavior regarding disease progression. Stem-like subpopulations of cancer cells show high migratory and metastatic capacity, thus we hypothesize that breast cancer stem cell markers evaluation in metastasized lymph nodes could provide a more accurate prediction of patient's prognosis. Therefore, the expression profile of P-cadherin, CD44, and CD49f, which have been already associated to stem cell properties in breast cancer, has been evaluated by immunohistochemistry in a series of 135 primary tumors and matched axillary lymph node metastases from 135 breast cancer patients. Taking in consideration the expression of the stem cell markers only in axillary nodes, P-cadherin was the only biomarker significantly associated with poor disease-free and overall patient's survival. Moreover, although a concordant expression between primary tumors and matched lymph nodes has been found in the majority of the cases, a small but significant percentage displayed divergent expression (18.2-26.2%). Remarkably, although CD44 and CD49f changes between primary tumors and lymph node metastasis did not impact survival, the cases that were positive for P-cadherin in lymph node metastases being negative in the primary tumor, presented the worst disease-free and overall survival of the whole series. Accordingly, negative cases for this marker in the lymph nodes with positive expression in the matched breast carcinoma demonstrated a better prognosis, which overlapped with tumors that were negative in both sites. P-cadherin and CD49f gain of expression was mainly found in triple-negative carcinomas. Our results indicate for the first time that the evaluation of P-cadherin expression in lymph node metastases is an important predictor of disease outcome, being a putative valuable marker for axillary-based breast cancer decisions in the clinical practice. PMID- 28084339 TI - Recurrent IDH2 R172X mutations in sinonasal undifferentiated carcinoma. AB - Sinonasal undifferentiated carcinoma is a rare and aggressive malignancy. Sinonasal undifferentiated carcinoma has long been considered a diagnosis of exclusion; to date, the molecular pathogenetic basis for sinonasal undifferentiated carcinoma is unknown. To identify potential oncogenic drivers in sinonasal undifferentiated carcinoma, targeted next-generation sequencing of 300 cancer-related genes was performed on 11 cases of sinonasal undifferentiated carcinoma. We identified IDH2 R172X mutations in 55% of sinonasal undifferentiated carcinomas including R172S, R172T, and R172M. Multispecific mutant IDH1/2 immunohistochemistry was performed and identified mutant-specific protein expression in all cases with available tissue: 3/3 sinonasal undifferentiated carcinomas with R172 mutations were positive and 4/4 wild-type cases were negative. Review of sequencing data for our institutional head and neck cohorts (n=412) confirmed the absence of IDH-activating mutations in other tumor types. Alterations in the IDH2-wild-type sinonasal undifferentiated carcinomas included SMARCA4 loss-of-function with confirmed loss of immunohistochemical expression, NOTCH1 gain-of-function, and TET2 loss-of function. We demonstrate that the majority of histologically defined sinonasal undifferentiated carcinomas are characterized by IDH2 R172X mutations and overexpression of mutant protein. IDH2 R172X mutations are specific to sinonasal undifferentiated carcinoma among carcinomas of the head and neck, confirming this tumor type as a distinct clinicopathologic entity. These findings have significant implications for diagnosis and therapy with IDH inhibitors for patients with this rare and poorly understood tumor. PMID- 28084340 TI - Claudin-4 expression distinguishes SWI/SNF complex-deficient undifferentiated carcinomas from sarcomas. AB - Inactivation of SWI/SNF (switch/sucrose non-fermentable) chromatin remodeling complex subunits is a feature shared by select carcinomas and sarcomas with epithelioid morphology and variable keratin expression, making the distinction between carcinoma and sarcoma challenging in some cases. The tight junction associated protein claudin-4 is a marker of epithelial differentiation that is expressed in nearly all carcinomas. Claudin-4 expression has been reported in the glandular component of biphasic synovial sarcoma but has not been systematically evaluated in other sarcoma types. In this study we assessed claudin-4 expression in SWI/SNF complex-deficient neoplasms showing loss of SMARCB1 (INI1), SMARCA4 (BRG1), or ARID1A and other sarcomas with epithelioid morphology. Immunohistochemistry for claudin-4 was performed on 130 neoplasms, including 90 soft tissue tumors with epithelioid morphology and/or SMARCB1 deficiency (20 epithelioid sarcomas (10 conventional, 10 proximal-type); 10 epithelioid angiosarcomas; 10 epithelioid hemangioendotheliomas; 15 epithelioid malignant peripheral nerve sheath tumors; 10 malignant rhabdoid tumors; 15 myoepithelial carcinomas; 10 biphasic synovial sarcomas), 10 ovarian clear cell carcinomas, 10 ovarian small cell carcinomas of hypercalcemic type, and 20 SWI/SNF complex deficient undifferentiated carcinomas (14 SMARCB1 deficient and 6 SMARCA4 deficient, including rhabdoid carcinomas of various sites and sinonasal carcinomas). Membranous expression of claudin-4 (>=5% of cells) was observed in all biphasic synovial sarcomas (epithelial component only), all ovarian clear cell carcinomas, and 16 (80%) SWI/SNF complex-deficient undifferentiated carcinomas. All other soft tissue tumors were negative for claudin-4, with the exception of two myoepithelial carcinomas and one malignant rhabdoid tumor. Interestingly, none of the ovarian small cell carcinomas of hypercalcemic type expressed claudin-4. In summary, expression of claudin-4 is highly specific for true epithelial differentiation and may be useful to distinguish SWI/SNF complex deficient undifferentiated carcinomas from sarcomas with epithelioid morphology. The lack of claudin-4 expression in ovarian small cell carcinomas of hypercalcemic type suggests that these tumors may be better regarded as sarcomas rather than carcinomas. PMID- 28084341 TI - #InSituPathologists: how the #USCAP2015 meeting went viral on Twitter and founded the social media movement for the United States and Canadian Academy of Pathology. AB - Professional medical conferences over the past five years have seen an enormous increase in the use of Twitter in real-time, also known as "live-tweeting". At the United States and Canadian Academy of Pathology (USCAP) 2015 annual meeting, 24 attendees (the authors) volunteered to participate in a live-tweet group, the #InSituPathologists. This group, along with other attendees, kept the world updated via Twitter about the happenings at the annual meeting. There were 6,524 #USCAP2015 tweets made by 662 individual Twitter users; these generated 5,869,323 unique impressions (potential tweet-views) over a 13-day time span encompassing the dates of the annual meeting. Herein we document the successful implementation of the first official USCAP annual meeting live-tweet group, including the pros/cons of live-tweeting and other experiences of the original #InSituPathologists group members. No prior peer-reviewed publications to our knowledge have described in depth the use of an organized group to "live-tweet" a pathology meeting. We believe our group to be the first of its kind in the field of pathology. PMID- 28084342 TI - Concurrent fine needle aspirations and core needle biopsies: a comparative study of substrates for next-generation sequencing in solid organ malignancies. AB - Minimally invasive procedures, such as fine needle aspiration and core needle biopsy, are commonly used for the diagnosis in solid organ malignancies. In the era of targeted therapy, it is crucial for molecular testing to be performed on these limited volume specimens. Although several recent studies have demonstrated the utility of small biopsy specimens for molecular testing, there remains debate as to whether core needle biopsy specimens are more reliable than fine needle aspiration for molecular studies. In this study, we reviewed concurrently acquired fine needle aspiration and core needle biopsy samples (n=24), and compared overall cellularity, tumor fraction, and the results of next-generation sequencing. All somatic mutations detected in core needle biopsy samples were also detected in fine needle aspiration samples. The estimated tumor fraction was significantly higher in fine needle aspiration smears than core needle biopsy samples (P=0.003), whereas the overall DNA yield from smears was significantly lower than that obtained from the core needle biopsy specimens (P=0.01). The normalized average amplicon coverage for the genes analyzed was significantly higher in cytology smears than paired core needle biopsy samples, with lower numbers of failed amplicons and higher overall mutation allelic frequencies seen in the former. We further evaluated 100 malignant fine needle aspiration and core needle biopsy samples, acquired concurrently, for overall cellularity and tumor fraction. Overall cellularity and tumor fraction of fine needle aspiration samples was significantly higher than concurrently acquired core needle biopsy samples (P<0.001). In conclusion, we show that fine needle aspiration samples frequently provide better cellularity, higher tumor fraction, and superior sequencing metrics than concurrently acquired core needle biopsy samples. Cytologic specimens, therefore, should be better integrated into routine molecular diagnostics workflow to maximize limited tissues for clinically relevant genomic testing. PMID- 28084343 TI - Recurrent GNAQ mutations in anastomosing hemangiomas. AB - Anastomosing hemangiomas are recently described benign vascular lesions that occur chiefly in the genitourinary tract and paravertebral soft tissues. Owing to their rarity and unusual cytoarchitectural features, anastomosing hemangiomas are frequently confused with low-grade angiosarcomas. The specific genetic alterations underlying these lesions are currently unknown. We performed capture based next-generation DNA sequencing analysis on 13 anastomosing hemangiomas and identified frequent somatic mutations in the heterotrimeric G-protein alpha subunit, GNAQ. Nine of 13 cases (69%) harbored a somatic mutation at GNAQ codon 209, a known hotspot that is commonly mutated in uveal melanoma and blue nevi, as well as various congenital vascular proliferations. No other pathogenic or likely pathogenic mutations were identified in these genetically simple lesions. The finding of a recurrent driver mutation in the G-protein signal transduction pathway provides strong evidence that anastomosing hemangiomas are indeed clonal vascular neoplasms. PMID- 28084344 TI - MCM2: An alternative to Ki-67 for measuring breast cancer cell proliferation. AB - Breast cancer is a heterogeneous disease comprising a diversity of tumor subtypes that manifest themselves in a wide variety of clinical, pathological, and molecular features. One important subset, luminal breast cancers, comprises two clinically distinct subtypes luminal A and B each of them endowed with its own genetic program of differentiation and proliferation. Luminal breast cancers were operationally defined as follows: Luminal A: ER+, PR+, HER2-, Ki-67<14% and Luminal B: ER+ and/or PR+, HER2-,Ki-67>=14% or, alternatively ER+ and/or PR+, HER2+, any Ki-67. There is currently a need for a clinically robust and validated immunohistochemical assay that can help distinguish between luminal A and B breast cancer. MCM2 is a family member of the minichromosome maintenance protein complex whose role in DNA replication and cell proliferation is firmly established. As MCM2 appears to be an attractive alternative to Ki-67, we sought to study the expression of MCM2 and Ki-67 in different histological grades and molecular subtypes of breast cancer focusing primarily on ER-positive tumors. MCM2 and Ki-67 mRNA expression were studied using in silico analysis of available DNA microarray and RNA-sequencing data of human breast cancer. We next used immunohistochemistry to evaluate protein expression of MCM2 and Ki-67 on tissue microarrays of invasive breast carcinoma. We found that MCM2 and Ki-67 are highly expressed in breast tumors of high histological grades, comprising clinically aggressive tumors such as triple-negative, HER2-positive and luminal B subtypes. MCM2 expression was detected at higher levels than that of Ki-67 in normal breast tissues and in breast cancers. The bimodal distribution of MCM2 scores in ER+/HER2- breast tumors led to the identification of two distinct subgroups with different relapse-free survival rates. In conclusion, MCM2 expression can help sorting out two clinically important subsets of luminal breast cancer whose treatment and clinical outcomes are likely to diverge. PMID- 28084345 TI - Synaptophysin-Ki67 double stain: a novel technique that improves interobserver agreement in the grading of well-differentiated gastrointestinal neuroendocrine tumors. AB - A common problem in the assessment of Ki67 proliferative index in well differentiated gastrointestinal neuroendocrine tumors is distinguishing tumor from non-tumor. This is because background stromal lymphocytes, entrapped non neoplastic glands, and the delicate vascular network characteristic of neuroendocrine tumors frequently contain a subset of proliferating cells. Furthermore, in small biopsies, crush and cautery artifact can alter the morphologic appearance of tumor cells, making the Ki67 proliferative index more difficult to assess. To address these issues, we developed a synaptophysin-Ki67 double stain using a commercially available immunohistochemistry kit, allowing simultaneous visualization of tumor and proliferating nuclei. To test this method, three gastrointestinal pathologists individually graded 50 gastrointestinal neuroendocrine tumors first using synaptophysin-Ki67 double stained slides and then, after a washout period, using Ki67-only stained slides (along with routine hematoxylin- and eosin-stained slides). Interobserver agreement on Ki67 proliferative index was moderate using the Ki67-only stained slides (intraclass correlation 0.51, 95% confidence interval: 0.35-0.66) and improved using the synaptophysin-Ki67 double stain (intraclass correlation 0.79, 95% confidence interval: 0.69-0.86). Similarly, interobserver agreement on tumor grade was fair with Ki67-only stained slides (kappa=0.39, P<0.001) and improved with the double stain (kappa=0.58, P<0.001). Analysis of individual pathologists' scores revealed that fewer total number of tumor cells counted correlated with higher grade designation and appeared to contribute to grade discordance. In tumors cited as particularly challenging to assess by the pathologists, three of four tumors were grade discordant with the Ki67-only stain, whereas all four tumors were grade concordant with the synaptophysin-Ki67 stain. The synaptophysin Ki67 double stain is the first technique to address specifically the histomorphologic challenges of evaluating Ki67 proliferative index in well differentiated gastrointestinal neuroendocrine tumors. Although further validation is needed, this study provides evidence that the synaptophysin-Ki67 double stain can improve interobserver agreement. PMID- 28084346 TI - Fear of fluoride. AB - Discusses how dental and medical scares have resulted in a "culture of fear" which has damaged patients and dentists. Forty years of pessimism have created a demoralised and risk-averse society. The reality of a steadily improving world demands a new attitude of rational optimism and a healthy scepticism about new scares. PMID- 28084350 TI - Can motivations for studying dentistry inform us about gender and BME differences in dental academic careers? AB - There are various motivators that prompt people to study dentistry but there is evidence that the salience of each varies according to gender and black and minority ethnic (BME) group. Given the current focus on inequality within the science, technology, engineering, medicine and mathematics (STEMM) academic disciplines where dentistry sits, it is important to understand the relevance of different motivators to different social groups if inequality is to be overcome. We carried out a survey of dental students from 11 out of the 18 dental schools in the UK to find out what prompted them to study dentistry. Our findings showed that most people make a personal choice to study dentistry and follow a patient focused career while the prospect of an academic career was important for less than half of our sample. Differences according to gender and BME group were apparent but did not follow these trends. In order to continue to improve the diversity within dental academia dental schools should consider the different preferences of the workforce and work to broaden its potential. PMID- 28084355 TI - Regulation: Bureaucratic behemoth. PMID- 28084356 TI - All about acid. AB - Interarch comparison of intraoral pH and temperature: a pilot study. PMID- 28084352 TI - Gastrointestinal diseases and their oro-dental manifestations: Part 2: Ulcerative colitis. AB - Ulcerative colitis is a rather common inflammatory bowel disease, especially in the industrialised world. A limited number of studies have reported the prevalence of oral signs and symptoms in these patients, and widely varying prevalence rates have been reported ranging from 2 to 34%. Pyostomatitis vegetans is the most pathognomonic oral sign but also other abnormalities as oral ulcerations, caries and periodontitis are more often seen in patients with ulcerative colitis. In this review we describe the oral manifestations of ulcerative colitis and their potential dental implications. PMID- 28084357 TI - The interdisciplinary management of hypodontia patients in the UK: a national service evaluation. AB - Objective To examine the distribution of interdisciplinary clinics for hypodontia patients in the UK and to assess the provision of orthodontic-restorative care for hypodontia patients in units where this service is and is not available.Design Prospective, online-questionnaire.Setting Hospital orthodontic departments in the UK.Participants In total, consultants from 92 orthodontic departments completed the questionnaire.Methods Orthodontic consultants were asked to complete a questionnaire regarding the provision of orthodontic restorative care for hypodontia patients in their units.Results Overall, 100% of teaching hospitals and 51% of district general hospitals (DGHs) that responded have an interdisciplinary clinic for hypodontia patients. In 51% of units, the majority of patients assessed on the interdisciplinary clinic undergo their restorative care at the same secondary care unit. In 59% of units where an interdisciplinary clinic is not available most of the restorative care for hypodontia patients is provided by the GDP, whilst in 38% of units a specialist restorative dentist in another secondary care unit provides most of the restorative care.Conclusions The provision of an interdisciplinary clinic for hypodontia patients varies amongst hospital units throughout the UK. The provision of orthodontic-restorative care for hypodontia patients also varies between these units. PMID- 28084358 TI - Brian Morrison Tweedie. PMID- 28084359 TI - Motivating motivation. AB - Motivational interviewing in general dental practice: A review of the evidence. PMID- 28084361 TI - Athiel Lushington King. PMID- 28084363 TI - The rise and fall of malpractice payments in the US. AB - Trends in US malpractice payments in dentistry compared to other health professions - dentistry payments increase, others fall. PMID- 28084364 TI - Smoking cessation: The role of e-cigarettes. PMID- 28084369 TI - New toolkit lets dentists build on antibiotic prescribing success. PMID- 28084370 TI - Referrals: Apicectomy. PMID- 28084371 TI - Impacted canines. PMID- 28084373 TI - Antimicrobial resistance: Refresh your memory. PMID- 28084374 TI - Agreed; but if...? PMID- 28084376 TI - Empowerment in a model of outreach undergraduate dental education. AB - Aim To undertake a quantitative and qualitative examination into what aspects of the students' experience in outreach at University of Portsmouth Dental Academy (UPDA) are encouraging their empowerment as autonomous practitioners, ready to graduate as 'safe beginners'.Methods The study was devised as part of the educational service evaluation of outreach education at the UPDA. For the two most recent cohorts of 160 students (2014-16) an additional domain was added specifically investigating the students' sense of how their experience of outreach at the UPDA has impacted on their development to be ready for independent practice (safe beginner). The questionnaire was completed anonymously in their last week of attendance just before graduation.Results A 91% response rate for the questionnaire was achieved. To the question about 'being given an opportunity to become an independent dentist', 83% of the respondents strongly agreed. Two themes with seven subthemes were identified from the free text responses. The two themes were 'self-actualisation: developing self-awareness and self-confidence' and 'delivery of care as a dentist'.Conclusion Within the limitations of this educational evaluation, students enjoyed the increase of autonomy they gained during the year-long placement and felt that the clinical teachers empowered, encouraged and supported them to develop as autonomous dental practitioners and as 'safe beginners', to deliver holistic care in the National Health Service. PMID- 28084377 TI - OMFS: Fortitude and dedication. PMID- 28084378 TI - Work begins on state of the art new facility. PMID- 28084380 TI - Enormous support for mouth cancer message. PMID- 28084382 TI - A paediatric DCT's life: 'I love the challenge of dealing with worried children'. PMID- 28084383 TI - Trends in US malpractice payments in dentistry compared to other health professions - dentistry payments increase, others fall. AB - Background Little is known about trends in the number of malpractice payments made against dentists and other health professionals. Knowledge of these trends will inform the work of our professional organisations.Methods The National Practitioner Data Bank (NPDB) in the United States was utilised. Data about malpractice payments against dentists, hygienists, nurses, optometrists, pharmacists, physicians (DO and MD), physicians' assistants, podiatrists, psychologists, therapists and counsellors during 2004-14 were studied. Variables include type of healthcare provider, year malpractice payment was made and range of payment amount.Results In 2004 there were 17,532 malpractice payments against the studied health professions. In 2014 there were 11,650. In 2004, the number of malpractice payments against dentists represented 10.3% of all payments and in 2014 it represented 13.4%. Number of malpractice payments against dentists in 2012-2014 increased from 1,388 to 1,555.Conclusions There is an upward pressure on the number of dental malpractice payments over the last 3 years. Concurrently, there is a downward pressure on the number of combined non-dentist healthcare professional malpractice payments. PMID- 28084386 TI - Multidisciplinary management: Inflammatory bowel disease. PMID- 28084385 TI - Anaesthesia: LA in pregnancy. PMID- 28084388 TI - Periodontal evaluation of crown-root fractured teeth following modified crown lengthening surgery. AB - Objectives To evaluate long-term outcomes of modified crown lengthening procedures for crown-root fractured teeth, and to analyse factors that affect the periodontal health of the treated teeth.Methods The present study retrospectively analysed data from 22 patients (13 males and 9 females) who had presented with crown-root fractured teeth and received modified crown lengthening procedures combined with crown restoration for >=13 months. In total, 26 crown-root fractured teeth were treated and examined for plaque index, probing depth, bleeding index, bleeding on probing, mobility and the crown margin location. The contralateral tooth and ipsilateral teeth mesial and distal to the treated tooth were used as controls. Data were assessed descriptively or analysed statistically with Mann-Whitney-U test at alpha=0.05.Results Recorded periodontal indices revealed stable periodontal status in 25 of 26 treated teeth with the mean values for aesthetic and functional VAS scores at 9.5. A negative correlation was observed between the subgingival crown margin location and the bleeding index.Conclusions The modified crown lengthening procedure is a feasible and minimally invasive therapeutic option for management of crown-root fractured cases. PMID- 28084389 TI - Case report: long term lingual arch - preventable iatrogenic damage. AB - Lingual arches are fixed space maintainers utilised for the preservation of leeway space in cases of mild mandibular crowding. They are normally bonded using glass-ionomer cement applied to the internal surface of molar bands. As with any fixed appliance/retainer, if molar bands are not sufficiently monitored they have the potential to pose a significant threat to an individual's dental health. Unconventionally, in our example a lingual arch was used as a long-term fixed retainer with harmful consequence to one of the banded first permanent molars. A general understanding of molar bands and fixed retainers is important for patients' general dental health by the prevention of discrete caries progression. PMID- 28084390 TI - Safe intrapulpal anaesthesia. PMID- 28084391 TI - BDA AGMs. PMID- 28084392 TI - Event report: Success for mouth cancer charity in Dundee. PMID- 28084394 TI - No longer 'written off' - times have changed for the BBV-infected dental professional. AB - There is a recognised potential risk of transmission of blood-borne viruses (BBVs) from infected healthcare workers to patients during exposure prone procedures (EPPs). The restrictions placed on performance of EPPs by infected clinicians in the UK have had a particularly significant impact on dentists because of the exposure-prone nature of most dental procedures and the difficulties in identifying alternative career pathways in the profession that do not involve EPPs. More recently, the significant positive impact of antiviral drugs on viral load, together with a re-categorisation of EPPs in dentistry have resulted in evolution of the guidance with a consequent significant improvement to the career prospects of dentists infected with BBVs. This paper provides an update for practitioners on the progress that has been made and outlines the current position with respect to practice restrictions. PMID- 28084395 TI - Integrin beta4 promotes cell invasion and epithelial-mesenchymal transition through the modulation of Slug expression in hepatocellular carcinoma. AB - Integrin beta4 (ITGB4) is a transmembrane receptor involved in tumorigenesis and the invasiveness of many cancers. However, its role in hepatocellular carcinoma (HCC), one of the most prevalent human cancers worldwide, remains unclear. Here, we examined the involvement of ITGB4 in HCC and explored the underlying mechanisms. Real-time PCR and immunohistochemical analyses of tissues from 82 patients with HCC and four HCC cell lines showed higher ITGB4 levels in tumor than in adjacent non-tumor tissues and in HCC than in normal hepatic cells. Silencing of ITGB4 repressed cell proliferation, colony forming ability and cell invasiveness, whereas ectopic expression of ITGB4 promoted the proliferation and invasion of HCC cells and induced epithelial to mesenchymal transition (EMT) in parallel with the upregulation of Slug, as shown by transwell assays, WB and immunocytochemistry. Knockdown of Slug reduced cell viability inhibited invasion and reversed the effects of ITBG4 overexpression on promoting EMT, and AKT/Sox2 Nanog may also be involved. In a xenograft tumor model induced by injection of ITGB4-overexpressing cells into nude mice, ITGB4 promoted tumor growth and metastasis to the lungs. Taken together, our results indicate that ITGB4 plays a tumorigenic and pro-metastatic role mediated by Slug and suggest IGTB4 could be a prognostic indicator or a therapeutic target in patients with HCC. PMID- 28084396 TI - Structural basis of the interaction between the putative adhesion-involved and iron-regulated FrpD and FrpC proteins of Neisseria meningitidis. AB - The iron-regulated protein FrpD from Neisseria meningitidis is an outer membrane lipoprotein that interacts with very high affinity (Kd ~ 0.2 nM) with the N terminal domain of FrpC, a Type I-secreted protein from the Repeat in ToXin (RTX) protein family. In the presence of Ca2+, FrpC undergoes Ca2+ -dependent protein trans-splicing that includes an autocatalytic cleavage of the Asp414-Pro415 peptide bond and formation of an Asp414-Lys isopeptide bond. Here, we report the high-resolution structure of FrpD and describe the structure-function relationships underlying the interaction between FrpD and FrpC1-414. We identified FrpD residues involved in FrpC1-414 binding, which enabled localization of FrpD within the low-resolution SAXS model of the FrpD-FrpC1-414 complex. Moreover, the trans-splicing activity of FrpC resulted in covalent linkage of the FrpC1-414 fragment to plasma membrane proteins of epithelial cells in vitro, suggesting that formation of the FrpD-FrpC1-414 complex may be involved in the interaction of meningococci with the host cell surface. PMID- 28084397 TI - Altered Pathway Analyzer: A gene expression dataset analysis tool for identification and prioritization of differentially regulated and network rewired pathways. AB - Gene connection rewiring is an essential feature of gene network dynamics. Apart from its normal functional role, it may also lead to dysregulated functional states by disturbing pathway homeostasis. Very few computational tools measure rewiring within gene co-expression and its corresponding regulatory networks in order to identify and prioritize altered pathways which may or may not be differentially regulated. We have developed Altered Pathway Analyzer (APA), a microarray dataset analysis tool for identification and prioritization of altered pathways, including those which are differentially regulated by TFs, by quantifying rewired sub-network topology. Moreover, APA also helps in re prioritization of APA shortlisted altered pathways enriched with context-specific genes. We performed APA analysis of simulated datasets and p53 status NCI-60 cell line microarray data to demonstrate potential of APA for identification of several case-specific altered pathways. APA analysis reveals several altered pathways not detected by other tools evaluated by us. APA analysis of unrelated prostate cancer datasets identifies sample-specific as well as conserved altered biological processes, mainly associated with lipid metabolism, cellular differentiation and proliferation. APA is designed as a cross platform tool which may be transparently customized to perform pathway analysis in different gene expression datasets. APA is freely available at http://bioinfo.icgeb.res.in/APA. PMID- 28084398 TI - Highly Stable Glassy Carbon Interfaces for Long-Term Neural Stimulation and Low Noise Recording of Brain Activity. AB - We report on the superior electrochemical properties, in-vivo performance and long term stability under electrical stimulation of a new electrode material fabricated from lithographically patterned glassy carbon. For a direct comparison with conventional metal electrodes, similar ultra-flexible, micro electrocorticography (MU-ECoG) arrays with platinum (Pt) or glassy carbon (GC) electrodes were manufactured. The GC microelectrodes have more than 70% wider electrochemical window and 70% higher CTC (charge transfer capacity) than Pt microelectrodes of similar geometry. Moreover, we demonstrate that the GC microelectrodes can withstand at least 5 million pulses at 0.45 mC/cm2 charge density with less than 7.5% impedance change, while the Pt microelectrodes delaminated after 1 million pulses. Additionally, poly(3,4 ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT-PSS) was selectively electrodeposited on both sets of devices to specifically reduce their impedances for smaller diameters (<60 MUm). We observed that PEDOT-PSS adhered significantly better to GC than Pt, and allowed drastic reduction of electrode size while maintaining same amount of delivered current. The electrode arrays biocompatibility was demonstrated through in-vitro cell viability experiments, while acute in vivo characterization was performed in rats and showed that GC microelectrode arrays recorded somatosensory evoked potentials (SEP) with an almost twice SNR (signal-to-noise ratio) when compared to the Pt ones. PMID- 28084399 TI - The short-term effects of air pollutants on respiratory disease mortality in Wuhan, China: comparison of time-series and case-crossover analyses. AB - Few studies have compared different methods when exploring the short-term effects of air pollutants on respiratory disease mortality in Wuhan, China. This study assesses the association between air pollutants and respiratory disease mortality with both time-series and time-stratified-case-crossover designs. The generalized additive model (GAM) and the conditional logistic regression model were used to assess the short-term effects of air pollutants on respiratory disease mortality. Stratified analyses were performed by age, sex, and diseases. A 10 MUg/m3 increment in SO2 level was associated with an increase in relative risk for all respiratory disease mortality of 2.4% and 1.9% in the case-crossover and time series analyses in single pollutant models, respectively. Strong evidence of an association between NO2 and daily respiratory disease mortality among men or people older than 65 years was found in the case-crossover study. There was a positive association between air pollutants and respiratory disease mortality in Wuhan, China. Both time-series and case-crossover analyses consistently reveal the association between three air pollutants and respiratory disease mortality. The estimates of association between air pollution and respiratory disease mortality from the case-crossover analysis displayed greater variation than that from the time-series analysis. PMID- 28084401 TI - Polarization Enhanced Charge Transfer: Dual-Band GaN-Based Plasmonic Photodetector. AB - Here, we report a dual-band plasmonic photodetector based on Ga-polar gallium nitride (GaN) for highly sensitive detection of UV and green light. We discover that decoration of Au nanoparticles (NPs) drastically increases the photoelectric responsivities by more than 50 times in comparition to the blank GaN photodetector. The observed behaviors are attributed to polarization enhanced charge transfer of optically excited hot electrons from Au NPs to GaN driven by the strong spontaneous polarization field of Ga-polar GaN. Moreover, defect ionization promoted by localized surface plasmon resonances (LSPRs) is also discussed. This novel type of photodetector may shed light on the design and fabrication of photoelectric devices based on polar semiconductors and microstructural defects. PMID- 28084400 TI - Rattlesnakes are extremely fast and variable when striking at kangaroo rats in nature: Three-dimensional high-speed kinematics at night. AB - Predation plays a central role in the lives of most organisms. Predators must find and subdue prey to survive and reproduce, whereas prey must avoid predators to do the same. The resultant antagonistic coevolution often leads to extreme adaptations in both parties. Few examples capture the imagination like a rapid strike from a venomous snake. However, almost nothing is known about strike performance of viperid snakes under natural conditions. We obtained high-speed (500 fps) three-dimensional video in the field (at night using infrared lights) of Mohave rattlesnakes (Crotalus scutulatus) attempting to capture Merriam's kangaroo rats (Dipodomys merriami). Strikes occurred from a range of distances (4.6 to 20.6 cm), and rattlesnake performance was highly variable. Missed capture attempts resulted from both rapid escape maneuvers and poor strike accuracy. Maximum velocity and acceleration of some rattlesnake strikes fell within the range of reported laboratory values, but some far exceeded most observations. Thus, quantifying rapid predator-prey interactions in the wild will propel our understanding of animal performance. PMID- 28084402 TI - SMIM1 variants rs1175550 and rs143702418 independently modulate Vel blood group antigen expression. AB - The Vel blood group antigen is expressed on the red blood cells of most individuals. Recently, we described that homozygosity for inactivating mutations in SMIM1 defines the rare Vel-negative phenotype. Still, Vel-positive individuals show great variability in Vel antigen expression, creating a risk for Vel blood typing errors and transfusion reactions. We fine-mapped the regulatory region located in SMIM1 intron 2 in Swedish blood donors, and observed a strong correlation between expression and rs1175550 as well as with a previously unreported tri-nucleotide insertion (rs143702418; C > CGCA). While the two variants are tightly linked in Caucasians, we separated their effects in African Americans, and found that rs1175550G and to a lesser extent rs143702418C independently increase SMIM1 and Vel antigen expression. Gel shift and luciferase assays indicate that both variants are transcriptionally active, and we identified binding of the transcription factor TAL1 as a potential mediator of the increased expression associated with rs1175550G. Our results provide insight into the regulatory logic of Vel antigen expression, and extend the set of markers for genetic Vel blood group typing. PMID- 28084403 TI - CIGS thin-film solar module processing: case of high-speed laser scribing. AB - In this paper, we investigate the laser processing of the CIGS thin-film solar cells in the case of the high-speed regime. The modern ultra-short pulsed laser was used exhibiting the pulse repetition rate of 1 MHz. Two main P3 scribing approaches were investigated - ablation of the full layer stack to expose the molybdenum back-contact, and removal of the front-contact only. The scribe quality was evaluated by SEM together with EDS spectrometer followed by electrical measurements. We also modelled the electrical behavior of a device at the mini-module scale taking into account the laser-induced damage. We demonstrated, that high-speed process at high laser pulse repetition rate induced thermal damage to the cell. However, the top-contact layer lift-off processing enabled us to reach 1.7 m/s scribing speed with a minimal device degradation. Also, we demonstrated the P3 processing in the ultra-high speed regime, where the scribing speed of 50 m/s was obtained. Finally, selected laser processes were tested in the case of mini-module scribing. Overall, we conclude, that the top contact layer lift-off processing is the only reliable solution for high-speed P3 laser scribing, which can be implemented in the future terawatt-scale photovoltaic production facilities. PMID- 28084404 TI - Pesticide-mediated interspecific competition between local and invasive thrips pests. AB - Competitive interactions between species can be mitigated or even reversed in the presence of anthropogenic influences. The thrips species Frankliniella occidentalis and Thrips tabaci are highly invasive and damaging agricultural pests throughout the world. Where the species co-occur, one species tends to eventually predominate over the other. Avermectin and beta-cypermethrin are commonly used insecticides to manage thrips in China, and laboratory bioassays demonstrated that F. occidentalis is significantly less susceptible than T. tabaci to these insecticides. In laboratory cage trials in which both species were exposed to insecticide treated cabbage plants, F. occidentalis became the predominant species. In contrast, T. tabaci completely displaced F. occidentalis on plants that were not treated with insecticides. In field trials, the species co-existed on cabbage before insecticide treatments began, but with T. tabaci being the predominant species. Following application of avermectin or beta cypermethrin, F. occidentalis became the predominant species, while in plots not treated with insecticides, T. tabaci remained the predominant species. These results indicate that T. tabaci is an intrinsically superior competitor to F. occidentalis, but its competitive advantage can be counteracted through differential susceptibilities of the species to insecticides. These results further demonstrate the importance of external factors, such as insecticide applications, in mediating the outcome of interspecific interactions and produce rapid unanticipated shifts in the demographics of pest complexes. PMID- 28084405 TI - Multiple quasicrystal approximants with the same lattice parameters in Al-Cr-Fe Si alloys. AB - By means of atomic-resolution high-angle annular dark-field scanning transmission electron microscopy, we found three types of giant approximants of decagonal quasicrystal in Al-Cr-Fe-Si alloys, where each type contains several structural variants possessing the same lattice parameters but different crystal structures. The projected structures of these approximants along the pseudo-tenfold direction were described using substructural blocks. Furthermore, the structural relationship and the plane crystallographic groups in the (a, c) plan of these structural variants was also discussed. The diversity of quasicrystal approximants with the same lattice parameters was shown to be closely related to the variety of shield-like tiles and their tiling patterns. PMID- 28084406 TI - In vitro gastrointestinal digestion promotes the protective effect of blackberry extract against acrylamide-induced oxidative stress. AB - Acrylamide (AA)-induced toxicity has been associated with accumulation of excessive reactive oxygen species. The present study was therefore undertaken to investigate the protective effect of blackberry digests produced after (BBD) in vitro gastrointestinal (GI) digestion against AA-induced oxidative damage. The results indicated that the BBD (0.5 mg/mL) pretreatment significantly suppressed AA-induced intracellular ROS generation (56.6 +/- 2.9% of AA treatment), mitochondrial membrane potential (MMP) decrease (297 +/- 18% of AA treatment) and glutathione (GSH) depletion (307 +/- 23% of AA treatment), thereby ameliorating cytotoxicity. Furthermore, LC/MS/MS analysis identified eight phenolic compounds with high contents in BBD, including ellagic acid, ellagic acid pentoside, ellagic acid glucuronoside, methyl-ellagic acid pentoside, methyl-ellagic acid glucuronoside, cyanidin glucoside, gallic acid and galloyl esters, as primary active compounds responsible for antioxidant action. Collectively, our study uncovered that the protective effect of blackberry was reserved after gastrointestinal digestion in combating exogenous pollutant-induced oxidative stress. PMID- 28084407 TI - Combining Chemical Profiling and Network Analysis to Investigate the Pharmacology of Complex Prescriptions in Traditional Chinese Medicine. AB - We present a paradigm, combining chemical profiling, absorbed components detection in plasma and network analysis, for investigating the pharmacology of combination drugs and complex formulae. On the one hand, the composition of the formula is investigated comprehensively via mass spectrometry analysis, followed by pharmacological studies of the fractions as well as the plasma concentration testing for the ingredients. On the other hand, both the candidate target proteins and the effective ingredients of the formula are predicted via analyzing the corresponding networks. The most probable active compounds can then be identified by combining the experimental results with the network analysis. In order to illustrate the performance of the paradigm, we apply it to the Danggui Jianzhong formula (DJF) from traditional Chinese medicine (TCM) and predict 4 probably active ingredients, 3 of which are verified experimentally to display anti-platelet activity, i.e., (Z)-Ligustilide, Licochalcone A and Pentagalloylglucose. Moreover, the 3-compound formulae composed of these 3 chemicals show better anti-platelet activity than DJF. In addition, the paradigm predicts the association between these 3 compounds and COX-1, and our experimental validation further shows that such association comes from the inhibitory effects of the compounds on the activity of COX-1. PMID- 28084408 TI - Germanium Sub-Microspheres Synthesized by Picosecond Pulsed Laser Melting in Liquids: Educt Size Effects. AB - Pulsed laser melting in liquid (PLML) has emerged as a facile approach to synthesize submicron spheres (SMSs) for various applications. Typically lasers with long pulse durations in the nanosecond regime are used. However, recent findings show that during melting the energy absorbed by the particle will be dissipated promptly after laser-matter interaction following the temperature decrease within tens of nanoseconds and hence limiting the efficiency of longer pulse widths. Here, the feasibility to utilize a picosecond laser to synthesize Ge SMSs (200~1000 nm in diameter) is demonstrated by irradiating polydisperse Ge powders in water and isopropanol. Through analyzing the educt size dependent SMSs formation mechanism, we find that Ge powders (200~1000 nm) are directly transformed into SMSs during PLML via reshaping, while comparatively larger powders (1000~2000 nm) are split into daughter SMSs via liquid droplet bisection. Furthermore, the contribution of powders larger than 2000 nm and smaller than 200 nm to form SMSs is discussed. This work shows that compared to nanosecond lasers, picosecond lasers are also suitable to produce SMSs if the pulse duration is longer than the material electron-phonon coupling period to allow thermal relaxation. PMID- 28084409 TI - A Conditional Knockout Mouse Model Reveals a Critical Role of PKD1 in Osteoblast Differentiation and Bone Development. AB - The protein kinase D family of serine/threonine kinases, particularly PKD1, has been implicated in the regulation of a complex array of fundamental biological processes. However, its function and mechanism underlying PKD1-mediated the bone development and osteoblast differentiation are not fully understood. Here we demonstrate that loss of PKD1 function led to impaired bone development and osteoblast differentiation through STAT3 and p38 MAPK signaling using in vitro and in vivo bone-specific conditional PKD1-knockout (PKD1-KO) mice models. These mice developed markedly craniofacial dysplasia, scapula dysplasia, long bone length shortage and body weight decrease compared with wild-type littermates. Moreover, deletion of PKD1 in vivo reduced trabecular development and activity of osteoblast development, confirmed by Micro-CT and histological staining as well as expression of osteoblastic marker (OPN, Runx2 and OSX). Mechanistically, loss of PKD1 mediated the downregulation of osteoblast markers and impaired osteoblast differentiation through STAT3 and p38 MAPK signaling pathways. Taken together, these results demonstrated that PKD1 contributes to the osteoblast differentiation and bone development via elevation of osteoblast markers through activation of STAT3 and p38 MAPK signaling pathways. PMID- 28084411 TI - Ciproxifan, a histamine H3 receptor antagonist, reversibly inhibits monoamine oxidase A and B. AB - Ciproxifan is a well-investigated histamine H3 receptor (H3R) inverse agonist/antagonist, showing an exclusively high species-specific affinity at rodent compared to human H3R. It is well studied as reference compound for H3R in rodent models for neurological diseases connected with neurotransmitter dysregulation, e.g. attention deficit hyperactivity disorder or Alzheimer's disease. In a screening for potential monoamine oxidase A and B inhibition ciproxifan showed efficacy on both enzyme isoforms. Further characterization of ciproxifan revealed IC50 values in a micromolar concentration range for human and rat monoamine oxidases with slight preference for monoamine oxidase B in both species. The inhibition by ciproxifan was reversible for both human isoforms. Regarding inhibitory potency of ciproxifan on rat brain MAO, these findings should be considered, when using high doses in rat models for neurological diseases. As the H3R and monoamine oxidases are all capable of affecting neurotransmitter modulation in brain, we consider dual targeting ligands as interesting approach for treatment of neurological disorders. Since ciproxifan shows only moderate activity at human targets, further investigations in animals are not of primary interest. On the other hand, it may serve as starting point for the development of dual targeting ligands. PMID- 28084410 TI - Non-interacting proteins may resemble interacting proteins: prevalence and implications. AB - The vast majority of proteins do not form functional interactions in physiological conditions. We have considered several sets of protein pairs from S. cerevisiae with no functional interaction reported, denoted as non-interacting pairs, and compared their 3D structures to available experimental complexes. We identified some non-interacting pairs with significant structural similarity with experimental complexes, indicating that, even though they do not form functional interactions, they have compatible structures. We estimate that up to 8.7% of non interacting protein pairs could have compatible structures. This number of interactions exceeds the number of functional interactions (around 0.2% of the total interactions) by a factor 40. Network analysis suggests that the interactions formed by non-interacting pairs with compatible structures could be particularly hazardous to the protein-protein interaction network. From a structural point of view, these interactions display no aberrant structural characteristics, and are even predicted as relatively stable and enriched in potential physical interactors, suggesting a major role of regulation to prevent them. PMID- 28084412 TI - Genome-wide DNA methylation profile in mungbean. AB - DNA methylation on cytosine residues is known to affect gene expression and is potentially responsible for the phenotypic variations among different crop cultivars. Here, we present the whole-genome DNA methylation profiles and assess the potential effects of single nucleotide polymorphisms (SNPs) for two mungbean cultivars, Sunhwanogdu (VC1973A) and Kyunggijaerae#5 (V2984). By measuring the DNA methylation levels in leaf tissue with the bisulfite sequencing (BSseq) approach, we show both the frequencies of the various types of DNA methylation and the distribution of weighted gene methylation levels. SNPs that cause nucleotide changes from/to CHH - where C is cytosine and H is any other nucleotide - were found to affect DNA methylation status in VC1973A and V2984. In order to better understand the correlation between gene expression and DNA methylation levels, we surveyed gene expression in leaf tissues of VC1973A and V2984 using RNAseq. Transcript expressions of paralogous genes were controlled by DNA methylation within the VC1973A genome. Moreover, genes that were differentially expressed between the two cultivars showed distinct DNA methylation patterns. Our mungbean genome-wide methylation profiles will be valuable resources for understanding the phenotypic variations between different cultivars, as well as for molecular breeding. PMID- 28084413 TI - Electrophoresis of polar fluorescent tracers through the nerve sheath labels neuronal populations for anatomical and functional imaging. AB - The delivery of tracers into populations of neurons is essential to visualize their anatomy and analyze their function. In some model systems genetically targeted expression of fluorescent proteins is the method of choice; however, these genetic tools are not available for most organisms and alternative labeling methods are very limited. Here we describe a new method for neuronal labelling by electrophoretic dye delivery from a suction electrode directly through the neuronal sheath of nerves and ganglia in insects. Polar tracer molecules were delivered into the locust auditory nerve without destroying its function, simultaneously staining peripheral sensory structures and central axonal projections. Local neuron populations could be labelled directly through the surface of the brain, and in-vivo optical imaging of sound-evoked activity was achieved through the electrophoretic delivery of calcium indicators. The method provides a new tool for studying how stimuli are processed in peripheral and central sensory pathways and is a significant advance for the study of nervous systems in non-model organisms. PMID- 28084414 TI - Increased Renal Clearance of Rocuronium Compensates for Chronic Loss of Bile Excretion, via upregulation of Oatp2. AB - Requirement for rocuronium upon surgery changes only minimally in patients with end-stage liver diseases. Our study consisted of both human and rat studies to explore the reason. The reduction rate of rocuronium infusion required to maintain neuromuscular blockade during the anhepatic phase (relative to paleohepatic phase) was examined in 16 children with congenital biliary atresia receiving orthotopic liver transplantation. Pharmacodynamics and pharmacokinetics of rocuronium were studied based on BDL rats. The role of increased Oatp2 and decrease Oatp1 expressions in renal compensation were explored. The reduction of rocuronium requirements significantly decreased in obstructively jaundiced children (24 +/- 9 vs. 39 +/- 11%). TOF50 in BDL rats was increased by functional removal of the kidneys but not the liver, and the percentage of rocuronium excretion through urine increased (20.3 +/- 6.9 vs. 8.6 +/- 1.8%), while that decreased through bile in 28d-BDL compared with control group. However, this enhanced renal secretion for rocuronium was eliminated by Oatp2 knock-down, rather than Oatp1 overexpression (28-d BDL vs. Oatp1-ShRNA or Oatp2-ShRNA, 20.3 +/- 6.9 vs. 17.0 +/- 6.6 or 9.3 +/- 3.2%). Upon chronic/sub-chronic loss of bile excretion, rocuronium clearance via the kidneys is enhanced, by Oatp2 up regulation. PMID- 28084415 TI - Lessons from temporal and spatial patterns in global use of N and P fertilizer on cropland. AB - In recent decades farmers in high-income countries and China and India have built up a large reserve of residual soil P in cropland. This reserve can now be used by crops, and in high-income countries the use of mineral P fertilizer has recently been decreasing with even negative soil P budgets in Europe. In contrast to P, much of N surpluses are emitted to the environment via air and water and large quantities of N are transported in aquifers with long travel times (decades and longer). N fertilizer use in high-income countries has not been decreasing in recent years; increasing N use efficiency and utilization of accumulated residual soil P allowed continued increases in crop yields. However, there are ecological risks associated with the legacy of excessive nutrient mobilization in the 1970s and 1980s. Landscapes have a memory for N and P; N concentrations in many rivers do not respond to increased agricultural N use efficiency, and European water quality is threatened by rapidly increasing N:P ratios. Developing countries can avoid such problems by integrated management of N, P and other nutrients accounting for residual soil P, while avoiding legacies associated with the type of past or continuing mismanagement of high-income countries, China and India. PMID- 28084416 TI - Shift of fleshy fruited species along elevation: temperature, canopy coverage, phylogeny and origin. AB - Plant communities differ in their fruit type spectra, especially in the proportions of fleshy and non-fleshy fruit types. However, which abiotic and biotic factors drive this variability along elevation gradient and what drives the evolution of fruit type diversity still are puzzling. We analyzed the variations in proportions and richness of fleshy-fruited species and their correlations to various abiotic and biotic variables along elevation gradients in three mountains in the Beijing region, northeast China. Fleshy-fruited species, which are characterized by high fruit water contents, were found in great proportion and richness at relatively low elevations, where soil water content is low compared to high elevations. High temperatures in low elevations increase water availability for plants. Plants that grow in the shaded low-elevation thick canopy forests are less exposed to evapotranspiration and thus possess water surpluses that can be invested in fleshy fruits. Such an investment in fleshy fruits is beneficial for these species because it makes the fruits more attractive to frugivores that act as seed dispersers in the close-canopied environments, where dispersion by wind is less effective. A hypothesis is proposed that plant internal water surpluses are the prerequisite conditions that permit evolution of fleshy fruits to occur. PMID- 28084417 TI - Repair of osteochondral defects with in vitro engineered cartilage based on autologous bone marrow stromal cells in a swine model. AB - Functional reconstruction of large osteochondral defects is always a major challenge in articular surgery. Some studies have reported the feasibility of repairing articular osteochondral defects using bone marrow stromal cells (BMSCs) and biodegradable scaffolds. However, no significant breakthroughs have been achieved in clinical translation due to the instability of in vivo cartilage regeneration based on direct cell-scaffold construct implantation. To overcome the disadvantages of direct cell-scaffold construct implantation, the current study proposed an in vitro cartilage regeneration strategy, providing relatively mature cartilage-like tissue with superior mechanical properties. Our strategy involved in vitro cartilage engineering, repair of osteochondral defects, and evaluation of in vivo repair efficacy. The results demonstrated that BMSC engineered cartilage in vitro (BEC-vitro) presented a time-depended maturation process. The implantation of BEC-vitro alone could successfully realize tissue specific repair of osteochondral defects with both cartilage and subchondral bone. Furthermore, the maturity level of BEC-vitro had significant influence on the repaired results. These results indicated that in vitro cartilage regeneration using BMSCs is a promising strategy for functional reconstruction of osteochondral defect, thus promoting the clinical translation of cartilage regeneration techniques incorporating BMSCs. PMID- 28084418 TI - Inference of immune cell composition on the expression profiles of mouse tissue. AB - Mice are some of the widely used experimental animal models for studying human diseases. Defining the compositions of immune cell populations in various tissues from experimental mouse models is critical to understanding the involvement of immune responses in various physiological and patho-physiological conditions. However, non-lymphoid tissues are normally composed of vast and diverse cellular components, which make it difficult to quantify the relative proportions of immune cell types. Here we report the development of a computational algorithm, ImmuCC, to infer the relative compositions of 25 immune cell types in mouse tissues using microarray-based mRNA expression data. The ImmuCC algorithm showed good performance and robustness in many simulated datasets. Remarkable concordances were observed when ImmuCC was used on three public datasets, one including enriched immune cells, one with normal single positive T cells, and one with leukemia cell samples. To validate the performance of ImmuCC objectively, thorough cross-comparison of ImmuCC predicted compositions and flow cytometry results was done with in-house generated datasets collected from four distinct mouse lymphoid tissues and three different types of tumor tissues. The good correlation and biologically meaningful results demonstrate the broad utility of ImmuCC for assessing immune cell composition in diverse mouse tissues under various conditions. PMID- 28084420 TI - Electronic Excitation Dynamics in Liquid Water under Proton Irradiation. AB - Molecular behaviour of liquid water under proton irradiation is of great importance to a number of technological and medical applications. The highly energetic proton generates a time-varying field that is highly localized and heterogeneous at the molecular scale, and massive electronic excitations are produced as a result of the field-matter interaction. Using first-principles quantum dynamics simulations, we reveal details of how electrons are dynamically excited through non-equilibrium energy transfer from highly energetic protons in liquid water on the atto/femto-second time scale. Water molecules along the path of the energetic proton undergo ionization at individual molecular level, and the excitation primarily derives from lone pair electrons on the oxygen atom of water molecules. A reduced charge state on the energetic proton in the condensed phase of water results in the strongly suppressed electronic response when compared to water molecules in the gas phase. These molecular-level findings provide important insights into understanding the water radiolysis process under proton irradiation. PMID- 28084421 TI - Diamond formation in the deep lower mantle: a high-pressure reaction of MgCO3 and SiO2. AB - Diamond is an evidence for carbon existing in the deep Earth. Some diamonds are considered to have originated at various depth ranges from the mantle transition zone to the lower mantle. These diamonds are expected to carry significant information about the deep Earth. Here, we determined the phase relations in the MgCO3-SiO2 system up to 152 GPa and 3,100 K using a double sided laser-heated diamond anvil cell combined with in situ synchrotron X-ray diffraction. MgCO3 transforms from magnesite to the high-pressure polymorph of MgCO3, phase II, above 80 GPa. A reaction between MgCO3 phase II and SiO2 (CaCl2-type SiO2 or seifertite) to form diamond and MgSiO3 (bridgmanite or post-perovsktite) was identified in the deep lower mantle conditions. These observations suggested that the reaction of the MgCO3 phase II with SiO2 causes formation of super-deep diamond in cold slabs descending into the deep lower mantle. PMID- 28084419 TI - LPS promotes Th2 dependent sensitisation leading to anaphylaxis in a Pru p 3 mouse model. AB - Pru p 3 is the major peach allergen in the Mediterranean area. It frequently elicits severe reactions, limiting its study in humans, raising the need for animal models to investigate the immunological mechanisms involved. However, no anaphylaxis model exists for Pru p 3. We aimed to develop a model of peach anaphylaxis by sensitising mice with Pru p 3 in combination with lipopolysaccharide (LPS) as an adjuvant. Four groups of mice were sensitised intranasally: untreated; treated with Pru p 3; treated with LPS; treated with Pru p 3 + LPS. After sensitisation mice were intraperitoneally challenged with Pru p 3 and in vivo and in vitro parameters were evaluated. Only mice in the Pru p 3 + LPS group showed anaphylaxis symptoms, including a decrease in temperature. Determination of in vitro parameters showed a Th2 response with an increase of Pru p 3-specific IgE and IgG1. Moreover, at the cellular level, we found increased levels of IgE and IgG1 secreting Pru p 3-specific cells and a proliferative CD4+ T-cell response. These results demonstrate that Pru p 3 specific anaphylaxis can be generated after nasal sensitisation to Pru p 3 in combination with LPS. This is a promising model for evaluating food allergy immunotherapies. PMID- 28084422 TI - Targeting pathogen metabolism without collateral damage to the host. AB - The development of drugs that can inactivate disease-causing cells (e.g. cancer cells or parasites) without causing collateral damage to healthy or to host cells is complicated by the fact that many proteins are very similar between organisms. Nevertheless, due to subtle, quantitative differences between the biochemical reaction networks of target cell and host, a drug can limit the flux of the same essential process in one organism more than in another. We identified precise criteria for this 'network-based' drug selectivity, which can serve as an alternative or additive to structural differences. We combined computational and experimental approaches to compare energy metabolism in the causative agent of sleeping sickness, Trypanosoma brucei, with that of human erythrocytes, and identified glucose transport and glyceraldehyde-3-phosphate dehydrogenase as the most selective antiparasitic targets. Computational predictions were validated experimentally in a novel parasite-erythrocytes co-culture system. Glucose transport inhibitors killed trypanosomes without killing erythrocytes, neurons or liver cells. PMID- 28084423 TI - Single PA mutation as a high yield determinant of avian influenza vaccines. AB - Human infection with an avian influenza virus persists. To prepare for a potential outbreak of avian influenza, we constructed a candidate vaccine virus (CVV) containing hemagglutinin (HA) and neuraminidase (NA) genes of a H5N1 virus and evaluated its antigenic stability after serial passaging in embryonated chicken eggs. The passaged CVV harbored the four amino acid mutations (R136K in PB2; E31K in PA; A172T in HA; and R80Q in M2) without changing its antigenicity, compared with the parental CVV. Notably, the passaged CVV exhibited much greater replication property both in eggs and in Madin-Darby canine kidney and Vero cells. Of the four mutations, the PA E31K showed the greatest effect on the replication property of reverse genetically-rescued viruses. In a further luciferase reporter, mini-replicon assay, the PA mutation appeared to affect the replication property by increasing viral polymerase activity. When applied to different avian influenza CVVs (H7N9 and H9N2 subtypes), the PA E31K mutation resulted in the increases of viral replication in the Vero cell again. Taken all together, our results suggest the PA E31K mutation as a single, substantial growth determinant of avian influenza CVVs and for the establishment of a high yield avian influenza vaccine backbone. PMID- 28084424 TI - FcRgamma-dependent immune activation initiates astrogliosis during the asymptomatic phase of Sandhoff disease model mice. AB - Sandhoff disease (SD) is caused by the loss of beta-hexosaminidase (Hex) enzymatic activity in lysosomes resulting from Hexb mutations. In SD patients, the Hex substrate GM2 ganglioside accumulates abnormally in neuronal cells, resulting in neuronal loss, microglial activation, and astrogliosis. Hexb-/- mice, which manifest a phenotype similar to SD, serve as animal models for examining the pathophysiology of SD. Hexb-/- mice reach ~8 weeks without obvious neurological defects; however, trembling begins at 12 weeks and is accompanied by startle reactions and increased limb tone. These symptoms gradually become severe by 16-18 weeks. Immune reactions caused by autoantibodies have been recently associated with the pathology of SD. The inhibition of immune activation may represent a novel therapeutic target for SD. Herein, SD mice (Hexb-/-) were crossed to mice lacking an activating immune receptor (FcRgamma-/-) to elucidate the potential relationship between immune responses activated through SD autoantibodies and astrogliosis. Microglial activation and astrogliosis were observed in cortices of Hexb-/- mice during the asymptomatic phase, and were inhibited in Hexb-/- FcRgamma-/- mice. Moreover, early astrogliosis and impaired motor coordination in Hexb-/- mice could be ameliorated by immunosuppressants, such as FTY720. Our findings demonstrate the importance of early treatment and the therapeutic effectiveness of immunosuppression in SD. PMID- 28084426 TI - Multimodality MRI assessment of grey and white matter injury and blood-brain barrier disruption after intracerebral haemorrhage in mice. AB - In this study, we examined injury progression after intracerebral haemorrhage (ICH) induced by collagenase in mice using a preclinical 11.7 Tesla MRI system. On T2-weighted MRI, lesion and striatal volumes were increased on day 3 and then decreased from days 7 to 28. On day 3, with an increase in striatal water content, vasogenic oedema in the perihaematomal region presented as increased T2 and increased apparent diffusion coefficient (ADC) signal. With a synchronous change in T2 and ADC signals, microglial activation peaked on day 3 in the same region and decreased over time. Iron deposition appeared on day 3 around the haematoma border but did not change synchronously with ADC signals. Vascular permeability measured by Evans blue extravasation on days 1, 3, and 7 correlated with the T1-gadolinium results, both of which peaked on day 3. On diffusion tensor imaging, white matter injury was prominent in the corpus callosum and internal capsule on day 3 and then partially recovered over time. Our results indicate that the evolution of grey/white matter injury and blood-brain barrier disruption after ICH can be assessed with multimodal MRI, and that perihaematomal vasogenic oedema might be attributable to microglial activation, iron deposition, and blood-brain barrier breakdown. PMID- 28084427 TI - Strain Gradient Modulated Exciton Evolution and Emission in ZnO Fibers. AB - One-dimensional semiconductor can undergo large deformation including stretching and bending. This homogeneous strain and strain gradient are an easy and effective way to tune the light emission properties and the performance of piezo phototronic devices. Here, we report that with large strain gradients from 2.1 3.5% MUm-1, free-exciton emission was intensified, and the free-exciton interaction (FXI) emission became a prominent FXI-band at the tensile side of the ZnO fiber. These led to an asymmetric variation in energy and intensity along the cross-section as well as a redshift of the total near-band-edge (NBE) emission. This evolution of the exciton emission was directly demonstrated using spatially resolved CL spectrometry combined with an in situ tensile-bending approach at liquid nitrogen temperature for individual fibers and nanowires. A distinctive mechanism of the evolution of exciton emission is proposed: the enhancement of the free-exciton-related emission is attributed to the aggregated free excitons and their interaction in the narrow bandgap in the presence of high bandgap gradients and a transverse piezoelectric field. These results might facilitate new approaches for energy conversion and sensing applications via strained nanowires and fibers. PMID- 28084425 TI - White to beige conversion in PDE3B KO adipose tissue through activation of AMPK signaling and mitochondrial function. AB - Understanding mechanisms by which a population of beige adipocytes is increased in white adipose tissue (WAT) reflects a potential strategy in the fight against obesity and diabetes. Cyclic adenosine monophosphate (cAMP) is very important in the development of the beige phenotype and activation of its thermogenic program. To study effects of cyclic nucleotides on energy homeostatic mechanisms, mice were generated by targeted inactivation of cyclic nucleotide phosphodiesterase 3b (Pde3b) gene, which encodes PDE3B, an enzyme that catalyzes hydrolysis of cAMP and cGMP and is highly expressed in tissues that regulate energy homeostasis, including adipose tissue, liver, and pancreas. In epididymal white adipose tissue (eWAT) of PDE3B KO mice on a SvJ129 background, cAMP/protein kinase A (PKA) and AMP-activated protein kinase (AMPK) signaling pathways are activated, resulting in "browning" phenotype, with a smaller increases in body weight under high-fat diet, smaller fat deposits, increased beta-oxidation of fatty acids (FAO) and oxygen consumption. Results reported here suggest that PDE3B and/or its downstream signaling partners might be important regulators of energy metabolism in adipose tissue, and potential therapeutic targets for treating obesity, diabetes and their associated metabolic disorders. PMID- 28084428 TI - Molecular phylogeny of a novel human adenovirus type 8 strain causing a prolonged, multi-state keratoconjunctivitis epidemic in Germany. AB - The German infectious disease surveillance system revealed an increase of epidemic keratoconjunctivitis (EKC) from an average of 320 cases/year (2001 to 2010) up to 2146 and 1986 cases in 2012 and 2013, respectively. From November 2011 until December 2013 (epidemic period) 85% of typed isolates were human adenovirus type 8 (HAdV-D8), whereas only low level circulation (19%) of HAdV-D8 was observed outside the epidemic period. In order to investigate whether a novel monophyletic HAdV-D8 strain prevailed during the epidemic period, complete genomic sequences of 23 HAdV-D8 isolates were generated by deep sequencing and analyzed phylogenetically. For comparison, eight HAdV-D8 isolates from outside the epidemic period were sequenced. HAdV-D8 isolates of the epidemic period had a very high sequence identity of at least 99.9% and formed a monophyletic cluster with two subclusters. A single outlier was closely related to HAdV-D8 strains isolated prior to the epidemic period. Circulation of the epidemic strain was detected as early as 2010 but not after the epidemic period in 2014. In conclusion, molecular phylogeny of complete genomic sequences proved a monophyletic HAdV-D8 epidemic. However, co-circulation of other HAdV types as well as better reporting may have contributed to the huge increase of reported cases. PMID- 28084429 TI - The Effect of a Transcranial Channel as a Skull/Brain Interface in High Definition Transcranial Direct Current Stimulation-A Computational Study. AB - A transcranial channel is an interface between the skull and brain; it consists of a biocompatible and highly conductive material that helps convey the current induced by transcranial direct current stimulation (tDCS) to the target area. However, it has been proposed only conceptually, and there has been no concrete study of its efficacy. In this work, we conducted a computational investigation of this conceptual transcranial model with high-definition tDCS, inducing focalized neuromodulation to determine whether inclusion of a transcranial channel performs effectively. To do so, we constructed an anatomically realistic head model and compartmental pyramidal neuronal models. We analyzed membrane polarization by extracellular stimulation and found that the inclusion of a transcranial channel induced polarization at the target area 11 times greater than conventional HD-tDCS without the transcranial channel. Furthermore, the stimulation effect of the transcranial channel persisted up to approximately 80%, even when the stimulus electrodes were displaced approximately 5 mm from the target area. We investigated the efficacy of the transcranial channel and found that greatly improved stimulation intensity and focality may be achieved. Thus, the use of these channels may be promising for clinical treatment. PMID- 28084430 TI - Optogenetic Control of Heart Rhythm by Selective Stimulation of Cardiomyocytes Derived from Pnmt+ Cells in Murine Heart. AB - In the present study, channelrhodopsin 2 (ChR2) was specifically introduced into murine cells expressing the Phenylethanolamine n-methyltransferase (Pnmt) gene, which encodes for the enzyme responsible for conversion of noradrenaline to adrenaline. The new murine model enabled the identification of a distinctive class of Pnmt-expressing neuroendocrine cells and their descendants (i.e. Pnmt+ cell derived cells) within the heart. Here, we show that Pnmt+ cells predominantly localized to the left side of the adult heart. Remarkably, many of the Pnmt+ cells in the left atrium and ventricle appeared to be working cardiomyocytes based on their morphological appearance and functional properties. These Pnmt+ cell derived cardiomyocytes (PdCMs) are similar to conventional myocytes in morphological, electrical and contractile properties. By stimulating PdCMs selectively with blue light, we were able to control cardiac rhythm in the whole heart, isolated tissue preparations and single cardiomyocytes. Our new murine model effectively demonstrates functional dissection of cardiomyocyte subpopulations using optogenetics, and opens new frontiers of exploration into their physiological roles in normal heart function as well as their potential application for selective cardiac repair and regeneration strategies. PMID- 28084431 TI - Effects of individual micronutrients on blood pressure in patients with type 2 diabetes: a systematic review and meta-analysis of randomized clinical trials. AB - To investigate the effects of micronutrients on blood pressure (BP) in patients with type 2 diabetes through a systematic review and meta-analysis, randomized clinical trials (RCTs) of the effects of individual micronutrients on BP in patients with type 2 diabetes were searched in the Medline, Embase, Cochrane, and Clinical Trials.gov databases through April 2016. From the 28,164 studies, 11 RCTs (13 interventions, 723 patients, 54% males) with 3 to 52 weeks of follow-up were classified according to the type of micronutrient intervention: sodium (n = 1), vitamin C (n = 2), vitamin D (n = 7), and magnesium (n = 1). The available data enabled us to perform meta-analyses of vitamins C and D. Vitamin C reduced diastolic BP [WMD -2.88 mmHg (95%CI -5.31, -0.46; P = 0.020)] but not systolic BP [WMD -3.93 mmHg (95%CI -14.78, 6.92; P = 0.478)]. Vitamin D caused a reduction of 4.56 mmHg (WMD; 95%CI -7.65, -1.47; P = 0.004) for systolic BP and 2.44 mm Hg (WMD; 95%CI -3.49, -1.39; P < 0.001) for diastolic BP. In conclusion, vitamin D and possibly vitamin C have beneficial effects on BP in patients with type 2 diabetes. These interventions might represent a novel approach to the treatment of hypertension in these patients. PMID- 28084433 TI - Effect of crystal plane orientation on tribochemical removal of monocrystalline silicon. AB - The effect of crystal plane orientation on tribochemical removal of monocrystalline silicon was investigated using an atomic force microscope. Experimental results indicated that the tribochemical removal of silicon by SiO2 microsphere presented strong crystallography-induced anisotropy. Further analysis suggested that such anisotropic tribochemical removal of silicon was not dependent on the crystallography-dependent surface mechanical properties (i.e., hardness and elastic modulus), but was mainly attributed to various atomic planar density and interplanar spacing in different crystal planes. Phenomenological results speculated that higher density of silicon atom could promote the formation of Si-O-Si bonds between the SiO2 microsphere and silicon substrate, resulting in more severe tribochemical material removal. Larger interplanar spacing with smaller energy barrier facilitated the rupture of the Si-Si network with the help of mechanical shearing stress, which caused more serious wear of the silicon surface. The results may help understand the material removal mechanism of silicon and provide useful knowledge for chemical mechanical polishing. PMID- 28084432 TI - Population genomic insights into variation and evolution of Xanthomonas oryzae pv. oryzae. AB - Xanthomonas oryzae pv. oryzae ( Xoo) is a serious pathogen of rice causing bacterial leaf blight disease. Resistant varieties and breeding programs are being hampered by the emergence of highly virulent strains. Herein we report population based whole genome sequencing and analysis of 100 Xoo strains from India. Phylogenomic analysis revealed the clustering of Xoo strains from India along with other Asian strains, distinct from African and US Xo strains. The Indian Xoo population consists of a major clonal lineage and four minor but highly diverse lineages. Interestingly, the variant alleles, gene clusters and highly pathogenic strains are primarily restricted to minor lineages L-II to L-V and in particularly to lineage L-III. We could also find the association of an expanded CRISPR cassette and a highly variant LPS gene cluster with the dominant lineage. Molecular dating revealed that the major lineage, L-I is youngest and of recent origin compared to remaining minor lineages that seems to have originated much earlier in the past. Further, we were also able to identify core effector genes that may be helpful in efforts towards building durable resistance against this pathogen. PMID- 28084434 TI - Impact and Origin of Interface States in MOS Capacitor with Monolayer MoS2 and HfO2 High-k Dielectric. AB - Two-dimensional layered semiconductors such as molybdenum disulfide (MoS2) at the quantum limit are promising material for nanoelectronics and optoelectronics applications. Understanding the interface properties between the atomically thin MoS2 channel and gate dielectric is fundamentally important for enhancing the carrier transport properties. Here, we investigate the frequency dispersion mechanism in a metal-oxide-semiconductor capacitor (MOSCAP) with a monolayer MoS2 and an ultra-thin HfO2 high-k gate dielectric. We show that the existence of sulfur vacancies at the MoS2-HfO2 interface is responsible for the generation of interface states with a density (Dit) reaching ~7.03 * 1011 cm-2 eV-1. This is evidenced by a deficit S:Mo ratio of ~1.96 using X-ray photoelectron spectroscopy (XPS) analysis, which deviates from its ideal stoichiometric value. First principles calculations within the density-functional theory framework further confirms the presence of trap states due to sulfur deficiency, which exist within the MoS2 bandgap. This corroborates to a voltage-dependent frequency dispersion of ~11.5% at weak accumulation which decreases monotonically to ~9.0% at strong accumulation as the Fermi level moves away from the mid-gap trap states. Further reduction in Dit could be achieved by thermally diffusing S atoms to the MoS2 HfO2 interface to annihilate the vacancies. This work provides an insight into the interface properties for enabling the development of MoS2 devices with carrier transport enhancement. PMID- 28084436 TI - Stress barriers controlling lateral migration of magma revealed by seismic tomography. AB - Understanding how monogenetic volcanic systems work requires full comprehension of the local and regional stresses that govern magma migration inside them and why/how they seem to change from one eruption to another. During the 2011-2012 El Hierro eruption (Canary Islands) the characteristics of unrest, including a continuous change in the location of seismicity, made the location of the future vent unpredictable, so short term hazard assessment was highly imprecise. A 3D P wave velocity model is obtained using arrival times of the earthquakes occurred during that pre-eruptive unrest and several latter post-eruptive seismic crises not related to further eruptions. This model reveals the rheological and structural complexity of the interior of El Hierro volcanic island. It shows a number of stress barriers corresponding to regional tectonic structures and blocked pathways from previous eruptions, which controlled ascent and lateral migration of magma and, together with the existence of N-S regional compression, reduced its options to find a suitable path to reach the surface and erupt. PMID- 28084435 TI - Comparative proteomic analysis of liver antioxidant mechanisms in Megalobrama amblycephala stimulated with dietary emodin. AB - Oxidative stress is a toxicological endpoint that correlates with the nutrition status of fish through cellular damage, inflammation, and apoptosis. In order to understand the antioxidant mechanism induced by dietary emodin in Megalobrama amblycephala liver, a comparative proteomic analysis was performed to investigate the proteome alteration under emodin administration. 27 altered protein spots were separated under 30 mg kg-1 emodin stimulation based on 2-DE, and were all successfully identified using MALDI-TOF/TOF, representing 17 unique proteins. These proteins were functionally classified into antioxidant, metabolism, cytoskeleton, chaperone, signal transduction and cofactor groups. Network interaction and Gene Ontology annotation indicated 10 unique proteins were closely related to antioxidation and directly regulated by each other. Compared with the control group, administration of 30 mg kg-1 emodin significantly increased the antioxidant-related mRNA expressions of GPx1, GSTm and HSP70, but decreased the mRNA expressions of GAPDH and Sord, which was consistent with the protein expression. Nevertheless, Pgk1 and Aldh8a1 were up- and down-regulated, and ALDOB was down- and up-regulated at the mRNA and protein levels, respectively. These results revealed that the altered proteins enhanced antioxidation via complex regulatory mechanisms, and 30 mg kg-1 emodin was a suitable immunostimulant for M. amblycephala. PMID- 28084437 TI - Observation of spin-polarized photoconductivity in (Ga,Mn)As/GaAs heterojunction without magnetic field. AB - In the absent of magnetic field, we have observed the anisotropic spin polarization degree of photoconduction (SPD-PC) in (Ga,Mn)As/GaAs heterojunction. We think three kinds of mechanisms contribute to the magnetic related signal, (i) (Ga,Mn)As self-producing due to the valence band polarization, (ii) unequal intensity of left and right circularly polarized light reaching to GaAs layer to excite unequal spin polarized carriers in GaAs layer, and (iii) (Ga,Mn)As as the spin filter layer for spin transport from GaAs to (Ga,Mn)As. Different from the previous experiments, the influence coming from the Zeeman splitting induced by an external magnetic field can be avoided here. While temperature dependence experiment indicates that the SPD-PC is mixed with the magnetic uncorrelated signals, which may come from current induced spin polarization. PMID- 28084438 TI - Quantitative Fluorescence Quenching on Antibody-conjugated Graphene Oxide as a Platform for Protein Sensing. AB - We created an immunosensing platform for the detection of proteins in a buffer solution. Our sensing platform relies on graphene oxide (GO) nanosheets conjugated with antibodies to provide quantitative binding sites for analyte proteins. When analyte proteins and standard fluorescein-labelled proteins are competing for the binding sites, the assay exhibits quantitative fluorescence quenching by GO for the fluorescein-labelled proteins as determined by the analyte protein concentration. Because of this mechanism, measured fluorescence intensity from unquenched fluorescein-labelled protein was shown to increase with an increasing analyte protein concentration. As an alternative to the conventional enzyme-linked immunosorbent assay (ELISA), our method does not require an enzyme-linked second antibody for protein recognition and the enzyme for optical signal measurement. Thus, it is beneficial with its low cost and fewer systematic errors caused by the series of antigen-antibody recognition steps in ELISA. Immune globulin G (IgG) was introduced as a model protein to test our method and our results showed that the limit of detection for IgG was 4.67 pmol mL-1 in the buffer solution. This sensing mechanism could be developed into a promising biosensor for the detection of proteins, which would broaden the spectrum of GO applications in both analytical biochemistry and clinical diagnosis. PMID- 28084440 TI - Common risk variants for colorectal cancer: an evaluation of associations with age at cancer onset. AB - Common genetic risk variants for colorectal cancer (CRC) have been identified at approximately 40 loci by genome-wide association studies (GWAS). We investigated the association of these risk variants by age at onset of CRC using case-only and case-control analysis. A total of 1,962 CRC cases and 2,668 controls from two independent case-control studies conducted by Korea's National Cancer Center were included in this study. We genotyped 33 GWAS-identified single-nucleotide polymorphisms (SNPs) associated with CRC risk. The risk allele in SNP rs704017, located at 10q22.3 in the ZMIZ1-AS1 gene, was consistently less frequent among CRC patients aged <50 years than among CRC patients aged >=50 years in the case only analysis (odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.66-0.92, P = 2.7 * 10-3, in an additive model), although this did not surpass the threshold for multiple testing. The direction of associations between rs704017 and CRC risk differed by age group in the combined case-control analysis (<50 years: OR = 0.77, 95% CI = 0.60-0.98, P = 0.03 and >=50 years: OR = 1.13, 95% CI = 0.98-1.29, P = 0.09, in a dominant model); the p-values for heterogeneity (Pheterogeneity = 7.5 * 10-3) and for interaction were statistically significant (Pinteraction = 7.8 * 10-3, in the dominant model). Our results suggest that the CRC susceptibility SNP rs704017 has a hereditary effect on onset age of CRC. PMID- 28084439 TI - De novo AML exhibits greater microenvironment dysregulation compared to AML with myelodysplasia-related changes. AB - The interaction between the bone marrow microenvironment and malignant hematopoietic cells can result in the protection of leukemia cells from chemotherapy in both myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We, herein, characterized the changes in cytokine expression and the function of mesenchymal stromal cells (MSC) in patients with MDS, AML with myelodysplasia-related changes (MRC), a well-recognized clinical subtype of secondary AML, and de novo AML. We observed a significant inhibitory effect of MDS-MSC on T lymphocyte proliferation and no significant differences in any of the cytokines tested. AML-MSC inhibited T-cell proliferation only at a very low MSC/T cell ratio. When compared to the control, AML-MRCderived MSC presented a significant increase in IL6 expression, whereas de novo AML MSC presented a significant increase in the expression levels of VEGFA, CXCL12, RPGE2, IDO, IL1beta, IL6 and IL32, followed by a decrease in IL10 expression. Furthermore, data indicate that IL-32 regulates stromal cell proliferation, has a chemotactic potential and participates in stromal cell crosstalk with leukemia cells, which could result in chemoresistance. Our results suggest that the differences between AML-MRC and de novo AML also extend into the leukemic stem cell niche and that IL 32 can participate in the regulation of the bone marrow cytokine milieu. PMID- 28084441 TI - Heterogeneous patterns of DNA methylation-based field effects in histologically normal prostate tissue from cancer patients. AB - Prostate cancer (PC) diagnosis is based on histological evaluation of prostate needle biopsies, which have high false negative rates. Here, we investigated if cancer-associated epigenetic field effects in histologically normal prostate tissue may be used to increase sensitivity for PC. We focused on nine genes (AOX1, CCDC181 (C1orf114), GABRE, GAS6, HAPLN3, KLF8, MOB3B, SLC18A2, and GSTP1) known to be hypermethylated in PC. Using quantitative methylation-specific PCR, we analysed 66 malignant and 134 non-malignant tissue samples from 107 patients, who underwent ultrasound-guided prostate biopsy (67 patients had at least one cancer-positive biopsy, 40 had exclusively cancer-negative biopsies). Hypermethylation was detectable for all genes in malignant needle biopsy samples (AUC: 0.80 to 0.98), confirming previous findings in prostatectomy specimens. Furthermore, we identified a four-gene methylation signature (AOX1xGSTP1xHAPLN3xSLC18A2) that distinguished histologically non-malignant biopsies from patients with vs. without PC in other biopsies (AUC = 0.65; sensitivity = 30.8%; specificity = 100%). This signature was validated in an independent patient set (59 PC, 36 adjacent non-malignant, and 9 normal prostate tissue samples) analysed on Illumina 450 K methylation arrays (AUC = 0.70; sensitivity = 40.6%; specificity = 100%). Our results suggest that a novel four gene signature may be used to increase sensitivity for PC diagnosis through detection of epigenetic field effects in histologically non-malignant prostate tissue samples. PMID- 28084442 TI - P-HYDROXYPHENYLPYRUVATE DIOXYGENASE from Medicago sativa is involved in vitamin E biosynthesis and abscisic acid-mediated seed germination. AB - P-HYDROXYPHENYLPYRUVATE DIOXYGENASE (HPPD) is the first committed enzyme involved in the biosynthesis of vitamin E, and is characterized by catalyzing the conversion of p-hydroxyphenyl pyruvate (HPP) to homogentisic acid (HGA). Here, an HPPD gene was cloned from Medicago sativa L. and designated MsHPPD, which was expressed at high levels in alfalfa leaves. PEG 6000 (polyethylene glycol), NaCl, abscisic acid and salicylic acid were shown to significantly induce MsHPPD expression, especially in the cotyledons and root tissues. Overexpression of MsHPPD was found to significantly increase the level of beta-tocotrienol and the total vitamin E content in Arabidopsis seeds. Furthermore, these transgenic Arabidopsis seeds exhibited an accelerated germination time, compared with wild type seeds under normal conditions, as well as under NaCl and ABA treatments. Meanwhile, the expression level of several genes associated with ABA biosynthesis (NCED3, NCED5 and NCED9) and the ABA signaling pathway (RAB18, ABI3 and ABI5) were significantly down-regulated in MsHPPD-overexpressing transgenic lines, as well as the total free ABA content. Taken together, these results demonstrate that MsHPPD functions not only in the vitamin E biosynthetic pathway, but also plays a critical role in seed germination via affecting ABA biosynthesis and signaling. PMID- 28084444 TI - Transparent EuTiO3 films: a possible two-dimensional magneto-optical device. AB - The magneto-optical activity of high quality transparent thin films of insulating EuTiO3 (ETO) deposited on a thin SrTiO3 (STO) substrate, both being non-magnetic materials, are demonstrated to be a versatile tool for light modulation. The operating temperature is close to room temperature and allows for multiple device engineering. By using small magnetic fields birefringence of the samples can be switched off and on. Similarly, rotation of the sample in the field can modify its birefringence Deltan. In addition, Deltan can be increased by a factor of 4 in very modest fields with simultaneously enhancing the operating temperature by almost 100 K. PMID- 28084443 TI - DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function. AB - Parkinson's disease is a neurodegenerative disorder characterized by the death of dopaminergic neurons and by accumulation of alpha-synuclein (aS) aggregates in the surviving neurons. The dopamine catabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is a highly reactive and toxic molecule that leads to aS oligomerization by covalent modifications to lysine residues. Here we show that DOPAL-induced aS oligomer formation in neurons is associated with damage of synaptic vesicles, and with alterations in the synaptic vesicles pools. To investigate the molecular mechanism that leads to synaptic impairment, we first aimed to characterize the biochemical and biophysical properties of the aS-DOPAL oligomers; heterogeneous ensembles of macromolecules able to permeabilise cholesterol-containing lipid membranes. aS-DOPAL oligomers can induce dopamine leak in an in vitro model of synaptic vesicles and in cellular models. The dopamine released, after conversion to DOPAL in the cytoplasm, could trigger a noxious cycle that further fuels the formation of aS-DOPAL oligomers, inducing neurodegeneration. PMID- 28084446 TI - A New Insight of Graphene oxide-Fe(III) Complex Photochemical Behaviors under Visible Light Irradiation. AB - Graphene oxide (GO) contains not only aromatic carbon lattice but also carboxyl groups which enhanced the aqueous solubility of GO. To study the transformation of GO nanosheets in natural environments, GO aqueous dispersion was mixed with Fe3+ ions to form photoactive complex. Under visible light irradiation, Fe(III) of the complex would be reduced to Fe(II) which could subsequently reduce highly toxic Cr(VI) to Cr3+. The electron of the reduction was contributed by the decarboxylation of carboxyl groups on GO and iron was acting as a catalyst during the photoreduction. On the other hand, the consumption of carboxyl groups may convert GO to rGO which are tend to aggregate since the decreased electrostatic repulsion and the increased pi-pi attraction. The formed Cr3+ may be electrostatically adsorbed by the rGO sheets and simultaneously precipitated with the aggregated rGO sheets, resulting the effective removal of chromium and GO nanosheets from the aqueous environment. This study may shed a light on understanding the environmental transformation of GO and guide the treatment of Cr(VI). PMID- 28084445 TI - TFEB-mediated increase in peripheral lysosomes regulates store-operated calcium entry. AB - Lysosomes are membrane-bound organelles mainly involved in catabolic processes. In addition, lysosomes can expel their contents outside of the cell via lysosomal exocytosis. Some of the key steps involved in these important cellular processes, such as vesicular fusion and trafficking, require calcium (Ca2+) signaling. Recent data show that lysosomal functions are transcriptionally regulated by transcription factor EB (TFEB) through the induction of genes involved in lysosomal biogenesis and exocytosis. Given these observations, we investigated the roles of TFEB and lysosomes in intracellular Ca2+ homeostasis. We studied the effect of transient modulation of TFEB expression in HeLa cells by measuring the cytosolic Ca2+ response after capacitative Ca2+ entry activation and Ca2+ dynamics in the endoplasmic reticulum (ER) and directly in lysosomes. Our observations show that transient TFEB overexpression significantly reduces cytosolic Ca2+ levels under a capacitative influx model and ER re-uptake of calcium, increasing the lysosomal Ca2+ buffering capacity. Moreover, lysosomal destruction or damage abolishes these TFEB-dependent effects in both the cytosol and ER. These results suggest a possible Ca2+ buffering role for lysosomes and shed new light on lysosomal functions during intracellular Ca2+ homeostasis. PMID- 28084447 TI - High response speed microfluidic ice valves with enhanced thermal conductivity and a movable refrigeration source. AB - Due to their ease of fabrication, facile use and low cost, ice valves have great potential for use in microfluidic platforms. For this to be possible, a rapid response speed is key and hence there is still much scope for improvement in current ice valve technology. Therefore, in this study, an ice valve with enhanced thermal conductivity and a movable refrigeration source has been developed. An embedded aluminium cylinder is used to dramatically enhance the heat conduction performance of the microfluidic platform and a movable thermoelectric unit eliminates the thermal inertia, resulting in a faster cooling process. The proposed ice valve achieves very short closing times (0.37 s at 10 MUL/min) and also operates at high flow rates (1150 MUL/min). Furthermore, the response time of the valve decreased by a factor of 8 when compared to current state of the art technology. PMID- 28084448 TI - Selective and Catalyst-free Oxidation of D-Glucose to D-Glucuronic acid induced by High-Frequency Ultrasound. AB - This systematic experimental investigation reveals that high-frequency ultrasound irradiation (550 kHz) induced oxidation of D-glucose to glucuronic acid in excellent yield without assistance of any (bio)catalyst. Oxidation is induced thanks to the in situ production of radical species in water. Experiments show that the dissolved gases play an important role in governing the nature of generated radical species and thus the selectivity for glucuronic acid. Importantly, this process yields glucuronic acid instead of glucuronate salt typically obtained via conventional (bio)catalyst routes, which is of huge interest in respect of downstream processing. Investigations using disaccharides revealed that radicals generated by high frequency ultrasound were also capable of promoting tandem hydrolysis/oxidation reactions. PMID- 28084449 TI - Population Structure Analysis of Bull Genomes of European and Western Ancestry. AB - Since domestication, population bottlenecks, breed formation, and selective breeding have radically shaped the genealogy and genetics of Bos taurus. In turn, characterization of population structure among diverse bull (males of Bos taurus) genomes enables detailed assessment of genetic resources and origins. By analyzing 432 unrelated bull genomes from 13 breeds and 16 countries, we demonstrate genetic diversity and structural complexity among the European/Western cattle population. Importantly, we relaxed a strong assumption of discrete or admixed population, by adapting latent variable models for individual-specific allele frequencies that directly capture a wide range of complex structure from genome-wide genotypes. As measured by magnitude of differentiation, selection pressure on SNPs within genes is substantially greater than that on intergenic regions. Additionally, broad regions of chromosome 6 harboring largest genetic differentiation suggest positive selection underlying population structure. We carried out gene set analysis using SNP annotations to identify enriched functional categories such as energy-related processes and multiple development stages. Our population structure analysis of bull genomes can support genetic management strategies that capture structural complexity and promote sustainable genetic breadth. PMID- 28084450 TI - Bleaching drives collapse in reef carbonate budgets and reef growth potential on southern Maldives reefs. AB - Sea-surface temperature (SST) warming events, which are projected to increase in frequency and intensity with climate change, represent major threats to coral reefs. How these events impact reef carbonate budgets, and thus the capacity of reefs to sustain vertical growth under rising sea levels, remains poorly quantified. Here we quantify the magnitude of changes that followed the ENSO induced SST warming that affected the Indian Ocean region in mid-2016. Resultant coral bleaching caused an average 75% reduction in coral cover (present mean 6.2%). Most critically we report major declines in shallow fore-reef carbonate budgets, these shifting from strongly net positive (mean 5.92 G, where G = kg CaCO3 m-2 yr-1) to strongly net negative (mean -2.96 G). These changes have driven major reductions in reef growth potential, which have declined from an average 4.2 to -0.4 mm yr-1. Thus these shallow fore-reef habitats are now in a phase of net erosion. Based on past bleaching recovery trajectories, and predicted increases in bleaching frequency, we predict a prolonged period of suppressed budget and reef growth states. This will limit reef capacity to track IPCC projections of sea-level rise, thus limiting the natural breakwater capacity of these reefs and threatening reef island stability. PMID- 28084451 TI - Optimization-based design of a heat flux concentrator. AB - To gain control over the diffusive heat flux in a given domain, one needs to engineer a thermal metamaterial with a specific distribution of the generally anisotropic thermal conductivity throughout the domain. Until now, the appropriate conductivity distribution was usually determined using transformation thermodynamics. By this way, only a few particular cases of heat flux control in simple domains having simple boundary conditions were studied. Thermal metamaterials based on optimization algorithm provides superior properties compared to those using the previous methods. As a more general approach, we propose to define the heat control problem as an optimization problem where we minimize the error in guiding the heat flux in a given way, taking as design variables the parameters that define the variable microstructure of the metamaterial. In the present study we numerically demonstrate the ability to manipulate heat flux by designing a device to concentrate the thermal energy to its center without disturbing the temperature profile outside it. PMID- 28084452 TI - A 'Landscape physiology' approach for assessing bee health highlights the benefits of floral landscape enrichment and semi-natural habitats. AB - Understanding how anthropogenic landscape alteration affects populations of ecologically- and economically-important insect pollinators has never been more pressing. In this context, the assessment of landscape quality typically relies on spatial distribution studies, but, whether habitat-restoration techniques actually improve the health of targeted pollinator populations remains obscure. This gap could be filled by a comprehensive understanding of how gradients of landscape quality influence pollinator physiology. We therefore used this approach for honey bees (Apis mellifera) to test whether landscape patterns can shape bee health. We focused on the pre-wintering period since abnormally high winter colony losses have often been observed. By exposing colonies to different landscapes, enriched in melliferous catch crops and surrounded by semi-natural habitats, we found that bee physiology (i.e. fat body mass and level of vitellogenin) was significantly improved by the presence of flowering catch crops. Catch crop presence was associated with a significant increase in pollen diet diversity. The influence of semi-natural habitats on bee health was even stronger. Vitellogenin level was in turn significantly linked to higher overwintering survival. Therefore, our experimental study, combining landscape ecology and bee physiology, offers an exciting proof-of-concept for directly identifying stressful or suitable landscapes and promoting efficient pollinator conservation. PMID- 28084453 TI - Wide-gamut plasmonic color filters using a complementary design method. AB - Plasmonic color filters (PCFs) can acquire primary colors from non-polarized incident light through a two-dimensional arrangement of subwavelength holes. However, owing to the geometry of the 2D array, unintended secondary transmitted peaks derived from the higher-order modes of the surface plasmon resonance (SPR) lead to color cross-talk with the primary peaks. Herein, we propose a complementary design method for generating high-purity red, green, and blue (R/G/B) by combining the G/B filters of hole-arrays with the R filters of dot arrays. Metallic dot-array filters, wherein the wavelength band under 575 nm was effectively blocked by the induction of peak broadening, operated as optical high pass filters exhibiting pure red, and consequently widen the color gamut of PCFs by 30% without loss of luminance and color tunability. This harmonious combination promises to yield competitiveness for a next-generation color filter by enhancing the color reproducibility of plasmonic nanostructures. PMID- 28084454 TI - Significantly enhanced osteoblast response to nano-grained pure tantalum. AB - Tantalum (Ta) metal is receiving increasing interest as biomaterial for load bearing orthopedic applications and the synthetic properties of Ta can be tailored by altering its grain structures. This study evaluates the capability of sliding friction treatment (SFT) technique to modulate the comprehensive performances of pure Ta. Specifically, novel nanocrystalline (NC) surface with extremely small grains (average grain size of <=20 nm) was fabricated on conventional coarse-grained (CG) Ta by SFT. It shows that NC surface possessed higher surface hydrophilicity and enhanced corrosion resistance than CG surface. Additionally, the NC surface adsorbed a notably higher percentage of protein as compared to CG surface. The in vitro results indicated that in the initial culture stages (up to 24 h), the NC surface exhibited considerably enhanced osteoblast adherence and spreading, consistent with demonstrated superior hydrophilicity on NC surface. Furthermore, within the 14 days culture period, NC Ta surface exhibited a remarkable enhancement in osteoblast cell proliferation, maturation and mineralization as compared to CG surface. Ultimately, the improved osteoblast functions together with the good mechanical and anti-corrosion properties render the SFT-processed Ta a promising alternative for the load bearing bone implant applications. PMID- 28084455 TI - Spectral responses of gravel beaches to tidal signals. AB - Tides have been recognized as a major driving forcing affecting coastal aquifer system, and deterministic modeling has been very effective in elucidating mechanisms caused by tides. However, such modeling does not lend itself to capture embedded information in the signal, and rather focuses on the primary processes. Here, using yearlong data sets measured at beaches in Alaska Prince William Sound, we performed spectral and correlation analyses to identify temporal behavior of pore-water pressure, temperature and salinity. We found that the response of the beach system was characterized by fluctuations of embedded diurnal, semidiurnal, terdiurnal and quarterdiurnal tidal components. Hydrodynamic dispersion of salinity and temperature, and the thermal conductivity greatly affected pore water signals. Spectral analyses revealed a faster dissipation of the semi-diurnal component with respect to the diurnal components. Correlation functions showed that salinity had a relatively short memory of the tidal signal when inland freshwater recharge was large. In contrast, the signature of the tidal signal on pore-water temperature persisted for longer times, up to a week. We also found that heterogeneity greatly affected beach response. The response varied from a simple linear mapping in the frequency domain to complete modulation and masking of the input frequencies. PMID- 28084456 TI - Synergy of Lewis and Bronsted acids on catalytic hydrothermal decomposition of carbohydrates and corncob acid hydrolysis residues to 5-hydroxymethylfurfural. AB - 5-hydroxymethylfurfural (HMF) is an important platform molecule in the synthesis of various chemicals and materials. Herein, we reported a simple and effective dehydration of glucose-based carbohydrates to HMF in a biphasic system containing cyclopentyl methyl ether as the organic phase and AlCl3 with minute amounts of HCl as co-catalysts. The results showed that the mixed catalysts had a positive synergistic catalytic effect on glucose conversion to HMF compared with single AlCl3 or HCl catalyst. For glucose, the highest HMF yield of 54.5% was achieved at 175 degrees C for 20 min. More importantly, the optimal catalytic system was so efficient that it achieved one of the highest reported yields of HMF (30.5%) directly from corncob acid hydrolysis residues. Thus, the catalytic system can become a promising route for effective utilization of biomass in future biorefineries. PMID- 28084457 TI - Atmospheric footprint of the recent warming slowdown. AB - Growing body of literature has developed to detect the role of ocean heat uptake and transport in the recent warming slowdown between 1998-2013; however, the atmospheric footprint of the slowdown in dynamical and physical processes remains unclear. Here, we divided recent decades into the recent hiatus period and the preceding warming period (1983-1998) to investigate the atmospheric footprint. We use a process-resolving analysis method to quantify the contributions of different processes to the total temperature changes. We show that the increasing rate of global mean tropospheric temperature was also reduced during the hiatus period. The decomposed trends due to physical processes, including surface albedo, water vapour, cloud, surface turbulent fluxes and atmospheric dynamics, reversed the patterns between the two periods. The changes in atmospheric heat transport are coupled with changes in the surface latent heat flux across the lower troposphere (below approximately 800 hPa) and with cloud-related processes in the upper troposphere (above approximately 600 hPa) and were underpinned by strengthening/weakening Hadley Circulation and Walker Circulation during the warming/hiatus period. This dynamical coupling experienced a phase transition between the two periods, reminding us of the importance of understanding the atmospheric footprint, which constitutes an essential part of internal climate variability. PMID- 28084459 TI - Can zinc aluminate-titania composite be an alternative for alumina as microelectronic substrate? AB - Alumina, thanks to its superior thermal and dielectric properties, has been the leading substrate over several decades, for power and microelectronics circuits. However, alumina lacks thermal stability since its temperature coefficient of resonant frequency (tauf) is far from zero (-60 ppmK-1). The present paper explores the potentiality of a ceramic composite 0.83ZnAl2O4-0.17TiO2 (in moles, abbreviated as ZAT) substrates for electronic applications over other commercially-used alumina-based substrates and synthesized using a non-aqueous tape casting method. The present substrate has tauf of + 3.9 ppmK-1 and is a valuable addition to the group of thermo-stable substrates. The ZAT substrate shows a high thermal conductivity of 31.3 Wm-1K-1 (thermal conductivity of alumina is about 24.5 Wm-1K-1), along with promising mechanical, electrical and microwave dielectric properties comparable to that of alumina-based commercial substrates. Furthermore, the newly-developed substrate material shows exceptionally good thermal stability of dielectric constant, which cannot be met with any of the alumina-based HTCC substrates. PMID- 28084458 TI - Targeting the miR-200c/LIN28B axis in acquired EGFR-TKI resistance non-small cell lung cancer cells harboring EMT features. AB - MicroRNA (miR)-200 family members (miR-200s) are frequently silenced in advanced cancer and have been implicated in the process of epithelial-to-mesenchymal transition (EMT). We previously reported that miR-200s were silenced through promoter methylation in acquired EGFR-tyrosine kinase inhibitor (TKI) resistant non-small cell lung cancer (NSCLC) cells harboring EMT features. In this study, we examined the functional role of miR-200s in NSCLC cells and investigated a novel approach to overcoming acquired EGFR-TKI resistance. In the analysis of NSCLC cell lines, each of the miR-200s expression-silenced cell lines showed promoter methylation. Significant correlations between miR-200c silencing and several oncogenic pathway alterations, including EMT-changes and LIN28B overexpression, were observed in the database analysis. In addition, EGFR-wild type cell lines had lower miR-200s expression levels than EGFR-mutant cell lines. The introduction of miR-200c using pre-miR-200c caused LIN28B suppression in cells with acquired EGFR-TKI resistance that harbored EMT features. Interestingly, both the introduction of miR-200c and the knockdown of LIN28B produced an antitumor effect in acquired EGFR-TKI resistance cells, whereas these manipulations were not effective in parental cells. The miR-200c/LIN28B axis plays an important role in cells with acquired resistance to EGFR-TKI that harbor EMT features and might be a useful therapeutic target for overcoming resistance. PMID- 28084460 TI - Transcript profile analysis reveals important roles of jasmonic acid signalling pathway in the response of sweet potato to salt stress. AB - Sweet potato is an important food and bio-energy crop, and investigating the mechanisms underlying salt tolerance will provide information for salt-tolerant breeding of this crop. Here, the root transcriptomes of the salt-sensitive variety Lizixiang and the salt-tolerant line ND98 were compared to identify the genes and pathways involved in salt stress responses. In total, 8,744 and 10,413 differentially expressed genes (DEGs) in Lizixiang and ND98, respectively, were involved in salt responses. A lower DNA methylation level was detected in ND98 than in Lizixiang. In both genotypes, the DEGs, which function in phytohormone synthesis and signalling and ion homeostasis, may underlie the different degrees of salt tolerance. Significant up-regulations of the genes involved in the jasmonic acid (JA) biosynthesis and signalling pathways and ion transport, more accumulation of JA, a higher degree of stomatal closure and a lower level of Na+ were found in ND98 compared to Lizixiang. This is the first report on transcriptome responses to salt tolerance in sweet potato. These results reveal that the JA signalling pathway plays important roles in the response of sweet potato to salt stress. This study provides insights into the mechanisms and genes involved in the salt tolerance of sweet potato. PMID- 28084462 TI - Corrigendum: Dynamics of plant DNA replication based on PCNA visualization. PMID- 28084461 TI - Dengue virus compartmentalization during antibody-enhanced infection. AB - Secondary infection with a heterologous dengue virus (DENV) serotype increases the risk of severe dengue, through a process termed antibody-dependent enhancement (ADE). During ADE, DENV is opsonized with non- or sub-neutralizing antibody levels that augment entry into monocytes and dendritic cells through Fc gamma receptors (FcgammaRs). We previously reported that co-ligation of leukocyte immunoglobulin-like receptor-B1 (LILRB1) by antibody-opsonized DENV led to recruitment of SH2 domain-containing phosphatase-1 (SHP-1) to dephosphorylate spleen tyrosine kinase (Syk) and reduce interferon stimulated gene induction. Here, we show that LILRB1 also signals through SHP-1 to attenuate the otherwise rapid acidification for lysosomal enzyme activation following FcgammaR-mediated uptake of DENV. Reduced or slower trafficking of antibody-opsonized DENV to lytic phagolysosomal compartments, demonstrates how co-ligation of LILRB1 also permits DENV to overcome a cell-autonomous immune response, enhancing intracellular survival of DENV. Our findings provide insights on how antiviral drugs that modify phagosome acidification should be used for viruses such as DENV. PMID- 28084463 TI - Sialic Acid-Responsive Polymeric Interface Material: From Molecular Recognition to Macroscopic Property Switching. AB - Biological systems that utilize multiple weak non-covalent interactions and hierarchical assemblies to achieve various bio-functions bring much inspiration for the design of artificial biomaterials. However, it remains a big challenge to correlate underlying biomolecule interactions with macroscopic level of materials, for example, recognizing such weak interaction, further transforming it into regulating material's macroscopic property and contributing to some new bio-applications. Here we designed a novel smart polymer based on polyacrylamide (PAM) grafted with lactose units (PAM-g-lactose0.11), and reported carbohydrate carbohydrate interaction (CCI)-promoted macroscopic properties switching on this smart polymer surface. Detailed investigations indicated that the binding of sialic acid molecules with the grafted lactose units via the CCIs induced conformational transformation of the polymer chains, further resulted in remarkable and reversible switching in surface topography, wettability and stiffness. With these excellent recognition and response capacities towards sialic acid, the PAM-g-lactose0.11 further facilitated good selectivity, strong anti-interference and high adsorption capacity in the capture of sialylated glycopeptides (important biomarkers for cancers). This work provides some enlightenment for the development of biointerface materials with tunable property, as well as high-performance glycopeptide enrichment materials. PMID- 28084465 TI - Inter-Layer Coupling Induced Valence Band Edge Shift in Mono- to Few-Layer MoS2. AB - Recent progress in the synthesis of monolayer MoS2, a two-dimensional direct band gap semiconductor, is paving new pathways toward atomically thin electronics. Despite the large amount of literature, fundamental gaps remain in understanding electronic properties at the nanoscale. Here, we report a study of highly crystalline islands of MoS2 grown via a refined chemical vapor deposition synthesis technique. Using high resolution scanning tunneling microscopy and spectroscopy (STM/STS), photoemission electron microscopy/spectroscopy (PEEM) and MU-ARPES we investigate the electronic properties of MoS2 as a function of the number of layers at the nanoscale and show in-depth how the band gap is affected by a shift of the valence band edge as a function of the layer number. Green's function based electronic structure calculations were carried out in order to shed light on the mechanism underlying the observed bandgap reduction with increasing thickness, and the role of the interfacial Sulphur atoms is clarified. Our study, which gives new insight into the variation of electronic properties of MoS2 films with thickness bears directly on junction properties of MoS2, and thus impacts electronics application of MoS2. PMID- 28084466 TI - Tip-Enhanced Raman Scattering Imaging of Two-Dimensional Tungsten Disulfide with Optimized Tip Fabrication Process. AB - We successfully achieve the tip-enhanced nano Raman scattering images of a tungsten disulfide monolayer with optimizing a fabrication method of gold nanotip by controlling the concentration of etchant in an electrochemical etching process. By applying a square-wave voltage supplied from an arbitrary waveform generator to a gold wire, which is immersed in a hydrochloric acid solution diluted with ethanol at various ratios, we find that both the conical angle and radius of curvature of the tip apex can be varied by changing the ratio of hydrochloric acid and ethanol. We also suggest a model to explain the origin of these variations in the tip shape. From the systematic study, we find an optimal condition for achieving the yield of ~60% with the radius of ~34 nm and the cone angle of ~35 degrees . Using representative tips fabricated under the optimal etching condition, we demonstrate the tip-enhanced Raman scattering experiment of tungsten disulfide monolayer grown by a chemical vapor deposition method with a spatial resolution of ~40 nm and a Raman enhancement factor of ~4,760. PMID- 28084464 TI - Proteoliposomal formulations of an HIV-1 gp41-based miniprotein elicit a lipid dependent immunodominant response overlapping the 2F5 binding motif. AB - The HIV-1 gp41 Membrane Proximal External Region (MPER) is recognized by broadly neutralizing antibodies and represents a promising vaccine target. However, MPER immunogenicity and antibody activity are influenced by membrane lipids. To evaluate lipid modulation of MPER immunogenicity, we generated a 1-Palmitoyl-2 oleoylphosphatidylcholine (POPC)-based proteoliposome collection containing combinations of phosphatidylserine (PS), GM3 ganglioside, cholesterol (CHOL), sphingomyelin (SM) and the TLR4 agonist monophosphoryl lipid A (MPLA). A recombinant gp41-derived miniprotein (gp41-MinTT) exposing the MPER and a tetanus toxoid (TT) peptide that favors MHC-II presentation, was successfully incorporated into lipid mixtures (>85%). Immunization of mice with soluble gp41 MinTT exclusively induced responses against the TT peptide, while POPC proteoliposomes generated potent anti-gp41 IgG responses using lower protein doses. The combined addition of PS and GM3 or CHOL/SM to POPC liposomes greatly increased gp41 immunogenicity, which was further enhanced by the addition of MPLA. Responses generated by all proteoliposomes targeted the N-terminal moiety of MPER overlapping the 2F5 neutralizing epitope. Our data show that lipids impact both, the epitope targeted and the magnitude of the response to membrane dependent antigens, helping to improve MPER-based lipid carriers. Moreover, the identification of immunodominant epitopes allows for the redesign of immunogens targeting MPER neutralizing determinants. PMID- 28084467 TI - Optimum Leaf Removal Increases Nitrogen Accumulation in Kernels of Maize Grown at High Density. AB - Increasing plant density is one of the main approaches of achieving higher yields for modern maize crop. However, there exists leaf redundancy for high-density maize, and leaves of the upper canopy shade more competent leaves at the middle strata. In a two-year field experiments, Jinhai5, a semi-compact corn cultivar, was grown at a density of 105,000 plants ha-1 grown until 3 days after silking (3DAS), when plants were subjected to removal of the uppermost two leaves (S2), four leaves (S4) or six leaves (S6), with no leaf removal as control (S0). We evaluated the effects of leaf removal on N remobilization, photosynthetic capacity of the remaining leaves for N uptake, and N accumulation in kernels. Our present results concluded that, under high plant density, excising the uppermost two leaves promoted N remobilization from vegetative organs to kernels and enhanced photosynthetic capacity for N uptake, leading to an increased N accumulation in kernels (19.6% higher than control). However, four or six uppermost leaves removal reduced N remobilization from stem and photosynthesis for poor N uptake, resulting in 37.5 and 50.2% significantly reduced N accumulation in kernels, respectively. PMID- 28084468 TI - Etanercept-Synthesising Mesenchymal Stem Cells Efficiently Ameliorate Collagen Induced Arthritis. AB - Mesenchymal stem cells (MSCs) have multiple properties including anti inflammatory and immunomodulatory effects in various disease models and clinical treatments. These beneficial effects, however, are sometimes inconsistent and unpredictable. For wider and proper application, scientists sought to improve MSC functions by engineering. We aimed to invent a novel method to produce synthetic biological drugs from engineered MSCs. We investigated the anti-arthritic effect of engineered MSCs in a collagen-induced arthritis (CIA) model. Biologics such as etanercept are the most successful drugs used in anti-cytokine therapy. Biologics are made of protein components, and thus can be theoretically produced from cells including MSCs. MSCs were transfected with recombinant minicircles encoding etanercept (trade name, Enbrel), which is a tumour necrosis factor alpha blocker currently used to treat rheumatoid arthritis. We confirmed minicircle expression in MSCs in vitro based on GFP. Etanercept production was verified from the conditioned media. We confirmed that self-reproduced etanercept was biologically active in vitro. Arthritis subsided more efficiently in CIA mice injected with mcTNFR2MSCs than in those injected with conventional MSCs or etanercept only. Although this novel strategy is in a very early conceptual stage, it seems to represent a potential alternative method for the delivery of biologics and engineering MSCs. PMID- 28084469 TI - Improvement of Uveal and Capsular Biocompatibility of Hydrophobic Acrylic Intraocular Lens by Surface Grafting with 2-Methacryloyloxyethyl Phosphorylcholine-Methacrylic Acid Copolymer. AB - Biocompatibility of intraocular lens (IOL) is critical to vision reconstruction after cataract surgery. Foldable hydrophobic acrylic IOL is vulnerable to the adhesion of extracellular matrix proteins and cells, leading to increased incidence of postoperative inflammation and capsule opacification. To increase IOL biocompatibility, we synthesized a hydrophilic copolymer P(MPC-MAA) and grafted the copolymer onto the surface of IOL through air plasma treatment. X-ray photoelectron spectroscopy, atomic force microscopy and static water contact angle were used to characterize chemical changes, topography and hydrophilicity of the IOL surface, respectively. Quartz crystal microbalance with dissipation (QCM-D) showed that P(MPC-MAA) modified IOLs were resistant to protein adsorption. Moreover, P(MPC-MAA) modification inhibited adhesion and proliferation of lens epithelial cells (LECs) in vitro. To analyze uveal and capsular biocompatibility in vivo, we implanted the P(MPC-MAA) modified IOLs into rabbits after phacoemulsification. P(MPC-MAA) modification significantly reduced postoperative inflammation and anterior capsule opacification (ACO), and did not affect posterior capsule opacification (PCO). Collectively, our study suggests that surface modification by P(MPC-MAA) can significantly improve uveal and capsular biocompatibility of hydrophobic acrylic IOL, which could potentially benefit patients with blood-aqueous barrier damage. PMID- 28084470 TI - A Nitric Oxide-Donating Statin Decreases Portal Pressure with a Better Toxicity Profile than Conventional Statins in Cirrhotic Rats. AB - Statins present many beneficial effects in chronic liver disease, but concerns about safety exist. We evaluated the hepatic effects of a nitric oxide-releasing atorvastatin (NCX 6560) compared to conventional statins. Simvastatin, atorvastatin and NCX 6560 were evaluated in four-week bile duct-ligated rats (BDL) simulating decompensated cirrhosis and in thirteen-week carbon tetrachloride (CCl4) intoxicated rats, a model of early cirrhosis. In the BDL model, simvastatin treated rats showed high mortality and the remaining animals presented muscular and hepatic toxicity. At equivalent doses, NCX 6560 eliminated hepatic toxicity and reduced muscular toxicity (60-74%) caused by atorvastatin in the more advanced BDL model; toxicity was minimal in the CCl4 model. Atorvastatin and NCX 6560 similarly reduced portal pressure without changing systemic hemodynamics in both models. Atorvastatin and NCX 6560 caused a mild decrease in liver fibrosis and inflammation and a significant increase in intrahepatic cyclic guanosine monophosphate. NCX 6560 induced a higher intrahepatic vasoprotective profile (activated endothelial nitric oxide synthase and decreased platelet/endothelial cell adhesion molecule-1), especially in the CCl4 model, suggesting a higher benefit in early cirrhosis. In conclusion, NCX 6560 improves the liver profile and portal hypertension of cirrhotic rats similarly to conventional statins, but with a much better safety profile. PMID- 28084471 TI - Fluorescence assay of dihydroorotate dehydrogenase that may become a cancer biomarker. AB - We developed an assay method for measuring dihydroorotate dehydrogenase (DHODH) activity in cultured HeLa cells and fibroblasts, and in stage III stomach cancer and adjacent normal tissues from the same patient. The assay comprised enzymatic reaction of DHODH with a large amount of dihydroorotic acid substrate, followed by fluorescence (FL) detection specific for orotic acid using the 4 trifluoromethyl-benzamidoxime fluorogenic reagent. The DHODH activities in the biologically complex samples were readily measured by the assay method. Our data indicate significantly higher DHODH activity in HeLa cells (340 +/- 25.9 pmol/105 cells/h) than in normal fibroblasts (54.1 +/- 7.40 pmol/105 cells/h), and in malignant tumour tissue (1.10 +/- 0.19 nmol/mg total proteins/h) than in adjacent normal tissue (0.24 +/- 0.11 nmol/mg total proteins/h). This is the first report that DHODH activity may be a diagnostic biomarker for cancer. PMID- 28084473 TI - Response to: Comment on "Invisible Victims: Delayed Onset Depression among Adults with Same-Sex Parents". PMID- 28084472 TI - Diabetes mellitus and the risk of total knee replacement among Chinese in Singapore, the Singapore Chinese Health Study. AB - Association between diabetes mellitus (diabetes) and risk of knee osteoarthritis (KOA) is confounded by high body mass index (BMI), a strong risk factor for both conditions. We evaluated the association between diabetes and incidence of total knee replacement (TKR) due to severe KOA in the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese men and women, aged 45-74 years at recruitment in 1993-1998, and re-interviewed in 1999-2004. Height, weight, lifestyle factors and history of diabetes were obtained through in-person interviews at recruitment and re-interview. Incident cases of TKR were identified via record linkage with nationwide hospital discharge database. Subjects with/without prevalent diabetes had comparable BMI (24.0 kg/m2 versus 23.0 kg/m2). After an average of 14-years, 1,973 subjects had TKR attributable to KOA. Compared to subjects without diabetes, hazard ratio (HR) of TKR for subjects with diabetes was 0.63 [95% confidence interval (CI), 0.52-0.75] after controlling for BMI and other risk factors. An inverse association was also observed between incident diabetes at re-interview and subsequent risk of TKR (HR = 0.74; 95% CI = 0.58-0.94). The inverse diabetes-TKR risk association was similar by gender and across three categories of BMI. Our study does not support diabetes as a risk factor of KOA. PMID- 28084474 TI - Increased solubility and fiber spinning of graphenide dispersions aided by crown ethers. AB - Graphenide solutions in NMP have been prepared by dispersing potassium intercalated graphite with the assistance of 18-crown-6. The highest graphenide solubility achieved is 1.5 mg mL-1. Graphenide solutions have been applied to spin graphene/SWCNT hybrid fibers. PMID- 28084475 TI - Harnessing ester bond chemistry for protein ligation. AB - The hydrolysis potential of ester bonds in covalently cross-linking proteins is captured in our novel protein ligation technology. This new type of "molecular superglue" based on the spontaneously-formed Thr-Gln ester bonds found in cell surface adhesins, affords a unique mechanism to both rationally assemble and disassemble complex protein nanomaterials. PMID- 28084476 TI - A conjugate Lewis base-Bronsted acid catalyst for the sulfenylation of nitrogen containing heterocycles under mild conditions. AB - Catalysts that contain a thiourea tethered to a carboxylic acid were found to affect the sulfenylation of indoles and other N-heterocycles on the hour time scale at room temperature. The mild nature of these conditions allowed for the incorporation of diverse functionalities into more complex heterocycles. PMID- 28084477 TI - Pick up, move and release of nanoparticles utilizing co-non-solvency of PNIPAM brushes. AB - A critical complication in handling nanoparticles is the formation of large aggregates when particles are dried e.g. when they need to be transferred from one liquid to another. The particles in these aggregates need to disperse into the destined liquid medium, which has been proven difficult due to the relatively large interfacial interaction forces between nanoparticles. We present a simple method to capture, move and release nanoparticles without the formation of large aggregates. To do so, we employ the co-non-solvency effect of poly(N isopropylacrylamide) (PNIPAM) brushes in water-ethanol mixtures. In pure water or ethanol, the densely end-anchored macromolecules in the PNIPAM brush stretch and absorb the solvent. We show that under these conditions, the adherence between the PNIPAM brush and a silicon oxide, gold, polystyrene or poly(methyl methacrylate) colloid attached to an atomic force microscopy cantilever is low. In contrast, when the PNIPAM brushes are in a collapsed state in a 30-70 vol% ethanol-water mixture, the adhesion between the brush and the different counter surfaces is high. For potential application, we demonstrate that this difference in adhesion can be utilized to pick up, move and release 900 silicon oxide nanoparticles of diameter 80 nm using only 10 * 10 MUm2 PNIPAM brush. PMID- 28084478 TI - Phase angle encoded upconversion luminescent nanocrystals for multiplexing applications. AB - Lanthanide-doped upconversion nanoparticles (UCNPs) are increasingly used as luminescent candidates in multiplexing applications due to their excellent optical properties. In the past, several encoding identities have been proposed for UCNPs, including emission colour, intensity ratio between different emission bands, colour spatial distribution, and luminescence lifetime. In this paper, a new optical encoding dimension for upconversion nanomaterials is developed by exploring their luminescence kinetics, i.e., the phase angle of upconversion luminescence in response to a harmonic-wave excitation. Our theoretical derivation shows that the phase angle is governed jointly by the rise and decay times, characterizing the upconversion luminescence kinetics. Experimentally, a full set of methods are developed to manage the upconversion luminescence kinetics, through which the rise and decay times can be manipulated dependently or independently. Furthermore, a large phase-angle space is achieved in which tens of unique codes can potentially be generated in the same colour channel. Our work greatly extends the multiplexing capacity of UCNPs, and offers new opportunities for their applications in a wide range such as microarray assays, bioimaging, anti-counterfeiting, deep tissue multiplexing labelling/detection and high-density data storage. In addition, the development of this luminescence kinetics-based optical encoding strategy is also instructive for developing multiplexing techniques using other cascade luminescent systems that inherently lack multi-spectral channels, such as triplet-triplet annihilation molecule pairs. PMID- 28084479 TI - Chemical modification improves the stability of the DNA aptamer GBI-10 and its affinity towards tenascin-C. AB - Aptamers are useful tools in molecular imaging due to their numerous attractive properties, such as excellent affinity and selectivity to diverse types of target molecules and biocompatibility. We carried out structure-activity relationship studies with the tenascin-C (TN-C) binding aptamer GBI-10, which is a promising candidate in tumor imaging. To increase the tumor targeting ability and nuclease resistance under physiological conditions, systematic modifications of GBI-10 with single and multiple 2'-deoxyinosine (2'-dI) or d-/l-isonucleoside (d-/l isoNA) were performed. Results indicated that sector 3 of the proposed secondary structure is the most important region for specific binding with TN-C. By correlating the affinity of eighty-four GBI-10 derivatives with their predicted secondary structure by Zuker Mfold, we first validated the preferred secondary structure at 37 degrees C. We found that d-/l-isoNA modified GBI-10 derivatives exhibited improved affinity to the target as well as plasma stability. Affinity measurement and confocal imaging analysis highlighted one potent compound: 4AL/26TL/32TL, which possessed a significantly increased targeting ability to tumor cells. These results revealed the types of modified nucleotides, and the position and number of substituents in GBI-10 that were critical to the TN-C binding ability. Stabilized TN-C-binding DNA aptamers were prepared and they could be further developed for tumor imaging. Our strategy to introduce 2'-dI and d-/l-isoNA modifications after the selection process is likely to be generally applicable to improve the in vivo stability of aptamers without compromising their binding ability. PMID- 28084480 TI - A cell-permeable and triazole-forming fluorescent probe for glycoconjugate imaging in live cells. AB - A new fluorescence-forming probe, coumOCT, designed by fusing cyclooctyne with a coumarin fluorophore was successfully used for the imaging of azido glycoconjugates in living HeLa cells. This probe is cell-permeable and generates fluorescence after triazole formation, thus minimizing the background signal and enabling the real-time intracellular imaging of glycoconjugate trafficking. PMID- 28084481 TI - Heparin triggered dose dependent multi-color emission switching in water: a convenient protocol for heparinase I estimation in real-life biological fluids. AB - Oligo(p-phenylenevinylene) based bis-pyridinium derivatives show 'ratiometric' detection of heparin in water. For the first time, we present a dose-dependent, multi-color emission switching in the presence of heparin. The reversible self assembly of probes with heparin as the stimulus is also exploited for the screening of heparinase I enzyme. PMID- 28084482 TI - Programmed dissociation of dimer and trimer origami structures by aptamer-ligand complexes. AB - Dimer- and trimer-origami frames are bridged by duplexes that include caged, sequence-specific, anti-ATP and/or anti-cocaine aptamer sequences. The programmed dissociation of the origami dimers or trimers in the presence of ATP and/or cocaine ligands is demonstrated. The processes are followed by AFM imaging and by electrophoretic experiments. PMID- 28084483 TI - Fluorescence enhancement of oligodeoxynucleotides modified with green fluorescent protein chromophore mimics upon triplex formation. AB - Green fluorescent protein (GFP)-based molecular-rotor chromophores were attached to the 5-positions of deoxyuridines, and subsequently, incorporated into the middle positions of oligodeoxynucleotides. These oligonucleotides were designed to form triplex DNA in order to encapsulate the GFP chromophores, mimicking GFP structures. Upon triplex formation, the embedded GFP chromophores exhibited fluorescence enhancement, suggesting the potential application of these fluorescent probes for the detection of nucleic acids. PMID- 28084484 TI - Singlet fission in pancake-bonded systems. AB - We theoretically investigate the potential of pancake-bonded systems for efficient singlet fission by examining phenalenyl radical dimer and tetramer models. In the dimer model, we propose an efficient way to satisfy the excitation energy level matching required for singlet fission by tuning the diradical character by changing the intermolecular distance. In the tetramer model, electronic couplings required for both singlet fission and charge mobility are found to be maximized simultaneously in the face-to-face configuration, which is usually known to be difficult to achieve due to a trade-off relationship between them in conventional pi-conjugated molecules like pentacene. In addition, on the basis of the quasi-degenerate second-order perturbation analysis, we obtain a simplified and more efficient crystal-structure design guideline that pancake bonded systems cause highly-active singlet fission. PMID- 28084485 TI - Molecular polypyridine-based metal complexes as catalysts for the reduction of CO2. AB - Polypyridyl transition metal complexes represent one of the more thoroughly studied classes of molecular catalysts towards CO2 reduction to date. Initial reports in the 1980s began with an emphasis on 2nd and 3rd row late transition metals, but more recently the focus has shifted towards earlier metals and base metals. Polypyridyl platforms have proven quite versatile and amenable to studying various parameters that govern product distribution for CO2 reduction. However, open questions remain regarding the key mechanistic steps that govern product selectivity and efficiency. Polypyridyl complexes have also been immobilized through a variety of methods to afford active catalytic materials for CO2 reductions. While still an emerging field, materials incorporating molecular catalysts represent a promising strategy for electrochemical and photoelectrochemical devices capable of CO2 reduction. In general, this class of compounds remains the most promising for the continued development of molecular systems for CO2 reduction and an inspiration for the design of related non polypyridyl catalysts. PMID- 28084486 TI - Selective sensing of ethylene and glucose using carbon-nanotube-based sensors: an ab initio investigation. AB - Functionalized carbon nanotubes have great potential for nanoscale sensing applications, yet many aspects of their sensing mechanisms are not understood. Here, two paradigmatic sensor configurations for detection of biologically important molecules are investigated through ab initio calculations: a non covalently functionalized nanotube for glucose detection and a covalently functionalized nanotube for ethylene detection. Glucose and ethylene control key life processes of humans and plants, respectively, despite of their structural and chemical simplicity. The sensors' electrical conductance and transmission coefficients are evaluated at the full density-functional theory level via the non-equilibrium Green's function method. We also investigate the effects of the density of the receptors, the band gaps of the nanotubes, the source-drain voltages, and the atomic modification of the receptor on detection sensitivities. A clear atomistic picture emerges about the mechanisms involved in glucose and ethylene sensing. While semiconducting nanotubes exhibit good sensitivities in both cases, the current through metallic nanotubes is only weakly affected by analyte attachment. These quantitative results could guide the design of improved sensors. PMID- 28084487 TI - Probing the triplet correlation function in liquid water by experiments and molecular simulations. AB - Despite very significant developments in scattering experiments like X-ray and neutron diffraction, it has been challenging to elucidate the nature of tetrahedral molecular configurations in liquid water. A key question is whether the pair correlation functions, which can be obtained from scattering experiments, are sufficient to describe the tetrahedral ordering of water molecules. In our previous study (Dhabal et al., J. Chem. Phys., 2014, 141, 174504), using data-sets generated from reverse Monte Carlo and molecular dynamics simulations, we showed that the triplet correlation functions contain important information on the tetrahedrality of water in the liquid state. In the present study, X-ray scattering experiments and molecular dynamics (MD) simulations are used to link the isothermal pressure derivative of the structure factor with the triplet correlation functions for water. Triplet functions are determined for water up to 3.3 kbar at 298 K to display the effect of pressure on the water structure. The results suggest that triplet functions (H[combining tilde](q)) obtained using a rigid-body TIP4P/2005 water model are consistent with the experimental results. The triplet functions obtained in experiment as well as in simulations evince that in the case of tetrahedral liquids, exertion of higher pressure leads to a better agreement with the Kirkwood superposition approximation (KSA). We further validate this observation using the triplet correlation functions (g(3)(r,s,t)) calculated directly from simulation trajectory, revealing that both H[combining tilde](q) in q-space and g(3)(r,s,t) in real-space contain similar information on the tetrahedrality of liquids. This study demonstrates that the structure factor, even though it has only pair correlation information of the liquid structure, can shed light on three-body correlations in liquid water through its isothermal pressure derivative term. PMID- 28084488 TI - Kinetic enantioselectivity of a protonated bis(diamido)-bridged basket resorcin[4]arene towards alanine peptides. AB - Efficient enantiodiscrimination of some alanine-containing di- and tri-peptides by using chiral protonated bis(diamido)-bridged basket resorcin[4]arenes depends on several factors, including the basicity of the amino acid residues at the C- and N-termini of the peptide. PMID- 28084489 TI - Renewable-emodin-based wearable supercapacitors. AB - With the increasing dependency of human life on wearable electronics, the development of corresponding energy-storage devices is being insensitively pursued. Considering the special usage locations of wearable energy-storage devices, the safety and non-toxicity of electrode materials adopted should be of concern. In this work, a novel all-solid-state wearable supercapacitor based on the renewable-biomolecule emodin, naturally derivable from traditional Chinese herbal rhubarb or Polygonum cuspidatum, was successfully fabricated. Such supercapacitors exhibited excellent charge storage and rate capability with great flexibility and could be integrated into wearable electronics. As a proof of concept, a strap-shaped supercapacitor was fabricated, and it was capable of powering an electronic watch. Our work will promote the development of safe wearable electronics. PMID- 28084490 TI - On the nature of the electronic effect of multiple hydroxyl groups in the 6 membered ring - the effects are additive but steric hindrance plays a role too. AB - Research during the last two decades has shown a remarkable directional component of the substituent effects of hydroxy groups, which has a profound effect on the properties of hydroxylated compounds such as carbohydrates. While the epimerisation of a single hydroxyl function is well studied the consequence of multiple epimerisations is more speculative. In this work the effect of three epimerisations was investigated. To this end epimeric 2-phenyl iminoxylitols that have a phenyl group as a conformational anchor and thus hydroxyl groups in the axial or equatorial position, respectively, were synthesized and their pKa and conformation were studied. The results show that the large difference in the electronic effect between the axial and equatorial hydroxyls is partially cancelled by counteracting steric hindrance from 1,3-diaxial interactions. Hydrogen bonding does not appear to play any role in the electronic influence of the hydroxyl groups. PMID- 28084491 TI - Fracture of a model cohesive granular material. AB - We study experimentally the fracture mechanisms of a model cohesive granular medium consisting of glass beads held together by solidified polymer bridges. The elastic response of this material can be controlled by changing the cross-linking of the polymer phase, for example. Here we show that its fracture toughness can be tuned over an order of magnitude by adjusting the stiffness and size of the polymer bridges. We extract a well-defined fracture energy from fracture testing under a range of material preparations. This energy is found to scale linearly with the cross-sectional area of the bridges. Finally, X-ray microcomputed tomography shows that crack propagation is driven by adhesive failure of about one polymer bridge per bead located at the interface, along with microcracks in the vicinity of the failure plane. Our findings provide insight into the fracture mechanisms of this model material, and the mechanical properties of disordered cohesive granular media in general. PMID- 28084492 TI - Chemoselective generation of acyl phosphates, acylium ion equivalents, from carboxylic acids and an organophosphate ester in the presence of a Bronsted acid. AB - We describe the chemoselective conversion of carboxylic acids to functional aromatic ketones promoted by a tailored organophosphate ester in the presence of a Bronsted acid. The protonated phosphate ester reacts with the carboxylic acid to form acyl phosphate, which reacts with benzenes to give aromatic ketones, probably through the acylium ion or its equivalent. The reaction time is short even at room temperature, and the reaction is compatible with various other functional groups, including amines, olefins, esters, amides and nitriles. PMID- 28084493 TI - Development of a BODIPY-based fluorescent probe for imaging pathological tau aggregates in live cells. AB - Neuronal accumulation of tau aggregates is a pathological hallmark in multiple neurodegenerative disorders, collectively called tauopathies. A tau aggregation sensor that can monitor abnormal tau aggregation in neurons would facilitate the study of tau aggregation processes and the discovery of tau aggregation blockers. Here, we describe a BODIPY-fluorescence sensor (BD-tau) that selectively responds to pathological tau aggregates in live cells. PMID- 28084494 TI - [Botox(r) treatments - still not reimbursed by insurance?] PMID- 28084495 TI - Midterm outcomes following anatomic-based popliteus tendon reconstructions. AB - PURPOSE: The purpose of this study was to document subjective outcomes following anatomic-based reconstruction of the popliteus tendon when the popliteus tendon was the only injured posterolateral knee structure. It was hypothesized that popliteus tendon reconstruction would result in improved patient outcomes after surgery regardless of the concurrent ligamentous or intra articular pathology. METHODS: A consecutive series of 5 patients with a median age of 23 years (range, 22-36 years) who underwent anatomic popliteus tendon reconstruction along with concomitant ligament reconstruction or meniscus repair (if needed) were included in this study. All patients completed pre-operative and post-operative subjective questionnaires, which included the Lysholm score to document function, the Tegner activity scale to document activity level, and a patient satisfaction with outcome question. RESULTS: All patients were available for a final follow-up at a median time of 2.8 years (range, 2-3.9 years) following the index surgery. Three patients had a combined popliteus tendon and posterior cruciate ligament reconstruction. Two of the three PCL reconstructions were revision procedures. The Lysholm score improved to from 53 (range, 34-90) to 91 (range, 44-100) at post-operative follow-up. The median pre-operative Tegner activity scale improved from 3 (range, 0-9) to a median score of 4.8 (range, 2-7) at post-operative follow-up. The median patient satisfaction with outcome was 9 (range, 7-10). The dial test at 30 degrees and 90 degrees improved in all patients following surgery. CONCLUSIONS: Anatomic-based popliteus tendon reconstructions resulted in improved outcomes and a high patient satisfaction in patients with a complete tear of the popliteus tendon and symptomatic knee instability. LEVEL OF EVIDENCE: IV, case series. PMID- 28084497 TI - [The skin and pregnancy]. PMID- 28084496 TI - A quick and robust MHC typing method for free-ranging and captive primate species. AB - Gene products of the major histocompatibility complex (MHC) of human and non human primates play a crucial role in adaptive immunity, and most of the relevant genes not only show a high degree of variability (polymorphism) but also copy number variation (CNV) is observed. Due to this diversity, MHC proteins influence the capability of individuals to cope with various pathogens. MHC and/or MHC linked gene products such as odorant receptor genes are thought to influence mate choice and reproductive success. Therefore, MHC typing of wild and captive primate populations is considered to be useful in conservation biology, which is, however, often hampered by the need of invasive and time-consuming methods. All intact Mhc-DRB genes in primates appear to possess a complex and highly divergent microsatellite, DRB-STR. A panel of 154 pedigreed olive baboons (Papio anubis) was examined for their DRB content by DRB-STR analysis of genomic DNA. Using the same methodology on DNA of feces samples, DRB variability of a silvery gibbon population (Hylobates moloch) (N = 24), an endangered species, could successfully be studied. In both species, length determination of the DRB-STR resulted in the definition of unique genotyping patterns that appeared to be specific for a certain chromosome. Moreover, the different STR lengths were shown to segregate with the allelic variation of the respective gene. The results obtained expand data gained previously on DRB-STR typing in macaques, great apes, and humans and strengthen the conclusion that this protocol is applicable in molecular ecology, conservation biology, and colony management, especially of endangered primate species. PMID- 28084498 TI - [Melasma : An update on the clinical picture, treatment, and prevention]. AB - Melasma, also known as chloasma or mask of pregnancy, presents clinically as hyperpigmented skin areas, which develop mostly in the face as a consequence of increased synthesis of melanin. The established treatment options, including topically applied agents and the use of various laser systems, mostly result in improvement but not in complete remission of the lesions. Because of its significant impact on quality of life and the limited effectivity of available treatment options, the management of melasma is challenging for the treating physician. Although many risk factors, including pregnancy and UV exposure, have been identified, the pathogenesis is not yet fully understood. Avoiding solar or artificial UV exposure is of high importance both for the prevention of melasma and for the clinical outcome of existing lesions. In order to avoid vitamin D deficiency, oral vitamin D supplementation should be recommended. In this review, we give an update on clinical aspects, epidemiology, pathogenesis and therapy of melasma and give an outlook on future developments. PMID- 28084499 TI - [Telemedical prenotification in acute stroke treatment : Experiences from the Stroke Angel initiative from 2004 until the present]. AB - OBJECTIVE: The Stroke Angel initiative investigates the implementation of telemedicine for improvement of preclinical communication between emergency medical services (EMS) and stroke units in cases of acute stroke. MATERIAL AND METHODS: Stroke Angel is a technical system for the telemedical prenotification of patients in cases of suspected stroke at a stroke unit by the EMS. Within the framework of an observational study, the team has been investigating the effects of the system on door-to-computed tomography (CT) and door-to-needle times as well as the lysis rate in the neighboring regions of Rhon-Grabfeld and Bad Kissingen since 2005. RESULTS: The system supports the acute treatment of neurological emergencies and functions as a catalyst for the interlinking of medical institutions in the region as well as for communication between emergency physicians/EMS and hospital physicians. The use of a computer-based data collection enables a continuous improvement process leading to an acceleration of internal clinical procedures and an increase of the lysis rate with the mortality rate staying constant. CONCLUSION: Telemedicine is applicable in the preclinical care of acute stroke and, thanks to the computer-based data collection, leads to an increase in process transparency, which helps to improve the internal clinical processes in and around a stroke unit. PMID- 28084500 TI - [Pros and cons of antipsychotic drugs in Prodromal stages of schizophrenia]. PMID- 28084501 TI - [Acute renal failure in a 75-year-old woman with a high-output ileostoma]. AB - We report on a 75-year old woman who presented with acute oliguric renal failure. The kidney biopsy revealed calcium oxalate depositions in the tubular lumen, caused by an overload of intravenous ascorbic acid (cumulative dose of 240 g). Due to a lack of specific therapeutic interventions, the patient remained dialysis-dependent. Iatrogenic causes of kidney failure play an important role in the pathogenesis of kidney diseases and should always be considered in patients with acute renal failure. Detailed evaluation of the patient history is often suggestive, while renal biopsy can establish the diagnosis. PMID- 28084502 TI - [Neurogenic dysphagia]. AB - Approximately half of neurological and geriatric inpatients suffer from oropharyngeal dysphagia. This often leads to pneumonia, malnutrition and dehydration; however, the underlying dysphagia is frequently not diagnosed and treated. This is particularly the case for patients with so-called silent aspiration. Knowledge on the physiology of swallowing, including the central nervous system control of swallowing and the therapeutic options have achieved considerable progress in recent years. In particular, the increasing implementation of flexible endoscopic evaluation of swallowing (FEES) has significantly contributed to this knowledge. It provides the ability to identify the individual pattern of oropharyngeal dysphagia leading to a suitable selection of therapeutic and compensatory strategies for individual patients. The various therapeutic options range from modification of the consistency of the diet, over diverse logopedic strategies and stimulation techniques up to interventional procedures. PMID- 28084503 TI - [Dementia and comorbid conditions]. AB - Dementia belongs to the most frequently occurring problems among older patients. For most types of dementia no causal therapy is currently available. Comorbid somatic conditions in patients with dementia are the rule rather than the exception. These potentially modifiable conditions are of major interest and they can therefore play an important role. This includes the strict management of risk factors as well as the avoidance of drugs with delirogenic, anticholinergic and dementing side effects. Thus, treatment of delirium, hypertension, heart failure, anemia, diabetes is important to reduce the symptoms of dementia itself. Possible therapeutic treatment options are described. PMID- 28084504 TI - Quality of pediatric abdominal CT scans performed at a dedicated children's hospital and its referring institutions: a multifactorial evaluation. AB - BACKGROUND: Pediatric patients requiring transfer to a dedicated children's hospital from an outside institution may undergo CT imaging as part of their evaluation. Whether this imaging is performed prior to or after transfer has been shown to impact the radiation dose imparted to the patient. Other quality variables could also be affected by the pediatric experience and expertise of the scanning institution. OBJECTIVE: To identify differences in quality between abdominal CT scans and reports performed at a dedicated children's hospital, and those performed at referring institutions. MATERIALS AND METHODS: Fifty consecutive pediatric abdominal CT scans performed at outside institutions were matched (for age, gender and indication) with 50 CT scans performed at a dedicated freestanding children's hospital. We analyzed the scans for technical parameters, report findings, correlation with final clinical diagnosis, and clinical utility. Technical evaluation included use of intravenous and oral contrast agents, anatomical coverage, number of scan phases and size-specific dose estimate (SSDE) for each scan. Outside institution scans were re-reported when the child was admitted to the children's hospital; they were also re interpreted for this study by children's hospital radiologists who were provided with only the referral information given in the outside institution's report. Anonymized original outside institutional reports and children's hospital admission re-reports were analyzed by two emergency medicine physicians for ease of understanding, degree to which the clinical question was answered, and level of confidence in the report. RESULTS: Mean SSDE was lower (8.68) for children's hospital scans, as compared to outside institution scans (13.29, P = 0.03). Concordance with final clinical diagnosis was significantly lower for original outside institution reports (38/48, 79%) than for both the admission and study children's hospital reports (48/50, 96%; P = 0.005). Children's hospital admission reports were rated higher than outside institution reports for completeness, ease of understanding, answering of clinical question, and level of confidence of the report (P < 0.001). CONCLUSION: Pediatric abdominal CT scans performed and interpreted at a dedicated children's hospital are associated with higher technical quality, lower radiation dose and a more clinically useful report than those performed at referring institutions. PMID- 28084505 TI - The Effects of Biochar and Intercropping on the Cd, Cr and Zn Speciation in Soils and Plant Uptake by Machilus pauhoi. AB - A greenhouse pot experiment with biochar (BC) applied at 0%, 1%, 4% and 8% (w/w) in monoculture and intercropping settings was used to investigate Cd, Cr and Zn speciation in contaminated soils, the growth of two different plant types, and the heavy metal concentrations within these plants. The results showed that BC application increased the soil pH, decreased the bioavailability of Cd, Cr and Zn, significantly increased the dry biomass of Cassia occidentalis and Machilus pauhoi shoots and slightly increased the root biomass. Both BC addition and intercropping decreased the Cd, Cr and Zn contents in the M. pauhoi shoots and roots, but the effect of BC addition was more significant than the effect of intercropping. The Cd, Cr and Zn uptake by M. pauhoi shoots was reduced by up to 93.91%, 96.41% and 76.76%, respectively, when the concentration and bioavailability of Cd, Cr, and Zn were reduced by using the combination of intercropping and BC application. This treatment resulted in the greatest reduction efficiency, and resulted in a shoot biomass increase of M. pauhoi of up to 122.52% compared to the control (M. pauhoi monoculture). These results could be used as a reference for the promotion of M. pauhoi growth and the utilization of contaminated land. PMID- 28084506 TI - Distribution and Risk Assessment of Antibiotics in a Typical River in North China Plain. AB - We evaluated the occurrence and distribution of 12 antibiotics from the sulfonamide (SAs), fluoroquinolone (FQs) and tetracycline (TCs) groups in the Weihe River, North China. The total antibiotic concentrations in surface water, pore water, and sediment samples ranged from 11.1 to 173.1 ng/L, 5.8 to 103.9 ng/L, and 9.5 to 153.4 MUg/kg, respectively. The values of the sediment-water partitioning coefficient in the Weihe River varied widely, from not detected to 943, 2213, and 2405 L/kg for SAs, FQs, and TCs, respectively. The values of the partitioning coefficients between sediment and surface water were generally lower than those between sediment and pore water, which indicated ongoing inputs to the water. The risk assessment showed that there were relatively high ecological risks to aquatic algae in this area from sulfamethoxazole, norfloxacin, tetracycline, ofloxacin, and ciprofloxacin. PMID- 28084507 TI - Arsenic Environmental Threshold Surpass in Estuarine Sediments: Effects of Bioturbation. AB - We investigate the distributions of the metalloid arsenic (As) and metals iron (Fe) and manganese (Mn) in the sediments of two pristine areas of a biological reserve in the Patos Lagoon Estuary. This area is occupied by Spartina alterniflora and by Neohelice granulata crab colonies and low concentrations of As are expected. The bioturbation/bioirrigation of sediments by crabs and the roots of plants lead to the penetration of oxygen below the oxic/suboxix division and the subsequent precipitation of Fe-Mn hydroxides. Ferruginous incrustations and nodules along roots and crab channels propagate to depths of over 35 cm and sediment contains up to 33 mg kg- 1 of As. The metalloid distribution in sediments is strongly correlated with that of Fe but not with Mn. This study revealed that areas with biologically disturbed sediments could demonstrate contamination in As, which is not anthropogenic in origin. PMID- 28084508 TI - Determination of Traces of Pb, Cu and Cd in Seawater around Thane Creek by Anodic Stripping Voltammetry Method. AB - Trace metals (Pb, Cu and Cd) in seawater samples were pre-concentrated for the simultaneous quantitative determination using solvent extraction procedure in the presence of ammonium pyrrolidine dithiocarbamate (APDC) as complexing agent and methyl isobutyl ketone (MIBK) as organic phase and acid exchange back - extraction followed by its determination by Differential Pulse Anodic Stripping Voltammetry (DPASV). Concentrations of Pb, Cu and Cd vary from 3.0 to 9.44 ng/mL, 12.7 to 28.6 ng/mL and 0.31 to 1.21 ng/mL respectively in seawater samples collected from different locations across Thane Creek area, Mumbai, India. Pb, Cu, Cd concentration were observed to be higher in the eastern side of the Thane Creek as it is covered by various industries. PMID- 28084509 TI - Preparation and characterization of carbon dot-decorated silica stationary phase in deep eutectic solvents for hydrophilic interaction chromatography. AB - In this paper, N-doped carbon dots (NCDs) were successfully decorated on the spherical porous silica surface in deep eutectic solvents (DESs) as a novel class of green solvents. The appropriate density and hydrophility of DESs guaranteed the fine dispersibility of silica particles and NCDs, resulting in a homogeneous and thin layer of NCDs immobilization. As compared with traditional organic solvents (DMF and THF), higher surface coverage was obtained in the medium of DES, proving its feasibility as a new kind of alternative solvent for hydrophilic nanomaterial-based surface modification of silica spheres. The resulting NCDs decorated silica particles (Sil-NCDs) were characterized in detail and packed into chromatographic columns to study their initial feasibility as adsorbent material for liquid chromatography. The resultant packing materials demonstrate a selective behavior for polar compounds in hydrophilic interaction liquid chromatography (HILIC) mode. This work gives a typical example of using carbon dots as stationary phase component, and such material is hopeful to be used in other research fields such as solid absorbents, recycling catalysts, and solid state electrochemistry etc. Graphical Abstract N-doped carbon dots (NCDs) were successfully coupled on the surface of porous silica spheres in a green strategy using deep eutectic solvents (DES) as media for HILIC. PMID- 28084510 TI - Optimization of sample treatment for the identification of anthraquinone dyes by surface-enhanced Raman spectroscopy. AB - The study and characterization of old artifacts such as pigments requires the use of techniques that need a small amount of sample to perform the analysis because of the high value of these samples. In recent years, organic molecules such as anthraquinone dyes have been identified by surface-enhanced Raman spectroscopy (SERS). However, different sample treatments must be applied to isolate the organic dye from the mordant, which produces great fluorescence in the Raman measurements. In this work, optimization of sample treatment for the SERS analysis of anthraquinone dyes was performed. Sample mass, the organic solvent, and its volume were optimized and different slide materials and excitation lasers were compared to choose the best conditions for the identification of the dyes. The optimization of sample treatment resulted in 5 mg of sample as the optimum amount. Further, two consecutive extractions with 0.5 mL of ethyl acetate was the best option for the extraction of the dye. A quartz slide was used instead of a glass slide to reduce background signal, and an excitation laser of 532 nm offers better results than one of 785 nm. The optimized method was applied to the characterization of the dyes used in Pompeian pink and purple lake pigments. Alizarin and purpurin anthraquinone dyes, obtained from madder lake, were identified as the organic colorants. The SERS results were confirmed by those obtained by means of UV-visible spectroscopy. Graphical Abstract ?. PMID- 28084511 TI - A versatile ratiometric nanosensing approach for sensitive and accurate detection of Hg2+ and biological thiols based on new fluorescent carbon quantum dots. AB - Herein, we first reported a facile synthesis method for fabrication of highly photoluminescent carbon quantum dots (CQDs) using sodium alginate as the carbon source and histidine as both the nitrogen source and functional monomer by one pot hydrothermal synthesis. The as-prepared CQDs gave a high quantum yield of 32%. By employing the new CQDs and rhodamine B (RhB), we demonstrated a simple, facile, sensitive, and accurate ratiometric sensor for detection of Hg2+ and biological thiols. The photoluminescence of CQDs in the ratiometric sensor can be selectively and intensively suppressed by Hg2+ due to strong electrostatic interaction between the surface functional groups of the CQDs and Hg2+. When glutathione (GSH) was introduced into the "Turn Off" CQDs-RhB-Hg2+ sensing system, the fluorescence of the CQDs can be recovered rapidly due to the stronger affinity between thiol and Hg2+, while the fluorescence of the RhB remained constant in this sensing process. Based on the above principle, the ratiometric strategy for detecting Hg2+ and GSH can be achieved readily, and gives satisfactory limit of detections (LODs) of 30 and 20 nM for Hg2+ and GSH, respectively. The dual-emission fluorescent CQDs-RhB sensor does not need the complicated molecular design and the synthesis of dual-emission fluorophores. Meanwhile, the feasibility of the proposed method for analysis of water samples, food samples, and biological samples (plasma from mice oxidative stress study) was investigated. The developed ratiometric nanosensor is proven to be facile, with less sample consumption, rapid, lost cost, highly sensitive, and very selective for Hg2+ and biological thiol detection, which offers a new approach for environmental, food, and biological analysis. Graphical abstract Ratiometric nanosensing approach detection of Hg2+ and biological thiols. PMID- 28084512 TI - Design of experiments for amino acid extraction from tobacco leaves and their subsequent determination by capillary zone electrophoresis. AB - In this study, we optimized a method for the determination of free amino acids in Nicotiana tabacum leaves. Capillary electrophoresis with contactless conductivity detector was used for the separation of 20 proteinogenic amino acids in acidic background electrolyte. Subsequently, the conditions of extraction with HCl were optimized for the highest extraction yield of the amino acids because sample treatment of plant materials brings some specific challenges. Central composite face-centered design with fractional factorial design was used in order to evaluate the significance of selected factors (HCl volume, HCl concentration, sonication, shaking) on the extraction process. In addition, the composite design helped us to find the optimal values for each factor using the response surface method. The limits of detection and limits of quantification for the 20 proteinogenic amino acids were found to be in the order of 10-5 and 10-4 mol l-1, respectively. Addition of acetonitrile to the sample was tested as a method commonly used to decrease limits of detection. Ambiguous results of this experiment pointed out some features of plant extract samples, which often required specific approaches. Suitability of the method for metabolomic studies was tested by analysis of a real sample, in which all amino acids, except for L methionine and L-cysteine, were successfully detected. The optimized extraction process together with the capillary electrophoresis method can be used for the determination of proteinogenic amino acids in plant materials. The resulting inexpensive, simple, and robust method is well suited for various metabolomic studies in plants. As such, the method represents a valuable tool for research and practical application in the fields of biology, biochemistry, and agriculture. PMID- 28084513 TI - Erratum to: Patient survey on Invisalign(r) treatment comparing the SmartTrack(r) material to the previously used aligner material. PMID- 28084514 TI - Dental Angle class asymmetry and temporomandibular disorders. AB - OBJECTIVES: The aim of this study was to determine whether there is an association between the presence of asymmetric molar or canine Angle classes on the two sides and the presence of temporomandibular joint dysfunction (TMD). MATERIALS AND METHODS: Participants to the study were divided into two groups: TMD group (90 patients) or a control group (58 patients). In the TMD group, clinical assessment for TMD was performed according to the Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) guidelines by the same two trained examiners. In both groups, all subjects underwent an assessment of dental occlusion, focusing on the assessment of bilateral canine and molar Angle class relationship. The study protocol was reviewed and approved by the Institutional Review Board of the University of Padova, and each participant gave written consent to take part in the investigation. RESULTS: TMJ pain was diagnosed in 58, disk displacement in 96, arthrosis in 17, and muscle pain in 46 individuals. Molar Angle class was symmetrical in 86 individuals and asymmetrical in 62 subjects. Molar Angle class was not correlated with any of the TMD diagnoses. Canine Angle class was correlated with TMJ arthrosis. Correlation values with the other TMD diagnoses were low and were not significant. CONCLUSIONS: It can be suggested that an association between dental Angle class asymmetry and TMDs does not exist and that the role of dental asymmetries as a factor correlated with the presence of TMD signs and symptoms is minimal. PMID- 28084515 TI - Soft tissue effects of three different Class II/1-camouflage treatment strategies. AB - OBJECTIVE: Aim of this retrospective study was to compare soft tissue effects of Class II treatments with the forsus fatigue resistant device (FRD), the pendulum appliance, and the extraction of two maxillary premolars, all of which were combined with pre-adjusted fixed appliances. PATIENTS AND METHODS: The sample of 54 patients with Class II malocclusions was divided in three groups: group I patients (mean age = 15.91 years) were treated with the FRD concurrently used with fixed appliances; group II patients (mean age = 16.08 years) were treated with the pendulum appliance combined with a Nance and headgear followed by fixed appliances; and group III patients (mean age = 19.04 years) were treated with the extraction of two maxillary premolars with miniscrew anchorage. Soft tissue and dentoskeletal parameters were measured on pretreatment (T1) and posttreatment (T2) lateral cephalograms. The changes from T1 to T2 were compared between the groups using Kruskal-Wallis test, and treatment differences were evaluated with the Wilcoxon test at p < 0.05. RESULT: Soft tissue measurement changes related to the upper and lower lips were significantly greater in group II than in group III (p < 0.05). Upper incisor measurement changes were significantly different between groups II and III. Lower incisor measurement changes were significantly different between groups I and III and groups II and III (p < 0.05). CONCLUSIONS: Pendulum and extraction treatment groups showed significant differences in relation with the upper and lower lip positional changes, which were significantly greater in the pendulum group. Treatment time with the extraction treatment was statistically shorter than with the nonextraction protocols. PMID- 28084516 TI - Preoperative bevacizumab and surgery for colorectal liver metastases: a propensity score analysis. AB - PURPOSE: Bevacizumab associated with conventional chemotherapy has become standard care in the management of metastatic colorectal cancer. However, its impact on outcomes after liver resections (LRs) remains debated. The aim of this study was to evaluate the impact of neoadjuvant bevacizumab-based chemotherapy (BBC) on postoperative outcomes of LR for colorectal liver metastasis (CLM) using a validated approach. METHODS: All patients who received neoadjuvant therapy for CLMs between January 2005 and May 2011 were included. Risk factors for major complications (Clavien >=3) were analyzed by univariate and multivariate analysis. Evaluation of BBC's impact on morbidity was conducted after a propensity score adjustment on factors identified to influence major complications (MCs). RESULTS: LR for CLMs after neoadjuvant chemotherapy was performed in 199 patients (127 men and 72 women). Major LR was performed on 111 patients (55.78%), and MCs occurred in 41 cases (20.6%). After multivariate analyses, major LR (OR 2.85; 95% CI 1.29-6.85; P = 0.013) and combined resections of both the primary tumor and CLMs (OR 7.12; 95% CI: 2.6-20.5; P < 0.001) were independent predictive factors for MCs. After a propensity score matching, 56 patients with a BBC regimen were compared to 112 patients without BBC. No difference in terms of biliary fistula occurrence (P = 0.94) or 90-day mortality (P = 0.66) was found. Both in the univariate and multivariate analyses, BBC was not associated with MCs (P = 0.95). CONCLUSION: The present study using propensity score matching demonstrated that BBC did not impair outcomes of LR for CLM. PMID- 28084517 TI - [Needs and quality of counseling in long-term care : User perspective on counseling services in Germany]. AB - BACKGROUND: A wide range of counseling services with a variety of counseling purposes have been established in Germany to support care recipients and their relatives; however, there is a lack of quality criteria that are based on the counseling needs from the user's perspective. OBJECTIVE: To summarize empirical knowledge on counseling needs and quality of counseling services from the user perspective and identification of counseling-specific understanding of users. MATERIAL AND METHODS: A literature search was conducted in the databases CareLit(r), LIVIVO and SpringerLink with additional online research via Google and MetaGer. Analysis of the literature and discussion on the state of research. RESULTS: A trustful relationship between counselor and user as well as the orientation to the user's individual situation are key elements of counseling that have been found helpful; however, a differentiated view of the diverse user groups and counseling purposes is lacking. CONCLUSION: In order to include the user's perspective in conceptual approaches for counseling and to define user generated quality criteria, further scientific research is needed regarding the counseling needs of different user groups. Consideration must be given to particular care situations that involve various counseling purposes. Particularly vulnerable groups need special support in working out their counseling needs. PMID- 28084519 TI - MUW Researcher of the Month Janner 2017. PMID- 28084520 TI - Women at medical conferences 2016 - still hitting their head at the glass ceiling. PMID- 28084518 TI - Prion disease: experimental models and reality. AB - The understanding of the pathogenesis and mechanisms of diseases requires a multidisciplinary approach, involving clinical observation, correlation to pathological processes, and modelling of disease mechanisms. It is an inherent challenge, and arguably impossible to generate model systems that can faithfully recapitulate all aspects of human disease. It is, therefore, important to be aware of the potentials and also the limitations of specific model systems. Model systems are usually designed to recapitulate only specific aspects of the disease, such as a pathological phenotype, a pathomechanism, or to test a hypothesis. Here, we evaluate and discuss model systems that were generated to understand clinical, pathological, genetic, biochemical, and epidemiological aspects of prion diseases. Whilst clinical research and studies on human tissue are an essential component of prion research, much of the understanding of the mechanisms governing transmission, replication, and toxicity comes from in vitro and in vivo studies. As with other neurodegenerative diseases caused by protein misfolding, the pathogenesis of prion disease is complex, full of conundra and contradictions. We will give here a historical overview of the use of models of prion disease, how they have evolved alongside the scientific questions, and how advancements in technologies have pushed the boundaries of our understanding of prion biology. PMID- 28084521 TI - Venous anastomosis in free flap reconstruction after radical neck dissection: is the external jugular vein a feasible option? AB - Free microvascular tissue transfer has become a reliable and wellestablished technique in reconstructive surgery. Success rates greater than 95% are constantly reported in the literature. End-to-end anastomosis to the external jugular vein (EJ) is supposed to be equally successful as anastomosis to the internal jugular vein (IJ) in patients treated with selective neck dissection. No data has been published so far when the IJ had to be resected during neck dissection. The purpose of this study was to evaluate the success rate and complications of end-to-end anastomosis to the EJ in cases of (modified) radical neck dissection with resected IJ. A retrospective mono-center cohort study was performed. All patients with end-to-end anastomosis to either the IJ or EJ-system were reviewed. 423 free-tissue transfers performed between 2009 and 2016 were included. The overall success rate was 97.0% with an anastomotic revision rate due to venous thrombosis of 12.3%. In patients when the IJ had to be resected and the venous anastomosis was performed at the ipsilateral side to the EJ (n = 53), overall flap loss was significantly higher (5/53; 9.4%). The revision rate in these cases was 22.6%. Success rate of anastomosis to the EJ when the ipsilateral IJ was still intact was 100% (n = 20). Success rate when the anastomosis was performed at the contralateral side was 100%. End-to-end anastomosis to the EJ in cases with resected IJ is more likely to result in free flap loss. Furthermore, it is associated with a higher revision rate. Therefore, in cases with resected IJ, we suggest to plan the operation beforehand with anastomosis at the contralateral side whenever possible. PMID- 28084522 TI - Downregulation of CITED2 contributes to TGFbeta-mediated senescence of tendon derived stem cells. AB - Tendon-derived stem cells (TDSCs) are multipotent adult stem cells with potential applications in tendon and tendon-bone junction repair. However, cellular characteristics change during in vitro passaging. Therefore, elucidation of the molecular and cellular mechanisms of tendon aging will be essential for the development of TDSC-based therapies. The aim of this study is to investigate the effect of CITED2, a nuclear regulator and transforming growth factor beta2 (TGFbeta2) on TDSC proliferation and senescence by comparing cells derived from Achilles tendon biopsies of young individuals (Y-TDSC) with those of older patients (O-TDSC). Our results showed that CITED2 mRNA and protein expression levels were significantly higher in Y-TDSCs than in O-TDSCs and O-TDSCs displayed decreased proliferation and increased senescence compared with Y-TDSCs. Furthermore, high levels of CITED2 protein expression in Y-TDSCs correlated with the downregulation of SP1 and p21 and the upregulation of MYC, potentially indicating the mechanism by which CITED2 upregulates TDSC proliferation. TGFbeta2 was found to downregulate the expression of the CITED2 gene and knockdown of CITED2 abolished the effect of TGFbeta2 on TDSC proliferation and senescence. Thus, the downregulation of CITED2 contributes to TGFbeta-mediated senescence providing an insight into the molecular and cellular mechanisms that contribute to tendon aging and degeneration. Our findings may aid the development of cell based therapies for tendon repair. PMID- 28084524 TI - Intraoperative nerve staining in nerve-sparing radical hysterectomy: a pilot study. AB - OBJECTIVE: To evaluate the feasibility and effectiveness of intraoperative nerve staining by modified leucomethylene blue (MLB). METHODS: Animal experiment was performed to assure whether the tissues dyed blue by MLB were nerves with microscopic examination. Ten patients with cervical cancer were performed by nerve-sparing radical hysterectomy (NSRH) and nerve staining intraoperatively by MLB. The status of staining was recorded. The post-void residual urine volume after removing was measured by ultrasound. The time to post-void residual urine volume of less than 100 ml and the first defecation were recorded. RESULTS: In animal experiment, the tissues dyed blue obviously showed abundant nerve fibers by microscopic examination. The minor nerves were dyed blue clearly in NSRH. The time to post-void residual urine volume of less than 100 ml after removal of the urethral catheter was 10.3 (7-13) days by records. The time to the first defecation was 67.7 (60-82) h. CONCLUSION: Intraoperative nerve staining by MLB provided a new method for nerve location in NSRH. It was safe, effective and convenient. PMID- 28084525 TI - ? PMID- 28084523 TI - Comparative analysis of the mechanical signals in lung development and compensatory growth. AB - This review compares the manner in which physical stress imposed on the parenchyma, vasculature and thorax and the thoraco-pulmonary interactions, drive both developmental and compensatory lung growth. Re-initiation of anatomical lung growth in the mature lung is possible when the loss of functioning lung units renders the existing physiologic-structural reserves insufficient for maintaining adequate function and physical stress on the remaining units exceeds a critical threshold. The appropriate spatial and temporal mechanical interrelationships and the availability of intra-thoracic space, are crucial to growth initiation, follow-on remodeling and physiological outcome. While the endogenous potential for compensatory lung growth is retained and may be pharmacologically augmented, supra-optimal mechanical stimulation, unbalanced structural growth, or inadequate remodeling may limit functional gain. Finding ways to optimize the signal response relationships and resolve structure-function discrepancies are major challenges that must be overcome before the innate compensatory ability could be fully realized. Partial pneumonectomy reproducibly removes a known fraction of functioning lung units and remains the most robust model for examining the adaptive mechanisms, structure-function consequences and plasticity of the remaining functioning lung units capable of regeneration. Fundamental mechanical stimulus-response relationships established in the pneumonectomy model directly inform the exploration of effective approaches to maximize compensatory growth and function in chronic destructive lung diseases, transplantation and bioengineered lungs. PMID- 28084526 TI - [Gastric tumors and tumor precursors]. AB - Gastric cancer is the fifth (men) and sixth (women) most common cause of cancer related death in Germany. Despite a declining incidence of distal gastric cancer, the prognosis remains dismal: the 5-year survival rate ranges between 35% for women and 31% for men. The majority are adenocarcinomas, which occur sporadically, familial or hereditary. Adenomas and intraepithelial neoplasms are considered as precursor lesions. Recently, whole genome sequencing and comprehensive molecular profiling described four molecular subtypes of gastric cancer: Epstein-Barr virus (EBV) positive, microsatellite unstable, chromosomal unstable and genomically stable gastric cancer. Currently, only the TNM classification has stood the test of time for the assessment of patient prognosis. Neuroendocrine tumor types 1-3 and soft tissue tumors occur significantly less often in the stomach. Gastrointestinal stromal tumors and inflammatory fibroid polyps are among the more common soft tissue tumors of the stomach and show distinct phenotypes. This review gives an overview of the current World Health Organization (WHO) classification of gastric tumors. PMID- 28084527 TI - [Indications for p16/Ki-67 in cervical cytology]. AB - BACKGROUND: The p16/Ki-67 immunocytochemistry has been used for more than five years in cervical cytology to detect transforming HPV infections. MATERIAL AND METHODS: Based on findings in the study presented here and data in the literature, practically relevant indications for this test are to be determined. The clinical course of 1109 patients with varying primary cytology results and simultaneous immunocytochemistry is analyzed. Short-term observations considering currently present lesions and long-term follow-up evaluation aimed at the prognostic evaluation are studied separately and compared with the literature. RESULTS: The p16/Ki-67 immunocytochemistry effectiveness is described by the relative risk (RR) for the positive endpoint CIN2+. For short-term observations (n = 409) a RR of 3.79 (CI 95% 2.15 to 6.67) and for long-term follow-up (n = 700) after an average 34.7 months a RR of 8.72 (CI 95% 5.77 to 13.17) was found. The highest RR of 6.32 (CI 95% 3.71 to 10.76) was determined for the group IIID1/LSIL, followed by 3.98 (95% CI 1.45 to 10.91) for the group III-p (ASC-H). DISCUSSION: Regardless of the study designs and significant differences of the resulting statistics in the literature, there is consensus concerning the significantly higher specificity and positive prediction of the p16/Ki-67 immunocytochemistry compared to cytology or HPV DNA test results. Therefore, p16/Ki-67 immunocytochemistry is useful in cases of persistent group IIID1/LSIL and equivocal cytological findings (group III-p/ASC-H). Especially in the former group, the frequency of colposcopic examinations can be reduced. In this respect, adding p16/Ki-67 immunochemistry likely improves patient management. However, an indication for treatment solely based upon a positive immunocytochemical finding is unjustified. PMID- 28084528 TI - [Recommendations for treatment of fibromyalgia : Where will we stand in 10 years?] AB - This article elucidates changes in the recommended diagnostics and therapy of fibromyalgia (FM). The recommendations from major internationally recognized guidelines are compared with the newest recommendations of the European League Against Rheumatism (EULAR) that in contrast to the guidelines surprisingly recommend physical exercise after patient education for all FM patients. The differences between the guidelines and the EULAR recommendations are critically discussed in particular because although the literature referred to in the guidelines was similar, the analysis led to different recommendations. Finally, we try to predict how patients will be treated 10 years from now, for which knowledge from the guidelines and the initial approaches that diagnosed heterogeneity in FM are included. Empirically based questions will drive mechanism-based approaches as opposed to simply reacting to symptoms, in order to meet the challenge of an individual, mechanism-oriented treatment. PMID- 28084529 TI - Comparison of macroscopic and microscopic (stereomicroscopy and scanning electron microscopy) features of bone lesions due to hatchet hacking trauma. AB - This experimental study examined the lesions produced by a hatchet on human bones (tibiae). A total of 30 lesions were produced and examined macroscopically (naked eye) and by stereomicroscopy. 13 of them were also analyzed using scanning electron microscopy. The general shape of the lesion, both edges, both walls, the kerf floor and the extremities were described. The length and maximum width of the lesions were also recorded. The microscopic analysis of the lesions led to the description of a sharp-blunt mechanism. Specific criteria were identified (lateral pushing back, fragmentation of the upraising, fossa dug laterally to the edge and vertical striae) enabling the forensic expert to conclude that a hacking instrument was used. These criteria are easily identifiable using scanning electron microscopy, but can also be observed with stereomicroscopy. Overall, lateral pushing back and vertical striae visible using stereomicroscopy and scanning electron microscopy signal the use of a hacking tool. PMID- 28084530 TI - Inducible defenses in Olympia oysters in response to an invasive predator. AB - The prey naivete hypothesis suggests that native prey may be vulnerable to introduced predators because they have not evolved appropriate defenses. However, recent evidence suggests that native prey sometimes exhibit induced defenses to introduced predators, as a result of rapid evolution or other processes. We examined whether Olympia oysters (Ostrea lurida) display inducible defenses in the presence of an invasive predator, the Atlantic oyster drill (Urosalpinx cinerea), and whether these responses vary among oyster populations from estuaries with and without this predator. We spawned oysters from six populations distributed among three estuaries in northern California, USA, and raised their offspring through two generations under common conditions to minimize effects of environmental history. We exposed second-generation oysters to cue treatments: drills eating oysters, drills eating barnacles, or control seawater. Oysters from all populations grew smaller shells when exposed to drill cues, and grew thicker and harder shells when those drills were eating oysters. Oysters exposed to drills eating other oysters were subsequently preyed upon at a slower rate. Although all oyster populations exhibited inducible defenses, oysters from the estuary with the greatest exposure to drills grew the smallest shells suggesting that oyster populations have evolved adaptive differences in the strength of their responses to predators. Our findings add to a growing body of literature that suggests that marine prey may be less likely to exhibit naivete in the face of invasive predators than prey in communities that are more isolated from native predators, such as many freshwater and terrestrial island ecosystems. PMID- 28084531 TI - Oncologists' negative attitudes towards expressing emotion over patient death and burnout. AB - PURPOSE: The aims of this study were to examine the relationship between negative attitudes towards expressing emotion following patient death and burnout in oncologists and to explore oncologists' preferences for institutional interventions to deal with patient death. METHODS: The participants included a convenience sample of 177 oncologists from Israel and Canada. Oncologists completed a questionnaire package that included a sociodemographic survey, a burnout measure, a survey assessing negative attitudes towards expressing emotion, and a survey assessing desired interventions to cope with patient death. To examine the association between burnout and negative attitudes while controlling for the effect of sociodemographic variables, a hierarchical linear regression was computed. RESULTS: Higher burnout scores were related to higher negative attitudes towards perceived expressed emotion (partial r = .25, p < .01) of those who viewed this affect as a weakness and as a sign of unprofessionalism. Approximately half of the oncologists found each of the five categories of institutional interventions (pedagogical strategies, emotional support, group/peer support, taking time off, and research and training) helpful in coping with patient death. CONCLUSIONS: Our findings suggest that high burnout scores are associated with negative attitudes towards expressing emotion and that there is a wide variation in oncologist preferences in coping with patient death. Institutions should promote interventions that are varied and that focus on the needs of oncologists in order to reduce burnout. Interventions that legitimize expression of emotion about patient death may be useful. Another way to reduce stigma would be to require oncologists to "opt out" rather than "opt in" to accessing a selection of social and/or individual interventions. PMID- 28084532 TI - Evaluation of validity and reliability of the Persian version of the functional index of hand osteoarthritis. AB - The Functional index of hand osteoarthritis (FIHOA) is a commonly used patient reported outcome questionnaire designed to measure function in patients with hand osteoarthritis. The objective of this study was to evaluate the validity and reliability of the Persian version of the FIHOA. The Persian-translated version of FIHOA was administered to 72 native Persian-speaking patients in Iran with hand osteoarthritis. Thirty-six of the patients completed the questionnaire on two occasions 1 week apart. The physical component of the SF-36 and a numerical rating scale were used to evaluate the construct validity of the Persian version of FIHOA. Internal consistency was high (Cronbach's alpha = 0.89). Test-retest reliability for the total score was excellent (weighted kappa = 0.89, 95% CI 0.79 0.94). A significant positive correlation between total FIHOA score and numerical rating scale (r = 0.70) and a significant negative correlation between total FIHOA score and the physical component scale of the SF-36 (r = -0.76) were observed. The Persian version of the FIHOA showed adequate validity and reliability to evaluate functional disability in Persian-speaking patients with hand osteoarthritis. PMID- 28084533 TI - CD4+CD28null T Cells are related to previous cytomegalovirus infection but not to accelerated atherosclerosis in ANCA-associated vasculitis. AB - Previous studies have suggested an increased risk for cardiovascular events in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). We analyzed the presence of atherosclerotic damage in patients with AAV in relation to the presence of CD4+CD28null T cells and antibodies against cytomegalovirus (CMV) and human Heat-Shock Protein 60 (hHSP60). In this cross-sectional study, patients with inactive AAV were compared with healthy controls (HC). Carotid intima-media thickness (IMT) and aortic pulse-wave velocity (PWV) were measured. In addition, CD4+CD28null T cells, anti-CMV, and anti-hHSP60 levels were determined. Forty patients with AAV were included. Patients' spouses were recruited as HC (N = 38). CD4+CD28null T cells are present in patients with AAV in a higher percentage (median 3.1, range 0.01-85) than in HC (0.28, 0-36, P < 0.0001). No significant difference in IMT (mm) between patients and controls was detected (mean 0.77 +/- standard deviation 0.15 and 0.73 +/- 0.11, respectively, P = 0.20). PWV standardized for MAP was increased in AAV patients (9.80 +/- 2.50 m/s, compared to 8.72 +/- 1.68 in HC, P = 0.04). There was a strong association between a previous CMV infection and the presence and percentage of CD4+CD28null T cells (0.33 vs 13.8, P < 0.001). There was no relationship between CD4+CD28null T cells and/or a previous CMV infection and IMT or PWV. There was no relation between anti-hHSP60 and CD4+CD28null T cells. Increased PWV values suggest atherosclerotic damage in patients with AAV. Plaque size, as determined by IMT, did not differ. CD4+CD28null T cells are increased in AAV and related to the previous CMV infection. PMID- 28084534 TI - Outcome of anti-thymocyte immunoglobulin plus cyclosporine A for severe aplastic anaemia with chronic hepatitis B virus infection. AB - The influence of chronic hepatitis B virus (HBV) infection on the efficacy of intensive immunosuppressive treatment (IST) of severe aplastic anaemia (SAA) patients remains unclear. Previous reports on this topic have been mostly case reports or have had a relatively short follow-up. Eight SAA patients carrying chronic HBV infection and 24 matched patients without HBV at a ratio of 1:3 were included in this retrospective analysis. The patients were treated with anti thymocyte globulin (ATG) and cyclosporine A. Entecavir was or was not administered throughout the IST course to patients with positive or negative HBV DNA results, respectively. No evident HBV reactivation developed. The overall response was 87.5% by 12 months, and the recurrence rate was 12.5%. There were no significant differences in overall response, overall survival and event-free survival between groups. Entecavir can effectively prevent reactivation of HBV in SAA patients with positive HBV-DNA who received intensive IST. Regular surveillance may be sufficient for HBV-DNA negative patients who should receive antiviral drugs immediately when their HBV-DNA status changes from negative to positive. The prognosis of SAA patients with chronic HBV infection after intensive IST treatment is not worse than those without HBV infection. PMID- 28084535 TI - DNA methylation is dispensable for changes in global chromatin architecture but required for chromocentre formation in early stem cell differentiation. AB - Epiblast stem cells (EpiSCs), which are pluripotent cells isolated from early post-implantation mouse embryos (E5.5), show both similarities and differences compared to mouse embryonic stem cells (mESCs), isolated earlier from the inner cell mass (ICM) of the E3.5 embryo. Previously, we have observed that while chromatin is very dispersed in E3.5 ICM, compact chromatin domains and chromocentres appear in E5.5 epiblasts after embryo implantation. Given that the observed chromatin re-organization in E5.5 epiblasts coincides with an increase in DNA methylation, in this study, we aimed to examine the role of DNA methylation in chromatin re-organization during the in vitro conversion of ESCs to EpiSCs. The requirement for DNA methylation was determined by converting both wild-type and DNA methylation-deficient ESCs to EpiSCs, followed by structural analysis with electron spectroscopic imaging (ESI). We show that the chromatin re organization which occurs in vivo can be re-capitulated in vitro during the ESC to EpiSC conversion. Indeed, after 7 days in EpiSC media, compact chromatin domains begin to appear throughout the nuclear volume, creating a chromatin organization similar to E5 epiblasts and embryo-derived EpiSCs. Our data demonstrate that DNA methylation is dispensable for this global chromatin re organization but required for the compaction of pericentromeric chromatin into chromocentres. PMID- 28084536 TI - Role of the pedunculopontine nucleus in controlling gait and sleep in normal and parkinsonian monkeys. AB - Patients with Parkinson's disease (PD) develop cardinal motor symptoms, including akinesia, rigidity, and tremor, that are alleviated by dopaminergic medication and/or subthalamic deep brain stimulation. Over the time course of the disease, gait and balance disorders worsen and become resistant to pharmacological and surgical treatments. These disorders generate debilitating motor symptoms leading to increased dependency, morbidity, and mortality. PD patients also experience sleep disturbance that raise the question of a common physiological basis. An extensive experimental and clinical body of work has highlighted the crucial role of the pedunculopontine nucleus (PPN) in the control of gait and sleep, and its potential major role in PD. Here, we summarise our investigations in the monkey PPN in the normal and parkinsonian states. We first examined the anatomy and connectivity of the PPN and the cuneiform nucleus which both belong to the mesencephalic locomotor region. Second, we conducted experiments to demonstrate the specific effects of PPN cholinergic lesions on locomotion in the normal and parkinsonian monkey. Third, we aimed to understand how PPN cholinergic lesions impair sleep in parkinsonian monkeys. Our final goal was to develop a novel model of advanced PD with gait and sleep disorders. We believe that this monkey model, even if it does not attempt to reproduce the exact human disease with all its complexities, represents a good biomedical model to characterise locomotion and sleep in the context of PD. PMID- 28084537 TI - Effect of childhood general traumas on suicide attempt depends on TPH2 and ADARB1 variants in psychiatric patients. AB - Suicidal behavior has been associated with a deficient serotonin neurotransmission which is likely a consequence of individual genetic architecture, exposure to environmental factors and interactions of those factors. We examined whether the interaction of child abuse, TPH2 (tryptophan hydroxylase 2) variant rs4290270, affecting alternative splicing and editing of TPH2 pre-mRNAs, and ADARB1 (adenosine deaminase acting on RNA B1) variants rs4819035 and rs9983925 may influence the risk for suicide attempt in psychiatric patients. TPH2 rs4290270 was genotyped in 165 suicide attempters and 188 suicide non-attempters diagnosed with major depressive disorder, bipolar disorder and schizophrenia. Genotyping data for ADARB1 variants were taken over from our previous study. Child abuse before the age of 18 years was assessed using the Early Trauma Inventory-Self Report. Generalized linear models and backward selection were applied to identify the main and interacting effects of environmental and genetic factors, including psychiatric diagnoses, patients' gender and age as covariates. Childhood general traumas were independently associated with suicide attempt. Two-way interaction between TPH2 rs4290270 and general traumas revealed that TT homozygotes with a history of general traumas had an increased risk for suicide attempt. Three-way interaction of general traumas, TPH2 rs4290270 and ADARB1 rs4819035 indicated that the highest predisposition to suicide attempt was observed in individuals who experienced general traumas and were TT homozygote for rs4290270 and TT homozygote for rs4819035. Our findings suggest that the risk for suicide attempt in psychiatric patients exposed to an adverse childhood environment may depend on TPH2 and ADARB1 variants. PMID- 28084538 TI - Mainstream partial nitritation-anammox in municipal wastewater treatment: status, bottlenecks, and further studies. AB - Driven by energy neutral/positive of wastewater treatment plants, significant efforts have been made on the research and development of mainstream partial nitritation and anaerobic ammonium oxidation (anammox) (PN/A) (deammonification) process since the early 2010s. To date, feasibility of mainstream PN/A process has been demonstrated and proven by experimental results at various scales although with the low loading rates and elevated nitrogen concentration in the effluent at low temperatures (15-10 degrees C). This review paper provides an overview of the current state of research and development of mainstream PN/A process and critically analyzes the bottlenecks for its full-scale application. The paper discusses the following: (i) the current status of research and development of mainstream PN/A process; (ii) the interactions among aerobic ammonium-oxidizing bacteria, aerobic nitrite-oxidizing bacteria, anammox bacteria, and heterotrophic bacteria; (iii) the suppression of aerobic nitrite oxidizing bacteria; (iv) process and bioreactors; and (v) suggested further studies including efficient and robust carbon concentrating pretreatment, deepening of understanding competition between autotrophic nitrogen-converting organisms, intensification of biofilm anammox activity, reactor design, and final polishing. PMID- 28084539 TI - McrA primers for the detection and quantification of the anaerobic archaeal methanotroph 'Candidatus Methanoperedens nitroreducens'. AB - The nitrogen and methane cycles are important biogeochemical processes. Recently, 'Candidatus Methanoperedens nitroreducens,' archaea that catalyze nitrate dependent anaerobic oxidation of methane (AOM), were enriched, and their genomes were analyzed. Diagnostic molecular tools for the sensitive detection of 'Candidatus M. nitroreducens' are not yet available. Here, we report the design of two novel mcrA primer combinations that specifically target the alpha sub-unit of the methyl-coenzyme M reductase (mcrA) gene of 'Candidatus M. nitroreducens'. The first primer pair produces a fragment of 186-bp that can be used to quantify 'Candidatus M. nitroreducens' cells, whereas the second primer pair yields an 1191-bp amplicon that is with sufficient length and well suited for more detailed phylogenetic analyses. Six different environmental samples were evaluated with the new qPCR primer pair, and the abundances were compared with those determined using primers for the 16S rRNA gene. The qPCR results indicated that the number of copies of the 'Candidatus M. nitroreducens' mcrA gene was highest in rice field soil, with 5.6 +/- 0.8 * 106 copies g-1 wet weight, whereas Indonesian river sediment had only 4.6 +/- 2.7 * 102 copies g-1 wet weight. In addition to freshwater environments, sequences were also detected in marine sediment of the North Sea, which contained approximately 2.5 +/- 0.7 * 104 copies g-1 wet weight. Phylogenetic analysis revealed that the amplified 1191-bp mcrA gene sequences from the different environments all clustered together with available genome sequences of mcrA from known 'Candidatus M. nitroreducens' archaea. Taken together, these results demonstrate the validity and utility of the new primers for the quantitative and sensitive detection of the mcrA gene sequences of these important nitrate-dependent AOM archaea. Furthermore, the newly obtained mcrA sequences will contribute to greater phylogenetic resolution of 'Candidatus M. nitroreducens' sequences, which have been only poorly captured by general methanogenic mcrA primers. PMID- 28084540 TI - Peroxisome proliferator-activated receptor alpha (PPARalpha) contributes to control of melanogenesis in B16 F10 melanoma cells. AB - Recent studies revealed the cooperation between peroxisome proliferator-activated receptor gamma (PPARgamma) and alpha-MSH signaling, which results in enhanced melanogenesis in melanocytes and melanoma cells. However, the agonists of PPARalpha, such as fenofibrate, exert depigmenting effect. Therefore, we aimed to check how the PPARalpha expression level affects the antimelanogenic activity of fenofibrate and whether PPARalpha modulates melanogenesis independently of its agonist. To answer these questions, we used three B16 F10-derived cell lines, which varied in the PPARalpha expression level and were developed by stable transfection with plasmids driving shRNA-based PPARalpha silencing or overexpression of PPARalpha-emerald GFP fusion protein. Melanin contents were assessed with electron paramagnetic resonance spectroscopy along with color component image analysis-a novel approach to pigment content characteristics in melanoma cells. B16 F10 wt and Ctrl shRNA lines showed intermediate pigmentation, whereas the pigmentation of the B16 F10-derived cell lines was inversely correlated with the PPARalpha expression level. We observed that cells overexpressing PPARalpha were almost amelanotic and cells with reduced PPARalpha protein level were heavily melanized. Furthermore, fenofibrate down-regulated the melanogenic apparatus (MITF, tyrosinase, and tyrosinase-related proteins) in the cells with the regular PPARalpha expression level resulting in their visibly lower total melanin content in all the cell lines. From these observations, we conclude that fenofibrate works as a strong depigmenting agent, which acts independently of PPARalpha, but in an additive fashion. Our results also indicate that alterations in PGC-1a acetylation and expression level might contribute to the regulation of melanogenesis by PPARalpha and fenofibrate. PMID- 28084541 TI - Reply to: Need for improvements in reported cost-effectiveness of adalimumab in rheumatoid arthritis. PMID- 28084542 TI - Need for improvements in reported cost effectiveness of adalimumab in rheumatoid arthritis. PMID- 28084543 TI - [Pregnancy and lactation-associated osteoporosis]. AB - Pregnancy and lactation-associated osteoporosis (PLO) is a rare form of osteoporosis, which occurs in the last trimester or postpartum. So far 100 cases have been published. The leading symptoms are severe low back pain or less frequently hip pain. Many patients develop postpartum depression due to inability to care for the baby and vertebral fractures. The therapeutic decision has to be made individually but teriparatid and bisphosphonates seem to be the best option. We report the clinical course (16 years) of a 37-year-old patient with PLO, who suffered 6 vertebral fractures. There were severe physical limitations and mental problems caused by the disease. The patient was treated by multimodal therapy including physiotherapy and psychotherapy and bisphosphonates were given. The time between the onset of symptoms and diagnosis was 5 months. No further fractures occurred in the following 16 years. The physical and mental condition significantly improved. PMID- 28084544 TI - Prospective comparison of dual-energy CT aortography using 70% reduced iodine dose versus single-energy CT aortography using standard iodine dose in the same patient. AB - PURPOSE: To compare dual-energy computed tomography (DECT) aortography using a 70% reduced iodine dose to single-energy CT (SECT) aortography using a standard iodine dose in the same patient. METHODS: Twenty-one patients with a prior SECT aortography using standard iodine dose had DECT aortography using 70% reduced iodine dose. Section 120 kVp images were compared to DECT images reconstructed at both 50 and 77 keV. Reviewers measured image noise and attenuation in the aorta at eight locations from proximal to distal and subjectively scored vascular enhancement on a four-point scale. Signal-to-noise ratio (SNR) and contrast-to noise ratio (CNR) were calculated. The volume CT dose index (CTDIvol) for each exam was recorded. RESULTS: Mean iodine dose was 50 g for SECT and 15 g for DECT (70% reduction). Mean aortic attenuation was similar for section 120 kVp (350 +/- 67 HU) and DECT 50 keV (338 +/- 57 HU, p = 0.547) but was lower at 77 keV (152 +/ 23 HU). Measured image noise was greatest at 50 keV (12 +/- 5 HU) and was lowest at 77 keV (7 +/- 2 HU, p > 0.001). There was no difference in SNR or CNR between 120 kVp and 50 keV (p > 0.05). Mean subjective vascular enhancement scores for SECT were between good and excellent (3.33-3.69), and for DECT at 50 keV were between moderate and good (2.54-2.93, p < 0.0001). CTDIvol was 13.6 mGy for SECT and 13.1 mGy for DECT (p = 0.637). CONCLUSION: 70% Reduced iodine DECT aortography may result in similar aortic attenuation, CNR, SNR, and lower although acceptable subjective image scores when compared to standard iodine SECT aortography in the same patient. PMID- 28084545 TI - Cross-sectional imaging in refractory celiac disease. AB - PURPOSE: The purpose of this study is to identify unique imaging findings of refractory celiac disease (RCD) including Type I RCD, Type II RCD versus healed celiac disease (CD). METHODS: A retrospective study of patients with known CD and refractory symptoms with cross-sectional imaging was performed. We included patients who underwent T cell receptor rearrangement or T-cell immunophenotyping studies on small bowel (SB) biopsies to classify patients into: healed CD, Type I RCD, or Type II RCD. GI radiologists performed a blinded review of the imaging studies. RESULTS: One-hundred eighteen patients (32 healed; 67 Type I RCD; 19 Type II RCD) were included (mean age 53 +/- 6 years; 62% female). The presence of any fold pattern abnormality was more likely to be found in Type II and Type I RCD than healed CD (53% vs. 43% vs.16%; p = 0.009). Type II RCD patients were more likely than Type I RCD and healed CD to have imaging findings of ulcerative jejunitis (26% vs. 6% vs. 3%; p = 0.009), SB wall thickening (37% vs. 16% vs. 0%; p = 0.002) and SB dilation (26% vs. 7% vs. 6%; p = 0.04). Type II RCD demonstrated non-significant trends for decreased number of jejunal folds only, SB mass, mesenteric lymphadenopathy, localized peri-mural edema, and intramural duodenal edema. CONCLUSIONS: Fold pattern abnormalities, ulcerative jejunitis, SB wall thickening, and SB dilation are more likely to be identified in cross sectional imaging of RCD than healed CD. SB dilatation and ulcerative jejunitis are more likely to be found in Type II than Type I RCD. PMID- 28084546 TI - Spectral detector CT-derived virtual non-contrast images: comparison of attenuation values with unenhanced CT. AB - PURPOSE: To assess virtual non-contrast (VNC) images obtained on a detection based spectral detector CT scanner and determine how attenuation on VNC images derived from various phases of enhanced CT compare to those obtained from true unenhanced images. METHODS: In this HIPAA compliant, IRB approved prospective multi-institutional study, 46 patients underwent pre- and post-contrast imaging on a prototype dual-layer spectral detector CT between October 2013 and November 2015, yielding 84 unenhanced and VNC pairs (25 arterial, 39 portal venous/nephrographic, 20 urographic). Mean attenuation was measured by one of three readers in the liver, spleen, kidneys, psoas muscle, abdominal aorta, and subcutaneous fat. Equivalence testing was used to determine if the mean difference between unenhanced and VNC attenuation was less than 5, 10, or 15 HU. VNC image quality was assessed on a 5 point scale. RESULTS: Mean difference between unenhanced and VNC attenuation was <15 HU in 92.6%, <10 HU in 75.2%, and <5 HU in 44.4% of all measurements. Unenhanced and VNC attenuation were equivalent in all tissues except fat using a threshold of <10 HU difference (p < 0.05). No significant variation was seen between phases. In fat, VNC overestimated the HU relative to unenhanced images. VNC image quality was rated as excellent or good in 84% of arterial phase and 85% of nephrographic phase cases, but only 40% of urographic phase. CONCLUSION: VNC images derived from novel dual layer spectral detector CT demonstrate attenuation values similar to unenhanced images in all tissues evaluated except for subcutaneous fat. Further study is needed to determine if attenuation thresholds currently used clinically for common pathology should be adjusted, particularly for lesions containing fat. PMID- 28084547 TI - Abdominal seeding of renal cell carcinoma: radiologic, pathologic, and prognostic features. AB - PURPOSE: We analyzed radiologic and histologic characteristics, and prognosis of abdominal seeding from renal cell carcinoma (RCC). METHODS: Consecutive 25 patients with RCC and histologically or radiologically diagnosed abdominal seeding were analyzed. No patient had another type of malignancy. Histologic subtype, Fuhrman grade, sarcomatoid differentiation, and T-stage of primary tumors were assessed. Pre- or postoperative presentation of seeding was investigated. Median survival time and RCC-specific survival rates were evaluated. RESULTS: Of 25 patients, 15 (60%) died and 4 (16%) were hopelessly discharged (median follow-up time, 6 months; range 1-62 months). Histologic subtypes were clear cell (76%, 19/25), papillary (16%, 4/25), chromophobe (4%, 1/25), and poorly differentiated (4%, 1/25). Fuhrman grades were 4 (48%, 12/25), 3 (36%, 9/25), 2 (12%, 3/25), and unknown (4%, 1/25). T-stage of the four patients with grade 2 or unknown was 3a. Sarcomatoid differentiation and postoperative occurrence were found in 32% (8/25) and 80% (20/25), respectively. Median survival time was 13 months, and 1-year, 2-year, and 3-year RCC-specific survival rates were 51%, 41%, and 31%, respectively. CONCLUSION: Abdominal seeding may occur in various subtypes of RCC with high Fuhrman grade including sarcomatoid differentiation or high T-stage, and appears to be related to poor prognosis. PMID- 28084548 TI - Cytomegalovirus, inflammatory bowel disease, and anti-TNFalpha. AB - BACKGROUND AND PURPOSE: Anti-TNFalpha agents emerged in inflammatory bowel disease (IBD) as an effective option in situations that, otherwise, would be refractory to medical therapy. Cytomegalovirus infection may present with a high spectrum of manifestations and lead to high morbidity and mortality. However, its clinical significance in IBD course remains unknown and data on its association with anti-TNFalpha are limited. AIMS: This study aims to evaluate cytomegalovirus (CMV) infection/disease in patients with IBD treated with anti-TNFalpha; if possible, possible risk factors associated with CMV infection/disease in IBD patients under anti-TNFalpha as well as the influence of CMV infection/disease in IBD course would be determined. METHODS: During three consecutive years, all IBD patients starting infliximab in our department were included. Cytomegalovirus status before anti-TNFalpha was evaluated. Data regarding IBD, therapeutic and IBD course after infliximab, were recorded. CMV analysis was performed with polymerase chain reaction (PCR)-cytomegalovirus in peripheral blood and colonoscopy with biopsies (histopathology/immunohistochemistry). RESULTS: We included 29 patients: female-83%; Crohn's disease-51.8%, ulcerative colitis 44.8%, non-classified colitis-3.4%; 23 cytomegalovirus seropositive. Median follow-up: 19 months (3-36). During follow-up, 14 patients were under combination therapy with azathioprine and 5 did at least 1 cycle of corticosteroids. Twenty one patients responded to infliximab. We registered 8 exacerbations of IBD. Four patients discontinued infliximab: none had CMV infection. We documented 1 case of intestinal cytomegalovirus infection-detected in biopsies performed per protocol in an asymptomatic UC patient, who responded to valganciclovir without infliximab discontinuation. CONCLUSIONS: Infliximab, with/without immunosuppression, does not confer an increased risk of (re)activation of cytomegalovirus. Cytomegalovirus was not responsible neither for significant morbidity nor mortality in IBD. PMID- 28084549 TI - Sigmoid resection for diverticulitis is more difficult than for malignancies. AB - PURPOSE: Sigmoid resection for diverticulitis is usually the first procedure performed when starting the learning process for laparoscopic colorectal surgery. The aim of this study is to evaluate the difficulty of laparoscopic sigmoid resection for diverticulitis in comparison to sigmoid malignancy in order to assess its role in the residents training program. METHODS: A cohort of patients was selected who suffered either from malignancy or recurrent diverticulitis in the sigmoid colon. Laparoscopic sigmoid resection was performed. The degree of difficulty was assessed by intraoperative complications and intraoperative technical challenges. Furthermore, take-overs from assistant to surgeon, surgeon to surgeon, and conversion were reported. RESULTS: A total of 224 patients were included, 119 (53.1%) men and 105 (46.9%) women. Patients suffering from diverticulitis had significantly less co-morbidities than those with malignancies. In the diverticulitis group, there were significantly more technical challenges. There was a higher rate in take-overs from residents (p = 0.02) as well as surgeon to surgeon (p = 0.04). The rate of conversions was also significantly higher in the diverticulitis group (p = 0.03) when compared to the malignancy group. CONCLUSIONS: The outcomes of our study show that diverticulitis may not be the ideal condition to start the learning process for laparoscopic colorectal surgery. PMID- 28084550 TI - Symptomatic oral lesions may be associated with contact allergy to substances in oral hygiene products. AB - OBJECTIVE: Dental materials and oral hygiene products may be responsible for oral contact allergic reactions. We aimed to determine the occurrence of allergies in patients with symptomatic oral lichen planus (OLP), oral lichenoid lesions (OLLs) and stomatitis and investigate if patch testing could identify contact allergies to dental materials and oral hygiene products in these patients. METHODS: Forty nine patients (7 men, 42 women) aged 31 to 77 years (61 +/- 10.3 years) with symptomatic OLP, OLL or stomatitis and 29 healthy age- and gender-matched control subjects were included. They underwent an interview, clinical examination, oral mucosal biopsy and epicutan testing to the European baseline series, a toothpaste and dental material series. RESULTS: Nineteen patients had OLP, 19 OLL and 11stomatitis. Oral burning/itching was the most common symptom (83.7%), and 65.3% patients had more than one symptom. Patients visited their dentist more often than the healthy subjects and had statistically higher DMF-T and DMF-S scores. Nineteen patients (38.8%) and 10 healthy control subjects (34.5%) had allergic contact reactions primarily to fragrance ingredients. No differences could be found between OLP, OLL, stomatitis and healthy controls with regard to allergic contact reactions. However, contact allergy to aroma substances differed significantly between the patients and the healthy control subjects (p = 0.02). This type of contact allergy was most common in patients with OLP and OLL (p = 0.01). Avoidance cleared symptoms in all cases. CONCLUSION/CLINICAL RELEVANCE: Allergic reactions to aroma substances in oral hygiene products are common in patients with symptomatic OLP, OLL and stomatitis. PMID- 28084553 TI - Application of semiempirical electronic structure theory to compute the force generated by a single surface-mounted switchable rotaxane. AB - Herein we report a study of the switchable [3]rotaxane reported by Huang et al. (Appl Phys Lett 85(22):5391-5393, 1) that can be mounted to a surface to form a nanomechanical, linear, molecular motor. We demonstrate the application of semiempirical electronic structure theory to predict the average and instantaneous force generated by redox-induced ring shuttling. Detailed analysis of the geometric and electronic structure of the system reveals technical considerations essential to success of the approach. The force is found to be in the 100-200 pN range, consistent with published experimental estimates. Graphical Abstract A single surface-mounted switchable rotaxane. PMID- 28084551 TI - Oxygen activation by mononuclear nonheme iron dioxygenases involved in the degradation of aromatics. AB - Molecular oxygen is utilized in numerous metabolic pathways fundamental for life. Mononuclear nonheme iron-dependent oxygenase enzymes are well known for their involvement in some of these pathways, activating O2 so that oxygen atoms can be incorporated into their primary substrates. These reactions often initiate pathways that allow organisms to use stable organic molecules as sources of carbon and energy for growth. From the myriad of reactions in which these enzymes are involved, this perspective recounts the general mechanisms of aromatic dihydroxylation and oxidative ring cleavage, both of which are ubiquitous chemical reactions found in life-sustaining processes. The organic substrate provides all four electrons required for oxygen activation and insertion in the reactions mediated by extradiol and intradiol ring-cleaving catechol dioxygenases. In contrast, two of the electrons are provided by NADH in the cis dihydroxylation mechanism of Rieske dioxygenases. The catalytic nonheme Fe center, with the aid of active site residues, facilitates these electron transfers to O2 as key elements of the activation processes. This review discusses some general questions for the catalytic strategies of oxygen activation and insertion into aromatic compounds employed by mononuclear nonheme iron-dependent dioxygenases. These include: (1) how oxygen is activated, (2) whether there are common intermediates before oxygen transfer to the aromatic substrate, and (3) are these key intermediates unique to mononuclear nonheme iron dioxygenases? PMID- 28084552 TI - A method of expression for an oxygen-tolerant group III alcohol dehydrogenase from Pyrococcus horikoshii OT3. AB - NAD(P)-dependent group III alcohol dehydrogenases (ADHs), well known as iron activated enzymes, generally lose their activities under aerobic conditions due to their oxygen-sensitivities. In this paper, we expressed an extremely thermostable group III ADH from the hyperthermophilic archaeon Pyrococcus horikoshii OT3 (PhADH) heterologously in Escherichia coli. When purified from a culture medium containing nickel, the recombinant PhADH (Ni-PhADH) contained 0.85 +/- 0.01 g-atoms of nickel per subunit. Ni-PhADH retained high activity under aerobic conditions (9.80 U mg-1), while the enzyme expressed without adding nickel contained 0.46 +/- 0.01 g-atoms of iron per subunit and showed little activity (0.27 U mg-1). In the presence of oxygen, the activity of the Fe2+ reconstituted PhADH prepared from the Ni-PhADH was gradually decreased, whereas the Ni2+-reconstituted PhADH maintained enzymatic activity. These results indicated that PhADH with bound nickel ion was stable in oxygen. The activity of the Ni2+-reconstituted PhADH prepared from the expression without adding nickel was significantly lower than that from the Ni-PhADH, suggesting that binding a nickel ion to PhADH in this expression system contributed to protecting against inactivation during the expression and purification processes. Unlike other thermophilic group III ADHs, Ni-PhADH showed high affinity for NAD(H) rather than NADP(H). Furthermore, it showed an unusually high k cat value toward aldehyde reduction. The activity of Ni-PhADH for butanal reduction was increased to 60.7 U mg-1 with increasing the temperature to 95 degrees C. These findings provide a new strategy to obtain oxygen-sensitive group III ADHs. PMID- 28084554 TI - Disentangling Neural Sources of the Motor Interference Effect in High Functioning Autism: An EEG-Study. AB - The role of imitation in autism spectrum disorder (ASD) is controversial. Researchers have argued that deficient control of self- and other-related motor representations (self-other distinction) might explain imitation difficulties. In a recent EEG study, we showed that control of imitation relies on high-level as well as on low-level cognitive processes. Here, we aimed to further our insights into control of imitation deficits in ASD. We focused on congruency effects in the P3 (high-level), the N190 and the readiness potential (RP; low-level). We predicted smaller congruency effects within the P3 in the ASD group. However, we found differences in the RP and not in the P3-component. Thus, high-level self other distinction centred on motor actions may be preserved in ASD, while impairments are reflected during motor preparation. PMID- 28084555 TI - An ESIPT-Based Fluorescent Probe for Hydrazine Detection in Aqueous Solution and its Application in Living Cells. AB - A new fluorescent probe based on "protection-deprotection" sequence and the excited-state intramolecular proton transfer (ESIPT) effect was designed and synthesized. The probe responds rapidly and high selectively toward hydrazine at room temperature, and exhibits a low detection limit of 0.016 MUM (0.512 ppb), which is well below the safety level (10 ppb) as regulated by EPA. Moreover, it can be applied for the imaging of hydrazine in living cells. PMID- 28084556 TI - Research on a New Micro-Volume Fluorescence Capillary Biosensor Assay for Sequentially Quantifying Pyruvate and Lactate. AB - It was studied that making conditions of a micro-volume fluorescence capillary biosensor for determining pyruvate (PA) and lactate (LA). The biosensor made under the optimized conditions could be used for sequential quantifications of LA in the range 0.10-1.2 mM and PA in 4-120 MUM, and its recovery for PA and LA was in a satisfactory range 97-106% for human serum samples, with detection limits of 0.023 mM for LA (RSD < 1.89%, n = 11) and 0.87 MUM for PA (RSD < 1.70%, n = 11). The new assay possessed these advantages that the LDH immobilizing on capillary realized the reuse of expensive enzyme in fluorospectrophotometry, and the consumption of serum samples or chemical reagents decreased to 9 MUL in per assay, and the analytes no needed to preseparation, and it also are accurate and reliable. Consequently, the fluorescence capillary biosensor should have a good prospect in assaying PA and LA or LA/PA ratios for clinical medicines or biology field. The optimization conditions and parameters obtained in this study have also a certain guiding significance for the development of biochip based on glass substrate. PMID- 28084557 TI - Microstructural and Radioluminescence Characteristics of Nd3+ Doped Columbite Type SrNb2O6 Phosphor. AB - Undoped and different concentration Nd3+ doped SrNb2O6 powders with columbite structure were synthesized by molten salt process using a mixture of strontium nitrate and niobium (V) oxide and NaCl-KCl salt mixture as a flux under relatively low calcining temperature. X-ray diffraction analysis results indicated that SrNb2O6 phases found to be orthorhombic columbite single phase for undoped, 0.5 and 3 mol% Nd3+ doping concentrations. Phase composition of the powders was examined by SEM-EDS analyses. Radioluminescence properties of Nd3+ doped samples from UV to near-IR spectral region were studied. The emissions increased with the doping concentration of up to 3 mol%, and then decreased due to concentration quenching effect. There is a sharp emission peak around 880 nm associated with 4F5/2 -> 4I9/2 transition in the Nd3+ ion between 300 and 1100 nm. The broad emission band intensity was observed from 400 to 650 nm where the peak intensities increased by increasing Nd3+ doping concentration. All the measurements were taken under the room temperature. PMID- 28084559 TI - Apodized adaptive beamformer. AB - PURPOSE: A number of studies aimed at improvement of ultrasound image quality, such as spatial resolution and contrast, have been conducted. Apodization is known as an important factor that determines image quality. However, in the case of amplitude and phase estimation (APES) beamforming, a kind of adaptive beamformer that has been employed in medical ultrasound recently, only rectangular apodization has been used in the previous studies. In this study, apodization was employed in adaptive beamforming, and its effects on image quality were examined in phantom experiments. METHODS: We recently proposed a modified APES beamformer that reduces the computational complexity significantly using sub-aperture beamforming. In this study, the total receiving aperture was divided into four sub-apertures, and the APES beamforming was applied to the output from the four sub-apertures. Before the delay-and-sum (DAS) beamforming in each sub-aperture, echoes received by individual transducer elements were apodized with rectangular, Gaussian, and two Hanning functions, where the apodization with two Hanning functions realized lateral modulation of the ultrasonic field. The lateral spatial resolution was evaluated by the full width at half maximum of an echo from a string phantom, and the image contrast was evaluated using a cyst phantom. RESULTS: The modified APES beamformer realized a significantly better spatial resolution of 0.38 mm than that of the conventional delay-and-sum beamformer (0.67 mm), even with rectangular apodization. Using Gaussian apodization, the spatial resolution was further improved to 0.34 mm, and contrast was also improved from 4.3 to 5.1 dB. Furthermore, an image obtained by the modified APES beamformer with apodization consisting of two Hanning functions was better "tagged" as compared with the conventional DAS beamformer with the same apodization. CONCLUSION: Apodization was shown to be effective in adaptive beamforming, and an image obtained by the adaptive beamformer with lateral modulation seemed to have potential for improvement of the accuracy in measurement of tissue lateral motion. PMID- 28084558 TI - PCSK9 in chronic kidney disease. AB - PURPOSE: Chronic kidney disease (CKD) is accompanied by a number of secondary metabolic dysregulations, such as lipid abnormalities, presenting with unique characteristics. Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors have been introduced as the new era in the management of dyslipidemia with promising results in groups with refractory lipid abnormalities. Increasing number of studies investigate the possible association of PCSK9 levels with kidney function, especially with nephrotic range proteinuria, as well as its role as a prognostic cardiovascular risk marker in CKD. In this review, we discuss the existing evidence for PCSK9 levels in patient groups with nephrotic syndrome, non dialysis CKD, end-stage renal disease and kidney transplantation. METHODS: Online research was conducted in MEDLINE database to identify articles investigating PCSK9 in all different aspects of CKD. References from relevant studies were screened for supplementary articles. RESULTS: Four cross-sectional studies, one secondary analysis, one publication from two independent cohort studies and one multicentre prospective cohort study assessed PCSK9 plasma levels in different subgroups of CKD patients. PCSK9 levels increase in nephrotic syndrome and have a positive correlation with proteinuria. In CKD patients, no correlation was found between PCSK9 levels and estimated GFR. Peritoneal dialysis patients have higher PCSK9 levels compared with hemodialysis and renal transplant patients as well as general population. CONCLUSION: Accumulative evidence focuses on the possible association of PCSK9 levels with kidney function. No data are available for the administration of PCSK9 inhibitors in CKD patients. Further research will optimize knowledge on the role of PCSK9 levels and PCSK9 inhibitors in CKD. PMID- 28084561 TI - Monitoring HIV-Related Laws and Policies: Lessons for AIDS and Global Health in Agenda 2030. AB - The National Commitments and Policy Instrument (NCPI) has been used to monitor AIDS-related laws and policies for over 10 years. What can be learnt from this process? Analyses draw on NCPI questionnaires, NCPI responses, the UNAIDS Law Database, survey data and responses to a 2014 survey on the NCPI. The NCPI provides the first and only systematic data on country self-reported national HIV laws and policies. High NCPI reporting rates and survey responses suggest the majority of countries consider the process relevant. Combined civil society and government engagement and reporting is integral to the NCPI. NCPI experience demonstrates its importance in describing the political and legal environment for the HIV response, for programmatic reviews and to stimulate dialogue among stakeholders, but there is a need for updating and in some instances to complement results with more objective quantitative data. We identify five areas that need to be updated in the next iteration of the NCPI and argue that the NCPI approach is relevant to participatory monitoring of targets in the health and other goals of the UN 2030 Agenda for Sustainable Development. PMID- 28084560 TI - Nematode Root Herbivory in Tomato Increases Leaf Defenses and Reduces Leaf Miner Oviposition and Performance. AB - The outcome of plant-mediated interactions among herbivores from several feeding guilds has been studied intensively. However, our understanding on the effects of nematode root herbivory on leaf miner oviposition behavior and performance remain limited. In this study, we evaluated whether Meloidogyne incognita root herbivory affects Tuta absoluta oviposition preference on Solanum lycopersicum plants and the development of the resulting offspring. To investigate the M. incognita herbivory induced plant systemic responses that might explain the observed biological effects, we measured photosynthetic rates, leaf trypsin protease inhibitor activities, and analyzed the profile of volatiles emitted by the leaves of root-infested and non-infested plants. We found that T. absoluta females avoided laying eggs on the leaves of root-infested plants, and that root infestation negatively affected the pupation process of T. absoluta. These effects were accompanied by a strong suppression of leaf volatile emissions, a decrease in photosynthetic rates, and an increase in the activity of leaf trypsin protease inhibitors. Our study reveals that root attack by nematodes can shape leaf physiology, and thereby increases plant resistance. PMID- 28084562 TI - Immunostimulatory effect of dried bonito extract on mouse macrophage cell lines and mouse primary peritoneal macrophages. AB - Dried bonito is a preserved food used in Japan, which contains abundant flavor ingredients and functional substances. We focused on the immunostimulatory effect of dried bonito extract (DBE) on mouse macrophage-like J774.1 cells, RAW264.7 cells, and mouse primary peritoneal macrophages. DBE significantly stimulated the production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) by both J774.1 cells and peritoneal macrophages by enhancing the cytokine gene expression levels. In addition, DBE stimulated nitric oxide production by enhancing the expression of inducible nitric oxide synthase in RAW264.7 cells. DBE also increased the phagocytosis activity of J774.1 cells. Immunoblot analysis revealed that DBE has an immunostimulatory effect on macrophages through activation of mitogen-activated protein kinase and nuclear factor-kappaB cascades. TNF-alpha production enhanced by DBE was partially inhibited by treatment with TLR4 inhibitor TAK-242, whereas IL-6 production enhanced by DBE was almost inhibited. These results suggested that DBE is thought to strongly stimulate the TLR4 signaling pathway for macrophage activation, and its activation is also involved in other signaling. Finally, the phagocytosis activity of peritoneal macrophages from DBE-administered BALB/c mice increased significantly, suggesting that DBE has the potential to stimulate macrophage activity in vivo. In conclusion, these data indicated that DBE contributes to activating host defense against pathogens by activating innate immunity. PMID- 28084563 TI - Efficacy and Safety of Tacrolimus Versus Cyclophosphamide for Primary Membranous Nephropathy: A Meta-Analysis. AB - OBJECTIVE: The objective of this systematic review was to compare the efficacy and safety of tacrolimus with cyclophosphamide in primary membranous nephropathy (PMN) patients. DATA SOURCES AND STUDY ELIGIBILITY CRITERIA: We conducted a literature search in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CCRCT). Any study that compared the efficacy or safety between tacrolimus and cyclophosphamide in the adult PMN patients was included. RESULTS: We included four randomized controlled trials and two prospective cohort studies with 389 PMN patients. The pooled results using the Dersimonian and Laird method showed that renal remission rates at the longest follow-up periods were not significantly different between the tacrolimus and cyclophosphamide groups (overall remission, six trials, n = 389, relative risk [RR] 0.994 [95% confidence interval [CI] 0.768-1.286); complete remission, six trials, n = 389, RR 1.256 [95% CI 0.733-2.150]). Further analyses found that tacrolimus was comparable with cyclophosphamide for inducing renal remission within 1 year but inferior to cyclophosphamide after 1-year follow-up. It should be noted that only two studies reported the outcomes after 1-year follow-up, which might be considered as weak evidence. The rates of relapse and the drop-outs due to adverse effects were not significantly different (relapse, six trials, n = 389, RR 2.244 [95% CI 0.892 5.644]; drop-outs, six trials, n = 389, RR 1.330 [95% CI 0.412-4.291]). However, the cyclophosphamide group had a significantly higher risk of leukopenia than the tacrolimus group (four trials, n = 216, RR 0.203 [95% CI 0.045-0.916]), whereas the rates of tremor were significantly higher in the tacrolimus group than in the cyclophosphamide group (three trials, n = 202, RR 8.939 [95% CI 1.694-47.173]). LIMITATIONS: The quality and short follow-up durations of the studies limited the reliability of our conclusions. CONCLUSIONS: Tacrolimus was comparable with cyclophosphamide for inducing renal remission of PMN patients within 1 year, but the long-term effects need to be investigated. The cyclophosphamide group had a significantly higher risk of leukopenia, whereas the tacrolimus group had significantly higher rates of tremor. These conclusions need to be further verified. PMID- 28084564 TI - Erratum to: Structural and functional analyses of human DDX41 DEAD domain. PMID- 28084565 TI - Acrolein Can Cause Cardiovascular Disease: A Review. AB - Acrolein is a highly reactive unsaturated aldehyde that is formed during the burning of gasoline and diesel fuels, cigarettes, woods and plastics. In addition, acrolein is generated during the cooking or frying of food with fats or oils. Acrolein is also used in the synthesis of many organic chemicals and as a biocide in agricultural and industrial water supply systems. The total emissions of acrolein in the United States from all sources are estimated to be 62,660 tons/year. Acrolein is classified by the Environmental Protection Agency as a high-priority air and water toxicant. Acrolein can exert toxic effects following inhalation, ingestion, and dermal exposures that are dose dependent. Cardiovascular tissues are particularly sensitive to the toxic effects of acrolein based primarily on in vitro and in vivo studies. Acrolein can generate free oxygen radical stress in the heart, decrease endothelial nitric oxide synthase phosphorylation and nitric oxide formation, form cytoplasmic and nuclear protein adducts with myocyte and vascular endothelial cell proteins and cause vasospasm. In this manner, chronic exposure to acrolein can cause myocyte dysfunction, myocyte necrosis and apoptosis and ultimately lead to cardiomyopathy and cardiac failure. Epidemiological studies of acrolein exposure and toxicity should be developed and treatment strategies devised that prevent or significantly limit acrolein cardiovascular toxicity. PMID- 28084566 TI - Hyperthermia Severely Affects the Vascular Effects of MDMA and Metabolites in the Human Internal Mammary Artery In Vitro. AB - 3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy") is a recreational drug used worldwide for its distinctive psychotropic effects. Although important cardiovascular effects, such as increased blood pressure and heart rate, have also been described, the vascular effects of MDMA and metabolites and their correlation with hyperthermia (major side effect of MDMA) are not yet fully understood and have not been previously reported. This study aimed at evaluating the effects of MDMA and its main catechol metabolites, alpha-methyldopamine (alpha-MeDA), N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA), 5-(glutathion-S yl)-alpha-methyldopamine [5-(GSH)-alpha-MeDA] and 5-(glutathion-S-yl)-N-methyl alpha-methyldopamine [5-(GSH)-N-Me-alpha-MeDA], on the 5-HT-dependent vasoactivity in normothermia (37 degrees C) and hyperthermia (40 degrees C) of the human internal mammary artery (IMA) in vitro. The results showed the ability of MDMA, alpha-MeDA and N-Me-alpha-MeDA to exert vasoconstriction of the IMA which was considerably higher in hyperthermic conditions (about fourfold for MDMA and alpha-MeDA and twofold for N-Me-alpha-MeDA). The results also showed that all the compounds may influence the 5-HT-mediated concentration-dependent response of IMA, as MDMA, alpha-MeDA and N-Me-alpha-MeDA behaved as partial agonists and 5 (GSH)-alpha-MeDA and 5-(GSH)-N-Me-alpha-MeDA as antagonists. In conclusion, MDMA abuse may imply a higher cardiovascular risk associated both to MDMA and its metabolites that might be relevant in patients with underlying cardiovascular diseases, particularly in hyperthermia. PMID- 28084567 TI - [The Well-Being Measure - dementia: A validation study]. AB - The Well-Being Measure - dementia is a digital observation instrument that assesses the well-being of persons with dementia on four domains of quality of life: Mental well-being, Physical well-being, Participation, and Living arrangements. Its goal is to assess the well-being of persons with dementia in an easy and positive way. Besides illness-related symptoms and problems, the instrument also assesses positive aspects of functioning. It visualizes the results and provides specific behavioural advice to the caregivers. The goal of the present article is to conduct a first psychometric analysis: factor structure, reliability (Cronbach's alpha), concurrent, and convergent validity.Observations were carried out among 168 persons with dementia in eleven different small-scale psychogeriatric wards. Five existing instruments were used among 63 persons to validate the Well-Being Measure-dementia: quality of life, neuropsychiatric symptoms, care dependency, depression, and agitation.The expected factor structure was found in each of the four domains. Coefficients were high on the expected factor and low on the other factor(s). The scale means were on the positive side, but showed an adequate range and variability. Reliability was satisfactory to good. The relation with existing scales was moderate to strong. The pattern of relations was consistent with the measurement intentions of the different existing instruments.The Well-Being Measure - dementia appears to be a valid and reliable scale. Further studies should assess its test-retest reliability, sensitivity to change and relation with the course of dementia. Current experience shows that the instrument is also useful in everyday practice. PMID- 28084568 TI - Technical characterization of dialysis fluid flow and mass transfer rate in dialyzers with various filtration coefficients using dimensionless correlation equation. AB - The objective of the present study is to evaluate the effect of filtration coefficient and internal filtration on dialysis fluid flow and mass transfer coefficient in dialyzers using dimensionless mass transfer correlation equations. Aqueous solution of vitamin B12 clearances were obtained for REXEED-15L as a low flux dialyzer, and APS-15EA and APS-15UA as high flux dialyzers. All the other design specifications were identical for these dialyzers except for filtration coefficient. The overall mass transfer coefficient was calculated, moreover, the exponents of Reynolds number (Re) and film mass transfer coefficient of the dialysis-side fluid (k D) for each flow rate were derived from the Wilson plot and dimensionless correlation equation. The exponents of Re were 0.4 for the low flux dialyzer whereas 0.5 for the high flux dialyzers. Dialysis fluid of the low flux dialyzer was close to laminar flow because of its low filtration coefficient. On the other hand, dialysis fluid of the high flux dialyzers was assumed to be orthogonal flow. Higher filtration coefficient was associated with higher k D influenced by mass transfer rate through diffusion and internal filtration. Higher filtration coefficient of dialyzers and internal filtration affect orthogonal flow of dialysis fluid. PMID- 28084569 TI - Specificity of Mechanisms of Memory Reconsolidation in Snails Trained for Rejection of Two Types of Food. AB - Specificity of behavioral and neuronal mechanisms of impairment of long-term memory reconsolidation was studied in edible snails trained for associative skill of rejection of two types of food: raw carrots (conditioned stimulus 1) and apple (conditioned stimulus 2). In 2 days after training, the snails received protein synthesis inhibitor cycloheximide and a reminder (conditioned stimulus 1 or 2). In 3 and 14 days after cycloheximide/reminder, we observed the absence of aversive responses to the conditioned stimulus used as the reminder and preserved responses to the conditioned stimulus not used as the reminder. Moreover, we observed specific suppression of synaptic responses of command neurons of snail defensive behavior induced by the conditioned stimulus used as the reminder after cycloheximide injection and preserved synaptic responses of neurons to the other conditioned stimulus. It was hypothesized that protein synthesis-dependent synapse-specific plasticity of command neurons can be a mechanism of selective preservation of conditioned food aversion memory in snails. PMID- 28084570 TI - Synthesis and evaluation of a radiolabeled bis-zinc(II)-cyclen complex as a potential probe for in vivo imaging of cell death. AB - The exposition of phosphatidylserine (PS) from the cell membrane is associated with most cell death programs (apoptosis, necrosis, autophagy, mitotic catastrophe, etc.), which makes PS an attractive target for overall cell death imaging. To this end, zinc(II) macrocycle coordination complexes with cyclic polyamine units as low-molecular-weight annexin mimics have a selective affinity for biomembrane surfaces enriched with PS, and are therefore useful for detection of cell death. In the present study, a 11C-labeled zinc(II)-bis(cyclen) complex (11C-CyclenZn2) was prepared and evaluated as a new positron emission tomography (PET) probe for cell death imaging. 11C-CyclenZn2 was synthesized by methylation of its precursor, 4-methoxy-2,5-di-[10-methyl-1,4,7,10-tetraazacyclododecane 1,4,7-tricarboxylic acid tri-tert-butyl ester] phenol (Boc-Cyclen2) with 11C methyl triflate as a prosthetic group in acetone, deprotection by hydrolysis in aqueous HCl solution, and chelation with zinc nitrate. The cell death imaging capability of 11C-CyclenZn2 was evaluated using in vitro cell uptake assays with camptothecin-treated PC-3 cells, biodistribution studies, and in vivo PET imaging in Kunming mice bearing S-180 fibrosarcoma. Starting from 11C-methyl triflate, the total preparation time for 11C-CyclenZn2 was ~40 min, with an uncorrected radiochemical yield of 12 +/- 3% (based on 11C-CH3OTf, n = 10), a radiochemical purity of greater than 95%, and the specific activity of 0.75-1.01 GBq/MUmol. The cell death binding specificity of 11C-CyclenZn2 was demonstrated by significantly different uptake rates in camptothecin-treated and control PC-3 cells in vitro. Inhibition experiments for 18F-radiofluorinated Annexin V binding to apoptotic/necrotic cells illustrated the necessity of zinc ions for zinc(II) bis(cyclen) complexation in binding cell death, and zinc(II)-bis(cyclen) complexe and Annexin V had not identical binding pattern with apoptosis/necrosis cells. Biodistribution studies of 11C-CyclenZn2 revealed a fast clearance from blood, low uptake rates in brain and muscle tissue, and high uptake rates in liver and kidney, which provide the main metabolic route. PET imaging using 11C-CyclenZn2 revealed that cyclophosphamide-treated mice (CP-treated group) exhibited a significant increase of uptake rate in the tumor at 60 min postinjection, compared with control mice (Control group). The results indicate that the ability of 11C-CyclenZn2 to detect cell death is comparable to Annexin V, and it has potential as a PET tracer for noninvasive evaluation and monitoring of anti-tumor chemotherapy. PMID- 28084571 TI - Xanthine Oxidase Induces Foam Cell Formation through LOX-1 and NLRP3 Activation. AB - PURPOSE: Xanthine oxidase catalyzes the oxidation of xanthine to uric acid. This process generates excessive reactive oxygen species (ROS) that play an important role in atherogenesis. Recent studies show that LRR and PYD domains-containing protein 3 (NLRP3), a component of the inflammasome, may be involved in the formation of foam cells, a hallmark of atherosclerosis. This study was designed to study the role of various scavenger receptors and NLRP3 inflammasome in xanthine oxidase and uric acid-induced foam cell formation. METHODS AND RESULTS: Human vascular smooth muscle cells (VSMCs) and THP-1 macrophages were treated with xanthine oxidase or uric acid. Xanthine oxidase treatment (of both VSMCs and THP-1 cells) resulted in foam cell formation in concert with generation of ROS and expression of cluster of differentiation 36 (CD36) and oxidized low density lipoprotein (lectin-like) receptor 1 (LOX-1), but not of scavenger receptor A (SRA). Uric acid treatment resulted in foam cell formation, ROS generation and expression of CD36, but not of LOX-1 or SRA. Further, treatment of cells with xanthine oxidase, but not uric acid, activated NLRP3 and its downstream pro inflammatory signals- caspase-1, interleukin (IL)-1beta and IL-18. Blockade of LOX-1 or NLRP3 inflammasome with specific siRNAs reduced xanthine oxidase-induced foam cell formation, ROS generation and activation of NLRP3 and downstream signals. CONCLUSIONS: Xanthine oxidase induces foam cell formation in large part through activation of LOX-1 - NLRP3 pathway in both VSMCs and THP-1 cells, but uric acid-induced foam cell formation is exclusively through CD36 pathway. Further, LOX-1 activation is upstream of NLRP3 activation. Graphical Abstract Steps in the formation of foam cells in response to xanthine oxidase and uric acid. Xanthine oxidase stimulates LOX-1 expression on the cell membrane of macrophages and vascular smooth muscle cells (VSMCs) and increases generation of ROS, which activate NLRP3 inflammasome and downstream pro-inflammatory mediators such as Caspase-1, IL-1beta and IL-18. Xanthine oxidase also induces CD36 expression. Activation of both LOX-1 and CD36 (LOX-1> > CD36) participates in the transformation of macrophages and VSMCs into foam cells. Uric acid formed from xanthine-xanthine oxidase interaction stimulates CD36 expression and triggers foam cell formation independent of NLRP3 activation. PMID- 28084572 TI - Clinical Implications of Cytotoxic T Lymphocyte Antigen-4 Expression on Tumor Cells and Tumor-Infiltrating Lymphocytes in Extrahepatic Bile Duct Cancer Patients Undergoing Surgery Plus Adjuvant Chemoradiotherapy. AB - BACKGROUND: There currently is only limited knowledge on the role of tumor specific immunity in cholangiocarcinoma. OBJECTIVE: This study evaluated the clinical implications of cytotoxic T lymphocyte antigen-4 (CTLA-4) expression levels and CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) in extrahepatic bile duct (EHBD) cancer. PATIENTS AND METHODS: Immunohistochemistry of CTLA-4, CD4, and CD8 was performed for 77 EHBD cancer patients undergoing surgery plus adjuvant chemoradiotherapy. CTLA-4 expression on tumor cells and TILs were assessed by using H-scores and the proportion of CTLA-4+ lymphocytes, respectively. RESULTS: With optimal cutoff values determined by a maximal chi square method with overall survival (OS) data, patients with CTLA-4 H-score >70 and a proportion of CTLA-4+ TILs >0.15 showed higher mean density of CD8+ and CD4+ TILs, respectively (P = 0.025 for CD8+ and P = 0.055 for CD4+ TILs). The high CTLA-4 H-score level was associated with prolonged OS and disease-free interval (DFI) (P = 0.025 and 0.004, respectively). With differential levels of CTLA-4 H-score according to hilar and non-hilar locations (high rate 32 vs. 68%, respectively; P = 0.013), an exploratory subgroup analysis demonstrated that the associations between the CTLA-4 expression and OS and DFI were confined to hilar tumors (P = 0.003 and <0.001, respectively), but not to non-hilar ones (P = 0.613 and 0.888, respectively). CONCLUSIONS: This study demonstrates a potential prognostic relevance of CTLA-4 expression in EHBD cancer. We suggest a differential survival impact of the CTLA-4 expression level according to different tumor locations. PMID- 28084573 TI - The Activities of Adhesion and Biofilm Formation by Candida tropicalis Clinical Isolates Display Significant Correlation with Its Multilocus Sequence Typing. AB - Adhesion and biofilm formation, which can occur on abiotic and biotic surfaces, are key components in Candida pathogenicity. The aims of this study were to infer about the C. tropicalis clinical isolates ability to adhere and form biofilm on abiotic and biotic surfaces and to correlate that with the multilocus sequence typing and other virulence factors. Adhesion and biofilm formation were measured in 68 C. tropicalis isolates from 3 hospitals in China on abiotic (polystyrene) and biotic (human urinary bladder epithelial cell) surfaces by crystal violet assay and 2,3-bis (2-methoxy-4-nitro-5-sulfo-phenyl)-2H-tetrazolium-5 carboxanilide reduction assay. In our study, almost all C. tropicalis isolates could adhere and produce biofilm on abiotic and biotic surfaces in a strain dependent manner. The isolates from blood showed relatively lower adhesion and biofilm capacity on polystyrene surface, but had strong secreted aspartyl proteinase activity. Moreover, significant differences were found among MLST groups for adhesion and biofilm capacity. C. tropicalis in multilocus sequence typing group5 and group6 showed high adhesion and biofilm, while isolates in group1 exhibited low adhesion and biofilm formation. Overall, it is important to note that C. tropicalis isolates adhere to and produce biofilm on abiotic and biotic surfaces with strain specificity. These data will play an important role in subsequent research on the pathogenesis of C. tropicalis. PMID- 28084574 TI - Large-Scale Land Development, Fugitive Dust, and Increased Coccidioidomycosis Incidence in the Antelope Valley of California, 1999-2014. AB - Ongoing large-scale land development for renewable energy projects in the Antelope Valley, located in the Western Mojave Desert, has been blamed for increased fugitive dust emissions and coccidioidomycosis incidence among the general public in recent years. Soil samples were collected at six sites that were destined for solar farm construction and were analyzed for the presence of the soil-borne fungal pathogen Coccidioides immitis which is endemic to many areas of central and southern California. We used a modified culture-independent nested PCR approach to identify the pathogen in all soil samples and also compared the sampling sites in regard to soil physical and chemical parameters, degree of disturbance, and vegetation. Our results indicated the presence of C. immitis at four of the six sites, predominantly in non-disturbed soils of the Pond-Oban complex, which are characterized by an elevated pH and salt bush communities, but also in grassland characterized by different soil parameters and covered with native and non-native annuals. Overall, we were able to detect the pathogen in 40% of the soil samples (n = 42). Incidence of coccidioidomycosis in the Antelope Valley was positively correlated with land use and particulate matter in the air (PM10) (Pearson correlation coefficient >0.5). With the predicted population growth and ongoing large-scale disturbance of soil in the Antelope Valley in coming years, incidence of coccidioidomycosis will likely further increase if policy makers and land developers continue to ignore the risk of grading land without implementing long-term dust mitigation plans in Environmental Impact Reports. PMID- 28084575 TI - Ethical Concerns and Procedural Pathways for Patients Who are Incapacitated and Alone: Implications from a Qualitative Study for Advancing Ethical Practice. AB - Adults who are incapacitated and alone, having no surrogates, may be known as "unbefriended." Decision-making for these particularly vulnerable patients is a common and vexing concern for healthcare providers and hospital ethics committees. When all other avenues for resolving the need for surrogate decision making fail, patients who are incapacitated and alone may be referred for "public guardianship" or guardianship of last resort. While an appropriate mechanism in theory, these programs are often under-staffed and under-funded, laying the consequences of inadequacies on the healthcare system and the patient him or herself. We describe a qualitative study of professionals spanning clinical, court, and agency settings about the mechanisms for resolving surrogate consent for these patients and problems therein within the state of Massachusetts. Interviews found that all participants encountered adults who are incapacitated and without surrogates. Four approaches for addressing surrogate needs were: (1) work to restore capacity; (2) find previously unknown surrogates; (3) work with agencies to obtain surrogates; and (4) access the guardianship system. The use of guardianship was associated with procedural challenges and ethical concerns including delays in care, short term gains for long term costs, inabilities to meet a patient's values and preferences, conflicts of interest, and ethical discomfort among interviewees. Findings are discussed in the context of resources to restore capacity, identify previously unknown surrogates, and establish improved surrogate mechanisms for this vulnerable population. PMID- 28084576 TI - Transgenerational Transmission of Preterm Birth Risk: The Role of Race and Generational Socio-Economic Neighborhood Context. AB - Objectives We investigated associations of mothers' preterm birth (PTB) status with her infants' PTB risk. We also examined whether this relationship differs by mothers' race and generational socio-economic neighborhood context. Methods Participants were 6592 non-Hispanic (NH) white and NH black mother-infant pairs born in 2009-2011 and 1979-1998, respectively, in Allegheny County, Pennsylvania. Birth records were used to determine gestational age at birth, PTB status (<37 completed weeks of gestation), and PTB subgroups-late and early PTB (34-36 weeks and <34 completed weeks of gestation, respectively). Census data on tract racial composition and household income were used to characterize residential race and economic environment. Logistic regression models were used to calculate Odds Ratios (ORs), Relative Risk Ratios (RRR), and 95% confidence intervals (CIs). Stratified analyses were conducted to assess effect modification. Results Overall, 8.21, 6.63 and 1.58% infants had PTB, LPTB, and EPTB, respectively. Maternal PTB status was associated with a 46% increase in infant PTB (95% CI: 1.08-1.98), EPTB (95% CI: 0.80-2.69), and LPTB (95% CI: 1.04-2.04) risk. Maternal PTB-infant PTB associations, particularly maternal PTB-infant LPTB associations, were stronger among NH blacks, mothers in neighborhoods with a high percentage of NH black residents in both generations, or mothers who moved to neighborhoods with a higher percentage of NH black residents. Conclusions for Practice Race and generational socio-economic neighborhood context modify transgenerational transmission of PTB risk. These findings are important for identification of at risk populations and to inform future mechanistic studies. PMID- 28084577 TI - Prevalence and Perceptions of Electronic Cigarette Use during Pregnancy. AB - Objectives The current study is the first to assess pregnant women's perceptions of e-cigarettes and the prevalence of e-cigarette use during pregnancy, using a national sample of pregnant women (N = 445) recruited online. Methods An online survey was used to assess the prevalence and perceptions of e-cigarette use among pregnant women, including perceptions of e-cigarette safety. Results In our sample, 5.62% (n = 25) of women solely used tobacco cigarettes, 6.52% (n = 29) solely used e-cigarettes, 8.54% (n = 38) used both tobacco cigarettes and e cigarettes, and 79.33% (n = 353) used neither tobacco cigarettes nor e-cigarettes during their current pregnancy. Overall, 64.27% (n = 286) of participants viewed e-cigarettes as being safer than tobacco cigarettes. Having seen advertisements for e-cigarettes increased likelihood of viewing them as safer than tobacco cigarettes (OR [Odds Ratio] = 2.5, p < .01). Conclusions for Practice Taken together, findings from this study suggest that at least as many women use e cigarettes during pregnancy as tobacco cigarettes, that pregnant women view e cigarettes as being safer than tobacco cigarettes, and that these views may be influenced by exposure to e-cigarette advertisements. PMID- 28084578 TI - Influence of Experiences and Perceptions Related to Breastfeeding One's First Child on Breastfeeding Initiation of Second Child. AB - Introduction Multiparas tend to initiate breastfeeding less than primiparas. While mothers often repeat the feeding method used for their first child with their second child, the way in which experiences and maternal perceptions related to breastfeeding one's first child may influence breastfeeding initiation with a second child remain underexplored. The objective of this study was to investigate whether physiological or social experiences, and related psychological factors, reported at the end of breastfeeding one's first child influence breastfeeding initiation with a second child. Methods Data from 174 multiparas who participated in the Infant Feeding Practices Study II, breastfed their first child, and completed the Year 6 Follow Up were analyzed using exact logistic regression. Results Mothers who reported experiencing trouble with the first baby's suck or latch had lower odds of initiating breastfeeding (OR 0.15, 95% CI 0.04-0.56) than those who did not report this experience, whereas mothers who agreed that breastfed children are less likely to become obese had greater odds of initiating breastfeeding with a second child (OR 11.49, 95% CI 1.56-513.18) than those who did not agree. Discussion Efforts to facilitate breastfeeding initiation among multiparas may consider mothers' previous experiences and beliefs associated with breastfeeding. Strategies to facilitate initiation may focus on addressing barriers mothers experienced while breastfeeding their first child and increasing awareness about how breastfeeding may prevent childhood obesity. Future research should explore how such approaches may impact breastfeeding outcomes with subsequent children. PMID- 28084579 TI - Who, What and Where (WWW) Problems in Scientific Communities. AB - The results of the National Higher Education Entrance Examination (Gaokao, in Chinese) have a life-long effect on most Chinese by labeling them clever or not. Some of the following rules of the Gaokao enhance the damage, for example, the rule of Who, What and Where. In general, Who you are and What you have done are of secondary importance, but Where you graduated from, especially the college of first-record is the most important, but discriminatory criterion in the recruitment courses of most of scientific communities and social organizations in China. PMID- 28084580 TI - Vasculogenic Mimicry in Clinically Non-functioning Pituitary Adenomas: a Histologic Study. AB - The term "vasculogenic mimicry" (VM) refers to the phenomenon in which vascular like channels, which are not lined by endothelial cells, are formed in tumors. Since its discovery in 1999, it has been observed in several tumor types and is proposed to provide blood perfusion to tumors in absence of co-apted or neo angiogenic blood vessels. Pituitary tumors are generally slow growing, benign adenomas which are less vascularized than the normal pituitary gland. To date, VM in pituitary adenomas has not been described. In this histological study, we assessed the presence of VM in a series of surgically resected clinically non functioning pituitary adenomas (NFPAs) using CD34 and Periodic Acid-Schiff (PAS) double staining. To identify VM, slides were assessed for the presence of CD34 negative and PAS-positive channels indicating that they were not lined by endothelial cells. The histological staining pattern suggestive of VM was noted in 22/49 (44.9%) of the specimens studied. VM was observed in both recurring and non-recurring NFPAs. The incidence of VM present varied from case to case and within groups. There was no association between the presence of VM and gender, tumor size, Ki-67 index, recurrence or cavernous sinus invasion. VM was not noted in cases of non-tumorous pituitaries. Our findings suggest the existence of a complementary perfusion system in pituitary adenomas, implying potential clinical implications with respect to response to therapy and clinical course. Further research is warranted to confirm the presence of VM in pituitary adenomas to elucidate its clinical relevance in patients diagnosed with a pituitary adenoma. PMID- 28084582 TI - Releasing Effect of Individual Potential: Formation of Productive Collective and Children's Self-Transcendence in a Chinese School. AB - We describe the intricate relations between social demand structures and their role in facilitation of individual development of children and teachers in a Chinese classroom. The relationship of an individual to the immediate social group is further qualified by the inclusion in a collective which enables the participants to transform their individual self-structures through taking on social roles in everyday collective activities, which release further potential for their individual development. We describe that releasing effect in the case of an intervention program in a Chinese school for the children of rural migrants re-settled in a city, demonstrating gradually how the inter-individual competitive orientation promoted by autocratic teaching style becomes transformed into collective good oriented joint actions towards excellence in educational endeavors (Jiti). The productive nature of the Jiti makes an ecology with multiple nested and open systems, in which every group and student is producer and consumer of each other, and personal self-transcendence is actualized in the process. The releasing effect is demonstrated through observing the co-emergence of new forms of progressive conduct and new problems, presented in pupils' positive participation in activities. The description of the intervention in a Chinese school provides us with insight on how concrete social inclusion frameworks with the underpinning Chinese philosophy of "acting up to trends" can prevent the emergence of direct animosities and lead to new integration of self and society. PMID- 28084581 TI - Colon capsule endoscopy: toward the future. AB - Colon capsule endoscopy is a wireless and minimally invasive technique for visualization of the whole colon. With recent improvements of technical features in second-generation systems, a more important role for colon capsule endoscopy is rapidly emerging. Although several limitations and drawbacks are yet to be resolved, its usefulness as a tool for colorectal cancer screening and monitoring disease activity in inflammatory bowel diseases has become more apparent with increased use. Further investigations, including multicenter trials, are required to evaluate the substantial role of the colon capsule in managing colorectal diseases. PMID- 28084583 TI - Brain metastasis in patients with metastatic breast cancer in the real world: a single-institution, retrospective review of 12-year follow-up. AB - PURPOSE: The data of 589 metastatic breast cancer (MBC) patients in a single institution were reviewed to determine the outcomes of patients with brain metastasis (BM) and assess the efficacy of BM screening. METHODS: The patients with BM among the 589 MBC patients who underwent treatment at Shizuoka Cancer Center (Shizuoka, Japan) from 09/2002 to 03/2014 were retrospectively analyzed. RESULTS: During the study period, BM developed in 187 (31.7%) patients. The tumor subtypes were as follows: luminal (hormone receptor [HR]+, HER2-), 44.9%; luminal HER2 (HR+, HER2+), 14.9%; HER2 (HR-, HER2+), 21.3%; and triple-negative (TN), 16.0%. BM was detected in 48.6% of the patients by screening MRI. While 137 of 187 patients underwent local therapy, whole-brain irradiation was the most frequently applied therapy (63.5%). The median overall survival from the diagnosis of BM was as follows: luminal, 7.0 months (M); luminal-HER2, 13.3 M; HER2, 17.7 M; TN, 4.2 M. The HER2 status (hazard ratio [HR]: 0.58, 95% confidence interval [CI] 0.38-0.88) and nonprogressive extracranial lesion(s) (HR: 0.45, 95% CI 0.29-0.71) were identified as prognostic factors in a multivariate analysis. When limited to HER2-overexpressed MBC patients, the multivariate analysis revealed that non-progressive extracranial lesion(s) (HR: 0.20, 95% CI 0.088 0.47) and stereotactic irradiation (STI) as an initial treatment (HR: 0.18, 95% CI 0.061-0.56) were prognostic factors. CONCLUSIONS: Our retrospective review showed that early detection of BM by screening MRI, followed by STI, improved the prognosis of HER2-overexpressed MBC patients with BM. A further prospective randomized study is needed to confirm our findings. PMID- 28084584 TI - Waterborne outbreak of cryptosporidiosis in the South East of Ireland: weighing up the evidence. AB - BACKGROUND: In late Spring 2012, 12 cases of cryptosporidiosis in a town in the South East of Ireland were notified to the regional Department of Public Health. AIM: The purpose of this paper is to describe the outbreak and the investigative process which led to the conclusion that the source was a public drinking water supply. METHODS: Outbreak and incident control teams were convened to investigate and control the outbreak. RESULTS: Eleven cases were speciated as Cryptosporidium parvum. GP60 analysis demonstrated that 10 were C. parvum IIaA20G3R1, indicating that the cases were linked. The public water supply was the only common risk factor identified. Increased water sampling identified Cryptosporidium muris/andersoni in the treated water at one of two water treatment plants (Water Treatment Plant, WTP A) for the supply, and on the network. C. parvum was subsequently identified in raw water from WTP A. CONCLUSIONS: The Health Service Executive (HSE) concluded that this outbreak was "probably associated with water" produced at WTP A based on (1) descriptive epidemiological evidence suggesting water-related illness and excluding other obvious explanations; and (2) water treatment failure at WTP A. WTP A was closed to facilitate an upgrade. No boil water notice was required as a supplementary supply was available. The upgrade was completed and the incident closed in 2013. PMID- 28084585 TI - Estimating the Cost of Illness of Giant Cell Arteritis in the United States. AB - INTRODUCTION: Giant cell arteritis (GCA) is a chronic vasculitis affecting approximately 230,000 Americans. Limited data exist on the healthcare resource utilization and costs attributable to GCA. The objective of this study was to estimate the cost of illness in patients with GCA in the US. METHODS: A cohort of patients with a new GCA diagnosis was identified from a large US claims database between 1 January 2008 and 31 December 2012. Newly diagnosed GCA patients were defined by two claims with GCA (ICD-9 446.5) as one of the listed diagnoses during the study period and no GCA diagnosis in the 12 months prior. Subjects without a GCA diagnosis were matched 5:1 to cases. One-year healthcare costs were compared among cases and controls, adjusting for covariates using generalized linear models. RESULTS: A cohort of 1293 GCA patients and 6465 controls was identified. The mean age was 73 years, and 69% were females. Mean Charlson Comorbidity Index was 1.9 for GCA patients and 1.0 for controls. Mean 1-year cost for GCA patients was $34,065 [standard deviation (SD) $52,411], and mean 1-year cost for controls was $12,890 (SD $37,345). After multivariate adjustment, the difference in 1-year cost between GCA patients and controls was $16,431 (95% CI $13,821-$19,041). CONCLUSIONS: Patients with GCA experience substantially higher healthcare costs in the first year following diagnosis compared to patients without GCA. These results add to the limited evidence available to inform researchers, clinicians, and policymakers on the cost burden of GCA in the US. FUNDING: Genentech Inc. PMID- 28084586 TI - Amelioration of high fat diet-induced nephropathy by cilostazol and rosuvastatin. AB - Multiple comorbidities of metabolic disorders are associated with facilitated chronic kidney disease progression. Anti-platelet cilostazol is used for the treatment of peripheral artery disease. In this study, we investigated the potential beneficial effects of cilostazol and rosuvastatin on metabolic disorder induced renal dysfunctions. C57BL/6 mice that received high fat diet (HFD) for 22 weeks and a low dose of streptozotocin (STZ, 40 mg/kg) developed albuminuria and had increased urinary cystatin C excretion, and cilostazol treatment (13 weeks) improved these markers. Histopathological changes, including glomerular mesangial expansion, tubular vacuolization, apoptosis, and lipid accumulation were ameliorated by cilostazol treatment. Tubulointerstitial fibrosis that was indicated by the increases in collagen and transforming growth factor-beta1 subsided by cilostazol. Renoprotective effects were also observed in rosuvastatin treated mice, and combinatorial treatment with cilostazol and rosuvastatin demonstrated enhanced ameliorative effects in histopathological evaluations. Notably, repressed renal heme oxygenase-1 (Ho-1) level in HFD/STZ mice was restored in cilostazol group. Further, we demonstrated that cilostazol enhanced Nrf2/Ho-1 signaling in cultured proximal tubular epithelial cells. Collectively, these results suggest the potential advantageous use of cilostazol as an adjunctive therapy with statins for the amelioration of metabolic disorder associated renal injury. PMID- 28084587 TI - Milestone Weight Loss Goals (Weight Normalization and Remission of Obesity) after Gastric Bypass Surgery: Long-Term Results from the University of Michigan. AB - BACKGROUND: Rates of weight normalization and obesity remission after Roux-en-Y gastric bypass (GB) are unknown. This study evaluated weight loss, rates of achieving body mass index (BMI) <25 or 30 kg/m2, recidivism, and predictors of success following GB. METHODS: We retrospectively studied weight and BMI at baseline, 2 and 6 months, and annually at 1-7 years in 219 patients undergoing GB at the University of Michigan from January 2008 to November 2010. RESULTS: Follow up was excellent for a population traditionally associated with high attrition rates with data availability of 157/219, 145/219, 144/219, 134/219, 123/219, 82/161, and 29/64 patients at 1-7 years, respectively. Mean baseline BMI was 47.0 kg/m2. Weight normalization (BMI <25 kg/m2) occurred in 2.3-6.8% of patients. More importantly, 47% of patients achieved remission of obesity (BMI <30 kg/m2) at some time point and 24% (52/219) at the last observed time point. BMI <30 kg/m2 was associated with a lower initial BMI and follow-up for more than 2 years. CONCLUSIONS: Rates of weight normalization are low after GB; however, a large number of patients achieved BMI <30 kg/m2. While the percent total weight loss and excess weight loss are both quite high in the entire cohort and this is likely associated with significant health benefits, our results still underscore the need to address obesity with intensive clinical attention earlier in its course. PMID- 28084588 TI - Regulation of miR-34 Family in Neuronal Development. AB - Differentiation of neural stem cells (NSC's) to mature and functional neurons requires coordinated expression of mRNA, microRNAs (miRNAs) and regulatory proteins. Our earlier unbiased miRNA profiling studies have identified miR-200, miR-34 and miR-221/222 as maximally up-regulated miRNA families in differentiating PC12 cells and demonstrated the capability of miR-200 family in inducing neuronal differentiation (J. Neurochem, 2015, 133, 640-652). In present study, we have investigated role of miR-34 family in neuronal differentiation and identified P53 as mediator of nerve growth factor (NGF) induced miR-34a expression in differentiating PC12 cells. Our studies have shown that NGF induced miR-34a, arrests proliferating PC12 cells to G1 phase, which is pre-requisite for neuronal differentiation. Our studies have also shown that increased expression of miR-34a controls the P53 level in differentiated PC12 cells in feedback inhibition manner, which probably prevents differentiated cells from P53 induced apoptosis. Expression profiling of miR-34 family in different neuronal, non neuronal and developing cells have identified differentiated and aged brain cells as richest source of miR-34, which also indicates that higher expression of miR 34 family helps in maintaining the mature neurons in non-proliferative stage. In conclusion, our studies have shown that miR-34 is brain enriched miRNA family, which up-regulates with neuronal maturation and brain ageing and co-operative regulation of P53 and miR-34a helps in neuronal differentiation by arresting cells in G1 phase. PMID- 28084589 TI - IL-17A Promotes Granulocyte Infiltration, Myelin Loss, Microglia Activation, and Behavioral Deficits During Cuprizone-Induced Demyelination. AB - Recent evidence suggests a pivotal role of the proinflammatory cytokine interleukin - 17A (IL-17) in demyelinating autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS). Nevertheless, it remains unclear if this cytokine exerts direct effects on CNS resident cells during MS or modulates the function of infiltrating immune cells towards a more detrimental phenotype. Here, we investigated the effects of locally produced IL-17 during experimental demyelination of the CNS using the cuprizone (CPZ) model in mice with (GF/IL17) or without transgenic production of IL-17 by astrocytes in the CNS. During early demyelination, GF/IL17 mice demonstrated enhanced activity and decreased anxiety-related behavior in the elevated plus maze suggesting a more severe disease course. Furthermore, in GF/IL17 mice, toxic demyelination was accelerated and synthesis of myelin proteins was reduced. Early demyelination was accompanied by an increased ratio of infiltrating granulocytes in GF/ILl17 mice. The presence of IL-17 during CPZ treatment increased the accumulation of activated microglia and sustained microglial proliferation during myelin loss. Taken together, our results argue for a detrimental role of IL-17 during demyelinating diseases. PMID- 28084590 TI - Effects of Hippocampal LIMK Inhibition on Memory Acquisition, Consolidation, Retrieval, Reconsolidation, and Extinction. AB - Long-lasting changes in dendritic spines provide a physical correlate for memory formation and persistence. LIM kinase (LIMK) plays a critical role in orchestrating dendritic actin dynamics during memory processing, since it is the convergent downstream target of both the Rac1/PAK and RhoA/ROCK pathways that in turn induce cofilin phosphorylation and prevent depolymerization of actin filaments. Here, using a potent LIMK inhibitor (BMS-5), we investigated the role of LIMK activity in the dorsal hippocampus during contextual fear memory in rats. We first found that post-training administration of BMS-5 impaired memory consolidation in a dose-dependent manner. Inhibiting LIMK before training also disrupted memory acquisition. We then demonstrated that hippocampal LIMK activity seems to be critical for memory retrieval and reconsolidation, since both processes were impaired by BMS-5 treatment. Contextual fear memory extinction, however, was not sensitive to the same treatment. In conclusion, our findings demonstrate that hippocampal LIMK activity plays an important role in memory acquisition, consolidation, retrieval, and reconsolidation during contextual fear conditioning. PMID- 28084591 TI - Carnosic Acid Suppresses the H2O2-Induced Mitochondria-Related Bioenergetics Disturbances and Redox Impairment in SH-SY5Y Cells: Role for Nrf2. AB - The phenolic diterpene carnosic acid (CA, C20H28O4) exerts antioxidant, anti inflammatory, anti-apoptotic, and anti-cancer effects in mammalian cells. CA activates the nuclear factor erythroid 2-related factor 2 (Nrf2), among other signaling pathways, and restores cell viability in several in vitro and in vivo experimental models. We have previously reported that CA affords mitochondrial protection against various chemical challenges. However, it was not clear yet whether CA would prevent chemically induced impairment of the tricarboxylic acid cycle (TCA) function in mammalian cells. In the present work, we found that a pretreatment of human neuroblastoma SH-SY5Y cells with CA at 1 MUM for 12 h prevented the hydrogen peroxide (H2O2)-induced impairment of the TCA enzymes (aconitase, alpha-ketoglutarate dehydrogenase (alpha-KGDH), succinate dehydrogenase (SDH)) and abolished the inhibition of the complexes I and V and restored the levels of ATP by a mechanism associated with Nrf2. CA also exhibited antioxidant abilities by enhancing the levels of reduced glutathione (GSH) and decreasing the content oxidative stress markers (cellular 8-oxo-2'-deoxyguanosine (8-oxo-dG), and mitochondrial malondialdehyde (MDA), protein carbonyl, and 3 nitrotyrosine). Silencing of Nrf2 by small interfering RNA (siRNA) abrogated the protective effects elicited by CA in mitochondria of SH-SY5Y cells. Therefore, CA prevented the H2O2-triggered mitochondrial impairment by an Nrf2-dependent mechanism. The specific role of Nrf2 in ameliorating the function of TCA enzymes function needs further research. PMID- 28084592 TI - Maternal Hypermethioninemia Affects Neurons Number, Neurotrophins Levels, Energy Metabolism, and Na+,K+-ATPase Expression/Content in Brain of Rat Offspring. AB - In the current study, we verified the effects of maternal hypermethioninemia on the number of neurons, apoptosis, nerve growth factor, and brain-derived neurotrophic factor levels, energy metabolism parameters (succinate dehydrogenase, complex II, and cytochrome c oxidase), expression and immunocontent of Na+,K+-ATPase, edema formation, inflammatory markers (tumor necrosis factor-alpha and interleukin-6), and mitochondrial hydrogen peroxide levels in the encephalon from the offspring. Pregnant Wistar rats were divided into two groups: the first one received saline (control) and the second group received 2.68 MUmol methionine/g body weight by subcutaneous injections twice a day during gestation (approximately 21 days). After parturition, pups were killed at the 21st day of life for removal of encephalon. Neuronal staining (anti-NeuN) revealed a reduction in number of neurons, which was associated to decreased nerve growth factor and brain-derived neurotrophic factor levels. Maternal hypermethioninemia also reduced succinate dehydrogenase and complex II activities and increased expression and immunocontent of Na+,K+-ATPase alpha subunits. These results indicate that maternal hypermethioninemia may be a predisposing factor for damage to the brain during the intrauterine life. PMID- 28084594 TI - Caspase-Cleaved Tau Impairs Mitochondrial Dynamics in Alzheimer's Disease. AB - Alzheimer's disease (AD) is characterized by the presence of aggregates of tau protein. Tau truncated by caspase-3 (D421) or tau hyperphosphorylated at Ser396/S404 might play a role in the pathogenesis of AD. Mitochondria are dynamic organelles that modify their size and function through mitochondrial dynamics. Recent studies have shown that alterations of mitochondrial dynamics affect synaptic communication. Therefore, we studied the effects of pathological forms of tau on the regulation of mitochondrial dynamics. We used primary cortical neurons from tau(-/-) knockout mice and immortalized cortical neurons (CN1.4) that were transfected with plasmids containing green fluorescent protein (GFP) or GFP with different tau forms: full-length (GFP-T4), truncated (GFP-T4C3), pseudophosphorylated (GFP-T42EC), or both truncated and pseudophosphorylated modifications of tau (GFP-T4C3-2EC). Cells expressing truncated tau showed fragmented mitochondria compared to cells that expressed full-length tau. These findings were corroborated using primary neurons from tau(-/-) knockout mice that expressed the truncated and both truncated and pseudophosphorylated forms of tau. Interestingly, mitochondrial fragmentation was accompanied by a significant reduction in levels of optic atrophy protein 1 (Opa1) in cells expressing the truncated form of tau. In addition, treatment with low concentrations of amyloid beta (Abeta) significantly reduced mitochondrial membrane potential, cell viability, and mitochondrial length in cortical cells and primary neurons from tau(-/-) mice that express truncated tau. These results indicate that the presence of tau pathology impairs mitochondrial dynamics by reducing Opa1 levels, an event that could lead to mitochondrial impairment observed in AD. PMID- 28084593 TI - Pinocembrin Suppresses H2O2-Induced Mitochondrial Dysfunction by a Mechanism Dependent on the Nrf2/HO-1 Axis in SH-SY5Y Cells. AB - Mitochondria are susceptible to redox impairment, which has been associated with neurodegeneration. These organelles are both a source and target of reactive species. In that context, there is increasing interest in finding natural compounds that modulate mitochondrial function and mitochondria-related signaling in order to prevent or to treat diseases involving mitochondrial impairment. Herein, we investigated whether and how pinocembrin (PB) would prevent mitochondrial dysfunction elicited by the exposure of human neuroblastoma SH-SY5Y cells to hydrogen peroxide (H2O2). PB (25 MUM) was administrated for 4 h before H2O2 treatment (300 MUM for 24 h). PB prevented H2O2-induced loss of cell viability mitochondrial depolarization in SH-SY5Y cells. PB also attenuated redox impairment in mitochondrial membranes. The production of superoxide anion radical (O2-*) and nitric oxide (NO*) was alleviated by PB in cells exposed to H2O2. PB suppressed the H2O2-induced inhibition of the tricarboxylic acid (TCA) cycle enzymes aconitase, alpha-ketoglutarate dehydrogenase, and succinate dehydrogenase. Furthermore, PB induced anti-inflammatory effects by abolishing the H2O2-dependent activation of the nuclear factor-kappaB (NF-kappaB) and upregulation of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF alpha). The PB-induced antioxidant and anti-inflammatory effects are dependent on the heme oxygenate-1 (HO-1) enzyme and on the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), since HO-1 inhibition (with 0.5 MUM ZnPP IX) or Nrf2 silencing (with small interfering RNA (siRNA)) abolished the effects of PB. Overall, PB afforded cytoprotection by the Nrf2/HO-1 axis in H2O2-treated SH-SY5Y cells. PMID- 28084595 TI - Molecular Neuro-Pathomechanism of Neurocysticercosis: How Host Genetic Factors Influence Disease Susceptibility. AB - Neurocysticercosis (NCC) is one of the most neglected tropical diseases among widely endemic neurological diseases. It is caused by cysticerci of Taenia solium. The clinical symptom for the outcome of infection and progression of disease is pleomorphic and its neuro-pathomechanism is still illusive. Identification of host genetic factors and their association with disease susceptibility is one of the most important areas of research towards personalized medicine in the era of omics. Several genes and their allelic variations had been identified to be associated with various neurological disorders; however, the information for parasitic diseases affecting the central nervous system is very limited. Both Th1 and Th2 arms of the immune system are reported to be active at different stages of T. solium infection in the brain. Recently, several papers had been published, where the role of host genetic makeup with NCC had been explored. Increased frequency of HLA-A28, HLA-B63, HLA B58, TLR 4 Asp299Gly, sICAM-1 gene K469E, GSTM1, and GSTT1 were found to be associated with increased risk of NCC occurrence, while HLA-DQW2 and HLA-A11 were shown to be providing protection from disease. In this review, we have summarized these findings and analyzed the influence of host genetic polymorphism on the susceptibility/resistance of host to NCC. PMID- 28084597 TI - Optimizing vermifilter depth by process performance collaborated with the evolutions of microbial characteristics during sewage sludge treatment. AB - The present study focuses on optimizing filter depth on sludge reduction in a four-stage vermifiltration during the course of treating excess sludge continuously. The results indicated that when the filter depth exceeded 75 cm, though the fourth stage can further advance the sludge reduction, its contribution for the total sludge reduction was lower than 10%, while the aerobic bacteria, especially the dominant bacteria (Proteobacteria and Bacteroidetes), kept a high similarity as the filter depth varied. Furthermore, earthworm activities attributed to aerobic bacteria being preferentially selected in the system, positively supporting the organic decomposition. As far as economic cost and process performance are concerned, a 75-cm vermifilter was recommended to efficiently and economically achieve the required standard for sewage sludge reduction and stabilization. PMID- 28084596 TI - Current Clinical Applications and Next Steps for Cardiac Innervation Imaging. AB - PURPOSE OF REVIEW: Autonomic innervation is crucial for regulating cardiac function. Sympathetic innervation imaging with 123I-mIBG and analogous PET tracers assesses disease in ways that differ from customary methods. This review describes practical use in various clinical scenarios, discusses recent guidelines, presents new data confirming risk stratification power, describes an ongoing prospective study, and looks forward to wider use in patient management. RECENT FINDINGS: ASNC 123I-mIBG guidelines are available, expanding on European guidelines. ADMIRE-HF patient follow-up increased to 2 years in ADMIRE HFX, demonstrating independent mortality risk reclassification. ADMIRE-HF findings were substantiated in a Japanese consortium study and in the PAREPET 11C-HED PET study. Exciting potential uses of adrenergic imaging are management of LVADs and VT ablation. CZT cameras provide advantages, but derived parameters differ from Anger camera values. Independent risk stratification utility of adrenergic imaging with 123I-mIBG and PET tracers is continuously being confirmed. An ongoing prospective randomized study promises to establish patient management utility. There is potential for wider use and improved images with newer cameras and PET. PMID- 28084598 TI - Amelioration of an acidic ultisol by straw-derived biochars combined with dicyandiamide under application of urea. AB - The rapid increase in agricultural pollution demands judicious use of inputs and outputs for sustainable crop production. Crop straws were pyrolyzed under oxygen limited conditions at 400 degrees C for 2 h to prepare peanut straw biochar (PB), canola straw biochar (CB), and wheat straw biochar (WB). Then, 300-g soils were incubated each with urea nitrogen (UN) and UN + biochars with or without dicyandiamide (DCD) for 60 days. During the incubations, soil acidification induced by urea was somewhat inhibited by biochars, but nitrification of hydrolyzed NH4+ produced much more acidity than the neutralization potential of the biochars. In single UN (200 mg/kg) treatment, soil pH decreased drastically and the final pH after incubation was lower than the control. Antagonistic to UN, all three biochars neutralized the soil acidity, which was consistent to their inherent alkalinity. DCD inhibited nitrification which was obvious throughout the incubations, as 30 mg/kg DCD + 200 mg/kg UN combined with 1 % PB, CB, and WB retained 0.94, 0.79, and 1.19 units higher pH, respectively, and significantly reduced exchangeable acidity over the treatments without DCD (P < 0.05). The treatments of UN + biochars with and without DCD had highly significant effects on soil pH, exchangeable Al3+, NH4+-N, (NO3-+NO2-)-N, and available P (P < 0.05). Amplified NH4+-N retentions at higher rates of PB referred increased negatively charged sites for nutrient adsorptions. Applied UN transformations varied among different treatments, and the maximum amounts of total mineral N recovered were 218.3, 218.5, and 223.8 mg/kg in the presence of DCD by PB, CB, and WB, compared to 198.2, 201.6, and 205.2 mg/kg, respectively, in no DCD treatments. Urea induced severe soil acidification and even lowered the ameliorative effects of applied biochars. Thus, ammonium-based fertilizers must include nitrification inhibitor (DCD) and, if used in combination with biochars will offer a suitable choice to reduce the acidity, improve base saturation and fertility of soil for sustainable agriculture. PMID- 28084599 TI - Real-time PCR assays for the detection and quantification of carbapenemase genes (bla KPC, bla NDM, and bla OXA-48) in environmental samples. AB - In this study, we have developed real-time PCR assays using SYBR Green chemistry to detect all known alleles of bla KPC, bla NDM, and bla OXA-48-like carbapenemase genes in water, sediment, and biofilm samples collected from hospital and wastewater treatment plant (WWTP) effluents and rivers receiving chronic WWTP discharges. The amplification of bla KPC, bla NDM, and bla OXA-48 DNA was linear over 7 log dilutions (R 2 between 0.995 and 0.997) and showing efficiencies ranging from 92.6% to 100.3%. The analytical sensitivity indicated that the reaction for bla KPC, bla NDM, and bla OXA-48-like genes was able to detect 35, 16, and 19 copy numbers per assay, respectively. The three carbapenemase genes were detected in hospital effluents, whereas only the bla KPC and bla NDM genes were detected in biofilm and sediment samples collected from wastewater-impacted rivers. The detection of bla KPC, bla NDM, and bla OXA-48 like genes in different matrices suggests that carbapenem-resistant bacteria occur in both planktonic and benthic habitats thus expanding the range of resistance reservoirs for last-resort antibiotics. We believe that these real time PCR assays would be a powerful tool for the rapid detection and quantification of bla KPC, bla NDM, and bla OXA-48-like genes in complex environmental samples. PMID- 28084600 TI - Effect of lantibiotic gallidermin against biogenic amine-producing faecal staphylococci from ostriches and pheasants. AB - In ostriches and pheasants, there is still limited information relating to staphylococci and their properties. Biogenic amines (BAs) are nitrogenous low molecular-weight substances with biological functions in animals, plants and microorganisms. In this study, we focused on BA production by targeted faecal staphylococci from ostriches and pheasants and their sensitivity to lantibiotic bacteriocin gallidermin. Gallidermin belongs in a group of polycyclic proteinaceous antimicrobial substances. Thirty-six faecal staphylococci (24 strains from 140 ostriches, 12 from 60 pheasants) comprising different species were tested. Staphylococci from ostriches and pheasants did not produce tryptamine-TRYP, putrescine-PUT, cadaverine-CAD or histamine-HIS. Production of tyramine-TYM, phenylethylamine-PEA was high or very high (100-1000 mg/L). Production of spermine-SPM and spermidine-SPD by staphylococci was very low or low although in the case of staphylococci from pheasants medium production of SPM was found. Because of the risk posed by BAs for consumers, the control of BA producing bacteria is important from the points of view not only of safety assessment of food-producing animals but also of human health safety. The sensitivity to gallidermin in biogenic amine-producing staphylococci from ostriches and pheasants detected here is the most promising indication for further application of gallidermin for veterinary purposes. The novelty of our study lies in testing the ability of faecal staphylococci from ostriches and pheasants to produce BAs and in their treatment with gallidermin which has so far not been tested in this way. PMID- 28084601 TI - Digitized Hand Skateboard Based on IR-Camera for Upper Limb Rehabilitation. AB - Abnormal upper limb function seriously impacts a patient's daily life. After receiving emergency treatment patient should receive function-rebuilding and recovery training. The objective of this study is to integrate IR-camera, an infrared emitter, with a conventional passive hand skateboard training device for conventional upper limb training and the training process is comprehensively recorded and analyzed. Patients participating in the occupational therapy have a binding band attached to hand skateboard on the table to guide the patient in moving the hand skateboard along the designated path to train the patient's upper limbs. Six people with normal upper limb function participated in the stability test. The device repeatability and test results were verified acceptable. Eight patients with abnormal upper limb function (their upper limb function was damaged due to stroke, MMSE > =27) were trained for 4 weeks. The patient scores in finishing rate and finishing time showed significant improvement. The paired T test results (satisfy p < 0.05 or p < 0.01) between wk-1 and wk-2 are significant. The paired T test results (satisfy p < 0.01) between wk-1 and wk-4 are extremely significant. The new IR-Camera system focuses continuously on the "Figure of eight" curve. The system is light weight and convenient for stroke in home use. The study applies IR-camera technology to the conventional hand skateboard for upper limb training. The experiments show that the hardware of the proposed device no longer delays in response and can result in obvious clinical advances. The proposed device is verified worthy of promotion. PMID- 28084602 TI - Identification of the Catalytic Residue of Rat Acyl-CoA Dehydrogenase 9 by Site Directed Mutagenesis. AB - Acyl-CoA dehydrogenase 9 (ACAD 9) is the ninth member of ACADs involved in mitochondrial fatty acid oxidation and possibly complex I assembly. Sequence alignment suggested that Glu389 of rat ACAD 9 was highly conserved and located near the active center and might act as an important base for the dehydrogenation reaction. The role of Glu389 in the catalytic reaction was investigated by site directed mutagenesis. Both wild-type and mutant ACAD 9 proteins were purified and their catalytic characterization was studied. When Glu389 was replaced by other residues, the enzyme activity could be lost to a large extent. Those results suggested that Glu389 could function as the catalytic base that abstracted the alpha-proton of the acyl-CoA substrate in a proposed catalytic mechanism. PMID- 28084603 TI - A synthesis of fused acenaphthopyrrolizines via the 1,3-dipolar cycloaddition reaction of azomethine ylides with acetylenic esters. AB - An efficient synthesis of tetraalkyl 6a-hydroxy-3-alkyl-3H,6aH-acenaphtho[1,2-g] pyrrolizine-1,2,5,6-tetracarboxylates via the 1,3-dipolar cycloaddition reaction of azomethine ylides (generated in situ from [Formula: see text]-amino acids and acenaphthylene-1,2-dione) with dialkyl acetylenedicarboxylates is described. When glycine was used instead of alanine, phenylalanine, valine, or isoleucine, dialkyl (E)-1[Formula: see text]-(1,4-dialkoxy-1,4-dioxobut-2-en-2-yl)-2-oxo [Formula: see text],5[Formula: see text]-dihydro-2H-spiro [acenaphthylene 1,2[Formula: see text]-pyrrole]-3[Formula: see text],4[Formula: see text] dicarboxylates were obtained. The steric effects of the [Formula: see text]-amino acids side chains may be responsible for their different behaviors. PMID- 28084604 TI - Laparoscopic Pancreatic Enucleation With End-to-End Pancreatic Duct Reconstruction. AB - BACKGROUND: Laparoscopic enucleation for neuroendocrine pancreatic tumors has become a feasible technique, with a reported incidence of pancreatic fistula ranging from 13 to 29 %.1 - 3 This report describes the first successful case of laparoscopic pancreatic enucleation with resection of the main pancreatic duct followed by end-to-end anastomosis. METHODS: A 41-year-old woman was admitted to the authors' hospital for repeated syncope. Hypoglycemia also was noted. A contrast-enhanced computed tomography examination showed a highly enhanced tumor measuring 22 mm in diameter on the ventral side of the pancreatic body adjacent to the main pancreatic duct. The patient's blood insulin level was elevated, and her diagnosis was determined to be pancreatic insulinoma. Laparoscopic pancreatic enucleation was performed. Approximately 2 cm of the main pancreatic duct was segmentally resected, and a short stent (Silicone tube: Silastic, Dow Corning Corporation, Midland, MI) was inserted. The direct anastomosis of the main pancreatic duct was performed using four separate sutures with an absorbable monofilament (6-0 PDS). RESULTS: The operation time was 166 min, and the estimated blood loss was 100 mL. The postoperative course was uneventful, and the patient was discharged from hospital on postoperative day 7. The pathologic findings showed a well-differentiated insulinoma and a negative surgical margin. A computed tomography examination performed 1 month after the operation showed a successful anastomosis with a patent main pancreatic duct. CONCLUSIONS: Laparoscopic segmental resection of the main pancreatic duct and end-to-end anastomosis can be performed safely with the insertion of a short stent. This technique also can be used for a central pancreatectomy. PMID- 28084605 TI - Diet to the Rescue: Cessation of Pharmacotherapy After Initiation of Exclusive Enteral Nutrition (EEN) Followed by Strict and Liberalized Specific Carbohydrate Diet (SCD) in Crohn's Disease. PMID- 28084606 TI - Optimizing patient-reported outcome and risk factor reporting from cancer survivors: a randomized trial of four different survey methods among colorectal cancer survivors. AB - PURPOSE: The goal of this study was to determine response rates and associated costs of different survey methods among colorectal cancer (CRC) survivors. METHODS: We assembled a cohort of 16,212 individuals diagnosed with CRC (2010 2014) from six health plans, and randomly selected 4000 survivors to test survey response rates across four mixed-mode survey administration protocols (in English and Spanish): arm 1, mailed survey with phone follow-up; arm 2, interactive voice response (IVR) followed by mail; arm 3; email linked to web-based survey with mail follow-up; and arm 4, email linked to web-based survey followed by IVR. RESULTS: Our overall response rate was 50.2%. Arm 1 had the highest response rate (59.9%), followed by arm 3 (51.9%), arm 2 (51.2%), and arm 4 (37.9%). Response rates were higher among non-Hispanic whites in all arms than other racial/ethnic groups (p < 0.001), among English (51.5%) than Spanish speakers (36.4%) (p < 0.001), and among higher (53.7%) than lower (41.4%) socioeconomic status (p < 0.001). Survey arms were roughly comparable in cost, with a difference of only 8% of total costs between the most (arm 2) and least (arm 3) expensive arms. CONCLUSIONS: Mailed surveys followed by phone calls achieved the highest response rate; email invitations and online surveys cost less per response. Electronic methods, even among those with email availability, may miss important populations including Hispanics, non-English speakers, and those of lower socioeconomic status. IMPLICATIONS FOR CANCER SURVIVORS: Our results demonstrate effective methods for capturing patient-reported outcomes, inform the relative benefits/disadvantages of the different methods, and identify future research directions. PMID- 28084607 TI - The role of social media use in improving cancer survivors' emotional well-being: a moderated mediation study. AB - PURPOSE: In the USA, levels of emotional well-being among cancer survivors remain low. Social media is recognized as important to improve their emotional well being. However, little is known about social mechanisms that underlie the impact of health-related social media in cancer care. This study proposed a moderated mediation model to signify a pathway linking social media use to emotional well being. METHODS: Four-hundred and fifty-nine cancer survivors identified through the 2013 US-based Health Information National Trends Survey were included for data analysis. First, structural equation modeling was conducted to examine the path from social media use to emotional well-being, mediated by patient activation. Second, hierarchical regression was performed to test the moderation effect of emotion management. Last, a normal theory-based approach was used to explore the final moderated mediation model. RESULTS: The effect of health related social media use on emotional well-being was completely mediated by patient activation. Also, emotion management positively moderated the effect of patient activation on emotional well-being. Last, emotion management positively moderated the mediation pathway from health-related social media use to patient activation, and finally, to emotional well-being. CONCLUSIONS: Health-related social media, by itself, is not sufficient to bring about improvement in cancer survivors' emotional well-being. Patient activation and emotion management play a significant role. IMPLICATIONS FOR CANCER SURVIVORS: In future interventions designed to improve cancer survivors' emotional health, health practitioners should not only encourage cancer survivors to use social media for health purposes, but also activate them in the course of care, and improve their emotion self-management skills. PMID- 28084608 TI - The Phenolic Contents and Antioxidant Activities of Infusions of Sambucus nigra L. AB - The aim of this work was to evaluate the antioxidant potential of teas prepared from twenty-four commercially available berries and flowers of Sambucus nigra L. in relation to their phenolic profile, as reflected by the most representative phenolic acids (caffeic, chlorogenic, p-coumaric, ferulic, gallic and syringic acids); flavonols (quercetin, kaempferol, myricetin and rutin); and total phenolic (TPC), phenolic acid (TAC) and flavonoid (TFC) contents. The infusions prepared from elderflowers contained more abundant phenolic compounds than the elderberry infusions. The TPC of these infusions ranged from 19.81 to 23.90 mg of gallic acid equivalents/g dry weight of sample (GAE/g DW) for elderberries and from 15.23 to 35.57 mg GAE/g DW for elderflowers, whereas the TFC ranged from 2.60 to 4.49 mg of rutin equivalents/g dry weight of sample (RUTE/g DW) in elderberry infusions and from 5.27 to 13.19 mg RUTE/g DW in elderflower infusions. Among the phenolic compounds quantified in this study, quercetin (2.07 9.48 mg/g DW) and myricetin (1.17-9.62 mg/g DW) had the highest concentrations in the teas prepared from berries and flowers, respectively. Moreover, the antioxidant potential of elder infusions assessed by 2,2-diphenyl-1 picrylhydrazyl (DPPH) radical and ferric reducing antioxidant power (FRAP) assays revealed that the teas prepared from flowers had higher mean DPPH and FRAP activities than the teas prepared from berries. Therefore, elder beverages could be important dietary sources of natural antioxidants that contribute to the prevention of diseases caused by oxidative stress. PMID- 28084609 TI - The mobile RNAs, StBEL11 and StBEL29, suppress growth of tubers in potato. AB - KEY MESSAGE: We demonstrate that RNAs of StBEL11 and StBEL29 are phloem-mobile and function antagonistically to the growth-promoting characteristics of StBEL5 in potato. Both these RNAs appear to inhibit tuber growth by repressing the activity of target genes of StBEL5 in potato. Moreover, upstream sequence driving GUS expression in transgenic potato lines demonstrated that both StBEL11 and -29 promoter activity is robust in leaf veins, petioles, stems, and vascular tissues and induced by short days in leaves and stolons. Steady-state levels of their mRNAs were also enhanced by short-day conditions in selective organs. There are thirteen functional BEL1-like genes in potato that encode for a family of transcription factors (TF) ubiquitous in the plant kingdom. These BEL1 TFs work in tandem with KNOTTED1-types to regulate the expression of numerous target genes involved in hormone metabolism and growth processes. One of the StBELs, StBEL5, functions as a long-distance mRNA signal that is transcribed in leaves and moves into roots and stolons to stimulate growth. The two most closely related StBELs to StBEL5 are StBEL11 and -29. Together these three genes make up more than 70% of all StBEL transcripts present throughout the potato plant. They share a number of common features, suggesting they may be co-functional in tuber development. Upstream sequence driving GUS expression in transgenic potato lines demonstrated that both StBEL11 and -29 promoter activity is robust in leaf veins, petioles, stems, and vascular tissues and induced by short-days in leaves and stolons. Steady-state levels of their mRNAs were also enhanced by short-day conditions in specific organs. Using a transgenic approach and heterografting experiments, we show that both these StBELs inhibit growth in correlation with the long distance transport of their mRNAs from leaves to roots and stolons, whereas suppression lines of these two RNAs exhibited enhanced tuber yields. In summary, our results indicate that the RNAs of StBEL11 and StBEL29 are phloem-mobile and function antagonistically to the growth-promoting characteristics of StBEL5. Both these RNAs appear to inhibit growth in tubers by repressing the activity of target genes of StBEL5. PMID- 28084610 TI - Immunoglobulin G4 (IgG4)-Related Hypophysitis. AB - We report two different cases of IgG4-related hypophysitis. In the first case, a pituitary lesion was accompanied by lymphocytic meningitis possibly mimicking tuberculous meningitis. The second case was unassociated with involvement of other organs. No histologic differences were noted between the two cases indicating that the morphologic features of the hypophysial lesion do not depend on the presence of other lesions. The pathogenesis of IgG4 hypophysitis is not known, and further study is necessary to explore the cause, progression, and influencing factors of this disease. PMID- 28084612 TI - An experimental phantom study of the effect of gadolinium-based MR contrast agents on PET attenuation coefficients and PET quantification in PET-MR imaging: application to cardiac studies. AB - BACKGROUND: Simultaneous cardiac perfusion studies are an increasing trend in PET MR imaging. During dynamic PET imaging, the introduction of gadolinium-based MR contrast agents (GBCA) at high concentrations during a dual injection of GBCA and PET radiotracer may cause increased attenuation effects of the PET signal, and thus errors in quantification of PET images. We thus aimed to calculate the change in linear attenuation coefficient (LAC) of a mixture of PET radiotracer and increasing concentrations of GBCA in solution and furthermore, to investigate if this change in LAC produced a measurable effect on the image-based PET activity concentration when attenuation corrected by three different AC strategies. FINDINGS: We performed simultaneous PET-MR imaging of a phantom in a static scenario using a fixed activity of 40 MBq [18 F]-NaF, water, and an increasing GBCA concentration from 0 to 66 mM (based on an assumed maximum possible concentration of GBCA in the left ventricle in a clinical study). This simulated a range of clinical concentrations of GBCA. We investigated two methods to calculate the LAC of the solution mixture at 511 keV: (1) a mathematical mixture rule and (2) CT imaging of each concentration step and subsequent conversion to LAC at 511 keV. This comparison showed that the ranges of LAC produced by both methods are equivalent with an increase in LAC of the mixed solution of approximately 2% over the range of 0-66 mM. We then employed three different attenuation correction methods to the PET data: (1) each PET scan at a specific millimolar concentration of GBCA corrected by its corresponding CT scan, (2) each PET scan corrected by a CT scan with no GBCA present (i.e., at 0 mM GBCA), and (3) a manually generated attenuation map, whereby all CT voxels in the phantom at 0 mM were replaced by LAC = 0.1 cm-1. All attenuation correction methods (1-3) were accurate to the true measured activity concentration within 5%, and there were no trends in image-based activity concentrations upon increasing the GBCA concentration of the solution. CONCLUSION: The presence of high GBCA concentration (representing a worst-case scenario in dynamic cardiac studies) in solution with PET radiotracer produces a minimal effect on attenuation-corrected PET quantification. PMID- 28084611 TI - Effect of Probiotic Bacillus Coagulans and Lactobacillus Plantarum on Alleviation of Mercury Toxicity in Rat. AB - The objective of this study was to evaluate the efficiency of probiotics (Lactobacillus plantarum and Bacillus coagulans) against mercury-induced toxicity using a rat model. Mercury (Hg) is a widespread heavy metal and was shown to be associated with various diseases. Forty-eight adult male Wistar rats were randomly divided into six groups (control, mercury-only, each probiotic-only, and mercury plus each probiotic group). Hg-treated groups received 10 ppm mercuric chloride, and probiotic groups were administrated 1 * 109 CFU of probiotics daily for 48 days. Levels of mercury were determined using cold vapor technique, and some biochemical factors (list like glutathione peroxidase (GPx), superoxide dismutase (SOD), creatinine, urea, bilirubin, alanine transaminase (ALT), and aspartate transaminase (AST)) were measured to evaluate changes in oxidative stress. Oral administration of either probiotic was found to provide significant protection against mercury toxicity by decreasing the mercury level in the liver and kidney and preventing alterations in the levels of GPx and SOD. Probiotic treatment generated marked reduction in the levels of creatinine, urea, bilirubin, ALT, and AST indicating the positive influence of the probiotics on the adverse effects of Hg in the body. PMID- 28084613 TI - Supramolecular Gel-Templated In Situ Synthesis and Assembly of CdS Quantum Dots Gels. AB - Although many studies have attempted to develop strategies for spontaneously organizing nanoparticles (NPs) into three-dimensional (3D) geometries, it remains a fascinating challenge. In this study, a method for in situ synthesis and self assembly of a CdS quantum dots (QDs) gel using a Cd supramolecular gel as a scaffold was demonstrated. During the QDs formation process, the Cd ions that constituted the Cd gels served as the precursors of the CdS QDs, and the oleic acid (OA) that ligated with the Cd in the supramolecular gels was capped on the surface of the CdS QDs in the form of carboxylate. The OA-stabilized CdS QDs were in situ synthesized in the entangled self-assembled fibrillar networks (SAFIN) of the Cd gels through reactions between the gelator and H2S. As a result, the QDs exactly replicated the framework of the SAFIN in the CdS QD gels instead of simply assembling along the SAFIN of the supramolecular gels. Moreover, the CdS QDs showed extraordinary sensitivity in the fluorescence detection of IO4- anions. The facile one-step method developed here is a new approach to assembling nanostructured materials into 3D architectures and has general implications for the design of low molecular mass gelators to bring desired functionality to the developed supramolecular gels. PMID- 28084614 TI - Nasogastric tube insertion in anaesthetized patients: a comprehensive review. AB - Nasogastric tubes (NGT) still remain the easiest and the best way for gastrointestinal tract access. There are various indications for the insertion of a nasogastric tube in anaesthetized and critically ill patients. Although many techniques have been introduced to facilitate nasogastric tube insertion using anatomic landmarks and a group of devices, there is no consensus on a standard method. Moreover, there are different methods for the assessment of the correct placement of a nasogastric tube. In addition to these challenges in insertion and assessment methods, there are varieties of major life-threatening and minor complications to be addressed. Thus, selecting the most appropriate approach requires enough knowledge in this area, considering patient condition and clinical factors, as well as the practitioners' sufficient education and experience, along with skill in performance. This is a comprehensive review of the literature evidence on different methods for nasogastric tube insertion, on the assessment of correct placement and the evaluation of complications, in addition to an approach to the effect of education on the quality of routine practice and patients' outcome.  . PMID- 28084616 TI - Piperacillin-tazobactam-induced linear IgA bullous dermatosis presenting clinically as Stevens-Johnson syndrome/toxic epidermal necrolysis overlap. AB - Linear IgA bullous dermatosis (LABD) is a subepidermal autoimmune bullous disease characterized by linear IgA deposition at the basement membrane zone, which is visualized by direct immunofluorescence. Patients with LABD typically present with widespread vesicles and bullae; however, this is not necessarily the case, as the clinical presentation of this disease is heterogeneous. LABD clinically presenting as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) is an infrequent, yet well-described phenomenon. Most cases of LABD are idiopathic, but some cases are drug-induced. Multiple drugs have been implicated in the development of LABD. We report a case of piperacillin-tazobactam-induced LABD presenting clinically as SJS/TEN overlap. This is the first reported case of a strong causal association between piperacillin-tazobactam and the development of LABD. PMID- 28084617 TI - ADAMTS-4 in central nervous system pathologies. AB - ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs type 4) is a metalloproteinase specialized in the degradation of chondroitin sulfate proteoglycans, contributing to cartilage breakdown during arthritis. In this review, we first focus on the modifications of ADAMTS-4 expression during CNS physiological and pathological conditions, including chronic diseases and injuries. Then, we discuss the contributions of ADAMTS-4 to mechanisms mediating neuroplasticity, neuroinflammation and neurodegeneration during spinal cord injury, ischemic stroke, amyotrophic lateral sclerosis and Alzheimer's disease. Here, we provide an overview of ADAMTS-4 functions and effects in the CNS, and we discuss directions for future studies and treatments. Overall, this review highlights that ADAMTS-4 is a unique multifaceted metalloproteinase which influences various CNS disease pathophysiologies. (c) 2017 Wiley Periodicals, Inc. PMID- 28084618 TI - Drugs in Clinical Trials for Alzheimer's Disease: The Major Trends. AB - Alzheimer's disease (AD) is characterized by a chronic and progressive neurodegenerative process resulting from the intracellular and extracellular accumulation of fibrillary proteins: beta-amyloid and hyperphosphorylated Tau. Overaccumulation of these aggregates leads to synaptic dysfunction and subsequent neuronal loss. The precise molecular mechanisms of AD are still not fully understood but it is clear that AD is a multifactorial disorder and that advanced age is the main risk factor. Over the last decade, more than 50 drug candidates have successfully passed phase II clinical trials, but none has passed phase III. Here, we summarize data on current "anti-Alzheimer's" agents currently in clinical trials based on findings available in the Thomson Reuters "Integrity" database, on the public website www.clinicaltrials.gov, and on database of the website Alzforum.org. As a result, it was possible to outline some major trends in AD drug discovery: (i) the development of compounds acting on the main stages of the pathogenesis of the disease (the so-called "disease-modifying agents") - these drugs could potentially slow the development of structural and functional abnormalities in the central nervous system providing sustainable improvements of cognitive functions, which persist even after drug withdrawal; (ii) focused design of multitargeted drugs acting on multiple molecular targets involved in the pathogenesis of the disease; (3) finally, the repositioning of old drugs for new (anti-Alzheimer's) application offers a very attractive approach to facilitate the completion of clinical trials. PMID- 28084619 TI - Life, death and rebirth of avirulence effectors in a fungal pathogen of Brassica crops, Leptosphaeria maculans. AB - Contents 526 I. 526 II. 527 III. 527 IV. 529 V. 529 VI. 530 VII. 530 531 References 531 SUMMARY: In agricultural systems, major (R) genes for resistance in plants exert strong selection pressure on cognate/corresponding avirulence effector genes of phytopathogens. However, a complex interplay often exists between trade-offs linked to effector function and the need to escape R gene recognition. Here, using the Leptosphaeria maculans-oilseed rape pathosystem we review evolution of effectors submitted to multiple resistance gene selection. Characteristics of this pathosystem include a crop in which resistance genes have been deployed intensively resulting in 'boom and bust' cycles; a fungal pathogen with a high adaptive potential in which seven avirulence genes are cloned and for which population surveys have been coupled with molecular analysis of events responsible for virulence. The mode of evolution of avirulence genes, all located in dispensable parts of the 'two-speed' genome, is a highly dynamic gene-specific process. In some instances, avirulence genes are readily deleted under selection. However, others, even when located in the most plastic genome regions, undergo only limited point mutations or their avirulence phenotype is 'camouflaged' by another avirulence gene. Thus, while hundreds of effector genes are present, some effectors are likely to have an important and nonredundant function, suggesting functional redundancy and dispensability of effectors might not be the rule. PMID- 28084620 TI - The long-term neuropsychological features of basal ganglia encephalitis. PMID- 28084621 TI - State of the art in microRNA as diagnostic and therapeutic biomarkers in chronic lymphocytic leukemia. AB - Early diagnostic is one of the most important steps in cancer therapy which helps to design and choose a better therapeutic approach. The finding of biomarkers in various levels including genomics, transcriptomics, and proteomics levels could provide better treatment for various cancers such as chronic lymphocytic leukemia (CLL). The CLL is the one of main lymphoid malignancies which is specified by aggregation of mature B lymphocytes. Among different biomarkers (e.g., CD38, chromosomes abnormalities, ZAP-70, TP53, and microRNA [miRNA]), miRNAs have appeared as new diagnostic and therapeutic biomarkers in patients with the CLL disease. Multiple lines of evidence indicated that deregulation of miRNAs could be associated with pathological events which are present in the CLL. These molecules have an effect on a variety of targets such as Bcl2, c-fos, c-Myc, TP53, TCL1, and STAT3 which play critical roles in the CLL pathogenesis. It has been shown that expression of miRNAs could lead to the activation of B cells and B cell antigen receptor (BCR). Moreover, exosomes containing miRNAs are one of the other molecules which could contribute to BCR stimulation and progression of CLL cells. Hence, miRNAs and exosomes released from CLL cells could be used as potential diagnostic and therapeutic biomarkers for CLL. This critical review focuses on a very important aspect of CLL based on biomarker discovery covers the pros and cons of using miRNAs as important diagnostics and therapeutics biomarkers for this deadly disease. PMID- 28084622 TI - Cardiac Implantable Electronic Device-Related Infection and Extraction Trends in the U.S. AB - BACKGROUND: Implantation of cardiac implanted electronic device (CIED) has surged lately. This resulted in a rise in cardiac device-related infections (CDI) and inevitably, lead extractions. We examined the recent national trend in the incidence of CIED infections and lead extractions in hospitalized patients and associated mortality. METHODS: Using the Nationwide Inpatient Sample for the years 2003-2011 we identified patients diagnosed with a CDI-associated infection as determined by discharge ICD-9 diagnostic codes. We examined the trend of device-related infections overall and in different subgroups. We studied mortality associated with device infections, lead extractions, associated costs, and length of stay. RESULTS: There is a significant increase in the number of hospitalizations due to CDI from 5,308 in the year 2003 to 9,948 in 2011. Males (68%), Caucasians (77%), and age group 65-84 years (56.4%) accounted for majority of CDI. The mortality associated with CDI was 4.5 %, and was worse in higher age groups (2.5% in 18-44 years compared to 5.3% in 85+ years, P < 0.001). Average length of stay was unchanged over the years remaining at 13.6 days; however, mean hospitalization charges increased from $91,348 in 2003 to $173,211 in 2011 (P < 0.001). Among all lead extraction procedures, the percentage of patients undergoing lead extraction secondary to CDI also increased from 2003 (59.1%) to 2011 (76.7%), P-value < 0.001. CONCLUSIONS: Healthcare burden associated with CDI infections and associated lead extractions has significantly increased in the recent years. Despite an increase in cost associated with CIED infections, mortality remains the same, and is higher in older patients. PMID- 28084623 TI - The effect of foraging and ontogeny on the prevalence and intensity of the invasive parasite Anguillicola crassus in the European eel Anguilla anguilla. AB - Infection patterns of the invasive Anguillicola crassus nematode were investigated in a population of the European eel Anguilla anguilla where parasite invasion is very recent, Loch Lomond, Scotland. Intensity levels of the parasite were associated with differences in fish ontogeny and trophic ecology. Although eels foraged on both fish and invertebrates, individuals which were smaller and fed on invertebrates (>70% contribution to diet) were found to contain a greater number of swim bladder parasites compared to larger eel with a predominance of fish (>60% contribution) in their diet. Within affected fish, a significant negative relationship was found between fish length and parasite intensity, with smaller individuals having higher parasite intensity than larger individuals. This study indicates that food intake and infection risk are linked in this recently infected host-parasite system. From a management perspective increasing our understanding of how infection intensity and repeated exposure is linked to resource use in an ecosystem is important for the future management of this endangered species in Europe. PMID- 28084624 TI - First-line combination therapy versus first-line monotherapy for primary hypertension. AB - BACKGROUND: Starting with one drug and starting with a combination of two drugs are strategies suggested in clinical guidelines as initial treatment of hypertension. The recommendations are not based on evidence about clinically relevant outcomes. Some antihypertensive combinations have been shown to be harmful. The actual harm-to-benefit balance of each strategy is unknown. OBJECTIVES: To determine if there are differences in clinical outcomes between monotherapy and combination therapy as initial treatment for primary hypertension. SEARCH METHODS: We searched the Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, 2016, Issue 2), Ovid MEDLINE, Ovid Embase, LILACS, ClinicalTrials.gov, Current Controlled Trials, and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) up to February 2016. We searched in clinical studies repositories of pharmaceutical companies, reviews of combination drugs in Food and Drug Administration and European Medicines Agency, and lists of references in reviews and clinical practice guidelines. SELECTION CRITERIA: Randomized, double-blind trials with at least 12 months' follow-up in adults with primary hypertension (systolic blood pressure/diastolic blood pressure 140/90 mmHg or higher, or 130/80 mmHg or higher if participants had diabetes), which compared combination of two first-line antihypertensive drug with monotherapy as initial treatment. Trials had to include at least 50 participants per group and report mortality, cardiovascular mortality, cardiovascular events or serious adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion, evaluated the risk of bias and entered the data. Primary outcomes were mortality, serious adverse events, cardiovascular events and cardiovascular mortality. Secondary outcomes were withdrawals due to drug-related adverse effects, reaching blood pressure control (as defined in each trial) and blood pressure change from baseline. Analyses were based on the intention-to treat principle. We summarized data on dichotomous outcomes as risk ratios with 95% confidence intervals. MAIN RESULTS: We found three studies in which a subgroup of participants met our inclusion criteria. None of the studies focused solely on people initiating antihypertensive treatment so we asked investigators for data for this subgroup (monotherapy: 335 participants; combination therapy: 233 participants). They included outpatients, and mostly European and white people. Two trials included only people with type 2 diabetes, whereas the other trial excluded people treated with diabetes, hypocholesterolaemia or cardiovascular drugs. The follow-up was 12 months in two trials and 36 months in one trial. Certainty of evidence was very low due to the serious imprecision, and for using a subgroup not defined in advance. Confidence intervals were extremely wide for all important outcomes and included both appreciable harm and benefit. AUTHORS' CONCLUSIONS: The numbers of included participants and, hence the number of events, were too small to draw any conclusion about the relative efficacy of monotherapy versus combination therapy as initial treatment for primary hypertension. There is a need for large clinical trials that address the question and report clinically relevant endpoints. PMID- 28084625 TI - Efficacy of peripheral lidocaine application (neural therapy) in the treatment of neurogenic detrusor overactivity in multiple sclerosis patients. AB - AIMS: Many agents and treatments are used in the treatment of neurogenic detrusor overactivity (NDO) in MS patients, but no study has been conducted on the use of peripheric lidocaine (neural therapy-NT) on MS patients. We evaluated the effects of local administration of lidocaine on NDO in Multiple Sclerosis (MS) patients. METHODS: For each patient local anesthetic lidocaine was injected at each session. Sessions were held once a week for 5 weeks. At each session, Th 10-L1, urogenital segment intradermal injections, Frankenhauser, and sacral epidural injections were given. The patients had clinical and urodynamic assessment 1 month before and 3, 9, and 12 months after NT. In addition, multiple sclerosis quality of life inventory (MSQL-54) and bladder control scale (BLCS) was performed for patients. RESULTS: Twenty-eight patients were included in the study (8 males, 20 females). The patients' average age was 31.7 +/- 8.1 years. The injection therapy significantly improved volume at first involuntary bladder contraction (FCV), maximal detrusor pression during filling (P det. max.), maximal cystometric bladder capacity (MCC) after 3 months. Also, the MSQL-54 and BLCS scores were improved with treatment. However, these improvements reached a maximum 3 months after treatment, but from the 9 month a regression was seen in the parameters, and after 12 months the findings were seen to be slightly above their basal levels. CONCLUSIONS: These results suggest that NDO treatment in MS patients could be an effective treatment which is easy and has very few side effects, and is cost effective. PMID- 28084626 TI - His-Bundle Pacing for Identifying Optimal Ablation Sites in Patients Undergoing Atrioventricular Junction Ablation: Teaching an Old Dog a New Trick. AB - BACKGROUND: Atrioventricular (AV) junction (AVJ) ablation is conventionally performed by localizing the His-bundle electrogram (HBE). Identification of HBE in the presence of atrial fibrillation (AF) can be difficult, and can make this simple procedure challenging. In this study, we describe our experience with an alternative approach to localize optimal ablation sites using His-bundle pacing (HBP). METHODS: Between 1/1/2014 and 12/31/2015, we performed 13 AVJ ablations using the standard electrogram-guided approach and 11 ablations using HBP. All cases utilized a long femoral guiding sheath and an 8-mm-tip electrode radiofrequency (RF) energy ablation catheter. Pacing was performed at high output (10 mA at 2 ms) to initially achieve right bundle branch capture. The catheter was withdrawn until a narrow QRS morphology and increased stim-to-QRS time were observed. HBP was confirmed when paced and native QRS were identical in morphology. RF energy was applied at the site of HBP capture until AV block was observed. RESULTS: Baseline characteristics of patients in each arm were not significantly different. Compared with the standard approach, HBP was associated with trends toward lower RF applications (3 vs. 2, P = 0.16) and shorter mean RF time (208 seconds vs. 128 seconds, P = 0.19). CONCLUSION: HBP is an effective technique to identify optimal ablation sites during AVJ ablation and may shorten procedure time. HBP can be used to identify the AV node during AF without recording the His potential. Future studies with larger sample size are needed to better characterize the utility of this technique. PMID- 28084627 TI - Carvacrol after status epilepticus (SE) prevents recurrent SE, early seizures, cell death, and cognitive decline. AB - OBJECTIVE: Carvacrol is a naturally occurring monoterpenic phenol that has been suggested to have an action at transient receptor potential cation subfamily M7 (TRPM7) channels, gamma-aminobutyric acid (GABAA receptors, and sodium channels, and has been shown to be antiinflammatory. Carvacrol is neuroprotective in models of cerebral ischemia in vivo and in vitro, probably through its action at TRPM7 channels. We therefore aimed to determine the effect of carvacrol on status epilepticus (SE), chronic epilepsy, cell death, and post-SE cognitive decline. METHODS: We performed long-term, continuous wireless electroencephalography (EEG) monitoring in vivo in rats who underwent perforant path stimulation (PPS) to induce SE and were then randomized to treatment with carvacrol or saline. We also evaluated TRPM7 receptor expression and quantified seizure-induced cell death. The alternating T-maze paradigm was used to assess memory function. RESULTS: Immunostaining showed that TRPM7 channels are widely expressed in neurons within the hippocampus. We found that carvacrol inhibited recurrent SE and early seizures in vivo, but had no detectable effect in the hippocampus on paired-pulse inhibition or the fiber volley, indicating that it was not acting through sodium channel inhibition or GABA receptors. Although the development and severity of chronic epilepsy were not altered by carvacrol, cognitive decline was significantly improved in animals treated with carvacrol. In keeping with preserved memory functions in animals treated with carvacrol, carvacrol had a protective effect against SE-induced cell death in CA1 and hilus, the hippocampal regions most affected by cell loss in the PPS epilepsy model. SIGNIFICANCE: Carvacrol, a naturally occurring inhibitor of TRPM7 channels, is a novel, promising treatment to prevent early recurrence of SE, SE-related neuronal damage, and cognitive decline. PMID- 28084628 TI - Disseminated nocardiosis associated with the isolation of Nocardia nova in a longsnout seahorse Hippocampus reidi (Ginsburg). PMID- 28084629 TI - How Postpartum Women With Depressive Symptoms Manage Sleep Disruption and Fatigue. AB - Postpartum sleep and fatigue have bidirectional relationships with depressive symptoms and challenge women's everyday functioning. The everyday process of managing postpartum sleep and fatigue in the context of depressive symptoms remains unexplored. We conducted a grounded theory study with a sample of 19 women who screened positive on the Postpartum Depression Screening Scale (PDSSTM) Short Form at 3 weeks postpartum. Women completed semi-structured in-home interviews and the full PDSS and Modified Fatigue Symptoms Checklist at 1, 3, and 6 months postpartum. The sample was on average 27 years old, with 2.8 children, and 63% were African-American. They described a basic social process of Finding a Routine Together, during which women's experiences with their infants progressed from Retreating at month 1 toward Finding a New Normal at month 6. In their work to Find a Routine Together, mothers' patterns of change over time were continuous, gradual, or prolonged. Their progress was influenced by depressive symptoms, social support, work and daycare, stability in social circumstances, and underlying stressors. This study's findings suggest the need to allocate resources and tailor interventions to meet the needs of women who are most vulnerable to the health effects of ongoing persistent severe fatigue, disordered sleep, and sub-clinical and clinical levels of depressive symptoms. (c) 2017 Wiley Periodicals, Inc. PMID- 28084630 TI - Validity of the Communication Function Classification System for use with preschool children with communication disorders. AB - AIM: To evaluate construct and predictive validity of the Communication Function Classification System (CFCS) for use with preschool children with a range of speech and language disorders. METHOD: Seventy-seven preschool children with speech and language disorders (50 males, 27 females; mean 2y 7mo, standard deviation [SD] 1y) participated in this cohort study. Preschool children had speech and language, language-only, or speech-only disorders. Together with parent input, speech-language pathologists (SLPs) completed the CFCS at time 1. Parents and SLPs then independently completed a validated change-detecting functional communication outcome measure, the Focus on the outcomes of Communication Under Six (FOCUS), three times: at assessment (time 1), at the start of treatment (time 2), and at the end of treatment (time 3). RESULTS: There was a significant negative correlation between CFCS classifications and FOCUS scores at all three measurement points for the ratings by both parents and SLPs (correlations ranged from -0.60 to -0.76). As expected, no correlations between CFCS classifications and FOCUS change scores were statistically significant. INTERPRETATION: This study provides evidence of construct and predictive validity of the CFCS, demonstrating its value as a discriminative tool for use with preschool children with a range of speech and language disorders. PMID- 28084631 TI - Differentiating the Effects of Familial Risk for Alcohol Dependence and Prenatal Exposure to Alcohol on Offspring Brain Morphology. AB - BACKGROUND: Offspring with a family history of alcohol dependence (AD) have been shown to have altered structural and functional integrity of corticolimbic brain structures. Similarly, prenatal exposure to alcohol is associated with a variety of structural and functional brain changes. The goal of this study was to differentiate the brain gray matter volumetric differences associated with familial risk and prenatal exposure to alcohol among offspring while controlling for lifetime personal exposures to alcohol and drugs. METHODS: A total of 52 high risk (HR) offspring from maternal multiplex families with a high proportion of AD were studied along with 55 low-risk (LR) offspring. Voxel-based morphometric analysis was performed using statistical parametric mapping (SPM8) software using 3T structural images from these offspring to identify gray matter volume differences associated with familial risk and prenatal exposure. RESULTS: Significant familial risk group differences were seen with HR males showing reduced volume of the left inferior temporal, left fusiform, and left and right insula regions relative to LR males, controlling for prenatal exposure to alcohol drugs and cigarettes. HR females showed a reduction in the right fusiform but also showed a reduction in volume in portions of the cerebellum (left crus I and left lobe 8). Prenatal alcohol exposure effects, assessed within the familial HR group, was associated with reduced right middle cingulum and left middle temporal volume. Even low exposure resulting from mothers drinking in amounts less than the median of those who drank (53 drinks or less over the course of the pregnancy) showed a reduction in volume in the right anterior cingulum and in the left cerebellum (lobes 4 and 5). CONCLUSIONS: Familial risk for AD and prenatal exposure to alcohol and other drugs show independent effects on brain morphology. PMID- 28084632 TI - Netrin-1 overexpression improves neurobehavioral outcomes and reduces infarct size via inhibition of the notch1 pathway following experimental stroke. AB - Stroke is a leading cause of morbidity and mortality worldwide. Administration of Netrin-1 during the peri-infarct period has been shown to decrease infarct size in rats; however, the underlying mechanism is unclear. We addressed this question in the present study by inducing stroke in rats via middle cerebral artery occlusion (MCAO), and evaluating the effects of Netrin-1 treatment by neurobehavioral testing, immunocytochemistry, and western blotting. Netrin-1 overexpression increased neurobehavioral test scores and reduced cerebral infarct volume following MCAO via inhibition of the Notch1 signaling pathway. These results demonstrate that early administration of Netrin-1 can is an effective therapeutic approach for improving outcome after stroke. (c) 2017 Wiley Periodicals, Inc. PMID- 28084633 TI - Shedding light on hematopoietic stem cells: formation, regulation, and utilization. PMID- 28084634 TI - Building a Values-Informed Mental Model for New Orleans Climate Risk Management. AB - Individuals use values to frame their beliefs and simplify their understanding when confronted with complex and uncertain situations. The high complexity and deep uncertainty involved in climate risk management (CRM) lead to individuals' values likely being coupled to and contributing to their understanding of specific climate risk factors and management strategies. Most mental model approaches, however, which are commonly used to inform our understanding of people's beliefs, ignore values. In response, we developed a "Values-informed Mental Model" research approach, or ViMM, to elicit individuals' values alongside their beliefs and determine which values people use to understand and assess specific climate risk factors and CRM strategies. Our results show that participants consistently used one of three values to frame their understanding of risk factors and CRM strategies in New Orleans: (1) fostering a healthy economy, wealth, and job creation, (2) protecting and promoting healthy ecosystems and biodiversity, and (3) preserving New Orleans' unique culture, traditions, and historically significant neighborhoods. While the first value frame is common in analyses of CRM strategies, the latter two are often ignored, despite their mirroring commonly accepted pillars of sustainability. Other values like distributive justice and fairness were prioritized differently depending on the risk factor or strategy being discussed. These results suggest that the ViMM method could be a critical first step in CRM decision-support processes and may encourage adoption of CRM strategies more in line with stakeholders' values. PMID- 28084635 TI - De novo SCN1A pathogenic variants in the GEFS+ spectrum: Not always a familial syndrome. AB - Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome characterized by heterogeneous phenotypes ranging from mild disorders such as febrile seizures to epileptic encephalopathies (EEs) such as Dravet syndrome (DS). Although DS often occurs with de novo SCN1A pathogenic variants, milder GEFS+ spectrum phenotypes are associated with inherited pathogenic variants. We identified seven cases with non-EE GEFS+ phenotypes and de novo SCN1A pathogenic variants, including a monozygotic twin pair. Febrile seizures plus (FS+) occurred in six patients, five of whom had additional seizure types. The remaining case had childhood-onset temporal lobe epilepsy without known febrile seizures. Although early development was normal in all individuals, three later had learning difficulties, and the twin girls had language impairment and working memory deficits. All cases had SCN1A missense pathogenic variants that were not found in either parent. One pathogenic variant had been reported previously in a case of DS, and the remainder were novel. Our finding of de novo pathogenic variants in mild phenotypes within the GEFS+ spectrum shows that mild GEFS+ is not always inherited. SCN1A screening should be considered in patients with GEFS+ phenotypes because identification of pathogenic variants will influence antiepileptic therapy, and prognostic and genetic counseling. PMID- 28084637 TI - Long-term compliance and results of intravesical botulinum toxin A injections in male patients. AB - INTRODUCTION: Intravesical injections with botulinum toxin A (BoNT-A) is an established treatment for patients with overactive bladder (OAB) symptoms. However, most studies have evaluated the efficacy of this treatment in women and report short-term results. In this study, we evaluated the long-term compliance of BoNT-A in a heterogeneous group of male patients. MATERIALS AND METHODS: This is a retrospective, single-centre study. We evaluated all male patients who have been treated with BoNT-A from 2004 until 2010 in a large teaching hospital. Patients received 100-300 U of onabotulinum toxin-A in 20 intravescial injections. Some patients received dose adjustment with repeated injections. RESULTS: In total, 88 male patients were included. The mean follow-up was almost 6 years (69 months). Of all patients, 22 (25%) continued BoNT-A treatment at last follow-up (success). Of the patients who discontinued treatment, 35 had insufficient effect and 27 had tolerability issues (eg, urinary retention, self catheterisation, voiding LUTS). Four patients abandoned treatment due to other reasons that were not related to BoNT-A. Of all patients, 24% had to use intermittent catheterisation (de novo) or indwelling catheters at some point during the follow-up. DISCUSSION: In this real-life, heterogeneous cohort of men, the long-term compliance with BoNT-A was 25%. Patients with neurogenic OAB symptoms appear to have the best results in our study with 36% of patients who were still on active treatment during last follow-up. Intravesical BoNT-A can be an effective treatment for men with OAB symptoms. In our study, only 25% of patients continued treatment during long-term follow-up. Larger, prospective trials are needed to confirm these results. PMID- 28084636 TI - Rubisco small subunits from the unicellular green alga Chlamydomonas complement Rubisco-deficient mutants of Arabidopsis. AB - Introducing components of algal carbon concentrating mechanisms (CCMs) into higher plant chloroplasts could increase photosynthetic productivity. A key component is the Rubisco-containing pyrenoid that is needed to minimise CO2 retro diffusion for CCM operating efficiency. Rubisco in Arabidopsis was re-engineered to incorporate sequence elements that are thought to be essential for recruitment of Rubisco to the pyrenoid, namely the algal Rubisco small subunit (SSU, encoded by rbcS) or only the surface-exposed algal SSU alpha-helices. Leaves of Arabidopsis rbcs mutants expressing 'pyrenoid-competent' chimeric Arabidopsis SSUs containing the SSU alpha-helices from Chlamydomonas reinhardtii can form hybrid Rubisco complexes with catalytic properties similar to those of native Rubisco, suggesting that the alpha-helices are catalytically neutral. The growth and photosynthetic performance of complemented Arabidopsis rbcs mutants producing near wild-type levels of the hybrid Rubisco were similar to those of wild-type controls. Arabidopsis rbcs mutants expressing a Chlamydomonas SSU differed from wild-type plants with respect to Rubisco catalysis, photosynthesis and growth. This confirms a role for the SSU in influencing Rubisco catalytic properties. PMID- 28084638 TI - Association analysis of KIT, MITF, and PAX3 variants with white markings in Spanish horses. AB - Several variants in the KIT, PAX3 and MITF genes have previously been associated with white markings in horses. In this study, we examined eight variants of these genes in 70 Menorca Purebred horses (PRMe, only black solid-coloured horses) and 70 Spanish Purebred horses (PRE, different coat colour patterns) that were scored for the extent of white markings. A maximum-likelihood chi-square test, logistic regression model and ridge regression analyses showed that a missense mutation (p.Arg682His) in KIT was associated with white facial markings (P < 0.05) and with total white markings (P < 0.05) in PRMe horses. The relative contribution of this variant to white markings in PRMe horses was estimated at 47.6% (head) and 43.4% (total score). In PRE horses, this variant was also associated with hindlimb scores (P < 0.05) with a relative contribution of 41.2%. The g.20147039C>T intronic variant located 29.9 kb downstream from the transcription start site of the MITF gene was associated with less white markings on forelimbs (P < 0.05) in PRMe horses, with a relative contribution of 63.9%, whereas in PRE horses this variant was associated with white facial markings (P < 0.05), with a relative contribution of 63.9%. No significant associations were found for PAX3 variants in these breeds. These results show that KIT and MITF variants are involved in the white marking patterns of both PRMe and PRE horses, providing breeders with an opportunity to use genetic testing to aid in breeding for their desired level of white markings. PMID- 28084639 TI - Bursts of seizures in long-term recordings of human focal epilepsy. AB - OBJECTIVE: We report on temporally clustered seizures detected from continuous long-term ambulatory human electroencephalographic data. The objective was to investigate short-term seizure clustering, which we have termed bursting, and consider implications for patient care, seizure prediction, and evaluating therapies. METHODS: Chronic ambulatory intracranial electroencephalography (EEG) data collected for the purpose of seizure prediction were annotated to identify seizure events. A detection algorithm was used to identify bursts of events. Burst events were compared to nonburst events to evaluate event dispersion, duration and dynamics. RESULTS: Bursts of seizures were present in 6 of 15 subjects, and detections were consistent over long-term monitoring (>2 years). Subjects with bursts of seizures had highly overdispersed seizure rates, compared to other subjects. There was a complicated relationship between bursts and clinical seizures, although bursts were associated with multimodal distributions of seizure duration, and poorer predictive outcomes. For three subjects, bursts demonstrated distinctive preictal dynamics compared to clinical seizures. SIGNIFICANCE: We have previously hypothesized that there are distinct physiologic pathways underlying short- and long-duration seizures. Herein we show that burst seizures fall almost exclusively within the short population of seizure durations; however, a short duration event was not sufficient to induce or imply bursting. We can therefore conclude that in addition to distinct mechanisms underlying seizure duration, there are separate factors regulating bursts of seizures. We show that bursts were a robust phenomenon in our patient cohort, which were consistent with overdispersed seizure rates, suggesting long-memory dynamics. PMID- 28084641 TI - Malformation risk of antiepileptic drug exposure during pregnancy in women with epilepsy: Results from a pregnancy registry in South India. AB - OBJECTIVE: Kerala Registry of Epilepsy and Pregnancy had been prospectively evaluating the reproductive issues of women with epilepsy since April 1998. This analysis aimed to estimate the relative risk of major congenital malformations (MCM) to the registrants. METHODS: All pregnancies with known outcome in this register until December 2013 were included. Malformation status was evaluated by antenatal ultrasonography, physical examination at birth, echocardiography, and abdomen ultrasonography at 3 months of age and a final review at 1 year of age. RESULTS: There were 1,688 fetuses (singlets 1,643, twins 21, and triplet 1) resulting in 1,622 live births. All were born to women of Asian origin living in South India. The MCM rate for all live births was 6.84% (95% confidence interval [CI] 5.71-8.18) and for all pregnancy outcomes including fetal loss was 7.11% (95% CI 5.98-8.44). The MCM rates (mean with 95% CI) for exposed group were 6.4% (5.03-8.03) for monotherapy and 9.9% (7.37-13.13) for polytherapy; internal control group (women with epilepsy [WWE] not on antiepileptic drugs [AEDs] in first trimester) 5.6% (3.34-9.11), external control group (women without epilepsy or AED exposure in first trimester) 3.45% (1.94-6.07). Valproate monotherapy group had a dose-dependent relative risk for MCM of 2.6 (95% CI 1.30-5.20) compared to the external control group. The preliminary data on MCM rate for the nine total clobazam monotherapy (22.2%; 95% CI 6.2-54.7) signals increased risk that needs further validation on larger sample size. There was no association between MCM rate and maternal socioeconomic status, epilepsy syndrome, or use of folic acid in first trimester. SIGNIFICANCE: This dataset from South India confirms the increased risk of MCM with exposure to AEDs, particularly polytherapy. A dose-dependent increased risk was observed with valproate. The increased risk associated with clobazam monotherapy is an important signal that needs to be confirmed in a larger sample. PMID- 28084640 TI - Diversity of immune cell types in multiple sclerosis and its animal model: Pathological and therapeutic implications. AB - Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system with an autoimmune attack on the components of the myelin sheath and axons. The etiology of the disease remains largely unknown, but it is commonly acknowledged that the development of MS probably results from the interaction of environmental factors in conjunction with a genetic predisposition. Current therapeutic approaches can only ameliorate the clinical symptoms or reduce the frequency of relapse in MS. Most drugs used in this disease broadly suppress the functions of immune effector cells, which can result in serious side effects. Thus, new therapeutic methods resulting in greater efficacy and lower toxicity are needed. Toward this end, cell-based therapies are of increasing interest in the treatment of MS. Several immunoregulatory cell types, including regulatory T cells, regulatory B cells, M2 macrophages, tolerogenic dendritic cells, and stem cells, have been developed as novel therapeutic tools for the treatment of MS. In this Review, we summarize studies on the application of these cell populations for the treatment of MS and its animal model, experimental autoimmune encephalomyelitis, and call for further research on applications and mechanisms by which these cells act in the treatment of MS. (c) 2017 The Authors Journal of Neuroscience Research Published by Wiley Periodicals, Inc. PMID- 28084644 TI - Designer Drugs 2.0. AB - This "Designer Drugs 2.0" issue of Clinical Pharmacology & Therapeutics focuses on novel psychoactive substances, primarily cannabinoids and cathinones, and the repurposing of established psychoactive compounds (e.g., modafinil, psilocybin, lysergic acid diethylamide, and 3,4-methylenedioxymethamphetamine) that simultaneously offer new pharmacotherapies and pose serious health problems. Novel psychoactive substances were initially used as potent tools to investigate endogenous neurotransmitter systems; for example, synthetic cannabinoids have much higher potency than Delta9-tetrahydrocannabinol at the cannabinoid receptors. However, they are now being used illicitly as well as being tested for their efficacy in numerous clinical indications. Likewise, previously established psychoactive drugs are being repurposed as treatments for a wide variety of indications where currently approved medications are ineffective. This set of papers examines the arising problems associated with designer drugs (e.g., adverse events, psychosis, rapid new synthesis, abuse liability testing, internet sales, scheduling) as well as the potential therapeutic promises in areas as diverse as cognition enhancement, exercise-mimetics, epilepsy, multiple sclerosis, and posttraumatic stress disorder. PMID- 28084647 TI - A novel model for testing the efficiency of removal of calcium hydroxide from complex root canal anatomies. AB - The purpose of this study was to evaluate the efficacy of several irrigation protocols in the removal of calcium hydroxide [Ca(OH)2 ] from simulated internal root resorption cavities in a complex root canal anatomy model. The 20 degrees to 35 degrees curved mesiobuccal roots of 94 maxillary molars were sectioned longitudinally; internal resorption cavities were prepared in the apical third of the canal walls. Calcium hydroxide was placed into the cavities and the root halves reassembled. Four teeth were used as controls, and 90 teeth were randomly divided into six experimental groups (n = 15), according to the irrigation protocols used: syringe irrigation; H2 O2 (HP); Navitip FX; Vibringe-syringe; Vibringe-NaviTip FX; ultrasonically activated irrigation (UAI) using an ultrasonic K-file. In the HP group, 2.5% NaOCl and 3% H2 O2 were used, while 2.5% NaOCl and 17% EDTA were used in the remaining groups. Stereomicroscope images and radiographs were used to measure the remaining Ca(OH)2 . The model proved to be suitable for simulating complex anatomy. Positive correlation was found between stereomicroscope and radiographic analyses (P < 0.05). UAI removed significantly more Ca(OH)2 than the other experimental groups (P < 0.05). The HP group was the least efficient protocol (P < 0.05). It would appear that a reliable model has been developed that simulates complex root canal anatomy. Irrigant activation protocols enhanced Ca(OH)2 removal. PMID- 28084648 TI - Hypophosphatasia: Enzyme Replacement Therapy Brings New Opportunities and New Challenges. AB - Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Autosomal inheritance (dominant or recessive) from among more than 300 predominantly missense defects of TNSALP (ALPL) explains HPP's broad-ranging severity, the greatest of all skeletal diseases. In health, TNSALP is linked to cell surfaces and richly expressed in the skeleton and developing teeth. In HPP,TNSALP substrates accumulate extracellularly, including inorganic pyrophosphate (PPi), an inhibitor of mineralization. The PPi excess can cause tooth loss, rickets or osteomalacia, calcific arthropathies, and perhaps muscle weakness. Severely affected infants may seize from insufficient hydrolysis of pyridoxal 5'-phosphate (PLP), the major extracellular vitamin B6 . Now, significant successes are documented for newborns, infants, and children severely affected by HPP given asfotase alfa, a hydroxyapatite-targeted recombinant TNSALP. Since fall 2015, this biologic is approved by regulatory agencies multinationally typically for pediatric-onset HPP. Safe and effective treatment is now possible for this last rickets to have a medical therapy, but a number of challenges involving diagnosis, understanding prognosis, and providing this treatment are reviewed herein. (c) 2017 American Society for Bone and Mineral Research. PMID- 28084646 TI - Treatments for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): an overview of systematic reviews. AB - BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic progressive or relapsing and remitting disease that usually causes weakness and sensory loss. The symptoms are due to autoimmune inflammation of peripheral nerves. CIPD affects about 2 to 3 per 100,000 of the population. More than half of affected people cannot walk unaided when symptoms are at their worst. CIDP usually responds to treatments that reduce inflammation, but there is disagreement about which treatment is most effective. OBJECTIVES: To summarise the evidence from Cochrane systematic reviews (CSRs) and non-Cochrane systematic reviews of any treatment for CIDP and to compare the effects of treatments. METHODS: We considered all systematic reviews of randomised controlled trials (RCTs) of any treatment for any form of CIDP. We reported their primary outcomes, giving priority to change in disability after 12 months.Two overview authors independently identified published systematic reviews for inclusion and collected data. We reported the quality of evidence using GRADE criteria. Two other review authors independently checked review selection, data extraction and quality assessments.On 31 October 2016, we searched the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects (in theCochrane Library), MEDLINE, Embase, and CINAHL Plus for systematic reviews of CIDP. We supplemented the RCTs in the existing CSRs by searching on the same date for RCTs of any treatment of CIDP (including treatment of fatigue or pain in CIDP), in the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL Plus. MAIN RESULTS: Five CSRs met our inclusion criteria. We identified 23 randomised trials, of which 15 had been included in these CSRs. We were unable to compare treatments as originally planned, because outcomes and outcome intervals differed. CorticosteroidsIt is uncertain whether daily oral prednisone improved impairment compared to no treatment because the quality of the evidence was very low (1 trial, 28 participants). According to moderate-quality evidence (1 trial, 41 participants), six months' treatment with high-dose monthly oral dexamethasone did not improve disability more than daily oral prednisolone. Observational studies tell us that prolonged use of corticosteroids sometimes causes serious side-effects. Plasma exchangeAccording to moderate-quality evidence (2 trials, 59 participants), twice-weekly plasma exchange produced more short-term improvement in disability than sham exchange. In the largest observational study, 3.9% of plasma exchange procedures had complications. Intravenous immunoglobulinAccording to high-quality evidence (5 trials, 269 participants), intravenous immunoglobulin (IVIg) produced more short-term improvement than placebo. Adverse events were more common with IVIg than placebo (high-quality evidence), but serious adverse events were not (moderate-quality evidence, 3 trials, 315 participants). One trial with 19 participants provided moderate-quality evidence of little or no difference in short-term improvement of impairment with plasma exchange in comparison to IVIg. There was little or no difference in short-term improvement of disability with IVIg in comparison to oral prednisolone (moderate-quality evidence; 1 trial, 29 participants) or intravenous methylprednisolone (high quality evidence; 1 trial, 45 participants). One unpublished randomised open trial with 35 participants found little or no difference in disability after three months of IVIg compared to oral prednisone; this trial has not yet been included in a CSR. We know from observational studies that serious adverse events related to IVIg do occur. Other immunomodulatory treatmentsIt is uncertain whether the addition of azathioprine (2 mg/kg) to prednisone improved impairment in comparison to prednisone alone, as the quality of the evidence is very low (1 trial, 27 participants). Observational studies show that adverse effects truncate treatment in 10% of people.According to low-quality evidence (1 trial, 60 participants), compared to placebo, methotrexate 15 mg/kg did not allow more participants to reduce corticosteroid or IVIg doses by 20%. Serious adverse events were no more common with methotrexate than with placebo, but observational studies show that methotrexate can cause teratogenicity, abnormal liver function, and pulmonary fibrosis.According to moderate-quality evidence (2 trials, 77 participants), interferon beta-1a (IFN beta-1a) in comparison to placebo, did not allow more people to withdraw from IVIg. According to moderate-quality evidence, serious adverse events were no more common with IFN beta-1a than with placebo.We know of no other completed trials of immunosuppressant or immunomodulatory agents for CIDP. Other treatmentsWe identified no trials of treatments for fatigue or pain in CIDP. Adverse effectsNot all trials routinely collected adverse event data; when they did, the quality of evidence was variable. Adverse effects in the short, medium, and long term occur with all interventions. We are not able to make reliable comparisons of adverse events between the interventions included in CSRs. AUTHORS' CONCLUSIONS: We cannot be certain based on available evidence whether daily oral prednisone improves impairment compared to no treatment. However, corticosteroids are commonly used, based on widespread availability, low cost, very low-quality evidence from observational studies, and clinical experience. The weakness of the evidence does not necessarily mean that corticosteroids are ineffective. High-dose monthly oral dexamethasone for six months is probably no more or less effective than daily oral prednisolone. Plasma exchange produces short-term improvement in impairment as determined by neurological examination, and probably produces short-term improvement in disability. IVIg produces more short-term improvement in disability than placebo and more adverse events, although serious side effects are probably no more common than with placebo. There is no clear difference in short-term improvement in impairment with IVIg when compared with intravenous methylprednisolone and probably no improvement when compared with either oral prednisolone or plasma exchange. According to observational studies, adverse events related to difficult venous access, use of citrate, and haemodynamic changes occur in 3% to17% of plasma exchange procedures.It is uncertain whether azathioprine is of benefit as the quality of evidence is very low. Methotrexate may not be of benefit and IFN beta-1a is probably not of benefit.We need further research to identify predictors of response to different treatments and to compare their long-term benefits, safety and cost-effectiveness. There is a need for more randomised trials of immunosuppressive and immunomodulatory agents, routes of administration, and treatments for symptoms of CIDP. PMID- 28084649 TI - Effect of sweet potato vines on performance parameters and some carcass characteristics of rabbits. AB - Conventional feedstuffs in Brazil are expensive, which has led to the search for less conventional cheaper and locally available feedstuffs. Thus, this study was carried out to determine the dietary effect of dry sweet potato vines (SPV) on the performance and some carcass characteristics of rabbits. A total of twenty seven weaned White New Zealand rabbits (14 male and 13 female) 35 days old with an average initial weight of 755 g were allocated into three treatments. Nine rabbits were assigned to each treatment in a completely randomized design. Three diets were formulated to similar protein and energy levels: 0SPV - diet without inclusion of dry sweet potato vines; 10SPV - diet with 10% alfalfa hay replaced by dry sweet potato vines; and 15SPV - diet with 15% of alfalfa hay replaced by dry sweet potato vines. The experiment lasted for 49 days during which data for feed intake and body weight were recorded. The daily feed intake ranged from 73.17 to 78.02 g; daily weight gain from 22.32 to 23.17 g; feed conversion ratio (FCR) from 3.16 to 3.49 and final live weight ranged from 1839.44 to 1880.55 g. None of the evaluated performance parameters as well as carcass weight, heart weight and percentages of fat and protein in meat were significantly affected by any of the tested dietary treatments. However, the liver weight was statistically lower in animals fed the diets containing 10% of SPV, mainly due to lower glucose content. Glycogen within the tissue, did not differ significantly among treatments. It was therefore concluded that up to 15% of SPV can successfully be included in the diet of rabbits as a cheaper replacement for alfalfa hay without adversely affecting performance. PMID- 28084650 TI - A Large Inversion Involving GNAS Exon A/B and All Exons Encoding Gsalpha Is Associated With Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B). AB - Pseudohypoparathyroidism type Ib (PHP1B) is characterized primarily by resistance to parathyroid hormone (PTH) and thus hypocalcemia and hyperphosphatemia, in most cases without evidence for Albright hereditary osteodystrophy (AHO). PHP1B is associated with epigenetic changes at one or several differentially-methylated regions (DMRs) within GNAS, which encodes the alpha-subunit of the stimulatory G protein (Gsalpha) and splice variants thereof. Heterozygous, maternally inherited STX16 or GNAS deletions leading to isolated loss-of-methylation (LOM) at exon A/B alone or at all maternal DMRs are the cause of autosomal dominant PHP1B (AD PHP1B). In this study, we analyzed three affected individuals, the female proband and her two sons. All three revealed isolated LOM at GNAS exon A/B, whereas the proband's healthy maternal grandmother and uncle showed normal methylation at this locus. Haplotype analysis was consistent with linkage to the STX16/GNAS region, yet no deletion could be identified. Whole-genome sequencing of one of the patients revealed a large heterozygous inversion (1,882,433 bp). The centromeric breakpoint of the inversion is located 7,225 bp downstream of GNAS exon XL, but its DMR showed no methylation abnormality, raising the possibility that the inversion disrupts a regulatory element required only for establishing or maintaining exon A/B methylation. Because our three patients presented phenotypes consistent with PHP1B, and not with PHP1A, the Gsalpha promoter is probably unaffected by the inversion. Our findings expand the spectrum of genetic mutations that lead to LOM at exon A/B alone and thus biallelic expression of the transcript derived from this alternative first GNAS exon. (c) 2017 American Society for Bone and Mineral Research. PMID- 28084651 TI - Intra- and inter-network functional alterations in Parkinson's disease with mild cognitive impairment. AB - Mild cognitive impairment (MCI) is prevalent in 15%-40% of Parkinson's disease (PD) patients at diagnosis. In this investigation, we study brain intra- and inter-network alterations in resting state functional magnetic resonance imaging (rs-fMRI) in recently diagnosed PD patients and characterise them as either cognitive normal (PD-NC) or with MCI (PD-MCI). Patients were divided into two groups, PD-NC (N = 62) and PD-MCI (N = 37) and for comparison, healthy controls (HC, N = 30) were also included. Intra- and inter-network connectivity were investigated from participants' rs-fMRIs in 26 resting state networks (RSNs). Intra-network differences were found between both patient groups and HCs for networks associated with motor control (motor cortex), spatial attention and visual perception. When comparing both PD-NC and PD-MCI, intra-network alterations were found in RSNs related to attention, executive function and motor control (cerebellum). The inter-network analysis revealed a hyper-synchronisation between the basal ganglia network and the motor cortex in PD-NC compared with HCs. When both patient groups were compared, intra-network alterations in RSNs related to attention, motor control, visual perception and executive function were found. We also detected disease-driven negative synchronisations and synchronisation shifts from positive to negative and vice versa in both patient groups compared with HCs. The hyper-synchronisation between basal ganglia and motor cortical RSNs in PD and its synchronisation shift from negative to positive compared with HCs, suggest a compensatory response to basal dysfunction and altered basal-cortical motor control in the resting state brain of PD patients. Hum Brain Mapp 38:1702-1715, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28084652 TI - Melt-Quenched Hybrid Glasses from Metal-Organic Frameworks. AB - While glasses formed by quenching the molten states of inorganic non-metallic, organic, and metallic species are known, those containing both inorganic and organic moieties are far less prevalent. Network materials consisting of inorganic nodes linked by organic ligands do however exist in the crystalline or amorphous domain. This large family of open framework compounds, called metal organic frameworks (MOFs) or coordination polymers, has been investigated intensively in the past two decades for a variety of applications, almost all of which stem from their high internal surface areas and chemical versatility. Recently, a selection of MOFs has been demonstrated to undergo melting and vitrification upon cooling. Here, these recent discoveries and the connections between the fields of MOF chemistry and glass science are summarized. Possible advantages and applications for MOF glasses produced by utilizing the tunable chemistry of the crystalline state are also highlighted. PMID- 28084653 TI - Predicting early symptomatic osteoarthritis in the human knee using machine learning classification of magnetic resonance images from the osteoarthritis initiative. AB - : The purpose of this study is to evaluate the ability of a machine learning algorithm to classify in vivo magnetic resonance images (MRI) of human articular cartilage for development of osteoarthritis (OA). Sixty-eight subjects were selected from the osteoarthritis initiative (OAI) control and incidence cohorts. Progression to clinical OA was defined by the development of symptoms as quantified by the Western Ontario and McMaster Universities Arthritis (WOMAC) questionnaire 3 years after baseline evaluation. Multi-slice T2 -weighted knee images, obtained through the OAI, of these subjects were registered using a nonlinear image registration algorithm. T2 maps of cartilage from the central weight bearing slices of the medial femoral condyle were derived from the registered images using the multiple available echo times and were classified for "progression to symptomatic OA" using the machine learning tool, weighted neighbor distance using compound hierarchy of algorithms representing morphology (WND-CHRM). WND-CHRM classified the isolated T2 maps for the progression to symptomatic OA with 75% accuracy. CLINICAL SIGNIFICANCE: Machine learning algorithms applied to T2 maps have the potential to provide important prognostic information for the development of OA. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2243-2250, 2017. PMID- 28084654 TI - Nanocomposites from Solution-Synthesized PbTe-BiSbTe Nanoheterostructure with Unity Figure of Merit at Low-Medium Temperatures (500-600 K). AB - A scalable, low-temperature solution process is used to synthesize precursor material for Pb-doped Bi0.7 Sb1.3 Te3 thermoelectric nanocomposites. The controllable Pb-doping leads to the increase in the optical bandgap, thus delaying the onset of bipolar conduction. Furthermore, the solution synthesis enables nanostructuring, which greatly reduces thermal conductivity. As a result, this material exhibits a zT = 1 over the 513-613 K range. PMID- 28084655 TI - Effects of local vanadium delivery on diabetic fracture healing. AB - This study evaluated the effect of local vanadyl acetylacetonate (VAC), an insulin mimetic agent, upon the early and late parameters of fracture healing in rats using a standard femur fracture model. Mechanical testing, and radiographic scoring were performed, as well as histomorphometry, including percent bone, percent cartilage, and osteoclast numbers. Fractures treated with local 1.5 mg/kg VAC possessed significantly increased mechanical properties compared to controls at 6 weeks post-fracture, including increased torque to failure (15%; p = 0.046), shear modulus (89%; p = 0.043), and shear stress (81%; p = 0.009). The radiographic scoring analysis showed increased cortical bridging at 4 weeks and 6 weeks (119%; p = 0.036 and 209%; p = 0.002) in 1.5 mg/kg VAC treated groups. Histomorphometry of the fracture callus at days 10 and 14 showed increased percent cartilage (121%; p = 0.009 and 45%; p = 0.035) and percent mineralized tissue (66%; p = 0.035 and 58%; p = 0.006) with local VAC treated groups compared to control. Additionally, fewer osteoclasts were observed in the local VAC treated animals as compared to controls at day 14 (0.45% +/- 0.29% vs. 0.83% +/- 0.36% of callus area; p = 0.032). The results suggest local administration of VAC acts to modulate osteoclast activity and increase percentage of early callus cartilage, ultimately enhancing mechanical properties comparably to non-diabetic animals treated with local VAC. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2174-2180, 2017. PMID- 28084656 TI - Common and distinct brain networks underlying verbal and visual creativity. AB - Creativity is imperative to the progression of human civilization, prosperity, and well-being. Past creative researches tends to emphasize the default mode network (DMN) or the frontoparietal network (FPN) somewhat exclusively. However, little is known about how these networks interact to contribute to creativity and whether common or distinct brain networks are responsible for visual and verbal creativity. Here, we use functional connectivity analysis of resting-state functional magnetic resonance imaging data to investigate visual and verbal creativity-related regions and networks in 282 healthy subjects. We found that functional connectivity within the bilateral superior parietal cortex of the FPN was negatively associated with visual and verbal creativity. The strength of connectivity between the DMN and FPN was positively related to both creative domains. Visual creativity was negatively correlated with functional connectivity within the precuneus of the pDMN and right middle frontal gyrus of the FPN, and verbal creativity was negatively correlated with functional connectivity within the medial prefrontal cortex of the aDMN. Critically, the FPN mediated the relationship between the aDMN and verbal creativity, and it also mediated the relationship between the pDMN and visual creativity. Taken together, decreased within-network connectivity of the FPN and DMN may allow for flexible between network coupling in the highly creative brain. These findings provide indirect evidence for the cooperative role of the default and executive control networks in creativity, extending past research by revealing common and distinct brain systems underlying verbal and visual creative cognition. Hum Brain Mapp 38:2094 2111, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28084658 TI - Degradability and Clearance of Silicon, Organosilica, Silsesquioxane, Silica Mixed Oxide, and Mesoporous Silica Nanoparticles. AB - The biorelated degradability and clearance of siliceous nanomaterials have been questioned worldwide, since they are crucial prerequisites for the successful translation in clinics. Typically, the degradability and biocompatibility of mesoporous silica nanoparticles (MSNs) have been an ongoing discussion in research circles. The reason for such a concern is that approved pharmaceutical products must not accumulate in the human body, to prevent severe and unpredictable side-effects. Here, the biorelated degradability and clearance of silicon and silica nanoparticles (NPs) are comprehensively summarized. The influence of the size, morphology, surface area, pore size, and surface functional groups, to name a few, on the degradability of silicon and silica NPs is described. The noncovalent organic doping of silica and the covalent incorporation of either hydrolytically stable or redox- and enzymatically cleavable silsesquioxanes is then described for organosilica, bridged silsesquioxane (BS), and periodic mesoporous organosilica (PMO) NPs. Inorganically doped silica particles such as calcium-, iron-, manganese-, and zirconium-doped NPs, also have radically different hydrolytic stabilities. To conclude, the degradability and clearance timelines of various siliceous nanomaterials are compared and it is highlighted that researchers can select a specific nanomaterial in this large family according to the targeted applications and the required clearance kinetics. PMID- 28084657 TI - Femoral Neck External Size but not aBMD Predicts Structural and Mass Changes for Women Transitioning Through Menopause. AB - The impact of adult bone traits on changes in bone structure and mass during aging is not well understood. Having shown that intracortical remodeling correlates with external size of adult long bones led us to hypothesize that age related changes in bone traits also depend on external bone size. We analyzed hip dual-energy X-ray absorptiometry images acquired longitudinally over 14 years for 198 midlife women transitioning through menopause. The 14-year change in bone mineral content (BMC, R2 = 0.03, p = 0.015) and bone area (R2 = 0.13, p = 0.001), but not areal bone mineral density (aBMD, R2 = 0.00, p = 0.931) correlated negatively with baseline femoral neck external size, adjusted for body size using the residuals from a linear regression between baseline bone area and height. The dependence of the 14-year changes in BMC and bone area on baseline bone area remained significant after adjusting for race/ethnicity, postmenopausal hormone use, the 14-year change in weight, and baseline aBMD, weight, height, and age. Women were sorted into tertiles using the baseline bone area-height residuals. The 14-year change in BMC (p = 0.009) and bone area (p = 0.001) but not aBMD (p = 0.788) differed across the tertiles. This suggested that women showed similar changes in aBMD for different structural and biological reasons: women with narrow femoral necks showed smaller changes in BMC but greater increases in bone area compared to women with wide femoral necks who showed greater losses in BMC but without large compensatory increases in bone area. This finding is opposite to expectations that periosteal expansion acts to mechanically offset bone loss. Thus, changes in femoral neck structure and mass during menopause vary widely among women and are predicted by baseline external bone size but not aBMD. How these different structural and mass changes affect individual strength-decline trajectories remains to be determined. (c) 2017 American Society for Bone and Mineral Research. PMID- 28084659 TI - Mixed-Linkage Glucan Oligosaccharides Produced by Automated Glycan Assembly Serve as Tools To Determine the Substrate Specificity of Lichenase. AB - The mixed-linkage (1->3),(1->4)-d-glucan (MLG) specific glycosyl hydrolase lichenase is an important biochemical tool for the structural characterization of MLGs. It holds potential for application in the brewery, animal feed, and biofuel industries. Several defined MLG oligosaccharides obtained by automated glycan assembly are used to analyze the substrate specificities of Bacillus subtilis lichenase. Two glucose building blocks (BBs), equipped with a temporary fluorenylmethyloxycarbonyl chloride (Fmoc) protecting group in the C-3 or C-4 position, served to assemble different oligosaccharides by using an automated oligosaccharide synthesizer. Light-induced cleavage of the glycan products from the solid support followed by global deprotection provided seven MLG oligosaccharides of different length and connectivity. After incubation of the MLG oligosaccharides with lichenase, the digestion products were analyzed by HPLC MS. These digestion experiments provided insights into the enzyme's active site that is in line with other recent evidence suggesting that the substrate specificity of lichenases has to be reconsidered. These results demonstrate that synthetic MLG oligosaccharides are useful tools to analyze mixed-linkage beta glucanases. PMID- 28084660 TI - Parasympathectomy increases resting salivary secretion in normal and irradiated submandibular glands of rats. AB - Fluid and ion secretion from the submandibular gland (SMG) is mainly regulated by parasympathetic nerves. This study evaluated the effect of parasympathectomy on salivary secretion from normal and irradiated rat SMGs from 1 to 24 wk after denervation. Although stimulated salivary secretion was significantly lower in denervated SMGs compared with contralateral self-controls, the resting salivary flow rates were markedly higher in the denervated SMGs at 1, 12, and 24 wk after denervation. The levels of muscarinic acetylcholine M1 and M3 receptors, as well as of aquaporin 5, were up-regulated. Notably, although irradiated SMGs showed significantly lower resting and stimulated salivary secretion rates than non irradiated SMGs, the resting salivary secretion rates of the irradiated and denervated SMGs were markedly higher than seen in the irradiated self-control SMGs at 1, 12, and 24 wk after parasympathectomy, and were even higher than seen in the non-irradiated sham-operated rats. The expression of M1 and M3 receptors was similarly elevated. Taken together, our results suggest that parasympathetic denervation increases resting salivary secretion of both normal and irradiated SMGs. This approach might provide a potential modality for relieving radiation induced xerostomia, which is a common complication following treatment of head and neck cancer. PMID- 28084661 TI - Improved milk production through PG-PL system by provision of in-house shelter management in lactating Murrah buffaloes during winter season. AB - Comprehensive information on the role of beta-casein and plasminogen-plasmin (PG PL) system in milk secretion of Murrah buffaloes during winter season is lacking, although effects of cold stress can be ameliorated to an extent by altering microclimate at farm level. Hence, this study was aimed to determine the changes in productivity along with PG-PL system of milk, plasma hormones and metabolites of buffaloes during winter (December-January) season under two different management systems. Average minimum temperature and wind chill index during this season were 7.02 and 12.74 degrees C respectively. Buffaloes were divided in two groups of six animals each: control and treatment, where treatment group animals were placed in-house with floor bedding of paddy straw and the control group animals in loose housing system without straw bedding. Physiological responses were recorded, and milk and blood samples were collected at weekly intervals for six-week experimental period. Under in-house management system, buffaloes experienced better comfort by alleviating environmental stress as their physiological responses such as respiration rate and pulse rate were significantly reduced (p < 0.01) as compared to the control, which subsequently resulted higher milk yield by 9.92% (p < 0.05). Analysis of milk samples revealed higher concentration of plasminogen (10.6 vs. 8.05 MUg/ml; p < 0.01) and beta casein (p < 0.05), and lower plasmin level (0.299 vs. 0.321 MUg/ml; p < 0.05) in buffaloes under treatment group. It was also found that plasma cortisol, glucose and non-esterified fatty acids levels were higher (p < 0.01) in control group as compared to the treatment animals by 13.6%, 8.14% and 12.6% respectively. However, milk composition, growth hormone, epinephrine and norepinephrine level in plasma were similar in both the groups. Hence, it may be concluded that provision of in-house shelter management with floor bedding of paddy straw during winter was effective to minimize environmental stress and improved milk production through manipulation of PG-PL system in buffaloes. PMID- 28084662 TI - Testimony Therapy With Ritual: A Pilot Randomized Controlled Trial. AB - Testimony therapy can provide low-cost, brief, simple, and culturally adaptable psychosocial services in low-income countries (Agger, Raghuvanshi, Khan, Polatin, & Laursen, 2009). Nonetheless, there have been no well-controlled studies of testimony therapy. We report the analyses of a randomized controlled trial designed to assess the effectiveness of testimony therapy plus a culturally adapted ceremony in reducing mental health symptoms among Khmer Rouge torture survivors from across Cambodia. Using multilevel modeling, we compared symptoms of posttraumatic stress disorder, anxiety, and depression between a treatment (n = 45) and a control group (n = 43) at baseline, 3 months, and 6 months. We found that testimony therapy plus ceremony significantly reduced symptoms of posttraumatic stress disorder (d = 0.49), anxiety (d = 0.44), and depression (d = 0.53). PMID- 28084663 TI - Comparison of apical centring ability between incisal-shifted access and traditional lingual access for maxillary anterior teeth. AB - The aim of this study was to compare the apical centring ability of incisal shifted access (ISA) with that of traditional lingual access (TLA). Fifteen three dimensional printed resin models were prepared from the computed tomography data for a human maxillary central incisor and divided into ISA (n = 7), TLA (n = 7) and control (n = 1) groups. After access preparation, these models were shaped to the working length using K-files up to #40, followed by step-back procedures. An apical portion of the model was removed at 0.5 mm coronal to the working length. Microscopic images of each cutting surface were taken to measure the preparation area and the distance of transportation. TLA created a larger preparation area than ISA (P < 0.05). The distance of transportation (mean +/- standard deviation) was 0.4 +/- 0.1 mm for ISA and 0.7 +/- 0.1 mm for TLA (P < 0.05). Access cavity preparation has a significant effect on apical centring ability. ISA is beneficial to maintaining apical configuration. PMID- 28084664 TI - Rome foundation Asian working team report: Real world treatment experience of Asian patients with functional bowel disorders. AB - BACKGROUND AND AIM: Information on real world treatment experiences of patients with functional bowel disorders is lacking from Asia. This study aimed to describe the medication exposure and treatment satisfaction of patients presenting to gastroenterology clinics across a sampling of Asian cities. METHODS: From March 2011 to October 2013, adult patients presenting to hospital based gastroenterology outpatient clinics in 11 cities across Asia, who fulfilled screening criteria for any functional gastrointestinal disorder, were asked to complete a validated culturally adapted translation of the Rome III diagnostic questionnaire, a checklist of medications received in the preceding 3 months and questions on treatment satisfaction. RESULTS: A total of 1376 patients (female 755, male 621, 41.36 +/- 13.25 years) comprising irritable bowel (621, 45.1%), unspecified functional bowel disorder (372, 27.8%), functional constipation (202, 14.7%), functional bloating (144, 10.5%), and functional diarrhea (56, 4.1%) completed the study. Of 1105 patients with a previous consultation, 509 (46.1%) were dissatisfied with their treatment, with ineffective treatment being the commonest reason. Satisfaction with previous consultation was lowest by diagnosis for functional constipation (29.2%), and the most bothersome symptom was straining (37.5%). Of 1046 patients who had taken medications for their gastrointestinal symptoms in the last 3 months, 793 (75.8%) had received two or more drugs. For irritable bowel syndrome patients, treatment with proton pump inhibitors and antispasmodics was recorded in 57% and 31%, with overlapping epigastric pain and heartburn predicting proton pump inhibitors use. CONCLUSIONS: More attention should be given to treatment gaps with regards to possible under treatment with antispasmodics in irritable bowel syndrome and to critically evaluating the efficacy of constipation management. PMID- 28084665 TI - Novel tRNA function in amino acid sensing of yeast Tor complex1. AB - TOR complex1 (TORC1), a master regulator of cell growth, is regulated by amino acids. Amino acids are fundamental nutrients, and 20 species of amino acids building proteins are not interchangeable with each other. Therefore, TORC1 should sense each amino acid individually. Mammalian mTORC1 is controlled by Rag GTPases and their regulators. However, Rag factors are dispensable for amino acid sensing by TORC1 in the budding yeast, suggesting an alternative mechanism of TORC1 regulation. Here, genetic investigation discovered the involvement of (aminoacyl-)tRNA ((aa-)tRNA) in TORC1 regulation. Biochemical TORC1 assay also showed that tRNA directly inhibits TORC1 kinase activity. Reducing cellular tRNA molecule desensitizes TORC1 inactivation by nitrogen starvation in vivo. Based on these results, I propose a model of the TORC1 regulatory mechanism in which free tRNA released from protein synthesis under amino acid starvation inhibits TORC1 activity. Therefore, TORC1 uses tRNA-mediated mechanism and Rag factors in parallel to sense intracellular amino acids. PMID- 28084666 TI - Comparison of intraoperative procedures for isolation of clinical grade stromal vascular fraction for regenerative purposes: a systematic review. AB - Intraoperative application of the stromal vascular fraction (SVF) of adipose tissue requires a fast and efficient isolation procedure of adipose tissue. This review was performed to systematically assess and compare procedures currently used for the intraoperative isolation of cellular SVF (cSVF) and tissue SVF (tSVF) that still contain the extracellular matrix. Pubmed, EMBASE and the Cochrane central register of controlled trials databases were searched for studies that compare procedures for intraoperative isolation of SVF (searched 28 September 2016). Outcomes of interest were cell yield, viability of cells, composition of SVF, duration, cost and procedure characteristics. Procedures were subdivided into procedures resulting in a cSVF or tSVF. Thirteen out of 3038 studies, evaluating 18 intraoperative isolation procedures, were considered eligible. In general, cSVF and tSVF intraoperative isolation procedures had similar cell yield, cell viability and SVF composition compared to a nonintraoperative (i.e. culture laboratory-based collagenase protocol) control group within the same studies. The majority of intraoperative isolation procedures are less time consuming than nonintraoperative control groups, however. Intraoperative isolation procedures are less time-consuming than nonintraoperative control groups with similar cell yield, viability of cells and composition of SVF, and therefore more suitable for use in the clinic. Nevertheless, none of the intraoperative isolation procedures could be designated as the preferred procedure to isolate SVF. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28084667 TI - Task-Sharing Approaches to Improve Mental Health Care in Rural and Other Low Resource Settings: A Systematic Review. AB - PURPOSE: Rural areas persistently face a shortage of mental health specialists. Task shifting, or task sharing, is an approach in global mental health that may help address unmet mental health needs in rural and other low-resource areas. This review focuses on task-shifting approaches and highlights future directions for research in this area. METHODS: Systematic review on task sharing of mental health care in rural areas of high-income countries included: (1) PubMed, (2) gray literature for innovations not yet published in peer-reviewed journals, and (3) outreach to experts for additional articles. We included English language articles published before August 31, 2013, on interventions sharing mental health care tasks across a team in rural settings. We excluded literature: (1) from low- and middle-income countries, (2) involving direct transfer of care to another provider, and (3) describing clinical guidelines and shared decision-making tools. FINDINGS: The review identified approaches to task sharing focused mainly on community health workers and primary care providers. Technology was identified as a way to leverage mental health specialists to support care across settings both within primary care and out in the community. The review also highlighted how provider education, supervision, and partnerships with local communities can support task sharing. Challenges, such as confidentiality, are often not addressed in the literature. CONCLUSIONS: Approaches to task sharing may improve reach and effectiveness of mental health care in rural and other low-resource settings, though important questions remain. We recommend promising research directions to address these questions. PMID- 28084668 TI - Humeral head circle-fit method greatly increases reliability and accuracy when measuring anterior-posterior radiographs of the proximal humerus. AB - Measurements made on routine A-P radiographs can predict strength/quality of the proximal humerus, as shown in terms of two easy-to-measure parameters: Cortical index (CI) and mean-combined cortical thickness (MCCT). Because of high variability inherent when using established methods to measure these parameters, we describe a new orientation system. Using digitized radiographs of 33 adult proximal humeri, five observers measured anatomical reference locations in accordance with: (i) Tingart et al. (2003) method, (ii) Mather et al. (2013) method, and (iii) our new humeral head Circle-Fit method (CFM). The Tingart and Mather methods measure CI and MCCT with respect to upper and lower edges of 20 mm tall rectangles fit to a proximal diaphyseal location where endosteal (Tingart) or periosteal (Mather) cortical margins become parallel. But high intra- and inter-observer variability occurs when placing the rectangles because of uncertainty in identifying cortical parallelism. With the CFM an adjustable circle is fit to the humeral head articular surface, which reliably and easily establishes a proximal metaphyseal landmark (M1) at the surgical neck. Distal locations are then designated at successive 10 mm increments below M1, including a second metaphyseal landmark (M2) followed by diaphyseal (D) locations (D1, D2 ?D6). D1 corresponds most closely to the proximal edges of the rectangles used in the other methods. Results showed minimal inter-observer variations (mean error, 1.5 +/- 1.1 mm) when the CFM is used to establish diaphyseal locations for making CI and MCCT measurements when compared to each of the other methods (mean error range, 10.7 +/- 5.9 to 13.3 +/- 6.7 mm) (p < 0.001). (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2313-2322, 2017. PMID- 28084669 TI - Polymorphisms in T helper 1 proinflammatory cytokine genes and the risk of psoriasis in a South Indian Tamil cohort. PMID- 28084670 TI - Biological effects of new-generation dialkyl phosphinate flame retardants and their hydrolysates in BALB/C mice. AB - Aluminum methylcyclohexylphosphinate (AMHP), calcium methylcyclohexylphosphinate (CMHP), aluminum diethylphosphinate (ADEP), and aluminum methylethylphosphinate (AMEP) are organic dialkyl phosphinates (DPs) and emerging phosphorus-based flame retardants. The broad-spectrum DPs flame retardants occupy high-end industrial markets, but their ecologic risk has been reported rarely. By exposing male BALB/c mice to DPs and dialkyl phosphinic acids, we studied the toxic effects of these chemicals, and measured AMHP and methylcyclohexylphosphinic acid (MHPA) in blood and feces. We found that DPs and their main hydrolysates had mild toxicity in BALB/c mice. Exposure to 10 and 50 mg/kg/d of AMEP and ADEP caused mild hepatotoxicity in mice. Toxicity of CMHP was in the liver and kidneys. Toxicity of AMHP and its hydrolysate MHPA was low and affected the liver. These data suggest that AMHP has lower toxicity than the other DPs that we tested. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1578-1586, 2017. PMID- 28084671 TI - Functional mutations in spike glycoprotein of Zaire ebolavirus associated with an increase in infection efficiency. AB - Ebola virus (EBOV) is extremely virulent, and its glycoprotein is necessary for viral entry. EBOV may adapt to its new host humans during outbreaks by acquiring mutations especially in glycoprotein, which allows EBOV to spread more efficiently. To identify these evolutionary selected mutations and examine their effects on viral infectivity, we used experimental-phylogenetic-structural interdisciplinary approaches. In evolutionary analysis of all available Zaire ebolavirus glycoprotein sequences, we detected two codon sites under positive selection, which are located near/within the region critical for the host-viral membrane fusion, namely alanine-to-valine and threonine-to-isoleucine mutations at 82 (A82V) and 544 (T544I), respectively. The fine-scale transmission dynamics of EBOV Makona variants that caused the 2014-2015 outbreak showed that A82V mutant was fixed in the population, whereas T544I was not. Furthermore, pseudotype assays for the Makona glycoprotein showed that the A82V mutation caused a small increase in viral infectivity compared with the T544I mutation. These findings suggest that mutation fixation in EBOV glycoprotein may be associated with their increased infectivity levels; the mutant with a moderate increase in infectivity will fix. Our findings showed that a driving force for Ebola virus evolution via glycoprotein may be a balance between costs and benefits of its virulence. PMID- 28084672 TI - Suppressing Self-Discharge and Shuttle Effect of Lithium-Sulfur Batteries with V2 O5 -Decorated Carbon Nanofiber Interlayer. AB - V2 O5 decorated carbon nanofibers (CNFs) are prepared and used as a multifunctional interlayer for a lithium-sulfur (Li-S) battery. V2 O5 anchored on CNFs can not only suppress the shuttle effect of polysulfide by the strong adsorption and redox reaction, but also work as a high-potential dam to restrain the self-discharge behavior in the battery. As a result, Li-S batteries with a high capacity and long cycling life can be stored and rested for a long time without obvious capacity fading. PMID- 28084673 TI - Applying the One Health Concept to Mycobacterial Research - Overcoming Parochialism. AB - Mycobacterial infections remain a public health problem. Historically important, globally ubiquitous and with a wide host range, we are still struggling to control mycobacterial infections in humans and animals. While previous reviews have focused on individual mycobacterial infections in either humans or animals, a comprehensive review of the zoonotic aspect of mycobacteria in the context of the One Health initiative is lacking. With the purpose of providing a concise and comprehensive resource, we have collated literature to address the zoonotic potential of different mycobacterial species and elaborate on the necessity for an inter-sectorial approach to attain a new vision to combat mycobacterial infections. PMID- 28084674 TI - Sodium chlorate, a major water disinfection byproduct, alters brush border membrane enzymes, carbohydrate metabolism and impairs antioxidant system of Wistar rat intestine. AB - Sodium chlorate (NaClO3 ) is a widely used nonselective herbicide. It is also generated as a by-product during disinfection of drinking water by chlorine dioxide. The purpose of this study was to evaluate the effect of NaClO3 on rat intestine. Adult male rats were randomly divided into five groups: control and remaining four groups were administered orally different doses of NaClO3 and sacrificed 24 h after the treatment. The administration of NaClO3 produced acute oxidative stress in the intestine, which manifested in the form of markedly enhanced malondialdehyde levels and carbonyl content and lowered total sulfhydryl groups and glutathione levels. The activities of several brush border membrane (BBM) enzymes were greatly reduced as compared to control. There were alterations in the activities of various enzymes of carbohydrate metabolism and those involved in maintaining the antioxidant defense system. Histological studies support the biochemical results showing NaClO3 dose-dependent increase in tissue damage. Thus, the present study shows that oral administration of NaClO3 decreases the activities of BBM enzymes, induces oxidative stress, alters metabolic pathways, and impairs the antioxidant system of rat intestine. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1607-1616, 2017. PMID- 28084675 TI - Transient juvenile myelomonocytic leukemia in the setting of PTPN11 mutation and Noonan syndrome with secondary development of monosomy 7. AB - Juvenile myelomonocytic leukemia (JMML) is a rare childhood neoplasm with poor prognosis except in the setting of Noonan syndrome, where prognosis is generally favorable. We present the case of a child with JMML in the setting of germline PTPN11 mutation and Noonan syndrome with suspected secondary development of monosomy 7 in the bone marrow. Diagnosed shortly after birth, she has been managed with active surveillance alone. Myeloblast percentages initially fluctuated; however, bone marrow biopsy at 4 years of age showed spontaneous remission despite persistence of the monosomy 7 clone, supporting a cautious approach in similar cases. PMID- 28084676 TI - Synthesis and Cytotoxic Activity of Triterpenoid Thiazoles Derived from Allobetulin, Methyl Betulonate, Methyl Oleanonate, and Oleanonic Acid. AB - A total of 41 new triterpenoids were prepared from allobetulone, methyl betulonate, methyl oleanonate, and oleanonic acid to study their influence on cancer cells. Each 3-oxotriterpene was brominated at C2 and substituted with thiocyanate; subsequent cyclization with the appropriate ammonium salts gave N substituted thiazoles. All compounds were tested for their in vitro cytotoxic activity on eight cancer cell lines and two non-cancer fibroblasts. 2 Bromoallobetulone (2 b) methyl 2-bromobetulonate (3 b), 2-bromooleanonic acid (5 b), and 2-thiocyanooleanonic acid (5 c) were best, with IC50 values less than 10 MUm against CCRF-CEM cells (e.g., 3 b: IC50 =2.9 MUm) as well as 2' (diethylamino)olean-12(13)-eno[2,3-d]thiazole-28-oic acid (5 f, IC50 =9.7 MUm) and 2'-(N-methylpiperazino)olean-12(13)-eno[2,3-d]thiazole-28-oic acid (5 k, IC50 =11.4 MUm). Compound 5 c leads to the accumulation of cells in the G2 phase of the cell cycle and inhibits RNA and DNA synthesis significantly at 1*IC50 . The G2 /M cell-cycle arrest probably corresponds to the inhibition of DNA/RNA synthesis, similar to the mechanism of action of actinomycin D. Compound 5 c is new, active, and nontoxic; it is therefore the most promising compound in this series for future drug development. Methyl 2-bromobetulonate (3 b) and methyl 2 thiocyanometulonate (3 c) were found to inhibit nucleic acid synthesis only at 5*IC50 . We assume that in 3 b and 3 c (unlike in 5 c), DNA/RNA inhibition is a nonspecific event, and an unknown primary cytotoxic target is activated at 1*IC50 or lower concentration. PMID- 28084677 TI - Location, location, location: Does it matter for childhood cancer survivors considering pediatric vs. adult care settings? PMID- 28084678 TI - Lichen myxedematosus: a case series focusing on clinical features, disease associations, and management. PMID- 28084679 TI - Impacts of donor-specific anti-HLA antibodies and antibody-mediated rejection on outcomes after intestinal transplantation in children. AB - AMR is a risk factor for graft failure after SBTx. We studied impact of DSAs and AMR in 22 children transplanted between 2008 and 2012 (11 isolated SBTx, 10 liver inclusive Tx, and one modified multivisceral Tx). Three patients never developed DSA, but DSAs were found in seven in the pre-Tx period and de novo post-Tx in 19 children. Pathology revealed cellular rejection (15/19), with vascular changes and C4d+. Patients were treated with IV immunoglobulins, plasmapheresis, and steroids. Rescue therapy included antithymocyte globulins, rituximab, eculizumab, and bortezomib. Pathology and graft function normalized in 13 patients, graft loss occurred in two, and death in seven. At the end of the follow-up, 15 children were alive (68%), 13 with functioning graft (59%). Prognosis factors for poor outcome after Tx were the presence of symptoms at AMR suspicion (P +.033). DSAs were often found following SBTx, mostly de novo. Resistant ACR or severe AMR is still difficult to differentiate, with a high need for immunosuppression in both. DSAs may precede development of severe disease and pathology features on the graft: relationship and correlation need to be better investigated with larger groups before and after Tx. PMID- 28084680 TI - Rapid and fulminant leptomeningeal spread following radiotherapy in diffuse intrinsic pontine glioma. AB - A 4-year-old male presented with rapid-onset cranial nerve palsy and ataxia. Brain magnetic resonance imaging (MRI) revealed a pontine mass lesion with discordant conventional and advanced imaging. A stereotactic core biopsy revealed glioblastoma with immunostaining suggestive of histone H3K27M and TP53 mutation, consistent with diffuse intrinsic pontine glioma. MRI 3 months after radiotherapy revealed extensive new leptomeningeal metastatic disease involving both the supra and infratentorial brain, as well as the imaged portion of the spine. Tissue procured at the time of needle biopsy has undergone striking in vivo expansion as an orthotopic xenograft. PMID- 28084681 TI - Diabetes coaching for individuals with type 2 diabetes: A state-of-the-science review and rationale for a coaching model. AB - Diabetes coaching is emerging as an important role in self-management and care. The conceptualization of coaching, and how to implement and evaluate coaching has not been articulated in the literature. The aim of the study was to review the literature to: (i) identify the components of coaching using a validated framework, including the description of the role of technology; (ii) describe the implementation and evaluation measures for diabetes coaching; and (iii) propose a diabetes coaching model for future implementation. The EMBASE, MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsychINFO and Cochrane Central Register of Controlled Trials databases were searched from inception to January 2015. Two evaluators independently screened and extracted data from eligible studies for descriptions of coaching. Eight trials met the selection criteria, with no consistency in the core components of coaching. However, elements noted across all studies included goal setting, diabetes knowledge acquisition, individualized care, and frequent follow-up. Only two studies leveraged technology for coaching communication purposes. Diabetes coaching is an intervention that can support the ongoing and complex needs of patients; however, implementation and evaluation strategies are limited in the literature. A diabetes coaching model is presented, derived from components identified throughout the literature with direction for implementation and evaluation approaches, and optimal integration into the healthcare system. PMID- 28084682 TI - Exogenous transforming growth factor-beta1 enhances smooth muscle differentiation in embryonic mouse jejunal explants. AB - An ex vivo experimental strategy that replicates in vivo intestinal development would in theory provide an accessible setting with which to study normal and dysmorphic gut biology. The current authors recently described a system in which mouse embryonic jejunal segments were explanted onto semipermeable platforms and fed with chemically defined serum-free media. Over 3 days in organ culture, explants formed villi and they began to undergo spontaneous peristalsis. As defined in the current study, the wall of the explanted gut failed to form a robust longitudinal smooth muscle (SM) layer as it would do in vivo over the same time period. Given the role of transforming growth factor beta1 (TGFbeta1) in SM differentiation in other organs, it was hypothesized that exogenous TGFbeta1 would enhance SM differentiation in these explants. In vivo, TGFbeta receptors I and II were both detected in embryonic longitudinal jejunal SM cells and, in organ culture, exogenous TGFbeta1 induced robust differentiation of longitudinal SM. Microarray profiling showed that TGFbeta1 increased SM specific transcripts in a dose dependent manner. TGFbeta1 proteins were detected in amniotic fluid at a time when the intestine was physiologically herniated. By analogy with the requirement for exogenous TGFbeta1 for SM differentiation in organ culture, the TGFbeta1 protein that was demonstrated to be present in the amniotic fluid may enhance intestinal development when it is physiologically herniated in early gestation. Future studies of embryonic intestinal cultures should include TGFbeta1 in the defined media to produce a more faithful model of in vivo muscle differentiation. Copyright (c) 2017 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons, Ltd. PMID- 28084684 TI - Secretome analysis to elucidate metalloprotease-dependent ectodomain shedding of glycoproteins during neuronal differentiation. AB - Many membrane proteins are subjected to limited proteolyses at their juxtamembrane regions, processes referred to as ectodomain shedding. Shedding ectodomains of membrane-bound ligands results in activation of downstream signaling pathways, whereas shedding those of cell adhesion molecules causes loss of cell-cell contacts. Secreted proteomics (secretomics) using high-resolution mass spectrometry would be strong tools for both comprehensive identification and quantitative measurement of membrane proteins that undergo ectodomain shedding. In this study, to elucidate the ectodomain shedding events that occur during neuronal differentiation, we establish a strategy for quantitative secretomics of glycoproteins released from differentiating neuroblastoma cells into culture medium with or without GM6001, a broad-spectrum metalloprotease inhibitor. Considering that most of transmembrane and secreted proteins are N-glycosylated, we include a process of N-glycosylated peptides enrichment as well as isotope tagging in our secretomics workflow. Our results show that differentiating N1E 115 neurons secrete numerous glycosylated polypeptides in metalloprotease dependent manners. They are derived from cell adhesion molecules such as NCAM1, CADM1, L1CAM, various transporters and receptor proteins. These results show the landscape of ectodomain shedding and other secretory events in differentiating neurons and/or during axon elongation, which should help elucidate the mechanism of neurogenesis and the pathogenesis of neurological disorders. PMID- 28084683 TI - Examination of high-antibiotic users in a multi-institutional cohort of chronic rhinosinusitis patients. AB - BACKGROUND: In addition to known concerns regarding antibiotic overuse, recent research indicates that excessive antibiotic use is associated with poorer long term health. Given that rhinosinusitis is the leading condition accounting for antibiotic prescriptions in the ambulatory setting, we aimed to evaluate characteristics associated with greater antibiotic use in chronic rhinosinusitis (CRS). METHODS: Adult CRS patients enrolled in a prospective, multi institutional, observational cohort study evaluating treatment outcomes were included in this analysis. Study participants were asked to report the number of days out of the previous 90 days that systemic antibiotics were taken for sinus disease. Patient demographics, disease characteristics, and measures of disease severity were evaluated. RESULTS: A total of 561 patients from 4 institutions were included in the analysis, with mean antibiotic use of 17.4 +/- 22.4 out of the prior 90 days. No differences between antibiotic-use groups were found for objective measures of disease severity (computed tomography [CT], endoscopy, Brief Smell Identification Test [BSIT] scores), however, increased patient reported symptom burden (22-item Sino-Nasal Outcome Test [SNOT-22], Rhinosinusitis Disability Index [RSDI]) was associated with more antibiotic use. Patients reporting the most antibiotic use were older (p = 0.004) but no ethnic or gender differences were seen. Comorbid diagnoses of allergy, asthma, diabetes, depression, or fibromyalgia were not associated with increased antibiotic use. In accordance with literature recommendations, CRS with nasal polyps (CRSwNP) patients were less likely to have used antibiotics. Endoscopic sinus surgery (ESS) significantly decreased antibiotic use. CONCLUSION: Variability in antibiotic use in CRS appears to be driven by symptom burden, independent of objective measures of disease severity, patient demographics, and presence of comorbid disease. Clear guidelines are essential to define appropriate antibiotic use in CRS. PMID- 28084685 TI - Fungal spores and fruiting bodies in cervicovaginal smears: Contaminant or infection? AB - BACKGROUND: Contaminants from various sources are curious findings in cervicovaginal smears and pose diagnostic challenges especially when they need to be distinguished from pathogens. Candidiasis is the most frequently encountered fungal infection but fungal contaminants are relatively common. Detection of fruiting bodies and spores of Aspergillus species is uncommon and may represent either a true infection or contamination. This study was undertaken to evaluate the presence of fungal spores, hyphae, and fruiting bodies in routine cervical smears and distinguish a true infection from contamination. METHODS: Conventional cervicovaginal smears collected from women were incidentally found to have fungal fruiting bodies and spores. All smears received in the Cytology Department during that one month were reviewed for the presence of these elements. RESULTS: Five out of the 120 smears, received from the outpatient department over a period of three consecutive days, showed evidence of fungal organisms. The patients were 28 59 years of age. While four patients were asymptomatic, only one patient complained of minimal vaginal discharge. All were immunocompetent. Cervicovaginal smears were prepared as part of routine screening. Fungal fruiting bodies, branching hyphae and numerous spores were seen in otherwise normal smears. Culture of scrapings from the surface of the wooden spatulas grew Aspergillus niger. CONCLUSIONS: Contamination of Pap smears by fungus must be distinguished from true infection, the latter being supported by positive clinical findings and the presence of significant inflammation in the smears. Literature review was done to see the range of contaminants detected in Pap smears. Diagn. Cytopathol. 2017;45:191-194. (c) 2016 Wiley Periodicals, Inc. PMID- 28084686 TI - Relationship between gustatory function and average number of taste buds per fungiform papilla measured by confocal laser scanning microscopy in humans. AB - The aim of this study was to elucidate the relationship between the gustatory function and average number of taste buds per fungiform papilla (FP) in humans. Systemically healthy volunteers (n = 211), pre-operative patients with chronic otitis media (n = 79), and postoperative patients, with or without a chorda tympani nerve (CTN) severed during middle ear surgery (n = 63), were included. Confocal laser scanning microscopy was employed to observe fungiform taste buds because it allows many FP to be observed non-invasively in a short period of time. Taste buds in an average of 10 FP in the midlateral region of the tongue were counted. In total, 3,849 FP were observed in 353 subjects. The gustatory function was measured by electrogustometry (EGM). An inverse relationship was found between the gustatory function and average number of fungiform taste buds per papilla. The healthy volunteers showed a lower EGM threshold (better gustatory function) and had more taste buds than did the patients with otitis media, and the patients with otitis media showed a lower EGM threshold and had more taste buds than did postoperative patients, reflecting the severity of damage to the CTN. It was concluded that the confocal laser scanning microscope is a very useful tool for using to observe a large number of taste buds non invasively. PMID- 28084689 TI - Corrigendum. PMID- 28084688 TI - Enamel and dental anomalies in latent-transforming growth factor beta-binding protein 3 mutant mice. AB - Latent-transforming growth factor beta-binding protein 3 (LTBP-3) is important for craniofacial morphogenesis and hard tissue mineralization, as it is essential for activation of transforming growth factor-beta (TGF-beta). To investigate the role of LTBP-3 in tooth formation we performed micro-computed tomography (micro CT), histology, and scanning electron microscopy analyses of adult Ltbp3-/- mice. The Ltbp3-/- mutants presented with unique craniofacial malformations and reductions in enamel formation that began at the matrix formation stage. Organization of maturation-stage ameloblasts was severely disrupted. The lateral side of the incisor was affected most. Reduced enamel mineralization, modification of the enamel prism pattern, and enamel nodules were observed throughout the incisors, as revealed by scanning electron microscopy. Molar roots had internal irregular bulbous-like formations. The cementum thickness was reduced, and microscopic dentinal tubules showed minor nanostructural changes. Thus, LTBP-3 is required for ameloblast differentiation and for the formation of decussating enamel prisms, to prevent enamel nodule formation, and for proper root morphogenesis. Also, and consistent with the role of TGF-beta signaling during mineralization, almost all craniofacial bone components were affected in Ltbp3-/- mice, especially those involving the upper jaw and snout. This mouse model demonstrates phenotypic overlap with Verloes Bourguignon syndrome, also caused by mutation of LTBP3, which is hallmarked by craniofacial anomalies and amelogenesis imperfecta phenotypes. PMID- 28084690 TI - Cytologic features of pleomorphic xanthoastrocytoma, WHO grade II. A comparative study with glioblastoma. AB - Pleomorphic xanthoastrocytoma (PXA) is a WHO grade II astrocytic tumor of children and young adults. It is characterized by pleomorphic, atypical astrocytes. Atypia is so remarkable, that PXA can be easily misdiagnosed as malignant glioma. If confused with a high-grade glioma the neurosurgeon may not proceed with a complete resection. Therefore, a specific recognition during intraoperative consultation is particularly important. We describe four cases of PXA evaluated during intraoperative procedures. Findings were compared with those of 22 glioblastomas. PXA smears were moderately cellular and showed a variable population of pleomorphic cells and fibrillary fragments with vessels. Tumoral cells were of intermediate size with a less frequent population of large, atypical cells. Some showed bi/trinucleation with bizarre nuclei. In two cases, tumoral cells with microvacuolization resembling xanthic astrocytes were present. No necrosis, mitotic activity, phagocytic macrophages or apoptotic fragments were seen. Smears from glioblastoma were more cellular than those of PXA with numerous neoplastic cells, branching vessels and myxoid substance. Cellular atypia was evident and mitoses were seen in all cases. Most cases showed an abundant population of accompanying macrophages and cellular debris. Differences between PXA and glioblastoma were related to cell turnover rather than cytomorphologic features. Glioblastoma shows features of high cellular replication showing a dirty background with necrosis and phagocytic macrophages as well as mitotic figures and apoptosis. On the other hand, smears from PXA have a clean background with no necrosis, cellular fragments or relevant mitotic activity. Diagn. Cytopathol. 2017;45:339-344. (c) 2016 Wiley Periodicals, Inc. PMID- 28084691 TI - Autoimmune progesterone dermatitis mimicking fixed drug eruption. PMID- 28084692 TI - Near-Infrared Fluorescent Ag2 Se-Cetuximab Nanoprobes for Targeted Imaging and Therapy of Cancer. AB - Theranostic nanoprobes integrated with diagnostic imaging and therapy capabilities have shown great potential for highly effective tumor therapy by realizing imaging-guided drug delivery and tumor treatment. Developing novel high performance nanoprobes is an important basis for tumor theranostic application. Here, near-infrared (NIR) fluorescent and low-biotoxicity Ag2 Se quantum dots (QDs) have been coupled with cetuximab, a clinical antiepidermal growth factor receptor antibody drug for tumor therapy, via a facile bioconjugation strategy to prepare multifunctional Ag2 Se-cetuximab nanoprobes. Compared with the Ag2 Se QDs alone, the Ag2 Se-cetuximab nanoprobes display faster and more enrichment at the site of orthotopic tongue cancer, and thus present better NIR fluorescence contrast between the tumor and the surrounding regions. At 24 h postinjection, the NIR fluorescence of Ag2 Se-cetuximab nanoprobes at the tumor site is still easily detectable, whereas no fluorescence is observed for the Ag2 Se QDs. Moreover, the Ag2 Se-cetuximab nanoprobes have also significantly inhibited the tumor growth and improved the survival rate of orthotopic tongue cancer-bearing nude mice from 0% to 57.1%. Taken together, the constructed multifunctional Ag2 Se-cetuximab nanoprobes have achieved combined targeted imaging and therapy of orthotopic tongue cancer, which may greatly contribute to the development of nanotheranostics. PMID- 28084693 TI - Multifunctional Conjugated Polymer Nanoparticles for Image-Guided Photodynamic and Photothermal Therapy. AB - A multifunctional theranostic platform based on conjugated polymer nanoparticles (CPNs) with tumor targeting, fluorescence detection, photodynamic therapy (PDT), and photothermal therapy (PTT) is developed for effective cancer imaging and therapy. Two conjugated polymers, poly[9,9-bis(2-(2-(2-methoxyethoxy)ethoxy) ethyl)fluorenyldivinylene]-alt-4,7-(2,1,3-benzothiadiazole) with bright red emission and photosensitizing ability and poly[(4,4,9,9-tetrakis(4 (octyloxy)phenyl)-4,9-dihydro-s-indacenol-dithiophene-2,7-diyl)-alt-co-4,9 bis(thiophen-2-yl)-6,7-bis(4-(hexyloxy)phenyl)-thiadiazolo-quinoxaline] with strong near-infrared absorption and excellent photothermal conversion ability are co-loaded into one single CPN via encapsulation approach using lipid-polyethylene glycol as the matrix. The obtained co-loaded CPNs show sizes of around 30 nm with a high singlet oxygen quantum yield of 60.4% and an effective photothermal conversion efficiency of 47.6%. The CPN surface is further decorated with anti HER2 affibody, which bestows the resultant anti-HER2-CPNs superior selectivity toward tumor cells with HER2 overexpression both in vitro and in vivo. Under light irradiation, the PDT and PTT show synergistic therapeutic efficacy, which provides new opportunities for the development of multifunctional biocompatible organic materials in cancer therapy. PMID- 28084694 TI - The Formation of Calcified Nanospherites during Micropetrosis Represents a Unique Mineralization Mechanism in Aged Human Bone. AB - Osteocytes-the central regulators of bone remodeling-are enclosed in a network of microcavities (lacunae) and nanocanals (canaliculi) pervading the mineralized bone. In a hitherto obscure process related to aging and disease, local plugs in the lacuno-canalicular network disrupt cellular communication and impede bone homeostasis. By utilizing a suite of high-resolution imaging and physics-based techniques, it is shown here that the local plugs develop by accumulation and fusion of calcified nanospherites in lacunae and canaliculi (micropetrosis). Two distinctive nanospherites phenotypes are found to originate from different osteocytic elements. A substantial deviation in the spherites' composition in comparison to mineralized bone further suggests a mineralization process unlike regular bone mineralization. Clearly, mineralization of osteocyte lacunae qualifies as a strong marker for degrading bone material quality in skeletal aging. The understanding of micropetrosis may guide future therapeutics toward preserving osteocyte viability to maintain mechanical competence and fracture resistance of bone in elderly individuals. PMID- 28084697 TI - Erratum. PMID- 28084695 TI - In Vitro Gene Delivery with Large Porous Silicon Nanoparticles Fabricated Using Cost-Effective, Metal-Assisted Chemical Etching. AB - The cytocompatibility, cell membrane affinity, and plasmid DNA delivery from surface oxidized, metal-assisted stain-etched mesoporous silicon nanoscale particles (pSiNPs) to human embryonic kidney (HEK293) cells is demonstrated, suggesting the possibility of using such material for targeted transfection and drug delivery. PMID- 28084698 TI - Mechanosensation across borders: fibroblasts inside a macroporous scaffold sense and respond to the mechanical environment beyond the scaffold walls. AB - In tissue defects, cells face distinct mechanical boundary conditions, but how this influences early stages of tissue regeneration remains largely unknown. Biomaterials are used to fill defects but also to provide specific mechanical or geometrical signals. However, they might at the same time shield mechanical information from surrounding tissues that is relevant for tissue functionalisation. This study investigated how fibroblasts in a soft macroporous biomaterial scaffold respond to distinct mechanical environments while they form microtissues. Different boundary stiffnesses counteracting scaffold contraction were provided via a newly developed in vitro setup. Online monitoring over 14 days revealed 3.0 times lower microtissue contraction but 1.6 times higher contraction force for high vs. low stiffness. This difference was significant already after 48 h, a very early stage of microtissue growth. The microtissue's mechanical and geometrical adaptation indicated a collective cellular behaviour and mechanical communication across scaffold pore walls. Surprisingly, the stiffness of the environment influenced cell behaviour even inside macroporous scaffolds where direct cell-cell contacts are hindered. Mechanical communication between cells via traction forces is essential for tissue adaptation to the environment and should not be blocked by rigid biomaterials. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28084700 TI - The Cholesterol Dilemma: Treating the Risk or Treating to LDL-C Goal? PMID- 28084703 TI - Giant Cell Arteritis: Biopsy After Corticosteroid Initiation. PMID- 28084704 TI - Hyperlipidemia: Drugs for Cardiovascular Risk Reduction in Adults. AB - Guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) and the U.K. National Institute for Health and Care Excellence (NICE) indicate that lipid-lowering drugs have benefit for primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) events. The evidence is strongest for statins. ACC/AHA, NICE, and U.S. Preventive Services Task Force (USPSTF) guidelines recommend statin therapy based on patients' risk of an ASCVD event, rather than treating to specific lipid levels. For patients with no previous ASCVD event, risk calculators should be used to determine the 10-year risk of ASCVD. The ACC/AHA guideline recommends starting moderate- to high intensity statins if the risk is 7.5% or greater, whereas the NICE and USPSTF guidelines recommend statins if the risk is 10% or greater. Patients with known ASCVD should receive high-intensity statins unless they fall into special categories (e.g., older age) or do not tolerate high-intensity statins, in which case moderate-intensity statins are appropriate. Liver transaminase levels should be checked before starting statins; guidelines vary on if and when to recheck them in the absence of symptoms. Lipid levels should be rechecked one to three months after starting statins, although guidelines differ on subsequent checks. Other lipid-lowering drugs (e.g., bile acid sequestrants, ezetimibe) can be considered if patients do not tolerate statins. Niacin should not be used. Some evidence supports adding ezetimibe to statin therapy in patients with acute coronary syndrome or chronic kidney disease. The role of proprotein convertase subtilisin/kexin type 9 inhibitors is unclear, but initial studies suggest a decrease in the rate of acute ASCVD events in patients with hypercholesterolemia. PMID- 28084706 TI - Acute Otitis Media in Children. PMID- 28084707 TI - Taking Care of Disadvantaged Patients. PMID- 28084708 TI - Respiratory Syncytial Virus Bronchiolitis in Children. AB - Bronchiolitis is a common lower respiratory tract infection in infants and young children, and respiratory syncytial virus (RSV) is the most common cause of this infection. RSV is transmitted through contact with respiratory droplets either directly from an infected person or self-inoculation by contaminated secretions on surfaces. Patients with RSV bronchiolitis usually present with two to four days of upper respiratory tract symptoms such as fever, rhinorrhea, and congestion, followed by lower respiratory tract symptoms such as increasing cough, wheezing, and increased respiratory effort. In 2014, the American Academy of Pediatrics updated its clinical practice guideline for diagnosis and management of RSV bronchiolitis to minimize unnecessary diagnostic testing and interventions. Bronchiolitis remains a clinical diagnosis, and diagnostic testing is not routinely recommended. Treatment of RSV infection is mainly supportive, and modalities such as bronchodilators, epinephrine, corticosteroids, hypertonic saline, and antibiotics are generally not useful. Evidence supports using supplemental oxygen to maintain adequate oxygen saturation; however, continuous pulse oximetry is no longer required. The other mainstay of therapy is intravenous or nasogastric administration of fluids for infants who cannot maintain their hydration status with oral fluid intake. Educating parents on reducing the risk of infection is one of the most important things a physician can do to help prevent RSV infection, especially early in life. Children at risk of severe lower respiratory tract infection should receive immunoprophylaxis with palivizumab, a humanized monoclonal antibody, in up to five monthly doses. Prophylaxis guidelines are restricted to infants born before 29 weeks' gestation, infants with chronic lung disease of prematurity, and infants and children with hemodynamically significant heart disease. PMID- 28084710 TI - Neck Crepitus in a Runner. PMID- 28084711 TI - Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: Recommendation Statement. PMID- 28084712 TI - Umeclidinium (Incruse Ellipta) for COPD. PMID- 28084714 TI - Uterine Fibroids: Diagnosis and Treatment. AB - Uterine fibroids are common benign neoplasms, with a higher prevalence in older women and in those of African descent. Many are discovered incidentally on clinical examination or imaging in asymptomatic women. Fibroids can cause abnormal uterine bleeding, pelvic pressure, bowel dysfunction, urinary frequency and urgency, urinary retention, low back pain, constipation, and dyspareunia. Ultrasonography is the preferred initial imaging modality. Expectant management is recommended for asymptomatic patients because most fibroids decrease in size during menopause. Management should be tailored to the size and location of fibroids; the patient's age, symptoms, desire to maintain fertility, and access to treatment; and the experience of the physician. Medical therapy to reduce heavy menstrual bleeding includes hormonal contraceptives, tranexamic acid, and nonsteroidal anti-inflammatory drugs. Gonadotropin-releasing hormone agonists or selective progesterone receptor modulators are an option for patients who need symptom relief preoperatively or who are approaching menopause. Surgical treatment includes hysterectomy, myomectomy, uterine artery embolization, and magnetic resonance-guided focused ultrasound surgery. PMID- 28084715 TI - Respiratory Syncytial Virus Infection. PMID- 28084716 TI - Manipulation of Optoelectronic Properties and Band Structure Engineering of Ultrathin Te Nanowires by Chemical Adsorption. AB - Band structure engineering is a powerful technique both for the design of new semiconductor materials and for imparting new functionalities to existing ones. In this article, we present a novel and versatile technique to achieve this by surface adsorption on low dimensional systems. As a specific example, we demonstrate, through detailed experiments and ab initio simulations, the controlled modification of band structure in ultrathin Te nanowires due to NO2 adsorption. Measurements of the temperature dependence of resistivity of single ultrathin Te nanowire field-effect transistor (FET) devices exposed to increasing amounts of NO2 reveal a gradual transition from a semiconducting to a metallic state. Gradual quenching of vibrational Raman modes of Te with increasing concentration of NO2 supports the appearance of a metallic state in NO2 adsorbed Te. Ab initio simulations attribute these observations to the appearance of midgap states in NO2 adsorbed Te nanowires. Our results provide fundamental insights into the effects of ambient on the electronic structures of low dimensional materials and can be exploited for designing novel chemical sensors. PMID- 28084717 TI - High-Efficiency Robust Free-Standing Composited Phosphor Films with 2D and 3D Nanostructures for High-Power Remote White LEDs. AB - This study demonstrated that combined free-standing quasi-amorphous/micropattern (QA/MP) composited resin film-assisted phosphor films enhanced the mechanical robustness, luminous efficacy, color rendering index (CRI), and special R9 of high-power remote warm white light-emitting diodes (WLEDs). Introducing QA/MP nanostructures into phosphor film resulted in high efficiency of remote warm WLEDs with low phosphor thickness (approximately 25 MUm) and reduced the correlated color temperature (CCT) from cold white light (approximately 5565 K) to warm white light (approximately 3178 K). The QA/MP composited phosphor films (CPFs) used for high-power remote WLEDs enhanced the CRI and special R9 and reduced the CCT. These results were attributed to that QA resin film reflected the blue light and re-emitted the added red emission. CIR (84), a natural warm white CCT (3178 K), and an acceptable luminous efficacy (102.5 lm/W) were achieved from the QA/MP CPFs of high-power remote WLEDs during operation at an input power of 10 W (current of 700 mA). The bending strength of QA/MP CPFs at approximately 112 N was significantly enhanced by 40% compared with that of flat CPFs. The QA/MP CPFs applied to high-power remote WLEDs exhibited good thermal and optical stability. QA/MP CPFs were also conducted to a reliability analysis (RA), in which temperature of 85 degrees C and relative humidity of 85% were applied for 3288 h. Lumen maintenance was degraded by 8% during RA test because the transmittance of trimethylolopropane ethoxylate triacrylate resins was degraded under high temperature. Overall, we implemented a reliable and inexpensive technology that can potentially reduce phosphor thickness, address the out-bin problems of defective WLEDs, and fabricate flat-panel lighting source with good lighting quality. PMID- 28084718 TI - Preparation and Properties of Bamboo Fiber/Nano-hydroxyapatite/Poly(lactic-co glycolic) Composite Scaffold for Bone Tissue Engineering. AB - In this study, bamboo fiber was first designed to incorporate into nano hydroxyapatite/poly(lactic-co-glycolic) to obtain a new composite scaffold of bamboo fiber/nano-hydroxyapatite/poly(lactic-co- glycolic) (BF/n-HA/PLGA) by freeze-drying method. The effect of their components and some factors consisting of different freeze temperatures, concentrations, and pore-forming agents on the porous morphology, porosity, and compressive properties of the scaffold were investigated by scanning electron microscope, modified liquid displacement method, and electromechanical universal testing machine. The results indicated that the 5% BF/30% n-HA/PLGA composite scaffold, prepared with 5% (w/v) high concentration and frozen at -20 degrees C without pore-forming agent, had the best ideal porous structure and porosity as well as compressive properties, which far exceed those of n-HA/PLGA composite scaffold. In addition, the in vitro simulated body fluids soaking and cell culture experiment showed the addition of BF into the scaffold accelerated the BF/n-HA/PLGA composite scaffolds degradation and exhibited good cytocompatibility, including attachment and proliferation. All the results of the study show that BF has improved the properties of n-HA/PLGA composite scaffolds and BF/n-HA/PLGA might have a great potential for bone tissue engineering scaffold. PMID- 28084719 TI - QD-Biopolymer-TSPP Assembly as Efficient BiFRET Sensor for Ratiometric and Visual Detection of Zinc Ion. AB - In this work, we report a new type of quantum dot (QD)-based fluorescence resonance energy transfer (FRET) assembly and its utility for sensing Zn2+ in different media. The assembly on the QD scaffold is via first coating of poly(dA) homopolymer/double-stranded DNA, followed by loading of meso-tetra(4 sulfonatophenyl)porphine dihydrochloride (TSPP), both of which are electrostatic, offering the advantages of cost-efficiency and simplicity. More importantly, the biopolymer coating minimizes the interfacial thickness to be <=2 nm for QD-TSPP FRET, which results in improvements of up to 60-fold for single FRET efficiency and nearly 4-fold for total FRET efficiency of the QD-biopolymer-TSPP assemblies in comparison with silica-coating-based QD-TSPP assemblies. On the basis of Zn2+ chelation-induced spectral modulation, dual-emission QD-poly(dA)-TSPP assemblies are developed as a ratiometric Zn2+ sensor with increased sensitivity and specificity. The sensor either in solution or on a paper substrate displays continuous color changes from yellow to bright green toward Zn2+, exhibiting excellent visualization capability. By utilizing the competitive displacement of Zn2+, the sensor is also demonstrated to have good reversibility. Furthermore, the sensor is successfully used to visualize exogenous Zn2+ in living cells. Together the QD-biopolymer-TSPP assembly provides an inexpensive, sensitive, and reliable sensing platform not only for on-site analytical applications but also for high-resolution cellular imaging. PMID- 28084720 TI - Porous Ga-In Bimetallic Oxide Nanofibers with Controllable Structures for Ultrasensitive and Selective Detection of Formaldehyde. AB - The design of appropriate composite materials with unique surface structures is an important strategy to achieve ideal chemical gas sensing. In this paper, efficient and selective detection of formaldehyde vapor has been realized by a gas sensor based on porous GaxIn2-xO3 nanofibers assembled by small building blocks. By tuning the Ga/In atomic ratios in the materials, crystallite phase, nanostructure, and band gap of as-obtained GaxIn2-xO3 nanofibers can be rationally altered. This further offers a good opportunity to optimize the gas sensing performances. In particular, the sensor based on porous Ga0.6In1.4O3 nanofibers assembled by small nanoparticles (~4.6 nm) exhibits best sensing performances. Toward 100 ppm formaldehyde, its highest response (Ra/Rg = 52.4, at 150 degrees C) is ~4 times higher than that of the pure In2O3 (Ra/Rg = 13.0, at 200 degrees C). Meanwhile, it has superior ability to selectively detect formaldehyde against other interfering volatile organic compound gases. The significantly improved sensing performance makes the Ga0.6In1.4O3 sensor very promising for selective detection of formaldehyde. PMID- 28084721 TI - Dual Functionalities of Carbon Nanotube Films for Dendrite-Free and High Energy High Power Lithium-Sulfur Batteries. AB - As a promising Li-metal battery, Li-S battery has an ultrahigh theoretical energy density of 2600 Wh kg-1. However, most of the previous work has mainly focused on tackling the "polysulfide shuttle" originating from the S cathode, while the dendrite problem coming from the Li-metal anode has often been overlooked. Herein, to solve the issues arising from both the cathode and anode simultaneously, we propose a novel cell configuration for the first time by inserting CNT films on both sides of the separator in Li-S batteries, in which the cathode-side CNT film works as a shield to suppress the "polysulfide shuttle" and the anode-side CNT film acts as a powerful shield to prevent the Li dendrite growth. In the new cell configuration, the S/rGO cathode with a high S loading of about 4.0 mg cm-2 displays a high specific capacity (1336 mAh g-1 at 0.2 C), excellent rate ability (1070, 833, 656, and 444 mAh g-1 at 0.5, 1, 2, and 5 C, respectively), and sustainable cycling stability for 150 cycles with high Coulombic efficiency (>99%) at 1 C, while the Li metal anode displays an ultrasmooth surface. We believe this work will aid in developing other metal based (e.g., Na, K, Zn, and Al) batteries. PMID- 28084722 TI - Novel Triazole-Piperazine Hybrid Molecules Induce Apoptosis via Activation of the Mitochondrial Pathway and Exhibit Antitumor Efficacy in Osteosarcoma Xenograft Nude Mice Model. AB - Mitochondria impart a crucial role in the regulation of programmed cell death and reactive oxygen species (ROS) generation, besides serving as a primary energy source. Mitochondria appeared as an important target for the therapy of cancer due to their significant contribution to cell survival and death. Here, we report the design and synthesis of a novel series of triazole-piperazine hybrids as potent anticancer agents. MCS-5 emerged as an excellent anticancer agent which showed better anticancer activity than the standard drug doxorubicin in in vitro and in vivo studies. MCS-5 displayed an IC50 value of 1.92 MUM and induced apoptosis in Cal72 (human osteosarcoma cell line) cells by targeting the mitochondrial pathway. This compound arrested the G2/M phase of the cell cycle and induced ROS production and mitochondrial potential collapse in Cal72 cells. MCS-5 displayed excellent anticancer activity in the Cal72 xenograft nude mice model, where it significantly reduced tumor progression, leading to enhanced life span in treated animals compared to control and doxorubicin treated animals without exerting noticeable toxicity. In addition, a 2DG optical probe guided study clearly evoked that MCS-5 remarkably reduced tumor metastasis in the Cal72 xenograft nude mice model. These results indicate that MCS-5 appeared as a novel chemical entity which is endowed with excellent in vitro as well as in vivo anticancer activity and may contribute significantly to the management of cancer in the future. PMID- 28084723 TI - Distinct Chromic and Magnetic Properties of Metal-Organic Frameworks with a Redox Ligand. AB - An electron-deficient and potentially chromic ligand has been utilized to impart redox activity, photo- and hydrochromism, and solvotomagnetism to metal-organic frameworks (MOFs). A pair of MOFs were constructed from the flexible zwitterionic viologen-tethered tetracarboxylate linker N,N'-bis(3,5-dicarboxylatobenzyl)-4,4' bipyridinium (L2-): [Co3(L)(N3)4] (1) and [Mn2(L)(N3)2(H2O)2].3H2O (2). Both compounds show three-dimensional frameworks in which mixed azido- and carboxylato bridged chains are connected through the electron-deficient viologen moieties. The chain in 1 is built from alternating bis(azide) and (azide)bis(carboxylate) bridges, while that in 2 contains uniform (azide) (carboxylate) bridges. The MOFs shows the characteristic redox properties of the viologen moieties. The redox activity affords the MOFs with different chromic properties, owing to subtle differences in chemical environments. 1 shows reversible photochromism, which is related to the radical formation through photoinduced electron transfer from azide-carboxylate to viologen according to UV-vis, X-ray photoelectron, and electron spin resonance spectroscopy and DFT calculations. 2 is nonphotochromic for lack of appropriate pathways for electron transfer. Unexpectedly, 2 shows a novel type of solid-state hydrochromism. Upon the removal and reabsorption of water, the compound shows remarkable color change because of reversible electron transfer accompanying a reversible structural transformation. The radical mechanism is distinct from those for traditional hydrochromic inorganic and organic materials. Magnetic studies indicate ferro- and antiferromagnetic coupling in 1 and 2, respectively. What's more, 2 shows marked magnetic response to the removal of water molecules owing to the formation of radicals. The compound illustrates a unique material exhibiting dual responses (color and magnetism) to water. PMID- 28084724 TI - Is the Solid Electrolyte Interphase an Extra-Charge Reservoir in Li-Ion Batteries? AB - Advanced metal oxide electrodes in Li-ion batteries usually show reversible capacities exceeding the theoretically expected ones. Despite many studies and tentative interpretations, the origin of this extra-capacity is not assessed yet. Lithium storage can be increased through different chemical processes developing in the electrodes during charging cycles. The solid electrolyte interface (SEI), formed already during the first lithium uptake, is usually considered to be a passivation layer preventing the oxidation of the electrodes while not participating in the lithium storage process. In this work, we combine high resolution soft X-ray absorption spectroscopy with tunable probing depth and photoemission spectroscopy to obtain profiles of the surface evolution of a well known prototype conversion-alloying type mixed metal oxide (carbon coated ZnFe2O4) electrode. We show that a partially reversible layer of alkyl lithium carbonates is formed (~5-7 nm) at the SEI surface when reaching higher Li storage levels. This layer acts as a Li reservoir and seems to give a significant contribution to the extra-capacity of the electrodes. This result further extends the role of the SEI layer in the functionality of Li-ion batteries. PMID- 28084725 TI - Broadening of Distribution of Trap States in PbS Quantum Dot Field-Effect Transistors with High-k Dielectrics. AB - We perform a quantitative analysis of the trap density of states (trap DOS) in PbS quantum dot field-effect transistors (QD-FETs), which utilize several polymer gate insulators with a wide range of dielectric constants. With increasing gate dielectric constant, we observe increasing trap DOS close to the lowest unoccupied molecular orbital (LUMO) of the QDs. In addition, this increase is also consistently followed by broadening of the trap DOS. We rationalize that the increase and broadening of the spectral trap distribution originate from dipolar disorder as well as polaronic interactions, which are appearing at strong dielectric polarization. Interestingly, the increased polaron-induced traps do not show any negative effect on the charge carrier mobility in our QD devices at the highest applied gate voltage, giving the possibility to fabricate efficient low-voltage QD devices without suppressing carrier transport. PMID- 28084726 TI - High-Performance Electron Field Emitters and Microplasma Cathodes Based on Conductive Hybrid Granular Structured Diamond Materials. AB - High-performance diamond electron field emitters (EFEs) with extremely low turn on field (E0 = 1.72 V/MUm) and high current density (1.70 mA/cm2 at an applied field of 3.86 V/MUm) were successfully synthesized by using a modified two-step microwave plasma chemical deposition process. Such emitters possess EFE properties comparable with most of carbon- or semiconductor-based EFE materials, but with markedly better lifetime stability. The superb EFE behavior of these materials was achieved owing to the reduction in the diamond-to-Si interfacial resistance and the increase in the conductivity of the bulk diamond films (HBD 400 V) via the applications of high bias voltage during the preparation of the ultrananocrystalline diamond (UNCD) primary layer and the subsequent plasma post treatment (PPT) process, respectively. The superior EFE properties along with enhanced robustness of HBD-400 V films compared with the existing diamond-based EFE materials rendered these materials of greater potential for applications in high brightness display and multifunctional microplasma. PMID- 28084727 TI - Organophosphate Esters in Sediment of the Great Lakes. AB - This is the first study on organophosphate ester (OPEs) flame retardants and plasticizers in the sediment of the Great Lakes. Concentrations of 14 OPEs were measured in three sediment cores and 88 Ponar surface grabs collected from Lakes Ontario, Michigan, and Superior of North America. The sum of these OPEs (Sigma14OPEs) in Ponar grabs averaged 2.2, 4.7, and 16.6 ng g-1 dw in Lakes Superior, Michigan, and Ontario, respectively. Multiple linear regression analyses demonstrated statistically significant associations between logarithm concentrations of Sigma14OPEs as well as selected congeners in surface grab samples and sediment organic carbon content as well as a newly developed urban distance factor. Temporal trends observed in dated sediment cores from Lake Michigan demonstrated that the recent increase in depositional flux to sediment is dominated by chlorinated OPEs, particularly tris(2-chloroisopropyl) phosphate (TCPP), which has a doubling time of about 20 years. Downward diffusion within sediment may have caused vertical fractionation of OPEs over time. Two relatively hydrophilic OPEs including TCPP had much higher concentrations in sediment than estimated based on equilibria between water and sediment organic carbon. Approximately a quarter (17 tonnes) of the estimated total OPE burden (63 tonnes) in Lake Michigan resides in sediment, which may act as a secondary source releasing OPEs to the water column for years to come. PMID- 28084728 TI - Cellulose Elementary Fibrils Assemble into Helical Bundles in S1 Layer of Spruce Tracheid Wall. AB - The ultrastructural organization of cellulose elementary fibrils (EFs) in wood cell wall is considered to be the prime factor regulating the material characteristics of wood in micro to macro levels and the conversion of delignified wood fibers into various products. Specifically, the complex assembly of EFs in wood cell wall limits its swellability, solubility, and reactivity, for example, in dissolution of cellulose for regeneration of textile fibers, fibril separation for the manufacture of nanocellulose, and enzymatic hydrolysis of cellulose into sugars for their subsequent fermentation to various products, like ethanol for future fossil fuels replacement. Here cryo-transmission electron tomography was applied on ultrathin spruce wood sections to reveal the EF assembly in S1 layer of the native cell wall. The resolution of these tomograms was then further enhanced by computational means. For the first time, cellulose in the intact cell wall was visualized to be assembled into helical bundles of several EFs, a structural feature that must have a significant impact on the swelling, accessibility, and solubility of woody biomass for its conversion into the aforementioned value added products. PMID- 28084729 TI - Super-Resolution Imaging and Plasmonics. AB - This review describes the growing partnership between super-resolution imaging and plasmonics, by describing the various ways in which the two topics mutually benefit one another to enhance our understanding of the nanoscale world. First, localization-based super-resolution imaging strategies, where molecules are modulated between emissive and nonemissive states and their emission localized, are applied to plasmonic nanoparticle substrates, revealing the hidden shape of the nanoparticles while also mapping local electromagnetic field enhancements and reactivity patterns on their surface. However, these results must be interpreted carefully due to localization errors induced by the interaction between metallic substrates and single fluorophores. Second, plasmonic nanoparticles are explored as image contrast agents for both superlocalization and super-resolution imaging, offering benefits such as high photostability, large signal-to-noise, and distance-dependent spectral features but presenting challenges for localizing individual nanoparticles within a diffraction-limited spot. Finally, the use of plasmon-tailored excitation fields to achieve subdiffraction-limited spatial resolution is discussed, using localized surface plasmons and surface plasmon polaritons to create confined excitation volumes or image magnification to enhance spatial resolution. PMID- 28084730 TI - Hexavalent Chromium Generation within Naturally Structured Soils and Sediments. AB - Chromium(VI) produced from the oxidation of indigenous Cr(III) minerals is increasingly being recognized as a threat to groundwater quality. A critical determinant of Cr(VI) generation within soils and sediments is the necessary interaction of two low-solubility phases-Cr(III) silicates or (hydr)oxides and Mn(III/IV) oxides-that lead to its production. Here we investigate the potential for Cr(III) oxidation by Mn oxides within fixed solid matrices common to soils and sediments. Artificial aggregates were constructed from Cr(OH)3- and Cr0.25Fe0.75(OH)3-coated quartz grains and either mixed with synthetic birnessite or inoculated with the Mn(II)-oxidizing bacterium Leptothrix cholodnii. In aggregates simulating low organic carbon environments, we observe Cr(VI) concentrations within advecting solutes at levels more than twenty-times the California drinking water standard. Chromium(VI) production is highly dependent on Cr-mineral solubility; increasing Fe-substitution (x = 0 to x = 0.75) decreases the solubility of the solid and concomitantly decreases total Cr(VI) generation by 37%. In environments with high organic carbon, reducing conditions within aggregate cores (microbially) generate sufficient Fe(II) to suppress Cr(VI) efflux. Our results illustrate Cr(VI) generation from reaction with Mn oxides within structured media simulating soils and sediments and provide insight into how fluctuating hydrologic and redox conditions impact coupled processes controlling Cr and Mn cycling. PMID- 28084731 TI - Luminescent CdSe Superstructures: A Nanocluster Superlattice and a Nanoporous Crystal. AB - Superstructures, combining nanoscopic constituents into micrometer-size assemblies, have a great potential for utilization of the size-dependent quantum confinement properties in multifunctional electronic and optoelectronic devices. Two diverse superstructures of nanoscopic CdSe were prepared using solvothermal conversion of the same cadmium selenophenolate precursor (Me4N)2[Cd(SePh)4]: the first is a superlattice of monodisperse [Cd54Se32(SePh)48(dmf)4]4- nanoclusters; the second is a unique porous CdSe crystal. Nanoclusters were crystallized as cubic crystals (<=0.5 mm in size) after solvothermal treatment at 200 degrees C in DMF. UV-vis absorption and PLE spectra of the reported nanoclusters are consistent with previously established trends for the known families of tetrahedral CdSe frameworks. In contrast to these, results of PL spectra are rather unexpected, as distinct room temperature emission is observed both in solution and in the solid state. The porous CdSe crystals were isolated as red hexagonal prisms (<=70 MUm in size) via solvothermal treatment under similar conditions but with the addition of an alkylammonium salt. The presence of a three-dimensional CdSe network having a coherent crystalline structure inside hexagonal prisms was concluded based on powder X-ray diffraction, selected area electron diffraction and electron microscopy imaging. Self-assembly via oriented attachment of crystalline nanoparticles is discussed as the most probable mechanism of formation. PMID- 28084732 TI - Novel Polyfluorinated Compounds Identified Using High Resolution Mass Spectrometry Downstream of Manufacturing Facilities near Decatur, Alabama. AB - Concern over persistence, bioaccumulation, and toxicity has led to international regulation and phase-outs of certain perfluorinated compounds and little is known about their replacement products. High resolution mass spectrometry was used to investigate the occurrence and identity of replacement fluorinated compounds in surface water and sediment of the Tennessee River near Decatur, Alabama. Analysis of legacy Per- and polyfluoroalkyl substances (PFASs) revealed a marked increase in concentrations downstream of manufacturing facilities, with the most abundant compounds being perfluorooctanesulfonate (PFOS), perfluorobutanesulfonate (PFBS), and perfluorooctanoic acid (PFOA) as high as 220 ng L-1, 160 ng L-1, and 120 ng L 1, respectively. A series of nine polyfluorinated carboxylic acids was discovered, each differing by CF2CH2. These acids are likely products or byproducts of a manufacturing process that uses 1,1-difluoroethene, which is registered to a manufacturing facility in the area. Two other predominant compounds discovered have structures consistent with perfluorobutanesulfonate and perfluoroheptanoic acid but have a single hydrogen substituted for a fluorine someplace in their structure. A polyfluoroalkyl sulfate with differing mixes of hydrogen and fluorine substitution was also observed. N-methyl perfluorobutane sulfonamidoacetic acid (MeFBSAA) was observed at high concentrations and several other perfluorobutane sulfonamido substances were present as well. PMID- 28084733 TI - Application of Ionic Liquids to Energy Storage and Conversion Materials and Devices. AB - Ionic liquids (ILs) are liquids consisting entirely of ions and can be further defined as molten salts having melting points lower than 100 degrees C. One of the most important research areas for IL utilization is undoubtedly their energy application, especially for energy storage and conversion materials and devices, because there is a continuously increasing demand for clean and sustainable energy. In this article, various application of ILs are reviewed by focusing on their use as electrolyte materials for Li/Na ion batteries, Li-sulfur batteries, Li-oxygen batteries, and nonhumidified fuel cells and as carbon precursors for electrode catalysts of fuel cells and electrode materials for batteries and supercapacitors. Due to their characteristic properties such as nonvolatility, high thermal stability, and high ionic conductivity, ILs appear to meet the rigorous demands/criteria of these various applications. However, for further development, specific applications for which these characteristic properties become unique (i.e., not easily achieved by other materials) must be explored. Thus, through strong demands for research and consideration of ILs unique properties, we will be able to identify indispensable applications for ILs. PMID- 28084734 TI - Macrocyclized Extended Peptides: Inhibiting the Substrate-Recognition Domain of Tankyrase. AB - We report a double-click macrocyclization approach for the design of constrained peptide inhibitors having non-helical or extended conformations. Our targets are the tankyrase proteins (TNKS), poly(ADP-ribose) polymerases (PARP) that regulate Wnt signaling by targeting Axin for degradation. TNKS are deregulated in many different cancer types, and inhibition of TNKS therefore represents an attractive therapeutic strategy. However, clinical development of TNKS-specific PARP catalytic inhibitors is challenging due to off-target effects and cellular toxicity. We instead targeted the substrate-recognition domain of TNKS, as it is unique among PARP family members. We employed a two-component strategy, allowing peptide and linker to be separately engineered and then assembled in a combinatorial fashion via click chemistry. Using the consensus substrate-peptide sequence as a starting point, we optimized the length and rigidity of the linker and its position along the peptide. Optimization was further guided by high resolution crystal structures of two of the macrocyclized peptides in complex with TNKS. This approach led to macrocyclized peptides with submicromolar affinities for TNKS and high proteolytic stability that are able to disrupt the interaction between TNKS and Axin substrate and to inhibit Wnt signaling in a dose-dependent manner. The peptides therefore represent a promising starting point for a new class of substrate-competitive inhibitors of TNKS with potential for suppressing Wnt signaling in cancer. Moreover, by demonstrating the application of the double-click macrocyclization approach to non-helical, extended, or irregularly structured peptides, we greatly extend its potential and scope, especially given the frequency with which such motifs mediate protein protein interactions. PMID- 28084736 TI - Study of the Impact of Polyanions on the Formation of Lipid Bilayers on Top of Polyelectrolyte Multilayers with Poly(allylamine hydrochloride) as the Top Layer. AB - The impact of polyanions on the formation of lipid bilayers on top of polyelectrolyte multilayers (PEMs) with poly(allylamine hydrochloride) (PAH) as the top layer is studied for the deposition of vesicles of mixed lipid composition, 50:50 molar ratio of zwitterionic 1,2-dioleoyl-sn-glycero-3 phosphocholine (DOPC) and negatively charged 1,2-dioleoyl-sn-glycero-3-phospho-l serine (DOPS). PEMs are assembled with polystyrene sulfonate (PSS), poly(acrylic acid) (PAA), and alginic acid sodium salt (Alg) as polyanions. The assembly of the vesicles on the PEMs is followed by means of the quartz crystal microbalance with dissipation. Fluorescence recovery after photobleaching measurements are applied to evaluate bilayer formation. Whereas a bilayer is formed on top of PAH/PSS multilayers, the vesicles are adsorbed on top of PAH/Alg and PAH/PAA multilayers, remaining unruptured or only partially fused. The influence of the surface composition of the PEM and of the bulk properties of the film are analyzed. The phosphate ions present in phosphate-buffered saline (PBS) play a fundamental role in bilayer formation on top of PAH/PSS as they complex with PAH and render the surface potential close to zero. For PAH/PAA and PAH/Alg, PBS renders the surface negative. X-ray photoelectron spectroscopy shows that the dibasic phosphate ions from PBS complex preferentially with PAH in PAH/PAA and PAH/Alg multilayers, whereas monobasic phosphates complex with PAH in PAH/PSS. An explanation for the absence of bilayer formation on PAH/PAA and PAH/Alg is given on the basis of the different affinities of phosphate ions for PAH in combination with the different polyanions. PMID- 28084735 TI - Real-Time Screening of Biocatalysts in Live Bacterial Colonies. AB - Screening of bacterial colonies to identify new biocatalytic activities is a widely adopted tool in biotechnology, but is constrained by the requirements for colorimetric or tag-based detection methods. Herein we report a label-free screening platform for biotransformations in live colonies using desorption electrospray ionization coupled with ion mobility mass spectrometry imaging (DiBT IMMS). The screening method is demonstrated for both ammonia lyases and P450 monooxygenases expressed within live bacterial colonies and is shown to enable multiplexing of enzyme variants and substrate libraries simultaneously. PMID- 28084737 TI - Theoretical Study of Silicon Monoxide Reactions with Ammonia and Methane. AB - High-accuracy calculations were performed to study the mechanisms of the reactions between the diatomic silicon monoxide (SiO) with NH3 and CH4. These reactions are relevant to the SiO-related astrochemistry and atmospheric chemistry as well as the activation of the N-H and C-H bonds by the SiO triple bond. Energetic data used in the construction of potential energy surfaces describing the SiO + NH3/CH4 reactions were obtained at the coupled-cluster theory with extrapolation to the complete basis set limit (CCSD(T)/CBS) using DFT/B3LYP/aug-cc-pVTZ optimized geometries. Standard heats of formation of a series of small Si-molecules were predicted. Insertion of SiO into the N-H bond is exothermic with a small energy barrier of ~8 kcal/mol with respect to the SiO + NH3 reactants, whereas the C-H bond activation by SiO involves a higher energy barrier of 45 kcal/mol. Eight product channels are opened in the SiO + NH3 reaction including dehydrations giving HNSi/HSiN and dehydrogenations. These reactions are endothermic by 16-119 kcal/mol (calculated at 298.15 K) with the CCSD(T)/CBS energy barriers of 21-128 kcal/mol. The most stable set of products, HNSi + H2O, was also the product of the reaction pathway having lowest energy barrier of 21 kcal/mol. Ten product channels of the SiO + CH4 reaction including decarbonylation, dehydration, dehydrogenation, and formation of Si + CH3OH are endothermic by 19-118 kcal/mol with the energy barriers in the range of 71-126 kcal/mol. The formation of H2CSiO + H2O has the lowest energy barrier of 71 kcal/mol, whereas the most stable set of products, SiH4 + CO, is formed via a higher energy barrier of 90 kcal/mol. Accordingly, while SiO can break the N-H bond of ammonia without the assistance of other molecules, it is not able to break the C-H bond of methane. PMID- 28084738 TI - Interactions in Water-Ionic Liquid Mixtures: Comparing Protic and Aprotic Systems. AB - The sensitivity of ionic liquids (ILs) to water affects their physical and chemical properties, even at relatively low concentrations, yet the structural thermodynamics of protic IL- (PIL-) water systems at low water concentrations still remains unclear. Using the rigorous Kirkwood-Buff theory of solutions, which can quantify the interactions between species in IL-water systems solely from thermodynamic data, we have shown the following: (1) Between analogous protic and aprotic ILs (AILs), the AIL cholinium bis(trifluoromethanesulfonyl)imide ([Ch][NTf2]) shows stronger interactions with water at low water concentrations, with the analogous PIL N,N dimethylethanolammonium bis(trifluoromethanesulfonyl)imide ([DMEtA][NTf2]) having stronger water-ion interactions at higher water contents, despite water-ion interactions weakening with increasing water content in both systems. (2) Water has little effect on the average ion-ion interactions in both protic and aprotic ILs, aside from the AIL [Ch][NTf2], which shows a strengthening of ion-ion interactions with increasing water content. (3) Self-association of water in both PIL-water systems leading to the presence of large aggregates of water in IL-rich compositions has been inferred. Water-water interactions in [DMEtA][NTf2] were found to be similar to those of dialkylimidazolium AILs, whereas these interactions were much larger in the PIL N,N-dimethylethanolammonium propionate ([DMEtA][Pr]), attributed to the change in anion-water interactions. PMID- 28084739 TI - Size-Dependent Optical Properties of Grana Inside Chloroplast of Plant Cells. AB - Well-packed thylakoids known as grana are one of the major functional sites for photosynthesis in algae and plants. Their highly ordered structures can be considered as a few hundred nanometer-sized particles having distinct scattering cross sections from other various macromolecular organizations inside plant cells. With this background we show that elastic light scattering imaging and microspectroscopy is an important tool for investigating structure and organization of grana inside a single chloroplast in plant cells. We have demonstrated this noninvasive method to identify the distribution of grana in intact fresh leaf of robust and rapidly growing Egaria densa, which is also known as Anachris and among the most popular aquarium plants. The scattering efficiency spectra of their individual grana fairly resemble cooperative absorption spectra of porphyrins and carotenoids. We found that the electronic structure of the stacked thylakoids shows granum size-dependence, indicating that size of grana is one of the critical parameters in the regulation of the photochemical functions in the thylakoid. PMID- 28084740 TI - Black Phosphorus Quantum Dots for Hole Extraction of Typical Planar Hybrid Perovskite Solar Cells. AB - Black phosphorus, famous as two-dimensional (2D) materials, shows such excellent properties for optoelectronic devices such as tunable direct band gap, extremely high hole mobility (300-1000 cm2/(V s)), and so forth. In this Letter, facile processed black phosphorus quantum dots (BPQDs) were successfully applied to enhance hole extraction at the anode side of the typical p-i-n planar hybrid perovskite solar cells, which remarkably improved the performance of devices with photon conversion efficiency ramping up from 14.10 to 16.69%. Moreover, more detailed investigations by c-AFM, SKPM, SEM, hole-only devices, and photon physics measurements discover further the hole extraction effect and work mechanism of the BPQDs, such as nucleation assistance for the growth of large grain size perovskite crystals, fast hole extraction, more efficient hole transfer, and suppression of energy-loss recombination at the anode interface. This work definitely paves the way for discovering more and more 2D materials with high electronic properties to be used in photovoltaics and optoelectronics. PMID- 28084741 TI - Biofunctionalization of Plasmonic Nanoparticles with Short Peptides Monitored by SERS. AB - In order for plasmonic nanoparticles to be usable in biomedical applications their surface requires functionalization with biocompatible material. For this purpose short peptides, CFY, CFFY, CLY, were designed and replacement of the capping agent poly(vinylpyrrolidone) (PVP) on the surface of silver nanocubes by the peptides was investigated. The primary sequences of the peptides were designed such that they enable the covalent attachment to silver via the cysteine thiols, contain amino acids that can interact via hydrophobic interactions, and therefore are likely to form tightly packed films. Finally, the peptides contained UV-vis and SERS markers, allowing the dynamics of the biomolecule attachment to the nanoparticles to be monitored spectroscopically. The ligand exchange was observed for nanocubes suspended in solution and supported on a dielectric substrate. Formation of the peptide film around the nanocubes was confirmed by electron microscopy and SERS measurements. The film thickness was found to be 4-6 nm and independent of peptide solution concentration, suggesting multilayer formation. The surface density of these cysteine-containing peptides was found to be between 0.59 and 4.92 molecules per nm2. PMID- 28084742 TI - Pharmacophore-Based 3D-QSAR Analysis of Thienyl Chalcones as a New Class of Human MAO-B Inhibitors: Investigation of Combined Quantum Chemical and Molecular Dynamics Approach. AB - Selective monoamine oxidase-B (MAO-B) inhibitors are imperative in the treatment of various neurodegenerative disorders. Herein, we describe the pharmacophore generation and atom-based three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses of previously reported thiophene-based hMAO-B inhibitors by our research group. The aim of this study was to identify the principal structural features that could potentially be responsible for the inhibitory activity of hMAO-B inhibitors. The best pharmacophore model generated was the four-point assay of AHRR.8. The pharmacophore model exhibited good correlation with its predictability of the statistically valid 3D-QSAR analyses. Density functional theory calculations were further employed on the lead molecule (2E)-1-(5-bromothiophen-2-yl)-3-[4-(dimethylamino) phenyl] prop-2-en-1-one (Tb5) to investigate the electrostatic potential surface and analyze the natural bond orbital toward the binding characteristics. Molecular dynamics simulations were performed to characterize the molecular level interactions and relative energies of the hMAO isoforms: hMAO-A and hMAO-B with three potent and selective hMAO-B inhibitors (Tb5, Tb6, and Tb9). The results of both continuous and accelerated molecular dynamics simulations demonstrate a distinct preference of the three ligands to bind to hMAO-B rather than hMAO-A. PMID- 28084743 TI - Azepinoindole Synthesis via a N-Bromosuccinimide-Induced Cycloisomerization of Enaminoester/Enaminone. AB - A protocol based on a newly developed N-bromosuccinimide (NBS)-induced cycloisomerization was described to prepare tricyclic azepino[4,5-b]indoles from simple beta-enaminoesters or beta-enaminones containing an indole unit. A mechanism involving a Pictet-Spengler cyclization, an aziridine ring formation, and a regioselective C-N bond cleavage was proposed to account for the medium sized ring formation and the migration of electron-withdrawing group (ester, ketone). PMID- 28084745 TI - First-Principles Free-Energy Barriers for Photoelectrochemical Surface Reactions: Proton Abstraction at TiO_{2}(110). AB - We explicitly calculate the free-energy barrier for the initial proton abstraction in the water splitting reaction at rutile TiO_{2}(110) through ab initio molecular dynamics. Combining solid-state embedding, an energy based reaction coordinate and state-of-the-art free-energy reconstruction techniques renders the calculation tractable at the hybrid density-functional theory level. The obtained free-energy barrier of approximately 0.2 eV, depending slightly on the orientation of the first acceptor water molecule, suggests a hindered reaction on the pristine rutile surface. PMID- 28084744 TI - Unusual Exciton-Phonon Interactions at van der Waals Engineered Interfaces. AB - Raman scattering is a ubiquitous phenomenon in light-matter interactions, which reveals a material's electronic, structural, and thermal properties. Controlling this process would enable new ways of studying and manipulating fundamental material properties. Here, we report a novel Raman scattering process at the interface between different van der Waals (vdW) materials as well as between a monolayer semiconductor and 3D crystalline substrates. We find that interfacing a WSe2 monolayer with materials such as SiO2, sapphire, and hexagonal boron nitride (hBN) enables Raman transitions with phonons that are either traditionally inactive or weak. This Raman scattering can be amplified by nearly 2 orders of magnitude when a foreign phonon mode is resonantly coupled to the A exciton in WSe2 directly or via an A1' optical phonon from WSe2. We further showed that the interfacial Raman scattering is distinct between hBN-encapsulated and hBN sandwiched WSe2 sample geometries. This cross-platform electron-phonon coupling, as well as the sensitivity of 2D excitons to their phononic environments, will prove important in the understanding and engineering of optoelectronic devices based on vdW heterostructures. PMID- 28084746 TI - Experimental Realization of a Thermal Squeezed State of Levitated Optomechanics. AB - We experimentally squeeze the thermal motional state of an optically levitated nanosphere by fast switching between two trapping frequencies. The measured phase space distribution of the center of mass of our particle shows the typical shape of a squeezed thermal state, from which we infer up to 2.7 dB of squeezing along one motional direction. In these experiments the average thermal occupancy is high and, even after squeezing, the motional state remains in the remit of classical statistical mechanics. Nevertheless, we argue that the manipulation scheme described here could be used to achieve squeezing in the quantum regime if preceded by cooling of the levitated mechanical oscillator. Additionally, a higher degree of squeezing could, in principle, be achieved by repeating the frequency-switching protocol multiple times. PMID- 28084747 TI - Weaving Knotted Vector Fields with Tunable Helicity. AB - We present a general construction of divergence-free knotted vector fields from complex scalar fields, whose closed field lines encode many kinds of knots and links, including torus knots, their cables, the figure-8 knot, and its generalizations. As finite-energy physical fields, they represent initial states for fields such as the magnetic field in a plasma, or the vorticity field in a fluid. We give a systematic procedure for calculating the vector potential, starting from complex scalar functions with knotted zero filaments, thus enabling an explicit computation of the helicity of these knotted fields. The construction can be used to generate isolated knotted flux tubes, filled by knots encoded in the lines of the vector field. Lastly, we give examples of manifestly knotted vector fields with vanishing helicity. Our results provide building blocks for analytical models and simulations alike. PMID- 28084748 TI - Tapered Glass-Fiber Microspike: High-Q Flexural Wave Resonator and Optically Driven Knudsen Pump. AB - Appropriately designed optomechanical devices are ideal for making ultra sensitive measurements. Here we report a fused-silica microspike that supports a flexural resonance with a quality factor greater than 100 000 at room temperature in vacuum. Fashioned by tapering single-mode fiber (SMF), it is designed so that the core-guided optical mode in the SMF evolves adiabatically into the fundamental mode of the air-glass waveguide at the tip. The very narrow mechanical linewidth (20 mHz) makes it possible to measure extremely small changes in resonant frequency. In a vacuum chamber at low pressure, the weak optical absorption of the glass is sufficient to create a temperature gradient along the microspike, which causes it to act as a microscopic Knudsen pump, driving a flow of gas molecules towards the tip where the temperature is highest. The result is a circulating molecular flow within the chamber. Momentum exchange between the vibrating microspike and the flowing molecules causes an additional restoring force that can be measured as a tiny shift in the resonant frequency. The effect is strongest when the mean free path of the gas molecules is comparable with the dimensions of the vacuum chamber. The system offers a novel means of monitoring the behavior of weakly absorbing optomechanical sensors operating in vacuum. PMID- 28084749 TI - Charge Transport by Superexchange in Molecular Host-Guest Systems. AB - Charge transport in disordered organic semiconductors is generally described as a result of incoherent hopping between localized states. In this work, we focus on multicomponent emissive host-guest layers as used in organic light-emitting diodes (OLEDs), and show using multiscale ab initio based modeling that charge transport can be significantly enhanced by the coherent process of molecular superexchange. Superexchange increases the rate of emitter-to-emitter hopping, in particular if the emitter molecules act as relatively deep trap states, and allows for percolation path formation in charge transport at low guest concentrations. PMID- 28084750 TI - Graphene Nanobubbles as Valley Filters and Beam Splitters. AB - The energy band structure of graphene has two inequivalent valleys at the K and K^{'} points of the Brillouin zone. The possibility to manipulate this valley degree of freedom defines the field of valleytronics, the valley analogue of spintronics. A key requirement for valleytronic devices is the ability to break the valley degeneracy by filtering and spatially splitting valleys to generate valley polarized currents. Here, we suggest a way to obtain valley polarization using strain-induced inhomogeneous pseudomagnetic fields (PMFs) that act oppositely on the two valleys. Notably, the suggested method does not involve external magnetic fields, or magnetic materials, unlike previous proposals. In our proposal the strain is due to experimentally feasible nanobubbles, whose associated PMFs lead to different real space trajectories for K and K^{'} electrons, thus allowing the two valleys to be addressed individually. In this way, graphene nanobubbles can be exploited in both valley filtering and valley splitting devices, and our simulations reveal that a number of different functionalities are possible depending on the deformation field. PMID- 28084751 TI - Detecting Rotational Superradiance in Fluid Laboratories. AB - Rotational superradiance was predicted theoretically decades ago, and is chiefly responsible for a number of important effects and phenomenology in black-hole physics. However, rotational superradiance has never been observed experimentally. Here, with the aim of probing superradiance in the lab, we investigate the behavior of sound and surface waves in fluids resting in a circular basin at the center of which a rotating cylinder is placed. We show that with a suitable choice for the material of the cylinder, surface and sound waves are amplified. Two types of instabilities are studied: one sets in whenever superradiant modes are confined near the rotating cylinder and the other, which does not rely on confinement, corresponds to a local excitation of the cylinder. Our findings are experimentally testable in existing fluid laboratories and, hence, offer experimental exploration and comparison of dynamical instabilities arising from rapidly rotating boundary layers in astrophysical as well as in fluid dynamical systems. PMID- 28084752 TI - Two-Step Phase Transition in SnSe and the Origins of its High Power Factor from First Principles. AB - The interest in improving the thermoelectric response of bulk materials has received a boost after it has been recognized that layered materials, in particular SnSe, show a very large thermoelectric figure of merit. This result has received great attention while it is now possible to conceive other similar materials or experimental methods to improve this value. Before we can now think of engineering this material it is important we understand the basic mechanism that explains this unusual behavior, where very low thermal conductivity and a high thermopower result from a delicate balance between the crystal and electronic structure. In this Letter, we present a complete temperature evolution of the Seebeck coefficient as the material undergoes a soft crystal transformation and its consequences on other properties within SnSe by means of first-principles calculations. Our results are able to explain the full range of considered experimental temperatures. PMID- 28084753 TI - Evaporation Spectrum of Black Holes from a Local Quantum Gravity Perspective. AB - We revisit the hypothesis of a possible line structure in the Hawking evaporation spectrum of black holes. Because of nonperturbative quantum gravity effects, this would take place arbitrarily far away from the Planck mass. We show, based on a speculative but consistent hypothesis, that this naive prediction might in fact hold in the specific context of loop quantum gravity. A small departure from the ideal case is expected for some low-spin transitions and could allow us to distinguish several quantum gravity models. We also show that the effect is not washed out by the dynamics of the process, by the existence of a mass spectrum up to a given width, or by the secondary component induced by the decay of neutral pions emitted during the time-integrated evaporation. PMID- 28084754 TI - Enhanced Nonadiabaticity in Vortex Cores due to the Emergent Hall Effect. AB - We present a combined theoretical and experimental study, investigating the origin of the enhanced nonadiabaticity of magnetic vortex cores. Scanning transmission x-ray microscopy is used to image the vortex core gyration dynamically to measure the nonadiabaticity with high precision, including a high confidence upper bound. We show theoretically, that the large nonadiabaticity parameter observed experimentally can be explained by the presence of local spin currents arising from a texture induced emergent Hall effect. This study demonstrates that the magnetic damping alpha and nonadiabaticity parameter beta are very sensitive to the topology of the magnetic textures, resulting in an enhanced ratio (beta/alpha>1) in magnetic vortex cores or Skyrmions. PMID- 28084755 TI - Wu and Gong Reply. PMID- 28084756 TI - Subcycle Optical Response Caused by a Terahertz Dressed State with Phase-Locked Wave Functions. AB - The coherent interaction of light with matter imprints the phase information of the light field on the wave function of the photon-dressed electronic state. A driving electric field, together with a stable phase that is associated with the optical probe pulses, enables the role of the dressed state in the optical response to be investigated. We observed optical absorption strengths modulated on a subcycle time scale in a GaAs quantum well in the presence of a multicycle terahertz driving pulse using a near-infrared probe pulse. The measurements were in good agreement with the analytical formula that accounts for the optical susceptibilities caused by the dressed state of the excitons, which indicates that the output probe intensity was coherently reshaped by the excitonic sideband emissions. PMID- 28084757 TI - Comment on "Clustering of Oxygen Vacancies at CeO_{2}(111): Critical Role of Hydroxyls". PMID- 28084758 TI - Generation and Evolution of Spin-, Valley-, and Layer-Polarized Excited Carriers in Inversion-Symmetric WSe_{2}. AB - We report the spin-selective optical excitation of carriers in inversion symmetric bulk samples of the transition metal dichalcogenide (TMDC) WSe_{2}. Employing time- and angle-resolved photoelectron spectroscopy (trARPES) and complementary time-dependent density functional theory (TDDFT), we observe spin-, valley-, and layer-polarized excited state populations upon excitation with circularly polarized pump pulses, followed by ultrafast (<100 fs) scattering of carriers towards the global minimum of the conduction band. TDDFT reveals the character of the conduction band, into which electrons are initially excited, to be two-dimensional and localized within individual layers, whereas at the minimum of the conduction band, states have a three-dimensional character, facilitating interlayer charge transfer. These results establish the optical control of coupled spin-, valley-, and layer-polarized states in centrosymmetric materials with locally broken symmetries and suggest the suitability of TMDC multilayer and heterostructure materials for valleytronic and spintronic device concepts. PMID- 28084759 TI - Coherence Times of Bose-Einstein Condensates beyond the Shot-Noise Limit via Superfluid Shielding. AB - We demonstrate a new way to extend the coherence time of separated Bose-Einstein condensates that involves immersion into a superfluid bath. When both the system and the bath have similar scattering lengths, immersion in a superfluid bath cancels out inhomogeneous potentials either imposed by external fields or inherent in density fluctuations due to atomic shot noise. This effect, which we call superfluid shielding, allows for coherence lifetimes beyond the projection noise limit. We probe the coherence between separated condensates in different sites of an optical lattice by monitoring the contrast and decay of Bloch oscillations. Our technique demonstrates a new way that interactions can improve the performance of quantum devices. PMID- 28084760 TI - Colloidal Surfaces with Boundaries, Apex Boojums, and Nested Elastic Self Assembly of Nematic Colloids. AB - Self-assembly of colloidal particles is poised to become a powerful composite material fabrication technique, but remains challenged by a limited control over the ensuing structures. We develop a new breed of nematic colloids that are physical analogs of a mathematical surface with boundary, interacting with the molecular alignment field without inducing defects when flat. However, made from a thin nanofoil, they can be shaped to prompt formation of self-compensating defects that drive preprogramed elastic interactions mediated by the nematic host. To show this, we wrap the nanofoil on all triangular side faces of a pyramid, except its square base. The ensuing pyramidal cones induce point defects with fractional hedgehog charges of opposite signs, spontaneously align with respect to the far-field director to form elastic dipoles and nested assemblies with tunable spacing. Nanofoils shaped into octahedrons interact as elastic quadrupoles. Our findings may drive realization of low-symmetry colloidal phases. PMID- 28084761 TI - Suppression of Interference in Quantum Hall Mach-Zehnder Geometry by Upstream Neutral Modes. AB - Mach-Zehnder interferometry has been proposed as a probe for detecting the statistics of anyonic quasiparticles in fractional quantum Hall (FQH) states. Here, we focus on interferometers made of multimode edge states with upstream modes. We find that the interference visibility is suppressed due to downstream upstream mode entanglement; the latter serves as a "which path" detector to the downstream interfering trajectories. Our analysis tackles a concrete realization of a filling factor of nu=2/3, but its applicability goes beyond that specific case, and encompasses the recent observation of the ubiquitous emergence of upstream neutral modes in FQH states. The latter, according to our analysis, goes hand in hand with the failure to observe Mach-Zehnder anyonic interference in fractional states. We point out how charge-neutral mode disentanglement will resuscitate the interference signal. PMID- 28084762 TI - Hourglass Dispersion and Resonance of Magnetic Excitations in the Superconducting State of the Single-Layer Cuprate HgBa_{2}CuO_{4+delta} Near Optimal Doping. AB - We use neutron scattering to study magnetic excitations near the antiferromagnetic wave vector in the underdoped single-layer cuprate HgBa_{2}CuO_{4+delta} (superconducting transition temperature T_{c}~88 K, pseudogap temperature T^{*}~220 K). The response is distinctly enhanced below T^{*} and exhibits a Y-shaped dispersion in the pseudogap state, whereas the superconducting state features an X-shaped (hourglass) dispersion and a further resonancelike enhancement. A large spin gap of about 40 meV is observed in both states. This phenomenology is reminiscent of that exhibited by bilayer cuprates. The resonance spectral weight, irrespective of doping and compound, scales linearly with the putative binding energy of a spin exciton described by an itinerant-spin formalism. PMID- 28084763 TI - Kibble-Zurek Mechanism in the Self-Organization of a Cold Atomic Cloud. AB - When applying two counterpropagating laser beams to a cold cloud of rubidium atoms, we observe the spontaneous formation of intensity patterns associated with a spatial structuration of the atomic spins. We study the average number of defects in these patterns as a function of the sweep time employed to cross the instability threshold. We observe a power-law decrease of the number of defects with increasing sweep time, typical of the Kibble-Zurek mechanism. The measured exponent is consistent with the prediction for a supercritical bifurcation. PMID- 28084764 TI - Itinerant Conductance in Fuse-Antifuse Networks. AB - We report on a novel dynamic phase in electrical networks, in which current channels perpetually change in time. This occurs when the elementary units of the network are fuse-antifuse devices, namely, become insulators within a certain finite interval of local applied voltages. As a consequence, the macroscopic current exhibits temporal fluctuations which increase with system size. We determine the conditions under which this exotic situation appears by establishing a phase diagram as a function of the applied field and the size of the insulating window. Besides its obvious application as a versatile electronic device, due to its rich variety of behaviors, this network model provides a possible description for particle-laden flow through porous media leading to dynamical clogging and reopening of the local channels in the pore space. PMID- 28084765 TI - Superdiffusive Dispersals Impart the Geometry of Underlying Random Walks. AB - It is recognized now that a variety of real-life phenomena ranging from diffusion of cold atoms to the motion of humans exhibit dispersal faster than normal diffusion. Levy walks is a model that excelled in describing such superdiffusive behaviors albeit in one dimension. Here we show that, in contrast to standard random walks, the microscopic geometry of planar superdiffusive Levy walks is imprinted in the asymptotic distribution of the walkers. The geometry of the underlying walk can be inferred from trajectories of the walkers by calculating the analogue of the Pearson coefficient. PMID- 28084767 TI - Exploiting Vibrational Strong Coupling to Make an Optical Parametric Oscillator Out of a Raman Laser. AB - When the collective coupling of the rovibrational states in organic molecules and confined electromagnetic modes is sufficiently strong, the system enters into vibrational strong coupling, leading to the formation of hybrid light-matter quasiparticles. In this Letter, we demonstrate theoretically how this hybridization in combination with stimulated Raman scattering can be utilized to widen the capabilities of Raman laser devices. We explore the conditions under which the lasing threshold can be diminished and the system can be transformed into an optical parametric oscillator. Finally, we show how the dramatic reduction of the many final molecular states into two collective excitations can be used to create an all-optical switch with output in the midinfrared. PMID- 28084766 TI - Si Nanoribbons on Ag(110) Studied by Grazing-Incidence X-Ray Diffraction, Scanning Tunneling Microscopy, and Density-Functional Theory: Evidence of a Pentamer Chain Structure. AB - We report a combined grazing incidence x-ray diffraction (GIXD), scanning tunneling microscopy (STM), and density-functional theory (DFT) study which clearly elucidates the atomic structure of the Si nanoribbons grown on the missing-row reconstructed Ag(110) surface. Our study allows us to discriminate between the theoretical models published in the literature, including the most stable atomic configurations and those based on a missing-row reconstructed Ag(110) surface. GIXD measurements unambiguously validate the pentamer model grown on the reconstructed surface, obtained from DFT. This pentamer atomistic model accurately matches the high-resolution STM images of the Si nanoribbons adsorbed on Ag(110). Our study closes the long-debated atomic structure of the Si nanoribbons grown on Ag(110) and definitively excludes a honeycomb structure similar to that of freestanding silicene. PMID- 28084768 TI - Dependence of the Spectrum of Shock-Accelerated Ions on the Dynamics at the Shock Crossing. AB - Diffusive shock acceleration (DSA) of ions occurs due to pitch-angle diffusion in the upstream and downstream regions of the shock and multiple crossing of the shock by these ions. The classical DSA theory implies continuity of the distribution at the shock transition and predicts a universal spectrum of accelerated particles, depending only on the ratio of the upstream and downstream fluid speeds. However, the ion dynamics at the shock front occurs within a collision-free region and is gyrophase dependent. The ions fluxes have to be continuous at the shock front. The matching conditions for the gyrophase-averaged distribution functions at the shock transition are formulated in terms of the transition and reflection probabilities. These probabilities depend on the shock angle and the magnetic compression as does the power spectrum of accelerated ions. Their spectral index is expressed in terms of the reflectivity. The spectrum is typically harder than the spectrum predicted by the classical DSA theory. PMID- 28084770 TI - Anionic Hydrogen Cluster Ions as a New Form of Condensed Hydrogen. AB - We report the first experimental observation of negatively charged hydrogen and deuterium cluster ions, H_{n}^{-} and D_{n}^{-}, where n>=5. These anions are formed by an electron addition to liquid helium nanodroplets doped with molecular hydrogen or deuterium. The ions are stable for at least the lifetime of the experiment, which is several tens of microseconds. Only anions with odd values of n are detected, and some specific ions show anomalously high abundances. The sizes of these "magic number" ions suggest an icosahedral framework of H_{2} (D_{2}) molecules in solvent shells around a central H^{-} (D^{-}) ion. The first three shells, which contain a total of 44 H_{2} or D_{2} molecules, appear to be solidlike, but thereafter a more liquidlike arrangement of the H_{2} (D_{2}) molecules is adopted. PMID- 28084769 TI - Time-Resolved Imaging of Negative Differential Resistance on the Atomic Scale. AB - Negative differential resistance remains an attractive but elusive functionality, so far only finding niche applications. Atom scale entities have shown promising properties, but the viability of device fabrication requires a fuller understanding of electron dynamics than has been possible to date. Using an all electronic time-resolved scanning tunneling microscopy technique and a Green's function transport model, we study an isolated dangling bond on a hydrogen terminated silicon surface. A robust negative differential resistance feature is identified as a many body phenomenon related to occupation dependent electron capture by a single atomic level. We measure all the time constants involved in this process and present atomically resolved, nanosecond time scale images to simultaneously capture the spatial and temporal variation of the observed feature. PMID- 28084771 TI - Honeycomb-Lattice Heisenberg-Kitaev Model in a Magnetic Field: Spin Canting, Metamagnetism, and Vortex Crystals. AB - The Heisenberg-Kitaev model is a paradigmatic model to describe the magnetism in honeycomb-lattice Mott insulators with strong spin-orbit coupling, such as A_{2}IrO_{3} (A=Na, Li) and alpha-RuCl_{3}. Here, we study in detail the physics of the Heisenberg-Kitaev model in an external magnetic field. Using a combination of Monte Carlo simulations and spin-wave theory, we map out the classical phase diagram for different directions of the magnetic field. Broken SU(2) spin symmetry renders the magnetization process rather complex, with sequences of phases and metamagnetic transitions. In particular, we find various large-unit cell and multi-Q phases including a vortex-crystal phase for a field in the [111] direction. We also discuss quantum corrections in the high-field phase. PMID- 28084772 TI - Enhancement of the Superconducting Gap by Nesting in CaKFe_{4}As_{4}: A New High Temperature Superconductor. AB - We use high resolution angle resolved photoemission spectroscopy and density functional theory with measured crystal structure parameters to study the electronic properties of CaKFe_{4}As_{4}. In contrast to the related CaFe_{2}As_{2} compounds, CaKFe_{4}As_{4} has a high T_{c} of 35 K at stochiometric composition. This presents a unique opportunity to study the properties of high temperature superconductivity in the iron arsenides in the absence of doping or substitution. The Fermi surface consists of several hole and electron pockets that have a range of diameters. We find that the values of the superconducting gap are nearly isotropic (within the explored portions of the Brillouin zone), but are significantly different for each of the Fermi surface (FS) sheets. Most importantly, we find that the momentum dependence of the gap magnitude plotted across the entire Brillouin zone displays a strong deviation from the simple cos(k_{x})cos(k_{y}) functional form of the gap function, proposed by the scenario of Cooper pairing driven by a short range antiferromagnetic exchange interaction. Instead, the maximum value of the gap is observed on FS sheets that are closest to the ideal nesting condition, in contrast to previous observations in other ferropnictides. These results provide strong support for the multiband character of superconductivity in CaKFe_{4}As_{4}, in which Cooper pairing forms on the electron and the hole bands interacting via a dominant interband repulsive interaction, enhanced by band nesting. PMID- 28084774 TI - Search for the Effect of Massive Bodies on Atomic Spectra and Constraints on Yukawa-Type Interactions of Scalar Particles. AB - We propose a new method to search for hypothetical scalar particles that have feeble interactions with standard-model particles. In the presence of massive bodies, these interactions produce a nonzero Yukawa-type scalar-field magnitude. Using radio-frequency spectroscopy data of atomic dysprosium, as well as atomic clock spectroscopy data, we constrain the Yukawa-type interactions of a scalar field with the photon, electron, and nucleons for a range of scalar-particle masses corresponding to length scales >10 cm. In the limit as the scalar particle mass m_{phi}->0, our derived limits on the Yukawa-type interaction parameters are Lambda_{gamma}?8*10^{19} GeV, Lambda_{e}?1.3*10^{19} GeV, and Lambda_{N}?6*10^{20} GeV. Our measurements also constrain combinations of interaction parameters, which cannot otherwise be probed with traditional anomalous-force measurements. We suggest further measurements to improve on the current level of sensitivity. PMID- 28084775 TI - Noncollinear Spin-Orbit Magnetic Fields in a Carbon Nanotube Double Quantum Dot. AB - We demonstrate experimentally that noncollinear intrinsic spin-orbit magnetic fields can be realized in a curved carbon nanotube two-segment device. Each segment, analyzed in the quantum dot regime, shows near fourfold degenerate shell structure allowing for identification of the spin-orbit coupling and the angle between the two segments. Furthermore, we determine the four unique spin directions of the quantum states for specific shells and magnetic fields. This class of quantum dot systems is particularly interesting when combined with induced superconducting correlations as it may facilitate unconventional superconductivity and detection of Cooper pair entanglement. Our device comprises the necessary elements. PMID- 28084773 TI - Slow Interatomic Coulombic Decay of Multiply Excited Neon Clusters. AB - Ne clusters (~5000 atoms) were resonantly excited (2p->3s) by intense free electron laser (FEL) radiation at FERMI. Such multiply excited clusters can decay nonradiatively via energy exchange between at least two neighboring excited atoms. Benefiting from the precise tunability and narrow bandwidth of seeded FEL radiation, specific sites of the Ne clusters were probed. We found that the relaxation of cluster surface atoms proceeds via a sequence of interatomic or intermolecular Coulombic decay (ICD) processes while ICD of bulk atoms is additionally affected by the surrounding excited medium via inelastic electron scattering. For both cases, cluster excitations relax to atomic states prior to ICD, showing that this kind of ICD is rather slow (picosecond range). Controlling the average number of excitations per cluster via the FEL intensity allows a coarse tuning of the ICD rate. PMID- 28084776 TI - Color-Kinematics Duality and Sudakov Form Factor at Five Loops for N=4 Supersymmetric Yang-Mills Theory. AB - Using color-kinematics duality, we construct for the first time the full integrand of the five-loop Sudakov form factor in N=4 super-Yang-Mills theory, including nonplanar contributions. This result also provides a first manifestation of the color-kinematics duality at five loops. The integrand is explicitly ultraviolet finite when D<26/5, coincident with the known finiteness bound for amplitudes. If the double-copy method could be applied to the form factor, this would indicate an interesting ultraviolet finiteness bound for N=8 supergravity at five loops. The result is also expected to provide an essential input for computing the five-loop nonplanar cusp anomalous dimension. PMID- 28084777 TI - Anomalous Lattice Dynamics of EuSi_{2} Nanoislands: Role of Interfaces Unveiled. AB - We report a systematic lattice dynamics study of EuSi_{2} films and nanoislands by in situ nuclear inelastic scattering on ^{151}Eu and ab initio theory. The Eu partial phonon density of states of the nanoislands exhibits anomalous excess of phonon states at low and high energies, not present in the bulk and at the EuSi_{2}(001) surface. We demonstrate that atomic vibrations along the island substrate interface give rise to phonon states both at low and high energies, while atomic vibrations across the island-island interface result in localized high-energy phonon modes. PMID- 28084778 TI - Resonator with Ultrahigh Length Stability as a Probe for Equivalence-Principle Violating Physics. AB - In order to investigate the long-term dimensional stability of matter, we have operated an optical resonator fabricated from crystalline silicon at 1.5 K continuously for over one year and repeatedly compared its resonance frequency f_{res} with the frequency of a GPS-monitored hydrogen maser. After allowing for an initial settling time, over a 163-day interval we found a mean fractional drift magnitude |f_{res}^{-1}df_{res}/dt|<1.4*10^{-20}/s. The resonator frequency is determined by the physical length and the speed of light and we measure it with respect to the atomic unit of time. Thus the bound rules out, to first order, a hypothetical differential effect of the Universe's expansion on rulers and atomic clocks. We also constrain a hypothetical violation of the principle of local position invariance for resonator-based clocks and derive bounds for the strength of space-time fluctuations. PMID- 28084779 TI - Shape Coexistence in ^{78}Ni as the Portal to the Fifth Island of Inversion. AB - Large-scale shell-model calculations predict that the region of deformation which comprises the heaviest chromium and iron isotopes at and beyond N=40 will merge with a new one at N=50 in an astonishing parallel to the N=20 and N=28 case in the neon and magnesium isotopes. We propose a valence space including the full pf shell for the protons and the full sdg shell for the neutrons, which represents a comeback of the the harmonic oscillator shells in the very neutron- rich regime. The onset of deformation is understood in the framework of the algebraic SU(3) like structures linked to quadrupole dominance. Our calculations preserve the doubly magic nature of the ground state of ^{78}Ni, which, however, exhibits a well-deformed prolate band at low excitation energy, providing a striking example of shape coexistence far from stability. This new IOI adds to the four well documented ones at N=8, 20, 28, and 40. PMID- 28084780 TI - Core Structure and Non-Abelian Reconnection of Defects in a Biaxial Nematic Spin 2 Bose-Einstein Condensate. AB - We calculate the energetic structure of defect cores and propose controlled methods to imprint a nontrivially entangled vortex pair that undergoes non Abelian vortex reconnection in a biaxial nematic spin-2 condensate. For a singular vortex, we find three superfluid cores in addition to depletion of the condensate density. These exhibit order parameter symmetries that are different from the discrete symmetry of the biaxial nematic phase, forming an interface between the defect and the bulk superfluid. We provide a detailed analysis of phase mixing in the resulting vortex cores and find an instability dependent upon the orientation of the order parameter. We further show that the spin-2 condensate is a promising system for observing spontaneous deformation of a point defect into an "Alice ring" that has so far avoided experimental detection. PMID- 28084781 TI - Soil trace element changes during a phytoremediation trial with willows in southern Quebec, Canada. AB - This study determined the changes in trace elements (TE) (As, Cd, Cu, Ni, Pb, Zn) chemistry in the soils of a willow ("Fish Creek" - Salix purpurea, SV1 - Salix x dasyclados and SX67 - Salix miyabeana) plantation growing under a cold climate during a three-year trial. The soil HNO3-extractable and H2O-soluble TE concentrations and pools significantly decreased under most cultivars (Fish, SX67). Yet, TE changes showed inconsistent patterns and localized soil TE increases (Ni, Pb) were measured. Temporal changes in soil TE were also detected in control plots and sometimes exceeded changes in planted plots. Discrepancies existed between the amount of soil TE change and the amount of TE uptake by willows, except for Cd and Zn. Phytoremediation with willows could reduce soil Cd and Zn within a decadal timeframe indicating that they can be remediated by willows in moderately contaminated soils. However, the time needed to reduce soil As, Cu, Ni and Pb was too long to be efficient. We submit that soil leaching contributed to the TE decrease in controls and the TE discrepancies, and that the plantation could have secondary effects such as the accelerated leaching of soil TE. PMID- 28084782 TI - Effects of prenatal iron status on child neurodevelopment and behavior: A systematic review. AB - Iron deficiency and iron-deficiency anemia are the main worldwide nutritional disorders. A good level of prenatal iron is essential for the correct child neurodevelopment but this association has been poorly investigated. To gather the scientific evidence on the relation between prenatal iron status and child neurodevelopment. To emphasize the importance of personalize the dose and type of supplementation. Wide search strategy was performed in electronic databases for English language articles with no limitations as regards the language or date of publication. Additional studies were selected by hand search. The inclusion criteria were pregnant women without high-risk pregnancy and their children as study population and neurodevelopment as the main outcome. Six RCTs and 13 observational studies were included. The majority concluded that deficit or excess iron during pregnancy injures the mental and psychomotor development of child. Other authors found no association of low iron level with troubles in neurodevelopment, recommended multi-micronutrients instead of iron alone and/or showed inconsistent results. Both iron deficiency as its excess are harmful for the child neurodevelopment. The prenatal iron supplementation should be adjusted for each woman, taking into account the iron stores, some genetic mutation and other health habits. PMID- 28084783 TI - Morphophysiological, ultrastructural, and nutritional changes induced by Cu toxicity in young Erythrina fusca plants. AB - Erythrina fusca is an important legume used for shade cover in cacao plantations in Brazil. Cacao plantations receive large quantities of copper (Cu)-containing agrochemicals, mainly for control of diseases. Therefore, Cu toxicity was investigated in seedlings grown in hydroponics with increasing concentrations of Cu (0.005-32 mg L-1) in a greenhouse. Ultrastructural analyses showed cell plasmolysis in the root cortical area and changes in thylakoid membranes at 8 mg Cu L-1 and higher. There were changes in epicuticular wax deposition on the leaf surface at the 16 and 32 mg Cu L-1 treatments. Leaf gas exchanges were highly affected 24 hours after application of treatments beginning at 8 mg Cu L-1 and higher Cu concentrations. Chemical analyses showed that Cu content in E. fusca roots increased as Cu concentration in the nutrient solution increased, whereas the shoot did not show significant changes. It is also observed that excess Cu interfered with Zn, Fe, Mn, Mg, K, P, and Ca content in the different E. fusca organs. Investigation of Cu toxicity symptoms focusing on morphophysiological, ultrastructural, gas exchange, and nutritional changes would be useful to alleviate Cu toxicity in E. fusca under field conditions, an important agroforestry species in cacao plantation. PMID- 28084784 TI - CYD-TDV dengue vaccine: systematic review and meta-analysis of efficacy, immunogenicity and safety. AB - INTRODUCTION: Dengue virus (DENV) is a serious global health problem. CYD-TDC (Dengvaxia(r)) was the first vaccine to gain regulatory approval to try and address this problem. AIM: Summarize all available evidence on the immunogenicity, efficacy and safety of the CYD-TDV dengue vaccine. METHOD: Meta analysis and systematic review. RESULTS: The best and worst immunogenicity results were for DENV4 and DENV1, respectively. Vaccine efficacy of 60% was derived from studies with participants aged 2-16 years old, with DENV4 and DENV2 presenting the best and worst results, respectively. Erythema and swelling were more frequent with CYD-TDV. No differences were detected for systemic adverse events. CONCLUSION: CYD-TDV showed moderate efficacy in children and adolescents. From the immunogenicity results in adults, we can expect satisfactory efficacy from vaccination in this population. PMID- 28084785 TI - Quantification of the force systems delivered by transpalatal arches activated in the six Burstone geometries. AB - OBJECTIVE: To evaluate the force systems produced by transpalatal arches (TPAs) activated according to the six classes of geometries described by Burstone and Koenig. MATERIALS AND METHODS: Sixty appliances were tested for first-order activations using a mechanical force testing system. The TPAs were first checked for passivity in sagittal, transverse, and vertical planes at the measuring machine. Then 10 appliances per group were activated using a millimeter template to obtain the six classes of geometries, and the activated appliances were inserted into lingual tubes of the Force System Identification machine that recorded the deactivation forces and moments delivered by both terminal ends of the TPAs. RESULTS: The overall force system with the actual values of forces and moments recorded by each type of activation was illustrated and compared with the mathematical model reported by Burstone and Koenig. Although a great consistency of the direction of forces and moments were observed, the theoretically feasible force systems could not be fully accomplished by the TPA activated for the six classes of geometries. CONCLUSION: The first-order activations of the TPA can deliver predictable force systems in respect to the direction of forces and moments attainable, but some unexpected forces and moments are also produced. Careful clinical monitoring is, therefore, strongly recommended when using this statically indeterminate system. PMID- 28084786 TI - Seafood allergen-induced hypersensitivity at the microbiota-mucosal site: Implications for prospective probiotic use in allergic response regulation. AB - Food allergy is a serious disease worldwide; it can significantly lower the standard of living of affected individuals and may be life-threatening. In particular, hypersensitivity to seafood has been increasing in recent years owing to rising consumption. The mucosal immune system plays a critical role in the onset of seafood allergy and other allergic diseases. Recently, experimental and clinical evidence has shown that probiotics significantly modulate immune responses and thus suppress allergic reactions. Therefore, in this review, we summarized the basic knowledge of seafood allergy, the mucosal immune system, and probiotic activities. We also reviewed the critical immune factors involved in allergic reactions, as well as the potential mechanism and the potential use of probiotics to ameliorate seafood allergy. The elucidation of these topics may help us to develop preventive and therapeutic approaches for seafood allergy and other immune disorders in the future. PMID- 28084787 TI - What can we do to refine the redundant data in LC-MS and GC-MS based metabolomics? PMID- 28084788 TI - Characteristics of Adults Who Used Mindfulness Meditation: United States, 2012. AB - OBJECTIVES: To describe estimates of the number and characteristics of persons who had used mindfulness meditation in the U.S. POPULATION: DESIGN: Data from 108,131 adults from the 2012 National Health Interview Survey were weighted to produce national estimates representative of the U.S. POPULATION: Persons who used mindfulness meditation were identified by their response to the question "During the past 12 months, did you use mindfulness meditation?" RESULTS: An estimated 2,029,720 adults had used mindfulness meditation. Compared with those who did not meditate, more meditators endorsed moderate exercise (79.6% vs. 54.8%; p < 0.0001). More meditators had low-back and neck pain and headache (36.7% vs. 28.9 [p = 0.0002]; 26.4% vs. 14.7% [p<0.0001]; 19.1% vs. 12.1% [p<0.0001], respectively). More meditators reported being nervous or feeling sad at least a little of the time (60.4% vs. 37.8% and 34% vs. 23.5%, respectively; p<0.0001) and being frequently stressed (56.4% vs. 29.0%; p<0.0001). CONCLUSIONS: Mindfulness meditation was used by an estimated 2,029,720 adults in the United States in 2012. More meditators than nonmeditators reported more pain and reported feeling nervous or sad and being stressed, suggesting a reason for using mindfulness meditation. PMID- 28084789 TI - Evaluation of immobilized hFMO3 on magnetic nanoparticles by capillary zone electrophoresis. AB - AIM: In this paper, we developed a method to immobilize human flavin-containing monooxygenase-3 (hFMO3) using glutaraldehyde as a cross-linker onto amino functionalized magnetic nanoparticles. MATERIALS & METHODS: All the analyses were done using capillary electrophoresis coupled with a diode array detector using clozapine as a substrate. RESULTS: The apparent Km with clozapine as substrate and inhibition of hFMO3 by methimazole were explored for immobilized hFMO3 and were found to be comparable to literature values. The immobilized enzyme could be used three-times continuously at 37 degrees C with no loss in enzyme activity. CONCLUSION: A method to immobilize hFMO3 on magnetic nanoparticles has been described and evaluated in terms of enzyme activity, inhibition, pH stability and reusability. PMID- 28084790 TI - As Above, So Below: Tumbling Silos at the Harvard Osher Center's 2016 Integrative Medicine Network Forum. PMID- 28084791 TI - Evaluation of the potential killing performance of novel percussive and cervical dislocation tools in chicken cadavers. AB - 1. Four mechanical poultry killing devices; modified Armadillo (MARM), modified Rabbit Zinger (MZIN), modified pliers (MPLI) and a novel mechanical cervical dislocation (NMCD) gloved device, were assessed for their killing potential in the cadavers of euthanised birds. 2. A 4 * 4 * 4 factorial design (batch * device * bird type + age) was employed. Ten bird cadavers per bird type and age were tested with each of the 4 devices (N = 160 birds). All cadavers were examined post-mortem to establish the anatomical damage caused. 3. NMCD, MARM and MZIN demonstrated killing potential, as well as consistency in their anatomical effects. NMCD had the highest killing potential, with 100% of birds sustaining the required physical trauma to have caused rapid death. 4. The MPLI was inconsistent, and only performed optimally for 27.5% of birds. Severe crushing injury was seen in >50% of MPLI birds, suggesting that birds would die of asphyxia rather than cerebral ischaemia, a major welfare concern. As a result, the MPLI are not recommended as a humane on-farm killing device for chickens. 5. This experiment provides important data on the killing potential of untried novel percussive and mechanical cervical dislocation methods, informing future studies. PMID- 28084792 TI - Antitrichomonal activity of Peganum harmala alkaloid extract against trichomoniasis in pigeon (Columba livia domestica). AB - 1. This study was designed to evaluate the antitrichomonal effects of P. harmala alkaloid extract against T. gallinae, both in vitro and in vivo, as well as comparing it to that of metronidazole, conventional antitrichomonal medication and harmine and harmaline, the two alkaloids present in P. harmala. 2. T. gallinae were collected by the wet mount method from infected free-living pigeons. The in vitro assay was performed using multi-well plates containing test compounds in final concentrations of 5, 10, 15, 20, 30, 50 or 100 MUg/ml. The in vivo assay was done on 60 experimentally infected pigeons dosed with metronidazole at 50 mg/kg body weight (BW) or alkaloids at 25 mg/kg BW. 3. The 24 h minimum inhibitory concentration (MIC) of alkaloid extract was 15 ug/ml while that of metronidazole was 50 ug/ml. Harmine and harmaline revealed 24 h MIC of 30 and 100 ug/ml, respectively. Treatment of infected pigeons with alkaloids led to a full recovery after 3 d but with metronidazole total eradication of trophozoites was not achieved. 4. In conclusion, data of the present study suggested P. harmala is a potent natural anti-trichomonal agent, effective against T. gallinae. PMID- 28084793 TI - Test-Retest Reproducibility of the Intrinsic Default Mode Network: Influence of Functional Magnetic Resonance Imaging Slice-Order Acquisition and Head-Motion Correction Methods. AB - Head motion is a known challenge in resting-state functional magnetic resonance imaging studies for biasing functional connectivity (FC) among distinct anatomical regions. These persist even with small motion, limiting comparisons of groups with different head-motion characteristics. This motivates an interest in the optimization of acquisition and correction strategies to minimize motion sensitivity. In this test-retest (TRT) study of healthy young volunteers (N = 23), we investigate the effects of slice-order acquisitions (sequential or interleaved) and head-motion correction methods (volume- or slice-based) on the TRT reproducibility of intrinsic connectivity of the default mode network (DMN). We evaluated the TRT reproducibility of the entire DMN and each main node using the absolute percentage error, intraclass correlation coefficient (ICC), and the Jaccard coefficient. Regardless of slice-order acquisition, the slice-based motion correction method systematically estimated larger motion and returned significantly higher temporal signal-to-noise ratio. Although consistently extracted across all acquisition and motion correction approaches, DMN connectivity was sensitive to these choices. However, the TRT reproducibility of the whole DMN was stable and showed no sensitivity to the methods tested (absolute reproducibility ~7%, ICC = 0.47, and Jaccard = 40%). Percentage errors and ICCs were consistent across single nodes, but the Jaccard coefficients were not. The posterior cingulate was the most reproducible node (Jaccard = 52%), whereas the anterior cingulate was the least reproducible (Jaccard = 30%). Our study suggests that the slice-order and motion correction methods evaluated offer comparable sensitivity to detect DMN connectivity changes in a longitudinal study of individuals with low head-motion characteristics, but that controlling for the consistency in acquisition and correction protocols is important in cross sectional studies. PMID- 28084794 TI - Inductive expression of the NOD1 signalling pathway in chickens infected with Salmonella pullorum. AB - 1. The aim of this study was to describe the role of Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) receptor signalling in chicken. 2. Tissue-specific expression analysis of NOD1, receptor-interacting serine-threonine kinase 2 (RIPK2), nuclear factor kappa B (NF-kappaB) and mitogen activated protein kinase 11 (MAPK11 or p38) by quantitative real-time PCR (qRT PCR) revealed their wide distribution in various organs and tissues. 3. Salmonella pullorum infection activated NOD1 receptor signalling in vivo and in vitro, resulting in significant induction of downstream signalling molecules RIPK2, NF-kappaB/p65, MAPK11/p38 and the effector molecules IL-1b and IL-8. 4. Activation of NOD1 by its agonist bacterial gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP) in HD11 cells induced the adapter molecular RIPK2 and activated the NF-kappaB/p65 and MAPK11/p38 pathways, resulting in an increase in IL-8 but not IL-1beta. Additionally, inhibition of NOD1 using NOD1-shRNA resulted in downregulation of RIPK2, MAPK11 and IL-8, while NF-kappaB/p65 and IL-1beta were unaltered. 5. These results highlight the important role of NOD1 receptors in eliciting the innate immune response following pathogenic invasion in chicken. PMID- 28084795 TI - Moderate physical activity promotes basal hepatic autophagy in diet-induced obese mice. AB - Obesity is a known risk factor for the development of hepatic disease; obesity induced fatty liver can lead to inflammation, steatosis, and cirrhosis and is associated with degeneration of the mitochondria. Lifestyle interventions such as physical activity may ameliorate this condition. The purpose of this study was to investigate regulation of mitochondrial and autophagy quality control in liver following Western diet-induced obesity and voluntary physical activity. Eight week-old C57BL/6J mice were fed a Western diet (WD) or normal chow (NC, control) for 4 weeks; afterwards, groups were divided into voluntary wheel running (VWR) or sedentary (SED) conditions for an additional 4 weeks. WD-SED animals had a median histology score of 2, whereas WD-VWR was not different from NC groups (median score 1). There was no difference in mRNA of inflammatory markers Il6 and Tnfa in WD animals. WD animals had 50% lower mitochondrial content (COX IV and Cytochrome C proteins), 50% lower Pgc1a mRNA content, and reduced content of mitochondrial fusion and fission markers. Markers of autophagy were increased in VWR animals, regardless of obesity, as measured by 50% greater LC3-II/I ratio and 40% lower p62 protein content. BNIP3 protein content was 30% less in WD animals compared with NC animals, regardless of physical activity. Diet-induced obesity results in derangements in mitochondrial quality control that appear to occur prior to the onset of hepatic inflammation. Moderate physical activity appears to enhance basal autophagy in the liver; increased autophagy may provide protection from hepatic fat accumulation. PMID- 28084797 TI - Phosphate-assisted phytoremediation of arsenic by Brassica napus and Brassica juncea: Morphological and physiological response. AB - In this study, we examined the potential role of phosphate (P; 0, 50, 100 mg kg 1) on growth, gas exchange attributes, and photosynthetic pigments of Brassica napus and Brassica juncea under arsenic (As) stress (0, 25, 50, 75 mg kg-1) in a pot experiment. Results revealed that phosphate supplementation (P100) to As stressed plants significantly increased shoot As concentration, dry biomass yield, and As uptake, in addition to the improved morphological and gas exchange attributes and photosynthetic pigments over P0. However, phosphate-assisted increase in As uptake was substantially (up to two times) greater for B. napus, notably due to higher shoot As concentration and dry biomass yield, compared to B. juncea at the P100 level. While phosphate addition in soil (P100) led to enhanced shoot As concentration in B. juncea, it reduced shoot dry biomass, primarily after 50 and 75 mg kg-1 As treatments. The translocation factor and bioconcentration factor values of B. napus were higher than B. juncea for all As levels in the presence of phosphate. This study demonstrates that phosphate supplementation has a potential to improve As phytoextraction efficiency, predominantly for B. napus, by minimizing As-induced damage to plant growth, as well as by improving the physiological and photosynthetic attributes. PMID- 28084798 TI - Antioxidant molecular targets of wheat bran fermented by white rot fungi and its potential modulation of antioxidative status in broiler chickens. AB - 1. The study focused on antioxidant molecular targets of wheat bran fermented by white rot fungi (WRF) in poultry. After solid-state fermentation of wheat bran by WRF for 12 d, scanning electron microscopy found that the lignocellulose structure showed degradation and fragmentation. 2. A total of 300 1-d-old broilers were evenly divided by gender and randomly allocated into the following treatments: (1) maize-soybean meal (control group), (2) 10% of wheat bran replacing maize (10% WB group) or (3) 10% of fermented wheat bran replacing maize (10% FWB group). 3. The results indicated that the antioxidant gene expression, such as haem oxygenase-1 and glutathione-S-transferase of chicken peripheral blood mononuclear cells, of the 10% FWB group was significantly higher than that of the control group at d 35. For genes of Nicotinamide adenine dinucleotide phosphate oxygenase 1 and reactive oxygen species modulator protein 1, the expression of the 10% FWB group was lower than that of the control group at d 21 and 35. 4. In conclusion, wheat bran fermented by WRF could increase lignocellulolytic enzyme activities and the levels of active components that further regulate the expression of antioxidant molecular targets in poultry. PMID- 28084796 TI - Beyond Viral Neutralization. AB - It has been known for more than 30 years that HIV-1 infection drives a very potent B cell response resulting in the production of anti-HIV-1 antibodies targeting several viral proteins, particularly its envelope glycoproteins (Env). Env epitopes are exposed on the surfaces of viral particles and infected cells where they are targets of potentially protective antibodies. These antibodies can interdict infection by neutralization and there is strong evidence suggesting that Fc-mediated effector function can also contribute to protection. Current evidence suggests that Fc-mediated effector function plays a role in protection against infection by broadly neutralizing antibodies and it might be important for protection by non-neutralizing antibodies. Fc-mediated effector function includes diverse mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), antibody-mediated complement activation, antibody-dependent cellular phagocytosis, antibody-dependent cell-mediated virus inhibition, antibody mediated trancytosis inhibition, and antibody-mediated virus opsonization. All these functions could be beneficial in fighting viral infections, including HIV 1. In this perspective, we discuss the latest developments in ADCC research discussed at the HIVR4P satellite session on non-neutralizing antibodies, with emphasis on the mechanisms of ADCC resistance used by HIV-1, the structural basis of epitopes recognized by antibodies that mediate ADCC, natural killer-cell education and ADCC, and murine models to study ADCC against HIV-1. PMID- 28084799 TI - Examining Clinics for Children with Autism: The Autism Translating To Treatment Study. AB - OBJECTIVES: Certain clinical providers specialize in providing complementary and integrative medicine (CIM) therapies for children with autism spectrum disorder (ASD). Because many of these providers and their patients/families have reported substantial improvement, the authors developed an online platform to carefully examine these clinical practices. The initial goal was to examine the feasibility of prospective data collection in this setting. The larger goals were to characterize the tests and treatments used in these clinics; examine associations between specific treatments, biomarkers, and improved outcomes; and identify promising treatments for future study. DESIGN: Prospective cohort study. SETTING: Four CIM clinics specializing in treating children with ASD. PATIENTS: Children with ASD age 2-8 years. INTERVENTIONS: The study protocol provided no interventions, but all interventions provided by the CIM clinical providers were recorded. OUTCOME MEASURES: Aberrant Behavior Checklist (ABC); Social Responsiveness Scale (SRS); and instruments that assessed sensory sensitivity, language, gastrointestinal (GI) symptoms, pediatric quality of life, and caregiver strain. RESULTS: Fourteen children were enrolled (mean age, 4.4 years). Over 3 months, the total behavior score (ABC) decreased (improved) from 110.8 to 103.8 (change, -7.0; 95% confidence interval [CI], -27.9 to 13.9), and the total social responsiveness score (SRS) decreased (improved) from 133.8 to 127.2 (change, -6.6; 95% CI, -30.5 to 17.3), but these changes were not statistically significant. Similarly, caregiver strain and pediatric quality of life decreased (improved) but by a nonsignificant amount. More severe GI symptoms and more severe ASD symptoms were associated with lower quality of life (p < 0.001). CONCLUSIONS: Barriers to successful data collection were identified. Despite these challenges, this study could confirm interesting associations between data elements, highlighting the future value of similar systems for improving evidence based care in this population. PMID- 28084800 TI - The use of halophytic plants for salt phytoremediation in constructed wetlands. AB - This research studied the use of constructed wetlands (CWs) to reduce water salinity. For this purpose, three halophytic species of the Chenopodiaceae family (Salicornia europaea, Salsola crassa, and Bienertia cycloptera) that are resistant to saline conditions were planted in the CWs, and experiments were conducted at three different salinity levels [electrical conductivity (EC)~2, 6, 10 dS/m]. EC and concentrations of calcium (Ca), magnesium (Mg), sodium (Na), and chlorine (Cl) were measured before and after phytoremediation with a retention time of 1 week. The results suggested that these plants were able to grow well and complete their life cycles at all the salinity levels within this study. Moreover, these plants reduced the measured parameters to acceptable levels. Therefore, these plants can be considered good options for salt phytoremediation. PMID- 28084801 TI - A narrative for bioanalytical method development. PMID- 28084802 TI - Comparison of electrogenic glucose transport processes and permeability between proximal and distal jejunum of laying hens. AB - 1. The current objective was to assess (1) differences in mucosal transepithelial short-circuit current (Isc) and tissue conductance (GT), (2) the effect of a glucose stimulus and (3) epithelial paracellular permeability in the proximal and distal jejunum of laying hens. 2. Proximal and distal jejunal segments used in the Ussing chambers were collected at 9 +/- 0.5 and 73 +/- 3.4% (SEM) of jejunal length, respectively. The proximal jejunal mucosa showed a small negative Isc ( 1.3 uA/cm2), whereas the distal jejunum had a higher Isc (32.9 uA/cm2). Similarly, GT was 2.5-fold greater in the distal compared to the proximal jejunum. 3. Increased paracellular permeability in the distal jejunum was displayed as demonstrated by a 5-fold higher mucosal to serosal flux of fluorescein isothiocyanate and horseradish peroxidase, representing molecules of low and high molecular weight, respectively. 4. Addition of glucose to the mucosal side (5 mmol/l, final concentration in the chamber) to stimulate an absorptive effect caused 3-fold greater GT in the distal compared to the proximal jejunum. 5. In conclusion, the present results supported site-specific electrogenic transport processes for the jejunal mucosa of laying hens. Therefore, precise description of the jejunal site may contribute to an improved comparability of electrophysiological data. PMID- 28084803 TI - Growth and nutrient removal of three macrophytes in response to concentrations and ratios of N and P. AB - Wastewater from different sources shows great differences in concentrations and ratios of N and P. In order to choose suitable plant species to remove excess N and/or P from polluted waters, it is important to know the performances of these plants under different N and P concentrations. In this study, we investigated the growth and N and P removal rate of three macrophytes, Coix lacryma-jobi, Iris wilsonii, and Arundo donax under six N and P combination treatments. C. lacryma jobi preferred higher N and P concentrations (16 mg N L-1 and 3.2 mg P L-1), and increasing N supply could increase its P removal rate. I. wilsonii exhibited a growth preference at a combination of moderate N and P concentrations (8 mg N L-1 and 0.8 mg P L-1). A. donax could grow well at all combinations of N and P and had significantly higher relative growth rate and N and P removal rates than the other two species. These results showed A. donax is a promising species to treat various polluted waters and the other two species can be used specifically to treat certain types of wastewater. PMID- 28084804 TI - Comparative effect of calcium and EDTA on arsenic uptake and physiological attributes of Pisum sativum. AB - In this study, we determined the effect of ethylenediaminetetraacetic acid (EDTA) and calcium (Ca) on arsenic (As) uptake and toxicity to Pisum sativum. Plants were treated with three levels of As (25, 125, and 250 uM) in the presence and absence of three levels of Ca (1, 5, and 10 mM) and EDTA (25, 125, and 250 uM). Exposure to As caused an overproduction of hydrogen peroxide (H2O2) in roots and leaves, which induced lipid peroxidation and decreased pigment contents. Application of both Ca and EDTA significantly reduced As accumulation by pea, Ca being more effective in reducing As accumulation. Both Ca and EDTA enhanced As induced H2O2 production, but reduced lipid peroxidation. In the case of pigment contents, EDTA significantly reduced pigment contents, whereas Ca significantly enhanced pigment contents compared to As alone. The effect of As treatment in the presence and absence of EDTA and Ca was more pronounced in younger leaves compared to older leaves. The effect of amendments varied greatly with their applied levels, as well as type and age of plant organs. Importantly, due to possible precipitation of Ca-As compounds, the soils with higher levels of Ca ions are likely to be less prone to food chain contamination. PMID- 28084805 TI - Assessment of health and welfare of Austrian laying hens at slaughter demonstrates influence of husbandry system and season. AB - 1. Selected health and welfare variables of laying hens from 79 flocks kept in alternative husbandry systems were assessed at the end of lay. 2. Investigations were carried out on 100 hens per flock at the slaughter line and recorded as part of a novel scoring system. In addition, post-mortem investigations as well as parasitological examinations were conducted on 10 birds from each flock. 3. Birds with access to free range had better plumage than birds kept in barn systems. Housing in aviaries was associated with a higher prevalence of foot pad lesions and keel bone deformations. In addition, poorer plumage, more and worse skin and foot pad lesions were documented in hens slaughtered during the winter months. 4. Oophoritis and/or salpingitis were the most prevalent pathomorphological changes observed. Intestinal parasites, especially Heterakis gallinarum and Ascaridia galli, were frequent. Hens kept indoors had fewer nematoda and cestoda than those from conventional and organic free range. 5. The slaughterhouse protocol allowed direct comparison of variables between flocks and specific problems to be identified in particular flocks. The results could be used to initiate detailed investigations into problematic issues on selected farms. PMID- 28084806 TI - Does coffee consumption alter plasma lipoprotein(a) concentrations? A systematic review. AB - Coffee consumption alters plasma lipid and cholesterol concentrations, however, its effects on lipoprotein(a) (Lp(a)) have received little study. The aim of this PRISMA compliant systematic review was to examine the role of coffee on serum Lp(a). This study was prospectively registered (PROSPERO 2015:CRD42015032335). PubMed, Scopus, Web of Science and Cochrane Central were searched from inception until 9th January 2016 to detect trials and epidemiological studies investigating the impact of coffee on serum Lp(a) concentrations in humans. We identified six relevant publications describing nine experimental trials of various designs. There were a total of 640 participants across all studies and experimental groups. In short-term controlled studies, consumption of coffee, or coffee diterpenes was associated with either a reduction in serum Lp(a) of <=11 mg/dL (6 trials, 275 participants), or no effect (2 trials, 56 participants). Conversely, one cross-sectional study with 309 participants showed serum Lp(a) was elevated in chronic consumers of boiled coffee who had a median Lp(a) of 13.0 mg/dL (range 0-130) compared with consumers of filtered coffee who had median Lp(a) 7.9 mg/dL (range 0-144). The effect of coffee on Lp(a) is complex and may follow a biphasic time-course. The type of coffee and the method of preparation appear to be important to determining the effect on Lp(a). PMID- 28084807 TI - Experiences of healthcare assistants working with clients with dementia in residential care homes. AB - The study aimed to explore the experiences of healthcare assistants working with people with dementia in UK residential care homes. Eight participants completed semi-structured interviews which were analysed by interpretative phenomenological analysis. Data analysis revealed three main themes representing healthcare assistants' experiences: the importance of relationships, which referred to the importance of their relationships with clients, families and colleagues as well as their attachment to clients; something special about the role, which referred to their perception that their role was unique and rewarding as well as their personal commitment to the job; and the other side of caring, which referred to the more difficult aspects of their role, including managing emotions and conflicts within the caring role. The findings indicate that staff should be supported to build strong and supportive relationships within their role and have opportunities to explore their emotional reactions to reduce any adverse impact on care provision. It is possible that this could be facilitated through reflective practice groups or clinical supervision. PMID- 28084808 TI - Police officer competence in handling Alzheimer's cases: The roles of AD knowledge, beliefs, and exposure. AB - This study seeks to understand the level of police officer competence for providing assistance during interactions with patients of Alzheimer's disease (AD), and to reveal the roles their knowledge of AD, beliefs of AD, and previous exposure to patients with AD play in influencing these competence levels. Data were collected from police officers in two Phoenix metropolitan-area police departments through focus group discussions and survey. Four focus groups comprised of 27 police officers discussed their perceptions of AD and challenges of dealing with individuals with AD. Building on the findings from the focus groups, an online survey ( n = 228) examined police officer AD knowledge, as well as their experience and competence in the handling of AD cases. Police participants had fair knowledge of AD with an average 71.8% accuracy rate. More AD knowledge ( B = 0.29) and higher levels of education ( B = 0.85) were associated with higher levels of competence of recognizing AD-related behaviors. Low levels of discomfort interacting with AD patients ( B = -0.75) and having a family member of dementia ( B = 1.32) were related to higher levels of competence of reacting appropriately to an AD patient. The findings suggest that information about the best practices for dealing with community residents with AD needs to be made available to police officers. To ensure a dementia-friendly environment, aging service providers need to reach out to local law enforcement departments and provide training that promotes AD knowledge, decreases AD-related stigma, and increases competence of handing dementia cases in a way that fits the policing culture. PMID- 28084809 TI - Mitochondrial genome of the sweet potato hornworm, Agrius convolvuli (Lepidoptera: Sphingidae), and comparison with other Lepidoptera species. AB - In the present study, we sequenced the complete mitochondrial genome (mitogenome) of Agrius convolvuli (Lepidoptera: Sphingidae) and compared it with previously sequenced mitogenomes of lepidopteran species. The mitogenome was a circular molecule, 15 349 base pairs (bp) long, containing 37 genes. The order and orientation of genes in the A. convolvuli mitogenome were similar to those in sequenced mitogenomes of other lepidopterans. All 13 protein-coding genes (PCGs) were initiated by ATN codons, except for the cytochrome c oxidase subunit 1 (cox1) gene, which seemed to be initiated by the codon CGA, as observed in other lepidopterans. Three of the 13 PCGs had the incomplete termination codon T, while the remainder terminated with TAA. Additionally, the codon distributions of the 13 PCGs revealed that Asn, Ile, Leu2, Lys, Phe, and Tyr were the most frequently used codon families. All transfer RNAs were folded into the expected cloverleaf structure except for tRNASer(AGN), which lacked a stable dihydrouridine arm. The length of the adenine (A) + thymine (T)-rich region was 331 bp. This region included the motif ATAGA followed by a 19-bp poly-T stretch and a microsatellite like (TA)8 element next to the motif ATTTA. Phylogenetic analyses (maximum likelihood and Bayesian methods) showed that A. convolvuli belongs to the family Sphingidae. PMID- 28084810 TI - Fluoroscopic-guided stent placement in failed tentative endoscopic approaches to malignant gastroduodenal obstructions. AB - Background Fluoroscopic or endoscopic placement of metallic stents is used as a safe, non-surgical, palliative treatment option for malignant gastroduodenal obstructions. However, endoscopic stent placement is not always feasible, due to the tight or tortuous stricture of the obstructed area and insufficient visualization of the stomach due to remnant food material. Purpose To assess the technical feasibility and clinical outcomes of fluoroscopic-guided stent placement in malignant gastroduodenal obstructions following the technical failure of endoscopic stent placement. Material and Methods In all, 19 patients (14 men, 5 women; age range, 36-85 years) were referred due to technical failures of tentative endoscopic stent placement. Indications were failure to pass the guide wire through the obstruction (n = 13), failure to reach the stricture lesion due to short endoscope (n = 5), and acute angulation of the stricture lesion (n = 1). Data were retrospectively collected regarding the technical and clinical success of the fluoroscopy, the dysphagia score before and after stent placement, and major complications and their management. Results Fluoroscopic stent placement was technically successful in 15/19 patients (79%). Failures were due to complete obstruction (n = 3) and acute angulation of the stricture lesion (n = 1). Clinical success was achieved in all 15 patients with successful stent placement. The dysphagia score significantly improved after stent placement ( P < 0.001). Complications occurred in 4/15 patients (27%), including tumor overgrowth (n = 2), stent collapse (n = 1), and jaundice (n = 1). Conclusion Fluoroscopic stent placement in malignant gastroduodenal obstructions following a technical failure of endoscopic stent placement is technically feasible and has an acceptable clinical outcome. PMID- 28084811 TI - Power Doppler signal calibration in the finger joint between two models of ultrasound machine: a pilot study using a phantom and joints in patients with rheumatoid arthritis. AB - Background Despite the advantages of ultrasound (US) in the management of rheumatoid arthritis (RA) patients, power Doppler (PD) US may be highly dependent on the type of US machine used. Purpose To present a method to calibrate the PD signal of two models of US machines by use of a flow phantom and finger joints of patients with RA. Material and Methods For the phantom study, the PD signal count was measured in the flow phantom perfusing blood mimicking fluid at various injection rates and pulse repetition frequencies (PRFs). The quantitative PD index was calculated with ImageJ. For the clinical study, the second and third metacarpophalangeal joints of five consecutive patients with RA were examined. The quantitative PD index was measured at various PRFs by use of two models of machine (the same models as the phantom study). Results For the phantom and clinical studies, negative correlations were found between the PRF and the quantitative PD index when the flow velocity was constant and positive correlations between flow velocity and the quantitative PD index at constant PRF. There was a significant difference in the depiction performance of synovial blood flow between the two models, which can be calibrated by adjusting the PRF values derived from the phantom study in each model. Conclusion Signal calibration of pannus vascularity between US machines may be possible by adjusting the PRF value according to flow phantom data. Different US machines can thus provide equivalent examination results concerning the pannus vascularity. PMID- 28084812 TI - Impact of transjugular intrahepatic portosystemic shunt implantation on liver perfusion measured by volume perfusion CT. AB - Background Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) induces changes of liver perfusion. Purpose To determine the changes in arterial, portal venous, and total perfusion of the liver parenchyma induced by TIPS using the technique of volume perfusion computed tomography (VPCT) and compare results with invasively measured hepatic intravascular pressure values. Material and Methods VPCT quantification of liver perfusion was performed in 23 patients (mean age, 62.5 +/- 8.8 years) with portal hypertension in the pre-TIPS and post-TIPS setting, respectively. A commercially available software package was used for post-processing, enabling separate calculation of the dual (arterial [ALP] and portal venous [PVP]) blood supply and additionally of the hepatic perfusion index (HPI) (HPI = ALP/(ALP + PVP)*100%). Invasive pressure measurements were performed during the intervention, before and after TIPS placement. Liver function tests performed before and after the procedure were compared. Results Mean decrease of pressure gradient through TIPS was 13.3 mmHg. Mean normal values for ALP, PVP, and total perfusion (ALP + PVP) before TIPS were 15.9, 37.7, and 53.5 mL/100 mL/min, respectively, mean HPI was 35.4%. After TIPS, ALP increased to a mean value of 37.7 mL/100 mL/min, PVP decreased (15.7 mL/100 mL/min, P < 0.05), whereas total perfusion remained unchanged (53.4 mL/100 mL/min, P = 0.97). HPI increased (71.9%; P < 0.05). No correlation between invasive pressure measurement and VPCT parameters was observed. After TIPS, liver function tests were found to worsen with a significant increase of bilirubin ( P < 0.05). Conclusion Following TIPS placement, ALP and HPI increased in all patients, whereas PVP markedly decreased. Interestingly, the magnitude of decrease in portosystemic pressure gradients was not found to correlate with VPCT parameters. PMID- 28084813 TI - MRI diagnosis of carpal boss and comparison with radiography. AB - Background A carpal boss is a potentially painful bony mass in the region of the second or third carpometacarpal joint. The combination of clinical examination and radiography is usually sufficient for the diagnosis. Purpose To determine whether magnetic resonance imaging (MRI) examination of the quadrangular joint can assist the diagnosis of persistent pain near a carpal boss. Material and Methods Fifty-seven patients with a carpal boss were retrospectively reviewed using MRI and conventional radiographs and compared to an asymptomatic control group. Results MRI demonstrated a variable morphology and a variety of bone and soft tissue abnormalities associated with carpal boss. Bone marrow edema around the quadrangular joint shows a significant correlation (Fisher's exact test: P < 0.001) and a positive correlation (Pearson's test r = 0.632, significant at the 0.01 level [two-tailed]) with a painful carpal boss. Conclusion MRI offers detailed examination of bone and soft tissue abnormalities associated with a carpal boss. Local bone marrow edema strongly correlates with a painful carpal boss. PMID- 28084814 TI - Feasibility of low-dose digital pulsed video-fluoroscopic swallow exams (VFSE): effects on radiation dose and image quality. AB - Background Fluoroscopy is a frequently used examination in clinical routine without appropriate research evaluation latest hardware and software equipment. Purpose To evaluate the feasibility of low-dose pulsed video-fluoroscopic swallowing exams (pVFSE) to reduce dose exposure in patients with swallowing disorders compared to high-resolution radiograph examinations (hrVFSE) serving as standard of reference. Material and Methods A phantom study (Alderson-Rando Phantom, 60 thermoluminescent dosimeters [TLD]) was performed for dose measurements. Acquisition parameters were as follows: (i) pVFSE: 76.7 kV, 57 mA, 0.9 Cu mm, pulse rate/s 30; (ii) hrVFSE: 68.0 kV, 362 mA, 0.2 Cu mm, pictures 30/s. The dose area product (DAP) indicated by the detector system and the radiation dose derived from the TLD measurements were analyzed. In a patient study, image quality was assessed qualitatively (5-point Likert scale, 5 = hrVFSE; two independent readers) and quantitatively (SNR) in 35 patients who subsequently underwent contrast-enhanced pVFSE and hrVFSE. Results Phantom measurements showed a dose reduction per picture of factor 25 for pVFSE versus hrVFSE images (0.0025 mGy versus 0.062 mGy). The DAP (uGym2) was 28.0 versus 810.5 (pVFSE versus hrVFSE) for an average examination time of 30 s. Direct and scattered organ doses were significantly lower for pVFSE as compared to hrVFSE ( P < 0.05). Image quality was rated 3.9 +/- 0.5 for pVFSE versus the hrVFSE standard; depiction of the contrast agent 4.8 +/- 0.3; noise 3.6 +/- 0.5 ( P < 0.05); SNR calculations revealed a relative decreased of 43.9% for pVFSE as compared to hrVFSE. Conclusion Pulsed VFSE is feasible, providing diagnostic image quality at a significant dose reduction as compared to hrVFSE. PMID- 28084815 TI - Diagnostic accuracy of diffusion restriction in intraductal papillary mucinous neoplasm of the pancreas in comparison with "high-risk stigmata" of the 2012 international consensus guidelines for prediction of the malignancy and invasiveness. AB - Background It is debated whether diagnostic performance of diffusion-weighted imaging (DWI), which is widely used for detection and characterization of various malignant tumors, is comparable with high-risk stigmata of 2012 international consensus guidelines (ICG) for diagnosis of intraductal papillary mucinous neoplasms (IPMNs). Purpose To evaluate the diagnostic accuracy of diffusion restriction in IPMNs for prediction of malignancy and invasiveness in comparison with high-risk stigmata of 2012 ICG. Material and Methods This retrospective study was institutional review board approved and informed consent was waived. A total of 132 patients with surgically proven IPMNs (49 malignant, 83 benign) who underwent gadoxetic acid-enhanced magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), and DWI with a b-value of 0, 100, and 800 s/mm2 using a 3.0 T MR system were included. Two radiologists independently evaluated imaging parameters of high-risk stigmata and worrisome features of 2012 ICG and diffusion restriction in IPMNs. Univariate and multivariate logistic regression analyses and McNemar's test were used for statistical analysis. Results The presence of diffusion restriction in IPMNs was the only independent imaging parameter for prediction of malignancy (odds ratio [OR], 11.98; 95% confidence interval [CI], 3.60-39.87; P < 0.001) and invasiveness (OR, 17.92; 95% CI, 3.91-82.03; P < 0.001) on multivariate analysis. The diagnostic accuracy and specificity of diffusion restriction were significantly improved compared to high risk stigmata of 2012 ICG to prediction of malignant ( P = 0.006 and P < 0.001, respectively) or invasive IPMNs ( P = 0.009 and P = 0.015, respectively). Conclusion The diffusion restriction in IPMNs could be considered as another high risk stigma of malignancy and predictor for invasiveness. PMID- 28084816 TI - Maternal Folate Intake during Pregnancy and Childhood Asthma. PMID- 28084817 TI - Bending the Twig Does the Tree Incline: Lung Function after Lower Respiratory Tract Illness in Infancy. PMID- 28084818 TI - Peripheral Artery Disease in Patients with Chronic Obstructive Pulmonary Disease. PMID- 28084819 TI - Can Bisphosphonates Prevent Vitamin K Antagonist Toxicity in Patients with Idiopathic Pulmonary Fibrosis? PMID- 28084820 TI - When Rhythm Changes Cause the Blues: New-Onset Atrial Fibrillation during Sepsis. PMID- 28084821 TI - Spirituality, Palliative Care, and the Intensive Care Unit. A New Approach. PMID- 28084823 TI - Reply: The New Idiopathic Pulmonary Fibrosis Acute Exacerbations Document: One Step Ahead but Still Suspended in the Air. PMID- 28084822 TI - An Official American Thoracic Society Research Statement: Current Challenges Facing Research and Therapeutic Advances in Airway Remodeling. AB - BACKGROUND: Airway remodeling (AR) is a prominent feature of asthma and other obstructive lung diseases that is minimally affected by current treatments. The goals of this Official American Thoracic Society (ATS) Research Statement are to discuss the scientific, technological, economic, and regulatory issues that deter progress of AR research and development of therapeutics targeting AR and to propose approaches and solutions to these specific problems. This Statement is not intended to provide clinical practice recommendations on any disease in which AR is observed and/or plays a role. METHODS: An international multidisciplinary group from within academia, industry, and the National Institutes of Health, with expertise in multimodal approaches to the study of airway structure and function, pulmonary research and clinical practice in obstructive lung disease, and drug discovery platforms was invited to participate in one internet-based and one face to-face meeting to address the above-stated goals. Although the majority of the analysis related to AR was in asthma, AR in other diseases was also discussed and considered in the recommendations. A literature search of PubMed was performed to support conclusions. The search was not a systematic review of the evidence. RESULTS: Multiple conceptual, logistical, economic, and regulatory deterrents were identified that limit the performance of AR research and impede accelerated, intensive development of AR-focused therapeutics. Complementary solutions that leverage expertise of academia and industry were proposed to address them. CONCLUSIONS: To date, numerous factors related to the intrinsic difficulty in performing AR research, and economic forces that are disincentives for the pursuit of AR treatments, have thwarted the ability to understand AR pathology and mechanisms and to address it clinically. This ATS Research Statement identifies potential solutions for each of these factors and emphasizes the importance of educating the global research community as to the extent of the problem as a critical first step in developing effective strategies for: (1) increasing the extent and impact of AR research and (2) developing, testing, and ultimately improving drugs targeting AR. PMID- 28084824 TI - Lung Function in Children from Sub-Saharan Africa and the Global Lung Initiative 2012 Reference Equations. PMID- 28084825 TI - Toward Predicting Individual Risk in Asthma Using Daily Home Monitoring of Resistance. PMID- 28084826 TI - The New Idiopathic Pulmonary Fibrosis Acute Exacerbations Document: One Step Ahead but Still Suspended in the Air. PMID- 28084827 TI - Reply: Can Bisphosphonates Prevent Vitamin K Antagonist Toxicity in Patients with Idiopathic Pulmonary Fibrosis? PMID- 28084828 TI - What is Hemodialysis? PMID- 28084829 TI - Reply: Is a Trial of Vitamin K Antagonists and Bisphosphonates Possible in IPF? PMID- 28084830 TI - Simplification of a Septic Shock Endotyping Strategy for Clinical Application. PMID- 28084831 TI - Toward Precision Medicine of Symptom Control in Asthma. PMID- 28084832 TI - Shoulder pain in the Swiss spinal cord injury community: prevalence and associated factors. AB - PURPOSE: To determine the prevalence of shoulder pain and to identify factors associated with shoulder pain in a nationwide survey of individuals living with spinal cord injury (SCI) in Switzerland. METHODS: Data was collected through the 2012 community survey of the Swiss SCI Cohort Study (SwiSCI) (N = 1549; age 52.3 +/- 14.8; 29% female). Sociodemographic and socioeconomic circumstances, SCI characteristics, health conditions as well as mobility independence and sporting activities were evaluated as predictor variables. Analyses were adjusted for item non-response (using multiple imputation) and unit-nonresponse (using inverse probability weighting). RESULTS: The adjusted prevalence of shoulder pain was 35.8% (95% CI: 33.4-38.3). Multivariable regression analysis revealed higher odds of shoulder pain in females as compared to males (odds ratio: 1.89; 95% CI: 1.44 2.47), and when spasticity (1.36; 1.00-1.85) and contractures (2.47; 1.91-3.19) were apparent. Individuals with complete paraplegia (1.62; 1.13-2.32) or any tetraplegia (complete: 1.63; 1.01-2.62; incomplete: 1.82; 1.30-2.56) showed higher odds of shoulder pain compared to those with incomplete paraplegia. CONCLUSIONS: This survey revealed a high prevalence of shoulder pain. Sex, SCI severity, and specific health conditions were associated with having shoulder pain. Implications for rehabilitation Individuals with spinal cord injury have a high prevalence of shoulder pain. Females, individuals with complete paraplegia or any tetraplegia and individuals with contractures and spasticity should receive considerable attention in rehabilitation programmes due to their increased odds of having shoulder pain. PMID- 28084833 TI - Specific balance training included in an endurance-resistance exercise program improves postural balance in elderly patients undergoing haemodialysis. AB - PURPOSE: The purpose of this study was to evaluate the effects of 6 months of specific balance training included in endurance-resistance program on postural balance in haemodialysis (HD) patients. METHODS: Forty-nine male patients undergoing HD were randomly assigned to an intervention group (balance training included in an endurance-resistance training, n = 26) or a control group (resistance-endurance training only, n = 23). Postural control was assessed using six clinical tests; Timed Up and Go test, Tinetti Mobility Test, Berg Balance Scale, Unipodal Stance test, Mini-Balance Evaluation Systems Test and Activities Balance Confidence scale. RESULTS: All balance measures increased significantly after the period of rehabilitation training in the intervention group. Only the Timed Up and Go, Berg Balance Scale, Mini-Balance Evaluation Systems Test and Activities Balance Confidence scores were improved in the control group. The ranges of change in these tests were greater in the balance training group. CONCLUSIONS: In HD patients, specific balance training included in a usual endurance-resistance training program improves static and dynamic balance better than endurance-resistance training only. Implications for rehabilitation Rehabilitation using exercise in haemodialysis patients improved global mobility and functional abilities. Specific balance training included in usual endurance resistance training program could lead to improved static and dynamic balance. PMID- 28084834 TI - The processes underpinning reductions in disability among people with chronic neck pain. A preliminary comparison between two distinct types of physiotherapy intervention. AB - PURPOSE: To establish whether different processes underpin changes in disability in people with neck pain who underwent two types of active physiotherapy intervention. MATERIALS AND METHODS: This study was a sub-analysis of a randomized controlled trial assessing whether the addition of Interactive Behavioral Modification Therapy (a cognitively informed physiotherapy treatment) to a Progressive Neck Exercise Program improved outcome in patients with chronic neck pain. Regression analyses were performed to determine the extent to which demographics, changes in pain, and changes in certain cognitive factors were related to changes in disability. RESULTS: In the progressive neck exercise group, changes in levels of pain intensity were the only factor significantly related to change in disability, explaining 33% of the variance. In the interactive behavioral modification therapy group, changes in pain intensity, and catastrophizing together explained 54% of the variance in change in disability. Only changes in catastrophizing displayed a significant beta value in the final model. CONCLUSIONS: Different processes appear to underpin changes in disability in patients undergoing cognitively informed physiotherapy to those undergoing a primarily exercise-based approach. Implications for rehabilitation Certain cognitive factors are known to be related to levels of disability in patients with chronic neck pain Specifically targeting these factors results in more patients making a clinically meaningful reduction in disability Different processes appear to underpin reductions in disability when people with neck pain are treated with cognitively informed physiotherapy to when treated with exercise alone, which may account for why more patients improve when treated in this manner. Reductions in catastrophizing appear to be particularly important and efforts should be made to assess and treat catastrophic thoughts in people with chronic neck pain. PMID- 28084835 TI - Induction of p53 suppresses chronic myeloid leukemia. AB - Chronic myeloid leukemia (CML) is characterized by the chromosomal translocation 9;22, known as the Philadelphia chromosome (Ph), which produces the BCR-ABL fusion tyrosine kinase. Although well-managed by BCR-ABL tyrosine kinase inhibitors (TKIs), treatment fails to eliminate Ph + primitive progenitors, and cessation of therapy frequently results in relapse. The p53 protein is an important regulator of cell cycle and apoptosis. The small molecules MI-219 target the interaction between p53 and its negative regulator HDM2, leading to its stabilization and activation. We show that treatment with MI-219 reduced the number of CML cells in both in vitro and in vivo settings but not that of normal primitive progenitors, and activated different gene signatures in CML potentially explaining the differential impact of this agent on each population. Our data suggest that a p53-activating agent may be an effective approach in the management and potential operational cure of CML. PMID- 28084836 TI - Towards a short questionnaire for stepwise assessment of upper limb function, pain and stiffness in Duchenne muscular dystrophy. AB - PURPOSE: Duchenne muscular dystrophy can lead to upper extremity limitations, pain and stiffness. In a previous study, these domains have been investigated using extensive questionnaires, which are too time-consuming for clinical practice. This study aimed at gaining insight into the underlying dimensions of these questionnaires, and to construct a short questionnaire that can be used for clinical assessment. METHODS: Exploratory factor analysis was performed on the responses of 213 participants to a web-based survey to find the underlying dimensions in the Capabilities of Upper Extremity questionnaire, the ABILHAND questionnaire, and questionnaires regarding pain and stiffness. Based on these underlying dimensions, a stepwise approach was formulated. In addition, construct validity of the factors was investigated. RESULTS: In total, 14 factors were identified. All had high internal consistency (Cronbach's alpha >0.89) and explained 80-88% of the variance of the original questionnaires. Construct validity was supported, because participants in the early ambulatory stage performed significantly better (p< 0.001) than participants in the late non ambulatory stage. CONCLUSION: The factors identified from the set of questionnaires provide a valid representation of upper extremity function, pain and stiffness in Duchenne muscular dystrophy. Based on the factor commonalities, the Upper Limb Short Questionnaire was formulated. Implications for Rehabilitation New insights into the underlying dimensions of upper extremity function, pain and stiffness in Duchenne muscular dystrophy are gained. Fourteen factors, with good internal consistency and construct validity, are identified regarding upper extremity function, pain and stiffness in Duchenne muscular dystrophy. Based on these factors, the Upper Limb Short Questionnaire is presented. The Upper Limb Short Questionnaire can be used as an identifier of arm hand limitations and the start of more thorough clinical investigation. PMID- 28084837 TI - A small variation in average particle size of PLGA nanoparticles prepared by nanoprecipitation leads to considerable change in nanoparticles' characteristics and efficacy of intracellular delivery. AB - In this study, it was aimed to investigate characteristics and intracellular delivery of two different-sized PLGA nanoparticles in ouzo region by considering number of nanoparticles. To determine the effect of formulation parameters on average particle size, Dil labeled nanoparticles were prepared using a three factor, two-level full factorial statistical experimental design. PLGA230 (230.8 +/- 4.32 nm) and PLGA160 (157.9 +/- 6.16 nm) nanoparticles were obtained by altering polymer amount based on experimental design results and characterized. Same number of PLGA230 and PLGA160 nanoparticles per cell were applied onto HEK293 cells; then, cytotoxicity, uptake kinetics and mechanism were evaluated by flow cytometry and fluorescent microscopy. Also same weight of PLGA230 and PLGA160 nanoparticles were applied and cellular uptake of these nanoparticles was evaluated. It was found that PLGA230 nanoparticles had higher encapsulation efficiency and slower dye release compared to PLGA160 nanoparticles. When they were applied at same counts per cell, PLGA230 nanoparticles displayed faster and higher intracellular dye transfer than PLGA160 nanoparticles. On the other hand, PLGA160 appeared to be a more effective vehicle than PLGA230 when applied at the same weight concentration. It was also shown that for both nanoparticles, HEK293 cells employed macropinocytic, caveolae- and clathrin-mediated endocytic pathways. PMID- 28084838 TI - Review e-health. PMID- 28084839 TI - An evaluation of an employment pilot to support forensic mental health service users into work and vocational activities. AB - BACKGROUND: Few employment programmes exist to support forensic service users with severe mental health problems and a criminal history. Little is known about how best to achieve this. The Employment and Social Inclusion Project (ESIP) was developed and piloted to support forensic service users into employment and vocational activities. AIMS: This pilot service evaluation aimed to assess the number of service users who secured employment/vocational activities and explored services users' and staff experiences. METHOD: Quantitative data were collected to record the characteristics of participating service users and how many secured employment and engaged in vocational activities. Eighteen qualitative interviews were conducted with service users and staff. RESULTS: Fifty-seven service users engaged with the project, most were men (93.0%) and previously employed (82.5%). Four service users (7.0%) secured paid competitive employment. Eight (14.0%) gained other paid employment. Tailored one-to-one support to increase skills and build confidence was an important feature of the project. Creation of a painting and decorating programme offered training and paid/flexible work. CONCLUSIONS: This exploratory project achieved some success in assisting forensic service users into paid employment. Further research to identify what works well for this important group will be of great value. PMID- 28084840 TI - Effect of directness of exposure and trauma type on Mental Health Literacy of PTSD. AB - BACKGROUND: Research has demonstrated that Post-Traumatic Stress Disorder (PTSD) is one of the most widely recognized mental disorders, but recognition is affected by trauma type. AIMS: The current study investigated the effect of direct versus indirect exposure to traumatic event and trauma types on Mental Health Literacy (MHL) of PTSD. METHODS: Two hundred and thirty-three participants were asked to identify the mental health problem after presentation of an unlabeled vignette describing a character experiencing PTSD symptoms. The six vignettes described the same symptoms but differed in directness (direct/indirect exposure) and trauma type (rape, military combat or man-made disaster). It was hypothesized that (1) recognition rate would be higher in direct than indirect conditions, and (2) higher in military combat, followed by man-made disaster, and lowest in rape condition. RESULTS: Overall, correct recognition of PTSD was 42.5%. Recognition in direct exposure vignettes was significantly higher than indirect, supporting the first hypothesis. The second hypothesis was only partly supported. While PTSD recognition in rape vignettes was significantly lower than the other two scenarios, no difference was found between combat and man-made disaster trauma types. CONCLUSIONS: Our findings implied under-recognition of PTSD, with lack of awareness of different causes of PTSD and of PTSD from indirect trauma exposure. The latter finding is important in the light of DSM-V revisions to diagnostic criteria for PTSD. PMID- 28084841 TI - Examining methods, messengers and behavioural theories to disseminate physical activity information to individuals with a diagnosis of schizophrenia: a scoping review. AB - BACKGROUND: Many individuals with a diagnosis of schizophrenia are not active and lack the necessary knowledge and confidence to become and stay active. To develop effective physical activity promotion interventions, it is necessary to identify credible messengers and effective methods to disseminate physical activity information to this population. AIMS: The purpose of this scoping review was to identify and examine knowledge mobilization theories, messengers and methods used to disseminate physical activity information to individuals with a diagnosis of schizophrenia. METHOD: This scoping review followed the methodological framework proposed by Arksey and O'Malley. RESULTS: In total, 43 studies and 7 reviews identified multiple messengers and methods used to disseminate physical activity information to individuals with a diagnosis of schizophrenia, but few attempts to structure information theoretically. Findings do not point to which messengers or methods are most effective or which theories should be used to construct information interventions. Studies show that physical activity information should be provided in an individualised manner from staff who could easily connect with patients. CONCLUSIONS: Few researchers have addressed the physical activity information needs of individuals with a diagnosis of schizophrenia. Researchers need to examine and implement effective knowledge mobilization strategies for this population. PMID- 28084842 TI - Aiming for a healthier life: a qualitative content analysis of rehabilitation goals in patients with rheumatic diseases. AB - PURPOSE: To explore and describe rehabilitation goals of patients with rheumatic diseases during rehabilitation stays, and examine whether goal content changed from admission to discharge. METHOD: Fifty-two participants were recruited from six rehabilitation centers in Norway. Goals were formulated by the participants during semi-structured goal-setting conversations with health professionals trained in motivational interviewing. An inductive qualitative content analysis was conducted to classify and quantify the expressed goals. Changes in goal content from admission to discharge were calculated as percentage differences. Goal content was explored across demographic and contextual characteristics. RESULTS: A total of 779 rehabilitation goals were classified into 35 categories, within nine overarching dimensions. These goals varied and covered a wide range of topics. Most common at admission were goals concerning healthy lifestyle, followed by goals concerning symptoms, managing everyday life, adaptation, disease management, social life, and knowledge. At discharge, goals about knowledge and symptoms decreased considerably, and goals about healthy lifestyle and adaptation increased. The health profession involved and patient gender influenced goal content. CONCLUSIONS: The rehabilitation goals of the patients with rheumatic diseases were found to be wide-ranging, with healthy lifestyle as the most prominent focus. Goal content changed between admission to, and discharge from, rehabilitation stays. Implications for rehabilitation Rehabilitation goals set by patients with rheumatic diseases most frequently concern healthy lifestyle changes, yet span a wide range of topics. Patient goals vary by gender and are influenced by the profession of the health care worker involved in the goal-setting process. To meet the diversity of patient needs, health professionals need to be aware of their potential influence on the actual goal-setting task, which may limit the range of topics patients present when they are asked to set rehabilitation goals. The proposed framework for classifying goal content has the capacity to detect changes in goals occurring during the rehabilitation process, and may be used as a clinical tool during goal-setting conversations for this patient group. PMID- 28084843 TI - Perspectives of individuals with sub-acute spinal cord injury after personalized adapted locomotor training. AB - PURPOSE: Locomotor training after incomplete spinal cord injury can improve walking function, and cardiovascular and muscle health. Participants' perspectives about locomotor training, however, have not been extensively studied. This study describes the experiences of individuals with sub-acute incomplete spinal cord injury who completed personalized adapted locomotor training; a locomotor-focused rehabilitation tailored to individual goals. Specifically, we examined how participation in this training impacted their lives and what challenges they encountered. MATERIALS AND METHODS: Following inpatient rehabilitation, seven participants completed 74-197 h of personalized adapted locomotor training. Using conventional content analysis, themes were identified from post-training interviews. Trustworthiness was enhanced through analysis trials, verbatim quotes, and triangulation. RESULTS: Three themes emerged: motives for participating, perceived benefits, and perceived challenges. Beliefs that higher intensity leads to quicker recovery of prior function motivated participation. Physical and psychological health improvements, favorable training structure, and empowerment to self-manage their rehabilitation were perceived benefits. Neglect of other commitments, acquiring extra services to participate (e.g. accessible transportation), limited transferability to daily walking, and a rigid training structure were perceived challenges. Program recommendations were formed from the perceived challenges. CONCLUSIONS: Personalized adapted locomotor training was positively regarded by participants. Addressing the perceived challenges may improve the training experience. Implications for Rehabilitation Personalized adapted locomotor training (PALT) is a high-intensity locomotor therapy tailored to an individual's goals. The experiences of individuals with iSCI highlight the impact of PALT on physical and psychological well-being. PALT has the potential to improve physical functioning and facilitate transitions from inpatient rehabilitation to community living. Findings suggest the need for adaptation of PALT to suit the unique needs of each individual. PMID- 28084844 TI - Poison exposures in young Israeli military personnel: a National Poison Center Data analysis. AB - CONTEXT: To characterize poison exposures in young Israeli military personnel as reported to the national poison center. METHODS: Retrospective poison center chart review over a 14-year period. Cases included were Israeli soldiers aged 18 21 years, the compulsory military service age required by the Israeli law. RESULTS: 1770 records of poison exposures in young military personnel were identified. Most exposed individuals involved males (n = 1268, 71.6%). Main routes of exposure were ingestion (n = 854, 48.3%), inhalation (n = 328, 18.6%) and ocular (n = 211, 11.9%). Accidents or misuse (n = 712, 40.2%) were the most frequently reported circumstances, followed by suicide attempts (370, 20.9%), and bites and stings (161, 9.1%). More than half of the cases involved chemicals (n = 939, 53.1%); hydrocarbons, gases and corrosives were the main causative agents. Pharmaceuticals (mainly analgesics) were involved in 519 (29.3%) cases, venomous animals (mainly scorpions, centipedes, and snakes) in 79 (4.5%). Clinical manifestations were reported in 666 (37.6%) cases, mostly gastrointestinal, neurologic, and respiratory. The vast majority of cases (1634, 92.3%) were asymptomatic or mildly affected; no fatalities were recorded. In 831 (46.9%) cases the clinical toxicologist recommended referral to an emergency department; ambulatory observation was recommended in 563 (31.8%) cases, and hospitalization in 86 (4.9%). CONCLUSIONS: Our data show that poison exposures among young soldiers involve mainly males, accidents, misuse and suicides, oral route and chemicals; most exposures were asymptomatic or with mild severity. Repeated evaluations of poison center data pertaining to military personnel is advised for identifying trends in poison exposure and characteristics in this particular population. PMID- 28084845 TI - A qualitative exploration of patient and family views and experiences of treatment decision-making in bipolar II disorder. AB - BACKGROUND: Treatment decision-making in bipolar II disorder (BPII) is challenging, yet the decision support needs of patients and family remain unknown. AIM: To explore patient and family perspectives of treatment decision making in BPII. METHOD: Semistructured, qualitative interviews were conducted with 28 patients with BPII-diagnosis and 13 family members with experience in treatment decision-making in the outpatient setting. Interviews were audiotaped, transcribed verbatim and analysed thematically using framework methods. Participant demographics, clinical characteristics and preferences for patient decision-making involvement were assessed. RESULTS: Four inter-related themes emerged: (1) Attitudes and response to diagnosis and treatment; (2) Influences on decision-making; (3) The nature and flow of decision-making; (4) Decision support and challenges. Views differed according to patient involvement preferences, time since diagnosis and patients' current mood symptoms. CONCLUSIONS: This is the first known study to provide in-depth patient and family insights into the key factors influencing BPII treatment decision-making, and potential improvements and challenges to this process. Findings will inform the development of BPII treatment decision-making resources that better meet the informational and decision-support priorities of end users. DECLARATION OF INTEREST: This research was partly funded by a Postgraduate Research Grant awarded to the first author by the University of Sydney. No conflicts of interest declared. PMID- 28084847 TI - Prescribing exercise for prevention and treatment of gestational diabetes: review of suggested recommendations. AB - Exercise has been proved to be safe during pregnancy and to offer benefits for both mother and fetus; moreover, physical activity may represent a useful tool for gestational diabetes prevention and treatment. Therefore, all women in uncomplicated pregnancy should be encouraged to engage in physical activity as part of a healthy lifestyle. However, exercise in pregnancy needs a careful medical evaluation to exclude medical or obstetric contraindications to exercise, and an appropriate prescription considering frequency, intensity, type and duration of exercise, to carefully balance between potential benefits and potential harmful effects. Moreover, some precautions related to anatomical and functional adaptations observed during pregnancy should be taken into consideration. This review summarized the suggested recommendations for physical activity among pregnant women with focus on gestational diabetes. PMID- 28084848 TI - The intriguing role of soluble urokinase receptor in inflammatory diseases. AB - Inflammation is a key player in the development of an increasing amount of diseases. The soluble urokinase plasminogen activator receptor (suPAR) is a highly flexible molecule with intrinsic chemotactic properties. This glycoprotein has been evaluated as a biomarker of inflammation, immune activation, organ damage and clinical outcome in several pathologies, including cardiovascular disease, hepatitis, renal disorders and rheumatic pathologies. The use of this early warning inflammatory biomarker could potentially improve the prediction of the severity of these diseases and mortality. In the present paper, we describe the general characteristics of suPAR and its intriguing role as a biomarker in different inflammatory diseases. PMID- 28084849 TI - Successful peripheral blood stem cell mobilization with a cost-efficient single fixed-dose plerixafor schedule in poor mobilizers. AB - Plerixafor, although costly, is added to mobilizing chemotherapy and G-CSF to overcome poor stem cell mobilization. We demonstrate that it can be safely administered mostly once as a single dose in preemptive and rescue settings, leading to apheresis yields of >2 and >4*106 CD34 + cells/kg body weight (bw) in 83% and 48%, respectively. Of note, 35/46 (76%) patients showed a substantial benefit with increased peripheral blood (PB) CD34 + cells prior to apheresis (8.84 vs. 1.72/MUl, p < .001), and 5-fold increased CD34 + cells collected per single apheresis (2.25 vs. 0.43 * 106 CD34+/kg bw, respectively, p < .001). Patients profiting most (76%) vs. less (24%) had >5 vs. <5/MUl PB CD34 + cells before plerixafor application, respectively, thus careful patient selection in the latter group is advised. To the best of our knowledge, this is the first report demonstrating that favorable apheresis results can be obtained using this cost-efficient, single fixed-dose plerixafor schedule. PMID- 28084851 TI - Effects of Ai Chi on balance, quality of life, functional mobility, and motor impairment in patients with Parkinson's disease. AB - PURPOSE: In this study, we aimed to investigate effects of Ai Chi on balance, functional mobility, health-related quality of life, and motor impairment in patients with Parkinson's disease. METHOD: This study was conducted as an open label randomized controlled trial (ISRCTN26292510) with repeated measures. Forty patients with Parkinson's disease stages 2 to 3 according to the Hoehn and Yahr Scale were randomly allocated to either an Ai Chi exercise group or a land-based exercise control group for 5 weeks. Balance was measured using the Biodex-3,1 and the Berg Balance Scale. Functional mobility was evaluated using the Timed Up and Go Test. Additionally, health-related quality of life and motor activity were assessed with the Parkinson's Disease Questionnaire-39 and the Unified Parkinson's Disease Rating Scale-III. RESULTS: Although patients in both groups showed significant improvement in all outcome variables, improvement of dynamic balance was significantly greater in the Ai Chi group (p < 0.001), Berg Balance Scale (p < 0.001), Timed Up and Go Test (p = 0.002), Parkinson's Disease Questionnaire-39 (p < 0.001), Unified Parkinson's Disease Rating Scale-III (p < 0.001). CONCLUSION: Our results suggest that an Ai Chi exercise program improves balance, mobility, motor ability, and quality of life. In addition, Ai Chi exercise was more effective as an intervention than land-based exercise in patients with mild to moderate Parkinson's disease. Implications for rehabilitation Ai Chi exercises (aquatic exercises) may help improve balance, functional mobility, health-related quality of life, and motor ability in patients with mild to moderate Parkinson's disease more efficiently than similar land-based exercises. Ai Chi exercises should be considered as a rehabilitation option for treatment of patients with mild or moderate Parkinson's disease. PMID- 28084850 TI - MicroRNAs and tRNA-derived fragments predict the transformation of myelodysplastic syndromes to acute myeloid leukemia. AB - Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders of the elderly that carry an increased risk of progression to acute myeloid leukemia (AML). Since small non-coding RNAs (sRNAs), including microRNA (miRNAs), act as regulators of cellular differentiation, we hypothesized that changes to sRNAs might be implicated in the progression of MDS to AML. We conducted sRNA sequencing on three sets of patients: Group A (MDS patients who never progressed to AML); Group B (MDS patients who later progressed to an AML); and Group C (AML patients with myelodysplasia-related changes, including patients with a known preceding diagnosis of MDS). We identified five miRNAs that differentiated Groups A and B, independent of bone marrow blast percentage, including three members of the miR-181 family, as well as differential patterns of miRNA isoforms (isomiRs) and tDRs. Thus, we have identified sRNA biomarkers that predict MDS cases that are likely to progress to AML. PMID- 28084852 TI - Effects of digoxin on cell cycle, apoptosis and NF-kappaB pathway in Burkitt's lymphoma cells and animal model. AB - Digoxin has potential antitumor properties. This study investigated whether digoxin suppressed Burkitt's lymphoma (BL) cells. Raji and NAMALWA cells were exposed to digoxin, followed by assay of cell viability, apoptosis and cell cycle. Western blotting was used to analyze NF-kappaB activity. A xenograft model was established for therapeutic efficacy evaluation. Digoxin inhibited cell growth and resulted in apoptosis and cell cycle arrest (G0/G1 for Raji cells; G2/M for NAMALWA cells). Digoxin inhibited DNA synthesis and induced morphological apoptotic characteristics. Besides, digoxin inhibited NF-kappaB and TNF-alpha-stimulated NF-kappaB activity, and suppressed NF-kappaB initiating genes (Bcl-2, Bcl-xL, cyclin D1, and c-myc), however, increased p21cip1. Digoxin activated caspase-9/3. Furthermore, digoxin inhibited xenograft tumors growth and reduced Ki-67 and c-myc. Digoxin exerted antitumor effects on BL cells in vitro and in vivo might through regulating NF-kappaB and caspase pathway. These outcomes highlight the potential of digoxin as a therapeutic agent for BL. PMID- 28084853 TI - Talc pleurodesis allows long-term remission in HIV-unrelated Human Herpesvirus 8 associated primary effusion lymphoma. PMID- 28084854 TI - Combined aphasia and apraxia of speech treatment (CAAST): Systematic replications in the development of a novel treatment. AB - PURPOSE: The purpose of this investigation was to examine the effects of a modified version of a newly developed therapy for aphasia and acquired apraxia of speech (AOS), Combined Aphasia and Apraxia of Speech Treatment (CAAST). METHOD: Four speakers with chronic AOS and aphasia received CAAST in the context of multiple baseline designs. Dependent variables included language measures (i.e. production of correct information units (CIUs)) and speech production measures (i.e. speech intelligibility and percent correct consonants (PCC) in sentence repetition). RESULT: Three of the participants demonstrated improved CIU production with treated picture sets and two also demonstrated generalization to untreated sets. All participants achieved substantially increased CIU production in an untrained discourse context. Speech intelligibility increased for three of the participants and increases in PCC were observed for all of the participants at two weeks post-treatment. However, PCC improvements were maintained for only two of the speakers at six weeks post-treatment. CONCLUSION: The revised CAAST protocol was associated with improved changes in speech and generalization across contexts in comparison to the previous iteration of CAAST. However, focus on sentence production in generalization practice may have been detrimental to CIU production for one participant. PMID- 28084855 TI - Occupational transdermal poisoning with synthetic cannabinoid cumyl-PINACA. AB - CONTEXT: Synthetic cannabinoids are getting more popular among young people and illicit manufacturers. We report a case series of occupational transdermal poisoning with synthetic cannabinoids. CASE DETAILS: Three customs inspectors got in contact with a sticky substance with their fingertips because they were not wearing protection gloves and the delivered package was damaged. Despite washing their hands with water, signs of synthetic cannabinoids intoxication started occurring half an hour after exposure. On arrival at the Emergency Department six hours later, they were somnolent, lethargic and confused. They showed signs of mydriasis, blurred vision, ataxia, weakness, numbness, tachycardia and one of them had orthostatic hypotension. Two days later, they were feeling much better and reported amnesia and slowed perception of time after exposure. Toxicology analysis by LC-MS/MS revealed synthetic cannabinoid cumyl-PINACA (SGT-24) in their blood samples taken on admission. cumyl-PINACA was also confirmed with NMR method in liquid samples seized at the airport. It was 98% pure substance with the purpose of being diluted and sold further in the drug market by drug dealer. DISCUSSION: This case series highlights the possible transdermal exposure to synthetic cannabinoids oil resulting in prolonged cannabinoid syndrome. PMID- 28084856 TI - Using decision trees to explore the association between the length of stay and potentially avoidable readmissions: A retrospective cohort study. AB - BACKGROUND: There is a growing concern that reduction in hospital length of stay (LOS) may raise the rate of hospital readmission. This study aims to identify the rate of avoidable 30-day readmission and find out the association between LOS and readmission. METHODS: All consecutive patient admissions to the internal medicine services (n = 5,273) at King Abdullah University Hospital in Jordan between 1 December 2012 and 31 December 2013 were analyzed. To identify avoidable readmissions, a validated computerized algorithm called SQLape was used. The multinomial logistic regression was firstly employed. Then, detailed analysis was performed using the Decision Trees (DTs) model, one of the most widely used data mining algorithms in Clinical Decision Support Systems (CDSS). RESULTS: The potentially avoidable 30-day readmission rate was 44%, and patients with longer LOS were more likely to be readmitted avoidably. However, LOS had a significant negative effect on unavoidable readmissions. CONCLUSIONS: The avoidable readmission rate is still highly unacceptable. Because LOS potentially increases the likelihood of avoidable readmission, it is still possible to achieve a shorter LOS without increasing the readmission rate. Moreover, the way the DT model classified patient subgroups of readmissions based on patient characteristics and LOS is applicable in real clinical decisions. PMID- 28084857 TI - Post-operative pain control after tonsillectomy: dexametasone vs tramadol. AB - CONCLUSION: Tramadol was found to be more effective than dexamethasone in post operative pain control, with long-lasting relief of pain. OBJECTIVE: This study aimed to compare the effects of pre-operative local injections of tramadol and dexamethasone on post-operative pain, nausea and vomiting in patients who underwent tonsillectomy. DESIGN: Sixty patients between 3-13 years of age who were planned for tonsillectomy were included in the study. Patients were divided into three groups. Group 1 was the control group. Patients in Group 2 received 0.3 mg/kg Dexamethasone and Group 3 received 0.1 mg/kg Tramadol injection to the peritonsillary space just before the operation. Patients were evaluated for nausea, vomiting, and pain. RESULTS: When the control and the dexamethasone groups were compared; there were statistically significant differences in pain scores at post-operative 15 and 30 min, whereas there was no statistically significant difference in pain scores at other hours. When the control and tramadol groups were compared, there was a statistically significant difference in pain scores at all intervals. When tramadol and dexamethasone groups were compared, there was no statistically significant difference in pain scores at post-operative 15 and 30 min, 1 and 2 h, whereas there was a statistically significant difference in pain scores at post-operative 6 and 24 h. PMID- 28084859 TI - Radiotherapy-induced vaginal fibrosis in cervical cancer survivors. AB - BACKGROUND: Cervical cancer survivors treated with radiotherapy report vaginal inelasticity and decreased lubrication that may affect their sexual health, but it is unknown which normal tissue reactions mediate these symptoms. The aim of this study was to investigate the morphology of the connective tissue of the vaginal wall in cervical cancer survivors treated with radiotherapy. MATERIAL AND METHODS: We recruited 34 cervical cancer survivors treated with radiotherapy and 37 age-matched controls. Via clinical examination the degree of vaginal atrophy and pelvic fibrosis were estimated. We collected vaginal biopsies, which underwent morphometric analysis focused on elastin and collagen. Additionally, radiation dose at biopsy site were calculated and correlated to the clinical and morphological findings. RESULTS: The survivors had marked morphological vaginal changes, most prominent in the survivors that had received the highest radiation dose at the biopsy site. Mucosal atrophy was observed in 91% and pelvic fibrosis in 97%. A shorter vagina was measured; 7.0 cm versus 10.3 cm in controls (p < 0.001). The area fraction of elastin was greater in survivors; 10.0% (range 5.8 12.9), compared with controls; 3.4% (range 1.8-5.8), p < 0.001. The survivors had signs of elastosis with thick aggregated elastin fibers irregularly scattered throughout the connective tissue, while the controls had elastin fibers in a thin sub-epithelial layer. The area fraction of high density collagen in the connective tissue was larger among the survivors (p < 0.001). The collagen with the highest density (fibrosis) was more common in the group of cancer survivors that had received external radiation. CONCLUSIONS: We found drastic differences in the vaginal wall between the irradiated cervical cancer survivors and the controls, indicating that radiotherapy-induced vaginal symptoms are mediated by connective tissue fibrosis and elastosis. Our results also support that patients treated with external radiation have the highest risk of developing vaginal fibrosis with impairment of their sexual health. PMID- 28084858 TI - Age-adjusted Charlson comorbidity index as a prognostic factor of hypopharyngeal cancer treated with chemoradiation therapy. AB - CONCLUSION: The age-adjusted Charlson comorbidity index (ACCI) was associated with overall survival, disease-specific survival, and non-cancer death in patients treated with chemoradiation therapy (CRT) for hypopharyngeal cancer (HPC). Further studies using other CRT regimens are required. OBJECTIVE: To investigate the impact of the ACCI on survival in patients with HPC. METHODS: This study reviewed 128 patients with HPC who received CRT between 2004-2012. The survival rates and the cumulative incidence of non-cancer death according to the ACCI were estimated. A Cox proportional hazard model was used to assess the hazard ratio (HR) of the ACCI. RESULTS: The disease-specific survival rates at 3 years for the low ACCI group, moderate group, and high group were 80.1%, 45.8%, and 54.8%, respectively (p = 0.007). The laryngectomy-free survival rates at 3 years were 61%, 39.7%, and 37.1%, respectively (p = 0.137). The cumulative incidences of non-HPC death were 5% for the low/moderate ACCI group and 15.5% for the high ACCI group (p = 0.031). The HRs compared to the low ACCI group for overall survival, disease-specific survival, and laryngectomy-free survival were 2.61 and 2.74, 2.55 and 2.27, and 1.75 and 1.97 in the moderate and high ACCI groups, respectively. PMID- 28084860 TI - Crude mortality and loss of life expectancy of patients diagnosed with urothelial carcinoma of the urinary bladder in Norway. AB - OBJECTIVE: Reports from cancer registries often lack clinically relevant information, which would be useful in estimating the prognosis of individual patients with urothelial carcinoma of the urinary bladder (UCB). This article presents estimates of crude probabilities of death due to UCB and the expected loss of lifetime stratified for patient characteristics. MATERIALS AND METHODS: In Norway, 10,332 patients were diagnosed with UCB between 2001 and 2010. The crude probabilities of death due to UCB were estimated, stratified by gender, age and T stage, using flexible parametric survival models. Based on these models, the loss in expectation of lifetime due to UCB was also estimated for the different strata. RESULTS: There is large variation in the estimated crude probabilities of death due to UCB (from 0.03 to 0.76 within 10 years since diagnosis) depending on age, gender and T stage. Furthermore, the expected loss of life expectancy is more than a decade for younger patients with muscle invasive UCB and between a few months and 5 years for nonmuscle-invasive UCB. CONCLUSIONS: The suggested framework leads to clinically relevant prognostic risk estimates for individual patients diagnosed with UCB and the consequence in terms of loss of lifetime expectation. The published probability tables can be used in clinical praxis for risk communication. PMID- 28084861 TI - Split-Belt Treadmill Walking Alters Lower Extremity Frontal Plane Mechanics. AB - Interventions that manipulate gait speed may also affect the control of frontal plane mechanics. Expanding the current knowledge of frontal plane adaptations during split-belt treadmill walking could advance our understanding of the influence of asymmetries in gait speed on frontal plane mechanics and provide insight into the breadth of adaptations required by split-belt walking (SBW). Thirteen young, healthy participants, free from lower extremity injury walked on a split-belt treadmill with belts moving simultaneously at different speeds. We examined frontal plane mechanics of the ankle, knee, and hip joints during SBW, as well as medio-lateral ground reaction forces (ML-GRF). We did not observe alterations in the frontal mechanics produced during early or late adaptation of SBW when compared to conditions where the belts moved together. We did observe that ML-GRF and hip moment impulse of the fast limb increased over time with adaptation to SBW. These results suggest this modality may provide a unique therapy for individuals with gait pathologies, impairments, or compensation(s). PMID- 28084862 TI - Visual outcome, endocrine function and tumor control after fractionated stereotactic radiation therapy of craniopharyngiomas in adults: findings in a prospective cohort. AB - BACKGROUND: The purpose of this study was to examine visual outcome, endocrine function and tumor control in a prospective cohort of craniopharyngioma patients, treated with fractionated stereotactic radiation therapy (FSRT). MATERIAL AND METHODS: Sixteen adult patients with craniopharyngiomas were eligible for analysis. They were treated with linear accelerator-based FSRT during 1999-2015. In all cases, diagnosis was confirmed by histological analysis. The prescription dose to the tumor was 54 Gy (median, range 48-54) in 1.8 or 2.0 Gy per fraction, and the maximum radiation dose to the optic nerves and chiasm was 54.2 Gy (median, range 48.6-60.0) for the cohort. Serial ophthalmological and endocrine evaluations and magnetic resonance imaging (MRI) scans were performed at regular intervals. Median follow-up was 3.3 years (range 1.1-14.1), 3.7 years (range 0.8 15.2), and 3.6 years (range 0.7-13.1) for visual outcome, endocrine function, and tumor control, respectively. RESULTS: Visual acuity impairment was present in 10 patients (62.5%) and visual field defects were present in 12 patients (75%) before FSRT. One patient developed radiation-induced optic neuropathy at seven years after FSRT. Thirteen of 16 patients (81.3%) had pituitary deficiency before FSRT, and did not develop further pituitary deficiency after FSRT. Mean tumor volume pre-FSRT was 2.72 cm3 (range 0.20-9.90) and post-FSRT 1.2 cm3 (range 0.00 13.10). Tumor control rate was 81.3% at two, five, and 10 years after FSRT. CONCLUSIONS: FSRT was relatively safe in this prospective cohort of craniopharyngiomas, with only one case of radiation-induced optic neuropathy and no case of new endocrinopathy. Tumor control rate was acceptable. PMID- 28084863 TI - Load Accommodation Strategies and Movement Variability in Single-Leg Landing. AB - Our purpose was to examine changes in participant-specific single-leg landing strategies and intra-individual movement variability following alterations in mechanical task demands via external load and landing height. Nineteen healthy volunteers (15M, 4 F, age: 24.3 +/- 4.9 y, mass: 78.5 +/- 14.7 kg, height: 1.73 +/- 0.08 m) were analyzed among 9 single-leg drop landing trials in each of 6 experimental conditions (3 load and 2 landing height) computed as percentages of participant bodyweight (BW, BW + 12.5%, BW + 25%) and height (H12.5% & H25%). Lower-extremity sagittal joint angles and moments (hip, knee, and ankle), vertical ground reaction forces (GRFz), and electrical muscle activities (gluteus maximus, biceps femoris, vastus medialis, medial gastrocnemius, and tibialis anterior muscles) were analyzed. Individual single-leg drop landing strategies were identified using landing impulse predictions and the Load Accommodation Strategies Model (James et al., 2014). Intra-individual movement variability was assessed from neuromechanical synergies extracted using single-case principal component analyses (PCA). Fewer contrasting single-leg landing strategies were identified among participants under greater mechanical task demands (p < .001) alongside lesser intra-individual movement variability (p < .001). These results reveal changes in movement control under greater mechanical task demands, which may have implications for understanding overuse injury mechanisms in landing. PMID- 28084864 TI - Inverse Dynamics Modeling of Paralympic Wheelchair Curling. AB - Paralympic wheelchair curling is an adapted version of Olympic curling played by individuals with spinal cord injuries, cerebral palsy, multiple sclerosis, and lower extremity amputations. To the best of the authors' knowledge, there has been no experimental or computational research published regarding the biomechanics of wheelchair curling. Accordingly, the objective of the present research was to quantify the angular joint kinematics and dynamics of a Paralympic wheelchair curler throughout the delivery. The angular joint kinematics of the upper extremity were experimentally measured using an inertial measurement unit system; the translational kinematics of the curling stone were additionally evaluated with optical motion capture. The experimental kinematics were mathematically optimized to satisfy the kinematic constraints of a subject specific multibody biomechanical model. The optimized kinematics were subsequently used to compute the resultant joint moments via inverse dynamics analysis. The main biomechanical demands throughout the delivery (ie, in terms of both kinematic and dynamic variables) were about the hip and shoulder joints, followed sequentially by the elbow and wrist. The implications of these findings are discussed in relation to wheelchair curling delivery technique, musculoskeletal modeling, and forward dynamic simulations. PMID- 28084865 TI - High efficient anti-cancer drug delivery systems using tea polyphenols reduced and functionalized graphene oxide. AB - Targeted drug delivery is urgently needed for cancer therapy, and green synthesis is important for the biomedical use of drug delivery systems in the human body. In this work, we report two targeted delivery systems for anticancer drugs based on tea polyphenol functionalized and reduced graphene oxide (TPGs). The obtained TPGs demonstrated an efficient doxorubicin loading capacity as high as 3.430 * 106 mg g-1 and 3.932 * 104 mg g-1, and exhibited pH-triggered release. Furthermore, the kinetic models, adsorption isotherms, and possible loading mechanisms were investigated in details. Compared to TPG1 and free doxorubicin, TPG2 is biocompatible to normal cells even at high concentrations and promotes tumor cells death by delivering the doxorubicin mainly to the nuclei. These results were confirmed using cell viability tests and confocal laser microscopy. Moreover, apoptosis tests showed that the mechanism of cancer cell death induced by TPG1 and TPG2 might follow the similar mechanisms. Taken together, these results demonstrate that TPGs provide a multifunctional drug delivery system with a greater loading capacity and pH-sensitive drug release for enhanced cancer therapy. The high drug payload capability and enhanced antitumor efficacy demonstrate that we developed systems are promising for various biomedical applications and cancer therapy. PMID- 28084866 TI - Population-based experience on primary central nervous system lymphoma 2000-2012: the incidence is increasing. AB - BACKGROUND: Primary central nervous system lymphomas (PCNSL) are rare lymphomas with a poor prognosis. Recently, an increased incidence has been reported. The present study is a population-based study of all patients with PCNSL in the Uppsala/Orebro region of middle Sweden. PATIENTS AND METHODS: All patients diagnosed with a PCNSL at Uppsala University Hospital 2000-2012 were identified. Altogether, 96 patients (50 women and 46 men) were included. The median age at diagnosis was 66 years (17-95). RESULTS: There was a statistically significant increase in age-standardized incidence during the study period, 30 patients were diagnosed in the first half and 66 in the second half of the period. No patient had an HIV-infection. Two patients had undergone kidney transplantation and were treated with immunosuppressive drugs. A high proportion of the patients, 29%, had a history of an autoimmune or inflammatory disease. The prognosis was poor with a median survival of only four months. In the 70 (73%) patients treated with curative intention the median survival was 12 months. Patients treated with high dose methotrexate, radiotherapy and/or temozolomide appeared to have a better survival. There was no improvement in survival during the study period or after the introduction of rituximab. There also was no difference in any of the analyzed variables that could explain the increased incidence. CONCLUSION: In this population-based study we could confirm the previously described increased incidence of PCNSL. The prognosis remains poor despite the inclusion of treatment with rituximab during the study period. A high proportion of the patients had a history of an autoimmune or inflammatory disease not previously described but there was no increase during the study period. PMID- 28084867 TI - Patient-reported outcomes in cancer survivorship. AB - BACKGROUND: There are currently 33 million cancer survivors worldwide. With improvements in early cancer detection and treatments, patients are living longer - and it is well-recognized that many survivors develop short- and long-term physical, psychosocial and spiritual effects as a result of their diagnoses and treatments. There is increasing awareness of the importance of using patient reported outcomes (PROs) to accurately assess these effects in cancer survivors. Validated patient-reported outcome instruments: Traditionally, physicians have assessed the acute and late side effects of cancer treatments with standardized scales such as the CTCAE. However, multiple studies have demonstrated that PROs more accurately capture patient symptoms than physician assessment. In this article we describe frequently used, validated, general and cancer-specific PRO instruments that assess symptoms. We describe additional PRO instruments that assess unmet needs, interpersonal relationship issues, and psychosocial and financial problems. Published studies using these instruments have identified issues commonly faced by cancer survivors worldwide. Discussion and summary: While PROs are increasingly used in research, further efforts are needed to integrate PRO assessment into routine clinical care, so that timely and accurate assessments can translate into better management of issues - ultimately improving the lives of cancer survivors. PMID- 28084868 TI - Physiological and Biomechanical Responses to Prolonged Heavy Load Carriage During Level Treadmill Walking in Females. AB - Heavy load carriage has been identified as a main contributing factor to the high incidence of overuse injuries in soldiers. Peak vertical ground reaction force (VGRFMAX) and maximal vertical loading rates (VLRMAX) may increase during heavy prolonged load carriage with the development of muscular fatigue and reduced shock attenuation capabilities. The objectives of the current study were (1) to examine physiological and biomechanical changes that occur during a prolonged heavy load carriage task, and (2) to examine if this task induces neuromuscular fatigue and changes in muscle architecture. Eight inexperienced female participants walked on an instrumented treadmill carrying operational loads for 60 minutes at 5.4 km.h-1. Oxygen consumption ( V O 2 ), heart rate, rating of perceived exertion (RPE), trunk lean angle, and ground reaction forces were recorded continuously during task. Maximal force and in-vivo muscle architecture were assessed pre- and posttask. Significant increases were observed for VGRFMAX, VLRMAX, trunk lean angle, [Formula: see text], heart rate, and RPE during the task. Increased vastus lateralis fascicle length and decreased maximal force production were also observed posttask. Prolonged heavy load carriage, in an inexperienced population carrying operational loads, results in progressive increases in ground reaction force parameters that have been associated with overuse injury. PMID- 28084869 TI - Crossed cerebellar diaschisis in acute ischemic stroke: Impact on morphologic and functional outcome. AB - Crossed cerebellar diaschisis (CCD) is the phenomenon of hypoperfusion and hypometabolism of the contralateral cerebellar hemisphere caused by dysfunction of the related supratentorial region. Our aim was to analyze its influence on morphologic and functional outcome in acute ischemic stroke. Subjects with stroke caused by a large vessel occlusion of the anterior circulation were selected from an initial cohort of 1644 consecutive patients who underwent multiparametric CT including whole-brain CT perfusion. Two experienced readers evaluated the posterior fossa in terms of CCD absence (CCD-) or presence (CCD+). A total of 156 patients formed the study cohort with 102 patients (65.4%) categorized as CCD- and 54 (34.6%) as CCD+. In linear and logistic regression analyses, no significant association between CCD and final infarction volume (beta = -0.440, p = 0.972), discharge mRS <= 2 (OR = 1.897, p = 0.320), or 90-day mRS <= 2 (OR = 0.531, p = 0.492) was detected. CCD+ patients had larger supratentorial cerebral blood flow deficits (median: 164 ml vs. 115 ml; p = 0.001) compared to CCD patients. Regarding complications, CCD was associated with a higher rate of parenchymal hematomas (OR = 4.793, p = 0.035). In conclusion, CCD is frequently encountered in acute ischemic stroke caused by large vessel occlusion of the anterior circulation. CCD was associated with the occurrence of parenchymal hematoma in the ipsilateral cerebral infarction but did not prove to significantly influence patient outcome. PMID- 28084870 TI - Reliability of Achilles Tendon Moment Arm Measured In Vivo Using Freehand Three Dimensional Ultrasound. AB - This study investigated reliability of freehand three-dimensional ultrasound (3DUS) measurement of in vivo human Achilles tendon (AT) moment arm. Sixteen healthy adults were scanned on 2 separate occasions by a single investigator. 3DUS scans were performed over the free AT, medial malleolus, and lateral malleolus with the ankle passively positioned in maximal dorsiflexion, mid dorsiflexion, neutral, mid plantar flexion and maximal plantar flexion. 3D reconstructions of the AT, medial malleolus, and lateral malleolus were created from manual segmentation of the ultrasound images and used to geometrically determine the AT moment arm using both a straight (straight ATMA) and curved (curved ATMA) tendon line-of-action. Both methods were reliable within- and between-session (intra-class correlation coefficients > 0.92; coefficient of variation < 2.5 %) and revealed that AT moment arm increased by ~ 7 mm from maximal dorsiflexion (~ 41mm) to maximal plantar flexion (~ 48 mm). Failing to account for tendon curvature led to a small overestimation (< 2 mm) of AT moment arm that was most pronounced in ankle plantar flexion, but was less than the minimal detectable change of the method and could be disregarded. PMID- 28084871 TI - Airtraq laryngoscope: a solution for difficult laryngeal exposure in phonomicrosurgery. AB - CONCLUSION: Airtraq(r) laryngoscope can obviously improve laryngeal visualization and may provide a useful solution to treatment of patients with difficult laryngeal exposure (DLE) under a conventional suspension laryngoscope in phonomicrosurgery. OBJECTIVE: In phonomicrosurgery, otolaryngologists may inevitably encounter DLE. Attempts to improve laryngeal exposure have yielded important advances, but the prevalence of DLE yet remains persistent. To overcome this problem, this study applied the Airtraq(r) laryngoscope to perform phonomicrosurgery combined with a video system. The aim of this study is, thus, to explore the clinical usefulness of the Airtraq(r) laryngoscope in patients with DLE. METHODS: One hundred and fifty-eight cases who underwent phonomicrosurgery for benign lesions of vocal cord at this hospital were enrolled in this study, of which nine patients were confirmed to be DLE under direct suspension laryngoscope. These nine patients were treated by Airtraq(r) laryngoscope together with a video system. RESULTS: In comparison with the traditional suspension laryngoscope, exposure of larynx was remarkably improved by Airtraq(r) laryngoscope. Under the excellent laryngeal visualization provided by Airtraq(r), phonomicrosurgery was successfully accomplished for vocal fold lesions without any severe complications in all cases with DLE. PMID- 28084872 TI - Swallowing disorders among patients with diffuse idiopathic skeletal hyperostosis. AB - CONCLUSION: Diffuse idiopathic skeletal hyperostosis (DISH) is a cause of swallowing disorders in elderly, and otolaryngologists should be aware of the disease on dealing with old patients complaining of dysphagia. The condition may be treated conservatively in most patients; however, surgical reduction of cervical osteophytes may be needed in severe cases. OBJECTIVE: Large cervical osteophytes may cause dysphagia; they compress the pharynx leading to mechanical impairment of swallowing. DISH is characterized by ossification of the anterior longitudinal spinal ligament with formation of osteophytes. The aim was to investigate swallowing disorders among patients with DISH. METHOD: The study included 139 patients with DISH. Their swallowing was evaluated using the eating assessment tool (EAT-10), and patients with swallowing disorders were subjected to fiber-optic endoscopic evaluation of swallowing (FEES), they received conservative treatment for 6 months. Patients were assessed again after treatment using the same measures that were employed before treatment. RESULTS: Twenty three patients (16.5%) demonstrated swallowing disorder, and FEES showed residues of food in the pharynx after swallow in all of them. Significant overall improvement after conservative treatment was achieved, with two patients resuming their normal regular diet. However, one patient demonstrated no improvement, and he needed surgical reduction of his large cervical osteophytes. PMID- 28084873 TI - Hypothermia revisited: Impact of ischaemic duration and between experiment variability. AB - To assess the true effect of novel therapies for ischaemic stroke, a positive control that can validate the experimental model and design is vital. Hypothermia may be a good candidate for such a positive control, given the convincing body of evidence from animal models of ischaemic stroke. Taking conditions under which substantial efficacy had been seen in a meta-analysis of hypothermia for focal ischaemia in animal models, we undertook three randomised and blinded studies examining the effect of hypothermia induced immediately following the onset of middle cerebral artery occlusion on infarct volume in rats (n = 15, 23, 264). Hypothermia to a depth of 33C and maintained for 130 min significantly reduced infarct volume compared to normothermia treatment (by 27-63%) and depended on ischaemic duration (F(3,244) = 21.242, p < 0.05). However, the protective effect varied across experiments with differences in both the size of the infarct observed in normothermic controls and the time to reach target temperature. Our results highlight the need for sample size and power calculations to take into account variations between individual experiments requiring induction of focal ischaemia. PMID- 28084874 TI - Human papillomavirus types 44, 52, 66 and 67 detected in a woman with squamous cell carcinoma of the urinary bladder. AB - Human papillomavirus (HPV) is an accepted causative agent in cervical cancer of the uterus, penile cancer, anal cancer and oropharyngeal carcinomas, while its role in other cancers such as urinary bladder cancer is still much discussed. This report presents a patient with multiple HPV types in a squamous cell carcinoma of the urinary bladder. PMID- 28084875 TI - Reliability and Validity of Kinetic and Kinematic Parameters Determined With Force Plates Embedded Under a Soil-Filled Baseball Mound. AB - We developed a force measurement system in a soil-filled mound for measuring ground reaction forces (GRFs) acting on baseball pitchers and examined the reliability and validity of kinetic and kinematic parameters determined from the GRFs. Three soil-filled trays of dimensions that satisfied the official baseball rules were fixed onto 3 force platforms. Eight collegiate pitchers wearing baseball shoes with metal cleats were asked to throw 5 fastballs with maximum effort from the mound toward a catcher. The reliability of each parameter was determined for each subject as the coefficient of variation across the 5 pitches. The validity of the measurements was tested by comparing the outcomes either with the true values or the corresponding values computed from a motion capture system. The coefficients of variation in the repeated measurements of the peak forces ranged from 0.00 to 0.17, and were smaller for the pivot foot than the stride foot. The mean absolute errors in the impulses determined over the entire duration of pitching motion were 5.3 Ns, 1.9 Ns, and 8.2 Ns for the X-, Y-, and Z directions, respectively. These results suggest that the present method is reliable and valid for determining selected kinetic and kinematic parameters for analyzing pitching performance. PMID- 28084876 TI - Theoretical observation on diagnosis maneuver for benign paroxysmal positional vertigo. AB - CONCLUSION: To make a comprehensive analysis with a variety of diagnostic maneuvers is conducive to the correct diagnosis and classification of BPPV. OBJECTIVE: Based on the standard spatial coordinate-based semicircular canal model for theoretical observation on diagnostic maneuvers for benign paroxysmal positional vertigo (BPPV) to analyze the meaning and key point of each step of the maneuver. MATERIALS AND METHODS: This study started by building a standard model of semicircular canal with space orientation by segmentation of the inner ear done with the 3D Slicer software based on MRI scans, then gives a demonstration and observation of BPPV diagnostic maneuvers by using the model. RESULTS: The supine roll maneuver is mainly for diagnosis of lateral semicircular canal BPPV. The Modified Dix-Hallpike maneuver is more specific for the diagnosis of posterior semicircular canal BPPV. The side-lying bow maneuver designed here is theoretically suitable for diagnosis of anterior semicircular canal BPPV. PMID- 28084877 TI - Clostridium difficile and the Consequences of Progress. PMID- 28084878 TI - Impact of Payer Constraints on Access to Genetic Testing. AB - BACKGROUND: With increased demand for hereditary cancer genetic testing, some large national health-care insurance payers (LNHPs) have implemented policies to minimize inappropriate testing by mandating consultation with a geneticist or genetic counselor (GC). We hypothesized such a restriction would reduce access and appropriate testing. METHODS: Test cancellation rates (ie, tests ordered that did not result in a reported test result), mutation-positive rates, and turnaround times for comprehensive BRCA1/2 testing for a study LNHP that implemented a GC-mandate policy were determined over the 12 months before and after policy implementation (excluding a 4-month transition period). Cancellation rates were evaluated based on the reason for cancellation, National Comprehensive Cancer Network testing criteria, and self-identified ancestry. A control LNHP was evaluated over the same period for comparison. RESULTS: The study LNHP cancellation rate increased from 13.3% to 42.1% ( P < .001) after policy implementation. This increase was also observed when only individuals who met National Comprehensive Cancer Network criteria for hereditary breast and ovarian cancer testing were considered (9.5% to 37.7%; P < .001). Cancellation rates increased after policy introduction for all ancestries; however, this was more pronounced among individuals of African or Latin American ancestry, for whom cancellation rates rose to 48.9% and 49.6%, respectively, compared with 33.9% for individuals of European ancestry. Over this same time period, control LNHP cancellation rates decreased or stayed the same for all subgroups. CONCLUSION: These findings demonstrate that a GC-mandate policy implemented by a LNHP substantially decreased access to appropriate genetic testing, disproportionately impacting minority populations without any evidence that inappropriate testing was decreased. PMID- 28084879 TI - American Society of Clinical Oncology Policy Brief: FDA's Regulation of Electronic Nicotine Delivery Systems and Tobacco Products. PMID- 28084880 TI - Clostridium difficile-Associated Diarrhea in the Oncology Patient. AB - Clostridium difficile is the most common cause of nosocomial diarrhea, resulting in significant morbidity and mortality in hospitalized patients. Oncology patients are particularly at risk of this infection secondary to frequent exposure to known risk factors. In a population in which diarrhea is a common adverse effect of chemotherapeutic regimens, diagnosis can be challenging secondary to current limitations in testing to differentiate between colonization and active infection. Although several currently available antimicrobial therapies achieve resolution of symptoms in this population, further research is needed to determine which agent least affects the host intestinal microbiota, especially in times of neutropenia and mucosal barrier injury. The purpose of this article is to review the current literature on the epidemiology, pathogenesis, and management of C difficile-associated diarrhea in the oncology population. PMID- 28084881 TI - Addressing Opioid-Associated Constipation Using Quality Oncology Practice Initiative Scores and Plan-Do-Study-Act Cycles. AB - Using the Quality Oncology Practice Initiative, an affiliate program of ASCO, we outlined opioid-associated constipation (OAC) as a subject in need of quality improvement (QI) in our fellowship program at the University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System. We initiated a fellow-led QI project to advance the quality of patient care and provide a valuable avenue for QI training of young physicians. Fellows organized meetings with all stakeholders, addressed the scope of the problem, and devised strategies for OAC management. Monthly meetings were organized using Plan-Do-Study-Act principles. Mandatory check boxes were inserted into our electronic medical record templates to remind all physicians to identify patients on opioid medications and assess and address OAC. Final chart audit and patient satisfaction surveys were performed 6 months after project initiation. Assessment of OAC improved from 52% at baseline to 92% ( P < .003). This improvement corresponded with high patient satisfaction scores, with 90% of surveyed patients reporting adequate management of their constipation. In this QI initiative, we showed that participation in ASCO's Quality Oncology Practice Initiative helps identify areas in need of QI, and such fellow-led QI projects can serve as models for QI training of young physicians. PMID- 28084882 TI - Mixed-Methods Study of the Impact of Chronic Patient Death on Oncologists' Personal and Professional Lives. AB - PURPOSE: Although some research has found that health care professionals experience grief when their patients die, within the oncology context, few studies have examined the impact of this loss on oncology personnel. Given the paucity of empirical studies on this topic, this research explored the impact of patient death on oncologists. Methods and Materials This study used a mixed methods design. The qualitative component used the grounded theory method of data collection and analysis. Twenty-two oncologists were recruited from three adult oncology centers. Purposive sampling was used to gain maximum variation in the sample. The quantitative component involved a convenience sample of 79 oncologists recruited through oncologist collaborators. RESULTS: The qualitative study indicated that frequent patient death has both personal and professional impacts on oncologists. Personal impacts included changes to their personality, gaining of perspective on their lives, and a strain to their social relationships. Professional impacts included exhaustion and burnout, learning from each patient death, and decision making. The frequency analysis indicated that oncologists experienced both positive and negative impacts of patient death. A majority reported that exposure to patient death gave them a better perspective on life (78.5%) and motivated them to improve patient care (66.7%). Negative consequences included exhaustion (62%) and burnout (75.9%) as well as compartmentalization of feelings at work and at home (69.6%). CONCLUSION: Frequent patient death has an impact on oncologists' lives, some of which negatively affect the quality of life for oncologists, their families, and their patients. PMID- 28084883 TI - Phase II Trial on Extending the Maintenance Flushing Interval of Implanted Ports. AB - PURPOSE: Retrospective studies suggest that it may be safe to extend the maintenance flushing interval of implanted ports from once every month, as recommended by the manufacturer, to once every 3 months, but no prospective cohort studies have been done specifically assessing the safety and feasibility of this intervention. METHODS: This was a phase II study in oncologic patients who retained a functional port after completion of systemic chemotherapy. Patients enrolled in the study had their port flushed once every 3 months and were observed until completion of five scheduled flushes (one on enrollment and four additional flushes, one every 3 months) or development of any port-related complication, including infections, thrombosis, and occlusions. The primary end points were frequency of port-related complications and port failure requiring removal. RESULTS: A total of 87 patients were enrolled in the study. The median follow-up time was 308 days, accounting for a total of 24,202 catheter-days. There were 10 port-related complications (11.49%; 95% CI, 4.85% to 18.14%). No infection or symptomatic thrombosis occurred. The mean time to port-related complication was 184 days. No patients developed port failure while on protocol, but on subsequent medical record review, four patients developed a complication that required port removal or port revision within 30 days of being removed from the trial (4.6%; 95% CI, 0.4% to 8.8%; 0.17/1,000 catheter-days). CONCLUSION: Extending the maintenance flushes of implanted ports in adult oncologic patients to once every 3 months is safe, effective, and likely to increase patient adherence and satisfaction while decreasing the associated cost. PMID- 28084884 TI - Risk Factors and Patterns of Potentially Avoidable Readmission in Patients With Cancer. AB - PURPOSE: Patients with cancer are particularly at risk for readmission within 30 days after discharge. To identify the patients who might benefit from more intensive discharge interventions, we identified the risk factors associated with 30-day potentially avoidable readmissions. METHODS AND MATERIALS: We included all consecutive discharges from the oncology division of an academic tertiary medical center in Boston, Massachusetts, between July 1, 2009, and June 30, 2010. Potentially avoidable 30-day readmissions to the index hospital and two other hospitals within its network were identified. We performed a multivariable logistic regression in which the final model included variables found in bivariable testing to be significantly associated with the outcome. RESULTS: Among the 2,916 patients discharged during the study period, 1,086 (37.3%) were readmitted within 30 days. Of these, 341 (31.4% of all readmissions, 11.7% of all discharges) were identified as potentially avoidable. In the multivariable analysis, the following patient factors were associated with a significantly higher risk of a potentially avoidable readmission: total number of medications at discharge, liver disease, last sodium level, and last hemoglobin level before discharge. In addition, potentially avoidable readmissions occurred significantly earlier than unavoidable readmissions (median, 10 v 13 days; P < .001). CONCLUSION: Almost 40% of patients with cancer had a 30-day readmission, and almost one third of these were deemed potentially avoidable, and several risk factors for this were identified. Interventions at discharge may be prioritized to patients with these risk factors. PMID- 28084885 TI - Diagnostic and Therapeutic Considerations for Oncology Patients With Clostridium difficile Infection. PMID- 28084886 TI - Telecardiology and its settings of application: An update. AB - Among the wide range of medical specialties in which telemedicine has been successfully applied, cardiology can be considered as one of the most important fields of application. Through the transmission of clinical data and the electrocardiogram, telecardiology allows access to a real-time assessment (teleconsultation) without any need to travel for both patient and cardiologist. This review discusses the impact of telecardiology in different clinical settings of application. Pre-hospital telecardiology has proved to be useful either in the clinical management of remote patients with acute coronary syndrome or in supporting the decision-making process of general practitioners. In the setting of in-hospital telecardiology, most of the applications refer to real-time echocardiography transmissions between rural small hospitals and tertiary care centres, particularly for the diagnosis or exclusion of congenital heart disease in newborns. Finally, many trials show that post-hospital telecardiology improves outcomes and reduces re-admissions or outpatient contacts in patients with heart failure, arrhythmias or implantable devices. PMID- 28084887 TI - The video ocular counter-roll (vOCR): a clinical test to detect loss of otolith ocular function. AB - CONCLUSION: vOCR can detect loss of otolith-ocular function without specifying the side of vestibular loss. Since vOCR is measured with a simple head tilt maneuver, it can be potentially used as a bedside clinical test in combination with video head impulse test. OBJECTIVE: Video-oculography (VOG) goggles are being integrated into the bedside assessment of patients with vestibular disorders. Lacking, however, is a method to evaluate otolith function. This study validated a VOG test for loss of otolith function. METHODS: VOG was used to measure ocular counter-roll (vOCR) in 12 healthy controls, 14 patients with unilateral vestibular loss (UVL), and six patients with bilateral vestibular loss (BVL) with a static lateral head tilt of 30 degrees . The results were compared with vestibular evoked myogenic potentials (VEMP), a widely-used laboratory test of otolith function. RESULTS: The average vOCR for healthy controls (4.6 degrees ) was significantly different from UVL (2.7 degrees ) and BVL (1.6 degrees ) patients (p < 0.0001). The vOCR and VEMP measurements were correlated across subjects, especially the click and tap oVEMPs (click oVEMP R = 0.45, tap oVEMP R = 0.51; p < 0.0003). The receiver operator characteristic (ROC) analysis showed that vOCR and VEMPs detected loss of otolith function equally well. The best threshold for vOCR to detect vestibular loss was at 3 degrees . The vOCR values from the side of vestibular loss and the healthy side were not different in UVL patients (2.53 degrees vs 2.8 degrees ; p = 0.59). PMID- 28084888 TI - Growth rate of invasive ductal carcinomas from a screened 50-74-year-old population. AB - Objective As breast cancer growth rate is associated with menopause, most screening programmes target mainly women aged 50-74. We studied the association between age at diagnosis and growth rate in this screening-specific age range. Methods We used data from breast cancer patients diagnosed in the screening programme in Nijmegen, the Netherlands. The data were restricted to the screening rounds when analogue mammography was used in both the screening and clinical setting. Growth rate expressed as tumour volume doubling time was based on increasing tumour size in longitudinal series of mammograms. Estimates were based on (a) tumours showing at least two measurable shadows, (b) tumours showing a shadow at detection only (left censored), and (c) tumours showing no growth (right-censored observation). All 293 tumours were consecutively diagnosed invasive ductal breast cancers in participants of the Nijmegen screening programme in the period 2000-2007. Results Depending on the assumptions made on tumour margins and mammographic density, the relation of volume doubling time with age non-significantly varies from a decrease of 3.3% to an increase of 1.4% for each year increase in age at diagnosis (all P-values >= 0.18). Applying left censoring on indistinct tumours, the geometric mean volume doubling time was 191 days (95% confidence interval 158-230). Conclusion We found no significant change in growth rate with age in women diagnosed with invasive ductal breast cancer in the screening age range 50-74. This outcome does not support differential screening intervals by age based solely on breast cancer growth rate for this particular group. PMID- 28084889 TI - Predicting the effectiveness of the Finnish population-based colorectal cancer screening programme. AB - Objective Because colorectal cancer (CRC) has a long natural history, estimating the effectiveness of CRC screening programmes requires long-term follow-up. As an alternative, we here demonstrate the use of a temporal multi-state natural history model to predict the effectiveness of CRC screening. Methods In the Finnish population-based biennial CRC screening programme using faecal occult blood tests (FOBT), which was conducted in a randomised health services study, we estimated the pre-clinical incidence, the mean sojourn time (MST), and the sensitivity of FOBT using a Markov model to analyse data from 2004 to 2007. These estimates were applied to predict, through simulation, the effects of five rounds of screening on the relative rate of reducing advanced CRC with 6 years of follow up, and on the reduction in mortality with 10 years of follow-up, in a cohort of 500,000 subjects aged 60 to 69. Results For localised and non-localised CRC, respectively, the MST was 2.06 and 1.36 years and the sensitivity estimates were 65.12% and 73.70%. The predicted relative risk of non-localised CRC and death from CRC in the screened compared with the control population was 0.86 (95% CI: 0.79-0.98) and 0.91 (95% CI: 0.85-1.02), respectively. Conclusion Based on the preliminary results of the Finnish CRC screening programme, our model predicted a 9% reduction in CRC mortality and a 14% reduction in advanced CRC. PMID- 28084890 TI - Self-reported physical activity behavior of breast cancer survivors during and after adjuvant therapy: 12 months follow-up of two randomized exercise intervention trials. AB - BACKGROUND: Exercise during and after breast cancer treatment has shown several health benefits. However, little is known about the courses, patterns, and determinants of physical activity of breast cancer patients, and the role of exercise interventions on their physical activity behavior in the long run. MATERIAL AND METHODS: Self-reported physical activity was assessed in 227 breast cancer survivors before, during, and three, six, and 12 months post-intervention within two randomized resistance exercise trials performed during adjuvant chemo- or radiotherapy, respectively, with similar designs. Multiple ordinal logistic regression analyses were performed to identify determinants of physical activity at these time points. RESULTS: While the intervention group exercised a median 1.8 h/week during adjuvant therapy (interquartile range 1.4-2.5), 68% of controls did not engage in any exercise. At 12-months follow-up 32% of patients did not engage in any exercise irrespective of the intervention. Of the patients who cycled for transportation pre-diagnosis about half stopped cycling in the long term in both groups. In contrast, walking was maintained over time. Major determinants of low levels of exercise at 12-months follow-up were low pre diagnosis levels of exercise, lower education, being postmenopausal, and having breast problems or depressive symptoms. Further, the intervention appeared to influence the type of sports performed, with strength exercise being the most common type of exercise at follow-up in the exercise group, more frequently compared to the control group. CONCLUSION: The exercise intervention effectively countervailed the decrease in physical activity during cancer therapy and boosted strength exercise in the months following the intervention, but in the longer term many survivors were insufficiently active. Breast cancer survivors may need continued motivation and practical support tailored to their individual characteristics and physical activity history to incorporate exercise in everyday routine in the long term. PMID- 28084891 TI - The Effect of Concussion or Mild Traumatic Brain Injury on School Grades, National Examination Scores, and School Attendance: A Systematic Review. AB - Concussion often results in symptoms, including difficulty concentrating, focusing, and remembering, that are typically managed with cognitive and physical rest. Often, the school environment is not conducive to cognitive rest and may lead to worsening or prolonged symptoms that can contribute to impaired academic performance. The objective of the review was to identify and summarize literature concerning the effects of concussion or mild traumatic brain injury (mTBI) on academic outcomes. MEDLINE, Embase, Scopus, and CINAHL were searched until June 1, 2016. Studies must have been primary literature examining students enrolled in primary, secondary, or post-secondary education, have received a physician diagnosis of concussion or mTBI, and have post-injury academic outcomes assessed in numeric or alphabet grade/grade point average (GPA), school attendance records, or national examination scores. Data were extracted and checked by a second reviewer for accuracy and completeness. Nine studies were included. Among four studies that examined grades, one found a significant difference in pre- and post-grades only in the subject Afrikaans. Three examined national test scores and no significant differences were found between cases and controls. Four examined school absenteeism and found that students who developed post-concussion syndrome missed significantly more school days and took longer to return to school than students with extremity injuries. Although mTBI or concussion is associated with missed school, the results demonstrate minimal impact on school grades and national examination scores at a group level. Further research is needed to identify risk factors for impaired school functioning following mTBI and concussion in individual patients. PMID- 28084892 TI - Sick leave among parents of children with cancer - a national cohort study. AB - BACKGROUND: Due to psychological distress and an increased care burden, parents of children diagnosed with cancer may face a higher risk of sickness absence from work. The objective of this study was to examine the association of childhood cancer with parents' sick leave. MATERIAL AND METHODS: The sample comprised 3626 parents of 1899 children diagnosed with cancer in Sweden during 2004-2009, and a matched control group of parents (n = 34 874). Sick leave was measured as number of days with sickness benefit, retrieved from national registries. Logistic and negative binomial regression models were used to compare outcomes with parents from the control cohort. RESULTS: The risk of sick leave was statistically significantly higher up to six years following a child's cancer diagnosis. The increase in number of days with sickness benefit was most pronounced the year after diagnosis. Although mothers' sick leave prevalence was higher, the increase in risk relative to control parents was similar for mothers and fathers. Bereavement was associated with a heightened risk of sick leave, especially on the year of the child's death. CONCLUSIONS: Findings confirm that mothers and fathers of children diagnosed with cancer are at higher risk of sickness absence from work, with particularly pronounced risk among bereaved parents. Acquisition of further knowledge is warranted regarding possibilities and constraints of parents trying to combine their work life with caring for both their child and themselves. PMID- 28084893 TI - Strategies of successful and unsuccessful simulators coached to feign traumatic brain injury. AB - OBJECTIVE: The present study evaluated strategies used by healthy adults coached to simulate traumatic brain injury (TBI) during neuropsychological evaluation. METHOD: Healthy adults (n = 58) were coached to simulate TBI while completing a test battery consisting of multiple performance validity tests (PVTs), neuropsychological tests, a self-report scale of functional independence, and a debriefing survey about strategies used to feign TBI. RESULTS: "Successful" simulators (n = 16) were classified as participants who failed 0 or 1 PVT and also scored as impaired on one or more neuropsychological index. "Unsuccessful" simulators (n = 42) failed >=2 PVTs or passed PVTs but did not score impaired on any neuropsychological index. Compared to unsuccessful simulators, successful simulators had significantly more years of education, higher estimated IQ, and were more likely to use information provided about TBI to employ a systematic pattern of performance that targeted specific tests rather than performing poorly across the entire test battery. CONCLUSION: Results contribute to a limited body of research investigating strategies utilized by individuals instructed to feign neurocognitive impairment. Findings signal the importance of developing additional embedded PVTs within standard cognitive tests to assess performance validity throughout a neuropsychological assessment. Future research should consider specifically targeting embedded measures in visual tests sensitive to slowed responding (e.g. response time). PMID- 28084894 TI - Donors FMO3 polymorphisms affect tacrolimus elimination in Chinese liver transplant patients. AB - AIM: Flavin-containing monooxygenase (FMO) variants were potentially involved in tacrolimus metabolism in kidney transplantion. The influences of FMO3 genotypes on tacrolimus elimination in Chinese liver transplant patients remained unclear. PATIENTS & METHODS: FMO3 SNPs and CYP3A5 rs776746 were analyzed in 110 Chinese patients. RESULTS: Donor FMO3 rs1800822 allele T and rs909530 allele T were associated with fast tacrolimus elimination. Combination of polymorphisms of donor FMO3 rs1800822 and rs909530 genotype impacted on tacrolimus elimination (p = 0.0221). The number of donor rs1800822 allele T and rs909530 allele T was confirmed to be an independent predictor of the tacrolimus concentration-to-dose ratios for weeks 2, 3 and 4 in the multivariate analysis. CONCLUSION: Donor's FMO3 polymorphisms might affect tacrolimus elimination. PMID- 28084896 TI - Addenda. PMID- 28084895 TI - Parents' Perceptions of Their Children as Overweight and Children's Weight Concerns and Weight Gain. AB - The global prevalence of childhood obesity is alarmingly high. Parents' identification of their children as overweight is thought to be an important prerequisite to tackling childhood obesity, but recent findings suggest that such parental identification is counterintuitively associated with increased weight gain during childhood. One possibility is that parental identification of their child as being overweight results in that child viewing his or her body size negatively and attempting to lose weight, which eventually results in weight gain. We used data from two longitudinal cohort studies to examine the relation between children's weight gain and their parents' identification of them as being overweight. Across both studies, children whose parents perceive them to be overweight are more likely to view their body size negatively and are more likely than their peers to be actively trying to lose weight. These child-reported outcomes explained part of the counterintuitive association between parents' perceptions of their children as being overweight and the children's subsequent weight. We propose that the stigma attached to being recognized and labeled as "overweight" may partly explain these findings. PMID- 28084897 TI - Modelling of human performance in complex systems with emphasis on nuclear power plant operations and probabilistic risk assessment. PMID- 28084898 TI - Editorial. PMID- 28084899 TI - Limited role of HLA DQ2/8 genotyping in diagnosing coeliac disease. AB - The European guidelines for diagnosing coeliac disease in children were revised in 2012. These recommend that in symptomatic children, a diagnosis of coeliac disease can be made without small-bowel biopsies provided their anti-tissue transglutaminase (anti-tTG) titre is >10 times of upper-limit-of-normal (>10*ULN) and anti-endomysial antibody is positive. In order to firm up the diagnosis in these children with very high anti-tTG titre, HLA-DQ2/DQ8 should be checked and be positive. Approximately 25-40% of white Caucasian population has HLA-DQ2/DQ8 haplotype. However, only 0.1-1% of the population will develop coeliac disease. Therefore, HLA-DQ2/DQ8 testing must not be done to 'screen' or 'diagnose' children with coeliac disease. Its use by paediatricians should be limited to children with anti-tTG>10*ULN, where the diagnosis of coeliac disease is being made on serology alone. A review of case referrals made to a tertiary paediatric gastroenterology centre in Southwest England demonstrated that HLA-DQ2/DQ8 testing is being requested inappropriately both in primary and secondary care suggesting a poor understanding of its role in diagnosis of coeliac disease. This article aims to clarify the role of HLA-DQ2/DQ8 testing for clinicians working in non-specialist settings. PMID- 28084900 TI - The reliability and validity of three questionnaires: The Student Satisfaction and Self-Confidence in Learning Scale, Simulation Design Scale, and Educational Practices Questionnaire. AB - PURPOSE: The purpose of this study was to adapt the "Student Satisfaction and Self-Confidence in Learning Scale" (SCLS), "Simulation Design Scale" (SDS), and "Educational Practices Questionnaire" (EPQ) developed by Jeffries and Rizzolo into Turkish and establish the reliability and the validity of these translated scales. METHODS: A sample of 87 nursing students participated in this study. These scales were cross-culturally adapted through a process including translation, comparison with original version, back translation, and pretesting. Construct validity was evaluated by factor analysis, and criterion validity was evaluated using the Perceived Learning Scale, Patient Intervention Self confidence/Competency Scale, and Educational Belief Scale. FINDINGS: Cronbach's alpha values were found as 0.77-0.85 for SCLS, 0.73-0.86 for SDS, and 0.61-0.86 for EPQ. CONCLUSIONS: The results of this study show that the Turkish versions of all scales are validated and reliable measurement tools. PMID- 28084901 TI - Lower limbs venous kinetics and consequent impact on drainage direction. AB - Background Literature concerning the lower limbs physiological venous haemodynamics is still lacking of reference velocity values and consequent impact on drainage direction. Aim of the present study is to assess the flow velocities in the different venous compartments, evaluating the possible Venturi effect role, thus finding clues for the identification of the physical model governing the flow direction. Methods Thirty-six lower limbs underwent a velocity and diameters echo-color-Doppler assessment in several anatomical point of analysis along both the deep and superficial venous systems. The investigation protocol included and compared two different manoeuvres to elicit the flow: manual calf compression/relaxation (CR) and active foot dorsiflexion (AFD). Both peak systolic (PSV) and time average velocities (TAV) were measured. Results The different venous segments demonstrated an overlap among the velocity values and the anatomical subdivision of the deep and superficial compartments. At the CR, TAV was 34 +/- 12 cm/s in the deep venous system (N1), 15 +/- 7 cm/s in the saphenous system (N2), 5 +/- 2 cm/s in the saphenous tributaries (N3); PSV was 89 +/- 35 cm/s in N1, 34 +/- 16 cm/s in N2, 11 +/- 4 cm/s in N3, p < 0.05. At the AFD, TAV was 33 +/- 13 cm/s in N1, 15 +/- 7 in N2, 9 +/- 5 in N3; PSV was 83 +/- 35 in N1, 32 +/- 17 in N2, 15 +/- 4 in N3, p < 0.05. A diameter decrease was reported from N1 to N3 ( p < 0.05). Conclusion This investigation provides evidences of the velocity decrease from the deepest to the most superficial compartments. These data introduce the Venturi effect as potential factor in the flow aspiration from the tributary to the deeper veins. The reported data represent a first step towards an objective evaluation of the physic laws governing the drainage. These values can constitute the basis for further investigations in pathological and post-procedural scenarios. PMID- 28084903 TI - Genetic variants associated with angiotensin-converting enzyme inhibitor-induced cough: a genome-wide association study in a Swedish population. AB - AIM: We conducted a genome-wide association study on angiotensin-converting enzyme inhibitor-induced cough and used our dataset to replicate candidate genes identified in previous studies. PATIENTS & METHODS: A total of 124 patients and 1345 treated controls were genotyped using Illumina arrays. The genome-wide significance level was set to p < 5 * 10-8. RESULTS: We identified nearly genome wide significant associations in CLASP1, PDE11A, KCNMB2, TGFA, SLC38A6 and MMP16. The strongest association was with rs62151109 in CLASP1 (odds ratio: 3.97; p = 9.44 * 10-8). All top hits except two were located in intronic or noncoding DNA regions. None of the candidate genes were significantly associated in our study. CONCLUSION: Angiotensin-converting enzyme inhibitor-induced cough is potentially associated with genes that are independent of bradykinin pathways. PMID- 28084904 TI - Associated Information Increases Subjective Perception of Duration. AB - Our sense of time is prone to various biases. For instance, one factor that can dilate an event's perceived duration is the violation of predictions; when a series of repeated stimuli is interrupted by an unpredictable oddball. On the other hand, when the probability of a repetition itself is manipulated, predictable conditions can also increase estimated duration. This suggests that manipulations of expectations have different or even opposing effects on time perception. In previous studies, expectations were generated because stimuli were repeated or because the likelihood of a sequence or a repetition was varied. In the natural environment, however, expectations are often built via associative processes, for example, the context of a kitchen promotes the expectation of plates, appliances, and other associated objects. Here, we manipulated such association-based expectations by using oddballs that were either contextually associated or nonassociated with the standard items. We find that duration was more strongly overestimated for contextually associated oddballs. We reason that top-down attention is biased toward associated information, and thereby dilates subjective duration for associated oddballs. Based on this finding, we propose an interplay between top-down attention and predictive processing in the perception of time. PMID- 28084905 TI - Relative Contribution of Odour Intensity and Valence to Moral Decisions. AB - Meta-analytic evidence showed that the chemical senses affect moral decisions. However, how odours impact on morality is currently unclear. Through a set of three studies, we assess whether and how odour intensity biases moral choices (Study 1a), its psychophysiological responses (Study 1b), as well as the behavioural and psychophysiological effects of odour valence on moral choices (Study 2). Study 1a suggests that the presence of an odour plays a role in shaping moral choice. Study 1b reveals that of two iso-pleasant versions of the same neutral odour, only the one presented sub-threshold (vs. supra-threshold) favours deontological moral choices, those based on the principle of not harming others even when such harm provides benefits. As expected, this odour intensity effect is tracked by skin conductance responses, whereas no difference in cardiac activity - proxy for the valence dimension - is revealed. Study 2 suggests that the same neutral odour presented sub-threshold increases deontological choices even when compared to iso-intense ambiguous odour, perceived as pleasant or unpleasant by half of the participants, respectively. Skin conductance responses, as expected, track odour pleasantness, but cardiac activity fails to do so. Results are discussed in the context of mechanisms alternative to disgust induction underlying moral choices. PMID- 28084906 TI - Endoscopic endonasal approach to the ventral brainstem: anatomical feasibility and surgical limitations. AB - OBJECTIVE Sporadic cases of endonasal intraaxial brainstem surgery have been reported in the recent literature. The authors endeavored to assess the feasibility and limitations of endonasal endoscopic surgery for approaching lesions in the ventral portion of the brainstem. METHODS Five human cadaveric heads were used to assess the anatomy and to record various measurements. Extended transsphenoidal and transclival approaches were performed. After exposing the brainstem, white matter dissection was attempted through this endoscopic window, and additional key measurements were taken. RESULTS The rostral exposure of the brainstem was limited by the sella. The lateral limits of the exposure were the intracavernous carotid arteries at the level of the sellar floor, the intrapetrous carotid arteries at the level of the petrous apex, and the inferior petrosal sinuses toward the basion. Caudal extension necessitated partial resection of the anterior C-1 arch and the odontoid process. The midline pons and medulla were exposed in all specimens. Trigeminal nerves were barely visible without the use of angled endoscopes. Access to the peritrigeminal safe zone for gaining entry into the brainstem is medially limited by the pyramidal tract, with a mean lateral pyramidal distance (LPD) of 4.8 +/- 0.8 mm. The mean interpyramidal distance was 3.6 +/- 0.5 mm, and it progressively decreased toward the pontomedullary junction. The corticospinal tracts (CSTs) coursed from deep to superficial in a craniocaudal direction. The small caliber of the medulla with very superficial CSTs left no room for a safe ventral dissection. The mean pontobasilar midline index averaged at 0.44 +/- 0.1. CONCLUSIONS Endoscopic endonasal approaches are best suited for pontine intraaxial tumors when they are close to the midline and strictly anterior to the CST, or for exophytic lesions. Approaching the medulla is anatomically feasible, but the superficiality of the eloquent tracts and interposed nerves limit the safe entry zones. Pituitary transposition after sellar opening is necessary to access the mesencephalon. PMID- 28084907 TI - Academic impact and rankings of neuroendovascular fellowship programs across the United States. AB - OBJECTIVE Publication has become a major criterion of success in the competitive academic environment of neurosurgery. This is the first study that has used departmental h index-and e index-based matrices to assess the academic output of neuroendovascular, neurointerventional, and interventional radiology fellowship programs across the continental US. METHODS Fellowship program listings were identified from academic and organization websites. Details for 37 programs were available. Bibliometric data for these programs were gathered from the Thomson Reuters Web of Science database. Citations for each publication from the fellowship's parent department were screened, and the h and e indices were calculated from non-open-surgical, central nervous system vascular publications. Variables including "high-productivity" centers, fellowship-comprehensive stroke center affiliation, fellowship accreditation status, neuroendovascular h index, e index ( h index supplement), h10 index (publications during the last 10 years), and departmental faculty-based h indices were created and analyzed. RESULTS A positive correlation was seen between the neuroendovascular fellowship h index and corresponding h10 index (R = 0.885; p < 0.0001). The mean, median, and highest faculty-based h indices exhibited positive correlations with the neuroendovascular fellowship h index (R = 0.662, p < 0.0001; R = 0.617, p < 0.0001; and R = 0.649, p < 0.0001, respectively). There was no significant difference (p = 0.824) in the median values for the fellowship h index based on comprehensive stroke center affiliation (30 of 37 programs had such affiliations) or accreditation (18 of 37 programs had accreditation) (p = 0.223). Based on the quartile analysis of the fellowship h index, 10 of 37 departments had an neuroendovascular h index of >= 54 ("high-productivity" centers); these centers had significantly more faculty (p = 0.013) and a significantly higher mean faculty h index (p = 0.0001). CONCLUSIONS The departmental h index and analysis of its publication topics can be used to calculate the h index of an associated subspecialty. The analysis was focused on the neuroendovascular specialty, and this methodology can be extended to other neurosurgical subspecialties. Individual faculty research interest is directly reflected in the research productivity of a department. High-productivity centers had significantly more faculty with significantly higher individual h indices. The current systems for neuroendovascular fellowship program accreditation do not have a meaningful impact on academic productivity. PMID- 28084902 TI - The Rotator Cuff Organ: Integrating Developmental Biology, Tissue Engineering, and Surgical Considerations to Treat Chronic Massive Rotator Cuff Tears. AB - The torn rotator cuff remains a persistent orthopedic challenge, with poor outcomes disproportionately associated with chronic, massive tears. Degenerative changes in the tissues that comprise the rotator cuff organ, including muscle, tendon, and bone, contribute to the poor healing capacity of chronic tears, resulting in poor function and an increased risk for repair failure. Tissue engineering strategies to augment rotator cuff repair have been developed in an effort to improve rotator cuff healing and have focused on three principal aims: (1) immediate mechanical augmentation of the surgical repair, (2) restoration of muscle quality and contractility, and (3) regeneration of native enthesis structure. Work in these areas will be reviewed in sequence, highlighting the relevant pathophysiology, developmental biology, and biomechanics, which must be considered when designing therapeutic applications. While the independent use of these strategies has shown promise, synergistic benefits may emerge from their combined application given the interdependence of the tissues that constitute the rotator cuff organ. Furthermore, controlled mobilization of augmented rotator cuff repairs during postoperative rehabilitation may provide mechanotransductive cues capable of guiding tissue regeneration and restoration of rotator cuff function. Present challenges and future possibilities will be identified, which if realized, may provide solutions to the vexing condition of chronic massive rotator cuff tears. PMID- 28084908 TI - A novel weighted scoring system for estimating the risk of rapid growth in untreated intracranial meningiomas. AB - OBJECTIVE Advances in neuroimaging techniques have led to the increased detection of asymptomatic intracranial meningiomas (IMs). Despite several studies on the natural history of IMs, a comprehensive evaluation method for estimating the growth potential of these tumors, based on the relative weight of each risk factor, has not been developed. The aim of this study was to develop a weighted scoring system that estimates the risk of rapid tumor growth to aid treatment decision making. METHODS The authors performed a retrospective analysis of 232 patients with presumed IM who had been prospectively followed up in the absence of treatment from 1997 to 2013. Tumor volume was measured by imaging at each follow-up visit, and the growth rate was determined by regression analysis. Predictors of rapid tumor growth (defined as >= 2 cm3/year) were identified using a logistic regression model; each factor was awarded a score based on its own coefficient value. The probability (P) of rapid tumor growth was estimated using the following formula:[Formula: see text] RESULTS Fifty-nine tumors (25.4%) showed rapid growth. Tumor size (OR per cm3 1.07, p = 0.000), absence of calcification (OR 3.87, p = 0.004), peritumoral edema (OR 2.74, p = 0.025), and hyperintense or isointense signal on T2-weighted MRI (OR 3.76, p = 0.049) were predictors of tumor growth rate. In the Asan Intracranial Meningioma Scoring System (AIMSS), tumor size was categorized into 3 groups of < 2.5 cm, >= 2.5 to < 4.0 cm, and >= 4.0 cm in diameter and awarded a score of 0, 3, and 6, respectively; the parameters of calcification and peritumoral edema were categorized into 2 groups based on their presence or absence and given a score of 0 or 2 and 1 or 0, respectively; and the signal on T2-weighted MRI was categorized into 2 groups of hypointense and hyperintense/isointense and given a score of 0 or 2, respectively. The risk of rapid tumor growth was estimated to be < 10% when the total score was 0-2, 10%-50% when the total score was 3-6, and >= 50% when the total score was 7-11 (Hosmer-Lemeshow goodness-of-fit test, p = 0.9958). The area under the receiver operating characteristic curve was 0.86. CONCLUSIONS The authors suggest a weighted scoring system (AIMSS) that predicts the specific probability of rapid tumor growth for patients with untreated IM. This scoring system will aid treatment decision making in clinical settings by screening out patients at high risk for rapid tumor growth. PMID- 28084909 TI - Comparison of endovascular and microsurgical management of 208 basilar apex aneurysms. AB - OBJECTIVE The deep and difficult-to-reach location of basilar apex aneurysms, along with their location near critical adjacent perforating arteries, has rendered the perception that microsurgical treatment of these aneurysms is risky. As a result, these aneurysms are considered more suitable for treatment by endovascular intervention. The authors attempt to compare the immediate and long term outcomes of microsurgery versus endovascular therapy for this aneurysm subtype. METHODS A prospectively maintained database of 208 consecutive patients treated for basilar apex aneurysms between 2000 and 2012 was reviewed. In this group, 161 patients underwent endovascular treatment and 47 were managed microsurgically. The corresponding records were analyzed for presenting characteristics, postoperative complications, discharge status, and Glasgow Outcome Scale (GOS) scores up to 1 year after treatment and compared using chi square and Student t-tests. RESULTS Among these 208 aneurysms, 116 (56%) were ruptured, including 92 (57%) and 24 (51%) of the endovascularly and microsurgically managed aneurysms, respectively. The average Hunt and Hess grade was 2.4 (2.4 in the endovascular group and 2.2 in the microsurgical group; p = 0.472). Postoperative complications of cranial nerve deficits and hemiparesis were more common in patients treated microsurgically than endovascularly (55.3% vs 16.2%, p < 0.05; and 27.7% vs 10.6%, p < 0.05, respectively). However, aneurysm remnants and need for retreatment were more common in the endovascular than the microsurgical group (41.3% vs 2.3%, p < 0.05; and 10.6% vs 0.0%, p < 0.05, respectively). Stent placement significantly reduced the need for retreatment. Rehemorrhage rates and average GOS score at discharge and 1 year after treatment were not statistically different between the two treatment groups. CONCLUSIONS Patients with basilar apex aneurysms were significantly more likely to be treated via endovascular management, but compared with those treated microsurgically, they had higher rates of recurrence and need for retreatment. The current study did not detect an overall difference in outcomes at discharge and 1 year after either treatment modality. Therefore, in a select group of patients, microsurgical treatment continues to play an important role. PMID- 28084910 TI - Early and late epilepsy surgery in focal epilepsies associated with long-term epilepsy-associated tumors. AB - OBJECTIVE Epilepsy surgery is an effective means of treating focal epilepsy associated with long-term epilepsy-associated tumors. This study evaluated a large population of surgically treated patients with childhood onset of epilepsy and a histologically confirmed diagnosis of long-term epilepsy-associated tumors. The authors analyzed long-term seizure outcomes to establish whether the time of surgery and patients' ages were determinant factors. METHODS The authors separately investigated several presurgical, surgical, and postsurgical variables in patients operated on before (pediatric group) and at or after (adult group) the age of 18 years. Patients with < 24 months of postsurgical follow-up were excluded from the analysis. RESULTS The patients who underwent surgery before 18 years of age showed better seizure outcomes than those after 18 years of age (80% vs 53.3% Engel Class Ia outcome, respectively; p < 0.001). Multivariate analysis showed that the only variables significantly associated with seizure freedom were complete resection of the lesion, a shorter duration of epilepsy, and temporal lobe resection. CONCLUSIONS The findings of this study indicate that pediatric patients are more responsive to epilepsy surgery and that a shorter duration of epilepsy, complete resection, and a temporal lobe localization are determinant factors for a positive seizure outcome. PMID- 28084911 TI - Anterior interhemispheric transsplenial approach to pineal region tumors: anatomical study and illustrative case. AB - Pineal region tumors are challenging to access because they are centrally located within the calvaria and surrounded by critical neurovascular structures. The goal of this work is to describe a new surgical trajectory, the anterior interhemispheric transsplenial approach, to the pineal region and falcotentorial junction area. To demonstrate this approach, the authors examined 7 adult formalin-fixed silicone-injected cadaveric heads and 2 fresh human brain specimens. One representative case of falcotentorial meningioma treated through an anterior interhemispheric transsplenial approach is also described. Among the interhemispheric approaches to the pineal region, the anterior interhemispheric transsplenial approach has several advantages. 1) There are few or no bridging veins at the level of the pericoronal suture. 2) The parietal and occipital lobes are not retracted, which reduces the chances of approach-related morbidity, especially in the dominant hemisphere. 3) The risk of damage to the deep venous structures is low because the tumor surface reached first is relatively vein free. 4) The internal cerebral veins can be manipulated and dissected away laterally through the anterior interhemispheric route but not via the posterior interhemispheric route. 5) Early control of medial posterior choroidal arteries is obtained. The anterior interhemispheric transsplenial approach provides a safe and effective surgical corridor for patients with supratentorial pineal region tumors that 1) extend superiorly, involve the splenium of the corpus callosum, and push the deep venous system in a posterosuperior or an anteroinferior direction; 2) are tentorial and displace the deep venous system inferiorly; or 3) originate from the splenium of the corpus callosum. PMID- 28084912 TI - External ventricular drain practice variations: results from a nationwide survey. AB - OBJECTIVE While guidelines exist for many neurosurgical procedures, external ventricular drain (EVD) insertion has yet to be standardized. The goal of this study was to survey the neurosurgical community and determine the most frequent EVD insertion practices. The hypothesis was that there would be no standard practices identified for EVD insertion or methods to avoid EVD-associated infections. METHODS The American Association of Neurological Surgeons membership database was queried for all eligible neurosurgeons. A 16-question, multiple choice format survey was created and sent to 7217 recipients. The responses were collected electronically, and the descriptive results were tabulated. Data were analyzed using the chi-square test. RESULTS In total, 1143 respondents (15.8%) completed the survey, and 705 respondents (61.6%) reported tracking EVD infections at their institution. The most common self-reported infection rate ranged from 1% to 3% (56.1% of participants), and 19.7% of respondents reported a 0% infection rate. In total, 451 respondents (42.7%) indicated that their institution utilizes a formal protocol for EVD placement. If a respondent's institution had a protocol, only 258 respondents (36.1%) always complied with the protocol. Protocol utilization for EVD insertion was significantly more frequent among residents, in academic/hybrid centers, in ICU settings, and if the institution tracked EVD-associated infection rates (p < 0.05). A self-reported 0% infection rate was significantly more commonly associated with a higher level of training (e.g., attending physicians), private center settings, a clinician performing 6 to 10 EVD insertions within the previous 12 months, and prophylactic continuous antibiotic utilization (p < 0.05). CONCLUSIONS This survey demonstrated heterogeneity in the practices for EVD insertion. No standard practices have been proposed or adopted by the neurosurgical community for EVD insertion or complication avoidance. These results highlight the need for the nationwide standardization of technique and complication prevention measures. PMID- 28084913 TI - Letter to the Editor. Unilateral or bilateral drainage for chronic subdural hematoma. PMID- 28084914 TI - Characterizing and predicting the Nelson-Salassa syndrome. AB - OBJECTIVE Nelson-Salassa syndrome (NSS) is a rare consequence of bilateral adrenalectomy (ADX) for refractory hypercortisolism due to Cushing disease (CD). Although classically defined by rapid growth of a large, invasive, adrenocorticotropin hormone (ACTH)-secreting pituitary tumor after bilateral ADX that causes cutaneous hyperpigmentation, visual disturbance, and high levels of ACTH, clinical experience suggests more variability. METHODS The authors conducted a retrospective chart review of all patients 18 years and older with a history of bilateral ADX for CD, adequate pituitary MRI, and at least 2 years of clinical follow-up. Statistical tests included Student's t-test, chi-square test, Fisher's exact test, multivariate analysis, and derived receiver operating characteristic curves. RESULTS Between 1956 and 2015, 302 patients underwent bilateral ADX for the treatment of hypercortisolism caused by CD; 88 had requisite imaging and follow-up (mean 16 years). Forty-seven patients (53%) had radiographic progression of pituitary disease and were diagnosed with NSS. Compared with patients who did not experience progression, those who developed NSS were significantly younger at the time of CD diagnosis (33 vs 44 years, p = 0.007) and at the time of bilateral ADX (35 vs 49 years, p = 0.007), had larger tumors at the time of CD diagnosis (6 mm vs 1 mm, p = 0.03), and were more likely to have undergone external-beam radiation therapy (EBRT, 43% vs 12%, p = 0.005). Among NSS patients, the mean tumor growth was 7 mm/yr (SE 6 mm/yr); the median tumor growth was 3 mm/yr. Prevalence of pathognomonic symptoms was low; the classic triad occurred in 9%, while hyperpigmentation without visual field deficit was observed in 23%, and 68% remained asymptomatic despite radiographic disease progression. NSS required treatment in 14 patients (30%). CONCLUSIONS NSS is a prevalent sequela of CD after bilateral ADX and affects more than 50% of patients. However, although radiological evidence of NSS is common, it is most often clinically indolent, with only a small minority of patients developing the more aggressive disease phenotype characterized by clinically meaningful symptoms and indications for treatment. Young age at the time of CD diagnosis or treatment with bilateral ADX, large tumor size at CD diagnosis, and EBRT are associated with progression to NSS and may be markers of aggressiveness. PMID- 28084915 TI - Trigeminal neuralgia and neuropathy in large sporadic vestibular schwannomas. AB - OBJECTIVE The aim of this study was to evaluate the incidence, presentation, and treatment outcomes of trigeminal nerve-mediated symptoms secondary to large vestibular schwannomas (VSs) with trigeminal nerve contact. Specifically, the symptomatic results of pain, paresthesias, and numbness after microsurgical resection or stereotactic radiosurgery (SRS) were examined. METHODS The authors conducted a retrospective review of a database for concomitant diagnosis of trigeminal neuralgia (TN) or trigeminal neuropathy and VS between 1994 and 2014 at a tertiary academic center. All patients with VS with TN or neuropathy were included, with the exception of those patients with neurofibromatosis Type 2 and patients who elected observation. Patient demographic data, symptom evolution, and treatment outcomes were collected. Population data were summarized, and outcome comparisons between microsurgery and SRS were analyzed at last follow-up. RESULTS Sixty (2.2%) of 2771 total patients who had large VSs and either TN or neuropathy symptoms met inclusion criteria. The average age of trigeminal symptom onset was 53.6 years (range 24-79 years), the average age at VS diagnosis was 54.4 years (range 25-79 years), and the average follow-up for the microsurgery and SRS groups was 30 and 59 months, respectively (range 3-132 months). Of these patients, 50 (83%) had facial numbness, 16 (27%) had TN pain, and 13 (22%) had paresthesias (i.e., burning or tingling). Subsequently, 50 (83%) patients underwent resection and 10 (17%) patients received SRS. Treatment of VS with SRS did not improve trigeminal symptoms in any patient. This included 2 subjects with unimproved facial numbness and 4 patients with worsened numbness. Similarly, SRS worsened TN pain and paresthesias in 5 patients and failed to improve pain in 2 additional patients. The Barrow Neurological Institute neuralgia and hypesthesia scale scores were significantly worse for patients undergoing SRS compared with microsurgery. Resection alleviated facial numbness in 22 (50%) patients, paresthesias in 5 (42%) patients, and TN in 7 (70%) patients. In several patients, surgery was not successful in relieving facial numbness, which failed to improve in 17 (39%) cases and became worse in 5 (11%) cases. Also, surgery did not change the intensity of facial paresthesias or neuralgia in 6 (50%) and 3 (25%) patients, respectively. Microsurgery exacerbated facial paresthesias in 1 (8%) patient but, notably, did not aggravate TN in any patient. CONCLUSIONS Overall, resection of large VSs provided improved outcomes for patients with concomitant TN, facial paresthesia, and numbness compared with SRS. However, caution should be used when counseling surgical candidates because a number of patients did not experience improvement. This was especially true in patients with preoperative facial numbness and paresthesias, who frequently reported that these symptoms were unchanged following surgery. PMID- 28084916 TI - Superior semicircular canal dehiscence syndrome. AB - Superior semicircular canal dehiscence (SSCD) syndrome is an increasingly recognized cause of vestibular and/or auditory symptoms in both adults and children. These symptoms are believed to result from the presence of a pathological mobile "third window" into the labyrinth due to deficiency in the osseous shell, leading to inadvertent hydroacoustic transmissions through the cochlea and labyrinth. The most common bony defect of the superior canal is found over the arcuate eminence, with rare cases involving the posteromedial limb of the superior canal associated with the superior petrosal sinus. Operative intervention is indicated for intractable or debilitating symptoms that persist despite conservative management and vestibular sedation. Surgical repair can be accomplished by reconstruction or plugging of the bony defect or reinforcement of the round window through a variety of operative approaches. The authors review the etiology, pathophysiology, presentation, diagnosis, surgical options, and outcomes in the treatment of this entity, with a focus on potential pitfalls that may be encountered during clinical management. PMID- 28084917 TI - Letter to the Editor. Mannitol for intraoperative brain relaxation. PMID- 28084918 TI - Don't get misdirected! Differences in overt and covert attentional inhibition between children and adults. AB - Previous research has revealed marked improvements in cognitive control between the age of 10 years and adulthood. The aim of the current study was to explore differences in attentional control between adults and children within a natural context, namely whilst they were watching a magic trick. We measured participants' eye movements whilst they watched a misdirection trick in which attentional misdirection was used to prevent observers from noticing a salient visual event. Half of our participants failed to detect this event even though it took place in full view. Children below the age of 10 were significantly less likely to notice the event than the adults and were also more reliably overtly misdirected (i.e., where they looked). Our results illustrate that within a more naturalistic context children are significantly more distracted than adults, and this distraction can have major implications on their visual awareness. PMID- 28084919 TI - The health belief model and factors associated with adherence to treatment recommendations for positional plagiocephaly. AB - OBJECTIVE This study aimed to examine factors associated with adherence to recommended treatment among pediatric patients with positional skull deformity by reviewing a single-institution experience (2007-2014) with the treatment of positional plagiocephaly. METHODS A retrospective chart review was conducted. Risk factors, treatment for positional head shape deformity, and parent-reported adherence were recorded. Univariate and multivariate analyses were used to assess the impact of patient clinical and demographic characteristics on adherence. RESULTS A total of 991 patients under age 12 months were evaluated for positional skull deformity at the Texas Children's Hospital Cranial Deformity Clinic between 2007 and 2014. According to an age- and risk factor-based treatment algorithm, patients were recommended for repositioning, physical therapy, or cranial orthosis therapy or crossover from repositioning/physical therapy into cranial orthosis therapy. The patients' average chronological age at presentation was 6.2 months; 69.3% were male. The majority were white (40.7%) or Hispanic (32.6%); 38.7% had commercial insurance and 37.9% had Medicaid. The most common initial recommended treatment was repositioning or physical therapy; 85.7% of patients were adherent to the initial recommended treatment. Univariate analysis showed differences in adherence rates among subgroups. Children's families with Medicaid were less likely to be adherent to treatment recommendations (adherence rate, 80.2%). Families with commercial insurance were more likely to be adherent to the recommended treatment (89.6%). Multivariate logistic regression confirmed that factors associated with parent-reported adherence to recommended treatment included primary insurance payer, diagnosis (plagiocephaly vs brachycephaly), and the nature of the recommended treatment. Families were less likely to be adherent if they had Medicaid, a child with a diagnosis of brachycephaly, or were initially recommended for cranial orthosis therapy than families with commercial insurance, a child with a diagnosis of plagiocephaly, or an initial recommendation for repositioning or physical therapy. Factors associated with treatment completion included corrected age, insurance, diagnosis, recommended treatment, and distance to provider from patient's residence. Patients with commercial insurance (OR 1.49, 95% CI 1.10-2.02, p = 0.009), those diagnosed with both brachycephaly and plagiocephaly (OR 2.26, 95% CI 1.31-3.90, p = 0.003), those recommended for treatment with cranial orthosis (OR 4.55, 95% CI = 3.24 6.38, p < 0.001), and those living in proximity to the provider (OR 1.40, 95% CI 1.00-1.96, p = 0.047) were more likely to complete treatment. CONCLUSIONS Insurance type, degree of head shape deformity, and types of recommended treatment appear to affect rates of adherence to recommended treatments for positional skull deformation. PMID- 28084920 TI - Letter to the Editor: Cranial vault remodeling. PMID- 28084921 TI - Factors influencing outcomes of the treatment of positional plagiocephaly in infants: a 7-year experience. AB - OBJECTIVE Following institution of the Back to Sleep Campaign, the incidence of sudden infant death syndrome decreased while the prevalence of positional skull deformation increased dramatically. The management of positional deformity is controversial, and treatment recommendations and outcomes reporting are variable. The authors reviewed their institutional experience (2008-2014) with the treatment of positional plagiocephaly to explore factors associated with measured improvement. METHODS A retrospective chart review was conducted with risk factors and treatment for positional head shape deformity recorded. Univariate and multivariate analyses were used to assess the impact of these variables on the change in measured oblique diagonal difference (ODD) on head shape surface scanning pre- and posttreatment. RESULTS A total of 991 infants aged less than 1 year were evaluated for cranial positional deformity in a dedicated clinical program. The most common deformity was occipital plagiocephaly (69.5%), followed by occipital brachycephaly (18.4%) or a combination of both deformities (12.1%). Recommended treatment included repositioning (RP), physical therapy (PT) if indicated, or orthotic treatment with a customized cranial orthosis (CO) according to an age- and risk factor-dependent algorithm that the authors developed for this clinic. Of the 991 eligible patients, 884 returned for at least 1 follow-up appointment. A total of 552 patients were followed to completion of their treatment and had a full set of records for analysis: these patients had pre- and posttreatment 2D surface scanner evaluations. The average presenting age was 6.2 months (corrected for prematurity for treatment considerations). Of the 991 patients, 543 (54.8%) had RP or PT as first recommended treatment. Of these 543 patients, 137 (25.2%) transitioned to helmet therapy after the condition did not improve over 4-8 weeks. In the remaining cases, RP/PT had already failed before the patients were seen in this program, and the starting treatment recommendation was CO. At the end of treatment, the measured improvements in ODD were 36.7%, 33.5%, and 15.1% for patients receiving CO, RP/PT/CO, and RP/PT, respectively. Univariate analysis showed that sex, race, insurance, diagnosis, sleep position preference, torticollis history, and multiple gestation were not significantly associated with magnitude of ODD change during treatment. On multivariate analysis, corrected age at presentation and type of treatment received were significantly associated with magnitude of ODD change. Orthotic treatment corresponded with the largest ODD change, while the RP/PT group had the least change in ODD. Earlier age at presentation corresponded with larger ODD change. CONCLUSIONS Earlier age at presentation and type of treatment impact the degree of measured deformational head shape correction in positional plagiocephaly. This retrospective study suggests that treatment with a custom CO can result in more improvement in objective measurements of head shape. PMID- 28084922 TI - Initial experience with endoscopic ultrasonic aspirator in purely neuroendoscopic removal of intraventricular tumors. AB - OBJECTIVE Neuroendoscopic removal of intraventricular tumors is difficult and time consuming because of the lack of an effective decompression system that can be used through the working channel of the endoscope. The authors report on the utilization of an endoscopic ultrasonic aspirator in the resection of intraventricular tumors. METHODS Twelve pediatric patients (10 male, 2 female), ages 1-15 years old, underwent surgery via a purely endoscopic approach using a Gaab rigid endoscope and endoscopic ultrasonic aspirator. Two patients presented with intraventricular metastases from high-grade tumors (medulloblastoma, atypical teratoid rhabdoid tumor), 2 with subependymal giant cell astrocytomas (associated with tuberous sclerosis), 2 with low-grade intraparaventricular tumors, 4 with suprasellar tumors (2 craniopharyngiomas and 2 optic pathway gliomas), and 2 with pineal tumors (1 immature teratoma, 1 pineal anlage tumor). Hydrocephalus was present in 5 cases. In all patients, the endoscopic trajectory and ventricular access were guided by electromagnetic neuronavigation. Nine patients underwent surgery via a precoronal bur hole while supine. In 2 cases, surgery was performed through a frontal bur hole at the level of the hairline. One patient underwent surgery via a posterior parietal approach to the trigone while in a lateral position. The endoscopic technique consisted of visualization of the tumor, ventricular washing to dilate the ventricles and to control bleeding, obtaining a tumor specimen with biopsy forceps, and ultrasonic aspiration of the tumor. Bleeding was controlled with irrigation, monopolar coagulation, and a thulium laser. RESULTS In 7 cases, the resection was total or near total (more than 90% of lesion removed). In 5 cases, the resection was partial. Histological evaluation of the collected material (withdrawn using biopsy forceps and aspirated with an ultrasonic aspirator) was diagnostic in all cases. The duration of surgery ranged from 30 to 120 minutes. One case was complicated by subdural hygroma requiring a subduro-peritoneal shunt implant. CONCLUSIONS In this preliminary series, endoscopic ultrasonic aspiration proved to be a safe and reliable method for achieving extensive decompression or complete removal in the management of intra- and/or paraventricular lesions in pediatric patients. PMID- 28084923 TI - Enacted cultural critique: Examining everyday violence in Garo Hills. AB - This article is a critical ethnographic illustration of community psychology praxis as enacted cultural critique. Community psychology praxis involves cultural critique so as to challenge, subvert, resist, and transform disempowering cultural constructions. Although it is important to appreciate and attend to cultural norms, there are many contexts where existing norms serve to marginalize communities. Drawing from a youth participatory action research initiative in the Garo Hills region of Northeast India, we examine the implications of community psychology praxis as enacted cultural critique in the context of endemic ethnic conflict. Enacted cultural critique in such a context entails deliberate, self-conscious efforts to interpret or make sense of the existing cultural context and create new ones. This creative activity involves collectively imagining, saying, writing, sculpting, fashioning and/or building new ways of being in and understanding our shared world. Our approach is characterized by an explicit recognition of the political nature of cultural analysis, which represents a significant departure from traditional, apolitical understanding of culture. Using the lens of community psychology praxis also allows for a more agentive view of culture-one that acknowledges that individuals and communities (re)create and (re)write culture through practices of everyday life and social and political mobilization. PMID- 28084924 TI - Implementing a cultural competence training as a psychopolitical empowerment process. AB - The cultural competence training (CCT) of health care professionals represents a useful resource to face the challenges involved in health care assistance for multicultural populations. However, the traditional perspective has shown limited results, as it does not consider professionals in their contexts and avoids continuous assessment processes. In response to these limitations, we describe a model of CCT implemented by two professors of the Faculty of Nursing at the University of Seville in Spain as a psychopolitical empowerment process, and exemplified by the experience of the emergency nurses at the Virgen Macarena Hospital. This process adds the notion of power to traditional CCT and uses dialogic learning to: (a) state a mission and develop critical thinking; (b) take stock of the actions for change and increase the capacity of nurses to respond; and (c) motivate nurses to plan the future and take action. As a result, professionals become a learning community, able to develop a new professional identity and role, and can also implement actions for the transformation of health care settings. PMID- 28084925 TI - Effects of the community engagement of migrants on their well-being: The case of Moroccan leaders in southern Spain. AB - Community engagement of migrants has been identified as an important element in developing both individual well-being and cohesive multicultural receiving communities. Through 10 in-depth interviews, this study explores the profile of Moroccan migrant leaders in community organizations in the receiving context (south of Spain) and the reasons for which they engage. Moreover, it analyzes the relationship established between community engagement and their well-being. The results show that migrants commit for both intrinsic (e.g., support their compatriots) and extrinsic (e.g., increase their social connection) reasons. Their social action has a positive influence on their well-being because it activates the following paths: (1) improvement of bicultural competences; (2) development of social relationships with receiving members; (3) strengthening of social bonds with compatriots; (4) increase of abilities in dealing with unjust social conditions in the new environment; and (5) decrease of prejudice towards their own cultural group. PMID- 28084926 TI - Implicit knowledge, critical reflection, and social change. PMID- 28084927 TI - Participatory action research from an intercultural and critical perspective. AB - The critical community psychology approach to intercultural issues constitutes the theoretical framework for this research. The work has been carried out in the Campania region, in the South of Italy, by a group of University researchers in collaboration with representatives of associations, members of the local community, and Maghrebi immigrants who reside in the local area of San Marcellino (Caserta). This participatory action research (PAR) was aimed at acquiring knowledge about the mutual interactions between migrants and inhabitants who share the same local context. The results show the participants' and researchers' reflexivity as a main investigation tool that enriched the quality of research. The role of power profile in community analysis, the thorough definition of the trustworthiness of the researchers within the local context-as well as the use of nonasymmetrical power-based interactions between researchers and participants (think-tank sessions)-and focused interviews are discussed. PMID- 28084928 TI - Partnership working as liberation psychology: Forced labor among UK Chinese migrant workers. AB - In this article we seek to reflect critically on some recent research we have carried out, in collaboration with a Chinese welfare NGO, on the experience of forced labor among Chinese migrant workers in the UK. We will (a) locate briefly the wider political context of migrant work (both regular and irregular) in the UK; (b) explore how and why the actual research methods and process of the research deviated in practice from those that were planned; and PMID- 28084929 TI - Practicing ethnography in migration-related detention centers: A reflexive account. AB - Feminist scholars, as well as community psychologists, have advocated the role of reflexive engagement in the research process in order to challenge power relations. Moreover, the liberating potential of storytelling, especially when working with issues of diversity and marginalization, has been stressed. The purpose of this article is to reflect on an ethnographic work underway in the Identification and Expulsion Center-CIE of Ponte Galeria, Rome. How the researcher's identities, values, and experiences, alongside power and privilege, have influenced her positioning in the research setting and the relationships formed with the different setting members is the subject of discussion. In sharing the story of this work, the final intent is to contribute to the joint effort to foster a reflexive community psychology practice incorporating feminist goals and a dialogue about ethnography in community psychology. PMID- 28084930 TI - Erratum: Radiation exposure in spine surgery using an image-guided system based on intraoperative cone-beam computed tomography: analysis of 107 consecutive cases. PMID- 28084931 TI - Noninfectious prevertebral soft-tissue inflammation and hematoma eliciting swelling after anterior cervical discectomy and fusion. AB - OBJECTIVE Anterior cervical discectomy and fusion (ACDF) procedures are performed to treat patients with cervical myelopathy or radiculopathy. Dysphagia is a post ACDF complication. When it coincides with prevertebral space enlargement and inflammation, surgical site infection and pharyngoesophageal perforation must be considered. The association between dysphagia and prevertebral inflammation has not been reported. The authors investigated factors eliciting severe dysphagia and its relationship with prevertebral inflammation in patients who had undergone ACDF. MATERIALS The clinical data of 299 patients who underwent 307 ACDF procedures for cervical radiculopathy or myelopathy at Kushiro Kojinkai Memorial Hospital and Kushiro Neurosurgical Hospital between December 2007 and August 2014 were reviewed. RESULTS After 7 ACDF procedures (2.3%), 7 patients suffered severe prolonged and/or delayed dysphagia and odynophagia that prevented ingestion. In all 7 patients the prevertebral space was enlarged. In 5 (1.6%) the symptom was thought to be associated with prevertebral soft-tissue edema; in all 5 an inflammatory response, hyperthermia, and an increase in the white blood cell count and in C-reactive protein level was observed. After 2 procedures (0.7%), we noted prevertebral hematoma without an inflammatory response. None of the patients who had undergone 307 ACDF procedures manifested pharyngoesophageal perforation or surgical site infection. CONCLUSIONS Severe dysphagia and odynophagia are post-ACDF complications. In most instances they are attributable to prevertebral soft-tissue edema accompanied by inflammatory responses such as fever and an increase in the white blood cell count and in C-reactive protein. In other cases these anomalies are elicited by hematoma not associated with inflammation. PMID- 28084932 TI - Letter to the Editor: Strategic use of cone-beam CT in modern spine surgery. PMID- 28084934 TI - Tribological concepts involved in slipping accident analysis. AB - According to tribology science, the friction force produced at the sliding interface between a rubber piece and an inflexible surface presents three main components: the first is due to molecular adhesion between the two bodies, it occurs at the regions of real contact; the second is a hysteresis component resulting from the periodic excitation of the bulk of the rubber by surface roughness; the third is due to effects of product shape. The shape of the elastomer product and the conditions in which the friction occurs (lubricant, roughness of the inflexible surface, etc.) determine the appearance of each one of these components and its importance. Experimentations made by the French national research and safety Institute (INRS) revealed adhesion and hysteresis components in the lubricated friction of an elastomer over a representative sample of industrial floor surfaces. Measurements have been made by means of a portable friction tester (PFT) assessing sliding resistance of floor coverings. The sliding movement takes place between a braked test wheel and the floor covering. The effect of product shape is insignificant as the wheel is covered with smooth elastomer. The friction force produced at the sliding interface between the elastomer and the floor covering has been evaluated on smooth and rough floors, and under different lubrication conditions (flooded with water, large, medium and small quantities of mineral oil). Several test wheels, with different and sometimes used rubber coverings, have been employed. The friction force is altered when the elastomer composition or the state of the elastomer that is covering the test wheel changes. The differences pointed out depend also on floor covering roughness and lubrication. The importance of either the adhesion or hysteresis components of the friction force in accordance with the composition and the state of the elastomer that is covering the test wheel, the lubricant amount, and the floor covering roughness enable the interpretation of these differences. Some experimental results are explained from the squeeze lubricant film process. This experimental study permits a better understanding of phenomena produced at the sliding interface between a rubber sole and a floor covering when a pedestrian slips. It also plays a great part in bringing the portable friction tester into operation in order to carry out a measurement campaign of slipping resistance of industrial floors. PMID- 28084933 TI - Clinical outcomes following resection of giant spinal schwannomas: a case series of 32 patients. AB - OBJECTIVE The objective of this study was to review clinical outcomes following resection of giant spinal schwannomas. METHODS The authors conducted a retrospective review of a case series of patients with giant spinal schwannomas at a tertiary cancer hospital. RESULTS Thirty-two patients with giant spinal schwannomas underwent surgery between September 1998 and May 2013. Tumor size ranged from 2.5 cm to 14.6 cm with a median size of 5.8 cm. There were 9 females (28.1%) and 23 males (71.9%), and the median age was 47 years (range 23-83 years). The median follow-up duration was 36.0 months (range 12.2-132.4 months). Three patients (9.4%) experienced recurrence and required further treatment. All recurrences developed following subtotal resection (STR) of cellular or melanotic schwannoma. There were 3 melanotic (9.4%) and 6 cellular (18.8%) schwannomas included in this study. Among these histological variants, a 33.3% recurrence rate was noted. In 1 case of melanotic schwannoma, malignant transformation occurred. No recurrence occurred following gross-total resection (GTR) or when a fibrous capsule remained due to its adherence to functional nerve roots. CONCLUSIONS Resection is the treatment of choice for symptomatic or growing giant schwannomas, frequently requiring anterior or combined approaches, with the goals of symptom relief and prevention of recurrence. In this series, tumors that underwent GTR, or where only capsule remained, did not recur. Only melanotic and cellular schwannomas that underwent STR recurred. PMID- 28084935 TI - Assessment of slipping resistance of footwear and floor surfaces. Influence of manufacture and utilization of the products. AB - The slipping resistance of footwear or floor surfaces is a characteristic which it is vital to be able to quantify. Work is being carried out at the International Standard Organization (ISO) and at the European Committee for Standardization (CEN) into the slip resistance of both work shoes and protective footwear, involving analysis of the latest developments in both the validity of measuring methods and the extent of the influence of certain experimental parameters on the slip resistance. Two industrial factors, independent of the measuring process but essential to the determination of the coefficient of friction of the models have been experimentally studied, namely the effect of the manufacture of the footwear or floor surfaces on the scattering of the specific coefficient of friction of a referenced model and the effect on the coefficient of friction of mechanical wear and tear on the soles as a result of their use respectively. Work into slipping on industrial floor surfaces is less advanced. Yet, problems raised call for the same approach than for problems linked to slipping resistance of footwear, and applications will be also at first related to standardized measurement conditions. PMID- 28084936 TI - The role of environmental factors in causing injury through falls in public places. AB - The physical and environmental factors leading to domestic falls in the elderly have been assessed in many published studies; only one includes some assessment of environmental factors causing the elderly to fall outside their homes (Consumer Safety Unit, 1986). Many patients of all ages attend Accident and Emergency Departments with injuries sustained through such falls. This prospective study was undertaken to determine the frequency with which uneven surface or inadequate lighting was thought by the patients to have contributed to falls in public places, and to survey injuries sustained. Two hundred and thirty seven consecutive patients attending the Accident and Emergency Department were entered into the study, information being obtained by patient questionnaire and from A&E records. An average of 7 patients were entered into the study each day. The ratio of women to men was 1.7 :1. Patients of both sexes were most commonly aged between 15 and 34 years, with a second peak in women over 55 years. Two thirds of falls occurred on pavements. Uneven surface underfoot or inadequate street lighting was implicated in over half the falls. Injuries were mostly sprains and bruises, but facial lacerations and upper limb fractures were also common. Sixty eight per cent of fractures occurred in women over 55 years of age. Medical follow up was required in 40% of all cases. Uneven paving and inadequate lighting in public places are potentially avoidable factors in causing falls which lead to appreciable morbidity in large numbers of young and elderly patients attending A&E Departments. PMID- 28084937 TI - Mechanisms of friction and assessment of slip resistance of new and used footwear soles on contaminated floors. AB - The great number of slipping accidents indicates that footwear providing good slip resistance must be rare. Slip resistance seems to be a purely physical phenomenon, however, more knowledge of the mechanisms of friction is needed to develop slip-resistant footwear and to ensure safer walking in slippery conditions. In the present study the influence of the normal wear of shoe heels and soles on their frictional properties was clarified. The slip resistance of three types of new and used safety shoes on four relatively slippery floor contaminant combinations, was assessed with a prototype apparatus, which simulates the movements of a human foot and the forces applied to the underfoot surface during an actual slip. The used shoes were collected from 27 workers in a shipbuilding company and classified by sight into four wear classes: Good, satisfactory, poor, and worn-out. The assessed shoe heels and soles were in general more slippery when new compared to used heels and soles. However, footwear must be discarded before the tread pattern is worn-out. Used microcellular polyurethane (PU) heels and soles gave a considerably higher coefficient of kinetic friction (MUk) on contaminated floors than used heels and soles made of compact nitrile (NR) and compact styrene rubber (SR). The heel slide coefficient of kinetic friction (MUkl) for used versus new shoes was on average 66% higher for PU (0.216 versus 0.130), 27% higher for SR (0.143 versus 0.113), and 7% lower for NR (0.098 versus 0.105). The fundamental mechanisms of friction between shoe soles and contaminated floors were also discussed, and experiments with seven slabs of sole materials were carried out to assess contact pressure effects from the viewpoint of slipping. Slip resistance particularly seemed to depend on the squeeze film and the contact pressure effects between the soling materials and the floor. An increasing contact pressure dramatically reduced the MUk, thus indicating that the slip resistance varies considerably during the normal gait cycle. Hence, average friction readings are probably not at all decisive from the slip resistance point of view. An instantaneous coefficient of friction may be more relevant, because in walking the time available to achieve a sufficient coefficient of friction to avoid a slip is only a few tenths of a second. PMID- 28084939 TI - Editorial 4th International Conference on Slipping, Tripping, and Falling Accidents. PMID- 28084938 TI - Editorial Electronic display as a key technology for society. PMID- 28084942 TI - Accurate movement of two-probe components. AB - A two-probe task, simulating the location of an electronic component into its socket, was studied using a reciprocal tapping method. Movement time was measured as a function of the lateral and longitudinal target constraints as well as the separation (L) of the two probes. A linear increase in movement time with separation was found. A geometric model that postulated different effects of target height and width in different length zones was supported by multiple regressions within each zone. Results for the single probe version of this task were similar in pattern and magnitude to those of Hoffmann and Sheikh (1994). PMID- 28084944 TI - Detecting and eliminating slippery footwear. AB - A recently developed walking traction test has proved to be a reliable and rapid method of measuring coefficient of friction (c.o.f.) of floor surfaces and footwear, and is a suitable method for ranking the grip of footwear solings on slippery floors. This paper describes four new experiments in which footwear samples were ranked. The first experiment compared mean rank orders on water wet (wet) and oily surfaces of seven flat solings. Spearman's rank correlation coefficient rs was 0.893, P < 0.005. In the second experiment, five pairs of women's shoes were ranked on wet and oily surfaces. On the wet surfaces, three samples recorded maximum attainable c.o.f. but rank orders on two oily surfaces were identical, rs = 1.0, P < 0.01. In the third experiment, thirteen pairs of discarded footwear were ranked using three different test methods. The test surfaces were oily stainless steel plates cut from the same sheet. Rank orders of the three test methods were significantly similar. Kendall's coefficient of concordance w = 8.68, P < 0.001. In another experiment samples of commercially available footwear were issued to factory workers and recalled for c.o.f. measurements at intervals. Their rank orders on wet and oily surfaces were not statistically similar but when wet surface results obtained at 4 months, were compared with those at 10 months, rank orders were significant; rs = 0.994, P < 0.01. Also on oily surfaces, rank orders of two measurements were significant, rs = 0.982, P <0.01. Although most experiments have revealed significant correlations between footwear samples on wet and oily surfaces there are examples where a soling performs well on wet surfaces but is at the lower end of rank order on oily surfaces. It is concluded that rank orders on wet, oily and icy surfaces should be calculated but also it is necessary to examine rank orders on each surface-lubricant combination, by comparing results obtained at intervals during the useful lives of the solings. In future, samples at the lower end of the rank orders of c.o.f. will be eliminated from the varieties available to workers. PMID- 28084946 TI - Measures to prevent portable ladder accidents in the construction industry. AB - Ladder accidents account for nearly 5% of all reported occupational accidents in the Swedish construction industry. Eighty-five ladder accident victims were interviewed to obtain detailed information about factors contributing to their accidents. Accidents were almost equally divided between straight ladders (N = 39) and step- ladder (N = 33). The majority of accidents occurred while the victim was working from the ladder. Climbing up and, particularly, down straight ladders was associated with numerous accidents. For straight ladders, sliding at the base was the most common event preceding the injury. Low angle of inclination was a common contributing factor. For step-ladders, tipping sideways was the most common preceding event. Misstepping the final step while descending accounted for 10% of all accidents. More than 90% of the victims fell from less than 4 m. The interviews provided detailed information which served as a basis for proposals for alternatives to portable ladders; a step-scaffold adjustable for work at levels up to 3 m and a portable scaffold for work at levels of 1-3 m. These alternatives are under development. In addition, proposals for improving the stability of current portable ladders are made. PMID- 28084949 TI - Effects of personality and task strength on performance in computerized tasks. AB - This study examines the effects of embedding human personality characteristics into the computer interface. Eighty university students were taught how to use HyperCard on the Macintosh computer in a 2 * 2 * 2 factorial design as follows: personality of the interface (extroverted/introverted), * subjects' personality (extroverted/introverted), * task strength (low and high). The results indicated that subjects do perceive computer software as having personalities similar to those of humans. A significant interaction existed between interface designs (extroverted vs. introverted) and user type (extroverted vs introverted people). Introverted users performed faster with introverted software interfaces than with the extroverted interfaces. There were no differences in the performance time of extroverted subjects between the two interfaces. The study results also indicated that task performance for extroverted and introverted subjects was not different for high task strength tasks but extroverted subjects performed significantly faster on low task strength than did the introverted subjects. PMID- 28084950 TI - An evaluation of the Circadian Type Questionnaire. AB - This study evaluates the psychometric properties and assesses the test-retest reliability and longer-term stability of scores on the Circadian Type Questionnaire (CTQ) of Folkard et al. (1979) in a sample of 445 students. The scales were found to lack internal consistency and the factor structure originally proposed was not replicated. Cultural variation in CTQ scores was suggested. Test-retest reliability, over three months in a subgroup of 36, was poor for the V and M scales. Longer-term stability, over nine months in a subgroup of 36 who were exposed to shiftwork, was better but significant decreases were found in rigidity of sleeping habits (Rs) and morningness (M) scores. A factor analysis suggested that the scales should be constructed differently; however, the properties of such scales were still not optimal. The CTQ has psychometric flaws and needs to be improved before it could be expected to reliably function as a predictive test of adaptation to shiftwork. PMID- 28084951 TI - Arrhythmogenic right ventricular dysplasia/cardiomyopathy. AB - Arrhythmogenic right ventricular dysplasia/cardiomyopathy is an inherited cardiomyopathy characterised by ventricular arrhythmias and an increased risk of sudden cardiac death. Arrhythmogenic right ventricular dysplasia/cardiomyopathy diagnosis is based on criteria that take into account electrical and structural cardiac abnormalities, as well as mutation analysis. Appropriate pharmacological therapy and the prevention of sudden death with implantable defibrillators are important in the management of these patients. Exercise is considered an important environmental factor for the development and progression of the disease. PMID- 28084952 TI - Sudden cardiac arrest in patients following surgery for CHD. AB - The prevalence of sudden cardiac arrest after surgery for CHD is primarily related to the complexity of the congenital defect and the presence of residual defects, especially ventricular dysfunction. Among all causes of death in patients having CHD, about 19% lead to sudden mortality. The specific risk factors associated with the various congenital defects are poorly understood. The lone exception is tetralogy of Fallot, largely due to its high prevalence and the historically high post-operative survival rate. In tetralogy of Fallot, historical, haemodynamic, and electrical features contribute to risk, and electrophysiologic testing may be helpful, particularly to rule out risk. An implantable cardioverter-defibrillator is highly effective for secondary prevention in most forms of CHD, and future advances will improve its role in primary prevention. PMID- 28084953 TI - Discrimination of the "Athlete's Heart" from real disease by electrocardiogram and echocardiogram. AB - Chronic physical training has been shown to produce multiple changes in the heart, resulting in the athlete's heart phenotype. Some of the changes can make it difficult to discern athlete's heart from true cardiac disease, most notably hypertrophic cardiomyopathy. Other diseases such as dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy may be difficult to rule in or out. In this article, the physiological cardiac changes of chronic athletic training are reviewed. A methodological approach using electrocardiography and echocardiography to differentiate between athlete's heart and cardiac disease is proposed. PMID- 28084954 TI - How to develop a clinic for sudden cardiac arrest survivors and families of non survivors. AB - The investigation of the aetiology of sudden cardiac arrest or death in a young person combines features of a traditional clinical medical examination with those of forensic medicine. Nuances of the immediate peri-event history, when available, can be paramount. New genetic tools have greatly improved the yield of such investigations, but they must be carefully interpreted by genetic specialists. The approach to surviving patients, their family members, and to family members of non-survivors is best achieved in a structured programme that includes all appropriate specialists and support personnel. As an example, this may include all appropriate paediatric and internal medicine specialists, a geneticist, a genetic counsellor, a clinical psychologist, nurse specialist(s), and a programme coordinator. This family-centred strategy affords the patient, if surviving, and all family members the necessary emotional and medical support while at the same time providing the necessary diagnostic and therapeutic approaches. PMID- 28084955 TI - Sudden cardiac death in the young: the value of exercise testing. AB - Paediatric exercise stress testing has historically been used to assess the functional status of patients after repair of CHDs and to assess the efficacy of medical or device therapy in patients with arrhythmias. Exercise stress testing is one of very few hospital- or clinic-based tests that can assess the response of the cardiopulmonary system in an environment that simulates the body's response to vigorous play and competitive sport. Exercise stress testing is therefore a useful modality in the assessment of child and athletes at risk for sudden cardiac death. The author discusses some cardiovascular maladies that can cause sudden cardiac death by utilising case illustrations as a learning tool. PMID- 28084956 TI - Evaluating the survivor or the relatives of those who do not survive: the role of genetic testing. AB - The molecular millennium has bestowed clinicians and researchers with the essential tools to identify the underlying genetic substrates for thousands of genetic disorders, most of which are rare and follow Mendelian inheritance patterns. The genetic basis of potentially lethal and heritable cardiomyopathies and cardiac channelopathies has been identified and are now better understood. Genetic testing for several of these heritable conditions has made its transition from discovery through translation and have been commercially available clinical tests for over a decade. Now that clinical genetic testing is available more readily and delivers a disease-specific impact across the triad of medicine - diagnostic, prognostic, and therapeutic - it is important for the community of cardiologists to not only be familiar with the language of genomic medicine but to also be wiser users and even wiser interpreters of genetic testing so that wise decisions can be rendered for those patients and their families being evaluated with respect to the presence or absence of one of these potentially lethal yet highly treatable genetic disorders. The purpose of this review is to provide the reader with a foundational understanding of genetic testing in clinical cardiology. Here, we will present some benefits of genetic testing: indications for either post-mortem genetic testing for the major cardiomyopathies and channelopathies or pre-mortem genetic testing among the decedent's surviving relatives; the need for careful interpretation of genetic testing results; the importance of genetic counselling; and some points on the ethical and societal implications of genetic testing. PMID- 28084957 TI - Hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy is a common, inherited heart disease with a heterogeneous clinical presentation and natural history. Recently, advances in diagnosis and treatment options have been instrumental in decreasing the frequency of adverse clinical events; however, complete elimination of sudden cardiac death still remains an elusive gain. This article discusses several aspects of this condition in the young: epidemiology, clinical phenotypes, risk factors, prevention of sudden cardiac death, and risks of athletic participation. PMID- 28084959 TI - Sudden death due to aortic pathology. AB - Sudden death from aortic dissection of an ascending aortic aneurysm is an uncommon but important finding in all series of sudden death in young, apparently healthy athletes. Individuals at risk include those having any of a variety of conditions in which structural weakness of the ascending aorta predisposes to pathological dilation under prolonged periods of increased wall stress. These conditions include Marfan syndrome, Loeys-Dietz syndrome, bicuspid aortic valve, and the vascular form of Ehlers-Danlos syndrome. Diagnostic criteria, surveillance strategies, medical management, and surgical indications are discussed. Finally, the current recommendations for sports participation are provided. PMID- 28084958 TI - Acquired and congenital coronary artery abnormalities. AB - Sudden unexpected cardiac deaths in approximately 20% of young athletes are due to acquired or congenital coronary artery abnormalities. Kawasaki disease is the leading cause for acquired coronary artery abnormalities, which can cause late coronary artery sequelae including aneurysms, stenosis, and thrombosis, leading to myocardial ischaemia and ventricular fibrillation. Patients with anomalous left coronary artery from the pulmonary artery can develop adequate collateral circulation from the right coronary artery in the newborn period, which remains asymptomatic only to manifest in adulthood with myocardial ischaemia, ventricular arrhythmias, and sudden death. Anomalous origin of coronary artery from the opposite sinus occurs in 0.7% of the young general population aged between 11 and 15 years. If the anomalous coronary artery courses between the pulmonary artery and the aorta, sudden cardiac death may occur during or shortly after vigorous exercise, especially in patients where the anomalous left coronary artery originates from the right sinus of Valsalva. Symptomatic patients with evidence of ischaemia should have surgical correction. No treatment is needed for asymptomatic patients with an anomalous right coronary artery from the left sinus of Valsalva. At present, there is no consensus regarding how to manage asymptomatic patients with anomalous left coronary artery from the right sinus of Valsalva and interarterial course. Myocardial bridging is commonly observed in cardiac catheterisation and it rarely causes exercise-induced coronary syndrome or cardiac death. In symptomatic patients, refractory or beta-blocker treatment and surgical un-bridging may be considered. PMID- 28084960 TI - Sports participation in long QT syndrome. AB - Untreated congenital long QT syndrome may result in potentially lethal ventricular tachycardia. In the most common type, risk of such an event has been linked to exercise. This originally resulted in very restrictive guidelines for sports participation in affected individuals. Although the complex interactions of a specific genotype, modifying cofactors, and risk are only now being explored, scientific evidence based on clinical experience now suggests that in many instances such restrictive guidelines are unwarranted. In particular, patients with this condition who are compliant with beta-blocker therapy and who have never had symptoms during exertion are now enjoying the benefits of athletic activity. PMID- 28084961 TI - Advances in the diagnosis and treatment of catecholaminergic polymorphic ventricular tachycardia. AB - Since the sentinel description of exercise-triggered ventricular arrhythmias in 21 children, our recognition and understanding of catecholaminergic polymorphic ventricular tachycardia has improved substantially. A variety of treatments are now available, but reaching a diagnosis before cardiac arrest remains a challenge. Most cases are related to variants in the gene encoding for ryanodine receptor-2 (RyR2), which mediates calcium-induced calcium release. Up to half of cases remain genetically elusive. The condition is presently incurable, but one basic intervention, the universal administration of beta-blockers, has improved survival. In the past, implantable cardioverter-defibrillators (ICDs) were frequently implanted, especially in those with a history of cardiac arrest. Treatment limitations include under-dosing and poor compliance with beta blockers, and potentially lethal ICD-related electrical storm. Newer therapies include flecainide and sympathetic ganglionectomy. Limited data have suggested that genotype may predict phenotype in catecholaminergic polymorphic ventricular tachycardia, including a higher risk of life-threatening cardiac events in subjects with variants in the C-terminus of ryanodine receptor-2 (RyR2). At present, international efforts are underway to better understand this condition through large prospective registries. The recent publication of gene therapy in an animal model of the recessive form of the disease highlights the importance of improving our understanding of the genetic underpinnings of the disease. PMID- 28084962 TI - Wolff-Parkinson-White syndrome: lessons learnt and lessons remaining. AB - The Wolff-Parkinson-White pattern refers to the electrocardiographic appearance in sinus rhythm, wherein an accessory atrioventricular pathway abbreviates the P R interval and causes a slurring of the QRS upslope - the "delta wave". It may be asymptomatic or it may be associated with orthodromic reciprocating tachycardia; however, rarely, even in children, it is associated with sudden death due to ventricular fibrillation resulting from a rapid response by the accessory pathway to atrial fibrillation, which itself seems to result from orthodromic reciprocating tachycardia. Historically, patients at risk for sudden death were characterised by the presence of symptoms and a shortest pre- excited R-R interval during induced atrial fibrillation <250 ms. Owing to the relatively high prevalence of asymptomatic Wolff-Parkinson-White pattern and availability of catheter ablation, there has been a need to identify risk among asymptomatic patients. Recent guidelines recommend invasive evaluation for such patients where pre-excitation clearly does not disappear during exercise testing. This strategy has a high negative predictive value only. The accuracy of this approach is under continued investigation, especially in light of other considerations: Patients having intermittent pre-excitation, once thought to be at minimal risk may not be, and the role of isoproterenol in risk assessment. PMID- 28084963 TI - The role of illicit drug use in sudden death in the young. AB - The recreational use of illicit drugs remains an enormous and growing problem throughout the United States of America and around the world. Cocaine is most frequently thought of when considering the cardiovascular toxicity of illicit drugs. The association of cocaine use with sudden death due to myocardial ischaemia and infarction is well recognised, and this risk appears to be amplified by concomitant cigarette smoking and alcohol consumption. Like cocaine, amphetamine and its derivatives lead to indirect stimulation of the autonomic nervous system through the release of norepinephrine, dopamine, and serotonin in nerve terminals of the central and autonomic nervous systems. However, amphetamine lacks the ion channel-blocking properties of cocaine. Also similar to cocaine, coronary artery spasm may be induced in individuals with or without atherosclerotic disease and may lead to myocardial infarction. With the movement across the United States of America to legalise marijuana, or cannabis, for medicinal and recreational purposes, it is important to consider its potential deleterious effects. Marijuana has long been thought to have very few adverse effects with the exception of long-term dependence. There are, however, scattered reports of acute adverse events up to and including sudden death. These appear to be due to myocardial infarction. In conclusion, the incidence of sudden death associated with the use of these drugs varies from rare in the case of marijuana use to not infrequent with some drugs such as cocaine. It is important for care providers to recognise the potential for drug abuse when caring for a sudden cardiac arrest survivor. PMID- 28084964 TI - Screening the apparently healthy athlete for risk: a paradigm in transition. AB - It has largely been accepted that pre-participation screening for student athletes is necessary, but there is still no consensus on the most effective and efficient ways to accomplish this. Most clinical strategies are based on retrospective case series. By applying the European Society of Cardiology and Seattle criteria, electrocardiography appears to afford the lowest false-positive rate for identifying potentially dangerous cardiac abnormalities in athletes. Prospective, randomised trials may help determine the most effective primary prevention. Normative data for age, gender, and ethnicity for screening tools need to be formulated to further reduce false-positive results. Targeted advanced screening aimed at the highest risk groups may be the most beneficial and cost effective application of primary prevention. PMID- 28084965 TI - How to develop and execute a public health agenda: From grass roots to legislation. AB - Recent experiences with lay public cardiopulmonary resuscitation and use of ambulatory external defibrillators have been demonstrated to improve survival from out-of-hospital cardiac arrests from an abysmal 10% or less to as high as 30%. Though rare, sudden cardiac arrest in presumably healthy young people have been highly publicised over the last 25 years and have motivated the institution of school- and community-based programmes that facilitate first-responder resuscitation, including defibrillation. These efforts often begin at a grass roots level (usually parent-inspired advocacy groups) and through collaborative activities involving the schools, local businesses, and local administrative agencies are now having a meaningful impact in selected communities. The current focus of these activities is on school- and sports venue-based ambulatory external defibrillator programmes and formal cardiopulmonary resuscitation education in high schools. The extension of these programmes to the level of state mandates has been slower, and even when enacted, public funding has usually not been approved. PMID- 28084966 TI - Morbidities in the ultra-athlete and marathoner. AB - The cardiovascular benefits of habitual exercise are well documented. In the current era, more of the population is exceeding the recommendations for physical activity as the popularity of endurance events increases. Recent data have proposed a U-shaped relationship between exercise intensity and cardiovascular outcomes. Regular participation in endurance activities has been shown to result in structural and functional changes in the heart. This re-modelling may be the substrate for cardiac dysfunction or arrhythmias. The risk of sudden cardiac death may also be elevated; however, in most cases of sudden cardiac death, the cause can be linked to an underlying cardiac pathology where exercise acted as the trigger for a lethal arrhythmia. This article serves to review whether excessive exercise may result in harm in some athletes. PMID- 28084967 TI - A legal perspective on athlete screening and disqualification. AB - Physicians participate in the screening, routine medical supervision, and disqualification of student-athletes. In doing so, they should understand that eligibility/disqualification decisions inevitably have associated liability issues. It is the responsibility of physicians to take the lead role in the student-athlete medical assessment process to allow for optimum safety in sports programmes. The first duty of the physician is to protect the health and well being of the student-athlete. However, because there is potential liability associated with the screening/disqualification process, physicians are wise to develop sound and reasonable strategies that are in strict compliance with the standard of care. This article focusses on cardiac screening and disqualification for participation in sports. PMID- 28084968 TI - How pacemakers work and simple programming: a primer for the non electrophysiologist. AB - Paediatric pacemaker management is challenging because of the small patient size, complex cardiac anatomy, and unique programming considerations. Hardware placement options include epicardial and transvenous systems. When pacemaker malfunction is suspected, a systematic approach is required to determine whether there is malfunction in pacing, sensing, or no output due to hardware problem. In most cases, simple reprogramming may circumvent the problem and allow retention of the pacemaker system. PMID- 28084969 TI - Return to play in the athlete with cardiac disease: who decides and what is the protocol? AB - Improved public awareness and advances in medical diagnostics have resulted in the development of criteria to determine eligibility or disqualification for the athlete with cardiovascular abnormalities. Simultaneously, protocols have been developed for athletes with concussion or orthopaedic injuries to guide team physicians and consultants in return-to-play decisions. However, there are currently inadequate data to allow the development of such protocols for athletes with cardiovascular abnormalities who have undergone treatment. Further complicating the decision process is the designation of the team physician as the ultimate authority in making return-to-play decisions - where the team physician often is an employee of the team and supports the team's goal and players as well as the individual athlete. This review will discuss the ethical dilemma of the team physician and the role of the cardiovascular consultant. Following this, current data and practices regarding return to play will be discussed for the following conditions or diagnoses: following catheter ablation for supraventricular tachycardia; following pacemaker or implantable cardioverter defibrillator implantation; unexplained syncope; and the athlete with a genetic mutation in the absence of any phenotype of associated disease. These recommendations will undoubtedly continue to evolve and improve and should be considered at this time as a point of departure. PMID- 28084970 TI - How implantable cardioverter-defibrillators work and simple programming. AB - Following the sudden death of a friend in 1966, Dr Michel Mirowski began pioneering work on the first implantable cardioverter-defibrillator. By 1969 he had developed an experimental model and performed the first transvenous defibrillation. In 1970 he reported on the use of a "standby automatic defibrillator" that was tested successfully in dogs. He postulated that such a device "when adapted for clinical use, might be implanted temporarily or permanently in selected patients particularly prone to develop ventricular fibrillation and thus provide them with some degree of protection from sudden coronary death". In 1980 he reported on the first human implants of an "electronic device designed to monitor cardiac electrical activity, to recognise ventricular fibrillation and ventricular tachyarrhythmias ... and then to deliver corrective defibrillatory discharges". Through innovations in circuitry, battery, and capacitor technologies, the current implantable cardioverter-defibrillator is 10 times smaller and exponentially more sophisticated than that first iteration. This article will review the inner workings of the implantable cardioverter defibrillator and outline several features that make it the wonder in technology that it has become. PMID- 28084971 TI - Athletic participation in the young patient with an implantable cardioverter defibrillator. AB - The decision of whether to allow a young patient with an implantable cardioverter defibrillator to continue to participate in sports is complex and multi factorial. The positive physical and psychosocial impact of sports participation must be weighed against the potential adverse events associated with implantable cardioverter-defibrillators. Arrhythmias appear to be more prevalent in athletes and occur more frequently during physical activity or competition/practice, but there is growing evidence that device therapy is effective in athletes across a wide range of competitive sports. Failure of a device to convert a life threatening arrhythmia, major injury from a shock, and increased lead failure have thus far not been reported in the prospective Implantable Cardioverter Defibrillator Sports Registry, but follow-up remains relatively short. Thoughtful consideration of disease state, arrhythmia risk, and the potential dangers of device therapy during the desired sports is imperative before allowing participation. Frank discussion with children and families regarding the possibility of shocks during sports, as well as at other times, is imperative. Ongoing and future studies will help guide these decisions. PMID- 28084972 TI - Implantable cardiac devices: the utility of remote monitoring in a paediatric and CHD population. AB - Remote monitoring in the modern era has improved outcomes for patients with cardiac implantable electronic devices. There are many advantages to remote monitoring, including improved quality of life for patients, decreased need for in-office interrogation, and secondary reduced costs. Patient safety and enhanced survival remain the most significant benefit. With most of the published literature on this topic being focussed on adults, paediatric outcomes continue to be defined. This is a review of the benefits of remote monitoring in paediatrics and in patients with CHD. PMID- 28084973 TI - Implantable cardioverter-defibrillator implantation for primary and secondary prevention: indications and outcomes. AB - Implantable cardioverter-defibrillators effectively reduce the rate of sudden cardiac death in children. Significant efforts have been made to better characterise the indications for their placement, and over the past two decades there has been a shift in their use from secondary to primary prevention. Primary prevention includes placement in patients thought to be at high risk of sudden cardiac death before the patient experiences any event. Secondary prevention includes placement after a high-risk event including sustained ventricular tachycardia or resuscitated cardiac arrest. Although liberal device implantation may be appealing even in patients having marginal indications, studies have shown high rates of adverse effects including inappropriate device discharges and the need for re-intervention because of hardware malfunction. The indications for placement of an implantable cardioverter-defibrillator, whether for primary or secondary prevention of sudden cardiac death, vary based on cardiac pathology. This review will assist the provider in understanding the risks and benefits of device implantation in order to enhance the shared decision-making capacity of patients, families, and providers. PMID- 28084974 TI - Behavioural and emotional implications of implantable cardioverter-defibrillators in the young and in athletes. AB - Despite the life-saving capabilities of implantable cardioverter-defibrillators, they may have implications on behavioural and emotional well-being and have been shown to negatively affect patients' psychosocial functioning. Children and CHD patients with these devices are at higher risk for complications, and therefore may have higher risk of psychosocial dysfunction including depression, anxiety, and a decrease in overall quality of life. In addition, these patients may be restricted from activities, which may also contribute to psychosocial dysfunction. Recommendations published in 2015 support a more liberal approach to athletic participation in this patient population compared with previous guidelines. Approaches to limit psychosocial dysfunction include education, minimisation of shocks, and psychosocial therapy. Psychosocial dysfunction should be assessed at each clinic visit, and information regarding intervention should be provided to patients and their families as needed. Psychosocial dysfunction may be debilitating, and healthcare providers should facilitate and support normal psychosocial function by offering resources as needed. PMID- 28084975 TI - Looking forward: PACES Task Force on prevention of sudden cardiac death in the young: a comprehensive approach to a preventable problem. PMID- 28084976 TI - A rose by any other name is still a rose--but why a rose? PMID- 28084977 TI - What is the role of roflumilast in chronic obstructive pulmonary disease? PMID- 28084978 TI - Lymphoplasmacytic lymphoma presenting as retinal hemorrhage. PMID- 28084979 TI - Erythematous patches with keratotic annular borders on the glans penis. PMID- 28084980 TI - Imaging suggestive, but symptoms atypical. PMID- 28084981 TI - A patient with altered mental status and an acid-base disturbance. PMID- 28084982 TI - Fall risk and anticoagulation for atrial fibrillation in the elderly: A delicate balance. AB - Guidelines for managing atrial fibrillation recommend systemic anticoagulation for almost all patients age 65 and older, but in practice up to 50% of older patients do not receive maintenance anticoagulation therapy. The most common reason physicians cite for withholding anticoagulation in older patients with atrial fibrillation is a perception of a high risk of falling and associated bleeding, especially intracranial hemorrhage. PMID- 28084983 TI - Whether to anticoagulate: Toward a more reasoned approach. PMID- 28084984 TI - Parsimonious blood use and lower transfusion triggers: What is the evidence? AB - Evidence supports a parsimonious approach to blood use for managing anemia, contrasting with the long-standing practice of blood transfusion targeting arbitrary hemoglobin levels. Hemodilution studies have demonstrated that humans can tolerate anemia. The cumulative data have confirmed and validated the safety of a conservative approach to transfusion. This has translated into formal national guidelines for blood transfusion as well as patient safety and quality markers supporting blood management stewardship to minimize unnecessary use of blood products. PMID- 28084985 TI - Benign prostatic hyperplasia: Evaluation and medical management in primary care. AB - Benign prostatic hyperplasia (BPH) is a common cause of lower urinary tract symptoms in aging men, worsening their quality of life. Primary care physicians are uniquely positioned to screen for BPH, conduct a timely diagnostic workup, and if indicated, initiate medical therapy. A number of safe and effective medical treatments are available to alleviate symptoms, delay disease progression, and lessen the chance of needing surgery for BPH. PMID- 28084986 TI - Postexposure management of infectious diseases. AB - Anyone exposed to an infectious disease--whether a healthcare provider, patient, or contact of a patient--should be evaluated promptly and the source of the infection identified. A systematic response entails postexposure prophylactic therapy if available and indicated, infection control measures to prevent further transmission, counseling and educating those involved, and assessing those who may require work restriction or modification. PMID- 28084987 TI - Zika Virus Seroprevalence, French Polynesia, 2014-2015. AB - During 2013-2014, French Polynesia experienced an outbreak of Zika virus infection. Serosurveys conducted at the end of the outbreak and 18 months later showed lower than expected disease prevalence rates (49%) and asymptomatic:symptomatic case ratios (1:1) in the general population but significantly different prevalence rates (66%) and asymptomatic:symptomatic ratios (1:2) in schoolchildren. PMID- 28084988 TI - Screening for Food Insecurity in Six Veterans Administration Clinics for the Homeless, June-December 2015. AB - OBJECTIVE: We assessed findings from a food-insecurity screening of a national sample of Veterans Administration clinics for homeless and formerly homeless veterans. METHODS: We reviewed results from initial screenings administered at 6 Veterans Administration primary care clinics for the homeless and responses from clinic staff members interviewed about the screening program. RESULTS: A total of 270 patients were screened. The average age was 53 years, and most were male (93.1%). Screening showed a high prevalence of food insecurity. Of the 270, 48.5% reported they experienced food insecurity in the previous 3 months, 55.0% reported averaging 2 meals a day, and 27.3% averaged 1 meal a day. Eighty-seven percent prepared their own meals, relying on food they bought (54.2%), help from friends and family (19.1%), and soup kitchens and food pantries (22%); 47.3% received Supplemental Nutrition Assistance Program benefits (food stamps). Additionally, of those who screened positive for food insecurity 19.8% had diabetes or prediabetes, and 43.5% reported hypoglycemia symptoms when without food. Clinic staff members responded positively to the screening program and described it as a good rapport builder with patients. CONCLUSIONS: Integrating screening for food insecurity among patients in clinical settings was well received by both patients and health care providers. Addressing these positive findings of food insecurity requires a multidisciplinary health care approach. PMID- 28084989 TI - Using School Staff Members to Implement a Childhood Obesity Prevention Intervention in Low-Income School Districts: the Massachusetts Childhood Obesity Research Demonstration (MA-CORD Project), 2012-2014. AB - INTRODUCTION: Although evidence-based interventions to prevent childhood obesity in school settings exist, few studies have identified factors that enhance school districts' capacity to undertake such efforts. We describe the implementation of a school-based intervention using classroom lessons based on existing "Eat Well and Keep Moving" and "Planet Health" behavior change interventions and schoolwide activities to target 5,144 children in 4th through 7th grade in 2 low-income school districts. METHODS: The intervention was part of the Massachusetts Childhood Obesity Research Demonstration (MA-CORD) project, a multisector community-based intervention implemented from 2012 through 2014. Using mixed methods, we operationalized key implementation outcomes, including acceptability, adoption, appropriateness, feasibility, implementation fidelity, perceived implementation cost, reach, and sustainability. RESULTS: MA-CORD was adopted in 2 school districts that were facing resource limitations and competing priorities. Although strong leadership support existed in both communities at baseline, one district's staff reported less schoolwide readiness and commitment. Consequently, fewer teachers reported engaging in training, teaching lessons, or planning to sustain the lessons after MA-CORD. Interviews showed that principal and superintendent turnover, statewide testing, and teacher burnout limited implementation; passionate wellness champions in schools appeared to offset implementation barriers. CONCLUSION: Future interventions should assess adoption readiness at both leadership and staff levels, offer curriculum training sessions during school hours, use school nurses or health teachers as wellness champions to support teachers, and offer incentives such as staff stipends or play equipment to encourage school participation and sustained intervention activities. PMID- 28084990 TI - High throughput in vivo functional validation of candidate congenital heart disease genes in Drosophila. AB - Genomic sequencing has implicated large numbers of genes and de novo mutations as potential disease risk factors. A high throughput in vivo model system is needed to validate gene associations with pathology. We developed a Drosophila-based functional system to screen candidate disease genes identified from Congenital Heart Disease (CHD) patients. 134 genes were tested in the Drosophila heart using RNAi-based gene silencing. Quantitative analyses of multiple cardiac phenotypes demonstrated essential structural, functional, and developmental roles for more than 70 genes, including a subgroup encoding histone H3K4 modifying proteins. We also demonstrated the use of Drosophila to evaluate cardiac phenotypes resulting from specific, patient-derived alleles of candidate disease genes. We describe the first high throughput in vivo validation system to screen candidate disease genes identified from patients. This approach has the potential to facilitate development of precision medicine approaches for CHD and other diseases associated with genetic factors. PMID- 28084991 TI - Reward-based training of recurrent neural networks for cognitive and value-based tasks. AB - Trained neural network models, which exhibit features of neural activity recorded from behaving animals, may provide insights into the circuit mechanisms of cognitive functions through systematic analysis of network activity and connectivity. However, in contrast to the graded error signals commonly used to train networks through supervised learning, animals learn from reward feedback on definite actions through reinforcement learning. Reward maximization is particularly relevant when optimal behavior depends on an animal's internal judgment of confidence or subjective preferences. Here, we implement reward-based training of recurrent neural networks in which a value network guides learning by using the activity of the decision network to predict future reward. We show that such models capture behavioral and electrophysiological findings from well-known experimental paradigms. Our work provides a unified framework for investigating diverse cognitive and value-based computations, and predicts a role for value representation that is essential for learning, but not executing, a task. PMID- 28084993 TI - Nomadic-colonial life strategies enable paradoxical survival and growth despite habitat destruction. AB - Organisms often exhibit behavioral or phenotypic diversity to improve population fitness in the face of environmental variability. When each behavior or phenotype is individually maladaptive, alternating between these losing strategies can counter-intuitively result in population persistence-an outcome similar to the Parrondo's paradox. Instead of the capital or history dependence that characterize traditional Parrondo games, most ecological models which exhibit such paradoxical behavior depend on the presence of exogenous environmental variation. Here we present a population model that exhibits Parrondo's paradox through capital and history-dependent dynamics. Two sub-populations comprise our model: nomads, who live independently without competition or cooperation, and colonists, who engage in competition, cooperation, and long-term habitat destruction. Nomads and colonists may alternate behaviors in response to changes in the colonial habitat. Even when nomadism and colonialism individually lead to extinction, switching between these strategies at the appropriate moments can paradoxically enable both population persistence and long-term growth. PMID- 28084992 TI - Framing of grid cells within and beyond navigation boundaries. AB - Grid cells represent an ideal candidate to investigate the allocentric determinants of the brain's cognitive map. Most studies of grid cells emphasized the roles of geometric boundaries within the navigational range of the animal. Behaviors such as novel route-taking between local environments indicate the presence of additional inputs from remote cues beyond the navigational borders. To investigate these influences, we recorded grid cells as rats explored an open field platform in a room with salient, remote cues. The platform was rotated or translated relative to the room frame of reference. Although the local, geometric frame of reference often exerted the strongest control over the grids, the remote cues demonstrated a consistent, sometimes dominant, countervailing influence. Thus, grid cells are controlled by both local geometric boundaries and remote spatial cues, consistent with prior studies of hippocampal place cells and providing a rich representational repertoire to support complex navigational (and perhaps mnemonic) processes. PMID- 28084994 TI - Flow environment and matrix structure interact to determine spatial competition in Pseudomonas aeruginosa biofilms. AB - Bacteria often live in biofilms, which are microbial communities surrounded by a secreted extracellular matrix. Here, we demonstrate that hydrodynamic flow and matrix organization interact to shape competitive dynamics in Pseudomonas aeruginosa biofilms. Irrespective of initial frequency, in competition with matrix mutants, wild-type cells always increase in relative abundance in planar microfluidic devices under simple flow regimes. By contrast, in microenvironments with complex, irregular flow profiles - which are common in natural environments wild-type matrix-producing and isogenic non-producing strains can coexist. This result stems from local obstruction of flow by wild-type matrix producers, which generates regions of near-zero shear that allow matrix mutants to locally accumulate. Our findings connect the evolutionary stability of matrix production with the hydrodynamics and spatial structure of the surrounding environment, providing a potential explanation for the variation in biofilm matrix secretion observed among bacteria in natural environments. PMID- 28084995 TI - Cochlear and Vestibular Effects of Combined Intratympanic Gentamicin and Dexamethasone. AB - OBJECTIVE: The aim of this study is to evaluate the effects of an intratympanic gentamicin-dexamethasone combination on the inner ear. MATERIALS AND METHODS: Twenty-six Wistar albino rats were divided into four groups: Group I (Control), group II (Intratympanic dexamethasone; ITD), group III (Intratympanic gentamicin; ITG), and group IV (Intratympanic gentamicin and dexamethasone; ITGD). On the first day after basal auditory brainstem response (ABR) measurements, the ITG group received 0.03 mL of intratympanic gentamicin (26.7 mg/mL). Intratympanic injection of 0.06 mL of a solution containing 13.35 mg/mL gentamicin and 2 mg/mL dexamethasone was performed in the ITGD group. 0.03 mL of physiological intratympanic serum and dexamethasone (4 mg/mL) was applied in control and ITD groups, respectively. On the 7th day, ABR measurements were repeated and vestibular functions were evaluated. On the 21th day, ABR and vestibular tests were repeated, and the animals were sacrificed for histopathological investigation. RESULTS: The ITG group's hearing thresholds deteriorated in all frequencies. The ITGD group's hearing thresholds were significantly better than the ITG group, except at 8 kHz on the 7th day and in all frequencies at the 21th day measurements. The vestibular function scores of the ITG and ITGD groups were higher than the controls. Apoptotic changes were seen in cochlea, spiral ganglion, and vestibule of the ITG group. Cochlear and vestibular structures were well preserved in the ITGD group, similar to the controls. CONCLUSION: The ITGD combination led to a significant hearing preservation. Although in subjective vestibular tests, it seemed that vestibulotoxicity was present in both ITG and ITGD groups the histopathological investigations revealed no signs of vestibulotoxicity in the ITGD group in contrast to the ITG group. Further studies using a combination of different concentrations of gentamicin and dexamethasone are needed. PMID- 28084996 TI - Platelet-Rich Plasma Application for Acute Tympanic Membrane Perforations. AB - OBJECTIVE: To assess the efficacy of the application of platelet-rich plasma (PRP) in the healing process of acute tympanic membrane perforations (TMPs). MATERIALS AND METHODS: Acute TMPs were made in both the ears of 12 New Zealand rabbits. Plasma gel was applied at the right tympanic membrane (TM) of the same animal until the perforations were closed. The left TM was left untreated. On days 1, 4, 7, 10, 13, 16, 21, 28, and 35, the TMs were monitored to check the closure of perforations. The days of perforation closure for the 2 groups were compared using the paired t-test. The animals were sacrificed 2 months after making the perforations. Seven histopathological parameters were reviewed by 2 blinded pathologists: acute inflammation, chronic inflammation, edema in the lamina propria, congestion in the lamina propria, sclerosis, fibroblastic reaction, and an increase in the thickness of the squamous epithelial layer. The presence or absence of each histological parameter in both groups was compared using the Pearson Chi-square test. RESULTS: The average number of days for closure in the plasma gel group was 12 (range 8-18 days) and that in the control group was 17.7 (range 8-31 days). The difference was statistically significant (p=0.0145). There was no sclerosis or fibroblastic reaction in any of the specimens. No statistically significant difference was seen between the 2 groups with respect to acute inflammation, chronic inflammation, edema in the lamina propria, congestion in the lamina propria, and an increase in thickness of the squamous epithelial layer (p>0.05). CONCLUSION: Platelet-rich plasma fastens TMP closure; in long term, the eventual outcome is both microscopically and macroscopically same for the control as well as study groups in a rabbit traumatic TMP model. We believe that this study will encourage the clinical use of PRP for acute TMPs and trigger clinical studies in this field. PMID- 28084997 TI - Audio-Vestibular Findings in Increased Intracranial Hypertension Syndrome. AB - OBJECTIVE: Idiopathic intracranial hypertension (IIH) can be manifested by audiological and vestibular complaints. The aim of the present study is to determine the audio-vestibular pathologies and their pathophysiologies in this syndrome by performing current audio-vestibular tests. MATERIALS AND METHODS: The study was performed prospectively on 40 individuals (20 IIH patients, 20 healthy volunteers). Pure tone audiometry, tympanometry, vestibular evoked myogenic potentials, and electronystagmography tests were performed in both groups and the results were compared. RESULTS: The mean age of both groups was found to be 30.2+/-18.7. There were 11 females and 9 males in each group. The study group patients had significantly worse hearing levels. Pure tone averages were significantly higher in both ears of the study group (p<0.05). Ten patients (50%) in the study group and one healthy volunteer (5%) had pathologic ENG, possibly related to central pathologies (p=0.008). Eight patients (40%) and one (5%) control had variable abnormal VEMP records (p=0008). CONCLUSION: Many IIH patients initially visit otolaryngology clinics since cochlear and vestibular systems are frequently affected in this condition. Our test results suggest inner ear pathologies in these patients. Higher incidence of inferior vestibular nerve and/or saccule dysfunction is detected as a novelty. Increased intracranial pressure may affect the inner ear with similar mechanisms as in hydrops. PMID- 28084998 TI - Comparison of Long-Term Outcome of Intratympanic Dexamethasone Therapy between Acute Noise-Induced Tinnitus and Acute Idiopathic Tinnitus. AB - OBJECTIVE: To compare the long-term outcomes of acute noise-induced tinnitus (ANT) and acute idiopathic tinnitus (AIT) to intratympanic dexamethasone (ITD) therapy. MATERIALS AND METHODS: Patients treated for tinnitus occurring immediately after noise exposure comprised the ANT group (n=20) and patients treated for idiopathic tinnitus comprised the AIT group (n=39). All patients were treated with ITD within 3 months of the onset of tinnitus. Quantitative assessment of the improvement in tinnitus using questionnaires and changes in hearing thresholds were compared between the two groups. RESULTS: Mean follow-up durations were 75.90+/-69.83 weeks in the ANT group and 93.41+/-101.43 weeks in the AIT group. Patients with ANT were younger in age than those with AIT (38.30+/ 18.28 vs. 53.56+/-14.08, p=0.00) and were predominately male (Male: Female, M:F 13:7 vs. 13:26, p=0.02, respectively). The subjective tinnitus loudness, time of tinnitus awareness, and Tinnitus Handicap Inventory score improved in both groups, although the changes in these parameters were not significantly different between the groups. The cure and overall improvement rates of the ANT group were and 10.00% and 25.00%, respectively. The cure and overall improvement rates of the AIT groups were 25.64% and 35.90%, respectively and there were no significant differences between the two groups in terms of the cure and overall improvement rates (p=0.19 and 0.40, respectively). CONCLUSION: The long-term outcome in terms of control of tinnitus with ITD in the ANT group was similar to that in the AIT group. Thus, ITD injection may be a useful treatment option for acute tinnitus caused by noise trauma. PMID- 28084999 TI - Otogenic Intracranial Abscesses, Our Experience Over the Last Four Decades. AB - OBJECTIVE: To evaluate the predisposing factors for otogenic intracranial abscesses, assess their changes over time, and analyze how they differ from those due to other causes. MATERIALS AND METHODS: The medical records of all patients treated for otogenic intracranial abscesses, between 1970 and 2012 at a tertiary referral center, were retrospectively analyzed. The analysis included patient demographics, clinical characteristics, causative pathogens, treatments, outcomes, and comparisons of otogenic and non-otogenic intracranial abscesses. RESULTS: Of all intracranial abscesses, 11% (n=18) were otogenic. In the 1970s, otogenic infections were a common predisposing factor for intracranial abscess; but within our study period, the incidence of otogenic intracranial abscesses decreased. Most (94%) otogenic cases were due to chronic suppurative otitis media and 78% were associated with cholesteatoma. Most patients (94%) had ear symptoms. The most common presenting symptoms were discharge from the infected ear (50%), headache (39%), neurological symptoms (28%), and fever (17%). The most common pathogens belonged to Streptococcus spp. (33%), Gram-negative enteric bacteria (22%), and Bacteroides spp. (11%). Neurosurgery was performed on all patients, 69% of which were prior to a later ear surgery. Surgery of the affected ear was performed on 14 patients (78%). A favorable recovery was typical (78%); however, one patient died. CONCLUSION: Otogenic intracranial abscesses were most commonly due to a chronic ear infection with cholesteatoma. Ear symptoms and Gram-negative enteric bacteria were more common among patients with otogenic than non-otogenic intracranial abscesses. PMID- 28085000 TI - Co-existence of Benign Paroxysmal Positional Vertigo and Meniere's Syndrome. AB - OBJECTIVE: Recent studies indicate interrelation of benign paroxysmal positional vertigo (BPPV) and Meniere's disease (MD). These two entities may have different clinical characteristics. MATERIALS AND METHODS: Five hundred thirty patients with BPPV evaluated between 2009-2015 were enrolled in the study. 351 patients who had no clear problem associated with BPPV (idiopathic) and 17 patients with MD were analyzed in detail. The age, sex, site of involvement, type of BPPV, symptom duration, and treatment outcome were compared. RESULTS: Meniere's disease + BPPV was more common in the female population (2/15; 7.5 v 127/224; 1.8, p<0.05). Comparative analysis of average age was not statistically significant (42.82+/-9.94 v. 40.29+/-1.65, p=0.601). There was no difference in right and left ear involvement between groups. Lateral canal involvement was more common in the BPPV + MD group (9/17; 53% v. 100/351; 28%, p<0.05). BPPV was ipsilateral to the ear with MD in 75% of patients and it was present before the diagnosis of BPPV in 82.3% of patients. Comparative analysis of cure rate between idiopathic BPPV and BPPV + MD after one session was significant (64.7% v 78%, p<0.05). CONCLUSION: Benign paroxysmal positional vertigo associated with MD presented a divergent picture. It was more frequent in females. Lateral canal involvement was higher. Patients had MD before the development of BPPV and they had prolonged symptoms, which raised a question of diagnostic delay since these two problems were in the same ear in majority of patients. Finally, relief of symptoms required more attempts of repositioning maneuvers. PMID- 28085001 TI - "Canalolabyrinthine Schwannoma," A Rare Variant of Intralabyrinthine Schwannoma: A Case Report. AB - Canalolabyrinthine schwannoma is a rare subtype of neuroma. Only 1 case has been described in the literature. We report the clinical case of a 51-year-old Caucasian female with Meniere's disease-like symptoms. Magnetic resonance imaging showed right VIII cranial nerve schwannoma that had different characteristics from the classical described types. The peculiar features of our case of intralabyrithine canalolabyrinthine schwannoma directed the surgeon and radiologist to tailored considerations for follow-up and therapy. PMID- 28085003 TI - Prevalence of sofosbuvir resistance-associated variants in Brazilian and worldwide NS5B sequences of genotype-1 HCV. AB - BACKGROUND: The prevalence of natural polymorphisms associated with resistance to NS5B nucleoside/nucleotide (NI) sofosbuvir is distinct in different geographical regions. In Brazil, direct-acting anti-HCV therapy has recently changed with the introduction of interferon (IFN)-free regimens with sofosbuvir; however, the presence of resistant variants on clinical outcomes remains unknown. The aim of this study was to assess the natural polymorphisms associated with resistance to the NS5B NI sofosbuvir in Brazilian HCV-1 isolates and to compare it with that from other geographical regions. METHODS: Nucleotide sequencing of the HCV NS5B gene was performed in serum samples of 95 therapy-naive Brazilian patients infected with subtype 1a (n=43) and 1b (n=52). The sequences were analysed along with 1,525 NS5B sequences from North America, Europe and Asia retrieved from public HCV databases. RESULTS: In Brazilian HCV-1b patients who have never been exposed to a direct-acting anti-HCV drug, the C316N was detected in 15/52 (28.85%) patients, of these, 2 (3.85%) had single C316N variant, while 13 (25%) presented the double L159F-C316N mutant. A lower rate of L159F-C316N variants was detected in North American (n=9/238; 3.78%, P<0.001), European (n=17/281; 6.05%, P<0.001) and Asian (n=2/173; 1.16%, P<0.001) isolates. No sofosbuvir resistance associated variants (RAVs) were identified in HCV-1a sequences. CONCLUSIONS: Resistant variants to sofosbuvir were found at different frequencies in worldwide HCV-1b sequences but not in HCV-1a sequences. The high frequency of double mutation L159F-C316N observed in Brazilian HCV-1b patients contrast with the lower rate observed in the three continents studied. The association of these findings and the clinical implications awaits further analysis. PMID- 28085002 TI - HCV intergenotype 2k/1b recombinant detected in a DAA-treated patient in Italy. AB - Direct-acting antiviral (DAA) combinations are potent and effective drugs currently recommended for treatment of chronic HCV infection. Difficult to treat genotypes are the most important predictors of treatment failure. We report a case of DAA treatment failure in an HCV-infected patient carrying a recombinant genotype 2k/1b. This strain, first isolated from a Russian patient in 2002, has now been observed for the first time in Italy. PMID- 28085004 TI - Nanoscale mapping of optical band gaps using monochromated electron energy loss spectroscopy. AB - Using monochromated electron energy loss spectroscopy in a probe-corrected scanning transmission electron microscope we demonstrate band gap mapping in ZnO/ZnCdO thin films with a spatial resolution below 10 nm and spectral precision of 20 meV. PMID- 28085006 TI - Reconstructing the distributed force on an atomic force microscope cantilever. AB - A methodology is developed to reconstruct the force applied to an atomic force microscopy (AFM) cantilever given the shape in which it vibrates. This is accomplished by rewriting Bernoulli-Euler beam theory such that the force on the cantilever is approximated as a linear superposition of the theoretical cantilever eigenmodes. The weighting factors in this summation are calculated from the amplitude and phase measured along the length of the cantilever. The accuracy of the force reconstruction is shown to depend on the frequency at which the measurement is performed, the number of discrete points measured along the length of the cantilever, and the signal-to-noise ratio of the measured signal. In contrast to other AFM force reconstruction techniques, this method can reconstruct the distribution of force applied over the length of the AFM cantilever. However, this method performs poorly for localized forces applied to the cantilever, such as is typical of most tip-sample interaction forces. Proof of concept experiments are performed on an electrostatically excited cantilever and the expected force distribution is recovered. This force reconstruction technique offers previously unavailable insight into the distributed forces experienced by an AFM cantilever. PMID- 28085005 TI - Potential of human dental stem cells in repairing the complete transection of rat spinal cord. AB - OBJECTIVE: The adult spinal cord of mammals contains a certain amount of neural precursor cells, but these endogenous cells have a limited capacity for replacement of lost cells after spinal cord injury. The exogenous stem cells transplantation has become a therapeutic strategy for spinal cord repairing because of their immunomodulatory and differentiation capacity. In addition, dental stem cells originating from the cranial neural crest might be candidate cell sources for neural engineering. APPROACH: Human dental follicle stem cells (DFSCs), stem cells from apical papilla (SCAPs) and dental pulp stem cells (DPSCs) were isolated and identified in vitro, then green GFP-labeled stem cells with pellets were transplanted into completely transected spinal cord. The functional recovery of rats and multiple neuro-regenerative mechanisms were explored. MAIN RESULTS: The dental stem cells, especially DFSCs, demonstrated the potential in repairing the completely transected spinal cord and promote functional recovery after injury. The major involved mechanisms were speculated below: First, dental stem cells inhibited the expression of interleukin-1beta to reduce the inflammatory response; second, they inhibited the expression of ras homolog gene family member A (RhoA) to promote neurite regeneration; third, they inhibited the sulfonylurea receptor1 (SUR-1) expression to reduce progressive hemorrhagic necrosis; lastly, parts of the transplanted cells survived and differentiated into mature neurons and oligodendrocytes but not astrocyte, which is beneficial for promoting axons growth. SIGNIFICANCE: Dental stem cells presented remarkable tissue regenerative capability after spinal cord injury through immunomodulatory, differentiation and protection capacity. PMID- 28085007 TI - Exfoliation of MoS2 and h-BN nanosheets by hydrolysis of LiBH4. AB - Efficient preparation of two-dimensional materials is still a great challenge. These materials possess unique electrical, optical, and thermal properties. In this study, few-layer MoS2 nanosheets and nanoflakes were exfoliated by the hydrolysis reaction of LiBH4. First, the layered MoS2 powder materials were mixed with LiBH4 to obtain a homogeneous powder mixture, and then the mixture was heated above the melting point of LiBH4 under 300 degrees C and 4 MPa H2 for 2 h, during which the layered materials were curled by liquid LiBH4. In the subsequent hydrolysis of LiBH4, the layered materials were split into nanosheets by H2 gas generation. The obtained MoS2 nanosheets show almost uniform thickness of ~4 nm, with a width of 2-10 MUm and a yield of more than 1.5 wt.%. The effectiveness of this method has also been verified by the preparation of few layer h-BN. This work provides a new high-yield route to producing two dimensional materials. PMID- 28085008 TI - Inhibition of Src by microRNA-23b increases the cisplatin sensitivity of chondrosarcoma cells. AB - Chondrosarcomas are malignant cartilage-forming tumors from low-grade to high grade aggressive tumors characterized by metastasis. Cisplatin is an effective DNA-damaging anti-tumor agent for the treatment against a wide variety of solid tumors. However, chondrosarcomas are notorious for their resistance to conventional chemo- and radio- therapies. In this study, we report miR-23b acts as a tumor suppressor in chondrosarcoma. The expressions of miR-23b are down regulated in chondrosarcoma patient samples and cell lines compared with adjacent normal tissues and human primary chondrocytes. In addition, overexpression of miR 23b suppresses chondrosarcoma cell proliferation. By comparison of the cisplatin resistant chondrosarcoma cells and parental cells, we observed miR-23b was significantly down regulated in cisplatin resistant cells. Moreover, we demonstrate here Src kinase is a direct target of miR-23b in chondrosarcoma cells. Overexpression of miR-23b suppresses Src-Akt pathway, leading to the sensitization of cisplatin resistant chondrosarcoma cells to cisplatin. This chemo-sensitivity effect by the miR-23b-mediated inhibition of Src-Akt pathway is verified with the restoration of Src kinase in miR-23b-overespressing chondrosarcoma cells, resulting in the acquirement of resistance to cisplatin. In summary, our study reveals a novel role of miR-23b in cisplatin resistance in chondrosarcoma and will contribute to the development of the microRNA-targeted anti-cancer therapeutics. PMID- 28085009 TI - Des-gamma carboxyprothrombin may not be a good biomarker for hepatocellular carcinoma in those chronically infected with hepatitis B virus with basal core promoter double mutations (T^{1762}, A^{1764}), a prospective study. AB - BACKGROUND: The accuracy of des-gamma -carboxyprothrombin (DCP) in the detection of hepatocellular carcinoma (HCC) in those infected hepatitis B virus (HBV) from cross-sectional or case-control studies is contradictory. OBJECTIVE: To resolve this contradiction using a prospective study. METHODS: Three hundred male individuals persistently infected with HBV were recruited from the Chinese cohort and followed up once per year from 2012 to 2015. Each subject was screened for HCC by measurements of serum alpha-fetoprotein (AFP), lectin-bound alpha fetoprotein (AFP-L3), DCP concentrations and ultrasonographic examinations. RESULTS: Nineteen HCC cases were identified. The area under receiver operating characteristic (AUROC) at first, second and third visit for AFP, AFP-L3 and DCP ranges from 0.710-0.897, 0.566-0.637 and 0.520-0.595, respectively. The rate of elevated DCP is not significantly different between the HCC cases and controls (52.6% vs. 47.4%) (P > 0.05). The incidence of HCC in subjects with elevated DCP is not significantly higher than that of those with normal DCP (9.5% vs. 4.6%) (P > 0.05). The AUROC of combinations of these biomarkers was higher than that of AFP alone at the first visit. However, it was reduced at the second visit. At the third visit, the AUROCs of AFP + DCP and AFP + AFP-L3 + DCP, but not that of AFP + AFP-L3, were higher than that of AFP alone. CONCLUSIONS: AFP but DCP or AFP-L3 remains a valuable biomarker for HCC in those chronically infected with HBV. The combination with AFP-L3 and DCP may not increase the accuracy of AFP in differentiating HCC cases from controls, among those infected with HBV. PMID- 28085010 TI - Upregulated lncRNA-PCAT1 is closely related to clinical diagnosis of multiple myeloma as a predictive biomarker in serum. AB - OBJECTIVE: The purpose of this study was to explore serum PCAT-1 expression in multiple myeloma (MM) and examine the potential usefulness of this molecule as a biomarker for diagnosis in MM. METHODS: Serum samples were collected from 60 newly diagnosed untreated MM patients, and 48 healthy controls. Serum PCAT-1 expression levels were detected by RT-qPCR. In addition, correlations between the relative expression of serum PCAT-1 and the concentrations of lactic acid dehydrogenase (LDH), beta2M, lambda light chain and kappa light chain were assessed. RESULTS: It was found that the relative expression of serum PCAT-1 in MM patients (81.02 +/- 136.9) was higher than that in healthy controls (3.17 +/- 5.75) (U= 307.0, P< 0.0001) and was significantly correlated with beta2M concentration (r= 0.461, P= 0.0002), but not with LDH, kappa light and lambda light chain concentration (r= 0.061, P= 0.641; r= 0.007, P= 0.956; r=-0.090, P= 0.499 respectively). Additionally, it was significantly correlated with different isotype of MM (H= 7.464, P= 0.024). The AUC of the ROC curve of serum PCAT-1 was 0.892 (95% CI 0.833-0.950), which was higher than other markers. Combining PCAT-1 and beta2M together, the sensitivity was highest compared with other markers alone, or combined. CONCLUSION: The expression levels of serum PCAT-1 in MM patients were significantly higher than that in healthy controls, suggesting that it may be useful in the auxiliary diagnosis of MM. PMID- 28085011 TI - Hydrogel microarray for detection of polymorphisms in the UGT1A1, DPYD, GSTP1 and ABCB1 genes. AB - BACKGROUND: Improving the efficacy of anticancer therapy remains an urgent and very important task. Screening of the individual genetic metabolism of cancer patients allows for prescribing adequate medication in the correct dose as well as for decreasing side effects associated with drug toxicity. OBJECTIVE: Estimation of a microarray-based method for genotyping of the UGT1A1, DPYD, GSTP1, and ABCB1 metabolic regulation genes to evaluate for an increased risk of toxicity of anticancer drugs. METHODS: The microarray was used to conduct genotyping of specimens taken from 115 cancer patients and 31 healthy donors. RESULTS: A microarray-based method for identification of the rs8175347, rs3918290, rs1695, and rs1045642 polymorphisms in the corresponding UGT1A1, DPYD, GSTP1, and ABCB1 genes has been developed for genotyping. The results obtained were in full concordance with those obtained using control sequencing. The frequencies of the rs8175347, rs3918290, rs1695, and rs1045642 genetic variations were 0.38, 0, 0.35, and 0.56, respectively. CONCLUSION: The implementation of this biochip-based method in diagnostic practice should increase the overall survival and quality of life of cancer patients, decrease the length of their hospital stay, and reduce treatment costs. PMID- 28085012 TI - Decreased expression of LncRNA SRA1 in hepatocellular carcinoma and its clinical significance. AB - BACKGROUND: Hepatocellular carcinoma (HCC), is an extremely aggressive malignancy with poor prognosis and high fatality rates worldwide. Accumulating evidence indicated that novel biomarkers are required to get a better understanding of the biological mechanisms of HCC. SRA1, a long non-coding RNA (lncRNA), serves as a critical regulator in several cancers. However, the association between SRA1 expression and tumorigenesis in HCC tissues remains unclear. OBJECTIVE: In the present study, we evaluated the expression of SRA1 in HCC and its clinical association. METHODS: The expression levels of SRA1 in 67 pairs of cancer tissues and adjacent normal tissues from HCC patients were detected using quantitative real-time PCR. Expression of SRA1 in HCC cell lines compared with normal human hepatocyte cell lines was also measured. Finally, the potential associations between its level in HCC tissues and the clinicopathological parameters were analyzed as well. RESULTS: The results indicated that the expression levels of SRA1 in HCC were remarkably decreased, compared with matched normal tissues (P< 0.001). Levels of SRA1 in HCC cell lines were also significantly decreased than that in normal human hepatocyte cell line L-02. Additionally, the levels of SRA1 were significantly associated with tumor size (P= 0.020) and serum GLU level (P= 0.046). CONCLUSIONS: This study highlighted that SRA1 was downregulated in HCC and might serve as a tumor suppressor in HCC, which laid a solid foundation for future research. PMID- 28085013 TI - Expressions of miRNAs in papillary thyroid carcinoma and their associations with the clinical characteristics of PTC. AB - BACKGROUND: The sensitivity and specificity of biomarkers which have been used in clinical practice for diagnosis of papillary thyroid carcinoma (PTC) are low, it is essential to develop novel diagnostic and prognostic biomarkers for PTC. OBJECTIVE: To explore the expressions of miR-940, miR-15a, miR-16 and IL-23 in PTC tissues and plasma and their associations with the clinical characteristics of PTC. METHODS: We investigated the expressions of miR-940, miR-15a, miR-16 and IL-23 in plasma and thyroid tissues of PTC, nodular goiter and healthy people with qRT-PCR, and further analyzed the associations between their levels and the clinical characteristics of PTC. RESULTS: Level of IL-23 expression was higher while levels of miR-940, miR-15a and miR-16 expression in the PTC tissues were lower compared with the nodular goiter tissues and perineoplastic thyroid tissues. And the levels of miR-940, miR-15a, miR-16 and IL-23 expression in the PTC tissues were associated with some clinical characteristics of PTC, including bilateral tumor, multicentricity, extrallyroidal invasion, cervical lymph node metastasis, distant metastasis and clinical advanced stages (III/IV). CONCLUSIONS: Expressions of miR-940, miR-15a, miR-16 and IL-23 in PTC tissues might be useful biomarkers and promising targets in the diagnosis of papillary thyroid carcinoma. PMID- 28085015 TI - Over expression of galectin-3 associates with short-term poor prognosis in stage II colon cancer. AB - BACKGROUND: Over expression of galectin-3 (gal-3) has been associated with tumor invasion and distant metastases, but few reports investigated the relation between gal-3 expression and prognosis in stage II colon cancer. OBJECTIVE: We studied the expressions of gal-3, E-cadherin, and vimentin in stage II colon cancer to identify predictive factors of clinical outcome. METHODS: Clinical and laboratory data from 117 consecutive patients of stage II colon cancer during 2008-2010 were collected and analyzed retrospectively. Expressions of gal-3, E cadherin, and vimentin in tumor tissue were investigated by immunohistochemistry. Potential correlations between these markers and various clinicopathological parameters as well as clinical outcomes were studied. Human colon cancer cell line SW480 was used to test the epithelial-mesenchymal transition (EMT) inducing effects of gal-3 in vitro. RESULTS: High expression of tumoral gal-3 was associated with tumor size, poor differentiation and negatively related to low E cadherin expression. Compare with adjacent normal colon tissue, most tumor tissues strongly expressed gal-3 and vimentin, but had lower E-cadherin expression. Univariate analysis showed that expressions of gal-3 and vimentin in tumor were predictors of tumor recurrence and overall survival. Multivariate analysis revealed that tumoral gal-3 expression was the only independent predictor of both tumor recurrence and overall survival after resection. Cell experiments and western blotting showed exogenous gal-3 could induce SW480 cells become more aggressive and express more hallmarks of EMT. CONCLUSIONS: Galectin-3 may be a useful marker for identification of poor prognosis in stage II colon cancer. Cell experiments and western blotting showed exogenous gal-3 could induce SW480 cells become more aggressive and express more hallmarks of EMT. PMID- 28085016 TI - Harnessing co-stimulatory TNF receptors for cancer immunotherapy: Current approaches and future opportunities. AB - Co-stimulatory tumor necrosis factor receptors (TNFRs) can sculpt the responsiveness of T cells recognizing tumor-associated antigens. For this reason, agonist antibodies targeting CD137, CD357, CD134 and CD27 have received considerable attention for their therapeutic utility in enhancing anti-tumor immune responses, particularly in combination with other immuno-modulatory antibodies targeting co-inhibitory pathways in T cells. The design of therapeutic antibodies that optimally engage and activate co-stimulatory TNFRs presents an important challenge of how to promote effective anti-tumor immunity while avoiding serious immune-related adverse events. Here we review our current understanding of the expression, signaling and structural features of CD137, CD357, CD134 and CD27, and how this may inform the design of pharmacologically active immuno-modulatory antibodies targeting these receptors. This includes the integration of our emerging knowledge of the role of Fcgamma receptors (FcgammaRs) in facilitating antibody-mediated receptor clustering and forward signaling, as well as promoting immune effector cell-mediated activities. Finally, we bring our current preclinical and clinical knowledge of co stimulatory TNFR antibodies into the context of opportunities for next generation molecules with improved pharmacologic properties. PMID- 28085018 TI - TFP5, a Peptide Inhibitor of Aberrant and Hyperactive Cdk5/p25, Attenuates Pathological Phenotypes and Restores Synaptic Function in CK-p25Tg Mice. AB - It has been reported that cyclin-dependent kinase 5 (cdk5), a critical neuronal kinase, is hyperactivated in Alzheimer's disease (AD) and may be, in part, responsible for the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs). It has been proposed by several laboratories that hyperactive cdk5 results from the overexpression of p25 (a truncated fragment of p35, the normal cdk5 regulator), which, when complexed to cdk5, induces hyperactivity, hyperphosphorylated tau/NFTs, amyloid-beta plaques, and neuronal death. It has previously been shown that intraperitoneal (i.p.) injections of a modified truncated 24-aa peptide (TFP5), derived from the cdk5 activator p35, penetrated the blood-brain barrier and significantly rescued AD-like pathology in 5XFAD model mice. The principal pathology in the 5XFAD mutant, however, is extensive amyloid plaques; hence, as a proof of concept, we believe it is essential to demonstrate the peptide's efficacy in a mouse model expressing high levels of p25, such as the inducible CK-p25Tg model mouse that overexpresses p25 in CamKII positive neurons. Using a modified TFP5 treatment, here we show that peptide i.p. injections in these mice decrease cdk5 hyperactivity, tau, neurofilament-M/H hyperphosphorylation, and restore synaptic function and behavior (i.e., spatial working memory, motor deficit using Rota-rod). It is noteworthy that TFP5 does not inhibit endogenous cdk5/p35 activity, nor other cdks in vivo suggesting it might have no toxic side effects, and may serve as an excellent therapeutic candidate for neurodegenerative disorders expressing abnormally high brain levels of p25 and hyperactive cdk5. PMID- 28085017 TI - Curing tumor-bearing mice by shifting a Th2 to a Th1 anti-tumor response. AB - Over the past several years remarkable therapeutic responses have been obtained with immunomodulatory monoclonal antibodies (mAbs), both in mice ?cite{10,18,20,48,54,61} and human cancer patients ?cite{1,3,14,28,30,39,80}. However, complete regressions and cures are infrequent and not predictable and some tumor types respond much worse than others. As an attempt to increase curability, we have investigated in mouse models the therapeutic efficacy of several mAb combinations, focusing on anti-PD-1/CTLA-4/CD137 and anti-PD-1/CTLA 4/CD137/CD19, and we have also combined mAbs with the chemotherapeutic drug cisplatin. Our data demonstrate an important contribution of anti-CD19 mAb to therapeutic efficacy, they show that intratumoral delivery of the mAbs is therapeutically more effective than systemic delivery, and that there is synergy when the mAbs are combined with cisplatin. In an attempt to improve predictability, we developed an in vitro model that may also be employed to search for novel immunomodulatory agents and combinations. This article reviews our data and discusses what is known about the underlying mechanisms. PMID- 28085019 TI - The neglected value of health information technologies in universal health coverage in developing countries. PMID- 28085020 TI - Development of a mobile application of Breast Cancer e-Support program for women with breast cancer undergoing chemotherapy. AB - BACKGROUND: Women with breast cancer undergoing chemotherapy experience a variety of physical and psychosocial symptoms, which have negative effect on women's quality of life and psychological well-being. Although M-health technologies provides innovative and easily accessible option to provide psychosocial support, mobile phone based interventions remain limited for these women in China. OBJECTIVE: To develop a new mobile application to offer information as well as social and emotional support to women with breast cancer undergoing chemotherapy to promote their self-efficacy and social support, thus improving symptom management strategies. METHODS: Basing on previous theoretical framework which incorporated Bandura's self-efficacy theory and the social exchange theory, a new mobile application, called Breast Cancer e-Support Program (BCS) was designed, with the content and functionality being validated by the expert panel and women with breast cancer. RESULTS: BCS App program has four modules: 1) Learning forum; 2) Discussion forum; 3) Ask-the-Expert forum; and 4) Personal Stories forum. BCS program can be applied on both android mobile phones and iPhones to reach more women. CONCLUSIONS: This is the first of its kind developed in China for women with breast cancer undergoing chemotherapy. A randomized controlled trial is undertaking to test the effectiveness of BCS program. PMID- 28085021 TI - Evaluation of the scattered radiations of lead and lead-free aprons in diagnostic radiology by MCNPX. AB - BACKGROUND: Over the past few years, because of high attenuation and lightweight, non-toxic, lead-free aprons (LFAs) have been replaced by lead aprons (LAs). Lots of studies declared that this fact was based on the interactions of diagnostic X ray with material such as the photoelectric effect (PE) and Compton scattering. These studies have demonstrated that in these types of aprons, due to the presence of different K-edge absorption, PE has a wide absorption in various metals with divers K-edges. The measurement geometry in most of these studies was narrow beam geometry, i.e. a collimated source and a collimated detector with a large source-detector distance. OBJECTIVE: The present study intended to evaluate the attenuation of radiology scattered radiations in LAs and LFAs in both narrow and broad beam geometries, which is a more realistic situation, in order to check whether or not the higher attenuation is valid. METHODS: In this study, a lead apron contains (Pb + EPV) and two non-lead compounds of (W + Sn + EPVC) with different weight percent (Wt%) were evaluated in the energy range of diagnostic radiology (100 kVp). The MCNPX code was applied to simulate broad - and narrow beam measurement geometries. The evaluations have been performed in three situations: 1st) the same density thickness of LA and LFAs 2nd) same line thickness of LA and LFAs 3rd) considering the thickness of LFAs which has the same attenuation with LAs i.e. lead equivalent thickness for LFAs in the narrow beam. Finally, the x-ray transmission ratio (I/I_0) of LAs and LFAs was compared in 100 kVp for three mentioned conditions. RESULTS: Our results indicated that LFAs had more radiation attenuation rather than LA in the 1st and 2nd conditions with both geometries. However, LFAs had lower attenuation in comparison to LAs in the 3rd condition with broad beam geometry. More importantly, the transmission ratio (I/I_0) of LFAs in the broad beam condition was more significant than LA. CONCLUSION: The scattered radiations produced by LFAs are more than LAs because of the production of characteristic radiations resulted from K-edge absorption in composited aprons. Consequently, the LFAs should be evaluated in both narrow and broad beam situation using the lead equivalent thickness of LFAs to make sure that the non-lead aprons do not increase the radiation dose of the user. PMID- 28085022 TI - A High Rate of Non-Compliance Confounds the Study of Whole Grains and Weight Maintenance in a Randomised Intervention Trial-The Case for Greater Use of Dietary Biomarkers in Nutrition Intervention Studies. AB - Observational studies consistently find an inverse relationship between whole grain intake and weight gain. We aimed to confirm this in an open-label researcher-blinded parallel design randomised trial. A total of 179 overweight/obese women with a habitually low whole-grain intake (<16 g/day) were randomised to a weight maintenance diet with refined-grain (RG) or whole-grain (WG) foods (80 g/day) for 12 weeks after an initial weight loss program over 8 weeks. Body weight and composition was assessed at baseline, after the initial weight loss, and after the 12-week dietary intervention. During the 12-week dietary intervention phase, there were no group differences in changes in body weight and total fat mass %, whereas abdominal fat mass tended to increase more during the dietary intervention phase in the WG compared to the RG group (0.7 (SD 3.6) vs. -0.3 (SD 3.8) %; p = 0.052). Plasma alkylresorcinol concentrations, biomarkers of wholegrain wheat and rye intake, indicated poor compliance, particularly in the WG group, where >60% of participants had alkylresorcinol concentrations below 70 nmol/L, a concentration indicating low or no intake of whole-grain wheat. Further, weight regain was lower than expected in both intervention groups, further supporting a lack of compliance to the post-weight loss diet. The rate of compliance was too low to conclude any effect of whole grain on weight maintenance, and reinforces the need to use objective measures of compliance in nutrition intervention studies. PMID- 28085023 TI - Preparation of Antioxidant Peptides from Salmon Byproducts with Bacterial Extracellular Proteases. AB - Bacterial extracellular proteases from six strains of marine bacteria and seven strains of terrestrial bacteria were prepared through fermentation. Proteases were analyzed through substrate immersing zymography and used to hydrolyze the collagen and muscle proteins from a salmon skin byproduct, respectively. Collagen could be degraded much more easily than muscle protein, but it commonly showed weaker antioxidant capability. The hydrolysate of muscle proteins was prepared with crude enzymes from Pseudoalteromonas sp. SQN1 displayed the strongest activity of antioxidant in DPPH and hydroxyl radical scavenging assays (74.06% +/ 1.14% and 69.71% +/- 1.97%), but did not perform well in Fe2+ chelating assay. The antioxidant fractions were purified through ultrafiltration, cation exchange chromatography, and size exclusion chromatography gradually, and the final purified fraction U2-S2-I displayed strong activity of antioxidant in DPPH, hydroxyl radical scavenging assays (IC50 = 0.263 +/- 0.018 mg/mL and 0.512 +/- 0.055 mg/mL), and oxygen radical absorption capability assay (1.960 +/- 0.381 mmol.TE/g). The final purified fraction U2-S2-I possessed the capability to protect plasmid DNA against the damage of hydroxyl radical and its effect was similar to that of the original hydrolysis product. It indicated that U2-S2-I might be the major active fraction of the hydrolysate. This study proved that bacterial extracellular proteases could be utilized in hydrolysis of a salmon byproduct. Compared with collagen, muscle proteins was an ideal material used as an enzymatic substrate to prepare antioxidant peptides. PMID- 28085024 TI - Dragmacidin G, a Bioactive Bis-Indole Alkaloid from a Deep-Water Sponge of the Genus Spongosorites. AB - A deep-water sponge of the genus Spongosorites has yielded a bis-indole alkaloid which we have named dragmacidin G. Dragmacidin G was first reported by us in the patent literature and has recently been reported by Hitora et al. from a sponge of the genus Lipastrotheya. Dragmacidin G is the first in this series of compounds to have a pyrazine ring linking the two indole rings. It also has a rare N-(2-mercaptoethyl)-guanidine side chain. Dragmacidin G shows a broad spectrum of biological activity including inhibition of methicillin-resistant Staphylococcus aureus, Mycobacterium tuberculosis, Plasmodium falciparum, and a panel of pancreatic cancer cell lines. PMID- 28085026 TI - Structural Hypervariability of the Two Human Protein Kinase CK2 Catalytic Subunit Paralogs Revealed by Complex Structures with a Flavonol- and a Thieno[2,3 d]pyrimidine-Based Inhibitor. AB - Protein kinase CK2 is associated with a number of human diseases, among them cancer, and is therefore a target for inhibitor development in industry and academia. Six crystal structures of either CK2alpha, the catalytic subunit of human protein kinase CK2, or its paralog CK2alpha' in complex with two ATP competitive inhibitors-based on either a flavonol or a thieno[2,3-d]pyrimidine framework-are presented. The structures show examples for extreme structural deformations of the ATP-binding loop and its neighbourhood and of the hinge/helix alphaD region, i.e., of two zones of the broader ATP site environment. Thus, they supplement our picture of the conformational space available for CK2alpha and CK2alpha'. Further, they document the potential of synthetic ligands to trap unusual conformations of the enzymes and allow to envision a new generation of inhibitors that stabilize such conformations. PMID- 28085027 TI - Cancer Immunology with a Focus on Understudied Cancers as Targets for Immunotherapy. AB - n/a. PMID- 28085032 TI - Correction: Jessri, M.; et al. Assessing the Nutritional Quality of Diets of Canadian Adults Using the 2014 Health Canada Surveillance Tool Tier System. Nutrients 2015, 7, 5543. AB - Due to a mistake in the publication process, "NS" symbols are missing from Figure 3 from this article [1].[...]. PMID- 28085031 TI - Perceptions of E-Cigarettes among Black Youth in California. AB - Research suggests that Black youth are less likely to use e-cigarettes than their white counterparts, yet little is known as to why. We examined perceptions of e cigarettes among Black young adults (ages 18-25) to explore the meanings these youth ascribe to e-cigarettes and the role that identity plays in how these devices are viewed. Analysis of in-depth interviews with 36 Black smokers and non smokers in the San Francisco Bay Area suggests that Black youth perceive e cigarettes as serving distinct, yet overlapping roles: a utilitarian function, in that they are recognized as legitimate smoking cessation tools, and a social function, insofar as they serve to mark social identity, specifically a social identity from which our participants disassociated. Participants described e cigarette users in highly racialized and classed terms and generally expressed disinterest in using e-cigarettes, due in part perhaps to the fact that use of these devices would signal alignment with a middle class, hipster identity. This analysis is discussed within a highly charged political and public health debate about the benefits and harms associated with e-cigarette use. PMID- 28085040 TI - Impact of Menthol Smoking on Nicotine Dependence for Diverse Racial/Ethnic Groups of Daily Smokers. AB - Introduction: The aims of this study were to evaluate whether menthol smoking and race/ethnicity are associated with nicotine dependence in daily smokers. Methods: The study used two subsamples of U.S. daily smokers who responded to the 2010 2011 Tobacco Use Supplement to the Current Population Survey. The larger subsample consisted of 18,849 non-Hispanic White (NHW), non-Hispanic Black (NHB), and Hispanic (HISP) smokers. The smaller subsample consisted of 1112 non-Hispanic American Indian/Alaska Native (AIAN), non-Hispanic Asian (ASIAN), non-Hispanic Hawaiian/Pacific Islander (HPI), and non-Hispanic Multiracial (MULT) smokers. Results: For larger (smaller) groups the rates were 45% (33%) for heavy smoking (16+ cig/day), 59% (51%) for smoking within 30 min of awakening (Sw30), and 14% (14%) for night-smoking. Overall, the highest prevalence of menthol smoking corresponded to NHB and HPI (>=65%), followed by MULT and HISP (31%-37%), and then by AIAN, NHW, and ASIAN (22%-27%) smokers. For larger racial/ethnic groups, menthol smoking was negatively associated with heavy smoking, not associated with Sw30, and positively associated with night-smoking. For smaller groups, menthol smoking was not associated with any measure, but the rates of heavy smoking, Sw30, and night-smoking varied across the groups. Conclusions: The diverse associations between menthol smoking and nicotine dependence maybe due to distinction among the nicotine dependence measures, i.e., individually, each measure assesses a specific smoking behavior. Menthol smoking may be associated with promoting smoking behaviors. PMID- 28085043 TI - Stylus Tip Center Position Self-Calibration Based on Invariable Distances in Light-Pen Systems. AB - The light-pen coordinate measuring machine (LPCMM for short) is portable and flexible to measure features including invisible ones in-situ. Since different styluses are needed to measure different features and even during the process of measuring a single workpiece with complicated configurations, to improve the system measurement accuracy it is beneficial to calibrate the stylus tip center position after it is mounted to the light-pen before measurement in an industrial field. A novel and simple method aiming at self-calibrating the position of the tip center based on invariable distances is presented. The distinguishing feature of the proposed method is that the center position of the tip can be calibrated by using a kinematic seat with an inverted cone hole without any external reference and auxiliary devices. Calibration is based on that the distance between the tip center and that of any LED is invariable when the light-pen is swung smoothly with its spherical tip firmly touching the fixed cone seat. To ensure the repeatability of the algorithm some error constraint parameters are given. Based on invariable distances, the tip center position in the light-pen coordinate system can be obtained. Experiment results show that the self calibration method has the advantage of good repeatability, with standard deviations 0.027, 0.023 and 0.014 mm in U, V and W directions, respectively. Experimental results of measuring a circle and a gauge block indirectly demonstrate the accuracy of the proposed self-calibration method. PMID- 28085044 TI - Epipolar Resampling of Cross-Track Pushbroom Satellite Imagery Using the Rigorous Sensor Model. AB - Epipolar resampling aims to eliminate the vertical parallax of stereo images. Due to the dynamic nature of the exterior orientation parameters of linear pushbroom satellite imagery and the complexity of reconstructing the epipolar geometry using rigorous sensor models, so far, no epipolar resampling approach has been proposed based on these models. In this paper for the first time it is shown that the orientation of the instantaneous baseline (IB) of conjugate image points (CIPs) in the linear pushbroom satellite imagery can be modeled with high precision in terms of the rows- and the columns-number of CIPs. Taking advantage of this feature, a novel approach is then presented for epipolar resampling of cross-track linear pushbroom satellite imagery. The proposed method is based on the rigorous sensor model. As the instantaneous position of sensors remains fixed, the digital elevation model of the area of interest is not required in the resampling process. Experimental results obtained from two pairs of SPOT and one pair of RapidEye stereo imagery with different terrain conditions shows that the proposed epipolar resampling approach benefits from a superior accuracy, as the remained vertical parallaxes of all CIPs in the normalized images are close to zero. PMID- 28085045 TI - Influence of Varroa Mite (Varroa destructor) Management Practices on Insecticide Sensitivity in the Honey Bee (Apis mellifera). AB - Since Varroa mites may cause devastating losses of honey bees through direct feeding, transmitting diseases, and increasing pathogen susceptibility, chemical and mechanical practices commonly are used to reduce mite infestation. While miticide applications are typically the most consistent and efficacious Varroa mite management method, miticide-induced insecticide synergism in honey bees, and the evolution of resistance in Varroa mites are reasonable concerns. We treated colonies with the miticide amitraz (Apivar(r)), used IPM practices, or left some colonies untreated, and then measured the effect of different levels of mite infestations on the sensitivity of bees to phenothrin, amitraz, and clothianidin. Sensitivity to all insecticides varied throughout the year among and within treatment groups. Clothianidin sensitivity decreased with increasing mite levels, but no such correlation was seen with phenothrin or amitraz. These results show that insecticide sensitivity is dynamic throughout the 5 months test. In-hive amitraz treatment according to the labeled use did not synergize sensitivity to the pesticides tested and this should alleviate concern over potential synergistic effects. Since IPM practices were largely ineffective at reducing Varroa mite infestation, reliance on chemical methods of Varroa mite management is likely to continue. However, miticides must be used judiciously so the long term effectiveness of these compounds can be maximized. These data demonstrate the complex and dynamic variables that contribute to honey bee colony health. The results underscore the importance of controlling for as many of these variables as possible in order to accurately determine the effects of each of these factors as they act alone or in concert with others. PMID- 28085046 TI - Multibeam Interferometer Using a Photonic Crystal Fiber with Two Asymmetric Cores for Torsion, Strain and Temperature Sensing. AB - We present a fiber-optic multibeam Mach-Zehnder interferometer (m-MZI) for simultaneous multi-parameter measurement. The m-MZI is comprised of a section of photonic crystal fiber integrated with two independent cores of distinct construction and birefringence properties characterized for torsion, strain and temperature sensing. Due to the presence of small core geometry and use of a short fiber length, the sensing device demonstrates inter-modal interference in the small core alongside the dominant inter-core interference between the cores for each of the orthogonal polarizations. The output spectrum of the device is characterized by the three-beam interference model and is polarization-dependent. The two types of interferometers present in the fiber m-MZI exhibit distinct sensitivities to torsion, strain and temperature for different polarizations, and matrix coefficients allowing simultaneous measurement of the three sensing parameters are proposed in experiment. PMID- 28085047 TI - Optimization of Polymer-ECM Composite Scaffolds for Tissue Engineering: Effect of Cells and Culture Conditions on Polymeric Nanofiber Mats. AB - The design of composite tissue scaffolds containing an extracellular matrix (ECM) and synthetic polymer fibers is a new approach to create bioactive scaffolds that can enhance cell function. Currently, studies investigating the effects of ECM deposition and decellularization on polymer degradation are still lacking, as are data on optimizing the stability of the ECM-containing composite scaffolds during prolonged cell culture. In this study, we develop fibrous scaffolds using three polymer compositions, representing slow (E0000), medium (E0500), and fast (E1000) degrading materials, to investigate the stability, degradation, and mechanics of the scaffolds during ECM deposition and decellularization, and during the complete cellularization-decell-recell cycle. We report data on percent molecular weight (% Mw) retention of polymeric fiber mats, changes in scaffold stiffness, ECM deposition, and the presence of fibronectin after decellularization. We concluded that the fast degrading E1000 (Mw retention <= 50% after 28 days) was not sufficiently stable to allow scaffold handling after 28 days in culture, while the slow degradation of E0000 (Mw retention >= 80% in 28 days) did not allow deposited ECM to replace the polymer support. The scaffolds made from medium degrading E0500 (Mw retention about 60% at 28 days) allowed the gradual replacement of the polymer network with cell-derived ECM while maintaining the polymer network support. Thus, polymers with an intermediate rate of degradation, maintaining good scaffold handling properties after 28 days in culture, seem best suited for creating ECM-polymer composite scaffolds. PMID- 28085048 TI - AR-Signaling in Human Malignancies: Prostate Cancer and Beyond. AB - In the 1940s Charles Huggins reported remarkable palliative benefits following surgical castration in men with advanced prostate cancer, and since then the androgen receptor (AR) has remained the main therapeutic target in this disease. Over the past couple of decades, our understanding of AR-signaling biology has dramatically improved, and it has become apparent that the AR can modulate a number of other well-described oncogenic signaling pathways. Not surprisingly, mounting preclinical and epidemiologic data now supports a role for AR-signaling in promoting the growth and progression of several cancers other than prostate, and early phase clinical trials have documented preliminary signs of efficacy when AR-signaling inhibitors are used in several of these malignancies. In this article, we provide an overview of the evidence supporting the use of AR-directed therapies in prostate as well as other cancers, with an emphasis on the rationale for targeting AR-signaling across tumor types. PMID- 28085049 TI - Wolbachia Affects Reproduction and Population Dynamics of the Coffee Berry Borer (Hypothenemus hampei): Implications for Biological Control. AB - Wolbachia are widely distributed endosymbiotic bacteria that influence the reproduction and fitness of their hosts. In recent years the manipulation of Wolbachia infection has been considered as a potential tool for biological control. The coffee berry borer (CBB), Hypothenemus hampei, is the most devastating coffee pest worldwide. Wolbachia infection in the CBB has been reported, but until now the role of Wolbachia in CBB reproduction and fitness has not been tested. To address this issue we reared the CBB in artificial diets with and without tetracycline (0.1% w/v) for ten generations. Tetracycline reduced significantly the relative proportion of Wolbachia in the CBB microbiota from 0.49% to 0.04%. This reduction affected CBB reproduction: females fed with tetracycline had significantly fewer progeny, lower fecundity, and fewer eggs per female. Tetracycline also reduced the population growth rate (lambda), net reproductive rate (R0), and mean generation time (T) in CBB; the reduction in population growth was mostly due to variation in fertility, according to life time response experiments (LTREs) analysis. Our results suggest that Wolbachia contribute to the reproductive success of the CBB and their manipulation represents a possible approach to CBB biocontrol mediated by microbiome management. PMID- 28085050 TI - Meta-Prediction of the Effect of Methylenetetrahydrofolate Reductase Polymorphisms and Air Pollution on Alzheimer's Disease Risk. AB - Background: Alzheimer's disease (AD) is a significant public health issue. AD has been linked with methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, but the findings have been inconsistent. The purpose of this meta-predictive analysis is to examine the associations between MTHFR polymorphisms and epigenetic factors, including air pollution, with AD risk using big data analytics approaches. Methods and Results: Forty-three studies (44 groups) were identified by searching various databases. MTHFR C677T TT and CT genotypes had significant associations with AD risk in all racial populations (RR = 1.13, p = 0.0047; and RR = 1.12, p < 0.0001 respectively). Meta-predictive analysis showed significant increases of percentages of MTHFR C677T polymorphism with increased air pollution levels in both AD case group and control group (p = 0.0021-0.0457); with higher percentages of TT and CT genotypes in the AD case group than that in the control group with increased air pollution levels. Conclusions: The impact of MTHFR C677T polymorphism on susceptibility to AD was modified by level of air pollution. Future studies are needed to further examine the effects of gene environment interactions including air pollution on AD risk for world populations. PMID- 28085051 TI - Perioperative Search for Circulating Tumor Cells in Patients Undergoing Prostate Brachytherapy for Clinically Nonmetastatic Prostate Cancer. AB - Despite the absence of local prostate cancer recurrence, some patients develop distant metastases after prostate brachytherapy. We evaluate whether prostate brachytherapy procedures have a potential risk for hematogenous spillage of prostate cancer cells. Fifty-nine patients who were undergoing high-dose-rate (HDR) or low-dose-rate (LDR) brachytherapy participated in this prospective study. Thirty patients with high-risk or locally advanced cancer were treated with HDR brachytherapy after neoadjuvant androgen deprivation therapy (ADT). Twenty-nine patients with clinically localized cancer were treated with LDR brachytherapy without neoadjuvant ADT. Samples of peripheral blood were drawn in the operating room before insertion of needles (preoperative) and again immediately after the surgical manipulation (intraoperative). Blood samples of 7.5 mL were analyzed for circulating tumor cells (CTCs) using the CellSearch System. While no preoperative samples showed CTCs (0%), they were detected in intraoperative samples in 7 of the 59 patients (11.8%; preoperative vs. intraoperative, p = 0.012). Positive CTC status did not correlate with perioperative variables, including prostate-specific antigen (PSA) at diagnosis, use of neoadjuvant ADT, type of brachytherapy, Gleason score, and biopsy positive core rate. We detected CTCs from samples immediately after the surgical manipulation. Further study is needed to evaluate whether those CTCs actually can survive and proliferate at distant sites. PMID- 28085053 TI - Socio-Environmental and Hematological Profile of Landfill Residents (Sao Jorge Landfill-Sao Paulo, Brazil). AB - We are experiencing an unprecedented urbanization process that, alongside physical, social and economic developments, has been having a significant impact on a population's health. Due to the increase in pollution, violence and poverty, our modern cities no longer ensure a good quality of life so they become unhealthy environments. This study aims to assess the effect of social, environmental and economic factors on the hematologic profile of residents of Santo Andre's landfill. In particular, we will assess the effect of social, economic, and environmental factors on current and potential disease markers obtained from hematological tests. The research method is the observational type, from a retrospective cohort, and by convenience sampling in Santo Andre in the Greater ABC (municipalities of Santo Andre, Sao Bernardo do Campo and Sao Caetano do Sul, southeast part of the Greater Sao Paulo Metropolitan Area, Brazil). The study determined a socio-environmental profile and the hematologic diseases screening related to a close location to the landfill. The disease manifests itself within a broad spectrum of symptoms that causes changes in blood count parameters. The objective of this work is to show that there is an association between social, environmental and economic factors and a variety of serious disease outcomes that may be detected from blood screening. A causal study of the effect of living near the landfill on these disease outcomes would be a very expensive and time-consuming study. This work we believe is sufficient for public health officials to consider policy and attempt remediation of the effects of living near a landfill. PMID- 28085056 TI - RnlB Antitoxin of the Escherichia coli RnlA-RnlB Toxin-Antitoxin Module Requires RNase HI for Inhibition of RnlA Toxin Activity. AB - The Escherichia coli RnlA-RnlB toxin-antitoxin system is related to the anti phage mechanism. Under normal growth conditions, an RnlA toxin with endoribonuclease activity is inhibited by binding of its cognate RnlB antitoxin. After bacteriophage T4 infection, RnlA is activated by the disappearance of RnlB, resulting in the rapid degradation of T4 mRNAs and consequently no T4 propagation when T4 dmd encoding a phage antitoxin against RnlA is defective. Intriguingly, E. coli RNase HI, which plays a key role in DNA replication, is required for the activation of RnlA and stimulates the RNA cleavage activity of RnlA. Here, we report an additional role of RNase HI in the regulation of RnlA-RnlB system. Both RNase HI and RnlB are associated with NRD (one of three domains of RnlA). The interaction between RnlB and NRD depends on RNase HI. Exogenous expression of RnlA in wild-type cells has no effect on cell growth because of endogenous RnlB and this inhibition of RnlA toxicity requires RNase HI and NRD. These results suggest that RNase HI recruits RnlB to RnlA through NRD for inhibiting RnlA toxicity and thus plays two contrary roles in the regulation of RnlA-RnlB system. PMID- 28085054 TI - Bioactive Nanocomposites for Tissue Repair and Regeneration: A Review. AB - This review presents scientific findings concerning the use of bioactive nanocomposites in the field of tissue repair and regeneration. Bioactivity is the ability of a material to incite a specific biological reaction, usually at the boundary of the material. Nanocomposites have been shown to be ideal bioactive materials due the many biological interfaces and structures operating at the nanoscale. This has resulted in many researchers investigating nanocomposites for use in bioapplications. Nanocomposites encompass a number of different structures, incorporating organic-inorganic, inorganic-inorganic and bioinorganic nanomaterials and based upon ceramic, metallic or polymeric materials. This enables a wide range of properties to be incorporated into nanocomposite materials, such as magnetic properties, MR imaging contrast or drug delivery, and even a combination of these properties. Much of the classical research was focused on bone regeneration, however, recent advances have enabled further use in soft tissue body sites too. Despite recent technological advances, more research is needed to further understand the long-term biocompatibility impact of the use of nanoparticles within the human body. PMID- 28085060 TI - Identification of the Ovine Keratin-Associated Protein 22-1 (KAP22-1) Gene and Its Effect on Wool Traits. AB - Keratin-associated proteins (KAPs) are structural components of wool and hair fibers. To date, eight high glycine/tyrosine KAP (HGT-KAP) families have been identified in humans, but only three have been identified in sheep. In this study, the putative ovine homolog of the human KAP22-1 gene (KRTAP22-1) was amplified using primers designed based on a human KRTAP22-1 sequence. Polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP) was used to screen for variation in KRTAP22-1 in 390 Merino * Southdown-cross lambs and 75 New Zealand (NZ) Romney sheep. Three PCR-SSCP banding patterns were detected and DNA sequencing revealed that the banding patterns represented three different nucleotide sequences (A-C). Two single nucleotide polymorphisms (SNPs) were identified in these sequences. Variant B was most common with a frequency of 81.3% in NZ Romney sheep, while in the Merino * Southdown-cross lambs, A was more common with a frequency of 51.8%. The presence of B was found to be associated with increased wool yield and decreased mean fiber curvature (MFC). Sheep of genotype BB or AB had a higher wool yield than those of genotype AA. These results suggest that ovine KRTAP22-1 variation may be useful when developing breeding programs based on increasing wool yield, or decreasing wool curvature. PMID- 28085057 TI - Ethical Challenges in Infant Feeding Research. AB - Infants have a complex set of nutrient requirements to meet the demands of their high metabolic rate, growth, and immunological and cognitive development. Infant nutrition lays the foundation for health throughout life. While infant feeding research is essential, it must be conducted to the highest ethical standards. The objective of this paper is to discuss the implications of developments in infant nutrition for the ethics of infant feeding research and the implications for obtaining informed consent. A search was undertaken of the papers in the medical literature using the PubMed, Science Direct, Web of Knowledge, Proquest, and CINAHL databases. From a total of 9303 papers identified, the full text of 87 articles that contained discussion of issues in consent in infant feeding trials were obtained and read and after further screening 42 papers were included in the results and discussion. Recent developments in infant nutrition of significance to ethics assessment include the improved survival of low birth weight infants, increasing evidence of the value of breastfeeding and evidence of the lifelong importance of infant feeding and development in the first 1000 days of life in chronic disease epidemiology. Informed consent is a difficult issue, but should always include information on the value of preserving breastfeeding options. Project monitoring should be cognisant of the long term implications of growth rates and early life nutrition. PMID- 28085061 TI - Origin DNA Melting-An Essential Process with Divergent Mechanisms. AB - Origin DNA melting is an essential process in the various domains of life. The replication fork helicase unwinds DNA ahead of the replication fork, providing single-stranded DNA templates for the replicative polymerases. The replication fork helicase is a ring shaped-assembly that unwinds DNA by a steric exclusion mechanism in most DNA replication systems. While one strand of DNA passes through the central channel of the helicase ring, the second DNA strand is excluded from the central channel. Thus, the origin, or initiation site for DNA replication, must melt during the initiation of DNA replication to allow for the helicase to surround a single-DNA strand. While this process is largely understood for bacteria and eukaryotic viruses, less is known about how origin DNA is melted at eukaryotic cellular origins. This review describes the current state of knowledge of how genomic DNA is melted at a replication origin in bacteria and eukaryotes. We propose that although the process of origin melting is essential for the various domains of life, the mechanism for origin melting may be quite different among the different DNA replication initiation systems. PMID- 28085062 TI - Radix isatidis Polysaccharides Inhibit Influenza a Virus and Influenza A Virus Induced Inflammation via Suppression of Host TLR3 Signaling In Vitro. AB - Influenza remains one of the major epidemic diseases worldwide, and rapid virus replication and collateral lung tissue damage caused by excessive pro inflammatory host immune cell responses lead to high mortality rates. Thus, novel therapeutic agents that control influenza A virus (IAV) propagation and attenuate excessive pro-inflammatory responses are needed. Polysaccharide extract from Radix isatidis, a traditional Chinese herbal medicine, exerted potent anti-IAV activity against human seasonal influenza viruses (H1N1 and H3N2) and avian influenza viruses (H6N2 and H9N2) in vitro. The polysaccharides also significantly reduced the expression of pro-inflammatory cytokines (IL-6) and chemokines (IP-10, MIG, and CCL-5) stimulated by A/PR/8/34 (H1N1) at a range of doses (7.5 mg/mL, 15 mg/mL, and 30 mg/mL); however, they were only effective against progeny virus at a high dose. Similar activity was detected against inflammation induced by avian influenza virus H9N2. The polysaccharides strongly inhibited the protein expression of TLR-3 induced by PR8, suggesting that they impair the upregulation of pro-inflammatory factors induced by IAV by inhibiting activation of the TLR-3 signaling pathway. The polysaccharide extract from Radix isatidis root therefore has the potential to be used as an adjunct to antiviral therapy for the treatment of IAV infection. PMID- 28085063 TI - Retinoic Acid Protects and Rescues the Development of Zebrafish Embryonic Retinal Photoreceptor Cells from Exposure to Paclobutrazol. AB - Paclobutrazol (PBZ) is a widely used fungicide that shows toxicity to aquatic embryos, probably through rain-wash. Here, we specifically focus on its toxic effect on eye development in zebrafish, as well as the role of retinoic acid (RA), a metabolite of vitamin A that controls proliferation and differentiation of retinal photoreceptor cells, in this toxicity. Embryos were exposed to PBZ with or without RA from 2 to 72 h post-fertilization (hpf), and PBZ-treated embryos (2-72 hpf) were exposed to RA for additional hours until 120 hpf. Eye size and histology were examined. Expression levels of gnat1 (rod photoreceptor marker), gnat2 (cone photoreceptor marker), aldehyde dehydrogenases (encoding key enzymes for RA synthesis), and phospho-histone H3 (an M-phase marker) in the eyes of control and treated embryos were examined. PBZ exposure dramatically reduces photoreceptor proliferation, thus resulting in a thinning of the photoreceptor cell layer and leading to a small eye. Co-treatment of PBZ with RA, or post treatment of PBZ-treated embryos with RA, partially rescues photoreceptor cells, revealed by expression levels of marker proteins and by retinal cell proliferation. PBZ has strong embryonic toxicity to retinal photoreceptors, probably via suppressing the production of RA, with effects including impaired retinal cell division. PMID- 28085064 TI - Antidiabetic, Lipid Normalizing, and Nephroprotective Actions of the Strawberry: A Potent Supplementary Fruit. AB - The study was designed to assess the effect of different strawberry extracts on glucose levels, lipid profiles, and oxidative stress in nicotinamide streptozotocin (NIC-STZ) induced diabetic rats. The associated changes were evaluated through biochemical, molecular, and histological assays. Diabetes was induced by intraperitoneal injection of STZ to albino Wistar rats after treatment with nicotinamide. Aqueous, hydroalcoholic, and alcoholic strawberry extracts were administrated orally to diabetic rats. Treatment of strawberry extracts improved lipid profile, liver function, and serum creatinine and led to a significant increase in antioxidant status in diabetic rats. Real-time PCR expression analysis of genes from the liver of animals treated with strawberry extracts exhibited downregulation of several fatty acid synthesis genes, transcription factors, such as Sterol regulatory Element Binding Transcription factor (SREBP) and Nuclear Factor-kappabeta (NF-kappabeta), and inflammatory markers, like Interleukin 6 (IL6) and Tumor Necrosis Factor-alpha (TNF-alpha). Strawberry extracts also upregulated liver Peroxisome Proliferator Activated Receptor-gamma (PPAR-gamma). Histological examination confirmed the nephroprotective and beta-cell regeneration/protection effects of strawberry extracts. The present study demonstrates several beneficial effects of strawberry extracts along with its probable mechanism of action. PMID- 28085065 TI - Characterization of the Micromorphology and Topochemistry of Poplar Wood during Mild Ionic Liquid Pretreatment for Improving Enzymatic Saccharification. AB - Ionic liquids (ILs) as designer solvents have been applied in biomass pretreatment to increase cellulose accessibility and therefore improve the enzymatic hydrolysis. We investigated the characterization of the micromorphology and the topochemistry of poplar wood during 1-ethyl-3-methylimidazolium acetate pretreatment with mild conditions (90 degrees C for 20 and 40 min) by multiple microscopic techniques (FE-SEM, CLSM, and CRM). Chemical composition analysis, XRD, cellulase adsorption isotherm, and enzymatic hydrolysis were also performed to monitor the variation of substrate properties. Our results indicated that the biomass conversion was greatly enhanced (from 20.57% to 73.64%) due to the cell wall deconstruction and lignin dissolution (29.83% lignin was removed after incubation for 40 min), rather than the decrystallization or crystallinity transformation of substrates. The mild ILs pretreatment, with less energy input, can not only enhance enzymatic hydrolysis, but also provide a potential approach as the first step in improving the sequential pretreatment effectiveness in integrated methods. This study provides new insights on understanding the ILs pretreatment with low temperature and short duration, which is critical for developing individual and/or combined pretreatment technologies with reduced energy consumption. PMID- 28085066 TI - Mutation-Structure-Function Relationship Based Integrated Strategy Reveals the Potential Impact of Deleterious Missense Mutations in Autophagy Related Proteins on Hepatocellular Carcinoma (HCC): A Comprehensive Informatics Approach. AB - Autophagy, an evolutionary conserved multifaceted lysosome-mediated bulk degradation system, plays a vital role in liver pathologies including hepatocellular carcinoma (HCC). Post-translational modifications (PTMs) and genetic variations in autophagy components have emerged as significant determinants of autophagy related proteins. Identification of a comprehensive spectrum of genetic variations and PTMs of autophagy related proteins and their impact at molecular level will greatly expand our understanding of autophagy based regulation. In this study, we attempted to identify high risk missense mutations that are highly damaging to the structure as well as function of autophagy related proteins including LC3A, LC3B, BECN1 and SCD1. Number of putative structural and functional residues, including several sites that undergo PTMs were also identified. In total, 16 high-risk SNPs in LC3A, 18 in LC3B, 40 in BECN1 and 43 in SCD1 were prioritized. Out of these, 2 in LC3A (K49A, K51A), 1 in LC3B (S92C), 6 in BECN1 (S113R, R292C, R292H, Y338C, S346Y, Y352H) and 6 in SCD1 (Y41C, Y55D, R131W, R135Q, R135W, Y151C) coincide with potential PTM sites. Our integrated analysis found LC3B Y113C, BECN1 I403T, SCD1 R126S and SCD1 Y218C as highly deleterious HCC-associated mutations. This study is the first extensive in silico mutational analysis of the LC3A, LC3B, BECN1 and SCD1 proteins. We hope that the observed results will be a valuable resource for in-depth mechanistic insight into future investigations of pathological missense SNPs using an integrated computational platform. PMID- 28085067 TI - The Impact of Heat Waves on Occurrence and Severity of Construction Accidents. AB - The impact of heat stress on human health has been extensively studied. Similarly, researchers have investigated the impact of heat stress on workers' health and safety. However, very little work has been done on the impact of heat stress on occupational accidents and their severity, particularly in South Australian construction. Construction workers are at high risk of injury due to heat stress as they often work outdoors, undertake hard manual work, and are often project based and sub-contracted. Little is known on how heat waves could impact on construction accidents and their severity. In order to provide more evidence for the currently limited number of empirical investigations on the impact of heat stress on accidents, this study analysed 29,438 compensation claims reported during 2002-2013 within the construction industry of South Australia. Claims reported during 29 heat waves in Adelaide were compared with control periods to elicit differences in the number of accidents reported and their severity. The results revealed that worker characteristics, type of work, work environment, and agency of accident mainly govern the severity. It is recommended that the implementation of adequate preventative measures in small sized companies and civil engineering sites, targeting mainly old age workers could be a priority for Work, Health and Safety (WHS) policies. PMID- 28085070 TI - Zinc as a Signal to Stimulate Red Blood Cell Formation in Fish. AB - The common carp can tolerate extremely low oxygen levels. These fish store zinc in a specific zinc-binding protein presented in digestive tract tissues, and under low oxygen, the stored zinc is released and used as a signal to stimulate erythropoiesis (red blood cell formation). To determine whether the environmental supply of zinc to other fish species can serve as a signal to induce erythropoiesis as in the common carp, head kidney cells of four different fish species were cultured with supplemental ZnCl2. Zinc stimulated approximately a three-fold increase in immature red blood cells (RBCs) in one day. The stimulation of erythropoiesis by zinc was dose-dependent. ZnSO4 solution was injected into an experimental blood loss tilapia model. Blood analysis and microscopic observation of the blood cells indicated that, in vivo, the presence of additional zinc induced erythropoiesis in the bled tilapia. In the fish species studied, zinc could be used as a signal to stimulate erythropoiesis both in vitro and in vivo. The present report suggests a possible approach for the induction of red blood cell formation in animals through the supply of a certain level of zinc through either diet or injection. PMID- 28085071 TI - Evaluation of the Performance of the Distributed Phased-MIMO Sonar. AB - A broadband signal model is proposed for a distributed multiple-input multiple output (MIMO) sonar system consisting of two transmitters and a receiving linear array. Transmitters are widely separated to illuminate the different aspects of an extended target of interest. The beamforming technique is utilized at the reception ends for enhancement of weak target echoes. A MIMO detector is designed with the estimated target position parameters within the general likelihood rate test (GLRT) framework. For the high signal-to-noise ratio case, the detection performance of the MIMO system is better than that of the phased-array system in the numerical simulations and the tank experiments. The robustness of the distributed phased-MIMO sonar system is further demonstrated in localization of a target in at-lake experiments. PMID- 28085069 TI - Pathophysiology and the Monitoring Methods for Cardiac Arrest Associated Brain Injury. AB - Cardiac arrest (CA) is a well-known cause of global brain ischemia. After CA and subsequent loss of consciousness, oxygen tension starts to decline and leads to a series of cellular changes that will lead to cellular death, if not reversed immediately, with brain edema as a result. The electroencephalographic activity starts to change as well. Although increased intracranial pressure (ICP) is not a direct result of cardiac arrest, it can still occur due to hypoxic-ischemic encephalopathy induced changes in brain tissue, and is a measure of brain edema after CA and ischemic brain injury. In this review, we will discuss the pathophysiology of brain edema after CA, some available techniques, and methods to monitor brain oxygen, electroencephalography (EEG), ICP (intracranial pressure), and microdialysis on its measurement of cerebral metabolism and its usefulness both in clinical practice and possible basic science research in development. With this review, we hope to gain knowledge of the more personalized information about patient status and specifics of their brain injury, and thus facilitating the physicians' decision making in terms of which treatments to pursue. PMID- 28085072 TI - Incidence and Simple Prediction Model of Hyperuricemia for Urban Han Chinese Adults: A Prospective Cohort Study. AB - BACKGROUND: Hyperuricemia (HUA) contributes to gout and many other diseases. Many hyperuricemia-related risk factors have been discovered, which provided the possibility for building the hyperuricemia prediction model. In this study we aimed to explore the incidence of hyperuricemia and develop hyperuricemia prediction models based on the routine biomarkers for both males and females in urban Han Chinese adults. METHODS: A cohort of 58,542 members of the urban population (34,980 males and 23,562 females) aged 20-80 years old, free of hyperuricemia at baseline examination, was followed up for a median 2.5 years. The Cox proportional hazards regression model was used to develop gender-specific prediction models. Harrell's C-statistics was used to evaluate the discrimination ability of the models, and the 10-fold cross-validation was used to validate the models. RESULTS: In 7139 subjects (5585 males and 1554 females), hyperuricemia occurred during a median of 2.5 years of follow-up, leading to a total incidence density of 49.63/1000 person years (64.62/1000 person years for males and 27.12/1000 person years for females). The predictors of hyperuricemia were age, body mass index (BMI) systolic blood pressure, serum uric acid for males, and BMI, systolic blood pressure, serum uric acid, triglycerides for females. The models' C statistics were 0.783 (95% confidence interval (CI), 0.779-0.786) for males and 0.784 (95% CI, 0.778-0.789) for females. After 10-fold cross validation, the C statistics were still steady, with 0.782 for males and 0.783 for females. CONCLUSIONS: In this study, gender-specific prediction models for hyperuricemia for urban Han Chinese adults were developed and performed well. PMID- 28085073 TI - Synthetic Strategies for Peroxide Ring Construction in Artemisinin. AB - The present review summarizes publications on the artemisinin peroxide fragment synthesis from 1983 to 2016. The data are classified according to the structures of a precursor used in the key peroxidation step of artemisinin peroxide cycle synthesis. The first part of the review comprises the construction of artemisinin peroxide fragment in total syntheses, in which peroxide artemisinin ring resulted from reactions of unsaturated keto derivatives with singlet oxygen or ozone. In the second part, the methods of artemisinin synthesis based on transformations of dihydroartemisinic acid are highlighted. PMID- 28085074 TI - The Impact of Efflux Pump Inhibitors on the Activity of Selected Non-Antibiotic Medicinal Products against Gram-Negative Bacteria. AB - The potential role of non-antibiotic medicinal products in the treatment of multidrug-resistant Gram-negative bacteria has recently been investigated. It is highly likely that the presence of efflux pumps may be one of the reasons for the weak activity of non-antibiotics, as in the case of some non-steroidal anti inflammatory drugs (NSAIDs), against Gram-negative rods. The activity of eight drugs of potential non-antibiotic activity, active substance standards, and relevant medicinal products were analysed with and without of efflux pump inhibitors against 180 strains of five Gram-negative rod species by minimum inhibitory concentration (MIC) value determination in the presence of 1 mM MgSO4. Furthermore, the influence of non-antibiotics on the susceptibility of clinical strains to quinolones with or without PAbetaN (Phe-Arg-beta-naphthylamide) was investigated. The impacts of PAbetaN on the susceptibility of bacteria to non antibiotics suggests that amitriptyline, alendronate, nicergoline, and ticlopidine are substrates of efflux pumps in Gram-negative rods. Amitriptyline/Amitriptylinum showed the highest direct antibacterial activity, with MICs ranging 100-800 mg/L against all studied species. Significant decreases in the MIC values of other active substances (acyclovir, atorvastatin, and famotidine) tested with pump inhibitors were not observed. The investigated non antibiotic medicinal products did not alter the MICs of quinolones in the absence and in the presence of PAbetaN to the studied clinical strains of five groups of species. PMID- 28085075 TI - Preclinical Study of Antineoplastic Sinoporphyrin Sodium-PDT via In Vitro and In Vivo Models. AB - Photodynamic therapy (PDT) investigations have seen stable increases and the development of new photosensitizers is a heated topic. Sinoporphyrin sodium is a new photosensitizer isolated from Photofrin. This article evaluated its anticancer effects by clonogenic assays, MTT assays and xenograft experiments in comparison to Photofrin. The clonogenicity inhibition rates of sinoporphyrin sodium-PDT towards four human cancer cell lines ranged from 85.5% to 94.2% at 0.5 MUg/mL under 630 nm irradiation of 30 mW/cm2 for 180 s. For MTT assays, the IC50 ranges of Photofrin-PDT and sinoporphyrin sodium-PDT towards human cancer cells were 0.3 MUg/mL to 5.5 MUg/mL and 0.1 MUg/mL to 0.8 MUg/mL under the same irradiation conditions, respectively. The IC50 values of Photofrin-PDT and sinoporphyrin sodium-PDT towards human skin cells, HaCaT, were 10 MUg/mL and 1.0 MUg/mL, respectively. Esophagus carcinoma and hepatoma xenograft models were established to evaluate the in vivo antineoplastic efficacy. A control group, Photofrin-PDT group (20 mg/kg) and sinoporphyrin sodium group at three doses, 0.5 mg/kg, 1 mg/kg and 2 mg/kg, were set. Mice were injected with photosensitizers 24 h before 60 J 630 nm laser irradiation. The tumor weight inhibition ratio of 2 mg/kg sinoporphyrin sodium-PDT reached approximately 90%. Besides, the tumor growths were significantly slowed down by 2 mg/kg sinoporphyrin sodium-PDT, which was equivalent to 20 mg/kg Photofrin-PDT. In sum, sinoporphyrin sodium-PDT showed great anticancer efficacy and with a smaller dose compared with Photofrin. Further investigations are warranted. PMID- 28085076 TI - Antioxidant and Anti-Osteoporotic Activities of Aromatic Compounds and Sterols from Hericium erinaceum. AB - Hericium erinaceum, commonly called lion's mane mushroom, is a traditional edible mushroom widely used in culinary applications and herbal medicines in East Asian countries. In this study, a new sterol, cerevisterol 6-cinnamate (6), was isolated from the fruiting bodies of H. erinaceum together with five aromatic compounds 1-5 and five sterols 7-11. The chemical structures of these compounds were elucidated using chemical and physical methods and comparison of HRESIMS, 1D NMR (1H, 13C, and DEPT) and 2D-NMR (COSY, HMQC, HMBC, and NOESY) spectra with previously reported data. The antioxidant and anti-osteoporotic activities of extracts and the isolated compounds 1-11 were investigated. All compounds exhibited peroxyl radical-scavenging capacity but only compounds 1, 3, and 4 showed potent reducing capacity. Moreover, compounds 1, 2, 4, and 5 showed moderate effects on cellular antioxidant activity and inhibited the receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclastic differentiation. These results suggested that H. erinaceum could be utilized in the development of natural antioxidant and anti-osteoporotic nutraceuticals and functional foods. PMID- 28085077 TI - 13C-NMR Spectral Data of Alkaloids Isolated from Psychotria Species (Rubiaceae). AB - The genus Psychotria (Rubiaceae) comprises more than 2000 species, mainly found in tropical and subtropical forests. Several studies have been conducted concerning their chemical compositions, showing that this genus is a potential source of alkaloids. At least 70 indole alkaloids have been identified from this genus so far. This review aimed to compile 13C-NMR data of alkaloids isolated from the genus Psychotria as well as describe the main spectral features of different skeletons. PMID- 28085079 TI - Synthetic Approaches to Mono- and Bicyclic Perortho-Esters with a Central 1,2,4 Trioxane Ring as the Privileged Lead Structure in Antimalarial and Antitumor Active Peroxides and Clarification of the Peroxide Relevance. AB - The synthesis of 4-styryl-substituted 2,3,8-trioxabicyclo[3.3.1]nonanes, peroxides with the core structure of the bioactive 1,2,4-trioxane ring, was conducted by a multistep route starting from the aryl methyl ketones 1a-1c. Condensation and reduction/oxidation delivered enals 4a-4c that were coupled with ethyl acetate and reduced to the 1,3-diol substrates 6a-6c. Highly diastereoselective photooxygenation delivered the hydroperoxides 7a-7c and subsequent PPTS (pyridinium-p-toluenesulfonic acid)-catalyzed peroxyacetalization with alkyl triorthoacetates gave the cyclic peroxides 8a-8e. These compounds in general show only moderate antimalarial activities. In order to extend the repertoire of cyclic peroxide structure, we aimed for the synthesis of spiro perorthocarbonates from orthoester condensation of beta-hydroxy hydroperoxide 9 but could only realize the monocyclic perorthocarbonate 10. That the central peroxide moiety is the key structural motif in anticancer active GST (glutathione S-transferase)-inhibitors was elucidated by the synthesis of a 1,3-dioxane 15 with a similar substitution pattern as the pharmacologically active peroxide 11 via a singlet oxygen ene route from the homoallylic alcohol 12. PMID- 28085080 TI - Exosomes in Cancer Diagnostics. AB - Exosomes are endosome derived extracellular vesicles of 30-120 nm size ranges. Exosomes have been identified as mediators of cell-to-cell communication by transferring bioactive molecules such as nucleic acids, proteins and lipids into recipient cells. While exosomes are secreted by multiple cell types, cancer derived exosomes not only influence the invasive potentials of proximally located cells, but also affect distantly located tissues. Based on their ability to alter tumor microenvironment by regulating immunity, angiogenesis and metastasis, there has been growing interest in defining the clinical relevance of exosomes in cancers. In particular, exosomes are valuable sources for biomarkers due to selective cargo loading and resemblance to their parental cells. In this review, we summarize the recent findings to utilize exosomes as cancer biomarkers for early detection, diagnosis and therapy selection. PMID- 28085081 TI - On Connectivity of Wireless Sensor Networks with Directional Antennas. AB - In this paper, we investigate the network connectivity of wireless sensor networks with directional antennas. In particular, we establish a general framework to analyze the network connectivity while considering various antenna models and the channel randomness. Since existing directional antenna models have their pros and cons in the accuracy of reflecting realistic antennas and the computational complexity, we propose a new analytical directional antenna model called the iris model to balance the accuracy against the complexity. We conduct extensive simulations to evaluate the analytical framework. Our results show that our proposed analytical model on the network connectivity is accurate, and our iris antenna model can provide a better approximation to realistic directional antennas than other existing antenna models. PMID- 28085083 TI - Morphological Characteristics of Terminalia of the Wasp-Mimicking Fly, Stomorhina discolor (Fabricius). AB - Stomorhina discolor (Fabricius), a species of blow fly that mimics wasps, is distributed worldwide, but detailed information about characteristics of its adult terminalia is incomplete. To help fill this gap in the information, the morphology of adult stages of S. discolor was investigated using light microscopy and scanning electron microscopy. Observations using the light microscope revealed unique characteristics of the male genitalia that are markedly different from other blow fly species. More morphological detail, including observation of several sensilla (e.g., sensilla trichoid and sensilla basiconica) along the male terminalia and female ovipositor, was seen under the scanning electron microscope. These details can be taxonomically valuable for identifying males and females of S. discolor and may help address matters concerning copulation in this species. PMID- 28085084 TI - Efficient DV-HOP Localization for Wireless Cyber-Physical Social Sensing System: A Correntropy-Based Neural Network Learning Scheme. AB - Integrating wireless sensor network (WSN) into the emerging computing paradigm, e.g., cyber-physical social sensing (CPSS), has witnessed a growing interest, and WSN can serve as a social network while receiving more attention from the social computing research field. Then, the localization of sensor nodes has become an essential requirement for many applications over WSN. Meanwhile, the localization information of unknown nodes has strongly affected the performance of WSN. The received signal strength indication (RSSI) as a typical range-based algorithm for positioning sensor nodes in WSN could achieve accurate location with hardware saving, but is sensitive to environmental noises. Moreover, the original distance vector hop (DV-HOP) as an important range-free localization algorithm is simple, inexpensive and not related to the environment factors, but performs poorly when lacking anchor nodes. Motivated by these, various improved DV-HOP schemes with RSSI have been introduced, and we present a new neural network (NN)-based node localization scheme, named RHOP-ELM-RCC, through the use of DV-HOP, RSSI and a regularized correntropy criterion (RCC)-based extreme learning machine (ELM) algorithm (ELM-RCC). Firstly, the proposed scheme employs both RSSI and DV-HOP to evaluate the distances between nodes to enhance the accuracy of distance estimation at a reasonable cost. Then, with the help of ELM featured with a fast learning speed with a good generalization performance and minimal human intervention, a single hidden layer feedforward network (SLFN) on the basis of ELM-RCC is used to implement the optimization task for obtaining the location of unknown nodes. Since the RSSI may be influenced by the environmental noises and may bring estimation error, the RCC instead of the mean square error (MSE) estimation, which is sensitive to noises, is exploited in ELM. Hence, it may make the estimation more robust against outliers. Additionally, the least square estimation (LSE) in ELM is replaced by the half-quadratic optimization technique. Simulation results show that our proposed scheme outperforms other traditional localization schemes. PMID- 28085082 TI - Use of Saliva Biomarkers to Monitor Efficacy of Vitamin C in Exercise-Induced Oxidative Stress. AB - Saliva is easily obtainable for medical research and requires little effort or training for collection. Because saliva contains a variety of biological compounds, including vitamin C, malondialdehyde, amylase, and proteomes, it has been successfully used as a biospecimen for the reflection of health status. A popular topic of discussion in medical research is the potential association between oxidative stress and negative outcomes. Systemic biomarkers that represent oxidative stress can be found in saliva. It is unclear, however, if saliva is an accurate biospecimen as is blood and/or plasma. Exercise can induce oxidative stress, resulting in a trend of antioxidant supplementation to combat its assumed detriments. Vitamin C is a popular antioxidant supplement in the realm of sports and exercise. One potential avenue for evaluating exercise induced oxidative stress is through assessment of biomarkers like vitamin C and malondialdehyde in saliva. At present, limited research has been done in this area. The current state of research involving exercise-induced oxidative stress, salivary biomarkers, and vitamin C supplementation is reviewed in this article. PMID- 28085085 TI - Wearable Sensors for Remote Health Monitoring. AB - Life expectancy in most countries has been increasing continually over the several few decades thanks to significant improvements in medicine, public health, as well as personal and environmental hygiene. However, increased life expectancy combined with falling birth rates are expected to engender a large aging demographic in the near future that would impose significant burdens on the socio-economic structure of these countries. Therefore, it is essential to develop cost-effective, easy-to-use systems for the sake of elderly healthcare and well-being. Remote health monitoring, based on non-invasive and wearable sensors, actuators and modern communication and information technologies offers an efficient and cost-effective solution that allows the elderly to continue to live in their comfortable home environment instead of expensive healthcare facilities. These systems will also allow healthcare personnel to monitor important physiological signs of their patients in real time, assess health conditions and provide feedback from distant facilities. In this paper, we have presented and compared several low-cost and non-invasive health and activity monitoring systems that were reported in recent years. A survey on textile-based sensors that can potentially be used in wearable systems is also presented. Finally, compatibility of several communication technologies as well as future perspectives and research challenges in remote monitoring systems will be discussed. PMID- 28085087 TI - Analysis of Ionospheric Scintillation Characteristics in Sub-Antarctica Region with GNSS Data at Macquarie Island. AB - Ionospheric scintillation has a great impact on radio propagation and electronic system performance, thus is extensively studied currently. The influence of scintillation on Global Navigation Satellite System (GNSS) is particularly evident, making GNSS an effective medium to study characteristics of scintillation. Ionospheric scintillation varies greatly in relation with temporal and spatial distribution. In this paper, both temporal and spatial characteristics of scintillation are investigated based on Macquarie Island's GNSS scintillation data collected from 2011 to 2015. Experiments demonstrate that occurrence rates of amplitude scintillation have a close relationship with solar activity, while phase scintillation is more likely to be generated by geomagnetic activity. In addition, scintillation distribution behaviors related to elevation and azimuth angles are statistically analyzed for both amplitude and phase scintillation. The proposed work is valuable for a deeper understanding of theoretical mechanisms of ionospheric scintillation in this region, and provides a reference for GNSS applications in certain regions around sub-Antarctica. PMID- 28085088 TI - Surface-Enhanced Raman Scattering-Based Immunoassay Technologies for Detection of Disease Biomarkers. AB - Detection of biomarkers is of vital importance in disease detection, management, and monitoring of therapeutic efficacy. Extensive efforts have been devoted to the development of novel diagnostic methods that detect and quantify biomarkers with higher sensitivity and reliability, contributing to better disease diagnosis and prognosis. When it comes to such devastating diseases as cancer, these novel powerful methods allow for disease staging as well as detection of cancer at very early stages. Over the past decade, there have been some advances in the development of platforms for biomarker detection of diseases. The main focus has recently shifted to the development of simple and reliable diagnostic tests that are inexpensive, accurate, and can follow a patient's disease progression and therapy response. The individualized approach in biomarker detection has been also emphasized with detection of multiple biomarkers in body fluids such as blood and urine. This review article covers the developments in Surface-Enhanced Raman Scattering (SERS) and related technologies with the primary focus on immunoassays. Limitations and advantages of the SERS-based immunoassay platform are discussed. The article thoroughly describes all components of the SERS immunoassay and highlights the superior capabilities of SERS readout strategy such as high sensitivity and simultaneous detection of a multitude of biomarkers. Finally, it introduces recently developed strategies for in vivo biomarker detection using SERS. PMID- 28085089 TI - Sex Differences in Neuromuscular Fatigability of the Knee Extensors Post-Stroke. AB - BACKGROUND AND PURPOSE: Despite the implications of optimizing strength training post-stroke, little is known about the differences in fatigability between men and women with chronic stroke. The purpose of this study was to determine the sex differences in knee extensor muscle fatigability and potential mechanisms in individuals with stroke. METHODS: Eighteen participants (10 men, eight women) with chronic stroke (>=6 months) and 23 (12 men, 11 women) nonstroke controls participated in the study. Participants performed an intermittent isometric contraction task (6 s contraction, 3 s rest) at 30% of maximal voluntary contraction (MVC) torque until failure to maintain the target torque. Electromyography was used to determine muscle activation and contractile properties were assessed with electrical stimulation of the quadriceps muscles. RESULTS: Individuals with stroke had a briefer task duration (greater fatigability) than nonstroke individuals (24.1 +/- 17 min vs. 34.9 +/- 16 min). Men were more fatigable than women for both nonstroke controls and individuals with stroke (17.9 +/- 9 min vs. 41.6 +/- 15 min). Individuals with stroke had less fatigue-related changes in muscle contractile properties and women with stroke differed in their muscle activation strategy during the fatiguing contractions. CONCLUSIONS: Men and women fatigue differently post-stroke and this may be due to the way they neurally activate muscle groups. PMID- 28085090 TI - Measurement of the Ecological Integrity of Cerrado Streams Using Biological Metrics and the Index of Habitat Integrity. AB - Generally, aquatic communities reflect the effects of anthropogenic changes such as deforestation or organic pollution. The Cerrado stands among the most threatened ecosystems by human activities in Brazil. In order to evaluate the ecological integrity of the streams in a preserved watershed in the Northern Cerrado biome corresponding to a mosaic of ecosystems in transition to the Amazonia biome in Brazil, biological metrics related to diversity, structure, and sensitivity of aquatic macroinvertebrates were calculated. Sampling included collections along stretches of 200 m of nine streams and measurements of abiotic variables (temperature, electrical conductivity, pH, total dissolved solids, dissolved oxygen, and discharge) and the Index of Habitat Integrity (HII). The values of the abiotic variables and the HII indicated that most of the streams have good ecological integrity, due to high oxygen levels and low concentrations of dissolved solids and electric conductivity. Two streams showed altered HII scores mainly related to small dams for recreational and domestic use, use of Cerrado natural pasture for cattle raising, and spot deforestation in bathing areas. However, this finding is not reflected in the biological metrics that were used. Considering all nine streams, only two showed satisfactory ecological quality (measured by Biological Monitoring Working Party (BMWP), total richness, and EPT (Ephemeroptera, Plecoptera, and Trichoptera) richness), only one of which had a low HII score. These results indicate that punctual measures of abiotic parameters do not reveal the long-term impacts of anthropic activities in these streams, including related fire management of pasture that annually alters the vegetation matrix and may act as a disturbance for the macroinvertebrate communities. Due to this, biomonitoring of low order streams in Cerrado ecosystems of the Northern Central Brazil by different biotic metrics and also physical attributes of the riparian zone such as HII is recommended for the monitoring and control of anthropic impacts on aquatic communities. PMID- 28085091 TI - Knowledge and Attitudes of Dentists with Respect to the Risks of Blood-Borne Pathogens-A Cross-Sectional Study in Poland. AB - Background: To analyze dentists' knowledge of blood-borne infections, their attitudes towards infected patients, and to determine the frequency of the contact with infectious material; Methods: We surveyed 192 dentists using an anonymous questionnaire. Results: Only a quarter of dentists responded correctly to all questions. 96% of the examined dentists confirmed that they were more cautious during treatment of patients with HBV, HCV and HIV. 25% of all respondents refuse to help infected patients due to concerns about their own health. The dentists occasionally removed protective clothing to make it "easier" to perform specific procedures. The dentists experienced contact with infectious material most frequently by splashes onto the conjunctiva or as a result of superficial injuries. The risk of injury by a medical tool increased with the years of employment. Re-capping needles was associated with an increased risk of injury; Conclusions: Despite the widespread tolerance of people infected with blood-borne viruses and the well-proven low infection risk to medical personnel, dentists continue to be prejudiced and concerned about their own health and may refuse to treat infected patients. It may be assumed that the proportion of refusing treatment is even greater. This attitude should imply the implementation of training in the field of pathogen transmission and the real risk of infection. PMID- 28085092 TI - New Synthesis, Structure and Analgesic Properties of Methyl 1-R-4-Methyl-2,2 Dioxo-1H-2lambda6,1-Benzothiazine-3-Carboxylates. AB - According to the principles of the methodology of bioisosteric replacements a series of methyl 1-R-4-methyl-2,2-dioxo-1H-2lambda6,1-benzothiazine-3 carboxylates has been obtained as potential analgesics. In addition, a fundamentally new strategy for the synthesis of compounds of this chemical class involving the introduction of N-alkyl substituent at the final stage in 2,1 benzothiazine nucleus already formed has been proposed. Using nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry and X-ray diffraction analysis it has been proven that in the DMSO/K2CO3 system the reaction of methyl 4-methyl-2,2 dioxo-1H-2lambda6,1-benzothiazine-3-carboxylate and alkyl halides leads to formation of N-substituted derivatives with good yields regardless of the structure of the alkylating agent. The peculiarities of NMR (1N and 13S) spectra of the compounds synthesized, their mass spectrometric behavior and the spatial structure are discussed. In N-benzyl derivative the ability to form a monosolvate with methanol has been found. According to the results of the pharmacological testing conducted on the model of the thermal tail-flick it has been determined that replacement of 4-ON-group in methyl 1-R-4-hydroxy-2,2-dioxo-1H-2lambda6,1 benzothiazine-3-carboxylates for the methyl group is actually bioisosteric since all methyl 1-R-4-methyl-2,2-dioxo-1H-2lambda6,1-benzothiazine-3-carboxylates synthesized demonstrated a statistically significant analgesic effect. The majority of the substances can inhibit the thermal pain response much more effective than piroxicam in the same dose. Under the same conditions as an analgesic the N-methyl-substituted analog exceeds not only piroxicam, but more active meloxicam as well. Therefore, it deserves in-depth biological studies on other experimental models. PMID- 28085095 TI - Erratum: Pan Y. et al. Cucumber Metallothionein-Like 2 (CsMTL2) Exhibits Metal Binding Properties. Genes 2016, 7, 106. AB - n/a. PMID- 28085094 TI - New Immunotherapy Strategies in Breast Cancer. AB - Breast cancer is the most commonly diagnosed cancer among women. Therapeutic treatments for breast cancer generally include surgery, chemotherapy, radiotherapy, endocrinotherapy and molecular targeted therapy. With the development of molecular biology, immunology and pharmacogenomics, immunotherapy becomes a promising new field in breast cancer therapies. In this review, we discussed recent progress in breast cancer immunotherapy, including cancer vaccines, bispecific antibodies, and immune checkpoint inhibitors. Several additional immunotherapy modalities in early stages of development are also highlighted. It is believed that these new immunotherapeutic strategies will ultimately change the current status of breast cancer therapies. PMID- 28085096 TI - Assessment of the Sustainability of the Mediterranean Diet Combined with Organic Food Consumption: An Individual Behaviour Approach. AB - Mediterranean diets are promising sustainable food models and the organic food system may provide health and environmental benefits. Combining the two models could therefore be a favourable approach for food sustainability. The aim of this study was to draw up a comparative description of four diets differing in the level of organic foods consumption and the adherence to the Mediterranean diet, using multidisciplinary indicators to assess the sustainability of these diets. Four groups of participants were defined and compared, combining the proportion of organic food in their diet (Org versus Conv) and the adherence to the Mediterranean diet (Med versus NoMed). Conv-NoMed: Conventional consumers and non Mediterranean diet followers; Conv-Med: Conventional consumers and Mediterranean diet followers; Org-NoMed: Organic consumers and non-Mediterranean diet followers; Org-Med: Organic consumers and Mediterranean diet followers. The adherence to nutritional recommendations was higher among the Org-Med and Conv Med groups compared to the Conv-NoMed group (using the mPNNS-GS (modified Programme National nutrition sante guidelines score/13.5 points): 9.29 (95% confidence intervals (CI) = 9.23-9.36) and 9.30 (95% CI = 9.24-9.35) versus 8.19 (95% CI = 8.17-8.22)) respectively. The mean plant/animal protein intake ratio was 1.38 (95% CI = 1.01-1.74) for the Org-Med group versus 0.44 (95% CI = 0.28 0.60) for the Conv-NoMed group. The average cost of the diet of Org-Med participants was the highest: 11.43 ?/day (95% CI = 11.34-11.52). This study highlighted the importance of promoting the Mediterranean diet combined with organic food consumption for individual health and environmental aspects but challenges with regard to the cost remain. PMID- 28085097 TI - Adaptive Information Dissemination Control to Provide Diffdelay for the Internet of Things. AB - Applications running on the Internet of Things, such as the Wireless Sensor and Actuator Networks (WSANs) platform, generally have different quality of service (QoS) requirements. For urgent events, it is crucial that information be reported to the actuator quickly, and the communication cost is the second factor. However, for interesting events, communication costs, network lifetime and time all become important factors. In most situations, these different requirements cannot be satisfied simultaneously. In this paper, an adaptive communication control based on a differentiated delay (ACCDS) scheme is proposed to resolve this conflict. In an ACCDS, source nodes of events adaptively send various searching actuators routings (SARs) based on the degree of sensitivity to delay while maintaining the network lifetime. For a delay-sensitive event, the source node sends a large number of SARs to actuators to identify and inform the actuators in an extremely short time; thus, action can be taken quickly but at higher communication costs. For delay-insensitive events, the source node sends fewer SARs to reduce communication costs and improve network lifetime. Therefore, an ACCDS can meet the QoS requirements of different events using a differentiated delay framework. Theoretical analysis simulation results indicate that an ACCDS provides delay and communication costs and differentiated services; an ACCDS scheme can reduce the network delay by 11.111%-53.684% for a delay-sensitive event and reduce the communication costs by 5%-22.308% for interesting events, and reduce the network lifetime by about 28.713%. PMID- 28085098 TI - Health Benefits of Urban Allotment Gardening: Improved Physical and Psychological Well-Being and Social Integration. AB - With an ever-increasing urban population, promoting public health and well-being in towns and cities is a major challenge. Previous research has suggested that participating in allotment gardening delivers a wide range of health benefits. However, evidence from quantitative analyses is still scarce. Here, we quantify the effects, if any, of participating in allotment gardening on physical, psychological and social health. A questionnaire survey of 332 people was performed in Tokyo, Japan. We compared five self-reported health outcomes between allotment gardeners and non-gardener controls: perceived general health, subjective health complaints, body mass index (BMI), mental health and social cohesion. Accounting for socio-demographic and lifestyle variables, regression models revealed that allotment gardeners, compared to non-gardeners, reported better perceived general health, subjective health complaints, mental health and social cohesion. BMI did not differ between gardeners and non-gardeners. Neither frequency nor duration of gardening significantly influenced reported health outcomes. Our results highlight that regular gardening on allotment sites is associated with improved physical, psychological and social health. With the recent escalation in the prevalence of chronic diseases, and associated healthcare costs, this study has a major implication for policy, as it suggests that urban allotments have great potential for preventative healthcare. PMID- 28085099 TI - Natural Products and Inflammation. AB - n/a. PMID- 28085100 TI - Effects of Ambient Fine Particles PM2.5 on Human HaCaT Cells. AB - The current study was conducted to observe the effects of fine particulate matter (PM2.5) on human keratinocyte cell line (HaCaT) cells. The potential mechanism linking PM2.5 and skin was explored. HaCaT cells were cultured and then accessed in plate with PM2.5. Cell viability was tested by Cell Counting Kit-8. The mRNA and protein expression of Filaggrin, Loricrin, Involucrin, and Repetin were analyzed. The levels of Granulocyte-macrophage Colony Stimulating Factor, Thymic Stromal Lymphopoietin, Tumor Necrosis Factor-alpha, Interleukin-1alpha, and Interleukin-8 were detected in the supernatant of the HaCaT cell with enzyme linked immunosorbent assay kits. Cell viability decreased with the increase in PM2.5. Compared with the control group, the protein expression of Filaggrin, Repetin, Involucrin, and Loricrin showed different expression patterns in PM2.5 treatment groups. The level of Tumor Necrosis Factor-alpha, Thymic Stromal Lymphopoietin, Interleukin-1alpha, and Interleukin-8 significantly increased in the cells treated with PM2.5. Ambient PM2.5 may increase the risk of eczema and other skin diseases. The relative mechanism may be associated with the impairment of the skin barrier and the elevation of inflammatory responses. PMID- 28085101 TI - Shp2 Inhibits Proliferation of Esophageal Squamous Cell Cancer via Dephosphorylation of Stat3. AB - Shp2 (Src-homology 2 domain-containing phosphatase 2) was originally reported as an oncogene in kinds of solid tumors and hematologic malignancies. However, recent studies indicated that Shp2 may act as tumor suppressors in several tumor types. We investigated the function of Shp2 in esophageal squamous cell cancer (ESCC). The expression level of Shp2 was analyzed in tumor tissues in comparison with adjacent normal tissues of ESCC patients by immunohistochemistry and Western blot. Shp2 was knocked down by Short hairpin RNA to evaluate its function in ESCC cell lines. The relationship between Shp2 and p-Stat3 (signal transducer and activator of transcription 3) in human ESCC tissues was statistically examined. A significant low expression of Shp2 was found in ESCC tissues. Low expression of Shp2 was related to poorer overall survival in patients from The Cancer Genome Atlas (TCGA) dataset. Knockdown of Shp2 increased the growth of ESCC cell lines both in vivo and vitro. Activation of Stat3 (p-Stat3) was induced by Shp2 depletion. Expression of p-Stat3 was negatively correlated with Shp2 expression in ESCC tissues. Furthermore, knockdown of Shp2 attenuated cisplatin-sensitivity of ESCC cells. Shp2 might suppress the proliferation of ESCC by dephosphorylation of p-Stat3 and represents a novel research field for targeted therapy. PMID- 28085102 TI - Impact of Dental Fluorosis, Socioeconomic Status and Self-Perception in Adolescents Exposed to a High Level of Fluoride in Water. AB - Objective: To identify adolescents' self-perception of dental fluorosis from two areas with different socioeconomic levels. Methods: A cross-sectional, descriptive study was conducted with 15-year-old youths by applying a questionnaire designed and validated to assess self-perceptions of dental fluorosis in two areas with different socioeconomic statuses (SESs). Fluorosis was clinically evaluated by applying the Thylstrup and Fejerkov (TF) index on the upper front teeth. Results: A total of 308 adolescents were included in the study. The medium-SES population, which was exposed to 2.5 ppm of fluoride in water, and the low-SES population, which was exposed to 5.1 ppm, presented the following levels of dental fluorosis: TF 2-3 (50%), TF 4-5 (45.6%) and TF 6-7 (4.4%) for medium SES and TF 2-3 (12.3%), TF 4-5 (67.1%) and TF 67 (20.6%) for low SES. A significant association was found between self-perception and dental fluorosis in those with medium and low SESs (p < 0.05). The multiple regression model found differences between TF levels and self-perception, with a 6-7 TF level for concerns about color (OR = 1.6), smile (OR = 1.2) and appearance (OR = 3.36). Conclusions: Self-perceptions of dental fluorosis affect adolescents such that adolescents with a medium SES have more negative perceptions than those with a low SES. Such perceptions increase as the TF index increases. PMID- 28085103 TI - A Cytotoxic and Anti-inflammatory Campesterol Derivative from Genetically Transformed Hairy Roots of Lopezia racemosa Cav. (Onagraceae). AB - The genetically transformed hairy root line LRT 7.31 obtained by infecting leaf explants of Lopezia racemosa Cav with the Agrobacterium rhizogenes strain ATCC15834/pTDT, was evaluated to identify the anti-inflammatory and cytotoxic compounds reported previously for the wild plant. After several subcultures of the LRT 7.31 line, the bio-guided fractionation of the dichloromethane-methanol (1:1) extract obtained from dry biomass afforded a fraction that showed important in vivo anti-inflammatory, and in vitro cytotoxic activities. Chemical separation of the active fraction allowed us to identify the triterpenes ursolic (1) and oleanolic (2) acids, and (23R)-2alpha,3beta,23,28-tetrahydroxy-14,15 dehydrocampesterol (3) as the anti-inflammatory principles of the active fraction. A new molecule 3 was characterized by spectroscopic analysis of its tetraacetate derivative 3a. This compound was not described in previous reports of callus cultures, in vitro germinated seedlings and wild plant extracts of whole L. racemosa plants. The anti-inflammatory and cytotoxic activities displayed by the fraction are associated to the presence of compounds 1-3. The present study reports the obtaining of the transformed hairy roots, the bioguided isolation of the new molecule 3, and its structure characterization. PMID- 28085104 TI - Mercury Exposure and Heart Diseases. AB - Environmental contamination has exposed humans to various metal agents, including mercury. It has been determined that mercury is not only harmful to the health of vulnerable populations such as pregnant women and children, but is also toxic to ordinary adults in various ways. For many years, mercury was used in a wide variety of human activities. Nowadays, the exposure to this metal from both natural and artificial sources is significantly increasing. Recent studies suggest that chronic exposure, even to low concentration levels of mercury, can cause cardiovascular, reproductive, and developmental toxicity, neurotoxicity, nephrotoxicity, immunotoxicity, and carcinogenicity. Possible biological effects of mercury, including the relationship between mercury toxicity and diseases of the cardiovascular system, such as hypertension, coronary heart disease, and myocardial infarction, are being studied. As heart rhythm and function are under autonomic nervous system control, it has been hypothesized that the neurotoxic effects of mercury might also impact cardiac autonomic function. Mercury exposure could have a long-lasting effect on cardiac parasympathetic activity and some evidence has shown that mercury exposure might affect heart rate variability, particularly early exposures in children. The mechanism by which mercury produces toxic effects on the cardiovascular system is not fully elucidated, but this mechanism is believed to involve an increase in oxidative stress. The exposure to mercury increases the production of free radicals, potentially because of the role of mercury in the Fenton reaction and a reduction in the activity of antioxidant enzymes, such as glutathione peroxidase. In this review we report an overview on the toxicity of mercury and focus our attention on the toxic effects on the cardiovascular system. PMID- 28085106 TI - Effective Detection of Porcine Cytomegalovirus Using Non-Invasively Taken Samples from Piglets. AB - Shortage of human organs forced the development of xenotransplantation using cells, tissues, and organs from pigs. Xenotransplantation may be associated with the transmission of porcine zoonotic microorganisms, among them the porcine cytomegalovirus (PCMV). To prevent virus transmission, pigs have to be screened using sensitive methods. In order to perform regular follow-ups and further breeding of the animals, samples for testing should be collected by low-invasive or non-invasive methods. Sera, ear biopsies, as well as oral and anal swabs were collected from ten 10-day-old Aachen minipigs (AaMP) and tested for PCMV using sensitive nested polymerase chain reaction (PCR) as well as uniplex and duplex real-time PCR. Porcine cytomegalovirus DNA was detected most frequently in oral and anal swabs. Comparison of duplex and uniplex real-time PCR systems for PCMV detection demonstrated a lower sensitivity of duplex real-time PCR when the copy numbers of the target genes were low (less 200). Therefore, to increase the efficacy of PCMV detection in piglets, early testing of oral and anal swabs by uniplex real-time PCR is recommended. PMID- 28085105 TI - Demographic and Substance Use Factors Associated with Non-Violent Alcohol-Related Injuries among Patrons of Australian Night-Time Entertainment Districts. AB - This study examined the relationship between patron demographics, substance use, and experience of recent alcohol-related accidents and injuries that were not due to interpersonal violence in night-time entertainment districts. Cross-sectional interviews (n = 4016) were conducted around licensed venues in entertainment districts of five Australian cities. Demographic factors associated with non violent alcohol-related injuries were examined, including gender, age, and occupation. The association between substance use on the night of interview; blood alcohol concentration (BAC), pre-drinking, energy drink consumption, and illicit drug use; and experience of injury was also explored. Thirteen percent of participants reported an alcohol-related injury within the past three months. Respondents aged younger than 25 years were significantly more likely to report an alcohol-related injury. Further, a significant occupation effect was found indicating the rate of alcohol-related injury was lower in managers/professionals compared to non-office workers. The likelihood of prior alcohol-related injury significantly increased with BAC, and self-reported pre-drinking, energy drink, or illicit drug consumption on the night of interview. These findings provide an indication of the demographic and substance use-related associations with alcohol related injuries and, therefore, potential avenues of population-level policy intervention. Policy responses to alcohol-related harm must also account for an assessment and costing of non-violent injuries. PMID- 28085107 TI - A Low Power Low Phase Noise Oscillator for MICS Transceivers. AB - A low-power, low-phase-noise quadrature oscillator for Medical Implantable Communications Service (MICS) transceivers is presented. The proposed quadrature oscillator generates 349~689 MHz I/Q (In-phase and Quadrature) signals covering the MICS band. The oscillator is based on a differential pair with positive feedback. Each delay cell consists of a few transistors enabling lower voltage operation. Since the oscillator is very sensitive to disturbances in the supply voltage and ground, a self-bias circuit for isolating the voltage disturbance is proposed to achieve bias voltages which can track the disturbances from the supply and ground. The oscillation frequency, which is controlled by the bias voltages, is less sensitive to the supply and ground noise, and a low phase noise is achieved. The chip is fabricated in the UMC (United Microelectronics Corporation) 0.18 MUm CMOS (Complementary Metal Oxide Semiconductor) process; the core just occupies a 28.5 * 22 MUm2 area. The measured phase noise is -108.45 dBc/Hz at a 1 MHz offset with a center frequency of 540 MHz. The gain of the oscillator is 0.309 MHz/mV with a control voltage from 0 V to 1.1 V. The circuit can work with a supply voltage as low as 1.2 V and the power consumption is only 0.46 mW at a 1.8 V supply voltage. PMID- 28085109 TI - A Mechanism for Reliable Mobility Management for Internet of Things Using CoAP. AB - Under unreliable constrained wireless networks for Internet of Things (IoT) environments, the loss of the signaling message may frequently occur. Mobile Internet Protocol version 6 (MIPv6) and its variants do not consider this situation. Consequently, as a constrained device moves around different wireless networks, its Internet Protocol (IP) connectivity may be frequently disrupted and power can be drained rapidly. This can result in the loss of important sensing data or a large delay for time-critical IoT services such as healthcare monitoring and disaster management. This paper presents a reliable mobility management mechanism in Internet of Things environments with lossy low-power constrained device and network characteristics. The idea is to use the Internet Engineering Task Force (IETF) Constrained Application Protocol (CoAP) retransmission mechanism to achieve both reliability and simplicity for reliable IoT mobility management. Detailed architecture, algorithms, and message extensions for reliable mobility management are presented. Finally, performance is evaluated using both mathematical analysis and simulation. PMID- 28085108 TI - Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions. AB - Dopamine-glutamate interplay dysfunctions have been suggested as pathophysiological key determinants of major psychotic disorders, above all schizophrenia and mood disorders. For the most part, synaptic interactions between dopamine and glutamate signaling pathways take part in the postsynaptic density, a specialized ultrastructure localized under the membrane of glutamatergic excitatory synapses. Multiple proteins, with the role of adaptors, regulators, effectors, and scaffolds compose the postsynaptic density network. They form structural and functional crossroads where multiple signals, starting at membrane receptors, are received, elaborated, integrated, and routed to appropriate nuclear targets. Moreover, transductional pathways belonging to different receptors may be functionally interconnected through postsynaptic density molecules. Several studies have demonstrated that psychopharmacologic drugs may differentially affect the expression and function of postsynaptic genes and proteins, depending upon the peculiar receptor profile of each compound. Thus, through postsynaptic network modulation, these drugs may induce dopamine glutamate synaptic remodeling, which is at the basis of their long-term physiologic effects. In this review, we will discuss the role of postsynaptic proteins in dopamine-glutamate signals integration, as well as the peculiar impact of different psychotropic drugs used in clinical practice on postsynaptic remodeling, thereby trying to point out the possible future molecular targets of "synapse-based" psychiatric therapeutic strategies. PMID- 28085110 TI - Ginsenoside Rg3 Improves Recovery from Spinal Cord Injury in Rats via Suppression of Neuronal Apoptosis, Pro-Inflammatory Mediators, and Microglial Activation. AB - Spinal cord injury (SCI) is one of the most devastating medical conditions; however, currently, there are no effective pharmacological interventions for SCI. Ginsenoside Rg3 (GRg3) is one of the protopanaxadiols that show anti inflammatory, anti-oxidant, and neuroprotective effects. The present study investigated the neuroprotective effect of GRg3 following SCI in rats. SCI was induced using a static compression model at vertebral thoracic level 10 for 5 min. GRg3 was administrated orally at a dose of 10 or 30 mg/kg/day for 14 days after the SCI. GRg3 (30 mg/kg) treatment markedly improved behavioral motor functions, restored lesion size, preserved motor neurons in the spinal tissue, reduced Bax expression and number of TUNEL-positive cells, and suppressed mRNA expression of pro-inflammatory cytokines including tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6. GRg3 also attenuated the over-production of cyclooxygenase-2 and inducible nitric oxide synthase after SCI. Moreover, GRg3 markedly suppressed microglial activation in the spinal tissue. In conclusion, GRg3 treatment led to a remarkable recovery of motor function and a reduction in spinal tissue damage by suppressing neuronal apoptosis and inflammatory responses after SCI. These results suggest that GRg3 may be a potential therapeutic agent for the treatment of SCI. PMID- 28085111 TI - NHERF1 Enhances Cisplatin Sensitivity in Human Cervical Cancer Cells. AB - Cervical cancer is one of the most common female malignancies, and cisplatin based chemotherapy is routinely utilized in locally advanced cervical cancer patients. However, resistance has been the major limitation. In this study, we found that Na+/H+ Exchanger Regulatory Factor 1 (NHERF1) was downregulated in cisplatin-resistant cells. Analysis based on a cervical cancer dataset from The Cancer Genome Atlas (TCGA) showed association of NHERF1 expression with disease free survival of patients received cisplatin treatment. NHERF1 overexpression inhibited proliferation and enhanced apoptosis in cisplatin-resistant HeLa cells, whereas NHERF1 knockdown had inverse effects. While parental HeLa cells were more resistant to cisplatin after NHERF1 knockdown, NHERF1 overexpression in CaSki cells promoted cisplatin sensitivity. Overexpression and knockdown studies also showed that NHERF1 significantly inhibited AKT and extracellular signal-regulated kinase (ERK) signaling pathways in cisplatin-resistant cells. Taken together, our results provide the first evidence that NHERF1 can sensitize cisplatin-refractory cervical cancer cells. This study may help to increase understanding of the molecular mechanisms underlying cisplatin resistance in tumors. PMID- 28085112 TI - Deep Eutectic Solvents as Novel and Effective Extraction Media for Quantitative Determination of Ochratoxin A in Wheat and Derived Products. AB - An unprecedented, environmentally friendly, and faster method for the determination of Ochratoxin A (OTA) (a mycotoxin produced by several species of Aspergillus and Penicillium and largely widespread in nature, in wheat and derived products) has, for the first time, been set up and validated using choline chloride (ChCl)-based deep eutectic solvents (DESs) (e.g., ChCl/glycerol (1:2) and ChCl/ urea (1:2) up to 40% (w/w) water) as privileged, green, and biodegradable extraction solvents. This also reduces worker exposure to toxic chemicals. Results are comparable to those obtained using conventional, hazardous and volatile organic solvents (VOCs) typical of the standard and official methods. OTA recovery from spiked durum wheat samples, in particular, was to up to 89% versus 93% using the traditional acetonitrile-water mixture with a repeatability of the results (RSDr) of 7%. Compatibility of the DES mixture with the antibodies of the immunoaffinity column was excellent as it was able to retain up to 96% of the OTA. Recovery and repeatability for durum wheat, bread crumbs, and biscuits proved to be within the specifications required by the current European Commission (EC) regulation. Good results in terms of accuracy and precision were achieved with mean recoveries between 70% (durum wheat) and 88% (bread crumbs) and an RSDr between 2% (biscuits) and 7% (bread). PMID- 28085113 TI - Comprehensive Quantitative Analysis of 32 Chemical Ingredients of a Chinese Patented Drug Sanhuang Tablet. AB - Sanhuang Tablet (SHT) is a Chinese patented drug commonly used for the treatment of inflammations of the respiratory tract, gastrointestinal tract, and skin. It contains a special medicinal composition including the single compound berberine hydrochloride, extracts of Scutellariae Radix and Rhei Radix et Rhizoma, as well as the powder of Rhei Radix et Rhizoma. Despite advances in analytical techniques, quantitative evaluation of a Chinese patented drug like SHT remains a challenge due to the complexity of its chemical profile. In this study, ultra high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was used to simultaneously quantify 29 non sugar small molecule components of SHT (11 flavonoids, two isoflavonoids, one flavanone, five anthraquinones, two dianthranones, five alkaloids, two organic acids and one stilbene). Three major saccharide components, namely fructose, glucose, and sucrose, were also quantitatively determined using high performance liquid chromatography-charged aerosol detector (HPLC-CAD) on an Asahipak NH2P-50 4E amino column. The established methods were validated in terms of linearity, sensitivity, precision, accuracy, and stability, and then successfully applied to analyze 27 batches of commercial SHT products. A total of up to 57.61% (w/w) of SHT could be quantified, in which the contents of the determined non-saccharide small molecules varied from 5.91% to 16.83% (w/w) and three saccharides accounted for 4.41% to 48.05% (w/w). The results showed that the quality of the commercial products was inconsistent, and only four of those met Chinese Pharmacopoeia criteria. PMID- 28085114 TI - Hydrostatic Pressure Regulates MicroRNA Expression Levels in Osteoarthritic Chondrocyte Cultures via the Wnt/beta-Catenin Pathway. AB - Mechanical loading and hydrostatic pressure (HP) regulate chondrocytes' metabolism; however, how mechanical stimulation acts remain unclear. MicroRNAs (miRNAs) play an important role in cartilage homeostasis, mechanotransduction, and in the pathogenesis of osteoarthritis (OA). This study investigated the effects of a cyclic HP (1-5 MPa), in both normal and OA human chondrocytes, on the expression of miR-27a/b, miR-140, miR-146a/b, and miR-365, and of their target genes (MMP-13, ADAMTS-5, IGFBP-5, and HDAC-4). Furthermore, we assessed the possible involvement of Wnt/beta-catenin pathway in response to HP. Chondrocytes were exposed to HP for 3h and the evaluations were performed immediately after pressurization, and following 12, 24, and 48 h. Total RNA was extracted and used for real-time PCR. beta-catenin was detected by Western blotting analysis and immunofluorescence. In OA chondrocytes, HP induced a significant increase (p < 0.01) of the expression levels of miR-27a/b, miR-140, and miR-146a, and a significant reduction (p < 0.01) of miR-365 at all analyzed time points. MMP-13, ADAMTS-5, and HDAC-4 were significantly downregulated following HP, while no significant modification was found for IGFBP-5. beta catenin levels were significantly increased (p < 0.001) in OA chondrocytes at basal conditions and significantly reduced (p < 0.01) by HP. Pressurization did not cause any significant modification in normal cells. In conclusion, in OA chondrocytes, HP restores the expression levels of some miRNAs, downregulates MMP 13, ADAMTS-5, and HDAC-4, and modulates the Wnt/beta-catenin pathway activation. PMID- 28085115 TI - Icaritin Reduces Oral Squamous Cell Carcinoma Progression via the Inhibition of STAT3 Signaling. AB - Icaritin, a traditional Chinese medicine, possesses antitumor activity. The current study aimed to investigate icaritin effect and potential mechanism on oral squamous cell carcinoma (OSCC) development. OSCC cells proliferation, apoptosis, and autophagy were analyzed after incubation with icaritin at different concentrations and incubation times. The expressions of proteins related to proliferation, apoptosis, and autophagy, as well as signal transducer and activator of transcription 3 (STAT3) signal network, were also evaluated by western blot. Furthermore, STAT3 was knocked down by siRNA transfection to determine STAT3 role in OSCC cell proliferation and apoptosis. An oral specific carcinogenesis mouse model was used to explore icaritin effect on OSCC in vivo. Icaritin significantly inhibited OSCC proliferation in vitro and reduced the expression of both the cell-cycle progression proteins cyclin A2 and cyclin D1. Besides, icaritin increased cleaved caspase 3 and cleaved poly-(ADP-ribose) polymerase expression leading to apoptosis, and it activated autophagy. Icaritin significantly inhibited the expression of phospho-STAT3 (p-STAT3) in a dose- and time-dependent manner. In the in vivo experiment, the number of malignant tumors in the icaritin-treated group was significantly lower than the control. Overall, icaritin suppressed proliferation, promoted apoptosis and autophagy, and inhibited STAT3 signaling in OSCC in vitro and in vivo. In conclusion, icaritin might be a potential therapeutic agent against OSCC development. PMID- 28085116 TI - Multiple Activities of Punica granatum Linne against Acne Vulgaris. AB - Acne is a common skin condition with sebum overproduction, hyperkeratosis, Propionibacterium acnes (P. acnes) and Staphylococcus aureus, and inflammation. Punica granatum (pomegranate) is well-known for its anti-inflammatory effects; however, few studies have discussed the anti-acne effects of pomegranate. In this study, we found that pomegranate extract (PG-E) significantly reduced P. acnes induced edema in Wistar rat ears. Therefore, an evaluation platform using multiple pathogenic mechanisms of acne was established to explore the anti-acne effects of pomegranate. Results showed that PG-E inhibited bacterial growth and lipase activity. Through a bioguided-fractionation-isolation system, four hydrolysable tannins, punicalagin (1), punicalin (2), strictinin A (3), and granatin B (4), were isolated. Compounds 1 and 2 had greater anti-bacterial activities and anti-testosterone-induced HaCaT proliferative effects than the others. Compounds 1, 3, and 4 displayed lipase inhibitory effects. Compound 4 decreased cyclooxygenase-2 expression and downregulated prostaglandin E2 production in heat-killed P. acnes-treated RAW 246.7 cells. In conclusion, PG-E is abundant in hydrolysable tannins that display multiple anti-acne capacities, including anti-bacterial, anti-lipase, anti-keratinocyte proliferation, and anti inflammatory actions. Hence, PG-E has great potential in the application of anti acne and skin-care products, and punicalagin (1), the most effective component in PG-E, can be employed as a quality control marker. PMID- 28085117 TI - Enantioselective Effects of Metalaxyl Enantiomers on Breast Cancer Cells Metabolic Profiling Using HPLC-QTOF-Based Metabolomics. AB - In this study, an integrative high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (HPLC-QTOF) based metabolomics approach was performed to evaluate the enantioselective metabolic perturbations in MCF-7 cells after treatment with R-metalaxyl and S-metalaxyl, respectively. Untargeted metabolomics profile, multivariate pattern recognition, metabolites identification, and pathway analysis were determined after metalaxyl enantiomer exposure. Principal component analysis (PCA) and partitial least-squares discriminant analysis (PLS-DA) directly reflected the enantioselective metabolic perturbations induced by metalaxyl enantiomers. On the basis of multivariate statistical results, a total of 49 metabolites including carbohydrates, amino acids, nucleotides, fatty acids, organic acids, phospholipids, indoles, derivatives, etc. were found to be the most significantly changed metabolites and metabolic fluctuations caused by the same concentration of R-metalaxyl and S metalaxyl were enantioselective. Pathway analysis indicated that R-metalaxyl and S-metalaxyl mainly affected the 7 and 10 pathways in MCF-7 cells, respectively, implying the perturbed pathways induced by metalaxyl enantiomers were also enantioselective. Furthermore, the significantly perturbed metabolic pathways were highly related to energy metabolism, amino acid metabolism, lipid metabolism, and antioxidant defense. Such results provide more specific insights into the enantioselective metabolic effects of chiral pesticides in breast cancer progression, reveal the underlying mechanisms, and provide available data for the health risk assessments of chiral environmental pollutants at the molecular level. PMID- 28085119 TI - Transgenic Tobacco Expressing the TAT-Helicokinin I-CpTI Fusion Protein Show Increased Resistance and Toxicity to Helicoverpa armigera (Lepidoptera: Noctuidae). AB - Insect kinins were shown to have diuretic activity, inhibit weight gain, and have antifeedant activity in insects. In order to study the potential of the TAT fusion approach to deliver diuretic peptides per os to pest insects, the HezK I peptide from Helicoverpa zea, as a representative of the kinin family, was selected. The fusion gene TAT-HezK I was designed and was used to transform tobacco plants. As a means to further improve the stability of TAT-HezK I, a fusion protein incorporating HezK I, transactivator of transcription (TAT), and the cowpea trypsin inhibitor (CpTI) was also designed. Finally, the toxicity of the different tobacco transgenic strains toward Helicoverpa armigera was compared. The results demonstrated that TAT-HezK I had high toxicity against insects via transgenic expression of the peptide in planta and intake through larval feeding. The toxicity of the fusion TAT-HezK I and CpTI was higher than the CpTI single gene in transgenic tobacco, and the fusion TAT-HezK I and CpTI further enhanced the stability and bioavailability of agents in oral administration. Our research helps in targeting new genes for improving herbivore tolerance in transgenic plant breeding. PMID- 28085118 TI - Ribosomal Proteins Control or Bypass p53 during Nucleolar Stress. AB - The nucleolus is the site of ribosome biogenesis, a complex process that requires the coordinate activity of all three RNA polymerases and hundreds of non ribosomal factors that participate in the maturation of ribosomal RNA (rRNA) and assembly of small and large subunits. Nevertheless, emerging studies have highlighted the fundamental role of the nucleolus in sensing a variety of cellular stress stimuli that target ribosome biogenesis. This condition is known as nucleolar stress and triggers several response pathways to maintain cell homeostasis, either p53-dependent or p53-independent. The mouse double minute (MDM2)-p53 stress signaling pathways are activated by multiple signals and are among the most important regulators of cellular homeostasis. In this review, we will focus on the role of ribosomal proteins in p53-dependent and p53-independent response to nucleolar stress considering novel identified regulators of these pathways. We describe, in particular, the role of ribosomal protein uL3 (rpL3) in p53-independent nucleolar stress signaling pathways. PMID- 28085121 TI - Maximalist vs. minimalist shoes: dose-effect response of elastic compression on muscular oscillations. AB - BACKGROUND: The aim of this study was to establish whether maximalist shoes engender fewer muscular oscillations than minimalist shoes and determine to what extent these shoes, when combined with elastic compression (EC), help reduce muscle oscillations. For that purpose, we tested the effects of various levels of compression on the muscular oscillations in maximalist and minimalist footwear. METHODS: Eleven volunteers executed 16 one-minute passages on a flat treadmill in a randomized order: maximalists or minimalists, walking (6 km/h) or running (10 km/h), without EC (control condition [CON]) or with EC applying different pressures (9.6 mmHg, 14.5 mmHg and 20.4 mmHg). The muscular oscillations were measured on both thighs, on the rectus femoris and on the vastus medialis with tri-axial accelerometers. RESULTS: Muscular oscillations are lower in maximalist shoes than in minimalist shoes, for both walking to 6 km/h and running to 10 km/h (P<0.05). Oscillations are also reduced with EC (P<0.05). This decrease is most marked when the pressure exercised by the EC is increased. CONCLUSIONS: Increased compression with minimalist shoes reduces muscular oscillations as much as maximalist shoes, when combined with lower compression. PMID- 28085122 TI - Effect of 7-minute workout on weight and body composition. AB - BACKGROUND: The 7-minute workout composed of aerobic and resistance exercises is becoming a very popular workout. It targets individuals with time constrains and low motivation to commit to lengthy and extensive workout programs. The objective of the study is to investigate if the 7-minute workout has a 6 week effect on body weight and composition. METHODS: The training group (N.=29, age 18-30) did the 7-minute workout 7 days a week during 6 weeks while the control group (N.=29) did not perform the workout. Measurements such as height, weight, body mass index, circumferences (middle upper arm, hip, and waist), blood pressure, heart rate, hand grip, and bioelectrical impedance were collected and recorded at week 1, 3 and 6. RESULTS: Mean BMI was 24.4kg/m2 at week 1, 24.01kg/m2 at week 3 (P=0.003). Waist circumference decreased between week 1 and 3 (P=0.003) and week 6 (P=0.01) by 4 cm on average. Hip circumference followed the same trend between week 1 and week 3 (P=-0.001). There was a decrease in fat mass and % fat mass between week 1, 3, and 6 (P=0.001). No changes were noted for mid-upper arm circumference or hand grip. CONCLUSIONS: The findings of this research show that even a very short duration workout affect the nutritional status in normal weight individuals who did not change any of their eating habits. This implies that even in normal weight individuals who perform the 7-minute workout, improvement through a decrease in waist circumference can be achieved thus leading to a better cardio-protective nutritional status. The 7 minutes workout can be a great solution for people to get started and to plan on continuing exercising, as it is simple and of minimal constraints. PMID- 28085123 TI - Rates and risk factors of injury in CrossFitTM: a prospective cohort study. AB - BACKGROUND: CrossFitTM is a strength and conditioning program that has gained widespread popularity since its inception approximately 15 years ago. However, at present little is known about the level of injury risk associated with this form of training. Movement competency, assessed using the Functional Movement ScreenTM (FMS), has been identified as a risk factor for injury in numerous athletic populations, but its role in CrossFit participants is currently unclear. The aim of this study was to evaluate the level of injury risk associated with CrossFit training, and examine the influence of a number of potential risk factors (including movement competency). METHODS: A cohort of 117 CrossFit participants were followed prospectively for 12 weeks. Participants' characteristics, previous injury history and training experience were recorded at baseline, and an FMS assessment was conducted. RESULTS: The overall injury incidence rate was 2.10 per 1000 training hours (90% confidence limits: 1.32-3.33). A multivariate Poisson regression model identified males (rate ratio [RR]: 4.44 *// 3.30, very likely harmful) and those with previous injuries (RR: 2.35 *// 2.37, likely harmful) as having a higher injury risk. Inferences relating to FMS variables were unclear in the multivariate model, although number of asymmetries was a clear risk factor in a univariate model (RR per two additional asymmetries: 2.62 *// 1.53, likely harmful). CONCLUSIONS: The injury incidence rate associated with CrossFit training was low, and comparable to other forms of recreational fitness activities. Previous injury and gender were identified as risk factors for injury, whilst the role of movement competency in this setting warrants further investigation. PMID- 28085120 TI - Astrovirus Diagnostics. AB - Various methods exist to detect an astrovirus infection. Current methods include electron microscopy (EM), cell culture, immunoassays, polymerase chain reaction (PCR) and various other molecular approaches that can be applied in the context of diagnostic or in surveillance studies. With the advent of metagenomics, novel human astrovirus (HAstV) strains have been found in immunocompromised individuals in association with central nervous system (CNS) infections. This work reviews the past and current methods for astrovirus detection and their uses in both research laboratories and for medical diagnostic purposes. PMID- 28085124 TI - Remnant preservation in anterior cruciate ligament reconstruction versus standard techniques: a meta-analysis of randomized controlled trials. AB - INTRODUCTION: Preserving the remnant during anterior cruciate ligament (ACL) reconstruction is considered beneficial for graft healing, but it might increase the technical difficulties and complications. This study was to compare outcomes of using the technique of remnant preservation during the ACL reconstruction versus the standard procedure with the debridement of remnant. EVIDENCE ACQUISITION: We searched PubMed and EMBASE and the Cochrane Library for randomized controlled trials comparing the outcomes of ACL reconstruction both with and without remnant preservation. The risk of bias was assessed in accordance with the Cochrane Collaboration's risk of bias tool. Meta-analysis was performed to compare results. EVIDENCE SYNTHESIS: Six randomized controlled trials with 346 patients were included. Statistically significant differences in favor of using technique of remnant preservation were observed for Lysholm Score, arthrometer measurements, and tibial tunnel enlargement. There was no significant difference between remnant technique of preservation and the standard procedure with respect to the IKDC (International Knee Documentation Committee) grade, IKDC score, Lachman Test, Pivot-shift Test, range of motion (ROM), and the incidence of the cyclops lesion. CONCLUSIONS: This meta-analysis of randomized controlled trials showed that ACL reconstruction with technique of remnant preservation cannot provide superior clinical outcomes compared with the standard procedure. PMID- 28085125 TI - Evaluation of hydration status by urine, body mass variation and plasma parameters during an official half-marathon. AB - BACKGROUND: The aim of this study was to verify the agreement of urine, body mass variations and plasma parameters to determine the hydration status of 14 male runners (29+/-4 years and 54.3+/-5.5 mLO2/kg/min) in an official 21.1 km road race. METHODS: The mean dry-bulb temperature and air relative humidity during the road race were 25.1+/-2.1 degrees C and 54.7+/-2.2%, respectively. The volume of water ingested by the runners was monitored using marked volumetric plastic bottles provided at the hydration stations located at 0, 2.5, 5.0, 7.5, 10.5, 14.0, 16.0 and 18.5 km from the starting line. Hydration status was assessed using urine specific gravity (USG), urine osmolality (UOSM) and plasma osmolality (POSM). Furthermore, body mass variation (?BM) was assessed by comparing body mass (BM) immediately prior and after the race. Total sweat was estimated by ?BM, added water volume ingested and deducted blood volume collected. The sweat rate was calculated through total sweat and total exercise time. RESULTS: The mean water intake was 0.82+/-0.40 L, and the mean sweat rate and total sweating were 1440.11+/-182.13 mL/h and 2.67+/-0.23 L. After the race, the BM reduced by 1.7+/ 0.4 kg. The ?BM was -2.41+/-0.47%, and the plasma volume variation was -9.79+/ 4.6% between pre- and post-running measurements. Despite the POSM increased post race compared to pre-race, the UOSM and USG did not change. No significant correlations were found between POSM variation with UOSM variation (r=-0.08; P=0.71), USG variation (r=-0.11; P=0.78) or ?BM (r=0.09; P=0.77). CONCLUSIONS: In conclusion, this study shows that both ?BM and ?POSM indicated a hypohydration state after exercise even though the ?BM did not correlate significantly with ?POSM. These results demonstrate that ?BM is a practical method and can be sufficiently sensitive to evaluate the hydration state, but it should be utilized with caution. PMID- 28085126 TI - The effect of acute fatigue on countermovement jump performance in rugby union players during preseason. AB - BACKGROUND: A countermovement jump (CMJ) is routinely used in many sporting settings to provide a functional measure of neuromuscular fatigue. However, the variables that are most sensitive to fatigue remain somewhat unclear. The purpose of this study was to determine the acute changes in neuromuscular fatigue in rugby union players during a period of preseason training. METHODS: Nine male (age: 19.0+/-1.5 years) academy rugby union players performed five CMJ trials on three occasions, at baseline, 24 hours and 48 hours postbaseline. The fatiguing protocol consisted of multiple high-intensity training sessions commensurate with the period of preparation and the sport. A total of 14 CMJ variables were derived from the force-time curve. Meaningful differences in CMJ performance were examined using the magnitude of change (effect sizes; ES) compared to baseline. RESULTS: Most variables, 9 of the 14, showed substantial decreases at 24 hours postbaseline. Mean concentric power, peak velocity, jump height and force at zero velocity were impaired by the greatest magnitude (ES=-0.98 to -1.57). At 48 hours postbaseline, substantial increases in eccentric duration, concentric duration and total duration were first observed (ES=0.48 to 0.61). Concomitantly, peak power, peak velocity and jump height, recovered to baseline levels. CONCLUSIONS: During the late regeneration phase, neuromuscular fatigue can manifest itself as an altered movement strategy, rather than as a simple reduction in physical output such as jump height. Practitioners are therefore advised to incorporate a wide range of variables when trying to identify subtle changes in the bimodal recovery pattern associated with stretch-shortening cycle induced fatigue. PMID- 28085127 TI - High-intensity interval training and athletic performance in Taekwondo athletes. AB - BACKGROUND: The purpose of this study was to determine the effects of high intensity interval training (HIIT) on athletic performance in Taekwondo athletes. METHODS: Thirty-three male and female collegiate Taekwondo athletes were randomly divided into a HIIT group (N.=16) or a high-intensity continuous running (HICR) group (N.=17). The HIIT group undertook training of high-intensity sprints interspersed with active rest periods whilst the HICR group participated in high intensity running for a continuous period. Both groups completed 11 sessions over 4 weeks. Physique, body composition, Wingate anaerobic test and VO2max test were measured. The vertical jump test, agility T-test and sit-ups were used to assess physical fitness. Repeated measures ANCOVAs with sex as a covariate were applied and significant level was set at 0.05. RESULTS: Following 11 sessions of training, significant improvements in anaerobic peak power (P<0.05), relative peak power (P<0.05), and mean power (P<0.05) were observed only in HIIT group compared to HICR group. A greater improvement of aerobic capacity was observed in HIIT group (8.8%) compared to the HICR group (1.7%). In relation to physical fitness, the HIIT group improved in the vertical jump while the HICR group did not change. Both the HIIT and HICR groups showed greater improvements in T-test and sit-ups during the intervention period. CONCLUSIONS: This study shows the effectiveness of eleven sessions of HIIT in producing significant improvements in anaerobic capacity relevant to successful Taekwondo competition performance in collegiate Taekwondo athletes. This could inform the future planning of Taekwondo athletes' pre-competition training, specifically the influence of training intensity on anaerobic capacity. PMID- 28085128 TI - Shuttle swimming test in young water polo players: reliability, responsiveness and age-related value. AB - BACKGROUND: This study investigated the applicability of a sport-specific test, the Shuttle Swim Test, in young water polo players to measure RSA. The aims were: to assess the reliability and to measure the responsiveness of the SST in young water polo athletes, and to provide age-related values of SST. METHODS: Three hundred thirty-three elite athletes (18.3+/-5.1 years) were involved in the study. Of these, 99 were young people under 13 (13.1+/-0.5 years) who also underwent measurements for reliability and responsiveness of the SST The following six measures was used to assess anthropometric characteristics of the sample: height, weight, chest circumference, hip circumference, waist circumference, and arm span. Two performance measures were performed on dry land: push up and chin up. RESULTS: Reliability and responsiveness were measured by comparing the average speed of two trials: SST1 was 1.48+/-0.13 m.s-1 and SST2 1.47+/-.12 m.s-1. The SST showed good reliability in younger athletes (r=0.96). The Minimal Detectable Change is 0.06 m.s-1 (6 seconds of the total time) which corresponds to 3.6% of the average value measured, confirming the good responsiveness of the test. CONCLUSIONS: Coaches and researchers can use this value in the interpretation of the SST test results: changes below these values could be related to a measurement error. The various age-related values reported may help technicians to better interpret the performance of their athletes during competition. PMID- 28085129 TI - Leg stiffness, valgus knee motion, and Q-angle are associated with hypertrophic soft patella tendon and idiopathic knee pain in adolescent basketball players. AB - BACKGROUND: Knee pain without knee degenerative symptoms is a common phenomenon among young basketball players. The aim of this study was to identify factors predisposing young basketball players to suffer from knee pain. METHODS: The study involved 20 male adolescent (14-15 years) basketball players who were divided into two equal groups based on knee pain symptoms. Legs torque was tested on an isokinetic dynamometer. The length, elongation and the cross-sectional area (CSA) of the patellar tendon were measured with ultrasonography. Quadriceps angle (Q-angle), knee valgus motion, and joint angular displacement in the sagittal plane were analyzed using video recording during countermovement jump. Ground reaction force was measured using a force platform. RESULTS: Knee pain (KP) participants had a significantly lower Q-angle (P=0.045) and lower maximum varus knee angle (P=0.035), and a greater knee inside displacement (P=0.039) during squat phase. In the KP group, the CSA at the top of the tendon was significantly greater than in the middle (P=0.006) and at the bottom (P=0.039). Absolute tendon stiffness (P=0.013) and Young's modulus (P=0.034) were significantly lower in the KP group compared with controls. Leg stiffness during landing was significantly greater in the control group (P=0.015). CONCLUSIONS: Leg stiffness, valgus knee motion, and Q-angle are associated with hypertrophic soft patella tendon and idiopathic knee pain in adolescent basketball players. PMID- 28085130 TI - Body composition and size in sprint athletes. AB - BACKGROUND: The aims of the present study were to assess competitive sprinters' body size and composition and to determine their impact on performance. METHODS: Ninety-eight competitive male sprinters (100 m) participated in this cross sectional study. A series of measurements was directly taken and data on muscular strength and power tests were self-reported. Body composition was assessed by skinfold method and somatotype was calculated by the Heath-Carter anthropometric method. Sprinters were classified into three groups depending on their personal best time and comparisons were performed between the athletes in the top and in the bottom tertiles. Relationships between anthropometric traits and performance were assessed by Pearson's correlation coefficients. RESULTS: Top sprinters had significantly greater body mass index, relaxed and contracted upper arm girths, thigh and calf girths, fat free mass and fat free mass index, and lower ectomorphy than the lowest tertile. Strength and power were significantly higher. Personal best time was significantly correlated with several anthropometric traits and indices of lean body mass. CONCLUSIONS: Body size, composition and somatotype differ between performance levels in speed running. Being less ectomorphic, with a greater fat free mass and strength, can explain significant differences in sprinting performances. The results presented in this study provide a point of reference about sprinter characteristics, which can help coaches and sport scientists to improve sprinter performance. PMID- 28085131 TI - Differences in anthropometric characteristics in relation to throwing velocity and competitive level in professional male team handball: a tool for talent profiling. AB - BACKGROUND: The primary aim of the study was to examine the anthropometric characteristics as well as throwing and sprinting performance of professional handball players classified by playing position and competition level. METHODS: 21 male players (age: 25.2+/-5.1 years) from the first German handball league (FGL) and 34 male players (age: 26.1+/-4.1 years) from the third German handball league (TGL) were categorized as backs, pivots, wings and goalkeepers. Measurements included anthropometric data (height, mass and body mass index (BMI)), throwing and sprinting performance selected out of a complex handball test (HBCT), which was conducted twice (2 rounds). During the HBCT, the subjects performed two sprints (10, 20 m), two standing throws with run-up (ST) and four vertical jump throws (VJT) over a hurdle (20 cm) with and without precision for goal shot. RESULTS: The anthropometric data revealed a significantly (P=0.038 and eta2=0.079) shorter body height for TGL than for FGL players. In the cohort of first league athletes the pivots were the tallest (1.98+/-0.04 m), backs in the third league showed the maximum body height (1.90+/-0.05 m). Regarding body mass, pivots were the heaviest players independent from the league membership. The FGL players showed a significantly (P<0.05 and eta2>0.10) higher throwing velocity in all type of throws. Body height was significantly related to ST (r=0.53) and VJT (r=0.52) in the first round of HBCT but only for the FGL athletes. Throwing velocity was also correlated with BMI (r=-0.50) among the TGL players. CONCLUSIONS: Substantial differences of body characteristics, throwing and sprinting performance between playing positions and competitive levels underline the importance of a careful scouting and position-specific training for professional handball players. PMID- 28085132 TI - Peak versus mean propulsive power outputs: which is more closely related to jump squat performance? AB - BACKGROUND: This study aimed to compare the predictive value of muscle power (peak power, mean power until the peak-velocity or mean propulsive power) in relation to the jump height achieved during the jump squat performed at different loads. METHODS: One hundred and ninety-four elite athletes performed jump squats against loads corresponding to 40%, 60%, and 80% of their respective body mass. A linear regression analysis was performed to establish the relationship between muscle power expressions and jump squat height. RESULTS: The coefficient of determination (R2) in the different linear regression models between muscle power related variables and jump squat height, for the different load ranges, varied from 0.50 to 0.57 (for absolute power values) and from 0.72 to 0.78 (for relative power values [W/kg]). The mean propulsive power presented similar capacity to predict the jump squat height as the peak power-related values. For all analyzed variables, this prediction power was increased when the absolute power values were normalized by the individuals' body mass. CONCLUSIONS: Selection of the values related to the mean propulsive phase to assess top-level athletes might be considered as an advantageous alternative, due to its adequacy to properly reflect the neuromuscular potential of the subjects in both ballistic and traditional exercises. PMID- 28085134 TI - 'Orbital volume restoration rate after orbital fracture'; a CT-based orbital volume measurement for evaluation of orbital wall reconstructive effect. AB - PurposeTo evaluate the effect of orbital reconstruction and factors related to the effect of orbital reconstruction by assessing of orbital volume using orbital computed tomography (CT) in cases of orbital wall fracture.MethodsIn this retrospective study, 68 patients with isolated blowout fractures were evaluated. The volumes of orbits and herniated orbital tissues were determined by CT scans using a three-dimensional reconstruction technique (the Eclipse Treatment Planning System). Orbital CT was performed preoperatively, immediately after surgery, and at final follow ups (minimum of 6 months). We evaluated the reconstructive effect of surgery making a new formula, 'orbital volume reconstruction rate' from orbital volume differences between fractured and contralateral orbits before surgery, immediately after surgery, and at final follow up.ResultsMean volume of fractured orbits before surgery was 23.01+/-2.60 cm3 and that of contralateral orbits was 21.31+/-2.50 cm3 (P=0.005). Mean volume of the fractured orbits immediately after surgery was 21.29+/-2.42 cm3, and that of the contralateral orbits was 21.33+/-2.52 cm3 (P=0.921). Mean volume of fractured orbits at final follow up was 21.50+/-2.44 cm3, and that of contralateral orbits was 21.32+/-2.50 cm3 (P=0.668). The mean orbital volume reconstruction rate was 100.47% immediately after surgery and 99.17% at final follow up. No significant difference in orbital volume reconstruction rate was observed with respect to fracture site or orbital implant type. Patients that underwent operation within 14 days of trauma had a better reconstruction rate at final follow up than patients who underwent operation over 14 days after trauma (P=0.039).ConclusionComputer-based measurements of orbital fracture volume can be used to evaluate the reconstructive effect of orbital implants and provide useful quantitative information. Significant reduction of orbital volume is observed immediately after orbital wall reconstruction surgery and the reconstruction effect is maintained for more than minimum 6 months. Patients that undergo surgery within 14 days of trauma has better reconstruction rates at final follow up, which supports the need for early surgery. PMID- 28085133 TI - EspL is a bacterial cysteine protease effector that cleaves RHIM proteins to block necroptosis and inflammation. AB - Cell death signalling pathways contribute to tissue homeostasis and provide innate protection from infection. Adaptor proteins such as receptor-interacting serine/threonine-protein kinase 1 (RIPK1), receptor-interacting serine/threonine protein kinase 3 (RIPK3), TIR-domain-containing adapter-inducing interferon-beta (TRIF) and Z-DNA-binding protein 1 (ZBP1)/DNA-dependent activator of IFN regulatory factors (DAI) that contain receptor-interacting protein (RIP) homotypic interaction motifs (RHIM) play a key role in cell death and inflammatory signalling1-3. RHIM-dependent interactions help drive a caspase independent form of cell death termed necroptosis4,5. Here, we report that the bacterial pathogen enteropathogenic Escherichia coli (EPEC) uses the type III secretion system (T3SS) effector EspL to degrade the RHIM-containing proteins RIPK1, RIPK3, TRIF and ZBP1/DAI during infection. This requires a previously unrecognized tripartite cysteine protease motif in EspL (Cys47, His131, Asp153) that cleaves within the RHIM of these proteins. Bacterial infection and/or ectopic expression of EspL leads to rapid inactivation of RIPK1, RIPK3, TRIF and ZBP1/DAI and inhibition of tumour necrosis factor (TNF), lipopolysaccharide or polyinosinic:polycytidylic acid (poly(I:C))-induced necroptosis and inflammatory signalling. Furthermore, EPEC infection inhibits TNF-induced phosphorylation and plasma membrane localization of mixed lineage kinase domain-like pseudokinase (MLKL). In vivo, EspL cysteine protease activity contributes to persistent colonization of mice by the EPEC-like mouse pathogen Citrobacter rodentium. The activity of EspL defines a family of T3SS cysteine protease effectors found in a range of bacteria and reveals a mechanism by which gastrointestinal pathogens directly target RHIM-dependent inflammatory and necroptotic signalling pathways. PMID- 28085135 TI - Branch retinal vein occlusion: the importance of the topographical distribution of retinal vessels among risk factors. AB - PurposeTo investigate the role of the topographical distribution of temporal retinal vessels in anatomical predisposition to branch retinal vein occlusion (BRVO).Patients and methodsSixty patients with BRVO and 60 control subjects were included in this retrospective-observational study. The fundus images of the individuals were classified into four topographical vessel positions: P1, the superior and inferior temporal retinal veins were closer to the foveal center; P2, the superior and inferior temporal retinal arteries were closer to the foveal center; and P3 and P4, the superior temporal retinal vein and inferior temporal retinal artery were closer to the foveal center or vice versa. The groups were compared in terms of demographics and topographical vessel positions.ResultsThere were no significant differences between the groups in terms of age and gender (P>0.05). The topographical distribution of temporal retinal vessels among the BRVO and control eyes were significant (P<0.001). P1 was less common in BRVO eyes (5%) when compared with control eyes (33.3%); however, P2 was more common in BRVO eyes (46.7 vs 20%). There were no significant differences in terms of the distribution of P3 and P4 vessel positions in the BRVO and control groups (P>0.05). A logistic regression test revealed that the risk of BRVO increases 15 fold in P2, 6-fold in P3, and 8-fold in P4 when compared with eyes having P1.ConclusionP1 eyes are less likely to be affected by BRVO. Therefore, the topographical distribution of retinal vessels can be assessed as a risk factor for BRVO. PMID- 28085136 TI - Protecting retinal ganglion cells. AB - Retinal ganglion cell degeneration underlies several conditions which give rise to significant visual compromise, including glaucoma, hereditary optic neuropathies, ischaemic optic neuropathies, and demyelinating disease. In this review, we discuss the emerging strategies for neuroprotection specifically in the context of glaucoma, including pharmacological neuroprotection, mesenchymal stem cells, and gene therapy approaches. We highlight potential pitfalls that need to be considered when developing these strategies and outline future directions, including the prospects for clinical trials. PMID- 28085137 TI - Biomarkers for glaucoma: from the lab to the clinic. AB - Glaucoma, a leading cause of irreversible blindness worldwide, is often not diagnosed until many years after disease onset. Early and objective diagnostic measures are yet missing. Besides the main risk factor, an elevated intraocular pressure (IOP), age, sex, and ethnicity are known to affect disease progression and severity. Furthermore, oxidative stress, elevated glutamate concentrations, and an autoimmune component are considered possible risk factors. We could identify several potential proteomic biomarkers in glaucoma and examine distinct changes in the glaucomatous human retina proteome. Using an experimental autoimmune glaucoma animal (EAG) model we could demonstrate an IOP-independent loss of retinal ganglion cells (RGC), which is accompanied by antibody depositions and increased levels of microglia. In a different animal model we showed that intermittent IOP elevations provoke neurodegeneration in the optic nerve and the retina and elicit changes of IgG autoantibody reactivities. The correlation between neuronal damage and changes in autoantibody reactivity suggests that autoantibody profiling could be a useful biomarker for glaucoma. In vivo studies on neuroretinal cells and porcine retinal explants demonstrated a protective effect of antibodies (eg, anti-GFAP) on RGC, which seems to be the result of reduced stress levels in the retina. We conclude that the absence of some autoantibodies in glaucoma patients reflects a loss of the protective potential of natural autoimmunity and may thus encourage neurodegenerative processes. Concluding, autoantibody profiles resemble useful biomarkers for diagnosis, progression and severity of glaucoma. Future longitudinal studies will help to improve early detection and enable better monitoring of disease progression. PMID- 28085138 TI - Success rate of nurse-led everting sutures for involutional lower lid entropion. AB - PurposeTo evaluate safety and long-term recurrence rate of entropion in patients having everting sutures (ES) for involutional entropion by ophthalmic nurses in a real clinical setting.Patients and methodsRetrospective notes review of all patients who had an outpatient ES by our trained ophthalmic nurses over 2 year's time period. Outcome measures were complication and recurrence rates. Those with less than 3 years' recorded follow-up were contacted by paper questionnaire.Results90 lids of 82 patients analysed. Mean age was 78 (range 54 97). In total, 82% had no entropion surgery before, whereas 13% had previous ES and 5% one or more other procedures. Questionnaires were sent to 38, with return rate of 81%. Recurrence rate was 21.1% after 36-60 months follow up from nurse performed ES, with mean time to recurrence of 15 months (SD 13 months). A total of 32% of patients died during the follow-up period. Mean time between the procedure and death is 20.5 months. When ES were repeated twice (11 patients), recurrence rate was still 20%. No patients had any complications.ConclusionES can be safely performed by ophthalmic nurses, with success rate comparable to the same technique performed by ophthalmologists. PMID- 28085139 TI - Efficacy of 0.2 MUg/day fluocinolone acetonide implant (ILUVIEN) in eyes with diabetic macular edema and prior vitrectomy. AB - PurposeLimited data are available on the efficacy of the 0.2 MUg/day fluocinolone acetonide (FAc) implant in eyes with prior vitrectomy. Here, we present a collection of 26 vitrectomized eyes treated with the 0.2 MUg/day FAc implant.MethodsRetrospective study involving six centers from four European countries analyzing the safety and efficacy data from patients (26 eyes from 25 patients) with DME and a prior vitrectomy that had been treated with one 0.2 MUg/day FAc implant.ResultsPrior intravitreal therapies included anti-VEGF (mean, 3.8 injections) and steroids (mean, 1.9 injections). Pars plana vitrectomy (PPV) was performed in these eyes primarily for abnormalities of vitreoretinal interface, followed by proliferative diabetic retinopathy and vitreous hemorrhage. The 0.2 MUg/day FAc implant was injected 24.2 months, on average, after PPV and the mean duration of follow-up after injection was 255 days (range, 90 to 759 days). The mean change in BCVA was +11.7 ETDRS letters (range, -19 to +40 letters; P<0.0004) and the mean change in central foveal thickness (CFT) was 233.5 MUm (range, -678 to 274 MUm; P<0.0001). The mean change in IOP from baseline at the last visit was +1.4 mm Hg (range, -9 to +8 mm Hg; P=0.0090). Eight eyes initiated or continued IOP lowering medications.ConclusionsThese data suggest the 0.2 MUg/day FAc implant is effective in vitrectomized patients with an acceptable safety profile. Further studies are still required to confirm the current findings and to assess the effect of the 0.2 MUg/day FAc implant over a longer period of follow-up. PMID- 28085140 TI - Nailfold capillary morphology in exfoliation syndrome. AB - PurposeThe purpose of the study was to investigate nailfold microvascular morphology in exfoliation syndrome with or without glaucoma (XFS/XFG) compared with primary open-angle glaucoma (POAG) and control subjects using nailfold capillary videomicroscopy.Patients and methodsWe used a JH-1004 capillaroscope to perform nailfold capillary videomicroscopy on the fourth and fifth digit of the non-dominant hand. We enrolled 56 XFS/XFG patients, 87 POAG patients, and 75 control subjects. Masked observers graded the videos for hemorrhages, avascular zones >=200 microns (MUm), and degree of microvascular tortuosity on a four-point subjective scale. Multivariable odds ratios, 95% confidence intervals and P-for trends for assessing the relation between morphological changes and POAG or XFS/XFG were obtained from logistic regression analyses. We also assessed this relation with XFS/XFG compared with POAG in multivariable models.ResultsAfter adjusting for multiple covariates, nailfold hemorrhages, avascular zones >=200 MUm, and higher degree of vascular tortuosity were more common in XFS/XFG vs controls (P-for trend <=0.0001) and in POAG vs controls (P-for trend <=0.01). For each 100 capillaries, the number of hemorrhages was similar (P-for trend=0.91) between XFS/XFG and POAG patients; however, there were more avascular zones per 100 capillaries with borderline significance (P-for trend=0.04) in the XFS/XFG group. XFS/XFG patients had more tortuosity than POAG patients; specifically, having a tortuosity score >=1.5 was associated with a 4.4-fold increased odds of XFS/XFG (95% confidence interval: 1.5-13.3) relative to a tortuosity score <1.0 (P-for trend=0.005).ConclusionA high degree of nailfold capillary tortuosity is a distinct non-ocular feature associated with XFS/XFG compared with either POAG or controls. PMID- 28085141 TI - Assessing retinal ganglion cell damage. AB - Retinal ganglion cell (RGC) loss is the hallmark of optic neuropathies, including glaucoma, where damage to RGC axons occurs at the level of the optic nerve head. In experimental glaucoma, damage is assessed at the axon level (in the retinal nerve fibre layer and optic nerve head) or at the soma level (in the retina). In clinical glaucoma where measurements are generally limited to non-invasive techniques, structural measurements of the retinal nerve fibre layer and optic nerve head, or functional measurements with perimetry provide surrogate estimates of RGC integrity. These surrogate measurements, while clinically useful, are several levels removed from estimating actual RGC loss. Advances in imaging, labelling techniques, and transgenic medicine are making enormous strides in experimental glaucoma, providing knowledge on the pathophysiology of glaucoma, its progression and testing new therapeutic avenues. Advances are also being made in functional imaging of RGCs. Future efforts will now be directed towards translating these advances to clinical care. PMID- 28085142 TI - Adenoid cystic carcinoma of the lacrimal gland is frequently characterized by MYB rearrangement. AB - PurposeAdenoid cystic carcinoma (ACC) represents ~10-15% of salivary neoplasms and almost universally exhibits a lethal clinical course. ACC is also known to occur in the lacrimal gland. ACC is characterized by its heterogeneous morphology and may demonstrate tubular, cribriform, and/or solid architectural patterns. Unfortunately, these histopathological features are not specific to ACC and can be seen in other salivary gland-type neoplasms, introducing a diagnostic dilemma. The discovery of fusion transcripts has revolutionized the diagnosis, surveillance, and treatment of epithelial malignancies. In several anatomic subsites ACC is frequently characterized by a fusion transcript involving genes MYB and NFIB; more specifically, t(6;9)(q22-23;p23-24). This study explores the incidence of MYB rearrangement in cases of lacrimal gland ACC using fluorescent in situ hybridization.Materials and methodsRetrospective clinical and histopathological review of 12 cases of lacrimal gland ACC seen at Mayo Clinic over a 25-year period (1990-2015) was performed. Demographic and clinical data were obtained from medical records. Surgical pathology archival material including H&E slides and immunostains was re-examined. Formalin-fixed paraffin embedded material was further evaluated using immunohistochemistry when appropriate. Fluorescent in situ hybridization (FISH) using a MYB break-apart probe was applied to all histologically confirmed cases of ACC and benign salivary gland parenchyma.ResultsThe median patient age was 53.6 years (range 12 64) and distributed equally by gender (six male and six female). Rearrangement of MYB was identified using FISH in seven cases (58%). Twenty-five sections of benign salivary gland parenchyma showed no evidence of MYB rearrangement. Primary surgical resection was most common treatment, and 78% of the patient received adjuvant radiation therapy. Median overall survival (OS) was 11 years. Rearrangement of MYB did not affect OS.ConclusionsIn summary, our results indicate that the MYB rearrangement defines a significant subset of lacrimal gland ACCs. Importantly, FISH for MYB rearrangement may be used as a diagnostic tool during pathological examination of lacrimal gland neoplasms. Our results showed no relationship between rearrangement status and clinical outcome. Lastly, the presence of t(6;9) in ACC may provide a platform for molecular-targeting strategies in the future. PMID- 28085143 TI - The clinical, histological and immunohistochemical characteristics and nomenclature of meibomian gland ductal cysts (intratarsal keratinous cysts) and eyelid steatocystomas. AB - PurposeMeibomian gland ductal cysts (MGDCs) and steatocystomas are epithelial lined, keratin-containing lesions of the eyelids. MDGCs are variably called tarsal keratinous cysts, intratarsal keratinous cysts of the meibomian glands, intratarsal inclusion cysts, epidermal cysts and epidermoid cysts. Both lesions are poorly described in the literature. We report a series of seven MGDC and steatocystomas, and examine their clinical, pathological and immunohistochemistry features and their management and outcomes.Patients and methodsA retrospective review of case notes and histopathology slides of all MGDCs and steatocystomas identified at one major histopathology service in South Australia between 2013 and 2015.ResultsSeven cases were identified, with an average age of 64. The lesions range from 4 to 18 mm diameter and are firm, well-circumscribed and non tender, and sometimes the keratin-filled cyst protrudes visibly under the tarsal conjunctiva. Two cases were previously misdiagnosed as chalazia but recurred after incision and curettage. Histologically, these lesions are lined by squamous epithelium but lack a well-formed stratum granulosum and can be distinguished by their immunohistochemical staining characteristics. Complete excision, including a wedge of underlying tarsal plate for MDGCs, is curative for with a follow up of 12-36 months.ConclusionsMGDCs and steatocystomas should be included in the differential of benign eyelid lesions. Diagnosing and differentiating these lesions from chalazia is important for determining the optimal management strategy. PMID- 28085144 TI - Surgical outcomes of external dacryocystorhinostomy and risk factors for functional failure: a 10-year experience. AB - PURPOSE: To analyze the surgical outcomes of external dacryocystorhinostomy (DCR) and the risk factors associated with functional failure. METHODS: We reviewed the medical records of 769 patients who underwent external DCR for primary lacrimal drainage obstruction between 2005 and 2014. Recorded data included intraoperative anatomical findings, postoperative diagnosis, and surgical outcomes. We performed univariate and multivariate analyses to identify risk factors for functional failure. RESULTS: Of the 769 cases, primary nasolacrimal duct obstruction (NLDO) was diagnosed in 457 cases; common canalicular obstruction in 228 cases; and canalicular obstruction in 84 cases. Anatomical success was achieved in 98.8% (760/769) and functional success in 81.9% (630/769) of the cases. An analysis of 760 anatomically successful DCRs showed that common canalicular obstruction (OR=1.752, P=0.014) and canalicular obstruction (OR=2.058, P=0.015) were independent risk factors for functional failure. In a subgroup analysis of patients with primary NLDO, patients with a small lacrimal sac had a significantly higher risk of functional failure (OR=2.500, P=0.018). CONCLUSIONS: The overall surgical outcomes of external DCR were favorable in this case series. Site of obstruction was an important risk factor for functional failure in cases with primary lacrimal drainage obstruction. A small lacrimal sac was also found to be a risk factor for functional failure in cases with primary NLDO. PMID- 28085145 TI - Ethnic variation in primary idiopathic macular hole surgery. AB - PurposeThe purpose of the study was to investigate the role of ethnicity on idiopathic macular holes (IMH) structure and surgical outcome. This was a retrospective review.Patients and methodsConsecutive patients undergoing primary IMH surgery at two surgical sites of Moorfields Eye Hospital (London, UK) between April 2012 and June 2013. The main outcome measure was post surgical anatomical closure of IMH.ResultsTwo hundred and twenty two primary IMH surgeries were undertaken. A standard procedure including pars plana vitrectomy, internal limiting membrane peeling, and gas tamponade was undertaken for all cases. 61.3% of patients were Caucasian, 21.2% were South Asian, and 16% were Afro-Caribbean. The mean minimum linear diameter (MLD) for our cohort was 434.6 mcm. Mean MLD was 395.3 mcm in Caucasian patients, 490.0 mcm in South Asians (P=0.006), and 491.4 mcm in Afro-Caribbeans (P=0.007). Regression analysis demonstrated that MLD and Afro-Caribbean ethnicity were independent significant risk factors for surgical failure (OR: 1.01, P<0.001 and OR: 5.73, P=0.008, respectively).ConclusionSouth Asian and Afro-Caribbean patients present with larger IMH than Caucasians. In addition to IMH diameter, Afro-Caribbean ethnicity is an independent risk factor for surgical failure. PMID- 28085146 TI - One size doesn't fit all: time to revisit patient-reported outcome measures (PROMs) in paediatric ophthalmology? AB - The purpose of this article is to summarise methodological challenges and opportunities in the development and application of patient reported outcome measures (PROMs) for the rare and complex population of children with visually impairing disorders. Following a literature review on development and application of PROMs in children in general, including those with disabilities and or/chronic condition, we identified and discuss here 5 key issues that are specific to children with visual impairment: (1) the conflation between theoretically distinct vision-related constructs and outcomes, (2) the importance of developmentally appropriate approaches to design and application of PROMs, (3) feasibility of standard questionnaire formats and administration for children with different levels of visual impairment, (4) feasibility and nature of self reporting by visually impaired children, and (5) epidemiological, statistical and ethical considerations. There is an established need for vision-specific age appropriate PROMs for use in paediatric ophthalmology, but there are significant practical and methodological challenges in developing and applying appropriate measures. Further understanding of the characteristics and needs of visually impaired children as questionnaire respondents is necessary for development of quality PROMs and their meaningful application in clinical practice and research. PMID- 28085147 TI - Seeing through their eyes: lived experiences of people with retinitis pigmentosa. AB - PurposeRetinitis pigmentosa (RP) is the most common retinal degeneration causing blindness. Although their clinical problems are amenable for the clinical diagnosis, their day-to-day problems for having to live with the disease are mostly unexplored. This study aims to explore and understand the issues and impact of people with RP on quality of life (QoL).MethodsA qualitative research methodology to facilitate the understanding of the experiences of people with RP was carried out. Data were collected through audio-recorded semi-structured interviews. Thematic analysis occurred through the process of line-by-line coding, aggregation, and theme development using the NVivo-10 software.ResultsTwenty-three interviews were conducted (mean age=56 years; females, 14). We identified five major QoL themes: (1) struggle to perform important day-to-day tasks; (2) concerns about disease progression, disease outcome and personal safety; (3) facing a lot of emotional and psychological challenges; (4) experiencing a myriad of visual symptoms; and (5) adopting different strategies to cope and manage stressful circumstances. Difficulty in performing important day-to-day tasks was the most prominent QoL issue among these people. Their major concerns were going blind and uncertainties about their future. They face a lot of emotional and psychological challenges to adapt to the physiological stress associated with the progressive vision loss. However, they adopt several coping strategies to manage the stressful circumstances.ConclusionsPeople with RP experience a myriad of QoL issues. Despite all the hardship, they remain optimistic and learn to accept their eye condition and move on in life. PMID- 28085148 TI - Occurrence and severity of upper eyelid skin contracture in facial nerve palsy. PMID- 28085149 TI - ApoSOD1 lacking dismutase activity neuroprotects motor neurons exposed to beta methylamino-L-alanine through the Ca2+/Akt/ERK1/2 prosurvival pathway. AB - Amyotrophic lateral sclerosis (ALS) is a severe human adult-onset neurodegenerative disease affecting lower and upper motor neurons. In >20% of cases, the familial form of ALS is caused by mutations in the gene encoding Cu,Zn superoxide dismutase (SOD1). Interestingly, administration of wild-type SOD1 to SOD1G93A transgenic rats ameliorates motor symptoms through an unknown mechanism. Here we investigated whether the neuroprotective effects of SOD1 are due to the Ca2+-dependent activation of such prosurvival signaling pathway and not to its catalytic activity. To this aim, we also examined the mechanism of neuroprotective action of ApoSOD1, the metal-depleted state of SOD1 that lacks dismutase activity, in differentiated motor neuron-like NSC-34 cells and in primary motor neurons exposed to the cycad neurotoxin beta-methylamino-L-alanine (L-BMAA). Preincubation of ApoSOD1 and SOD1, but not of human recombinant SOD1G93A, prevented cell death in motor neurons exposed to L-BMAA. Moreover, ApoSOD1 elicited ERK1/2 and Akt phosphorylation in motor neurons through an early increase of intracellular Ca2+ concentration ([Ca2+]i). Accordingly, inhibition of ERK1/2 by siMEK1 and PD98059 counteracted ApoSOD1- and SOD1-induced neuroprotection. Similarly, transfection of the dominant-negative form of Akt in NSC-34 motor neurons and treatment with the selective PI3K inhibitor LY294002 prevented ApoSOD1- and SOD1-mediated neuroprotective effects in L-BMAA-treated motor neurons. Furthermore, ApoSOD1 and SOD1 prevented the expression of the two markers of L-BMAA-induced ER stress GRP78 and caspase-12. Collectively, our data indicate that ApoSOD1, which is devoid of any catalytic dismutase activity, exerts a neuroprotective effect through an early activation of Ca2+/Akt/ERK1/2 pro-survival pathway that, in turn, prevents ER stress in a neurotoxic model of ALS. PMID- 28085150 TI - Characterisation of mice lacking all functional isoforms of the pro-survival BCL 2 family member A1 reveals minor defects in the haematopoietic compartment. AB - The pro-survival proteins of the BCL-2 family regulate the survival of all cells, and genetic deletion models for these proteins have revealed which specific BCL-2 family member(s) is/are critical for the survival of particular cell types. A1 is a pro-survival BCL-2-like protein that is expressed predominantly in haematopoietic cells, and here we describe the characterisation of a novel mouse strain that lacks all three functional isoforms of A1 (A1-a, A1-b and A1-d). Surprisingly, complete loss of A1 caused only minor defects, with significant, although relatively small, decreases in gammadeltaTCR T cells, antigen experienced conventional as well as regulatory CD4 T cells and conventional dendritic cells (cDCs). When examining these cell types in tissue culture, only cDC survival was significantly impaired by the loss of A1. Therefore, A1 appears to be a surprisingly redundant pro-survival protein in the haematopoietic system and other tissues, suggesting that its targeting in cancer may be readily tolerated. PMID- 28085151 TI - The BCL-2 pro-survival protein A1 is dispensable for T cell homeostasis on viral infection. AB - The physiological role of the pro-survival BCL-2 family member A1 has been debated for a long time. Strong mRNA induction in T cells on T cell receptor (TCR)-engagement suggested a major role of A1 in the survival of activated T cells. However, the investigation of the physiological roles of A1 was complicated by the quadruplication of the A1 gene locus in mice, making A1 gene targeting very difficult. Here, we used the recently generated A1-/- mouse model to examine the role of A1 in T cell immunity. We confirmed rapid and strong induction of A1 protein in response to TCR/CD3 stimulation in CD4+ as well as CD8+ T cells. Surprisingly, on infection with the acute influenza HKx31 or the lymphocytic choriomeningitis virus docile strains mice lacking A1 did not show any impairment in the expansion, survival, or effector function of cytotoxic T cells. Furthermore, the ability of A1-/- mice to generate antigen-specific memory T cells or to provide adequate CD4-dependent help to B cells was not impaired. These results suggest functional redundancy of A1 with other pro-survival BCL-2 family members in the control of T cell-dependent immune responses. PMID- 28085152 TI - RodA as the missing glycosyltransferase in Bacillus subtilis and antibiotic discovery for the peptidoglycan polymerase pathway. AB - The bacterial cell wall is a highly conserved essential component of most bacterial groups. It is the target for our most frequently used antibiotics and provides important small molecules that trigger powerful innate immune responses. The wall is composed of glycan strands crosslinked by short peptides. For many years, the penicillin-binding proteins were thought to be the key enzymes required for wall synthesis. RodA and possibly other proteins in the wider SEDS (shape, elongation, division and sporulation) family have now emerged as a previously unknown class of essential glycosyltranferase enzymes, which play key morphogenetic roles in bacterial cell wall synthesis. We provide evidence in support of this role and the discovery of small natural product molecules that probably target these enzymes. The SEDS proteins have exceptional potential as targets for new antibacterial therapeutic agents. PMID- 28085153 TI - An NPF transporter exports a central monoterpene indole alkaloid intermediate from the vacuole. AB - Plants sequester intermediates of metabolic pathways into different cellular compartments, but the mechanisms by which these molecules are transported remain poorly understood. Monoterpene indole alkaloids, a class of specialized metabolites that includes the anticancer agent vincristine, antimalarial quinine and neurotoxin strychnine, are synthesized in several different cellular locations. However, the transporters that control the movement of these biosynthetic intermediates within cellular compartments have not been discovered. Here we present the discovery of a tonoplast localized nitrate/peptide family (NPF) transporter from Catharanthus roseus, CrNPF2.9, that exports strictosidine, the central intermediate of this pathway, into the cytosol from the vacuole. This discovery highlights the role that intracellular localization plays in specialized metabolism, and sets the stage for understanding and controlling the central branch point of this pharmacologically important group of compounds. PMID- 28085154 TI - Genomic reconstruction of multiple lineages of uncultured benthic archaea suggests distinct biogeochemical roles and ecological niches. AB - Genomic bins belonging to multiple archaeal lineages were recovered from distinct redox regimes in sediments of the White Oak River estuary. The reconstructed archaeal genomes were identified as belonging to the rice cluster subgroups III and V (RC-III, RC-V), the Marine Benthic Group D (MBG-D), and a newly described archaeal class, the Theionarchaea. The metabolic capabilities of these uncultured archaea were inferred and indicated a common capability for extracellular protein degradation, supplemented by other pathways. The multiple genomic bins within the MBG-D archaea shared a nearly complete reductive acetyl-CoA pathway suggesting acetogenic capabilities. In contrast, the RC-III metabolism appeared centered on the degradation of detrital proteins and production of H2, whereas the RC-V archaea lacked capabilities for protein degradation and uptake, and appeared to be specialized on carbohydrate fermentation. The Theionarchaea appeared as complex metabolic hybrids; encoding a complete tricarboxylic acid cycle permitting carbon (acetyl-CoA) oxidation, together with a complete reductive acetyl-CoA pathway and sulfur reduction by a sulfhydrogenase. The differentiated inferred capabilities of these uncultured archaeal lineages indicated lineage specific linkages with the nitrogen, carbon and sulfur cycles. The predicted metabolisms of these archaea suggest preferences for distinct geochemical niches within the estuarine sedimentary environment. PMID- 28085155 TI - Shift in fungal communities and associated enzyme activities along an age gradient of managed Pinus sylvestris stands. AB - Forestry reshapes ecosystems with respect to tree age structure, soil properties and vegetation composition. These changes are likely to be paralleled by shifts in microbial community composition with potential feedbacks on ecosystem functioning. Here, we assessed fungal communities across a chronosequence of managed Pinus sylvestris stands and investigated correlations between taxonomic composition and extracellular enzyme activities. Not surprisingly, clear-cutting had a negative effect on ectomycorrhizal fungal abundance and diversity. In contrast, clear-cutting favoured proliferation of saprotrophic fungi correlated with enzymes involved in holocellulose decomposition. During stand development, the re-establishing ectomycorrhizal fungal community shifted in composition from dominance by Atheliaceae in younger stands to Cortinarius and Russula species in older stands. Late successional ectomycorrhizal taxa correlated with enzymes involved in mobilisation of nutrients from organic matter, indicating intensified nutrient limitation. Our results suggest that maintenance of functional diversity in the ectomycorrhizal fungal community may sustain long-term forest production by retaining a capacity for symbiosis-driven recycling of organic nutrient pools. PMID- 28085156 TI - Divergent functional isoforms drive niche specialisation for nutrient acquisition and use in rumen microbiome. AB - Many microbes in complex competitive environments share genes for acquiring and utilising nutrients, questioning whether niche specialisation exists and if so, how it is maintained. We investigated the genomic signatures of niche specialisation in the rumen microbiome, a highly competitive, anaerobic environment, with limited nutrient availability determined by the biomass consumed by the host. We generated individual metagenomic libraries from 14 cows fed an ad libitum diet of grass silage and calculated functional isoform diversity for each microbial gene identified. The animal replicates were used to calculate confidence intervals to test for differences in diversity of functional isoforms between microbes that may drive niche specialisation. We identified 153 genes with significant differences in functional isoform diversity between the two most abundant bacterial genera in the rumen (Prevotella and Clostridium). We found Prevotella possesses a more diverse range of isoforms capable of degrading hemicellulose, whereas Clostridium for cellulose. Furthermore, significant differences were observed in key metabolic processes indicating that isoform diversity plays an important role in maintaining their niche specialisation. The methods presented represent a novel approach for untangling complex interactions between microorganisms in natural environments and have resulted in an expanded catalogue of gene targets central to rumen cellulosic biomass degradation. PMID- 28085159 TI - Efficient electrocatalytic O2 reduction at copper complexes grafted onto polyvinylimidazole coated carbon nanotubes. AB - A facile approach to prepare Cu complexes for an efficient oxygen reduction reaction (ORR) was developed. Copper complexes of 5-nitrophenanthroline were sandwiched between polyvinylimidazole layers wrapped on carbon nanotubes, which showed ORR activity comparable to a Pt/C catalyst in alkaline media. PMID- 28085157 TI - Temperature is a key factor in Micromonas-virus interactions. AB - The genus Micromonas comprises phytoplankton that show among the widest latitudinal distributions on Earth, and members of this genus are recurrently infected by prasinoviruses in contrasted thermal ecosystems. In this study, we assessed how temperature influences the interplay between the main genetic clades of this prominent microalga and their viruses. The growth of three Micromonas strains (Mic-A, Mic-B, Mic-C) and the stability of their respective lytic viruses (MicV-A, MicV-B, MicV-C) were measured over a thermal range of 4-32.5 degrees C. Similar growth temperature optima (Topt) were predicted for all three hosts but Mic-B exhibited a broader thermal tolerance than Mic-A and Mic-C, suggesting distinct thermoacclimation strategies. Similarly, the MicV-C virus displayed a remarkable thermal stability compared with MicV-A and MicV-B. Despite these divergences, infection dynamics showed that temperatures below Topt lengthened lytic cycle kinetics and reduced viral yield and, notably, that infection at temperatures above Topt did not usually result in cell lysis. Two mechanisms operated depending on the temperature and the biological system. Hosts either prevented the production of viral progeny or maintained their ability to produce virions with no apparent cell lysis, pointing to a possible switch in the viral life strategy. Hence, temperature changes critically affect the outcome of Micromonas infection and have implications for ocean biogeochemistry and evolution. PMID- 28085158 TI - New insights into marine group III Euryarchaeota, from dark to light. AB - Marine Euryarchaeota remain among the least understood major components of marine microbial communities. Marine group II Euryarchaeota (MG-II) are more abundant in surface waters (4-20% of the total prokaryotic community), whereas marine group III Euryarchaeota (MG-III) are generally considered low-abundance members of deep mesopelagic and bathypelagic communities. Using genome assembly from direct metagenome reads and metagenomic fosmid clones, we have identified six novel MG III genome sequence bins from the photic zone (Epi1-6) and two novel bins from deep-sea samples (Bathy1-2). Genome completeness in those genome bins varies from 44% to 85%. Photic-zone MG-III bins corresponded to novel groups with no similarity, and significantly lower GC content, when compared with previously described deep-MG-III genome bins. As found in many other epipelagic microorganisms, photic-zone MG-III bins contained numerous photolyase and rhodopsin genes, as well as genes for peptide and lipid uptake and degradation, suggesting a photoheterotrophic lifestyle. Phylogenetic analysis of these photolyases and rhodopsins as well as their genomic context suggests that these genes are of bacterial origin, supporting the hypothesis of an MG-III ancestor that lived in the dark ocean. Epipelagic MG-III occur sporadically and in relatively small proportions in marine plankton, representing only up to 0.6% of the total microbial community reads in metagenomes. None of the reconstructed epipelagic MG-III genomes were present in metagenomes from aphotic zone depths or from high latitude regions. Most low-GC bins were highly enriched at the deep chlorophyll maximum zones, with the exception of Epi1, which appeared evenly distributed throughout the photic zone worldwide. PMID- 28085160 TI - Ferromagnetism in nitrogen-doped BaO: a self-interaction corrected DFT study. AB - The nature of isolated nitrogen-dopants in bulk BaO (N-BaO) and their magnetic interaction have been investigated by means of density functional theory calculations based on hybrid, self-interaction corrected functionals. A thermodynamic analysis shows that N is preferably incorporated into interstitial sites. Only at very high temperatures and under oxygen poor-conditions the formation of N dopants substitutional to O is preferred. The spin density is rather localized in both cases, as proven by the calculation of the hyperfine coupling constants of the electron spin with the nuclear spin of nitrogen. The magnetic interaction of two N defects in various configurations has been considered as a function of their distance. Different behaviors have been observed, depending on the position of the N defects and on the nature of the dominating magnetic mechanism. In any case, the computed Curie temperature is below room temperature, suggesting that RT ferromagnetism cannot be attained for this kind of doping in BaO. Finally, the interplay of oxygen vacancies with the N dopants has been studied. The inclusion of nitrogen has the effect of drastically reducing the cost to create oxygen vacancies. These in turn quench the magnetic moment of N-dopants, contributing to reducing the concentration of magnetic impurities. PMID- 28085161 TI - Dinuclear indium and thallium diyls: biscarbenoids or metal cluster? AB - Using bis(beta-diketiminate) ligands we were able to synthesize unprecedented indium and thallium biscarbenoids. For indium, a novel four-membered metallacycle is derived from intra- and intermolecular In-In interactions in the solid state, while for thallium only an intramolecular Tl2-pseudo-dimer is obtained. Computational studies revealed that the solid-state structures benefit significantly from dispersion stabilization. PMID- 28085162 TI - High-resolution sub-cellular imaging by correlative NanoSIMS and electron microscopy of amiodarone internalisation by lung macrophages as evidence for drug induced phospholipidosis. AB - Correlative NanoSIMS and EM imaging of amiodarone-treated macrophages shows the internalisation of the drug at a sub-cellular level and reveals its accumulation within the lysosomes, providing direct evidence for amiodarone-induced phospholipidosis. Chemical fixation using tannic acid effectively seals cellular membranes aiding intracellular retention of diffusible drugs. PMID- 28085164 TI - Photocatalytic ATRA reaction promoted by iodo-Bodipy and sodium ascorbate. AB - Using ascorbate as a sacrificial reductant, iodo-Bodipy dye 1b is able to promote the ATRA reaction between bromoderivatives and alkenes. This finding expands the possibility of using Bodipy dyes to promote photocatalytic reactions in efficient ways. PMID- 28085163 TI - PSMA-targeted contrast agents for intraoperative imaging of prostate cancer. AB - Prostate-specific membrane antigen (PSMA) can serve as a molecular cell surface target for the detection and treatment of prostate cancer. Near-infrared (NIR) fluorescence imaging enables highly sensitive, rapid, and non-radioactive imaging of PSMA, though specific targeting still remains a challenge because no optimized contrast agents exist. PMID- 28085165 TI - Nanostructure, hydrogen bonding and rheology in choline chloride deep eutectic solvents as a function of the hydrogen bond donor. AB - Deep eutectic solvents (DESs) are a mixture of a salt and a molecular hydrogen bond donor, which form a eutectic liquid with a depressed melting point. Quantum mechanical molecular dynamics (QM/MD) simulations have been used to probe the 1 : 2 choline chloride-urea (ChCl : U), choline chloride-ethylene glycol (ChCl : EG) and choline chloride-glycerol (ChCl : Gly) DESs. DES nanostructure and interactions between the ions is used to rationalise differences in DES eutectic point temperatures and viscosity. Simulations show that the structure of the bulk hydrogen bond donor is largely preserved for hydroxyl based hydrogen bond donors (ChCl:Gly and ChCl:EG), resulting in a smaller melting point depression. By contrast, ChCl:U exhibits a well-established hydrogen bond network between the salt and hydrogen bond donor, leading to a larger melting point depression. This extensive hydrogen bond network in ChCl:U also leads to substantially higher viscosity, compared to ChCl:EG and ChCl:Gly. Of the two hydroxyl based DESs, ChCl:Gly also exhibits a higher viscosity than ChCl:EG. This is attributed to the over-saturation of hydrogen bond donor groups in the ChCl:Gly bulk, which leads to more extensive hydrogen bond donor self-interaction and hence higher cohesive forces within the bulk liquid. PMID- 28085166 TI - Correction: Double-emulsion drops with ultra-thin shells for capsule templates. AB - Correction for 'Double-emulsion drops with ultra-thin shells for capsule templates' by Shin-Hyun Kim et al., Lab Chip, 2011, 11, 3162-3166. PMID- 28085167 TI - Correction: Tuneable light-emitting carbon-dot/polymer flexible films prepared through one-pot synthesis. AB - Correction for 'Tuneable light-emitting carbon-dot/polymer flexible films prepared through one-pot synthesis' by Susanta Kumar Bhunia, et al., Nanoscale, 2016, 8, 3400-3406. PMID- 28085168 TI - Ultrafast dynamics of the photo-excited hemes b and cn in the cytochrome b6f complex. AB - The dynamics of hemes b and cn within the cytochrome b6f complex are investigated by means of ultrafast broad-band transient absorption spectroscopy. On the one hand, the data reveal that, subsequent to visible light excitation, part of the b hemes undergoes pulse-limited photo-oxidation, with the liberated electron supposedly being transferred to one of the adjacent aromatic amino acids. Photo oxidation is followed by charge recombination in about 8.2 ps. Subsequent to charge recombination, heme b is promoted to a vibrationally excited ground state that relaxes in about 4.6 ps. On the other hand, heme cn undergoes ultrafast ground state recovery in about 140 fs. Interestingly, the data also show that, in contrast to previous beliefs, Chl a is involved in the photochemistry of hemes. Indeed, subsequent to heme excitation, Chl a bleaches and recovers to its ground state in 90 fs and 650 fs, respectively. Chl a bleaching allegedly corresponds to the formation of a short lived Chl a anion. Beyond the previously suggested structural role, this study provides unique evidence that Chl a is directly involved in the photochemistry of the hemes. PMID- 28085169 TI - Wrinkling of milk skin is mediated by evaporation. AB - Wrinkling of thin films and membranes can occur due to various mechanisms such as growth and/or mismatch between the mechanical properties of the film and substrate. However, the physical origins of dynamic wrinkling in soft membranes are still not fully understood. Here we use milk skin as a tractable experimental system to investigate the physics of wrinkle formation in a thin, poroelastic film. Upon heating milk, a micron-thick hydrogel of denatured proteins and fat globules forms at the air-water interface. Over time, we observe an increase in the total length of wrinkles. By confocal imaging and profilometry, we determine that the composition and thickness of the milk skin appears to be homogeneous over the length scale of the wrinkles, excluding differences in milk skin composition as a major contributor to wrinkling. To explain the physical origins of wrinkle growth, we describe theory that considers the milk skin as a thin, poroelastic film where pressure is generated by the evaporative-driven flow of solvent across the film; this imparts in-plane stresses in the milk skin, which cause wrinkling. Viscous effects can explain the time-dependent growth of wrinkles. Our theoretical predictions of the effects of relative humidity on the total length of wrinkles over time are consistent with our experimental results. Our findings provide insight into the physics of the common phenomenon of milk skin wrinkling, and identify hydration gradients as another physical mechanism that can drive morphological instabilities in soft matter. PMID- 28085170 TI - Idiopathic infantile arterial calcification: a case report of successful extracorporeal membrane oxygenation support. AB - Idiopathic infantile arterial calcification is a rare cause of infantile ischemic cardiac failure with extremely poor prognosis. We present the first case report of successful extracorporeal membrane oxygenation support and outcome in a child with idiopathic infantile arterial calcification (IIAC). This 6-week-old infant presented with cardiogenic shock and circulatory collapse. The patient underwent extracorporeal cardiopulmonary resuscitation, allowing stabilization, diagnosis, and treatment with etidronate, followed by successful discharge to home. PMID- 28085171 TI - Assessment of the optimal operating parameters during extracorporeal CO2 removal with the Abylcap(r) system. AB - PURPOSE: Lung protective ventilation is recommended in patients with acute respiratory distress syndrome (ARDS) needing mechanical ventilation. This can however be associated with hypercapnia and respiratory acidosis, such that extracorporeal CO2 removal (ECCO2R) can be applied. The aim of this study was to derive optimal operating parameters for the ECCO2R Abylcap(r) system (Bellco, Italy). METHODS: We included 4 ARDS patients with a partial arterial oxygen tension over the fraction of inspired oxygen (PaO2/FiO2) lower than 150 mmHg, receiving lung-protective ventilation and treated with the Abylcap(r) via a double lumen 13.5-Fr dialysis catheter in the femoral vein. Every 24 hours during 5 consecutive days, blood was sampled at the Abylcap(r) inlet and outlet for different blood flows (QB:200-300-400 mL/min) with 100% O2 gas flow (QG) of 7 L/min, and for different QG (QG: 0.5-1-1.5-3-6-8 L/min) with QB400 mL/min. CO2 and O2 transfer remained constant over 5 days for a fixed QB. RESULTS: We found that, for a fixed QG of 7 L/min, CO2 transfer linearly and significantly increased with QB (i.e. from 58 +/- 8 to 98 +/- 16 mL/min for QB 200 to 400 mL/min). For a fixed QB of 400 mL/min, CO2 transfer non-linearly increased with QG (i.e. from 39 +/- 9 to 98 +/- 16 mL/min for QG 0.5 to 8 L/min) reaching a plateau at QG of 6 L/min. CONCLUSIONS: Hence, when using the Abylcap(r) ECCO2R in the treatment of ARDS patients the O2 flow should be at least 6 L/min while QB should be set at its maximum. PMID- 28085172 TI - Development of the first adult respiratory extracorporeal membrane oxygenation center in Croatia under emergency circumstances. AB - INTRODUCTION: We report on the challenges of establishing a successful adult respiratory extracorporeal membrane oxygenation (ECMO) center in a developing country like Croatia under emergency conditions. We further introduce measures that would improve the outcome of patients treated with ECMO for respiratory failure at the national level. METHODS: 100 consecutive adult patients treated with venovenous (VV) ECMO for acute respiratory failure were enrolled to the database prospectively from October 2009 until June 2016. A review of methodology in establishing an adult respiratory ECMO center is provided. RESULTS: 7 years after the establishment of the first respiratory ECMO center in Croatia the hospital mortality was 44% and ECMO procedure survival was 71%. With this data, our results are comparable to an average extracorporeal life support organization (ELSO) center. CONCLUSIONS: Our results demonstrate that a successful adult respiratory ECMO center can be established under emergency conditions even in less developed countries like Croatia. Today Croatia's respiratory ECMO network is insufficiently organized and the Ministry of Health should provide a comprehensive, national, ECMO network strategy. Currently, and contrary to the opinion of the world's leading experts, any hospital in Croatia is allowed to perform the ECMO procedure without any control or validation. Only if health policy makers in Croatia reconsider this issue will we be able to provide the best care possible for respiratory ECMO patients at the national level. PMID- 28085173 TI - Impact of chlorhexidine gluconate intolerance on driveline infection during chronic HeartMate II left ventricular assist device support. AB - PURPOSE: Driveline exit site (DLES) management following left ventricular assist device implantation is important for preventing driveline infection (DLI). While chlorhexidine gluconate (CHG) is generally recommended for DLES antisepsis, CHG intolerance can develop, resulting in a need for alternative antiseptics. We reviewed our institutional experience with DLES antisepsis methods in HeartMate II patients, comparing outcomes of patients with and without CHG intolerance. METHODS: Between October 2011 and March 2016, 44 patients underwent primary HeartMate II implantation. CHG was used for DLES antisepsis and povidone-iodine (PVP-I) was used in patients with CHG intolerance. DLI was defined by Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) criteria. RESULTS: Of 44 patients, 37 (84%) received CHG and 7 (16%) received PVP-I antisepsis due to CHG intolerance. Five patients (11.4%) developed a DLI, with an event per patient-year rate of 0.07. Median length of support was 521 days (interquartile range 202-881 days). Characteristics were similar between patients with and without DLI. However, a larger proportion of patients with DLI had CHG intolerance compared to patients without DLI (60.0% vs. 10.3%, p:0.05). Causative organisms were Staphylococcus aureus in CHG-intolerant patients and Stenotrophomonas and Acinetobacter in CHG-tolerant patients. Kaplan-Meier method and log-rank test demonstrated decreased infection-free days in patients using PVP-I rather than CHG (p:0.01). CONCLUSIONS: While the etiology of DLI is multifactorial, CHG intolerance appears to be a risk factor. Our findings highlight the need for larger studies comparing the efficacy of antiseptics for DLES care, particularly for patients with CHG contraindications. PMID- 28085174 TI - Mannose receptor as a potential biomarker for gastric cancer: a pilot study. AB - BACKGROUND: The mannose receptor is an immune adhesion molecule mainly expressed on the surface of antigen-presenting cells such as nonmature dendritic cells and macrophages. This study aimed to investigate mannose receptor expression and its predictive role in papillary gastric cancer patients. METHODS: The expression of the mannose receptor was measured in 120 samples of gastric cancer tissues and corresponding paracarcinoma tissues, by immunohistochemical and quantitative real time PCR analysis. The relationships between mannose receptor expression and clinicopathological features of gastric cancer patients were analyzed. RESULTS: The expression rate of the mannose receptor in gastric cancer cells was 45.8% (54/120), significantly higher than that in the paracarcinoma tissue (20.0%, 36/120) (chi2 = 6.286, p = 0.012). High expression of the mannose receptor was closely related to tumor size, T stage, N stage and Union for International Cancer Control (UICC) stage of gastric cancer (p<0.05). A Kaplan-Meier survival model indicated that the survival of patients in the high-expression mannose receptor group was significantly shorter than in the low-expression mannose receptor group (p<0.05). Cox regression analysis showed that high mannose receptor expression was an independent predictor for the prognosis of patients with gastric cancer. CONCLUSIONS: High mannose receptor expression indicates poor prognosis for gastric cancer patients. The mannose receptor may be an important molecular marker for gastric cancer prognosis. PMID- 28085175 TI - Cathepsin K expression in castration-resistant prostate carcinoma: a therapeutical target for patients at risk for bone metastases. AB - BACKGROUND: The lysosomal cysteine protease cathepsin K is involved in bone remodeling and is also expressed in the peritumoral stroma of carcinomas arising from different organs. A new generation of cathepsin K inhibitors blocking the RANKL/RANK pathway are being developed. We sought to investigate cathepsin K expression in a cohort of castration-resistant prostate carcinomas. METHODS: Sixteen cases of castration-resistant disease with at least 5 years of follow-up were selected from a cohort of 280 patients who underwent surgery. Cathepsin K was evaluated on formalin-fixed and paraffin-embedded tissue microarrays with 5 tissue spots per case. These were scored as high 2+ (>=30% of cells), low 1+ (<30% of cells) or zero (absence), distinguishing tumor cells and peritumoral stroma cells. Low (1+) and absence (0) of scoring were interpreted as negative, and high (2+) as positive. RESULTS: The castration-resistant group was composed of 15 acinar adenocarcinomas and 1 neuroendocrine carcinoma, and all showed at least Gleason score 8 at prostatectomy. Two out of 16 cases (12%) scored positive for cathepsin K in tumor cells; and 5 of 16 cases (31%) scored positive in peritumoral stroma cells. The neuroendocrine and acinar subtypes of carcinoma with positive immunoexpression in neoplastic cells developed bone metastases after 4 and 5 years, respectively, and subsequently died. CONCLUSIONS: Patients affected by castration-resistant prostate carcinoma may be tested for cathepsin K, and a positive strong expression (2+) could be a useful predictive biomarker of response to targeted agents, aiding in the selection of patients eligible for these treatments. PMID- 28085176 TI - Integration between oncology and palliative care: a plan for the next decade? AB - With the groundbreaking work of three Milan professors-Bonadonna, Veronesi, and Ventafridda-in the 1980s as the starting point, this article aims to shed light on the potential benefits of a closer and more formal integration between oncology and palliative care. More specifically, we address why integration is needed, how to do it, and the potential benefits to the patients, families, and society. The costs for cancer care are increasing rapidly. Especially during the last year of life, some treatments are futile and expensive without proven benefit for patients in terms of prolonged survival with adequate quality of life (QoL). The latest WHO definition of palliative care supports an upstream introduction of palliative care. More recent studies indicate that such an early integration has the potential to improve the patients' QoL and reduce their symptom burden. Successful integration presupposes formal structures and explicit obligations on how and when to integrate. The Norwegian model for palliative care is presented. It covers the range of oncologic and palliative services from community health care via the local hospital to the tertiary hospital and rests on standardized care pathway as the key instrument to promote integration. Our present state of knowledge indicates that integration does not shorten life; perhaps even the opposite. Futile oncological treatment can be reduced and the QoL of patients and carers improved. We need more evidence on the potential effect upon costs, but present data indicate that integration does not increase them. PMID- 28085177 TI - Surgery of locally advanced and metastatic kidney cancer after tyrosine kinase inhibitors therapy: single institute experience. AB - PURPOSE:: Renal cell carcinoma (RCC) is the most common tumor of the kidney. Considering the TNM classification of 2009, locally advanced and metastatic diseases are included in the groups stage III and IV. The surgical treatment of these tumors could be divided into 3 categories: (1) curative (nephrectomy and/or metastasectomy), (2) cytoreductive, and (3) palliative. Targeted agents showed impressive antitumor efficacy and prolongation of progression-free survival. The integration between target therapy and surgery in patients with locally advanced or metastatic RCC has sometimes facilitated surgery. We aimed to evaluate patients' response to tyrosine kinase inhibitor (TKI) therapy and the feasibility of surgery after that and to observe complications related to surgery. METHODS:: From February 2007 to September 2014 in the Istituto Tumori of Milan, IRCCS, we selected patients with locally advanced or metastatic diseases, treated with target therapy before surgery (which comprised nephrectomy or partial nephrectomy, cytoreductive surgery, and metastasectomy) and cryoablation. RESULTS:: We selected 33 patients who underwent surgery after TKI therapy. As for response to TKIs, 20 patients (60%) had stable disease, 9 patients (28%) had a partial response, and 4 patients (12%) had progressive disease. A total of 17 patients (51%) presented complications directly or indirectly related to surgery and most of those were classified as grade II Clavien-Dindo score. CONCLUSIONS:: The association between TKI and surgery seems to have no contraindications. Our dataset provides an example of how surgery after TKI is possible in locally advanced metastatic tumor and does not have an excessive rate of postoperative complications. PMID- 28085178 TI - Diabetes mellitus increases the risk of intrahepatic recurrence of hepatocellular carcinoma after surgical resection. AB - AIMS AND BACKGROUND: The relationship between cancer and metabolism has recently been receiving attention. We investigated the prognostic influence of type 2 diabetes mellitus in patients with hepatocellular carcinoma (HCC) treated with curative resection. METHODS AND STUDY DESIGN: The records of 58 patients who underwent curative resection for HCC pT1-2N0M0 between 2010 and 2014 were reviewed retrospectively. Fourteen patients (24.1%) had diabetes mellitus at diagnosis. Local control (LC) was defined as time to recurrence in the liver. RESULTS: The median follow-up was 23.3 months. Relapses occurred in 20 patients (34.5%) during the follow-up period; 17 of them developed intrahepatic recurrence, which was associated with diabetes mellitus (p = 0.013) and alpha fetoprotein (AFP) levels >500 ng/mL (p = 0.019). Overall relapses (n = 20) were related to T stage (p = 0.044), AFP level (p = 0.005), and diabetes (p = 0.044). The 3-year local control (intrahepatic control), disease-free survival, and overall survival rates were 56.7%, 50.5%, and 84.3%, respectively. LC was affected by diabetes mellitus (p = 0.046), Barcelona Clinic Liver Cancer staging (p<0.001), Milan criteria for transplantation (p = 0.041), serosal invasion (p = 0.032), and microvascular invasion (p = 0.043). Diabetes was also associated with reduced LC in the subgroup with hepatitis B-related HCC (n = 44, p = 0.028). CONCLUSIONS: Diabetes mellitus is correlated with intrahepatic HCC recurrence after surgery. Greater attention should be paid to managing patients with HCC and diabetes mellitus. PMID- 28085179 TI - Comparison of neoadjuvant vs concurrent/adjuvant androgen deprivation in men with high-risk prostate cancer receiving definitive radiation therapy. AB - PURPOSE: It is unknown whether there is a benefit to starting androgen deprivation therapy (ADT) prior to rather than concurrently with definitive radiation therapy in men with high-risk prostate cancer. We studied the National Cancer Data Base to determine whether the timing of ADT impacts survival. METHODS: Men diagnosed with high-risk prostate adenocarcinoma who received external beam radiation therapy (EBRT) to a dose of 70-81 Gy along with ADT from 2004-2011 were included. Those who started ADT 42-90 days before EBRT were identified as having received neoadjuvant hormonal therapy (N-HT) and those who received ADT from 14 days before their radiation until 84 days after the start of EBRT were categorized as receiving concurrent/adjuvant treatment (C-HT). We used the log-rank test to compare Kaplan-Meier survival curves and multivariable Cox regression to assess the impact of covariables on overall survival (OS). RESULTS: Among 11,491 included patients, those receiving N-HT were 1 year older (p<0.001) and more likely to have Gleason 8-10 disease (p = 0.01) and cT3-4 disease (p = 0.002). Men receiving N-HT had a 5-year and median OS of 80.6% and 111.4 months, respectively, compared to 78.3% and 108.9 months, respectively, in those receiving C-HT (p = 0.03). This benefit remained significant on multivariable analysis (hazard ratio 0.86, 95% confidence interval 0.77-0.96, p = 0.008). Duration of ADT was not available to report. CONCLUSIONS: External beam radiation therapy with N-HT was associated with improved overall survival compared to C-HT. This study is hypothesis-generating and further studies are needed to best qualify the sequencing of hormone therapy with the duration of treatment. PMID- 28085180 TI - Log D versus HPLC derived hydrophobicity: The development of predictive tools to aid in the rational design of bioactive peptoids. AB - Hydrophobicity has proven to be an extremely useful parameter in small molecule drug discovery programmes given that it can be used as a predictive tool to enable rational design. For larger molecules, including peptoids, where folding is possible, the situation is more complicated and the average hydrophobicity (as determined by RP-HPLC retention time) may not always provide an effective predictive tool for rational design. Herein, we report the first ever application of partitioning experiments to determine the log D values for a series of peptoids. By comparing log D and average hydrophobicities we highlight the potential advantage of employing the former as a predictive tool in the rational design of biologically active peptoids. PMID- 28085181 TI - Selection of effects in Cox frailty models by regularization methods. AB - In all sorts of regression problems, it has become more and more important to deal with high-dimensional data with lots of potentially influential covariates. A possible solution is to apply estimation methods that aim at the detection of the relevant effect structure by using penalization methods. In this article, the effect structure in the Cox frailty model, which is the most widely used model that accounts for heterogeneity in survival data, is investigated. Since in survival models one has to account for possible variation of the effect strength over time the selection of the relevant features has to distinguish between several cases, covariates can have time-varying effects, time-constant effects, or be irrelevant. A penalization approach is proposed that is able to distinguish between these types of effects to obtain a sparse representation that includes the relevant effects in a proper form. It is shown in simulations that the method works well. The method is applied to model the time until pregnancy, illustrating that the complexity of the influence structure can be strongly reduced by using the proposed penalty approach. PMID- 28085182 TI - A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes. AB - BACKGROUND: As panel testing becomes more common in clinical practice, it is important to understand the prevalence and trends associated with the pathogenic variants (PVs) identified. This is especially true for genetically heterogeneous cancers, such as breast cancer (BC), in which PVs in different genes may be associated with various risks and cancer subtypes. The authors evaluated the outcomes of genetic testing among women who had a personal history of BC. METHODS: A total of 35,409 women with a single diagnosis of BC who underwent clinical genetic testing with a 25-gene panel were included in the current analysis. Women with multiple BCs and men with BC were excluded. The frequency and distribution of PVs were assessed for the overall cohort, among women with triple-negative BC (TNBC) (n = 4797), and by age at diagnosis. RESULTS: PVs were identified in 9.3% of women tested; 51.5% of PVs were identified in genes other than breast cancer 1 (BRCA1) and BRCA2, including checkpoint kinase 2 (CHEK2) (11.7%), ataxia telangiectasia mutated (ATM; ATM serine/threonine kinase) (9.7%), and partner and localizer of BRCA2 (PALB2) (9.3%). The prevalence of PVs in BRCA1, PALB2, BRCA1-associated RING domain 1 (BARD1), BRCA1-interacting protein C terminal helicase 1 (BRIP1), and RAD51 paralog C (RAD51C) was statistically higher among women with TNBC. The PV rate was higher among women aged <40 years, lower among women aged >59 years, and relatively constant (8.5%-9.0%) among women who were diagnosed between ages 40 and 59 years. CONCLUSIONS: These results demonstrate that panel testing increased the number of women identified as carrying a PV in this cohort compared with BRCA testing alone. Furthermore, the proportion of women identified who carried a PV in this cohort did not decrease between ages 40 and 59 years. Cancer 2017;123:1721-1730. (c) 2017 American Cancer Society. PMID- 28085183 TI - Topical capsaicin (high concentration) for chronic neuropathic pain in adults. AB - BACKGROUND: This review is an update of 'Topical capsaicin (high concentration) for chronic neuropathic pain in adults' last updated in Issue 2, 2013. Topical creams with capsaicin are used to treat peripheral neuropathic pain. Following application to the skin, capsaicin causes enhanced sensitivity, followed by a period with reduced sensitivity and, after repeated applications, persistent desensitisation. High-concentration (8%) capsaicin patches were developed to increase the amount of capsaicin delivered; rapid delivery was thought to improve tolerability because cutaneous nociceptors are 'defunctionalised' quickly. The single application avoids noncompliance. Only the 8% patch formulation of capsaicin is available, with a capsaicin concentration about 100 times greater than conventional creams. High-concentration topical capsaicin is given as a single patch application to the affected part. It must be applied under highly controlled conditions, often following local anaesthetic, due to the initial intense burning sensation it causes. The benefits are expected to last for about 12 weeks, when another application might be made. OBJECTIVES: To review the evidence from controlled trials on the efficacy and tolerability of topically applied, high-concentration (8%) capsaicin in chronic neuropathic pain in adults. SEARCH METHODS: For this update, we searched CENTRAL, MEDLINE, Embase, two clinical trials registries, and a pharmaceutical company's website to 10 June 2016. SELECTION CRITERIA: Randomised, double-blind, placebo-controlled studies of at least 6 weeks' duration, using high-concentration (5% or more) topical capsaicin to treat neuropathic pain. DATA COLLECTION AND ANALYSIS: Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. Where pooled analysis was possible, we used dichotomous data to calculate risk ratio and numbers needed to treat for one additional event, using standard methods.Efficacy outcomes reflecting long-duration pain relief after a single drug application were from the Patient Global Impression of Change (PGIC) at specific points, usually 8 and 12 weeks. We also assessed average pain scores over weeks 2 to 8 and 2 to 12 and the number of participants with pain intensity reduction of at least 30% or at least 50% over baseline, and information on adverse events and withdrawals.We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We included eight studies, involving 2488 participants, two more studies and 415 more participants than the previous version of this review. Studies were of generally good methodological quality; we judged only one study at high risk of bias, due to small size. Two studies used a placebo control and six used 0.04% topical capsaicin as an 'active' placebo to help maintain blinding. Efficacy outcomes were inconsistently reported, resulting in analyses for most outcomes being based on less than complete data.For postherpetic neuralgia, we found four studies (1272 participants). At both 8 and 12 weeks about 10% more participants reported themselves much or very much improved with high-concentration capsaicin than with 'active' placebo, with point estimates of numbers needed to treat for an additional beneficial outcome (NNTs) of 8.8 (95% confidence interval (CI) 5.3 to 26) with high-concentration capsaicin and 7.0 (95% CI 4.6 to 15) with 'active' placebo (2 studies, 571 participants; moderate quality evidence). More participants (about 10%) had average 2 to 8-week and 2 to 12-week pain intensity reductions over baseline of at least 30% and at least 50% with capsaicin than control, with NNT values between 10 and 12 (2 to 4 studies, 571 to 1272 participants; very low quality evidence).For painful HIV neuropathy, we found two studies (801 participants). One study reported the proportion of participants who were much or very much improved at 12 weeks (27% with high-concentration capsaicin and 10% with 'active' placebo). For both studies, more participants (about 10%) had average 2 to 12-week pain intensity reductions over baseline of at least 30% with capsaicin than control, with an NNT of 11 (very low quality evidence).For peripheral diabetic neuropathy, we found one study (369 participants). It reported about 10% more participants who were much or very much improved at 8 and 12 weeks. One small study of 46 participants with persistent pain following inguinal herniorrhaphy did not show a difference between capsaicin and placebo for pain reduction (very low quality evidence).We downgraded the quality of the evidence for efficacy outcomes by one to three levels due to sparse data, imprecision, possible effects of imputation methods, and susceptibility to publication bias.Local adverse events were common, but not consistently reported. Serious adverse events were no more common with active treatment (3.5%) than control (3.2%). Adverse event withdrawals did not differ between groups, but lack of efficacy withdrawals were somewhat more common with control than active treatment, based on small numbers of events (six to eight studies, 21 to 67 events; moderate quality evidence, downgraded due to few events). No deaths were judged to be related to study medication. AUTHORS' CONCLUSIONS: High-concentration topical capsaicin used to treat postherpetic neuralgia, HIV-neuropathy, and painful diabetic neuropathy generated more participants with moderate or substantial levels of pain relief than control treatment using a much lower concentration of capsaicin. These results should be interpreted with caution as the quality of the evidence was moderate or very low. The additional proportion who benefited over control was not large, but for those who did obtain high levels of pain relief, there were usually additional improvements in sleep, fatigue, depression, and quality of life. High concentration topical capsaicin is similar in its effects to other therapies for chronic pain. PMID- 28085184 TI - Comparative effectiveness of first-line radiofrequency ablation versus surgical resection and transplantation for patients with early hepatocellular carcinoma. AB - BACKGROUND: Significant controversy exists as to which treatment modality is most effective for small, solitary hepatocellular carcinomas (HCCs): radiofrequency ablation (RFA), surgical resection (RXN), or transplantation (TXP). Size cutoff values ranging from 20 to 50 mm have been proposed to achieve complete ablation. The current study compares outcomes between RFA, RXN, and TXP as first-line therapy for patients with HCC tumors measuring as large as 50 mm. METHODS: The Surveillance, Epidemiology, and End Results database was queried for patients with HCC tumors measuring up to 50 mm who were treated with RFA, RXN, or TXP between 2004 and 2013. Overall survival (OS) and disease-specific survival (DSS) were examined in patients with tumors measuring <=20 mm, 21 to 30 mm, or 31 to 50 mm. The impact of an increase in tumor size of only 5 mm beyond 30 mm was evaluated by also examining outcomes in patients with tumors measuring 31 to 35 mm. RESULTS: Of 1894 cases, patients with HCC tumors measuring <=20 mm and 21 to 30 mm demonstrated no difference in OS or DSS regardless of whether RFA and RXN was used. RFA was associated with a worse OS and DSS than TXP, whereas there was no difference in OS observed between RXN and TXP. In patients with tumors measuring 31 to 50 mm, OS and DSS were worse with RFA compared with RXN or TXP. Most important, the inferior DSS and OS noted with RFA were observed with only a 5-mm increase in tumors measuring >30 mm. CONCLUSIONS: Although RFA frequently is used as first-line treatment of HCC tumors measuring as large as 50 mm, it is associated with worse results than RXN or TXP for tumors measuring >30 mm. To the best of the authors' knowledge, the results of the current study are the first to demonstrate that although RFA is an appropriate option for patients with HCC tumors measuring <=30 mm, its use for tumors even slightly larger than 30 mm is associated with inferior outcomes. Cancer 2017;123:1817-1827. (c) 2017 American Cancer Society. PMID- 28085185 TI - Reply to Management of hepatocellular carcinoma in thalassemia and importance of the human factor. PMID- 28085186 TI - The ability of Drosophila hybrids to locate food declines with parental divergence. AB - Hybrids are generally less fit than their parental species, and the mechanisms underlying their fitness reductions can manifest through different traits. For example, hybrids can have physiological, behavioral, or ecological defects, and these defects can generate reproductive isolation between their parental species. However, the rate that mechanisms of postzygotic isolation other than hybrid sterility and inviability evolve has remained largely uninvestigated, despite isolated studies showing that behavioral defects in hybrids are not only possible but might be widespread. Here, we study a fundamental animal behavior-the ability of individuals to find food-and test the rate at which it breaks down in hybrids. We measured the ability of hybrids from 94 pairs of Drosophila species to find food and show that this ability decreases with increasing genetic divergence between the parental species and that male hybrids are more strongly (and negatively) affected than females. Our findings quantify the rate that hybrid dysfunction evolves across the diverse radiation of Drosophila and highlights the need for future investigations of the genetic and neurological mechanisms that affect a hybrid's ability to find a suitable substrate on which to feed and breed. PMID- 28085187 TI - Digest: Climate effects on chipmunk cranial morphology. PMID- 28085188 TI - Racial disparities in treatment use for multiple myeloma. AB - BACKGROUND: Recent treatment advances have greatly improved the prognosis of patients with multiple myeloma. However, some of these newer, more effective treatments are intensive and expensive and their use remains low, particularly among black patients. METHODS: In the current study, the authors reviewed the use patterns of stem cell transplantation and bortezomib using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. RESULTS: After controlling for overall health and potential access barriers, black patients were found to be 37% (P<.0001) less likely to undergo stem cell transplantation, and 21% (P<.0001) less likely to be treated with bortezomib. Moreover, the authors found that the underuse of these treatments was associated with a 12% increase in the hazard ratio for death among black patients (P = 0.0007). CONCLUSIONS: Eliminating health disparities, a current focus of US public policy, is highly complex, as illustrated by the results of the current study. In patients with multiple myeloma, treatment disparities are not completely explained by potential access barriers. Additional factors, such as structural barriers in the health care system and individual decision making among black and white patients, must be explored to fully explain the disparity. Cancer 2017;123:1590-1596. (c) 2017 American Cancer Society. PMID- 28085189 TI - Digest: Splendid (continental) radiations. PMID- 28085190 TI - Digest: Beating pathogens at their own game. PMID- 28085191 TI - Developmental dynamics of ecomorphological convergence in a transcontinental lizard radiation. AB - Phenotypic convergence has confounded evolutionary biologists for centuries, explained as adaptations to shared selective pressures, or alternatively, the result of limited developmental pathways. We tested the relative roles of adaptation and constraint in generating convergent cranial morphologies across a large lizard radiation, the Lacertidae, whose members inhabit diverse environments throughout the Old World and display high amounts of homoplasy associated with ecological niche. Using 3D X-ray computed tomography, we quantified cranial shape variation associated with ontogeny, allometry, and ecology, covering all lacertid genera and one-third of species diversity. Landmark-based geometric morphometrics showed that cranial shape varied significantly among biomes, with substantial convergence among arid-dwelling lineages. Comparisons of species cranial growth trajectories between biomes revealed that allometric postdisplacement, as evidenced by decreased elevation of a constant ontogenetic slope, drives the convergent paedomorphic appearance of independent arid-dwelling forms. We hypothesize that observed heterochronic changes reflect temporal compression of ancestral life history in response to extreme environments, with associated phenotypes occurring as by-products of adaptive shifts in reproductive investment. Although allometry has long been considered a developmental constraint, our results demonstrate that allometric flexibility during early ontogeny produces convergent ecomorphologies over vast temporal and spatial scales, thus dramatically obscuring underlying phylogenetic signals. PMID- 28085192 TI - Macroevolutionary synthesis of flowering plant sexual systems. AB - Sexual system is a key determinant of genetic variation and reproductive success, affecting evolution within populations and within clades. Much research in plants has focused on evolutionary transitions away from the most common state of hermaphroditism and toward the rare state of dioecy (separate sexes). Rather than transitions predominantly toward greater sexual differentiation, however, evolution may proceed in the direction of lesser sexual differentiation. We analyzed the macroevolutionary dynamics of sexual system in angiosperm genera that contain both dioecious and nondioecious species. Our phylogenetic analyses encompass a total of 2145 species from 40 genera. Overall, we found little evidence that rates of sexual system transitions are greater in any direction. Counting the number of inferred state changes revealed a mild prevalence of transitions away from hermaphroditism and away from dioecy, toward states of intermediate sexual differentiation. We identify genera in which future studies of sexual system evolution might be especially productive, and we discuss how integrating genetic or population-level studies of sexual system could improve the power of phylogenetic comparative analyses. Our work adds to the evidence that different selective pressures and constraints act in different groups, helping maintain the variety of sexual systems observed among plants. PMID- 28085193 TI - Changes in spatiotemporal gait parameters following intravenous immunoglobulin treatment for chronic inflammatory demyelinating polyneuropathy. AB - INTRODUCTION: Gait impairment is a common presenting symptom in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). However, gait parameters have not previously been evaluated in detail as potential independent outcome measures. METHODS: We prospectively measured changes in spatiotemporal gait parameters of 20 patients with CIDP at baseline and following treatment with intravenous immunoglobulin (IVIG), using GAITRite(r) a computerized walkway system with embedded sensors. RESULTS: Overall, study patients showed significant improvements in gait velocity, cadence, stride length, double support time, stance phase, and swing phase following IVIG treatment. Mean changes in velocity, stance phase, and swing phase, exhibited the greatest statistical significance among the subgroup that exhibited clinically meaningful improvement in Inflammatory Neuropathy Cause and Treatment disability score, Medical Research Council sum score, and grip strength. CONCLUSIONS: Assessment of gait parameters, in particular velocity, step phase and swing phase, is a potentially sensitive outcome measure for evaluating treatment response in CIDP. Muscle Nerve 56: 732 736, 2017. PMID- 28085194 TI - Case Mis-Conceptualization in Psychological Treatment: An Enduring Clinical Problem. AB - Case conceptualization, an integral component of mental health treatment, aims to facilitate therapeutic gains by formulating a clear picture of a client's psychological presentation. However, despite numerous attempts to improve this clinical activity, it remains unclear how well existing methods achieve their purported purpose. Case formulation is inconsistently defined in the literature and implemented in practice, with many methods varying in complexity, theoretical grounding, and empirical support. In addition, many of the methods demand a precise clinical acumen that is easily influenced by judgmental and inferential errors. These errors occur regardless of clinicians' level of training or amount of clinical experience. Overall, the lack of a consensus definition, a diversity of methods, and susceptibility of clinicians to errors are manifestations of the state of crisis in case conceptualization. This article, the 2nd in a series of 5 on thematic mapping, argues the need for more reliable and valid models of case conceptualization. PMID- 28085195 TI - A Case Conceptualization Using Thematic Mapping. AB - This article, the last in a series of 5, presents a detailed case summary in which thematic mapping, a novel method of case conceptualization, was used to conceptualize an adult struggling with chronic depression. The case illustrates the process and therapeutic outcomes that resulted from the therapist's use of the 3-stage thematic mapping model: theme identification, theme interpretation, and theme intervention. The article also demonstrates how the case formulation guided the therapist in selecting therapeutic techniques that matched to the client's goals, needs, and interpersonal style. Overall, this article aims to demonstrate how thematic mapping utilizes transtheoretical and transdiagnostic approaches to create a case formulation that is client-centered, process oriented, and useful across a broad spectrum of training. PMID- 28085196 TI - Management of hepatocellular carcinoma in thalassemia and importance of the human factor. PMID- 28085197 TI - The Process of Thematic Mapping in Case Conceptualization. AB - This article, the 4th in a series of 5, introduces the 3-stage process of thematic mapping: theme identification, theme interpretation, and theme intervention. Theme identification is based on inductive reasoning, in which clinicians seek to discover and describe behavioral patterns in emotionally charged episodes. Theme interpretation subsequently initiates a process of deductive reasoning, wherein clinicians distill the generalized pattern into dominant and subthemes. Each theme is then labeled with a compelling metaphor that is representative of the theme interpretation. In the 3rd stage, theme intervention, clinicians seek to change the dysfunctional dominant and subthemes through collaboration with the clients. The process unfolds within 5 overarching parameters: a focus on comprehensiveness, simplification, maximal objectivity/impartial subjectivity, observation and inference, and an idiographic approach. Alternative models of case formulation are offered in comparison to thematic mapping. PMID- 28085198 TI - The Conceptual Framework of Thematic Mapping in Case Conceptualization. AB - This article, the 3rd in a series of 5, introduces the conceptual framework for thematic mapping, a novel approach to case conceptualization. The framework is transtheoretical in that it is not constrained by the tenets or concepts of any one therapeutic orientation and transdiagnostic in that it conceptualizes clients outside the constraints of diagnostic criteria. Thematic mapping comprises 4 components: a definition, foundational principles, defining features, and core concepts. These components of the framework, deemed building blocks, are explained in this article. Like the foundation of any structure, the heuristic value of the method requires that the building blocks have integrity, coherence, and sound anchoring. We assert that the conceptual framework provides a solid foundation, making thematic mapping a potential asset in mental health treatment. PMID- 28085199 TI - Thematic Mapping in Case Conceptualization: An Introduction to the Special Section. AB - Case conceptualization is an essential clinical activity in which clinicians, in one form or another, gather and synthesize data about their clients in order to formulate clinical pictures and maximize therapeutic gains. However, a myriad of methods of case conceptualization that vary in complexity and theoretical bases currently reflects an almost complete lack of standardization in this most fundamental activity of mental health treatment. The lack of standardization in case conceptualization is especially daunting to trainees and clinicians who are early in their careers. This special section, comprising 5 articles, introduces thematic mapping, a transtheoretical and transdiagnostic method of case conceptualization. The method aims to overcome or minimize many of the problems inherent in current practice. In this first article, we provide a rationale for the special section and lay the groundwork for the subsequent four articles. Overall, we assert that thematic mapping holds promise as a systematic method of case conceptualization. PMID- 28085200 TI - "Are You Having Thoughts of Suicide?" Examining Experiences With Disclosing and Denying Suicidal Ideation. AB - OBJECTIVE: To characterize individuals' prior experiences with being asked whether they are having thoughts of suicide and to understand factors that affected their response accuracy. METHOD: Undergraduates (N = 306) reporting a lifetime history of suicidal ideation completed a web-based survey about their experiences being probed about suicidal thoughts. RESULTS: Nearly two-thirds of participants (63.1%) reported having been previously asked whether they were having thoughts of suicide, with health care providers comprising the plurality of probers. Individuals reported the greatest accuracy of ideation disclosure to mental health professionals. Stigma-related concerns were the most common barriers to accurate disclosure of ideation, whereas wanting emotional support and the prober to understand them were cited as facilitators for accurately responding. CONCLUSION: A number of factors influence the accurate and inaccurate disclosure of suicidal ideation. Further research is needed to understand how to facilitate accurate disclosure of suicidal ideation across settings and populations. PMID- 28085201 TI - What do these scores mean? Presenting patient-reported outcomes data to patients and clinicians to improve interpretability. AB - BACKGROUND: Patient-reported outcomes (PROs) (eg, symptoms, functioning) can inform patient management. However, patients and clinicians often have difficulty interpreting score meaning. The authors tested approaches for presenting PRO data to improve interpretability. METHODS: This mixed-methods study included an Internet survey of cancer patients/survivors, oncology clinicians, and PRO researchers circulated via snowball sampling, plus individual in-person interviews. Clinical importance was conveyed using 3 approaches (presented in random order): normal score range shaded green, concerning scores circled in red, and red threshold lines indicating normal versus concerning scores. Versions also tested 2 approaches to score directionality: higher = more (better for function, worse for symptoms) and higher = better for both function and symptoms. Qualitative data from online comments and in-person interviews supplemented quantitative results on interpretation accuracy, clarity, and the "most useful" format. RESULTS: The survey included 1113 respondents: 627 survivors, 236 clinicians, and 250 researchers, plus 10 patients and 10 clinicians who were purposively sampled interviewees. Interpretation accuracy ranged from 53% to 100%. The formats in which higher = better were interpreted more accurately versus those in which higher = more (odds ratio [OR], 1.30; 95% confidence interval [CI], 1.07-1.58) and were more likely to be rated "very"/"somewhat" clear (OR, 1.39; 95% CI, 1.13-1.70) and "very" clear (OR, 1.36; 95% CI, 1.18 1.58). Red circle formats were interpreted more accurately than green-shaded formats when the first format presented (OR, 1.29; 95% CI, 1.00-1.65). Threshold line formats were more likely to be rated "very" clear than green-shaded (OR, 1.43; 95% CI, 1.19-1.71) and red-circled (OR, 1.22, 95% CI, 1.02-1.46) formats. Threshold lines were most often selected as "most useful." CONCLUSIONS: The current results support presenting PRO data with higher = better directionality and threshold lines indicating normal versus concerning scores. Cancer 2017;123:1848-1859. (c) 2017 The Authors. Cancer published byWiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations aremade. PMID- 28085202 TI - A Prospective Examination of Perceived Burdensomeness and Thwarted Belongingness As Risk Factors for Suicide Ideation In Adult Outpatients Receiving Cognitive Behavioral Therapy. AB - OBJECTIVE: The interpersonal-psychological theory of suicidal behavior posits that 2 proximal, causal, and interactive risk factors must be present for someone to desire suicide: perceived burdensomeness and thwarted belongingness. The purpose of the present study was to evaluate the predictive power of these 2 risk factors in a prospective study. METHOD: A total of 231 adult outpatients (age: mean = 38.1, standard deviation = 12.3) undergoing cognitive-behavioral therapy took part in a pretreatment and a midtreatment assessment after the 10th therapy session. RESULTS: Perceived burdensomeness, thwarted belongingness, and the interaction between these 2 risk factors did not add incremental variance to the prediction of midtreatment suicide ideation after controlling for age, gender, depression, hopelessness, impulsivity, lifetime suicide attempts, and pretreatment suicide ideation. The best predictor of midtreatment suicide ideation was pretreatment suicide ideation. CONCLUSION: Results offer only limited support to the assumptions of the interpersonal theory of suicide. PMID- 28085204 TI - Exercise in myasthenia gravis: A feasibility study of aerobic and resistance training. AB - INTRODUCTION: It has not been established whether progressive resistance training (PRT) and aerobic training (AT) are feasible and efficient in myasthenia gravis (MG). METHODS: Fifteen subjects with generalized MG (Myasthenia Gravis Foundation of America (MGFA) clinical classification II-IV) were randomly assigned to 20 training sessions during 8 weeks of either PRT or AT. Feasibility was evaluated based on adherence, drop-out rate, adverse events, and Quantitative Myasthenia Gravis (QMG) score. RESULTS: Twelve subjects (MGFA II, n = 11; MGFA III, n=1) completed the intervention with a mean adherence of 95 % +/- 8. One dropout (PRT) could potentially be related to PRT. Both groups reported adverse events, including bulbar symptoms (n = 2) and increased fatigue (n = 3), but no change in QMG score was observed in either group. The PRT group showed increases in maximal strength and functional capacity. CONCLUSIONS: Eight weeks of moderate to high intensity AT and PRT were feasible for most patients with mild MG. Maximal strength and functional capacity increased in the PRT group. Muscle Nerve 56: 700 709, 2017. PMID- 28085205 TI - NAFLD, Hepatotropic Viruses, and Cardiometabolic Risk. PMID- 28085203 TI - Extensive recent secondary contacts between four European white oak species. AB - Historical trajectories of tree species during the late Quaternary have been well reconstructed through genetic and palaeobotanical studies. However, many congeneric tree species are interfertile, and the timing and contribution of introgression to species divergence during their evolutionary history remains largely unknown. We quantified past and current gene flow events between four morphologically divergent oak species (Quercus petraea, Q. robur, Q. pyrenaica, Q. pubescens), by two independent inference methods: diffusion approximation to the joint frequency spectrum (?a?i) and approximate Bayesian computation (ABC). For each pair of species, alternative scenarios of speciation allowing gene flow over different timescales were evaluated. Analyses of 3524 single nucleotide polymorphisms (SNPs) randomly distributed in the genome, showed that these species evolved in complete isolation for most of their history, but recently came into secondary contact, probably facilitated by the most recent period of postglacial warming. We demonstrated that: there was sufficient genetic differentiation before secondary contact for the accumulation of barriers to gene flow; and current European white oak genomes are a mosaic of genes that have crossed species boundaries and genes impermeable to gene flow. PMID- 28085206 TI - Reply. PMID- 28085207 TI - Serum creatine kinase isoenzymes and macroenzymes in dogs with different neurologic diseases. AB - BACKGROUND: Increased serum activity of CK isoenzymes and macroenzymes, and in particular of the brain isoenzyme (CK-BB) has been reported in dogs with central nervous system (CNS) disorders. However, no studies on the possible differences in serum activities of CK iso- or macroenzymes (Macro-CK1 and Macro-CK2) in different neurologic diseases are available. OBJECTIVE: The aim of this study was to describe the electrophoretic distribution of CK iso- and macroenzymes in dogs with CNS disorders in order to assess whether this distribution depends on a specific neurologic disease. METHODS: This study was done on sera from 45 dogs with neurologic diseases (degenerative, n = 7; idiopathic epilepsy [IE], n = 14; inflammatory, n = 16; space occupying lesions [SOL], n = 8) and from 10 clinically healthy dogs. The separation of serum CK isoenzymes and macroenzymes was performed using an automated electrophoretic method already validated in dogs. RESULTS: Compared with healthy dogs, dogs with CNS disorders had significantly higher total CK and CK-BB activities, and a significantly lower Macro-CK2 activity (P < .001). Comparison of pathologic subgroups and healthy dogs revealed significant differences (P < .01) in dogs with IE and inflammatory disorders for total CK activity, in all the subgroups for CK-BB (P < .01), and in dogs with IE and SOL for Macro-CK2 (P < .01). CONCLUSIONS: The results of this study suggest that CK-BB is released by neurons damaged by inflammatory or degenerative conditions or due to compressive effects of SOL. However, the neurologic diseases cannot be differentiated based on CK-BB or Macro-CK2 activities, unless further studies allow the definition of diagnostic thresholds. PMID- 28085208 TI - Evaluation of congress abstracts for improving publishing ethics. PMID- 28085209 TI - Augmenter of liver regeneration: A fundamental life protein. PMID- 28085210 TI - Disruption of amygdala-entorhinal-hippocampal network in late-life depression. AB - Episodic memory deficits are evident in late-life depression (LLD) and are associated with subtle synaptic and neurochemical changes in the medial temporal lobes (MTL). However, the particular mechanisms by which memory impairment occurs in LLD are currently unknown. We tested older adults with (DS+) and without (DS-) depressive symptoms using high-resolution fMRI that is capable of discerning signals in hippocampal subfields and amygdala nuclei. Scanning was conducted during performance of an emotional discrimination task used previously to examine the relationship between depressive symptoms and amygdala-mediated emotional modulation of hippocampal pattern separation in young adults. We found that hippocampal dentate gyrus (DG)/CA3 activity was reduced during correct discrimination of negative stimuli and increased during correct discrimination of neutral items in DS+ compared to DS- adults. The extent of the latter increase was correlated with symptom severity. Furthermore, DG/CA3 and basolateral amygdala (BLA) activity predicted discrimination performance on negative trials, a relationship that depended on symptom severity. The impact of the BLA on depressive symptom severity was mediated by the DG/CA3 during discrimination of neutral items, and by the lateral entorhinal cortex (LEC) during false recognition of positive items. These results shed light on a novel mechanistic account for amygdala-hippocampal network changes and concurrent alterations in emotional episodic memory in LLD. The BLA-LEC-DG/CA3 network, which comprises a key pathway by which emotion modulates memory, is specifically implicated in LLD. (c) 2017 Wiley Periodicals, Inc. PMID- 28085211 TI - Evaluating kurtosis-based diffusion MRI tissue models for white matter with fiber ball imaging. AB - In order to quantify well-defined microstructural properties of brain tissue from diffusion MRI (dMRI) data, tissue models are typically employed that relate biological features, such as cell morphology and cell membrane permeability, to the diffusion dynamics. A variety of such models have been proposed for white matter, and their validation is a topic of active interest. In this paper, three different tissue models are tested by comparing their predictions for a specific microstructural parameter to a value measured independently with a recently proposed dMRI method known as fiber ball imaging (FBI). The three tissue models are all constructed with the diffusion and kurtosis tensors, and they are hence compatible with diffusional kurtosis imaging. Nevertheless, the models differ significantly in their details and predictions. For voxels with fractional anisotropies (FAs) exceeding 0.5, all three are reasonably consistent with FBI. However, for lower FA values, one of these, called the white matter tract integrity (WMTI) model, is found to be in much better accord with FBI than the other two, suggesting that the WMTI model has a broader range of applicability. PMID- 28085212 TI - Identification of a conserved gene signature associated with an exacerbated inflammatory environment in the hippocampus of aging rats. AB - There have been a few descriptive studies in aged rodents about transcriptome changes in the hippocampus, most of them in males. Here, we assessed the age changes in spatial memory performance and hippocampal morphology in female rats and compared those changes with changes in the hippocampal transcriptome. Old rats displayed significant deficits in spatial memory. In both age groups, hole exploration frequency showed a clear peak at hole 0 (escape hole), but the amplitude of the peak was significantly higher in the young than in the old animals. In the hippocampus, there was a dramatic reduction in neurogenesis, whereas reactive microglial infiltrates revealed an inflammatory hippocampal state in the senile rats. Hippocampal RNA-sequencing showed that 210 genes are differentially expressed in the senile rats, most of them being downregulated. Our RNA-Seq data showed that various genes involved in the immune response, including TYROBP, CD11b, C3, CD18, CD4, and CD74, are overexpressed in the hippocampus of aged female rats. Enrichment analysis showed that the pathways overrepresented in the senile rats matched those of an exacerbated inflammatory environment, reinforcing our morphologic findings. After correlating our results with public data of human and mouse hippocampal gene expression, we found an 11 gene signature of overexpressed genes related to inflammatory processes that was conserved across species. We conclude that age-related hippocampal deficits in female rats share commonalities between human and rodents. Interestingly, the 11 gene signature that we identified may represent a cluster of immune and regulatory genes that are deregulated in the hippocampus and possibly other brain regions during aging as well as in some neurodegenerative diseases and low-grade brain tumors. Our study further supports neuroinflammation as a promising target to treat cognitive dysfunction in old individuals and some brain tumors. (c) 2017 Wiley Periodicals, Inc. PMID- 28085213 TI - Transarterial chemoembolization prior to liver transplantation for patients with hepatocellular carcinoma: A meta-analysis. AB - BACKGROUND AND AIM: A debate exists over whether using preoperative transarterial chemoembolization for patients with hepatocellular carcinoma before liver transplantation. Numerous studies have been investigating on this, but there is still no unanimous conclusion about the effect of preoperative transarterial chemoembolization. We conducted the meta-analysis of all available studies to systematically evaluate the influence of preoperative transarterial chemoembolization on liver transplant. METHODS: A systematic search was performed by two authors (Si TF. and Guan RY.) through PubMed, Embase, Cochrane, and Science Citation Index Expanded, combined with Manual Retrieval and Cited Reference Search. The searching cut-off date was 2016/07/31, and all the data obtained were statistically analyzed using Review Manager version 5.1 software (Copenhagen, The Nordic Cochrane Center, The Cochrane Collaboration, 2011) recommended by Cochrane Collaboration. RESULTS: The study showed that there was no difference between the experimental group and the control group on perioperative mortality (RR = 1.10, 95% confidence interval (CI) = [0.49-2.48], P = 0.82) or biliary complications (RR = 0.96, 95%CI = [0.66-1.39], P = 0.83). Preoperative transarterial chemoembolization had no obvious effect on improving overall survival (HR = 1.05, 95%CI = [0.65-1.72], P = 0. 83) but would result in a higher rate of vascular complications (RR = 2.01, 95%CI = [1.23-3.27], P = 0.005) and a reduction of disease free survival (HR = 1.66, 95%CI = [1.02-2.70], P = 0.04). Subgroup analysis also revealed that patients from transarterial chemoembolization group in Asia had a much lower overall survival rate (HR = 2.65, 95%CI = [1.49-4.71], P = 0.0009) compared with the control group. CONCLUSIONS: Considering the possible adverse impacts on liver transplantation and the variation in sensitivity to transarterial chemoembolization, clinicians should be more cautious when considering transarterial chemoembolization as the bridging therapy for patients in the waiting list. PMID- 28085214 TI - Morphological and functional changes in RAW264 macrophage-like cells in response to a hydrated layer of carbonate-substituted hydroxyapatite. AB - Synthetic hydroxyapatite (HAp) is used clinically as a material for bone prostheses owing to its good bone-bonding ability; however, it does not contribute to bone remodeling. Carbonate-substituted hydroxyapatite (CAp) has greater bioresorption capacity than HAp while having similar bone-bonding potential, and is therefore considered as a next promising material for bone prostheses. However, the effects of the CAp instability on inflammatory and immune responses are unknown in detail. Here, we show that the surface layer of CAp is more hydrated than that of HAp and induces changes in the shape and function of macrophage-like cells. HAp and CAp were synthesized by wet method and molded into disks. The carbonate content of CAp disks was 6.2% as determined by Fourier transform (FT) infrared spectral analysis. Diffuse reflectance infrared FT analysis confirmed that physisorbed water and surface hydroxyl groups (OH- ) were increased whereas structural OH- was decreased on the CAp as compared to the HAp surface. The degree of hydroxylation in CAp was comparable to that in bone apatite structures, and the CAp surface exhibited greater hydrophilicity and solubility than HAp. We investigated immune responses to these materials by culturing RAW264 cells (macrophage precursors) on their surfaces. Cell spreading on the CAp disk was suppressed and the secretion level of inflammatory cytokines was reduced as compared to cells grown on HAp. These results indicate that the greater surface hydration of CAp surface can attenuate adverse inflammatory responses to implanted bone prostheses composed of this material. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1063-1070, 2017. PMID- 28085215 TI - Interactions of human embryonic stem cell-derived cardiovascular progenitor cells with immobilized extracellular matrix proteins. AB - Human embryonic stem cell-derived cardiovascular progenitor cells (hESC-CVPCs) hold great promise for cell-based therapies of heart diseases. However, little is known about their niche microenvironment and in particular the required extracellular matrix (ECM) components. Here we screened combinations of surface immobilized ECM proteins to identify substrates that support the attachment and survival of hESC-CVPCs. Covalent immobilization of ECM proteins laminin (Lm), fibronectin (Fn), collagen I (CI), collagen III (CIII), and collagen IV (CIV) in multiple combinations and concentrations was achieved by reductive amination on transparent acetaldehyde plasma polymer (AAPP) interlayer coatings. We identified that CI, CIII, CIV, and Fn and their combinations were important for hESC-CVPC attachment and survival, while Lm was dispensable. Moreover, for coatings displaying single ECM proteins, CI and CIII performed better than CIV and Fn, while coatings displaying the combined ECM proteins CIII + CIV and Fn + CIII + CIV at 100 ug/mL were comparable to Matrigel in regard to supporting hESC-CVPC attachment and viability. Our results identify ECM proteins required for hESC CVPCs and demonstrate that coatings displaying multiple immobilized ECM proteins offer a suitable microenvironment for the attachment and survival of hESC-CVPCs. This knowledge contributes to the development of approaches for maintaining hESC CVPCs and therefore to advances in cardiovascular regeneration. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1094-1104, 2017. PMID- 28085216 TI - Simultaneous determination of volatile organic compounds with a wide range of polarities in urine by headspace solid-phase microextraction coupled to gas chromatography/mass spectrometry. AB - RATIONALE: Volatile organic compounds (VOCs) are ubiquitous environmental pollutants that have a high vapor pressure at room temperature. Some VOCs have been classified as carcinogenic to humans by the International Agency for Research on Cancer (IARC), because they can bind to DNA and cause cell mutations. Therefore, monitoring of VOCs in human urine is very important to evaluate the correlation between exposure to VOCs and human disease. METHODS: We have developed an improved analytical method for the simultaneous determination of VOCs with a wide range of polarities in human urine samples by headspace solid phase microextraction (HS-SPME) coupled to gas chromatography/mass spectrometry (GC/MS). In the improved method, a bi-polar carboxen-polydimethylsiloxane (CAR/PDMS) fiber was used for the optimized extraction of 15 VOCs with a wide range of polarities, including benzene, toluene, ethylbenzene, xylenes (BTEX), alkylbenzenes, cresols, and naphthalene, in human urine samples. Extracted VOCs from the human urine were effectively separated by GC using a mid-polarity column (DB-35, 35% phenylmethylpolysiloxane) and monitored by MS using extracted ion monitoring (EIM) mode. RESULTS: Under the optimized method, the linearity of the calibration curves was greater than 0.993. The limits of detection (LODs) at a signal-to-noise (S/N) ratio of 3 were 0.3-0.6 ng/mL. The coefficients of variation were in the range of 0.1-9.7% for within-day variation and 0.2-14.2% for day-to-day variation. CONCLUSIONS: The method was shown to be rapid and simple for the simultaneous determination of VOCs with a wide range of polarities in human urine and it could be applied to monitoring and to biomedical investigations to check exposure to VOCs. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28085217 TI - The Patient-Worker: A Model for Human Research Subjects and Gestational Surrogates. AB - We propose the 'patient-worker' as a theoretical construct that responds to moral problems that arise with the globalization of healthcare and medical research. The patient-worker model recognizes that some participants in global medical industries are workers and are owed worker's rights. Further, these participants are patient-like insofar as they are beneficiaries of fiduciary relationships with healthcare professionals. We apply the patient-worker model to human subjects research and commercial gestational surrogacy. In human subjects research, subjects are usually characterized as either patients or as workers. Through questioning this dichotomy, we argue that some subject populations fit into both categories. With respect to commercial surrogacy, we enrich feminist discussions of embodied labor by describing how surrogates are beneficiaries of fiduciary obligations. They are not just workers, but patient-workers. Through these applications, the patient-worker model offers a helpful normative framework for exploring what globalized medical industries owe to the individuals who bear the bodily burdens of medical innovation. PMID- 28085218 TI - Comment on "Cryptosporidium Infection Risk: Results of New Dose-Response Modeling" - Discussion of Underlying Assumptions and Their Implications. PMID- 28085219 TI - From the Editors. PMID- 28085220 TI - Chemotype diversity in Planktothrix rubescens (cyanobacteria) populations is correlated to lake depth. AB - The cyanobacterial species Planktothrix rubescens is known to preferably inhabit deep, stratified, oligo- to mesotrophic lakes. It is also known for the production of diverse bioactive peptides, including the hepatotoxic microcystins. A number of studies showed that P. rubescens populations generally consist of multiple distinct genotypes or chemotypes, respectively. In the present study, variability of chemotype diversity was analysed. Filaments of P. rubescens were isolated from water samples originating from 10 European lakes and analysed by MALDI-TOF mass spectrometry. In most of the analysed filaments multiple peptides belonging to multiple peptide classes could be detected. A resulting data matrix of 964 filaments and 37 individual peptides was subjected to correspondence analysis and K-means clustering. From the latter analysis the distribution of chemotypes among the lakes was established and diversity estimated by computing Shannon-Indices. Diversity varied strongly among lakes with the lowest diversity found in non-alpine lakes. Further, chemotype diversity was strongly correlated to the maximum depth of the sampled lakes in alpine and non-alpine lakes. The possible influence of both factors, geographic isolation and water column depth, on the observed patterns of chemotype diversity of P. rubescens populations is discussed. PMID- 28085221 TI - Understanding the molecular mechanisms driving metastasis. PMID- 28085222 TI - Epithelial-mesenchymal transition in tumor metastasis. AB - The epithelial-mesenchymal transition (EMT) is a developmental program that enables stationary epithelial cells to gain the ability to migrate and invade as single cells. Tumor cells reactivate EMT to acquire molecular alterations that enable the partial loss of epithelial features and partial gain of a mesenchymal phenotype. Our understanding of the contribution of EMT to tumor invasion, migration, and metastatic outgrowth has evolved over the past decade. In this review, we provide a summary of both historic and recent studies on the role of EMT in the metastatic cascade from various experimental systems, including cancer cell lines, genetic mouse tumor models, and clinical human breast cancer tissues. PMID- 28085226 TI - Sensitivity and Specificity of Radiographic Scoring Instruments for Detecting Change in Axial Psoriatic Arthritis. AB - OBJECTIVE: There is no widely recognized method used to assess axial disease in psoriatic arthritis (PsA). We aimed to determine the sensitivity to change of the Bath Ankylosing Spondylitis Radiology Index for the spine (BASRI-s), the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), the Radiographic Ankylosing Spondylitis Spine Score (RASSS), and the PsA Spondylitis Radiology Index (PASRI) in axial PsA. METHODS: Radiographs of 105 patients with axial PsA were retrieved for 2 time points at least 2 years apart and subsequently anonymized. All radiographs were scored by 3 rheumatologists blinded to name and order of examination using an electronic application that allowed recording of disease manifestations specific to axial PsA and automatically calculated the BASRI-s, mSASSS, RASSS, and PASRI scores. An independent expert determined whether there was true radiographic progression from an overall impression after viewing the radiographs with knowledge of chronologic order. The sensitivity, specificity, and odds ratios for every 1-unit increase in the scores were determined to identify true change. RESULTS: Of the patients studied, 25 (24%) showed progression, as determined by the independent expert. The respective sensitivity and specificity values for an increase in score to detect true change were as follows: 0.48 and 0.78 (BASRI-s), 0.52 and 0.84 (mSASSS), 0.44 and 0.84 (RASSS), and 0.52 and 0.74 (PASRI). Logistic regression analyses showed that an increase of 1 point in the respective scores was associated with the following odds ratios for identifying true progression: BASRI-s 3.0, mSASSS 5.27, RASSS 3.70, and PASRI 3.06. CONCLUSION: Available scoring systems for quantifying radiographic axial PsA have moderate sensitivity but high specificity for detecting true change. PMID- 28085223 TI - Circulating and disseminated tumor cells: harbingers or initiators of metastasis? AB - Tumor cells leave the primary tumor and enter the circulation. Once there, they are called circulating tumor cells (CTCs). A fraction of CTCs are capable of entering distant sites and persisting as disseminated tumor cells (DTCs). An even smaller fraction of DTCs are capable of progressing toward metastases. It is known that the DTC microenvironment plays an important role in sustaining their survival, regulating their growth, and conferring resistance to therapy. But we still have much to learn about the nature of these rare cell populations to predict which will progress and what exactly should cause concern for future relapse. Although recent technological advances in our ability to detect and molecularly and functionally characterize CTCs and DTCs promise to unravel this ambiguity, the timing of dissemination and the precise source of CTCs and DTCs profiled will impact the conclusions that can be made from these endeavors. In this review, we discuss the biology of CTCs and DTCs; the technologies to detect, isolate, and profile these cells; and the exceptions we must apply to our understanding of what role these cells play in the metastatic process. We conclude that a greater effort to understand the unique biology of these cells in context will positively impact our ability to use these cells to predict outcome, monitor treatment efficacy, and reveal therapeutically relevant targets to deplete these populations and ultimately prevent metastasis. PMID- 28085227 TI - Snoring and components of metabolic syndrome in Southeastern Chinese adults: A community-based study. AB - INTRODUCTION: Snoring has been associated with a number of abnormal conditions, but little work has been done on its association with components of metabolic syndrome based on the epidemiology in Chinese adults. OBJECTIVE: This study aimed to investigate the association between snoring and components of metabolic syndrome in southeastern Chinese adults. METHODS: A two-stage, cross-sectional community-based study was performed in Fuzhou, Southeast China, from 2005 to 2009. Stage 1: 5500 subjects were administered a questionnaire. Data on self reported snoring status, daytime somnolence, demographic data, disease histories, and potential confounders were collected and anthropometric measurements were performed. Stage 2: 1000 subjects who were already investigated underwent a blood test and measurement of blood pressure. RESULTS: Data from 4286 subjects were available; 606 subjects were habitual snorers. The prevalence of overweight or obesity, hyperglycemia, hypertension, and dyslipidemia in occasional and habitual snorers was higher than that in the study population (16.66%, 7.89%, 10.52%, and 5.81%, respectively). A significantly increasing trend based on snoring frequency existed in the prevalence of metabolic disorders. The prevalence of components of metabolic syndrome continued to be significantly associated with snoring frequency after controlling confounding factors. Odds ratios of suffering from the aforementioned conditions for occasional and habitual snorers were 1.5-2.5 (P < 0.05) and 2.4-4.8 (P < 0.001) times higher, respectively, compared with nonsnorers. CONCLUSIONS: The prevalence of snoring and components of metabolic syndrome is high in southeastern Chinese adults. Both habitual and occasional snoring are closely associated with metabolic disorders independent of confounding factors. PMID- 28085228 TI - The LpxL acyltransferase is required for normal growth and penta-acylation of lipid A in Burkholderia cenocepacia. AB - Lipid A anchors the lipopolysaccharide (LPS) to the outer membrane and is usually composed of a hexa-acylated diglucosamine backbone. Burkholderia cenocepacia, an opportunistic pathogen, produces a mixture of tetra- and penta-acylated lipid A. "Late" acyltransferases add secondary acyl chains to lipid A after the incorporation of four primary acyl chains to the diglucosamine backbone. Here, we report that B. cenocepacia has only one late acyltransferase, LpxL (BCAL0508), which adds a myristoyl chain to the 2' position of lipid A resulting in penta acylated lipid A. We also identified PagL (BCAL0788), which acts as an outer membrane lipase by removing the primary beta-hydroxymyristate (3-OH-C14:0) chain at the 3 position, leading to tetra-acylated lipid A. Unlike PagL, LpxL depletion caused reduced cell growth and defects in cell morphology, both of which were suppressed by overexpressing the LPS flippase MsbA (BCAL2408), suggesting that lipid A molecules lacking the fifth acyl chain contributed by LpxL are not good substrates for the flippase. We also show that intracellular B. cenocepacia within macrophages produced more penta-acylated lipid A, suggesting lipid A penta acylation in B. cenocepacia is required not only for bacterial growth and morphology but also for adaptation to intracellular lifestyle. PMID- 28085224 TI - Modes of invasion during tumour dissemination. AB - Cancer cell migration and invasion underlie metastatic dissemination, one of the major problems in cancer. Tumour cells exhibit a striking variety of invasion strategies. Importantly, cancer cells can switch between invasion modes in order to cope with challenging environments. This ability to switch migratory modes or plasticity highlights the challenges behind antimetastasis therapy design. In this Review, we present current knowledge on different tumour invasion strategies, the determinants controlling plasticity and arising therapeutic opportunities. We propose that targeting master regulators controlling plasticity is needed to hinder tumour dissemination and metastasis. PMID- 28085225 TI - Determinants of metastatic competency in colorectal cancer. AB - Colorectal cancer (CRC) is one of the most common cancer types and represents a major therapeutic challenge. Although initial events in colorectal carcinogenesis are relatively well characterized and treatment for early-stage disease has significantly improved over the last decades, the mechanisms underlying metastasis - the main cause of death - remain poorly understood. Correspondingly, no effective therapy is currently available for advanced or metastatic disease. There is increasing evidence that colorectal cancer is hierarchically organized and sustained by cancer stem cells, in concert with various stromal cell types. Here, we review the interplay between cancer stem cells and their microenvironment in promoting metastasis and discuss recent insights relating to both patient prognosis and novel targeted treatment strategies. A better understanding of these topics may aid the prevention or reduction of metastatic burden. PMID- 28085230 TI - Reply. PMID- 28085229 TI - Importance of pulmonary artery to ascending aorta ratio in chronic obstructive pulmonary disease. AB - INTRODUCTION: Recent articles revealed that an increased main pulmonary artery to ascending aorta ratio (PA/A) in thorax computed tomography (CT) correlated with pulmonary hypertension, and might be linked to a high probability of chronic obstructive pulmonary disease (COPD) exacerbations. OBJECTIVES: In this study, our aim was to evaluate the clinical importance of PA/A in patients with exacerbations of COPD and investigate its relationship with the number of exacerbations in 1 year or short/long-term mortality after hospital discharge. METHODS: One hundred fifty-six patients hospitalized for COPD exacerbations who fulfilled our inclusion criteria were enrolled in the study. We recorded the number of exacerbations in 1 year from hospital records, checked mortality status, and calculated the PA/A ratio from thorax CT images. RESULTS: PA/A ratio positively correlated with the number of hospitalizations for COPD exacerbations and the total number of exacerbations (hospitalized or not) in 1 year, and baseline PaCO2 level during hospitalization (r = 0.376, P < 0.001, r = 0.230, P = 0.004, and r = 0.328, P < 0.001, respectively). There was no relationship between mortality and PA/A. CONCLUSION: Our study showed that PA/A was related with the number of hospitalizations and the total number of exacerbations due to COPD in 1 year. However, there was no relationship between PA/A and mortality. PMID- 28085231 TI - Long-term prevalence of the protists Crithidia bombi and Apicystis bombi and detection of the microsporidium Nosema bombi in invasive bumble bees. AB - An initial survey in 2009 carried out at a site in northwestern Patagonia region, Argentina, revealed for the first time in South America the presence of the flagellate Crithidia bombi and the neogregarine Apicystis bombi, two pathogens associated with the Palaearctic invasive bumble bee Bombus terrestris. In order to determine the long-term persistence and dynamics of this microparasite complex, four additional collections at the same site (San Carlos de Bariloche) were conducted along the following seven years. Both protists were detected in all collections: prevalence was 2%-21.6% for C. bombi and 1.2%-14% for A. bombi. In addition, the microsporidium Nosema bombi was recorded for the first time in the country in the last two collections, at prevalences of 12.4% and 2.4% and unusually high infection intensities (Average = 6.56 * 107 spores per individual). Due to the exceptional dispersal ability of the exotic B. terrestris, these three multihost pathogens should be considered as potential threats to South American native bumble bees. PMID- 28085232 TI - Comparison of treatment outcomes between balloon-occluded retrograde transvenous obliteration and transjugular intrahepatic portosystemic shunt for gastric variceal bleeding hemostasis. AB - BACKGROUND AND AIM: Both balloon-occluded retrograde transvenous obliteration (BRTO) and transjugular intrahepatic portosystemic shunt (TIPS) are considered effective treatments for gastric variceal bleeding (GVB). In this study, outcomes of these two procedures were compared in managing patients with GVB. METHODS: A total of 142 patients undergoing BRTO (n = 95) or TIPS (n = 47) between 2005 and 2012 at two tertiary centers were selected for retrospective review. RESULTS: Mean patient age (male, 115; female, 27) was 58.1 years. Alcoholic liver cirrhosis was the most common underlying cause (n = 63, 44.4%), followed by hepatitis B (n = 60, 42.3%) and hepatitis C (n = 7, 4.9%) viral infections. Concurrent hepatocellular carcinoma (HCC) was identified in 64 (45.1%) patients. During the follow-up period (mean, 28.2 months), 27 patients (19%) experienced re bleeding. Cumulative re-bleeding rates after BRTO (8.6% at 1 year; 22.7% at 3 years) were significantly lower than those after TIPS (19.8% at 1 year; 48.2% at 3 years; P = 0.006, log-rank test). In multivariate analysis, TIPS (vs BRTO) was found independently predictive of re-bleeding (hazard ratio [HR] = 2.174; P = 0.048), in addition to concurrent HCC and poor baseline Child-Pugh score (both P < 0.05). Although BRTO surpassed TIPS (P = 0.026, log-rank test) in terms of overall postprocedural survival, independent factors predictive of poor overall survival after hemostasis were concurrent HCC (HR = 3.106), high Child-Pugh score (HR = 1.886 per 1-point increase), and postprocedural hepatic encephalopathy (HR = 3.014; all P < 0.05). CONCLUSION: Balloon-occluded retrograde transvenous obliteration proved more effective than TIPS in hemostasis of GVB, associated with significantly less risk of re-bleeding. PMID- 28085234 TI - Clarification of modeling procedures and results are needed in a study of the prognostic role of dietary fiber on activity-related knee pain: comment on the article by Dai et al. PMID- 28085233 TI - Next-generation sequencing of liquid-based cytology non-small cell lung cancer samples. AB - BACKGROUND: The detection of mutated epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) with residual cell pellets derived from liquid based cytology (LBC) samples (eg, endoscopic ultrasound-guided fine-needle aspiration) has been validated with allele-specific polymerase chain reaction. The aim of this study was to validate next-generation sequencing (NGS) technology for detecting gene mutations with residual cell pellets from LBC. METHODS: Archived DNA extracted from LBC samples of adenocarcinoma stored in PreservCyt with a known EGFR mutation status was retrieved. Genomic DNA was multiplex amplified and enriched with Ion AmpliSeq Cancer Hotspot Panel v2 chemistry and the OneTouch 2 instrument; this was followed by semiconductor sequencing on the Ion Personal Genome Machine platform. The mutation hotspots of 6 NSCLC-related genes (BRAF, EGFR, ERBB2, KRAS, MET, and phosphatidylinositol-4,5-bisphosphate 3 kinase catalytic subunit alpha [PIK3CA]) were analyzed with NextGENe and Torrent Suite bioinformatics tools. RESULTS: The commonly identified EGFR sequence changes, including 4 L858R mutations, 3 exon 19 deletions, and 1 exon 20 insertion, were in 100% concordance between the assay platforms. Less common NSCLC variants were also found in the mutation hotspots of ERBB2, KRAS, MET, and PIK3CA genes. CONCLUSIONS: NSCLC mutation analysis using NGS can be successfully performed on residual cell pellets derived from LBC samples. This approach allows the simultaneous examination of multiple mutation hotspots in a timely manner to improve patient care. Cancer Cytopathol 2017;125:178-187. (c) 2016 American Cancer Society. PMID- 28085235 TI - Antinuclear Matrix Protein 2 Autoantibodies and Edema, Muscle Disease, and Malignancy Risk in Dermatomyositis Patients. AB - OBJECTIVE: Dermatomyositis (DM) patients typically present with proximal weakness and autoantibodies that are associated with distinct clinical phenotypes. We observed that DM patients with autoantibodies recognizing the nuclear matrix protein NXP-2 often presented with especially severe weakness. The aim of this study was to characterize the clinical features associated with anti-NXP-2 autoantibodies. METHODS: There were 235 DM patients who underwent testing for anti-NXP-2 autoantibodies. Patient characteristics, including muscle strength, were compared between those with and without these autoantibodies. The number of cancer cases observed in anti-NXP-2-positive subjects was compared with the number expected in the general population. RESULTS: Of the DM patients, 56 (23.8%) were anti-NXP-2-positive. There was no significant difference in the prevalence of proximal extremity weakness in patients with and without anti-NXP 2. In contrast, anti-NXP-2-positive patients had more prevalent weakness in the distal arms (35% versus 20%; P = 0.02), distal legs (25% versus 8%; P < 0.001), and neck (48% versus 23%; P < 0.001). Anti-NXP-2-positive subjects were also more likely to have dysphagia (62% versus 35%; P < 0.001), myalgia (46% versus 25%; P = 0.002), calcinosis (30% versus 17%; P = 0.02), and subcutaneous edema (36% versus 19%; P = 0.01) than anti-NXP-2-negative patients. Five anti-NXP-2-positive subjects (9%) had cancer-associated myositis, representing a 3.68-fold increased risk (95% confidence interval 1.2-8.6) compared to the expected prevalence in the general population. CONCLUSION: In DM, anti-NXP-2 autoantibodies are associated with subcutaneous edema, calcinosis, and a muscle phenotype characterized by myalgia, proximal and distal weakness, and dysphagia. As anti-NXP-2-positive patients have an increased risk of cancer, we suggest that they undergo comprehensive cancer screening. PMID- 28085236 TI - Budesonide reduces hospital admission rates in preschool children with acute wheezing. AB - BACKGROUND: The object of this study was to determine whether high doses of inhaled budesonide provide additional benefits to a standardized treatment regimen that includes systemic steroids and salbutamol in preschool patients presented to the emergency department (ED) with acute wheezing attacks. Methods This randomized, double-blind, placebo-controlled, parallel group trial was conducted in children, 6 months-6 years with moderate or severe acute wheezing epizode, as determined based on a pulmonary index score (PIS) of 7-13 points. We compared the addition of budesonide 3 mg versus placebo to standard acute asthma treatment, which included salbutamol and a single 1 mg/kg dose of methylprednisolone given at the beginning of therapy. The primary outcome was differences in hospitalization rates within 4 hr. Secondary outcome was difference in median PIS between treatment groups at 2 hr. Results One hundred patients were enrolled. Cumulative hospitalization rate at 120, 180, and 240 min were 0.72, 0.62, and 0.58 in placebo group; and 0.44, 0.30, and 0.24 in budesonide group. Discharged rate in budesonide group was significantly higher than the placebo group (log-rank = 12.407 ve P < 0.001). Expected mean discharged times were 200.4 (95%CI = 185.3-215.5) min in placebo group and 164.4 (95%CI = 149.4-179.4) min in budesonide group. Median (25-75%) PIS at the 120th min was significantly lower in budesonide group than the placebo group (5 [4-8] vs. 8 [5 9] respectively, P = 0.006). Conclusions The addition of budesonide nebulization may decrease the admission rate of preschool children who have moderate to severe acute wheezing epizodes. Pediatr Pulmonol. 2017;52:720-728. (c) 2017 Wiley Periodicals, Inc. PMID- 28085237 TI - Cancer Cytopathology enters its third decade. PMID- 28085239 TI - Iron Oxide Nanosheets and Pulse-Electrodeposited Ni-Co-S Nanoflake Arrays for High-Performance Charge Storage. AB - Nanostructured nickel cobalt sulfide (Ni4.5Co4.5S8) has been prepared through a single-step pulse-electrodeposition method. Iron oxide nanosheets at hollow graphite shells (Fe3O4@g-shells) were prepared from graphite-coated iron carbide/alpha-Fe (g-Fe3C/Fe) in a two-step annealing/electrochemical cycling process. Electrochemical characterization of the Ni4.5Co4.5S8 and g-Fe3C/Fe materials showed that both have high specific capacities (206 mAh g-1 and 147 mAh g-1 at 1 A g-1) and excellent rate capabilities (~95% and ~83% retention at 20 A g-1, respectively). To demonstrate the advantageous pairing of these high rate materials, a full-cell battery with supercapacitor-like power behavior was assembled with Ni4.5Co4.5S8 and g-Fe3C/Fe as the positive and negative electrodes, respectively. The (Ni4.5Co4.5S8//g-Fe3C/Fe) device could be reversibly operated in a 0.0-1.6 V potential window, delivering an impressive specific energy of 89 Wh kg-1 at 1.1 kW kg-1 and a remarkable rate performance of 61 Wh kg-1 at a very high specific power of 38.5 kW kg-1. Additionally, long-term cycling demonstrated that the asymmetric full cell assembly retained 91% of its initial specific capacity after 2500 cycles at 40 A g-1. The performance features of this device are among the best for iron oxide/hydroxide and bimetallic sulfide based energy storage devices to date, thereby giving insight into design principles for the next generation high-energy-density devices. PMID- 28085238 TI - Comparison of sitting and supine forced vital capacity in collagen VI-related dystrophy and laminin alpha2-related dystrophy. AB - BACKGROUND: Progressive, restrictive, respiratory insufficiency is the major cause of morbidity and mortality in Congenital Muscular Dystrophy (CMD). Nocturnal hypoventilation precedes daytime alveolar hypoventilation, and if untreated, may lead to respiratory failure and cor pulmonale. CMD consensus care guidelines recommend screening for respiratory insufficiency by conventional and dynamic (sitting to supine) pulmonary function testing (PFT) and evaluating for sleep disordered breathing if there is more than 20% relative reduction from sitting to supine FVC(L) (DeltaFVC). OBJECTIVE: The objective of this retrospective study was to explore and characterize dynamic FVC measures in 51 individuals with two common subtypes of CMD, COL6-RD, and LAMA2-RD. METHODS: We compared sitting and supine FVC in patients with confirmed mutation(s) in either COL6 or LAMA2. We investigated influences of age, CMD subtype, gender, race, ambulatory status, and non-invasive positive pressure ventilation (NIPPV) status on FVC percent predicted (FVCpp) and DeltaFVC. RESULTS: COL6-RD participants exhibited a significant difference between sitting and supine mean FVCpp (sitting 66.1, supine 55.1; P < 0.0001) and were 5.4 times more likely to have -DeltaFVC >20% than those with LAMA2-RD when controlling for ambulant status. FVCpp sitting correlated inversely with age in individuals <=18 years. CONCLUSION: FVCpp sitting decreases progressively in childhood in both CMD subtypes. However, our results point to a difference in diaphragmatic involvement, with COL6-RD individuals having more disproportionate diaphragmatic weakness than LAMA2-RD. A DeltaFVC of greater than -20% should continue to be used to prompt evaluation of sleep-disordered breathing. Timely initiation of NIPPV may be indicated to treat nocturnal hypoventilation. Pediatr Pulmonol. 2017;52:524-532. (c) 2017 Wiley Periodicals, Inc. PMID- 28085240 TI - Design of Hierarchical Surfaces for Tuning Wetting Characteristics. AB - Patterned surfaces with tunable wetting properties are described. A hybrid hierarchical surface realized by combining two different materials exhibits different wetting states, depending on the speed of impingement of the water droplets. Both "lotus" (high contact angle and low adhesion) and "petal" (high contact angle and high adhesion) states were observed on the same surface without the need of any modification of the surface. The great difference between the capillary pressures exerted by the microstructures and nanostructures was the key factor that allowed us to tailor effectively the adhesiveness of the water droplets. Having a low capillary pressure for the microstructures and a high capillary pressure for the nanostructures, we allow to the surface the possibility of being in a lotus state or in a petal state. PMID- 28085241 TI - Specifically Formed Corona on Silica Nanoparticles Enhances Transforming Growth Factor beta1 Activity in Triggering Lung Fibrosis. AB - A corona is a layer of macromolecules formed on a nanoparticle surface in vivo. It can substantially change the biological identity of nanomaterials and possibly trigger adverse responses from the body tissues. Dissecting the role of the corona in the development of a particular disease may provide profound insights for understanding toxicity of nanomaterials in general. In our present study, we explored the capability of different silica nanoparticles (SiNPs) to induce silicosis in the mouse lung and analyzed the composition of coronas formed on these particles. We found that SiNPs of certain size and surface chemistry could specifically recruit transforming growth factor beta1 (TGF-beta1) into their corona, which subsequently induces the development of lung fibrosis. Once embedded into the corona on SiNPs, TGF-beta1 was remarkably more stable than in its free form, and its fibrosis-triggering activity was significantly prolonged. Our study meaningfully demonstrates that a specific corona component on a certain nanoparticle could initiate a particular pathogenic process in a clinically relevant disease model. Our findings may shed light on the understanding of molecular mechanisms of human health risks correlated with exposure to small scale substances. PMID- 28085242 TI - Layered Poly(ethylene-co-vinyl acetate)/Poly(ethylene-co-vinyl alcohol) Membranes with Enhanced Water Separation Selectivity and Performance. AB - A three-layered membrane based on poly(ethylene-co-vinyl acetate) (EVA) and hydrolyzed EVA-poly(ethylene-co-vinyl alcohol) (EVOH), was elaborated by the surface hydrolysis of a dense EVA membrane. Because of the chemical modifications, the three-layered EVOH/EVA/EVOH membrane was characterized by the particular microstructure (amorphous EVA and semicrystalline EVOH) and the tunable hydrophilic/hydrophobic balance. Also, these modifications led to the membrane with the selective barrier properties compared with the pure EVA and completely hydrolyzed EVOH membranes. The water barrier behavior was related to the strong hydrogen-bond interactions of water and vinyl alcohol groups, whereas the weak chemical interactions were revealed for gases (N2 and O2). Furthermore, the influence of the polymer rubbery or glassy state on the permeation kinetics was established. In the case of the three-layered membrane, the considerably high selectivity values were obtained for H2O/O2 (~11 900) and H2O/N2 (~48 000) at 25 degrees C. In addition to these highly selective properties, the three-layered structure does not present delamination features due to its elaboration procedure. Thus, these new layered membranes are very promising as selective materials for the water and gas separation and can be potentially used in food packaging or for the gas dehydration. PMID- 28085243 TI - Optimally Functionalized Adhesion for Contact Transfer Printing of Plasmonic Nanostructures on Flexible Substrate. AB - This paper demonstrates a facile method to achieve high yield and uniform fabrication for the transfer printing of nanoplasmonic structures on a flexible substrate by providing novel understanding on adhesion layers. The mercapto alkyl carboxylic acids and the alkyl dithiols are used as functionalized adhesion layers and further optimized by controlling the terminal group as well as the length and composition of the functionalization on flat and nanostructured gold surfaces. Our approach of optimized adhesion has been successfully implemented to the transfer printing of functionalized gold nanostructure arrays, thus producing much higher yield of 97.6% and uniform fabrication of nanostructures on a flexible substrate and enabling applications such as flexible nanoplasmonic devices and biosensing platforms. PMID- 28085244 TI - Submolecular Electroluminescence Mapping of Organic Semiconductors. AB - The electroluminescence of organic films is the central aspect in organic light emitting diodes (OLEDs) and widely used in current display technology. However, its spatial variation on the molecular scale is essentially unexplored. Here, we address this issue by using scanning tunneling microscopy (STM) and present an in depth study of the electroluminescence from thin C60 films (<10 monolayers) on Ag(111) and Au(111) surfaces. Similar to an OLED, the metal substrate and STM tip inject complementary charge carriers that may recombine within the molecular film; however, the atomically defined charge injection by the tip enables mapping of the local electroluminescence down to the submolecular scale. We show that the radiative recombination in solid C60 is restricted to various structural defects, whose emission characteristics can be addressed individually. The emission fine structure reveals a coupling to Jahn-Teller active vibrational modes of C60, which implies that its parity-forbidden lowest singlet transition becomes locally allowed at the emission centers. At lateral distances of a few nanometers, only a weak emission from tip-induced plasmons is detectable. Their excitation evidences the injection of both charge carrier types and confirms that they are unable to recombine radiatively at positions far from structural defects. Finally, we demonstrate that the molecular orbital pattern visible in electroluminescence maps enables an unambiguous discrimination between the intrinsic radiative recombination of electron-hole pairs in the organic film and the technique related emission of tip-induced plasmons. This capability is essential to consolidate STM as a tool to explore the light generation from organic films on the nanoscale. PMID- 28085245 TI - Stereoselective Polymer-Supported Synthesis of Morpholine- and Thiomorpholine-3 carboxylic Acid Derivatives. AB - Herein we report the polymer-supported synthesis of 3,4-dihydro-2H-1,4-oxazine-3 carboxylic acid derivatives using immobilized Fmoc-Ser(tBu)-OH and Fmoc-Thr(tBu) OH as the starting materials. After the solid-phase-synthesis of N-alkyl-N sulfonyl/acyl intermediates, the target dihydrooxazines were obtained using trifluoroacetic acid-mediated cleavage from the resin. This approach was also studied for the preparation of dihydrothiazines from immobilized Fmoc-Cys(Trt) OH. Inclusion of triethylsilane in the cleavage cocktail resulted in the stereoselective formation of the corresponding morpholine/thiomorpholine-3 carboxylic acids. Stereochemical studies revealed the specific configuration of the newly formed stereocenter and also the formation of stable N-acylmorpholine rotamers. PMID- 28085247 TI - The Quarter-Century Anniversary of Carbon Nanotube Research. PMID- 28085246 TI - Genetic Organization of Anabaenopeptin and Spumigin Biosynthetic Gene Clusters in the Cyanobacterium Sphaerospermopsis torques-reginae ITEP-024. AB - Cyanobacteria produce a broad range of natural products, many of which are potent protease inhibitors. Biosynthetic gene clusters encoding the production of novel protease inhibitors belonging to the spumigin and anabaenopeptin family of nonribosomal peptides were identified in the genome of the bloom-forming cyanobacterium Sphaerospermopsis torques-reginae ITEP-024. The genetic architecture and gene organization of both nonribosomal peptide biosynthetic clusters were compared in parallel with their chemical structure variations obtained by liquid chromatography (LC-MS/MS). The spumigin (spu) and anabaenopeptin (apt) gene clusters are colocated in the genomes of S. torques reginae ITEP-024 and Nodularia spumigena CCY9414 and separated by a 12 kb region containing genes encoding a patatin-like phospholipase, l-homophenylalanine (l Hph) biosynthetic enzymes, and four hypothetical proteins. hphABCD gene cluster encoding the production of l-Hph was linked to all eight apt gene clusters investigated here. We suggest that while the HphABCD enzymes are an integral part of the anabaenopeptin biosynthetic pathway, they provide substrates for the biosynthesis of both anabaenopeptins and spumigins. The organization of the spu and apt suggests a plausible model for the biosynthesis of the 4-(4 hydroxyphenyl)-2-acid (Hpoba) precursor of spumigin variants in S. torques reginae ITEP-024 based on the acceptable substrates of HphABCD enzymes. PMID- 28085248 TI - Robust Gold Nanoparticle Sheets by Ligand Cross-Linking at the Air-Water Interface. AB - We report the results of cross-linking of two-dimensional gold nanoparticle (Au NP) assemblies at the air-water interface in situ. We introduce an aqueous soluble ruthenium benzylidene catalyst into the water subphase to generate a robust, elastic two-dimensional network of nanoparticles containing cyclic olefins in their ligand framework. The most striking feature of the cross-linked Au-NP assemblies is that the extended connectivity of the nanoparticles enables the film to preserve much of its integrity under compression and expansion, features that are absent in its non-cross-linked counterparts. The cross-linking process appears to "stitch" the nanoparticle crystalline domains together, allowing the cross-linked monolayers to behave like a piece of fabric under lateral compression. PMID- 28085250 TI - Self-Assembly of Hierarchical DNA Nanotube Architectures with Well-Defined Geometries. AB - An essential motif for the assembly of biological materials such as actin at the scale of hundreds of nanometers and beyond is a network of one-dimensional fibers with well-defined geometry. Here, we demonstrate the programmed organization of DNA filaments into micron-scale architectures where component filaments are oriented at preprogrammed angles. We assemble L-, T-, and Y-shaped DNA origami junctions that nucleate two or three micron length DNA nanotubes at high yields. The angles between the nanotubes mirror the angles between the templates on the junctions, demonstrating that nanoscale structures can control precisely how micron-scale architectures form. The ability to precisely program filament orientation could allow the assembly of complex filament architectures in two and three dimensions, including circuit structures, bundles, and extended materials. PMID- 28085249 TI - Enhanced Cell Capture on Functionalized Graphene Oxide Nanosheets through Oxygen Clustering. AB - With the global rise in incidence of cancer and infectious diseases, there is a need for the development of techniques to diagnose, treat, and monitor these conditions. The ability to efficiently capture and isolate cells and other biomolecules from peripheral whole blood for downstream analyses is a necessary requirement. Graphene oxide (GO) is an attractive template nanomaterial for such biosensing applications. Favorable properties include its two-dimensional architecture and wide range of functionalization chemistries, offering significant potential to tailor affinity toward aromatic functional groups expressed in biomolecules of interest. However, a limitation of current techniques is that as-synthesized GO nanosheets are used directly in sensing applications, and the benefits of their structural modification on the device performance have remained unexplored. Here, we report a microfluidic-free, sensitive, planar device on treated GO substrates to enable quick and efficient capture of Class-II MHC-positive cells from murine whole blood. We achieve this by using a mild thermal annealing treatment on the GO substrates, which drives a phase transformation through oxygen clustering. Using a combination of experimental observations and MD simulations, we demonstrate that this process leads to improved reactivity and density of functionalization of cell capture agents, resulting in an enhanced cell capture efficiency of 92 +/- 7% at room temperature, almost double the efficiency afforded by devices made using as synthesized GO (54 +/- 3%). Our work highlights a scalable, cost-effective, general approach to improve the functionalization of GO, which creates diverse opportunities for various next-generation device applications. PMID- 28085251 TI - Differential Ability of Five DNA Glycosylases to Recognize and Repair Damage on Nucleosomal DNA. AB - Damage to genomic DNA leads to mutagenesis and disease. Repair of single base damage is initiated by DNA glycosylases, the first enzymes in the base excision repair pathway. Although eukaryotic packaging of chromosomal DNA in nucleosomes is known to decrease DNA glycosylase efficiency, the impact on individual glycosylases is unclear. Here, we present a model system in which we examine the repair of site-specific base damage in well-characterized nucleosome core particles by five different DNA glycosylases. We find that DNA glycosylase efficiency on nucleosome substrates depends not only on the geometric orientation of the damaged base but also on its identity, as well as on the size, structure, and mechanism of the glycosylase. We show via molecular modeling that inhibition of glycosylase activity is largely due to steric obstruction by the nucleosome core. PMID- 28085252 TI - Effective Propagation of Surface Plasmon Polaritons on Graphene-Protected Single Crystalline Silver Films. AB - Silver (Ag) is a promising material for manipulation of surface plasmon polaritons (SPPs), due to its optical and electrical properties; however, the intrinsic properties are easily degraded by surface corrosion under atmospheric conditions, restricting its applications in plasmonics. Here, we address this issue via single-crystalline Ag films protected with graphene layers and demonstrate effective propagation of SPPs on the graphene-protected Ag films. Single-crystalline Ag films with atomically flat surfaces are prepared by epitaxial growth; graphene layers are then transferred onto the Ag films. The propagation lengths of SPPs on the graphene-protected Ag films are measured, and their variations under corrosive conditions are investigated. The initial SPP propagation lengths for the bare Ag films are very long (about 50 MUm in the wavelength range 550-700 nm). However, the values decrease significantly (11-13 MUm) under corrosive conditions. On the contrary, the double-layer-graphene protected Ag films exhibit SPP propagation lengths of about 23 MUm and retain over 90% (21-23 MUm) of the propagation lengths even after exposure to corrosive conditions, guaranteeing the reliability of Ag plasmonic devices. This approach can encourage extending the application of the graphene-metal hybrid structure and thus developing Ag plasmonic devices. PMID- 28085253 TI - Crowd-Sourced Verification of Computational Methods and Data in Systems Toxicology: A Case Study with a Heat-Not-Burn Candidate Modified Risk Tobacco Product. AB - Systems toxicology intends to quantify the effect of toxic molecules in biological systems and unravel their mechanisms of toxicity. The development of advanced computational methods is required for analyzing and integrating high throughput data generated for this purpose as well as for extrapolating predictive toxicological outcomes and risk estimates. To ensure the performance and reliability of the methods and verify conclusions from systems toxicology data analysis, it is important to conduct unbiased evaluations by independent third parties. As a case study, we report here the results of an independent verification of methods and data in systems toxicology by crowdsourcing. The sbv IMPROVER systems toxicology computational challenge aimed to evaluate computational methods for the development of blood-based gene expression signature classification models with the ability to predict smoking exposure status. Participants created/trained models on blood gene expression data sets including smokers/mice exposed to 3R4F (a reference cigarette) or noncurrent smokers/Sham (mice exposed to air). Participants applied their models on unseen data to predict whether subjects classify closer to smoke-exposed or nonsmoke exposed groups. The data sets also included data from subjects that had been exposed to potential modified risk tobacco products (MRTPs) or that had switched to a MRTP after exposure to conventional cigarette smoke. The scoring of anonymized participants' predictions was done using predefined metrics. The top 3 performers' methods predicted class labels with area under the precision recall scores above 0.9. Furthermore, although various computational approaches were used, the crowd's results confirmed our own data analysis outcomes with regards to the classification of MRTP-related samples. Mice exposed directly to a MRTP were classified closer to the Sham group. After switching to a MRTP, the confidence that subjects belonged to the smoke-exposed group decreased significantly. Smoking exposure gene signatures that contributed to the group separation included a core set of genes highly consistent across teams such as AHRR, LRRN3, SASH1, and P2RY6. In conclusion, crowdsourcing constitutes a pertinent approach, in complement to the classical peer review process, to independently and unbiasedly verify computational methods and data for risk assessment using systems toxicology. PMID- 28085254 TI - "Click Chip" Conjugation of Bifunctional Chelators to Biomolecules. AB - There is a growing demand for diagnostic procedures including in vivo tumor imaging. Radiometal-based imaging agents are advantageous for tumor imaging because radiometals (i) have a wide range of half-lives and (ii) are easily incorporated into imaging probes via a mild, rapid chelation event with a bifunctional chelator (BFC). Microfluidic platforms hold promise for synthesis of radiotracers because they can easily handle minute volumes, reduce consumption of expensive reagents, and minimize personnel exposure to radioactive compounds. Here we demonstrate the use of a "click chip" with an immobilized Cu(I) catalyst to facilitate the "click chemistry" conjugation of BFCs to biomolecules (BMs); a key step in the synthesis of radiometal-based imaging probes. The "click chip" was used to synthesize three different BM-BFC conjugates with minimal amounts of copper present in reaction solutions (~20 ppm), which reduces or obviates the need for a copper removal step. These initial results are promising for future endeavors of synthesizing radiometal-based imaging agents completely on chip. PMID- 28085255 TI - Enhancing the Efficiency of Silicon-Based Solar Cells by the Piezo-Phototronic Effect. AB - Although there are numerous approaches for fabricating solar cells, the silicon based photovoltaics are still the most widely used in industry and around the world. A small increase in the efficiency of silicon-based solar cells has a huge economic impact and practical importance. We fabricate a silicon-based nanoheterostructure (p+-Si/p-Si/n+-Si (and n-Si)/n-ZnO nanowire (NW) array) photovoltaic device and demonstrate the enhanced device performance through significantly enhanced light absorption by NW array and effective charge carrier separation by the piezo-phototronic effect. The strain-induced piezoelectric polarization charges created at n-doped Si-ZnO interfaces can effectively modulate the corresponding band structure and electron gas trapped in the n+-Si/n ZnO NW nanoheterostructure and thus enhance the transport process of local charge carriers. The efficiency of the solar cell was improved from 8.97% to 9.51% by simply applying a static compress strain. This study indicates that the piezo phototronic effect can enhance the performance of a large-scale silicon-based solar cell, with great potential for industrial applications. PMID- 28085256 TI - Chronic Exposure Effects of Silver Nanoparticles on Stream Microbial Decomposer Communities and Ecosystem Functions. AB - With the accelerated use of silver nanoparticles (AgNP) in commercial products, streams will increasingly serve as recipients of, and repositories for, AgNP. This raises concerns about the potential toxicity of these nanomaterials in the environment. Here we aimed to assess the impacts of chronic AgNP exposure on the metabolic activities and community structure of fungal and bacterial plant litter decomposers as central players in stream ecosystems. Minimal variation in the size and surface charge of AgNP indicated that nanoparticles were rather stable during the experiment. Five days of exposure to 0.05 and 0.5 MUM AgNP in microcosms shifted bacterial community structure but had no effect on a suite of microbial metabolic activities, despite silver accumulation in the decomposing leaf litter. After 25 days, however, a broad range of microbial endpoints, as well as rates of litter decomposition, were strongly affected. Declines matched with the total silver concentration in the leaves and were accompanied by changes in fungal and bacterial community structure. These results highlight a distinct sensitivity of litter-associated microbial communities in streams to chronic AgNP exposure, with effects on both microbial functions and community structure resulting in notable ecosystem consequences through impacts on litter decomposition and further biogeochemical processes. PMID- 28085257 TI - Formation Mechanisms in beta-Ca3(PO4)2-ZnO Composites: Structural Repercussions of Composition and Heat Treatments. AB - Composites with varied proportions of beta-Ca3(PO4)2 and ZnO were obtained through an in situ aqueous precipitation method under slightly basic (pH ~ 8) conditions. The formation of beta-Ca3(PO4)2 phase starts at an early heat treatment stage (~800 degrees C) and incorporates Zn2+ ions at both Ca2+(4) and Ca2+(5) sites of the lattice up to its occupancy saturation limit. The incorporation of Zn2+ in the beta-Ca3(PO4)2 lattice enhances its thermal stability delaying the allotropic beta-Ca3(PO4)2->alpha-Ca3(PO4)2 phase transformation. The excess zinc beyond the occupancy saturation limit precipitates as Zn(OH)2 and undergoes dehydroxylation to form ZnO at elevated temperatures. The presence of ZnO in the beta-Ca3(PO4)2 matrix yields denser microstructures and thus improves the mechanical features of sintered composites up to an optimal ZnO concentration beyond which it tends to exert an opposite effect. PMID- 28085258 TI - New Insight into the Synthesis of Large-Pore Ordered Mesoporous Materials. AB - Ordered mesoporous materials (OMMs) have received increasing interest due to their uniform pore size, high surface area, various compositions and wide applications in energy conversion and storage, biomedicine and environmental remediation, etc. The soft templating synthesis using surfactants or amphiphilic block copolymers is the most efficient method to produce OMMs with tailorable pore structure and surface property. However, due to the limited choice of commercially available soft templates, the common OMMs usually show small pore size and amorphous (or semicrystalline) frameworks. Tailor-made amphiphilic block copolymers with controllable molecular weights and compositions have recently emerged as alternative soft templates for synthesis of new OMMs with many unique features including adjustable mesostructures and framework compositions, ultralarge pores, thick pore walls, high thermal stability and crystalline frameworks. In this Perspective, recent progresses and some new insights into the coassembly process about the synthesis of OMMs based on these tailor-made copolymers as templates are summarized, and typical newly developed synthesis methods and strategies are discussed in depth, including solvent evaporation induced aggregation, ligand-assisted coassembly, solvent evaporation induced micelle fusion-aggregation assembly, homopolymer assisted pore expanding and carbon-supported crystallization strategy. Then, the applications of the obtained large-pore OMMs in catalysis, sensor, energy conversion and storage, and biomedicine by loading large-size guest molecules (e.g., protein and RNA), precious metal nanoparticles and quantum dots, are discussed. At last, the outlook on the prospects and challenges of future research about the synthesis of large-pore OMMs by using tailor-made amphiphilic block copolymers are included. PMID- 28085259 TI - Unique Approach to Copper(I) Silylene Chalcogenone Complexes. AB - Silylene-S-thione [PhC(NtBu)2Si(?S)N(SiMe3)2] (2) and silylene-Se-selone [PhC(NtBu)2Si(?Se)N(SiMe3)2] (3) compounds were prepared from the silylene [PhC(NtBu)2SiN(SiMe3)2] (1) with 1 equiv of 1/8 S8 and 1 equiv of Se powder, respectively, in high yields. Furthermore, compounds 2 and 3 reacted with CuCl and CuBr and yielded [{PhC(NtBu)2}Si(?S->CuX)N(SiMe3)2] (X = Cl (4), Br (5)) and [{PhC(NtBu)2}Si(?Se->CuX)N(SiMe3)2] (X = Cl (6), Br (7)), respectively. Complexes 4-7 can also be obtained from the direct reaction of sulfur and selenium with the corresponding silylene copper complexes [{PhC(NtBu)2}Si{N(SiMe3)2}]2Cu2X2 (X = Cl (8), Br (9)). The latter route avoids the preparation of the highly reactive silylene chalcogenones. For comparison purposes the silylene PhC(NtBu)2SiN(SiMe3)2 in 2 and 3 was replaced by NHC (1,3-bis(2,6 bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene) (10). The resulting products NHC?S (thione 11) and NHC?Se (selenone 12) react with CuBr and lead to the expected complexes (NHC?S->CuBr) (13) and (NHC?Se->CuBr) (14). However, unlike silylene complexes, 13 and 14 cannot be prepared by reacting NHC-CuBr (15) with chalcogens. PMID- 28085260 TI - Surface Coordination Chemistry of Metal Nanomaterials. AB - Surface coordination chemistry of nanomaterials deals with the chemistry on how ligands are coordinated on their surface metal atoms and influence their properties at the molecular level. This Perspective demonstrates that there is a strong link between surface coordination chemistry and the shape-controlled synthesis, and many intriguing surface properties of metal nanomaterials. While small adsorbates introduced in the synthesis can control the shapes of metal nanocrystals by minimizing their surface energy via preferential coordination on specific facets, surface ligands properly coordinated on metal nanoparticles readily promote their catalysis via steric interactions and electronic modifications. The difficulty in the research of surface coordination chemistry of nanomaterials mainly lies in the lack of effective tools to characterize their molecular surface coordination structures. Also highlighted are several model material systems that facilitate the characterizations of surface coordination structures, including ultrathin nanostructures, atomically precise metal nanoclusters, and atomically dispersed metal catalysts. With the understanding of surface coordination chemistry, the molecular mechanisms behind various important effects (e.g., promotional effect of surface ligands on catalysis, support effect in supported metal nanocatalysts) of metal nanomaterials are disclosed. PMID- 28085261 TI - Fermentation Results in Quantitative Changes in Milk-Derived Exosomes and Different Effects on Cell Growth and Survival. AB - The discovery of microRNAs encapsulated in milk-derived exosomes has revealed stability under extreme conditions reflecting the protection of membranes. We attempted to determine the variations in nanoparticles derived from milk after fermentation, and provide evidence to determine the effects of these exosomes on cells with potential bioactivity. Using scanning electron microscopy and dynamic light scattering, we compared the morphology and particle size distribution of exosomes from yogurt fermented with three different combinations of strains with those from raw milk. The protein content of the exosome was significantly reduced in fermented milk. The cycle threshold showed that the expression of miR-29b and miR-21 was relatively high in raw milk, indicating a loss of microRNA after fermentation. Milk-derived exosomes could promote cell growth and activate the mitogen-activated protein kinase pathway. These findings demonstrated biological functions in milk exosomes and provided new insight into the nutrient composition of dairy products. PMID- 28085262 TI - Effect of Disinfectant Exposure on Legionella pneumophila Associated with Simulated Drinking Water Biofilms: Release, Inactivation, and Infectivity. AB - Legionella pneumophila, the most commonly identified causative agent in drinking water associated with disease outbreaks, can be harbored by and released from drinking water biofilms. In this study, the release of biofilm-associated L. pneumophila under simulated drinking water flow containing a disinfectant residual was examined. Meanwhile, the inactivation and infectivity (to amoebae) of the released L. pneumophila were studied. To simulate drinking water system conditions, biofilms were prepared under either disinfectant exposure (predisinfected biofilms) or disinfectant-free (untreated biofilms) conditions, respectively. For experiments with water flow containing a disinfectant to release the biofilm-associated L. pneumophila from these two types of biofilms, the L. pneumophila release kinetics values from predisinfected and untreated biofilms under flow condition were not statistically different (one-way ANOVA, p > 0.05). However, inactivation of the L. pneumophila released from predisinfected biofilms was 1-2 times higher and amoeba infectivity was 2-29 times lower than that from untreated biofilms. The higher disinfectant resistance of L. pneumophila released from untreated biofilms was presumably influenced by the detachment of a larger amount of biofilm material (determined by 16S rRNA qPCR) surrounding the released L. pneumophila. This study highlights the interaction among disinfectant residual, biofilms, and L. pneumophila, which provides guidelines to assess and control pathogen risk. PMID- 28085263 TI - Structure and Dynamics of the Huntingtin Exon-1 N-Terminus: A Solution NMR Perspective. AB - Many neurodegenerative diseases are characterized by misfolding and aggregation of an expanded polyglutamine tract (polyQ). Huntington's Disease, caused by expansion of the polyQ tract in exon 1 of the Huntingtin protein (Htt), is associated with aggregation and neuronal toxicity. Despite recent structural progress in understanding the structures of amyloid fibrils, little is known about the solution states of Htt in general, and about molecular details of their transition from soluble to aggregation-prone conformations in particular. This is an important question, given the increasing realization that toxicity may reside in soluble conformers. This study presents an approach that combines NMR with computational methods to elucidate the structural conformations of Htt Exon 1 in solution. Of particular focus was Htt's N17 domain sited N-terminal to the polyQ tract, which is key to enhancing aggregation and modulate Htt toxicity. Such in depth structural study of Htt presents a number of unique challenges: the long homopolymeric polyQ tract contains nearly identical residues, exon 1 displays a high degree of conformational flexibility leading to a scaling of the NMR chemical shift dispersion, and a large portion of the backbone amide groups are solvent-exposed leading to fast hydrogen exchange and causing extensive line broadening. To deal with these problems, NMR assignment was achieved on a minimal Htt exon 1, comprising the N17 domain, a polyQ tract of 17 glutamines, and a short hexameric polyProline region that does not contribute to the spectrum. A pH titration method enhanced this polypeptide's solubility and, with the aid of <=5D NMR, permitted the full assignment of N17 and the entire polyQ tract. Structural predictions were then derived using the experimental chemical shifts of the Htt peptide at low and neutral pH, together with various different computational approaches. All these methods concurred in indicating that low-pH protonation stabilizes a soluble conformation where a helical region of N17 propagates into the polyQ region, while at neutral pH both N17 and the polyQ become largely unstructured-thereby suggesting a mechanism for how N17 regulates Htt aggregation. PMID- 28085264 TI - Urea Metal-Organic Frameworks for Nitro-Substituted Compounds Sensing. AB - Urea groups are known to form strong hydrogen bonds with molecules containing atom(s) that can act as hydrogen bond acceptor(s). Thus, urea is a particularly interesting building block for designing receptors for neutral or charged guests. In the quest for new sensors with enhanced performance for the detection of nitro substituted compounds, two pillared metal-organic frameworks containing urea functional groups were synthesized and structurally characterized. The sensing properties of these frameworks toward nitro-analytes were investigated and compared to each other. The study clearly reveals the importance of urea groups orientation inside the pore cavity of MOFs, as well as the supramolecular interactions between the interpenetrated networks. This work is interesting as it represents the first example of urea-functionalized MOFs for nitro-analytes recognition. PMID- 28085265 TI - Radical Ring-Opening Polymerization: Scope, Limitations, and Application to (Bio)Degradable Materials. AB - Cyclic monomers bearing either vinyl or exomethylene groups have the ability to be polymerized through a radical pathway via a ring-opening mechanism (addition fragmentation process), leading to the introduction of functionalities in the polymer backbone. Radical ring-opening polymerization (rROP) combines the advantages of both ring-opening polymerization and radical polymerization, that is the preparation of polymers bearing heteroatoms in the backbone but with the ease and robustness of a radical process. This current review presents a comprehensive description of rROP by detailing: (i) the various monomers that polymerize through rROP; (ii) the main parameters that govern the rROP mechanism; (iii) the copolymerization by conventional or controlled/living radical polymerization between rROP monomers and traditional vinyl monomers to obtain copolymers with advanced properties; (iv) the different applications (low shrinkage materials and preparation of (bio)degradable materials) of rROP monomer containing materials, and (v) the main alternatives to rROP to induce degradability to materials obtained by a radical polymerization. PMID- 28085266 TI - A Ternary Alloy Substrate to Synthesize Monolayer Graphene with Liquid Carbon Precursor. AB - Here we demonstrate a ternary Cu2NiZn alloy substrate for controllably synthesizing monolayer graphene using a liquid carbon precursor cyclohexane via a facile CVD route. In contrast with elemental metal or bimetal substrates, the alloy-induced synergistic effects that provide an ideal metallic platform for much easier dehydrogenation of hydrocarbon molecules, more reasonable strength of adsorption energy of carbon monomer on surface and lower formation energies of carbon chains, largely renders the success growth of monolayer graphene with higher electrical mobility and lower defects. The growth mechanism is systemically investigated by our DFT calculations. This study provides a selective route for realizing high-quality graphene monolayer via a scalable synthetic method by using economic liquid carbon supplies and multialloy metal substrates. PMID- 28085267 TI - Cyclotide Structure and Function: The Role of Membrane Binding and Permeation. AB - There is growing interest in the use of peptides as therapeutic drugs and, in particular, in the potential of cyclotides, a family of cyclic peptides with remarkable stability and amenability to sequence engineering, as scaffolds in drug design. As well as having an ultrastable structure, many natural cyclotides have intrinsic biological activities with potential pharmaceutical or agricultural applications. Some cyclotides also have the ability to cross membrane barriers and to enter into cells; in particular, cyclotides that belong to the Mobius and bracelet subfamilies have been found to harbor lipid-binding domains, which allow for the specific recognition of phosphatidylethanolamine phospholipids in biological membranes. This lipid selectivity is intimately correlated with the highly conserved three-dimensional structures of cyclotides and is important for their reported biological properties and cell penetration ability. The membrane binding features of Mobius and bracelet cyclotides contrast with the lack of membrane binding of trypsin inhibitor cyclotides, which have physicochemical properties and bioactivities different from those of the other two subfamilies of cyclotides but are also able to enter cells. This review discusses the structures of cyclotides with regard to their myriad of biological activities and describes the role of membrane binding in their functions and ability to enter cells. PMID- 28085268 TI - Effect of Interlayer Spacing on the Activity of Layered Manganese Oxide Bilayer Catalysts for the Oxygen Evolution Reaction. AB - We investigated the dependence of the electrocatalytic activity for the oxygen evolution reaction (OER) on the interlayer distance of five compositionally distinct layered manganese oxide nanostructures. Each individual electrocatalyst was assembled with a different alkali metal intercalated between two nanosheets (NS) of manganese oxide to form a bilayer structure. Manganese oxide NS were synthesized via the exfoliation of a layered material, birnessite. Atomic force microscopy was used to determine the heights of the bilayer catalysts. The interlayer spacing of the supported bilayers positively correlates with the size of the alkali cation: NS/Cs+/NS > NS/Rb+/NS > NS/K+/NS > NS/Na+/NS > NS/Li+/NS. The thermodynamic origins of these bilayer heights were investigated using molecular dynamics simulations. The overpotential (eta) for the OER correlates with the interlayer spacing; NS/Cs+/NS has the lowest eta (0.45 V), while NS/Li+/NS exhibits the highest eta (0.68 V) for OER at a current density of 1 mA/cm2. Kinetic parameters (eta and Tafel slope) associated with NS/Cs+/NS for the OER were superior to that of the bulk birnessite phase, highlighting the structural uniqueness of these nanoscale assemblies. PMID- 28085269 TI - Immobilization of N-Heterocyclic Carbene Compounds: A Synthetic Perspective. AB - Over the course of the past 15 years the success story of N-heterocyclic carbene (NHC) compounds in organic, inorganic, and organometallic chemistry has been extended to another dimension. The immobilization of NHC compounds, undergoing continuous diversification, broadens their range of applications and leads to new solutions for challenges in catalytic and synthetic chemistry. This review intends to present a synthetic toolkit for the immobilization of NHC compounds, giving the reader an overview on synthetic techniques and strategies available in the literature. By individually summarizing and assessing the synthetic steps of the immobilization process, a comprehensive picture of the strategies and methodologies for the immobilization of NHC compounds is presented. Furthermore, the characterization of supported NHC compounds is discussed in detail in order to set up necessary criteria for an in-depth analysis of the immobilized derivatives. Finally, the catalytic applications of immobilized NHC compounds are briefly reviewed to illustrate the practical use of this technique for a broad variety of reaction types. PMID- 28085270 TI - Site-Specific Biomimetic Precision Chemistry of Bimodal Contrast Agent with Modular Peptides for Tumor-Targeted Imaging. AB - Various biomimetic nanoparticles have been fabricated for cancer nanotheranostics with a diverse range of proteins. However, the operating mechanisms of these reactions are still unclear, especially on the interaction between metal ions and protein, the precise binding sites, and the existence format of nanoparticles. Assuming the shortening of the amino acids sequence into several, namely short peptides, it would be much easier to investigate the biomimetic reaction mechanism. In this study, a modular peptide, possessing Au3+ ion coordination motifs and a Gd3+ ion chelation sequence, is designed and synthesized. This peptide is experimentally found effective in site-specific biomimetic synthesis of paramagnetic fluorescent gold nanoclusters (pAuNCs) with a quantum yield of 6.8%, deep red emission at 676 nm, and potent relaxivity. The gel electrophoresis result declares that the two imaging motifs in pAuNCs are quite stable. In vivo fluorescence-magnetic resonance bimodal imaging show significant tumor enhancement by pAuNCs in tumor-bearing mice. In vivo biodistribution and toxicity studies reveal that pAuNCs can be gradually cleared from the body without damage. This study presents a modular peptide that can incubate multifunctional nanoparticles in a biomimetic fashion and hopefully provides a strategy for the investigation of the mechanism of protein-mediated biomimetic synthesis. PMID- 28085271 TI - First-Order Phase Transition in BaNi2Ge2 and the Influence of the Valence Electron Count on Distortion of the ThCr2Si2 Structure Type. AB - Structural instability has a strong influence on the understanding of superconductivity in iron-containing 122 phases. Similar to the 122 iron-based high-temperature superconductors, the intermetallic compound BaNi2Ge2 undergoes an orthorhombic-to-tetragonal structural phase transition. The compound was prepared by arc-melting mixtures of the elements under an argon atmosphere. Single crystals were obtained by a special heat treatment in a welded tantalum ampule. The crystal structure of the compound was investigated by powder and single-crystal X-ray diffraction. Differential thermal analysis of BaNi2Ge2 showed a reversible phase transition at ca. 480 degrees C. In situ temperature dependent synchrotron powder X-ray diffraction studies revealed that below 480 degrees C the crystal structure of BaNi2Ge2 is orthorhombic [own structure type, space group Pnma, a = 8.3852(4) A, b = 11.3174(8) A, and c = 4.2902(9) A at 30 degrees C] and the high-temperature phase above 510 degrees C belongs to the tetragonal ThCr2Si2-type structure [space group I4/mmm, a = 4.2664(1) A, and c = 11.2537(3) A at 510 degrees C]. The reversible first-order low-temperature <-> high-temperature phase transition around 480 degrees C is associated with distortion of the [Ni2Ge2] layer of low-temperature modification. The anisotropy of thermal expansion of the unit cell in BaNi2Ge2 was analyzed. The crystal chemistry and chemical bonding are discussed in terms of linear muffin-tin orbital band structure calculations and a topological analysis using the electron localization function. In related compounds, the level of distortion of the uncollapsed tetragonal ThCr2Si2-type structure depends on the valence electron count (VEC). PMID- 28085272 TI - Oxidative C-H/C-H Coupling Reactions between Two (Hetero)arenes. AB - Transition metal-mediated C-H bond activation and functionalization represent one of the most straightforward and powerful tools in modern organic synthetic chemistry. Bi(hetero)aryls are privileged pi-conjugated structural cores in biologically active molecules, organic functional materials, ligands, and organic synthetic intermediates. The oxidative C-H/C-H coupling reactions between two (hetero)arenes through 2-fold C-H activation offer a valuable opportunity for rapid assembly of diverse bi(hetero)aryls and further exploitation of their applications in pharmaceutical and material sciences. This review provides a comprehensive overview of the fundamentals and applications of transition metal mediated/catalyzed oxidative C-H/C-H coupling reactions between two (hetero)arenes. The substrate scope, limitation, reaction mechanism, regioselectivity, and chemoselectivity, as well as related control strategies of these reactions are discussed. Additionally, the applications of these established methods in the synthesis of natural products and exploitation of new organic functional materials are exemplified. In the last section, a short introduction on oxidant- or Lewis acid-mediated oxidative Ar-H/Ar-H coupling reactions is presented, considering that it is a very powerful method for the construction of biaryl units and polycylic arenes. PMID- 28085273 TI - New Insights on the Nitrogen Footprint of a Coastal Megalopolis from Coral-Hosted Symbiodinium delta15N. AB - The development of megalopolises in coastal areas is often linked with severe eutrophication, requiring mitigation of anthropogenic dissolved inorganic nitrogen (DIN) pollution. Yet, identifying the DIN-sources responsible for eutrophication is challenging, hampering mitigation efforts. Here, we utilize the stable nitrogen isotope ratio of endosymbiotic dinoflagellate Symbiodinium spp. (delta15Nsym) associated with the hard coral Porites to trace DIN sources in one of the most urbanized areas of the planet: the Pearl River Delta (PRD). The mean delta15Nsym value found in the coastal waters of Hong Kong (HK), located on the eastern edge of the PRD, (7.40/00 +/- 1.20/00) was +2.70/00 higher than at Dongsha Atoll, a reference site unaffected by anthropogenic-DIN (4.70/00 +/- 0.40/00). The isotopic enrichment suggested a consistent dominance of DIN deriving from local and regional sewage discharges on the eastern edge of HK. Furthermore, the strong depletion of the summer delta15Nsym value (-1.60/00) observed in southern HK revealed that the Pearl River plume strongly modulates the coastal DIN pool. Our results revealed the value of benthic marine organisms' delta15N for deciphering the complex dynamics of coastal eutrophication and highlighted the pivotal role of transboundary coordination in DIN-pollution mitigation. PMID- 28085274 TI - Development of a qPCR Method for the Identification and Quantification of Two Closely Related Tuna Species, Bigeye Tuna (Thunnus obesus) and Yellowfin Tuna (Thunnus albacares), in Canned Tuna. AB - Bigeye tuna (Thunnus obesus) and yellowfin tuna (Thunnus albacares) are among the most widely used tuna species for canning purposes. Not only substitution but also mixing of tuna species is prohibited by the European regulation for canned tuna products. However, as juveniles of bigeye and yellowfin tunas are very difficult to distinguish, unintentional substitutions may occur during the canning process. In this study, two mitochondrial markers from NADH dehydrogenase subunit 2 and cytochrome c oxidase subunit II genes were used to identify bigeye tuna and yellowfin tuna, respectively, utilizing TaqMan qPCR methodology. Two different qPCR-based methods were developed to quantify the percentage of flesh of each species used for can processing. The first one was based on absolute quantification using standard curves realized with these two markers; the second one was founded on relative quantification with the universal 12S rRNA gene as the endogenous gene. On the basis of our results, we conclude that our methodology could be applied to authenticate these two closely related tuna species when used in a binary mix in tuna cans. PMID- 28085275 TI - Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker. AB - A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double digit nanomolar FXIa inhibitors, were further optimized with assistance from utilization of structure-based drug design and ligand bound X-ray crystal structures. This effort resulted in the discovery of a macrocyclic amide linker which was found to form a key hydrogen bond with the carbonyl of Leu41 in the FXIa active site, resulting in potent FXIa inhibitors. The macrocyclic FXIa series, exemplified by compound 16, had a FXIa Ki = 0.16 nM with potent anticoagulant activity in an in vitro clotting assay (aPTT EC1.5x = 0.27 MUM) and excellent selectivity against the relevant blood coagulation enzymes. PMID- 28085276 TI - Enantiodivergence in the Biosynthesis of Bromotyrosine Alkaloids from Sponges? AB - The isolation of bromotyrosine alkaloids, some of which are enantiomers of previously isolated compounds, has highlighted a possible enantiodivergence in their biosynthesis. Two new (1, 2) and six known bromotyrosine alkaloids (4-9), and the enantiomer (10) of a known compound, have been isolated from a Western Australian marine sponge, Pseudoceratina cf. verrucosa. The compounds inhibited the growth of multidrug-resistant and methicillin-resistant Staphylococcus aureus with comparable activity to vancomycin. In addition, one possible artifact of extraction (3) containing an ethoxy group was isolated. From analysis of the known bromotyrosine alkaloids, a biogenesis is proposed that explains the formation of antipodal natural products within this family of sponges. PMID- 28085277 TI - pi-Conjugated Triazenes: Intermediates That Undergo Oxidation and Substitution Reactions. AB - Novel reactivity for pi-conjugated triazenes is herein reported. This observed and unprecedented triazene reactivity gave access to oxidation and substitution reactions. These transformations include successful synthesis of aldehydes, ketones, ethers, and sulfides from readily available organic azides via pi conjugated triazene intermediates. Notably, the afforded adducts were obtained in good yields, at room temperature, and in the absence of added metal catalysts. PMID- 28085278 TI - Enhanced Thermal Stability and UV-Shielding Properties of Poly(vinyl alcohol) Based on Esculetin. AB - In this article, PVA composites with outstanding thermal stability, UV shielding, and high transparency were fabricated on the basis of traditional Chinese medicine (esculetin). Characterization data have suggested in which the resulting PVA/esculetin (ESC) composites display excellent thermal stability compared to pure PVA and most of the PVA nanocomposites. The pyrolysis mechanism of PVA before and after modification with esculetin varies from chain unzipping degradation followed by chain random scission. The DPPH scavenging activity and FTIR measurements have illustrated that esculetin can scavenge reactive radicals, which leads to improvements in thermal stability and a change in the pyrolysis mechanism of PVA. More importantly, the resulting composites can almost completely block the whole UV region (200-400 nm) without any deterioration of the high transparency of the composites. Therefore, the composites can convert harmful UV light into blue light effectively, which is beneficial for their application as optical materials and devices. PMID- 28085279 TI - Resonantly Enhanced Nonlinear Optical Probes of Oxidized Multiwalled Carbon Nanotubes at Supported Lipid Bilayers. AB - With production of carbon nanotubes surpassing billions of tons per annum, concern about their potential interactions with biological systems is growing. Herein, we utilize second harmonic generation spectroscopy, sum frequency generation spectroscopy, and quartz crystal microbalance with dissipation monitoring to probe the interactions between oxidized multiwalled carbon nanotubes (O-MWCNTs) and supported lipid bilayers composed of phospholipids with phosphatidylcholine head groups as the dominant component. We quantify O-MWCNT attachment to supported lipid bilayers under biogeochemically relevant conditions and discern that the interactions occur without disrupting the structural integrity of the lipid bilayers for the systems probed. The extent of O-MWCNT sorption was far below a monolayer even at 100 mM NaCl and was independent of the chemical composition of the supported lipid bilayer. PMID- 28085280 TI - Protonation-Induced Sign Inversion of the Cotton Effects of Pyridinophanes. A Combined Experimental and Theoretical Study. AB - The circular dichroisms (CDs) of planar chiral [2.2]- and [3.3]-pyridinophanes were investigated experimentally and theoretically. Strong multisignate Cotton effects, typical for cyclophane derivatives, were observed. The CD spectra of [2.2]- and [3.3]-paracyclophanes closely resembled in pattern each other, despite the much greater conformational variations in the latter. Upon protonation, both of the cyclophanes suffered dramatic CD spectral changes with accompanying complete sign inversion, which was attributed to the reversal of diploe moment of pyridinium versus pyridine moiety. This chiroptical property switching driven by protonation/deprotonation was temperature-dependent and hence applicable to thermal sensing. The protonated forms of pyridinophanes served as ideal model systems for studying the cation-pi interactions and their effects on chiroptical properties. Thus, the molar CD (Deltaepsilon) of the charge-transfer band of protonated [2.2]pyridinophane was 10-fold larger than that of protonated [3.3]pyridinophane, which exceeds the increased interplane electronic interactions assessed from the electronic coupling element values. PMID- 28085281 TI - alpha-Ketothioamide Derivatives: A Promising Tool to Interrogate Phosphoglycerate Dehydrogenase (PHGDH). AB - Given the putative role of PHGDH in cancer, development of inhibitors is required to explore its function. In this context, we established and validated a straightforward enzymatic assay suitable for high-throughput screening and we identified inhibitors with similar chemical scaffolds. Through a convergent pharmacophore approach, we synthesized alpha-ketothioamides that exhibit interesting in vitro PHGDH inhibition and encouraging cellular results. These novel probes may be used to understand the emerging biology of this metabolic target. PMID- 28085282 TI - Gold-Catalyzed Regio- and Stereoselective Addition of Carboxylic Acids to Iodoalkynes: Access to (Z)-beta-Iodoenol Esters and 1,4-Disubstituted (Z)-Enynyl Esters. AB - In the presence of catalytic amounts of the Au(I) cation [Au(PPh3)]+, a large variety of (Z)-beta-iodoenol esters (39 examples) could be synthesized under mild reaction conditions through the regio- and stereospecific intermolecular addition of carboxylic acids to iodoalkynes. Sonogashira coupling of representative (Z) beta-iodoenol esters with terminal alkynes, alkynols, and 1,3-enynes allowed also the access to different 1,4-disubstituted (Z)-enynyl esters in excellent yields. PMID- 28085283 TI - Design, Synthesis, and Biological Evaluation of Novel, Non-Brain-Penetrant, Hybrid Cannabinoid CB1R Inverse Agonist/Inducible Nitric Oxide Synthase (iNOS) Inhibitors for the Treatment of Liver Fibrosis. AB - We report the design, synthesis, and structure-activity relationships of novel dual-target compounds with antagonist/inverse agonist activity at cannabinoid receptor type 1 (CB1R) and inhibitory effect on inducible nitric oxide synthase (iNOS). A series of 3,4-diarylpyrazolinecarboximidamides were synthesized and evaluated in CB1 receptor (CB1R) binding assays and iNOS activity assays. The novel compounds, designed to have limited brain penetrance, elicited potent in vitro CB1R antagonist activities and iNOS inhibitory activities. Some key compounds displayed high CB1R binding affinities. Compound 7 demonstrated potent in vivo pharmacological activities such as reduction of food intake mediated by the antagonism of the CB1Rs and antifibrotic effect in the animal models of fibrosis mediated by iNOS inhibition and CB1R antagonism. PMID- 28085284 TI - Quantitative Assessment of Molecular Dynamics Sampling for Flexible Systems. AB - Molecular dynamics (MD) simulation is a natural method for the study of flexible molecules but at the same time is limited by the large size of the conformational space of these molecules. We ask by how much the MD sampling quality for flexible molecules can be improved by two means: the use of diverse sets of trajectories starting from different initial conformations to detect deviations between samples and sampling with enhanced methods such as accelerated MD (aMD) or scaled MD (sMD) that distort the energy landscape in controlled ways. To this end, we test the effects of these approaches on MD simulations of two flexible biomolecules in aqueous solution, Met-Enkephalin (5 amino acids) and HIV-1 gp120 V3 (a cycle of 35 amino acids). We assess the convergence of the sampling quantitatively with known, extensive measures of cluster number Nc and cluster distribution entropy Sc and with two new quantities, conformational overlap Oconf and density overlap Odens, both conveniently ranging from 0 to 1. These new overlap measures quantify self-consistency of sampling in multitrajectory MD experiments, a necessary condition for converged sampling. A comprehensive assessment of sampling quality of MD experiments identifies the combination of diverse trajectory sets and aMD as the most efficient approach among those tested. However, analysis of Odens between conventional and aMD trajectories also reveals that we have not completely corrected aMD sampling for the distorted energy landscape. Moreover, for V3, the courses of Nc and Odens indicate that much higher resources than those generally invested today will probably be needed to achieve convergence. The comparative analysis also shows that conventional MD simulations with insufficient sampling can be easily misinterpreted as being converged. PMID- 28085285 TI - Stereoselective Total Syntheses of Polyacetylene Plant Metabolites via Ester Tethered Ring Closing Metathesis. AB - Total syntheses of five naturally occurring polyacetylenes from three different plants are described. These natural products have in common an E,Z-configured conjugated diene linked to a di- or triyne chain. As the key method to stereoselectively establish the E,Z-diene part, an ester-tethered ring-closing metathesis/base-induced eliminative ring opening sequence was used. The results presented herein do not only showcase the utility of this tethered RCM variant but have also prompted us to suggest that the originally assigned absolute configurations of chiral polyacetylenes from Atractylodes macrocephala should be revised or at least reconsidered. PMID- 28085287 TI - A Useful Allene for the Stereoselective Synthesis of Protected Quaternary 2-Amino 2-vinyl-1,3-diols. AB - Treatment of readily available allene 1 with Cy2BH followed by addition of an aldehyde led to quaternary protected 2-amino-2-vinyl-1,3-diols in high yield and excellent stereochemical purity. The choice of benzoyl as N-protecting group is critical since the observed N- to O-Bz transfer during the process prevents later undesired isomerizations in the adducts and keeps all heteroatoms protected. PMID- 28085286 TI - Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors. AB - Pyruvate dehydrogenase kinases 1-4 (PDK1-4) negatively control activity of the pyruvate dehydrogenase complex (PDC) and are up-regulated in obesity, diabetes, heart failure, and cancer. We reported earlier two novel pan-PDK inhibitors PS8 [4-((5-hydroxyisoindolin-2-yl)sulfonyl)benzene-1,3-diol] (1) and PS10 [2-((2,4 dihydroxyphenyl)sulfonyl)isoindoline-4,6-diol] (2) that targeted the ATP-binding pocket in PDKs. Here, we developed a new generation of PDK inhibitors by extending the dihydroxyphenyl sulfonylisoindoline scaffold in 1 and 2 to the entrance region of the ATP-binding pocket in PDK2. The lead inhibitor (S)-3-amino 4-(4-((2-((2,4-dihydroxyphenyl)sulfonyl)isoindolin-5-yl)amino)piperidin-1-yl)-4 oxobutanamide (17) shows a ~8-fold lower IC50 (58 nM) than 2 (456 nM). In the crystal structure, the asparagine moiety in 17 provides additional interactions with Glu-262 from PDK2. Treatment of diet-induced obese mice with 17 resulted in significant liver-specific augmentation of PDC activity, accompanied by improved glucose tolerance and drastically reduced hepatic steatosis. These findings support 17 as a potential glucose-lowering therapeutic targeting liver for obesity and type 2 diabetes. PMID- 28085288 TI - Novel Two-Dimensional Silicon Dioxide with in-Plane Negative Poisson's Ratio. AB - Silicon dioxide or silica, normally existing in various bulk crystalline and amorphous forms, was recently found to possess a two-dimensional structure. In this work, we use ab initio calculation and evolutionary algorithm to unveil three new two-dimensional (2D) silica structures whose thermal, dynamical, and mechanical stabilities are compared with many typical bulk silica. In particular, we find that all three of these 2D silica structures have large in-plane negative Poisson's ratios with the largest one being double of penta graphene and three times of borophenes. The negative Poisson's ratio originates from the interplay of lattice symmetry and Si-O tetrahedron symmetry. Slab silica is also an insulating 2D material with the highest electronic band gap (>7 eV) among reported 2D structures. These exotic 2D silica with in-plane negative Poisson's ratios and widest band gaps are expected to have great potential applications in nanomechanics and nanoelectronics. PMID- 28085289 TI - Synthesis and Reactivity of 18F-Labeled alpha,alpha-Difluoro-alpha (aryloxy)acetic Acids. AB - In this work, we describe the 18F-labeling of alpha,alpha-difluoro-alpha (aryloxy)acetic acid derivatives and demonstrate that these building blocks are amenable to post-18F-fluorination functionalization. Protodecarboxylation offers a new entry to 18F-difluoromethoxyarene, and the value of this approach is further demonstrated with coupling processes leading to representative 18F labeled TRPV1 inhibitors and TRPV1 antagonists. PMID- 28085290 TI - Magnetic Control of the Charge-Separated State Lifetime Realized by Covalent Attachment of a Platinum Complex. AB - Dynamics of the photogenerated charge-separated (CS) state is studied for a newly synthesized molecular triad, in which the donor (D) dimethoxytriphenylamine, 1,3 bis(2-pyridylimino)isoindolate platinum (BPIPt), and the acceptor (A) naphthaldiimide are linked with a triethynylbenzene unit (BPIPt-DA). Photoexcitation of BPIPt gives rise to generation of a long-lived (~4 MUs) CS state BPIPt-D+A-, of which the lifetime is considerably increased by an applied magnetic field of 270 mT. The positive magnetic field effect (MFE) is in contrast to the negative MFE for the reference DA molecule, which indicates successful switching of the initial spin state of the CS state from singlet to triplet. Simulations of the MFE and time-resolved electron paramagnetic resonance show that spin-selective charge recombination and spin relaxation are unaffected by attachment of BPIPt. The minimum impact of heavy atom substitution on the electronic and magnetic properties has been realized by the small electronic coupling mediated by the rigid meta-triethynylbenzene. PMID- 28085291 TI - Solvation Shell Structure of Small Molecules and Proteins by IR-MCR Spectroscopy. AB - The flexibility of the hydrogen-bonded network of water is the basis for its excellent solvation properties. Accordingly, it is valuable to understand the properties of water in the solvation shell surrounding small molecules and biomolecules. Recent high-quality Raman spectra analyzed with Self-Modeling Curve Resolution (SMCR) have provided Raman spectra of small-molecule solvation shells. Here we apply SMCR to the complementary technique of Fourier transform infrared (FTIR) spectroscopy in the attenuated total reflection (ATR) configuration to extract the IR spectra of solvation shells. We first illustrate the method by obtaining the IR-MCR solvation shell spectra of tert-butanol (TBA), before applying it to antifreeze protein type III. Our results show that IR-SMCR spectroscopy is a powerful method for studying the solvation shell structure of small molecules and biomolecules. Given the wide availability of FTIR-ATR instruments, the method could prove to be an impactful tool for studying solvation and solvent-mediated interactions. PMID- 28085292 TI - Inducing isolated-desynchronization states in complex network of coupled chaotic oscillators. AB - In a recent study about chaos synchronization in complex networks [Nat. Commun. 5, 4079 (2014)NCAOBW2041-172310.1038/ncomms5079], it is shown that a stable synchronous cluster may coexist with vast asynchronous nodes, resembling the phenomenon of a chimera state observed in a regular network of coupled periodic oscillators. Although of practical significance, this new type of state, namely, the isolated-desynchronization state, is hardly observed in practice due to its strict requirements on the network topology. Here, by the strategy of pinning coupling, we propose an effective method for inducing isolated-desynchronization states in symmetric networks of coupled chaotic oscillators. Theoretical analysis based on eigenvalue analysis shows that, by pinning a group of symmetric nodes in the network, there exists a critical pinning strength beyond which the group of pinned nodes can completely be synchronized while the unpinned nodes remain asynchronous. The feasibility and efficiency of the control method are verified by numerical simulations of both artificial and real-world complex networks with the numerical results in good agreement with the theoretical predictions. PMID- 28085293 TI - Statistical entropy of open quantum systems. AB - Dissipative quantum systems are frequently described within the framework of the so-called "system-plus-reservoir" approach. In this work we assign their description to the Maximum Entropy Formalism and compare the resulting thermodynamic properties with those of the well-established approaches. Due to the non-negligible coupling to the heat reservoir, these systems are nonextensive by nature, and the former task may require the use of nonextensive parameter dependent informational entropies. In doing so, we address the problem of choosing appropriate forms of those entropies in order to describe a consistent thermodynamics for dissipative quantum systems. Nevertheless, even having chosen the most successful and popular forms of those entropies, we have proven our model to be a counterexample where this sort of approach leads us to wrong results. PMID- 28085294 TI - Probing the shear viscosity of an active nematic film. AB - In vitro reconstituted active systems, such as the adenosine triphosphate (ATP) driven microtubule bundle suspension developed by the Dogic group [T. Sanchez, D. T. Chen, S. J. DeCamp, M. Heymann, and Z. Dogic, Nature (London) 491, 431 (2012)10.1038/nature11591], provide a fertile testing ground for elucidating the phenomenology of active liquid crystalline states. Controlling such novel phases of matter crucially depends on our knowledge of their material and physical properties. In this Rapid Communication, we show that the shear viscosity of an active nematic film can be probed by varying its hydrodynamic coupling to a bounding oil layer. Using the motion of disclinations as intrinsic tracers of the flow field and a hydrodynamic model, we obtain an estimate for the shear viscosity of the nematic film. Knowing this now provides us with an additional handle for robust and precision tunable control of the emergent dynamics of active fluids. PMID- 28085295 TI - Estimation of Reynolds number for flows around cylinders with lattice Boltzmann methods and artificial neural networks. AB - The present work investigates the application of artificial neural networks (ANNs) to estimate the Reynolds (Re) number for flows around a cylinder. The data required to train the ANN was generated with our own implementation of a lattice Boltzmann method (LBM) code performing simulations of a two-dimensional flow around a cylinder. As results of the simulations, we obtain the velocity field (v[over ?]) and the vorticity (?[over ?]*v[over ?]) of the fluid for 120 different values of Re measured at different distances from the obstacle and use them to teach the ANN to predict the Re. The results predicted by the networks show good accuracy with errors of less than 4% in all the studied cases. One of the possible applications of this method is the development of an efficient tool to characterize a blocked flowing pipe. PMID- 28085296 TI - Rotational diffusion of shape switching particles in nematic liquid crystals. AB - The theory of rotational diffusion of particles of various symmetry embedded in a liquid crystal host, essential to interpret a variety of spectroscopic observables, has been available for some time, but only for the case of rigid molecules. Here we generalize the treatment and present a theory to describe the rotational diffusion of shape-changing particles dispersed in nematic liquid crystals. The interaction of the particles with the environment is modeled by an effective field potential, while the particles are allowed to assume an arbitrary discrete number of shapes. The transition between shapes is modeled by a Markovian process which is combined with rotational diffusion. Our model is applied to the simple case of a particle that can exchange between three shapes: a rod, a disk, and a sphere. We consider in detail the effect of shape transitions in some selected correlation functions which are relevant for experiments. PMID- 28085297 TI - Nonvibrating granular model for a glass-forming liquid: Equilibration and aging. AB - We studied experimentally a model of a glass-forming liquid on the basis of a nonvibrating magnetic granular system under an unsteady magnetic field. A sudden quenching was produced that drove the system from a liquid state to a different final state with lower temperature; the latter could be a liquid state or a solid state. We determined the mean-squared displacement in temporal windows to obtain the dynamic evolution of the system, and we determined the radial distribution function to obtain its structural characteristics. The results were analyzed using the intermediate scattering function and the effective potential between two particles. We observed that when quenching drives the system to a final state in the liquid phase far from the glass-transition temperature, equilibration occurs very quickly. When the final state has a temperature far below the glass transition temperature, the system reaches its equilibrium state very quickly. In contrast, when the final state has an intermediate temperature but is below that corresponding to the glass transition, the system falls into a state that evolves slowly, presenting aging. The system evolves by an aging process toward more ordered states. However, after a waiting time, the dynamic behavior changes. It was observed that some particles get close enough to overpass the repulsive interactions and form small stable aggregates. In the effective potential curves, it was observed that the emergence of a second effective well due to the attraction quickly evolves and results in a deeper well than the initial effective well due to the repulsion. With the increase in time, more particles fall in the attractive well forming inhomogeneities, which produce a frustration in the aging process. PMID- 28085298 TI - Free-energy functional of the Debye-Huckel model of simple fluids. AB - The Debye-Huckel approximation to the free energy of a simple fluid is written as a functional of the pair correlation function. This functional can be seen as the Debye-Huckel equivalent to the functional derived in the hypernetted chain framework by Morita and Hiroike, as well as by Lado. It allows one to obtain the Debye-Huckel integral equation through a minimization with respect to the pair correlation function, leads to the correct form of the internal energy, and fulfills the virial theorem. PMID- 28085299 TI - Deviation-angle and trajectory statistics for inertial particles in turbulence. AB - Small particles in suspension in a turbulent fluid have trajectories that do not follow the pathlines of the flow exactly. We investigate the statistics of the angle of deviation phi between the particle and fluid velocities. We show that, when the effects of particle inertia are small, the probability distribution function (PDF) P_{phi} of this deviation angle shows a power-law region in which P_{phi}~phi^{-4}. We also find that the PDFs of the trajectory curvature kappa and modulus theta of the torsion theta have power-law tails that scale, respectively, as P_{kappa}~kappa^{-5/2}, as kappa->infinity, and P_{theta}~theta^{-3}, as theta->infinity: These exponents are in agreement with those previously observed for fluid pathlines. We propose a way to measure the complexity of heavy-particle trajectories by the number N_{I}(t,St) of points (up until time t) at which the torsion changes sign. We present numerical evidence that n_{I}(St)=lim_{t->infinity}N_{I}(t,St)/t~St^{-Delta} for large St, with Delta?0.5. PMID- 28085300 TI - Analytic framework for a stochastic binary biological switch. AB - We propose and solve analytically a stochastic model for the dynamics of a binary biological switch, defined as a DNA unit with two mutually exclusive configurations, each one triggering the expression of a different gene. Such a device has the potential to be used as a memory unit for biological computing systems designed to operate in noisy environments. We discuss a recent implementation of this switch in living cells, the recombinase addressable data (RAD) module. In order to understand the behavior of a RAD module we compute the exact time-dependent joint distribution of the two expressed genes starting in one state and evolving to another asymptotic state. We consider two operating regimes of the RAD module, a fast and a slow stochastic switching regime. The fast regime is aggregative and produces unimodal distributions, whereas the slow regime is separative and produces bimodal distributions. Both regimes can serve to prepare pure memory states when all cells are expressing the same gene. The slow regime can also separate mixed states by producing two subpopulations, each one expressing a different gene. Compared to the genetic toggle switch based on positive feedback, the RAD module ensures more rapid memory operations for the same quality of the separation between binary states. Our model provides a simplified phenomenological framework for studying RAD memory devices and our analytic solution can be further used to clarify theoretical concepts in biocomputation and for optimal design in synthetic biology. PMID- 28085301 TI - Thermalization of oscillator chains with onsite anharmonicity and comparison with kinetic theory. AB - We perform microscopic molecular dynamics simulations of particle chains with an onsite anharmonicity to study relaxation of spatially homogeneous states to equilibrium, and directly compare the simulations with the corresponding Boltzmann-Peierls kinetic theory. The Wigner function serves as a common interface between the microscopic and kinetic level. We demonstrate quantitative agreement after an initial transient time interval. In particular, besides energy conservation, we observe the additional quasiconservation of the phonon density, defined via an ensemble average of the related microscopic field variables and exactly conserved by the kinetic equations. On superkinetic time scales, density quasiconservation is lost while energy remains conserved, and we find evidence for eventual relaxation of the density to its canonical ensemble value. However, the precise mechanism remains unknown and is not captured by the Boltzmann Peierls equations. PMID- 28085302 TI - Anisotropic macroturbulence and diffusion associated with a westward zonal jet: From laboratory to planetary atmospheres and oceans. AB - Turbulence with inverse energy cascade and its transport properties are investigated experimentally in a flow associated with a westward propagating jet. Turbulence and the jet were produced by an electromagnetic force in a rotating tank filled with an electrolytic saline solution. The parabolic free surface emulated the topographic beta effect which evoked the zonation. The spectral and transport flow characteristics were highly anisotropic. Turbulence is diagnosed by exploring the analogy between vertical and horizontal turbulent overturns in, respectively, stably stratified and quasigeostrophic flows which gives rise to a method of potential vorticity (PV) monotonizing. The anisotropization of transport properties of the flow is investigated using the finite scale Lyapunov exponent technique. After initial exponential particle separation, radial (meridional in geophysical and planetary applications) diffusion attains a short ranged Richardson regime which transitions to the Taylor (scale-independent diffusivity) one. The azimuthal (zonal) diffusion exhibits a double-plateau structure which attains a superdiffusive regime on large scales. The transition to the Taylor regime for the radial diffusion takes place at a scale of turbulence anisotropization. The radial eddy diffusivity in both regimes as well as the transition scale are all determined by the rate of the inverse energy cascade, epsilon, that can be diagnosed by the PV monotonizing. Conversely, epsilon can be deduced from the scale of the Richardson-Taylor regime transition in the radial eddy diffusivity which, thus, provides an additional tool of diagnosing anisotropic macroturbulence with inverse energy cascade. PMID- 28085303 TI - Exact distributions of cover times for N independent random walkers in one dimension. AB - We study the probability density function (PDF) of the cover time t_{c} of a finite interval of size L by N independent one-dimensional Brownian motions, each with diffusion constant D. The cover time t_{c} is the minimum time needed such that each point of the entire interval is visited by at least one of the N walkers. We derive exact results for the full PDF of t_{c} for arbitrary N>=1 for both reflecting and periodic boundary conditions. The PDFs depend explicitly on N and on the boundary conditions. In the limit of large N, we show that t_{c} approaches its average value of ~L^{2}/(16DlnN) with fluctuations vanishing as 1/(lnN)^{2}. We also compute the centered and scaled limiting distributions for large N for both boundary conditions and show that they are given by nontrivial N independent scaling functions. PMID- 28085304 TI - Complete coverage of space favors modularity of the grid system in the brain. AB - Grid cells in the entorhinal cortex fire when animals that are exploring a certain region of space occupy the vertices of a triangular grid that spans the environment. Different neurons feature triangular grids that differ in their properties of periodicity, orientation, and ellipticity. Taken together, these grids allow the animal to maintain an internal, mental representation of physical space. Experiments show that grid cells are modular, i.e., there are groups of neurons which have grids with similar periodicity, orientation, and ellipticity. We use statistical physics methods to derive a relation between variability of the properties of the grids within a module and the range of space that can be covered completely (i.e., without gaps) by the grid system with high probability. Larger variability shrinks the range of representation, providing a functional rationale for the experimentally observed comodularity of grid cell periodicity, orientation, and ellipticity. We obtain a scaling relation between the number of neurons and the period of a module, given the variability and coverage range. Specifically, we predict how many more neurons are required at smaller grid scales than at larger ones. PMID- 28085305 TI - Lagrangian statistics of mesoscale turbulence in a natural environment: The Agulhas return current. AB - The properties of mesoscale geophysical turbulence in an oceanic environment have been investigated through the Lagrangian statistics of sea surface temperature measured by a drifting buoy within the Agulhas return current, where strong temperature mixing produces locally sharp temperature gradients. By disentangling the large-scale forcing which affects the small-scale statistics, we found that the statistical properties of intermittency are identical to those obtained from the multifractal prediction in the Lagrangian frame for the velocity trajectory. The results suggest a possible universality of turbulence scaling. PMID- 28085306 TI - Direct numerical simulation of gas-solid-liquid flows with capillary effects: An application to liquid bridge forces between spherical particles. AB - In this study, a numerical method is developed to perform the direct numerical simulation (DNS) of gas-solid-liquid flows involving capillary effects. The volume-of-fluid method employed to track the free surface and the immersed boundary method is adopted for the fluid-particle coupling in three-phase flows. This numerical method is able to fully resolve the hydrodynamic force and capillary force as well as the particle motions arising from complicated gas solid-liquid interactions. We present its application to liquid bridges among spherical particles in this paper. By using the DNS method, we obtain the static bridge force as a function of the liquid volume, contact angle, and separation distance. The results from the DNS are compared with theoretical equations and other solutions to examine its validity and suitability for modeling capillary bridges. Particularly, the nontrivial liquid bridges formed in triangular and tetrahedral particle clusters are calculated and some preliminary results are reported. We also perform dynamic simulations of liquid bridge ruptures subject to axial stretching and particle motions driven by liquid bridge action, for which accurate predictions are obtained with respect to the critical rupture distance and the equilibrium particle position, respectively. As shown through the simulations, the strength of the present method is the ability to predict the liquid bridge problem under general conditions, from which models of liquid bridge actions may be constructed without limitations. Therefore, it is believed that this DNS method can be a useful tool to improve the understanding and modeling of liquid bridges formed in complex gas-solid-liquid flows. PMID- 28085307 TI - Delocalization of disturbances and the stability of ac electricity grids. AB - In order to study how local disturbances affect the ac grid stability, we start from nonlinear power balance equations and map them to complex linear wave equations. Having obtained stationary solutions with phases phi_{i} at generator and consumer nodes i, we next study the dynamics of deviations. Starting with an initially localized perturbation, it is found to spread in a periodic grid diffusively throughout the grid. We find the parametric dependence of diffusion constant D. We apply the same solution strategy to general grid topologies and analyze their stability against local perturbations. The perturbation remains either localized or becomes delocalized, depending on grid topology, power capacity, and distribution of consumers and generator power P_{i}. Delocalization is found to increase the lifetime of perturbations and thereby their influence on grid stability, whereas localization results in an exponentially fast decay of perturbations at all grid sites. These results may therefore lead to new strategies to control the stability of electricity grids. PMID- 28085308 TI - Speed and efficiency limits of multilevel incoherent heat engines. AB - We present a comprehensive theory of heat engines (HE) based on a quantum mechanical "working fluid" (WF) with periodically modulated energy levels. The theory is valid for any periodicity of driving Hamiltonians that commute with themselves at all times and do not induce coherence in the WF. Continuous and stroke cycles arise in opposite limits of this theory, which encompasses hitherto unfamiliar cycle forms, dubbed here hybrid cycles. The theory allows us to discover the speed, power, and efficiency limits attainable by incoherently operating multilevel HE depending on the cycle form and the dynamical regimes. PMID- 28085309 TI - Regularity criterion for solutions of the three-dimensional Cahn-Hilliard-Navier Stokes equations and associated computations. AB - We consider the three-dimensional (3D) Cahn-Hilliard equations coupled to, and driven by, the forced, incompressible 3D Navier-Stokes equations. The combination, known as the Cahn-Hilliard-Navier-Stokes (CHNS) equations, is used in statistical mechanics to model the motion of a binary fluid. The potential development of singularities (blow-up) in the contours of the order parameter phi is an open problem. To address this we have proved a theorem that closely mimics the Beale-Kato-Majda theorem for the 3D incompressible Euler equations [J. T. Beale, T. Kato, and A. J. Majda, Commun. Math. Phys. 94, 61 (1984)CMPHAY0010 361610.1007/BF01212349]. By taking an L^{infinity} norm of the energy of the full binary system, designated as E_{infinity}, we have shown that ?_{0}^{t}E_{infinity}(tau)dtau governs the regularity of solutions of the full 3D system. Our direct numerical simulations (DNSs) of the 3D CHNS equations for (a) a gravity-driven Rayleigh Taylor instability and (b) a constant-energy-injection forcing, with 128^{3} to 512^{3} collocation points and over the duration of our DNSs confirm that E_{infinity} remains bounded as far as our computations allow. PMID- 28085310 TI - Work fluctuation and total entropy production in nonequilibrium processes. AB - Work fluctuation and total entropy production play crucial roles in small thermodynamic systems subject to large thermal fluctuations. We investigate a trade-off relation between them in a nonequilibrium situation in which a system starts from an arbitrary nonequilibrium state. We apply a variational method to study this problem and find a stationary solution against variations over protocols that describe the time dependence of the Hamiltonian of the system. Using the stationary solution, we find the minimum of the total entropy production for a given amount of work fluctuation. An explicit protocol that achieves this is constructed from an adiabatic process followed by a quasistatic process. The obtained results suggest how one can control the nonequilibrium dynamics of the system while suppressing its work fluctuation and total entropy production. PMID- 28085311 TI - Quantum statistics of classical particles derived from the condition of a free diffusion coefficient. AB - We derive an equation for the current of particles in energy space; particles are subject to a mean-field effective potential that may represent quantum effects. From the assumption that noninteracting particles imply a free diffusion coefficient in energy space, we derive Maxwell-Boltzmann, Fermi-Dirac, and Bose Einstein statistics. Other new statistics are associated to a free diffusion coefficient; their thermodynamic properties are analyzed using the grand partition function. A negative relation between pressure and energy density for low temperatures can be derived, suggesting a possible connection with cosmological dark energy models. PMID- 28085312 TI - Statistical theory of reversals in two-dimensional confined turbulent flows. AB - It is shown that the truncated Euler equation (TEE), i.e., a finite set of ordinary differential equations for the amplitude of the large-scale modes, can correctly describe the complex transitional dynamics that occur within the turbulent regime of a confined two-dimensional flow obeying Navier-Stokes equation (NSE) with bottom friction and a spatially periodic forcing. The random reversals of the NSE large-scale circulation on the turbulent background involve bifurcations of the probability distribution function of the large-scale circulation. We demonstrate that these NSE bifurcations are described by the related TEE microcanonical distribution which displays transitions from Gaussian to bimodal and broken ergodicity. A minimal 13-mode model reproduces these results. PMID- 28085313 TI - Why patchy diffusion-limited aggregation belongs to the directed-percolation universality class. AB - We present a possible link between nonequilibrium phase transition observed in patchy diffusion-limited aggregation (DLA) [M. J. Kartha and A. Sayeed, Phys. Lett. A 380, 2791 (2016)10.1016/j.physleta.2016.06.036] and directed bond percolation (DP). A system of directed percolation with patchy particles (patchy DP) in which the bond connectivity is established depending on patch size p is analyzed. It is observed that patchy DP starting from a single seed shows a nonequilibrium phase transition. Below a critical value of the patch size p_{c}, the system reaches an absorbing state above which is a fluctuating active state as observed in the DP system. The value of this nonuniversal parameter p_{c} is observed to be slightly higher than the value observed in patchy DLA. Close to the critical value, the order parameter P(infinity)~(p-p_{c})^{beta} where beta=0.272+/-0.010, which is consistent with the directed-percolation universality class. Therefore the intrinsic nature of patchy DP is responsible for the phase transition in patchy DLA. This study reveals that the estimated critical value of patch size p_{c}=0.80625+/-0.00020 in patchy DP is different from the critical bond probability p_{c}=0.6447 in the DP system. This elucidates that the bond probability in DP is not equivalent to the patch probability of a particular site. Our work also gives an insight into the problem related with formation of an extended network of pentagon subunits in connection with the virus capsid. PMID- 28085314 TI - Mechanics and stability of vesicles and droplets in confined spaces. AB - The permeation and trapping of soft colloidal particles in the confined space of porous media are of critical importance in cell migration studies, design of drug delivery vehicles, and colloid separation devices. Our current understanding of these processes is however limited by the lack of quantitative models that can relate how the elasticity, size, and adhesion properties of the vesicle-pore complex affect colloid transport. We address this shortcoming by introducing a semianalytical model that predicts the equilibrium shapes of a soft vesicle driven by pressure in a narrow pore. Using this approach, the problem is recast in terms of pressure and energy diagrams that characterize the vesicle stability and permeation pressures in different conditions. We particularly show that the critical permeation pressure for a vesicle arises from a compromise between the critical entry pressure and exit pressure, both of which are sensitive to geometrical features, mechanics, and adhesion. We further find that these results can be leveraged to rationally design microfluidic devices and diodes that can help characterize, select, and separate colloids based on physical properties. PMID- 28085315 TI - Competition of simple and complex adoption on interdependent networks. AB - We consider the competition of two mechanisms for adoption processes: a so-called complex threshold dynamics and a simple susceptible-infected-susceptible (SIS) model. Separately, these mechanisms lead, respectively, to first-order and continuous transitions between nonadoption and adoption phases. We consider two interconnected layers. While all nodes on the first layer follow the complex adoption process, all nodes on the second layer follow the simple adoption process. Coupling between the two adoption processes occurs as a result of the inclusion of some additional interconnections between layers. We find that the transition points and also the nature of the transitions are modified in the coupled dynamics. In the complex adoption layer, the critical threshold required for extension of adoption increases with interlayer connectivity whereas in the case of an isolated single network it would decrease with average connectivity. In addition, the transition can become continuous depending on the detailed interlayer and intralayer connectivities. In the SIS layer, any interlayer connectivity leads to the extension of the adopter phase. Besides, a new transition appears as a sudden drop of the fraction of adopters in the SIS layer. The main numerical findings are described by a mean-field type analytical approach appropriately developed for the threshold-SIS coupled system. PMID- 28085316 TI - Finger evolution of a gas bubble driven by atmospheric pressure plasma. AB - We report the generation and evolution of a finger-shaped bubble in liquid by dielectric discharge setup. The spherical gas bubble is deformed into a finger shaped bubble after the ignition of plasma. The presence of the filamentary discharge in the bubble not only provides the local heating to the bubble, it also changes the distribution of the electric field in the bubble and the bubble mutually provides the pathway to the discharge. The reduced surface tension on the liquid-gas interface due to the rise of temperature by plasma heating and the nonuniform electric field caused by the presence of filamentary discharge might induce the concave-shaped bubble. We also observe the formation of the quasi-two dimensional bubble, which is generated from the bubble and attached on one side of the electrodes. It is found that the discharge induces the growth of the periodic fluctuations in the thin layer of gas. PMID- 28085317 TI - Turbulent Rayleigh-Benard convection with polymers: Understanding how heat flux is modified. AB - We study how polymers affect the heat flux in turbulent Rayleigh-Benard convection at moderate Rayleigh numbers using direct numerical simulations with polymers of different relaxation times. We find that heat flux is enhanced by polymers and the amount of heat enhancement first increases and then decreases with the Weissenberg number, which is the ratio of the polymer relaxation time to the typical time scale of the flow. We show that this nonmonotonic behavior of the heat flux enhancement is the combined effect of the decrease in the viscous energy dissipation rate due to the viscosity of the Newtonian fluid and the increase in the energy dissipation rate due to polymers when Weissenberg number is increased. We explain why the viscous energy dissipation rate decreases with the Weissenberg number. Then by carrying out a generalized boundary layer analysis supplemented by a space-dependent effective viscosity from the numerical simulations, we provide a theoretical understanding of the change of the heat flux when the viscous energy dissipation rate is held constant. Our analysis thus provides a physical way to understand the numerical results. PMID- 28085318 TI - Alternative mechanism for coffee-ring deposition based on active role of free surface. AB - When a colloidal sessile droplet dries on a substrate, the particles suspended in it usually deposit in a ringlike pattern. This phenomenon is commonly referred to as the "coffee-ring" effect. One paradigm for why this occurs is as a consequence of the solutes being transported towards the pinned contact line by the flow inside the drop, which is induced by surface evaporation. From this perspective, the role of the liquid-gas interface in shaping the deposition pattern is somewhat minimized. Here, we propose an alternative mechanism for the coffee-ring deposition. It is based on the bulk flow within the drop transporting particles to the interface where they are captured by the receding free surface and subsequently transported along the interface until they are deposited near the contact line. That the interface captures the solutes as the evaporation proceeds is supported by a Lagrangian tracing of particles advected by the flow field within the droplet. We model the interfacial adsorption and transport of particles as a one-dimensional advection-generation process in toroidal coordinates and show that the theory reproduces ring-shaped depositions. Using this model, deposition patterns on both hydrophilic and hydrophobic surfaces are examined in which the evaporation is modeled as being either diffusive or uniform over the surface. PMID- 28085319 TI - Static and dynamic friction of hierarchical surfaces. AB - Hierarchical structures are very common in nature, but only recently have they been systematically studied in materials science, in order to understand the specific effects they can have on the mechanical properties of various systems. Structural hierarchy provides a way to tune and optimize macroscopic mechanical properties starting from simple base constituents and new materials are nowadays designed exploiting this possibility. This can be true also in the field of tribology. In this paper we study the effect of hierarchical patterned surfaces on the static and dynamic friction coefficients of an elastic material. Our results are obtained by means of numerical simulations using a one-dimensional spring-block model, which has previously been used to investigate various aspects of friction. Despite the simplicity of the model, we highlight some possible mechanisms that explain how hierarchical structures can significantly modify the friction coefficients of a material, providing a means to achieve tunability. PMID- 28085320 TI - Mass-flow-rate-controlled fluid flow in nanochannels by particle insertion and deletion. AB - A nonequilibrium molecular dynamics method to induce fluid flow in nanochannels, the insertion-deletion method (IDM), is introduced. IDM inserts and deletes particles within distinct regions in the domain, creating locally high and low pressures. The benefits of IDM are that it directly controls a physically meaningful quantity, the mass flow rate, allows for pressure and density gradients to develop in the direction of flow, and permits treatment of complex aperiodic geometries. Validation of IDM is performed, yielding good agreement with the analytical solution of Poiseuille flow in a planar channel. Comparison of IDM to existing methods indicates that it is best suited for gases, both because it intrinsically accounts for compressibility effects on the flow and because the computational cost of particle insertion is lowest for low-density fluids. PMID- 28085321 TI - Multifractals embedded in short time series: An unbiased estimation of probability moment. AB - An exact estimation of probability moments is the base for several essential concepts, such as the multifractals, the Tsallis entropy, and the transfer entropy. By means of approximation theory we propose a new method called factorial-moment-based estimation of probability moments. Theoretical prediction and computational results show that it can provide us an unbiased estimation of the probability moments of continuous order. Calculations on probability redistribution model verify that it can extract exactly multifractal behaviors from several hundred recordings. Its powerfulness in monitoring evolution of scaling behaviors is exemplified by two empirical cases, i.e., the gait time series for fast, normal, and slow trials of a healthy volunteer, and the closing price series for Shanghai stock market. By using short time series with several hundred lengths, a comparison with the well-established tools displays significant advantages of its performance over the other methods. The factorial moment-based estimation can evaluate correctly the scaling behaviors in a scale range about three generations wider than the multifractal detrended fluctuation analysis and the basic estimation. The estimation of partition function given by the wavelet transform modulus maxima has unacceptable fluctuations. Besides the scaling invariance focused in the present paper, the proposed factorial moment of continuous order can find its various uses, such as finding nonextensive behaviors of a complex system and reconstructing the causality relationship network between elements of a complex system. PMID- 28085322 TI - Decomposition of powerful axisymmetrically polarized laser pulses in underdense plasma. AB - Interaction of relativistically intense axisymmetrically polarized (radially or azimuthally polarized) laser pulses (RIAPLP) with underdense plasma is shown experimentally and theoretically to be essentially different from the interaction of conventional Gaussian pulses. The difference is clearly observed in distinct spectra of the side-scattered laser light for the RIAPLP and Gaussian pulses, as well as in the appearance of a spatially localized strong side emission of second harmonic of the laser pulse in the case of RIAPLP. According to our analysis based on three-dimensional particle-in-cell simulations, this is a result of instability in the propagation of RIAPLP in uniform underdense plasma. PMID- 28085323 TI - Nonlinear inhomogeneous Fokker-Planck equations: Entropy and free-energy time evolution. AB - We extend a recently introduced free-energy formalism for homogeneous Fokker Planck equations to a wide, and physically appealing, class of inhomogeneous nonlinear Fokker-Planck equations. In our approach, the free-energy functional is expressed in terms of an entropic functional and an auxiliary potential, both derived from the coefficients of the equation. With reference to the introduced entropic functional, we discuss the entropy production in a relaxation process towards equilibrium. The properties of the stationary solutions of the considered Fokker-Planck equations are also discussed. PMID- 28085324 TI - Control of epidemics via social partnership adjustment. AB - Epidemic control is of great importance for human society. Adjusting interacting partners is an effective individualized control strategy. Intuitively, it is done either by shortening the interaction time between susceptible and infected individuals or by increasing the opportunities for contact between susceptible individuals. Here, we provide a comparative study on these two control strategies by establishing an epidemic model with nonuniform stochastic interactions. It seems that the two strategies should be similar, since shortening the interaction time between susceptible and infected individuals somehow increases the chances for contact between susceptible individuals. However, analytical results indicate that the effectiveness of the former strategy sensitively depends on the infectious intensity and the combinations of different interaction rates, whereas the latter one is quite robust and efficient. Simulations are shown to verify our analytical predictions. Our work may shed light on the strategic choice of disease control. PMID- 28085325 TI - Braess paradox in a network of totally asymmetric exclusion processes. AB - We study the Braess paradox in the transport network as originally proposed by Braess with totally asymmetric exclusion processes (TASEPs) on the edges. The Braess paradox describes the counterintuitive situation in which adding an edge to a road network leads to a user optimum with higher travel times for all network users. Travel times on the TASEPs are nonlinear in the density, and jammed states can occur due to the microscopic exclusion principle, leading to a more realistic description of trafficlike transport on the network than in previously studied linear macroscopic mathematical models. Furthermore, the stochastic dynamics allows us to explore the effects of fluctuations on network performance. We observe that for low densities, the added edge leads to lower travel times. For slightly higher densities, the Braess paradox occurs in its classical sense. At intermediate densities, strong fluctuations in the travel times dominate the system's behavior due to links that are in a domain-wall state. At high densities, the added link leads to lower travel times. We present a phase diagram that predicts the system's state depending on the global density and crucial path-length ratios. PMID- 28085326 TI - Discontinuous transitions in globally coupled potential systems with additive noise. AB - An infinite array of globally coupled overdamped constituents moving in a double well potential with nth order saturation term under the influence of additive Gaussian white noise is investigated. The system exhibits a continuous phase transition from a symmetric phase to a symmetry-broken phase. The qualitative behavior is independent on n. The critical point is calculated for strong and for weak noise; these limits are also bounds for the critical point. Introducing an additional nonlinearity, such that the potential can have up to three minima, leads to richer behavior. There the parameter space divides into three regions: a region with a symmetric phase, a region with a phase of broken symmetry and a region where both phases coexist. The region of coexistence collapses into one of the others via a discontinuous phase transition, whereas the transition between the symmetric phase and the phase of broken symmetry is continuous. The tricritical point where the three regions intersect can be calculated for strong and for weak noise. These limiting values form tight bounds on the tricritical point. In the region of coexistence simulations of finite systems are performed. One finds that the stationary distribution of finite but large systems differs qualitatively from the one of the infinite system. Hence the limits of stationarity and large system size do not commute. PMID- 28085327 TI - Non-Boltzmann stationary distributions and nonequilibrium relations in active baths. AB - Most natural and engineered processes, such as biomolecular reactions, protein folding, and population dynamics, occur far from equilibrium and therefore cannot be treated within the framework of classical equilibrium thermodynamics. Here we experimentally study how some fundamental thermodynamic quantities and relations are affected by the presence of the nonequilibrium fluctuations associated with an active bath. We show in particular that, as the confinement of the particle increases, the stationary probability distribution of a Brownian particle confined within a harmonic potential becomes non-Boltzmann, featuring a transition from a Gaussian distribution to a heavy-tailed distribution. Because of this, nonequilibrium relations (e.g., the Jarzynski equality and Crooks fluctuation theorem) cannot be applied. We show that these relations can be restored by using the effective potential associated with the stationary probability distribution. We corroborate our experimental findings with theoretical arguments. PMID- 28085328 TI - Publisher's Note: Laser propagation in dense magnetized plasma [Phys. Rev. E 94, 053207 (2016)]. AB - This corrects the article DOI: 10.1103/PhysRevE.94.053207. PMID- 28085330 TI - Relaxation dynamics of a compressible bilayer vesicle containing highly viscous fluid. AB - We study the relaxation dynamics of a compressible bilayer vesicle with an asymmetry in the viscosity of the inner and outer fluid medium. First we explore the stability of the vesicle free energy which includes a coupling between the membrane curvature and the local density difference between the two monolayers. Two types of instabilities are identified: a small wavelength instability and a larger wavelength instability. Considering the bulk fluid viscosity and the inter monolayer friction as the dissipation sources, we next employ Onsager's variational principle to derive the coupled equations both for the membrane and the bulk fluid. The three relaxation modes are coupled to each other due to the bilayer and the spherical structure of the vesicle. Most importantly, a higher fluid viscosity inside the vesicle shifts the crossover mode between the bending and the slipping to a larger value. As the vesicle parameters approach the unstable regions, the relaxation dynamics is dramatically slowed down, and the corresponding mode structure changes significantly. In some limiting cases, our general result reduces to the previously obtained relaxation rates. PMID- 28085329 TI - Comment on "Critical wind speed at which trees break". AB - Virot et al. [E. Virot et al., Phys. Rev. E 93, 023001 (2016)10.1103/PhysRevE.93.023001] assert that the critical wind speed at which ?50% of all trees in a population break is ~42 m/s, regardless of tree characteristics. We show that empirical data do not support this assertion, and that the assumptions underlying the theory used by Virot et al. are inconsistent with the biomechanics of trees. PMID- 28085331 TI - Gaussian orthogonal ensemble statistics in graphene billiards with the shape of classically integrable billiards. AB - A crucial result in quantum chaos, which has been established for a long time, is that the spectral properties of classically integrable systems generically are described by Poisson statistics, whereas those of time-reversal symmetric, classically chaotic systems coincide with those of random matrices from the Gaussian orthogonal ensemble (GOE). Does this result hold for two-dimensional Dirac material systems? To address this fundamental question, we investigate the spectral properties in a representative class of graphene billiards with shapes of classically integrable circular-sector billiards. Naively one may expect to observe Poisson statistics, which is indeed true for energies close to the band edges where the quasiparticle obeys the Schrodinger equation. However, for energies near the Dirac point, where the quasiparticles behave like massless Dirac fermions, Poisson statistics is extremely rare in the sense that it emerges only under quite strict symmetry constraints on the straight boundary parts of the sector. An arbitrarily small amount of imperfection of the boundary results in GOE statistics. This implies that, for circular-sector confinements with arbitrary angle, the spectral properties will generically be GOE. These results are corroborated by extensive numerical computation. Furthermore, we provide a physical understanding for our results. PMID- 28085332 TI - Microscopic theory of a nonequilibrium open bosonic chain. AB - Quantum master equations form an important tool in the description of transport problems in open quantum systems. However, they suffer from the difficulty that the shape of the Lindblad dissipator depends sensibly on the system Hamiltonian. Consequently, most of the work done in this field has focused on phenomenological dissipators which act locally on different parts of the system. In this paper we show how to construct Lindblad dissipators to model a one-dimensional bosonic tight-binding chain connected to two baths at the first and last site, kept at different temperatures and chemical potentials. We show that even though the bath coupling is local, the effective Lindblad dissipator stemming from this interaction is inherently nonlocal, affecting all normal modes of the system. We then use this formalism to study the current of particles and energy through the system and find that they have the structure of Landauer's formula, with the bath spectral density playing the role of the transfer integral. Finally, we consider infinitesimal temperature and chemical potential gradients and show that the currents satisfy Onsager's reciprocal relations, which is a consequence of the fact that the microscopic quantum dynamics obeys detailed balance. PMID- 28085334 TI - Vertical dynamics of a horizontally oscillating active object in a two dimensional granular medium. AB - We use a discrete-element method simulation and analytical considerations to study the dynamics of a self-energized object, modeled as a disk, oscillating horizontally within a two-dimensional bed of denser and smaller particles. We find that, for given material parameters, the immersed object (IO) may rise, sink, or not change depth, depending on the oscillation amplitude and frequency, as well as on the initial depth. With time, the IO settles at a specific depth that depends on the oscillation parameters. We construct a phase diagram of this behavior in the oscillation frequency and velocity amplitude variable space. We explain the observed rich behavior by two competing effects: climbing on particles, which fill voids opening under the disk, and sinking due to bed fluidization. We present a cavity model that allows us to derive analytically general results, which agree very well with the observations and explain quantitatively the phase diagram. Our specific analytical results are the following. (i) Derivation of a critical frequency, f_{c}, above which the IO cannot float up against gravity. We show that this frequency depends only on the gravitational acceleration and the IO size. (ii) Derivation of a minimal amplitude, A_{min}, below which the IO cannot rise even if the frequency is below f_{c}. We show that this amplitude also depends only on the gravitational acceleration and the IO size. (iii) Derivation of a critical value, g_{c}, of the IO's acceleration amplitude, below which the IO cannot sink. We show that the value of g_{c} depends on the characteristics of both the IO and the granular bed, as well as on the initial IO's depth. PMID- 28085333 TI - Asymptotic self-restabilization of a continuous elastic structure. AB - A challenge in soft robotics and soft actuation is the determination of an elastic system that spontaneously recovers its trivial path during postcritical deformation after a bifurcation. The interest in this behavior is that a displacement component spontaneously cycles around a null value, thus producing a cyclic soft mechanism. An example of such a system is theoretically proven through the solution of the elastica and a stability analysis based on dynamic perturbations. It is shown that the asymptotic self-restabilization is driven by the development of a configurational force, of similar nature to the Peach Koehler interaction between dislocations in crystals, which is derived from the principle of least action. A proof-of-concept prototype of the discovered elastic system is designed, realized, and tested, showing that this innovative behavior can be obtained in a real mechanical apparatus. PMID- 28085335 TI - Metastable localization of diseases in complex networks. AB - We describe the phenomenon of localization in the epidemic susceptible-infective susceptible model on highly heterogeneous networks in which strongly connected nodes (hubs) play the role of centers of localization. We find that in this model the localized states below the epidemic threshold are metastable. The longevity and scale of the metastable outbreaks do not show a sharp localization transition; instead there is a smooth crossover from localized to delocalized states as we approach the epidemic threshold from below. Analyzing these long lasting local outbreaks for a random regular graph with a hub, we show how this localization can be detected from the shape of the distribution of the number of infective nodes. PMID- 28085336 TI - Gaussian theory for spatially distributed self-propelled particles. AB - Obtaining a reduced description with particle and momentum flux densities outgoing from the microscopic equations of motion of the particles requires approximations. The usual method, we refer to as truncation method, is to zero Fourier modes of the orientation distribution starting from a given number. Here we propose another method to derive continuum equations for interacting self propelled particles. The derivation is based on a Gaussian approximation (GA) of the distribution of the direction of particles. First, by means of simulation of the microscopic model, we justify that the distribution of individual directions fits well to a wrapped Gaussian distribution. Second, we numerically integrate the continuum equations derived in the GA in order to compare with results of simulations. We obtain that the global polarization in the GA exhibits a hysteresis in dependence on the noise intensity. It shows qualitatively the same behavior as we find in particles simulations. Moreover, both global polarizations agree perfectly for low noise intensities. The spatiotemporal structures of the GA are also in agreement with simulations. We conclude that the GA shows qualitative agreement for a wide range of noise intensities. In particular, for low noise intensities the agreement with simulations is better as other approximations, making the GA to an acceptable candidates of describing spatially distributed self-propelled particles. PMID- 28085337 TI - Characteristic functions based on a quantum jump trajectory. AB - Characteristic functions (CFs) provide a very efficient method for evaluating the probability density functions of stochastic thermodynamic quantities and investigating their statistical features in quantum master equations (QMEs). A conventional procedure for obtaining these functions is to resort to a first principles approach; namely, the evolution equations of the CFs of the combined system and its environment are obtained and then projected into the degrees of freedom of the system. However, the QMEs can be unraveled by a quantum jump trajectory. Thermodynamic quantities such as the heat, work, and entropy production can be well defined along a trajectory. Hence, on the basis of the notion of a trajectory, can we straightforwardly derive these CFs, e.g., their evolution equations? This is essential to establish the self-contained stochastic thermodynamics of a QME. In this paper, we show that it is indeed plausible and also simple. Particularly, these equations are fully consistent with those obtained by the first-principles method. Our results have practical significance; they indicate that the quantum fluctuation relations could be verified by more realistic photocounting experiments. PMID- 28085338 TI - Phase diagram of matrix compressed sensing. AB - In the problem of matrix compressed sensing, we aim to recover a low-rank matrix from a few noisy linear measurements. In this contribution, we analyze the asymptotic performance of a Bayes-optimal inference procedure for a model where the matrix to be recovered is a product of random matrices. The results that we obtain using the replica method describe the state evolution of the Parametric Bilinear Generalized Approximate Message Passing (P-BiG-AMP) algorithm, recently introduced in J. T. Parker and P. Schniter [IEEE J. Select. Top. Signal Process. 10, 795 (2016)1932-455310.1109/JSTSP.2016.2539123]. We show the existence of two different types of phase transition and their implications for the solvability of the problem, and we compare the results of our theoretical analysis to the numerical performance reached by P-BiG-AMP. Remarkably, the asymptotic replica equations for matrix compressed sensing are the same as those for a related but formally different problem of matrix factorization. PMID- 28085339 TI - Lattice Boltzmann simulations of droplet formation in confined channels with thermocapillary flows. AB - Based on mesoscale lattice Boltzmann simulations with the "Shan-Chen" model, we explore the influence of thermocapillarity on the breakup properties of fluid threads in a microfluidic T-junction, where a dispersed phase is injected perpendicularly into a main channel containing a continuous phase, and the latter induces periodic breakup of droplets due to the cross-flowing. Temperature effects are investigated by switching on-off both positive-negative temperature gradients along the main channel direction, thus promoting a different thread dynamics with anticipated-delayed breakup. Numerical simulations are performed at changing the flow rates of both the continuous and dispersed phases, as well as the relative importance of viscous forces, surface tension forces, and thermocapillary stresses. The range of parameters is broad enough to characterize the effects of thermocapillarity on different mechanisms of breakup in the confined T-junction, including the so-called "squeezing" and "dripping" regimes, previously identified in the literature. Some simple scaling arguments are proposed to rationalize the observed behavior, and to provide quantitative guidelines on how to predict the droplet size after breakup. PMID- 28085340 TI - Effect of long-range electrostatic repulsion on pore clogging during microfiltration. AB - We perform computer simulations based on adhesive contact mechanics to demonstrate the clogging process of charged microparticles at the single-pore level. The effect of long-range Coulomb repulsion on clogging is characterized in terms of bulk permeability, the number of penetrating particles, and particle capture efficiency. Results indicate that the repulsion among particles delays or even totally prevents the formation of clogs. A clogging phase diagram, in the form of the driving pressure and a proposed charge parameter kappa_{q}, is constructed to quantify the clogging-nonclogging transition. In addition, a critical state, where the capture efficiency of particles decreases to its minimum, is identified as a clogging-nonclogging criterion for repulsive particles. The distributions of the local volume fraction show that the structure of clogs is mainly determined by short-range adhesion. With relatively strong adhesion, a loose clog will be formed and it is easier for particles to penetrate. Finally, a schematic representation of the clogging process, considering both long-range repulsion and adhesion, is proposed to show the relationship between the clogging results and the interparticle interactions. PMID- 28085341 TI - Zero-temperature directed polymer in random potential in 4+1 dimensions. AB - Zero-temperature directed polymer in random potential in 4+1 dimensions is described. The fluctuation DeltaE(t) of the lowest energy of the polymer varies as t^{beta} with beta=0.159+/-0.007 for polymer length t and DeltaE follows DeltaE(L)~L^{alpha} at saturation with alpha=0.275+/-0.009, where L is the system size. The dynamic exponent z~1.73 is obtained from z=alpha/beta. The estimated values of the exponents satisfy the scaling relation alpha+z=2 very well. We also monitor the end to end distance of the polymer and obtain z independently. Our results show that the upper critical dimension of the Kardar-Parisi-Zhang equation is higher than d=4+1 dimensions. PMID- 28085342 TI - Inhibitory neurons promote robust critical firing dynamics in networks of integrate-and-fire neurons. AB - We study the firing dynamics of a discrete-state and discrete-time version of an integrate-and-fire neuronal network model with both excitatory and inhibitory neurons. When the integer-valued state of a neuron exceeds a threshold value, the neuron fires, sends out state-changing signals to its connected neurons, and returns to the resting state. In this model, a continuous phase transition from non-ceaseless firing to ceaseless firing is observed. At criticality, power-law distributions of avalanche size and duration with the previously derived exponents, -3/2 and -2, respectively, are observed. Using a mean-field approach, we show analytically how the critical point depends on model parameters. Our main result is that the combined presence of both inhibitory neurons and integrate-and fire dynamics greatly enhances the robustness of critical power-law behavior (i.e., there is an increased range of parameters, including both sub- and supercritical values, for which several decades of power-law behavior occurs). PMID- 28085343 TI - Master equation approach to reversible and conservative discrete systems. AB - A master equation approach is applied to a reversible and conservative cellular automaton model (Q2R). The Q2R model is a dynamical variation of the Ising model for ferromagnetism that possesses quite a rich and complex dynamics. The configuration space is composed of a huge number of cycles with exponentially long periods. Following Nicolis and Nicolis [G. Nicolis and C. Nicolis, Phys. Rev. A 38, 427 (1988)0556-279110.1103/PhysRevA.38.427], a coarse-graining approach is applied to the time series of the total magnetization, leading to a master equation that governs the macroscopic irreversible dynamics of the Q2R automata. The methodology is replicated for various lattice sizes. In the case of small systems, we show that the master equation leads to a tractable probability transfer matrix of moderate size, which provides a master equation for a coarse grained probability distribution. The method is validated and some explicit examples are discussed. PMID- 28085344 TI - Effects of Landau-Lifshitz-Gilbert damping on domain growth. AB - Domain patterns are simulated by the Landau-Lifshitz-Gilbert (LLG) equation with an easy-axis anisotropy. If the Gilbert damping is removed from the LLG equation, it merely describes the precession of magnetization with a ferromagnetic interaction. However, even without the damping, domains that look similar to those of scalar fields are formed, and they grow with time. It is demonstrated that the damping has no significant effects on domain growth laws and large-scale domain structure. In contrast, small-scale domain structure is affected by the damping. The difference in small-scale structure arises from energy dissipation due to the damping. PMID- 28085345 TI - Depinning and heterogeneous dynamics of colloidal crystal layers under shear flow. AB - Using Brownian dynamics (BD) simulations and an analytical approach we investigate the shear-induced, nonequilibrium dynamics of dense colloidal suspensions confined to a narrow slit-pore. Focusing on situations where the colloids arrange in well-defined layers with solidlike in-plane structure, the confined films display complex, nonlinear behavior such as collective depinning and local transport via density excitations. These phenomena are reminiscent of colloidal monolayers driven over a periodic substrate potential. In order to deepen this connection, we present an effective model that maps the dynamics of the shear-driven colloidal layers to the motion of a single particle driven over an effective substrate potential. This model allows us to estimate the critical shear rate of the depinning transition based on the equilibrium configuration, revealing the impact of important parameters, such as the slit-pore width and the interaction strength. We then turn to heterogeneous systems where a layer of small colloids is sheared with respect to bottom layers of large particles. For these incommensurate systems we find that the particle transport is dominated by density excitations resembling the so-called "kink" solutions of the Frenkel Kontorova (FK) model. In contrast to the FK model, however, the corresponding "antikinks" do not move. PMID- 28085346 TI - Thermal unfolding of myoglobin in the Landau-Ginzburg-Wilson approach. AB - The Landau-Ginzburg-Wilson paradigm is applied to model the low-temperature crystallographic Calpha backbone structure of sperm whale myoglobin. The Glauber protocol is employed to simulate its response to an increase in ambient temperature. The myoglobin is found to unfold from its native state by a succession of alpha-helical intermediates, fully in line with the observed folding and unfolding patterns in denaturation experiments. In particular, a molten globule intermediate is identified with experimentally correct attributes. A detailed, experimentally testable contact map is constructed to characterize the specifics of the unfolding pathway, including the formation of long-range interactions. The results reveal how the unfolding process of a protein is driven by the interplay between, and a successive melting of, its modular secondary structure components. PMID- 28085347 TI - Stabilizing effect of tip splitting on the interface motion. AB - Pattern-forming processes, such as electrodeposition, dielectric breakdown, or viscous fingering, are often driven by instabilities. Accordingly, the resulting growth patterns are usually highly branched fractal structures. However, in some of the unstable growth processes the envelope of the structure grows in a highly regular manner, with the perturbations smoothed out over the course of time. In this paper we show that the regularity of the envelope growth can be connected to small-scale instabilities leading to the tip splitting of the fingers at the advancing front of the structure. Whenever the growth velocity becomes too large, the finger splits into two branches. In this way it can absorb an increased flux and thus damp the instability. Hence, somewhat counterintuitively, the instability at a small scale results in a stability at a larger scale. The quantitative analysis of these effects is provided by means of the Loewner equation, which one can use to reduce the problem of the interface motion to that of the evolution of the conformal mapping onto the complex plane. This allows an effective analysis of the multifingered growth in a variety of different geometries. We show how the geometry impacts the shape of the envelope of the growing pattern and compare the results with those observed in natural systems. PMID- 28085348 TI - Multicritical absorbing phase transition in a class of exactly solvable models. AB - We study diffusion of hard-core particles on a one-dimensional periodic lattice subjected to a constraint that the separation between any two consecutive particles does not increase beyond a fixed value n+1; an initial separation larger than n+1 can however decrease. These models undergo an absorbing state phase transition when the conserved particle density of the system falls below a critical threshold rho_{c}=1/(n+1). We find that the phi_{k}, the density of 0 clusters (0 representing vacancies) of size 0<=k0. In the large-q limit the free-energy of random samples of length L<=2048 is calculated exactly by a combinatorial optimization algorithm. The phase transition stays first order for sigmaz^{*}) for an ideal classical gas. Also, according to the singular point of thermodynamic curvature, we consider the condensation of nonextensive Boson gas. PMID- 28085372 TI - Experimental observation of phase-flip transitions in two inductively coupled glow discharge plasmas. AB - We report an experimental observation of a phase-flip transition in the frequency synchronization of two dc glow discharge plasma sources that are coupled in a noninvasive fashion. When the fundamental oscillation frequency of the potential fluctuations of one of the sources is progressively increased, by raising its discharge voltage, a frequency pulling regime is observed, followed by a synchronized regime that shows a frequency jump phenomenon. The jump is associated with a phase-flip transition that takes the synchronized state from an in-phase to an antiphase state. When the process is reversed, the transition takes place at a different frequency, thereby exhibiting a hysteresis effect. A heuristic model, consisting of two van der Pol oscillators that are coupled to each other through a dynamic common medium, eminently captures the essential features of our experimental observations. PMID- 28085373 TI - Unsupervised feature learning from finite data by message passing: Discontinuous versus continuous phase transition. AB - Unsupervised neural network learning extracts hidden features from unlabeled training data. This is used as a pretraining step for further supervised learning in deep networks. Hence, understanding unsupervised learning is of fundamental importance. Here, we study the unsupervised learning from a finite number of data, based on the restricted Boltzmann machine where only one hidden neuron is considered. Our study inspires an efficient message-passing algorithm to infer the hidden feature and estimate the entropy of candidate features consistent with the data. Our analysis reveals that the learning requires only a few data if the feature is salient and extensively many if the feature is weak. Moreover, the entropy of candidate features monotonically decreases with data size and becomes negative (i.e., entropy crisis) before the message passing becomes unstable, suggesting a discontinuous phase transition. In terms of convergence time of the message-passing algorithm, the unsupervised learning exhibits an easy-hard-easy phenomenon as the training data size increases. All these properties are reproduced in an approximate Hopfield model, with an exception that the entropy crisis is absent, and only continuous phase transition is observed. This key difference is also confirmed in a handwritten digits dataset. This study deepens our understanding of unsupervised learning from a finite number of data and may provide insights into its role in training deep networks. PMID- 28085374 TI - Exact scaling laws for helical three-dimensional two-fluid turbulent plasmas. AB - We derive exact scaling laws for a three-dimensional incompressible helical two fluid plasma, without the assumption of isotropy. For each ideal invariant of the two-fluid model, i.e., the total energy, the electron helicity, and the proton helicity, we derive simple scaling laws in terms of two-point increment correlation functions expressed in terms of the velocity field of each species and the magnetic field. These variables are appropriate for comparison with direct numerical simulation data and with in situ measurements in the near-Earth space over a broad range of spatial scales. Finally, using the exact scaling laws and dimensional analysis we predict the magnetic energy and electron helicity spectra for different ranges of scales. PMID- 28085375 TI - Relaxational processes in the one-dimensional Ising model with long-range interactions. AB - Relaxational processes in ordered phases of one-dimensional Ising models with long-range interactions are investigated by Monte Carlo simulations. Three types of spin model, the pure ferromagnetic, the diluted ferromagnetic, and the spin glass models, are examined. The effective dimension of the one-dimensional systems are controlled by a parameter sigma, which tunes the rate of interaction decay. Systematical investigations of droplet dynamics, from the lower to the upper critical dimension, are conducted by changing the value of sigma. Comparing numerical data with the droplet theory, it is found that the surface dimension of droplets is distributed around the effective dimension. The distribution in the surface dimension makes the droplet dynamics complex and extremely enhances dynamical crossover. PMID- 28085376 TI - Modes of electrokinetic instability for imperfect electric membranes. AB - The direct transition to overlimiting current bypassing the stage of limiting currents is considered for imperfect membranes. Instability of the quiescent steady-state one-dimensional solution, which is the result of a balance of diffusion and electromigration, is investigated on the basis of the full Nernst Planck-Poisson-Stokes system and a simplified quasielectroneutral system. A three layer geometry, electrolyte-porous membrane-electrolyte, is considered. The usual assumption of a constant electrochemical potential along the membrane surface is removed from consideration. The effect of bulk and surface effects on the instability and transition to the overlimiting currents is evaluated for a different membrane selectivity. It becomes clear that for sufficiently small fixed charge concentration (large ion concentration in the electrolyte), the monotonic instability is replaced by an oscillatory one. The dependence of instability on the membrane porosity is found to be weak. PMID- 28085377 TI - Effective slip for flow in a rotating channel bounded by stick-slip walls. AB - This paper aims to look into how system rotation may modify the role played by boundary slip in controlling flow through a rotating channel bounded by stick slip walls. A semianalytical model is developed for pressure-driven flow in a slit channel that rotates about an axis perpendicular to its walls, which are superhydrophobic surfaces patterned with periodic alternating no-shear and no slip stripes. The cases where the flow is driven by a pressure gradient parallel or normal to the stripes are considered. The effects of the no-shear area fraction on the velocities and effective slip lengths for the primary and secondary flows are investigated as functions of the rotation rate and the channel height. It is mathematically proved that the secondary flow rate is exactly the same in the two cases, irrespective of whether the primary flow is parallel or normal to the wall stripes. For any rotation speed, there is an optimal value of the no-shear area fraction at which the primary flow rate is maximum. This is a consequence of two competing effects: the no-shear part of the wall may serve to reduce the wall resistance, thereby enhancing the flow especially at low rotation, but it also weakens the formation of the near-wall Ekman layer, which is responsible for pumping the flow especially at high rotation. Wall slip in a rotating environment is to affect flow in the Ekman layer, but not flow in the geostrophic core. PMID- 28085378 TI - Noisy-flow-induced instability in a reaction-diffusion system. AB - We consider a generic reaction-diffusion-advection system where the flow velocity of the advection term is subjected to dichotomous noise with zero mean and Ornstein-Zernike correlation. A general condition for noisy-flow-induced instability is derived in the flow velocity-correlation rate parameter plane. Full numerical simulations on Gierer-Meinhardt model with activator-inhibitor kinetics have been performed to show how noisy differential flow can lead to symmetry breaking of a homogeneous stable state in the presence of noise resulting in traveling waves. PMID- 28085379 TI - Extracting work from a single reservoir in the non-Markovian underdamped regime. AB - We derive optimal-work finite time protocols for a colloidal particle in a harmonic well in the general non-Markovian underdamped regime in contact with a single reservoir. Optimal-work protocols with and without measurements of position and velocity are shown to be linear in time. In order to treat the underdamped regime one must address forcing the particle at the start and at the end of a protocol, conditions which dominate the short time behavior of the colloidal particle. We find that for protocols without measurement the least work by an external agent decreases linearly for forced start-stop conditions while those only forced at starting conditions are quadratic (slower) at short times, while both decrease asymptotically to zero for quasistatic processes. When measurements are performed, protocols with start-end forcing are still more efficient at short times but can be overtaken by start-only protocols at a threshold time. Measurement protocols derive work from the reservoir but always below that predicted by Sagawa's generalization of the second law. Velocity measurement protocols are more efficient in deriving work than position measurements. PMID- 28085380 TI - Numerical study of the tight-binding approach to overdamped Brownian motion on a tilted periodic potential. AB - We present a numerical study of the tight-binding approach to overdamped Brownian motion on a tilted periodic potential. In the tight-binding method the probability density is expanded on a basis of Wannier states to transform the Smoluchowski equation to a discrete master equation that can be interpreted in terms of thermal hopping between potential minima. We calculate the Wannier states and hopping rates for a variety of potentials, including tilted cosine and ratchet potentials. For deep potential minima the Wannier states are well localized and the hopping rates between nearest-neighbor states are qualitatively well described by Kramers' escape rate. The next-nearest-neighbor hopping rates are negative and must be negligible compared to the nearest-neighbor rates for the discrete master equation treatment to be valid. We find that the validity of the master equation extends beyond the quantitative applicability of Kramers' escape rate. PMID- 28085381 TI - Constrained sampling method for analytic continuation. AB - A method for analytic continuation of imaginary-time correlation functions (here obtained in quantum Monte Carlo simulations) to real-frequency spectral functions is proposed. Stochastically sampling a spectrum parametrized by a large number of delta functions, treated as a statistical-mechanics problem, it avoids distortions caused by (as demonstrated here) configurational entropy in previous sampling methods. The key development is the suppression of entropy by constraining the spectral weight to within identifiable optimal bounds and imposing a set number of peaks. As a test case, the dynamic structure factor of the S=1/2 Heisenberg chain is computed. Very good agreement is found with Bethe ansatz results in the ground state (including a sharp edge) and with exact diagonalization of small systems at elevated temperatures. PMID- 28085382 TI - Eigenvalue tunneling and decay of quenched random network. AB - We consider the canonical ensemble of N-vertex Erdos-Renyi (ER) random topological graphs with quenched vertex degree, and with fugacity MU for each closed triple of bonds. We claim complete defragmentation of large-N graphs into the collection of [p^{-1}] almost full subgraphs (cliques) above critical fugacity, MU_{c}, where p is the ER bond formation probability. Evolution of the spectral density, rho(lambda), of the adjacency matrix with increasing MU leads to the formation of a multizonal support for MU>MU_{c}. Eigenvalue tunneling from the central zone to the side one means formation of a new clique in the defragmentation process. The adjacency matrix of the network ground state has a block-diagonal form, where the number of vertices in blocks fluctuates around the mean value Np. The spectral density of the whole network in this regime has triangular shape. We interpret the phenomena from the viewpoint of the conventional random matrix model and speculate about possible physical applications. PMID- 28085383 TI - Gaseous microflow modeling using the Fokker-Planck equation. AB - We present a comparative study of gaseous microflow systems using the recently introduced Fokker-Planck approach and other methods such as: direct simulation Monte Carlo, lattice Boltzmann, and variational solution of Boltzmann-BGK. We show that this Fokker-Plank approach performs efficiently at intermediate values of Knudsen number, a region where direct simulation Monte Carlo becomes expensive and lattice Boltzmann becomes inaccurate. We also investigate the effectiveness of a recently proposed Fokker-Planck model in simulations of heat transfer, as a function of relevant parameters such as the Prandtl, Knudsen numbers. Furthermore, we present simulation of shock wave as a function of Mach number in transonic regime. Our results suggest that the performance of the Fokker-Planck approach is superior to that of the other methods in transition regime for rarefied gas flow and transonic regime for shock wave. PMID- 28085384 TI - Influence of e^{-}e^{+} creation on the radiative trapping in ultraintense fields of colliding laser pulses. AB - The behavior of a thin plasma target irradiated by two counterpropagating laser pulses of ultrahigh intensity is studied in the framework of one- and two dimensional particle-in-cell simulations. It is found that above an intensity threshold, radiative trapping can focus electrons in the peaks of the electromagnetic field. At even higher intensities, the trapping effect cannot be maintained according to the increasing influence of electron-positron pair production on the laser-plasma dynamics. PMID- 28085385 TI - Numerical stabilization of entanglement computation in auxiliary-field quantum Monte Carlo simulations of interacting many-fermion systems. AB - In the absence of a fermion sign problem, auxiliary-field (or determinantal) quantum Monte Carlo (DQMC) approaches have long been the numerical method of choice for unbiased, large-scale simulations of interacting many-fermion systems. More recently, the conceptual scope of this approach has been expanded by introducing ingenious schemes to compute entanglement entropies within its framework. On a practical level, these approaches, however, suffer from a variety of numerical instabilities that have largely impeded their applicability. Here we report on a number of algorithmic advances to overcome many of these numerical instabilities and significantly improve the calculation of entanglement measures in the zero-temperature projective DQMC approach, ultimately allowing us to reach similar system sizes as for the computation of conventional observables. We demonstrate the applicability of this improved DQMC approach by providing an entanglement perspective on the quantum phase transition from a magnetically ordered Mott insulator to a band insulator in the bilayer square lattice Hubbard model at half filling. PMID- 28085386 TI - Coupled-mode-theory framework for nonlinear resonators comprising graphene. AB - A general framework combining perturbation theory and coupled-mode theory is developed for analyzing nonlinear resonant structures comprising dispersive bulk and sheet materials. To allow for conductive sheet materials, a nonlinear current term is introduced in the formulation in addition to the more common nonlinear polarization. The framework is applied to model bistability in a graphene-based traveling-wave resonator system exhibiting third-order nonlinearity. We show that the complex conductivity of graphene disturbs the equality of electric and magnetic energies on resonance (a condition typically taken for granted), due to the reactive power associated with the imaginary part of graphene's surface conductivity. Furthermore, we demonstrate that the dispersive nature of conductive materials must always be taken into account, since it significantly impacts the nonlinear response. This is explained in terms of the energy stored in the surface current, which is zeroed-out when linear dispersion is neglected. The results obtained with the proposed framework are compared with full-wave nonlinear finite-element simulations with excellent agreement. Very low characteristic power for bistability is obtained, indicating the potential of graphene for nonlinear applications. PMID- 28085387 TI - Diffusion of active chiral particles. AB - The diffusion of chiral active Brownian particles in three-dimensional space is studied analytically, by consideration of the corresponding Fokker-Planck equation for the probability density of finding a particle at position x and moving along the direction v[over ] at time t, and numerically, by the use of Langevin dynamics simulations. The analysis is focused on the marginal probability density of finding a particle at a given location and at a given time (independently of its direction of motion), which is found from an infinite hierarchy of differential-recurrence relations for the coefficients that appear in the multipole expansion of the probability distribution, which contains the whole kinematic information. This approach allows the explicit calculation of the time dependence of the mean-squared displacement and the time dependence of the kurtosis of the marginal probability distribution, quantities from which the effective diffusion coefficient and the "shape" of the positions distribution are examined. Oscillations between two characteristic values were found in the time evolution of the kurtosis, namely, between the value that corresponds to a Gaussian and the one that corresponds to a distribution of spherical shell shape. In the case of an ensemble of particles, each one rotating around a uniformly distributed random axis, evidence is found of the so-called effect "anomalous, yet Brownian, diffusion," for which particles follow a non-Gaussian distribution for the positions yet the mean-squared displacement is a linear function of time. PMID- 28085388 TI - Phase separation transition in a nonconserved two-species model. AB - A one-dimensional stochastic exclusion process with two species of particles, + and -, is studied where density of each species can fluctuate but the total particle density is conserved. From the exact stationary state weights we show that, in the limiting case where density of negative particles vanishes, the system undergoes a phase separation transition where a macroscopic domain of vacancies form in front of a single surviving negative particle. We also show that the phase-separated state is associated with a diverging correlation length for any density and that the critical exponents characterizing the behavior in this region are different from those at the transition line. The static and the dynamical critical exponents are obtained from the exact solution and numerical simulations, respectively. PMID- 28085389 TI - Can phoretic particles swim in two dimensions? AB - Artificial phoretic particles swim using self-generated gradients in chemical species (self-diffusiophoresis) or charges and currents (self-electrophoresis). These particles can be used to study the physics of collective motion in active matter and might have promising applications in bioengineering. In the case of self-diffusiophoresis, the classical physical model relies on a steady solution of the diffusion equation, from which chemical gradients, phoretic flows, and ultimately the swimming velocity may be derived. Motivated by disk-shaped particles in thin films and under confinement, we examine the extension to two dimensions. Because the two-dimensional diffusion equation lacks a steady state with the correct boundary conditions, Laplace transforms must be used to study the long-time behavior of the problem and determine the swimming velocity. For fixed chemical fluxes on the particle surface, we find that the swimming velocity ultimately always decays logarithmically in time. In the case of finite Peclet numbers, we solve the full advection-diffusion equation numerically and show that this decay can be avoided by the particle moving to regions of unconsumed reactant. Finite advection thus regularizes the two-dimensional phoretic problem. PMID- 28085390 TI - Ring correlations in random networks. AB - We examine the correlations between rings in random network glasses in two dimensions as a function of their separation. Initially, we use the topological separation (measured by the number of intervening rings), but this leads to pseudo-long-range correlations due to a lack of topological charge neutrality in the shells surrounding a central ring. This effect is associated with the noncircular nature of the shells. It is, therefore, necessary to use the geometrical distance between ring centers. Hence we find a generalization of the Aboav-Weaire law out to larger distances, with the correlations between rings decaying away when two rings are more than about three rings apart. PMID- 28085391 TI - Emergence and analysis of Kuramoto-Sakaguchi-like models as an effective description for the dynamics of coupled Wien-bridge oscillators. AB - We derive the Kuramoto-Sakaguchi model from the basic circuit equations governing two coupled Wien-bridge oscillators. A Wien-bridge oscillator is a particular realization of a tunable autonomous oscillator that makes use of frequency filtering (via an RC bandpass filter) and positive feedback (via an operational amplifier). In the past few years, such oscillators have started to be utilized in synchronization studies. We first show that the Wien-bridge circuit equations can be cast in the form of a coupled pair of van der Pol equations. Subsequently, by applying the method of multiple time scales, we derive the differential equations that govern the slow evolution of the oscillator phases and amplitudes. These equations are directly reminiscent of the Kuramoto-Sakaguchi-type models for the study of synchronization. We analyze the resulting system in terms of the existence and stability of various coupled oscillator solutions and explain on that basis how their synchronization emerges. The phase-amplitude equations are also compared numerically to the original circuit equations and good agreement is found. Finally, we report on experimental measurements of two coupled Wien-bridge oscillators and relate the results to the theoretical predictions. PMID- 28085392 TI - Erratum: Collective dynamics of soft active particles [Phys. Rev. E 91, 032706 (2015)]. AB - This corrects the article DOI: 10.1103/PhysRevE.91.032706. PMID- 28085393 TI - Correlation between temperature variations of static and dynamic properties in glass-forming liquids. AB - Detailed analysis of the static structure factor S(Q) in several glass-forming liquids reveals that the temperature variations of the width of the main diffraction peak DeltaQ(T) correlate with the fragility of these liquids. This observation suggests a direct connection between rather subtle structural changes and sharp slowing down of structural relaxation in glass-forming liquids. We show that this observation can be rationalized using the Adam-Gibbs approach, through a connection between temperature variations of structural correlation length, l_{c}~2pi/DeltaQ, and the size of cooperatively rearranging regions. PMID- 28085394 TI - Tuning the phase diagram of colloid-polymer mixtures via Yukawa interactions. AB - Theory that predicts the phase behavior of interacting Yukawa spheres in a solution containing nonadsorbing polymer is presented. Our approach accounts for multiple overlap of depletion zones. It is found that additional Yukawa interactions beyond hard core interactions strongly affect the location and presence of coexistence regions and phase states. The theoretical phase diagrams are compared with Monte Carlo simulations. The agreement between the two approaches supports the validity of the theoretical approximations made and confirms that, by choosing the parameters of the interaction potentials, tuning of the binodals is possible. The critical end point characterizes the phase diagram topology. It is demonstrated how an additional Yukawa interaction shifts this point with respect to the hard sphere case. Provided a certain depletant-to colloid size ratio for which a stable colloidal gas-liquid phase coexistence takes place for hard spheres, added direct interactions turn this into a metastable gas-liquid equilibrium. The opposite case, the induction of a stable gas-liquid coexistence where only fluid-solid was present for hard spheres, is also reported. PMID- 28085395 TI - Erratum: Numerical computations of the dynamics of fluidic membranes and vesicles [Phys. Rev. E 92, 052704 (2015)]. AB - This corrects the article DOI: 10.1103/PhysRevE.92.052704. PMID- 28085396 TI - Interplay of degree correlations and cluster synchronization. AB - We study the evolution of coupled chaotic dynamics on networks and investigate the role of degree-degree correlation in the networks' cluster synchronizability. We find that an increase in the disassortativity can lead to an increase or a decrease in the cluster synchronizability depending on the degree distribution and average connectivity of the network. Networks with heterogeneous degree distribution exhibit significant changes in cluster synchronizability as well as in the phenomena behind cluster synchronization as compared to those of homogeneous networks. Interestingly, cluster synchronizability of a network may be very different from global synchronizability due to the presence of the driven phenomenon behind the cluster formation. Furthermore, we show how degeneracy at the zero eigenvalues provides an understanding of the occurrence of the driven phenomenon behind the synchronization in disassortative networks. The results demonstrate the importance of degree-degree correlations in determining cluster synchronization behavior of complex networks and hence have potential applications in understanding and predicting dynamical behavior of complex systems ranging from brain to social systems. PMID- 28085397 TI - Viscoelastic nematodynamics. AB - Nematic liquid crystals exhibit both crystallike and fluidlike features. In particular, the propagation of an acoustic wave shows an interesting occurrence of some of the solidlike features at the hydrodynamic level, namely, the frequency-dependent anisotropy of sound velocity and acoustic attenuation. The non-Newtonian behavior of nematics also emerges from the frequency-dependent viscosity coefficients. To account for these phenomena, we put forward a viscoelastic model of nematic liquid crystals, and we extend our previous theory to fully include the combined effects of compressibility, anisotropic elasticity, and dynamic relaxation, at any shear rate. The low-frequency limit agrees with the compressible Ericksen-Leslie theory, while at intermediate frequencies the model correctly captures the relaxation mechanisms underlying finite shear and bulk elastic moduli. We show that there are only four relaxation times allowed by the uniaxial symmetry. PMID- 28085398 TI - Critical dynamics on a large human Open Connectome network. AB - Extended numerical simulations of threshold models have been performed on a human brain network with N=836733 connected nodes available from the Open Connectome Project. While in the case of simple threshold models a sharp discontinuous phase transition without any critical dynamics arises, variable threshold models exhibit extended power-law scaling regions. This is attributed to fact that Griffiths effects, stemming from the topological or interaction heterogeneity of the network, can become relevant if the input sensitivity of nodes is equalized. I have studied the effects of link directness, as well as the consequence of inhibitory connections. Nonuniversal power-law avalanche size and time distributions have been found with exponents agreeing with the values obtained in electrode experiments of the human brain. The dynamical critical region occurs in an extended control parameter space without the assumption of self-organized criticality. PMID- 28085399 TI - Stationary waves on nonlinear quantum graphs. II. Application of canonical perturbation theory in basic graph structures. AB - We consider exact and asymptotic solutions of the stationary cubic nonlinear Schrodinger equation on metric graphs. We focus on some basic example graphs. The asymptotic solutions are obtained using the canonical perturbation formalism developed in our earlier paper [S. Gnutzmann and D. Waltner, Phys. Rev. E 93, 032204 (2016)2470-004510.1103/PhysRevE.93.032204]. For closed example graphs (interval, ring, star graph, tadpole graph), we calculate spectral curves and show how the description of spectra reduces to known characteristic functions of linear quantum graphs in the low-intensity limit. Analogously for open examples, we show how nonlinear scattering of stationary waves arises and how it reduces to known linear scattering amplitudes at low intensities. In the short-wavelength asymptotics we discuss how genuine nonlinear effects may be described using the leading order of canonical perturbation theory: bifurcation of spectral curves (and the corresponding solutions) in closed graphs and multistability in open graphs. PMID- 28085400 TI - Solitonlike attractor for blood vessel tip density in angiogenesis. AB - Recently, numerical simulations of a stochastic model have shown that the density of vessel tips in tumor-induced angiogenesis adopts a solitonlike profile [Sci. Rep. 6, 31296 (2016)2045-232210.1038/srep31296]. In this work, we derive and solve the equations for the soliton collective coordinates that indicate how the soliton adapts its shape and velocity to varying chemotaxis and diffusion. The vessel tip density can be reconstructed from the soliton formulas. While the stochastic model exhibits large fluctuations, we show that the location of the maximum vessel tip density for different replicas follows closely the soliton peak position calculated either by ensemble averages or by solving an alternative deterministic description of the density. The simple soliton collective coordinate equations may also be used to ascertain the response of the vessel network to changes in the parameters and thus to control it. PMID- 28085401 TI - How to connect time-lapse recorded trajectories of motile microorganisms with dynamical models in continuous time. AB - We provide a tool for data-driven modeling of motility, data being time-lapse recorded trajectories. Several mathematical properties of a model to be found can be gleaned from appropriate model-independent experimental statistics, if one understands how such statistics are distorted by the finite sampling frequency of time-lapse recording, by experimental errors on recorded positions, and by conditional averaging. We give exact analytical expressions for these effects in the simplest possible model for persistent random motion, the Ornstein-Uhlenbeck process. Then we describe those aspects of these effects that are valid for any reasonable model for persistent random motion. Our findings are illustrated with experimental data and Monte Carlo simulations. PMID- 28085402 TI - Critical behavior of k-core percolation: Numerical studies. AB - k-core percolation has served as a paradigmatic model of discontinuous percolation for a long time. Recently it was revealed that the order parameter of k-core percolation of random networks additionally exhibits critical behavior. Thus k-core percolation exhibits a hybrid phase transition. Unlike the critical behaviors of ordinary percolation that are well understood, those of hybrid percolation transitions have not been thoroughly understood yet. Here, we investigate the critical behavior of k-core percolation of Erdos-Renyi networks. We find numerically that the fluctuations of the order parameter and the mean avalanche size diverge in different ways. Thus, we classify the critical exponents into two types: those associated with the order parameter and those with finite avalanches. The conventional scaling relations hold within each set, however, these two critical exponents are coupled. Finally we discuss some universal features of the critical behaviors of k-core percolation and the cascade failure model on multiplex networks. PMID- 28085403 TI - Comment on "Finite-size scaling of survival probability in branching processes". AB - R. Garcia-Millan et al. [Phys. Rev. E 91, 042122 (2015)PLEEE81539 375510.1103/PhysRevE.91.042122] reported a universal finite-size scaling form of the survival probability in discrete time branching processes. In this comment, we generalize the argument to a wide range of continuous time branching processes. Owing to the continuity, the resulting differential (rather than difference) equations can be solved in closed form, rendering some approximations by R. Garcia-Millan et al. superfluous, although we work along similar lines. In the case of binary branching, our results are in fact exact. Demonstrating that discrete time and continuous time models have their leading order asymptotics in common, raises the question to what extent corrections are identical. PMID- 28085404 TI - Parsimonious modeling with information filtering networks. AB - We introduce a methodology to construct parsimonious probabilistic models. This method makes use of information filtering networks to produce a robust estimate of the global sparse inverse covariance from a simple sum of local inverse covariances computed on small subparts of the network. Being based on local and low-dimensional inversions, this method is computationally very efficient and statistically robust, even for the estimation of inverse covariance of high dimensional, noisy, and short time series. Applied to financial data our method results are computationally more efficient than state-of-the-art methodologies such as Glasso producing, in a fraction of the computation time, models that can have equivalent or better performances but with a sparser inference structure. We also discuss performances with sparse factor models where we notice that relative performances decrease with the number of factors. The local nature of this approach allows us to perform computations in parallel and provides a tool for dynamical adaptation by partial updating when the properties of some variables change without the need of recomputing the whole model. This makes this approach particularly suitable to handle big data sets with large numbers of variables. Examples of practical application for forecasting, stress testing, and risk allocation in financial systems are also provided. PMID- 28085405 TI - Energy spectrum of a Langevin oscillator. AB - We derive analytical solutions for the autocorrelation and cross-correlation functions of the kinetic, potential, and total energy of a Langevin oscillator. These functions are presented in both the time and frequency domains and validated by independent numerical simulations. The results are applied to address the long-standing issue of temperature fluctuations in canonical systems. PMID- 28085406 TI - Fronts under arrest: Nonlocal boundary dynamics in biology. AB - We introduce a minimal geometric partial differential equation framework to understand pattern formation from interacting, counterpropagating fronts. Our approach concentrates on the interfaces between different states in a system, and relies on both nonlocal interactions and mean-curvature flow to track their evolution. As an illustration, we use this approach to describe a phenomenon in bacterial colony formation wherein sibling colonies can arrest each other's growth. This arrested motion leads to static separations between healthy, growing colonies. As our minimal model faithfully recovers the geometry of these competing colonies, it captures and elucidates the key leading-order mechanisms responsible for such patterned growth. PMID- 28085407 TI - Empty smectic liquid crystals of hard nanorings: Insights from a second-virial theory. AB - Inspired by recent simulations on highly open liquid crystalline structures formed by rigid planar nanorings, we present a simple theoretical framework explaining the prevalence of smectic over nematic ordering in systems of ring shaped objects. The key part of our study is a calculation of the excluded volume of such nonconvex particles in the limit of vanishing thickness to diameter ratio. Using a simple stability analysis we then show that dilute systems of ring shaped particles have a strong propensity to order into smectic structures with an unusual antinematic order while solid disks of the same dimensions exhibit nematic order. Since our model rings have zero internal volume, these smectic structures are essentially empty, resembling the strongly porous structures found in simulation. We argue that the antinematic intralamellar order of the rings plays an essential role in stabilizing these smectic structures. PMID- 28085408 TI - Spectral energy cascade of body rotations and oscillations under turbulence. AB - The rotation of rigid bodies and oscillation of flexible structures under turbulence are described and characterized in the spectral domain. Laboratory experiments combined with theory are used to unravel and explain the characteristic power-law decay of the spectrum of rotation and oscillation of simple structures. It is shown that the energy-containing eddies and inertial subrange of the incoming velocity spectrum strongly modulate the unsteady motions of structures. The spectra of the rotation and oscillation of the structures exhibit distinctive power-law decays f^{+2} and f^{-5/3-2} in the comparatively low- and high-frequency regions. The range of these regions depends on the phenomenon triggering the motions, i.e., thrust or vortex-induced motions. PMID- 28085409 TI - Experimental study of energy exchanges between two coupled granular gases. AB - We report on the energy exchanges between two granular gases of different densities coupled electromechanically by immersed blades attached to dc motors. Zeroing the energy flux between the two subsystems, we demonstrate that an immersed blade is a convenient way to assess the properties of the granular gases, provided that the dissipation in the motor is properly taken into account. In addition, when the two gases have different densities, the fluctuations of the energy flux are asymmetric, very intermittent, and with most probable zero flux. We show that, for weak coupling, the main features of the energy exchanges can be explained considering the fluctuations of the two subsystems. PMID- 28085410 TI - Instability to a heterogeneous oscillatory state in randomly connected recurrent networks with delayed interactions. AB - Oscillatory dynamics are ubiquitous in biological networks. Possible sources of oscillations are well understood in low-dimensional systems but have not been fully explored in high-dimensional networks. Here we study large networks consisting of randomly coupled rate units. We identify a type of bifurcation in which a continuous part of the eigenvalue spectrum of the linear stability matrix crosses the instability line at nonzero frequency. This bifurcation occurs when the interactions are delayed and partially antisymmetric and leads to a heterogeneous oscillatory state in which oscillations are apparent in the activity of individual units but not on the population-average level. PMID- 28085411 TI - Shape transitions during clathrin-induced endocytosis. AB - Endocytosis is among the most common transport mechanisms which cells employ to receive macromolecules, the so-called cargo, from its extra cellular environment. Clathrin-mediated endocytosis (CME), in particular, involves the cytoplasmic protein clathrin which induces formation and internalization of clathrin-coated membrane buds that contain extra-cellular cargo. Decades of experimental work have established that the morphology of the clathrin coat evolves with time and induces its curvature on the membrane bud; but energetics of the process remain unclear. Recent experiments by Avinoam et al. [Science 348, 1369 (2015)SCIEAS0036 807510.1126/science.aaa9555] reported that the area of the clathrin coat remains fixed while its curvature increases with time and also the clathrin molecules in the coat turn over rapidly. We show that these observations challenge existing models of coated membrane bud formation. We analyze their data to bring out certain features consistent with the underlying lattice structure of the coat. We hypothesize that membrane curvature inhibits clathrin deposition and propose a kinetic model that explains the area distribution of clathrin coats. We also show that their data on shape evolution of the coated membrane bud can be approximately understood from simple geometric considerations. However, the energetics of the coat formation which controls the kinetics of the process remains a puzzle. PMID- 28085412 TI - Phase-flip and oscillation-quenching-state transitions through environmental diffusive coupling. AB - We study the dynamics of nonlinear oscillators coupled through environmental diffusive coupling. The interaction between the dynamical systems is maintained through its agents which, in turn, interact globally with each other in the common dynamical environment. We show that this form of coupling scheme can induce an important transition like phase-flip transition as well transitions among oscillation quenching states in identical limit-cycle oscillators. This behavior is analyzed in the parameter plane by analytical and numerical studies of specific cases of the Stuart-Landau oscillator and van der Pol oscillator. Experimental evidences of the phase-flip transition and quenching states are shown using an electronic version of the van der Pol oscillators. PMID- 28085413 TI - Dynamics of comb-of-comb-network polymers in random layered flows. AB - We analyze the dynamics of comb-of-comb-network polymers in the presence of external random flows. The dynamics of such structures is evaluated through relevant physical quantities, viz., average square displacement (ASD) and the velocity autocorrelation function (VACF). We focus on comparing the dynamics of the comb-of-comb network with the linear polymer. The present work displays an anomalous diffusive behavior of this flexible network in the random layered flows. The effect of the polymer topology on the dynamics is analyzed by varying the number of generations and branch lengths in these networks. In addition, we investigate the influence of external flow on the dynamics by varying flow parameters, like the flow exponent alpha and flow strength W_{alpha}. Our analysis highlights two anomalous power-law regimes, viz., subdiffusive (intermediate-time polymer stretching and flow-induced diffusion) and superdiffusive (long-time flow-induced diffusion). The anomalous long-time dynamics is governed by the temporal exponent nu of ASD, viz., nu=2-alpha/2. Compared to a linear polymer, the comb-of-comb network shows a shorter crossover time (from the subdiffusive to superdiffusive regime) but a reduced magnitude of ASD. Our theory displays an anomalous VACF in the random layered flows that scales as t^{-alpha/2}. We show that the network with greater total mass moves faster. PMID- 28085414 TI - Shear-induced solidification of athermal systems with weak attraction. AB - We find that unjammed packings of frictionless particles with rather weak attraction can always be driven into solidlike states by shear. The structure of shear-driven solids evolves continuously with packing fraction from gel-like to jamminglike, but is almost independent of the shear stress. In contrast, both the density of vibrational states (DOVS) and force network evolve progressively with the shear stress. There exists a packing fraction independent shear stress sigma_{c}, at which the shear-driven solids are isostatic and have a flattened DOVS. Solidlike states induced by a shear stress greater than sigma_{c} possess properties of marginally jammed solids and are thus strictly defined shear jammed states. Below sigma_{c}, shear-driven solids with rather different structures are all under isostaticity and share common features in the DOVS and force network. Our study leads to a jamming phase diagram for weakly attractive particles, which reveals the significance of the shear stress in determining properties of shear driven solids and the connections and distinctions between jamminglike and gel like states. PMID- 28085415 TI - Correlated and cooperative motions in segmental relaxation: Influence of constitutive unit weight and intermolecular interactions. AB - This work clarifies the notion of correlated and cooperative motions appearing during the alpha-relaxation process through the role of the molecular weight of the constitutive units and of the interchain dipolar interactions. By studying amorphous copolymers of poly(ethylene-co-vinyl acetate) with different vinyl acetate contents, we show that the correlated motions are not sensitive to the interchain dipolar interactions, in contrast to the cooperative motions, which increase with a strengthening of the intermolecular interactions for this sample family. Concerning the influence of the molecular weight m_{0}, the notion of "correlated motions" seems to be equivalent to the notion of "cooperative motions" only for low m_{0} systems. PMID- 28085416 TI - Exact probability distribution functions for Parrondo's games. AB - We study the discrete time dynamics of Brownian ratchet models and Parrondo's games. Using the Fourier transform, we calculate the exact probability distribution functions for both the capital dependent and history dependent Parrondo's games. In certain cases we find strong oscillations near the maximum of the probability distribution with two limiting distributions for odd and even number of rounds of the game. Indications of such oscillations first appeared in the analysis of real financial data, but now we have found this phenomenon in model systems and a theoretical understanding of the phenomenon. The method of our work can be applied to Brownian ratchets, molecular motors, and portfolio optimization. PMID- 28085417 TI - From degree-correlated to payoff-correlated activity for an optimal resolution of social dilemmas. AB - An active participation of players in evolutionary games depends on several factors, ranging from personal stakes to the properties of the interaction network. Diverse activity patterns thus have to be taken into account when studying the evolution of cooperation in social dilemmas. Here we study the weak prisoner's dilemma game, where the activity of each player is determined in a probabilistic manner either by its degree or by its payoff. While degree correlated activity introduces cascading failures of cooperation that are particularly severe on scale-free networks with frequently inactive hubs, payoff correlated activity provides a more nuanced activity profile, which ultimately hinders systemic breakdowns of cooperation. To determine optimal conditions for the evolution of cooperation, we introduce an exponential decay to payoff correlated activity that determines how fast the activity of a player returns to its default state. We show that there exists an intermediate decay rate at which the resolution of the social dilemma is optimal. This can be explained by the emerging activity patterns of players, where the inactivity of hubs is compensated effectively by the increased activity of average-degree players, who through their collective influence in the network sustain a higher level of cooperation. The sudden drops in the fraction of cooperators observed with degree correlated activity therefore vanish, and so does the need for the lengthy spatiotemporal reorganization of compact cooperative clusters. The absence of such asymmetric dynamic instabilities thus leads to an optimal resolution of social dilemmas, especially when the conditions for the evolution of cooperation are strongly adverse. PMID- 28085418 TI - Packing of nonoverlapping cubic particles: Computational algorithms and microstructural characteristics. AB - Packing of cubic particles arises in a variety of problems, ranging from biological materials to colloids and the fabrication of new types of porous materials with controlled morphology. The properties of such packings may also be relevant to problems involving suspensions of cubic zeolites, precipitation of salt crystals during CO_{2} sequestration in rock, and intrusion of fresh water in aquifers by saline water. Not much is known, however, about the structure and statistical descriptors of such packings. We present a detailed simulation and microstructural characterization of packings of nonoverlapping monodisperse cubic particles, following up on our preliminary results [H. Malmir et al., Sci. Rep. 6, 35024 (2016)2045-232210.1038/srep35024]. A modification of the random sequential addition (RSA) algorithm has been developed to generate such packings, and a variety of microstructural descriptors, including the radial distribution function, the face-normal correlation function, two-point probability and cluster functions, the lineal-path function, the pore-size distribution function, and surface-surface and surface-void correlation functions, have been computed, along with the specific surface and mean chord length of the packings. The results indicate the existence of both spatial and orientational long-range order as the the packing density increases. The maximum packing fraction achievable with the RSA method is about 0.57, which represents the limit for a structure similar to liquid crystals. PMID- 28085419 TI - Thermal effects in dislocation theory. AB - The mechanical behaviors of polycrystalline solids are determined by the interplay between phenomena governed by two different thermodynamic temperatures: the configurational effective temperature that controls the density of dislocations, and the ordinary kinetic-vibrational temperature that controls activated depinning mechanisms and thus deformation rates. This paper contains a review of the effective-temperature theory and its relation to conventional dislocation theories. It includes a simple illustration of how these two thermal effects can combine to produce a predictive theory of spatial heterogeneities such as shear-banding instabilities. Its main message is a plea that conventional dislocation theories be reformulated in a thermodynamically consistent way so that the vast array of observed behaviors can be understood systematically. PMID- 28085420 TI - Theory of terahertz emission from femtosecond-laser-induced microplasmas. AB - We present a theoretical investigation of terahertz (THz) generation in laser induced gas plasmas. The work is strongly motivated by recent experimental results on microplasmas, but our general findings are not limited to such a configuration. The electrons and ions are created by tunnel ionization of neutral atoms, and the resulting plasma is heated by collisions. Electrons are driven by electromagnetic, convective, and diffusive sources and produce a macroscopic current which is responsible for THz emission. The model naturally includes both ionization current and transition-Cherenkov mechanisms for THz emission, which are usually investigated separately in the literature. The latter mechanism is shown to dominate for single-color multicycle laser pulses, where the observed THz radiation originates from longitudinal electron currents. However, we find that the often discussed oscillations at the plasma frequency do not contribute to the THz emission spectrum. In order to predict the scaling of the conversion efficiency with pulse energy and focusing conditions, we propose a simplified description that is in excellent agreement with rigorous particle-in-cell simulations. PMID- 28085421 TI - Monte Carlo simulation of evaporation-driven self-assembly in suspensions of colloidal rods. AB - The vertical drying of a colloidal film containing rodlike particles was studied by means of kinetic Monte Carlo (MC) simulation. The problem was approached using a two-dimensional square lattice, and the rods were represented as linear k-mers (i.e., particles occupying k adjacent sites). The initial state before drying was produced using a model of random sequential adsorption (RSA) with isotropic orientations of the k-mers (orientation of the k-mers along horizontal x and vertical y directions are equiprobable). In the RSA model, overlapping of the k mers is forbidden. During the evaporation, an upper interface falls with a linear velocity of u in the vertical direction and the k-mers undergo translation Brownian motion. The MC simulations were run at different initial concentrations, p_{i}, (p_{i}?[0,p_{j}], where p_{j} is the jamming concentration), lengths of k mers (k?[1,12]), and solvent evaporation rates, u. For completely dried films, the spatial distributions of k-mers and their electrical conductivities in both x and y directions were examined. Significant evaporation-driven self-assembly and orientation stratification of the k-mers oriented along the x and y directions were observed. The extent of stratification increased with increasing value of k. The anisotropy of the electrical conductivity of the film can be finely regulated by changes in the values of p_{i}, k, and u. PMID- 28085422 TI - Interaction between Lienard and Ikeda dynamics in a nonlinear electro-optical oscillator with delayed bandpass feedback. AB - We report on experimental and theoretical analysis of the complex dynamics generated by a nonlinear time-delayed electro-optic bandpass oscillator. We investigate the interaction between the slow- and fast-scale dynamics of autonomous oscillations in the breather regime. We analyze in detail the coupling between the fast-scale behavior associated to a characteristic low-pass Ikeda behavior and the slow-scale dynamics associated to a Lienard limit-cycle. Finally, we show that when projected onto a two-dimensional phase space, the attractors corresponding to periodic and chaotic breathers display a spiral-like pattern, which strongly depends on the shape of the nonlinear function. PMID- 28085423 TI - Stochastic epidemic dynamics on extremely heterogeneous networks. AB - Networks of contacts capable of spreading infectious diseases are often observed to be highly heterogeneous, with the majority of individuals having fewer contacts than the mean, and a significant minority having relatively very many contacts. We derive a two-dimensional diffusion model for the full temporal behavior of the stochastic susceptible-infectious-recovered (SIR) model on such a network, by making use of a time-scale separation in the deterministic limit of the dynamics. This low-dimensional process is an accurate approximation to the full model in the limit of large populations, even for cases when the time-scale separation is not too pronounced, provided the maximum degree is not of the order of the population size. PMID- 28085425 TI - Time-dependent cavitation in a viscous fluid. AB - Kinetics of nucleation and growth of empty bubbles in a nonvolatile incompressible fluid under negative pressure is considered within the generalized Zeldovich framework. The transient matched asymptotic solution obtained earlier for predominantly viscous nucleation is used to evaluate the distribution of growing cavities over sizes. Inertial effects described by the Rayleigh-Plesset equation are further included. The distributions are used to estimate the volume occupied by cavities, which leads to increase of pressure and eventual self quenching of nucleation. Numerical solutions are obtained and compared with analytics. Due to rapid expansion of cavities the conventional separation of the nucleation and the growth time scales can be less distinct, which increases the role of transient effects. In particular, in the case of dominant viscosity a typical power-law tail of the quasistationary distribution is replaced by a time dependent exponential tail. For fluids of the glycerin type such distributions can extend into the micrometer region, while in low-viscosity liquids (water, mercury) exponential distributions are short lived and are restricted to nanometer scales due to inertial effects. PMID- 28085424 TI - Rotational tumbling of Escherichia coli aggregates under shear. AB - Growing living cultures of Escherichia coli bacteria are investigated using real time in situ rheology and rheoimaging measurements. In the early stages of growth (lag phase) and when subjected to a constant stationary shear, the viscosity slowly increases with the cell's population. As the bacteria reach the exponential phase of growth, the viscosity increases rapidly, with sudden and temporary abrupt decreases and recoveries. At a certain stage, corresponding grossly to the late phase of growth, when the population stabilizes, the viscosity also keeps its maximum constant value, with drops and recoveries, for a long period of time. This complex rheological behavior, which is observed to be shear strain dependent, is a consequence of two coupled effects: the cell density continuous increase and its changing interacting properties. Particular attention is given to the late phase of growth of E. coli populations under shear. Rheoimaging measurements reveal, near the static plate, a rotational motion of E. coli aggregates, collectively tumbling and flowing in the shear direction. This behavior is interpreted in the light of a simple theoretical approach based on simple rigid body mechanics. PMID- 28085426 TI - Dynamics of phase oscillators with generalized frequency-weighted coupling. AB - Heterogeneous coupling patterns among interacting elements are ubiquitous in real systems ranging from physics, chemistry to biology communities, which have attracted much attention during recent years. In this paper, we extend the Kuramoto model by considering a particular heterogeneous coupling scheme in an ensemble of phase oscillators, where each oscillator pair interacts with different coupling strength that is weighted by a general function of the natural frequency. The Kuramoto theory for the transition to synchronization can be explicitly generalized, such as the expression for the critical coupling strength. Also, a self-consistency approach is developed to predict the stationary states in the thermodynamic limit. Moreover, Landau damping effects are further revealed by means of linear stability analysis and resonance poles theory below the critical threshold, which turns to be far more generic. Our theoretical analysis and numerical results are consistent with each other, which can help us understand the synchronization transition in general networks with heterogenous couplings. PMID- 28085427 TI - Effect of fluid inertia on the motion of a collinear swimmer. AB - The swimming of a two-sphere system and of a three-sphere chain in an incompressible viscous fluid is studied on the basis of simplified equations of motion which take account of both Stokes friction and added mass effects. The analysis is based on an explicit expression for the asymptotic periodic swimming velocity and a corresponding evaluation of the mean rate of dissipation. The mean swimming velocity of the two-sphere system is found to be nonvanishing provided that the two spheres are not identical. The swimming of a comparable chain of three identical spheres is much more efficient. PMID- 28085428 TI - Reply to "Comment on 'Critical wind speed at which trees break' ". AB - In the preceding comment [A. Albrecht et al., Phys. Rev. E 94, 067001 (2016)10.1103/PhysRevE.94.067001], Albrecht et al. argue that important biomechanical ingredients are missing in our model about the wind speed at which trees break [Phys. Rev. E 93, 023001 (2016)10.1103/PhysRevE.93.023001]. Here we wish to emphasize that our model is an idealization, which primarily aims at evidencing the dominant ingredients of the problem. Since it captures both observed trends and orders of magnitude, we believe that the essential parameters in tree breakage have been identified, a useful step to make further progress and more detailed descriptions. PMID- 28085429 TI - Oscillation-induced sand dunes in a liquid-filled rotating cylinder. AB - The dynamics of granular medium in a liquid-filled horizontal cylinder with a time-varying rotation rate is experimentally studied. When the cylinder is purely rotated, the granular medium develops an annular layer near the cylindrical wall. The interface between fluid and sand is smooth and axisymmetric. The time variation of the rotation rate initiates the azimuthal oscillation of the liquid in the cylinder's frame of reference and provokes the onset of quasisteady relief in the form of regular dunes. The stability of the axisymmetric sand surface and dynamics of regular dunes are examined. It is found that the ripple formation is provoked by the quasisteady instability of the Stokes boundary layer. In the range of high Reynolds numbers, the ripple formation occurs at a constant critical Shields number theta_{c}?0.05. The spatial period of the relief is not sensitive to the fluid viscosity and granule diameter; it is determined by the amplitude of oscillation and ratio between the oscillation frequency and mean rotation rate. Long-term experiments show that there are forward and backward azimuthal drifts of dunes. An initial analysis of the issues related to the dune migration is provided. PMID- 28085431 TI - Negative pressure in shear thickening band of a dilatant fluid. AB - We perform experiments and numerical simulations to investigate spatial distribution of pressure in a sheared dilatant fluid of the Taylor-Couette flow under a constant external shear stress. In a certain range of shear stress, the flow undergoes the shear thickening oscillation around 20 Hz. We find that, during the oscillation, a localized thickened band rotates around the axis with the flow. Based upon experiments and numerical simulations, we show that a major part of the thickened band is under negative pressure even in the case of discontinuous shear thickening, which indicates that the thickening is caused by Reynolds dilatancy; the dilatancy causes the negative pressure in interstitial fluid, which generates contact structure in the granular medium, then frictional resistance hinders rearrangement of the structure and solidifies the medium. PMID- 28085430 TI - Compensatory interactions to stabilize multiple steady states or mitigate the effects of multiple deregulations in biological networks. AB - Complex diseases can be modeled as damage to intracellular networks that results in abnormal cell behaviors. Network-based dynamic models such as Boolean models have been employed to model a variety of biological systems including those corresponding to disease. Previous work designed compensatory interactions to stabilize an attractor of a Boolean network after single node damage. We generalize this method to a multinode damage scenario and to the simultaneous stabilization of multiple steady state attractors. We classify the emergent situations, with a special focus on combinatorial effects, and characterize each class through simulation. We explore how the structural and functional properties of the network affect its resilience and its possible repair scenarios. We demonstrate the method's applicability to two intracellular network models relevant to cancer. This work has implications in designing prevention strategies for complex disease. PMID- 28085432 TI - Passive swimming in viscous oscillatory flows. AB - Fluid-based locomotion at low Reynolds number is subject to the constraints of Purcell's scallop theorem: reciprocal shape kinematics identical under a time reversal symmetry cannot cause locomotion. In particular, a single degree-of freedom scallop undergoing opening and closing motions cannot swim. Most strategies for symmetry breaking and locomotion rely on direct control of the swimmer's shape kinematics. Less is known about indirect control via actuation of the fluid medium. To address how such indirect actuation strategies can lead to locomotion, we analyze a Lambda-shaped model system analogous to Purcell's scallop but able to deform passively in oscillatory flows. Neutrally buoyant scallops undergo no net locomotion. We show that dense, elastic scallops can exhibit passive locomotion in zero-mean oscillatory flows. We examine the efficiency of swimming parallel to the background flow and analyze the stability of these motions. We observe transitions from stable to unstable swimming, including ordered transitions from fluttering to chaoticlike motions and tumbling. Our results demonstrate that flow oscillations can be used to passively actuate and control the motion of microswimmers, which may be relevant to applications such as surgical robots and cell sorting and manipulation in microfluidic devices. PMID- 28085433 TI - Contact changes of sheared systems: Scaling, correlations, and mechanisms. AB - We probe the onset and effect of contact changes in two-dimensional soft harmonic particle packings which are sheared quasistatically under controlled strain. First, we show that, in the majority of cases, the first contact changes correspond to the creation or breaking of contacts on a single particle, with contact breaking overwhelmingly likely for low pressures and/or small systems, and contact making and breaking equally likely for large pressures and in the thermodynamic limit. The statistics of the corresponding strains are near Poissonian, in particular for large-enough systems. The mean characteristic strains exhibit scaling with the number of particles N and pressure P and reveal the existence of finite-size effects akin to those seen for linear response quantities [C. P. Goodrich et al., Phys. Rev. Lett. 109, 095704 (2012)PRLTAO0031 900710.1103/PhysRevLett.109.095704; C. P. Goodrich et al., Phys. Rev. E 90, 022138 (2014)].PLEEE81539-375510.1103/PhysRevE.90.022138 Second, we show that linear response accurately predicts the strains of the first contact changes, which allows us to accurately study the scaling of the characteristic strains of making and breaking contacts separately. Both of these show finite-size scaling, and we formulate scaling arguments that are consistent with the observed behavior. Third, we probe the effect of the first contact change on the shear modulus G and show in detail how the variation of G remains smooth and bounded in the large-system-size limit: Even though contact changes occur then at vanishingly small strains, their cumulative effect, even at a fixed value of the strain, are limited, so, effectively, linear response remains well defined. Fourth, we explore multiple contact changes under shear and find strong and surprising correlations between alternating making and breaking events. Fifth, we show that by making a link with extremal statistics, our data are consistent with a very slow crossover to self-averaging with system size, so the thermodynamic limit is reached much more slowly than expected based on finite-size scaling of elastic quantities or contact breaking strains. PMID- 28085434 TI - Strength of anisotropy in a granular material: Linear versus nonlinear contact model. AB - In this paper, we deal with anisotropy in an idealized granular material made of a collection of frictional, elastic, contacting particles. We present a theoretical analysis for an aggregate of particles isotropically compressed and then sheared, in which two possible contacts laws between particles are considered: a linear contact law, where the contact stiffness is constant; and a nonlinear contact law, where the contact stiffness depends on the overlapping between particles. In the former case the anisotropy observed in the aggregate is associated with particle arrangement. In fact, although the aggregate is initially characterized by an isotropic network of contacts, during the loading, an anisotropic texture develops, which is measured by a fabric tensor. With a nonlinear contact law it is possible to develop anisotropy because contacting stiffnesses are different, depending on the orientation of the contact vectors with respect to the axis of the applied deformation. We find that before the peak load is reached, an aggregate made of particles with a linear contact law develops a much smaller anisotropy compared with that of an aggregate with a nonlinear law. PMID- 28085435 TI - Harvesting wind energy to detect weak signals using mechanical stochastic resonance. AB - Wind is free and ubiquitous and can be harnessed in multiple ways. We demonstrate mechanical stochastic resonance in a tabletop experiment in which wind energy is harvested to amplify weak periodic signals detected via the movement of an inverted pendulum. Unlike earlier mechanical stochastic resonance experiments, where noise was added via electrically driven vibrations, our broad-spectrum noise source is a single flapping flag. The regime of the experiment is readily accessible, with wind speeds ~20 m/s and signal frequencies ~1 Hz. We readily obtain signal-to-noise ratios on the order of 10 dB. PMID- 28085436 TI - Response to a periodic stimulus in a perfect integrate-and-fire neuron model driven by colored noise. AB - The output interspike interval statistics of a stochastic perfect integrate-and fire neuron model driven by an additive exogenous periodic stimulus is considered. The effect of temporally correlated random activity of synaptic inputs is modeled by an additive symmetric dichotomous noise. Using a first passage-time formulation, exact expressions for the output interspike interval density and for the serial correlation coefficient are derived in the nonsteady regime, and their dependence on input parameters (e.g., the noise correlation time and amplitude as well as the frequency of an input current) is analyzed. It is shown that an interplay of a periodic forcing and colored noise can cause a variety of nonequilibrium cooperation effects, such as sign reversals of the interspike interval correlations versus noise-switching rate as well as versus the frequency of periodic forcing, a power-law-like decay of oscillations of the serial correlation coefficients in the long-lag limit, amplification of the output signal modulation in the instantaneous firing rate of the neural response, etc. The features of spike statistics in the limits of slow and fast noises are also discussed. PMID- 28085437 TI - Lagrangian coherent structures during combustion instability in a premixed-flame backward-step combustor. AB - This paper quantitatively examines the occurrence of large-scale coherent structures in the flow field during combustion instability in comparison with the flow-combustion-acoustic system when it is stable. For this purpose, the features in the recirculation zone of the confined flow past a backward-facing step are studied in terms of Lagrangian coherent structures. The experiments are conducted at a Reynolds number of 18600 and an equivalence ratio of 0.9 of the premixed fuel-air mixture for two combustor lengths, the long duct corresponding to instability and the short one to the stable case. Simultaneous measurements of the velocity field using time-resolved particle image velocimetry and the CH^{*} chemiluminescence of the flame along with pressure time traces are obtained. The extracted ridges of the finite-time Lyapunov exponent (FTLE) fields delineate dynamically distinct regions of the flow field. The presence of large-scale vortical structures and their modulation over different time instants are well captured by the FTLE ridges for the long combustor where high-amplitude acoustic oscillations are self-excited. In contrast, small-scale vortices signifying Kelvin-Helmholtz instability are observed in the short duct case. Saddle-type flow features are found to separate the distinct flow structures for both combustor lengths. The FTLE ridges are found to align with the flame boundaries in the upstream regions, whereas farther downstream, the alignment is weaker due to dilatation of the flow by the flame's heat release. Specifically, the FTLE ridges encompass the flame curl-up for both the combustor lengths, and thus act as the surrogate flame boundaries. The flame is found to propagate upstream from an earlier vortex roll-up to a newer one along the backward-time FTLE ridge connecting the two structures. PMID- 28085438 TI - Numerical simulations of the Princeton magnetorotational instability experiment with conducting axial boundaries. AB - We investigate numerically the Princeton magnetorotational instability (MRI) experiment and the effect of conducting axial boundaries or endcaps. MRI is identified and found to reach a much higher saturation than for insulating endcaps. This is probably due to stronger driving of the base flow by the magnetically rather than viscously coupled boundaries. Although the computations are necessarily limited to lower Reynolds numbers (Re) than their experimental counterparts, it appears that the saturation level becomes independent of Re when Re is sufficiently large, whereas it has been found previously to decrease roughly as Re^{-1/4} with insulating endcaps. The much higher saturation levels will allow for the positive detection of MRI beyond its theoretical and numerical predictions. PMID- 28085439 TI - Stiffer double-stranded DNA in two-dimensional confinement due to bending anisotropy. AB - Using analytical approach and Monte Carlo (MC) simulations, we study the elastic behavior of the intrinsically twisted elastic ribbons with bending anisotropy, such as double-stranded DNA (dsDNA), in two-dimensional (2D) confinement. We show that, due to the bending anisotropy, the persistence length of dsDNA in 2D conformations is always greater than three-dimensional (3D) conformations. This result is in consistence with the measured values for DNA persistence length in 2D and 3D in equal biological conditions. We also show that in two dimensions, an anisotropic, intrinsically twisted polymer exhibits an implicit twist-bend coupling, which leads to the transient curvature increasing with a half helical turn periodicity along the bent polymer. PMID- 28085440 TI - Ensemble-free configurational temperature for spin systems. AB - An estimator for the dynamical temperature in an arbitrary ensemble is derived in the framework of the conjugate variables theorem. We prove directly that its average indeed gives the inverse temperature and that it is independent of the ensemble. We test this estimator numerically by a simulation of the two dimensional XY model in the canonical ensemble. As this model is critical in the whole region of temperatures below the Berezinski-Kosterlitz-Thouless critical temperature T_{BKT}, we use a generalization of Wolff's unicluster algorithm. The numerical results allow us to confirm the robustness of the analytical expression for the microscopic estimator of the temperature. This microscopic estimator has also the advantage that it gives a direct measure of the thermalization process and can be used to compute absolute errors associated with statistical fluctuations. In consequence, this estimator allows for a direct, absolute, and stringent test of the ergodicity of the underlying Markov process, which encodes the algorithm used in a numerical simulation. PMID- 28085441 TI - Publisher's Note: Cascading failures in interdependent networks with finite functional components [Phys. Rev. E 94, 042304 (2016)]. AB - This corrects the article DOI: 10.1103/PhysRevE.94.042304. PMID- 28085442 TI - Discontinuous thinning in active microrheology of soft complex matter. AB - Employing theory and numerical simulations, we demonstrate discontinuous force thinning due to the driven motion of an external probe in a host medium. We consider two cases: an ideal structureless medium (modeling ultrasoft materials such as polymer melts) and a dilute bath of interacting repulsive particles. When the driving of the probe exceeds a critical force, the microviscosity of the medium drops abruptly by about an order of magnitude. This phenomenon occurs for strong attractive interactions between a large probe and a sufficiently dense host medium. PMID- 28085443 TI - Spatial dispersal of bacterial colonies induces a dynamical transition from local to global quorum sensing. AB - Bacteria communicate using external chemical signals called autoinducers (AI) in a process known as quorum sensing (QS). QS efficiency is reduced by both limitations of AI diffusion and potential interference from neighboring strains. There is thus a need for predictive theories of how spatial community structure shapes information processing in complex microbial ecosystems. As a step in this direction, we apply a reaction-diffusion model to study autoinducer signaling dynamics in a single-species community as a function of the spatial distribution of colonies in the system. We predict a dynamical transition between a local quorum sensing (LQS) regime, with the AI signaling dynamics primarily controlled by the local population densities of individual colonies, and a global quorum sensing (GQS) regime, with the dynamics being dependent on collective intercolony diffusive interactions. The crossover between LQS to GQS is intimately connected to a trade-off between the signaling network's latency, or speed of activation, and its throughput, or the total spatial range over which all the components of the system communicate. PMID- 28085444 TI - Percolation in real multiplex networks. AB - We present an exact mathematical framework able to describe site-percolation transitions in real multiplex networks. Specifically, we consider the average percolation diagram valid over an infinite number of random configurations where nodes are present in the system with given probability. The approach relies on the locally treelike ansatz, so that it is expected to accurately reproduce the true percolation diagram of sparse multiplex networks with negligible number of short loops. The performance of our theory is tested in social, biological, and transportation multiplex graphs. When compared against previously introduced methods, we observe improvements in the prediction of the percolation diagrams in all networks analyzed. Results from our method confirm previous claims about the robustness of real multiplex networks, in the sense that the average connectedness of the system does not exhibit any significant abrupt change as its individual components are randomly destroyed. PMID- 28085445 TI - Entropy production and thermalization in the one-atom maser. AB - In the configuration in which two-level atoms with an initial thermal distribution of their states are sent in succession to a cavity sustaining a single mode of electromagnetic radiation, one atom leaving the cavity as the next one enters it (as in the one-atom maser), Jaynes and Cummings showed that the steady state of the field, when many atoms have traversed the cavity, is thermal with a temperature different than that of the atoms in the off-resonant situation. Having an interaction between two subsystems which maintains them at different temperatures was then understood as leading to an apparent violation of energy conservation. Here we show, by calculating the quantum entropy production in the system, that this difference of temperatures is consistent with having the subsystems adiabatically insulated from each other as the steady state is approached. At resonance the insulation is removed and equilibration of the temperatures is achieved. PMID- 28085446 TI - Fluctuation relation for qubit calorimetry. AB - Motivated by proposed thermometry measurement on an open quantum system, we present a simple model of an externally driven qubit interacting with a finite sized fermion environment acting as a calorimeter. The derived dynamics is governed by a stochastic Schrodinger equation coupled to the temperature change of the calorimeter. We prove a fluctuation relation and deduce from it a notion of entropy production. Finally, we discuss the first and second law associated with the dynamics. PMID- 28085447 TI - Dissipative stochastic sandpile model on small-world networks: Properties of nondissipative and dissipative avalanches. AB - A dissipative stochastic sandpile model is constructed and studied on small-world networks in one and two dimensions with different shortcut densities phi, where phi=0 represents regular lattice and phi=1 represents random network. The effect of dimension, network topology, and specific dissipation mode (bulk or boundary) on the the steady-state critical properties of nondissipative and dissipative avalanches along with all avalanches are analyzed. Though the distributions of all avalanches and nondissipative avalanches display stochastic scaling at phi=0 and mean-field scaling at phi=1, the dissipative avalanches display nontrivial critical properties at phi=0 and 1 in both one and two dimensions. In the small world regime (2^{-12}<=phi<=0.1), the size distributions of different types of avalanches are found to exhibit more than one power-law scaling with different scaling exponents around a crossover toppling size s_{c}. Stochastic scaling is found to occur for ss_{c}. As different scaling forms are found to coexist in a single probability distribution, a coexistence scaling theory on small world network is developed and numerically verified. PMID- 28085448 TI - Effects of grain size distribution on the packing fraction and shear strength of frictionless disk packings. AB - Using discrete element methods, the effects of the grain size distribution on the density and the shear strength of frictionless disk packings are analyzed. Specifically, two recent findings on the relationship between the system's grain size distribution and its rheology are revisited, and their validity is tested across a broader range of distributions than what has been used in previous studies. First, the effects of the distribution on the solid fraction are explored. It is found that the distribution that produces the densest packing is not the uniform distribution by volume fractions as suggested in a recent publication. In fact, the maximal packing fraction is obtained when the grading curve follows a power law with an exponent close to 0.5 as suggested by Fuller and Thompson in 1907 and 1919 [Trans Am. Soc. Civ. Eng. 59, 1 (1907) and A Treatise on Concrete, Plain and Reinforced (1919), respectively] while studying mixtures of cement and stone aggregates. Second, the effects of the distribution on the shear strength are analyzed. It is confirmed that these systems exhibit a small shear strength, even if composed of frictionless particles as has been shown recently in several works. It is also found that this shear strength is independent of the grain size distribution. This counterintuitive result has previously been shown for the uniform distribution by volume fractions. In this paper, it is shown that this observation keeps true for different shapes of the grain size distribution. PMID- 28085449 TI - Portfolio optimization problem with nonidentical variances of asset returns using statistical mechanical informatics. AB - The portfolio optimization problem in which the variances of the return rates of assets are not identical is analyzed in this paper using the methodology of statistical mechanical informatics, specifically, replica analysis. We defined two characteristic quantities of an optimal portfolio, namely, minimal investment risk and investment concentration, in order to solve the portfolio optimization problem and analytically determined their asymptotical behaviors using replica analysis. Numerical experiments were also performed, and a comparison between the results of our simulation and those obtained via replica analysis validated our proposed method. PMID- 28085450 TI - Rheology of sediment transported by a laminar flow. AB - Understanding the dynamics of fluid-driven sediment transport remains challenging, as it occurs at the interface between a granular material and a fluid flow. Boyer, Guazzelli, and Pouliquen [Phys. Rev. Lett. 107, 188301 (2011)]PRLTAO0031-900710.1103/PhysRevLett.107.188301 proposed a local rheology unifying dense dry-granular and viscous-suspension flows, but it has been validated only for neutrally buoyant particles in a confined and homogeneous system. Here we generalize the Boyer, Guazzelli, and Pouliquen model to account for the weight of a particle by addition of a pressure P_{0} and test the ability of this model to describe sediment transport in an idealized laboratory river. We subject a bed of settling plastic particles to a laminar-shear flow from above, and use refractive-index-matching to track particles' motion and determine local rheology-from the fluid-granular interface to deep in the granular bed. Data from all experiments collapse onto a single curve of friction MU as a function of the viscous number I_{v} over the range 3*10^{-5}<=I_{v}<=2, validating the local rheology model. For I_{v}<3*10^{-5}, however, data do not collapse. Instead of undergoing a jamming transition with MU->MU_{s} as expected, particles transition to a creeping regime where we observe a continuous decay of the friction coefficient MU<=MU_{s} as I_{v} decreases. The rheology of this creep regime cannot be described by the local model, and more work is needed to determine whether a nonlocal rheology model can be modified to account for our findings. PMID- 28085451 TI - Linear perturbation renormalization group for the two-dimensional Ising model with nearest- and next-nearest-neighbor interactions in a field. AB - The linear perturbation renormalization group (LPRG) is used to study the phase transition of the weakly coupled Ising chains with intrachain (J) and interchain nearest-neighbor (J_{1}) and next-nearest-neighbor (J_{2}) interactions forming the triangular and rectangular lattices in a field. The phase diagrams with the frustration point at J_{2}=-J_{1}/2 for a rectangular lattice and J_{2}=-J_{1} for a triangular lattice have been found. The LPRG calculations support the idea that the phase transition is always continuous except for the frustration point and is accompanied by a divergence of the specific heat. For the antiferromagnetic chains, the external field does not change substantially the shape of the phase diagram. The critical temperature is suppressed to zero according to the power law when approaching the frustration point with an exponent dependent on the value of the field. PMID- 28085452 TI - Interacting Brownian dynamics in a nonequilibrium particle bath. AB - We set up a mesoscopic theory for interacting Brownian particles embedded in a nonequilibrium environment, starting from the microscopic interacting many-body theory. Using nonequilibrium linear-response theory, we characterize the effective dynamical interactions on the mesoscopic scale and the statistics of the nonequilibrium environmental noise, arising upon integrating out the fast degrees of freedom. As hallmarks of nonequilibrium, the breakdown of the fluctuation-dissipation and action-reaction relations for Brownian degrees of freedom is exemplified with two prototypical models for the environment, namely active Brownian particles and stirred colloids. PMID- 28085453 TI - Thermal convection in a cylinder and the problem of planform selection in an internally heated fluid layer. AB - The paper deals with the hexagonal convective flow near the stability threshold in an internally heated fluid layer. In our previous numerical study of convection near the stability threshold in a square box with internal heat generation [Phys. Lett. A 377, 2111 (2013)]PYLAAG0375 960110.1016/j.physleta.2013.06.013 for a region of large horizontal extent, it has been shown that at small values of Prandtl number (Pr), convection sets in as a pattern of hexagonal cells with upward motion in the center (up-hexagons), whereas at large Pr, a stable flow pattern is formed by hexagonal cells with a downward motion in the center (down-hexagons). Here, we study axisymmetric convection in a cylinder as a model of motion in a single hexagonal cell. The radius of the cylinder matches the size of hexagons observed in our three dimensional simulation. The lateral boundary of the cylinder is free and heat insulated. Horizontal bounding surfaces are rigid. The upper boundary is maintained at a constant temperature; the lower one is insulated. Two stable, steady-state motions with the upward and downward flow at the cylinder axis have been attained in calculations, irrespective of Pr. Cylindrical motion with the same direction of circulation as in the stable hexagons has a maximum temperature drop measured along the radius at the bottom of the cell. We suggest maximization of the temperature drop as a selection criterion, which determines the preferred state of motion in an internally heated fluid layer. This new selection principle is validated by the comparative analysis of the dominant nonlinear effects in low and high-Prandtl number convection. PMID- 28085454 TI - Depletion forces on circular and elliptical obstacles induced by active matter. AB - Depletion forces exerted by self-propelled particles on circular and elliptical passive objects are studied using numerical simulations. We show that a bath of active particles can induce repulsive and attractive forces which are sensitive to the shape and orientation of the passive objects (either horizontal or vertical ellipses). The resultant force on the passive objects due to the active particles is studied as a function of the shape and orientation of the passive objects, magnitude of the angular noise, and distance between the passive objects. By increasing the distance between obstacles the magnitude of the repulsive depletion force increases, as long as such a distance is less than one active particle diameter. For longer distances, the magnitude of the force always decreases with increasing distance. We also found that attractive forces may arise for vertical ellipses at high enough area fraction. PMID- 28085455 TI - Impulse-induced generation of stationary and moving discrete breathers in nonlinear oscillator networks. AB - We study discrete breathers in prototypical nonlinear oscillator networks subjected to nonharmonic zero-mean periodic excitations. We show how the generation of stationary and moving discrete breathers are optimally controlled by solely varying the impulse transmitted by the periodic excitations, while keeping constant the excitation's amplitude and period. Our theoretical and numerical results show that the enhancer effect of increasing values of the excitation's impulse, in the sense of facilitating the generation of stationary and moving breathers, is due to a correlative increase of the breather's action and energy. PMID- 28085456 TI - Oscillation structure of localized perturbations in modulationally unstable media. AB - We characterize the properties of the asymptotic stage of modulational instability arising from localized perturbations of a constant background, including the number and location of the individual peaks in the oscillation region. We show that, for long times, the solution tends to an ensemble of classical (i.e., sech-shaped) solitons of the focusing nonlinear Schrodinger equation (as opposed to the various breatherlike solutions of the same equation with a nonzero background). We also confirm the robustness of the theoretical results by comparing the analytical predictions with careful numerical simulations with a variety of initial conditions, which confirm that the evolution of modulationally unstable media in the presence of localized initial perturbations is indeed described by the same asymptotic state. PMID- 28085457 TI - Inverted cones and their elastic creases. AB - We study the elastic inversion of a right circular cone, in particular, the uniform shape of the narrow crease that divides its upright and inverted parts. Our methodology considers a cylindrical shell analogy for simplicity where the crease is the boundary layer deformation. Solution of its governing equation of deformation requires careful crafting of the underlying assumptions and boundary conditions in order to reveal an expression for the crease shape in closed form. We can then define the characteristic width of crease exactly, which is compared to a geometrically nonlinear, large displacement finite element analysis. This width is shown to be accurately predicted for shallow and steep cones, which imparts confidence to our original assumptions. Using the shape of crease, we compute the strain energy stored in the inverted cone, in order to derive an expression for the applied force of inversion by a simple energy method. Again, our predictions match finite element data very well. This study may complement other studies of creases traditionally formed in a less controlled manner, for example, during crumpling of lightweight sheets. PMID- 28085458 TI - Minimum relative entropy distributions with a large mean are Gaussian. AB - Entropy optimization principles are versatile tools with wide-ranging applications from statistical physics to engineering to ecology. Here we consider the following constrained problem: Given a prior probability distribution q, find the posterior distribution p minimizing the relative entropy (also known as the Kullback-Leibler divergence) with respect to q under the constraint that mean(p) is fixed and large. We show that solutions to this problem are approximately Gaussian. We discuss two applications of this result. In the context of dissipative dynamics, the equilibrium distribution of a Brownian particle confined in a strong external field is independent of the shape of the confining potential. We also derive an H-type theorem for evolutionary dynamics: The entropy of the (standardized) distribution of fitness of a population evolving under natural selection is eventually increasing in time. PMID- 28085459 TI - Single-particle dynamics near the glass transition of a metallic glass. AB - The single-particle dynamics of the glass-forming Cu_{50}Zr_{50} alloy, from the supercooled liquid well above the glass-transition temperature, T_{g} to the glassy state, is studied by using the molecular dynamics simulations. When the liquid is cooled below 1.2T_{g}, the dynamics heterogeneity characterized by the cage-jump motion becomes increasingly pronounced. The analyses based on the continuous time random walk method indicate that the liquid falls out of equilibrium in the present simulation time scale when it is cooled into the regime below 1.02T_{g}. However, we find that the jump length and the jump rate do not display the non-equilibrium behaviors even in the glassy state below T_{g}, which allows us to study the intrinsic dynamic characteristics through T_{g}. The mean waiting time between two successive jumps has a rapid growth following the Vogel-Fulcher-Tammann law as the non-equilibrium regime is approached, in analogy with the temperature behaviors of transport properties for fragile supercooled liquids. In contrast, the jump rate maintains the Arrhenius decay and the jump length has even a weaker temperature dependence when the liquid is cooled into glassy state. We find that a pronounced enhancement of the spatial correlation of jumps occurs accompanied by the glass transition: the string-like cooperative jumps dominate the fast motion instead of the uncorrelated and individual jumps. Our work offers an insight into the equilibrium effect of the single-particle dynamics in glass transition. PMID- 28085460 TI - Numerical analysis of long-range spatial correlations in surface growth. AB - To analyze long-range spatial correlations in surface growth, we study numerically a class of generalized Kardar-Parisi-Zhang equation with a fractional Laplacian and driven by long-range spatially correlated noise, and investigate interplay of the fractional Laplacian and correlated noise. We find that the growth system with long-range correlation exhibits nontrivial scaling properties, such as strong dependence on the noise correlation and weak dependence on the fractional order. The growth instability is also discussed in various parameter regimes. PMID- 28085461 TI - Elastic interactions between topological defects in chiral nematic shells. AB - We present a self-consistent and robust theoretical model to investigate elastic interactions between topological defects in liquid crystal shells. Accounting for the nonconcentric nature of the shell in a simple manner, we are able to successfully and accurately explain and predict the positions of the defects, most relevant in the context of colloidal self-assembly. We calibrate and test our model on existing experimental data and extend it to all observed defects configurations in chiral nematic shells. We perform experiments to check further and confirm the validity of the present model. Moreover, we are able to obtain quantitative estimates of the energies of +1 or +3/2 disclination lines in cholesterics, whose intricate nature was only reported recently [A. Darmon, et al. Proc. Natl. Acad. Sci. USA 113, 9469 (2016)10.1073/pnas.1525059113]. PMID- 28085462 TI - Optimal waveform for the entrainment of oscillators perturbed by an amplitude modulated high-frequency force. AB - We analyze limit cycle oscillators under perturbation constructed as a product of two signals, namely, an envelope with a period close to natural period of an oscillator and a high-frequency carrier signal. A theory for obtaining an envelope waveform that achieves the maximal frequency interval of entrained oscillators is presented. The optimization problem for fixed power and maximal allowed amplitude is solved by employing the phase reduction method and the Pontryagin's maximum principle. We have shown that the optimal envelope waveform is a bang-bang-type solution. Also, we have found "inversion" symmetry that relates two signals with different powers but the same interval of entrained frequencies. The theoretical results are confirmed numerically on FitzHugh-Nagumo oscillators. PMID- 28085463 TI - Thermodynamics of a time-dependent and dissipative oval billiard: A heat transfer and billiard approach. AB - We study some statistical properties for the behavior of the average squared velocity-hence the temperature-for an ensemble of classical particles moving in a billiard whose boundary is time dependent. We assume the collisions of the particles with the boundary of the billiard are inelastic, leading the average squared velocity to reach a steady-state dynamics for large enough time. The description of the stationary state is made by using two different approaches: (i) heat transfer motivated by the Fourier law and (ii) billiard dynamics using either numerical simulations and theoretical description. PMID- 28085464 TI - Nonsingular defects and self-assembly of colloidal particles in cholesteric liquid crystals. AB - Cholesteric liquid crystals can potentially provide a means for tunable self organization of colloidal particles. However, the structures of particle-induced defects and the ensuing elasticity-mediated colloidal interactions in these media remain much less explored and understood as compared to their nematic liquid crystal counterparts. Here we demonstrate how colloidal microspheres of varying diameter relative to the helicoidal pitch can induce dipolelike director field configurations in cholesteric liquid crystals, where these particles are accompanied by point defects and a diverse variety of nonsingular line defects forming closed loops. Using laser tweezers and nonlinear optical microscopy, we characterize the ensuing medium-mediated elastic interactions and three dimensional colloidal assemblies. Experimental findings show a good agreement with numerical modeling based on minimization of the Landau-de Gennes free energy and promise both practical applications in the realization of colloidal composite materials and a means of controlling nonsingular topological defects that attract a great deal of fundamental interest. PMID- 28085465 TI - Perturbation-free prediction of resonance-assisted tunneling in mixed regular chaotic systems. AB - For generic Hamiltonian systems we derive predictions for dynamical tunneling from regular to chaotic phase-space regions. In contrast to previous approaches, we account for the resonance-assisted enhancement of regular-to-chaotic tunneling in a nonperturbative way. This provides the foundation for future semiclassical complex-path evaluations of resonance-assisted regular-to-chaotic tunneling. Our approach is based on a new class of integrable approximations which mimic the regular phase-space region and its dominant nonlinear resonance chain in a mixed regular-chaotic system. We illustrate the method for the standard map. PMID- 28085466 TI - Densification and structural transitions in networks that grow by node copying. AB - We introduce a growing network model, the copying model, in which a new node attaches to a randomly selected target node and, in addition, independently to each of the neighbors of the target with copying probability p. When p<1/2, this algorithm generates sparse networks, in which the average node degree is finite. A power-law degree distribution also arises, with a nonuniversal exponent whose value is determined by a transcendental equation in p. In the sparse regime, the network is "normal," e.g., the relative fluctuations in the number of links are asymptotically negligible. For p>=1/2, the emergent networks are dense (the average degree increases with the number of nodes N), and they exhibit intriguing structural behaviors. In particular, the N dependence of the number of m cliques (complete subgraphs of m nodes) undergoes m-1 transitions from normal to progressively more anomalous behavior at an m-dependent critical values of p. Different realizations of the network, which start from the same initial state, exhibit macroscopic fluctuations in the thermodynamic limit: absence of self averaging. When linking to second neighbors of the target node can occur, the number of links asymptotically grows as N^{2} as N->infinity, so that the network is effectively complete as N->infinity. PMID- 28085467 TI - Percolation in finite matching lattices. AB - We derive an exact, simple relation between the average number of clusters and the wrapping probabilities for two-dimensional percolation. The relation holds for periodic lattices of any size. It generalizes a classical result of Sykes and Essam, and it can be used to find exact or very accurate approximations of the critical density. The criterion that follows is related to the criterion used by Scullard and Jacobsen to find precise approximate thresholds, and our work provides a different perspective on their approach. PMID- 28085468 TI - Velocity autocorrelation function in supercooled liquids: Long-time tails and anomalous shear-wave propagation. AB - Molecular dynamic simulations are performed to reveal the long-time behavior of the velocity autocorrelation function (VAF) by utilizing the finite-size effect in a Lennard-Jones binary mixture. Whereas in normal liquids the classical positive t^{-3/2} long-time tail is observed, we find in supercooled liquids a negative tail. It is strongly influenced by the transfer of the transverse current wave across the period boundary. The t^{-5/2} decay of the negative long time tail is confirmed in the spectrum of VAF. Modeling the long-time transverse current within a generalized Maxwell model, we reproduce the negative long-time tail of the VAF, but with a slower algebraic t^{-2} decay. PMID- 28085469 TI - Comparing the locking threshold for rings and chains of oscillators. AB - We present a case study of how topology can affect synchronization. Specifically, we consider arrays of phase oscillators coupled in a ring or a chain topology. Each ring is perfectly matched to a chain with the same initial conditions and the same random natural frequencies. The only difference is their boundary conditions: periodic for a ring and open for a chain. For both topologies, stable phase-locked states exist if and only if the spread or "width" of the natural frequencies is smaller than a critical value called the locking threshold (which depends on the boundary conditions and the particular realization of the frequencies). The central question is whether a ring synchronizes more readily than a chain. We show that it usually does, but not always. Rigorous bounds are derived for the ratio between the locking thresholds of a ring and its matched chain, for a variant of the Kuramoto model that also includes a wider family of models. PMID- 28085470 TI - Death and revival of chaos. AB - We investigate the death and revival of chaos under the impact of a monotonous time-dependent forcing that changes its strength with a non-negligible rate. Starting on a chaotic attractor it is found that the complexity of the dynamics remains very pronounced even when the driving amplitude has decayed to rather small values. When after the death of chaos the strength of the forcing is increased again with the same rate of change, chaos is found to revive but with a different history. This leads to the appearance of a hysteresis in the complexity of the dynamics. To characterize these dynamics, the concept of snapshot attractors is used, and the corresponding ensemble approach proves to be superior to a single trajectory description, that turns out to be nonrepresentative. The death (revival) of chaos is manifested in a drop (jump) of the standard deviation of one of the phase-space coordinates of the ensemble; the details of this chaos nonchaos transition depend on the ratio of the characteristic times of the amplitude change and of the internal dynamics. It is demonstrated that chaos cannot die out as long as underlying transient chaos is present in the parameter space. As a condition for a "quasistatically slow" switch-off, we derive an inequality which cannot be fulfilled in practice over extended parameter ranges where transient chaos is present. These observations need to be taken into account when discussing the implications of "climate change scenarios" in any nonlinear dynamical system. PMID- 28085471 TI - Effects of confinement between attractive and repulsive walls on the thermodynamics of an anomalous fluid. AB - We study via molecular-dynamics simulations the thermodynamics of an anomalous fluid confined in a slit pore with one wall structured and attractive and another unstructured and repulsive. We find that the phase diagram of the homogeneous part of the confined fluid is shifted to higher temperatures, densities, and pressures with respect to the bulk, but it can be rescaled on the bulk case. We calculate a moderate increase of mobility of the homogeneous confined fluid that we interpret as a consequence of the layering due to confinement and the collective modes due to long-range correlations. We show that, as in bulk, the confined fluid has structural, diffusion, and density anomalies that order in the waterlike hierarchy, and a liquid-liquid critical point (LLCP). The overall anomalous region moves to higher temperatures, densities, and pressure, and the LLCP displaces to higher temperature compared to bulk. Motivated by experiments, we calculate also the phase diagram not just for the homogeneous part of the confined fluid but for the entire fluid in the pore, and we show that it is shifted toward higher pressures but preserves the thermodynamics, including the LLCP. Because our model has waterlike properties, we argue that in experiments with supercooled water confined in slit pores with a width of >3 nm if hydrophilic and of >1.5 nm if hydrophobic, the existence of the LLCP could be easier to test than in bulk, where it is not directly accessible. PMID- 28085472 TI - Dynamic properties of the energy loss of multi-MeV charged particles traveling in two-component warm dense plasmas. AB - The energy loss of multi-MeV charged particles moving in two-component warm dense plasmas (WDPs) is studied theoretically beyond the random-phase approximation. The short-range correlations between particles are taken into account via dynamic local field corrections (DLFC) in a Mermin dielectric function for two-component plasmas. The mean ionization states are obtained by employing the detailed configuration accounting model. The Yukawa-type effective potential is used to derive the DLFC. Numerically, the DLFC are obtained via self-consistent iterative operations. We find that the DLFC are significant around the maximum of the stopping power. Furthermore, by using the two-component extended Mermin dielectric function model including the DLFC, the energy loss of a proton with an initial energy of ~15 MeV passing through a WDP of beryllium with an electronic density around the solid value n_{e}~3*10^{23}cm^{-3} and with temperature around ~40 eV is estimated numerically. The numerical result is reasonably consistent with the experimental observations [A. B. Zylsta et al., Phys. Rev. Lett. 111, 215002 (2013)PRLTAO0031-900710.1103/PhysRevLett.111.215002]. Our results show that the partial ionization and the dynamic properties should be of importance for the stopping of charged particles moving in the WDP. PMID- 28085473 TI - Probing heterogeneous dynamics from spatial density correlation in glass-forming liquids. AB - We numerically investigate the connection between spatial density correlation and dynamical heterogeneity in glass-forming liquids. We demonstrate that the cluster size defined by the spatial aggregation of densely packed particles (DPPs) can better capture the difference between the dynamics of the Lennard-Jones glass model and the Weeks-Chandler-Andersen truncation model than the commonly used pair correlation functions. More interestingly, we compare the mobility of DPPs and loosely packed particles, and we find that high local density correlates well with slow dynamics in systems with relatively hard repulsive interactions but links to mobile ones in the system with soft repulsive interactions at one relaxation time scale. Our results show clear evidence that the above model dependence behavior stems from the hopping motion of DPPs at the end of the caging stage due to the compressive nature of soft repulsive spheres, which activates the dynamics of DPPs in the alpha relaxation stage. PMID- 28085474 TI - Kinetics of aggregation with choice. AB - We generalize the ordinary aggregation process to allow for choice. In ordinary aggregation, two random clusters merge and form a larger aggregate. In our implementation of choice, a target cluster and two candidate clusters are randomly selected and the target cluster merges with the larger of the two candidate clusters. We study the long-time asymptotic behavior and find that as in ordinary aggregation, the size density adheres to the standard scaling form. However, aggregation with choice exhibits a number of different features. First, the density of the smallest clusters exhibits anomalous scaling. Second, both the small-size and the large-size tails of the density are overpopulated, at the expense of the density of moderate-size clusters. We also study the complementary case where the smaller candidate cluster participates in the aggregation process and find an abundance of moderate clusters at the expense of small and large clusters. Additionally, we investigate aggregation processes with choice among multiple candidate clusters and a symmetric implementation where the choice is between two pairs of clusters. PMID- 28085475 TI - Application of the dissipative particle dynamics method to the instability problem of a liquid thread. AB - We investigate the application of the dissipative particle dynamics method to the instability problem of a long liquid thread surrounded by another fluid. The dispersion curves obtained from simulations are compared with classic theoretical predictions. The results from standard dissipative particle dynamics (DPD) simulations at first have a tendency of gradually approaching to Tomotika's Stokes flow prediction when the Reynolds number is decreased. But they then abnormally deviate again when the viscosity is very large. The same phenomenon is also confirmed in droplet retraction simulations when also compared with theoretical Stokes flow results. On the other hand, when a hard-core DPD model is used, with the decrease of the Reynolds number the simulation results did finally approach Tomotika's predictions when Re~0.1. A combined presentation of the hard core DPD results and the standard DPD results, excluding the abnormal ones, demonstrates that they are approximately on a continuum when labeled with Reynolds number. These results suggest that the standard DPD method is a suitable method for investigation of the instability problem of immersed liquid thread in the inertioviscous regime (0.1 and in the nematic (N) and twist-bend nematic (N_{tb}) phases of the liquid crystal dimer CB7CB have been measured using x-ray and polarized Raman scattering. The obtained from both techniques are the same, while , determined by Raman scattering is, as expected, systematically larger than its x-ray value. Both order parameters increase in the N phase with decreasing temperature, drop across the N-N_{tb} transition, and continue to decrease. In the N_{tb} phase, the x-ray value of eventually becomes negative, providing a direct and independent confirmation of a conical molecular orientational distribution. The heliconical tilt angle alpha, determined from orientational distribution functions in the N_{tb} phase, increases to ~24^{?} at ~15 K below the transition. In the N_{tb} phase, alpha(T)?(T^{*}-T)^{lambda}, with lambda=0.19+/-0.03. The transition supercools by 1.7 K, consistent with its weakly first-order nature. The value of lambda is close to 0.25 indicating close proximity to a tricritical point. PMID- 28085479 TI - Shift in membrane miscibility transition temperature upon addition of short-chain alcohols. AB - I consider the effect of a small concentration of a molecule, such as a short chain alcohol, on the miscibility transition temperature of a giant plasma membrane vesicle. For concentrations sufficiently small such that the system can be treated as a dilute solution, the change in transition temperature is known to depend upon the extent of the molecule's partition into the coexisting liquid disordered and liquid-ordered phases. Preferential partitioning into the former decreases the miscibility temperature, while preferential partitioning into the latter causes an increase. The analysis, combined with calculated values of the partition coefficient of saturated chains, illuminates the results of recent experiments on the change in miscibility transition temperatures with changing alcohol chain length, and makes several testable predictions. PMID- 28085480 TI - Origin of two maxima in specific heat in enthalpy relaxation under thermal history composed of cooling, annealing, and heating. AB - The origin of two maxima in specific heat observed at the higher and the lower temperatures in the glass-transition region in the heating process has been studied for polymethyl methacrylate and polyvinyl chloride using differential scanning calorimetry, and the calculation was done using the phenomenological model equation under a thermal history of the typical annealing experiment composed of cooling, annealing, and heating. The higher maximum is observed above the glass-transition temperature, and it remains almost unchanged independent of annealing time t_{a}, while the lower one is observed above an annealing temperature T_{a} and shifts toward the higher one, increasing its magnitude with t_{a}. The analysis by the phenomenological model equation proposed in order to interpret the memory effect in the glassy state clarifies that under a typical annealing history, two maxima in specific heat essentially appear. The shift of the lower maximum toward higher temperatures from above T_{a} is caused by an increase in the amount of relaxation during annealing with t_{a}. The annealing temperature and the amount of relaxation during annealing play a major role in the determination of the number of maxima in the specific heat. PMID- 28085481 TI - Chebyshev-polynomial expansion of the localization length of Hermitian and non Hermitian random chains. AB - We study Chebyshev-polynomial expansion of the inverse localization length of Hermitian and non-Hermitian random chains as a function of energy. For Hermitian models, the expansion produces this energy-dependent function numerically in one run of the algorithm. This is in strong contrast to the standard transfer-matrix method, which produces the inverse localization length for a fixed energy in each run. For non-Hermitian models, as in the transfer-matrix method, our algorithm computes the inverse localization length for a fixed (complex) energy. We also find a formula of the Chebyshev-polynomial expansion of the density of states of non-Hermitian models. As explained in detail, our algorithm for non-Hermitian models may be the only available efficient algorithm for finding the density of states of models with interactions. PMID- 28085482 TI - Disorder-induced phase transition in an opinion dynamics model: Results in two and three dimensions. AB - We study a model of continuous opinion dynamics with both positive and negative mutual interactions. The model shows a continuous phase transition between a phase with consensus (order) and a phase having no consensus (disorder). The mean field version of the model was already studied. Using extensive numerical simulations, we study the same model in two and three dimensions. The critical points of the phase transitions for various cases and the associated critical exponents have been estimated. The universality class of the phase transitions in the model is found to be same as Ising model in the respective dimensions. PMID- 28085483 TI - Equilibrium dynamical correlations in the Toda chain and other integrable models. AB - We investigate the form of equilibrium spatiotemporal correlation functions of conserved quantities in the Toda lattice and in other integrable models. From numerical simulations we find that the correlations satisfy ballistic scaling with a remarkable collapse of data from different times. We examine special limiting choices of parameter values, for which the Toda lattice tends to either the harmonic chain or the equal mass hard-particle gas. In both these limiting cases, one can obtain the correlations exactly and we find excellent agreement with the direct Toda simulation results. We also discuss a transformation to "normal mode" variables, as commonly done in hydrodynamic theory of nonintegrable systems, and find that this is useful, to some extent, even for the integrable system. The striking differences between the Toda chain and a truncated version, expected to be nonintegrable, are pointed out. PMID- 28085484 TI - Droplet impact on soft viscoelastic surfaces. AB - In this work, we experimentally investigate the impact of water droplets onto soft viscoelastic surfaces with a wide range of impact velocities. Several impact phenomena, which depend on the dynamic interaction between the droplets and viscoelastic surfaces, have been identified and analyzed. At low We, complete rebound is observed when the impact velocity is between a lower and an upper threshold, beyond which droplets are deposited on the surface after impact. At intermediate We, entrapment of an air bubble inside the impinging droplets is found on soft surfaces, while a bubble entrapment on the surface is observed on rigid surfaces. At high We, partial rebound is only identified on the most rigid surface at We?92. Rebounding droplets behave similarly to elastic drops rebounding on superhydrophobic surfaces and the impact process is independent of surface viscoelasticity. Further, surface viscoelasticity does not influence drop spreading after impact-as the surfaces behave like rigid surfaces-but it does affect drop recoiling. Also, the postimpact drop oscillation on soft viscoelastic surfaces is influenced by dynamic wettability of these surfaces. Comparing sessile drop oscillation with a damped harmonic oscillator allows us to conclude that surface viscoelasticity affects the damping coefficient and liquid surface tension sets the spring constant of the system. PMID- 28085485 TI - Infrequent social interaction can accelerate the spread of a persuasive idea. AB - We study the spread of a persuasive new idea through a population of continuous time random walkers in one dimension. The idea spreads via social gatherings involving groups of nearby walkers who act according to a biased "majority rule": After each gathering, the group takes on the new idea if more than a critical fraction 1-E/2<1/2 of them already hold it; otherwise they all reject it. The boundary of a domain where the new idea has taken hold expands as a traveling wave in the density of new idea holders. Our walkers move by Levy motion, and we compute the wave velocity analytically as a function of the frequency of social gatherings and the exponent of the jump distribution. When this distribution is sufficiently heavy tailed, then, counter to intuition, the idea can propagate faster if social gatherings are held less frequently. When jumps are truncated, a critical gathering frequency can emerge which maximizes propagation velocity. We explore our model by simulation, confirming our analytical results. PMID- 28085486 TI - Host-Microbial Interactions in Idiopathic Pulmonary Fibrosis. AB - RATIONALE: Changes in the respiratory microbiome are associated with disease progression in idiopathic pulmonary fibrosis (IPF). The role of the host response to the respiratory microbiome remains unknown. OBJECTIVES: To explore the host microbial interactions in IPF. METHODS: Sixty patients diagnosed with IPF were prospectively enrolled together with 20 matched control subjects. Subjects underwent bronchoalveolar lavage (BAL), and peripheral whole blood was collected into PAXgene tubes for all subjects at baseline. For subjects with IPF, additional samples were taken at 1, 3, and 6 months and (if alive) 1 year. Gene expression profiles were generated using Affymetrix Human Gene 1.1 ST arrays. MEASUREMENTS AND MAIN RESULTS: By network analysis of gene expression data, we identified two gene modules that strongly associated with a diagnosis of IPF, BAL bacterial burden (determined by 16S quantitative polymerase chain reaction), and specific microbial operational taxonomic units, as well as with lavage and peripheral blood neutrophilia. Genes within these modules that are involved in the host defense response include NLRC4, PGLYRP1, MMP9, and DEFA4. The modules also contain two genes encoding specific antimicrobial peptides (SLPI and CAMP). Many of these particular transcripts were associated with survival and showed longitudinal overexpression in subjects experiencing disease progression, further strengthening the relationship of the transcripts with disease. CONCLUSIONS: Integrated analysis of the host transcriptome and microbial signatures demonstrated an apparent host response to the presence of an altered or more abundant microbiome. These responses remained elevated in longitudinal follow-up, suggesting that the bacterial communities of the lower airways may act as persistent stimuli for repetitive alveolar injury in IPF. PMID- 28085487 TI - Prevalence, Virulence Potential, and Antibiotic Susceptibility Profile of Listeria monocytogenes Isolated From Bovine Raw Milk Samples Obtained From Rajasthan, India. AB - Listeriosis is a serious foodborne disease of a global concern, and can effectively be controlled by a continuous surveillance of the virulent and multidrug-resistant strains of Listeria monocytogenes. This study was planned to investigate prevalence of L. monocytogenes in bovine raw milk samples. A total of 457 raw milk samples collected from 15 major cities in Rajasthan, India, were analyzed for the presence of L. monocytogenes by using standard microbiological and molecular methods. Five of the 457 samples screen tested positive for L. monocytogenes. Multiplex serotyping showed that 3/5 strains belonged to serotype 4b followed by one strain each to 1/2a and to 1/2c. Further virulence potential assessment indicated that all strains possessed inlA and inlC internalins, and, in addition, two strains also possessed the gene for inlB. All strains were positive for Listeriolysin O (LLO) and showed phosphatidylinositol-specific phospholipase C (PI-PLC) activity on an in vitro agar medium with variations in production levels among the strains. A good correlation between the in vitro pathogenicity test and the chick embryo test was observed, as the strains showing higher LLO and PI-PLC activity were found to be lethal to fertilized chick embryos. All strains were resistant to the majority of antibiotics and were designated as multidrug-resistant strains. However, these strains were susceptible to 9 of the 22 tested antibiotics. The maximum zone of inhibition (mm) and acceptable minimum inhibitory concentration were observed with azithromycin, and thus it could be the first choice of a treatment. Overall, the presence of multidrug-resistant L. monocytogenes strains in the raw milk of Rajasthan region is an indicator of public health hazard and highlighting the need of consumer awareness in place and implementation of stricter food safety regulations at all levels of milk production. PMID- 28085490 TI - Internet Gaming Disorder Explains Unique Variance in Psychological Distress and Disability After Controlling for Comorbid Depression, OCD, ADHD, and Anxiety. AB - This study extends knowledge about the relationship of Internet Gaming Disorder (IGD) to other established mental disorders by exploring comorbidities with anxiety, depression, Attention Deficit Hyperactivity Disorder (ADHD), and obsessive compulsive disorder (OCD), and assessing whether IGD accounts for unique variance in distress and disability. An online survey was completed by a convenience sample that engages in Internet gaming (N = 404). Participants meeting criteria for IGD based on the Personal Internet Gaming Disorder Evaluation-9 (PIE-9) reported higher comorbidity with depression, OCD, ADHD, and anxiety compared with those who did not meet the IGD criteria. IGD explained a small proportion of unique variance in distress (1%) and disability (3%). IGD accounted for a larger proportion of unique variance in disability than anxiety and ADHD, and a similar proportion to depression. Replications with clinical samples using longitudinal designs and structured diagnostic interviews are required. PMID- 28085489 TI - microRNA-130a Promotes Human Keratinocyte Viability and Migration and Inhibits Apoptosis Through Direct Regulation of STK40-Mediated NF-kappaB Pathway and Indirect Regulation of SOX9-Meditated JNK/MAPK Pathway: A Potential Role in Psoriasis. AB - Psoriasis is a chronic inflammatory skin disorder. The aim of this study was to determine a potential role of microRNA (miR)-130a in psoriasis, and underlying mechanism. Expression levels of miR-130a in psoriasis specimens and normal skin tissues were analyzed. MiR-130a mimic, inhibitor, miR-control, small interfering RNA (siRNA) specific serine/threonine kinase 40 (STK40), or sex-determining region Y chromosome-box 9 (SOX9) were transfected to human keratinocyte HaCaT cells, respectively. After transfection, the cell viability, apoptosis, and migration were determined. Luciferase reporter assay, quantitative reverse transcription-polymerase chain reaction, and western blot were performed to explore whether STK40 was a target of miR-130a. The effects of aberrant expressions of miR-130a, STK40, or SOX9 on key proteins of NF-kappaB and c-Jun N terminal kinase (JNK)/mitogen-activated protein kinase (MAPK) pathway were assessed. The miR-130a levels were significantly higher in patients with psoriasis compared to the healthy controls (p < 0.01). Overexpressing miR-130a strikingly promoted HaCaT cell viability and migration and inhibited apoptosis (p < 0.01 or p < 0.05). We confirmed that STK40 was a direct target of miR-130a, and STK40 was involved in miR-130a-induced cell functions. Overexpressing miR-130a significantly upregulated NF-kappaB p65, SOX9, p-c-Jun, p-JNK, and p-p38MAPK proteins and silencing miR-130a downregulated them. In addition, silencing STK40 alleviated the effects of anti-miR-130a on SOX9 expression. Furthermore, silencing SOX9 also decreased levels of p-c-Jun, p-JNK, and p-p38MAPK proteins. MiR-130a regulates human keratinocyte HaCaT viability, migration and apoptosis might be by direct regulation of STK40-mediated NF-kappaB pathway and by indirect regulation of SOX9-mediated downstream JNK/MAPK signaling pathway. PMID- 28085488 TI - Lactoferrin and prematurity: a promising milk protein? AB - Lactoferrin (Lf) is the major whey protein in milk, with multiple beneficial health effects including direct antimicrobial activities, anti-inflammatory effects, and iron homeostasis. Oral Lf supplementation in human preterm infants has been shown to reduce the incidence of sepsis and necrotizing enterocolitis. In preclinical models of antenatal stress and perinatal brain injury, bovine Lf protected the developing brain from neuronal loss, improved connectivity, increased neurotrophic factors, and decreased inflammation. It also supported brain development and cognition. Further, Lf can prevent preterm delivery by reducing proinflammatory factors and inhibiting premature cervix maturation. We review here the latest research on Lf in the field of neonatology. PMID- 28085491 TI - Research and development on lactoferrin and its derivatives in China from 2011 2015. AB - Lactoferrin (Lf), a multifunctional glycoprotein, is an important antimicrobial and immune regulatory protein present in neutrophils and most exocrine secretions of mammals. Lactoferricin (Lfcin) is located in the N-terminal region of this protein. In this review, the current state of research into Lf and Lfcin in China is described. Searching with HistCite software in Web Sci located 118 papers published by Chinese researchers from 2011-2015, making China one of the top 3 producers of Lf research and development in the world. The biological functions of Lf and Lfcin are discussed, including antibacterial, antiviral, antifungal, anticarcinogenic, and anti-inflammatory activities; targeted drug delivery, induction of neurocyte, osteoblast, and tenocyte growth, and possible mechanisms of action. The preparation and heterologous expression of Lf in animals, bacteria, and yeast are discussed in detail. Five Lf-related food additive factories and 9 Lf-related health food production companies are certified by the China Food and Drug Administration (CFDA). The latest progress in the generation of transgenic livestock in China, the safety of the use of transgenic animals, and future prospects for the uses of Lf and Lfcin are also covered. PMID- 28085492 TI - Mucosal Type 2 Innate Lymphoid Cells Are a Key Component of the Allergic Response to Aeroallergens. AB - RATIONALE: Newly characterized type 2 innate lymphoid cells (ILC2s) display potent type 2 effector functionality; however, their contribution to allergic airways inflammation and asthma is poorly understood. Mucosal biopsy used to characterize the airway mucosa is invasive, poorly tolerated, and does not allow for sequential sampling. OBJECTIVES: To assess the role of ILC2s during nasal allergen challenge in subjects with allergic rhinitis using novel noninvasive methodology. METHODS: We used a human experimental allergen challenge model, with flow cytometric analysis of nasal curettage samples, to assess the recruitment of ILC2s and granulocytes to the upper airways of subjects with atopy and healthy subjects after allergen provocation. Soluble mediators in the nasal lining fluid were measured using nasosorption. MEASUREMENTS AND MAIN RESULTS: After an allergen challenge, subjects with atopy displayed rapid induction of upper airway symptoms, an enrichment of ILC2s, eosinophils, and neutrophils, along with increased production of IL-5, prostaglandin D2, and eosinophil and T-helper type 2 cell chemokines compared with healthy subjects. The most pronounced ILC2 recruitment was observed in subjects with elevated serum IgE and airway eosinophilia. CONCLUSIONS: The rapid recruitment of ILC2s to the upper airways of allergic patients with rhinitis, and their association with key type 2 mediators, highlights their likely important role in the early allergic response to aeroallergens in the airways. The novel methodology described herein enables the analysis of rare cell populations from noninvasive serial tissue sampling. PMID- 28085493 TI - Metabolism and Skeletal Muscle Homeostasis in Lung Disease. AB - There is increased awareness that patients with lung diseases develop muscle dysfunction. Muscle dysfunction is a major contributor to a decreased quality of life in patients with chronic pulmonary diseases. Furthermore, muscle dysfunction exacerbates lung disease outcome, as a decrease in muscle mass and function are associated with increased morbidity, often long after critical illness or lung disease has been resolved. As we are learning more about the role of metabolism in health and disease, we are appreciating more the direct role of metabolism in skeletal muscle homeostasis. Altered metabolism is associated with numerous skeletal muscle pathologies and, conversely, skeletal muscle diseases are associated with significant changes in metabolic pathways. In this review, we highlight the role of metabolism in the regulation of skeletal muscle homeostasis. Understanding the metabolic pathways that underlie skeletal muscle wasting is of significant clinical interest for critically ill patients as well as patients with chronic lung disease, in which proper skeletal muscle function is essential to disease outcome. PMID- 28085494 TI - Impact of human aging and modern lifestyle on gut microbiota. AB - Human evolution and lifestyle changes caused by the agricultural and industrial revolutions have led to great advances in medicine and increased life expectancy, whilst also profoundly altering the ecological relationships and disease patterns of populations. Studies involving populations that still enjoy a rural way of life and with traits similar to the Paleolithic period reveal them to present a more robust, resistant and diverse gut microbiota, in comparison to highly industrialized civilizations. The human diet has expanded and broadened to include the consumption of high-calorie foods, particularly from animal sources such as game meat and eggs. For some time, authors have been alert to the fact that a modern lifestyle leads to reduced intake of beneficial bacteria, suggesting that nonpathogenic bacteria are being eradicated. Furthermore, therapeutic procedures, including the use of probiotics and prebiotics, have been proposed to lead to recovery of this microbiota, which is altered due to both the ageing process and lifestyle related aspects. Accordingly, this article aims to review the impact of human aging and modern lifestyle on gut microbiota, within an evolutionary, ecological, epidemiological and therapeutic context. PMID- 28085495 TI - Response: upfront nilotinib therapy among patients with chronic myeloid leukemia in chronic phase. PMID- 28085496 TI - Association of Apolipoprotein E Polymorphism with Impact on Overweight University Pupils. AB - BACKGROUND: Obesity is known to be a complex disorder caused by both genetic and environmental factors. Patients with obesity tend to develop cardiovascular disease and type 2 diabetes. Previous studies have revealed that obesity is associated with genetic variations including those found in the apolipoprotein E (APOE) gene, which also affects lipid profiles. Hence, in this study, we aimed to perform a molecular characterization of APOE gene polymorphisms found in overweight subjects within a Saudi population. METHODS: A case-control study was performed consisting of 198 cases and 198 controls, selected from participants at the King Saud University. TaqMan genotyping was performed to characterize the APOE gene polymorphisms. RESULTS: The present study identified the E4 allele of the APOE gene as being significantly associated with obesity in the Saudi population (p = 0.0001). We found a statistically significant difference in the genotype distribution between cases and controls [for E3/E4: OR, 2.16 (95% CI: 1.19-3.91); p = 0.009]. DISCUSSION: Significant differences were observed in the APOE allele profiles (p < 0.001) and lipid profile parameters, including triglycerides and low-density lipoprotein among the obese patients compared with the non-obese control population. CONCLUSION: Our results confirm that APOE variants are associated with obesity in the Saudi population. PMID- 28085497 TI - Harnessing the Power of Next-Generation Sequencing. PMID- 28085498 TI - Mouse Genome-Wide Association Study of Preclinical Group II Pulmonary Hypertension Identifies Epidermal Growth Factor Receptor. AB - Pulmonary hypertension (PH) is associated with features of obesity and metabolic syndrome that translate to the induction of PH by chronic high-fat diet (HFD) in some inbred mouse strains. We conducted a genome-wide association study (GWAS) to identify candidate genes associated with susceptibility to HFD-induced PH. Mice from 36 inbred and wild-derived strains were fed with regular diet or HFD for 20 weeks beginning at 6-12 weeks of age, after which right ventricular (RV) and left ventricular (LV) end-systolic pressure (ESP) and maximum pressure (MaxP) were measured by cardiac catheterization. We tested for association of RV MaxP and RV ESP and identified genomic regions enriched with nominal associations to both of these phenotypes. We excluded genomic regions if they were also associated with LV MaxP, LV ESP, or body weight. Genes within significant regions were scored based on the shortest-path betweenness centrality, a measure of network connectivity, of their human orthologs in a gene interaction network of human PH related genes. WSB/EiJ, NON/ShiLtJ, and AKR/J mice had the largest increases in RV MaxP after high-fat feeding. Network-based scoring of GWAS candidates identified epidermal growth factor receptor (Egfr) as having the highest shortest path betweenness centrality of GWAS candidates. Expression studies of lung homogenate showed that EGFR expression is increased in the AKR/J strain, which developed a significant increase in RV MaxP after high-fat feeding as compared with C57BL/6J, which did not. Our combined GWAS and network-based approach adds evidence for a role for Egfr in murine PH. PMID- 28085499 TI - A sperm-specific proteome-scale metabolic network model identifies non-glycolytic genes for energy deficiency in asthenozoospermia. AB - : About 15% of couples experience difficulty in conceiving a child, of which half of the cases are thought to be male-related. Asthenozoospermia, or low sperm motility, is one of the frequent types of male infertility. Although energy metabolism is suggested to be central to the etiology of asthenozoospermia, very few attempts have been made to identify its underlying metabolic pathways. Here, we reconstructed SpermNet, the first proteome-scale model of the sperm cell by using whole-proteome data and the mCADRE algorithm. The reconstructed model was then analyzed using the COBRA toolbox. Genes were knocked-out in the model to investigate their effect on ATP production. A total of 78 genes elevated ATP production rate considerably of which most encode components of oxidative phosphorylation, fatty acid oxidation, the Krebs cycle, and members of the solute carrier 25 family. Among them, we identified 11 novel genes which have previously not been associated with sperm cell energy metabolism and may thus be implicated in asthenozoospermia. We further examined the reconstructed model by in silico knock out of currently known asthenozoospermia implicated-genes that were not predicted by our model. The pathways affected by knocking out these genes were also related to energy metabolism, confirming previous findings. Therefore, our model not only predicts the known pathways, it also identifies several non glycolytic genes for deficient energy metabolism in asthenozoospermia. Finally, this model supports the notion that metabolic pathways besides glycolysis such as oxidative phosphorylation and fatty acid oxidation are essential for sperm energy metabolism and if validated, may form a basis for fertility recovery. ABBREVIATIONS: mCADRE: metabolic context-specificity assessed by deterministic reaction evaluation; ATP: adenosine triphosphate; RNA: ribonucleic acid; FBA: flux balance analysis; FVA: flux variability analysis; DAVID: database for annotation, visualization and integrated discovery; OXPHOS: oxidative phosphorylation; ETC: electron transfer chain; SLC: solute carrier; DLD: dihydrolypoamide dehydrogenase; DLST: dihydrolypoamide S-succinyl transferase; OGDH: oxoglutarate dehydrogenase; CS: citrate synthase; FH: fumarate hydratase; IDH: isocitrate dehydrogenase; SUCLG1: succinate-CoA ligase; SD: succinate dehydrogenase; HADHA: hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl CoA hydratase, subunit A; HADHB: hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, subunit B; PPA2: pyrophosphatase (inorganic) 2; PPi: inorganic phosphate; GALT: galactose-1-phosphate uridylyltransferase. PMID- 28085501 TI - Aqueous Humor Antimicrobial Activity: In Vitro Analysis after Topical 0.5% Chloramphenicol Application. AB - PURPOSE: To assess aqueous humor antimicrobial activity in vitro after topical 0.5% chloramphenicol application. MATERIALS AND METHODS: This investigation included 63 eyes from 65 cataract surgery patients. The study group of 48 eyes received preoperatively four topical applications of 0.5% chloramphenicol. The control group of 15 eyes was given no topical applications. Aqueous humor samples were collected for in vitro antimicrobial analysis using Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Pasteurella multocida organisms by means of disk diffusion test. RESULTS: No inhibition halo was observed around all aqueous humor samples from all chloramphenicol-treated patients, irrespective of the sample quantity added to the paper disks, with no significant difference from aqueous humor from untreated control patients. CONCLUSIONS: Aqueous humor displayed no bactericidal effect against any of the microorganisms evaluated after topical 0.5% chloramphenicol application. PMID- 28085500 TI - A Pilot Study Linking Endothelial Injury in Lungs and Kidneys in Chronic Obstructive Pulmonary Disease. AB - RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) frequently have albuminuria (indicative of renal endothelial cell injury) associated with hypoxemia. OBJECTIVES: To determine whether (1) cigarette smoke (CS)-induced pulmonary and renal endothelial cell injury explains the association between albuminuria and COPD, (2) CS-induced albuminuria is linked to increases in the oxidative stress-advanced glycation end products (AGEs) receptor for AGEs (RAGE) pathway, and (3) enalapril (which has antioxidant properties) limits the progression of pulmonary and renal injury by reducing activation of the AGEs-RAGE pathway in endothelial cells in both organs. METHODS: In 26 patients with COPD, 24 ever-smokers without COPD, 32 nonsmokers who underwent a renal biopsy or nephrectomy, and in CS-exposed mice, we assessed pathologic and ultrastructural renal lesions, and measured urinary albumin/creatinine ratios, tissue oxidative stress levels, and AGEs and RAGE levels in pulmonary and renal endothelial cells. The efficacy of enalapril on pulmonary and renal lesions was assessed in CS exposed mice. MEASUREMENTS AND MAIN RESULTS: Patients with COPD and/or CS-exposed mice had chronic renal injury, increased urinary albumin/creatinine ratios, and increased tissue oxidative stress and AGEs-RAGE levels in pulmonary and renal endothelial cells. Treating mice with enalapril attenuated CS-induced increases in urinary albumin/creatinine ratios, tissue oxidative stress levels, endothelial cell AGEs and RAGE levels, pulmonary and renal cell apoptosis, and the progression of chronic renal and pulmonary lesions. CONCLUSIONS: Patients with COPD and/or CS-exposed mice have pulmonary and renal endothelial cell injury linked to increased endothelial cell AGEs and RAGE levels. Albuminuria could identify patients with COPD in whom angiotensin-converting enzyme inhibitor therapy improves renal and lung function by reducing endothelial injury. PMID- 28085502 TI - Urea, Uric Acid, Prolactin and fT4 Concentrations in Aqueous Humor of Keratoconus Patients. AB - PURPOSE: Keratoconus is a noninflammatory disease of the cornea associated with progressive thinning and conical shape. Metabolic alterations in the urea cycle, with changes in collagen fibril stability, oxidative stress, thyroid hormones and prolactin with regulatory effect on biosynthesis and biomechanical stability of corneal stroma, may all play a role in keratoconus etiology. Our purpose was to determine urea, uric acid, prolactin and free thyroxin (fT4) concentrations in human aqueous humor (hAH) of keratoconus and cataract patients. METHODS: hAH was collected from 100 keratoconus (penetrating keratoplasty) (41.9 +/- 14.9 years, 69 males) and 100 cataract patients (cataract surgery) (71.2 +/- 12.4 years, 58 males). Urea, uric acid, prolactin and fT4 concentrations were measured by Siemens clinical chemistry or immunoassay system. For statistical analysis, a generalized linear model (GLM) was used. RESULTS: Urea concentration was 11.88 +/ 3.03 mg/dl in keratoconus and 16.44 +/- 6.40 mg/dl in cataract patients, uric acid 2.04 +/- 0.59 mg/dl in keratoconus and 2.18 +/- 0.73 mg/dl in cataract groups. Prolactin concentration was 3.18 +/- 0.34 ng/ml in keratoconus and 3.33 +/- 0.32 ng/ml in cataract patients, fT4 20.57 +/- 4.76 pmol/l in KC and 19.06 +/ 3.86 pmol/l in cataract group. Urea concentration was effected through gender (p = 0.039), age (p = 0.001) and diagnosis (p = 0.025). Uric acid concentration was not effected through any of the analyzed parameters (p > 0.056). Prolactin and fT4 concentration were effected only through diagnosis (p = 0.009 and p = 0.006). CONCLUSIONS: Urea and prolactin concentrations are decreased, fT4 concentration is increased in aqueous humor of keratoconus patients, and uric acid concentration remains unchanged. Urea concentration in aqueous humor is also increased in older and male patients. Therefore, metabolic disorder and hormonal balance may both have an impact on keratoconus development. Further studies are necessary to assess the specific impact. PMID- 28085503 TI - Dupilumab for the treatment of asthma. AB - INTRODUCTION: Dupilumab (REGN668/SAR231893), produced by a collaboration between Regeneron and Sanofi, is a monoclonal antibody currently in phase III for moderate-to-severe asthma. Dupilumab is directed against the alpha-subunit of the interleukin (IL)-4 receptor and blocks the IL-4 and IL-13 signal transduction. Areas covered: Pathophysiological role of IL-4 and IL-13 in asthma; mechanism of action of dupilumab; pharmacology of IL-4 receptor; phase I and phase II studies with dupilumab; regulatory affairs. Expert opinion: Patients with severe asthma who are not sufficiently controlled with standard-of-care represent the target asthma population for dupilumab. If confirmed, efficacy of dupilumab in both eosinophilic and non-eosinophilic severe asthma phenotype might represent an advantage over approved biologics for asthma, including omalizumab, mepolizumab, and reslizumab. Head-to-head studies to compare dupilumab versus other biologics with different mechanism of action are required. Pediatric studies with dupilumab are currently lacking and should be undertaken to assess efficacy and safety of this drug in children with severe asthma. The lack of preclinical data and published results of the completed four phase I studies precludes a complete assessment of the pharmacological profile of dupilumab. Dupilumab seems to be generally well tolerated, but large studies are required to establish its long term safety and tolerability. PMID- 28085504 TI - Differences between the production of [s] and [?] in the speech of adults, typically developing children, and children with speech sound disorders: An ultrasound study. AB - This study describes the criteria that are used in ultrasound to measure the differences between the tongue contours that produce [s] and [?] sounds in the speech of adults, typically developing children (TDC), and children with speech sound disorder (SSD) with the phonological process of palatal fronting. Overlapping images of the tongue contours that resulted from 35 subjects producing the [s] and [?] sounds were analysed to select 11 spokes on the radial grid that were spread over the tongue contour. The difference was calculated between the mean contour of the [s] and [?] sounds for each spoke. A cluster analysis produced groups with some consistency in the pattern of articulation across subjects and differentiated adults and TDC to some extent and children with SSD with a high level of success. Children with SSD were less likely to show differentiation of the tongue contours between the articulation of [s] and [?]. PMID- 28085505 TI - Effect of Porcine Chondrocyte-Derived Extracellular Membrane (CDECM) on Postoperative Wound Healing in an Experimental Rabbit Model of Glaucoma Filtration Surgery. AB - PURPOSE: We investigated whether a chondrocyte-derived extracellular membrane (CDECM) could reduce postoperative scar formation in an experimental rabbit model of glaucoma filtration surgery. METHODS: Thirty-six male New Zealand white rabbits underwent experimental glaucoma filtration surgeries on the right eye and were randomly divided into the following two treatment groups: the CDECM group was treated with subconjunctival injections of 0.1ml CDECM (25 mg/ml; n = 18 eyes), and the operation (OP) group was treated with subconjunctival injections of 0.1 ml balanced salt solution (n = 18 eyes). The left eyes were used as controls (n = 36 eyes). The effects of the CDECM on the experimental rabbit model were investigated using histopathological, immunochemical analyses and Western blotting analyses of the inflammation, fibrosis and angiogenesis. RESULTS: On the 14th postoperative day, the eyes of the CDECM group displayed reduced vascularity and fibrosis compared with the OP group. The vascular endothelial growth factor (VEGF), CD31 and TNFbeta immunostaining were also reduced in the CDECM group. The level of TNFalpha mRNA was increased in the OP group. On the 28th postoperative day, the eyes of the CDECM group also exhibited reduced vascularity and less inflammation and fibrosis than those of the OP group. The expressions of VEGF, CD31, macrophage, TNFbeta and NF-kappaB p65 were also decreased in the CDECM group. The levels of TNFalpha mRNA significantly differ, and the level of matrix metallopeptidase 9 (MMP9) was increased in the OP group. To determine the specific upstream pathway that was associated with NF-kappaB activation due to glaucoma filtration surgery, we measured Akt, PKCs and MAPKs signaling. The phosphorylation of p38 MAPK was increased in the OP group, whereas this expression was decreased by CDECM treatment. CONCLUSIONS: CDECM seems to suppress angiogenesis, inflammation and fibrosis, which were related to wound healing in the experimental rabbit model of glaucoma filtration surgery. This effect, resulting from the inhibition of NF-kappaB expression, may be the blocking of the p38 MAPK signaling pathway. PMID- 28085506 TI - Immunohistochemical Profiles of LOXL-1, FBN1, TGF-beta1, and COX-2 in Pseudoexfoliation Syndrome. AB - PURPOSES: To (i) determine expression patterns of lysyl oxidase-like 1 (LOXL1), fibrillin-1 (FBN1), transforming growth factor beta-1 (TGF-beta1), and cyclooxygenase-2 (COX-2) in lens epithelium and anterior lens capsule in pseudoexfoliation (PEX) syndrome and (ii) delineate the roles of these proteins in the etiopathogenesis of PEX. MATERIALS AND METHODS: Study participants, all of whom had undergone cataract surgery, comprised 47 patients with and 27 patients without (controls) PEX syndrome. Immunohistochemistry on paraffin sections of lens capsule and lens epithelium was performed. RESULTS: Immunoexpression of LOXL1 and FBN1 on the outer surface of the lens capsule was significantly higher (p < 0.001), and nuclear immunopositivity for LOXL1 was more frequently observed (p = 0.017), in PEX patients compared with control patients. Cytoplasmic expression of LOXL1 and COX-2 was significantly lower (p = 0.015 and p = 0.042, respectively) in PEX patients compared with controls. TGF-beta1 exhibited diffuse immunostaining detected in all cell layers in PEX patients (p <0.001). Significant direct correlations of cytoplasmic LOXL1 with FBN1 and TGF-beta1, and of COX-2 with FBN1, TGF-beta1, and LOXL-1, were observed only in PEX patients. CONCLUSIONS: Results of our study provide valuable information vis-a-vis expression and localization of TGF-beta1, LOXL1, and FBN1, as well as their associations in the lens epithelium and lens capsule. These data not only advance our knowledge of the etiopathogenesis of PEX syndrome, but also include novel findings, for example, immunostaining patterns of TGF-beta1 in PEX syndrome. We suggest that COX-2 plays a role in the pathobiology of PEX syndrome and should be the subject of future investigations. PMID- 28085507 TI - Thiol Disulfide Homeostasis in Pseudoexfoliation Syndrome. AB - PURPOSE: To determine the serum thiol disulfide homeostasis in patients with pseudoexfoliation (PEX) syndrome. METHOD: Thirty-five patients with PEX syndrome and forty healthy subjects were included in this observational case-control study. Serum native thiol, total thiol, disulfide, and native thiol/disulfide ratio were determined using a novel and automated assay. RESULTS: The mean serum total thiol and native thiol levels were significantly lower in patients with PEX syndrome compared to healthy controls (p = 0.001). The mean serum disulfide level was significantly higher in patients with PEX syndrome compared to healthy controls (p = 0.023). The serum native thiol/disulfide ratio was lower in patients with PEX syndrome compared to healthy subjects (16 +/- 10.1 vs 22.3 +/- 11.5, respectively, p = 0.014). CONCLUSION: Our findings provide evidence that the dynamic native thiol/disulfide ratio is lower in PEX syndrome, which shows a reduction in the natural cell reductive capacity reservoir. PMID- 28085508 TI - Validation of the Intelligibility in Context Scale for school students in Fiji. AB - Fiji is a multilingual nation with few assessment tools addressing children's communication. This article describes the validation of the Intelligibility in Context Scale for Fiji English, Standard Fijian, and Fiji Hindi. Informants were caregivers of 65 typically developing multilingual children (aged 5;3-10;5) attending a Fiji primary school. The students spoke an average of 2.9 languages (range = 1-5). Their main language was Standard Fijian (41.5%), Fiji Hindi (23.1%), Fiji English (20.0%), or Fijian dialect (15.4%). An ICS mean score of 4.6 was obtained for main language (ICS-ML) and 4.4 for Fiji English (ICS-FE) indicating that students were usually to always intelligible. There were no significant differences between main language, number of languages spoken, gender, age, or socio-economic status. Both scales had good internal consistency, but were not correlated with speech accuracy measures possibly due to ceiling effects. Further validation with younger children is recommended. The ICS may be a useful tool for Fiji with comparative results to other international studies. PMID- 28085509 TI - Voiceless alveolar stop coarticulation in typically developing 5-year-olds and 13 year-olds. AB - In this study, vowel-on-consonant lingual coarticulation at [t] closure offset was compared in 5-year-old children and 13-year-old adolescents. The study aimed to establish whether, by the end of the closure, children from the younger age group adjust the tongue shape to the following vowels to the same extent as adolescents. Ten 5-year-olds and ten 13-year-olds, all speakers of Scottish Standard English, produced [t]-vowel syllables with the vowels [i] and [a], in a carrier phrase. Measures of tongue shape based on midsagittal ultrasound imaging data were used to compare anticipatory coarticulation and within-speaker variability across groups. Both age groups changed the extent of tongue dorsum bunching in order to coarticulate the consonant with the following vowels. The 5 year-old children, unlike the adolescents, did not consistently modify the bunching location within the tongue curve to accommodate the tongue shape to that of the upcoming vowel. Token-to-token variability was significantly greater in the younger age group. The results suggest that vowel-on-[t] coarticulatory patterns produced by typically developing children are affected by the development of motor control, with articulatory constraints on the tongue limiting the extent of lingual coarticulation in 5-year-old children. The findings on typical coarticulation development are relevant for clinical practice, and they highlight the need for more detailed descriptions of how phonetic characteristics of speech sounds affect coarticulation throughout childhood. PMID- 28085511 TI - Epigenetics and Orofacial Clefts: A Brief Introduction. PMID- 28085512 TI - TFII-I and AP2alpha Co-Occupy the Promoters of Key Regulatory Genes Associated with Craniofacial Development. AB - OBJECTIVES: The aim of this study is to define the candidate target genes for TFII-I and AP2alpha regulation in neural crest progenitor cells. DESIGN: The GTF2I and GTF2IRD1 genes encoding the TFII-I family of transcription factors are prime candidates for the Williams-Beuren syndrome, a complex multisystem disorder characterized by craniofacial, skeletal, and neurocognitive deficiencies. AP2alpha, a product of the TFAP2A gene, is a master regulator of neural crest cell lineage. Mutations in TFAP2A cause branchio-oculo-facial syndrome characterized by dysmorphic facial features and orofacial clefts. In this study, we examined the genome-wide promoter occupancy of TFII-I and AP2alpha in neural crest progenitor cells derived from in vitro-differentiated human embryonic stem cells. RESULTS: Our study revealed that TFII-I and AP2alpha co-occupy a selective set of genes that control the specification of neural crest cells. CONCLUSIONS: The data suggest that TFII-I and AP2alpha may coordinately control the expression of genes encoding chromatin-modifying proteins, epigenetic enzymes, transcription factors, and signaling proteins. PMID- 28085510 TI - Age-Dependent Changes in AMPK Metabolic Pathways in the Lung in a Mouse Model of Hemorrhagic Shock. AB - The development of multiple organ failure in patients with hemorrhagic shock is significantly influenced by patient age. Adenosine monophosphate-activated protein kinase (AMPK) is a crucial regulator of energy homeostasis, which coordinates metabolic repair during cellular stress. We investigated whether AMPK regulated signaling pathways are age-dependent in hemorrhage-induced lung injury and whether AMPK activation by 5-amino-4-imidazole carboxamide riboside (AICAR) affords lung protective effects. Male C57/BL6 young mice (3-5 mo), mature adult mice (9-12 mo), and young AMPKalpha1 knockout mice (3-5 mo) were subjected to hemorrhagic shock by blood withdrawing, followed by resuscitation with shed blood and lactated Ringer's solution. Plasma proinflammatory cytokines were similarly elevated in C57/BL6 young and mature adult mice after hemorrhagic shock. However, mature adult mice exhibited more severe lung edema and neutrophil infiltration, and higher mitochondrial damage in alveolar epithelial type II cells, than did young mice. No change in autophagy was observed. At molecular analysis, the phosphorylation of the catalytic subunit AMPKalpha1 was associated with nuclear translocation of peroxisome proliferator-activated receptor gamma co-activator alpha in young, but not mature, adult mice. Treatment with AICAR ameliorated the disruption of lung architecture in mice of both ages; however, effects in mature adult mice were different than young mice and also involved inhibition of nuclear factor-kappaB. In young AMPKalpha1 knockout mice, AICAR failed to improve hypotension and lung neutrophil infiltration. Our data demonstrate that during hemorrhagic shock, AMPK-dependent metabolic repair mechanisms are important for mitigating lung injury. However, these mechanisms are less competent with age. PMID- 28085513 TI - #Cleft: The use of Social Media Amongst Parents of Infants with Clefts. AB - INTRODUCTION: Many societies and organizations are using social media to reach their target audience. The extent to which parents of patients with craniofacial anomalies use social media has yet to be determined. The goal of this study is to characterize and describe the use of social media by the parents of children with cleft lip and palate as it pertains to the care of their child. MATERIALS AND METHODS: Parents or guardian of all patients presenting for initial consultation regarding a child's congenital cleft anomaly were contacted by phone or mail to complete a survey regarding their use of social media vis-a-vis their child's cleft anomaly. Participants were asked to answer a 19-question survey. RESULTS: Thirty-two families were contacted and 25 surveys were completed. Ninety-two percent of respondents used social media to learn about their child's diagnosis. Facebook (76%) and blogs (24%) were the most commonly accessed social media outlets, followed by Instagram (8%). Education about the diagnosis and treatment of cleft pathology (87%) was the most common reason for accessing social media, followed by companionship and support (56%), and advice about perioperative care (52%). Almost half (43%) of parents used social media to obtain information on their caregiver and treatment team, and 26% of parents used information gained on social media to guide their decision on where to seek care. CONCLUSION: Social media is a readily available resource, one that will certainly shape the experiences of our patients and families for years to come. PMID- 28085514 TI - A Sustainable Model for Patient follow-up following an International Cleft Mission: A Proof of Concept. AB - PURPOSE: Patient follow-up after cleft missions is imperative if we are to critically assess the quality of care provided in these settings. The adoption of mobile telephones among disadvantaged families abroad may enable such an undertaking in a cost-effective manner. This project aimed to assess the efficacy of cellular phone-based follow-up in a developing country following a cleft mission to Thailand. METHODS: Changing Children's Lives Inc. performed a cleft surgical mission to Udon Thani, Thailand, in January 2013. Telephone numbers collected at that time were used to survey the patients or their parents 1.5 years postoperatively. RESULTS: Of the 56 patients who underwent cleft lip and/or palate surgery during the mission, more than 50% ( n = 30, 54%) were reachable by telephone; all chose to participate in the study. The cost for families was U.S. $124.92 (56.15); 26 families (87%) believed their money was well spent. Follow-up care was received by 22 (73%) patients, and all but one family ( n = 29, 97%) felt that their child received all of the medical care and support required. All families ( N = 30) would recommend similar cleft care to a friend. Of the patients younger than 18 years of age ( n = 24, 80%), 20 (80%) families found their child more comfortable interacting with peers, more comfortable interacting with adults, and more confident postoperatively. CONCLUSION: In one month, a survey response rate of more than 50% was obtained by leveraging the increased adoption of mobile phones in rural settings. Nearly all patients/families treated during the cleft mission were satisfied with the care that they received. PMID- 28085515 TI - Effect of Presurgical Nasoalveolar Molding on Nasal Symmetry in Unilateral Complete Cleft Lip/Palate Patients after Primary Cheiloplasty without Concomitant Nasal Cartilage Dissection: Early Childhood Evaluation. AB - OBJECTIVE: The objective of this study was to assess the efficacy of presurgical nasoalveolar molding (PNAM) on long-term nasal symmetry and shaping after primary cheiloplasty in patients with unilateral complete cleft lip/palate (UCL/P). DESIGN: This was a two-group, parallel, retrospective, randomized clinical trial. SETTING: The setting for this study was the Chang Gung Craniofacial Center in Taoyuan, Taiwan. PATIENTS: Patients were divided into one of the following two groups: infants with UCL/P who underwent PNAM (PNAM group, n = 42) and infants with UCL/P who did not undergo PNAM (non-PNAM group, n = 42). INTERVENTIONS: Interventions included PNAM and primary cheiloplasty without nasal cartilage dissection. MAIN OUTCOME MEASURES: In this study, 4- to 5-year postoperative full face and submental oblique photographs were taken of all patients and scored from 1 to 5 points by 10 medical evaluators. The scores were statistically analyzed using repeated-measures analysis of variance, and P < .05 was considered to represent statistical significance. RESULTS: After 1 to 3 months of PNAM but before primary cheiloplasty, the displaced nasal and alveolar cartilage showed obvious improvement. However, the scores in the PNAM and non-PNAM groups at 4 to 5 years postoperatively were 66.62 +/- 14.25 and 66.31 +/- 15.08, respectively. There was no significant difference between the two groups ( F = 0.009, P = .923). CONCLUSION: PNAM as an early-stage adjunctive therapy for nasal deformity correction is beneficial before primary cheiloplasty, but it is insufficient to maintain long-term nostril symmetry after primary cheiloplasty without nasal cartilage dissection. PMID- 28085516 TI - Obtaining source current density related to irregularly structured electromagnetic target field inside human body using hybrid inverse/FDTD method. AB - Inverse method is inherently suitable for calculating the distribution of source current density related with an irregularly structured electromagnetic target field. However, the present form of inverse method cannot calculate complex field tissue interactions. A novel hybrid inverse/finite-difference time domain (FDTD) method that can calculate the complex field-tissue interactions for the inverse design of source current density related with an irregularly structured electromagnetic target field is proposed. A Huygens' equivalent surface is established as a bridge to combine the inverse and FDTD method. Distribution of the radiofrequency (RF) magnetic field on the Huygens' equivalent surface is obtained using the FDTD method by considering the complex field-tissue interactions within the human body model. The obtained magnetic field distributed on the Huygens' equivalent surface is regarded as the next target. The current density on the designated source surface is derived using the inverse method. The homogeneity of target magnetic field and specific energy absorption rate are calculated to verify the proposed method. PMID- 28085517 TI - Cyclic AMP-dependent signaling system is a primary metabolic target for non thermal effect of microwaves on heart muscle hydration. AB - Previously, we have suggested that cell hydration is a universal and extra sensitive sensor for the structural changes of cell aqua medium caused by the impact of weak chemical and physical factors. The aim of present work is to elucidate the nature of the metabolic messenger through which physiological solution (PS) treated by non-thermal (NT) microwaves (MW) could modulate heart muscle hydration of rats. For this purpose, the effects of NT MW-treated PS on heart muscle hydration, [3H]-ouabain binding with cell membrane, 45Ca2+ uptake and intracellular cyclic nucleotides contents in vivo and in vitro experiments were studied. It is shown that intraperitoneal injections of both Sham-treated PS and NT MW-treated PS elevate heart muscle hydration. However, the effect of NT MW treated PS on muscle hydration is more pronounced than the effect of Sham-treated PS. In vitro experiments NT MW-treated PS has dehydration effect on muscle, which is not changed by decreasing Na+ gradients on membrane. Intraperitoneal injection of Sham- and NT MW-treated PS containing 45Ca2+ have similar dehydration effect on muscle, while NT MW-treated PS has activation effect on Na+/Ca2+ exchange in reverse mode. The intraperitoneal injection of NT MW-treated PS depresses [3H] ouabain binding with its high-affinity membrane receptors, elevates intracellular cAMP and decreases cGMP contents. Based on the obtained data, it is suggested that cAMP-dependent signaling system serves as a primary metabolic target for NT MW effect on heart muscle hydration. PMID- 28085518 TI - Upfront nilotinib therapy among patients with chronic myeloid leukemia in chronic phase. PMID- 28085519 TI - Association of retinal vein occlusion, homocysteine, and the thrombophilic mutations in a Turkish population: A case-control study. AB - PURPOSE: To compare homocysteine and thrombophilic mutations for the methylenetetrahydrofolate reductase (MTHFR) C677T, factor V Leiden, and prothrombin G20210A between retinal vein occlusion (RVO) and healthy controls in a Turkish population. MATERIALS AND METHODS: Forty-nine subjects with RVO were compared for homocysteine status and the MTHFR C677T, prothrombin G20210A, and factor V Leiden mutations with those of 68 healthy controls. Then, the groups were subdivided into two subgroups according to age (less than 50 years old, equal to or more than 50 years old) and were further compared. RESULTS: Mean plasma level of homocysteine was similar, but the frequency of hyperhomocysteinemia was significantly higher in the RVO group when compared with the control group (22.5% and 8.8%, respectively, p = 0.037). The frequency of all thrombophilic mutations was similar between the groups (p > 0.05). The frequency of all thrombophilic mutations and homocysteine levels was also similar between age subgroups (p > 0.05). Only hyperhomocysteinemia was significantly different between subgroups (p = 0.037); the frequency of hyperhomocysteinemia was significantly different in RVO patients less than 50 years old (22.7%) from that in healthy controls less than 50 years old (11.1%). Two RVO patients (4.1%) with bilateral involvement had MTHFR C677T mutation. CONCLUSIONS: Screening for thrombophilic mutations such as MTHFR C677T, factor V Leiden, and prothrombin G20210A in RVO patients at all ages seems to be unnecessary and not cost effective. However, thrombophilic disorders should be screened selectively, focusing on young individuals, especially with bilateral involvement, without additional cardiovascular risk factors, or a family history of thrombosis. PMID- 28085520 TI - Psychosocial determinants for treatment decisions in familial retinoblastoma. PMID- 28085521 TI - Exenatide: pharmacokinetics, clinical use, and future directions. AB - INTRODUCTION: The first-in-class glucagon-like peptide-1 receptor agonist (GLP 1RA) exenatide, which was initially approved in 2005, is available in twice-daily (BID) and once-weekly (QW) formulations. Clinical trial data suggest both formulations are effective and safe for patients with type 2 diabetes (T2D), both as monotherapy and as part of combination therapy. Since exenatide was approved, several other GLP-1RAs have become available for clinical use. Areas covered: Many ongoing clinical trials involving exenatide BID and exenatide QW are investigating new indications (exenatide BID) and new end points and combination therapies (exenatide QW). This review provides an overview of the delivery and pharmacokinetics of both formulations of exenatide, reviews existing data in T2D, and summarizes ongoing investigations. Expert opinion: Exenatide BID and QW have substantial clinical benefits. Comparisons with other GLP-1RAs demonstrate some differences in efficacy and safety profiles that make assessment of benefit:risk ratios complex. Head-to-head comparisons of QW GLP-1RA formulations may assist in the ranking of GLP-1RAs according to efficacy and safety. Results on the impact of exenatide QW on cardiovascular outcomes are eagerly awaited. The potential clinical utility of exenatide BID in other indications will clarify whether exenatide holds clinical promise in diagnoses other than T2D. PMID- 28085522 TI - Elderly onset vitreous opacities as the initial manifestation in hereditary transthyretin (ATTR Val30Met) carries. AB - Familial amyloid polyneuropathy (FAP) is a systemic disorder transmitted as an autosomal dominant trait and is characterized by deposits of protein fibrils in various organs leading to physiologic dysfunction. In cases with FAP in Japanese endemic foci, their signs and symptoms often develop before the age of 40 years. We report on two elderly patients (an 80-year-old woman and an 83-year-old man) with progressive vitreous opacities (VOs) as the initial manifestation of hereditary transthyretin (ATTR Val30Met) carries, who had no evidence of systemic involvement or family history of amyloidosis and lived in non-endemic areas. Therapeutic vitrectomy with extensive vitreous removal combined with cataract surgery was performed. Clinicians should consider the possibility of hereditary transthyretin carries in cases presenting with VOs of undetermined etiology to avoid misdiagnosis. PMID- 28085523 TI - A novel homozygous variant in the SMOC1 gene underlying Waardenburg anophthalmia syndrome. AB - BACKGROUND: Waardenburg anophthalmia syndrome (WAS), also known as ophthalmo acromelic syndrome or anophthalmia-syndactyly, is a rare congenital disorder that segregates in an autosomal recessive pattern. Clinical features of the syndrome include malformation of the eyes and the skeleton. Mostly, WAS is caused by mutations in the SMOC-1 gene. MATERIALS AND METHODS: The present report describes a large consanguineous family of Pakistani origin segregating Waardenburg anophthalmia syndrome in an autosomal recessive pattern. Genotyping followed by Sanger sequencing was performed to search for a candidate gene. RESULTS: SNP genotyping using AffymetrixGeneChip Human Mapping 250K Nsp array established a single homozygous region among affected members on chromosome 14q23.1-q24.3 harboring the SMOC1 gene. Sequencing of the gene revealed a novel homozygous missense mutation (c.812G>A; p.Cys271Tyr) in the family. CONCLUSION: This is the first report of Waardenburg anophthalmia syndrome caused by a SMOC1 variant in a Pakistani population. The mutation identified in the present investigation extends the body of evidence implicating the gene SMOC-1 in causing WAS. PMID- 28085525 TI - Unilateral breast reconstruction after mastectomy - patient satisfaction, aesthetic outcome and quality of life. AB - BACKGROUND: An increasing number of women undergo a breast reconstruction (BR) after treatment for breast cancer. The aim of the present study was to evaluate patient-reported esthetic satisfaction, quality of life (QoL), and the association between these, following different types of BR. MATERIALS AND METHODS: All women who underwent unilateral BR in Central Denmark Region between January 2005 and July 2011 were included. Participants were sent a questionnaire package, which included the Body Image Scale, The Beck Depression Inventory, the Impact of Event Scale, and a study-specific patient-reported esthetic satisfaction scale. Additionally, patients were asked if they experienced a change in QoL owing to the BR. Based on reconstructive method and timing, participants were divided into four groups, three delayed: an abdominal flap group, a latissimus dorsi flap group, an implant +/- thoracodorsal flap group; and one immediate BR group. RESULTS: Of 166 eligible participants, a total of 144 women (87%) completed the questionnaire. The mean follow-up was 3.8 years. Esthetic satisfaction differed significantly between groups [F(3,139) = 8.55; p < 0.001], with abdominal flap recipients reporting the highest levels of esthetic satisfaction. No between-group differences were observed for the remaining psychosocial measures. Higher satisfaction with esthetic outcome was associated with reporting higher QoL owing to the BR (odds ratio 1.10, p<0.001; 95% CI 1.06 1.15). CONCLUSIONS: Abdominal flap recipients expressed higher satisfaction with their esthetic outcome, compared to the remaining BR types. Higher esthetic satisfaction was strongly associated with reporting an experience of higher QoL. PMID- 28085524 TI - Evaluation of genome-wide susceptibility loci for high myopia in a Han Chinese population. AB - PURPOSE: High myopia (HM) is a common cause of visual impairment worldwide. Previous genome-wide association studies have reported that seven single nucleotide polymorphisms (SNPs), including rs1254319, rs3138144, rs12205363, rs17648524, rs7829127, rs1656404, and rs7084402, are associated with HM in Caucasians. The aim of this study was to investigate the association of these SNPs in Han Chinese. METHODS: SNPs were genotyped by SNaPshot method in a Chinese cohort composed of 830 HM patients and 1140 controls. RESULTS: Rs17648524 (C/G) and rs7084402 (A/G) were significantly associated with HM (p = 3.0 * 10-3, OR = 0.43; p = 3.7 * 10-2, OR = 1.25, respectively). The association of rs17648524 was also observed under the heterozygous model (CG vs. GG, p = 7.0 * 10-3, OR = 0.43) and the dominant model (CC + CG vs. GG, p = 4.0 * 10-3, OR = 0.42). The association of rs7084402 was found under the homozygous model (GG vs. AA, p = 4.0 * 10-2, OR = 1.56) and the dominant model (GG+ AG vs. AA, p = 3.8 * 10-2, OR = 1.41). Another SNP, rs7829127 (A/G), was found to be significantly associated with HM under the heterozygous model (AG vs. AA, p = 4.6 * 10-2, OR = 0.67). Furthermore, the associations of rs17648524 and rs7084402 with HM were gender specific, with significance observed only in females but not in males. As for the other four SNPs, no associations were detected under these genetic models. CONCLUSIONS: Our findings suggested rs17648524 (intronic RBFOX1 gene) and rs7084402 (7.5kb 5' of the BICC1 gene) showed gender-specific associations with high myopia in the Han Chinese. PMID- 28085526 TI - Prothrombin polymorphism A19911G, factor V HR2 haplotype A4070G, and plasminogen activator-inhibitor-1 polymorphism 4G/5G and the risk of retinal vein occlusion. AB - BACKGROUND: Thus far, no data has become available to evaluate systematically the prevalences of prothrombin polymorphism A19911G (PT A19911G), factor V HR2 haplotype A4070G (FV A4070G), or plasminogen activator-inhibitor-1 polymorphism 4G/5G (PAI-1 4G/5G) in patients who develop retinal vein occlusion (RVO) without cardiovascular risk factors. MATERIALS AND METHODS: We retrospectively evaluated comprehensive thrombophilia data from 42 preselected RVO patients without cardiovascular risk factors. The prevalences of different gene mutations and polymorphisms including factor V Leiden mutation G1691A (FVL), FV A4070G, prothrombin mutation G20210A, PT A19911G, and PAI-1 4G/5G were compared with 241 healthy controls matched for age and sex. RESULTS: A total of 20 patients (47.7%) were found to carry thrombophilic gene polymorphisms including FVL, FV A4070G, and homozygous PT A19911G compared with 72 of 241 controls (29.9%; p = 0.03). Subgroup analysis of patients with a significant personal or family history of thromboembolism revealed a high prevalence of FVL, FV A4070G, and homozygous PT A19911G (p = 0.005). FV A4070G was found to be significantly associated with at least two other heterozygous or one homozygous gene polymorphisms (p = 0.02). Multivariate analysis revealed the presence of FVL (p = 0.0017) and homozygous PT A19911G (p = 0.03) polymorphism as independent risk factors for the development of RVO. CONCLUSIONS: Our results indicate that in selected RVO patients screening for thrombophilic gene polymorphisms including FVL, FV A4070G and homozygous PT G19911A may be helpful in a high percentage of cases. Our findings suggest that hereditary thrombophilia associated with RVO is more likely to be multigenic than caused by any single risk factor. PMID- 28085527 TI - A multidisciplinary approach to improving the care and outcomes of patients with retinoblastoma at a pediatric cancer hospital in Egypt. AB - BACKGROUND: Retinoblastoma poses a substantial burden in developing countries. We conducted this study to assess the effect of implementing a multidisciplinary approach and standardized protocols for treating pediatric patients with retinoblastoma at the Children's Cancer Hospital Egypt (CCHE). MATERIALS AND METHODS: In January 2011, the CCHE implemented standardized protocols for the diagnosis, treatment, and reporting of retinoblastoma cases. The hospital also introduced a new retinoblastoma management algorithm and data analysis system. In this study, we compared the pathologic features, tumor invasiveness, reporting, and survival of 276 pediatric patients who underwent enucleations of 290 eyes before or after the implementation of the retinoblastoma protocols. RESULTS: Time to enucleation (indicating time needed for decision taking) decreased significantly within the neoadjuvant chemotherapy group for intraocular disease after January 2011 (68.7 +/- 48 weeks vs. 47.3 +/- 28.3 weeks; p < 0.05). Mean optic nerve stump length increased from 5.6 mm in the earlier period to 7.2 mm in the later period (p = 0.004). The overall quality of pathology reporting also improved during the later period. The probability of 3-year survival was significantly higher for patients during the later period (94.2% vs. 79.2%; p = 0.018). CONCLUSIONS: The implementation of standardized protocols and a multidisciplinary approach improved reporting; discrepancies in disease classification and the amount of missing data were reduced; and quality measures and prognostic capabilities of the team were substantially improved. Such established data-driven practice supports faster decision making to enucleate diseased eyes and save patients' lives through providing measurable indicators. PMID- 28085528 TI - Patient-centered knowledge sharing in healthcare organizations: Identifying the external barriers. AB - OBJECTIVE: This paper reports on a research study, which aims to identify, qualify, and theorize the external barriers that prevent and hinder the exercises and activities of patient-centered knowledge sharing (KS) in healthcare organizations. METHODS: The project adopted a qualitative secondary analysis approach as the overarching methodology to guide the analysis of data collected in a previously completed research study. Specifically, 46 semi-structured interview data were included and analyzed using a thematic analysis approach. RESULTS: The secondary analysis showed that healthcare KS is strongly influenced and hindered by five external barriers: social belief and preference, cultural values, healthcare education structure, political decisions, and economic environment and constraints. Moreover, the research findings suggest that these external barriers cannot be overlooked in KS implementation and operation in healthcare organizations and should be carefully assessed beginning in the early stages of KS design and strategic planning. DISCUSSION AND CONCLUSIONS: Based on the secondary analysis, this paper proposes a conceptual model, which will contribute to the development of hypotheses in the future for building a generalized knowledge. The case study used is Chinese healthcare, but the KS problems studied can be shared across international borders. PMID- 28085529 TI - Neutropenic acute acalculous cholecystitis (AAC) in a 12-year-old boy with T acute lymphoblastic leukemia successfully managed with conservative treatment. AB - : Acute acalculous cholecystitis (AAC) is an inflammation of the gallbladder without the presence of gallstones. In children with malignancies or chemotherapy induced neutropenia, AAC is very rare. Clinical diagnosis of AAC remains difficult in this patient population but an early recognition followed by an appropriate intervention may confer a benefit. Only three pediatric patients with underlying hematological malignancies whose clinical treatment course was complicated by the development of AAC have been described. We describe a neutropenic pediatric patient who developed AAC following chemotherapy for acute T-cell acute lymphoblastic leukemia (T-ALL), which was successfully managed with conservative treatment. ABBREVIATIONS: AAC: Acute acalculous cholecystitis; T ALL: T-cell acute lymphoblastic leukemia; TPN: Total parenteral nutrition. PMID- 28085530 TI - Invasive fungal infections in renal transplant patients: a single center study. AB - BACKGROUND: Timely diagnosis of invasive fungal infections (IFI) in renal transplant (RT) patients on immunosuppression is often difficult, jeopardizing their life and graft. We reported IFI and their causative fungal agents in post RT patients. MATERIALS AND METHODS: This was a retrospective 6-year clinical study carried out from 2010 to 2015 on 1900 RT patients. Clinical data included patient-donor demographics, time to onset of infection, risk factors and graft function in terms of serum creatinine (SCr). To identify IFI, we examined bronchoalveolar lavage (BAL), blood, tissue, and wound swab samples by conventional mycological methods. RESULTS: IFI were diagnosed in 30 (1.56%) patients on triple immunosuppression, mainly males (n = 25) with mean age of 36.57 +/- 11.9 years at 13.12 +/- 18.35 months post-RT. Aspergillus species was identified in 11 BAL, one tissue, and one wound specimen each, 30.76% of these were fatal and 15.38% caused graft loss; Candida albicans was in nine BAL, four blood, two wound swab, and one tissue specimens, 25% of these were fatal and 25% had graft loss and one mucor in BAL which was fatal. Seven patients were diabetic, 10 had superadded cytomegalovirus infection, and 15 were anti-rejected. CONCLUSION: IFI are associated with increased morbidity and mortality in RT patients. Triple immunosuppression, broad spectrum antibiotics for >= two weeks, diabetes and superadded infection are added risks for these patients. Prevention, early diagnosis, and appropriate management are necessary to improve their prognosis. PMID- 28085531 TI - Reconciling genotype with phenotype: Lessons learned on the Arabian Peninsula. AB - On the Arabian Peninsula, where consanguineous/endogamous marriages are customary, hereditary eye disease is often autosomal recessive and genotype phenotype correlation is typically straightforward. However, this is not always the case. Lessons I have learned in the course of reconciling genotype with phenotype in the region include the following: (1) although autosomal recessive disease is common, autosomal dominant disease still occurs; (2) an individual or family can be affected by more than one genetic eye disease; and (3) phenotype trumps genotype. PMID- 28085533 TI - Drug-Drug Interactions between Methadone and Apixaban. PMID- 28085532 TI - Advance of autophagy in chronic kidney diseases. AB - Autophagy, a highly conserved mechanism for cell survival, emerges as an important pathway in many biological processes and diseases conditions. Studies of cultured renal cells, human kidney tissues and experimental animal models implicate that autophagy regulation is the critical aspects in chronic kidney diseases (CKD). Here, we summarize the current studies on the role of autophagy in CKD. Unveiling the precise regulation mechanism of autophagy in CKD is essential for developing potential prevention, diagnostic and therapeutic targets of these sticky clinical challenges. PMID- 28085534 TI - Photoelectric Dye Used for Okayama University-Type Retinal Prosthesis Reduces the Apoptosis of Photoreceptor Cells. AB - PURPOSE: Our previous study demonstrated that photoelectric dye-coupled polyethylene film (Okayama University-type retinal prosthesis), which was implanted in subretinal space of the eyes of Royal College of Surgeons (RCS) rats, prevented retinal neurons from apoptotic death. In this study, we aimed to examine whether photoelectric dye itself would protect retinal neurons from apoptosis in RCS rats. METHODS: RCS rats received intravitreous injection of different concentrations of the dye in the left eye and housed under a 12-h light dark cycle. Saline injection in the right eye served as control. In addition, RCS rats with dye injection were kept in 24-h daily dark condition. Sections were processed for terminal deoxynucleotidyl transferase-mediated fluorescein conjugated-dUTP nick-end-labeling (TUNEL) assay and immunohistochemical staining of glial fibrillary acidic protein (GFAP) and protein kinase Calpha (PKCalpha). RESULTS: The number of TUNEL-positive cells significantly decreased in the retina of dye-injected eyes compared with those in saline-injected eyes (P = 0.0001, 2 factor analysis of variance [ANOVA]), under 12-h light-dark cycle. Significant decrease of TUNEL-positive cells was noted in the retina of rats with dye injection compared with those with saline injection, kept under 24-h dark condition (P = 0.0001, 2-factor ANOVA). Immunoreactive area for GFAP decreased significantly in the retina of dye-injected eyes compared with that in controls (P = 0.0001, 2-factor ANOVA), whereas immunoreactive area for PKCalpha increased significantly in the retina of dye-injected eyes compared with that in controls (P = 0.01, 2-factor ANOVA). CONCLUSIONS: Photoelectric dye inhibits apoptotic death of photoreceptor cells in RCS rats and downregulates GFAP expression in retinal Muller cells. Photoelectric dye may be a candidate agent for neuroprotection in retinitis pigmentosa and other retinal diseases. PMID- 28085535 TI - Fertility-Sparing Surgery Should Be the Standard Treatment in Patients with Malignant Ovarian Germ Cell Tumors. AB - PURPOSE: To validate the oncological safety of fertility preservation in malignant ovarian germ cell tumors (MOGCTs) and to define the significance of maximal cytoreduction in early stage MOGCTs. MATERIALS AND METHODS: Sixty-nine patients with stage I and II MOGCTs who underwent surgical treatment were included in the study. Fertility-sparing surgery is defined as conservative surgery and hysterectomy and contralateral salpingo-oophorectomy were defined as definitive surgery. Both surgical approaches involved lymphadenectomy and omentectomy. Most patients received platinum-based combinations for adjuvant therapy. Survival outcomes of the conservative surgery group were compared with the definitive surgery group. RESULTS: Median age of the study group was 21 years (range: 12-40 years). Median tumor size measured 150 mm (range, 20-300 mm). Surgery type (conservative surgery vs. definitive surgery) and lymphadenectomy (performed vs. not performed) were insignificant for the recurrence (p = 0.758, p = 0.271). However, surgical outcome (maximal vs. optimal and suboptimal) and type of tumor (dysgerminoma vs. nondysgerminoma) determined the recurrence (p = 0.001, p = 0.021). CONCLUSION: Fertility-conserving approach is safe in early stage MOGCTs. However, maximal cytoreduction should be achieved in this group of patients, without conceding fertility-conserving approach. On the other hand, development of chemotherapy options with less gonadotoxic effects, but equal or stronger efficiency in comparison with platinum-based chemotherapy, will certainly facilitate management of this patient group. PMID- 28085536 TI - Liver transplantation as a potentially lifesaving measure in neuroblastoma stage 4S. AB - Neuroblastoma (NBL) stage 4s is an incompletely understood phenomenon with variable clinical course. While the majority of patients may undergo spontaneous regression and achieve complete resolution without intensive therapy, a small proportion is at increased risk of developing secondary complications. One such situation is liver insufficiency due to diffuse metastases. We report a patient suffering from NBL 4S who required double lifesaving liver transplantation. Abdominal and respiratory complications due to hepatomegaly are crucial determinants for treatment intensity and duration in 4S NBL [1,2] . We provide an algorithm in order to facilitate the clinical decision when dealing with similar potentially life-threatening events. PMID- 28085537 TI - Inhibitory effect of an aqueous extract of Radix Paeoniae Alba on calcium oxalate nephrolithiasis in a rat model. AB - OBJECTIVE: To examine the effect of an aqueous extract of Radix Paeoniae Alba (RPA) on the formation of calcium oxalate (CaOx) stones and the potential mechanism underlying the effect. MATERIALS AND METHODS: An in vitro assay was used to determine whether the RPA extract prevents the formation of CaOx or promotes CaOx dissolution. We also investigated the efficacy of the extract in vivo as a preventive and therapeutic agent for experimentally induced CaOx nephrolithiasis in rats. Various biochemical, molecular, and histological parameters were assessed in kidney tissue and urine at the end of the in vivo experiment. RESULTS: Significant dissolution of formed crystals (8.99 +/- 1.43) and inhibition of crystal formation (2.55 +/- 0.21) were observed in vitro after treatment with 64 mg/mL of the RPA extract compared with a control treatment (55.10 +/- 4.98 and 54.57 +/- 5.84, respectively) (p < .05). In preventive protocols, the RPA extract significantly reduced urinary and renal oxalate levels and increased urinary calcium and citrate levels compared to the control. In addition, the RPA preventive protocol significantly decreased osteopontin expression, renal crystallization, and pathological changes compared to the control. These changes were not observed in rats on the therapeutic protocol. CONCLUSIONS: RPA is a useful agent that prevents the formation of CaOx kidney stones. PMID- 28085538 TI - Myths and misconceptions concerning contrast media-induced anaphylaxis: a narrative review. AB - Contrast-enhanced radiological examinations are an increasingly important diagnostic tool in modern medicine. All approved and available contrast media (iodinated and gadolinium-based) are safe compounds that are well-tolerated by most patients. However, a small percentage of patients exhibit contrast medium induced adverse drug reactions that are dose-dependent and predictable (type A) or an even smaller cohort experience so-called type B (dose-independent, non predictable). To increase patients' safety, recommendations/guidelines have been put forth in the literature and advice passed down informally by radiologists in practice to ensure contrast media safety. Through these, both reasonable suggestions as well as misinterpretations and myths (such as the misleading terms "allergy-like" reactions, and "iodine-allergy", the wrong assumption that the initial contact to a contrast medium could not induce an allergy, the estimation that an anti-allergy premedication could suppress all possible adverse reactions, and interleukin-2 as a risk/trigger for contrast medium adverse events) have arisen. Since the latter are not only unhelpful but also potentially reduce patients' safety, such myths and misconceptions are the focus of this review. PMID- 28085539 TI - Mutations in DZIP1 and XYLT1 are associated with nonsyndromic early onset high myopia in the Korean population. PMID- 28085540 TI - Sharing health data in Belgium: A home care case study using the Vitalink platform. AB - In 2013, the Flemish Government launched the Vitalink platform. This initiative focuses on the sharing of health and welfare data to support primary healthcare. In this paper, the objectives and mission of the Vitalink initiative are discussed. Security and privacy measures are reviewed, and the technical implementation of the Vitalink platform is presented. Through a case study, the possibility of interaction with cloud solutions for healthcare is also investigated upon; this was initially not the focus of Vitalink. The Vitalink initiative provides support for secure data sharing in primary healthcare, which in the long term will improve the efficiency of care and will decrease costs. Based on the results of the case study, Vitalink allowed cloud solutions or applications not providing end-to-end security to use their system. The most important lesson learned during this research was the need for firm regulations and stipulations for cloud solutions to interact with the Vitalink platform. However, these are currently still vague. PMID- 28085541 TI - Deliberate Practice with Standardized Patient Actors and the Development of Formative Feedback for Advance Care Planning Facilitators. AB - OBJECTIVE: Multimodal curricular assessment after adding standardized patient (SP) actor-based simulation to an advance care planning (ACP) facilitator training course and development of a formative feedback tool. BACKGROUND: ACP represents a highly valued service requiring more and better trained facilitators. METHODS: Participants were primarily nurses and social workers in a large multisite health system. The course included a precourse video demonstration of ACP, traditional lectures, and four 30-minute simulations with SPs. Knowledge was tested with a multiple choice question (MCQ) test. In addition to standard postcourse/postsimulation evaluations, learners were surveyed pre/post/30-90 days delayed for self-perceived confidence. A linear mixed-effects model was used to analyze changes over time. Trained faculty rated performance in simulations with an observational mini-clinical examination (mini-CEX)-type rating form with a checklist, global competency, and global communication rating. Inter-rater reliability (IRR) was calculated on randomly selected paired ratings. RESULTS: Sixty-seven individuals consented to participate. MCQ scores improved from 83% +/- 10% to 92% +/- 8% (p < 0.001). Paired learner surveys of self confidence across six domains were available for 65 pre, 65 post, and 40 delayed with a mean positive change on a 0 to 10 point scale from pre-post (2.32 +/- 1.65; p < 0.001) and predelayed (2.34 +/- 1.96; p < 0.001) time frames. For the faculty observation ratings of simulation performance, the average raw agreement for critical actions was 82% and IRR was 0.71. CONCLUSIONS: Learner feedback and self-assessment suggest that actor-based simulation contributed to improved confidence in conducting ACP. The mini-CEX observation form is adequate for formative feedback, with further testing needed to make judgments of competence. PMID- 28085542 TI - Involvement of intracellular transport in TREK-1c current run-up in 293T cells. AB - The TREK-1 channel, the TWIK-1-related potassium (K+) channel, is a member of a family of 2-pore-domain K+ (K2P) channels, through which background or leak K+ currents occur. An interesting feature of the TREK-1 channel is the run-up of current: i.e. the current through TREK-1 channels spontaneously increases within several minutes of the formation of the whole-cell configuration. To investigate whether intracellular transport is involved in the run-up, we established 293T cell lines stably expressing the TREK-1c channel (K2P2.1) and examined the effects of inhibitors of membrane protein transport, N-methylmaleimide (NEM), brefeldin-A, and an endocytosis inhibitor, pitstop2, on the run-up. The results showing that NEM and brefeldin-A inhibited and pitstop2 facilitated the run-up suggest the involvement of intracellular protein transport. Correspondingly, in cells stably expressing the mCherry-TREK-1 fusion protein, NEM decreased and pitstop2 increased the cell surface localization of the fusion protein. Furthermore, the run-up was inhibited by the intracellular application of a peptide of the C-terminal fragment TREK335-360, corresponding to the interaction site with microtubule-associated protein 2 (Mtap2). This peptide also inhibited the co-immunoprecipitation of Mtap2 with anti-mCherry antibody. The extracellular application of an ezrin inhibitor (NSC668394) also suppressed the run-up and surface localization of the fusion protein. The co-application of these inhibitors abolished the TREK-1c current, suggesting that the additive effects of ezrin and Mtap2 enhance the surface expression of TREK-1c channels and the run up. These findings clearly showed the involvement of intracellular transport in TREK-1c current run-up and its mechanism. PMID- 28085545 TI - Methadone Inpatient and Discharge Prescribing Patterns for Pain at an Academic Health System. AB - BACKGROUND: Methadone is effective for the treatment of chronic pain, but its unique pharmacology requires additional considerations with dosing and monitoring. OBJECTIVE: The study objective was to evaluate methadone prescribing for pain and subsequent monitoring. METHODS: This retrospective chart review at a single center reviewed patients who received methadone over a two-year period. RESULTS: Of the 100 patients, most were noncancer cases (60%) with unspecified pain (50%). The majority of methadone treatments were initiated by medicine service (37%), followed by burn service (27%), and trauma (10%). Forty-two percent of the patients were being followed by the palliative care team, primarily for the medicine patients (80%). Patients on the burn service had significantly higher oral morphine equivalent (chi2 = 10.6, p = 0.01) and longest length of stay (chi2 = 37.9, p = 0.0001). Patients on medicine service were significantly more likely to have an outpatient discharge plan for methadone starts in the hospital (odds ratio = 3.7, confidence interval: 1.4, 9.7). Only 45% of patients had an electrocardiogram (EKG) checked seven days before methadone start and 37% of those have a measured corrected QT (QTc) of greater than 450 milliseconds. Electrolytes (potassium and magnesium) were not consistently checked and, of those that were evaluated, 15-20% were abnormal. There was an average of 2.6 severe or major drug interactions per patient related to methadone, with the most common being related to concomitant sedatives and other medications that prolonged the QTc. CONCLUSIONS: Prescribing guidelines for methadone would provide a consistent approach for all practitioners involved in using methadone safely and effectively for chronic pain. PMID- 28085544 TI - Identification of immunoglobulin V(D)J recombinations in solid tumor specimen exome files: Evidence for high level B-cell infiltrates in breast cancer. AB - It has recently become apparent that it is possible to characterize productively recombined, T-cell receptor (TcR) gene segments in tumor exome files, which presumably include representations of the DNA of other cells in the microenvironment. Similar characterizations have been done for TcR recombinations in tumor specimen RNASeq files. While exome files have been used to characterize immunoglobulin gene segment recombinations for tumors closely related to B-cells, immunoglobulin recombinations have yet to be characterized for putative microenvironment cells for solid tumors. Here we report a novel scripted algorithm that detects productive and unproductive immunoglobulin recombinations in both B-cell related tumor exome files and in solid tumor exome files, with the most important result being the relatively high level B-cell infiltrate in breast cancer. This analysis has the potential of streamlining and dramatically augmenting the knowledge base regarding B-cell infiltrates into solid tumors; and leading to antibody reagents directed against tumor antigens and tissue resident, infectious pathogens. PMID- 28085547 TI - Defining Success in Pediatric Palliative Care While Tackling the Quadruple Aim. PMID- 28085543 TI - Deletion of PRKAA triggers mitochondrial fission by inhibiting the autophagy dependent degradation of DNM1L. AB - PRKAA (protein kinase, AMP-activated, alpha catalytic subunit) regulates mitochondrial biogenesis, function, and turnover. However, the molecular mechanisms by which PRKAA regulates mitochondrial dynamics remain poorly characterized. Here, we report that PRKAA regulated mitochondrial fission via the autophagy-dependent degradation of DNM1L (dynamin 1-like). Deletion of Prkaa1/AMPKalpha1 or Prkaa2/AMPKalpha2 resulted in defective autophagy, DNM1L accumulation, and aberrant mitochondrial fragmentation in the mouse aortic endothelium. Furthermore, autophagy inhibition by chloroquine treatment or ATG7 small interfering RNA (siRNA) transfection, upregulated DNM1L expression and triggered DNM1L-mediated mitochondrial fragmentation. In contrast, autophagy activation by overexpression of ATG7 or chronic administration of rapamycin, the MTOR inhibitor, promoted DNM1L degradation and attenuated mitochondrial fragmentation in Prkaa2-deficient (prkaa2-/-) mice, suggesting that defective autophagy contributes to enhanced DNM1L expression and mitochondrial fragmentation. Additionally, the autophagic receptor protein SQSTM1/p62, which bound to DNM1L and led to its translocation into the autophagosome, was involved in DNM1L degradation by the autophagy-lysosome pathway. Gene silencing of SQSTM1 markedly reduced the association between SQSTM1 and DNM1L, impaired the degradation of DNM1L, and enhanced mitochondrial fragmentation in PRKAA-deficient endothelial cells. Finally, the genetic (DNM1L siRNA) or pharmacological (mdivi 1) inhibition of DNMA1L ablated mitochondrial fragmentation in the mouse aortic endothelium and prevented the acetylcholine-induced relaxation of isolated mouse aortas. This suggests that aberrant DNM1L is responsible for enhanced mitochondrial fragmentation and endothelial dysfunction in prkaa knockout mice. Overall, our results show that PRKAA deletion promoted mitochondrial fragmentation in vascular endothelial cells by inhibiting the autophagy-dependent degradation of DNM1L. PMID- 28085548 TI - Are We Making a Difference? PMID- 28085549 TI - Integrating Dignity Therapy and Family Therapy in Palliative Care: A Case Study of Multiple Sclerosis, Depression, and Comorbid Cancer. PMID- 28085551 TI - Advancing Stage 2 Research on Measures for Monitoring Kindergarten Reading Progress. AB - Although several measures exist for frequently monitoring early reading progress, little research has specifically investigated their technical properties when administered on a frequent basis with kindergarten students. In this study, kindergarten students ( N = 137) of whom the majority was receiving supplemental intervention for reading skills were monitored using Letter Sound Fluency, Phoneme Segmentation Fluency, Word Reading Fluency, Nonsense Word Fluency, Highly Decodable Passages, and Spelling on a biweekly basis between February and May. Acceptable reliability was observed for all measures. Analyses of slope validity using latent growth models, latent change score models, and slope differences according to level of year-end achievement indicated that the relation of slope to overall reading skills varied across the measures. A suggested approach to kindergarten students' reading progress is offered that includes Letter Sound Fluency and a measure of word-reading skills to provide a comprehensive picture of student growth toward important year-end reading outcomes. PMID- 28085550 TI - MicroRNA-432 targeting E2F3 and P55PIK inhibits myogenesis through PI3K/AKT/mTOR signaling pathway. AB - Skeletal muscle is the dominant executant in locomotion and regulator in energy metabolism. Embryonic myogenesis and postnatal muscle growth are controlled by a cascade of transcription factors and epigenetic regulatory mechanisms. MicroRNAs (miRNAs), a family of non-coding RNA of 22 nucleotides in length, post transcriptionally regulates expression of mRNA by pairing the seed sequence to 3' UTR of target mRNA. Increasing evidence has demonstrated that miRNAs are important regulators in diverse myogenic processes. The profiling of miRNA expression revealed that miR-432 is more enriched in the longissimus dorsi of 35 day-old piglets than that of adult pigs. Our gain of function study showed that miR-432 can negatively regulate both myoblast proliferation and differentiation. Mechanically, we found that miR-432 is able to down-regulate E2F transcription factor 3 (E2F3) to inactivate the expression of cell cycle and myogenic genes. We also identified that phosphatidylinositol 3-kinase regulatory subunit (P55PIK) is another target gene of miR-432 in muscle cells. downregulation of P55PIK by miR 432 leads to inhibition of P55PIK-mediated PI3K/AKT/mTOR signaling pathway during differentiation. The blocking effect of miR-432 on this pathway can be rescued by insulin treatment. Taken together, our findings identified microRNA-432 as a potent inhibitor of myogenesis which functions by targeting E2F3 and P55PIK in muscle cells. PMID- 28085552 TI - Comprehensive estimate of the theoretical maximum daily intake of pesticide residues for chronic dietary risk assessment in Argentina. AB - A chronic dietary risk assessment for pesticide residues was conducted for four age groups of the Argentinian population following the procedure recommended by the WHO. The National Theoretical Maximum Daily Intake (NTMDI) for 308 pesticides was calculated for the first time, using the Maximum Residue Limits (MRLs) from several Argentinean regulations and food consumption data from a comprehensive National Nutrition and Health Survey. The risk was estimated by comparing the TMDI with the Acceptable Daily Intakes (ADI) identified by various sources. Furthermore, for each of the compounds with a TMDI >65% of the ADI, a probabilistic analysis was conducted to quantify the probability of exceeding the ADI. In this study 27, 22, 10, and 6 active ingredients (a.i.) were estimated to exceed the 100% of the ADI for the different population groups: 6-23 month-old children, 2-5 year-old children, pregnant women, and 10-49 year-old women, respectively. Some of these ADI-exceeding compounds (carbofuran, diazinon, dichlorvos, dimethoate, oxydemeton-methyl and methyl bromide) were found in all four of these groups. Milk, apples, potatoes, and tomatoes were the foods that contributed most to the intake of these pesticides. The study is of primary importance for the improvement of risk assessment, regulations, and monitoring activities. PMID- 28085553 TI - Emergence of Imipenem-Resistant Pseudomonas aeruginosa Clinical Isolates from Egypt Coharboring VIM and IMP Carbapenemases. AB - Pseudomonas aeruginosa is an important human pathogen and the leading cause of nosocomial infections. P. aeruginosa is characterized by massive intrinsic resistance to a multiple classes of antibiotics with carbapenems being the most potent inhibitor of P. aeruginosa and considered the first choice for its treatment. Therefore, it is crucial to investigate novel mechanisms of resistance of P. aeruginosa to carbapenems for achieving successful therapy. A total of 114 P. aeruginosa isolates from two university hospitals in Egypt were recruited in this study. Antimicrobial susceptibility testing revealed that 50 isolates (43.8%) exhibited multidrug-resistant (MDR) phenotype, of them 14 isolates (12.2%) were imipenem (IPM)-resistant. Of these 14 isolates, 13 isolates (11.4%) exhibited the metallo-beta-lactamase (MBL) phenotype. MBLs encoding genes, VIM and IMP, were identified by PCR. PCR results revealed that four isolates harbored the VIM gene alone, one isolate harbored IMP gene alone, and four isolates harbored both genes. The correct size of PCR products of VIM and IMP genes (390 and 188 bp, respectively) were sequenced to confirm results of PCR and to look for any possible polymorphism among MBL genes of tested isolates. Data analysis of these sequences showed 100% identity of nucleotide sequences of MBL genes among tested Egyptian patients. To our knowledge, this is the first report of IMP carbapenemase-encoding gene in Africa and the first detection of the emergence of P. aeruginosa coproducing VIM and IMP genes in Egypt. PMID- 28085554 TI - Caenorhabditis elegans as a model to study the impact of exposure to light emitting diode (LED) domestic lighting. AB - This study aimed to investigate the biological impact of exposure on domestic light emitting diodes (LED) lighting using the free-living nematode Caenorhabditis elegans as a model. Nematodes were separately exposed to white LED light covering the range of 380-750 nm, blue light at 450 nm and black light at 380-420 nm for one life cycle (egg to adult) with dark exposure as the control. Each light range induced stress to the nematode C. elegans such as reducing the number of the hatched eggs and/or delayed the maturation of the hatched eggs to the adult stage. In addition, it lowered or prevented the ability of adults to lay eggs and impaired the locomotion in the exposed worms. The observed type of biological stress was also associated with the production of reactive oxygen species (ROS) as compared to nematodes grown in the dark. It is concluded that the blue light component of white LED light may cause health problems, and further investigation is required to test commercial brands of white LEDs that emit different amounts of blue light. PMID- 28085555 TI - SOX9 chromatin folding domains correlate with its real and putative distant cis regulatory elements. AB - Evolutionary conserved transcription factor SOX9, encoded by the dosage sensitive SOX9 gene on chromosome 17q24.3, plays an important role in development of multiple organs, including bones and testes. Heterozygous point mutations and genomic copy-number variant (CNV) deletions involving SOX9 have been reported in patients with campomelic dysplasia (CD), a skeletal malformation syndrome often associated with male-to-female sex reversal. Balanced and unbalanced structural genomic variants with breakpoints mapping up to 1.3 Mb up- and downstream to SOX9 have been described in patients with milder phenotypes, including acampomelic campomelic dysplasia, sex reversal, and Pierre Robin sequence. Based on the localization of breakpoints of genomic rearrangements causing different phenotypes, 5 genomic intervals mapping upstream to SOX9 have been defined. We have analyzed the publically available database of high-throughput chromosome conformation capture (Hi-C) in multiple cell lines in the genomic regions flanking SOX9. Consistent with the literature data, chromatin domain boundaries in the SOX9 locus exhibit conservation across species and remain largely constant across multiple cell types. Interestingly, we have found that chromatin folding domains in the SOX9 locus associate with the genomic intervals harboring real and putative regulatory elements of SOX9, implicating that variation in intra-domain interactions may be critical for dynamic regulation of SOX9 expression in a cell type-specific fashion. We propose that tissue-specific enhancers for other transcription factor genes may similarly utilize chromatin folding sub-domains in gene regulation. PMID- 28085556 TI - Salt stress-induced changes in antioxidative defense system and proteome profiles of salt-tolerant and sensitive Frankia strains. AB - An appreciation of comparative microbial survival is most easily done while evaluating their adaptive strategies during stress. In the present experiment, antioxidative and whole cell proteome variations based on spectrophotometric analysis and SDS-PAGE and 2-dimensional gel electrophoresis have been analysed among salt-tolerant and salt-sensitive Frankia strains. This is the first report of proteomic basis underlying salt tolerance in these newly isolated Frankia strains from Hippophae salicifolia D. Don. Salt-tolerant strain HsIi10 shows higher increment in the contents of superoxide dismutase, catalase and ascorbate peroxidase as compared to salt-sensitive strain HsIi8. Differential 2-DGE profile has revealed differential profiles for salt-tolerant and salt-sensitive strains. Proteomic confirmation of salt tolerance in the strains with inbuilt efficiency of thriving in nitrogen-deficient locales is a definite advantage for these microbes. This would be equally beneficial for improvement of soil nitrogen status. Efficient protein regulation in HsIi10 suggests further exploration for its potential use as biofertilizer in saline soils. PMID- 28085557 TI - Two-Incision Laparoscopic Cholecystectomy in Children. AB - PURPOSE: To evaluate two-incision laparoscopic cholecystectomy (2I-LC) in children, and compare outcomes with four-port laparoscopic cholecystectomy (4P LC). METHODS: A retrospective review was performed on children (<=21 years) with gallbladder disease treated with 2I-LC or 4P-LC between February 2010 and February 2016. 2I-LC is performed using two 5-mm ports and a 2-mm endoscopic grasper within a 12-mm umbilical incision, and a 3-mm subxiphoid port for dissection. Demographic, diagnostic, operative, and outcome data were recorded, and the two groups were compared with chi-squared, Fisher, and t-tests. Patients requiring conversion from 2I-LC to 4P-LC were examined to determine factors predicting the need for additional ports. RESULTS: Three hundred eighty-nine laparoscopic cholecystectomies were performed (2I-LC 72.0%, 4P-LC 19.0%). Body mass index (BMI) was greater in the 4P-LC group. 2I-LC was more commonly performed for biliary dyskinesia, but not biliary colic, acute cholecystitis, choledocholithiasis, and gallstone pancreatitis. Operative time was greater in 4P LC. There were 6 wound infections (2I-LC 1.8%, 4P-LC 1.5%), 1 common bile duct injury (2I-LC 0.4%, 4P-LC 0.0%), and 1 small bowel injury (2I-LC 0.0%, 4P-LC 1.5%). 2.4% of 2I-LC required conversion to 4P-LC, with BMI and operative time greater than the 2I-LC group, but not different from 4P-LC with no complications. CONCLUSIONS: 2I-LC is a safe alternative to 4P-LC for pediatric gallbladder disease, allowing for traction and countertraction to expose the critical view. Operative time was longer in the 4P-LC group, likely secondary to selection bias with higher BMI and preoperative diagnosis of gallstone disease. Overweight patients are more likely to require additional ports. PMID- 28085558 TI - Net positive energy wastewater treatment plant via thermal pre-treatment of sludge: A theoretical case study. AB - In a wastewater treatment process, energy is mainly used in sludge handling and heating, while energy is recovered by biogas production in anaerobic digestion process. Thermal pre-treatment of sludge can change the energy balance in a wastewater treatment process since it reduces the viscosity and yield stress of sludge and increases the biogas production. In this study, a calculation based on a hypothetical wastewater treatment plant is provided to show the possibility of creating a net positive energy wastewater treatment plant as a result of implementing thermal pre-treatment process before the anaerobic digester. The calculations showed a great energy saving in pumping and mixing of the sludge by thermal pre-treatment of sludge before anaerobic digestion process. PMID- 28085559 TI - Enrichment and assessment of the health risks posed by heavy metals in PM1 in Changji, Xinjiang, China. AB - The present study aims to investigate the influence of human activity on heavy metals in a typical arid urban area of China and assess human health risks posed by heavy metals in PM1 (particles <1.0 MUm in diameter) for different people. In this paper, Changji (Xinjiang, China) was selected as the study area, and samples were collected from March 2014 to March 2015. A total 14 elements in PM1 were quantified using ICP-MS. An enrichment factor (EF) was used to assess the influence of human activity on the contamination of these metals. The results indicated that Mn was not enriched; Co, Cu, Cr, Ni, Tl, and V were slightly enriched; Mo, Pb, and Sb were moderately enriched; and Ag, As, and Cd were strongly enriched. To assess the health risks associated with inhaling PM1, the risk assessment code and loss in life expectancy based on the individual metals were calculated. The results showed that the elements Ag, Cu, Mo, Pb, Sb, Tl, and V in PM1 posed low levels of non-carcinogenic risks, but these metals may still pose risks to certain susceptible populations. In addition, the results also showed that As, Co, and Cr posed an appreciable carcinogenic risk, while Cd and Ni posed low levels of carcinogenic risk. The total predicted loss of life expectancy caused by the three metals As, Co, and Ni was 63.67 d for the elderly, 30.95 d for adult males, 26.62 d for adult females, and 48.22 d for children. Therefore, the safety of the elderly and children exposed to PM1 should be given more attention than the safety of adults. The results from this study demonstrate that the health risks posed by heavy metals in PM1 in Changji, Xinjiang, China should be examined. PMID- 28085560 TI - Validating Translations of Rating Scale Questionnaires Using Rasch Analysis. PMID- 28085561 TI - Focal Issue on Gender and Eye Care. PMID- 28085562 TI - In Vitro Development of Ciprofloxacin Resistance of Salmonella enterica Serovars Typhimurium, Enteritidis, and Indiana Isolates from Food Animals. AB - Difference in the development of resistance may be associated with the epidemiological spread and drug resistance of different Salmonella enterica serovar strains. In the present study, three susceptible S. enterica serovars, Typhimurium (ST), Enteritidis (SE), and Indiana (SI) strains, were subjected to stepwise selection with increasing ciprofloxacin concentrations. The results indicated that the mutation frequencies of the SI group were 101-104 higher and developed resistance to ciprofloxacin more rapidly compared with the ST and SE groups. Ciprofloxacin accumulation in the SI strain was also higher than the other two strains in the presence of an efflux pump inhibitor. The development of ciprofloxacin resistance was quite different among the three serovar strains. In SI, increasing AcrAB-TolC efflux pump expression and single or double mutations in gyrA with or without a single parC mutation (T57S) were found in the development of ciprofloxacin resistance. In SE, an increase in the AcrAB-TolC efflux pump regulatory gene ramA gradually decreased as resistant bacteria developed; then resistance resulted from gyrA D87G and gyrB E466D mutations and/or in other active efflux pumps besides AcrAB-TolC. For ST, ramA expression increased rapidly along with gyrA D87 N and/or gyrB S464F mutations. In conclusion, persistent use of ciprofloxacin may aggravate the resistance of different S. enterica serovars and prudent use of the fluoroquinolones is needed. The quicker resistance and higher mutation frequency of the SI isolates present a potential public health threat. PMID- 28085563 TI - The E3 ubiquitin ligase NEDD4 is an LC3-interactive protein and regulates autophagy. AB - The MAP1LC3/LC3 family plays an essential role in autophagosomal biogenesis and transport. In this report, we show that the HECT family E3 ubiquitin ligase NEDD4 interacts with LC3 and is involved in autophagosomal biogenesis. NEDD4 binds to LC3 through a conserved WXXL LC3-binding motif in a region between the C2 and the WW2 domains. Knockdown of NEDD4 impaired starvation- or rapamycin-induced activation of autophagy and autophagosomal biogenesis and caused aggregates of the LC3 puncta colocalized with endoplasmic reticulum membrane markers. Electron microscopy observed gigantic deformed mitochondria in NEDD4 knockdown cells, suggesting that NEDD4 might function in mitophagy. Furthermore, SQSTM1 is ubiquitinated by NEDD4 while LC3 functions as an activator of NEDD4 ligase activity. Taken together, our studies define an important role of NEDD4 in regulation of autophagy. PMID- 28085564 TI - Optimal conditions for chlorothalonil and dissolved organic carbon in horizontal subsurface flow constructed wetlands. AB - The most efficient system of horizontal subsurface flow constructed wetlands (HSSFCW) for removing dissolved organic carbon (DOC) in the presence of chlorothalonil pesticide (CLT) present in synthetic domestic wastewater was determined using the macrophyte Phragmites australis. Two concentrations of CLT (85 and 385 MUg L-1) and one concentration of glucose (20 mg L-1) were evaluated in four pilot scale horizontal surface flow constructed wetlands coupled with two sizes of silica gravel, igneous gravel, fine chalky gravel (3.18-6.35 mm), coarse gravel (12.70-25.40 mm) and two water surface heights (20 and 40 cm). For a month, wetlands were acclimated with domestic wastewater. Some groups of bacteria were also identified in the biofilm attached to the gravel. In each treatment periodic samplings were conducted in the influent and effluent. Chlorothalonil was quantified by gas chromatography (GC-ECD m), DOC by an organic carbon analyzer and bacterial groups using conventional microbiology in accordance with Standard Methods. The largest removals of DOC (85.82%-85.31%) were found when using fine gravel (3.18-6.35 mm) and the lower layer of water (20 cm). The bacterial groups quantified in the biofilm were total heterotrophic, revivable heterotrophic, Pseudomonas and total coliforms. The results of this study indicate that fine grain gravel (3.18-6.35 mm) and both water levels (20 to 40 cm) can be used in the removal of organic matter and for the treatment of agricultural effluents contaminated with organo-chloride pesticides like CLT in HSSFCW. PMID- 28085569 TI - Immediate Implant Combined With Modified Socket-Shield Technique: A Case Letter. PMID- 28085570 TI - Small-Diameter Implants: A 7-Year Retrospective Study. AB - Oral implantology has become a major discipline within the field of dentistry. Small or mini dental implants have demonstrated success in the retention of removable and fixed prostheses. Small-diameter implants (SDI) and mini-diameter implants (MDI) describe a group of implants that demonstrate a diameter less than 3 mm. This retrospective study reports on 335 SDI placed during a 7-year period. All implants were placed in healed sites (>6 months) and loaded immediately or after waiting 3 months. A total of 321 implants were restored and functional within the study's time interval. A total of 14 implants failed, resulting in a 96.1% implant success rate. Treatment plan considerations should include prosthetic design, specific arch, and immediate load. Overall, SDI can be utilized as an alternative implant treatment option for patients with atrophic bone, compromised medical histories and financial constraints. PMID- 28085565 TI - Resting-State Functional Connectivity Alterations Associated with Six-Month Outcomes in Mild Traumatic Brain Injury. AB - Brain lesions are subtle or absent in most patients with mild traumatic brain injury (mTBI) and the standard clinical criteria are not reliable for predicting long-term outcome. This study investigates resting-state functional MRI (rsfMRI) to assess semiacute alterations in brain connectivity and its relationship with outcome measures assessed 6 months after injury. Seventy-five mTBI patients were recruited as part of the prospective multicenter Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) pilot study and compared with matched 47 healthy subjects. Patients were classified following radiological criteria: CT/MRI positive, evidence of lesions; CT/MRI negative, without evidence of brain lesions. rsfMRI data were acquired and then processed using probabilistic independent component analysis. We compared the functional connectivity of the resting-state networks (RSNs) between patients and controls, as well as group differences in the interactions between RSNs, and related both to cognitive and behavioral performance at 6 months post-injury. Alterations were found in the spatial maps of the RSNs between mTBI patients and healthy controls in networks involved in behavioral and cognition processes. These alterations were predictive of mTBI patients' outcomes at 6 months post-injury. Moreover, different patterns of reduced network interactions were found between the CT/MRI positive and CT/MRI negative patients and the control group. These rsfMRI results demonstrate that even mTBI patients not showing brain lesions on conventional CT/MRI scans can have alterations of functional connectivity at the semiacute stage that help explain their outcomes. These results suggest rsfMRI as a sensitive biomarker both for early diagnosis and for prediction of the cognitive and behavioral performance of these patients. PMID- 28085571 TI - Systematic Review of Antimicrobial Resistance of Clinical Acinetobacter baumannii Isolates in Iran: An Update. AB - Treatment of Acinetobacter baumannii has become a medical challenge because of the increasing incidence of multiresistant strains and a lack of viable treatment alternatives. This systematic review attempts to investigate the changes in resistance of A. baumannii to different classes of antibiotics in Iran, with emphasis on the antimicrobial activity of polymyxin B (PMB) and colistin (COL). Biomedical databases were searched for English-published articles evaluating microbiological activity of various antimicrobial agents, including PMB and COL. Then, the available data were extracted and analyzed. Thirty-one studies, published from 2009 to 2015, were identified which contain data for 3,018 A. baumannii clinical isolates. With the exception of polymyxins and tigecycline (TIG), there was a high rate of resistance to various groups of antibiotics, including carbapenems. The minimum inhibitory concentration (MIC) ranges for PMB and COL on A. baumannii isolates tested were 0.12-64 MUg/ml and 0.001-128 MUg/ml, respectively. Polymyxins showed adequate activity with no significant trends in the resistance rate during most of the study period. The incidence of resistance to TIG was estimated low from 2% to 38.4% among the majority of A. baumannii. The present systematic review of the published literatures revealed that multidrug resistant (including carbapenem-resistant) strains of A. baumannii have increased in Iran. In these circumstances, the older antibiotics, such as COL or PMB, preferably in combination with other antimicrobials (rifampicin, meropenem), could be considered as the therapeutic solution against the healthcare-associated infections. Designing rational dosage regimens for patients to maximize the antimicrobial activity and minimize the emergence and prevalence of resistance is recommended. PMID- 28085572 TI - Effect of Laser-Activated Irrigation on the Push-Out Bond Strength of ProRoot Mineral Trioxide Aggregate and Biodentine in Furcal Perforations. AB - OBJECTIVE: The objective of the present study was to assess the effect of erbium, chromium: yttrium-scandium-gallium-garnet (Er,Cr:YSGG) laser-activated irrigation (LAI) of NaOCl on the push-out bond strength of furcal perforations repaired with ProRoot mineral trioxide aggregate (MTA) and Biodentine. BACKGROUND DATA: Several studies investigated the adhesion of calcium silicate-based cements after exposure to endodontic irrigants, while effect of LAI on bond strength remains to be elucidated. MATERIALS AND METHODS: Bur-cut furcal perforations with standard dimensions were created in 100 extracted human mandibular molars. Teeth were randomly distributed into two groups (n = 50/group) according to the repair material applied: (1) ProRoot MTA or (2) Biodentine. The specimens were further assigned into five subgroups according to the irrigation regimens used over the set materials: (a) distilled water with needle irrigation; (b) 5.25% NaOCl with needle irrigation; (c) distilled water with LAI; (d) 5.25% NaOCl with LAI; and (e) no irrigation (control). Bond strengths of the test materials were assessed by using push-out bond strength test. RESULTS: Biodentine showed significantly higher dislocation resistance than ProRoot MTA (p < 0.05). Laser activation of 5.25% NaOCl and distilled water did not significantly affect the push-out bond strength results (p > 0.05). CONCLUSIONS: Biodentine showed higher dislocation resistance than ProRoot MTA as a perforation repair material. Er,Cr:YSGG laser activation of irrigation aqueous solutions had no adverse effect on push-out bond strength of Biodentine and ProRoot MTA. PMID- 28085573 TI - The Surgical Infection Society Revised Guidelines on the Management of Intra Abdominal Infection. AB - BACKGROUND: Previous evidence-based guidelines on the management of intra abdominal infection (IAI) were published by the Surgical Infection Society (SIS) in 1992, 2002, and 2010. At the time the most recent guideline was released, the plan was to update the guideline every five years to ensure the timeliness and appropriateness of the recommendations. METHODS: Based on the previous guidelines, the task force outlined a number of topics related to the treatment of patients with IAI and then developed key questions on these various topics. All questions were approached using general and specific literature searches, focusing on articles and other information published since 2008. These publications and additional materials published before 2008 were reviewed by the task force as a whole or by individual subgroups as to relevance to individual questions. Recommendations were developed by a process of iterative consensus, with all task force members voting to accept or reject each recommendation. Grading was based on the GRADE (Grades of Recommendation Assessment, Development, and Evaluation) system; the quality of the evidence was graded as high, moderate, or weak, and the strength of the recommendation was graded as strong or weak. Review of the document was performed by members of the SIS who were not on the task force. After responses were made to all critiques, the document was approved as an official guideline of the SIS by the Executive Council. RESULTS: This guideline summarizes the current recommendations developed by the task force on the treatment of patients who have IAI. Evidence-based recommendations have been made regarding risk assessment in individual patients; source control; the timing, selection, and duration of antimicrobial therapy; and suggested approaches to patients who fail initial therapy. Additional recommendations related to the treatment of pediatric patients with IAI have been included. SUMMARY: The current recommendations of the SIS regarding the treatment of patients with IAI are provided in this guideline. PMID- 28085574 TI - A Large-Scale Test of the Goldilocks Hypothesis. AB - Although the time adolescents spend with digital technologies has sparked widespread concerns that their use might be negatively associated with mental well-being, these potential deleterious influences have not been rigorously studied. Using a preregistered plan for analyzing data collected from a representative sample of English adolescents ( n = 120,115), we obtained evidence that the links between digital-screen time and mental well-being are described by quadratic functions. Further, our results showed that these links vary as a function of when digital technologies are used (i.e., weekday vs. weekend), suggesting that a full understanding of the impact of these recreational activities will require examining their functionality among other daily pursuits. Overall, the evidence indicated that moderate use of digital technology is not intrinsically harmful and may be advantageous in a connected world. The findings inform recommendations for limiting adolescents' technology use and provide a template for conducting rigorous investigations into the relations between digital technology and children's and adolescents' health. PMID- 28085575 TI - Continuous Wave Fractional CO2 Laser for the Treatment of Upper Eyelid Dermatochalasis and Periorbital Rejuvenation. AB - Fractional continuous wave CO2 laser resurfacing is used to improve photodamage, wrinkles, and acne scarring by surface ablation and by using heat to activate natural collagen production and dermal remodeling. In this study, the author examined the efficacy and safety of nonincisional continuous wave fractional CO2 laser blepharoplasty in the upper lid. Standard lid measurements including marginal reflex distance, palpebral fissure, and upper lid crease were performed preoperatively and at 6 months by the surgeon. All patients underwent full facial MIXTO continuous wave CO2 laser treatment (MIXTO Slim Evolution 2; MIXTOLasering USA, San Ramon, CA), including resurfacing on the upper eyelid from lashes to brow. We evaluated results at 6 months after laser treatment and found that on average, after MIXTO continuous wave laser treatment, marginal reflex distance of the upper lid increased from baseline from 0.7 to 2.2 mm, palpebral fissures increased from 5.6 to 7.4 mm, the upper lid crease was unchanged at 5.7 mm as was the upper lid excursion at 14.7 mm compared with those before treatment. Patients reported postoperative erythema, edema, crusting, and oozing that resolved within 14 days. These data demonstrate the safety and efficacy of noninvasive continuous wave fractional CO2 laser in the treatment of mild and moderate upper eyelid dermatochalasis. PMID- 28085577 TI - Apparent decline in male nurses may be due to recording method. AB - Male nurses appear to be leaving the profession at the rate of 100 a month, according to latest statistics - although the apparent decline might be due in part to non-recording of gender. PMID- 28085576 TI - Contact Isolation Precautions in Trauma Patients: An Analysis of Infectious Complications. AB - BACKGROUND: Victims of traumatic injuries represent a population at risk for a wide variety of complications. Contact isolation (CI) is a set of restrictions designed to help prevent the transmission of medically significant organisms in the healthcare setting. A growing body of literature demonstrates that CI can have significant implications for the individual isolated patient. Our goal was to characterize the use of contact isolation at our Level I trauma center and investigate the association of CI with infectious complications. PATIENTS AND METHODS: An existing trauma database containing data on patients admitted at our Level I trauma center between January 1, 2011 and December 31, 2012, along with their contact isolation status, was queried. Demographics, injuries, and the presence of infections were collected. Diagnosis of pneumonia or UTI was based on clinical documentation in the patient's medical record. A chart review was performed to ascertain the reason for CI including specific organisms. Because of differences in patient demographics between the CI and non-CI groups, linear regression was performed to adjust for the effects of different variables. RESULTS: A total of 4,423 patients were admitted over this period. Of these, 4,318 (97.6%) had complete records and were included in the subsequent analysis. The CI was in place in 249 (5.8%) patients; 4,069 (94.2%) were not isolated. The number who had CI initiated for MRSA nasal colonization was 173 (69.5%). Twenty two (8.9%) had no reason for CI documented. Pneumonia occurred in 190 (4.4%), 54 (21.7) in the CI group versus 136 (3.3%) in the non-CI group. Urinary tract infection (UTI) was diagnosed in 166 (3.8%), 48 (19.3%) in the CI group versus 118 (2.9%) in the non-CI group. Using logistic regression and excluding patients placed on contact isolation for the development of a new resistant nosocomial infection, CI, Injury Severity Score, gender, length of stay, and mechanical ventilation were identified as common covariates for pneumonia (PNA) and UTI. Chronic obstructive pulmonary disease COPD was specifically identified for PNA. Spinal cord injury, vertebral column injury and pelvic-urogenital injury were also significant for UTI. CONCLUSIONS: The development of pneumonia and UTI in patients with trauma was significantly associated with the use of CI. Because the majority of these patients had CI precautions in place for asymptomatic colonization, the CI provided them no direct benefit. Because the use of CI is associated with multiple negative outcomes, its use in the trauma population needs to be carefully re-evaluated. PMID- 28085578 TI - Impact of recession on NHS discussed at highest level. AB - Downing Street officials have met senior NHS managers to discuss the impact of the recession on health service spending. PMID- 28085579 TI - Call for staff involvement in health bill. AB - The RCN wants legislative guarantees that NHS staff will be involved in the evolution of the government's forthcoming Health Bill to ensure transparency. PMID- 28085580 TI - Boosting the physical health of people with schizophrenia. AB - In response to Steven Pack's article on the poor physical health of patients with schizophrenia (art & science January 28), I found it interesting that the psychiatric symptoms and effects of substance misuse on the physical health of patients with schizophrenia were mentioned but not related to the physical health problems. PMID- 28085581 TI - Private sector leads the way in looking after older nurses. AB - The NHS needs to look after its ageing workforce and help older nurses who want to continue working (features February 4). PMID- 28085582 TI - Oprah needs to change her lifestyle to remain healthy. AB - American talk show host Oprah Winfrey has again put on weight and says she is furious with herself (reflections February 4). She has gained and lost weight in the public eye for a number of years. PMID- 28085583 TI - I did not save for my retirement and will have to work until I drop. AB - I can relate to Connie Amaning (features February 4), who at 65 is still working to save for her retirement. I cannot afford to retire and will have to work until I drop. PMID- 28085584 TI - Back on the ward. PMID- 28085585 TI - Starting out i learned why it is important to adopt a family approach to care. AB - During morning handover on the medical cardiology ward I was told that a new patient, Liz, had been admitted with post-partum cardiomyopathy after giving birth to her first child. PMID- 28085586 TI - Alzheimer's disease. AB - Alzheimer's disease is a complex condition with medical, social and psychological aspects. It is a degenerative disorder and a type of dementia that affects the brain. Symptoms can include cognitive impairment, social withdrawal, communication problems, impairment of complex motor tasks and spatial disorientation. PMID- 28085587 TI - Reflexivity:promoting rigour in qualitative research. PMID- 28085588 TI - Voices-Scary though it may sound, the introduction of nursing metrics is a good thing. AB - Afraid of maths? Not really a figures person? Join the club. For many nurses, acquiring just enough mathematical knowledge to get onto a nursing course and pass the calculations assessment was the pinnacle of our achievement. PMID- 28085589 TI - Difference matters. AB - I travelled extensively before beginning my nursing career, so when an opportunity arose to do one of my nursing placements abroad, I took it. PMID- 28085592 TI - Animal experimentation is a fraudulent science. AB - Further to the recent feature on animal experimentation (January 28), I draw your attention to the words of Claude Reiss on vivisection: 'No lie can remain buried forever.' PMID- 28085591 TI - Mind over matter. PMID- 28085593 TI - Nurses should be up to speed on pharmacogenetic testing. AB - The expectations for pharmacogenetic testing have been high, partly because of the hype surrounding the human genome project (art & science January 28). But pharmacogenetics will soon become a reality in everyday health care in the UK. Pharmacogenetic testing may not be necessary for the vast numbers of drugs with a wide therapeutic margin and few or no serious side effects. However, it will be helpful in preventing harm when there are difficulties in finding the specific therapeutic dose for a patient. PMID- 28085594 TI - Sheelagh Brewer. AB - Sheelagh Brewer, who died on February 4, a few weeks short of her 61st birthday, was a respected colleague and trusted friend. Sadly, what should have been a long and happy retirement in France was cut short. Sheelagh fought her illness with characteristic courage and black humour but, ultimately, an aggressive cancer defeated her. PMID- 28085595 TI - Highlight the threat of knife crime to nursing staff in a&e. AB - Your article on the care and management of patients with stab wounds in A&E (learning zone January 28) highlights the dramatic increase in knife crime in the UK. PMID- 28085596 TI - Fruit and vegetables trialled for people with schizophrenia. AB - Commenting on the poor physical health and mortality of patients with schizophrenia (art & science January 28), Steven Pack writes: 'Health interventions, such as the provision of free fruit and vegetables and the prescription of vitamin supplements, would be a start.' PMID- 28085597 TI - Almost half of NHS staff are missing out on career development scheme. AB - After assimilating their staff onto the Agenda for Change (AfC) pay system, NHS organisations across the UK were expected to turn their attention to the training and development of employees. PMID- 28085598 TI - Uptake of free online KSF tool proves patchy. AB - Some NHS organisations are not giving information to staff about an online version of the NHS Knowledge and Skills Framework (KSF) because they have failed to introduce it fully, Nursing Standard has learned. PMID- 28085599 TI - Debate on spirituality needed. AB - There was an unfortunate predictability in public responses to the suspension of nurse Caroline Petrie on the grounds that she offered to pray for a patient. Christian organisations leapt to her defence while others applauded the actions of North Somerset Primary Care Trust management. And inevitably such a high profile case was pounced on by those desperate for a martyr to their own particular cause. PMID- 28085600 TI - Dedicated staff ensure smooth hospital service despite the snow. AB - Nurses have been praised for battling the elements during the heaviest snowfall in 18 years. PMID- 28085601 TI - Working with a united vision. AB - The Great North Children's Hospital will open later this year, heralding a new era of health care for children and their families in Newcastle upon Tyne. PMID- 28085602 TI - NHS Employers calls for more 'honesty' with staff about diversity. AB - Managers should be more honest with their staff about why they need to monitor the race, sex and gender of their employees, according to new guidance. PMID- 28085604 TI - Nutrition for patients in hospital. PMID- 28085603 TI - 'Birth mirror' designed to ease labour. AB - A midwife has designed a mirror for mothers to use during labour in a bid to boost the number of natural births. PMID- 28085605 TI - Win-win treatment. AB - Addiction to gambling tends to be a hidden problem but now the UK's first NHS funded treatment unit is attempting to tackle it. PMID- 28085606 TI - Child obesity scheme could target pregnant women. AB - A national nutrition programme could be extended to midwives to enable them to anticipate and tackle obesity issues in children - before birth. PMID- 28085608 TI - Study finds 'second degree nurses' cope better with stress. AB - Nurses who obtain their nursing qualification as a second degree or diploma are more likely to stay in their job and cope better with stress, a study has found. PMID- 28085607 TI - Ministers told proposed workforce planning centre must be independent. AB - A proposed centre of excellence to help employers calculate how many nurses they require should be independent of the government, a Department of Health (DH) commissioned report recommends. PMID- 28085609 TI - Depression in early pregnancy can lead to preterm delivery. AB - Pregnant women with symptoms of depression are at an increased risk of preterm delivery and this is exacerbated by social and reproductive risk factors, obesity and stressful events. PMID- 28085610 TI - Family history linked to development of head and neck cancer. AB - Familial factors play a role in the aetiology of head and neck cancer. PMID- 28085612 TI - Strictly barmy. AB - One of the barmiest things I have heard in a long time is the idea of patients giving 'consumer feedback' about their GP surgery on the NHS Choices website. PMID- 28085613 TI - Assessment and management of patients with varicose veins. PMID- 28085614 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28085615 TI - Standard life. AB - I want to talk about my teeth. Not strictly your domain, I know, but bear with me. PMID- 28085616 TI - Health minister highlights need for more specialist stroke nurses. AB - The Department of Health (DH) has begun a hard-hitting campaign to halve the number of stroke deaths in England. PMID- 28085617 TI - Royal mail adviser to join NHS. AB - The Royal Mail's chief medical adviser has been hired by the Department of Health to review the health and wellbeing of the NHS workforce. PMID- 28085618 TI - Mobile phones - a tricky call. AB - Our experts consider a hot topic of the day. PMID- 28085620 TI - Key role for nurse specialists in L150 million dementia strategy. AB - Nurses will receive better support, guidance and education to improve the care they give to people with dementia, according to England's first national dementia strategy. PMID- 28085619 TI - Lobby for colour-coded food labelling. AB - Organisations representing health professions have been asked to campaign harder for better food labelling to help consumers make informed decisions about healthy eating. PMID- 28085621 TI - Corrie's Janice wants to be a nurse. AB - It is a soap opera storyline that could leave many hospital patients quaking in their beds - Coronation Street's outspoken factory worker Janice Battersby wants to become a nurse. PMID- 28085622 TI - Prayer row sparks calls for clear guidance on spirituality in care. AB - Religious leaders and charities have called for employers to provide spirituality guidance to staff, following the suspension of a nurse who offered to pray for a patient. PMID- 28085625 TI - Outside in. AB - The family story goes like this. Great Aunt Edie was an amateur cellist who lost an arm to tuberculosis (TB). Unable to play, she was utterly devastated and died soon after - not of TB but of a broken heart. PMID- 28085626 TI - Webwise. AB - More than three million people of all ages are living with kidney disease in the UK. The inter-relationship between kidney disease and many other conditions makes it of particular interest to nurses. PMID- 28085627 TI - Reducing the risk of fractures improves with persistence. AB - Improvements in treatment persistence and concordance might improve the impact of bisphosphonates in reducing the risk of fractures in people with osteoporosis. PMID- 28085628 TI - Researchers warn of M. bovis infection threat in rural areas. AB - Bovine tuberculosis (TB), caused by Mycobacterium bovis, remains a serious animal health problem in the UK, in spite of longstanding statutory surveillance and control measures. Endemic infection in the Eurasian badger population is thought to complicate bovine TB eradication efforts. Sporadic cases of M. bovis infection have also been reported in domestic animals other than cattle. Human M. bovis infection is extremely rare in the UK population in the absence of unpasteurised milk consumption or residence abroad. PMID- 28085629 TI - Care standards for IBD unveiled. AB - Standards to improve the quality of care for patients with inflammatory bowel disease (IBD) are due to be published in the House of Lords this week. PMID- 28085630 TI - Mechanosensitive ion channel Piezo2 is inhibited by D-GsMTx4. AB - Enterochromaffin (EC) cells are the primary mechanosensors of the gastrointestinal (GI) epithelium. In response to mechanical stimuliEC cells release serotonin (5-hydroxytryptamine; 5-HT). The molecular details ofEC cell mechanosensitivity are poorly understood. Recently, our group found that human and mouseEC cells express the mechanosensitive ion channel Piezo2. The mechanosensitive currents in a humanEC cell model QGP-1 were blocked by the mechanosensitive channel blocker D-GsMTx4. In the present study we aimed to characterize the effects of the mechanosensitive ion channel inhibitor spider peptide D-GsMTx4 on the mechanically stimulated currents from both QGP-1 and human Piezo2 transfected HEK-293 cells. We found co-localization of 5-HT and Piezo2 in QGP-1 cells by immunohistochemistry. QGP-1 mechanosensitive currents had biophysical properties similar to dose-dependently Piezo2 and were inhibited by D-GsMTx4. In response to direct displacement of cell membranes, human Piezo2 transiently expressed in HEK-293 cells produced robust rapidly activating and inactivating inward currents. D-GsMTx4 reversibly and dose-dependently inhibited both the potency and efficacy of Piezo2 currents in response to mechanical force. Our data demonstrate an effective inhibition of Piezo2 mechanosensitive currents by the spider peptide D-GsMTx4. PMID- 28085632 TI - Displacement of Dental Implants Into the Mandibular Bone Marrow Space: Cause and Treatment. A Case Study and Literature Review. PMID- 28085633 TI - A Focus on the Program of All-Inclusive Care for the Elderly (PACE). AB - For over four decades, the Program of All-Inclusive Care for the Elderly (PACE) has been operated by nonprofit organizations. Research has demonstrated that nonprofit PACE provides quality, cost-effective community-based care to older adults who would otherwise require a nursing home level of care. Recently, the U.S. Secretary of the Department of Health and Human Services has authorized for profit entities to operate PACE, contingent on their ability to demonstrate that they can provide care that is similar to nonprofit PACE with regard to access to care, quality of care, and cost-effectiveness. In 2013, a study was conducted to evaluate how PACE operates under for-profit versus nonprofit status. The results were presented to Congress which, in turn, authorized for-profit PACE providers. This article critiques the 2013 study, offers a comparison to for-profit hospice, and argues that at best there is not enough evidence to conclude that for-profit PACE provides the same quality of care as existing nonprofit operators. PMID- 28085631 TI - Reliability of Robotic Telemedicine for Assessing Critically Ill Patients with the Full Outline of UnResponsiveness Score and Glasgow Coma Scale. AB - PURPOSE: Telemedicine is increasingly utilized in the evaluation of critically ill patients, including those with decreased level of consciousness (LOC) or coma. Improving access to providers with neurologic expertise affords earlier triage and directed patient management. However, objective data regarding the reliability of using standardized coma scales, traditionally employed at the bedside for remote assessment, are largely lacking. HYPOTHESIS: Bedside and remote assessments of patients with decreased LOC, using either the Glasgow Coma Scale (GCS) or Full scale Of UnResponsiveness (FOUR), score are equivalent. METHODS: Prospective trial comparing the reliability of bedside and remote coma assessments using GCS or FOUR score clinical evaluation tools utilizing robotic telepresence technology. Total scores of the GCS and FOUR score were compared between bedside and remote physician assessors by paired t-test and Pearson correlation coefficient (PCC). RESULTS: One hundred subjects were enrolled. Mean age was 70.8 (+/-15.9) years and the average examination time took 5.16 (+/-2.04) minutes. Mean GCS total score at bedside was 7.5 (+/-3.67) versus examination conducted remotely 7.23 (+/-3.85); difference in scores was 0.25 (+/-0.10); p = 0.01. Mean FOUR total score at bedside was 9.63 (+/-4.76) versus remote 9.21 (+/ 4.74); difference in scores was 0.40 (+/-2.00); p = 0.05. PCC for GCS was 0.966; p < 0.001, and for FOUR score 0.912; p < 0.001. Ninety-five percent of remote providers rated GCS and 89% rated FOUR score as good (4/5) regarding overall satisfaction and ease of use. CONCLUSIONS: Differences between total bedside and remote GCS and FOUR scores were small. Furthermore, PCCs between remote and bedside assessments were excellent: 0.97 (GCS) and 0.91 (FOUR). These results suggest that LOC can be reliably assessed using existing robotic telemedicine technology. Telemedicine could be adopted to help evaluate critically ill patients in neurologically underserved areas. PMID- 28085634 TI - An Interleukin 12 Adjuvanted Herpes Simplex Virus 2 DNA Vaccine Is More Protective Than a Glycoprotein D Subunit Vaccine in a High-Dose Murine Challenge Model. AB - Vaccination is a proven intervention against human viral diseases; however, success against Herpes Simplex Virus 2 (HSV-2) remains elusive. Most HSV-2 vaccines tested in humans to date contained just one or two immunogens, such as the virion attachment receptor glycoprotein D (gD) and/or the envelope fusion protein, glycoprotein B (gB). At least three factors may have contributed to the failures of subunit-based HSV-2 vaccines. First, immune responses directed against one or two viral antigens may lack sufficient antigenic breadth for efficacy. Second, the antibody responses elicited by these vaccines may have lacked necessary Fc-mediated effector functions. Third, these subunit vaccines may not have generated necessary protective cellular immune responses. We hypothesized that a polyvalent combination of HSV-2 antigens expressed from a DNA vaccine with an adjuvant that polarizes immune responses toward a T helper 1 (Th1) phenotype would compose a more effective vaccine. We demonstrate that delivery of DNA expressing full-length HSV-2 glycoprotein immunogens by electroporation with the adjuvant interleukin 12 (IL-12) generates substantially greater protection against a high-dose HSV-2 vaginal challenge than a recombinant gD subunit vaccine adjuvanted with alum and monophosphoryl lipid A (MPL). Our results further show that DNA vaccines targeting optimal combinations of surface glycoproteins provide better protection than gD alone and provide similar survival benefits and disease symptom reductions compared with a potent live attenuated HSV-2 0DeltaNLS vaccine, but that mice vaccinated with HSV-2 0DeltaNLS clear the virus much faster. Together, our data indicate that adjuvanted multivalent DNA vaccines hold promise for an effective HSV-2 vaccine, but that further improvements may be required. PMID- 28085635 TI - Access to all components of scanned mathematical documents by vision-impaired students. AB - Vision-impaired people access documents using screen readers. Electronic documents may contain non-textual components, non-linear components, and multidimensional components, such as mathematical expressions and graphs. These components create a number of accessibility issues for those who use screen readers as assistive technology. The research presented here describes mathematical information retrieval, and accessible and navigable representation of mathematical function graphs as solutions to these issues. Additionally, this research study is about how to present course materials to vision-impaired students, and is not about how to teach them. The system shows promise, given an initial evaluation by a vision-impaired person, and an encouraging review by three blind professionals. The next step is to perform a full evaluation of the system employing a larger number of vision-impaired students. PMID- 28085636 TI - "You Need to Be a Good Listener": Recruiters' Use of Relational Communication Behaviors to Enhance Clinical Trial and Research Study Accrual. AB - Medical and research professionals who discuss clinical trials and research studies with potential participants face an often daunting challenge, particularly when recruiting from minority and underserved populations. This study reports on findings from a focus group study of 63 research coordinators, study nurses, professional recruiters, and other professionals in Indianapolis, IN and Miami, FL who work to recruit from minority and underserved populations. These professionals discussed the importance of creating a sense of connection with potential participants as part of the recruitment and retention process. Building a relationship, however fleeting, involved a number of concrete behaviors, including listening to personal information, expressing empathy, and then providing reciprocal self-disclosures; having repeated contact, usually by working in the same environment over an extended period of time; demonstrating respect through politeness and the use of honorifics; going the extra mile for participants; offering flexibility in scheduling follow-up appointments; and creating a sense of personal and community trust by being truthful. The implications of these findings for clinical trial and research study accrual are discussed. PMID- 28085637 TI - Co-Occurrence of and Recovery from Substance Abuse and Lifespan Victimization: A Qualitative Study of Female Residents in Trauma-Informed Sober Living Homes. AB - Despite the co-occurrence of substance use disorders (SUDs) and domestic and/or sexual violence (DSV) in the lives of women, there remains a dearth of research on how and why these phenomena intersect as well as the role that trauma-informed sober living homes (SLHs) may play in promoting recovery. Following a detailed description of a unique trauma-informed SLH (Support, Education, Empowerment, and Directions [SEEDs]), we present findings from a qualitative study that documented the perceptions and lived experiences of 28 female current or former residents of a trauma-informed SLH; all women had histories of SUDs and DSV. Results uncovered four themes (fractured foundations, points of intersection of SUDs and DSV, pervasiveness of SUDS and DSV, resiliency) and a constitutive pattern (moving away from instability and harnessing self-agency). Women noted that their engagement with SEEDs played a significant role in their recovery, specifically through fulfilling their needs for tangible resources (e.g., food, clothing, shelter) and the community's provision of emotional support (e.g., family, love, consistency) to promote recovery. These findings provide new insights on SUDs and DSV and preliminary support for the effectiveness of a trauma-informed SLH. PMID- 28085638 TI - Spatial Memory Performance of Socially Mature Wistar Rats is Impaired after Exposure to Low (5 cGy) Doses of 1 GeV/n 48Ti Particles. AB - Prolonged deep space missions to planets and asteroids will expose astronauts to galactic cosmic radiation (GCR), a mixture of low-LET ionizing radiations, high energy protons and high-Z and energy (HZE) particles. Ground-based experiments are used to determine whether this radiation environment will have an effect on the long-term health of astronauts and their ability to complete various tasks during their mission. Emerging data suggest that mission-relevant HZE doses impair several hippocampus-dependent neurocognitive processes in rodents, but that there is substantial interindividual variation in the severity of neurocognitive impairment, ranging from no observable effects to severe impairment. While the majority of studies have established the effect that the most abundant HZE species (56Fe) has on neurocognition, some studies suggest that the lighter 48Ti HZE particles may be equally, if not more, potent at impairing neurocognition. In this study, we assessed the effect that exposure to 5-20 cGy 1 GeV/n 48Ti had on the spatial memory performance of socially mature male Wistar rats. Acute exposures to mission-relevant doses (<=5 cGy) of 1 GeV/n 48Ti significantly (P < 0.05) reduced the mean spatial memory performance of the rats at three months after exposure, and significantly (P < 0.015) increased the percentage of rats that have severe (Z score >= 2) impairment, i.e., poor performers. Collectively, these data further support the notion that the LET dependency of neurocognitive impairment may differ from that of cell killing. PMID- 28085640 TI - Seeking Beta: Experimental Considerations and Theoretical Implications Regarding the Detection of Curvature in Dose-Response Relationships for Chromosome Aberrations. AB - The concept of curvature in dose-response relationships figures prominently in radiation biology, encompassing a wide range of interests including radiation protection, radiotherapy and fundamental models of radiation action. In this context, the ability to detect even small amounts of curvature becomes important. Standard (ST) statistical approaches used for this purpose typically involve least-squares regression, followed by a test on sums of squares. Because we have found that these methods are not particularly robust, we investigated an alternative information theoretic (IT) approach, which involves Poisson regression followed by information-theoretic model selection. Our first objective was to compare the performances of the ST and IT methods by using them to analyze mFISH data on gamma-ray-induced simple interchanges in human lymphocytes, and on Monte Carlo simulated data. Real and simulated data sets that contained small-to moderate curvature were deliberately selected for this exercise. The IT method tended to detect curvature with higher confidence than the ST method. The finding of curvature in the dose response for true simple interchanges is discussed in the context of fundamental models of radiation action. Our second objective was to optimize the design of experiments aimed specifically at detecting curvature. We used Monte Carlo simulation to investigate the following parameters. Constrained by available resources (i.e., the total number of cells to be scored) these include: the optimal number of dose points to use; the best way to apportion the total number of cells among these dose points; and the spacing of dose intervals. Counterintuitively, our simulation results suggest that 4-5 radiation doses were typically optimal, whereas adding more dose points may actually prove detrimental. Superior results were also obtained by implementing unequal dose spacing and unequal distributions in the number of cells scored at each dose. PMID- 28085639 TI - Significant Radiation Enhancement Effects by Gold Nanoparticles in Combination with Cisplatin in Triple Negative Breast Cancer Cells and Tumor Xenografts. AB - Gold nanoparticles (AuNPs) and cisplatin have been explored in concomitant chemoradiotherapy, wherein they elicit their effects by distinct and overlapping mechanisms. Cisplatin is one of the most frequently utilized radiosensitizers in the clinical setting; however, the therapeutic window of cisplatin-aided chemoradiotherapy is limited by its toxicity. The goal of this study was to determine whether AuNPs contribute to improving the treatment response when combined with fractionated cisplatin-based chemoradiation in both in vitro and in vivo models of triple-negative breast cancer (MDA-MB-231Luc+). Cellular-targeting AuNPs with receptor-mediated endocytosis (AuNP-RME) in vitro at a noncytotoxic concentration (0.5 mg/ml) or cisplatin at IC25 (12 MUM) demonstrated dose enhancement factors (DEFs) of 1.25 and 1.14, respectively; the combination of AuNP-RME and cisplatin resulted in a significant DEF of 1.39 in vitro. Transmission electron microscopy (TEM) images showed effective cellular uptake of AuNPs at tumor sites 24 h after intratumoral infusion. Computed tomography (CT) images demonstrated that the intratumoral levels of gold remained stable up to 120 h after infusion. AuNPs (0.5 mg gold per tumor) demonstrated a radiation enhancement effect that was equivalent to three doses of cisplatin at IC25 (4 mg/kg), but did not induce intrinsic toxicity or increased radiotoxicity. Results from this study suggest that AuNPs are the true radiosensitizer in these settings. Importantly, AuNPs enhance the treatment response when combined with cisplatin-based fractionated chemoradiation. This combination of AuNPs and cisplatin provides a promising approach to improving the therapeutic ratio of fractionated radiotherapy. PMID- 28085642 TI - Developmental and interactive effects of arsenic and chromium to developing Ambystoma maculatum embryos: Toxicity, teratogenicity, and whole-body concentrations. AB - Anthropogenic activity has contributed to elevated environmental concentrations of arsenic (As) and chromium (Cr). The spotted salamander, Ambystoma maculatum, may be useful for identifying developmental effects produced by exposure to these contaminants as adults breed and larvae develop in water that may contain As or Cr. Three sample sets among 700 developing larvae were exposed to a range of As, Cr, or 2.5:1 mixture of As:Cr concentrations, respectively. From these 700 larvae, samples containing approximately 24 larvae showed different patterns of whole-body As and Cr from individual and mixture exposure. Whole-body As concentrations were 20.27 and 45.4 ug/g dry weight for larvae exposed to 20 mg/L As and 25:10 mg/L As:Cr, respectively, while whole-body Cr concentrations were 24.8 and 22 ug/g dry weight for larvae exposed to 20 mg/L Cr and 25:10 As:Cr, respectively. Observed malformations included edema, tail kinking, facial deformities, and abnormal bending. Twelve-day lethal concentrations for As and Cr in Ambystoma maculatum larvae were 261.17 mg/L and 71.93 mg/L, respectively, while 12-d effective concentrations to induce malformations were 158.82 and 26.05 mg/L, giving teratogenic indices of 1.64 and 2.76 for individual metal exposure. Exposure to a mixture of As and Cr resulted in a response addition and yielded lower lethal and effective concentration values with a teratogenic index of 2.78, indicating that these contaminants are developmentally toxic at lower concentrations when exposed as a mixture. Data demonstrate that As and Cr affect development of amphibian larvae, and that Ambystoma maculatum may be a useful indicator of environmental toxicity for these metals. PMID- 28085641 TI - Longitudinal changes in anthropometry and body composition in university freshmen. AB - OBJECTIVE: We investigated predictors of weight gain in college freshmen. PARTICIPANTS: A longitudinal cohort study followed a representative sample of freshmen (N = 264) from 8/2011 to 6/2012. METHODS: Repeated measurements of anthropometry, dual-energy X-ray absorptiometry (DXA), physical activity, and diet were collected. We investigated predictors of 9-month weight gain using regression models. RESULTS: 172 participants completed follow-up: 75% gained >0.5 kg. Mean weight change was +2.3 kg (SD 3.2) and +2.0 kg (SD 3.2) and mean adiposity change was +1.3% (SD 1.6) and +0.7% (SD 2.2) in men and women, respectively. In participants gaining >0.5 kg, weight increased 5.6% and body fat increased 1.6%. Anthropometric change in men occurred in the first semester, while women increased in both semesters. Leaner DXA-defined body composition at baseline was consistently associated with greater weight gain (p-values 0.029 0.049). CONCLUSIONS: Freshman weight gain is common and reflects increased adiposity. Leaner body composition at the beginning of college predicted greater weight gain in men and women during the first year of college. PMID- 28085644 TI - Informal Caregiving and the Politics of Policy Drift in the United States. AB - Informal caregivers play an increasingly important role in caring for aging Americans. Yet existing social policies that could support informal caregiving have experienced "policy drift," a failure to adapt to social risks that develop after policies are initially enacted. This article examines policy makers' success at updating seven major policies to address caregiver needs. It draws on an original data set of legislation in this area introduced between 1991 and 2006 (n = 96). Findings indicate that drift is more likely when policy updates are costly, lack support from members of majority parties in the House and Senate, and fail to generate bipartisan support. PMID- 28085643 TI - Presentation of a Conserved Adenoviral Epitope on HLA-C*0702 Allows Evasion of Natural Killer but Not T Cell Responses. AB - Infection with adenovirus is a major cause of infectious mortality in children following hematopoietic stem-cell transplantation. While adoptive transfer of epitope-specific T cells is a particularly effective therapeutic approach, there are few suitable adenoviral peptide epitopes described to date. Here, we describe the adenoviral peptide epitope FRKDVNMVL from hexon protein, and its variant FRKDVNMIL, that is restricted by human leukocyte antigen (HLA)-C*0702. Since HLA C*0702 can be recognized by both T cells and natural killer (NK) cells, we characterized responses by both cell types. T cells specific for FRKDVNMVL were detected in peripheral blood mononuclear cells expanded from eight of ten healthy HLA-typed donors by peptide-HLA multimer staining, and could also be detected by cultured interferon gamma ELISpot assays. Surprisingly, HLA-C*0702 was not downregulated during infection, in contrast to the marked downregulation of HLA A*0201, suggesting that adenovirus cannot evade T cell responses to HLA-C*0702 restricted peptide epitopes. By contrast, NK responses were inhibited following adenoviral peptide presentation. Notably, presentation of the FRKDVNMVL peptide enhanced binding of HLA-C*0702 to the inhibitory receptor KIR2DL3 and decreased NK cytotoxic responses, suggesting that adenoviruses may use this peptide to evade NK responses. Given the immunodominance of FRKDVNMVL-specific T cell responses, apparent lack of HLA-C*0702 downregulation during infection, and the high frequency of this allotype, this peptide epitope may be particularly useful for adoptive T cell transfer therapy of adenovirus infection. PMID- 28085646 TI - Effects of Indoor Pyrotechnic Displays on the Air Quality in the Houston Astrodome. AB - Fine and coarse particulate mass samples were collected during baseball games with pyrotechnic displays and control games without displays. The average fine and coarse particulate masses were 173 and 141 mg/m3, respectively, for the one hour period immediately following the pyrotechnic displays. The particulate matter generated by the pyrotechnic displays was composed of the following elements (arranged from most to least abundant): K, S, Mg,Ti, Cl, Si, Ca, Al, Sr, V, Zn, Mn, and Pb. Although the average particulate mass concentrations were high during the first hour, the ventilation system reduced the concentrations by up to 41% during the second hour after the display. PMID- 28085645 TI - A physiologically based pharmacokinetic model for the broad-spectrum antimicrobial zinc pyrithione: I. Development and verification. AB - The broad-spectrum antimicrobial zinc pyrithione (ZnPT) is used in numerous products ranging from in-can preservative/mildicide in paints to antidandruff shampoo. Although products containing ZnPT have a long history of safe use, regulatory agencies routinely set limits of exposure based upon toxicological considerations. The objective of this study was to create a physiologically based pharmacokinetic (PBPK) model for ZnPT in the rat for improving dose-response analysis of ZnPT-induced toxicity, reversible hindlimb weakness, the endpoint that has been used as the basis for ZnPT risk assessments. A rat oral PBPK model was developed that includes compartments for plasma, liver, kidneys, muscle, brain, and rapidly and slowly perfused tissues. Pyrithione metabolism to 2 (methylsulfonyl)pyridine (MSP) and glucuronide conjugates was incorporated into the model. The model was parameterized and optimized based upon data from single dose intravenous (iv) and oral gavage pharmacokinetic studies of radiolabeled pyrithione ([14C]PT) administered as zinc [14C]-pyrithione (Zn-[14C]PT) to adult female rats. It was further evaluated and refined using data from repeated, multidose oral gavage and dietary studies of Zn[14C]PT in the adult female rat that included measurements of plasma PT concentration, the putative toxic species. The model replicated the observed short-term elimination kinetics of PT in plasma and [14C]PT in whole blood following single doses and longer term temporal patterns of plasma and blood concentrations during repeated dosing schedules. The model also accounted for production and rapid elimination of S glucuronide conjugates (SG) of 2-pyridinethiol and 2-pyridinethiol-1-oxide in urine, as well as production and slower elimination of MSP, the major [14C]PT species in blood within several hours following administration of ZnPT. The model provided internal dosimetry predictions for a benchmark dose (BMD) analysis of hindlimb weakness in rats, and was used to combine gavage and dietary studies into a single internal dose-response model with area under the curve (AUC) for plasma PT as the internal dose metric. This PBPK model has predictive validity for calculating internal doses of PT and/or [14C]PT from different routes of exposure in the rat. PMID- 28085647 TI - Environmental Beneficiation of Machining Wastes-Part I: Material Characterization of Machining Swarf. AB - There are many industrial waste streams that currently are being deposited in landfills despite having the potential to be recycled and converted into useful products. A good example of this is automobile industry machining operations, which generate finely divided metal particles ("swarf"). Swarf has a very high iron content and great potential for re-use. However, it has a tendency to spontaneously oxidize, which leads to self-heating and obstructs recycling efforts. There is a need to limit the self-heating of swarf, but such control is difficult, because little information is available about the physical characteristics of swarf. Hence, the objective of this study was to determine the properties of swarf and to identify promising methods to prevent spontaneous heating. The properties examined were particle morphology, composition, size distribution, and surface properties. PMID- 28085648 TI - Contribution of Nitrate and Carbonaceous Species to PM2.5 Observed in Canadian Cities. AB - At a variety of Canadian monitoring sites, carbonaceous compounds were estimated to account for an average of 50% of fine particle mass. These estimates were determined by subtracting the total fine particle mass associated with inorganic compounds from the total fine mass determined gravimetrically. This approach, which yields an upper limit estimate of the total amount of carbon-related mass was necessary since particulate carbon was not measured in the Canadian National Air Pollution Surveillance (NAPS) network. In this paper, total carbon estimates are evaluated against organic and elemental carbon measurements at locations in the Greater Vancouver area and Toronto. In addition, particle nitrate measurements at seven Canadian locations are used to determine the importance of nitrate relative to total mass and to examine the sampling artifacts due to the loss of particle nitrate from Teflon filters used in the NAPS di-chotomous samplers. Measurements of organic and elemental carbon indicated that the total carbon estimation approach provides representative estimates of the average contribution by carbonaceous material to the total fine and coarse mass. The average total carbon among all Vancouver area measurements (N = 225) was 4.28 MUg m-3, while the estimated value was 4.34 MUg m-3. There was a larger discrepancy between Toronto total carbon measurements (12.1 MUg m-3) and estimates (8.8 MUg m 3), which is attributed in part to sampling of particles above 10 mm in diameter. However, the R2 relating the measurements and estimates was about 0.71 for both areas. Linear regression slopes of 0.98 for Vancouver and 0.78 for Toronto (nonsignificant intercepts) indicate little bias in the Vancouver estimates, but a tendency for underestimation as the observed total carbon concentration increased in Toronto. Annually, nitrate was responsible for 17% and 12% of the fine mass in the Vancouver area and Ontario, respectively. In contrast, at two rural locations in southern Quebec and Nova Scotia, only 6% of fine mass was associated with nitrate. Due to filter losses, nitrate concentrations determined through the NAPS dichot sampling were much lower than actual concentrations (0.44 MUg m-3 vs. 2.63 MUg m-3). As a result of these losses (attributed mostly to loss during laboratory storage), previous total carbon estimates for the Canadian NAPS sites were likely to have been overestimated on average by about 10%. PMID- 28085650 TI - Cleaning Flue Gas from Sewage Sludge Incinerators Using an Electrostatic Precipitator and Polystage Chemical Scrubber. AB - A study of a wet electrostatic precipitator (ESP) and chemical scrubber for flue gas cleaning was conducted on the multiple hearth sewage sludge incinerator at the New England Treatment Company (NETCO) facility in Woonsocket, RI. The ESP achieved the highest removal rate for heavy metals and particulate matter to a submicron range, while the two-stage chemical scrubber was able to oxidize and dissolve the incoming NOx in the scrubbing solutions. This paper describes the details of sewage sludge incineration systems, NOx emissions from a multiple hearth sludge incinerator, and the current regulatory status; it also presents the results obtained from the commercial-scale ESP and the portable scrubber. PMID- 28085649 TI - A High Performance Biofilter for VOC Emission Control. AB - Biofiltration is a cleaning technique for waste air contaminated with some organic compounds. The advantages of the conventional biofilter over other biological systems are a high-superficial area best suited for the treatment of some compounds with poor water solubility, ease of operation, and low operating costs. It has crucial disadvantages, however; for example, it is not suitable to treat waste gases with high VOC concentrations and it has poor control of reaction conditions. To improve on these problems and to build a high-performance biofilter, three structured peat media and two trickling systems have been introduced in this study. The influences of media size and composition have been investigated experimentally. Peat bead blended with 30% (w/w) certain mineral material with a good binding capacity has advantages over other packing materials, for example, suitable size to prevent blockage due to microbial growth, strong buffering capacity to neutralize acidic substances in the system, and a pH range of 7.0-7.2 suitable for the growth of bacteria. Dropwise trickling system offers an effective measure to easily control the moisture content of the bed and the reaction conditions (pH, nutrient) and to partially remove excess biomass produced during the metabolic processes of microorganisms. The influence of nutrient supplementation has also been investigated in this study, which has revealed that the biological system was in a condition of nutrient limitation instead of carbon limitation. The biofilters built in our laboratory were used to treat waste gas contaminated with toluene in a concentration range of 1 to 3.2 g/m3 and at the specific gas flow rate of 24 to120 m3/m2.hr. Under the conditions employed, a high elimination capacity (135 g/m3.hr) was obtained in the biofilter packed with peat beads (blended with 30% of the mineral material), and no blockage problem was observed in an experimental period of 2-3 months. PMID- 28085651 TI - Effects of Outdoor Pyrotechnic Displays on the Regional Air Quality of Western Washington State. AB - Data from a PM25 (i.e., Dp < 2.5 mm) particulate matter monitoring network was used to quantify the effects of outdoor pyrotechnic displays on the regional air quality of western Washington State. Linear regression and principal component analysis demonstrated that the fine par-ticulate matter generated by these displays was primarily composed of Sr, K, V, Ti, Ba, Cu, Pb, Mg, Al, S, Mn, Zn,and soot. The maximum 24-hour averaged PM2.5 mass concentration apportioned to the pyrotechnic displays by absolute principal component scores regression analysis was 18.5 mg/m3. The majority of this mass (54%) was composed of K and S, which originated from the combustion of black powder. The distribution of smoke emissions from the displays closely resembled the population distribution of western Washington. The PM2.5 aerosol monitoring network tracked the pyrotechnic smoke plume for a period of two days as it was advected by low-level winds. The geometric mass mean diameter of the K particles was ~0.7 mm after transport of ~100 km. In the absence of rain, which is the primary sink for particles of this size, the particulate matter generated by the pyrotechnic displays could have an atmospheric residence time of more than one week. PMID- 28085652 TI - Residual Perchloroethylene in Dry-Cleaned Acetate: The Effect of Pressing and Extent of Inter-Dry-Cleaner Variability. AB - Measurements of residual perchloroethylene (PCE), a dry-cleaning solvent associated with human health effects, were made in dry-cleaned acetate cloth to enable improved characterizations of both occupational and environmental exposure. A limited sample size (25 acetate cloths) was used to explore the extent of inter-dry-cleaner variability in residual PCE and to characterize the effect of the pressing operation on residual PCE. A new method, which uses carbon disulfide as the direct extracting agent, proved effective in the analysis of residual PCE, with a recovery-efficiency ~ 75%. Inter-dry-cleaner variability of residual PCE, although marginally statistically significant, was relatively low, showing only a fourfold range compared to a 5-order-of-magnitude range obtained from Kawauchi and Nishiyama1. Pairwise comparison of residual PCE in nonpressed versus pressed acetate samples revealed a statistically significant reduction (p < 0.008), which amounted to a consistent (among dry-cleaners) pressing-related removal efficiency of 75 +/- 4%. A preliminary assessment of the source term associated with the pressing operation (mass PCE liberated per kg cloth dry cleaned, SPCE ~ 30 mg/kg) indicates a minor contribution to the average ambient air concentrations within dry-cleaning establishments. PMID- 28085653 TI - Peroxyacetyl Nitrate in Atlanta, Georgia: Comparison and Analysis of Ambient Data for Suburban and Downtown Locations. AB - Peroxyacetyl nitrate (PAN) concentrations were measured at downtown and suburban locations in Atlanta, GA, in July and August 1992 as part of the SOS-SORP/ONA (Southern Oxidants Study-Southern Oxidants Research Program on Ozone Non Attainment). PAN concentrations were generally higher at the downtown location than at the suburban location, but on days when the O3 concentration exceeded 80 ppbv, PAN concentrations were similar at both locations. On days when O3 did not exceed 80 ppbv, suburban PAN concentrations were much lower than downtown concentrations and resembled those reported for rural areas in the eastern United States. Regression analysis of PAN and O3 on NOx and total non-methane hydrocarbons (TNMHC) showed PAN to be most strongly dependent on morning NOx concentrations, while O3 was most dependent on morning TNMHC concentrations. NOx, PAN, and meteorological data from the suburban site were used in a one dimensional transport model to estimate the accumulation rate of PAN to be ~1.5 x 106 molecules cm-3 sec-1. A simple kinetic model estimated peroxyacetyl radical concentrations to be ~0.5 pptv at the suburban location. PMID- 28085654 TI - Application of the Shifting Method as a Technique to Correct for the Background in Quantitative Analysis by Open-Path FTIR. AB - In open-path Fourier Transform Infrared spectroscopy, the generation of a suitable background single-beam spectrum is of major concern. The Shifting Method is a derivative-like approach to correct for the background without the need to actually measure a background spectrum using the sample single-beam spectrum. A thorough study of the Shifting Method was conducted. A set of guidelines was developed based on the results of artificial and closed cell data. These guidelines were applied to three different data sets, consisting of cell and open path data with multiple compounds, overlapping peaks, and high water vapor and aerosol levels. PMID- 28085655 TI - A Fuel-Based Approach to Estimating Motor Vehicle Cold-Start Emissions. AB - The temporary ineffectiveness of motor vehicle emission controls at startup causes emission rates to be much higher for a short period after starting than during fully warmed, or stabilized, vehicle operation. Official motor vehicle emission inventories estimate that excess emissions during cold-start operation contribute a significant fraction of all hydrocarbon, carbon monoxide (CO), and nitrogen oxide (NOx) emissions from California vehicles. In an effort to verify these estimates under real-world conditions, vehicle emissions were measured in an underground parking garage in Oakland, CA, during March 1997. Hot stabilized emissions were measured as vehicles arrived at the garage in the morning, and cold-start emissions were measured as vehicles exited in the afternoon; the incremental, or excess, emissions associated with vehicle starting were calculated by difference. Composite emissions from ~135 vehicles were sampled during each of six morning and six afternoon periods. Measured stabilized exhaust emissions were 19 +/- 2 g nonmethane hydrocarbons (NMHC), 223 +/- 17 g CO, and 8.6 +/- 1.3 g NOx per gal of gasoline consumed. Cold-start emissions of 69 +/- 2 g NMHC/gal, 660 +/- 15 g CO/gal, and 27.8 +/- 1.2 g NOx/gal were measured for vehicles spending an average of ~60 sec in the garage after starting in the afternoon. Using second-by-second emissions data from California's light-duty vehicle surveillance program, average fuel use during cold start was estimated to be ~0.07 gal, and the cold-start period was estimated to last for ~200 sec. When cold-start emission factors measured in the garage were scaled to represent the full 200-sec cold-start period, incremental start emission factors of 2.1 g NMHC, 16 g CO, and 2.1 g NOx per vehicle start were calculated. These emission factors are lower than those used by California's motor vehicle emission inventory model (MVEI 7G) by 45% for NMHC, 65% for CO, and 12% for NOx. This suggests that the importance of cold-start emissions may be overstated in current emission inventories. Overall, the composition of volatile organic compound (VOC) emissions measured during cold start was similar to that of hot stabilized VOC emissions. However, the weight fractions of unburned fuel and acetylene were higher during cold start than during hot stabilized driving. PMID- 28085656 TI - Radio Frequency Heating for Soil Remediation. AB - Radio frequency heating (RFH) is a technology that increases the cost effectiveness of a variety of site remediation technologies by accelerating the rate of contaminant removal. Heating makes the physical, chemical, and biological properties of materials such as contaminants, soil, and groundwater more amenable to remediation. RFH brings controlled heating to the subsurface, enhancing the removal of contaminants by soil vapor extraction (SVE), groundwater aeration (air sparging), bioremediation, and product recovery. The results presented are from a bench-scale study and a field demonstration that both used RFH to enhance the performance of SVE. The bench-scale study performed on PCE-contaminated soil revealed an increase, by a factor of 8, in the removal rate when RFH was used to heat soil to 90 degrees C. The application of RFH for a three-week period at a former gasoline station near St. Paul, MN, resulted in raising the ambient soil temperature from 8 degrees C to 100 degrees C in the immediate vicinity of the RFH applicator and to 40 degrees C 1.5 m (5 ft) away. Most significantly, the use of an integrated RFH/SVE system achieved an overall 50% reduction in gasoline range organics (GRO) in soil over a two- to three-month period. The discussion includes applications of RFH for enhancing bioremediation and product recovery. PMID- 28085657 TI - Economic Study of the Tunable Electron Beam Plasma Reactor for Volatile Organic Compound Treatment. AB - A tunable electron beam generated plasma system has been developed for selective cold plasma treatment of dilute concentrations (1-3,000 ppm range) of hazardous compounds in gaseous waste treatment. This system, referred to as the Tunable Hybrid Plasma (THP), has shown a high degree of efficiency and effectiveness in both laboratory and field tests. Decomposition energy requirements are in the 100 eV per molecule range for treatment of carbon tetrachloride and 10 eV for treatment of trichloroethylene. A cost comparison has been made between the Tunable Hybrid Plasma (THP) technology and three conventional technologies used for emission control of volatile organic compounds (VOCs): granular activated carbon, thermal incineration, and catalytic oxidation. In addition to its environmentally attractive features, THP technology has the potential to be lower cost than other technologies over a range of concentrations and flow rates. Cost projections for the THP system for decomposition of trichloroet-hylene are around 50 cents/lb for initial concentrations in the few hundred ppm range and flow rates of 5,000 cfm or greater and around $1/lb for 1,000 cfm flow rates. Cost projections for carbon tetrachloride and trichloroethane decomposition using the THP technology are several dollars per pound. The costs for THP treatment are generally significantly lower than costs for use of granular activated carbon and are also quite competitive with costs for thermal incineration and catalytic oxidation. PMID- 28085658 TI - Metal Emissions from Joule-Heated Vitrification Systems. AB - Vitrification demonstrations were conducted for surrogates of three inorganic wastewater sludges in a high-temperature, refractory-lined, slurry-fed melter. The total par-ticulate concentrations and melter decontamination factors were determined for selected elements. The decontamination factors were less than 10 for cadmium and lead in all three demonstrations. The decontamination factors for chromium were less than 30 in the two demonstrations using refractories containing chromium, and they were greater than 150 for the demonstrations using refractories without chromium. Except for one demonstration on a surrogate waste with a high sulfate content, decontamination factors were above 80 for the other heavy metals in the demonstrations. PMID- 28085660 TI - Airborne Particulate Matter Size Distributions in an Arid Urban Area. AB - While there is a growing body of data on the health effects of particulate matter, there is little information available from areas that experience frequent dust storms, such as Spokane, WA. As part of a three-year study to investigate the health effects associated with exposure to atmospheric aerosols, ambient particulate matter in Spokane is being characterized according to particle size and chemical composition. In this report, particulate matter concentrations measured using continuous tapered-element oscillating microbalances for three size ranges are discussed. Particles with aerodynamic diameters less than 10 micrometers (PM10), less than 2.5 micrometers (PM25), and less than 1.0 micrometer (PM1.0) were measured at a residential site; PM10 and PM2.5 were measured at an industrial site. Based upon 1.5 years of data, PM10 was found, on average, to consist of approximately 40% PM2.5 at the industrial site and approximately 50% at the residential site, with higher fractions (up to 50% at the industrial site and up to 80% at the residential site) observed in the late fall or early winter (October-November). At the residential site, PM25 was comprised of approximately 80% particles 1.0 micrometer and smaller. Only one windblown dust storm occurred during the sampling period, on July 24, 1994, during which both PM10 and PM2.5 concentrations were enhanced. PMID- 28085661 TI - Characteristics of university students who mix alcohol and energy drinks. AB - OBJECTIVE: Research has identified correlates (eg, drug use, risky sex, smoking) of using alcohol mixed with energy drinks (AMEDs). Few studies have investigated common mental health-related concerns (eg, depression, sleep). PARTICIPANTS: Alcohol-using college students (n = 380 never used AMEDs, n = 180 used AMEDs) were recruited in the study during the fall 2011 semester. METHODS: The study examined demographics, substance use, depressive symptoms, and sleep problems in association with AMED use. RESULTS: Multivariable logistic regression indicated that alcohol use severity (AOR = 1.24; 95% CI = 1.14+1.34), drug use severity (AOR = 1.20; 95% CI = 1.04-1.39), depressive symptoms (AOR = 1.06; 95% CI = 1.01 1.12), and smoking (AOR = 2.12; 95% CI = 1.22-3.68) were independently associated with AMED use; sleep problems were non-significant. CONCLUSIONS: Administrators may consider policies regarding energy drink availability on campus, and campus health personnel may increase screening and education surrounding AMED use to reduce risks among students. PMID- 28085663 TI - How to make plasmapheresis more efficient: a study model: Naples, 29 May 2015. PMID- 28085662 TI - 17th International Haemovigilance Seminar: Paris (France), 9-11 March 2016. PMID- 28085664 TI - XXIV National Congress of the Italian Society for Thrombosis and Hemostasis - SISET: Abano Terme (PD), Italy 9-12 November 2016. PMID- 28085665 TI - Impaired retrograde transport of axonal autophagosomes contributes to autophagic stress in Alzheimer's disease neurons. AB - Neurons face unique challenges of transporting nascent autophagic vacuoles (AVs) from distal axons toward the soma, where mature lysosomes are mainly located. Autophagy defects have been linked to Alzheimer's disease (AD). However, the mechanisms underlying altered autophagy remain unknown. Here, we demonstrate that defective retrograde transport contributes to autophagic stress in AD axons. Amphisomes predominantly accumulate at axonal terminals of mutant hAPP mice and AD patient brains. Amyloid-beta (Abeta) oligomers associate with AVs in AD axons and interact with dynein motors. This interaction impairs dynein recruitment to amphisomes through competitive interruption of dynein-Snapin motor-adaptor coupling, thus immobilizing them in distal axons. Consistently, deletion of Snapin in mice causes AD-like axonal autophagic stress, whereas overexpressing Snapin in hAPP neurons reduces autophagic accumulation at presynaptic terminals by enhancing AV retrograde transport. Altogether, our study provides new mechanistic insight into AD-associated autophagic stress, thus establishing a foundation for ameliorating axonal pathology in AD. PMID- 28085667 TI - Proliferation-independent regulation of organ size by Fgf/Notch signaling. AB - Organ morphogenesis depends on the precise orchestration of cell migration, cell shape changes and cell adhesion. We demonstrate that Notch signaling is an integral part of the Wnt and Fgf signaling feedback loop coordinating cell migration and the self-organization of rosette-shaped sensory organs in the zebrafish lateral line system. We show that Notch signaling acts downstream of Fgf signaling to not only inhibit hair cell differentiation but also to induce and maintain stable epithelial rosettes. Ectopic Notch expression causes a significant increase in organ size independently of proliferation and the Hippo pathway. Transplantation and RNASeq analyses revealed that Notch signaling induces apical junctional complex genes that regulate cell adhesion and apical constriction. Our analysis also demonstrates that in the absence of patterning cues normally provided by a Wnt/Fgf signaling system, rosettes still self organize in the presence of Notch signaling. PMID- 28085668 TI - Zero-fragment Nephrolithotomy: A Multi-center Evaluation of Robotic Pyelolithotomy and Nephrolithotomy for Treating Renal Stones. AB - BACKGROUND: Robotic pyelolithotomy (RPL) and robotic nephrolithotomy (RNL) may be utilized for treating kidney stones as an alternative to percutaneous nephrolithotomy or flexible ureteroscopy. OBJECTIVE: To describe the techniques of RPL and RNL, and present multi-center outcome data for patients undergoing these procedures. DESIGN, SETTING, AND PARTICIPANTS: This study was a retrospective analysis of 27 patients undergoing RPL and RNL at five tertiary academic institutions between 2008 and 2014. SURGICAL PROCEDURE: RPL and RNL without use of renal ischemia. MEASUREMENTS: We assessed stone clearance by visual assessment and postoperative imaging. We also examined other factors, including complications (Clavien grade), estimated blood loss, operative time, and length of stay. RESULTS AND LIMITATIONS: Twenty-seven patients underwent 28 procedures for a mean renal stone size of 2.74cm (standard deviation: 1.4, range: 0.8-5.8). The mean stone volume was 10.2cm3. RPL accounted for 26 of these procedures. RNL was performed in one patient, while another underwent combined RPL-RNL. Indications included failed previous endourological management (13), staghorn calculi (five), gas containing stone (one), calyceal diverticulum (one), complex urinary tract reconstruction (two), and patient preference (four). The mean patient age was 35.6 yr and mean body mass index was 25.5kg/m2. Mean operative time/console times were 182min and 128min, respectively. The mean estimated blood loss was 38ml. The mean length of stay was 1.7 d. There was no significant change in preoperative and postoperative serum creatinine levels. The overall complication rate was 18.5% (Clavien 1=3.7%; 2=7.4%; 3b=7.4%). The complete stone-free rate was 96%. CONCLUSIONS: RPL and RNL are safe and reasonable options for removing renal stones in select patients. In particular, RPL allows the removal of stones without transgressing the parenchyma, reducing potential bleeding and nephron loss. PATIENT SUMMARY: The robotic approach allows for complete removal of the renal stone without fragmentation, thereby maximizing chances for complete stone clearance in one procedure. PMID- 28085669 TI - Adjuvant Treatment of High-risk Renal Cell Carcinoma: Leaving the Desert? AB - In a recent trial, adjuvant treatment with sunitinib significantly prolonged disease-free survival compared to placebo. This positive result is muted by the rate of side effects and overtreatment, raising the question of proper patient and agent selection in the adjuvant setting. PMID- 28085670 TI - When, how and why? Regulated proteolysis by the essential FtsH protease in Escherichia coli. AB - Cellular proteomes are dynamic and adjusted to permanently changing conditions by ATP-fueled proteolytic machineries. Among the five AAA+ proteases in Escherichia coli FtsH is the only essential and membrane-anchored metalloprotease. FtsH is a homohexamer that uses its ATPase domain to unfold and translocate substrates that are subsequently degraded without the need of ATP in the proteolytic chamber of the protease domain. FtsH eliminates misfolded proteins in the context of general quality control and properly folded proteins for regulatory reasons. Recent trapping approaches have revealed a number of novel FtsH substrates. This review summarizes the substrate diversity of FtsH and presents details on the surprisingly diverse recognition principles of three well-characterized substrates: LpxC, the key enzyme of lipopolysaccharide biosynthesis; RpoH, the alternative heat-shock sigma factor and YfgM, a bifunctional membrane protein implicated in periplasmic chaperone functions and cytoplasmic stress adaptation. PMID- 28085666 TI - NADPH oxidase-mediated redox signaling promotes oxidative stress resistance and longevity through memo-1 in C. elegans. AB - Transient increases in mitochondrially-derived reactive oxygen species (ROS) activate an adaptive stress response to promote longevity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases produce ROS locally in response to various stimuli, and thereby regulate many cellular processes, but their role in aging remains unexplored. Here, we identified the C. elegans orthologue of mammalian mediator of ErbB2-driven cell motility, MEMO-1, as a protein that inhibits BLI-3/NADPH oxidase. MEMO-1 is complexed with RHO-1/RhoA/GTPase and loss of memo-1 results in an enhanced interaction of RHO-1 with BLI-3/NADPH oxidase, thereby stimulating ROS production that signal via p38 MAP kinase to the transcription factor SKN-1/NRF1,2,3 to promote stress resistance and longevity. Either loss of memo-1 or increasing BLI-3/NADPH oxidase activity by overexpression is sufficient to increase lifespan. Together, these findings demonstrate that NADPH oxidase-induced redox signaling initiates a transcriptional response that protects the cell and organism, and can promote both stress resistance and longevity. PMID- 28085671 TI - Exercise-induced effects on UCP1 expression in classical brown adipose tissue: a systematic review. AB - Understanding the impact of regular exercise training on uncoupling protein 1 (UCP1) activity in classical brown adipose tissue (CBAT) is vital to our knowledge of whole-body thermogenic activity. The purpose of this systematic review was to evaluate the available experimental evidence on the effect of regular exercise training on UCP1 expression in CBAT. We performed a literature search using PubMed (1966-2016), Scopus, and EMBASE (1974-2016). Studies in any language that examined the effect of regular exercise training on UCP1 expression in CBAT, and not white adipose tissue (WAT), were eligible. Reviews, editorials, and conference proceedings were excluded. Nine studies fulfilled the set criteria. Risk of bias was assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. The quality of reporting the results in the included studies was assessed using the 38-item checklist of the Animal Research Reporting of In Vivo Experiments (ARRIVE). Based on the evidence available and a comprehensive analysis of different confounding factors, we conclude that regular exercise training does not represent a major stimulus of UCP1 expression in CBAT. However, regular exercise training may induce adaptive responses to CBAT thermogenic activity in cases where: (i) animals consume a high fat diet, (ii) exercise is combined with cold exposure, and (iii) animals show endogenously low UCP1 levels. Finally, it is important to note an inconsistency in the results from the analysed studies, which may be attributed to a number of confounding factors, increased risk of bias, as well as low quality of reporting the results. PMID- 28085672 TI - Seven cases with Williams-Beuren syndrome: endocrine evaluation and long-term follow-up. AB - BACKGROUND: Endocrine evaluation and long-term follow-up of seven (six male) patients with Williams-Beuren syndrome (WBS) are given. METHOD: Data were obtained from patients' medical records. All patients underwent hormonal analyses and four of them underwent oral glucose tolerance test (OGTT). RESULTS: They all had mild hypercalcemia. Three of them had overt hypothyroidism while subclinical hypothyroidism was detected in three patients. Four patients had thyroid hypoplasia and one had thyroid agenesis. Growth hormone deficiency (GHD) was determined in one patient. Impaired glucose tolerance (IGT) was found in three adolescents. All adolescents had early-onset puberty. The follow-up duration was 5.7+/-2.1 years. The mean growth velocity (GV) was 12.9+/-7.2 cm and 7.6+/-2 cm at the end of the first and second years of therapy, respectively. All patients had neurodevelopment retardation and were continuing to special education. CONCLUSIONS: Thyroid hypoplasia is common and agenesis can be seen in patients with WBS; therefore, thyroid hormones should be measured in the newborn period and annually. GHD should be kept in mind in patients with decreased GV. IGT might be detected in patients with WBS even in adolescence. PMID- 28085673 TI - Total body fat, abdominal fat, body fat distribution and surrogate markers for health related to adipocyte fatty acid-binding protein (FABP4) in children. AB - BACKGROUND: The aim of the study was to assess possible relationships between adipocyte fatty acid-binding protein (FABP4) and total body fat (TBF), abdominal fat, body fat distribution, aerobic fitness, blood pressure, cardiac dimensions and the increase in body fat over 2 years in a community sample of children. METHODS: A cross-sectional study was used in a community sample of 170 (92 boys and 78 girls) children aged 8-11 years. TBF and abdominal fat (AFM) were measured by dual-energy X-ray absorptiometry (DXA). TBF was also expressed as percentage of total body mass (BF%), and body fat distribution was calculated as AFM/TBF. Maximal oxygen uptake (VO2PEAK) was assessed by indirect calorimetry during a maximal exercise test and scaled to body mass. Systolic and diastolic blood pressure (SBP and DBP) and pulse pressure (PP) were measured. Echocardiography was performed. Left atrial (LA) size was measured, and left ventricular mass (LVM) was calculated. A follow-up DXA scan was available in 152 children (84 boys and 68 girls). Frozen serum samples were analyzed for FABP4. RESULTS: Partial correlations, with adjustment for sex, between FABP4 vs. ln TBF, ln BF%, ln AFM, AFM/TBF and VO2PEAK were (r=0.69, 0.68, 0.69, 0.49 and -0.39, p<0.05 for all). Moreover, SBP, PP, LVM and LA were also weakly correlated with FABP4 (r=0.23, 0.22, 0.28 and 0.21, p<0.05 for all). Correlations between FABP4 vs. increase in TBF and AFM over 2 years were 0.29 and 0.26, p<0.05, for both. (Increase in percent body fat or change in fat distribution were not correlated.) Conclusions: Findings from this community-based cohort of young children show that increased body fat and abdominal fat, more abdominal body fat distribution, low fitness, more LVM and increased LA, increased SBP and PP were all associated with increased levels of FABP4. Increase in TBF and abdominal fat over 2 years were also associated with increased levels of FABP4. PMID- 28085674 TI - An ignored cause of red urine in children: rhabdomyolysis due to carnitine palmitoyltransferase II (CPT-II) deficiency. AB - Carnitine palmitoyltransferase II (CPT-II) deficiency is an autosomal recessively inherited disorder involving the beta-oxidation of long-chain fatty acids, which leads to rhabdomyolysis and subsequent acute renal failure. The clinical phenotype varies from a severe infantile form to a milder muscle form. Here, we report a 9-year-old boy referred to our hospital for the investigation of hematuria with a 2-day history of dark urine and malaise. As no erythrocytes in the microscopic examination of the urine and hemoglobinuria were present, myoglobinuria due to rhabdomyolysis was the most probable cause of dark urine. After excluding the other causes of rhabdomyolysis, with the help of metabolic investigations, the patient was suspected to have CPT-II deficiency, the most common cause of metabolic rhabdomyolysis. Our aim in presenting this case is to emphasize considering rhabdomyolysis in the differential diagnosis of dark urine in order to prevent recurrent rhabdomyolysis and renal injury. PMID- 28085675 TI - Glycogen storage disease type IX and growth hormone deficiency presenting as severe ketotic hypoglycemia. AB - BACKGROUND: Glycogen storage disease (GSD) type IX and growth hormone (GH) deficiency cause ketotic hypoglycemia via different mechanisms and are not known to be associated. We describe a patient presenting with severe ketotic hypoglycemia found to have both GSD IX and isolated GH deficiency. CASE PRESENTATION: A 3-year-and-11-month-old boy with a history of prematurity, autism, developmental delay, seizures, and feeding difficulty was admitted for poor weight gain and symptomatic hypoglycemia. He was nondysmorphic, with a height of 93.8 cm (2%, -1.97 SDS), and has no hepatomegaly. He developed symptomatic hypoglycemia, with a serum glucose level of 37 mg/dL after 14 h of fasting challenge. Critical sample showed a GH of 0.24 ng/mL. GH provocative stimulation testing was done with a peak GH of 2.8 ng/mL. Brain magnetic resonance imaging showed a hypoplastic pituitary gland. Given the clinical symptoms, suspicion for mitochondrial disease was high. Dual Genome Panel by Massively Parallel Sequencing revealed a hemizygous variant c.721A>G (p1241V) in the X-linked PHKA2 gene, a causative gene for GSD IX. Red blood cell PhK enzyme activity testing was low, supporting the diagnosis. CONCLUSIONS: Given the patient's developmental delays that were not explained by GH deficiency alone, further investigation showed two unrelated conditions resulting in deranged metabolic adaptation to fasting leading to severe hypoglycemia. PMID- 28085676 TI - Growth-hormone deficiency in mitochondrial disorders. PMID- 28085677 TI - The thalamus as a relay station and gatekeeper: relevance to brain disorders. AB - Here, we provide a review of behavioural, cognitive, and neural studies of the thalamus, including its role in attention, consciousness, sleep, and motor processes. We further discuss neuropsychological and brain disorders associated with thalamus function, including Parkinson's disease, Alzheimer's disease, Korsakoff's syndrome, and sleep disorders. Importantly, we highlight how thalamus related processes and disorders can be explained by the role of the thalamus as a relay station. PMID- 28085678 TI - Combining in silico evolution and nonlinear dimensionality reduction to redesign responses of signaling networks. AB - The rational design of network behavior is a central goal of synthetic biology. Here, we combine in silico evolution with nonlinear dimensionality reduction to redesign the responses of fixed-topology signaling networks and to characterize sets of kinetic parameters that underlie various input-output relations. We first consider the earliest part of the T cell receptor (TCR) signaling network and demonstrate that it can produce a variety of input-output relations (quantified as the level of TCR phosphorylation as a function of the characteristic TCR binding time). We utilize an evolutionary algorithm (EA) to identify sets of kinetic parameters that give rise to: (i) sigmoidal responses with the activation threshold varied over 6 orders of magnitude, (ii) a graded response, and (iii) an inverted response in which short TCR binding times lead to activation. We also consider a network with both positive and negative feedback and use the EA to evolve oscillatory responses with different periods in response to a change in input. For each targeted input-output relation, we conduct many independent runs of the EA and use nonlinear dimensionality reduction to embed the resulting data for each network in two dimensions. We then partition the results into groups and characterize constraints placed on the parameters by the different targeted response curves. Our approach provides a way (i) to guide the design of kinetic parameters of fixed-topology networks to generate novel input-output relations and (ii) to constrain ranges of biological parameters using experimental data. In the cases considered, the network topologies exhibit significant flexibility in generating alternative responses, with distinct patterns of kinetic rates emerging for different targeted responses. PMID- 28085679 TI - Radiotherapy in combination with immune checkpoint inhibitors. AB - PURPOSE OF REVIEW: The immunomodulatory effects of ionizing radiation have long been recognized; however, so far these have not been fully exploited in clinical practice. We review the rationale to combine radiation with immune checkpoint inhibitors, which are used in standard practice. RECENT FINDINGS: Preclinical research suggests a synergy between radiotherapy and these immune checkpoint inhibitors. Whether or not this benefit translates into a clinical benefit is currently subject of ongoing research. SUMMARY: It is highly rational to combine radiation with immune therapy as in preclinical models and in proof of concept trials in humans it clearly can increase the antitumor immunity when given together with other immune interventions. PMID- 28085680 TI - Can we define the optimal sequence of epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of epidermal growth factor receptor-mutant nonsmall cell lung cancer? AB - PURPOSE OF REVIEW: The most common mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is acquisition of the T790M gatekeeper mutation. Third-generation EGFR TKIs irreversibly inhibit EGFR mutants (EGFRm), especially T790M, while sparing wild-type EGFR. There are several third-generation EGFR TKIs under development, including osimertinib, CO 1686 (rociletinib), HM61713 (olmutinib), ASP8273, and EGF816. These third generation EGFR TKIs have shown promising efficacy with favorable toxicity profiles in the management of advanced nonsmall cell lung cancer (NSCLC) with an acquired T790M mutation (EGFR). In the present review, we will discuss the evolving treatment landscape of EGFRm NSCLC. RECENT FINDINGS: The LUX-Lung 7 study demonstrated superior progression-free survival, time-to-treatment failure, and objective response rate with afatinib versus gefitinib, but no significant overall survival improvement in TKI-naive EGFRm NSCLC patients. In EGFRm NSCLC patients harboring T790M after treatment with first-generation or second generation EGFR TKIs, third-generation EGFR TKIs showed robust efficacy with tolerable toxicity. The updated results of phase I studies have demonstrated encouraging activity of first-line osimertinib in patients with EGFRm NSCLC. SUMMARY: Following progression with first-generation or second-generation EGFR TKIs, osimertinib was recently approved for the treatment of EGFR NSCLC. Encouraging early results with osimertinib have sparked interest in first-line treatment of EGFRm NSCLC, and head-to-head comparison studies of third-generation versus first-generation EGFR TKIs are being developed. PMID- 28085681 TI - Basal Ganglion Hemorrhage as Delayed Complication of Diethylene Glycol Ingestion. AB - Diethylene glycol (DEG), an organic compound (HOCH2CH2)2O is a commonly used solvent. Mass poisoning outbreaks have been reported because of frequent contaminations. A PubMed search for diethylene resulted in 795 publications with 151 specifically discussing the toxicity. Of the 151 reported toxicity reviews/case reports, only 6 publications discussed the long-term neurological effects of diethylene toxicity. We report a fatal case of oral ingestion of DEG with complications from delayed toxicity. She died 7 days after the second admission. Autopsy disclosed a right basal ganglia hemorrhage within the brain and microscopic deposits of polarizable crystals into small cerebral blood vessels. Both kidneys illustrate tubular necrosis with scattered tubular deposition of polarizable calcium oxalate crystals. PubMed search leads to only 2 reported cases of basal ganglia hemorrhage (based on radiological findings) after ethylene glycol intoxication. Our case is the first reportable case of basal ganglia hemorrhage after DEG ingestion. PMID- 28085682 TI - Prophylaxis of Venous Thrombosis in Neurocritical Care Patients: An Executive Summary of Evidence-Based Guidelines: A Statement for Healthcare Professionals From the Neurocritical Care Society and Society of Critical Care Medicine. PMID- 28085683 TI - Oxygen saturation targeting by pulse oximetry in the extremely low gestational age neonate: a quixotic quest. AB - PURPOSE OF REVIEW: A collaboration of comparative effectiveness research trials of pulse oximeter saturation (SpO2) targeting in extremely low-gestational-age neonates have begun to report their aggregate results. We examine the results of those trials, collectively referred to as the Neonatal Oxygenation Prospective Meta-analysis or NeOProM. We also discuss the uncertainties that remain and the clinical challenges that lie ahead. RECENT FINDINGS: The primary outcome from NeOProM was a composite of death or disability at 18-24 months corrected age. In 2016 the last of these reports was published. Although there were no differences in the primary outcome overall, analyses of secondary outcomes and data subsets following a pulse oximeter revision show significant treatment differences between targeting a lower compared with a higher SpO2. SUMMARY: NeOProM represents the largest collaborative clinical research study of SpO2 targets in extremely low-gestational-age neonates. Although aggregate results give us some insight into the feasibility and efficacy of SpO2 targeting in this population, many questions remain. A patient-level analysis, tracking individual outcomes based on actual SpO2 experienced, may shed some light on these questions. However, finding a single optimal SpO2 range seems unlikely. PMID- 28085684 TI - Continuous noninvasive monitoring in the neonatal ICU. AB - PURPOSE OF REVIEW: Standard hemodynamic monitoring such as heart rate and systemic blood pressure may only provide a crude estimation of organ perfusion during neonatal intensive care. Pulse oximetry monitoring allows for continuous noninvasive monitoring of hemoglobin oxygenation and thus provides estimation of end-organ oxygenation. This review aims to provide an overview of pulse oximetry and discuss its current and potential clinical use during neonatal intensive care. RECENT FINDINGS: Technological advances in continuous assessment of dynamic changes in systemic oxygenation with pulse oximetry during transition to extrauterine life and beyond provide additional details about physiological interactions among the key hemodynamic factors regulating systemic blood flow distribution along with the subtle changes that are frequently transient and undetectable with standard monitoring. SUMMARY: Noninvasive real-time continuous systemic oxygen monitoring has the potential to serve as biomarkers for early organ dysfunction, to predict adverse short-term and long-term outcomes in critically ill neonates, and to optimize outcomes. Further studies are needed to establish values predicting adverse outcomes and to validate targeted interventions to normalize abnormal values to improve outcomes. PMID- 28085685 TI - CE: Improving Outcomes for Patients with Chronic Kidney Disease: Part 1. AB - : The burden of chronic kidney disease (CKD) is rising both in this country and worldwide. An estimated 10% to 15% of U.S. adults are currently living with CKD. Reducing the CKD burden requires a systematic, interdisciplinary approach to care. The greatest opportunities to reduce the impact of CKD arise early, when most patients are being followed in primary care; yet many clinicians are inadequately educated on this disease. Nurses are well positioned to facilitate the implementation of collaborative care. This two-part article aims to provide nurses with the basic information necessary to assess and manage patients with CKD. Part 1 offers an overview of the disease, describes identification and etiology, and discusses ways to slow disease progression. Part 2, which will appear next month, addresses disease complications and treatment of kidney failure. PMID- 28085686 TI - CE: Nursing's Evolving Role in Patient Safety. AB - : : Background: In its 1999 report To Err Is Human: Building a Safer Health System, the Institute of Medicine (IOM) suggested that between 44,000 and 98,000 Americans die annually as a result of medical errors. The report urged health care institutions to break the silence surrounding such errors and to implement changes that would promote a culture of safety. OBJECTIVE: Our aim in conducting this content analysis of AJN articles was to explore the nurse's historical and contemporary role in promoting patient safety. We chose to focus on AJN because, as the oldest continuously published nursing journal, it provided a unique opportunity for us to view trends in nursing practice over more than 100 years. METHODS: We reviewed all AJN tables of contents from 1900 through 2015, identifying for inclusion articles with titles that suggested a focus on nursing care, patient safety, or clinical content. We then read and analyzed each of the final 1,086 articles over a period of nine months. FINDINGS: Our content analysis indicates that the early articles (from 1900 through 1920) focused on such safety measures as asepsis and the newly understood germ theory. In the 1930s, articles proposed methods for preventing medication errors and encouraged the development of written procedures to standardize care. During World War II, nurse authors identified improved patient survival rates with the use of "shock wards" and recovery rooms. The 1950s saw the emergence of progressive patient care initiatives, through which patients were assigned to various levels of care (intensive, intermediate, self, long-term, or home care) based on patient acuity. The 1960s brought increasingly complex equipment and medication regimens, which created safety problems. Hospital-acquired infections were recognized. Unit-dose medication was instituted in the 1970s. In the next two decades, medication and nursing-procedure safety were emphasized. From 2000 to 2015, articles looked beyond human performance as causes of health care errors to systemic factors, such as poor communication, patient-nurse ratios, provider skill mix, disruptive or inappropriate provider behavior, shift work, and long working hours. CONCLUSIONS: Emphasis on patient safety increased as patient care became more complex. As nurses developed a professional identity, they often put a spotlight on safety concerns and solutions. The IOM report, which encouraged research focused on systemic solutions to errors, was instrumental in furthering the very culture of safety that the nursing profession had championed. PMID- 28085687 TI - Length of Recovery From Sports-Related Concussions in Pediatric Patients Treated at Concussion Clinics. AB - OBJECTIVES: We quantified the length of recovery time by week in a cohort of pediatric sports-related concussion patients treated at concussion clinics, and examined patient and injury characteristics associated with prolonged recovery. DESIGN: A retrospective, cohort design. SETTING: Seven concussion clinics at a Midwest children's hospital. PATIENTS: Patients aged 10 to 17 years with a diagnosed sports-related concussion presenting to the clinic within 30 days of injury. MAIN OUTCOME MEASURES: Length of recovery by week. METHODS: Unadjusted and adjusted multinomial logistic regression analyses were used to model the effect of patient and injury characteristics on length of recovery by week. RESULTS: Median length of recovery was 17 days. Only 16.3% (299/1840) of patients recovered within one week, whereas 26.4% took longer than four weeks to recover. By 2 months postinjury, 6.7% of patients were still experiencing symptoms. Higher symptom scores at injury and initial visit were significantly associated with prolonged symptoms by week. Patients who presented to the clinic more than 2 weeks postinjury or who had 2 or more previous concussions showed increased risk for prolonged recovery. Females were at greater risk for prolonged recovery than males (odds ratio = 2.08, 95% confidence interval = 1.49-2.89). Age was not significantly associated with recovery length. CONCLUSIONS: High symptom scores at injury and initial visit, time to initial clinical presentation, presence of 2 or more previous concussions, and female sex are associated with prolonged concussion recovery. Further research should aim to establish objective measures of recovery, accounting for treatment received during the recovery. CLINICAL RELEVANCE: The median length of recovery is 17 days among pediatric sports related concussion patients treated at concussion clinics. Only 16.3% of patients recovered within one week, whereas 26.4% took longer than 4 weeks to recover. PMID- 28085688 TI - Schwannoma of the Recurrent Laryngeal Nerve: A Rare Entity. AB - Neurogenic tumors are the most common posterior mediastinal tumors in adults. Schwannomas originating from the recurrent laryngeal nerve are rare. The present study describes a 46-year-old man with a tumor in the left superior mediastinum. Because of the narrow relationship with the aorta and the left pulmonary artery, the tumor was excised by left-sided minithoracotomy. The tumor, a schwannoma, originated from and encased the left recurrent laryngeal nerve. Six months after surgery, the patient was free of recurrence without symptoms other than hoarseness. "Additional imaging by magnetic resonance imaging could raise the probability of a neurogenic origin of the mass, eventually leading to collaboration with the neurosurgeon in this case." PMID- 28085689 TI - Consideration of Native Coronary Disease Progression in the Decision to Perform Hybrid Coronary Revascularization. PMID- 28085690 TI - A Novel Robotic Bilateral Internal Mammary Artery Harvest Using Double Docking Technique for Coronary Artery Bypass Grafting. AB - da Vinci Surgical System (da Vinci) enabled port access for internal mammary arteries (IMA) harvesting. However, bilateral IMA (BIMA) harvesting is difficult when performed on single side. We developed a novel technique of double docking the da Vinci by transpositioning from the left side to the right and examined the feasibility. Twelve patients underwent BIMA harvesting using the double-docking technique. First, the da Vinci was set on the patient's left side for the right IMA harvesting. Afterward, the da Vinci was undocked and transpositioned from the patient's left side to the right side. The time elapsed during rotation was measured. Subsequently, the left IMA was harvested from patient's right side. Distal anastomoses were performed by a small anterolateral thoracotomy. All of the IMAs were harvested and then bypassed without damage. The mean +/- SD time that elapsed during rotation was 6.5 +/- 0.6 minutes. There was no conversion to sternotomy. Bilateral IMA harvesting by the bilateral docking technique was performed successfully with acceptable feasibility. PMID- 28085691 TI - Robot-Assisted Mitral Valve Repair With Posterior Leaflet Extension for Rheumatic Disease. AB - Mitral valve repair has been one of the widely used applications of robotic surgery. Patients with rheumatic mitral disease usually present at an early age with thickening, retraction, or fusion of the leaflets and subvalvular apparatus. Robotic mitral repair can be feasible among this group of patients, rather than replacement. Herein, we describe a young woman who presented with rheumatic mitral valve insufficiency. A complex mitral repair with posterior leaflet extension with an autologous pericardial patch was successfully conducted using robot assistance. PMID- 28085692 TI - Negative Stress Examination Under Anesthesia Reliably Predicts Pelvic Ring Union Without Displacement. AB - OBJECTIVES: To identify the negative predictive value of examination under anesthesia (EUA) for determining pelvic ring stability and union without further displacement. DESIGN: Retrospective cohort study. SETTING: Two academic Level 1 trauma centers. PATIENTS/PARTICIPANTS: Thirty-four adult patients with closed pelvic ring injuries treated over a 5-year period. INTERVENTIONS: Pelvic stress EUA. MAIN OUTCOME MEASURES: Pelvic ring union and pelvic ring displacement at final follow-up. RESULTS: Thirty-four patients with closed pelvic ring injuries who underwent pelvic EUA during the study period and had a negative examination (indicating a stable pelvis) were identified. Mean age was 38 years (range 16 76), and 19 patients (55.9%) were male. Twenty-two patients (64.7%) had Young Burgess lateral compression (LC)-1 injuries with complete sacral fractures, 4 patients (11.8%) had LC-2 injuries, and 8 patients (23.5%) had anteroposterior compression (APC)-1 injuries. Eight patients (23.5%) had associated injuries requiring restricted weight-bearing on one or both lower extremities and were excluded from the analysis. Immediate weight-bearing as tolerated was permitted bilaterally in the remaining 26 patients. Mean pelvic ring displacement at the time of injury was 3.8 mm (range 1-15 mm) for LC injuries and 9.1 mm (range 2-20 mm) for APC injuries. Patients were followed for a mean of 8 months (range 3-34 months). At final follow-up, mean displacement was 3.7 mm (range 0-17 mm) for LC injuries and 7.1 mm (range 2-19 mm) for APC injuries. Mean change in displacement from injury to union was -0.1 mm for LC injuries and -2.0 mm for APC injuries, indicating decreased pelvic ring displacement at union. All patients were able to tolerate full weight-bearing bilaterally with no pain, and there were no instances of delayed operative fixation after negative EUA. CONCLUSIONS: Negative pelvic EUA after closed pelvic ring injury accurately predicts pelvic stability and union without displacement after nonoperative treatment with full weight bearing bilaterally. Unless otherwise dictated by associated injuries, immediate weight-bearing as tolerated seems safe in patients with pelvic ring injuries who have had a negative EUA. LEVEL OF EVIDENCE: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28085693 TI - Anxiety and the Quality of Life of Children Living With Parental Cancer. AB - BACKGROUND: Previous research on children living with parental cancer has mainly focused on the psychosocial challenges, but few studies have explored their health-related quality of life (HRQOL). This is important to promote well-being and discover areas of distress, as well as positive aspects of the children's life. OBJECTIVE: The aim of this study was to study how children's HRQOL is influenced by anxiety and whether age and gender act as moderators for this relationship. METHODS: This study used a survey with a cross-sectional design, including 35 children between 8 and 18 years old (mean, 13.3 years old) living with parental cancer. Questionnaires of HRQOL (Kinder Lebensqualitat) and anxiety (Revised Child Manifest Anxiety Scale) were used. RESULTS: The children reported higher anxiety and lower HRQOL than the controls. The children's physiological (P = .03), emotional (P = .04), and school (P = .00) functions were significantly impaired, whereas they scored in line with the controls on self-esteem, family, friends, and overall HRQOL. A negative correlation (r = -0.707, P < .01) between anxiety and HRQOL was found. Neither age nor gender acted as a moderator between anxiety and HRQOL. CONCLUSIONS: A one-dimensional focus on anxiety may not capture these children's multidimensional challenges. In contrast, a focus on HRQOL may give important knowledge of the children's challenges, as well as areas where they function well. IMPLICATIONS FOR PRACTICE: Healthcare professionals need to work collaboratively across disciplines and have a multidimensional focus in caring for patients with cancer who have children. They must provide both the parents and children with adequate information and tools to handle their family health situation to promote the children's HRQOL. PMID- 28085694 TI - Bioengineering Human Lung Grafts on Porcine Matrix. AB - OBJECTIVE: Bioengineering of viable, functional, and implantable human lung grafts on porcine matrix. SUMMARY BACKGROUND DATA: Implantable bioartificial organ grafts could revolutionize transplant surgery. To date, several milestones toward that goal have been achieved in rodent models. To make bioengineered organ grafts clinically relevant, scaling to human cells and graft size are the next steps. METHODS: We seeded porcine decellularized lung scaffolds with human airway epithelial progenitor cells derived from rejected donor lungs, and banked human umbilical vein endothelial cells. We subsequently enabled tissue formation in whole organ culture. The resulting grafts were then either analyzed in vitro (n = 15) or transplanted into porcine recipients in vivo (n = 3). RESULTS: By repopulating porcine extracellular matrix scaffolds with human endothelial cells, we generated pulmonary vasculature with mature endothelial lining and sufficient anti-thrombotic function to enable blood perfusion. By repopulating the epithelial surface with human epithelial progenitor cells, we created a living, functioning gas exchange graft. After surgical implantation, the bioengineered lung grafts were able to withstand physiological blood flow from the recipient's pulmonary circulation, and exchanged gases upon ventilation during the 1-hour observation. CONCLUSIONS: Engineering and transplantation of viable lung grafts based on decellularized porcine lung scaffolds and human endothelial and epithelial cells is technically feasible. Further graft maturation will be necessary to enable higher-level functions such as mucociliary clearance, and ventilation-perfusion matching. PMID- 28085695 TI - Incidence of Occult Intrahepatic Metastasis in Hepatocellular Carcinoma Treated With Transplantation Corresponds to Early Recurrence Rates After Partial Hepatectomy. AB - OBJECTIVE: This study aimed to compare the incidence of radiologically unrecognized (occult) hepatocellular carcinoma (HCC) lesions in explant hepatectomy specimens from orthotopic liver transplants (OLTs) performed for HCC with rates of HCC intrahepatic recurrence after resection. SUMMARY OF BACKGROUND DATA: Resection of HCC is associated with high rates of intrahepatic HCC recurrence. However, it is unclear whether these recurrences represent incomplete resection of unrecognized metastatic lesions from the primary tumor or subsequent de novo tumor formation due to inherent biological proclivity for HCC formation. METHODS: We collected patient, tumor, and pathology data on HCC patients treated surgically from 3696 OLTs in the Organ Procurement and Transplantation (OPTN) national database, 299 OLTs at a single transplant center, and 232 partial hepatectomies from a hepatobiliary cancer center. RESULTS: In the OPTN and high volume transplant center cohorts, 37% and 42% of patients had occult HCC lesions on explant pathology, respectively. Among cancer center patients, the 2-year recurrence rate was 46%, and 74% of patients who recurred presented with liver only recurrence. CONCLUSION: Although the transplant and resection populations differ, occult multifocality is common in transplant explants and similar to the 46% early recurrence rate following partial hepatectomy. These data suggest that noncurative resection often results from occult intrahepatic multifocality present at the time of resection rather than a malignant predisposition of the remnant liver with de novo tumorigenesis. PMID- 28085696 TI - Commentary on "A Proposed Road Map for the Ethical Evaluation of Sham (Placebo) Surgery". PMID- 28085698 TI - New technologies for upper tract urothelial carcinoma management. AB - PURPOSE OF REVIEW: Image enhancement techniques and optical diagnostic tools have emerged in the quest to improve diagnostics and treatment in patients with upper urinary tract carcinoma (UTUC). The aim of the present report is to describe their mechanisms of action and to assess the current evidence on applicability and utility in UTUC. RECENT FINDINGS: Image enhancement techniques including narrow band imaging, Image1 S, and photodynamic diagnosis aim at better visualization of malignant urothelium and especially flat tumours or carcinoma in situ which are often difficult to see with white light endoscopy. Conducted studies in the upper tract are scarce but first results show that tumour detection seems to be better for narrow band imaging and photodynamic diagnosis guided inspection.Optical diagnostic tools as confocal laser endomicroscopy and optical coherence tomography aim at providing real time optical biopsies giving pathologic information. A pilot study of optical coherence tomography proved its feasibility to visualize, grade and stage low and high-grade UTUC. SUMMARY: Better visualization of suspect lesions and optical diagnostic techniques providing real time optical biopsies aim to facilitate in higher diagnostic precision and optimal individualized treatment of our patients with UTUC. As the disease is rare, studies are scarce but indispensable for future implication of these techniques. PMID- 28085699 TI - A Collaborative State of the Science Initiative: Transforming Moral Distress into Moral Resilience in Nursing. AB - : To examine practices for addressing moral distress, a collaborative project was developed by the Johns Hopkins Berman Institute of Bioethics, the Johns Hopkins School of Nursing, the American Journal of Nursing, and the Journal of Christian Nursing, along with the American Association of Critical-Care Nurses and the American Nurses Association. Its purpose was to identify strategies that individuals and systems can use to mitigate the detrimental effects of moral distress and foster moral resilience. On August 11 and 12, 2016, an invitational symposium, State of the Science: Transforming Moral Distress into Moral Resilience in Nursing, was held at the Johns Hopkins School of Nursing in Baltimore, Maryland. Forty-five nurse clinicians, researchers, ethicists, organization representatives, and other stakeholders took part. The result of the symposium was group consensus on recommendations for addressing moral distress and building moral resilience in four areas: practice, education, research, and policy. Participants and the organizations represented were energized and committed to moving this agenda forward. PMID- 28085697 TI - AKT activation was not essential for hepatocellular carcinoma cell survival under glucose deprivation. AB - Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, with a dismal 5-year survival rate less than 15%. The present study aimed to investigate whether AKT inhibition and glucose deprivation could synergistically kill HCC cells and the molecular mechanisms involved. HCC cells were starved in glucose deprivation, and then the resultant cell death was determined by flow cytometry and mitochondrial oxygen consumption rates using a Seahorse XF-24 Extracellular Flux Analyzer. Glucose deprivation reduced mitochondrial oxygen consumption rates for ATP production, enhanced mitochondrial proton leaks, reduced Mcl-1 expression, and subsequently caused significant cell death in the sensitive HepG2 and HCC-M cells. In the resistant Hep3B and Huh7 cells that survived, glucose starvation induced time-dependent AKT activation. However, blockage of AKT activation using chemical inhibitors (ZSTK474 and LY290042) or specific AKT1-targeting siRNAs could not markedly sensitize glucose deprivation-induced cell death. In contrast, AKT inhibitors or AKT1-targeting siRNAs significantly protected the sensitive HepG2 cells from glucose deprivation induced cell death. More importantly, AKT inhibition mechanically suppressed mTOR activity and induced the prosurvival autophagy pathway in the sensitive HCC cells. Taken together, these data demonstrated that AKT activity was not essential for HCC cell survival during glucose deprivation. The reduction of mTOR activity and induction of the autophagy pathway may hinder the potential application of AKT inhibitors in the cancer therapy of solid tumors such as HCC. PMID- 28085700 TI - What We Know About Moral Distress. AB - : This article provides an overview of moral distress, including the existing research on the concept, and a discussion of ways to evolve our understanding of moral distress in order to meet current and future practice challenges. PMID- 28085701 TI - Cultivating Moral Resilience. AB - : Decades of research have documented the frequency, sources, and consequences of moral distress. However, few studies have focused on interventions designed to diminish its negative effects. The cultivation of moral resilience-the ability to respond positively to the distress and adversity caused by an ethically complex situation-is proposed as a method to transform moral distress. PMID- 28085702 TI - Panel Discussion 1: Promising Interventions for Building Individual Capacities for Moral Resilience. AB - On day 1 of the symposium, panelists discussed moral distress intervention programs they've helped lead. PMID- 28085703 TI - Panel Discussion 2: Promising System and Environmental Strategies for Addressing Moral Distress and Building Moral Resilience. AB - On day 2 of the symposium, panelists talked about efforts to create environments that diminish moral distress and improve moral resilience. PMID- 28085704 TI - Themes of the Symposium. AB - A summary of the major themes that emerged over the two days. PMID- 28085707 TI - Citicoline Combination Therapy for Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - OBJECTIVE: Residual symptoms of major depressive disorder are a source of long term morbidity. New therapeutic strategies are required to alleviate this morbidity and enhance patient quality of life. Citicoline has been used for vascular accidents and has been effective in cognitive rehabilitation. It has been used successfully to reduce craving in patients with substance abuse disorder and for mood management of bipolar disorder. Here, we test citicoline effectiveness as an adjuvant therapy in major depression. METHOD: A double-blind randomized trial was designed on 50 patients with major depressive disorder who were under treatment with citalopram. Patients were allocated to 2 groups and received citicoline (100 mg twice a day) or placebo as an adjuvant treatment for 6 weeks. Depressive symptoms were assessed by the Hamilton Depression Rating Scale (HDRS) at baseline and at weeks 2, 4, and 6. RESULTS: Significantly greater improvement was observed in the HDRS scores of the citicoline group compared with the placebo group from baseline to weeks 2, 4, and 6 (Ps = 0.030, 0.032, and 0.021, respectively). Repeated-measures general linear model demonstrated a significant effect for time * treatment interaction on the HDRS score (F2.10,101.22 = 3.12, P = 0.04). Remission rate was significantly higher in the citicoline group compared with the placebo group (P = 0.045). CONCLUSIONS: Citicoline was an effective adjuvant to citalopram in the therapy of major depressive disorder. PMID- 28085708 TI - Coronary spasm-induced recurrent ventricular fibrillation: insights into possible mechanisms by a multimodality approach. PMID- 28085709 TI - Hemotherapy algorithm for the management of trauma-induced coagulopathy: the German and European perspective. AB - PURPOSE OF REVIEW: This review presents a synopsis of best current knowledge with reference to the updated German and European guidelines and recommendations on the management of severe trauma hemorrhage and trauma-induced coagulopathy as well as a viscoelastic-based treatment algorithm based upon international expert consensus to trigger the administration of hemostatic agents and blood products. RECENT FINDINGS: Uncontrolled hemorrhage and trauma-induced coagulopathy are the major causes for preventable death after trauma and early detection and aggressive management have been associated with improved outcomes. However, best practice to treat this newly defined entity is still under debate. In the acute phase, the clinical management usually follows the 'Damage Control Resuscitation' concept, which advocates the empiric administration of blood products in predefined and fixed ratios. As an alternative, several European but also a few US trauma centers have instituted the concept of 'Goal-directed Coagulation Therapy' based upon results obtained from early point-of-care viscoelastic testing. SUMMARY: Current guidelines urge for the implementation of evidence based local protocols and algorithms including clinical quality and safety management systems together with parameters to assess key measures of bleeding control and outcome. PMID- 28085710 TI - Risk Assessment and Antibiotic Administration Model. PMID- 28085712 TI - Nostrilplasty by Manipulating the Dilator Naris Muscles: A Pilot Study. PMID- 28085714 TI - Modified Lipoabdominoplasty: Updating Concepts. PMID- 28085715 TI - Surgical Scar Revision with A-Plasty. PMID- 28085716 TI - Does the Use of Incisional Negative-Pressure Wound Therapy Prevent Mastectomy Flap Necrosis in Immediate Expander-Based Breast Reconstruction? PMID- 28085717 TI - Is Single-Stage Prosthetic Reconstruction Cost Effective? A Cost-Utility Analysis for the Use of Direct-to-Implant Breast Reconstruction Relative to Expander Implant Reconstruction in Postmastectomy Patients. PMID- 28085718 TI - Reply: Is Single-Stage Prosthetic Reconstruction Cost Effective? A Cost-Utility Analysis for the Use of Direct-to-Implant Breast Reconstruction Relative to Expander-Implant Reconstruction in Postmastectomy Patients. PMID- 28085719 TI - Risky business 'mis'interpretation of observational evidence. PMID- 28085720 TI - The influence of diabetes mellitus and obesity on upper limb arthroplasty outcomes: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to locate and synthesize the best available evidence investigating the impact of selected comorbidities on upper limb arthroplasty outcomes.The review question is: Are patients with diabetes mellitus or obesity at an increased risk of complications and/or poorer postoperative outcomes following total shoulder, reverse total shoulder and total elbow arthroplasty? PMID- 28085722 TI - The effect of moisturizers or creams on scars: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objectives of the review are to identify the effect of any moisturizers or creams (medicated or unmedicated) on immature scars (linear, keloid or hypertrophic) on any persons of any age. Effects will be assessed by changes in scar activity, changes in the final appearance/cosmesis of the scar, improvements in patient reported features of scars (e.g. itch, tightness, range of movement) and/or by altering measurable features of the scar such as vascularity, color, height, length, pliability and/or transepidermal water loss.Specifically the review question is: are moisturizers or creams effective in modifying immature scars? PMID- 28085721 TI - Aboriginal and Torres Strait Islander health promotion programs for the prevention and management of chronic diseases: a scoping review protocol. AB - REVIEW OBJECTIVES: The scoping review project will identify and describe the existing research on health promotion programs and activities focusing on modifying risk factors (specifically to reduce smoking and alcohol consumption, increase physical activity and improve nutrition and social and emotional wellbeing) and/or improving the management of chronic diseases (specifically obesity, type 2 diabetes, chronic kidney disease and cardiovascular disease) for Aboriginal and Torres Strait Islander peoples across a diverse range of health and community settings. PMID- 28085723 TI - The effect of involving significant others in chronic pain programs for adult patients with chronic non-malignant pain: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to identify the effect of the involvement of significant others in chronic pain management programs for adult patients with chronic non-malignant pain on function, self-efficacy and pain.More specifically, the objectives are to identify the effect of involving significant others in chronic management programs for adults with chronic non malignant pain in primary, secondary or tertiary health care. This is compared to those receiving usual care or other self-management interventions. PMID- 28085724 TI - Efficacy of thoracic paravertebral block versus systemic analgesia for postoperative thoracotomy pain: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of the systematic review is to synthesize the best available evidence on the effectiveness of thoracic paravertebral block compared with the use of systemic analgesia on postoperative pain in patients who have undergone a thoracotomy procedure. PMID- 28085725 TI - Effectiveness of robotic assisted rehabilitation for mobility and functional ability in adult stroke patients: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to synthesize the best available evidence on the effectiveness of robotic assistive devices in the rehabilitation of adult stroke patients for recovery of impairments in the upper and lower limbs. The secondary objective is to investigate the sustainability of treatment effects associated with use of robotic devices.The specific review question to be addressed is: can robotic assistive devices help adult stroke patients regain motor movement of their upper and lower limbs? PMID- 28085726 TI - Physical impairments and activity limitations experienced by people with tuberculosis: a scoping review protocol. AB - REVIEW OBJECTIVE/QUESTION: The objective of this review is to examine and map the range of physical impairments and activity limitations experienced by people infected with tuberculosis (TB). The levels of evidence that are currently available on this topic will also be reported. More specifically, the review questions are: What types of physical impairments and activity limitations have been reported for people infected with TB? What types of rehabilitation strategies are used for people with TB infection to address physical impairments and activity limitations?Findings from this scoping review may inform a systematic review to explore the effectiveness of rehabilitation strategies used to address physical impairments and activity limitations in people with TB infection. PMID- 28085727 TI - Effectiveness of patient-centered interventions on falls in the acute care setting: a quantitative systematic review protocol. AB - REVIEW OBJECTIVE: The quantitative objective of this review is to identify the effectiveness of patient-centered interventions on fall rates in adult patients in the acute care setting. PMID- 28085728 TI - Effectiveness of collaboration between emergency department and intensive care unit teams on mortality rates of patients presenting with critical illness: a quantitative systematic review protocol. AB - REVIEW OBJECTIVE: The objective of this review is to identify the effectiveness of collaboration between emergency department (ED) and intensive care unit teams on mortality rates of critically ill adult patients in the ED. PMID- 28085729 TI - Effectiveness of provider strategies for the early recognition of clinical deterioration due to sepsis in pediatric patients: a systematic review protocol. AB - REVIEW QUESTION: The objective of this review is to determine the effectiveness of provider strategies for the early recognition of clinical deterioration due to sepsis in pediatric patients. Specifically, the review question is: among pediatric, hospitalized patients, up to 18 years of age, what is the effectiveness of clinical assessment compared with use of early recognition screening tools for the recognition of clinical deterioration due to sepsis? PMID- 28085730 TI - The use of therapeutic magnesium for neuroprotection during global cerebral ischemia associated with cardiac arrest and cardiac surgery in adults: a systematic review. AB - BACKGROUND: Global cerebral ischemia occurs due to reduced blood supply to the brain. This is commonly caused by a cessation of myocardial activity associated with cardiac arrest and cardiac surgery. Survival is not the only important outcome because neurological dysfunction impacts on quality of life, reducing independent living. Magnesium has been identified as a potential neuroprotective agent; however, its role in this context is not yet clear. OBJECTIVES: The objective of this review was to present the best currently available evidence related to the neuroprotective effects of magnesium during a period of global cerebral ischemia in adults with cardiac arrest or cardiac surgery. INCLUSION CRITERIA TYPES OF PARTICIPANTS: The current review considered adults aged over 18 years who were at risk of global cerebral ischemia associated with cardiac arrest or cardiac surgery. Studies of patients with existing neurological deficits or under the age of 18 years were excluded from the review. TYPES OF INTERVENTION(S)/PHENOMENA OF INTEREST: The intervention of interest was magnesium administered in doses of at least of 2 g compared to placebo to adult patients within 24 hours of cardiac arrest or cardiac surgery. TYPES OF STUDIES: The current review considered experimental designs including randomized controlled trials, non-randomized controlled trials and quasi-experimental designs. OUTCOMES: The outcome of interest were neurological recovery post-cardiac arrest or cardiac surgery, as measured by objective scales, such as but not limited to, cerebral performance category, brain stem reflexes, Glasgow Coma Score and independent living or dependent living status. To enable assessment of the available data, neuroprotection was examined by breaking down neurological outcomes into three domains - functional neurological outcomes, neurophysiological outcomes and neuropsychological outcomes. SEARCH STRATEGY: The search strategy aimed to find both published and unpublished studies between January 1980 and August 2014, utilizing the Joanna Briggs Institute (JBI) three step search strategy. Databases searched included PubMed, Embase, CINAHL, Cochrane Central Register of Controlled Trials, Australian Clinical Trials Register, Australian and New Zealand Clinical Trials Register, Clinical Trials, European Clinical Trials Register and ISRCTN Registry. METHODOLOGICAL QUALITY: The studies included in this review were of moderate-to-good-quality randomized controlled trials. Studies included measured neurological outcome using functional neurological assessment, neuropsychiatric assessment or neurophysiological assessment. DATA EXTRACTION: Data were extracted using standardized templates provided by the JBI Meta-analysis of Statistics Assessment and Review Instrument software. DATA SYNTHESIS: Quantitative data were, where possible, pooled in statistical meta-analysis using Review Manager 5.3 (The Nordic Cochrane Centre, Cochrane; Copenhagen, Denmark). Where statistical pooling was not possible, the findings were presented in narrative form, including tables and figures, to aid in data presentation, where appropriate. RESULTS: Seven studies with a total of 1164 participants were included in this review. Neurological outcome was categorized into three domains: functional neurological, neurophysiological and neuropsychological outcomes. Meta-analysis of three studies assessing the neuroprotective properties of magnesium administration post cardiac arrest found improved functional neurological outcome (odds ratio 0.44; 95% confidence interval 0.24-0.81). CONCLUSION: Magnesium may improve functional neurological outcome in patients who suffer global cerebral ischemia associated with cardiac surgery and cardiac arrest. Magnesium does not decrease neuropsychological decline.Further testing of neurological outcomes in the domains of functional outcomes, neurophysiological markers and neuropsychological tests are required to further understanding of the neuroprotective effects of magnesium. Suitable dosing regimens should be investigated prior to introduction into clinical practice. Further research is required to investigate the optimal magnesium dose. PMID- 28085731 TI - Effectiveness of rifampicin-streptomycin for treatment of Buruli ulcer: a systematic review. AB - BACKGROUND: Buruli ulcer (BU) disease is a chronic ulcerative skin disease caused by Mycobacterium ulcerans, which can lead to extensive destruction of the skin, soft tissues and occasionally of bones. Although several antibiotics have demonstrated bactericidal activity against M. ulcerans in vitro, no consensus on their clinical efficacy against M. ulcerans in humans has been reached. OBJECTIVES: The objective of the systematic review was to examine the clinical effectiveness of various antibiotic regimens for the treatment of BUs. INCLUSION CRITERIA TYPES OF PARTICIPANTS: The current review considered trials that included patients of all ages with BUs. TYPES OF INTERVENTION(S): The current review considered trials that evaluated antibiotic regimens compared to no antibiotics or surgery in patients with BUs. TYPES OF STUDIES: The current review considered randomized and non-randomized controlled trials (RCTs). In the absence of RCTs, other research designs such as before and after trials and clinical trials with only an intervention arm were considered for inclusion in a narrative summary. OUTCOMES: The primary outcome of interest were the treatment success rates among the various antibiotics used. Secondary outcomes included changes in lesion size, recurrence of ulcers and incidence of adverse events. SEARCH STRATEGY: The search strategy aimed to find both published and unpublished trials. A three-step search strategy was utilized in this review and included English language trials published after 1990. A search across the major databases was conducted up to December 2014. METHODOLOGICAL QUALITY: Using the Joanna Briggs Institute (JBI) standardized appraisal tool, two reviewers independently assessed the methodological quality of the trials. A third independent reviewer was available to appraise trials if the two original reviewers disagreed in their assessments. There were no disagreements in findings between the two independent reviewers. DATA EXTRACTION: Data were extracted using the standardized JBI data extraction instruments. DATA SYNTHESIS: Statistical pooling was not possible due to heterogeneity, hence results have been presented in the narrative form. RESULTS: Seven studies involving a total of 712 patients were included in the final review. Higher treatment success rates ranging from 96% to 100% at the six months follow-up were reported among patients treated with rifampicin streptomycin for eight weeks (RS8) in two studies. Treatment success with rifampicin-streptomycin for 12 weeks, with surgery at the 12 weeks follow-up, was 91%. In the two studies that investigated the effect of rifampicin-streptomycin for two weeks followed by rifampicin-clarithromycin for six weeks and rifampicin streptomycin for four weeks followed by rifampicin-clarithromycin for four weeks, treatment success was reported to be 93% and 91%, respectively, at the 12 months follow-up. A significant decrease in the median lesion size at the eight weeks follow-up was reported in patients who were treated with RS8, and a 10-30% decrease in lesion size was reported in those treated with RS12 at the four weeks follow-up. CONCLUSION: Treatment success and reduction in lesion size were higher in patients treated with RS8 in the only RCT that compared rifampicin streptomycin for four weeks followed by rifampicin-clarithromycin for six weeks to RS8, and there was no difference in outcomes, which indicates that local preferences could dictate the treatment option. Evidence obtained from this systematic review indicates that surgery will remain necessary for some ulcers; however, detection of early lesions and treatment with antibiotics would have a greater impact on the control of M. ulcerans disease. Further large multicenter RCTs investigating the type and optimal duration of oral antibiotic treatment for patients with M. ulcerans disease are urgently needed. PMID- 28085732 TI - Effectiveness of probiotics in reducing the incidence of Clostridium difficile associated diarrhea in elderly patients: a systematic review. AB - BACKGROUND: Clostridium difficile bacteria are a leading cause of infectious diarrhea. This is an anaerobic, gram-positive and spore-forming rod responsible for significant morbidity and mortality, especially among elderly hospitalized patients. Standard management of C. difficile-associated diarrhea (CDAD) consists of discontinuing a causative antibiotic, correcting fluid-electrolytes imbalance and initiating an antibiotic treatment for CDAD. Alternative approaches for prevention of CDAD include probiotics. This systematic review will provide a comprehensive, unbiased summary of the available research on the effectiveness of probiotics in decreasing the incidence of infectious diarrhea in elderly hospitalized patients. OBJECTIVES: To conduct a systematic review to determine the best available evidence related to the effectiveness of probiotics in the prevention of CDAD in elderly hospitalized patients. The review question was: are probiotics effective in decreasing the incidence of CDAD in elderly hospitalized patients? INCLUSION CRITERIA TYPES OF PARTICIPANTS: The current review included studies of participants who were aged 60 years and more and who were residents of acute- and post-acute care facilities undergoing or planning to undergo antibiotic treatment for the management of any infectious conditions, except CDAD. TYPES OF INTERVENTION(S): The current review included studies that evaluated the effectiveness of probiotics for prevention of CDAD in elderly hospitalized patients in acute- and post-acute care settings compared to usual care. OUTCOMES: The current review included studies examining the following outcome measures: incidence or relapse of CDAD. Cases of CDAD were defined by presence of diarrhea and verified by positive results for stool enzyme immunoassay for toxins A and B. TYPES OF STUDIES: The current review included only experimental study designs including randomized controlled trials. SEARCH STRATEGY: The search strategy included studies published in English between 1978, when the first case of CDAD was reported, and 2015. ASSESSMENT OF METHODOLOGICAL QUALITY: Papers selected for retrieval were assessed by two independent reviewers for methodological quality prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute (JBI). DATA EXTRACTION: Data were extracted from papers included in the review using the standardized data extraction tool from the JBI Meta-Analysis of Statistics Assessment and Review Instrument. The data extracted included specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. DATA SYNTHESIS: Quantitative data were pooled using statistical meta-analysis. Effect sizes were expressed as odds ratios, and their 95% confidence intervals were calculated to determine if probiotic treatment was superior to placebo in reducing CDAD incidence. Heterogeneity was assessed using the standard I statistic. RESULTS: Five studies were included in the review. The individual study results were conflicting, including non-significant results for four studies and statistically significant results in one that demonstrated fewer cases of CDAD among patients receiving probiotics compared to placebo. The meta-analysis finding indicated that there was no statistically significant difference in CDAD incidence in elderly hospitalized patients taking probiotics when compared to a placebo. CONCLUSION: Probiotics were not found to be more effective than placebo for reducing CDAD incidence in elderly hospitalized patients. However, studies that demonstrate improved outcomes must be examined to determine future needs for research. Studies varied with regard to the dose, frequency, method of administration (probiotic drinks versus capsule), length of administration and the number of strains of bacteria administered. Further studies are needed to evaluate the effectiveness of probiotics for CDAD prevention in this population. Clinical trials with evidence-based administration methods and meta-analyses that pool the results of studies with congruent methodologies are needed to enable conclusions to be drawn on the effectiveness of probiotic administration for CDAD prevention. PMID- 28085733 TI - Management of perineal pain among postpartum women in an obstetric and gynecological hospital in China: a best practice implementation project. AB - BACKGROUND: Perineal pain is a serious condition that may negatively impact a significant number of postpartum women. Healthcare professionals, including midwives and nurses, are available to support women 24 hours a day during this period in hospital and are in an ideal position to assist in the management of perineal pain for postpartum women. OBJECTIVES: The aim of this evidence implementation project was to improve management of perineal pain among postpartum women in Ward 21 of the Obstetric and Gynecological Hospital, Fudan University. METHODS: This evidence implementation project utilized the Joanna Briggs Institute Practical Application of Clinical Evidence System, and Getting Research into Practice audit and feedback tools. Six best practice recommendations were used for the audit cycle. A total of 18 nurses, three midwives and 30 female patients participated in the project. A baseline audit was conducted, followed by the implementation of strategies targeted to address the identified barriers. A follow-up audit was then conducted to evaluate change in practice. RESULTS: Improvements in practice were observed for all six criteria. Significant improvements were found for the following: staff education increased compliance by 76% (from 24% to 100%). Education regarding antenatal perineal massage technique increased by 97% (from 3% to 100%). Compliance rates for use of ice packs increased by 63% (from 17 to 80%). Compliance rates for daily perineal pain assessment conducted for three days following childbirth increased by 100%, and analgesia administration rates increased by 27% (from 1% to 40%). Compliance rates for women's acceptance of postnatal perineal care education increased by 70% (from 30 to 100%). CONCLUSION: The current clinical audit project has made a significant improvement in establishing evidence-based practice of management of perineal pain among postpartum women in the gynecologic and obstetric hospital in Shanghai. It has been effective in increasing staff compliance and reducing the perineal pain among postpartum women. PMID- 28085734 TI - Implementing evidence-based continuous quality improvement strategies in an urban Aboriginal Community Controlled Health Service in South East Queensland: a best practice implementation pilot. AB - BACKGROUND: The Institute for Urban Indigenous Health believes that continuous quality improvement (CQI) contributes to the delivery of high-quality care, thereby improving health outcomes for Aboriginal and Torres Strait Islander people. The opening of a new health service in 2015 provided an opportunity to implement best practice CQI strategies and apply them to a regional influenza vaccination campaign. OBJECTIVE: The aim of this project was to implement an evidence-based CQI process within one Aboriginal Community Controlled Health Service in South East Queensland and use staff engagement as a measure of success. METHOD: A CQI tool was selected from the Joanna Briggs Institute Practical Application of Clinical Evidence System (PACES) to be implemented in the study site. The study site was a newly established Aboriginal and Torres Strait Islander Community Controlled Health Service located in the northern suburbs of Brisbane. This project used the evidence-based information collected in PACES to develop a set of questions related to known variables resulting in proven CQI uptake. A pre implementation clinical audit, education and self directed learning, using the Plan Do Study Act framework, included a total of seven staff and was conducted in April 2015. A post implementation audit was conducted in July 2015. RESULTS: There were a total of 11 pre- and post-survey respondents which included representation from most of the clinical team and medical administration. The results of the pre implementation audit identified a number of possible areas to improve engagement with the CQI process including staff training and support, understanding CQI and its impacts on individual work areas, understanding clinical data extraction, clinical indicator benchmarking, strong internal leadership and having an external data extractor. There were improvements to all audit criteria in the post-survey, for example, knowledge regarding the importance of CQI activity, attendance at education and training sessions on CQI, active involvement with CQI activity and a multidisciplinary team approach to problem solving within the CQI process. CONCLUSION: The study found that the implementation of regular, formally organized CQI strategies does have an immediate impact on clinical practice, in this case, by increasing staff awareness regarding the uptake of influenza vaccination against regional targets. The Plan Do Study Act cycle is an efficient tool to record and monitor the change and to guide discussions. For the CQI process to be effective, continued education and training on data interpretation is pivotal to improve staff confidence to engage in regular data discussions, and this should be incorporated into all future CQI sessions. PMID- 28085735 TI - Transcranial Direct Current Stimulation Improves Audioverbal Memory in Stroke Patients. AB - OBJECTIVE: The aim of this study was to investigate whether anodal transcranial direct current stimulation over the left temporoparietal area improved audioverbal memory performance in stroke patients. DESIGN: Twelve stroke patients with audioverbal memory impairment participated in a single-masked, crossover, and sham-controlled experiment. The anodal or sham transcranial direct current stimulation was applied during the Rey Auditory Verbal Learning Test, which evaluates the ability to recall a list of 15 heard words over five trials. The number of correctly recalled words was compared between the anodal and sham conditions and the influence of transcranial direct current stimulation on serial position effect of the 15 words was also examined. RESULTS: The increase in the number of correctly recalled words from the first to the fifth trial was significantly greater in the anodal condition than in the sham condition (P < 0.01). There was a significant difference (P < 0.01) between the anodal and sham conditions in the number of correctly recalled words within the first five words (primacy region) over the second to fifth trial trials, but not in the middle (next five words) or recency (last five words) regions. CONCLUSIONS: Anodal transcranial direct current stimulation over the left temporoparietal area improved audioverbal memory performance and induced the primacy effect in stroke patients. PMID- 28085736 TI - Sockets Manufactured by CAD/CAM Method Have Positive Effects on the Quality of Life of Patients With Transtibial Amputation. AB - OBJECTIVE: Patients with amputation need prosthesis to comfortably move around. One of the most important parts of a good prosthesis is the socket. Currently, the most commonly used method is the traditional socket manufacturing method, which involves manual work; however, computer-aided design/computer-aided manufacturing (CAD/CAM) is also being used in the recent years. The present study aimed to investigate the effects of sockets manufactured by traditional and CAD/CAM method on clinical characteristics and quality of life of patients with transtibial amputation. DESIGN: The study included 72 patients with transtibial amputation using prosthesis, 36 of whom had CAD/CAM prosthetic sockets (group 1) and 36 had traditional prosthetic sockets (group 2). Amputation reason, prosthesis lifetime, walking time and distance with prosthesis, pain-free walking time with prosthesis, production time of the prosthesis, and adaptation time to the prosthesis were questioned. Quality of life was assessed using the 36-item Short Form Health Survey questionnaire and the Trinity Amputation and Prosthesis Experience Scales. RESULTS: Walking time and distance and pain-free walking time with prosthesis were significantly better in group 1 than those in group 2. Furthermore, the prosthesis was applied in a significantly shorter time, and socket adaptation time was significantly shorter in group 1. Except emotional role limitation, all 36-item Short Form Healthy Survey questionnaire parameters were significantly better in group 1 than in group 2. Trinity Amputation and Prosthesis Experience Scales activity limitation scores of group 1 were lower, and Trinity Amputation and Prosthesis Experience Scales satisfaction with the prosthesis scores were higher than those in group 2. CONCLUSION: Our study demonstrated that the sockets manufactured by CAD/CAM methods yield better outcomes in quality of life of patients with transtibial amputation than the sockets manufactured by the traditional method. PMID- 28085737 TI - Grip Strength on the Unaffected Side as an Independent Predictor of Functional Improvement After Stroke. AB - OBJECTIVE: The aim of this study was to investigate the association between grip strength on the unaffected side and post-stroke functional improvement. DESIGN: A total of 127 patients with unilateral stroke were included in this study. Demographic data, clinical data on initial grip strength, initial National Institutes of Health Stroke Scale, admission and discharge Modified Barthel Index (MBI), and stroke profiles were retrospectively reviewed. RESULTS: Univariate and multiple linear regression analyses were carried out to evaluate the predictive values of each variable. In the model for discharge MBI, age, initial National Institutes of Health Stroke Scale, grip strength on the unaffected side, lesion side, and admission MBI were shown to be independent predictors. Meanwhile, grip strength on the unaffected side, lesion side, and admission MBI had significant predictive values in the model for difference between admission and discharge MBI. CONCLUSION: The current study suggests for the first time that grip strength on the unaffected side is an independent predictor for short-term functional gain and outcome after stroke. This result may change post-stroke rehabilitation strategies to emphasize exercises to prevent loss of muscle strength. In addition, this implies the possibility of a relationship between sarcopenia and post-stroke function. Further research is needed to reveal the effect of sarcopenia on stroke patients and its mechanism. PMID- 28085738 TI - Using Neural Response Telemetry to Monitor Physiological Responses to Acoustic Stimulation in Hybrid Cochlear Implant Users. AB - OBJECTIVE: This report describes the results of a series of experiments where we use the neural response telemetry (NRT) system of the Nucleus cochlear implant (CI) to measure the response of the peripheral auditory system to acoustic stimulation in Nucleus Hybrid CI users. The objectives of this study were to determine whether they could separate responses from hair cells and neurons and to evaluate the stability of these measures over time. DESIGN: Forty-four CI users participated. They all had residual acoustic hearing and used a Nucleus Hybrid S8, S12, or L24 CI or the standard lateral wall CI422 implant. The NRT system of the CI was used to trigger an acoustic stimulus (500-Hz tone burst or click), which was presented at a low stimulation rate (10, 15, or 50 per second) to the implanted ear via an insert earphone and to record the cochlear microphonic, the auditory nerve neurophonic and the compound action potential (CAP) from an apical intracochlear electrode. To record acoustically evoked responses, a longer time window than is available with the commercial NRT software is required. This limitation was circumvented by making multiple recordings for each stimulus using different time delays between the onset of stimulation and the onset of averaging. These recordings were then concatenated off-line. Matched recordings elicited using positive and negative polarity stimuli were added off-line to emphasize neural potentials (SUM) and subtracted off-line to emphasize potentials primarily generated by cochlear hair cells (DIF). These assumptions regarding the origin of the SUM and DIF components were tested by comparing the magnitude of these derived responses recorded using various stimulation rates. Magnitudes of the SUM and DIF components were compared with each other and with behavioral thresholds. RESULTS: SUM and DIF components were identified for most subjects, consistent with both hair cell and neural responses to acoustic stimulation. For a subset of the study participants, the DIF components grew as stimulus level was increased, but little or no SUM components were identified. Latency of the CAPs in response to click stimuli was long relative to reports in the literature of recordings obtained using extracochlear electrodes. This difference in response latency and general morphology of the CAPs recorded was likely due to differences across subjects in hearing loss configuration. The use of high stimulation rates tended to decrease SUM and CAP components more than DIF components. We suggest this effect reflects neural adaptation. In some individuals, repeated measures were made over intervals as long as 9 months. Changes over time in DIF, SUM, and CAP thresholds mirrored changes in audiometric threshold for the subjects who experienced loss of acoustic hearing in the implanted ear. CONCLUSIONS: The Nucleus NRT software can be used to record peripheral responses to acoustic stimulation at threshold and suprathreshold levels, providing a window into the status of the auditory hair cells and the primary afferent nerve fibers. These acoustically evoked responses are sensitive to changes in hearing status and consequently could be useful in characterizing the specific pathophysiology of the hearing loss experienced by this population of CI users. PMID- 28085739 TI - Benefits of Music Training for Perception of Emotional Speech Prosody in Deaf Children With Cochlear Implants. AB - OBJECTIVES: Children who use cochlear implants (CIs) have characteristic pitch processing deficits leading to impairments in music perception and in understanding emotional intention in spoken language. Music training for normal hearing children has previously been shown to benefit perception of emotional prosody. The purpose of the present study was to assess whether deaf children who use CIs obtain similar benefits from music training. We hypothesized that music training would lead to gains in auditory processing and that these gains would transfer to emotional speech prosody perception. DESIGN: Study participants were 18 child CI users (ages 6 to 15). Participants received either 6 months of music training (i.e., individualized piano lessons) or 6 months of visual art training (i.e., individualized painting lessons). Measures of music perception and emotional speech prosody perception were obtained pre-, mid-, and post-training. The Montreal Battery for Evaluation of Musical Abilities was used to measure five different aspects of music perception (scale, contour, interval, rhythm, and incidental memory). The emotional speech prosody task required participants to identify the emotional intention of a semantically neutral sentence under audio only and audiovisual conditions. RESULTS: Music training led to improved performance on tasks requiring the discrimination of melodic contour and rhythm, as well as incidental memory for melodies. These improvements were predominantly found from mid- to post-training. Critically, music training also improved emotional speech prosody perception. Music training was most advantageous in audio-only conditions. Art training did not lead to the same improvements. CONCLUSIONS: Music training can lead to improvements in perception of music and emotional speech prosody, and thus may be an effective supplementary technique for supporting auditory rehabilitation following cochlear implantation. PMID- 28085740 TI - Sound Localization and Speech Perception in Noise of Pediatric Cochlear Implant Recipients: Bimodal Fitting Versus Bilateral Cochlear Implants. AB - OBJECTIVES: The aim of this study was to compare binaural performance of auditory localization task and speech perception in babble measure between children who use a cochlear implant (CI) in one ear and a hearing aid (HA) in the other (bimodal fitting) and those who use bilateral CIs. DESIGN: Thirteen children (mean age +/- SD = 10 +/- 2.9 years) with bilateral CIs and 19 children with bimodal fitting were recruited to participate. Sound localization was assessed using a 13-loudspeaker array in a quiet sound-treated booth. Speakers were placed in an arc from -90 degrees azimuth to +90 degrees azimuth (15 degrees interval) in horizontal plane. To assess the accuracy of sound location identification, we calculated the absolute error in degrees between the target speaker and the response speaker during each trial. The mean absolute error was computed by dividing the sum of absolute errors by the total number of trials. We also calculated the hemifield identification score to reflect the accuracy of right/left discrimination. Speech-in-babble perception was also measured in the sound field using target speech presented from the front speaker. Eight-talker babble was presented in the following four different listening conditions: from the front speaker (0 degrees ), from one of the two side speakers (+90 degrees or -90 degrees ), from both side speakers (+/-90 degrees ). Speech, spatial, and quality questionnaire was administered. RESULTS: When the two groups of children were directly compared with each other, there was no significant difference in localization accuracy ability or hemifield identification score under binaural condition. Performance in speech perception test was also similar to each other under most babble conditions. However, when the babble was from the first device side (CI side for children with bimodal stimulation or first CI side for children with bilateral CIs), speech understanding in babble by bilateral CI users was significantly better than that by bimodal listeners. Speech, spatial, and quality scores were comparable with each other between the two groups. CONCLUSIONS: Overall, the binaural performance was similar to each other between children who are fit with two CIs (CI + CI) and those who use bimodal stimulation (HA + CI) in most conditions. However, the bilateral CI group showed better speech perception than the bimodal CI group when babble was from the first device side (first CI side for bilateral CI users or CI side for bimodal listeners). Therefore, if bimodal performance is significantly below the mean bilateral CI performance on speech perception in babble, these results suggest that a child should be considered to transit from bimodal stimulation to bilateral CIs. PMID- 28085742 TI - Neuroblastoma in a Child With Wolf-Hirschhorn Syndrome. AB - Neuroblastoma is the most common extracranial solid tumor of childhood originating from sympathetic nervous system cells. Neuroblastoma has also been diagnosed in conjunction with other congenital conditions such as Hirschsprung's disease, congenital hypoventilation disorder, and neurofibromatosis type 1. Wolf Hirschhorn syndrome is a congenital disorder caused by microdeletion of short arm of chromosome 4 encoding MSX1 gene with characteristic facial features. We describe a child with dysmorphic features, developmental delay, mental retardation who developed neuroblastoma at 2 years of age and cytogenetic analysis of blood lymphocytes revealed an interstitial deletion of 4p(15,2). To best our knowledge, this report is the first report of neuroblastoma in a child with Wolf-Hirschhorn syndrome; and the reported association may be an important clue for oncological follow-up of patients with Wolf-Hirschhorn syndrome. PMID- 28085741 TI - The Behavior Rating Inventory of Executive Function (BRIEF) to Identify Pediatric Acute Lymphoblastic Leukemia (ALL) Survivors At Risk for Neurocognitive Impairment. AB - Neurocognitive problems, including executive dysfunction, are potential late effects of pediatric acute lymphoblastic leukemia treatment. Surveillance for neurocognitive impairment in a timely and efficient manner is imperative to ongoing clinical care. We sought to determine if the Behavior Rating Inventory of Executive Function (BRIEF) Parent Form identified leukemia survivors with cognitive impairment. In this 28-site cross-sectional study, parents of 256 children, a mean of 8.9+/-2.2 years after treatment for standard-risk precursor-B acute lymphoblastic leukemia and in first remission, completed the BRIEF. We used a multivariate logistic regression to calculate the association between elevated scores on 3 composite BRIEF indices (Behavioral Regulation Index, Metacognition Index, Global Executive Composite [GEC]) and special education and attention deficit/hyperactivity disorder (ADHD) outcomes. All BRIEF index scores were significantly associated with receipt of special education services or ADHD. The BRI was most strongly associated with ADHD (odds ratios=4.33; 95% confidence interval, 1.72-10.9). The GEC was most strongly associated with ADHD (odds ratios=4.46; 95% confidence interval, 1.77-11.22). Elevated scores on the BRIEF GEC were associated with low sensitivity (24.1 to 39.1) for detecting the outcomes but better specificity (range, 87.7 to 89.3). These results suggest that the parent-completed BRIEF is associated with clinical outcomes but is not a sensitive tool to identify leukemia survivors that require a comprehensive neuropsychological assessment. PMID- 28085743 TI - T2* Magnetic Resonance Imaging Study of Pancreatic Iron Overload and its Relation With the Diabetic State in Thalassemic Patients. AB - The present study was performed to evaluate pancreatic hemosiderosis by means of magnetic resonance imaging (MRI) T2* and its relation to the diabetic state in thalassemic patients. One hundred thirty transfusion-dependent thalassemic patients from Zafar adult thalassemia clinic, Tehran, Iran, were enrolled in the study. Data such as age, type of thalassemia, age at diagnosis, transfusion duration, ferritin level, and fasting blood sugar results were gathered. Pancreatic MRI T2* was performed for all patients. One hundred four thalassemic patients with no sign of diabetes mellitus and 26 thalassemic patients with diabetes mellitus entered the study. Out of a total of 130 patients, 102 had pancreatic hemosiderosis. Among them, 23 of 26 diabetic patients (88.5%) and 79 of 104 nondiabetic patients (76%) showed pancreatic hemosiderosis, indicating no statistically significant difference between the 2 groups. The mean pancreatic MRI T2* relaxation time for all patients was 13.99+/-12.43 ms. The mean relaxation was 13.62+/-8.38 and 14.08+/-13.28 ms for diabetic and nondiabetic patients, respectively, showing no statistical difference (P=0.202). In conclusion, we did not find a significant difference between diabetic and nondiabetic thalassemic patients regarding the MRI T2* relaxation time readings or the rate of pancreatic hemosiderosis. We recommend performing studies with a higher sample size and including patients from different age groups to further evaluate the role of T2* MRI of pancreatic iron overload and its relation with the diabetic state in thalassemic patients. PMID- 28085744 TI - An Unusual Pelvic Mass in a Pediatric Patient: A Case Report and Review of the Pathology. AB - INTRODUCTION: Neurofibromatosis type 1 (NF1) is the most commonly inherited autosomal dominant disorder in humans. NF1 patients have increased risk for gastrointestinal stromal tumors (GISTs). A Meckel's diverticulum (MD) represents a persistent embryonic omphalomesenteric duct characterized as a true diverticulum located near the ileocecal valve. We report a unique clinical case whereby a patient with NF1 developed a GIST within a MD. CASE: An adolescent male with NF1 presented with persistent lower abdominal pain. Clinical evaluation demonstrated a large pelvic mass. In the operating room, the mass was noted to emerge from a MD. Final pathology demonstrated a GIST with negative margins and CD117 positivity. DISCUSSION: Patients with NF1 are at increased risk for mesenchymal tumors including malignant peripheral nerve sheath tumors. GISTs are the most important and frequent non-neurological malignancy in NF1 and develop in ~7% of NF1 patients. GISTs tend to be multifocal in NF1; however, they rarely occur within a Meckel's diverticula. CONCLUSIONS: Our case represents a rare case of a patient with NF1 who developed a symptomatic GIST within a MD. We recommend utilizing laparoscopy to determine resectability and clarify the diagnosis in this unique patient population who are at risk for multiple neoplasms. PMID- 28085745 TI - A Rare Case of Perinatal Intrarenal Neuroblastoma. AB - Perinatal neuroblastoma is the most common solid malignant tumor in infancy which comprises one fifth of all neuroblastomas. Most of them are of adrenal origin and extra-adrenal neuroblastoma is uncommon. We present a rare case of perinatal intrarenal neuroblastoma in a neonate who presented with an incidentally detected abdominal mass. These tumors cause diagnostic and therapeutic dilemma because of its uncommon location. Although very rare, neuroblastoma should be considered in the differential diagnosis of perinatally detected renal tumors. PMID- 28085746 TI - Cytogenetic and Cytogenomic Microarray Characterization of Chromothripsis in Chromosome 8 Affecting MOZ/NCOA2 (TIF2), FGFR1, RUNX1T1, and RUNX1 in a Pediatric Acute Myeloid Leukemia. AB - Concurrent perturbations in different driver genes have been reported primarily in lymphoma. In acute myeloid leukemia (AML), cases with concurrent alterations in 2 driver genes are infrequently reported. In contrast to pathogenetic pathways in lymphoma with concurrently perturbed genes, the initial gene alteration in AML arrests maturation and the alteration in the second gene promote self-renewal of the blasts. Here, we report a unique case of infantile leukemia in which chromothripsis in chromosome 8 completely altered the G-band structure and resulted in concurrent changes in MOZ/NCOA2, FGFR1, RUNX1T1, and RUNX1. These multiple-hit abnormalities in AML have not been reported previously. PMID- 28085747 TI - Survival Outcome of Filipino Children With Acute Lymphoblastic Leukemia Treated With Modified Berlin-Frankfurt-Muenster/Hong Kong Acute Lymphoblastic Leukemia (BFM95/HKALL97) Protocol in a Tertiary General Hospital From January 2005 to December 2009: A Retrospective Cohort Study. AB - This retrospective cohort study is primarily aimed to evaluate the outcome of children ages 0 to 18 years old, with acute lymphoblastic leukemia and treated with a modified Berlin-Frankfurt-Muenster/Hong Kong Acute Lymphoblastic Leukemia (BFM95-HKALL97) protocol at University of Santo Tomas Hospital from January 2005 to December 2009. Seventy-eight patients were included. Majority were between 1 and 10 years old (87.2%), male (61.5%), with normal nutritional status, and classified as upper socioeconomic class (65.3%), mainly from National Capital Region (24.3%). Eighty percent had mild anemia and a white cell count <50,000/mm. No patient had an initial platelet count <20,000/mm. More than 90% were standard risk, with FAB L1 morphology and pre-B immunophenotype. Five-year overall survival (OS) and event-free survival (EFS) rates were 86.94% and 86.2%, respectively. Among the 69 patients in the efficacy subset analysis, the 5-year OS and EFS rates were 98.36% and 86.80%, respectively. Relapse rate was 14.5%. Only FAB morphology and risk classification were correlated with relapse. Most common complications were febrile neutropenia, sepsis, and oral mucositis during induction phase. No deaths occurred due to treatment complications. In conclusion, using higher doses of methotrexate during consolidation phase improved the 5-year OS and EFS rates of our patients, without an increase in complications or deaths. Other contributing factors include improved adherence to treatment and risk-based treatment classification. PMID- 28085748 TI - Klf10 Gene, a Secondary Modifier and a Pharmacogenomic Biomarker of Hydroxyurea Treatment Among Patients With Hemoglobinopathies. AB - BACKGROUND: The klf10 gene could indirectly modify gamma-globin chain production and hence the level of fetal hemoglobin (HbF) ameliorating the phenotype of beta hemoglobinopathies and the response to hydroxycarbamide (hydroxyurea [HU]) therapy. In this study, we aimed to evaluate the frequency of different genotypes for the klf10 gene in beta-thalassemia major (B-TM), beta-thalassemia intermedia (B-TI), and sickle cell disease (SCD) patients by polymerase chain reaction and to assess its relation to disease phenotypes and HU response. METHODS: This cross sectional study included 75 patients: 50 B-TM, 12 SCD, and 13 B-TI patients (on stable HU dose). The relation of the klf10 gene polymorphism (TIEG, TIEG1, EGRalpha) (rs3191333: c*0.141C>T) to phenotype was studied through baseline mean corpuscular volume, HbF, and transfusion history, whereas evaluation of response to HU therapy was carried out clinically and laboratory. RESULTS: The frequency of the mutant klf10 genotype (TT) and that of the mutant allele (T) was significantly higher among B-TM patients compared with those with B-TI and SCD patients. Only homozygous SCD patients for the wild-type allele within the klf10 gene had a significantly lower transfusion frequency. The percentage of HU responders and nonresponders between different klf10 polymorphic genotypes among B-TI or SCD patients was comparable. CONCLUSIONS: Although the klf10 gene does not play a standalone role as an HbF modifier, our data support its importance in ameliorating phenotype among beta-hemoglobinopathies. PMID- 28085749 TI - Sinusoidal Obstruction Syndrome During Maintenance Therapy for Acute Lymphoblastic Leukemia With 6-Mercaptopurine and Methotrexate: A Pediatric Case Report. AB - We report a case of a child with pre-B cell acute lymphoblastic leukemia undergoing maintenance chemotherapy with 6-mercaptopurine and methotrexate (MTX) who developed sinusoidal obstruction syndrome after being treated with ciprofloxacin for BK viremia. This case represents a rare complication of maintenance therapy with MTX and 6-mercaptopurine, and suggests a drug interaction between ciprofloxacin and MTX. PMID- 28085750 TI - Parent-perceived Facilitators in the Transition of Care for Young Adult Survivors of Childhood Cancer. AB - Most childhood cancer survivors need life-long care with specialized late-effects surveillance and screening. As these children age into adulthood, it is imperative to continue their survivor-focused care. To do so, health care systems must be prepared to care for this growing and aging population. This includes creating models of care that take into account the needs and desires of all key stakeholders: survivors, parents, pediatric providers, and adult providers. This clinical observation describes that parents desire comprehensive and highly accessible survivorship care that promotes survivor independence; yet, they also want to have a central role in their child's survivorship care. PMID- 28085751 TI - Lemierre's Syndrome as a Trigger for Secondary Hemophagocytic Lymphohistiocytosis. AB - Secondary hemophagocytic lymphohistiocytosis (sHLH) is a rare hyperinflammatory disorder caused by an aberrant immune response to a number of infectious or inflammatory conditions. Successful treatment of this potentially fatal condition requires early recognition and prompt therapy directed at the underlying trigger. In this report, we describe the clinical presentation, diagnostic findings, management, and outcome of a child with Lemierre's syndrome-associated sHLH. This is the first reported association of these 2 rare conditions and expands the number of known triggers for sHLH. PMID- 28085752 TI - Kruppel-Like Factor 4 Promotes Pancreatic Acinar-to-Ductal Metaplasia and Tumor Initiation. PMID- 28085754 TI - Limitations of Postoperative Assessment for Pancreatic Exocrine Insufficiency in Pancreatic Malignancy. PMID- 28085753 TI - Preclinical Rationale for the Phase III Trials in Metastatic Pancreatic Cancer: Is Wishful Thinking Clouding Successful Drug Development for Pancreatic Cancer? AB - Prior phase III trials in advanced pancreatic cancer have been predominantly unsuccessful. In this review, we attempt to understand how past preclinical data were translated into phase III clinical trials in metastatic pancreatic cancer as described in the article. A systematic literature review conducted through the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases, from January 1997 to June 2015 using key words-phase III clinical trials, metastatic/advanced pancreatic adenocarcinoma or pancreatic cancer identified 30 randomized controlled trials (RCTs) that met criteria. The trials were limited to RCTs in the first-line treatment of patients with metastatic pancreatic cancer. The success rate of first-line phase III studies in advanced pancreatic cancer was only 13%. In 60% of the RCTs, no preclinical experiments were referenced in biologically cognate pancreatic models. Nine (30%) of the RCTs were designed based on preclinical evidence from in vitro cell lines alone without additional in vivo validation in xenograft models. It remains uncertain how strongly the preclinical data influence the development of clinical regimens but so far the studies developed based on more solid preclinical evidence have been successful. PMID- 28085755 TI - Percutaneous Irreversible Electroporation for Ablation of Locally Advanced Pancreatic Cancer: Experience From a Chinese Institution. PMID- 28085756 TI - Spontaneous Resolution of Pancreatic Cyst After Treatment for Giardiasis. PMID- 28085757 TI - Disseminated Intravascular Coagulation on Admission Predicts Complications and Poor Prognosis of Acute Pancreatitis: Analysis of the Nationwide Epidemiological Survey in Japan. PMID- 28085758 TI - CENTRAL RETINAL ARTERY OCCLUSION WITH DOUBLE CILIORETINAL ARTERY SPARING. AB - PURPOSE: To report a patient with central retinal artery occlusion with double cilioretinal artery sparing. METHODS: Retrospective case report. RESULTS: A 45 year-old woman presented with sudden vision loss in her left eye for 10 days. Her best-corrected visual acuity was counting fingers at 2 meters in the left eye and 20/20 in the right eye. Funduscopy showed retinal opacity of posterior fundus, most marked in the macular region, and two small areas of the normal retina; one temporal to the optic disk and the other superior to the optic disk corresponding to the patent cilioretinal retinal arteries in the left eye; the right eye was normal. Fundus fluorescein angiography showed rapid filling of the two cilioretinal vessels and delayed filling of the central retinal artery at initial and last visits. Spectral domain optical coherence tomography findings disclosed diffuse thickening of the neurosensory retina in the perifoveolar area except two small areas at the first visit. After 6 months, spectral domain optical coherence tomography revealed diffuse thinning of the neurosensory retina except two small areas of the retina fed from two patent cilioretinal arteries. CONCLUSION: In this report, we documented double cilioretinal artery sparing in a patient with central retinal artery occlusion. It seems that a second cilioretinal artery can be present in some patients with central retinal artery occlusion. PMID- 28085759 TI - SURGICAL MANAGEMENT OF RETINAL DETACHMENT IN OSTEOGENESIS IMPERFECTA: CASE REPORT AND REVIEW OF THE LITERATURE. AB - PURPOSE: To describe a case of scleral buckling in a patient with severe (Type III) osteogenesis imperfecta. METHODS: Single interventional case report of a 37 year-old woman, with clinically diagnosed osteogenesis imperfecta Type III, presenting with an inferior retinal detachment of the right eye. The patient was promptly treated with scleral buckling. RESULTS: Long-term follow-up has shown a good clinical outcome, with no recurrence of the retinal detachment. Eighteen months postsurgery, an ischemic branch retinal vein obstruction has developed in the right eye, complicated by macular edema. The patient was treated successfully with bevacizumab injections, with restoration of visual acuity to 20/25. CONCLUSION: Scleral buckle may provide a good surgical option in selected patients with osteogenesis imperfecta, yielding excellent anatomical and functional results. PMID- 28085760 TI - OUTER RETINAL TUBULATIONS IN CHRONIC RHEGMATOGENOUS RETINAL DETACHMENT. AB - BACKGROUND/PURPOSE: To present the first reported case of outer retinal tubulations in the setting of a rhegmatogenous retinal detachment. METHODS: Case report. PATIENTS: A 56-year-old man presented with a right eye retinal detachment of unclear duration. On examination, he was found to have a chronic-appearing rhegmatogenous retinal detachment involving the peripheral macula with a demarcation line. RESULTS: Spectral-domain optical coherence tomography revealed outer retinal tubulations in the area of demarcation but not in the area of the detached retina. CONCLUSION: Outer retinal tubulations have been described in a wide spectrum of retinal diseases. The authors herein present the first reported case of outer retinal tubulations in the setting of a rhegmatogenous retinal detachment which may further aid in describing their pathogenesis. PMID- 28085761 TI - NEW FINDINGS FROM MULTIMODAL FUNDUS IMAGING OVER 3 YEARS OF A PATIENT WITH MICROCEPHALY, CHORIORETINOPATHY, AND KIF11 MUTATION. AB - PURPOSE: To describe ocular features and long-term follow-up in a patient with microcephaly, chorioretinopathy, and KIF11 mutation. METHODS: Multimodal imaging including fundus color photography, autofluorescence, spectral-domain optical coherence tomography, visual fields, electrophysiologic assessment, and neuroimaging. RESULTS: A 44-year-old man with microcephaly and long-standing poor vision in his right eye presented for general ophthalmic review. Fundus examination revealed bilateral, symmetrical, inferior, atrophic chorioretinal lacunae, outer retinal and retinal pigment epithelial atrophy, curvilinear streaks, and retinal arteriolar sheathing. These findings were documented over a 3-year period by multimodal imaging and showed slow progressive deterioration in visual acuity, visual field testing, and fundus autofluorescence appearance. Genetic testing confirmed a KIF11 gene mutation. CONCLUSION: Curvilinear streaks and retinal arteriolar sheathing in this patient expand on the more typical fundus findings of KIF11 mutations. The outer retina is preferentially involved, and there is anatomical sparing of the macula until later in the disease state when multifocal electroretinography indicates functional impairment. Lacunae represent scleral depressions with the loss of overlying choroid and outer retina. Slow atrophic progression with loss of vision may occur over time. PMID- 28085762 TI - PARACENTRAL ACUTE MIDDLE MACULOPATHY ASSOCIATED WITH POSTVIRAL PURTSCHER-LIKE RETINOPATHY. AB - PURPOSE: To report the imaging findings of a single case of paracentral acute middle maculopathy associated with bilateral Purtscher-like retinopathy in the setting of recent viral illness. METHODS: Case report, multimodal imaging. RESULTS: A 21-year-old woman who awoke with sudden-onset bilateral finger count vision in the setting of a recent viral illness. Initial examination and imaging was consistent with a bilateral Purtscher-like retinopathy with evidence of paracentral acute middle maculopathy and ellipsoid zone thickening and hyperreflectivity on spectral domain optical coherence tomography (OCT). Baseline fluorescein angiography and OCT angiography revealed normal perfusion and flow, respectively. All laboratory investigation was negative for possible causative etiology. The patient was followed for 6 months with steady visual improvement to 20/20 in both eyes. En face OCT demonstrated near-complete restoration of the ellipsoid layer. The patient still noted bilateral scotomas which were mapped out on microperimetry and found to correlate to en face OCT findings. CONCLUSION: Purtscher-like retinopathy in the setting of recent viral illness is a rare cause of vision loss that may be associated with the finding of paracentral acute middle maculopathy on spectral domain OCT. Despite poor presenting vision, in the presence of normal perfusion near total visual recovery is possible. PMID- 28085763 TI - The Use of Double-Layer Collagen Membrane for the Improvement of Nasal Dorsum Skin Thickness and Texture in Primary Nose Surgery. AB - OBJECTIVES: To place a collagen membrane containing crushed nasal septal cartilage over the nasal dorsum to see how this graft can improve the results of visible postsurgical irregularities in thin skinned patients. METHODS: Fifty seven patients were treated between 2006 and 2010 (26 males and 31 females) whose ages ranged between 31 and 55 years old. They were divided into group a, defect <1 mm, group b defect between 1 and 2 mm, group c defect >3 mm. These patients presented intraoperative nasal dorsum irregularities that were corrected with 57 cartilage grafts in conjunction with collagen membrane. RESULTS: All of our patients showed an initial over-correction. A dense network of collagen fiber bundles was observed running parallel to the surface of the membrane at the connective tissue-membrane interface. The clinical percentage of volume reabsorption was about 5% after 6 months, measured with clinical pictures and a clinical follow-up. No infection was noted, only 1 patient of dislocation was observed, and 5 patients required some refinements at the long-term follow-up. CONCLUSIONS: In the authors' experience the use of bilayered combined cartilage and collagen membrane grafts gives the best aesthetic results with balanced tip projection and dorsum fullness, and avoids thickness and texture modification of the skin above the graft. The use of Bio-gide membrane avoids all problems related to the donor site and shortens surgical time. PMID- 28085764 TI - Spontaneous Intraventricular Pneumocephalus. AB - BACKGROUD: Pneumocephalus without a known underlying cause is defined as spontaneous pneumocephalus. Few patients of intraventricular pneumocephalus have been reported. PATIENT PRESENTATION: An 84-year-old man presented with dysarthria and incontinence. Computed tomography revealed an intraventricular pneumocephalus, thinning in the petrous bone, fluid in the air cells, and cleft in temporal lobe. A right subtemporal extradural approach was taken to detect bone-/-dural defects, and a reconstruction was performed using a musculo pericranial flap. CONCLUSION: This is the first patient of an isolated intraventricular spontaneous pneumocephalus without any other site air involved. Surgical approaches to repair such bone and dura defects should be considered an appropriate option. PMID- 28085765 TI - Quantitative Correlation Between Hyaluronic Acid Filler and Hyaluronidase. AB - The hyaluronic acid-based filler (HA filler) is used worldwide in various applications. In particular, the HA filler is used in the plastics and cosmetic medical field for facial rejuvenation and contouring. In this setting, it is injected into the skin or underlying tissue. Complications of HA filler injection have been relieved using hyaluronidase. However, there is no standard dose to adjust for undesirable HA filler lumpness. In this study, the authors tried to analyze any quantitative correlation between HA filler and hyaluronidase. The back of each rat (total 14 rats) was divided into 4 sites. A volume of 0.5 mL HA filler was injected into the subdermal layer at each site and HA filler nodules were created on the dorsum of each rat. Each nodule was allocated to groups 1, 2, 3, and 4 according to the different concentrations of hyaluronidase. As a result, the injected HA filler volume doubled within 4 days of injection, and then decreased slowly thereafter in group 1 (control group with normal saline only). A 30 unit hyaluronidase treatment compensated for the initial volume increase (approximately 30%) with HA filler (0.5 ml) at the fourth day. Sixty units of hyaluronidase reduced the initial volume (0.5 mL) of overinjected or misplaced HA filler on the fourth day. Approximately 90 units of hyaluronidase can reduce to the volume by 0.25 mL (50%) of the injected HA filler on the fourth day. The authors believe that this quantitative analysis of hyaluronidase concentration is helpful to plan the amount of hyaluronidase for correction of HA filler injection errors. PMID- 28085766 TI - Development of One-Step Drill-Tap for a Resorbable Screw. PMID- 28085768 TI - Use of Pedicled Buccal Fat Pad for Cranial Base Reconstruction. AB - Craniofacial reconstruction for closure of skull base defects after removal of anterior cranial base lesions is challenging. Persistent skull base defect produces extremely high risk of cerebrospinal fluid leaks and consecutive infectious complications. The authors' article focuses on the use of pedicled buccal fat pad for the reconstruction of anterior cranial base defects using combined endoscope-assisted approach and Lefort I access osteotomy. High effectiveness and minimal invasiveness are principal advantages of the technique. Other benefits include proximity of donor site to defect, simplicity of surgical technique, minimal postoperative discomfort, and very low risk of benign complications. Local pedicled grafts are the preferred material for plasty, adding aesthetic results in an ablative surgery using intraoral incision and access osteotomy. Thus, the technique solves the problem of relying on complex alloplastic reconstruction of anterior craniobasal defects. PMID- 28085769 TI - Laparoscopic Free Omental Flap for Craniofacial Reconstruction: A Video Article Demonstrating Operative Technique and Surgical Applications. AB - The omental flap is a well described pedicled flap for surgical reconstruction of multiple body locations. As a laparoscopically harvested free flap, the omentum offers a minimally invasive solution to many reconstructive problems including extremity and head and neck wounds. This video article highlights the operative technique involved in flap harvest and inset for a cranial defect. An illustrative case involving a 23-year-old female's traumatic scalp degloving injury that was resurfaced by free omental flap and split-thickness skin graft is presented. This patient had stable long-term wound coverage for a very severe injury. Through video media we demonstrate that the laparoscopically harvested free omental flap is a minimally invasive, 2-team operation that provides soft tissue coverage of severe, remote wounds. This video demonstrates a safe operative technique and nuances specific to laparoscopic harvest of this flap. PMID- 28085770 TI - Endoscopic-Assisted Palatal Surgery Via Transoral and Intranasal Approach. AB - Palate carcinoma often challenges to the treatment options. It depends on the histologic type, local invasion, and nodal or distant metastasis. Hard palate tumors that invade the nasal cavity can be operated by midfacial degloving approach, lateral rhinotomy approach, and lip splitting incision with infrastructure maxillectomy. These approaches inevitably coincide with facial scars, nerve injuries, facial swelling, and long hospital stay. Transoral robotic assisted surgery can be applied; however, this needs high price and has a weakness of accurate handling about intranasal lesion. The authors have performed transoral and intranasal endoscopic-assisted palatal removal of recurrent palatal carcinoma for a patient and herein report their technique and result. PMID- 28085772 TI - RETINAL PIGMENT EPITHELIAL ATROPHY AFTER ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR INJECTIONS FOR RETINAL ANGIOMATOUS PROLIFERATION. AB - PURPOSE: To investigate the incidence rate and risk factors for development of retinal pigment epithelial (RPE) atrophy during anti-vascular endothelial growth factor (anti-VEGF) treatment for retinal angiomatous proliferation. METHODS: This study included 46 eyes with treatment-naive retinal angiomatous proliferation. All patients were treated with ranibizumab or aflibercept injections. Color fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence were evaluated for RPE atrophy diagnosis. Baseline characteristics and gene polymorphisms of ARMS2 A69S, and CFH I62V were analyzed for association with development and progression of RPE atrophy. RESULTS: Among 21 eyes treated with ranibizumab without preexisting RPE atrophy at baseline, 5 eyes (23.8%) developed RPE atrophy at 12 months. Among 20 eyes treated with aflibercept without preexisting RPE atrophy at baseline, 10 eyes (50.0%) developed RPE atrophy at 12 months. Refractile drusen at baseline was associated with RPE atrophy development at 12 months (P = 0.014), and the progression rate of RPE atrophy area was negatively correlated with subfoveal choroidal thickness at baseline (R = -0.595, P = 0.019). Gene polymorphisms were not associated with RPE atrophy. CONCLUSION: Retinal pigment epithelial atrophy developed in 36.6% during 12 months after anti-VEGF treatment for retinal angiomatous proliferation. The presence of refractile drusen at baseline was identified as a novel significant risk factor for RPE atrophy development. PMID- 28085773 TI - Epiretinal Membrane With Foveal Herniation. PMID- 28085774 TI - BRUCH MEMBRANE AND THE MECHANISM OF MYOPIZATION: A New Theory. AB - BACKGROUND: The process of emmetropization is the adjustment of the length of the optical axis to the given optical properties of the cornea and lens after the end of the second year of life. Since its underlying mechanisms have not been fully explored yet, we reviewed findings available in the literature to discuss its potential etiology and the mechanism of myopization as an overshooting of emmetropization. METHODS: Literature review. RESULTS: The process of emmetropization occurs by axial elongation. Up to the end of the second year of life, the eye grows spherically by active increase in scleral volume. Axial elongation in the process of emmetropization is associated with thinning of the retina and reduced density of retinal pigment epithelium cells (RPE) in the retro equatorial region, and with thinning more of the choroid than of the sclera, starting at the equator and being most marked at the posterior pole. In contrast, retinal thickness and RPE density in the macular region and thickness of Bruch's membrane (BM) in any region are independent of axial length. CONCLUSIONS: It led to the hypothesis that axial elongation occurs by production of BM in the retro equatorial region leading to a decreased RPE density and retinal thinning in that region and a more tube-like than spherical enlargement of the globe, without compromise in the density of the macular RPE cells and in macular retinal thickness. The increased disc-fovea distance in axially myopic eyes is caused by the development and enlargement of parapapillary, BM free, gamma zone while the length of macular BM, and indirectly macular RPE cell density and macular retinal thickness, remain constant. The target tissue for medical modification of emmetropization/myopization may be the RPE, producing and elongating BM in the retro-equatorial region. PMID- 28085775 TI - ASSESSMENT OF THE RETINAL STRUCTURE IN CHILDREN WITH INCONTINENTIA PIGMENTI. AB - PURPOSE: This report aims at expanding the current knowledge of retinal microanatomy in children with incontinentia pigmenti using hand-held spectral domain optical coherence tomography (SDOCT). METHODS: We reviewed OCT scans from 7 children (4 weeks-13 years) obtained either in the clinic or during an examination under anesthesia. The scans were analyzed for anatomical changes in the outer and inner retina, by certified graders. Medical records were assessed for systemic findings. RESULTS: We observed abnormal retinal findings unilaterally in three children. We found inner and outer retinal thinning temporally in two participants. This thinning was present prior to and persisted after treatment. One child showed a distorted foveal contour and significant retinal thickening secondary to dense epiretinal membrane and vitreomacular traction. All other children had normal retinae. CONCLUSION: Hand-held SDOCT imaging of the retina has brought to light additional retinal structural defects that were not previously reported or visualized via routine clinical ophthalmic examination including retinal photography. Despite a normal foveal structure and visual acuity, we identified inner and outer retinal thinning on SDOCT which may benefit from future functional assessment such as visual field testing. PMID- 28085778 TI - Have a heart: Celebrate American Heart Month. PMID- 28085776 TI - VITREOUS INCARCERATION IN SCLEROTOMIES AFTER VALVED 23-, 25-, OR 27-GAUGE AND NONVALVED 23- OR 25-GAUGE MACULAR SURGERY. AB - PURPOSE: To study the patterns of vitreous incarceration at sclerotomy sites by ultrasound biomicroscopy in patients subjected to valved or nonvalved small-gauge pars plana vitrectomy. METHODS: A prospective comparative study of 88 eyes affected by epiretinal membrane and macular hole. Patients were divided into four groups: valved or nonvalved 23-gauge (16 eyes each) and valved or nonvalved 25 gauge (20 eyes each); their vitreal disposition was compared by ultrasound biomicroscopy. Vitreal disposition was also assessed in 16 eyes of 16 patients subjected to valved 27-gauge pars plana vitrectomy. RESULTS: Three vitreal patterns were identified: P0 (vitreous not visible or vitreous strand distant from the sclerotomy site), P1 (vitreous strand parallel to and in contact with the sclerotomy site), and P2 (vitreous strand entrapped in the sclerotomy site). The effect of valved trocar use on vitreous incarceration seemed to be somewhat beneficial, but no statistically significant effect could be shown (odds ratio: 0.85, 95% confidence interval: 0.42-1.74, P = 0.657). Similarly, no differences in vitreous incarceration were shown among vitrectomy gauges (23, 25, or 27) both in a model including valved trocars only (P = 0.858) and in a model with all available data (P = 0.935). CONCLUSION: In 23- and 25-gauge macular surgeries, postoperative vitreous incarceration does not seem to be reduced using valved cannulas and was similar to that observed in 27-gauge surgery. PMID- 28085777 TI - What's New in Shock, February 2017? PMID- 28085780 TI - Albiglutide for the treatment of type 2 diabetes mellitus. PMID- 28085779 TI - Working together to make things better. PMID- 28085781 TI - The transition of care from hospital to home for patients with hypertension. PMID- 28085782 TI - Opioids for pain management in older adults: Strategies for safe prescribing. PMID- 28085783 TI - Approaches to male hypogonadism in primary care. AB - Evidence suggests that providers are not adhering to current testosterone replacement therapy guidelines when treating male hypogonadism. Understanding the diagnosis and management of this condition is further complicated by conflicting recommendations among available guidelines. NPs must select and follow the best guideline recommendations available to optimally treat male hypogonadism. PMID- 28085784 TI - NCNP 2016: Poster presentation winner. PMID- 28085785 TI - Interpreting measures of risk: Translating evidence into practice. AB - Advanced practice registered nurses must have a working knowledge of statistical principles in order to provide high-quality, evidence-based care. This article presents basic concepts of risk indexes and case study examples illustrating how these measures can inform practice. PMID- 28085787 TI - A missed diagnosis of trichomoniasis. PMID- 28085788 TI - Essentials of Our Current Understanding: Abdominal Wall Blocks. AB - Abdominal wall blocks rely on the spread of local anesthetic within musculofascial planes to anesthetize multiple small nerves or plexuses, rather than targeting specific nerve structures. Ultrasonography is primarily responsible for the widespread adoption of techniques including transversus abdominis plane and rectus sheath blocks, as well as the introduction of novel techniques such as quadratus lumborum and transversalis fascia blocks. These blocks are technically straightforward and relatively safe and reduce pain and opioid requirements in many clinical settings. The data supporting these outcomes, however, can be inconsistent because of heterogeneity of study design. The extent of sensory blockade is also somewhat variable, because it depends on the achieved spread of local anesthetic and the anatomical course of the nerves being targeted. The blocks mainly provide somatic analgesia and are best used as part of a multimodal analgesic regimen. This review summarizes the anatomical, sonographic, and technical aspects of the abdominal wall blocks in current use, examining the current evidence for the efficacy and safety of each. PMID- 28085789 TI - Reporting of Design Features and Analysis Details in Randomized Clinical Trials of Procedural Treatments for Cancer Pain: An ACTTION Systematic Review. AB - BACKGROUND AND OBJECTIVES: The objective of this study was to assess the reporting of randomized clinical trials investigating procedural treatments (eg, nerve blocks, targeted drug delivery) for cancer pain, with a focus on aspects that are particularly challenging in these trials. METHODS: This article presents results from a systematic review of reporting of randomized clinical trials of procedural interventions for cancer pain. Articles were identified by searching PubMed from 1966 to June 2014. Data related to quality of reporting are presented for early (1985-2004) and late periods (2005-2014). RESULTS: A total of 35 published trials were included. Approximately two-thirds of the articles clearly indicated the level of blinding. Only 26% reported a primary outcome measure. Less than half explicitly reported the number of patients who completed the trial, and only 1 reported a method that was used to accommodate missing data. Almost one-third of articles included a responder analysis, all of which specified the definition of a responder. CONCLUSIONS: The goal of highlighting these deficiencies in reporting is to promote transparent reporting of details affecting the completion and interpretation of procedural cancer pain trials so that their quality can be more easily evaluated. PMID- 28085790 TI - Epidermal Growth Factor-Containing Fibulin-Like Extracellular Matrix Protein 1 (EFEMP1) Acts as a Potential Diagnostic Biomarker for Prostate Cancer. AB - BACKGROUND The aim of this study was to detect the expression of epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) and estimate its diagnostic value in prostate cancer (PCa). MATERIAL AND METHODS EFEMP1 expression in serum and urine of patients with PCa, benign controls and healthy controls at mRNA and protein level were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) analysis, respectively. The chi-square test was used to analyze the relationship between EFEMP1 expression and clinical factors of patients with PCa. A receiver operating characteristic (ROC) curve was established to evaluate the potential values of EFEMP1 for the diagnosis of PCa. RESULTS The relative expression of EFEMP1 was significantly decreased in patients with PCa compared with that in the benign controls and healthy individuals, both at mRNA and protein levels (P<0.05). In the postoperative serum, the EFEMP1 expression was significantly higher than that in preoperative serum at 2 levels. Urine EFEMP1 expression was also down-regulated in patients with PCa compared to that in the other 2 control groups. The low expression of EFEMP1 was obviously affected by Gleason's score, serum PSA, pathological stage, and lymph node metastasis. Moreover, there was a significant inverse correlation between EFEMP1 expression and PSA levels. The ROC curve revealed that EFEMP1 distinguished PCa patients from healthy controls, with a high AUC of 0.908, corresponding with high sensitivity and specificity, which was significantly higher than the PSA value. CONCLUSIONS Serum EFEMP1 is down-regulated and involved in the progression of PCa. It may serve as a useful diagnostic biomarker, with better diagnostic accuracy than PSA in PCa. PMID- 28085791 TI - Relevance of C5b9 immunostaining in the diagnosis of neonatal hemochromatosis. AB - BACKGROUND: Neonatal hemochromatosis caused by a gestational alloimmune mechanism or gestational alloimmune liver disease (GALD) is a rare perinatal disorder characterized by intra- and extrahepatic iron overload. It is believed to result from complement-mediated liver injury, in which the classical complement pathway is activated by maternal antibody/fetal antigen complexes, leading to hepatocyte lysis by the membrane attack complex C5b9. According to some authors, C5b9 expression in more than 75% of liver parenchyma is specific for GALD. METHODS: We conducted a retrospective multicentric immunohistochemical study with anti-C5b9 in GALD cases (n = 25) and non-GALD cases with iron overload (n = 36) and without iron overload (n = 18). RESULTS: C5b9 was expressed in 100% of GALD cases but involved more than 75% of the liver parenchyma in only 26% of the cases. C5b9 was detected in 26.75% of the non-GALD cases with more than 75% of positive parenchyma in maternal erythrocytic alloimmunization, herpes and enterovirus hepatitis, bile acid synthetic defect, DGUOK mutation, Gaucher disease, cystic fibrosis, and giant-cell hepatitis with autoimmune hemolytic anemia. CONCLUSION: Diagnosis and therapeutic management of GALD cannot only be based on C5b9 expression in liver samples as it is not specific of this disease. PMID- 28085795 TI - Improving performance of mobile fronthaul architecture employing high order delta sigma modulator with PAM-4 format. AB - An improved high-order delta-sigma modulator with multi-level quantizer is proposed to enable carrier aggregation of 4G-LTE signals in mobile fronthaul. Different from conventional delta-sigma modulation-based digital mobile fronthaul, a 2-bit quantizer is employed to reduce the quantization noise, which enabling the transmission via PAM-4 based IM-DD channel. Moreover, we employ the 4th-order high-pass filter (HPF) to replace the 1st-order HPF in the conventional delta-sigma modulator, resulting in a much better noise shaping performance. In the experiment, a PAM-4 based mobile fronthaul transmission of 32 aggregated 4G LTE signals with a CPRI equivalent data rate of 39.32-Gb/s is demonstrated in a single-lambda 10-Gb/s IM-DD channel. Significant improvement of 68% is achieved in the average EVM performance compared to the previous delta-sigma modulation based digital mobile fronthaul. PMID- 28085793 TI - 25-hydroxyvitamin D correlates with inflammatory markers in cord blood of healthy newborns. AB - BACKGROUND: Vitamin D is a potent immunomodulator and may play a role in the development of the fetal innate immune functions. The aim of our study was to evaluate inflammatory markers in cord blood of healthy newborns in relation to vitamin D status at birth. METHODS: We studied the concentrations of inflammatory markers, matrix metalloproteinase 8 (MMP-8) and high sensitivity CRP (hs-CRP), and 25-hydroxyvitamin D (25(OH)D) in cord blood of 939 healthy term infants born to mothers of Caucasian origin. We evaluated perinatal factors that affect the concentrations of MMP-8 and hs-CRP, and further explored associations between cord blood 25(OH)D and these inflammatory biomarkers. RESULTS: Majority (99%) of the cohort was vitamin D sufficient (>50 nmol/l or 20 ng/ml). We observed a positive correlation between cord blood 25(OH)D and MMP-8 concentrations, and between 25(OH)D and hs-CRP concentrations. After adjustment for potential confounders (parity, antenatal antibiotic treatment, gestational age, mode of delivery, and maternal prepregnancy BMI), the association of 25(OH)D with MMP-8 and hs-CRP remained significant. CONCLUSION: Cord blood 25(OH)D correlates with inflammatory markers MMP-8 and hs-CRP. The findings may reflect the diverse immunomodulatory functions of vitamin D in the innate immune response of the newborn. PMID- 28085796 TI - Quantum-limited timing jitter characterization of mode-locked lasers by asynchronous optical sampling. AB - We demonstrate a novel time domain timing jitter characterization method for ultra-low noise mode-locked lasers. An asynchronous optical sampling (ASOPS) technique is employed, allowing timing jitter statistics on a magnified timescale. As a result, sub femtosecond period jitter of an optical pulse train can be readily accessible to slow detectors and electronics (~100 MHz). The concept is applied to determine the quantum-limited timing jitter for a passively mode-locked Er-fiber laser. Period jitter histogram is acquired following an eye diagram analysis routinely used in electronics. The identified diffusion constant for pulse timing agrees well with analytical solution of perturbed master equation. PMID- 28085792 TI - Neonatal mice with necrotizing enterocolitis-like injury develop thrombocytopenia despite increased megakaryopoiesis. AB - BACKGROUND: Thrombocytopenia is frequently encountered in infants with necrotizing enterocolitis (NEC). To develop a preclinical model of NEC-related thrombocytopenia, we measured serial platelet counts in 10-d-old (P10) mouse pups with trinitrobenzene sulfonic acid (TNBS)-induced NEC-like injury. We also measured platelet volume indices, immature platelet fraction (IPF), and megakaryocyte number/ploidy in these animals. METHODS: Platelet counts, platelet volume indices, and IPF were measured in control (N = 65) and TNBS-treated pups (N = 104) using an automated hematology analyzer. Bone marrow megakaryocyte number, ploidy and CD41 expression were measured by flow cytometry. These findings were confirmed in a small cohort of P3 mice with NEC-like injury. RESULTS: Murine pups with TNBS-mediated NEC-like injury developed thrombocytopenia at 15-24 h after exposure to TNBS. Intestinal injury was associated with increased platelet volume indices (mean platelet volume, platelet to-large cell ratio, and platelet distribution width), and IPF, indicating increased thrombopoiesis. These mice also showed increased megakaryocyte number, ploidy, and CD41 expression, indicating increased megakaryocyte differentiation. CONCLUSION: Similar to human NEC, murine NEC-like injury was also associated with decreased platelet counts. There was evidence of increased megakaryocyte differentiation and thrombopoiesis, which favors peripheral consumption of platelets as the likely mechanism of thrombocytopenia in these animals, over decreased platelet production. PMID- 28085797 TI - Enlarging the color gamut of liquid crystal displays with a functional reflective polarizer. AB - We propose to add a functional reflective polarizer (FRP) in the backlight unit to suppress the crosstalk between red, green and blue color filters of a liquid crystal display (LCD) panel. When incorporated with a commercial two-phosphor converted white light-emitting diode (2pc-WLED), the color gamut of the LCD can be improved from 92% to 115% NTSC standard, which is comparable to the cadmium based quantum dot (QD) backlight. If a narrow-band color filter is employed, the color gamut can be further enhanced to 135% NTSC. Our design offers an alternative approach to QDs, while keeping low cost and long lifetime. Such a simple yet efficient approach would find widespread applications for enlarging the color gamut of LCDs. PMID- 28085798 TI - Fast computer generated hologram calculation with a mini look-up table incorporated with radial symmetric interpolation. AB - The amount of heavy computation in Computer Generated Hologram (CGH) can be significantly reduced by pre-computing look-up tables. However, the huge memory usage of look-up tables is a major challenge. To address this problem, the Look up tables can be efficiently compressed by methods such as radial symmetric interpolation. In this paper, we notice that there is still data redundancy in the look-up table of radial symmetric interpolation method and the table size can be further compressed to 5%-10% or even less of original, by our proposed mini look-up table approach based on Principal Component Analysis (PCA). The compressed look-up table in our scheme only occupies a memory size of around 200 300 KB or even less. Moreover, the proposed scheme will introduce almost no extra cost of computation speed slowdown and reconstructed image quality degradation, compared to conventional method. PMID- 28085799 TI - On-chip electro-optic tuning of a lithium niobate microresonator with integrated in-plane microelectrodes. AB - We demonstrate electro-optic tuning of an on-chip lithium niobate microresonator with integrated in-plane microelectrodes. First, the metallic microelectrodes were fabricated on the substrate using a femtosecond laser. Then high-Q lithium niobate microresonator located between the microelectrodes was further fabricated by femtosecond laser direct writing accompanied by focused ion beam milling. Thanks to the efficient design, a high electro-optical tuning coefficient of 3.41 pm/V has been obtained. PMID- 28085800 TI - Modeling the depth-sectioning effect in reflection-mode dynamic speckle-field interferometric microscopy. AB - Unlike most optical coherence microscopy (OCM) systems, dynamic speckle-field interferometric microscopy (DSIM) achieves depth sectioning through the spatial coherence gating effect. Under high numerical aperture (NA) speckle-field illumination, our previous experiments have demonstrated less than 1 MUm depth resolution in reflection-mode DSIM, while doubling the diffraction limited resolution as under structured illumination. However, there has not been a physical model to rigorously describe the speckle imaging process, in particular explaining the sectioning effect under high illumination and imaging NA settings in DSIM. In this paper, we develop such a model based on the diffraction tomography theory and the speckle statistics. Using this model, we calculate the system response function, which is used to further obtain the depth resolution limit in reflection-mode DSIM. Theoretically calculated depth resolution limit is in an excellent agreement with experiment results. We envision that our physical model will not only help in understanding the imaging process in DSIM, but also enable better designing such systems for depth-resolved measurements in biological cells and tissues. PMID- 28085801 TI - Fiber Bragg grating sensors in hollow single- and two-core eccentric fibers. AB - Fiber Bragg gratings (FBGs) in a hollow eccentric fiber (HEF) have been proposed and demonstrated experimentally. The single-core and two-core HEF FBGs have been inscribed successfully using KrF excimer laser (248 nm), respectively. The temperature and axial strain sensing properties of the two samples have been measured. The experimental results indicate that the temperature and axial strain sensitivities of the two samples are similar, but they are smaller than that of conventional SMF-FBGs. Furthermore, the bending characteristics of the two-core HEF-FBG strongly depend on the bending direction due to the asymmetry of the fiber. Therefore, the proposed two-core HEF-FBGs facilitate temperature compensated vector-bending sensing by measuring the difference between peak shifts of the two gratings. In addition, the two-core HEF-FBG can be a promising candidate for achieving two-channel filter since the signal crosstalk between the two cores can be largely eliminated by the central air hole. PMID- 28085802 TI - Quasi-classical analysis of the dynamics of the high-order harmonic generation from solids. AB - We introduce a quasi-classical model in the k space combined with the energy band structure of solids to understand the mechanisms of high-order harmonic generation (HHG) process occurring in a subcycle timescale. This model interprets the multiple plateau structure in HHG spectra well and the linear dependence of cutoff energies on the amplitude of vector potential A0 of the laser fields. It also predicts the emission time of HHG, which agrees well with the results by solving the time-dependent Schrodinger equation (TDSE). It provides a scheme to reconstruct the energy dispersion relations in Brillouin zone and to control the trajectories of HHG by varying the shape of laser pulses. This model is instructive for experimental measurements. PMID- 28085803 TI - Shortcuts to adiabaticity in optical waveguides using fast quasiadiabatic dynamics. AB - We propose a fast quasiadiabatic approach to the design of optical waveguide devices. This approach distributes the system adiabaticity homogeneously over the device length, thus providing a shortcut to adiabaticity at a shorter device length. A mode sorting asymmetric Y junction is designed by redistributing the adiabaticity of a conventional linearly separating Y junction. Simple procedures for the design of fast quasiadiabatic devices are outlined, and the designed Y junction features large bandwidth at a shorter length than the conventional linearly separating Y junction. The proposed device is verified with beam propagation simulations. A mode conversion efficiency of larger than 99% is observed for the designed Y junction over a 220 nm range. PMID- 28085804 TI - Fourier ptychographic microscopy using a generalized Anscombe transform approximation of the mixed Poisson-Gaussian likelihood. AB - Fourier ptychographic microscopy (FPM) is a novel computational microscopy technique that provides intensity images with both wide field-of-view (FOV) and high-resolution (HR). By combining ideas from synthetic aperture and phase retrieval, FPM iteratively stitches together a number of variably illuminated, low-resolution (LR) intensity images in Fourier space to reconstruct an HR complex sample image. In practice, however, the reconstruction of FPM is sensitive to the input noise, including Gaussian noise, Poisson shot noise or mixed Poisson-Gaussian noise. To efficiently address these noises, we developed a novel FPM reconstruction method termed generalized Anscombe transform approximation Fourier ptychographic (GATFP) reconstruction. The method utilizes the generalized Anscombe transform (GAT) approximation for the noise model, and a maximum likelihood theory is employed for formulating the FPM optimization problem. We validated the proposed method with both simulated data for quantitative evaluation and real experimental data captured using FPM setup. The results show that the proposed method achieves state-of-the-art performance in comparison with other approaches. PMID- 28085805 TI - Ion-redistribution induced efficient upconversion in beta NaYF4:20%Yb3+,2%Er3+ microcrystals with well controlled morphology and size. AB - We develop an efficient green upconversion (UC) beta NaYF4:20%Yb3+,2%Er3+ microcrystal with well controlled morphology and size by hydrothermal method using two different chelating agents of CIT and EDTA-2Na via a simple ion-exchange reaction. Importantly, the UC emission efficiency of newly developed CIT and EDTA-2Na beta NaYF4:20%Yb3+,2%Er3+ microcrystals is almost as strong as that of commercial counterpart by solid-state method. A proof-of concept beta-NaYF4:20%Yb3+,2%Er3+ microcrystal waveguide is demonstrated to extend their applications in modern micro optoelectronics. The local ion-redistribution process during the ion-exchange reaction, which effectively disperses the locally clustered Yb3+, accounts for the enormously enhanced UC emission in beta NaYF4:20%Yb3+,2%Er3+ microcrystals. PMID- 28085806 TI - Experimental realization of a terahertz all-dielectric metasurface absorber. AB - Metamaterial absorbers consisting of metal, metal-dielectric, or dielectric materials have been realized across much of the electromagnetic spectrum and have demonstrated novel properties and applications. However, most absorbers utilize metals and thus are limited in applicability due to their low melting point, high Ohmic loss and high thermal conductivity. Other approaches rely on large dielectric structures and / or a supporting dielectric substrate as a loss mechanism, thereby realizing large absorption volumes. Here we present a terahertz (THz) all dielectric metasurface absorber based on hybrid dielectric waveguide resonances. We tune the metasurface geometry in order to overlap electric and magnetic dipole resonances at the same frequency, thus achieving an experimental absorption of 97.5%. A simulated dielectric metasurface achieves a total absorption coefficient enhancement factor of FT=140, with a small absorption volume. Our experimental results are well described by theory and simulations and not limited to the THz range, but may be extended to microwave, infrared and optical frequencies. The concept of an all-dielectric metasurface absorber offers a new route for control of the emission and absorption of electromagnetic radiation from surfaces with potential applications in energy harvesting, imaging, and sensing. PMID- 28085807 TI - Mitigation of relative intensity noise of quantum dash mode-locked lasers for PAM4 based optical interconnects using encoding techniques. AB - Quantum dash (Q-Dash) passively mode-locked lasers (PMLLs) exhibit significant low frequency relative intensity noise (RIN), due to the high mode partition noise (MPN), which prevents the implementation of multilevel amplitude modulation formats such as PAM4. The authors demonstrate low frequency RIN mitigation by employing 8B/10B and Manchester encoding with PAM4 modulation format. These encoding techniques reduce the overlap between the modulation spectral content and the low-frequency RIN of the Q-dash devices, at the expense of increased overhead. The RIN of the 33.6 GHz free spectral range Q-dash PMLL was characterized, and the results obtained show very high levels of RIN from DC to 4 GHz, but low levels for higher frequencies. The performance improvement for 28 GBaud 8B/10B and Manchester encoded PAM4 signal has been demonstrated compared to the case when no encoding is used. Finally, the effect of RIN on the system performance was demonstrated by comparing the bit error rate (BER) performance of the PAM4 signaling obtained with an external cavity laser (ECL) to those obtained with Q-dash PMLL. PMID- 28085808 TI - Information gain versus interference in Bohr's principle of complementarity. AB - We study the wave and particle nature in a symmetric Mach-Zehnder interferometer from the viewpoint of quantum information theory. By introducing either the von Neumann or Zurek's model of quantum measurement, we find that the classical correlation can be used to quantify the particle nature since its monotonicity is similar to the path distinguishability. The environment in Zurek's model induces the emergence of the optimal measuring basis, and reduces the classical and quantum correlation comparing to the von Neumann's model. A way is presented analytically to calculate the quantum correlation of a two-qubit separable state other than X-type. PMID- 28085809 TI - Wavelength-locked vectorial fiber laser manipulated by Pancharatnam-Berry phase. AB - We report a wavelength-locked cladding-pumped ytterbium-doped fiber laser that can simultaneously emit radially and azimuthally polarized beams based on Pancharatnam-Berry phase optical elements. Multi-wavelength free running operation of the radially and azimuthally polarized laser beams can be switched to a single-wavelength one assisted by volume Bragg grating, with wavelength locked at around 1053.4 nm and spectral linewidth of 0.06 nm (FWHW). By rotating the glan-taylor polarizer, we can obtain switchable radially and azimuthally polarized beams output. The radially and azimuthally polarized beams mode purity can maintain 97.3% and 96.3% at maximum output power, and the polarization extinction ratio (PER) can reach 97.8% and 95.9% for the radially and azimuthally polarized laser, respectively. PMID- 28085810 TI - Real-time kinetic binding studies at attomolar concentrations in solution phase using a single-stage opto-biosensing platform based upon infrared surface plasmons. AB - Here we present a new generic opto-bio-sensing platform combining immobilised aptamers on an infrared plasmonic sensing device generated by nano-structured thin film that demonstrates amongst the highest index spectral sensitivities of any optical fibre sensor yielding on average 3.4 * 104 nm/RIU in the aqueous index regime (with a figure of merit of 330) This offers a single stage, solution phase, atto-molar detection capability, whilst delivering real-time data for kinetic studies in water-based chemistry. The sensing platform is based upon optical fibre and has the potential to be multiplexed and used in remote sensing applications. As an example of the highly versatile capabilities of aptamer based detection using our platform, purified thrombin is detected down to 50 attomolar concentration using a volume of 1mm3 of solution without the use of any form of enhancement technique. Moreover, the device can detect nanomolar levels of thrombin in a flow cell, in the presence of 4.5% w/v albumin solution. These results are important, covering all concentrations in the human thrombin generation curve, including the problematic initial phase. Finally, selectivity is confirmed using complementary and non-complementary DNA sequences that yield performances similar to those obtained with thrombin. PMID- 28085811 TI - Distance measurement based on light field geometry and ray tracing. AB - In this paper, we propose a geometric optical model to measure the distances of object planes in a light field image. The proposed geometric optical model is composed of two sub-models based on ray tracing: object space model and image space model. The two theoretic sub-models are derived on account of on-axis point light sources. In object space model, light rays propagate into the main lens and refract inside it following the refraction theorem. In image space model, light rays exit from emission positions on the main lens and subsequently impinge on the image sensor with different imaging diameters. The relationships between imaging diameters of objects and their corresponding emission positions on the main lens are investigated through utilizing refocusing and similar triangle principle. By combining the two sub-models together and tracing light rays back to the object space, the relationships between objects' imaging diameters and corresponding distances of object planes are figured out. The performance of the proposed geometric optical model is compared with existing approaches using different configurations of hand-held plenoptic 1.0 cameras and real experiments are conducted using a preliminary imaging system. Results demonstrate that the proposed model can outperform existing approaches in terms of accuracy and exhibits good performance at general imaging range. PMID- 28085812 TI - Fast generation of computer-generated holograms using wavelet shrinkage. AB - Computer-generated holograms (CGHs) are generated by superimposing complex amplitudes emitted from a number of object points. However, this superposition process remains very time-consuming even when using the latest computers. We propose a fast calculation algorithm for CGHs that uses a wavelet shrinkage method, eliminating small wavelet coefficient values to express approximated complex amplitudes using only a few representative wavelet coefficients. PMID- 28085813 TI - Dissipative preparation of distributed steady entanglement: an approach of unilateral qubit driving. AB - We propose a nonlocal scheme for preparing a distributed steady-state entanglement of two atoms trapped in separate optical cavities coupled through an optical fiber based on the combined effect of the unitary dynamics and dissipative process. In this scheme, only the qubit of one node is driven by an external classical field, while the other one does not need to be manipulated by an external field. This is meaningful for long distance quantum information processing tasks, and the experimental implementation is greatly simplified due to the unilateral manipulation on one node and the process of entanglement distribution can be avoided. This guarantees the absolute security of long distance quantum information processing tasks and makes the scheme more robust than that based on the unitary dynamics. We introduce the purity to characterize the mixture degree of the target steady-state. The steady entanglement can be obtained independent of the initial state. Furthermore, based on the dissipative entanglement preparation scheme, we construct a quantum teleportation setup with multiple nodes as a practical application, and the numerical simulation demonstrates the scheme can be realized effectively under the current experimental conditions.. PMID- 28085814 TI - High dynamic spectroscopy using a digital micromirror device and periodic shadowing. AB - We present an optical solution called DMD-PS to boost the dynamic range of 2D imaging spectroscopic measurements up to 22 bits by incorporating a digital micromirror device (DMD) prior to detection in combination with the periodic shadowing (PS) approach. In contrast to high dynamic range (HDR), where the dynamic range is increased by recording several images at different exposure times, the current approach has the potential of improving the dynamic range from a single exposure and without saturation of the CCD sensor. In the procedure, the spectrum is imaged onto the DMD that selectively reduces the reflection from the intense spectral lines, allowing the signal from the weaker lines to be increased by a factor of 28 via longer exposure times, higher camera gains or increased laser power. This manipulation of the spectrum can either be based on a priori knowledge of the spectrum or by first performing a calibration measurement to sense the intensity distribution. The resulting benefits in detection sensitivity come, however, at the cost of strong generation of interfering stray light. To solve this issue the Periodic Shadowing technique, which is based on spatial light modulation, is also employed. In this proof-of-concept article we describe the full methodology of DMD-PS and demonstrate - using the calibration based concept - an improvement in dynamic range by a factor of ~100 over conventional imaging spectroscopy. The dynamic range of the presented approach will directly benefit from future technological development of DMDs and camera sensors. PMID- 28085815 TI - Simple geometric interpretation of signal evolution in phase-sensitive fibre optic parametric amplifier. AB - Visualisation of complex nonlinear equation solutions is a useful analysis tool for various scientific and engineering applications. We have re-examined the geometrical interpretation of the classical nonlinear four-wave mixing equations for the specific scheme of a phase sensitive one-pump fiber optical parametric amplification, which has recently attracted revived interest in the optical communications due to potential low noise properties of such amplifiers. Analysis of the phase portraits of the corresponding dynamical systems provide valuable additional insight into field dynamics and properties of the amplifiers. Simple geometric approach has been proposed to describe evolution of the waves, involved in phase-sensitive fiber optical parametric amplification (PS-FOPA) process, using a Hamiltonian structure of the governing equations. We have demonstrated how the proposed approach can be applied to the optimization problems arising in the design of the specific PS-FOPA scheme. The method considered here is rather general and can be used in various applications. PMID- 28085816 TI - Software-defined control-plane for wavelength selective unicast and multicast of optical data in a silicon photonic platform. AB - We demonstrate a programmable control-plane based on field programmable gate array (FPGA) with a power-efficient algorithm for optical unicast, multicast, and broadcast functionalities in a silicon photonic platform. The platform includes a silicon photonic 1*8 microring array chip which in conjunction with a fast tunable laser over the C-band is capable of delivering software controlled wavelength selective functionality on top of spatial switching. We characterize the thermo-optic response of microring resonators and extract key parameters necessary for the development of the control-plane. The performance of the proposed architecture is tested with 10 Gb/s on-off keying (OOK) optical data and error-free operation is verified for various wavelength and spatial switching scenarios. Lastly, we evaluate electrical power and energy consumption required to reconfigure the silicon photonic device for all possible wavelength operations and output ports combinations and show that unicast, multicast of two, three, four, five, six, seven, and broadcast functions are achieved with energy overheads of 0.02, 0.07, 0.18, 0.49, 0.76, 1.01, 1.3, and 1.55 pJ/bit, respectively. PMID- 28085817 TI - Concurrency of anisotropy and spatial dispersion in low refractive index dielectric composites. AB - The article demonstrates uncommon manifestation of spatial dispersion in low refractive index contrast 3D periodic dielectric composites with periods of about one tenth of the wavelength. First principles simulations by the well established plane wave method reveal that spatial dispersion leads to appearance of additional optical axes and can compensate anisotropy in certain directions. PMID- 28085818 TI - Compressive holographic video. AB - Compressed sensing has been discussed separately in spatial and temporal domains. Compressive holography has been introduced as a method that allows 3D tomographic reconstruction at different depths from a single 2D image. Coded exposure is a temporal compressed sensing method for high speed video acquisition. In this work, we combine compressive holography and coded exposure techniques and extend the discussion to 4D reconstruction in space and time from one coded captured image. In our prototype, digital in-line holography was used for imaging macroscopic, fast moving objects. The pixel-wise temporal modulation was implemented by a digital micromirror device. In this paper we demonstrate 10* temporal super resolution with multiple depths recovery from a single image. Two examples are presented for the purpose of recording subtle vibrations and tracking small particles within 5 ms. PMID- 28085819 TI - Low-loss curved waveguides in polymers written with a femtosecond laser. AB - We present straight and s-curve waveguides in polymers fabricated by femtosecond laser writing. A number of parallel tracks are written inside the bulk material with a well-defined gap in the middle that forms the waveguide core. This approach offers the flexibility to tailor the mode-field diameter of the waveguide by adjusting the size of the gap. The waveguides exhibit very low propagation losses of 0.3 dB/cm and no significant bend losses for curve radii of R >= 20 mm. This fabrication process will allow for the realization of complex waveguide networks in a compact footprint chip. PMID- 28085820 TI - Room-temperature Fabry-Perot resonances in suspended InGaAs/InP quantum-well nanopillars on a silicon substrate. AB - We present a new platform based on suspended III-V semiconductor nanopillars for direct integration of optoelectronic devices on a silicon substrate. Nanopillars grown in core-shell mode with InGaAs/InP quantum wells can support long wavelength Fabry-Perot resonances at room temperature with this novel configuration. Experimental results are demonstrated at a silicon-transparent wavelength of 1460 nm, facilitating integration with silicon platform. PMID- 28085821 TI - Enhanced terahertz sensing with a coupled comb-shaped spoof surface plasmon waveguide. AB - A comb-shaped waveguide based on the excitation of coupled spoof surface plasmon (CSSP) mode is investigated, and is found to have a pronounced effect for the enhancement of fingerprint detection sensitivity in the terahertz (THz) regime. Composed of two oppositely oriented metal stripes with single-side comb-shaped corrugations, the waveguide is formed due to the coupling of SSP modes supported by metal corrugations on both sides and the mode is tightly localized between the central gap, which provides a perfect site for accommodating the samples in THz sensing. The effective detection of thin-layer lactose is given as an example to demonstrate the sensitive detection of it at a thickness of only a few microns. A transmission spectrum through the waveguide with a pronounced dip at its characteristic absorption frequency of 0.529THz is shown, which can never be observed using the transmission through a lactose layer with the same thickness. PMID- 28085822 TI - Phase matching alters spatial multiphoton processes in dense atomic ensembles. AB - Multiphoton processes in dense atomic vapors such as four-wave mixing or coherent blue light generation are typically viewed from single-atom perspective. Here we study the surprisingly important effect of phase matching near two-photon resonances that arises due to spatial extent of the atomic medium within which the multiphoton process occurs. The non-unit refractive index of the atomic vapor may inhibit generation of light in nonlinear processes, significantly shift the efficiency maxima in frequencies and redirect emitted beam. We present these effects on an example of four-wave mixing in dense rubidium vapors in a double ladder configuration. By deriving a simple theory that takes into account essential spatial properties of the process, we give precise predictions and confirm their validity in the experiment. The model allows us to improve on the geometry of the experiment and engineer more efficient four-wave mixing. PMID- 28085823 TI - High efficiency, low cost holographic optical elements for ultracold atom trapping. AB - We demonstrate a method of creating high efficiency, high fidelity, holographic optical elements for the generation of complex optical fields, in a low cost photopolymer, Bayfol HX. The desired optical field profile is generated by a spatial light modulator and written into an optically addressable photopolymer as a volume hologram. We demonstrate the utility of this approach by trapping a Bose Einstein condensate of rubidium-87 atoms in the nodal plane of an HG0,1 mode generated by one of these holographic optical elements. We also extend this method to the generation holograms with twice the angular momentum per photon than can be generated with a given spatial light modulator. PMID- 28085824 TI - Laser damage properties of broadband low-dispersion mirrors in sub-nanosecond laser pulse. AB - Broadband low dispersion (BBLD) mirrors are an essential component in femto second (fs) pulse laser systems. We designed and produced Ta2O5-HfO2/SiO2 composite quarter wave and non-quarter-wave HfO2/SiO2 BBLD mirrors for the 30fs petawatt laser system. The laser damage properties of the BBLD mirrors were investigated in an uncompressed sub-nanosecond laser pulse. It showed that the Ta2O5-HfO2/SiO2 composite BBLD mirror possessed higher LIDT due to the low electric-field intensity (EFI) in the case of the coating without artificial nodules. Nevertheless, the LIDT of the composite mirror was significantly lower than the non-quarter-wave HfO2/SiO2 mirror when the nodules exist. The EFI simulation and damage morphology of the nodules analysis demonstrated that the nodule leading to the light intensification in the middle of the boundary between the nodular and the surrounding coating, thus the outermost HfO2/SiO2 layers cannot protect the Ta2O5/SiO2 layers, and resulting to the significantly low LIDT. This study shed some light on the development of high laser-damage BBLD mirrors for pulse compression laser systems. PMID- 28085825 TI - Simultaneous measurement of thermo-optic and thermal expansion coefficients with a single arm double interferometer. AB - A low-cost single arm double interferometer was developed for the concurrent measurement of linear thermal expansion (alpha) and thermo-optic (dn/dT) coefficients of transparent samples with plane and parallel surfaces. Owing to its common-path optical arrangement, the device is compact and stable, and allows the simultaneous measurement of interferences arising from a low-finesse Fabry Perot etalon and from a Mach-Zehnder-type interferometer. The method was demonstrated with measurements of solid (silica, BK7, SF6) and liquid (water, ethanol and acetone) samples. PMID- 28085826 TI - Characterization and adaptive compression of a multi-soliton laser source. AB - Ultrashort pulse generation in the 1600 nm wavelength region is required for deep tissue biomedical imaging. We report on the characterization and adaptive compression of a multi-soliton output spanning >300 nm from a large-mode area photonic-crystal fiber rod for two separate laser setups. Sub-30 fs pulses are generated by first compressing of each soliton individually, and then followed by coherently combining all of the pulses in the train, which are separated by hundreds of femtoseconds. Simulations of the source, together with amplitude and phase coherence measurements are provided. PMID- 28085827 TI - High-efficient computer-generated integral imaging based on the backward ray tracing technique and optical reconstruction. AB - A high-efficient computer-generated integral imaging (CGII) method is presented based on the backward ray-tracing technique. In traditional CGII methods, the total rendering time is long, because a large number of cameras are established in the virtual world. The ray origin and the ray direction for every pixel in elemental image array are calculated with the backward ray-tracing technique, and the total rendering time can be noticeably reduced. The method is suitable to create high quality integral image without the pseudoscopic problem. Real time and non-real time CGII rendering images and optical reconstruction are demonstrated, and the effectiveness is verified with different types of 3D object models. Real time optical reconstruction with 90 * 90 viewpoints and the frame rate above 40 fps for the CGII 3D display are realized without the pseudoscopic problem. PMID- 28085828 TI - Stability of steady and periodic states through the bifurcation bridge mechanism in semiconductor ring lasers subject to optical feedback. AB - With the development of new applications using semiconductor ring lasers (SRLs) subject to optical feedback, the stability properties of their outputs becomes a crucial issue. We propose a systematic bifurcation analysis in order to properly identify the best parameter ranges for either steady or self-pulsating periodic regimes. Unlike conventional semiconductor lasers, we show that SRLs exhibit both types of outputs for large and well defined ranges of the feedback strength. We determine the stability domains in terms of the pump parameter and the feedback phase. We find that the feedback phase is a key parameter to achieve a stable steady output. We demonstrate that the self-pulsating regime results from a particular Hopf bifurcation mechanism referred to as bifurcation bridges. These bridges connect two distinct external cavity modes and are fully stable, a scenario that was not possible for diode lasers under the same conditions. PMID- 28085829 TI - Raman-shifted wavelength-selectable pulsed fiber laser with high repetition rate and high pulse energy in the visible. AB - A high-pulse-energy, diffraction-limited, wavelength-selectable, visible source, based on Raman frequency shifting of a frequency-doubled Yb-doped fiber laser, has been studied. The relative length-scaling laws of Raman gain and self-phase modulation push the design towards short fiber lengths with large core size. It is experimentally demonstrated that the Raman clean-up effect in a graded-index multi-mode fiber is not sufficient to obtain diffraction-limited beam quality in the short fiber length. Thus, a large-core photonic crystal fiber is used to maintain diffraction-limited performance and output pulse energies of ~1 MUJ, at a 1-MHz repetition rate and 1.3-ns pulse-width are successfully achieved. This step-tunable visible source should find applications in photoacoustic microscopy. PMID- 28085830 TI - Gain dynamics of clad-pumped Yb-fiber amplifier and intensity noise control. AB - Gain dynamics study provides an attractive method to understand the intensity noise behavior in fiber amplifiers. Here, the gain dynamics of a medium power (5 W) clad-pumped Yb-fiber amplifier is experimentally evaluated by measuring the frequency domain transfer functions for the input seed and pump lasers from 10 Hz to 1 MHz. We study gain dynamic behavior of the fiber amplifier in the presence of significant residual pump power (compared to the seed power), showing that the seed transfer function is strongly saturated at low Fourier frequencies while the pump power modulation transfer function is nearly unaffected. The characterization of relative intensity noise (RIN) of the fiber amplifier is well explained by the gain dynamics analysis. Finally, a 600 kHz bandwidth feedback loop using an acoustic-optical modulator (AOM) controlling the seed intensity is successfully demonstrated to suppress the broadband laser intensity noise. A maximum noise reduction of about 30 dB is achieved leading to a RIN of -152 dBc/Hz (~1 kHz-10 MHz) at 2.5 W output power. PMID- 28085831 TI - Analysis of high-Q photonic crystal L3 nanocavities designed by visualization of the leaky components. AB - We experimentally study photonic crystal L3 nanocavities whose design Q factors (Qdesign) have been improved with the visualization of leaky components design method. The experimental Q values (Qexp) are monotonically increased from 6,000 to 2,100,000 by iteratively modifying the positions of some of the air holes, as determined by the referred design method. We investigate the Qexp tolerance to imperfections in the fabricated samples, which reveals that the cavities improved by the visualization method tend to lose some tolerance to structural differences between the fabricated samples and the design values. PMID- 28085832 TI - Spin-to-orbital angular momentum conversion in dielectric metasurfaces. AB - Vortex beams are characterized by a helical wavefront and a phase singularity point on the propagation axis that results in a doughnut-like intensity profile. These beams carry orbital angular momentum proportional to the number of intertwined helices constituting the wavefront. Vortex beams have many applications in optics, such as optical trapping, quantum optics and microscopy. Although beams with such characteristics can be generated holographically, spin to-orbital angular momentum conversion has attracted considerable interest as a tool to create vortex beams. In this process, the geometrical phase is exploited to create helical beams whose handedness is determined by the circular polarization (left/right) of the incident light, that is by its spin. Here we demonstrate high-efficiency Spin-to-Orbital angular momentum-Converters (SOCs) at visible wavelengths based on dielectric metasurfaces. With these SOCs we generate vortex beams with high and fractional topological charge and show for the first time the simultaneous generation of collinear helical beams with different and arbitrary orbital angular momentum. This versatile method of creating vortex beams, which circumvents the limitations of liquid crystal SOCs and adds new functionalities, should significantly expand the applications of these beams. PMID- 28085833 TI - Characterization of CMOS metal based dielectric loaded surface plasmon waveguides at telecom wavelengths. AB - Dielectric loaded surface plasmon waveguides (DLSPPWs) comprised of polymer ridges deposited on top of CMOS compatible metal thin films are investigated at telecom wavelengths. We perform a direct comparison of the properties of copper (Cu), aluminum (Al), titanium nitride (TiN) and gold (Au) based waveguides by implementing the same plasmonic waveguiding configuration for each metal. The DLSPPWs are characterized by leakage radiation microscopy and a fiber-to-fiber configuration mimicking the cut-back method. We introduce the ohmic loss rate (OLR) to analyze quantitatively the properties of the CMOS metal based DLSPPWs relative to the corresponding Au based waveguides. We show that the Cu, Al and TiN based waveguides feature extra ohmic loss compared to Au of 0.027 dB/MUm, 0.18 dB/MUm and 0.52 dB/MUm at 1550nm respectively. The dielectric function of each metal extracted from ellipsometric spectroscopic measurements is used to model the properties of the DLSP-PWs. We find a fairly good agreement between experimental and modeled DLSPPWs properties except for Al featuring a large surface roughness. Finally, we conclude that TiN based waveguides sustaining intermediate effective index (in the range 1.05-1.25) plasmon modes propagate over very short distances restricting the the use of those modes in practical situations. PMID- 28085834 TI - Reduction of the operating voltage of a nanoencapsulated liquid crystal display by using a half-wall structure. AB - We proposed a half-wall structure in the in-plane switching (IPS) configuration of the nanoencapsulated liquid crystal (LC) display for reducing a driving voltage. The IPS electrodes were fabricated on top of the half-walls to enhance electric field strength through the whole LC layer. In addition, we demonstrated a self-masking process for the half-wall structure and the IPS electrodes without any additional mask-aligning process. PMID- 28085835 TI - Green laser diodes with low threshold current density via interface engineering of InGaN/GaN quantum well active region. AB - By observing the morphology evolution of green InGaN/GaN quantum well (QW) and studying the catholuminescence (CL) property, we investigate indium-segregation related defects that are formed at green InGaN/GaN QW interfaces. Meanwhile, we also propose the approach and suggest the mechanism to remove them for green InGaN/GaN QW grown on both GaN templates and free-standing GaN substrates. By engineering the interface of green InGaN/GaN QWs, we have achieved green laser diode (LD) structure with low threshold current density of 1.85 kA cm 2. The output power of the green LD is 58 mW at a current density of 6 kA cm-2 under continuous-wave operation at room temperature. PMID- 28085836 TI - Microring modulator matrix integrated with mode multiplexer and de-multiplexer for on-chip optical interconnect. AB - We experimentally demonstrate a 4 * 4 microring modulator matrix integrated with the asymmetrical directional couplers based mode multiplexer and de-multiplexer photonic circuit for on-chip optical interconnect. The inter-mode optical crosstalk of the device is less than -20 dB in the wavelength range from 1525 nm to 1565 nm. Data transmission with a throughput capacity of 4 * 4 * 32 Gbps is achieved by utilizing four wavelengths and four spatial modes multiplexing. We envision this structure as a potential solution to increase the communication capacity for on-chip interconnect within limited chip area. PMID- 28085837 TI - Enhanced optical magnetism for reversed optical binding forces between silicon nanoparticles in the visible region. AB - We perform a comprehensive numerical analysis on the optical binding forces of a multiple-resonant silicon nanodimer induced by the normal illumination of a plane wave in the visible region. The silicon nanodimer provides either repulsive or attractive forces in water while providing only attractive forces in air. The enhancement of the magnetic dipole mode is attributed to the generation of repulsive forces. The sign (attractive/repulsive) and the amplitude of the optical forces are controlled by incident polarization and separation distance between the silicon nanoparticles. These optomechanical effects demonstrate a key step toward the optical sorting and assembly of silicon nanoparticles. PMID- 28085838 TI - Improvement of Swanepoel method for deriving the thickness and the optical properties of chalcogenide thin films. AB - A tangencypoint method (TPM) is presented to derive the thickness and optical constants of chalcogenide thin films from their transmission spectra. It solves the problem of the abnormal value of thickness in the strong absorption region obtained by Swanepoel method. The accuracy of the thickness and refractive index is better than 0.5% by using this method. Moreover, comparing with Swanepoel method by using the same simulation and experimental data from the transmission spectrum, the accuracy of the thickness and refractive index obtained by the TPM is higher in the strong absorption region. Finally the dispersion and absorption coefficient of the chalcogenide films are obtained based on the experimental data of the transmission spectrum by using the TPM. PMID- 28085839 TI - Amorphous-Si waveguide on a garnet magneto-optical isolator with a TE mode nonreciprocal phase shift. AB - We fabricated a magneto-optical (MO) isolator with a TE mode nonreciprocal phase shift. The isolator is based on a Mach-Zehnder interferometer composed of 3-dB directional couplers, a reciprocal phase shifter, and a nonreciprocal phase shifter. To realize TE mode operation in the optical isolator, we designed a novel waveguide structure composed of a hydrogenated amorphous silicon waveguide with an asymmetric MO garnet lateral clad on a garnet substrate. The isolator operation is successfully demonstrated in a fabricated device showing the different transmittances between forward and backward directions. The maximum isolation of the fabricated isolator is 17.9 dB at a wavelength of 1561 nm for the TE mode. PMID- 28085840 TI - RF-pilot aided modulation format identification for hitless coherent transceiver. AB - We propose a RF-pilot aided modulation format identification (MFI) technique to enable a hitless flexible coherent transceiver with fast format switching. For the MFI, modulation format information is encoded to the amplitude of the RF pilot, which can be simultaneously used for the compensation of both laser phase noise and fiber nonlinearity. The proposed MFI technique is able to identify arbitrary modulation formats including multi-dimensional formats and hybrid QAM formats. The high accuracy of the proposed MFI scheme is experimentally demonstrated without sacrificing the tolerance of both laser phase noise and fiber nonlinearity for various modulation formats up to dual-polarization (DP) 64QAM. Finally, over 2240 km standard single mode fiber (SSMF) link, we experimentally demonstrate a hitless coherent transceiver with a fast block-by block modulation format switching enabled by the proposed MFI. PMID- 28085841 TI - Real-time phase delay compensation of PGC demodulation in sinusoidal phase modulation interferometer for nanometer displacement measurement. AB - As the phase delay between the carrier component of the detected interference signal and the carrier has adverse effect for phase generated carrier (PGC) demodulation, it is essential to compensate the phase delay to improve the accuracy of precision displacement measurement in sinusoidal phase-modulation interferometer (SPMI). In this paper, a real-time phase delay compensation method is proposed by regulating a compensating phase introduced to the carrier to maximize the output of the low pass filter so as to make the carrier synchronize with the interference signal. The influence of phase delay for PGC demodulation is analyzed and the method for real-time phase delay compensation is described in detail. The simulation of the method was performed to verify the validity of the phase delay compensation algorithm. A SPMI using an EOM was constructed and several comparative experiments were carried out to demonstrate the feasibility of the proposed method. The experimental results show that the phase delay can be compensated accurately in real time, and nanometer accuracy is achieved for precision displacement measurement. PMID- 28085843 TI - Theoretical investigation of a multi-resonance plasmonic substrate for enhanced coherent anti-Stokes Raman scattering. AB - The development of new substrates for surface-enhanced spectroscopy is primarily motivated by the ability to design such substrates to provide the maximum signal enhancement. In this paper, we theoretically design and investigate a crisscross dimer array as a plasmonic substrate for enhancing coherent anti-Stokes Raman scattering (CARS). The plasmonic film-crisscross dimer array system can excite multiple resonances at optical frequencies. By properly designing structure parameters, three plasmon resonances with large field enhancements and same spatial hot spot regions can spectrally match with the pump, Stokes and anti Stokes beams, respectively. The CARS signals are strongly enhanced by multi resonance plasmon field enhancements. The estimated CARS factor can reach as high order as ~1016 over conventional CARS without the plasmonic substrate. PMID- 28085842 TI - Quasi-continuous frequency tunable terahertz quantum cascade lasers with coupled cavity and integrated photonic lattice. AB - We demonstrate quasi-continuous tuning of the emission frequency from coupled cavity terahertz frequency quantum cascade lasers. Such coupled cavity lasers comprise a lasing cavity and a tuning cavity which are optically coupled through a narrow air slit and are operated above and below the lasing threshold current, respectively. The emission frequency of these devices is determined by the Vernier resonance of longitudinal modes in the lasing and the tuning cavities, and can be tuned by applying an index perturbation in the tuning cavity. The spectral coverage of the coupled cavity devices have been increased by reducing the repetition frequency of the Vernier resonance and increasing the ratio of the free spectral ranges of the two cavities. A continuous tuning of the coupled cavity modes has been realized through an index perturbation of the lasing cavity itself by using wide electrical heating pulses at the tuning cavity and exploiting thermal conduction through the monolithic substrate. Single mode emission and discrete frequency tuning over a bandwidth of 100 GHz and a quasi continuous frequency coverage of 7 GHz at 2.25 THz is demonstrated. An improvement in the side mode suppression and a continuous spectral coverage of 3 GHz is achieved without any degradation of output power by integrating a pi-phase shifted photonic lattice in the laser cavity. PMID- 28085844 TI - Active-target-based calibration of relative poses of mirrors in intraoral scanners. AB - This paper describes a practical method using an active target to calibrate relative poses of mirrors in intraoral scanners. Intraoral scanning is a fast growing technology. Mirrors are widely used in intraoral scanners to increase the measuring area of a single view. The relative poses of these mirrors must be calibrated for accurate three-dimensional profiling. We present and analyze the geometric model of multiview mirrors. A calibration method for relative poses of mirrors is developed based on fringe projection. Vertical and horizontal fringes are displayed on an active target, and every pixel can be viewed as a calibration marker. This calibration method allows the mirrors to have a narrow common field of view. A cell phone display is chosen as the active target, and experimental results demonstrate the effectiveness of the proposed method compared to traditional methods. PMID- 28085845 TI - Highly sensitive temperature sensor using a Sagnac loop interferometer based on a side-hole photonic crystal fiber filled with metal. AB - A highly sensitive temperature sensor based on an all-fiber Sagnac loop interferometer combined with metal-filled side-hole photonic crystal fiber (PCF) is proposed and demonstrated. PCFs containing two side holes filled with metal offer a structure that can be modified to create a change in the birefringence of the fiber by the expansion of the filler metal. Bismuth and indium were used to examine the effect of filler metal on the temperature sensitivity of the fiber optic temperature sensor. It was found from measurements that a very high temperature sensitivity of -9.0 nm/ degrees C could be achieved with the indium filled side-hole PCF. The experimental results are compared to numerical simulations with good agreement. It is shown that the high temperature sensitivity of the sensor is attributed to the fiber microstructure, which has a significant influence on the modulation of the birefringence caused by the expansion of the metal-filled holes. PMID- 28085846 TI - Super-flat coherent supercontinuum source in As38.8Se61.2 chalcogenide photonic crystal fiber with all-normal dispersion engineering at a very low input energy. AB - We numerically report super-flat coherent mid-infrared supercontinuum (MIR-SC) generation in a chalcogenide As38.8Se61.2 photonic crystal fiber (PCF). The dispersion and nonlinear parameters of As38.8Se61.2 chalcogenide PCFs by varying the diameter of the air holes are engineered to obtain all-normal dispersion (ANDi) with high nonlinearities. We show that launching low-energy 50 fs optical pulses with 0.88 kW peak power (corresponding to pulse energy of 0.05 nJ) at a central wavelength of 3.7 MUm into a 5 cm long ANDi-PCF generates a flat-top coherent MIR-SC spanning from 2900 to 4575 nm with a high spectral flatness of 3 dB. This ultra wide and flattened spectrum has excellent stability and coherence properties that can be used for MIR applications such as medical diagnosis of diseases, atmospheric pollution monitoring, and drug detection. PMID- 28085847 TI - Visualization of oscillatory stresses in transparent media using a beta Ga2O3 adaptive detector. AB - The phase-modulated optical signal produced by light propagation through stressed transparent media is detected using the non-steady-state photoelectromotive force technique. The mechanical system, including the glass plate and piezoelectric transducer, demonstrates resonant behavior in the vicinity of 100 kHz. The measured distribution of the optical phase is a bell-shaped surface for these frequencies. The simulation of the piezo-optic response shows qualitative coincidence with the experimental data and provides maps of the stress field. The characterization of the beta-Ga2O3 adaptive detector is performed for the light wavelength lambda=532 nm. PMID- 28085848 TI - Defect-controlled transverse localization of light in triangular optical lattices. AB - We present a detailed analysis of the transverse localization of light in a triangular optical lattice with a negative defect of different depths and positions. The analysis allows us to explore some essentials of the localization behavior. We characterize the localization strength by global propagation of the signal beam and its properties on the output plane. It is demonstrated that the enhancement of the localization is dependent on the defect depth. Additionally, the calculation of the ray trace of the signal beam shows that the position of the defect has a crucial influence on the localization. PMID- 28085849 TI - Automated surface inspection for steel products using computer vision approach. AB - Surface inspection is a critical step in ensuring the product quality in the steel-making industry. In order to relieve inspectors of laborious work and improve the consistency of inspection, much effort has been dedicated to the automated inspection using computer vision approaches over the past decades. However, due to non-uniform illumination conditions and similarity between the surface textures and defects, the present methods are usually applicable to very specific cases. In this paper a new framework for surface inspection has been proposed to overcome these limitations. By investigating the image formation process, a quantitative model characterizing the impact of illumination on the image quality is developed, based on which the non-uniform brightness in the image can be effectively removed. Then a simple classifier is designed to identify the defects among the surface textures. The significance of this approach lies in its robustness to illumination changes and wide applicability to different inspection scenarios. The proposed approach has been successfully applied to the real-time surface inspection of round billets in real manufacturing. Implemented on a conventional industrial PC, the algorithm can proceed at 12.5 frames per second with the successful detection rate being over 90% for turned and skinned billets. PMID- 28085850 TI - Glucose solution determination based on liquid photoacoustic resonance. AB - Noninvasive blood glucose determination has received considerable attention in the past from both patients and scientists all over the world, and it is becoming increasingly important as a research focus. The two most difficult problems leading to no breakthrough in this area are sensitivity and specificity in determination. In order to obtain reliable measurement results of blood glucose levels, we propose a new liquid photoacoustic resonance theory that can significantly enhance the intensity of the signal and improve the sensitivity. This paper demonstrates the theory of liquid photoacoustic resonance, gives a rigorous mathematical expression, and analyzes the variation of the transducer output in the case of liquid photoacoustic resonance. A signal processing method is demonstrated at the same time under the liquid photoacoustic resonance condition. Meanwhile, the feasibility and validity are verified by experiments with different concentrations of glucose solution. The result shows that liquid photoacoustic resonance can strengthen the signal, and the resolution achieves 20 mg/dL. This method overcomes the issue of low sensitivity and the inaccurate detection in the nonresonant case, and gets accurate results. This result could provide a theoretical basis for realization of noninvasive measurement of blood glucose. PMID- 28085851 TI - All-fiber magnetic field sensor based on tapered thin-core fiber and magnetic fluid. AB - A method for the measurement of a magnetic field by combining a tapered thin-core fiber (TTCF) and magnetic fluid is proposed and experimentally demonstrated. The modal interference effect is caused by the core mode and excited eigenmodes in the TTCF cladding. The transmission spectra of the proposed sensor are measured and theoretically analyzed at different magnetic field strengths. The results field show that the magnetic sensitivity reaches up to -0.1039 dB/Oe in the range of 40-1600 e. The proposed method possesses high sensitivity and low cost compared with other expensive methods. PMID- 28085852 TI - Synchronous driving scheme for silicon-based optical switches to critically compensate for thermo-optic effect in carrier injection. AB - The switching performance of high-speed optical-switching-integrated chips is to a great extent dependent on the carrier injection technique, which is accompanied by the thermo-optic effect. In this paper, we put forward a synchronous driving scheme for the silicon-based Mach-Zehnder interferometer (MZI) optical switches, which is capable of critically compensating for the temperature variation with carrier injection to the p-i-n diode on one arm of the MZI by applying a synchronous modulating voltage to the silicon resistive heater on the other MZI arm. The synchronous compensation mechanism is identified by experiments and simulation. Our experimental data show that, by comparison with the traditional driving scheme, the synchronous driving scheme can improve the extinction ratio by 1 dB, along with a better switching waveform. PMID- 28085853 TI - Fiber Bragg grating-based measurement of random-rotation parameters. AB - A preloaded rotational sensor featuring a spring packaged within the magnetic head has been proposed and experimentally demonstrated. The aforementioned fiber Bragg grating-based system can convert the strain information into rotation angles without rotation angle limitations in terms of the proposed angle transfer mathematical model. The random-angular displacements were well fitted by the model with the maximum deviation of 0.5 degrees . The linearity of the calculated rotational velocity reaches up to 0.998 in the range of 0 to 2021.4 rpm. This sensor can also be applied in the angular acceleration measurement. PMID- 28085854 TI - Phase extraction from fringe pattern via light propagation. AB - A phase demodulation method via light propagation is proposed, where one or two fringe patterns are viewed as the superposition of complex amplitudes, and then the phase is reconstructed by separating the light field via light propagation. Simulation and experimental results indicated that the proposed method can extract the phase from a single shot effectively, thereby realizing dynamic phase retrieval. In addition, the accuracy of phase reconstruction can be improved by adding another fringe pattern with an unknown phase shift. The carrier requirement is relatively low, and, thus, the proposed method can be applied to the measurements with an environment disturbance, an inaccurate phase shift, and the requirement of a high speed capture. PMID- 28085855 TI - Potassium permanganate (KMnO4) sensing based on microfiber sensors. AB - Two straight microfiber sensors are proposed and demonstrated for the detection of various concentrations of a potassium permanganate (KMnO4) solution. Two types of straight microfibers, namely, silica microfiber and poly(methyl methacrylate) microfiber, have been fabricated by using the flame brushing technique and the direct drawing technique, respectively. Based on the varied KMnO4 concentrations of the solution from 1% to 6%, the measurement of the peak voltage of the transmission power was made. The results show that the sensitivity of the silica microfiber sensor and the polymer microfiber is obtained at 184.5 MUW/% and 32.57 MUW/% with a resolution of 0.0035% and 0.0064%, respectively. Hence, the silica microfiber is more sensitive than the polymer microfiber for KMnO4 concentration measurements. PMID- 28085856 TI - Electrostrictive optical resonators for non-contact displacement measurement. AB - This paper describes a non-contact transduction mechanism for the measurement of linear displacements that is based on the electrostrictive properties of a polymeric optical resonator. The spherical resonators, with a diameter of ~1 mm and an average optical quality factor of ~106, are made using a commercially available polymer (Super Soft Plastic-Manufacturing Company). The spherical resonator is immersed in a homogeneous electric field that is generated by applying a voltage difference between two metallic plates. One of the plates is fixed, whereas the other one is movable. By changing the distance between the plates, the electric field intensity changes, leading to a variation of the mechanical forces (electrostrictive effect) acting on the resonator. This effect, in turn, leads to a change in the morphology of the optical resonator and therefore to a shift of its optical resonances. By tracking the shift of the optical modes, it is possible to determine the displacement of the movable plate. Our results indicate a sensitivity ranging from 0.008 to 0.642 pm/MUm with a resolution on the order of a few hundreds of nanometers. PMID- 28085857 TI - Dispersion analysis and measurement of potassium tantalate niobate crystals by broadband optical interferometers. AB - Electro-optic crystals, such as potassium tantalate niobate [KTa1 xNbxO3(KTN)], are enabling materials for many optical devices. Their utility in broadband applications heavily depends on their dispersion property. To this end, an analysis of dispersion mismatch in broadband optical interferometers is first presented. Then a method utilizing polynomial phase fitting to measure the dispersion property of materials composing the arms of an interferometer is introduced. As a demonstration, an interferometry system based on optical coherence tomography (OCT) was built, where, for the first time, the group velocity dispersion of a KTN crystal around 1310 nm was measured and numerically compensated for OCT imaging. Several advantages over a widely used method in OCT, which is based on metric functions, are discussed. The results show the fitting method can provide a more reliable measurement with reduced computation complexity. PMID- 28085858 TI - Spectroscopic thermometry for long-distance surveying. AB - Electronic distance meters are routinely used to accurately determine the distance between two points. To reach relative measurement uncertainties of 10-7, the average temperature along the beam has to be known within 100 mK since it is a key component in determining the refractive index of air. Temperature measurements at this level are extremely challenging over long distances and especially in an outdoor environment. This paper presents a thermometer for accurate temperature measurements over distances up to a few km. The thermometer is based on direct laser absorption spectroscopy of oxygen near 770 nm. The thermometer yields a spatially continuous measurement of air temperature, and it can provide spatially and temporally well-matching data with an actual distance-measuring laser beam. A field measurement campaign at the 864 m Nummela standard baseline demonstrates applicability of the developed thermometer for improving the refractive index compensation of current high performance electronic distance meters. PMID- 28085859 TI - Study on a wideband, variable aperture, high resolution scatterometer for planar diffraction grating stray light measurement. AB - Stray light is one of the important factors for evaluating the quality of gratings. Therefore, it has become an important problem in the field of grating development to measure the stray light of planar diffraction gratings accurately. For that reason, a planar grating stray light testing instrument based on a Czerny-Turner (C-T) structure has been studied. On the premise of the low stray light of the instrument itself, the instrument is capable of measuring wideband, variable aperture, and high resolution stray light for planar gratings. A scatterometer dynamic range of over nine orders has been demonstrated. Based on the scalar diffraction theory and classical Fresnel-Kirchhoff diffraction theory, the optical and mechanical model of the scatterometer is designed, which is irradiated by parallel light, and the simulation results are analyzed. The instrument realizes the measurement of the grating distribution function (GDF). And with reference to the expression form of the bidirectional reflectance distribution function (BRDF), the measurement data of the instrument is associated with the power spectral density (PSD). Through the optical integrated design and stray light suppression design, full aperture (15 mm*15 mm-200 mm*200 mm) and wideband (380-900 nm) measurement for any number of lines grating is realized, and the efficiency of equipment usage is improved. Experimental results show that based on the attenuation method, the accuracy of measurement can be 10-9 by the replacement of the neutral density filters. PMID- 28085860 TI - Miniaturized fiber-taper-based Fabry-Perot interferometer for high-temperature sensing. AB - A microminiaturized all-fiber Fabry-Perot interferometer (FPI) for high temperature sensing has been proposed and experimentally demonstrated. The FPI is composed of a micro-air bubble and a taper probe with a tip less than 2 MUm in diameter as reflected interfaces. A temperature sensitivity of 14.68 pm/ degrees C near the wavelength of 1550 nm is obtained. The sensor, with its miniature size, can work in an ultra-small space with a large range of temperature variation. PMID- 28085861 TI - Modeling Herriott cells using the linear canonical transform. AB - We demonstrate a new way to analyze stable, multipass optical cavities (Herriott cells), using the linear canonical transform formalism, showing that re-entrant designs reproduce an arbitrary input field at the output, resulting in useful symmetries. We use this analysis to predict the stability of cavities used in interferometric delay lines for temporal pulse addition. PMID- 28085862 TI - Thermal-induced phase-shift error of a fiber-optic gyroscope due to fiber tail length asymmetry. AB - As a high-precision angular sensor, the fiber-optic gyroscope (FOG) usually shows high sensitivity to disturbances of the environmental temperature. Research on thermal-induced error of the FOG is meaningful to improve its robust performance and reliability in practical applications. In this paper, thermal-induced nonreciprocal phase-shift error of the FOG due to asymmetric fiber tail length is discussed in detail, based on temperature diffusion theory. Theoretical analysis shows that the increase of thermal-induced nonreciprocal phase shift of the FOG is proportional to the asymmetric tail length. Moreover, experiments with temperature ranging from -40 degrees C to 60 degrees C are performed to confirm the analysis. The analysis and experiment results indicate that we may compensate the asymmetry of fiber coil due to imperfect winding and the assembly process by adjusting the fiber tail length, which can reduce the thermal-induced phase-shift error and further improve the adaptability of the FOG in a changing ambient temperature. PMID- 28085863 TI - Effect of laser speckle on light from laser diode-pumped phosphor-converted light sources. AB - Laser diode (LD) pumped white light sources are being developed as an alternative to light-emitting diode-pumped sources for high efficiency and/or high brightness applications. While several performance metrics of laser-pumped phosphor converted light sources have been investigated, the effect of laser speckle has not been sufficiently explored. This paper describes our experimental studies on how laser speckle affects the behavior of light from laser-excited phosphor lamps. A single LD pumping a phosphor plate was the geometry explored in this work. Overall, our findings are that the down-converted light did not exhibit any speckle, whereas speckle was present in the residual pump light but much reduced from that in direct laser light. Furthermore, a thicker coating of small-grained phosphors served to effectively reduce speckle through static pump light diffusion in the phosphor coating. Our investigations showed that speckle is not of concern in illumination from LD-pumped phosphor-converted light sources. PMID- 28085864 TI - Improve optics fabrication efficiency by using a radio frequency ion beam figuring tool. AB - An ion beam with high removal rate and small diameter is expected in ion beam figuring. For an ion beam figuring tool, reducing the extraction grid opening is a feasible method to decrease the ion beam diameter, but the ion beam removal rate decreases at the same time. The ion beam removal rate depends much on the ion density in the ion source discharge room. The plasma in a hollow cathode (HC) ion source and a radio frequency (RF) ion source was simulated. The simulations suggested that the ion density in the RF ion source is higher than that of the HC one. Then, a RF ion source with an integrative matching network was developed and tested in this paper, where the ion beam removal rate reached up to 193 nm/min for 10 mm opening extraction grids. PMID- 28085865 TI - Slant-path coherent free space optical communications over the maritime and terrestrial atmospheres with the use of adaptive optics for beam wavefront correction. AB - As a continuation of our previous work [Appl. Opt.54, 1453 (2015)APOPAI0003 693510.1364/AO.54.001453] in which we have studied the performance of coherent free space optical (FSO) communication systems operating over a horizontal path, in this paper we study the coherent FSO system operating over a general slant path. We evaluated system bit-error-rate (BER) in the case when the quadrature phase-shift keying (QPSK) modulation format is applied and when an adaptive optics (AO) system is employed to mitigate the air turbulence effects for both maritime and terrestrial air transmission scenarios. We adopted a multiple-layer scheme to efficiently model the FSO slant-path links. The atmospheric channel fading was characterized by the wavefront phase distortions and the log-amplitude fluctuations. We derived analytical expressions to characterize log-amplitude fluctuations of air turbulence by asserting the aperture averaging within the frame of the multiple-layer model. The obtained results showed that use of AO enabled improvement of system performance for both uplinks and downlinks, and also revealed that it is more beneficial for the FSO downlinks. Also, AO employment brought larger enhancements in BER performance for the maritime slant path FSO links than for the terrestrial ones, with an additional striking increase in performance when the AO correction is combined with the aperture averaging. PMID- 28085866 TI - Improved master-replica separation process for fabrication of a blazed concave grating by using a combination-type convex grating. AB - An imprinting process that enables fabrication of blazed concave gratings with small radius and large curvature is presented. In this process, a combination type convex grating substrate is used as a master to replace the single part used in the traditional process. The two parts of the combined convex grating are independently separated from the resist layer. In this manner, the concave blazed grating pattern in the resist can maintain maximum consistency with that on the combined convex grating. Experiments are conducted to demonstrate the feasibility of a two-step fabrication technology. PMID- 28085867 TI - Combined diffuse optical tomography and photoacoustic tomography for enhanced functional imaging of small animals: a methodological study on phantoms. AB - Hybrid imaging methods combining diffuse optical tomography (DOT) and other anatomical or nonoptical functional modalities have been widely investigated to improve imaging performance degraded by the strong optical scattering of biological tissues, through constraining the reconstruction process by prior structures. However, these modalities with different contrast mechanisms may be ineffective in revealing early-staged lesions with high optical contrast but no morphological changes. Photoacoustic tomography (PAT) is particularly useful for visualizing light-absorbing structures embedded in soft tissues with high spatial resolution. Although it is still challenging for PAT to quantitatively disclose the absorption distribution, the modality does provide reliable and specific a priori information differentiating light-absorbing structures of soft tissues and might be more appropriate to guide DOT in lesion diagnosis, as compared with other anatomical or nonoptical functional modalities. In this study, a PAT-guided DOT approach is introduced with both soft- and hard-prior regularizations. The methodology is experimentally validated on small-animal-sized phantoms using a computed-tomography-analogous (CT-analogous) PAT/DOT dual-modality system, focusing on future whole-body applications. The results show that the proposed scheme is capable of effectively improving the quantitative accuracy and spatial resolution of DOT reconstruction. PMID- 28085868 TI - Laser-damage characteristics of Nd:glass active mirrors. AB - The active-mirror architecture is widely used in high-power laser systems. In this study, the laser-damage characteristics of Nd:glass active mirrors are investigated. They are exposed to nanosecond 1064 nm laser incident from the Nd:glass. The laser-induced damage thresholds (LIDTs) of the coated sides are lower than those of the uncoated sides. The LIDT of the active mirror whose substrate is manually scrubbed is lower than that of one whose substrate is ultrasonically cleaned. Analysis shows that the absorbing surface defects on the manually scrubbed Nd:glass surface are responsible for the lower LIDT of the active mirror prepared via manual scrubbing, while the subsurface defects in the ultrasonically cleaned Nd:glass substrate are the main reason for the damage of the active mirror prepared via ultrasonic cleaning. The strong standing-wave electric field near the interface between the coating and the Nd:glass substrate is another factor affecting the damage of the active mirror. PMID- 28085869 TI - Optical properties of a one-dimensional photonic crystal containing a graphene based hyperbolic metamaterial defect layer. AB - The transmission properties of a one-dimensional defective photonic crystal have been investigated using the transfer matrix method. A layer of graphene-based hyperbolic metamaterial whose optical axis is tilted with respect to the interface is taken as a defect. It is shown that two kinds of the defect modes can be found in the band gaps of the structure for TM-polarized waves. One kind is created at the frequency range in which the principle elements of the effective permittivity tensor of the defect layer have the same signs. The frequency of this kind of defect mode is independent from the orientation of the optical axis of the defect layer. The other one is created at the hyperbolic dispersion frequency range. Such a defect mode appears due to the anisotropic behavior of the defect layer and its frequency strongly depends on the orientation of the optical axis. Unlike the conventional defect modes, the magnetic field of this defect mode is localized around the defect layer. PMID- 28085870 TI - Representation of image distortion by Moire fringes at phase singularity state. AB - When a grating is imaged by an optical imaging system, due to the aberrations of the system, the parameters of the image grating suffer minute gradual changes across the image. Superimposing an ideal grating image over the real grating image at the phase singularity state of the two gratings leads to phase contours, special Moire fringes, which directly represent the distortions over the image. In this report, after a brief review of the required theoretical bases, we show when the parameters of a grating change linearly the corresponding Moire fringes at the singularity state are represented by quadratic functions, and for nonlinear changes higher order functions are involved. Thus, by imposing desired changes on the parameters of a grating one can produce Moire fringes satisfying functions of required orders. In the experimental part of the report we apply the technique to evaluate the image distortions imposed by a conventional camera and cameras installed in a mobile and in a tablet. PMID- 28085871 TI - Combined effect of turbulence and aerosol on free-space optical links. AB - Despite the benefits of free-space optical (FSO) communications, their full utilization is limited by the influence of atmospheric weather conditions, such as fog, turbulence, smoke, snow, etc. In urban environments, additional environmental factors such as smog and dust particles due to air pollution caused by industry and motor vehicles may affect FSO link performance, which has not been investigated in detail yet. Both smog and dust particles cause absorption and scattering of the propagating optical signal, thus resulting in high attenuation. This work investigates the joint impact of atmospheric turbulence and dust particle-imposed scattering on FSO link performance as part of the last mile access network in urban areas. Propagation of an optical wave is at first analyzed based on the microphysic approach, and the extinction caused by small particles is determined. An experimental measurement campaign using a dedicated test chamber is carried out to assess FSO link performance operating wavelengths of 670 nm and 830 nm and under dust and turbulent conditions. The measured attenuation and the Q factor in terms of the velocity of particle flow and turbulence strength are analyzed. We show that for an airflow of 2 m/s, the Q factor is almost 3.5 higher at the wavelength of 830 nm than at 670 nm. However, for a wavelength of 670 nm, the FSO link is less affected by the increase in airflow compared to 830 nm. The Q factor reduces with turbulence. Under similar turbulence conditions, for ash particles, the Q factor is higher than that of sand particles. PMID- 28085872 TI - Speckle patterns produced by an optical vortex and its application to surface roughness measurements. AB - In this work, we report on the analysis of speckle patterns produced by illuminating different rough surfaces with an optical vortex, a first-order (l=1) Laguerre-Gaussian beam. The generated speckle patterns were observed in the normal direction exploring four different planes: the diffraction plane, image plane, focal plane, and exact Fourier transform plane. The digital speckle patterns were analyzed using the Hurst exponent of digital images, an interesting tool used to study surface roughness. We show a proof of principle that the Hurst exponent of a digital speckle pattern is more sensitive with respect to the surface roughness when the speckle pattern is produced by an optical vortex and observed at a focal plane. We also show that Hurst exponents are not so sensitive with respect to the topological charge l. These results open news possibilities of investigation into speckle metrology once we have several techniques that use speckle patterns for different applications. PMID- 28085873 TI - Robust motion-free and error-correcting method of estimating the focal length of a lens. AB - This paper presents a motion-free technique to characterize the focal length of any spherical convex or concave lens. The measurement test-bench uses a Gaussian laser beam, an electronically controlled variable focus lens (ECVFL), a digital micro-mirror device (DMD), and a standard photo-detector (PD). The method requires measuring beam spot sizes for different focal length settings of the ECVFL and using the measurement data to obtain a focal length estimate through an iterative least-squares-based curve-fitting algorithm. The method is also shown to overcome potential measurement errors that arise due to inaccurate placement of optical components on the test-bench as well as unknown principal plane locations of asymmetric lens samples such as plano-convex lenses. Contrary to the commercially deployed and other proposed methods of focal length characterization, this method does not involve any bulk mechanical motion of optical elements. This approach eliminates measurement errors due to gradual mechanical wear and tear and improves measurement repeatability by minimizing mechanical hysteresis. The compact and fully automated method delivers fast, repeatable, and reliable measurements, which we believe makes it ideal for deployment in industrial lens production units and characterizing lenses used in sensitive imaging systems and various other optical experiments and systems. Measured focal lengths are within the 1% manufacturer-provided tolerance values showing excellent agreement between theory and experiments. We also demonstrate measurement robustness by rectifying discrepancies between known and actual separation distances on the measurement test bench. PMID- 28085874 TI - Rayleigh backscattering from the fundamental mode in step-index multimode optical fibers. AB - The Rayleigh backscattering produced by an incident fundamental mode in a multimode step-index optical fiber was analyzed using a recently developed diffraction technique. The complete set of backward propagating modes, both radial and azimuthal, was determined and regarded. For this type of fiber, normalized mode functions were constructed in an explicit form, thus providing a unified power scale to characterize the relationships between various excited modes. The dependencies of the mode excitation efficiencies on the technical parameters of the fiber and the frequency of the launched radiation were studied. A comparison of the mode excitation efficiencies was performed with those in the fiber with quadratic refractive index profiles. PMID- 28085875 TI - Is the Conformational Ensemble of Alzheimer's Abeta10-40 Peptide Force Field Dependent? AB - By applying REMD simulations we have performed comparative analysis of the conformational ensembles of amino-truncated Abeta10-40 peptide produced with five force fields, which combine four protein parameterizations (CHARMM36, CHARMM22*, CHARMM22/cmap, and OPLS-AA) and two water models (standard and modified TIP3P). Abeta10-40 conformations were analyzed by computing secondary structure, backbone fluctuations, tertiary interactions, and radius of gyration. We have also calculated Abeta10-40 3JHNHalpha-coupling and RDC constants and compared them with their experimental counterparts obtained for the full-length Abeta1-40 peptide. Our study led us to several conclusions. First, all force fields predict that Abeta adopts unfolded structure dominated by turn and random coil conformations. Second, specific TIP3P water model does not dramatically affect secondary or tertiary Abeta10-40 structure, albeit standard TIP3P model favors slightly more compact states. Third, although the secondary structures observed in CHARMM36 and CHARMM22/cmap simulations are qualitatively similar, their tertiary interactions show little consistency. Fourth, two force fields, OPLS-AA and CHARMM22* have unique features setting them apart from CHARMM36 or CHARMM22/cmap. OPLS-AA reveals moderate beta-structure propensity coupled with extensive, but weak long-range tertiary interactions leading to Abeta collapsed conformations. CHARMM22* exhibits moderate helix propensity and generates multiple exceptionally stable long- and short-range interactions. Our investigation suggests that among all force fields CHARMM22* differs the most from CHARMM36. Fifth, the analysis of 3JHNHalpha-coupling and RDC constants based on CHARMM36 force field with standard TIP3P model led us to an unexpected finding that in silico Abeta10-40 and experimental Abeta1-40 constants are generally in better agreement than these quantities computed and measured for identical peptides, such as Abeta1-40 or Abeta1-42. This observation suggests that the differences in the conformational ensembles of Abeta10-40 and Abeta1-40 are small and the former can be used as proxy of the full-length peptide. Based on this argument, we concluded that CHARMM36 force field with standard TIP3P model produces the most accurate representation of Abeta10-40 conformational ensemble. PMID- 28085876 TI - Inference of Transmission Network Structure from HIV Phylogenetic Trees. AB - Phylogenetic inference is an attractive means to reconstruct transmission histories and epidemics. However, there is not a perfect correspondence between transmission history and virus phylogeny. Both node height and topological differences may occur, depending on the interaction between within-host evolutionary dynamics and between-host transmission patterns. To investigate these interactions, we added a within-host evolutionary model in epidemiological simulations and examined if the resulting phylogeny could recover different types of contact networks. To further improve realism, we also introduced patient specific differences in infectivity across disease stages, and on the epidemic level we considered incomplete sampling and the age of the epidemic. Second, we implemented an inference method based on approximate Bayesian computation (ABC) to discriminate among three well-studied network models and jointly estimate both network parameters and key epidemiological quantities such as the infection rate. Our ABC framework used both topological and distance-based tree statistics for comparison between simulated and observed trees. Overall, our simulations showed that a virus time-scaled phylogeny (genealogy) may be substantially different from the between-host transmission tree. This has important implications for the interpretation of what a phylogeny reveals about the underlying epidemic contact network. In particular, we found that while the within-host evolutionary process obscures the transmission tree, the diversification process and infectivity dynamics also add discriminatory power to differentiate between different types of contact networks. We also found that the possibility to differentiate contact networks depends on how far an epidemic has progressed, where distance-based tree statistics have more power early in an epidemic. Finally, we applied our ABC inference on two different outbreaks from the Swedish HIV-1 epidemic. PMID- 28085877 TI - Forecasting Zika Incidence in the 2016 Latin America Outbreak Combining Traditional Disease Surveillance with Search, Social Media, and News Report Data. AB - BACKGROUND: Over 400,000 people across the Americas are thought to have been infected with Zika virus as a consequence of the 2015-2016 Latin American outbreak. Official government-led case count data in Latin America are typically delayed by several weeks, making it difficult to track the disease in a timely manner. Thus, timely disease tracking systems are needed to design and assess interventions to mitigate disease transmission. METHODOLOGY/PRINCIPAL FINDINGS: We combined information from Zika-related Google searches, Twitter microblogs, and the HealthMap digital surveillance system with historical Zika suspected case counts to track and predict estimates of suspected weekly Zika cases during the 2015-2016 Latin American outbreak, up to three weeks ahead of the publication of official case data. We evaluated the predictive power of these data and used a dynamic multivariable approach to retrospectively produce predictions of weekly suspected cases for five countries: Colombia, El Salvador, Honduras, Venezuela, and Martinique. Models that combined Google (and Twitter data where available) with autoregressive information showed the best out-of-sample predictive accuracy for 1-week ahead predictions, whereas models that used only Google and Twitter typically performed best for 2- and 3-week ahead predictions. SIGNIFICANCE: Given the significant delay in the release of official government-reported Zika case counts, we show that these Internet-based data streams can be used as timely and complementary ways to assess the dynamics of the outbreak. PMID- 28085878 TI - Restoring the Duality between Principal Components of a Distance Matrix and Linear Combinations of Predictors, with Application to Studies of the Microbiome. AB - Appreciation of the importance of the microbiome is increasing, as sequencing technology has made it possible to ascertain the microbial content of a variety of samples. Studies that sequence the 16S rRNA gene, ubiquitous in and nearly exclusive to bacteria, have proliferated in the medical literature. After sequences are binned into operational taxonomic units (OTUs) or species, data from these studies are summarized in a data matrix with the observed counts from each OTU for each sample. Analysis often reduces these data further to a matrix of pairwise distances or dissimilarities; plotting the first two or three principal components (PCs) of this distance matrix often reveals meaningful groupings in the data. However, once the distance matrix is calculated, it is no longer clear which OTUs or species are important to the observed clustering; further, the PCs are hard to interpret and cannot be calculated for subsequent observations. We show how to construct approximate decompositions of the data matrix that pair PCs with linear combinations of OTU or species frequencies, and show how these decompositions can be used to construct biplots, select important OTUs and partition the variability in the data matrix into contributions corresponding to PCs of an arbitrary distance or dissimilarity matrix. To illustrate our approach, we conduct an analysis of the bacteria found in 45 smokeless tobacco samples. PMID- 28085879 TI - Acylation of the Type 3 Secretion System Translocon Using a Dedicated Acyl Carrier Protein. AB - Bacterial pathogens often deliver effectors into host cells using type 3 secretion systems (T3SS), the extremity of which forms a translocon that perforates the host plasma membrane. The T3SS encoded by Salmonella pathogenicity island 1 (SPI-1) is genetically associated with an acyl carrier protein, IacP, whose role has remained enigmatic. In this study, using tandem affinity purification, we identify a direct protein-protein interaction between IacP and the translocon protein SipB. We show, by mass spectrometry and radiolabelling, that SipB is acylated, which provides evidence for a modification of the translocon that has not been described before. A unique and conserved cysteine residue of SipB is identified as crucial for this modification. Although acylation of SipB was not essential to virulence, we show that this posttranslational modification promoted SipB insertion into host-cell membranes and pore-forming activity linked to the SPI-1 T3SS. Cooccurrence of acyl carrier and translocon proteins in several gamma- and beta-proteobacteria suggests that acylation of the translocon is conserved in these other pathogenic bacteria. These results also indicate that acyl carrier proteins, known for their involvement in metabolic pathways, have also evolved as cofactors of new bacterial protein lipidation pathways. PMID- 28085880 TI - A Computational Approach for Identifying Synergistic Drug Combinations. AB - A promising alternative to address the problem of acquired drug resistance is to rely on combination therapies. Identification of the right combinations is often accomplished through trial and error, a labor and resource intensive process whose scale quickly escalates as more drugs can be combined. To address this problem, we present a broad computational approach for predicting synergistic combinations using easily obtainable single drug efficacy, no detailed mechanistic understanding of drug function, and limited drug combination testing. When applied to mutant BRAF melanoma, we found that our approach exhibited significant predictive power. Additionally, we validated previously untested synergy predictions involving anticancer molecules. As additional large combinatorial screens become available, this methodology could prove to be impactful for identification of drug synergy in context of other types of cancers. PMID- 28085881 TI - European Aedes albopictus and Culex pipiens Are Competent Vectors for Japanese Encephalitis Virus. AB - BACKGROUND: Japanese encephalitis virus (JEV) is the causative agent of Japanese encephalitis, the leading cause of viral encephalitis in Asia. JEV transmission cycle involves mosquitoes and vertebrate hosts. The detection of JEV RNA in a pool of Culex pipiens caught in 2010 in Italy raised the concern of a putative emergence of the virus in Europe. We aimed to study the vector competence of European mosquito populations, such as Cx. pipiens and Aedes albopictus for JEV genotypes 3 and 5. FINDINGS: After oral feeding on an infectious blood meal, mosquitoes were dissected at various times post-virus exposure. We found that the peak for JEV infection and transmission was between 11 and 13 days post-virus exposure. We observed a faster dissemination of both JEV genotypes in Ae. albopictus mosquitoes, when compared with Cx. pipiens mosquitoes. We also dissected salivary glands and collected saliva from infected mosquitoes and showed that Ae. albopictus mosquitoes transmitted JEV earlier than Cx. pipiens. The virus collected from Ae. albopictus and Cx. pipiens saliva was competent at causing pathogenesis in a mouse model for JEV infection. Using this model, we found that mosquito saliva or salivary glands did not enhance the severity of the disease. CONCLUSIONS: In this study, we demonstrated that European populations of Ae. albopictus and Cx. pipiens were efficient vectors for JEV transmission. Susceptible vertebrate species that develop high viremia are an obligatory part of the JEV transmission cycle. This study highlights the need to investigate the susceptibility of potential JEV reservoir hosts in Europe, notably amongst swine populations and local water birds. PMID- 28085882 TI - A Stable Finite-Difference Scheme for Population Growth and Diffusion on a Map. AB - We describe a general Godunov-type splitting for numerical simulations of the Fisher-Kolmogorov-Petrovski-Piskunov growth and diffusion equation on a world map with Neumann boundary conditions. The procedure is semi-implicit, hence quite stable. Our principal application for this solver is modeling human population dispersal over geographical maps with changing paleovegetation and paleoclimate in the late Pleistocene. As a proxy for carrying capacity we use Net Primary Productivity (NPP) to predict times for human arrival in the Americas. PMID- 28085883 TI - The Yin and Yang of Memory Consolidation: Hippocampal and Neocortical. AB - While hippocampal and cortical mechanisms of memory consolidation have long been studied, their interaction is poorly understood. We sought to investigate potential interactions with respect to trace dominance, strengthening, and interference associated with postencoding novelty or sleep. A learning procedure was scheduled in a watermaze that placed the impact of novelty and sleep in opposition. Distinct behavioural manipulations-context preexposure or interference during memory retrieval-differentially affected trace dominance and trace survival, respectively. Analysis of immediate early gene expression revealed parallel up-regulation in the hippocampus and cortex, sustained in the hippocampus in association with novelty but in the cortex in association with sleep. These findings shed light on dynamically interacting mechanisms mediating the stabilization of hippocampal and neocortical memory traces. Hippocampal memory traces followed by novelty were more dominant by default but liable to interference, whereas sleep engaged a lasting stabilization of cortical traces and consequent trace dominance after preexposure. PMID- 28085884 TI - A Looping-Based Model for Quenching Repression. AB - We model the regulatory role of proteins bound to looped DNA using a simulation in which dsDNA is represented as a self-avoiding chain, and proteins as spherical protrusions. We simulate long self-avoiding chains using a sequential importance sampling Monte-Carlo algorithm, and compute the probabilities for chain looping with and without a protrusion. We find that a protrusion near one of the chain's termini reduces the probability of looping, even for chains much longer than the protrusion-chain-terminus distance. This effect increases with protrusion size, and decreases with protrusion-terminus distance. The reduced probability of looping can be explained via an eclipse-like model, which provides a novel inhibitory mechanism. We test the eclipse model on two possible transcription factor occupancy states of the D. melanogaster eve 3/7 enhancer, and show that it provides a possible explanation for the experimentally-observed eve stripe 3 and 7 expression patterns. PMID- 28085886 TI - Validation of the Regicor Short Physical Activity Questionnaire for the Adult Population. AB - OBJECTIVE: To develop and validate a short questionnaire to estimate physical activity (PA) practice and sedentary behavior for the adult population. METHODS: The short questionnaire was developed using data from a cross-sectional population-based survey (n = 6352) that included the Minnesota leisure-time PA questionnaire. Activities that explained a significant proportion of the variability of population PA practice were identified. Validation of the short questionnaire included a cross-sectional component to assess validity with respect to the data collected by accelerometers and a longitudinal component to assess reliability and sensitivity to detect changes (n = 114, aged 35 to 74 years). RESULTS: Six types of activities that accounted for 87% of population variability in PA estimated with the Minnesota questionnaire were selected. The short questionnaire estimates energy expenditure in total PA and by intensity (light, moderate, vigorous), and includes 2 questions about sedentary behavior and a question about occupational PA. The short questionnaire showed high reliability, with intraclass correlation coefficients ranging between 0.79 to 0.95. The Spearman correlation coefficients between estimated energy expenditure obtained with the questionnaire and the number of steps detected by the accelerometer were as follows: 0.36 for total PA, 0.40 for moderate intensity, and 0.26 for vigorous intensity. The questionnaire was sensitive to detect changes in moderate and vigorous PA (correlation coefficients ranging from 0.26 to 0.34). CONCLUSION: The REGICOR short questionnaire is reliable, valid, and sensitive to detect changes in moderate and vigorous PA. This questionnaire could be used in daily clinical practice and epidemiological studies. PMID- 28085887 TI - Diversity in the Globally Distributed Diatom Genus Chaetoceros (Bacillariophyceae): Three New Species from Warm-Temperate Waters. AB - Chaetoceros is one of the most species rich, widespread and abundant diatom genera in marine and brackish habitats worldwide. It therefore forms an excellent model for in-depth biodiversity studies, assessing morphological and genetic differentiation among groups of strains. The global Chaetoceros lorenzianus complex presently comprises three species known to science. However, our recent studies have shown that the group includes several previously unknown species. In this article, 50 strains, mainly from high latitudes and from warm-temperate waters, were examined morphologically and genetically and the results compared with those of field studies from elsewhere. The strains clustered into five groups, two of which are formed by C. decipiens Cleve and C. mitra (Bailey) Cleve, respectively. Their species descriptions are emended based on samples collected close to the type localities. The three other groups are formed by new species, C. elegans sp. nov., C. laevisporus sp. nov. and C. mannaii sp. nov. Characters used to distinguish each species are: orientation of setae, shape and size of the apertures, shape, size and density of the poroids on the setae and, at least in some species, characters of the resting spores. Our aim is to cover the global species diversity in this complex, as correct species delineation is the basis for exploring biodiversity, distribution of organisms, interactions in the food web and effects of environmental changes. PMID- 28085885 TI - Inhibition of a NF-kappaB/Diap1 Pathway by PGRP-LF Is Required for Proper Apoptosis during Drosophila Development. AB - NF-kappaB pathways are key signaling cascades of the Drosophila innate immune response. One of them, the Immune Deficiency (IMD) pathway, is under a very tight negative control. Although molecular brakes exist at each step of this signaling module from ligand availability to transcriptional regulation, it remains unknown whether repressors act in the same cells or tissues and if not, what is rationale behind this spatial specificity. We show here that the negative regulator of IMD pathway PGRP-LF is epressed in ectodermal derivatives. We provide evidence that, in the absence of any immune elicitor, PGRP-LF loss-of-function mutants, display a constitutive NF-kappaB/IMD activation specifically in ectodermal tissues leading to genitalia and tergite malformations. In agreement with previous data showing that proper development of these structures requires induction of apoptosis, we show that ectopic activation of NF-kappaB/IMD signaling leads to apoptosis inhibition in both genitalia and tergite primordia. We demonstrate that NF-kappaB/IMD signaling antagonizes apoptosis by up-regulating expression of the anti-apoptotic protein Diap1. Altogether these results show that, in the complete absence of infection, the negative regulation of NF-kappaB/IMD pathway by PGRP-LF is crucial to ensure proper induction of apoptosis and consequently normal fly development. These results highlight that IMD pathway regulation is controlled independently in different tissues, probably reflecting the different roles of this signaling cascade in both developmental and immune processes. PMID- 28085888 TI - Medium Cut-Off (MCO) Membranes Reduce Inflammation in Chronic Dialysis Patients-A Randomized Controlled Clinical Trial. AB - BACKGROUND: To increase the removal of middle-sized uremic toxins a new membrane with enhanced permeability and selectivity, called Medium Cut-Off membrane (MCO Ci) has been developed that at the same time ensures the retention of albumin. Because many middle-sized substances may contribute to micro-inflammation we hypothesized that the use of MCO-Ci influences the inflammatory state in hemodialysis patients. METHODS: The randomized crossover trial in 48 patients compared MCO-Ci dialysis to High-flux dialysis of 4 weeks duration each plus 8 weeks extension phase. Primary endpoint was the gene expression of TNF-alpha and IL-6 in peripheral blood mononuclear cells (PBMCs), secondary endpoints were plasma levels of specified inflammatory mediators and cytokines. RESULTS: After four weeks of MCO-Ci the expression of TNF-alpha mRNA (Relative quantification (RQ) from 0.92 +/- 0.34 to 0.75 +/- 0.31, -18.5%, p<0.001)-alpha and IL-6 mRNA (RQ from 0.78 +/- 0.80 to 0.60 +/- 0.43, -23.1%, p<0.01) was reduced to a significantly greater extent than with High-flux dialyzers (TNF mRNA-RQ: -14.3%; IL-6 mRNA-RQ: -3.5%). After retransformation of logarithmically transformed data, measurements after MCO were reduced to 82% of those after HF (95% CI 74%-91%). 4 weeks use of MCO-Ci resulted in long-lasting change in plasma levels of several cytokines and other substances with a significant decrease for sTNFR1, kappa and lambda free light chains, urea and an increase for Lp-PLA2 (PLA2G7) compared to High-flux. Albumin levels dropped significantly after 4 weeks of MCO dialysis but increased after additional 8 weeks of MCO dialysis. Twelve weeks treatment with MCO-Ci was well tolerated regarding the number of (S)AEs. In the extension period levels of CRP, TNF-alpha-mRNA and IL-6 mRNA remained stable in High-flux as well as in MCO-Ci. CONCLUSIONS: MCO-Ci dialyzers modulate inflammation in chronic HD patients to a greater extent compared to High-flux dialyzers. Transcription of pro-inflammatory cytokines in peripheral leukocytes is markedly reduced and removal of soluble mediators is enhanced with MCO dialysis. Serum albumin concentrations stabilize after an initial drop. These results encourage further trials with longer treatment periods and clinical endpoints. PMID- 28085889 TI - High Resolution Spatial Mapping of Human Footprint across Antarctica and Its Implications for the Strategic Conservation of Avifauna. AB - Human footprint models allow visualization of human spatial pressure across the globe. Up until now, Antarctica has been omitted from global footprint models, due possibly to the lack of a permanent human population and poor accessibility to necessary datasets. Yet Antarctic ecosystems face increasing cumulative impacts from the expanding tourism industry and national Antarctic operator activities, the management of which could be improved with footprint assessment tools. Moreover, Antarctic ecosystem dynamics could be modelled to incorporate human drivers. Here we present the first model of estimated human footprint across predominantly ice-free areas of Antarctica. To facilitate integration into global models, the Antarctic model was created using methodologies applied elsewhere with land use, density and accessibility features incorporated. Results showed that human pressure is clustered predominantly in the Antarctic Peninsula, southern Victoria Land and several areas of East Antarctica. To demonstrate the practical application of the footprint model, it was used to investigate the potential threat to Antarctica's avifauna by local human activities. Relative footprint values were recorded for all 204 of Antarctica's Important Bird Areas (IBAs) identified by BirdLife International and the Scientific Committee on Antarctic Research (SCAR). Results indicated that formal protection of avifauna under the Antarctic Treaty System has been unsystematic and is lacking for penguin and flying bird species in some of the IBAs most vulnerable to human activity and impact. More generally, it is hoped that use of this human footprint model may help Antarctic Treaty Consultative Meeting policy makers in their decision making concerning avifauna protection and other issues including cumulative impacts, environmental monitoring, non-native species and terrestrial area protection. PMID- 28085890 TI - The Paucity of Frugivores in Madagascar May Not Be Due to Unpredictable Temperatures or Fruit Resources. AB - The evolution of ecological idiosyncrasies in Madagascar has often been attributed to selective pressures stemming from extreme unpredictability in climate and resource availability compared to other tropical areas. With the exception of rainfall, few studies have investigated these assumptions. To assess the hypothesis that Madagascar's paucity of frugivores is due to unreliability in fruiting resources, we use statistical modeling to analyze phenology datasets and their environmental correlates from two tropical wet forests, the Reserve Naturelle Integrale Betampona in Madagascar, and Kibale National Park in Uganda. At each site we found that temperature is a good environmental predictor of fruit availability. We found no evidence of a significant difference in the predictability of fruit availability between the two sites, although the shorter duration of phenological monitoring at Betampona (two years, versus 15 years at Kibale) limits our ability to infer long-term patterns. Comparisons of long-term temperature data from each site (15 years from Kibale and 14 from Betampona) indicate that temperature is more predictable at Betampona than at Kibale. However, there does appear to be a difference between the two sites in the total fruit availability at any given time, with fruit being generally less abundant at Betampona. Our results appear contrary to the prevailing hypothesis of a selective force imposed by unpredictable resource availability or temperature, and we suggest other possible explanations for Madagascar's unique biota. PMID- 28085891 TI - Generalising Ward's Method for Use with Manhattan Distances. AB - The claim that Ward's linkage algorithm in hierarchical clustering is limited to use with Euclidean distances is investigated. In this paper, Ward's clustering algorithm is generalised to use with l1 norm or Manhattan distances. We argue that the generalisation of Ward's linkage method to incorporate Manhattan distances is theoretically sound and provide an example of where this method outperforms the method using Euclidean distances. As an application, we perform statistical analyses on languages using methods normally applied to biology and genetic classification. We aim to quantify differences in character traits between languages and use a statistical language signature based on relative bi gram (sequence of two letters) frequencies to calculate a distance matrix between 32 Indo-European languages. We then use Ward's method of hierarchical clustering to classify the languages, using the Euclidean distance and the Manhattan distance. Results obtained from using the different distance metrics are compared to show that the Ward's algorithm characteristic of minimising intra-cluster variation and maximising inter-cluster variation is not violated when using the Manhattan metric. PMID- 28085892 TI - Extending Whole Slide Imaging: Color Darkfield Internal Reflection Illumination (DIRI) for Biological Applications. AB - Whole slide imaging (WSI) is a useful tool for multi-modal imaging, and in our work, we have often combined WSI with darkfield microscopy. However, traditional darkfield microscopy cannot use a single condenser to support high- and low numerical-aperture objectives, which limits the modality of WSI. To overcome this limitation, we previously developed a darkfield internal reflection illumination (DIRI) microscope using white light-emitting diodes (LEDs). Although the developed DIRI is useful for biological applications, substantial problems remain to be resolved. In this study, we propose a novel illumination technique called color DIRI. The use of three-color LEDs dramatically improves the capability of the system, such that color DIRI (1) enables optimization of the illumination color; (2) can be combined with an oil objective lens; (3) can produce fluorescence excitation illumination; (4) can adjust the wavelength of light to avoid cell damage or reactions; and (5) can be used as a photostimulator. These results clearly illustrate that the proposed color DIRI can significantly extend WSI modalities for biological applications. PMID- 28085893 TI - Automated Sound Recognition Provides Insights into the Behavioral Ecology of a Tropical Bird. AB - Computer-assisted species recognition facilitates the analysis of relevant biological information in continuous audio recordings. In the present study, we assess the suitability of this approach for determining distinct life-cycle phases of the Southern Lapwing Vanellus chilensis lampronotus based on adult vocal activity. For this purpose we use passive 14-min and 30-min soundscape recordings (n = 33 201) collected in 24/7 mode between November 2012 and October 2013 in Brazil's Pantanal wetlands. Time-stamped detections of V. chilensis call events (n = 62 292) were obtained with a species-specific sound recognizer. We demonstrate that the breeding season fell in a three-month period from mid-May to early August 2013, between the end of the flood cycle and the height of the dry season. Several phases of the lapwing's life history were identified with presumed error margins of a few days: pre-breeding, territory establishment and egg-laying, incubation, hatching, parental defense of chicks, and post-breeding. Diurnal time budgets confirm high acoustic activity levels during midday hours in June and July, indicative of adults defending young. By August, activity patterns had reverted to nonbreeding mode, with peaks around dawn and dusk and low call frequency during midday heat. We assess the current technological limitations of the V. chilensis recognizer through a comprehensive performance assessment and scrutinize the usefulness of automated acoustic recognizers in studies on the distribution pattern, ecology, life history, and conservation status of sound producing animal species. PMID- 28085895 TI - Lactobacillus rhamnosus GR-1 Attenuates Induction of Hypertrophy in Cardiomyocytes but Not through Secreted Protein MSP-1 (p75). AB - Previous animal studies have shown that the administration of probiotic Lactobacillus rhamnosus can provide a protective effect against ischemia/reperfusion and necrotic injury to the intestine, liver, and heart, as well as a therapeutic effect to the outcome of ischemic injury to the heart, including cardiac hypertrophy and heart failure. We hypothesized that L. rhamnosus GR-1 major secreted protein 1 (MSP-1), also known as p75, plays a major role in this phenomenon. Experiments using neonatal rat ventricular cardiomyocytes showed that live and dead GR-1 bacteria, probiotic-conditioned media, and other probiotic species and strains inhibited the alpha1-adrenergic receptor agonist phenylephrine-induced hypertrophy as assessed by markers atrial natriuretic peptide and alpha-skeletal actin. However, using a mutant strain, we showed that this MSP-1 was not required for the inhibition. The ability of factors produced by lactobacilli to improve cardiac function warrants further study for the management of cardiac hypertrophy and heart failure. PMID- 28085894 TI - Where You Look Matters for Body Perception: Preferred Gaze Location Contributes to the Body Inversion Effect. AB - The Body Inversion Effect (BIE; reduced visual discrimination performance for inverted compared to upright bodies) suggests that bodies are visually processed configurally; however, the specific importance of head posture information in the BIE has been indicated in reports of BIE reduction for whole bodies with fixed head position and for headless bodies. Through measurement of gaze patterns and investigation of the causal relation of fixation location to visual body discrimination performance, the present study reveals joint contributions of feature and configuration processing to visual body discrimination. Participants predominantly gazed at the (body-centric) upper body for upright bodies and the lower body for inverted bodies in the context of an experimental paradigm directly comparable to that of prior studies of the BIE. Subsequent manipulation of fixation location indicates that these preferential gaze locations causally contributed to the BIE for whole bodies largely due to the informative nature of gazing at or near the head. Also, a BIE was detected for both whole and headless bodies even when fixation location on the body was held constant, indicating a role of configural processing in body discrimination, though inclusion of the head posture information was still highly discriminative in the context of such processing. Interestingly, the impact of configuration (upright and inverted) to the BIE appears greater than that of differential preferred gaze locations. PMID- 28085896 TI - Urinary Biomarkers IGFBP7 and TIMP-2 for the Diagnostic Assessment of Transient and Persistent Acute Kidney Injury in Critically Ill Patients. AB - OBJECTIVE: The capability of urinary TIMP-2 (tissue inhibitor of metalloproteinase) and IGFBP7 (insulin-like growth factor binding protein) NephroCheck Test (NC) = ([TIMP-2] x [IGFBP7]) / 1000)-to predict renal recovery from acute kidney injury (AKI) has been poorly studied. The aim of this study was to assess the performance of measurements of ([TIMP-2] x [IGFBP7]) / 1000) over 24 hours to differentiate transient from persistent AKI. METHODS: Of 460 consecutive adult patients admitted to the ICU, 101 were prospectively studied: 56 men, 62 (52-71) years old. A fresh urine sample was collected at H0, H4, H12 and H24 to determine ([TIMP-2] x [IGFBP7]) / 1000) levels. Areas under the curves of Delta NC H4-Ho and H12-H4 and serum creatinine (sCr) for detection of AKI recovery were compared. RESULTS: Forty-one (40.6%) patient were diagnosed with AKI: 27 transient and 14 persistent AKI. At admission (H0), AKI patients had a significantly higher NC score than patients without AKI (0.43 [0.07-2.06] vs 0.15 [0.07-0.35], p = 0.027). In AKI groups, transient AKI have a higher NC, at H0 and H4, than persistent AKI (0.87 [0.09-2.82] vs 0.13 [0.05-0.66] p = 0.035 and 0.13 [0.07-0.61] vs 0.05 [0.02-0.13] p = 0.013). Thereafter, NC level decreased in both AKI groups with a Delta NC score H4-H0 and H12-H4 significantly more important in transient AKI. Roc curves showed however that delta NC scores did not discriminate between transient and persistent AKI. CONCLUSION: In our population, absolute urinary levels of NC score were higher at early hours after ICU admission (H0 and H4) in transient AKI as compared to persistent AKI patients. NC variations (Delta NC scores) over the first 12 hours may indicate the AKI's evolving nature with a more significant decrease in case of transient AKI but were not able to differentiate transient from persistent AKI. PMID- 28085897 TI - Mumps Epidemiology and Mumps Virus Genotypes Circulating in Mainland China during 2013-2015. AB - With the implementation of mumps virus (MuV) vaccination in the expanded program on immunization (EPI) in mainland China since 2008, the incidence of mumps has decreased, and the natural epidemic pattern of mumps has slightly changed during 2013-2015. The two epidemic peaks (April-July and November-December) became less obvious than those observed from 2004 to 2012. Children and adolescents younger than 15, particularly in the five-to-nine-year-old age group, remain the target group and should be the focus of high-quality immunization activities in mainland China. However, it was also found that the incidence and reported cases of mumps decreased in each age group during 2013-2015, particularly in the five-to-nine year-old and ten-to-fourteen-year-old age groups. The proportion of mumps cases among adults in some provinces also increased. Unlike the changes in the epidemiological characteristics of mumps affected by vaccination, the data of MuV virology surveillance indicated that most of the MuV transmission chains have not yet been effectively interrupted, and MuV remains a natural epidemic pattern in mainland China. In the MuV virology surveillance, 194 MuV strains during 2013 2015 were isolated from 10 of 31 provinces in mainland China. Based on the phylogenetic analysis of the small hydrophobic (SH) gene, both genotype F (99.0%) and G (1.0%) were identified, and genotype F was still the predominant genotype continuously circulating in mainland China. Representative genotype F and G strains isolated in China from 1995 to 2012 were selected for further analysis. The results indicated that there were multiple transmission chains within genotype F, with no obvious geographical or time differences. The high genetic diversity of genotype F strains could be a result of the continuous transmission and evolution of the MuV in mainland China. Genotype G was also detected in four provinces in mainland China. Because of the limited epidemiological data, it was uncertain whether the genotype G MuV strains found in 2011 and 2013 were imported from other countries. Therefore, combined high-quality epidemiological and virological surveillance is necessary for mumps control; it can also be used to observe the changes in epidemiological characteristics and viral transmission of mumps over time after mumps-containing vaccine (MuCV) implementation and to provide a comprehensive epidemiological and genetic baseline for mumps elimination in mainland China. PMID- 28085898 TI - Profiles of Amino Acids and Acylcarnitines Related with Insecticide Exposure in Culex quinquefasciatus (Say). AB - Culex quinquefasciatus Say is a vector of many pathogens of humans, and both domestic and wild animals. Personal protection, reduction of larval habitats, and chemical control are the best ways to reduce mosquito bites and, therefore, the transmission of mosquito-borne pathogens. Currently, to reduce the risk of transmission, the pyrethroids, and other insecticide groups have been extensively used to control both larvae and adult mosquitoes. In this context, amino acids and acylcarnitines have never been associated with insecticide exposure and or insecticide resistance. It has been suggested that changes in acylcarnitines and amino acids profiles could be a powerful diagnostic tool for metabolic alterations. Monitoring these changes could help to better understand the mechanisms involved in insecticide resistance, complementing the strategies for managing this phenomenon in the integrated resistance management. The purpose of the study was to determine the amino acids and acylcarnitines profiles in larvae of Cx. quinquefasciatus after the exposure to different insecticides. Bioassays were performed on Cx. quinquefasciatus larvae exposed to the diagnostic doses (DD) of the insecticides chlorpyrifos (0.001 MUg/mL), temephos (0.002 MUg/mL) and permethrin (0.01 MUg/mL). In each sample, we analyzed the profile of 12 amino acids and 31 acylcarnitines by LC-MS/MS. A t-test was used to determine statistically significant differences between groups and corrections of q-values. Results indicates three changes, the amino acids arginine (ARG), free carnitine (C0) and acetyl-carnitine (C2) that could be involved in energy production and insecticide detoxification. We confirmed that concentrations of amino acids and acylcarnitines in Cx. quinquefasciatus vary with respect to different insecticides. The information generated contributes to understand the possible mechanisms and metabolic changes occurring during insecticide exposure. PMID- 28085899 TI - Evaluation of the Antibody in Lymphocyte Supernatant Assay to Detect Active Tuberculosis. AB - BACKGROUND: We aimed to evaluate the antibody in lymphocyte supernatant (ALS) assay as a biomarker to diagnose tuberculosis among adults from Tanzania with and without HIV. METHODS: Adults admitted with suspicion for tuberculosis had sputa obtained for GeneXpert MTB/RIF, acid-fast bacilli smear and mycobacterial culture; blood was obtained prior to treatment initiation and after 4 weeks. Adults hospitalized with non-infectious conditions served as controls. Peripheral blood mononuclear cells were cultured unstimulated for 72 hours. Anti mycobacterial antibodies were measured from culture supernatants by ELISA, using BCG vaccine as the coating antigen. Median ALS responses were compared between cases and controls at baseline and between cases over time. RESULTS: Of 97 TB cases, 85 were microbiologically confirmed and 12 were clinically diagnosed. Median ALS responses from TB cases (0.366 OD from confirmed cases and 0.285 from clinical cases) were higher compared to controls (0.085, p<0.001). ALS responses did not differ based on HIV status, CD4 count or sputum smear status. Over time, the median ALS values declined significantly (0.357 at baseline; 0.198 after 4 weeks, p<0.001). CONCLUSIONS: Robust ALS responses were mounted by patients with TB regardless of HIV status, CD4 count, or low sputum bacillary burden, potentially conferring a unique niche for this immunologic biomarker for TB. PMID- 28085900 TI - Genome-Wide DNA Methylation Analysis of Chinese Patients with Systemic Lupus Erythematosus Identified Hypomethylation in Genes Related to the Type I Interferon Pathway. AB - BACKGROUND: Epigenetic variants have been shown in recent studies to be important contributors to the pathogenesis of systemic lupus erythematosus (SLE). Here, we report a 2-step study of discovery followed by replication to identify DNA methylation alterations associated with SLE in a Chinese population. Using a genome-wide DNA methylation microarray, the Illumina Infinium HumanMethylation450 BeadChip, we compared the methylation levels of CpG sites in DNA extracted from white blood cells from 12 female Chinese SLE patients and 10 healthy female controls. RESULTS: We identified 36 CpG sites with differential loss of DNA methylation and 8 CpG sites with differential gain of DNA methylation, representing 25 genes and 7 genes, respectively. Surprisingly, 42% of the hypomethylated CpG sites were located in CpG shores, which indicated the functional importance of the loss of DNA methylation. Microarray results were replicated in another cohort of 100 SLE patients and 100 healthy controls by performing bisulfite pyrosequencing of four hypomethylated genes, MX1, IFI44L, NLRC5 and PLSCR1. In addition, loss of DNA methylation in these genes was associated with an increase in mRNA expression. Gene ontology analysis revealed that the hypomethylated genes identified in the microarray study were overrepresented in the type I interferon pathway, which has long been implicated in the pathogenesis of SLE. CONCLUSION: Our epigenetic findings further support the importance of the type I interferon pathway in SLE pathogenesis. Moreover, we showed that the DNA methylation signatures of SLE can be defined in unfractionated white blood cells. PMID- 28085901 TI - Task-Difficulty Homeostasis in Car Following Models: Experimental Validation Using Self-Paced Visual Occlusion. AB - Car following (CF) models used in traffic engineering are often criticized for not incorporating "human factors" well known to affect driving. Some recent work has addressed this by augmenting the CF models with the Task-Capability Interface (TCI) model, by dynamically changing driving parameters as function of driver capability. We examined assumptions of these models experimentally using a self paced visual occlusion paradigm in a simulated car following task. The results show strong, approximately one-to-one, correspondence between occlusion duration and increase in time headway. The correspondence was found between subjects and within subjects, on aggregate and individual sample level. The long time scale aggregate results support TCI-CF models that assume a linear increase in time headway in response to increased distraction. The short time scale individual sample level results suggest that drivers also adapt their visual sampling in response to transient changes in time headway, a mechanism which isn't incorporated in the current models. PMID- 28085902 TI - Pathway-Consensus Approach to Metabolic Network Reconstruction for Pseudomonas putida KT2440 by Systematic Comparison of Published Models. AB - Over 100 genome-scale metabolic networks (GSMNs) have been published in recent years and widely used for phenotype prediction and pathway design. However, GSMNs for a specific organism reconstructed by different research groups usually produce inconsistent simulation results, which makes it difficult to use the GSMNs for precise optimal pathway design. Therefore, it is necessary to compare and identify the discrepancies among networks and build a consensus metabolic network for an organism. Here we proposed a process for systematic comparison of metabolic networks at pathway level. We compared four published GSMNs of Pseudomonas putida KT2440 and identified the discrepancies leading to inconsistent pathway calculation results. The mistakes in the models were corrected based on information from literature so that all the calculated synthesis and uptake pathways were the same. Subsequently we built a pathway consensus model and then further updated it with the latest genome annotation information to obtain modelPpuQY1140 for P. putida KT2440, which includes 1140 genes, 1171 reactions and 1104 metabolites. We found that even small errors in a GSMN could have great impacts on the calculated optimal pathways and thus may lead to incorrect pathway design strategies. Careful investigation of the calculated pathways during the metabolic network reconstruction process is essential for building proper GSMNs for pathway design. PMID- 28085903 TI - Mechanism of Collaborative Enhancement of Binding of Paired Antibodies to Distinct Epitopes of Platelet Endothelial Cell Adhesion Molecule-1. AB - Monoclonal antibodies (mAbs) directed to extracellular epitopes of human and mouse Platelet Endothelial Cell Adhesion Molecule-1 (CD31 or PECAM-1) stimulate binding of other mAbs to distinct adjacent PECAM-1 epitopes. This effect, dubbed Collaborative Enhancement of Paired Affinity Ligands, or CEPAL, has been shown to enhance delivery of mAb-targeted drugs and nanoparticles to the vascular endothelium. Here we report new insights into the mechanism underlying this effect, which demonstrates equivalent amplitude in the following models: i) cells expressing a full length PECAM-1 and mutant form of PECAM-1 unable to form homodimers; ii) isolated fractions of cellular membranes; and, iii) immobilized recombinant PECAM-1. These results indicate that CEPAL is mediated not by interference in cellular functions or homophilic PECAM-1 interactions, but rather by conformational changes within the cell adhesion molecule induced by ligand binding. This mechanism, mediated by exposure of partially occult epitopes, is likely to occur in molecules other than PECAM-1 and may represent a generalizable phenomenon with valuable practical applications. PMID- 28085904 TI - Can a Toy Encourage Lower Calorie Meal Bundle Selection in Children? A Field Experiment on the Reinforcing Effects of Toys on Food Choice. AB - The goal of this research was to test whether including an inexpensive nonfood item (toy) with a smaller-sized meal bundle (420 calories), but not with the regular-sized meal bundle version (580 calories), would incentivize children to choose the smaller-sized meal bundle, even among children with overweight and obesity. Logistic regression was used to evaluate the effect in a between subjects field experiment of a toy on smaller-sized meal choice (here, a binary choice between a smaller-sized or regular-sized meal bundles). A random sample of 109 elementary school children from two schools in the Tucson, Arizona metropolitan area (55 females; Mage = 8.53 years, SDage = 2.14; MBMI = 18.30, SDBMI = 4.42) participated. Children's height and weight were measured and body mass-index (BMI) was calculated, adjusting for age and sex. In our sample, 21 children were considered to be either overweight or obese. Logistic regression was used to evaluate the effect of a toy on smaller-sized meal choice. Results revealed that the inclusion of a toy with a smaller-sized meal, but not with the regular-sized version, predicted smaller-sized meal choice (P < .001), suggesting that children can be incentivized to choose less food when such is paired with a toy. BMI neither moderated nor nullified the effect of toy on smaller-sized meal choice (P = .125), suggesting that children with overweight and obesity can also be incentivized to choose less. This article is the first to suggest that fast food restaurant chains may well utilize toys to motivate children to choose smaller-sized meal bundles. Our findings may be relevant for consumers, health advocates, policy makers, and marketers who would benefit from a strategy that presents healthier, but still desirable, meal bundle options. PMID- 28085905 TI - Study of the Antimicrobial Activity of Tilapia Piscidin 3 (TP3) and TP4 and Their Effects on Immune Functions in Hybrid Tilapia (Oreochromis spp.). AB - To address the growing concern over antibiotic-resistant microbial infections in aquatic animals, we tested several promising alternative agents that have emerged as new drug candidates. Specifically, the tilapia piscidins are a group of peptides that possess antimicrobial, wound-healing, and antitumor functions. In this study, we focused on tilapia piscidin 3 (TP3) and TP4, which are peptides derived from Oreochromis niloticus, and investigated their inhibition of acute bacterial infections by infecting hybrid tilapia (Oreochromis spp.) with Vibrio vulnificus and evaluating the protective effects of pre-treating, co-treating, and post-treating fish with TP3 and TP4. In vivo experiments showed that co treatment with V. vulnificus and TP3 (20 MUg/fish) or TP4 (20 MUg/fish) achieved 95.3% and 88.9% survival rates, respectively, after seven days. When we co injected TP3 or TP4 and V. vulnificus into tilapia and then re-challenged the fish with V. vulnificus after 28 days, the tilapia exhibited survival rates of 35.6% and 42.2%, respectively. Pre-treatment with TP3 (30 MUg/fish) or TP4 (20 MUg/fish) for 30 minutes prior to V. vulnificus infection resulted in high survival rates of 28.9% and 37.8%, respectively, while post-treatment with TP3 (20 MUg/fish or 30 MUg/fish) or TP4 (20 MUg/fish) 30 minutes after V. vulnificus infection yielded high survival rates of 33.3% and 48.9%. In summary, pre treating, co-treating, and post-treating fish with TP3 or TP4 all effectively decreased the number of V. vulnificus bacteria and promoted significantly lower mortality rates in tilapia. The minimum inhibitory concentrations (MICs) of TP3 and TP4 that were effective for treating fish infected with V. vulnificus were 7.8 and 62.5 MUg/ml, respectively, whereas the MICs of kanamycin and ampicillin were 31.2 and 3.91 MUg/ml. The antimicrobial activity of these peptides was confirmed by transmission electron microscopy (TEM) and scanning electron microscopy (SEM), both of which showed that V. vulnificus disrupted the outer membranes of cells, resulting in the loss of cell shape and integrity. We examined whether TP3 and TP4 increased the membrane permeability of V. vulnificus by measuring the fluorescence resulting from the uptake of 1-N-phenyl naphthylamine (NPN). Treating fish with TP3 and TP4 under different pH and temperature conditions did not significantly increase MIC values, suggesting that temperature and the acid-base environment do not affect AMP function. In addition, the qPCR results showed that TP3 and TP4 influence the expression of immune-responsive genes, including interleukin (IL)-1beta, IL-6, and IL-8. In this study, we demonstrate that TP3 and TP4 show potential for development as drugs to combat fish bacterial infections in aquaculture. PMID- 28085906 TI - Buzz Factor or Innovation Potential: What Explains Cryptocurrencies' Returns? AB - Cryptocurrencies have become increasingly popular since the introduction of bitcoin in 2009. In this paper, we identify factors associated with variations in cryptocurrencies' market values. In the past, researchers argued that the "buzz" surrounding cryptocurrencies in online media explained their price variations. But this observation obfuscates the notion that cryptocurrencies, unlike fiat currencies, are technologies entailing a true innovation potential. By using, for the first time, a unique measure of innovation potential, we find that the latter is in fact the most important factor associated with increases in cryptocurrency returns. By contrast, we find that the buzz surrounding cryptocurrencies is negatively associated with returns after controlling for a variety of factors, such as supply growth and liquidity. Also interesting is our finding that a cryptocurrency's association with fraudulent activity is not negatively associated with weekly returns-a result that further qualifies the media's influence on cryptocurrencies. Finally, we find that an increase in supply is positively associated with weekly returns. Taken together, our findings show that cryptocurrencies do not behave like traditional currencies or commodities-unlike what most prior research has assumed-and depict an industry that is much more mature, and much less speculative, than has been implied by previous accounts. PMID- 28085907 TI - An Activation Threshold Model for Response Inhibition. AB - Reactive response inhibition (RI) is the cancellation of a prepared response when it is no longer appropriate. Selectivity of RI can be examined by cueing the cancellation of one component of a prepared multi-component response. This substantially delays execution of other components. There is debate regarding whether this response delay is due to a selective neural mechanism. Here we propose a computational activation threshold model (ATM) and test it against a classical "horse-race" model using behavioural and neurophysiological data from partial RI experiments. The models comprise both facilitatory and inhibitory processes that compete upstream of motor output regions. Summary statistics (means and standard deviations) of predicted muscular and neurophysiological data were fit in both models to equivalent experimental measures by minimizing a Pearson Chi-square statistic. The ATM best captured behavioural and neurophysiological dynamics of partial RI. The ATM demonstrated that the observed modulation of corticomotor excitability during partial RI can be explained by nonselective inhibition of the prepared response. The inhibition raised the activation threshold to a level that could not be reached by the original response. This was necessarily followed by an additional phase of facilitation representing a secondary activation process in order to reach the new inhibition threshold and initiate the executed component of the response. The ATM offers a mechanistic description of the neural events underlying RI, in which partial movement cancellation results from a nonselective inhibitory event followed by subsequent initiation of a new response. The ATM provides a framework for considering and exploring the neuroanatomical constraints that underlie RI. PMID- 28085908 TI - Quantification of Plasmid Copy Number with Single Colour Droplet Digital PCR. AB - Bacteria can be considered as biological nanofactories that manufacture a cornucopia of bioproducts most notably recombinant proteins. As such, they must perfectly match with appropriate plasmid vectors to ensure successful overexpression of target genes. Among many parameters that correlate positively with protein productivity plasmid copy number plays pivotal role. Therefore, development of new and more accurate methods to assess this critical parameter will result in optimization of expression of plasmid-encoded genes. In this study, we present a simple and highly accurate method for quantifying plasmid copy number utilizing an EvaGreen single colour, droplet digital PCR. We demonstrate the effectiveness of this method by examining the copy number of the pBR322 vector within Escherichia coli DH5alpha cells. The obtained results were successfully validated by real-time PCR. However, we observed a strong dependency of the plasmid copy number on the method chosen for isolation of the total DNA. We found that application of silica-membrane-based columns for DNA purification or DNA isolation with use of bead-beating, a mechanical cell disruption lead to determination of an average of 20.5 or 7.3 plasmid copies per chromosome, respectively. We found that recovery of the chromosomal DNA from purification columns was less efficient than plasmid DNA (46.5 +/- 1.9% and 87.4 +/- 5.5%, respectively) which may lead to observed differences in plasmid copy number. Besides, the plasmid copy number variations dependent on DNA template isolation method, we found that droplet digital PCR is a very convenient method for measuring bacterial plasmid content. Careful determination of plasmid copy number is essential for better understanding and optimization of recombinant proteins production process. Droplet digital PCR is a very precise method that allows performing thousands of individual PCR reactions in a single tube. The ddPCR does not depend on running standard curves and is a straightforward and reliable method to quantify the plasmid copy number. Therefore we believe that the ddPCR designed in this study will be widely used for any plasmid copy number calculation in the future. PMID- 28085909 TI - Impact of Orexin-A Treatment on Food Intake, Energy Metabolism and Body Weight in Mice. AB - Orexin-A and -B are hypothalamic neuropeptides of 33 and 28-amino acids, which regulate many homeostatic systems including sleep/wakefulness states, energy balance, energy homeostasis, reward seeking and drug addiction. Orexin-A treatment was also shown to reduce tumor development in xenografted nude mice and is thus a potential treatment for carcinogenesis. The aim of this work was to explore in healthy mice the consequences on energy expenditure components of an orexin-A treatment at a dose previously shown to be efficient to reduce tumor development. Physiological approaches were used to evaluate the effect of orexin A on food intake pattern, energy metabolism body weight and body adiposity. Modulation of the expression of brain neuropeptides and receptors including NPY, POMC, AgRP, cocaine- and amphetamine related transcript (CART), corticotropin releasing hormone (CRH) and prepro-orexin (HCRT), and Y2 and Y5 neuropeptide Y, MC4 (melanocortin), OX1 and OX2 orexin receptors (Y2R, Y5R, MC4R, OX1R and OX2R, respectively) was also explored. Our results show that orexin-A treatment does not significantly affect the components of energy expenditure, and glucose metabolism but reduces intraperitoneal fat deposit, adiposity and the expression of several brain neuropeptide receptors suggesting that peripheral orexin-A was able to reach the central nervous system. These findings establish that orexin-A treatment which is known for its activity as an inducer of tumor cell death, do have minor parallel consequence on energy homeostasis control. PMID- 28085910 TI - Histamine H2-Blocker and Proton Pump Inhibitor Use and the Risk of Pneumonia in Acute Stroke: A Retrospective Analysis on Susceptible Patients. AB - BACKGROUND: Although histamine H2-blockers (H2B) and proton pump inhibitors (PPI) are used commonly to prevent gastrointestinal bleeding in acute stroke, they are implicated in the increased risk of pneumonia in other disease populations. In acute stroke, the presence of distinctive risk factors of pneumonia, including dysphagia and impaired consciousness, makes inclusive analysis vulnerable to confounding. Our aim was to assess whether acid-suppressive drugs increase pneumonia in acute stroke in a population controlled for confounding. METHODS: We analyzed acute stroke patients admitted to a tertiary care hospital. To minimize confounding, we only included subjects who could not feed orally during 14 days of hospitalization. Exposure was defined as H2B or PPI, given in days; the outcome was development of pneumonia within this period. The incidence was calculated from the total number of pneumonias divided by the sum of person-days at risk. We additionally performed multivariate Poisson regression and propensity score analyses, although the restriction largely eliminated the need for multivariate adjustment. RESULTS: A total of 132 pneumonias occurred in 3582 person-days. The incidence was 3.69%/person-day (95% confidence interval (CI); 3.03-4.37%/day). All subjects had dysphagia. Stroke severity and consciousness disturbances were well-balanced between the groups exposed to H2B, PPI, or none. The relative risk (RR) compared with the unexposed was 1.22 in H2B (95%CI; 0.83 1.81) and 2.07 in PPI (95% CI; 1.13-3.62). The RR of PPI compared with H2B was 1.69 (95%CI; 0.95-2.89). In multivariate regression analysis, the RRs of H2B and PPI were 1.24 (95% CI; 0.85-1.81) and 2.00 (95% CI; 1.12-3.57), respectively; in propensity score analyses they were 1.17 (95% CI; 0.89-1.54) and 2.13 (95% CI; 1.60-2.84). CONCLUSIONS: The results of this study suggested that prophylactic acid-suppressive therapy with PPI may have to be avoided in acute stroke patients susceptible to pneumonia. PMID- 28085911 TI - D-Dimer Use and Pulmonary Embolism Diagnosis in Emergency Units: Why Is There Such a Difference in Pulmonary Embolism Prevalence between the United States of America and Countries Outside USA? AB - OBJECTIVE: Although diagnostic guidelines are similar, there is a huge difference in pulmonary embolism (PE) prevalence between the United States of America (US) and countries outside the USA (OUS) in the emergency care setting. In this study, we prospectively analyze patients' characteristics and differences in clinical care that may influence PE prevalence in different countries. METHODS: An international multicenter prospective diagnostic study was conducted in a standard-of-care setting. Consecutive outpatients presenting to the emergency unit and suspected for PE were managed using the Wells score, STA-Liatest(r) D Dimers and imaging. RESULTS: The prevalence of PE in the study was 7.9% in low and moderate risk patients. Among the 1060 patients with low or moderate pre-test probability (PTP), PE prevalence was four times higher in OUS (10.7%) than in the US (2.5%) (P < 0.0001). The mean number of imaging procedures performed for one new PE diagnosis was 3.3 in OUS vs 17 in the US (P < 0.001). Stopping investigation in the case of negative D-dimers (DD combined) with low/moderate PTP was more frequent in OUS (92.7%) than in the US (75.7%) (P < 0.01). Moreover, the use of imaging was much higher in the US (44.4% vs 19.2% in OUS) in the case of moderate PTP combined with negative DD. CONCLUSION: Differences between US and OUS PE prevalence in emergency setting might be explained by differences in patients' characteristics and mostly in care patterns. US physicians performed computed tomographic pulmonary angiography more often than in Europe in cases of low/moderate PTP combined with negative DD. TRIAL REGISTRATION: ClinicalTrials.gov NCT01221805. PMID- 28085912 TI - A Liquid Chromatography - Tandem Mass Spectrometry Approach for the Identification of Mebendazole Residue in Pork, Chicken, and Horse. AB - A confirmatory and quantitative method of liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the determination of mebendazole and its hydrolyzed and reduced metabolites in pork, chicken, and horse muscles was developed and validated in this study. Anthelmintic compounds were extracted with ethyl acetate after sample mixture was made alkaline followed by liquid chromatographic separation using a reversed phase C18 column. Gradient elution was performed with a mobile phase consisting of water containing 10 mM ammonium formate and methanol. This confirmatory method was validated according to EU requirements. Evaluated validation parameters included specificity, accuracy, precision (repeatability and within-laboratory reproducibility), analytical limits (decision limit and detection limit), and applicability. Most parameters were proved to be conforming to the EU requirements. The decision limit (CCalpha) and detection capability (CCbeta) for all analytes ranged from 15.84 to 17.96 MUgkg 1. The limit of detection (LOD) and the limit of quantification (LOQ) for all analytes were 0.07 MUgkg-1 and 0.2 MUgkg-1, respectively. The developed method was successfully applied to monitoring samples collected from the markets in major cities and proven great potential to be used as a regulatory tool to determine mebendazole residues in animal based foods. PMID- 28085913 TI - Impact of a Home-Based Physical and Nutritional Intervention Program Conducted by Lay-Volunteers on Handgrip Strength in Prefrail and Frail Older Adults: A Randomized Control Trial. AB - A randomized controlled trial was performed to compare the effects of a home based physical and nutritional intervention program carried out by lay-volunteers to home visits with social support alone. Buddies visited 80 prefrail or frail older persons at home twice a week for 12 weeks. The physical training and nutrition group (PTN, n = 39) performed two sets of six strength exercises, discussed nutritional topics and received social support. The social support group (SoSu, n = 41) received home visits with social support only. In the PTN group, handgrip strength increased significantly by 2.4 kg (95% CI: 1.0-3.8). In the SoSu group we did not see a significant improvement. However, no significant between-group difference was found. Physical performance increased in both groups, although with a higher increase of 1.0 point (95% CI: 0.1-2.0) in the PTN group. In none of the groups muscle mass changed. Further results showed that frail individuals benefit more from the intervention than prefrail individuals (OR: 2.78; 95% CI: 1.01-7.66). Handgrip strength in the intervention group increased by a clinically relevant value and this effect is comparable to that obtained by health-care professionals. Therefore, home visits with a physical training and nutritional program could offer a new perspective in the care of community-dwelling prefrail and frail older persons. PMID- 28085914 TI - Obesity May Not Induce Dynamic Stability Disadvantage during Overground Walking among Young Adults. AB - Obesity has been related to postural instability during static standing. It remains unknown how obesity influences stability during dynamic movements like gait. The primary aim of this study was to investigate the effects of obesity on dynamic gait stability control in young adults during gait. Forty-four young adults (21 normal-weight and 23 obese) participated in this study. Participants walked five times at their self-selected gait speeds on a linear walkway. Their full-body kinematics were gathered by a motion capture system. Compared with normal-weight group, individuals with obesity walked more slowly with a shorter but wider step. People with obesity also spent an elongated double stance phase than those with normal weight. A reduced gait speed decreases the body center of mass's velocity relative to the base of support, leading to a reduction in dynamic stability. On the other hand, a shortened step in accompanying with a less backward-leaning trunk has the potential to bring the center of mass closer to the base of support, resulting in an increase in dynamic stability. As the result of these adaptive changes to the gait pattern, dynamic gait stability among people with obesity did not significantly differ from the one among people with normal weight. Obesity seems to not be inducing dynamic stability disadvantage in young adults during level overground walking. These findings could provide insight into the mechanisms of stability control among people affected by obesity during dynamic locomotion. PMID- 28085915 TI - Sequential Targeting of CD52 and TNF Allows Early Minimization Therapy in Kidney Transplantation: From a Biomarker to Targeting in a Proof-Of-Concept Trial. AB - BACKGROUND: There is high medical need for safe long-term immunosuppression monotherapy in kidney transplantation. Selective targeting of post-transplant alloantigen-(re)activated effector-T cells by anti-TNF antibodies after global T cell depletion may allow safe drug minimization, however, it is unsolved what might be the best maintenance monotherapy. METHODS: In this open, prospective observational single-centre trial, 20 primary deceased donor kidney transplant recipients received 2x20 mg Alemtuzumab (d0/d1) followed by 5 mg/kg Infliximab (d2). For 14 days all patients received only tacrolimus, then they were allocated to either receive tacrolimus (TAC, n = 13) or sirolimus (SIR, n = 7) monotherapy, respectively. Protocol biopsies and extensive immune monitoring were performed and patients were followed-up for 60 months. RESULTS: TAC-monotherapy resulted in excellent graft survival (5yr 92%, 95%CI: 56.6-98.9) and function, normal histology, and no proteinuria. Immune monitoring revealed low intragraft inflammation (urinary IP-10) and hints for the development of operational tolerance signature in the TAC- but not SIR-group. Remarkably, the TAC monotherapy was successful in all five presensitized (ELISPOT+) patients. However, recruitment into SIR-arm was stopped (after n = 7) because of high incidence of proteinuria and acute/chronic rejection in biopsies. No opportunistic infections occurred during follow-up. CONCLUSIONS: In conclusion, our novel fast-track TAC-monotherapy protocol is likely to be safe and preliminary results indicated an excellent 5-year outcome, however, a full-scale study will be needed to confirm our findings. TRIAL REGISTRATION: EudraCT Number: 2006-003110-18. PMID- 28085916 TI - Association between Grape Yeast Communities and the Vineyard Ecosystems. AB - The grape yeast biota from several wine-producing areas, with distinct soil types and grapevine training systems, was assessed on five islands of Azores Archipelago, and differences in yeast communities composition associated with the geographic origin of the grapes were explored. Fifty-seven grape samples belonging to the Vitis vinifera grapevine cultivars Verdelho dos Acores (Verdelho), Arinto da Terceira (Arinto) and Terrantez do Pico (Terrantez) were collected in two consecutive years and 40 spontaneous fermentations were achieved. A total of 1710 yeast isolates were obtained from freshly crushed grapes and 1200 from final stage of fermentations. Twenty-eight species were identified, Hanseniaspura uvarum, Pichia terricola and Metschnikowia pulcherrima being the three most representative species isolated. Candida carpophila was encountered for the first time as an inhabitant of grape or wine-associated environments. In both sampling years, a higher proportion of H. uvarum in fresh grapes from Verdelho cultivar was observed, in comparison with Arinto cultivar. Qualitatively significant differences were found among yeast communities from several locations on five islands of the Archipelago, particularly in locations with distinctive agro-ecological compositions. Our results are in agreement with the statement that grape-associated microbial biogeography is non-randomly associated with interactions of climate, soil, cultivar, and vine training systems in vineyard ecosystems. Our observations strongly support a possible linkage between grape yeast and wine typicality, reinforcing the statement that different viticultural terroirs harbor distinctive yeast biota, in particular in vineyards with very distinctive environmental conditions. PMID- 28085918 TI - When a Step Is Not a Step! Specificity Analysis of Five Physical Activity Monitors. AB - INTRODUCTION: Physical activity is an essential aspect of a healthy lifestyle for both physical and mental health states. As step count is one of the most utilized measures for quantifying physical activity it is important that activity monitoring devices be both sensitive and specific in recording actual steps taken and disregard non-stepping body movements. The objective of this study was to assess the specificity of five activity monitors during a variety of prescribed non-stepping activities. METHODS: Participants wore five activity monitors simultaneously for a variety of prescribed activities including deskwork, taking an elevator, taking a bus journey, automobile driving, washing and drying dishes; functional reaching task; indoor cycling; outdoor cycling; and indoor rowing. Each task was carried out for either a specific duration of time or over a specific distance. Activity monitors tested were the ActivPAL microTM, NL-2000TM pedometer, Withings Smart Activity Monitor Tracker (Pulse O2)TM, Fitbit OneTM and Jawbone UPTM. Participants were video-recorded while carrying out the prescribed activities and the false positive step count registered on each activity monitor was obtained and compared to the video. RESULTS: All activity monitors registered a significant number of false positive steps per minute during one or more of the prescribed activities. The WithingsTM activity performed best, registering a significant number of false positive steps per minute during the outdoor cycling activity only (P = 0.025). The JawboneTM registered a significant number of false positive steps during the functional reaching task and while washing and drying dishes, which involved arm and hand movement (P < 0.01 for both). The ActivPALTM registered a significant number of false positive steps during the cycling exercises (P < 0.001 for both). CONCLUSION: As a number of false positive steps were registered on the activity monitors during the non-stepping activities, the authors conclude that non-stepping physical activities can result in the false detection of steps. This can negatively affect the quantification of physical activity with regard to step count as an output. The WithingsTM activity monitor performed best with regard to specificity during the activities of daily living tested. PMID- 28085917 TI - Quantification of Polychlorinated Biphenyls and Polybrominated Diphenyl Ethers in Commercial Cows' Milk from California by Gas Chromatography-Triple Quadruple Mass Spectrometry. AB - We determined 12 polybrominated diphenyl ethers (PBDEs) and 19 polychlorinated biphenyls (PCBs) congeners in eight different brands of commercial whole milk (WM) and fat free milk (FFM) produced and distributed in California. Congeners were extracted using a modified quick, easy, cheap, effective, rugged and safe (QuEChERS) method, purified by gel permeation chromatography, and quantified using gas chromatography-triple quadruple mass spectrometry. PBDEs and PCBs were detected in all FFM and WM samples. The most prevalent PBDE congeners in WM were BDE-47 (geometric mean: 18.0 pg/mL, 0.51 ng/g lipid), BDE-99 (geometric mean: 9.9 pg/mL, 0.28 ng/g lipid), and BDE-49 (geometric mean: 6.0 pg/mL, 0.17 ng/g lipid). The dominant PCB congeners in WM were PCB-101(geometric mean: 23.6 pg/mL, 0.67 ng/g lipid), PCB-118 (geometric mean: 25.2 pg/mL, 0.72 ng/g lipid), and PCB-138 (geometric mean: 25.3 pg/mL, 0.72 ng/g lipid). The sum of all 19 PCB congeners in FFM and WM were several orders of magnitude below the U.S. FDA tolerance. The sum of PBDEs in milk samples suggest close proximity to industrial emissions, and confirm previous findings of elevated PBDE levels in California compared to other regions in the United States. PMID- 28085919 TI - Modeling sRNA-Regulated Plasmid Maintenance. AB - We study a theoretical model for the toxin-antitoxin (hok/sok) mechanism for plasmid maintenance in bacteria. Toxin-antitoxin systems enforce the maintenance of a plasmid through post-segregational killing of cells that have lost the plasmid. Key to their function is the tight regulation of expression of a protein toxin by an sRNA antitoxin. Here, we focus on the nonlinear nature of the regulatory circuit dynamics of the toxin-antitoxin mechanism. The mechanism relies on a transient increase in protein concentration rather than on the steady state of the genetic circuit. Through a systematic analysis of the parameter dependence of this transient increase, we confirm some known design features of this system and identify new ones: for an efficient toxin-antitoxin mechanism, the synthesis rate of the toxin's mRNA template should be lower that of the sRNA antitoxin, the mRNA template should be more stable than the sRNA antitoxin, and the mRNA-sRNA complex should be more stable than the sRNA antitoxin. Moreover, a short half-life of the protein toxin is also beneficial to the function of the toxin-antitoxin system. In addition, we study a therapeutic scenario in which a competitor mRNA is introduced to sequester the sRNA antitoxin, causing the toxic protein to be expressed. PMID- 28085920 TI - E2F6 Impairs Glycolysis and Activates BDH1 Expression Prior to Dilated Cardiomyopathy. AB - RATIONALE: The E2F pathway plays a critical role in cardiac growth and development, yet its role in cardiac metabolism remains to be defined. Metabolic changes play important roles in human heart failure and studies imply the ketogenic enzyme beta-hydroxybutyrate dehydrogenase I (BDH1) is a potential biomarker. OBJECTIVE: To define the role of the E2F pathway in cardiac metabolism and dilated cardiomyopathy (DCM) with a focus on BDH1. METHODS AND RESULTS: We previously developed transgenic (Tg) mice expressing the transcriptional repressor, E2F6, to interfere with the E2F/Rb pathway in post-natal myocardium. These Tg mice present with an E2F6 dose dependent DCM and deregulated connexin-43 (CX-43) levels in myocardium. Using the Seahorse platform, a 22% decrease in glycolysis was noted in neonatal cardiomyocytes isolated from E2F6-Tg hearts. This was associated with a 39% reduction in the glucose transporter GLUT4 and 50% less activation of the regulator of glucose metabolism AKT2. The specific reduction of cyclin B1 (70%) in Tg myocardium implicates its importance in supporting glycolysis in the postnatal heart. No changes in cyclin D expression (known to regulate mitochondrial activity) were noted and lipid metabolism remained unchanged in neonatal cardiomyocytes from Tg hearts. However, E2F6 induced a 40-fold increase of the Bdh1 transcript and 890% increase in its protein levels in hearts from Tg pups implying a potential impact on ketolysis. By contrast, BDH1 expression is not activated until adulthood in normal myocardium. Neonatal cardiomyocytes from Wt hearts incubated with the ketone beta hydroxybutyrate (beta-OHB) showed a 100% increase in CX-43 protein levels, implying a role for ketone signaling in gap junction biology. Neonatal cardiomyocyte cultures from Tg hearts exhibited enhanced levels of BDH1 and CX-43 and were not responsive to beta-OHB. CONCLUSIONS: The data reveal a novel role for the E2F pathway in regulating glycolysis in the developing myocardium through a mechanism involving cyclin B1. We reveal BDH1 expression as an early biomarker of heart failure and its potential impact, through ketone signaling, on CX-43 levels in E2F6-induced DCM. PMID- 28085921 TI - The APPLE Score - A Novel Score for the Prediction of Rhythm Outcomes after Repeat Catheter Ablation of Atrial Fibrillation. AB - BACKGROUND: Arrhythmia recurrences after catheter ablation occur in up to 50% within one year but their prediction remains challenging. Recently, we developed a novel score for the prediction of rhythm outcomes after single AF ablation demonstrating superiority to other scores. The current study was performed to 1) prove the predictive value of the APPLE score in patients undergoing repeat AF ablation and 2) compare it with the CHADS2 and CHA2DS2-VASc scores. METHODS: Rhythm outcome between 3-12 months after AF ablation were documented. The APPLE score (one point for Age >65 years, Persistent AF, imPaired eGFR (<60 ml/min/1.73m2), LA diameter >=43 mm, EF <50%) was calculated in every patient before procedure. RESULTS: 379 consecutive patients from The Leipzig Heart Center AF Ablation Registry (60+/-10 years, 65% male, 70% paroxysmal AF) undergoing repeat AF catheter ablation were included. Arrhythmia recurrences were observed in 133 patients (35%). While the CHADS2 (AUC 0.577, p = 0.037) and CHA2DS2-VASc scores (AUC 0.590, p = 0.015) demonstrated low predictive value, the APPLE score showed better prediction of arrhythmia recurrences (AUC 0.617, p = 0.002) than other scores (both p<0.001). Compared to patients with an APPLE score of 0, the risk (OR) for arrhythmia recurrences was 2.9, 3.0 and 6.0 (all p<0.01) for APPLE scores 1, 2, or >=3, respectively. CONCLUSIONS: The novel APPLE score is superior to the CHADS2 and CHA2DS2-VASc scores for prediction of rhythm outcomes after repeat AF catheter ablation. It may be helpful to identify patients with low, intermediate or high risk for recurrences after repeat procedure. PMID- 28085922 TI - The Effectiveness of Teamwork Training on Teamwork Behaviors and Team Performance: A Systematic Review and Meta-Analysis of Controlled Interventions. AB - The objective of this study was to conduct a systematic review and meta-analysis of teamwork interventions that were carried out with the purpose of improving teamwork and team performance, using controlled experimental designs. A literature search returned 16,849 unique articles. The meta-analysis was ultimately conducted on 51 articles, comprising 72 (k) unique interventions, 194 effect sizes, and 8439 participants, using a random effects model. Positive and significant medium-sized effects were found for teamwork interventions on both teamwork and team performance. Moderator analyses were also conducted, which generally revealed positive and significant effects with respect to several sample, intervention, and measurement characteristics. Implications for effective teamwork interventions as well as considerations for future research are discussed. PMID- 28085923 TI - Striatofrontal Deafferentiation in MSA-P: Evaluation with [18F]FDG Brain PET. AB - BACKGROUND: Although cognitive impairment is not a consistent feature of multiple system atrophy (MSA), increasing evidence suggests that cognitive impairment is common in MSA with predominant parkinsonism (MSA-P). It is assumed that the cognitive impairment in MSA-P is caused by the striatal dysfunction and disruption of striatofrontal connections. The aim of this study was to evaluate the relationship between regional glucose metabolism in the frontal cortex and striatum in patients with MSA-P using [18F]FDG brain PET. METHODS: Twenty-nine patients with MSA-P and 28 healthy controls underwent [18F]FDG brain PET scan. The [18F]FDG brain PET images were semiquantitatively analyzed on the basis of a template in standard space. The regional glucose metabolism of the cerebral cortex and striatum were compared between MSA-P and healthy control groups. The correlations between age, symptom duration, H&Y stage, UPDRS III score, MMSE score, and glucose metabolism in the cerebellum and striatum to glucose metabolism in the frontal cortex were evaluated by multivariate analysis. RESULTS: The glucose metabolism in the frontal cortex and striatum in MSA-P patients were significantly lower than those in healthy controls. Glucose metabolism in the striatum was the most powerful determinant of glucose metabolism in the frontal cortex in MSA-P. Only age and glucose metabolism in the cerebellum were independent variables affecting the glucose metabolism in the frontal cortex in healthy controls. CONCLUSION: The decrease in frontal glucose metabolism in MSA-P is related to the decrease in striatal glucose metabolism. This result provided evidence of striatofrontal deafferentiation in patients with MSA-P. PMID- 28085924 TI - Microfluidic Biopsy Trapping Device for the Real-Time Monitoring of Tumor Microenvironment. AB - The tumor microenvironment is composed of cellular and stromal components such as tumor cells, mesenchymal cells, immune cells, cancer associated fibroblasts and the supporting extracellular matrix. The tumor microenvironment provides crucial support for growth and progression of tumor cells and affects tumor response to therapeutic interventions. To better understand tumor biology and to develop effective cancer therapeutic agents it is important to develop preclinical platforms that can faithfully recapitulate the tumor microenvironment and the complex interaction between the tumor and its surrounding stromal elements. Drug studies performed in vitro with conventional two-dimensional cancer cell line models do not optimally represent clinical drug response as they lack true tumor heterogeneity and are often performed in static culture conditions lacking stromal tumor components that significantly influence the metabolic activity and proliferation of cells. Recent microfluidic approaches aim to overcome such obstacles with the use of cell lines derived in artificial three-dimensional supportive gels or micro-chambers. However, absence of a true tumor microenvironment and full interstitial flow, leads to less than optimal evaluation of tumor response to drug treatment. Here we report a continuous perfusion microfluidic device coupled with microscopy and image analysis for the assessment of drug effects on intact fresh tumor tissue. We have demonstrated that fine needle aspirate biopsies obtained from patient-derived xenograft models of adenocarcinoma of the lung can successfully be analyzed for their response to ex vivo drug treatment within this biopsy trapping microfluidic device, wherein a protein kinase C inhibitor, staurosporine, was used to assess tumor cell death as a proof of principle. This approach has the potential to study tumor tissue within its intact microenvironment to better understand tumor response to drug treatments and eventually to choose the most effective drug and drug combination for individual patients in a cost effective and timely manner. PMID- 28085925 TI - The First Chloroplast Genome Sequence of Boswellia sacra, a Resin-Producing Plant in Oman. AB - Boswellia sacra (Burseraceae), a keystone endemic species, is famous for the production of fragrant oleo-gum resin. However, the genetic make-up especially the genomic information about chloroplast is still unknown. Here, we described for the first time the chloroplast (cp) genome of B. sacra. The complete cp sequence revealed a circular genome of 160,543 bp size with 37.61% GC content. The cp genome is a typical quadripartite chloroplast structure with inverted repeats (IRs 26,763 bp) separated by small single copy (SSC; 18,962 bp) and large single copy (LSC; 88,055 bp) regions. De novo assembly and annotation showed the presence of 114 unique genes with 83 protein-coding regions. The phylogenetic analysis revealed that the B. sacra cp genome is closely related to the cp genome of Azadirachta indica and Citrus sinensis, while most of the syntenic differences were found in the non-coding regions. The pairwise distance among 76 shared genes of B. sacra and A. indica was highest for atpA, rpl2, rps12 and ycf1. The cp genome of B. sacra reveals a novel genome, which could be used for further studied to understand its diversity, taxonomy and phylogeny. PMID- 28085926 TI - Bcl-xL Affects Group A Streptococcus-Induced Autophagy Directly, by Inhibiting Fusion between Autophagosomes and Lysosomes, and Indirectly, by Inhibiting Bacterial Internalization via Interaction with Beclin 1-UVRAG. AB - Anti-apoptotic Bcl-2 and Bcl-xL are proposed to regulate starvation-induced autophagy by directly interacting with Beclin 1. Beclin 1 is also thought to be involved in multiple vesicle trafficking pathways such as endocytosis by binding to Atg14L and UVRAG. However, how the interaction of Bcl-2 family proteins and Beclin 1 regulates anti-bacterial autophagy (xenophagy) is still unclear. In this study, we analyzed these interactions using Group A Streptococcus (GAS; Streptococcus pyogenes) infection as a model. GAS is internalized into epithelial cells through endocytosis, while the intracellular fate of GAS is degradation by autophagy. Here, we found that Bcl-xL but not Bcl-2 regulates GAS-induced autophagy. Autophagosome-lysosome fusion and the internalization process during GAS infection were promoted in Bcl-xL knockout cells. In addition, knockout of Beclin 1 phenocopied the internalization defect of GAS. Furthermore, UVRAG interacts not only with Beclin 1 but also with Bcl-xL, and overexpression of UVRAG partially rescued the internalization defect of Beclin 1 knockout cells during GAS infection. Thus, our results indicate that Bcl-xL inhibits GAS-induced autophagy directly by suppressing autophagosome-lysosome fusion and indirectly by suppressing GAS internalization via interaction with Beclin 1-UVRAG. PMID- 28085927 TI - Community Laboratory Testing for Cryptosporidium: Multicenter Study Retesting Public Health Surveillance Stool Samples Positive for Cryptosporidium by Rapid Cartridge Assay with Direct Fluorescent Antibody Testing. AB - Cryptosporidium is a common cause of sporadic diarrheal disease and outbreaks in the United States. Increasingly, immunochromatography-based rapid cartridge assays (RCAs) are providing community laboratories with a quick cryptosporidiosis diagnostic method. In the current study, the Centers for Disease Control and Prevention (CDC), the Association of Public Health Laboratories (APHL), and four state health departments evaluated RCA-positive samples obtained during routine Cryptosporidium testing. All samples underwent "head to head" re-testing using both RCA and direct fluorescence assay (DFA). Community level results from three sites indicated that 54.4% (166/305) of Meridian ImmunoCard STAT! positives and 87.0% (67/77) of Remel Xpect positives were confirmed by DFA. When samples were retested by RCA at state laboratories and compared with DFA, 83.3% (155/186) of Meridian ImmunoCard STAT! positives and 95.2% (60/63) of Remel Xpect positives were confirmed. The percentage of confirmed community results varied by site: Minnesota, 39.0%; New York, 63.9%; and Wisconsin, 72.1%. The percentage of confirmed community results decreased with patient age; 12.5% of community positive tests could be confirmed by DFA for patients 60 years of age or older. The percentage of confirmed results did not differ significantly by sex, storage temperature, time between sample collection and testing, or season. Findings from this study demonstrate a lower confirmation rate of community RCA positives when compared to RCA positives identified at state laboratories. Elucidating the causes of decreased test performance in order to improve overall community laboratory performance of these tests is critical for understanding the epidemiology of cryptosporidiosis in the United States (US). PMID- 28085928 TI - Critical Features of Fragment Libraries for Protein Structure Prediction. AB - The use of fragment libraries is a popular approach among protein structure prediction methods and has proven to substantially improve the quality of predicted structures. However, some vital aspects of a fragment library that influence the accuracy of modeling a native structure remain to be determined. This study investigates some of these features. Particularly, we analyze the effect of using secondary structure prediction guiding fragments selection, different fragments sizes and the effect of structural clustering of fragments within libraries. To have a clearer view of how these factors affect protein structure prediction, we isolated the process of model building by fragment assembly from some common limitations associated with prediction methods, e.g., imprecise energy functions and optimization algorithms, by employing an exact structure-based objective function under a greedy algorithm. Our results indicate that shorter fragments reproduce the native structure more accurately than the longer. Libraries composed of multiple fragment lengths generate even better structures, where longer fragments show to be more useful at the beginning of the simulations. The use of many different fragment sizes shows little improvement when compared to predictions carried out with libraries that comprise only three different fragment sizes. Models obtained from libraries built using only sequence similarity are, on average, better than those built with a secondary structure prediction bias. However, we found that the use of secondary structure prediction allows greater reduction of the search space, which is invaluable for prediction methods. The results of this study can be critical guidelines for the use of fragment libraries in protein structure prediction. PMID- 28085929 TI - Transcriptomic Analysis of Laribacter hongkongensis Reveals Adaptive Response Coupled with Temperature. AB - Bacterial adaptation to different hosts requires transcriptomic alteration in response to the environmental conditions. Laribacter hongkongensis is a gram negative, facultative anaerobic, urease-positive bacillus caused infections in liver cirrhosis patients and community-acquired gastroenteritis. It was also found in intestine from commonly consumed freshwater fishes and drinking water reservoirs. Since L. hongkongensis could survive as either fish or human pathogens, their survival mechanisms in two different habitats should be temperature-regulated and highly complex. Therefore, we performed transcriptomic analysis of L. hongkongensis at body temperatures of fish and human in order to elucidate the versatile adaptation mechanisms coupled with the temperatures. We identified numerous novel temperature-induced pathways involved in host pathogenesis, in addition to the shift of metabolic equilibriums and overexpression of stress-related proteins. Moreover, these pathways form a network that can be activated at a particular temperature, and change the physiology of the bacteria to adapt to the environments. In summary, the dynamic of transcriptomes in L. hongkongensis provides versatile strategies for the bacterial survival at different habitats and this alteration prepares the bacterium for the challenge of host immunity. PMID- 28085930 TI - Measurement of Tip Apex Distance and Migration of Lag Screws and Novel Blade Screw Used for the Fixation of Intertrochanteric Fractures. AB - Fixation with a dynamic hip screw (DHS) is one of the most common methods for stabilizing intertrochanteric fractures, except for unstable and reverse oblique fracture types. However, failure is often observed in osteoporotic patients whereby the lag screw effectively 'cuts out' through the weak bone. Novel anti migration blades have been developed to be used in combination with a lag screw ('Blade Screw') to improve the fixation strength in osteoporotic intertrochanteric fractures. An in-vitro biomechanical study and a retrospective clinical study were performed to evaluate lag screw migration when using the novel Blade Screw and a traditional threaded DHS. The biomechanical study showed both the Blade Screw and DHS displayed excessive migration (>=10 mm) before reaching 20,000 loading cycles in mild osteoporotic bone, but overall migration of the Blade Screw was significantly less (p <= 0.03). Among the patients implanted with a Blade Screw in the clinical study, there was no significant variation in screw migration at 3-months follow-up (P = 0.12). However, the patient's implanted with a DHS did display significantly greater migration (P<0.001) than those implanted with the Blade Screw. In conclusion, the Blade Screw stabilizes the bone fragments during dynamic loading so as to provide significantly greater resistance to screw migration in patients with mild osteoporosis. PMID- 28085931 TI - Broad-Range Detection of Microorganisms Directly from Bronchoalveolar Lavage Specimens by PCR/Electrospray Ionization-Mass Spectrometry. AB - The clinical demand on rapid microbiological diagnostic is constantly increasing. PCR coupled to electrospray ionization-mass spectrometry, PCR/ESI-MS, offers detection and identification of over 750 bacteria and Candida species directly from clinical specimens within 6 hours. In this study, we investigated the clinical performance of the IRIDICA BAC LRT Assay for detection of bacterial pathogens in 121 bronchoalveolar lavage (BAL) samples that were received consecutively at our bacterial laboratory for BAL culture. Commensal or pathogenic microorganisms were detected in 118/121 (98%) BAL samples by PCR/ESI MS, while in 104/121 (86%) samples by routine culture (P<0.01). Detection of potentially pathogenic microorganisms by PCR/ESI-MS was evaluated in comparison with conventional culture-based or molecular methods. The agreement between positive findings was overall good. Most Staphylococcus aureus-positive PCR/ESI MS results were confirmed by culture or species-specific PCR (27/33, 82%). The identity of Streptococcus pneumoniae could however be confirmed for only 6/17 (35%) PCR/ESI-MS-positive samples. Non-cultivable and fastidious pathogens, which were not covered by standard culture procedures were readily detected by PCR/ESI MS, including Legionella pneumophila, Bordetella pertussis, Norcadia species and Mycoplasma pneumoniae. In conclusion, PCR/ESI-MS detected a broad range of potential pathogens with equal or superior sensitivity compared to conventional methods within few hours directly from BAL samples. This novel method might thus provide a relevant tool for diagnostics in critically ill patients. PMID- 28085933 TI - Wind Energy Conversion by Plant-Inspired Designs. AB - In 2008 the U.S. Department of Energy set a target of 20% wind energy by 2030. To date, induction-based turbines form the mainstay of this effort, but turbines are noisy, perceived as unattractive, a potential hazard to bats and birds, and their height hampers deployment in residential settings. Several groups have proposed that artificial plants containing piezoelectric elements may harvest wind energy sufficient to contribute to a carbon-neutral energy economy. Here we measured energy conversion by cottonwood-inspired piezoelectric leaves, and by a "vertical flapping stalk"-the most efficient piezo-leaf previously reported. We emulated cottonwood for its unusually ordered, periodic flutter, properties conducive to piezo excitation. Integrated over 0 degrees -90 degrees (azimuthal) of incident airflow, cottonwood mimics outperformed the vertical flapping stalk, but they produced << daW per conceptualized tree. In contrast, a modest-sized cottonwood tree may dissipate ~ 80 W via leaf motion alone. A major limitation of piezo transduction is charge generation, which scales with capacitance (area). We thus tested a rudimentary, cattail-inspired leaf with stacked elements wired in parallel. Power increased systematically with capacitance as expected, but extrapolation to acre-sized assemblages predicts << daW. Although our results suggest that present piezoelectric materials will not harvest mid-range power from botanic mimics of convenient size, recent developments in electrostriction and triboelectric systems may offer more fertile ground to further explore this concept. PMID- 28085932 TI - Dynamic Voltage Frequency Scaling Simulator for Real Workflows Energy-Aware Management in Green Cloud Computing. AB - Nowadays, the growing computational capabilities of Cloud systems rely on the reduction of the consumed power of their data centers to make them sustainable and economically profitable. The efficient management of computing resources is at the heart of any energy-aware data center and of special relevance is the adaptation of its performance to workload. Intensive computing applications in diverse areas of science generate complex workload called workflows, whose successful management in terms of energy saving is still at its beginning. WorkflowSim is currently one of the most advanced simulators for research on workflows processing, offering advanced features such as task clustering and failure policies. In this work, an expected power-aware extension of WorkflowSim is presented. This new tool integrates a power model based on a computing-plus communication design to allow the optimization of new management strategies in energy saving considering computing, reconfiguration and networks costs as well as quality of service, and it incorporates the preeminent strategy for on host energy saving: Dynamic Voltage Frequency Scaling (DVFS). The simulator is designed to be consistent in different real scenarios and to include a wide repertory of DVFS governors. Results showing the validity of the simulator in terms of resources utilization, frequency and voltage scaling, power, energy and time saving are presented. Also, results achieved by the intra-host DVFS strategy with different governors are compared to those of the data center using a recent and successful DVFS-based inter-host scheduling strategy as overlapped mechanism to the DVFS intra-host technique. PMID- 28085934 TI - Housing Systems Influence Gut Microbiota Composition of Sows but Not of Their Piglets. AB - Different housing systems can be used in pig production and little is known about their effect on gut microbiota composition. In this study we characterized fecal microbiota by sequencing the rRNA genes in sows kept during gestation in conventional pens with a slatted floor and in enriched pens with a floor covered with deep straw. After farrowing, microbiota of 1- and 4-day-old piglets were also monitored. Microbiota of sows from the enriched system contained significantly more Prevotella, Parabacteroides, CF231, Phascolarctobacterium, Fibrobacter, Anaerovibrio and YRC22 and significantly less Lactobacillus, Bulleidia, Lachnospira, Dorea, Ruminococcus and Oscillospira than microbiota of sows from the conventional system. The Firmicutes to Bacteroidetes ratio was 0.96 in the microbiota of sows kept in the enriched pens and this increased to 1.66 in the microbiota of sows kept in the conventional system. The production system therefore influenced microbiota composition, most likely due the ingestion of the straw. The microbiota of 1- and 4-day-old piglets differed from the microbiota of sows and sows therefore did not represent the most important source for their colonization in early days of life. PMID- 28085935 TI - Life-Course Relationship between Socioeconomic Circumstances and Timing of First Birth in a Birth Cohort. AB - OBJECTIVES: This study examines the influence of socioeconomic circumstances in childhood (childhood SES) and adulthood (adult SES) on timing of first birth by age 37. METHODS: A longitudinal study of a 1972-1973 New Zealand birth cohort collected information on socioeconomic characteristics from age 3-32 and reproductive histories at 21, 26, 32 and 38; information on first birth was available from 978 of the original 1037. Relative Risks (RR) and 95% Confidence Intervals (CI) were calculated using Poisson regression to examine first live birth prior to age 21, from 21-25, from 26-31, and from 32-37, by socioeconomic characteristics at different ages. RESULTS: Overall, 68.5% of men had fathered a child and 75.9% of women had given birth, by age 37; with overall differences in parenthood to age 31 for men, and 37 for women evident by childhood SES. While parenthood by age 20 was strongly associated with lower childhood SES for both sexes, first entry into motherhood from 32-37 was more likely with higher adult SES at age 32 (RR = 1.8, 95% CI 1.1-3.0 for medium and RR = 1.9, 95% CI 1.1-3.3 for high compared with low). Education also differientated age at parenthood, with those with higher education more likely to defer fatherhood past age 31, and motherhood past age 25 followed by a period of increased likelihood of motherhood for women with higher levels of education from age 32-37 (RR = 1.4, 95% CI 0.87 2.2 and RR = 1.7, 95% CI 1.1-2.6 for medium and high respectively compared with low). CONCLUSIONS: SES varies across the lifecourse, and SES at the time has the strongest association with first births at that time. Low childhood SES drives adolescent parenthood, with resulting cumulative differences in parenthood past age 30. Those with more education and higher adult SES are deferring parenthood but attempt to catch up in the mid to late thirties. PMID- 28085936 TI - Coordinated Control of Acoustical Field of View and Flight in Three-Dimensional Space for Consecutive Capture by Echolocating Bats during Natural Foraging. AB - Echolocating bats prey upon small moving insects in the dark using sophisticated sonar techniques. The direction and directivity pattern of the ultrasound broadcast of these bats are important factors that affect their acoustical field of view, allowing us to investigate how the bats control their acoustic attention (pulse direction) for advanced flight maneuvers. The purpose of this study was to understand the behavioral strategies of acoustical sensing of wild Japanese house bats Pipistrellus abramus in three-dimensional (3D) space during consecutive capture flights. The results showed that when the bats successively captured multiple airborne insects in short time intervals (less than 1.5 s), they maintained not only the immediate prey but also the subsequent one simultaneously within the beam widths of the emitted pulses in both horizontal and vertical planes before capturing the immediate one. This suggests that echolocating bats maintain multiple prey within their acoustical field of view by a single sensing using a wide directional beam while approaching the immediate prey, instead of frequently shifting acoustic attention between multiple prey. We also numerically simulated the bats' flight trajectories when approaching two prey successively to investigate the relationship between the acoustical field of view and the prey direction for effective consecutive captures. This simulation demonstrated that acoustically viewing both the immediate and the subsequent prey simultaneously increases the success rate of capturing both prey, which is considered to be one of the basic axes of efficient route planning for consecutive capture flight. The bat's wide sonar beam can incidentally cover multiple prey while the bat forages in an area where the prey density is high. Our findings suggest that the bats then keep future targets within their acoustical field of view for effective foraging. In addition, in both the experimental results and the numerical simulations, the acoustic sensing and flights of the bats showed narrower vertical ranges than horizontal ranges. This suggests that the bats control their acoustic sensing according to different schemes in the horizontal and vertical planes according to their surroundings. These findings suggest that echolocating bats coordinate their control of the acoustical field of view and flight for consecutive captures in 3D space during natural foraging. PMID- 28085937 TI - A Global User-Driven Model for Tile Prefetching in Web Geographical Information Systems. AB - A web geographical information system is a typical service-intensive application. Tile prefetching and cache replacement can improve cache hit ratios by proactively fetching tiles from storage and replacing the appropriate tiles from the high-speed cache buffer without waiting for a client's requests, which reduces disk latency and improves system access performance. Most popular prefetching strategies consider only the relative tile popularities to predict which tile should be prefetched or consider only a single individual user's access behavior to determine which neighbor tiles need to be prefetched. Some studies show that comprehensively considering all users' access behaviors and all tiles' relationships in the prediction process can achieve more significant improvements. Thus, this work proposes a new global user-driven model for tile prefetching and cache replacement. First, based on all users' access behaviors, a type of expression method for tile correlation is designed and implemented. Then, a conditional prefetching probability can be computed based on the proposed correlation expression mode. Thus, some tiles to be prefetched can be found by computing and comparing the conditional prefetching probability from the uncached tiles set and, similarly, some replacement tiles can be found in the cache buffer according to multi-step prefetching. Finally, some experiments are provided comparing the proposed model with other global user-driven models, other single user-driven models, and other client-side prefetching strategies. The results show that the proposed model can achieve a prefetching hit rate in approximately 10.6% ~ 110.5% higher than the compared methods. PMID- 28085938 TI - Rare Synaptogenesis-Impairing Mutations in SLITRK5 Are Associated with Obsessive Compulsive Disorder. AB - Obsessive compulsive disorder (OCD) is substantially heritable, but few molecular genetic risk factors have been identified. Knockout mice lacking SLIT and NTRK Like Family, Member 5 (SLITRK5) display OCD-like phenotypes including serotonin reuptake inhibitor-sensitive pathologic grooming, and corticostriatal dysfunction. Thus, mutations that impair SLITRK5 function may contribute to the genetic risk for OCD. We re-sequenced the protein-coding sequence of the human SLITRK5 gene (SLITRK5) in three hundred and seventy seven OCD subjects and compared rare non-synonymous mutations (RNMs) in that sample with similar mutations in the 1000 Genomes database. We also performed in silico assessments and in vitro functional synaptogenesis assays on the Slitrk5 mutations identified. We identified four RNM's among these OCD subjects. There were no significant differences in the prevalence or in silico effects of rare non synonymous mutations in the OCD sample versus controls. Direct functional testing of recombinant SLITRK5 proteins found that all mutations identified in OCD subjects impaired synaptogenic activity whereas none of the pseudo-matched mutations identified in 1000 Genomes controls had significant effects on SLITRK5 function (Fisher's exact test P = 0.028). These results demonstrate that rare functional mutations in SLITRK5 contribute to the genetic risk for OCD in human populations. They also highlight the importance of biological characterization of allelic effects in understanding genotype-phenotype relationships as there were no statistical differences in overall prevalence or bioinformatically predicted effects of OCD case versus control mutations. Finally, these results converge with others to highlight the role of aberrant synaptic function in corticostriatal neurons in the pathophysiology of OCD. PMID- 28085939 TI - Up, Down, Near, Far: An Online Vestibular Contribution to Distance Judgement. AB - Whether a visual stimulus seems near or far away depends partly on its vertical elevation. Contrasting theories suggest either that perception of distance could vary with elevation, because of memory of previous upwards efforts in climbing to overcome gravity, or because of fear of falling associated with the downwards direction. The vestibular system provides a fundamental signal for the downward direction of gravity, but the relation between this signal and depth perception remains unexplored. Here we report an experiment on vestibular contributions to depth perception, using Virtual Reality. We asked participants to judge the absolute distance of an object presented on a plane at different elevations during brief artificial vestibular inputs. Relative to distance estimates collected with the object at the level of horizon, participants tended to overestimate distances when the object was presented above the level of horizon and the head was tilted upward and underestimate them when the object was presented below the level of horizon. Interestingly, adding artificial vestibular inputs strengthened these distance biases, showing that online multisensory signals, and not only stored information, contribute to such distance illusions. Our results support the gravity theory of depth perception, and show that vestibular signals make an on-line contribution to the perception of effort, and thus of distance. PMID- 28085940 TI - Location of Receipt of Initial Treatment and Outcomes in Long-Term Breast Cancer Survivors. AB - PURPOSE: Cancer outcomes differ depending on where treatment is received. We assessed differences in outcomes in long-term breast cancer survivors at a specialty care hospital by location of their initial treatment. METHODS: We retrospectively examined a cohort of women diagnosed with invasive early-stage breast cancer who did not experience recurrence for at least 5 years after the date of diagnosis and were evaluated at The University of Texas MD Anderson Cancer Center between January 1997 and August 2008. The location of initial treatment was categorized as MD Anderson (MDA-treated) or other (OTH-treated). Outcomes analyzed included recurrence-free survival (RFS), distant relapse-free survival (DRFS), and overall survival (OS). The Kaplan-Meier product-limit method was used to compare outcomes between the two groups. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: We identified 5,091 breast cancer survivors (median follow-up 8.6 years), of whom 89.1% were MDA-treated. The 10-year OS, RFS, and DRFS rates were 90.9%, 88.4%, and 89.0% in the MDA-treated group and 74.3%, 49.8%, and 52.7% in the OTH-treated group, respectively. We observed worse outcomes in the OTH-group in both the univariate analysis and the multivariable analysis (OS: HR = 4.8, 95% CI = 3.9-6.0; RFS: HR = 5.8, 95% CI = 4.8-7.0; DRFS: HR = 5.4, 95% CI = 4.5-6.6). CONCLUSION: Long-term breast cancer survivors who initiated their treatment at MD Anderson had better outcomes. Location of initial treatment could be an independent risk factor for survival outcomes at specialty care hospitals. This analysis has limitations inherent to retrospective observational studies such as other unmeasured variables may be associated with worse prognosis. PMID- 28085941 TI - A Split-GFP Gateway Cloning System for Topology Analyses of Membrane Proteins in Plants. AB - To understand the function of membrane proteins, it is imperative to know their topology. For such studies, a split green fluorescent protein (GFP) method is useful. GFP is barrel-shaped, consisting of 11 beta-sheets. When the first ten beta-sheets (GFP1-10) and the 11th beta-sheet (GFP11) are expressed from separate genes they will self-assembly and reconstitute a fluorescent GFP protein. However, this will only occur when the two domains co-localize in the same cellular compartment. We have developed an easy-to-use Gateway vector set for determining on which side of the membrane the N- and C-termini are located. Two vectors were designed for making N- and C-terminal fusions between the membrane proteins-of-interest and GFP11, while another three plasmids were designed to express GFP1-10 in either the cytosol, the endoplasmic reticulum (ER) lumen or the apoplast. We tested functionality of the system by applying the vector set for the transmembrane domain, CNXTM, of the ER membrane protein, calnexin, after transient expression in Nicotiana benthamiana leaves. We observed GFP signal from the ER when we reciprocally co-expressed GFP11-CNXTM with GFP1-10-HDEL and CNXTM GFP with cytosolic GFP1-10. The opposite combinations did not result in GFP signal emission. This test using the calnexin ER-membrane domain demonstrated its C-terminus to be in the cytosol and its N-terminus in the ER lumen. This result confirmed the known topology of calnexin, and we therefore consider this split GFP system highly useful for ER membrane topology studies. Furthermore, the vector set provided is useful for detecting the topology of proteins on other membranes in the cell, which we confirmed for a plasma membrane syntaxin. The set of five Ti-plasmids are easily and efficiently used for Gateway cloning and transient transformation of N. benthamiana leaves. PMID- 28085942 TI - Correction: Intermittent Hypoxia Effect on Osteoclastogenesis Stimulated by Neuroblastoma Cells. AB - [This corrects the article DOI: 10.1371/journal.pone.0105555.]. PMID- 28085943 TI - Identifying Risk: Concurrent Overlap of the Antarctic Krill Fishery with Krill Dependent Predators in the Scotia Sea. AB - Mitigating direct and indirect interactions between marine predators and fisheries is a motivating factor for ecosystem-based fisheries management (EBFM), especially where predators and fisheries compete for a shared resource. One difficulty in advancing EBFM is parameterizing clear functional responses of predators to indices of prey availability. Alternative characterizations of fishery-predator interactions may therefore benefit the implementation of EBFM. Telemetry data identify foraging areas used by predators and, therefore, represent critical information to mitigate potential competition between predators and fisheries. We analyzed six years (2009-2014) of telemetry data collected at Cape Shirreff, Livingston Island and Admiralty Bay, King George Island, Antarctica, on three species of Pygoscelid penguins and female Antarctic fur seals. In this region, all four species are primarily dependent on Antarctic krill. The tracking data demonstrate local movements near breeding colonies during the austral summer and dispersal from breeding colonies during the winter. We then assessed overlap between predators and the Antarctic krill fishery on a suite of spatiotemporal scales to examine how different data aggregations affect the extent and location of overlap. Concurrent overlap was observed on all spatiotemporal scales considered throughout the Antarctic Peninsula and South Orkney Islands region, including near tagging locations and in distant areas where recent fishing activity has concentrated. Overlap occurred at depths where mean krill densities were relatively high. Our results demonstrate that direct overlap of krill-dependent predators with the krill fishery on small spatiotemporal scales is relatively common throughout the Antarctic Peninsula region. As the krill fishery continues to develop and efforts to implement ecosystem-based management mature, indices of overlap may provide a useful metric for indicating where the risks of fishing are highest. A precautionary approach to allocating krill catches in space would be to avoid large increases in catch where overlap on small spatiotemporal scales is common. PMID- 28085945 TI - Long-Distance Travellers: Phylogeography of a Generalist Parasite, Pholeter gastrophilus, from Cetaceans. AB - We studied the phylogeography and historical demography of the most generalist digenean from cetaceans, Pholeter gastrophilus, exploring the effects of isolation by distance, ecological barriers and hosts' dispersal ability on the population structure of this parasite. The ITS2 rDNA, and the mitochondrial COI and ND1 from 68 individual parasites were analysed. Worms were collected from seven oceanic and coastal cetacean species from the south western Atlantic (SWA), central eastern Atlantic, north eastern Atlantic (NEA), and Mediterranean Sea. Pholeter gastrophilus was considered a single lineage because reciprocal monophyly was not detected in the ML cladogram of all individuals, and sequence variability was <1% for mtDNA and 0% for ITS2. These results rule out a recent suggestion that P. gastrophilus would actually be a cryptic-species complex. The genetic cohesion of P. gastrophilus could rely on the extensive exploitation of wide-ranging and highly mobile cetaceans, with a putative secondary role, if any, of intermediate hosts. Unique haplotypes were detected in SWA and NEA, and an AMOVA revealed significant population structure associated to the genetic variation in these regions. The Equator possibly acts as a significant geographical barrier for cetacean movements, possibly limiting gene flow between northern and southern populations of P. gastrophilus. A partial Mantel tests revealed that the significant isolation of NEA populations resulted from geographic clustering. Apparently, the limited mobility of cetaceans used by P. gastrophilus as definitive hosts in this region, coupled with oceanographic barriers and a patchy distribution of potential intermediate hosts could contribute to significant ecological isolation of P. gastrophilus in NEA. Rather unexpectedly, no genetic differentiation was found in the Mediterranean samples of this parasite. Historical demographic analyses suggested a recent population expansion of P. gastrophilus in the Atlantic Ocean, perhaps linked to initial association and subsequent spreading in cetaceans. PMID- 28085944 TI - General Practitioners' Decision Making about Primary Prevention of Cardiovascular Disease in Older Adults: A Qualitative Study. AB - BACKGROUND: Primary cardiovascular disease (CVD) prevention in older people is challenging as they are a diverse group with varying needs, frequent presence of comorbidities, and are more susceptible to treatment harms. Moreover the potential benefits and harms of preventive medication for older people are uncertain. We explored GPs' decision making about primary CVD prevention in patients aged 75 years and older. METHOD: 25 GPs participated in semi-structured interviews in New South Wales, Australia. Transcribed audio-recordings were thematically coded and Framework Analysis was used. RESULTS: Analysis identified factors that are likely to contribute to variation in the management of CVD risk in older people. Some GPs based CVD prevention on guidelines regardless of patient age. Others tailored management based on factors such as perceptions of prevention in older age, knowledge of limited evidence, comorbidities, polypharmacy, frailty, and life expectancy. GPs were more confident about: 1) medication and lifestyle change for fit/healthy older patients, and 2) stopping or avoiding medication for frail/nursing home patients. Decision making for older patients outside of these categories was less clear. CONCLUSION: Older patients receive different care depending on their GP's perceptions of ageing and CVD prevention, and their knowledge of available evidence. GPs consider CVD prevention for older patients challenging and would welcome more guidance in this area. PMID- 28085946 TI - OCLI-023, a Novel Pyrimidine Compound, Suppresses Osteoclastogenesis In Vitro and Alveolar Bone Resorption In Vivo. AB - An abnormal increase in osteoclast differentiation and activation results in various bone-resorptive diseases, including periodontitis, rheumatoid arthritis, and osteoporosis. Chemical compounds containing pyrimidine ring have been shown to regulate a variety of biological processes. Therefore, in order to identify an antiresorptive agent, we synthesized a series of pyrimidine ring-containing chemical compounds, and found that OCLI-023 suppressed the differentiation and activation of osteoclasts in vitro. OCLI-023 directly inhibited receptor activator of nuclear factor-kappaB ligand (RANKL)-induced differentiation of bone marrow macrophages into osteoclasts, without a cytotoxic response. OCLI-023 also downregulated the RANKL-induced mRNA expression of osteoclast markers as well as inhibited the formation of actin rings and resorption pits. OCLI-023 attenuated the RANKL-induced activation of c-Jun N-terminal kinase and nuclear factor kappa light-chain-enhancer of activated B cell signaling pathways. In a mouse model of periodontitis, ligature induced an increase of distance between cementoenamel junction (CEJ) and alveolar bone crest (ABC) in the second molar, and OCLI-023 significantly reduced it. Histological analysis showed ligature-induced increase of osteoclast numbers was also significantly reduced by OCLI-023. These data demonstrated the inhibitory effect of OCLI-023 on osteoclast differentiation and activity of osteoclasts in vitro, as well as on ligature-induced bone loss in vivo, and OCLI-023 can be proposed as a novel anti-resorptive compound. PMID- 28085947 TI - Distinctions in Breast Tumor Recurrence Patterns Post-Therapy among Racially Distinct Populations. AB - BACKGROUND: Clinical studies have revealed a higher risk of breast tumor recurrence in African-American (AA) patients compared to European-American (EA) patients, contributing to the alarming inequality in clinical outcomes among the ethnic groups. However, distinctions in recurrence patterns upon receiving hormone, radiation, and/or chemotherapy between the races remain poorly characterized. METHODS: We compared patterns and rates (per 1000 cancer patients per 1 year) of recurrence following each form of treatment between AA (n = 1850) and EA breast cancer patients (n = 7931) from a cohort of patients (n = 10504) treated between 2005-2015 at Northside Hospital in Atlanta, GA. RESULTS: Among patients who received any combination of adjuvant therapy, AA displayed higher overall rates of recurrence than EA (p = 0.015; HR: 1.699; CI: 1.108-2.606). Furthermore, recurrence rates were higher in AA than EA among stage I (p = 0.031; HR: 1.736; CI: 1.052-2.864) and T1 classified patients (p = 0.003; HR: 2.009; CI: 1.263-3.197). Interestingly, among patients who received neoadjuvant chemotherapy, AA displayed higher rates of local recurrence than EA (p = 0.024; HR: 7.134; CI: 1.295-39.313). CONCLUSION: Our analysis revealed higher incidence rates of recurrence in AA compared to EA among patients that received any combination of adjuvant therapy. Moreover, our data demonstrates an increased risk of tumor recurrence in AA than EA among patients diagnosed with minimally invasive disease. This is the first clinical study to suggest that neoadjuvant chemotherapy improves breast cancer recurrence rates and patterns in AA. PMID- 28085948 TI - Correction: Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma. AB - [This corrects the article DOI: 10.1371/journal.pone.0158888.]. PMID- 28085949 TI - The Association between Exposure to Environmental Bisphenol A and Gonadotropic Hormone Levels among Men. AB - Bisphenol A (BPA) is an extensively used chemical with endocrine disrupting properties. Although animal and in vivo studies have suggested possible effects of BPA on levels of gonadotropic hormones, human studies are limited and inconclusive. The study examined whether environmental BPA exposure was associated with gonadotropic hormones levels in men. A total of 560 men aged 18 55 years were recruited from Sandu County, Guizhou Province, China. We collected urine samples for measurement of BPA, and blood samples for measurement of reproductive hormones. We examined serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and total testosterone (T). Relative risk (RR) was obtained by log-binominal regression to explore the association between urinary BPA level and hormone levels. BPA was detected in 70.4% of urine samples, with a geometric mean of 0.50 MUg/gCr. Men with detectable levels of BPA had a 1.52-fold increased risk of having a high LH level (>75th percentile) when compared with men with undetectable levels of BPA, after adjustment for potential confounders (95% confidence interval (CI): 1.04-2.21). The association persisted and slightly intensified among current smokers (adjusted RR (aRR) = 1.76, 95%CI: 1.05-2.95), while it weakened among non-smokers (aRR = 1.17, 95%CI: 0.69-1.96). Urinary BPA level was associated with an increased FSH level among smokers (aRR = 1.64, 95%CI: 1.01-2.67). Urinary BPA level was inversely associated with total T level among males with body max index (BMI) >=25 kg/m2 although this association was of borderline significance (aRR = 0.52, 95%CI: 0.26-1.05). In conclusion, environmental exposure to BPA was associated with increased serum levels of LH and FSH in male smokers, along with decreased serum levels of total T in men with BMI>=25 kg/m2. These findings suggest that the effects of environmental BPA exposure on hormone levels might be modified by smoking and BMI. PMID- 28085950 TI - Impact of DRD2/ANKK1 and COMT Polymorphisms on Attention and Cognitive Functions in Schizophrenia. AB - BACKGROUND: Cognitive deficits such as poor selective attention and executive functions decline have been reported in patients with schizophrenia. Many studies have emphasized the role of dopamine in regulating cognitive functions in the general population as well as in schizophrenia. However, the relationship between cognitive processes, schizophrenia and dopaminergic candidate genes is an original approach given interesting results. The purpose of the current exploratory study was to examine the interaction of dopaminergic genes (coding for dopamine receptor D2, DRD2, and for Catecholamine-O-Methyl-Transferase, COMT) with the diagnostic of schizophrenia in (i) the executive control of attention, (ii) selective attention, and (iii) executive functions. METHODS AND RESULTS: We recruited 52 patients with schizophrenia and 53 healthy controls who performed the Stroop Color-Word Test, the Attention Network Test and the Wisconsin Card Sorting test. Four single nucleotide polymorphisms (SNPs) in the DRD2 gene (rs6275, rs6277, rs2242592 and rs1800497) and two SNPs in the COMT gene (rs4680 and rs165599) have been genotyped. Patients with schizophrenia performed significantly worse than controls in all cognitive performance, taking into account demographic variables. A significant gene by disease interaction was found for the Stroop interference (p = 0.002) for rs6275 of the DRD2 gene. The COMT Val/Val genotype and schizophrenia were associated with increased number of perseverative errors (p = 0.01). CONCLUSIONS: In our study, the DRD2 gene is involved in attention while the COMT gene is implicated in executive functions in patients with schizophrenia. PMID- 28085951 TI - Association of Body Mass Index with Timing of Death during Tuberculosis Treatment. AB - BACKGROUND: The association between body mass index and mortality in patients with tuberculosis has not been extensively studied, and the existing evidence is inconsistent. This study aimed to investigate the impact of body mass index on timing of death in patients with tuberculosis. METHODS: All Taiwanese adults with tuberculosis in Taipei, Taiwan, were included in a retrospective cohort study in 2011-2012. Multinomial logistic regression was used to evaluate the association between body mass index and timing of death in patients with tuberculosis. RESULTS: Among 1557 eligible patients, 84.1% (1310), 8.2% (128), and 7.6% (119) underwent successful treatment, early death, and late death, respectively. The mean age of the patients with tuberculosis was 64.2 years old, and 67.7% were male. After controlling for potential confounding variables, underweight with body mass index less than 18.5 kg/ m2 was significantly associated with elevated risk of all-cause mortality [Adjusted odds ratio (AOR), 1.64; 95% confidence interval (CI), 1.17-2.30]. Considering timing of death, underweight with body mass index less than 18.5 was significantly associated only with elevated risk of early mortality within the first 8 weeks of treatment onset (AOR, 2.22; 95% CI, 1.45-3.40). CONCLUSIONS: For patients with tuberculosis infection, underweight with body mass index less than 18.5 kg/ m2 is an independent predictor for early mortality within the first 8 weeks of treatment. PMID- 28085953 TI - Classification of Partial Discharge Measured under Different Levels of Noise Contamination. AB - Cable joint insulation breakdown may cause a huge loss to power companies. Therefore, it is vital to diagnose the insulation quality to detect early signs of insulation failure. It is well known that there is a correlation between Partial discharge (PD) and the insulation quality. Although many works have been done on PD pattern recognition, it is usually performed in a noise free environment. Also, works on PD pattern recognition in actual cable joint are less likely to be found in literature. Therefore, in this work, classifications of actual cable joint defect types from partial discharge data contaminated by noise were performed. Five cross-linked polyethylene (XLPE) cable joints with artificially created defects were prepared based on the defects commonly encountered on site. Three different types of input feature were extracted from the PD pattern under artificially created noisy environment. These include statistical features, fractal features and principal component analysis (PCA) features. These input features were used to train the classifiers to classify each PD defect types. Classifications were performed using three different artificial intelligence classifiers, which include Artificial Neural Networks (ANN), Adaptive Neuro-Fuzzy Inference System (ANFIS) and Support Vector Machine (SVM). It was found that the classification accuracy decreases with higher noise level but PCA features used in SVM and ANN showed the strongest tolerance against noise contamination. PMID- 28085952 TI - Metabolic Dysregulation in Hepacivirus Infection of Common Marmosets (Callithrix jacchus). AB - Chronic hepatitis C has been associated with metabolic syndrome that includes insulin resistance, hepatic steatosis and obesity. These metabolic aberrations are risk factors for disease severity and treatment outcome in infected patients. Experimental infection of marmosets with GBV-B serves as a tangible, small animal model for human HCV infection, and while virology and pathology are well described, a full investigation of clinical disease and the metabolic milieu is lacking. In this study six marmosets were infected intravenously with GBV-B and changes in hematologic, serum biochemical and plasma metabolic measures were investigated over the duration of infection. Infected animals exhibited signs of lymphocytopenia, but platelet and RBC counts were generally stable or even increased. Although most animals showed a transient decline in blood glucose, infection resulted in several fold increases in plasma insulin, glucagon and glucagon-like peptide 1 (GLP-1). All infected animals experienced transient weight loss within the first 28 days of infection, but also became hypertriglyceridemic and had up to 10-fold increases in adipocytokines such as resistin and plasminogen activator inhibitor 1 (PAI-1). In liver, moderate to severe cytoplasmic changes associated with steatotic changes was observed microscopically at 168 days post infection. Collectively, these results suggest that GBV-B infection is accompanied by hematologic, biochemical and metabolic abnormalities that could lead to obesity, diabetes, thrombosis and atherosclerosis, even after virus has been cleared. Our findings mirror those found in HCV patients, suggesting that metabolic syndrome could be conserved among hepaciviruses, and both mechanistic and interventional studies for treating HCV-induced metabolic complications could be evaluated in this animal model. PMID- 28085954 TI - Leptin-Induced Endothelium-Independent Vasoconstriction in Thoracic Aorta and Pulmonary Artery of Spontaneously Hypertensive Rats: Role of Calcium Channels and Stores. AB - Decreased leptin-induced endothelium-dependent vasodilation has been reported in spontaneously hypertensive rats (SHR). Here, we report leptin-induced vasoconstriction in endothelium-denuded pulmonary artery and thoracic aorta from SHR and sought to characterize calcium handling underlying these mechanisms. Vasoreactivity to leptin was evaluated on pulmonary artery and thoracic aorta rings from 18 weeks old male SHR with or without calcium free medium, caffeine + thapsigargin + carbonyl cyanide-4-trifluoromethoxyphenylhydrazone emptying intracellular calcium stores, nifedipine a voltage-gated calcium channel inhibitor, SKF-96365 a transient receptor potential cation channels (TRPC) inhibitor, wortmaninn, a phosphatidylinositide 3-kinases (PI3K) inhibitor, or PD98059 a mitogen-activated protein kinase kinase (MAPKK) inhibitor. Calcium imaging was performed on cultured vascular smooth muscle cells incubated with leptin in presence or not of wortmaninn or PD98059. Leptin induced vasoconstriction in denuded pulmonary artery and thoracic aorta from SHR. Response was abolished when intra- or extracellular calcium stores were emptied, after blocking TRPC or voltage-dependent calcium channels or when using MAPKK or PI3K inhibitors. In vascular smooth muscle cells, leptin increased intracellular calcium. This rise was higher in SHR and abolished by MAPKK or PI3K inhibitors. TRPC6 gene expression was upregulated in arteries from SHR. Leptin-induced vasoconstriction in denuded arteries of SHR requires intracellular stores and is TRPC- and voltage-gated calcium channels dependent. Intracellular calcium increase is more pronounced in spontaneously hypertensive rats. PMID- 28085955 TI - An Empirical Assessment of Transgene Flow from a Bt Transgenic Poplar Plantation. AB - To assess the possible impact of transgenic poplar plantations on the ecosystem, we analyzed the frequency and distance of gene flow from a mature male transgenic Populus nigra plantation carrying the Bacillus thuringiensis toxin gene (Bt poplar) and the survival of Bt poplar seeds. The resultant Bt poplar seeds occurred at a frequency of ~0.15% at 0 m to ~0.02% at 500 m from the Bt poplar plantation. The germination of Bt poplar seeds diminished within three weeks in the field (germination rate from 68% to 0%) compared to 48% after three weeks of storage at 4 degrees C. The survival rate of seedlings in the field was 0% without any treatment but increased to 1.7% under the addition of four treatments (cleaning and trimming, watering, weeding, and covering with plastic film to maintain moisture) after being seeded in the field for eight weeks. The results of this study indicate that gene flow originating from the Bt poplar plantation occurred at an extremely low level through pollen or seeds under natural conditions. This study provides first-hand field data on the extent of transgene flow in poplar plantations and offers guidance for the risk assessment of transgenic poplar plantations. PMID- 28085957 TI - 25-Hydroxivitamin D Serum Concentration, Not Free and Bioavailable Vitamin D, Is Associated with Disease Activity in Systemic Lupus Erythematosus Patients. AB - We aim to evaluate the prevalence of vitamin D deficiency in patients with systemic lupus erythematosus (SLE) and investigate the association between total, free and bioavailable vitamin D serum concentrations and disease activity. Patients with SLE (ACR 1997) consecutively seen at UNIFESP's outpatient's clinics had disease activity measured after clinical and laboratory evaluation using SLEDAI (Systemic Lupus Erythematosus Disease Activity Index). 25-hydroxyvitamin D (25(OH)D) serum concentrations measured by chemiluminescence and vitamin D binding protein (DBP) measured by ELISA were used to calculate free and bioavailable vitamin D. Healthy blood donors were used as controls. A total of 142 patients (71.4%) had 25(OH)D serum concentrations below 30 ng/mL. Total 25(OH)D serum concentration was associated with disease activity categorized in 5 continuous groups of SLEDAI. 25(OH)D serum concentrations were higher among patients with SLEDAI 1-5 and lower in those with severe activity (SLEDAI>=20) (p <0.05). On the other hand, no statistically significant difference was observed for DBP, free and bioavailable vitamin D measurements in the disease activity subgroups evaluated. Vitamin D deficiency is highly prevalent among patients with SLE and was associated with higher disease activity. DBP serum level and calculation of free and bioavailable vitamin D were not associated with SLE disease activity. PMID- 28085956 TI - MiRNAs Predict the Prognosis of Patients with Triple Negative Breast Cancer: A Meta-Analysis. AB - PURPOSE: miRNAs are stable and can be extracted from tissues, blood and other body fluid without degradation. miRNAs are abnormally expressed in the presence of a pathological status, including cancer. Therefore, miRNAs are ideal biomarkers for cancer diagnosis and prognosis. Patients with triple negative breast cancer (TNBC) suffer the worst prognosis, although great efforts have been made. Many studies have investigated the role of miRNAs in predicting the outcomes of TNBC patients for better adjustment of treatment. However, results were inconsistent. Thus, we performed a meta-analysis to summarize the published studies for conclusive results. METHODS: Eligible studies from different database were retrieved from the online databases, and we used STSTA 12.0 to analysis the prognostic role of miRNAs in triple negative breast cancer. RESULTS: Overall high miRNA expression indicated a worse survival with HR value of 1.78 (95% CI: 0.97 3.25). However, subtotal HRs of oncogenic miRNAs and tumor suppressive miRNAs were 2.73 (95% CI: 2.08-3.57; P<0.001) and 0.44 (95% CI: 0.21-0.90; P = 0.024), respectively, and no heterogeneity was observed within the subgroups. CONCLUSIONS: The miRNAs showed a slightly stronger prognostic value for disease free survival, relapse-free survival and distant metastasis-free survival compared to the overall survival of TNBC patients. Circulating miRNAs could serve as potential biomarkers for the prognosis of TNBC patients and need further investigation. PMID- 28085959 TI - Allelopatic Potential of Dittrichia viscosa (L.) W. Greuter Mediated by VOCs: A Physiological and Metabolomic Approach. AB - Dittrichia viscosa (L.) W. Greuter is a pioneer species belonging to the Compositae family. It is widespread in the Mediterranean basin, where it is considered invasive. It is a source of secondary metabolites, playing an important ecological role. D. viscosa plant extracts showed a phytotoxic activity on several physiological processes of different species. In the current study, the allelopathic potential of D. viscosa VOCs, released by its foliage, was evaluated on seed germination and root growth of lettuce. The VOCs effect was also studied on lettuce adult plants in microcosm systems, which better mimicked the open field conditions. D. viscosa VOCs inhibited both seed germination and root growth of lettuce. The VOCs composition revealed a large presence of terpenoids, responsible of the effects observed. Moreover, D. viscosa VOCs caused an alteration on plant water status accompanied by oxidative damages and photoinhibition on lettuce adult plants. PMID- 28085958 TI - Alveolar Macrophages Prevent Lethal Influenza Pneumonia By Inhibiting Infection Of Type-1 Alveolar Epithelial Cells. AB - The Influenza A virus (IAV) is a major human pathogen that produces significant morbidity and mortality. To explore the contribution of alveolar macrophages (AlvMPhis) in regulating the severity of IAV infection we employed a murine model in which the Core Binding Factor Beta gene is conditionally disrupted in myeloid cells. These mice exhibit a selective deficiency in AlvMPhis. Following IAV infection these AlvMPhi deficient mice developed severe diffuse alveolar damage, lethal respiratory compromise, and consequent lethality. Lethal injury in these mice resulted from increased infection of their Type-1 Alveolar Epithelial Cells (T1AECs) and the subsequent elimination of the infected T1AECs by the adaptive immune T cell response. Further analysis indicated AlvMPhi-mediated suppression of the cysteinyl leukotriene (cysLT) pathway genes in T1AECs in vivo and in vitro. Inhibition of the cysLT pathway enzymes in a T1AECs cell line reduced the susceptibility of T1AECs to IAV infection, suggesting that AlvMPhi-mediated suppression of this pathway contributes to the resistance of T1AECs to IAV infection. Furthermore, inhibition of the cysLT pathway enzymes, as well as blockade of the cysteinyl leukotriene receptors in the AlvMPhi deficient mice reduced the susceptibility of their T1AECs to IAV infection and protected these mice from lethal infection. These results suggest that AlvMPhis may utilize a previously unappreciated mechanism to protect T1AECs against IAV infection, and thereby reduce the severity of infection. The findings further suggest that the cysLT pathway and the receptors for cysLT metabolites represent potential therapeutic targets in severe IAV infection. PMID- 28085960 TI - Decreasing Seroprevalence of Measles Antibodies after Vaccination - Possible Gap in Measles Protection in Adults in the Czech Republic. AB - AIMS: In recent years, Europe has recorded an increase in the number of measles outbreaks despite the implementation of vaccination into the National Immunization Programs. The Czech Republic introduced vaccination against measles into National Immunization Program in 1969. The aim of this study was to determine seroprevalence of IgG antibodies against measles in adults. METHODS: Our study was designed as a prospective, multicenter cohort study. Samples of blood were taken from adults aged 18 years and over. Specific IgG antibodies were determined by ELISA method. RESULTS: A number of 1911 sera samples were obtained. The total seropositivity reached 83.3%, 14.3% of the results were negative and 2.4% were borderline. When comparing the individual age groups, the highest antibody seropositivity (> 96%) was detected in persons aged 50 years and over who were naturally infected in pre-vaccine era. The lowest seropositivity was recorded in the age groups 30-39 years (61.5%), 40-49 years (77.5%) and 18-29 years (81.1%). CONCLUSIONS: A long term high rate of seropositivity persists after natural measles infection. By contrast, it decreases over time after vaccination. Similarly, the concentrations of antibodies in persons with measles history persist for a longer time at a higher level than in vaccinated persons. Our results indicate possible gap in measles protection in adults born after implementation of vaccination into the National Immunization Programs. There are two probable reasons, decrease of measles antibody seropositivity in time after vaccination in setting of limited natural booster and one-dose vaccination schedule used in the first years after implementation. PMID- 28085961 TI - Association between Immune Markers and Surrogate Markers of Cardiovascular Disease in HIV Positive Patients: A Systematic Review. AB - BACKGROUND: HIV infection is associated with an increased risk of cardiovascular disease (CVD). Chronic low-grade immune activation is likely one of the driving mechanisms. This systematic review provides an overview of the evidence addressing the relation between immune markers and surrogate markers of CVD (except CIMT) in HIV infection. METHODS: A systematic search was performed in PubMed, Embase and Cochrane Library identifying all articles from 1996 to April 2015. It addressed the relation between immune markers and surrogate markers of CVD (except Carotid Intima-media Thickness) in HIV-positive adults. Two authors, using predefined criteria, independently conducted the selection of articles, critical appraisal and extraction of the data. Analysis focused on immune markers that were assessed most frequently. The review was conducted according to the PRISMA guideline and performed as part of an overarching review registered with PROSPERO (CRD42014010516). FINDINGS: Twenty-nine articles were selected, describing 34 immune markers and nine different CVD surrogate outcomes: coronary calcium score (13 times) and flow-mediated dilation (10 times) were used most frequently. Twenty-seven studies had a cross-sectional design. CRP, IL-6 and sVCAM-1 were assessed most frequently. None of the immune markers were clearly associated with any of the surrogate CVD outcomes. No effect estimate could be calculated due to marked heterogeneity in study populations, immune markers, outcomes and statistical approaches. INTERPRETATION: This review could not identify a clear association between any of the immune markers and surrogate CVD outcomes. This may reflect a true lack of association, or may be explained by heterogeneity across studies and lack of follow-up data. Future research should focus on longitudinal studies measuring a select set of immune markers and surrogate CVD outcomes awaiting the primary outcome of clinical cardiovascular events. PMID- 28085962 TI - Do Large Carnivores and Mesocarnivores Have Redundant Impacts on Intertidal Prey? AB - The presence of large carnivores can affect lower trophic levels by suppressing mesocarnivores and reducing their impacts on prey. The mesopredator release hypothesis therefore predicts prey abundance will be higher where large carnivores are present, but this prediction assumes limited dietary overlap between large and mesocarnivores. Where dietary overlap is high, e.g., among omnivorous carnivore species, or where prey are relatively easily accessible, the potential exists for large and mesocarnivores to have redundant impacts on prey, though this possibility has not been explored. The intertidal community represents a potentially important but poorly studied resource for coastal carnivore populations, and one for which dietary overlap between carnivores may be high. To evaluate usage of the intertidal community by coastal carnivores and the potential for redundancy between large and mesocarnivores, we surveyed (i) intertidal prey abundance (crabs and fish) and (ii) the abundance and activity of large carnivores (predominantly black bears) and mesocarnivores (raccoons and mink) in an area with an intact carnivore community in coastal British Columbia, Canada. Overall carnivore activity was strongly related to intertidal prey availability. Notably, this relationship was not contingent on carnivore species identity, suggestive of redundancy-high intertidal prey availability was associated with either greater large carnivore activity or greater mesocarnivore activity. We then compared intertidal prey abundances in this intact system, in which bears dominate, with those in a nearby system where bears and other large carnivores have been extirpated, and raccoons are the primary intertidal predator. We found significant similarities in intertidal species abundances, providing additional evidence for redundancy between large (bear) and mesocarnivore (raccoon) impacts on intertidal prey. Taken together, our results indicate that intertidal prey shape habitat use and competition among coastal carnivores, and raise the interesting possibility of redundancy between mesocarnivores and large carnivores in their role as intertidal top predators. PMID- 28085963 TI - Testicular Dysgenesis Syndrome and Long-Lasting Epigenetic Silencing of Mouse Sperm Genes Involved in the Reproductive System after Prenatal Exposure to DEHP. AB - The endocrine disruptor bis(2-ethylhexyl) phthalate (DEHP) has been shown to exert adverse effects on the male animal reproductive system. However, its mode of action is unclear and a systematic analysis of its molecular targets is needed. In the present study, we investigated the effects of prenatal exposure to 300 mg/kg/day DEHP during a critical period for gonads differentiation to testes on male mice offspring reproductive parameters, including the genome-wide RNA expression and associated promoter methylation status in the sperm of the first filial generation. It was observed that adult male offspring displayed symptoms similar to the human testicular dysgenesis syndrome. A combination of sperm transcriptome and methylome data analysis allowed to detect a long-lasting DEHP induced and robust promoter methylation-associated silencing of almost the entire cluster of the seminal vesicle secretory proteins and antigen genes, which are known to play a fundamental role in sperm physiology. It also resulted in the detection of a DEHP-induced promoter demethylation associated with an up regulation of three genes apparently not relevant for sperm physiology and partially related to the immune system. As previously reported, DEHP induced an increase in mir-615 microRNA expression and a genome-wide decrease in microRNA promoter methylation. A functional analysis revealed DEHP-induced enrichments in down-regulated gene transcripts coding for peroxisome proliferator-activated receptors and tumor necrosis factor signaling pathways, and in up-regulated gene transcripts coding for calcium binding and numerous myosin proteins. All these enriched pathways and networks have been described to be associated in some way with the reproductive system. This study identifies a large new array of genes dysregulated by DEHP that may play a role in the complex system controlling the development of the male reproductive system. PMID- 28085964 TI - Aminoalcohol-Induced Activation of Organophosphorus Hydrolase (OPH) towards Diisopropylfluorophosphate (DFP). AB - Aminoalcohols have been addressed as activating buffers for alkaline phosphatase. However, there is no record on the buffer activation regarding organophosphorus hydrolase (OPH). Here we reported the activating effects of aminoalcohols on OPH catalyzed hydrolysis of diisopropylfluorophosphate (DFP), an analog molecule of G type warfare agents. The kinetic parametors kcat, Vmax and kcat/Km in the OPH reaction were remarkably increased in the buffers (pH 8.0, 25 degrees C) containing aminoalcohols with C2 between nitrogen (N) and oxygen (O) in their structures, including triethanolamine (TEA), diethanolamine, monoethanolamine, 1 amino-2-propanol, 2-amino-2-methyl-1-propanol, and triisopropanolamine. In contrast, much lower or no rate-enhancing effects were observed in the adding of amines, alcohols, amine/alcohol mixtures, or 3-amino-1-propanol (C3 between N and O). The 300 mM TEA further increased DFP-degrading activities of OPH mutants F132Y and L140Y, the previously reported OPH mutants with desirable activities towards DFP. However, the treatment of ethylenediaminetetraacetate (EDTA) markedly abolished the TEA-induced activation of OPH. The product fluoride effectively inhibited OPH-catalyzed hydrolysis of DFP by a linear mixed inhibition (inhibition constant Ki ~ 3.21 mM), which was partially released by TEA adding at initial or later reaction stage. The obtained results indicate the activation of OPH by aminoalcohol buffers could be attributed to the reduction of fluoride inhibition, which would be beneficial to the hydrolase-based detoxification of organophosphofluoridate. PMID- 28085965 TI - Assessment of Corneal Sensation, Innervation and Retinal Nerve Fiber Layer in Patients Treated with Multiple Intravitreal Ranibizumab Injections. AB - PURPOSE: To evaluate the effects of repeated intravitreal ranibizumab injections on corneal sensitivity, corneal sub-basal nerve plexus (SBNP) and peripapillary retinal nerve fiber layer (RNFL) thickness in patients with neovascular age related macular degeneration (AMD). METHODS: Sixty-six eyes of 33 patients who had received unilateral repeated intravitreal ranibizumab injections (0.5 mg/0.05 ml) for the treatment of AMD and 25 eyes of 25 healthy subjects were included in the study. Central corneal sensation was measured using the contact Cochet-Bonnet esthesiometer. The laser scanning in vivo corneal confocal microscope was used to determine corneal SBNP parameters. The peripapillary RNFL thickness was assessed with spectral-domain optical coherence tomography. Data obtained from the ranibizumab-injected eyes were compared with those of the fellow non-treated eyes and the eyes of the healthy control subjects. RESULTS: The mean number of ranibizumab injections per eye was 8.9+/-5.0 (range 3-20). There were no statistically significant differences in the central corneal sensitivity threshold and corneal SBNP parameters between the ranibizumab-injected eyes and the fellow untreated eyes or between those with neovascular AMD and the healthy control group (P>0.05 for all). The average peripapillary RNFL thickness of the treated eyes did not differ significantly to the fellow eyes (P = 0.237), and the eyes of healthy control subjects (P = 0.918). There were no significant correlations between the number of ranibizumab injections and any of the study parameters. CONCLUSIONS: Multiple intravitreal injections of ranibizumab seem to have no harmful effects on corneal sensitivity, innervation and peripapillary RNFL thickness in patients with AMD. PMID- 28085966 TI - A Cross-Sectional Study of Colonization Rates with Methicillin-Resistant Staphylococcus aureus (MRSA) and Extended-Spectrum Beta-Lactamase (ESBL) and Carbapenemase-Producing Enterobacteriaceae in Four Swiss Refugee Centres. AB - BACKGROUND: The recent crisis of refugees seeking asylum in European countries challenges public health on many levels. Most refugees currently arrive from Syria, Afghanistan, or Eritrea. Data about multidrug resistant bacteria (MDR) prevalence are not present for these countries. However, when entering the European heath care systems, data about colonisation rates regarding highly resistant bacterial pathogens are important. METHODS: We performed a cross sectional screening in four Swiss refugee centres to determine the colonization rates for MRSA and ESBL- and carbapenemase-producing Enterobacteriaceae. We used pharyngeal, nasal, and inguinal swabs for MRSA and rectal swabs and urine for ESBL and carbapenemase screening using standard microbiological procedures. Whole genome sequencing (WGS) was used to determine the relatedness of MRSA isolates with high resolution due to a suspected outbreak. RESULTS: 41/261(15.7%) refugees were colonized with MRSA. No differences regarding the country of origin were observed. However, in a single centre significantly more were colonized, which was confirmed to be a recent local outbreak. 57/241 (23.7%) refugees were colonized with ESBL with significantly higher colonisation in persons originating from the Middle East (35.1%, p<0.001). No carbapenemase producers were detected. CONCLUSION: The colonisation rate of the refugees was about 10 times higher for MRSA and 2-5 times higher for ESBL compared to the Swiss population. Contact precaution is warranted for these persons if they enter medical care. In cases of infections, MRSA and ESBL-producing Enterobacteriaceae should be considered regarding antibiotic treatment choices. PMID- 28085967 TI - Levo-Tetrahydroberberrubine Produces Anxiolytic-Like Effects in Mice through the 5-HT1A Receptor. AB - Tetrahydroprotoberberines (THPBs) are isoquinoline alkaloids isolated from the Chinese herb Corydalis yanhusuo. In the present study, we performed competitive binding assays to examine the binding of l-THBr to neurotransmitter receptors known to be involved in sedation, hypnosis and anxiety. Our results show that l THBr does not interact with GABAergic receptors but has binding affinities for dopamine and serotonin receptors. In addition, cAMP and [35S]GTPgammaS assays were used to determine the agonist or antagonist properties of l-THBr at dopamine (D1, D2) or serotonin (5-HT) receptors. Our results show that l-THBr displays D1 and D2 antagonist and 5-HT1A agonist properties. Moreover, l-THBr-treated rodents exhibit anxiolytic-like effects in the light/dark box and elevated plus-maze tests, and the anxiolytic effect of l-THBr can be reduced by WAY-100635, a selective 5-HT1A receptor antagonist. Our results suggest that l-THBr may produce potent anxiolytic-like effects mainly through serotonin receptors. PMID- 28085968 TI - Mass Potentials Recorded at the Round Window Enable the Detection of Low Spontaneous Rate Fibers in Gerbil Auditory Nerve. AB - Auditory nerve fibers (ANFs) transmit acoustic information from the sensory hair cells to the cochlear nuclei. In experimental and clinical audiology, probing the whole ANF population remains a difficult task, as the ANFs differ greatly in their threshold and onset response to sound. Thus, low spontaneous rate (SR) fibers, which have rather higher thresholds, delay and larger jitter in their first spike latency are not detectable in the far-field compound action potential of the auditory nerve. Here, we developed a new protocol of acoustic stimulation together with electrophysiological signal processing to track the steady state activity of ANFs. Mass potentials at the round window were recorded in response to repetitive 300-ms bursts of 1/3 octave band noise centered on a frequency probe. Analysis was assessed during the last 200-ms of the response to capture the steady-state response of ANFs. To eliminate the microphonic component reflecting the sensory cells activity, repetitive pairs of sounds of opposite polarities were used. The spectral analysis was calculated on the average of two consecutive responses, and the neural gain was calculated by dividing point-by point the spectrum to sound over unstimulated condition. In response to low-sound level stimulation, neural gain predominated in the low-frequency cochlear regions, while a second component of responses centered on higher cochlear frequency regions appeared beyond 30 dB SPL. At 60 dB SPL, neural gain showed a bimodal shape, with a notch near 5.6 kHz. In addition to correlate with the functional mapping of ANFs along the tonotopic axis, the deletion of low-SR fibers leads to a reduction in the high-frequency response, where the low-SR fibers are preferentially located. Thus, mass potentials at the round window may provide a useful tool to probe the SR-based distribution of ANFs in humans and in other species in which direct single-unit recordings are difficult to achieve or not feasible. PMID- 28085969 TI - A Common Variant in SCN5A and the Risk of Ventricular Fibrillation Caused by First ST-Segment Elevation Myocardial Infarction. AB - BACKGROUND: Several common genetic variants have been associated with either ventricular fibrillation (VF) or sudden cardiac death (SCD). However, replication efforts have been limited. Therefore, we aimed to analyze whether such variants may contribute to VF caused by first ST-elevation myocardial infarction (STEMI). METHODS: We analyzed 27 single nucleotide polymorphisms (SNP) previously associated with SCD/VF in other cohorts, and examined whether these SNPs were associated with VF caused by first STEMI in the GEnetic causes of Ventricular Arrhythmias in patients with first ST-elevation Myocardial Infarction (GEVAMI) study on ethnical Danes. The GEVAMI study is a prospective case-control study involving 257 cases (STEMI with VF) and 537 controls (STEMI without VF). RESULTS: Of the 27 candidate SNPs, one SNP (rs11720524) located in intron 1 of SCN5A which was previously associated with SCD was significantly associated with VF caused by first STEMI. The major C-allele of rs11720524 was present in 64% of the cases and the C/C genotype was significantly associated with VF with an odds ratio (OR) of 1.87 (95% CI: 1.12-3.12; P = 0.017). After controlling for clinical differences between cases and controls such as age, sex, family history of sudden death, alcohol consumption, previous atrial fibrillation, statin use, angina, culprit artery, and thrombolysis in myocardial infarction (TIMI) flow, the C/C genotype of rs11720524 was still significantly associated with VF with an OR of 1.9 (95% CI: 1.05-3.43; P = 0.032). Marginal associations with VF were also found for rs9388451 in HEY2 gene. The CC genotype showed an insignificant risk for VF with OR = 1.50 (95% CI: 0.96-2.40; P = 0.070). CONCLUSION: One common intronic variant in SCN5A suggested an association with VF caused by first STEMI. Further studies into the functional abnormalities associated with the noncoding variant in SCN5A may lead to important insights into predisposition to VF during STEMI. PMID- 28085970 TI - Invited Commentary: On Knowledge Update in Planning Comprehensive Dental Treatment: A Personal Overview. AB - No abstract available. PMID- 28085971 TI - A Critical Review of Search Strategies Used in Recent Systematic Reviews Published in Selected Prosthodontic and Implant-Related Journals: Are Systematic Reviews Actually Systematic? AB - PURPOSE: The aim of this study was to outline how search strategies can be systematic, to examine how the searches in recent systematic reviews in prosthodontic and implant-related journals were structured, and to determine whether the search strategies used in those articles were systematic. MATERIALS AND METHODS: A total of 103 articles published as systematic reviews and indexed in Medline between January 2013 and May 2016 were identified from eight prosthodontic and implant journals and reviewed. The search strategies were considered systematic when they met the following criteria: (1) more than one electronic database was searched, (2) more than one searcher was clearly involved, (3) both text words and indexing terms were clearly included in the search strategy, (4) a hand search of selected journals or reference lists was undertaken, (5) gray research was specifically sought, and (6) the articles were published in English and at least one other language. The data were tallied and qualitatively assessed. RESULTS: The majority of articles reported on implants (54%), followed by tooth-supported fixed prosthodontics (13%). A total of 23 different electronic resources were consulted, including Medline (by 100% of articles), the Cochrane Library (52%), and Embase (37%). The majority consulted more than one electronic resource (71%), clearly included more than one searcher (73%), and employed a hand search of either selected journals or reference lists (86%). Less than half used both text words and indexing terms to identify articles (42%), while 15% actively sought gray research. Articles published in languages other than English were considered in 63 reviews, but only 14 had no language restrictions. Of the 103 articles, 5 completed search strategies that met all 6 criteria, and a further 12 met 5 criteria. Two articles did not fulfill any of the criteria. CONCLUSION: More than 95% of recent prosthodontic and implant review articles published in the selected journals failed to use search strategies that were systematic, and this undermines the conclusions. Many resources are available to help investigators design search strategies for systematic reviews that minimize the risk of omitting important data, including the simple criteria presented in this paper. PMID- 28085972 TI - Enamel Renal Syndrome: A Case History Report. AB - Enamel renal syndrome (ERS) is a rare, commonly misdiagnosed condition that results in amelogenesis imperfecta and nephrocalcinosis and can lead to renal impairment in adulthood. This case history report describes a multidisciplinary dental management approach in a young adult patient with ERS. PMID- 28085973 TI - The Fracture Resistance of Composite Core Materials Reinforced by Varying Fiber Orientations. AB - This study aimed to compare the fracture resistance of composite core materials reinforced with varying fiber orientations. Composite cores of endodontically treated roots were prepared by reinforcing with woven fiber discs, fiber strips, or fiber chips, and their fracture resistance was compared to those with no reinforcement using a universal test machine (Instron, Lloyd Instruments). Reinforcement with fiber chips showed the highest fracture resistance and 50% retrievability, while no reinforcement showed the lowest fracture resistance with 62.5% retrievability. It can be concluded that the use of fiber chips may be an effective and practical method for reinforcement of the core material. PMID- 28085974 TI - Intraoral Scanning Systems: Need for Maintenance. AB - PURPOSE: This study aimed to analyze a possible gain in accuracy in intraoral scanning systems by manufacturer calibration. MATERIALS AND METHODS: A master model was scanned tenfold with a Lava Chairside Oral Scanner (3m ESPE) and a CEREC Bluecam suspected to be decalibrated. Thereafter the scanners were calibrated and the model was scanned again. An iTero system served as comparison. All scans were compared to the master scan, and the mean deviation (entire arch, single tooth) was calculated. RESULTS: After calibration, there was a significant gain in accuracy for both systems. CONCLUSIONS: Intraoral digital scanners may be sensitive to hardware decalibration invisible to the user and therefore need maintenance. PMID- 28085975 TI - The Evaluation of Unscrewing Torque Values of Implant-Abutment Connections: An In Vitro Study. AB - PURPOSE: This study investigated the stability of titanium screws in implant abutment connections by measuring the force necessary to induce unscrewing. MATERIALS AND METHODS: A total of 60 implant-abutment couplings were assigned to two groups (n = 30 each). The sequence 10-20-32 Ncm was tested in Group 1; the sequence 10-20-32-32-32 Ncm was tested in Group 2. The force necessary to unscrew each abutment-implant sample was recorded and statistically analyzed. The significance level was set at P < .05. RESULTS: Significant differences were found between the two sequences. Group 2 required higher forces than Group 1 to unscrew. CONCLUSION: The stability of the implant-abutment joint may be improved by tightening with the sequence 10-20-32-32-32 Ncm. PMID- 28085976 TI - Clinical Fit of Partial Removable Dental Prostheses Based on Alginate or Polyvinyl Siloxane Impressions. AB - PURPOSE: The aim of this study was to analyze the clinical fit of metal-frame partial removable dental prostheses (PRDPs) based on custom trays used with alginate or polyvinyl siloxane impression material. MATERIALS AND METHODS: Fifth year students of the Nijmegen Dental School made 25 correct impressions for 23 PRDPs for 21 patients using alginate, and 31 correct impressions for 30 PRDPs for 28 patients using polyvinyl siloxane. Clinical fit of the framework as a whole and of each retainer separately were evaluated by calibrated supervisors during framework try-in before (first evaluation) and after (second evaluation) possible adjustments (score 0 = poor fit, up to score 3 = good fit). Framework fit and fit of the denture base were evaluated at delivery (third evaluation). Finally, postinsertion sessions were evaluated and total number of sessions needed, sore spots, adjustments to the denture base, and reported food-impaction were recorded. RESULTS: No significant differences in clinical fit (of the framework as a whole, for the retainers, or for the denture base) were found between the groups in the three evaluation sessions. Differences were not found for postinsertion sessions with one exception: in the alginate group, four subjects reported food impaction, versus none in the polyvinyl siloxane group. CONCLUSION: Clinical fit of metal-frame PRDPs based on impressions with custom trays combined with alginate or polyvinyl siloxane was similar. PMID- 28085977 TI - Effect of a Calcium Phosphate Desensitizer on Pre- and Postcementation Sensitivity of Teeth Prepared for Full-Coverage Restorations: A Randomized, Placebo-Controlled Clinical Study. AB - PURPOSE: The aim of this study was to investigate the effect of Teethmate Desensitizer (TD), an aqueous slurry of calcium phosphates, on the pre- and postcementation sensitivity of contralateral premolars prepared for full-coverage restorations. MATERIALS AND METHODS: In this clinical study, using a split-mouth design, 20 patients were allocated and two contralateral vital premolars per patient were randomly assigned to treatment with TD and placebo (PLA; distilled water). One day after preparation and temporization, sensitivity (PRE) upon air blast (AB) and probe scratch (PS) was determined using a 10-cm-long visual analog scale (VAS). The trial was double-blinded; neither the patient nor the investigator knew the treatment performed. Sensitivity was assessed immediately after treatment, before seating the final crowns after 1 week, and 1 month after cementation. Statistical data analysis was performed with one-way analysis of variance followed by Tukey post hoc test and two-sided paired t test. Statistical significance was determined at alpha < .05. RESULTS: VAS scores upon stimulation with AB and PS were significantly lower at POST and 1 week, and with AB after 1 month. TD-treated teeth showed significantly less sensitivity than PLA. At the postcementation recall, TD and PLA were not significantly different and the average pain scores were almost 0. CONCLUSION: Treatment of teeth prepared for full crown restorations with TD can significantly reduce pre- and postcementation sensitivity. PMID- 28085979 TI - Sociodemographic, Educational, Behavioral, and Psychologic Factors Underlying Orofacial Esthetics and Self-Reported Oral Health. AB - PURPOSE: The aim of the present study was to compare sociodemographic, behavioral, and educational characteristics, together with personality traits, on perceptions of individuals' own oral health and orofacial esthetics. MATERIALS AND METHODS: The participants had different educational backgrounds: dentistry students and students not following health care-related courses (university groups), and volunteers with no university studies (nonstudent group). The age range was 18 to 30 years. Sociodemographic and behavioral data and data on facial and dental attractiveness were gathered via personalized interviews. Personality traits were measured using the Big Five Inventory (BFI) (extroversion, agreeableness, conscientiousness, neuroticism, openness), and the Life Orientation Test was used to measure optimism and pessimism. RESULTS: No statistically significant differences were observed among the three educational groups regarding the mean scores on the five personality variables. The nonstudent group accorded significantly greater importance to tooth color, whereas the university groups considered tooth alignment more important (P = .016). The logistic regression model used to predict perceptions about orofacial health and esthetics revealed that underlying behavioral (pattern of visits to dentist and brushing habits), psychologic (pessimism and agreeableness), and educational (training in dentistry) factors affected the participants' perceptions of orofacial attractiveness, oral satisfaction, and self-rated oral health. CONCLUSIONS: The results of this study show that there are behavioral, psychologic, and educational factors that significantly modulate people's perceptions of orofacial esthetics, oral satisfaction, and self-rated oral health. PMID- 28085978 TI - Single Mandibular Implant Study: Recruitment Considerations. AB - PURPOSE: The aim of this multicenter single mandibular implant study was to compare the clinical outcome of an immediately loaded implant placed in the midline of an edentulous mandible with the clinical outcome when closed healing and delayed loading is chosen. Here, the patient recruitment period and the main reasons for exclusion were analyzed. MATERIALS AND METHODS: Patient recruitment was performed at nine German universities. Rather conservative inclusion and exclusion criteria, including denture satisfaction, denture status, a psychologic symptom checklist, and a defined bone height in the posterior mandible, had to be fulfilled. It was initially calculated that 230 persons would have to be screened within 13 months to include 180 persons in the trial. RESULTS: Within 13 months (December 2012 to December 2013), 201 patients were screened for possible inclusion in the trial and 148 met the inclusion criteria. Finally, after the recruitment period was extended by 2.5 months, 224 patients were screened and 169 were included. Of those screened, 55 (24.6%) did not meet the inclusion criteria and were excluded. Another 4 patients (1.8%) were excluded based on their psychologic symptom checklist score, while 5 others (2.8%) showed signs of noncompliance. A further 8 patients (4.4%) decided not to participate and withdrew their informed consent, and another 3 (1.3%) were no longer available after screening. Another 2 patients were excluded due to medical contraindications and 1 due to an insufficient mandibular denture. In 34 cases (15.2%), the residual bone height did not comply with McGarry type II or III. CONCLUSION: Within the limitations of this patient recruitment period, it can be concluded that residual bone height is the most important factor when considering elderly edentulous patients for implant therapy. The psychologic symptom checklist score was less important. PMID- 28085980 TI - Influence of Abutment Angle on Implant Strain When Supporting a Distal Extension Removable Partial Dental Prosthesis: An In Vitro Study. AB - PURPOSE: This study evaluated the impact of angled abutments on strain in implants supporting a distal extension removable partial denture. MATERIALS AND METHODS: An in vitro model of an implant supporting a distal extension removable partial denture was developed. The implant was positioned with a 17- or 30-degree mesial inclination, with either a healing abutment or a corrective multiunit abutment. Levels of strain under load were compared, and the results were compared using t test (P = .05). RESULTS: Correcting angulation with a multiunit angled abutment significantly decreased strain (P < .05) when compared with a healing abutment. CONCLUSION: An angled abutment decreased the strain on an inclined implant significantly more than a healing abutment when loaded under a distal extension removable partial denture. PMID- 28085981 TI - Implant-Retained Prosthetic Auricular Reconstruction in a Hemifacial Microsomia Individual: A Clinical Report. AB - Hemifacial microsomia is the second most frequently encountered congenital facial anomaly after cleft lip and palate. This case history report describes a two implant-supported auricular prosthetic reconstruction in a young patient with an absent auricle and malpositioned lobule. The selected treatment protocol was chosen because of its superior retention when compared with alternative retention systems. Moreover, a clip-bar attachment system is more reliable and easier to use when availability of anatomical landmarks is limited, and especially in active adolescents. PMID- 28085982 TI - Determining Favorable Maxillary Implant Locations Using Three-Dimensional Simulation Software and Computed Tomography Data. AB - PURPOSE: Success rates for maxillary implant treatment are lower than for mandibular treatment because of the presence of poorer bone quality or quantity in the maxilla. The purpose of this study was to determine favorable implant positions in the maxilla using implant simulation software and clinical anatomical morphology together with bone quality data obtained by computed tomography (CT). MATERIALS AND METHODS: A convenience research sample of 10 edentulous subjects was recruited, and research information from right and left edentulous sites was obtained from each subject. The height, width, angulation, and Hounsfield unit value of the maxillary alveolar bone were measured using CT data obtained from the subjects. RESULTS: Bone height in the incisor area was significantly greater than in the molar area, and bone width in the incisor area was significantly narrower than in the molar area. The average bone quality in the maxillary molar area was significantly higher when compared with the premolar and incisor areas. The angle between the occlusal plane and the bisector of the alveolar bone in the incisor area was reduced when compared with the molar area. CONCLUSION: The premolar region appears to be the most favorable area in the maxillary arch for implant placement with regard to bone height, width, angulation, and quality. PMID- 28085983 TI - The Clinical Performance of Monolithic Lithium Disilicate Posterior Restorations After 5, 10, and 15 Years: A Retrospective Case Series. AB - PURPOSE: Lithium disilicate (LDS) glass-ceramic restorations are routinely used, but results over a period longer than 10 years are rare. The objective of this study was to obtain long-term clinical data on monolithic LDS posterior crowns provided by a single restorative dentist. MATERIALS AND METHODS: Eligible patients who received a circumferential LDS crown in the posterior region between 1997 and 2010 were invited to participate in a clinical examination in 2015. This consisted of intraoral inspection and radiographs, performed by one observer and according to standardized criteria. Probability of survival was estimated using Kaplan-Meier survival analysis. RESULTS: A total of 13 patients (n = 87 restorations) fulfilled the inclusion criteria. Of these, 12 patients were available for clinical evaluation (n = 74 restorations). After 5, 10, and 15 years, the cumulative chance of survival of the restoration was 92%, 85.5%, and 81.9%, respectively, with a median observation period of 12.8 years. Of the 74 restorations, 13 failed: 4 because of secondary caries, 2 because of debonding, and 7 because of fracture of the restoration. CONCLUSION: Lithium disilicate can be regarded as a strong and fracture-load-resistant restorative material providing reliable long-term clinical performance. PMID- 28085984 TI - Using Bar and Ball Attachments in Maxillary and Mandibular Implant-Supported Overdentures in a Patient with Adenoid Cystic Carcinoma Associated with Microstomia: A Clinical Report. AB - Many clinical studies and literature reviews have suggested that bar and ball attachments in maxillary and mandibular implant-supported overdentures (ISOs) should be indicated only when there is sufficient interocclusal space (IOS; minimum = 30 mm). The aim of this clinical report was to present the prosthetic rehabilitation of a patient with adenoid cystic carcinoma associated with microstomia due to radiotherapy (IOS = 23 mm). ISOs offer superior retention and greater stability than conventional obturators, so that base extensions were kept to the minimum. Placing the balls parallel to the prosthesis path of insertion is much easier with this treatment modality. PMID- 28085985 TI - Effect of Configurations of Implants Supporting a Four-Unit Fixed Partial Denture on Loading Distribution. AB - This study aimed to evaluate the effect of the configuration of implants supporting a four-unit fixed partial denture on load distribution. An epoxy resin model missing teeth from the first premolar to the second molar was used. Three dimensional piezoelectric force transducers were set on implants placed in the missing teeth area with a four-unit experimental superstructure. Three dimensional loads on the implants were measured with four different implant configurations when a static load of 100 N was applied. The loads on the implants changed significantly depending on the implant number and position and the applied loading points. PMID- 28085986 TI - Controlled Clinical Trial on the Outcome of Glass Fiber Composite Cores Versus Wrought Posts and Cast Cores for the Restoration of Endodontically Treated Teeth: A 5-Year Follow-up Study. AB - PURPOSE: The aim of this study was to compare the 5-year outcomes of glass fiber composite with cast posts and cores for the restoration of endodontically treated teeth. MATERIALS AND METHODS: A total of 143 patients in need of 203 full ceramic restorations on endodontically treated teeth were included. After primary stratification based on the need for post or no post, teeth were randomly allotted to test group 1 (prefabricated glass fiber posts), 2 (custom-made glass fiber posts), or 3 (composite cores without posts). The control group was treated with gold alloy-based wrought posts and cast cores. Success (original present) and survival (present after intervention) probability lifetime curves, corrected for clustering, were drawn over the entire data set. RESULTS: The mean follow-up time was 5.8 years (range: 0.5 to 7.2 years). At 5 years, the success and survival probabilities were 85.2% and 91.5%, respectively. Lifetime curves did not show any significant differences between the test and control groups for success (P = .85) or survival (P = .57). Moreover, no significant differences for success or survival could be found among the four groups (the three test groups and the control group). CONCLUSION: After 5 years of follow-up, cast gold and composite post-and-core systems on teeth with ceramic full restorations provided with a ferrule performed equally well. PMID- 28085987 TI - Inflammatory Papillary Hyperplasia in a Non-Denture-Wearing Patient: A Case History Report. AB - Inflammatory papillary hyperplasia (IPH) is a benign lesion of the palatal mucosa. It is usually found in denture wearers but has also been reported in dentate patients with no history of wearing maxillary prostheses. This case history report describes an example of the latter and highlights the importance of professional awareness to diagnose IPH among non-denture-wearing patients. PMID- 28085988 TI - Survey of Dental Materials Used by Dentists for Indirect Restorations in Saudi Arabia. AB - The purpose of this study was to investigate the use and selection of materials for indirect restorations by dentists in Saudi Arabia. A structured 18-item questionnaire was designed and sent via email to all dentists with active memberships in the Saudi Dental Society. A total of 373 dentists (20.2%) out of the 1,846 contacted answered the questionnaire. The majority of the responding dentists (81.5%) prefer to use porcelain-fused-to-metal crowns for posterior teeth, while 77.5% use all-ceramic crowns for anterior teeth. Only 29.8% reported using computer-aided design/computer-assisted manufacture in their practice. There was inconsistency among dentists in material selection, and this was affected by the dentist's gender, years of experience, specialty, and service sector. PMID- 28085989 TI - Real-World Clinical Quality Improvement for Complex Abdominal Wall Reconstruction. AB - INTRODUCTION: Traditional methods of clinical research may not be adequate to improve the value of care for patients undergoing abdominal wall reconstruction (AWR). These patients are prone to high complication rates and high costs. Here, we describe a clinical quality improvement (CQI) effort to enhance outcomes for patients undergoing AWR. MATERIALS AND METHODS: CQI was applied for the entire care cycle for consecutive patients who underwent AWR from August 2011-September 2015. Initiatives for improving value during this period included use of long term resorbable synthetic mesh as well as administration of preoperative bilateral transversus abdominus plane (TAP), and intraoperative abdominal wall blocks using long-acting bupivacaine as a part of a multimodal regimen. Outcomes data that measure value in the context of AWR were collected to compare outcomes for the patients who received TAP blocks only, TAP and intraoperative blocks, and those who received no block. RESULTS: One hundred and two patients who had AWR for abdominal wall pathology were included. Outcomes including total opioid use, duration of stay and opioid use in the postanesthesia care unit (PACU), length of hospital stay (LOS), major wound complications, and costs, all improved over time. Specifically, PACU opioid use, total opioid use, and LOS were decreased in the two groups that received blocks versus a group that did not have any type of block. CONCLUSIONS: CQI program implementation in patients undergoing AWR resulted in measurable improvement of value-based outcomes over time. A CQI effort applied to the entire patient cycle of care should be routinely utilized. PMID- 28085990 TI - Clinical Profiles of Young Adults With Juvenile-Onset Fibromyalgia With and Without a History of Trauma. AB - OBJECTIVE: To examine the differential presentation(s) of psychological and health-related outcomes in young adults with juvenile-onset fibromyalgia (FM) with and without a history of trauma, compared to healthy controls. METHODS: In total, 110 participants (86 with juvenile-onset FM and 24 healthy controls, with a mean age of 23.4 years) completed a structured clinical interview to assess for trauma and psychological comorbidities, as well as self-report questionnaires on pain, physical functioning, and health care utilization. RESULTS: Of the juvenile onset FM participants, 37% (n = 32) reported a history of trauma. Three group comparisons (i.e., juvenile-onset FM with trauma versus juvenile-onset FM with no trauma versus healthy controls) revealed that juvenile-onset FM participants significantly differed from healthy controls on all psychological and health related outcomes. Further, although juvenile-onset FM participants with and without a history of trauma did not significantly differ on pain and physical functioning, juvenile-onset FM participants with a history of trauma were significantly more likely to have psychological comorbidities. CONCLUSION: This is the first controlled study to examine the differential outcomes between juvenile-onset FM participants with and without a history of trauma. Group comparisons between juvenile-onset FM participants and healthy controls were consistent with previous research. Further, our findings indicate that juvenile onset FM participants with a history of trauma experience greater psychological, but not physical, impairment than juvenile-onset FM participants without a history of trauma. PMID- 28085992 TI - Bariatric surgery and diabetic retinopathy: a systematic review and meta-analysis of controlled clinical studies. AB - BACKGROUND: Uncontrolled studies have indicated appearance or progression of diabetic retinopathy in obese diabetic patients after bariatric surgery. The aim of this systematic review and meta-analysis was to compare the rate of appearance, as well as progression or regression of diabetic retinopathy in studies comparing medical and surgical treatment of obese type 2 diabetes. METHODS AND FINDINGS: Intervention effect (new cases of retinopathy, and cases with any change of diabetic retinopathy score) was expressed as odds ratio (OR), with 95% confidence intervals (CIs); change of diabetic retinopathy score was expressed as standardized mean difference (SMD), with 95% CIs. Meta-analyses were performed by a random-effects model according to DerSimonian and Laird. Heterogeneity was assessed through Q and I2 statistics for each comparison, and potential sources of heterogeneity were discussed where appropriate. Appropriate methodology [preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement] was used. Seven studies were analyzed, and incident cases of retinopathy were fewer with bariatric surgery than with medical treatment; change of retinopathy score (three studies) was not different, while only two studies were available on numbers of patients showing progression or regression of retinopathy. Heterogeneity was not significant, and publication bias was not present. CONCLUSIONS: Bariatric surgery seems to prevent new cases of diabetic retinopathy, but available studies are not sufficient to support progression or regression of retinopathy. Further studies are needed to draw firm conclusions on the effect of bariatric surgery on diabetic retinopathy. PMID- 28085991 TI - Maternal body mass index and post-term birth: a systematic review and meta analysis. AB - Post-term birth is a preventable cause of perinatal mortality and severe morbidity. This review examined the association between maternal body mass index (BMI) and post-term birth at >=42 and >=41 weeks' gestation. Five databases, reference lists and citations were searched from May to November 2015. Observational studies published in English since 1990 were included. Linear and nonlinear dose-response meta-analyses were conducted by using random effects models. Sensitivity analyses assessed robustness of the results. Meta-regression and sub-group meta-analyses explored heterogeneity. Obesity classes were defined as I (30.0-34.9 kg m-2 ), II (35.0-39.9 kg m-2 ) and III (>=40 kg m-2 ; IIIa 40.0 44.9 kg m-2 , IIIb >= 45.0 kg m-2 ). Searches identified 16,375 results, and 39 studies met the inclusion criteria (n = 4,143,700 births). A nonlinear association between maternal BMI and births >=42 weeks was identified; odds ratios and 95% confidence intervals for obesity classes I-IIIb were 1.42 (1.27 1.58), 1.55 (1.37-1.75), 1.65 (1.44-1.87) and 1.75 (1.50-2.04) respectively. BMI was linearly associated with births >=41 weeks: odds ratio is 1.13 (95% confidence interval 1.05-1.21) for each 5-unit increase in BMI. The strength of the association between BMI and post-term birth increases with increasing BMI. Odds are greatest for births >=42 weeks among class III obesity. Targeted interventions to prevent the adverse outcomes associated with post-term birth should consider the difference in risk between obesity classes. PMID- 28085993 TI - N-Acetylgalactosamine-Targeted Delivery of Dendrimer-Doxorubicin Conjugates Influences Doxorubicin Cytotoxicity and Metabolic Profile in Hepatic Cancer Cells. AB - This study describes the development of targeted, doxorubicin (DOX)-loaded generation 5 (G5) polyamidoamine dendrimers able to achieve cell-specific DOX delivery and release into the cytoplasm of hepatic cancer cells. G5 is functionalized with poly(ethylene glycol) (PEG) brushes displaying N acetylgalactosamine (NAcGal) ligands to target hepatic cancer cells. DOX is attached to G5 through one of two aromatic azo-linkages, L3 or L4, achieving either P1 ((NAcGalbeta -PEGc)16.6 -G5-(L3-DOX)11.6 ) or P2 ((NAcGalbeta PEGc)16.6 -G5-(L4-DOX)13.4 ) conjugates. After confirming the conjugates' biocompatibility, flow cytometry studies show P1/P2 achieve 100% uptake into hepatic cancer cells at 30-60 * 10-9 m particle concentration. This internalization correlates with cytotoxicity against HepG2 cells with 50% inhibitory concentration (IC50 ) values of 24.8, 1414.0, and 237.8 * 10-9 m for free DOX, P1, and P2, respectively. Differences in cytotoxicity prompted metabolomics analysis to identify the intracellular release behavior of DOX. Results show that P1/P2 release alternative DOX metabolites than free DOX. Stable isotope tracer studies show that the different metabolites induce different effects on metabolic cycles. Namely, free DOX reduces glycolysis and increases fatty acid oxidation, while P1/P2 increase glycolysis, likely as a response to high oxidative stress. Overall, P1/P2 conjugates offer a platform drug delivery technology for improving hepatic cancer therapy. PMID- 28085994 TI - Tough, Semisynthetic Hydrogels for Adipose Derived Stem Cell Delivery for Chondral Defect Repair. AB - Cell-based therapies have great potential to regenerate and repair injured articular cartilage, and a range of synthetic and natural polymer-based hydrogels have been used in combination with stem cells and growth factors for this purpose. Although the hydrogel scaffolds developed to date possess many favorable characteristics, achieving the required mechanical properties has remained a challenge. A hydrogel system with tunable mechanical properties, composed of a mixture of natural and synthetic polymers, and its use for the encapsulation of adipose derived stem/stromal cells (ASCs) is described. Solutions of methacrylated chondroitin sulfate (MCS) are mixed with solutions of acrylate poly(trimethylene carbonate)-b-poly(ethylene glycol)-b-poly(trimethylene carbonate)-acrylate (PEG-(PTMC-A)2 ) in phosphate buffered saline and crosslinked via thermally initiated free radical polymerization. The hydrogel compressive equilibrium moduli and toughness are readily tailored by varying the concentration of the pre-polymers, as well as the molecular weight of the PEG used to prepare the PEG-(PTMC-A)2 . Two peptide sequences, GVOGEA and GGGGRGDS, are individually conjugated to the MCS to facilitate cell binding. The presence of the peptide ligands yields high ASC viability and long term metabolic activity following encapsulation in hydrogels prepared using the thermal initiator system. Overall, these hydrogels show promise as a minimally invasive ASC delivery strategy for chondral defect repair. PMID- 28085995 TI - Fibrin glue for pilonidal sinus disease. AB - BACKGROUND: Pilonidal sinus disease is a common condition that mainly affects young adults. This condition can cause significant pain and impairment of normal activities. No consensus currently exists on the optimum treatment for pilonidal sinus and current therapies have various advantages and disadvantages. Fibrin glue has emerged as a potential treatment as both monotherapy and an adjunct to surgery. OBJECTIVES: To assess the effects of fibrin glue alone or in combination with surgery compared with surgery alone in the treatment of pilonidal sinus disease. SEARCH METHODS: In December 2016 we searched: the Cochrane Wounds Specialised Register; CENTRAL; MEDLINE; Embase and CINAHL Plus. We also searched clinical trials registries and conference proceedings for ongoing and unpublished studies and scanned reference lists to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: We included randomised controlled trials (RCTs) only. We included studies involving participants of all ages and studies conducted in any setting. We considered studies involving people with both new and recurrent pilonidal sinus. We included studies which evaluated fibrin glue monotherapy or as an adjunct to surgery. DATA COLLECTION AND ANALYSIS: Two study authors independently extracted data and assessed risk of bias. We used standard methods expected by Cochrane. MAIN RESULTS: We included four RCTs with 253 participants, all were at risk of bias. One unpublished study evaluated fibrin glue monotherapy compared with Bascom's procedure, two studies evaluated fibrin glue as an adjunct to Limberg flap and one study evaluated fibrin glue as an adjunct to Karydakis flap.For fibrin glue monotherapy compared with Bascom's procedure, there were no data available for the primary outcomes of time to healing and adverse events. There was low-quality evidence of less pain on day one after the procedure with fibrin glue monotherapy compared with Bascom's procedure (mean difference (MD) 2.50, 95% confidence interval (CI) -4.03 to -0.97) (evidence downgraded twice for risk of performance and detection bias). Fibrin glue may reduce the time taken to return to normal activities compared with Bascom's procedure (mean time 42 days with surgery and 7 days with glue, MD -34.80 days, 95% CI -66.82 days to -2.78 days) (very low-quality evidence, downgraded as above and for imprecision).Fibrin glue as an adjunct to the Limberg flap may reduce the healing time from 22 to 8 days compared with the Limberg flap alone (MD -13.95 days, 95% CI -16.76 days to 11.14 days) (very low-quality evidence, downgraded twice for risk of selection, performance and detection bias and imprecision). It is uncertain whether use of fibrin glue affects the incidence of postoperative seroma (an adverse event) (risk ratio (RR) 0.27, 95% CI 0.05 to 1.61; very low-quality evidence, downgraded twice for risk of selection, performance and detection bias and imprecision). There was low-quality evidence that fibrin glue, as an adjunct to Limberg flap, may reduce postoperative pain (median 2 versus 4; P < 0.001) and time to return to normal activities (median 8 days versus 17 days; P < 0.001). The addition of fibrin glue to the Limberg flap may reduce the length of hospital stay (MD -1.69 days, 95% CI -2.08 days to -1.29 days) (very low-quality evidence, downgraded twice for risk of selection, performance and detection bias and for unexplained heterogeneity).A single RCT evaluating fibrin glue as an adjunct to the Karydakis flap did not report data for the primary outcome of time to healing. It is uncertain whether fibrin glue with the Karydakis flap affects the incidence of postoperative seroma (adverse event) (RR 3.00, 95% CI 0.67 to 13.46) (very low quality evidence, downgraded twice for risk of selection, performance and detection bias and for imprecision). Fibrin glue as an adjunct to Karydakis flap may reduce length of stay but this is highly uncertain (mean 2 days versus 3.7 days; P < 0.001, low-quality evidence downgraded twice for risk of selection, performance and detection bias). AUTHORS' CONCLUSIONS: Current evidence is uncertain regarding any benefits associated with fibrin glue either as monotherapy or as an adjunct to surgery for people with pilonidal sinus disease. We identified only four RCTs and each was small and at risk of bias resulting in very low-quality evidence for the primary outcomes of time to healing and adverse events. Future studies should enrol many more participants, ensure adequate randomisation and blinding, whilst measuring clinically relevant outcomes. PMID- 28085996 TI - Biocatalysis with Unnatural Amino Acids: Enzymology Meets Xenobiology. AB - The goal of xenobiology is to design biological systems endowed with unusual biochemical functions, whereas enzymology concerns the study of enzymes, the workhorses of biocatalysis. Biocatalysis employs enzymes and organisms to perform useful biotransformations in synthetic chemistry and biotechnology. During the past few years, the effects of incorporating noncanonical amino acids (ncAAs) into enzymes with potential applications in biocatalysis have been increasingly investigated. In this Review, we provide an overview of the effects of new chemical functionalities that have been introduced into proteins to improve various facets of enzymatic catalysis. We also discuss future research avenues that will complement unnatural mutagenesis with standard protein engineering to produce novel and versatile biocatalysts with applications in synthetic organic chemistry and biotechnology. PMID- 28085999 TI - Review: Immune-Related Adverse Events With Use of Checkpoint Inhibitors for Immunotherapy of Cancer. PMID- 28085997 TI - Association Between Menopausal Factors and the Risk of Seronegative and Seropositive Rheumatoid Arthritis: Results From the Nurses' Health Studies. AB - OBJECTIVE: To investigate whether menopausal factors are associated with the development of serologic rheumatoid arthritis (RA) phenotypes. METHODS: Data were analyzed from the Nurses' Health Studies (NHS; 1976-2010 and NHSII 1989-2011). A total of 120,700 female nurses ages 30-55 years in the NHS, and a total of 116,430 female nurses ages 25-42 years in the NHSII, were followed via biennial questionnaires on lifestyle and disease outcomes. In total, 1,096 incident RA cases were confirmed by questionnaire and chart review. Seropositive RA was defined as rheumatoid factor positive (RF) or antibodies to citrullinated protein antigen (ACPA) positive, and seronegative RA was defined as RF negative and ACPA negative. We used Cox proportional hazards models to obtain multivariable adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) of seropositive/seronegative RA associated with menopausal status, age at menopause, type of menopause, ovulatory years, and postmenopausal hormone therapy (PMH) use. RESULTS: Postmenopausal women had a 2-fold increased risk of seronegative RA, compared with premenopausal women (NHS: HR 1.8 [95% CI 1.1-3.0], NHSII: HR 2.4 [95% CI 1.4-3.9], and pooled HR 2.1 [95% CI 1.4-3.0]). Natural menopause at early age (<=44 years) was associated with an increased risk of seronegative RA (pooled HR 2.4 [95% CI 1.5-4.0]). None of the menopausal factors was significantly associated with seropositive RA. We observed no association between PMH use and the risk of seronegative or seropositive RA, except that PMH use of >=8 years was associated with increased risk of seropositive RA (pooled HR 1.4 [95% CI 1.1 1.9]). CONCLUSION: Postmenopause and natural menopause at an early age were strongly associated with seronegative RA, but only marginally with seropositive RA, suggesting potential differences in the etiology of RA subtypes. PMID- 28085998 TI - Validity and Responsiveness of the Knee Injury and Osteoarthritis Outcome Score: A Comparative Study Among Total Knee Replacement Patients. AB - OBJECTIVE: To evaluate validity and responsiveness of the Knee Injury and Osteoarthritis Outcome Score (KOOS) in relation to other patient-reported outcome measures before and after total knee replacement (TKR). METHODS: Pre-TKR and 6 month post-TKR data from 1,143 patients in a US joint replacement cohort were used to compare the KOOS, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the SF-36 Health Survey (SF-36). Validity was evaluated with multiple methods, including correlations of pre-TKR scale scores and analysis of variance models that used pre-TKR data to compare the relative validity of scales in discriminating between groups differing in assistive walking device use and number of comorbid conditions. Validity was also evaluated by using post-TKR minus pre-TKR change scores to assess relative validity of scales in discriminating between groups rating themselves as better, same, or worse (BSW) in their capability to do activities at 6 months. Responsiveness also was described using effect sizes and standardized response means. RESULTS: In support of convergent and discriminant validity, KOOS scale scores were worse for patients using an assistive device but only declined weakly with increasing comorbid conditions. While all knee-specific scales discriminated between BSW groups, the KOOS quality of life (QOL) scale was significantly better (P < 0.05) than all measures except the SF-36 physical component summary. KOOS QOL also had the highest effect size, while SF-36 measures had lower effect sizes and standardized response means. KOOS pain and symptoms scales discriminated better than WOMAC pain and stiffness scales among BSW groups. CONCLUSION: KOOS scales were valid and responsive in this cohort of US TKR patients. KOOS QOL performed particularly well in capturing aggregate knee-specific outcomes. PMID- 28086001 TI - Clinical Images: Hematoidin in Synovial Fluid. PMID- 28086000 TI - A Dual Role of Upper Zone of Growth Plate and Cartilage Matrix-Associated Protein in Human and Mouse Osteoarthritic Cartilage: Inhibition of Aggrecanases and Promotion of Bone Turnover. AB - OBJECTIVE: Cartilage damage and subchondral bone changes are closely connected in osteoarthritis. Nevertheless, how these processes are interlinked is, to date, incompletely understood. This study was undertaken to investigate the mechanistic role of a cartilage-derived protein, upper zone of growth plate and cartilage matrix-associated protein (UCMA), in osteoarthritis-related cartilage and bone changes. METHODS: UCMA expression was assessed in healthy and osteoarthritic human and mouse cartilage. For analysis of cartilage and bone changes, osteoarthritis was induced by destabilization of the medial meniscus (DMM) in wild-type (WT) and Ucma-deficient mice. UCMA-collagen interactions, the effect of UCMA on aggrecanase activity, and the impact of recombinant UCMA on osteoclast differentiation were studied in vitro. RESULTS: UCMA was found to be overexpressed in human and mouse osteoarthritic cartilage. DMM-triggered cartilage changes, including increased structural damage, proteoglycan loss, and chondrocyte cell death, were aggravated in Ucma-deficient mice compared to WT littermates, thereby demonstrating the potential chondroprotective effects of UCMA. Moreover, UCMA inhibited ADAMTS-dependent aggrecanase activity and directly interacted with cartilage-specific collagen types. In contrast, osteoarthritis related bone changes were significantly reduced in Ucma-deficient mice, showing less pronounced osteophyte formation and subchondral bone sclerosis. Mechanistically, UCMA directly promoted osteoclast differentiation in vitro. CONCLUSION: UCMA appears to link cartilage with bone changes in osteoarthritis by supporting cartilage integrity as an endogenous inhibitor of aggrecanases while also promoting osteoclastogenesis and subchondral bone turnover. Thus, UCMA represents an important link between cartilage and bone in osteoarthritis. PMID- 28086004 TI - Evidence to Support Montgomery-Asberg Depression Rating Scale Administration Every 24 Hours to Assess Rapid Onset of Treatment Response. AB - OBJECTIVE: This study investigated the suitability of the Montgomery-Asberg Depression Rating Scale (MADRS), with a 24-hour recall period (MADRS-24hr), to assess the rapid onset of the antidepressant effect of a treatment in patients with treatment-resistant depression (TRD). Psychometric properties of the MADRS 24hr were assessed together with qualitative assessment of content validity. METHODS: Content validity was assessed using semistructured interviews conducted from November 2013 to December 2013 in patients (18-64 years old) with TRD who met DSM-IV diagnostic criteria and health care professionals (HCPs) experienced in treating major depressive disorder and familiar with using the MADRS. The psychometric properties of MADRS-24hr were evaluated using data from 2 randomized clinical studies involving patients with TRD. RESULTS: A total of 23 patients (15 [65%] women) with TRD (mean age = 45 years) and 11 HCPs were interviewed. With the exception of reduced sleep, the majority of patients and HCPs reported that the items captured in the MADRS can fluctuate in a 24-hour period. The majority of participants also reported that a meaningful change in depression symptoms could be assessed in a 24-hour recall period, except for reduced sleep and appetite. Assessment of the psychometric properties of the MADRS-24hr showed that this instrument had high internal consistency reliability (Cronbach alpha of 0.84 and 0.91) and test-retest reliability (intraclass correlation coefficients of 0.96 and 0.91), had construct validity, and was responsive to change following an intervention. CONCLUSIONS: Overall, results suggest that MADRS-24hr can be used to assess the rapid onset of antidepressant efficacy of a treatment in patients with TRD. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01627782 and NCT01640080. PMID- 28086003 TI - Medication Nonadherence in Systemic Lupus Erythematosus: A Systematic Review. AB - OBJECTIVE: Medication nonadherence has not been well characterized in systemic lupus erythematosus (SLE). Our objective was to a conduct a systematic review of the literature, examining the burden and determinants of medication nonadherence in SLE. METHODS: We conducted a systematic search of Medline (1946-2015), Embase (1974-2015), and Web of Science (1900-2015) databases and selected original studies of SLE patients that evaluated nonadherence to SLE therapies as the primary study outcome. We extracted information on study design, sample size, length of followup, data sources, type of nonadherence problem examined, adherence measures and reported estimates, and determinants of adherence reported in multivariable analyses. RESULTS: After screening 4,111 titles, 11 studies met the inclusion criteria. Study sample sizes ranged from 32 to 246 patients, and studies were categorized according to data source: self-report (5), electronic monitoring devices (1), clinical records from rheumatology clinics (3), and refill information from pharmacy records (2). Overall, the percentage of nonadherent patients ranged from 43% to 75%, with studies consistently reporting that over half of patients are nonadherent. Studies also showed that up to 33% of patients discontinue therapy after 5 years. Determinants of nonadherence included having depression, rural residence, lower education level, and polypharmacy. CONCLUSION: Overall, synthesis of current evidence suggests that the burden of medication nonadherence is substantial in SLE. Findings highlight the importance of developing interventions to support adherence and improve outcomes among patients. PMID- 28086002 TI - Immune-Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA-DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum. AB - OBJECTIVE: Inclusion body myositis (IBM) is characterized by a combination of inflammatory and degenerative changes affecting muscle. While the primary cause of IBM is unknown, genetic factors may influence disease susceptibility. To determine genetic factors contributing to the etiology of IBM, we conducted the largest genetic association study of the disease to date, investigating immune related genes using the Immunochip. METHODS: A total of 252 Caucasian patients with IBM were recruited from 11 countries through the Myositis Genetics Consortium and compared with 1,008 ethnically matched controls. Classic HLA alleles and amino acids were imputed using SNP2HLA. RESULTS: The HLA region was confirmed as the most strongly associated region in IBM (P = 3.58 * 10-33 ). HLA imputation identified 3 independent associations (with HLA-DRB1*03:01, DRB1*01:01, and DRB1*13:01), although the strongest association was with amino acid positions 26 and 11 of the HLA-DRB1 molecule. No association with anti cytosolic 5'-nucleotidase 1A-positive status was found independent of HLA DRB1*03:01. There was no association of HLA genotypes with age at onset of IBM. Three non-HLA regions reached suggestive significance, including the chromosome 3 p21.31 region, an established risk locus for autoimmune disease, where a frameshift mutation in CCR5 is thought to be the causal variant. CONCLUSION: This is the largest, most comprehensive genetic association study to date in IBM. The data confirm that HLA is the most strongly associated region and identifies novel amino acid associations that may explain the risk in this locus. These amino acid associations differentiate IBM from polymyositis and dermatomyositis and may determine properties of the peptide-binding groove, allowing it to preferentially bind autoantigenic peptides. A novel suggestive association within the chromosome 3 p21.31 region suggests a role for CCR5. PMID- 28086005 TI - Reducing Dropout in Treatment for Depression: Translating Dropout Predictors Into Individualized Treatment Recommendations. AB - OBJECTIVE: Premature discontinuation of therapy is a widespread problem that hampers the delivery of mental health treatment. A high degree of variability has been found among rates of premature treatment discontinuation, suggesting that rates may differ depending on potential moderators. In the current study, our aim was to identify demographic and interpersonal variables that moderate the association between treatment assignment and dropout. METHODS: Data from a randomized controlled trial conducted from November 2001 through June 2007 (N = 156) comparing supportive-expressive therapy, antidepressant medication, and placebo for the treatment of depression (based on DSM-IV criteria) were used. Twenty prerandomization variables were chosen based on previous literature. These variables were subjected to exploratory bootstrapped variable selection and included in the logistic regression models if they passed variable selection. RESULTS: Three variables were found to moderate the association between treatment assignment and dropout: age, pretreatment therapeutic alliance expectations, and the presence of vindictive tendencies in interpersonal relationships. When patients were divided into those randomly assigned to their optimal treatment and those assigned to their least optimal treatment, dropout rates in the optimal treatment group (24.4%) were significantly lower than those in the least optimal treatment group (47.4%; P = .03). CONCLUSIONS: Present findings suggest that a patient's age and pretreatment interpersonal characteristics predict the association between common depression treatments and dropout rate. If validated by further studies, these characteristics can assist in reducing dropout through targeted treatment assignment. TRIAL REGISTRATION: Secondary analysis of data from ClinicalTrials.gov identifier: NCT00043550. PMID- 28086006 TI - Generalizability of Neuroimaging Studies in 5 Common Psychiatric Disorders Based on the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). AB - OBJECTIVE: Although neuroimaging studies have an important role in psychiatric nosology and treatment development, little is known about the representativeness of participants in neuroimaging research. We estimated the effects of commonly used study eligibility criteria on the representativeness of neuroimaging research participants in relation to the general population with the psychiatric disorders of interest. METHODS: Common eligibility criteria were applied from 112 published neuroimaging studies of DSM-IV nicotine dependence (13 studies), alcohol dependence (12 studies), drug use disorders (13 studies), major depressive disorder (MDD) (37 studies), and posttraumatic stress disorder (PTSD) (36 studies) to representative US samples with these conditions from the 2001 2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) (n = 43,093). The analyses were repeated with NESARC respondents with the disorders and substantial psychosocial impairment. RESULTS: Most NESARC respondents with nicotine dependence (64.1%), alcohol dependence (57.7%), drug use disorders (86.6%), and PTSD (66.9%), though not with MDD (18.2%), would have been excluded by eligibility criteria used in at least half of the relevant neuroimaging studies. Across the diagnostic groups, comorbid psychiatric and general medical conditions resulted in the largest percentages of exclusions. Corresponding analyses limited to respondents with substantial impairment excluded larger percentages with nicotine dependence (77.6%), alcohol dependence (75.8%), drug use disorders (93.5%), and PTSD (76.8%), though not MDD (18.3%). CONCLUSIONS: Neuroimaging studies tend to recruit highly selected samples with the psychiatric disorders of interest that markedly underrepresent individuals with common comorbid conditions. Larger studies with less restrictive eligibility criteria may promote translation of advances in neuroimaging research to populations commonly encountered in clinical practice. PMID- 28086007 TI - A Radical Proposal to Address the Problem of the Lack of Generalizability of Placebo-Controlled Studies of Antidepressants. PMID- 28086008 TI - Introduction. PMID- 28086009 TI - Adherence to Selective Serotonin and Serotonin-Norepinephrine Reuptake Inhibitor Prescriptions Affects Overall Medication Adherence in Older Persons: Evidence From the Italian Nationwide OsMed Health-DB Database. AB - OBJECTIVE: This study aimed to evaluate prevalence of prescription of and adherence to selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) and whether adherence to these classes of drugs affects overall medication adherence in older persons. METHODS: In a cross-sectional analysis of administrative data comprehensive of all prescribed drugs reimbursed by the Italian national health care system, new prescriptions of SSRIs and SNRIs to persons aged 65 years or older were analyzed (n = 380,400 in 2011; 395,806 in 2012; 409,741 in 2013, from a total sample of 3,762,299 persons aged 65 years or older) as well as prescriptions of antihypertensives, statins, other psychiatric drugs, antidiabetics, antiplatelets, anticoagulants, drugs for chronic obstructive pulmonary disease, and antiosteoporotics. Adherence was estimated by calculating the proportion of days covered by drugs dispensed during a period of 365 days. Adherence was defined as a proportion of days covered of more than 80%. RESULTS: Prevalence of SSRI and SNRI prescriptions varied from 11.4% in 2011 to 12.1% in 2013. Adherence to SSRI and SNRI prescriptions ranged from 31.2% in persons aged >= 95 years in 2011 to 41.8% in persons aged 75-84 years in 2013. Persons adherent to SSRI and SNRI prescriptions were more likely to be adherent to the other medications, after adjustment for age, gender, and number of drugs prescribed. The highest association was found for adherence to psychiatric drugs (OR = 1.9; 95% CI, 1.8-2.0). CONCLUSIONS: Adherence to SSRI and SNRI prescriptions is poor in older persons. However, people adherent to these classes of antidepressants are more likely to be adherent to the other medications they are prescribed. Studies are needed to evaluate the reasons for and the potential benefits of increasing adherence to antidepressants on overall adherence. PMID- 28086010 TI - Threshold of Dopamine D2/3 Receptor Occupancy for Hyperprolactinemia in Older Patients With Schizophrenia. AB - OBJECTIVE: Although hyperprolactinemia carries a long-term risk of morbidity, the threshold of dopamine D2/3 receptor (D2/3R) occupancy for hyperprolactinemia has not been investigated in older patients with schizophrenia. Data were taken from a positron emission tomography (PET) study conducted between August 2007 and August 2015. The present post hoc study included 42 clinically stable outpatients with schizophrenia (DSM-IV) (mean +/- SD age = 60.2 +/- 6.7 years) taking olanzapine or risperidone. Subjects underwent [11C]-raclopride PET scans to measure D2/3R occupancy before and after reducing their dose of antipsychotic by up to 40%. Blood samples were collected before each PET scan to measure prolactin levels. METHODS: The relationship between prolactin levels and D2/3R occupancy was examined using stepwise linear regression analyses. The D2/3R occupancy thresholds for hyperprolactinemia were explored using Fisher exact tests. RESULTS: Prolactin levels decreased following dose reduction (mean +/- SD = 24.1 +/- 30.2 ng/mL to 17.2 +/- 15.1 ng/mL; P < .001). Prolactin levels were associated with female gender (beta = .32, P = .006, vs male), antipsychotics (beta = .23, P = .02, risperidone vs olanzapine), and D2/3R occupancy (beta = .23, P = .04). Those with D2/3R occupancy of 66% or higher were more likely to have hyperprolactinemia than those with D2/3R occupancy lower than 66% (P = .03). Sensitivity, specificity, positive predictive value, and negative predictive value of this threshold were 0.44, 0.81, 0.78, and 0.48, respectively. We identified a D2/3R occupancy threshold for hyperprolactinemia of 66% in older patients with schizophrenia, which is lower than that reported in younger patients (73%) by other researchers. CONCLUSIONS: Our results suggest a higher sensitivity to antipsychotics in older patients. Prolactin levels could assist in the determination of appropriate antipsychotic dosing to minimize adverse effects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00716755. PMID- 28086011 TI - Incident Psychosis in Subjects With Mild Cognitive Impairment or Alzheimer's Disease. AB - OBJECTIVE: To estimate the incidence of psychotic symptoms in Alzheimer's disease. METHODS: The study consists of 776 elderly subjects presenting to the Alzheimer Disease Research Center at the University of Pittsburgh (Pittsburgh, Pennsylvania) between May 9, 2000, and August 19, 2014. All participants were diagnosed with mild cognitive impairment (National Institute on Aging-Alzheimer's Association workgroup criteria) or possible or probable Alzheimer's disease (National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria) and were without psychosis at entry. Psychotic symptoms were evaluated using the Consortium to Establish a Registry for Alzheimer's Disease Behavioral Rating Scale every 6 months. One-, 3- and 5-year cumulative incidences of psychosis were calculated. RESULTS: The 1-year psychosis incidence was 10% (95% CI, 8%-12%), and this annual rate remained remarkably consistent at 3 and 5 years. Psychosis incidence was related to cognitive status at all time points. However, the incidence rate reached a plateau during the disease course. Cumulative psychosis incidence at 5 years was 61% (95% CI, 52%-69%) in individuals with moderate to severe Alzheimer's disease, not statistically significantly different from the cumulative incidence at 3 years in this group, which was 48% (95% CI, 40%-55%) or from the 5-year incidence in individuals who entered the study with mild Alzheimer's disease, which was 48% (95% CI, 41%-56%). CONCLUSIONS: Psychosis in Alzheimer's disease has been associated with a number of adverse clinical outcomes. We provide estimates of the risk of psychosis onset within clinically defined subgroups of individuals, a tool clinicians can use in treatment planning. Anticipating which subjects are at high risk for psychosis and the poor outcomes associated with it can help with family education and support decisions to implement nonpharmacologic strategies that may reduce or prevent symptoms. PMID- 28086012 TI - The Need to Assess Suicidal Risk in the Checklist for Prescribing Opioids. PMID- 28086013 TI - Clinical Correlates of Oral Glucose Tolerance Test Performance in Olanzapine Treated Patients with Schizophrenia or Schizoaffective Disorder. PMID- 28086014 TI - Considering the Complexity of Treatment Response in Psychiatric Clinical Trials. PMID- 28086015 TI - Antibiotics or Infection Itself? The Possible Importance of Inflammatory Cytokines on Mental States. PMID- 28086016 TI - Dr Lurie and Colleagues Reply. Antibiotics or Infection Itself? The Possible Importance of Inflammatory Cytokines on Mental States PMID- 28086017 TI - Correction. Nocturnal Wakefulness Is Associated With Next-Day Suicidal Ideation in Major Depressive Disorder and Bipolar Disorder PMID- 28086018 TI - Antipsychotic Drugs in Schizophrenia: Relative Effects in Patients With and Without Treatment Resistance. AB - How antipsychotic drugs compare in schizophrenia, and especially in medication refractory schizophrenia, is a subject of considerable interest. Two network meta analyses and 1 direct comparison meta-analysis recently compared antipsychotics in schizophrenia patients with and without documented treatment resistance. One network meta-analysis of antipsychotic drugs in non-refractory patients found clear efficacy advantages for clozapine, amisulpride, olanzapine, and risperidone. One network meta-analysis of antipsychotic drugs in refractory patients found a clear efficacy advantage for olanzapine; surprisingly, in this meta-analysis, clozapine was superior to first-generation but not second generation antipsychotics. One direct comparison meta-analysis found clozapine generally superior to first- and second-generation antipsychotics, with advantages more clearly apparent in studies that were 3 months in duration or less. Drug discontinuation and adverse effect data from these meta-analyses are presented, and issues arising from the results are briefly discussed. At the risk of oversimplification, it appears that clozapine retains its preeminence in medication-refractory schizophrenia and that clozapine and olanzapine are both associated with superior efficacy outcomes in non-refractory patients. Interestingly, haloperidol, generally considered a reference neuroleptic and a reference comparator drug, fared poorly in most comparisons. PMID- 28086019 TI - HK2 Recruitment to Phospho-BAD Prevents Its Degradation, Promoting Warburg Glycolysis by Theileria-Transformed Leukocytes. AB - Theileria annulata infects bovine leukocytes, transforming them into invasive, cancer-like cells that cause the widespread disease called tropical theileriosis. We report that in Theileria-transformed leukocytes hexokinase-2 (HK2) binds to B cell lymphoma-2-associated death promoter (BAD) only when serine (S) 155 in BAD is phosphorylated. We show that HK2 recruitment to BAD is abolished by a cell penetrating peptide that acts as a nonphosphorylatable BAD substrate that inhibits endogenous S155 phosphorylation, leading to complex dissociation and ubiquitination and degradation of HK2 by the proteasome. As HK2 is a critical enzyme involved in Warburg glycolysis, its loss forces Theileria-transformed macrophages to switch back to HK1-dependent oxidative glycolysis that down regulates macrophage proliferation only when they are growing on glucose. When growing on galactose, degradation of HK2 has no effect on Theileria-infected leukocyte proliferation, because metabolism of this sugar is independent of hexokinases. Thus, targeted disruption of the phosphorylation-dependent HK2/BAD complex may represent a novel approach to control Theileria-transformed leukocyte proliferation. PMID- 28086025 TI - Zeitschrift fur Arbeitswissenschaft Abstracts of papers, Vol. 43 (15 NF), Parts 1 3, 1989. PMID- 28086028 TI - "Busy Being Born": My Path in Medical Education. PMID- 28086029 TI - Implementation of a Professional Society Core Curriculum and Integrated Maintenance of Certification Program. AB - Medical professional societies exist to foster collaboration, guide career development, and provide continuing medical education opportunities. Maintenance of certification is a process by which physicians complete formal educational activities approved by certifying organizations. The American Thoracic Society (ATS) established an innovative maintenance of certification program in 2012 as a means to formalize and expand continuing medical education offerings. This program is unique as it includes explicit opportunities for collaboration and career development in addition to providing continuing medical education and maintenance of certification credit to society members. In describing the development of this program referred to as the "Core Curriculum," the authors highlight the ATS process for content design, stages of curriculum development, and outcomes data with an eye toward assisting other societies that seek to program similar content. The curriculum development process described is generalizable and positively influences individual practitioners and professional societies in general, and as a result, provides a useful model for other professional societies to follow. PMID- 28086031 TI - Function of Platelet-Induced Epithelial Attachment at Titanium Surfaces Inhibits Microbial Colonization. AB - The aim of this study was to evaluate the barrier function of platelet-induced epithelial sheets on titanium surfaces. The lack of functional peri-implant epithelial sealing with basal lamina (BL) attachment at the interface of the implant and the adjacent epithelium allows for bacterial invasion, which may lead to peri-implantitis. Although various approaches have been reported to combat bacterial infection by surface modifications to titanium, none of these have been successful in a clinical application. In our previous study, surface modification with protease-activated receptor 4-activating peptide (PAR4-AP), which induced platelet activation and aggregation, was successful in demonstrating epithelial attachment via BL and epithelial sheet formation on the titanium surface. We hypothesized that the platelet-induced epithelial sheet on PAR4-AP-modified titanium surfaces would reduce bacterial attachment, penetration, and invasion. Titanium surface was modified with PAR4-AP and incubated with platelet-rich plasma (PRP). The aggregated platelets released collagen IV, a critical BL component, onto the PAR4-AP-modified titanium surface. Then, human gingival epithelial cells were seeded on the modified titanium surface and formed epithelial sheets. Green fluorescent protein (GFP)-expressing Escherichia coli was cultured onto PAR4-AP-modified titanium with and without epithelial sheet formation. While Escherichia coli accumulated densely onto the PAR4-AP titanium lacking epithelial sheet, few Escherichia coli were observed on the epithelial sheet on the PAR4-AP surface. No bacterial invasion into the interface of the epithelial sheet and the titanium surface was observed. These in vitro results indicate the efficacy of a platelet-induced epithelial barrier that functions to prevent bacterial attachment, penetration, and invasion on PAR4-AP-modified titanium. PMID- 28086032 TI - Liver injury associated with dimethyl fumarate in multiple sclerosis patients. AB - BACKGROUND: In pre-approval trials, there was an increased incidence of mild, transient elevations of liver aminotransferases in study subjects treated with dimethyl fumarate (DMF). OBJECTIVE/METHODS: To evaluate post-marketing cases of drug-induced liver injury associated with DMF. RESULTS: We identified 14 post marketing cases of clinically significant liver injury. Findings included newly elevated serum liver aminotransferase and bilirubin levels that developed as early as a few days after the first dose of DMF. The pattern of liver injury was primarily hepatocellular. No cases resulted in liver failure. CONCLUSION: Health professionals should be alerted to possible serious liver injury in patients receiving DMF. PMID- 28086034 TI - Frontispiece. PMID- 28086035 TI - Hippocampal dysfunction is associated with memory impairment in multiple sclerosis: A volumetric and functional connectivity study. AB - BACKGROUND: Previous studies have suggested a relationship between neuroanatomical and neurofunctional hippocampal alterations and episodic memory impairments in multiple sclerosis (MS) patients. OBJECTIVE: We examined hippocampus volume and functional connectivity (FC) changes in MS patients with different episodic memory capabilities. METHODS: Hippocampal subfield volume and FC changes were compared in two subgroups of MS patients with and without episodic memory impairment (multiple sclerosis impaired (MSi) and multiple sclerosis preserved (MSp), respectively) and healthy controls (HC). A discriminant function (DF) analysis was used to identify which of these neuroanatomical and neurofunctional parameters were the most relevant components of the mnemonic profiles of HC, MSp, and MSi. RESULTS: MSi showed reduced volume in several hippocampal subfields compared to MSp and HC. Ordinal gradation (MSi > MSp > HC) was also observed for FC between the posterior hippocampus and several cortical areas. DF-based analyses revealed that reduced right fimbria volume and enhanced FC at the right posterior hippocampus were the main neural signatures of the episodic memory impairments observed in the MSi group. CONCLUSION: Before any sign of episodic memory alterations (MSp), FC increased on several pathways that connect the hippocampus with cortical areas. These changes further increased when the several hippocampal volumes reduced and memory deficits appeared (MSi). PMID- 28086036 TI - Foot Pedal Forces for Seated Operators. AB - The foot controls of spot welding machines were orgonomicnlly evaluated, and redesign recammondations put forward. Ten male and ten female subjects were tested to dotermine the maximum isometric force that a seated operator could exert on a horizontal foot pedal. The experimental results showed no significant strength differences between right arid left legs and mole legs strengths were 9% to 50% greater than female leg strengths depending on the position of the foot pedal. PMID- 28086037 TI - A Simulator and Training Technique for Diagnosing Plant Failures from Control Panels. AB - The paper describes (1) the development of a simulator and (2) the first results of a training technique for the identification of plant failures from control panel indications. Input or signal features of the task present more simulation fidelity problems than its response or output features. Current, techniques for identifying effective signals, e.g. ' blanking-off ' information, or protocol analysis, bias any description of problem solving since they require serial reporting, if not serial collection, of information by the operator. They also require inferences as to what is an effective item of information. It is therefore argued that simulation should preserve all those features which may in principle provide, or influence acquisition of, diagnostic information, specifically panel layout, instrument design and display size. Further fidelity problems are the stress from operating in a dangerous environment; stress from hazards or sanctions following mistaken diagnosis; and the stress of diagnosing in a short time interval. The simulator uses bock-projection to life size of slides of control panel mock-ups by a random access projector. Under an adaptive cumulative part regime, trainees saw on average 89 failure arrays in 30 min, an obvious advantage over the operational situation. In a test 24 hr after training, consisting of the eight faults each presented four times in random order, 4 out of 17 trainees made only one error in 32 diagnosos; the other trainees performed perfectly. Subjects' reports indicate very different solution strategies, e.g., recognition of alarm patterns; serial instrument checking determined by heuristics of plant functioning. Several features of performance arc consistent with the view that trainees use a minimal number of dimensions for correct discrimination and that these change as the number of different fault arrays increases. It is argued that this training regime should reduce stress. In particular it is argued that, according to current theories of stress, the fewer dimensions needed for diagnosis, the more robust will be diagnostic performance in dangerous environments. PMID- 28086043 TI - Memoriam. PMID- 28086061 TI - Welcome to a Special Issue from the Specialty Conference on PM2000: Particulate Matter and Health-The Scientific Basis for Regulatory Decision-Making. PMID- 28086065 TI - Defective autophagy is associated with neuronal injury in a mouse model of multiple sclerosis. AB - Neurodegeneration, along with inflammatory demyelination, is an important component of multiple sclerosis (MS) pathogenesis. Autophagy is known to play a pivotal role in neuronal homeostasis and is implicated in several neurodegenerative disorders. However, whether autophagy is involved in the mechanisms of neuronal damage during MS remains to be investigated. Experimental autoimmune encephalomyelitis (EAE), an in vivo model of MS, was induced in female C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein p35-55. After that, autophagic flux in the spinal cord of mice was evaluated by detection of LC3-II and Beclin1 protein expressions. EAE mice were then administered with rapamycin and 3-methyladenine (3-MA) for 10 days. Afterward, the changes in LC3 II, Beclin1, and p62 expression, number of infiltrated inflammatory cells, demyelinated lesion area, and neuronal damage, as well as clinical scores, were assessed. Further, apoptotic cell rate and apoptosis-related protein expressions were monitored. We observed an impaired autophagic flux and increased neuronal damage in the spinal cords of EAE mice. We also found that rapamycin, an autophagy inducer, mitigated EAE-induced autophagy decrease, inflammation, demyelination and neuronal injury, as well as the abnormal clinical score. In addition, rapamycin suppressed cell apoptosis, and decreased Bax/Bcl-2 ratio and cleaved caspase-3 expression. Conversely, the effect of autophagy inhibitor 3-MA on EAE mice resulted in completely opposite results. These results indicated that autophagy deficiency, at least in part, contributed to EAE-induced neuronal injury and that pharmacological modulation of autophagy might be a therapeutic strategy for MS. PMID- 28086064 TI - Dose- and time-dependent effects of clodronate on orthodontic tooth movement. AB - Orthodontic tooth movement is the result of bone remodeling that occurs in periodontal ligament and alveolar bone tissue as a response to mechanical loading of the tooth. The aim of this study is to investigate the time- and dose-response effects of locally administered clodronate on tooth movement. Sixty Wistar rats were randomly assigned to 4 groups of 15 specimens: E1 - application of 10 mMol of clodronate in 3-day intervals; E2 - application of 2.5 mMol of clodronate in 3 day intervals; E3 - application of 10 mMol of clodronate in 7-day intervals; E4 - application of 2.5 mMol of clodronate in 7-day intervals. A 50 MUL clodronate solution was injected into a subperiosteal area to the right maxillary incisor. The left maxillary incisor served as a control, with an injection of saline solution. In 3-day interval application regime, there was no effect of clodronate dosing on tooth movement. In 7-day interval application regime, decreased tooth movement was observed with 10 mMol compared with 2.5 mMol clodronate concentration. However, decreased tooth movement was also observed when 2.5 mMol of clodronate was applied in 7-versus 3-day intervals. Conversely, no difference was observed when 10 mMol concentration was applied in 3- versus 7-day intervals. When clodronate is applied subperiosteally in the root area, it decreases the tooth movement. Tooth movement is impeded by the higher clodronate dosing, as well as by shorter application interval even with lower dosing. The purpose of future trials should, therefore, be to determine a safe therapeutic dose/interval application of clodronate in humans and their potential side effects. PMID- 28086066 TI - Description of Auricoccus indicus gen. nov., sp. nov., isolated from skin of human ear. AB - A Gram-stain-positive, non-motile, non-spore-forming, small spherical bacterium, strain S31T, was isolated from skin surface (external ear lobe) of a healthy human subject and characterized using a polyphasic approach. On the basis of 1507 bp 16S rRNA gene sequence comparison, S31T showed highest (92.8 %, AY119686) sequence similarity with Macrococcus brunensis CCUG 47200T followed by Macrococcus caseolyticus DSM 20597T (92.7 % AP009484) and formed a separate clade with 65 % bootstrap support. The DNA G+C content was found to be 34 mol%. Anteiso C15 : 0, anteiso-C17 : 0 and iso-C16 : 0 are the predominant fatty acids in fatty acid methyl ester (FAME) profile of strain S31T. It contained A3alpha type peptidoglycan with l-Lys-Gly3-l-Ala peptide. Comparative study of morphological and physiological traits indicated that S31T has phenetically diverged from its closest relatives. On the basis of morphological, chemotaxonomic and genotypic data, S31T showed marked distinctions from its closest relatives of the family Staphylococcaceae and is proposed to represent a novel genus Auricoccus with Auricoccus indicus as type species of the genus. S31T (CCUG 69858T=KCTC 33611T=MCC 3027T) is the type strain of the species. PMID- 28086067 TI - Bacillus zeae sp. nov., isolated from the rhizosphere of Zea mays. AB - A Gram-positive-staining, aerobic organism, isolated from the rhizosphere of Zea mays, was investigated in detail. Based on 16S rRNA gene sequence similarity comparisons, strain JJ-247T was grouped into the genus Bacillus, most closely related to Bacillus foraminis (98.4 %). The 16S rRNA gene sequence similarity to the sequences of the type strains of other species of the genus Bacillus was <97.4 %. The fatty acid profile with the major fatty acids, anteiso-C15 : 0, iso C15 : 0, iso-C14 : 0 and iso-C16 : 0 supported the grouping of the strain to the genus Bacillus. The polar lipid profile contained the major components diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and an unidentified aminophospholipid. The major quinone was menaquinone MK-7, and the major polyamine was spermidine. The genomic DNA G+C content of strain JJ-247T was 44.5 mol%. DNA-DNA hybridizations with the type strain B. foraminis LMG 23147T resulted in values below 70 %. In addition, physiological and biochemical test results allowed a clear phenotypic differentiation of strain JJ-247T from B. foraminis. As a consequence, JJ-247T represents a novel species of the genus Bacillus, for which we propose the name Bacillus zeae sp. nov., with JJ-247T (=CCM 8726T=LMG 29876T) as the type strain. PMID- 28086069 TI - Explanation of the Nagoya Protocol on Access and Benefit Sharing and its implication for microbiology. AB - Working with genetic resources and associated data requires greater attention since the Nagoya Protocol on Access and Benefit Sharing (ABS) came into force in October 2014. Biologists must ensure that they have legal clarity in how they can and cannot use the genetic resources on which they carry out research. Not only must they work within the spirit in the Convention on Biological Diversity (https://www.cbd.int/convention/articles/default.shtml?a=cbd-02) but also they may have regulatory requirements to meet. Although the Nagoya Protocol was negotiated and agreed globally, it is the responsibility of each country that ratifies it to introduce their individual implementing procedures and practices. Many countries in Europe, such as the UK, have chosen not to put access controls in place at this time, but others already have laws enacted providing ABS measures under the Convention on Biological Diversity or specifically to implement the Nagoya Protocol. Access legislation is in place in many countries and information on this can be found at the ABS Clearing House (https://absch.cbd.int/). For example, Brazil, although not a Party to the Nagoya Protocol at the time of writing, has Law 13.123 which entered into force on 17 November 2015, regulated by Decree 8.772 which was published on 11 May 2016. In this case, export of Brazilian genetic resources is not allowed unless the collector is registered in the National System for Genetic Heritage and Associated Traditional Knowledge Management (SisGen). The process entails that a foreign scientist must first of all be registered working with someone in Brazil and have authorization to collect. The enactment of European Union Regulation po. 511/2014 implements Nagoya Protocol elements that govern compliance measures for users and offers the opportunity to demonstrate due diligence in sourcing their organisms by selecting from holdings of 'registered collections'. The UK has introduced a Statutory Instrument that puts in place enforcement measures within the UK to implement this European Union Regulation; this is regulated by Regulatory Delivery, Department for Business, Energy and Industrial Strategies. Scientific communities, including the private sector, individual institutions and organizations, have begun to design policy and best practices for compliance. Microbiologists and culture collections alike need to be aware of the legislation of the source country of the materials they use and put in place best practices for compliance; such best practice has been drafted by the Microbial Resource Research Infrastructure, and other research communities such as the Consortium of European Taxonomic Facilities, the Global Genome Biodiversity Network and the International Organisation for Biological Control have published best practice and/or codes of conduct to ensure legitimate exchange and use of genetic resources. PMID- 28086072 TI - Identification of Naegleria fowleri proteins linked to primary amoebic meningoencephalitis. AB - Naegleria fowleri (N. fowleri) causes primary amoebic meningoencephalitis, a rapidly fatal disease of the central nervous system. N. fowleri can exist in cyst, flagellate or amoebic forms, depending on environmental conditions. The amoebic form can invade the brain following introduction into the nasal passages. When applied intranasally to a mouse model, cultured N. fowleri amoebae exhibit low virulence. However, upon serial passage in mouse brain, the amoebae acquire a highly virulent state. In the present study, a proteomics approach was applied to the identification of N. fowleri amoeba proteins whose expression was associated with the highly virulent state in mice. Mice were inoculated intranasally with axenically cultured amoebae or with mouse-passaged amoebae. Examination by light and electron microscopy revealed no morphological differences. However, mouse passaged amoebae were more virulent in mice as indicated by exhibiting a two log10 titre decrease in median infective dose 50 (ID50). Scatter plot analysis of amoebic lysates revealed a subset of proteins, the expression of which was associated with highly virulent amoebae. MS-MS indicated that this subset contained proteins that shared homology with those linked to cytoskeletal rearrangement and the invasion process. Invasion assays were performed in the presence of a select inhibitor to expand on the findings. The collective results suggest that N. fowleri gene products linked to cytoskeletal rearrangement and invasion may be candidate targets in the management of primary amoebic meningoencephalitis. PMID- 28086071 TI - 155R is a novel structural protein of bovine adenovirus type 3, but it is not essential for virus replication. AB - Bovine adenovirus (AdV) type 3 (BAdV-3) E1 region shares functional homology with E1 of human AdV type C5. Sequence analysis of the BAdV-3 E1 region revealed the presence of a novel 155R ORF that is not observed in other AdVs, on the lower strand antiparallel to a portion of the E1B region. The 155R gene products in BAdV-3-infected cells were identified by Northern blot, reverse transcriptase PCR followed by sequencing and Western blot analysis using the155R-specific antibody. 155R seems to be a late protein and is present in purified BAdV-3 particles. Replication kinetics of BAdV mutants with either one (BAdV/155R/mt1) or two (BAdV/155R/mt2) stop codons in the 155R ORF were comparable to those of BAdV-3, indicating that 155R is not essential for virus replication in cell culture. These results suggest that 155R-deleted BAdV-3 vectors could be generated in a cell line that fully complements BAdV-3 E1 functions. PMID- 28086073 TI - Evolutionary and genetic analysis of human bocavirus genotype-1 strains reveals an evidence of intragenomic recombination. AB - PURPOSE: Human bocavirus (HBoV) exsits in four genotypes: 1 to 4, with HBoV-1 being the most prevalent genotype. The aim of the current study was to genetically analyze the full-length genome of the HBoV-1 of recently detected Egyptian strains. METHODOLOGY: Seven overlapping sets of primers were developed to amplify an almost complete HBoV-1 genome from the clinical samples. The primer sets were tested on three recently identified Egyptian HBoV-1 strains with viral loads >=105 ml-1. Sequencing was conducted using the same sets of primers. HBoV-1 virus strains were genetically analyzed based on the sequences of their complete genomes and the individual ORFs. RESULTS: The new sets of primers successfully amplified the three tested strains. Sequence analysis of the full-length genome of the HBoV-1 revealed a considerable level of genetic heterogenicity between different strains. Based on the full genome and VP1 ORF, HBoV-1 viruses were clustered into three main lineages, A to C, and lineage A was further subdivided into three sublineages, A1-A3. The Egyptian strains were clustered within two sublineages, A1 and A2. New amino acid substitutions were detected in NS1 and VP1/VP2 proteins. Both inter- and intragenomic recombination events were detected among the Egyptian strains. CONCLUSION: The existence of both intragenomic recombination event and multiple amino acid substitutions in the examined Egyptian HBoV-1 strains elucidates considerable level of genetic alterations among bocaviruses. Their possible effects on the virus virulence and multiplication efficiency need to be investigated. PMID- 28086074 TI - Mangrovibacter phragmitis sp. nov., an endophyte isolated from the roots of Phragmites karka. AB - A facultatively anaerobic, Gram-stain-negative, rod-shaped, nitrogen-fixing, endophytic bacterial strain designated MP23T was isolated from the roots of Phragmites karka growing in Chilika Lagoon, Odisha, India. Strain MP23T was slightly halophilic, and the optimal NaCl concentration and temperature for growth were 1 % and 30 degrees C, respectively. On the basis of 16S rRNA gene sequence similarities, strain MP23T was affiliated to the family Enterobacteriaceae and most closely related to Mangrovibacter yixingensis KCTC 42181T and Mangrovibacter plantisponsor DSM 19579T with 99.71 % similarity, followed by Salmonella enterica subsp. salamae DSM 9220T (97.22 %), Cronobacter condimenti LMG 26250T (97.14 %) and Salmonella enterica subsp. diarizonae DSM 14847T (97 %). Sequence analysis of 16S rRNA, hsp60, gyrB and rpoB genes showed that strain MP23T formed a phylogenetic cluster with M. yixingensis KCTC 42181T and M. plantisponsor DSM 19579T indicating that it belongs to the genus Mangrovibacter. The major cellular fatty acids were C16 : 0, C18 : 1omega6c and/or C18 : 1omega7c, C16 : 1omega6c and/or C16 : 1omega7c, C14 : 0, C14 : 0 3 OH and/or iso-C16 : 1 I and C17 : 0 cyclo. Polar lipids of strain MP23T consisted of phosphatidylglycerol, diphosphatidylglycerol and phosphatidylethanolamine. The DNA G+C content was 50.3 mol%. Based on experimental DNA-DNA hybridization values and average nucleotide identity derived from in silico comparison of whole-genome sequences, strain MP23T could be distinguished from its closest neighbours. We therefore conclude that strain MP23T represents a novel species of the genus Mangrovibacter for which the name Mangrovibacter phragmitis sp. nov. is proposed. The type strain is MP23T (=DSM 100250T=KCTC 42580T). PMID- 28086075 TI - Cellular microRNA miR-10a-5p inhibits replication of porcine reproductive and respiratory syndrome virus by targeting the host factor signal recognition particle 14. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically important viruses affecting the swine industry worldwide. MicroRNAs have recently been demonstrated to play vital roles in virus-host interactions. Our previous research on small RNA deep sequencing showed that the expression level of miR-10a increased during the viral life cycle. The present study sought to determine the function of miR-10a and its molecular mechanism during PRRSV infection. In the current study, the result of PRRSV infection inducing miR-10a expression was validated by quantitative reverse transcriptase PCR. Overexpression of miR-10a-5p using its mimics markedly reduced the expression level of intracellular PRRSV ORF7 mRNA and N protein. Simultaneously, overexpression of miR-10a-5p also significantly decreased the expression level of extracellular viral RNA and virus titres in the supernatants. These results demonstrated that miR-10a-5p could suppress the replication of PRRSV. A direct interaction between miR-10a-5p and signal recognition particle 14 (SRP14) was confirmed using bioinformatic prediction and experimental verification. miR-10a 5p could directly target the 3'UTR of pig SRP14 mRNA in a sequence-specific manner and decrease SRP14 expression through translational repression but not mRNA degradation. Further, knockdown of SRP14 by small interfering RNA also inhibits the replication of PRRSV. Collectively, these results suggested that miR 10a-5p inhibits PRRSV replication through suppression of SRP14 expression, which not only provides new insights into virus-host interactions during PRRSV infection but also suggests potential new antiviral strategies against PRRSV infection. PMID- 28086076 TI - Hymenobacter aquaticus sp. nov., a radiation-resistant bacterium isolated from a river. AB - A Gram-stain-negative, non-motile, non-spore-forming, rod-shaped, aerobic bacterial strain, designated 16F3PT, was isolated from the Han River, South Korea, and characterized taxonomically using a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequences revealed 16F3PT to be within the genus Hymenobacter, and most closely related to Hymenobacterchitinivorans Txc1T (98.62 %) and Hymenobacterelongatus VUG-A112T (98.46 %). The phylogenetic distance from other species of the genus Hymenobacter with validly published names was greater than 4 % (i.e. sequence similarity was less than 96.0 %). Chemotaxonomic data also supported the classification of strain 16F3PT within the genus Hymenobacter. C16 : 0 (19.8 %), summed feature 3 (C16 : 1omega7c/C16 : 1omega6c; 15.4 %) and iso-C15 : 0 (13.0 %) were the major fatty acids, MK-7 was the predominant respiratory quinone, and phosphatidylethanolamine was the major polar lipid. The G+C content of the genomic DNA of strain 16F3PT was 61.9 mol%. DNA-DNA hybridization experiments showed that the values for DNA-DNA relatedness between strain 16F3PT and the phylogenetically closest neighbours were below 19 %. On the basis of its phenotypic properties and phylogenetic distinctiveness, strain 16F3PT represents a novel species of the genus Hymenobacter, for which the name Hymenobacter aquaticus sp. nov. is proposed. The type strain is 16F3PT (=KCTC 52194T=JCM 31653T). PMID- 28086077 TI - Muricauda lutea sp. nov., isolated from seawater. AB - A Gram-stain-negative, strictly aerobic, non-flagellated, non-gliding, catalase positive, long-rod-shaped bacterium designated strain CSW06T, was isolated from surface seawater of the Bohai Sea. Optimal growth occurred in the presence of 4 % (w/v) NaCl, at pH 7 and at 28 degrees C. The predominant fatty acids (>10 % of total fatty acids) were iso-C15 : 1G, iso-C17 : 0 3-OH and summed feature 3 (iso C15 : 0 2-OH and/or C16 : 1omega7c). The major polar lipids were phosphatidylethanolamine, two unidentified phospholipids and one unidentified aminolipid. The DNA G+C content of CSW06T was 50.3 mol%. The predominant isoprenoid quinone detected was menaquinone with six isoprene units (MK-6). On the basis of the results of polyphasic analyses, CSW06T was considered to represent a novel species of the genus Muricauda in the family Flavobacteriaceae, for which the name Muricauda lutea sp. nov. is proposed. The type strain is CSW06T (=CGMCC 1.15761T=JCM 31455T=KCTC 52375T=MCCC 1K03195T). PMID- 28086078 TI - Role and mechanism of the Hsp70 molecular chaperone machines in bacterial pathogens. AB - Heat shock proteins are highly conserved, stress-inducible, ubiquitous proteins that maintain homeostasis in both eukaryotes and prokaryotes. Hsp70 proteins belong to the heat shock protein family and enhance bacterial survival in hostile environments. Hsp70, known as DnaK in prokaryotes, supports numerous processes such as the assembly and disassembly of protein complexes, the refolding of misfolded and clustered proteins, membrane translocation and the regulation of regulatory proteins. The chaperone-based activity of Hsp70 depends on dynamic interactions between its two domains, known as the ATPase domain and the substrate-binding domain. It also depends on interactions between these domains and other co-chaperone molecules such as the Hsp40 protein family member DnaJ and nucleotide exchange factors. DnaJ is the primary chaperone that interacts with nascent polypeptide chains and functions to prevent their premature release from the ribosome and misfolding before it is targeted by DnaK. Adhesion of bacteria to host cells is mediated by both host and bacterial Hsp70. Following infection of the host, bacterial Hsp70 (DnaK) is in a position to initiate bacterial survival processes and trigger an immune response by the host. Any mutations in the dnaK gene have been shown to decrease the viability of bacteria inside the host. This review will give insights into the structure and mechanism of Hsp70 and its role in regulating the protein activity that contributes to pathogenesis. PMID- 28086079 TI - A large prolonged outbreak of hepatitis A associated with consumption of frozen berries, Italy, 2013-14. AB - PURPOSE: In 2013/2014, Italy experienced one of the largest community-wide prolonged outbreaks of hepatitis A virus (HAV) throughout the country. The article provides a comprehensive description of the outbreak and the investigation carried out by a multidisciplinary National Task Force, in collaboration with regional and local public health authorities. Control strategies of food-borne HAV infection in both the human and food sectors are also described. METHODOLOGY: Enhanced human epidemiological and microbiological surveillance together with microbiological monitoring of HAV in food and trace back investigation were conducted. RESULTS: A total of 1803 HAV cases were identified from 1 January 2013 to 31 August 2014, in Italy. Sequencing was possible for 368 cases (20.4 %), mostly collected between 1 January 2013 and 28 February 2014, and 246 cases (66.8 %) harboured an HAV outbreak strain. Imported frozen berries contaminated with HAV were identified as the vehicle of the outbreak which also involved many other European countries in 2013 and 2014. Epidemiological evidence obtained through a case-control study was supported by the finding of a 100 % nucleotide similarity of the VP1/2A sequences of HAVs detected in human and food samples. Trace-back investigation revealed an extremely complex supplying network with no possibility for a point source potentially explaining the vast contamination of berries found in Italy. CONCLUSION: The investigation benefited from an excellent collaboration among different sectors who shared proactively the available information. Our findings highlight the importance of considering frozen berries among the highest risk factors for HAV. PMID- 28086081 TI - Redefining Biology via Enzyme Engineering. PMID- 28086080 TI - Modelling the effect on injuries and fatalities when changing mode of transport from car to bicycle. AB - BACKGROUND: Several studies have estimated the health effects of active commuting, where a transport mode shift from car to bicycle reduces risk of mortality and morbidity. Previous studies mainly assess the negative aspects of bicycling by referring to fatalities or police reported injuries. However, most bicycle crashes are not reported by the police and therefore hospital reported data would cover a much higher rate of injuries from bicycle crashes. The aim of the present study was to estimate the effect on injuries and fatalities from traffic crashes when shifting mode of transport from car to bicycle by using hospital reported data. METHODS: This present study models the change in number of injuries and fatalities due to a transport mode change using a given flow change from car to bicycle and current injury and fatality risk per distance for bicyclists and car occupants. RESULTS: show that bicyclists have a much higher injury risk (29 times) and fatality risk (10 times) than car occupants. In a scenario where car occupants in Stockholm living close to their work place shifts transport mode to bicycling, injuries, fatalities and health loss expressed in Disability-Adjusted Life Years (DALY) were estimated to increase. The vast majority of the estimated DALY increase was caused by severe injuries and fatalities and it tends to fluctuate so that the number of severe crashes may exceed the estimation with a large margin. CONCLUSION: Although the estimated increase of traffic crashes and DALY, a transport mode shift is seen as a way towards a more sustainable society. Thus, this present study highlights the need of strategic preventive measures in order to minimize the negative impacts from increased bicycling. PMID- 28086082 TI - Structure of a Pancreatic ATP-Sensitive Potassium Channel. AB - ATP-sensitive potassium channels (KATP) couple intracellular ATP levels with membrane excitability. These channels play crucial roles in many essential physiological processes and have been implicated extensively in a spectrum of metabolic diseases and disorders. To gain insight into the mechanism of KATP, we elucidated the structure of a hetero-octameric pancreatic KATP channel in complex with a non-competitive inhibitor glibenclamide by single-particle cryoelectron microscopy to 5.6-A resolution. The structure shows that four SUR1 regulatory subunits locate peripherally and dock onto the central Kir6.2 channel tetramer through the SUR1 TMD0-L0 fragment. Glibenclamide-bound SUR1 uses TMD0-L0 fragment to stabilize Kir6.2 channel in a closed conformation. In another structural population, a putative co-purified phosphatidylinositol 4,5-bisphosphate (PIP2) molecule uncouples Kir6.2 from glibenclamide-bound SUR1. These structural observations suggest a molecular mechanism for KATP regulation by anti-diabetic sulfonylurea drugs, intracellular adenosine nucleotide concentrations, and PIP2 lipid. PMID- 28086083 TI - Shining a Light on Phase Separation in the Cell. AB - Phase separation of proteins is recognized as an important aspect of cellular organization and disease mechanisms. Shin et al. introduce a novel optogenetic tool, which enables different phase-space regimes inside living cells to be assessed and the transition paths between them to be studied with unprecedented spatiotemporal control. PMID- 28086085 TI - Two Distant Catalytic Sites Are Responsible for C2c2 RNase Activities. AB - C2c2, the effector of type VI CRISPR-Cas systems, has two RNase activities-one for cutting its RNA target and the other for processing the CRISPR RNA (crRNA). Here, we report the structures of Leptotrichia shahii C2c2 in its crRNA-free and crRNA-bound states. While C2c2 has a bilobed structure reminiscent of all other Class 2 effectors, it also exhibits different structural characteristics. It contains the REC lobe with a Helical-1 domain and the NUC lobe with two HEPN domains. The two RNase catalytic pockets responsible for cleaving pre-crRNA and target RNA are independently located on Helical-1 and HEPN domains, respectively. crRNA binding induces significant conformational changes that are likely to stabilize crRNA binding and facilitate target RNA recognition. These structures provide important insights into the molecular mechanism of dual RNase activities of C2c2 and establish a framework for its future engineering as a RNA editing tool. PMID- 28086084 TI - Structures of the Human HCN1 Hyperpolarization-Activated Channel. AB - Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels underlie the control of rhythmic activity in cardiac and neuronal pacemaker cells. In HCN, the polarity of voltage dependence is uniquely reversed. Intracellular cyclic adenosine monophosphate (cAMP) levels tune the voltage response, enabling sympathetic nerve stimulation to increase the heart rate. We present cryo electron microscopy structures of the human HCN channel in the absence and presence of cAMP at 3.5 A resolution. HCN channels contain a K+ channel selectivity filter-forming sequence from which the amino acids create a unique structure that explains Na+ and K+ permeability. The voltage sensor adopts a depolarized conformation, and the pore is closed. An S4 helix of unprecedented length extends into the cytoplasm, contacts the C-linker, and twists the inner helical gate shut. cAMP binding rotates cytoplasmic domains to favor opening of the inner helical gate. These structures advance understanding of ion selectivity, reversed polarity gating, and cAMP regulation in HCN channels. PMID- 28086086 TI - Vesicles Spread Susceptibility to Phages. AB - Extracellular membrane vesicles from bacteria are now shown to transfer phage receptors from susceptible to resistant cells, thus making them transiently sensitive to phage infection (Tzipilevich et al.). PMID- 28086088 TI - Staying in Touch while on the Go. AB - While chemical forms of cell-to-cell communication are well recognized to coordinate bacterial populations, electrical signaling has been relatively ignored. Humphries et al. show that Bacillus subtilis biofilms utilize potassium production to attract far away, motile cells of even phylogenetically distant species by altering their membrane potential. PMID- 28086089 TI - Blood on the Tracks: Two Pathways for Predation. AB - Accurate predatory behavior requires coordination between pursuit activity and prey consumption, yet the underlying neuronal circuits are unknown. A novel study published in this issue of Cell identifies two coordinated circuits emanating from the central amygdala that control the efficiency of prey capture and the ability to deliver fatal bites to prey. PMID- 28086087 TI - RNA Binding to CBP Stimulates Histone Acetylation and Transcription. AB - CBP/p300 are transcription co-activators whose binding is a signature of enhancers, cis-regulatory elements that control patterns of gene expression in multicellular organisms. Active enhancers produce bi-directional enhancer RNAs (eRNAs) and display CBP/p300-dependent histone acetylation. Here, we demonstrate that CBP binds directly to RNAs in vivo and in vitro. RNAs bound to CBP in vivo include a large number of eRNAs. Using steady-state histone acetyltransferase (HAT) assays, we show that an RNA binding region in the HAT domain of CBP-a regulatory motif unique to CBP/p300-allows RNA to stimulate CBP's HAT activity. At enhancers where CBP interacts with eRNAs, stimulation manifests in RNA dependent changes in the histone acetylation mediated by CBP, such as H3K27ac, and by corresponding changes in gene expression. By interacting directly with CBP, eRNAs contribute to the unique chromatin structure at active enhancers, which, in turn, is required for regulation of target genes. PMID- 28086090 TI - A Periplasmic Polymer Curves Vibrio cholerae and Promotes Pathogenesis. AB - Pathogenic Vibrio cholerae remains a major human health concern. V. cholerae has a characteristic curved rod morphology, with a longer outer face and a shorter inner face. The mechanism and function of this curvature were previously unknown. Here, we identify and characterize CrvA, the first curvature determinant in V. cholerae. CrvA self-assembles into filaments at the inner face of cell curvature. Unlike traditional cytoskeletons, CrvA localizes to the periplasm and thus can be considered a periskeletal element. To quantify how curvature forms, we developed QuASAR (quantitative analysis of sacculus architecture remodeling), which measures subcellular peptidoglycan dynamics. QuASAR reveals that CrvA asymmetrically patterns peptidoglycan insertion rather than removal, causing more material insertions into the outer face than the inner face. Furthermore, crvA is quorum regulated, and CrvA-dependent curvature increases at high cell density. Finally, we demonstrate that CrvA promotes motility in hydrogels and confers an advantage in host colonization and pathogenesis. PMID- 28086091 TI - Species-Independent Attraction to Biofilms through Electrical Signaling. AB - Bacteria residing within biofilm communities can coordinate their behavior through cell-to-cell signaling. However, it remains unclear if these signals can also influence the behavior of distant cells that are not part of the community. Using a microfluidic approach, we find that potassium ion channel-mediated electrical signaling generated by a Bacillus subtilis biofilm can attract distant cells. Integration of experiments and mathematical modeling indicates that extracellular potassium emitted from the biofilm alters the membrane potential of distant cells, thereby directing their motility. This electrically mediated attraction appears to be a generic mechanism that enables cross-species interactions, as Pseudomonas aeruginosa cells also become attracted to the electrical signal released by the B. subtilis biofilm. Cells within a biofilm community can thus not only coordinate their own behavior but also influence the behavior of diverse bacteria at a distance through long-range electrical signaling. PAPERCLIP. PMID- 28086092 TI - Nuclear Localization of Mitochondrial TCA Cycle Enzymes as a Critical Step in Mammalian Zygotic Genome Activation. AB - Transcriptional control requires epigenetic changes directed by mitochondrial tricarboxylic acid (TCA) cycle metabolites. In the mouse embryo, global epigenetic changes occur during zygotic genome activation (ZGA) at the 2-cell stage. Pyruvate is essential for development beyond this stage, which is at odds with the low activity of mitochondria in this period. We now show that a number of enzymatically active mitochondrial enzymes associated with the TCA cycle are essential for epigenetic remodeling and are transiently and partially localized to the nucleus. Pyruvate is essential for this nuclear localization, and a failure of TCA cycle enzymes to enter the nucleus correlates with loss of specific histone modifications and a block in ZGA. At later stages, however, these enzymes are exclusively mitochondrial. In humans, the enzyme pyruvate dehydrogenase is transiently nuclear at the 4/8-cell stage coincident with timing of human embryonic genome activation, suggesting a conserved metabolic control mechanism underlying early pre-implantation development. PMID- 28086094 TI - In Search of Scientific Inspiration. AB - In the ever-expanding sea of scientific advances, how do you find inspiration for your own study? Cell editor Jiaying Tan talked with Mark Lemmon and Joseph (Yossi) Schlessinger about the importance of fueling your research creativity with the conceptual excitement and technical advance from the broad scientific field. An excerpt of the conversation appears below. PMID- 28086093 TI - Dynamic Remodeling of Membrane Composition Drives Cell Cycle through Primary Cilia Excision. AB - The life cycle of a primary cilium begins in quiescence and ends prior to mitosis. In quiescent cells, the primary cilium insulates itself from contiguous dynamic membrane processes on the cell surface to function as a stable signaling apparatus. Here, we demonstrate that basal restriction of ciliary structure dynamics is established by the cilia-enriched phosphoinositide 5-phosphatase, Inpp5e. Growth induction displaces ciliary Inpp5e and accumulates phosphatidylinositol 4,5-bisphosphate in distal cilia. This change triggers otherwise-forbidden actin polymerization in primary cilia, which excises cilia tips in a process we call cilia decapitation. While cilia disassembly is traditionally thought to occur solely through resorption, we show that an acute loss of IFT-B through cilia decapitation precedes resorption. Finally, we propose that cilia decapitation induces mitogenic signaling and constitutes a molecular link between the cilia life cycle and cell-division cycle. This newly defined ciliary mechanism may find significance in cell proliferation control during normal development and cancer. PMID- 28086096 TI - The C. elegans Taste Receptor Homolog LITE-1 Is a Photoreceptor. PMID- 28086095 TI - Integrated Control of Predatory Hunting by the Central Nucleus of the Amygdala. AB - Superior predatory skills led to the evolutionary triumph of jawed vertebrates. However, the mechanisms by which the vertebrate brain controls predation remain largely unknown. Here, we reveal a critical role for the central nucleus of the amygdala in predatory hunting. Both optogenetic and chemogenetic stimulation of central amygdala of mice elicited predatory-like attacks upon both insect and artificial prey. Coordinated control of cervical and mandibular musculatures, which is necessary for accurately positioning lethal bites on prey, was mediated by a central amygdala projection to the reticular formation in the brainstem. In contrast, prey pursuit was mediated by projections to the midbrain periaqueductal gray matter. Targeted lesions to these two pathways separately disrupted biting attacks upon prey versus the initiation of prey pursuit. Our findings delineate a neural network that integrates distinct behavioral modules and suggest that central amygdala neurons instruct predatory hunting across jawed vertebrates. PMID- 28086097 TI - SnapShot: Class 2 CRISPR-Cas Systems. AB - Class 2 CRISPR-Cas systems are characterized by effector modules consisting of single, large, multidomain proteins that appear to have been derived from mobile genetic elements. Some Class 2 effector proteins, such as Cas9 and Cas12a (Cpf1), have been successfully repurposed for genome engineering. PMID- 28086099 TI - GABA Signaling Stimulates beta Cell Regeneration in Diabetic Mice. AB - GABA and the antimalarial drug artemether, which acts on GABAergic pathways, can drive pancreatic cells with an alpha-cell phenotype toward a beta-cell-like phenotype. As reported in two papers (Ben-Othman et al. and Li et al.), these drugs can stimulate the production of sufficient numbers of new beta-like cells to reverse severe diabetes in mice. PMID- 28086100 TI - The Interfaces of Genetic Conflict Are Hot Spots for Innovation. AB - RNA-guided Cas9 endonucleases protect bacteria from viral infection and have been creatively repurposed as programmable molecular scalpels for surgical manipulation of DNA. Now, two papers in Cell (Pawluk et al. and Rauch et al.) identify viral proteins that suppress Cas9 and may function like molecular sheaths for the Cas9 scalpel. PMID- 28086098 TI - 30 Years of NF-kappaB: A Blossoming of Relevance to Human Pathobiology. AB - NF-kappaB was discovered 30 years ago as a rapidly inducible transcription factor. Since that time, it has been found to have a broad role in gene induction in diverse cellular responses, particularly throughout the immune system. Here, we summarize elaborate regulatory pathways involving this transcription factor and use recent discoveries in human genetic diseases to place specific proteins within their relevant medical and biological contexts. PMID- 28086101 TI - Measurements of intermediate-frequency electric and magnetic fields in households. AB - Historically, assessment of human exposure to electric and magnetic fields has focused on the extremely-low-frequency (ELF) and radiofrequency (RF) ranges. However, research on the typically emitted fields in the intermediate-frequency (IF) range (300Hz to 1MHz) as well as potential effects of IF fields on the human body remains limited, although the range of household appliances with electrical components working in the IF range has grown significantly (e.g., induction cookers and compact fluorescent lighting). In this study, an extensive measurement survey was performed on the levels of electric and magnetic fields in the IF range typically present in residences as well as emitted by a wide range of household appliances under real-life circumstances. Using spot measurements, residential IF field levels were found to be generally low, while the use of certain appliances at close distance (20cm) may result in a relatively high exposure. Overall, appliance emissions contained either harmonic signals, with fundamental frequencies between 6kHz and 300kHz, which were sometimes accompanied by regions in the IF spectrum of rather noisy, elevated field strengths, or much more capricious spectra, dominated by 50Hz harmonics emanating far in the IF domain. The maximum peak field strengths recorded at 20cm were 41.5V/m and 2.7A/m, both from induction cookers. Finally, none of the appliance emissions in the IF range exceeded the exposure summation rules recommended by the International Commission on Non-Ionizing Radiation Protection guidelines and the International Electrotechnical Commission (IEC 62233) standard at 20cm and beyond (maximum exposure quotients EQE 1.0 and EQH 0.13). PMID- 28086103 TI - Preparation and evaluation of pH-responsive charge-convertible ternary complex FA PEI-CCA/PEI/DNA with low cytotoxicity and efficient gene delivery. AB - Because the surface of the cationic polymer gene complex is positively charged, it can result in problems such as poor blood stability and cytotoxicity. Therefore, reducing the positive charge of the cationic gene complex without affecting its transfection efficiency is crucial. To achieve this objective, a pH responsive charge-convertible ternary complex was developed in this study. Modified plyethylenimine (PEI) with two different degrees of substitution of NH2 (plyethylenimine-1,2-cyclohexanedicarboxylic anhydride, PEI-CCA, and folic acid plyethylenimine-1,2-cyclohexanedicarboxylic anhydride, FA-PEI-CCA) were first obtained by a chemical graft reaction. PEI-CCA and FA-PEI-CCA have significantly lower cytotoxicities and much better blood compatibilities than PEI does, and the former have an undifferentiated compression capability of DNA. The zeta potential values of the as-prepared ternary complexes (PEI-CCA/PEI/DNA and FA-PEI CCA/PEI/DNA) were negative at pH 7.4 and positive at pH 6.5, with particle sizes of approximately 150nm. MTT assays demonstrated the significantly lower cytotoxicities of the ternary complexes compared to that of PEI/DNA. Moreover, the cytotoxicities of the ternary complexes were lower at pH 7.4 than pH 6.5. Transfection experiments in vitro revealed that the mean fluorescence intensities and transfection efficiencies of the ternary complexes were lower than for PEI/DNA at pH 7.4 but were almost the same at pH 6.5. The ternary complex with a FA group had significantly higher mean fluorescence intensity and transfection efficiency than did the ternary complex without it. In addition, the transfection experiment in 293T cells preliminarily validated the targeting function of the FA group of the ternary complex. PMID- 28086102 TI - Fertilisers production from ashes after sewage sludge combustion - A strategy towards sustainable development. AB - Sustainable development and circular economy rules force the global fertilizer industry to develop new phosphorous recovery methods from alternative sources. In this paper a phosphorus recovery technology from Polish industrial Sewage Sludge Ashes was investigated (PolFerAsh - Polish Fertilizers form Ash). A wet method with the use of mineral acid and neutralization was proposed. Detailed characteristic of SSA from largest mono-combustion plans were given and compared to raw materials used on the market. The technological factors associated with such materials were discussed. The composition of the extracts was compared to typical industrial phosphoric acid and standard values characterizing suspension fertilizers. The most favorable conditions for selective precipitation of phosphorus compounds were revealed. The fertilizers obtained also meet EU regulations in the case of the newly discussed Cd content. The process was scaled up and a flow mass diagram was defined. PMID- 28086104 TI - Label-free quantitative proteome analysis of the surface-bound salivary pellicle. AB - The salivary pellicle, covering natural as well as restored tooth surfaces in the oral cavity as an immobilized protein-rich layer, acts as an important physico chemical and biological mediator at the tooth-saliva-interface. For the first time, the pellicle's proteome of individual volunteers were analyzed separately on three consecutive days and the relative protein abundance determined by a label-free quantitative nano-LC-MS/MS approach. A total of 72 major proteins were identified in the initial pellicles formed intraorally on dental ceramic specimens already after 3min with high inter-individual and inter-day consistency. In comparison, significant differences in protein abundance were evident between subjects, thus indicating unique individual pellicle profiles. Furthermore, the relative protein abundance in pellicles was compared to the proteome pattern in the corresponding saliva samples of the same individuals to provide first data on significantly enriched and depleted salivary proteins (p <0.05) within the surface-bound salivary pellicle. Our findings reveal the initial adsorption of salivary proteins at the solid-liquid interface to be a rapid, highly selective, and reproducible process leading to the immobilization of a broad range of protective proteins and enzymes on the substratum surface within a few minutes. This provides evidence that the pellicle layer might be physiologically functional even without further maturation. PMID- 28086105 TI - Structural diversity of lytic polysaccharide monooxygenases. AB - Lytic polysaccharide monooxygenases (LPMOs) catalyze the oxidative cleavage of glycosidic bonds and represent a promising resource for development of industrial enzyme cocktails for biomass processing. LPMOs show high sequence and modular diversity and are known, so far, to cleave insoluble substrates such as cellulose, chitin and starch, as well as hemicelluloses such as beta-glucan, xyloglucan and xylan. All LPMOs share a catalytic histidine brace motif to bind copper, but differ strongly when it comes to the nature and arrangement of residues on the substrate-binding surface. In recent years, the number of available LPMO structures has increased rapidly, including the first structure of an enzyme-substrate complex. The insights gained from these structures is reviewed below. PMID- 28086106 TI - Inverse design of high-Q wave filters in two-dimensional phononic crystals by topology optimization. AB - Topology optimization of a waveguide-cavity structure in phononic crystals for designing narrow band filters under the given operating frequencies is presented in this paper. We show that it is possible to obtain an ultra-high-Q filter by only optimizing the cavity topology without introducing any other coupling medium. The optimized cavity with highly symmetric resonance can be utilized as the multi-channel filter, raising filter and T-splitter. In addition, most optimized high-Q filters have the Fano resonances near the resonant frequencies. Furthermore, our filter optimization based on the waveguide and cavity, and our simple illustration of a computational approach to wave control in phononic crystals can be extended and applied to design other acoustic devices or even opto-mechanical devices. PMID- 28086107 TI - The adaptive computer-aided diagnosis system based on tumor sizes for the classification of breast tumors detected at screening ultrasound. AB - Screening ultrasound (US) is increasingly used as a supplement to mammography in women with dense breasts, and more than 80% of cancers detected by US alone are 1cm or smaller. An adaptive computer-aided diagnosis (CAD) system based on tumor size was proposed to classify breast tumors detected at screening US images using quantitative morphological and textural features. In the present study, a database containing 156 tumors (78 benign and 78 malignant) was separated into two subsets of different tumor sizes (<1cm and ?1cm) to explore the improvement in the performance of the CAD system. After adaptation, the accuracies, sensitivities, specificities and Az values of the CAD for the entire database increased from 73.1% (114/156), 73.1% (57/78), 73.1% (57/78), and 0.790 to 81.4% (127/156), 83.3% (65/78), 79.5% (62/78), and 0.852, respectively. In the data subset of tumors larger than 1cm, the performance improved from 66.2% (51/77), 68.3% (28/41), 63.9% (23/36), and 0.703 to 81.8% (63/77), 85.4% (35/41), 77.8% (28/36), and 0.855, respectively. The proposed CAD system can be helpful to classify breast tumors detected at screening US. PMID- 28086108 TI - Analysis of high frequency guided wave scattering at a fastener hole with a view to fatigue crack detection. AB - The scattering of high frequency guided ultrasonic waves by a fatigue crack at the side of a fastener hole has been studied. The guided wave pulse consists of the superposition of the two fundamental Lamb modes A0 and S0 above the cut-off frequencies of the higher modes. The scattered field was simulated using a three dimensional finite difference algorithm with a staggered, Cartesian grid for the limited area of interest around the hole and an analytical phase angle correction for the additional, variable propagation distance. Experimentally, the modes were selectively excited using a standard ultrasonic wedge transducer and measured using a laser interferometer, resulting in good spatial resolution. The scattered field was measured and simulated for an undamaged hole, a small, part-thickness quarter-elliptical fatigue crack, and a through-thickness fatigue crack. Good agreement was found and a significant influence of the fatigue cracks on the scattered field was observed. The complex difference of the scattered field due to additional scattered waves at the fatigue cracks of variable depth and length was evaluated. This allows for the prediction of high frequency guided wave sensitivity for fatigue crack detection at fastener holes, a significant maintenance problem for ageing aircraft. PMID- 28086109 TI - Temperature compensation of the SAW yarn tension sensor. AB - The objective of this research was to investigate the possibility of the temperature compensation for the surface acoustic wave (SAW) yarn tension sensor. The motivation for this work was prompted by the oscillation frequency of the SAW yarn tension sensor varying with the temperature. In this paper, we deduce the functional relationship between the temperature variation and the oscillation frequency shift caused by the temperature. This functional relationship and the temperature sensor are used to get the oscillation frequency shift caused by the temperature, so that we can use the oscillation frequency shift caused by the temperature to implement the temperature compensation of the SAW yarn tension sensor. In this paper, we also get the relative error of the temperature compensation. The theoretical and experimental results confirm that this temperature compensation method can implement the temperature compensation of the SAW yarn tension sensor. PMID- 28086111 TI - Wave propagation and absorption of sandwich beams containing interior dissipative multi-resonators. AB - In this study, a sandwich beam with periodic multiple dissipative resonators in the sandwich core material is investigated for broadband wave mitigation and/or absorption. An analytical approach based on the transfer matrix method and Bloch theorem is developed for both infinite and finite sandwich structures. Wave attenuation constants are theoretically obtained to examine the effects of various system parameters on the position, width and wave attenuation performance of the band gaps. The wave absorption coefficient of the sandwich beam is quantitatively studied to distinguish wave attenuation mechanisms caused by reflection and absorption. It is numerically demonstrated that a transient blast induced elastic wave with broadband frequencies can be almost completely mitigated or absorbed at a subwavelength scale. The results of this study could be used for developing new multifunctional composite materials to suppress impact induced and/or blast-induced elastic waves which may cause severe local damage to engineering structures. PMID- 28086110 TI - Annular phased array transducer for preclinical testing of anti-cancer drug efficacy on small animals. AB - A technique using pulsed High Intensity Focused Ultrasound (HIFU) to destroy deep seated solid tumors is a promising noninvasive therapeutic approach. A main purpose of this study was to design and test a HIFU transducer suitable for preclinical studies of efficacy of tested, anti-cancer drugs, activated by HIFU beams, in the treatment of a variety of solid tumors implanted to various organs of small animals at the depth of the order of 1-2cm under the skin. To allow focusing of the beam, generated by such transducer, within treated tissue at different depths, a spherical, 2-MHz, 29-mm diameter annular phased array transducer was designed and built. To prove its potential for preclinical studies on small animals, multiple thermal lesions were induced in a pork loin ex vivo by heating beams of the same: 6W, or 12W, or 18W acoustic power and 25mm, 30mm, and 35mm focal lengths. Time delay for each annulus was controlled electronically to provide beam focusing within tissue at the depths of 10mm, 15mm, and 20mm. The exposure time required to induce local necrosis was determined at different depths using thermocouples. Location and extent of thermal lesions determined from numerical simulations were compared with those measured using ultrasound and magnetic resonance imaging techniques and verified by a digital caliper after cutting the tested tissue samples. Quantitative analysis of the results showed that the location and extent of necrotic lesions on the magnetic resonance images are consistent with those predicted numerically and measured by caliper. The edges of lesions were clearly outlined although on ultrasound images they were fuzzy. This allows to conclude that the use of the transducer designed offers an effective noninvasive tool not only to induce local necrotic lesions within treated tissue without damaging the surrounding tissue structures but also to test various chemotherapeutics activated by the HIFU beams in preclinical studies on small animals. PMID- 28086112 TI - The Little Schmidy Pediatric Hospital Fall Risk Assessment Index: A diagnostic accuracy study. AB - BACKGROUND: Falls are among the most common potentially preventable adverse events. Current pediatric falls risk assessment methods have poor precision and accuracy. OBJECTIVE: To evaluate an inpatient pediatric fall risk assessment index, known as the Little Schmidy, and describe characteristics of pediatric falls. DESIGN: Retrospective case control and descriptive study. The dataset included 114 reported falls and 151,678 Little Schmidy scores documented in medical records during the 5-year study period (2007-2011). SETTING: Pediatric medical and surgical inpatient units of an academic medical center in the western United States. PARTICIPANTS: Pediatric hospital inpatients <25 years of age. METHODS: Nurses used the 5-item, 7-point Little Schmidy to assess fall risk each day and night shift throughout the patient's hospitalization. Conditional fixed effects logistic regressions were used to examine predictive relationships between Little Schmidy scores (at admission, highest prior to fall, and just prior to fall) and the patient's fall status (fell or not). The sensitivity and specificity of different cut-off scores were explored. Associations between Little Schmidy scores and patient and hospitalization factors were examined using multilevel mixed-effects logistic regression and multilevel mixed-effects ordinal logistic regression. RESULTS: Little Schmidy scores were significantly associated with pediatric falls (p<0.005). Maximal performance was achieved with a 4-item, 4 point, Little Schmidy index (LS4) using a cut-off score of 1 to indicate fall risk with sensitivity of 79% and specificity of 49%. Patients with an LS4 score >=1 were 4 times more likely to fall before the next assessment than patients with a score of 0. LS4 scores indicative of fall risk were associated with age >=5 years, neurological diagnosis, multiple hospitalizations, and night shift, but not with sex, length of hospital stay, or hospital unit. Of the 114 reported falls, 64% involved a male patient, nearly one third (32%) involved adolescents (13-17 years), most resulted in no (59%) or mild (36%) injury, and most (54%) were related to diagnosis or clinical characteristics. For 60% of the falls, fall precautions had been implemented prior to the fall. CONCLUSIONS: The revised 4 item Little Schmidy, the LS4, predicts pediatric falls when administered every day and night shift, but identifies most patients (65%) as being at risk for fall. Strategies for improving the accuracy and efficiency of the assessments are proposed. Further research is needed to develop more effective pediatric fall prevention strategies tailored to patient's age, diagnosis, and time of day. PMID- 28086113 TI - General combined model for the hydrodynamic behaviour of fixed and fluidised granular beds. AB - This work describes the derivation of a general mathematical model applicable to both fixed and fluidised granular beds, operating within the full hydrodynamic spectrum from viscous to inertial flows. The fundamental insight for the derivation of the model is that practical fluidised beds and fixed beds have similar hydrodynamic properties. The validity of the general model is demonstrated for fluid fractions up to 0.90. A crucial development in the general model is the replacement of hydraulic diameter, which has served as the size descriptor of flow paths in most fixed-bed models derived since the advent of the classic Blake-Kozeny equation. The new, replacement expression is based on the physical structure of the cross section of random porous beds. In addition, the general model contains a tortuosity factor, derived from the results of previous works involving computational fluid dynamics, to correct flow path length and fluid velocity. The model is constructed using regression analysis of experimental data from six previous major works and tested against previous models. PMID- 28086114 TI - Microbial source tracking in shellfish harvesting waters in the Gulf of Nicoya, Costa Rica. AB - Current microbial water quality monitoring is generally limited to culture-based measurements of fecal indicator bacteria (FIB). Given the many possible sources of fecal pollution within a watershed and extra-intestinal FIB reservoirs, it is important to determine source(s) of fecal pollution as a means to improve water quality and protect public health. The principal objective of this investigation was to characterize the microbial water quality of shellfish harvesting areas in the Gulf of Nicoya, Costa Rica during 2015. In order to achieve this objective, the specificity and sensitivity of 11 existing microbial source tracking (MST) PCR assays, associated with cows (BacCow), dogs (BacCan, DogBac), domestic wastewater (PMMoV), general avian (GFD), gulls (Gull2), horses (HorseBac, HoF), humans (HF183, HPyV), and pigs (PF), were evaluated using domestic wastewater and animal fecal samples collected from the region. The sensitivity of animal associated assays ranged from 13 to 100%, while assay specificity ranged from 38 to 100%. The specificity of pepper mild mottle virus (PMMoV) and human polyomavirus (HPyV) was 100% for domestic wastewater, as compared to 94% specificity of the HF183 Bacteroidales marker. PMMoV was identified as a useful domestic wastewater-associated marker, with concentrations as high as 1.1 * 105 copies/ml and 100% sensitivity and specificity. Monthly surface water samples collected from four shellfish harvesting areas were analyzed using culture-based methods for Escherichia coli as well as molecular methods for FIB and a suite of MST markers, which were selected for their specificity in the region. While culturable E. coli results suggested possible fecal pollution during the monitoring period, the absence of human/domestic wastewater-associated markers and low FIB concentrations determined using molecular methods indicated sufficient microbial water quality for shellfish harvesting. This is the first study to our knowledge to test the performance of MST markers in Costa Rica as well as in Central America. Given the lack of wastewater treatment and the presence of secondary sources of FIB, this study highlights the importance of an MST toolbox approach to characterize water quality in tropical regions. Furthermore, it confirms and extends the geographic range of PMMoV as an effective tool for monitoring domestic wastewater pollution. PMID- 28086115 TI - Voluntary intake of paracetamol-enriched drinking water and its influence on the success of embryo transfer in mice. AB - Embryo transfer (ET) in mice is a key technique in biomedical research, and is carried out mostly via surgery by transferring founder embryos into pseudo pregnant recipient females. To cover post-operative analgesic requirements in surrogate mothers, oral self-administration of painkillers has several advantages, but its effectiveness has also been criticized as voluntary ingestion of the drug can be uncertain. Additionally, concerns about potential negative side effects of analgesics on embryo viability and development have been raised. In this regard, we investigated the impact of orally administered analgesia by comparing the outcome of ET with and without paracetamol in the drinking water (3.5mg/ml) of surrogate mothers. Water intake increased significantly when paracetamol, as a sweet-tasting formulation (children's syrup), was added to the drinking water. Measurements of paracetamol concentrations in blood serum confirmed reasonable drug uptake. Success rate of ETs and the body weight of newborn offspring were not different whether paracetamol was administered for two days after surgery or not. In conclusion, paracetamol in drinking water was consumed voluntarily in substantial doses, without detectable side-effects, by freshly operated surrogate mothers, and can therefore be recommended as a feasible method for providing analgesic treatment for surgical ET in mice. PMID- 28086116 TI - Relaxometric property of organosilica nanoparticles internally functionalized with iron oxide and fluorescent dye for multimodal imaging. AB - Multimodal imaging using novel multifunctional nanoparticles provides a new approach for the biomedical field. Thiol-organosilica nanoparticles containing iron oxide magnetic nanoparticles (MNPs) as the core and rhodamine B in the thiol organosilica layer (thiol OS-MNP/Rho) were synthesized in a one-pot process. The thiol OS-MNP/Rho showed enhanced magnetic resonance imaging (MRI) contrast and high fluorescence intensity. The relaxometry of thiol OS-MNP/Rho revealed a novel coating effect of the organosilica layer to the MNPs. The organosilica layer shortened the T2 relaxation time but not the T1 relaxation time of the MNPs. We injected thiol-OS-MNP/Rho into normal mice intravenously. Injected mice revealed an alteration of the liver contrast in the MRI and a fluorescent pattern based on the liver histological structure at the level between macroscopic and microscopic fluorescent imaging (mesoscopic FI). In addition, the labeled macrophages were observed at the single cell level histologically. We demonstrated a new approach to evaluate the liver at the macroscopic, microscopic level as well as the mesoscopic level using multimodal imaging. PMID- 28086117 TI - Lithium ion-imprinted polymers with hydrophilic PHEMA polymer brushes: The role of grafting density in anti-interference and anti-blockage in wastewater. AB - Hydrophilic poly(2-hydroxyethyl methacrylate) (PHEMA) brushes were modified onto the surface of ion-imprinted polymers (IIPs) via addition-fragmentation chain transfer (RAFT) polymerization. Four different grafting densities (1.43, 1.31, 1.17 and 1.06chains/nm2) of IIPs were obtained, revealed by analysis using gel permeation chromatograph (GPC) and Brunauer-Emmett-Teller (BET). All the grafted IIPs had good anti-interference properties compared to the ungrafted IIPs, although the adsorption capacity of the ungrafted IIPs was higher than that of grafted IIPs in pure water. Among them, the grafted IIP3, with a grafting density of beta=1.17chains/nm2, exhibited superior anti-interference ability in silica and polymer flocculant simulated wastewater; moreover, it remained steady after 10 adsorption-desorption cycles. SEM-EDX and XPS data revealed anti-interference and anti-blockage mechanisms in which hydrophilic PHEMA brushes could effectively adhere to fine particles and flocculants through Van der Waals force interactions, which make the imprinted cavities well protected in a complex wastewater environment. Moreover, these grafted IIPs exhibit similar adsorption rate constants that are approximately 2 times greater than those of ungrafted IIPs, indicating that the PHEMA brushes increased the accessibility to Li(I) due to hydrophilic modification. PMID- 28086119 TI - The decisive effect of interface states on the photocatalytic activity of the silver(I) oxide/titanium dioxide heterojunction. AB - A one-step hydrothermal method was adopted to synthesize the Ag2O/TiO2 nanoheterojunction. Its photocatalytic activity was evaluated by degrading methylene blue (MB) aqueous solution under UV and visible light. The MB degradation results showed that the Ag2O/TiO2 nanoheterojunction enhances the photocatalytic activity under UV irradiation rather than visible light. X-ray photoelectron spectroscopy (XPS) was performed to detect the electronic structure at the interface of Ag2O and TiO2. The XPS results confirmed that the electronic band structure of the nanoheterojunction was determined by the interface states between the Ag2O and TiO2 interface. Thus, the photocatalytic enhancement mechanism can be ascribed to the creation of an additional potential barrier in the conduction band between Ag2O and TiO2, which facilitates the transport of holes from TiO2 to Ag2O but inhibits the flow of electrons in the reverse direction unless sufficient potential energy is provided to overcome the additional barrier. Our results have provided a new insight on the role of interface states between the p-n nanojunction in the photocatalytic activity. PMID- 28086118 TI - Advanced surface chemical analysis of continuously manufactured drug loaded composite pellets. AB - The aim of the present study was to develop and characterise polymeric composite pellets by means of continuous melt extrusion techniques. Powder blends of a steroid hormone (SH) as a model drug and either ethyl cellulose (EC N10 and EC P7 grades) or hydroxypropyl methylcellulose (HPMC AS grade) as polymeric carrier were extruded using a Pharma 11mm twin screw extruder in a continuous mode of operation to manufacture extruded composite pellets of 1mm length. Molecular modelling study using commercial Gaussian 09 software outlined a possible drug polymer interaction in the molecular level to develop solid dispersions of the drug in the pellets. Solid-state analysis conducted via a differential scanning calorimetry (DSC), hot stage microscopy (HSM) and X-ray powder diffraction (XRPD) analyses revealed the amorphous state of the drug in the polymer matrices. Surface analysis using SEM/energy dispersive X-ray (EDX) of the produced pellets arguably showed a homogenous distribution of the C and O atoms in the pellet matrices. Moreover, advanced chemical surface analysis conducted via atomic force microscopy (AFM) showed a homogenous phase system having the drug molecule dispersed onto the amorphous matrices while Raman mapping confirmed the homogenous single-phase drug distribution in the manufactured composite pellets. Such composite pellets are expected to deliver multidisciplinary applications in drug delivery and medical sciences by e.g. modifying drug solubility/dissolutions or stabilizing the unstable drug (e.g. hormone, protein) in the composite network. PMID- 28086120 TI - Photochemoprotective effects against UVA and UVB irradiation and photosafety assessment of Litchi chinensis leaves extract. AB - Actually, there has been an increase in the use of natural products as skin photoprotective agents. In this way, the aim of present study was to investigate the L. chinensis leaves extract photochemoprotection potential and photosafety using in vitro methods. The extract cytotoxicity, cytoprotection and photochemoprotection against UVA and UVB radiation were assayed in L929 cells. The DNA damage was evaluated by comet assay. DCFH-DA, SOD, CAT and GSH assays were employed to verify the oxidative stress. We also determined the spectrophotometric Solar Protection Factor (SPF) of the extract. The photosafety was evaluated in red blood cells (RBC). In addition, the HET-CAM and agarose overlay tests were employed to evaluate the irritant potential. The results obtained show that extract is not cytotoxic and present cytoprotective activity against H2O2 and is able to protect the cells against DNA damage induced by UVA and UVB radiation. The extract was able to reduce the ROS production. The SPF obtained was 18.9 at 1mg/mL. We demonstrate that L. chinensis extract is photosafe and protect RBCs against oxidative damage, and did not induce irritation. Data herein obtained pointed out the potential of L. chinensis extract for photochemoprotection against UVA/UVB radiation and its damaging effects on human skin. PMID- 28086121 TI - Photodynamic therapy using chloro-aluminum phthalocyanine decreases inflammatory response in an experimental rat periodontal disease model. AB - BACKGROUND AND OBJECTIVE: Emerging evidence suggests that photodynamic therapy (PDT) can exhibit immunomodulatory activity. The purpose of the present study was to analyse cytokine profiles after application of PDT in gingival tissues of rats with ligature-induced periodontal disease (PD). STUDY DESIGN/MATERIAL AND METHODS: Periodontal disease was induced through the introduction of a cotton thread around the first left mandibular molar, while the right side molars did not receive ligatures. After 7days of PD evolution, ligatures were removed from the left side, and the animals were randomically divided into the following treatment groups: I, rats without treatment; II, rats received chloro-aluminum phthalocyanine (AlClPc); III, rats received low-level laser alone; and IV, rats received AlClPc associated with low-level laser (PDT). The animals were killed 7days after the treatments, and the mandibles were histologically processed to assess morphological and immunohistochemical profile, while gingival tissues were removed for quantification of tumor necrosis factor (TNF)-alpha, interleukin (IL )1beta and IL-10 expression (by ELISA). RESULTS: Histomorphological analysis of periodontal tissues demonstrated that PDT-treated animals show tissue necrosis, as well as lower TNF- alpha expression, compared to ligatured animals treated with AlClPc alone. CONCLUSIONS: It was concluded that PDT using AlClPc entrapped in a lipid nanoemulsion may be useful in therapies, because of immunomodulatory effects that decreased the inflammatory response and cause tissue destruction. PMID- 28086122 TI - Increasing the physical size and nucleation status of human pluripotent stem cell derived ventricular cardiomyocytes by cell fusion. AB - Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) provide an unlimited source of donor cells for potential cardiac regenerative therapies. However, hPSC-CMs are immature. For instance, hPSC-CMs are only 1/10 of the physical size of their adult counterparts; the majority are mono- rather than bi- or multi-nucleated, which is an evolutionary adaptive feature in metabolically active cells such as adult CMs. Here, we attempted to increase the physical size and nucleation status of hPSC-derived ventricular (V) cardiomyocytes (hPSC-VCMs) using chemically-induced cell fusion, and examined the subsequent functional effects. Polyethylene glycol (PEG) was employed to fuse a 1:1 mixture of lentiviral vectors LV-MLC2v-GFP- or -tdTomato-labeled hPSC-VCMs, such that hPSC VCMs fused syncytia (FS) were identified as doubly GFP+/tdTomato+ multi-nucleated cells. These microscopically-identified FS were doubled in size as gauged by their capacitance when compared to the control mononucleated hPSC-VCMs using patch-clamp analysis. Reduced automaticity or action potential (AP) firing rate and moderately prolonged AP duration were observed in FS from day 6 post-fusion induction. However, Ca2+ handling, mitochondrial biogenesis and the extent of apoptosis were not significantly altered. We conclude that larger, multi nucleated hPSC-VCMs FS can be created by chemically-induced cell fusion but global maturation requires additional triggering cues. PMID- 28086123 TI - Fabrication strategies, sensing modes and analytical applications of ratiometric electrochemical biosensors. AB - Previously developed electrochemical biosensors with single-electric signal output are probably affected by intrinsic and extrinsic factors. In contrast, the ratiometric electrochemical biosensors (RECBSs) with dual-electric signal outputs have an intrinsic built-in correction to the effects from system or background electric signals, and therefore exhibit a significant potential to improve the accuracy and sensitivity in electrochemical sensing applications. In this review, we systematically summarize the fabrication strategies, sensing modes and analytical applications of RECBSs. First, the different fabrication strategies of RECBSs were introduced, referring to the analytes-induced single- and dual dependent electrochemical signal strategies for RECBSs. Second, the different sensing modes of RECBSs were illustrated, such as differential pulse voltammetry, square wave voltammetry, cyclic voltammetry, alternating current voltammetry, electrochemiluminescence, and so forth. Third, the analytical applications of RECBSs were discussed based on the types of target analytes. Finally, the forthcoming development and future prospects in the research field of RECBSs were also highlighted. PMID- 28086124 TI - An ultrasensitive aptasensor for Ochratoxin A using hexagonal core/shell upconversion nanoparticles as luminophores. AB - We developed an ultrasensitive luminescence resonance energy transfer (LRET) aptasensor for Ochratoxin A (OTA) detection, using core/shell upconversion nanoparticles (CS-UCNPs) as luminophores. The OTA aptamer was tagged to CS-UCNPs as energy donor and graphene oxide (GO) acted as energy acceptor. The pi-pi stacking interaction between the aptamer and GO brought CS-UCNPs and GO in close proximity hence initiated the LRET process resulting in quenching of CS-UCNPs luminescence. A linear calibration was obtained between the luminescence intensity and the logarithm of OTA concentration in the range from 0.001ngmL-1 to 250ngmL-1, with a detection limit of 0.001ngmL-1. The aptasensor showed good specificity towards OTA in beer samples. The ultrahigh sensitivity and pronounced robustness in beer sample matrix suggested promising prospect of the aptasensor inpractical applications. PMID- 28086126 TI - Reelin (RELN) DNA methylation in the peripheral blood of schizophrenia. AB - The epigenetic changes of RELN that are involved in the development of dopaminergic neurons may fit the developmental theory of schizophrenia. However, evidence regarding the association of RELN DNA methylation with schizophrenia is far from sufficient, as studies have only been conducted on a few limited brain samples. As DNA methylation in the peripheral blood may mirror the changes taking place in the brain, the use of peripheral blood for a DNA methylation study in schizophrenia is feasible due to the scarcity of brain samples. Therefore, the aim of our study was to examine the relationship of DNA methylation levels of RELN promoters with schizophrenia using genomic DNA derived from the peripheral blood of patients with the disorder. The case control studies consisted of 110 schizophrenia participants and 122 healthy controls who had been recruited from the same district. After bisufhite conversion, the methylation levels of the DNA samples were calculated based on their differences of the Cq values assayed using the highly sensitive real-time MethyLight TaqMan(r) procedure. A significantly higher level of methylation of the RELN promoter was found in patients with schizophrenia compared to controls (p = 0.005) and also in males compared with females (p = 0.004). Subsequently, the RELN expression of the methylated group was 25 fold less than that of the non-methylated group. Based upon the assumption of parallel methylation changes in the brain and peripheral blood, we concluded that RELN DNA methylation might contribute to the pathogenesis of schizophrenia. However, the definite effects of methylation on RELN function during development and also in adult life still require further elaboration. PMID- 28086125 TI - Highly sensitive ratiometric detection of heparin and its oversulfated chondroitin sulfate contaminant by fluorescent peptidyl probe. AB - The selective and sensitive detection of heparin, an anticoagulant in clinics as well as its contaminant oversulfated chondroitin sulfate (OSCS) is of great importance. We first reported a ratiometric sensing method for heparin as well as OSCS contaminants in heparin using a fluorescent peptidyl probe (Pep1, pyrene GSRKR) and heparin-digestive enzyme. Pep1 exhibited a highly sensitive ratiometric response to nanomolar concentration of heparin in aqueous solution over a wide pH range (2~11) and showed highly selective ratiometric response to heparin among biological competitors such as hyaluronic acid and chondroitin sulfate. Pep1 showed a linear ratiometric response to nanomolar concentrations of heparin in aqueous solutions and in human serum samples. The detection limit for heparin was calculated to be 2.46nM (R2=0.99) in aqueous solutions, 2.98nM (R2=0.98) in 1% serum samples, and 3.43nM (R2=0.99) in 5% serum samples. Pep1 was applied to detect the contaminated OSCS in heparin with heparinase I, II, and III, respectively. The ratiometric sensing method using Pep1 and heparinase II was highly sensitive, fast, and efficient for the detection of OSCS contaminant in heparin. Pep1 with heparinase II could detect as low as 0.0001% (w/w) of OSCS in heparin by a ratiometric response. PMID- 28086127 TI - Benefits and harms of low and high second-generation antipsychotics doses for bipolar depression: A meta-analysis. AB - The aim of this systematic review and meta-analysis was testing whether low versus high doses of second-generation antipsychotics (SGAs) are associated with different clinical benefits and harms for the acute treatment of bipolar depression. We included clinical trials comparing different doses of the same SGA monotherapy for bipolar depression. SGAs defined daily doses were used to define high and low doses. Clinical benefit outcomes included improvement, response and remission rates on Montgomery-Asberg Depression Rating Scale. Clinical harm outcomes included all-cause and adverse effect-related discontinuation rates. Data from seven clinical trials testing high and low doses of quetiapine (4 trials), cariprazine, lurasidone, and ziprasidone (1 trial each), showed no differences between lower and higher doses of selected SGAs on improvement, response and remission rates, without significant heterogeneity across studies (I2 = 0%). Subgroup analyses based on single SGAs confirmed the clinical benefit comparability between low and high doses. However, clinical harm favorable differences for low doses on all-cause (p = 0.01) and adverse effects-related discontinuation (p = 0.001) were found. In sum, this meta-analysis showed that, although no benefits were found in terms of symptoms improvement, response and remission rates, there were clear disadvantages in prescribing higher rather than lower doses of selected SGAs. The uniform methodological strength of studies increases confidence in our findings. These data need to be integrated with individual patient characteristics (e.g., clinical urgency and adverse effect sensitivity) to optimize management of acute bipolar depression. PMID- 28086128 TI - Widespread reduction in sleep spindle activity in socially anxious children and adolescents. AB - Social anxiety disorder (SAD) is one of the most prevalent psychiatric diseases typically emerging during childhood and adolescence. Biological vulnerabilities such as a protracted maturation of prefrontal cortex functioning together with heightened reactivity of the limbic system leading to increased emotional reactivity are discussed as factors contributing to the emergence and maintenance of SAD. Sleep slow wave activity (SWA, 0.75-4.5 Hz) and sleep spindle activity (9 16 Hz) reflect processes of brain maturation and emotion regulation. We used high density electroencephalography to characterize sleep SWA and spindle activity and their relationship to emotional reactivity in children and adolescents suffering from SAD and healthy controls (HC). Subjectively rated arousal was assessed using an emotional picture-word association task. SWA did not differ between socially anxious and healthy participants. We found a widespread reduction in fast spindle activity (13-16 Hz) in SAD patients compared to HC. SAD patients rated negative stimuli to be more arousing and these arousal ratings were negatively correlated with fast spindle activity. These results suggest electrophysiological alterations that are evident at an early stage of psychopathology and that are closely linked to one core symptom of anxiety disorders such as increased emotional reactivity. The role of disturbed GABAergic neurotransmission is discussed as an underlying factor. PMID- 28086130 TI - Effects of environmental pollutants on gut microbiota. AB - Environmental pollutants have become an increasingly common health hazard in the last several decades. Recently, a number of studies have demonstrated the profound relationship between gut microbiota and our health. Gut microbiota are very sensitive to drugs, diet, and even environmental pollutants. In this review, we discuss the possible effects of environmental pollutants including antibiotics, heavy metals, persistent organic pollutants, pesticides, nanomaterials, and food additives on gut microbiota and their subsequent effects on health. We emphasize that gut microbiota are also essential for the toxicity evaluation of environmental pollution. In the future, more studies should focus on the relationship between environmental pollution, gut microbiota, and human health. PMID- 28086131 TI - Export of aquatic productivity, including highly unsaturated fatty acids, to terrestrial ecosystems via Odonata. AB - Based on 31-year field study of the abundance and biomass of 18 species of odonates in the Barabinsk Forest-Steppe (Western Siberia, Russia), we quantified the contribution of odonates to the export of aquatic productivity to surrounding terrestrial landscape. Emergence varied from 0.8 to 4.9g of wet biomass per m2 of land area per year. Average export of organic carbon was estimated to be 0.30g.m 2.year-1, which is comparable with the average production of herbivorous terrestrial insects in temperate grasslands. Moreover, in contrast to terrestrial insects, emerging odonates contained high quantities of highly unsaturated fatty acids (HUFA), namely eicosapentaenoic acid (20:5n-3, EPA), and docosahexaenoic acid (22:6n-3, DHA), which are known to be essential for many terrestrial animals, especially for birds. The export of EPA+DHA by odonates was found to be 1.92-11.76mg.m-2.year-1, which is equal to an average general estimation of the export of HUFA by emerging aquatic insects. Therefore, odonates appeared to be a quantitatively and qualitatively important conduit of aquatic productivity to forest-steppe ecosystem. PMID- 28086129 TI - Hyper-modulation of brain networks by the amygdala among women with Borderline Personality Disorder: Network signatures of affective interference during cognitive processing. AB - Emotion dysregulation is a core characteristic of patients with Borderline Personality Disorder (BPD), and is often attributed to an imbalance in fronto limbic network function. Hyperarousal of amygdala, especially in response to negative affective stimuli, results in affective interference with cognitive processing of executive functions. Clinical consequences include the impulsive aggression, suicidal and self-injurious behaviors which characterize BPD. Dysfunctional interactions between amygdala and its network targets have not been well characterized during cognitive task performance. Using psychophysiological interaction analysis (PPI), we mapped network profiles of amygdala interaction with key regulatory regions during a Go No-Go task, modified to use negative, positive and neutral Ekman faces as targets. Fifty-six female subjects, 31 BPD and 25 healthy controls (HC), completed the affectively valenced Go No-Go task during fMRI scanning. In the negative affective condition, the amygdala exerted greater modulation of its targets in BPD compared to HC subjects in Rt. OFC, Rt. dACC, Rt. Parietal cortex, Rt. Basal Ganglia, and Rt. dlPFC. Across the spectrum of affective contrasts, hypermodulation in BPD subjects observed the following ordering: Negative > Neutral > Positive contrast. The amygdala seed exerted modulatory effects on specific target regions important in processing response inhibition and motor impulsiveness. The vulnerability of BPD subjects to affective interference with impulse control may be due to specific network dysfunction related to amygdala hyper-arousal and its effects on prefrontal regulatory regions such as the OFC and dACC. PMID- 28086132 TI - Characterization of ferruginous cements related with weathering of slag in a temperate anthropogenic beachrock. AB - This work outlines a temperate latitude beachrock occurrence, which represents the legacy of heavy anthropogenic environmental disturbance. The units contain high amounts of slag and iron-rich wastes derived from metallurgical activities that attest the impact of the past industrial development on such coastal systems. The exposition of the anthropogenic wastes to weathering processes, such as the influence of marine aerosols and the chemical attack of acid gases like the SOx coming from the nearby urban-industrial atmosphere, gave rise to the formation of early diagenetic ferruginous cements. A new analytical methodology based on the combination of micro-Raman spectroscopy (MRS), Raman chemical imaging, SEM-EDS and the Structural and Chemical Analyzer (SCA, an emerging system that hyphenates micro-Raman and SEM-EDS), was applied for the first time to characterize the ferruginous cements. The MRS analyses revealed Fe2+/Fe3+ oxides and oxyhydroxides, CaCO3 polymorphs and less frequently silicates. The Fe mineral species detected were hydrated goethite, hematite, magnetite, magnesioferrite, lepidocrocite and goethite. Complementary Raman imaging, SEM-EDS and SCA analyses unraveled the preferential distribution of hydrated goethite. The identified iron mineral phases are weathering sub-products of hematite commonly derived from atmospheric/aqueous leaching processes triggered by the chemical attack of the acid gases. EDS showed the existence of other elements such as Si, Mg, Cl, Na, Al, K and sporadically S that indicated the importance of permeability, atmospheric deposition and the acid attack. Additionally, calcite and gypsum minerals also evidenced the action of meteoric waters, dry deposition processes or the attack of SOx acid gases. The presence of such compounds is modifying the cement stratigraphy and suggests that the dissolution of carbonates is currently taking place. Those facts influence the erosive susceptibility and the release of the anthropogenic materials trapped originally in the beachrocks, which could act as potential secondary sources of contaminants to the coastal environment. PMID- 28086133 TI - Autobiographical episodic memory-based training for the treatment of mood, anxiety and stress-related disorders: A systematic review and meta-analysis. AB - We review evidence for training programmes that manipulate autobiographical processing in order to treat mood, anxiety, and stress-related disorders, using the GRADE criteria to judge evidence quality. We also position the current status of this research within the UK Medical Research Council's (2000, 2008) framework for the development of novel interventions. A literature search according to PRISMA guidelines identified 15 studies that compared an autobiographical episodic memory-based training (AET) programme to a control condition, in samples with a clinician-derived diagnosis. Identified AET programmes included Memory Specificity Training (Raes, Williams, & Hermans, 2009), concreteness training (Watkins, Baeyens, & Read, 2009), Competitive Memory Training (Korrelboom, van der Weele, Gjaltema, & Hoogstraten, 2009), imagery-based training of future autobiographical episodes (Blackwell & Holmes, 2010), and life review/reminiscence therapy (Arean et al., 1993). Cohen's d was calculated for between-group differences in symptom change from pre- to post-intervention and to follow-up. We also completed meta-analyses for programmes evaluated across multiple studies, and for the overall effect of AET as a treatment approach. Results demonstrated promising evidence for AET in the treatment of depression (d=0.32), however effect sizes varied substantially (from -0.18 to 1.91) across the different training protocols. Currently, research on AET for the treatment of anxiety and stress-related disorders is not yet at a stage to draw firm conclusions regarding efficacy as there were only a very small number of studies which met inclusion criteria. AET offers a potential avenue through which low intensity treatment for affective disturbance might be offered. PMID- 28086134 TI - Tithonia diversifolia saponin-blood lipid interaction and its influence on immune system of normal wistar rats. AB - This study investigated the effect of saponins (20-100mg/kg) from Tithonia diversifolia leaf (STD) on the liver, kidney, heart, lipid profile and hematological parameters of normal rats. The results showed that STD (20 100mg/kg) though caused a slight increase in the liver, heart and kidney activity of ALT, AST, ALP and GGT (p<0.05), did not result in corresponding increase in the serum level of these enzymes. A significant reduction in the level of triglycerides, LDL and cholesterol, creatinine, urea, LDH, PCV and hemoglobin were observed with a concomitant increase in HDL, white blood cell and lymphocyte. These study demonstrated the role of STD in enhancing immune response and in reducing cholesterol and triglycerides in normal rats at studied dosages. PMID- 28086135 TI - Epigenetic modifications and epigenetic based medication implementations of autoimmune diseases. AB - Recent genome-wide association studies have documented a number of genetic variants to explain mechanisms underlying autoimmune diseases. However, the precise etiology of autoimmune diseases remains largely unknown. Epigenetic mechanisms like alterations in the post-translational modification of histones and DNA methylation may potentially cause a breakdown of immune tolerance and the perpetuation of autoreactive responses. Recently, several studies both in experimental models and clinical settings proposed that the epigenome may hold the key to a better understanding of autoimmunity initiation and perpetuation. More specifically, data support the impact of epigenetic changes in autoimmune diseases, in some cases based on mechanistical observations. Epigenetic therapy already being employed in hematopoietic malignancies may also be associated with beneficial effects in autoimmune diseases. In this review, we will discuss on what we know and expect about the treatment of autoimmune disease based on epigenetic aberrations. PMID- 28086136 TI - MiR-451 suppresses proliferation, migration and promotes apoptosis of the human osteosarcoma by targeting macrophage migration inhibitory factor. AB - Previous studies have shown that MiR-451 plays an important role in human osteosarcoma carcinogenesis, but the underlying mechanism by which MiR-451 affects the osteosarcoma has not been fully understood. This study intends to uncover the mechanism by which MiR-451 functions as a tumor suppressor. The expression of MiR-451 in osteosarcoma tissues and osteosarcoma cell lines was monitored by real-time PCR. The proliferation ability was examined by MTT and cell cycle assay. The migration and apoptosis of cells were monitored by migration assay and flow cytometry, respectively. Moreover, the angiogenesis of HUVEC cells transfected with MiR-451 mimics was examined by tube formation assay. The effect of MiR-451 on MIF was determined by luciferase assays and Western blot assay. The results showed that MiR-451 expression level was significantly reduced in the osteosarcoma compared with normal bone tissues. Overexpression of MiR-451 significantly attenuated the proliferation and migration, and induced the apoptosis of osteosarcoma cells. Furthermore, the angiogenesis of HUVEC cells transfected with MiR-451 mimics was assayed and the decreased angiogenic ability was detected compared to the controls. Finally, we demonstrated that MiR-451 overexpression inhibited the malignant behavior of osteosarcoma by downregulating MIF. These findings suggest that MiR-451 may act as a tumor suppressor in osteosarcoma. MiR-451 inhibited cell proliferation, migration and angiogenesis and promoted apoptosis of human osteosarcoma cells, at least partially, by inhibiting the expression of MIF. MiR-451/MIF may be a novel therapeutic target in treatment of osteosarcoma. PMID- 28086137 TI - Comparative study of therapeutic response to baclofen vs tolperisone in spasticity. AB - BACKGROUND: Spasticity from the upper motor neuron syndrome can result from a variety of conditions affecting the cortex or spinal cord. Some of the more common conditions associated with spasticity include spinal cord injury, cerebral palsy, and post-stroke syndrome. In this study we compared the efficacy and safety of baclofen vs tolperisone in spasticity. One hundred fifty patients with cerebral palsy or post stroke or spinal cord injury associated spasticity were enrolled in present study. Group I comprised of Seventy-five patients receiving baclofen and group II comprised of 75 patients receiving tolperisone. For efficacy measurement 4 evaluation methods were used, 1) Modified Ashworth Scale for muscle tone, 2) Medical research council scale for muscle strength and 3) Barthel Index for functional outcome 4) Coefficient of efficacy. In efficacy evaluation, both groups showed significant improvement in muscle tone, muscle strength and functional outcome at week 6 (Group I, 1.55+/-0.053, 2.79+0.032, 59.31+/-1.32; Group II, 1.57+/-0.053, 3.04+/-0.032, 73+/-1.32 respectively). In between the group analysis, there was no significant difference in muscle tone improvement in both the groups after 6 weeks (Group I, 1.055+/-0.053 vs Group II, 1.57+/-0.053, p>0.05). Group II showed non-significant but greater improvement in muscle strength (Week 6; Group I, 2.79+/-0.032 vs Group II, 3.04+/-0.032, p>0.07). Improvement in functional outcomes was greater in group II as compared to group I (Group I, 59.31+/-1.32 vs Group II, 73+/-1.32, p<0.05). Overall efficacy coefficient was greater for group II (3.6) as compared to group I (2.3). Baclofen showed more side effects compared to tolperisone in, asthenia being the most frequent. Tolperisone offers greater improvement in activities of daily living compared to baclofen. Tolperisone is more tolerable drug as compared to baclofen. PMID- 28086138 TI - Hookah tobacco smoking in a large urban sample of adult cigarette smokers: Links with alcohol and poly-tobacco use. AB - Hookah tobacco smoking (HTS) has been increasing, particularly among young adults and has similar health effects compared to cigarette smoking. The link between HTS and poly-tobacco use is well documented, but fewer show an association between HTS and alcohol use. It is essential to identify factors that increase the risk for or addictiveness and consequences of HTS, given its growing prevalence. This study examined whether the association between HTS and poly tobacco use differed as a function of age and alcohol consumption within in a sample of 1223 adult cigarette smokers. Approximately 20% of participants reported HTS. Compared to non-users, hookah users were more likely to be male, highly educated, and to report drug and alcohol use, binge drinking, and poly tobacco use but were less likely to be heavy smokers (>=10 cigarettes per day). Regression analyses predicting number of tobacco products used (excluding cigarettes and HTS) indicated a three-way interaction of HTS, frequency of alcohol use, and age such that the association between HTS and number of tobacco products used was strongest for younger respondents who consumed alcohol more frequently. As observed in previous studies, alcohol is an important risk factor in the relationship between HTS and poly-tobacco use, particularly among younger cigarette smokers. The links between alcohol, HTS, and poly-tobacco use should be considered when developing HTS education and prevention materials directed toward younger cigarette smokers. Findings provide information relevant to FDA's interest in the addiction potential of HTS and its link to poly-tobacco use. PMID- 28086139 TI - Effects of a wood-based biochar on the leaching of pesticides chlorpyrifos, diuron, glyphosate and MCPA. AB - We studied the ability of a wood-based biochar to reduce the leaching of the pesticides chlorpyrifos, diuron, glyphosate and MCPA in a sand column test system. In addition, time-dependent adsorption of the pesticides to the biochar and to the sand used in the columns was determined. The sorption kinetics was shown to be controlled by the log Kow-values of the pesticides and sorption rates varied in the order: chlorpyrifos (log Kow = 4.7) > diuron (log Kow = 2.87) > MCPA (log Kow = -0.8) > glyphosate (log Kow = -3.2). Glyphosate sorbed very weakly to the biochar but strongly to the sand. Biochar was most effective at retaining the pesticides if applied as a distinct layer rather than mixed with the sand. Leaching of diuron and MCPA was reduced by biochar application, and the retention was linearly related to the thickness of the biochar layers. However, leaching of chlorpyrifos and glyphosate was not affected by biochar addition. Leaching was low for all pesticides when the pesticides were added directly to biochar that was then added to the column. Together, our results suggest that a viable strategy for using biochar as a means to mitigate leaching of pesticides may be to use it as an adsorptive layer directly on or close to the soil surface. This would be especially useful in areas where pesticides are routinely handled and potentially spilled. PMID- 28086140 TI - An update on synthetic dyes adsorption onto clay based minerals: A state-of-art review. AB - Dyes are growing to be a problematic class of pollutants to the environment. The disposal of dyes in water resources has bad aesthetic and health effects, hence the need to remove them from the environment. The need for treatment methods that are effective and low in price is rising hence a lot of research interest is being diverted towards adsorbents that are cheap, preferable naturally occurring materials like clays. In most reported dye adsorption studies, limited information on the relationship between characterization results with adsorbent performance on dye removal has been given. This review article seeks to report on the link between the adsorption characteristics of the clays and their adsorption capacities and to gather information on the modifications done on clays to improve their adsorption capacities. A critical analysis of the different mechanisms involved during the decolouration process and their application for dye removal has been discussed in detail in this up-to-date review. From a wide range of consulted literature review, it is evident that some clays have appreciable adsorption capacities on top of being widely available. It was also noted that several parameters like contact time, dosage, concentration, temperature and pH affect the removal of dyes. Furthermore, the application of clay minerals for decolourising water represents economic viable and locally available materials that can be used substantially for pollution control and management. Conclusions were also drawn and suggestions for future research perspectives are proposed. PMID- 28086141 TI - Effects of compound chemical activators on the hydration of low-carbon ferrochrome slag-based composite cement. AB - Low-carbon ferrochrome slag (LCFS), a by-product of the ferrochrome alloy industry, has potential for use as a cementitious material due to its pozzolanic characteristic. The objective of the present study was to determine the optimum compound chemical activators for LCFS-based composite cement using an orthogonal test, in which 7 d and 28 d compressive strengths were used as the evaluating indices. The influences of compound chemical activators on the hydration of a composite cement mix were investigated using X-ray diffraction (XRD), scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM/EDS) and thermogravimetry-differential scanning calorimetry (TG-DSC). The optimum activator to activate the composite cement was a compound of NaCl (NC) at a dosage of 0.6%, Na2SO4 (NS) at a dosage of 1.2%, NaF (NF) at a dosage of 0.6% and Al2(SO4)3 (AS) at a dosage of 0.9% or 0.7%. The compressive strengths of the optimum composite cement mix at ages of 3, 28 and 180 d increased by 50.1%, 22.4% and 16.5%, respectively. More hydration products including ettringite and calcium silicate hydrate were formed at an early age of hydration. The compound chemical activators effectively activated the ferrochrome slag (FS), blast-furnace slag (BFS) and fly ash (FA) in the composite cement. PMID- 28086143 TI - Doing for others: Youth's contributing behaviors and psychological engagement in youth-adult partnerships. AB - Youth contributions to others (e.g., volunteering) have been connected to indicators of successful development, including self-esteem, optimism, social support, and identity development. Youth-adult partnerships, which involve youth and adults working together towards a shared goal in activity settings, such as youth-serving agencies or recreation organizations, provide a unique opportunity for examining youth contributions. We examined associations between measures of youth's participation in youth-adult partnerships (psychological engagement and degree of partnering) in activity settings and youth contributing behaviors, in two Canadian samples: (a) community-involved youth (N = 153, mean age = 17.1 years, 65% female) and (b) undergraduates (N = 128, mean age = 20.1 years, 92.2% female). We found that degree of partnering and psychological engagement were related to each other yet independently predicted contributing behaviors. Our findings suggest that youth-adult partnerships might be one potentially rich context for the promotion of youth's contributions to others. PMID- 28086142 TI - Visual statistical learning is related to natural language ability in adults: An ERP study. AB - Statistical learning (SL) is believed to enable language acquisition by allowing individuals to learn regularities within linguistic input. However, neural evidence supporting a direct relationship between SL and language ability is scarce. We investigated whether there are associations between event-related potential (ERP) correlates of SL and language abilities while controlling for the general level of selective attention. Seventeen adults completed tests of visual SL, receptive vocabulary, grammatical ability, and sentence completion. Response times and ERPs showed that SL is related to receptive vocabulary and grammatical ability. ERPs indicated that the relationship between SL and grammatical ability was independent of attention while the association between SL and receptive vocabulary depended on attention. The implications of these dissociative relationships in terms of underlying mechanisms of SL and language are discussed. These results further elucidate the cognitive nature of the links between SL mechanisms and language abilities. PMID- 28086144 TI - Synthesis, spectral characterization of novel Pd(II), Pt(II) pi-coordination compounds based on N-allylthioureas. Cytotoxic properties and DNA binding ability. AB - Four novel Pd2+ and Pt2+ mononuclear pi-coordination compounds with general formula [M(HL)1,2Cl2], M=Pd2+, Pt2+ have been synthesized by reaction of [PdCl4]2 , [PtCl4]2- anions with N-allyl-4-morpholinethiocarboxamide (HL1) and N-Allyl-N' tert-butylthiourea (HL2). All complexes have been characterized by single-crystal X-ray diffraction study and 1H, 13C NMR spectroscopy. Cytotoxic, cytostatic and proapoptotic activities of compounds have been determined in vitro on HeLa cell line and compared with cisplatin as etalon drug. All complex compounds possessed pronounced cytotoxic activity with IC50 indexes in range of 2.10-6-1.5.10-4M (IC50 of cisplatin is 5.7?10-5M) and showed proapoptotic, cytostatic and antisyntetic influence higher or comparable with cisplatin. The comparative influence of cisplatin and synthesized metal complexes on pTZ19R* plasmid DNA was monitored by agarose gel electrophoresis. All compounds showed high affinity to DNA that correlates with observed cytostatic and proapoptotic levels. In general Pd(II) compounds showed higher activity than Pt(II) ones. PMID- 28086145 TI - Aggression and related stressful life events among Chinese adolescents living in rural areas: A cross-sectional study. AB - BACKGROUND: Aggression is a serious problem for both individuals and society. Despite progress in aggression research, its persistence among adolescents living in rural areas remains to be investigated. We evaluate the prevalence of aggression and the association between stressful life events and aggression in a nationwide, school-based sample of adolescents living in rural areas of China. METHODS: A sample of 13,495 Chinese rural students (7065 boys and 6430 girls; 11 20 years old) was selected from 15 representative rural areas from 5 provinces in China using stratified randomized cluster sampling. Aggression, stressful life events, neglect, emotional management, social support, and demographic characteristics were assessed via self-report questionnaires. Multivariate logistic regressions were used to estimate the association of stressful life events and aggression after controlling for confounds. RESULTS: The prevalence of aggressive behavior among Chinese adolescents living in rural areas was 24.3%. Regression analyses indicated that the odds of aggression were negatively influenced by chronic long-term stressors related to interpersonal problems (OR=2.03, 95% CI [1.75-2.36]), health adaptation difficulties (OR=1.21, 95% CI [1.09-1.34]), and other troubles (OR=1.93, 95% CI [1.74-2.14]), even after adjustment for parental neglect, emotional management, social support, and other relevant factors. LIMITATIONS: This study was cross-sectional; thus, it is necessary to validate the causal relationship between stressful life events and aggression via follow-up studies. CONCLUSIONS: Aggression was prevalent among Chinese adolescents living in rural areas, and interpersonal problems, health adaption difficulties, and other troubles were considered potential independent risk factors for aggression. PMID- 28086146 TI - Cost-effectiveness of structured group psychoeducation versus unstructured group support for bipolar disorder: Results from a multi-centre pragmatic randomised controlled trial. AB - BACKGROUND: Bipolar disorder (BD) costs the English economy an estimated L5.2billion/year, largely through incomplete recovery. This analysis estimated the cost-effectiveness of group psychoeducation (PEd), versus group peer support (PS), for treating BD. METHODS: A 96-week pragmatic randomised controlled trial (RCT), conducted in NHS primary care. The primary analysis compared PEd with PS, using multiple imputed datasets for missing values. An economic model was used to compare PEd with treatment as usual (TAU). The perspective was Health and Personal Social Services. RESULTS: Participants receiving PEd (n=153) used more (costly) health-related resources than PS (n=151) (net cost per person L1098 (95% CI, L252-L1943)), with a quality-adjusted life year (QALY) gain of 0.023 (95% CI, 0.001-0.056). The cost per QALY gained was L47,739. PEd may be cost-effective (versus PS) if decision makers are willing to pay at least L37,500 per QALY gained. PEd costs L10,765 more than PS to avoid one relapse. The economic model indicates that PEd may be cost-effective versus TAU if it reduces the probability of relapse (by 15%) or reduces the probability of and increases time to relapse (by 10%). LIMITATIONS: Participants were generally inconsistent in attending treatment sessions and low numbers had complete cost/QALY data. Factors contributing to pervasive uncertainty of the results are discussed. CONCLUSIONS: This is the first economic evaluation of PEd versus PS in a pragmatic trial. PEd is associated with a modest improvement in health status and higher costs than PS. There is a high level of uncertainty in the data and results. PMID- 28086147 TI - In situ exposure to wastewater effluent reduces survival but has little effect on the behaviour or physiology of an invasive Great Lakes fish. AB - Treated effluents from wastewater treatment plants (WWTP) are a significant source of anthropogenic contaminants, such as pharmaceuticals, in the aquatic environment. Although our understanding of how wastewater effluent impacts fish reproduction is growing, we know very little about how effluent affects non reproductive physiology and behaviours associated with fitness (such as aggression and activity). To better understand how fish cope with chronic exposure to wastewater effluent in the wild, we caged round goby (Neogobius melanostomus) for three weeks at different distances from a wastewater outflow. We evaluated the effects of this exposure on fish survival, behaviour, metabolism, and respiratory traits. Fish caged inside the WWTP and close to the outfall experienced higher mortality than fish from the reference site. Interestingly, those fish that survived the exposure performed similarly to fish caged at the reference site in tests of aggressive behaviour, startle-responses, and dispersal. Moreover, the fish near WWTP outflow displayed similar resting metabolism (O2 consumption rates), hypoxia tolerance, haemoglobin concentration, haematocrit, and blood-oxygen binding affinities as the fish from the more distant reference site. We discuss our findings in relation to exposure site water quality, concentrations of pharmaceutical and personal care product pollutants, and our test species tolerance. PMID- 28086148 TI - A comparative study of mechanical properties of fresh and frozen-thawed porcine intervertebral discs in a bioreactor environment. AB - Limited availability of fresh intervertebral discs (IVDs) necessitates the use of frozen-thawed samples in biomechanical investigations. Several authors have reported the mechanical properties of frozen-thawed IVDs, but few studies have investigated the effects of storage temperature and cooling rate. The validity and reliability of the applied freezing-thawing procedures are still relatively unknown. The study aims to compare the mechanical responses of fresh porcine IVDs and porcine IVDs, which were frozen at different freezing temperatures with a controlled-rate cooling process and then thawed. The specimens were obtained from pigs aged 6 months. A total of 18 functional spine units (FSUs) were taken from seven porcine lumbar spines (L1-L6). The specimens were then split into three groups. The first group was tested fresh immediately and the other two groups were frozen at the same cooling rate and stored at -20 degrees C and -80 degrees C, respectively, before testing. The period of storage ranged between 12 and 43 days. The frozen specimens were thawed for 9h at room temperature before the tests. A special IVD bioreactor, which maintained the realistic behaviour of IVDs under various loading conditions, was developed. The analysis of variance (ANOVA) was used to determine if the observed results were statistically significant. The results indicated that frozen storage at -20 degrees C decreases the comprehensive stiffness. In contrast, freezing to -80 degrees C did not seem to have any effect on the mechanical properties of IVDs. No significant differences in outcome were observed for the samples, which had different spine levels. The study confirmed the reliability and usability of frozen-thawed samples stored at 80 degrees C for biomechanical investigations. PMID- 28086149 TI - Shear waves elastography for assessment of human Achilles tendon's biomechanical properties: an experimental study. AB - INTRODUCTION: Achilles tendon is the most frequently ruptured tendon, but its optimal treatment is increasingly controversial. The mechanical properties of the healing tendon should be studied further. Shear waves elastography (SWE) measures the shear modulus, which is proven to be correlated to elastic modulus in animal tendons. The aim of our study was to study whether the shear moduli of human cadaveric Achilles tendon, given by SWE, were correlated with the apparent elastic moduli of those tendons given by tensile tests. MATERIALS AND METHODS: Fourteen cadaveric lower-limbs were studied. An elastographic study of the Achilles tendon (AT) was first done in clinical-like conditions. SWE was performed at three successive levels (0, 3 and 6cm from tendon insertion) with elastographic probe oriented parallel to tendon fibers, blindly, for three standardized ankle positions (25 degrees plantar flexion, neutral position, and maximal dorsal flexion). The mean shear moduli were collected through blind offline data-analysis. Then, AT with triceps were harvested. They were subjected to tensile tests. A continuous SWE of the Achilles tendon was performed simultaneously. The apparent elastic modulus was obtained from the experimental stress-strain curve, and correlation with shear modulus (given by SWE) was studied. RESULTS: Average shear moduli of harvested AT, given by SWE made an instant before the tensile tests, were significantly correlated with shear moduli of the same AT made at the same level, previously in clinical-like condition (p<0.05), only in neutral position. There was a statistical correlation (p<0.005) and a correlation coefficient R2 equal to 0.95+/-0.05, between shear moduli (SWE) and apparent elastic moduli (tensile tests), for 11 tendons (3 tendons were inoperable due to technical error), before a constant disruption in the correlation curves. DISCUSSION: We demonstrated a significant correlation between SWE of Achilles tendon performed in clinical-like conditions (in neutral position) and SWE performed in harvested tendon. We also found a correlation between SWE performed on harvested tendon and apparent elastic moduli obtained with tensile tests (for 11 specimens). As a consequence, we can suppose that SWE of AT in clinical-like conditions is related to tensile tests. To our knowledge, the ability of SWE to reliably assess biomechanical properties of a tendon or muscle was, so far, only demonstrated in animal models. CONCLUSION: SWE can provide biomechanical information of the human AT non-invasively. PMID- 28086150 TI - The role of CD27 in anti-viral T-cell immunity. AB - CD27 is a co-stimulatory immune-checkpoint receptor, constitutively expressed on a broad range of T-cells (alphabeta and gammadelta), NK-cells and B-cells. Ligation of CD27 with CD70 results in potent co-stimulatory effects. In mice, co stimulation of CD8+ T-cells through CD27 promotes immune activation and enhances primary, secondary, memory and recall responses towards viral infections. Limited in vitro human studies support mouse experiments and show that CD27 co stimulation enhances antiviral T-cell immunity. Given the potent co-stimulatory effects of CD27, manipulating CD27 signalling is of interest for viral, autoimmune and anti-tumour immunotherapies. This review focuses on the role of CD27 co-stimulation in anti-viral T-cell immunity and discusses clinical studies utilising the CD27 co-stimulation pathway for anti-viral, anti-tumour and autoimmune immunotherapy. PMID- 28086151 TI - Childhood parental bonding affects adulthood trait anxiety through self-esteem. AB - INTRODUCTION: The association between trait anxiety and parental bonding has been suggested. However, the mechanism remains uncertain and there is no study focused on general adult population. We investigated the association and the mechanism between childhood parental bonding and adulthood trait anxiety in the general adult population. MATERIAL AND METHODS: A cross-sectional retrospective survey was conducted in 2014 with 853 adult volunteers from the general population. The Parental Bonding Instrument, Rosenberg Self-Esteem Scale, and State-Trait Anxiety Inventory Form Y (STAI-Y) were self-administered. Structural equation modelling was used for the analysis. RESULTS: Childhood parental bonding affected adulthood trait anxiety indirectly mediated by self-esteem. Trait anxiety was decreased by parental care and increased by parental overprotection through self-esteem. This model explained 51.1% of the variability in STAI-Y trait anxiety scores. CONCLUSIONS: This study suggests an important role of self-esteem as a mediator between childhood parental bonding and adulthood trait anxiety. PMID- 28086152 TI - Time dependent deformation behavior of dentin. AB - OBJECTIVE: The viscoelastic behavior of dentin and its ability to undergo time dependent deformation are considered to be important to oral functions and its capacity to resist fracture. There are spatial variations in the microstructure of dentin within the crown, which could be important to the viscous behavior. However, a spatially resolved description for the viscoelastic behavior of coronal dentin has not been reported. METHODS: In this investigation spherical indentations were made in three regions of coronal dentin including the outer, middle and inner regions. Power law relations were developed to quantitatively describe the stress-strain responses of the tissue. RESULTS: Results showed that the deformation behavior was strongly dependent on the composition (mineral to collagen ratio) and microstructure (tubule density), which contributed to an increase in the rate of viscous deformation with increasing proximity to the pulp. CONCLUSIONS: A model accounting for spatial variations in composition and microstructure was developed to describe the steady-state time dependent deformation behavior of coronal dentin, and a good agreement was found with the experimental results. PMID- 28086153 TI - Sulfur dioxide addition at crush alters Saccharomyces cerevisiae strain composition in spontaneous fermentations at two Canadian wineries. AB - During winemaking, sulfur dioxide (SO2) is often added prior to the onset of alcoholic fermentation to prevent the growth of spoilage microorganisms and to create an environment that promotes the rapid colonization of the grape must by Saccharomyces cerevisiae. Most recent research has focused on the impacts of SO2 additions on spoilage microorganisms or on the yeast community at a species level, but less is known about the impacts that SO2 additions have on S. cerevisiae populations. We investigated whether different levels of SO2 addition at crush (0, 20, or 40mg/L SO2) have an effect upon the relative abundance and composition of S. cerevisiae strains conducting spontaneous fermentations of two grape varietals at two commercial wineries. Yeast isolates collected from fermentations were identified to the strain level using microsatellite analysis. Commercial strains made up the majority (64-98%) of the S. cerevisiae strains isolated during fermentation, and most of these commercial strains were used as inoculants by their respective wineries. Different SO2 additions were found to significantly alter S. cerevisiae strain compositions at both wineries (p<=0.002). The results of this study demonstrate that initial SO2 addition significantly alters the S. cerevisiae strain composition in spontaneous fermentations, and highlights the dominance of commercial strains in commercial winery environments. Because different yeast strains are known to produce different chemical and sensory profiles, our findings have important implications for winemakers. In addition, adding different concentrations of SO2 may be a way for winemakers to manage or control the strain composition during spontaneous fermentations. PMID- 28086154 TI - Full-endoscopic versus micro-endoscopic and open discectomy: A systematic review and meta-analysis of outcomes and complications. AB - OBJECTIVES: The purpose of this study was to systematically compare the effectiveness and safety of full-endoscopic discectomy (FED) and micro-endoscopic discectomy (MED) with open discectomy (OD) for the treatment of symptomatic lumbar disc herniation. METHODS: Electronic searches were performed using six databases from their inception to February 2016, identifying all relevant randomized controlled trials and comparative observational studies comparing either FED or MED with OD. Data were extracted and analyzed according to predefined clinical endpoints. RESULTS: Twenty three studies were selected for analysis, including 421 FED, 6914 MED, and 21,152 OD cases. No significant difference was found between FED and OD in regards to postoperative visual analog scale (VAS) leg pain scores (WMD 0.03, P=0.93). Similar results were obtained for MED vs OD (WMD 0.09, P=0.18). In terms of postoperative Oswestry disability index (ODI), both FED and MED were similar to OD (WMD -2.60, P=0.32 and WMD -1.00, P=0.21, respectively). FED had a significantly shorter operative duration compared to OD (54.6 vs 102.6min, P=0.0001). MED alone and endoscopic approaches overall (including MED and FED) demonstrated significantly lower estimated blood loss (44.3 vs 194.4mL, P=0.03 and 38.2 vs 203.5mL, respectively, both p<0.05). FED alone demonstrated a trend towards lower estimated blood loss in comparison to OD (3.3 vs 244.9mL, P=0.07). No difference was found in overall complications, recurrence or reoperation rates, dural tears, root injury, wound infections, and spondylodiscitis between FED vs OD, or MED vs OD. CONCLUSIONS: Based on this meta analysis, FED and MED appear to be safe and efficacious alternatives to traditional approaches, but these results require further investigation and validation by prospective randomized studies. PMID- 28086155 TI - Kinetics, mechanisms, and influencing factors on the treatment of haloacetonitriles (HANs) in water by two household heating devices. AB - Haloacetonitriles (HANs) are a group of nitrogenous disinfection by-products (DBPs) commonly found in treated water with potential carcinogenic, cytotoxic, and genotoxic risks. In order to control HANs and understand their real intake levels by people via drinking water, this study evaluated a list of structural, operational, and environmental factors affecting the treatment of HANs by two domestic heating devices, i.e., an electric boiler and a microwave oven. Results show that the concentrations of HANs decreased exponentially over time with increasing temperature, water turbulence, and bubbles, and the phenomena were most likely due to a combined effect of volatilization and hydrolysis. Among HANs, the lability increased with increasing halogenation degrees (i.e., tri- > di- > mono- HANs) yet decreasing halogen molecular weights (i.e., Cl- > Br- > I- HANs); such trends were well captured by quantitative structure activity relationship models (R2 = 0.99). Operational factors played critical roles in controlling HANs too, including the rate of heating, water volume, water temperature at time of pouring, cooling method, and capping condition, suggesting that people could benefit from proper handling methods and procedures. In addition, HANs added to tap water exhibited higher removals than those added to ultrapure water, probably because of the presence of free chlorine in tap water. PMID- 28086156 TI - Effects of different agricultural wastes on the dissipation of PAHs and the PAH degrading genes in a PAH-contaminated soil. AB - Land application of agricultural wastes is considered as a promising bioremediation approach for cleaning up soils contaminated by aged polycyclic aromatic hydrocarbons (PAHs). However, it remains largely unknown about how microbial PAH-degraders, which play a key role in the biodegradation of soil PAHs, respond to the amendments of agricultural wastes. Here, a 90-day soil microcosm study was conducted to compare the effects of three agricultural wastes (i.e. WS, wheat stalk; MCSW, mushroom cultivation substrate waste; and CM, cow manure) on the dissipation of aged PAHs and the abundance and community structure of PAH-degrading microorganisms. The results showed that all the three agricultural wastes accelerated the dissipation of aged PAHs and significantly increased abundances of the bacterial 16S rRNA and PAH-degrading genes (i.e. pdo1 and nah). CM and MCSW with lower ratios of C:N eliminated soil PAHs more efficiently than WS with a high ratio of C:N. Low molecular weight PAHs were dissipated more quickly than those with high molecular weight. Phylogenetic analysis revealed that all of the nah and C12O clones were affiliated within Betaproteobacteria and Gammaproteobacteria, and application of agricultural wastes significantly changed the community structure of the microorganisms harboring nah and C12O genes, particularly in the CM treatment. Taken together, our findings suggest that the three tested agricultural wastes could accelerate the degradation of aged PAHs most likely through changing the abundances and community structure of microbial PAH degraders. PMID- 28086157 TI - Identification of critical contaminants in wastewater effluent for managed aquifer recharge. AB - Managed aquifer recharge (MAR) using highly treated effluent from municipal wastewater treatment plants has been recognized as a promising strategy for indirect potable water reuse. Treated wastewater effluent can contain a number of residual contaminants that could have adverse effects on human health, and some jurisdictions have regulations in place to govern these. For those that do not, but where reuse may be under consideration, it is of crucial importance to develop a strategy for identifying priority contaminants, which can then be used to understand the water treatment technologies that might be required. In this study, a multi-criteria approach to identify critical contaminants in wastewater effluent for MAR was developed and applied using a case study site located in southern Ontario, Canada. An important aspect of this approach was the selection of representative compounds for each group of contaminants, based on potential for occurrence in wastewater and expected health or environmental impacts. Due to a lack of MAR regulations in Canada, the study first proposed potential recharge water quality targets. Predominant contaminants, potential additional contaminants, and potential emerging contaminants, which together comprise critical contaminants for MAR with reclaimed water, were then selected based on the case study wastewater effluent monitoring data and literature data. This paper proposes an approach for critical contaminant selection, which will be helpful to guide future implementation of MAR projects using wastewater treatment plant effluents. PMID- 28086158 TI - Bioleaching of manganese by Aspergillus sp. isolated from mining deposits. AB - A comprehensive study on fungus assisted bioleaching of manganese (Mn) was carried out to demonstrate Mn solubilization of collected low grade ore from mining deposits of Sanindipur, Odisha, India. A native fungal strain MSF 5 was isolated and identified as Aspergillus sp. by Inter Transcribed Spacer (ITS) sequencing. The identified strain revealed an elevated tolerance ability to Mn under varying optimizing conditions like initial pH (2, 3, 4, 5, 6, 7), carbon sources (dextrose, sucrose, fructose and glucose) and pulp density (2%, 3%, 4%, 5% and 6%). Bioleaching studies carried out under optimized conditions of 2% pulp density of Mn ore at pH 6, temperature 37 degrees C and carbon dosage (dextrose) resulted with 79% Mn recovery from the ore sample within 20 days. SEM-EDX characterization of the ore sample and leach residue was carried out and the micrographs demonstrated porous and coagulated precipitates scattered across the matrix. The corresponding approach of FTIR analysis regulating the Mn oxide formation shows a distinctive peak of mycelium cells with and without treated Mn, resulting with generalized vibrations like MnOx stretching and CH2 stretch. Thus, our investigation endeavors' the considerate possible mechanism involved in fungal surface cells onto Mn ore illustrating an alteration in cellular Mn interaction. PMID- 28086159 TI - No effect of digestate amendment on Cs-137 and Sr-90 translocation in lysimeter experiments. AB - The soil-plant transfer of Cs-137 and Sr-90 in different crops was determined with respect to the present-day amendment practice of using digestate from biogas fermenters. The studies were performed using large lysimeters filled with undisturbed luvisol monoliths. In contrast to the conservative tracer, Br-, neither of the studied radionuclides showed a significant vertical translocation nor effect of the applied digestate amendment compared to a non-amended control was found. Furthermore, no significant plant uptake was measured for both nuclides in wheat or oat as indicated by the low transfer factors between soil shoot for Cs-137 (TF 0.001-0.010) and for Sr-90 (0.10-0.51). The transfer into nutritionally relevant plant parts was even lower with transfer factors for soil grain for Cs-137 (TF 0.000-0.001) and for Sr-90 (0.01-0.06). Hence, the amendment with biogas digestate is unfortunately not an option to further reduce plant uptake of these radionuclides in agricultural crops, but it does not increase plant uptake either. PMID- 28086160 TI - Phosphorus saturation and mobilization in two typical Chinese greenhouse vegetable soils. AB - Chinese greenhouse vegetable production can cause eutrophication of fresh waters due to heavy use of fertilizers. To address this, phosphorus (P) leaching was compared between two major greenhouse vegetable soils from Jiangsu Province, Southeast China: clayey and acid-neutral Guli Orthic Anthrosols and sandy and alkaline Tongshan Ustic Cambosols. A total of 20 intact soil columns were collected based on differences in total P content varying between 1360 and 11,220 mg kg-1. Overall, six leaching experiments were carried out with collection of leachates over 24 h. Very high P concentrations, with a mean of 3.43 mg L-1, were found in the leachates from P rich Tongshan soils. In contrast, P leaching from fine-textured but less P rich Guli soils rarely exceeded the suggested environmental P threshold of 0.1 mg L-1. Strong linear correlations were found between different soil test P measures (STPs) or degree of P saturations (DPSs) and dissolved reactive P (DRP) for Tongshan soil columns. The correlations with Olsen P (r2 = 0.91) and DPS based on MehlichIII extractable calcium (DPSM3-Ca) (r2 = 0.87) were the most promising. An Olsen P value above 41 mg kg-1 or a DPSM3 Ca above 3.44% led to DRP leaching exceeding 0.1 mg L-1. Accordingly, more than 80% of Tongshan soils resulted in DRP leaching exceeding the environmental P threshold. In conclusion P rich alkaline sandy soils used for greenhouse vegetable production are at high risk of P mobilization across China. PMID- 28086161 TI - A-type lamins and cardiovascular disease in premature aging syndromes. AB - Lamin A is a nuclear intermediate filament protein with important structural and regulatory roles in most differentiated mammalian cells. Excessive accumulation of its precursor prelamin A or the mutant form called 'progerin' causes premature aging syndromes. Progeroid 'laminopathies' are characterized by severe cardiovascular problems (cardiac electrical defects, vascular calcification and stiffening, atherosclerosis, myocardial infarction, and stroke) and premature death. Here, we review studies in cell and mouse models and patients that are unraveling how abnormal prelamin A and progerin accumulation accelerates cardiovascular disease and aging. This knowledge is essential for developing effective therapies to treat progeria and may help identify new mechanisms underlying normal aging. PMID- 28086162 TI - Getting to and through the inner nuclear membrane during herpesvirus nuclear egress. AB - Herpesviruses, like most DNA viruses, replicate and package their genomes into capsids in the host cell nucleus. Capsids then transit to the cytoplasm in a fascinating process called nuclear egress, which includes several unusual steps: Movement of capsids from the nuclear interior to the periphery, disruption of the nuclear lamina, capsid budding through the inner nuclear membrane, and fusion of enveloped particles with the outer nuclear membrane. Here, we review recent advances and emerging questions relating to herpesvirus nuclear egress, emphasizing controversies regarding mechanisms for capsid trafficking to the nuclear periphery, and implications of recent structures of the two-subunit, viral nuclear egress complex for the process, particularly at the step of budding through the inner nuclear membrane. PMID- 28086163 TI - Changes in lower limb muscle activity after walking on a split-belt treadmill in individuals post-stroke. AB - BACKGROUND: There is growing evidence that stroke survivors can adapt and improve step length symmetry in the context of split-belt treadmill (SBT) walking. However, less knowledge exists about the strategies involved for such adaptations. This study analyzed lower limb muscle activity in individuals post stroke related to SBT-induced changes in step length. METHODS: Step length and surface EMG activity of six lower limb muscles were evaluated in individuals post stroke (n=16) during (adaptation) and after (after-effects) walking at unequal belt speeds. RESULTS: During adaptation, significant increases in EMG activity were mainly found in proximal muscles (p?0.023), whereas after-effects were observed particularly in the distal muscles. The plantarflexor EMG increased after walking on the slow belt (p?0.023) and the dorsiflexors predominantly after walking on the fast belt (p?0.017) for both, non-paretic and paretic-fast conditions. Correlation analysis revealed that after-effects in step length were mainly associated with changes in distal paretic muscle activity (0.522?r?0.663) but not with functional deficits. Based on our results, SBT walking could be relevant for training individuals post-stroke who present shorter paretic step length combined with dorsiflexor weakness, or individuals with shorter nonparetic step length and plantarflexor weakness. PMID- 28086164 TI - Lacosamide for uncontrolled primary generalized tonic-clonic seizures: An open label pilot study with 59-week extension. AB - OBJECTIVE: Assess the safety of adjunctive lacosamide for the treatment of uncontrolled primary generalized tonic-clonic seizures in patients (16-65 years) with primary generalized (genetic) epilepsy (PGE). METHODS: An open-label pilot safety study (SP0961; NCT01118949), comprising 12 weeks' historical baseline, 4 weeks' prospective baseline, 3 weeks' titration (target: 400mg/day adjunctive lacosamide) and 6 weeks' maintenance. Patients who continued to the extension study (SP0962; NCT01118962) then received <=59 weeks of flexible treatment (100 800mg/day lacosamide with flexible dosing of concomitant antiepileptic drugs). The primary outcomes for SP0961 were the mean change (+/-standard deviation) in absence seizure or myoclonic seizure days per 28days from prospective baseline to maintenance; for SP0962, the incidence of treatment-emergent adverse events (TEAEs) and withdrawals because of TEAEs. RESULTS: Of the 49 patients who enrolled, 40 (82%) completed the pilot study and 9 discontinued (5 because of adverse events). Of the 39 patients who continued to the extension study, 10 discontinued (2 owing to TEAEs) and 29 (74%) completed the study. During the pilot study, patients reported a reduction in mean (+/-standard deviation) absence and myoclonic seizure days per 28days (-0.37+/-4.80, -2.19+/-5.80). Reductions were also observed during the extension study (-2.38+/-5.54, -2.78+/ 6.43). Five patients in SP0961 and 2 patients in SP0962 experienced TEAEs of new or increased frequency of absence seizures or myoclonic seizures. The most common TEAEs during SP0961 were dizziness (39%) and nausea (27%), and during SP0962 were dizziness (26%) and upper respiratory tract infection (26%). CONCLUSIONS: The safety profile of adjunctive lacosamide was similar to that previously published. Adjunctive lacosamide did not systematically worsen absence or myoclonic seizures, and appears to be well tolerated in patients with PGE. PMID- 28086165 TI - Simultaneous quantification of twenty-one ginsenosides and their three aglycones in rat plasma by a developed UFLC-MS/MS assay: Application to a pharmacokinetic study of red ginseng. AB - To track the pharmacokinetic features of red ginseng (RG), a rapid and sensitive ultra fast liquid chromatographic coupled with electrospray ionization triple quadrupole tandem mass spectrometry (UFLC-MS/MS) method was developed for simultaneous quantification of twenty-one ginsenosides and their three aglycones, including 18 prototype compounds (ginsenosides Rb1, Rb2, Rc, Rd, Re, Rg1, Rg5, Rh4, Rk1, Rk3, 20(S)-Rf, 20(S)-Rg2, 20(R)-Rg2, 20(S)-Rg3, 20(R)-Rg3, 20(S)-Rh1, 20(R)-Rh1, 20(S)-NG-R2), and 6 metabolites (ginsenosides 20(S)-Rh2 and Rh3, 20(S) protopanaxadiol (PPD), 20(S)-protopanaxatriol (PPT), 20(R)-PPT, ginseng saponin compound K) of RG in rat plasma after oral administration of RG water extract at a single dose of 4g/kg body weight to rats. All analytes with internal standard (digoxin) were detected by multiple reaction monitoring in negative ionization mode and separated on an ACQUITY UPLC(r) BEH RP-C18 column (1.7MUm, 100*2.1mm). This established method was well validated in terms of linearity, sensitivity, intra- and inter-day precisions, accuracy, recovery, matrix effect, stability, and had a lower limit of quantification at the concentration range of 0.12 8.12ng/mL for all of analytes. This UFLC-MS/MS approach was successfully applied to the pharmacokinetic study for RG water extract in rats. We firstly proposed that Rb1, Rb2, Rc, Rd, Rg1, Rg5, 20(S)-Rg3, 20(S)-Rh2, and 20(S)-PPD measured in rat plasma were suitable pharmacokinetic markers of RG extract in rats due to their high systemic exposure levels. Thus, this specific and reliable method will be useful for future applications to pharmacokinetic studies for various sources of ginsenoside samples and Panax herbs in vivo. PMID- 28086166 TI - On the spectroscopic analyses of 3-Hydroxy-1-Phenyl-Pyridazin-6(2H)one (HPHP): A comparative experimental and computational study. AB - We have systematically calculated various physical characteristics such as optimized molecular structural parameters, vibrational frequencies, HOMO-LUMO energy gap, total dipole moment and thermochemical parameters: nuclear repulsion energy, ionization energy, electron affinity, global hardness, electronic chemical potential, global electrophilicity index and finally softness (zeta) using DFT/B3LYP utilizing 6-311G(d,p) basis set for 3-Hydroxy-1-Phenyl-Pyridazin 6(2H)one (HPHP). Also, HPHP nonlinear optical (NLO) properties have been checked by DFT/B3LYP utilizing 6-311G(d,p) basis set. In addition, we have investigated the influence of exposure to UV radiation on HPHP physical properties at the same level of theory. Our results show that HPHP possesses a dipole moment (2.68Debye) and HOMO-LUMO energy gap of 3.99eV that emphasize its high applicability for manufacturing photovoltaic devices such as solar cells. After exposure to UV radiation, the HPHP dipole moment has been lowered from 2.68 to 2.3Debye due to UV radiation. Moreover, a double spin in HPHP has been observed, as electrons are aligned according to their spin state. Electrons (spin ?) and (spin ?) are aligned in alpha and beta levels with energy gaps 3.82 and 3.17eV, respectively. This anomalous behavior may be justified by considering that HPHP undergoes anomalous Zeeman-like effect. The presence of this phenomenon in HPHP introduces it as a modern organic semiconductor which has high applicability to be used in modern spintronics. PMID- 28086167 TI - Genetic analysis in post-mortem samples with micro-ischemic alterations. AB - Sudden cardiac arrest is a leading cause of death worldwide. Most cardiac arrests happen in patients who have previously suffered a myocardial infarct. The risk of sudden death after infarction may increase in people who carry a pathogenic genetic alteration in cardiac ion channels. We hypothesized that micro-ischemia could trigger lethal arrhythmogenesis, thus we sought to identify genetic alterations in cardiac ion channels in patients with micro-ischemic disease. We studied a cohort of 56 post-mortem samples. Autopsy studies identified myocardial infarction as the cause of death in each case. We used both Sanger sequencing and next-generation sequencing to screen candidate genes associated with sudden cardiac death. We identified six rare missense genetic variations in five unrelated patients. Two variants have been previously reported; one is associated with atrial fibrillation (SCN5A_p.H445D), and the other is predicted to be benign (ANK2_p.T2059M). The novel variants were predicted in silico as benign, except for one (RyR2_p.M4019T), which was classified as deleterious. Our post-mortem, micro-infarction cohort displayed a rate of nearly 10% non-common genetic variants. However, the clinical significance of most of the identified variants remains unknown due to lack of family assessment. Further analyses should be performed in large cohorts to clarify the role of ion-channel gene analysis in samples showing microscopic ischemic alterations. PMID- 28086168 TI - Diagnostic performance of dual-staining cytology for cervical cancer screening: A systematic literature review. AB - Cervical cancer screening saves lives. Secondary prevention in cervical cancer screening relies on the results of primary cytology and/or HPV testing. However, primary screening with cytology has a low sensitivity, and HPV screening has a low specificity. This means that either cancers are missed, or women are over treated. To improve performance outcomes, the concept of dual-stain cytology (CINtec(r) PLUS Cytology test) has been introduced. In this approach, additional staining with p16/Ki-67 is performed in cases where cytology results are abnormal (LSIL or ASCUS) and/or HPV-positive. Another way to describe this approach might be "diagnostic" cytology. In order to assess the value of this "diagnostic cytology", a systematic literature review was conducted of dual-stain cytology performance across multiple studies until May 2016. In a Belgian screening population (women age 25-65 years), dual-stain cytology was significantly more sensitive (66%) and slightly less specific (-1.0%) than cytology. In the population referred to colposcopy or with abnormal cytology (ASCUS, LSIL), dual staining showed a significantly higher increase in specificity, and a slightly lower sensitivity than HPV testing. Specificity gains resulted in fewer false positives and an increase in the number of correct referrals to colposcopy. Dual staining with p16/Ki-67 cytology is an attractive biomarker approach for triage in cervical cancer screening. PMID- 28086169 TI - Functional characterization of a novel jasmonate ZIM-domain interactor (NINJA) from upland cotton (Gossypium hirsutum). AB - The jasmonic acid (JA) signalling pathway plays roles in plant development and defence against biotic and abiotic stresses. We isolated a cotton NINJA (novel interactor of JA ZIM-domain) gene, designated GhNINJA, which contains a 1305 bp open read frame. The GhNINJA gene encodes a 434 amino acid peptide. According to quantitative real-time PCR analysis, GhNINJA is preferentially expressed in roots, and its expression level is greatly induced by Verticillium dahliae infection. Through a virus-induced gene silencing technique, we developed GhNINJA silenced cotton plants, which had significantly decreased expression of the target gene with an average expression of 6% of the control. The regenerating lateral root growth of silenced plants was largely inhibited compared to the control. Analysis by microscopy demonstrated that the cell length of the root differentiation zone in GhNINJA-silenced plants is significantly shorter than those of the control. Moreover, the silenced plants exhibited higher tolerance to V. dahliae infection compared to the control, which was linked to the increased expression of the defence marker genes PDF1.2 and PR4. Together, these data indicated that knockdown of GhNINJA represses the root growth and enhances the tolerance to V. dahliae. Therefore, GhNINJA gene can be used as a candidate gene to breed the new cultivars for improving cotton yield and disease resistance. PMID- 28086170 TI - Process enhancement of supercritical methanol biodiesel production by packing beds. AB - Continuous fixed bed reactors filled by three kinds of packing which were glass bead, glass spring and Dixon rings were investigated. The effect of temperature, pressure, the molar ratio of methanol to oil, flow rate, the size and shape of the packing were researched. The highest yield 90.84% of FAME was obtained by filling Dixon rings as packing with the condition of the temperature was 350 degrees C, the pressure was 22MPa, the molar ratio of methanol to oil was 42:1. In addition, the reusability of Dixon rings was perfect. Numerical simulation was researched to provide theoretical basis for experimental results, besides the kinetics and thermodynamics behavior were investigated to explore the reaction mechanism. PMID- 28086171 TI - Co-pyrolysis mechanism of seaweed polysaccharides and cellulose based on macroscopic experiments and molecular simulations. AB - Co-pyrolysis conversion of seaweed (Enteromorpha clathrat and Sargassum fusiforme) polysaccharides and cellulose has been investigated. From the Py-GC/MS results, Enteromorpha clathrata (EN) polysaccharides pyrolysis mainly forms furans; while the products of Sargassum fusiforme (SA) polysaccharides pyrolysis are mainly acid esters. The formation mechanisms of H2O, CO2, and SO2 during the pyrolysis of seaweed polysaccharides were analyzed using the thermogravimetric mass spectrometry. Meanwhile the pyrolysis of seaweed polysaccharide based on the Amber and the ReaxFF force fields, has also been proposed and simulated respectively. The simulation results coincided with the experimental results. During the fast pyrolysis, strong synergistic effects among cellulose and seaweed polysaccharide molecules have been simulated. By comparing the experimental and simulation value, it has been found that co-pyrolysis could increase the number of molecular fragments, increase the pyrolysis conversion rate, and increase gas production rate at the middle temperature range. PMID- 28086172 TI - Short-term and long-term effects of Zn (II) on the microbial activity and sludge property of partial nitrification process. AB - Autotrophic nitrogen removal was an innovative and economical nitrogen removal technology with less oxygen and no organics consumption, in which partial nitrification (PN) is the key component. It is necessary to clear the impact of metal ions on PN since the development of industry increased their opportunity for entering into wastewater. In this study, PN process was successfully started up in an SBR, the short-term and long-term effects of Zn (II) on microbial bioactivity and the sludge adsorption ability for Zn (II) were investigated. Results suggested that low Zn (II) were favorable for AOB bioactivity, while the long-term effect also induced NOB bioactivity. The suppression threshold of Zn (II) on AOB in short-term effect was 10mgL-1, which rose to 50mgL-1 in the long term effect due to the self-adaption. The PN sludge presented prominent absorbability for zinc and performed a quadratic relation with the Zn (II) concentration. PMID- 28086173 TI - Novel bio-electro-Fenton technology for azo dye wastewater treatment using microbial reverse-electrodialysis electrolysis cell. AB - Development of sustainable technologies for treatment of azo dyes containing wastewaters has long been of great interest. In this study, we proposed an innovative concept of using microbial reverse-electrodialysis electrolysis cell (MREC) based Fenton process to treat azo dye wastewater. In such MREC-Fenton integrated process, the production of H2O2 which is the key reactant of fenton reaction was driven by the electrons harvested from the exoelectrogens and salinity-gradient between sea water and fresh water in MREC. Complete decolorization and mineralization of 400mgL-1 Orange G was achieved with apparent first order rate constants of 1.15+/-0.06 and 0.26+/-0.03h-1, respectively. Furthermore, the initial concentration of orange G, initial solution pH, catholyte concentration, high and low concentration salt water flow rate and air flow rate were all found to significantly affect the dye degradation. This study provides an efficient and cost-effective system for the degradation of non biodegradable pollutants. PMID- 28086174 TI - Assessment of solvents for cellulose dissolution. AB - A necessary step in the processing of biomass is the pretreatment and dissolution of cellulose. A good solvent for cellulose involves high diffusivity, aggressiveness in decrystallization, and capability of disassociating the cellulose chains. However, it is not clear which of these factors and under what conditions should be improved in order to obtain a more effective solvent. To this end, a newly-developed phenomenological model has been applied to assess the controlling mechanism of cellulose dissolution. Among the findings, the cellulose fibers remain crystalline almost to the end of the dissolution process for decrystallization-controlled kinetics. In such solvents, decreasing the fiber crystallinity, e.g., via pretreatment, would result in a considerable increase in the dissolution rate. Such insights improve the understanding of cellulose dissolution and facilitate the selection of more efficient solvents and processing conditions for biomass. Specific examples of solvents are provided where dissolution is limited due to decrystallization or disentanglement. PMID- 28086175 TI - Updating the African human mitochondrial DNA tree: Relevance to forensic and population genetics. AB - Analysis of human mitochondrial DNA (mtDNA) variation plays an important role in forensic genetic investigations, especially in degraded biological samples and hair shafts. There are many issues of the mtDNA phylogeny that are of special interest to the forensic community, such as haplogroup classification or the post hoc investigation of potential errors in mtDNA datasets. We have analyzed >2200 mitogenomes of African ancestry with the aim of improving the known worldwide phylogeny. More than 300 new minor subclades were identified, and the Time to the Most Recent Common Ancestor (TMRCA) was estimated for each node of the phylogeny. Phylogeographic details are provided which might also be relevant to forensic genetics. The present study has special interest for forensic investigations because current analysis and interpretation of mtDNA casework rest on a solid worldwide phylogeny, as is evident from the role that phylogeny plays in popular resources in the field (e.g. PhyloTree), software (e.g. Haplogrep 2), and databases (e.g. EMPOP). Apart from this forensic genetic interest, we also highlight the impact of this research in anthropological studies, such as those related to the reconstruction of the transatlantic slave trade. PMID- 28086176 TI - Short communication: Genetic association between schizophrenia and cannabis use. AB - BACKGROUND AND AIM: Previous studies have shown a relationship between schizophrenia and cannabis use. As both traits are substantially heritable, a shared genetic liability could explain the association. We use two recently developed genomics methods to investigate the genetic overlap between schizophrenia and cannabis use. METHODS: Firstly, polygenic risk scores for schizophrenia were created based on summary statistics from the largest schizophrenia genome-wide association (GWA) meta-analysis to date. We analysed the association between these schizophrenia polygenic scores and multiple cannabis use phenotypes (lifetime use, regular use, age at initiation, and quantity and frequency of use) in a sample of 6,931 individuals. Secondly, we applied LD-score regression to the GWA summary statistics of schizophrenia and lifetime cannabis use to calculate the genome-wide genetic correlation. RESULTS: Polygenic risk scores for schizophrenia were significantly (alpha<0.05) associated with five of the eight cannabis use phenotypes, including lifetime use, regular use, and quantity of use, with risk scores explaining up to 0.5% of the variance. Associations were not significant for age at initiation of use and two measures of frequency of use analyzed in lifetime users only, potentially because of reduced power due to a smaller sample size. The LD-score regression revealed a significant genetic correlation of rg=0.22 (SE=0.07, p=0.003) between schizophrenia and lifetime cannabis use. CONCLUSIONS: Common genetic variants underlying schizophrenia and lifetime cannabis use are partly overlapping. Individuals with a stronger genetic predisposition to schizophrenia are more likely to initiate cannabis use, use cannabis more regularly, and consume more cannabis over their lifetime. PMID- 28086177 TI - Prescription opioid abuse in prison settings: A systematic review of prevalence, practice and treatment responses. AB - BACKGROUND: To systematically review the quantitative and qualitative evidence base pertaining to the prevalence, practice of, and treatment response to the diversion of prescribed opiates in the prison setting. METHODS: Medline, Embase, CINAHL, PsycINFO, Google Scholar, ASSIA and Science Direct databases were searched for papers from 1995 to the present relevant to the abuse of prescribed opiate medication. Identified journals and their reference lists were hand searched for other relevant articles. Of the abstracts identified as relevant, full text papers were retrieved and critiqued against the inclusion criteria for the review. RESULTS: Three hundred and fifty-five abstracts were identified, leading to 42 full-text articles being retrieved. Of those, 10 papers were included in the review. Significant differences in abuse behaviours between different countries were reported. However, a key theme emerged from the data regarding a culture of nasal administration of prescribed sublingual buprenorphine within some prisons due to both reduced prevalence of injection within prison and reduced supplies of illicit drugs within prison. The buprenorphine/naloxone preparation appears to be less amenable to abuse. The review highlighted a paucity of empirical research pertaining to both prevalence of the phenomenon and treatment responses. CLINICAL AND RESEARCH IMPLICATIONS: Healthcare providers within prisons need to prescribe opioids in the least abuseable preparation since the risk of abuse is significant, despite widespread processes of supervised dispensing. Prescription medication abuse is not limited to opioids and the predominant drug of abuse in an individual prison can rapidly change according to availability. PMID- 28086178 TI - Adverse childhood experiences among children placed in and adopted from foster care: Evidence from a nationally representative survey. AB - Despite good reason to believe that children in foster care are disproportionately exposed to adverse childhood experiences (ACEs), relatively little research considers exposure to ACEs among this group of vulnerable children. In this article, we use data from the 2011-2012 National Survey of Children's Health (NSCH), a nationally representative sample of non institutionalized children ages 0-17 in the United States, to estimate the association between foster care placement and exposure to an array of ACEs. In adjusted logistic regression models, we find that children placed in foster care or adopted from foster care, compared to their counterparts, were more likely to experience parental divorce or separation, parental death, parental incarceration, parental abuse, violence exposure, household member mental illness, and household member substance abuse. These children were also more likely to experience ACEs than children across different thresholds of socioeconomic disadvantage (e.g., children in households with incomes below the poverty line) and across different family structures (e.g., children in single mother families). These results advance our understanding of how children in foster care, an already vulnerable population, are disproportionately exposed to ACEs. This exposure, given the link between ACEs and health, may have implications for children's health and wellbeing throughout the life course. PMID- 28086180 TI - Exosome-SIRPalpha, a CD47 blockade increases cancer cell phagocytosis. AB - CD47, a "don't eat me" signal, is over-expressed on the surface of most tumors that interacts with signal regulatory protein alpha (SIRPalpha) on phagocytic cells. By engaging SIRPalpha, CD47 limits the ability of macrophages to engulf tumor cells, which acts as a major phagocytic barrier. In this study, we developed an exosome-based immune checkpoint blockade that antagonizes the interaction between CD47 and SIRPalpha. These exosomes harboring SIRPalpha variants (SIRPalpha-exosomes) were sufficient to induce remarkably augmented tumor phagocytosis, lead to prime effective anti-tumor T cell response. Given that clustering of native CD47 provides a high binding avidity to ligate dimerized SIRPalpha on macrophage, nature-derived exosomes could be appreciable platform to antagonize CD47. Disruption of CD47-SIRPalpha interaction by SIRPalpha-exosomes leads to an increase in cells being engulfed by macrophages and a concomitant inhibition of tumor growth in tumor-bearing mice. Moreover, SIRPalpha-exosomes therapy promotes an intensive T cell infiltration in syngeneic mouse models of cancer, raising the possibility of CD47-targeted therapies to unleash both an innate and adaptive anti-tumor response. Note that very small amount of exosomal SIRPalpha proteins could effectively lead to phagocytic elimination of tumor cells both in vitro and in vivo. Our results suggest that superlative exosome-based platform has broad potential to maximize the therapeutic efficacy of membrane-associated protein therapeutics. PMID- 28086179 TI - Engineered gadolinium-doped carbon dots for magnetic resonance imaging-guided radiotherapy of tumors. AB - The effectiveness of radiotherapy can decrease due to inaccurate positioning of machinery and inherent radioresistance of tumors. To address this issue, we present a novel theranostic nanoplatform based on gadolinium-doped carbon dots (Gd-doped CDs) designed specifically for magnetic resonance imaging (MRI)-guided radiotherapy of tumors. The Gd-doped CDs (~18 nm) with dispersibility in water and stable photoluminescence were synthesized via a one-step hydrothermal approach. After tail vein injection of the Gd-doped CDs, they exhibited a relatively long circulation time (~6 h), enabled efficient passive tumor targeting. Gd-doped CDs accumulate in the kidney and could be cleared out of the body from bladder. Importantly, they exhibited favorable biocompatibility with excellent performance in longitudinal relaxivity rate (r1) of 6.45 mM-1S-1 and radiosensitization enhancements. These results show that Gd-doped CDs are excellent T1 contrast agents and radiosensitizers, possessing great promise for MRI-guided radiotherapy of tumors. PMID- 28086181 TI - Cognitive behavioral therapy for posttraumatic stress disorder in individuals with severe mental illness and borderline personality disorder. AB - Secondary analyses were performed on data from two randomized controlled trials of a cognitive behavioral therapy (CBT) program for posttraumatic stress disorder (PTSD) in individuals with severe mental illness (SMI) to examine the feasibility, tolerability, and effectiveness for individuals with borderline personality disorder (BPD). In Study 1, 27 participants received CBT or treatment as usual. In Study 2, 55 participants received CBT or a Brief treatment. Feasibility and tolerability of CBT, PTSD symptoms, and other mental health and functional outcomes were examined, with assessments at baseline, post-treatment, and two follow-up time points. CBT was feasible and tolerable in this population. Study 1 participants in CBT improved significantly more in PTSD symptoms, depression, and self-reported physical health. Study 2 participants in both CBT and Brief improved significantly in PTSD symptoms, posttraumatic cognitions, depression, and overall functioning, with those in CBT acquiring significantly more PTSD knowledge, and having marginally significantly greater improvement in PTSD symptoms. CBT for PTSD was feasible and tolerated in individuals with SMI, BPD, and PTSD, and associated with improvements in PTSD symptoms and related outcomes. Prospective research is needed to evaluate CBT in individuals with BPD, including comparing it with staged interventions for this population. PMID- 28086182 TI - Graphene oxide coated with porous iron oxide ribbons for 2, 4 Dichlorophenoxyacetic acid (2,4-D) removal. AB - Graphene oxide (GO) was prepared from commercially available graphite powder. Porous iron oxide ribbons were grown on the surface of GO by solvothermal process. The prepared GO-Fe3O4 nanocomposites are characterized by FT-IR, XRD, VSM, SEM, TEM, Raman spectroscopy, surface functionality and zero point charge studies. The morphology of the iron oxide ribbons grown on GO is demonstrated with TEM at various magnifications. The presence of magnetite nanoparticles is evident from XRD peaks and the magnetization value is found to be 37.28emu/g. The ratio of intensity of D-peak to G-peak from Raman spectrum is 0.995. The synthesized Graphene oxide-Fe3O4 nanocomposites (GO-Fe3O4) were explored for its surface adsorptive properties by using a model organic compound, 2,4 Dichlorophenoxy acetic acid (2,4-D) from aqueous solution. Batch adsorption studies were performed and the equilibrium data are modelled with Langmuir, Freundlich and Temkin isotherms. The maximum monolayer capacity from Langmuir isotherm is 67.26mg/g. Kinetic studies were also carried out and the studied adsorption process followed pseudo second-order rate equation. Mechanism of the adsorption process is studied by fitting the data with intraparticle diffusion model and Boyd plot. The studied adsorption process is both by film diffusion and intraparticle diffusion. PMID- 28086183 TI - Mode of action of Cr(VI) in immunocytes of earthworms: Implications for animal health. AB - Chromium (Cr) is one of the major and most detrimental pollutant, widely present in the environment as a result of several anthropogenic activities. In mammalian cells, Cr(VI) is known to enhance reactive oxygen species (ROS) production and to cause toxic and genotoxic effects. Less commonly investigated are the effects and mode of action of this contaminant in invertebrates, particularly in soil organisms. In this work, earthworms of the species Eisenia andrei were exposed for 1 and 3 days to various sublethal concentrations of Cr(VI) (2, 15, 30ugmL-1) using the paper contact toxicity test. In amoeboid leukocytes we investigated intracellular ROS and lipoperoxide production, oxidative DNA damage, and the effects on different cell functions. The analysis of the results shows that Cr(VI) triggered severe adverse reactions; the first events were an increase of intracellular ROS levels, generating in the cells oxidative stress conditions leading to membrane lipid peroxidation and oxidative DNA damage. Lysosomes showed relevant changes such as a strong membrane destabilization, which was accompanied by an increased catabolism of cytoplasmic proteins and accumulation of lipofuscin. With an increase in the dose and/or time of exposure, the physiological status of intracellular organelles (such as lysosomes, nucleus and mitochondria) showed further impairment and amoebocyte immune functions were adversely affected, as shown by the decrease of the phagocytic activity. By mapping the responses of the different parameters evaluated, diagnostic of (oxidative) stress events, against lysosomal membrane stability, a "health status" indicator (able to describe the stress syndrome from its early phase to pathology), we have shown that this biomarker is suitable as a prognostic test for health of earthworms. This is viewed as a crucial step toward the derivation of explanatory frameworks for prediction of pollutant impact on animal health. PMID- 28086185 TI - Attenuation of the NMR signal in a field gradient due to stochastic dynamics with memory. AB - The attenuation function S(t) for an ensemble of spins in a magnetic-field gradient is calculated by accumulation of the phase shifts in the rotating frame resulting from the displacements of spin-bearing particles. The found S(t), expressed through the particle mean square displacement, is applicable for any kind of stationary stochastic motion of spins, including their non-markovian dynamics with memory. The known expressions valid for normal and anomalous diffusion are obtained as special cases in the long time approximation. The method is also applicable to the NMR pulse sequences based on the refocusing principle. This is demonstrated by describing the Hahn spin echo experiment. The attenuation of the NMR signal is also evaluated providing that the random motion of particle is modeled by the generalized Langevin equation with the memory kernel exponentially decaying in time. The models considered in our paper assume massive particles driven by much smaller particles. PMID- 28086184 TI - Sex and APOE: A memory advantage in male APOE epsilon4 carriers in midlife. AB - Short-term memory in middle-aged individuals with different APOE alleles was examined using a recently developed task which is sensitive to medial temporal lobe (MTL) damage. Individuals (age-range: 40-51 years) with epsilon3/epsilon3, epsilon3/epsilon4 and epsilon4/epsilon4 APOE genotypes (N = 60) performed a delayed estimation task with a sensitive continuous measure of report. The paradigm allowed us to measure memory for items and their locations, as well as maintenance of identity-location feature binding in memory. There was a significant gene-dosage dependent effect of the epsilon4 allele on performance: memory decay or forgetting was slower in epsilon4 carriers, as measured by localization error and after controlling for misbinding errors. Furthermore epsilon4 carriers made less misbinding errors. These findings were specific to male carriers only. Thus, male epsilon4 carriers are at a behavioral advantage in midlife on a sensitive task of short-term memory. The results would be consistent with an antagonistic pleiotropy hypothesis and hightight the interaction of gender on the influence of APOE in cognition. PMID- 28086186 TI - Wet deposition and soil content of Beryllium - 7 in a micro-watershed of Minas Gerais (Brazil). AB - Beryllium-7 (7Be) is a natural radionuclide of cosmogenic origin, normally used as a tracer for several environmental processes; such as soil redistribution, sediment source discrimination, atmospheric mass transport, and trace metal scavenging from the atmosphere. In this research the content of 7Be in soil, its seasonal variation throughout the year and its relationship with the rainfall regime in the Mato Frio creek micro-watershed was investigated, to assess its potential use in estimating soil erosion. The 7Be content in soil shows a marked variation throughout the year. Minimum 7Be values were observed in the dry season (from April to September) and were between 7 and 14 times higher in the rainy season (from October to March). The seasonal oscillations in 7Be soil content could be explained by the asymmetric rainfall regime. A highly linear relationship between rainfall amount and 7Be deposition was observed in rain water. A good agreement between 7Be soil content and 7Be atmospheric deposition was noticed, mainly in wet months. 7Be penetration in soil reaches a 5 cm depth, this could be explained by the soil type in the region. The soils are Acrisol type, characterized by low pH values and clay illuviation in deeper layers of the soil. In some regions of Brazil special attention should be paid if this radionuclide will be used as soil erosion tracer, taking into account the soil origin and its particular properties. PMID- 28086187 TI - Exposure of luminous marine bacteria to low-dose gamma-radiation. AB - The study addresses biological effects of low-dose gamma-radiation. Radioactive 137Cs-containing particles were used as model sources of gamma-radiation. Luminous marine bacterium Photobacterium phosphoreum was used as a bioassay with the bioluminescent intensity as the physiological parameter tested. To investigate the sensitivity of the bacteria to the low-dose gamma-radiation exposure (<=250 mGy), the irradiation conditions were varied as follows: bioluminescence intensity was measured at 5, 10, and 20 degrees S for 175, 100, and 47 h, respectively, at different dose rates (up to 4100 MUGy/h). There was no noticeable effect of gamma-radiation at 5 and 10 degrees S, while the 20 degrees S exposure revealed authentic bioluminescence inhibition. The 20 degrees S results of gamma-radiation exposure were compared to those for low-dose alpha- and beta-radiation exposures studied previously under comparable experimental conditions. In contrast to ionizing radiation of alpha and beta types, gamma emission did not initiate bacterial bioluminescence activation (adaptive response). As with alpha- and beta-radiation, gamma-emission did not demonstrate monotonic dose-effect dependencies; the bioluminescence inhibition efficiency was found to be related to the exposure time, while no dose rate dependence was found. The sequence analysis of 16S ribosomal RNA gene did not reveal a mutagenic effect of low-dose gamma radiation. The exposure time that caused 50% bioluminescence inhibition was suggested as a test parameter for radiotoxicity evaluation under conditions of chronic low-dose gamma irradiation. PMID- 28086188 TI - Self and informant report ratings of psychopathology in genetic generalized epilepsy. AB - The psychological sequelae of genetic generalized epilepsies (GGE) is of growing research interest, with up to a third of all adults with GGE experiencing significant psychiatric comorbidity according to a recent systematic review. A number of unexplored questions remain. Firstly, there is insufficient evidence to determine relative prevalence of psychopathology between GGE syndromes. Secondly, the degree to which self-report and informant-report questionnaires accord in adults with epilepsy is unknown. Finally, while epilepsy severity is one likely predictor of worse psychopathology in GGE, evidence regarding other possible contributing factors such as epilepsy duration and antiepileptic drugs (AEDs) has been equivocal. The potential impact of subclinical epileptiform discharges remains unexplored. Self-report psychopathology symptoms across six DSM-Oriented Subscales were prospectively measured in 60 adults with GGE, with informant report provided for a subset of 47. We assessed the burden of symptoms from both self- and informant-report, and the relationship between clinical epilepsy variables and self-reported symptoms. Results showed elevated symptoms in almost half of the sample overall. Depression and anxiety were the most commonly reported types of symptoms. There was a trend towards greater symptoms endorsement by self-report, and relatively modest interrater agreement. Symptoms of ADHD were significantly positively associated with number of AEDs currently prescribed. Other psychopathology symptoms were not significantly predicted by epilepsy duration, seizure-free duration or total duration of epileptiform discharges over a 24-hour period. The high prevalence of psychological needs suggests that routine screening of psychopathology and provision of psychoeducation may be essential to improving patient care and outcomes. Further investigation is required to better understand predictive and causal factors for psychopathology in GGE. PMID- 28086189 TI - 'Epileptic', 'epileptic person' or 'person with epilepsy'? Bringing quantitative and qualitative evidence on the views of UK patients and carers to the terminology debate. AB - How to refer to someone with epilepsy is a divisive topic. Arguments for and against different approaches, including traditional adjective labels, disability first labels, and person-first terms have been presented. The preferences of those with epilepsy and their family and friends have, though, never been determined. This study provides this information for the first time. Via epilepsy interest groups and organizations in the UK and Republic of Ireland, 638 patients and 333 significant others completed an online survey. Three distinct phrases were presented: "They're epileptic" (traditional label), "They're an epileptic person" (disability-first) and "That person has epilepsy" (person-first). Participants identified which they preferred and explained their choices. Patients' median age was 39, with 69% having experienced seizures in the prior 12months. Significant others were typically parents. Most (86.7%) patients and significant others (93.4%) favored the person-first term. Traditional and disability-first terms were "Disliked"/"Strongly disliked". Regression found it was not possible to reliably distinguish between participants favoring the different terms on the basis of demographics. Qualitative analysis of answers to open-ended questions, however, revealed most favored person-first terminology as by not including the word 'epileptic' and by affirming personhood before disability, it was felt to less likely restrict a listener's expectations or evoke the condition's negative association. It was also considered to suggest the person being referred to might have some mastery over their condition. The findings indicate consensus amongst these key stakeholders others for the use of person-first terminology in English. A truly informed debate on the topic can now begin. PMID- 28086190 TI - Attention deficits in children with epilepsy: Preliminary findings. AB - OBJECTIVE: Attention difficulties are a common clinical complaint among children with epilepsy. We aimed to compare a range of attentional abilities between groups of children with two common epilepsy syndromes, Temporal Lobe Epilepsy (TLE) and Idiopathic Generalized Epilepsy (IGE), and to healthy controls. We also investigated whether epilepsy factors (laterality of seizure focus, epilepsy onset, duration, and severity) were related to attentional abilities. METHODS: Multiple dimensions of attention (selective, sustained, and divided attention and attentional control) were assessed directly with standardized neuropsychological measures in 101 children aged 6-16years (23 children with TLE, 20 with IGE and 58 healthy controls). Attention was also assessed indirectly, via a parent-report measure. RESULTS: Children with TLE performed worse than children with IGE (p=0.013) and healthy controls (p<0.001) on a test of attentional control, but no between-group differences were apparent on tests of other attentional abilities. Compared to healthy controls, greater attention problems were reported by parents of children with TLE (p=0.006) and IGE (p=0.012). Left-hemisphere seizure focus and greater epilepsy severity were associated with poorer attentional control and sustained-divided attention, respectively, but no other epilepsy factors were associated with attentional abilities. SIGNIFICANCE: These findings suggest that children with localization-related epilepsy, but not generalized epilepsy, may be at risk of deficits in attentional control. Interventions aimed at improving attentional control may be targeted at children with localization-related epilepsy, particularly those with a left-hemisphere seizure focus, who appear to be particularly susceptible to this type of attentional deficit. PMID- 28086191 TI - Rationalising vitamin B6 biofortification in crop plants. AB - Vitamin B6 encompasses a group of related compounds (vitamers) that can only be biosynthesised de novo by plants and microorganisms. Enzymatic cofactor and antioxidant functions for vitamin B6 are established in all kingdoms. Human vitamin B6 dietary insufficiency or genetic defects in B6 vitamer interconversion result in various neurological and inflammatory pathologies with several populations at-risk or marginal for vitamin B6 status. Three (rice, wheat and cassava) of the world's top five staple crops do not meet the recommended dietary allowance for vitamin B6, when consumed as a major proportion of the diet. In addition, controlled enhancement of the appropriate B6 vitamer in crops has the potential to confer stress resistance. Thus, crop biofortification strategies represent an opportunity to reduce the risk of deficiency in populations with limited diet diversity and quality, as well as improving stress tolerance. PMID- 28086192 TI - From single cells to our planet-recent advances in using mass spectrometry for spatially resolved metabolomics. AB - Spatial information in the form of 3D digital content has been increasingly integrated into our daily lives. Metabolomic studies parallel this trend with spatial and time resolved information being acquired. Mass spectrometry imaging (MSI), which combines qualitative and quantitative molecular information with spatial information, plays a crucial role in mass spectrometry-based metabolomics. The lateral spatial resolution obtained by MSI continues to improve and allows mass spectrometers to be used as molecular microscopes-enabling the exploration of the cellular and subcellular metabolome. Towards the other end of the scale, MS is also being used to map (image) molecules on our skin, habitats, and entire ecosystems. In this article, we provide a perspective of imaging mass spectrometry for metabolomic studies from the subcellular to planetary scale. PMID- 28086194 TI - Parkin deficiency exacerbate ethanol-induced dopaminergic neurodegeneration by P38 pathway dependent inhibition of autophagy and mitochondrial function. AB - Parkinson's disease (PD) is a neurodegenerative disease characterized by selective degeneration of dopaminergic neurons in the substantia nigra. Parkin (which encoded by Park2), an E3 ubiquitin ligase, is the most frequently mutated gene that has casually been linked to autosomal recessive early onset familial PD. We tested the effect of Park2 on ethanol-induced dopaminergic neurodegeneration in Park2 knockout (KO) transgenic mice after chronic ethanol feeding. Male Park2 wild type (WT) and KO mice (8 weeks old) were fed on a Lieber DeCarli diet containing 6.6% ethanol for 2 weeks, and compared their responses. We found that knockout of Park2 exacerbates ethanol-induced behavioral impairment as well as dopamine depletion. In the mechanism study, we found that knockout of Park2 increased reactive oxygen species (ROS) production, mitophagy formation, mitochondrial dysfunction, and expression of pro-apoptotic proteins, but decreased expression of pro-autophagic proteins. Knockout of Park2 also increased ethanol-induced activation of p38 mitogen-activated protein kinase. In addition, ROS production, mitophagy formation, mitochondrial dysfunction, and expression of pro-apoptotic proteins were increased, but expression of pro-autophagic proteins were decreased by a treatment of ethanol (100MUM) in Park2 siRNA-transfacted PC12 cells (5MUM). Moreover, the exacerbating effects of Park2 deletion on ethanol induced ROS generation, mitophagy, mitochondrial dysfunction as well as cell death were reduced by p38 specific inhibitor (SB203580) in in vitro (10MUM) and in vivo 10mg/kg). Park2 deficiency exacerbates ethanol-induced dopaminergic neuron damage through p38 kinase dependent inhibition of autophagy and mitochondrial function. PMID- 28086193 TI - Cross-talk between lipid and protein carbonylation in a dynamic cardiomyocyte model of mild nitroxidative stress. AB - Reactive oxygen and nitrogen species (ROS/RNS) play an important role in the regulation of cardiac function. Increase in ROS/RNS concentration results in lipid and protein oxidation and is often associated with onset and/or progression of many cardiovascular disorders. However, interplay between lipid and protein modifications has not been simultaneously studied in detail so far. Biomolecule carbonylation is one of the most common biomarkers of oxidative stress. Using a dynamic model of nitroxidative stress we demonstrated rapid changes in biomolecule carbonylation in rat cardiomyocytes. Levels of carbonylated species increased as early as 15min upon treatment with the peroxynitrite donor, 3 morpholinosydnonimine (SIN-1), and decreased to values close to control after 16h. Total (lipids+proteins) vs. protein-specific carbonylation showed different dynamics, with a significant increase in protein-bound carbonyls at later time points. Treatment with SIN-1 in combination with inhibitors of proteasomal and autophagy/lysosomal degradation pathways allowed confirmation of a significant role of the proteasome in the degradation of carbonylated proteins, whereas lipid carbonylation increased in the presence of autophagy/lysosomal inhibitors. Electrophilic aldehydes and ketones formed by lipid peroxidation were identified and relatively quantified using LC-MS/MS. Molecular identity of reactive species was used for data-driven analysis of their protein targets. Combination of different enrichment strategies with LC-MS/MS analysis allowed identification of more than 167 unique proteins with 332 sites modified by electrophilic lipid peroxidation products. Gene ontology analysis of modified proteins demonstrated enrichment of several functional categories including proteins involved in cytoskeleton, extracellular matrix, ion channels and their regulation. Using calcium mobilization assays, the effect of nitroxidative stress on the activity of several ion channels was further confirmed. PMID- 28086195 TI - Zinc deficiency affects the STAT1/3 signaling pathways in part through redox mediated mechanisms. AB - Zinc deficiency affects the development of the central nervous system (CNS) through mechanisms only partially understood. We previously showed that zinc deficiency causes CNS oxidative stress, damaging microtubules and impairing protein nuclear shuttling. STAT1 and STAT3 transcription factors, which require nuclear import for their functions, play major roles in CNS development. Thus, we investigated whether zinc deficiency disrupts STAT1 and STAT3 signaling pathways in the developing fetal CNS, characterizing the involvement of oxidative stress and the cytoskeleton in the adverse effects. Maternal (gestation day 0-19) marginal zinc deficiency (MZD) reduced STAT1 and STAT3 tyrosine phosphorylation and their nuclear translocation in the embryonic day 19 (E19) rat brain. Similar effects were observed in zinc depleted IMR-32 neuroblastoma cells, with an associated decrease in STAT1- and STAT3-dependent gene transactivation. Zinc deficiency caused oxidative stress (increased 4-hydroxynonenal-protein adducts) in E19 brain and IMR-32 cells, which was prevented in cells by supplementation with 0.5mM alpha-lipoic acid (LA). In zinc depleted IMR-32 cells, the low tyrosine phosphorylation of STAT1, but not that of STAT3, recovered upon incubation with LA. STAT1 and STAT3 nuclear transports were also restored by LA. Accordingly, chemical disruption of the cytoskeleton partially reduced STAT1 and STAT3 nuclear levels. In summary, the redox-dependent tyrosine phosphorylation, and oxidant-mediated disruption of the cytoskeleton are involved in the deleterious effects of zinc deficit on STAT1 and STAT3 activation and nuclear translocation. Therefore, disruption of the STAT1 and STAT3 signaling pathways may in part explain the deleterious effects of maternal MZD on fetal brain development. PMID- 28086198 TI - Gastric adenocarinoma of the upper oesophagus: A literature review and case report. AB - BACKGROUND: Ectopic gastric mucosa (EGM) otherwise termed gastric heterotopia or gastric inlet patch occurs in approximately 2.5% of the population. Adenocarcinoma uncommonly involves the upper oesophagus, rarely arising from gastric heterotopia or submucosal glands. Currently, there are 58 cases in the literature of oesophageal adenocarcinoma arising within areas of EGM. To date no paper has differentiated between gastric or intestinal type adenocarcinoma. This case, which describes adenocarcinoma arising within EGM, exhibited a different immunophenotype reminiscent of gastric type glands, in the absence of intestinal metaplasia. This case should be regarded as a different type of carcinoma, consistent with a non-Barrett's oesophagus-associated adenocarcinoma. CLINICAL PRESENTATION: A 63year old female presented with a three month history of progressive cervical dysphagia with no associated weight loss or general malaise. Gastroscopy revealed a suspicious lesion at the cricopharyngeus. Positron emission tomography demonstrated a metabolically active primary lesion without evidence of distant disease. The patient received neo-adjuvant chemotherapy followed by a three stage total oesophagectomy. Histology demonstrated a moderately differentiated adenocarcinoma with gastric immunophenotype and background changes of gastric heterotopia. CONCLUSION: EGM is common but scarcely biopsied for evidence of dysplasia or adenocarcinoma. Whilst malignant progression is rare it is important that endoscopists are aware of the potential. Determining the exact type of adenocarcinoma may have implications for therapeutic approaches. Recognition of EGM at endoscopy may identify patients at greater risk of developing adenocarcinomas of the proximal oesophagus, however, this relationship and the necessity for screening requires more study. PMID- 28086197 TI - Non-linear impact of glutathione depletion on C. elegans life span and stress resistance. AB - The redox environment in cells and organisms is set by low-molecular mass and protein-bound thiols, with glutathione (GSH) representing a major intracellular redox buffer. Subtle thiol oxidation elicits signal transduction processes and adaptive responses to cope with stressors, whereas highly oxidizing conditions may provoke cell death. We here tested how thiol depletion affects life span, stress resistance and stress signaling in the model organism Caenorhabditis elegans. Diethyl maleate (DEM), an alpha,beta-unsaturated carbonyl compound that conjugates to GSH and other thiols, decreased C. elegans life span at a concentration of 1mM. In contrast, low and moderate doses of DEM (10-100uM) increased mean and maximum life span and improved resistance against oxidative stress. DEM-induced life span extension was not detectable in worms deficient in either the FoxO orthologue, DAF-16, or the Nrf2 orthologue, SKN-1, pointing to a collaborative role of the two transcription factors in life span extension induced by thiol depletion. Cytoprotective target genes of DAF-16 and SKN-1 were upregulated after at least 3 days of exposure to 100uM DEM, but not 1mM DEM, whereas only 1mM DEM caused upregulation of egl-1, a gene controlled by a p53 orthologue, CEP-1. In order to test whether depletion of GSH may elicit effects similar to DEM, we suppressed GSH biosynthesis in worms by attenuating gamma glutamylcysteine synthetase (gcs-1) expression through RNAi. The decline in GSH levels elicited by gcs-1 knockdown starting at young adult stage did not impair viability, but increased both stress resistance and life expectancy of the worms. In contrast, gcs-1 knockdown commencing right after hatching impaired nematode stress resistance and rendered young adult worms prone to vulval ruptures during egg-laying. Thus, modest decrease in GSH levels in young adult worms may promote stress resistance and life span, whereas depletion of GSH is detrimental to freshly hatched and developing worms. PMID- 28086199 TI - Association between comorbidity and participation in breast and cervical cancer screening: A systematic review and meta-analysis. AB - BACKGROUND: Comorbidity is associated with poor outcomes for cancer patients but it is less clear how it influences cancer prevention and early detection. This review synthesizes evidence from studies that have quantified the association between comorbidity and participation in breast and cervical screening. METHODS: PubMed, CINAHL and EMBASE databases were systematically searched using key terms related to cancer screening and comorbidity for original research articles published between 1 January 1991 and 21 March 2016. Two reviewers independently screened 1283 studies that met eligibility criteria related to Population (adult, non-cancer populations), Exposure (comorbidity), Comparison (a 'no comorbidity' group), and Outcome (participation in breast cancer or cervical screening). Data was extracted and risk of bias assessed using a standardised tool from the 22 studies identified for inclusion (17 breast; 13 cervical). Meta-analyses were performed for participation in breast and cervical screening, stratified by important study characteristics. RESULTS: The majority of studies were conducted in the United States. Results of individual studies were variable. Most had medium to high risk of bias. Based on the three "low risk of bias" studies, mammography screening was less common among those with comorbidity (pooled Odds Ratio 0.66, 95%CI 0.44-0.88). The one "low risk of bias" study of cervical screening reported a negative association between comorbidity and participation. CONCLUSION: While a definitive conclusion could not be drawn, the results from high quality studies suggest that women with comorbidity are less likely to participate in breast, and possibly cervical, cancer screening. PMID- 28086200 TI - An expert system for selecting wart treatment method. AB - As benign tumors, warts are made through the mediation of Human Papillomavirus (HPV) and may grow on all parts of body, especially hands and feet. There are several treatment methods for this illness. However, none of them can heal all patients. Consequently, physicians are looking for more effective and customized treatments for each patient. They are endeavoring to discover which treatments have better impacts on a particular patient. The aim of this study is to identify the appropriate treatment for two common types of warts (plantar and common) and to predict the responses of two of the best methods (immunotherapy and cryotherapy) to the treatment. As an original work, the study was conducted on 180 patients, with plantar and common warts, who had referred to the dermatology clinic of Ghaem Hospital, Mashhad, Iran. In this study, 90 patients were treated by cryotherapy method with liquid nitrogen and 90 patients with immunotherapy method. The selection of the treatment method was made randomly. A fuzzy logic rule-based system was proposed and implemented to predict the responses to the treatment method. It was observed that the prediction accuracy of immunotherapy and cryotherapy methods was 83.33% and 80.7%, respectively. According to the results obtained, the benefits of this expert system are multifold: assisting physicians in selecting the best treatment method, saving time for patients, reducing the treatment cost, and improving the quality of treatment. PMID- 28086201 TI - The effects of GLP-1 based therapies on postprandial haemodynamics: Two randomised, placebo-controlled trials in overweight type 2 diabetes patients. AB - AIMS: To assess the effects of glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors on postprandial haemodynamics. METHODS: 57 patients with type 2 diabetes (mean+/-SD age 62.8+/-6.9years; BMI 31.8+/-4.1kg/m2; HbA1c 7.3+/-0.6%) were included in an acute (exenatide- or placebo-infusion) and 12-week (liraglutide, sitagliptin or placebo) randomised, placebo-controlled, double-blind trial. Systemic haemodynamics (oscillometric technique and finger photoplethysmography), vascular stiffness (tonometry), and sympathetic nervous system (SNS)-activity (heart rate variability) were determined in the fasting state and following a standardised mixed meal. RESULTS: In both studies, postprandial blood pressure (BP) decreased during placebo intervention. Compared with placebo, acute exenatide-infusion increased postprandial diastolic BP (6.7 [95%-confidence interval 3.6-9.9]mmHg, p<0.001) and vascular resistance (683.6 [438.5-928.8]dyn*s/cm5/1.73m2, p<0.001), while cardiac index decreased (0.6 [0.40.8]L/min/1.73m2; p<0.001). Systolic BP, augmentation index and SNS-activity were unaffected. Twelve-week liraglutide treatment did not affect postprandial haemodynamics, while sitagliptin decreased diastolic BP (3.5 [0.0-6.9] mmHg; p=0.050), vascular resistance (309.9 [66.6 553.1]dyn*s/cm5/1.73m2; p=0.013) and cardiac index (0.3 [0.0-0.6]L/min/1.73m2; p=0.040), compared with placebo. Neither liraglutide nor sitagliptin affected SNS activity or augmentation index. All treatments significantly lowered postprandial glucose levels. CONCLUSIONS: Acute exenatide-infusion prevented the meal-induced decline in diastolic BP, although prolonged liraglutide intervention did not affect postprandial haemodynamics. The meal-induced drop in BP was augmented during sitagliptin-treatment. PMID- 28086202 TI - Easy, fast and environmental friendly method for the simultaneous extraction of the 16 EPA PAHs using magnetic molecular imprinted polymers (mag-MIPs). AB - An easy and environmental friendly method, based on the use of magnetic molecular imprinted polymers (mag-MIPs) is proposed for the simultaneous extraction of the 16 U.S. EPA polycyclic aromatic hydrocarbons (PAHs) priority pollutants. The mag MIPs based extraction protocol is simple, more sensitive and low organic solvent consuming compared to official methods and also adequate for those PAHs more retained in the particulate matter. The new proposed extraction method followed by HPLC determination has been validated and applied to different types of water samples: tap water, river water, lake water and mineral water. PMID- 28086203 TI - MiRNA-34 and stress response. PMID- 28086196 TI - Happily (n)ever after: Aging in the context of oxidative stress, proteostasis loss and cellular senescence. AB - Aging is a complex phenomenon and its impact is becoming more relevant due to the rising life expectancy and because aging itself is the basis for the development of age-related diseases such as cancer, neurodegenerative diseases and type 2 diabetes. Recent years of scientific research have brought up different theories that attempt to explain the aging process. So far, there is no single theory that fully explains all facets of aging. The damage accumulation theory is one of the most accepted theories due to the large body of evidence found over the years. Damage accumulation is thought to be driven, among others, by oxidative stress. This condition results in an excess attack of oxidants on biomolecules, which lead to damage accumulation over time and contribute to the functional involution of cells, tissues and organisms. If oxidative stress persists, cellular senescence is a likely outcome and an important hallmark of aging. Therefore, it becomes crucial to understand how senescent cells function and how they contribute to the aging process. This review will cover cellular senescence features related to the protein pool such as morphological and molecular hallmarks, how oxidative stress promotes protein modifications, how senescent cells cope with them by proteostasis mechanisms, including antioxidant enzymes and proteolytic systems. We will also highlight the nutritional status of senescent cells and aged organisms (including human clinical studies) by exploring trace elements and micronutrients and on their importance to develop strategies that might increase both, life and health span and postpone aging onset. PMID- 28086204 TI - Understanding histone deacetylation in Huntington's disease. PMID- 28086205 TI - Regulation of RIC-3 and of nAChR expression. PMID- 28086206 TI - VTA BDNF enhances social stress-induced compulsive cocaine bingeing. PMID- 28086207 TI - Progress in CSF biomarker discovery in sCJD. PMID- 28086208 TI - Glutamate transporters: The arrestin connection. PMID- 28086209 TI - Pathophysiological role of zinc in ischemic brain injury. PMID- 28086210 TI - Neurons from skin mimic brain holes. PMID- 28086211 TI - Parkinson's disease: no NOP, new hope. PMID- 28086213 TI - Epigenetic regulation of general anesthesia-induced neonatal neurodegeneration. PMID- 28086212 TI - High TMPRSS11D protein expression predicts poor overall survival in non-small cell lung cancer. AB - TMPRSS11D (HAT) belongs to the large type II transmembrane serine protease (TTSP) family, participating in various biological and physiological processes. TMPRSS11D expression has been reported during squamous cell carcinogenesis, however, its expression during non-small cell lung cancer (NSCLC) development has not been studied. In this study, we determined the mRNA and protein expression of TMPRSS11D in NSCLC tumorous and matched adjacent normal tissues by quantitative reverse transcription PCR (qRT-PCR) and tissue microarray immunohistochemistry analysis (TMA-IHC) respectively. TMPRSS11D protein expression in tumorous tissues were correlated with NSCLC patients' clinical characteristics and overall survival. Both TMPRSS11D mRNA and protein expression levels were significantly higher in NSCLC tumorous tissues than in adjacent normal tissues. High TMPRSS11D protein expression was associated with high TNM stages, and high TMPRSS11D protein expression is an independent prognostic marker in NSCLC. Based on our results, we conclude that TMPRSS11D could play a role in NSCLC development and progression. Because of its role in proteolysis of extracellular matrix, targeting TMPRSS11D may prevent the development of metastasis in NSCLC. PMID- 28086214 TI - Weight loss effects of methotrexate and cyclophosphamide. PMID- 28086215 TI - Predictive value of glucose transporter-1 and glucose transporter-3 for survival of cancer patients: A meta-analysis. AB - BACKGROUND AND OBJECTIVE: The role of glucose transporters in cancers remains contradictory. We conducted a systematic review and meta-analysis to assess the association between overall survival and glucose transporter s (GLUTs) 1 and 3 to find an accurate prognostic biomarker. METHODS: We systematically searched the PubMed, EMbase and Medline databases for relevant published studies that were consistent with the eligible criteria up to January 2016, and calculated pooled estimated hazard ratios of GLUT-1 and -3's expressions in different cancer types and ethnic populations. Random-effects models were used to assess estimates from studies with significant heterogeneities. RESULTS: Overall, 12 studies concerning GLUT 1 and 2 studies concerning GLUT 3, which involved 2008 participants when combined, were included in this analysis. We found that overexpression of GLUTs were significantly correlated to poorer survival rates (HR=1.63, 95%CI=1.09-2.44 and HR=1.89, 95%CI=1.28-2.81). In the subgroup analysis, the GLUT 1 up-regulation was correlated with negative overall survival in pancreatic cancer and gastric cancer and with better overall survival in colorectal cancer. In addition, overexpression of GLUT 1 was associated with a poorer prognosis in the Asian population, while no significance was found in the non-Asian subgroup. However, limitations do exist, which could be handled better. CONCLUSIONS: A combination of GLUTs 1 and 3 might help predict malignancy of cancers and direct effective cancer therapy. PMID- 28086216 TI - Galectin-1 inhibits oral-intestinal allergy syndrome. AB - BACKGROUND AND AIMS: The pathogenesis of oral-intestinal allergy syndrome (OIAS) has not been well understood. Published data indicate that galectin (Gal) 1 has immune regulatory functions. This study tests a hypothesis that Gal1 inhibits oral-intestinal allergy syndrome. METHODS: Mice were sensitized to peanut extracts (PE) via the buccal mucosa with or without using Gal1 together. RESULTS: Upon re-exposure to specific antigen, the OIAS mice showed the systemic allergic response, the oral allergic reactions, and intestinal allergic inflammation, including increases in serum histamine, drop of the core temperature, higher levels of PE-specific IgE and interleukin (IL)-4. Increases in mast cell and eosinophil in the oral mucosa and intestinal mucosa were also observed. The OIAS was inhibited by co-administration with Gal1 via a mechanism of suppressing micro RNA (miR)-98 and reversing the expression of IL-10 in CD14+ cells in the intestine. CONCLUSIONS: The OIAS can be induced by applying specific antigens to the oral mucosa, which can be inhibited by co-administration with Gal1. PMID- 28086217 TI - Repurposing an antidandruff agent to treating cancer: zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases. AB - The ubiquitin-proteasome system (UPS) plays a central role in various cellular processes through selectively degrading proteins involved in critical cellular functions. Targeting UPS has been validated as a novel strategy for treating human cancer, as inhibitors of the 20S proteasome catalytic activity are currently in clinical use for treatment of multiple myeloma and other cancers, and the deubiquitinase activity associated with the proteasome is also a valid target for anticancer agents. Recent studies suggested that zinc pyrithione, an FDA-approved antidandruff agent, may have antitumor activity, but the detailed molecular mechanisms remain unclear. Here we report that zinc pyrithione (ZnPT) targets the proteasome-associated DUBs (USP14 and UCHL5) and inhibits their activities, resulting in a rapid accumulation of protein-ubiquitin conjugates, but without inhibiting the proteolytic activities of 20S proteasomes. Furthermore, ZnPT exhibits cytotoxic effects against various cancer cell lines in vitro, selectively kills bone marrow cells from leukemia patients ex vivo, and efficiently inhibits the growth of lung adenocarcinoma cancer cell xenografts in nude mice. This study has identified zinc pyrithione, an FDA-approved pharmacological agent with potential antitumor properties as a proteasomal DUB inhibitor. PMID- 28086218 TI - Sensitization of glycoengineered interferon-beta1a-resistant cancer cells by cFLIP inhibition for enhanced anti-cancer therapy. AB - In this study, we examined the molecular mechanism underlying the resistance of cancer cells to R27T, a glycoengineered version of recombinant human interferon (IFN)-beta1a, and sought to overcome R27T resistance through combination therapy. R27T has been shown to induce anti-proliferation and apoptosis in human OVCAR-3 and MCF-7 cells, but not in HeLa cells. R27T treatment increased caspase-8 activity and the consequent cleavage of caspase-8 and -3 in R27T-sensitive OVCAR 3 cells, but not in R27T-resistant HeLa cells. Conversely, R27T increased the expression of cellular FLICE-like inhibitory protein (cFLIP) in HeLa cells, but not in OVCAR-3 cells. The sensitization of HeLa cells with cFLIP small interfering RNA or 4,5,6,7-tetrabromobenzotriazole (TBB, an inhibitor of casein kinase-2) facilitated R27T-induced caspase activation, and consequently apoptosis. In OVCAR-3-xenografted mice, intraperitoneal administration of R27T showed 2.1-fold higher anti-tumor efficacy than did the control vehicle. The combined administration of R27T and TBB showed the greatest anti-tumor effect in HeLa tumor-bearing mice, reducing the relative tumor volume by 35.7% compared to that in R27T-treated mice. Taken together, our results suggest that R27T has potential as an anti-cancer drug, and combination therapy with cFLIP inhibitors may be an effective strategy for overcoming R27T resistance. PMID- 28086219 TI - Gadd45a deficiency accelerates BCR-ABL driven chronic myelogenous leukemia. AB - The Gadd45a stress sensor gene is a member in the Gadd45 family of genes that includes Gadd45b & Gadd45g. To investigate the effect of GADD45A in the development of CML, syngeneic wild type lethally irradiated mice were reconstituted with either wild type or Gadd45a null myeloid progenitors transduced with a retroviral vector expressing the 210-kD BCR-ABL fusion oncoprotein. Loss of Gadd45a was observed to accelerate BCR-ABL driven CML resulting in the development of a more aggressive disease, a significantly shortened median mice survival time, and increased BCR-ABL expressing leukemic stem/progenitor cells (GFP+Lin- cKit+Sca+). GADD45A deficient progenitors expressing BCR-ABL exhibited increased proliferation and decreased apoptosis relative to WT counterparts, which was associated with enhanced PI3K-AKT-mTOR-4E BP1 signaling, upregulation of p30C/EBPalpha expression, and hyper-activation of p38 and Stat5. Furthermore, Gadd45a expression in samples obtained from CML patients was upregulated in more indolent chronic phase CML samples and down regulated in aggressive accelerated phase CML and blast crisis CML. These results provide novel evidence that Gadd45a functions as a suppressor of BCR/ABL driven leukemia and may provide a unique prognostic marker of CML progression. PMID- 28086220 TI - B-cell lymphomas involving Waldeyer's ring characterized by distinctive clinical and histopathological features: a comparison of pediatric to adult patients. AB - B-cell lymphomas involving Waldeyer's ring (WR) comprise heterogeneous histolopathological subtypes with a wide age range and distinctive clinical features. However, the comparison between pediatric and adult patients is scarce and limited in the literature. Thirty-three cases of B-cell lymphomas involving WR, were collected and evaluated by histolopathological, immunohistochemical and FISH analyses. The 33 cases were categorized into children and adolescents referred as pediatric group (n = 12), aged (3-19) years and the adult group (n = 21), aged (20-84) years. The pediatric group included Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and MUM1-positive-lymphoma in 7, 3 and 2 cases, respectively. While the adult cases comprised of DLBCL, follicular lymphoma, and mucosa associated lymphoid tissue (MALT) lymphoma in 18, 2 and 1 case, respectively. Male gender was predominant in both groups with 3 folds frequency in the pediatric cases compared to 2 folds in the adults counterpart. Pediatric cases showed a significantly higher frequency of stage I disease (P = 0.019), germinal center B-cell (GCB) phenotype (P = 0.011), CD10-positive expression (P = 0.003), and MYC breaks (P = 0.029) compared to adults. However, MUM1 positive expression was less frequently detected in pediatric patients than adults (P = 0.082). BCL2 rearrangement was undetectable in both pediatric and adult groups. On the other hand, adult group had the significantly higher proportion of DLBCL (P < 0.001), BCL2 expression (P = 0.027) and stage II disease (P = 0.047) compared to pediatric group.In conclusion, B-cell lymphomas involving WR presented with a wide age range, and evident variation in clinical features, histopathological subtypes and immunophenotypes between pediatric and adult age groups. PMID- 28086221 TI - Radioprotective effects of Keratinocyte Growth Factor-1 against irradiation induced salivary gland hypofunction. AB - Irradiation can cause salivary gland hypofunction, with hyposalivation producing discomfort, health risks, and reducing function in daily life. Despite increasing translational research interest in radioprotection, there are no satisfactory treatments available. Keratinocyte growth factor-1 stimulates proliferation of salivary epithelial cells or salivary stem/progenitor cells. However, the exact mechanism of its radioprotection against radiation-induced salivary hypofunction is not fully elucidated. Our results reveal that the radioprotective effects of keratinocyte growth factor-1 involved alleviation of growth inhibition and anti apoptotic cell death of human parotid epithelial cells. Furthermore, keratinocyte growth factor-1 protected human parotid epithelial cells through the phosphoinositide 3-kinase - protein kinase B (Akt) pathway and inhibition of p53 mediated apoptosis through activation of mouse double minute 2. Local delivery of keratinocyte growth factor-1 into the irradiated salivary glands could protect radiation-induced salivary cell damages, suppress p53-mediated apoptosis and prevent salivary hypofunction in vivo. This suggests that keratinocyte growth factor-1 is a promising candidate to prevent radiation-induced salivary hypofunction and raise rational development keratinocyte growth factor-1 local delivery system. PMID- 28086222 TI - Leukocytosis and neutrophilia predict outcome in locally advanced esophageal cancer treated with definitive chemoradiation. AB - PURPOSE: To investigate the prognostic value of leukocyte and neutrophil count as biomarkers in patients with locally advanced esophageal squamous cell carcinoma (SCC) undergoing exclusive chemoradiation. RESULTS: A total of 126 patients were identified. Respectively, 33% and 35% displayed baseline leukocytosis and neutrophilia. Estimated 3-year OS and PFS from chemoradiation completion were 31% and 25%, respectively. In univariate analysis, both leukocytosis and neutrophilia were associated with worse OS, PFS, and LRC (p < 0.01). In multivariate analysis, leukocytosis remained an independent risk factor associated with poorer OS, PFS and LRC (p < 0.05), independently from tumor stage and length, with higher prognostic value for OS compared with patients' performance status (PS). MATERIALS AND METHODS: Bi-institutional clinical records from consecutive non operable patients treated between 2003 and 2015 with definitive chemoradiation for locally advanced esophageal carcinoma were reviewed. Leukocytosis and neutrophilia were defined as a leukocyte or neutrophil count over 10 G/L and 7 G/L, respectively. These parameters were studied for their potential correlation with overall survival (OS), progression free survival (PFS), locoregional control (LRC) and distant metastases control (DMC). CONCLUSIONS: Leukocytosis and neutrophilia were independent prognostic factors of poor OS, PFS, and LRC in this bi-institutional series of locally advanced esophageal SCC treated with definitive chemoradiation. Although prospective confirmation is warranted, it is suggested that the leukocyte and neutrophil count parameters might be clinically relevant biomarkers to be considered for further clinical investigations. PMID- 28086224 TI - Asthma and the risk of lung cancer: a meta-analysis. AB - Some studies found that there was a significant association between asthma and the risk of lung cancer. However, the results are inconclusive. Therefore, we performed a meta-analysis. We searched the electronic databases for all relevant articles. Odds ratio (OR) with 95% confidence interval (CI) were used to calculate the strength of the association between asthma and lung cancer risk. Asthma was significantly associated with the increased risk of lung cancer (OR = 1.44; 95% CI 1.31-1.59; P < 0.00001; I2 = 83%). Additionally, asthma patients without smoking also had the increased lung cancer risk. In the subgroup analysis of race and gender, Caucasians, Asians, male, and female patients with asthma showed the increased risk of lung cancer. However, asthma was not significantly associated with lung adenocarcinoma risk. In the stratified analysis by asthma definition, significant associations were found between asthma and lung cancer in self-reported subgroup, questionnaire subgroup, and register databases subgroup. However, no significant association was observed in physician-diagnosed asthma subgroup. In conclusion, this meta-analysis suggested that asthma might be significantly associated with lung cancer risk. PMID- 28086223 TI - Aberrant methylation patterns in colorectal cancer: a meta-analysis. AB - Colorectal cancer is among the leading causes of cancer death worldwide. Despite numerous molecular characterizations of the phenomenon, the exact dynamics of its onset and progression remain elusive. Colorectal cancer onset has been characterized by changes in DNA methylation profiles, that, owing to the stability of their patterns, are promising candidates to shed light on the molecular events laying at the base of this phenomenon.To exploit this stability and reinforce it, we conducted a meta-analysis on publicly available DNA methylation datasets generated on: normal colorectal, adenoma (ADE) and adenocarcinoma (CRC) samples using the Illumina 450k array, in the systems medicine frame, searching for tumor gene episignatures, to produce a carefully selected list of potential drivers, markers and targets of the disease. The analysis proceeds from a differential meta-analysis of the methylation profiles using an analytical pipeline recently developed by our group [1], through network reconstruction, topological and functional analyses, to finally highlight relevant epigenomic features. Our results show that genes already highlighted for their genetic or transcriptional alteration in colorectal cancer are also differentially methylated, reinforcing -regardless of the level of cellular control- their role in the complex of alterations involved in tumorigenesis.These findings were finally validated in an independent cohort from The Cancer Genome Atlas (TCGA). PMID- 28086225 TI - The expression of podoplanin protein is a diagnostic marker to distinguish the early infiltration of esophageal squamous cell carcinoma. AB - The esophageal squamous cell carcinoma (ESCC) is usually develped from low-grade intraepithelial neoplasia (LGIEN) and high-grade intraepithelial neoplasia (HGIEN) to infiltrative squamous cell carcinoma. Till now, it remains hard to screen for infiltration at earlier stages, especially the differentiation between HGEIN and early infiltrative carcinoma. The purpose of this study is to determine a role of podoplanin in differentiating between HGEIN and early infiltrative squamous cell carcinoma. Totally 133 patients pathologically diagnosed with early ESCC and/or precancerous lesions were enrolled.The EnVision two-step IHC staining technique was applied using the monoclonal mouse anti-human Podoplanin antibody (clone number: D2-40). The expressions of PDPN protein on the basal layer of squamous epithelium lesions could be divided into three different patterns: complete type, incomplete (non-continuous) type, or missing type. A diagnosis of HGEIN can be made if the basal layer showed non-continuous or complete expression of PDPN and a diagnosis of early infiltration can be made if the expression of PDPN is completely missing. Our study confirmed that PDPN was a potential biomarker to identify the presence of early infiltrative squamous cell carcinoma. PMID- 28086226 TI - Preclinical pharmacodynamic evaluation of drug candidate SKLB-178 in the treatment of non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is a serious life-threatening malignancy. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as Gefitinib and Erlotinib, are effective clinical medicines for advanced NSCLC patients harboring EGFR-activating mutations. However, this therapy just benefits a small percentage of sufferers. Worse still, all patients treated with drugs ultimately develop resistance. Hence, there is still an unmet medical need among patients with NSCLC. In this account, we report a novel multikinase inhibitor SKLB-178, which potently inhibits both EGFR-activating and resistant mutations, as well as the activities of Src and VEGFR2 kinases. SKLB-178 potently inhibited cancer cell growth in both Gefitinib-sensitive and resistant NSCLC cells. Meanwhile, SKLB-178 significantly suppressed the migration, invasion and tube formation of endothelial cells, and the growth of intersegmental vessel in zebrafish. The in vivo pharmacodynamic studies further demonstrated that SKLB-178 had wider potency than Gefitinib, and could significantly prolong survival of animals in A549 experimental metastasis model. These advantages together with the low toxicity of SKLB-178 indicate that SKLB-178 deserves to be further developed as a potential drug candidate for NSCLC therapy. PMID- 28086227 TI - Matrine alleviates lipopolysaccharide-induced intestinal inflammation and oxidative stress via CCR7 signal. AB - The aim of this study was to investigate the protective effects of matrine on lipopolysaccharide (LPS)-induced inflammation and oxidative stress in vivo and in vitro. The results showed that matrine improved intestinal inflammatory status and oxidative balance and enhanced chemokine receptor 7 (CCR7) expression. In LPS challenged mice and Caco-2 cells, matrine alleviated LPS-induced inflammation and oxidative stress via downregulating pro-inflammatory cytokines (IL-1beta and IL 17) and malondialdehyde (MDA) production. CCR7-siRNA transfection blocked the protective effects of matrine on LPS-induced inflammation and oxidative stress and exacerbated LPS caused injury. In conclusion, matrine alleviates LPS-induced intestinal inflammation and oxidative stress in mice and Caco-2 cells, which may be associated with CCR7 signal. PMID- 28086228 TI - Allergies and risk of colorectal cancer: a systematic review and meta-analysis of observational studies. AB - A history of allergy or allergic condition has been reported to be associated with reduced risk of some types of malignancies. However, the understanding of this association for colorectal cancer (CRC) is controversial. We conducted a meta-analysis of CRC risk in individuals who had history of allergy compared to those without the history of allergic condition. Pumbed and Embase databases were searched for relevant studies. The adjusted relative risk (RR) and 95% confidence interval (CI) were pooled using the random-effects model. Nine studies, including 775, 178 individuals, were eligible for inclusion. The pooled estimate showed no significant association between history of allergy and CRC risk (adjusted RR 1.01, 95 % CI 0.88-1.17). Subgroup analyses confirmed the neutral association stratified by tumor location (colon: n = 6 studies; adjusted RR 1.01, 95 % CI 0.81-1.25; rectum: n = 6 studies; adjusted RR 0.94, 95% CI 0.77-1.15; colorectum: n = 3 studies; adjusted RR 0.92, 95 % CI 0.70 to 1.21), sex (male: n = 4 studies; adjusted RR 0.93, 95 % CI 0.81-1.07; female: n = 6 studies; adjusted RR 0.94, 95 % CI 0.80-1.09) or by allery type (asthma: n = 5 studies; adjusted RR 1.16, 95 % CI 0.96-1.42; hay fever: n = 4 studies; adjusted RR 0.93, 95 % CI 0.86-1.03). Meta-analysis of existing evidence provides a neutral association between allergies and CRC risk. Future well-designed prospective cohort studies should be conducted to better understand this association. PMID- 28086229 TI - Targeting dopamine receptor D3 signalling in inflammation. PMID- 28086230 TI - Environment as therapy: neuroscience for intellectual disability and dementia. PMID- 28086231 TI - Assessing alcohol and nicotine co-consumption in mice. PMID- 28086232 TI - Probing the prostate tumour microenvironment I: impact of glucose deprivation on a cell model of prostate cancer progression. AB - In the developed world, prostate cancer is the most common cancer diagnosis in men. Although prostate cancer initially presents as a non life-threatening disease, 90% of patients will develop castration resistant prostate cancer (CRPC), which preludes distant metastasis and is largely accountable for prostate cancer associated deaths. This is because as yet, there are no viable molecular therapeutic targets for effective treatment of CRPC. It is now widely accepted that cancer cells can alter their metabolic profile during the course of tumourgenesis and metastasis such that they are able to survive in oxygen and nutrient-poor environments. This work was aimed towards gaining greater mechanistic understanding of how such 'stresses' in the tumour microenvironment impact on both androgen sensitive (LNCaP) and androgen independent (LNCaP-abl and LNCaP-abl-Hof) prostate cancer cell lines. Here we have applied technically robust and reproducible label-free liquid chromatography mass spectrometry analysis for comprehensive proteomic profiling of prostate cancer cell lines under nutrient deficient (low glucose) conditions. This led to the identification of approximately 4,000 proteins - one of the largest protein datasets for prostate cancer cell lines established to date. The biological and clinical significance of proteins showing a significant change in expression as result of low glucose conditions was established. Novel, intuitive workflows were subsequently implemented to ensure the verification of selected proteins of interest in a robust, reproducible and high throughput manner. Overall, these data suggest that this strategy supports identification of protein biomarkers of prostate cancer progression and potential therapeutic targets for CRPC. PMID- 28086234 TI - A circuitry for sleep in Parkinson's disease. PMID- 28086233 TI - A novel benzimidazole derivative, MBIC inhibits tumor growth and promotes apoptosis via activation of ROS-dependent JNK signaling pathway in hepatocellular carcinoma. AB - A prior screening programme carried out using MTT assay by our group identified a series of novel benzimidazole derivatives, among which Methyl 2-(5-fluoro-2 hydroxyphenyl)-1H- benzo[d]imidazole-5-carboxylate (MBIC) showed highest anticancer efficacy compared to that of chemotherapeutic agent, cisplatin. In the present study, we found that MBIC inhibited cell viability in different hepatocellular carcinoma (HCC) cell lines without exerting significant cytotoxic effects on normal liver cells. Annexin V-FITC/PI flow cytometry analysis and Western blotting results indicated that MBIC can induce apoptosis in HCC cells, which was found to be mediated through mitochondria associated proteins ultimately leading to the activation of caspase-3. The exposure to MBIC also resulted in remarkable impairment of HCC cell migration and invasion. In addition, treatment with MBIC led to a rapid generation of reactive oxygen species (ROS) and substantial activation of c-Jun-N-terminal kinase (JNK). The depletion of ROS by N-Acetyl cysteine (NAC) partially blocked MBIC-induced apoptosis and JNK activation in HCC cells. Finally, MBIC significantly inhibited tumor growth at a dose of 25 mg/kg in an orthotopic HCC mouse model. Taken together, these results demonstrate that MBIC may inhibit cell proliferation via ROS-mediated activation of the JNK signaling cascade in HCC cells. PMID- 28086235 TI - A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer. AB - Cancer metastasis is the main reason for poor patient survival. Tumor cells delaminate from the primary tumor by induction of epithelial-mesenchymal transition (EMT). EMT is mediated by key transcription factors, including ZEB1, activated by tumor cell interactions with stromal cells and the extracellular matrix (ECM). ZEB1-mediated EMT and motility is accompanied by substantial cell reprogramming and the acquisition of a stemness phenotype. However, understanding of the underlying mechanism is still incomplete. We identified hyaluronic acid (HA), one major ECM proteoglycan and enriched in mammary tumors, to support EMT and enhance ZEB1 expression in cooperation with CD44s. In breast cancer cell lines HA is synthesized mainly by HAS2, which was already shown to be implicated in cancer progression. ZEB1 and HAS2 expression strongly correlates in various cancer entities and high HAS2 levels associate with an early relapse. We identified HAS2, tumor cell-derived HA and ZEB1 to form a positive feedback loop as ZEB1, elevated by HA, directly activates HAS2 expression. In an in vitro differentiation model HA-conditioned medium of breast cancer cells is enhancing osteoclast formation, an indicator of tumor cell-induced osteolysis that facilitates formation of bone metastasis. In combination with the previously identified ZEB1/ESRP1/CD44s feedback loop, we found a novel autocrine mechanism how ZEB1 is accelerating EMT. PMID- 28086236 TI - RYK promotes the stemness of glioblastoma cells via the WNT/ beta-catenin pathway. AB - Glioblastoma multiforme (GBM) is characterized by a strong self-renewal potential and a poor differentiation state. Since receptor-like tyrosine kinase (RYK) activates the WNT/beta-catenin pathway essential for cancer stem cell maintenance, we evaluated its contribution in conferring stemness to GBM cells. Here, we report that Ryk (related-to-receptor tyrosine kinase), an atypical tyrosine kinase receptor, is upregulated in samples from GBM patients as well as in GSCs. Ryk overexpression confers stemness properties to GBM cells through the modulation of the canonical Wnt signaling and by promoting the activation of pluripotency-related transcription factor circuitry and neurosphere formation ability. In contrast, siRNA-mediated knockdown of Ryk expression suppresses this stem-like phenotype. Rescue experiments reveal that stemness-promoting activity of Ryk is attributable, at least in part, to beta-catenin stabilization. Furthermore, Ryk overexpression improves cell motility and anchorage independent cell growth. Taken together, our findings demonstrate that Ryk promotes stem cell like and tumorigenic features to glioma cells its essential for the maintenance of GSCs and could be a target of novel therapies. PMID- 28086237 TI - A prospective birth cohort study of different risk factors for development of allergic diseases in offspring of non-atopic parents. AB - BACKGROUND: Allergic diseases are thought to be inherited. Prevalence of allergic diseases has, however, increased dramatically in last decades, suggesting environmental causes for the development of allergic diseases. OBJECTIVE: We studied risk factors associated with the development of atopic dermatitis (AD), allergic rhinitis (AR) and asthma (AS) in children of non-atopic parents in a subtropical country. METHODS: In a birth cohort of 1,497 newborns, parents were prenatally enrolled and validated for allergic diseases by questionnaire, physician-verified and total or specific Immunoglobulin E (IgE) levels; 1,236 and 756 children, respectively, completed their 3-year and 6-year follow-up. Clinical examination, questionnaire, and blood samples for total and specific IgE of the children were collected at each follow-up visit. RESULTS: Prevalence of AD, AR and AS was, respectively, 8.2%, 30.8% and 12.4% in children of non-atopic parents. Prevalence of AR (p<.001) and AS (p=.018) was significantly higher in children of parents who were both atopic. A combination of Cesarean section (C/S) and breastfeeding for more than 1 month showed the highest risk for AD (OR=3.111, p=.006). Infants living in homes with curtains and no air filters had the highest risk for AR (OR=2.647, p<.001), and male infants of non-atopic parents living in homes without air filters had the highest risk for AS (OR=1.930, p=.039). CONCLUSIONS: Breastfeeding and C/S affect development of AD. Gender, use of curtains and/or air filters affect AR and AS, suggesting that control of the perinatal environment is necessary for the prevention of atopic diseases in children of non-atopic parents. PMID- 28086238 TI - Exploring the medication duration based on the effect of traditional Chinese medicine on postoperative stage I-III colorectal patients: a retrospective cohort study. AB - PURPOSE: To clarify the effect of tradional Chinese medicine (TCM) on different stage patients and to explore medication duration based on survival analysis. RESULTS: 523 and 294 patients were respectively in the TCM group and the control group. For all patients, 6-year disease-free survival (DFS) was 57.6% after TCM and 46.6% after non-TCM (p = 0.0006). 6-year DFS for patients with stage I disease in the TCM group was 79.5% compared with 89.1% in the control group (p = 0.65). For patients with stage II disease, 6-year DFS was 63.1% in the TCM group compared with 50.2% in the control group (p = 0.054), and for patients with stage III disease, it was 43.3% in the TCM group compared with 22.0% in the control group (p = 0.0000). MATERIALS AND METHODS: Data for patients with stage I-III disease between 2004 and 2013 were retrieved for this study, who underwent TCM after surgery were in the TCM group and the others were in the control group. Clinic appointments or phone were used to collect data by research assistants. Survival data were collected on Nov 2015 from the database, which is continuously updated by the researchers. CONCLUSIONS: TCM is associated with significantly improved disease-free survival, in particular for patients with stage III disease. Among of these, TCM is not necessary for patients with stage I disease, and postoperative patients with stage II disease should be recommended to take 2 years of TCM. For patients with stage III disease, adherence to medication of TCM during the 6-year follow-up is worthy of being recommended. PMID- 28086239 TI - Elevated fibrous sheath interacting protein 1 levels are associated with poor prognosis in non-small cell lung cancer patients. AB - In this study, we examined the expression and prognostic value of fibrous sheath interacting protein 1 (FSIP1) in 202 non-small cell lung cancer (NSCLC) patients who underwent lung cancer resection at Shengjing Hospital of China Medical University. FSIP1 mRNA and protein expression were measured in NSCLC tissues and non-tumor adjacent tissues (NATs), and Harrell's concordance index (c-index) was used to evaluate the ability of FSIP1 to predict prognosis. FSIP1 mRNA and protein expression was higher in NSCLC tissues than in NATs. Survival analysis revealed the 5-year overall survival rate to be 35.4% in the FSIP1-positive group and 56.3% in the FSIP1-negative group, and FSIP1-positive status was an independent prognostic factor for poor overall survival. The c-index value of FSIP1 for overall survival was greater than that of Ki67, and the addition of FSIP1 status increased the c-index value of the TNM staging system. These results suggest that evaluating FSIP1 status in addition to TNM stage during routine pathological examinations could improve prognostic predictions in NSCLC patients. PMID- 28086240 TI - ABL2 suppresses FLT3-ITD-induced cell proliferation through negative regulation of AKT signaling. AB - The type III receptor tyrosine kinase FLT3 is one of the most commonly mutated oncogenes in acute myeloid leukemia (AML). Inhibition of mutated FLT3 in combination with chemotherapy has displayed promising results in clinical trials. However, one of the major obstacles in targeting FLT3 is the development of resistant disease due to secondary mutations in FLT3 that lead to relapse. FLT3 and its oncogenic mutants signal through associating proteins that activate downstream signaling. Thus, targeting proteins that interact with FLT3 and their downstream signaling cascades can be an alternative approach to treat FLT3 dependent AML. We used an SH2 domain array screen to identify novel FLT3 interacting proteins and identified ABL2 as a potent interacting partner of FLT3. To understand the role of ABL2 in FLT3-mediated biological and cellular events, we used the murine pro-B cell line Ba/F3 as a model system. Overexpression of ABL2 in Ba/F3 cells expressing an oncogenic mutant of FLT3 (FLT3-ITD) resulted in partial inhibition of FLT3-ITD-dependent cell proliferation and colony formation. ABL2 expression did not alter the kinase activity of FLT3, its ubiquitination or its stability. However, it partially blocked FLT3-induced AKT phosphorylation without affecting ERK1/2 and p38 activation. Taken together our data suggest that ABL2 acts as negative regulator of signaling downstream of FLT3. PMID- 28086241 TI - LncRNA-SLC6A9-5:2: A potent sensitizer in 131I-resistant papillary thyroid carcinoma with PARP-1 induction. AB - Recent studies have indicated that long non-coding RNAs play crucial roles in numerous cancers, including thyroid cancer, while their function in the mechanism of thyroid cancer 131I resistance has not been elucidated to date. The present study identified a functional long non-coding RNA, SLC6A9-5:2, which was involved in the radioactive therapy resistance of thyroid cancer. We demonstrated that SLC6A9-5:2 was remarkably downregulated in 131I-resistant thyroid cancer cell lines and 131I-insensitive patients and was positively correlated with Poly (ADP ribose) polymerase 1 (PARP-1) expression and its activation. After downregulating SLC6A9 or blocking PARP-1 artificially, the sensitive thyroid cancer cells mostly displayed a tolerant phenotype under 131I exposure. Furthermore, SLC6A9-5:2 overexpression was positively correlated with PARP-1 mRNA and protein levels, which restored the sensitivity of resistant thyroid cancer cells. The present study further revealed that cancer cell death was primarily caused by ATP exhaustion in excessive DNA repair with high PARP-1 activity. In patients with thyroid cancer, a positive correlation between SLC6A9-5:2 and PARP-1 was identified, and low SLC6A9-5:2 expression was associated with a worse prognosis of papillary thyroid carcinoma. Hence, our data provide a new lncRNA-mediated regulatory mechanism implying that SLC6A9-5:2 can be used as a novel therapeutic target for 131I-resistant thyroid cancer. PMID- 28086244 TI - Approach to Total Knee Replacement: A Randomized Double Blind Study between Medial Parapatellar and Midvastus Approach in the Early Postoperative Period in Asian Population. AB - The purpose of this randomized study was to compare clinical and surgical outcomes of total knee replacements (TKRs) in the early postoperative period using midvastus approach versus medial parapatellar approach in Asian population in a double blind manner. Forty-two knees each were operated using midvastus approach and the medial parapatellar approach. Clinical parameters that were evaluated included Knee Society score (KSS); knee pain using visual analogue scale (VAS) on day 1, 1 week, and 1 month; time required to straight leg raise (SLR); patellar tracking; mean extensor lag at 1 week and 1 month; and time of discharge from the hospital. Surgical parameters that were evaluated included tourniquet time, incidence of lateral retinacular release, estimated blood loss, and any complications during the surgery. KSS at 1 week and 1 month postoperatively were significantly higher in the midvastus group as compared with medial parapatellar group; though similar at 3 months, 6 months, and 1 year. The patients in midvastus group required fewer number of lateral retinacular releases; achieved SLR earlier; had less mean extensor lag at 1 week; had less mean VAS score at day 1, 1 week, and 1 month; and had shorter hospital stay. There was no significant difference in the mean tourniquet time and estimated blood loss. One patient had patellar maltracking in the medial parapatellar group as compared with none in midvastus group. Midvastus approach to TKR results in quicker functional recovery with early discharge and rehabilitation in the Asian population as compared with medial parapatellar approach. PMID- 28086243 TI - Multi-level suppression of receptor-PI3K-mTORC1 by fatty acid synthase inhibitors is crucial for their efficacy against ovarian cancer cells. AB - Receptor-PI3K-mTORC1 signaling and fatty acid synthase (FASN)-regulated lipid biosynthesis harbor numerous drug targets and are molecularly connected. We hypothesize that unraveling the mechanisms of pathway cross-talk will be useful for designing novel co-targeting strategies for ovarian cancer (OC). The impact of receptor-PI3K-mTORC1 onto FASN is already well-characterized. However, reverse actions-from FASN towards receptor-PI3K-mTORC1-are still elusive. We show that FASN-blockade impairs receptor-PI3K-mTORC1 signaling at multiple levels. Thin layer chromatography and MALDI-MS/MS reveals that FASN-inhibitors (C75, G28UCM) augment polyunsaturated fatty acids and diminish signaling lipids diacylglycerol (DAG) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) in OC cells (SKOV3, OVCAR-3, A2780, HOC-7). Western blotting and micropatterning demonstrate that FASN-blockers impair phosphorylation/expression of EGF-receptor/ERBB/HER and decrease GRB2-EGF-receptor recruitment leading to PI3K-AKT suppression. FASN inhibitors activate stress response-genes HIF-1alpha-REDD1 (RTP801/DIG2/DDIT4) and AMPKalpha causing mTORC1- and S6-repression. We conclude that FASN-inhibitor mediated blockade of receptor-PI3K-mTORC1 occurs due to a number of distinct but cooperating processes. Moreover, decrease of PI3K-mTORC1 abolishes cross repression of MEK-ERK causing ERK activation. Consequently, the MEK-inhibitor selumetinib/AZD6244, in contrast to the PI3K/mTOR-inhibitor dactolisib/NVP BEZ235, increases growth inhibition when given together with a FASN-blocker. We are the first to provide deep insight on how FASN-inhibition blocks ERBB-PI3K mTORC1 activity at multiple molecular levels. Moreover, our data encourage therapeutic approaches using FASN-antagonists together with MEK-ERK-inhibitors. PMID- 28086245 TI - Use of All-polyethylene Tibial Components in Unicompartmental Knee Arthroplasty Increases the Risk of Early Failure. AB - All-polyethylene (all-poly) tibial designs in primary total knee arthroplasty (TKA) have been reconsidered with excellent clinical outcomes, survivorship, and cost-effectiveness. However, whether all-poly tibial components provided comparable results to metal-backed modular components during unicompartmental knee arthroplasty (UKA) remains unclear. This study compared the clinical outcomes and prevalence of early failure between all-poly and metal-backed modular components in UKA. We retrospectively reviewed the records and radiographs of 101 consecutive UKAs. In total, 51 UKAs were performed using all poly tibial components; 50 others used metal-backed modular components. Clinical and radiographic outcomes, adaptive bone remodeling assessed by radiographic bone density, and early failure prevalence rates were compared. Despite a lack of group differences in clinical and radiographic outcomes (p > 0.1 in all comparisons), adaptive bone remodeling at 2 years after surgery of all-poly UKAs was more progressive compared with metal-backed UKAs (1.2 in all-poly UKA group vs. 0.9 in metal-backed UKA group, p < 0.001). In addition, 6 of 51 all-poly UKAs failed within 2 years postoperatively, whereas no metal-backed UKAs failed (11% in all-poly UKA group vs. 0% in metal-backed UKA group, p = 0.027). All-poly tibial component use during UKA increased the risk of early failure, which may be due to a failure in tibial loading distribution. PMID- 28086246 TI - [Sleep at Altitude]. AB - Advancing infrastructure of mountain regions allows not only well-prepared mountaineers, but also elderly people with pre-existing illness the stay at high altitudes. Based on the hypoxic conditions, low oxygen saturation values are reached, which cause severe hypoxemia in the tissue. Symptoms of acute mountain sickness appear even at moderate altitude, which are manifested during sleep. Patients suffering from sleep apnea are at high risk, because of the obstructive ventilation disorder in combination with less oxygen availability. Concurrently, gender differences play a decisive role. Due to the respiratory stabilizing impact of estrogen, women are faster in adapting to altitude differences. A reduction of sleep duration and extended wake phases are shown, which causes lower sleep sufficiency. With continued rise of altitude, the arousal-index increases. For individual differences concerning altitude induced problems, individual acclimatization protocols are needed. Well prepared pre acclimatization could prevent altitude induced sleep problems, as well as the treatment of such. PMID- 28086247 TI - [Social Medical Consequences of Uveitis in Childhood and Adolescence: Results of a Pilot Study]. AB - Background Chronic illness - such as uveitis - may lead to socio-economic consequences, and poorer quality of life. Objective To study the influence of uveitis on quality of life and professional development. Material and Methods Prospective evaluation of juvenile patients with uveitis (age < 18 years, classification of uveitis as in Standardization of Uveitis Nomenclature [SUN] criteria, duration of disease >= 12 months) seen in a tertiary referral centre. Influence of uveitis on quality of life, recreational activities, educational training and development of severe disability were analysed. Results were correlated to clinical data, and analysed by descriptive statistics. Results 39 patients of 49 (80 %) had anterior uveitis (69.4 % in both eyes), of which 34 (69 %) presented with associated systemic disease (juvenile idiopathic arthritis, n = 28). 33 (80 %) had developed complications caused by uveitis. 15 patients (31 %) had undergone ophthalmic surgery due to these complications. Many patients were treated with conventional (n = 37; 76 %) and biological (n = 18; 37 %) disease modifying antirheumatic drugs (DMARDs). In 41 % of the cases, quality of life and recreational time (23 %) were markedly reduced. Sick leave from pre-school or school because of uveitis (mean 12.5 days/year; 15 % > 20 days) was recorded in 32 patients (65 %). Uveitis negatively influenced school education in 29 %, and resulted in the necessity to repeat class (n = 3) or to change school (n = 3). Severe disability due to uveitis was found in 30 % of the patients. Conclusions Uveitis in childhood and adolescence may have a substantial impact on social and professional perspectives. Uveitis may result in severe disability even in early childhood. PMID- 28086248 TI - [Development of Endothelial Cell Density after Penetrating Keratoplasty in Patients with Fuchs Dystrophy or Keratoconus - Comparison of Excimer Laser and Mechanical Trephination]. AB - Purpose The aim of this retrospective study was to compare the development of endothelial cell density (ECD) after penetrating keratoplasty (PKP) in patients with Fuchs dystrophy (FD), keratoconus (KC) or "other diagnoses" (OD), depending on the type of trephination. Patients and Methods In 104 eyes with Fuchs dystrophy, keratoconus or "other diagnoses", the ECD after PKP using either excimer laser (EXC) or mechanical trephination (MECH) was registered after 1.5, 6, 12, 18 and 24 months. With linear and exponential regression models, the endothelial cell loss (ECL) was determined as absolute and percentage cell loss per year. Results For the entire group of patients, ECD was significantly higher after EXC-PKP during the full range of follow-up (except 6 months). With a linear regression model, there was no significant difference in the absolute ECL per year (p = 0.084), but with an exponential regression model, there was a significant difference in the percentage ECL per year (p = 0.021) in favour of EXC trephination. For keratoconus (n = 33), except for the 24-month-follow-up (p = 0.035), ECD was not significantly different on the basis of EXC vs. MECH. With a linear regression model, there was a significant difference in the absolute ECL per year (p = 0.015) in favour of EXC-trephination, but with an exponential regression model there was no significant difference in the percentage ECL per year (p = 0.088) between the two types of threphination. In patients with FUCHS (n = 35) - except for the 6-week-follow-up (p = 0.024) - ECD was not significantly different for EXC vs. MECH. With linear/exponential regression model, the ECL per year was not significantly different in favour of any type of trephination (p = 0.287/p = 0.121). In patients with OD (n = 36), ECD was not significantly different for EXC vs. MECH. With a linear/exponential regression model, the ECL per year was not significantly different in favour of any type of trephination (p = 0.494/p = 0.787). Conclusion During the first 24 months after PKP, a significantly higher ECD and a significantly lower percentage of ECL per year was observed after EXC trephination for the entire group of patients. For the different diagnostic groups KC, FD and OD, no significant difference in ECD or ECL loss was noticed over a range of follow-up intervals. This may most likely be attributed to the small number of patients in the three subgroups. PMID- 28086249 TI - [Classical Medical Mistakes - Lack of Appreciation of Psychological Components]. AB - Detailed evidence for psychogenic effects after an accident: evidence from 3 expert reports. PMID- 28086250 TI - [New Developments in Cataract Surgery]. AB - Recent technological innovations in cataract surgery have made the procedure even more precise and safe and the odds of having a highly satisfied patient even higher. These innovations include visualisation systems - such as intraoperative aberrometry - which are particularly helpful when it comes to implanting toric IOLs, where even a slight rotation or misalignment can significantly reduce the postoperative visual quality. Another way to ensure the exact positioning of a toric IOL is to create a mark by making an intrastromal incision using the femtosecond laser. The latter technology has increased the precision of capsulotomy and other steps of the operation and has been successfully employed in patients with a challenging clinical profile, including paediatric and hypermature cataracts. The femtosecond laser, however, induces an increase in intraocular prostaglandins, which can lead to miosis. Applying topical NSAIDs before starting surgery has proved to be effective in coping with the consequences of the increase in prostaglandins. Good vision without using glasses for near, intermediate and far distances remains a goal for many patients. IOLs with extended depths of focus (EDOF) technology can provide this comfort - to some but not all patients. An intraocular sensor, Eyemate, that is implanted during cataract surgery, enables the glaucoma patient to check his or her IOP at any time and improves the management of glaucoma and its main risk factor, elevated IOP. Several methods - drugs or nutritive agents - are said to prevent cataractogenesis. These studies have probably to be taken with the proverbial grain of salt. PMID- 28086251 TI - [Current Status of Electronic "Continuous" Eye Pressure Measurements]. AB - Intraocular pressure (IOP) is generally measured at individual points and usually only once, but rarely more often, during office hours and with various different instruments. This is probably inadequate for diagnosis, assessment of progression, and therapeutic decision making, since the IOP is not a static measurement, but rather one that is subject to greater or lesser fluctuations over shorter or longer periods. This has prompted the desire for more regular or even continuous measurements. This can be achieved with self-tonometers (not discussed in this article) or by using electronic aids with sensors in the eye (invasive; in the intraocular lens, in the ciliary sulcus, on the iris, in the posterior or anterior chamber, suprachoroidal or subconjunctival) or on the eye (non-invasive; sensor contact lens). Despite numerous advances and miniaturisations, there is as yet still no continuous measurement technique (either invasive or non-invasive) that can be used routinely, but development of such a device is at an advanced stage. PMID- 28086252 TI - [Buckling Surgery: Old Fashioned or Cutting Edge?] AB - For many decades, scleral buckling surgery was the only reasonable surgical procedure in eyes with primary rhegmatogenous retinal detachment. In recent years, primary vitrectomy has apparently become the treatment of choice, although evidence from comparative clinical trials is missing. In this article, data from clinical trials and indications for buckling surgery are presented. PMID- 28086253 TI - [Vision Loss after Silicone Oil Surgery]. AB - Silicone oil is an intraocular tamponade that is essential for the treatment of complicated retinal detachment. As a long-term tamponade, it improves retinal reattachment and visual outcome. Unexpectedly, surgery with silicone oil tamponade may result in irreversible visual loss of unknown origin. In this report, we provide a general overview of unexplained visual loss after surgery with silicone oil. The frequency of such reports has increased continuously in recent years. The German Retina Society - supported by Retinanet (http://retina net.uni-koeln.de) - has initiated data collection to gather information about such cases, in cooperation with Cologne University Eye Hospital. Ophthalmologists can provide data about cases of unexplained visual loss anonymously via the "Cologne Clinical Trials Centre" or via augenklinik-silikonoel@uk-koeln.de. PMID- 28086254 TI - [Music and Glaucoma]. AB - Music may have multiple influences on the human organism. A possible therapeutic effect for patients with glaucoma has been postulated, aside from the known impact of music on the cardiovascular system, psychogenic effects and a short term improvement in mental performance (Mozart effect). The higher level of mental stress in patients with glaucoma and type-A personality behaviour may be related to higher intraocular pressure in patients with glaucoma. Relaxing music may have a positive impact in these patients, related to a reduction in intraocular pressure or its fluctuations. However, only limited data exist on the effects of music on intraocular pressure. No clinical studies have yet been performed to investigate the effect of music or music therapy on glaucoma progression. The music of Mozart may influence visual field examinations, possibly due to a positive short term effect on mental performance. This factor needs to be addressed in studies dealing with the effect of music in glaucoma. The relevance of intraocular pressure increases in professional wind instrument players is controversial. An increased level of care might be advisable in patients with advanced glaucoma. The influences of music on humans, altered personality profiles in patients with glaucoma and the studies showing some effect of stress on intraocular pressure stress the relevance of psychological support for glaucoma patients, who are confronted with a disease with a high longterm risk of blindness. PMID- 28086255 TI - [Patient Positioning after Intraocular Surgery]. AB - Gas tamponades are widely used during intraocular surgery. The high surface tension at the intraocular liquid to gas interface is used in retinal detachment and macular surgery, as well as in lamellar corneal transplant surgery. The patient's postoperative posture determines the position of the gas bubble inside the eye. The article describes the development, physical laws and methods for postoperative positioning after intraocular surgery. PMID- 28086256 TI - [Glaucoma Drainage Devices: Tube versus Trabeculectomy Study]. AB - While trabeculectomy with mitomycin C has previously been the gold standard in penetrating glaucoma surgery, glaucoma drainage implants used early within glaucoma surgery were examined in the course of the tube versus trabeculectomy (TVT) study. Glaucoma drainage implants are now being used earlier, as materials are tissue-compatible and surgery has been improved. While in the past, the use of such implants was often carried out after multiple preoperations, implants are now being used at an earlier stage. Glaucoma drainage implants are typically still used in the pseudophakic eye, where 1-2 glaucoma preoperations (e.g. trabeculectomy) have already been performed. PMID- 28086257 TI - [Sport and Glaucoma]. AB - Traumatic changes in the iridocorneal angle, e.g. in ball sports, can lead to secondary glaucoma. High intensity resistance exercise or yoga exercises - such as the headstand - can increase IOP, and deterioration in the visual field and acute narrow angle glaucoma attacks have been described in some case reports. Glaucoma therapy of professional athletes with steroids, carbonic anhydrase inhibitors and beta-blockers can result in positive doping tests. In manifest glaucoma, moderate aerobic exercise is presumably of use because of the IOP lowering effect, improved retinal perfusion and reduction in oxidative stress. PMID- 28086258 TI - [Gonioscopy - How, Why, What for?] AB - Aim Gonioscopy is used to exam the anterior chamber angle and the neighbouring structures. Gonioscopy can be performed using a contact lens, with the patient sitting at the slit lamp or in a supine position. Due to the total inner reflection of the cornea, the anterior chamber angle would otherwise be invisible in a healthy eye. During normal daily clinical routine, gonioscopy is often omitted, due to lack of time, although additional information could be gained. Materials and Methods The aim is to give a summary of the diagnostic possibilities using gonioscopy and to emphasise the importance of this relatively easy clinical method. Results The development of gonioscopy, the appropriate tools, proper procedure at the slit lamp and the most popular grading systems are described. In addition, an overview of detectable pathological changes in the anterior chamber angle is given and future prospects about developments in gonioscopy. Conclusion Gonioscopy can provide additional information otherwise missed by slit lamp examination or ophthalmoscopy alone. Up to now, no (semi )automatic devices have been developed which could completely replace gonioscopy. Therefore gonioscopy remains an important part of a complete ophthalmological examination and should be learned, mastered and performed regularly by every ophthalmologist. PMID- 28086259 TI - Gastrointestinal disorders in joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type: A review for the gastroenterologist. AB - BACKGROUND: Joint hypermobility syndrome (JHS)/Ehlers-Danlos syndrome hypermobility type (EDS-HT) is the most common hereditary non-inflammatory disorder of connective tissue, characterized by a wide range of symptoms, mainly joint hyperextensibility and musculoskeletal symptoms. A majority of patients also experiences gastrointestinal (GI) symptoms. Furthermore, JHS/EDS-HT has specifically been shown to be highly prevalent in patients with functional GI disorders, such as functional dyspepsia and irritable bowel syndrome. PURPOSE: The aim of this review was to examine the nature of GI symptoms and their underlying pathophysiology in JHS/EDS-HT. In addition, we consider the clinical implications of the diagnosis and treatment of JHS/EDS-HT for practicing clinicians in gastroenterology. Observations summarized in this review may furthermore represent the first step toward the identification of a new pathophysiological basis for a substantial subgroup of patients with functional GI disorders. PMID- 28086260 TI - A baseline impedance analysis in neurologically impaired children: A potent parameter for estimating the condition of the esophageal mucosa. AB - BACKGROUND: The aim of the present study was to investigate whether the baseline impedance (BI) value is a useful parameter to evaluate the condition of the esophageal mucosa in neurologically impaired (NI) children undergoing multichannel intraluminal impedance pH measurements (pH/MII). METHODS: The retrospective study included 55 NI patients <=15 years. The patients were divided into acid gastroesophageal reflux disease (GERD), non-acid GERD and GERD (-) groups. Furthermore, the patients in the acid GERD group were subdivided into erosive reflux disease (ERD) and non-erosive reflux disease (NERD) groups. pH/MII parameters and BI values (Z1-6) were compared among three groups or between two groups, respectively. A Spearman's correlation analysis was used for the correlation analysis of pH/MII parameters and BI values. A receiver operator characteristic curve analysis was used to evaluate the optimum cut-off values of BI to discriminate ERD patients. KEY RESULTS: The BI values of the proximal and the distal channels in ERD group were significantly lower than those in NERD group. The BI values of the distal channels demonstrated significant negative correlations with acid exposure related pH/MII parameters. The optimal cut off value of BI in the most distal channel was determined to be 1500 Omega. CONCLUSIONS & INFERENCES: The present study suggested that NI children with reflux esophagitis were likely to suffer mucosal damage up to the proximal esophagus and cut-off BI values may help estimate the presence of reflux esophagitis. Baseline impedance is a potent parameter, reflecting the esophageal mucosal damage in NI children who have difficulty in undergoing endoscopic examinations. PMID- 28086261 TI - Established and emerging methods for assessment of small and large intestinal motility. AB - BACKGROUND: Gastrointestinal symptoms are common in the general population and may originate from disturbances in gut motility. However, fundamental mechanistic understanding of motility remains inadequate, especially of the less accessible regions of the small bowel and colon. Hence, refinement and validation of objective methods to evaluate motility of the whole gut is important. Such techniques may be applied in clinical settings as diagnostic tools, in research to elucidate underlying mechanisms of diseases, and to evaluate how the gut responds to various drugs. A wide array of such methods exists; however, a limited number are used universally due to drawbacks like radiation exposure, lack of standardization, and difficulties interpreting data. In recent years, several new methods such as the 3D-Transit system and magnetic resonance imaging assessments on small bowel and colonic motility have emerged, with the advantages that they are less invasive, use no radiation, and provide much more detailed information. PURPOSE: This review outlines well-established and emerging methods to evaluate small bowel and colonic motility in clinical settings and in research. The latter include the 3D-Transit system, magnetic resonance imaging assessments, and high-resolution manometry. Procedures, indications, and the relative strengths and weaknesses of each method are summarized. PMID- 28086263 TI - Observation of the Ring-Puckering Vibrational Mode in Thietane Cation. AB - We have measured the high-resolution vibrational spectra of a thietane (trimethylene sulfide) cation in the gas phase by employing the vacuum ultraviolet mass-analyzed threshold ionization (VUV-MATI) spectroscopic technique. Peaks in the low-frequency region of the observed MATI spectrum of thietane originate from a progression of the ring-puckering vibrational mode (typical in small heterocyclic molecules), which is successfully reproduced by quantum-chemical calculations with 1D symmetric double-well potentials along the ring puckering coordinates on both the S0 and D0 states, the ground electronic states of neutral and cation of thietane, respectively. The values of the interconversion barrier and the ring-puckering angle on the S0 state, the parameters used for the quantum-chemical calculations, were assumed to be 274 cm 1 and 26 degrees . The barrier and the angle on the D0 state, however, are found to be 48.0 cm-1 and 18.2 degrees , respectively, where such small barrier height and puckering angle for the cation suggest that the conformation of thietane cation on the D0 state should be more planar than that of the thietane neutral. PMID- 28086262 TI - Parenting styles and body mass index: a systematic review of prospective studies among children. AB - BACKGROUND: Parenting style may be an important determinant of an individual's future weight status. However, reviews that evaluate the relationship between parenting style and weight-related outcomes have not focused on prospective studies. METHODS: We systematically searched PubMed, Embase and PsychInfo for studies published between 1995 and 2016 that evaluated the prospective relationship between parenting style experienced in childhood and subsequent weight outcomes. RESULTS: We identified 11 prospective cohort studies. Among the eight studies that categorized parenting style into distinct groups (i.e. authoritative, authoritarian, permissive and neglectful), five provided evidence that authoritative parenting was associated with lower body mass index gains. Among the six highest quality studies, four suggested a protective role of authoritative parenting style against adverse weight-related outcomes. However, only one study controlled for a comprehensive set of confounders, and the small number of studies conducted within certain age groups precluded our ability to ascertain critical periods when parenting style is most strongly related to child weight. CONCLUSIONS: The present literature supports the idea that authoritative parenting may be protective against later overweight and obesity, although findings are mixed. More prospective cohort studies of longer durations, with more sophisticated methods that examine age-varying relationships, and that control for a comprehensive set of confounders, are needed. PMID- 28086264 TI - Structural Insights into the Redox-Sensing Mechanism of MarR-Type Regulator AbfR. AB - As a master redox-sensing MarR-family transcriptional regulator, AbfR participates in oxidative stress responses and virulence regulations in Staphylococcus epidermidis. Here, we present structural insights into the DNA binding mechanism of AbfR in different oxidation states by determining the X-ray crystal structures of a reduced-AbfR/DNA complex, an overoxidized (Cys13-SO2H and Cys13-SO3H) AbfR/DNA, and 2-disulfide cross-linked AbfR dimer. Together with biochemical analyses, our results suggest that the redox regulation of AbfR sensing displays two novel features: (i) the reversible disulfide modification, but not the irreversible overoxidation, significantly abolishes the DNA-binding ability of the AbfR repressor; (ii) either 1-disulfide cross-linked or 2 disulfide cross-linked AbfR dimer is biologically significant. The overoxidized species of AbfR, resembling the reduced AbfR in conformation and retaining the DNA-binding ability, does not exist in biologically significant concentrations, however. The 1-disulfide cross-linked modification endows AbfR with significantly weakened capability for DNA-binding. The 2-disulfide cross-linked AbfR adopts a very "open" conformation that is incompatible with DNA-binding. Overall, the concise oxidation chemistry of the redox-active cysteine allows AbfR to sense and respond to oxidative stress correctly and efficiently. PMID- 28086265 TI - Frontispiece. PMID- 28086275 TI - Studies of Visual Inspection. AB - This paper describes the results of four experiments in a series aimed at understanding and improving visual inspection in general and of small integrated circuits (i.e. 'chips') in particular. Stimuli consisted of chips that, although electrically sound, contained visual anomalies. The first experiment found that the modal duration of eye fixations of trained inspectors was about 200 msec. The most accurate inspectors made the fewest eye fixations and were the fastest. The second experiment evaluated the performance of inspectors at one of the many sequential stages of chip inspection and found that 23% of the chips containing anomalies were accepted, whereas only 2% of the chips without anomalies were rejected. When the same chip was judged more than once by an individual inspector the consistency of her judgment was very high whereas the consistency between inspectors was somewhat less. The third experiment showed that variation by a factor of six in inspection speed led to variation of less than a factor of two in inspection accuracy. The fourth experiment showed that inspection via a ground glass screen is only a little worse than the usual method of looking through a binocular microscope. This was true even though the inspectors had no previous experience with the screen. PMID- 28086276 TI - Monitoring up to 16 Synthetic Television Pictures Showing a Great Deal of Movement. AB - A total of 204 observes watched usually 16 synthetic television pictures for 1 hr. The 8 pictures in the middle 2 columns of the display showed activity inside prison. The 8 pictures in the 2 side columns of the display showed activity just outside prison walls. There were 14 suspicious incidents inside prison, 7 of them serious, and 170 other movements. Just outside prison there were fl auspicious incidents, 1 of them serious, and 5,300 other movements. The observer had to press an alarm button whenever he or she saw a suspicious incident. Suspicious incidents were missed reliably more often when they were in the distance, or of brief duration. When matched for distance and duration, incidents were missed reliably less often inside prison, where there was less other activity, than just outside prison. Inside incidents were missed reliably less often when only 8 inside pictures were watched, than when 4 inside and 4 outside pictures were watched- A telephone call about 10 see before an incident reliably reduced the proportion of detections. If more than 1 picture has to be watched, the maximum desirable number is about 9 when there is a lot of movement. The maximum desirable duration for a spell of work is about 1 hr. Reducing the size of pictures from 40 * 30 cm to 20 * 1.1 cm reliably reduced the proportion of detections. Halving the distance of the observer from the small pictures from 9 to 4-5 ft still left a reliable reduction in the proportion of detections of distant incidents. Observers under 30 yr detected reliably more incidents, and made reliably fewer false detections, than observers over 45yr. When matched for age, prison officers who had previously monitored television pictures were reliably better than prison officers who had not. The experienced prison officers detected reliably more suspicious incidents inside prison than did the civilian observers. PMID- 28086279 TI - Equipment Note The Use of Real-Time Simulation by Means of Animation Film As an Analytical Design Tool in Certain Spatial-Temporal Situations. AB - An animated-film sequence simulating the significant visual aspects of a vehicular trip on a projected but nonexistent airport road system was produced in order to provide a direct, essentially realistic, and immediately comprehensible means of s 'experiencing ' the process of data perception and response required in negotiating the road system safely and accurately to a selected destination. The film objectively and incontrovertibly confirmed the existence of a problem caused by a suspected ergonomic defect in the road-system design. It seems unlikely that such could have been confirmed to the satisfaction of all concerned by the use of any other method before the actual road system was completed and its negotiation could be experienced in situ. The history of this project suggests that film-animation simulation can be a valuable design tool in situations where the fourth dimension is an important factor. Further, it suggests that live-action film of existing situations can be a more valuable aid in analysing and correcting design defects than has been generally appreciated. PMID- 28086289 TI - Use of a Digital Computer For Studying Velocity Judgements of Radar Targets. AB - Ten subjects estimated the velocity of simulated radar targets according to the method of constant stimuli. The experimental procedure was rendered automatic through a PDP 12 digital computer, and the data were processed on line. Less than 50 man-hours were required to complete the experiment, a fact which demonstrates the suitability of a small computer when solving specific problems for system designers. PMID- 28086293 TI - Backmatter. PMID- 28086290 TI - Phonemic Analysis as a Predictor of Error in Aural Communication. AB - A technique is proposed and evaluated for predicting the confusability of elements of an aural message transmitted by native English speakers against a noise background. The results suggest that a relatively simple comparison of the phonemic elements of a message with correspondingly located elements of other possible messages in a communication link allows a good prediction of potential confusions between correspondingly located segments of messages. PMID- 28086294 TI - Regional Photochemical Measurement and Modeling Studies: A Summary of the Air & Waste Management Association International Specialty Conference. AB - This paper summarizes the Air & Waste Management Association's International Specialty Conference, "Regional Photochemical Measurement and Modeling Studies," held in San Diego, California, on November 8-12,1993. The purpose of the conference was to facilitate exchange of information and to initiate better communication and interaction among scientists, air quality managers, regulators, and others involved in or applying tools (models and measurements to support the modeling efforts) that can be used to develop equitable and effective emissions management practices for attainment of ozone standards. Attendees heard more than 350 presentations from authors representing nearly 30 air quality and meteorological measurement and modeling studies from 18 countries. While the primary emphasis of the conference was technical, two policy sessions were included (Plenary and Concluding Sessions) to place the technical results in perspective with the policy issues. The technical agenda was divided into three subjects: Analysis of Field Measurements (results and interpretation), Modeling (status and results), and Other Topics. Papers presented at the conference are being published in a variety of journals or books to meet the needs of the scientific and policy communities. A complete bibliographical listing of the papers presented at the conference is included with this paper. An unexpected outcome of the conference has been the development of an initiative for continuing the intercomparison of goals and scientific findings from regional air quality studies in Europe and North America, entitled "Regional Oxidants Programs Intercomparison" (ROxPIn). This paper will also discuss the goals and objectives of ROxPIn. PMID- 28086295 TI - Polymers as Solid Waste in Municipal Landfills. AB - Synthetic polymers reach municipal landfills as components of products such as waste household paints, packaging films, storage containers, carpet fibers, and absorbent sanitary products. Some polymers in consumer products that reach landfills are designed to photodegrade or biodegrade. This article examines the significance of degradable polymers in management of solid waste in municipal landfills. Most landfills are not designed to photodegrade or biodegrade solid waste. Landfill disposal of stable polymers such as polyacrylics and polyethylenes is not associated with significant polymer degradation or mobility. Stability to photodegradation and biodegradation is an advantage when municipal landfills are used for disposal of polymer products as solid waste. Use of landfill disposal can be a responsible means to manage polymer waste and can be part of an overall waste management plan which includes source reduction, recycling, reuse, composting, and waste-to-energy incineration. PMID- 28086296 TI - Ozone Regimes in or near Forests of the Western United States: I. Regional Patterns. AB - Similarities in ozone regimes at sites in or near forests of the western United States were investigated using hierarchical cluster analysis on a (63 * 17) matrix of frequencies of occurrence of 17 characteristic diurnal patterns in hourly ozone concentrations. Eight groups of sites with similar ozone patterns were identified. Sites within these groups showed geographical consistency at a local scale, but more complex spatial relationships exist regionally. Unlike kriging analyses of ozone concentrations over the United States as a whole and California in particular, our analysis does not identify large areas of gradation in ozone levels. Instead, hotspots linked to populated valleys were identified with gradations in ozone exposure occurring from these hotspot areas. Considering the complex nature of terrain across the West and the restrictive role that such topography plays in atmospheric transport, hotspots in ozone concentrations are more likely than regional gradation from large urban centers. Comparisons of group memberships determined from common univariate statistics (SUM06, SUM08, 7 hour and 24-hour) with our results lead to the conclusion that regional analyses of ozone concentrations using univariate statistics are insensitive to important differences in ozone exposure regimes. Of particular concern is the inability of univariate statistics to consistently discriminate between sites with urban and non-urban characteristics. PMID- 28086299 TI - Super educators. AB - When Cathy Young wants to explain attention deficit hyperactivity disorder (ADHD) to the children she works with, she gives them a Medikidz guide called What's up with Astra? ' Five comic book heroes are on hand to explain health and medical conditions to young adolescents and their parents. PMID- 28086300 TI - MSc Adult Nursing with registration/MSc Mental Health Nursing with registration. PMID- 28086301 TI - Space nursing - the final frontier. AB - A nurse has become president of the Aerospace Medical Association for the first time in its 81-year history. PMID- 28086302 TI - Age-appropriate care. AB - Project groups are working to improve the move between paediatric and adult services for adolescents who receive kidney care. PMID- 28086303 TI - A cause for celebration. AB - One of the buildings reduced to rubble by the earthquake that hit Haiti 12 months ago was the Leogane school of nursing. Many of its students were among those killed in the disaster, which has been made worse by a cholera epidemic. PMID- 28086304 TI - Was the unions' decision right? we asked nurses their opinion. AB - James Broughton, organ donation nurse specialist, NHS Blood and Transplant, Maidstone and Tunbridge Wells: 'The future is unclear at the moment for nurses. I am sure the unions are doing what is right and in their members' best interests.' PMID- 28086305 TI - Work-related allergies can be controlled and prevented. AB - Occupational allergies and irritants often fail to be recognised because many people do not want to admit that they have a problem that is being exacerbated by something they are working with. I am sure that nurses are no different to anyone else in this regard. PMID- 28086306 TI - Cancer survivorship project offers people help and hope. AB - It was good to read of the success of the Helping to Overcome Problems Effectively (HOPE) self-management courses for cancer survivors (features January 5). PMID- 28086307 TI - Obituary. AB - As a sister in Queen Alexandra's Imperial Military Nursing Service, Dora Thornburn, who has died at the age of 90, nursed back to health two Belgian heroes of the Resistance. PMID- 28086308 TI - Screening emergency admissions for MRSA. AB - Dinah Gould's learning zone article on meticillin-resistant Staphylococcus aureus (MRSA) (January 5) is timely. Categories of patients for routine screening must now include relevant emergency admissions (MRSA screening: operational guidance 3 - Department of Health 2010). PMID- 28086310 TI - Flexible model of work-based learning boosts development. AB - I was interested to read your news story, 'Nurses miss out on essential training due to staff shortages' (January 5). As director of the Open University-RCN strategic alliance I would emphasise the importance of investing in continuing professional development (CPD), particularly in times of change and service redesign. PMID- 28086309 TI - An erudite article on the prevention of infection. AB - Preventing healthcare-associated infection (HCAI) is an important challenge to nurses, but it can often Be a dry subject of study. i must congratulate dinah gould on her excellent learning zone article, 'mrsa: implications for hospitals and nursing homes' (January 5). PMID- 28086311 TI - Telephone counselling helps smokers to quit. AB - As a stop smoking trainer and author of You Can Stop Smoking, I was interested to read that Australians who were offered proactive telephone counselling to help them stop smoking had improved abstinence rates and were significantly more likely to have attempted to quit (clinical digest January 5). PMID- 28086312 TI - Starting out passing on a loving message was a huge responsibility. AB - In the final year of my diploma the university gave me the opportunity to choose my final placement. One of the options was a 13-week placement in a hospice. PMID- 28086313 TI - Ministers have a cheek to say nurses should be grateful for NHS salaries. AB - The Department of Health (DH) wants nurses to be more grateful for being NHS employees and plans to spell this out in annual letters telling us how well rewarded we are (news January 5). PMID- 28086314 TI - Cuts to health services leaves region's staff at breaking point. AB - The decision to close 30 beds at Clatterbridge Hospital in Merseyside as part of a drive to save L14 million has prompted an angry reaction from nurses. PMID- 28086315 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28086317 TI - Dig deeper to spot depression in male patients. AB - Nurses should look beyond men and boys' physical condition to identify concerns about their mental health, according to guidelines published last week. PMID- 28086318 TI - Mid Staffs' standards still cause for concern. AB - Worries about nurse training and medication errors persist at Mid Staffordshire NHS Foundation Trust, say health service regulators. PMID- 28086319 TI - New class of haitian nurses graduates. AB - Haiti is celebrating the graduation of its first nurses since its national school of nursing was destroyed by a devastating earthquake last January. PMID- 28086320 TI - Readers panel - Public health on the market. AB - Our experts consider a hot topic of the day. PMID- 28086321 TI - Why I have to keep my head down at the hairdressers. AB - There is an occupational hazard associated with working in primary care - everyone you know is a patient. PMID- 28086322 TI - Care packages for people with stroke 'often in disarray'. AB - Stroke patients are being failed by a lack of community-based rehabilitation, according to a major health watchdog review. PMID- 28086323 TI - Former smokers still at risk of hearing loss from others' smoke. AB - Exposure to second-hand cigarette smoke is linked to hearing loss in adults who do not smoke. PMID- 28086324 TI - Legislative control of mephedrone may be harmful to health. AB - Reclassification of mephedrone as a class B drug has had a limited effect in controlling its availability and use. PMID- 28086325 TI - Frustration over delays in controlled medicines law. AB - Nurse prescribers have described how a delay in changes to controlled drugs laws is restricting their work. PMID- 28086326 TI - Prepare for equality law, trusts told. AB - The Nursing and Midwifery Council and NHS organisations must be ready for the introduction of new equality laws in England, the government has warned. PMID- 28086327 TI - Call for standardised care protocol for patients experiencing pain. AB - Demands for a care pathway for pain services and for chronic pain to be declared a disease in its own right have been welcomed by nurses. PMID- 28086328 TI - Binge drinking increases risk of ischaemic heart disease. AB - Regular and moderate alcohol intake, the typical pattern in middle-aged men in France, is associated with a low risk of ischaemic heart disease. The binge drinking pattern more prevalent in Belfast carries a higher risk. PMID- 28086329 TI - Voices - Patients swamped by information need help, says Rosemary Cook. AB - The Department of Health has been consulting recently on the 'information revolution' and 'choice and control'. Both are at least as important as the restructuring of the architecture of the NHS, but have made far less impact on health professionals. PMID- 28086331 TI - In a stew. AB - Oscar Wilde said that, in life, one should try everything once - except for incest and country dancing. PMID- 28086332 TI - Women with chance of familial cancer likely to benefit from screening. AB - Annual mammography in women with a medium familial risk of breast cancer is likely to prevent deaths from the disease. PMID- 28086334 TI - Reaching out to black women. AB - Black women are significantly less likely to develop breast cancer than their white counterparts, but a higher percentage of black women die from the disease than white women. PMID- 28086336 TI - Outsidein. AB - When the subject of car sickness arises, I am always tempted to bring up a story told to me by my friend Martin when we were kids. PMID- 28086337 TI - Changes to NHS are 'extremely risky and potentially disastrous'. AB - Unions issued a last-ditch warning to the government about the risks of restructuring the NHS as ministers prepared to publish their Health Bill this week. PMID- 28086338 TI - Fresh call for staff to be immunised against flu. AB - The RCN has urged nurses who have so far failed to get vaccinated against flu to get the seasonal flu jab. PMID- 28086339 TI - RCM refutes baby weaning research. AB - The Royal College of Midwives (RCM) has challenged claims that babies breastfed exclusively for six months are at risk of iron deficiency. PMID- 28086340 TI - Where in England do older people feel most vulnerable? AB - One in seven people aged 65 and over in England live alone. Latest figures show that one fifth of these people feel unsafe. The map below reveals the local authority areas in England where older people feel safest and where they feel most at risk. PMID- 28086341 TI - Webwise. AB - A scoping workshop for a national guideline on the management of osteoporosis was carried out in 2003. To date, this is still under review. In the past few years there has been much controversy about who to treat and at what stage of the condition. In addition, there is debate on whether or not bone densitometry is needed before treatment in all cases. PMID- 28086342 TI - Babs steele was a fighter who will be sorely missed. AB - I was sad to read that Barbara (Babs) Steele has died (obituary December 2). She was an active RCN London region board member and worked tirelessly for the college's Work Injured Nursing Group (WING). PMID- 28086345 TI - Inspections at Basildon may lead to fitness to practise charges. AB - The Nursing and Midwifery Council (NMC) will carry out urgent inspections this week at a hospital trust criticised for poor nursing care. It will then decide whether to remove students from the wards. PMID- 28086343 TI - Ongoing support is needed to prevent repeat crises. AB - I read with interest the article on community mental health teams being a catch all for those clients who do not fit the criteria for other teams (reflections November 18), and I can sympathise with this. PMID- 28086346 TI - Dismissed director to appeal. AB - A director of nursing and midwifery has appealed against his dismissal for gross misconduct following an investigation into how A&E waiting times were recorded. PMID- 28086347 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28086348 TI - Nursing students' attitudes to biomedical science lectures. AB - Aim To explore what first-year nursing students believe to be the preferred characteristics of common foundation programme biomedical science lecturers, and to investigate whether students prefer active or passive learning. Method Survey and interview methodologies were used to explore the attitudes of a cohort of first-year nursing students at Queen's University Belfast. Questionnaires were distributed among 300 students. Individuals were asked to select five of a list of 14 criteria that they believed characterised the qualities of an effective lecturer. Informal interviews were carried out with five participants who were randomly selected from the sample to investigate which teaching methods were most beneficial in assisting their learning. Results Nursing students favoured didactic teaching and found interactivity in lectures intimidating. Students preferred to learn biomedical science passively and depended heavily on their instructors. Conclusion In response to the survey, the authors propose a set of recommendations to enhance the learning process in large classes. This guidance includes giving clear objectives and requirements to students, encouraging active participation, and sustaining student interest through the use of improved teaching aids and innovative techniques. PMID- 28086349 TI - Honour for reducing trust infection rates. AB - Nursing director Tricia Hart (pictured centre), who has overseen dramatic reductions in healthcare associated infections (HCAIs) and improvements in patient safety, has won a leadership award. PMID- 28086350 TI - Prescribing law changes delayed again. AB - Plans to give independent nurse and pharmacist prescribers the power to prescribe all controlled drugs have been put back yet again. PMID- 28086351 TI - Webwise. AB - The NHS Primary Care Commissioning website is a comprehensive and well structured resource for the primary care workforce and those involved in commissioning the services. PMID- 28086352 TI - ? PMID- 28086353 TI - Supporting patients undergoing cataract extraction surgery. PMID- 28086354 TI - Peer casts doubt on viability of family nurse partnership posts. AB - Ministers have written to NHS trusts in England urging them to take part in a programme supporting vulnerable mothers - in the same week as the scheme's financial viability was questioned. PMID- 28086358 TI - Hypothyroidism. AB - As a newly qualified nurse working in a coronary care unit (CCU), I am learning about how different diseases affect the cardiovascular system. There are a number of patients in the unit with hypothyroidism, but I had not made the link between this condition and acute coronary syndrome. PMID- 28086359 TI - Student life - More than merely 'clever'. AB - What is education for? At first, the answer seems obvious. Education is intended to equip students with the knowledge and skills they need to undertake their jobs, a purpose known as instrumentalism. PMID- 28086360 TI - Choosing from a wider pool of talent. AB - Spotting the qualities needed in the nursing workforce is complex. Moves to more costly graduate pre-registration programmes make it important to identify predictors of good nurses and potential leaders of the profession. Recent reports of poor care confirm that selectors need to do better. PMID- 28086361 TI - Relieving staff stress would boost safety and efficiency. AB - While I applaud the work of major employers such as Cadbury and Royal Mail in helping their staff to deal with stress (features October 28), the NHS could be doing more. PMID- 28086362 TI - An unbearable power. PMID- 28086363 TI - Rotating shift patterns are as strenuous as night shifts. AB - Having many years' experience of permanent night duty, I am all too aware of the effects that working nights can have on one's physical and mental wellbeing. Today's rotating shift patterns can be equally strenuous. PMID- 28086365 TI - Dr Foster considers adding nurse staffing levels to hospital guide. AB - Patients could be told how many nurses are on the wards of each English hospital, Nursing Standard has learned. PMID- 28086364 TI - Without an nhs email account i cannot access research. AB - Rosemary Cook, director of the Queen's Nursing Institute, says many nurses who work in hospices, charities or nursing homes assume they cannot join events or programmes because they think they are only for NHS staff (reflections December 2). PMID- 28086366 TI - Body piercing game wins grant. AB - A nurse who invented a game to explain the risks of body piercings has won L4,000 to extend her project. PMID- 28086368 TI - Starting out-Smallgestureofrespecthelped adyingchild'sgrievingfamily. AB - The staff on the paediatric ward drink from chipped cups. The mugs are freebies from drug reps that have been stained black from yet another strong coffee on a night shift. There is, however, a tea service that sits in a cupboard, beautiful and clean. PMID- 28086367 TI - RCN urges compulsory training for every healthcare support worker. AB - The government should introduce mandatory training for healthcare support workers (HCSWs) to ensure they work towards the same education levels and have clear roles, says the RCN. PMID- 28086369 TI - Nurse directors do not have the time to take on a heavy clinical caseload. AB - Why do we constantly try to measure ourselves against our medical colleagues? Simply because some medical directors retain some clinical input does not necessarily mean it is right for us. PMID- 28086370 TI - Readers panel - Do patients care about 'choice'? We asked our readers panel. AB - Our experts consider a hot topic of the day. PMID- 28086371 TI - Nurses given power to remove antisocial patients and relatives. AB - Senior nurses can order the removal of people causing disturbance in hospitals after a change in the law took effect last week. PMID- 28086373 TI - 'Pension penalises me for being a man'. AB - A community nurse has spoken out about his frustration at losing several thousands pounds a year from his NHS pension because of his gender. PMID- 28086372 TI - A creative connection. PMID- 28086374 TI - High oxygen level does not reduce surgical site sepsis. AB - Administration of 80 per cent oxygen versus 30 per cent oxygen does not affect the risk of surgical site infection after abdominal surgery. PMID- 28086375 TI - Lung cancer services audit points to value of specialist practitioners. AB - Patients with access to lung cancer specialist nurses are twice as likely to receive treatment compared to those without their support, research shows. PMID- 28086376 TI - Eye spy. AB - It was a bad day for glasses. First, my colleagues conducted a lengthy search for a patient's bifocals. The woman insisted she had left them in the doctor's consulting room. PMID- 28086377 TI - Inspectors say nursing agencies are getting better. AB - Three-quarters of nursing agencies in England have been rated as good or excellent by their regulator, a 2 per cent increase on last year. PMID- 28086378 TI - Ginkgo offers benefit in treatment of postviral smell loss. AB - Olfactory function in patients with postviral olfactory loss is significantly improved by treatment with prednisolone alone or a combination of prednisolone and ginkgo biloba. PMID- 28086379 TI - Midwifery in the spotlight as politicians vie for votes. AB - The 850 midwives and students who gathered in Manchester last month for the Royal College of Midwives' (RCM) annual conference shared a vision for the future: a passion for supporting normal births where possible. PMID- 28086380 TI - Outsidein - David Newnham puts his finger on yet another ailment. AB - If the reader who once joked that 'Mr Newnham seems to have suffered every minor ailment in the book except housemaid's knee and gout' is still out there, then I have something to report. You can tick off gout. PMID- 28086381 TI - All measures of obesity associated with venous thromboembolism. AB - All obesity measures can be used to predict the risk of venous thromboembolism (VTE). PMID- 28086382 TI - Proactive approach is linked to improved neck pain relief. AB - A semi-hard cervical collar, rest or physiotherapy and home exercises can reduce neck and arm pain substantially compared with a wait-and-see policy. PMID- 28086383 TI - A third of acute trusts has no early warning system for patients. AB - Figures have shown that around one third of NHS acute trusts in England do not have guidelines telling nurses when to seek medical help if a patient's condition deteriorates. PMID- 28086385 TI - A winning attitude. AB - Sian middleton graduated from swanesa university this year with a first class honours degree in nursing.she was given a L200 award for outstanding scholarship. PMID- 28086386 TI - Team prepares for action. AB - A team of 55 Territorial Army nurses and doctors met Scotland's health secretary and deputy first minister Nicola Sturgeon last week before being deployed to Afghanistan. PMID- 28086387 TI - Salary body likely to approverise. AB - Nurses are expected to find out next week whether negotiations for 2010's planned 2.25 per cent pay rise will be re-opened. PMID- 28086389 TI - Giving the benefit of her experience. AB - 'I had asthma as a child and found it frustrating when I ran out of breath while playing sports. It was not until I was a practice nurse and I went on a course about the condition that I realised my asthma was poorly controlled,' recalls Sally Atkins, who now works for Asthma UK. PMID- 28086388 TI - Extra training essential for staff redeployed to children's ICUs. AB - Nurses redeployed to work in intensive care units (ICUs) if the swine flu pandemic escalates should first receive critical care training, says the Department of Health (DH). PMID- 28086390 TI - Vocationally related qualification in understanding HIV and AIDS. AB - Venue Distance learning by telephone and email plus nationwide training days. PMID- 28086392 TI - You get what you pay for. AB - As Nursing Standard went to press, chancellor Alistair Darling was putting the finishing touches to his pre-budget report. Speculation was rife that he would announce efficiency savings - or cuts to use more direct language - across the public sector, including the NHS. PMID- 28086391 TI - VOICES-Nurses have plenty of political clout - especially with an election looming. AB - There are more nurses on the Nursing and Midwifery Council register than there are members of any of the UK's political parties - even the largest have far fewer members than the professional nursing organisations and unions. PMID- 28086393 TI - Radical changes. AB - On a bank holiday Monday this year my 92-year-old mother was admitted to an acute trust after sustaining a fractured neck of femur. PMID- 28086395 TI - Slow progress on scottish hospital food. AB - More effort is needed to improve food and nutrition in Scotland's hospitals, health minister Andy Kerr said last week. PMID- 28086394 TI - Good mews for NMC as London property gets hefty price tag. AB - Valued at L1.3 million when it went on the market last week, the Nursing and Midwifery Council's (NMC) bolt-hole just off Oxford Street in the west end of London is definitely out of the price range of most nurses. PMID- 28086396 TI - Concern over rise in emergency readmissions. AB - The RCN is calling for better discharge planning in response to new government figures showing the rate of emergency hospital readmissions has risen by nearly a third since 2002. PMID- 28086397 TI - Joint training with doctors could be key to eliminating drug errors. AB - Nurses and doctors should study medicines jointly to ensure fewer drug errors occur, according to a leading nurse prescriber. PMID- 28086399 TI - Jail smoking ban 'is workable'. AB - Prison nurses have held talks with government officials over smoking bans on inmates. PMID- 28086398 TI - Support for mystery illness. AB - Behcet's disease is a rare autoimmune condition that can be difficult to diagnose and treat. Specialist nurse Gill Grundy is there to help. PMID- 28086400 TI - Antenatal steroids cut respiratory distress in preterm infants. AB - Repeat doses of corticosteroids given to mothers at risk of preterm delivery reduce neonatal morbidity from respiratory distress syndrome. PMID- 28086401 TI - Limb fractures more common in French than British jockeys. AB - French jockeys suffer more severe injuries when they fall off their horses than their British counterparts. While it has been shown that jockeys suffer high rates of fatal and non-fatal injuries, little is known about differences in injury rates between countries. To investigate this, researchers from Australia, France and the UK used prospectively collected data on the rates of fatal and non fatal injuries in flat and jump jockeys in France and compared them with data from the UK. PMID- 28086402 TI - Dirty work. AB - If I started to tip my household waste on to the pavement I would have the heavies from environmental health around in no time - and quite right too. The needs of the community outweigh my 'right' to do what I please with my rubbish. PMID- 28086403 TI - Speaking volumesWin or lose in this week's final Big Brother's Pete Bennett is already a star. Judith Kidd assesses his role in improving perceptions of Tourette syndrome. AB - I would be delighted if Pete Bennett (pictured) won this series of the Big Brother contest on Channel 4. As chief executive of the Tourette Syndrome (UK) Association, I cannot think of a more deserving winner. Thanks to Pete, millions of people now understand the problems that Tourette syndrome can cause. PMID- 28086404 TI - 'Scary'Star Wars trilogy may not be the best medicine for sick children. AB - Bringing cinema magic to patients in state-of-the-art facilities will surely constitute a welcome break from the monotony of the ward (news August 9). The fact that MediCinema is offering the service for free is a bonus. PMID- 28086405 TI - Outside In. AB - An apple a day might keep the doctor away, but my two cartons of apple juice are doing my head in. PMID- 28086406 TI - Morale plummets as NHS Direct staff threaten to strike over cuts. AB - Nurses at NHS Direct are threatening strike action over proposals to axe nearly 600 jobs and close 12 centres. PMID- 28086407 TI - New mothers should hold on to babies for longer, says midwife. AB - Mothers are being encouraged by a midwife to keep their newborn babies close to their skin for about an hour after birth. She has been awarded a PhD for her research. PMID- 28086408 TI - In-flight nurses fear for patient health after terrorism alert. AB - Nurses caring for patients on board aircraft are concerned that they will face new restrictions as a result of terrorism threats. PMID- 28086409 TI - Nurse campaigns for protection at work. AB - A nurse who was attacked by a patient is urging hospitals to display posters of her injury to publicise the impact of violence against NHS staff. PMID- 28086410 TI - Different patterns of alcohol use in fatal injuries. AB - Almost every third fatal injury event in females and almost every other event in males are alcohol related, Swedish researchers report. PMID- 28086411 TI - Communicating with older people about the end of life. AB - Lecturers at the School of Nursing and Midwifery at the University of Sheffield undertook an exploratory study investigating nurses' perceptions and their experiences of listening and talking to dying older people in their care about issues relating to the end of life. PMID- 28086413 TI - Voices-Collective provision of health care has saved the lives of millions since 1948 - we should never put that at risk, says beverly malone. AB - The NHS opened its doors for business on July 5 1948 in a healthcare environment that was very different from the one we live and work in today. PMID- 28086414 TI - I lived in fear of colleagues who bullied me on the ward. AB - During my nursing career of 26 years, I have experienced bullying in a mild form (editorial July 26). But 18 months ago I had to leave the ward where I worked because I lived in fear. My family was the only thing that kept me going. Even now, as I write, I am crying. PMID- 28086415 TI - Overseas nurses are welcome assets to British hospitals. AB - Nursing students and qualified nurses should stop moaning about overseas nurses working in the UK. They have often travelled many thousands of miles to take up posts when there was a shortage of skilled nurses. They have proved to be caring, skilful and hard working. They are an asset to any hospital. PMID- 28086416 TI - Choosing industrial action will alienate public opinion. AB - Although morale in the NHS is generally low, industrial action is not the answer (news August 9). Nurses should lobby their MPs and pressure the government over job cuts. If nurses opt for industrial action, it will alienate the public, who mostly support nurses. PMID- 28086417 TI - 'Being there' for relatives can be best kind of support. AB - Adele Lea says she was shocked by her inability to support a grieving relative (reflections August 9). But it is admirable that she sat quietly and simply listened. The quietness of caring was evident and rather than not helping, as she thought, Adele was in fact a great support. She was 'there'. In sad times, just being there listening is often enough. I wish her well with the rest of her training. PMID- 28086418 TI - Feelings are the invisible 'added value' of nursing. AB - I was saddened to read Thomas Arlarch's letter (August 9) claiming that subjective feelings have no place in the provision of care. PMID- 28086419 TI - Heart of nursing series. AB - In our ten-part series, leading nurse authors address. PMID- 28086420 TI - Science alone cannot provide quality care to patients. AB - As a learning disabilities nursing student, I am taught the importance of meeting a person's emotional, spiritual, social, mental and physical needs. I therefore read with concern a qualified nurse's opinion (letters August 9) that there is no place in health care for subjective feelings. PMID- 28086421 TI - Statistics agency does not calculate attrition rates. AB - The article 'Government data on attrition rates unreliable, experts claim' (news August 2), refers to 'the methodology used by the Higher Education Statistics Agency (HESA) on behalf of the Department of Health (DH), which earlier this year produced an attrition rate of 16 per cent'. PMID- 28086422 TI - A quick wash is preferable to missing out on sleep. AB - As a night sister in a nursing home, I would like to respond to 'Night-time bathing would ease pressure on wards' (letters August 2). I agree that patients should ideally have a bath or wash whenever they wish. PMID- 28086423 TI - L60,000 to train me and then let me go - what a waste. AB - I am a nursing student due to qualify next March. In my final theoretical block, I have to submit two 2,500- word assignments, a 2,000-word assignment, a 1,000 word CV/action plan and a 6,500-word portfolio, all to obtain a qualification that is unlikely to lead to employment. So forgive me if my enthusiasm is muted. PMID- 28086424 TI - Are HCAs the new nurses? AB - There has long been a view of future healthcare provision in which an army of unqualified healthcare assistants (HCAs) carries out all the hands-on 'menial' nursing care while a much smaller number of highly skilled qualified nurses occupies parts of the higher ground currently held by doctors. A nightmare scenario for some; utopia for others. PMID- 28086425 TI - US nurses allege mass wage fixing. AB - Nurses have filed lawsuits against hospitals in four cities in the United States, accusing them of conspiring to keep nurses' wages low. PMID- 28086426 TI - Webwise. AB - The Picker Institute is an independent, not-for-profit research and development unit that focuses on the patient experience and improving care. It undertakes research, development and policy activities to make sure that patients' views are heard. PMID- 28086427 TI - Pioneering service will move treatment for self-harm out of A&E. AB - A team of nurses has received training to run a service - believed to be the first of its kind in the country - for people who self-harm. PMID- 28086430 TI - Union in dark about trust's plan for practice assessment. AB - Managers at a large NHS trust will consult nurses on plans for a three- yearly test that will indicate whether they remain fit for practice, but unions complain they have been left in the dark. PMID- 28086432 TI - Student life-Wake up and learn. AB - Many students return from practice saying they did not learn anything. But we constantly learn about the world around us through our senses. So if these students truly did not learn anything, were they asleep through the whole placement? And how did they manage to pass their practice assessment? PMID- 28086433 TI - Fears for literacy and numeracy as new nurses fail basic tests. AB - The Nursing and Midwifery Council (NMC) has voiced concern over nurses' poor levels of English and maths after a third of newly qualified nurses failed a basic test set by a hospital as part of anew selection process. PMID- 28086434 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28086435 TI - Pay increase wiped out by registration fee rise. AB - I am incensed that the Nursing and Midwifery Council is looking to increase the cost of nurse registration from L43 to L80 a year. We spend years fighting for a decent increase in pay and any paltry sums are immediately wiped out by increased fees and charges. When I first registered as a nurse, there was a one-off payment to register for life. How things change. PMID- 28086437 TI - Starting out - happy to be a softie if it means remaining true to my values. AB - During this term's placement a member of the ward team teased me with a nickname: Softie. PMID- 28086438 TI - Webwise correction. AB - John Thain was mistakenly credited as the author of the Webwise review of www.trauma.org (July 26). Liz Gormley-Fleming, senior lecturer at the University of Hertfordshire, was the author. Nursing Standard would like to apologise for the error. PMID- 28086439 TI - Nurse heads new quality regulation scheme at healthcare commission. AB - A nurse has been put in charge of a new system to investigate the quality of NHS and independent health care. PMID- 28086440 TI - Readers panel - Overseas limit- right or wrong? AB - Our experts consider a hot topic of the day. PMID- 28086442 TI - Norfolk and Norwich: a howling success. AB - Hospital staff who made a patient's hearing dog especially welcome have received an accolade in the Hearing Dog Friendly awards. PMID- 28086441 TI - Standard life. AB - Reap reward from your strategic agenda. No, I have no idea what that means either. But it is the slogan for August on my desk calendar beneath a picture of a racing yacht - so I assume it relates to achieving success. PMID- 28086443 TI - Healthcare assistants seen as more involved in patient care than nurses. AB - Patients have said that healthcare assistants (HCAs), not nurses, give most of the direct care they receive in hospital, research published in this week's Nursing Standard reveals. PMID- 28086447 TI - Small babies fare better without dexamethasone. AB - Giving extremely low birthweight babies dexamethasone to prevent chronic lung disease canhave serious complications without discerniblebenefits. PMID- 28086446 TI - Nasal diamorphine faster and preferred by children. AB - Nasal diamorphine spray should be used in preference to injection in children and adolescents who have sustained fractures, according to a multicentre study. PMID- 28086448 TI - Strategies needed for post-transplant fractures. AB - Patients who undergo a cardiac or liver transplant have a high risk of osteoporitic fracture, particularly in the first two years after transplantation. PMID- 28086449 TI - A lesson in demotivation. AB - SORRY TO bang on about this yetagain, but it does seem ridiculousthat the internal rotation system of working continues to be imposed on nurses who find it stressful and difficult. Nursing Standard reports this week on a snapshot survey of Linda Thomas readers that set out to discoverhow much progress has been made in implementing employee-friendly policiessince the Making Time campaign we ran with the Royal College of Nursing nearly two years ago. PMID- 28086450 TI - Cold comfort. AB - WHEN MAUREEN Gill was a child her grandmother always threatened to send her to am Siberia if she did not wash behind her ears. Nearly 50 years later she finally visited the region that had seemed almost mythical to her, with clean ears and a mission to help improve the area's palliative care. PMID- 28086451 TI - Call to action for Scottish health care. AB - SCOTLAND'S NEWLY published strategy for nursing and midwifery, Caring for Scotland, is a reminder of how different professional life can be for nurses across the UK. For example, while developments in telehealth and telemedicine facilities are certainly not unique to the remote rural areas of Scotland, there can be few nurses who can claim to be the sole health professional on a non doctor island. One such district nurse looks forward with optimism to seeing the effect of the World Health Organization pilot family health nursing programme on her professional credibility. Perhaps not surprisingly, there is a fair bit of emphasis on helping nurses who work in remote and rural areas to develop their practice. PMID- 28086452 TI - Meeting students' learning needs is a priority. AB - I wish to respond to a letter by student nurse Rebecca O'Brien (Letters February 2). As one of the nurses on ward 16 at Solihull Hospital who participated in supervising Rebecca, I would like to thank her for taking the time and trouble to write to Nursing Standard to thank us for mentoring her. PMID- 28086453 TI - Outside in. AB - If I read one more magazine article aboutmen's cavalier attitude to their health. Ishall have a stupid male tantrum. PMID- 28086454 TI - If you can use a pen and calculator, you can use a computer. AB - I was pleased to see the report on the British Computer Society conference (Analysis February 21). However, the problem is that such conferences speak only to the small audience of the already converted. Only two of those present were the 'clinical' nurses who need to get the messages, which are. PMID- 28086455 TI - First and foremost private care is a business. AB - I would like to respond to Sally Taber's criticisms (Letters February 21). PMID- 28086456 TI - The christine hancock column. AB - At the launch of the RCN's manifesto in February a hopeful journalist asked if I knew the date of the next general selection. A good question to which I don't have the answer However, we are preparingfor when it does take place. This month, initiallyon the RCN website, we are launching Let's Get Lobbying, a guide for any nurse who wants toraise issues with prospective MPs. PMID- 28086457 TI - Time's up. AB - IT'S NEARLY 18 months since Nursing Standard and the RCN launched Making Time, the campaign designed to arm nurses and their managers with the information they need to implement employee-friendly policies. The campaign was designed to give impetus to the many fine words and policy statements (see box right) coming from government ministers as they tried to confront desperate staff shortages. It became more and more apparent that a better life-work balance would result in improved staff retention, more returners to the profession and even enhanced recruitment. PMID- 28086458 TI - Rotation project fills vacancies. AB - A PROJECT that rotates nurses at various trusts has helped areas of London overcome long-term vacancies. PMID- 28086459 TI - Caution over clinical ladders. AB - INCREASING NURSES' pay as they gain skills rather than when they move to specialist are as can improve patients'experiences and enhancenurses' professional identity, the conference was told. But such a system can create greater disparity in pay rates between clinicians and managers. PMID- 28086460 TI - On the move. AB - Promotions / new appointments. PMID- 28086461 TI - An active remainder. AB - A motorist in the City of York gets the message on the back of a pay and display car park ticket which urges people to get out of the car and walk or cycle in the fight against coronary heart disease. PMID- 28086462 TI - Credit card scheme in demand. AB - HALF THE ward sisters and charge nurses in England should be using a credit card to spend their L5,000 ward environment budget by March next year, the health department says. PMID- 28086463 TI - Nurses should only make essential visits to farms. AB - AS THE foot and mouth crisis continues to paralyse large parts ofthe countryside, nursing staff inrural areas have been told to avoidnon-essential visits. PMID- 28086465 TI - Flexibility key to keeping staff. AB - SIX IN TEN nurses think employee-friendly policies such as flexible shifts and creche facilities would be most effective in retaining staff, a Nursing Standard survey shows. PMID- 28086464 TI - Unions call for greater health focus in budget. AB - HEALTHCARE UNIONS have called on chancellor Cordon Brown to increase health service spending when he announces his Budget this week. PMID- 28086466 TI - Audit reveals course cost variations. AB - MASSIVE VARIATIONS in the costof training nursing students havebeen exposed in an audit orderedby the government. PMID- 28086467 TI - Council to decide on unit's right to action. AB - THE RCN's governing council is expected to rule this week on whether college members at a leading A&E unit can ballot on industrial action. PMID- 28086468 TI - Money wasted on unfilled places. AB - MILLIONS OF pounds of NHS funds are being wasted because places onpost registration education courses are not being filled, according to an Audit Commission report published last week. PMID- 28086469 TI - Notes and queries. AB - What's happening in the other three countries? The Scottish minister Susan Deacon launched a package of six guidelines in January including what the Scottish Executive (SE) refers to as family friendly policies. The SE is in the process of developing a people governance standard equivalent to the IWL in England. Wales and Northern Ireland are likely to follow suit but are still working on their human resource strategies and haven't got specific policies on employee-friendly working yet. PMID- 28086470 TI - Royal honour. AB - RCN adviser in nursing practice Susan Scott visited Buckingham Palace last week to receive her MBE from the Queen. Ms Scott, who received the honour for services to nursing and the RCN, is pictured with her granddaughter Mollie. PMID- 28086471 TI - Reviewer glossed over dermatology glossary. AB - I read the book review by Mary Finch with interest (Perspectives February 28) as I am one of the contributors. However, Ms Finch mentioned the lack of a glossary. PMID- 28086472 TI - Standard life. AB - Bonjour, my little cauliflowers. I've been to Paris for le weekend and have returned with a firm grip on the lingo. PMID- 28086473 TI - Control in the community. AB - Our experts consider a hot topic of the day. PMID- 28086474 TI - Doesn't PREP contravene the human rights act? AB - On October 2 2000 the Human Rights Act (HRA) 1998came into force in the UK. Its purpose is to incorporate the various rights and freedoms contained in the European Convention of Human Rights into UK law. PMID- 28086476 TI - Where credit's due. AB - Nurse manager Beverley Stephens (centre right). Nursing Leadership awardwinner, and lecturer/practitioner Naomi Sharpies(centre left), Mental Health award commendee, were among a group of Nursing Standard Nurse 2000 award winners andcommendees whoseachievements were acknowledged at a meetingwith health minister John Denham and England'schief nurse Sarah Mullallyat the health departmentlast week. PMID- 28086475 TI - Nurse-doctor teamwork could save nhs millions. AB - JOINT PROFESSIONAL working between nurses and doctors could cut the number of adverse events in hospital, which a study has shown costs the NHS at least L1 billion a year. PMID- 28086477 TI - UKCC changes procedures. AB - NURSES UP before the UKCCaccused of misconduct or not beingfit to practise will now be given biographical details of the councilmembers judging their case. PMID- 28086478 TI - Nurse exonerated after18-month investigation. AB - ELAINE CHASE, the nurse cleared of involvement in the deaths of 18babies and children, was told last week she will also not be charged for possession, theft or supply of class A drugs. PMID- 28086479 TI - Ask the experts. AB - I have been qualified for ten years and workin the private sector. I have just started abasic counselling course and am interested infinding out some background information. Any tips on where I can find some good, basic, counselling infonnation? PMID- 28086480 TI - Health service will have tocompete with USA for staff. AB - FOREIGN NURSES bailing out the NHS by coming to work in the UK could soon be tempted to the United States because of growing shortages there, an employment expert has warned. PMID- 28086481 TI - Would-be 'magnet' lets nurses lead. AB - A TRUST HOPING to be the first in the UK to achieve 'magnet' status has sent 800 staff on leadership programmes and has nurses setting clinical indicators. PMID- 28086483 TI - Nursing homes ensure patients' needs are met. AB - I feel I cannot let yet another 'knock the nursing homes 'comment go unchallenged (Perspectives February 7). There aders panel 'Death duties' is not even about nursing homes. PMID- 28086482 TI - Don't ignore colleagueson A and B grades. AB - As an advocate for nursing assistants/healthcare assistants to join the RCN, and in light of the acceptance of this at last year'sRCN AGM, I was astounded that Nursing Standard produced the current nurses' pay poster starting at grade C. This ignores our colleagues and friends who work alongside us at grades A and B and could under minethe hard work many of us have made in showing the'assistants' that some members of the RCN value their input to nursing? PMID- 28086484 TI - Unfilled posts are increasing. AB - LAST YEAR saw further increases in nurse shortages right across the NHS, despite an expansion in the nursing workforce. PMID- 28086485 TI - Lest we for get. AB - A DISCUSSION IN a student tutorial on ethics was the start for nurse lecturer Alison O'Donnell's inves-tigation into nursing during them Third Reich in Germany. 'We were talking about the virtues of nursing and one student asked why, if caring was central to nursing, could nurses actcruelly?" she says. PMID- 28086486 TI - Animal rights campaigners have gone too far. AB - The attacks on laboratory staff at Huntingdon Life Sciences should be condemned. The research into diseases such as cystic fibrosis, which my one-year-old niece has, is vitally important and should not be compromised by the animal 'rights' lobby. PMID- 28086487 TI - Paediatric palliative care guidance doesn't exist. AB - You report the Essex policehaving to 'call on experts' (News February 21) when carrying out investigations such as that into Elaine Chase's care of dying children. PMID- 28086488 TI - Emergency contraceptionis always a last resort. AB - With reference to 'Emergencymeasures' (Perspectives February21) about over-the counter(OTC) emergency contraception, surely we are forgetting sexuallytransmitted diseases and HIV. PMID- 28086490 TI - Write all about it. AB - The Radio Times is calling on readers to write a script for the TV soap Casualty, as part of the BBC talent drama writer scheme. Scripts should be about 12,000words long and submitted by May 31. BBC talent spotters will then draw up a shortlist of 15 would-be drama writers before a final selection by the cast. For more information, call 09065550000 or visit www.bbc.co.uk/talent. PMID- 28086492 TI - Alarm raised over health boards. AB - THE RCN HAS expressed alarm at government plans to establish 15NHS health boards in Scotland that will co-ordinate services across the country. PMID- 28086491 TI - Healthcare assistants do not make good assessors. AB - In reply to 'The NVQ question'(Perspectives January 24), I do notbelieve that healthcare assistants(HCAs) should become assessors. PMID- 28086493 TI - Opportunities to treat liver disease are being missed. AB - Abnormal results for liver function are often not adequately investigated, say researchers from Nottingham. PMID- 28086494 TI - What's on: the best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28086497 TI - Scottish nursing strategy puts focus on leadership. AB - NURSES IN Scotland are to be sent on courses to improve their leadership skills as part of the government's strategy for the profession published last week. PMID- 28086498 TI - Homes slam new standards. AB - MINISTERS HAVE failed to quell criticism over newly-launched national standards for nursing and residential homes. PMID- 28086499 TI - Celebrity cleaners tell us a thing or two about mrsa. AB - I watched a television programme recently in which the celebrity cleaners Kim and Agie went into a hospital. I was pleased to hear Kim say that a reduction in the spread of MRSA infection is everyone's responsibility, from doctors and nurses to relatives and patients. The media is too quick to point the finger at nurses as the main culprits for the spread of infection. PMID- 28086500 TI - I may be lured away by the benefits of agency work. AB - As a full-time bank nurse working for the NHS in Tayside I am not surprised that agency nurses are more satisfied than me - they are on twice my salary. PMID- 28086501 TI - In death, as in life, patients deserve respect and dignity. AB - Two things struck me when I read Roswyn Hakesley-Brown's account of helping an inexperienced doctor fulfil a dying patient's wish (reflections August 23). PMID- 28086502 TI - Emptying commodes and washing patients are vital. AB - The statement about qualified nurses looking down on HCAs as if all they can do is 'empty commodes, wash and dress patients and make beds' horrified me (letters September 6). I was a nursing auxiliary for ten years before becoming a registered nurse. I have the utmost respect for all members of the nursing team, especially the HCAs, as do my qualified colleagues. Emptying commodes, washing and dressing patients and making beds are vital components of caring for patients. PMID- 28086504 TI - Nominations sought for rcn fellowship awards. AB - Do you know of an RCN member who has made an outstanding contribution either to nursing or to the RCN? If so, there is an opportunity for you to nominate them for an award. The RCN is looking for nominations for RCN fellowships, honorary fellowships and the awards of merit. These honours are awarded by RCN council and will be given at congress 2007 in Harrogate. The nomination forms and guidance are available at the RCN website, www.rcn.org.uk . The closing date is November 16. PMID- 28086505 TI - Correction. AB - Please note that an error occurred in the article 'A new way of caring for older people in the community' (art&science July 26). In table three, point number four in the first column, under the heading United States, it should state that community patients are first assessed via the telephone. It should also state that in the UK, community patients are first assessed via a home visit. A correct version of the table appears on our website. We would like to apologise for the error. PMID- 28086506 TI - Allowing HCAs to develop is good for patients and nurses. AB - As a former HCA about to begin my second year of nurse training, I was disappointed to read David Salvage's views on caring responsibilities (reflections August 30). PMID- 28086507 TI - Thanks, MR Blair, for wasting the past three years of my life. AB - Three years ago last February I began my nurse training, giving up a lucrative career for a more fulfilling and family-friendly profession. Given that my husband and I had become accustomed to living on his income, we decided to start a family before my career took off. PMID- 28086508 TI - Charities hit by cash-strapped trusts' reluctance to fund specialist posts. AB - A charity has struggled to secure places at NHS trusts for its fully funded nurse specialists because hospitals fear they will be unable to afford the posts once charity funding ends. PMID- 28086509 TI - Red trays for people at nutritional risk have boosted patient satisfaction. AB - I thought the original idea for the 'red tray' food delivery system devised by Lindsey Bradley in 2003 was superb (news September 6). PMID- 28086510 TI - Gloopy yoghurt, a sandwich and fruit on a day-glo tray. AB - I have two observations to make about the recent debates in Nursing Standard - one on the role of healthcare assistants (HCAs) and the other on the nourishment of patients. PMID- 28086512 TI - Nurses asked to join discrimination study. AB - Researchers examining whether nurses with impairments suffer discrimination are seeking clinicians to take part in a study. PMID- 28086511 TI - Hobson's choice for patients who need to travel. AB - The rights of poorer patients to choose the best hospital for their care may be threatened by the NHS funding crisis, according to the Liberal Democrats. PMID- 28086514 TI - Acute wound closure. AB - As an A&E nurse, I care for clients requiring acute wound closure and I enjoy the challenge it presents. This article reviewed the rationale of wound closure. It enabled me to revise the principles and to discover new techniques. PMID- 28086513 TI - Starting out - I learnt to adapt to different mentor-student relationships. AB - My second year of nursing has been a long one. No more excitement and chaos living in student halls; no more concessions on the ward for being on my first placement; no more messing around. I have had to learn, because some day in the not too distant future I will be a staff nurse. I will get handed the keys, my superior will go for a tea break and I will be the 'nurse in charge'. PMID- 28086515 TI - Back to basics. AB - A friend had an allergic reaction while we were on holiday this year. We spent an hour or so in the local GP's waiting room, which, on a hot July day, was as gloomy as a funeral parlour. It was square, with benches arranged against the walls, which made conversation difficult especially as everyone else sat mutely gazing into space. PMID- 28086516 TI - Safety in numbers. AB - An organisation with royal college status thinks long and hard before quantifying something as fundamental as safe staffing levels. This week the RCN launches its recommended skill-mix ratio for registered and non-registered staff on general wards in NHS acute trusts, a move that should be welcomed by everyone from patients to ministers. The two thirds registered, one third unregistered benchmark provides a reference point when calculating workforce demands. And there is no organisation better placed to set down this marker for nursing care than nurses' own royal college. PMID- 28086517 TI - ? AB - Courses, events, grants, and awards to progress your career. PMID- 28086518 TI - Leak reveals plan to axe 48 nurse specialists. AB - Senior nurses are furious after a leaked consultation document revealed that Leeds Teaching Hospitals NHS Trust is planning to cut 48 clinical nursing posts - one in five of its total - to save L1.6 million. PMID- 28086520 TI - US nurses work too much and without enough rest. AB - Extended work schedules - those that vary from the standard eight hours per day, 35 to 40 hours per week - are common in nursing and contribute to problems with nursing recruitment and retention, in addition to compromising patient safety and the health and wellbeing of nurses. PMID- 28086519 TI - RCN sets out safe staffing ratio to maintain skill mix. AB - The RCN has for the first time recommended a safe staffing ratio for registered and unregistered nurses working in general wards. PMID- 28086521 TI - Copper rather than steel surfaces for infection control. AB - The use of stainless steel for work surfaces or door furniture in hospitals is not recommended on the grounds of infection control. PMID- 28086522 TI - Outside in. AB - Have you ever tried to say 'city break' with a mouth full of fingers? Could you get your tongue around 'baggage reclaim' while a stranger took a metal spike to your teeth? It is not easy, telling the hygienist what you did on your holidays. PMID- 28086523 TI - 'Broken leg taught me the value of nurses'. AB - Sandra Arthur has spent 31 years working in the NHS, 26 of those as a midwife. The care Ms Arthur received as a five year old influenced her decision to became a nurse. She had broken her leg and spent 12 weeks in hospital because, at that time, it was believed children would recover better in hospital rather than at home. PMID- 28086524 TI - Who has the time for a break? AB - As a nursing student it took just a week on placement before I realised that I was lucky if I managed to have a coffee without interruption. Innocently, I thought this was par for the course since the nurse in charge would ensure that chores were lined up and had to be completed by the end of the shift. PMID- 28086525 TI - Readers panel - Yet another blow to salaries. AB - Our experts consider a hot topic of the day. PMID- 28086526 TI - Standard life. AB - Whatever happened to whistleblowing? There was a time - blimey, was it really in the early 1990s? - when you could not pick up a paper without stumbling across some humble nurse or doctor lifting the lid on bad practice. PMID- 28086527 TI - Diabetes triples risk of admission to a nursing home. AB - Lifestyle factors are important contributors to the risk of admission to a nursing home. PMID- 28086528 TI - Drivers of 4x4s less compliant with laws on mobile phone use. AB - The level of non-compliance with the law on the use of handheld phones and seat belts by drivers in London is high, according to researchers from London and Australia. PMID- 28086529 TI - Raising standards - and fees - are priorities for new NMC president. AB - The new president of the Nursing and Midwifery Council (NMC) wants nurses to be proud of their profession. Sandra Arthur believes nurses have lost this pride and that regaining it could be the key to cutting the number of misconduct cases. PMID- 28086530 TI - Voices - Our new voices columnist Rosemary Cook celebrates nurses' courage. AB - The conflict between Lebanon and Israel has gripped our attention with shocking pictures of death and destruction. One story to emerge from the carnage concerned the nurses who stayed behind in a damaged hospital because they would not abandon their patients. PMID- 28086531 TI - Foundation trusts for community services. AB - Details on the feasibility of primary care trusts (PCTs) acquiring foundation status will be published by the Department of Health later this year, health secretary Patricia Hewitt revealed last week. PMID- 28086534 TI - Staff value personnel role of nurse partners, independent study finds. AB - Practice staff find nurse partners more approachable than medics and believe they are better placed to mediate between salaried staff and partners, an evaluation of the role has indicated. PMID- 28086532 TI - Unions claim politics is driving cuts. AB - Unions have accused the government of prioritising political gains above the welfare of the NHS, following warnings that A&E departments and maternity services could face imminent closure. PMID- 28086535 TI - Voice of nursing in primary care threatened by government review. AB - The makeup and function of professional executive committees (PECs), which include nurses who advise primary care trusts (PCTs) on service planning, is to be reviewed by the government. PMID- 28086538 TI - Take action on alcohol use in wales, says RCN. AB - Political parties in Wales are being urged to develop policies that reduce alcohol consumption in the principality. PMID- 28086536 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28086539 TI - Impact of NHS logistics strike played down. AB - Unison and the Department of Health have played down the likely impact of this Thursday's planned one-day strike by staff at NHS Logistics. PMID- 28086540 TI - Deprived areas are focus for intensive health visiting. AB - Deprived families will receive intensive visits from health visitors and midwives as part of a scheme to reduce social exclusion, the government has said. PMID- 28086541 TI - Resignations after agency hires private eye to spy on nurse. AB - A private detective was hired to spy on a community nurse in Australia who was suspected of not fulfilling work obligations. When she was then fired, 19 colleagues resigned in support. PMID- 28086542 TI - Damning report shows unequal care for people with disabilities. AB - Annual health checks and improved medication advice are required for people with learning disabilities and mental health problems, a report into their treatment recommends. PMID- 28086543 TI - Webwise. AB - The Cancer Help UK section of the Cancer Research UK website is not particularly eye-catching but it has useful information for patients with a cancer diagnosis, their families, and for healthcare professionals. PMID- 28086546 TI - I feel privileged and valued as a nursing assistant. AB - I agree with Devon Chambers that HCAs are the new nurses (letters September 6). I feel privileged to be a nursing assistant. Very often we are the first on the scene with the patient and we can pass on vital information to the registered nurses. PMID- 28086548 TI - Rcn demands nurse presence on planned gp consortia boards. AB - Nurses must have an automatic place on GP consortia boards, the RCN said last week in a briefing paper sent to MPs on the Health and Social Care Bill. PMID- 28086547 TI - Become a role model for good practice. AB - Handwashing is a vital part of the job yet not everyone does it. PMID- 28086549 TI - Local talks planned on freezing pay increments. AB - More NHS trusts are to discuss freezing pay increments locally for staff, it has been revealed. PMID- 28086550 TI - Rota changescould spark strike action. AB - Theatre staff at an NHS trust are considering strike action over plans to change their rotas. PMID- 28086551 TI - Northern Ireland's nurses braced for cull of 1,500 posts. AB - The Northern Ireland assembly's planned health budget paints a bleak picture for those who work for and use the NHS. PMID- 28086552 TI - Prison staff fear training cutbacks after transfer to NHS. AB - About 250 nurses being transferred from the Scottish Prison Service to the NHS in October fear the move could reduce training opportunities. PMID- 28086553 TI - Private company wins L53m health contract. AB - Around 200 prison nurses employed by NHS organisations in the north east of England could be transferred to a private health and social care provider. PMID- 28086554 TI - Charity designs leadership course for lesbian, gay, bisexual and trans staff. AB - Lesbian, gay, bisexual and trans nurses who are keen to take up managerial roles can now apply for a leadership programme run by equality charity Stonewall. PMID- 28086555 TI - Test failures raise questions about fitness to practise. AB - Five times as many nursing students fail theory assessments compared with practical assessments, a survey undertaken in 27 higher education institutions shows. PMID- 28086556 TI - European nurses face skills quiz. AB - European nurses whose qualifications fall short of those required to practise in the UK will be allowed to prove their competence under a new testing regime. PMID- 28086558 TI - Lung cancer awareness initiative set to expand. AB - A nurse-led campaign to increase awareness of the early stages of lung cancer has led to a 60 per cent rise in the number of diagnosed cases in parts of South Yorkshire. PMID- 28086559 TI - We need to document every incident where care is poor. AB - I have great sympathy with chief nursing officer for Northern Ireland Martin Bradley who has said that team support is needed to face the challenge of improving patient safety (letters December 15). PMID- 28086560 TI - Dora opoku's achievements made inspirational reading. AB - I was shocked to learn of the death of midwife and educationalist Dora Opoku (obituary January 26). PMID- 28086561 TI - Rcn congress to debate pay and mandatory staffing. AB - Social networking, nurses' pay, legally enforceable staffing levels, and a one year job guarantee for nursing students are among topics set to be debated at RCN congress in April. PMID- 28086562 TI - Removal of profit cap sparks fears of two-tier care. AB - Foundation trusts will soon be able to generate as much income as they like from private patients under government plans to overhaul the NHS. PMID- 28086563 TI - Quartet to perform atroyal albert hall. AB - A group formed by a nurse and three midwives will sing at a Dusty Springfield tribute in May at London's Royal Albert Hall in aid of Macmillan Cancer Support. PMID- 28086564 TI - Are palliative care nurses on lord falconer's commission? AB - I am concerned after reading Harriet Copperman's claim that nurses' attitudes to assisted dying have changed (features January 26). Where is her evidence for this? PMID- 28086565 TI - Pain and suffering focus the debate on assisted dying. AB - As a former chair of the RCN palliative nurses forum, I find it commendable that nurses are contributing to the debate on assisted dying (features January 26). PMID- 28086567 TI - Meet my new sister. PMID- 28086566 TI - Obituary. AB - Doreen McCullough OBE, who has died aged 90, was one of Northern Ireland's best known and most successful nurses. PMID- 28086568 TI - Call for help to standardise phototherapy regimes. AB - I am a dermatology nurse and provide light therapy to patients with skin problems. I would like to see phototherapy regimes standardised throughout the UK to help avoid errors, but do not know where to start. PMID- 28086569 TI - Fight for equality still on. AB - Considerable progress has been made to improve care for patients who are lesbian, gay, bisexual or trans. Healthcare staff from these groups are also less likely to be on the receiving end of discrimination than they might have been a few years ago. But there is still a long way to go before the UK becomes a truly equal society. PMID- 28086570 TI - Modern teaching methods fail to focus on patient care. AB - It can be argued that the standard of clinical nursing care has fallen since nurse training became more academic. PMID- 28086571 TI - Annual statement will make no difference to me. AB - The government wants nurses to be more grateful and is planning to send out annual letters telling us how well rewarded we are (news January 5, letters January 19). I would be more interested in receiving a statement outlining the salaries, benefits and bonuses of bankers. PMID- 28086572 TI - An awful placement persuaded me to be a good mentor to my students. AB - After reading the Starting Out column, 'Speaking out made me feel like a horrible and isolated person' (reflections January 12), I was sad that nursing students can still be treated so badly on placements. PMID- 28086574 TI - Book chronicles dementia journey. AB - A nurse whose father died after an eight-year battle with dementia has written a book about the impact of the condition. PMID- 28086573 TI - Chronic illness scheme saves NHS L400,000 in nine months. AB - A nurse-led scheme that has dramatically reduced the amount of time older people with chronic conditions spend in hospital has won an RCN award. PMID- 28086575 TI - Safety fears as government plansto ditch statutory HCA regulation. AB - Mandatory regulation of healthcare assistants in England is unlikely to go ahead despite long-standing concerns over patient safety. PMID- 28086577 TI - The best of the week's health-related tv and radio. AB - Our roundup of what's on. PMID- 28086576 TI - Starting out - Research placement offered a unique learning opportunity. AB - After showing an interest in clinical research, I was given the opportunity during my third year to go on a placement in a clinical research facility. I was the first pre-registration nursing student to work alongside staff on the ward. PMID- 28086578 TI - I want to give the same care that Grandpa received. AB - After a week in the intensive care unit we were told that nothing more could be done for Grandpa. He hated being in hospital and, as a family, we agreed that we should care for him at home. PMID- 28086579 TI - Readers panel - Gauging gratitude. AB - Our experts consider a hot topic of the day. PMID- 28086581 TI - Resting heart rate associated with survival in diabetes. AB - There is an association between resting heart rate and cardiovascular events in people with coronary artery disease and diabetes. PMID- 28086580 TI - Diet and sun exposure needed to prevent breast cancer. AB - A threshold of vitamin D exposure from both sun and diet is required to prevent breast cancer. But this threshold is difficult to reach for postmenopausal women living at northern latitudes where the quality of sunlight is too poor for adequate vitamin D production, according to French researchers. PMID- 28086583 TI - Seeing sense. AB - If I came from another world - Planet Common Sense - there would be many things I would struggle to understand about the NHS. PMID- 28086584 TI - VOICES-Sexually sidelined Elizabeth Anionwu says that fresh air and spring flowers lift her spirits. AB - I have never understood why my mood seems to lift once January is over. Is it because I have submitted my online tax return by the dreaded deadline? Or maybe it is hope that the weather will start to improve. PMID- 28086587 TI - Assault injuries highest among city-dwelling teens. AB - Incidents of adolescents being injured as a result of violence increase with deprivation in cities and their feeder towns. This applies to both boys and girls, although rates for boys are consistently higher. PMID- 28086585 TI - Subclinical thyroid disorders increase hip fractures in men. AB - Older men with subclinical hyper or hypothyroidism are at increased risk of hip fracture. PMID- 28086589 TI - Sexually sidelined. AB - My heart sank during yet another negative conversation about a patient who is transgender. PMID- 28086591 TI - Outside in. AB - I met up recently with an old friend after 30 years and was gratified to discover that he had been ageing at almost the same rate as I had. PMID- 28086592 TI - Webwise. AB - It arranges conferences and seminars, publishes policies and reports, and its website is a rich resource. Many political websites are no more than promotional tools for their conferences and seminars. Fortunately, there is much more to this one. PMID- 28086593 TI - HIV tests 'could deter recruits'. AB - UNISON AND the Nursing and Midwifery Council (NMC) this week said they would oppose any government proposal to order HIV tests on new recruits to the NHS from overseas. PMID- 28086594 TI - Trial run may be delayed. AB - Government hopes that the new pay and grading system will be piloted in 12 NHS trusts from April 1 could be in jeopardy. PMID- 28086595 TI - Rheumatoid arthritis reduces women's lifespans. AB - Rheumatoid arthritis (RA) is associated with a significantly increased risk of mortality, researchers from the United States say. PMID- 28086596 TI - Impact felt in higher education. AB - NURSE EDUCATORS are to carry out a study comparing their pay with posts in the NHS if the Agenda for Change proposals are accepted. PMID- 28086597 TI - Women could take their own swabs for infection screening. AB - Self-obtained low vaginal swabs are a simple and sensitive diagnostic test for the detection of Chlamydia, gonorrhoea and Trichomonas. PMID- 28086598 TI - Union members to have formal vote on pay deal. AB - NURSES THROUGHOUT the NHS will get to vote on the new pay and grading system after three of the four biggest unions confirmed they would ballot their members. PMID- 28086599 TI - Oral alternative to penicillin for adult erysipelas. AB - Pristinamycin could be an alternative to the standard regimen of penicillin for treating erysipelas with the advantage of an oral route of administration. PMID- 28086600 TI - Death rates reduced as a result of banning coal. AB - Reducing particulate air pollution could save more lives than previously reported, according to researchers from Ireland and the United States. Particulate air pollution has been associated with increased daily death rates but there is little direct evidence that diminished particulate air pollution would lead to a reduction in death rates. Concentrations of air pollution and directly standardised non-trauma, respiratory and cardiovascular death rates were compared for 72 months before and after the banning of coal sales in Dublin. PMID- 28086601 TI - Research notes. AB - Asystematic review of the clinical effectiveness of psychosocial interventions for people in the early stages of a dementing illness is currently being conducted in Sheffield. The review is revealing a surprising scarcity of well conducted research papers on this subject. PMID- 28086602 TI - Standard life. AB - Did you see those press reports that said in six months' time surgeons will be able to slap a dead bod's mug onto the be-barked bonce of anyone who had been scarred or disfigured? It seems that face transplants are coming and, after due reflection, I offer this considered response: yuck! what a terrible prospect. But then I have never been pulled more dead than alive from a blazing wreck with no hair and molten features, and if I had maybe I would react more effusively. PMID- 28086603 TI - Gossip column. AB - Mike, a charge nurse on a surgical day unit, told me about Janice, his ward clerk who was always gossiping and causing trouble between people in his team. I asked what he had tried to do about it. He said that when he noticed her gossiping he had asked her for something to try to distract her. Although this put an end to the immediate problem, Mike wanted a long-term solution, especially as a new team member had asked for advice because she felt uncomfortable hearing 'stories' about her colleagues from Janice. PMID- 28086604 TI - Readers Panel - Qualified to care. AB - As a discarded EN I find the idea of an all-graduate workforce perplexing. Having several levels of nurses at the bedside has many advantages. In my day the auxiliaries often teamed up with the EN while the SRN took charge of the medications. The versatile EN stepped in while the SRN was away. PMID- 28086607 TI - RCN board chiefs to stay at top table. AB - RCN ACTIVISTS in Scotland, Wales and Northern Ireland have welcomed news that their board secretaries will continue to report directly to general secretary Beverly Malone. PMID- 28086605 TI - Award winners take the nursing message to Blair. AB - NURSING STANDARD Nurse 2002 award winners met the prime minister and senior Department of Health officials at Downing Street last week to tell them about their prize-winning work. PMID- 28086608 TI - Ask the experts. AB - I have recently taken over as matron of a nursing home. Going over staff records I found that a number of qualified and non-qualified staff have not had Criminal Records Bureau checks. Do I have to suspend them until checks are completed? PMID- 28086609 TI - Nurse prescribing is a step forward for patient care. AB - It is vital that nurses move forward with Agenda for Change. Nurse prescribing in particular is a great leap in improving patient care. PMID- 28086611 TI - Happy outcome after 18 months in 'job from hell'. AB - A NURSE from India who says she endured 18 months of hell working at a nursing home finally has a reason to smile after landing a job at a London hospital. PMID- 28086610 TI - I wanted to be cool. AB - I feel sorry for the youth of today. There isn't much to rebel against, is there? In my day it was easy. All you had to do was leave off your vest. As children of the 1950s we were brought up haunted by the spectre of 'new-monia'. 'Don't wear that, you'll catch new-monia,' my gran warned if I wore less than five layers in the winter, or dispensed with my liberty bodice before the first of June. PMID- 28086612 TI - NHS Professionals: good idea but it does not work. AB - I would like to reply to Nigel Northcott's letter about NHS Professionals (letters November 27). The trust I work for has been using NHS Professionals for about a year, pioneering the service in the south west. PMID- 28086613 TI - The UK's loss will be my own country's gain. AB - Zita McGregor (perspectives November 27) has made me think. I am a foreign student and have experienced similar difficulties obtaining a visa, in my case to study in the UK. PMID- 28086615 TI - No need to fear net-savvy patients. AB - PATIENTS WHO present their nurse with reams of research from the internet on methods of treatment are more likely to be a help than a hindrance, a health adviser has claimed. PMID- 28086614 TI - Adequate school toilet facilities are essential. AB - The excellent initiative of the Community Practitioners' and Health Visitors' Association - that school nurses investigate poor toilet facilities - is to be applauded (news November 27). PMID- 28086616 TI - Staff appraisals improve mortality. AB - RESEARCH INTO patient mortality rates has revealed that fewer people die in hospitals where staff receive better training and undergo appraisals. PMID- 28086617 TI - Remove the blame culture. AB - THE BEST way to encourage nurses to report 'near-miss' incidents is by removing the fear of blame or suspension, claims a clinical risk adviser. PMID- 28086618 TI - Nurses are to get a schizophrenia guide. AB - NEW NATIONAL guidelines on how to treat patients with schizophrenia are to be issued to nurses. PMID- 28086619 TI - Sick and tired. AB - Managing post-operative nausea and vomiting (PONV) is a daily challenge for nursing staff in a day surgery department. Advances in anaesthetic drugs and techniques mean more rapid recovery times, which in turn allows more invasive procedures to be performed as day cases. PMID- 28086621 TI - Disappointment over drugs role. AB - Nurses should be given a greater role in the treatment of drug users as part of the government's updated drugs strategy, says a nurse specialist in substance abuse. PMID- 28086620 TI - Core group singled out for smallpox vaccination. AB - SMALLPOX VACCINATION will be offered to nurses in the NHS and the armed forces as a pre-caution against possible terrorist attacks. PMID- 28086622 TI - On the move. AB - Promotions / new appointments. PMID- 28086623 TI - What's on: the best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28086625 TI - Occupational Health Nursing: Second Edition Second Edition Katie Oakley Whurr Occupational Health Nursing: Second Edition 307pp; L25 1 86156 294 2 1861562942. AB - Fully updated with nine new chapters, this edition is aimed at students and educators of occupational health (OH) nursing. PMID- 28086624 TI - Learning to nurse in care homes: student support. PMID- 28086627 TI - Human rights claim succeeds. AB - THE MINISTRY of Defence has admitted it breached a nurse's human rights when it refused to provide accommodation for her, her partner and two young children. PMID- 28086629 TI - Gay partners ruling expected. AB - NURSES COULD be legally allowed to consult the partners of gay patients about their hospital treatment under government plans to recognise civil partnerships. PMID- 28086628 TI - Will nurses get recognition for taking on prescribing? AB - In principle I agree with the idea of nurse prescribing (news November 27). There are many skilled nurses who could quite safely prescribe. However, I worry that without adequate recognition we are yet again selling ourselves and our skills short. PMID- 28086631 TI - Training key to pre-op assessments. AB - NURSES ARE as competent as junior doctors at carrying out preoperative assessments and often order fewer unnecessary investigations, according to a study. PMID- 28086630 TI - Life and death. AB - NURSES ARE identified by the government as being at higher than average risk of suicide. Around 27 nurses kill themselves every year, or one a fortnight. That is fewer than in farming, 52 a year, but more than in the medical profession- 17 a year. In England 5,000 people kill themselves annually, many of them men under 35. Preferred methods are hanging and self-poisoning by psychotropic drugs or analgesics. If you are male, living alone, unemployed, misuse drugs or alcohol and have a history of mental illness, you score top marks for all major risk factors. In such circumstances, it is unlikely that you were much moved by the Department of Health's National Suicide Prevention Strategy for England, published earlier this year, and its plan to reduce suicide by at least 20 per cent by 2010. PMID- 28086632 TI - Growing need. AB - THE INCIDENCE of paediatric respiratory disease has increased over recent years giving nurses an opportunity to grow with the specialty and become providers of high quality care. Respiratory disease can affect all ages but advances in neonatal intensive care have given rise to a group of children who have persistent respiratory disease into early life. Asthma incidence continues to rise, for example, and can affect children of any age with many attendant clinical and management problems. PMID- 28086633 TI - Lung-term strategy. AB - Transport policy changes in Oxford city centre, including pedestrianisation and restrictions on traffic, may be linked to improvements in the lung health of local children, according to research presented to a British Thoracic Society meeting last week. A positive change in peak flow levels and a reduction in wheeze were observed in a study of 1,386 children after changes in transport policy were introduced. PMID- 28086634 TI - A&E best source of violence data. AB - A&E STAFF have a better idea of how many violent assaults take place in a community than the police, a research study has found. PMID- 28086635 TI - Boxing clever. AB - Debates about banning boxing crop up regularly. Organisations representing nurses, such as the RCN and Unison, have generally steered clear of a formal position on the subject, however the British Medical Association favours a total ban. Its arguments concentrate on the possible adverse medical consequences, but ignore sociological, cultural and alternative ethical viewpoints. PMID- 28086636 TI - An overview of chronic fatigue syndrome. PMID- 28086637 TI - 'Extended roles' will mean a decline in quality of care. AB - Nursing in this country is on the brink of declining standards. Most hospitals are suffering from a shortage of staff and funding. When managers and government officials start talking about nurses developing more skills (news december 4), they are actually talking about increasing nurses' workload. PMID- 28086638 TI - It depends on. AB - Despite an ageing population we live in a culture full of fear about becoming older. Old age is seen as an almost entirely negative phenomenon with decline on all fronts. In a brilliant speech at a recent conference, Rosalie Hudson (2002) joined those pushing back the boundaries of the way we think about ageing. After all, the way we think about ageing is just that, thoughts, and thoughts have no power of their own except that which we choose to give them. PMID- 28086639 TI - Statutory minimum entry requirements for nurses. AB - I would like to respond to Maggie Fenby-Taylor (letters November 27) who writes about my article 'Pointing the way' (perspectives November 6). The qualifications mentioned in my article are the statutory minimum entry requirements referred to in the Nursing and Midwifery Admissions Service handbook. PMID- 28086640 TI - There is no hidden agenda. AB - Much is expected of Agenda for Change. A briefing note has been sent to NHS chief executives and human resource directors, from Andrew Foster the NHS human resource director, outlining the rationale for the proposals. PMID- 28086641 TI - Outside in. AB - If God had meant us to fly he would have given us tickets. No? Well a little more room to stretch then. Is another inch or two all round too much to ask? PMID- 28086642 TI - District nurses urged to use strict referral criteria. AB - DISTRICT NURSES have been urged to develop strict referral criteria so that they know when to say no to a request for their services. PMID- 28086643 TI - TB specialists' crucial work is recognised. AB - TUBERCULOSIS (TB) specialist nurses have welcomed recognition that they have a potentially crucial role in the fight against the disease. PMID- 28086644 TI - Starting out. AB - I was in the first semester of my second year and about to have my first adult ward experience - on an elderly ward. I was panic stricken and not very excited. All my colleagues said it was horrible, there was too much work and they could not wait to leave. PMID- 28086646 TI - Tour bus is just the ticket for students hoping to go places. AB - A bus that will visit students across the country set off from the RCN's London headquarters last week. PMID- 28086645 TI - Press must take some responsibility for fear. AB - Jeremy Laurence's description of the mental health services (perspectives November 17) will ring true for many practitioners. He says it is obsessed with the prevention of violence and suicide to the detriment of collaborative engagement with service users. PMID- 28086647 TI - A more traditional uniform reflects core nursing values. AB - I share Doreen Robinson's enthusiasm for a return to a more traditional nursing uniform at the Heart of England NHS Foundation Trust (letters November 4), and I hope other hospitals will follow this lead. PMID- 28086648 TI - Cash squeeze forces charity to shed ten cancer care posts. AB - Specialist cancer nurses in Wales are looking for new jobs after pledged funding for their roles fell through. PMID- 28086649 TI - Duty of care takes precedence over our personal beliefs. AB - What is all this talk about religion (reflections October 28, letters November 4 and 11)? I am astonished that anyone, but especially nurses, would think that being religious somehow makes them superior, better nurses, less cruel and more likely to report abuse. PMID- 28086650 TI - Drive to halve sickness rates. AB - Chief nursing officer Dame Chris Beasley wants to cut nurses' sickness absence by more than half - to not more than 3 per cent - in two years. PMID- 28086651 TI - New degree-level programmes will be backed by preceptorship. AB - New standards for degree-level nursing courses will be published in draft form in January, according to the Nursing and Midwifery Council (NMC). PMID- 28086653 TI - Webwise. AB - Nurses and nurse historians with an interest in the profession as a political and social power should watch these three short films on the California Nurses Association, available for free on YouTube. PMID- 28086652 TI - Liz Fradd gets to the heart of the pressing need for better nursing leadership at the strategic level (reflections October 14). Nurse directors need to have specific training to help them be more effective at board level. AB - Senior nurses should be at the board table where their clinical authority can be used to inform and influence a more holistic approach to quality monitoring across the care pathway. Meeting government time targets for seeing a GP, consultant or moving out of A&E are only small pieces of the quality jigsaw. PMID- 28086657 TI - It is good to confront and challenge our prejudices. AB - It is reassuring to read in the first of a four-part series on prejudice (features November 11) that prejudice is viewed bysocial scientists as a normal part of psychological processing, when we try to make sense of the world. PMID- 28086658 TI - War widows and veterans need the best nhs care. AB - I write as an ex-RAF nursing sister and war widow who lost my husband in a Vulcan bomber crash in 1975. There are many more recent war widows who need our help, including the relatives of the Nimrod explosion in Afghanistan in 2006, which killed 14 members of the armed forces. PMID- 28086661 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28086660 TI - We need more nurses who qualify, not more students. AB - Erin Dean (news October 28) writes: 'Nursing as a career continues to enjoy a surge in popularity, with 20 per cent more undergraduates starting degrees this year than last.' PMID- 28086662 TI - Obituary. AB - Born in Hulme, Manchester, on February 24 1941, Pat Morris was an inspirational nurse who campaigned for the rights of patients. PMID- 28086663 TI - Awards ceremony shines a light on the pride of the profession. AB - The winner of this year's Nursing Standard Nurse of the Year award has praised young people in care and the clinicians who look after them. PMID- 28086664 TI - Management of procedures and reactions following first aid. PMID- 28086665 TI - C. difficile infection extends hospital stay for ventilated patients. AB - Patients on prolonged, acute mechanical ventilation have a higher risk of Clostridium difficile -associated disease than other hospital patients. Concurrent C. difficile infection is associated with longer hospital stay and costs. PMID- 28086666 TI - Study authors say parents need more support to help children lead healthy lifestyles. AB - There is little known about parental mechanisms underlying the association between maternal employment and childhood obesity. Researchers in London investigated the relationship between maternal hours worked per week and children's dietary and activity/inactivity habits. Where mothers were employed, the relationship between flexible working and these health indicators were also examined. Data from 12,578 children aged five were analysed. PMID- 28086667 TI - Pioneer's legacy of change. AB - Marcelle de Sousa is doubly proud of the MBE she received from the Queen last week. PMID- 28086668 TI - Readers panel - To pay or not to pay. AB - Our experts consider a hot topic of the day. PMID- 28086669 TI - Addressing patients' spiritual beliefs helps them deal with fear. AB - During my early nursing years in the late 1970s, there was little mention of patients' spiritual needs. The phrase 'psychological wellbeing' was used frequently, however. PMID- 28086670 TI - Cost of student attrition causes concern as colleges reveal figures. AB - More than half the nursing students on some nursing courses leave before completing their training, figures obtained by Nursing Standard show. PMID- 28086671 TI - The conkerer. AB - It is causing much hilarity among friends and family that I have conkers strewn all around my house. They are used as arachnid-deterrents. PMID- 28086672 TI - Nurse directors struggling due to lack of training. AB - Almost every week a director of nursing gets into serious difficulties at work, RCN general secretary Peter Carter told a seminar hosted by King's College London last week. PMID- 28086673 TI - University challenge. AB - The notion that it is impossible to be academically bright while retaining the ability to show care and compassion was presented in some quarters as an undeniable truth. In an outspoken attack on all nurses trained since 1990, the Patients Association put it like this: 'The academic must be secondary to the practical. Only then will patients get the nurses they want and trust - the right ones with the right attitude.' Nurses and patients of all generations know this is nonsense. PMID- 28086674 TI - Obsession about extreme obesity feeds voyeurism. AB - Britain's Paul Mason acquired the dismal title 'world's heaviest man' recently. Mr Mason weighs 70 stone. According to newspaper reports he. PMID- 28086675 TI - Starting out - My cheerful attitude upset an anxious pre-op patient. AB - It was my second clinical placement and I was working on a surgical ward when I was asked to accompany a patient to theatre. PMID- 28086676 TI - Voices - Is Mary Seacole a worthy black role model? Elizabeth Anionwu argues the case. AB - I gave a fair number of talks about Mary Seacole during Black History Month. Audiences donated more than L1,000 to the campaign to honour her with a statue in the grounds of St Thomas' Hospital, London. However, not everyone was in the mood to celebrate Mrs Seacole's achievements. PMID- 28086678 TI - Cranial irradiation in childhood decreases likelihood of marriage. AB - Adults who have survived childhood cancer are less likely to get married than their peers. Those who had central nervous system tumours, cranial irradiation, impaired processing efficiency and short stature were least likely to marry. PMID- 28086680 TI - Outsidein. AB - I call it Sleeper syndrome. Remember the Woody Allen film? Our hero is cryogenically frozen and wakes up after 200 years to find that doctors now consider alcohol, smoking and saturated fat essential to good health. PMID- 28086679 TI - Estimates of children exposed to drug use revised upwards. AB - The number of children living with substance-misusing parents exceeds previous estimates. PMID- 28086681 TI - Support staff will plan patient care. AB - The RCN has renewed its calls for the regulation of healthcare support workers following the publication last week of standards for assistant practitioners (APs). PMID- 28086682 TI - Department of health formulates ground rules for deploying students during a swine flu epidemic. AB - Nursing students who are employed to deal with swine flu must get honorary contracts from their employers and have the same access to antivirals and vaccines as other staff, the Department of Health (DH) said last week. PMID- 28086683 TI - Investment, recruitment and support: initiatives to tackle the midwifery crisis. AB - When the Royal College of Midwives (RCM) responded to the prime minister's Commission on the Future of Nursing and Midwifery, the comment from one midwife was so resonant it was printed in full in the submission. PMID- 28086684 TI - Health act confers new rights. AB - NHS trusts will have to provide staff with personal development, access to appropriate training and support from line managers under the Health Act 2009, which received royal assent last week. PMID- 28086686 TI - Specialist training to combat over-prescribing in dementia care. AB - Healthcare staff are to receive specialist training in working with patients who have dementia as part of the government's plan to tackle the over-prescribing of drugs. PMID- 28086685 TI - Nursing experts question viability of extending infection surveillance. AB - Calls for the introduction of mandatory surveillance of all healthcare-associated infections (HCAIs) has received a mixed reception from nursing experts. PMID- 28086687 TI - All-graduate entry will enhance the image of nursing. AB - I am delighted that England is now to follow the rest of the UK and move towards all-graduate entry to the profession. The Department of Health (DH) is to be congratulated for steering this forward. PMID- 28086688 TI - Student life - Beyond the call of duty. AB - Supernumerary status for nursing students in clinical practice settings is a relatively recent policy. Previously education had been based in hospital nursing schools and followed an apprenticeship model. PMID- 28086697 TI - Letter to the Editor. PMID- 28086693 TI - Laboratory and Field Evaluation of Measurement Methods for One-Hour Exposures to O3, PM25, and CO. AB - While researchers have linked acute (less than 12-hr) ambient O3, PM25, and CO concentrations to a variety of adverse health effects, few studies have characterized short-term exposures to these air pollutants, in part due to the lack of sensitive, accurate, and precise sampling technologies. In this paper, we present results from the laboratory and field evaluation of several new (or modified) samplers used in the "roll-around" system (RAS), which was developed to measure 1-hr O3, PM25, and CO exposures simultaneously. All the field evaluation data were collected during two sampling seasons: the summer of 1998 and the winter of 1999. To measure 1-hr O3 exposures, a new active O3 sampler was developed that uses two nitrite-coated filters to measure O3 concentrations. Laboratory chamber tests found that the active O3 sampler performed extremely well, with a collection efficiency of 0.96 that did not vary with temperature or relative humidity (RH). In field collocation comparisons with a reference UV photometric monitor, the active O3 sampler had an effective collection efficiency ranging between 0.92 and 0.96 and a precision for 1-hr measurements ranging between 4 and 6 parts per billion (ppb). The limits of detection (LOD) of this method were 9 ppb-hr for the chamber tests and ~16 ppb-hr for the field comparison tests. PM2.5 and CO concentrations were measured using modified continuous monitors-the DustTrak and the Langan, respectively. A size-selective inlet and a Nafion dryer were placed upstream of the DustTrak inlet to remove particles with aerodynamic diameters greater than 2.5 um and to dry particles prior to the measurements, respectively. During the field validation tests, the DustTrak consistently reported higher PM2.5 concentrations than those obtained by the collocated 12-hr PM2 5 PEM samples, by approximately a factor of 2. After the DustTrak response was corrected (correction factor of 2.07 in the summer and 2.02 in the winter), measurements obtained using these methods agreed well with R2 values of 0.87 in the summer and 0.81 in the winter. The results showed that the DustTrak can be used along with integrated measurements to measure the temporal and spatial variation in PM2 5 exposures. Finally, during the field validation tests, CO concentrations measured using the Langan were strongly correlated with those obtained using the reference method when the CO levels were above the LOD of the instrument [~1 part per million (ppm)]. PMID- 28086704 TI - Newborns unaffected by smoke if mothers quit at conception. AB - Women who give up smoking when pregnancy is confirmed can boost the health of their baby dramatically. PMID- 28086705 TI - Trust fends off mrsa for two years. AB - Trafford Healthcare NHS Trust in Manchester has gone two years without a single case of MRSA infection. Among Trafford General Hospital staff who gathered to celebrate the achievement were (from left) domestic Joanne Morton, microbiologist Barzo Faris and matron Julie Treadgold. In the foreground, infection control nurse Paula Halsall demonstrates a specialised microbe testing machine. PMID- 28086706 TI - Sick leave chart halves absence rate. AB - An NHS trust in West Yorkshire has seen staff sick leave rates fall by around 50 per cent after levels were displayed in staff areas. PMID- 28086707 TI - Healthcare regulator inspections may become annual. AB - The health and social care regulator is considering introducing annual inspections of hospitals, care homes and independent sector providers, Nursing Standard has learned. PMID- 28086708 TI - Court backs council's withdrawal of night help. AB - A court ruling that backed a local authority's decision to withdraw night time help to a stroke sufferer will have major implications for older people, according to the RCN. PMID- 28086709 TI - Student life - Off to a flying start. AB - Completing your final year as a nursing student can be exhilarating, but also a time of concern. Some students may feel unprepared to start work as a registered nurse or may feel they cannot measure up to the expert colleagues they worked with and learnt from during their training. PMID- 28086710 TI - It is time for others to take over Jennifer worth's legacy. AB - The stories in the late Jennifer Worth's Call the Midwife trilogy (obituary June 15) lead us into a different time and place. As the chapters unfold, we get to know some of her colleagues and patients from London's East End in the 1950s. PMID- 28086712 TI - UCLH has no 'knowledge amnesty' or plans for one. AB - I would like to clarify the comments I made at a recent conference that were reported under the headline 'Night staff skills gap identified' (news June 22). PMID- 28086714 TI - College wants more health visitor training options. AB - The RCN wants health visiting to be 'reinvigorated as an exciting career choice' by increasing nurses' access to training in the role. PMID- 28086713 TI - Being open will show people that we have nothing to hide. AB - Jan Halstead says that instances of poor care taint the public's trust in the caring profession (reflections July 6). PMID- 28086715 TI - Round the clock care. AB - An intensive home treatment team operating around the clock is improving care for people with mental health problems. PMID- 28086716 TI - Albertina Sisulu 1918-2011 Nurse and South African anti-apartheid activist. AB - Albertina Sisulu, nurse and political activist, has died at the age of 92. In a message read to mourners at her state funeral, former president Nelson Mandela paid tribute to her as 'one of the greatest South Africans'. PMID- 28086717 TI - Peers look into quality of UK care. AB - Members of the House of Lords are holding high-level talks with Nursing and Midwifery Council officials ahead of debates on the Health and Social Care (Re committed) Bill in the upper chamber later this year. PMID- 28086718 TI - Nurses bring touch of glamour to insulin pumps with a range of stylish covers. AB - Two innovative nurses have developed colourful covers for patients with diabetes to place over their insulin pumps. PMID- 28086719 TI - Southern cross staff jobs will be 'safeguarded'. AB - Nurses working at Southern Cross Healthcare's homes will be transferred on their current terms and conditions to new providers after the company suspended its shares, the organisation has said. PMID- 28086721 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28086722 TI - Experiment highlights ageing and isolation. AB - Volunteers struggled to cope without human contact for a week as part of a social experiment that examined the effect of isolation on older people. PMID- 28086723 TI - David Newnham wonders whether increased longevity is merely a luxury of the rich. AB - If I sound grumpy it is because everyone I speak to tells me we are living longer. Is that not a reason to be cheerful? It would be if I believed it. PMID- 28086726 TI - Webwise. AB - Health Research Web is an online interactive platform for the Council on Health Research for Development. This is an international non-governmental organisation supporting national health research and health research management in low and middle-income countries. PMID- 28086728 TI - Help at your fingertips. AB - Many healthcare faculties in higher education now use social network sites to keep students in touch with each other, and as a marketing tool to promote educational opportunities. PMID- 28086729 TI - An unmissable opportunity. AB - Andrew Dilnot's long-awaited report on how to pay for adult social care received a worryingly muted response from ministers last week. Even before the report was published there was widespread speculation that the government would reject his proposals on the grounds that they are too expensive. PMID- 28086730 TI - Royal newlyweds meet canada's war veterans. AB - The Duke and Duchess of Cambridge met nurses who served during the second world war on their first joint official overseas tour of Canada. PMID- 28086731 TI - 'we get the care that we pay for'. AB - The financial difficulties faced by the Southern Cross care homes group raise questions about the stability of the long-term care model. Since the late 1980s, long-stay hospitals have closed and the care of older people has been taken up mostly by the private sector. PMID- 28086732 TI - More choice will result in overstretched surgeries. AB - Nurses are also patients, and we all understand the frustrations of trying to fit GP appointments around work commitments. PMID- 28086733 TI - Voices. AB - With the strikes on June 30 by teaching staff and others, there has been a lot in the news recently about public sector pensions. PMID- 28086734 TI - Perception of keyboard use correlates with repetitive motion pain. AB - There is no association between software-recorded duration of computer use and wrist-hand and neck-shoulder symptoms. In contrast, there is a positive association between the self-reported duration of computer use at work and the onset of severe arm-wrist-hand and neck-shoulder symptoms. PMID- 28086735 TI - Readers panel - An unfair proposal. AB - Our experts consider a hot topic of the day. PMID- 28086736 TI - Engaging in cultural activities improves health in adults. AB - There is a gender-dependent association between cultural participation and perceived health, anxiety, depression and satisfaction with life. PMID- 28086738 TI - Data on school rugby injuries help pre-empt risk factors. AB - A community-based rugby injury surveillance system in Scotland's schools is feasible and should be encouraged, say researchers. PMID- 28086739 TI - Chloroquine proves ineffective as a flu virus vaccine. AB - Although well-tolerated by a healthy community population, chloroquine does not prevent infection with influenza. PMID- 28086737 TI - Age concern. AB - How does a woman make herself invisible? By reaching the age of 60. An old chestnut - but one with a kernel of truth. Those of a certain age often feel like white noise, humming away in the background but hardly noticed at all. PMID- 28086740 TI - Students who buy essays online do not learn anything. AB - I disagree with David Scott (letters July 6), who says that buying essays and coursework on eBay can be beneficial to learning. PMID- 28086741 TI - Court decision mocks the dignity in care campaign. AB - I am appalled that Elaine McDonald's appeal for an overnight carer has been turned down by the Supreme Court. PMID- 28086742 TI - Downbanding of 28 nursing posts was 'critical to improving outcomes'. AB - Nurses have quit their posts over a workforce review at a foundation trust that saw senior nursing posts downgraded, according to the RCN. PMID- 28086743 TI - 'The health service needs a wider, long-term strategic plan'. AB - There are pockets of health service provision across the UK that are indisputably successful. An annual stroke audit by the Royal College of Physicians, for example, rated stroke care in London as among the best in England, Wales and Northern Ireland. PMID- 28086744 TI - The jury is out on the importance and usefulness of nurse consultants. AB - I agree with readers panellist Kate Tantam (reflections July 6) that the word 'consultant' implies a powerful role in today's NHS, but the role of nurse consultant may have lost its shine. PMID- 28086745 TI - Starting out-I missed an opportunity to help a vulnerable patient. AB - I am a third-year nursing student undertaking my surgical attachment. Recently, I arrived in theatre and was told that we would be taking the voluntary termination of pregnancy list. PMID- 28086746 TI - MVIAeval: a web tool for comprehensively evaluating the performance of a new missing value imputation algorithm. AB - BACKGROUND: Missing value imputation is important for microarray data analyses because microarray data with missing values would significantly degrade the performance of the downstream analyses. Although many microarray missing value imputation algorithms have been developed, an objective and comprehensive performance comparison framework is still lacking. To solve this problem, we previously proposed a framework which can perform a comprehensive performance comparison of different existing algorithms. Also the performance of a new algorithm can be evaluated by our performance comparison framework. However, constructing our framework is not an easy task for the interested researchers. To save researchers' time and efforts, here we present an easy-to-use web tool named MVIAeval (Missing Value Imputation Algorithm evaluator) which implements our performance comparison framework. RESULTS: MVIAeval provides a user-friendly interface allowing users to upload the R code of their new algorithm and select (i) the test datasets among 20 benchmark microarray (time series and non-time series) datasets, (ii) the compared algorithms among 12 existing algorithms, (iii) the performance indices from three existing ones, (iv) the comprehensive performance scores from two possible choices, and (v) the number of simulation runs. The comprehensive performance comparison results are then generated and shown as both figures and tables. CONCLUSIONS: MVIAeval is a useful tool for researchers to easily conduct a comprehensive and objective performance evaluation of their newly developed missing value imputation algorithm for microarray data or any data which can be represented as a matrix form (e.g. NGS data or proteomics data). Thus, MVIAeval will greatly expedite the progress in the research of missing value imputation algorithms. PMID- 28086747 TI - MicroRNA based Pan-Cancer Diagnosis and Treatment Recommendation. AB - BACKGROUND: The current state-of-the-art in cancer diagnosis and treatment is not ideal; diagnostic tests are accurate but invasive, and treatments are "one-size fits-all" instead of being personalized. Recently, miRNA's have garnered significant attention as cancer biomarkers, owing to their ease of access (circulating miRNA in the blood) and stability. There have been many studies showing the effectiveness of miRNA data in diagnosing specific cancer types, but few studies explore the role of miRNA in predicting treatment outcome. METHODS: Here we go a step further, using tissue miRNA and clinical data across 21 cancers from the 'The Cancer Genome Atlas' (TCGA) database. We use machine learning techniques to create an accurate pan-cancer diagnosis system, and a prediction model for treatment outcomes. Finally, using these models, we create a web-based tool that diagnoses cancer and recommends the best treatment options. RESULTS: We achieved 97.2% accuracy for classification using a support vector machine classifier with radial basis. The accuracies improved to 99.9-100% when climbing up the embryonic tree and classifying cancers at different stages. We define the accuracy as the ratio of the total number of instances correctly classified to the total instances. The classifier also performed well, achieving greater than 80% sensitivity for many cancer types on independent validation datasets. Many miRNAs selected by our feature selection algorithm had strong previous associations to various cancers and tumor progression. Then, using miRNA, clinical and treatment data and encoding it in a machine-learning readable format, we built a prognosis predictor model to predict the outcome of treatment with 85% accuracy. We used this model to create a tool that recommends personalized treatment regimens. Both the diagnosis and prognosis model, incorporating semi-supervised learning techniques to improve their accuracies with repeated use, were uploaded online for easy access. CONCLUSION: Our research is a step towards the final goal of diagnosing cancer and predicting treatment recommendations using non-invasive blood tests. PMID- 28086748 TI - Genetic mechanisms of bone digestion and nutrient absorption in the bone-eating worm Osedax japonicus inferred from transcriptome and gene expression analyses. AB - BACKGROUND: Bone-eating worms of the genus Osedax (Annelida, Siboglinidae) have adapted to whale fall environments by acquiring a novel characteristic called the root, which branches and penetrates into sunken bones. The worms lack a digestive tract and mouth opening, and it has been suggested that Osedax degrade vertebrate bones and uptake nutrients through acidification and secretion of enzymes from the root. Symbiotic bacteria in the root tissue may have a crucial role in the metabolism of Osedax. However, the molecular mechanisms and cells responsible for bone digestion and nutrient uptake are still unclear, and information on the metabolic interaction between Osedax and symbiotic bacteria is limited. RESULTS: We compared transcriptomes from three different RNA samples from the following tissues: trunk + palps, root + ovisac, and larva + male. A Pfam domain enrichment analysis revealed that protease- and transporter-related genes were enriched in the root + ovisac specific genes compared with the total transcriptome. Through targeted gene annotation we found gene family expansions resulting in a remarkably large number of matrix metalloproteinase (mmp) genes in the Osedax compared with other invertebrates. Twelve of these Osedax mmp genes were expressed in the root epidermal cells. Genes encoding various types of transporters, including amino acid, oligopeptide, bicarbonate, and sulfate/carboxylate transporters, were also expressed in root epidermal cells. In addition, amino acid and other metabolite transporter genes were expressed in bacteriocytes. These protease and transporter genes were first expressed in root tissues at the juvenile stage, when the root starts to develop. CONCLUSIONS: The expression of various proteinase and transporter genes in the root epidermis supports the theory that the root epidermal cells are responsible for bone digestion and subsequent nutrient uptake. Expression of transporter genes in the host bacteriocytes suggests the presence of metabolic interaction between Osedax and symbiotic bacteria. PMID- 28086749 TI - Evolution of the angiopoietin-like gene family in teleosts and their role in skin regeneration. AB - BACKGROUND: The skin in vertebrates is a protective barrier and damage is rapidly repaired to re-establish barrier function and maintain internal homeostasis. The angiopoietin-like (ANGPTL) proteins are a family of eight secreted glycoproteins with an important role in skin repair and angiogenesis in humans. In other vertebrates their existence and role in skin remains largely unstudied. The present study characterizes for the first time the homologues of human ANGPTLs in fish and identifies the candidates that share a conserved role in skin repair using a regenerating teleost skin model over a 4-day healing period. RESULTS: Homologues of human ANGPTL1-7 were identified in fish, although ANGPTL8 was absent and a totally new family member designated angptl9 was identified in fish and other non-mammalian vertebrates. In the teleost fishes a gene family expansion occurred but all the deduced Angptl proteins retained conserved sequence and structure motifs with the human homologues. In sea bream skin angptl1b, angptl2b, angptl4a, angptl4b and angptl7 transcripts were successfully amplified and they were differentially expressed during skin regeneration. In the first 2 days of skin regeneration, re-establishment of the physical barrier and an increase in the number of blood vessels was observed. During the initial stages of skin regeneration angptl1b and angptl2b transcripts were significantly more abundant (p < 0.05) than in intact skin and angptl7 transcripts were down regulated (p < 0.05) throughout the 4-days of skin regeneration that was studied. No difference in angptl4a and angptl4b transcript abundance was detected during regeneration or between regenerating and intact skin. CONCLUSIONS: The angptl gene family has expanded in teleost genomes. In sea bream, changes in the expression of angptl1b, angptl2b and angptl7 were correlated with the main phases of skin regeneration, indicating the involvement of ANGPTL family members in skin regeneration has been conserved in the vertebrates. Exploration of the fish angptl family in skin sheds new light on the understanding of the molecular basis of skin regeneration an issue of importance for disease control in aquaculture. PMID- 28086750 TI - A genome-wide scan for genes under balancing selection in Drosophila melanogaster. AB - BACKGROUND: In the history of population genetics balancing selection has been considered as an important evolutionary force, yet until today little is known about its abundance and its effect on patterns of genetic diversity. Several well known examples of balancing selection have been reported from humans, mice, plants, and parasites. However, only very few systematic studies have been carried out to detect genes under balancing selection. We performed a genome scan in Drosophila melanogaster to find signatures of balancing selection in a derived (European) and an ancestral (African) population. We screened a total of 34 genomes searching for regions of high genetic diversity and an excess of SNPs with intermediate frequency. RESULTS: In total, we found 183 candidate genes: 141 in the European population and 45 in the African one, with only three genes shared between both populations. Most differences between both populations were observed on the X chromosome, though this might be partly due to false positives. Functionally, we find an overrepresentation of genes involved in neuronal development and circadian rhythm. Furthermore, some of the top genes we identified are involved in innate immunity. CONCLUSION: Our results revealed evidence of genes under balancing selection in European and African populations. More candidate genes have been found in the European population. They are involved in several different functions. PMID- 28086751 TI - Quantifying predictors for the spatial diffusion of avian influenza virus in China. AB - BACKGROUND: Avian influenza virus (AIV) causes both severe outbreaks and endemic disease among poultry and has caused sporadic human infections in Asia, furthermore the routes of transmission in avian species between geographic regions can be numerous and complex. Using nucleotide sequences from the internal protein coding segments of AIV, we performed a Bayesian phylogeographic study to uncover regional routes of transmission and factors predictive of the rate of viral diffusion within China. RESULTS: We found that the Central area and Pan Pearl River Delta were the two main sources of AIV diffusion, while the East Coast areas especially the Yangtze River delta, were the major targets of viral invasion. Next we investigated the extent to which economic, agricultural, environmental and climatic regional data was predictive of viral diffusion by fitting phylogeographic discrete trait models using generalised linear models. CONCLUSIONS: Our results highlighted that the economic-agricultural predictors, especially the poultry population density and the number of farm product markets, are the key determinants of spatial diffusion of AIV in China; high human density and freight transportation are also important predictors of high rates of viral transmission; Climate features (e.g. temperature) were correlated to the viral invasion in the destination to some degree; while little or no impacts were found from natural environment factors (such as surface water coverage). This study uncovers the risk factors and enhances our understanding of the spatial dynamics of AIV in bird populations. PMID- 28086752 TI - Single genome retrieval of context-dependent variability in mutation rates for human germline. AB - BACKGROUND: Accurate knowledge of the core components of substitution rates is of vital importance to understand genome evolution and dynamics. By performing a single-genome and direct analysis of 39,894 retrotransposon remnants, we reveal sequence context-dependent germline nucleotide substitution rates for the human genome. RESULTS: The rates are characterised through rate constants in a time domain, and are made available through a dedicated program (Trek) and a stand alone database. Due to the nature of the method design and the imposed stringency criteria, we expect our rate constants to be good estimates for the rates of spontaneous mutations. Benefiting from such data, we study the short-range nucleotide (up to 7-mer) organisation and the germline basal substitution propensity (BSP) profile of the human genome; characterise novel, CpG independent, substitution prone and resistant motifs; confirm a decreased tendency of moieties with low BSP to undergo somatic mutations in a number of cancer types; and, produce a Trek-based estimate of the overall mutation rate in human. CONCLUSIONS: The extended set of rate constants we report may enrich our resources and help advance our understanding of genome dynamics and evolution, with possible implications for the role of spontaneous mutations in the emergence of pathological genotypes and neutral evolution of proteomes. PMID- 28086753 TI - Better care provided to patients with tuberculosis at county designated TB hospitals (CTD) compared to non-CTDs in rural China. AB - BACKGROUND: The primary unit of tuberculosis (TB) medical care in China is the county TB dispensary or county designated hospital (CTD), where patients can receive free diagnosis and treatment. However, a substantial number of patients seek their anti-TB treatment from general health facilities (Non-CTDs). This study aimed to investigate the first anti-TB treatment experience and choice of health facilities of retreated TB patients and their determinants. METHODS: A cross-sectional study was conducted in Jiangsu, Shandong and Sichuan provinces. All registered re-treated TB patients were investigated using a structured questionnaire covering information on demographics, socio-economic characteristics, and previous anti-TB treatment experiences. RESULTS: Totally, 75.3% of 544 patients visited CTD directly for initial treatment. Patients who were female (OR:1.71, 95% CI: 1.01-2.87), over 40 years of age (OR:2.80, 95% CI: 1.24-6.33), from Jiangsu (OR:3.07, 95% CI: 1.57-6.01) and Sichuan (OR:4.47, 95% CI: 2.29-8.73) and those diagnosed before 2005 (OR:6.87, 95% CI: 4.24-11.13) had a significant higher risk receiving their initial treatment at a non-CTD. Patients were more likely to have standardized diagnosis and treatment regimens in CTD (89.8%) than in non-CTDs (65.9%). Patients treated in non-CTDs versus in CTD had a lower possibility to complete their treatment course during first TB episode (chi 2 = 3.926, P = 0.048), but there was no significant difference in the cure rate between different facilities (CTD 60.8%, Non-CTDs 59.1%). Patients in non-CTDs incurred higher costs (1,360 CNY) than those treated in CTD (920CNY). CONCLUSION: CTD play a key role in the National Tuberculosis Control Program. Patients should be guided to seek health care in county designated hospital, where they are more likely to receive appropriate examinations, treatment regimens and rigorous supervision, and to bear a lighter economic burden. PMID- 28086755 TI - Vitamin D deficiency as a risk factor for dementia: a systematic review and meta analysis. AB - BACKGROUND: Sunlight exposure and high vitamin D status have been hypothesised to reduce the risk of developing dementia. The objective of our research was to determine whether lack of sunlight and hypovitaminosis D over time are associated with dementia. METHODS: We systematically searched MEDLINE (via PubMed), Cochrane Library, EMBASE, SCOPUS, Web of Science, ICONDA, and reference lists of pertinent review articles from 1990 to October 2015. We conducted random effects meta analyses of published and unpublished data to evaluate the influence of sunlight exposure or vitamin D as a surrogate marker on dementia risk. RESULTS: We could not identify a single study investigating the association between sunlight exposure and dementia risk. Six cohort studies provided data on the effect of serum vitamin D concentration on dementia risk. A meta-analysis of five studies showed a higher risk for persons with serious vitamin D deficiency (<25 nmol/L or 7-28 nmol/L) compared to persons with sufficient vitamin D supply (>=50 nmol/L or 54-159 nmol/L) (point estimate 1.54; 95% CI 1.19-1.99, I2 = 20%). The strength of evidence that serious vitamin D deficiency increases the risk of developing dementia, however, is very low due to the observational nature of included studies and their lack of adjustment for residual or important confounders (e.g. ApoE epsilon4 genotype), as well as the indirect relationship between Vitamin D concentrations as a surrogate for sunlight exposure and dementia risk. CONCLUSIONS: The results of this systematic review show that low vitamin D levels might contribute to the development of dementia. Further research examining the direct and indirect relationship between sunlight exposure and dementia risk is needed. Such research should involve large-scale cohort studies with homogeneous and repeated assessment of vitamin D concentrations or sunlight exposure and dementia outcomes. PMID- 28086756 TI - Concomitant disseminated histoplasmosis and disseminated tuberculosis after tumor necrosis factor inhibitor treatment: a case report. AB - BACKGROUND: Tumor necrosis factor antagonist inhibitors have transformed the approach to patients with severe autoimmune conditions, such as rheumatoid arthritis. Although the therapy can be highly effective, TNF-alpha inhibitors are associated with an increased risk of opportunistic infections. CASE PRESENTATION: Here, we report a case of concomitant disseminated histoplasmosis and tuberculosis in a 65-year-old female with rheumatoid arthritis treated with TNF alpha inhibitor. Both conditions can be found in disseminated form in immunosuppressed hosts, but co-infection is rare with only a few cases having been reported, to our knowledge, all in HIV patients. CONCLUSIONS: This case posed a considerable challenge for diagnosis and treatment due to the unusual disseminated co-infection, the overlapping symptoms, and the interactions between medications. PMID- 28086754 TI - Making the Most of Mealtimes (M3): protocol of a multi-centre cross-sectional study of food intake and its determinants in older adults living in long term care homes. AB - BACKGROUND: Older adults living in long term care (LTC) homes are nutritionally vulnerable, often consuming insufficient energy, macro- and micronutrients to sustain their health and function. Multiple factors are proposed to influence food intake, yet our understanding of these diverse factors and their interactions are limited. The purpose of this paper is to fully describe the protocol used to examine determinants of food and fluid intake among older adults participating in the Making the Most of Mealtimes (M3) study. METHODS: A conceptual framework that considers multi-level influences on mealtime experience, meal quality and meal access was used to design this multi-site cross sectional study. Data were collected from 639 participants residing in 32 LTC homes in four Canadian provinces by trained researchers. Food intake was assessed with three-days of weighed food intake (main plate items), as well as estimations of side dishes, beverages and snacks and compared to the Dietary Reference Intake. Resident-level measures included: nutritional status, nutritional risk; disease conditions, medication, and diet prescriptions; oral health exam, signs of swallowing difficulty and olfactory ability; observed eating behaviours, type and number of staff assisting with eating; and food and foodservice satisfaction. Function, cognition, depression and pain were assessed using interRAI LTCF with selected items completed by researchers with care staff. Care staff completed a standardized person-directed care questionnaire. Researchers assessed dining rooms for physical and psychosocial aspects that could influence food intake. Management from each site completed a questionnaire that described the home, menu development, food production, out-sourcing of food, staffing levels, and staff training. Hierarchical regression models, accounting for clustering within province, home and dining room will be used to determine factors independently associated with energy and protein intake, as proxies for intake. Proportions of residents at risk of inadequate diets will also be determined. DISCUSSION: This rigorous and comprehensive data collection in a large and diverse sample will provide, for the first time, the opportunity to consider important modifiable factors associated with poor food intake of residents in LTC. Identification of factors that are independently associated with food intake will help to develop effective interventions that support food intake. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02800291 , retrospectively registered June 7, 2016. PMID- 28086757 TI - A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT mTOR pathway-associated megalencephaly. AB - BACKGROUND: Constitutive activation of the PI3K-AKT-mTOR pathway (mTOR pathway) underlies megalencephaly in many patients. Yet, prevalence of the involvement of the PI3K-AKT-mTOR pathway in patients with megalencephaly remains to be elucidated, and molecular diagnosis is challenging. Here, we have successfully established a combination of genetic and biochemical methods for diagnosis of mTOR pathway-associated megalencephaly, and have attempted to delineate the clinical characteristics of the disorder. METHODS: Thirteen patients with an increased head circumference and neurological symptoms participated in the study. To evaluate the activation of the mTOR pathway, we performed western blot analysis to determine the expression levels of phosphorylated S6 ribosomal protein (phospho-S6 protein) in lymphoblastoid cell lines from 12 patients. Multiplex targeted sequencing analysis for 15 genes involved in the mTOR pathway was performed on 12 patients, and whole-exome sequencing was performed on one additional patient. Clinical features and MRI findings were also investigated. RESULTS: We identified pathogenic mutations in six (AKT3, 1 patient; PIK3R2, 2 patients; PTEN, 3 patients) of the 13 patients. Increased expression of phospho S6 protein was demonstrated in all five mutation-positive patients in whom western blotting was performed, as well as in three mutation-negative patients. Developmental delay, dysmorphic facial features were observed in almost all patients. Syndactyly/polydactyly and capillary malformations were not observed, even in patients with AKT3 or PIK3R2 mutations. There were no common phenotypes or MRI findings among these patients. CONCLUSIONS: A combination of genetic and biochemical methods successfully identified mTOR pathway involvement in nine of 13 (approximately 70%) patients with megalencephaly, indicating a major contribution of the pathway to the pathogenesis of megalencephaly. Our combined approach could be useful to identify patients who are suitable for future clinical trials using an mTOR inhibitor. PMID- 28086759 TI - Urinary incontinence and its association with functional physical and cognitive health among female nursing home residents in Switzerland. AB - BACKGROUND: Specific knowledge of urinary incontinence (UI) and its interrelation with physical and cognitive health is essential to working towards prevention of UI and to improving quality of treatment and care. The purpose of this study was to determine the association between UI and the activities of daily living (ADL) hierarchy scale, the cognitive performance scale (CPS) and comorbid conditions. METHODS: The cross-sectional retrospective analysis of 357 nursing homes in Switzerland was based on data of the Minimum Data Set of the Resident Assessment Instrument 2.0 (RAI-MDS). The analysis examined the effect of ADL hierarchy scale, CPS, joint motion and comorbidities on UI. Women >=65 years were included (n = 44'811; January 2005 to September 2014) at the time of admission to a nursing home. Statistical analysis was done by means of descriptive statistics and logistic regression analysis. RESULTS: The prevalence of UI was 54.7%, the mean ADL hierarchy scale (+/- SD) 2.42 +/- 3.26 (range = 0-6), the mean CPS 1.95 +/- 1.67 (range = 0-6). There was a gradual increase in the odds ratio (OR) for UI depending on the ADL hierarchy scale, from the hierarchy scales of "supervised" to "total dependence" of 1.43 - 30.25. For CPS, the OR for UI from "borderline intact" to "very severe impairment" was 1.35 - 5.99. Considering the interaction between ADL and CPS, all ADL hierarchies remained significantly associated with UI, however for CPS this was the case only in the lower hierarchies. Of the 11 examined comorbid conditions, only diabetes mellitus (OR 1.19), dementia (OR 1.01) and arthrosis/arthritis (OR 1.53) were significantly associated with UI. CONCLUSION: The study indicated that impairment in ADL performance is strongly associated with UI, more than CPS performance and comorbidities. Physical more than cognitive training in order to improve or at least stabilize ADL performance could be a way to prevent or reduce the process of developing UI. PMID- 28086758 TI - Toxoplasmosis-associated IRIS involving the CNS: a case report with longitudinal analysis of T cell subsets. AB - BACKGROUND: HIV-infected patients may present an unforeseen clinical worsening after initiating antiretroviral therapy known as immune reconstitution inflammatory syndrome (IRIS). This syndrome is characterized by a heightened inflammatory response toward infectious or non-infectious triggers, and it may affect different organs. Diagnosis of IRIS involving the central nervous system (CNS-IRIS) is challenging due to heterogeneous manifestations, absence of biomarkers to identify this condition, risk of long-term sequelae and high mortality. Hence, a deeper knowledge of CNS-IRIS pathogenesis is needed. CASE PRESENTATION: A 37-year-old man was diagnosed with AIDS and cerebral toxoplasmosis. Anti-toxoplasma treatment was initiated immediately, followed by active antiretroviral therapy (HAART) 1 month later. At 2 months of HAART, he presented with progressive hyposensitivity of the right lower limb associated with brain and dorsal spinal cord lesions, compatible with paradoxical toxoplasmosis-associated CNS-IRIS, a condition with very few reported cases. A stereotactic biopsy was planned but was postponed based on its inherent risks. Patient showed clinical improvement with no requirement of corticosteroid therapy. Routine laboratorial analysis was complemented with longitudinal evaluation of blood T cell subsets at 0, 1, 2, 3 and 6 months upon HAART initiation. A control group composed by 9 HIV-infected patients from the same hospital but with no IRIS was analysed for comparison. The CNS-IRIS patient showed lower percentage of memory CD4+ T cells and higher percentage of activated CD4+ T cells at HAART initiation. The percentage of memory CD4+ T cells drastically increased at 1 month after HAART initiation and became higher in comparison to the control group until clinical recovery onset; the percentage of memory CD8+ T cells was consistently lower throughout follow-up. Interestingly, the percentage of regulatory T cells (Treg) on the CNS-IRIS patient reached a minimum around 1 month before symptoms onset. CONCLUSION: Although both stereotactic biopsies and steroid therapy might be of use in CNS-IRIS cases and should be considered for these patients, they might be unnecessary to achieve clinical improvement as shown in this case. Immunological characterization of more CNS-IRIS cases is essential to shed some light on the pathogenesis of this condition. PMID- 28086760 TI - Education of pediatric subspecialty fellows in transport medicine: a national survey. AB - BACKGROUND: The transport of critically ill patients to children's hospitals is essential to current practice. The AAP Section on Transport Medicine has raised concerns about future leadership in the field as trainees receive less exposure to transport medicine. This study identifies the priorities of pediatric subspecialty fellows, fellowship directors and nursing directors in transport medicine education. METHODS: Internet based surveys were distributed to fellows, fellowship directors and nursing directors of transport teams affiliated with ACGME-approved fellowships in Neonatal-Perinatal Medicine (NPM), Pediatric Critical Care Medicine (PCCM), and Pediatric Emergency Medicine (PEM). Data collection occurred November 2013 to March 2014. RESULTS: Four hundred and sixty six responses were collected (357 fellows, 82 directors, 27 nursing directors): Six curricular elements were ranked by respondents: Transport Physiology (TP), Medical Control (MC), Vehicle Safety (VS), Medicolegal Issues (ML), Medical Protocols (MP) and State and Federal Regulations (SFR). Fellows and fellowship directors were not significantly different: TP (p = 0.63), VS (p = 0.45), SFR (p = 0.58), ML (p = 0.07), MP (p = 0.98), and MC (p = 0.36). Comparison of subspecialties found significant differences: PEM considered TP less important than NPM and PCCM (p < 0.001, p < 0.001), VS less important than NPM (p = 0.001). PEM viewed SFR and MC more important than PCCM (p = 0.006, p = 0.002); ML more important than PCCM and NPM (p = 0.001, p < 0.001). PCCM ranked MC more important than NPM (p = 0.004). Nursing directors considered TP less important than NPM and PCCM (p < 0.001, p = 0.002). CONCLUSIONS: When ranking curricular elements in transport medicine, fellows and fellowship directors do not differ, but comparison of subspecialties notes significant differences. A fellow curriculum in transport medicine will utilize these results. PMID- 28086762 TI - Prevalence and risk factors of congenital heart defects among live births: a population-based cross-sectional survey in Shaanxi province, Northwestern China. AB - BACKGROUND: Nearly half of the population of Northwest China live in Shaanxi province, but population-based data on the epidemiologic characteristics of congenital heart defects (CHD) in this population is limited. The study aimed to investigate the prevalence and epidemiologic characteristics of the CHD among infants born between 2010 and 2013 in Shaanxi province. METHODS: Infants born between 2010 and 2013 in Shaanxi province were surveyed using a stratified multi stage sampling method. Participant characteristics were recorded by questionnaire, medical records were reviewed and CHD was diagnosed using a specialized neonatal echocardiography. A Poisson regression model was applied to assess the association between any CHD and possible risk factors. RESULTS: A total of 29098 live infants were surveyed with an overall prevalence of 76.0 (95% CI: 66.3, 86.7) per 10000 live infants. The prevalence of major and minor CHD were 26.1 and 49.8 per 10000 live infants, respectively, in surveyed areas. Poisson regression analysis indicated that, compared with singleton infants, the prevalence rate ratio of CHD was higher in twin and multi-fetal infants (PRR:3.1, 95% CI:1.6, 6.1). Using southern Shaanxi as a reference, the PRR of CHD were lower in northern (PRR:0.4, 95% CI:0.3, 0.6) and central Shaanxi province (PRR:0.5, 95% CI:0.4, 0.7). PRR was higher in mothers over 30 years of age than in those under 25 years (PRR:1.6, 95% CI:1.0, 2.5), and in mothers with >=3 parity than that in mothers with only one parity (PRR:2.2, 95% CI:1.2, 4.2). The risk for CHD among live infants was positively associated with family history of CHD (PRR: 9.8, 95% CI: 5.3, 18.1). Additionally, CHD was less common in the floating population than the permanent population (PRR: 0.6, 95% CI: 0.4, 0.9). CONCLUSION: The CHD among live infants seemed to be a serious health problem in Shaanxi province as well as in Northwestern China. Our research have important policy implications for recommendations on CHD intervention in Northwest China. PMID- 28086761 TI - Is treatment-resistant schizophrenia categorically distinct from treatment responsive schizophrenia? a systematic review. AB - BACKGROUND: Schizophrenia is a highly heterogeneous disorder, and around a third of patients are treatment-resistant. The only evidence-based treatment for these patients is clozapine, an atypical antipsychotic with relatively weak dopamine antagonism. It is plausible that varying degrees of response to antipsychotics reflect categorically distinct illness subtypes, which would have significant implications for research and clinical practice. If these subtypes could be distinguished at illness onset, this could represent a first step towards personalised medicine in psychiatry. This systematic review investigates whether current evidence supports conceptualising treatment-resistant and treatment responsive schizophrenoa as categorically distinct subtypes. METHOD: A systematic literature search was conducted, using PubMed, EMBASE, PsycInfo, CINAHL and OpenGrey databases, to identify all studies which compared treatment-resistant schizophrenia (defined as either a lack of response to two antipsychotic trials or clozapine prescription) to treatment-responsive schizophrenia (defined as known response to non-clozapine antipsychotics). RESULTS: Nineteen studies of moderate quality met inclusion criteria. The most robust findings indicate that treatment-resistant patients show glutamatergic abnormalities, a lack of dopaminergic abnormalities, and significant decreases in grey matter compared to treatment-responsive patients. Treatment-resistant patients were also reported to have higher familial loading; however, no individual gene-association study reported their findings surviving correction for multiple comparisons. CONCLUSIONS: Tentative evidence supports conceptualising treatment-resistant schizophrenia as a categorically different illness subtype to treatment responsive schizophrenia. However, research is limited and confirmation will require replication and rigorously controlled studies with large sample sizes and prospective study designs. PMID- 28086763 TI - The prevalence and factors associated with malnutrition among infants with cleft palate and/or lip at a hospital in Uganda: a cross-sectional study. AB - BACKGROUND: To determine the prevalence and factors associated with malnutrition among infants with Cleft palate and/or cleft lip (CP+/-L) at Comprehensive Rehabilitation for Uganda Hospital (CoRSU) in Uganda. METHODS: This was a cross sectional study done on infants with CP+/-L and their caretakers admitted between November 2013 and October 2014 at CoRSU hospital which was the study setting. A questionnaire was answered by the infants' caretakers. The main outcome measure, malnutrition was defined and classified based on Z-scores obtained using the W.H.O Z-calculator in which weights of the infants in kilograms and lengths in centimeters respectively were placed. The values obtained were expressed as a proportion using all enrolled infants with CP+/-L as denominator. Multivariable analysis was used to determine the risk factors. RESULTS: A total of 44 infants with CP+/-L were enrolled. Of these, 77% were below 4 months of age and 97.7% were immunized. The male-to-female ratio was 1.06:1. About 59% had unilateral CP+/-L. A total of 93.2% were delivered at term with 69.4% having a birth weight greater than 3 kg. Generally, 68% were malnourished, with the highest burden among females (71.4%), infants below 4 months (73.5%) and those with unilateral CP+/-L (77%). About 57% had moderate-to-severe malnutrition. There was delayed supplementation to breast milk, with cow-milk as the main supplemental feed for all the infants. In the multivariable analysis, factors associated with malnutrition included, having caretakers lacking nutritional information post delivery (OR = 3.8, p = 0.17), low birth weight (OR = 3.4, p = 0.20), and having less than 10 feeds/day (OR = 4.9, p = 0.09). CONCLUSION: CP+/-L infants born in Uganda suffer a high-burden of malnutrition. Preventional strategies are needed with focus on proper feeding information. Research on cost-effective feeds, feeding methods and reasons behind gender disparities in these infants is also required. PMID- 28086764 TI - An audit of the quality of online immunisation information available to Australian parents. AB - BACKGROUND: The Internet is increasingly a source of health information for parents, who use the Internet alongside health care providers for immunisation information. Concerns have been raised about the reliability of online immunisation information, however to date there has been no audit of the quality or quantity of what is available to Australian parents. The objective of this study was to address this gap by simulating a general online search for immunisation information, and assessing the quality and quantity of the web sites returned by the search. METHODS: We used Google trends to identify the most common immunisation search terms used in Australia. The ten most common terms were entered into five search engines and the first ten non-commercial results from each search collated. A quality assessment tool was developed using the World Health Organization Global Advisory Committee on Vaccine Safety (GACVS) criteria for assessing the quality of vaccine safety web sites, and used to assess and score the quality of the sites. RESULTS: Seven hundred web pages were identified, of which 514 were duplicates, leaving 186 pages from 115 web sites which were audited. Forty sites did not include human immunisation information, or presented personal opinion about individuals, and were not scored. Of the 75 sites quality scored, 65 (87%) were supportive of immunisation, while 10 (13%) were not supportive. The overall mean quality score was 57/100 (range 14/100 to 92/100). When stratified by pro and anti-vaccination stance, the average quality score for pro-vaccine sites was 61/100, while the average score for anti-vaccine sites was 30/100. Pro-vaccine information could be divided into three content groups: generalist overview with little detail; well-articulated and understandable detail; and lengthy and highly technical explanations. The main area found to be lacking in pro-vaccine sites was lack of transparent authorship. CONCLUSION: Our findings suggest a need for information which is easily found, transparently authored, well-referenced, and written in a way that is easily understood. PMID- 28086765 TI - Health-related quality of life (HRQOL) and its associated factors in children with Type 1 Diabetes Mellitus (T1DM). AB - BACKGROUND: The objective of the study was to describe the baseline health related quality of life (HRQOL) in a cohort of children and adolescents with type 1 diabetes mellitus (T1DM), and analyze its associated clinical and sociodemographic factors, assessing HRQOL through internet. METHODS: This was a descriptive study of 136 patients with T1DM from 5 hospitals in Catalonia, Spain (72 girls, mean age 13.4 years (range 8-19). Inclusion criteria were more than 6 months from diagnosis, more than 8 years old and without cognitive problems. Sociodemographic (age, sex, family level of education, type of family and origin) and clinical variables (type of insulin therapy, duration of disease, adherence to treatment, body mass index and HbA1c) were collected. HRQOL was assessed using the EuroQol-5D (EQ-5D-Y) and KIDSCREEN, collected via web. Mental health status was assessed using the Strengths and Difficulties Questionnaire. Multiple linear regression models were adjusted. RESULTS: Physical-well-being mean scores were lower (worse) than the European average (<50) and especially in girls, older children (>11 years old), those from single-parent families, and those with low adherence. Older children and patients with poor metabolic control (HbA1c >7,5% [58 mmol/mol]) showed worse scores in the KIDSCREEN-10 index. Similar results were observed with the EQ-5D-Y. Multivariate models showed that age, single parent families, adherence and mental health were the most influential factors. CONCLUSIONS: Diabetic patients report similar HRQOL than the population of the same age with slightly worse physical well-being. The study shows some factors to be taken into account to improve HRQOL, and also the feasibility of using web to collect information in clinical practice. PMID- 28086766 TI - Psychoeducational preventive treatment for women at risk of postpartum depression: study protocol for a randomized controlled trial, PROGEA. AB - BACKGROUND: Postpartum depression is a disease with a prevalence of 20% that has deleterious consequences not only for the mother but also for the baby and can cause delays in physical, social and cognitive development. In this context, the European Union Committee on Public Health has declared it essential that preventative measures are taken by centres providing care for women with a multidisciplinary approach. PROGEA is a multicentre, single-blind randomized, 3 year, longitudinal clinical trial aiming to evaluate the efficacy of a psychoeducational programme in preventing postpartum depression in at-risk women, based on a range of clinical variables, and explore prognostic factors. This paper describes the methods and rationale behind the study. METHODS: We will study women receiving treatment as usual plus a psychoeducation cognitive behavioural therapy (CBT)-based intervention and a control group receiving only treatment as usual. The sample will be recruited from an incidental sampling of pregnant women in two health regions. We will recruit 600 women in the third trimester of pregnancy who consent to take part in the study. Almost half of the women, about 280, would be expected to have some risk factors for postpartum depression. All those found to have risk factors will be evaluated, and we estimate that a quarter will be classified as at-risk of developing postpartum depression as measured with the Edinburgh Postnatal Depression Scale. This subset will be randomly allocated to receive treatment as usual with or without the CBT intervention. Six sessions of CBT (1 individual and 5 group) will be offered by a psychologist. DISCUSSION: Findings from this study will be used to design a definitive study that will examine the clinical and cost-effectiveness of the CBT based intervention in improving the mood of women in the postpartum period. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02323152 ; Date: December 2014. PMID- 28086767 TI - Quantifying traditional Chinese medicine patterns using modern test theory: an example of functional constipation. AB - BACKGROUND: The study aimed to validate a scale to assess the severity of "Yin deficiency, intestine heat" pattern of functional constipation based on the modern test theory. METHODS: Pooled longitudinal data of 237 patients with "Yin deficiency, intestine heat" pattern of constipation from a prospective cohort study were used to validate the scale. Exploratory factor analysis was used to examine the common factors of items. A multidimensional item response model was used to assess the scale with the presence of multidimensionality. RESULTS: The Cronbach's alpha ranged from 0.79 to 0.89, and the split-half reliability ranged from 0.67 to 0.79 at different measurements. Exploratory factor analysis identified two common factors, and all items had cross factor loadings. Bidimensional model had better goodness of fit than the unidimensional model. Multidimensional item response model showed that the all items had moderate to high discrimination parameters. Parameters indicated that the first latent trait signified intestine heat, while the second trait characterized Yin deficiency. Information function showed that items demonstrated highest discrimination power among patients with moderate to high level of disease severity. CONCLUSIONS: Multidimensional item response theory provides a useful and rational approach in validating scales for assessing the severity of patterns in traditional Chinese medicine. PMID- 28086768 TI - Probiotic mixture improves fatty liver disease by virtue of its action on lipid profiles, leptin, and inflammatory biomarkers. AB - BACKGROUND: A high fat diet has an essential role in the pathogenesis of non alcoholic fatty liver disease (NAFLD). This condition is characterized by hepatic fat accumulation (steatosis) and is associated with obesity, diabetes, and fibrosis or cirrhosis of the liver. Probiotics may be useful in the treatment of steatosis. This study examined the effects of an ingested probiotic formulation on the lipid profiles, liver functions, leptin levels, and inflammatory marker levels of rats with NAFLD that had been induced via high fat and sucrose diet (HFSD). METHODS: Young male albino rats were randomly divided into three groups: a control group that was fed a standard diet; a second group that was fed a HFSD; and a third group that was given both a HFSD and ingestible probiotic mixtures. The groups were fed these diets for 16 weeks, and were then examined. RESULTS: HFSD-only rats showed hypertriglyceridemia, hypercholesterolemia, and elevated low density lipoprotein (LDL) levels, and their serum alanine transaminase (ALT) and bilirubin levels were significantly higher than those of the control group. Compared to rats on the standard diet, HFSD-only rats showed higher levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6), increased serum leptin levels, and increased resistin hormone levels in the adipose tissues. In the third group, the inclusion of the probiotic mixture seemed to ameliorate the effects of the HFSD diet. The NAFD + probiotics group showed improved lipid profiles, better leptin and resistin levels, and better TNF-alpha and IL-6 levels than the NAFD-only group. They also showed no signs of NAFLD. CONCLUSIONS: The probiotic mixture showed promise as a treatment for NAFLD pathogenesis, and may improve HFSD-induced steatosis through its effects on leptin, resistin, inflammatory biomarkers, and hepatic function markers. We also established that gut microbiota-mediated regulation of lipid profiles was dependent on dietary lipids and carbohydrates. PMID- 28086769 TI - Effect of ginseng extract on the TGF-beta1 signaling pathway in CCl4-induced liver fibrosis in rats. AB - BACKGROUND: Liver diseases are major global health problems. Ginseng extract has antioxidant, immune-modulatory and anti-inflammatory activities. This study investigated the effect of ginseng extract on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. METHODS: Male Wistar rats were divided into four groups: control group, ginseng group, CCl4 group and CCl4 + ginseng group. Liver injury was induced by the intraperitoneal (I.P) injection of 3 ml/kg CCl4 (30% in olive oil) weekly for 8 weeks. The control group was I.P injected with olive oil. The expression of genes encoding transforming growth factor beta (TGF-beta), type I TGF-beta receptor (TbetaR-1), type II TGF-beta receptor (TbetaR-II), mothers against decapentaplegic homolog 2 (Smad2), Smad3, Smad4, matrix metalloproteinase 2 (MMP2), MMP9, tissue inhibitor matrix metalloproteinase-1 (TIMP-1), Collagen 1a2 (Col1a2), Collagen 3a1 (Col3a1), interleukin-8 (IL-8) and interleukin -10 (IL 10) were measured by real-time PCR. RESULTS: Treatment with ginseng extract decreased hepatic fat deposition and lowered hepatic reticular fiber accumulation compared with the CCl4 group. The CCl4 group showed a significant increase in hepatotoxicity biomarkers and up-regulation of the expression of genes encoding TGF-beta, TbetaR-I, TbetaR-II, MMP2, MMP9, Smad-2,-3, -4, and IL-8 compared with the control group. However, CCl4 administration resulted in the significant down regulation of IL-10 mRNA expression compared with the control group. Interestingly, ginseng extract supplementation completely reversed the biochemical markers of hepatotoxicity and the gene expression alterations induced by CCl4. CONCLUSION: ginseng extract had an anti-fibrosis effect via the regulation of the TGF-beta1/Smad signaling pathway in the CCl4-induced liver fibrosis model. The major target was the inhibition of the expression of TGF beta1, Smad2, and Smad3. PMID- 28086770 TI - Social pediatrics: weaving horizontal and vertical threads through pediatric residency. AB - BACKGROUND: Social pediatrics teaches pediatric residents how to understand disease within their patients' social, environmental and political contexts. It's an essential component of pediatric residency training; however there is very little literature that addresses how such a broad-ranging topic can be taught effectively. The aim of this study was to determine and characterize social pediatric education in our pediatric residency training in order to identify strengths and gaps. METHODS: A social pediatrics curriculum map was developed, attending to 3 different dimensions: (1) the intended curriculum as prescribed by the Objectives of Training for Pediatrics of the Royal College of Physicians and Surgeons of Canada (RCPSC), (2) the formal curriculum defined by rotation specific learning objectives, and (3) the informal/hidden curriculum as reflected in resident and teacher experiences and perceptions. RESULTS: Forty-one social pediatric learning objectives were extracted from the RCPSC Objectives of Training for Pediatrics, most were listed in the Medical Expert (51%) and Health Advocate competencies (24%). Almost all RCPSC social pediatric learning objectives were identified in more than one rotation and/or seminar. Adolescent Medicine (29.2%), Pediatric Ambulatory Medicine (26.2%) and Developmental Pediatrics (25%) listed the highest proportion of social pediatric learning objectives. Four (10%) RCPSC social pediatric objectives were not explicitly named within learning objectives of the formal curriculum. The informal curriculum revealed that both teachers and residents viewed social pediatrics as integral to all clinical encounters. Perceived barriers to teaching and learning of social pediatrics included time constraints, particularly in a tertiary care environment, and the value of social pediatrics relative to medical expert knowledge. CONCLUSIONS: Despite the lack of an explicit thematic presentation of social pediatric learning objectives by the Royal College and residency training program, social pediatric topics are integrated, taught and learned throughout the entire curriculum. Special attention needs to be given to the hidden curriculum and system barriers that may impede social pediatric education. PMID- 28086771 TI - Naturalistic study of guideline implementation tool use via evaluation of website access and physician survey. AB - BACKGROUND: Clinical guidelines support decision-making at the point-of-care but the onus is often on individual users such as physicians to implement them. Research shows that the inclusion of implementation tools in or with guidelines (GItools) is associated with guideline use. However, there is little research on which GItools best support implementation by individual physicians. The purpose of this study was to investigate naturalistic access and use of GItools produced by the American Academy of Neurology (AAN) to inform future tool development. METHODS: Website accesses over six months were summarized for eight AAN guidelines and associated GItools published between July 2012 and August 2013. Academy members were surveyed about use of tools accompanying the sport concussion guideline. Data were analyzed using summary statistics and the Chi square test. RESULTS: The clinician summary was accessed more frequently (29.0%, p < 0.001) compared with the slide presentation (26.8%), patient summary (23.2%) or case study (20.9%), although this varied by guideline topic. For the sport concussion guideline, which was accompanied by a greater variety of GItools, the mobile phone quick reference check application was most frequently accessed, followed by the clinician summary, patient summary, and slide presentation. For the sports concussion guideline survey, most respondents (response rate 21.8%, 168/797) were aware of the guideline (88.1%) and had read the guideline (78.6%). For GItool use, respondents indicated reading the reference card (51.2%), clinician summary (45.2%), patient summary (28.0%), mobile phone application (26.2%), and coach/athletic trainer summary (20.2%). Patterns of sports concussion GItool use were similar between respondents who said they had and had not yet implemented the guideline. CONCLUSIONS: Developers faced with resource limitations may wish to prioritize the development of printable or mobile application clinician summaries, which were accessed significantly more than other types of GItools. Further research is needed to understand how to optimize the design of such GItools. PMID- 28086772 TI - Scutellaria barbata D. Don extract inhibits the tumor growth through down regulating of Treg cells and manipulating Th1/Th17 immune response in hepatoma H22-bearing mice. AB - BACKGROUND: Previous studies showed Scutellaria barbata D. Don extract (SBE) is a potent inhibitor in hepatoma and could improve immune function of hepatoma H22 bearing mice. However, the immunomodulatory function of SBE on the tumor growth of hepatoma remains unclear. This study aimed to investigate the anti-tumor effects of SBE on hepatoma H22-bearing mice and explore the underlying immunomodulatory function. METHODS: The hepatoma H22-bearing mice were treated by SBE for 30 days. The effect of SBE on the proliferation of HepG2 cells in vitro, the growth of transplanted tumor, the cytotoxicity of natural killer (NK) cells in spleen, the amount of CD4+CD25+Foxp3+ Treg cells and Th17 cells in tumor tissue, and the levels of IL-10, TGF-beta, IL-17A, IL-2, and IFN-gamma in serum of the hepatoma H22-bearing mice was observered. IL-17A was injected to the SBE treated mice from day 9 post H22 inoculation to examine its effect on tumor growth. RESULTS: SBE treatment inhibited the proliferation of HepG2 cells in vitro with a dose-dependent manner and significantly suppressed the tumor growth of hepatoma H22-bearing mice. Meanwhile, it increased NK cells' cytotoxicity in spleen, down-regulated the amount of CD4+CD25+Foxp3+ Treg cells and Th17 cells in tumor tissue, and decreased IL-10, TGF-beta, and IL-17A levels (P < 0.01) whereas increased IL-2 and IFN-gamma levels (P < 0.01) in the serum of hepatoma H22 bearing mice. Moreover, administration of recombinant mouse IL-17A reversed the anti-tumor effects of SBE. CONCLUSION: SBE could inhibit the proliferation of HepG2 cells in vitro. Meanwhile, SBE also could inhibit the growth of H22 implanted tumor in hepatoma H22-bearing mice, and this function might be associated with immunomodulatory activity through down-regulating of Treg cells and manipulating Th1/Th17 immune response. PMID- 28086773 TI - Pleurotus giganteus (Berk. Karun & Hyde), the giant oyster mushroom inhibits NO production in LPS/H2O2 stimulated RAW 264.7 cells via STAT 3 and COX-2 pathways. AB - BACKGROUND: Pleurotus giganteus (Berk. Karunarathna and K.D. Hyde), has been used as a culinary mushroom and is known to have medicinal properties but its potential as an anti-inflammatory agent to mitigate inflammation triggered diseases is untapped. In this study, the molecular mechanism underlying the protective effect of ethanol extract of P. giganteus (EPG) against lipopolysaccharide (LPS) and combination of LPS and hydrogen peroxide (H2O2) induced inflammation on RAW 264.7 macrophages was investigated. METHOD: The effect of EPG on nitric oxide (NO) production as an indicator of inflammation in RAW 264.7 macrophages was estimated based on Griess reaction that measures nitrite level. The expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), NF-kB activating protein (NKAP), signal transducer and activator of transcription 3 protein (STAT 3) and glutathione peroxidase (GPx) genes were assessed using real time reverse transcription polymerase chain reaction (RT-PCR) approach. RESULTS: EPG (10 MUg/ml) showed the highest reduction in the LPS-induced NO production in RAW 264.7 macrophages and significantly suppressed (p < 0.05) the expression iNOS, STAT 3 and COX-2. There was a significant increase (p < 0.05) in combination of LPS and H2O2- induced iNOS production when compared to the LPS-induced iNOS production in RAW 264.7 macrophages and this concurred with the NO production which was attenuated by EPG at 10 MUg/ml. A significant (p < 0.05) down regulation was observed in the combination of LPS and H2O2-induced iNOS and GPx expression by EPG. CONCLUSIONS: Our data suggest that the anti-inflammatory activity of EPG is mediated via the suppression of the STAT 3 and COX-2 pathways and can serve as potential endogenous antioxidant stimulant. PMID- 28086774 TI - Androgenic effects of aqueous and methanolic extracts of Ficus asperifolia in male Wistar rats. AB - BACKGROUND: Androgen deficiency is a clinical syndrome resulting from the inability of the testes to produce physiological levels of testosterone due to a disturbance occurring at one or more levels of the hypothalamic-pituitary testicular axis. The present study was undertaken to evaluate the androgenic properties of aqueous and methanolic extracts of Ficus asperifolia on normal and castrated immature rats. METHODS: Normal rats were treated either per os with aqueous or methanolic extract of Ficus asperifolia (100 mg/kg or 500 mg/kg b.w.), distilled water (10 ml/kg b.w.), 5% Tween 80 (10 ml/kg b.w.) or subcutaneously with testosterone propionate (0.5 mg/kg b.w.). Castrated rats were treated with plant extracts (100 mg/kg b.w. or 500 mg/kg b.w.) alone or with the co administration of plant extracts and testosterone propionate (s.c., 0.5 mg/kg b.w.) or bicalutamide (2 mg/kg b.w. per os). Animals were treated once a day during four weeks. Body weight growth and relative sexual organ weights were recorded at the end of each treatment. Some biomedical parameters were measured in the plasma (proteins, cholesterol), testes (cholesterol) and epididymis (proteins). RESULTS: In normal rats, Ficus asperifolia significantly (p < 0.05) increased the relative weights of the testes and all sexual-dependent organs whereas total testicular cholesterol concentration was significantly (p < 0.05) decreased. In castrated groups, treatment with Ficus asperifolia was followed by an increase in the sexual organ weights, epididymal protein and prostatic acid phosphatase concentrations. The co-administration of testosterone and plant extracts significantly (p < 0.05) increased the weight of accessory sexual organs and epididymal protein contents. In the presence of bicalutamide (an anti androgen), the sexual stimulating activity of Ficus asperifolia was diminished with remarkable effects on vas deferens weight (p < 0.05), plasma (p < 0.01) and epididymal (p < 0.05) protein contents. CONCLUSION: Ficus asperifolia possesses androgen-like activity through possible stimulation of cytoplasmic and/or nuclear receptors by the bioactive compounds found in its extracts. PMID- 28086775 TI - Rapid decline in the susceptibility of Plasmodium falciparum to dihydroartemisinin-piperaquine in the south of Vietnam. AB - BACKGROUND: Artemisinin resistant Plasmodium falciparum has emerged in the countries of the Greater Mekong sub-region posing a serious threat to global malaria elimination efforts. The relationship of artemisinin resistance to treatment failure has been unclear. METHODS: In annual studies conducted in three malaria endemic provinces in the south of Vietnam (Binh Phuoc, Ninh Thuan and Gia Lai) between 2011 and 2015, 489 patients with uncomplicated P. falciparum malaria were enrolled in detailed clinical, parasitological and molecular therapeutic response assessments with 42 days follow up. Patients received the national recommended first-line treatment dihydroartemisinin-piperaquine for three days. RESULTS: Over the 5 years the proportion of patients with detectable parasitaemia on day 3 rose steadily from 38 to 57% (P < 0.001). In Binh Phuoc province, the parasite clearance half-life increased from 3.75 h in 2011 to 6.60 h in 2015 (P < 0.001), while treatment failures rose from 0% in 2012 and 2013, to 7% in 2014 and 26% in 2015 (P < 0.001). Recrudescence was associated with in vitro evidence of artemisinin and piperaquine resistance. In the treatment failures cases of 2015, all 14 parasite isolates carried the C580Y Pfkelch 13 gene, marker of artemisinin resistance and 93% (13/14) of them carried exoE415G mutations, markers of piperaquine resistance. CONCLUSIONS: In the south of Vietnam recent emergence of piperaquine resistant P. falciparum strains has accelerated the reduced response to artemisinin and has led to treatment failure rates of up to 26% to dihydroartemisinin-piperaquine, Vietnam's current first-line ACT. Alternative treatments are urgently needed. PMID- 28086776 TI - Comparison of two adult mosquito sampling methods with human landing catches in south-central Ethiopia. AB - BACKGROUND: The human landing catch (HLC) is the standard reference method for measuring human exposure to mosquito bites. However, HLC is labour-intensive, exposes collectors to infectious mosquito bites and is subjected to collector bias. These necessitate local calibration and application of alternative methods. This study was undertaken to determine the relative sampling efficiency (RSE) of light traps with or without yeast-produced carbon dioxide bait vs. HLC in south central Ethiopia. METHODS: The experiment was conducted for 39 nights in a 3 * 3 Latin square randomized design with Anopheles arabiensis as the target species in the period between July and November 2014 in Edo Kontola village, south-central Ethiopia. Center for Disease Control and Prevention light trap catches (LTC) and yeast-generated carbon dioxide-baited light trap catches (CB-LTC) were each evaluated against HLC. The total nightly mosquito catches for each Anopheles species in either method was compared with HLC by Pearson correlation and simple linear regression analysis on log-transformed [log10(x + 1)] values. To test if the RSE of each alternative method was affected by mosquito density, the ratio of the number of mosquitoes in each method to the number of mosquitoes in HLC was plotted against the average mosquito abundance. RESULTS: Overall, 7606 Anopheles females were collected by the three sampling methods. Among these 5228 (68.7%) were Anopheles ziemanni, 1153 (15.2%) An. arabiensis, 883 (11.6%) Anopheles funestus s.l., and 342 (4.5%) Anopheles pharoensis. HLC yielded 3392 (44.6%), CB LTC 2150 (28.3%), and LTC 2064 (27.1%) Anopheles females. The RSEs of LTC and HLC for An. arabiensis were significantly correlated (p < 0.001) and density independent (p = 0.65). However, for outdoor collection of the same species, RSEs of LTC and CB-LTC were density dependent (p < 0.001). It was estimated that on average, indoor LTC and CB-LTC each caught 0.35 and 0.44 times that of indoor HLC for An. arabiensis respectively. CONCLUSIONS: Results showed that HLC was the most efficient method for sampling An. arabiensis. LTC can be used for large scale indoor An. arabiensis surveillance and monitoring when it is difficult to use HLC. CB-LTC does not substantially improve sampling of this major vector compared to LTC in this setting. Trial registration PACTR201411000882128 (retrospectively registered 8 September, 2014). PMID- 28086778 TI - Diabetes does not impact the diagnostic performance of contrast-based fractional flow reserve: insights from the CONTRAST study. AB - BACKGROUND: Adenosine-free coronary pressure wire metrics have been proposed to test the functional significance of coronary artery lesions, but it is unexplored whether their diagnostic performance might be altered in patients with diabetes. METHODS: We performed a post-hoc analysis of the CONTRAST study, which prospectively enrolled an international cohort of patients undergoing routine fractional flow reserve (FFR) assessment for standard indications. Paired, repeated measurements of all physiology metrics (Pd/Pa, iFR, contrast-based FFR, and FFR) were made. A central core laboratory analyzed blinded pressure tracings in a standardized fashion. RESULTS: Of 763 subjects enrolled at 12 international centers, 219 (29%) had diabetes. The two groups were well-balanced for age, clinical presentation (stable or unstable), coronary vessel studied, volume and type of intracoronary contrast, and volume of intracoronary adenosine. A binary threshold of cFFR <= 0.83 produced an accuracy superior to both Pd/Pa and iFR when compared with FFR <= 0.80 in the absence of significant interaction with diabetes status; indeed, accuracy in subgroups of patients with or without diabetes was similar for cFFR (86.7 vs 85.4% respectively; p = 0.76), iFR (84.2 vs 80.0%, p = 0.29) and Pd/Pa (81.3 vs 78.9%, p = 0.55). There was no significant heterogeneity between patients with or without diabetes in terms of sensitivity and specificity of all metrics. The area under the receiver operating characteristic (ROC) curve was largest for cFFR compared with Pd/Pa and iFR which were equivalent (cFFR 0.961 and 0.928; Pd/Pa 0.916 and 0.870; iFR 0.911 and 0.861 in diabetic and non-diabetic patients respectively). CONCLUSIONS: cFFR provides superior diagnostic performance compared with Pd/Pa or iFR for predicting FFR irrespective of diabetes (clinicaltrials.gov identifier NCT02184117). PMID- 28086777 TI - Profile of molecular mutations in pfdhfr, pfdhps, pfmdr1, and pfcrt genes of Plasmodium falciparum related to resistance to different anti-malarial drugs in the Bata District (Equatorial Guinea). AB - BACKGROUND: The emergence of drug resistance in Plasmodium falciparum has been a major contributor to the global burden of malaria. Drug resistance complicates treatment, and it is one of the most important problems in malaria control. This study assessed the level of mutations in P. falciparum genes, pfdhfr, pfdhps, pfmdr1, and pfcrt, related to resistance to different anti-malarial drugs, in the Continental Region of Equatorial Guinea, after 8 years of implementing artesunate combination therapies as the first-line treatment. RESULTS: A triple mutant of pfdhfr (51I/59R/108N), which conferred resistance to sulfadoxine/pyrimethamine (SP), was found in 78% of samples from rural settings; its frequency was significantly different between urban and rural settings (p = 0.007). The 164L mutation was detected for the first time in this area, in rural settings (1.4%). We also identified three classes of previously described mutants and their frequencies: the partially resistant (pfdhfr 51I/59R/108N + pfdhps 437G), found at 54% (95% CI 47.75-60.25); the fully resistant (pfdhfr 51I/59R/108N + pfdhps 437G/540E), found at 28% (95% CI 7.07-14.93); and the super resistant (pfdhfr 51I/59R/108N + pfdhps 437G/540E/581G), found at 6% (95% CI 0.48-4.32). A double mutation in pfmdr1 (86Y + 1246Y) was detected at 2% (95% CI 0.24-3.76) frequency, distributed in both urban and rural samples. A combination of single mutations in the pfmdr1 and pfcrt genes (86Y + 76T), which was related to resistance to chloroquine and amodiaquine, was detected in 22% (95% CI 16.8-27.2) of samples from the area. CONCLUSIONS: The high level of mutations detected in P. falciparum genes related to SP resistance could be linked to the unsuccessful withdrawal of SP treatment in this area. Drug resistance can reduce the efficacy of intermittent prophylactic treatment with SP for children under 5 years old and for pregnant women. Although a high number of mutations was detected, the efficacy of the first-line treatment, artemisinin/amodiaquine, was not affected. To avoid increases in the numbers, occurrence, and spread of mutations, and to protect the population, the Ministry of Health should ensure that health centres and hospitals are supplied with appropriate first-line treatments for malaria. PMID- 28086779 TI - The effect of electrical conductivity of myocardium on cardiac pumping efficacy: a computational study. AB - BACKGROUND AND AIMS: The existence of non-excitable cells in the myocardium leads to the increasing conduction non-uniformity and decreasing myocardial electrical conductivity. Slowed myocardial conduction velocity (MCV) believed to enhance the probability of cardiac arryhthmia and alter the cardiac mechanical pumping efficacy, even in sinus rhythm. Though several studies on the correlation between MCV and cardiac electrical instabilities exist, there has been no study concerning correlation or causality between MCV and cardiac mechanical pumping efficacy, due to the limitation in clinical methods to document and evaluate cardiac mechanical responses directly. The goal of this study was to examine quantitatively the cardiac pumping efficacy under various MCV conditions using three-dimensional (3D) electromechanical model of canine's failing ventricle. METHODS: The electromechanical model used in this study composed of the electrical model coupled with the mechanical contraction model along with a lumped model of the circulatory system. The electrical model consisted of 241,725 nodes and 1,298,751 elements of tetrahedral mesh, whereas the mechanical model consisted of 356 nodes and 172 elements of hexahedral mesh with Hermite basis. First, we performed the electrical simulation for five different MCV conditions, from 30 to 70 cm/s with 10 cm/s interval during sinus pacing. Then, we compared the cardiac electrical and mechanical responses of each MCV condition, such as the electrical activation time (EAT), pressure, volume, and energy consumption of the myocardium. The energy consumption of the myocardium was calculated by integrating ATP consumption rate of each node in myofilament model. RESULTS: The result showed that under higher MCV conditions, the EAT, energy consumption, end diastolic and systolic volume are gradually decreased. Meanwhile, the systolic pressure, stroke volume, stroke work, and stroke work to ATP are increased as the MCV values increased. The cardiac functions and performances are more efficient under higher MCV conditions by consuming smaller energy (ATP) while carrying more works. CONCLUSION: In conclusion, this study reveals that MCV has strong correlation with the cardiac pumping efficacy. The obtained results provide useful information to estimate the effect of MCV on the electro-physiology and hemodynamic responses of the ventricle and can be used for further study about arrhythmogeneis and heart failure. PMID- 28086780 TI - The Zygosaccharomyces bailii transcription factor Haa1 is required for acetic acid and copper stress responses suggesting subfunctionalization of the ancestral bifunctional protein Haa1/Cup2. AB - BACKGROUND: The food spoilage yeast species Zygosaccharomyces bailii exhibits an extraordinary capacity to tolerate weak acids, in particular acetic acid. In Saccharomyces cerevisiae, the transcription factor Haa1 (ScHaa1) is considered the main player in genomic expression reprogramming in response to acetic acid stress, but the role of its homologue in Z. bailii (ZbHaa1) is unknown. RESULTS: In this study it is demonstrated that ZbHaa1 is a ScHaa1 functional homologue by rescuing the acetic acid susceptibility phenotype of S. cerevisiae haa1Delta. The disruption of ZbHAA1 in Z. bailii IST302 and the expression of an extra ZbHAA1 copy confirmed ZbHAA1 as a determinant of acetic acid tolerance. ZbHaa1 was found to be required for acetic acid stress-induced transcriptional activation of Z. bailii genes homologous to ScHaa1-target genes. An evolutionary analysis of the Haa1 homologues identified in 28 Saccharomycetaceae species genome sequences, including Z bailii, was carried out using phylogenetic and gene neighbourhood approaches. Consistent with previous studies, this analysis revealed a group containing pre-whole genome duplication species Haa1/Cup2 single orthologues, including ZbHaa1, and two groups containing either Haa1 or Cup2 orthologues from post-whole genome duplication species. S. cerevisiae Cup2 (alias Ace1) is a transcription factor involved in response and tolerance to copper stress. Taken together, these observations led us to hypothesize and demonstrate that ZbHaa1 is also involved in copper-induced transcriptional regulation and copper tolerance. CONCLUSIONS: The transcription factor ZbHaa1 is required for adaptive response and tolerance to both acetic acid and copper stresses. The subfunctionalization of the single ancestral Haa1/Cup2 orthologue that originated Haa1 and Cup2 paralogues after whole genome duplication is proposed. PMID- 28086781 TI - Effects of the intradiscal implantation of stromal vascular fraction plus platelet rich plasma in patients with degenerative disc disease. AB - BACKGROUND: Stromal vascular fraction (SVF) can easily be obtained from a mini lipoaspirate procedure of fat tissue and platelet rich plasma (PRP) can be obtained from peripheral blood. The SVF contains a mixture of cells including ADSCs and growth factors and has been depleted of the adipocyte (fat cell) population. We evaluated the safety and efficacy of administering SVF and PRP intra-discally into patients with degenerative disc disease. METHODS: A total of 15 patients underwent a local tumescent liposuction procedure to remove approximately 60 ml of fat tissue. The fat was separated to isolate the SVF and the cells were delivered into the disc nucleus of patients with degenerative disc disease. The subjects were then monitored for adverse events, range of motion, visual analog scale (VAS), present pain intensity (PPI), Oswestry Disability Index (ODI), Beck Depression Inventory (BDI), Dallas Pain Questionnaire and Short Form (SF)-12 scores over a period of 6 months. Safety events were followed for 12 months. RESULTS: No severe adverse events (SAEs) were reported during a 12 month follow up period with no incidences of infection. Patients demonstrated statistically significant improvements in several parameters including flexion, pain ratings, VAS, PPI, and short form questionnaires. In addition, both ODI and BDI data was trending positive and a majority of patients reported improvements in their Dallas Pain Questionnaire scores. CONCLUSIONS: Overall, patients were pleased with the treatment results. More importantly, the procedure demonstrated a strong safety profile with no severe adverse events or complications linked to the therapy. Trial registration NCT02097862. Name of registry: www.clinicaltrials.gov . https://clinicaltrials.gov/ct2/show/NCT02097862?term=bioheart&rank=6 . Date of registration: March 25, 2014; Date of enrollment: March 2014. PMID- 28086782 TI - In vivo antiplasmodial activity and toxicological assessment of hydroethanolic crude extract of Ajuga remota. AB - BACKGROUND: Malaria is one of the most life-threatening health problems worldwide and treatment has been compromised by drug resistance. Identifying lead molecules from natural products might help to find better anti-malarial drugs, since those obtained from natural sources are still effective against malarial parasites. This study aimed at investigating the in vivo antiplasmodial activity of crude extract of the leaves of Ajuga remota together with its safety in mice models. METHODS: In vivo parasite growth inhibitory effect of crude extract was assessed in mice inoculated with Plasmodium berghei (ANKA strain). The in vivo antiplasmodial activity of the test extract was performed against early infection (4-day suppressive test), curative effect against established infection and prophylactic effect against residual infection. Acute and sub-acute toxicity were carried out according to OECD guidelines. RESULTS: In vivo parasite growth inhibition effect of hydroethanolic crude extract of A. remota was evaluated at 30, 50 and 100 mg/kg dose levels. It suppressed parasitaemia by 77.34% at 100 mg/kg dose level in the 4-day test. In curative and prophylactic potential tests, it suppressed parasitaemia by 66.67 and 59.66% at 100 mg/kg dose level, respectively. In vivo toxicity tests revealed no toxicity. All parasitaemia suppressions were statistically significant at P < 0.05 as compared to the vehicle-treated group. The crude extract also prolonged survival time in a dose dependent manner. CONCLUSIONS: The investigation results suggest that the leave extract of Ajuga remota possesses antimalarial activity. PMID- 28086783 TI - De novo transcriptome analysis of rose-scented geranium provides insights into the metabolic specificity of terpene and tartaric acid biosynthesis. AB - BACKGROUND: Rose-scented geranium (Pelargonium sp.) is a perennial herb that produces a high value essential oil of fragrant significance due to the characteristic compositional blend of rose-oxide and acyclic monoterpenoids in foliage. Recently, the plant has also been shown to produce tartaric acid in leaf tissues. Rose-scented geranium represents top-tier cash crop in terms of economic returns and significance of the plant and plant products. However, there has hardly been any study on its metabolism and functional genomics, nor any genomic expression dataset resource is available in public domain. Therefore, to begin the gains in molecular understanding of specialized metabolic pathways of the plant, de novo sequencing of rose-scented geranium leaf transcriptome, transcript assembly, annotation, expression profiling as well as their validation were carried out. RESULTS: De novo transcriptome analysis resulted a total of 78,943 unique contigs (average length: 623 bp, and N50 length: 752 bp) from 15.44 million high quality raw reads. In silico functional annotation led to the identification of several putative genes representing terpene, ascorbic acid and tartaric acid biosynthetic pathways, hormone metabolism, and transcription factors. Additionally, a total of 6,040 simple sequence repeat (SSR) motifs were identified in 6.8% of the expressed transcripts. The highest frequency of SSR was of tri-nucleotides (50%). Further, transcriptome assembly was validated for randomly selected putative genes by standard PCR-based approach. In silico expression profile of assembled contigs were validated by real-time PCR analysis of selected transcripts. CONCLUSION: Being the first report on transcriptome analysis of rose-scented geranium the data sets and the leads and directions reflected in this investigation will serve as a foundation for pursuing and understanding molecular aspects of its biology, and specialized metabolic pathways, metabolic engineering, genetic diversity as well as molecular breeding. PMID- 28086784 TI - Health related quality of life assessment in acute coronary syndrome patients: the effectiveness of early phase I cardiac rehabilitation. AB - BACKGROUND: Acute Coronary Syndrome (ACS) is one of the most burdensome cardiovascular diseases in terms of the cost of interventions. The Cardiac Rehabilitation Programme (CRP) is well-established in improving clinical outcomes but the assessment of actual clinical improvement is challenging, especially when considering pharmaceutical care (PC) values in phase I CRP during admission and upon discharge from hospital and phase II outpatient interventions. This study explores the impact of pharmacists' interventions in the early stages of CRP on humanistic outcomes and follow-up at a referral hospital in Malaysia. METHODS: We recruited 112 patients who were newly diagnosed with ACS and treated at the referral hospital, Sarawak General Hospital, Malaysia. In the intervention group (modified CRP), all medication was reviewed by the clinical pharmacists, focusing on drug indication; understanding of secondary prevention therapy and adherence to treatment strategy. We compared the "pre-post" quality of life (QoL) of three groups (intervention, conventional and control) at baseline, 6 months and 12 months post-discharge with Malaysian norms. QoL data was obtained using a validated version of Short-Form 36 Questionnaire (SF-36). Analysis of variance (ANOVA) with repeated measure tests was used to compare the mean differences of scores over time. RESULTS: A pre-post quasi-experimental non-equivalent group comparison design was applied to 112 patients who were followed up for one year. At baseline, the physical and mental health summaries reported poor outcomes in all three groups. However, these improved gradually but significantly over time. After the 6-month follow-up, the physical component summary reported in the modified CRP (MCRP) participants was higher, with a mean difference of 8.02 (p = 0.015) but worse in the mental component summary, with a mean difference of 4.13. At the 12-month follow-up, the MCRP participants performed better in their physical component (PCS) than those in the CCRP and control groups, with a mean difference of 11.46 (p = 0.008), 10.96 (p = 0.002) and 6.41 (p = 0.006) respectively. Comparing the changes over time for minimal important differences (MICD), the MCRP group showed better social functioning than the CCRP and control groups with mean differences of 20.53 (p = 0.03), 14.47 and 8.8, respectively. In role emotional subscales all three groups showed significant improvement in MCID with mean differences of 30.96 (p = 0.048), 31.58 (p = 0.022) and 37.04 (p < 0.001) respectively. CONCLUSION: Our results showed that pharmaceutical care intervention significantly improved HRQoL. The study also highlights the importance of early rehabilitation in the hospital setting. The MCRP group consistently showed better QoL, was more highly motivated and benefitted most from the CRP. TRIAL REGISTRATION: Medical Research and Ethics Committee (MREC) Ministry of Health Malaysia, November 2007, NMRR-08-246-1401. PMID- 28086785 TI - Whole genome resequencing reveals diagnostic markers for investigating global migration and hybridization between minke whale species. AB - BACKGROUND: In the marine environment, where there are few absolute physical barriers, contemporary contact between previously isolated species can occur across great distances, and in some cases, may be inter-oceanic. An example of this can be seen in the minke whale species complex. Antarctic minke whales are genetically and morphologically distinct from the common minke found in the north Atlantic and Pacific oceans, and the two species are estimated to have been isolated from each other for 5 million years or more. Recent atypical migrations from the southern to the northern hemisphere have been documented and fertile hybrids and back-crossed individuals between both species have also been identified. However, it is not known whether this represents a contemporary event, potentially driven by ecosystem changes in the Antarctic, or a sporadic occurrence happening over an evolutionary time-scale. We successfully used whole genome resequencing to identify a panel of diagnostic SNPs which now enable us address this evolutionary question. RESULTS: A large number of SNPs displaying fixed or nearly fixed allele frequency differences among the minke whale species were identified from the sequence data. Five panels of putatively diagnostic markers were established on a genotyping platform for validation of allele frequencies; two panels (26 and 24 SNPs) separating the two species of minke whale, and three panels (22, 23, and 24 SNPs) differentiating the three subspecies of common minke whale. The panels were validated against a set of reference samples, demonstrating the ability to accurately identify back-crossed whales up to three generations. CONCLUSIONS: This work has resulted in the development of a panel of novel diagnostic genetic markers to address inter oceanic and global contact among the genetically isolated minke whale species and sub-species. These markers, including a globally relevant genetic reference data set for this species complex, are now openly available for researchers interested in identifying other potential whale hybrids in the world's oceans. The approach used here, combining whole genome resequencing and high-throughput genotyping, represents a universal approach to develop similar tools for other species and population complexes. PMID- 28086786 TI - Widespread introgression in deep-sea hydrothermal vent mussels. AB - BACKGROUND: The analysis of hybrid zones is crucial for gaining a mechanistic understanding of the process of speciation and the maintenance of species boundaries. Hybrid zones have been studied intensively in terrestrial and shallow water ecosystems, but very little is known about their occurrence in deep-sea environments. Here we used diagnostic, single nucleotide polymorphisms in combination with one mitochondrial gene to re-examine prior hypotheses about a contact zone involving deep-sea hydrothermal vent mussels, Bathymodiolus azoricus and B. puteoserpentis, living along the Mid-Atlantic Ridge. RESULTS: Admixture was found to be asymmetric with respect to the parental species, while introgression was more widespread geographically than previously recognized. Admixed individuals with a majority of alleles from one of the parental species were most frequent in habitats corresponding to that species. Mussels found at a geographically intermediate vent field constituted a genetically mixed population that showed no evidence for hybrid incompatibilities, a finding that does not support a previously inferred tension zone model. CONCLUSIONS: Our analyses indicate that B. azoricus and B. puteoserpentis hybridize introgressively across a large geographic area without evidence for general hybrid incompatibilities. While these findings shed new light onto the genetic structure of this hybrid zone, many aspects about its nature still remain obscure. Our study sets a baseline for further research that should primarily focus on the acquisition of additional mussel samples and environmental data, a detailed exploration of vent areas and hidden populations as well as genomic analyses in both mussel hosts and their bacterial symbionts. PMID- 28086787 TI - Perceptions of a drug prevention public service announcement campaign among street-involved youth in Vancouver, Canada: a qualitative study. AB - BACKGROUND: Due to the popularity of public service announcements (PSAs), as well as the broader health and social harms associated with illicit drug use, this study sought to investigate how drug prevention messages found in the Government of Canada's DrugsNot4Me campaign were understood, experienced, and engaged with among a group of street-involved young people in Vancouver, Canada. METHODS: Qualitative interviews were conducted with 25 individuals enrolled in the At-Risk Youth Study, and a thematic analysis was conducted. RESULTS: Findings indicate that the campaign's messages neither resonated with "at-risk youth", nor provided information or resources for support. In some cases, the messaging exacerbated the social suffering experienced by these individuals. CONCLUSIONS: This study underscores the importance of rigorous evaluation of PSAs and the need to consider diverting funds allocated to drug prevention campaigns to social services that can meaningfully address the structural drivers of drug-related harms among vulnerable youth populations. PMID- 28086788 TI - Comprehensive CircRNA expression profile and selection of key CircRNAs during priming phase of rat liver regeneration. AB - BACKGROUND: Rat liver regeneration (LR) proceeds along a process of highly organized and ordered tissue growth in response to the loss or injury of liver tissue, during which many physiological processes may play important roles. The molecular mechanism of hepatocyte proliferation, energy metabolism and substance metabolism during rat LR had been elucidated. Further, the correlation of circular RNA (circRNA) abundance with proliferation has recently been clarified. However, the regulatory capacity of circRNA in rat LR remains a fascinating topic. RESULTS: To investigate the regulatory mechanism of circRNA during priming phase of rat LR, high-throughput RNA sequencing technology was performed to unbiasedly profile the expression of circRNA during priming phase of rat LR. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway analysis was conducted to predict the functions of differentially expressed circRNAs and their host linear transcripts. Co-expression networks of circRNA-miRNA were constructed based on the correlation analysis between the differentially expressed LR-related circRNAs and the condition of their miRNA binding sites. To excavate the key circRNAs in the early phase of rat LR, we comprehensively evaluated and integrated the relationship of expression level between the circRNAs and the linear transcripts as well as the distribution of miRNA binding sites in circRNA sequences. CONCLUSIONS: This paper is the first to employ the comprehensive circRNA expression profile and to investigate circRNA miRNA interactions during priming phase of rat LR. Two thousand four hundred twelve circRNAs were detected, and 159 circRNAs deriving from 116 host linear transcripts differentially expressed (p < 0.05). Six significantly changed circRNAs during priming phase of rat LR were screened as key circle molecules, and then were validated by qRT-PCR. This study will lay the foundation for revealing the functional roles of circRNAs during rat LR and help solve the remaining clinical problems. PMID- 28086789 TI - Detection of Plasmodium knowlesi, Plasmodium falciparum and Plasmodium vivax using loop-mediated isothermal amplification (LAMP) in a co-endemic area in Malaysia. AB - BACKGROUND: Plasmodium knowlesi is the most common cause of malaria in Malaysia. However, microscopic diagnosis is inaccurate and rapid diagnostic tests (RDTs) are insufficiently sensitive. PCR is sensitive and specific but not feasible at a district level. Loop-mediated isothermal amplification (LAMP) shows potential with only basic requirements. A commercially available LAMP assay, the Eiken LoopampTM MALARIA Pan Detection kit, is sensitive for Plasmodium falciparum and Plasmodium vivax, but has not previously been evaluated for P. knowlesi. This study aims to determine the sensitivity of this LAMP assay for detecting P. knowlesi infection. METHODS: Study participants included 73 uncomplicated malaria patients with PCR species confirmation: 50 P. knowlesi, 20 P. falciparum and 3 P. vivax. Nineteen malaria-negative, non-endemic area controls were also included. The sensitivity of the Eiken LoopampTM MALARIA Pan Detection kit (Pan LAMP) for detecting each Plasmodium species was evaluated. Sensitivity and specificity of the Eiken LoopampTM MALARIA Pf Detection kit (Pf LAMP) for P. falciparum were also determined. The limit of detection for each LAMP assay was evaluated, with results compared to PCR. All P. knowlesi patients were also tested by CareStartTM (Pf/VOM) and OptiMAL-ITTM (Pan/Pf) RDTs. RESULTS: The sensitivity of the Pan LAMP assay was 100% for P. knowlesi (95% CI 92.9-100), P. falciparum (95% CI 83.2 100), and P. vivax (95% CI 29.2-100). The Pf LAMP was 100% sensitive and specific for P. falciparum detection, with all P. knowlesi samples having a negative reaction. LAMP sensitivity was superior to both RDTs, with only 10 and 28% of P. knowlesi samples testing positive to CareStartTM and OptiMAL-ITTM, respectively. Limit of detection using the Pan LAMP for both P. knowlesi and P. vivax was 2 parasites/MUL, comparable to PCR. For P. falciparum both the Pan LAMP and Pf LAMP demonstrated a limit of detection of 20 parasites/MUL. CONCLUSIONS: The Eiken LoopampTM MALARIA Pan Detection kit is sensitive for detection of P. knowlesi in low parasitaemia clinical infections, as well as P. falciparum and P. vivax. However, a P. knowlesi-specific field assay in a simpler format would assist correct species identification and initiation of optimal treatment for all malaria patients. PMID- 28086790 TI - RNA sequencing for global gene expression associated with muscle growth in a single male modern broiler line compared to a foundational Barred Plymouth Rock chicken line. AB - BACKGROUND: Modern broiler chickens exhibit very rapid growth and high feed efficiency compared to unselected chicken breeds. The improved production efficiency in modern broiler chickens was achieved by the intensive genetic selection for meat production. This study was designed to investigate the genetic alterations accumulated in modern broiler breeder lines during selective breeding conducted over several decades. METHODS: To identify genes important in determining muscle growth and feed efficiency in broilers, RNA sequencing (RNAseq) was conducted with breast muscle in modern pedigree male (PeM) broilers (n = 6 per group), and with an unselected foundation broiler line (Barred Plymouth Rock; BPR). The RNAseq analysis was carried out using Ilumina Hiseq (2 x 100 bp paired end read) and raw reads were assembled with the galgal4 reference chicken genome. With normalized RPM values, genes showing >10 average read counts were chosen and genes showing <0.05 p-value and >1.3 fold change were considered as differentially expressed (DE) between PeM and BPR. DE genes were subjected to Ingenuity Pathway Analysis (IPA) for bioinformatic functional interpretation. RESULTS: The results indicate that 2,464 DE genes were identified in the comparison between PeM and BPR. Interestingly, the expression of genes encoding mitochondrial proteins in chicken are significantly biased towards the BPR group, suggesting a lowered mitochondrial content in PeM chicken muscles compared to BPR chicken. This result is inconsistent with more slow muscle fibers bearing a lower mitochondrial content in the PeM. The molecular, cellular and physiological functions of DE genes in the comparison between PeM and BPR include organismal injury, carbohydrate metabolism, cell growth/proliferation, and skeletal muscle system development, indicating that cellular mechanisms in modern broiler lines are tightly associated with rapid growth and differential muscle fiber contents compared to the unselected BPR line. Particularly, PDGF (platelet derived growth factor) signaling and NFE2L2 (nuclear factor, erythroid 2-like 2; also known as NRF2) mediated oxidative stress response pathways appear to be activated in modern broiler compared to the foundational BPR line. Upstream and network analyses revealed that the MSTN (myostatin) -FST (follistatin) interactions and inhibition of AR (androgen receptor) were predicted to be effective regulatory factors for DE genes in modern broiler line. PRKAG3 (protein kinase, AMP activated, gamma 3 non-catalytic subunit) and LIPE (lipase E) are predicted as core regulatory factors for myogenic development, nutrient and lipid metabolism. CONCLUSION: The highly upregulated genes in PeM may represent phenotypes of subclinical myopathy commonly observed in the commercial broiler breast tissue, that can lead to muscle hardening, named as woody breast. By investigating global gene expression in a highly selected pedigree broiler line and a foundational breed (Barred Plymouth Rock), the results provide insight into cellular mechanisms that regulate muscle growth, fiber composition and feed efficiency. PMID- 28086791 TI - Identification of functional enolase genes of the silkworm Bombyx mori from public databases with a combination of dry and wet bench processes. AB - BACKGROUND: Various insect species have been added to genomic databases over the years. Thus, researchers can easily obtain online genomic information on invertebrates and insects. However, many incorrectly annotated genes are included in these databases, which can prevent the correct interpretation of subsequent functional analyses. To address this problem, we used a combination of dry and wet bench processes to select functional genes from public databases. RESULTS: Enolase is an important glycolytic enzyme in all organisms. We used a combination of dry and wet bench processes to identify functional enolases in the silkworm Bombyx mori (BmEno). First, we detected five annotated enolases from public databases using a Hidden Markov Model (HMM) search, and then through cDNA cloning, Northern blotting, and RNA-seq analysis, we revealed three functional enolases in B. mori: BmEno1, BmEno2, and BmEnoC. BmEno1 contained a conserved key amino acid residue for metal binding and substrate binding in other species. However, BmEno2 and BmEnoC showed a change in this key amino acid. Phylogenetic analysis showed that BmEno2 and BmEnoC were distinct from BmEno1 and other enolases, and were distributed only in lepidopteran clusters. BmEno1 was expressed in all of the tissues used in our study. In contrast, BmEno2 was mainly expressed in the testis with some expression in the ovary and suboesophageal ganglion. BmEnoC was weakly expressed in the testis. Quantitative RT-PCR showed that the mRNA expression of BmEno2 and BmEnoC correlated with testis development; thus, BmEno2 and BmEnoC may be related to lepidopteran-specific spermiogenesis. CONCLUSIONS: We identified and characterized three functional enolases from public databases with a combination of dry and wet bench processes in the silkworm B. mori. In addition, we determined that BmEno2 and BmEnoC had species specific functions. Our strategy could be helpful for the detection of minor genes and functional genes in non-model organisms from public databases. PMID- 28086792 TI - Irish general practitioner attitudes toward decriminalisation and medical use of cannabis: results from a national survey. AB - BACKGROUND: Governmental debate in Ireland on the de facto decriminalisation of cannabis and legalisation for medical use is ongoing. A cannabis-based medicinal product (Sativex(r)) has recently been granted market authorisation in Ireland. This unique study aimed to investigate Irish general practitioner (GP) attitudes toward decriminalisation of cannabis and assess levels of support for use of cannabis for therapeutic purposes (CTP). METHODS: General practitioners in the Irish College of General Practitioner (ICGP) database were invited to complete an online survey. Anonymous data yielded descriptive statistics (frequencies, percentages) to summarise participant demographic information and agreement with attitudinal statements. Chi-square tests and multi-nominal logistic regression were included. RESULTS: The response rate was 15% (n = 565) which is similar to other Irish national GP attitudinal surveys. Over half of Irish GPs did not support the decriminalisation of cannabis (56.8%). In terms of gender, a significantly higher proportion of males compared with females (40.6 vs. 15%; p < 0.0001) agreed or strongly agreed with this drug policy approach. A higher percentage of GPs with advanced addiction specialist training (level 2) agreed/strongly agreed that cannabis should be decriminalised (54.1 vs. 31.5%; p = 0.021). Over 80% of both genders supported the view that cannabis use has a significant effect on patients' mental health and increases the risk of schizophrenia (77.3%). Over half of Irish GPs supported the legalisation of cannabis for medical use (58.6%). A higher percentage of those who were level 1 trained (trained in addiction treatment but not to an advanced level) agreed/strongly agreed cannabis should be legalised for medical use (p = 0.003). Over 60% agreed that cannabis can have a role in palliative care, pain management and treatment of multiple sclerosis (MS). In the regression response predicator analysis, females were 66.2% less likely to agree that cannabis should be decriminalised, 42.5% less likely to agree that cannabis should be legalised for medical use and 59.8 and 37.6% less likely to agree that cannabis has a role in palliative care and in the treatment of multiple sclerosis (respectively) than males. CONCLUSIONS: The majority of Irish GPs do not support the present Irish governmental drug policy of decriminalisation of cannabis but do support the legalisation of cannabis for therapeutic purposes. Male GPs and those with higher levels of addiction training are more likely to support a more liberal drug policy approach to cannabis for personal use. A clear majority of GPs expressed significant concerns regarding both the mental and physical health risks of cannabis use. Ongoing research into the health and other effects of drug policy changes on cannabis use is required. PMID- 28086793 TI - Methicillin resistance and virulence genes in invasive and nasal Staphylococcus epidermidis isolates from neonates. AB - BACKGROUND: Staphylococcus epidermidis is an opportunistic pathogen involved in hospital-acquired infections, particularly in those related to medical devices. This study characterized 50 genetically unrelated S. epidermidis isolates from bloodstream infections (BSIs, n = 31) and nares (n = 19) of neonates in relation to staphylococcal chromosomal cassette mec (SCCmec) type, biofilm production and associated genes, and the arginine catabolic mobile elements (ACME), in order to detect virulence factors that could discriminate a potential invasiveness isolate or predict an increasing pathogenicity. RESULTS: Isolates from both groups showed no difference for biofilm production and ACME genes detection. However, BSI isolates harbored more frequently the sdrF and sesI genes (p < 0.05), whereas biofilm producer isolates were associated with presence of the aap gene. The sdrF gene was also significantly more in the biofilm producer isolates from BSI. The SCCmec type IV and the ccr2 complex were related to BSI isolates (p < 0.05), while 83% of the nasal isolates were non-typeable for the SCCmec elements, with the mec complex and ccr undetectable as the most frequent profile. CONCLUSIONS: Despite the great clonal diversity displayed by S. epidermidis isolates from neonates, BSI isolates harbored more frequently the sdrF and sesI adhesin genes, while nasal isolates were very variable in SCCmec composition. These aspects could be advantageous to improve colonization in the host increasing its pathogenicity. PMID- 28086794 TI - Characterization of the sdw1 semi-dwarf gene in barley. AB - BACKGROUND: The dwarfing gene sdw1 has been widely used throughout the world to develop commercial barley varieties. There are at least four different alleles at the sdw1 locus. RESULTS: Mutations in the gibberellin 20-oxidase gene (HvGA20ox2) resulted in multiple alleles at the sdw1 locus. The sdw1.d allele from Diamant is due to a 7-bp deletion in exon 1, while the sdw1.c allele from Abed Denso has 1 bp deletion and a 4-bp insertion in the 5' untranslated region. The sdw1.a allele from Jotun resulted from a total deletion of the HvGA20ox2 gene. The structural changes result in lower gene expression in sdw1.d and lack of expression in sdw1.a. There are three HvGA20ox genes in the barley genome. The partial or total loss of function of the HvGA20ox2 gene could be compensated by enhanced expression of its homolog HvGA20ox1and HvGA20ox3. A diagnostic molecular marker was developed to differentiate between the wild-type, sdw1.d and sdw1.a alleles and another molecular marker for differentiation of sdw1.c and sdw1.a. The markers were further tested in 197 barley varieties, out of which 28 had the sdw1.d allele and two varieties the sdw1.a allele. To date, the sdw1.d and sdw1.a alleles have only been detected in the modern barley varieties and lines. CONCLUSIONS: The results provided further proof that the gibberellin 20-oxidase gene (HvGA20ox2) is the functional gene of the barley sdw1 mutants. Different deletions resulted in different functional alleles for different breeding purposes. Truncated protein could maintain partial function. Partial or total loss of function of the HvGA20ox2 gene could be compensated by enhanced expression of its homolog HvGA20ox1 and HvGA20ox3. PMID- 28086796 TI - Prophylaxis of post-ERC infectious complications in patients with biliary obstruction by adding antimicrobial agents into ERC contrast media- a single center retrospective study. AB - BACKGROUND: Patients with biliary obstruction are at high risk to develop septic complications after endoscopic retrograde cholangiography (ERC). We evaluated the benefits of local application of antimicrobial agents into ERC contrast media in preventing post-ERC infectious complications in a high-risk study population. METHODS: Patients undergoing ERC at our tertiary referral center were retrospectively included. Addition of vancomycin, gentamicin and fluconazol into ERC contrast media was evaluated in a case-control design. Outcomes comprised infectious complications within 3 days after ERC. RESULTS: In total, 84 ERC cases were analyzed. Primarily indications for ERC were sclerosing cholangitis (75%) and malignant stenosis (9.5%). Microbial testing of collected bile fluid in the treatment group was positive in 91.4%. Detected organisms were sensitive to the administered antimicrobials in 93%. The use of antimicrobials in contrast media was associated with a significant decrease in post-ERC infectious complications compared to non-use (14.3% vs. 33.3%; odds ratio [OR]: 0.33, 95% confidence interval [CI]: 0.114-0.978). After adjusting for the variables acute cholangitis prior to ERC and incomplete biliary drainage, the beneficial effect of intraductal antibiotic prophylaxis was even more evident (OR = 0.153; 95% CI: 0.039-0.598, p = 0.007). Patients profiting most obviously from intraductal antimicrobials were those with secondary sclerosing cholangitis. CONCLUSION: Local application of a combination of antibiotic and antimycotic agents to ERC contrast media efficiently reduced post-ERC infectious events in patients with biliary obstruction. This is the first study that evaluates ERC-related infectious complications in patients with secondary sclerosing cholangitis. Our first clinical results should now be prospectively evaluated in a larger patient cohort to improve the safety of ERC, especially in patients with secondary sclerosing cholangitis. PMID- 28086795 TI - Atherosclerotic and thrombotic genetic and environmental determinants in Egyptian coronary artery disease patients: a pilot study. AB - BACKGROUND: Coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide. Multiple genetic variants in combination with various environmental risk factors have been implicated. This study aimed to investigate the association of twelve thrombotic and atherosclerotic gene variants in combination with other environmental risk factors with CAD risk in a preliminary sample of Egyptian CAD patients. METHODS: Twenty three consecutive CAD patients undergoing diagnostic coronary angiography and 34 unrelated controls, have been enrolled in the study. Genotyping was based on polymerase chain reaction and reverse multiplex hybridization. Five genetic association models were tested. Data distribution and variance homogeneity have been checked by Shapiro-Wilk test and Levene test, respectively; then the appropriate comparison test was applied. Spearman's rank correlation coefficient was used for correlation analysis and logistic regression has been performed to adjust for significant risk factors. Clustering the study participants according to gene-gene and gene-environment interaction has been done by Detrended Correspondence Analysis (DCA). RESULTS: The univariate analysis indicated that the five variants; rs1800595 (FVR2; factor 5), rs1801133 (MTHFR; 5,10-methylenetetrahydrofolate reductase), rs5918 (HPA-1; human platelet antigen 1), rs1799752 (ACE; angiotensin-converting enzyme), and rs7412 and rs429358 (ApoE; apolipoprotein E) were significantly associated with CAD susceptibility under different genetic models. Multivariate analysis revealed clustering of the study population into three patient groups (P) and one control group. FVR2 was the most variant associated with CAD patients, combined with the factor V Leiden (FVL) variant in P1 cluster and with both ACE and MTHFR 667C > T in P2. Whereas, P3 was mostly affected by both MTHFR 667C > T and FXIII (factor 13) V89L mutations. When combined with traditional risk factors, P1 was mostly affected by dyslipidemia, smoking and hypertension, while P2 was mostly affected by their fasting blood sugar levels and ApoE variant. CONCLUSIONS: Taken together, these preliminary results could have predictive value to be applied in refining a risk profile for our CAD patients, in order to implement early preventive interventions including specific antithrombotic therapy. Further large scale and follow-up studies are highly recommended to confirm the study findings. PMID- 28086797 TI - SEP-class genes in Prunus mume and their likely role in floral organ development. AB - BACKGROUND: Flower phylogenetics and genetically controlled development have been revolutionised during the last two decades. However, some of these evolutionary aspects are still debatable. MADS-box genes are known to play essential role in specifying the floral organogenesis and differentiation in numerous model plants like Petunia hybrida, Arabidopsis thaliana and Antirrhinum majus. SEPALLATA (SEP) genes, belonging to the MADS-box gene family, are members of the ABCDE and quartet models of floral organ development and play a vital role in flower development. However, few studies of the genes in Prunus mume have yet been conducted. RESULTS: In this study, we cloned four PmSEPs and investigated their phylogenetic relationship with other species. Expression pattern analyses and yeast two-hybrid assays of these four genes indicated their involvement in the floral organogenesis with PmSEP4 specifically related to specification of the prolificated flowers in P. mume. It was observed that the flower meristem was specified by PmSEP1 and PmSEP4, the sepal by PmSEP1 and PmSEP4, petals by PmSEP2 and PmSEP3, stamens by PmSEP2 and PmSEP3 and pistils by PmSEP2 and PmSEP3. CONCLUSION: With the above in mind, flower development in P. mume might be due to an expression of SEP genes. Our findings can provide a foundation for further investigations of the transcriptional factors governing flower development, their molecular mechanisms and genetic basis. PMID- 28086798 TI - Genome-wide association analysis of seedling traits in diverse Sorghum germplasm under thermal stress. AB - BACKGROUND: Climate variability due to fluctuation in temperature is a worldwide concern that imperils crop production. The need to understand how the germplasm variation in major crops can be utilized to aid in discovering and developing breeding lines that can withstand and adapt to temperature fluctuations is more necessary than ever. Here, we analyzed the genetic variation associated with responses to thermal stresses in a sorghum association panel (SAP) representing major races and working groups to identify single nucleotide polymorphisms (SNPs) that are associated with resilience to temperature stress in a major cereal crop. RESULTS: The SAP exhibited extensive variation for seedling traits under cold and heat stress. Genome-wide analyses identified 30 SNPs that were strongly associated with traits measured at seedling stage under cold stress and tagged genes that act as regulators of anthocyanin expression and soluble carbohydrate metabolism. Meanwhile, 12 SNPs were significantly associated with seedling traits under heat stress and these SNPs tagged genes that function in sugar metabolism, and ion transport pathways. Evaluation of co-expression networks for genes near the significantly associated SNPs indicated complex gene interactions for cold and heat stresses in sorghum. We focused and validated the expression of four genes in the network of Sb06g025040, a basic-helix-loop-helix (bHLH) transcription factor that was proposed to be involved in purple color pigmentation of leaf, and observed that genes in this network were upregulated during cold stress in a moderately tolerant line as compared to the more sensitive line. CONCLUSION: This study facilitated the tagging of genome regions associated with variation in seedling traits of sorghum under cold and heat stress. These findings show the potential of genotype information for development of temperature resilient sorghum cultivars and further characterization of genes and their networks responsible for adaptation to thermal stresses. Knowledge on the gene networks from this research can be extended to the other cereal crops to better understand the genetic basis of resilience to temperature fluctuations during plant developmental stages. PMID- 28086799 TI - Gender-specific association of decreased estimated glomerular filtration rate and left vertical geometry in the general population from rural Northeast China. AB - BACKGROUND: Left ventricular hypertrophy (LVH) is common and associated with cardiovascular outcomes among patients with known chronic kidney disease (CKD). However, the link between decreased estimated glomerular filtration rate (eGFR) and left ventricular (LV) geometry remains poorly explored in general population. In this study, we examined the gender-specific association between eGFR and LVH in the general population from rural Northeast China. METHODS: This survey was conducted from July 2012 to August 2013. A total of 10907 participants (5,013 men and 5,894 women) from the rural Northeast China were randomly selected and examined. LV mass index (LVMI) was used to define LVH (LVMI > 46.7 g/m2.7 in women; > 49.2 g/m2.7 in men). LV geometry was defined as normal, or with concentric remodeling, eccentric or concentric hypertrophy, according to relative wall thickness (RWT) and LVMI. Mildly decreased eGFR was defined as eGFR >= 60 and < 90 ml/min/1.73 m2, and moderate-severely decreased eGFR was defined as eGFR < 60 ml/min/1.73 m2. RESULTS: As eGFR decreased, LVH showed a gradual increase in the entire study population. Multivariate analysis revealed a gender-specific relationship between eGFR and LV geometry. Only in men, mildly decreased eGFR was associated with concentric remodeling [odds ratio (OR): =1.58; 95% CI: 1.14-2.20; P < 0.01] and concentric LVH OR = 1.63; 95% CI: 1.15-2.31; P < 0.01). And only in men, moderate-severely decreased eGFR was a risk factor for concentric LVH (OR = 4.56; 95% CI: 2.14-9.73; P < 0.001) after adjusting for confounding factors. CONCLUSIONS: These findings suggested that decreased eGFR was a risk factor for LV geometry in men, and a gender-specific difference should be taken into account in clinical practice. PMID- 28086800 TI - Relevance of FXR-p62/SQSTM1 pathway for survival and protection of mouse hepatocytes and liver, especially with steatosis. AB - BACKGROUND: Liver injury and regeneration involve complicated processes and are affected by various physio-pathological conditions. Surgically, severe liver injury after surgical resection often leads to fatal liver failure, especially with some underlying pathological conditions such as steatosis. Therefore, protection from the injury of hepatocytes and liver is a serious concern in various clinical settings. METHODS: We studied the effects of the farnesoid X receptor (FXR) on cell survival and steatosis in mouse hepatocytes (AML12 mouse liver cells) and investigated their molecular mechanisms. We next studied whether or not FXR improves liver injury, regeneration and steatosis in a mouse model of partial hepatectomy (PH) with steatosis. RESULTS: An FXR-specific agonist, GW4064, induced expressions of the p62/SQSTM1 gene and protein in AML12 mouse liver cells. Because we previously reported p62/SQSTM1 as a key molecule for antioxidation and cell survival in hepatocytes, we next examined the activation of nuclear factor erythroid 2-related factor-2 (Nrf2) and induction of the antioxidant molecules by GW4064. GW4064 activated Nrf2 and subsequently induced antioxidant molecules (Nrf2, catalase, HO-1, and thioredoxin). We also examined expressions of pro-survival and cell protective molecules associated with p62/SQSTM1. Expectedly, GW4064 induced phosphorylation of Akt, expression of the anti-apoptotic molecules (Bcl-xL and Bcl-2), and reduced harmful hepatic molecules (Fas ligand and Fas). GW4064 promoted hepatocyte survival, which was cancelled by p62/SQSTM1 siRNA. These findings suggest the potential relevance of the FXR-p62/SQSTM1 pathway for the survival and protection of hepatocytes. Furthermore, GW4064 induced the expression of small heterodimer partners (SHP) and suppressed liver X receptor (LXR)-induced steatosis in hepatocytes, expecting the in vivo protective effect of FXR on liver injury especially with steatosis. In the hepatectomy model of db/db mice with fatty liver, pre-treatment by GW4064 significantly reduced post-PH liver injury (serum levels of LDH, AST & ALT and histological study) and improved steatosis. The key molecules, p62/SQSTM1, Nrf2 and SHP were upregulated in fatty liver tissue by GW4064 treatment. CONCLUSIONS: The present study is the first to demonstrate the relevance of FXR-p62/SQSTM1 and -SHP in the protection against injury of hepatocytes and post-PH liver, especially with steatosis. PMID- 28086801 TI - Two-dimensional speckle-tracking echocardiography for evaluation of dilative ascending aorta biomechanics. AB - BACKGROUND: Two-dimensional (2D) echocardiography is one of the most feasible, noninvasive methods for assessing the aortic diameter and biomechanical changes. We studied possible interfaces between noninvasive biomechanical and speckle tracking (ST) echocardiographic data from dilated aortas. METHODS: Altogether, 44 patients with dilative pathology of ascending aorta (DPAA) were compared with subjects without ascending aortic dilation (diameter <40 mm). DPAA patients formed two groups based on diameter size: group 1, <=45 mm diameter; group 2, >45 mm. Conventional and 2D-ST echocardiography were performed to evaluate peak longitudinal strain (LS), longitudinal (LD) and transverse (TD) displacement, and longitudinal velocity (VL). Aortic strain, distensibility, elastic modulus, stiffness index beta of Valsalva sinuses and ascending aorta were also evaluated. SPSS version 20 was used for all analyses. RESULTS: All linear diameters of the ascending aorta were increased in group 2 (>45 mm diameter) (p < 0.05). LD of the anterior aortic wall (p < 0.05) and TD of both aortic walls (p < 0.001) were least in group 2. VL of the posterior and anterior walls diminished in group 2 (p = 0.01). Aortic strain and distensibility were least (p = 0.028 and p = 0.001, respectively) and elastic modulus and stiffness index beta values were greatest in group 2, although without statistical significance. CONCLUSIONS: Ascending aortas of both DPAA groups had reduced elasticity and increased stiffness. The greatest changes in biomechanical parameters occurred in ascending aortas >45 mm. Longitudinal ascending aortic wall motion was mostly impaired in patients with aortas >45 mm (i.e., anterior aortic wall LD, VL of the posterior and anterior walls. TD of the posterior and anterior aortic walls was significantly lower in >45 mm aortic diameter patients. TD of 5.2 mm could predict aortic dilation >45 mm (area under the curve 0.76, p < 0.001, confidence interval 0.65-0.87; sensitivity 87%; specificity 63%). Greater aortic dilation is associated with reduced aortic stiffness parameters and increased elastic modulus and stiffness index beta. Lower LD and LS were associated with less aortic strain and distensibility. There were no significant differences in 2D-ST echocardiographic or stiffness parameters between patients with tricuspid or bicuspid aortic valves. PMID- 28086802 TI - Brain metabolic pattern analysis using a magnetic resonance spectra classification software in experimental stroke. AB - BACKGROUND: Magnetic resonance spectroscopy (MRS) provides non-invasive information about the metabolic pattern of the brain parenchyma in vivo. The SpectraClassifier software performs MRS pattern-recognition by determining the spectral features (metabolites) which can be used objectively to classify spectra. Our aim was to develop an Infarct Evolution Classifier and a Brain Regions Classifier in a rat model of focal ischemic stroke using SpectraClassifier. RESULTS: A total of 164 single-voxel proton spectra obtained with a 7 Tesla magnet at an echo time of 12 ms from non-infarcted parenchyma, subventricular zones and infarcted parenchyma were analyzed with SpectraClassifier ( http://gabrmn.uab.es/?q=sc ). The spectra corresponded to Sprague-Dawley rats (healthy rats, n = 7) and stroke rats at day 1 post-stroke (acute phase, n = 6 rats) and at days 7 +/- 1 post-stroke (subacute phase, n = 14). In the Infarct Evolution Classifier, spectral features contributed by lactate + mobile lipids (1.33 ppm), total creatine (3.05 ppm) and mobile lipids (0.85 ppm) distinguished among non-infarcted parenchyma (100% sensitivity and 100% specificity), acute phase of infarct (100% sensitivity and 95% specificity) and subacute phase of infarct (78% sensitivity and 100% specificity). In the Brain Regions Classifier, spectral features contributed by myoinositol (3.62 ppm) and total creatine (3.04/3.05 ppm) distinguished among infarcted parenchyma (100% sensitivity and 98% specificity), non-infarcted parenchyma (84% sensitivity and 84% specificity) and subventricular zones (76% sensitivity and 93% specificity). CONCLUSION: SpectraClassifier identified candidate biomarkers for infarct evolution (mobile lipids accumulation) and different brain regions (myoinositol content). PMID- 28086803 TI - Compendium of TCDD-mediated transcriptomic response datasets in mammalian model systems. AB - BACKGROUND: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most potent congener of the dioxin class of environmental contaminants. Exposure to TCDD causes a wide range of toxic outcomes, ranging from chloracne to acute lethality. The severity of toxicity is highly dependent on the aryl hydrocarbon receptor (AHR). Binding of TCDD to the AHR leads to changes in transcription of numerous genes. Studies evaluating the transcriptional changes brought on by TCDD may provide valuable insight into the role of the AHR in human health and disease. We therefore compiled a collection of transcriptomic datasets that can be used to aid the scientific community in better understanding the transcriptional effects of ligand-activated AHR. RESULTS: Specifically, we have created a datasets package - TCDD.Transcriptomics - for the R statistical environment, consisting of 63 unique experiments comprising 377 samples, including various combinations of 3 species (human derived cell lines, mouse and rat), 4 tissue types (liver, kidney, white adipose tissue and hypothalamus) and a wide range of TCDD exposure times and doses. These datasets have been fully standardized using consistent preprocessing and annotation packages (available as of September 14, 2015). To demonstrate the utility of this R package, a subset of "AHR-core" genes were evaluated across the included datasets. Ahrr, Nqo1 and members of the Cyp family were significantly induced following exposure to TCDD across the studies as expected while Aldh3a1 was induced specifically in rat liver. Inmt was altered only in liver tissue and primarily by rat-AHR. CONCLUSIONS: Analysis of the "AHR core" genes demonstrates a continued need for studies surrounding the impact of AHR-activity on the transcriptome; genes believed to be consistently regulated by ligand-activated AHR show surprisingly little overlap across species and tissues. Until now, a comprehensive assessment of the transcriptome across these studies was challenging due to differences in array platforms, processing methods and annotation versions. We believe that this package, which is freely available for download ( http://labs.oicr.on.ca/boutros-lab/tcdd-transcriptomics ) will prove to be a highly beneficial resource to the scientific community evaluating the effects of TCDD exposure as well as the variety of functions of the AHR. PMID- 28086804 TI - Comparative analysis of the root transcriptomes of cultivated sweetpotato (Ipomoea batatas [L.] Lam) and its wild ancestor (Ipomoea trifida [Kunth] G. Don). AB - BACKGROUND: The complex process of formation of storage roots (SRs) from adventitious roots affects sweetpotato yield. Identifying the genes that are uniquely expressed in the SR forming cultivated species, Ipomoea batatas (Ib), and its immediate ancestral species, Ipomoea trifida (It), which does not form SRs, may provide insights into the molecular mechanisms underlying SR formation in sweetpotato. RESULTS: Illumina paired-end sequencing generated ~208 and ~200 million reads for Ib and It, respectively. Trinity assembly of the reads resulted in 98,317 transcripts for Ib and 275,044 for It, after post-assembly removal of trans-chimeras. From these sequences, we identified 4,865 orthologous genes in both Ib and It, 60 paralogous genes in Ib and 2,286 paralogous genes in It. Among paralogous gene sets, transcripts encoding the transcription factor RKD, which may have a role in nitrogen regulation and starch formation, and rhamnogalacturonate lyase (RGL) family proteins, which produce the precursors of cell wall polysaccharides, were found only in Ib. In addition, transcripts encoding a K+ efflux antiporter (KEA5) and the ERECTA protein kinase, which function in phytohormonal regulation and root proliferation, respectively, were also found only in Ib. qRT-PCR indicated that starch and sucrose metabolism genes, such as those encoding ADP-glucose pyrophosphorylase and beta-amylase, showed lower expression in It than Ib, whereas lignin genes such as caffeoyl-CoA O-methyltransferase (CoMT) and cinnamyl alcohol dehydrogenase (CAD) showed higher expression in It than Ib. A total of 7,067 and 9,650 unique microsatellite markers, 1,037,396 and 495,931 single nucleotide polymorphisms (SNPs) and 103,439 and 69,194 InDels in Ib and It, respectively, were also identified from this study. CONCLUSION: The detection of genes involved in the biosynthesis of RGL family proteins, the transcription factor RKD, and genes encoding a K+ efflux antiporter (KEA5) and the ERECTA protein kinase only in I. batatas indicate that these genes may have important functions in SR formation in sweetpotato. Potential molecular markers (SNPs, simple sequence repeats and InDels) and sequences identified in this study may represent a valuable resource for sweetpotato gene annotation and may serve as important tools for improving SR formation in sweetpotato through breeding. PMID- 28086805 TI - The safety of introducing a new generation TAVR device: one departments experience from introducing a second generation repositionable TAVR. AB - BACKGROUND: In the evolving field of transcatheter aortic valve replacements a new generation of valves have been introduced to clinical practice. With the complexity of the TAVR procedure and the unique aspects of each TAVR device, there is a perceived risk that changing or adding a new valve in a department could lead to a worse outcome for patients, especially during the learning phase. The objective was to study the safety aspect of introducing a second generation repositionable transcatheter valve (Boston Scientific Lotus valve besides Edwards Sapien valve) in a department. METHODS: In a retrospective study, 53 patients receiving the Lotus system, and 47 patients receiving the Sapien system over a period of three years were compared for short-term outcome according to VARC-2 definitions and 1-year survival. RESULTS: Outcome in terms VARC-2 criteria for early safety and clinical efficacy, stroke rate, and survival at 30 days and at 1 year were similar. The Lotus valve had less paravalvular leakage, where 90% had none or trace aortic insufficiency as compared to only 48% for the Sapien system. CONCLUSIONS: Introduction of a new generation valve can be done with early device success and safety, and without jeopardizing the outcome for patients up to one year. We found no adverse effects by changing valve type and observed improved outcome in terms of lower PVL-rates. Both existing and new centers starting a TAVR program can benefit from the use of a new generation device. PMID- 28086806 TI - Age-related macular degeneration associated polymorphism rs10490924 in ARMS2 results in deficiency of a complement activator. AB - BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. The polymorphism rs10490924 in the ARMS2 gene is highly associated with AMD and linked to an indel mutation (del443ins54), the latter inducing mRNA instability. At present, the function of the ARMS2 protein, the exact cellular sources in the retina and the biological consequences of the rs10490924 polymorphism are unclear. METHODS: Recombinant ARMS2 was expressed in Pichia pastoris, and protein functions were studied regarding cell surface binding and complement activation in human serum using fluoresence-activated cell sorting (FACS) as well as laser scanning microscopy (LSM). Biolayer interferometry defined protein interactions. Furthermore, endogenous ARMS2 gene expression was studied in human blood derived monocytes and in human induced pluripotent stem cell-derived microglia (iPSdM) by PCR and LSM. The ARMS2 protein was localized in human genotyped retinal sections and in purified monocytes derived from AMD patients without the ARMS2 risk variant by LSM. ARMS2 expression in monocytes under oxidative stress was determined by Western blot analysis. RESULTS: Here, we demonstrate for the first time that ARMS2 functions as surface complement regulator. Recombinant ARMS2 binds to human apoptotic and necrotic cells and initiates complement activation by recruiting the complement activator properdin. ARMS2-properdin complexes augment C3b surface opsonization for phagocytosis. We also demonstrate for the first time expression of ARMS2 in human monocytes especially under oxidative stress and in microglia cells of the human retina. The ARMS2 protein is absent in monocytes and also in microglia cells, derived from patients homozygous for the ARMS2 AMD risk variant (rs10490924). CONCLUSIONS: ARMS2 is likely involved in complement-mediated clearance of cellular debris. As AMD patients present with accumulated proteins and lipids on Bruch's membrane, ARMS2 protein deficiency due to the genetic risk variant might be involved in drusen formation. PMID- 28086807 TI - Detection of critical cerebral desaturation thresholds by three regional oximeters during hypoxia: a pilot study in healthy volunteers. AB - BACKGROUND: Regional oximetry is increasingly used to monitor post-extraction oxygen status of the brain during surgical procedures where hemodynamic fluctuations are expected. Particularly in cardiac surgery, clinicians employ an interventional algorithm to restore baseline regional oxygen saturation (rSO2) when a patient reaches a critical desaturation threshold. Evidence suggests that monitoring cardiac surgery patients and intervening to maintain rSO2 can improve postoperative outcomes; however, evidence generated with one manufacturer's device may not be applicable to others. We hypothesized that regional oximeters from different manufacturers respond uniquely to changes in oxygen saturation in healthy volunteers. METHODS: Three devices were tested: INVOSTM 5100C (Medtronic), EQUANOXTM 7600 (Nonin), and FORE-SIGHTTM (CASMED) monitors. We divided ten healthy subjects into two cohorts wearing a single sensor each from INVOS and EQUANOX (n = 6), or INVOS and FORE-SIGHT (n = 4). We induced and reversed hypoxia by adjusting the fraction of inspired oxygen. We calculated the magnitude of absolute rSO2 change and rate of rSO2 change during desaturation and resaturation, and determined if and when each device reached a critical interventional rSO2 threshold during hypoxia. RESULTS: All devices responded to changes in oxygen directionally as expected. The median absolute rSO2 change and the rate of rSO2 change was significantly greater during desaturation and resaturation for INVOS compared with EQUANOX (P = 0.04). A similar but nonsignificant trend was observed for INVOS compared with FORE-SIGHT; our study was underpowered to definitively conclude there was no difference. A 10% relative decrease in rSO2 during desaturation was detected by all three devices across the ten subjects. INVOS met a 20% relative decrease threshold in all subjects of both cohorts, compared to 1 with EQUANOX and 2 with FORE-SIGHT. Neither EQUANOX nor FORE-SIGHT reached a 50% absolute rSO2 threshold compared with 4 and 3 subjects in each cohort with INVOS, respectively. CONCLUSIONS: Significant differences exist between the devices in how they respond to changes in oxygen saturation in healthy volunteers. We suggest caution when applying evidence generated with one manufacturer's device to all devices. PMID- 28086808 TI - A quiet harvest: linkage between ritual, seed selection and the historical use of the finger-bladed knife as a traditional plant breeding tool in Ifugao, Philippines. AB - The transverse harvest knife, also commonly called the finger or finger-bladed knife, has been utilized by rice farmers in southeast Asia for many centuries. The finger knife persisted in many traditional cultures long after the introduction of the sickle, a tool which provided farmers with the means to execute a much faster harvest. Several theories in interpretative archaeology have attempted to account for this rejection of more modern technological innovations. These theories, which include community-based social organization ideas and practical reasons for the continued use of the finger knife, are presented in this paper. Here I suggest an alternate theory based on a re interpretation of existing research and fusion of existing theories: the primary reason for the historical and continued use of the finger knife is for seed selection through a centuries old tradition of plant breeding. Though I accept the accuracy of the practical and community-based, socio-cultural reasons for the use of the finger knife put forth by other authors, I suggest that seed selection and genetic improvement was the driving factor in the use of the finger knife. Indeed, intricate planting and harvesting rituals, which both ensured and encouraged varietal conservation and improvement co-evolved with the use of the finger knife as the primary harvest tool due to its unique ability to aid the farmer in the art and science of seed selection. When combined with previous ideas, this interpretative theory, based on the connection between ethnoagronomy and material culture, may provide a more complete picture of the story around the persistence of the finger knife in traditional rice-growing cultures in southeast Asia. I focus my theory on the terrace-building Ifugao people in the mountainous Cordillera region of northcentral Philippines; however, to put the use of the finger into a wider regional context, I draw from examples of the use of the finger knife in other traditional cultures throughout the region of southeast Asia. PMID- 28086809 TI - Primary mediastinal clear cell sarcoma: a case report and review of the literature. AB - BACKGROUND: Clear cell sarcoma (CCS) is a rare malignant soft-tissue neoplasm that displays melanocytic markers and exhibits striking histopathological features. The tumour has a predilection for the lower extremities and rarely presents in the mediastinum. CASE PRESENTATION: We present a case of primary mediastinal CCS in a 57-year-old man. Computer tomography (CT) revealed a 12 * 12 * 7.5 cm mass in the anterior mediastinum. Microscopically, the tumour mainly consisted of epithelioid cells with oval vesicular nuclei and eosinophilic cytoplasm. Immunohistochemically, the tumour was positive for human melanoma black 45 (HMB-45) and vimentin but negative for S-100 and Melan-A. Fluorescence in situ hybridisation (FISH) showed a translocation involving the EWSR1 gene region. CONCLUSION: This report will illustrate that the mediastinum is a potential site for primary CCS and FISH plays an important role in making a conclusive diagnosis. PMID- 28086810 TI - Genotypic characterization of Orientia tsutsugamushi from patients in two geographical locations in Sri Lanka. AB - BACKGROUND: To date more than 20 antigenically distinct strains of Orientia tsutsugamushi (OT) reported within the tsutsugamushi triangle that cause an undifferentiated acute febrile illness in humans. Genotypic characterization of OT in different geographic regions or within the same country, is important in order to establish effective diagnostics, clinical management and to develop effective vaccines. Genetic and antigenic characterization of OT causing human disease in OT-endemic regions is not known for Sri Lanka. METHODS: Adult patients and children who were admitted with an acute febrile illness and presumed to having acute scrub typhus based on presence of an eschar and other supporting clinical features were recruited. Eschar biopsies and buffy coat samples collected from patients who were confirmed having OT by IFA were further studied by real time PCR (Orientia 47 kD) and nested PCR (Orientia 56 kD) amplification. DNA sequences were obtained for 56 kD gene amplicons and phylogenetic comparisons were analyzed using currently available data in GenBank [Neucleotide substitution per 100 residues, 1000 Bootstrap Trials]. RESULTS: Twenty eschar biopsies (Location1,19, Location 2,1) and eight buffy coat samples (Location1,6, Location2,2) examined by real time PCR revealed Orientia amplicons in 16 samples. DNA sequences were obtained for the 56 kD gene amplicons in 12 eschars and 4 buffy coat samples. The genotypes of the Location1 samples revealed that, 7 exhibiting close homology with JP1 [distantly related to UT177 Thai (Karp related)], five had close homology with Kato strain, two had close homology with JGv and JG AF [Distantly related to Kawasaki M63383] and one had close homology with Gilliam strain. The Location 2 strain was closely related to Kuroki-Boryong L04956, the genotype which is distributed in far eastern Asia. Similar to other patients in the cohort this patient also had never travelled out of Sri Lanka. CONCLUSIONS: We observed all three main OT genotypes in Sri Lanka, and the majority fell into Thai Karp related clade. These results demonstrate great antigenic diversity of OT in the studied areas of Sri Lanka. PMID- 28086811 TI - Study of the microRNA expression profile of foreskin derived mesenchymal stromal cells following inflammation priming. AB - BACKGROUND: Due to their self-renewal capacity, multi-lineage potential, and immunomodulatory properties, mesenchymal stromal cells (MSCs) are an attractive tool for different therapeutic strategies. Foreskin (FSK), considered as a biological waste material, has already been shown to be a valuable source of MSCs. Besides their typical fibroblast like morphology and International Society for cellular Therapy compliant phenotype, foreskin-MSCs (FSK-MSCs) are clonogenic, and highly proliferative cells with multi-lineage and strong immunomodulatory capacities. Of importance, FSK-MSCs properly adjust their fate following exposure to inflammatory signals. Being potent regulators of gene expression, miRNAs are involved in modulating nearly all cellular processes and in orchestrating the roles of different immune cells. In this study, we characterized the miRNome of FSK-MSCs by determining the expression profile of 380 different miRNAs in inflammation primed vs. control non-primed cells. METHODS: TaqMan low density array (TLDA) was performed to identify dysregulated miRNAs after exposing FSK-MSCs to inflammatory signals. Quantitative real-time RT PCR was carried out to validate the observations. DIANA-miRPath analysis web server was used to identify potential pathways that could be targeted by the dysregulated miRNAs. RESULTS: Sixteen miRNAs were differentially expressed in inflammation-primed vs. non-primed FSK-MSCs. The expression level of miR-27a, 145, -149, -194, -199a, -221, -328, -345, -423-5p, -485-3p, -485-5p, -615-5p and 758 was downregulated whilst that of miR-155, -363 and -886-3p was upregulated. Target pathway prediction of those differentially expressed miRNAs identified different inflammation linked pathways. CONCLUSIONS: After determining their miRNome, we identified a striking effect of inflammatory signals on the miRNAs' expression levels in FSK-MSCs. Our results highlight a potential role of miRNAs in modulating the transcription programs of FSK-MSCs in response to inflammatory signals. Further, we propose that specific miRNAs could serve as interesting targets to manipulate some functions of FSK-MSCs, thus ameliorating their therapeutic potential. PMID- 28086812 TI - Person-centred care in chronic kidney disease: a cross-sectional study of patients' desires for self-management support. AB - BACKGROUND: People with chronic kidney disease (CKD) must self-manage their illness to assist with slowing disease-progression, but this is a complex task requiring support from healthcare professionals. Despite the established importance of person-centred care, people with CKD are rarely consulted regarding their desires for self-management support (SMS). METHODS: A cross-sectional survey was conducted face-to-face in a Queensland primary care clinic and distributed Australia-wide via an online interface promoted by Kidney Health Australia during 2015. Participants were >=18 years old and had a self-reported doctor's diagnosis of CKD (any stage; N = 97). The survey was based upon existent literature which identified 10 areas that those with CKD believe require additional support. Descriptive data were generated and Mann-Whitney U tests were performed to compare the desires of different groups of participants. RESULTS: Of the 97 participants, 36 completed a hardcopy survey in clinic, and 61 completed the online version. Just over half (60.8%) were female, age ranged from 16-89 (M = 56.44), and time since diagnosis ranged from just diagnosed to 60 years (Mdn = 8.08 years). Strong interest in receiving additional support across all 10 areas was reported (Mdns = 8.00-10.00), with "keeping a positive attitude and taking care of mental and physical health" receiving the highest rating. Those who were: younger (p < .001); more highly educated (p < .001); working (p < .001); diagnosed longer ago (p = .015); and women (p = .050) expressed stronger overall desire for additional support. CONCLUSIONS: In addition to information about CKD and medications, everyday strategies ought to be prioritised in patient education. Varying levels of engagement and eagerness to learn more about self management highlight the need for a person-centred approach to SMS. PMID- 28086813 TI - Information exchange networks of health care providers and evidence-based cardiovascular risk management: an observational study. AB - BACKGROUND: Although a wide range of preventive and clinical interventions has targeted cardiovascular risk management (CVRM), outcomes remain suboptimal. Therefore, the question is what additional determinants of CVRM and outcomes can be identified and addressed to optimize CVRM. In this study, we aimed to identify new perspectives for improving healthcare delivery and explored associations between information exchange networks of health care providers and evidence-based CVRM. METHODS: This observational study was performed parallel to a randomized clinical trial which aimed to improve professional performance of practice nurses in the Netherlands. Information exchange on medical policy for CVRM ("general information networks") and CVRM for individual patients ("specific information networks") of 180 health professionals in 31 general practices was measured with personalized questionnaires. Medical record audit was performed concerning 1620 patients in these practices to document quality of care delivery and two risk factors (systolic blood pressure (SBP) and LDL cholesterol level). Hypothesized effects of five network characteristics (density, frequency of contact, centrality of CVRM-coordinators, homophily on positive attitudes for treatment target achievement, and presence of an opinion leader for CVRM) constructed on both general and specific information exchange networks were tested and controlled for practice and patient factors using logistic multilevel analyses. RESULTS: Odds for adequate performance were enhanced in practices with an opinion leader for CVRM (OR 2.75, p < .05). Odds for achievement of SBP targets were reduced in practices who had networks with low homophily on positive attitudes for SBP and LDL targets (homophily for SBP targets OR 0.57, p < .05 and OR 0.60, p < .05, homophily for LDL targets OR 0.59, p < .05 and OR 0.61, p < .05 in general and specific information networks, respectively). No effects of network characteristics on cholesterol were found. CONCLUSIONS: Delivery of evidence based CVRM is associated with homophily of clinical attitudes and presence of opinion leaders in primary care teams. These results signal the potential of social networks to be taken into account in further attempts to improve the implementation of evidence-based care for CVRM. Future research is needed to identify and formulate optimal strategies for using opinion leaders to improve CVRM. Future interventions may be more effective if they target a common vision on CVRM within practices. PMID- 28086814 TI - Intestinal helminth co-infection and associated factors among tuberculosis patients in Arba Minch, Ethiopia. AB - BACKGROUND: Helminths affect the outcome of tuberculosis by shifting cell mediated immune response to humoral and by total suppression of the host immune system. On the reverse, Mycobacterium infection favors immune escape of helminths. Therefore assessing helminth co-infection rate and predisposing factors in tuberculosis patients is mandatory to set strategies for better case management. METHODS: Facility based cross-sectional study was conducted in Arba Minch to assess the prevalence and associated factors of intestinal helminths among pulmonary tuberculosis patients from January to August, 2016. A structured questionnaire was used to capture data about socio-demographic characteristics, clinical history and possible risk factors for intestinal helminth infections. Height and weight were measured to calculate body-mass index. Appropriate amount of stool was collected and processed by direct saline and formol-ether concentration techniques following standard protocols. All the data were analyzed using SPSS version 20.0. RESULTS: A total of 213 (57.3% male and 42.7% female) pulmonary tuberculosis patients were participated in the study. The overall co infection rate of intestinal parasites was 26.3%. The infection rate of intestinal helminths account 24.4% and that of intestinal protozoa was 6.1%. Ascaris lumbricoides accounted the highest frequency of 11.3%. Living in rural residence (AOR = 3.175, 95% CI: 1.102-9.153, p = 0.032), Eating vegetables/ fruits without washing or peeling off (AOR = 2.208, 95% CI: 1.030-4.733, p = 0.042) and having body-mass index <18.5 (AOR = 3.511, 95% CI: 1.646-7.489, p = 0.001) were associated with intestinal helminth infection. CONCLUSION: The infection rate by intestinal helminths was 24.4%. Ascaris lumbricoides was the most prevalent helminth. Residence, habit of washing vegetables/fruits before use and body-mass index were associated factors with intestinal helminthiasis. Therefore health care providers should screen and treat TB patients for intestinal helminthiasis in order to ensure good prognosis. PMID- 28086815 TI - Antibiotics-induced depletion of mice microbiota induces changes in host serotonin biosynthesis and intestinal motility. AB - BACKGROUND: The gastrointestinal motility is affected by gut microbiota and the relationship between them has become a hot topic. However, mechanisms of microbiota in regulating motility have not been well defined. We thus investigated the effect of microbiota depletion by antibiotics on gastrointestinal motility, colonic serotonin levels, and bile acids metabolism. METHODS: After 4 weeks with antibiotics treatments, gastrointestinal and colon transit, defecation frequency, water content, and other fecal parameters were measured and analyzed in both wild-type and antibiotics-treated mice, respectively. Contractility of smooth muscle, serotonin levels, and bile acids levels in wild-type and antibiotics-treated mice were also analyzed. RESULTS: After antibiotics treatment, the richness and diversity of intestinal microbiota decreased significantly, and the fecal of mice had less output (P < 0.01), more water content (P < 0.01), and longer pellet length (P < 0.01). Antibiotics treatment in mice also resulted in delayed gastrointestinal and colonic motility (P < 0.05), and inhibition of phasic contractions of longitudinal muscle from isolated proximal colon (P < 0.01). In antibiotics-treated mice, serotonin, tryptophan hydroxylase 1, and secondary bile acids levels were decreased. CONCLUSION: Gut microbiota play an important role in the regulation of intestinal bile acids and serotonin metabolism, which could probably contribute to the association between gut microbiota and gastrointestinal motility as intermediates. PMID- 28086816 TI - Rationale, description and baseline findings of a community-based prospective cohort study of kidney function amongst the young rural population of Northwest Nicaragua. AB - BACKGROUND: An epidemic of Mesoamerican Nephropathy (MeN) is killing thousands of agricultural workers along the Pacific coast of Central America, but the natural history and aetiology of the disease remain poorly understood. We have recently commenced a community-based longitudinal study to investigate Chronic Kidney Disease (CKD) in Nicaragua. Although logistically challenging, study designs of this type have the potential to provide important insights that other study designs cannot. In this paper we discuss the rationale for conducting this study and summarize the findings of the baseline visit. METHODS: The baseline visit of the community-based cohort study was conducted in 9 communities in the North Western Nicaragua in October and November 2014. All of the young men, and a random sample of young women (aged 18-30) without a pre-existing diagnosis of CKD were invited to participate. Glomerular filtration rate (eGFR) was estimated with CKD-EPI equation, along with clinical measurements, questionnaires, biological and environmental samples to evaluate participants' exposures to proposed risk factors for MeN. RESULTS: We identified 520 young adults (286 males and 234 females) in the 9 different communities. Of these, 16 males with self-reported CKD and 5 females with diagnoses of either diabetes or hypertension were excluded from the study population. All remaining 270 men and 90 women, selected at random, were then invited to participate in the study; 350 (97%) agreed to participate. At baseline, 29 (11%) men and 1 (1%) woman had an eGFR <90 mL/min/1.73 m2. CONCLUSION: Conducting a community based study of this type requires active the involvement of communities and commitment from local leaders. Furthermore, a research team with strong links to the area and broad understanding of the context of the problem being studied is essential. The key findings will arise from follow-up, but it is striking that 5% of males under aged 30 had to be excluded because of pre-existing kidney disease, and that despite doing so 11% of males had an eGFR <90 mL/min/1.73 m2 at baseline. PMID- 28086817 TI - Cost of shingles: population based burden of disease analysis of herpes zoster and postherpetic neuralgia. AB - BACKGROUND: Around 30% of the population will experience herpes zoster (HZ), 10% of whom develop postherpetic neuralgia (PHN). Together, these illnesses produce a significant economic burden to the healthcare system. METHODS: Administrative healthcare data collected over the period of April 1st 1997 to March 31st 2014 were analyzed to determine the healthcare system burden of HZ using direct medical costs. Episodes of HZ were identified using international classification of disease (ICD) codes. Trends in age-adjusted (AA) HZ-rates were analyzed by piecewise-regression. Total annual and per-episode costs were determined for drug treatment, medical care, and hospitalizations within each year. RESULTS: The incidence of HZ increased by 49.5% from 1997/98 to 2013/14. Piecewise-regression of AA-rates revealed a steady AA-rate of 4.7 episodes/1000 person-years (PY) from 1997/98 to a breakpoint in 2008/09, after which rates began to increase reaching 5.7 episodes/1000 PY in 2013/14. Drug costs rose significantly (p <0.03) from $89.77/episode (95% CI: $82.96, $96.59) to $127.34/episode (95% CI: $117.24, $137.44). Medical costs increased (p <0.0001) from $57.98/episode (95% CI; $55.26, $60.70) to $78.84/episode (95% CI; $74.08, $83.61). Hospitalization rates declined from 3.10% in 1997/98 to 1.36% in 2011/12, resulting in cost dropping from $397/episode (95% CI; $284, $511) to $195/episode (95% CI; $129, $260). Total annual costs of HZ and PHN were $1,997,183 in 2011/12, 4.7% lower than the 1997/98 costs of $2,095,633. CONCLUSION: A significant increase in annual number of HZ cases was observed, driven largely by demographic factors. A 21% increase in the AA-incidence reveals changes in HZ rates beyond those expected by population shifts. The large increase in incidence of HZ, with rising per episode medical and prescription costs were offset by dramatic drops in hospitalization rates, the net effect of which has been to hold the total costs relatively constant. However, the decrease in hospitalization rates slowed over the last half of the study, settling at 1.3% in the last 4 study years. The likely future of HZ burden is one of rising costs, primarily driven by the demographic shifts of an increasing and aging population. PMID- 28086818 TI - Narrow band imaging versus lugol chromoendoscopy to diagnose squamous cell carcinoma of the esophagus: a systematic review and meta-analysis. AB - BACKGROUND: In the early stage esophageal cancer, changes in the mucosa are subtle and pass unnoticed in endoscopic examinations using white light. To increase sensitivity, chromoscopy with Lugol's solution has been used. Technological advancements have led to the emergence of virtual methods of endoscopic chromoscopy, including narrow band imaging (NBI). NBI enhances the relief of the mucosa and the underlying vascular pattern, providing greater convenience without the risks inherent to the use of vital dye. The purpose of this systematic review and meta-analysis was to evaluate the ability of NBI to diagnose squamous cell carcinoma of the esophagus and to compare it to chromoscopy with Lugol's solution. METHODS: This systematic review included all studies comparing the diagnostic accuracy of NBI and Lugol chromoendoscopy performed to identify high-grade dysplasia and/or squamous cell carcinoma in the esophagus. In the meta-analysis, we calculated and demonstrated sensitivity, specificity, and positive and negative likelihood values in forest plots. We also determined summary receiver operating characteristic (sROC) curves and estimates of the areas under the curves for both per-patient and per-lesion analysis. RESULTS: The initial search identified 7079 articles. Of these, 18 studies were included in the systematic review and 12 were used in the meta-analysis, for a total of 1911 patients. In per-patient and per-lesion analysis, the sensitivity, specificity, and positive and negative likelihood values for Lugol chromoendoscopy were 92% and 98, 82 and 37%, 5.42 and 1.4, and 0.13 and 0.39, respectively, and for NBI were 88 and 94%, 88 and 65%, 8.32 and 2.62, and 0.16 and 0.12, respectively. There was a statistically significant difference in only specificity values, in which case NBI was superior to Lugol chromoendoscopy in both analyses. In the per-patient analysis, the area under the sROC curve for Lugol chromoendoscopy was 0.9559. In the case of NBI, this value was 0.9611; in the per-lesion analysis, this number was 0.9685 and 0.9587, respectively. CONCLUSIONS: NBI was adequate in evaluating the esophagus in order to diagnose high-grade dysplasia and squamous cell carcinoma. In the differentiation of those disorders from other esophageal mucosa alterations, the NBI was shown to be superior than Lugol. PMID- 28086819 TI - Efficacy, safety and effectiveness of licensed rotavirus vaccines: a systematic review and meta-analysis for Latin America and the Caribbean. AB - BACKGROUND: RotaTeqTM (RV5; Merck & Co. Inc., USA) and RotarixTM (RV1, GlaxoSmithKline, Belgium) vaccines, developed to prevent rotavirus diarrhea in children under five years old, were both introduced into national immunization programs in 2006. As many countries in Latin America and the Caribbean have included either RV5 or RV1 in their routine childhood vaccination programs, we conducted a systematic review and meta-analysis to analyze efficacy, safety and effectiveness data from the region. METHODS: We conducted a systematic search in PubMed, EMBASE, Scielo, Lilacs and the Cochrane Central Register, for controlled efficacy, safety and effectiveness studies published between January 2000 until December 2011, on RV5 and RV1 across Latin America (where both vaccines are available since 2006). The primary outcome measures were: rotavirus-related gastroenteritis of any severity; rotavirus emergency department visits and hospitalization; and severe adverse events. RESULTS: The results of the meta analysis for efficacy show that RV1 reduced the risk of any-severity rotavirus related gastroenteritis by 65% (relative risk (RR) 0.35, 95% confidence interval (CI) 0.25; 0.50), and of severe gastroenteritis by 82% (RR 0.18, 95%CI 0.12; 0.26) versus placebo. In trials, both vaccines significantly reduced the risk of hospitalization and emergency visits by 85% (RR 0.15, 95%CI 0.09; 0.25) for RV1 and by 90% (RR 0.099, 95%CI 0.012; 0.77) for RV5. Vaccination with RV5 or RV1 did not increase the risk of death, intussusception, or other severe adverse events which were previously associated with the first licensed rotavirus vaccine. Real world effectiveness studies showed that both vaccines reduced rotavirus hospitalization in the region by around 45-50% for RV5 (for 1 to 3 doses, respectively), and, by around 50-80% for RV1 (for 1 to 2 doses, respectively). For RV1, effectiveness against hospitalization was highest (around 80-96%) for children vaccinated before 12 months of age, compared with 5-60% effectiveness in older children. Both vaccines were most effective in preventing more severe gastroenteritis (70% for RV5 and 80-90% for RV1) and severe gastroenteritis (50% for RV5 and 70-80% for RV1). CONCLUSION: This systematic literature review confirms rotavirus vaccination has been proven effective and well tolerated in protecting children in Latin America and the Caribbean. PMID- 28086820 TI - Primary prevention of gestational diabetes mellitus through nutritional factors: a systematic review. AB - BACKGROUND: Gestational diabetes mellitus (GDM), defined as any degree of glucose intolerance with onset during pregnancy, is increasing worldwide, mostly because obesity among women of reproductive age is continuously escalating. GDM is associated with adverse maternal and fetal outcomes. The aim of this article was to systematically review literature on the effectiveness of nutritional factors before or during pregnancy to prevent GDM. METHODS: We assessed the primary prevention of GDM through nutritional factors, as diet and supplements. We searched on PubMed, Cochrane Databases and ClinicalTrials.gov from inception to June 2016. Clinical trials and adjusted prospective cohort studies were included. RESULTS: Eight clinical trials and twenty observational studies assessing the association between dietary factors and primary prevention of GDM were included. Furthermore, six clinical trials and two observational studies related to supplements were also added. Only two nutritional interventions were found to significantly reduce the incidence of GDM, besides the supplements. However, the observational studies showed that a higher adherence to a healthier dietary pattern can prevent the incidence of GDM, especially in high risk population before getting pregnant. CONCLUSIONS: The results indicate that there may be some benefits of some nutritional factors to prevent GDM. However, better-designed studies are required to generate higher quality evidence. At the moment, no strong conclusions can be drawn with regard to the best intervention for the prevention of GDM. PMID- 28086821 TI - A transcriptome profile in hepatocellular carcinomas based on integrated analysis of microarray studies. AB - BACKGROUND: Despite new treatment options for hepatocellular carcinomas (HCC) recently, 5-year survival remains poor, ranging from 50 to 70%, which may attribute to the lack of early diagnostic biomarkers. Thus, developing new biomarkers for early diagnosis of HCC, is extremely urgent, aiming to decrease HCC-related deaths. METHODS: In the study, we conducted a comprehensive characterization of gene expression data of HCC based on a bioinformatics method. The results were confirmed by real time polymerase chain reaction (RT-PCR) and TCGA database to prove the credibility of this integrated analysis. RESULTS: After integrating analysis of seven HCC gene expression datasets, 1167 differential expressed genes (DEGs) were identified. These genes mainly participated in the process of cell cycle, oocyte meiosis, and oocyte maturation mediated by progesterone. The results of experiments and TCGA database validation in 10 genes was in full accordance with findings in integrated analysis, indicating the high credibility of our integrated analysis of different gene expression datasets. ASPM, CCT3, and NEK2 was showed to be significantly associated with overall survival of HCC patients in TCGA database. CONCLUSION: This method of integrated analysis may be a useful tool to minish the heterogeneity of individual microarray, hopefully outputs more accurate HCC transcriptome profiles based on large sample size, and explores some potential biomarkers and therapy targets for HCC. PMID- 28086822 TI - Assessment of quality of care among in-patients with postpartum haemorrhage and severe pre-eclampsia at st. Francis hospital nsambya: a criteria-based audit. AB - BACKGROUND: The maternal mortality ratio of Uganda is still high and the leading causes of maternal mortality are postpartum haemorrhage (PPH), severe pre eclampsia and eclampsia. Criteria-based audit (CBA) is a way of improving quality of care that has not been commonly used in low income countries. This study aimed at finding out the quality of care provided to patients with these conditions and to find out if the implementation of recommendations from the audit cycle resulted in improvement in quality of care. METHODS: This study was a CBA following a time series study design. It was done in St. Francis Hospital Nsambya and it involved assessment of adherence to standards of care for PPH, severe pre eclampsia and eclampsia. An initial audit was done for 3 consecutive months, then findings were presented to health workers and recommendations made; we implemented the recommendations in a subsequent month and this comprised three interventions namely continuing medical education (CME), drills and displaying guidelines; a re-audit was done in the proceeding 3 consecutive months and analysis compared adherence rates of the initial audit with those of the re audit. RESULTS: Pearson Chi-Square test revealed that the adherence rates of 7 out of 10 standards of care for severe pre-eclampsia/eclampsia were statistically significantly higher in the re-audit than in the initial audit; also, the adherence rates of 3 out of 4 standards of care for PPH were statistically significantly higher in the re-audit than in the initial audit. CONCLUSION: The giving of feedback on quality of care and the implementation of recommendations made during the CBA including CME, drills and displaying guidelines was associated with improvements in the quality of care for patients with PPH, severe pre-eclampsia and eclampsia. PMID- 28086823 TI - A realist review of the partograph: when and how does it work for labour monitoring? AB - BACKGROUND: The partograph (or partogram) is recommended by the World Health Organisation (WHO), for monitoring labour wellbeing and progress. Concerns about limitations in the way the partograph is used in the clinical context and the potential impact on its effectiveness have led to this realist systematic review of partograph use. METHODS: This review aimed to answer two key questions, 1) What is it about the partograph that works (or does not work); for whom does it work; and in what circumstances? 2) What are the essential inputs required for the partograph to work? A comprehensive search strategy encompassed key databases; including papers of varying methodologies. Papers were selected for inclusion if the focus of the paper was the partograph and related to context, mechanism or outcome. Ninety five papers were included for data synthesis. Two authors completed data extraction and synthesis. RESULTS: The evidence synthesis relates the evidence to identified theories of health worker acceptability, health system support, effective referral systems, human resources and health worker competence, highlighting barriers and facilitators. CONCLUSIONS: This first comprehensive realist synthesis of the partograph, provides the international community of maternity clinicians with a picture of potential issues and solutions related to successful labour recording and management, which is also translatable to other monitoring approaches. PMID- 28086824 TI - D-dimer is an essential accompaniment of circulating tumor cells in gastric cancer. AB - BACKGROUND: Fibrinogen (FIB) is an important source of fibrin, which plays a crucial role in circulating tumor cells (CTCs) extravasation and distant metastasis development. We hypothesize it's stable final product, plasma D-dimer, may be associated with CTCs appearance and can reflect the metastatic phenotype in cancer patients. METHODS: We first verified our hypothesis in different murine gastric cancer metastasis models in vivo, plasma D-dimer and fibrinogen as well as its degradation products were directly examined in three metastasis immune deficient mouse models and in controls. Next, we gathered and analyzed the result of plasma D-dimer levels and CTCs numbers in 41 advanced primary gastric cancer (GC) patients. A follow-up study was conducted in these patients. RESULTS: In three in vivo murine metastasis models, plasma D-dimer levels were extremely elevated in a hematogenous and intraperitoneal murine model of metastasis compared with a subcutaneous tumor model and the control group, supporting our previous hypothesis. While in 41 GC patients, the result displayed that plasma D dimer levels were remarkably increased in patients with distant metastases, especially in visceral metastases patients. Additionally, linear association was shown between D-dimer level and CTCs numbers (R 2 = 0.688, p < 0.001), additionally, plasma D-dimer represent a better survival predictor than CTCs. CONCLUSIONS: Plasma D-dimer is an essential accompaniment of CTCs in GC that is easy to measure and lower in cost, and can be used in the detection of hematogenous metastasis. PMID- 28086825 TI - Toxicity and quality of life report of a phase II study of stereotactic body radiotherapy (SBRT) for low and intermediate risk prostate cancer. AB - BACKGROUND: Clinical data indicates that delivery of larger daily doses of radiation may improve the therapeutic ratio for prostate cancer compared to conventional fractionation. A phase II study of stereotactic body radiotherapy with real-time motion management and daily plan re-optimization for low to intermediate risk prostate cancer was undertaken to evaluate this hypothesis. This report details the toxicity and quality of life following treatment. METHODS: From 2009 to 2013, 60 patients with T1-T2c prostate cancer with a Gleason score of 6 and PSA <= 15 or Gleason score of 7 and PSA <= 10 were enrolled. Patients with nodal metastases, an American Urological Association symptom score > 18, or gland size > 100 g were not eligible. Patients were treated to 37 Gy in 5 fractions. Early and late genitourinary and gastrointestinal toxicity were graded based on NCI CTCAE v4.0 and quality of life was assessed by the American Urological Association symptom score, International Index of Erectile Function, and Expanded Prostate cancer Index Composite Short Form up to 36 months after treatment. RESULTS: After a median follow-up of 27.6 months, no grade 3 or greater genitourinary toxicity was observed. Four patients (6.7%) reported a late grade 2 genitourinary toxicity. One patient (1.7%) reported a late grade 3 gastrointestinal toxicity. Five patients (8.3%) developed a late grade 2 gastrointestinal toxicity. The median American Urological Association symptom score increased from 4.5 prior to treatment to 11 while on treatment (p < 0.01), but was 5 at 36 months post-treatment (p = 0.65). Median International Index of Erectile Function scores decreased from 19 to 17 over the course of follow-up (p < 0.01). Only median scores within the Expanded Prostate Cancer Index Composite Short Form sexual domain were significantly decreased at 36 months post-treatment (67.9 vs 45.2, p = 0.02). There was no significant difference in median score within the urinary, bowel, or hormonal domains at 36 months of follow-up. CONCLUSIONS: Stereotactic body radiotherapy for low to intermediate risk prostate cancer is well tolerated with limited toxicity or decrease in quality of life. Longer follow-up is necessary to assess the efficacy of treatment. TRIAL REGISTRATION: Clinicaltrials.gov NCT00941915 Registered 17 June 2009. PMID- 28086826 TI - Offering Patients Therapy Options in Unplanned Start (OPTiONS): Implementation of an educational program is feasible and effective. AB - BACKGROUND: Patients with unplanned dialysis start (UPS) have worse clinical outcomes than non-UPS patients, and receive peritoneal dialysis (PD) less frequently. In the OPTiONS study of UPS patients, an educational programme (UPS EP) aiming at improving care of UPS patients by facilitating care pathways and enabling informed choice of dialysis modality was implemented. We here report on impact of UPS-EP on modality choice and clinical outcomes in UPS patients. METHODS: This non-interventional, prospective, multi-center, observational study included 270 UPS patients from 26 centers in 6 European countries (Austria, Germany, Denmark, France, United Kingdom and Sweden) who prior to inclusion presented acutely, or were being followed by nephrologists but required urgent dialysis commencement by an acutely placed CVC or PD catheter. Effects of UPS-EP on choice and final decision of dialysis therapy and outcomes within 12 months of follow up were analysed. RESULTS: Among 270 UPS patients who had an unplanned start to dialysis, 214 were able to receive and 203 complete UPS-EP while 56 patients - who were older (p = 0.01) and had higher Charlson comorbidity index (CCI; p < 0.01) - did not receive UPS-EP. Among 177 patients who chose dialysis modality after UPS-EP, 103 (58%) chose PD (but only 86% of them received PD) and 74 (42%) chose HD (95% received HD). Logistic regression analysis showed that diabetes 1.88 (1.05 - 3.37) and receiving UPS-EP, OR = 4.74 (CI, 2.05 - 10.98) predicted receipt of PD. Patients choosing PD had higher CCI (p = 0.01), higher prevalence of congestive heart failure (p < 0.01) and myocardial infarction (p = 0.02), and were more likely in-patients (p = 0.02) or referred from primary care (p = 0.02). One year survival did not differ significantly between PD and HD patients. Peritonitis and bacteraemia rates were better than international guideline standards. CONCLUSIONS: UPS-EP predicted patient use of PD but 14% of those choosing PD after UPS-EP still did not receive the modality they preferred. Patient survival in patients choosing and/or receiving PD was similar to HD despite age and comorbidity disadvantages of the PD groups. PMID- 28086827 TI - Mothers' accounts of the impact on emotional wellbeing of organised peer support in pregnancy and early parenthood: a qualitative study. AB - BACKGROUND: The transition to parenthood is a potentially vulnerable time for mothers' mental health and approximately 9-21% of women experience depression and/or anxiety at this time. Many more experience sub-clinical symptoms of depression and anxiety, as well as stress, low self-esteem and a loss of confidence. Women's emotional wellbeing is more at risk if they have little social support, a low income, are single parents or have a poor relationship with their partner. Peer support can comprise emotional, affirmational, informational and practical support; evidence of its impact on emotional wellbeing during pregnancy and afterwards is mixed. METHODS: This was a descriptive qualitative study, informed by phenomenological social psychology, exploring women's experiences of the impact of organised peer support on their emotional wellbeing during pregnancy and in early parenthood. Semi-structured qualitative interviews were undertaken with women who had received peer support provided by ten projects in different parts of England, including both projects offering 'mental health' peer support and others offering more broadly-based peer support. The majority of participants were disadvantaged Black and ethnic minority women, including recent migrants. Interviews were audio-recorded and transcripts were analysed using inductive thematic analysis. RESULTS: 47 mothers were interviewed. Two key themes emerged: (1) 'mothers' self-identified emotional needs', containing the subthemes 'emotional distress', 'stressful circumstances', 'lack of social support', and 'unwilling to be open with professionals'; and (2) 'how peer support affects mothers', containing the subthemes 'social connection', 'being heard', 'building confidence', 'empowerment', 'feeling valued', 'reducing stress through practical support' and 'the significance of "mental health" peer experiences'. Women described how peer support contributed to reducing their low mood and anxiety by overcoming feelings of isolation, disempowerment and stress, and increasing feelings of self-esteem, self-efficacy and parenting competence. CONCLUSION: One to-one peer support during pregnancy and after birth can have a number of interrelated positive impacts on the emotional wellbeing of mothers. Peer support is a promising and valued intervention, and may have particular salience for ethnic minority women, those who are recent migrants and women experiencing multiple disadvantages. PMID- 28086828 TI - Subjective and objective assessment of physical activity in multiple sclerosis and their relation to health-related quality of life. AB - BACKGROUND: Physical activity (PA) is frequently restricted in people with multiple sclerosis (PwMS) and aiming to enhance PA is considered beneficial in this population. We here aimed to explore two standard methods (subjective plus objective) to assess PA reduction in PwMS and to describe the relation of PA to health-related quality of life (hrQoL). METHODS: PA was objectively measured over a 7-day period in 26 PwMS (EDSS 1.5-6.0) and 30 matched healthy controls (HC) using SenseWear mini(r) armband (SWAmini) and reported as step count, mean total and activity related energy expenditure (EE) as well as time spent in PA of different intensities. Measures of EE were also derived from self-assessment with IPAQ (International Physical Activity Questionnaire) long version, which additionally yielded information on the context of PA and a classification into subjects' PA levels. To explore the convergence between both types of assessment, IPAQ categories (low, moderate, high) were related to selected PA parameters from objective assessment using ANOVA. Group differences and associated effect sizes for all PA parameters as well as their relation to clinical and hrQoL measures were determined. RESULTS: Both, SWAmini and IPAQ assessment, captured differences in PA between PwMS and HC. IPAQ categories fit well with common cut-offs for step count (p = 0.002) and mean METs (p = 0.004) to determine PA levels with objective devices. Correlations between specifically matched pairs of IPAQ and SWAmini parameters ranged between r .288 and r .507. Concerning hrQoL, the lower limb mobility subscore was related to four PA measures, while a relation with patients' report of general contentment was only seen for one. CONCLUSIONS: Both methods of assessment seem applicable in PwMS and able to describe reductions in daily PA at group level. Whether they can be used to track individual effects of interventions to enhance PA levels needs further exploration. The relation of PA measures with hrQoL seen with lower limb mobility suggests lower limb function not only as a major target for intervention to increase PA but also as a possible surrogate for PA changes. PMID- 28086829 TI - Genomic pathways modulated by Twist in breast cancer. AB - BACKGROUND: The basic helix-loop-helix transcription factor TWIST1 (Twist) is involved in embryonic cell lineage determination and mesodermal differentiation. There is evidence to indicate that Twist expression plays a role in breast tumor formation and metastasis, but the role of Twist in dysregulating pathways that drive the metastatic cascade is unclear. Moreover, many of the genes and pathways dysregulated by Twist in cell lines and mouse models have not been validated against data obtained from larger, independant datasets of breast cancer patients. METHODS: We over-expressed the human Twist gene in non-metastatic MCF-7 breast cancer cells to generate the estrogen-independent metastatic breast cancer cell line MCF-7/Twist. These cells were inoculated in the mammary fat pad of female severe compromised immunodeficient mice, which subsequently formed xenograft tumors that metastasized to the lungs. Microarray data was collected from both in vitro (MCF-7 and MCF-7/Twist cell lines) and in vivo (primary tumors and lung metastases) models of Twist expression. Our data was compared to several gene datasets of various subtypes, classes, and grades of human breast cancers. RESULTS: Our data establishes a Twist over-expressing mouse model of breast cancer, which metastasizes to the lung and replicates some of the ontogeny of human breast cancer progression. Gene profiling data, following Twist expression, exhibited novel metastasis driver genes as well as cellular maintenance genes that were synonymous with the metastatic process. We demonstrated that the genes and pathways altered in the transgenic cell line and metastatic animal models parallel many of the dysregulated gene pathways observed in human breast cancers. CONCLUSIONS: Analogous gene expression patterns were observed in both in vitro and in vivo Twist preclinical models of breast cancer metastasis and breast cancer patient datasets supporting the functional role of Twist in promoting breast cancer metastasis. The data suggests that genetic dysregulation of Twist at the cellular level drives alterations in gene pathways in the Twist metastatic mouse model which are comparable to changes seen in human breast cancer s. Lastly, we have identified novel genes and pathways that could be further investigated as targets for drugs to treat metastatic breast cancer. PMID- 28086830 TI - Sigma-2 receptor agonist derivatives of 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4 tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) induce cell death via mitochondrial superoxide production and caspase activation in pancreatic cancer. AB - BACKGROUND: Despite considerable efforts by scientific research, pancreatic cancer is the fourth leading cause of cancer related mortalities. Sigma-2 receptors, which are overexpressed in several tumors, represent promising targets for triggering selective pancreatic cancer cells death. METHODS: We selected five differently structured high-affinity sigma-2 ligands (PB28, PB183, PB221, F281 and PB282) to study how they affect the viability of diverse pancreatic cancer cells (human cell lines BxPC3, AsPC1, Mia PaCa-2, and Panc1 and mouse Panc-02, KCKO and KP-02) and how this is reflected in vivo in a tumor model. RESULTS: Important cytotoxicity was shown by the compounds in the aggressive Panc02 cells, where cytotoxic activity was caspase-3 independent for four of the five compounds. However, both cytotoxicity and caspase-3 activation involved generation of Reactive Oxygen Species (ROS), which could be partially reverted by the lipid antioxidant alpha-tocopherol, but not by the hydrophilic N acetylcysteine (NAC) indicating crucial differences in the intracellular sites exposed to oxidative stress induced by sigma-2 receptor ligands. Importantly, all the compounds strongly increased the production of mitochondrial superoxide radicals except for PB282. Despite a poor match between in vitro and the in vivo efficacy, daily treatment of C57BL/6 mice bearing Panc02 tumors resulted in promising effects with PB28 and PB282 which were similar compared to the current standard-of-care chemotherapeutic gemcitabine without showing signs of systemic toxicities. CONCLUSIONS: Overall, this study identified differential sensitivities of pancreatic cancer cells to structurally diverse sigma-2 receptor ligands. Of note, we identified the mitochondrial superoxide pathway as a previously unrecognized sigma-2 receptor-activated process, which encourages further studies on sigma-2 ligand-mediated cancer cell death for the targeted treatment of pancreatic tumors. PMID- 28086831 TI - Evaluation of the cytotoxicity of the Bithionol - cisplatin combination in a panel of human ovarian cancer cell lines. AB - BACKGROUND: Combination drug therapy appears a promising approach to overcome drug resistance and reduce drug-related toxicities in ovarian cancer treatments. In this in vitro study, we evaluated the antitumor efficacy of cisplatin in combination with Bithionol (BT) against a panel of ovarian cancer cell lines with special focus on cisplatin-sensitive and cisplatin-resistant cell lines. The primary objectives of this study are to determine the nature of the interactions between BT and cisplatin and to understand the mechanism(s) of action of BT cisplatin combination. METHODS: The cytotoxic effects of drugs either alone or in combination were evaluated using presto-blue assay. Cellular reactive oxygen species were measured by flow cytometry. Immunoblot analysis was carried out to investigate changes in levels of cleaved PARP, XIAP, bcl-2, bcl-xL, p21 and p27. Luminescent and colorimetric assays were used to test caspases 3/7 and ATX activity. RESULTS: The efficacy of the BT-cisplatin combination depends upon the cell type and concentrations of cisplatin and BT. In cisplatin-sensitive cell lines, BT and cisplatin were mostly antagonistic except when used at low concentrations, where synergy was observed. In contrast, in cisplatin-resistant cells, BT-cisplatin combination treatment displayed synergistic effects at most of the drug ratios/concentrations. Our results further revealed that the synergistic interaction was linked to increased reactive oxygen species generation and apoptosis. Enhanced apoptosis was correlated with loss of pro survival factors (XIAP, bcl-2, bcl-xL), expression of pro-apoptotic markers (caspases 3/7, PARP cleavage) and enhanced cell cycle regulators p21 and p27. CONCLUSION: In cisplatin-resistant cell lines, BT potentiated cisplatin-induced cytotoxicity at most drug ratios via enhanced ROS generation and modulation of key regulators of apoptosis. Low doses of BT and cisplatin enhanced efficiency of cisplatin treatment in all the ovarian cancer cell lines tested. Our results suggest that novel combinations such as BT and cisplatin might be an attractive therapeutic approach to enhance ovarian cancer chemosensitivity. Combining low doses of cisplatin with subtherapeutic doses of BT can ultimately lead to the development of an innovative combination therapy to reduce/prevent the side effects normally occurring when high doses of cisplatin are administered. PMID- 28086832 TI - Norcantharidin Inhibits cell growth by suppressing the expression and phosphorylation of both EGFR and c-Met in human colon cancer cells. AB - BACKGROUND: Norcantharidin (NCTD) is a Chinese FDA approved, chemically synthesized drug for cancer treatment. The effect of NCTD on signaling proteins of EGFR and c-Met was systematically elucidated in current study. METHODS: Two human colon cancer cell lines, HCT116 and HT29, were used as model systems to investigate the anti-cancer molecular mechanism of NCTD. Cell cycle arrest and early/late apoptosis were analyzed by flow cytometry. The levels of EGFR, phospho EGFR, c-Met, phospho-c-Met and other related proteins were quantified by western blot analysis. RESULTS: NCTD induced cell cycle arrest at G2/M phase in both cell lines. The early and late apoptosis was also observed. Further investigation indicated that NCTD suppressed not only the expression of the total EGFR and the phosphorylated EGFR but also the expression of the total c-Met and the phosphorylated c-Met in colon cancer cells. Moreover, EGFR expression could be mostly restored by co-treatment with MG132, a proteasome inhibitor. In addition, NCTD-induced cell death was comparable to that of the anti-cancer drug gefitinib, a tyrosine kinase inhibitor for EGFR, based on the immunoblot analysis of the expressed proteins after the drug treatment. CONCLUSIONS: NCTD might be a useful and inexpensive drug candidate to substitute for gefitinib to serve the treatment needs of cancer patients. PMID- 28086833 TI - Delta-like 4/Notch signaling promotes Apc Min/+ tumor initiation through angiogenic and non-angiogenic related mechanisms. AB - BACKGROUND: Delta like 4 (Dll4)/Notch signaling is a key regulator of tumor angiogenesis. Additionally, the role of Dll4 has been studied on tumor stem cells. However, as these cells are implicated in tumor angiogenesis, it is conceivable that the effect of Dll4 on these cells may be a consequence of its angiogenic function. Our aim was to evaluate the expression and dissect the functions of Dll4 in the Apc Min/+ model of colorectal cancer. METHODS: We evaluated the protein expression pattern of Dll4 and other Notch members in the Apc Min/+ tumors relatively to the normal gut and compared endothelial-specific with ubiquitous Dll4 knockout mice on an Apc Min/+ background. RESULTS: All Notch pathway members were present in the normal small and large intestine and in the adenomas of the same regions. Dll4, all Notch receptors and Hes1 expression seemed upregulated in the tumors, with some regional differences. The same members and Hes5, instead of Hes1, presented ectopic expression in the tumor parenchyma. Dll4 expression was most pronounced in the tumor cells but it was also present in the tumor blood vessels and in other stromal cells. Ubiquitous and endothelial-specific Dll4 deletion led to an equivalent reduction of tumor growth because of a similarly marked tumoral angiogenic phenotype promoting non productive vasculature and consequently hypoxia and apoptosis. The ubiquitous Dll4 inhibition led to a stronger decrease of tumor multiplicity than the endothelial-specific deletion by further reducing tumor proliferation and tumor stem cell density through upregulation of the cyclin-dependent kinase inhibitors 1C and 1B and downregulation of Myc, Cyclin D1 and D2 independently of beta catenin activation. This phenotype was associated to the observed increased epithelial differentiation deviated towards the secretory lineages by Atoh1 and Klf4 upregulation only in the ubiquitous Dll4 mutants. CONCLUSIONS: Dll4 seems to promote Apc Min/+ tumorigenesis through both angiogenic and non-angiogenic related mechanisms. PMID- 28086834 TI - Detection of circulating tumor cells with CK20 RT-PCR is an independent negative prognostic marker in colon cancer patients - a prospective study. AB - BACKGROUND: Detection of circulating (CTC) or disseminated tumor cells (DTC) has been associated with negative prognosis and outcome in patients with colorectal cancer, though testing for these cells is not yet part of clinical routine. There are several different methodological approaches to detect tumor cells but standardized detection assays are not implemented so far. METHODS: In this prospective monocentric study 299 patients with colon cancer were included. CTC and DTC were detected using CK20 RT-PCR as well as immunocytochemistry staining with anti-pan-keratin and anti-EpCAM antibodies. The primary endpoints were: Evaluation of CTC and DTC at the time of surgery and correlation with main tumor characteristics and overall (OS) and disease free survival (DFS). RESULTS: Patients with detectable CTC had a 5-year OS rate of 68% compared to a 5-year OS rate of 85% in patients without detectable CTC in the blood (p = 0.002). Detection of DTC in the bone marrow with CK20 RT-PCR was not associated with a worse OS or DFS. Detection of pan-cytokeratin positive DTC in the bone marrow correlated with a significantly reduced 5-year OS rate (p = 0.048), but detection of DTC in the bone marrow with the anti-EpCAM antibody did not significantly influence the 5-year OS rate (p = 0.958). By multivariate analyses only detection of CTC with CK20 RT-PCR in the blood was revealed to be an independent predictor of worse OS (HR1.94; 95% CI 1.0-3.7; p = 0.04) and DFS (HR 1.94; 95% CI 1.1-3.7; p = 0.044). CONCLUSIONS: Detection of CTC with CK20 RT-PCR is a highly specific and independent prognostic marker in colon cancer patients. Detection of DTC in the bone marrow with CK20 RT-PCR or immunohistochemistry with anti-EpCAM antibody is not associated with a negative prognostic influence. PMID- 28086835 TI - Stunting and severe stunting among children under-5 years in Nigeria: A multilevel analysis. AB - BACKGROUND: Stunting has been identified as one of the major proximal risk factors for poor physical and mental development of children under-5 years. Stunting predominantly occurs in the first 1000 days of life (0-23 months) and continues to the age of five. This study examines factors associated with stunting and severe stunting among children under-5 years in Nigeria. METHODS: The sample included 24,529 children aged 0-59 months from the 2013 Nigeria Demographic and Health Survey (NDHS). Height-for-age z-scores (HFAz), generated using the 2006 World Health Organisation (WHO) growth reference, were used to define stunting (HFAz < -2SD) and severe stunting (HFAz < -3SD). Multilevel logistic regression analyses that adjusted for cluster and survey weights were used to determine potential risk factors associated with stunting and severe stunting among children under-5 years in Nigeria. RESULTS: The prevalence of stunting and severe stunting were 29% [95% Confidence interval (Cl): 27.4, 30.8] and 16.4% [95%Cl: 15.1, 17.8], respectively for children aged 0-23 months, and 36.7% [95%Cl: 35.1, 38.3] and 21% [95%Cl: 19.7, 22.4], respectively for children aged 0-59 months. Multivariate analysis revealed that the most consistent significant risk factors for stunting and severe stunting among children aged 0 23 months and 0-59 months are: sex of child (male), mother's perceived birth size (small and average), household wealth index (poor and poorest households), duration of breastfeeding (more than 12 months), geopolitical zone (North East, North West, North Central) and children who were reported to having had diarrhoea in the 2 weeks prior to the survey [Adjusted odds ratio (AOR) for stunted children 0-23 months = 1.22 (95%Cl: 0.99, 1.49)];[AOR for stunted children 0-59 months = 1.31 (95%Cl: 1.16, 1.49)], [AOR for severely stunted children 0-23 months = 1.31 (95%Cl: 1.03, 1.67)]; [AOR for severely stunted children 0-59 months = 1.58 (95%Cl: 1.38, 1.82)]. CONCLUSIONS: In order to meet the post-2015 sustainable development goals, policy interventions to reduce stunting in Nigeria should focus on poverty alleviation as well as improving women's nutrition, child feeding practices and household sanitation. PMID- 28086836 TI - An internet-based self-help intervention for older adults after marital bereavement, separation or divorce: study protocol for a randomized controlled trial. AB - BACKGROUND: Marital bereavement and separation or divorce are among the most stressful critical life events in later life. These events require a dissolution of social and emotional ties, adjustments in daily routine and changes in identity and perspectives for the future. After a normative grief or distress reaction, most individuals cope well with the loss. However, some develop a prolonged grief reaction. Internet-based self-help interventions have proved beneficial for a broad range of disorders, including complicated grief. Based on the task model and the dual-process model of coping with bereavement, we developed a guided internet-based self-help intervention for individuals who experienced marital bereavement, separation or divorce at least 6 months prior to enrolment. The intervention consists of 10 text-based self-help sessions and one supportive email a week. The primary purpose of this study is the evaluation of the feasibility and efficacy of the intervention compared with a waiting control group. The secondary purpose is to compare the effects in bereaved and separated participants. Furthermore, we aim to analyze other predictors, moderators and mediators of the outcome, such as age, psychological distress and intensity of use of the intervention. METHODS: The design is a randomized controlled trial with a waiting control condition of 12 weeks and a 24-weeks follow-up. At least 72 widowed or separated participants will be recruited via our study website and internet forums. Primary outcomes are reductions in grief symptoms, depression and psychological distress. Secondary outcome measures are related to loneliness, satisfaction with life, embitterment and the sessions. DISCUSSION: The trial will provide insights into the acceptance and efficacy of internet-based interventions among adults experiencing grief symptoms, psychological distress and adaptation problems in daily life after spousal bereavement, separation or divorce. Findings will add to existing knowledge by (1) evaluating an internet-based intervention specifically designed for spousal bereavement and its consequences; (2) testing whether this intervention is equally effective for individuals after separation or divorce; and (3) suggesting adaptations to improve the efficacy of the intervention, selective indication and adaptations for different needs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02900534 . Registered on 1 September 2016. PMID- 28086837 TI - Systemic and individual factors in the buprenorphine treatment-seeking process: a qualitative study. AB - BACKGROUND: Opioid use is a significant problem in Alaska. Medication-assisted treatment for opioid use, including buprenorphine, reduces withdrawal symptoms and the harm associated with opioid abuse. Understanding consumers' treatment seeking process is important for addressing barriers to treatment, facilitating effective service utilization, and informing policy. METHODS: To understand treatment-seeking behavior, we examined the attitudes, perceptions, and knowledge of those who would benefit from the medication-assisted treatment (MAT) buprenorphine. Qualitative data from 2 focus groups (each including 4 participants) and 3 in-depth interviews with people who have used or considered using buprenorphine in treatment for an opioid use disorder were analyzed using grounded theory and directed content analysis approaches. RESULTS: Key findings suggest that individual (withdrawal process, individual motivation) and systemic (sociocultural, political, societal values) factors frame the treatment seeking process. Participants' progress on the treatment-seeking road was affected by models of addiction and MAT, which related to facilitators and barriers encountered in seeking treatment (e.g. support, resources, treatment structure). These factors shaped the longer-term road to recovery, which was seen as on ongoing process. CONCLUSIONS: The findings of this study suggest it is crucial for interventionists to take a contextual approach that considers individual and systemic factors involved in opioid addiction, treatment, and recovery. This study highlights ways policy makers and treatment providers can address the barriers consumers face in their treatment-seeking process in order to increase treatment access. PMID- 28086838 TI - Clinical characteristics of genital chlamydia infection in pelvic inflammatory disease. AB - BACKGROUND: Chlamydia infection in acute pelvic inflammatory disease (PID) is associated with serious complications including ectopic pregnancy, tubal infertility, Fitz-Hugh-Curtis syndrome and tubo-ovarian abscess (TOA). This study compared clinical and laboratory data between PID with and without chlamydia infection. METHODS: The medical records of 497 women who were admitted with PID between 2002 and 2011 were reviewed. The patients were divided into two groups (PID with and without chlamydia infection), which were compared in terms of the patients' characteristics, clinical presentation, and laboratory findings, including inflammatory markers. RESULTS: The chlamydia and non-chlamydia groups comprised 175 and 322 women, respectively. The patients in the chlamydia group were younger and had a higher rate of TOA, a longer mean hospital stay, and had undergone more surgeries than the patients in the non- chlamydia group. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and CA-125 level were higher in the chlamydia group than in the non-chlamydia group, but there was no significant difference in the white blood cell count between the two groups. The CA-125 level was the strongest predictor of chlamydia infection, followed by the ESR and CRP level. The area under the receiving operating curve for CA-125, ESR, and CRP was 0.804, 0.755, and 0.663, respectively. CONCLUSIONS: Chlamydia infection in acute PID is associated with increased level of inflammatory markers, such as CA-125, ESR and CRP, incidence of TOA, operation risk, and longer hospitalization. PMID- 28086839 TI - Ethnobotanical knowledge acquisition during daily chores: the firewood collection of pastoral Maasai girls in Southern Kenya. AB - BACKGROUND: Researchers considering children's traditional ecological knowledge (TEK) highlighted the importance of examining children's daily activities as empirical contexts for its acquisition. Many of them evaluated children's TEK acquisition linearly as gain or loss, and paid less attention to the adaptive nature of this knowledge system and the social relationships arising from its acquisition processes. This study approaches children's TEK acquisition considering these abovementioned aspects. I utilize pastoral Maasai girls' firewood collection as a case study, and analyze the personal, interpersonal and cultural institutional aspects of girls' Ethnobotanical knowledge (EK) acquisition within this chore. METHODS: Participant observation and unstructured interviews were used for data collection. I joined 12 girls (6 to 15 years old) on day trips for firewood collection, and documented their participation and performance during this chore. I observed interactions among girls and between girls and women concerning this activity, and investigated girls' perceptions of local wood species via their descriptions. I also informally interviewed 15 women, between 20 and 80 years old on their evaluation of the wood species to be used as firewood. RESULTS: Current diet change and gender-age roles in chore participation in Maasai society require females to continually participate in firewood collection. Within this social context, girls intensively participated in day trips of firewood collection during the long-term vacation in the dry season. They collected a sizable amount from 24 plant species, and generated EK through personal sensual experiences, such as fragrance, hardness, and heaviness of different wood species. They acquired local taxonomy and terminology of different wood species, and learned others preferences for wood species used as fuel through interpersonal communication. These personal and interpersonal aspects, together with current diet change and division of labor within gender age roles in Maasai society, provide EK with multi-dimensional meanings in current subsistence strategies. CONCLUSIONS: Results of this study show that girls acquired EK with multi-dimensional meanings through daily firewood collection, which cannot be only evaluated in a linear manner. Future studies focused on children's TEK acquisition should consider the personal, interpersonal, and cultural institutional aspects of this adaptive knowledge system and children's roles within it. PMID- 28086840 TI - Evidence of multiple insecticide resistance mechanisms in Anopheles gambiae populations in Bangui, Central African Republic. AB - BACKGROUND: Knowledge of insecticide resistance status in the main malaria vectors is an essential component of effective malaria vector control. This study presents the first evaluation of the status of insecticide resistance in Anopheles gambiae populations from Bangui, the Central African Republic. METHODS: Anopheles mosquitoes were reared from larvae collected in seven districts of Bangui between September to November 2014. The World Health Organisation's bioassay susceptibility tests to lambda-cyhalothrin (0.05%), deltamethrin (0.05%), DDT (4%), malathion (5%), fenitrothion (1%) and bendiocarb (0.1%) were performed on adult females. Species and molecular forms as well as the presence of L1014F kdr and Ace-1 R mutations were assessed by PCR. Additional tests were conducted to assess metabolic resistance status. RESULTS: After 1 h exposure, a significant difference of knockdown effect was observed between districts in all insecticides tested except deltamethrin and malathion. The mortality rate (MR) of pyrethroids group ranging from 27% (CI: 19-37.5) in Petevo to 86% (CI: 77.6-92.1) in Gbanikola; while for DDT, MR ranged from 5% (CI: 1.6-11.3) in Centre-ville to 39% (CI: 29.4-49.3) in Ouango. For the organophosphate group a MR of 100% was observed in all districts except Gbanikola where a MR of 96% (CI: 90-98.9) was recorded. The mortality induced by bendiocarb was very heterogeneous, ranging from 75% (CI: 62.8-82.8) in Yapele to 99% (CI: 84.5-100) in Centre-ville. A high level of kdr-w (L1014F) frequency was observed in all districts ranging from 93 to 100%; however, no kdr-e (L1014S) and Ace-1 R mutation were found in all tested mosquitoes. Data of biochemical analysis showed significant overexpression activities of cytochrome P450, GST and esterases in Gbanikola and Yapele (chi 2 = 31.85, df = 2, P < 0.001). By contrast, esterases activities using alpha and beta naphthyl acetate were significantly low in mosquitoes from PK10 and Ouango in comparison to Kisumu strain (chi 2 = 17.34, df = 2, P < 0.005). CONCLUSIONS: Evidence of resistance to DDT and pyrethroids as well as precocious emergence of resistance to carbamates were detected among A. gambiae mosquitoes from Bangui, including target-site mutations and metabolic mechanisms. The co-existence of these resistance mechanisms in A. gambiae may be a serious obstacle for the future success of malaria control programmes in this region. PMID- 28086841 TI - Good outcome following liver transplantation using pericardial-peritoneum window for hepato-atrial anastomosis to overcome advanced hepatic alveolar echinococcosis and secondary Budd-Chiari Syndrome - a case report. AB - BACKGROUND: This report presents a case of a 57- year old female with advanced Hepatic Alveolar Echinococcosis causing a secondary Budd-Chiari Syndrome due to infiltration of the suprahepatic inferior vena cava treated successfully by liver transplantation. CASE PRESENTATION: A temporary veno-venous bypass was introduced, but a typical end to end cavo-caval anastomosis wasn't possible in this case. In order to access a disease free part of the inferior vena cava, an oval window of the diaphragm was excised, providing communication between the peritoneum and pericardium. A vascular clamp was placed onto the right atrium which allowed for an atrial-caval anastomosis. The remainder of hepatectomy was performed in a conventional manner. In the post-operative period and during the 18 month follow-up there were no complications. The patient remains in good general condition with optimal graft function. CONCLUSIONS: A hepato-atrial anastomosis with a pericardial-peritoneum window during liver transplantation is feasible and extends the curability potential for patients with advanced Hepatic Alveolar Echinococcosis considered for liver transplantation. PMID- 28086843 TI - Evaluation of the Good Start Program: a healthy eating and physical activity intervention for Maori and Pacific Islander children living in Queensland, Australia. AB - BACKGROUND: Reducing the prevalence of obesity and chronic disease are important priorities. Maori and Pacific Islander communities living in Australia have higher rates of obesity and chronic disease than the wider Australian population. This study aims to assess the effectiveness of the Good Start program, which aims to improve knowledge, attitudes and practices related to healthy eating and physical activity amongst Maori and Pacific Islander communities living in Queensland. METHODS: The intervention was delivered to children aged 6-19 years (N = 375) in schools by multicultural health workers. Class activities focused on one message each term related to healthy eating and physical activity using methods such as cooking sessions and cultural dance. The evaluation approach was a quantitative uncontrolled pre-post design. Data were collected each term pre- and post-intervention using a short questionnaire. RESULTS: There were significant increases in knowledge of correct servings of fruit and vegetables, knowledge of sugar and caffeine content of common sugar-sweetened drinks, recognition of the consequences of marketing and upsizing, and the importance of controlling portion size (all P < 0.05). There was also increases in knowledge of physical activity recommendations (P < 0.001), as well as the importance of physical activity for preventing heart disease (P < 0.001) and improving self esteem (P < 0.001). In terms of attitudes, there were significant improvements in some attitudes to vegetables (P = 0.02), and sugar-sweetened drinks (P < 0.05). In terms of practices and behaviours, although the reported intake of vegetables increased significantly (P < 0.001), the proportion of children eating discretionary foods regularly did not change significantly, suggesting that modifying the program with an increased emphasis on reducing intake of junk food may be beneficial. CONCLUSION: The study has shown that the Good Start Program was effective in engaging children from Maori and Pacific Island backgrounds and in improving knowledge, and some attitudes and practices, related to healthy eating and physical activity. The evaluation contributes valuable information about components and impacts of this type of intervention, and considerations relevant to this population in order to successfully change behaviours and reduce the burden of chronic disease. PMID- 28086842 TI - Socioeconomic inequality of overweight and obesity of the elderly in Iran: Bushehr Elderly Health (BEH) Program. AB - BACKGROUND: The objective of this population-based, large sample size study was to investigate the socioeconomic inequality of overweight and obesity among the elderly in Iran. METHODS: Baseline data of 3000 persons aged >=60 years who participated in the Bushehr Elderly Health (BEH) program was analyzed. Overweight and obesity were defined as a body mass index (BMI) equal to or higher than 25 and 30, respectively. Socioeconomic status (SES) was measured by an asset index, constructed using principal component analysis, income, education level, and employment status. The Concentration Index and the Lorenz curve were used to illustrate the levels of inequality for overweight and obesity by gender. RESULTS: The frequencies among men and women were, respectively, 840 (57.7%) and 1131 (73.2%), P < 0.001, for overweight, and 211 (14.7%) and 511 (33.7%), P < 0.001, for obesity. There were direct associations between asset index quintiles and both overweight and obesity among both genders (Ps for trend <0.01) except for obesity among men (P for trend = 0.118). The overall Concentration Indices for overweight and obesity were 0.031 (95%CI = 0.016-0.046, P < 0.001) and 0.041 (95%CI = 0.004-0.078, p = 0.028), respectively. CONCLUSION: Findings support the direct relationship between SES and obesity among women as previously reported in developing countries. PMID- 28086844 TI - Are risk predicting models useful for estimating survival of patients with rheumatoid arthritis-associated interstitial lung disease? AB - BACKGROUND: Risk predicting models have been applied in idiopathic pulmonary fibrosis (IPF), but still not validated in patients with rheumatoid arthritis associated interstitial lung disease (RA-ILD). The purpose of this study was to test the suitability of three prediction models as well as individual lung function and demographic factors for evaluating the prognosis of RA-ILD patients. METHODS: Clinical and radiological data of 59 RA-ILD patients was re-assessed. GAP (gender, age, physiologic variables) and the modified interstitial lung disease (ILD)-GAP as well as the composite physiologic indexes (CPI) were tested for predicting mortality using the goodness-of-fit test and Cox model. Potential predictors of mortality were also sought from single lung function parameters and clinical characteristics. RESULTS: The median survival was 152 and 61 months in GAP / ILD-GAP stages I and II (p = 0.017). Both GAP and ILD-GAP models accurately estimated 1-year, 2-year and 3-year mortality. CPI (p = 0.025), GAP (p = 0.008) and ILD-GAP (p = 0.028) scores, age (p = 0.002), baseline diffusion capacity to carbon monoxide (DLCO) (p = 0.014) and hospitalization due to respiratory reasons (p = 0.039), were significant predictors of mortality in the univariate analysis, whereas forced vital capacity (FVC) was not predictive. CPI score (HR 1.03, p = 0.018) and baseline DLCO (HR 0.97, p = 0.011) remained significant predictors of mortality after adjusting for age. CONCLUSIONS: GAP and ILD-GAP are applicable for evaluating the risk of death of patients with RA-ILD in a similar manner as in those with IPF. Baseline DLCO and CPI score also predicted survival. PMID- 28086846 TI - Stochastic agent-based modeling of tuberculosis in Canadian Indigenous communities. AB - BACKGROUND: In Canada, active tuberculosis (TB) disease rates remain disproportionately higher among the Indigenous population, especially among the Inuit in the north. We used mathematical modeling to evaluate how interventions might enhance existing TB control efforts in a region of Nunavut. METHODS: We developed a stochastic, agent-based model of TB transmission that captured the unique household and community structure. Evaluated interventions included: (i) rapid treatment of active cases; (ii) rapid contact tracing; (iii) expanded screening programs for latent TB infection (LTBI); and (iv) reduced household density. The outcomes of interest were incident TB infections and total diagnosed active TB disease over a 10- year time period. RESULTS: Model-projected incidence in the absence of additional interventions was highly variable (range: 33-369 cases) over 10 years. Compared to the 'no additional intervention' scenario, reducing the time between onset of active TB disease and initiation of treatment reduced both the number of new TB infections (47% reduction, relative risk of TB = 0.53) and diagnoses of active TB disease (19% reduction, relative risk of TB = 0.81). Expanding general population screening was also projected to reduce the burden of TB, although these findings were sensitive to assumptions around the relative amount of transmission occurring outside of households. Other potential interventions examined in the model (school-based screening, rapid contact tracing, and reduced household density) were found to have limited effectiveness. CONCLUSIONS: In a region of northern Canada experiencing a significant TB burden, more rapid treatment initiation in active TB cases was the most impactful intervention evaluated. Mathematical modeling can provide guidance for allocation of limited resources in a way that minimizes disease transmission and protects population health. PMID- 28086845 TI - The social determinants of tuberculosis treatment adherence in a remote region of Papua New Guinea. AB - BACKGROUND: Papua New Guinea (PNG) is a diverse and culturally-rich country with severe infrastructural and health problems. Tuberculosis (TB) is widespread, and the number of cases with drug resistance is rising. Treatment adherence is known to be important for both effective treatment and limiting the emergence of drug resistance. The aim of this study was to construct a matrix of the factors that act as facilitators or barriers to TB treatment adherence in a remote region of PNG. METHODS: The study was based in the Balimo region of the Western Province. People known to have undergone TB treatment, as well as staff involved in managing people with TB, were asked to participate in an in-depth interview about their experiences. Purposive sampling was used to identify a diverse range of participants, from different geographic locations, social backgrounds, and with successful and unsuccessful treatment outcomes. The interview data was analysed based on grounded theory methodology. RESULTS: The study identified a range of factors that influence TB treatment adherence, with these being classified as personal, systems, and sociocultural. These factors are presented along with suggested recommendations for adaptations to DOTS-based treatment in this region. Barriers included the challenges associated with travel to treatment sites, and the difficulties of undertaking treatment alongside the daily need to maintain subsistence food production. However, facilitators were also identified, including the positive influence of religious beliefs, and high confidence in the ability of DOTS-based treatment to cure TB. CONCLUSIONS: Documenting the wide range of factors that influence treatment adherence in a severely affected remote population will assist in improving TB control. These results provide impetus for further community-based efforts aimed at improving access to TB diagnosis and treatment, and maintaining successful treatment outcomes in the face of emerging drug resistance. PMID- 28086847 TI - Cardiac sarcoidosis resembling panic disorder: a case report. AB - BACKGROUND: Sarcoidosis is a systemic disease of unknown etiology, in which granulomas develop in various organs, including the skin, lungs, eyes, or heart. It has been reported that patients with sarcoidosis are more likely to develop panic disorder than members of the general population. However, there are many unknown factors concerning the causal relationship between these conditions. CASE PRESENTATION: We present the case of a 57-year-old woman who appeared to have panic disorder, as she experienced repeated panic attacks induced by transient complete atrioventricular block, associated with cardiac sarcoidosis. Psychotherapy and pharmacotherapy were not effective in the treatment of her panic attacks. However, when we implanted a permanent pacemaker and initiated steroid treatment for cardiac sarcoidosis, panic attacks were ameliorated. Based on these findings, we diagnosed the patient's symptoms as an anxiety disorder associated with cardiac sarcoidosis, rather than panic disorder. CONCLUSIONS: This report highlights the importance of considering cardiac sarcoidosis in the differential diagnosis of panic disorder. This cardiac disease should be considered especially in patients have a history of cardiac disease (e.g., arrhythmia) and atypical presentations of panic symptoms. Panic disorder is a psychiatric condition that is typically diagnosed after other medical conditions have been excluded. Because the diagnosis of sarcoidosis is difficult in some patients, caution is required. The palpitations and symptoms of heart failure associated with cardiac sarcoidosis can be misdiagnosed as psychiatric symptoms of panic disorder. The condition described in the current case study appears to constitute a physical disease, the diagnosis of which requires significant consideration and caution. PMID- 28086848 TI - Using Intervention Mapping to develop the Parents as Agents of Change (PAC(c)) intervention for managing pediatric obesity. AB - BACKGROUND: Pediatric obesity has become increasingly prevalent over recent decades. In view of the psychosocial and physical health risks, and the high likelihood that children with obesity will grow to become adults with obesity, there is a clear need to develop evidence-based interventions that can be delivered in the health care system to optimize the health and well-being of children with obesity and their families. The aim of this paper is to describe the development, implementation, and planned evaluation of a parent-based weight management intervention designed for parents of 8-12 year olds with obesity. METHODS/RESULTS: The principles of Intervention Mapping (IM) were used to develop an intervention called Parents as Agents of Change (PAC(c)). From 2006 to 2009, an environmental scan plus qualitative (individual interviews with parents and children), quantitative (medical record reviews), and literature review data were collected to gain broad insight into family factors related to pediatric obesity and its management. Theoretical frameworks and empirical evidence guided curriculum development, which was founded primarily on the tenets of family systems theory and cognitive behavioral theory. PAC was developed as a manualized, 16-session, group-based, health care professional-led intervention for parents to address individual, family, and environmental factors related to the management of pediatric obesity. The intervention was refined based on feedback from local and international experts, and has been implemented successfully in a multi-disciplinary weight management centre in a children's hospital. CONCLUSION: IM provided a practical framework to guide the systematic development of a pediatric weight management intervention for parents of children with obesity. This logical, step-by-step process blends theory and practice and is broadly applicable in the context of obesity management intervention development and evaluation. Following intervention development, the PAC intervention was evaluated within a randomized clinical trial. Trial registration NCT01267097; clinicaltrials.gov. PMID- 28086849 TI - Successful outcome following pneumonectomy in a teenage boy with cystic fibrosis: a case report. AB - BACKGROUND: Cystic fibrosis lung disease is generally a diffuse process however rarely one lung may become particularly damaged through chronic collapse and consolidation resulting in end-stage bronchiectasis with relative sparing of the contralateral lung. This clinical situation is sometimes referred to as "destroyed lung". Lung resection surgery is seldom indicated in cystic fibrosis and the associated medical literature is relatively sparse. CASE PRESENTATION: A 14 year old boy was referred to our centre for lung transplantation assessment. He had a chronic history of complete collapse and consolidation of his entire right lung. This was causing severe morbidity in terms of a continuous requirement for intravenous antibiotics over the last year, poor exercise tolerance with forced expiratory volume in 1 s of 35-40% predicted and need for home tuition. He also had significant nutritional problems and gastrointestinal symptoms following a Nissen's fundoplication operation a year earlier. His nutritional status was firstly improved by the institution of jejunal feeding, which also greatly improved his distressing symptoms of nausea and wretching. After thorough multidisciplinary assessment the therapeutic option of performing a right pneumonectomy was considered due to relative sparing of the left lung, which demonstrated only mild bronchiectasis on computed tomography scan. This was performed uneventfully with a smooth peri-operative course. Targeted antimicrobials were used to treat the multiresistant organisms colonising his airways. Subsequently his quality of life, nutritional status and lung function all improved significantly and requirement for lung transplantation has been delayed. CONCLUSIONS: We report a successful outcome following pneumonectomy in a teenage boy with cystic fibrosis referred to our centre for lung transplantation assessment with chronic unilateral collapse and consolidation of his right lung. We believe that improvement of nutritional status pre-operatively and targeted antimicrobial therapy, all contributed to the smooth peri-operative course. Pneumonectomy can be a feasible option in this clinical situation in cystic fibrosis but the associated risks must be considered carefully on a case-by-case basis. PMID- 28086850 TI - The prevalence trend of metabolic syndrome and its components and risk factors in Korean adults: results from the Korean National Health and Nutrition Examination Survey 2008-2013. AB - BACKGROUND: Abnormalities in the clinical markers of metabolic syndrome (MS) are associated with the development of cardiovascular disease, type 2 diabetes mellitus, and some cancers. MS prevalence in Korea increased between the mid 1990s and mid-2000s; however, no data on the recent trends of MS prevalence are available. Thus, we aimed to investigate the prevalence of MS, the five components of MS, and the related risk factors in Korean adults by using recent data. METHODS: Data from the Korean National Health and Nutrition Examination Survey conducted between 2008 and 2013 were used. The revised National Cholesterol Education Program criteria were used for defining MS. A multivariate logistic regression analyses was used to estimate the relationship between the related risk factors including behaviors, dietary factors, and the prevalence of MS. RESULTS: A total of 34,587 men and women were included in the analysis. Age adjusted prevalence of MS in 2013 was 28.9% without a significant increasing or decreasing trend between 2008 and 2013. Among the five components of MS, abdominal obesity decreased in both men and women (annual percent change: -2.0 and -2.5%, respectively), the decrease being significant only in women, whereas blood pressure and blood glucose significantly increased in men (+1.9 and +2.7%, respectively). Age and obesity (odds ratio = 6.7, 95% confidence interval = 5.9 7.5 for body mass index >=25 kg/m2 vs. body mass index <25 kg/m2) were associated with increased MS risk in both men and women. Smoking and alcohol drinking were significantly associated with increased MS risk in men, and association between MS and vitamin D deficiency was at the edge of statistical significance. Higher education and income level were significantly associated with decreased MS risk in women. During this period, smoking rate and physical activity, sodium intake, and serum vitamin D level significantly decreased. Education level, calorie intake, and intake of carbohydrate, fat, protein and calcium significantly increased. CONCLUSION: Several factors contribute to the stable MS prevalence-on the one hand, increased prevalence of high blood sugar, high blood pressure, calorie intake, and physical inactivity, and on the other hand, decreased prevalence of abdominal obesity and smoking. Lifestyle interventions to prevent and control non-communicable diseases should be implemented at the national level to reduce the burden of MS. PMID- 28086851 TI - Efficacy of intermittent Theta Burst Stimulation (iTBS) and 10-Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant unipolar depression: study protocol for a randomised controlled trial. AB - BACKGROUND: The treatment of depression remains a challenge since at least 40% of patients do not respond to initial antidepressant therapy and 20% present chronic symptoms (more than 2 years despite standard treatment administered correctly). Repetitive transcranial magnetic stimulation (rTMS) is an effective adjuvant therapy but still not ideal. Intermittent Theta Burst Stimulation (iTBS), which has only been used recently in clinical practice, could have a faster and more intense effect compared to conventional protocols, including 10-Hz high-frequency rTMS (HF-rTMS). However, no controlled study has so far highlighted the superiority of iTBS in resistant unipolar depression. METHODS/DESIGN: This paper focuses on the design of a randomised, controlled, double-blind, single-centre study with two parallel arms, carried out in France, in an attempt to assess the efficacy of an iTBS protocol versus a standard HF- rTMS protocol. Sixty patients aged between 18 and 75 years of age will be enrolled. They must be diagnosed with major depressive disorder persisting despite treatment with two antidepressants at an effective dose over a period of 6 weeks during the current episode. The study will consist of two phases: a treatment phase comprising 20 sessions of rTMS to the left dorsolateral prefrontal cortex, localised via a neuronavigation system and a 6-month longitudinal follow-up. The primary endpoint will be the number of responders per group, defined by a decrease of at least 50% in the initial score on the Montgomery and Asberg Rating Scale (MADRS) at the end of rTMS sessions. The secondary endpoints will be: response rate 1 month after rTMS sessions; number of remissions defined by a MADRS score of <8 at the endpoint and 1 month after; the number of responses and remissions maintained over the next 6 months; quality of life; and the presence of predictive markers of the therapeutic response: clinical (dimensional scales), neuropsychological (evaluation of cognitive functions), motor (objective motor testing) and neurophysiological (cortical excitability measurements). DISCUSSION: The purpose of our study is to check the assumption of iTBS superiority in the management of unipolar depression and we will discuss its effect over time. In case of a significant increase in the number of therapeutic responses with a prolonged effect, the iTBS protocol could be considered a first-line protocol in resistant unipolar depression. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier NCT02376491 . Registered on 17 February 2015 at http://clinicaltrials.gov . PMID- 28086852 TI - PD-L1 expression in papillary renal cell carcinoma. AB - BACKGROUND: The immune escape or tolerance of cancer cells is considered to be closely involved in cancer progression. Programmed death-1 (PD-1) is an inhibitory receptor expressed on activating T cells, and several types of cancer cells were found to express PD-1 ligand 1 (PD-L1) and ligand 2 (PD-L2). METHODS: In the present study, we investigated PD-L1/2 expression in papillary renal cell carcinoma (pRCC). RESULT: We found PD-L1 expression in 29 of 102 cases, but no PD L2 expression was seen. PD-L1 expression was not significantly correlated with any clinicopathological factor, including progression-free survival and overall survival. The frequency of PD-L1-positive cases was higher in type 2 (36%) than in type 1 (22%) pRCC; however, there was no significant difference in the percentages of score 0 cases (p value = 0.084 in Chi-square test). The frequency of high PD-L1 expression cases was higher in type 2 (23%) than in type 1 (11%), and the frequency of high PD-L1 expression cases was higher in grade 3/4 (21%) than in grade 1/2 (13%). However, no significant association was found between PD L1 expression and all clinicopathological factors in pRCC. CONCLUSION: High expression of PD-L1 in cancer cells was potentially associated to highly histological grade of malignancy in pRCC. The evaluation of the PD-L1 protein might still be useful for predicting the efficacy of anti-cancer immunotherapy using immuno-checkpoint inhibitors, however, not be useful for predicting the clinical prognosis. PMID- 28086853 TI - Taking ACTION to reduce pain: ACTION study rationale, design and protocol of a randomized trial of a proactive telephone-based coaching intervention for chronic musculoskeletal pain among African Americans. AB - BACKGROUND: Rates of chronic pain are rising sharply in the United States and worldwide. Presently, there is evidence of racial disparities in pain treatment and treatment outcomes in the United States but few interventions designed to address these disparities. There is growing consensus that chronic musculoskeletal pain is best addressed by a biopsychosocial approach that acknowledges the role of psychological and environmental factors, some of which differ by race. METHODS/DESIGN: The primary aim of this randomized controlled trial is to test the effectiveness of a non-pharmacological, self-regulatory intervention, administered proactively by telephone, at improving pain outcomes and increasing walking among African American patients with hip, back and knee pain. Participants assigned to the intervention will receive a telephone counselor delivered pedometer-mediated walking intervention that incorporates action planning and motivational interviewing. The intervention will consist of 6 telephone counseling sessions over an 8-10 week period. Participants randomly assigned to Usual Care will receive an informational brochure and a pedometer. The primary outcome is chronic pain-related physical functioning, assessed at 6 months, by the revised Roland and Morris Disability Questionnaire, a measure recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT). We will also examine whether the intervention improves other IMMPACT-recommended domains (pain intensity, emotional functioning, and ratings of overall improvement). Secondary objectives include examining whether the intervention reduces health care service utilization and use of opioid analgesics and whether key contributors to racial/ethnic disparities targeted by the intervention mediate improvement in chronic pain outcomes Measures will be assessed by mail and phone surveys at baseline, three months, and six months. Data analysis of primary aims will follow intent-to-treat methodology. DISCUSSION: We will tailor our intervention to address key contributors to racial pain disparities and examine the effects of the intervention on important pain treatment outcomes for African Americans with chronic musculoskeletal pain. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01983228 . Registered 6 November 2013. PMID- 28086854 TI - In vitro assessment of hepatoprotective agents against damage induced by acetaminophen and CCl4. AB - BACKGROUND: In vitro bioassays are important in the evaluation of plants with possible hepatoprotective effects. The aims of this study were to evaluate the pretreatment of HepG2 cells with hepatoprotective agents against the damage induced by carbon tetrachloride (CCl4) and paracetamol (APAP). METHODS: Antioxidative activity was measured using an assay to measure 2,2-diphenyl-1 picrylhydrazyl (DPPH) free radical scavenging. The in vitro hepatotoxicity of CCl4 and APAP, and the cytotoxic and hepatoprotective properties of silymarin (SLM), silybinin (SLB), and silyphos (SLP) were evaluated by measuring cell viability; activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH); total antioxidant capacity (TAOxC); and reduced glutathione (GSH), superoxide dismutase (SOD), and lipid peroxidation (malondialdehyde (MDA) levels). RESULTS: Only SLB and SLM showed strong antioxidative activity in the DPPH assay (39.71 +/- 0.85 MUg/mL and 14.14 +/- 0.65 MUg/mL, respectively). CCl4 induced time- and concentration dependent changes. CCl4 had significant effects on cell viability, enzyme activities, lipid peroxidation, TAOxC, and SOD and GSH levels. These differences remained significant up to an exposure time of 3 h. APAP induced a variety of dose- and time-dependent responses up to 72 h of exposure. SLM, SLB, and SLP were not cytotoxic. Only SLB at a concentration of 100 MUg/mL or 150 MUg/mL significantly decreased the enzyme activities and MDA level, and prevented depletion of total antioxidants compared with CCl4. CONCLUSIONS: CCl4 was more consistent than APAP in inducing cell injury. Only SLB provided hepatoprotection. AST, LDH, and MDA levels were good markers of liver damage. PMID- 28086855 TI - Postoperative fluid overload is a risk factor for adverse surgical outcome in patients undergoing esophagectomy for esophageal cancer: a retrospective study in 335 patients. AB - BACKGROUND: Restrictive intraoperative fluid management is increasingly recommended for patients undergoing esophagectomy. Controversy still exists about the impact of postoperative fluid management on perioperative outcome. METHODS: We retrospectively examined 335 patients who had undergone esophagectomy for esophageal cancer at the University Hospital Freiburg between 1996 and 2014 to investigate the relation between intra- and postoperative fluid management and postoperative morbidity after esophagectomy. RESULTS: Perioperative morbidity was 75%, the in-hospital mortality 8%. A fluid balance above average on the operation day was strongly associated with a higher rate of postoperative mortality (21% vs 3%, p < 0.001) and morbidity (83% vs 66%, p = 0.001). Univariate analysis for risk factors for adverse surgical outcome (Clavien >= III) identified ASA-score (p = 0.002), smoking (p = 0.036), reconstruction by colonic interposition (p = 0.036), cervical anastomosis (p = 0.017), blood transfusion (p = 0.038) and total fluid balance on the operation day and on POD 4 (p = 0.001) as risk factors. Multivariate analysis confirmed only ASA-score (p = 0.001) and total fluid balance (p = 0.001) as independent predictors of adverse surgical outcome. CONCLUSION: Intra- and postoperative fluid overload is strongly associated with increased postoperative morbidity. Our results suggest restrictive intra- and especially postoperative fluid management to optimize the outcome after esophagectomy. PMID- 28086856 TI - The addition of a sagittal image fusion improves the prostate cancer detection in a sensor-based MRI /ultrasound fusion guided targeted biopsy. AB - BACKGROUND: To explore the diagnostic benefit of an additional image fusion of the sagittal plane in addition to the standard axial image fusion, using a sensor based MRI/US fusion platform. METHODS: During July 2013 and September 2015, 251 patients with at least one suspicious lesion on mpMRI (rated by PI-RADS) were included into the analysis. All patients underwent MRI/US targeted biopsy (TB) in combination with a 10 core systematic prostate biopsy (SB). All biopsies were performed on a sensor-based fusion system. Group A included 162 men who received TB by an axial MRI/US image fusion. Group B comprised 89 men in whom the TB was performed with an additional sagittal image fusion. RESULTS: The median age in group A was 67 years (IQR 61-72) and in group B 68 years (IQR 60-71). The median PSA level in group A was 8.10 ng/ml (IQR 6.05-14) and in group B 8.59 ng/ml (IQR 5.65-12.32). In group A the proportion of patients with a suspicious digital rectal examination (DRE) (14 vs. 29%, p = 0.007) and the proportion of primary biopsies (33 vs 46%, p = 0.046) were significantly lower. The rate of PI-RADS 3 lesions were overrepresented in group A compared to group B (19 vs. 9%; p = 0.044). Classified according to PI-RADS 3, 4 and 5, the detection rates of TB were 42, 48, 75% in group A and 25, 74, 90% in group B. The rate of PCa with a Gleason score >=7 missed by TB was 33% (18 cases) in group A and 9% (5 cases) in group B; p-value 0.072. An explorative multivariate binary logistic regression analysis revealed that PI-RADS, a suspicious DRE and performing an additional sagittal image fusion were significant predictors for PCa detection in TB. 9 PCa were only detected by TB with sagittal fusion (sTB) and sTB identified 10 additional clinically significant PCa (Gleason >=7). CONCLUSION: Performing an additional sagittal image fusion besides the standard axial fusion appears to improve the accuracy of the sensor-based MRI/US fusion platform. PMID- 28086857 TI - Evaluating a multicomponent social behaviour change communication strategy to reduce intimate partner violence among married couples: study protocol for a cluster randomized trial in Nepal. AB - BACKGROUND: Intimate partner violence (IPV) is a significant public health issue that affects 1 in 3 women globally and a similarly large number of women in Nepal. Over the past decade, important policy and programmatic steps have been taken to address violence against women in Nepal. There remains a dearth of evidence on the effectiveness of primary violence prevention strategies. The Change Starts at Home study begins to fill this gap by utilizing a multi component social behaviour change communication (SBCC) strategy involving a radio drama and community mobilization to shift attitudes, norms and behaviours that underpin IPV perpetration in Nepal. METHODS/DESIGN: The study uses a concurrent mixed-methods design. The quantitative aspect of the evaluation is a pair matched, repeated cross-sectional 2-armed, single-blinded cluster trial (RCT: N = 36 clusters, 1440 individuals), comparing a social behaviour change communication (SBCC) strategy to radio programming alone for its impact on physical and / or sexual IPV at the end of programming (12 months' post-baseline) and 6-months post the cessation of project activities (18-months post baseline). The qualitative aspects of the design include several longitudinal approaches to understand the impact of the intervention and to examine mechanisms of change including in-depth interviews with participants (N = 18 couples), and focus group discussions with community leaders (N = 3 groups), and family members of participants (N = 12 groups). Treatment effects will be estimated with generalized logistic mixed models specified to compare differences in primary outcome from baseline to 12 month follow-up, and baseline to 18-months follow-up in accordance with intention to-treat principles. DISCUSSION: The study rigorously evaluates the effectiveness of a promising strategy to prevent IPV. The results of the trial will be immediately useful for governmental, nongovernmental, and donor funded programs targeting partner violence or social norms that underpin it. Findings of the study will also contribute to global knowledge on the effectiveness of media and community engagement as a primary prevention strategy for IPV. TRIAL REGISTRATION: Trial was registered in clinicaltrials.gov, NCT02942433 , 10/13/2016, retrospectively registered. PMID- 28086858 TI - The influence of adding modified zirconium oxide-titanium dioxide nano-particles on mechanical properties of orthodontic adhesive: an in vitro study. AB - BACKGROUND: The purpose of this in-vitro study was to examine the effect of incorporating different concentrations of Zirconium oxide-Titanium dioxide (ZrO2 TiO2) nanoparticles, which can have antibacterial properties, on the mechanical properties of an orthodontic adhesive. METHODS: ZrO2-TiO2 (Zirconium oxide, HWNANO, Hongwu International Group Ltd, China) -Titanium dioxide, Nanoshell, USA) nanopowder were incorporated into orthodontic adhesive (Transbond XT, 3 M Unitek, Monrovia, USA) with different concentrations (0.5% weight nonofiller and 1% weight nanofiller). The size of nanoparticle was 70-80 nm for ZrO2 and less than 50 nm for TiO2. For measuring the shear bond strength of the three groups of orthodontic adhesives [Transbond (control), Transbond mixed with 0.5% weight ZrO2 TiO2, and Transbond mixed with 1% weight ZrO2-TiO2], 30 freshly extracted human first premolars were used and bonded with stainless steel metal brackets (Dentaurum(r), Discovery(r), Deutschland), using the 3 orthodontic adhesives and 3 M Unitek; Transbond TM Plus Self-Etching Primer (10 samples in each group). The recorded values of compressive strength and tensile strength (measured separately on 10 samples of orthodontic adhesives (add the 3 D size of sample, light cured for 40 s on both sides) of each orthodontic adhesives), as well as the shear bond strength in Mega Pascal unit (MPa) were collected and exposed to one-way analysis of variance (ANOVA) and Tukey's post-hoc tests. RESULTS: orthodontic adhesive with 1% weight ZrO2-TiO2 showed the highest mean compressive (73.42 +/- 1.55 MPa, p: 0.003, F: 12.74), tensile strength (8.65 +/- 0.74 MPa, p: 0.001, F: 68.20), and shear bond strength (20.05 +/- 0.2 MPa, p: 0.001, F: 0.17). CONCLUSIONS: Adding ZrO2-TiO2 nanoparticle to orthodontic adhesive increased compressive strength, tensile strength, and shear bond strength in vitro, but in vivo studies and randomized clinical trials are needed to validate the present findings. PMID- 28086859 TI - Cheongsangbangpung-tang ameliorated the acute inflammatory response via the inhibition of NF-kappaB activation and MAPK phosphorylation. AB - BACKGROUND: Cheongsangbangpung-tang (CBT) is a traditional herbal formula used in Eastern Asia to treat heat-related diseases and swellings in the skin. The present study was conducted to evaluate the anti-inflammatory effects of cheongsangbangpung-tang extract (CBTE) both in vitro and in vivo. METHODS: The in vitro effects of CBTE on the lipopolysaccharide (LPS)-induced production of inflammation-related proteins were examined in RAW 264.7 cells. The levels of nitric oxide (NO) were measured with the Griess reagent. Inflammatory cytokines and prostaglandin E2 (PGE2) were detected using the enzyme-linked immunosorbent assay (ELISA) method. Inflammation-related proteins were detected by Western blot. The effect of CBTE on acute inflammation in vivo was evaluated using carrageenan (CA)-induced paw oedema. To evaluate the anti-inflammatory effect, paw oedema volume, thickness of the dorsum and ventrum pedis skin, number of infiltrated inflammatory cells, and number of COX-2-, iNOS-immunoreactive cells were measured. RESULTS: In an in vitro study, CBTE inhibited the production of NO and PGE2 and also decreased the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) activity, interleukin (IL)-1beta, IL-6 and tumuor necrosis factor-alpha. In LPS-activated macrophages, nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) signalling is a pivotal pathway in the inflammatory process. These plausible molecular mechanisms increased the phosphorylation of I-kappaBalpha, while the activation of NF-kappaB and the phosphorylation of MAPK by LPS were blocked by CBTE treatment. In our in vivo study, a CA-induced acute oedematous paw inflammation rat model was used to evaluate the anti-inflammatory effect of CBTE. CBTE significantly reduced the increases in paw swelling, skin thicknesses, infiltrated inflammatory cells and iNOS-, COX-2 positive cells induced by CA injection. CONCLUSIONS: Based on these results, CBTE should favourably inhibit the acute inflammatory response through modulation of NF-kappaB activation and MAPK phosphorylation. Furthermore, the inhibition of CBTE in rat paw oedema induced by CA is considered to be clear evidence that CBTE may be a useful source to treat inflammation. PMID- 28086860 TI - Nicotiana attenuata Data Hub (NaDH): an integrative platform for exploring genomic, transcriptomic and metabolomic data in wild tobacco. AB - BACKGROUND: Nicotiana attenuata (coyote tobacco) is an ecological model for studying plant-environment interactions and plant gene function under real-world conditions. During the last decade, large amounts of genomic, transcriptomic and metabolomic data have been generated with this plant which has provided new insights into how native plants interact with herbivores, pollinators and microbes. However, an integrative and open access platform that allows for the efficient mining of these -omics data remained unavailable until now. DESCRIPTION: We present the Nicotiana attenuata Data Hub (NaDH) as a centralized platform for integrating and visualizing genomic, phylogenomic, transcriptomic and metabolomic data in N. attenuata. The NaDH currently hosts collections of predicted protein coding sequences of 11 plant species, including two recently sequenced Nicotiana species, and their functional annotations, 222 microarray datasets from 10 different experiments, a transcriptomic atlas based on 20 RNA seq expression profiles and a metabolomic atlas based on 895 metabolite spectra analyzed by mass spectrometry. We implemented several visualization tools, including a modified version of the Electronic Fluorescent Pictograph (eFP) browser, co-expression networks and the Interactive Tree Of Life (iTOL) for studying gene expression divergence among duplicated homologous. In addition, the NaDH allows researchers to query phylogenetic trees of 16,305 gene families and provides tools for analyzing their evolutionary history. Furthermore, we also implemented tools to identify co-expressed genes and metabolites, which can be used for predicting the functions of genes. Using the transcription factor NaMYB8 as an example, we illustrate that the tools and data in NaDH can facilitate identification of candidate genes involved in the biosynthesis of specialized metabolites. CONCLUSION: The NaDH provides interactive visualization and data analysis tools that integrate the expression and evolutionary history of genes in Nicotiana, which can facilitate rapid gene discovery and comparative genomic analysis. Because N. attenuata shares many genome-wide features with other Nicotiana species including cultivated tobacco, and hence NaDH can be a resource for exploring the function and evolution of genes in Nicotiana species in general. The NaDH can be accessed at: http://nadh.ice.mpg.de/ . PMID- 28086861 TI - Managing 'shades of grey': a focus group study exploring community-dwellers' views on advance care planning in older people. AB - BACKGROUND: Community-dwelling consumers of healthcare are increasing, many aging with life-limiting conditions and deteriorating cognition. However, few have had advance care planning discussions or completed documentation to ensure future care preferences are acted upon. This study examines the awareness, attitudes, and experiences of advance care planning amongst older people and unrelated offspring/caregivers of older people residing in the community. METHODS: Qualitative descriptive research, which included focus groups with older people (55+ years) and older people's offspring/caregivers living in an Australian city and surrounding rural region. Data was analysed using an inductive and comparative approach. Sampling was both convenience and purposive. Participants responded to web-based, newsletter or email invitations from an agency, which aims to support healthcare consumers, a dementia support group, or community health centres in areas with high proportions of culturally and linguistically diverse community-dwellers. RESULTS: Eight focus groups were attended by a homogenous sample of 15 older people and 27 offspring/caregivers, with 43% born overseas. The overarching theme, 'shades of grey': struggles in transition, reflects challenges faced by older people and their offspring/caregivers as older people often erratically transition from independence and capacity to dependence and/or incapacity. Offspring/caregivers regularly struggled with older people's fluctuating autonomy and dependency as older people endeavoured to remain at home, and with conceptualising "best times" to actualise advance care planning with substitute decision maker involvement. Advance care planning was supported and welcomed, x advance care planning literacy was evident. Difficulties planning for hypothetical health events and socio-cultural attitudes thwarting death related discussions were emphasised. Occasional offspring/caregivers with previous substitute decision maker experience reported distress related to their decisions. CONCLUSIONS: Advance care planning programs traditionally assume participants are 'planning ready' to legally appoint a substitute decision maker (power of attorney) and record end-of-life treatment preferences in short time frames. This contrasts with how community dwelling older people and offspring/caregivers conceive future care decisions over time. Advance care planning programs need to include provision of information, which supports older people's advance care planning understanding and management, and also supports offspring/caregivers' development of strategies for broaching advance care planning with older people, and preparing for potential substitute decision maker roles. Development and integration of strategies to support older people's decision-making when in the 'grey zone', with fluctuating cognitive capacities, needs further consideration. Findings support an advance care planning model with conversations occurring at key points across a person's lifespan. PMID- 28086862 TI - Management of Dentin Hypersensitivity by National Dental Practice-Based Research Network practitioners: results from a questionnaire administered prior to initiation of a clinical study on this topic. AB - BACKGROUND: Dentin hypersensitivity (DH) is a common problem encountered in clinical practice. The purpose of this study was to identify the management approaches for DH among United States dentists. METHODS: One hundred eighty five National Dental Practice-Based Research Network clinicians completed a questionnaire regarding their preferred methods to diagnose and manage DH in the practice setting, and their beliefs about DH predisposing factors. RESULTS: Almost all dentists (99%) reported using more than one method to diagnose DH. Most frequently, they reported using spontaneous patient reports coupled with excluding other causes of oral pain by direct clinical examination (48%); followed by applying an air blast (26%), applying cold water (12%), and obtaining patient reports after dentist's query (6%). In managing DH, the most frequent first choice was desensitizing, over-the-counter (OTC), potassium nitrate toothpaste (48%), followed by fluorides (38%), and glutaraldehyde/HEMA (3%). A total of 86% of respondents reported using a combination of products when treating DH, most frequently using fluoride varnish and desensitizing OTC potassium nitrate toothpaste (70%). The most frequent predisposing factor leading to DH, as reported by the practitioners, was recessed gingiva (66%), followed by abrasion, erosion, abfraction/attrition lesions (59%) and bruxism (32%). CONCLUSIONS: The majority of network practitioners use multiple methods to diagnose and manage DH. Desensitizing OTC potassium nitrate toothpaste and fluoride formulations are the most widely used products to manage DH in dental practice setting. PMID- 28086864 TI - Direct detection of falciparum and non-falciparum malaria DNA from a drop of blood with high sensitivity by the dried-LAMP system. AB - BACKGROUND: Because of the low sensitivity of conventional rapid diagnostic tests (RDTs) for malaria infections, the actual prevalence of the diseases, especially those caused by non-Plasmodium falciparum (non-Pf) species, in asymptomatic populations remain less defined in countries lacking in well-equipped facilities for accurate diagnoses. Our direct blood dry LAMP system (CZC-LAMP) was applied to the diagnosis of malaria as simple, rapid and highly sensitive method as an alternative for conventional RDTs in malaria endemic areas where laboratory resources are limited. RESULTS: LAMP primer sets for mitochondria DNAs of Plasmodium falciparum (Pf) and human-infective species other than Pf (non-Pf; P. vivax, P. ovale, P. malariae) were designed and tested by using human blood DNA samples from 74 residents from a malaria endemic area in eastern Zambia. These malaria dry-LAMPs were optimized for field or point-of-care operations, and evaluated in the field at a malaria endemic area in Zambia with 96 human blood samples. To determine the sensitivities and specificities, results obtained by the on-site LAMP diagnosis were compared with those by the nested PCR and nucleotide sequencing of its product. The dry LAMPs showed the sensitivities of 89.7% for Pf and 85.7% for non-Pf, and the specificities of 97.2% for Pf and 100% for non-Pf, with purified blood DNA samples. The direct blood LAMP diagnostic methods, in which 1 MUl of anticoagulated blood were used as the template, showed the sensitivities of 98.1% for Pf, 92.1% for non-Pf, and the specificities of 98.1% for Pf, 100% for non-Pf. The prevalences of P. falciparum, P. malariae and P. ovale in the surveyed area were 52.4, 25.3 and 10.6%, respectively, indicating high prevalence of asymptomatic carriers in endemic areas in Zambia. CONCLUSIONS: We have developed new field-applicable malaria diagnostic tests. The malaria CZC LAMPs showed high sensitivity and specificity to both P. falciparum and non-P. falciparum. These malaria CZC-LAMPs provide new means for rapid, sensitive and reliable point-of-care diagnosis for low-density malaria infections, and are expected to help update current knowledge of malaria epidemiology, and can contribute to the elimination of malaria from endemic areas. PMID- 28086865 TI - RNAi reveals proteins for metabolism and protein processing associated with Langat virus infection in Ixodes scapularis (black-legged tick) ISE6 cells. AB - BACKGROUND: Tick-borne flaviviruses (TBFs) cause thousands of human cases of encephalitis worldwide each year, with some TBF infections progressing to hemorrhagic fever. TBFs are of medical and veterinary importance and strategies to reduce flavivirus transmission by the tick vector may have significant application. Analyses of the proteome of ISE6 cells derived from the black legged tick, Ixodes scapularis infected with the TBF, Langat virus (LGTV), have provided insights into proteins and cellular processes involved with LGTV infection. METHODS: RNA interference (RNAi)-induced knockdown of transcripts was used to investigate the role of ten tick proteins in the LGTV infection cycle in ISE6 cells. LGTV-infected cells were separately transfected with dsRNA corresponding to each gene of interest and the effect on LGTV genome replication and release of infectious virus was assessed by RT-qPCR and plaque assays, respectively. RESULTS: RNAi-induced knockdown of transcripts for two enzymes that likely function in amino acid, carbohydrate, lipid, terpenoid/polykeytide and vitamin metabolism, and a transcript for one protein of unknown function were associated with decreased replication of the LGTV genome and release of infectious virus from cells. The knockdown of transcripts for five enzymes predicted to function in metabolism, a protein likely associated with folding, sorting and degradation, and a protein of unknown function was associated with a decrease only in the amount of infectious LGTV released from cells. CONCLUSIONS: These data suggest tick proteins potentially associated with metabolism and protein processing may be involved in LGTV infection of ISE6 cells. Our study provides information to begin to elucidate the function of these proteins and identify targets for the development of new interventions aimed at controlling the transmission of TBFs. PMID- 28086866 TI - Perceptions and utilization of generic medicines in Guatemala: a mixed-methods study with physicians and pharmacy staff. AB - BACKGROUND: Access to low-cost essential generic medicines is a critical health policy goal in low-and-middle income countries (LMICs). Guatemala is an LMIC where there is both limited availability and affordability of these medications. However, attitudes of physicians and pharmacy staff regarding low-cost generics, especially generics for non-communicable diseases (NCDs), have not been fully explored in Guatemala. METHODS: Semi-structured interviews with 30 pharmacy staff and 12 physicians in several highland towns in Guatemala were conducted. Interview questions related to perceptions of low-cost generic medicines, prescription and dispensing practices of generics in the treatment of two NCDs, diabetes and hypertension, and opinions about the roles of pharmacy staff and physicians in selecting medicines for patients. Pharmacy staff were recruited from a random sample of pharmacies and physicians were recruited from a convenience sample. Interview data were analyzed using a thematic approach for qualitative data as well as basic quantitative statistics. RESULTS: Pharmacy staff and physicians expressed doubt as to the safety and efficacy of low-cost generic medicines in Guatemala. The low cost of generic medicines was often perceived as proof of their inferior quality. In the case of diabetes and hypertension, the decision to utilize a generic medicine was based on multiple factors including the patient's financial situation, consumer preference, and, to a large extent, physician recommendations. CONCLUSIONS: Interventions to improve generic medication utilization in Guatemala must address the negative perceptions of physicians and pharmacy staff toward low-cost generics. Strengthening state capacity and transparency in the regulation and monitoring of the drug supply is a key goal of access-to-medicines advocacy in Guatemala. PMID- 28086863 TI - Exercise mediated protection of diabetic heart through modulation of microRNA mediated molecular pathways. AB - Hyperglycaemia, hypertension, dyslipidemia and insulin resistance collectively impact on the myocardium of people with diabetes, triggering molecular, structural and myocardial abnormalities. These have been suggested to aggravate oxidative stress, systemic inflammation, myocardial lipotoxicity and impaired myocardial substrate utilization. As a consequence, this leads to the development of a spectrum of cardiovascular diseases, which may include but not limited to coronary endothelial dysfunction, and left ventricular remodelling and dysfunction. Diabetic heart disease (DHD) is the term used to describe the presence of heart disease specifically in diabetic patients. Despite significant advances in medical research and long clinical history of anti-diabetic medications, the risk of heart failure in people with diabetes never declines. Interestingly, sustainable and long-term exercise regimen has emerged as an effective synergistic therapy to combat the cardiovascular complications in people with diabetes, although the precise molecular mechanism(s) underlying this protection remain unclear. This review provides an overview of the underlying mechanisms of hyperglycaemia- and insulin resistance-mediated DHD with a detailed discussion on the role of different intensities of exercise in mitigating these molecular alterations in diabetic heart. In particular, we provide the possible role of exercise on microRNAs, the key molecular regulators of several pathophysiological processes. PMID- 28086867 TI - Process evaluation of an integrated care pathway in geriatric rehabilitation for people with complex health problems. AB - BACKGROUND: An integrated care pathway in geriatric rehabilitation was developed to improve coordination and continuity of care for community-living older adults in the Netherlands, who go through the process of hospital admission, admission to a geriatric rehabilitation facility and discharge back to the home situation. This pathway is a complex intervention and is focused on improving communication, triage and transfers of patients between the hospital, geriatric rehabilitation facility and primary care organisations. A process evaluation was performed to assess the feasibility of this pathway. METHODS: The study design incorporated mixed methods. Feasibility was assessed thru if the pathway was implemented according to plan (fidelity and dose delivered), (b) if patients, informal caregivers and professionals were satisfied with the pathway (dose received) and (c) which barriers and facilitators influenced implementation (context). These components were derived from the theoretical framework of Saunders and colleagues. Data were collected using three structured face-to-face interviews with patients, self-administered questionnaires among informal caregivers, and group interviews with professionals. Furthermore, data were collected from the information transfer system in the hospital, patient files of the geriatric rehabilitation facility and minutes of evaluation meetings. RESULTS: In total, 113 patients, 37 informal caregivers and 19 healthcare professionals participated in this process evaluation. The pathway was considered largely feasible as two components were fully implemented according to plan and two components were largely implemented according to plan. The timing and quality of medical discharge summaries were not sufficiently implemented according to plan and professionals indicated that the triage instrument needed refinement. Healthcare professionals were satisfied with the implementation of the pathway and they indicated that due to improved collaboration, the quality of care provision improved. Although patients and informal caregivers were also satisfied with the care provision in the pathway, they indicated that the care organisations involved should pay more attention towards providing information about their treatment. CONCLUSIONS: This process evaluation showed that patients, informal caregivers and professionals are fairly satisfied with the care provision in the pathway and professionals reported that collaboration improved. Extra attention should be paid to the components in the pathway that were not implemented according to plan. TRIAL REGISTRATION: ISRCTN90000867 Registered 7 April 2016. PMID- 28086868 TI - The impact of students and curriculum on self-study during clinical training in medical school: a multilevel approach. AB - BACKGROUND: In higher education, the focus has shifted from the acquisition of knowledge to learning objectives and skills. This means that, the majority of student learning time is spent independently working outside the classroom. Students take an active role in setting goals, deciding how to achieve them, and planning individual study time. Although extensive research has recognized the importance of curriculum and students' characteristics in time devoted to self study, it is still unclear to what extent these variables affect time to study. Due to the growing reliance on self-directed learning in medical education, and in an attempt to elucidate this issue, this research aims to evaluate self-study time during clinical training and assess whether this is more influenced by the student or the curriculum. METHODS: A questionnaire was given to 1220 medical students (43.3% of the enrolled students). The students were asked to indicate the average number of study hours per week beyond the time allocated to classes for each clerkship (rotation) attended. Variation and generalizability of students' self-study were estimated using linear mixed models. RESULTS: Findings showed that the intrinsic differences within students were a greater source of variation in self-study time than differences within clerkships (56.0% vs. 6.9%). If the amount of self-study dedicated to an individual clerkship is to be determined, at least 32 students are needed to achieve acceptable reliability. However, this data with two clerkships per student can used to retrospectively measure the self-study reported by students in clinical training. CONCLUSIONS: The findings suggest that, both, curriculum and student characteristics influence self-study in undergraduate clinical training. Indeed, students' characteristics play a significant role in time devoted to study. Further research should be undertaken to investigate students' characteristics that may predict self-study during undergraduate medical training. PMID- 28086869 TI - Evaluation of an aged care nurse practitioner service: quality of care within a residential aged care facility hospital avoidance service. AB - BACKGROUND: Reducing avoidable hospitialisation of aged care facility (ACF) residents can improve the resident experience and their health outcomes. Consequently many variations of hospital avoidance (HA) programs continue to evolve. Nurse practitioners (NP) with expertise in aged care have the potential to make a unique contribution to hospital avoidance programs. However, little attention has been dedicated to service evaluation of this model and the quality of care provided. The purpose of this study was to evaluate the quality of an aged care NP model of care situated within a HA service in a regional area of Australia. METHODS: Donabedian's structure, process and outcome framework was applied to evaluate the quality of the NP model of care. The Australian Nurse Practitioner Study standardised interview schedules for evaluating NP models of care guided the semi-structured interviews of nine health professionals (including ACF nurses, medical doctors and allied health professionals), four ACF residents and their families and two NPs. Theory driven coding consistent with the Donabedian framework guided analysis of interview data and presentation of findings. RESULTS: Structural dimensions identified included the 'in-reach' nature of the HA service, distance, limitations of professional regulation and the residential care model. These dimensions influenced the process of referring the resident to the NP, the NPs timely response and interactions with other professionals. The processes where the NPs take time connecting with residents, initiating collaborative care plans, up-skilling aged care staff and function as intra and interprofessional boundary spanners all contributed to quality outcomes. Quality outcomes in this study were about timely intervention, HA, timely return home, partnering with residents and family (knowing what they want) and resident and health professional satisfaction. CONCLUSIONS: This study provides valuable insights into the contribution of the NP model of care within an aged care, HA service and how staff manipulated the process dimensions to improve referral to the NPs. NP service in this study was dynamic, flexible and responsive to both patient and organisational demands. PMID- 28086870 TI - A pilot study of a Community Health Agent-led type 2 diabetes self-management program using Motivational Interviewing-based approaches in a public primary care center in Sao Paulo, Brazil. AB - BACKGROUND: Rates of noncommunicable diseases (NCDs) such as type 2 diabetes are escalating in low and middle-income countries such as Brazil. Scalable primary care-based interventions are needed to improve self-management and clinical outcomes of adults with diabetes. This pilot study examines the feasibility, acceptability, and outcomes of training community health agents (CHAs) in Motivational Interviewing (MI)-based counseling for patients with poorly controlled diabetes in a primary care center in Sao Paulo, Brazil. METHODS: Nineteen salaried CHAs participated in 32 h of training in MI and behavioral action planning. With support from booster training sessions, they used these skills in their regular monthly home visits over a 6 month period with 57 diabetes patients with baseline HbA1cs > 7.0%. The primary outcome was patients' reports of the quality of diabetes care as measured by the Portuguese version of the Patient Assessment of Chronic Illness Care (PACIC) scale. Secondary outcomes included changes in patients' reported diabetes self-management behaviors and in A1c, blood pressure, cholesterol and triglycerides. We also examined CHAs' fidelity to and experiences with the intervention. RESULTS: Patients reported improvements over the 6 month period in quality of diabetes care received (PACIC score improved 33 (+/-19) to 68 (+/-21) (p < .001)). They reported increases in physical activity (p = .001), consumption of fruits and vegetables (p < .001) and medication adherence (p = .002), but no decreases in consumption of high-fat foods (p = .402) or sweets (p = .436). Participants had mean 6-month A1c levels 0.34% points lower than at baseline (p = .08) and improved mean LDL (-16.1 mg/dL, p = .005) and triglyceride levels (-38.725 mg/dL, p = .002). Of the 16 CHAs observed in fidelity assessments, 13 were categorized as medium- or high performing on MI skills, while 3 were low-performing. CHAs expressed enthusiasm about learning new skills, and many described a shift from advice-giving to encouraging patients to define their own goals. CONCLUSION: In resource-scarce settings, it is essential to fully utilize existing primary care resources to stem the epidemic of diabetes and other NCDs. Our pilot results support the potential of training CHAs to incorporate effective diabetes self-management support into their routine patient encounters. TRIAL REGISTRATION: NCT02994095 12/14/2016 Registered retrospectively. PMID- 28086871 TI - The integrated care pathway for post stroke patients (iCaPPS): a shared care approach between stakeholders in areas with limited access to specialist stroke care services. AB - BACKGROUND: Lack of intersectoral collaboration within public health sectors compound efforts to promote effective multidisciplinary post stroke care after discharge following acute phase. A coordinated, primary care-led care pathway to manage post stroke patients residing at home in the community was designed by an expert panel of specialist stroke care providers to help overcome fragmented post stroke care in areas where access is limited or lacking. METHODS: Expert panel discussions comprising Family Medicine Specialists, Neurologists, Rehabilitation Physicians and Therapists, and Nurse Managers from Ministry of Health and acadaemia were conducted. In Phase One, experts chartered current care processes in public healthcare facilities, from acute stroke till discharge and also patients who presented late with stroke symptoms to public primary care health centres. In Phase Two, modified Delphi technique was employed to obtain consensus on recommendations, based on current evidence and best care practices. Care algorithms were designed around existing work schedules at public health centres. RESULTS: Indication for patients eligible for monitoring by primary care at public health centres were identified. Gaps in transfer of care occurred either at post discharge from acute care or primary care patients diagnosed at or beyond subacute phase at health centres. Essential information required during transfer of care from tertiary care to primary care providers was identified. Care algorithms including appropriate tools were summarised to guide primary care teams to identify patients requiring further multidisciplinary interventions. Shared care approaches with Specialist Stroke care team were outlined. Components of the iCaPPS were developed simultaneously: (i) iCaPPS-Rehab(c) for rehabilitation of stroke patients at community level (ii) iCaPPS-Swallow(c) guided the primary care team to screen and manage stroke related swallowing problems. CONCLUSION: Coordinated post stroke care monitoring service for patients at community level is achievable using the iCaPPS and its components as a guide. The iCaPPS may be used for post stroke care monitoring of patients in similar fragmented healthcare delivery systems or areas with limited access to specialist stroke care services. TRIAL REGISTRATION: No.: ACTRN12616001322426 (Registration Date: 21st September 2016). PMID- 28086872 TI - Dapagliflozin decreases small dense low-density lipoprotein-cholesterol and increases high-density lipoprotein 2-cholesterol in patients with type 2 diabetes: comparison with sitagliptin. AB - BACKGROUND: The sodium-glucose co-transporter-2 (SGLT-2) inhibitors have been reported to increase both low-density lipoprotein (LDL) and high-density lipoprotein (HDL)-cholesterol (C). This study aimed to determine how SGLT-2 inhibitors affect LDL and HDL-C subspecies. METHODS: This single center, open label, randomized, prospective study included 80 patients with type 2 diabetes taking prescribed oral hypoglycemic agents. Patients were allocated to receive dapagliflozin (n = 40) or sitagliptin (n = 40) as add-on treatment. Fasting blood samples were collected before and 12 weeks after this intervention. Small dense (sd) LDL-C, large buoyant (lb) LDL-C, HDL2-C, and HDL3-C levels were determined using our established homogeneous assays. Statistical comparison of blood parameters before and after treatment was performed using the paired t test. RESULTS: Dapagliflozin and sitagliptin comparably decreased HbA1c (0.75 and 0.63%, respectively). Dapagliflozin significantly decreased body weight, systolic blood pressure, plasma triglycerides and liver transaminases, and increased adiponectin; sitagliptin did not alter these measurements. LDL-C and apolipoprotein (apo) B were not significantly changed by dapagliflozin, whereas HDL-C and apo AI were increased. Dapagliflozin did not alter concentrations of LDL-C, but sd LDL-C decreased by 20% and lb LDL-C increased by 18%. Marked elevation in lb LDL-C (53%) was observed in individuals (n = 20) whose LDL-C was elevated by dapagliflozin. However, sd LDL-C remained suppressed (20%). Dapagliflozin increased HDL2-C by 18% without affecting HDL3-C. Sitagliptin did not alter plasma lipids or lipoprotein subspecies. CONCLUSIONS: A SGLT-2 inhibitor, dapagliflozin suppresses potent atherogenic sd LDL-C and increased HDL2-C, a favorable cardiometabolic marker. Although LDL-C levels are elevated by treatment with dapagliflozin, this was due to increased concentrations of the less atherogenic lb LDL-C. However, these findings were not observed after treatment with dipeptidyl peptidase-4 inhibitor, sitagliptin. Trial registration UMIN Clinical Trials Registry (UMIN000020984). PMID- 28086873 TI - Cecal MicroRNAome response to Salmonella enterica serovar Enteritidis infection in White Leghorn Layer. AB - BACKGROUND: Salmonella enterica serovar Enteritidis (SE) is a food-borne pathogen and of great threat to human health through consuming the contaminated poultry products. MicroRNAs (miRNAs) play an important role in different biological activities and have been shown to regulate the innate immunity in the bacterial infection. The objective of this study is to identify miRNAs associated with SE infection in laying chicken cecum. RESULTS: Average number of reads of three libraries constructed from infected and non-infected chickens was 12,476,156 and 10,866,976, respectively. There were 598 miRNAs including 194 potential novel miRNAs identified in which 37 miRNAs were significantly differentially expressed between infected and non-infected chickens. In total, 2897 unique target genes regulated by differentially expressed miRNAs were predicted, in which, 841 genes were uniquely regulated by up-regulated miRNAs (G1), 636 genes were uniquely regulated by down-regulated miRNAs (G2), and 1420 were co-regulated by both up and down- regulated miRNAs (G3). There were 118, 73 and 178 GO (Gene ontology) BP (Biological process) terms significantly enriched in G1, G2 and G3 groups, respectively. More immune-related GO BP terms than metabolism-related terms were found in G1. Expression of 12 immune-related genes of four differentially expressed miRNAs was detected through qRT-PCR. The regulatory direction of gga miR-1416-5p, gga-miR-1662, and gga-miR-34a-5p were opposite with the target genes of TLR21, BCL10, TLR1LA, NOTCH2 and THBS1, respectively. CONCLUSION: The miRNAs contribute to the response to SE infection at the onset of egg laying through regulating the homeostasis between metabolism and immunity. The gga-miR-125b-5p, gga-miR-34a-5p, gga-miR-1416-5p and gga-miR-1662 could play an important role in SE infection through regulating their target genes. The finding herein will pave the foundation for the studies of microRNA regulation in SE infection in laying hens. PMID- 28086875 TI - Learning global health: a pilot study of an online collaborative intercultural peer group activity involving medical students in Australia and Indonesia. AB - BACKGROUND: There is limited research to inform effective pedagogies for teaching global health to undergraduate medical students. Theoretically, using a combination of teaching pedagogies typically used in 'international classrooms' may prove to be an effective way of learning global health. This pilot study aimed to explore the experiences of medical students in Australia and Indonesia who participated in a reciprocal intercultural participatory peer e-learning activity (RIPPLE) in global health. METHODS: Seventy-one third year medical students (49 from Australia and 22 from Indonesia) from the University of Tasmania (Australia) and the University of Nusa Cendana (Indonesia) participated in the RIPPLE activity. Participants were randomly distributed into 11 intercultural 'virtual' groups. The groups collaborated online over two weeks to study a global health topic of their choice, and each group produced a structured research abstract. Pre- and post-RIPPLE questionnaires were used to capture students' experiences of the activity. Descriptive quantitative data were analysed with Microsoft Excel and qualitative data were thematically analysed. RESULTS: Students' motivation to volunteer for this activity included: curiosity about the innovative approach to learning; wanting to expand knowledge of global health; hoping to build personal and professional relationships; and a desire to be part of an intercultural experience. Afer completing the RIPPLE program, participants reported on global health knowledge acquisition, the development of peer relationships, and insight into another culture. Barriers to achieving the learning outcomes associated with RIPPLE included problems with establishing consistent online communication, and effectively managing time to simultaneously complete RIPPLE and other curricula activities. CONCLUSIONS: Medical students from both countries found benefits in working together in small virtual groups to complement existing teaching in global health. However, our pilot study demonstrated that while intercultural collaborative peer learning activities like RIPPLE are feasible, they require robust logistical support and an awareness of the need to manage curriculum alignment in ways that facilitate more effective student engagement. PMID- 28086876 TI - Fulfillment of administrative and professional obligations of hospitals and mission motivation of physicians. AB - BACKGROUND: To be successful, hospitals must increasingly collaborate with their medical staff. One strategic tool that plays an important role is the mission statement of hospitals. The goal of this research was to study the relationship between the fulfillment of administrative and professional obligations of hospitals on physicians' motivation to contribute to the mission of the hospital. Furthermore the mediating role of the physicians' emotional attachment to the hospital and moderation effect of the exchange with the head physicians were considered. METHODS: Self-employed physicians of six hospitals participated in a survey. Descriptive analyses and linear regression were used to analyse the data. RESULTS: The results indicate that affective commitment mediated the relationship between psychological contract fulfillment and mission statement motivation. In addition, the quality of exchange with the Chief Medical Officer moderated the relationship between the fulfillment of administrative obligations and affective commitment positively. CONCLUSION: This study extends our understanding of social exchange processes and mission statement motivation of physicians. We showed that when physicians perceive a high level of fulfillment of their psychological contract they are more committed and more motivated to contribute to the mission statement. A high quality relationship between physician and Chief Medical Officer can enhance this reciprocity dynamic. PMID- 28086874 TI - New developments in anti-malarial target candidate and product profiles. AB - A decade of discovery and development of new anti-malarial medicines has led to a renewed focus on malaria elimination and eradication. Changes in the way new anti malarial drugs are discovered and developed have led to a dramatic increase in the number and diversity of new molecules presently in pre-clinical and early clinical development. The twin challenges faced can be summarized by multi-drug resistant malaria from the Greater Mekong Sub-region, and the need to provide simplified medicines. This review lists changes in anti-malarial target candidate and target product profiles over the last 4 years. As well as new medicines to treat disease and prevent transmission, there has been increased focus on the longer term goal of finding new medicines for chemoprotection, potentially with long-acting molecules, or parenteral formulations. Other gaps in the malaria armamentarium, such as drugs to treat severe malaria and endectocides (that kill mosquitoes which feed on people who have taken the drug), are defined here. Ultimately the elimination of malaria requires medicines that are safe and well tolerated to be used in vulnerable populations: in pregnancy, especially the first trimester, and in those suffering from malnutrition or co-infection with other pathogens. These updates reflect the maturing of an understanding of the key challenges in producing the next generation of medicines to control, eliminate and ultimately eradicate malaria. PMID- 28086877 TI - Treating the invisible: Gaps and opportunities for enhanced TB control along the Thailand-Myanmar border. AB - BACKGROUND: In Thailand's northwestern Tak province, contextual conditions along the border with Myanmar pose difficulties for TB control among migrant populations. Incomplete surveillance data, migrant patient mobility, and loss to follow-up make it difficult to estimate the TB burden and implement effective TB control measures. This multi-methods study examined tuberculosis, tuberculosis and human immunodeficiency virus co-infection, and multidrug-resistant tuberculosis treatment accessibility for migrants and refugees in Tak province, health system response, and public health surveillance. METHODS: In this study we conducted 13 interviews with key informants working in public health or TB treatment provision to elicit information on TB treatment availability and TB surveillance practices. In addition we organized 15 focus group discussions with refugee and migrant TB, TB/HIV, and MDR-TB patients and non-patients to discuss treatment access. We analyzed the data using thematic analysis and created treatment availability maps with Google maps. RESULTS: The study identified surveillance, treatment, and funding gaps. Migrant TB cases are underreported in the provincial statistics due to jurisdictional interpretations and resource barriers. Our results suggest that TB/HIV and MDR-TB treatment options are limited for migrants and a heavy reliance on donor funding may lead to potential funding gaps for migrant TB services. We identified several opportunities that positively contribute to TB control in Tak province: improved diagnostics, comprehensive care, and collaboration through data sharing, planning, and patient referrals. The various organizations providing TB treatment to migrant and refugee populations along the border and the Tak Provincial Public Health Office are highly collaborative which offers a strong foundation for future TB control initiatives. CONCLUSIONS: Our findings suggest the need to enhance the surveillance system to include all migrant TB patients who seek treatment in Tak province and support efforts by stakeholders on both sides of the border to continue to share data and engage in collaborative planning on TB, TB/HIV, and MDR-TB treatment provision for migrant populations. PMID- 28086878 TI - A case of cranium bifidum with meningocele in Ayrshire calf. AB - BACKGROUND: Congenital cranial bone defects predispose to herniation of meninges, sometimes with brain tissue involvement, to form a cerebrospinal fluid (CSF) filled cyst in the head. Such defects mainly results from focal failure of neural tube closure during fetal development and has been reported in various species of domestic mammals. CASE PRESENTATION: A one week old Ayrshire calf with a fluctuant swelling on parieto-occipital region of the head was referred to the faculty. The calf was always lying on lateral recumbency and exhibited resistance to deep palpation around the swelling and neck flexion. Embedded to the midline of the dorso-caudal surface of the cyst's wall was a hard longitudinally oriented structure. The case was diagnosed as meningocele by means of radiographic examination. As the likelihood to full recovery was greatly reduced due to the negative impact already meted on brain tissue by intracranial pressure, the calf was euthanized on grounds of animal welfare and the diagnosis confirmed by anatomopathological findings which also revealed a circular bone defect in parieto-occipital region of the skull vault and a flattened bony structure embedded to the cyst's wall. CONCLUSION: Anatomopathological findings confirmed the diagnosis as cranial bifidum with meningocele at the parieto-occipital region of the skull vault. The presence of a bony structure embedded to the wall of meningeal sac was rather unusual and could not be sufficiently explained. It was however thought to, most likely, represent a part of interparietal bone that failed to get incorporated into squamous part of occipital bone as a result of the defect. The report also highlights challenges that work against timely delivery of urgent veterinary interventions in rural set ups of Africa and rest of the developing world, often leaving veterinarians with animal welfare consideration as main determinant of intervention measures. PMID- 28086879 TI - Validity evidence for two objective structured clinical examination stations to evaluate core skills of the shoulder and knee assessment. AB - BACKGROUND: We developed two objective structured clinical examinations (OSCEs) to educate and evaluate trainees in the evaluation and management of shoulder and knee pain. Our objective was to examine the evidence for validity of these OSCEs. METHODS: A multidisciplinary team of content experts developed checklists of exam maneuvers and criteria to guide rater observations. Content was proposed by faculty, supplemented by literature review, and finalized using a Delphi process. One faculty simulated the patient, another rated examinee performance. Two faculty independently rated a portion of cases. Percent agreement was calculated and Cohen's kappa corrected for chance agreement on binary outcomes. Examinees' self-assessment was explored by written surveys. Responses were stratified into 3 categories and compared with similarly stratified OSCE scores using Pearson's coefficient. RESULTS: A multi-disciplinary cohort of 69 examinees participated. Examinees correctly identified rotator cuff and meniscal disease 88% and 89% of the time, respectively. Inter-rater agreement was moderate for the knee (87%; k = 0.61) and near perfect for the shoulder (97%; k = 0.88). No correlation between stratified self-assessment and OSCE scores were found for either shoulder (0.02) or knee (-0.07). CONCLUSIONS: Validity evidence supports the continuing use of these OSCEs in educational programs addressing the evaluation and management of shoulder and knee pain. Evidence for validity includes the systematic development of content, rigorous control of the response process, and demonstration of acceptable interrater agreement. Lack of correlation with self-assessment suggests that these OSCEs measure a construct different from learners' self confidence. PMID- 28086880 TI - Influence of border disease virus (BDV) on serological surveillance within the bovine virus diarrhea (BVD) eradication program in Switzerland. AB - BACKGROUND: In 2008, a program to eradicate bovine virus diarrhea (BVD) in cattle in Switzerland was initiated. After targeted elimination of persistently infected animals that represent the main virus reservoir, the absence of BVD is surveilled serologically since 2012. In view of steadily decreasing pestivirus seroprevalence in the cattle population, the susceptibility for (re-) infection by border disease (BD) virus mainly from small ruminants increases. Due to serological cross-reactivity of pestiviruses, serological surveillance of BVD by ELISA does not distinguish between BVD and BD virus as source of infection. RESULTS: In this work the cross-serum neutralisation test (SNT) procedure was adapted to the epidemiological situation in Switzerland by the use of three pestiviruses, i.e., strains representing the subgenotype BVDV-1a, BVDV-1h and BDSwiss-a, for adequate differentiation between BVDV and BDV. Thereby the BDV seroprevalence in seropositive cattle in Switzerland was determined for the first time. Out of 1,555 seropositive blood samples taken from cattle in the frame of the surveillance program, a total of 104 samples (6.7%) reacted with significantly higher titers against BDV than BVDV. These samples originated from 65 farms and encompassed 15 different cantons with the highest BDV-seroprevalence found in Central Switzerland. On the base of epidemiological information collected by questionnaire in case- and control farms, common housing of cattle and sheep was identified as the most significant risk factor for BDV infection in cattle by logistic regression. CONCLUSION: This indicates that pestiviruses from sheep should be considered as a source of infection of domestic cattle and might well impede serological BVD surveillance. PMID- 28086881 TI - Dengue fever in renal transplant patients: a systematic review of literature. AB - BACKGROUND: Dengue fever in renal transplanted patients has not been studied well, and we review all the literature about episodes dengue fever in renal transplant patients. METHODS: The aim was to describe clinico-pathological characteristics, immunosuppressive protocols, need renal outcome and mortality. PubMed, LILACS, Google Scholar and Research Gate were searched for "Dengue" and "Renal/Kidney Transplantation" with no date limits. Hits were analyzed by two researchers separately. RESULTS: Fever, myalgia, arthralgia and headache was significantly lower than normal population, while pleural effusions and ascites were observed more. Incidence of severe dengue is significantly higher among transplant patients in this review, as well as they had a significantly higher mortality (8.9% vs 3.7%, p = 0.031). Age, period after transplantation and immunosuppressive profile had no effect on disease severity, mortality or graft out come. Presence of new bleeding complications and ascites was associated with more severe disease (p < 0.001 and p = 0.005), death (p = 0.033) or graft loss (p = 0.035). Use of tacrolimus was associated with new bleeding complications (p = 0.027), and with ascites (p = 0.021), but not with thrombocytopenia. 25% of patients with primary disease fail to mount an IgG response by 15 weeks of the illness. 58.9% had graft dysfunction during illness. Postoperative transplanted patients were at risk of severe disease and unfavorable outcome. CONCLUSIONS: The physical and laboratory findings in dengue fever in renal transplanted patients differ from the general population. Some degree of graft dysfunction is common during the illness, but only a minority develops graft failure. PMID- 28086882 TI - Differential effects of glucagon-like peptide-1 receptor agonists on heart rate. AB - While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known to increase heart rate (HR), it is insufficiently recognized that the extent varies greatly between the various agonists and is affected by the assessment methods employed. Here we review published data from 24-h time-averaged HR monitoring in healthy individuals and subjects with type 2 diabetes mellitus (T2DM) treated with either short-acting GLP-1 RAs, lixisenatide or exenatide, or long-acting GLP-1 RAs, exenatide LAR, liraglutide, albiglutide, or dulaglutide (N = 1112; active treatment arms). HR effects observed in two independent head-to-head trials of lixisenatide and liraglutide (N = 202; active-treatment arms) are also reviewed. Short-acting GLP-1 RAs, exenatide and lixisenatide, are associated with a transient (1-12 h) mean placebo- and baseline-adjusted 24-h HR increase of 1-3 beats per minute (bpm). Conversely, long-acting GLP-1 RAs are associated with more pronounced increases in mean 24-h HR; the highest seen with liraglutide and albiglutide at 6-10 bpm compared with dulaglutide and exenatide LAR at 3-4 bpm. For both liraglutide and dulaglutide, HR increases were recorded during both the day and at night. In two head-to-head comparisons, a small, transient mean increase in HR from baseline was observed with lixisenatide; liraglutide induced a substantially greater increase that remained significantly elevated over 24 h. The underlying mechanism for increased HR remains to be elucidated; however, it could be related to a direct effect at the sinus node and/or stimulation of the sympathetic nervous system, with this effect related to the duration of action of the respective GLP-1 RAs. In conclusion, this review indicates that the effects on HR differ within the class of GLP-1 RAs: short-acting GLP-1 RAs are associated with a modest and transient HR increase before returning to baseline levels, while some long-acting GLP-1 RAs are associated with a more pronounced and sustained increase during the day and night. Findings from recently completed trials indicate that a GLP-1 RA-induced increase in HR, regardless of magnitude, does not present an increased cardiovascular risk for subjects with T2DM, although a pronounced increase in HR may be associated with adverse clinical outcomes in those with advanced heart failure. PMID- 28086883 TI - Which factors affect health care use among older Germans? Results of the German ageing survey. AB - BACKGROUND: It remains an open question how changes in predisposing, enabling, and need factors affect health care use. Consequently, we aimed to investigate how changes in these variables affect health care use in community-dwelling older persons longitudinally. METHODS: Data from two waves of the German Ageing Survey (DEAS), a representative sample of the community-dwelling German population aged >=40 years, was used. Predictors of visits to general practitioners and specialists as well as hospital stays during a 12-month period were analyzed by fixed effects regressions. RESULTS: Regressions revealed that the need factors 'self-rated health' and the number of chronic diseases affected all measures of health care use (except for the number of chronic diseases on hospital care). An increased duration of physical activities increased GP visits. A decrease of excess weight decreased the number of specialist visits. CONCLUSIONS: Our findings underline the importance of need factors for health care use. Virtually none of the predisposing factors nor enabling resources affected health care use. These findings might indicate that individuals in the second half of life use health care services adequately, i.e. when medically indicated. PMID- 28086884 TI - Transfer factor for carbon monoxide in patients with COPD and diabetes: results from the German COSYCONET cohort. AB - BACKGROUND: An impairment of CO diffusing capacity has been shown in diabetic patients without lung disease. We analyzed how diffusing capacity in patients with COPD is affected by the concurrent diagnosis of diabetes. METHODS: Data from the initial visit of the German COPD cohort COSYCONET were used for analysis. 2575 patients with complete lung function data were included, among them 358 defined as diabetics with a reported physician diagnosis of diabetes and/or specific medication. Pairwise comparisons between groups and multivariate regression models were used to identify variables predicting the CO transfer factor (TLCO%pred) and the transfer coefficient (KCO%pred). RESULTS: COPD patients with diabetes differed from those without diabetes regarding lung function, anthropometric, clinical and laboratory parameters. Moreover, gender was an important covariate. After correction for lung function, gender and body mass index (BMI), TLCO%pred did not significantly differ between patients with and without diabetes. The results for the transfer coefficient KCO were similar, demonstrating an important role of the confounding factors RV%pred, TLC%pred, ITGV%pred, FEV1%pred, FEV1/FVC, age, packyears, creatinine and BMI. There was not even a tendency towards lower values in diabetes. CONCLUSION: The analysis of data from a COPD cohort showed no significant differences of CO transport parameters between COPD patients with and without diabetes, if BMI, gender and the reduction in lung volumes were taken into account. This result is in contrast to observations in lung-healthy subjects with diabetes and raises the question which factors, among them potential anti-inflammatory effects of anti-diabetes medication are responsible for this finding. PMID- 28086885 TI - Harnessing the early post-injury inflammatory responses for cardiac regeneration. AB - Cardiac inflammation is considered by many as the main driving force in prolonging the pathological condition in the heart after myocardial infarction. Immediately after cardiac ischemic injury, neutrophils are the first innate immune cells recruited to the ischemic myocardium within the first 24 h. Once they have infiltrated the injured myocardium, neutrophils would then secret proteases that promote cardiac remodeling and chemokines that enhance the recruitment of monocytes from the spleen, in which the recruitment peaks at 72 h after myocardial infarction. Monocytes would transdifferentiate into macrophages after transmigrating into the infarct area. Both neutrophils and monocytes derived macrophages are known to release proteases and cytokines that are detrimental to the surviving cardiomyocytes. Paradoxically, these inflammatory cells also play critical roles in repairing the injured myocardium. Depletion of either neutrophils or monocytes do not improve overall cardiac function after myocardial infarction. Instead, the left ventricular function is further impaired and cardiac fibrosis persists. Moreover, the inflammatory microenvironment created by the infiltrated neutrophils and monocytes-derived macrophages is essential for the recruitment of cardiac progenitor cells. Recent studies also suggest that treatment with anti-inflammatory drugs may cause cardiac dysfunction after injury. Indeed, clinical studies have shown that traditional ant inflammatory strategies are ineffective to improve cardiac function after infarction. Thus, the focus should be on how to harness these inflammatory events to either improve the efficacy of the delivered drugs or to favor the recruitment of cardiac progenitor cells. PMID- 28086886 TI - Biochemical mechanism underlying hypertriglyceridemia and hepatic steatosis/hepatomegaly induced by acute schisandrin B treatment in mice. AB - BACKGROUND: It has been demonstrated that acute oral administration of schisandrin B (Sch B), an active dibenzocyclooctadiene isolated from Schisandrae Fructus (a commonly used traditional Chinese herb), increased serum and hepatic triglyceride (TG) levels and hepatic mass in mice. The present study aimed to investigate the biochemical mechanism underlying the Sch B-induced hypertriglyceridemia, hepatic steatosis and hepatomegaly. METHODS: Male ICR mice were given a single oral dose of Sch B (0.25-2 g/kg). Sch B-induced changes in serum levels of biomarkers, such as TG, total cholesterol (TC), apolipoprotein B48 (ApoB 48), very-low-density lipoprotein (VLDL), non-esterified fatty acid (NEFA) and hepatic growth factor (HGF), as well as hepatic lipids and mass, epididymal adipose tissue (EAT) and adipocyte size, and histological changes of the liver and EAT were examined over a period of 12-120 h after Sch B treatment. RESULTS: Serum and hepatic TG levels were increased by 1.0-4.3 fold and 40-158% at 12-72 h and 12-96 h, respectively, after Sch B administration. Sch B treatment elevated serum ApoB 48 level (up to 12%), a marker of exogenous TG, but not VLDL, as compared with the vehicle treatment. Treatment with Sch B caused a time-/dose dependent reduction in EAT index (up to 39%) and adipocyte size (up to 67%) and elevation in serum NEFA level (up to 55%). Sch B treatment induced hepatic steatosis in a time-/dose-dependent manner, as indicated by increases in total vacuole area (up to 3.2 fold vs. the vehicle control) and lipid positive staining area (up to 17.5 * 103 MUm2) in liver tissue. Hepatic index and serum HGF levels were increased by 18-60% and 42-71% at 12-120 h and 24-72 h post-Sch B dosing, respectively. In addition, ultrastructural changes, such as increase in size and disruption of cristae, in hepatic mitochondria were observed in Sch B-treated mice. CONCLUSION: Our findings suggest that exogenous sources of TG and the breakdown of fat storage in the body contribute to Sch B-induced hypertriglyceridemia and hepatic steatosis in mice. Hepatomegaly (a probable hepatotoxic action) caused by Sch B may result from the fat accumulation and mitochondrial damage in liver tissue. PMID- 28086887 TI - Patients' and physicians' perceptions and attitudes about oral anticoagulation and atrial fibrillation: a qualitative systematic review. AB - BACKGROUND: Oral anticoagulant therapy reduces the risk of stroke in patients with atrial fibrillation, but many patients are still not prescribed this therapy. The causes of underuse of vitamin K antagonists oral anticoagulants are not clear but could be related, in part, to patients' and physicians' perceptions and attitudes towards the benefits and downsides of this treatment. The purpose of this systematic review was to evaluate and synthesize patients' and physicians' perceptions and attitudes towards the benefits and downsides of vitamin K antagonist, in order to explore potential factors related with its underuse. METHODS: We included studies that used qualitative or mixed methods and focused on patients' and/or physicians' perceptions and attitudes towards oral anticoagulation. We systematically searched PubMed, EMBASE, ISI WoK, and PsycINFO from their inception until May 2013. Two reviewers independently assessed the quality of the included studies and synthesized results using a thematic analysis approach. RESULTS: We included a total of nine studies. In four studies, the quality assessed was excellent and in five was moderate. We identified three themes that were of interest to both physicians and patients: information to reinforce anticoagulation use, balance of benefits and downsides, roles in decision-making and therapy management. Three additional themes were of interest to patients: knowledge and understanding, impact on daily life, and satisfaction with therapy. The main difficulties with the use of anticoagulant treatment according to physicians were the perceived uncertainty, need of individualised decision-making, and the feeling of delegated responsibility as their main concerns. The main factors for patients were the lack of information and understanding. CONCLUSION: Physicians' and patients' perceptions and attitudes might be potential factors in the underuse of treatment with vitamin K antagonists. Improving the quality and usability of clinical guidelines, developing tools to help with the decision-making, enhancing coordination between primary care and hospital care, and improving information provided to patients could help improve the underuse of anticoagulation. PMID- 28086888 TI - Non-rigid MR-TRUS image registration for image-guided prostate biopsy using correlation ratio-based mutual information. AB - BACKGROUND: To improve the accuracy of ultrasound-guided biopsy of the prostate, the non-rigid registration of magnetic resonance (MR) images onto transrectal ultrasound (TRUS) images has gained increasing attention. Mutual information (MI) is a widely used similarity criterion in MR-TRUS image registration. However, the use of MI has been challenged because of intensity distortion, noise and down sampling. Hence, we need to improve the MI measure to get better registration effect. METHODS: We present a novel two-dimensional non-rigid MR-TRUS registration algorithm that uses correlation ratio-based mutual information (CRMI) as the similarity criterion. CRMI includes a functional mapping of intensity values on the basis of a generalized version of intensity class correspondence. We also analytically acquire the derivative of CRMI with respect to deformation parameters. Furthermore, we propose an improved stochastic gradient descent (ISGD) optimization method based on the Metropolis acceptance criteria to improve the global optimization ability and decrease the registration time. RESULTS: The performance of the proposed method is tested on synthetic images and 12 pairs of clinical prostate TRUS and MR images. By comparing label map registration frame (LMRF) and conditional mutual information (CMI), the proposed algorithm has a significant improvement in the average values of Hausdorff distance and target registration error. Although the average Dice Similarity coefficient is not significantly better than CMI, it still has a crucial increase over LMRF. The average computation time consumed by the proposed method is similar to LMRF, which is 16 times less than CMI. CONCLUSION: With more accurate matching performance and lower sensitivity to noise and down-sampling, the proposed algorithm of minimizing CRMI by ISGD is more robust and has the potential for use in aligning TRUS and MR images for needle biopsy. PMID- 28086889 TI - Hybrid brain-computer interface for biomedical cyber-physical system application using wireless embedded EEG systems. AB - BACKGROUND: One of the key challenges of the biomedical cyber-physical system is to combine cognitive neuroscience with the integration of physical systems to assist people with disabilities. Electroencephalography (EEG) has been explored as a non-invasive method of providing assistive technology by using brain electrical signals. METHODS: This paper presents a unique prototype of a hybrid brain computer interface (BCI) which senses a combination classification of mental task, steady state visual evoked potential (SSVEP) and eyes closed detection using only two EEG channels. In addition, a microcontroller based head mounted battery-operated wireless EEG sensor combined with a separate embedded system is used to enhance portability, convenience and cost effectiveness. This experiment has been conducted with five healthy participants and five patients with tetraplegia. RESULTS: Generally, the results show comparable classification accuracies between healthy subjects and tetraplegia patients. For the offline artificial neural network classification for the target group of patients with tetraplegia, the hybrid BCI system combines three mental tasks, three SSVEP frequencies and eyes closed, with average classification accuracy at 74% and average information transfer rate (ITR) of the system of 27 bits/min. For the real-time testing of the intentional signal on patients with tetraplegia, the average success rate of detection is 70% and the speed of detection varies from 2 to 4 s. PMID- 28086890 TI - Feasibility and preliminary efficacy of the 'HEYMAN' healthy lifestyle program for young men: a pilot randomised controlled trial. AB - BACKGROUND: In young men, unhealthy lifestyle behaviours can be detrimental to their physical and/or mental health and set them on a negative health trajectory into adulthood. Despite this, there is a lack of evidence to guide development of effective health behaviour change interventions for young men. This study assessed the feasibility and preliminary efficacy of the 'HEYMAN' (Harnessing Ehealth to enhance Young men's Mental health, Activity and Nutrition) healthy lifestyle program for young men. METHODS: A pilot RCT with 50 young men aged 18 25 years randomised to the HEYMAN intervention (n = 26) or waitlist control (n = 24). HEYMAN was a 3-month intervention, targeted for young men to improve eating habits, activity levels and well-being. Intervention development was informed by a participatory research model (PRECEDE-PROCEED). Intervention components included eHealth support (website, wearable device, Facebook support group), face to-face sessions (group and individual), a personalised food and nutrient report, home-based resistance training equipment and a portion control tool. Outcomes included: feasibility of research procedures (recruitment, randomisation, data collection and retention) and of intervention components. Generalized linear mixed models estimated the treatment effect at 3-months for the primary outcomes: pedometer steps/day, diet quality, well-being and several secondary outcomes. RESULTS: A 7-week recruitment period was required to enrol 50 young men. A retention rate of 94% was achieved at 3-months post-intervention. Retained intervention participants (n = 24) demonstrated reasonable usage levels for most program components and also reported reasonable levels of program component acceptability for attractiveness, comprehension, usability, support, satisfaction and ability to persuade, with scores ranging from 3.0 to 4.6 (maximum 5). No significant intervention effects were observed for the primary outcomes of steps/day (1012.7, 95% CI = -506.2, 2531.6, p = 0.191, d = 0.36), diet quality score (3.6, 95% CI = -0.4, 7.6, p = 0.081, d = 0.48) or total well-being score (0.4, 95% CI = -1.6, 2.5, p = 0.683, d = 0.11). Significant intervention effects were found for daily vegetable servings, energy-dense, nutrient-poor foods, MVPA, weight, BMI, fat mass, waist circumference and cholesterol (all p < 0.05). CONCLUSIONS: The HEYMAN program demonstrated feasibility in assisting young men to make some positive lifestyle changes. This provides support for the conduct of a larger, fully-powered RCT, but with minor amendments to research procedures and intervention components required. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616000350426 . PMID- 28086891 TI - Measurement of electrocardiograms in a bath through tap water utilizing capacitive coupling electrodes placed outside the bathtub wall. AB - BACKGROUND: Taking a bath sometimes poses a risk for subjects with chronic cardiopulmonary disorders, due to the thermal effect and water pressure on his/her body. The ECG measurement would be helpful for the early recognition of abnormal cardiac beats and respiratory conditions. This paper describes a new attempt to improve on previous bathtub ECG measurement techniques that had electrodes placed inside the bathtub that were intrusive to the subjects' bathing experience. This study is concerned with the initial development of a method to measure an electrocardiogram (ECG) through tap water without conscious awareness of the presence of electrodes that are placed outside the bathtub wall. METHODS: A configuration of capacitive coupling electrodes placed outside the bathtub was designed so that the electrodes could be hidden. The capacitive coupling was made from the electrodes to the water through the bathtub wall. Two electrodes with an active shielding amplifier covered further by an electromagnetic shield were fixed to the outside surface of the bathtub wall, near the bather's right scapula and left foot. The potential difference between these two electrodes, similar to the bipolar lead-II ECG, was amplified to obtain raw signals inclusive of ECG/QRS components. Respiration intervals were also derived from ECG/RR intervals. Comparison experiments between this bathtub method and conventional direct methods with spot-electrodes and a chest-band sensor were made using 10 healthy male volunteers (22.2 +/- 0.98 years). RESULTS: The ECG signal was detectable through tap water as well as water with differing conductivity resulting from mixing bathwater additives with the water. ECG signals and respiration curves derived from ECG/RR intervals were successfully obtained in all subjects. The intervals of the ECG/RR and respiration obtained by the bathtub system and by the direct method were respectively agreed well with each other. CONCLUSION: The ECG signal, in particular ECG/QRS components, were successfully detected utilizing capacitive coupling electrodes placed outside the bathtub wall. Also, the ECG/RR and respiration intervals were determined with reasonable accuracy as compared with the conventional direct methods. PMID- 28086892 TI - Pressure ulcer image segmentation technique through synthetic frequencies generation and contrast variation using toroidal geometry. AB - BACKGROUND: Pressure ulcers have become subject of study in recent years due to the treatment high costs and decreased life quality from patients. These chronic wounds are related to the global life expectancy increment, being the geriatric and physical disable patients the principal affected by this condition. Injuries diagnosis and treatment usually takes weeks or even months by medical personel. Using non-invasive techniques, such as image processing techniques, it is possible to conduct an analysis from ulcers and aid in its diagnosis. METHODS: This paper proposes a novel technique for image segmentation based on contrast changes by using synthetic frequencies obtained from the grayscale value available in each pixel of the image. These synthetic frequencies are calculated using the model of energy density over an electric field to describe a relation between a constant density and the image amplitude in a pixel. A toroidal geometry is used to decompose the image into different contrast levels by variating the synthetic frequencies. Then, the decomposed image is binarized applying Otsu's threshold allowing for obtaining the contours that describe the contrast variations. Morphological operations are used to obtain the desired segment of the image. RESULTS: The proposed technique is evaluated by synthesizing a Data Base with 51 images of pressure ulcers, provided by the Centre IGURCO. With the segmentation of these pressure ulcer images it is possible to aid in its diagnosis and treatment. To provide evidences of technique performance, digital image correlation was used as a measure, where the segments obtained using the methodology are compared with the real segments. The proposed technique is compared with two benchmarked algorithms. The results over the technique present an average correlation of 0.89 with a variation of +/-0.1 and a computational time of 9.04 seconds. CONCLUSIONS: The methodology presents better segmentation results than the benchmarked algorithms using less computational time and without the need of an initial condition. PMID- 28086893 TI - Seasonal variation in geographical access to maternal health services in regions of southern Mozambique. AB - BACKGROUND: Geographic proximity to health facilities is a known determinant of access to maternal care. Methods of quantifying geographical access to care have largely ignored the impact of precipitation and flooding. Further, travel has largely been imagined as unimodal where one transport mode is used for entire journeys to seek care. This study proposes a new approach for modeling potential spatio-temporal access by evaluating the impact of precipitation and floods on access to maternal health services using multiple transport modes, in southern Mozambique. METHODS: A facility assessment was used to classify 56 health centres. GPS coordinates of the health facilities were acquired from the Ministry of Health while roads were digitized and classified from high-resolution satellite images. Data on the geographic distribution of populations of women of reproductive age, pregnancies and births within the preceding 12 months, and transport options available to pregnant women were collected from a household census. Daily precipitation and flood data were used to model the impact of severe weather on access for a 17-month timeline. Travel times to the nearest health facilities were calculated using the closest facility tool in ArcGIS software. RESULTS: Forty-six and 87 percent of pregnant women lived within a 1-h of the nearest primary care centre using walking or public transport modes respectively. The populations within these catchments dropped by 9 and 5% respectively at the peak of the wet season. For journeys that would have commenced with walking to primary facilities, 64% of women lived within 2 h of life-saving care, while for those that began journeys with public transport, the same 2-hour catchment would have contained 95% of the women population. The population of women within two hours of life-saving care dropped by 9% for secondary facilities and 18% for tertiary facilities during the wet season. CONCLUSIONS: Seasonal variation in access to maternal care should not be imagined through a dichotomous and static lens of wet and dry seasons, as access continually fluctuates in both. This new approach for modelling spatio-temporal access allows for the GIS output to be utilized not only for health services planning, but also to aid near real time community-level delivery of maternal health services. PMID- 28086894 TI - C60 fullerene as promising therapeutic agent for correcting and preventing skeletal muscle fatigue. AB - BACKGROUND: Bioactive soluble carbon nanostructures, such as the C60 fullerene can bond with up to six electrons, thus serving by a powerful scavenger of reactive oxygen species similarly to many natural antioxidants, widely used to decrease the muscle fatigue effects. The aim of the study is to define action of the pristine C60 fullerene aqueous colloid solution (C60FAS), on the post-fatigue recovering of m. triceps surae in anaesthetized rats. RESULTS: During fatigue development, we observed decrease in the muscle effort level before C60FAS administration. After the application of C60FAS, a slower effort decrease, followed by the prolonged retention of a certain level, was recorded. An analysis of the metabolic process changes accompanying muscle fatigue showed an increase in the oxidative stress markers H 2 O 2 (hydrogen peroxide) and TBARS (thiobarbituric acid reactive substances) in relation to the intact muscles. After C60FAS administration, the TBARS content and H 2 O 2 level were decreased. The endogenous antioxidant system demonstrated a similar effect because the GSH (reduced glutathione) in the muscles and the CAT (catalase) enzyme activity were increased during fatigue. CONCLUSIONS: C60FAS leads to reduction in the recovery time of the muscle contraction force and to increase in the time of active muscle functioning before appearance of steady fatigue effects. Therefore, it is possible that C60FAS affects the prooxidant-antioxidant muscle tissue homeostasis, subsequently increasing muscle endurance. PMID- 28086895 TI - Design optimization of stent and its dilatation balloon using kriging surrogate model. AB - BACKGROUND: Although stents have great success of treating cardiovascular disease, it actually undermined by the in-stent restenosis and their long-term fatigue failure. The geometry of stent affects its service performance and ultimately affects its fatigue life. Besides, improper length of balloon leads to transient mechanical injury to the vessel wall and in-stent restenosis. Conventional optimization method of stent and its dilatation balloon by comparing several designs and choosing the best one as the optimal design cannot find the global optimal design in the design space. In this study, an adaptive optimization method based on Kriging surrogate model was proposed to optimize the structure of stent and the length of stent dilatation balloon so as to prolong stent service life and improve the performance of stent. METHODS: A finite element simulation based optimization method combing with Kriging surrogate model is proposed to optimize geometries of stent and length of stent dilatation balloon step by step. Kriging surrogate model coupled with design of experiment method is employed to construct the approximate functional relationship between optimization objectives and design variables. Modified rectangular grid is used to select initial training samples in the design space. Expected improvement function is used to balance the local and global searches to find the global optimal result. Finite element method is adopted to simulate the free expansion of balloon-expandable stent and the expansion of stent in stenotic artery. The well-known Goodman diagram was used for the fatigue life prediction of stent, while dogboning effect was used for stent expansion performance measurement. As the real design cases, diamond-shaped stent and sv-shaped stent were studied to demonstrate how the proposed method can be harnessed to design and refine stent fatigue life and expansion performance computationally. RESULTS: The fatigue life and expansion performance of both the diamond-shaped stent and sv-shaped stent are designed and refined, respectively. (a) diamond-shaped stent: The shortest distance from the data points to the failure line in the Goodman diagram was increased by 22.39%, which indicated a safer service performance of the optimal stent. The dogboning effect was almost completely eliminated, which implies more uniform expansion of stent along its length. Simultaneously, radial elastic recoil (RR) at the proximal and distal ends was reduced by 40.98 and 35% respectively and foreshortening (FS) was also decreased by 1.75%. (b) sv-shaped stent: The shortest distance from the data point to the failure line in the Goodman diagram was increased by 15.91%. The dogboning effect was also completely eliminated, RR at the proximal and distal ends was reduced by 82.70 and 97.13%, respectively, and the FS was decreased by 16.81%. Numerical results showed that the fatigue life of both stents was refined and the comprehensive expansion performance of them was improved. CONCLUSIONS: This article presents an adaptive optimization method based on the Kriging surrogate model to optimize the structure of stents and the length of their dilatation balloon to prolong stents fatigue life and decreases the dogboning effect of stents during expansion process. Numerical results show that the adaptive optimization method based on Kriging surrogate model can effectively optimize the design of stents and the dilatation balloon. Further investigations containing more design goals and more effective multidisciplinary design optimization method are warranted. PMID- 28086896 TI - Fast-track surgery versus conventional perioperative management of lung cancer associated pneumonectomy: a randomized controlled clinical trial. AB - BACKGROUND: The aim of this study is to investigate the effects of fast-track surgery (FTS) on postoperative recovery, hospital stay, total medical costs, and the complications of pneumonectomy in patients with non-small cell lung cancer (NSCLC). METHODS: Studies were performed between June 2012 and March 2014 in 17 patients received FTS and 18 patients given conventional management (control) after pneumonectomy in the Department of Thoracic Surgery, the Fourth Affiliated Hospital of Harbin Medical University. Patients were evaluated based on their days to achieve the first postoperative flatus, C-reactive protein (CRP) at postoperative day (POD) 1-7, the length of hospital stay, the medical costs, and postoperative complications. RESULTS: The results showed that in the FTS group, latency to the first postoperative flatus (1.5 +/- 0.6 versus 3.1 +/- 0.8 s in controls, P < 0.0001), CRP (71.36 +/- 5.48 versus 80.71 +/- 8.32 mg/L in at POD 7, P < 0.0001), the length of hospital stay (18.1 +/- 1.4 versus 27.4 +/- 6.6 days, P < 0.0001), and the medical costs (29.9 +/- 2.7 versus 37.2 +/- 3.6 thousand Chinese Yuan, P < 0.0001) were significantly reduced compared to the group receiving conventional management. FTS group also had a relatively lower postoperative complication rate (23.5% of 17 versus 33.3% of 18 in control group) although it was statistically insignificant (P = 0.711). CONCLUSIONS: These results indicate that application of the FTS in NSCLC pneumonectomy efficiently accelerates postoperative recovery, shortens hospital stay, reduces the total medical costs of the patients and thus is more acceptable than conventional management. PMID- 28086897 TI - Application of the analytic hierarchy approach to the risk assessment of Zika virus disease transmission in Guangdong Province, China. AB - BACKGROUND: An international spread of Zika virus (ZIKV) infection has attracted global attention in 2015. The infection also affected Guangdong province, which is located in southern China. Multiple factors, including frequent communication with South America and Southeast Asia, suitable climate (sub-tropical) for the habitat of Aedes species, may increase the risk of ZIKV disease transmission in this region. METHODS: An analytic hierarchy process (AHP) method was used to develop a semi-quantitative ZIKV risk assessment model. After selecting indicators, we invited experts in related professions to identify the index weight and based on that a hierarchical structure was generated. Then a series of pairwise comparisons were used to determine the relative importance of the criteria. Finally, the optimal model was established to estimate the spatial and seasonal transmission risk of ZIKV. RESULTS: A total of 15 factors that potentially influenced the risk of ZIKV transmission were identified. The factor that received the largest weight was epidemic of ZIKV in Guangdong province (combined weight [CW] =0.37), followed by the mosquito density (CW = 0.18) and the epidemic of DENV in Guangdong province (CW = 0.14). The distribution of 123 districts/counties' RIs of ZIKV in Guangdong through different seasons were presented, respectively. CONCLUSIONS: Higher risk was observed within Pearl River Delta including Guangzhou, Shenzhen and Jiangmen, and the risk is greater in summer and autumn compared to spring and winter. PMID- 28086898 TI - The intergenerational production of depression in South Korea: results from a cross-sectional study. AB - BACKGROUND: Although a number of studies have uncovered relationships between parental capital and the manifestation of depression in their children, little is known about the mechanisms that undergird the relationships. This study investigates the intergenerational effects of the cultural and economic capitals of South Korean parents on depressive symptoms in their adult children and the degree to which the capitals of the adult children explain them. METHODS: We employed nationally representative cross-sectional survey data from the 2006 Korea Welfare Panel Study. A sample of 11,576 adults over thirty years of age was used to investigate the intergenerational production of depression in South Korea. We applied binary logistic regression modelling to the Center for Epidemiological Studies Depression Scale (CES-D). RESULTS: Parental education (institutionalized cultural capital) manifested an independent and statistically significant inverse association with depressive symptoms [OR = 1.680 (95% CI: 1.118-2.523) for men; OR = 2.146 (95% CI: 1484-3.102) for women]. Childhood economic circumstances (economic capital) had an independent and statistically significant inverse association with depressive symptoms among adult women only [OR = 2.009 (95% CI: 1.531-2.635)]. The education of the adult children themselves was strongly associated with depressive symptoms in the expected direction [OR = 4.202 (95% CI: 2.856-6.181) for men; OR = 4.058 (95% CI: 2.824 5.830)] and the most of the association between parental capitals and depressive symptoms was explained by the educational attainment of the children. Receipt of monetary inheritance from parents had a weak but statistically significant association with depression among men [OR = 1.248 (95% CI: 1.041-1.496)] but was unrelated to depression among women. A large portion of the association between respondent education and depressive symptoms was explained by household income. Finally, childhood economic circumstances were associated with depressive symptoms among women over and above the cultural and economic capitals held by the women themselves [OR = 1.608 (95% CI: 2.08-2.139)]. CONCLUSIONS: Our study illuminates the importance of the intergenerational transmission of capitals for the development of depressive symptoms among adults in South Korea. PMID- 28086899 TI - Evaluations of diffusion tensor image registration based on fiber tractography. AB - BACKGROUND: Diffusion Tensor Magnetic Resonance Imaging (DT-MRI, also known as DTI) measures the diffusion properties of water molecules in tissues and to date is one of the main techniques that can effectively study the microstructures of the brain in vivo. Presently, evaluation of DTI registration techniques is still in an initial stage of development. METHODS AND RESULTS: In this paper, six well known open source DTI registration algorithms: Elastic, Rigid, Affine, DTI-TK, FSL and SyN were applied on 11 subjects from an open-access dataset, among which one was randomly chosen as the template. Eight different fiber bundles of 10 subjects and the template were obtained by drawing regions of interest (ROIs) around various structures using deterministic streamline tractography. The performances of the registration algorithms were evaluated by computing the distances and intersection angles between fiber tracts, as well as the fractional anisotropy (FA) profiles along the fiber tracts. Also, the mean squared error (MSE) and the residual MSE (RMSE) of fibers originating from the registered subjects and the template were calculated to assess the registration algorithm. Twenty-seven different fiber bundles of the 10 subjects and template were obtained by drawing ROIs around various structures using probabilistic tractography. The performances of registration algorithms on this second tractography method were evaluated by computing the spatial correlation similarity of the fibers between subjects as well as between each subject and the template. CONCLUSION: All experimental results indicated that DTI-TK performed the best under the study conditions, and SyN ranked just behind it. PMID- 28086901 TI - GPU accelerated voxel-driven forward projection for iterative reconstruction of cone-beam CT. AB - BACKGROUND: For cone-beam computed tomography (CBCT), which has been playing an important role in clinical applications, iterative reconstruction algorithms are able to provide advantageous image qualities over the classical FDK. However, the computational speed of iterative reconstruction is a notable issue for CBCT, of which the forward projection calculation is one of the most time-consuming components. METHOD AND RESULTS: In this study, the cone-beam forward projection problem using the voxel-driven model is analysed, and a GPU-based acceleration method for CBCT forward projection is proposed with the method rationale and implementation workflow detailed as well. For method validation and evaluation, computational simulations are performed, and the calculation times of different methods are collected. Compared with the benchmark CPU processing time, the proposed method performs effectively in handling the inter-thread interference problem, and an acceleration ratio as high as more than 100 is achieved compared to a single-threaded CPU implementation. CONCLUSION: The voxel-driven forward projection calculation for CBCT is highly paralleled by the proposed method, and we believe it will serve as a critical module to develop iterative reconstruction and correction methods for CBCT imaging. PMID- 28086900 TI - The role of birthplace and educational attainment on induced abortion inequalities. AB - BACKGROUND: Induced abortion (IA) has shown social inequality related to birthplace and education with higher rates of IAs in immigrant and in less educated women relative to their native and highly educated counterparts. This study examined the independent and joint effects of birthplace and education on IA, repeated and IA performed during the 2nd trimester of pregnancy among women residing in the Basque Country, Spain. METHODS: We conducted a cross-sectional population-based study of IA among women aged 25-49 years residing in the Basque Country, Spain, between 2011 and 2013. Log-binomial regression was used to quantify the independent and joint effects of birthplace and education attainment on all outcomes. RESULTS: Immigrant women exhibited higher probability of having an IAs (PR: 5.31), a repeated (PR: 7.23) or a 2nd trimester IAs (PR: 4.07) than women born in Spain. We observed higher probabilities for all outcomes among women with a primary or less education relative to those with a graduate education (All IAs PR: 2.51; repeated PR: 6.00; 2nd trimester PR: 3.08). However, no significant heterogeneity was observed for the effect of education on the association of birthplace with IAs, repeated or 2nd trimester IAs. CONCLUSIONS: Birthplace and education are key factors to explain not only an IA decision but also having a repeated or a 2nd trimester IA. However, the effects of birthplace and education may be independent from each other on these outcomes. A better understanding of these factors on IAs is needed when designing programs for sexual and reproductive health aimed to reduce inequalities among women. PMID- 28086902 TI - Exploiting temporal and nonstationary features in breathing sound analysis for multiple obstructive sleep apnea severity classification. AB - BACKGROUND: Polysomnography (PSG) is the gold standard test for obstructive sleep apnea (OSA), but it incurs high costs, requires inconvenient measurements, and is limited by a one-night test. Thus, a repetitive OSA screening test using affordable data would be effective both for patients interested in their own OSA risk and in-hospital PSG. The purpose of this research was to develop a four-OSA severity classification model using a patient's breathing sounds. METHODS: Breathing sounds were recorded from 83 subjects during a PSG test. There was no exclusive experimental protocol or additional recording instruments use throughout the sound recording procedure. Based on the Apnea-Hypopnea Index (AHI), which indicates the severity of sleep apnea, the subjects' sound data were divided into four-OSA severity classes. From the individual sound data, we proposed two novel methods which were not attempted in previous OSA severity classification studies. First, the total transition probability of approximated sound energy in time series, and second, the statistical properties derived from the dimension-reduced cyclic spectral density. In addition, feature selection was conducted to achieve better results with a more relevant subset of features. Then, the classification model was trained using support vector machines and evaluated using leave-one-out cross-validation. RESULTS: The overall results show that our classification model is better than existing multiple OSA severity classification method using breathing sounds. The proposed method demonstrated 79.52% accuracy for the four-class classification task. Additionally, it demonstrated 98.0% sensitivity, 75.0% specificity, and 92.78% accuracy for OSA subject detection classification with AHI threshold 5. CONCLUSIONS: The results show that our proposed method can be used as part of an OSA screening test, which can provide the subject with detailed OSA severity results from only breathing sounds. PMID- 28086903 TI - Negative immune factors might predominate local tumor immune status and promote carcinogenesis in cervical carcinoma. AB - BACKGROUND: The disequilibrium of local immune microenvironment is an essential element during tumorigenesis. METHOD: By conducting real-time polymerase chain reaction, we identified the mRNA level of immune factors, FoxP3 (forkhead box protein P3), CCL22/CCR4 (chemokine (C-C motif) ligand 22/CC chemokine receptor 4), OX40L/OX40 (tumor necrosis factor superfamily member 4/tumor necrosis factor receptor superfamily member 4) and Smad3 (SMAD family member 3) in neoplastic foci and its periphery tissues from 30 cases of squamous cervical carcinoma and 20 cases of normal cervix. RESULT: The FoxP3, CCL22 and CCR4 mRNA level in local immune microenvironment of normal cervix was lower than that in cervical cancer. While OX40L, OX40 and Smad3 mRNA level profile in normal cervix was higher than that in cervical cancer. Beyond individual effect, the pairwise positive correlations were demonstrated among the mRNA level of FoxP3, CCL22 and CCR4. The mRNA level of OX40 negatively correlated with CCL22, but positively correlated with Smad3. Moreover, the mRNA level of FoxP3 and CCL22 was increased while Smad3 was decreased in cervical tissue with HPV (human papilloma virus) infection. CONCLUSION: Our data yields insight into the roles of these immune factors in cervical carcinogenesis. It may therefore be that, in microenvironment of cervical squamous cell carcinoma, along with the context of HPV infection, negative immune regulators FoxP3, CCL22 and CCR4 might overwhelm positive immune factors OX40L, OX40 and Smad3, giving rise to an immunosuppressive status and promote the progression of cervical carcinogenesis. TRIAL REGISTRATION: Not applicable. PMID- 28086905 TI - Reduction of eddy current losses in inductive transmission systems with ferrite sheets. AB - BACKGROUND: Improvements in eddy current suppression are necessary to meet the demand for increasing miniaturization of inductively driven transmission systems in industrial and biomedical applications. The high magnetic permeability and the simultaneously low electrical conductivity of ferrite materials make them ideal candidates for shielding metallic surfaces. For systems like cochlear implants the transmission of data as well as energy over an inductive link is conducted within a well-defined parameter set. For these systems, the shielding can be of particular importance if the properties of the link can be preserved. RESULTS: In this work, we investigate the effect of single and double-layered substrates consisting of ferrite and/or copper on the inductance and coupling of planar spiral coils. The examined link systems represent realistic configurations for active implantable systems such as cochlear implants. Experimental measurements are complemented with analytical calculations and finite element simulations, which are in good agreement for all measured parameters. The results are then used to study the transfer efficiency of an inductive link in a series-parallel resonant topology as a function of substrate size, the number of coil turns and coil separation. CONCLUSIONS: We find that ferrite sheets can be used to shield the system from unwanted metallic surfaces and to retain the inductive link parameters of the unperturbed system, particularly its transfer efficiency. The required size of the ferrite plates is comparable to the size of the coils, which makes the setup suitable for practical implementations. Since the sizes and geometries chosen for the studied inductive links are comparable to those of cochlear implants, our conclusions apply in particular to these systems. PMID- 28086904 TI - The lncRNA CRNDE promotes colorectal cancer cell proliferation and chemoresistance via miR-181a-5p-mediated regulation of Wnt/beta-catenin signaling. AB - BACKGROUND: With more than 600,000 mortalities each year, colorectal cancer (CRC) is the third most commonly diagnosed type of cancer worldwide. Recently, mechanisms involving noncoding RNAs have been implicated in the development of CRC. METHODS: We examined expression levels of lncRNA CRNDE and miR-181a-5p in 64 cases of CRC tissues and cell lines by qRT-PCR. Gain-of-function and loss-of function assays were performed to examine the effect of CRNDE and miR-181a-5p on proliferation and chemoresistance of CRC cells. Using fluorescence reporter and western blot assays, we also explored the possible mechanisms of CRNDE in CRC cells. RESULTS: In this study, we found that the expression levels of the CRNDE were upregulated in CRC clinical tissue samples. We identified microRNA miR-181a 5p as an inhibitory target of CRNDE. Both CRNDE knockdown and miR-181a-5p overexpression in CRC cell lines led to inhibited cell proliferation and reduced chemoresistance. We also determined that beta-catenin and TCF4 were inhibitory targets of miR-181a-5p, and that Wnt/beta-catenin signaling was inhibited by both CRNDE knockdown and miR-181a-5p overexpression. Significantly, we found that the repression of cell proliferation, the reduction of chemoresistance, and the inhibition of Wnt/beta-catenin signaling induced by CRNDE knockdown would require the increased expression of miR-181a-5p. CONCLUSIONS: Our study demonstrated that the lncRNA CRNDE could regulate the progression and chemoresistance of CRC via modulating the expression levels of miR-181a-5p and the activity of Wnt/beta catenin signaling. PMID- 28086906 TI - Physical activity and nutrition behaviour outcomes of a cluster-randomized controlled trial for adults with metabolic syndrome in Vietnam. AB - BACKGROUND: Metabolic syndrome is prevalent among Vietnamese adults, especially those aged 50-65 years. This study evaluated the effectiveness of a 6 month community-based lifestyle intervention to increase physical activity levels and improve dietary behaviours for adults with metabolic syndrome in Vietnam. METHODS: Ten communes, involving participants aged 50-65 years with metabolic syndrome, were recruited from Hanam province in northern Vietnam. The communes were randomly allocated to either the intervention (five communes, n = 214) or the control group (five communes, n = 203). Intervention group participants received a health promotion package, consisting of an information booklet, education sessions, a walking group, and a resistance band. Control group participants received one session of standard advice during the 6 month period. Data were collected at baseline and after the intervention to evaluate programme effectiveness. The International Physical Activity Questionnaire - Short Form and a modified STEPS questionnaire were used to assess physical activity and dietary behaviours, respectively, in both groups. Pedometers were worn by the intervention participants only for 7 consecutive days at baseline and post intervention testing. To accommodate the repeated measures and the clustering of individuals within communes, multilevel mixed regression models with random effects were fitted to determine the impacts of intervention on changes in outcome variables over time and between groups. RESULTS: With a retention rate of 80.8%, the final sample comprised 175 intervention and 162 control participants. After controlling for demographic and other confounding factors, the intervention participants showed significant increases in moderate intensity activity (P = 0.018), walking (P < 0.001) and total physical activity (P = 0.001), as well as a decrease in mean sitting time (P < 0.001), relative to their control counterparts. Significant improvements in dietary behaviours were also observed, particularly reductions in intake of animal internal organs (P = 0.001) and in using cooking oil for daily meal preparation (P = 0.001). CONCLUSIONS: The prescribed community-based physical activity and nutrition intervention programme successfully improved physical activity and dietary behaviours for adults with metabolic syndrome in Vietnam. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12614000811606 . Registered on 31 July 2014. PMID- 28086907 TI - Identification of the main determinants of abdominal aorta size: a screening by Pocket Size Imaging Device. AB - BACKGROUND: Ultrasound exam as a screening test for abdominal aorta (AA) can visualize the aorta in 99% of patients and has a sensitivity and specificity approaching 100% in screening settings for aortic aneurysm. Pocket Size Imaging Device (PSID) has a potential value as a screening tool, because of its possible use in several clinical settings. Our aim was to assess the impact of demographics and cardiovascular (CV) risk factors on AA size by using PSID in an outpatient screening. METHODS: Consecutive patients, referring for a CV assessment in a 6 months period, were screened. AA was visualized by subcostal view in longitudinal and transverse plans in order to determine the greatest anterior-posterior diameter. After excluding 5 patients with AA aneurysm, 508 outpatients were enrolled. All patients underwent a sequential assessment including clinical history with collection of CV risk factors, physical examination, PSID exam and standard Doppler echoc exam using a 2.5 transducer with harmonic capability, both by expert ultrasound operators, during the same morning. Standard echocardiography operators were blinded on PSID exam and viceversa. RESULTS: Diagnostic accuracy of AA size by PSID was tested successfully with standard echo machine in a subgroup (n = 102) (rho = 0.966, p < 0.0001). AA diameter was larger in men than in women and in >=50 -years old subjects than in those <50 -years old (both p < 0.0001). AA was larger in patients with coronary artery disease (CAD) (p < 0.0001). By a multivariate model, male sex (p < 0.0001), age and body mass index (both p < 0.0001), CAD (p < 0.01) and heart rate (p = 0.018) were independent predictors of AA size (cumulative R 2 = 0.184, p < 0.0001). CONCLUSION: PSID is a reliable tool for the screening of determinants of AA size. AA diameter is greater in men and strongly influenced by aging and overweight. CAD may be also associated to increased AA diameter. PMID- 28086908 TI - HIV integration sites in latently infected cell lines: evidence of ongoing replication. AB - BACKGROUND: Assessing the location and frequency of HIV integration sites in latently infected cells can potentially inform our understanding of how HIV persists during combination antiretroviral therapy. We developed a novel high throughput sequencing method to evaluate HIV integration sites in latently infected cell lines to determine whether there was virus replication or clonal expansion in these cell lines observed as multiple integration events at the same position. RESULTS: We modified a previously reported method using random DNA shearing and PCR to allow for high throughput robotic processing to identify the site and frequency of HIV integration in latently infected cell lines. Latently infected cell lines infected with intact virus demonstrated multiple distinct HIV integration sites (28 different sites in U1, 110 in ACH-2 and 117 in J1.1 per 150,000 cells). In contrast, cell lines infected with replication-incompetent viruses (J-Lat cells) demonstrated single integration sites. Following in vitro passaging of the ACH-2 cell line, we observed a significant increase in the frequency of unique HIV integration sites and there were multiple mutations and large deletions in the proviral DNA. When the ACH-2 cell line was cultured with the integrase inhibitor raltegravir, there was a significant decrease in the number of unique HIV integration sites and a transient increase in the frequency of 2-LTR circles consistent with virus replication in these cells. CONCLUSION: Cell lines latently infected with intact HIV demonstrated multiple unique HIV integration sites indicating that these cell lines are not clonal and in the ACH 2 cell line there was evidence of low level virus replication. These findings have implications for the use of latently infected cell lines as models of HIV latency and for the use of these cells as standards. PMID- 28086909 TI - Fast detection and data compensation for electrodes disconnection in long-term monitoring of dynamic brain electrical impedance tomography. AB - BACKGROUND: Electrode disconnection is a common occurrence during long-term monitoring of brain electrical impedance tomography (EIT) in clinical settings. The data acquisition system suffers remarkable data loss which results in image reconstruction failure. The aim of this study was to: (1) detect disconnected electrodes and (2) account for invalid data. METHODS: Weighted correlation coefficient for each electrode was calculated based on the measurement differences between well-connected and disconnected electrodes. Disconnected electrodes were identified by filtering out abnormal coefficients with discrete wavelet transforms. Further, previously valid measurements were utilized to establish grey model. The invalid frames after electrode disconnection were substituted with the data estimated by grey model. The proposed approach was evaluated on resistor phantom and with eight patients in clinical settings. RESULTS: The proposed method was able to detect 1 or 2 disconnected electrodes with an accuracy of 100%; to detect 3 and 4 disconnected electrodes with accuracy of 92 and 84% respectively. The time cost of electrode detection was within 0.018 s. Further, the proposed method was capable to compensate at least 60 subsequent frames of data and restore the normal image reconstruction within 0.4 s and with a mean relative error smaller than 0.01%. CONCLUSIONS: In this paper, we proposed a two-step approach to detect multiple disconnected electrodes and to compensate the invalid frames of data after disconnection. Our method is capable of detecting more disconnected electrodes with higher accuracy compared to methods proposed in previous studies. Further, our method provides estimations during the faulty measurement period until the medical staff reconnects the electrodes. This work would improve the clinical practicability of dynamic brain EIT and contribute to its further promotion. PMID- 28086910 TI - Identifying youth-friendly service practices associated with adolescents' use of reproductive healthcare services in post-conflict Burundi: a cross-sectional study. AB - BACKGROUND: Very little is known about reproductive health service (RHS) availability and adolescents' use of these services in post-conflict settings. Such information is crucial for targeted community interventions that aim to improve quality delivery of RHS and outcomes in post-conflict settings. The objectives of this study therefore was to examine the density of RHS availability; assess spatial patterns of RHC facilities; and identify youth friendly practices associated with adolescents' use of services in post-conflict Burundi. METHODS: A cross-sectional survey was conducted from a full census of all facilities (n = 892) and provider interviews in Burundi. Surveyed facilities included all public, private, religious and community association owned-centers and hospitals. At each facility efforts were made to interview the officer-in charge and a group of his/her staff. We applied both geospatial and non-spatial analyses, to examine the density of RHS availability and density, and to explore the association between youth-friendly practices and adolescents' use of RHS in post-conflict Burundi. RESULTS: High spatial patterning of distances of RHC facilities was observed, with facilities clustered predominantly in districts exhibiting persistent violence. But, use of services remained undeterred. We further found a stronger association between use of RHS and facility and programming characteristics. Community outreach, designated check-in/exam rooms, educational materials (posters, print, and pictures) in waiting rooms, privacy and confidentiality were significantly associated with adolescents' use of RHS across all facility types. Cost was associated with use only at religious facilities and youth involvement at private facilities. No significant association was found between provider characteristics and use of RHS at any facility. CONCLUSIONS: Our findings indicate the need to improve youth-friendly service practices in the provision of RHS to adolescents in Burundi and suggest that current approaches to provider training may not be adequate for improving these vital practices. Our mixed methods approach and results are generalizable to other countries and post-conflict settings. In post-conflict settings, the methods can be used to identify service availability and spatial patterns of RHC facilities to plan for targeted service interventions, to increase demand and uptake of services by youth and young adults. PMID- 28086911 TI - Enhanced neuroinflammation mediated by DNA methylation of the glucocorticoid receptor triggers cognitive dysfunction after sevoflurane anesthesia in adult rats subjected to maternal separation during the neonatal period. AB - BACKGROUND: Mounting evidence indicates that children who experience abuse and neglect are prone to chronic diseases and premature mortality later in life. One mechanistic hypothesis for this phenomenon is that early life adversity alters the expression or functioning of the glucocorticoid receptor (GR) throughout the course of life and thereby increases sensitivity to inflammatory stimulation. An exaggerated pro-inflammatory response is generally considered to be a key cause of postoperative cognitive dysfunction (POCD). The aim of this study was to examine the effects of early life adversity on cognitive function and neuroinflammation after sevoflurane anesthesia in adult rats and to determine whether such effects are associated with the epigenetic regulation of GR. METHODS: Wistar rat pups were repeatedly subjected to infant maternal separation (early life stress) from postnatal days 2-21. In adulthood, their behavior and the signaling of hippocampal pro-inflammatory factors and nuclear factor-kappa B (NF-kappaB) after sevoflurane anesthesia were evaluated. We also examined the effects of maternal separation (MS) on the expression of GR and the DNA methylation status of the promoter region of exon 17 of GR and whether behavioral changes and neuroinflammation after anesthesia were reversible when the expression of GR was increased by altering DNA methylation. RESULTS: MS induced cognitive decline after sevoflurane inhalation in the Morris water maze and context fear conditioning tests and enhanced the release of cytokines and the activation of astrocyte intracellular NF-kappaB signaling induced by sevoflurane in the hippocampus of adult rats. Blocking NF-kappaB signaling by pyrrolidine dithiocarbamate (PDTC) inhibited the release of cytokines. MS also reduced the expression of GR and upregulated the methylation levels of the promoter region of GR exon 17, and such effects were reversed by treatment with the histone deacetylase inhibitor trichostatin A (TSA) in adult rats. Moreover, TSA treatment in adult MS rats inhibited the overactivation of astrocyte intracellular NF kappaB signaling and the release of cytokines and alleviated cognitive dysfunction after sevoflurane anesthesia. CONCLUSIONS: Early life stress induces cognitive dysfunction after sevoflurane anesthesia, perhaps due to the aberrant methylation of the GR gene promoter, which reduces the expression of the GR gene and facilitates exaggerated inflammatory responses. PMID- 28086913 TI - Correction of irregular and induced regular corneal astigmatism with toric IOL after posterior segment surgery: a case series. AB - BACKGROUND: Toric intraocular lens (IOL) implantation can be an effective method for correcting corneal astigmatism in patients with vitreoretinal diseases and cataract. Our purpose is to report the outcome of toric IOL implantation in two cases - a patient with scleral-buckle-induced regular corneal astigmatism and a patient with keratoconus following pars plana vitrectomy. As far as we are aware, there are no reported cases of toric IOL implantation in a vitrectomized eye with keratoconus nor of toric IOL implantation in patients with scleral-buckle-induced regular corneal astigmatism. CASE PRESENTATION: Two patients with myopia and high corneal astigmatism underwent cataract operation with toric IOL implantation after posterior segment surgery. Myopia and high astigmatism (>2.5 diopter) were caused by previous scleral buckling in one case and by keratoconus in the other case. Pre- and postoperative examinations during the follow-up of included uncorrected and spectacle corrected distance visual acuity (UCDVA/CDVA), automated kerato-refractometry (Topcon), Pentacam HR, IOL Master (Zeiss) axial length measurements and fundus optical coherence tomography (Zeiss). One year postoperatively, the UCDVA and CDVA were 20/25 and 20/20 in both cases, respectively. The absolute residual refractive astigmatism was 1.0 and 0.75 Diopters, respectively. The IOL rotation was within 3 degrees in both eyes, therefore IOL repositioning was not necessary. Complications were not observed in our cases. CONCLUSION: These cases demonstrate that toric IOL implantation is a predictable and safe method for the correction of high corneal astigmatism in complicated cases with different origins. Irregular corneal astigmatism in keratoconus or scleral-buckle-induced regular astigmatisms can be equally well corrected with the use of toric IOL during cataract surgery. Previous scleral buckling or pars plana vitrectomy seem to have no impact on the success of the toric IOL implantation, even in keratoconus. IOL rotational stability and refractive predictability in patients with a previous vitreoretinal surgery can be as good as in uncomplicated cases. PMID- 28086912 TI - WWL70 attenuates PGE2 production derived from 2-arachidonoylglycerol in microglia by ABHD6-independent mechanism. AB - BACKGROUND: alpha/beta-Hydrolase domain 6 (ABHD6) is one of the major enzymes for endocannabinoid 2-arachidonoylglycerol (2-AG) hydrolysis in microglia cells. Our recent studies have shown that a selective ABHD6 inhibitor WWL70 has anti inflammatory and neuroprotective effects in animal models of traumatic brain injury and multiple sclerosis. However, the role of ABHD6 in the neuroinflammatory response and the mechanisms by which WWL70 suppresses inflammation has not yet been elucidated in reactive microglia. METHODS: The hydrolytic activity and the levels of 2-AG in BV2 cells were measured by radioactivity assay and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The expression of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) synthases in microglia treated with lipopolysaccharide (LPS) with/without WWL70 was determined by western blot and quantitative RT-PCR. The conversion of 2-AG to PGE2 or PGE2-glyceryl ester (PGE2-G) was assessed by enzyme-linked immunoassay (EIA) or LC-MS/MS. The involvement of ABHD6 in PGE2 production was assessed using pharmacological inhibitors and small interfering RNA (siRNA). The effect of WWL70 on PGE2 biosynthesis activity in the microsome fraction from BV2 cells and experimental autoimmune encephalopathy (EAE) mouse brain was also examined. RESULTS: We found that WWL70 suppressed PGE2 production in LPS-activated microglia via cannabinoid receptor-independent mechanisms, although intracellular levels of 2-AG were elevated by WWL70 treatment. This reduction was not attributable to WWL70 inhibition of ABHD6, given the fact that downregulation of ABHD6 by siRNA or use of KT182, an alternative ABHD6 inhibitor failed to suppress PGE2 production. WWL70 attenuated the expression of COX-2 and PGES-1/2 leading to the downregulation of the biosynthetic pathways of PGE2 and PGE2-G. Moreover, PGE2 production from arachidonic acid was reduced in the microsome fraction, indicating that WWL70 also targets PGE2 biosynthetic enzymes, which are likely to contribute to the therapeutic mechanisms of WWL70 in the EAE mouse model. CONCLUSIONS: WWL70 is an anti-inflammatory therapeutic agent capable of inhibiting PGE2 and PGE2-G production, primarily due to its reduction of COX-2 and microsomal PGES-1/2 expression and their PGE2 biosynthesis activity in microglia cells, as well as in the EAE mouse brain. PMID- 28086914 TI - Delivering HIV services in partnership: factors affecting collaborative working in a South African HIV programme. AB - BACKGROUND: The involvement of Global Health Initiatives (GHIs) in delivering health services in low and middle income countries (LMICs) depends on effective collaborative working at scales from the local to the international, and a single GHI is effectively constructed of multiple collaborations. Research is needed focusing on how collaboration functions in GHIs at the level of health service management. Here, collaboration between local implementing agencies and departments of health involves distinct power dynamics and tensions. Using qualitative data from an evaluation of a health partnership in South Africa, this article examines how organisational power dynamics affected the operation of the partnership across five dimensions of collaboration: governance, administration, organisational autonomy, mutuality, and norms of trust and reciprocity. RESULTS: Managing the tension between the power to provide resources held by the implementing agency and the local Departments' of Health power to access the populations in need of these resources proved critical to ensuring that the collaboration achieved its aims and shaped the way that each domain of collaboration functioned in the partnership. CONCLUSIONS: These findings suggest that it is important for public health practitioners to critically examine the ways in which collaboration functions across the scales in which they work and to pay particular attention to how local power dynamics between partner organisations affect programme implementation. PMID- 28086915 TI - Comparative study in infertile couples with and without Chlamydia trachomatis genital infection. AB - BACKGROUND: Chlamydia, caused by the bacterium Chlamydia trachomatis(C. trachomatis), is the most common sexually transmitted disease. The incidence is not clear due to the asymptomatic nature of early stage of infections. The incidence of Chlamydia has not been fully investigated in the Chinese Han population. Since chronic infection with can C. trachomatis can lead to infertility in males and females, it is important to determine the impact of infection on clinical outcomes. The aim of this study is to explore the epidemiology of C. trachomatis in subfertile couples and to determine whether infections will adversely affect clinical outcomes after assisted reproduction technique (ART) treatment. METHODS: Subfertile patients (n = 30760) were screened in the research for C. trachomatis in our center from January 2010 to December 2014. C. trachomatis-specific DNA was detected by Taq-man PCR from semen or swabs from the urethral, endocervix or vaginal. The control group consisted of 1140 subfertile patients without C. trachomatis infection. The prevalence and characteristics of C. trachomatis were identified for subfertile couples and clinical outcomes were collected and analyzed. A retrospective study was performed. RESULTS: Nine hundred and seventy patients were diagnosed with C. trachomatis infection, and the overall prevalence was 3.15% in the most recent five years, with a yearly increasing. The incidence was a higher in the second half of the year (3.40%) compared to the first half (2.69%). The age group with the highest-risk of infection with C. trachomatis was between 26 to 35 years old, and in about one third of the couples, both partners were infected. The basic parameters and clinical outcomes were not statistically significant between different the groups (P > 0.05), even though some minor data were different (P < 0.05). CONCLUSIONS: C. trachomatis is a common infection in subfertile people and it is essential to test for this organism in ART couples' screening. This study identified no adverse on clinical outcomes after successful treatment of C. trachomatis infection, regardless of gender, age and number of C. trachomatis copies. PMID- 28086916 TI - Microglial activation in Parkinson's disease using [18F]-FEPPA. AB - BACKGROUND: Neuroinflammatory processes including activated microglia have been reported to play an important role in Parkinson's disease (PD). Increased expression of translocator protein (TSPO) has been observed after brain injury and inflammation in neurodegenerative diseases. Positron emission tomography (PET) radioligand targeting TSPO allows for the quantification of neuroinflammation in vivo. METHODS: Based on the genotype of the rs6791 polymorphism in the TSPO gene, we included 25 mixed-affinity binders (MABs) (14 PD patients and 11 age-matched healthy controls (HC)) and 27 high-affinity binders (HABs) (16 PD patients and 11 age-matched HC) to assess regional differences in the second-generation radioligand [18F]-FEPPA between PD patients and HC. FEPPA total distribution volume (V T) values in cortical as well as subcortical brain regions were derived from a two-tissue compartment model with arterial plasma as an input function. RESULTS: Our results revealed a significant main effect of genotype on [18F]-FEPPA V T in every brain region, but no main effect of disease or disease * genotype interaction in any brain region. The overall percentage difference of the mean FEPPA V T between HC-MABs and HC-HABs was 32.6% (SD = 2.09) and for PD-MABs and PD-HABs was 43.1% (SD = 1.21). CONCLUSIONS: Future investigations are needed to determine the significance of [18F]-FEPPA as a biomarker of neuroinflammation as well as the importance of the rs6971 polymorphism and its clinical consequence in PD. PMID- 28086918 TI - Atypical monoarthritis presentation in children with oligoarticular juvenile idiopathic arthritis: a case series. AB - BACKGROUND: Oligoarticular juvenile idiopathic arthritis (oligoJIA), the most common chronic inflammatory arthritis of childhood, usually involves the knees and ankles. Severe oligoJIA monoarthritis presenting in a joint other than knees and ankles, is rare. FINDINGS: We report four children who presented with severe isolated arthritis of the hip, wrist or elbow and were diagnosed with oligoJIA. All four were girls with a median age of 11.5 years. Those with hip arthritis also met the classification criteria for juvenile-onset spondylarthopathy. Median duration of symptoms prior to diagnosis was 9.5 months. Three children had already cartilage loss or erosive disease at diagnosis. CONCLUSIONS: Children diagnosed with oligoJIA that present with monoarthritis of the hip, wrist and elbow can have aggressive disease. Girls with positive HLA-B27 presenting with isolated hip arthritis could meet the classification criteria for both oligoJIA and juvenile-onset SpA. Early referral to specialized care may improve their diagnosis, treatment and outcome. PMID- 28086917 TI - Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer's disease. AB - BACKGROUND: Treatment of mild-moderate Alzheimer's disease (AD) subjects (N = 119) for 52 weeks with the SIRT1 activator resveratrol (up to 1 g by mouth twice daily) attenuates progressive declines in CSF Abeta40 levels and activities of daily living (ADL) scores. METHODS: For this retrospective study, we examined banked CSF and plasma samples from a subset of AD subjects with CSF Abeta42 <600 ng/ml (biomarker-confirmed AD) at baseline (N = 19 resveratrol-treated and N = 19 placebo-treated). We utilized multiplex Xmap technology to measure markers of neurodegenerative disease and metalloproteinases (MMPs) in parallel in CSF and plasma samples. RESULTS: Compared to the placebo-treated group, at 52 weeks, resveratrol markedly reduced CSF MMP9 and increased macrophage-derived chemokine (MDC), interleukin (IL)-4, and fibroblast growth factor (FGF)-2. Compared to baseline, resveratrol increased plasma MMP10 and decreased IL-12P40, IL12P70, and RANTES. In this subset analysis, resveratrol treatment attenuated declines in mini-mental status examination (MMSE) scores, change in ADL (ADCS-ADL) scores, and CSF Abeta42 levels during the 52-week trial, but did not alter tau levels. CONCLUSIONS: Collectively, these data suggest that resveratrol decreases CSF MMP9, modulates neuro-inflammation, and induces adaptive immunity. SIRT1 activation may be a viable target for treatment or prevention of neurodegenerative disorders. TRIAL REGISTRATION: ClinicalTrials.gov NCT01504854. PMID- 28086919 TI - The safety attitudes questionnaire - ambulatory version: psychometric properties of the Slovenian version for the out-of-hours primary care setting. AB - BACKGROUND: Several tools have been developed to measure safety attitudes of health care providers, out of which the Safety Attitudes Questionnaire (SAQ) is regarded as one of the most appropriate ones. In 2007, it was adapted to outpatient (primary health care) settings and in 2014 it was tested in out-of hours health care settings in Norway. The purpose of this study was to translate the English version of the SAQ-Ambulatory Version (SAQ-AV) to Slovenian language; to test its reliability; and to explore its factor structure. METHODS: This was a cross-sectional study that took place in Slovenian out-of-hours primary care clinics in March-May 2015 as a part of an international study entitled Patient Safety Culture in European Out-of-hours services. The questionnaire consisted of the Slovenian version of the SAQ-AV. The link to the questionnaire was emailed to health care workers in the out-of-hours clinics. A total of 438 participants were invited. We performed exploratory factor analysis. RESULTS: Out of 438 invited participants, 250 answered the questionnaire (response rate 57.1%). Exploratory factor analysis put forward five factors: 1) Perceptions of management, 2) Job satisfaction, 3) Safety climate, 4) Teamwork climate, and 5) Communication. Cronbach's alpha of the whole SAQ-AV was 0.922. Cronbach's alpha of the five factors ranged from 0.587 to 0.791. Mean total score of the SAQ-AV was 56.6 +/- 16.0 points. The factor with the highest average score was Teamwork climate and the factor with the lowest average was Job satisfaction. CONCLUSIONS: Based on the results in our study, we cannot state that the SAQ-AV is a reliable tool for measuring safety culture in the Slovenian out-of-hours care setting. Our study also showed that there might be other safety culture factors in out-of-hours care not recognised before. We therefore recommend larger studies aiming to identify an alternative factor structure. PMID- 28086920 TI - Absence of system xc- on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis. AB - BACKGROUND: Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System xc- or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration. METHODS: Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system xc-, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT-/-) mice and irradiated mice reconstituted in xCT-/- bone marrow (BM), to their proper wild type (xCT+/+) controls. RESULTS: xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT+/+ mice, xCT-/- mice were equally susceptible to EAE, whereas mice transplanted with xCT-/- BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above described conditions, demyelination, microglial activation, or infiltration of immune cells were affected. CONCLUSIONS: Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system xc- on immune cells invading the CNS participates to EAE. Since a total loss of system xc- had no net beneficial effects, these results have important implications for targeting system xc- for treatment of MS. PMID- 28086921 TI - A randomized-controlled trial focusing on socio-economic status for promoting vegetable intake among adults using a web-based nutrition intervention programme: study protocol. AB - BACKGROUND: Web-based nutritional education programmes appear to be comparable to those delivered face-to-face. However, no existing web-based nutrition education or similar programme has yet been evaluated with consideration of socio-economic status. The objective of a nutritional education programme of promoting vegetable intake designed a randomized controlled trial (RCT) is to evaluate the results of intervention and to determine how socio-economic status influences the programme effects. METHODS/DESIGN: Participants will be randomly sampled individuals (aged 30-59) stratified according national population statistics for sex, age, and household income. Participants were consented to survey participation (n = 1500), and will be randomly divided into intervention and control groups. The intervention period is 5 weeks with one step of diet-related education per week. The main outcome of the programme is dietary behaviour as eating vegetable (350 g per day, five small bowl). To encourage behavioural changes, the programme contents are prepared using behavioural theories and techniques tailored to the assumed group stages of behavioural change. In the first step, we employ the health belief model to encourage a shift from the pre-contemplative to the contemplative phase; in the second and third steps, social cognitive theory is used to encourage transition to the preparatory phase; in the fourth step, social cognitive theory and strengthening social support are used to promote progression to the execution phase; finally, in the fifth step, strengthening social capital and social support are used to promote the shift to the maintenance phase. The baseline, post intervention and follow-up survey was assessed using a self administered questionnaire. For process evaluation, we use five items relating to programme participation and satisfaction. A follow-up survey of participants will be carried out 3 months after intervention completion. DISCUSSION: The fact that this study is an RCT with an established control group is a strong advantage. Information and communications technology is not limited by time or place. If we could show this web-based nutrition education programmes has a positive effect, it may be an appropriate tool for reaching individuals in lower socio-economic state. TRIAL REGISTRATION: Current Controlled Trials UMIN-ICDR UMIN 000019376 (Registered October 16, 2015). PMID- 28086923 TI - Multiple HIV-1/M + HIV-1/O dual infections and new HIV-1/MO inter-group recombinant forms detected in Cameroon. AB - BACKGROUND: Due to the prevalence of HIV-1 group M and the endemicity of HIV-1 group O infections in Cameroon, patients may be infected with both viruses and/or with HIV-1/MO recombinant forms. Such atypical infections may be deleterious in terms of diagnosis and therapeutic management due to the high divergence of HIV 1/O. The aim of this study was to identify prospectively such atypical infections in Cameroon. RESULTS: Based on serological screening by env-V3 serotyping and a molecular strategy using group-specific (RT)-PCRs, we identified 10 Cameroonian patients harboring three different profiles of infection: (1) 4 HIV-1/M + O dual infections without evidence of recombinant; (2) 5 recombinants associated with one or both parental strains; and (3) 1 new recombinant form without parental strains. CONCLUSIONS: This work highlights the dynamic co-evolution of these two HIV groups in Cameroon that could lead to the emergence of a circulating recombinant form MO, and the need for accurate identification of such atypical infections for precise diagnosis, virological monitoring and therapeutic management with adapted tools. PMID- 28086922 TI - Transcriptional profiles in bursal B-lymphoid DT40 cells infected with very virulent infectious bursal disease virus. AB - BACKGROUND: Infectious bursal disease virus (IBDV) causes a highly contagious, immunosuppressive disease in chickens. The virus mainly infects immature B lymphocytes in the bursa of Fabricius (BF). Chicken B cell line DT40, an avian leukosis virus-induced B cell line, supports very virulent IBDV (vvIBDV) infection in vitro and thereby serves as a good model for investigating the infection and pathogenesis of this virus. However, a transcriptome-wide understanding of the interaction between vvIBDV and B cells has not yet been achieved. This study aimed to employ time-course DNA microarrays to investigate gene expression patterns in DT40 cells after infection with vvIBDV strain LX. RESULTS: DT40 cells infected with vvIBDV exhibited alterations in the expression of many important host genes involved in signal transduction pathways, including MAPK signaling, PI3K/mTOR signaling, cell death and survival, BCR signaling, and antigen presentation. The changes in cellular mRNA levels identified by microarray analysis were confirmed for 8 selected genes using real-time reverse transcription-PCR. The upregulation of inflammatory cytokines and Toll-like receptors (TLRs) in the bursa of vvIBDV-infected chickens might involve excessive activation of the innate immune and inflammatory responses and contribute to tissue damage. CONCLUSIONS: The present study is the first to provide a comprehensive differential transcriptional profile of cultured DT40 cells in response to vvIBDV infection and further extends our understanding of the molecular mechanisms underlying vvIBDV infection and pathogenesis. PMID- 28086924 TI - Treating infants with frigg: linking disease aetiologies, medicinal plant use and care-seeking behaviour in southern Morocco. AB - BACKGROUND: Although most Moroccans rely to some extent on traditional medicine, the practice of frigg to treat paediatric ailments by elderly women traditional healers known as ferraggat, has not yet been documented. We describe the role of these specialist healers, document the medicinal plants they use, and evaluate how and why their practice is changing. METHODS: Ethnomedicinal and ethnobotanical data were collected using semi-structured interviews and observations of medical encounters. Information was collected from traditional healers, namely ferraggat, patients, herbalists and public health professionals. Patients' and healers' narratives about traditional medicine were analysed and medicinal plant lists were compiled from healers and herbalists. Plants used were collected, vouchered and deposited in herbaria. RESULTS: Ferragat remain a key health resource to treat infant ailments in the rural High Atlas, because mothers believe only they can treat what are perceived to be illnesses with a supernatural cause. Ferragat possess baraka, or the gift of healing, and treat mainly three folk ailments, taqait, taumist and iqdi, which present symptoms similar to those of ear infections, tonsillitis and gastroenteritis. Seventy plant species were used to treat these ailments, but the emphasis on plants may be a recent substitute for treatments that used primarily wool and blood. This change in materia medica is a shift in the objects of cultural meaningfulness in response to the increasing influence of orthodox Islam and state-sponsored modernisation, including public healthcare and schooling. CONCLUSIONS: Religious and other sociocultural changes are impacting the ways in which ferraggat practice. Treatments based on no-longer accepted symbolic elements have been readily abandoned and substituted by licit remedies, namely medicinal plants, which play a legitimisation role for the practice of frigg. However, beliefs in supernatural ailment aetiologies, as well as lack or difficult access to biomedical alternatives, still underlie the need for specialist traditional healers. PMID- 28086926 TI - Maternal health care service seeking behaviors and associated factors among women in rural Haramaya District, Eastern Ethiopia: a triangulated community-based cross-sectional study. AB - BACKGROUND: Regular utilization of maternal health care services reduces maternal morbidity and mortality. This study assessed the maternal health care seeking behavior and associated factors of reproductive age women in rural villages of Haramaya district, East Ethiopia. METHODS: Community based cross sectional study supplemented with qualitative data was conducted in Haramaya district from November 15 to Decemeber 30, 2015. A total of 561 women in reproductive age group and who gave birth in the last 2 years were randomly included. Bivariate and multivariate logistic regressions model was used to identify the associated factors. Odds ratios with 95% CI were used to measure the strength of association. RESULT: Maternal health care service seeking of women was found as; antenatal care 74.3% (95% CI; 72.5, 76.14), attending institutional delivery 28.7% (95% CI; 26.8, 30.6) and postnatal care 22.6% (95% CI; 20.84, 24.36). Knowledge of pregnancy complications, Educational status, and religion of women were found to be significantly associated with antenatal health care, delivery and postnatal health care service seeking behaviours triangulated with individual, institutional and socio-cultural qualitative data. CONCLUSION: The maternal health care service seeking behavior of women in the study area was low. Educational status of the women, birth order and knowledge about pregnancy complications were the major factors associated with maternal health care service seeking behavior Focused health education with kind and supportive health care provider counseling will improve the maternal health care seeking behaviors of women. PMID- 28086927 TI - Can pegylated interferon improve the outcome of polycythemia vera patients? AB - Pegylated interferon (peg-IFN) was proven by phase II trials to be effective in polycythemia vera (PV); however, it is not clear whether it could improve patient outcome compared to hydroxyurea (HU). Here, we present an observational study on 65 PV patients aged 65 years or younger, who received either peg-IFN (30) or HU (35) according to the physician choice. Median follow-up was 75 months. The two cohorts were comparable for patient and disease characteristics. Eighty-seven percent of the patients treated with peg-INF responded, with a CR rate of 70% as compared to 100 and 49% with HU, respectively. Discontinuation rate was similar in the two groups (20% in peg-IFN vs 17% in HU). JAK2 allele burden was monitored in peg-INF arm only, and a reduction was observed in 88% of the patients. No thrombotic events were observed during peg-IFN treatment compared to three on HU. Disease progression to myelofibrosis or acute myeloid leukemia occurred to a patient only in peg-INF, compared to three in HU. Overall, three second malignancies were observed during the study, two in patients who received HU only, and one in a patient largely treated HU who received also peg-IFN for 3 months. Overall survival was significantly better for peg-IFN patients compared to HU, p = 0.027. Our study, albeit limited by small patient and event number and lack of randomization, confirms the efficacy of peg-INF in PV and shows a significant survival advantage for peg-INF-treated patients. Waiting for confirming data from the ongoing phase III trials, our study can support peg-INF as a first-line treatment option for PV, at least for younger patients. PMID- 28086925 TI - Partnerships in mental healthcare service delivery in low-resource settings: developing an innovative network in rural Nepal. AB - BACKGROUND: Mental illnesses are the largest contributors to the global burden of non-communicable diseases. However, there is extremely limited access to high quality, culturally-sensitive, and contextually-appropriate mental healthcare services. This situation persists despite the availability of interventions with proven efficacy to improve patient outcomes. A partnerships network is necessary for successful program adaptation and implementation. PARTNERSHIPS NETWORK: We describe our partnerships network as a case example that addresses challenges in delivering mental healthcare and which can serve as a model for similar settings. Our perspectives are informed from integrating mental healthcare services within a rural public hospital in Nepal. Our approach includes training and supervising generalist health workers by off-site psychiatrists. This is made possible by complementing the strengths and weaknesses of the various groups involved: the public sector, a non-profit organization that provides general healthcare services and one that specializes in mental health, a community advisory board, academic centers in high- and low-income countries, and bicultural professionals from the diaspora community. CONCLUSIONS: We propose a partnerships model to assist implementation of promising programs to expand access to mental healthcare in low- resource settings. We describe the success and limitations of our current partners in a mental health program in rural Nepal. PMID- 28086928 TI - Resolvin RvD2 reduces hypothalamic inflammation and rescues mice from diet induced obesity. AB - BACKGROUND: Diet-induced hypothalamic inflammation is an important mechanism leading to dysfunction of neurons involved in controlling body mass. Studies have shown that polyunsaturated fats can reduce hypothalamic inflammation. Here, we evaluated the presence and function of RvD2, a resolvin produced from docosahexaenoic acid, in the hypothalamus of mice. METHODS: Male Swiss mice were fed either chow or a high-fat diet. RvD2 receptor and synthetic enzymes were evaluated by real-time PCR and immunofluorescence. RvD2 was determined by mass spectrometry. Dietary and pharmacological approaches were used to modulate the RvD2 system in the hypothalamus, and metabolic phenotype consequences were determined. RESULTS: All enzymes involved in the synthesis of RvD2 were detected in the hypothalamus and were modulated in response to the consumption of dietary saturated fats, leading to a reduction of hypothalamic RvD2. GPR18, the receptor for RvD2, which was detected in POMC and NPY neurons, was also modulated by dietary fats. The substitution of saturated by polyunsaturated fats in the diet resulted in increased hypothalamic RvD2, which was accompanied by reduced body mass and improved glucose tolerance. The intracerebroventricular treatment with docosahexaenoic acid resulted in increased expression of the RvD2 synthetic enzymes, increased expression of anti-inflammatory cytokines and improved metabolic phenotype. Finally, intracerebroventricular treatment with RvD2 resulted in reduced adiposity, improved glucose tolerance and increased hypothalamic expression of anti-inflammatory cytokines. CONCLUSIONS: Thus, RvD2 is produced in the hypothalamus, and its receptor and synthetic enzymes are modulated by dietary fats. The improved metabolic outcomes of RvD2 make this substance an attractive approach to treat obesity. PMID- 28086929 TI - Early virological failure and HIV drug resistance in Ugandan adults co-infected with tuberculosis. AB - PURPOSE: This cross-sectional study took place in the integrated tuberculosis (TB) clinic of a large outpatient clinic for HIV-infected patients in Kampala, Uganda. The purpose of this study was to describe the proportion of TB/HIV co infected adults with virological failure, type and frequency of HIV drug resistance-associated mutations, and the proportion of patients with suboptimal efavirenz levels. METHODS: HIV-1 plasma viral loads, CD4 cell count measurements, and efavirenz serum concentrations were done in TB/HIV co-infected adults. Genotypic resistance testing was performed in case of confirmed virological failure. RESULTS: After a median time on ART of 6 months, virological failure was found in 22/152 patients (14.5%). Of 147 participants with available efavirenz serum concentration, 26 (17.6%) had at least one value below the reference range, including 20/21 (95.2%) patients with confirmed virological failure. Genotypic resistance testing was available for 16/22 (72.7%) patients, of which 15 (93.8%) had at least one major mutation, most commonly M184V (81.2%) and K103NS (68.8%). CONCLUSION: We found a high proportion of TB/HIV co-infected patients with virological failure, the majority of which had developed relevant resistance mutations after a median time on anti-retroviral treatment (ART) of 6 months. Virological monitoring should be prioritized in TB/HIV co-infected patients in resource-limited settings. PMID- 28086930 TI - Mannose-binding lectin-associated serine protease 2 (MASP-2) contributes to poor disease outcome in humans and mice with pneumococcal meningitis. AB - BACKGROUND: Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the pro-inflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies. METHODS: We investigated mannose-binding lectin-associated serine protease (MASP 2) levels in cerebrospinal fluid (CSF) samples derived from the diagnostic lumbar puncture, which was available for 307 of 792 pneumococcal meningitis episodes included in our prospective nationwide cohort study (39%), and the association between these levels and clinical outcome. Subsequently, we studied the role of MASP-2 in our experimental pneumococcal meningitis mouse model using Masp2 -/- mice and evaluated the potential of adjuvant treatment with MASP-2-specific monoclonal antibodies in wild-type (WT) mice. RESULTS: MASP-2 levels in cerebrospinal fluid of patients with bacterial meningitis were correlated with poor functional outcome. Consistent with these human data, Masp2-deficient mice with pneumococcal meningitis had lower cytokine levels and increased survival compared to WT mice. Adjuvant treatment with MASP-2-specific monoclonal antibodies led to reduced complement activation and decreased disease severity. CONCLUSIONS: MASP-2 contributes to poor disease outcome in human and mice with pneumococcal meningitis. MASP-2-specific monoclonal antibodies can be used to attenuate the inflammatory response in pneumococcal meningitis. PMID- 28086931 TI - The release and trans-synaptic transmission of Tau via exosomes. AB - BACKGROUND: Tau pathology in AD spreads in a hierarchical pattern, whereby it first appears in the entorhinal cortex, then spreads to the hippocampus and later to the surrounding areas. Based on this sequential appearance, AD can be classified into six stages ("Braak stages"). The mechanisms and agents underlying the progression of Tau pathology are a matter of debate. Emerging evidence indicates that the propagation of Tau pathology may be due to the transmission of Tau protein, but the underlying pathways and Tau species are not well understood. In this study we investigated the question of Tau spreading via small extracellular vesicles called exosomes. METHODS: Exosomes from different sources were analyzed by biochemical methods and electron microscopy (EM) and cryo-EM. Microfluidic devices that allow the culture of cell populations in different compartments were used to investigate the spreading of Tau. RESULTS: We show that Tau protein is released by cultured primary neurons or by N2a cells overexpressing different Tau constructs via exosomes. Neuron-derived exosomal Tau is hypo-phosphorylated, compared with cytosolic Tau. Depolarization of neurons promotes release of Tau-containing exosomes, highlighting the importance of neuronal activity. Using microfluidic devices we show that exosomes mediate trans neuronal transfer of Tau depending on synaptic connectivity. Tau spreading is achieved by direct transmission of exosomes between neurons. In organotypic hippocampal slices, Tau-containing exosomes in conditioned medium are taken up by neurons and microglia, not astrocytes. In N2a cells, Tau assemblies are released via exosomes. They can induce inclusions of other Tau molecules in N2a cells expressing mutant human Tau. We also studied exosomes from cerebrospinal fluid in AD and control subjects containing monomeric and oligomeric Tau. Split-luciferase complementation reveals that exosomes from CSF can promote Tau aggregation in cultured cells. CONCLUSION: Our study demonstrates that exosomes contribute to trans-synaptic Tau transmission, and thus offer new approches to control the spreading of pathology in AD and other tauopathies. PMID- 28086932 TI - Spontaneous ischaemic stroke lesions in a dog brain: neuropathological characterisation and comparison to human ischaemic stroke. AB - BACKGROUND: Dogs develop spontaneous ischaemic stroke with a clinical picture closely resembling human ischaemic stroke patients. Animal stroke models have been developed, but it has proved difficult to translate results obtained from such models into successful therapeutic strategies in human stroke patients. In order to face this apparent translational gap within stroke research, dogs with ischaemic stroke constitute an opportunity to study the neuropathology of ischaemic stroke in an animal species. CASE PRESENTATION: A 7 years and 8 months old female neutered Rottweiler dog suffered a middle cerebral artery infarct and was euthanized 3 days after onset of neurological signs. The brain was subjected to histopathology and immunohistochemistry. Neuropathological changes were characterised by a pan-necrotic infarct surrounded by peri-infarct injured neurons and reactive microglia/macrophages and astrocytes. CONCLUSIONS: The neuropathological changes reported in the present study were similar to findings in human patients with ischaemic stroke. The dog with spontaneous ischaemic stroke is of interest as a complementary spontaneous animal model for further neuropathological studies. PMID- 28086933 TI - Self-collection based HPV testing for cervical cancer screening among women living with HIV in Uganda: a descriptive analysis of knowledge, intentions to screen and factors associated with HPV positivity. AB - BACKGROUND: Women living with HIV (WHIV) are disproportionately impacted by cervical dysplasia and cancer. The burden is greatest in low-income countries where limited or no access to screening exists. The goal of this study was to describe knowledge and intentions of WHIV towards HPV self-collection for cervical cancer screening, and to report on factors related to HPV positivity among women who participated in testing. METHODS: A validated survey was administered to 87 HIV positive women attending the Kisenyi Health Unit aged 30 69 years old, and data was abstracted from chart review. At a later date, self collection based HPV testing was offered to all women. Specimens were tested for high risk HPV genotypes, and women were contacted with results and referred for care. Descriptive statistics, Chi Square and Fischer-exact statistical tests were performed. RESULTS: The vast majority of WHIV (98.9%) women did not think it necessary to be screened for cervical cancer and the majority of women had never heard of HPV (96.4%). However, almost all WHIV found self-collection for cervical cancer screening to be acceptable. Of the 87 WHIV offered self-collection, 40 women agreed to provide a sample at the HIV clinic. Among women tested, 45% were oncogenic HPV positive, where HPV 16 or 18 positivity was 15% overall. CONCLUSIONS: In this group of WHIV engaged in HIV care, there was a high prevalence of oncogenic HPV, a large proportion of which were HPV genotypes 16 or 18, in addition to low knowledge of HPV and cervical cancer screening. Improved education and cervical cancer screening for WHIV are sorely needed; self collection based screening has the potential to be integrated with routine HIV care in this setting. PMID- 28086934 TI - Electroacupuncture plus moxibustion therapy for patients with major depressive disorder: study protocol for a randomized controlled trial. AB - BACKGROUND: Major depressive disorder (MDD) is one of the most prevalent mental health disorders and has a significant societal economic burden. Antidepressants and cognitive behavioral therapy are two primary interventions for the standardized treatment of MDD. However, their weaknesses, such as a low response rate, a high risk of adverse events from medication, and the high cost of cognitive behavioral therapy, have resulted in a need for complementary and alternative medicine (CAM). Among the various therapeutic interventions in CAM, electroacupuncture and moxibustion have been widely used to treat various mental illnesses, including MDD. The aim of this study is to evaluate the feasibility of conducting a full-scale randomized controlled trial to investigate the efficacy and safety of electroacupuncture plus moxibustion therapy for MDD. METHODS/DESIGN: We will include patients between the ages of 19 to 65 years with MDD. A total of 30 participants will be recruited, and they will be randomly allocated into two groups at a 1:1 ratio. Patients in the treatment and control groups will, respectively, receive real and sham electroacupuncture/moxibustion treatments, for a total of 20 sessions over 8 weeks. The primary outcome will be the Hamilton Rating Scale for Depression, and the secondary outcomes will be Beck's Depression Inventory, the Insomnia Severity Index, the State-Trait Anxiety Inventory, the EuroQol 5-Dimension Index, the Measure Yourself Medical Outcome Profile version 2, and electroencephalography. Adverse events will be monitored at each visit to assess safety. All outcomes will be assessed and analyzed by researchers blinded to the treatment allocation. DISCUSSION: This is a two-armed, parallel-design, patient-assessor blinded, multicenter, randomized, sham controlled pilot clinical trial. Data will be analyzed before and after treatment and during a 4-week follow-up. The results of the trial will provide a basis for further studies assessing the efficacy and safety of electroacupuncture plus moxibustion treatment for MDD. TRIAL REGISTRATION: Korean Clinical Trial Registry, CRIS-KCT0001810 . Registered on 5 February 2016 (retrospectively registered; date of enrollment of the first participant to the trial: 2 December 2015). PMID- 28086935 TI - Does the transfer of a poor quality embryo together with a good quality embryo affect the In Vitro Fertilization (IVF) outcome? AB - BACKGROUND: IVF cycles which result in only one good quality embryo, and a second poor quality embryo present a dilemma when the decision involves transferring two embryos. The aim of this study was to evaluate whether a poor quality embryo has a negative effect on a good quality embryo when transferred along with a good quality embryo. METHODS: We retrospectively evaluated in vitro fertilization (IVF) cycles involving single embryo transfers (SET) and double embryo transfers (DET). Embryo quality was divided into poor "P" and good "G" quality. The main outcome measures were: live birth, implantation rate, miscarriage rate, clinical pregnancy rate and multiple pregnancy ratio. RESULTS: Six hundred three women were included. The study group consisted of 180 (29.9%) patients who had a double embryo transfer (DET) with one poor quality embryo and one good quality embryo (P + G). Control 1 group included 303 (50.2%) patients who had DET with two good quality embryos (G + G), and control 2 group consisted of 120 (19.9%) patients who had a single embryo transfer (SET) with one good quality embryo (G). Live birth rates were not significantly different when compared between study groups: 30.8% in the SET group (G), 27.2% in the (G + P) group and 33.7% in the (G + G) group. The SET group had the highest implantation rate (33.9%) compared to the DET groups (21.8% (G + P), 25.4% (G + G)) (P =0.022). The clinical pregnancy rate was 33.3% in the SET group (G), 33.3% in the (G + P) group, and 39.3% in the (G + G) group (P =0.39). The miscarriage rate was comparable in all groups. CONCLUSION: A poor quality embryo does not negatively affect a good quality embryo, when transferred together in a double embryo transfer. PMID- 28086936 TI - Association between Low blood lead levels and increased risk of dental caries in children: a cross-sectional study. AB - BACKGROUND: The objective of this study was to examine the association between low blood lead levels of <5 MUg/dL and the development of dental caries among children. METHODS: The Children's Health and Environment Research (CHEER) group recruited a cohort of 7,059 school-aged children from six Korean cities. The final study populations in the permanent and deciduous teeth groups were 1,564 and 1,241 children, respectively, after excluding 4 children with blood lead levels of >5 MUg/dL. Compared with the children who did not have dental caries, the risk of having dental caries according to blood lead level was estimated by using the zero-inflated negative binomial model. RESULTS: The geometric mean (geometric standard deviation, maximum) blood lead level was 1.53 MUg/dL (1.57, 4.89 MUg/dL), and 74.4% of children had a level of <2 MUg/dL. Blood lead level was significantly higher in the children with than in those without deciduous dental caries (1.59 vs. 1.51 MUg/dL), similarly with permanent dental caries (1.65 vs. 1.51 MUg/dL). After adjustment for covariates, deciduous teeth surfaces that were decayed and filled increased significantly with increasing blood lead levels in a dose-dependent manner (prevalence ratio, 1.14; 95% confidence interval: 1.02-1.27). However, the risk of having dental caries in permanent teeth was not linearly associated with the increase in blood lead level. CONCLUSIONS: In the sum of decayed and filled surfaces, we found a significant increase in risk of dental caries of the deciduous teeth with an increase in blood lead levels (<5 MUg/dL) but found no statistical significance in the association with decayed and filled surfaces of caries separately. PMID- 28086937 TI - A meta-analysis of randomized control trials of surgical methods with osteosarcoma outcomes. AB - BACKGROUND: Osteosarcoma is a high malignant neoplasm, and conflicting findings have been reported on the survival and function recovery of osteosarcoma patients experiencing limb salvage or amputation. In the present study, we compared limb salvage surgery (LSS) with amputation in clinical outcomes of osteosarcoma patients by a meta-analysis. METHODS: The survival rate of osteosarcoma patients was collected from research reports from CNKI, MEDLINE, EMBASE, the Cochrane Database, and Google Scholar till April 30, 2016. The quality of including articles was evaluated by two independent reviewers. Differences between patients undergoing limb salvage surgery and amputation were analyzed based on postoperative survival rates. RESULTS: Ten articles were included according to selection criteria. There were 1343 patients in total from these studies. Our results showed that there was no significant difference between limb salvage surgery and amputation according to local recurrence; however, patients with limb salvage surgery had a higher 5-year overall survival. CONCLUSIONS: LSS results in higher 5-year survival rates and better survival, while not increasing the risk of local recurrence. This study provided more evidences to support limb salvage surgery as a considerable treatment of osteosarcoma patients. PMID- 28086939 TI - Feasibility study for the non-invasive blood pressure estimation based on ppg morphology: normotensive subject study. AB - BACKGROUND: Blood pressure is a critical bio-signal and its importance has been increased with the aged society and the growth of cardiovascular disease population. However, most of hypertensive patients have been suffered the inconvenience in monitoring blood pressure in daily life because the measurement of the blood pressure depends on the cuff-based technique. Nowadays there are many trials to measure blood pressure without cuff, especially, photoplethysmography (PPG) based research is carried out in various ways. METHODS: Our research is designed to hypothesis the relationship between vessel wall movement and pressure-flow relationship of PPG and to validate its appropriateness by experimental methods. PPG waveform is simplified by approximate model, and then it is analyzed as the velocity and the acceleration of blood flow using the derivatives of PPG. Finally, we develop pressure index (PI) as an estimation factor of blood pressure by combining of statistically significant segments of photoplethysmographic waveform. RESULTS: Twenty-five subjects were participated in the experiment. As a result of simulation, correlation coefficients between developed PI and blood pressure were represented with R = 0.818, R = 0.827 and R = 0.615 in systolic blood pressure, pulse pressure and mean arterial pressure, respectively, and both of result showed the meaningful statistically significance (P < 0.05). CONCLUSIONS: Current study can estimate only the relative variation of blood pressure but could not find the absolute pressure value. Moreover, proposed index has the limitation of diastolic pressure tracing. However, the result shows that the proposed PI is statistically significantly correlated with blood pressures, and it suggests that the proposed PI as a promising additional parameter for the cuff less blood pressure monitoring. PMID- 28086938 TI - Alpha-enolase (ENO1) controls alpha v/beta 3 integrin expression and regulates pancreatic cancer adhesion, invasion, and metastasis. AB - BACKGROUND: We have previously shown that in pancreatic ductal adenocarcinoma (PDA) cells, the glycolytic enzyme alpha-enolase (ENO1) also acts as a plasminogen receptor and promotes invasion and metastasis formation. Moreover, ENO1 silencing in PDA cells induces oxidative stress, senescence and profoundly modifies PDA cell metabolism. Although anti-ENO1 antibody inhibits PDA cell migration and invasion, little is known about the role of ENO1 in regulating cell cell and cell-matrix contacts. We therefore investigated the effect of ENO1 silencing on the modulation of cell morphology, adhesion to matrix substrates, cell invasiveness, and metastatic ability. METHODS: The membrane and cytoskeleton modifications that occurred in ENO1-silenced (shENO1) PDA cells were investigated by a combination of confocal microscopy and atomic force microscopy (AFM). The effect of ENO1 silencing was then evaluated by phenotypic and functional experiments to identify the role of ENO1 in adhesion, migration, and invasion, as well as in senescence and apoptosis. The experimental results were then validated in a mouse model. RESULTS: We observed a significant increase in the roughness of the cell membrane due to ENO1 silencing, a feature associated with an impaired ability to migrate and invade, along with a significant downregulation of proteins involved in cell-cell and cell-matrix adhesion, including alpha v/beta 3 integrin in shENO1 PDA cells. These changes impaired the ability of shENO1 cells to adhere to Collagen I and IV and Fibronectin and caused an increase in RGD independent adhesion to vitronectin (VN) via urokinase plasminogen activator receptor (uPAR). Binding of uPAR to VN triggers integrin-mediated signals, which result in ERK1-2 and RAC activation, accumulation of ROS, and senescence. In shENO1 cancer cells, the use of an anti-uPAR antibody caused significant reduction of ROS production and senescence. Overall, a decrease of in vitro and in vivo cell migration and invasion of shENO1 PDA cells was observed. CONCLUSION: These data demonstrate that ENO1 promotes PDA survival, migration, and metastasis through cooperation with integrins and uPAR. PMID- 28086941 TI - Diversity in breeding sites and distribution of Anopheles mosquitoes in selected urban areas of southern Ghana. AB - BACKGROUND: Anopheles vectors of malaria are supposedly less common in urban areas as a result of pollution, but there is increasing evidence of their adaptation to organically polluted water bodies. This study characterized the breeding habitats of Anopheles mosquitoes in the two major urban areas in southern Ghana; Accra (AMA) and Sekondi-Takoradi (STMA) Metropolitan Areas, during dry and wet seasons. METHODS: Anopheles mosquito larvae were sampled using standard dipping methods to determine larval densities. The origin, nature and stability of 21 randomly selected sites were observed and recorded. Mosquito larvae were reared to adults and Anopheles species identified by both morphological and molecular means. RESULTS: Sixty-six percent of Anopheles habitats were permanent and 34% temporal, and 74.5% man-made while 25.5% were natural. Puddles and urban farm sites accounted for over 51% of all Anopheles mosquitoes sampled. The mean larval densities among the habitat types was highest of 13.7/dip for puddles and lowest of 2.3/dip for stream/river, and the variation between densities were significant (P = 0.002). The mean larval densities were significantly higher in the wet season than in the dry season for the two study areas combined (P = 0.0191) and AMA (P = 0.0228). Over 99% of the 5,802 morphologically identified Anopheles species were An. gambiae (s.l.) of which more than 99% of the studied 898 were An. coluzzii (62%) and An. gambiae (s.s.) (34%). Urban farms, puddles, swamps and ditches/ dugouts accounted for approximately 70% of all An. coluzzii identified. Conversely, drains, construction sites, streams/rivers and "others" contributed 80% of all An. gambiae (s.s.) sampled. The wet season had significantly higher proportion of Anopheles larvae compared to the dry season (Z = 8.3683, P < 0.0001). Also, the proportion of Anopheles mosquitoes produced by permanent breeding sites was 61.3% and that of temporary sites was 38.7%. CONCLUSION: Taken together, the data suggest that man-made and/ or permanent habitats were the main contributors to Anopheles larval populations in the cities and that regulation of the anthropogenic processes that lead to development of breeding places and proper environmental management can drastically reduce mosquito breeding sites in urban areas of Ghana. PMID- 28086940 TI - Ultrasound-guided percutaneous peripheral nerve stimulation for analgesia following total knee arthroplasty: a prospective feasibility study. AB - BACKGROUND: Peripheral nerve stimulation has been used for decades to treat chronic pain but has not been used for postoperative analgesia due to multiple limitations, beginning with invasive electrode placement. With the development of small-diameter/gauge leads enabling percutaneous insertion, ultrasound guidance for accurate introduction, and stimulators small enough to be adhered to the skin, neurostimulation may now be provided in a similar manner to continuous peripheral nerve blocks. Here, we report on the use of ultrasound-guided percutaneous peripheral nerve stimulation to treat postoperative pain. MATERIALS AND METHODS: Subjects within 60 days of a total knee arthroplasty with pain insufficiently treated with oral analgesics had a 0.2-mm-diameter electrical lead (pre-loaded into a 20 gauge needle) introduced percutaneously using ultrasound guidance with the tip located approximately 0.5-1.0 cm from the femoral nerve (a second lead was inserted approximately 1.0-3.0 cm from the sciatic nerve for posterior knee pain). An external stimulator delivered current. Endpoints were assessed before and after lead insertion and the leads subsequently removed. Due to the small sample size for this pilot/feasibility study, no statistics were applied to the data. RESULTS: Leads were inserted in subjects (n = 5) 8-58 days postoperatively. Percutaneous peripheral nerve stimulation decreased pain an average of 93% at rest (from a mean of 5.0 to 0.2 on a 0-10 numeric rating scale), with 4 of 5 subjects experiencing complete resolution of pain. During passive and active knee motion pain decreased an average of 27 and 30%, respectively. Neither maximum passive nor active knee range-of-motion was consistently affected. CONCLUSIONS: Ultrasound-guided percutaneous peripheral nerve stimulation may be a practical modality for the treatment of postoperative pain following orthopedic surgical procedures, and further investigation appears warranted. PMID- 28086943 TI - A lifestyle intervention among elderly men on active surveillance for non aggressive prostate cancer: a randomised feasibility study with whole-grain rye and exercise. AB - BACKGROUND: The prognosis for men with non-aggressive prostate cancer is good, and several studies have investigated the impact of lifestyle changes including physical activity and diet on the prognosis. Despite positive results in animal studies and a few human interventions with whole-grain rye on markers of prostate cancer progression, the feasibility of trials investigating such dietary changes in combination with physical activity remains largely unstudied. The primary aim was to investigate the feasibility of an intervention with high whole-grain rye intake and vigorous physical activity for 6 months in men diagnosed with prostate cancer. METHODS: In total, 26 men (53-72 years) recently diagnosed with non aggressive prostate cancer and on active surveillance, were enrolled in 2011-2012 and randomly assigned to an intervention or a control group. The intervention included 170 g/day of whole-grain rye and 3 * 45 minutes/week of vigorous physical activity. The duration of the intervention was 6 months and end of follow-up 12 months after baseline. Clinic visits were scheduled at baseline and 3, 6 and 12 months after baseline. Compliance with the intervention was evaluated by diaries, food frequency questionnaires, biomarkers, and heart rate monitor data. The effect of the intervention was evaluated by linear multiple regression analysis. RESULTS: In the intervention group, the mean daily intake of whole grain rye measured from diaries was 146 g (SD: 19) for the first 3 months and 125 g (SD: 40) for the last 3 months of the intervention. The median level (5th and 95th percentiles) of vigorous physical activity was 91 (17, 193) min/week for the first 3 months and 66 (13, 259) min/week for the last 3 months. No recordings of physical activity were done for the control group. Aerobic fitness (VO2 peak) increased in the intervention group compared to the control group after the intervention. No effects were found on other cardio-metabolic outcomes or prostate cancer progression. CONCLUSIONS: The lifestyle intervention appeared feasible for 6 months among Danish men and the results are encouraging for conducting full-scale studies, where the impact of whole-grain rye and vigorous physical activity on prostate cancer progression and metabolic parameters can be evaluated. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01300104 . Registered on 18 February 2011. PMID- 28086944 TI - Prenatal treatment for opioid dependency: observations from a large inner-city clinic. AB - BACKGROUND: The objective of this study was to review changes in the prevalence of opioid use disorder in pregnancy, and to describe the prenatal care and neonatal outcomes following the implementation of buprenorphine treatment at a large US obstetrical clinic during the on-going opioid epidemic. METHODS: We conducted a retrospective cohort study of 310 women (332 pregnancies) with opioid use disorders and their neonates delivered between June 2006 and December 2010 at an obstetrical clinic in the US. Trends in patient volume, characteristics and outcomes by calendar year were assessed using the Cochran-Armitage test and linear regression. RESULTS: There was an almost two-fold increase in the volume of pregnant women treated annually from 2006 through 2010. Most women were treated with methadone (74%), with buprenorphine becoming more common over calendar time: 3.0% in 2006 to 41% in 2010. The mean dose of buprenorphine at delivery was: 11.4 mg in 2007, 14.1 mg in 2008, 14.1 mg in 2009, and 16.8 mg in 2010; an average increase of 2.1 mg year. There were no differences in mean methadone dose over time. From 2006 to 2010 there were increases in the prevalence of prescribed concomitant psychotropic medications and vaginal deliveries, and in the proportion of neonates treated pharmacologically for neonatal abstinence syndrome (NAS). NAS pharmacologic management also varied by calendar year with more use of neonatal morphine and clonidine in later years. CONCLUSIONS: The number of mother-infant pairs increased significantly from 2006 to 2010 and the clinical characteristics of these patients changed over time. Our experience reflects the rising increase in opioid use disorders in pregnancy and NAS, mandating the need for expansion of comprehensive prenatal care options for these women and their children. PMID- 28086942 TI - External beam radiotherapy for unresectable hepatocellular carcinoma, an international multicenter phase I trial, SAKK 77/07 and SASL 26. AB - PURPOSE: To assess feasibility and safety of conventionally fractionated radiotherapy (cfRT) in patients with hepatocellular carcinoma (HCC). METHODS: Patients with histologically confirmed stage cT1-4, cN0-1 HCC and Child-Pugh Score (CPS) A or B disease were included in a phase I multicenter trial. Metastatic HCC were allowed if >=90% of total tumor volume was located within the liver. Patients were enrolled onto five dose-escalation levels (54-70Gy in 2Gy fractions) based on a modified 3 + 3 design, with cohorts of five patients instead of three patients in dose levels 4 and 5. Primary trial endpoint was dose limiting toxicity (DLT), as specifically defined for 17 clinical and nine laboratory parameters as grade >=3 or >=4 toxicity (CTCAE vs. 3). The threshold to declare a dose level as maximum tolerated dose (MTD) was defined as a DLT rate of <=16.7% in dose levels 1-3, and <=10% in dose levels 4-5. Best objective response of target liver lesions and adverse events (AE's) were assessed as secondary endpoints. RESULTS: The trial was terminated early in DL 3 due to low accrual. Nineteen patients were recruited. Fifteen patients were evaluable for the primary and 18 for the secondary endpoints. Maximum tolerated dose was not reached. One patient in dose level 1, and one patient in dose level 2 experienced DLT (lipase > 5xULN, and neutrophils <500/MUL respectively). However, dose level 3 (62Gy) was completed, with no DLTs in 3 patients. Overall, 56% of patients had a partial response and 28% showed stable disease according to RECIST. No signs of radiation induced liver disease (RILD). Two patients in dose level 3 experienced lymphocytopenia grade 4, with no clinical impact. CONCLUSION: Conventionally fractionated radiotherapy of 58Gy to even large HCC was safe for patients with CPS A and B. 62Gy was delivered to three patients without any sign of clinically relevant increased toxicity. The maximum tolerated dose could not be determined. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00777894 , registered October 21st, 2008. PMID- 28086945 TI - Complete deltoid resection in early childhood without muscle transfer results in normal shoulder function at long-term follow-up: a case report. AB - BACKGROUND: Musculoskeletal tumors involving the deltoid muscle and necessitating its complete resection are rare. The function after complete deltoid resection is reported to be limited, and several authors consider muscle transfer to improve shoulder motion. However, it still remains unclear whether such transfer adds function. To the best of our knowledge, all reports on complete deltoid resection refer to adult patients, and it is unknown what function results after deltoid resection in childhood. The remaining muscles may have the potential to compensate for the loss of deltoid function. CASE PRESENTATION: Here we report the case of a 5-year-old white boy with complete (isolated) deltoid muscle resection in infancy for a large aggressive soft tissue tumor. No reconstructive procedure or muscle transfer was performed at the time of index surgery. Pathology revealed an angiomatoid fibrous histiocytoma. His postoperative course was uneventful. At 11 years of follow-up, he remained disease-free and had excellent shoulder function, including normal range of motion. CONCLUSIONS: This report implies that major muscles such as the deltoid can be resected in a child without compromising long-term function. Therefore, a muscle transfer at index surgery is probably not necessary. PMID- 28086947 TI - Quantifying growing versus non-growing ovarian follicles in the mouse. AB - BACKGROUND: A standard histomorphometric approach has been used for nearly 40 years that identifies atretic (e.g., dying) follicles by counting the number of pyknotic granulosa cells (GC) in the largest follicle cross-section. This method holds that if one pyknotic granulosa nucleus is seen in the largest cross section of a primary follicle, or three pyknotic cells are found in a larger follicle, it should be categorized as atretic. Many studies have used these criteria to estimate the fraction of atretic follicles that result from genetic manipulation or environmental insult. During an analysis of follicle development in a mouse model of Fragile X premutation, we asked whether these 'historical' criteria could correctly identify follicles that were not growing (and could thus confirmed to be dying). METHODS: Reasoning that the fraction of mitotic GC reveals whether the GC population was increasing at the time of sample fixation, we compared the number of pyknotic nuclei to the number of mitotic figures in follicles within a set of age-matched ovaries. RESULTS: We found that, by itself, pyknotic nuclei quantification resulted in high numbers of false positives (improperly categorized as atretic) and false negatives (improperly categorized intact). For preantral follicles, scoring mitotic and pyknotic GC nuclei allowed rapid, accurate identification of non-growing follicles with 98% accuracy. This method most often required the evaluation of one follicle section, and at most two serial follicle sections to correctly categorize follicle status. For antral follicles, we show that a rapid evaluation of follicle shape reveals which are intact and likely to survive to ovulation. CONCLUSIONS: Combined, these improved, non-arbitrary methods will greatly improve our ability to estimate the fractions of growing/intact and non-growing/atretic follicles in mouse ovaries. PMID- 28086946 TI - MiR-1307 promotes ovarian cancer cell chemoresistance by targeting the ING5 expression. AB - BACKGROUND: We aimed to investigate the function of miR-1307 in chemoresistance and to explore its chemoresistance mechanism in ovarian cancer. METHODS: IC50 determination was used to test the chemoresistance profling in ovarian cancer cells. QRT-PCR or western blot was used to validate the expression level of miR 1307 and candidate gene or protein. Colony formation assay and FITC-labeled enhanced Annexin V immunofluorescence were used to compare cell proliferation and apoptosis ability, respectively. The potential target gene and its biological function of miRNA-1307 were also analyzed. Bioinformatics and Luciferase Reporter Gene Assay were conducted to validate the regulation of miRNA-1307 on the ING5 expression. Xenografts assay was used to demonstrate the inhibiting effect of miR 1307 ASO and Taxol therapy against ovarian cancer in vivo. RESULTS: MiR-1307 was over-expressed in chemoresistant ovarian cancer cell line A2780/Taxol, and over expression or loss of miR-1307 promoted or inhabited chemoresistance. And we also found that the over-expression of miR-1307 promoted proliferation and inhibited apoptosis in ovarian cancer cells. Besides, we demonstrated that ING5 was a direct target of miR-1307 and miR-1307 down-regulated the ING5 expression in ovarian cancer cells. Additionally, we showed that ING5 inhibited cell proliferation, promoted cell apoptosis and inhabited chemoresistance reversely. Furthermore, the up-regulated ability of cell apoptosis and down-regulated ability of chemoresistance following the loss of miR-1307 was reversed by adding ING5 siRNA in vitro. Finally, we proved the inhibiting effect of miR-1307 ASO and Taxol therapy by increasing the ING5 expression against ovarian cancer through xenografts assay in vivo. CONCLUSION: Our results suggested that miR-1307 could promote ovarian cancer chemoresistance by targeting the ING5 expression and miR 1307 might serve as a therapeutic target for ovarian cancer. PMID- 28086948 TI - Is there still a role for cytotoxic chemotherapy after targeted therapy and immunotherapy in metastatic melanoma? A case report and literature review. AB - Metastatic melanoma has long been considered to have a very poor prognosis and to be chemo-resistant. However, a subgroup of patients with metastatic melanoma presents remarkable responses to chemotherapeutic agents, even in the absence of a response to modern targeted therapies and immunotherapies; accordingly, determining predictive biomarkers of the response to chemotherapies for metastatic melanoma remains a priority to guide treatment in these patients. We report a case study of a patient with B-Raf proto-oncogene serine/threonine kinase-mutated metastatic melanoma harbouring many genetic mutations. The patient did not respond to prior targeted therapies or immunotherapies but experienced a dramatic objective radiological and clinical response to subsequent dacarbazine based chemotherapy. In the era of targeted therapies and immunotherapies for metastatic melanoma, cytotoxic chemotherapies may still represent an interesting therapeutic weapon in a well-defined subgroup of patients presenting with specific genetic and molecular features. PMID- 28086949 TI - NEK2 Promotes Aerobic Glycolysis in Multiple Myeloma Through Regulating Splicing of Pyruvate Kinase. AB - BACKGROUND: Aerobic glycolysis, a hallmark of cancer, is characterized by increased metabolism of glucose and production of lactate in normaxia. Recently, pyruvate kinase M2 (PKM2) has been identified as a key player for regulating aerobic glycolysis and promoting tumor cell proliferation and survival. METHODS: Tandem affinity purification followed up by mass spectrometry (TAP-MS) and co immunoprecipitation (Co-IP) were used to study the interaction between NIMA (never in mitosis gene A)-related kinase 2 (NEK2) and heterogeneous nuclear ribonucleoproteins (hnRNP) A1/2. RNA immunoprecipitation (RIP) was performed to identify NEK2 binding to PKM pre-mRNA sequence. Chromatin-immunoprecipitation (ChIP)-PCR was performed to analyze a transcriptional regulation of NEK2 by c Myc. Western blot and real-time PCR were executed to analyze the regulation of PKM2 by NEK2. RESULTS: NEK2 regulates the alternative splicing of PKM immature RNA in multiple myeloma cells by interacting with hnRNPA1/2. RIP shows that NEK2 binds to the intronic sequence flanking exon 9 of PKM pre-mRNA. Knockdown of NEK2 decreases the ratio of PKM2/PKM1 and also other aerobic glycolysis genes including GLUT4, HK2, ENO1, LDHA, and MCT4. Myeloma patients with high expression of NEK2 and PKM2 have lower event-free survival and overall survival. Our data indicate that NEK2 is transcriptionally regulated by c-Myc in myeloma cells. Ectopic expression of NEK2 partially rescues growth inhibition and cell death induced by silenced c-Myc. CONCLUSIONS: Our studies demonstrate that NEK2 promotes aerobic glycolysis through regulating splicing of PKM and increasing the PKM2/PKM1 ratio in myeloma cells which contributes to its oncogenic activity. PMID- 28086950 TI - Healthcare system responsiveness in Jiangsu Province, China. AB - BACKGROUND: The perceived responsiveness of a healthcare system reflects its ability to satisfy reasonable expectations of the public with respect to non medical services. Recently, there has been increasing attention paid to responsiveness in evaluating the performance of a healthcare system in a variety of service settings. However, the factors that affect the responsiveness have been inconclusive so far and measures of improved responsiveness have not always thoroughly considered the factors. The aim of this study was to evaluate both the responsiveness of the healthcare system in Jiangsu Province, China, the factors that influence responsiveness and the measures of improved responsiveness considering it, as determined by a responsiveness survey. METHODS: A multistage, stratified random sampling method was used to select 1938 adult residents of Jiangsu Province in 2011. Face-to-face interviews were conducted using a self designed questionnaire modeled on the World Health Organization proposal. The final analysis was based on 1783 (92%) valid questionnaires. Canonical correlation analysis was used to assess the factors that affect responsiveness. RESULTS: The average score of all responsiveness-related domains in the surveyed healthcare system was satisfactory (7.50 out of a maximum 10.0). The two highest scoring domains were dignity and confidentiality, and the two lowest scoring domains choice and prompt attention. The factors affecting responsiveness were age, regional economic development level, and geographic area (urban vs. rural). The responsiveness regarding basic amenities was rated worse by the elderly than by younger respondents. Responsiveness ranked better by those with a poorer economic status. Choice in cities was better than in rural regions. CONCLUSIONS: The responsiveness of the Jiangsu healthcare system was considered to be satisfactory but could be improved by offering greater choice and providing more prompt attention. Perceptions of healthcare system responsiveness differ with age, regional economic development level, and geographic area (urban vs. rural). Measures to increase the perceived level of responsiveness include better service at higher level hospitals, shorter waiting time, more hospitals in rural regions, an improved medical environment, and provision of infrastructures that makes the medical environments more comfortable. PMID- 28086952 TI - Glucagon-like peptide-1 analogues - an efficient therapeutic option for the severe insulin resistance of lipodystrophic syndromes: two case reports. AB - BACKGROUND: Lipodystrophic syndromes are uncommon medical conditions which are normally associated with metabolic disorders, such as diabetes mellitus, dyslipidemia, and fatty liver disease. These complications are generally difficult to treat, particularly diabetes, due to severe insulin resistance. We present two case reports of successful treatment of diabetes with glucagon-like peptide-1 analogues in patients with clinical features of lipodystrophic syndromes. CASE PRESENTATION: Two white women aged 49 and 60 years manifested marked central body fat deposition with severe lipoatrophy of their limbs and buttocks and pronounced acanthosis nigricans. They had hypertension, dyslipidemia, fatty liver disease, and poorly controlled diabetes (glycated hemoglobin 8.3% and 10.2%, respectively) despite the use of three classes of oral antidiabetic drugs taken in combination in the first case, and high doses of insulin in the second case. Four months after the addition of glucagon-like peptide-1 analogue to their previous treatment they both showed a pronounced improvement in metabolic control (glycated hemoglobin 5.6% and 6.2%, respectively). In the first case, a weight loss of nearly 30 kg was recorded. CONCLUSIONS: We intend to demonstrate that glucagon-like peptide-1 analogues could be a valuable tool for patients with lipodystrophic disorders, probably by improving body fat distribution, with favorable results in insulin-sensitivity and glycemic control. PMID- 28086951 TI - Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes. AB - Obese and diabetic individuals are at increased risk for impairments in diastolic relaxation and heart failure with preserved ejection fraction. The impairments in diastolic relaxation are especially pronounced in obese and diabetic women and predict future cardiovascular disease (CVD) events in this population. Recent clinical data suggest sodium glucose transporter-2 (SGLT2) inhibition reduces CVD events in diabetic individuals, but the mechanisms of this CVD protection are unknown. To determine whether targeting SGLT2 improves diastolic relaxation, we utilized empagliflozin (EMPA) in female db/db mice. Eleven week old female db/db mice were fed normal mouse chow, with or without EMPA, for 5 weeks. Blood pressure (BP), HbA1c and fasting glucose were significantly increased in untreated db/db mice (DbC) (P < 0.01). EMPA treatment (DbE) improved glycemic indices (P < 0.05), but not BP (P > 0.05). At baseline, DbC and DbE had already established impaired diastolic relaxation as indicated by impaired septal wall motion (>tissue Doppler derived E'/A' ratio) and increased left ventricular (LV) filling pressure (50 years, suffering from at least 3 chronic diseases, receiving more than 4 drugs, and being at high risk for medication-related events according to the assessment of the treating GP were enrolled. The tailored program consisted of a workshop for GPs and health care assistants, educational materials and reminders for patients, and the elaboration of implementation action plans. The primary outcome was the change in the degree of implementation between baseline and follow-up, measured by a summary score of 10 indicators. The indicators were based on structured surveys with patients and GPs. RESULTS: We analyzed the data of 21 GPs (10 - intervention group, 11 - control group) and 273 patients (130 - intervention group, 143 - control group). The increase in the degree of implementation was 4.2 percentage points (95% confidence interval: 0.3, 8.6) higher in the intervention group compared to the control group (p = 0.1). Two of the 10 indicators were significantly improved in the intervention group: medication counseling (p = 0.017) and brown bag review (p = 0.012). Secondary outcomes showed an effect on patients' self-reported use of medication lists when buying drugs in the pharmacy (p = 0.03). CONCLUSIONS: The tailored program may improve implementation of medication counseling and brown bag review whereas the use of medication lists and medication reviews did not improve. No effect of the tailored program on the combined primary outcome could be substantiated. Due to limitations of the study, results have to be interpreted carefully. The factors facilitating and hindering successful implementation will be examined in a comprehensive process evaluation. TRIAL REGISTRATION NUMBER: ISRCTN34664024 , assigned 14/08/2013. PMID- 28086978 TI - Correlation of cytokine level with the severity of severe fever with thrombocytopenia syndrome. AB - BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) was an emerging hemorrhagic fever that was caused by a tick-borne bunyavirus, SFTSV. Although SFTSV nonstructural protein can inhibit type I interferon (IFN-I) production Ex Vivo and IFN-I played key role in resistance SFTSV infection in animal model, the role of IFN-I in patients is not investigated. METHODS: We have assayed the concentration of IFN-alpha, a subtype of IFN-I as well as other cytokines in the sera of SFTS patients and the healthy population with CBA (Cytometric bead array) assay. RESULTS: The results showed that IFN-alpha, tumor necrosis factor (TNF alpha), granulocyte colony-stimulating factor (G-CSF), interferon-gamma (IFN gamma), macrophage inflammatory protein (MIP-1alpha), interleukin-6 (IL-6), IL 10, interferon-inducible protein (IP-10), monocyte chemoattractant protein (MCP 1) were significantly higher in SFTS patients than in healthy persons (p < 0.05); the concentrations of IFN-alpha, IFN-gamma, G-CSF, MIP-1alpha, IL-6, and IP-10 were significant higher in severe SFTS patients than in mild SFTS patients (p < 0.05). CONCLUSION: The concentration of IFN-alpha as well as other cytokines (IFN gamma, G-CSF, MIP-1alpha, IL-6, and IP-10) is correlated with the severity of SFTS, suggesting that type I interferon may not be significant in resistance SFTSV infection in humans and it may play an import role in cytokine storm. PMID- 28086979 TI - B cell repertoires in HLA-sensitized kidney transplant candidates undergoing desensitization therapy. AB - BACKGROUND: Kidney transplantation is the most effective treatment for end-stage renal disease. Sensitization refers to pre-existing antibodies against human leukocyte antigen (HLA) protein and remains a major barrier to successful transplantation. Despite implementation of desensitization strategies, many candidates fail to respond. Our objective was to determine whether measuring B cell repertoires could differentiate candidates that respond to desensitization therapy. METHODS: We developed an assay based on high-throughput DNA sequencing of the variable domain of the heavy chain of immunoglobulin genes to measure changes in B cell repertoires in 19 highly HLA-sensitized kidney transplant candidates undergoing desensitization and 7 controls with low to moderate HLA sensitization levels. Responders to desensitization had a decrease of 5% points or greater in cumulated calculated panel reactive antibody (cPRA) levels, and non responders had no decrease in cPRA. RESULTS: Dominant B cell clones were not observed in highly sensitized candidates, suggesting that the B cells responsible for sensitization are either not present in peripheral blood or present at comparable levels to other circulating B cells. Candidates that responded to desensitization therapy had pre-treatment repertoires composed of a larger fraction of class-switched (IgG and IgA) isotypes compared to non-responding candidates. After B cell depleting therapy, the proportion of switched isotypes increased and the mutation frequencies of the remaining non-switched isotypes (IgM and IgD) increased in both responders and non-responders, perhaps representing a shift in the repertoire towards memory B cells or plasmablasts. Conversely, after transplantation, non-switched isotypes with fewer mutations increased, suggesting a shift in the repertoire towards naive B cells. CONCLUSIONS: Relative abundance of different B cell isotypes is strongly perturbed by desensitization therapy and transplantation, potentially reflecting changes in the relative abundance of memory and naive B cell compartments. Candidates that responded to therapy experienced similar changes to those that did not respond. Further studies are required to understand differences between these two groups of highly sensitized kidney transplant candidates. PMID- 28086981 TI - Does antiretroviral treatment change HIV-1 codon usage patterns in its genes: a preliminary bioinformatics study. AB - BACKGROUND: Codon usage bias has been described for various organisms and is thought to contribute to the regulation of numerous biological processes including viral infections. HIV-1 codon usage has been previously shown to be different from that of other viruses and man. It is evident that the antiretroviral drugs used to restrict HIV-1 replication also select for resistance variants. We wanted to test whether codon frequencies in HIV-1 sequences from treatment-experienced patients differ from those of treatment naive individuals due to drug pressure affecting codon usage bias. RESULTS: We developed a JavaScript to determine the codon frequencies of aligned nucleotide sequences. Irrespective of subtypes, using HIV-1 pol sequences from 532 treatment naive and 52 treatment-experienced individuals, we found that pol sequences from treatment-experienced patients had significantly increased AGA (arginine; p = 0.0002***) and GGU (glycine; p = 0.0001***), and decreased AGG (arginine; p = 0.0001***) codon frequencies. The same pattern was not observed when subtypes B and C sequences were analyzed separately. Additionally, irrespective of subtypes, using HIV-1 gag sequences from 524 treatment-naive and 54 treatment-experienced individuals, gag sequences from treatment-experienced patients had significantly increased CUA (leucine; p < 0.0001***), CAG (glutamine; p = 0.0006***), AUC (isoleucine; p < 0.0001***) and UCU (serine; p = 0.0005***), and decreased AUA (isoleucine; p = 0.0003***) and CAA (glutamine; p = 0.0006***) codon frequencies. CONCLUSION: Using pol and gag genes derived from the same HIV-1 genome, we show that antiretroviral therapy changed certain HIV-1 codon frequencies in a subtype specific way. PMID- 28086982 TI - Reproductive factors and the risk of triple-negative breast cancer in white women and African-American women: a pooled analysis. AB - BACKGROUND: Early age at menarche, nulliparity, late age at first completed pregnancy, and never having breastfed, are established breast cancer risk factors. However, among breast cancer subtypes, it remains unclear whether all of these are risk factors for triple-negative breast cancer (TNBC). METHODS: We evaluated the associations of these reproductive factors with TNBC, in 2658 patients with breast cancer (including 554 with TNBC) and 2448 controls aged 20 64 years, who participated in one of the three population-based case-control studies: the Women's Contraceptive and Reproductive Experiences Study, the Women's Breast Carcinoma in situ Study, or the Women's Learning the Influence of Family and Environment Study. We used multivariable polychotomous unconditional logistic regression methods to conduct case-control comparisons among breast cancer subtypes defined by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 expression status. RESULTS: TNBC risk decreased with increasing duration of breastfeeding (P trend = 0.006), but age at menarche, age at first completed pregnancy, and nulliparity were not associated with risk of TNBC. Parous women who breastfed for at least one year had a 31% lower risk of TNBC than parous women who had never breastfed (odds ratio, OR = 0.69; 95% confidence interval, CI = 0.50-0.96). The association between breastfeeding and risk of TNBC was modified by age and race. Parous African American women aged 20-44 years who breastfed for 6 months or longer had an 82% lower risk of TNBC than their counterparts who had never breastfed (OR = 0.18, 95% CI = 0.07-0.46). CONCLUSIONS: Our data indicate that breastfeeding decreases the risk of TNBC, especially for younger African-American women. PMID- 28086980 TI - Inflammation in epileptogenesis after traumatic brain injury. AB - BACKGROUND: Epilepsy is a common and debilitating consequence of traumatic brain injury (TBI). Seizures contribute to progressive neurodegeneration and poor functional and psychosocial outcomes for TBI survivors, and epilepsy after TBI is often resistant to existing anti-epileptic drugs. The development of post traumatic epilepsy (PTE) occurs in a complex neurobiological environment characterized by ongoing TBI-induced secondary injury processes. Neuroinflammation is an important secondary injury process, though how it contributes to epileptogenesis, and the development of chronic, spontaneous seizure activity, remains poorly understood. A mechanistic understanding of how inflammation contributes to the development of epilepsy (epileptogenesis) after TBI is important to facilitate the identification of novel therapeutic strategies to reduce or prevent seizures. BODY: We reviewed previous clinical and pre clinical data to evaluate the hypothesis that inflammation contributes to seizures and epilepsy after TBI. Increasing evidence indicates that neuroinflammation is a common consequence of epileptic seizure activity, and also contributes to epileptogenesis as well as seizure initiation (ictogenesis) and perpetuation. Three key signaling factors implicated in both seizure activity and TBI-induced secondary pathogenesis are highlighted in this review: high-mobility group box protein-1 interacting with toll-like receptors, interleukin-1beta interacting with its receptors, and transforming growth factor-beta signaling from extravascular albumin. Lastly, we consider age-dependent differences in seizure susceptibility and neuroinflammation as mechanisms which may contribute to a heightened vulnerability to epileptogenesis in young brain-injured patients. CONCLUSION: Several inflammatory mediators exhibit epileptogenic and ictogenic properties, acting on glia and neurons both directly and indirectly influence neuronal excitability. Further research is required to establish causality between inflammatory signaling cascades and the development of epilepsy post-TBI, and to evaluate the therapeutic potential of pharmaceuticals targeting inflammatory pathways to prevent or mitigate the development of PTE. PMID- 28086985 TI - External validation of a clinical decision rule: we need events in a population in order to rule them out! AB - We respond to the Lorton et al. article on external validation of the PECARN study. With an event rate of only 0.6%, we believe that their study failed to confirm the safety of this rule. Such a low number of events should call for caution when interpreting the results of diagnostic tests. PMID- 28086983 TI - Mailed HPV self-sampling for cervical cancer screening among underserved minority women: study protocol for a randomized controlled trial. AB - BACKGROUND: Underserved ethnic minority women experience significant disparities in cervical cancer incidence and mortality, mainly due to lack of cervical cancer screening. Barriers to Pap smear screening include lack of knowledge, lack of health insurance and access, and cultural beliefs regarding disease prevention. In our previous SUCCESS trial, we demonstrated that HPV self-sampling delivered by a community health worker (CHW) is efficacious in circumventing these barriers. This approach increased screening uptake relative to navigation to Pap smear screening. SUCCESS trial participants, as well as our community partners, provided feedback that women may prefer the HPV self-sampler to be delivered through the mail, such that they would not need to schedule an appointment with the CHW. Thus, our current trial aims to elucidate the efficacy of the HPV self sampling method when delivered via mail. DESIGN: We are conducting a randomized controlled trial among 600 Haitian, Hispanic, and African-American women from the South Florida communities of Little Haiti, Hialeah, and South Dade. Women between the ages of 30 and 65 years who have not had a Pap smear within the past 3 years are eligible for the study. Women are recruited by CHWs and complete a structured interview to assess multilevel determinants of cervical cancer risk. Women are then randomized to receive HPV self-sampling delivered by either the CHW (group 1) or via mail (group 2). The primary outcome is completion of HPV self-sampling within 6 months post enrollment. DISCUSSION: Our trial is among the first to examine the efficacy of the mailed HPV self-sampling approach. If found to be efficacious, this approach may represent a cost-effective strategy for cervical cancer screening within underserved and underscreened minority groups. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02202109 . Registered on 9 July 2014. PMID- 28086984 TI - Deptor: not only a mTOR inhibitor. AB - Deptor is an important protein that belongs to the mTORC1 and mTORC2 complexes, able to interact with mTOR and to inhibit its kinase activity. As a natural mTOR inhibitor, Deptor is involved in several molecular pathways, such as cell growth, apoptosis, autophagy and ER stress response. For this reason, Deptor seems to play an important role in controlling cellular homeostasis. Despite several recent insights characterizing Deptor functions and regulation, its complete role within cells has not yet been completely clarified. Indeed, quite recently, Deptor has been associated with chromatin, and it has been demonstrated having a role in transcriptional regulation, controlling in such way endoplasmatic reticulum activity.From all these observations it is not surprising that Deptor can behave either as an oncogene or oncosuppressor, depending on the cell- or tissue-contexts. This review highlights recent progresses made in our understanding of the many activities of Deptor, describing its transcriptional and post-transcriptional regulation in different cancer cell types. Moreover, here we discuss the possibility of using compounds able to inhibit Deptor or to disrupt its interaction with mTOR as novel approaches for cancer therapy. PMID- 28086986 TI - Radioiodine sinus uptake related to mucosal thickening or aspergilloma: a case series of an unrecognized event well evidenced by SPECT/CT. AB - BACKGROUND: False-positive radioiodine (RAI) uptake related to chronic sinusitis and mucocele has only rarely been reported in patients with differentiated thyroid cancer (DTC) even with the recent use of single photon emission tomography with computed tomography (SPECT/CT) acquisition. No other etiology of sinus RAI uptake has been mentioned to date. OBJECTIVES: We report five cases of DTC patients with sinus RAI uptake on post-RAI scintigraphy. SPECT/CT clearly localized RAI uptake either in the sphenoid, the maxillary or the frontal sinus and highly suspected mucosal thickening in four patients and sinus aspergilloma in one patient. CONCLUSION: These data confirm the possibility of false-positive sinus RAI uptake, provide a new cause of such benign uptake, i.e. sinus aspergilloma, and demonstrate the clinical relevance of head and neck SPECT/CT acquisition in the diagnosis of such uptake. Nuclear medicine physicians should be aware of this pitfall when interpreting post-RAI scintigraphy. PMID- 28086987 TI - A systematic review and meta-analysis of the seroprevalence of Toxoplasma gondii in cats in mainland China. AB - BACKGROUND: Toxoplasmosis is caused by Toxoplasma gondii which can infect all warm-blooded animals. As the most common feline definitive host, cats play a vital role in the transmission of T. gondii. However, national estimates of the seroprevalence of T. gondii in cats in mainland China are lacking, and therefore a systematic review and meta-analysis were performed to provide insight into national environmental transmission levels and potential transmission to humans. METHODS: Studies published up until July 1, 2016, on T. gondii seroprevalence in cats within mainland China were searched for in CNKI, WanFang, CBM, PubMed, Embase and through the reference lists of resulting articles. The seroprevalence with its 95% confidence interval (CI) for each individual study was presented, and then point estimates and their 95% confidence intervals (CIs) of pooled seroprevalence were calculated. Subgroup analyses were performed according to potential risk factors. RESULTS: A total of 38 eligible studies, published between 1995 to 2016, covering fifteen provinces and municipalities, and involving 7,285 cats, were included. The seroprevalence in cats per study ranged from 3.9 to 79.4% with a median of 20.3%. As substantial heterogeneity existed among studies, a random-effects model was used to estimate the pooled seroprevalence. The value of the point estimate seroprevalence was 24.5% (95% CI: 20.1-29.0). Seroprevalence in stray cats was significantly higher than in pet cats (OR = 3.00, 95% CI: 1.60-5.64). The seroprevalence increased significantly with cat age (P = 0.018) with 17.4% (95% CI: 7.6-27.2) in the group of <= 1 year old, 19.5% (95% CI: 12.7-26.3) in the group of <= 3 year-old and 31.6% (95% CI: 22.9-40.3) in the group of > 3 year-old. CONCLUSIONS: The seroprevalence of T. gondii in cats in mainland China was moderate and was associated with cat ownership and age. Due to the increasing prevalence of pet cats in China and the intimate relationship between these cats and humans, this might present a significant exposure risk, particularly for China's large susceptible population. Therefore, further research is needed into the links between cat ownership and human T. gondii infection and how to reduce T. gondii exposure in humans via cat contacts and the environmental contamination with T. gondii oocysts by cats. PMID- 28086988 TI - Computed tomographic findings and treatment of a bull with pituitary gland abscess. AB - BACKGROUND: In cattle, the prognosis of brain abscess is unfavourable and treatment is therefore not recommended. To the knowledge of the authors, there has been no report of successful treatment of a brain abscess in cattle.This report describes the clinical, computed tomographic and postmortem findings in a Holstein-Friesian bull with a hypophyseal abscess. CASE REPORT: The main clinical findings were generalised ataxia, ptyalism, prolapse of the tongue, dropped jaw, dysphagia, head tilt and unilateral ptosis. Cerebrospinal fluid evaluation revealed 2437 leukocytes/ul and severe pleocytosis. CT examination of the head showed a cavitary lesion consistent with an abscess in the hypophysis. Treatment consisted of gentamicin and flunixin meglumine for 3 days and amoxicillin for 40 days. The neurological signs resolved within 8 days of the start of treatment. The bull was slaughtered 11 months later because of infertility, and a postmortem examination was carried out. Histologically, a mild chronic non suppurative meningoencephalitis restricted to the ventral diencephalon was diagnosed. In addition, there was mild to moderate multifocal chronic lymphoplasmacytic hypophysitis with mild multifocal fibrosis. CONCLUSIONS: This case report stresses the significance of CT in confirming the clinical and laboratory diagnosis of central nervous system disorders in cattle and for localising brain lesions. Treatment of the brain abscess resulted, with respect to the central nervous disorder, in a successful outcome and was encouraging considering that most cases have an unfavourable prognosis. PMID- 28086989 TI - Correlation between the Ki-67 proliferation index and response to radiation therapy in small cell lung cancer. AB - BACKGROUND: In the breast cancer, the decision whether to administer adjuvant therapy is increasingly influenced by the Ki-67 proliferation index. In the present retrospective study, we investigated if this index could predict the therapeutic response to radiation therapy in small cell lung cancer (SCLC). METHODS: Data from 19 SCLC patients who received thoracic radiation therapy were included. Clinical staging was assessed using the TNM classification system (UICC, 2009; cstage IIA/IIB/IIIA/IIIB = 3/1/7/8). Ki-67 was detected using immunostained tumour sections and the Ki-67 proliferation index was determined using e-Count software. Radiation therapy was administered at total doses of 45 60 Gy. A total of 16 of the 19 patients received chemotherapy. RESULTS: Patients were divided into two groups, one with a Ki-67 proliferation index >=79.77% (group 1, 8 cases) and the other with a Ki-67 proliferation index <79.77% (group 2, 11 cases). Following radiation therapy, a complete response (CR) was observed in six cases from group 1 (75.0%) and three cases from group 2 (27.3%). The Ki-67 proliferation index was significantly correlated with the CR rate (P = 0.05), which was significantly higher in group 1 than in group 2 (P = 0.04). The median survival time was 516 days for all patients, and the survival rates did not differ significantly between groups 1 and 2. CONCLUSIONS: Our study is the first to evaluate the correlation between the Ki-67 proliferation index and SCLC tumour response to radiation therapy. Our findings suggest that a high Ki-67 proliferation index might represent a predictive factor for increased tumour radiosensitivity. PMID- 28086990 TI - The efficacy of fluoropyrimidine-based adjuvant chemotherapy on biliary tract cancer after R0 resection. AB - BACKGROUND: The optimal treatment strategy for biliary tract cancer (BTC) after curative-intent resection remains controversial. The purpose of this study was to evaluate the efficacy of fluoropyrimidine-based adjuvant chemotherapy for BTC patients undergoing microscopically margin-negative (R0) resection. METHODS: We retrospectively analyzed the clinical data of BTC patients who underwent curative intent R0 resection. Patients were eligible if they received either fluoropyrimidine-based adjuvant chemotherapy or observation after R0 resection. RESULTS: A total of 153 patients were included. In the entire patient cohort, no significant differences were observed in 5-year overall survival (OS) rates (48.4% vs. 39.6%, P = 0.439) or 3-year recurrence-free survival (RFS) rates (49.1% vs. 39.5%, P = 0.299) between patients who received fluoropyrimidine-based adjuvant chemotherapy or observation. However, for patients with stages II and III BTC, chemotherapy significantly improved 5-year OS rate (52.4% vs. 35.6%, P = 0.002) and 3-year RFS rate (55.5% vs. 39.1%, P = 0.021) compared with observation. CONCLUSION: Fluoropyrimidine-based adjuvant chemotherapy may prolong the survival of patients with stages II and III BTC after R0 resection. PMID- 28086991 TI - Does waterfall aerosol influence mucosal immunity and chronic stress? A randomized controlled clinical trial. AB - BACKGROUND: The specific microclimate of alpine waterfalls with high levels of ionized water aerosols has been suggested to trigger beneficial immunological and psychological effects. In the present three-armed randomized controlled clinical study, we focused on effects on (i) immunological reagibility, on (ii) physiological stress responses, and on (iii) stress-related psychological parameters. METHODS: People with moderate to high stress levels (n = 65) spent an active sojourn with daily hiking tours in the National Park Hohe Tauern (Grobetakirchheim, Austria). Half of the group was exposed to water aerosol of an alpine waterfall for 1 h/day (first arm, n = 33), whereas the other half spent the same time at a distant site (second arm, n = 32). A third arm (control, n = 26) had no intervention (except vaccination) and stayed at home, maintaining their usual lifestyle. The effect of the interventions on the immune system was tested by oral vaccination with an approved cholera vaccine and measuring specific salivary IgA antibody titers. Lung function was determined by peak expiratory flow measurement. Electric skin conductance, heart rate, and adaption of respiration rate were assessed as physiological stress parameters. Psychological stress-related parameters were analyzed by questionnaires and scales. RESULTS: Compared to the control group, both intervention groups showed improvement of the lung function and of most physiological stress test parameters. Analysis of the mucosal immune response revealed a waterfall-specific beneficial effect with elevated IgA titers in the waterfall group. In line with these results, exposure to waterfall revealed an additional benefit concerning psychological parameters such as subjective stress perception (measured via visual analog scale), the Global Severity Index (GSI), and the Positive Symptom Total (PST). CONCLUSIONS: Our study provides new data, which strongly support an "added value" of exposure to waterfall microclimate when combined with a therapeutic sojourn at high altitude including regular physical activity. PMID- 28086992 TI - Therapies for bruxism: a systematic review and network meta-analysis (protocol). AB - BACKGROUND: Bruxism is a sleep disorder characterized by grinding and clenching of the teeth that may be related to irreversible tooth injuries. It is a prevalent condition occurring in up to 31% of adults. However, there is no definitive answer as to which of the many currently available treatments (including drug therapy, intramuscular injections, physiotherapy, biofeedback, kinesiotherapy, use of intraoral devices, or psychological therapy) is the best for the clinical management of the different manifestations of bruxism. The aim of this systematic review and network meta-analysis is to answer the following question: what is the best treatment for adult bruxists? METHODS/DESIGN: Comprehensive searches of the Cochrane Library, MEDLINE (via PubMed), Scopus, and LILACS will be completed using the following keywords: bruxism and therapies and related entry terms. Studies will be included, according to the eligibility criteria (Controlled Clinical Trials and Randomized Clinical Trials, considering specific outcome measures for bruxism). The reference lists of included studies will be hand searched. Relevant data will be extracted from included studies using a specially designed data extraction sheet. Risk of bias of the included studies will be assessed, and the overall strength of the evidence will be summarized (i.e., GRADE). A random effects model will be used for all pairwise meta-analyses (with a 95% confidence interval). A Bayesian network meta-analysis will explore the relative benefits between the various treatments. The review will be reported using the Preferred Reporting Items for Systematic Reviews incorporating Network Meta-Analyses (PRISMA-NMA) statement. DISCUSSION: This systematic review aims at identifying and evaluating therapies to treat bruxism. This systematic review may lead to several recommendations, for both patients and researchers, as which is the best therapy for a specific patient case and how future studies need to be designed, considering what is available now and what is the reality of the patient. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015023308. PMID- 28086993 TI - Lack of partial renal response by 12 weeks after induction therapy predicts poor renal response and systemic damage accrual in lupus nephritis class III or IV. AB - BACKGROUND: Lupus nephritis class III or IV is associated with a poor prognosis for both patient and renal survival. Recommendations for the management of lupus nephritis have recently been established, and changing therapies is recommended for patients who do not respond adequately to induction therapy. However, it remains a major challenge to determine when to switch the treatment. In this study, we identified early prognostic factors capable of predicting poor renal outcome as well as overall damage accrual in patients with lupus nephritis class III or IV. METHODS: Eighty patients with biopsy-proven lupus nephritis class III or IV were retrospectively recruited and divided into two groups: those with complete renal response (CR) or non-CR at 3 years after induction therapy. We investigated when clinical responses were obtained at each observational period from baseline to year 3. Clinical responses were divided into three groups: CR, partial renal response (PR), and non-PR. Furthermore, patients were assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) and cumulative dose of corticosteroid for 3 years. RESULTS: Forty-four patients with CR and thirty-six with non-CR were enrolled. The cumulative CR rate was 85.0%. PR rates of patients with CR were significantly higher than those with non-CR from week 12 (p < 0.01). We identified the achievement of PR at 12 weeks as an independent predictor (OR 3.57, p = 0.03) by multivariate analysis. We next divided all patients into two groups according to PR achievement at week 12. The cumulative CR rate of the patients who achieved PR at week 12 was significantly higher than that of those who did not (96.5% vs 69.2%, p < 0.001). Furthermore, a significantly higher SDI and cumulative dose of corticosteroid were seen in the patients who did not achieve PR at week 12 than in those who did, regardless of their CR status, at year 3. CONCLUSIONS: Lack of PR at week 12 predicts a lower likelihood of achieving CR at 3 years and a higher SDI. PMID- 28086994 TI - Retraction notice to "Calponin and caldesmon cellular domains in reacting microvessels following traumatic brain injury" [Microvasc. Res. 71 (2006) 7]. PMID- 28086995 TI - [Evidence-based public health in Gaceta Sanitaria: a nod to Latin America]. PMID- 28086996 TI - [La Societe Francaise du Cancer is moving forward]. PMID- 28086997 TI - Enamel-renal syndrome in 2 patients with a mutation in FAM20 A and atypical hypertrichosis and hearing loss phenotypes. AB - Enamel-renal syndrome (OMIM #204690) is an uncommon disorder characterized by amelogenesis imperfecta and nephrocalcinosis and is caused by mutations in FAM20 A. We report 2 patients with enamel-renal syndrome who exhibited the typical features of this syndrome and a homozygous nonsense mutation in the FAM20 A gene (c.406 C>T), genetically confirming the diagnosis. They also exhibited 2 undescribed clinical features, hypertrichosis and hearing loss. Alterations in genes frequently associated with nonsyndromic hearing loss in the Brazilian population, including connexin 26 (GJB2), connexin 30 (GJB6) and mitochondrial 12 S rRNA (m.A1555 G mutation), were not found. These results suggest a putative function of FAM20 A in the development of the inner ear and in the formation of hair. The presence of nephrocalcinosis is a risk factor for renal impairment, and it is important to perform regular renal monitoring in order to avoid renal failure. PMID- 28086998 TI - Evaluation of artifacts generated by zirconium implants in cone-beam computed tomography images. AB - OBJECTIVE: To evaluate zirconium implant artifact production in cone beam computed tomography images obtained with different protocols. STUDY DESIGN: One zirconium implant was inserted in an edentulous mandible. Twenty scans were acquired with a ProMax 3D unit (Planmeca Oy, Helsinki, Finland), with acquisition settings ranging from 70 to 90 peak kilovoltage (kVp) and voxel sizes of 0.32 and 0.16 mm. A metal artifact reduction (MAR) tool was activated in half of the scans. An axial slice through the middle region of the implant was selected for each dataset. Gray values (mean +/- standard deviation) were measured in two regions of interest, one close to and the other distant from the implant (control area). The contrast-to-noise ratio was also calculated. RESULTS: Standard deviation decreased with greater kVp and when the MAR tool was used. The contrast to-noise ratio was significantly higher when the MAR tool was turned off, except for low resolution with kVp values above 80. Selection of the MAR tool and greater kVp resulted in an overall reduction of artifacts in images acquired with low resolution. CONCLUSIONS: Although zirconium implants do produce image artifacts in cone-bean computed tomography scans, the setting that best controlled artifact generation by zirconium implants was 90 kVp at low resolution and with the MAR tool turned on. PMID- 28087000 TI - Commentary from the Editor. PMID- 28086999 TI - Prognosis Disclosure in Spinal Cord Injury. PMID- 28087001 TI - Coming of age of the World Muscle Society Granada 2016. PMID- 28087003 TI - In vitro generation of renal tubular epithelial cells from fibroblasts: implications for precision and regenerative medicine in nephrology. AB - Prior efforts to generate renal epithelial cells in vitro have relied on pluripotent or bone marrow-derived mesenchymal stem cells. A recent publication in Nature Cell Biology describes the generation of induced tubular epithelial cells from fibroblasts, potentially offering a novel platform for personalized drug toxicity screening and in vitro disease modeling. This report serves as a promising proof of principle study and opens future research directions, including the optimization of the reprogramming process, efficient translation to adult human fibroblasts, and the generation of highly specific functional renal cell types. PMID- 28087004 TI - Gimme a complex! Resident mononuclear phagocytes in the kidney as monitors of circulating antigens and immune complexes. AB - Over the past decade, researchers have made substantial progress in characterizing a network of mononuclear phagocytes in the kidney, which variously have been referred to as resident macrophages or dendritic cells. Two recent studies, published in Cell and Kidney International, have identified these resident macrophages/dendritic cells as local immune monitors of peritubular capillaries for circulating antigens and immune complexes. These cells appear to represent an early line of defense against circulating infectious particles and immune complexes, but the resulting inflammatory response may also contribute to interstitial inflammation and kidney disease progression. PMID- 28087005 TI - And the fat lady sings about phosphate and calcium. AB - Adipose tissue has been long recognized as secreting various endocrine factors. Emerging evidence demonstrates that adipokines play a role in modulating systemic mineral homeostasis through endocrine loops involving interleukin-6, leptin, and now also adiponectin, which all interact with FGF23 and vitamin D and thereby change the renal control of calcium and phosphate metabolism. Understanding these regulatory loops may shed light on a complex interorgan crosstalk controlling mineral homeostasis and its dysregulation in diseases associated with obesity. PMID- 28087006 TI - New insights into the pathogenesis and treatment of heavy chain deposition disease. AB - Heavy chain deposition disease is defined by the presence of tissue deposits of truncated monoclonal Ig heavy chains, usually associated with an underlying plasma cell clone. In this issue of Kidney International, Bridoux et al. described the clinical, histologic, and molecular characterization of 15 patients with heavy chain deposition disease, which is the largest case series to date. Notable findings included the frequent presence of C3 deposits and hypocomplementemia, the uniform finding of truncated heavy chains with the deletion in the heavy chain constant region 1, and the common occurrence of an abnormal serum-free kappa:lambda ratio, despite the absence of light-chain tissue deposition. Importantly, this study showed that clinical outcomes are improved significantly with modern antiplasma cell therapies such as bortezomib. PMID- 28087007 TI - Manipulating the microbiome. AB - The application of molecular methods has provided a new picture of the colon microbial flora, or microbiome. The microbiome has been found to be a complex ecosystem with multiple influences on its human host. In renal medicine, interest has focused on the microbiome as a source of toxic waste chemicals and a stimulant to unwanted systemic inflammation. Early attempts to manipulate the microbiome have yielded limited benefit, but further research is strongly motivated. PMID- 28087008 TI - APOL1 genotype, blood pressure, and survival in African Americans with nondiabetic nephropathy. AB - Several landmark trials have assessed the effects of aggressive hypertension control on the progression of nondiabetic chronic kidney disease. Results generally have been disappointing. With the realization that lowering blood pressure, including with renin-angiotensin system blockade, failed to reliably prevent end-stage kidney disease, studies now are analyzing longer-term effects of hypertension control on survival in chronic kidney disease. This commentary reviews the current findings and extends the discussion to apolipoprotein L1 gene by blood pressure (or gene by environment) interactions. PMID- 28087009 TI - Improving kidney disease in obese adolescents: a surgical approach. AB - Obesity has been associated with chronic kidney disease in adult studies, but little data exist in pediatrics. Nehus et al. offer the first study to show that bariatric surgery in severely obese adolescents is associated with improved renal outcomes. Despite limitations, this study provided compelling evidence that aggressive weight loss intervention can improve renal outcomes in young, severely obese subjects. Further investigation is required to determine mechanisms by which this may occur. PMID- 28087011 TI - Acute aortic syndrome in autosomal dominant polycystic kidney disease. PMID- 28087010 TI - Breaking the ice: urine proteomics of medullary sponge kidney disease. AB - Urinary proteomics is a promising tool for biomarker investigation, particularly in complex kidney diseases. Fabris and colleagues report that urinary laminin subunit alpha-2 is a potential diagnostic marker of medullary sponge kidney (MSK) disease by using a label-free quantitative proteomics platform and a clinically compatible enzyme-linked immunosorbent assay. The neglected issue of stone pathogenesis was also evidenced. This commentary discusses several considerations in biomarker validation, and how urinary proteomics breaks new ground in MSK research. PMID- 28087012 TI - To Be or not To Be: a rare cause of AKI in a renal allograft. PMID- 28087013 TI - The Case | Nephrotic syndrome with corneal opacities. PMID- 28087014 TI - Parallel globules on the ridges caused by transepidermal elimination of melanocytic nests: A new dermoscopic pattern of acral melanoma. PMID- 28087015 TI - Acral persistent papular mucinosis (APPM): Dermoscopy of an uncommon disease. PMID- 28087016 TI - Familial outbreak of eruptive pseudoangiomatosis with dermoscopic and histopathologic correlation. PMID- 28087017 TI - Solitary angiokeratoma with Meyerson phenomenon. PMID- 28087018 TI - A case of onychomatricoma: Classic clinical, dermoscopic, and nail-clipping histologic findings. PMID- 28087019 TI - Desmoplastic trichilemmoma dermoscopically mimicking molluscum contagiosum. PMID- 28087020 TI - Acral pseudolymphomatous angiokeratoma of children with rainbow pattern: A mimicker of Kaposi sarcoma. PMID- 28087021 TI - Ultraviolet dermoscopy for the diagnosis of tinea capitis. PMID- 28087022 TI - Peripilar hair casts. PMID- 28087023 TI - Dermoscopic presentation of Hailey-Hailey disease. PMID- 28087024 TI - Acral melanoma. PMID- 28087025 TI - Dermoscopy of isolated syringoma of the vulva. PMID- 28087026 TI - Dermoscopy of pigmented fungiform papillae of the tongue. PMID- 28087027 TI - Dermoscopy confirms diagnosis of circumscribed plantar hypokeratosis. PMID- 28087028 TI - Nodular hidradenoma: Dermoscopic presentation. PMID- 28087029 TI - Lichen sclerosus of the glans simulating melanoma. PMID- 28087030 TI - Dermoscopic characteristics of a cutaneous histiocytic sarcoma in a young patient. PMID- 28087031 TI - Dermoscopic diagnosis of scurvy. PMID- 28087032 TI - A rare dermoscopic pattern of nodular basal cell carcinoma with amyloid deposition. PMID- 28087033 TI - Keratoacanthoma-like dermatofibroma: A dermoscopic challenge. PMID- 28087034 TI - Dermoscopy of Grover disease. PMID- 28087035 TI - The anal groove sign: The use of dermatoscopy for identification of Ixodes ticks. PMID- 28087036 TI - Dermoscopy, reflectance confocal microscopy, and high-definition optical coherence tomography in the diagnosis of generalized argyria. PMID- 28087037 TI - Dermoscopy of pseudoxanthoma elasticum. PMID- 28087038 TI - Dermoscopy of cutaneous involvement by multiple myeloma. PMID- 28087039 TI - Dermoscopic and reflectance confocal microscopic presentation of relapsing eccrine porocarcinoma. PMID- 28087040 TI - Dermoscopy of giant juvenile xanthogranuloma. PMID- 28087041 TI - Dermoscopy of Langerhans cell histiocytosis. PMID- 28087042 TI - Dermoscopic features of a solitary fibrofolliculoma on the left cheek. PMID- 28087043 TI - Diagnosing squamous cell carcinoma of the lip using dermoscopy. PMID- 28087044 TI - Homogeneous white patch in dermoscopy of solitary circumscribed neuroma. PMID- 28087045 TI - Dermoscopy of adenoma sebaceum. PMID- 28087046 TI - Morel-Lavallee Injuries: A Multimodality Approach to Imaging Characteristics. AB - Morel-Lavallee lesions are relatively rare closed degloving injuries caused by a shearing force resulting in separation of the dermis and the hypodermis from the subjacent deeper fascia. Although most commonly encountered lateral to the greater trochanter, these injuries may occur throughout the body in a variety of locations. Separation of the hypodermal tissue planes results in a complex serosanguinous fluid collection with areas of internal fat necrosis. The imaging appearance is variable and nonspecific, potentially mimicking superficial hemorrhagic bursitis, or cystic or necrotic primary soft tissue neoplasms. If not treated in the acute or early subacute setting, these collections are at risk of superinfection, overlying tissue necrosis, and continued expansion. In this article, we will review the pathophysiology, cross-sectional imaging features, and differential diagnostic considerations of Morel-Lavallee lesions as well as discuss management and treatment options. PMID- 28087047 TI - Rational design of low immunogenic anti CD25 recombinant immunotoxin for T cell malignancies by elimination of T cell epitopes in PE38. AB - LMB-2, is a potent recombinant immunotoxin (RIT) that is composed of scFv antibody that targets CD25 (Tac) and a toxin fragment (PE38). It is used to treat T cell leukemias and lymphomas. To make LMB-2 less immunogenic, we introduced a large deletion in domain II and six point mutations in domain III that were previously shown to reduce T cell activation in other RITs. We found that unlike other RITs, deletion of domain II from LMB-2 severely compromised its activity. Rather than deletion, we identified T cell epitopes in domain II and used alanine substitutions to identify point mutations that diminished those epitopes. The novel RIT, LMB-142 contains a 38kDa toxin and nine point mutations that diminished T cell response to the corresponding peptides by an average of 75%. LMB-142 has good cytotoxic activity and has lower nonspecific toxicity in mice. LMB-142 should be more efficient in cancer therapy because more treatment cycles can be given. PMID- 28087048 TI - [Characteristics and risk factors for recurrence of cutaneous squamous cell carcinoma with conventional surgery and surgery with delayed intraoperative margin assessment]. AB - BACKGROUND: Non-melanoma skin cancer includes basal cell carcinoma and squamous cell carcinoma (SCC). Basal cell carcinoma is the most common and least aggressive but in a low percentage of cases, despite appropriate wide surgical margins, it can be aggressive, producing local invasion, recurrences and distance metastasis. SCC has a more aggressive behaviour invading first the skin, the lymph nodes and less frequently produces distance metastasis OBJECTIVE: To identify the characteristics of recurrent SCC and frequency of new SCC after conventional surgical and primary closure or closure delayed until a histological reporting of tumour-free surgical margins, in order to achieve a better surgical option, in our Mexican population. MATERIALS AND METHOD: We reviewed clinical records from the last 10 years, and included those with a diagnosis of SCC. RESULTS: One hundred and fourteen tumours in 103 patients were included. The mean new tumour diagnosis was 32.2 per year; there were 46.6% men and 53.4% women. Age range 19-91, with mean 71.94 years (SD=13.34). The evolution time was from 1-112 months (mean=12 months, SD=2.65). The most affected site was the cheek. In addition, an invasive tumour was reported in 54% in the histopathological study. At 10-year follow-up we found a second SCC in 14 patients and only 4 recurrences, between the 1st and 4th year and 3were treated with delayed closure until margins were tumour-free. CONCLUSION: In this study we demonstrated that delayed closure technique is easy and adaptable in our population in the treatment of SCC, achieving good results with very low recurrences at 10- year follow -up. PMID- 28087050 TI - State of the art review and future directions in oil spill modeling. AB - A review of the state of the art in oil spill modeling, focused on the period from 2000 to present is provided. The review begins with an overview of the current structure of spill models and some lessons learned from model development and application and then provides guiding principles that govern the development of the current generation of spill models. A review of the basic structure of spill models, and new developments in specific transport and fate processes; including surface and subsurface transport, spreading, evaporation, dissolution, entrainment and oil droplet size distributions, emulsification, degradation, and sediment oil interaction are presented. The paper concludes with thoughts on future directions in the field with a primary focus on advancements in handling interactions between Lagrangian elements. PMID- 28087049 TI - [The benefits of digital chest drainage in pleural decortication in thoracic empyema. Prospective, randomized, control trial]. AB - BACKGROUND: Prolonged air leak after pleural decortication is one of the most frequent complications. OBJECTIVE: The aim of this study is to compare the effects of prolonged air leak between the digital chest drainage (DCD) system and the classic drainage system in patients with empyema class IIB or III (American Thoracic Society classification) in pleural decortication patients. MATERIAL AND METHODS: A total of 37 patients were enrolled in a prospective randomized control trial over one year, consisting of 2blinded groups, comparing prolonged air leak as a main outcome, the number of days until removal of chest drain, length of hospital stay and complications as secondary outcomes. RESULTS: The percentage of prolonged air leak was 11% in the DCD group and 5% in the classic group (P=0.581); the mean number of days of air leak was 2.5+/-1.8 and 2.4+/-2.2, respectively (P=0.966). The mean number of days until chest tube removal was 4.5+/-1.8 and 5.1+/-2.5 (P=0.41), the length of hospital stay was 7.8+/-3.7 and 8.9+/-4.0 (P=0.441) and the complication percentages were 4 (22%) and 7 (36%), respectively (P=0.227). DISCUSSION: In this study, no significant difference was observed when the DCD was compared with the classic system. This was the first randomized clinical trial for this indication; thus, future complementing studies are warranted. PMID- 28087051 TI - Beta-blockers and Cocaine-Associated ST-Segment Elevation Myocardial Infarction in an Inner-City Community. PMID- 28087052 TI - Contraceptive Practices of Women With Complex Congenital Heart Disease. AB - Understanding the contraceptive practices of women with complex congenital heart disease (CHD) and providing them individualized contraception counseling may prevent adverse events and unplanned high-risk pregnancies. Given this, we sought to examine the contraceptive practices in women with CHD, describe adverse events associated with contraceptive use, and describe the provision of contraception counseling. Women >18 years were recruited from 2011 to 2014 from 9 adult CHD (ACHD) centers throughout North America. Subjects completed a 48-item questionnaire regarding contraceptive use and perceptions of contraception counseling, and a medical record review was performed. Of 505 subjects, median age was 33 (interquartile range 26 to 44) and 81% had CHD of moderate or great complexity. The majority (86%, 435 of 505) of the cohort had used contraception. The types included barrier methods (87%), oral contraception (OC) 84%, intrauterine device (18%), Depo-Provera (15%), vaginal ring (7%), patch (6%), hormonal implant (2%), Plan B (19%), and sterilization (16%). Overall OC use was not significantly different by CHD complexity. Women with CHD of great complexity were more likely to report a thrombotic event while taking OC than those with less complex CHD (9% vs 1%, p = 0.003). Contraception counseling by the ACHD team was noted by 43% of subjects. Unplanned pregnancy was reported by 25% with no statistical difference by CHD complexity. In conclusion, contraceptive practices of women with complex CHD are highly variable, and the prevalence of blood clots while taking OC is not insignificant while provision of contraception counseling by ACHD providers appears lacking. PMID- 28087053 TI - Six-Minute Walk Test Results Predict Risk of Hospitalization for Youths with Cystic Fibrosis: A 5-Year Follow-Up Study. AB - OBJECTIVE: To evaluate the association of 6-minute walk test (6MWT) and other variables (anthropometry, chronic Pseudomonas aeroginosa colonization, pulmonary function, and respiratory muscle strength) with the risk of hospitalization for pulmonary exacerbation in children and adolescents with cystic fibrosis (CF). STUDY DESIGN: Cohort study that included patients with CF aged 6-18 years. All participants underwent spirometry, manovacuometry, and 6MWT during the 5-year follow-up. Anthropometric and clinical data were collected and the time to first hospitalization, total days of hospitalization, and antibiotic use during follow up was recorded. RESULTS: A total of 26 patients with CF, mean age 10.2 +/- 2.8 years, were included. The group had mild impairment of lung function with a significant decline in forced expiratory volume in 1 second (P = .019) over the 5 years. Respiratory muscle strength and 6MWT proved to be preserved, although maximum inspiratory pressure increased (P < .001) and maximum expiratory pressure and 6-minute walk distance (6MWD) remained stable. There were inverse associations of 6MWD in meters (r = -0.813, P < .001) and z score (r = -0.417, P = .015) with total days of hospitalization. Moreover, there was a reduction in the risk of a first hospitalization (Cox HR 0.32; P = .037) in patients with a greater 6MWD. CONCLUSIONS: We found an association between the 6MWT and the risk of hospitalization in children and adolescents with CF. Furthermore, functional capacity apparently does not follow the expected decline in pulmonary function over time, whereas inspiratory muscle strength increases with disease progression. PMID- 28087054 TI - Care pathway of patients with metastatic pancreatic cancer in daily practice in France: Results from the REPERE national survey. AB - Data in the literature regarding the care pathway of pancreatic cancer patients are limited. The objective of the REPERE survey was to identify and describe the initial stages of the care pathway of pancreatic patients in the metastatic phase. From May to October 2015, 62 oncologists (ON) or gastroenterologists specialized in digestive oncology (GESDO) and 300 general practitioners (GP) completed an electronic questionnaire on the pathway of 728 patients recently diagnosed with metastatic pancreatic adenocarcinoma. Of these patients, 200 completed a questionnaire given by a specialized physician (ON/GESDO). Weight loss (65%), fatigue (53%) or anorexia (49%) were the main signs/symptoms that motivated the patients to seek medical advice. For 87% of patients, the general practitioner was the first medicine doctor they consulted. According to the respondents (patient, general practitioner or specialist), the median delay between the onset of the first symptoms and the final diagnosis of pancreatic cancer was between 41 and 65 days. This time lapse tended to decrease with associated jaundice (-15 days on average, standard deviation=8, P<0.1 NS) or with patient concerns triggered by the first symptoms (-11 days on average, standard deviation=6, P<0.05). On the contrary, the time lapse was longer (+14 days on average, standard deviation=6, P<0.05) when the general practitioner prescribed symptomatic treatment. In conclusion, diagnostic management of patients with metastatic pancreatic cancer should be accelerated with efforts to raise practitioners' awareness. PMID- 28087055 TI - Graft modification of cotton with phosphate group and its application to the enrichment of phosphopeptides. AB - Grafting copolymerization, especially "grafting from" approach, has attracted a great attention for the preparation of cellulose-based materials with various functionalities. In this study, a novel phosphate group-containing cotton fiber based material, CF-NH2-AZO-p(VPA-x), was successfully synthesized by a "grafting from" radical polymerization approach using vinyl phosphonic acid (VPA) as monomer. The phosphate group content of CF-NH2-AZO-p(VPA-x) could be easily regulated by adjusting the concentration of VPA monomer. Subsequently, titanium ions immobilized CF-NH2-AZO-p(VPA-x) (CF-NH2-AZO-p(VPA-x)-Ti4+) was prepared and used as an immobilized metal affinity chromatography (IMAC) adsorbent for the selective enrichment of phosphopeptides from various biological samples. The relationship between enrichment efficiency and phosphate group content of CF-NH2 AZO-p(VPA-x)-Ti4+ was investigated. The optimized CF-NH2-AZO-p(VPA-2)-Ti4+ (x=2) exhibited high selectivity and extraction capacity in phosphopeptides enrichment from standard peptides mixture, non-fat milk digests and protein-rich human serum. In addition, CF-NH2-AZO-p(VPA-2)-Ti4+ was further applied for the specific capture of phosphopeptides from tryptic digests of rat brain lysate, and 3241 unique phosphopeptides were identified from 0.5mg of rat brain by combining CF NH2-AZO-p(VPA-2)-Ti4+ pretreatment with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. We expect the proposed method can promote the development of "grafting from" approach in the preparation of cellulose-based adsorbents and broaden the application of cellulose-based adsorbents for biological analysis. PMID- 28087057 TI - 120 Years of Tuberculosis Research: An Historical Perspective from the Archive of the Journal of Comparative Pathology. PMID- 28087056 TI - Extraction chromatographic separations of tantalum and tungsten from hafnium and complex matrix constituents. AB - Tantalum (Ta), hafnium (Hf), and tungsten (W) analyses from complex matrices require high purification of these analytes from each other and major/trace matrix constituents, however, current state-of-the-art Ta/Hf/W separations rely on traditional anion exchange approaches that show relatively similar distribution coefficient (Kd) values for each element. This work reports an assessment of three commercially available extraction chromatographic resins (TEVA, TRU, and UTEVA) for Ta/Hf/W separations. Batch contact studies show differences in Ta/Hf and Ta/W Kd values of up to 106 and 104 (respectively), representing an improvement of a factor of 100 and 300 in Ta/Hf and Ta/W Kd values (respectively) over AG1*4 resin. Variations in the Kd values as a function of HCl concentration for TRU resin show that this resin is well suited for Ta/Hf/W separations, with Ta/Hf, Ta/W, and W/Hf Kd value improvements of 10, 200, and 30 (respectively) over AG1*4 resin. Analyses of digested soil samples (NIST 2710a) using TRU resin and tandem TEVA-TRU columns demonstrate the ability to achieve extremely high purification (>99%) of Ta and W from each other and Hf, as well as enabling very high purification of Ta and W from the major and trace elemental constituents present in soils using a single chromatographic step. PMID- 28087058 TI - Robust observer-based passive control for uncertain singular time-delay systems subject to actuator saturation. AB - This paper investigates the problem of robust observer-based passive control for uncertain singular time-delay system subject to actuator saturation. A polytopic approach is used to describe the saturation behavior. First, by constructing Lyapunov-Krasovskii functional, a less conservative sufficient condition is obtained which guarantees that the closed-loop system is regular, impulse free, stable and robust strictly passive. Then, with this condition, the design method of state feedback controller and the observer are given by solving linear matrix inequalities. In addition, a domain of attraction in which the admissible initial states are ensured to converge asymptotically to the origin is solved as a convex optimization problem. Finally, some simulations are provided to demonstrate the effectiveness and superiority of the proposed method. PMID- 28087059 TI - Fatigue in Parkinson's disease. AB - Fatigue is one of the most common nonmotor symptoms in Parkinson's disease and may affect a wide range of everyday activities, cause disability and reduce quality of life. It occurs at every stage of PD, and once present will often persist and may worsen over time. Lack of a consensus of definition and classification, and a range of different self-reporting scales has so far made the study of fatigue challenging. We review a unifying taxonomy for defining fatigue in clinical and research contexts as well as case definition criteria for PD-related fatigue. The potential causes of fatigue in PD are discussed as are recommendations for treatment. PMID- 28087060 TI - Personality in Parkinson's disease: Clinical, behavioural and cognitive correlates. AB - Affective disorders and personality changes have long been considered pre-motor aspects of Parkinson's disease (PD). Many authors have used the term "premorbid personality" to define distinctive features of PD patients' personality characterized by reduced exploration of new environmental stimuli or potential reward sources ("novelty seeking") and avoidance behaviour ("harm avoidance") present before motor features. The functional correlates underlying the personality changes described in PD, implicate dysfunction of meso-cortico-limbic and striatal circuits. As disease progresses, the imbalance of neurotransmitter systems secondary to degenerative processes, along with dopamine replacement therapy, can produce a reversal of behaviours and an increase in reward seeking, laying the foundations for the emergence of the impulse control disorders. Personality disorders can be interpreted, therefore, as the result of individual susceptibility arising from intrinsic degenerative processes and individual personality features, in combination with extrinsic factors such as lifestyle, PD motor dysfunction and drug treatment. For a better understanding of personality disorders observed in PD and their relationship with the prodromal stage of the disease, prospective clinical studies are needed that correlate different personality profiles with other disease progression markers. Here, we review previous studies investigating the clinical, cognitive and behavioural correlates of personality traits in PD patients. PMID- 28087061 TI - Editorial and introduction: Behavioral aspects of Parkinson's disease. PMID- 28087063 TI - Spatial-dependent mechanical properties of the heel pad by shear wave elastography. AB - The heel pad plays an important role in gait, and its biomechanical behavior and functionality are determined by its specialized architecture and mechanical properties. The purpose of this study was to apply supersonic shear wave elastography, an ultrasound-based noninvasive modality that can quantitatively estimate the shear stiffness of the tissue, to investigate the spatial-dependent mechanical properties of the heel pad. Measurements were conducted in 40 heel pads of 20 normal participants aged between 20 and 30 years by shear wave elastography. The continuous change in local shear stiffness of the heel pad along the depth direction of the heel pad was measured. The result showed that the mechanical properties of the heel pad were highly heterogeneous but followed a simple and specific pattern that local heel pad shear stiffness was highest beneath the plantar skin and decreased continuously with increasing depth. This finding provides a better understanding of the heel pad biomechanics and basis for further investigation of the heterogeneous properties of the heel pad. PMID- 28087062 TI - Timing and magnitude of lumbar spine contribution to trunk forward bending and backward return in patients with acute low back pain. AB - Alterations in the lumbo-pelvic coordination denote changes in neuromuscular control of trunk motion as well as load sharing between passive and active tissues in the lower back. Differences in timing and magnitude aspects of lumbo pelvic coordination between patients with chronic low back pain (LBP) and asymptomatic individuals have been reported; yet, the literature on lumbo-pelvic coordination in patients with acute LBP is scant. A case-control study was conducted to explore the differences in timing and magnitude aspects of lumbo pelvic coordination between females with (n=19) and without (n=19) acute LBP. Participants in each group completed one experimental session wherein they performed trunk forward bending and backward return at preferred and fast paces. The amount of lumbar contribution to trunk motion (as the magnitude aspect) as well as the mean absolute relative phase (MARP) and deviation phase (DP) between thoracic and pelvic rotations (as the timing aspect) of lumbo-pelvic coordination were calculated. The lumbar contribution to trunk motion in the 2nd and the 3rd quarters of both forward bending and backward return phases was significantly smaller in the patient than the control group. The MARP and the DP were smaller in the patient vs. the control group during entire motion. The reduced lumbar contribution to trunk motion as well as the more in-phase and less variable lumbo pelvic coordination in patients with acute LBP compared to the asymptomatic controls is likely the result of a neuromuscular adaptation to reduce painful deformation and to protect injured lower back tissues. PMID- 28087064 TI - Effect of CYP2D6 polymorphisms on the pharmacokinetics of propafenone and its two main metabolites. AB - AIM OF THE STUDY: Propafenone (PPF) is an antiarrhythmic drug, metabolized mainly by CYP2D6 to 5-hydroxypropafenone (5OH-PPF) and by CYP3A4 to norpropafenone (NOR PPF). CYP2D6 shows a high degree of genetic polymorphism which is associated with diminished antiarrhythmic efficacy or cardiac seizures/cardiotoxicity. This study aimed to investigate the effect of the CYP2D6 polymorphism on the pharmacokinetics of PPF and its two main metabolites. The usefulness of PPF/5OH PPF ratio for CYP2D6 phenotyping in healthy adults was also evaluated. METHODS: Twelve healthy volunteers, 3 poor metabolizers (PM), 2 intermediate metabolizers (IM) and seven extensive metabolizers (EM) received an oral dose of PPF. Concentrations of PPF and its metabolites were analyzed in serum samples over 27h. RESULTS: The PPF/5OH-PPF ratio distinguished EMs from PMs, but not from IMs. In PMs, the mean transit time (MTT) values were almost the same for PPF and NOR PPF and much higher than those of EMs and IMs. 5OH-PPF was not detected in EMs. Mean MTT values of 5OH-PPF and NOR-PPF in IMs were 5.27- and 1.52-fold higher than those of EMs. CONCLUSION: A single time point serum PPF-MR approach is a useful tool to identify PMs. CYP2D6 polymorphism significantly affects the pharmacokinetics of PPF and its two metabolites. PMID- 28087065 TI - A bibliometric study of the scientific publications on patient-reported outcomes in rheumatology. AB - INTRODUCTION: We have conducted a bibliometric study of the scientific publications on patient-reported outcomes in the field of rheumatology. METHODS: SCOPUS was the database used in this bibliometric study. We performed two searches. The main search involved selecting the documents published between 2000 and 2014 limited to top-tier journals addressing rheumatic and musculoskeletal diseases, using specific descriptors together with the operator and main descriptor "patient-reported outcomes" (PROs), and we performed a secondary search, with the following specific descriptors: "pain," "functional capacity," and "fatigue." We used bibliometric indicators for articles distribution (Price's law for the increase of scientific literature and Bradford's law for dispersion of articles). We also calculated the participation index of the different countries. RESULTS: A total of 983 original articles were published between 2000 and 2014. Our results confirmed the fulfilment of Price's law (correlation coefficient r = 0.9385 after linear adjustment). The average number of articles per Bradford Zone was 327.6. A total of 30 different journals were published. The type of growth for the descriptors "pain" (r2 = 0.5417 compared to r2 = 0.4839) and "fatigue" (r2 = 06276 compared to r2 = 0.5544) is exponential, whereas it is linear for the descriptor "functional capacity" (r2 = 0.6769 compared to r2 = 0.3779). DISCUSSION: This study revealed significant linear growth of patient related outcomes in global terms, as well as upward trends for most of the citation-based bibliometric indices, especially significant from 2010 to 2014. Pain and fatigue have greater growth as PRO concepts. PMID- 28087066 TI - Use of water-soluble contrast medium (gastrografin) does not decrease the need for operative intervention nor the duration of hospital stay in uncomplicated acute adhesive small bowel obstruction? A multicenter, randomized, clinical trial (Adhesive Small Bowel Obstruction Study) and systematic review. AB - BACKGROUND: This study evaluated the association between oral gastrografin administration and the need for operative intervention in patients with presumed adhesive small bowel obstruction. METHODS: Between October 2006 and August 2009, 242 patients with uncomplicated acute adhesive small bowel obstruction were included in a randomized, controlled trial (the Adhesive Small Bowel Obstruction Study, NCT00389116) and allocated to a gastrografin arm or a saline solution arm. The primary end point was the need for operative intervention within 48 hours of randomization. The secondary end points were the resection rate, the time interval between the initial computed tomography and operative intervention, the time interval between oral refeeding and discharge, risk factors for the failure of nonoperative management, in-hospital mortality, duration of stay, and recurrence or death after discharge. We performed a systematic review of the literature in order to evaluate the relationship between use of gastrografin as a diagnostic/therapeutic measure, the need for operative intervention, and the duration of stay. RESULTS: In the gastrografin and saline solution arms, the rate of operative intervention was 24% and 20%, respectively, the bowel resection rate was 8% and 4%, the time interval between the initial computed tomography and operative intervention, and the time interval between oral refeeding and discharge were similar in the 2 arms. Only age was identified as a potential risk factor for the failure of nonoperative management. The in-hospital mortality was 2.5%, the duration of stay was 3.8 days for patients in the gastrografin arm and 3.5 days for those in the saline solution arm (P = .19), and the recurrence rate of adhesive small bowel obstruction was 7%. These results and those of 10 published studies suggest that gastrografin did not decrease either the rate of operative intervention (21% in the saline solution arm vs 26% in the gastrografin arm) or the number of days from the initial computed tomography to discharge (3.5 vs 3.5; P = NS for both). CONCLUSION: The results of the present study and those of our systematic review suggest that gastrografin administration is of no benefit in patients with adhesive small bowel obstruction. PMID- 28087067 TI - [Successful use of sugammadex for caesarean section in a patient with myasthenia gravis]. AB - Myasthenia gravis is an autoimmune disorder that is characterized by muscle weakness that fluctuates, worsening with exertion, and improving with rest. Diagnosis of myasthenia gravis is made following clinical and physical examination and is confirmed by serum immunoassays to measure autoantibody levels. Myasthenia gravis especially when associated with pregnancy is a high risk disease, and its course is unpredictable. We described the second report about use of sugammadex after rocuronium for a caesarean delivery with myasthenia gravis, but, unlike our case that formerly was diagnosed with myasthenia gravis, the patient was extubated on postoperative successfully and we did not encounter any respiratory problems. PMID- 28087068 TI - Clinical development of hepatitis C virus host-targeting agents. PMID- 28087069 TI - Safety, tolerability, and antiviral effect of RG-101 in patients with chronic hepatitis C: a phase 1B, double-blind, randomised controlled trial. AB - BACKGROUND: miR-122 is an important host factor for hepatitis C virus (HCV) replication. The aim of this study was to assess the safety and tolerability, pharmacokinetics, and antiviral effect of a single dose of RG-101, a hepatocyte targeted N-acetylgalactosamine conjugated oligonucleotide that antagonises miR 122, in patients with chronic HCV infection with various genotypes. METHODS: In this randomised, double-blind, placebo-controlled, multicentre, phase 1B study, patients were randomly assigned to RG-101 or placebo (7:1). We enrolled men and postmenopausal or hysterectomised women (aged 18-65 years) with chronic HCV genotype 1, 3, or 4 infection diagnosed at least 24 weeks before screening who were either treatment naive to or relapsed after interferon-alpha based therapy. Patients with co-infection (hepatitis B virus or HIV infection), evidence of decompensated liver disease, or a history of hepatocellular carcinoma were excluded. Randomisation was done by an independent, unblinded, statistician using the SAS procedure Proc Plan. The first cohort received one subcutaneous injection of 2 mg/kg RG-101 or placebo; the second cohort received one subcutaneous injection of 4 mg/kg or placebo. Patients were followed up for 8 weeks (all patients) and up to 76 weeks (patients with no viral rebound and excluding those who were randomised to the placebo group) after randomisation. The primary objective was safety and tolerability of RG-101. This trial was registered with EudraCT, number 2013-002978-49. FINDINGS: Between June 4, 2014, and Oct 27, 2014, we enrolled 32 patients with chronic HCV genotype 1 (n=16), 3 (n=10), or 4 (n=6) infections. In the first cohort, 14 patients were randomly assigned to receive 2 mg/kg RG-101 and two patients were randomly assigned to receive placebo, and in the second cohort, 14 patients were randomly assigned to receive 4 mg/kg RG-101 and two patients were randomly assigned to receive placebo. Overall, 26 of the 28 patients dosed with RG-101 reported at least one treatment-related adverse event. At week 4, the median viral load reduction from baseline was 4.42 (IQR 3.23-5.00) and 5.07 (4.19-5.35) log10 IU/mL in patients dosed with 2 mg/kg RG-101 or 4 mg/kg RG-101. Three patients had undetectable HCV RNA levels 76 weeks after a single dose of RG-101. Viral rebound at or before week 12 was associated with the appearance of resistance associated substitutions in miR-122 binding regions in the 5' UTR of the HCV genome. INTERPRETATION: This study showed that one administration of 2 mg/kg or 4 mg/kg RG-101, a hepatocyte targeted N acetylgalactosamine conjugated anti-miR-122 oligonucleotide, was well tolerated and resulted in substantial viral load reduction in all treated patients within 4 weeks, and sustained virological response in three patients for 76 weeks. FUNDING: Regulus Therapeutics, Inc. PMID- 28087070 TI - Can Evolution Supply What Ecology Demands? AB - A simplistic view of the adaptive process pictures a hillside along which a population can climb: when ecological 'demands' change, evolution 'supplies' the variation needed for the population to climb to a new peak. Evolutionary ecologists point out that this simplistic view can be incomplete because the fitness landscape changes dynamically as the population evolves. Geneticists meanwhile have identified complexities relating to the nature of genetic variation and its architecture, and the importance of epigenetic variation is under debate. In this review, we highlight how complexity in both ecological 'demands' and the evolutionary 'supply' influences organisms' ability to climb fitness landscapes that themselves change dynamically as evolution proceeds, and encourage new synthetic effort across research disciplines towards ecologically realistic studies of adaptation. PMID- 28087071 TI - Development of delineation for the left anterior descending coronary artery region in left breast cancer radiotherapy: An optimized organ at risk. AB - BACKGROUND AND PURPOSE: The left anterior descending coronary artery (LAD) and diagonal branches (DBs) are blurred on computed tomography (CT). We aimed to define the LAD region (LADR) with adequate inclusion of the LAD and DBs and contouring consistency. METHODS AND MATERIALS: The LADR was defined using coronary CT angiograms. The inclusion ratio was used to assess the LAD and DBs inclusion by the LADR. Four radiation oncologists delineated the LAD and LADR, using contrast-enhanced CT of 15 patients undergoing left breast radiotherapy. The Sorensen-Dice similarity index (DSI), Jaccard similarity index (JSI), and Hausdorff distance (HD) were calculated to assess similarity. The mean dose (Dmean) and maximum dose (Dmax) to the LAD and LADR were calculated to compare consistency. Correlations were evaluated using Pearson's correlation coefficient. RESULTS: The inclusion ratio of the LAD by the LADR was 96%. The mean DSI, JSI, and HD values were respectively 27.9%, 16.7%, and 0.42mm for the LAD, and 83.1%, 73.0%, and 0.18mm for the LADR. The Dmean between the LAD and LADR were strongly correlated (r=0.93). CONCLUSION: Delineation of the LADR significantly improved contouring similarity and consistency for dose reporting. This could optimize dose estimation for breast radiotherapy. PMID- 28087072 TI - Enhancing Delirium Case Definitions in Electronic Health Records Using Clinical Free Text. AB - BACKGROUND: Delirium is an acute confusional state, associated with morbidity and mortality in diverse medically ill populations. Delirium is preventable and treatable when diagnosed but the diagnosis is often missed. This important and difficult diagnosis is an attractive candidate for computer-aided decision support if it can be reliably identified at scale. OBJECTIVE: Here, using an electronic health record-based case definition of delirium, we characterize incidence of this highly morbid condition in 2 large academic medical centers. METHODS: Using the electronic health record of 2 large New England academic medical centers, we calculated and compared the rate of the diagnosis of delirium using a range of administrative and discharge summary text-based case definitions over an 8-year period. RESULTS: Depending on case definitions, the overall delirium rate ranged from 2.0-5.4% of 809,512 admissions identified. The identified rate of delirium increased between 2005 and 2013, such that by the final year of the study, one of the two sites reported delirium in 7.0% of cases. The concordance between case definitions was low; only half of the cases identified by text analysis were captured by administrative data. CONCLUSION: Delirium may be better captured by composite outcomes, including both administrative claims data and elements drawn from unstructured data sources. That the rate of delirium observed in this study is far lower than the current literature estimates suggests that further work on case definitions, identification, and documented diagnosis is required. PMID- 28087073 TI - Abnormal mortality of octopus after a storm water event: Accumulated lead and lead isotopes as fingerprints. AB - Octopus vulgaris is a sedentary organism that inhabits coastal waters being exposed to anthropogenic compounds. Lead concentration in coastal environments reflects many processes and activities namely weathering, industrial and domestic discharges, and atmospheric deposition. Since lead isotopic composition is little affected by kinetic processes occurring between source and sink, its signature has been used to identify different Pb sources. After a short-term heavy rainfall, hundreds of octopus appeared dead in two Portuguese coastal areas. Histopathology and Pb levels and its stable isotopes were determined in tissues, such as digestive gland, of stranded octopus and compared to alive specimens, sediments and runoff material from the same areas. Histology results showed severe damage in stranded octopus tissues suggesting that death was probably associated to multiple organ failure linked to hypertrophy and exudates input. In addition, Pb in stranded specimens reach concentrations up to one order of magnitude above the levels reported for alive octopus. Pb isotopic signatures in stranded organisms were closer to runoff material pointing to a similar origin of Pb. In summary, the results in this study showed that a short-term runoff event might change abruptly the salinity leading to the disruption of the osmoregulation function of octopus and consequently leading to its death. The analyses of stable isotopic Pb signature in octopus tissues corroborate these results and points to a change in the Pb source due to runoff after the storm water event. Pb stable isotopes in octopus proved to be an adequate tool to confirm the cause of death and linking it to the environment conditions. PMID- 28087074 TI - Quantifying loading, toxic concentrations, and systemic persistence of chloride in a contemporary mixed-land-use watershed using an experimental watershed approach. AB - A nested-scale experimental watershed study was implemented to quantify loading and persistence of chloride in an urbanizing, mixed-land-use watershed. A Midwest USA (Missouri) watershed was partitioned into five sub-basins with contrasting dominant land use. Streamwater was tested for chloride concentration four days per week from October 2009 through May 2014 at each site. Monitoring sites included co-located gauging and climate stations recording variables at 30-minute intervals. Results indicate significant (p<0.01) differences in chloride concentrations and loading between sites. Loading consistently increased from the forested headwaters (average=507kgday-1) to primarily urban watershed terminus (average=7501kgday-1). Chloride concentrations were highest (average=83.9mgL-1) with the greatest frequency of acutely toxic conditions (i.e. 860mgL-1) mid watershed. This finding is in-part attributable to the ratio of chloride application to streamflow volume (i.e. increasing flow volume with stream distance resulted in chloride dilution, offsetting increased percent urban land use with stream distance). Results highlight the important, yet often confounding, interactions between pollutant loading and flow dynamics. Chloride peaks occurred during late winter/early spring melting periods, implicating road salt application as the primary contributor to the chloride regime. Floodplain groundwater analysis indicated seasonal sink/source relationships between the stream and floodplain, which could contribute to chronic toxicity and persistent low Cl- concentrations in streamwater year-round. Results hold important implications for resource managers wishing to mitigate water quality and aquatic habitat degradation, and suggest important water quality limitations to stream restoration success in complex urban aquatic ecosystems. PMID- 28087075 TI - Cellular transcriptional response to zirconia-based implant materials. AB - OBJECTIVE: To adequately address clinically important issues such as osseointegration and soft tissue integration, we screened for the direct biological cell response by culturing human osteoblasts and gingival fibroblasts on novel zirconia-based dental implant biomaterials and subjecting them to transcriptional analysis. METHODS: Biomaterials used for osteoblasts involved micro-roughened surfaces made of a new type of ceria-stabilized zirconia composite with two different topographies, zirconium dioxide, and yttria stabilized zirconia (control). For fibroblasts smooth ceria- and yttria stabilized zirconia surface were used. The expression of 90 issue-relevant genes was determined on mRNA transcription level by real-time PCR Array technology after growth periods of 1 and 7 days. RESULTS: Generally, modulation of gene transcription exhibited a dual dependence, first by time and second by the biomaterial, whereas biomaterial-triggered changes were predominantly caused by the biomaterials' chemistry rather than surface topography. Per se, modulated genes assigned to regenerative tissue processes such as fracture healing and wound healing and in detail included colony stimulating factors (CSF2 and CSF3), growth factors, which regulate bone matrix properties (e.g. BMP3 and TGFB1), osteogenic BMPs (BMP2/4/6/7) and transcription factors (RUNX2 and SP7), matrix collagens and osteocalcin, laminins as well as integrin beta1 and MMP-2. SIGNIFICANCE: With respect to the biomaterials under study, the screening showed that a new zirconia-based composite stabilized with ceria may be promising to provide clinically desired periodontal tissue integration. Moreover, by detecting biomarkers modulated in a time- and/or biomaterial-dependent manner, we identified candidate genes for the targeted analysis of cell-implant bioresponse during biomaterial research and development. PMID- 28087076 TI - Polarization of microglia and its role in bacterial sepsis. AB - Microglial polarization in response to brain inflammatory conditions is a crescent field in neuroscience. However, the effect of systemic inflammation, and specifically sepsis, is a relatively unexplored field that has great interest and relevance. Sepsis has been associated with both early and late harmful events of the central nervous system, suggesting that there is a close link between sepsis and neuroinflammation. During sepsis evolution it is supposed that microglial could exert both neurotoxic and repairing effects depending on the specific microglial phenotype assumed. In this context, here it was reviewed the role of microglial polarization during sepsis-associated brain dysfunction. PMID- 28087078 TI - Donald H. Gilden, M.D. PMID- 28087077 TI - Alteration of CD39+Foxp3+ CD4 T cell and cytokine levels in EAE/MS following anti CD52 treatment. AB - While examining the therapeutic value of anti-CD52 antibody against EAE/MS, we identified a unique subset of CD39+ Tregs in repopulating GALT tissues, a major lymphoid reservoir, which was accompanied by amelioration of disease. Furthermore, anti-CD52 treatment leads to increased expression of BDNF, IL-10, and SMAD3 in the brains of EAE mice. This condition is associated with suppression of IL-17, a critical inflammatory factor in EAE/MS progression. Additionally, we found elevated levels of CD4+CD39+ Tregs in PBMCs of RRMS patients treated with humanized anti-CD52 mAb. Thus, anti-CD52 can affect multiple immune mediated pathways involved in the pathogenesis of EAE/MS. PMID- 28087081 TI - [Retinal arteriovenous malformation]. PMID- 28087080 TI - [Retinal capillary hemangioblastoma in Von Hippel-Lindau disease]. PMID- 28087082 TI - [Erratum to "Management of ophthalmologic emergencies in general emergency departments: A retrospective multicenter study" [J. Fr. Ophtalmol. 39 (7) (2016) 589-95]]. PMID- 28087079 TI - The STIM-Orai coupling interface and gating of the Orai1 channel. AB - In virtually all cells, store-operated Ca2+ entry signals are vital in controlling a spectrum of functions. The signals are mediated by STIM proteins in the ER and Orai channels in the PM which undergo a dynamic coupling process within discrete ER-PM junctional regions. This coupling is initiated by depletion of ER stored Ca2+ triggering STIM proteins to undergo an intricate activation process. Thereafter, STIM proteins become trapped in the ER-PM junctions where they tether and gate PM Orai Ca2+ channels. STIM1 exists as a dimer, with a single STIM-Orai activating region (SOAR) buried in the resting protein that becomes exposed upon activation. An exposed region on SOAR including the Phe-394 residue forms a critical Orai1 interacting site. Using dimeric SOAR concatemers, we reveal only one of the two sites in the SOAR dimer is needed for Orai1 activation. This unimolecular interaction of SOAR with Orai1 suggests STIM1 can cross-link Orai channels with important significance for Ca2+ signaling. A critical "nexus" region in Orai1 close to the STIM1-binding site can be mutated to constitutively activate the channel mimicking the gating action of STIM1. This indicates STIM1 remotely controls Orai1 channel gating through an allosteric switch triggered by STIM1 binding only to the exposed C-terminal tail of the Orai1 channel. PMID- 28087083 TI - [Isolated microspherophakia in a Senegalese family]. AB - PURPOSE: To report the clinical investigation of isolated microspherophakia involving a Senegalese family in order to appreciate its functional impact. OBSERVATIONS: This is a rural family comprised of 7 members. The sibship included three girls and two boys. One of the girls, who lived in a distant zone, was unable to be examined. Of all the examined members of the family, only the father was unaffected by the illness. There was no consanguinity. The general medical examination was normal. The best-corrected visual acuity (VA) for the girls was 2/10. For one of the boys, BCVA was 8/10 for both eyes, and for the other, BCVA was 10/10 for the right eye and 8/10 for the left eye. The mother's VA was 10/10 and P2 without correction. Myopia and astigmatism were present in the 4 children of the sibship. During the examination, we noted the presence of small crystalline lenses, which were very round and presented an abnormal visibility of the lens equator and zonular fibers. The diagnosis of microspherophakia was confirmed by measurement of the lens diameters by ultrasound biomicroscopy. Complications were present in the girls, including pupillary block glaucoma and amblyopia for the elder, and retinal degeneration and amblyopia for the younger daughter. The elder daughter was managed medically with glaucoma drops. The younger daughter received optical correction and a prophylactic Argon LASER treatment. The two boys received optical correction. No treatment was recommended for the mother. CONCLUSION: Microspherophakia is a rare condition. Some serious complications can lead to amblyopia. A better multidisciplinary evaluation would allow for early detection and a better prognosis. PMID- 28087084 TI - The impact of IMF conditionality on government health expenditure: A cross national analysis of 16 West African nations. AB - How do International Monetary Fund (IMF) policy reforms-so-called 'conditionalities'-affect government health expenditures? We collected archival documents on IMF programmes from 1995 to 2014 to identify the pathways and impact of conditionality on government health spending in 16 West African countries. Based on a qualitative analysis of the data, we find that IMF policy reforms reduce fiscal space for investment in health, limit staff expansion of doctors and nurses, and lead to budget execution challenges in health systems. Further, we use cross-national fixed effects models to evaluate the relationship between IMF-mandated policy reforms and government health spending, adjusting for confounding economic and demographic factors and for selection bias. Each additional binding IMF policy reform reduces government health expenditure per capita by 0.248 percent (95% CI -0.435 to -0.060). Overall, our findings suggest that IMF conditionality impedes progress toward the attainment of universal health coverage. PMID- 28087085 TI - Bilateral blepharoptosis in a juvenile. AB - In adults, aponeurotic blepharoptosis is the most common type of ptosis. However, myogenic ptosis is the predominant cause, and bilateral aponeurotic ptosis is very rare among children. Here, we report a previously healthy 10-year-old Japanese girl with bilateral aponeurotic blepharoptosis who presented initially with bilateral blepharoptosis for about 4years. This case report shows that history taking and careful observation of the patient lead to an accurate diagnosis, and aponeurotic ptosis should be considered in the differential diagnosis of bilateral blepharoptosis among children. PMID- 28087086 TI - Headache in young patients: Clinical characteristics of a series of 651 cases. AB - INTRODUCTION: Headache has a negative impact on health-related quality of life in young patients. We aim to analyse the characteristics of a series of young patients visiting a headache clinic and estimate the burden of different types of headaches listed by the International Classification of Headache Disorders (ICHD). METHODS: We prospectively recruited patients aged 14 to 25 years who were treated at our clinic during a period of 6.5 years. We recorded each patient's sex, complementary test results, and previous treatment. We subsequently compared the characteristics of our sample to those of patients older than 25. RESULTS: During the study period, we treated 651 patients aged 14 to 25 years; 95.6% had received symptomatic treatment, and 30.1% had received preventive treatment. A total of 755 headaches were recorded. Only 80 were secondary headaches, most of which were included in Group 8; 77.2% were included in Group 1, 3.1% in Group 2, 1.2% in Group 3, 5% in Group 4, 0.6% in Group 13, and 0.9% in Group 14. According to Headache Impact Test (HIT-6) scores, headache had at least a moderate impact on the quality of life of 449 patients. CONCLUSION: Most headaches in young patients can be classified according to ICHD criteria. Migraine was the most frequent diagnosis in our sample. Although headache was commonly associated with a negative impact on quality of life, most patients had received little preventive treatment before being referred to our clinic. PMID- 28087087 TI - Pediatric nurse practitioners effective in teaching providers the Asthma Action Plan using simulation. AB - Despite traditional education regarding the Asthma Action Plan (AAP), providers in the inpatient setting of a pediatric hospital reported lack of knowledge regarding the AAP and lack of confidence in teaching the AAP to patients and families. The purpose of this study was to assess the effect of a pediatric nurse practitioner (PNP)-led class incorporating simulation on resident physician knowledge of the AAP and confidence in teaching families the AAP. The study setting was a 250 bed Midwest academic pediatric hospital. The 26 participants were second year residents completing a four-week pediatric pulmonary rotation. The class consisted of a brief didactic component regarding the AAP, simulation to teach a patient/parent actor the AAP based on PNP-developed scenarios, and debriefing of the experience. The average composite score on the pre- and post simulation knowledge assessment showed improvement from 44.8% to 80.4% (p<0.001). All participants answered favorably on questions regarding perceived benefit of the class and 80.8% strongly agreed that they felt more confident teaching the AAP after the class. This study demonstrates that resident physician knowledge of the AAP and confidence in teaching the AAP improved after a PNP-led simulation class. PMID- 28087088 TI - Discharge Teaching, Readiness for Discharge, and Post-discharge Outcomes in Parents of Hospitalized Children. AB - PURPOSE: This study explored the sequential relationships of parent perceptions of the quality of their discharge teaching and nurse and parent perceptions of discharge readiness to post-discharge outcomes (parental post-discharge coping difficulty, readmission and emergency department visits). DESIGN/METHODS: In this secondary analysis of data from a longitudinal pilot study of family self management discharge preparation, the correlational design used regression modeling with data from a convenience sample of 194 parents from two clinical units at a Midwest pediatric hospital. Data were collected on the day of discharge (Quality of Discharge Teaching Scale; Readiness for Hospital Discharge Scale), at 3weeks post-discharge (Post-Discharge Coping Difficulty Scale), and from electronic records (readmission, ED visits). RESULTS: Parent-reported quality of discharge teaching delivery (the way nurses teach), but not the amount of content, was positively associated with parent perception (B=0.54) and nurse assessment (B=0.16) of discharge readiness. Parent-reported discharge readiness was negatively associated with post-discharge coping difficulty (B=-0.52). Nurse assessment of discharge readiness was negatively associated with readmission; a one point increase in readiness (on a 10 point scale) decreased the likelihood of readmission by 52%. CONCLUSION: There is a sequential effect of quality of discharge teaching delivery on parent discharge readiness, which is associated with parent coping difficulty and child readmission. PRACTICE IMPLICATIONS: Efforts to improve discharge outcomes should include strategies to build nurse teaching skills for high-quality delivery of discharge teaching. In addition, routine nurse assessment of discharge readiness can be used to identify children at risk for readmission and trigger anticipatory interventions. PMID- 28087089 TI - Point-of-Care Ultrasound Diagnosis of Posterior Sternoclavicular Joint Dislocation. AB - BACKGROUND: Posterior sternoclavicular dislocations can be challenging diagnostically, as traumatic force often happens to the lateral shoulder rather than directly to the sternoclavicular joint. Shoulder radiographs do not illustrate the sternoclavicular joint well, and can miss the diagnosis. This injury, however, has the potential for life-threatening complications due to proximity of mediastinal structures that might also be injured. CASE REPORT: The following case illustrates a delayed diagnosis of posterior sternoclavicular dislocation. It also shows how point-of-care ultrasound can diagnose a dislocation, confirm persistence of a dislocation diagnosis when patients are transported from a referring facility, as well as educate the patient and family. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Point-of-care ultrasound can be used to rapidly diagnose posterior sternoclavicular dislocations and to provide patients education about their injury. PMID- 28087090 TI - Quantifying exposure of wild bumblebees to mixtures of agrochemicals in agricultural and urban landscapes. AB - The increased use of pesticides has caused concern over the possible direct association of exposure to combinations of these compounds with bee health problems. There is growing proof that bees are regularly exposed to mixtures of agrochemicals, but most research has been focused on managed bees living in farmland, whereas little is known about exposure of wild bees, both in farmland and urban habitats. To determine exposure of wild bumblebees to pesticides in agricultural and urban environments through the season, specimens of five different species were collected from farms and ornamental urban gardens in three sampling periods. Five neonicotinoid insecticides, thirteen fungicides and a pesticide synergist were analysed in each of the specimens collected. In total, 61% of the 150 individuals tested had detectable levels of at least one of the compounds, with boscalid being the most frequently detected (35%), followed by tebuconazole (27%), spiroxamine (19%), carbendazim (11%), epoxiconazole (8%), imidacloprid (7%), metconazole (7%) and thiamethoxam (6%). Quantifiable concentrations ranged from 0.17 to 54.4 ng/g (bee body weight) for individual pesticides. From all the bees where pesticides were detected, the majority (71%) had more than one compound, with a maximum of seven pesticides detected in one specimen. Concentrations and detection frequencies were higher in bees collected from farmland compared to urban sites, and pesticide concentrations decreased through the season. Overall, our results show that wild bumblebees are exposed to multiple pesticides when foraging in agricultural and urban landscapes. Such mixtures are detected in bee tissues not just during the crop flowering period, but also later in the season. Therefore, contact with these combinations of active compounds might be more prolonged in time and widespread in the environment than previously assumed. These findings may help to direct future research and pesticide regulation strategies to promote the conservation of wild bee populations. PMID- 28087091 TI - Effect of single-dose of tolvaptan in neurocritical patients with hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion. PMID- 28087092 TI - Drug thromboprophylaxis in critical patients and the accumulation of low molecular weight heparins. PMID- 28087093 TI - Audiologic and radiologic findings in cochlear hypoplasia. AB - OBJECTIVE: The aim of the current study is to evaluate audiologic and radiologic findings of cochlear hypoplasia which is a subgroup of inner ear malformations. METHODS: This study was a prospective clinical study and based on voluntary participation from cases with cochlear hypoplasia diagnosis. The study was conducted at Hacettepe University, Department of Otolaryngology, Head and Neck Surgery and Department of Audiology. Subjects were selected from an inner ear malformations database. Inclusion criteria were having cochlear hypoplasia for at least one ear. There were 66 subjects with an age range of 12 months and 60 years 5 months. For each subject, pure tone audiometry and tympanometry were applied according to chronological and cognitive age. And also, auditory brainstem response test was applied to when it is need. Subjects' radiologic results were reevaluated to confirm cochlear hypoplasia, cochlear nerve and cochlear aperture. RESULTS: Cochlear hypoplasia types were statistically significantly different in terms of HL degree. This difference was caused by cochlear hypoplasia type IV group being was statistically different from the other three groups. Like with degree of HL, cochlear hypoplasia groups were statistically different from other three groups in terms of type of hearing loss. Cochlear aperture and cochlear nerve status showed variation according to cochlear hypoplasia type but these differences were not statistically approved. CONCLUSIONS: In the current study, incidence of cochlear hypoplasia was 23.5% in all inner ear malformation. With this study, it was seen that subtypes of cochlear hypoplasia showed variability in terms of degree and type of hearing loss and also cochlear aperture and cochlear nerve status. Especially cochlear hypoplasia type IV differs from other three cochlear hypoplasia types. PMID- 28087094 TI - In Defense of Randomized Clinical Trials in Surgery: Let Us Not Forget Archie Cochrane's Legacy. PMID- 28087095 TI - Some questions on the use of Xuebijing in treating patients with sepsis. AB - A meta-analysis of randomized controlled trials on evaluating the clinical efficacy of Xuebijing in treating patients with sepsis had been recently published in this journal, however, in our opinion, at least 6 questions or doubts existed about the content and methodology of the systematic review, thus, we write this letter to the journal to share these questions with the editor and readers with the hope of getting these questions solved and learning more about the true effects which Xuebijing should have on in treating patients with sepsis. PMID- 28087096 TI - A Letter to the Editor: Treatment in carbon monoxide poisoning patients with headache: A prospective, multicenter, double-blind, controlled clinical trial. PMID- 28087097 TI - Quick epinephrine administration induces favorable neurological outcomes in out of-hospital cardiac arrest patients. AB - OBJECTIVE: This research is to study if quick administration of adrenaline on OHCA prior to hospitalization has an effect on improving CPC1-2 at one month. METHODOLOGY: A total 13,326 cases were extracted from 2011 to 2014 Utstein data for this retrospective cohort study, also, EMT reached the patients within 16min after 119 called and adrenaline was then administered within 22min of after contact. PATIENTS DIVIDED INTO TWO GROUPS: Patients were contacted within 8min of the 119 call (n=6956), and were contacted between 8 and 16min after the call (n=6370). Further divided into groups in which the adrenaline was administered within/without 10min after contact. Primary outcome was the rate of a good prognosis for cerebral performance (CPC1-2) at 1 month and secondary outcome was the return of spontaneous circulation (ROSC) rate. RESULTS: The odds ratio of the CPC1-2 at 1month by the EMS reached within 8min after 119 call and then adrenaline administered within 10min was 2.12 (1.54-2.92).Those reached between 8 and 16min was 2.66 (1.97-3.59). However, the ROSC rate was 2.00 (1.79-2.25) for those reached within 8min and also 2.00 (1.79-2.25) for those reached between 8min and 16min. CONSIDERATIONS: In cases of OHCA, it appears that the CPC1-2 rate after 1month can be improved even in cases where the victim is reached >8min after the 119 call, as long as the victim is reached within 16min and emergency responders administer the adrenaline as quickly as possible. PMID- 28087098 TI - Emergency department crowding associated with differences in CXR interpretations between emergency physicians and radiologists. PMID- 28087099 TI - Prognostic and predictive indicators in early-stage breast cancer and the role of genomic profiling: Focus on the Oncotype DX(r) Breast Recurrence Score Assay. AB - Although useful prognostic and predictive insights can be gained from patient and tumour characteristics in early-stage breast cancer, it is not always straightforward to predict the likely risk of recurrence for each individual patient following breast surgery. One of the most difficult challenges faced by clinicians is identifying patients who may benefit most from adjuvant chemotherapy, and distinguishing these cases from those where endocrine therapy may be sufficient for cure. Genomic tests such as the Oncotype DX(r) Breast Recurrence Score(r) Assay have been developed to provide a robust and clinically validated assessment of a patient's individual tumour signature. The Oncotype DX Assay is included in treatment guidelines for estimating both the risk of distant recurrence and predicting adjuvant chemotherapy benefit for early-stage breast cancer patients with human epidermal growth factor receptor 2-negative, oestrogen receptor positive, and axillary lymph node negative or positive (1-3 positive nodes) disease. In this article, we review unmet needs for prognostication and prediction in early-stage breast cancer, and consider how the information provided by the Recurrence Score is complementary to that gained from the assessment of more traditional clinicopathologic criteria. Routine use of the assay in clinical practice, limitations and possible future directions are also discussed. PMID- 28087100 TI - [Improving prevention: Integrative model and recommendations intended for public health professionals]. AB - Public health policies aim to diminish people's exposure to negative factors, behaviors or determinants of health. Despite awareness-raising campaigns, health recommendations are still not sufficiently followed. First, the article wondered the reasons behind this observation. In order to do this, we present a theoretical model incorporating: (a) the motivational theories of communication processing; (b) the theories of motivation and volition; (c) self-regulation and self-determination theories. In a second part, the paper describes five principles for improving communication. PMID- 28087101 TI - Current Management of Low Risk Differentiated Thyroid Cancer and Papillary Microcarcinoma. AB - Each year, the proportion of thyroid cancer patients presenting with low risk disease is increasing. Moreover, the definition of low risk thyroid cancer is expanding and several histological subtypes beyond papillary microcarcinomas are now classified as low risk disease. This shift in the landscape of thyroid cancer presentation is forcing clinicians to critically re-evaluate whether or not traditional management paradigms that were effective in treating intermediate and high risk disease are applicable to these low risk patients. Here we review the definition of low risk disease, examine the various histological subtypes that are considered low risk in the 2015 American Thyroid Association guidelines for the management of thyroid nodules and thyroid cancer, and review our current approach to the management of these low risk tumours. PMID- 28087102 TI - Feature selection for outcome prediction in oesophageal cancer using genetic algorithm and random forest classifier. AB - The outcome prediction of patients can greatly help to personalize cancer treatment. A large amount of quantitative features (clinical exams, imaging, ...) are potentially useful to assess the patient outcome. The challenge is to choose the most predictive subset of features. In this paper, we propose a new feature selection strategy called GARF (genetic algorithm based on random forest) extracted from positron emission tomography (PET) images and clinical data. The most relevant features, predictive of the therapeutic response or which are prognoses of the patient survival 3 years after the end of treatment, were selected using GARF on a cohort of 65 patients with a local advanced oesophageal cancer eligible for chemo-radiation therapy. The most relevant predictive results were obtained with a subset of 9 features leading to a random forest misclassification rate of 18+/-4% and an areas under the of receiver operating characteristic (ROC) curves (AUC) of 0.823+/-0.032. The most relevant prognostic results were obtained with 8 features leading to an error rate of 20+/-7% and an AUC of 0.750+/-0.108. Both predictive and prognostic results show better performances using GARF than using 4 other studied methods. PMID- 28087104 TI - Improved outcomes from extracorporeal membrane oxygenation versus ventricular assist device temporary support of primary graft dysfunction in heart transplant. AB - BACKGROUND: Primary graft dysfunction (PGD) is one of the most common causes of early death after orthotopic heart transplantation. Mechanical circulatory support devices are required for severe forms of PGD. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) and temporary ventricular assist device (VAD) support have both been reported to be useful for severe PGD. METHODS: Between January 2007 and December 2015, 597 patients received a heart transplant at our center. Of those, severe PGD developed in 44 patients (7.4%), and they received a continuous-flow external VAD (n = 17) or VA-ECMO (n = 27) support within 24 hours after transplant. We compared early and late outcomes between groups. RESULTS: Baseline characteristics were similar between groups. Implantation of the temporary VAD required longer cardiopulmonary bypass time compared with VA-ECMO (323 +/- 86 minutes vs 216 +/- 65 minutes, p < 0.0001). Patients who received a VAD were more likely to have longer support time (14 +/- 17 days vs 5.2 +/- 3.9 days, p = 0.011), a higher incidence of major bleeding requiring chest reexploration (77% vs 30%, p = 0.0047), and a higher incidence of renal failure requiring renal replacement therapy (53% vs 11%, p = 0.0045) after surgery. Overall hospital mortality was 27%. In-hospital mortality for VAD and VA-ECMO patients were 41% and 19%, respectively (p = 0.16). Ten patients (59%) were weaned from VAD support, and 24 (89%) were weaned from VA-ECMO support after adequate graft function recovery (p = 0.03). The 3-year post-transplant survival was 41% in the VAD group and 66% in the VA-ECMO group (p = 0.13). CONCLUSIONS: For severe PGD, support with VA-ECMO appears to result in better clinical outcomes compared with VAD. PMID- 28087103 TI - Identifying methanogen community structures and their correlations with performance parameters in four full-scale anaerobic sludge digesters. AB - Four full-scale mesophilic anaerobic digesters treating waste sludge were monitored to characterize methanogen communities and their relationship with process parameters. The performance of the four digesters were dissimilar with the average chemical oxygen demand removal efficiencies between 24 and 45% and differing pH. Real-time quantitative PCR showed that archaeal 16S rRNA gene concentration ([ARC]) and, more pronouncedly, its ratio to bacterial counterpart ([ARC]/[BAC]) correlated positively with the performance parameters, including the lipid removal efficiency. Pyrosequencing identified 12 methanogen genera, of which Methanolinea, Methansaeta, and Methanospirillum collectively accounted for 79.2% of total archaeal reads. However, Methanoculleus, a numerically minor (1.9+/-2.6%) taxa, was the most promising biomarker for positive performance, while Methanoregula was abundant in samples with poor performance. These results could be useful for the control and management of anaerobic sludge digestion. PMID- 28087105 TI - Left ventricular assist device outcomes based on flow configuration and pre operative left ventricular dimension: An Interagency Registry for Mechanically Assisted Circulatory Support Analysis. AB - BACKGROUND: Axial configuration (AC) and centrifugal configuration (CC) left ventricular assist devices (LVAD) have different flow characteristics, and whether the interaction between device flow configuration and the pre-operative left ventricular internal diastolic diameter (LVIDD) mediates adverse events after LVAD implantation is unknown. METHODS: We queried 9,424 continuous-flow LVAD recipients who received LVADs from April 2008 to June of 2015 in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). The pre-operative LVIDD * flow configuration interaction term was tested in multivariable models to determine its relationship to adverse events. RESULTS: The pre-operative LVIDD * flow configuration interaction was a significant predictor of device thrombosis. As the LVIDD increased, the risk of AC device thrombosis increased compared with CC devices (p = 0.0099). At 7.0 cm, the hazard ratio (HR) for AC device thrombosis compared with the CC device was 1.61 (95% confidence interval [CI], 1.17-2.22; p = 0.004) and continued to rise as the LVIDD increased. The LVIDD * flow configuration interaction did not predict stroke, gastrointestinal bleeding, or patient survival. In multivariable models, the hazard of stroke was higher with the CC device regardless of the LVIDD (HR, 1.96; 95% CI, 1.64-2.36; p < 0.0001). Adjusted analyses showed LVAD implantation into a larger left ventricle was associated with a lower risk of death (HR, 0.90; 95% CI, 0.85-0.95; p = 0.0004) per centimeter of LVIDD. CONCLUSIONS: Our study suggests that the pre-operative LVIDD, flow configuration, and interaction terms should be considered individually when choosing the appropriate LVAD to mitigate the rates of device thrombosis, stroke, and death. PMID- 28087106 TI - Charge variant analysis of proposed biosimilar to Trastuzumab. AB - Trastuzumab is a humanized monoclonal antibody (mAb) employed for the treatment of HER2 Positive Breast Cancer. A HER2 overexpressing tumor cell binds to Trastuzumab and attracts immune cells which lead to induction of Antibody Dependent Cellular Cytotoxicity (ADCC) by binding to Fc receptors (CD16a or FcgammaRIIIa) on an effector cell, such as natural killer (NK) cells. The most commonly expressed receptor on NK cell is CD16a which binds to the Fc portion of Trastuzumab. The ligand-independent HER2-HER3 dimerization is the most potent stimulator of downstream pathways for regulation of cell growth and survival. An attempt has been made in this study to understand the impact of charge heterogeneity on the binding kinetics and potency of the monoclonal antibody. Trastuzumab has a pI range of 8.7-8.9 and is composed of mixture of acidic and basic variants beside the main peak. Ion exchange chromatography was used to isolate the acidic, basic, and main peak fractions from in-house proposed biosimilar to Trastuzumab and their activities were compared to the Innovator Trastuzumab Herclon(r). Data from the mass analysis confirmed the potential modifications in both acidic and basic variant. Binding activity studies performed using Surface Plasmon Resonance (SPR) revealed that acidic variants had lesser binding to HER2 in comparison to the basic variants. Both acidic and basic variant showed no significant changes in their binding to soluble CD16a receptors. In vitro assay studies using a breast cancer cell line (BT-474) confirmed the binding potency of acidic variant to be lesser than basic variant, along with reduced anti-proliferative activity for the acidic variant of Trastuzumab. Overall, these data has provided meaningful insights to the impact of antibody charge variants on in vitro potency and CD16 binding affinity of trastuzumab. PMID- 28087107 TI - Establishment of the 2nd Korean national biological reference standard for blood coagulation factor VIII:C concentrate. AB - Since the 1st Korean national biological reference standard for factor (F)VIII concentrate, established in 2001, has shown declining potency, we conducted this study to replace this standard with a 2nd Korean national biological reference standard for blood coagulation FVIII concentrate. The candidate materials for the 2nd standard were prepared in 8000 vials with 10 IU/ml of target potency, according to the approved manufacturing process of blood coagulation Factor VIII:C Monoclonal Antibody-purified, Freeze-dried Human Blood Coagulation Factor VIII:C. Potency was evaluated by one-stage clotting and chromogenic methods and the stability was confirmed to meet the specifications during a period of 73 months. Since the potencies obtained by the two methods differed significantly (P < 0.015), the values were determined separately according to the geometric means (8.9 and 7.4 IU/vial, respectively). The geometric coefficients of interlaboratory variability were 3.4% and 7.6% by the one-stage clotting and chromogenic assays, respectively. PMID- 28087108 TI - Shunt right or left? Decision 2016. PMID- 28087109 TI - Stargazing or scientific yardstick? The future of speckle tracking echocardiography in the management of ascending aortic aneurysm. PMID- 28087110 TI - Systematic review and meta-analysis of randomized controlled trials assessing safety and efficacy of posterior pericardial drainage in patients undergoing heart surgery. AB - OBJECTIVES: To investigate the potential beneficial effects of posterior pericardial drainage in patients undergoing heart surgery. METHODS: Multiple online databases and relevant congress proceedings were screened for randomized controlled trials assessing the efficacy and safety of posterior pericardial drainage, defined as posterior pericardiotomy incision, chest tube to posterior pericardium, or both. Primary endpoint was in-hospital/30 days' cardiac tamponade. Secondary endpoints comprised death or cardiac arrest, early and late pericardial effusion, postoperative atrial fibrillation (POAF), acute kidney injury, pulmonary complications, and length of hospital stay. RESULTS: Nineteen randomized controlled trials that enrolled 3425 patients were included. Posterior pericardial drainage was associated with a significant 90% reduction of the odds of cardiac tamponade compared with the control group: odds ratio (95% confidence interval) 0.13 (0.07-0.25); P < .001. The corresponding event rates were 0.42% versus 4.95%. The odds of early and late pericardial effusion were reduced significantly in the intervention arm: 0.20 (0.11-0.36); P < .001 and 0.05 (0.02 0.10); P < .001, respectively. Posterior pericardial drainage significantly reduced the odds of POAF by 58% (P < .001) and was associated with significantly shortened (by nearly 1 day) overall length of hospital stay (P < .001). Reductions in postoperative complications translated into significantly reduced odds of death or cardiac arrest (P = .03) and numerically lower odds of acute kidney injury (P = .08). CONCLUSIONS: Posterior pericardial drainage is safe and simple technique that significantly reduces not only the prevalence of early pericardial effusion and POAF but also late pericardial effusion and cardiac tamponade. These benefits, in turn, translate into improved survival after heart surgery. PMID- 28087111 TI - Keep moving forward. PMID- 28087112 TI - The impact of temperature in aortic arch surgery patients receiving antegrade cerebral perfusion for >30 minutes: How relevant is it really? AB - OBJECTIVE: We examined the early outcomes and the long-term survival associated with different degrees of hypothermia in patients who received antegrade cerebral perfusion (ACP) for >30 minutes. METHODS: During a 10-year period, 544 consecutive patients underwent proximal and total aortic arch surgery and received ACP for >30 minutes and 1 of 3 levels of hypothermia: deep (14.1 degrees C-20 degrees C; n = 116 [21.3%]), low-moderate (20.1 degrees C-23.9 degrees C; n = 262 [48.2%]), and high-moderate (24 degrees C-28 degrees C; n = 166 [30.5%]). A variable called "predicted temperature" was used in propensity-score analysis. Multivariate analysis was done to evaluate the effect of actual temperature on outcomes. RESULTS: The operative mortality rate was 12.5% (n = 68) overall and was 15.5%, 11.8%, and 11.5% in the deep, low-moderate, and high-moderate hypothermia patients, respectively (P = .54). The persistent stroke rate was 6.6% overall and 12.2%, 4.6%, and 6.0% in these 3 groups, respectively (P = .024 on univariate analysis). On multivariate analysis, actual temperature was not associated with mortality, but lower temperatures predicted persistent stroke and reoperation for bleeding. In the propensity-matched subgroups, the patients with predicted deep hypothermia had (nonsignificantly) greater rates of persistent stroke (12.2% vs 4.9%; relative risk, 1.08; 95% CI, 0.87-1.15) and reoperation for bleeding (14.6% vs 2.4%; relative risk, 1.14; 95% CI, 0.87-1.15) than the patients with predicted moderate hypothermia. On long-term follow-up (mean duration, 5.12 years), 4- and 8-year survival rates were 62.3% and 55.7% in the deep hypothermia group and 75.4% and 74.2% in the moderate hypothermia group (P = .0015). CONCLUSIONS: In proximal and arch operations involving ACP for >30 minutes, greater actual temperatures were associated with less stroke and reoperation for bleeding. There were no significant differences among the predicted hypothermia levels, although a trend toward a higher rate of adverse events was noticed in the deep hypothermia group. Long-term survival was better in the moderate hypothermia group. PMID- 28087113 TI - Video-assisted thoracoscopic diaphragm plication using a running suture technique is durable and effective. AB - OBJECTIVE: Surgeons have hesitated to adopt minimally invasive diaphragm plication techniques because of technical limitations rendering the procedure cumbersome or leading to early failure or reduced efficacy. We sought to demonstrate efficacy and durability of our thoracoscopic plication technique using a single running suture. METHODS: We retrospectively reviewed patients who underwent our technique for diaphragm plication since 2008. We used a single, buttressed, double-layered, to-and-fro running suture with additional plicating horizontal mattress sutures as needed. RESULTS: Eighteen patients underwent thoracoscopic plication from 2008 to 2015. There were no operative mortalities and 2 unrelated late deaths. Median hospital stay was 3 days (range, 1-12). Atrial fibrillation occurred in 1 patient (5.5%), pneumonia occurred in 2 patients (11%), reintubation occurred in 1 patient (5.5%), and ileus occurred in 1 patient (5.5%). Of 14 patients with complete follow-up, median follow-up was 29.4 months (range, 3.4-84.7). Significant increases between preoperative and postoperative pulmonary function tests (% predicted values) were found for mean forced expiratory volume in 1 second (73.5% +/- 3.5% to 88.8% +/- 4.5%, P = .002) and mean forced vital capacity (70.6% +/- 3.5% to 82.3% +/- 3.5%, P = .002). Preoperative mean Baseline Dyspnea Index was 8.1 +/- 0.7. Mean Transitional Dyspnea Index 6 months postoperatively was 7.1 +/- 0.6 (moderate to major improvement). Transitional Dyspnea Index at last contact (median 29.4 months postoperatively) was 7.2 +/- 0.6 (P = .38). Compared with previously published results, this is at least equivalent. CONCLUSIONS: Thoracoscopic diaphragm plication with a running suture is safe and achieves excellent early and long term improvements. This addresses technical challenges of tying multiple interrupted sutures by video-assisted thoracoscopic surgery without any apparent compromise to efficacy or durability. PMID- 28087114 TI - Erratum to "Mechanistic Studies of the Negative Epistatic Malaria-protective Interaction Between Sickle Cell Trait and alpha+thalassemia" [EBioMedicine 1 (2014) 29-36]. PMID- 28087115 TI - A Fatty Acid Synthase Inhibitor Shows New Anticancer Mechanisms. PMID- 28087116 TI - Application of whole exome sequencing in elucidating the phenotype and genotype spectrum of junctional epidermolysis bullosa: A preliminary experience of a tertiary care centre in India. AB - BACKGROUND: Junctional epidermolysis bullosa (JEB) is a diverse group of genodermatoses associated with extreme skin fragility. Despite several well characterized genetic studies, molecular diagnosis of this heterogeneous group is still challenging. Recent advances in the field of genomics have seen the successful implementation of whole exome sequencing (WES) as a fast and efficient diagnostic strategy in several genodermatoses. OBJECTIVE: In view of the scarcity and need of molecular studies for JEB in India, we sought to explore the potential of WES in understanding the mutational spectrum of this rare, in certain subtypes lethal, sub-group of EB. METHODS: WES was performed using genomic DNA from each case of EB, followed by massively parallel sequencing. Resulting reads were mapped to the human reference genome hg19. Sanger sequencing subsequently confirmed the potentially pathogenic mutations. RESULTS: Overall, four unrelated families (6 patients) of JEB with a highly variable clinical presentation including a rare case of LOC syndrome were studied. WES revealed 4 variations in 3 genes (LAMA3, LAMB3 and COL17A1) that are implicated in JEB. None of the variations were recurrent. In addition we proposed the probable molecular consequence of a missense mutation on the structure-function relationship of lamininbeta3 protein through computational modeling studies. CONCLUSIONS: Being the first report documenting the phenotype-genotype correlations of JEB patients from India, our preliminary experience with WES is clearly encouraging and serves as a nidus for future large-scale molecular studies to actively identify and understand JEB patients in Indian population. PMID- 28087117 TI - Erythropoietin attenuates experimental haemorrhagic shock-induced renal damage through an iNOS- dependent mechanism in male Wistar rats. AB - AIM: Erythropoietin (EPO) is shown to exert protective effects on different tissues in haemorrhagic shock (HS) states. Nitric oxide (NO), as a multifunctional signaling molecule, is implicated in diverse physiologic and pathologic processes. In order to understand the exact mechanism of EPO protection, in this study we evaluated the role of different NOS enzymes in the EPO signaling pathway in male rats. METHODS: Rats were randomized to five groups: 1) Sham, 2) HS 3) EPO 4) L-NAME, a non-specific NOS inhibitor 5) 1400W, a specific iNOS inhibitor. HS was induced by withdrawal of 50% of total blood volume. After 2h, resuscitation was performed with the shed blood and Ringer's lactate. In group 3, rats were treated with EPO (300IU/kg, i.v.) over 10min before HS induction. In the L-NAME and 1400W groups, L-NAME (10mg/kg, i.p.) and 1400W (2mg/kg, i.p.) were administered 30min before EPO injection. Blood and kidney tissue samples were obtained 3h after resuscitation. RESULTS: EPO increased the survival rate and significantly improved kidney function and histology compared to the HS group. There were less renal oxidative stress, apoptosis and systemic inflammatory responses in the EPO group. EPO increased eNOS and more abundantly iNOS mRNA expressions. L-NAME and 1400W significantly abolished all beneficial effects of EPO. CONCLUSION: In this in vivo animal model, we showed that EPO administration prior to HS attenuates renal injury and dysfunction in rats. The protective effects of EPO may be mediated by nitric oxide and the expression of different NOS enzymes, especially iNOS isoform. PMID- 28087118 TI - Open lower limb fractures in Major Trauma Centers - A loss leader? AB - PURPOSE: Open lower limb fractures are resource intensive injuries. Regardless of the financing model, the cost of treatment is an important consideration for any healthcare provider. METHODS: Open lower limb fractures treated at our centre were identified over a six-month period. Isolated open femur or tibia fractures were included as well as cases with multiple fractures. Direct inpatient care costs were calculated and income was reviewed for each case according to 'Healthcare Resource Group' (HRG) cost codes. RESULTS: A total of 41 open lower limb fractures (32 patients) were identified. There were isolated open fractures in twenty-five and multiple lower limb open fractures in seven patients. Twenty three patients (72%) were male and nine were female (28%) with an average age of 40 years (range 10-89 years). The fractures were classified according to Gustilo and Anderson (GA) and divided into two main groups; there were 13 mild and 28 severe open fractures. The median direct cost of inpatient treatment for open lower limb fractures was L19,189 per patient. There was a net gain of L6,288 per fracture in the mild group and a loss of L7,582 in the severe group. The total deficit was L149,545 over the six-month period for this cohort of 41 fractures. CONCLUSION: Open lower limb fractures are expensive to treat at a cost of approximately L19,200 per patient and associated with a significant loss of income in our MTC. Cost codes should reflect the complex and more expensive treatment of these patients to avoid the inadvertent financial 'penalties' of treating such patients. This study is the first to calculate the direct inpatient treatment costs of open lower limb fractures in a major trauma centre. It highlights the need for cost saving strategies and for appropriate remuneration in MTCs. PMID- 28087119 TI - Editorial overview: Proteins: bridging theory and experiment. PMID- 28087120 TI - Response. PMID- 28087121 TI - Upper extremity outcome measures for collagen VI-related myopathy and LAMA2 related muscular dystrophy. AB - Congenital muscular dystrophy (CMD) comprises a rare group of genetic muscle diseases that present at birth or early during infancy. Two common subtypes of CMD are collagen VI-related muscular dystrophy (COL6-RD) and laminin alpha 2 related dystrophy (LAMA2-RD). Traditional outcome measures in CMD include gross motor and mobility assessments, yet significant motor declines underscore the need for valid upper extremity motor assessments as a clinical endpoint. This study validated a battery of upper extremity measures in these two CMD subtypes for future clinical trials. For this cross-sectional study, 42 participants were assessed over the same 2-5 day period at the National Institutes of Health Clinical Center. All upper extremity measures were correlated with the Motor Function Measure 32 (MFM32). The battery of upper extremity assessments included the Jebsen Taylor Hand Function Test, Quality of Upper Extremity Skills Test (QUEST), hand held dynamometry, goniometry, and MyoSet Tools. Spearman Rho was used for correlations to the MFM32. Pearson was performed to correlate the Jebsen, QUEST, hand-held dynamometry, goniometry and the MyoSet Tools. Correlations were considered significant at the 0.01 level (2-tailed). Significant correlations were found between both the MFM32 and MFM Dimension 3 only (Distal Motor function) and the Jebsen, QUEST, MyoGrip and MyoPinch, elbow flexion/extension ROM and myometry. Additional correlations between the assessments are reported. The Jebsen, the Grasp and Dissociated Movements domains of the QUEST, the MyoGrip and the MyoPinch tools, as well as elbow ROM and myometry were determined to be valid and feasible in this population, provided variation in test items, and assessed a range of difficulty in CMD. To move forward, it will be of utmost importance to determine whether these upper extremity measures are reproducible and sensitive to change over time. PMID- 28087123 TI - Conversational Entrainment of Vocal Fry in Young Adult Female American English Speakers. AB - OBJECTIVE: Conversational entrainment, the natural tendency for people to modify their behaviors to more closely match their communication partner, is examined as one possible mechanism modulating the prevalence of vocal fry in the speech of young American women engaged in spoken dialogue. METHOD: Twenty young adult female American English speakers engaged in two spoken dialogue tasks-one with a young adult female American English conversational partner who exhibited substantial vocal fry and one with a young adult female American English conversational partner who exhibited quantifiably less vocal fry. Dialogues were analyzed for proportion of vocal fry, by speaker, and two measures of communicative success (efficiency and enjoyment). RESULTS: Participants employed significantly more vocal fry when conversing with the partner who exhibited substantial vocal fry than when conversing with the partner who exhibited quantifiably less vocal fry. Further, greater similarity between communication partners in their use of vocal fry tracked with higher scores of communicative efficiency and communicative enjoyment. CONCLUSIONS: Conversational entrainment offers a mechanistic framework that may be used to explain, to some degree, the frequency with which vocal fry is employed by young American women engaged in spoken dialogue. Further, young American women who modulated their vocal patterns during dialogue to match those of their conversational partner gained more efficiency and enjoyment from their interactions, demonstrating the cognitive and social benefits of entrainment. PMID- 28087122 TI - Human trophoblast stem cells: Real or not real? AB - Abnormal trophoblast differentiation is the root cause of many placenta-based pregnancy complications, including preeclampsia and fetal growth restriction. Human trophoblast differentiation is difficult to study due to the lack of a stem cell model. Such a multipotent "trophoblast stem" (TS) cell, with the ability to differentiate into all trophoblast subtypes, has been derived from mouse blastocysts, but attempts to derive similar human cells have failed. We consider here several possibilities for the TS cell niche in the human placenta. Aside from discussion of such a niche in the pre-implantation blastocyst, we discuss evidence for these TS cells residing in the post-implantation villous cytotrophoblast layer, or even in the non-trophoblast portions, of the human placenta. It is our hope that recognition of the niche would lead to successful derivation and in vitro establishment of such cells, which could then be disseminated widely to the placental biology community for advancing the field. Availability of self-renewing human TS cells, whose gene expression and environment could be manipulated, will provide a platform, not just for the study of pathophysiology of placental disease, but also for the discovery of diagnostic biomarkers and therapeutic targets for common pregnancy complications. PMID- 28087124 TI - The Acoustic Breathiness Index (ABI): A Multivariate Acoustic Model for Breathiness. AB - OBJECTIVE: The evaluation of voice quality is a major component of voice assessment. The aim of the present study was to develop a new multivariate acoustic model for the evaluation of breathiness. METHOD: Concatenated voice samples of continuous speech and the sustained vowel [a:] from 970 subjects with dysphonia and 88 vocally healthy subjects were perceptually judged for breathiness severity. Acoustic analyses were conducted on the same concatenated voice samples after removal of the non-voiced segments of the continuous speech sample. The development of an acoustic model for breathiness was based on stepwise multiple linear regression analysis. Concurrent validity, diagnostic accuracy, and cross validation were statistically verified on the basis of the Spearman rank-order correlation coefficient (rs), several estimates of the receiver operating characteristics plus the likelihood ratio, and iterated internal cross correlations. RESULTS: Ratings of breathiness from four experts with moderate reliability were used. Stepwise multiple regression analysis yielded a nine-variable acoustic model for the multiparametric measurement of breathiness (Acoustic Breathiness Index [ABI]). A strong correlation was found between ABI and auditory-perceptual rating (rs = 0.840, P = 0.000). The cross correlations confirmed a comparably high degree of association. Additionally, the receiver operating characteristics and likelihood ratio results showed the best diagnostic outcome at a threshold of ABI = 3.44 with a sensitivity of 82.4% and a specificity of 92.9%. CONCLUSIONS: This study developed a new acoustic multivariate correlate for the evaluation of breathiness in voice. The ABI model showed valid and robust results and is therefore proposed as a new acoustic index for the evaluation of breathiness. PMID- 28087125 TI - Hydroxy-Carboxylic Acid Receptor Actions in Metabolism. AB - Lactic acid, the ketone body 3-hydroxy-butyric acid, also known as beta hydroxybutyrate, and the beta-oxidation intermediate 3-hydroxy-octanoic acid are hydroxy-carboxylic acids (HCAs) that serve as intermediates of energy metabolism. However, they also regulate cellular functions, in part by directly activating the G protein-coupled receptors HCA1/GPR81, HCA2/GPR109A, and HCA3/GPR109B. During the past decade, it has become clear that HCA receptors help to maintain homeostasis under changing metabolic and dietary conditions, by controlling metabolic, immune, and other body functions. Work based on genetic mouse models and synthetic ligands of HCA receptors has, in addition, shown that members of this receptor family can serve as targets for the prevention and therapy of diseases such as metabolic and inflammatory disorders. PMID- 28087126 TI - Cardiac Lymphatics - A New Avenue for Therapeutics? AB - Recent progress in lymphatic vessel biology and in novel imaging techniques has established the importance of the lymphatic vasculature as part of the cardiovascular system. The lymphatic vessel network regulates many physiological processes important for heart function such as fluid balance, transport of extravasated proteins, and trafficking of immune cells. Therefore, lymphangiogenic therapy could be beneficial in the treatment of cardiovascular diseases, for example by improving reverse cholesterol transport (RCT) from atherosclerotic lesions or by resolving edema and fibrosis after myocardial infarction. In this review we first describe recent findings on the development and function of cardiac lymphatic vessels, and subsequently focus on the prospects of pro- and anti-lymphangiogenic therapies in cardiovascular diseases. PMID- 28087127 TI - The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds. AB - Recent advances in the field of continuous flow chemistry allow the multistep preparation of complex molecules such as APIs (Active Pharmaceutical Ingredients) in a telescoped manner. Numerous examples of laboratory-scale applications are described, which are pointing towards novel manufacturing processes of pharmaceutical compounds, in accordance with recent regulatory, economical and quality guidances. The chemical and technical knowledge gained during these studies is considerable; nevertheless, connecting several individual chemical transformations and the attached analytics and purification holds hidden traps. In this review, we summarize innovative solutions for these challenges, in order to benefit chemists aiming to exploit flow chemistry systems for the synthesis of biologically active molecules. PMID- 28087128 TI - Intranasal Oxytocin to Prevent Posttraumatic Stress Disorder Symptoms: A Randomized Controlled Trial in Emergency Department Patients. AB - BACKGROUND: There are currently few preventive interventions available for posttraumatic stress disorder (PTSD). Intranasal oxytocin administration early after trauma may prevent PTSD, because oxytocin administration was previously found to beneficially impact PTSD vulnerability factors, including neural fear responsiveness, peripheral stress reactivity, and socioemotional functioning. Therefore, we investigated the effects of intranasal oxytocin administration early after trauma on subsequent clinician-rated PTSD symptoms. We then assessed whether baseline characteristics moderated the intervention's effects. METHODS: We performed a multicenter, randomized, double-blind, placebo-controlled clinical trial. Adult emergency department patients with moderate to severe acute distress (n = 120; 85% accident victims) were randomized to intranasal oxytocin (8 days/40 IU twice daily) or placebo (8 days/10 puffs twice daily), initiated within 12 days posttrauma. The Clinician-Administered PTSD Scale (CAPS) was administered at baseline (within 10 days posttrauma) and at 1.5, 3, and 6 months posttrauma. The intention-to-treat sample included 107 participants (oxytocin: n = 53; placebo: n = 54). RESULTS: We did not observe a significant group difference in CAPS total score at 1.5 months posttrauma (primary outcome) or across follow-up (secondary outcome). Secondary analyses showed that participants with high baseline CAPS scores receiving oxytocin had significantly lower CAPS scores across follow-up than participants with high baseline CAPS scores receiving placebo. CONCLUSIONS: Oxytocin administration early after trauma did not attenuate clinician-rated PTSD symptoms in all trauma-exposed participants with acute distress. However, participants with high acute clinician-rated PTSD symptom severity did show beneficial effects of oxytocin. Although replication is warranted, these findings suggest that oxytocin administration is a promising preventive intervention for PTSD for individuals with high acute PTSD symptoms. PMID- 28087129 TI - Childhood Maltreatment and Unprotected Sex among Female Juvenile Offenders: Evidence of Mediation by Substance Abuse and Psychological Distress. AB - PURPOSE: Research has shown that childhood maltreatment is associated with sexual risk taking among female juvenile offenders; however, the mechanisms by which maltreatment influences sexual risk remain poorly understood. We assessed whether substance abuse, psychological distress, and dating violence mediate the relationship between childhood maltreatment and unprotected sex. METHODS: Sexually active female juvenile offenders (13-17 years of age) completed audio computer-assisted self-interviews (n = 232). Logistic regression with a risk decrement approach, the Sobel test, and the Goodman I test were used to evaluate mediation. RESULTS: Maltreatment before sixth grade was common in our sample, including physical abuse (48.7%), sexual abuse (14.7%), supervision neglect (57.3%), and physical neglect (18.5%). Cumulative childhood maltreatment was also high with 42.2% reporting two or more types. In the fully adjusted model, cumulative childhood maltreatment remained associated with unprotected sex (odds ratio, 2.43; 95% confidence interval, 1.27, 4.65). The percent of the total effect in the relationship between childhood maltreatment and unprotected sex that was mediated by substance abuse was 16.4% (Sobel = 2.54 [p = .01]; Goodman I = 2.49 [p = .01]) and psychological distress accounted for 23.7% (Sobel = 2.55 [p = .01]; Goodman I = 2.51 [p = .01]). Dating violence was not a significant mediator in our analyses. CONCLUSION: We found a strong relationship between childhood maltreatment and unprotected sex among female juvenile offenders that was partially mediated through substance abuse and psychological distress. These findings can be used to develop public health strategies to increase condom use among female juvenile offenders. Trauma-informed approaches to sexual health promotion that address substance abuse and psychological distress are warranted. PMID- 28087130 TI - Attitudes, Practices, and Experiences with Implementing a Patient-Centered Medical Home for Women Veterans. AB - BACKGROUND: Despite the growing demand for health care among women veterans in the Veterans Health Administration (VHA), little is known about the perspectives of primary care providers (PCPs) and other primary care staff about the care they provide to women veterans. We sought to understand whether barriers to, attitudes about, and practices in caring for women veterans were associated with two measures of implementation of the VHA patient-centered medical home for women veterans (self-efficacy and satisfaction). METHODS: We administered a cross sectional survey by Internet from September 8, 2014, through April 27, 2015 (and by mail from December 16, 2014, through June 18, 2015) to all PCPs and affiliated primary care staff in 12 VHA medical centers. We used descriptive and bivariate analyses to characterize their barriers, attitudes, and practices regarding care for women veterans; and ordinary least squares regression to identify associations with satisfaction and self-efficacy regarding medical home implementation for women veterans among members of a VHA patient-centered medical home teamlet for women patients. RESULTS: Of 775 surveys sent, 288 were completed (94 PCPs and 194 staff) for a response rate of 37% (33% for PCPs; 39% for staff). On average, providers had one female patient for every five patients in their panels. Lower perceived barriers, higher gender-sensitive attitudes, and being a PCP were significantly associated with satisfaction and self-efficacy of patient centered medical home for women patients. CONCLUSIONS: Training efforts focused on eliminating perceived barriers and strengthening positive attitudes toward women may be more successful than changing women's health practice characteristics alone. PMID- 28087131 TI - Incidence and effect of variant histology on oncological outcomes in patients with bladder cancer treated with radical cystectomy. AB - INTRODUCTION: We sought to describe incidence of histological variants after radical cystectomy (RC) due to bladder cancer (BCa). Moreover, we investigated survival outcomes accounting for this parameter. METHODS: We retrospectively evaluated data from 1,067 patients with BCa treated with RC between 1990 and 2013 at a single tertiary care referral center. All specimen were evaluated by dedicated uropathologists. Univariable and multivariable Cox regression analyses tested the effect of different histopathological variant on recurrence, cancer specific mortality (CSM), and overall mortality (OM) after accounting for all available confounders. RESULTS: Of 1,067 patients, 729 (68.3%) harbored pure urothelial BCa while 338 (31.7%) were found to have a variant. Considering uncommon variants, 21 (2.0%) were sarcomatoid, 10 (0.9%) lymphoepitelial, 19 (1.8%) small cell, 109 (10.2%) squamous, 89 (8.3%) micropapillary, 23 (2.2%) glandular, 34 (3.2%) mixed variants, and 33 (3.1%) were found with other types of variants. With a median follow-up of 6.2 years, 343 recurrence, 365 CSM, and 451 OM were recorded, respectively. At multivariable Cox regression analyses, the presence of small cell variant was associated with higher recurrence (hazard ratio [HR] = 3.47, P<0.001), CSM (HR = 3.30, P<0.04), and OM (HR = 2.97, P<0.003) as compared with pure urothelial cancer. Conversely, no survival differences were recorded considering other histological variants (all P> 0.1). CONCLUSION: Our study confirms that histological variant is not an infrequent event at RC specimen. However, in our single-center series, only patients found with small cell variant were associated with a negative effect on survival after RC. PMID- 28087132 TI - Practice Patterns of Thoracic Radiotherapy for Extensive-Stage Small-Cell Lung Cancer: Survey of US Academic Thoracic Radiation Oncologists. AB - PURPOSE: Despite the recent CREST trial demonstrating a survival benefit to thoracic radiotherapy (TRT) for patients with extensive-stage small-cell lung cancer (ES-SCLC) with response to chemotherapy, as well as endorsement by current National Comprehensive Cancer Network guidelines, TRT may not be uniformly delivered in clinical practice across all circumstances. METHODS AND MATERIALS: We surveyed US academic thoracic radiation oncologists regarding their practice patterns for TRT and assessed conditions in which withholding TRT could be warranted. A 27-question survey of demographics and practice patterns, including 5 clinical cases, was sent to 111 physicians. RESULTS: Response rate was 39% (43/111). Among respondents, 60% have at least 6 years of work experience following residency; 77% and 71% respectively see > 50 lung cancer and > 11 SCLC cases annually. Regarding practice patterns, 74% use TRT in 26% to 75% of patients with ES-SCLC. Respondents would withhold TRT in cases with Eastern Cooperative Oncology Group performance status >= 3 (91%), when pulmonary function necessitates continuous oxygen via nasal cannula (62%), for postchemotherapy tumor progression (58%), and if > 4 postchemotherapy extrathoracic metastases were present (58%). The 5 clinical cases highlighted practice variability, although 1 case had 100% agreement among respondents. CONCLUSIONS: Despite support of TRT administration from the CREST trial, there are several conditions associated with frequently withholding TRT. The most common reasons include performance status, postchemotherapy extent of disease, and pulmonary function; age and prechemotherapy extent of disease were least associated. Further research should aim to identify which subgroups of ES-SCLC benefit most from TRT. PMID- 28087133 TI - Secukinumab sustains early patient-reported outcome benefits through 1 year: Results from 2 phase III randomized placebo-controlled clinical trials comparing secukinumab with etanercept. AB - BACKGROUND: Psoriasis is a chronic condition with negative impact on patients' quality of life that most often requires lifelong effective and safe treatment. OBJECTIVE: This analysis focused on the effect of secukinumab treatment on patient-reported health-related quality of life as assessed by the Dermatology Life Quality Index (DLQI) in patients with moderate to severe psoriasis. METHODS: The proportion of subjects achieving DLQI score 0/1 response at week 24, time to DLQI score 0/1 response, and sustained DLQI score 0/1 response up to week 52 were compared between secukinumab and etanercept. RESULTS: Of 1470 subjects, 1144 received secukinumab and 326 received etanercept. DLQI score 0/1 response rates were significantly higher for secukinumab than for etanercept at week 24. The median time to DLQI score 0/1 response was significantly shorter for secukinumab versus etanercept (12 vs 24 weeks; P < .01). The majority of secukinumab-treated subjects achieved DLQI score 0/1 response at week 24 and sustained it through week 52 along with a 90% to 100% reduction in the Psoriasis Area and Severity Index total score response. LIMITATIONS: Placebo comparisons are limited during the maintenance period because of rerandomization at week 12. CONCLUSION: Secukinumab treatment provided faster and greater sustained improvements in quality of life than etanercept over 52 weeks, consistent with greater clinical response. PMID- 28087134 TI - Factors influencing and modifying the decision to pursue genetic testing for skin cancer risk. AB - BACKGROUND: Across cancers, the decision to pursue genetic testing is influenced more by subjective than objective factors. However, skin cancer, which is more prevalent, visual, and multifactorial than many other malignancies, may offer different motivations for pursuing such testing. OBJECTIVES: The primary objective was to determine factors influencing the decision to receive genetic testing for skin cancer risk. A secondary objective was to assess the impact of priming with health questions on the decision to receive testing. METHODS: We distributed anonymous online surveys through ResearchMatch.org to assess participant health, demographics, motivations, and interest in pursuing genetic testing for skin cancer risk. Two surveys with identical questions but different question ordering were used to assess the secondary objective. RESULTS: We received 3783 responses (64% response rate), and 85.8% desired testing. Subjective factors, including curiosity, perceptions of skin cancer, and anxiety, were the most statistically significant determinants of the decision to pursue testing (P < .001), followed by history of sun exposure (odds ratio 1.85, P < .01) and history of skin cancer (odds ratio 0.5, P = .01). Age and family history of skin cancer did not influence this decision. Participants increasingly chose testing if first queried about health behaviors (P < .0001). LIMITATIONS: The decision to pursue hypothetical testing may differ from in-clinic decision making. Self-selected, online participants may differ from the general population. Surveys may be subject to response bias. CONCLUSION: The decision to pursue genetic testing for skin cancer is primarily determined by subjective factors, such as anxiety and curiosity. Health factors, including skin cancer history, also influenced decision-making. Priming with consideration of objective health factors can increase the desire to pursue testing. PMID- 28087135 TI - Surgical site infection related to use of elastomeric pumps in pectus excavatum repair. Lessons learned from root cause analysis. AB - BACKGROUND: Pectus excavatum repair (PEX) is among the most painful thoracic procedures performed. Continuous peripheral nerve blockade (CPNB) is known to be efficacious in optimizing pain control while limiting narcotic use in adult thoracic procedures. It was introduced in May 2015 as a bridge to oral pain control in children undergoing PEX. Consequently, the surgical site infection (SSI) rate increased from 2.7% to 27.7%. METHODS: SSI surveillance followed national guidelines. The abrupt increase prompted root cause analysis and cessation of CPNB use. A dynamic systems model of SSI in PEX was developed. Statistical analysis compared SSI outcomes with and without CPNB. RESULTS: From May 2015 to June 2015, 21 PEX were performed; 11 with CPNB. 6 SSIs were observed. Use of CPNB significantly (p=0.008) increased SSI incidence. Haller index, number of bars, usage of Fiberwire(r), methicillin resistant S. aureus colonization and length of stay did not differ. Root cause analysis revealed the proximity of CPNB catheters to the wound, the use of CPNB with implanted hardware and a delayed utilization of CPNB catheters to be of concern. CONCLUSION: Introduction of CPNB coincided with a significant increase in SSI. Further study is needed to assess the safety of CPNB in pediatric PEX. LEVEL OF EVIDENCE: Level III treatment study. PMID- 28087136 TI - Global general pediatric surgery partnership: The UCLA-Mozambique experience. AB - BACKGROUND/PURPOSE: There has been increasing recognition of the disparities in surgical care throughout the world. Increasingly, efforts are being made to improve local infrastructure and training of surgeons in low-income settings. The purpose of this study was to review the first 5-years of a global academic pediatric general surgery partnership between UCLA and the Eduardo Mondlane University in Maputo, Mozambique. METHODS: A mixed-methods approach was utilized to perform an ongoing needs assessment. A retrospective review of admission and operative logbooks was performed. Partnership activities were summarized. RESULTS: The needs assessment identified several challenges including limited operative time, personnel, equipment, and resources. Review of logbooks identified a high frequency of burn admissions and colorectal procedures. Partnership activities focused on providing educational resources, on-site proctoring, training opportunities, and research collaboration. CONCLUSION: This study highlights the spectrum of disease and operative case volume of a referral center for general pediatric surgery in sub-Saharan Africa, and it provides a context for academic partnership activities to facilitate training and improve the quality of pediatric general surgical care in limited-resource settings. LEVEL OF EVIDENCE: Level IV. PMID- 28087137 TI - Decreased expression of Kv7 channels in Hirchsprung's disease. AB - PURPOSE: Voltage-dependent K+ channels (Kv channels) participate in electrical rhythmicity and smooth muscle responses and are regulated by excitatory and inhibitory neurotransmitters. Kv channels also participate in the interstitial cell of Cajal (ICC) and smooth muscle cell (SMC) responses to neural inputs. The Kv family consists of 12 subfamilies, Kv1-Kv12, with five members of the Kv7 family identified to date: Kv7.1-Kv7.5. A recent study identified the potassium channel Kv7.5 as having a role in the excitability of ICC-IM in the mouse colon. We therefore designed this study to test the hypothesis that Kv7 channels are present in the normal human colon and are reduced in Hirschprung's disease (HSCR). MATERIAL AND METHODS: HSCR tissue specimens were collected at the time of pull-through surgery (n=10), while normal control tissue specimens were obtained at the time of colostomy closure in patients with imperforate anus (n=10). Kv7.3 Kv7.5 immunohistochemistry was performed and visualized using confocal microscopy to assess their distribution. Western blot analysis was undertaken to determine Kv7.3-Kv7.5 protein quantification. RESULTS: Kv7.3 and Kv7.4-immunoreactivity was co-localized with neuron and ICC markers, while Kv7.5 was found to be expressed on both ICCs and SMCs. Western blot analysis revealed similar levels of Kv7.3 and Kv7.5 expression in the normal colon and HSCR colon, while Kv7.4 proteins were found to be markedly decreased in ganglionic specimens and decreased further in aganglionic specimens. CONCLUSION: A deficiency of Kv7.4 channels in the ganglionic and aganglionic bowel may place a role in colonic dysmotility in HSCR. PMID- 28087138 TI - Corrigendum to "delayed presentation of congenital diaphragmatic hernia manifesting as combined-type acute gastric volvulus: A case report and review of the literature" J Pediatr Surg 43 (3) (2008):E35-9. doi: 10.1016/j.Jpedsurg.2007.11.015. PMID- 28087139 TI - Retention of faculty of color in academic nursing. AB - BACKGROUND: Racial and ethnic diversity among nursing faculty is low, preventing schools of nursing (SON) from reflecting the populations that they serve academically and clinically. Few studies address the experience and success of faculty of color (FOC) in nursing. PURPOSE: The purpose of this article is to summarize the current literature related to FOC retention and promotion. METHODS: We reviewed 25 articles from the nursing literature following PRISMA guidelines, using a critical race theory framework. DISCUSSION: We describe barriers and promoters to retention, benefits of retaining FOC, and proposed solutions to FOC attrition. We also highlight polices by several SON that netted increased retention and promotion of nursing FOC. CONCLUSION: FOC meet substantial challenges that influence their career pathway. SON can improve faculty retention through focused efforts on improving the institutional culture to promote an inclusive environment. PMID- 28087140 TI - Tanning the bugs - a pilot study of an innovative approach to stethoscope disinfection. PMID- 28087141 TI - Preoperative skin antisepsis - it ain't what you do but the way that you do it. PMID- 28087142 TI - Ultrastructural characteristics of the mature spermatozoon of the digenean Sclerodistomum italicum (Stossich, 1893) (Hemiuroidea, Sclerodistomidae) intestinal parasite of Hypocanthus amia (Teleostei, Carangidae). AB - The mature spermatozoon of Sclerodistomum italicum is filiform, tapered at both ends and shows the following features: 2 axonemes of the 9+"1" pattern of the Trepaxonemata, mitochondrion, nucleus and parallel cortical microtubules. The specific features of the spermatozoon of S. italicum include the simultaneous presence of two types of extramembranous ornamentations, the presence of short cortical microtubules in the anterior part of the spermatozoon and the presence of only one bundle of cortical microtubules in the median part of the spermatozoon. Thus far these structures are known only in the Hemiuroidea. The presence of filamentous ornamentation in the anterior extremity of the spermatozoon has not previously been described in the Sclerodistomidae. Similar to spermatozoa of other hemiuroideans, S. italicum lack spine-like bodies described in spermatozoa of many digenean taxa. The posterior extremity of the spermatozoon exhibits the same ultrastructural characteristics typical of the Hemiuroidea. PMID- 28087143 TI - Contribution of age to clinical trial enrollment and tolerance with ovarian cancer. AB - INTRODUCTION: Increasing age has been correlated with shorter survival in ovarian cancer patients, a finding attributed to diminished tolerance of standard therapy. Elderly patients, however, are less likely to enroll on clinical trials; thus, limited data exists to evaluate their response to front line treatment. This study describes how elderly patients on trial fared, with respect to toxicity and response, compared to younger women. METHODS: A retrospective cohort study was performed of ovarian cancer patients enrolled in front line chemotherapy trials at our institution between 2000 and 2013. Patients were dichotomized by age: <70 and >=70years. Clinical, pathologic, and treatment characteristics were recorded and analyzed using SAS version 9.3. RESULTS: 336 patients were enrolled. Of these, 79 (23.5%) were >=70yrs. Demographics were similar between the two groups. Compared to patients <70, those >=70 completed a comparable number of chemotherapy cycles (p=0.16) and had similar numbers of dose modifications (p=0.40) and delays (p=0.26). Both hematologic and non-hematologic toxicities occurred at similar rates as well. Age>=70 (HR 1.8, 95% CI 1.27-2.54, p=0.0009), stage III/IV (HR 3.44, 95% CI 1.08-10.95, p=0.036), and residual disease (HR 2.63, 95% CI 1.82-3.78, p<0.0001) were independently predictive of shorter overall survival. CONCLUSION: Our data continues to support reports of shorter survival for older women with ovarian cancer. With physician bias removed and similar chemotherapy tolerance noted, our study suggests that inherent tumor biology may be a significant contributor. Further research is needed to identify the mechanisms which contribute to the inequality that age imposes on outcomes. PMID- 28087144 TI - Contribution of microbiology in the diagnosis of tuberculosis in Castile and Leon (Spain): Findings of the GRUMICALE 2013 study. AB - INTRODUCTION AND OBJECTIVES: A retrospective study was conducted by collecting microbiological tuberculosis (TB) data in Castile and Leon during the year 2013 in order to determine the incidence and distribution of TB, and resistance to the tuberculostatic drug, and compare them with the epidemiological data provided by the Department of Epidemiological Surveillance (SIVE). MATERIAL AND METHODS: Microbiologists of the 14 hospitals of the Castile and Leon public health network (GRUMICALE) collected epidemiological, microbiological, and management data from the Microbiology laboratories in the community during the year 2013. A single isolate of Mycobacterium tuberculosis complex (MTC) per patient was considered. RESULTS: The study included a total of 270 MTC isolates (an incidence rate of 11.63 cases/100,000 inhab./year). A total of 288 cases of TB (11.43 cases/100,000 inhab. year) were recovered using epidemiological data, which included 243 confirmed, 29 suspected, and 16 as probable cases. Pulmonary TB was predominant, followed a long way off by the pleural TB and the remaining locations. A total of 27,620 samples were processed for mycobacterial detection. Mycobacterial growth was observed in 3.46% of automated fluid cultures, and 50.37% were positive by direct staining of the smear. Resistance to one tuberculostatic drug, mostly to isoniazid, was observed in 16 (5.92%) isolates of Mycobacterium tuberculosis (MT). The province with greater incidence and number of isolates was Leon (24.23 cases/100,000 inhab./year), with the highest being observed in El Bierzo health area (30.46 cases/100,000 inhab./year). CONCLUSIONS: An adequate collection of microbiological information is essential to determine the epidemiology of TB in our region. PMID- 28087145 TI - Computerised sepsis protocol management. Description of an early warning system. AB - INTRODUCTION: New strategies need to be developed for the early recognition and rapid response for the management of sepsis. To achieve this purpose, the Multidisciplinary Sepsis Team (MST) developed the Computerised Sepsis Protocol Management (PIMIS). The aim of this study was to evaluate the convenience of using PIMIS, as well as the activity of the MST. METHODS: An analysis was performed on the data collected from solicited MST consultations (direct activation of PIMIS by attending physician or telephone request) and unsolicited ones (by referral from the microbiology laboratory or an automatic referral via the hospital vital signs recording software [SIDCV]), as well as the hospital department, source of infection, treatment recommendation, and acceptance of this. RESULTS: Of the 1,581 first consultations, 65.1% were solicited consultations (84.1% activation of PIMIS and 15.9% by telephone). The majority of unsolicited consultations were generated by the microbiology laboratory (95.2%), and 4.8% from the SIDCV. Referral from solicited consultations were generated sooner (5.63days vs 8.47days; P<.001) and came from clinical specialties rather than from the surgical ward (73.0% vs 39.1%; P<.001). A recommendation was made for antimicrobial prescription change in 32% of first consultations. The treating physician accepted 78.1% of recommendations. CONCLUSIONS: The high rate of solicited consultations and acceptance of recommended prescription changes suggest that a MST is seen as a helpful resource, and that PIMIS software is perceived to be useful and convenient to use, as it is the main source of referral. PMID- 28087146 TI - PCV13-vaccinated children still carrying PCV13 additional serotypes show similar carriage density to a control group of PCV7-vaccinated children. AB - BACKGROUND: In addition to reducing vaccine-type nasopharyngeal carriage rates, pneumococcal conjugate vaccines (PCVs) may decrease carriage density in vaccinated individuals still carrying vaccine serotypes. However, reduction of carriage density has not been systematically studied. This study compared the effect of PCV13 versus PCV7 on carriage density of the serotypes in PCV13 that are not included in PCV7. METHODS: This randomized, double-blind study was conducted in southern Israel and included Jewish and Bedouin subjects. Per protocol, 881 and 873 infants received PCV13 and PCV7, respectively, at ages 2, 4, 6, and 12months. Nasopharyngeal cultures at ages 7, 12, 13, 18, and 24months were plated using the 4-quadrant semiquantitative method and graded 0 (negative) to 4 (growth in all plate quadrants). In this post hoc analysis, the least squares means of cumulative colonization densities per serotype and serotype combination of the total population and each ethnic subpopulation in each vaccine group were calculated, and differences between vaccine groups derived from a linear model. RESULTS: PCV13-vaccinated children still carrying the 6 additional PCV13 serotypes unique to PCV13 showed no significant differences in carriage density compared with the PCV7-vaccinated control group. No differences in carriage density were shown between Jewish and Bedouin subpopulations despite higher carriage rates among Bedouin subjects. CONCLUSIONS: Although PCV13 vaccination reduces vaccine-type carriage compared with PCV7 vaccination by reducing nasopharyngeal acquisition of the additional PCV13 serotypes as previously reported, the current study lacks evidence of a decrease in carriage density of these serotypes when acquired in vaccinated children. Despite the lack of effect on carriage density observed, surveillance data suggest a dramatic decrease in disease rates after PCV implementation. Thus, the current analysis suggests that PCV's impact on carriage density has minimal or no impact on vaccine success. (www.ClinicalTrials.gov: NCT00508742). PMID- 28087147 TI - Immune responses to in ovo vaccine formulations containing inactivated fowl adenovirus 8b with poly[di(sodium carboxylatoethylphenoxy)]phosphazene (PCEP) and avian beta defensin as adjuvants in chickens. AB - Inclusion body hepatitis (IBH) is one of the major viral infections causing substantial economic loss to the global poultry industry. The disease is characterized by a sudden onset of mortality (2-30%) and high morbidity (60-70%). IBH is caused by a number of serotypes of fowl adenovirus with substantially low levels of serotype cross protection. Thus far, there is no effective and safe vaccine commercially available in the North America for the control of IBH in chickens. Poly[di(sodium carboxylatoethylphenoxy)]phosphazene (PCEP) is a high molecular weight, biodegradable water soluble polymer that has been well characterized as a safe and effective adjuvant for a number of experimental veterinary vaccines. Similarly, host defence peptides, including beta-defensins, have also been shown to exhibit strong adjuvant potential. In this study, we evaluated the adjuvant activity of PCEP and avian beta defensin (ABD) in a vaccine formulation containing inactivated fowl adenovirus (FAdV) serotype 8b administered in ovo. Our data showed that a combination of PCEP and inactivated virus is capable of inducing a robust and long lasting antibody response. Moreover, significant enhancement of IFN-gamma, IFN-alpha, IL-12(p40) and IL-6 gene expression under the influence of PCEP suggests that as an in ovo adjuvant PCEP has the ability to activate a substantial balanced immune response in chickens. To our knowledge, these are the first studies in which PCEP and ABD have been characterized as adjuvants for the development of an in ovo poultry vaccine. It is expected that these preliminary studies will be helpful in the development of safer and more effective in ovo vaccine against IBH and other infectious diseases affecting chickens. PMID- 28087149 TI - Seasonal vaccines - Critical path to pandemic influenza response. PMID- 28087148 TI - Immunogenicity differences of a 15-valent pneumococcal polysaccharide conjugate vaccine (PCV15) based on vaccine dose, route of immunization and mouse strain. AB - Pneumococcal disease continues to be a medical need even with very effective vaccines on the market. Globally, there are extensive research efforts to improve serotype coverage with novel vaccines; therefore, conducting preclinical studies in different animal models becomes essential. The work presented herein focuses on evaluating a 15-valent pneumococcal conjugate vaccine (PCV15) in mice. Initially we evaluated several doses of PCV15 in Balb/c mice. The optimal vaccine dose was determined to be 0.4MUg per pneumococcal polysaccharide (PS) (0.8MUg of 6B) for subsequent studies. This PS dose was chosen for PCV evaluation in mice based on antibody levels determined by multiplexed electrochemiluminescent (ECL) assays, T-cell responses following in vitro stimulation with CRM197 peptides and protection from pneumococcal challenge. We then selected four mouse strains for evaluation: Balb/c, C3H/HeN, CD1 and Swiss Webster (SW), immunized with PCV15 by either intraperitoneal (IP) or intramuscular (IM) routes. We assessed IgG responses by ECL assays and functional antibody activity by multiplexed opsonophagocytic assays (MOPA). Every mouse strain evaluated responded to all 15 serotypes contained in the vaccine. Mice tended to have lower responses to serotypes 6B, 23F and 33F. The IP route of immunization resulted in higher antibody titers for most serotypes in Balb/c, C3H and SW. CD1 mice tended to respond similarly for most serotypes, regardless of route of immunization. Similar trends were observed with the four mouse strains when evaluating functional antibody activity. Given the differences in antibody responses based on mouse strain and route of immunization, it is critical to evaluate pneumococcal vaccines in multiple animal models to determine the optimal formulation before moving to clinical trials. PMID- 28087150 TI - Apelin protects against NMDA-induced retinal neuronal death via an APJ receptor by activating Akt and ERK1/2, and suppressing TNF-alpha expression in mice. AB - Glutamate excitotoxicity mediated by N-methyl-d-aspartate (NMDA) receptors is an important cause of retinal ganglion cell death in glaucoma. To elucidate whether apelin protects against retinal neuronal cell death, we examined protective effects of exogenous and endogenous apelin on neuronal cell death induced by intravitreal injection of NMDA in the retinas of mice. An intravitreal injection of NMDA induced neuronal cell death in both the retinal ganglion cell layer and inner nuclear layer, and reduced the amplitudes of scotopic threshold response (STR) in electroretinography studies. Both cell death and STR amplitudes decrease induced by NMDA were prevented by a co-injection of [Pyr1]-apelin-13, and were facilitated by apelin deficiency. The neuroprotective effects of [Pyr1]-apelin-13 were blocked by an apelin receptor APJ antagonist, and by inhibitors of Akt and extracellular signal-regulated kinase 1/2 signaling pathways. Additionally, an intravitreal injection of tumor necrosis factor-alpha (TNF-alpha) neutralizing antibody prevented NMDA-induced retinal neuronal cell death, and exogenous and endogenous apelin suppressed NMDA-induced upregulation of TNF-alpha in the retina. These results suggest that apelin protects neuronal cells against NMDA induced death via an APJ receptor in the retina, and that apelin may have beneficial effects in the treatment of glaucoma. PMID- 28087151 TI - The Key to Mn Homeostasis in Plants: Regulation of Mn Transporters. AB - Plants only require small amounts of manganese (Mn) for healthy growth, but Mn concentrations in soil solution vary from sub-micromolar to hundreds of micromolar across the growth period. Therefore, plants must deal with large Mn concentration fluctuations, but the molecular mechanisms underlying how plants cope with low and high Mn concentrations are poorly understood. In this Opinion we discuss the role of Mn transporters in the uptake, distribution, and detoxification of Mn in response to changes in Mn concentrations through their regulation at the transcriptional and protein levels, mainly focusing on rice, an Mn-tolerant and -accumulating species. We also propose mechanisms involved in the hyperaccumulation of Mn and future prospects for studying this specific trait. PMID- 28087152 TI - Corrigendum to "Numerical study of the effects of lamp configuration and reactor wall roughness in an open channel water disinfection UV reactor" [Chemosphere 155 (2016) 170-179]. PMID- 28087153 TI - Lipoprotein Subfractions in Type 2 Diabetes. PMID- 28087155 TI - Population genetic data of 38 insertion-deletion markers in six populations of the northern fringe of the Iberian Peninsula. AB - Insertion-deletions have been reported very useful markers for forensic purposes. To further deepen in this matter, 38 non-coding bi-allelic autosomal indels were analyzed in 575 individuals representing six populations from the northern fringe of the Iberian Peninsula. Autochthonous populations from the Basque Country, northern Navarre, the Pas Valley in Cantabria and Aragon were analyzed, together with non-autochthonous populations from the Basque Country and northern Navarre. At the intra-population level, all loci analyzed were in Hardy-Weinberg equilibrium except for marker rs33917182 in autochthonous Basques. Linkage disequilibrium (LD) test did not reveal statistically significant allelic association between the different loci pairs in all six populations. Forensic parameters proved to be highly informative in the six populations analyzed, even if a scenario with population substructure and local inbreeding was considered for match probability calculations, and the potential of this indels set to be used in combination with other genetic markers is remarkable. As for inter population analyses, in general terms the six populations showed low but statistically significant genetic distances. However, though this indels set efficiently differentiate between main ancestries, it does not allow an accurate separation at a local level and, for the time being, their combination with other informative markers is needed to maximize the power to accurately differentiate populations with close genetic ancestry. PMID- 28087154 TI - Evaluation of Serial High Sensitivity Troponin T Levels in Individuals Without Overt Coronary Heart Disease Following Exercise Stress Testing. AB - BACKGROUND: Detectable levels of high sensitivity (cardiac) troponin T (HsTnT), occur in the majority of patients with stable coronary heart disease (CHD), and often in 'healthy' individuals. Extreme physical activity may lead to marked elevations in creatine kinase MB and TnT levels. However, whether HsTnT elevations occur commonly after exercise stress testing (EST), and if so, whether this has clinical significance, needs clarification. METHODS: To determine whether HsTnT levels become elevated after EST (Bruce protocol) to >=95% of predicted maximum heart rate in presumed healthy subjects without overt CHD, we assayed HsTnT levels for ~5h post-EST in 105 subjects (median age 37 years). RESULTS: Pre-EST HsTnT levels <5 ng/L were present in 31/32 (97%) of females and 52/74 (70%) of males. Post-EST, 13 (12%) subjects developed HsTnT levels >14 ng/L, with troponin elevation occurring at least three hours post-EST. Additionally, a detectable >= 50% increase in HsTnT levels (4.9->9ng/L) occurred in 28 (27%) of subjects who during EST achieved >= 95% of their predicted target heart rate. The median age of the subjects with HsTnT elevations to > 14ng/L post EST was higher than those without such elevation (42 and 36 years respectively; p=0.038). At a median follow-up of 13 months no adverse events were recorded. CONCLUSION: The current study demonstrates that detectable elevations occur in HsTnT post-EST in 'healthy' subjects without overt CHD. Future studies should evaluate the clinical significance of detectable elevations in post-EST HsTnT with long-term follow-up for adverse cardiac events. PMID- 28087156 TI - French national consensus clinical guidelines for the management of Crohn's disease. AB - BACKGROUND: Crohn's disease (CD) is a chronic and disabling condition. There is no curative medical treatment but current treatments provide increasingly sustainable control of the disease and allow patients a better quality of life. There is limited evidence supporting CD management in specific clinical situations, thus precluding an evidence-based approach. AIMS: To help clinicians in making informed treatment decisions, a group of 59 French gastroenterologists with experience in the management of CD met to develop straightforward and practical algorithms based on the European Crohn's and Colitis Organisation (ECCO) recommendations. METHODS: This experts' opinion was developed following a Nominal Group consensus methodology. Nine clinical situations were identified: mildly active CD; uncomplicated moderately active CD, with, and without poor prognostic factors; uncomplicated severely active CD; perianal CD with a single fistula; perianal CD with complex fistula with or without abscess; complicated CD with abscess; intestinal stricture; and post-operative CD. Two working groups were formed and proposed algorithms that were then approved by a two-thirds majority of the Nominal Group. RESULTS: These algorithms represent the pragmatic consensus of a group of experts in gastroenterology on the modalities of therapeutic care in different clinical situations in CD. They are available via a web application at: www.algorithmici.com. PMID- 28087157 TI - The association of blood urea nitrogen levels with mortality in acute pulmonary embolism. AB - BACKGROUND: The aim of this study was to investigate the association of BUN levels with in-hospital and long-term adverse clinical outcomes in acute pulmonary embolism (APE) patients treated with tissue-plasminogen activator (t PA). METHODS: This retrospective study included 252 consecutive confirmed APE patients treated with t-PA. An admission BUN of 34.5 mg/dL was identified through an ROC analysis as an optimal cutoff value to predict the in-hospital mortality with 85% sensitivity and 91% specificity (AUC: 0.91; 95% CI: 0.84-0.96; P<.001). RESULTS: Our study showed that an increase in BUN levels was independently associated with a high risk of in-hospital all-cause mortality, low admission systolic blood pressure, use of inotropic drugs, and cardiogenic shock. In hospital mortality rates were 51.1% in higher BUN group, and 1.9% in lower BUN group (P<.001). CONCLUSION: In this study, elevated admission BUN level was found to be a predictor of all-cause in-hospital mortality. BUN testing is commonly part of the basic metabolic panel; and it can be used to detect high-risk patients with APE, and it bears little risk, is inexpensive, and easy to perform. PMID- 28087158 TI - Echocardiographic approach to cardiac tamponade in critically ill patients. AB - Cardiac tamponade should be considered in a critically ill patient in whom the cause of haemodynamic shock is unclear. When considering tamponade, transthoracic echocardiography plays an essential role and is the initial investigation of choice. Diagnostic sensitivity of transthoracic echocardiography is dependent on image quality, and in some cases a transoesophageal approach may be required to confirm the diagnosis. Knowledge of the pathophysiology and echocardiographic features of cardiac tamponade are essential for the practicing Intensivist. This review presents an approach to the recognition, diagnosis, and treatment of cardiac tamponade in critically ill patients. PMID- 28087159 TI - The Direct Anterior Approach for Complex Primary Total Hip Arthroplasty: The Extensile Acetabular Approach on a Regular Operating Room Table. AB - BACKGROUND: The direct anterior approach on a regular operating room table has been reported with low dislocation rates. This might be beneficial for complex primary total hip arthroplasty (THA) such as in patients with cerebral palsy or following femoral or pelvic osteotomies. Extending the approach is often required to overcome problems such as acetabular deformities or severe contractures. METHODS: We retrospectively evaluated the results and complications of 29 patients with 37 complex primary THA in which an extensile approach was used. The extensile approach is described. Functional scores were collected in case the patient was ambulatory independently (n = 17). RESULTS: The average age was 35 years (range 15-85) with a mean follow-up of 39 months (range 12-60). There were 3 (8%) intra-operative and 4 (11%) early post-operative complications (<3 months), of which 3 (8%) were anterior dislocations. Late complications (>3 months) consisted of a fibrous ingrown stem, a socket loosening following a pelvic fracture, and a late hematogenous infection (8%). Seventy-one percent of the complications occurred in the first 18 cases (49%) indicating a learning curve. The mean post-operative Harris Hip Score was 79 (range 56-97). CONCLUSION: Complex THA can be safely conducted through the extensile anterior approach on a regular operating room table with the use of conventional implants, even in cases with a high risk of dislocation. PMID- 28087160 TI - MRI, Retrieval Analysis, and Histologic Evaluation of Adverse Local Tissue Reaction in Metal-on-Polyethylene Total Hip Arthroplasty. AB - BACKGROUND: The severity and location of adverse local tissue reaction (ALTR) seen in metal-on-polyethylene total hip arthroplasty (THA) is not well described. METHODS: We retrospectively reviewed the records of patients who underwent a revision THA using our biomechanics database. We included all patients who underwent revision surgery for the diagnosis of ALTR with THA implants that had modularity solely at the head-neck junction and excluded patients with implant modularity at sites other than the head-neck junction. Magnetic resonance imaging (MRI) was evaluated by a fellowship-trained radiologist who specializes in evaluating metal artifact reducing MRI sequences to quantify the ALTR lesions. Histology was evaluated for findings of ALTR using the Campbell score. RESULTS: We identified 11 patients in the database. Eight patients had an MRI ALTR grade of severe and 7 did based on the histology score. The mean synovial volume was 218,658 mm3 (range 23,461-451,435 mm3) with a mean maximal synovial thickness of 15.3 mm (range 3-34.3 mm). A disruptive infiltration of the abductors due to pseudocapsule invasion was seen in 67% of the patients with 3 not having abductor involvement. Mean preoperative cobalt and chromium levels were 5.4 ppb (range 1 12.3 ppb) and 1.1 ppb (range 0.6-2.4 ppb), respectively. CONCLUSION: Patients with ALTR from head-neck junction corrosion in metal-on-polyethylene THA may present with large pseudotumors that have previously been under appreciated. Mean preoperative serum cobalt and chromium ion levels remained relatively low, and MRI was an effective way to characterize the size and location of these lesions. PMID- 28087161 TI - Effect of Acetabular Position on Polyethylene Liner Wear Measured Using Simultaneous Biplanar Acquisition. AB - BACKGROUND: Studies that have previously examined the relationship between acetabular component inclination angle and polyethylene wear have shown increased wear of conventional polyethylene with high inclination angles. To date, there are no long-term in vivo studies examining the correlation between cup position and polyethylene wear with highly crosslinked polyethylene. METHODS: An institutional arthroplasty database was used to identify patients who had metal on-highly crosslinked polyethylene primary total hip arthroplasty using the same component design with a minimum follow-up of 10 years. A modified radiostereometric analysis examination setup was utilized, recreating standard anteroposterior and cross-table lateral examinations in a single stereo radiostereometric analysis acquisition. The same radiographs were used to measure inclination angle and anteversion. RESULTS: A total of 43 hips were included for analysis in this study. Average follow-up was 12.3 +/- 1.2 years. The average linear wear rate was calculated to be 0.066 +/- 0.066 mm/y. Inclination angle was not correlated with polyethylene wear rate (P = .82). Anteversion was also not correlated with polyethylene wear rate (P = .11). CONCLUSION: At long-term follow up of >10 years, highly crosslinked polyethylene has a very low wear rate. This excellent tribology is independent of acetabular position. The low wear rate highlights the excellent results of metal on highly crosslinked polyethylene, and supports its use in total hip arthroplasty. PMID- 28087163 TI - Clinical Studies of Ex Vivo Expansion to Accelerate Engraftment After Umbilical Cord Blood Transplantation: A Systematic Review. AB - Cell dose limits greater use of umbilical cord blood (UCB) in hematopoietic cell transplantation. The clinical benefits of ex vivo expansion need clarity to understand its potential impact. A systematic search of studies addressing UCB ex vivo expansion was conducted. Fifteen clinical studies (349 transplanted patients) and 13 registered trials were identified. The co-infusion of an expanded unit and a second unmanipulated unit (8 studies), the fractional expansion of 12% to 60% of a single unit (5 studies), and the infusion of a single expanded unit (2 studies) were reported. More recently, published studies and 12 of 13 ongoing trials involve the use of novel small molecules in addition to traditional cytokine cocktails. Higher total cell number was closely associated with faster neutrophil engraftment. Compared with historical controls, neutrophil engraftment was significantly accelerated in more recent studies using small molecules or mesenchymal stromal cells (MSC) co-culture, and in some cases, platelet recovery was also statistically improved. Recent studies using nicotinamide and StemRegenin-1 reported long-term chimerism of the expanded unit. No significant improvement in survival or other transplant-related outcomes was demonstrated for any of the strategies. Ex vivo expansion of UCB can accelerate initial neutrophil engraftment after transplant. More recent studies suggest that long-term engraftment of ex vivo expanded cord blood units is achievable. Results of larger randomized controlled trials are needed to understand the impact on patient outcomes and health care costs. PMID- 28087162 TI - miR-24 Inhibition Increases Menin Expression and Decreases Cholangiocarcinoma Proliferation. AB - Menin (MEN1) is a tumor-suppressor protein in neuroendocrine tissue. Therefore, we tested the novel hypothesis that menin regulates cholangiocarcinoma proliferation. Menin and miR-24 expression levels were measured in the following intrahepatic and extrahepatic cholangiocarcinoma (CCA) cell lines, Mz-ChA-1, TFK 1, SG231, CCLP, HuCCT-1, and HuH-28, as well as the nonmalignant human intrahepatic biliary line, H69. miR-24 miRNA and menin protein levels were manipulated in vitro in Mz-ChA-1 cell lines. Markers of proliferation and angiogenesis (Ki-67, vascular endothelial growth factors A/C, vascular endothelial growth factor receptors 2/3, angiopoietin 1/2, and angiopoietin receptors 1/2) were evaluated. Mz-ChA-1 cells were injected into the flanks of nude mice and treated with miR-24 inhibitor or inhibitor scramble. Menin expression was decreased in advanced CCA specimens, whereas miR-24 expression was increased in CCA. Menin overexpression decreased proliferation, angiogenesis, migration, and invasion. Inhibition of miR-24 increased menin protein expression while decreasing proliferation, angiogenesis, migration, and invasion. miR-24 was shown to negatively regulate menin expression by luciferase assay. Tumor burden and expression of proliferative and angiogenic markers was decreased in the miR 24 inhibited tumor group compared to controls. Interestingly, treated tumors were more fibrotic than the control group. miR-24-dependent expression of menin may be important in the regulation of nonmalignant and CCA proliferation and may be an additional therapeutic tool for managing CCA progression. PMID- 28087164 TI - Anatomic study and electromyographic analysis of the teres minor muscle. AB - BACKGROUND: The teres minor muscle is a focused topic on the treatment of massive rotator cuff tears and reverse total shoulder arthroplasty. Its precise anatomy and function have not been completely investigated. The purposes of this study were to anatomically investigate the muscle and analyze electromyographic (EMG) activities during shoulder motion. METHODS: This anatomic study used 20 shoulders from deceased donors (mean age, 75.0 years). EMG data were recorded from 10 healthy volunteers (mean age, 21.7 years) during flexion, abduction, and external rotations at 0 degrees of abduction, at 90 degrees of abduction, and at 90 degrees of flexion in their dominant arms synchronized with a computerized 3 dimensional motion analysis system. RESULTS: The muscle in all specimens consisted of 2 distinct muscular bundles: the upper and lower portions. The upper portion attached to the round area of the greater tuberosity, and the lower portion inserted into the linear shaped area. Both portions were independent in their origins, insertions, and innervation. The muscle engaged force during each shoulder motion. EMG activities of abduction and the 3 forms of external rotation were similar. Maximal voluntary contraction in the 3 forms of external rotation was 32% in maximum external rotation in the neutral position, 25% in flexion, and 40% in abduction. CONCLUSIONS: The teres minor consists of independent upper and lower portions. The muscle engages force in all ranges of 5 shoulder motions, and maximum external rotation in abduction is a reliable method to evaluate potential activity of the muscle. PMID- 28087165 TI - Radiographic comparison of adolescent athletes with elbow osteochondritis dissecans to ulnar collateral ligament injuries and controls. AB - BACKGROUND: There are excellent data supporting recommendations to prevent elbow injuries (osteochondritis dissecans [OCD] and ulnar collateral ligament [UCL] injuries), such as pitch count and pitch type in baseball, but anatomic risk factors have not been thoroughly examined. This study aimed to evaluate radiographic measurements in adolescents with elbow OCD lesions or UCL injuries and controls. METHODS: We retrospectively identified adolescent patients between 2011 and 2016 with isolated capitellum OCD, UCL tear, or normal elbows based on magnetic resonance imaging. Nineteen patients (mean age, 13.5 years) had isolated OCD defects of the capitellum, 8 patients (mean age, 16.9 years) had isolated UCL complete tear, and the remaining 16 patients (mean age, 14.6 years) were normal controls. Radiographic measurements from corresponding anterior-posterior elbow radiographs were taken, including carrying angle, distal humeral articular surface angle, and radial neck-shaft angle. On the lateral radiograph, anterior angulation of the articular surface of distal humerus was measured. RESULTS: Significant differences were observed in carrying angle between controls (15.7 degrees ) and OCD patients (11.6 degrees ; P = .03) as well as between controls and UCL patients (10.3 degrees , P = .02), with the OCD and UCL patients tending to be in more varus. Significant differences were also found between controls (88.5 degrees ) and OCD patients (93.6 degrees ; P = .01) and between controls and UCL patients (93.3 degrees ; P = .03) in distal humeral articular surface angle, with OCD and UCL patients with increased valgus at the distal humerus articular surface. There were no significant differences between groups in radial neck-shaft angle or anterior angulation of articular surface of distal humerus. CONCLUSIONS: Patients with OCD and UCL injuries have anatomic differences compared with normal controls that can be measured radiographically. PMID- 28087166 TI - Future surgery after revision shoulder arthroplasty: the impact of unexpected positive cultures. AB - BACKGROUND: The clinical implications and treatment of unexpected positive cultures (UPCs) in revision shoulder arthroplasty are not well defined. The purpose of this study was to describe results of patients with and without UPCs after revision shoulder arthroplasty. METHODS: A single institutional database was used to retrospectively identify all revision shoulder arthroplasties performed between January 1, 2011, and December 31, 2013. Patients with preoperative suspicion of infection were excluded. Multivariable regression analysis was used to identify risk factors for future surgery after revision shoulder arthroplasty. RESULTS: There were 117 revision shoulder arthroplasties without preoperative suspicion of infection. There were 28 of 117 (23.9%) with UPCs, of which 15 (57.1%) were Propionibacterium acnes; 18 of 28 (64.3%) patients received antibiotics for 6 weeks postoperatively without complications compared with 10 of 28 (35.7%) who received a routine 2-week empirical antibiotic regimen; 2 of 28 (7.1%) patients with UPCs required future surgery, and only 1 (3.6%) had a recurrent infection. Comparatively, 18 of 89 (20.2%) patients without UPCs (P = .109) required 25 additional surgeries. Average time to UPC was 4.3 years after index revision. Multivariable regression analysis of patient demographics, comorbidities, surgical procedure, and presence of UPCs found no independent predictors of reoperation. DISCUSSION: Nearly one-quarter of our institution's revision shoulder arthroplasties had UPCs. The patients without UPCs had a nonsignificantly higher risk of reoperation compared with those with UPCs. We did not identify clinical or demographic variables that independently correlated with reoperation. Further study will be necessary to determine the true clinical benefit of routine culture acquisition in cases with low suspicion for prosthetic joint infection. PMID- 28087168 TI - Synthesis, structure-activity relationships studies of benzoxazinone derivatives as alpha-chymotrypsin inhibitors. AB - A series of benzoxazinones 1-28 were synthesized via reaction of anthranilic acid with various substituted benzoyl chlorides in the presence of triethylamine in chloroform. Compounds 1-18 showed a good inhibition of alpha-chymotrypsin with IC50+/-SEM values between 6.5 and 341.1MUM. Preliminary structure-activity relationships studies indicated that the presence of substituents on benzene ring reduces the inhibitory potential of benzoxazinone. Also the increased inhibitory potential due to fluoro group at phenyl substituent was observed followed by chloro and bromo substituents. Compounds with strong electron donating or withdrawing groups on phenyl substituent, showed a good inhibitory potential at ortho>meta>para position. Kinetics studies showed diverse types of inhibition, except uncompetitive-type inhibition. The Ki values ranged between 4.7 and 341.2MUM. Interestingly, most of these compounds were non-cytotoxic to 3T3 cell line at 30MUM, except compounds 6, 14 and 15. Competitive inhibitors of chymotrypsin are like to inhibit other alpha-chymotrypsin-like serine proteases due to structural and functional similarities between them. The inhibitors identified during the current study deserve to be further studied for their therapeutic potential against abnormalities mediated by chymotrypsin or other serine protease. PMID- 28087167 TI - Lingering Questions about Enhancer RNA and Enhancer Transcription-Coupled Genomic Instability. AB - Intergenic and intragenic enhancers found inside topologically associated regulatory domains (TADs) express noncoding RNAs, known as enhancer RNAs (eRNAs). Recent studies have indicated these eRNAs play a role in gene regulatory networks by controlling promoter and enhancer interactions and topology of higher-order chromatin structure. Misregulation of enhancer and promoter associated noncoding RNAs (ncRNAs) could stabilize deleterious secondary DNA structures, noncoding RNA associated DNA/RNA hybrid formation, and promote collisions of transcription complexes with replisomes. It is revealing that many chromosomal aberrations, some associated with malignancies, are present inside enhancer and/or promoter sequences. Here, we expand on current concepts to discuss enhancer RNAs and enhancer transcription, and how enhancer transcription influences genomic organization and integrity. PMID- 28087169 TI - Antibiotic knowledge and self-medication practices in a developing country: A cross-sectional study. AB - BACKGROUND: Self-medication is identified by the World Health Organization as a major factor leading to antibiotics overuse, misuse and resistance. This study's objectives were to evaluate the knowledge and self-medication with antibiotics in a sample of the population of Lebanon. METHODS: This study surveyed a sample of adults (over 18 years of age) residing in 2 major cities in Lebanon about their knowledge and self-medication with antibiotics. Health care professionals were excluded from the study. RESULTS: Four hundred questionnaires were completed. Of the responders, 72% were between 18 and 45 years of age with an overall 86% having completed at least high school. For their knowledge about antibiotics, 61% thought that antibiotics should be taken for common cold and 83% knew that misuse of antibiotics could result in microbial resistance. Self-medication significantly correlated with a lower educational level (P = .036). Those with lower knowledge about antibiotics stopped antibiotics at the inappropriate time (P = .002). Socioeconomic status, gender and age did not correlate with self medication. CONCLUSION: Self-medication was associated with a person's educational level and knowledge of antibiotics. Awareness campaigns and enforcing medication dispensing laws are needed in to avoid self-medication with antibiotics. PMID- 28087170 TI - Clostridium difficile rates in asymptomatic and symptomatic hospitalized patients using nucleic acid testing. AB - BACKGROUND: The Clostridium difficile rate in symptomatic patients represents both those with C. difficile infection (CDI) and those with colonization. To predict the extent of CDI overdiagnosis, we compared the asymptomatic colonization rate to the symptomatic positivity rate in hospitalized patients using nucleic acid testing. METHODS: Between July 2014 and April 2015, formed stool samples were collected from asymptomatic patients after admission to 3 hospital wards at the Stanford Hospital. Stool samples from symptomatic patients with suspected CDI in the same wards were collected for testing per provider order. The GeneXpert C. difficile tcdB polymerase chain reaction (PCR) assay (Cepheid, Sunnyvale, CA, USA) was performed on all stool samples and PCR cycle threshold was used as a measure of genomic equivalents. Chart review was performed to obtain clinical history and medication exposure. RESULTS: We found an asymptomatic C. difficile carriage rate of 11.8% (43/365) (95% confidence interval [CI], 8.5-15.1%) and a positivity rate in symptomatic patients of 15.4% (54/351) (95% CI, 11.6-19.2%; P=0.19). The median PCR cycle thresholds was not significantly different between asymptomatic carriers and symptomatic positives (29.5 versus 27.3; P=0.07). Among asymptomatic patients, 11.6% (5/43) of carriers and 8.4% (27/322; P=0.56) of noncarriers subsequently became symptomatic CDI suspects within the same hospitalization. Single and multivariate analysis did not identify any demographic or clinical factors as being significantly associated with C. difficile carriage. CONCLUSIONS: Asymptomatic C. difficile carriage rate was similar to symptomatic positivity rate. This suggests the majority of PCR-positive results in symptomatic patients are likely due to C. difficile colonization. Disease-specific biomarkers are needed to accurately diagnose patients with C. difficile disease. PMID- 28087171 TI - A propensity score-matched analysis of the impact of minimum inhibitory concentration on mortality in patients with Pseudomonas aeruginosa bacteremia treated with cefepime or ceftazidime. AB - The United States Clinical and Laboratory Standards Institute recently elected not to revise ceftazidime and cefepime Pseudomonas aeruginosa minimum inhibitory concentration (MIC) susceptibility breakpoints but rather recommended specific dosage regimens to correspond to breakpoints. This study's objective was to examine mortality of low and high MIC P. aeruginosa isolates in bacteremic patients treated with cefepime or ceftazidime. Data were gathered through a Veterans Health Administration national administrative database for veterans with P. aeruginosa blood cultures who received cefepime or ceftazidime. Seventy-four patients in the low MIC (<=2 MUg/mL) group and 29 patients in the high (4-8 MUg/mL) MIC group were included. Independent baseline variables associated with 30-day all-cause mortality were determined through multivariate analysis to calculate propensity scores and perform matching. All-cause 30-day mortality was not statistically significant between the 2 resultant propensity score-matched groups (17.2% mortality in the low MIC group versus 27.6% in the high MIC group; P=0.34). Data suggested that P. aeruginosa bacteremia episodes where the cephalosporin MIC = 8 MUg/mL may have higher mortality, however this may be reflective of higher propensity scores. Our study suggests that it is reasonable to designate a cefepime or ceftazidime MIC <=8 MUg/mL as susceptible for P. aeruginosa bacteremia infections, but potential suboptimal outcomes in episodes for which the P. aeruginosa MIC is 8 MUg/mL may need further investigation. PMID- 28087172 TI - Endothelial function impairment in STEMI patients with out-of-hospital cardiac arrest under therapeutic hypothermia treatment. AB - BACKGROUND: Therapeutic hypothermia (HT) in out-of-hospital cardiac arrest STEMI patients aims to improve their neurological prognosis, but it has been associated with slow coronary flow and cardiac thrombotic events. We sought to serially assess endothelial function during the first 48h after admission in out-of hospital cardiac arrest STEMI patients, under therapeutic hypothermia (HT). METHODS: From January 2015 to August 2015, eighteen consecutive out-of-hospital cardiac arrest STEMI patients eligible for primary PCI received HT at admission and were included in the study (HT group). During the same time period, eight consecutive patients with large anterior STEMI who received primary PCI but not HT were included as control group. Serial endothelial function by measuring flow mediated dilatation (FMD) in the brachial artery, biomarkers of endothelial function and oxidative stress were assessed during the first 48h after admission in both groups. RESULTS: HT group showed worse FMD as compared to the control group (p<0.001). Glutathione peroxidase-3 (GPx-3) values were higher in control as compared to HT group (p=0.019), without any interaction between time of observation and HT (p=0.864). A significant interaction between time and HT was found in the levels of sVCAM-1, which reached an earlier peak in control than in HT group (p=0.019). ET-1 values generally increase overtime (p=0.005), but without any main effect of HT (p=0.175). CONCLUSIONS: HT is associated with endothelial dysfunction in out-of-hospital cardiac arrest STEMI patients during the first 48h after admission. This vascular dysfunction may be related to increased oxidative stress due to deficiency of GPx-3 in HT patients. PMID- 28087174 TI - HGDB: A web retrieving cardiovascular-associated gene data. AB - BACKGROUND: The use of data obtained from high throughput techniques in genetics studies is an essential subject in biology. The system approaches of networking and enriching may improve the data management. Here, we annotated the molecular features for cardiovascular-associated genes and presented the HGDB search-based database (www.hgdb.ir). METHODS: The initial seed data was primarily used from Gene Ontology and was automatically enriched with other molecular features. The data was managed in a SQL popular and open source. RESULTS: The search tabs on the HGDB homepage were applied for ID/Name Gene, chromosome, cell organelle and all gene options. The search results were presented on the gene text-based and source link-based descriptions. CONCLUSIONS: The HGDB is a friendly website to present gene data in the cardiovascular field. PMID- 28087173 TI - At the heart of the problem - A person-centred, developmental perspective on the link between alcohol consumption and cardio-vascular events. AB - INTRODUCTION: The cardio-protective effect of alcohol has been the subject of a long-standing scientific controversy. Emerging evidence remains equivocal, as the validity of the dose-dependent J-shape association is tainted by conceptual, theoretical and methodological problems. A major impediment for a resolution on the matter is the lack of a life-long developmental approach to pinpoint alcohol's specific impact on the risk for cardio-vascular events (CVE). OBJECTIVE: Using retrospective and prospective individual-level data of alcohol consumption (AC) we applied a model-based clustering technique to uncover life course trajectories of AC and explored their links to CVE. METHODS: Data stemmed from a random sub-cohort of a large-scale, longitudinal study conducted in the Netherlands (N=2288). Group Based Trajectory Model (GBTM) was applied to extract distinct progressions of AC over time. Stratified by sex, the association between the developmental trajectories and CVE was examined with multiple logistic regression models, with adjustment for traditional risk factors. RESULTS: GBTM analysis laid bare the heterogeneity of AC dynamics over the life-course, reiterating sex differences in drinking habits and CVE risk. AC temporal behaviors during adolescence and adulthood were diverse, but showed relative stability in in middle-age and elderly years. For males, adjusted odds for CVE differed among the uncovered developmental classes. CONCLUSIONS: The findings elicited supportive evidence for a J-shape, but with a new twist. Besides moderation the results indicate that onset, timing, duration and stability of AC over the life-course are major aspects to be accounted for when attempting to elucidate alcohol's cardio-vascular role. PMID- 28087175 TI - Continuous improvement in outcome after heart transplantation - Long-term follow up after three decades of experience. AB - AIMS: Heart transplantation (HTx) has become the standard treatment for patients with end-stage heart disease. We report on the long-term outcome after HTx at our centre and investigate trends in outcome over time. METHODS: During the period, between 1984 and 2014, a total of 610 HTx procedures were performed in 595 patients (median 48years; IQR 31-57years; range 24days-71years; mean 43years; 75% male) in our institution. Long-term outcome was investigated in the whole cohort, among children (n=76), bridged with mechanical circulatory support (MCS, n=131), re-transplanted (n=17), and concomitant kidney transplantation (n=12). RESULTS: Long-term survival was at 1, 5, 10, 15 and 20years: 86% (95CI 0.83-0.89); 77% (95CI 0.73-0.80); 63% (95CI 0.59-0.68); 48% (95CI 0.43-0.54) and 30% (95CI 0.25 0.36), respectively. The median survival for the whole cohort was 14.1years. Patients transplanted during the most recent time period (2010-2014) had a better survival compared to previous eras, with a 1- and 3-year survival of 94% (95CI 0.89-0.97) and 93% (95CI 0.88-0.96), respectively (p<0.001). However, when survival was analysed for long-term MCS (n=80) versus short term MCS (n=35), there was a significantly poorer survival for the short-term MCS group (p=0.001). Independent predictors of long-term mortality included recipient age (p=0.041); previous smoking (p=0.034); ischemic heart disease (p=0.002); and preoperative ventilator therapy (p=0.004). CONCLUSIONS: We have shown that continuous improvement in outcome after HTx still occurs. In the last time era, direct transplantation from short-term MCS was abandoned, which may have inflicted outcome during the last time era. PMID- 28087177 TI - Lymphocytic myocarditis occurs with myocardial infarction and coincides with increased inflammation, hemorrhage and instability in coronary artery atherosclerotic plaques. AB - OBJECTIVE: Although lymphocytic myocarditis (LM) clinically can mimic myocardial infarction (MI), they are regarded as distinct clinical entities. However, we observed a high prevalence (32%) of recent MI in patients diagnosed post-mortem with LM. To investigate if LM changes coronary atherosclerotic plaque, we analyzed in autopsied hearts the inflammatory infiltrate and stability in coronary atherosclerotic lesions in patients with LM and/or MI. METHODS: The three main coronary arteries were isolated at autopsy of patients with LM, with MI of 3-6h old, with LM and MI of 3-6h old (LM+MI) and controls. In tissue sections of atherosclerotic plaque-containing coronary segments inflammatory infiltration, plaque stability, intraplaque hemorrhage and thrombi were determined via (immuno)histological criteria. RESULTS: In tissue sections of those coronary segments the inflammatory infiltrate was found to be significantly increased in patients with LM, LM+MI and MI compared with controls. This inflammatory infiltrate consisted predominantly of macrophages and neutrophils in patients with only LM or MI, of lymphocytes in LM+MI and MI patients and of mast cells in LM+MI patients. Moreover, in LM+MI and MI patients this coincided with an increase of unstable plaques and thrombi. Finally, LM and especially MI and LM+MI patients showed significantly increased intraplaque hemorrhage. CONCLUSIONS: This study demonstrates prevalent co-occurrence of LM with a very recent MI at autopsy. Moreover, LM was associated with remodeling and inflammation of atherosclerotic plaques indicative of plaque destabilization pointing to coronary spasm, suggesting that preexistent LM, or its causes, may facilitate the development of MI. PMID- 28087176 TI - Carotid plaque detection improves the predictive value of CHA2DS2-VASc score in patients with non-valvular atrial fibrillation: The ARAPACIS Study. AB - BACKGROUND AND AIMS: Vascular disease (VD), as assessed by history of myocardial infarction or peripheral artery disease or aortic plaque, increases stroke risk in atrial fibrillation (AF), and is a component of risk assessment using the CHA2DS2-VASc score. We investigated if systemic atherosclerosis as detected by ultrasound carotid plaque (CP) could improve the predictive value of the CHA2DS2 VASc score. METHODS: We analysed data from the ARAPACIS study, an observational study including 2027 Italian patients with non-valvular AF, in whom CP was detected using Doppler Ultrasonography. RESULTS: VD was reported in 351 (17.3%) patients while CP was detected in 16.6% patients. Adding CP to the VD definition leaded to higher VD prevalence (30.9%). During a median [IQR] follow-up time of 36months, 56 (2.8%) stroke/TIA events were recorded. Survival analysis showed that conventional VD alone did not increase the risk of stroke (Log-Rank: 0.009, p=0.924), while addition of CP to conventional VD was significantly associated to an increased risk of stroke (LR: 5.730, p=0.017). Cox regression analysis showed that VD+CP was independently associated with stroke (HR: 1.78, 95% CI: 1.05-3.01, p=0.0318). Reclassification analysis showed that VD+CP allowed a significant risk reclassification when compared to VD alone in predicting stroke at 36months (NRI: 0.192, 95% CI: 0.028-0.323, p=0.032). CONCLUSIONS: In non-valvular AF patients the addition of ultrasound detection of carotid plaque to conventional VD significantly increases the predictive value of CHA2DS2-VASc score for stroke. PMID- 28087178 TI - Acupuncture for serum uric acid in patients with asymptomatic hyperuricemia: A randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Hyperuricemia (HUA) is the most common disease associated with cardiovascular disease, metabolic syndrome, hypertension, and kidney disease. The objective of the current study was to evaluate the preliminary efficacy, mechanism, and safety of acupuncture on serum uric acid in patients with asymptomatic HUA. METHODS: A randomized, placebo-controlled trial among 123 patients with asymptomatic HUA was conducted. The acupoints used in the acupuncture group were bilateral Five Shu in Spleen Meridian. Each participant received the intervention once daily for 10 consecutive days. The sham group received the same treatment duration on the same acupoints by the Park Sham Device. All patients underwent measurements of serum or urine creatinine, uric acid, serum lipid profiles, fasting plasma glucose, HbA1c, xanthine oxidase (XOD) and urate-anion exchanger (URAT-1). RESULTS: At the end of the intervention, the individuals in the acupuncture group were found to have significantly less levels of serum uric acid than those in the sham group [(453+/-65 vs. 528+/-81) MUmol/L, p<0.01]. Acupuncture was effective on increasing the urine uric acid level, urine pH value and 24-hour urine volume than the sham treatment (p<0.05 for all). Interestingly, acupuncture significantly decreased the level of URAT-1 (p<0.01) but not XOD than that of the sham intervention. The adverse events were that 3 patients experienced severe pain. CONCLUSIONS: Acupuncture on Five Shu in Spleen Meridian appeared to be safe and efficacious for decreasing serum uric acid in a Chinese HUA patient population. The mechanism might be associated with the decrease level of enzyme URAT-1. CHINESE CLINICAL TRIAL REGISTRATION: ChiCTR-TRC 13004122. PMID- 28087179 TI - Value of serum N-terminal B-type natriuretic peptide in asymptomatic structural heart disease in Taiwanese population: Comparisons with current ESC Guidelines. AB - BACKGROUND: The relationship between N-terminal pro-brain natriuretic peptide (NT proBNP) and cardiac structural or functional anomalies in pre-clinical, asymptomatic Asian populations has not been well identified. METHODS: From October 2005 to March 2008, we enrolled consecutive asymptomatic adults with preserved global left ventricular (LV) function (ejection fraction>50%) who underwent annual cardiovascular health survey. Circulating NT-proBNP was used to identify echo-defined cardiac structural/functional anomalies and compared to current recommended cut-off from the European Society of Heart Failure. RESULTS: Among 976 eligible subjects, 371 (38%) had structural heart diseases. Echocardiography-based left atrial diameter (Coef: 71.2), diastolic dysfunction (Coef: 35.4), and presence of pulmonary hypertension (Coef: 83.1) or valvular heart disease (Coef: 56.1, all p<0.05) of any form independently predicted circulating NT-ProBNP. NT-ProBNP cut-off values of 32.8 and 115.4pg/ml for subjects aged <= and >75years, respectively, demonstrated areas under the receiver operating characteristic curve of 0.76 (95% CI: 0.73-0.80) and 0.70 (95% CI: 0.52-0.88) for predicting structural or functional anomaly. CONCLUSION: We examined the feasibility of NT-ProBNP for identifying cardiac structural and functional anomaly in an asymptomatic ethnic Taiwanese population with a relatively lower cut-off value, indicating its potential role for pre-clinical screening of Asian patients. PMID- 28087180 TI - A comparison of HFrEF vs HFpEF's clinical workload and cost in the first year following hospitalization and enrollment in a disease management program. AB - BACKGROUND: Admission with heart failure (HF) is a milestone in the progression of the disease, often resulting in higher intensity medical care and ensuing readmissions. Whilst there is evidence supporting enrolling patients in a heart failure disease management program (HF-DMP), not all reported HF-DMPs have systematically enrolled patients with HF with preserved ejection fraction (HFpEF) and there is a scarcity of literature differentiating costs based on HF phenotype. METHODS: 1292 consenting, consecutive patients admitted with a primary diagnosis of HF were enrolled in a hospital based HF-DMP and categorized as HFpEF (EF>=45%) or HFrEF (EF<45%). Hospitalizations, primary care, medications, and DMP workload with associated costs were evaluated assessing DMP clinic-visits, telephonic contact, medication changes over 1year using a mixture of casemix and micro-costing techniques. RESULTS: The total average annual cost per patient was marginally higher in patients with HFrEF ?13,011 (12,011, 14,078) than HFpEF, ?12,206 (11,009, 13,518). However, emergency non-cardiovascular admission rates and average cost per patient were higher in the HFpEF vs HFrEF group (0.46 vs 0.31 per patient/12months) & ?655 (318, 1073) vs ?584 (396, 812). In the first 3months of the outpatient HF-DMP the HFrEF population cost more on average ?791 (764, 819) vs ?693 (660, 728). CONCLUSION: There are greater short-term (3-month) costs of HFrEF versus HFpEF as part of a HF-DMP following an admission. However, long-term (3-12month) costs of HFpEF are greater because of higher non cardiovascular rehospitalisations. As HFpEF becomes the dominant form of HF, more work is required in HF-DMPs to address prevention of non-cardiovascular rehospitalisations and to integrate hospital based HF-DMPs into primary healthcare structures. PMID- 28087181 TI - Challenging the 99th percentile: A lower troponin cutoff leads to low mortality of chest pain patients. AB - BACKGROUND: Rule-out of non-ST-elevation myocardial infarction is based on consecutive measurements of cardiac troponins using the 99th percentile of the respective assay as cutoff. The new ESC guidelines alternatively offer rapid 1h algorithms with lower cutoffs than the 99th percentile for rule-out of non-ST elevation myocardial infarction. We aimed to compare a recently introduced 1h algorithm based on a high-sensitivity cardiac troponin I (hs-TnI) cutoff of 6ng/L at 0h and 1h to the current standard of care using the 99th percentile (27ng/L) as cutoff with reference to follow-up events in a large chest pain cohort. METHODS: Hs-TnI was measured at three time points (0h, 1h and 3h) in 1625 patients presenting with suspected myocardial infarction to the emergency department of the University-Medical Center Hamburg-Eppendorf. Seventy-five patients with ST-elevation myocardial infarction were excluded from the analysis. All-cause mortality, cardiac death, acute myocardial infarction, revascularization and cardiac rehospitalization after 12months were assessed. RESULTS: Patients ruled out by the 1h algorithm showed significantly less cardiac rehospitalizations (12.84% vs. 17.66%; p<0.001), and overall mortality (1.30% vs 3.46%, p<0.001) compared to using the 99th percentile as cutoff. The majority of deaths were caused by non-cardiac reasons. Cardiac deaths were rare using the 1h algorithm (0.21%). CONCLUSION: The commonly used 99th percentile as cutoff neglects patients with a high risk in the setting of acute chest pain. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT02355457). PMID- 28087182 TI - Multimorbidity and acute heart failure in internal medicine. AB - AIMS: To analyse the characteristics of hospitalized patients for AHF, with special attention to the clustering of morbidities. METHODS AND RESULTS: Clinical records of patients, admitted in Internal Medicine due to AHF, during three years, were reviewed. The characteristics of patients-episodes were registered and key indicators of performance. Multiple correspondence analysis (MCA) was used to assess the distribution of morbidities. LR models were used to study clinical variables related with death or readmission. The median age was 80y, predominantly women and with multiple morbidities. As it was expected, CVRF were the main associated comorbidities followed by respiratory diseases, CKD and chronic anaemia. In the MCA, all the CVRF clustered around the origin so they explained little of the total inertia. Male sex, young age, IHD, obesity and lung disease were more common in reduced EF whereas female, older age and thyroid disease were more common in preserved EF. The confidence ellipses for death in hospitalization or during the follow-up or for readmissions overlapped, so it was not possible to identify clusters of morbidities to predict outcomes. The main causes for AHF were infections, anaemia and RVR in AF. Nearly 16% died during the hospitalization whereas 25.6% died and 56.3% were re-hospitalized during the following year after the discharge. Previous or repeated admissions to the hospital were the best single predictors for death or readmission. CONCLUSIONS: Strategies to control infections, anaemia and AF, in the outpatient settings, might help to reduce the burden of AHF, although this remains to be proven. PMID- 28087183 TI - Co-expression of tissue factor and IL-6 in immature endothelial cells of cerebral cavernous malformations. AB - Cerebral cavernous malformations (CCMs) are congenital abnormal clusters of capillaries that are prone to leaking and thought to result from a disorder of endothelial cells. The underlying pathology of CCM is not fully understood. We analyzed the expression of tissue factor (TF) and interleukin-6 (IL-6) in CCMs to determine the association of TF and IL-6 with clinical and pathological findings. Thirteen cases of operative specimens of sporadic CCMs were included in this study. The expression of messenger RNA of TF and IL-6 was assayed and the association with clinical factors was investigated. Then, the distribution of TF and IL-6 was examined with immunofluorescence. The mRNA expression of TF of CCMs was significantly higher than that of the control (p=0.017), and was correlated with the number of hemorrhage appearances (p=0.190, rho=0.62). The mRNA expression level of IL-6 was significantly correlated with the mRNA expression level of TF (p=0.034, rho=0.58). Examination of immunostained sections indicated that TF+ cells were also positive for IL-6, and distributed around normal endothelial cells. Moreover, the TF+/IL-6+ cells expressed CD31 and VEGFR2. The expressions of IL-6 and TF were correlated, and both were present in the same immature endothelial cells. TF is elevated in CCM and might mediate progressive events. These factors may play a prognostic role in CCM. PMID- 28087184 TI - Clinical characteristics of ruptured distal middle cerebral artery aneurysms: Review of the literature. AB - Middle cerebral artery (MCA) aneurysms usually arise at the primary MCA bifurcation or trifurcation. Distal MCA aneurysms are rarely considered as sources of aneurysmal subarachnoid hemorrhage (SAH). It has been reported that ruptured distal MCA aneurysms are associated with head trauma, neoplastic emboli, arterial dissection, or bacterial infection. We experienced five cases of ruptured distal MCA aneurysms and evaluated their clinical characteristics. Retrospective analysis of aneurysmal SAH at Kobayashi Neurosurgical Neurological Hospital was performed from January, 2004 to December, 2014. Clinical characteristics of ruptured distal MCA aneurysms were analyzed using our database. Among 191 aneurysmal SAH patients, there were five ruptured distal MCA aneurysms. All patients did not have any specific medical problems such as infectious disease, head trauma, or cardiac disorders. The incidence of ruptured distal MCA aneurysm was higher than expected and was equivalent to 9.4% of the total ruptured MCA aneurysms. Strong male predominance (80%) and M2-3 junction aneurysm preponderance (80%) were observed. In addition, there were only two patients (40%) with intracerebral hematoma in our study. We reported five cases of ruptured distal MCA aneurysms. Although ruptured distal MCA aneurysms are thought to be rare as sources of aneurysmal SAH, the incidence of ruptured distal MCA aneurysm was 9.4% of all ruptured MCA aneurysms in our study. Ruptured distal MCA aneurysms should be considered as sources of aneurysmal SAH without intracerebral hematoma. PMID- 28087185 TI - The filum terminale internum and externum: A comprehensive review. AB - INTRODUCTION: The filum terminale has oven been overlooked in the literature probably due to its small size and historical lack of research on its true morphology. However, this structure's roll in the tethered cord syndrome has become more apparent. Therefore, the current comprehensive review seemed timely. METHODS: Using standard search engines, the history, embryology, anatomy, pathology and surgery of the filum terminale were reviewed. CONCLUSIONS: It is only recently that the true anatomy and pathological involvement of the filum terminale in the tethered cord syndrome have been elucidated. PMID- 28087186 TI - Spontaneous subdural haemorrhage due to meningioma in the post-partum setting. AB - An acute presentation of a meningioma with spontaneous haemorrhage is rare, with mechanisms of haemorrhage remaining unclear. Here, we present a case of a meningioma causing spontaneous intra-tumoural and subdural haemorrhage in the post-partum setting, to our knowledge not previously described, with review of pertinent literature. PMID- 28087187 TI - Gender ratio trends over time in multiple sclerosis patients from Argentina. AB - : Several studies in multiple sclerosis (MS) suggest a trend of increasing disease frequency in women during the last decades. A direct comparison of gender ratio trends among MS populations from Argentina remains to be carried out. The objective of the study was to compare gender ratio trends, over a 50-year span in MS populations from Argentina. METHODS: multicenter study that included patients from 14 MS Centers of Argentina. Patients with definite MS with birth years ranging from 1940 to 1989 were included. Gender ratios were calculated by five decades based on year of birth and were adjusted for the F/M born-alive ratio derived from the Argentinean national registry of births. The F/M ratios were calculated using a multivariate logistic regression per five decades by the year of birth approach. Analyses were performed using Stata 10.1. RESULTS: 1069 patients were included. Gender ratios showed a significant increase from the first to the last decade in the whole MS sample (from 1.8 to 2.7; p value for trend=0.023). The Gender ratio did not show differences considering MS subtype. CONCLUSION: our study showed a modest increase of the F/M ratio (from 1.8 to 2.7) over time among patients affected by MS in Argentina. PMID- 28087188 TI - Operative fusion of multilevel cervical spondylotic myelopathy: Impact of patient demographics. AB - Cervical spondylotic myelopathy (CSM) is the most common cause of spinal cord dysfunction in patients older than age 55, with operative management being a widely adopted approach. Previous work has shown that private insurance status, gender and patient race are predictive of the operative approach patients receive (anterior-only, posterior-only, combined anterior-posterior). The Nationwide Inpatient Sample from 2001 to 2010 was used to assess the potential role of multilevel CSM as a contributing factor in determining which operative approach CSM patients receive, as it is rare for an anterior-only approach to be sufficient for CSM patients requiring fusion of four or more involved levels. Multivariate analyses revealed that female sex (OR=3.78; 95% CI=2.08-6.89; p<0.0001), private insurance (OR=5.02; 95% CI=2.26-11.12; p<0.0001), and elective admission type (OR=4.12; 95% CI=1.65-10.32; p=0.0025) were predictive of increased receipt of a 3+ level fusion in CSM. No other variables, including patient age, race, income, or admission source were predictive of either increased or decreased likelihood of receiving fusion of at least three levels for CSM. In conclusion, female sex, private insurance status, and elective admission type are each independent predictors in CSM for receipt of a 3+ level fusion, while patient age, race and income are not. Given the propensity of fusions greater than three levels to require posterior approaches and the association between posterior CSM approaches and increased morbidity/mortality, these findings may prove useful as to which patient demographics are predictive of increased morbidity and mortality in operative treatment of CSM. PMID- 28087189 TI - Assessment of GAPDH expression by quantitative real time PCR in blood of Moroccan AD cases. AB - INTRODUCTION: Neuroproteomics studies have showed the high affinity interactions between GAPDH - beta-amyloid in Alzheimer disease. The aim of our study is to complete our previous studies by assessing the mechanism responsible of decreased expression of GAPDH protein in the blood of Moroccan AD cases probably due to an alteration at the transcriptional level or at the post translational level. METHODS: The mRNA expression of GAPDH was assessed by quantitative real time PCR in AD cases and healthy controls. RESULTS: Our result revealed a significant difference of mRNA expression level of GAPDH in AD cases as compared to healthy controls (P<0.05). CONCLUSION: This data is consistent with several studies by showing the direct involvement of GAPDH in amyloid aggregation by undergoing several modifications, which influence its chemical structure and its biological activity. PMID- 28087190 TI - Report of a familial case of proatlas segmentation abnormality with late clinical onset. AB - Although proatlas segmentation abnormalities as developmental remnants around the foramen magnum have been reported in postmortem studies, they are rarely documented in a clinical setting. This report details the clinical and radiological characteristics of a rare case of proatlas segmentation abnormalities with clinical onset during the seventh decade of life. This case was suspected to have a familial factor. We also review the literature regarding this condition. PMID- 28087191 TI - Alterations of brain activity in fibromyalgia patients. AB - Fibromyalgia is a chronic pain syndrome, characterized by widespread musculoskeletal pain with diffuse tenderness at multiple tender points. Despite intense investigations, the pathophysiology of fibromyalgia remains elusive. Evidence shows that it could be due to changes in either the peripheral or central nervous system (CNS). For the CNS changes, alterations in the high brain area of fibromyalgia patients have been investigated but the definite mechanisms are still unclear. Magnetic Resonance Imaging (MRI) and Functional Magnetic Resonance (fMRI) have been used to gather evidence regarding the changes of brain morphologies and activities in fibromyalgia patients. Nevertheless, due to few studies, limited knowledge for alterations in brain activities in fibromyalgia is currently available. In this review, the changes in brain activity in various brain areas obtained from reports in fibromyalgia patients are comprehensively summarized. Changes of the grey matter in multiple regions such as the superior temporal gyrus, posterior thalamus, amygdala, basal ganglia, cerebellum, cingulate cortex, SII, caudate and putamen from the MRI as well as the increase of brain activities in the cerebellum, prefrontal cortex, anterior cingulate cortex, thalamus, somatosensory cortex, insula in fMRI studies are presented and discussed. Moreover, evidence from pharmacological interventions offering benefits for fibromyalgia patients by reducing brain activity is presented. Because of limited knowledge regarding the roles of brain activity alterations in fibromyalgia, this summarized review will encourage more future studies to elucidate the underlying mechanisms involved in the brains of these patients. PMID- 28087192 TI - Spontaneous peritoneal catheter knot formation: A rare cause of ventriculoperitoneal shunt malfunction. AB - Ventriculoperitoneal (VP) shunting remains invaluable in the management of hydrocephalus. It is a common procedure that can be complicated by shunt malfunction due to infection, blockage and disconnection. Spontaneous peritoneal catheter knot formation causing CSF flow obstruction is a rare phenomenon. We present a case of a 12years old boy with spontaneous knot formation in the peritoneal catheter causing VP shunt obstruction and hydrocephalus. PMID- 28087193 TI - Immunohistochemical study of Metallothionein in patients with temporal lobe epilepsy. AB - Epilepsy is characterized by spontaneous recurrent seizures and temporal lobe epilepsy (TLE) is the most common serious neurological example of acquired and frequent epilepsy. Oxidative stress is recognized as playing a contributing role in several neurological disorders, and most recently have been implicated in acquired epilepsies. The MTs occur in several brain regions and may serve as neuroprotective proteins against reactive oxygen species causing oxidative damage and stress. The main aim of this work was to describe the immunohistochemical localization of MT in the specimens derived from the patients affected by TLE. Histopathological examination showed NeuN, GFAP and MT immunopositive cells that were analyzed for determinate in hippocampal and parietal cortex samples. An increase in the reactive gliosis associated with increased MT expression was observed in patients with TLE. PMID- 28087194 TI - Fifth Terrestrial Radioisotopes in Environment - International Conference on Environmental Protection (TREICEP). PMID- 28087195 TI - Endoepicardial Ventricular Tachycardia Ablation With a New High-density Non fluoroscopic Navigation System. PMID- 28087196 TI - Improving hospital care of patients with intellectual and developmental disabilities. AB - People with intellectual disabilities and developmental disabilities (IDD) face poorer care and outcomes when hospitalized than patients without IDD. A panel discussion Hospital care for individuals with IDD: The Issues and Challenges was held at the Annual Conference of the American Academy of Developmental Medicine and Dentistry, held in Chicago July 8-10, 2016. Among the panelists were representatives from Rush University Medical Center in Chicago, IL and Saint Barnabas Medical Center in Livingston, NJ who discussed efforts to improve hospital care of patients with IDD at their institutions. Systemic changes are needed to improve care, however, programs that target improving care for patients with IDD are possible within current systems and with current staff who are empowered to make changes that improve the quality of care. PMID- 28087197 TI - MicroRNA: Defining a new niche in Leukemia. AB - MicroRNAs (miRNAs) are endogenous short non-coding RNAs found to play key roles in the pathogenesis of leukemia. Apart from being traditionally identified as modulators of oncogenes, the potential roles of miRNAs seems to be growing with novel and recent findings among different subtypes of hematological malignancies. Leukemia is one of the earliest malignancies to be linked to abnormal expression of miRNAs. However, a clear understanding of the involvement of miRNAs in intricate mechanisms of leukemogenesis is still a necessity. This review summarizes the multiple roles of miRNAs in the pathogenesis of leukemia and highlights major research findings contributing to these aspects. PMID- 28087198 TI - Cloning, characterization and transmission blocking potential of midgut carboxypeptidase A in Anopheles stephensi. AB - Transmission-blocking vaccines (TBV) interrupt malaria parasite transmission and hence form an important component for malaria eradication. Mosquito midgut exopeptidases such as aminopeptidase N & carboxypeptidase B have demonstrated TBV potential. In the present study, we cloned and characterized carboxypeptidase A (CPA) from the midgut of an important malarial vector, Anopheles stephensi. ClustalW amino acid alignment and in silico 3-dimensional structure analysis of CPA predicted the presence of active sites involved in zinc and substrate binding that are conserved among all the known mosquito species. Real-time PCR analysis demonstrated that CPA is predominantly expressed in the midgut throughout the mosquito life cycle and that this gene is significantly elevated in P. berghei infected mosquitoes compared to uninfected blood-fed controls. The high midgut CPA activity correlated with the prominent mRNA levels observed. Peptide-based anti-CPA antibodies were raised that cross-reacted specifically to ~48kDa and ~37kDa bands, which correspond to zymogen and active forms of CPA. Further, the addition of CPA-directed antibodies to P. berghei-containing blood meal significantly reduced the mosquito infection rate in the test group compared to control and blocked the parasite development in the midgut. These results support further development of A. stephensi CPA as a candidate TBV. PMID- 28087199 TI - Posttraumatic hemothorax with active bleeding: A dual origin from intercostal and pulmonary arteries should be considered. PMID- 28087200 TI - Adolescent depression and the treatment gap. PMID- 28087201 TI - Reduction in adolescent depression after contact with mental health services: a longitudinal cohort study in the UK. AB - BACKGROUND: Evidence regarding the association between service contact and subsequent mental health in adolescents is scarce, and previous findings are mixed. We aimed to longitudinally assess the extent to which depressive symptoms in adolescents change after contact with mental health services. METHODS: As part of a longitudinal cohort study, between April 28, 2005, and March 17, 2010, we recruited 1238 14-year-old adolescents and their primary caregivers from 18 secondary schools in Cambridgeshire, UK. Participants underwent follow-up assessment at months 18 and 36. Trained researchers assessed the adolescents for current mental disorder using the Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime version (K-SADS-PL). Caregivers and adolescents reported contact with mental health services in the year before baseline. Adolescents self-reported depressive symptoms (Mood and Feelings Questionnaire [MFQ]) at each timepoint. We assessed change in MFQ sum scores from baseline contact with mental health services using multilevel mixed effects regression adjusted for sociodemographic, environmental, individual, and mental health confounders, with multiple imputation of missing data. We used propensity score weighting to balance confounders between treatment (users of mental health services) and control (non-users of mental health services) groups. We implemented an MFQ clinical cutoff following the results of receiver operating characteristic analysis. FINDINGS: 14-year-old adolescents who had contact with mental health services in the past year had a greater decrease in depressive symptoms than those without contact (adjusted coefficient -1.68, 95% CI -3.22 to 0.14; p=0.033). By age 17 years, the odds of reporting clinical depression were more than seven times higher in individuals without contact than in service users who had been similarly depressed at baseline (adjusted odds ratio 7.38, 1.73 31.50; p=0.0069). INTERPRETATION: Our findings show that contact with mental health services at age 14 years by adolescents with a mental disorder reduced the likelihood of depression by age 17 years. This finding supports the improvement of access to adolescent mental health services. FUNDING: Wellcome Trust, National Institute for Health Research. PMID- 28087203 TI - The use of modified ride-on cars to maximize mobility and improve socialization-a group design. AB - AIM: To examine the effects of ride-on car (ROC) training versus conventional therapy on mobility and social function in young children with disabilities in a hospital-based environment. METHODS AND PROCEDURES: Twenty young children with disabilities, aged 1-3 years, were recruited. The treatment group (n=10) received ROC training of 2h/session, 2 sessions/week for a total of 9 weeks in the hospital environment. The control group (n=10) received conventional therapy alone. Assessments included the Chinese version of the Pediatric Evaluation of Disability Inventory and the Parenting Stress Index. OUTCOMES AND RESULTS: After a 9-week intervention, the treatment group showed improvements in mobility and social function, whereas the control group showed improvements in social function alone. Four children in the treatment group had clinically meaningful changes in mobility and 3 in social function, as compared to 2 and 1, respectively, in the control group. CONCLUSIONS AND IMPLICATIONS: This is the first group study that demonstrated the potential benefits of ROC training on mobility and social function in young children with disabilities in the hospital environment. Future studies should include a larger sample size to detect any differences between ROC training and conventional therapy. PMID- 28087202 TI - Family adaptation to cerebral palsy in adolescents: A European multicenter study. AB - BACKGROUND AND AIM: Factors promoting family adaptation to child's disability are poorly studied together. The aim of the study was to describe the family adaptation to disability and to identify determinants associated with using a global theoretical model. MATERIALS AND METHODS: 286 families of teenagers [13-17 years] with cerebral palsy (CP) from 4 European disability registers were included and visited at home. Face to face interviews were performed in order to measure parental distress, perceived impact in various dimensions of family life, family resources and stressors. Relationships were modelled with structural equations. RESULTS: 31.8% of parents living with an adolescent with CP showed clinically significant high stress requiring professional assistance. The main stressors were the level of motor impairment and behavioural disorders in adolescent. A good family functioning was the best protective factor. Respite in care and a parents' positive attitude were significantly related to less parental distress. Material support, socioeconomical level, marital status or parental qualifications did not appear to be significant protector factors. CONCLUSIONS: Particular attention must be paid not only on physical condition but also on adolescent psychological problems to improve family adaptation. Families at risk of experiencing severe distress should be targeted early and proactive caregiver interventions on the whole family should be performed. WHAT THIS PAPER ADDS: Family is a dynamic system: facing disability, it tries to recover its balance with available resources and its perception of the situation. Literature highlights potential stressors and protecting factors that could affect the disabled child's family adaptation but few papers study a global model including most of these factors. This study validated a global theoretical model of family adaptation to disability at adolescence. It identified behaviour disorders and motor impairment level as main stressors, family functioning as the largest protecting factors, and equipment and financial support as non significant protective factors. PMID- 28087204 TI - Assessment of Nurse Perspectives on an Emergency Department-Based Routine Opt-Out HIV Screening Program. AB - Routine opt-out HIV screening is recommended for everyone between 13 and 64 years of age. An urban, academic emergency department implemented a nurse-driven routine opt-out HIV screening program. The aim of our study was to assess program uptake and opportunities to improve the program from the perspectives of emergency nurses. Emergency nurses completed a brief prediscussion questionnaire and then participated in a focus group or semi-structured one-on-one interview to elicit feedback on the routine opt-out HIV screening program. All 16 participants felt adequately prepared for the screening program. Several themes emerged from the discussions, including challenges of specific patient characteristics and overall nurse and patient support for the program. One thread across themes was the importance of good language and communication skills in such programs. While there are opportunities to improve nurse-driven routine opt-out HIV testing programs in emergency settings, this program was found to be accepted by emergency nurses. PMID- 28087205 TI - Elevated fasting glucose and albuminuria may be a marker for all-cause mortality in Indigenous adults in North Queensland - a follow up study, 1998-2006. AB - AIMS: To document risk factors of all-cause mortality in a cohort of indigenous Australians from 23 communities of North Queensland during 1998-2006. METHODS: Among 2787 indigenous adults, baseline weight, waist circumference, blood pressure, fasting glucose, lipids, gamma-glutamyl transferase, urine albumin creatinine ratio, smoking, alcohol intake and physical activity were measured in 1998-2000. Deaths were ascertained from State Registry of Deaths, hospitalization and clinical records till 2006. Mortality risk factors were assessed using a Cox proportional-hazards model. RESULTS: The standardized all-cause mortality rate was 23.2/1000 person-years (95% CI 20.3-26.3/1000 pys). After adjusting for age, sex, and ethnicity, baseline plasm fasting glucose >=5.5mmol/L was associated with a 50% increased risk of death (HR 1.5, 95% CI 1.2-2.0). Albuminuria was associated with all-cause mortality with a hazards ratio of 1.4 for microalbuminuria (95% CI 1.0-1.9) and 2.6 (95% CI 1.8-3.7) for macroalbuminuria. Gamma-glutamyl transferase >=50IU was associated with an increased risk of all cause mortality by 40% (95% CI 1.04-1.8). CONCLUSIONS: Fasting glycaemia, albuminuria, and gamma-glutamyl transferase, may be a marker for all-cause mortality within this cohort. PMID- 28087206 TI - Spatial relationships between entomopathogenic nematodes and nematophagous fungi in Florida citrus orchards. AB - Relationships between entomopathogenic nematodes (EPNs), nematophagous fungi (NF) and soil physical and chemical properties were studied in a survey of 53 citrus orchards in central ridge and flatwoods ecoregions of Florida. Seven species of NF associated with nematodes were quantified directly using a real time qPCR assay. All nematophagous fungi studied except Arthrobotrys musiformis and Hirsutella rhossiliensis were frequently detected (24-56%) in both regions. Paecilomyces lilacinus and Gamsylella gephyropagumwere encountered more frequently in the flatwoods (P=0.03) and on the ridge (P=0.02), respectively. Redundancy analysis revealed seven abiotic and biotic factors as significantly related to the NF occurrence. Multiple regression of fungi on these variables explained 78%, 66%, 48%, 36%, 23% and 4% of the variation in Catenaria sp., A. musiformis, A. dactyloides, P. lilacinus, A. oligospora and G. gepharopagum, respectively. When the data from citrus were pooled with those reported previously from natural areas and subjected to principle component analysis, the first two principle components explained 43% of the variation in NF communities. The surveys (citrus vs natural areas) were discriminated by PC2 (P<0.001) and the ecoregion by PC1 (P<0.002), and all but one NF species were related (P<0.01) to one or both components. NF communities tended to have more species and greater diversity in the flatwoods, where EPN richness and diversity were the least. However, the strength of associations between individual EPN and NF species as measured by SADIE reflected the associations between each species and ground water depth, suggesting that ecoregion preferences affected the species associations. Within each ecoregion, significant relationships between the individual NF and EPN species measured by stepwise regression tended to be positive. The results did not support the hypothesis that NF modulate the spatial patterns of EPN species between or within these two ecoregions. PMID- 28087207 TI - Continuous Medication Monitoring (CoMM): A foundational model to support the clinical work of community pharmacists. AB - BACKGROUND: Under the Continuous Medication Monitoring (CoMM) approach, community pharmacists prevent, identify, resolve, and document drug therapy problems during the dispensing process. OBJECTIVE: To describe the patients receiving CoMM interventions and the pattern of delivery of CoMM interventions. METHODS: Pharmacy dispensing and clinical records were reviewed for patients filling at least one prescription and receiving at least one continuous medication monitoring intervention at a community pharmacy from April 2014 through March 2015. The proportion of patients receiving an intervention type and the number of interventions per patient were computed. RESULTS: Nearly 2500 patients received 16,986 continuous medication monitoring interventions over the year. The average age of the patients receiving the interventions was 59.1 years, and they filled an average of 8.0 unique medications. An average of 6.8 interventions was delivered to each patient. About half (49.7%) of interventions addressed drug therapy problems. The pharmacists delivered 3.0 patient counseling and education and 3.4 drug therapy problem interventions per patient on average. CONCLUSION: There are many opportunities to improve patients' medication use that can be identified and addressed under a Continuous Medication Monitoring model. Movement to this model of practice is desirable, but changes are needed to facilitate the shift. PMID- 28087208 TI - [Child Langerhans cell histiocytosis]. AB - DEFINITION: Langerhans cell histiocytosis (LCH) is defined by the association of a clinical and radiological involvement and a biopsy of a pathological tissue. Extension: it can affect any organ or system of the body but most commonly the bone (80% of cases), the skin (33%) and the pituitary (25%). Other organs are concerned such as liver, spleen, hematopoietic system and the lungs (15% each), lymph nodes (5-10%) and central nervous system (CNS) excluding the pituitary (2 4%). Natural history: the natural history of the disease is very heterogeneous, ranging from auto-regressive lesions to a disease affecting multiple organs with fatal consequences, while some lesions may be responsible for permanent sequels. A multidisciplinary approach: the perception of disease from physicians varies greatly depending on their speciality and experience, as well as the presentation of the disease or the short-term treatment outcomes. But whatever the initial view of the treating physician, a multidisciplinary approach to the LCH is recommended as well as the coordination of the necessary care of this systemic disease and its associated morbidity. THERAPY: current treatment protocols, adapted to the situation of each patient, provide a survival of 98% in children. The sequels, such as diabetes insipidus, hormonal deficits, deafness and even more rarely respiratory failure and sclerosing cholangitis are seen in up to 30% of children. PMID- 28087209 TI - [Hyperleucocytosis with acute uric acid nephropathy in a patient with hepatocellular carcinoma]. PMID- 28087210 TI - Evaluation of lip force in patients with unilateral and bilateral cleft lip. AB - Our aim was to investigate the differences in the dynamics of lip force between a group of participants with repaired cleft lips and a group of patients the same age but without clefts. We evaluated 101 children between the ages of 10 to 15 years (unilateral clefts n=35, bilateral clefts n=15, class I malocclusion n=25, and class III malocclusion n=26). Maximum and minimum forces required to close the lips were evaluated with the Lip De Cum(r) device (Cosmos Instruments Co Ltd, Tokyo, Japan) for the all groups. We found no significant differences between the maximum and minimum values between boys and girls within the groups, whereas the mean maximum and minimum lip force of the boys was higher than those of the girls in all the groups. This study showed that maximum and minimum lip closing force values were statistically similar in all groups. We conclude, therefore, that patients with bilateral cleft lip have reduced maximum and minimum lip force. PMID- 28087211 TI - The effect of bone growth onto massive prostheses collars in protecting the implant from fracture. AB - Limb-sparing distal femoral endoprotheses used in cancer patients have a high risk of aseptic loosening. It had been reported that young adolescent patients have a higher rate of loosening and fatigue fracture of intramedullary stems because the implant becomes undersized as patients grow. Extracortical bone growth into the grooved hydroxyapatite-coated collar had been shown to reduce failure rates. The stresses in the implant and femur have been calculated from Finite Element models for different stages of bone growth onto the collar. For a small diameter stem without any bone growth, a large stress concentration at the implant shoulder was found, leading to a significant fracture risk under normal walking loads. Bone growth and osseointergration onto the implant collar reduced the stress level in the implant to safe levels. For small bone bridges a risk of bone fracture was observed. PMID- 28087212 TI - Associations between thin slice ratings of affect and rapport and perceived patient-centeredness in primary care: Comparison of audio and video recordings. AB - OBJECTIVE: To investigate associations between ratings of "thin slices" from recorded clinic visits and perceived patient-centeredness; to compare ratings from video recordings (sound and images) versus audio recordings (sound only). METHODS: We analyzed 133 video-recorded primary care visits and patient perceptions of patient-centeredness. Observers rated thirty-second thin slices on variables assessing patient affect, physician affect, and patient-physician rapport. Video and audio ratings were collected independently. RESULTS: In multivariable analyses, ratings of physician positive affect (but not patient positive affect) were significantly positively associated with perceived patient centeredness using both video and audio thin slices. Patient-physician rapport was significantly positively associated with perceived patient-centeredness using audio, but not video thin slices. Ratings from video and audio thin slices were highly correlated and had similar underlying factor structures. CONCLUSION: Physician (but not patient) positive affect is significantly associated with perceptions of patient-centeredness and can be measured reliably using either video or audio thin slices. Additional studies are needed to determine whether ratings of patient-physician rapport are associated with perceived patient centeredness. PRACTICE IMPLICATIONS: Observer ratings of physician positive affect have a meaningful positive association with patients' perceptions of patient-centeredness. Patients appear to be highly attuned to physician positive affect during patient-physician interactions. PMID- 28087214 TI - Three-vessel Chimney Technique Combined with Endovascular Aortic Sealing Device for the Treatment of a Type Ia Endoleak. PMID- 28087213 TI - Cholesterolomics: An update. AB - Cholesterolomics can be regarded as the identification and quantification of cholesterol, its precursors post squalene, and metabolites of cholesterol and of its precursors, in a biological sample. These molecules include 1,25 dihydroxyvitamin D3, steroid hormones and bile acids and intermediates in their respective biosynthetic pathways. In this short article we will concentrate our attention on intermediates in bile acid biosynthesis pathways, in particular oxysterols and cholestenoic acids. These molecular classes are implicated in the aetiology of a diverse array of diseases including autoimmune disease, Parkinson's disease, motor neuron disease, breast cancer, the lysosomal storage disease Niemann-Pick type C and the autosomal recessive disorder Smith-Lemli Opitz syndrome. Mass spectrometry (MS) is the dominant technology for sterol analysis including both gas-chromatography (GC)-MS and liquid chromatography (LC) MS and more recently matrix-assisted laser desorption/ionisation (MALDI)-MS for tissue imaging studies. Here we will discuss exciting biological findings and recent analytical improvements. PMID- 28087216 TI - Denosumab and alendronate treatment in patients with back pain due to fresh osteoporotic vertebral fractures. AB - INTRODUCTION: Denosumab specifically inhibits the receptor activator for nuclear factor-kappa B ligand (RANKL), and prevents osteoporotic fractures. Several reports have analyzed the effects of denosumab and alendronate alone on bone mineral density (BMD) or reduction of fracture risk. The objective of this study was to analyze the effects of antiresorptive osteoporosis pharmacotherapy on pain relief in patients with fresh vertebral fracture. METHODS: This retrospective, single-center study included 80 patients (10 males, 70 females) with fresh osteoporotic vertebral fractures treated using denosumab at a dose of 60 mg subcutaneously every 6 months (40 patients) or alendronate at a dose of 35 mg orally every week (40 patients) for 6 months in our hospital. The mean age of subjects was 77 years (range, 55-92 years). The primary outcome was duration of back pain. Secondary outcomes included changes in BMD, serum type 1 collagen cross-linked N-telopeptide (NTX), and serum N-terminal propeptide of type 1 collagen (P1NP) from baseline to 6 months. Pain catastrophizing due to back pain was assessed using the Pain Catastrophizing Scale (PCS). The incidences of further vertebral fracture and adverse events were also assessed. RESULTS: Pain relief was obtained at a mean of 3.3 weeks with denosumab and 5.4 weeks with alendronate. Pain relief was achieved significantly earlier with denosumab than with alendronate. At 6 months, change in BMD was higher with denosumab (6.1%) than with alendronate (0.8%). No significant differences in changes in NTX and P1NP were observed between groups. Scores for PCS were significantly lower for denosumab than for alendronate. The incidence of further vertebral fractures was 5% with denosumab and 10% with alendronate. Adverse event rates were similar between groups. CONCLUSIONS: Denosumab enabled earlier pain relief than alendronate and avoided catastrophizing in patients with osteoporotic vertebral fractures after 6 months of treatment. PMID- 28087215 TI - Surgical outcome of posterior ankle impingement syndrome with concomitant ankle disorders treated simultaneously in patient engaged in athletic activity. AB - BACKGROUND: It is unclear whether simultaneous surgery for posterior ankle impingement syndrome (PAIS) and concomitant ankle disorders, such as anterior ankle impingement syndrome (AAIS), lateral ankle instability (LAI), and osteochondral lesion of the talus (OLT), allows for early return to athletic activity. METHODS: Ninety-seven patients who engaged in athletic activity (mean age 27 [range 18-43] years) and were treated by a hindfoot endoscopic approach for PAIS alone or simultaneously for PAIS and concomitant ankle disorders were included in this study. The patients were divided into four groups: PAIS alone (group A, n = 61), PAIS with AAIS (group B, n = 8), PAIS with LAI with or without AAIS (group C, n = 20), and PAIS with OLT with or without AAIS/LAI (group D, n = 8). In all patients, the concomitant ankle disorder was treated simultaneously by arthroscopic debridement for AAIS, bone marrow stimulation or autologous cancellous bone transplantation for OLT, and anterior talofibular ligament repair or reconstruction for LAI. American Orthopedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale scores before and 2 years after surgery and times from surgery to resuming training and athletic activity were compared between the groups. RESULTS: Mean AOFAS score improved significantly after surgery in all groups (groups A and C, P < .0001; groups B and D: P < .05). The time taken to return to training was significantly longer in group D than in groups A, B, and C (all P < .01) as was the time taken to return to athletic activity in groups C and D when compared with group A (P < .01); however, there were no significant differences in this regard between groups B and C. CONCLUSION: Concomitant surgery for AAIS and LAI with PAIS did not delay the postoperative start of training, however, concomitant surgery for LAI and OLT delayed the return to athletic activity when compared with PAIS surgery alone. STUDY DESIGN: Clinical Retrospective Comparative Study. PMID- 28087217 TI - Psychometric properties of the Japanese version of short forms of the Pain Catastrophizing Scale in participants with musculoskeletal pain: A cross sectional study. AB - BACKGROUND: The Pain Catastrophizing Scale (PCS) is a commonly used as measure of pain catastrophizing. The scale comprises 13 items related to magnification, rumination, and helplessness. To facilitate quick screening and to reduce participant's burden, the four-item and six-item short forms of the English version of the PCS were developed. The purpose of the present study was to evaluate the psychometric properties of a Japanese version of the short forms of PCS using a contemporary approach called Rasch analysis. METHODS: A total of 216 patients with musculoskeletal disorders were recruited in this study. Participants completed study measures, which included the pain intensity, the Pain Catastrophizing Scale (PCS), and the Tampa Scale of Kinesiophobia (TSK). Furthermore, the four-item (items 3, 6, 8, and 11) and six-item (items 4, 5, 6, 10, 11, and 13) short forms of the Japanese version of PCS were measured. We used Rasch analysis to analyze the psychometric properties of the original, four-item, and six-item short forms of PCS. RESULTS: Rasch analysis showed that both short forms of PCS had acceptable internal consistency, unidimensionality, and no notable DIF and were functional on the category rating scale. However, four-item short form of PCS had two misfit items. CONCLUSIONS: Six-item short form of PCS has acceptable psychometric properties and is suitable for use in participants with musculoskeletal pain. Thus, six-item can be used as brief instruments to evaluate pain catastrophizing. PMID- 28087218 TI - Relationship among motor function, ADL disability, and psychological concerns in elderly people with locomotive disorders. AB - BACKGROUND: Locomotive disorders are one of the main causative pathologies for the condition requiring assistance on activities of daily living (ADL). Although psychological concerns such as feeling of depression and anxiety are prevalent in elderly people, the causal relation among motor function, ADL disability, and psychological concerns is controversial. PURPOSE: Purpose of this study was to investigate causal relationship among motor function, ADL disability, and psychological concerns in elderly people with locomotive disorders. METHODS: The data for this study were from a community-dwelling sample of 314 elderly persons with locomotive disorders aged 65 and older who visited orthopedic clinics and/or affiliated institutions. Motor function was assessed by one-leg standing time with eyes open, leg extension power and grip power. We assessed ADL disability using the 25-question Geriatric Locomotive Function Scale (GLFS-25), and psychological concerns by three self-reported questions. We constructed two models and tested fitness of the models to the data using a structural equation modeling (SEM). Model 1: motor function affects ADL disability and ADL disability affects psychological concerns, Model 2: motor function affects psychological concerns and psychological concerns affects ADL disability. RESULTS: The fit indices were chi-square = 23.152 (p = 0.081), RMSEA = 0.042, GFI = 0.981, AGFI = 0.955, CFI = 0.987 for Model 1, and chi-square = 84.583 (p < 0.001), RMSEA = 0.119, GFI = 0.935, AGFI = 0.854, CFI = 0.892 for Model 2. These fit indices indicated a good fit of the model 1 and inadequate fit of model 2 to the data. CONCLUSION: Decline of motor function contributed toward psychological concerns via ADL disability in elderly people with locomotive disorders. PMID- 28087219 TI - Acute medical units, providing continuity of care may be the next focus. PMID- 28087220 TI - New-onset atrial fibrillation after percutaneous coronary intervention with stent: Updated proposal of an algorithm for the choice of oral anticoagulant and its dose. PMID- 28087221 TI - Varenicline provokes impulsive action by stimulating alpha4beta2 nicotinic acetylcholine receptors in the infralimbic cortex in a nicotine exposure status dependent manner. AB - Higher impulsivity is a risk factor for criminal involvement and drug addiction. Because nicotine administration enhances impulsivity, the effects of stop-smoking aids stimulating nicotinic acetylcholine receptors (nAChRs) on impulsivity must be determined in different conditions. Our goals were 1) to confirm the relationship between varenicline, a stop-smoking aid and alpha4beta2 nAChR partial agonist, and impulsivity, 2) to elucidate the mechanisms underlying the effects of varenicline, 3) to examine whether a low dose of varenicline that does not evoke impulsive action could block the stimulating effects of nicotine on impulsive action, 4) to determine whether the route of administration could modulate the effects of varenicline on impulsive action, and 5) to determine whether the effects of varenicline on impulsivity could be altered by smoking status. We used a 3-choice serial reaction time task to assess impulsivity and other cognitive functions in rats. Our findings are as follows: 1) acute subcutaneous (s.c.) injection of varenicline evoked impulsive action in a dose dependent manner; 2) the effects of varenicline on impulsivity were blocked by the microinjection of dihydro-beta-erythroidine, a alpha4beta2 nAChR antagonist, into the infralimbic cortex; 3) the low dose of varenicline did not attenuate the effects of nicotine on impulsive action at all; 4) oral administration of varenicline evoked impulsive action in a similar manner to s.c. injection; and 5) the stimulating effects of varenicline on impulsive action were not observed in rats that received nicotine infusion for 8days or nicotine-abstinent rats after discontinuing infusion. Additionally, we found that oral varenicline administration enhanced attentional function whether nicotine was infused or not. Thus, although varenicline administration could be harmless to heavy smokers or ex-smokers, it could be difficult for non-smokers with respect to impulsivity, whereas it may be beneficial with respect to attentional function. PMID- 28087222 TI - Revisiting the refeeding syndrome: Results of a systematic review. AB - OBJECTIVE: Although described >70 y ago, the refeeding syndrome (RFS) remains understudied with lack of standardized definition and treatment recommendations. The aim of this systematic review was to gather evidence regarding standardized definition, incidence rate and time course of occurrence, association with adverse clinical outcomes, risk factors, and therapeutic strategies to prevent or treat this condition. METHODS: We searched MEDLINE and EMBASE for interventional and observational clinical trials focusing on RFS, excluding case reports and reviews. We extracted data based on a predefined case report form and assessed bias. RESULTS: Of 2207 potential abstracts, 45 records with a total of 6608 patients were included (3 interventional trials, 16 studies focusing on anorexic patients). Definitions for RFS were highly heterogenous with most studies relying on blood electrolyte disturbances only and others also including clinical symptoms. Incidence rates varied between 0% and 80%, depending on the definition and patient population studied. Occurrence was mostly within the first 72 h of start of nutritional therapy. Most of the risk factors were in accordance with National Institute for Health and Care Excellence guidelines, with older age and enteral feeding being additional factors. There was no strong evidence regarding association of RFS and adverse outcomes, as well as regarding preventive measures and treatment algorithms. CONCLUSION: This systematic review focusing on RFS found consensus regarding risk factors and timing of occurrence, but wide variations regarding definition, reported incidence rates, preventive measures and treatment recommendations. Further research to fill this gap is urgently needed. PMID- 28087223 TI - Increased affinity of ghrelin-reactive immunoglobulins in obese Zucker rats. PMID- 28087225 TI - Assessing the therapeutic index of inhaled corticosteroids in children: Is knemometry the answer? PMID- 28087226 TI - Pathways to limit group 2 innate lymphoid cell activation. PMID- 28087224 TI - 5-HT6 receptor blockade regulates primary cilia morphology in striatal neurons. AB - The 5-HT6 receptor has been implicated in a variety of cognitive processes including habitual behaviors, learning, and memory. It is found almost exclusively in the brain, is expressed abundantly in striatum, and localizes to neuronal primary cilia. Primary cilia are antenna-like, sensory organelles found on most neurons that receive both chemical and mechanical signals from other cells and the surrounding environment; however, the effect of 5-HT6 receptor function on cellular morphology has not been examined. We confirmed that 5-HT6 receptors were localized to primary cilia in wild-type (WT) but not 5-HT6 knockout (5-HT6KO) in both native mouse brain tissue and primary cultured striatal neurons then used primary neurons cultured from WT or 5-HT6KO mice to study the function of these receptors. Selective 5-HT6 antagonists reduced cilia length in neurons cultured from wild-type mice in a concentration and time dependent manner without altering dendrites, but had no effect on cilia length in 5-HT6KO cultured neurons. Varying the expression levels of heterologously expressed 5-HT6 receptors affected the fidelity of ciliary localization in both WT and 5-HT6KO neurons; overexpression lead to increasing amounts of 5-HT6 localization outside of the cilia but did not alter cilia morphology. Introducing discrete mutations into the third cytoplasmic loop of the 5-HT6 receptor greatly reduced, but did not entirely eliminate, trafficking of the 5-HT6 receptor to primary cilia. These data suggest that blocking 5-HT6 receptor activity reduces the length of primary cilia and that mechanisms that regulate trafficking of 5 HT6 receptors to cilia are more complex than previously thought. PMID- 28087227 TI - A novel kindred with inherited STAT2 deficiency and severe viral illness. PMID- 28087228 TI - Insights into the mast cell-microbiome connection in the skin. PMID- 28087229 TI - Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling. AB - BACKGROUND: Gain-of-function mutations in transmembrane protein 173 (TMEM173) encoding stimulator of interferon genes (STING) underlie a recently described type I interferonopathy called STING-associated vasculopathy with onset in infancy (SAVI). OBJECTIVES: We sought to define the molecular and cellular pathology relating to 3 individuals variably exhibiting the core features of the SAVI phenotype including systemic inflammation, destructive skin lesions, and interstitial lung disease. METHODS: Genetic analysis, conformational studies, in vitro assays and ex vivo flow-cytometry were performed. RESULTS: Molecular and in vitro data demonstrate that the pathology in these patients is due to amino acid substitutions at positions 206, 281, and 284 of the human STING protein. These mutations confer cGAMP-independent constitutive activation of type I interferon signaling through TBK1 (TANK-binding kinase), independent from the alternative STING pathway triggered by membrane fusion of enveloped RNA viruses. This constitutive activation was abrogated by ex vivo treatment with the janus kinase 1/2 inhibitor ruxolitinib. CONCLUSIONS: Structural analysis indicates that the 3 disease-associated mutations at positions 206, 281, and 284 of the STING protein define a novel cluster of amino acids with functional importance in the regulation of type I interferon signaling. PMID- 28087230 TI - The impact of obesity on febrile urinary tract infection and renal scarring in children with vesicoureteral reflux. AB - INTRODUCTION: It has become clear that obesity is associated with a variety of infectious diseases, including urinary tract infection (UTI) and renal scarring. OBJECTIVE: The aim of this study was to evaluate the association between obesity and the degree of febrile UTI (fUTI) and renal scarring in children with vesicoureteral reflux (VUR), and to stratify the results into obesity subcategories. STUDY DESIGN: A total of 186 patients were diagnosed with VUR between January 2002 and December 2008. This study retrospectively reviewed the medical records of 72 children with primary VUR who had recurrent fUTI (more than twice). Overweight or obese status of the patients aged <2 years was defined using weight-for-length (WFL) measurements. For 2-5 year old children, body mass index (BMI) percentile-for-age was used. They were divided into three groups as follows; standard (<85%), overweight (85-95%), and obese (>=95%). The following clinical variables were compared: age at diagnosis of primary VUR (months), sex, VUR grade, hydronephrosis grade, presence of renal scarring, surgical treatment, and degree of inflammation during fUTI. RESULTS: In the overweight and obese groups, VUR was diagnosed at a young age (P = 0.05), the degree of renal scarring was more severe (P = 0.006), and serum white blood cell count, C-reactive protein, and erythrocyte sedimentation rate (ESR) levels were significantly higher (P < 0.001, P < 0.001, and P < 0.001, respectively). Abnormal focal dimercaptosuccinic acid (DMSA) defects were present in 25 of the 72 children (35%). Cortical defects occurred more frequently in children with obesity, and they were associated with a higher grade of reflux and serum ESR levels (P = 0.007, P = 0.042, and P = 0.021, respectively). Among these risk factors, high grade VUR (OR = 9.93, 95% CI = 1.13-86.71), and being overweight and obese (OR = 5.26, 95% CI = 1.75-15.82) were associated with increased renal scarring. However, ESR was not associated with renal scarring (OR = 1.01, 95% CI = 0.95 1.07). DISCUSSION: The relationships between obesity and UTI are controversial. Some studies have shown positive results; however, other studies have shown opposite results. The main limitations of this study were the retrospective data collection via electronic medical records, and the small number of subjects. CONCLUSIONS: This study showed that obesity in patients with VUR has an effect on fUTI and renal scar formation. If the patients with VUR have obesity, close follow-up should be performed, and VUR patients should be started on a weight loss program, which could reduce the number of patients with chronic kidney disease in the future. PMID- 28087231 TI - Psychosocial outcome in adult men born with hypospadias. AB - INTRODUCTION: Hypospadias, which is a surgically treated congenital malformation of the male urethra, may have a negative impact on quality of life. This aspect has previously been subject to limited research. This study examined the long term psychosocial outcome of a large cohort of adult males born with hypospadias. OBJECTIVE: The purpose of this case-control study was to assess a possible negative influence on the psychosocial outcome in adult males with hypospadias. STUDY DESIGN: Males with hypospadias treated in Sweden and aged >=18 years old participated in this follow-up study. Age-matched men and university students were recruited as controls. The participants answered a questionnaire designed to reflect the subjective quality of life, social factors, need of support and follow-up, and the perceived impact of the disease upon upbringing. It also looked at the validated Psychological General Well-Being (PGWB) questionnaire and Relationship Questionnaire (RQ). RESULTS AND DISCUSSION: A total of 167 patients (median age 34 years, 63% distal, 24% mid, and 13% proximal hypospadias) and 169 controls (median age 33 years) participated in the study. Patients had their first operation at 4 years of age (median) and the median follow-up time was 29 years following the first surgery. Men with hypospadias had a comparable total quality of life level with a mean total PGWB score of 82 (normal range 78-83) compared with 85.6 in controls. Scores on wellbeing and vitality were lower, even if the differences were small. Hypospadias did not affect marital status, presence of children in the family, frequency of employment or experience of bullying. These men more often lived at home with their parents (P=0.001) and had a lower level of education (P=0.004), even if the educational level in both patients and controls was high compared with the general Swedish population. Patients with proximal hypospadias were shorter compared with controls (P=0.003), which was consistent with the prenatal growth restriction associated with hypospadias. The group with proximal hypospadias expressed a greater need for medical (45.5%) follow-up compared with mid (28.2%) and distal (18.1%) cases (P=0.001). Patients with proximal hypospadias tended to avoid close relationships because of fear of being hurt. CONCLUSIONS: The findings suggested that patients treated for hypospadias have a good HRQoL, can be expected to have a normal psychosocial life, and marry and have children. Repeated follow-up and psychological support during childhood/adolescence is however of great importance for patients with more proximal hypospadias. PMID- 28087232 TI - Comparison of Medial Malleolar Fracture Healing at 8 Weeks After Open Reduction Internal Fixation Versus Percutaneous Fixation: A Retrospective Cohort Study. AB - Unstable medial malleolar fractures are treated with either standard open reduction internal fixation (ORIF) or a percutaneous approach. The percutaneous approach avoids the potentially excessive soft tissue dissection associated with an open approach but can also result in inadequate anatomic reduction. No studies have compared the incidence of radiographic healing of medial malleolar fractures between an open approach and percutaneous fixation. A retrospective comparative study was performed at a single institution across multiple sites. Electronic medical records and digital radiographs were reviewed for 845 patients who had undergone either ORIF or percutaneous screw fixation (PSF) of a medial malleolar fracture. The interval to fracture healing was measured. Logistic regression analysis was used. Of the 490 included patients, 458 (93.44%) underwent standard ORIF and 32 (6.53%) underwent PSF. Patients who underwent ORIF were 5 times more likely to have a healed fracture at 8 weeks than were patients who had undergone PSF (p < .001). Compared with standard ORIF, PSF of medial malleolar fractures leads to an increased risk of an unhealed fracture at 8 weeks. This was likely due to a combination of soft tissue interposition within the fracture site and inadequate fluoroscopic reliability, leading to poor anatomic reduction and inaccurate fixation. PMID- 28087233 TI - Anti-diabetic effects of Inonotus obliquus polysaccharides-chromium (III) complex in type 2 diabetic mice and its sub-acute toxicity evaluation in normal mice. AB - Polysaccharides are important bioactive ingredients from Inonotus obliquus. This study aimed to synthesize and characterize a novel I. obliquus polysaccharides chromium (III) complex (UIOPC) and investigate the anti-diabetic effects in streptozotocin (STZ) induced type 2 diabetes mellitus (T2DM) mice and sub-acute toxicity in normal mice. The molecular weight of UIOPC was about 11.5 * 10 4 Da with the chromium content was 13.01% and the chromium was linked with polysaccharides through coordination bond. After treatment of UIOPC for four weeks, the body weight, fasting blood glucose (FBG) levels, plasma insulin levels of the diabetic mice were significantly reduced when compared with those of the diabetic mice (p < 0.05). The results on serum profiles and antioxidant enzymes activities revealed that UIOPC had a positive effect on hypoglycemic and antioxidant ability. Histopathology results showed that UIOPC could effectively alleviate the STZ-lesioned tissues in diabetic mice. Furthermore, high dose administration of UIOPC had no obviously influence on serum profiles levels and antioxidant ability of the normal mice and the organ tissues maintained organized and integrity in the sub-acute toxicity study. These results suggested that UIOPC might be a good candidate for the functional food or pharmaceuticals in the treatment of T2DM. PMID- 28087234 TI - Interference from related actions in spoken word production: Behavioural and fMRI evidence. AB - Few investigations of lexical access in spoken word production have investigated the cognitive and neural mechanisms involved in action naming. These are likely to be more complex than the mechanisms involved in object naming, due to the ways in which conceptual features of action words are represented. The present study employed a blocked cyclic naming paradigm to examine whether related action contexts elicit a semantic interference effect akin to that observed with categorically related objects. Participants named pictures of intransitive actions to avoid a confound with object processing. In Experiment 1, body-part related actions (e.g., running, walking, skating, hopping) were named significantly slower compared to unrelated actions (e.g., laughing, running, waving, hiding). Experiment 2 employed perfusion functional Magnetic Resonance Imaging (fMRI) to investigate the neural mechanisms involved in this semantic interference effect. Compared to unrelated actions, naming related actions elicited significant perfusion signal increases in frontotemporal cortex, including bilateral inferior frontal gyrus (IFG) and hippocampus, and decreases in bilateral posterior temporal, occipital and parietal cortices, including intraparietal sulcus (IPS). The findings demonstrate a role for temporoparietal cortex in conceptual-lexical processing of intransitive action knowledge during spoken word production, and support the proposed involvement of interference resolution and incremental learning mechanisms in the blocked cyclic naming paradigm. PMID- 28087235 TI - Hemodynamic Consequence of Hand Ventilation Versus Machine Ventilation During Transport After Cardiac Surgery. AB - OBJECTIVES: The hemodynamic consequences of ventilation of intubated patients during transport either by hand or using a transport ventilator have not been reported in patients after cardiac surgery. The authors hypothesized that bag mask ventilation would alter end-tidal CO2 during transport and hemodynamic parameters in patients post-cardiac surgery. DESIGN: A prospective, randomized trial. SETTING: A university-affiliated tertiary care hospital. PARTICIPANTS: Cardiac surgery patients. INTERVENTIONS: Thirty-six patients were randomized to hand ventilation or machine ventilation. Hemodynamic variables including blood pressure, heart rate, peripheral saturation of oxygen, and end-tidal carbon dioxide (ETCO2) were measured in these patients prior to transport, every 2 minutes during transport and upon arrival in the intensive care unit (ICU). Pulmonary artery pressure (PA) pressures were measured at origin and at destination. MEASUREMENTS AND MAIN RESULTS: Outcomes were changes from baseline in end-tidal CO2, hemodynamic changes from baseline and pulmonary artery pressure changes from origin to destination. The average transport time between the 2 groups was not different: 5 minutes for patients ventilated by hand and 5.47 minutes for patients ventilated with a transport ventilator (p = 0.369 by 2-sided t-test). The difference in all measured changes in ETCO2 between hand-ventilated and machine-ventilated patients during transport was 2.74 mmHg (p = 0.013). The difference between operating room and ICU ETCO2 from each cohort was 1.31 mmHg (p = 0.067). The difference in PAmean measured at origin and destination was 0.783 mmHg (p = 0.622). All other hemodynamic variables were not different during transport. CONCLUSIONS: Hand ventilation during transport was associated with greater change from baseline of ETCO2 compared to machine ventilation during transport after cardiac surgery, but this did not translate into any difference in hemodynamic changes upon arrival in ICU. A hemodynamic benefit of machine transport ventilation to cardiac patients was not demonstrated. PMID- 28087236 TI - Determination of the feasibility of a multicomponent intervention program to prevent delirium in the Intensive Care Unit: A modified RAND Delphi study. AB - BACKGROUND: Delirium is common in Intensive Care Unit (ICU) patients and associated with poor outcome. In non-ICU patients a multicomponent intervention program with non-pharmacological interventions has shown to reduce delirium. Currently, there is insufficient evidence regarding the effects of such a program in ICU patients. We developed a draft program based on a review. As most studies were conducted in non-ICU patients, the feasibility of the program in ICU patients needs to be assessed before investigating its effectiveness. OBJECTIVES: To determine experts' opinion and to achieve group consensus on the feasibility and completeness of the multicomponent intervention program for ICU patients. METHODS: A modified RAND/UCLA Appropriateness Method Delphi study was used. A total of 38 experts were selected following purposive sampling. Round one informed the experts about the draft program and asked for their opinion about its feasibility and completeness. In round two the experts were asked to reconsider their opinion based on changes made, and to rank the interventions in order of importance. The feasibility was scored using a 9-point Likert scale. A disagreement index (DI) and panel median were calculated to determine the level of agreement. RESULTS: During Delphi round one 100% of the questionnaires was completed, during round two 79%. After two rounds the experts agreed on the feasibility of the interventions targeting sleep deprivation (panel median 7.00, DI 0.26), immobility (panel median 8.00, DI 0.22), visual and hearing impairment (panel median 8.00, DI 0.19), and cognitive impairment (panel median 8.00, DI 0.23), except for cognitive training (panel median 5.00, DI 0.52). CONCLUSIONS: During this study a feasible multicomponent intervention program to prevent ICU delirium was developed based on expert consensus. As no consensus was reached on cognitive training, a pilot study is planned to determine the feasibility of cognitive training in the ICU. PMID- 28087237 TI - What Is the Real Impact of Urinary Incontinence on Female Sexual Dysfunction? A Case Control Study. AB - INTRODUCTION: Urinary incontinence (UI) has been associated with negative effects on women's sexuality. Women's sexuality and sexual function are a complex issue, and the role of UI is not completely clear. AIM: To assess the impact of UI on female sexual function by comparing this population with a control group of continent women. METHODS: We performed a case-control study from August 2012 to September 2013. We evaluated continent and incontinent women (age range = 30-70 years) for their sexuality. MAIN OUTCOME MEASURES: All patients were evaluated by anamnesis, physical examination, and self-report quality-of-life questionnaires. In addition, incontinent women underwent a 1-hour pad test. Patients without sexual activity were evaluated for the role of UI in their sexual abstinence. Sexual abstinence was defined as the absence of sexual activity for more than 6 months. All sexually active women completed the self-report Sexuality Quotient Female Version (SQ-F) questionnaire. RESULTS: A total of 356 women were included in the study (incontinent, n = 243; continent, n = 113). Sexual abstinence was found in 162 women (45%). Incontinent women presented a higher prevalence (P < .001) of sexual abstinence than their counterparts (129 [53%] and 33 [29.2%], respectively). Age, marital status, and UI were found to be isolated predictive factors for more sexual abstinence in incontinent women. Sexually active women (incontinent, n = 114; continent, n = 80) presented similar demographic data. Despite a similar frequency of sexual activity, incontinent women had less sexual desire, foreplay, harmony with a partner, sexual comfort, and sexual satisfaction than their counterparts. Women with greater urinary leakage during the 1-hour pad test (weight > 11 g) had the worst sexual function (SQ-F) score. CONCLUSION: Women with UI were more likely to be sexual abstinent than continent women. Furthermore, women with UI showed less sexual desire, sexual comfort, and sexual satisfaction than their counterparts despite having a similar frequency of sexual activity. PMID- 28087238 TI - Lymphocyte Circadian Clocks Control Lymph Node Trafficking and Adaptive Immune Responses. AB - Lymphocytes circulate through lymph nodes (LN) in search for antigen in what is believed to be a continuous process. Here, we show that lymphocyte migration through lymph nodes and lymph occurred in a non-continuous, circadian manner. Lymphocyte homing to lymph nodes peaked at night onset, with cells leaving the tissue during the day. This resulted in strong oscillations in lymphocyte cellularity in lymph nodes and efferent lymphatic fluid. Using lineage-specific genetic ablation of circadian clock function, we demonstrated this to be dependent on rhythmic expression of promigratory factors on lymphocytes. Dendritic cell numbers peaked in phase with lymphocytes, with diurnal oscillations being present in disease severity after immunization to induce experimental autoimmune encephalomyelitis (EAE). These rhythms were abolished by genetic disruption of T cell clocks, demonstrating a circadian regulation of lymphocyte migration through lymph nodes with time-of-day of immunization being critical for adaptive immune responses weeks later. PMID- 28087239 TI - On-going Mechanical Damage from Mastication Drives Homeostatic Th17 Cell Responses at the Oral Barrier. AB - Immuno-surveillance networks operating at barrier sites are tuned by local tissue cues to ensure effective immunity. Site-specific commensal bacteria provide key signals ensuring host defense in the skin and gut. However, how the oral microbiome and tissue-specific signals balance immunity and regulation at the gingiva, a key oral barrier, remains minimally explored. In contrast to the skin and gut, we demonstrate that gingiva-resident T helper 17 (Th17) cells developed via a commensal colonization-independent mechanism. Accumulation of Th17 cells at the gingiva was driven in response to the physiological barrier damage that occurs during mastication. Physiological mechanical damage, via induction of interleukin 6 (IL-6) from epithelial cells, tailored effector T cell function, promoting increases in gingival Th17 cell numbers. These data highlight that diverse tissue-specific mechanisms govern education of Th17 cell responses and demonstrate that mechanical damage helps define the immune tone of this important oral barrier. PMID- 28087241 TI - Chest imaging in CF studies - Commentary. PMID- 28087240 TI - Lactobacillus-Deficient Cervicovaginal Bacterial Communities Are Associated with Increased HIV Acquisition in Young South African Women. AB - Elevated inflammation in the female genital tract is associated with increased HIV risk. Cervicovaginal bacteria modulate genital inflammation; however, their role in HIV susceptibility has not been elucidated. In a prospective cohort of young, healthy South African women, we found that individuals with diverse genital bacterial communities dominated by anaerobes other than Gardnerella were at over 4-fold higher risk of acquiring HIV and had increased numbers of activated mucosal CD4+ T cells compared to those with Lactobacillus crispatus dominant communities. We identified specific bacterial taxa linked with reduced (L. crispatus) or elevated (Prevotella, Sneathia, and other anaerobes) inflammation and HIV infection and found that high-risk bacteria increased numbers of activated genital CD4+ T cells in a murine model. Our results suggest that highly prevalent genital bacteria increase HIV risk by inducing mucosal HIV target cells. These findings might be leveraged to reduce HIV acquisition in women living in sub-Saharan Africa. PMID- 28087242 TI - Brains for birds and babies: Neural parallels between birdsong and speech acquisition. AB - Language as a computational cognitive mechanism appears to be unique to the human species. However, there are remarkable behavioral similarities between song learning in songbirds and speech acquisition in human infants that are absent in non-human primates. Here we review important neural parallels between birdsong and speech. In both cases there are separate but continually interacting neural networks that underlie vocal production, sensorimotor learning, and auditory perception and memory. As in the case of human speech, neural activity related to birdsong learning is lateralized, and mirror neurons linking perception and performance may contribute to sensorimotor learning. In songbirds that are learning their songs, there is continual interaction between secondary auditory regions and sensorimotor regions, similar to the interaction between Wernicke's and Broca's areas in human infants acquiring speech and language. Taken together, song learning in birds and speech acquisition in humans may provide useful insights into the evolution and mechanisms of auditory-vocal learning. PMID- 28087243 TI - Using deep learning to investigate the neuroimaging correlates of psychiatric and neurological disorders: Methods and applications. AB - Deep learning (DL) is a family of machine learning methods that has gained considerable attention in the scientific community, breaking benchmark records in areas such as speech and visual recognition. DL differs from conventional machine learning methods by virtue of its ability to learn the optimal representation from the raw data through consecutive nonlinear transformations, achieving increasingly higher levels of abstraction and complexity. Given its ability to detect abstract and complex patterns, DL has been applied in neuroimaging studies of psychiatric and neurological disorders, which are characterised by subtle and diffuse alterations. Here we introduce the underlying concepts of DL and review studies that have used this approach to classify brain-based disorders. The results of these studies indicate that DL could be a powerful tool in the current search for biomarkers of psychiatric and neurologic disease. We conclude our review by discussing the main promises and challenges of using DL to elucidate brain-based disorders, as well as possible directions for future research. PMID- 28087244 TI - Practice Makes Perfect: Correlations Between Prior Experience in High-level Athletics and Robotic Surgical Performance Do Not Persist After Task Repetition. AB - OBJECTIVE: Robotic surgical skill development is central to training in urology as well as in other surgical disciplines. Here, we describe a pilot study assessing the relationships between robotic surgery simulator performance and 3 categories of activities, namely, videogames, musical instruments, and athletics. DESIGN: A questionnaire was administered to preclinical medical students for general demographic information and prior experiences in surgery, videogames, musical instruments, and athletics. For follow-up performance studies, we used the Matchboard Level 1 and 2 modules on the da Vinci Skills Simulator, and recorded overall score, time to complete, economy of motion, workspace range, instrument collisions, instruments out of view, and drops. Task 1 was run once, whereas task 2 was run 3 times. SETTING: All performance studies on the da Vinci Surgical Skills Simulator took place in the Simulation Center at Dartmouth Hitchcock Medical Center. PARTICIPANTS: All participants were medical students at the Geisel School of Medicine. After excluding students with prior hands-on experience in surgery, a total of 30 students completed the study. RESULTS: We found a significant correlation between athletic skill level and performance for both task 1 (p = 0.0002) and task 2 (p = 0.0009). No significant correlations were found for videogame or musical instrument skill level. Students with experience in certain athletics (e.g., volleyball, tennis, and baseball) tended to perform better than students with experience in other athletics (e.g., track and field). For task 2, which was run 3 times, this association did not persist after the third repetition due to significant improvements in students with low level athletic skill (levels 0-2). CONCLUSIONS: Our study suggests that prior experience in high-level athletics, but not videogames or musical instruments, significantly influences surgical proficiency in robot-naive students. Furthermore, our study suggests that practice through task repetition can overcome initial differences that may be related to a background in athletics. These novel relationships may have broader implications for the future recruitment and training of robotic surgeons and may warrant further investigation. PMID- 28087245 TI - The severe clinical phenotype for a heterozygous Fabry female patient correlates to the methylation of non-mutated allele associated with chromosome 10q26 deletion syndrome. AB - Heterozygous Fabry females usually have an attenuated form of Fabry disease, causing them to be symptomatic; however, in rare cases, they can present with a severe phenotype. In this study, we report on a 37-year-old woman with acroparesthesia, a dysmorphic face, left ventricular hypertrophy, and intellectual disability. Her father had Fabry disease and died due to chronic renal and congestive cardiac failure. Her paternal uncle had chronic renal failure and intellectual disability, and her paternal aunt was affected with congestive cardiac failure. The patient has two sisters with no significant medical illness. However, her nephew has acroparesthesia, anhidrosis, and school phobia, and her niece shows mild phenotypes. The patient's enzyme analysis showed very low alpha-galactosidase A (alpha-gal A) activity in dried blood spot (DBS), lymphocytes, and skin fibroblasts with massive excretion of Gb3 and Gb2 in urine and lyso-Gb3 in DBS and plasma. Electron microscopic examination showed a large accumulation of sphingolipids in vascular endothelial cells and keratinocytes. Chromosomal analysis and comparative genomic hybridization microarray showed 10q26 terminal deletion. Molecular data showed a novel heterozygous stop codon mutation in exon 1 of the GLA gene in her sisters and niece, and a hemizygous state in her nephew. When we checked the methylation status, we found her non mutated allele in the GLA gene was methylated. However, the non-mutated alleles of her sisters were non-methylated, and those of her niece were partially methylated. The chromosomal and methylation study may speculate the severity of her clinical phenotypes. PMID- 28087246 TI - Adipocytokines and anthropometric measures in type 2 diabetics. AB - AIM: Type 2 diabetes mellitus has assumed pandemic proportions worldwide. Aggressive management of hyperglycemia in diabetics is a primary goal of treatment. We have previously reported favorable effects of oral hypoglycemic agents on adipocytokines. Aim of the present study was to investigate the relationship of adipocytokines with anthropometric measures and biochemical parameters in type 2 diabetics. METHODS: Clinically diagnosed type 2 diabetics and age, gender matched healthy volunteers were recruited for study. Anthropometric measurements like height, weight, waist-circumference, hip circumference were recorded and BMI, waist-hip ratio were calculated. Fasting blood samples were collected from participants and sera were analyzed for glucose, glycated haemoglobin, total cholesterol, SGOT, SGPT, insulin, adiponectin and leptin. Correlation of adipocytokines with anthropometric and biochemical parameters was assessed in healthy and diabetic individuals. RESULTS: BMI and WHR in diabetics were significantly higher than healthy population. BMI did not show significant association with adipocytokines. Diabetic males with WHR>=0.9 showed negative association with adiponectin and positive association with leptin. WC did not show significant association with adipocytokines in males. Irrespective of WC, healthy females exhibited positive association with leptin. Diabetic females with WC>=88cm showed leptin to be positively associated with WC. Such association of adipocytokines with WHR was not detected in females. CONCLUSIONS: Body fat distribution can be considered as a parameter in assessing adipokine imbalance. Central adiposity is a better measure of adipokine imbalance than BMI. Abdominal obesity in diabetics correlates with altered levels of adipocytokines indicating its importance in diabetic individuals. PMID- 28087247 TI - Activity of Von Willebrand factor and levels of VWF-cleaving protease (ADAMTS13) in preterm and full term neonates. AB - Von Willebrand Factor (VWF) has a central role in primary hemostasis. Its biological activity is related to the size of VWF multimers, spontaneously binding to platelets and inducing circulating microthrombi formation. This process is down-regulated by the VWF cleaving protease ADAMTS13 (A Disintegrin and Metalloprotease with ThromboSpondin motif). To date, information regarding the levels of ADAMTS13 in neonates and preterm infants is scarce. Our aim was to study ADAMTS13, VWF antigen (Ag) and Ristocetin cofactor (RiCof) activity in neonates and evaluate potential correlations with perinatal complications. Our cohort consisted of 128 (48/128: born preterm) neonates, born in Sheba Medical Center and followed until hospital discharge. Control group consisted of 20 healthy adults. As expected, a significant elevation of VWF:Ag was observed in preterm and term infants compared to adults. VWF:Ag levels were highest in full term infants (Median 129.0 IQR 33.8) and lowest in adults (Median 119.0 IQR 58.5) (p<0.05), and RiCoF levels in neonates were higher than in adults. ADAMTS13 was significantly (p<0.05) higher in preterm babies in comparison to full term and adult controls. Neonates that underwent stressful conditions or experienced vascular complications such as IUGR, ROP, NEC, had lower levels of ADAMTS13 in our study. Further studies are required to validate and asses potential significance of these findings. PMID- 28087248 TI - Corrigendum to "GIT1/betaPIX signaling proteins and PAK1 kinase regulate microtubule nucleation" [Biochim. Biophys. Acta 1863/6PA (2016) 1282-1297]. PMID- 28087249 TI - Nick-initiated homologous recombination: Protecting the genome, one strand at a time. AB - Homologous recombination (HR) is an essential, widely conserved mechanism that utilizes a template for accurate repair of DNA breaks. Some early HR models, developed over five decades ago, anticipated single-strand breaks (nicks) as initiating lesions. Subsequent studies favored a more double-strand break (DSB) centered view of HR initiation and at present this pathway is primarily considered to be associated with DSB repair. However, mounting evidence suggests that nicks can indeed initiate HR directly, without first being converted to DSBs. Moreover, recent studies reported on novel branches of nick-initiated HR (nickHR) that rely on single-, rather than double-stranded repair templates and that are characterized by mechanistically and genetically unique properties. The physiological significance of nickHR is not well documented, but its high fidelity nature and low mutagenic potential are relevant in recently developed, precise gene editing approaches. Here, we review the evidence for stimulation of HR by nicks, as well as the data on the interactions of nickHR with other DNA repair pathways and on its mechanistic properties. We conclude that nickHR is a bona-fide pathway for nick repair, sharing the molecular machinery with the canonical HR but nevertheless characterized by unique properties that secure its inclusion in DNA repair models and warrant future investigations. PMID- 28087250 TI - Pharmacology of cannabinoids in the treatment of epilepsy. AB - The use of cannabis products in the treatment of epilepsy has long been of interest to researchers and clinicians alike; however, until recently very little published data were available to support its use. This article summarizes the available scientific data of pharmacology from human and animal studies on the major cannabinoids which have been of interest in the treatment of epilepsy, including ?9-tetrahydrocannabinol (?9-THC), cannabidiol (CBD), ?9 tetrahydrocannabivarin (?9-THCV), cannabidivarin (CBDV), and ?9 tetrahydrocannabinolic acid (Delta9-THCA). It has long been known that ?9-THC has partial agonist activity at the endocannabinoid receptors CB1 and CB2, though it also binds to other targets which may modulate neuronal excitability and neuroinflammation. The actions of Delta9-THCV and Delta9-THCA are less well understood. In contrast to ?9-THC, CBD has low affinity for CB1 and CB2 receptors and other targets have been investigated to explain its anticonvulsant properties including TRPV1, voltage gated potassium and sodium channels, and GPR55, among others. We describe the absorption, distribution, metabolism, and excretion of each of the above mentioned compounds. Cannabinoids as a whole are very lipophilic, resulting in decreased bioavailability, which presents challenges in optimal drug delivery. Finally, we discuss the limited drug-drug interaction data available on THC and CBD. As cannabinoids and cannabis-based products are studied for efficacy as anticonvulsants, more investigation is needed regarding the specific targets of action, optimal drug delivery, and potential drug-drug interactions. This article is part of a Special Issue titled Cannabinoids and Epilepsy. PMID- 28087251 TI - Obesity and epilepsy: The first step of a long road. PMID- 28087252 TI - Novel method for evaluation of eye movements in patients with narcolepsy. AB - BACKGROUND: Narcolepsy causes abnormalities in the control of wake-sleep, non rapid-eye-movement (non-REM) sleep and REM sleep, which includes specific eye movements (EMs). In this study, we aim to evaluate EM characteristics in narcolepsy as compared to controls using an automated detector. METHODS: We developed a data-driven method to detect EMs during sleep based on two EOG signals recorded as part of a polysomnography (PSG). The method was optimized using the manually scored hypnograms from 36 control subjects. The detector was applied on a clinical sample with subjects suspected for central hypersomnias. Based on PSG, multiple sleep latency test and cerebrospinal fluid hypocretin-1 measures, they were divided into clinical controls (N = 20), narcolepsy type 2 (NT2, N = 19), and narcolepsy type 1 (NT1, N = 28). We investigated the distribution of EMs across sleep stages and cycles. RESULTS: NT1 patients had significantly less EMs during wake, N1, and N2 sleep and more EMs during REM sleep compared to clinical controls, and significantly less EMs during wake and N1 sleep compared to NT2 patients. Furthermore, NT1 patients showed less EMs during NREM sleep in the first sleep cycle and more EMs during NREM sleep in the second sleep cycle compared to clinical controls and NT2 patients. CONCLUSIONS: NT1 patients show an altered distribution of EMs across sleep stages and cycles compared to NT2 patients and clinical controls, suggesting that EMs are directly or indirectly controlled by the hypocretinergic system. A data-driven EM detector may contribute to the evaluation of narcolepsy and other disorders involving the control of EMs. PMID- 28087253 TI - What is an "ideal" antibiotic? Discovery challenges and path forward. AB - An ideal antibiotic is an antibacterial agent that kills or inhibits the growth of all harmful bacteria in a host, regardless of site of infection without affecting beneficial gut microbes (gut flora) or causing undue toxicity to the host. Sadly, no such antibiotics exist. What exist are many effective Gram positive antibacterial agents as well as broad-spectrum agents that provide treatment of certain Gram-negative bacteria but not holistic treatment of all bacteria. However effectiveness of all antibacterial agents is being rapidly eroded due to resistance. This viewpoint provides an overview of today's antibiotics, challenges and potential path forward of discovery and development of new (ideal) antibiotics. PMID- 28087254 TI - Anti-diabetic drug metformin dilates retinal blood vessels through activation of AMP-activated protein kinase in rats. AB - The aim of this study was to examine whether metformin, a biguanide anti hyperglycemic drug, dilates retinal blood vessels in rats. Ocular fundus images were captured with an original high-resolution digital fundus camera in vivo and diameters of retinal blood vessels were measured. Both systemic blood pressure and heart rate were continuously recorded. Metformin (0.01-0.3mg/kg/min) increased diameters of retinal blood vessels in a dose-dependent manner. This retinal vasodilator effect of metformin was abolished by compound C, an inhibitor of AMP-activated protein kinase (AMPK), and NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide (NO) synthase. Similar results were obtained with the AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside (AICAR, 0.01-1mg/kg/min). Neither metformin nor AICAR exerted significant effect on mean blood pressure and heart rate. However, a significant pressor response to AICAR was observed upon inhibition of NO synthase. These results suggest that metformin dilates retinal blood vessels through activation of AMPK, and NO plays an important role in the retinal vasodilator response following AMPK activation. PMID- 28087255 TI - Unknown face of known drugs - what else can we expect from angiotensin converting enzyme inhibitors? AB - The renin-angiotensin system (RAS) is one of important systems among homeostatic mechanisms that control the function of cardiovascular, renal and adrenal systems. As RAS has a very complex nature, it has been also found as related to the control of cell migration and apoptosis. Angiotensin-converting enzyme inhibitors (ACEI) are drugs most commonly used in the modulation of RAS activity. ACEI have been extensively described as effective in the treatment of hypertension among adults, but also as drugs delaying progression in diabetic nephropathy and reducing mortality in left ventricular dysfunction and congestive heart failure. What is less obvious, ACEI are also widely used in pediatric nephrology and cardiology. Moreover, there are more and more reports showing evidence that ACEI can be beneficial in the treatment of many other diseases and the pleiotropic activity of ACEI is mainly based on their antioxidant properties. In this paper we focus on the less obvious possibilities of the clinical use of ACEI in neurological or oncological patients, discuss the role of ACE gene polymorphism and show the perspectives of potentially new applications of ACEI in contemporary pharmacotherapy. PMID- 28087256 TI - Manganese superoxide dismutase and glutathione peroxidase-1 contribute to the rise and fall of mitochondrial reactive oxygen species which drive oncogenesis. AB - Reactive oxygen species (ROS) largely originating in the mitochondria play essential roles in the metabolic and (epi)genetic reprogramming of cancer cell evolution towards more aggressive phenotypes. Recent studies have indicated that the activity of superoxide dismutase (SOD2) may promote tumor progression by serving as a source of hydrogen peroxide (H2O2). H2O2 is a form of ROS that is particularly active as a redox agent affecting cell signaling due to its ability to freely diffuse out of the mitochondria and alter redox active amino acid residues on regulatory proteins. Therefore, there is likely a dichotomy whereas SOD2 can be considered a protective antioxidant, as well as a pro-oxidant during cancer progression, with these effects depending on the accumulation and detoxification of H2O2. Glutathione peroxidase-1 GPX1, is a selenium-dependent scavenger of H2O2 which partitions between the mitochondria and the cytosol. Epidemiologic studies indicated that allelic variations in the SOD2 and GPX1 genes alter the distribution and relative concentrations of SOD2 and GPX1 in mitochondria, thereby affecting the dynamic between the production and elimination of H2O2. Experimental and epidemiological evidence supporting a conflicting role of SOD2 in tumor biology, and epidemiological evidence that SOD2 and GPX1 can interact to affect cancer risk and progression indicated that it is the net accumulation of mitochondrial H2O2 (mtH2O2) resulting from of the balance between the activities SOD2 and anti-oxidants such as GPX1 that determines whether SOD2 prevents or promotes oncogenesis. In this review, research supporting the idea that GPX1 is a gatekeeper restraining the oncogenic power of mitochondrial ROS generated by SOD2 is presented. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux. PMID- 28087257 TI - Calcium regulates cell death in cancer: Roles of the mitochondria and mitochondria-associated membranes (MAMs). AB - Until 1972, the term 'apoptosis' was used to differentiate the programmed cell death that naturally occurs in organismal development from the acute tissue death referred to as necrosis. Many studies on cell death and programmed cell death have been published and most are, at least to some degree, related to cancer. Some key proteins and molecular pathways implicated in cell death have been analyzed, whereas others are still being actively researched; therefore, an increasing number of cellular compartments and organelles are being implicated in cell death and cancer. Here, we discuss the mitochondria and subdomains of the endoplasmic reticulum (ER) that interact with mitochondria, the mitochondria associated membranes (MAMs), which have been identified as critical hubs in the regulation of cell death and tumor growth. MAMs-dependent calcium (Ca2+) release from the ER allows selective Ca2+ uptake by the mitochondria. The perturbation of Ca2+ homeostasis in cancer cells is correlated with sustained cell proliferation and the inhibition of cell death through the modulation of Ca2+ signaling. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux. PMID- 28087258 TI - Hyponatremic Hypertensive Syndrome in a Preterm Infant with Twin Anemia Polycythemia Sequence. PMID- 28087259 TI - Clinical Manifestations, Outcomes, and Etiologies of Perinatal Stroke in Taiwan: Comparisons between Ischemic, and Hemorrhagic Stroke Based on 10-year Experience in A Single Institute. AB - BACKGROUND: Perinatal stroke is a common cause of established neurological sequelae. Although several risk factors have been identified, many questions regarding causes and clinical outcomes remain unanswered. This study investigated the clinical manifestations and outcomes of perinatal stroke and identified its etiologies in Taiwan. METHODS: We searched the reports of head magnetic resonance imaging and computed tomography performed between January 2003 and December 2012. The medical records of enrolled infants with perinatal stroke were also reviewed. RESULTS: Thirty infants with perinatal stroke were identified; 10 infants had perinatal arterial ischemic stroke (PAIS) and 20 had perinatal hemorrhagic stroke (PHS). Neonatal seizure was the most common manifestation and presented in 40% of infants with PAIS and 50% of infants with PHS. All survivors with PAIS and 77% of the surviving infants with PHS developed neurological sequelae. Acute seizure manifestation was associated with poststroke epilepsy in infants with PHS but not in infants with PAIS (86% vs. 0%, p=0.005). PAIS was mostly caused by dysfunctional hemostasis (20%) and embolism (20%), whereas PHS was mostly attributable to birth asphyxia (30%). CONCLUSION: Perinatal stroke is associated with high mortality and morbidity rates in infants. Clinically, it can be difficult to distinguish PAIS and PHS. One should keep a high level of suspicion, especially for PHS, if infants develop unexplained seizure, cyanosis, conscious change, anemia, and/or thrombocytopenia. A systematic diagnostic approach is helpful in identifying the etiologies of perinatal stroke. PMID- 28087260 TI - Seizure Recurrence in Children after Stopping Antiepileptic Medication: 5-Year Follow-Up. AB - BACKGROUND: We wanted to identify in children with epilepsy the factors associated with seizure control and recurrence after a 2-year remission. METHODS: We did a 5-year follow-up of epileptic children whose antiepileptic medication had been stopped. Bivariate and multivariate analyses were used to compare features of electroencephalograms (EEGs) and clinical findings. In this study, 43 patients with and 64 without a seizure recurrence (SR) were enrolled. RESULTS: Clinical features strongly associated with SR in the univariate analysis included a symptomatic etiology for seizures, a history of status epilepticus, treatment duration before stopping antiepileptic drugs, and abnormal EEG findings at the time of stopping antiepileptic drugs. CONCLUSION: We found that a history of status epilepticus, symptomatic partial epilepsy, treatment duration before stopping antiepileptic drugs, and an abnormal EEG when the medication was stopped are important predictors of SR. The risk factors of SR after discontinuing antiepileptic drugs have been investigated in several studies. However, a history of status epilepticus as a predictive factor is rarely mentioned. PMID- 28087262 TI - Molecular Mechanisms of Autophagy-Part B. PMID- 28087261 TI - DNA aptamer probes for detection of estrogen receptor alpha positive carcinomas. AB - Estrogen receptor alpha (ERalpha) also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1) is a ligand-activated transcription factor. It is an important biomarker for breast cancer metastasis. In the present study, we report a novel DNA aptamer candidate against estrogen receptor (ER) alpha structure. The enriched aptamer candidate was obtained after 14 iterative cycles of in vitro protein-SELEX process. Isothermal calorimetry study suggests the nanomolar sensitivity of the candidate ER_Apt1 to its target protein. Fluorescence- and chemiluminescence-binding assays confirm the specificity of the candidate aptamer to ER alpha positive breast cancer cell line. Comparative analysis of ER_Apt1 to ER alpha monoclonal antibody was also performed to analyze the expression of ER alpha in various malignant cancer cell line. Cytochemical and immunohistochemistry assay indicates its potential use as a diagnostic agent against ERalpha positive carcinomas. The nucleotide aptamer sequences described in the present study can be used for the detection, treatment, prophylaxis and diagnosis of ERalpha-related disorder. PMID- 28087263 TI - Sacroiliitis due to calcium pyrophosphate deposition disease. PMID- 28087264 TI - Independent impedimetric analysis of two cell populations co-cultured on opposite sides of a porous support. AB - The transepithelial or -endothelial electrical resistance (TEER) is a very common and routinely recorded parameter describing the expression of barrier-forming cell-cell contacts (tight junctions) in quantitative terms. To determine TEER, barrier-forming cell monolayers are cultured on porous filter supports that separate two fluid compartments. The frequency-dependent impedance of the cell layer is then recorded and analyzed by means of equivalent circuit modelling providing TEER and the cell layer capacitance. The latter serves as a quantitative indicator for membrane topography. When cells are co-cultured on opposite sides of such a porous support to model more complex biological barriers, TEER readings will integrate over both cell layers and the individual contributions are not assessable. This study describes the modification of commonly used porous filter inserts by coating their backside with a thin gold film. When this gold-film is used as an additional electrode, both cell layers can be studied separately by impedance analysis. The electrical parameters of either cell layer are assessable independently by switching between different electrode combinations. The performance of this new approach is illustrated and documented by experiments that (i) follow the de novo formation of cell junctions between initially suspended cells and (ii) the manipulation of mature cell-cell junctions by cytoskeleton-active drugs. Both assays confirm that both cell layers are monitored entirely independently. PMID- 28087265 TI - Myocardial relaxation is accelerated by fast stretch, not reduced afterload. AB - Fast relaxation of cross-bridge generated force in the myocardium facilitates efficient diastolic function. Recently published research studying mechanisms that modulate the relaxation rate has focused on molecular factors. Mechanical factors have received less attention since the 1980s when seminal work established the theory that reducing afterload accelerates the relaxation rate. Clinical trials using afterload reducing drugs, partially based on this theory, have thus far failed to improve outcomes for patients with diastolic dysfunction. Therefore, we reevaluated the protocols that suggest reducing afterload accelerates the relaxation rate and identified that myocardial relengthening was a potential confounding factor. We hypothesized that the speed of myocardial relengthening at end systole (end systolic strain rate), and not afterload, modulates relaxation rate and tested this hypothesis using electrically stimulated trabeculae from mice, rats, and humans. We used load-clamp techniques to vary afterload and end systolic strain rate independently. Our data show that the rate of relaxation increases monotonically with end systolic strain rate but is not altered by afterload. Computer simulations mimic this behavior and suggest that fast relengthening quickens relaxation by accelerating the detachment of cross-bridges. The relationship between relaxation rate and strain rate is novel and upends the prevailing theory that afterload modifies relaxation. In conclusion, myocardial relaxation is mechanically modified by the rate of stretch at end systole. The rate of myocardial relengthening at end systole may be a new diagnostic indicator or target for treatment of diastolic dysfunction. PMID- 28087266 TI - Assessment of Sex Differences in Body Composition Among Adolescents With Anorexia Nervosa. AB - PURPOSE: To compare deficits in fat mass (FM) and lean body mass (LM) among male and female adolescents with anorexia nervosa (AN) and to identify other covariates associated with body composition. METHODS: We retrospectively reviewed electronic medical records of all subjects aged 9-20 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of AN and dual energy x-ray absorptiometry scans after initial evaluation at Stanford between March 1997 and February 2011. From the dual-energy x-ray absorptiometry scans, LM and FM results were converted to age-, height-, sex-, and race-specific Z-scores for age using the National Health and Nutrition Examination Survey reference data. RESULTS: A total of 16 boys and 119 girls with AN met eligibility criteria. The FM Z-score in girls with AN (-3.24 +/- 1.50) was significantly lower than that in boys with AN (-2.41 +/- .96) in unadjusted models (p = .007). LM was reduced in both girls and boys with AN, but there was no significant sex difference in LM Z-scores. In multivariate models, lower percentage median body mass index was significantly associated with lower FM Z-scores (beta = .08, p < .0001) and lower LM Z-score (beta = .03, p = .0002), whereas lower whole body bone mineral content Z-score was significantly associated with lower LM Z-score (beta = .21, p = .0006). CONCLUSIONS: FM deficits in girls were significantly greater than those in boys with AN in unadjusted models; however, the degree of malnutrition appeared to be the primary factor accounting for this difference. There were no significant sex differences in FM or LM in adjusted models. PMID- 28087268 TI - A Review of Effective Youth Engagement Strategies for Mental Health and Substance Use Interventions. AB - The majority of adult mental health and substance use (MH&SU) conditions emerge in adolescence. Prevention, diagnosis, and treatment programs targeting this age group have a unique opportunity to significantly impact the well-being of the future generation of adults. At the same time, youth are reluctant to seek treatment and have high rates of dropout from interventions. An emphasis on youth engagement in prevention and treatment interventions for MH&SU results in better health outcomes for those youth. This literature review was undertaken to evaluate opportunities to improve youth engagement in MH&SU programs. The intent was to determine best practices in the field that combined community-level improvement in clinical outcomes with proven strategies in engagement enhancement to inform program development at a local level. The results discuss 40 studies, reviews, and program reports demonstrating effective youth engagement. These have been grouped into six themes based on the underlying engagement mechanism: youth participation in program development, parental relationships, technology, the health clinic, school, and social marketing. A broad range of tools are discussed that intervention developers can leverage to improve youth engagement in prevention or treatment programs. PMID- 28087267 TI - Research in the Integration of Behavioral Health for Adolescents and Young Adults in Primary Care Settings: A Systematic Review. AB - Despite the recognition that behavioral and medical health conditions are frequently intertwined, the existing health care system divides management for these issues into separate settings. This separation results in increased barriers to receipt of care and contributes to problems of underdetection, inappropriate diagnosis, and lack of treatment engagement. Adolescents and young adults with mental health conditions have some of the lowest rates of treatment for their conditions of all age groups. Integration of behavioral health into primary care settings has the potential to address these barriers and improve outcomes for adolescents and young adults. In this paper, we review the current research literature for behavioral health integration in the adolescent and young adult population and make recommendations for needed research to move the field forward. PMID- 28087269 TI - Mitochondrial roles of the psychiatric disease risk factor DISC1. AB - Ion transport during neuronal signalling utilizes the majority of the brain's energy supply. Mitochondria are key sites for energy provision through ATP synthesis and play other important roles including calcium buffering. Thus, tightly regulated distribution and function of these organelles throughout the intricate architecture of the neuron is essential for normal synaptic communication. Therefore, delineating mechanisms coordinating mitochondrial transport and function is essential for understanding nervous system physiology and pathology. While aberrant mitochondrial transport and dynamics have long been associated with neurodegenerative disease, they have also more recently been linked to major mental illness including schizophrenia, autism and depression. However, the underlying mechanisms have yet to be elucidated, due to an incomplete understanding of the combinations of genetic and environmental factors contributing to these conditions. Consequently, the DISC1 gene has undergone intense study since its discovery at the site of a balanced chromosomal translocation, segregating with mental illness in a Scottish pedigree. The precise molecular functions of DISC1 remain elusive. Reported functions of DISC1 include regulation of intracellular signalling pathways, neuronal migration and dendritic development. Intriguingly, a role for DISC1 in mitochondrial homeostasis and transport is fast emerging. Therefore, a major function of DISC1 in regulating mitochondrial distribution, ATP synthesis and calcium buffering may be disrupted in psychiatric disease. In this review, we discuss the links between DISC1 and mitochondria, considering both trafficking of these organelles and their function, and how, via these processes, DISC1 may contribute to the regulation of neuronal behavior in normal and psychiatric disease states. PMID- 28087271 TI - Mesoionic pyrido[1,2-a]pyrimidinones: Discovery of dicloromezotiaz as a lepidoptera insecticide acting on nicotinic acetylcholine receptors1,2. AB - A novel class of mesoionic pyrido[1,2-a]pyrimidinones has been discovered with exceptional insecticidal activity controlling a number of insect species. In this communication, we report the part of the optimization program that led to the identification of dicloromezotiaz as a potent insecticide to control a broad range of lepidoptera. Our efforts in discovery, synthesis, structure-activity relationship elucidation, and biological activity evaluation are also presented. PMID- 28087270 TI - Examining the reliability and validity of the Clinical Assessment Interview for Negative Symptoms within the Management of Schizophrenia in Clinical Practice (MOSAIC) multisite national study. AB - The current study sought to expand on prior reports of the validity and reliability of the CAINS (CAINS) by examining its performance across diverse non academic clinical settings as employed by raters not affiliated with the scale's developers and across a longer test-retest follow-up period. The properties of the CAINS were examined within the Management of Schizophrenia in Clinical Practice (MOSAIC) schizophrenia registry. A total of 501 participants with a schizophrenia spectrum diagnosis who were receiving usual care were recruited across 15 national Patient Assessment Centers and evaluated with the CAINS, other negative symptom measures, and assessments of functioning, quality of life and cognition. Temporal stability of negative symptoms was assessed across a 3-month follow-up. Results replicated the two-factor structure of the CAINS reflecting Motivation and Pleasure and expression symptoms. The CAINS scales exhibited high internal consistency and temporal stability. Convergent validity was supported by significant correlations between the CAINS subscales with other negative symptom measures. Additionally, the CAINS was significantly correlated with functioning and quality of life. Discriminant validity was demonstrated by small to moderate associations between the CAINS and positive symptoms, depression, and cognition (and these associations were comparable to those found with other negative symptom scales). Findings suggest that the CAINS is a reliable and valid tool for measuring negative symptoms in schizophrenia across diverse clinical samples and settings. PMID- 28087272 TI - Synthesis and evaluation of 5-(1H-indol-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines as Bcl-2 inhibitory anticancer agents. AB - A series of 5-(1H-indol-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines 8a-j has been designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2 inhibitory anticancer agents based on our previous lead compound 8a. Synthesis of the target compounds was readily accomplished through a cyclisation reaction between indole-3-carboxylic acid hydrazide (5) and substituted isothiocyanates 6a j, followed by oxidative cyclodesulfurization of the corresponding thiosemicarbazide 7a-j using 1,3-dibromo-5,5-dimethylhydantoin. Active compounds of the series 8a-j were found to have sub-micromolar IC50 values selectively in Bcl-2 expressing human cancer cell lines; notably the 2-nitrophenyl analogue 8a was found to exhibit potent activity, and compounds 8a and 8e possessed comparable Bcl-2 binding affinity (ELISA assay) to the established natural product-based Bcl-2 inhibitor, gossypol. Molecular modeling studies helped to further rationalise anti-apoptotic Bcl-2 binding, and identified compounds 8a and 8e as candidates for further development as Bcl-2 inhibitory anticancer agents. PMID- 28087273 TI - Chitosan cross-linked with poly(ethylene glycol)dialdehyde via reductive amination as effective controlled release carriers for oral protein drug delivery. AB - The covalently cross-linked chitosan-poly(ethylene glycol)1540 derivatives have been developed as a controlled release system with potential for the delivery of protein drug. The swelling characteristics of the hydrogels based on these derivatives as the function of different PEG content and the release profiles of a model protein (bovine serum albumin, BSA) from the hydrogels were evaluated in simulated gastric fluid with or without enzyme in order to simulate the gastrointestinal tract conditions. The derivatives cross-linked with difunctional PEG1540-dialdehyde via reductive amination can swell in alkaline pH and remain insoluble in acidic medium. The cumulative release amount of BSA was relatively low in the initial 2h and increased significantly at pH 7.4 with intestinal lysozyme for additional 12h. The results proved that the release-and-hold behavior of the cross-linked CS-PEG1540H-CS hydrogel provided a swell and intestinal enzyme controlled release carrier system, which is suitable for oral protein drug delivery. PMID- 28087275 TI - Sequence, structure and function relationships in flaviviruses as assessed by evolutive aspects of its conserved non-structural protein domains. AB - Flaviviruses are responsible for serious diseases such as dengue, yellow fever, and zika fever. Their genomes encode a polyprotein which, after cleavage, results in three structural and seven non-structural proteins. Homologous proteins can be studied by conservation and coevolution analysis as detected in multiple sequence alignments, usually reporting positions which are strictly necessary for the structure and/or function of all members in a protein family or which are involved in a specific sub-class feature requiring the coevolution of residue sets. This study provides a complete conservation and coevolution analysis on all flaviviruses non-structural proteins, with results mapped on all well-annotated available sequences. A literature review on the residues found in the analysis enabled us to compile available information on their roles and distribution among different flaviviruses. Also, we provide the mapping of conserved and coevolved residues for all sequences currently in SwissProt as a supplementary material, so that particularities in different viruses can be easily analyzed. PMID- 28087274 TI - Study of antileishmanial activity of 2-aminobenzoyl amino acid hydrazides and their quinazoline derivatives. AB - A new small library of 2-aminobenzoyl amino acid hydrazide derivatives and quinazolinones derivatives was synthesized and fully characterized by IR, NMR, and elemental analysis. The activity of the prepared compounds on the growth of Leishmania aethiopica promastigotes was evaluated. 2-Benzoyl amino acid hydrazide showed higher inhibitory effect than the quinazoline counterpart. The in vitro antipromastigote activity demonstrated that compounds 2a, 2b, 2f and 4a had IC50 better than standard drug miltefosine and comparable activity to amphotericin B deoxycholate, which indicates their high antileishmanial activity against Leishmania. aethiopica. Among the prepared compounds; 2-amino-N-(6-hydrazinyl-6 oxohexyl)benzamide 2f (IC50=0.051MUM) has the best activity, 154 folds more active than reference standard drug miltefosine (IC50=7.832MUM), and half fold the activity of amphotericin B (IC50=0.035MUM). In addition, this compound was safe and well tolerated by experimental animals orally up to 250mg/kg and parenterally up to 100mg/kg. PMID- 28087276 TI - Drosophila Argonaute2 turnover is regulated by the ubiquitin proteasome pathway. AB - Argonaute (AGO) proteins play a central role in the RNA interference (RNAi) pathway, which is a cytoplasmic mechanism important for post-transcriptional regulation of gene expression. In Drosophila, AGO2 also functions in the nucleus to regulate chromatin insulator activity and transcription. Although there are a number of studies focused on AGO2 function, the regulation of AGO2 turnover is not well understood. We found that mutation of T1149 or R1158 in the conserved PIWI domain causes AGO2 protein instability, but only T1149 affects RNAi activity. Mass spec analysis shows that several proteasome components co-purify with both wildtype and mutant AGO2, and knockdown of two proteasome pathway components results in AGO2 protein accumulation. Finally, AGO2 protein levels increase after treatment with the proteasome inhibitor MG132. Our results indicate that the ubiquitin-proteasome pathway is involved in AGO2 protein turnover. PMID- 28087277 TI - Identification of UBact, a ubiquitin-like protein, along with other homologous components of a conjugation system and the proteasome in different gram-negative bacteria. AB - Systems analogous to the eukaryotic ubiquitin-proteasome system have been previously identified in Archaea, and Actinobacteria (gram-positive), but not in gram-negative bacteria. Here, we report the bioinformatic identification of a novel prokaryotic ubiquitin-like protein, which we name UBact. The phyletic distribution of UBact covers at least five gram-negative bacterial phyla, including Nitrospirae, Armatimonadetes, Verrucomicroba, Nitrospinae, and Planctomycetes. Additionally, it was identified in seven candidate (uncultured) phyla and one Archaeon. UBact might have been overlooked because only few species in the phyla where it is found have been sequenced. In most of the species where we identified UBact, its neighbors in the genome code for proteins homologous to those involved in conjugation and/or degradation of Pup and Pup-tagged substrates. Among them are PafA-, Dop-, Mpa- and proteasome-homologous proteins. This gene association as well as UBact's size and conserved C-terminal G[E/Q] motif, strongly suggest that UBact is used as a conjugatable tag for degradation. With regard to its C-terminus, UBact differs from ubiquitin and most ubiquitin like proteins (including the mycobacterial Pup) in that it lacks the characteristic C-terminal di-glycine motif, and it usually ends with the sequence R[T/S]G[E/Q]. The phyla that contain UBact are thought to have diverged over 3000 million years ago, indicating that either this ubiquitin-like conjugation system evolved early in evolution or that its occurrence in distant gram-negative phyla is due to multiple instances of horizontal gene transfer. PMID- 28087278 TI - Prolyl-tRNA synthetase inhibition promotes cell death in SK-MEL-2 cells through GCN2-ATF4 pathway activation. AB - Protein translation is highly activated in cancer tissues through oncogenic mutations and amplifications, and this can support survival and aberrant proliferation. Therefore, blocking translation could be a promising way to block cancer progression. The process of charging a cognate amino acid to tRNA, a crucial step in protein synthesis, is mediated by tRNA synthetases such as prolyl tRNA synthetase (PRS). Interestingly, unlike pan-translation inhibitors, we demonstrated that a novel small molecule PRS inhibitor (T-3861174) induced cell death in several tumor cell lines including SK-MEL-2 without complete suppression of translation. Additionally, our findings indicated that T-3861174-induced cell death was caused by activation of the GCN2-ATF4 pathway. Furthermore, the PRS inhibitor exhibited significant anti-tumor activity in several xenograft models without severe body weight losses. These results indicate that PRS is a druggable target, and suggest that T-3861174 is a potential therapeutic agent for cancer therapy. PMID- 28087279 TI - Alpha-2-macroglobulin and heparin cofactor II and the vulnerability of carotid atherosclerotic plaques: An iTRAQ-based analysis. AB - Rupture of carotid atherosclerotic plaque may cause stroke, while few biomarker in clinic can evaluate carotid plaque vulnerability. In this study, we divided the recruited participants into no plaque, stable plaque, and vulnerable plaque group according to carotid ultrasonography, and screened the differentially expressed proteins in plasma of these participants using isobaric tags for relative and absolute quantitation labeling coupled with liquid chromatography tandem mass spectrometry. 28 proteins were identified differentially expressed, among which alpha-2-macroglobulin (alpha2M) and heparin cofactor II (HCII) were found to be at hub position in the interactions of these proteins by STRING analysis and were selected for enzyme-linked immunosorbent assay measurement to assess their relevance with carotid plaques vulnerability and diagnostic efficiency. The plasma level of alpha2M was found positively correlated, while HCII level was negatively correlated with higher vulnerability of carotid plaques. Both proteins were efficient in differentiating stable and vulnerable carotid plaques. These findings provide potential new targets for the research of carotid plaque vulnerability. Plasma alpha2M and HCII may be potential biomarkers for evaluation of the vulnerability of carotid plaques if further studied. PMID- 28087280 TI - Increased homocysteine levels impair reference memory and reduce cortical levels of acetylcholine in a mouse model of vascular cognitive impairment. AB - Folates are B-vitamins that are vital for normal brain function. Deficiencies in folates either genetic (methylenetetrahydrofolate reductase, MTHFR) or dietary intake of folic acid result in elevated levels of homocysteine. Clinical studies have shown that elevated levels of homocysteine (Hcy) may be associated with the development of dementia, however this link remains unclear. The purpose of this study was to evaluate the impact of increased Hcy levels on a mouse model of vascular cognitive impairment (VCI) produced by chronic hypoperfusion. Male and female Mthfr+/+ and Mthfr+/- mice were placed on either control (CD) or folic acid deficient (FADD) diets after which all animals underwent microcoil implantation around each common carotid artery or a sham procedure. Post operatively animals were tested on the Morris water maze (MWM), y-maze, and rotarod. Animals had no motor impairments on the rotarod, y-maze, and could learn the location of the platform on the MWM. However, on day 8 of testing of MWM testing during the probe trial, Mthfr+/- FADD microcoil mice spent significantly less time in the target quadrant when compared to Mthfr+/- CD sham mice, suggesting impaired reference memory. All FADD mice had elevated levels of plasma homocysteine. MRI analysis revealed arterial remodeling was present in Mthfr+/- microcoil mice not Mthfr+/+ mice. Acetylcholine and related metabolites were reduced in cortical tissue because of microcoil implantation and elevated levels of homocysteine. Deficiencies in folate metabolism resulting in increased Hcy levels yield a metabolic profile that increases susceptibility to neurodegeneration in a mouse model of VCI. PMID- 28087281 TI - Monopolar Transurethral Enucleation of Prostatic Adenoma: Preliminary Report. AB - OBJECTIVE: To describe preliminary results of our monopolar transurethral enucleation of prostatic adenoma (mTUEPA). MATERIALS AND METHODS: A consecutive series of male patients treated with mTUEPA, a retrograde enucleation of the prostatic adenoma performed by means of a standard monopolar resectoscope, were prospectively enrolled. Symptoms, uroflowmetry parameters, and post-voiding residual were assessed at baseline and at 1, 6, and 12 months postoperatively. Prostate volume was evaluated at baseline by means of transrectal ultrasound. Antiplatelet and anticoagulant drugs were stopped at least 1 week before the operation. RESULTS: Forty-seven patients were enrolled. Mean preoperative prostate volume was 64.9 +/- 28.5 g. When assessed at baseline, the mean total International Prostatic Symptoms Score was 15.2 +/- 3.9, peak flow rate (Qmax) was 8.4 +/- 2.9 mL/s and the post-voiding residual was 103.2 +/- 90.6 mL. Four weeks after surgery, patients reported a mean International Prostatic Symptoms Score of 5.3 +/- 3. This lower urinary tract symptoms relief was further maintained at 6 and 12 months after surgery. A significant postoperative improvement in uroflowmetry parameters was described, being the 6 and 12 months mean Qmax of 23.4 +/- 10.6 mL/s and 18.8 +/- 9.2 mL/s, respectively (P < .001). Overall, 14 postoperative complications were reported by 13 of 47 (27.6%) patients: most of them were minor complications (Clavien-Dindo Grade I-II), whereas 1 patient reported capsule perforation during surgery, requiring interruption of the procedure and its further completion (Clavien-Dindo IIIb). CONCLUSION: mTUEPA is a safe and effective technique, merging the principles of laser enucleation and the advantages of mechanical enucleation with standard monopolar transurethral resection of the prostate equipment. PMID- 28087282 TI - Short-term perioperative teriparatide therapy for the prevention of medication related osteonecrosis of the jaw: A randomized, controlled preclinical study in rats. AB - OBJECTIVE: Dentoalveolar procedures in patients receiving bisphosphonates and other antiresorptive agents are associated with an increased risk of medication related osteonecrosis of the jaw (MRONJ). The aim of present study was to evaluate the effects of perioperative teriparatide (TPD) therapy in prevention of MRONJ. SUBJECTS AND METHODS: Two protocols of TPD therapy were studied. For protocol A, 25 TPD-treated (AT) and 25 control (AC) rats received 5 weekly injection of 0.06 mg/kg zoledronate. At the end of week 5, extraction of bilateral mandibular first molars was performed for all rats, and 4-week TPD (20 MUg/kg/day) and saline therapy was started for AT and AC rats, respectively. For protocol B, 25 TPD-treated (BT) and 25 control (BC) rats received 5 weekly injection of 0.06 mg/kg zoledronate. One week later, 4-week TPD and saline therapy was started for BT and BC rats, respectively. Both groups underwent tooth extraction at the end of week 7 of the experiment. All rats were sacrificed 8 weeks after tooth extraction and assessed clinically for bone exposure/fistula, and histologically for density of osteocytes in newly formed bone and empty osteocyte lacunae in alveolar bone. RESULTS: Incidence of bone exposure/fistula and mean numbers of osteocytes and empty lacunae per 25 mm2 (at 400* magnification) were 20%, 15.36, and 2.63 in AT group; 78%, 5.78, and 6.81 in AC group; 14%, 16.94, and 2.08 in BT group; and 78%, 7.54, and 5.95 in BC group; respectively. The differences between AT and AC and between BT and BC were statistically significant (P < 0.001). However, no statistically significant difference between AT and BT and between AC and BC was found. CONCLUSION: Four weeks of TPD therapy, beginning at the same day or 2 weeks before tooth extraction, had a potential role in prevention of ONJ. PMID- 28087283 TI - Benefits of using the ultrasonic BoneScalpelTM in temporomandibular joint reconstruction. AB - PURPOSE: The main objective of this retrospective study is to analyze and report on our operative experiences and outcomes using the ultrasonic BoneScalpelTM (BoneScalpel) versus a conventional reciprocating saw (RecipSaw) for the purpose of completing the osteotomies in total temporomandibular joint reconstruction (TJR) surgery. MATERIALS AND METHODS: 23 consecutive patients presented with a diagnosis of either degenerative joint disease (n = 23), a failing autogenous TJR (n = 1), heterotrophic bone formation (n = 1) or a subcondylar fracture (n = 1) for a total of 26 joints that received a TJR. 13 unique TJR surgeries employed the use of the BoneScalpel to perform the osteotomies and 13 used the RecipSaw. RESULTS: There was a 49% reduction in the average volume of blood loss in the BoneScalpel group compared to the RecipSaw group (130cc vs. 268cc, p <= 0.004), unpaired t-test). For the other variables it was observed that there were more favorable clinical results using the BoneScalpel but without statistically significant differences given the small sample size relative to the prevalence of the outcome that was being measured. CONCLUSIONS: Use of the BoneScalpel in TMJ reconstruction is overall safer and results in less blood loss compared to surgeries employing the use of the conventional RecipSaw for completing osteotomies. PMID- 28087284 TI - Pharmacological and surgical therapy for the central giant cell granuloma: A long term retrospective cohort study. AB - PURPOSE: This is a retrospective cohort study of patients with a central giant cell granuloma (CGCG) treated at a single center to assess and compare the different surgical and non-surgical approaches. MATERIAL AND METHODS: A cohort with a single histologically proven non-syndrome-related CGCG was selected and reviewed. Patients were allocated to group I (surgery), group II (pharmacotherapy), and group III (pharmacotherapy and surgery). The primary outcome was long-term radiologic response using computed tomography. Secondary outcomes were intermediate radiologic responses and occurrence and severity of side effects. RESULTS: Thirty-three subjects were included in the study. The surgical group (n = 4) included 1 patient with progression during follow-up and a relatively high post-surgical morbidity. Twenty-nine patients started on various pharmacological treatment regimens (groups II and III). Fourteen patients could be managed without additional surgery. One of these lesions showed progression during follow-up. The other 15 lesions underwent additional surgery, and none showed progression during follow-up. Interferon treatment was associated with the most side effects. CONCLUSION: Pharmacological agents have a role in the treatment of aggressive and non-aggressive CGCGs by limiting the renewed progression during long-term follow up and the extent and morbidity of surgical treatment. PMID- 28087285 TI - Apert syndrome: A consensus on the management of Apert hands. AB - INTRODUCTION: Apert Syndrome is a congenital condition characterised by primary craniosynostosis, midfacial malformations and complex symmetrical malformations of the hands and feet. The hands demonstrate one of the most complex collections of congenital upper limb deformities, posing a significant challenge for the paediatric hand surgeon. This study examines the extant literature and current practice of the four UK specialist craniofacial units regarding the management of Apert hands in order to provide a basis for guideline development. METHODS: The current literature was reviewed. Survey-type questionnaires were distributed to the four UK specialist craniofacial units and responses analysed. RESULTS: Management of the Apert hand is largely dictated by the degree of malformation present. Although all units aim to achieve a five digit hand, variation in the timing of surgery, operative protocols and mobilisation policies exist. CONCLUSION: The results of this study provide an interesting snapshot of the current management of Apert hands across four UK craniofacial surgery units. The four UK units remain congruent on most areas surrounding the management of Apert hands although some minor inter-unit variation exists. A multidisciplinary approach to management remains fundamental in optimising the regain of function and aesthetically acceptable hands. PMID- 28087287 TI - Clinical documentation of in-hospital cardiac arrest in a large national health system. PMID- 28087286 TI - Incidence and survival outcome according to heart rhythm during resuscitation attempt in out-of-hospital cardiac arrest patients with presumed cardiac etiology. AB - BACKGROUND: Knowledge about heart rhythm conversion from non-shockable to shockable rhythm during resuscitation attempt after out-of-hospital cardiac arrest (OHCA) and following chance of survival is limited and inconsistent. METHODS: We studied 13,860 patients with presumed cardiac-caused OHCA not witnessed by the emergency medical services from the Danish Cardiac Arrest Register (2005-2012). Patients were stratified according to rhythm: shockable, converted shockable (based on receipt of subsequent defibrillation) and sustained non-shockable rhythm. Multiple logistic regression was used to identify predictors of rhythm conversion and to compute 30-day survival chances. RESULTS: Twenty-five percent of patients who received pre-hospital defibrillation by ambulance personnel were initially found in non-shockable rhythms. Younger age, males, witnessed arrest, shorter response time, and heart disease were significantly associated with conversion to shockable rhythm, while psychiatric- and chronic obstructive pulmonary disease were significantly associated with sustained non-shockable rhythm. Compared to sustained non-shockable rhythms, converted shockable rhythms and initial shockable rhythms were significantly associated with increased 30-day survival (Adjusted odds ratio (OR) 2.6, 95% confidence interval (CI): 1.8-3.8; and OR 16.4, 95% CI 12.7-21.2, respectively). From 2005 to 2012, 30-day survival chances increased significantly for all three groups: shockable rhythms, from 16.3% (CI: 14.2%-18.7%) to 35.7% (CI: 32.5% 38.9%); converted rhythms, from 2.1% (CI: 1.6%-2.9%) to 5.8% (CI: 4.4%-7.6%); and sustained non-shockable rhythms, from 0.6% (CI: 0.5%-0.8%) to 1.8% (CI: 1.4% 2.2%). CONCLUSION: Converting to shockable rhythm during resuscitation attempt was common and associated with nearly a three-fold higher odds of 30-day survival compared to sustained non-shockable rhythms. PMID- 28087288 TI - Outcome of adult patients attended by rapid response teams: A systematic review of the literature. AB - BACKGROUND: An abundance of studies have investigated the impact of rapid response teams (RRTs) on in-hospital cardiac arrest rates. However, existing RRT data appear highly variable in terms of both study quality and reported uses of limitations of care, patient survival and patient long-term outcome. METHODS: A systematic electronic literature search (January, 1990-March, 2016) of the PubMed and Cochrane databases was performed. Bibliographies of articles included in the full-text review were searched for additional studies. A predefined RRT cohort quality score (range 0-17) was used to evaluate studies independently by two reviewers. RESULTS: Twenty-nine studies with a total of 157,383 RRT activations were included in this review. The quality of data reporting related to RRT patients was assessed as modest, with a median quality score of 8 (range 2-11). Data from the included studies indicate that a median 8.1% of RRT reviews result in limitations of medical treatment (range 2.1-25%) and 23% (8.2-56%) result in a transfer to intensive care. A median of 29% (6.9-35%) of patients transferred to intensive care died during that admission. The median hospital mortality of patients reviewed by RRT is 26% (12-60%), and the median 30-day mortality rate is 29% (8-39%). Data on long-term survival is minimal. No data on functional outcomes was identified. CONCLUSIONS: Patients reviewed by rapid response teams have a high and variable mortality rate, and limitations of care are commonly used. Data on the long-term outcomes of RRT are lacking and needed. PMID- 28087289 TI - Clinical utility and functional analysis of variants in atrial fibrillation associated locus 4q25. AB - BACKGROUND: Chromosome 4q25 has been repeatedly identified as atrial fibrillation (AF)-sensitive locus in multiple genome-wide association studies (GWAS) and is considered to hold some clues to AF pathogenesis. We aimed to investigate the clinical utilities in Japanese and to unveil the function of the 4q25 locus in affecting transcription of adjacent genes. METHODS: We conducted AF GWAS in Japanese population (1382 AF cases and 1478 controls) and the replication panel (1666 AF cases and 1229 controls) with detailed clinical information which showed the acceleration of AF onset. Stepwise investigations with linkage disequilibrium analysis, histone code patterns, and reporter assay in the 4q25 locus were performed. RESULTS: The AF GWAS confirmed a significant association of rs4611994 and rs1906617 in chromosome 4q25 with AF. In the clinical analysis, AF onset of the individuals with risk allele accelerated 2.5 years compared with those with protective allele (p=0.00012). Next, in the functional analysis, three single nucleotide polymorphisms (SNPs) in the variant group selected by linkage disequilibrium analysis were identified as candidates for the cis-regulatory element toward adjacent genes in chromatin immunoprecipitation assay. Among them, rs4611994 and rs72900144 regions showed higher effects on the transcriptional activity of luciferase gene in the risk alleles than those in the protective alleles (p<0.0001, p<0.005, respectively). CONCLUSIONS: AF GWAS in Japanese confirmed the association with 4q25 locus and indicated that its SNP affected the acceleration of AF onset. The candidate regions of the causative SNPs, rs4611994 and rs72900144, could alter the adjacent gene expression level. PMID- 28087290 TI - Inferior J waves in patients with vasospastic angina might be a risk factor for ventricular fibrillation. AB - BACKGROUND: There is little information about the relationship between J waves and the occurrence of ventricular fibrillation (VF) in patients with vasospastic angina (VSA). The present study aimed to assess the incidence of J waves and the occurrence of VF in patients with VSA. METHODS: The subjects consisted of 62 patients with VSA diagnosed by acetylcholine provocation tests in our institution from 2002 to 2014. We investigated the VF events, prevalence of J waves, and relationship between the VF events and J waves. RESULTS: J waves were observed in 16 patients (26%) and VF events were documented in 11 (18%). The incidence of VF in the patients with J waves was significantly higher than that in those without J waves (38% vs 11%, p=0.026). J waves were observed in the inferior leads in 14 patients, lateral leads in 5, and anterior leads in 3. A univariate analysis indicated that the incidence of VF in the inferior leads of J wave positive patients (46%=6/14) was significantly (p=0.01) higher than that in the inferior leads of J wave negative patients (10%=5/48). The J waves in the anterior and/or lateral leads were not related to the incidence of VF. Notched type and slurred type J waves were not associated with VF. A multivariate analysis revealed that J waves in VSA patients were associated with VF [odds ratio (OR) 6.41, 95% confidence interval (CI) 1.37-29.93, p=0.02] and organic stenosis (OR 6.98, 95% CI 1.39-35.08, p=0.02). Further, J waves in the inferior leads were strongly correlated with VF (OR 11.85, 95% CI 2.05-68.42, p=0.006). CONCLUSIONS: The results suggest that the existence of J waves, especially in the inferior leads, might be a risk factor for VF in VSA patients. PMID- 28087291 TI - Primary Care Perspectives on Hepatitis C Virus Screening, Diagnosis and Linking Patients to Appropriate Care. AB - Enormous progress has been made in recent years toward effectively treating and curing patients with chronic hepatitis C (CHC). However, at least half of the possible 7 million individuals infected with hepatitis C virus (HCV) in the US remain undiagnosed. The formidable task of increasing the number of patients diagnosed, and subsequently linked to appropriate care has fallen to primary care clinicians, who are mandated by some US States to offer screening to individuals born between 1945 and 1965 (the Baby Boomer Generation). This peer-reviewed video roundtable discussion http://hepcresource.amjmed.com/Content/jplayer/video_roundtable.html#video0 addresses the challenges encountered by primary care clinicians faced with the increasing societal need to screen for HCV, make appropriate diagnoses, and subsequently link infected patients to appropriate care. Discussion in this roundtable initially focuses on the offering of HCV screening to patients in primary care settings. Roundtable participants discuss the need for primary care clinicians to ask appropriate risk factor-based questions of their patients, especially if the ongoing HCV epidemic is to be curtailed. The participants note, however, that the majority of patients currently infected with HCV in the US are Baby Boomers, and USPTF guidelines require this population to be tested for HCV regardless of any past risk-taking behaviors. So while asking the right questions is important, the failure of a Baby Boomer to recall risk-taking behavior does not preclude HCV screening. In fact, clinicians should proactively screen all persons in this birth cohort, and be more sensitive and open to screening requests from these individuals. Roundtable participants also discuss how HCV screening results should be communicated to patients, and how physicians can keep patients engaged and not lost to follow-up after an initial positive HCV antibody test. Patients screened and found to be HCV antibody positive require a follow-up HCV RNA test, and every effort must be made to overcome the challenge of losing patients between these two steps. Good communication between the physician, the physician's office staff, and the patient is necessary. In addition, point-of care tests and PCR reflex testing can alleviate the need for HCV antibody positive patients to arrange subsequent office visits to undergo confirmatory HCV RNA testing. Physician and patient perspectives are presented throughout this roundtable discussion to obtain a complete picture of the management barriers encountered prior to initiation of therapy. Physician perspectives are provided by Edward Lebovics, the Upham Professor of Gastroenterology and Director of the Sarah C. Upham Division of Gastroenterology and Hepatobiliary Diseases at New York Medical College and Westchester Medical Center in Valhalla, New York, and Richard Torres, Chief Medical Officer at Optimus Health Care and an Associate Professor of Medicine at Yale School of Medicine. Torres has been a primary care provider for 29 years, working at the largest federally qualified community health center in Southwestern CT, which provides over 240,000 patient visits annually primarily to populations that are underserved and suffering from healthcare disparities. Patient perspectives in this roundtable are provided by Lucinda K. Porter, RN, who is the author of two books for hepatitis C patients, and is a former hepatology nurse and hepatitis C patient. She has been advocating for others since 1997, and writes for the HCV Advocate. Lucinda is a contributing editor of HEP magazine, and she blogs at www.LucindaPorterRN.com. The overall goal of this video roundtable discussion is to demonstrate that when provided with appropriate clinical knowledge, and aided by supportive collaborations with appropriate specialists, primary care clinicians should be able to effectively screen, diagnose, and link patients with hepatitis C to appropriate care. While patients need to be educated on the possible outcomes of a positive HCV antibody test, the significance of a positive HCV RNA test, and how to prevent further transmission, they should also be assured that currently available therapies have dramatically increased the chances of being cured. Appropriate education and the availability of excellent treatment options will hopefully quell fears and increase the morale of patients as they navigate the process of HCV screening and diagnosis. PMID- 28087292 TI - Loss of CD28 within CD4+ T cell subsets from cervical cancer patients is accompanied by the acquisition of intracellular perforin, and is further enhanced by NKG2D expression. AB - CD28 is well characterized as an essential co-stimulatory receptor critical for activation, proliferation and survival processes in CD4+ T cells. Populations of CD4+CD28null T cells, with apparently contradictory physiological roles, have recently been reported, along with the co-expression of the NK activating receptor NKG2D, in autoimmune diseases and chronic viral inflammation. Paradoxically, studies in cancer suggest that an expanded CD4+NKG2D+ population may be armed with immunosuppressive properties. We have recently reported the existence of two separate CD4+NKG2D+ T cell populations, which were defined by the presence or absence of the co-stimulatory molecule CD28, with the CD4+CD28nullNKG2D+ population more frequently observed in women with cervical cancer. This has led to the present effort to further characterize this population and to determine if the loss of CD28 influences the acquisition of cytotoxic or regulatory markers. In the present work, a multicolor flow cytometry protocol was used to analyze the expression of cytotoxic and immunoregulatory markers on circulating CD4+ T cells characterized by the presence or absence of CD28 and NKG2D in patients with invasive cervical carcinoma and age/gender matched healthy controls. A noticeable expansion of CD4+CD28null cells, many of them NKG2D+, were observed in selected cervical cancer samples. This CD4+CD28null T cell population was characterized by a lack of immunoregulatory markers, as well as very low basal levels of intracellular IFN-gamma, TNF-alpha, TGF-beta, and IL-10. Intracellular perforin, however, was found to be significantly increased in this CD4+CD28null population, and increases in the mean fluorescence intensity of perforin were found to be enhanced by the presence of NKG2D. In conclusion, our data provide the first evidence of a strict link between the absence of CD28 and the expression of perforin, which is likewise enhanced by the expression of NKG2D, within selected CD4+ T cells from cervical cancer patients. PMID- 28087293 TI - First itraconazole resistant Aspergillus fumigatus clinical isolate harbouring a G54E substitution in Cyp51Ap in South America. AB - BACKGROUND: A 27-year-old male rural worker was admitted with a fungal keratitis due to an injury involving plant detritus. MATERIALS AND METHODS: Specimens were collected for microscopy examination and culture. The isolate was identified by morphological and molecular criteria. Susceptibility testing was performed using CLSI methods. CYP51A gene was PCR amplified and sequenced. RESULTS: An Aspergillus fumigatus strain resistant to itraconazole (MIC>8MUg/ml) was isolated. The isolate was susceptible to amphotericin B, posaconazole, voriconazole and caspofungin. CYP51A sequencing showed two mutations leading on the G54E substitution. The patient received natamycin as treatment. CONCLUSIONS: This is the first report in South America of a clinical A. fumigatus strain carrying the substitution G54E at Cyp51Ap associated with itraconazole resistance. Considering the patient was azole-naive, this resistant isolate may have been acquired from the environment. PMID- 28087294 TI - Bioactive metabolites of docosahexaenoic acid. AB - Docosahexaenoic acid (DHA) is an essential fatty acid that is recognized as a beneficial dietary constituent and as a source of the anti-inflammatory specialized proresolving mediators (SPM): resolvins, protectins and maresins. Apart from SPMs, other metabolites of DHA also exert potent biological effects. This article summarizes current knowledge on the metabolic pathways involved in generation of DHA metabolites. Over 70 biologically active metabolites have been described, but are often discussed separately within specific research areas. This review follows DHA metabolism and attempts to integrate the diverse DHA metabolites emphasizing those with identified biological effects. DHA metabolites could be divided into DHA-derived SPMs, DHA epoxides, electrophilic oxo derivatives (EFOX) of DHA, neuroprostanes, ethanolamines, acylglycerols, docosahexaenoyl amides of amino acids or neurotransmitters, and branched DHA esters of hydroxy fatty acids. These bioactive metabolites have pleiotropic effects that include augmenting energy expenditure, stimulating lipid catabolism, modulating the immune response, helping to resolve inflammation, and promoting wound healing and tissue regeneration. As a result they have been shown to exert many beneficial actions: neuroprotection, anti-hypertension, anti-hyperalgesia, anti-arrhythmia, anti-tumorigenesis etc. Given the chemical structure of DHA, the number and geometry of double bonds, and the panel of enzymes metabolizing DHA, it is also likely that novel bioactive derivatives will be identified in the future. PMID- 28087295 TI - Postconditioning-induced neuroprotection, mechanisms and applications in cerebral ischemia. AB - Ischemic postconditioning (PostC) is defined as a series of rapid intermittent interruptions of blood flow at the phase of reperfusion, which produces neuroprotection against cerebral ischemia/reperfusion injury via mobilizing the brain's own endogenous adaptive mechanisms. Now the concept of conventional ischemic PostC has been extended to limb remote ischemic PostC and chemical PostC with hypoxia, volatile anesthetic, CO2, etc. According to the different temporal profile of PostC, it is divided into rapid and delayed PostC. Rapid PostC is applied within a few seconds to minutes after reperfusion, while delayed PostC is applied at a few hours to days after reperfusion. Although the neuroprotective mechanisms of PostC are not completely elucidated, a series of mechanisms have been found to connect with PostC in the central nervous system, such as regulating synaptic signaling, attenuating oxidative stress and inflammation, maintaining mitochondrial integrity, inhibiting endoplasmic reticulum stress, regulating autophagy, activating PI3K/Akt pathway, inhibiting apoptosis, protecting neurovascular unit, etc. Based on these multiple protective mechanisms, PostC has high expectations to translate to the clinic, but a few issues should be resolved such as the time window, risks, efficiency, the impact of age, gender, hypertension, hyperlipidemia and t-PA, and clinical maneuverability. Even so, PostC could soon be at the bedside if the clinical trials are carefully planned. PMID- 28087296 TI - Defining digital dentistry: A survey of recent literature. PMID- 28087297 TI - Inhibition of streptococcal biofilm by hydrogen water. AB - OBJECTIVES: The accumulation of oral bacterial biofilm is the main etiological factor of oral diseases. Recently, electrolyzed hydrogen-rich water (H-water) has been shown to act as an effective antioxidant by reducing oxidative stress. In addition to this general health benefit, H-water has antibacterial activity for disease-associated oral bacteria. However, little is known about the effect of H water on oral bacterial biofilm. The objective of this study was to confirm the effect of H-water on streptococcal biofilm formation. METHODS: In vitro streptococcal biofilm was quantified using crystal violet staining after culture on a polystyrene plate. The effect of H-water on the expression of genes involved in insoluble glucan synthesis and glucan binding, which are critical steps for oral biofilm formation, was evaluated in MS. In addition, we compared the number of salivary streptococci after oral rinse with H-water and that with control tap water. Salivary streptococci were quantified by counting viable colonies on Mitis Salivarius agar-bacitracin. RESULTS: Our data showed that H-water caused a significant decrease in in vitro streptococcal biofilm formation. The expression level of the mRNA of glucosyltransferases (gtfB, gtfc, and gtfI) and glucan binding proteins (gbpC, dblB) were decreased remarkably in MS after H-water exposure for 60s. Furthermore, oral rinse with H-water for 1 week led to significantly fewer salivary streptococci than did that with control tap water. CONCLUSIONS: Our data suggest that oral rinse with H-water would be helpful in treating dental biofilm-dependent diseases with ease and efficiency. PMID- 28087298 TI - The Utility of Sex Hormone-Binding Globulin in Hypogonadism and Infertile Males. AB - PURPOSE: We sought to determine the role of sex hormone-binding globulin in patients with male infertility. MATERIALS AND METHODS: We retrospectively reviewed the records of 168 males seen at a fertility clinic from 2012 to 2014 to investigate the accuracy of total testosterone in the biochemical diagnosis of hypogonadism using calculated bioavailable testosterone as the reference value. We used multivariable analysis to assess sex hormone-binding globulin as an independent predictor of infertility. RESULTS: Computations using calculated bioavailable testosterone as a standard in the measurement of definitive biochemical hypogonadism (less than 156 ng/dl) revealed 81% sensitivity, 83% specificity, 81% positive predictive value and 82% negative predictive value for diagnosing hypogonadism with total testosterone alone. Of the 90 men with total testosterone greater than 300 ng/dl, 20% had low bioavailable testosterone less than 156 ng/dl, 52% had borderline low bioavailable testosterone less than 210 ng/dl and only 48% could be considered biochemically eugonadal according to calculated bioavailable testosterone. Of the 80 patients with total testosterone less than 300 ng/dl, 19% had free testosterone levels greater than 6.5 ng/dl and, thus, could be considered to be eugonadal. By a magnitude similar to that of follicle-stimulating hormone, sex hormone-binding globulin independently predicted decreased sperm concentration (p = 0.0027) and motility (p = 0.0447). After excluding men with azoospermia, only sex hormone-binding globulin levels differed significantly in classically hypogonadal men (group 1-total testosterone less than 300 ng/dl) and those missed but hypogonadal (group 2-calculated bioavailable testosterone less than 210 ng/dl) (p = 0.0001). At a more stringent cutoff of calculated bioavailable testosterone less than 156 ng/dl, sperm motility was significantly different for groups 1 and 2 (p = 0.014). CONCLUSIONS: Adding sex hormone-binding globulin to total testosterone serum testing facilitates more accurate diagnosis with free testosterone and calculated bioavailable testosterone, and clinical implications of decreased semen parameters to a magnitude similar to that of follicle-stimulating hormone. This warrants further study of the role of sex hormone-binding globulin in male infertility. PMID- 28087299 TI - When Partial Nephrectomy is Unsuccessful: Understanding the Reasons for Conversion from Robotic Partial to Radical Nephrectomy at a Tertiary Referral Center. AB - PURPOSE: We sought to identify the preoperative factors associated with conversion from robotic partial nephrectomy to radical nephrectomy. We report the incidence of this event. MATERIALS AND METHODS: Using our institutional review board approved database, we abstracted data on 1,023 robotic partial nephrectomies performed at our center between 2010 and 2015. Standard and converted cases were compared in terms of patients and tumor characteristics, and perioperative, functional and oncologic outcomes. Logistic regression analysis was done to identify predictors of radical conversion. RESULTS: The overall conversion rate was 3.1% (32 of 1,023 cases). The most common reasons for conversion were tumor involvement of hilar structures (8 cases or 25%), failure to achieve negative margins on frozen section (7 or 21.8%), suspicion of advanced disease (5 or 15.6%) and failure to progress (5 or 15.6%). Patients requiring conversion were older and had a higher Charlson score (both p <0.01), including an increased prevalence of chronic kidney disease (p = 0.02). Increasing tumor size (5 vs 3.1 cm, p <0.01) and R.E.N.A.L. (radius, exophytic/endophytic properties, nearness of tumor to collecting system or sinus, anterior/posterior, location relative to polar lines and hilar location) score (9 vs 8, p <0.01) were also associated with an increased risk of conversion. Worse baseline renal function (OR 0.98, 95% CI 0.96-0.99, p = 0.04), large tumor size (OR 1.44, 95% CI 1.22-1.7, p <0.01) and increasing R.E.N.A.L. score (p = 0.02) were independent predictors of conversion. Compared to converted cases, at latest followup standard robotic partial nephrectomy cases had similar short-term oncologic outcomes but better renal functional preservation (p <0.01). CONCLUSIONS: At a high volume center the rate of robotic partial nephrectomy conversion to radical nephrectomy was 3.1%, including 2.2% of preoperatively anticipated nephrectomy cases. Increasing tumor size and complexity, and poor preoperative renal function are the main predictors of conversion. PMID- 28087300 TI - Mutual regulation by GnRH and kisspeptin of their receptor expression and its impact on the gene expression of gonadotropin subunits. AB - Hypothalamic kisspeptin plays a pivotal role in the regulation of the hypothalamic-pituitary-gonadal axis by stimulating gonadotropin-releasing hormone (GnRH) release into the portal circulation, with the subsequent release of gonadotropins. Kisspeptin and its receptor, the kisspeptin 1 receptor (Kiss1R), are also expressed in the pituitary gland. This study demonstrates the interaction between GnRH and kisspeptin within the pituitary gonadotrophs by altering their individual receptor expression. Our results show that kisspeptin and Kiss1R are expressed in the mouse pituitary gonadotroph cell line LbetaT2. Endogenous Kiss1R did not respond to kisspeptin and failed to stimulate gonadotropin LHbeta and FSHbeta expression in LbetaT2 cells; however, kisspeptin increased both LHbeta and FSHbeta promoter activity in Kiss1R-overexpressing LbetaT2 cells. Stimulating the cells with GnRH significantly increased Kiss1R expression, whereas kisspeptin increased the expression of the GnRH receptor (GnRHR) in these cells. Elevating the Kiss1R concentration led to an increase in the basal activities of gonadotropin LHbeta- and FSHbeta-subunit promoters. In addition, the level of kisspeptin-induced LHbeta promoter activity, but not that of FSHbeta, was significantly increased when a large number of Kiss1R expression vectors was introduced into the cells. The level of induction of GnRH-induced gonadotropin promoter activities was not significantly changed by increasing Kiss1R expression. Increasing the amount of GnRHR by overexpressing cellular GnRHR did not potentiate basal gonadotropin promoter activities; however, kisspeptin- and GnRH-stimulated increases in gonadotropin promoter activities were significantly potentiated (except GnRH-induced LHbeta promoters). The activities of serum response element-containing promoters were also modified in cells overexpressing Kiss1R or GnRHR. Our current observations demonstrate that GnRH and kisspeptin affect each other's function to stimulate gonadotropin subunit gene expression by reciprocally increasing the expression of their receptors. PMID- 28087301 TI - Molecular characterization and quantification of estrogen receptors in turbot (Scophthalmus maximus). AB - Estrogens regulate various reproductive processes via estrogen receptor (ER) mediated signaling pathway in vertebrates. In this study, full-length sequences coding for ERalpha, ERbeta1 and ERbeta2 were isolated from female turbot (Scophthalmus maximus) by homology cloning and a strategy based on rapid amplification of cDNA end-polymerase chain reaction (RACE-PCR). The nucleotide and amino acid sequences of turbot ERs showed high homologies with the corresponding sequences of other fish species and significant homology with the Japanese flounder (Paralichthys olivaceus) and the European sea bass (Dicentrarchus labrax). Turbot ERs contained six typical nuclear receptor characteristic domains and exhibited high evolutionary conservation in the functional domains. Quantitative real-time polymerase chain reaction analysis revealed that the eralpha and erbeta (beta1, beta2) mRNAs were abundant in the liver and ovary, respectively. Furthermore, hepatic mRNA levels of eralpha and vitellogenin (vtg) were found increased gradually from pre-vitellogenesis to late vitellogenesis stages, with the highest values observed at the late vitellogenesis stage, and then decreased from migratory-nucleus to atresia stages. However, mRNA levels of eralpha in the ovary remained unchanged during ovarian development. Hepatosomatic index, gonadosomatic index, serum estradiol 17beta and the mRNA levels of erbeta1 and erbeta2 in the ovary manifested results similar to the expression of eralpha mRNAs in the liver. These findings indicated that ERalpha is mainly involved in hepatic vitellogenesis, and ERbetas may play crucial roles to regulate ovarian development in turbot. Overall, this study improves understanding of the physiological functions of turbot ERs, which will be valuable for fish reproduction and broodstock management. PMID- 28087302 TI - The Long-term Effect of Bacille Calmette-Guerin Vaccination on Tuberculin Skin Testing: A 55-Year Follow-Up Study. AB - BACKGROUND: Bacille Calmette-Guerin (BCG) vaccination is known to cause false positive tuberculin skin test (TST) results from cross-reactions with mycobacterial antigens. However, the duration of BCG vaccination influence on the TST is poorly characterized. The objective of this study was to assess the long term effect of BCG vaccination on TST reactivity. METHODS: Data on TST reactivity were prospectively collected during 1935 to 1947 as part of a clinical trial among Native Americans/Alaskan Natives and were retrospectively collected thereafter between 1948 and 1998. TST induration of >= 10 mm was defined as a positive reaction. Kaplan-Meier analysis and multivariate Cox regression were used to compare the time to TST conversion and reversion between the BCG and placebo groups. RESULTS: BCG vaccination after infancy was associated with an increased risk of TST reactivity in the first 15 years after vaccination (adjusted hazard ratio [HR], 2.33). This association remained during the interval 16 to 55 years after vaccination, although the effect was attenuated (adjusted HR, 1.26). Age at vaccination modestly impacted the effect of BCG on TST results in the first 15 years. Positive TST results among the BCG-vaccinated group were more likely to revert to negative results during the first 15 years but not in the latter period. CONCLUSIONS: This study provides evidence that BCG vaccination after infancy may influence TST results beyond the 10-year period conventionally accepted by the Centers for Disease Control and Prevention (CDC), extending up to 55 years after vaccination. This suggests that BCG vaccination should be taken into account when interpreting TST results regardless of the time elapsed since vaccination. PMID- 28087304 TI - Sleep and Neurodegeneration: A Critical Appraisal. AB - Sleep abnormalities are clearly recognized as a distinct clinical symptom of concern in neurodegenerative disorders. Appropriate management of sleep-related symptoms has a positive impact on quality of life in patients with neurodegenerative disorders. This review provides an overview of mechanisms that are currently being considered that tie sleep with neurodegeneration. It appraises the literature regarding specific sleep changes seen in common neurodegenerative diseases, with a focus on Alzheimer disease and synucleinopathies (ie, Parkinson disease, dementia with Lewy bodies, multiple system atrophy), that have been better studied. Sleep changes may also serve as markers to identify patients in the preclinical stage of some neurodegenerative disorders. A hypothetical model is postulated founded on the conjecture that specific sleep abnormalities, when noted to increase in severity beyond that expected for age, could be a surrogate marker reflecting pathophysiological processes related to neurodegenerative disorders. This provides a clinical strategy for screening patients in the preclinical stages of neurodegenerative disorders to enable therapeutic trials to establish the efficacy of neuroprotective agents to prevent or delay the development of symptoms and functional decline. It is unclear if sleep disturbance directly impacts neurodegenerative processes or is a secondary outcome of neurodegeneration; this is an active area of research. The clinical importance of recognizing and managing sleep changes in neurodegenerative disorders is beyond doubt. PMID- 28087303 TI - Activity Levels and Exercise Motivation in Patients With COPD and Their Resident Loved Ones. AB - BACKGROUND: Resident loved ones of patients with COPD can play an important role in helping these patients engage in physical activity. We aimed to compare activity levels and exercise motivation between patients with COPD and their resident loved ones; to compare the same outcome measures in patients after stratification for the physical activity level of the loved ones; and to predict the likelihood of being physically active in patients with a physically active resident loved one. METHODS: One hundred twenty-five patient/loved one dyads were cross-sectionally and simultaneously assessed. Sedentary behavior, light activities, and moderate to vigorous physical activity (MVPA) were measured with a triaxial accelerometer during free-living conditions for at least 5 days. Five exercise-motivation constructs were investigated: amotivation, external regulation, introjected regulation, identified regulation, and intrinsic regulation. RESULTS: Patients spent more time in sedentary behavior and less time in physical activity than their loved ones (P < .0001). More intrinsic regulation was observed in loved ones compared with patients (P = .003), with no differences in other constructs. Despite similar exercise motivation, patients with an active loved one spent more time in MVPA (mean 31 min/d; 95% CI, 24-38 min/d vs mean, 18 min/d; 95% CI, 14-22 min/d; P = .002) and had a higher likelihood of being active (OR, 4.36; 95% CI, 1.41-13.30; P = .01) than did patients with an inactive loved one after controlling for age, BMI, and degree of airflow limitation. CONCLUSIONS: Patients with COPD are more physically inactive and sedentary than their loved ones, despite relatively similar exercise motivation. Nevertheless, patients with an active loved one are more active themselves and have a higher likelihood of being active. TRIAL REGISTRY: Dutch Trial Register (NTR3941). PMID- 28087305 TI - Circulating interleukin-18 (IL-18) is a predictor of response to gemcitabine based chemotherapy in patients with pancreatic adenocarcinoma. AB - BACKGROUND: This study was conducted to investigate the serum levels of interleukin-18 (IL-18) in patients with pancreatic adenocarcinoma (PA) and the relationship with tumor progression and known prognostic parameters. METHODS: Thirty-three patients with PA were studied. Serum samples were obtained on first admission before any treatment. Serum IL-18 levels were analyzed using enzyme linked immunosorbent assay (ELISA). Age- and sex-matched 30 healthy controls were included in the analysis. RESULTS: The median age at diagnosis was 59 years, range 32-84 years; 20 (61%) patients were men and the remaining were women. The median follow-up time was 26.0 weeks (range: 1.0-184.0 weeks). The median overall survival of the whole group was 41.3 +/- 8.3 weeks [95% confidence interval (CI) = 25-58 weeks]. The baseline serum IL-18 levels were significantly higher in patients with PA than in the control group (p < 0.001). Serum IL-18 levels were significantly higher in the patients with high erythrocyte sedimentation rate (ESR) and lactate dehydrogenase (LDH) (p = 0.01 and p = 0.05). Moreover, the chemotherapy-(CTx) unresponsive patients had higher serum IL-18 levels compared to CTx-responsive (p = 0.04) subjects. Conversely, serum IL-18 concentration was found to have no prognostic role on survival (p = 0.45). CONCLUSION: Serum levels of IL-18 can be a good diagnostic and predictive marker; especially for predicting the response to gemcitabine based CTx in patients with PA but it has no prognostic role. PMID- 28087306 TI - Molecular epidemiological analysis of human- and chicken-derived isolates of Campylobacter jejuni in Japan using next-generation sequencing. AB - In this research, we analyzed the main sequence types (ST) and ST complexes of human- and chicken-derived isolates of Campylobacter jejuni in Japan by using multilocus sequence typing (MLST). We also analyzed lipooligosaccharide biosynthesis locus classes (LOS locus classes) and the numbers of isolates carrying genes coding resistance factors against various antibiotics, and observed their relationships. ST-21 complex was the main ST complex in isolates from humans (n = 38) and chickens (n = 25). None of the isolates showed resistance to imipenem, chloramphenicol, or erythromycin. Few isolates were resistant to ampicillin and streptomycin (1.3%-15%), whereas many showed resistance to tetracycline, ciprofloxacin, and nalidixic acid (38%-48%). Among the ST-21 complex isolates, ST4526 was detected at a very high rate. Those isolates showed resistance to tetracycline and ciprofloxacin, and were susceptible to ampicillin. Among the chicken-derived isolates, 37 of the 38 isolates that showed resistance to ciprofloxacin and nalidixic acid had threonine to isoleucine amino acid substitution in GyrA at codon 86 (T86I). Among the human derived isolates, 17 of the 47 isolates that showed resistance to ciprofloxacin and 16 of the 48 isolates that showed resistance to nalidixic acid did not have T86I amino acid mutations in GyrA. The human-derived ST-21 complex isolates were classified into LOS locus classes A, B, C, D, and E. The chicken-derived ST-21 complex isolates, with the exception of one isolate, were all classified into LOS locus classes C and D. Among chicken-derived isolates, the most prevalent was ST51 (ST-443 complex) (10 isolates) and all of those were LOS locus class E. PMID- 28087308 TI - Myocardial inotropic reserve: An old twist that constitutes a reliable index in the modern era of heart failure. AB - Current national and international guidelines, including those of the European Society of Cardiology, recognize that the assessment of prognosis should be a part of the standard management for patients with chronic heart failure (CHF). However, these same guidelines recognize the inherent difficulty of this process. A variety of factors contribute to this difficulty, including the varying etiology, frequent co-morbidity and, perhaps most importantly, huge inter individual variability in the disease progression and outcome. Although CHF is chronic, it is also a condition in which significant proportions of patients experience apparently 'sudden' death, which almost certainly contributes to our difficulty in assessing individual patient prognosis. A useful tool for the risk stratification of heart failure patients is dobutamine stress echocardiography (DSE), which determines the myocardial viability in ischemic cardiomyopathy and myocardial contractile reserve in idiopathic cardiomyopathy. PMID- 28087307 TI - Predictors of left ventricular diastolic dysfunction in type 2 diabetes patients: A 4-year prospective study. PMID- 28087309 TI - Relationships between heart rate variability and aortic hemodynamic variables in healthy subjects. PMID- 28087310 TI - Clinical features and three-year outcomes of Takotsubo (stress) cardiomyopathy: Observational data from one center. AB - OBJECTIVE: The natural history, management, and outcome of Takotsubo (stress) cardiomyopathy (TTC) is not clear. The aim of this study was to investigate clinical features, define prognostic predictors, and assess the clinical course and outcomes of patients with TTC. METHODS: We analyzed 64 patients (52 women) meeting the proposed Mayo Clinic diagnostic criteria for TTC. All patients were treated at Vilnius University Hospital Santariskiu Klinikos from 2001-01-01 to 2014-11-27. Data were collected on the basis of medical records and follow-up data was collected by phone. RESULTS: The mean age of analyzed patients was 63.4 +/- 14.6 years; the mean follow-up was 2.9 years. More than half of the patients (52%) did not have any clear stressful triggers. During admission, symptoms such as chest pain (64%) and general weakness (45%) were reported more often than other symptoms. Almost all patients (94%) had the classical TTC form; the remaining 6% of patients had "inverted" TTC. The mean left ventricular ejection fraction (LVEF) on admission was 37.7% (+/- 8.2%). A pseudonormal or restrictive pattern of LV filling, moderate to severe mitral regurgitation (MR), and right ventricular involvement were uncommon in the patients. The in-hospital course showed cardiogenic shock in 23% of the cases, resulting in the death of 5 (8%) patients. We discovered that only peak concentration of troponin I was a significant predictor of in-hospital mortality (HR 1.067, 95%CI 1.022-1.113, p=0.003). At the end of the follow-up period, 45 (87%) women and 8 (67%) men were alive. This makes the overall observed mortality at 3 years approximately 17.2%. Using multivariate analysis, elevation of BNP (HR for increase by 10 ng/l 1.002, 95%CI 1-1.003, p=0.022) and cardiogenic shock on admission (HR 8.696, 95%CI 1.198 63.124, p=0.032) were significant predictors of overall mortality. Other prognostic factors assessed on admission were nonsignificant predictors of overall mortality. CONCLUSIONS: Our analysis shows that in-hospital mortality is influenced by the peak concentration of troponin I, and overall mortality is affected by cardiogenic shock and the elevation of BNP during admission. The assessment of troponin I and BNP can help with the prognostication of TTC patients in our daily clinical practice. PMID- 28087311 TI - 'The role of novel oral anticoagulants in patients undergoing cryoballoon ablation for atrial fibrillation'. AB - AIM: Peri-procedural thromboembolic (TE) and hemorrhagic events are complications of major concern for patients undergoing cryoballoon (CB) ablation for atrial fibrillation (AF). While peri-procedural anticoagulation management could decrease the incidence of these complications, data on CB ablation are scarce. The role of novel oral anticoagulants (NOACs) has not been thoroughly tested in this population. METHODS: In the present study, we sought to assess acute peri procedural complications in patients undergoing CB ablation for AF under different anticoagulation regimens; anticoagulation administration was performed according to the CHA2DS2-VASc score guidelines. To the best of our knowledge, this is the first study that compares 1) uninterrupted warfarin, 2) bridging therapy with low molecular weight heparin (LMWH), 3) aspirin and 4) NOACs in this subgroup of patients. RESULTS: NOACs were as effective as uninterrupted warfarin in terms of bleeding complications and TE events. Surprisingly, the aspirin group had more hemorrhagic complications than both the warfarin and NOACs groups. CONCLUSION: In the current study, the use of NOACs was an effective and safe approach in CB ablation. PMID- 28087312 TI - Immunisation - Choice of host, adjuvants and boosting schedules with emphasis on polyclonal antibody production. AB - Polyclonal antibodies are frequently used as immunodiagnostic tools in fundamental research. They are also used for routine diagnostic purposes in human and veterinary medicine and for quality control procedures in the food-processing industry. The antibody is a major component of the detection system. It binds with the molecule to be identified. This conjugate is subsequently revealed by means of binding the antibody with a radio-isotope, a fluorescent substance, an enzyme inducing a color change, or a biosensor based analytical system. Polyclonal antibodies are also used for treatment purposes in various pathologies. They might have immunomodulating or anti-inflammatory properties. Snake venom, rabies and tetanus antisera are examples of a therapeutic application; immunosuppressive antithymocyte serum used in order to avoid rejection in organ transplantation is another example from human medicine. These therapeutic aids need hyperimmunisation of animals. Since these are subject to a certain number of interventions such as injections and blood samplings, animal welfare prescriptions have to be taken into account. The optimisation of the immunisation protocol allows for reducing the numbers of animals used as well as reducing stress and pain while obtaining high quality antibodies. This article describes the critical steps in polyclonal antibody production with a particular focus on the choice of the animal species, the age of the subjects, the injection protocol and the sampling times. PMID- 28087313 TI - An M2-V27A channel blocker demonstrates potent in vitro and in vivo antiviral activities against amantadine-sensitive and -resistant influenza A viruses. AB - Adamantanes such as amantadine (1) and rimantadine (2) are FDA-approved anti influenza drugs that act by inhibiting the wild-type M2 proton channel from influenza A viruses, thereby inhibiting the uncoating of the virus. Although adamantanes have been successfully used for more than four decades, their efficacy was curtailed by emerging drug resistance. Among the limited number of M2 mutants that confer amantadine resistance, the M2-V27A mutant was found to be the predominant mutant under drug selection pressure, thereby representing a high profile antiviral drug target. Guided by molecular dynamics simulations, we previously designed first-in-class M2-V27A inhibitors. One of the potent lead compounds, spiroadamantane amine (3), inhibits both the M2-WT and M2-V27A mutant with IC50 values of 18.7 and 0.3 MUM, respectively, in in vitro electrophysiological assays. Encouraged by these findings, in this study we further examine the in vitro and in vivo antiviral activity of compound 3 in inhibiting both amantadine-sensitive and -resistant influenza A viruses. Compound 3 not only had single to sub-micromolar EC50 values against M2-WT- and M2-V27A containing influenza A viruses in antiviral assays, but also rescued mice from lethal viral infection by either M2-WT- or M2-V27A-containing influenza A viruses. In addition, we report the design of two analogs of compound 3, and one was found to have improved in vitro antiviral activity over compound 3. Collectively, this study represents the first report demonstrating the in vivo antiviral efficacy of inhibitors targeting M2 mutants. The results suggest that inhibitors targeting drug-resistant M2 mutants are promising antiviral drug candidates worthy of further development. PMID- 28087314 TI - A protective role of cumulus cells after short-term exposure of rat cumulus cell oocyte complexes to lifestyle or environmental contaminants. AB - Ovarian follicular fluid provides a potential reservoir for exogenous compounds that may adversely affect oocyte quality. This study examined the effects of common lifestyle and environmental contaminants, namely bisphenol-A (BPA), caffeine, 3,4-methylenedioxymethamphetamine (MDMA), nicotine and Delta9 tetrahydrocannabinol (THC) on gap junction genes (Gja1, Gja4) and proteins (GJA1), glucose metabolism genes (Gfpt1, Pfkp) and oocyte growth factor genes (Bmp15, Gdf9), as well as gap junction transfer rate, in rat cumulus-oocyte complexes (COCs). In vitro exposure to MDMA and THC accelerated the timing of meiotic resumption and all contaminants altered either gap junction gene expression (BPA, caffeine, MDMA and THC) or transfer rate (BPA and nicotine). In vitro exposure of COCs to MDMA also altered glucose metabolism genes. Overall, oocyte-derived genes were largely unaffected following exposure to any contaminant. In summary, the impact of short-term exposure to lifestyle and environmental contaminants on oocyte function may be diminished due to protective properties of cumulus cells. PMID- 28087315 TI - Assessing light-independent effects of hypericin on cell viability, ultrastructure and metabolism in human glioma and endothelial cells. AB - Cell exposure to light-independent effects of photosensitizers (PS) used in PDT is clinically relevant when PS affect the pro-apoptotic cascade. In many malignant cells, Hypericin (Hyp) has PS displayed light-dependent anti proliferative and cytotoxic effects with no cytotoxicity in the dark. Recent studies have shown that Hyp also exhibited light-independent cytotoxic effects in a wide range of concentrations. The molecular mechanisms underlying Hyp light independent (dark) toxicity may be due to its interaction with different molecules at the Hyp accumulation sites including mitochondria, and these mechanisms are not understood in detail. Here, we demonstrate that in human glioma and endothelial cells, Hyp displayed light-independent effects at several sub-cellular levels (ultrastructure, mitochondria function and metabolism, and protein synthesis). Taking together previously published and our present results, the findings strongly suggest that Hyp light independent effects: (i) depend on the cell type and metabolism; (ii) underlying molecular mechanisms are due to Hyp interaction with the multiple target molecules including Bcl2 family of proteins. In addition, the findings suggest that Hyp without illumination can be explored as an adjuvant therapeutic drug in combination with chemo- or radiation cancer therapy. PMID- 28087316 TI - Self-Nanoemulsifying Lyophilized Tablets for Flash Oral Transmucosal Delivery of Vitamin K: Development and Clinical Evaluation. AB - Owing to limited solubility, vitamin K undergoes low bioavailability with large inter-individual variability after oral administration. This article aimed to prepare self-nanoemulsifying lyophilized tablets (SNELTs) for the flash oral transmucosal delivery of vitamin K. Twenty-one formulae of vitamin K self nanoemulsifying drug delivery systems (SNEDDS) were prepared using different concentrations of vitamin K, Labrasol, and Transcutol according to mixture design. The SNEDDS was loaded on porous carriers and formulated as lyophilized tablets. The release profile and the pharmacokinetic parameters of vitamin K SNELTs were evaluated in comparison with commercial tablets and ampoules on human volunteers. Results revealed that the optimized SNEDDS showed the smallest and most stable nanoemulsion globules. SNELTs were prepared successfully and showed substantial superiority drug release compared with the commercial tablets. Interestingly, SNELTs enhanced both rate and extent of vitamin K absorption as well as relative bioavailability (169.67%) in healthy subjects compared with the commercial tablets. SNELTs revealed promising no significant difference in the area under the curve compared with the commercial intramuscular injection. SNELTs enhanced dissolution and bioavailability that expected to have the strong impact on the efficiency of vitamin K in the prophylaxis and treatment of bleeding disorders in patients with hepatic dysfunction. PMID- 28087317 TI - Acute otitis media caused by Streptococcus pneumoniae serotype 19A ST320 clone: epidemiological and clinical characteristics. AB - BACKGROUND: Streptococcus pneumoniae serotype 19A ST320, a highly multiresistant and virulent clone, has emerged as a common pathogen causing acute otitis media (AOM) in children. METHODS: Patients aged 0-18 years with AOM who presented at Mackay Memorial Hospital, Taipei, Taiwan were prospectively enrolled between December 1, 2009, and November 30, 2012. For each patient, a specimen of middle ear fluid was obtained and cultured. S. pneumoniae isolates were tested by serotyping, antibiotic-resistance profiling, and multilocus sequence typing. Demographic characteristics and clinical history of patients with pneumococcal AOM were recorded. RESULTS: Pneumococcal AOM was observed in 108 (24.8%) of 436 episodes. One hundred and four isolates of S. pneumoniae were available for study. The most common serotypes were 19A (67 isolates, 64.4%), followed by 19F (16 isolates, 15.4%), and 3 (7 isolates, 6.7%). Among the 85 sequence-typed isolates, Serotype 19A ST320 (50, 58.8%) was the most frequent. Children with AOM caused by Serotype 19A ST320 were younger (33.9 +/- 21.4 months vs. 46.7 +/- 35.9 months, p = 0.04) and had a higher rate of spontaneous rupture of the tympanic membrane (64.0% vs. 40%, p = 0.05) than those caused by isolates of other sequence types. Serotype 19A ST320 caused 90% of AOM episodes in children aged <= 12 months and had had higher resistance rates to penicillin according to meningeal breakpoints (p = 0.011), amoxicillin (p < 0.001) and trimethoprim/sulfamethoxazol (p < 0.001). CONCLUSIONS: It is better to use pneumococcal conjugate vaccine effective against Serotype 19A in early infancy to prevent the first and subsequent episodes of AOM in children in Taiwan. PMID- 28087318 TI - Etiologies of community-onset urinary tract infections requiring hospitalization and antimicrobial susceptibilities of causative microorganisms. AB - BACKGROUND: Community-onset urinary tract infections (CoUTIs) are the most common bacterial infections, and a decline in antibiotic susceptibility causes many clinical challenges. Adequate empiric antibiotic treatment can decrease unnecessary hospital stays and complications, while reducing the antimicrobial resistance progression. METHODS: From October 2014 to April 2015, we retrospectively enrolled patients who were at least 18 years old and required hospitalization for CoUTIs. Demographic variables of these patients, and uropathogens and their antimicrobial susceptibilities were evaluated. RESULTS: In total, 457 patients were enrolled in this study. Their mean age was 71.9 years, and 35.2% of the patients were male. Escherichia coli (54.5%) was the most common uropathogen, followed by Klebsiella pneumoniae (13.1%), Enterococcus spp. (7.1%), Pseudomonas aeruginosa (4.6%), and Proteus mirabilis (3.5%). Bacteremia was present in 25.2% of patients. Diabetes mellitus and acute kidney injury at admission were risk factors for CoUTIs with concomitant bacteremia. Among the UTI associated bloodstream strains, E. coli (53.1%) was also the most predominant pathogen, followed by K. pneumoniae (11.3%), Staphylococcus aureus (6.1%), and P. mirabilis (4.3%). The overall susceptibility of cefazolin was 62.8%, ceftriaxone 71.4%, ceftazidime 82.8%, flomoxef 82%, cefepime 94.5%, ampicillin-sulbactam 41.6%, piperacillin-tazobactam 85%, levofloxacin 65.2%, trimethoprim sulfamethoxazole 61.5%, imipenem 92.3%, gentamicin 76.1%, and amikacin 97.5%. Cefazolin-susceptible isolates could be found more frequently among patients who are less than 65 years of age and without diabetes mellitus, had no UTI episode in the past year, and have no bacteremia risk. Patients with nasogastric tube retention more commonly experienced antimicrobial resistance to all the third generation cephalosporins. CONCLUSION: Third-generation cephalosporins effectively treated CoUTIs. However, patients with nasogastric tube retention more commonly experienced cephalosporin resistance. Cefepime, imipenem, and amikacin may be used in patients with higher antimicrobial resistance. In selected patients, cefazolin may still be an adequate drug of choice for CoUTIs. PMID- 28087319 TI - Biliary fistula after pancreaticoduodenectomy: data from 1618 consecutive pancreaticoduodenectomies. AB - BACKGROUND: Biliary fistula (BF) occurs in 3-8% of patients following pancreaticoduodenectomy (PD). It usually pursues a benign course, but rarely may represent a life-threatening event. STUDY DESIGN: Data from 1618 PDs were collected prospectively. BF was defined as the presence of bile stained fluid from drains by post-operative day 3 and confirmed by sinogram in the majority of cases. Three classifications were validated. RESULTS: BF occurred in 58 (3.6%) patients. In 22 cases was associated with pancreatic fistula (POPF). POPF, PPH, operative time and a smaller common bile duct (CBD) were significantly associated with BF. Only CBD diameter (HR 0.55, CI 95% 0.44-0.7, p < 0.01) was an independent predictor of BF. Patients with smaller CBDs developing concomitant BF and POPF carried the highest mortality rate (34.8%, n = 8/22). All the existing classifications resulted in discrete categories of BFs when considering hospital stay and total cost as dependent variables. CONCLUSIONS: Biliary fistula is rare, but it can be life threatening when associated with POPF. As the sole independent risk factor is the CBD diameter, surgical technique is crucial. Regardless of the existing classification systems, further studies must assess the additive burden of BF when a concomitant POPF is present. PMID- 28087320 TI - Poly(ADP-ribose) polymerase activity and inhibition in cancer. AB - Genomic instability resultant from defective DNA repair mechanisms is a fundamental hallmark of cancer. The poly(ADP-ribose) polymerase (PARP) proteins 1, 2 and 3 catalyze the polymerization of poly(ADP-ribose) and covalent attachment to proteins in a phylogenetically ancient form of protein modification. PARPs play a role in base excision repair, homologous recombination, and non-homologous end joining. The discovery that loss of PARP activity had cytotoxic effects in cells deficient in homologous recombination has sparked a decade of translational research efforts that culminated in the FDA approval of an oral PARP inhibitor for clinical use in patients with ovarian cancer and defective homologous recombination. Five PARP inhibitors are now in late-stage development in clinical trials that are seeking to expand the understanding of targeted therapies and DNA repair defects in human cancer. This review examines the cell biology of PARP, the discovery of synthetic lethality with HR deficiency, the clinical development of PARP inhibitors, and the role of PARP inhibitors in ongoing clinical trials and clinical practice. PMID- 28087322 TI - Cutaneous exposure to vesicant phosgene oxime: Acute effects on the skin and systemic toxicity. AB - Phosgene Oxime (CX), an urticant or nettle agent categorized as a vesicant, is a potential chemical warfare and terrorist weapon. Its exposure can result in widespread and devastating effects including high mortality due to its fast penetration and ability to cause immediate severe cutaneous injury. It is one of the least studied chemical warfare agents with no effective therapy available. Thus, our goal was to examine the acute effects of CX following its cutaneous exposure in SKH-1 hairless mice to help establish a relevant injury model. Results from our study show that topical cutaneous exposure to CX vapor causes blanching of exposed skin with an erythematous ring, necrosis, edema, mild urticaria and erythema within minutes after exposure out to 8h post-exposure. These clinical skin manifestations were accompanied with increases in skin thickness, apoptotic cell death, mast cell degranulation, myeloperoxidase activity indicating neutrophil infiltration, p53 phosphorylation and accumulation, and an increase in COX-2 and TNFalpha levels. Topical CX-exposure also resulted in the dilatation of the peripheral vessels with a robust increase in RBCs in vessels of the liver, spleen, kidney, lungs and heart tissues. These events could cause a drop in blood pressure leading to shock, hypoxia and death. Together, this is the first report on effects of CX cutaneous exposure, which could help design further comprehensive studies evaluating the acute and chronic skin injuries from CX topical exposure and elucidate the related mechanism of action to aid in the identification of therapeutic targets and mitigation of injury. PMID- 28087325 TI - Does size really matter?: Relationship of particle size to lung deposition and exhaled fraction. PMID- 28087323 TI - Severe Hemorrhagic Syndrome After Lonomia Caterpillar Envenomation in the Western Brazilian Amazon: How Many More Cases Are There? AB - Contact with Lonomia caterpillars can cause a hemorrhagic syndrome. In Brazil, Lonomia obliqua and Lonomia achelous are known to cause this venom-induced disease. In the Brazilian Amazon, descriptions of this kind of envenomation are scarce. Herein, we report a severe hemorrhagic syndrome caused by Lonomia envenomation in the Amazonas state, Western Brazilian Amazon. The patient showed signs of hemorrhage lasting 8 days and required Lonomia antivenom administration, which resulted in resolution of hemorrhagic syndrome. Thus, availability of Lonomia antivenom as well as early antivenom therapy administration should be addressed across remote areas in the Amazon. PMID- 28087321 TI - Enteric nervous system development: A crest cell's journey from neural tube to colon. AB - The enteric nervous system (ENS) is comprised of a network of neurons and glial cells that are responsible for coordinating many aspects of gastrointestinal (GI) function. These cells arise from the neural crest, migrate to the gut, and then continue their journey to colonize the entire length of the GI tract. Our understanding of the molecular and cellular events that regulate these processes has advanced significantly over the past several decades, in large part facilitated by the use of rodents, avians, and zebrafish as model systems to dissect the signals and pathways involved. These studies have highlighted the highly dynamic nature of ENS development and the importance of carefully balancing migration, proliferation, and differentiation of enteric neural crest derived cells (ENCCs). Proliferation, in particular, is critically important as it drives cell density and speed of migration, both of which are important for ensuring complete colonization of the gut. However, proliferation must be tempered by differentiation among cells that have reached their final destination and are ready to send axonal extensions, connect to effector cells, and begin to produce neurotransmitters or other signals. Abnormalities in the normal processes guiding ENCC development can lead to failure of ENS formation, as occurs in Hirschsprung disease, in which the distal intestine remains aganglionic. This review summarizes our current understanding of the factors involved in early development of the ENS and discusses areas in need of further investigation. PMID- 28087326 TI - Autoimmune lymphoproliferative syndrome caused by homozygous FAS mutations with normal or residual protein expression. PMID- 28087327 TI - IgE cross-linking impairs monocyte antiviral responses and inhibits influenza driven TH1 differentiation. PMID- 28087328 TI - Identification of drug- and drug-metabolite immune responses originating from both naive and memory T cells. PMID- 28087329 TI - Influence of Health and Functional Status and Co-occurring Chronic Conditions on Healthcare Expenditures Among Community-dwelling Adults With Kidney Cancer in the United States: A Propensity-score-matched Analysis. AB - BACKGROUND: Health and functional status, as well as co-occurring chronic conditions, have a profound influence on healthcare expenditures. However, no study to date has assessed their influence among community-dwelling adults with kidney cancer (KC) in the United States (US). This study assessed the impact of health and functional status, along with co-occurring chronic conditions, on KC healthcare expenditures. METHODS: This study used a retrospective, cross sectional, propensity-score-matched, case-control study design using 2002 to 2011 Medical Expenditure Panel Survey data. The case group was comprised of adults with KC, whereas the control group consisted of propensity-score matched adults with other forms of cancer. To examine the impact of health and functional status and co-occurring chronic conditions, ordinary least square regressions on log transformed expenditures were conducted on total and subtypes of healthcare expenditures. The percentage change in expenditure was calculated using the formula (expbeta - 1). RESULTS: Findings from this study indicate that the annual average total healthcare expenditures ($15,078 vs. $8182; P < .001) for adults with KC were significantly higher compared with propensity-score-matched adults with other forms of cancer. Total healthcare expenditures for adults with KC were 80% (beta = 0.588; P < .001) higher compared with propensity-score-matched controls when only demographic characteristics were adjusted. After adjusting for health and functional status and co-occurring chronic conditions, the percentage decreased from 80% to 43% (beta = 0.359; P < .01). CONCLUSIONS: Findings from this nationally representative sample suggest that health and functional status and co-occurring chronic conditions have a significant impact on healthcare expenditures among community-dwelling adults with KC in the US. PMID- 28087330 TI - Molecular characterization and functional analysis of a salmon louse (Lepeophtheirus salmonis, Kroyer 1838) heme peroxidase with a potential role in extracellular matrixes. AB - Heme peroxidases are the most abundant type of peroxidase catalyzing a H2O2 dependent oxidation of a wide variety of substrates. They are involved in numerous processes like the innate immune response, hormone and prostaglandin synthesis and crosslinking of proteins within extracellular matrixes (ECM) as well as molecules within the cuticle and chorion of arthropods and nematodes. In the present study, a Lepeophtheirus salmonis heme peroxidase (LsHPX) 1 was characterized. Amino acids in the active site of heme peroxidases were conserved, and the predicted protein sequence showed the highest similarity to genes annotated as chorion peroxidases and genes suggested to be involved in cuticle hardening or adhesion. LsHPX1 exhibited a dynamic expression during ontogenesis and during the nauplius molting cycle. Transcripts were localized to muscle cells near the muscle-tendon junction, in nerve tissue especially at neuromuscular junctions, subcuticular epithelium, subepithelial cells facing the hemolymph, exocrine glands within the subepithelial tissue and in isolated cells within the testis. Knock-down of LsHPX1 in nauplius larvae decreased the swimming activity of emerging copepodids. Histological analysis of knock-down animals revealed increased spacing between myofibers and changes in subepithelial and exocrine gland tissue. Considering these results, the potential role of LsHPX1 in crosslinking molecules of salmon louse ECMs is discussed. PMID- 28087331 TI - Different age-dependent performance in Drosophila wild-type Canton-S and the white mutant w1118 flies. AB - Aging has significant effects on the locomotor performance of insects including Drosophila. Using a protocol for the high-throughput analysis of fly locomotion in a circular arena, we examined age-dependent behavioral characteristics in adult flies. There are widely used wild-type and genetically engineered background lines including the Canton-S strain and the w1118 strain, which has a null mutation of the white gene. Under standard rearing conditions, we found similar survival and median lifespans in Canton-S (50days) and w1118 (54days) strains, however, w1118 flies maintained stable body mass for up to 43days, whereas Canton-S flies gained body mass at young age, followed by a gradual decline. We also tested the behavioral performance of young and old flies. Compared with young w1118 flies (5-10days), old w1118 flies (40-45days) had an increased boundary preference during locomotion in small circular arenas, and increased speed of locomotor recovery from anoxia. Old Canton-S files, however, exhibited unchanged boundary preference and reduced recovery speed from anoxia relative to young flies. In addition, old w1118 flies showed decreased path length per minute and reduced 0.2s path increment compared with young flies, whereas old Canton-S flies displayed the same path length per minute and the same 0.2s path increment compared with young flies. We conclude that age-dependent behavioral and physiological changes differ between Canton-S and w1118 flies. These results illustrate that phenotypic differences between strains can change qualitatively, as well as quantitatively, as the animals age. PMID- 28087332 TI - Exo-MFA - A 13C metabolic flux analysis framework to dissect tumor microenvironment-secreted exosome contributions towards cancer cell metabolism. AB - Dissecting the pleiotropic roles of tumor micro-environment (TME) on cancer progression has been brought to the foreground of research on cancer pathology. Extracellular vesicles such as exosomes, transport proteins, lipids, and nucleic acids, to mediate intercellular communication between TME components and have emerged as candidates for anti-cancer therapy. We previously reported that cancer associated fibroblast (CAF) derived exosomes (CDEs) contain metabolites in their cargo that are utilized by cancer cells for central carbon metabolism and promote cancer growth. However, the metabolic fluxes involved in donor cells towards packaging of metabolites in extracellular vesicles and exosome-mediated metabolite flux upregulation in recipient cells are still not known. Here, we have developed a novel empirical and computational technique, exosome-mediated metabolic flux analysis (Exo-MFA) to quantify flow of cargo from source cells to recipient cells via vesicular transport. Our algorithm, which is based on 13C metabolic flux analysis, successfully predicts packaging fluxes to metabolite cargo in CAFs, dynamic changes in rate of exosome internalization by cancer cells, and flux of cargo release over time. We find that cancer cells internalize exosomes rapidly leading to depletion of extracellular exosomes within 24h. However, metabolite cargo significantly alters intracellular metabolism over the course of 24h by regulating glycolysis pathway fluxes via lactate supply. Furthermore, it can supply up to 35% of the TCA cycle fluxes by providing TCA intermediates and glutamine. Our algorithm will help gain insight into (i) metabolic interactions in multicellular systems (ii) biogenesis of extracellular vesicles and their differential packaging of cargo under changing environments, and (iii) regulation of cancer cell metabolism by its microenvironment. PMID- 28087333 TI - Nicotinamide nucleotide transhydrogenase activity impacts mitochondrial redox balance and the development of hypertension in mice. AB - Oxidant stress contributes to the initiation and progression of hypertension (HTN) by enhancing endothelial dysfunction and/or causing perturbations in nitric oxide homeostasis. Differences in mitochondrial function may augment this process and provide insight into why age of onset and clinical outcomes differ among individuals from distinct ethnic groups. We have previously demonstrated that variation in normal mitochondrial function and oxidant production exists in endothelial cells from individuals of Caucasian and African-American ethnicity and that this variation contributes to endothelial dysfunction. To model these distinct mitochondrial redox phenotypes, we used C57Bl/6N (6N) and C57Bl/6J (6J) mice that also display unique mitochondrial functional properties due to the differential expression nicotinamide nucleotide transhydrogenase (NNT). We demonstrate that the absence of NNT in 6J cells led to distinct mitochondrial bioenergetic profiles and a pro-oxidative mitochondrial phenotype characterized by increased superoxide production and reduced glutathione peroxidase activity. Interestingly, we found that 6J animals have significantly higher systolic blood pressure compared to 6N animals, and this difference is exacerbated by angiotensin II treatment. The changes in pressure were accompanied by both mitochondrial and vascular dysfunction revealed by impaired respiratory control ratios and endothelial-dependent vessel dilation. All end points could be significantly ameliorated by treatment with the mitochondria-targeted superoxide dismutase mimetic MitoTEMPO demonstrating a critical role for the production of mitochondrial reactive oxygen species in the development of HTN in these animals. Taken together, these data indicate that the absence of NNT leads to variation in mitochondrial function and contributes to a unique mitochondrial redox phenotype that influences susceptibility to HTN by contributing to endothelial and vascular dysfunction. PMID- 28087334 TI - The short- and long-term proteomic effects of sleep deprivation on the cortical and thalamic synapses. AB - Acute total sleep deprivation (SD) impairs memory consolidation, attention, working memory and perception. Structural, electrophysiological and molecular experimental approaches provided evidences for the involvement of sleep in synaptic functions. Despite the wide scientific interest on the effects of sleep on the synapse, there is a lack of systematic investigation of sleep-related changes in the synaptic proteome. We isolated parietal cortical and thalamic synaptosomes of rats after 8h of total SD by gentle handling and 16h after the end of deprivation to investigate the short- and longer-term effects of SD on the synaptic proteome, respectively. The SD efficiency was verified by electrophysiology. Protein abundance alterations of the synaptosomes were analyzed by fluorescent two-dimensional differential gel electrophoresis and by tandem mass spectrometry. As several altered proteins were found to be involved in synaptic strength regulation, our data can support the synaptic homeostasis hypothesis function of sleep and highlight the long-term influence of SD after the recovery sleep period, mostly on cortical synapses. Furthermore, the large scale and brain area-specific protein network change in the synapses may support both ideas of sleep-related synaptogenesis and molecular maintenance and reorganization in normal rat brain. PMID- 28087335 TI - The lower alkyl methacrylates: Genotoxic profile of non-carcinogenic compounds. AB - All of the lower alkyl methacrylates are high production chemicals with potential for human exposure. The genotoxicity of seven mono-functional alkyl esters of methacrylic acid, i.e. methyl methacrylate, ethyl methacrylate, hydroxyethyl methacrylate, n-, i- and t-butyl methacrylate and 2 ethyl hexyl methacrylate, as well as methacrylic acid itself, the acyl component common to all, is reviewed and compared with the lack of carcinogenicity of methyl methacrylate, the representative member of the series so evaluated. Also reviewed are the similarity of structure, chemical and biological reactivity, metabolism and common metabolic products of this group of compounds which allows a category approach for assessing genotoxicity. As a class, the lower alkyl methacrylates are universally negative for gene mutations in prokaryotes but do exhibit high dose clastogenicity in mammalian cells in vitro. There is no convincing evidence that these compounds induce genotoxic effects in vivo in either sub-mammalian or mammalian species. This dichotomy of effects can be explained by the potential genotoxic intermediates generated in vitro. This genotoxic profile of the lower alkyl methacrylates is consistent with the lack of carcinogenicity of methyl methacrylate. PMID- 28087337 TI - Tunicamycin impairs olfactory learning and synaptic plasticity in the olfactory bulb. AB - Tunicamycin (TM) induces endoplasmic reticulum (ER) stress and inhibits N glycosylation in cells. ER stress is associated with neuronal death in neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease, and most patients complain of the impairment of olfactory recognition. Here we examined the effects of TM on aversive olfactory learning and the underlying synaptic plasticity in the main olfactory bulb (MOB). Behavioral experiments demonstrated that the intrabulbar infusion of TM disabled aversive olfactory learning without affecting short-term memory. Histological analyses revealed that TM infusion upregulated C/EBP homologous protein (CHOP), a marker of ER stress, in the mitral and granule cell layers of MOB. Electrophysiological data indicated that TM inhibited tetanus-induced long-term potentiation (LTP) at the dendrodendritic excitatory synapse from mitral to granule cells. A low dose of TM (250nM) abolished the late phase of LTP, and a high dose (1MUM) inhibited the early and late phases of LTP. Further, high-dose, but not low-dose, TM reduced the paired-pulse facilitation ratio, suggesting that the inhibitory effects of TM on LTP are partially mediated through the presynaptic machinery. Thus, our results support the hypothesis that TM-induced ER stress impairs olfactory learning by inhibiting synaptic plasticity via presynaptic and postsynaptic mechanisms in MOB. PMID- 28087338 TI - Auditory hindbrain atrophy and anomalous calcium binding protein expression after neonatal exposure to monosodium glutamate. AB - Glutamate is the most abundant excitatory neurotransmitter in the central nervous system, and is stored and released by both neurons and astrocytes. Despite the important role of glutamate as a neurotransmitter, elevated extracellular glutamate can result in excitotoxicity and apoptosis. Monosodium glutamate (MSG) is a naturally occurring sodium salt of glutamic acid that is used as a flavor enhancer in many processed foods. Previous studies have shown that MSG administration during the early postnatal period results in neurodegenerative changes in several forebrain regions, characterized by neuronal loss and neuroendocrine abnormalities. Systemic delivery of MSG during the neonatal period and induction of glutamate neurotoxicity in the cochlea have both been shown to result in fewer neurons in the spiral ganglion. We hypothesized that an MSG induced loss of neurons in the spiral ganglion would have a significant impact on the number of neurons in the cochlear nuclei and superior olivary complex (SOC). Indeed, we found that exposure to MSG from postnatal days 4 through 10 resulted in significantly fewer neurons in the cochlear nuclei and SOC and significant dysmorphology in surviving neurons. Moreover, we found that neonatal MSG exposure resulted in a significant decrease in the expression of both calretinin and calbindin. These results suggest that neonatal exposure to MSG interferes with early development of the auditory brainstem and impacts expression of calcium binding proteins, both of which may lead to diminished auditory function. PMID- 28087336 TI - Oleate induces KATP channel-dependent hyperpolarization in mouse hypothalamic glucose-excited neurons without altering cellular energy charge. AB - The unsaturated fatty acid, oleate exhibits anorexigenic properties reducing food intake and hepatic glucose output. However, its mechanism of action in the hypothalamus has not been fully determined. This study investigated the effects of oleate and glucose on GT1-7 mouse hypothalamic cells (a model of glucose excited (GE) neurons) and mouse arcuate nucleus (ARC) neurons. Whole-cell and perforated patch-clamp recordings, immunoblotting and cell energy status measures were used to investigate oleate- and glucose-sensing properties of mouse hypothalamic neurons. Oleate or lowered glucose concentration caused hyperpolarization and inhibition of firing of GT1-7 cells by the activation of ATP-sensitive K+ channels (KATP). This effect of oleate was not dependent on fatty acid oxidation or raised AMP-activated protein kinase activity or prevented by the presence of the UCP2 inhibitor genipin. Oleate did not alter intracellular calcium, indicating that CD36/fatty acid translocase may not play a role. However, oleate activation of KATP may require ATP metabolism. The short-chain fatty acid octanoate was unable to replicate the actions of oleate on GT1-7 cells. Although oleate decreased GT1-7 cell mitochondrial membrane potential there was no change in total cellular ATP or ATP/ADP ratios. Perforated patch and whole-cell recordings from mouse hypothalamic slices demonstrated that oleate hyperpolarized a subpopulation of ARC GE neurons by KATP activation. Additionally, in a separate small population of ARC neurons, oleate application or lowered glucose concentration caused membrane depolarization. In conclusion, oleate induces KATP-dependent hyperpolarization and inhibition of firing of a subgroup of GE hypothalamic neurons without altering cellular energy charge. PMID- 28087340 TI - Electrophysiological alterations in diaphragm muscle caused by abdominal ischemia reperfusion. AB - Ischemia-reperfusion injury is the major complication of abdominal aortic surgery, and it mainly affects the lower extremities and remote organs. In the present study, the electrophysiological alterations in diaphragm that underlie the post-operative respiratory dysfunction were investigated. Wistar Albino rats were randomly divided into two groups: SHAM (only laparotomy was performed) and IR (abdominal aorta was clamped for 30min and reperfused for 2h). Following the operational period diaphragm muscles were isolated and electrophysiological experiments were carried out in-vitro. 3nM Ryanodine application, Na+ and K+ current blockage (0.3mM 4-Aminopyridine and 127mM N-methyl-d-glukamine) experiments were also conducted to further reveal any alterations. Twitch and tetanic force were decreased significantly. Action potential overshoot, amplitude and area were increased while diaphragm muscle cells were found to be hyperpolarized significantly. Mechanical alterations were shown to be caused by deterioration of Ca++ homeostasis. At resting state, a decrease in persistent Na+ current was found. The reshaping of action potential, on the other hand, was shown to be due to altered kinetics of Na+ channels and delayed activation of voltage dependent K+ channels. PMID- 28087339 TI - Differential behavioral sensitivity to carbon dioxide (CO2) inhalation in rats. AB - Inhalation of carbon dioxide (CO2) is frequently employed as a biological challenge to evoke intense fear and anxiety. In individuals with panic disorder, CO2 reliably evokes panic attacks. Sensitivity to CO2 is highly heterogeneous among individuals, and although a genetic component is implicated, underlying mechanisms are not clear. Preclinical models that can simulate differential responsivity to CO2 are therefore relevant. In the current study we investigated CO2-evoked behavioral responses in four different rat strains: Sprague-Dawley (SD), Wistar (W), Long Evans (LE) and Wistar-Kyoto, (WK) rats. We also assessed tryptophan hydroxylase 2 (TPH-2)-positive serotonergic neurons in anxiety/panic regulatory subdivisions of the dorsal raphe nucleus (DR), as well as dopamine beta hydroxylase (DbetaH)-positive noradrenergic neurons in the locus coeruleus, implicated in central CO2-chemosensitivity. Behavioral responsivity to CO2 inhalation varied between strains. CO2-evoked immobility was significantly higher in LE and WK rats as compared with W and SD cohorts. Differences were also observed in CO2-evoked rearing and grooming behaviors. Exposure to CO2 did not produce conditioned behavioral responses upon re-exposure to CO2 context in any strain. Reduced TPH-2-positive cell counts were observed specifically in the panic-regulatory dorsal raphe ventrolateral (DRVL)-ventrolateral periaqueductal gray (VLPAG) subdivision in CO2-sensitive strains. Conversely, DbetaH-positive cell counts within the LC were significantly higher in CO2-sensitive strains. Collectively, our data provide evidence for strain dependent, differential CO2 sensitivity and potential differences in monoaminergic systems regulating panic and anxiety. Comparative studies between CO2-vulnerable and resistant strains may facilitate the mechanistic understanding of differential CO2-sensitivity in the development of panic and anxiety disorders. PMID- 28087341 TI - Lung diffusing capacity in sub-Saharan Africans versus European Caucasians. AB - Single breath measurements of lung diffusing capacity (DL) for carbon monoxide (CO) and nitric oxide (NO) were performed in age-, sex-, weight- and height matched 32 sub-Saharan Africans (13 women) and 32 Caucasian Europeans, and repeated in 14 of each group at 80% of maximum exercise capacity. In Africans versus Caucasians respectively, DLNO was 153+/-31 vs 176+/-38ml/mmHg/min at rest (P<0.001) and 210+/-48 vs 241+/-52ml/mmHg/min at exercise (P<0.01) while hemoglobin-adjusted DLCO was 29+/-6 vs 34+/-6ml/mmHg/min at rest (P<0.001), and 46+/-11 vs 51+/-13ml/mmHg/min at exercise (P<0.01). However there were no differences in DLCO/alveolar volume(VA) (KCO) and DLNO/VA(KNO). The sitting-to standing height ratio was lower in the Africans. Differences in lung volume with respect to body height explain lower DLNO and DLCO in sub-Saharan Africans as compared to Caucasian Europeans. PMID- 28087342 TI - Myeloid leukemia factor-1 is a novel modulator of neonatal rat cardiomyocyte proliferation. AB - The present study focuses on the identification of the gene expression profile of neonatal rat cardiomyocytes (NRVCMs) after dynamic mechanical stretch through microarrays of RNA isolated from cells stretched for 2, 6 or 24h. In this analysis, myeloid leukemia factor-1 (MLF1) was found to be significantly downregulated during the course of stretch. We found that MLF1 is highly expressed in the heart, however, its cardiac function is unknown yet. In line with microarray data, MLF1 was profoundly downregulated in in vivo mouse models of cardiomyopathy, and also significantly reduced in the hearts of human patients with dilated cardiomyopathy. Our data indicates that the overexpression of MLF1 in NRVCMs inhibited cell proliferation while augmenting apoptosis. Conversely, knockdown of MLF1 protected NRVCMs from apoptosis and promoted cell proliferation. Moreover, we found that knockdown of MLF1 protected NRVCMs from hypoxia-induced cell death. The observed accelerated apoptosis is attributed to the activation of caspase-3/-7/PARP-dependent apoptotic signaling and upregulation of p53. Most interestingly, MLF1 knockdown significantly upregulated the expression of D cyclins suggesting its possible role in cyclin-dependent cell proliferation. Taken together, we, for the first time, identified an important role for MLF1 in NRVCM proliferation. PMID- 28087343 TI - Calcium remodeling in colorectal cancer. AB - : Colorectal cancer (CRC) is the third most frequent form of cancer and the fourth leading cause of cancer-related death in the world. Basic and clinical data indicate that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) may prevent colon cancer but mechanisms remain unknown. Aspirin metabolite salicylate and other NSAIDs may inhibit tumor cell growth acting on store-operated Ca2+ entry (SOCE), suggesting an important role for this pathway in CRC. Consistently, SOCE is emerging as a novel player in different forms of cancer, including CRC. SOCE and store-operated currents (SOCs) are dramatically enhanced in CRC while Ca2+ stores are partially empty in CRC cells. These features may contribute to CRC hallmarks including enhanced cell proliferation, migration, invasion and survival. At the molecular level, enhanced SOCE and depleted stores are mediated by overexpression of Orai1, Stromal interaction protein 1 (STIM1) and Transient receptor protein channel 1 (TRPC1) and downregulation of STIM2. In normal colonic cells, SOCE is mediated by Ca2+ release activated Ca2+ channels made of STIM1, STIM2 and Orai1. In CRC cells, SOCE is mediated by different store-operated currents (SOCs) driven by STIM1, Orai1 and TRPC1. Loss of STIM2 contributes to depletion of Ca2+ stores and enhanced resistance to cell death in CRC cells. Thus, SOCE is a novel key player in CRC and inhibition by salicylate and other NSAIDs may contribute to explain chemoprevention activity. SUMMARY: Colorectal cancer (CRC) is the third most frequent form of cancer worldwide. Recent evidence suggests that intracellular Ca2+ remodeling may contribute to cancer hallmarks. In addition, aspirin and other NSAIDs might prevent CRC acting on remodeled Ca2+ entry pathways. In this review, we will briefly describe 1) the players involved in intracellular Ca2+ homeostasis with a particular emphasis on the mechanisms involved in SOCE activation and inactivation, 2) the evidence that aspirin metabolite salicylate and other NSAIDs inhibits tumor cell growth acting on SOCE, 3) evidences on the remodeling of intracellular Ca2+ in cancer with a particular emphasis in SOCE, 4) the remodeling of SOCE and Ca2+ store content in CRC and, finally, 5) the molecular basis of Ca2+ remodeling in CRC. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech. PMID- 28087344 TI - Up-regulation of the active form of small GTPase Rab13 promotes macroautophagy in vascular endothelial cells. AB - The importance of macroautophagy (hereafter referred to as autophagy) in vascular endothelial cell (VEC) biology and dysfunction is increasingly recognized, but the molecular mechanisms of autophagy in VECs in the presence of serum are still poorly understood. Previously, we identified pterostilbene as a potent autophagy inducer of VECs in the presence of serum. In this study, we used pterostilbene as a tool to induce VEC autophagy and identified the differentially expressed genes using high-throughput DAN microarray. The small GTPase Ras-related protein in brain 13 (Rab13) was found to be the most significantly up-regulated gene in pterostilbene-treated human umbilical VECs (HUVECs). Knockdown of Rab13 blocked pterostilbene-induced mTOR inhibition and autophagy, whereas overexpression of the GTP-containing active form of Rab13 induced mTOR inhibition and autophagy in HUVECs. Using a combination of immunofluorescence and co-immunoprecipitation (co IP) assays, we demonstrated that pterostilbene or up-regulation of the active form of Rab13 promoted the interaction between Rab13 and growth factor receptor bound protein 2 (Grb2). Knockdown of Grb2 suppressed pterostilbene or up regulation of the active form of Rab13-induced autophagy. Further mechanistic studies revealed that Rab13 activated the downstream AMP-activated protein kinase (AMPK) and blocked mammalian target of rapamycin (mTOR) signaling by its functional interaction with Grb2 to regulate autophagy in HUVECs. Our study firmly establishes Rab13 as a novel regulator of autophagy in VECs under nutrient enriched conditions. PMID- 28087345 TI - Steroid-induced glaucoma in the pediatric population. AB - Steroid medications may cause elevation of intraocular pressure, sometimes with permanent damage to the optic nerve. These therapies, via various routes of administration, are commonly prescribed for children, but the potential sequelae of elevated intraocular pressure and glaucomatous optic nerve damage can be even more severe and devastating in children than in adults. This review discusses the pathophysiology and potential risk factors, including the impact of intraocular pressure elevation via the different common routes of administration of steroids, clinical evaluation, and management of steroid response and steroid-induced glaucoma in children. PMID- 28087346 TI - Patterns of retinal hemorrhage associated with pediatric cerebral sinovenous thrombosis. AB - BACKGROUND: Cerebral sinovenous thrombosis (CSVT) has been proposed as an alternative cause of retinal hemorrhage (RH) in children being evaluated for abusive head trauma. This study investigated the prevalence and characteristics of RH in children with CSVT. METHODS: The medical records of children >6 weeks of age with newly diagnosed CSVT and fundus examination by an ophthalmologist were examined retrospectively. Primary outcomes were presence and patterns of RH. RESULTS: A total of 29 children (median age, 9 years; range, 7 weeks to 17 years) were studied. Of these, 5 (17%) had RH, in 4 of whom RH were peripapillary, superficial, intraretinal, and adjacent to a swollen optic disk. In the fifth child, who had meningitis, sepsis, and multiple cerebral infarcts, there were a moderate number of posterior pole intraretinal hemorrhages. Eighteen children (62%) had optic disk swelling. In 13 children, cerebrospinal fluid opening pressure was recorded (range, 27-59 cm H2O). CSVT risk factors included meningitis, mastoiditis, and hypercoagulability. CONCLUSIONS: RH in pediatric CSVT was uncommon. When RHs were present, the appearance matched RH patterns known to be caused by medical conditions, such as raised intracranial pressure and sepsis, also present in these children. These findings suggest that the RHs are due to these other causes and not directly to CSVT itself. In children with CSVT, if RHs are multilayered, extend beyond the peripapillary region into the rest of the posterior pole or retinal periphery, or occur in the absence of optic disk swelling, another etiology for the RH should be sought. PMID- 28087347 TI - OCT-documented optic atrophy in nonsyndromic craniosynostosis and lacunar skull. AB - We report the case of 6-year-old boy who presented with mild redness in the left eye. On fundus examination, disk pallor was noted in both eyes. He did not complain of headache, vomiting, or blurred vision. Three-dimensional computed tomography (CT) imaging was suggestive of craniosynostosis and lacunar skull (luckenschadel). Magnetic resonance imaging findings were suggestive of intracranial hypertension. HD-OCT imaging revealed optic neuropathy in both eyes. The patient underwent sutural release and expansion cranioplasty surgery. PMID- 28087348 TI - The eyes of children with celiac disease. AB - PURPOSE: To determine possible eye involvement in pediatric patients with celiac disease. METHODS: Children (aged 5-18 years) with classic celiac disease and sex- and age-matched controls were included. In addition to a complete ophthalmologic examination, all patients were scanned by a Scheimpflug camera and spectral domain optical coherence tomography, and Schirmer and break-up time (BUT) tests were performed. Data were evaluated by paired t test, with a P value of <0.05 considered statistically significant. RESULTS: A total of 31 celiac patients (19 females [61%]) and 34 controls (20 females [59%]) were included. Mean age of the celiac patients was 11.0 +/- 4.4 years (range, 4-18 years); of the controls, 10.4 +/- 2.6 years (range, 5-15 years; P = 0.473). Mean follow-up of patients was 5.4 +/- 1.7 years (range, 3-7.2 years). The eyes of children with celiac disease, compared to controls, did show decreased anterior chamber depth (3.5 +/- 0.2 vs 3.7 +/- 0.2, resp.; P < 0.001), decreased anterior chamber volume (170.8 +/- 25.5 vs 190.7 +/- 27.4; P < 0.001), lower Schirmer (17.9 +/- 9.1 vs 21.6 +/- 4.1; P = 0.038), and lower BUT (10.8 +/- 3.8 vs 12.1 +/- 1.7; P = 0.046), as well as lower retinal nerve fiber layer (general 102.8 +/- 8.2 vs 108.9 +/- 10.1; P < 0.001). CONCLUSIONS: Decreases in retinal nerve fiber, anterior chamber shallowing, and qualitative and quantitative reduction in tears can occur in celiac patients, even if routine ocular examination reveals no abnormality. PMID- 28087349 TI - Combination of Multiple Ligation-Dependent Probe Amplification and Illumina MiSeq Amplicon Sequencing for TSC1/TSC2 Gene Analyses in Patients with Tuberous Sclerosis Complex. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by tumor growth in multiple organs and caused by mutations in either TSC1 or TSC2 genes. Because of their relatively large genomic sizes, absence of hotspots, and common type of mutations, mutation detection in TSC1 and TSC2 genes has been challenging. We devised a combination of multiple ligation dependent probe amplification (MLPA) and amplicon sequencing (AS) to simplify the detection strategy, yet we come up with reasonably high detection rate. Thirty four Malaysian patients diagnosed with TSC were referred to Human Genome Center, Universiti Sains Malaysia. We used a combination of MLPA to detect large copy number changes and AS to detect smaller mutations. TSC1 pathogenic or likely pathogenic mutations were found in 6 patients (18%) and TSC2 in 21 patients (62%), whereas 6 patients (18%) show no mutations and 1 patient (2%) showed only TSC2 missense variant with uncertain significance. Six of the mutations are novel. Our detection strategy costs 81% less and require 1 working week less than the conventional strategy. Confirmatory sequencing using Sanger method on a few representative mutations showed agreement with results of the AS. Combination of MLPA and Illumina MiSeq AS provides a simplified strategy and reasonably high detection rate for TSC1/TSC2 mutation, which suggested application of the strategies into clinical molecular diagnostics. PMID- 28087350 TI - Corrigendum to 'Pregnancy derived from human zygote pronuclear transfer in a patient who had arrested embryos after IVF' [Reproductive BioMedicine Online 33 (2016) 529-533]. PMID- 28087351 TI - Central nervous system vasculitis in adults: An update. AB - Primary central nervous system vasculitis (PCNSV) is a challenging diagnosis due to broad clinical manifestations and variable specificity and sensitivity of laboratory and imaging diagnostic tools. Differential diagnosis includes reversible cerebral vasoconstriction syndrome (RCVS), secondary vasculitis of the CNS and other noninflammatory vasculopathies. Brain biopsy is essential for definitive diagnosis and to exclude mimickers. Recent data show that data large vessel PCNSV present worse prognosis when compared to small-vessel PCNSV. Herein we review diagnosis and management of PCNSV, secondary vasculitis of CNS and RCVS. PMID- 28087352 TI - Engineering hot-melt extruded solid dispersion for controlled release of hydrophilic drugs. AB - It is often challenging to precisely manipulate the release behavior of hydrophilic drugs that is believed to be crucial for a satisfactory therapeutic outcome. The aim of this work was to regulate the dissolution of hydrophilic drug from hot-melt extruded solid dispersion via rational screening of the pore forming agents. Venlafaxine hydrochloride and Compritol(r) 888 ATO was selected as the model drug and carrier excipient, respectively. Hydrophilic polyethylene glycol (PEG 6000) and polyvinylpyrolidone (PVP K30) were chosen as the transient pore-forming agents. The X-ray diffraction and thermal analysis showed that both drug and carrier existed in the crystalline form. Both types of polymers could generate pores upon dissolution test and the drug release rate was proportionally correlated to the pore-forming agent content. The mathematical modelling showed that the Ritger-Peppas model gave the best fit to the release curves, which demonstrates a diffusion-dominant release mechanism. The scanning electron microscopy and mercury intrusion porosimetry analysis proved that PVP K30 could generate large pores with low porosity, but PEG 6000 produced smaller pores with relatively high porosity. The in vivo pharmacokinetics study in rat revealed that solid dispersions containing either PEG 6000 or PVP K30 (both at 2.5%, w/w) exhibited an elevated bioavailability compared to the commercial product, Effexor(r) XR. The current work implied that rational screening of transient pore forming polymer in solid dispersion could be a robust approach for controlling hydrophilic drug release. PMID- 28087353 TI - Thiolated polymers as mucoadhesive drug delivery systems. AB - Mucoadhesion is the process of binding a material to the mucosal layer of the body. Utilising both natural and synthetic polymers, mucoadhesive drug delivery is a method of controlled drug release which allows for intimate contact between the polymer and a target tissue. It has the potential to increase bioavailability, decrease potential side effects and offer protection to more sensitive drugs such as proteins and peptide based drugs. The thiolation of polymers has, in the last number of years, come to the fore of mucoadhesive drug delivery, markedly improving mucoadhesion due to the introduction of free thiol groups onto the polymer backbone while also offering a more cohesive polymeric matrix for the slower and more controlled release of drug. This review explores the concept of mucoadhesion and the recent advances in both the polymers and the methods of thiolation used in the synthesis of mucoadhesive drug delivery devices. PMID- 28087354 TI - Effect of piroxicam on lipid membranes: Drug encapsulation and gastric toxicity aspects. AB - Uptake of piroxicam, a non-steroidal anti-inflammatory drug, from the intestines after oral intake is limited due to its low solubility and its wide use is associated with several side effects related to the gastrointestinal tract. In this study, all-atom molecular dynamics (MD) simulations and fluorescent spectroscopy were employed to investigate the interaction of piroxicam in neutral, zwitterionic, and cationic forms with lipid bilayers composed of phosphatidylcholine, cholesterol, and PEGylated lipids. Our study was aimed to assess the potential for encapsulation of piroxicam in liposomal carriers and to shed more light on the process of gastrointestinal tract injury by the drug. Through both the MD simulations and laser scanning confocal microscopy, we have demonstrated that all forms of piroxicam can associate with the lipid bilayers and locate close to the water-membrane interface. Conventional liposomes used in drug delivery are usually stabilized by the addition of cholesterol and have their bloodstream lifetime extended through the inclusion of PEGylated lipids in the formulation to create a protective polymer corona. For this reason, we tested the effect of these two modifications on the behavior of piroxicam in the membrane. When the bilayer was PEGylated, piroxicam localize to the PEG layer and within the lipid headgroup region. This suggests that PEGylated liposomes are capable of carrying a larger quantity of piroxicam than the conventional ones. PMID- 28087355 TI - Generation of quercetin/cellulose acetate phthalate systems for delivery by supercritical antisolvent process. AB - Supercritical antisolvent process (SAS) has been used to precipitate microparticles of quercetin, a plant pigment found in many foods and used for medical treatments, pharmaceutical and cosmetic industries, together with nanoparticles of cellulose acetate phthalate (CAP), a polymer quite frequently used in drug delivery. Previously, precipitation of nanoparticles of CAP by the same process was studied at different conditions of pressure, temperature, CO2 and solution flow rates, nozzle diameter and initial concentration of the solution. Morphologies of the precipitates were analyzed by scanning electron microscopy (SEM). A range between 84 and 145nm of diameter in spherical particle were achievement in CAP precipitation. A same range of semi-spherical particles of CAP around 145nm and needle-like particle of quercetin was obtained in the coprecipitation experiments. X-ray diffraction (XRD) and Fourier Transform Infrared Spectroscopy (FTIR) were carried out to find out the possible loss of crystallinity of the coprecipitates and the possible interactions between the polymer and quercetin, respectively. Release profiles of quercetin were carried out in simulated gastric and intestinal fluids. Higher quercetin:polymer ratios in the coprecipitates are recommended to achieve faster release and higher solubilities of quercetin in the assayed time. This fact would allow its use in pharmaceutical, cosmetic or nutraceutical applications. PMID- 28087356 TI - Long-Term Sensitivity and Patient-Reported Functionality of the Neoclitoris After Gender Reassignment Surgery. AB - INTRODUCTION: A cornerstone of treating gender dysphoria for transgender women is gender reassignment surgery (GRS) encompassing vaginoplasty and clitoroplasty. The neoclitoris is harvested as a flap with a neurovascular pedicle from the proximal dorsal part of the glans penis. Few long-term follow-ups exist on postoperative sensation and patient-reported sexual functionality of the neoclitoris. AIM: To examine the sensitivity of the neoclitoris and its relation to orgasm and sexual function at least 1 year after GRS. METHODS: Twenty-two patients were included, with a mean follow-up of 37 months (range = 12-63) after initial surgery. Tactile and vibratory sensitivities were measured with Semmes Weinstein monofilaments and the Bio-Thesiometer vibratory measurement device, respectively. A questionnaire was provided to the patients, as were interview questions about body image, orgasm, pain, and general satisfaction with the surgery. MAIN OUTCOME MEASURES: Tactile and vibratory sensitivities of the neoclitoris and questionnaire on satisfaction with orgasm, sexual function, and general satisfaction. RESULTS: The average tactile threshold for the clitoris was 12.5 g/mm2 and the average vibratory threshold was 0.3 MUm. Most participants (86%) experienced orgasm after surgery, had no or little pain, and were satisfied with the surgery. No statistical correlation was found between better or worse objective pressure and vibratory thresholds and patient answers to questions about the clitoris in the Body Image Scale for Transsexuals questionnaire. CONCLUSION: The neoclitoris derived from the glans penis in GRS provides long term clitoral sensation that is erogenous. Overall, the vast majority of patients who undergo male-to female GRS experience orgasm and are satisfied with the surgery. PMID- 28087357 TI - Early Effect of Bariatric Surgery on Urogenital Function in Morbidly Obese Men. AB - INTRODUCTION: Obesity is an independent risk factor for erectile dysfunction (ED) and lower urinary tract symptoms (LUTS). Bariatric surgery has been shown to improve erectile function and urinary symptoms in medium- to long-term studies (3 to 12-month postoperative follow-up). AIM: To investigate the early effect (1 month postoperatively) of bariatric surgery on ED and LUTS, which has not previously been investigated. METHODS: Morbidly obese men (body mass index > 35 kg/m2) undergoing bariatric surgery were asked to complete the International Index of Erectile Function (IIEF) and International Prostate Symptom Score (IPSS) questionnaires before surgery and 1, 3, and 6 months after surgery. MAIN OUTCOME MEASURE: The influence of bariatric surgery on urogenital function, body mass index, fasting blood glucose, and glycated hemoglobin were analyzed using parametric and non-parametric tests for paired samples. RESULTS: Of 30 patients who completed the study, 18 reported ED (IIEF score < 25) and 14 reported moderate or severe LUTS (IPSS >= 8) before the operation. Twelve patients had ED and moderate or severe LUTS. IIEF score, IPSS, body mass index, percentage of weight loss, fasting blood glucose, and glycated hemoglobin showed significant and rapid improvement after bariatric surgery starting at the 1-month postoperative time point and improvement continued throughout the study in all patients with ED or moderate to severe LUTS. CONCLUSION: This is the first study showing improvement in erectile and urinary function within 1 month after bariatric surgery, an effect that was parallel to glycemic improvement and weight loss. PMID- 28087358 TI - Vascular calcification abrogates the nicorandil mediated cardio-protection in ischemia reperfusion injury of rat heart. AB - The present study was aimed to determine the efficacy of nicorandil in treating cardiac reperfusion injury with an underlying co-morbidity of vascular calcification (VC). Adenine diet was used to induce VC in Wistar rat and the heart was isolated to induce global ischemia reperfusion (IR) by Langendorff method, with and without the nicorandil (7.5mg/kg) pre-treatment and compared with those fed on normal diet. The adenine-treated rats displayed abnormal ECG changes and altered mitochondrial integrity compared to a normal rat heart. These hearts, when subjected to IR increased the infarct size, cardiac injury (measured by lactate dehydrogenase and creatine kinase activity in the coronary perfusate) and significantly altered the hemodynamics compared to the normal perfused heart. Nicorandil pretreatment in rat fed on normal diet enhanced the hemodynamics significantly (P<0.05) along with a substantial reduction in the mitochondrial dysfunction (measured by high ADP to oxygen consumption ratio, respiratory control ratio, enzyme activities and less swelling behavior) when subjected to IR. However, this cardio-protective effect of nicorandil was absent in rat heart with underlying calcification. Our results suggest that, the protective effect of nicorandil, a known mitochondrial ATP linked K+ channel opener, against myocardial reperfusion injury was confined to normal rat heart. PMID- 28087359 TI - The effect of NMDA-R antagonism on simultaneously acquired local field potentials and tissue oxygen levels in the brains of freely-moving rats. AB - Non-competitive NMDA receptor antagonists are known to induce psychosis-like symptoms in rodents. Administration of such compounds cause behavioural effects such as memory impairment and hyperlocomotion. Additionally, drugs such as phencyclidine (PCP), ketamine and MK-801 all cause distinctive increases in striatal local field potential (LFP) in the high frequency oscillation (HFO) band in the power spectrum (140-180 Hz). Amperometric sensors provide a means to measure tissue oxygen (tO2; a BOLD-like signal) in the brains of freely-moving rats while simultaneously acquiring LFP using the same electrode. Carbon paste electrodes were implanted into the striatum and hippocampus of male Wistar rats. Rats were administered with saline, ketamine (10 mg/kg), MK-801 (0.1 mg/kg) and PCP (2.5 mg/kg) and recordings were made at 1 kHz using three different potentials (-650 mV to measure tO2; 0 mV and +700 mV as control conditions). NMDA receptor antagonism caused significant increases in tO2 in both the striatum and the hippocampus. Power spectrum analysis showed significant increases in HFO power in the striatum but not in the hippocampus. Conversely, there were significant decreases in delta and alpha power along with increases in theta and gamma power in the hippocampus that were absent in the striatum. This supports findings that LFP can be obtained from an amperometric sensor signal; allowing simultaneous acquisition of two translational biomarkers of neuronal activity (LFP and tO2). PMID- 28087360 TI - The synthetic peptide PnPP-19 induces peripheral antinociception via activation of NO/cGMP/KATP pathway: Role of eNOS and nNOS. AB - BACKGROUND: and purpose: The peptide PnPP-19, derived from the spider toxin PnTx2 6 (renamed as delta-CNTX-Pn1c), potentiates erectile function by activating the nitrergic system. Since NO has been studied as an antinociceptive molecule and PnPP-19 is known to induce peripheral antinociception, we intended to evaluate whether PnPP-19 could induce peripheral antinociception through activation of this pathway. EXPERIMENTAL APPROACH: Nociceptive thresholds were measured by paw pressure test. PGE2 (2 MUg/paw) was administered intraplantarly together with PnPP-19 and inhibitors/blockers of NOS, guanylyl cyclase and KATP channels. The nitrite concentration was accessed by Griess test. The expression and phosphorylation of eNOS and nNOS were determined by western blot. KEY RESULTS: PnPP-19 (5, 10 and 20 MUg/paw) induced peripheral antinociception in rats. Administration of NOS inhibitor (L-NOarg), selective nNOS inhibitor (L-NPA), guanylyl cyclase inhibitor (ODQ) and the blocker of KATP (glibenclamide) partially inhibited the antinociceptive effect of PnPP-19 (10 MUg/paw). Tissue nitrite concentration increased after PnPP-19 (10 MUg/paw) administration. Expression of eNOS and nNOS remained the same in all tested groups, however the phosphorylation of nNOS Ser852 (inactivation site) increased and phosphorylation of eNOS Ser1177 (activation site) decreased after PGE2 injection. Administration of PnPP-19 reverted this PGE2-induced effect. CONCLUSIONS AND IMPLICATIONS: The peripheral antinociceptive effect induced by PnPP-19 is resulting from activation of NO-cGMP-KATP pathway. Activation of eNOS and nNOS might be required for such effect. Our results suggest PnPP-19 as a new drug candidate to treat pain and reinforce the importance of nNOS and eNOS activation, as well as endogenous NO release, for induction of peripheral antinociception. PMID- 28087361 TI - Pulmonary veno-occlusive disease: characterising a rare but important disease. PMID- 28087362 TI - Clinical phenotypes and outcomes of heritable and sporadic pulmonary veno occlusive disease: a population-based study. AB - BACKGROUND: Bi-allelic mutations of the EIF2AK4 gene cause heritable pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis (PVOD/PCH). We aimed to assess the effect of EIF2AK4 mutations on the clinical phenotypes and outcomes of PVOD/PCH. METHODS: We did a population-based study using clinical, functional, and haemodynamic data from the registry of the French Pulmonary Hypertension Network. We reviewed the clinical data and outcomes from all patients referred to the French Referral Centre (Pulmonary Department, Hospital Kremlin-Bicetre, University Paris-Sud) with either confirmed or highly probable PVOD/PCH with DNA available for mutation screening (excluding patients with other risk factors of pulmonary hypertension, such as chronic respiratory diseases). We sequenced the coding sequence and intronic junctions of the EIF2AK4 gene, and compared clinical characteristics and outcomes between EIF2AK4 mutation carriers and non-carriers. Medical therapies approved for pulmonary arterial hypertension (prostacyclin derivatives, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors) were given to patients according to the clinical judgment and discretion of treating physicians. The primary outcome was the event-free survival (death or transplantation). Secondary outcomes included response to therapies for pulmonary arterial hypertension and survival after lung transplantation. A satisfactory clinical response to specific therapy for pulmonary arterial hypertension was defined by achieving New York Heart Association functional class I or II, a 6-min walk distance of more than 440 m, and a cardiac index greater than 2.5 L/min per m2 at the first reassessment after initiation of specific therapy for pulmonary arterial hypertension. FINDINGS: We obtained data from Jan 1, 2003, to June 1, 2016, and identified 94 patients with sporadic or heritable PVOD/PCH (confirmed or highly probable). 27 (29%) of these patients had bi-allelic EIF2AK4 mutations. PVOD/PCH due to EIF2AK4 mutations occurred from birth to age 50 years, and these patients were younger at presentation than non-carriers (median 26.0 years [range 0-50.3] vs 60.0 years [6.7-81.4] years; p<0.0001). At diagnosis, both mutations carriers and non carriers had similarly severe precapillary pulmonary hypertension and functional impairment. 22 (81%) of mutations carriers and 63 (94%) of non-carriers received therapy approved for pulmonary arterial hypertension. Drug-induced pulmonary oedema occurred in five (23%) of treated EIF2AK4 mutations carriers and 13 (21%) of treated non-carriers. Follow-up assessment after initiation of treatment showed that only three (4%) patients with PVOD/PCH reached the predefined criteria for satisfactory clinical response. The probabilities of event-free survival (death or transplantation) at 1 and 3 years were 63% and 32% in EIF2AK4 mutations carriers, and 75% and 34% in non-carriers. No significant differences occurred in event-free survival between the 2 groups (p=0.38). Among the 33 patients who had lung transplantation, estimated post-transplantation survival rates at 1, 2, and 5 years were 84%, 81%, and 73%, respectively. INTERPRETATION: Heritable PVOD/PCH due to bi-allelic EIF2AK4 mutations is characterised by a younger age at diagnosis but these patients display similar disease severity compared with mutation non-carriers. Response to therapy approved for pulmonary arterial hypertension in PVOD/PCH is rare. PVOD/PCH is a devastating condition and lung transplantation should be considered for eligible patients. FUNDING: None. PMID- 28087363 TI - Membrane restructuring following in situ sialidase digestion of gangliosides: Complex model bilayers by synchrotron radiation reflectivity. AB - Synchrotron radiation reflectometry was used to access the transverse structure of model membranes under the action of the human sialidase NEU2, down to the Angstrom length scale. Model membranes were designed to mimic the lipid composition of so-called Glycosphingolipids Enriched Microdomains (GEMs), which are membrane platforms specifically enriched in cholesterol and sphingolipids, and where also typical signalling molecules are hosted. Gangliosides, glycosphingolipids containing one or more sialic acid residues, are asymmetrically embedded in GEMs, in the outer membrane leaflet where gangliosides are claimed to interact directly with growth-factor receptors, modulating their activation and then the downstream intracellular signalling pathways. Thus, membrane dynamics and signalling could be strongly influenced by the activity of enzymes regulating the membrane ganglioside composition, including sialidases. Our results, concerning the structure of single membranes undergoing in-situ enzymatic digestion, show that the outcome of the sialidase action is not limited to the emergence of lower-sialylated ganglioside species. In fact, membrane reshaping occurs, involving a novel arrangement of the headgroups on its surface. Thus, sialidase activity reveals to be a potential tool to control dynamically the structural properties of the membrane external leaflet of living cells, influencing both the morphology of the close environment and the extent of interaction among active molecules belonging to signalling platforms. PMID- 28087365 TI - Parasite-induced increases in the energy costs of movement of host freshwater fish. AB - Parasitization by the larvae (glochidia) of freshwater mussels can cause harm to a fish's gills, resulting in less effective respiration and/or reduced activity by the host fish. The impact of glochidia infections on the host's physiology remains poorly understood, and no information is available concerning energy consumption in parasitized fish. Hence, we obtained glochidia of the invasive unionid mussel Sinanodonta (Anodonta) woodiana and experimentally infected common carp, Cyprinus carpio, tagged with physiological sensors to measure energy consumption. We tested the hypothesis that parasitization affects energy consumption in the host fish, reflected as higher energy costs for movement and reduced movement activity over eight days post-infection within a twenty-four hour cycle. Parasitized fish showed higher energy costs of movement; however, no changes in movement activity were found compared with activity in control fish. Significantly increased biochemical indices were measured in host fish blood samples, including aspartate (AST) and alanine (ALT) aminotransferase levels, indicating liver injury, and high concentrations of potassium (K+), signifying kidney injury (hyperkalemia). Increased Cl- concentrations indicate gill dysfunction. Our results show that the energy costs due to glochidia parasitization are independent of overall movement activity patterns and vary in time according to the parasitic phase and the diurnal cycle. Moreover, the side effects of parasitization have a more important impact on fish hosts than has been shown in previous reports. PMID- 28087364 TI - Aquaglyceroporins Are the Entry Pathway of Boric Acid in Trypanosoma brucei. AB - The boron element possesses a range of different effects on living beings. It is essential to beneficial at low concentrations, but toxic at excessive concentrations. Recently, some boron-based compounds have been identified as promising molecules against Trypanosoma brucei, the causative agent of sleeping sickness. However, until now, the boron metabolism and its access route into the parasite remained elusive. The present study addressed the permeability of T. brucei aquaglyceroporins (TbAQPs) for boric acid, the main natural boron species. To this end, the three TbAQPs were expressed in Saccharomyces cerevisiae and Xenopus laevis oocytes. Our findings in both expression systems showed that all three TbAQPs are permeable for boric acid. Especially TbAQP2 is highly permeable for this compound, displaying one of the highest conductances reported for a solute in these channels. Additionally, T. brucei aquaglyceroporin activities were sensitive to pH. Taken together, these results establish that TbAQPs are channels for boric acid and are highly efficient entry pathways for boron into the parasite. Our findings stress the importance of studying the physiological functions of boron and their derivatives in T. brucei, as well as the pharmacological implications of their uptake by trypanosome aquaglyceroporins. PMID- 28087366 TI - A Program to Prevent Burnout, Depression, and Anxiety in First-Year Pediatric Residents. PMID- 28087368 TI - Trends in wild food plants uses in Gorbeialdea (Basque Country). AB - Despite wild food plants' potential nutritional and economic value, their knowledge and consumption is quickly decreasing throughout the world. We examine how the consideration that a wild plant use is within the cultural tradition of a given area relates to its consumption by analysing 1) current perception and 2) past and present use of six wild plants' food-uses, of which only three are locally perceived as being part of the local tradition. Research was conducted in Gorbeialdea, an area in the Basque Country with a clearly marked Basque identity opposed to the Spanish identity. Overall, there is a clear decrease in the knowledge and consumption of the selected uses and especially of the three uses acquired from local sources (i.e., the consumption of the raw leaves of Fagus sylvatica and Rumex acetosa and of the fruits of Pyrus cordata). The trend is likely driven by the disappearance of the traditional agrarian lifestyle. Among the uses not acquired from local sources, the use recently adopted from another Basque-speaking area (i.e., macerating the fruits of Prunus spinosa to elaborate a liqueur) is now considered part of the local tradition by young generations, whereas the use acquired from southern Spanish migrants (i.e., using Laurus nobilis leaves as condiments) is not. While lifestyle changes largely explain overall trends in wild edibles consumption, other cultural aspects -in our case study the stigmatization of a given source of information associated to cultural identity- might help shape which new uses of wild plants become embedded in local traditions. PMID- 28087367 TI - Production of recombinant proteins in Escherichia coli tagged with the fusion protein CusF3H. AB - Recombinant protein expression in the bacterium Escherichia coli still is the number one choice for large-scale protein production. Nevertheless, many complications can arise using this microorganism, such as low yields, the formation of inclusion bodies, and the requirement for difficult purification steps. Most of these problems can be solved with the use of fusion proteins. Here, the use of the metal-binding protein CusF3H+ is described as a new fusion protein for recombinant protein expression and purification in E. coli. We have previously shown that CusF produces large amounts of soluble protein, with low levels of formation of inclusion bodies, and that proteins can be purified using IMAC resins charged with Cu(II) ions. CusF3H+ is an enhanced variant of CusF, formed by the addition of three histidine residues at the N-terminus. These residues then can bind Ni(II) ions allowing improved purity after affinity chromatography. Expression and purification of Green Fluorescent Protein tagged with CusF3H+ showed that the mutation did not alter the capacity of the fusion protein to increase protein expression, and purity improved considerably after affinity chromatography with immobilized nickel ions; high yields are obtained after tag-removal since CusF3H+ is a small protein of just 10 kDa. Furthermore, the results of experiments involving expression of tagged proteins having medium to large molecular weights indicate that the presence of the CusF3H+ tag improves protein solubility, as compared to a His-tag. We therefore endorse CusF3H+ as a useful alternative fusion protein/affinity tag for production of recombinant proteins in E. coli. PMID- 28087369 TI - Multidimensional assessment of impulsivity in relation to obesity and food addiction. AB - Based on similarities between overconsumption of food and addictive drugs, there is increasing interest in "food addiction," a compulsive eating pattern defined using symptoms parallel to substance use disorders. Impulsivity, a multidimensional construct robustly linked to drug addiction, has been increasingly examined as an obesity determinant, but with mixed findings. This study sought to clarify relations between three major domains of impulsivity (i.e., impulsive personality traits, discounting of delayed rewards, and behavioral inhibition) in both obesity and food addiction. Based on the association between impulsivity and compulsive drug use, the general hypothesis was that the impulsivity-food addiction relation would be stronger than and responsible for the impulsivity-obesity relation. Using a cross-sectional dimensional design, participants (N = 181; 32% obese) completed a biometric assessment, the Yale Food Addiction Scale (YFAS), the UPPS-P Impulsive Behavior Scales, a Go/NoGo task, and measures of monetary delay discounting. Results revealed significantly higher prevalence of food addiction among obese participants and stronger zero-order associations between impulsivity indices and YFAS compared to obesity. Two aspects of impulsivity were independently significantly associated with food addiction: (a) a composite of Positive and Negative Urgency, reflecting proneness to act impulsively during intense mood states, and (b) steep discounting of delayed rewards. Furthermore, the results supported food addiction as a mediator connecting both urgency and delay discounting with obesity. These findings provide further evidence linking impulsivity to food addiction and obesity, and suggest that food addiction may be a candidate etiological pathway to obesity for individuals exhibiting elevations in these domains. PMID- 28087370 TI - Laparoscopic versus open surgery for rectal cancer: A meta-analysis of classic randomized controlled trials and high-quality Nonrandomized Studies in the last 5 years. AB - OBJECTIVE: To present a meta-analysis of high-quality published reports comparing laparoscopic rectal resection (LRR) and open rectal resection (ORR) for rectal cancer. METHODS: Studies that compared LRR and ORR and were published within the last 5 years were identified. All eligible randomized controlled trials (RCTs) and non-randomized comparative trials (NRCTs) were evaluated based on the Jadad score, the Cochrane risk of bias assessment tool and modified Methodological Indices for Nonrandomized Studies (MINORS). The mean differences (MD) and odds ratios (OR) were used to compare the operative time, blood loss, mortality, complications, harvested lymph nodes, hospital stay, distal resection margin, and circumferential resection margin. The risk ratio (RR) method was used to examine recurrence and survival. RESULTS: Fourteen studies were identified and included 7 RCTs and 7 NRCTs and 4353 patients (2251 LRR, 2102 ORR). Although the operation time of the LRR group was obviously longer than that of the conventional surgery group (MD = 25.64, 95%CI = [5.17,46.10], P = 0.01), LRR was associated with fewer overall complications (OR = 0.67, 95%CI = [0.52,0.87], P = 0.002), less blood loss (MD = -66.49, 95%CI = [-88.31, -44.66], P < 0.00001), shorter postoperative hospital stays (OR = -1.26,95%CI = [-2.45, -0.07],P = 0.004) and shorter bowel function recovery times (MD = -0.93, 95%CI = [-1.27,-0.58], P < 0.00001). Moreover, the difference in the DRM was statistically clear (MD = 0.14, 95%CI = [0.02,0.27], P = 0.03). However, no significant differences between the LRR and ORR groups were observed in terms of the number of lymph nodes harvested, mortality, positive CRM, local and distal recurrence, or overall and disease-free survival. CONCLUSIONS: This study indicates that there are no significant differences between LRR and ORR in terms of survival and pathological outcomes with the exception of the DRM. Moreover, this study suggests that LRR can be performed safely and elicits faster recovery times compared with conventional surgery. PMID- 28087371 TI - Use of the HEART Pathway with high sensitivity cardiac troponins: A secondary analysis. AB - OBJECTIVES: The HEART Pathway combines a decision aid and serial contemporary cardiac troponin I (cTnI) measures to achieve >99% sensitivity for major adverse cardiac events (MACE) at 30days and early discharge rates >20%. However, the impact of integrating high-sensitivity troponin (hs-cTn) measures into the HEART Pathway has yet to be determined. In this analysis we compare test characteristics of the HEART Pathway using hs-cTnI, hs-cTnT, or cTnI. DESIGN & METHODS: A secondary analysis of participants enrolled in the HEART Pathway RCT was conducted. Each patient was risk stratified by the cTn-HEART Pathway (Siemens TnI-Ultra at 0- and 3-h) and a hs-cTn-HEART Pathway using hs-cTnI (Abbott) or hs cTnT (Roche) at 3-h. The early discharge rate, sensitivity, specificity, and negative predictive value (NPV) for MACE (death, myocardial infarction, or coronary revascularization) at 30days were calculated. RESULTS: hs-cTnI measures were available on 133 patients. MACE occurred in 11/133 (8%) of these patients. Test characteristics for the HEART Pathway using serial cTnI vs 3hour hs-cTnI were the same: sensitivity (100%, 95%CI: 72-100%), specificity (49%, 95%CI: 40 58%), NPV (100%, 95%CI: 94-100%), and early discharge rate (45%, 95%CI: 37-54%). The HEART Pathway using hs-cTnT missed one MACE event (myocardial infarction): sensitivity (91%, 95%CI: 59-100%), specificity (48%, 95%CI: 39-57%), NPV (98%, 95%CI: 91-100%), and early discharge rate (45%, 95%CI: 37-54%). CONCLUSIONS: There was no difference in the test characteristics of the HEART Pathway whether using cTnI or hs-cTnI, with both achieving 100% sensitivity and NPV. Use of hs cTnT with the HEART Pathway was associated with one missed MACE. PMID- 28087372 TI - The future of artificial intelligence and interpretative specialization in clinical biochemistry. PMID- 28087373 TI - Chronoinflammaging in Alzheimer; A systematic review on the roles of toll like receptor 2. AB - Aging is associated with a range of chronic low-grade inflammation (Chronoinflammaging) which may play a significant role in some chronic inflammatory based diseases, such as Alzheimer disease (AD). However, the events which lead to the induction of chronoinflammaging in AD are yet to be clarified. It has been proposed that the recognition of endogenous ligands by pathogen recognition receptors (PRRs) may be involved in the induction of chronoinflammaging. Toll like receptors (TLRs) are a family of PRRs which recognize endogenous damage associated molecular patterns (DAMPs) and subsequently induce inflammation. Therefore, TLRs are worthy of investigation to elucidate their roles in chronoinflammaging associated AD. This review article explores the main roles played by TLR2 in the pathogenesis of chronoinflammaging in patients suffering from AD. PMID- 28087374 TI - What stoichiometries determined by mass spectrometry reveal about the ligand binding mode to G-quadruplex nucleic acids. AB - G-quadruplexes (G4s) have become important drug targets to regulate gene expression and telomere maintenance. Many studies on G4 ligand binding focus on determining the ligand binding affinities and selectivities. Ligands, however, can also affect the G4 conformation. Here we explain how to use electrospray ionization mass spectrometry (ESI-MS) to monitor simultaneously ligand binding and cation binding stoichiometries. The changes in potassium binding stoichiometry upon ligand binding hint at ligand-induced conformational changes involving a modification of the number of G-quartets. We investigated the interaction of three quadruplex ligands (PhenDC3, 360A and Pyridostatin) with a variety of G4s. Electrospray mass spectrometry makes it easy to detect K+ displacement (interpreted as quartet disruption) upon ligand binding, and to determine how many ligand molecules must be bound for the quartet opening to occur. The reasons for ligand-induced conversion to antiparallel structures with fewer quartets are discussed. Conversely, K+ intake (hence quartet formation) was detected upon ligand binding to G-rich sequences that did not form quadruplexes in 1mM K+ alone. This demonstrates the value of mass spectrometry for assessing not only ligand binding, but also ligand-induced rearrangements in the target sequence. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. PMID- 28087375 TI - Super-oxidized water inactivates major viruses circulating in swine farms. AB - Disinfectant is commonly employed to eliminate infectious agents and prevent its transmission. In this study, we investigated the efficacy of Medilox(r) super oxidized water on inactivating veterinary viruses mainly circulating in swine farms. The results demonstrated that this super-oxidized water could effectively inactivate porcine viruses. PMID- 28087376 TI - IR780-loaded TPGS-TOS micelles for breast cancer photodynamic therapy. AB - IR780 iodide is a near-infrared (NIR) dye with a huge potential for cancer imaging and phototherapy. However, its biomedical application is strongly impaired by its lipophilic character. Herein, amphiphilic micelles based on d alpha-tocopheryl polyethylene glycol succinate (TPGS) and d-alpha-tocopheryl succinate (TOS), two vitamin E derivatives with intrinsic anticancer activity, are explored to load IR780. IR780-loaded micelles with suitable sizes are obtained by using specific TPGS and TOS weight feed ratios during micelles formulation and these are able to encapsulate IR780 with high efficiency. In in vitro assays, the IR780-loaded micelles induce a cytotoxic effect in cancer cells upon exposure to NIR irradiation through the generation of reactive oxygen species (photodynamic therapy). This effective ablation of cancer cells is achieved using an ultra-low IR780 concentration. Moreover, IR780-loaded micelles also have the ability to act as photothermal and imaging agents, which widens their therapeutic and diagnostic potential. Overall, TPGS-TOS micelles are promising nanoplatforms for IR780-mediated cancer phototherapy and imaging. PMID- 28087377 TI - In vivo biodistribution and imaging studies with a 99mTc-radiolabeled derivative of the C-terminus of prothymosin alpha in mice bearing experimentally-induced inflammation. AB - Prothymosin alpha (ProTalpha) is a highly conserved mammalian polypeptide (109 amino acids in man) exerting in vitro and in vivo immunoenhancing activities. Recently, our team has developed a 99mTc-radiolabeled derivative of the C terminal bioactive decapeptide of ProTalpha ([99mTc]C1) and employed it in in vitro studies, the results of which support the existence of binding sites on human neutrophils that recognize [99mTc]C1, intact ProTalpha as well as the C terminal decapeptide of ProTalpha and presumably involve Toll-like receptor 4. In the present work, [99mTc]C1 was administered to Swiss albino mice with experimentally-induced inflammation for in vivo biodistribution and imaging studies, in parallel with a suitable negative control, which differs from [99mTc]C1 only in bearing a scrambled version of the ProTalpha decapeptide. The biodistribution data obtained with [99mTc]C1 demonstrated fast clearance of radioactivity from blood, heart, lungs, normal muscle, and predominantly urinary excretion. Most importantly, slow clearance of radioactivity from the inflammation focus was observed, resulting in a high ratio of inflamed/normal muscle tissue (9.15 at 30min post injection, which remained practically stable up to 2h). The inflammation-targeting capacity of [99mTc]C1 was confirmed by imaging studies and might be attributed to neutrophils, which are recruited at the inflamed areas and bear binding sites for [99mTc]C1. In this respect, apart from being a valuable tool for further studies on ProTalpha in in vitro and in vivo systems, [99mTc]C1 merits further evaluation as a radiopharmaceutical for specific imaging of inflammation foci. PMID- 28087378 TI - New scaffolds encapsulating TGF-beta3/BMP-7 combinations driving strong chondrogenic differentiation. AB - The regeneration of articular cartilage remains an unresolved question despite the current access to a variety of tissue scaffolds activated with growth factors relevant to this application. Further advances might result from combining more than one of these factors; here, we propose a scaffold composition optimized for the dual delivery of BMP-7 and TGF-beta3, two proteins with described chondrogenic activity. First, we tested in a mesenchymal stem cell micromass culture with TGF-beta3 whether the exposure to microspheres loaded with BMP-7 would improve cartilage formation. Histology and qRT-PCR data confirmed that the sustained release of BMP-7 cooperates with TGF-beta3 towards chondrogenic differentiation. Then, we optimized a scaffold prototype for tissue culture and dual encapsulation of BMP-7 and TGF-beta3. The scaffolds were prepared from poly(lactic-co-glycolic acid), and BMP-7/TGF-beta3 were loaded as nanocomplexes with heparin and Tetronic 1107. The scaffolds showed the sustained release of both proteins over four weeks, with minimal burst effect. We finally cultured human mesenchymal stem cells on these scaffolds, in the absence of exogenous chondrogenic factor supplementation. The cells cultured on the scaffolds loaded with BMP-7 and TGF-beta3 showed clear signs of cartilage formation macroscopically and histologically. RT-PCR studies confirmed a clear upregulation of cartilage markers SOX9 and Aggrecan. In summary, scaffolds encapsulating BMP-7 and TGF-beta3 can efficiently deliver a cooperative growth factor combination that drives efficient cartilage formation in human mesenchymal stem cell cultures. These results open attractive perspectives towards in vivo translation of this technology in cartilage regeneration experiments. PMID- 28087379 TI - PEGylated liposomes for topical vaginal therapy improve delivery of interferon alpha. AB - Recent studies regarding mucosal drug delivery indicate that nanosystems with surface-available polyethylene glycol (PEG) are able to penetrate mucus barrier, assure closer contact with the epithelium, and improve drug delivery to vagina. In the present work, we developed the mucus-penetrating PEGylated liposomes containing interferon alpha-2b (IFN alpha-2b), destined to provide localized therapy for human papilloma virus (HPV) vaginal infections. The PEGylated liposomes were of a mean size of 181+/-8nm, bearing a negative zeta potential of 13mV and an entrapment efficiency of 81+/-10%. In vitro release experiments on model membrane showed a nearly non-existent IFN alpha-2b release from both the control and liposomally-associated IFN alpha-2b. However, the ex vivo penetration studies performed on the vaginal tissue obtained from pregnant sheep, showed the clear elevated IFN alpha-2b penetration from PEGylated liposomes as compared to the control. Furthermore, mucin studies confirmed the absence of interaction between the PEG-modified liposomes and mucin, confirming their ability to penetrate mucus and reach the deeper epithelium. The system holds a promise in improving topical delivery of IFN alpha-2b through enhanced efficacy of local anti-viral therapy. PMID- 28087380 TI - Polymeric mixed micelles as nanomedicines: Achievements and perspectives. AB - During the past few decades, polymeric micelles have raised special attention as novel nano-sized drug delivery systems for optimizing the treatment and diagnosis of numerous diseases. These nanocarriers exhibit several in vitro and in vivo advantages as well as increased stability and solubility to hydrophobic drugs. An interesting approach for optimizing these properties and overcoming some of their disadvantages is the combination of two or more polymers in order to assemble polymeric mixed micelles. This review article gives an overview on the current state of the art of several mixed micellar formulations as nanocarriers for drugs and imaging probes, evaluating their ongoing status (preclinical or clinical stage), with special emphasis on type of copolymers, physicochemical properties, in vivo progress achieved so far and toxicity profiles. Besides, the present article presents relevant research outcomes about polymeric mixed micelles as better drug delivery systems, when compared to polymeric pristine micelles. The reported data clearly illustrates the promise of these nanovehicles reaching clinical stages in the near future. PMID- 28087381 TI - Prevalence, risk factors, and clinical outcomes of atopic and nonatopic asthma among rural children. AB - BACKGROUND: Because of time and cost constraints, objective classification of atopic and nonatopic asthma has been limited in large epidemiologic studies. However, as we try to better understand exposure-outcome associations and ensure appropriate treatment of asthma, it is important to focus on phenotype-defined asthma classification. OBJECTIVE: To compare atopic and nonatopic asthma in rural children with regard to risk factors and clinical outcomes. METHODS: We conducted a cross-sectional study in rural Saskatchewan, Canada, in 2011. Parents of 6- to 14-year-old children completed a health and exposure survey. Skin prick tests were completed in a subsample of 529 children. Asthma was based physician diagnosis. Asthma status was defined as no asthma, nonatopic asthma, and atopic asthma. RESULTS: Asthma prevalence was 14.7% of which 32.1% of cases were atopic. After adjustment, early respiratory illness and a family history of asthma were predictors of childhood asthma, regardless of atopic status (P < .05). Being overweight and having a dog in the home were associated with an increased risk of nonatopic asthma (P < .05). A mother with a history of smoking increased the risk of atopic asthma (P = .01). Compared with those with nonatopic asthma, in the past 12 months, children with atopic asthma were more likely to report a sneezy, runny, or blocked nose or have shortness of breath (odds ratio >2), whereas those with nonatopic asthma were more likely to have parents who missed work (odd ratio >3). Those with nonatopic asthma had significantly lower forced expiratory volume in 1 second compared w2ith those with atopic asthma. CONCLUSION: Exposures may contribute differentially to atopic and nonatopic asthma and result in differential clinical presentation or burden. The study of these characteristics is important for etiologic understanding and management decisions. PMID- 28087382 TI - Efficacy and safety of high-dose rush oral immunotherapy in persistent egg allergic children: A randomized clinical trial. AB - BACKGROUND: Egg oral immunotherapy is effective but time consuming. OBJECTIVE: To assess the efficacy and safety of egg rush oral immunotherapy (ROIT) with a targeted dose equivalent to a raw egg white. METHODS: Thirty-three persistent egg allergic children confirmed by double-blind, placebo-controlled food challenge (DBPCFC) were randomized to receive egg ROIT immediately after randomization (ROIT1 group), or to continue an egg avoidance diet for 5 months after randomization (control group [CG]). A 5-day build-up phase starting with the highest single tolerated dose at baseline DBPCFC was scheduled and several doses administered daily until achieving a dose of approximately 2,808 mg of egg white protein. In the maintenance phase, patients ate an undercooked egg every 48 hours for 5 months. The CG participants who failed the DBPCFC at 5 months began active treatment. Children from the ROIT1 group plus children from the CG who failed a second DBPCFC at 5 months and then received egg ROIT were randomized to the ROIT2 group. Adverse events (AEs) and immune marker evolution were recorded. RESULTS: A total of 17 (89%) of 19 children in the ROIT1 group and no CG patients were desensitized at 5 months (P < .001). A total of 31 (97%) of the 32 children in the ROIT2 group completed the build-up phase in a median of 3 days (range, 1-14 days), and 30 (94%) of 32 maintained desensitization at 5 months. From baseline to 5 months of treatment, skin prick test, specific IgE, and specific IgE/IgG4 ratio to egg fractions significantly decreased, whereas specific IgG4 increased. During the build-up phase, AEs occurred in 69% of patients (50% had <=2 AEs) and 31% of doses (2% severe, 55% gastrointestinal). Lower threshold dose in the DBPCFC and higher egg white and ovalbumin specific IgE levels at baseline revealed an association with a higher rate of AEs. CONCLUSION: The proposed 5-day egg ROIT desensitized 94% of the allergic patients, with most AEs being mild or moderate. PMID- 28087383 TI - Stratified premedication strategy for the prevention of contrast media hypersensitivity in high-risk patients. AB - BACKGROUND: Although the severity of hypersensitivity reactions to iodinated contrast media varies, it is well correlated with the severity of recurrent reactions; however, prophylaxis protocols are not severity-stratified. OBJECTIVE: To assess the outcomes of tailored prophylaxis according to the severity of hypersensitivity reactions to iodinated contrast media. METHODS: Our premedication protocols were stratified based on the severity of previous reactions: (1) 4 mg of chlorpheniramine for mild reactions, (2) adding 40 mg of methylprednisolone for moderate reactions, and (3) adding multiple doses of 40 mg of methylprednisolone for severe index reactions. Cases of reexposure in patients with a history of hypersensitivity reactions were routinely monitored and mandatorily recorded. RESULTS: Among a total of 850 patients who underwent enhanced computed tomography after severity-tailored prophylaxis, breakthrough reactions occurred in 17.1%, but most breakthrough reactions (89.0%) were mild and did not require medical treatment. Additional corticosteroid use did not reduce the breakthrough reaction rate in cases with a mild index reaction (16.8% vs 17.2%, P = .70). However, underpremedication with a single dose of corticosteroid revealed significantly higher rates of breakthrough reaction than did double doses of corticosteroid in cases with a severe index reaction (55.6% vs 17.4%, P = .02). Changing the iodinated contrast media resulted in an additional reduction of the breakthrough reaction rate overall (14.9% vs 32.1%, P = .001). CONCLUSION: In a total severity-based stratified prophylaxis regimens and changing iodinated contrast media can be considered in patients with a history of previous hypersensitivity reaction to iodinated contrast media to reduce the risk of breakthrough reactions. PMID- 28087384 TI - Epidermal growth factor (EGF) fragment-guided anticancer theranostic particles for pH-responsive release of doxorubicin. AB - EGF fragment (EGFfr) and doxorubicin were chemically co-decorated on single magnetic nanoparticles (MNPs) for concomitant cancer targeting and treatment. Magnetic nanoparticles were prepared by the precipitation of ferric chloride hydrates in an ammonia solution and subsequent surface-functionalization with amines. The terminal thiol group of the EGF fragment was first conjugated to surface amines of the MNPs using a heterofunctional crosslinker, and doxorubicin was sequentially conjugated to the MNPs via a hydrazone linker, where the degree of subsitution of the surface amines to EGFfr was varied from 1% to 40%. The decorated doxorubicin showed clear pH-dependency in the release profile, and doxorubicin showed fast release at pH 5.0 in comparison to pH 7.4. The EGF decorated MNPs were tested for differential cellular uptakes against EGF overexpressing cells (A549), and the uptake levels gradually increased to 10% and saturated, which was quantified by ICP-OES. Internalized doxorubicin was also visualized by confocal microscopy, and A549 cells with EGF-decorated MNPs with EGF decoration showed higher fluorescence intensity of doxorubicin than those with non-decorated MNPs. Anti-cancer activity of the MNPs was compared at various concentrations of doxorubicin and EGFfr. Decoration of EGFfr significantly increased the anti-cancer activity of doxorubicin-incorporated MNPs in A549 cells; however, EGFfr alone did not affect the viability of the cells. Thus, we concluded that MNPs with optimized EGFfr and doxorubicin ratios showed higher targeting and drug payload against EGF receptor overexpressing cancer cells. PMID- 28087385 TI - Berberine exerts renoprotective effects by regulating the AGEs-RAGE signaling pathway in mesangial cells during diabetic nephropathy. AB - In this study, we explored the effect of berberine treatment on the AGEs-RAGE pathway in a rat model of diabetic nephropathy, and we investigated the mechanism by which key factors caused kidney injury and the effects of berberine. In vivo, berberine improved fasting blood glucose, body weight, the majority of biochemical and renal function parameters and histopathological changes in the diabetic kidney. Western blotting and immunohistochemistry revealed significant increases in the levels of AGEs, RAGE, P-PKC-beta and TGF-beta1 in injured kidneys, and these levels were markedly decreased by treatment with berberine. In vitro, berberine inhibited mesangial cell proliferation. Cells treated with berberine showed reduced levels of AGEs, accompanied by decreased RAGE, p-PKC and TGF-beta1 levels soon afterwards. Berberine exhibited renoprotective effects in diabetic nephropathy rats, and the molecular mechanism was associated with changes in the levels and regulation of the AGEs-RAGE-PKC-beta-TGF-beta1 signaling pathway. PMID- 28087386 TI - Androgens and androgen receptor signaling contribute to ovarian development in the chicken embryo. AB - Androgens and androgen receptor (AR) signaling play important roles throughout development. In the chicken, AR signaling is involved in reproduction; however, its specific role is unclear. We show that AR signaling is involved in the normal development of the female embryonic gonads. The AR mRNA level was detected in male and female embryonic gonads by quantitative RT-PCR, and its expression was higher in females than in males at all developmental stages examined. In female embryos, the AR localized to nuclei of cells in the left gonad. Although AR expression was low in the majority of the medulla, high expression was detected in cells of lacunae within the medulla. In addition, AR expression increased in cells of cortical cords within the cortex with the progression of development. AR expression in the right gonad was lower than that in left gonad throughout development. In the male gonad, the AR localized to the cytoplasm of cells in seminiferous tubules at all stages. Female AR knockdown (ARKD) embryos infected with a retrovirus expressing micro RNAs targeting the AR showed normal asymmetric gonads (development of the left and depression of the right gonads), whereas the number of lacunae decreased. Furthermore, there was a disruption in the structure of cortical cords. By contrast, the gonads of ARKD males developed normally during embryogenesis. These results indicate that androgens and AR signaling are essential for the development of lacunae and cortical cords in gonads of female embryos. PMID- 28087387 TI - Orbital fibroblasts of Graves' orbitopathy stimulated with proinflammatory cytokines promote B cell survival by secreting BAFF. AB - The success of rituximab for the treatment of active Graves' orbitopathy (GO) suggests that B cells play a critical role in intraorbital inflammation. B cell activating factor (BAFF) and its homolog a proliferation-inducing ligand (APRIL) are critical for B cell survival. However, the contribution of BAFF/APRIL to GO remains unclear. We sought to determine the role of BAFF/APRIL in the orbits of GO, and found that BAFF was markedly upregulated, while APRIL was not. Additionally, cultured GO orbital fibroblasts (GO-OFs)2 expressing BAFF were induced to produce a large amount of BAFF. In contrast, a weak APRIL expression was detected in the OFs, and they exhibited a slight response to stimulation. Notably, pretreated GO-OFs promoted B cell survival, and this effect was significantly inhibited by a BAFF-R neutralizing antibody. This study indicates that OFs from GO can express BAFF and mediate the intraorbital survival of B cells via BAFF mechanism. PMID- 28087388 TI - Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis. AB - Obesity and cachexia represent divergent states of nutritional and metabolic imbalance but both are intimately linked to cancer. There is an extensive overlap in their signalling pathways and molecular components involved such as fatty acids (FAs), which likely play a crucial role in cancer. Forkhead box (FOX) proteins are responsible of a wide range of transcriptional programmes during normal development, and the FOXO3-FOXM1 axis is associated with cancer initiation, progression and drug resistance. Free fatty acids (FFAs), FA synthesis and beta-oxidation are associated with cancer development and progression. Meanwhile, insulin and some adipokines, that are up-regulated by FAs, are also involved in cancer development and poor prognosis. In this review, we discuss the role of FA metabolism in cancer and how FA metabolism integrates with the FOXO3-FOXM1 axis. These new insights may provide leads to better cancer diagnostics as well as strategies for tackling cancer development, progression and drug resistance. PMID- 28087389 TI - Evaluation of Local Oncologic Safety in Nipple-Areola Complex-sparing Mastectomy After Primary Chemotherapy: A Propensity Score-matched Study. AB - BACKGROUND: Nipple-areola complex-sparing mastectomy (NSM), extending the concept of skin-sparing mastectomy, allows for the provision of a better cosmetic result. Large operable T2-T3 breast cancer might theoretically appear suitable for this surgical option as an alternative to conventional mastectomy or breast-conserving surgery, when a good response to primary chemotherapy has been achieved. PATIENTS AND METHODS: From January 2009 to May 2013, 422 patients with invasive breast cancer were progressively accrued to NSM. Of the 422 patients, 361 underwent NSM as first-line treatment (NSM group), and 61 underwent surgery after primary chemotherapy (NSM-PC group). A total of 151 breast cancer patients, who had undergone PC and conventional total mastectomy (TM-PC group) from 2004 to 2009 were evaluated as comparative group with respect to the NSM-PC group. Using propensity score matching, local disease-free survival (LDFS) was evaluated comparatively. RESULTS: The rate of nipple-areola involvement in the NSM and NSM PC groups was 13.3% and 9.8%, respectively (P = .539). The nipple-areola involvement in the NSM and NSM-PC groups was significantly associated with the tumor size (odds ratio [OR], 1.48; 95% confidence interval [CI], 1.13-1.95; P = .004), plurifocal or pluricentric tumor (OR, 3.18; 95% CI, 1.72-5.89; P < .001), and the presence of an intraductal component (OR, 2.38; 95% CI, 1.22-4.64; P = .011). The LDFS in the NSM-PC and TM-PC matched cohorts did not show a significant difference, with a 4-year LDFS of 0.89 (95% CI, 0.77-0.95) and 0.93 (95% CI, 0.83-0.97), respectively (hazard ratio [HR], 1.31; 95% CI, 0.40-4.35; P = .655). The NSM-PC cohort was also compared with the NSM cohort in terms of LDFS using 2 different matching criteria, with the tumor size before and after neoadjuvant chemotherapy as the balancing covariate. In the first of the 2 comparisons, the hazards of local relapse were comparable between the 2 matched groups (HR, 1.23; 95% CI, 0.37-4.04; P = .739). In the second comparison, the NSM PC patients showed a significant greater hazard of local relapse than did the NSM patients (HR, 3.60; 95% CI, 1.10-11.80; P = .035). CONCLUSION: NSM might be a valuable option for large breast cancer treated by primary chemotherapy. The rate of local relapse seemed to be related to the disease stage, and no significant association with the type of surgery was detected. PMID- 28087390 TI - Family-building After Breast Cancer: Considering the Effect on Adherence to Adjuvant Endocrine Therapy. AB - Adherence to endocrine therapy (ET) is a longstanding problem in breast cancer (BC) survivorship care, particularly among younger women. Younger patients have reported lower ET initiation rates and greater rates of early discontinuation and are considered an "at risk" group for nonadherence. For women who hope to have children in the future, concerns about premature menopause and the implications of postponing childbearing for the 5 to 10 years of ET are widespread. Preliminary evidence suggests that prioritizing fertility, along with concerns about side effects, leads to ET noninitiation and early discontinuation. Clinical efforts to improve adherence might need to consider patients' family-building goals during the course of treatment and to appropriately counsel patients according to their priorities and family-building intentions. Educational materials about family building after cancer are still not consistently available or provided. Helping patients to access trusted informational resources and decision support tools, in conjunction with medical counseling, will promote informed decisions regarding ET adherence and pregnancy that are medically appropriate. Such shared patient-provider decision-making about ET adherence and pregnancy could help to maximize patient autonomy by incorporating their values, preferences, and priorities into decisions, using providers' medical expertise. PMID- 28087391 TI - Clonal cytogenetic abnormalities are predictor in developing non-Hodgkin lymphomas? AB - Pathological analysis is the cornerstone for diagnosing malignant lymphoma. Status of cytogenetic abnormalities is frequently left unexamined if no evidence of malignancy is found in pathological analysis. In this study, we presented 3 cases in which clonal cytogenetic abnormalities were detected but morphological alterations of the same tissue did not support malignant non Hodgkin lymphoma at the first lymph node biopsy. Case 1 is a 55-year-old female with lymphadenopathy neoplastic process confirmed by flow cytometry and polymerase chain reaction (PCR). Chromosome analysis revealed 47,XX,t(3;22)(q27;q11),+del(9)(p12)[16]/46,XX[4]. The pathological analysis of subsequent lymph node biopsy indicated diffuse large B-cell lymphoma (DLBCL). Case 2, a 74-year-old female, for whom the pathological analysis, molecular studies and flow cytometric analysis of the first lymph node biopsy found no evidence of clonal cell. Cytogenetic analysis demonstrated a terminal deletion of chromosome 7 and 1, and the patient received a second lymph node biopsy and splenectomy. A pathological diagnosis of splenic marginal zone lymphoma (SMZL) was made. In Case 3 who was a 66-year-old female with right cervical and axillary lymph node enlargement. Cytogenetic analysis showed clonal karyotypic abnormalities: 48,XX, t(14;18)(q32;q21) [13]/46, XY [7]. The diagnosis of follicular lymphoma was rendered by the second biopsy of axillary lymph node according to the analysis of morphology and immunohistochemistry. We propose that clonal cytogenetic abnormalities may be a high potential risk for developing non Hodgkin lymphomas. Follow-up and rebiopsy must be performed in patients who are cytogenetically abnormal but morphologically benign. PMID- 28087392 TI - Predictors and mechanisms of epilepsy occurrence in cerebral gliomas: What to look for in clinicopathology. AB - Gliomas, especially low-grade gliomas, are highly epileptogenic brain tumors. Histopathological information is valuable in evaluating the diagnosis and/or biologic behavior of various gliomas. Here we explored the clinical data and histopathological predictors of the occurrence of epilepsy in patients with gliomas. A retrospective study examined 310 consecutive patients who had undergone surgical treatment for gliomas in our institution from January 2013 to January 2015. Clinical data and pathological examination results were analyzed. Literatures regarding the predictors and etiology of glioma associated epileptic seizures in the period of 1995-2015 were also reviewed. A total of 234 (75.5%) astrocytic tumors and 76 (24.5%) oligodendrial tumors were included. At diagnosis, 33.6% of patients had epileptic seizures. Multivariate analysis revealed cortex involvement (OR=7.991, 95%CI=1.599-39.926), lower World Health Organization grade (OR=3.584, 95%CI=1.032-12.346) and topoisomerase II (TopoII) positivity (OR=0.943, 95%CI=0.903-0.982) were strong predictors for preoperative epileptic seizures. Gender, disease course, tumor classification, location or volume did not significantly affect epileptic seizure occurrence. Forty-three publications involved glioma-associated epilepsy were found in PubMed online database and key data were extracted and summarized. The present studies on glioma-related epilepsy are relatively limited and inconsistent. Low-grade gliomas, cortex involvement and TopoII positivity were independent predictors of a history of epileptic seizures at diagnosis. Further studies to examine the underlying mechanism of topoisomerase II as well as other molecules in epilepsy occurrence in brain gliomas are needed in the future. PMID- 28087393 TI - William Glenn: Surgeon-Scientist and Leader of New England Surgery. PMID- 28087394 TI - Hawkins' type-II talar fracture with subtalar dislocation: A very unusual combination. AB - We report the unusual case of a 16-year-old young man who sustained a rare association of a Hawkins' type-II talar neck fracture with a complete medial subtalar dislocation (Hawkins type-IIB) that occurred as an isolated injury after indirect trauma during a soccer game. Following closed reduction of the subtalar dislocation, standard radiographs and computed tomography (CT) demonstrated a comminuted fracture of the talus involving the base of the talar neck. Open reduction was performed and the fracture was stabilized by ORIF. At 1-year follow up, functional and radiographic outcomes were graded as excellent, with no radiographic evidence of talar osteonecrosis. PMID- 28087395 TI - Lumbar spinal muscles and spinal canal study by MRI three-dimensional reconstruction in adult lumbar spinal stenosis. AB - BACKGROUND: Lumbar spinal stenosis is degenerative disc disease most common manifestation. If stenosis degree seems poorly related to symptom severity, lumbar muscles role is recognized. Many studies report imaging methods, to analyze muscle volumes and fat infiltration (FI), but remain limited due to the difficulty to represent entire muscle volume variability. Recently a 3D muscle reconstruction protocol (using the deformation of a parametric specific object method (DPSO) and three-point Dixon images) was reported. It offers the ability to evaluate, muscles volumes and muscle FI. PURPOSE: To describe, in a lumbar spinal stenosis population, muscle volumes, muscle FI and lumbar spinal canal volume with 3D MRI images reconstructions. MATERIALS AND METHODS: Ten adults presenting L4-L5 lumbar stenosis, were included. After specific MRI protocol, three-dimensional, muscle and spinal canal, reconstructions were performed. Muscle (psoas and paraspinal muscles) volumes and fat infiltration (FI), the spinal canal volume, age, and height were correlated one to each other with Spearman correlation factor. An ANOVA was performed to evaluate the intervertebral level influence (P<=0.05). RESULTS: Muscle volumes correlated with height (r=0.68 for psoas). Muscles FI correlated with age (r=0.66 for psoas) and lumbar spinal canal volume (r=0.91). Psoas and paraspinal volumes were maximum at L3-L4 level whereas FI increased from L1-L2 to L5-S1 level. DISCUSSION: These first results illustrate the importance to consider muscles entirely and report correlations between muscles FI, lumbar spinal canal volume and age; and between muscle volumes and patients height. Muscle degeneration seems more related to muscle FI than muscle volume. LEVEL OF EVIDENCE: 3. PMID- 28087396 TI - Influence of coronal bowing on the lower alignment and the positioning of component in navigation and conventional total knee arthroplasty. AB - BACKGROUND: Coronal alignment is an important factor for the function and longevity of total knee arthroplasty (TKA). Coronal bowing of the lower extremity is common among Asians and it may pose a risk for malalignment of the lower leg and malposition of component. HYPOTHESIS: We hypothesized that coronal bowing itself has a risk for malalignment of the lower leg and malposition of femoral/tibial components and that navigation TKA is beneficial for patients with coronal bowing. We investigated the incidence of femoral/tibial bowing in patients treated with TKA and compared the radiographic parameters between the navigation group and the conventional group. Additionally, the influence of coronal bowing on these radiographic parameters was investigated. MATERIALS AND METHODS: We enrolled 35 patients with knee osteoarthritis and 70 bilateral simultaneous TKAs. The patients underwent TKA with the use of a computer tomography-free navigation in one knee and conventional TKA in the contralateral knee. Preoperative coronal bowing were measured, and the subjects were divided into 2 subgroups, i.e. the bowing group and the non-bowing group. Lateral bowing was expressed as plus (+) and medial bowing was expressed as minus (-). Various radiographic parameters, including coronal bowing, lower leg alignment, component position, and outliers were compared between the navigation group and the conventional group. RESULTS: Femoral bowing varied from -7.4 degrees to 10.9 degrees with an average of 3.0 degrees . Tibial bowing varied from -4.1 degrees to 4.6 degrees with an average of 0.4 degrees . The femoral component was placed more properly in the navigation group. Number of outlier regarding to the coronal femoral component angle to the femoral mechanical axis was 14 cases (37.8%) in the bowing group and 6 cases (18.2%) in the non-bowing group (P=0.04). DISCUSSION: In conclusion, coronal femoral bowing has an important effect on femoral bone cut in TKA. The navigated TKA was more consistent than conventional TKA in aiding proper alignments of femoral component. LEVEL OF EVIDENCE: Level II, comparative prospective study. PMID- 28087397 TI - Elbow locking in a patient with a congenital radial head dislocation: Case report. AB - Snapping elbow is a rare condition, which has various possible causes such as impinged plica, annular ligament, or other extra-articular causes. We report a case of 15-year-old boy who had snapping elbow and sudden-onset flexion contracture of the elbow. Simple radiographs showed bilateral anterior dislocation of hypoplastic radial heads. Magnetic resonance images with the elbow extended as much as possible showed that the annular ligament hemmed the dislocated radial neck. By surgical incision of the annular ligament which checkreined the radial neck, the patients could regain full extension of the elbow. We recommend careful consideration of surgical excision of ligamentous structure which blocks extension in the patients who have history of snapping elbow with congenital radial head dislocation. PMID- 28087398 TI - Interaction of Mal de Rio Cuarto virus (Fijivirus genus) proteins and identification of putative factors determining viroplasm formation and decay. AB - Mal de Rio Cuarto virus (MRCV) is a member of the Fijivirus genus, within the Reoviridae family, that replicates and assembles in cytoplasmic inclusion bodies called viroplasms. In this study, we investigated interactions between ten MRCV proteins by yeast two-hybrid (Y2H) assays and identified interactions of non structural proteins P6/P6, P9-2/P9-2 and P6/P9-1. P9-1 and P6 are the major and minor components of the viroplasms respectively, whereas P9-2 is an N glycosylated membrane protein of unknown function. Interactions involving P6 and P9-1 were confirmed by bimolecular fluorescence complementation (BiFC) in rice protoplasts. We demonstrated that a region including a predicted coiled-coil domain within the C-terminal moiety of P6 was necessary for P6/P6 and P6/P9-1 interactions. In turn, a short C-terminal arm was necessary for the previously reported P9-1 self-interaction. Transient expression of these proteins by agroinfiltration of Nicotiana benthamiana leaves showed very low accumulation levels and further in silico analyses allowed us to identify conserved PEST degradation sequences [rich in proline (P), glutamic acid (E), serine (S), and threonine (T)] within P6 and P9-1. The removal of these PEST sequences resulted in a significant increase of the accumulation of both proteins. PMID- 28087399 TI - Advances with using CRISPR/Cas-mediated gene editing to treat infections with hepatitis B virus and hepatitis C virus. AB - Chronic infections with hepatitis B and hepatitis C viruses (HBV and HCV) account for the majority of cases of cirrhosis and hepatocellular carcinoma. Current therapies for the infections have limitations and improved efficacy is necessary to prevent complications in carriers of the viruses. In the case of HBV persistence, the replication intermediate comprising covalently closed circular DNA (cccDNA) is particularly problematic. Licensed therapies have little effect on cccDNA and HBV replication relapses following treatment withdrawal. Disabling cccDNA is thus key to curing HBV infections and application of gene editing technology, such as harnessing the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system, has curative potential. Several studies have reported good efficacy when employing CRISPR/Cas technologies to disable HBV replication in cultured cells and in hydrodynamically injected mice. Recent advances with HCV drug development have revolutionized treatment of the infection. Nevertheless, individuals may be refractory to treatment. Targeting RNA from HCV with CRISPR/Cas isolated from Francisella novicida may have therapeutic utility. Although preclinical work shows that CRISPR/Cas technology has potential to overcome infection with HBV and HCV, significant challenges need to be met. Ensuring specificity for viral targets and efficient delivery of the gene editing sequences to virus-infected cells are particularly important. The field is at an interesting stage and the future of curative antiviral drug regimens, particularly for treatment of chronic HBV infection, may well entail use of combinations that include derivatives of CRISPR/Cas. PMID- 28087401 TI - How the EUCERD Joint Action supported initiatives on Rare Diseases. AB - Joint Actions are successful initiatives from the European Commission (EC) that have helped to raise awareness and to bring significant benefit to those suffering from a rare disease (RD). In this paper, we will focus on the activities developed by the EUCERD Joint Action (EJA) and by the Orphanet Joint Action ("Orphanet Europe"). EUCERD Joint Action was co-funded by the EC and the Member States between 2012 and 2015 to help to define the activities and policies in the field of RD and foster exchange of experiences amongst Member States. This project is the continuation of previous efforts to turn RD a priority in the EC Health Programmes. "Orphanet Europe" was a Joint Action co-funded by INSERM, the French Directorate General for Health and the EC to address the need for a common portal that would gather the most update information regarding RD. This need was identified in the European Commission report "Rare Diseases: Europe's challenge" and in the Recommendation of the Council for a European RD portal. These joint actions have supported the policy development work of the European Commission, through the support of their committees for rare diseases. In this paper, the authors aim to raise awareness of the work done by the EUCERD Joint Action on behalf of the rare disease community and the policies established. PMID- 28087400 TI - Plus Disease in Retinopathy of Prematurity: Diagnostic Trends in 2016 Versus 2007. AB - PURPOSE: To identify any temporal trends in the diagnosis of plus disease in retinopathy of prematurity (ROP) by experts. DESIGN: Reliability analysis. METHODS: ROP experts were recruited in 2007 and 2016 to classify 34 wide-field fundus images of ROP as plus, pre-plus, or normal, coded as "3," "2," and "1," respectively, in the database. The main outcome was the average calculated score for each image in each cohort. Secondary outcomes included correlation on the relative ordering of the images in 2016 vs 2007, interexpert agreement, and intraexpert agreement. RESULTS: The average score for each image was higher for 30 of 34 (88%) images in 2016 compared with 2007, influenced by fewer images classified as normal (P < .01), a similar number of pre-plus (P = .52), and more classified as plus (P < .01). The mean weighted kappa values in 2006 were 0.36 (range 0.21-0.60), compared with 0.22 (range 0-0.40) in 2016. There was good correlation between rankings of disease severity between the 2 cohorts (Spearman rank correlation rho = 0.94), indicating near-perfect agreement on relative disease severity. CONCLUSIONS: Despite good agreement between cohorts on relative disease severity ranking, the higher average score and classifications for each image demonstrate that experts are diagnosing pre-plus and plus disease at earlier stages of disease severity in 2016, compared with 2007. This has implications for patient care, research, and teaching, and additional studies are needed to better understand this temporal trend in image-based plus disease diagnosis. PMID- 28087403 TI - Hepatic Hydatid Cysts Causing Biliary Obstruction. PMID- 28087402 TI - Accuracy is in the eyes of the pathologist: The visual interpretive process and diagnostic accuracy with digital whole slide images. AB - Digital whole slide imaging is an increasingly common medium in pathology, with application to education, telemedicine, and rendering second opinions. It has also made it possible to use eye tracking devices to explore the dynamic visual inspection and interpretation of histopathological features of tissue while pathologists review cases. Using whole slide images, the present study examined how a pathologist's diagnosis is influenced by fixed case-level factors, their prior clinical experience, and their patterns of visual inspection. Participating pathologists interpreted one of two test sets, each containing 12 digital whole slide images of breast biopsy specimens. Cases represented four diagnostic categories as determined via expert consensus: benign without atypia, atypia, ductal carcinoma in situ (DCIS), and invasive cancer. Each case included one or more regions of interest (ROIs) previously determined as of critical diagnostic importance. During pathologist interpretation we tracked eye movements, viewer tool behavior (zooming, panning), and interpretation time. Models were built using logistic and linear regression with generalized estimating equations, testing whether variables at the level of the pathologists, cases, and visual interpretive behavior would independently and/or interactively predict diagnostic accuracy and efficiency. Diagnostic accuracy varied as a function of case consensus diagnosis, replicating earlier research. As would be expected, benign cases tended to elicit false positives, and atypia, DCIS, and invasive cases tended to elicit false negatives. Pathologist experience levels, case consensus diagnosis, case difficulty, eye fixation durations, and the extent to which pathologists' eyes fixated within versus outside of diagnostic ROIs, all independently or interactively predicted diagnostic accuracy. Higher zooming behavior predicted a tendency to over-interpret benign and atypia cases, but not DCIS cases. Efficiency was not predicted by pathologist- or visual search-level variables. Results provide new insights into the medical interpretive process and demonstrate the complex interactions between pathologists and cases that guide diagnostic decision-making. Implications for training, clinical practice, and computer-aided decision aids are considered. PMID- 28087404 TI - Mood and Anxiety Disorders Precede Development of Functional Gastrointestinal Disorders in Patients but Not in the Population. AB - BACKGROUND & AIMS: Understanding the interactions between brain and gastrointestinal disorders requires analysis of the order of disease onset. We analyzed data from 2 independent studies to determine the proportion of individuals with diagnoses of functional gastrointestinal disorders (FGIDs) before diagnoses of mood or anxiety disorders (gut to brain), and vice versa (brain to gut). METHODS: We collected data from a retrospective study of 4966 patients diagnosed with a FGID (irritable bowel syndrome, dyspepsia, or constipation) and mood or anxiety disorder at general practices in the United Kingdom (health care seekers) over an average period of 13.1 years; we recorded which diagnosis appeared first and compared these with patients' sex and socioeconomic factors. We also collected data from a population study of 1002 randomly selected individuals in Australia (non-heath care seekers) followed from 1997 through 2009; we determined whether subjects were free of either FGID or an anxiety or mood disorder at baseline but developed either one after a 12-year follow-up period. RESULTS: Among the 4966 health care seekers, 3279 patients were diagnosed with a mood or anxiety disorder before an FGID (ratio of 2:1). This ratio increased with socioeconomic disadvantage. The time period between diagnosis of mood or anxiety disorder and FGID was longer (median, 3.5 years) than time period between diagnosis of an FGID and a mood or anxiety disorder (median, 1.8 years). Among non-heath care seekers (population study), equal proportions were diagnosed with a mood or anxiety disorder before versus after an FGID. CONCLUSIONS: In an analysis of data from a study of patients and a population-based study of individuals with these diagnoses, we found 2-fold more patients to receive a diagnosis of a mood or anxiety disorder before an FGID, but equal proportions of individuals in the population to be diagnosed with the mood or anxiety disorder before versus after an FGID. Among patients, the mood or anxiety disorder was on average diagnosed more than 3 years before the FGID, offering opportunity for prevention. Our findings support a role for adverse socioeconomic factors in development of FGIDs in patients with psychological disorders. PMID- 28087405 TI - Reply to letter regarding submission entitled: Cracking the perfusion code? - Laser-assisted indocyanine green angiography and combined laser Doppler spectrophotometry for intraoperative evaluation of tissue perfusion in autologous breast reconstruction with DIEP or ms-TRAM flaps. PMID- 28087406 TI - Erythrocyte membrane-coated nanogel for combinatorial antivirulence and responsive antimicrobial delivery against Staphylococcus aureus infection. AB - We reported an erythrocyte membrane-coated nanogel (RBC-nanogel) system with combinatorial antivirulence and responsive antibiotic delivery for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection. RBC membrane was coated onto the nanogel via a membrane vesicle templated in situ gelation process, whereas the redox-responsiveness was achieved by using a disulfide bond based crosslinker. We demonstrated that the RBC-nanogels effectively neutralized MRSA-associated toxins in extracellular environment and the toxin neutralization in turn promoted bacterial uptake by macrophages. In intracellular reducing environment, the RBC-nanogels showed an accelerated drug release profile, which resulted in more effective bacterial inhibition. When added to the macrophages infected with intracellular MRSA bacteria, the RBC-nanogels significantly inhibited bacterial growth compared to free antibiotics and non-responsive nanogel counterparts. These results indicate the great potential of the RBC nanogel system as a new and effective antimicrobial agent against MRSA infection. PMID- 28087408 TI - Effects of loading concentration, blood and synovial fluid on antibiotic release and anti-biofilm activity of bone cement beads. AB - Antibiotic loaded cement beads are commonly used for the treatment of biofilm related orthopaedic periprosthetic infections; however the effects of antibiotic loading and exposure of beads to body fluids on release kinetics are unclear. The purpose of this study was to determine the effects of (i) antibiotic loading density (ii) loading amount (iii) material type and (iv) exposure to body fluids (blood or synovial fluid) on release kinetics and efficacy of antibiotics against planktonic and lawn biofilm bacteria. Short-term release into an agar gel was evaluated using a fluorescent tracer (fluorescein) incorporated in the carrier materials calcium sulfate (CaSO4) and poly methyl methacrylate (PMMA). Different fluorescein concentrations in CaSO4 beads were evaluated. Mechanical properties of fluorescein-incorporated beads were analyzed. Efficacy of the antibiotics vancomycin (VAN) or tobramycin (TOB) alone and in combination was evaluated against lawn biofilms of bioluminescent strains of Staphylococcus aureus and Pseudomonas aeruginosa. Zones of inhibition of cultures (ZOI) were measured visually and using an in-vivo imaging system (IVIS). The influence of body fluids on release was assessed using CaSO4 beads that contained fluorescein or antibiotics and were pre-coated with human blood or synovial fluid. The spread from the beads followed a square root of time relationship in all cases. The loading concentration had no influence on short-term fluorescein release and pre coating of beads with body fluids did not affect short-term release or antibacterial activity. Compared to PMMA, CaSO4 had a more rapid short term rate of elution and activity against planktonic and lawn biofilms. This study highlights the importance of considering antibiotic loading and packing density when investigating the clinical application of bone cements for infection management. PMID- 28087409 TI - Thioredoxin a novel biomarker of post-injury sepsis. AB - BACKGROUND: Thioredoxin (TRX), an endogenous anti-oxidant protein induced in inflammatory conditions, has been shown to increase in plasma and to be associated with outcome in septic patients. This biomarker has never been studied in a trauma setting. We hypothesized that TRX would be increased after trauma and associated with post-injury sepsis. METHODS: Single-centre prospective observational study conducted at the intensive care unit (ICU) at the Karolinska University Hospital, Stockholm, Sweden, a level-1 trauma centre. Eighty-three severely injured trauma patients, 18 years or older, with an ICU stay of three days or more were included. Plasma samples were obtained on day 1 and 3 after informed consent. Clinical, physiological and outcome data were retrieved from the trauma and ICU research registries. Plasma samples were also obtained from 15 healthy subjects. In addition, a standardized porcine trauma model was conducted where a femur fracture followed by a controlled hemorrhage period were inflicted in four pigs. RESULTS: In pigs, however not significant, there was a continuing increase in plasma-TRX after femur fracture and sequential hemorrhage despite near normalisation of cardiac index and lactate levels. In patients, median injury severity score was 29 and 48 patients developed sepsis during their ICU stay. A three-fold increase in initial TRX was seen in trauma patients when compared to healthy volunteers. Thioredoxin was significantly higher in patients in shock on admission, those subject to massive transfusion and in the most severely injured patients. No difference was seen between survivors and non survivors. Plasma-TRX on day 1 was significantly increased in patients who later developed post-injury sepsis. In a logistic regression analysis including TRX, C reactive protein, injury severity, massive transfusion, and admission blood pressure, TRX was the only variable independently associated with post-injury sepsis. CONCLUSIONS: This study demonstrates that TRX is released into plasma in response to severe trauma and independently associated with post-injury sepsis. The use of TRX as a biomarker in trauma patients needs further evaluation in larger studies. LEVEL OF EVIDENCE: Retrospective cohort study, level III. PMID- 28087407 TI - Polymeric micelles for ocular drug delivery: From structural frameworks to recent preclinical studies. AB - Effective intraocular drug delivery poses a major challenge due to the presence of various elimination mechanisms and physiological barriers that result in low ocular bioavailability after topical application. Over the past decades, polymeric micelles have emerged as one of the most promising drug delivery platforms for the management of ocular diseases affecting the anterior (dry eye syndrome) and posterior (age-related macular degeneration, diabetic retinopathy and glaucoma) segments of the eye. Promising preclinical efficacy results from both in-vitro and in-vivo animal studies have led to their steady progression through clinical trials. The mucoadhesive nature of these polymeric micelles results in enhanced contact with the ocular surface while their small size allows better tissue penetration. Most importantly, being highly water soluble, these polymeric micelles generate clear aqueous solutions which allows easy application in the form of eye drops without any vision interference. Enhanced stability, larger cargo capacity, non-toxicity, ease of surface modification and controlled drug release are additional advantages with polymeric micelles. Finally, simple and cost effective fabrication techniques render their industrial acceptance relatively high. This review summarizes structural frameworks, methods of preparation, physicochemical properties, patented inventions and recent advances of these micelles as effective carriers for ocular drug delivery highlighting their performance in preclinical studies. PMID- 28087411 TI - Aspirin prevents TNF-alpha-induced endothelial cell dysfunction by regulating the NF-kappaB-dependent miR-155/eNOS pathway: Role of a miR-155/eNOS axis in preeclampsia. AB - Preeclampsia is an inflammatory disease with endothelial cell dysfunction that occurs via decreased endothelial nitric oxide synthase/nitric oxide (eNOS/NO) activity. Aspirin reduces the incidence of hypertensive pregnancy complications. However, the underlying mechanism has not been clearly explained. Here, we found that tumor necrosis factor (TNF)-alpha, microRNA (miR)-155, and eNOS levels as well as endothelial redox phenotype were differentially regulated in preeclamptic patients, implying the involvement of TNF-alpha- and redox signal-mediated miR 155 biogenesis and eNOS downregulation in the pathogenesis of preeclampsia. Aspirin prevented the TNF-alpha-mediated increase in miR-155 biogenesis and decreases in eNOS expression and NO/cGMP production in cultured human umbilical vein endothelial cells (HUVECs). Similar effects of aspirin were also observed in HUVECs treated with H2O2. The preventive effects of aspirin was associated with the inhibition of nuclear factor-kappaB (NF-kappaB)-dependent MIR155HG (miR-155 host gene) expression. Aspirin recovered the TNF-alpha-mediated decrease in wild type, but not mutant, eNOS 3'-untranslated region reporter activity, whose effect was blocked by miR-155 mimic. Moreover, aspirin prevented TNF-alpha-mediated endothelial cell dysfunction associated with impaired vasorelaxation, angiogenesis, and trophoblast invasion, and the preventive effects were blocked by miR-155 mimic or an eNOS inhibitor. Aspirin rescued TNF-alpha-mediated eNOS downregulation coupled with endothelial dysfunction by inhibiting NF-kappaB dependent transcriptional miR-155 biogenesis. Thus, the redox-sensitive NF kappaB/miR-155/eNOS axis may be crucial in the pathogenesis of vascular disorders including preeclampsia. PMID- 28087412 TI - Pain prediction by serum biomarkers of bone turnover in people with knee osteoarthritis: an observational study of TRAcP5b and cathepsin K in OA. AB - OBJECTIVES: To investigate serum biomarkers, tartrate resistant acid phosphatase 5b (TRAcP5b) and cathepsin K (cath-K), indicative of osteoclastic bone resorption, and their relationship to pain and pain change in knee osteoarthritis (OA). METHODS: Sera and clinical data were collected from 129 people (97 with 3 year follow-up) with knee OA from the Prediction of Osteoarthritis Progression (POP) cohort. Knee OA-related outcomes in POP included: WOMAC pain, National Health and Nutrition Examination Survey (NHANES) I (pain, aching and stiffness), subchondral sclerosis, and radiographically determined tibiofemoral and patellofemoral OA. Two putative osteoclast biomarkers were measured in sera: TRAcP5b and cath-K. Medial tibia plateaux were donated at knee arthroplasty for symptomatic OA (n = 84) or from 16 post mortem (PM) controls from the Arthritis Research UK (ARUK) Pain Centre joint tissue repository. Osteoclasts were stained for tartrate resistant acid phosphatase (TRAcP) within the subchondral bone of the medial tibia plateaux. RESULTS: Serum TRAcP5b activity, but not cath-K immunoreactivity, was associated with density of TRAcP-positive osteoclasts in the subchondral bone of medial tibia plateaux. TRAcP-positive osteoclasts were more abundant in people with symptomatic OA compared to controls. Serum TRAcP5b activity was associated with baseline pain and pain change. CONCLUSIONS: Our observations support a role for subchondral osteoclast activity in the generation of OA pain. Serum TRAcP5b might be a clinically relevant biomarker of disease activity in OA. PMID- 28087410 TI - Repair of 8-oxoG:A mismatches by the MUTYH glycosylase: Mechanism, metals and medicine. AB - Reactive oxygen and nitrogen species (RONS) may infringe on the passing of pristine genetic information by inducing DNA inter- and intra-strand crosslinks, protein-DNA crosslinks, and chemical alterations to the sugar or base moieties of DNA. 8-Oxo-7,8-dihydroguanine (8-oxoG) is one of the most prevalent DNA lesions formed by RONS and is repaired through the base excision repair (BER) pathway involving the DNA repair glycosylases OGG1 and MUTYH in eukaryotes. MUTYH removes adenine (A) from 8-oxoG:A mispairs, thus mitigating the potential of G:C to T:A transversion mutations from occurring in the genome. The paramount role of MUTYH in guarding the genome is well established in the etiology of a colorectal cancer predisposition syndrome involving variants of MUTYH, referred to as MUTYH associated polyposis (MAP). In this review, we highlight recent advances in understanding how MUTYH structure and related function participate in the manifestation of human disease such as MAP. Here we focus on the importance of MUTYH's metal cofactor sites, including a recently discovered "Zinc linchpin" motif, as well as updates to the catalytic mechanism. Finally, we touch on the insight gleaned from studies with MAP-associated MUTYH variants and recent advances in understanding the multifaceted roles of MUTYH in the cell, both in the prevention of mutagenesis and tumorigenesis. PMID- 28087413 TI - Nesfatin-1 modulates murine gastric vagal afferent mechanosensitivity in a nutritional state dependent manner. AB - Food intake is regulated by vagal afferent signals from the stomach. Nesfatin-1 is an anorexigenic peptide produced within the gastrointestinal tract and has well defined central effects. We aimed to determine if nesfatin-1 can modulate gastric vagal afferent signals in the periphery and further whether this is altered in different nutritional states. Female C57BL/6J mice were fed either a standard laboratory diet (SLD) or a high fat diet (HFD) for 12 weeks or fasted overnight. Plasma nucleobindin-2 (NUCB2; nesfatin-1 precursor)/nesfatin-1 levels were assayed, the expression of NUCB2 in the gastric mucosa and adipose tissue was assessed using real-time quantitative reverse-transcription polymerase chain reaction. An in vitro preparation was used to determine the effect of nesfatin-1 on gastric vagal afferent mechanosensitivity. HFD mice exhibited an increased body weight and adiposity. Plasma NUCB2/nesfatin-1 levels were unchanged between any of the groups of mice. NUCB2 mRNA was detected in the gastric mucosa and gonadal fat of SLD, HFD and fasted mice with no difference in mRNA abundance between groups in either tissue. In SLD and fasted mice nesfatin-1 potentiated mucosal receptor mechanosensitivity, an effect not observed in HFD mice. Tension receptor mechanosensitivity was unaffected by nesfatin-1 in SLD and fasted mice, but was inhibited in HFD mice. In conclusion, Nesfatin-1 modulates gastric vagal afferent mechanosensitivity in a nutritional state dependent manner. PMID- 28087414 TI - Consumption of Low-Calorie Sweeteners among Children and Adults in the United States. AB - BACKGROUND: Consumption of low-calorie sweeteners (LCSs) has increased markedly during the past several decades, yet the prevalence of LCS consumption in recent years is currently unknown. OBJECTIVE: The aim of this study was to describe LCS consumption in the United States and to characterize consumption by sociodemographic subgroups, source, frequency, eating occasion, and location. DESIGN: Cross-sectional study using National Health and Nutrition Examination Survey data from 2009 to 2012. The prevalence of LCS consumption was assessed using two 24-hour dietary recalls, while the frequency (number of times per day), occasion (meal vs snack vs alone), and location of LCS consumption (at home vs away from home) was assessed using data from the one, in-person, 24-hour dietary recall. PARTICIPANTS: National Health and Nutrition Examination Survey participants (2 years old or older) either in 2009-2010 (n=9,047) or in 2011-2012 (n=7,939). After excluding participants with implausible energy intake (n=44), the final sample size was 16,942. MAIN OUTCOME MEASURES: The primary outcome was the proportion of individuals consuming one or more foods, beverages, or packets containing LCSs during at least one of their two dietary recalls. STATISTICAL ANALYSES PERFORMED: Data were weighted to provide national estimates and Stata frequency procedures for complex survey design were used for all analyses. RESULTS: Our findings were that 25.1% of children and 41.4% adults reported consuming LCSs. Most LCS consumers reported use once daily (80% of children, 56% of adults) and frequency of consumption increased with body weight in adults. LCS consumption was higher in females compared with males among adults, and in obese individuals, compared with overweight and normal-weight individuals. Individuals of non-Hispanic white race/ethnicity also had higher prevalence of consumption compared with non-Hispanic blacks and Hispanics and those in the highest tertile of income had higher LCS consumption compared with individuals of middle or low income across LCS product categories in adults, and for LCS beverages and LCS foods in children. Most LCS consumers reported consuming LCS with meals (64% of adults, 62% of children) and the majority of LCS consumption occurred at home (71% and 72% among adults and children, respectively). CONCLUSIONS: LCS consumption is highly prevalent in the United States, among both children and adults. Well-controlled, prospective trials are required to understand the health impact of this widespread LCS exposure. PMID- 28087415 TI - Estimation of the Young's modulus of the human pars tensa using in-situ pressurization and inverse finite-element analysis. AB - Finite-element models of the tympanic membrane are sensitive to the Young's modulus of the pars tensa. The aim of this work is to estimate the Young's modulus under a different experimental paradigm than currently used on the human tympanic membrane. These additional values could potentially be used by the auditory biomechanics community for building consensus. The Young's modulus of the human pars tensa was estimated through inverse finite-element modelling of an in-situ pressurization experiment. The experiments were performed on three specimens with a custom-built pressurization unit at a quasi-static pressure of 500 Pa. The shape of each tympanic membrane before and after pressurization was recorded using a Fourier transform profilometer. The samples were also imaged using micro-computed tomography to create sample-specific finite-element models. For each sample, the Young's modulus was then estimated by numerically optimizing its value in the finite-element model so simulated pressurized shapes matched experimental data. The estimated Young's modulus values were 2.2 MPa, 2.4 MPa and 2.0 MPa, and are similar to estimates obtained using in-situ single-point indentation testing. The estimates were obtained under the assumptions that the pars tensa is linearly elastic, uniform, isotropic with a thickness of 110 MUm, and the estimates are limited to quasi-static loading. Estimates of pars tensa Young's modulus are sensitive to its thickness and inclusion of the manubrial fold. However, they do not appear to be sensitive to optimization initialization, height measurement error, pars flaccida Young's modulus, and tympanic membrane element type (shell versus solid). PMID- 28087416 TI - The path of a click stimulus from ear canal to umbo. AB - The tympanic membrane (TM) has a key role in transmitting sounds to the inner ear, but a concise description of how the TM performs this function remains elusive. This paper probes TM operation by applying a free field click stimulus to the gerbil ear and exploring the consequent motions of the TM and umbo. Motions of the TM were measured both on radial tracks starting close to the umbo and on a grid distal and adjacent to the umbo. The experimental results confirmed the high fidelity of sound transmission from the ear canal to the umbo. A delay of 5-15 MUs was seen in the onset of TM motion between points just adjacent to the umbo and mid-radial points. The TM responded with a ringing motion, with different locations possessing different primary ringing frequencies. A simple analytic model from the literature, treating the TM as a string, was used to explore the experimental results. The click-based experiments and analysis led to the following description of TM operation: A transient sound pressure on the TM causes a transient initial TM motion that is maximal ~ at the TM's radial midpoints. Mechanical forces generated by this initial prominent TM distortion then pull the umbo inward, leading to a delayed umbo response. The initial TM deformation also gives rise to prolonged mechanical ringing on the TM that does not result in significant umbo motion, likely due to destructive interference from the range of ringing frequencies. Thus, the umbo's response is a high fidelity representation of the transient stimulus. Because any sound can be considered as a consecutive series of clicks, this description is applicable to any sound stimulus. PMID- 28087417 TI - Culture media-based selection of endothelial cells, pericytes, and perivascular resident macrophage-like melanocytes from the young mouse vestibular system. AB - The vestibular blood-labyrinth barrier (BLB) is comprised of perivascular resident macrophage-like melanocytes (PVM/Ms) and pericytes (PCs), in addition to endothelial cells (ECs) and basement membrane (BM), and bears strong resemblance to the cochlear BLB in the stria vascularis. Over the past few decades, in vitro cell-based models have been widely used in blood-brain barrier (BBB) and blood retina barrier (BRB) research, and have proved to be powerful tools for studying cell-cell interactions in their respective organs. Study of both the vestibular and strial BLB has been limited by the unavailability of primary culture cells from these barriers. To better understand how barrier component cells interact in the vestibular system to control BLB function, we developed a novel culture medium-based method for obtaining EC, PC, and PVM/M primary cells from tiny explants of the semicircular canal, sacculus, utriculus, and ampullae tissue of young mouse ears at post-natal age 8-12 d. Each phenotype is grown in a specific culture medium which selectively supports the phenotype in a mixed population of vestibular cell types. The unwanted phenotypes do not survive passaging. The protocol does not require additional equipment or special enzyme treatment. The harvesting process takes less than 2 h. Primary cell types are generated within 7 10 d. The primary culture ECs, PCs, and PVM/M shave consistent phenotypes more than 90% pure after two passages (~ 3 weeks). The highly purified primary cell lines can be used for studying cell-cell interactions, barrier permeability, and angiogenesis. PMID- 28087418 TI - Degeneration of auditory nerve fibers in guinea pigs with severe sensorineural hearing loss. AB - Damage to and loss of the organ of Corti leads to secondary degeneration of the spiral ganglion cell (SGC) somata of the auditory nerve. Extensively examined in animal models, this degeneration process of SGC somata following deafening is well known. However, degeneration of auditory nerve axons, which conduct auditory information towards the brainstem, and its relation to SGC soma degeneration are largely unknown. The consequences of degeneration of the axons are relevant for cochlear implantation, which is applied to a deafened system but depends on the condition of the auditory nerve. We investigated the time sequence of degeneration of myelinated type I axons in deafened guinea pigs. Auditory nerves in six normal-hearing and twelve deafened animals, two, six and fourteen weeks (for each group four) after deafening were histologically analyzed. We developed a semi-automated method for axon counting, which allowed for a relatively large sample size (20% of the total cross-sectional area of the auditory nerve). We observed a substantial loss of auditory nerve area (29%), reduction in axon number (59%) and decrease in axoplasm area (41%) fourteen weeks after deafening compared to normal-hearing controls. The correlation between axonal degeneration and that of the SGC somata in the same cochleas was high, although axonal structures appeared to persist longer than the somata, suggesting a slower degeneration process. In the first two weeks after induction of deafness, the axonal cross-sectional area decreased but the axon number did not. In conclusion, the data strongly suggest that each surviving SGC possesses an axon. PMID- 28087420 TI - On the quirks of maximum parsimony and likelihood on phylogenetic networks. AB - Maximum parsimony is one of the most frequently-discussed tree reconstruction methods in phylogenetic estimation. However, in recent years it has become more and more apparent that phylogenetic trees are often not sufficient to describe evolution accurately. For instance, processes like hybridization or lateral gene transfer that are commonplace in many groups of organisms and result in mosaic patterns of relationships cannot be represented by a single phylogenetic tree. This is why phylogenetic networks, which can display such events, are becoming of more and more interest in phylogenetic research. It is therefore necessary to extend concepts like maximum parsimony from phylogenetic trees to networks. Several suggestions for possible extensions can be found in recent literature, for instance the softwired and the hardwired parsimony concepts. In this paper, we analyze the so-called big parsimony problem under these two concepts, i.e. we investigate maximum parsimonious networks and analyze their properties. In particular, we show that finding a softwired maximum parsimony network is possible in polynomial time. We also show that the set of maximum parsimony networks for the hardwired definition always contains at least one phylogenetic tree. Lastly, we investigate some parallels of parsimony to different likelihood concepts on phylogenetic networks. PMID- 28087421 TI - Physiology, anaerobes, and the origin of mitosing cells 50 years on. AB - Endosymbiotic theory posits that some organelles or structures of eukaryotic cells stem from free-living prokaryotes that became endosymbionts within a host cell. Endosymbiosis has a long and turbulent history of controversy and debate going back over 100 years. The 1967 paper by Lynn Sagan (later Lynn Margulis) forced a reluctant field to take endosymbiotic theory seriously and to incorporate it into the fabric of evolutionary thinking. Margulis envisaged three cellular partners associating in series at eukaryotic origin: the host (an engulfing bacterium), the mitochondrion (a respiring bacterium), and the flagellum (a spirochaete), with lineages descended from that flagellated eukaryote subsequently acquiring plastids from cyanobacteria, but on multiple different occasions in her 1967 account. Today, the endosymbiotic origin of mitochondria and plastids (each single events, the data now say) is uncontested textbook knowledge. The host has been more elusive, recent findings identifying it as a member of the archaea, not as a sister group of the archaea. Margulis's proposal for a spirochaete origin of flagellae was abandoned by everyone except her, because no data ever came around to support the idea. Her 1967 proposal that mitochondria and plastids arose from different endosymbionts was novel. The paper presented an appealing narrative that linked the origin of mitochondria with oxygen in Earth history: cyanobacteria make oxygen, oxygen starts accumulating in the atmosphere about 2.4 billion years ago, oxygen begets oxygen-respiring bacteria that become mitochondria via symbiosis, followed by later (numerous) multiple, independent symbioses involving cyanobacteria that brought photosynthesis to eukaryotes. With the focus on oxygen, Margulis's account of eukaryote origin was however unprepared to accommodate the discovery of mitochondria in eukaryotic anaerobes. Today's oxygen narrative has it that the oceans were anoxic up until about 580 million years ago, while the atmosphere attained modern oxygen levels only about 400 million years ago. Since eukaryotes are roughly 1.6 billion years old, much of eukaryotic evolution took place in low oxygen environments, readily explaining the persistence across eukaryotic supergroups of eukaryotic anaerobes and anaerobic mitochondria at the focus of endosymbiotic theories that came after the 1967 paper. PMID- 28087419 TI - Cochlear synaptopathy in acquired sensorineural hearing loss: Manifestations and mechanisms. AB - Common causes of hearing loss in humans - exposure to loud noise or ototoxic drugs and aging - often damage sensory hair cells, reflected as elevated thresholds on the clinical audiogram. Recent studies in animal models suggest, however, that well before this overt hearing loss can be seen, a more insidious, but likely more common, process is taking place that permanently interrupts synaptic communication between sensory inner hair cells and subsets of cochlear nerve fibers. The silencing of affected neurons alters auditory information processing, whether accompanied by threshold elevations or not, and is a likely contributor to a variety of perceptual abnormalities, including speech-in-noise difficulties, tinnitus and hyperacusis. Work described here will review structural and functional manifestations of this cochlear synaptopathy and will consider possible mechanisms underlying its appearance and progression in ears with and without traditional 'hearing loss' arising from several common causes in humans. PMID- 28087422 TI - Nano-QSAR in cell biology: Model of cell viability as a mathematical function of available eclectic data. AB - The prediction of biochemical endpoints is an important task of the modern medicinal chemistry, cell biology, and nanotechnology. Simplified molecular input line entry system (SMILES) is a tool for representation of the molecular structure. In particular, SMILES can be used to build up the quantitative structure - property/activity relationships (QSPRs/QSARs). The QSPR/QSAR is a tool to predict an endpoint for a new substance, which has not been examined in experiment. Quasi-SMILES are representation of eclectic data related to an endpoint. In contrast to traditional SMILES, which are representation of the molecular structure, the quasi-SMILES are representation of conditions (in principle, the molecular structure also can be taken into account in quasi SMILES). In this work, the quasi-SMILES were used to build up model for cell viability under impact of the metal-oxides nanoparticles by means of the CORAL software (http://www.insilico.eu/coral). The eclectic data for the quasi-SMILES are (i) molecular structure of metals-oxides; (ii) concentration of the nanoparticles; and (iii) the size of nanoparticles. The significance of different eclectic facts has been estimated. Mechanistic interpretation and the domain of applicability for the model are suggested. The statistical quality of the models is satisfactory for three different random distribution of available data into the training (sub-training and calibration) and the validation sets. PMID- 28087424 TI - Clinical applications of MALDI imaging technologies in cancer and neurodegenerative diseases. AB - Matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) imaging mass spectrometry (IMS) enables localization of analytes of interest along with histology. More specifically, MALDI-IMS identifies the distributions of proteins, peptides, small molecules, lipids, and drugs and their metabolites in tissues, with high spatial resolution. This unique capacity to directly analyze tissue samples without the need for lengthy sample preparation reduces technical variability and renders MALDI-IMS ideal for the identification of potential diagnostic and prognostic biomarkers and disease gradation. MALDI-IMS has evolved rapidly over the last decade and has been successfully used in both medical and basic research by scientists worldwide. In this review, we explore the clinical applications of MALDI-IMS, focusing on the major cancer types and neurodegenerative diseases. In particular, we re-emphasize the diagnostic potential of IMS and the challenges that must be confronted when conducting MALDI IMS in clinical settings. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann. PMID- 28087423 TI - Is middle cerebral artery Doppler related to neonatal and 2-year infant outcome in early fetal growth restriction? AB - BACKGROUND: Reduced fetal middle cerebral artery Doppler impedance is associated with hypoxemia in fetal growth restriction. It remains unclear as to whether this finding could be useful in timing delivery, especially in the third trimester. In this regard there is a paucity of evidence from prospective studies. OBJECTIVES: The aim of this study was to determine whether there is an association between middle cerebral artery Doppler impedance and its ratio with the umbilical artery in relation to neonatal and 2 year infant outcome in early fetal growth restriction (26+0-31+6 weeks of gestation). Additionally we sought to explore which ratio is more informative for clinical use. STUDY DESIGN: This is a secondary analysis from the Trial of Randomized Umbilical and Fetal Flow in Europe, a prospective, multicenter, randomized management study on different antenatal monitoring strategies (ductus venosus Doppler changes and computerized cardiotocography short-term variation) in fetal growth restriction diagnosed between 26+0 and 31+6 weeks. We analyzed women with middle cerebral artery Doppler measurement at study entry and within 1 week before delivery and with complete postnatal follow-up (374 of 503). The primary outcome was survival without neurodevelopmental impairment at 2 years corrected for prematurity. Neonatal outcome was defined as survival until first discharge home without severe neonatal morbidity. Z-scores were calculated for middle cerebral artery pulsatility index and both umbilicocerebral and cerebroplacental ratios. Odds ratios of Doppler parameter Z-scores for neonatal and 2 year infant outcome were calculated by multivariable logistic regression analysis adjusted for gestational age and birthweight p50 ratio. RESULTS: Higher middle cerebral artery pulsatility index at inclusion but not within 1 week before delivery was associated with neonatal survival without severe morbidity (odds ratio, 1.24; 95% confidence interval, 1.02-1.52). Middle cerebral artery pulsatility index Z-score and umbilicocerebral ratio Z-score at inclusion were associated with 2 year survival with normal neurodevelopmental outcome (odds ratio, 1.33; 95% confidence interval, 1.03-1.72, and odds ratio, 0.88; 95% confidence interval, 0.78-0.99, respectively) as were gestation at delivery and birthweight p50 ratio (odds ratio, 1.41; 95% confidence interval, 1.20-1.66, and odds ratio, 1.86; 95% confidence interval, 1.33-2.60, respectively). When comparing cerebroplacental ratio against umbilicocerebral ratio, the incremental range of the cerebroplacental ratio tended toward zero, whereas the umbilicocerebral ratio tended toward infinity as the values became more abnormal. CONCLUSION: In a monitoring protocol based on ductus venosus and cardiotocography in early fetal growth restriction (26+0-31+6 weeks of gestation), the impact of middle cerebral artery Doppler and its ratios on outcome is modest and less marked than birthweight and delivery gestation. It is unlikely that middle cerebral artery Doppler and its ratios are informative in optimizing the timing of delivery in fetal growth restriction before 32 weeks of gestation. The umbilicocerebral ratio allows for a better differentiation in the abnormal range than the cerebroplacental ratio. PMID- 28087425 TI - Variations of metabolites and proteome in Lonicera japonica Thunb. buds and flowers under UV radiation. AB - Lonicera japonica Thunb., also known as Jin Yin Hua and Japanese honeysuckle, is used as a herbal medicine in Asian countries. Its flowers have been used in folk medicine in the clinic and in making food or healthy beverages for over 1500years in China. To investigate the molecular processes involved in L. japonica development from buds to flowers exposed to UV radiation, a comparative proteomics analysis was performed. Fifty-four proteins were identified as differentially expressed, including 42 that had increased expression and 12 that had decreased expression. The levels of the proteins related to glycolysis, TCA/organic acid transformation, major carbohydrate metabolism, oxidative pentose phosphate, stress, secondary metabolism, hormone, and mitochondrial electron transport were increased during flower opening process after exposure to UV radiation. Six metabolites in L. japonica buds and flowers were identified and relatively quantified using LC-MS/MS. The antioxidant activity was performed using a 1,1-diphenyl-2-picrylhydrazyl assay, which revealed that L. japonica buds had more activity than the UV irradiated flowers. This suggests that UV-B radiation induces production of endogenous ethylene in L. japonica buds, thus facilitating blossoming of the buds and activating the antioxidant system. Additionally, the higher metabolite contents and antioxidant properties of L. japonica buds indicate that the L. japonica bud stage may be a more optimal time to harvest than the flower stage when using for medicinal properties. PMID- 28087426 TI - Next-generation sequencing of a large gene panel in patients initially diagnosed with idiopathic ventricular fibrillation. AB - BACKGROUND: Idiopathic ventricular fibrillation (IVF) is a rare primary cardiac arrhythmia syndrome that is diagnosed in a resuscitated cardiac arrest victim, with documented ventricular fibrillation, in whom no underlying cause is identified after comprehensive clinical evaluation. In some patients, causative genetic mutations are detected that facilitate patient treatment and follow-up. The feasibility of next-generation sequencing (NGS) has increased with its greater availability and decreasing costs. OBJECTIVE: The aim of this study was to assess the diagnostic yield of NGS in patients with IVF. METHODS: A total of 33 patients initially diagnosed with IVF were included (mean age 53 +/- 15 years; 14(42%) men). In all included patients, NGS of 33 genes and the DPP6 haplotype revealed no pathogenic mutations. Genetic screening comprised NGS of a panel of 179 additional genes. Variants with a minor allele frequency of <0.05% were assessed for pathogenicity by using existing mutation databases and in silico predictive algorithms. RESULTS: In 1 of 33 patients, a likely pathogenic mutation was detected. The added yield of genetic testing with NGS of 179 additional genes is 3% in patients with IVF. In 15% of patients, 1 or multiple variants of uncertain clinical significance were detected. CONCLUSION: The added yield of genetic screening of extended NGS panels in patients initially diagnosed with IVF is minimal. Routine analysis of large diagnostic NGS panels is therefore not recommended. PMID- 28087427 TI - Gender Difference in the Association between Aortic Pulse Pressure and Left Ventricular Filling Pressure in the Elderly: An Invasive Hemodynamic Study. AB - BACKGROUND: This study was conducted to determine the association between aortic pulse pressure (APP) and left ventricular (LV) filling pressure in the elderly of both genders. METHODS: A total of 211 stable elderly subjects (age >=65 years, mean age 72.1 +/- 5.2 years, 53.6% women) who underwent invasive coronary angiography (ICA) for the evaluation of coronary artery disease (CAD) were prospectively investigated. APP was measured in the ascending aorta using a pigtail catheter immediately before ICA. E/e', reflecting LV filling pressure, was assessed by transthoracic echocardiography. RESULTS: There were positive linear correlations between APP and E/e' in both genders, but the correlation power was stronger in women than in men (r = 0.402, P <.001 vs r = 0.208, P = .040). The significance of this association between APP and E/e' remained after controlling for potential confounders in multiple linear regression analysis in women (beta = 0.359, P <.001), but not in men (r = 0.139, P = .108). CONCLUSIONS: Invasively measured APP is independently associated with E/e' in elderly women, but not in elderly men undergoing ICA. Aortic stiffness may be a potential mechanism for more prevalent LV diastolic dysfunction and heart failure with preserved ejection fraction in elderly women. PMID- 28087428 TI - Polycomb complexes PRC1 and their function in hematopoiesis. AB - Hematopoiesis, the process by which blood cells are continuously produced, is one of the best studied differentiation pathways. Hematological diseases are associated with reiterated mutations in genes encoding important gene expression regulators, including chromatin regulators. Among them, the Polycomb group (PcG) of proteins is an essential system of gene silencing involved in the maintenance of cell identities during differentiation. PcG proteins assemble into two major types of Polycomb repressive complexes (PRCs) endowed with distinct histone-tail modifying activities. PRC1 complexes are histone H2A E3 ubiquitin ligases and PRC2 trimethylates histone H3. Established conceptions about their activities, mostly derived from work in embryonic stem cells, are being modified by new findings in differentiated cells. Here, we focus on PRC1 complexes, reviewing recent evidence on their intricate architecture, the diverse mechanisms of their recruitment to targets, and the different ways in which they engage in transcriptional control. We also discuss hematopoietic PRC1 gain- and loss-of function mouse strains, including those that model leukemic and lymphoma diseases, in the belief that these genetic analyses provide the ultimate test for molecular mechanisms driving normal hematopoiesis and hematological malignancies. PMID- 28087429 TI - Analysis of parameters that affect human hematopoietic cell outputs in mutant c kit-immunodeficient mice. AB - Xenograft models are transforming our understanding of the output capabilities of primitive human hematopoietic cells in vivo. However, many variables that affect posttransplantation reconstitution dynamics remain poorly understood. Here, we show that an equivalent level of human chimerism can be regenerated from human CD34+ cord blood cells transplanted intravenously either with or without additional radiation-inactivated cells into 2- to 6-month-old NOD-Rag1-/- IL2Rgammac-/- (NRG) mice given a more radioprotective conditioning regimen than is possible in conventionally used, repair-deficient NOD-Prkdcscid/scid IL2Rgammac-/- (NSG) hosts. Comparison of sublethally irradiated and non irradiated NRG mice and W41/W41 derivatives showed superior chimerism in the W41 deficient recipients, with some differential effects on different lineage outputs. Consistently superior outputs were observed in female recipients regardless of their genotype, age, or pretransplantation conditioning, with greater differences apparent later after transplantation. These results define key parameters for optimizing the sensitivity and minimizing the intraexperimental variability of human hematopoietic xenografts generated in increasingly supportive immunodeficient host mice. PMID- 28087430 TI - Ryanodine Receptor 1 Polymorphism Is Not Associated with Aneurysmal Subarachnoid Hemorrhage or its Clinical Sequelae. AB - OBJECTIVE: The pathophysiologic mechanisms underlying cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH) remain poorly understand. Ryanodine receptors (RYR) are intracellular calcium channels involved in the regulation of vascular smooth muscle cells and cerebrovascular tone and diameter. Previous work reported an association between an RYR polymorphism and cerebral vasospasm. Here, we sought to assess the impact of that RYR polymorphism on aSAH and its clinical sequelae. METHODS: Blood samples from all patients enrolled in the CARAS (Cerebral Aneurysm Renin Angiotensin System) study were used for genetic evaluation. The RYR1 single nucleotide polymorphism (SNP) rs35364374 was detected using 5'exonuclease (Taqman) genotyping assays. Associations between the RYR1 polymorphism and aSAH and its clinical sequelae were analyzed. RESULTS: Samples from 149 patients with aSAH and 50 controls were available for analysis. Multivariable regression analysis did not show an association of RYR1 SNP rs35364374 with aSAH. Moreover, there was no association of RYR1 SNP rs35364374 with clinical vasospasm, delayed cerebral ischemia, functional outcome at discharge, or functional outcome at last follow-up. CONCLUSIONS: Contrary to a previous report, the RYR1 SNP rs35364374 was not associated with aSAH or its clinical sequelae. PMID- 28087431 TI - Characteristics of Moderate and Severe Traumatic Brain Injury of Motorcycle Crashes in Bandung, Indonesia. AB - BACKGROUND: Traumatic brain injury (TBI) constitutes a critical public health and socioeconomic problem. As one of the leading causes of mortality and disability from road traffic crashes, the incidence of TBIs is increasing with increasing motor vehicle usage. Understanding the prevalence and describing the characteristics of TBI are crucial for successful implementation of prevention and treatment efforts to reduce the mortality and morbidity caused by TBIs. METHODS: We studied cases of moderate and severe TBI resulting from motorcycle crashes from January 1, 2013 to June 30, 2014. Variables studied included sex, age, time interval (from crash to arrival at the emergency department), alcohol consumption, helmet use, severity of TBI, choice of treatment, and the outcome. RESULTS: A total of 2108 head injury cases were seen at the emergency department during this period, 1324 (62.8%) of which resulted from motorcycle crashes. Of those cases, 30.7% (407 cases) were categorized as moderate or severe TBI with 29.2% mortality. Most of the patients were male (80.8%), <60 years old (96.1%), and did not wear a helmet (71.2%). More than half of the cases (56.7%) arrived at the emergency department within 6 hours, 14.0% of the cases were under alcohol intoxication, and 37.8% of the cases were operated on. CONCLUSIONS: This preliminary analysis highlights the need to address road safety, especially with respect to helmet use and drink driving, to reduce the burden of TBIs in Bandung. PMID- 28087432 TI - Stenting After Coiling Using a Single Microcatheter for Treatment of Ruptured Intracranial Fusiform Aneurysms with Parent Arteries Less Than 1.5 mm in Diameter. AB - BACKGROUND: Ruptured intracranial fusiform aneurysms involving small-diameter parent arteries are difficult to treat. Parent artery occlusion is a relatively simple and reliable treatment. However, occasionally, the parent arteries have to be retained. The arrival of the low-profile stent (LVIS Jr.) has made reconstructive endovascular treatment for fusiform aneurysms involving small diameter parent arteries possible. CASE DESCRIPTION: This report describes an innovative method for stent-assisted coiling (stenting after coiling technique using only 1 microcatheter) and describes our initial experience and feasibility of this technique. However, this report carries all limitations of a technical case report of a single patient, including reproducibility, unknown potential of complications, absence of long-term follow-up, and comparative effectiveness or safety with current known techniques. CONCLUSIONS: Stenting after a coiling technique using the LVIS Jr. stent provides a possible method for reconstructive endovascular treatment of intracranial fusiform aneurysms with parent arteries <1.5 mm in diameter. PMID- 28087433 TI - Exploration of the Most Effective Dural Incision Design in a Decompressive Craniectomy. AB - OBJECTIVE: During a decompressive craniectomy performed for a severe cerebral infarction, sufficient coverage of the underlying bulging brain by converting the flat dura mater to a more domelike shape is essential. In this procedure, suturing to patch dural substitutes on the dural rifts occupies most of the operative time and is cumbersome. We present a new dural incision design that provides an appropriate volume of subdural space with minimal incisions. METHODS: The ideal incision design was geometrically analyzed and verified by simulations using a physics engine. RESULTS: Assuming a quadrilateral area on the dura mater surface termed S, expanding the entire area of S requires 2d (where d is the skull thickness) + a 30-mm extension of the shortest set of line segments connecting each vertex (LSCV) of S to cover the necessary volume of bulging brain. The shortest LSCV comprises 5 line segments connected with two 3-pronged intersections. The ideal incision design consists of a pair of curved line segments that maintain plane continuity along the LSCV, which automatically limits the maximum expansion. The ideal incision design of S consists of 5 uncinate line segments. Four of the line segments originate from each vertex of S and end by crossing over the LSCV, and one of the line segments crosses over 2 separate LSCV. A representative case is shown. CONCLUSIONS: This technique minimizes the complexity of the operation and shortens the operation time. PMID- 28087434 TI - Bone Grafting of Atlantoaxial Joints and Occipitocervical or Atlantoaxial Fusion for the Reduction and Fixation of Basilar Invagination with Atlantoaxial Dislocation by a Posterior Approach: A Preliminary Study. AB - BACKGROUND: Basilar invagination (BI) with atlantoaxial dislocation (AAD) is a complex disease to manage. We have developed a new technique of bone grafting the atlantoaxial joints and occipitocervical fusion using a posterior approach for the reduction and fixation of BI with AAD with complete retention of the C2 nerve root. METHODS: Thirty-two patients underwent bone grafting of the atlantoaxial joints and occipitocervical fusion for the reduction and fixation of BI with AAD by the posterior approach in our department between January 2015 and February 2016. All patients underwent plain radiography, computed tomography (CT) scanning, and magnetic resonance imaging evaluation. The atlantodens interval and cervicomedullary angle were evaluated preoperatively and 5 days after surgery on sagittal reconstructed CT scans to evaluate BI with AAD. CT scans of sagittal reconstruction were acquired at each follow-up until bone fusion was confirmed. RESULTS: All patients were followed up for 6-19 months. No patient required re exploration for failure of implant fixation. At the last follow-up, all patients had achieved fusion (32/32). Japanese Orthopedic Association score, atlantodens interval, and cervicomedullary angle were significantly improved in these patients compared with preoperative measurements (P < 0.05). The duration of symptoms ranged from 5 days to 11 months (mean duration, 2 months). No serious complication was observed. CONCLUSIONS: In this preliminary study, our operation technique could treat BI with AAD by using only a posterior approach, which could retain C2 nerve roots and fuse atlantoaxial joints. This technique may be extended to other diseases requiring treatment by C1-C2 fusion. PMID- 28087435 TI - Postmyelotomy Closure of Spinal Cord-"Zip Lock Technique": An Initial Experience. AB - Proper closure of the pia matter is necessary to restore normal anatomy and prevent postoperative painful dysesthesia after excision of intramedullary spinal cord tumor. Two methods of closure of the pia have been described: welding technique and conventional suturing. Here, we report our initial experience with a new "pial press" or "zip lock" technique for pial closure, where pial layers are simply held together and plunged into each other with small microtooth forceps. Advantages of the technique over other techniques are it has less chance of suture-related complications or trauma to the posterior column and the simplicity of the technique. PMID- 28087436 TI - Functional connectivity analysis using fNIRS in healthy subjects during prolonged simulated driving. AB - Noninvasive and accurate assessment of driving fatigue in relation to brain activity during long-term driving can contribute to traffic safety and accident prevention. This study evaluated functional connectivity (FC) in relevant brain regions. Synergistic mechanisms in different brain regions were detected by a novel simulator, which combined semi-immersive virtual reality technology and functional near-infrared spectroscopy. Each subject was instructed to complete driving tasks coupled with a mental calculation task. Wavelet coherence (WCO) and wavelet phase coherence (WPCO) were calculated and assessed in frequency intervals (I) 0.6-2 and (II) 0.145-0.6Hz as global connectivity measures; (III) 0.052-0.145, (IV) 0.021-0.052, (V) 0.0095-0.021 and (VI) 0.005-0.0095Hz as FC. WCO and WPCO revealed the strength and synchronization of cerebral connectivity, respectively. Significantly low WCO levels were found in intervals I and III in prefrontal cortex (PFC) and IV in motor cortex (MC) at the end of the driving task. Furthermore, significantly low WPCO were found in intervals I, and III in PFC and interval IV in MC. Experimental findings suggested that progressive mental fatigue adversely influences the cognitive function in the PFC and the cooperative mechanism between the PFC and MC. PMID- 28087437 TI - Hydrogen-rich saline attenuates hippocampus endoplasmic reticulum stress after cardiac arrest in rats. AB - BACKGROUND: Hydrogen-rich saline can selectively scavenge reactive oxygen species (ROS) and protect brain against ischemia reperfusion (I/R) injury. Endoplasmic reticulum stress (ERS) has been implicated in the pathological process of cerebral ischemia. However, very little is known about the role of hydrogen-rich saline in mediating pathophysiological reactions to ERS after I/R injury caused by cardiac arrest. METHODS: The rats were randomly divided into three groups, sham group (n=30), ischemia/reperfusion group (n=40) and hydrogen-rich saline group (n=40). The rats in experimental groups were subjected to 4min of cardiac arrest and followed by resuscitation. Then they were randomized to receive 5ml/kg of either hydrogen-rich saline or normal saline. RESULTS: Hydrogen-rich saline significantly improves survival rate and neurological function. The beneficial effects of hydrogen-rich saline were associated with decreased levels of oxidative products, as well as the increased levels of antioxidant enzymes. Furthermore, the protective effects of hydrogen-rich saline were accompanied by the increased activity of glucose-regulated protein 78 (GRP78), the decreased activity of cysteinyl aspartate specific proteinase-12 (caspase-12) and C/EBP homologous protein (CHOP). CONCLUSIONS: Hydrogen-rich saline attenuates brain I/R injury may through inhibiting hippocampus ERS after cardiac arrest in rats. PMID- 28087438 TI - Dopa-responsive dystonia in Chinese patients: Including a novel heterozygous mutation in the GCH1 gene with an intermediate phenotype and one case of prenatal diagnosis. AB - Dopa-responsive dystonia (DRD) is a rare inherited disorder characterized by childhood-onset dystonia with diurnal fluctuation and dramatic response to levodopa. DRD is caused by the mutations in the genes encoding the enzymes involved in the dopamine and tetrahydrobiopterin (BH4) biosynthesis, including the GTP cyclohydrolase 1 (GCH1) gene and the tyrosine hydroxylase (TH) gene. In order to improve the diagnosis and expand the knowledge of the disease, we collected and analyzed relevant data of clinical diagnosis and molecular mutational analysis in five Chinese patients with DRD. The patients presented with heterogenous symptoms of neurologic disorders. One novel mutation p.Leu117Arg was identified in GCH1 gene with an intermediate phenotype which was predicted in sillico to have a deleterious effect on the GCH1 protein function. Seven different mutations were identified in TH gene including four known mutations: p.Arg233His, p.Gly315Ser, p.Gly247Ser, p.Arg153X, and three novel mutations: p.Arg476Ser, IVS6-34G > C, p.Arg328Gln. The mutation p.Arg233His was predicted to link to the second type of TH deficiency (dopa-responsive infantile parkinsonism with delayed motor development). The mutation p.Arg153X may link to the first type of TH deficiency (typical DRD). The three novel mutations were predicted to be damaging in sillico. A prenatal diagnosis was made in the fourth pregnancy of the parents of patient 2 and proved to be a carrier of a heterozygous mutation. Our study expands the spectrum of genotype of DRD in China, provides new insights into the molecular mechanism of DRD and help to the diagnosis and treatment of this disease. PMID- 28087439 TI - Cerebrovascular heterogeneity and neuronal excitability. AB - The cerebral vasculature is a complex tridimensional network of arterial and venous vessels which are anatomically in proximity of and functionally coupled to neurons. Depending on the cellular composition of the vascular wall and size, cerebral vessels control regional blood flow, define interstitial homeostasis or cerebrospinal fluid circulation and influence immune cell patrolling. Pathological deviations from these functions promote or are a consequence of brain diseases, directly impacting neuronal firing. We propose that specific cerebrovascular segments are differentially implicated in the pathophysiology of epilepsy, including difference between white and grey matter. We offer plasticity of perivascular mural cells and endothelial-pericyte interactions as emerging players. We outline the potential for MRI vascular biomarkers tailored to the epileptic brain, specifically cerebral blood volume and flow, tissue oxygen saturation and microvessel permeability. Finally, we show the advantages of the guinea pig whole brain preparation to study the link between cerebrovascular permeability, expression of vascular adhesion molecules, inflammation and neuronal excitability. PMID- 28087440 TI - An overlooked horticultural crop, Smyrnium olusatrum, as a potential source of compounds effective against African trypanosomiasis. AB - Among natural products, sesquiterpenes have shown promising inhibitory effects against bloodstream forms of Trypanosoma brucei, the protozoan parasite causing human African trypanosomiasis (HAT). Smyrnium olusatrum (Apiaceae), also known as Alexanders or wild celery, is a neglected horticultural crop characterized by oxygenated sesquiterpenes containing a furan ring. In the present work we explored the potential of its essential oils obtained from different organs and the main oxygenated sesquiterpenes, namely isofuranodiene, germacrone and beta acetoxyfuranoeudesm-4(15)-ene, as inhibitors of Trypanosoma brucei. All essential oils effectively inhibited the growth of parasite showing IC50 values of 1.9 4.0MUg/ml. Among the main essential oil constituents, isofuranodiene exhibited a significant and selective inhibitory activity against T. brucei (IC50 of 0.6MUg/ml, SI=30), with beta-acetoxyfuranoeudesm-4(15)-ene giving a moderate potentiating effect. These results shed light on the possible application of isofuranodiene as an antiprotozoal agent to be included in combination treatments aimed not only at curing patients but also at preventing the diffusion of HAT. PMID- 28087441 TI - Blastocystis and irritable bowel syndrome: Frequency and subtypes from Iranian patients. AB - There are inconsistent findings about the role of Blastocystis infection in irritable bowel syndrome (IBS). The present study was aimed to determine the frequency of Blastocystis and their subtypes (ST) in patients with IBS. A total of 122 patients with IBS and 122 healthy individuals referred to the medical laboratory centers in Ahvaz (southwest of Iran) participated in the study. The frequency of Blastocystis was determined. Blastocystis genomic DNA was extracted from positive feces, and PCR was performed using seven primer pairs targeting the SSU rDNA gene. Blastocystis was detected in 19.67% of patients with IBS and 17.2% of individuals without IBS. The difference between two groups was not statistically significant (P=0.3). Among the five subtypes of Blastocystis, ST3 was more common in patients with IBS and control group. However, there were no significant differences between two groups in terms of subtypes of Blastocystis (P=0.6). It seems, the role of Blastocystis in the etiology of IBS should be further investigated. Furthermore, a model of study should be designed to investigate the role of host factors in severity of parasitic disease. PMID- 28087442 TI - Hydrogen sulfide protects against endoplasmic reticulum stress and mitochondrial injury in nucleus pulposus cells and ameliorates intervertebral disc degeneration. AB - It has been suggested that excessive apoptosis in intervertebral disc cells induced by inflammatory cytokines, such as interleukin (IL)-1beta, is related to the process of intervertebral disc degeneration (IVDD). Hydrogen sulfide (H2S), a gaseous signaling molecule, has drawn attention for its anti-apoptosis role in various pathophysiological processes in degenerative diseases. To date, there has been no investigation of the correlation of H2S production and IVDD or of the effects of H2S on IL-1beta-induced apoptosis in nucleus pulposus (NP) cells. Here, we found that the expression levels of cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE), two key enzymes in the generation of H2S, were significantly decreased in human degenerate NP tissues as well as in IL 1beta-treated NP cells. NaHS (H2S donor) administration showed a protective effect by inhibiting the endoplasmic reticulum (ER) stress response and mitochondrial dysfunction induced by IL-1beta stimulation in vitro, the effect was related to activation of the PI3K/Akt and ERK1/2 signaling pathways. Suppression of these pathways by specific inhibitors, LY294002 and PD98059, partially reduced the protective effect of NaHS. Moreover, in the percutaneous needle puncture disc degeneration rat tail model, disc degeneration was partially reversed by NaHS administration. Taken together, our results suggest that H2S plays a protective role in IVDD and the underlying mechanism involves PI3K/Akt and ERK1/2 signaling pathways-mediated suppression of ER stress and mitochondrial dysfunction in IL-1beta-induced NP cells. PMID- 28087443 TI - An update on the physiological and therapeutic relevance of GPCR oligomers. AB - The traditional view on GPCRs held that they function as single monomeric units composed of identical subunits. This notion was overturned by the discovery that GPCRs can form homo- and hetero-oligomers, some of which are obligatory, and can further assemble into receptor mosaics consisting of three or more protomers. Oligomerisation exerts significant impacts on receptor function and physiology, offering a platform for the diversification of receptor signalling, pharmacology, regulation, crosstalk, internalization and trafficking. Given their involvement in the modulation of crucial physiological processes, heteromers could constitute important therapeutic targets for a wide range of diseases, including schizophrenia, Parkinson's disease, substance abuse or obesity. This review aims at depicting the current developments in GPCR oligomerisation research, documenting various class A, B and C GPCR heteromers detected in vitro and in vivo using biochemical and biophysical approaches, as well as recently identified higher-order oligomeric complexes. It explores the current understanding of dimerization dynamics and the possible interaction interfaces that drive oligomerisation. Most importantly, it provides an inventory of the wide range of physiological processes and pathophysiological conditions to which GPCR oligomers contribute, surveying some of the oligomers that constitute potential drug targets. Finally, it delineates the efforts to develop novel classes of ligands that specifically target and tether to receptor oligomers instead of a single monomeric entity, thus ameliorating their ability to modulate GPCR function. PMID- 28087444 TI - The mechanistic role of chemically diverse metal ions in the induction of autophagy. AB - Autophagy is an evolutionary conserved cellular catabolic degradation process in response to stress which involves lysosomal degradation of unnecessary or damaged organelles and misfolded proteins. This is primarily a pro-survival pathway providing the cell with essential nutrients during stressful conditions. There are number of essential metal ions, which are required for normal physiological functioning of cells. Studies have shown that autophagy can be regulated by cellular metal ion concentrations. On the other hand, autophagy is also shown to regulate intracellular levels of certain metal ions. This review discusses recent advances in the research examining the role of metal ions in the autophagic pathway. PMID- 28087445 TI - Distinct subcomponents of mouse retinal ganglion cell receptive fields are differentially altered by light adaptation. AB - The remarkable dynamic range of vision is facilitated by adaptation of retinal sensitivity to ambient lighting conditions. An important mechanism of sensitivity adaptation is control of the spatial and temporal window over which light is integrated. The retina accomplishes this by switching between parallel synaptic pathways with differing kinetics and degrees of synaptic convergence. However, the relative shifts in spatial and temporal integration are not well understood - particularly in the context of the antagonistic spatial surround. Here, we resolve these issues by characterizing the adaptation-induced changes to spatiotemporal integration in the linear receptive field center and surround of mouse retinal ganglion cells. While most ganglion cells lose their antagonistic spatial surround under scotopic conditions, a strong surround is maintained in a subset. We then applied a novel technique that allowed us to analyze the receptive field as a triphasic temporal filter in the center and a biphasic filter in the surround. The temporal tuning of the surround was relatively maintained across adaptation conditions compared to the center, which greatly increased its temporal integration. Though all phases of the center's triphasic temporal response slowed, some shifted significantly less. Additionally, adaptation differentially shifted ON and OFF pathway temporal tuning, reducing their asymmetry under scotopic conditions. Finally, spatial integration was significantly increased by dark adaptation in some cells while it decreased it in others. These findings provide novel insight into how adaptation adjusts visual information processing by altering fundamental properties of ganglion cell receptive fields, such as center-surround antagonism and space-time integration. PMID- 28087446 TI - Editorial Comment. PMID- 28087447 TI - Structures, biological activities, and industrial applications of the polysaccharides from Hericium erinaceus (Lion's Mane) mushroom: A review. AB - Hericium erinaceus (Bull.) Pers., also known as Yamabushitake, Houtou and Lion's Mane, is capable of fortifying the spleen and nourishing the stomach, tranquilizing the mind, and fighting cancer. Over the past decade, it has been demonstrated that H. erinaceus polysaccharides possess various promising bioactivities, including antitumor and immunomodulation, anti-gastric ulcer, neuroprotection and neuroregeneration, anti-oxidation and hepatoprotection, anti hyperlipidemia, anti-hyperglycemia, anti-fatigue and anti-aging. The purpose of the present review is to provide systematically reorganized information on extraction and purification, structure characteristics, biological activities, and industrial applications of H. erinaceus polysaccharides to support their therapeutic potentials and sanitarian functions. PMID- 28087448 TI - Fabrication and characterization of electrospun cellulose/nano-hydroxyapatite nanofibers for bone tissue engineering. AB - Nanofibrous scaffolds from cotton cellulose and nano-hydroxyapatite (nano-HA) were electrospun for bone tissue engineering. The solution properties of cellulose/nano-HA spinning dopes and their associated electrospinnability were characterized. Morphological, thermal and mechanical properties of the electrospun cellulose/nano-HA nanocomposite nanofibers (ECHNN) were measured and the biocompatibility of ECHNN with human dental follicle cells (HDFCs) was evaluated. Scanning electron microscope (SEM) images indicated that the average diameter of ECHNN increased with a higher nano-HA loading and the fiber diameter distributions were well within the range of natural ECM (extra cellular matrix) fibers (50-500nm). The ECHNN exhibited extraordinary mechanical properties with a tensile strength and a Young's modulus up to 70.6MPa and 3.12GPa respectively. Moreover, it was discovered that the thermostability of the ECHNN could be enhanced with the incorporation of nano-HA. Cell culture experiments demonstrated that the ECHNN scaffolds were quite biocompatible for HDFCs attachment and proliferation, suggesting their great potentials as scaffold materials in bone tissue engineering. PMID- 28087449 TI - Highly biocompatible chitosan with super paramagnetic calcium ferrite (CaFe2O4) nanoparticle for the release of ampicillin. AB - The CaFe2O4 nanoparticles (CFNP) were synthesized using the solution combustion method. The CFNP-chitosan-ampicillin was prepared by the ionic gelation method using tripolyphosphate (TPP). The CFNP, chitosan-CFNP, chitosan-CFNP-ampicillin materials were characterized by XRD, FT-IR and TGA analysis in order to evaluate the particle nature and size, the presence of functional groups and their thermal stability. The FESEM and EDAX analysis were performed to understand the surface morphology of the materials and the presence of CFNP in the material, respectively. The vibrating sample magnetometer (VSM) analysis was performed to analyze the magnetic property of the chitosan-CFNP material. The squareness value of 0.1733 obtained by VSM measurements indicates the super paramagnetic nature of chitosan-CFNP. Taguchi orthogonal array method was applied to identify the significant impacting parameters for maximizing the drug encapsulation of chitosan-CFNP. The drug release studies showed that the drug was released rapidly in acidic medium as compared to the basic or neutral medium. The drug release kinetic data were fitted with different linear kinetic model equations and the best fit was obtained with Korsmeyer-Peppas model. The model drug ampicillin release from chitosan-CFNP was tested against staphylococcus epidermis bacteria through disc diffusion method for checking biocompatibility and antibacterial activity. PMID- 28087450 TI - Item response theory analysis to evaluate reliability and minimal clinically important change of the Roland-Morris Disability Questionnaire in patients with severe disability due to back pain from vertebral compression fractures. AB - BACKGROUND CONTEXT: The majority of validation done on the Roland-Morris Disability Questionnaire (RMDQ) has been in patients with mild or moderate disability. There is paucity of research focusing on the psychometric quality of the RMDQ in patients with severe disability. PURPOSE: To evaluate the psychometric quality of the RMDQ in patients with severe disability. STUDY DESIGN/SETTING: Observational clinical study. SAMPLE: The sample consisted of 214 patients with painful vertebral compression fractures who underwent vertebroplasty or kyphoplasty. OUTCOME MEASURES: The 23-item version of the RMDQ was completed at two time points: baseline and 30-day postintervention follow-up. METHODS: With the two-parameter logistic unidimensional item response theory (IRT) analyses, we derived the range of scores that produced reliable measurement and investigated the minimal clinically important difference (MCID). RESULTS: Scores for 214 (100%) patients at baseline and 108 (50%) patients at follow-up did not meet the reliability criterion of 0.90 or higher, with the majority of patients having disability due to back pain that was too severe to be reliably measured by the RMDQ. Depending on methodology, MCID estimates ranged from 2 to 8 points and the proportion of patients classified as having experienced meaningful improvement ranged from 26% to 68%. A greater change in score was needed at the extreme ends of the score scale to be classified as having achieved MCID using IRT methods. CONCLUSIONS: Replacing items measuring moderate disability with items measuring severe disability could yield a version of the RMDQ that better targets patients with severe disability due to back pain. Improved precision in measuring disability would be valuable to clinicians who treat patients with greater functional impairments. Caution is needed when choosing criteria for interpreting meaningful change using the RMDQ. PMID- 28087451 TI - In-depth comparative analysis of the chicken eggshell membrane proteome. AB - : The avian eggshell membrane (ESM) is stabilized by extensive cross-linkages, making the identification of its protein constituents technically challenging. Herein, we applied various extraction/solubilization conditions followed by proteomic analysis to characterize the protein constituents of ESM derived from the unfertilized chicken eggs. The egg white and eggshell proteomes (including previous published work) were determined and compared to ESM to identify proteins that are relatively or highly specific to ESM. Merging the results from different extraction/solubilization conditions with various proteomes allowed the identification of 472, 225, and 488 proteins in the ESM, egg white, and eggshell proteomes, respectively. Of these, 163 and 124 proteins were relatively or highly specific to ESM, respectively. GO term analysis of the common proteins and ESM unique proteins generated 8 and 9 significantly enriched functional groups, respectively. Different families of proteins that were identified as ESM-specific included collagens, CREMPs, histones, AvBDs, lysyl oxidase-like 2 (LOXL2), and ovocalyxin-36 (OCX36). These proteins serve as a foundation for the mechanically stable ESM that rests upon the egg white compartment and is a physical barrier against pathogen invasion. Overall, our results highlight the structural nature of the ESM constituents that are relevant to various biomedical applications, such as wound healing. BIOLOGICAL SIGNIFICANCE: The eggshell membranes (ESM) are a highly resilient double-layered fibrous meshwork that is secreted while the forming egg transits a specialized oviduct segment, the white isthmus. The ESM protects against pathogen invasion and provides a platform for nucleation of the calcitic eggshell (ES). ESM is greatly stabilized by the extensive desmosine, isodesmosine and disulfide cross-linkages which make the identification of its protein constituents by standard proteomic approaches technically challenging. Comparative proteomic analyses of ESM, egg white, and ES proteins showed proteins groups that are relatively or highly specific to ESM. These groups of proteins serve as a foundation for the mechanically stable ESM that rests upon the egg white compartment and is a physical barrier against pathogen invasion. These features are essential for eggshell quality and for the prevention of pathogen invasion which reinforce food safety of the table egg. PMID- 28087452 TI - Congenital Anonychia and Uncombable Hair Syndrome: Coinheritance of Homozygous Mutations in RSPO4 and PADI3. PMID- 28087453 TI - The impact of ISGylation during Mycobacterium tuberculosis infection in mice. AB - Mycobacterium tuberculosis infection results in 1.5 million deaths annually. Type I interferon (IFN) signaling through its receptor IFNAR correlates with increased severity of disease, although how this increases susceptibility to M. tuberculosis remains uncertain. ISG15 is one of the most highly induced interferon stimulated genes (ISGs) during M. tuberculosis infection. ISG15 functions by conjugation to target proteins (ISGylation), by noncovalent association with intracellular proteins, and by release from the cell. Recent studies indicated that ISG15 can function via conjugation-independent mechanisms to suppress the type I IFN response. These data raised the question of whether ISG15 may have diverse and sometimes opposing functions during M. tuberculosis infection. To address this, we analyzed ISGylation during M. tuberculosis infection and show that ISGylated proteins accumulate following infection in an IFNAR-dependent manner. Type I IFN and ISG15 both play transient roles in promoting bacterial replication. However, as the disease progresses, ISGylation deviates from the overall effect of type I IFN and, ultimately, mice deficient in ISGylation are significantly more susceptible than IFNAR mice. Our data demonstrate that ISGs can both protect against and promote disease and are the first to report a role for ISGylation during M. tuberculosis infection. PMID- 28087454 TI - An observational study of phagocytes and Klebsiella pneumoniae relationships: different behaviors. AB - Klebsiella pneumoniae is a bacterium that can be in relation with free living amoebae like Acanthamoeba castellanii in natural environments such as soil and water. This pathogen, which is responsible for community-acquired pneumonia and for nosocomial infections, also has interactions with host defense mechanisms like macrophages. As it has been shown that A. castellanii shares some traits with macrophages, in particular the ability to phagocyte bacteria, we have studied the uptake and the fate of the bacteria after contact with the two phagocytic cells. In our conditions, K. pneumoniae growth was increased in coculture in presence of A. castellanii or Thp-1 macrophagic cells and bacterial development was also increased by A. castellanii supernatant. In addition, we showed that the presence of the bacteria had a negative effect on the macrophages whereas it does not affect amoeba viability. Using gentamicin, which kills bacteria outside cells, we showed that only macrophages were able to internalize K. pneumoniae. This result was confirmed by electron microscopy. We have consequently reported some differences in bacterial uptake and internalization between a free living amoeba and macrophagic cells, highlighting the fact that results obtained with this amoebal model should not be extrapolated to the relationships between K. pneumoniae and macrophages. PMID- 28087455 TI - Correlation between antigenicity and variability in the vls antigenic variation system of Borrelia burgdorferi. AB - Many parasites have evolved antigenic variation systems that alter surface proteins in order to evade recognition by presently expressed antibodies and subsequent death. Although the amino acid positions in antigens to which antibodies most commonly target are expected to be the most variable, this assumption has not been investigated. Using the vls antigenic variation system of Borrelia burgdorferi as a model, we first investigated this assumption computationally and then developed a sensitive immunoassay to experimentally validate the computational results. There was a strong correlation between variability at an amino acid position and each of the computational metrics associated with antibody reactivity. However, empirical measures of antibody reactivity were not consistently greater at the variable amino acid positions than at the invariant amino acid positions. The inconsistent experimental support for this hypothesis suggests that the biological effect of variability at an amino acid position is obfuscated by other factors. PMID- 28087456 TI - Phase I Trial of Total Marrow and Lymphoid Irradiation Transplantation Conditioning in Patients with Relapsed/Refractory Acute Leukemia. AB - Current conditioning regimens provide insufficient disease control in relapsed/refractory acute leukemia patients undergoing hematopoietic stem cell transplantation (HSCT) with active disease. Intensification of chemotherapy and/or total body irradiation (TBI) is not feasible because of excessive toxicity. Total marrow and lymphoid irradiation (TMLI) allows for precise delivery and increased intensity treatment via sculpting radiation to sites with high disease burden or high risk for disease involvement, while sparing normal tissue. We conducted a phase I trial in 51 patients (age range, 16 to 57 years) with relapsed/refractory acute leukemia undergoing HSCT (matched related, matched unrelated, or 1-allele mismatched unrelated) with active disease, combining escalating doses of TMLI (range, 1200 to 2000 cGy) with cyclophosphamide (CY) and etoposide (VP16). The maximum tolerated dose was declared at 2000 cGy, as TMLI simulation studies indicated that >2000 cGy might deliver doses toxic for normal organs at or exceeding those delivered by standard TBI. The post-transplantation nonrelapse mortality (NRM) rate was only 3.9% (95% confidence interval [CI], .7 to 12.0) at day +100 and 8.1% (95% CI, 2.5 to 18.0) at 1 year. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 43.1% (95% CI, 29.2 to 56.3) and for grade III and IV, it was 13.7% (95% CI, 6.9 to 27.3). The day +30 complete remission rate for all patients was 88% and was 100% for those treated at 2000 cGy. The overall 1-year survival was 55.5% (95% CI, 40.7 to 68.1). The TMLI/CY/VP16 conditioning regimen is well tolerated at TMLI doses up to 2000 cGy with a low 100-day and 1-year NRM rate and no increased risk of GVHD with higher doses of radiation. PMID- 28087457 TI - T Cell-Replete Peripheral Blood Haploidentical Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide Results in Outcomes Similar to Transplantation from Traditionally Matched Donors in Active Disease Acute Myeloid Leukemia. AB - Outcomes for patients with acute myeloid leukemia (AML) who fail to achieve complete remission remain poor. Hematopoietic cell transplantation (HCT) has been shown to induce long-term survival in AML patients with active disease. HCT is largely performed with HLA-matched unrelated or HLA-matched related donors. Recently, HCT with HLA-haploidentical related donors has been identified as a feasible option when HLA-matched donors are not immediately available. However, there are little data comparing outcomes for AML patients with active disease who receive haploidentical versus traditionally matched HCT. We retrospectively analyzed data from 99 AML patients with active disease undergoing allogeneic HCT at a single institution. Forty-three patients received unrelated donor HCT, 32 patients received matched related donor HCT, and 24 patients received peripheral blood haploidentical HCT with post-transplantation cyclophosphamide. We found no significant differences between treatment groups in terms of overall survival (OS), event-free survival, transplantation-related mortality, cumulative incidence of relapse, and cumulative incidence of acute and chronic graft-versus host disease (GVHD). We performed univariate regression analysis of variables that modified OS in all patients and found only younger age at transplantation and development of chronic GVHD significantly improved outcome. Although limited by our relatively small sample size, these results indicate that haploidentical HCT in active AML patients have comparable outcomes to HCT with traditionally matched donors. Haploidentical HCT can be considered in this population of high risk patients when matched donors are unavailable or when wait times for transplantation are unacceptably long. PMID- 28087458 TI - Medication Adherence in Hematopoietic Stem Cell Transplantation: A Review of the Literature. AB - Adherence to oral medications has been repeatedly shown to fall below the recommended 80% to 95% in pediatric and adult cancer populations. The purpose of this review is to report the state of the science about oral medication adherence during the acute phase of hematopoietic stem cell transplantation across the lifespan. An exhaustive search of the literature yielded 5 records for inclusion in the review. Two studies examined adherence in pediatrics, 2 in adults, and 1 included both pediatric and adult patients. Three studies were descriptive and 2 were interventional in design. The rate of adherence to oral medications ranged from 33% to 94.7%. Adherence decreased over time in all studies except in 1 pharmacist-led intervention study. Different methods were used to measure adherence, but most relied on self-report. Further research is needed in medication adherence in hematopoietic stem cell transplantation to better understand facilitators, barriers, and relationships to health outcomes. PMID- 28087460 TI - Identification of the Doublesex protein binding sites that activate expression of lozenge in the female genital disc in Drosophila melanogaster. AB - Normal sexual differentiation in the genital organs is essential for the animal species that use sexual reproduction. Although it is known that doublesex (dsx) is required for the sexual development of the genitalia in various insect species, the direct target genes responsible for the sexual differentiation of the genitalia have not been identified. The lozenge (lz) gene is expressed in the female genital disc and is essential for developments of spermathecae and accessory glands in Drosophila melanogaster. The female-specific isoform of DSX (DSXF) is required for activating lz expression in the female genital disc. However, it still remains unclear whether the DSXF directly activates the transcription of lz in the female genital disc. In this study, we found two sequences (lz-DBS1 and lz-DBS2) within lz locus that showed high homoloty to the DSX binding motif identified previously. Competition assays using recombinant DSX DNA-binding domain (DSX-DBD) protein verified that the DSX-DBD protein bound to lz-DBS1 and lz-DBS2 in a sequence-specific manner with lower affinity than to the known DSX binding site in the bric-a-brac 1 (bab1) gene. Reporter gene analyses revealed that a 2.5-kbp lz genomic fragment containing lz-DBS1 and lz-DBS2 drove reporter gene (EGFP) expression in a manner similar to endogenous lz expression in the female genital disc. Mutations in lz-DBS1 alone significantly reduced the area of EGFP-expressing region, while EGFP expression in the female genital disc was abolished when both sites were mutated. These results demonstrated that DSX directly activates female-specific lz expression in the genital disc through lz DBS1 and lz-DBS2. PMID- 28087459 TI - Wnt signaling balances specification of the cardiac and pharyngeal muscle fields. AB - Canonical Wnt/beta-catenin (Wnt) signaling plays multiple conserved roles during fate specification of cardiac progenitors in developing vertebrate embryos. Although lineage analysis in ascidians and mice has indicated there is a close relationship between the cardiac second heart field (SHF) and pharyngeal muscle (PM) progenitors, the signals underlying directional fate decisions of the cells within the cardio-pharyngeal muscle field in vertebrates are not yet understood. Here, we examined the temporal requirements of Wnt signaling in cardiac and PM development. In contrast to a previous report in chicken embryos that suggested Wnt inhibits PM development during somitogenesis, we find that in zebrafish embryos Wnt signaling is sufficient to repress PM development during anterior posterior patterning. Importantly, the temporal sensitivity of dorso-anterior PMs to increased Wnt signaling largely overlaps with when Wnt signaling promotes specification of the adjacent cardiac progenitors. Furthermore, we find that excess early Wnt signaling can cell autonomously promote expansion of the first heart field (FHF) progenitors at the expense of PM and SHF within the anterior lateral plate mesoderm (ALPM). Our study provides insight into an antagonistic developmental mechanism that balances the sizes of the adjacent cardiac and PM progenitor fields in early vertebrate embryos. PMID- 28087461 TI - Low glucose stress decreases cellular NADH and mitochondrial ATP in colonic epithelial cancer cells: Influence of mitochondrial substrates. AB - In this study, we investigated how colonic epithelial cells maintained pyridine nucleotide (NADH/NAD+) redox homeostasis upon acute metabolic variation imposed by glucose deprivation or supplementation with mitochondrial substrates, succinate and malate/glutamate (M/G). Our results showed that low glucose caused cellular NADH/NAD+ redox imbalance that diminished lactate dehydrogenase (LDH) activity and resulted in lower lactate contents. The concurrent activation of malic enzyme (ME) suggested a role for malate in preserving cellular pyruvate that remained unchanged at low glucose. Mitochondrial substrates restored cellular NADH/NAD+ redox homeostasis at low glucose in association with specific compartmental catabolism of mitochondrial substrates. As compared with normal glucose, M/G and low glucose promoted glycolytic ATP production but inhibited mitochondrial-derived ATP generation in association with decreased glucose availability for mitochondrial respiration. At normal glucose, succinate and M/G enhanced mitochondrial respiratory activity, but had minimal impact on mitochondrial-derived ATP production. Collectively, these results are consistent with low glucose-induced NADH/NAD+ redox imbalance in association with decreased aerobic glycolysis that is reversed by supplementation with M/G but not succinate. PMID- 28087462 TI - Impact of disease-Linked mutations targeting the oligomerization interfaces of aldehyde dehydrogenase 7A1. AB - Aldehyde dehydrogenase 7A1 (ALDH7A1) is involved in lysine catabolism, catalyzing the oxidation of alpha-aminoadipate semialdehyde to alpha-aminoadipate. Certain mutations in the ALDH7A1 gene, which are presumed to reduce catalytic activity, cause an autosomal recessive seizure disorder known as pyridoxine-dependent epilepsy (PDE). Although the genetic association between ALDH7A1 and PDE is well established, little is known about the impact of PDE-mutations on the structure and catalytic function of the enzyme. Herein we report the first study of the molecular consequences of PDE mutations using purified ALDH7A1 variants. Eight variants, with mutations in the oligomer interfaces, were expressed in Escherichia coli: P78L, G83E, A129P, G137V, G138V, A149E, G255D, and G263E. All but P78L and G83E were soluble and could be purified. All six soluble mutants were catalytically inactive. The impact of the mutations on oligomerization was assessed by analytical ultracentrifugation. Wild-type ALDH7A1 is shown to exist in a dimer-tetramer equilibrium with a dissociation constant of 16 MUM. In contrast to the wild-type enzyme, the variants reside in monomer-dimer equilibria and are apparently incapable of forming a tetrameric species, even at high enzyme concentration. The available evidence suggests that they are misfolded assemblies lacking the three-dimensional structure required for catalysis. PMID- 28087464 TI - Mitochondrial reactive oxygen species regulate fungal protease-induced inflammatory responses. AB - Epidemiological studies have shown that fungal infections are a main cause of respiratory tract diseases, such as asthma, bronchopneumonia, intoxication, and invasive fungal disease. Fungi such as Aspergillus and Candida species have become increasingly important pathogens as the global climate changes. Accordingly, in this study, we evaluated the toxicological potential of Aspergillus protease in the lower respiratory tract. Exposure of Aspergillus protease to A549 cells induced upregulation of tumor necrosis factor (TNF)-alpha, monocyte chemoattractant protein (MCP)-1, and intercellular adhesion molecule (ICAM)-1 mRNAs and increased production of interleukin (IL)-8 and MCP-1 protein through enhanced mitochondrial reactive oxygen species (ROS) generation and activation of mitogen-activated protein kinase (MAPK) and activator protein (AP) 1. Furthermore, the mitochondrial ROS scavenger Mito-TEMPO, which inhibited MAPK and AP-1, significantly reduced MCP-1 and IL-1beta mRNA expression and reduced HL 60 cell migration through the suppression of MCP-1 and IL-8 protein secretion. Thus, our results demonstrated that mitochondria were an important source of Aspergillus protease-stimulated ROS and that regulation of mitochondrial ROS modulated inflammatory responses by preventing activation of MAPK and AP-1 in A549 cells. PMID- 28087463 TI - Effect of 22 CYP2D6 variants found in the Chinese population on tolterodine metabolism in vitro. AB - Cytochrome P450 2D6 (CYP2D6) is an important member of the cytochrome P450 enzyme superfamily. We recently identified 22 novel variants in the Chinese population using PCR and bidirectional sequencing methods. The aim of this study is to characterize the enzymatic activity of these variants and their effects on the metabolism of the antimuscarinic drug tolterodine in vitro. A baculovirus mediated expression system was used to express wild-type CYP2D6 and 24 variants (CYP2D6*2, CYP2D6*10, and 22 novel CYP2D6 variants) at high levels. The insect microsomes expressing CYP2D6 proteins were incubated with 0.1-50 MUM tolterodine at 37 degrees C for 30 min and the metabolites were analyzed by high-performance liquid chromatography-tandem mass spectrometry system. Of the 24 CYP2D6 variants tested, 2 variants (CYP2D6*92 and CYP2D6*96) were found to be catalytically inactive, 4 variants (CYP2D6*94, F164L, F219S and D336N) exhibited markedly increased intrinsic clearance values (Vmax/Km) compared with the wild-type (from 66.34 to 99.79%), whereas 4 variants (CYP2D6*10, *93, *95 and E215K) exhibited significantly decreased values (from 49.02 to 98.50%). This is the first report of all these rare alleles for tolterodine metabolism and these findings suggest that more attention should be paid to subjects carrying these infrequent CYP2D6 alleles when administering tolterodine in the clinic. PMID- 28087465 TI - Are cardiovascular disease risk assessment and management programmes cost effective? A systematic review of the evidence. AB - The World Health Organization recommends that countries implement population-wide cardiovascular disease (CVD) risk assessment and management programmes. The aim of this study was to conduct a systematic review to evaluate whether this recommendation is supported by cost-effectiveness evidence. Published economic evaluations were identified via electronic medical and social science databases (including Medline, Web of Science, and the NHS Economic Evaluation Database) from inception to March 2016. Study quality was evaluated using a modified version of the Consolidated Health Economic Evaluation Reporting Standards. Fourteen economic evaluations were included: five studies based on randomised controlled trials, seven studies based on observational studies and two studies using hypothetical modelling synthesizing secondary data. Trial based studies measured CVD risk factor changes over 1 to 3years, with modelled projections of longer term events. Programmes were either not, or only, cost-effective under non verified assumptions such as sustained risk factor changes. Most observational and hypothetical studies suggested programmes were likely to be cost-effective; however, study deigns are subject to bias and subsequent empirical evidence has contradicted key assumptions. No studies assessed impacts on inequalities. In conclusion, recommendations for population-wide risk assessment and management programmes lack a robust, real world, evidence basis. Given implementation is resource intensive there is a need for robust economic evaluation, ideally conducted alongside trials, to assess cost effectiveness. Further, the efficiency and equity impact of different delivery models should be investigated, and also the combination of targeted screening with whole population interventions recognising that there multiple approaches to prevention. PMID- 28087466 TI - "Monkey see, monkey do": Peers' behaviors predict preschoolers' physical activity and dietary intake in childcare centers. AB - Preschoolers observe and imitate the behaviors of those who are similar to them. Therefore, peers may be role models for preschoolers' dietary intake and physical activity in childcare centers. This study examined whether peers' behaviors predict change in preschoolers' dietary intake and physical activity in childcare centers over 9months. A total of 238 preschoolers (3 to 5years old) from 23 childcare centers in two Canadian provinces provided data at the beginning (October 2013 and 2014) and the end (June 2014 and 2015) of a 9-month period for this longitudinal study. Dietary intake was collected at lunch using weighed plate waste and digital photography on two consecutive weekdays. Physical activity was assessed using accelerometers over five days. Multilevel linear regressions were used to estimate the influence of peers' behaviors on preschoolers' change in dietary intake and physical activity over 9months. Results showed that preschoolers whose dietary intake or physical activity level deviated the most from those of their peers at the beginning of the year demonstrated greater change in their intakes and activity levels over 9months, which enabled them to become more similar to their peers (all beta 95% CI ranged from -0.835 to -0.074). This study suggests that preschoolers' dietary intake and physical activity may be influenced by the behaviors of their peers in childcare centers. Since peers could play an important role in promoting healthy eating behaviors and physical activity in childcare centers, future studies should test interventions based on positive role modeling by children. PMID- 28087467 TI - Positive childhood experiences and ideal cardiovascular health in midlife: Associations and mediators. AB - In 2010, the American Heart Association introduced a new conceptual framework to encourage a focus on primary prevention and provided a definition for "ideal cardiovascular health". In this study we examined the relationship between positive childhood experience and ideal cardiovascular health in mid-life, and the extent to which education, depression, and social support mediate this association. Data are from participants in the Midlife and Aging in the United States study who completed a clinic-based assessment of health (N=1255, aged 34 84years, 2004-2005). We created a positive childhood experiences index based on retrospective report of eight childhood experiences, and calculated a continuous ideal cardiovascular health score for each participant following the American Heart Association's definition of ideal, intermediate and poor cardiovascular health across seven health metrics (analyses conducted in 2015-2016). Positive childhood experiences were associated with ideal cardiovascular health: compared to individuals in the lowest quartile, respondents in the second, third, and fourth quartile of positive childhood experiences scored 0.42 (standard error (SE)=0.18), 0.92 (SE=0.18) and 1.04 (SE=0.18) units higher on ideal cardiovascular health, adjusting for age, sex, and race. Respondent's education, depression status, and social support fully mediated the direct effect of positive childhood experiences on ideal cardiovascular health, with the largest indirect effect for education. These results suggest that positive childhood experiences are associated with ideal cardiovascular health in midlife. Strategies to promote cardiovascular wellbeing may benefit from a focus on social interventions early in life; educational attainment, major depression, and social support may represent key points of intervention. PMID- 28087468 TI - Smoking selectivity among Mexican immigrants to the United States using binational data, 1999-2012. AB - Mexican immigrants have lower smoking rates than US-born Mexicans, which some scholars attribute to health selection-that individuals who migrate are healthier and have better health behaviors than their non-migrant counterparts. Few studies have examined smoking selectivity using binational data and none have assessed whether selectivity remains constant over time. This study combined binational data from the US and Mexico to examine: 1) the extent to which recent Mexican immigrants (<10years) in the US are selected with regard to cigarette smoking compared to non-migrants in Mexico, and 2) whether smoking selectivity varied between 2000 and 2012-a period of declining tobacco use in Mexico and the US. We combined repeated cross-sectional US data (n=10.901) on adult (ages 20-64) Mexican immigrants and US-born Mexicans from the 1999/2000 and 2011/2012 National Health Interview Survey, and repeated cross-sectional Mexican data on non migrants (n=67.188) from the 2000 Encuesta Nacional de Salud and 2012 Encuesta Nacional de Salud y Nutricion. Multinomial logistic regressions, stratified by gender, predicted smoking status (current, former, never) by migration status. At both time points, we found lower overall smoking prevalence among recent US immigrants compared to non-migrants for both genders. Moreover, from the regression analyses, smoking selectivity remained constant between 2000 and 2012 among men, but increased among women. These findings suggest that Mexican immigrants are indeed selected on smoking compared to their non-migrating counterparts, but that selectivity is subject to smoking conditions in the sending countries and may not remain constant over time. PMID- 28087469 TI - Tofacitinib ameliorates inflammation in a rat model of airway neutrophilia induced by inhaled LPS. AB - BACKGROUND AND PURPOSE: The Janus Kinase (JAK) family mediates the cytokine receptor-induced signalling pathways involved in inflammatory processes. The activation of the signal transducers and activators of transcription (STATs) by JAK kinases is a key point in these pathways. Four JAK proteins, JAK1, JAK2, JAK3 and tyrosine kinase 2 (Tyk2) associate with the intracellular domains of surface cytokine receptors are phosphorylating STATs and modulating gene expression. The aim of this study was to explore the role of JAK inhibition in an acute model of inhaled lipopolysaccharide (LPS)-induced airway inflammation in rats through evaluating the effects of tofacitinib, a marketed pan-JAK inhibitor. Specifically, some pulmonary inflammation parameters were studied and the lung STAT3 phosphorylation was assessed as a target engagement marker of JAK inhibition in the model. EXPERIMENTAL APPROACH: Rats were exposed to an aerosol of LPS (0.1 mg/ml) or phosphate-buffered saline (PBS) during 40 min. Bronchoalveolar lavage fluid (BALF) and lung samples were collected 4 h after PBS or LPS exposure. Neutrophils in BALF were counted and a panel of cytokines were measured in BALF. Phosphorylation of STAT3 was studied in lung homogenates by ELISA and localization of phospho-STAT3 (pSTAT3) in lung tissue was also evaluated by immunohistochemistry. In order to assess the effect of JAK inhibition, tofacitinib was administered 1 h before challenge at doses of 3, 10 and 30 mg/kg p.o. KEY RESULTS: Inhaled LPS challenge induced an augment of neutrophils and cytokines in the BALF as well as an increase in pSTAT3 expression in the lungs. Tofacitinib by oral route inhibited the LPS-induced airway neutrophilia, the levels of some cytokines in the BALF and the phosphorylation of STAT3 in the lung tissue. CONCLUSIONS AND IMPLICATIONS: In summary, this study shows that JAK inhibition ameliorates inhaled LPS-induced airway inflammation in rats, suggesting that at least JAK/STAT3 signalling is involved in the establishment of the pulmonary neutrophilia induced by LPS. JAKs inhibitors should be further investigated as a potential therapy for respiratory inflammatory diseases. PMID- 28087470 TI - A development and an improvement of selectable markers in Pleurotus ostreatus transformation. AB - Pleurotus ostreatus was transformed using the nourseothricin-resistant gene for the first time. The transformation efficiency was 1.3+/-0.6transformants/MUg plasmid DNA. In addition, the transformation efficiency of the bialaphos resistant gene was increased to 26.7+/-11.5transformants/MUg plasmid DNA. PMID- 28087471 TI - IL-6 promotes M2 macrophage polarization by modulating purinergic signaling and regulates the lethal release of nitric oxide during Trypanosoma cruzi infection. AB - The production of nitric oxide (NO) is a key defense mechanism against intracellular pathogens but it must be tightly controlled in order to avoid excessive detrimental oxidative stress. In this study we described a novel mechanism through which interleukin (IL)-6 mediates the regulation of NO release induced in response to Trypanosoma cruzi infection. Using a murine model of Chagas disease, we found that, in contrast to C57BL/6 wild type (WT) mice, IL-6 deficient (IL6KO) mice exhibited a dramatic increase in plasma NO levels concomitant with a significantly higher amount of circulating IL-1beta and inflammatory monocytes. Studies on mouse macrophages and human monocytes, revealed that IL-6 decreased LPS-induced NO production but this effect was abrogated in the presence of anti-IL-1beta and in macrophages deficient in the NLRP3 inflammasome. In accordance, while infected WT myocardium exhibited an early shift from microbicidal/M1 to anti-inflammatory/M2 macrophage phenotype, IL6KO cardiac tissue never displayed a dominant M2 macrophage profile that correlated with decreased expression of ATP metabolic machinery and a lower cardiac parasite burden. The deleterious effects of high NO production-induced oxidative stress were evidenced by enhanced cardiac malondialdehyde levels, myocardial cell death and mortality. The survival rate was improved by the treatment of IL-6-deficient mice with a NO production-specific inhibitor. Our data revealed that IL-6 regulates the excessive release of NO through IL-1beta inhibition and determines the establishment of an M2 macrophage profile within infected heart tissue. PMID- 28087472 TI - Extract of Clinopodium bolivianum protects against E. coli invasion of uroepithelial cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Clinopodium bolivianum is a South American plant with anti-inflammatory and anti-infective activities. The increasing antibiotic resistance urges for alternative therapy. Based on its use in traditional medicine, we investigated the effect of C. bolivianum on the ability to defend bladder epithelial cells from E. coli infection. MATERIALS AND METHODS: The extract was analyzed by LC-MS. Bladder epithelial cell lines T24 and 5637 and uropathogenic E. coli No. 12, its isogenic mutant WE16 csgBA bscA::Cm and CFT073 were used to investigate the effect of C. bolivianum on uroepithelial infection. Bacterial adherence and invasion to cells treated with C. bolivianum were analyzed. Expression of uroplakin 1a, beta1 integrin, caveolin-1, IL-8 and antimicrobial peptides in response to C. bolivianum treatment was assessed using RT-PCR. Protein expression was confirmed by Western blot analysis or ELISA. The antimicrobial effects of C. bolivianum on bacteria and fungus were investigated using minimum inhibitory concentration. Furthermore, the formation of biofilm was investigated with crystal violet assay. RESULTS: C. bolivianum extract consisted of more than 70 different types of phytochemicals including sugars and phenolic compounds. The extract decreased the uroplakin 1a expression and E. coli adhesion and invasion of uroepithelial cells while up-regulated caveolin-1. In uninfected C. bolivianum treated cells, IL-8 was lower than in non-treated cells. In infected cells, however, no difference was observed between treated and non treated cells. Further, C. bolivianum treatment reduced uropathogenic E. coli (UPEC) biofilms but did not inhibit bacterial growth. CONCLUSIONS: Our results show that C. bolivianum has a protective role on bladder epithelial cells against UPEC infection by decreasing the bacterial adhesion, invasion and biofilm formation. PMID- 28087473 TI - Salvianolic Acids for Injection (SAFI) suppresses inflammatory responses in activated microglia to attenuate brain damage in focal cerebral ischemia. AB - BACKGROUND: Inflammatory reactions induced by microglia in the brain play crucial roles in ischemia/reperfusion (I/R) cerebral injuries. Microglia activation has been shown to be closely related to TLR4/NF-kappaB signal pathways. Salvianolic acids for injection (SAFI) have been used in clinical practice to treat ischemic stroke with reported neuroprotective effects; however, the underlying mechanisms are still uncertain. OBJECTIVE AND METHODS: First, we studied the effect of SAFI on inflammatory responses in LPS-stimulated BV-2 microglia. Then, to discover whether the beneficial in vitro effects of SAFI lead to in vivo therapeutic effects, an MCAO (Middle cerebral artery occlusion) rat model was further employed to elucidate the probable mechanism of SAFI in treating ischemic stroke. Rats in the SAFI group were given SAFI (23 or 46mg/kg) before I/R injury. RESULTS: The results showed that SAFI treatment significantly decreased neuroinflammation and the infarction volume compared with the vehicle group. Activation of microglia cells was reduced, and TLR4/NF-kappaB signals, which were markedly inhibited by SAFI treatment in ischemic hemisphere, were accompanied by reduced expression and release of cytokines IL-1beta and IL-6. CONCLUSION: This study provides evidence that SAFI effectively protects the brain after cerebral ischemia, which may be caused by attenuating inflammation in microglia. PMID- 28087474 TI - FOXO1 down-regulation is associated with worse outcome in bladder cancer and adds significant prognostic information to p53 overexpression. AB - Nuclear FOXOs mediate cell cycle arrest and promote apoptosis. FOXOs and p53 could have similar effects as tumor suppressor genes. In spite of extensive literature, little is known about the role of FOXO1 and its relationship with p53 status in bladder cancer. Expression of FOXO1 and p53 were analyzed by immunohistochemistry in 162 urothelial carcinomas (UC). Decreased FOXO1 expression, p53 overexpression and the combination FOXO1 down-regulation/p53 overexpression were strongly associated with high grade (P=.030; P=.017; P=.004, respectively), high stage (P=.0001; P<.0001; P<.0001, respectively) or both (P=.0004; P<.0001; P<.0001, respectively). In the overall series of cases, p53 overexpression was associated with tumor progression (hazard ratio [HR]=3.18, 95% confidence interval [CI] 1.19-8.48, P=.02), but this association was even stronger if having any alteration in any of the 2 genes was considered (HR=3.51, 95% CI 1.34-9.21, P=.01). Having both FOXO1 down-regulation and p53 overexpression was associated with disease recurrence (HR=2.75, 95% CI 1.06-7.13, P=.03). In the analysis of the different subgroups, having any alteration in any of the 2 genes was associated with progression in low-grade (P=.005) and pTa (P=.006) tumors. Finally, the combined FOXO1 down-regulation/p53 overexpression was associated with disease recurrence specifically in high-grade (P=.04) and in pT1 stage tumors (P=.007). Adding FOXO1 expression to the immunohistochemical analysis of p53 can provide relevant prognostic information on progression and recurrence of bladder cancer. It may be particularly informative on the risk of progression in the more indolent and on the risk of recurrence in the more aggressive tumors. PMID- 28087475 TI - Immunohistochemical approach for the diagnosis of a liver mass on small biopsy specimens. AB - Well-differentiated hepatocellular carcinoma (HCC) shares overlapping histological features with benign hepatocellular lesions, including hepatocellular adenoma and focal nodular hyperplasia in non-cirrhotic liver, and with high-grade dysplastic nodule in cirrhotic liver. Several metastatic tumors, such as neuroendocrine tumor, renal cell carcinoma, adrenocortical carcinoma, melanoma, and epithelioid angiomyolipoma, can be indistinguishable from HCC on histologic grounds. Since this distinction has important therapeutic implications, judicious use of immunohistochemical markers plays an important role in establishing an accurate diagnosis, especially when limited material of tumor is available on cell block or a small core biopsy. This review describes commonly used immunohistochemical markers used in the diagnosis of HCC, highlighting advantages and disadvantages of each marker, and suggests appropriate immunohistochemical panels for specific clinicopathologic situations. PMID- 28087476 TI - Phospholipase D messenger RNA expression and clinical role in high-grade serous carcinoma. AB - The objective of this study was to analyze the expression and clinical role of phospholipase D (PLD) in high-grade serous carcinoma (HGSC). PLD1 and PLD2 isoform expression was studied in 125 HGSC specimens (73 effusions, 28 ovarian tumors, 24 solid metastases) using quantitative real-time reverse-transcription polymerase chain reaction. Expression levels were analyzed for association with clinicopathological parameters, including chemoresponse, and survival. PLD1 and PLD2 isoforms were found in most specimens at all anatomic sites, and their levels were strongly positively related (P<.001 for effusions and solid lesions). PLD2 messenger RNA (mRNA) expression was significantly higher in effusions compared with both carcinomas in the ovary and solid metastases (P<.001). Higher levels of both isoforms were associated with higher CA 125 levels at diagnosis (P<.001), and higher PLD2 mRNA levels in effusions were associated with unfavorable response to chemotherapy (P=.021). Expression levels of the studied isoforms were unrelated to the levels of previously studied mRNAs that form part of the phospholipase A2 pathway or to survival. The present study provides the first evidence of PLD expression in HGSC and suggests a role in mediating progression to effusions and chemoresistance in this cancer. PMID- 28087477 TI - Overexpression of TNFAIP8 is associated with tumor aggressiveness and poor prognosis in patients with invasive ductal breast carcinoma. AB - Tumor necrosis factor alpha-induced protein 8 (TNFAIP8), a transcription factor nuclear factor kappaB-inducible, antiapoptotic and oncogenic molecule, is associated with prognosis of several human malignancies. However, the relationship between TNFAIP8 and the prognosis of the invasive ductal carcinoma (IDC) of the breast remains unclear. TNFAIP8 expression was evaluated using real time polymerase chain reaction (PCR) and Western blot analysis in 20 fresh IDC tissues and immunohistochemical analysis in 351 paraffin-embedded IDC tissues. Real-time PCR and Western blot analysis demonstrated that both TNFAIP8 messenger RNA and protein were up-regulated in IDC tissues compared with the paired adjacent noncancerous tissues. Immunohistochemistry revealed that TNFAIP8 expression was significantly correlated with some clinicopathological factors, including axillary lymph node metastasis (P=.001), advanced TNM stage (P<.001), high histologic grade (P<.001), molecular subtype (P<.001), and postoperative recurrence (P<.001). Univariate and multivariate logistic regression analyses demonstrated that TNFAIP8 overexpression was strongly associated with axillary lymph node metastasis (odds ratio, 1.818; 95% confidence interval, 1.167-2.832; P=.008). Moreover, Kaplan-Meier analysis indicated that IDC patients with high TNFAIP8 expression had a shorter survival time than did those with low TNFAIP8 expression, and multivariate analysis indicated that TNFAIP8 was an independent prognostic factor for overall survival and disease-free survival in IDC (P=.041 and P=.020, respectively). Therefore, TNFAIP8 overexpression may contribute to tumor progression, and it may be a novel prognostic biomarker for the patients with IDC. PMID- 28087478 TI - Renal involvement in lysinuric protein intolerance: contribution of pathology to assessment of heterogeneity of renal lesions. AB - Lysinuric protein intolerance (LPI) is a rare autosomal recessive disease caused by mutations in the SLC7A7 gene encoding the light subunit of a cationic amino acid transporter. Symptoms mimic primary urea cycle defects but dysimmune symptoms are also described. Renal involvement in LPI was first described in the 1980s. In 2007, it appeared that it could concern as much as 75% of LPI patients and could lead to end-stage renal disease. The most common feature is proximal tubular dysfunction and nephrocalcinosis but glomerular lesions are also reported. However, very little is known regarding histological lesions associated with LPI. We gathered every kidney biopsy of LPI-proven patients in our highly specialized pediatric and adult institution. Clinical, biological, and histological information was analyzed. Five LPI patients underwent kidney biopsy in our institution between 1986 and 2015. Clinically, 4/5 presented with proximal tubular dysfunction and 3/5 with nephrotic range proteinuria. Histology showed unspecific tubulointerstitial lesions and nephrocalcinosis in 3/5 biopsies and marked peritubular capillaritis in one child. Glomerular lesions were heterogeneous: lupus-like-full house membranoproliferative glomerulonephritis (MPGN) in one child evolved towards monotypic IgG1kappa MPGN sensitive to immunomodulators. One patient presented with glomerular non-AA non-AL amyloidosis. Renal biopsy is particularly relevant in LPI presenting with glomerular symptoms for which variable histological lesions can be responsible, implying specific treatment and follow-up. PMID- 28087479 TI - Synthesis and characterization of gold nanostructured Chorin e6 for Photodynamic Therapy. AB - Photodynamic therapy is an alternative treatment for cancer based on cellular uptake of a photosensitizer, illuminated with an appropriate wavelength in the presence of oxygen. A cascade of reactions generates reactive oxygen species leading to cell death. Using carbodiimide chemistry, chlorin e6 (Ce6) was covalently bonded to thiourea, and (via the sulphur end group) to gold nanoparticles (AuNPs), forming the Ce6-AuNP complex. Ce6 absorbs in the range 650 680nm, where the coefficient of biological tissue absorption is low (part of the therapeutic window), which is ideal for biological application. Transmission Electron Microscopy, UV-vis spectroscopy, Fourier transform Infrared Spectroscopy and Zeta potential measurements were completed to characterize the Ce6-AuNP complex. The bare AuNPs have an average diameter of 18+/-4nm. A line of human breast carcinoma cells (MDA-MB-468) was used to determine whether Ce6 functionalization to AuNPs potentiate its activity. Trypan blue assays were used to assess cell viability. In the absence of light, Ce6 either alone or bounded to AuNPs was not cytotoxic. When irradiated at 660nm, the cytotoxicity of Ce6-AuNP was higher than Ce6 alone for MDA-MB-468 cells using 4h incubation. AuNPs without Ce6 showed no cytotoxic. PMID- 28087480 TI - The Role of Opportunistic Bilateral Salpingectomy vs Tubal Occlusion or Ligation for Ovarian Cancer Prophylaxis. AB - Bilateral tubal ligation (BTL) for sterilization has been known to decrease the risk of ovarian cancer. Recent studies have suggested that bilateral salpingectomy (BS) may be an alternative to BTL or tubal occlusion for women desiring permanent sterilization, owing to a possibly greater protective effect against ovarian cancer. We conducted a PubMed/MEDLINE review of the literature for original studies, opinion articles, and meta-analyses published between 2010 and 2016 addressing the role of BS at the time of sterilization and comparing its efficacy with BTL in terms of ovarian cancer prevention, operative outcomes, and ovarian function. BTL has been found to decrease the risk of any ovarian cancer by 13% to 41%, compared with 42% to 78% for BS. Although operative time is increased with BS compared with BTL, no differences in complication rates or ovarian reserve between the 2 procedures have been demonstrated. Our review suggests that BS should be discussed when BTL is being considered, and that patients should be counseled about the risks and benefits of both procedures based on the current available evidence. PMID- 28087481 TI - Transrectal Mesh Erosion Requiring Bowel Resection. AB - STUDY OBJECTIVE: To report a case of a transrectal mesh erosion as complication of laparoscopic promontofixation with mesh repair, necessitating bowel resection and subsequent surgical interventions. INTRODUCTION: Sacrocolpopexy has become a standard procedure for vaginal vault prolapse [1], and the laparoscopic approach has gained popularity owing to more rapid recovery and less morbidity [2,3]. Mesh erosion is a well-known complication of surgical treatment for prolapse as reported in several negative evaluations, including a report from the US Food and Drug Administration in 2011 [4]. Mesh complications are more common after surgeries via the vaginal approach [5]; nonetheless, the incidence of vaginal mesh erosion after laparoscopic procedures is as high as 9% [6]. The incidence of transrectal mesh exposure after laparoscopic ventral rectopexy is roughly 1% [7]. The diagnosis may be delayed because of its rarity and variable presentation. In addition, polyester meshes, such as the mesh used in this case, carry a higher risk of exposure [8]. CASE REPORT: A 57-year-old woman experiencing genital prolapse, with the cervix classified as +3 according to the Pelvic Organ Prolapse Quantification system, underwent laparoscopic standard sacrocolpopexy using polyester mesh. Subtotal hysterectomy and bilateral adnexectomy were performed concomitantly. A 3-year follow-up consultation demonstrated no signs or symptoms of erosion of any type. At 7 years after the surgery, however, the patient presented with rectal discharge, diagnosed as infectious rectocolitis with the isolation of Clostridium difficile. She underwent a total of 5 repair surgeries in a period of 4 months, including transrectal resection of exposed mesh, laparoscopic ablation of mesh with digestive resection, exploratory laparoscopy with abscess drainage, and exploratory laparoscopy with ablation of residual mesh and transverse colostomy. She recovered well after the last intervention, exhibiting no signs of vaginal or rectal fistula and no recurrence of pelvic floor descent. Her intestinal transit was reestablished, and she was satisfied with the treatment. CONCLUSION: None of the studies that represent the specific female population submitted to laparoscopic promontofixation with transrectal mesh erosion describe the need for more than one intervention or digestive resection [9-12]. Physicians dealing with patients submitted to pelvic reconstructive surgeries with mesh placement should be aware of transrectal and other nonvaginal erosions of mesh, even being rare events. Moreover, they should perform an active search for unusual gynecologic and anorectal signs and symptoms. Most importantly, patients undergoing mesh repair procedures must be warned of the risks of the surgery, including the possibility of several subsequent interventions. PMID- 28087482 TI - Prolonged, acute suppression of cysteinyl leukotriene to reduce capsular contracture around silicone implants. AB - : We hypothesize that periodically early, local suppression of cysteinyl leukotrienes (CysLTs), which are potent inflammatory mediators, can reduce the fibrotic capsular contracture around silicone implants. We tested this hypothesis with the silicone implants enabled with the sustained release of montelukast, a CysLT receptor antagonist, for 3 and 15days. In this work, we inserted each of the distinct implants into the pocket of the subpanniculus carnosus plane of living rats and performed histological and immunofluorescent (IF) analyses of the tissues biopsied at predetermined periods for 12weeks after implant insertion. The implants with montelukast exhibited significantly reduced polymorphonuclear leukocytes (i.e., PMNs), implying a concurrent reduction of CysLT. This effect was more prominent after long-term local montelukast exposure. Thus, fewer fibroblasts were recruited, thereby reducing transforming growth factor (TGF) beta and myofibroblasts in the tissue around the implant. Therefore, the fibrotic capsule formation, which was assessed using the capsule thickness and collagen density, decreased along with the myofibroblasts. Additionally, the tissue biopsied at the experimental end point exhibited significantly decreased mechanical stiffness. STATEMENT OF SIGNIFICANCE: Capsular contracture is troublesome, making the tissues hardened around the silicone implant. This causes serious pain and discomfort to the patients, often leading to secondary surgery for implant replacement. To resolve this, we suggest a strategy of long-term, local suppression of cysteinyl leukotriene, an important mediator present during inflammation. For this, we propose a silicone implant abled to release a drug, montelukast, in a sustained manner. We tested our drug-release implant in living animals, which exhibited a significant decrease in capsule formation compared with the intact silicone implant. Therefore, we conclude that the sustained release of montelukast at the local insertion site represents a promising way to reduce capsular contracture around silicone implants. PMID- 28087483 TI - Cell number per spheroid and electrical conductivity of nanowires influence the function of silicon nanowired human cardiac spheroids. AB - : Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide an unlimited cell source to treat cardiovascular diseases, the leading cause of death worldwide. However, current hiPSC-CMs retain an immature phenotype that leads to difficulties for integration with adult myocardium after transplantation. To address this, we recently utilized electrically conductive silicon nanowires (e-SiNWs) to facilitate self-assembly of hiPSC-CMs to form nanowired hiPSC cardiac spheroids. Our previous results showed addition of e SiNWs effectively enhanced the functions of the cardiac spheroids and improved the cellular maturation of hiPSC-CMs. Here, we examined two important factors that can affect functions of the nanowired hiPSC cardiac spheroids: (1) cell number per spheroid (i.e., size of the spheroids), and (2) the electrical conductivity of the e-SiNWs. To examine the first factor, we prepared hiPSC cardiac spheroids with four different sizes by varying cell number per spheroid (~0.5k, ~1k, ~3k, ~7k cells/spheroid). Spheroids with ~3k cells/spheroid was found to maximize the beneficial effects of the 3D spheroid microenvironment. This result was explained with a semi-quantitative theory that considers two competing factors: 1) the improved 3D cell-cell adhesion, and 2) the reduced oxygen supply to the center of spheroids with the increase of cell number. Also, the critical role of electrical conductivity of silicon nanowires has been confirmed in improving tissue function of hiPSC cardiac spheroids. These results lay down a solid foundation to develop suitable nanowired hiPSC cardiac spheroids as an innovative cell delivery system to treat cardiovascular diseases. STATEMENT OF SIGNIFICANCE: Cardiovascular disease is the leading cause of death and disability worldwide. Due to the limited regenerative capacity of adult human hearts, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have received significant attention because they provide a patient specific cell source to regenerate damaged hearts. Despite the progress, current human hiPSC CMs retain an immature phenotype that leads to difficulties for integration with adult myocardium after transplantation. To address this, we recently utilized electrically conductive silicon nanowires (e-SiNWs) to facilitate self-assembly of hiPSC-CMs to form nanowired hiPSC cardiac spheroids. Our previous results showed addition of e-SiNWs effectively enhanced the functions of the cardiac spheroids and improved the cellular maturation of hiPSC-CMs. In this manuscript, we examined the effects of two important factors on the functions of nanowired hiPSC cardiac spheroids: (1) cell number per spheroid (i.e., size of the spheroids), and (2) the electrical conductivity of the e-SiNWs. The results from these studies will allow for the development of suitable nanowired hiPSC cardiac spheroids to effectively deliver hiPSC-CMs for heart repair. PMID- 28087484 TI - Inhibition of bacterial adhesion and biofilm formation by dual functional textured and nitric oxide releasing surfaces. AB - : In separate prior studies, physical topographic surface modification or nitric oxide (NO) release has been demonstrated to each be an effective approach to inhibit and control bacterial adhesion and biofilm formation on polymeric surfaces. Such approaches can prevent biomaterial-associated infection without causing the antibiotic resistance of the strain. In this work, both techniques were successfully integrated and applied to a polyurethane (PU) biomaterial surface that bears ordered pillar topographies (400/400nm and 500/500nm patterns) at the top surface and a S-nitroso-N-acetylpenicillamine (SNAP, NO donor) doped sub-layer in the middle, via a soft lithography two-stage replication process. Upon placing the SNAP textured PU films into PBS at 37 degrees C, the decomposition of SNAP within polymer film initiates NO release with a lifetime of up to 10days at flux levels >0.5*10-10molmin-1cm-2 for a textured polyurethane layer containing 15wt% SNAP. The textured surface reduces the accessible surface area and the opportunity of bacteria-surface interaction, while the NO release from the same surface further inhibits bacterial growth and biofilm formation. Such dual functionality surfaces are shown to provide a synergistic effect on inhibition of Staphylococcus epidermidis bacterial adhesion that is significantly greater than the inhibition of bacterial adhesion achieved by either single treatment approach alone. Longer term experiments to observe biofilm formation demonstrate that the SNAP doped-textured PU surface can inhibit the biofilm formation for >28d and provide a practical approach to improve the biocompatibility of current biomimetic biomaterials and thereby reduce the risk of pathogenic infection. STATEMENT OF SIGNIFICANCE: Microbial infection remains a significant barrier to development and implementation of advanced blood contacting medical devices. Clearly, determining how to design and control material properties that can reduce microbial infection is a central question to biomaterial researchers. In separate prior studies, physical topographic surface modification or nitric oxide (NO) release has been demonstrated to each be an effective approach to inhibit and control bacterial adhesion and biofilm formation on polymeric surfaces. Such approaches can prevent biomaterial associated infection without causing antibiotic resistance of the bacterial strain. However, efficiency of antimicrobial properties of each approach is still limited and far from sufficient for widespread clinical use. This work successfully integrates both techniques and applies them to a polyurethane (PU) biomaterial surface that bears dual functions, surface topographic modification and NO release. The former reduces the surface contact area and changes surface wettability, resulting in reduction of bacterial adhesion, and NO release further inhibits bacteria growth. Such dual functionalized surfaces provide a synergistic effect on inhibition of Staphylococcus epidermidis bacterial adhesion that is significantly greater than the inhibition of bacterial adhesion achieved by either single treatment approach alone. Furthermore, longer-term experiments demonstrate that the dual functionalized surfaces can inhibit biofilm formation for >28days. The success of this work provides a practical approach to improve the biocompatibility of current biomaterials and thereby reduce the risk of pathogenic infection. PMID- 28087485 TI - Stepwise targeted drug delivery to liver cancer cells for enhanced therapeutic efficacy by galactose-grafted, ultra-pH-sensitive micelles. AB - : To promote drug accumulation and cell-killing ability at tumor tissue, we have prepared a stepwise targeted drug delivery system that can remain stealthy and long-circulating in the blood vessels, improve drug retention at extracellular stimuli, enhance cellular uptake through special targeting ligands, and then achieve rapid drug release to improve toxicity to tumor cells at intracellular stimuli. Herein, galactose-grafted, ultra-pH-sensitive drug carriers (POEAd-g-LA DOX micelles), which could respond to both extracellular and intracellular pH, and combine with galactose-receptors in cell membrane, were constructed by a facile method, therefore achieving: (i) remaining stable at pH 7.4; (ii) responding to tumoral extracellular pH following gradually larger nanoparticles (NPs); (iii) conjugating receptors in the cell membrane of liver cancer through surface galactose-ligands of micelles; (iv) being sensitive to tumoral intracellular pH following further swelling for rapid drug release. In vitro cytotoxicity and cellular uptake measurement showed that POEAd-g-LA20-DOX micelle was more easily internalized and more toxic effect on tumor cells than free DOX. Moreover, in vivo biodistribution and tumor inhibition examinations demonstrated that POEAd-g-LA20-DOX formulation had more superior efficacy to significantly enhance drug accumulation in tumor, and then restrain tumor growth while decreasing drug concentration in heart. STATEMENT OF SIGNIFICANCE: Chemotherapeutic efficacy is limited by poor tumor selectivity, which also causes severe toxicity in normal tissues and organs, although many targeted drug delivery systems have been developed by passive targeting strategies or active targeting strategies with specific targeting ligands in recent years. Herein, galactose-grafted, ultra-pH-sensitive, ortho ester-based drug carriers, which can respond to both extracellular and intracellular pH, and target to galactose receptors in cell membrane, have been successfully constructed by facile method, therefore achieving stepwise targeting to microenvironment of liver cancer and then enhancing drug accumulation and tumor inhibition. The strategy of designing dual-stimuli-responsive copolymers can be potentially useful, and extrapolated to synthesizing other categories of highly labile drug carriers in a range of biomedical applications. PMID- 28087487 TI - Bioprinting for vascular and vascularized tissue biofabrication. AB - : Bioprinting is a promising technology to fabricate design-specific tissue constructs due to its ability to create complex, heterocellular structures with anatomical precision. Bioprinting enables the deposition of various biologics including growth factors, cells, genes, neo-tissues and extra-cellular matrix like hydrogels. Benefits of bioprinting have started to make a mark in the fields of tissue engineering, regenerative medicine and pharmaceutics. Specifically, in the field of tissue engineering, the creation of vascularized tissue constructs has remained a principal challenge till date. However, given the myriad advantages over other biofabrication methods, it becomes organic to expect that bioprinting can provide a viable solution for the vascularization problem, and facilitate the clinical translation of tissue engineered constructs. This article provides a comprehensive account of bioprinting of vascular and vascularized tissue constructs. The review is structured as introducing the scope of bioprinting in tissue engineering applications, key vascular anatomical features and then a thorough coverage of 3D bioprinting using extrusion-, droplet- and laser-based bioprinting for fabrication of vascular tissue constructs. The review then provides the reader with the use of bioprinting for obtaining thick vascularized tissues using sacrificial bioink materials. Current challenges are discussed, a comparative evaluation of different bioprinting modalities is presented and future prospects are provided to the reader. STATEMENT OF SIGNIFICANCE: Biofabrication of living tissues and organs at the clinically relevant volumes vitally depends on the integration of vascular network. Despite the great progress in traditional biofabrication approaches, building perfusable hierarchical vascular network is a major challenge. Bioprinting is an emerging technology to fabricate design-specific tissue constructs due to its ability to create complex, heterocellular structures with anatomical precision, which holds a great promise in fabrication of vascular or vascularized tissues for transplantation use. Although a great progress has recently been made on building perfusable tissues and branched vascular network, a comprehensive review on the state-of-the-art in vascular and vascularized tissue bioprinting has not reported so far. This contribution is thus significant because it discusses the use of three major bioprinting modalities in vascular tissue biofabrication for the first time in the literature and compares their strengths and limitations in details. Moreover, the use of scaffold-based and scaffold-free bioprinting is expounded within the domain of vascular tissue fabrication. PMID- 28087488 TI - Cathepsin K-targeted sub-micron particles for regenerative repair of vascular elastic matrix. AB - : Abdominal Aortic Aneurysms (AAA) involve slow dilation and weakening of the aortic wall due to breakdown of structural matrix components, such as elastic fibers by chronically overexpressed matrix metalloproteinases (MMPs), primarily, MMPs-2 and -9. Auto-regenerative repair of disrupted elastic fibers by smooth muscle cells (SMCs) at the AAA site is intrinsically poor and together with chronic proteolysis prevents restoration of elastin homeostasis, necessary to enable AAA growth arrest or regression to a healthy state. Oral doxycycline (DOX) therapy can inhibit MMPs to slow AAA growth, but has systemwide side-effects and inhibits new elastin deposition within AAA tissue, diminishing prospects for restoring elastin homeostasis preventing the arrest/regression of AAA growth. We have thus developed cationic amphiphile (DMAB)-modified submicron particles (SMPs) that uniquely exhibit pro-elastogenic and anti-proteolytic properties, separate from similar effects of the encapsulated drug. These SMPs can enable sustained, low dose DOX delivery within AAA tissue to augment elastin regenerative repair. To provide greater specificity of SMP targeting, we have conjugated the DOX-SMP surface with an antibody against cathepsin K, a lysosomal protease that is highly overexpressed within AAA tissue. We have determined conditions for efficient cathepsin K Ab conjugation onto the SMPs, improved SMP binding to aneurysmal SMCs in culture and to injured vessel walls ex vivo, conjugation did not affect DOX release from the SMPs, and improved pro elastogenic and anti-proteolytic effects due to the SMPs likely due to their increased proximity to cells via binding. Our study results suggest that cathepsin K Ab conjugation is a useful targeting modality for our pro regenerative SMPs. Future studies will investigate SMP retention and biodistribution following targeting to induced AAAs in rat models through intravenous or catheter-based aortal infusion and thereafter their efficacy for regenerative elastic matrix repair in the AAA wall. STATEMENT OF SIGNIFICANCE: Proactive screening of high risk elderly patients now enables early detection of Abdominal Aortic Aneurysms (AAAs). Current management of small, growing AAAs is limited to passive, imaging based growth monitoring. There are also no established drug-based therapeutic alternatives to surgery for AAAs, which is unsuitable for many elderly patients, and none which can achieve restore disrupted and lost elastic matrix in the AAA wall, which is essential to achieve growth arrest or regression. We seek to test the feasibility of a regenerative therapy based on localized, one time delivery of drug-releasing Sub-Micron-sized drug delivery polymer Particles (SMPs) that are also uniquely chemically functionalized on their surface to also provide them pro-elastin-regenerative & anti-matrix degradative properties, and also conjugated with antibodies targeting cathepsin K, an elastolytic enzyme that is highly overexpressed in AAA tissues; the latter serves as a modality to enable targeted binding of the SMPs to the AAA wall following intravenous infusion, or intraoartal, catheter-based delivery. Such SMPs can potentially stimulate structural repair in the AAA wall following one time infusion to delay or prevent AAA growth to rupture. The therapy can provide a non-surgical treatment option for high risk AAA patients. PMID- 28087486 TI - Enhanced articular cartilage by human mesenchymal stem cells in enzymatically mediated transiently RGDS-functionalized collagen-mimetic hydrogels. AB - : Recapitulation of the articular cartilage microenvironment for regenerative medicine applications faces significant challenges due to the complex and dynamic biochemical and biomechanical nature of native tissue. Towards the goal of biomaterial designs that enable the temporal presentation of bioactive sequences, recombinant bacterial collagens such as Streptococcal collagen-like 2 (Scl2) proteins can be employed to incorporate multiple specific bioactive and biodegradable peptide motifs into a single construct. Here, we first modified the backbone of Scl2 with glycosaminoglycan-binding peptides and cross-linked the modified Scl2 into hydrogels via matrix metalloproteinase 7 (MMP7)-cleavable or non-cleavable scrambled peptides. The cross-linkers were further functionalized with a tethered RGDS peptide creating a system whereby the release from an MMP7 cleavable hydrogel could be compared to a system where release is not possible. The release of the RGDS peptide from the degradable hydrogels led to significantly enhanced expression of collagen type II (3.9-fold increase), aggrecan (7.6-fold increase), and SOX9 (5.2-fold increase) by human mesenchymal stem cells (hMSCs) undergoing chondrogenesis, as well as greater extracellular matrix accumulation compared to non-degradable hydrogels (collagen type II; 3.2 fold increase, aggrecan; 4-fold increase, SOX9; 2.8-fold increase). Hydrogels containing a low concentration of the RGDS peptide displayed significantly decreased collagen type I and X gene expression profiles, suggesting a major advantage over either hydrogels functionalized with a higher RGDS peptide concentration, or non-degradable hydrogels, in promoting an articular cartilage phenotype. These highly versatile Scl2 hydrogels can be further manipulated to improve specific elements of the chondrogenic response by hMSCs, through the introduction of additional bioactive and/or biodegradable motifs. As such, these hydrogels have the possibility to be used for other applications in tissue engineering. STATEMENT OF SIGNIFICANCE: Recapitulating aspects of the native tissue biochemical microenvironment faces significant challenges in regenerative medicine and tissue engineering due to the complex and dynamic nature of the tissue. The ability to take advantage of, mimic, and modulate cell-mediated processes within novel naturally-derived hydrogels is of great interest in the field of biomaterials to generate constructs that more closely resemble the biochemical microenvironment and functions of native biological tissues such as articular cartilage. Towards this goal, the temporal presentation of bioactive sequences such as RGDS on the chondrogenic differentiation of human mesenchymal stem cells is considered important as it has been shown to influence the chondrogenic phenotype. Here, a novel and versatile platform to recreate a high degree of biological complexity is proposed, which could also be applicable to other tissue engineering and regenerative medicine applications. PMID- 28087489 TI - Neurite density index is sensitive to age related differences in the developing brain. AB - PURPOSE: White matter development during childhood and adolescence is characterised by increasing white matter coherence and organisation. Commonly used scalar metrics, such as fractional anisotropy (FA), are sensitive to multiple mechanisms of white matter change and therefore unable to distinguish between mechanisms that change during development. We investigate the relationship between age and neurite density index (NDI) from neurite orientation dispersion and density imaging (NODDI), and the age-classification accuracy of NDI compared with FA, in a developmental cohort. METHOD: Diffusion-weighted imaging data from 72 children and adolescents between the ages of 4-19 was collected (M=10.42, SD=3.99, 36 male). We compared NODDI metrics against conventional DTI metrics (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD] and radial diffusivity [RD]) in terms of their relationship to age. An ROC analysis was also performed to assess the ability of each metric to classify older and younger participants. RESULTS: NDI exhibited a stronger relationship with age (median R2=.60) compared with MD (median R2=.39), FA (median R2=.27), AD (median R2=.14), and RD (median R2=.35) in a high proportion of white matter tracts. When participants were divided into an older and younger group, NDI achieved the best classification (median area under the curve [AUC]=.89), followed by MD (median AUC=.81), FA (median AUC=.80), RD (median AUC=.81), and AD (median AUC=.64). CONCLUSION: Our results demonstrate the sensitivity of NDI to age-related differences in white matter microstructural organisation over development. Importantly, NDI is more sensitive to such developmental changes compared to commonly used DTI metrics. This knowledge provides justification for implementing NODDI metrics in developmental studies. PMID- 28087491 TI - Dynamics of bacterial class Bacilli in the deepest valley lake of Kashmir-the Manasbal Lake. AB - In recognition of the importance of bacteria as ecological indicators of the aquatic systems a comprehensive and systematic analysis was carried out on Manasbal Lake, the deepest spring fed valley lake of Kashmir. The main objective envisaged was to analyze bacterial community composition (BCC) and for this purpose systematic and regular sampling of waters from ten different sampling stations, predetermined in the Lake according to differences in degree of human interference and also as zones of special ecological interests were selected. The isolated species were identified according to Bergey's Manual specification by examining their micro and macro morphological characteristics and biochemical characteristics on different culture media. Further confirmation was done by sequencing the 16s rRNA gene by using universal bacterial primers 27F and 1429R. From all the sampling stations the class Bacilli showed a maximum relative abundance with a contribution of 16 bacterial species. The whole process resulted in the identification of Bacillus aerius, Bacillus altitudinis, Bacillus anthracis, Bacillus cereus, Bacillus ginsengisoli, Bacillus pumilus, Bacillus safensis, Bacillus stratosphericus, Bacillus subtilis, Bacillus tequilensis, Bacillus thermocopriae, Bacillus thuringiensis, Brevibacillus agri strain, Lysinibacillus boronitolerans, Lysinibacillus pakistanensis and Lysinibacillus sphaericus. PMID- 28087492 TI - Multi-antibiotic resistant and putative virulence gene signatures in Enterococcus species isolated from pig farms environment. AB - The continuous misuse of antimicrobials in food animals both orally and subcutaneously as therapeutic and prophylactic agents to bacterial infections could be detrimental and contribute to the dissemination of resistant clones in livestock production. The present study was carried out to determine the antibiogram and virulence gene characteristics of Enterococcus species from pig farms. A total of 300 faecal samples were obtained from two pig farms in Benin City between February and July 2016. Standard culture-based and polymerase chain reaction (PCR) assay were adopted in the detection and characterization of the Enterococcus species. Antimicrobial susceptibility profile was determined using disc diffusion method. A total of 268 enterococci isolates were recovered from both farms investigated. In Farm A, 94/95 (99%) of E. faecalis isolates were resistant to clindamycin; while 23/25 (92%) of E. faecium isolates were resistant to clindamycin. In farm B, all E. faecalis isolates 119/119 (100%) were resistant to clindamycin; while 26/29 (90%) of E. faecium isolates were resistant to clindamycin. Virulence gene detected in the enterococci isolates includes aggregation (asa1) [Farm A (E. faecalis 66%, E. faecium 76%), Farm B (E. faecalis 71%, E. faecium 13%)] and others. Multidrug resistant profile of the isolates revealed that 17/95 (18%) of E. faecalis and 3/25 (12%) of E. faecium isolates from Farm A as well as, 16/119 (14%) of E. faecalis and 5/29 (17%) of E. faecium isolates from Farm B were resistant to CLIR, PENR, ERYR, GENR, TETR, MEMR, KANR, and PTZR. The high level of resistance observed in the study and their virulence gene signatures, calls for effective environmental monitoring to circumvent the environmental dissemination of resistant pathogenic clones. Thus environmental hygiene should be provided to food animals to prevent the proliferation and spread of resistant bacteria. PMID- 28087490 TI - Longitudinal multiple sclerosis lesion segmentation: Resource and challenge. AB - In conjunction with the ISBI 2015 conference, we organized a longitudinal lesion segmentation challenge providing training and test data to registered participants. The training data consisted of five subjects with a mean of 4.4 time-points, and test data of fourteen subjects with a mean of 4.4 time-points. All 82 data sets had the white matter lesions associated with multiple sclerosis delineated by two human expert raters. Eleven teams submitted results using state of-the-art lesion segmentation algorithms to the challenge, with ten teams presenting their results at the conference. We present a quantitative evaluation comparing the consistency of the two raters as well as exploring the performance of the eleven submitted results in addition to three other lesion segmentation algorithms. The challenge presented three unique opportunities: (1) the sharing of a rich data set; (2) collaboration and comparison of the various avenues of research being pursued in the community; and (3) a review and refinement of the evaluation metrics currently in use. We report on the performance of the challenge participants, as well as the construction and evaluation of a consensus delineation. The image data and manual delineations will continue to be available for download, through an evaluation website2 as a resource for future researchers in the area. This data resource provides a platform to compare existing methods in a fair and consistent manner to each other and multiple manual raters. PMID- 28087493 TI - Antioxidant and antiproliferative potential of biosurfactants isolated from Lactobacillus casei and their anti-biofilm effect in oral Staphylococcus aureus strains. AB - Biosurfactants also called bioemulsifiers are amphipathic compounds produced by many microorganisms that allow them to exhibit a wide range of biological activities. The aim of this study was to determine the antioxidant and antiproliferative potential of biosurfactants isolated from Lactobacillus casei and to assess their anti-adhesive and anti-biofilm abilities against oral opportunistic Staphylococcus aureus strains. The antioxidant activity of biosurfactant was evaluated using the in vitro scavenging ability on 1,1-diphenyl 2-picrylhydrazyl (DPPH) radical. The antiproliferative activity was determined on epithelial cell line (HEp-2) by the Methylthiazole tetrazolium (MTT) reduction assay. The anti-adhesive and antibiofilm activity against S. aureus strains were achieved using crystal violet staining. Our results revealed that the DPPH scavenging activity of biosurfactants at 5.0 mg/mL concentration is between 74.6 and 77.3%. Furthermore, biosurfactants showed antiproliferative potency against studied epithelial cells as judged by IC50 and its value ranged from 109.1 +/- 0.84 mg/mL to 129.7 +/- 0.52 mg/mL. The results of the growth inhibition indicate that biosurfactant BS-LBl was more effective against oral S. aureus strains 9P and 29P with an IC50 of 1.92 +/- 0.26 mg/mL and 2.16 +/- 0.12 mg/mL respectively. Moreover, both biosurfactants displayed important antibiofilm activity with eradication percentages ranging from 80.22 +/- 1.33% to 86.21 +/- 2.94% for the BS-LBl, and from 53.38 +/- 1.77% to 64.42 +/- 2.09% for the BS-LZ9. Our findings demonstrate that biosurfactants from L. casei strains exhibited considerable antioxidant and antiproliferative potencies and were able to inhibit oral S. aureus strains with important antibiofilm efficacy. They could have a promising role in the prevention of oral diseases. PMID- 28087494 TI - Porcine kobuvirus 1 in healthy and diarrheic pigs: Genetic detection and characterization of virus and co-infection with rotavirus A. AB - The porcine kobuvirus 1 (PKV-1) is believed to be an enteric virus. To investigate the prevalence of PKV-1 in pigs, virus was detected by RT-PCR in rectal swabs originating from 414 healthy and diarrheic pigs of different age categories on farms in Slovakia. Among all ages of animals, PKV-1 was detected equally in diarrheic (63.8%) and clinically healthy (62.9%) pigs. PKV-1 was more often detected in diarrheic (74.6%) than in healthy (64.4%) suckling piglets (<28days) but data was not statistically significant. Results in weaned (28 70days) and fattening (>70days) of both healthy and diarrheic pigs were inconsistent ranging in interval 56.2% to 67.9%. This study did not confirm a clear relationship of PKV-1 infection with diarrhea in pigs. Rotavirus A infection was detected among the same animals in 39% diarrheic and 9.2% healthy suckling piglets (p<0.001) confirming rotavirus as a causative agent of diarrhea in this age group. The difference was not significant in older pigs with both diarrheic and healthy pigs being infected within a range of 0% to 12.2%. Co infection with PKV-1 and rotavirus A was detected overall in 5.6% of healthy and in 13.5% of diarrheic pigs and was highest in suckling piglets (33.9%). The PKV 1sequences from pigs in Slovakia were analyzed at the genetic level in the partial 3D gene region for the first time. The viral sequences were grouped in phylogenetic clusters according to their farm of origin. When compared with 157 nucleotide sequences originating from pig samples of different countries around the world Slovakian PKV-1 sequences were clustered in the phylogenetic tree with Asian sequences but not with nucleotide sequences from the neighbouring countries of Czech Republic or Hungary. PMID- 28087495 TI - Comparative analysis of variation and selection in the HCV genome. AB - Genotype 1 of the hepatitis C virus (HCV) is the most prevalent of the variants of this virus. Its two main subtypes, HCV-1a and HCV-1b, are associated to differences in epidemic features and risk groups, despite sharing similar features in most biological properties. We have analyzed the impact of positive selection on the evolution of these variants using complete genome coding regions, and compared the levels of genetic variability and the distribution of positively selected sites. We have also compared the distributions of positively selected and conserved sites considering different factors such as RNA secondary structure, the presence of different epitopes (antibody, CD4 and CD8), and secondary protein structure. <10% of the genome was found to be under positive selection, and purifying selection was the main evolutionary process acting in both subtypes. We found differences in the number of positively selected sites between subtypes in several genes (Core, HVR2 in E2, P7, helicase in NS3 and NS4a). Heterozygosity values in positively selected sites and the rate of non synonymous substitutions were significantly higher in subtype HCV-1b. Logistic regression analyses revealed that similar selective forces act at the genome level in both subtypes: RNA secondary structure and CD4 T-cell epitopes are associated with conserved sites, while CD8 T-cell epitopes are associated with positive selection in both subtypes. These results indicate that similar selective constraints are acting along HCV-1a and HCV-1 b genomes, despite some differences in the distribution of positively selected sites at independent genes. PMID- 28087498 TI - David Oliver: Older doctors revisited. PMID- 28087496 TI - Digital Pills to Measure Opioid Ingestion Patterns in Emergency Department Patients With Acute Fracture Pain: A Pilot Study. AB - BACKGROUND: Nonadherence to prescribed regimens for opioid analgesic agents contributes to increasing opioid abuse and overdose death. Opioids are frequently prescribed on an as-needed basis, placing the responsibility to determine opioid dose and frequency with the patient. There is wide variability in physician prescribing patterns because of the lack of data describing how patients actually use as-needed opioid analgesics. Digital pill systems have a radiofrequency emitter that directly measures medication ingestion events, and they provide an opportunity to discover the dose, timing, and duration of opioid therapy. OBJECTIVE: The purpose of this study was to determine the feasibility of a novel digital pill system to measure as-needed opioid ingestion patterns in patients discharged from the emergency department (ED) after an acute bony fracture. METHODS: We used a digital pill with individuals who presented to a teaching hospital ED with an acute extremity fracture. The digital pill consisted of a digital radiofrequency emitter within a standard gelatin capsule that encapsulated an oxycodone tablet. When ingested, the gastric chloride ion gradient activated the digital pill, transmitting a radiofrequency signal that was received by a hip-worn receiver, which then transmitted the ingestion data to a cloud-based server. After a brief, hands-on training session in the ED, study participants were discharged home and used the digital pill system to ingest oxycodone prescribed as needed for pain for one week. We conducted pill counts to verify digital pill data and open-ended interviews with participants at their follow-up appointment with orthopedics or at one week after enrollment in the study to determine the knowledge, attitudes, beliefs, and practices regarding digital pills. We analyzed open-ended interviews using applied thematic analysis. RESULTS: We recruited 10 study participants and recorded 96 ingestion events (87.3%, 96/110 accuracy). Study participants reported being able to operate all aspects of the digital pill system after their training. Two participants stopped using the digital pill, reporting they were in too much pain to focus on the novel technology. The digital pill system detected multiple simultaneous ingestion events by the digital pill system. Participants ingested a mean 8 (SD 5) digital pills during the study period and four participants continued on opioids at the end of the study period. After interacting with the digital pill system in the real world, participants found the system highly acceptable (80%, 8/10) and reported a willingness to continue to use a digital pill to improve medication adherence monitoring (90%, 9/10). CONCLUSIONS: The digital pill is a feasible method to measure real-time opioid ingestion patterns in individuals with acute pain and to develop real-time interventions if opioid abuse is detected. Deploying digital pills is possible through the ED with a short instructional course. Patients who used the digital pill accepted the technology. PMID- 28087497 TI - Developing Nutrition Label Reading Skills: A Web-Based Practice Approach. AB - BACKGROUND: Nutrition labels offer the information needed to follow Dietary Guidelines for Americans, yet many individuals use labels infrequently or ineffectively due to limited comprehension and the effort required to use them. OBJECTIVE: The objective of our study was to develop and test a Web-based label reading training tool to improve individuals' ability to use labels to select more healthful foods. We were particularly interested in determining whether practice can lead to increased accuracy using labels as well as decreased effort, together reflecting greater efficiency. We compared a basic and an enhanced, prior-knowledge version of the tool that contained an additional component, a brief nutrition tutorial. METHODS: Participants were 140 college students with an average age of 20.7 (SD 2.1) years and education 14.6 (SD 1.2) years, who completed 3 sets of practice that were designed to teach them, through repetition and feedback, how to use nutrition labels to select more healthful products. Prior to training, participants in the prior-knowledge group viewed a multimedia nutrition presentation, which those in the basic group did not receive. Mixed effects models tested for improvement in accuracy and speed with practice, and whether improvements varied by group. RESULTS: The training led to significant increases in average accuracy across the 3 practice sets (averaging 79% [19/24 questions], 92% [22/24], 96% [23/24] respectively, P<.001), as well as decreases in time to complete with mean (SD) values of 8.7 (2.8), 4.6 (1.8), and 4.1 (1.7) seconds, respectively. In block 3, the odds of a correct answer for the prior knowledge group were 79% higher (odds ratio, OR=1.79, 95% CI 1.1-2.9) than those for the basic group (P=.02). There was no significant difference between the groups in block 2 (P=.89). CONCLUSIONS: Practice led to improvements in nutrition label reading skills that are indicative of early stages of automatic processing. To the extent that automatic processes are at the core of healthy habit change, this may be an efficient way to improve dietary decision-making. PMID- 28087499 TI - Emergency admissions for diabetes increase more quickly in deprived areas of England. PMID- 28087500 TI - Christopher James Stevenson. PMID- 28087501 TI - Employers should not add management objectives to revalidation process, GMC says. PMID- 28087502 TI - John Frederick Perren. PMID- 28087503 TI - Lindsey Dow. PMID- 28087504 TI - Does inflammation predict radiographic progression in hand osteoarthritis? PMID- 28087505 TI - 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. AB - To update and integrate the recommendations for ankylosing spondylitis and the recommendations for the use of tumour necrosis factor inhibitors (TNFi) in axial spondyloarthritis (axSpA) into one set applicable to the full spectrum of patients with axSpA. Following the latest version of the European League Against Rheumatism (EULAR) Standardised Operating Procedures, two systematic literature reviews first collected the evidence regarding all treatment options (pharmacological and non-pharmacological) that were published since 2009. After a discussion of the results in the steering group and presentation to the task force, overarching principles and recommendations were formulated, and consensus was obtained by informal voting. A total of 5 overarching principles and 13 recommendations were agreed on. The first three recommendations deal with personalised medicine including treatment target and monitoring. Recommendation 4 covers non-pharmacological management. Recommendation 5 describes the central role of non-steroidal anti-inflammatory drugs (NSAIDs) as first-choice drug treatment. Recommendations 6-8 define the rather modest role of analgesics, and disprove glucocorticoids and conventional synthetic disease-modifying antirheumatic drugs (DMARDs) for axSpA patents with predominant axial involvement. Recommendation 9 refers to biological DMARDs (bDMARDs) including TNFi and IL-17 inhibitors (IL-17i) for patients with high disease activity despite the use (or intolerance/contraindication) of at least two NSAIDs. In addition, they should either have an elevated C reactive protein and/or definite inflammation on MRI and/or radiographic evidence of sacroiliitis. Current practice is to start with a TNFi. Switching to another TNFi or an IL-17i is recommended in case TNFi fails (recommendation 10). Tapering, but not stopping a bDMARD, can be considered in patients in sustained remission (recommendation 11). The final two recommendations (12, 13) deal with surgery and spinal fractures. The 2016 Assessment of SpondyloArthritis international Society-EULAR recommendations provide up-to-date guidance on the management of patients with axSpA. PMID- 28087507 TI - Response to 'Does inflammation predict radiographic progression in hand osteoarthritis?' by Li et al. PMID- 28087506 TI - A randomised phase II study evaluating the efficacy and safety of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis despite treatment with methotrexate. AB - OBJECTIVE: Interleukin (IL)-12 and IL-23 have been implicated in the pathogenesis of rheumatoid arthritis (RA). The safety and efficacy of ustekinumab, a human monoclonal anti-IL-12/23 p40 antibody, and guselkumab, a human monoclonal anti-IL 23 antibody, were evaluated in adults with active RA despite methotrexate (MTX) therapy. METHODS: Patients were randomly assigned (1:1:1:1:1) to receive placebo at weeks 0, 4 and every 8 weeks (n=55), ustekinumab 90 mg at weeks 0, 4 and every 8 weeks (n=55), ustekinumab 90 mg at weeks 0, 4 and every 12 weeks (n=55), guselkumab 50 mg at weeks 0, 4 and every 8 weeks (n=55), or guselkumab 200 mg at weeks 0, 4 and every 8 weeks (n=54) through week 28; all patients continued a stable dose of MTX (10-25 mg/week). The primary end point was the proportion of patients with at least a 20% improvement in the American College of Rheumatology criteria (ACR 20) at week 28. Safety was monitored through week 48. RESULTS: At week 28, there were no statistically significant differences in the proportions of patients achieving an ACR 20 response between the combined ustekinumab group (53.6%) or the combined guselkumab group (41.3%) compared with placebo (40.0%) (p=0.101 and p=0.877, respectively). Through week 48, the proportions of patients with at least one adverse event (AE) were comparable among the treatment groups. Infections were the most common type of AE. CONCLUSIONS: Treatment with ustekinumab or guselkumab did not significantly reduce the signs and symptoms of RA. No new safety findings were observed with either treatment. TRIAL REGISTRATION NUMBER: NCT01645280. PMID- 28087508 TI - International Variation in Outcomes Among People with Cardiovascular Disease or Cardiovascular Risk Factors and Impaired Glucose Tolerance: Insights from the NAVIGATOR Trial. AB - BACKGROUND: Regional differences in risk of diabetes mellitus and cardiovascular outcomes in people with impaired glucose tolerance are poorly characterized. Our objective was to evaluate regional variation in risk of new-onset diabetes mellitus, cardiovascular outcomes, and treatment effects in participants from the NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) trial. METHODS AND RESULTS: NAVIGATOR randomized people with impaired glucose tolerance and cardiovascular risk factors or with established cardiovascular disease to valsartan (or placebo) and to nateglinide (or placebo) with a median 5-year follow-up. Data from the 9306 participants were categorized by 5 regions: Asia (n=552); Europe (n=4909); Latin America (n=1406); North America (n=2146); and Australia, New Zealand, and South Africa (n=293). Analyzed outcomes included new-onset diabetes mellitus; cardiovascular death; a composite cardiovascular outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke; and treatment effects of valsartan and nateglinide. Respective unadjusted 5-year risks for new-onset diabetes mellitus, cardiovascular death, and the composite cardiovascular outcome were 33%, 0.4%, and 4% for Asia; 34%, 2%, and 6% for Europe; 37%, 4%, and 8% for Latin America; 38%, 2%, and 6% for North America; and 32%, 4%, and 8% for Australia, New Zealand, and South Africa. After adjustment, compared with North America, European participants had a lower risk of new-onset diabetes mellitus (hazard ratio 0.86, 95% CI 0.78-0.94; P=0.001), whereas Latin American participants had a higher risk of cardiovascular death (hazard ratio 2.68, 95% CI 1.82-3.96; P<0.0001) and the composite cardiovascular outcome (hazard ratio 1.48, 95% CI 1.15-1.92; P=0.003). No differential interactions between treatment and geographic location were identified. CONCLUSIONS: Major regional differences regarding the risk of new-onset diabetes mellitus and cardiovascular outcomes in NAVIGATOR participants were identified. These differences should be taken into account when planning global trials. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00097786. PMID- 28087509 TI - Use of Both Serum Cystatin C and Creatinine as Diagnostic Criteria for Contrast Induced Acute Kidney Injury and Its Clinical Implications. AB - BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) was traditionally defined as an increase in serum creatinine (sCr) after contrast media exposure. Recently, serum cystatin C (sCyC) has been proposed as an alternative to detect acute changes in renal function. The clinical implications of combining sCyC and sCr to diagnose CI-AKI remain unknown. METHODS AND RESULTS: One thousand seventy one consecutive patients undergoing coronary angiography/intervention were prospectively enrolled. SCyC and sCr were assessed at baseline and 24 to 48 hours after contrast media exposure. CI-AKI determined by sCr (CI-AKIsCr) was defined as an sCr increase greater than 0.3 mg/dL or 50% from baseline. Major adverse events at 12 months were assessed. CI-AKIsCr developed in 25 patients (2.3%). Twelve-month follow-up was available for 1063 patients; major adverse events occurred in 61 patients (5.7%). By receiver operating characteristic curve analysis, an sCyC increase of greater than 15% was the optimal cutoff for CI AKIsCr detection, which occurred in 187 patients (17.4%). To evaluate the use of both sCyC and sCr as CI-AKI diagnostic criteria, we stratified patients into 3 groups: no CI-AKI, CI-AKI detected by a single marker, and CI-AKI detected by both markers. Multivariable logistic regression revealed that the predictability of major adverse events increased in a stepwise fashion in the 3 groups (no-CI AKI group as the reference, CI-AKI detected by a single marker: odds ratio=2.25, 95% CI: 1.24-4.10, P<0.01; CI-AKI detected by both markers: odds ratio=10.00, 95% CI: 3.13-31.91, P<0.001). CONCLUSIONS: Combining sCyC and sCr to diagnose CI-AKI would be beneficial for risk stratification and prognosis in patients after contrast media exposure. PMID- 28087510 TI - Effectiveness of flexible sigmoidoscopy screening in men and women and different age groups: pooled analysis of randomised trials. AB - OBJECTIVE: To compare the effectiveness of flexible sigmoidoscopy in screening for colorectal cancer by patient sex and age. DESIGN: Pooled analysis of randomised trials (the US Prostate, Lung, Colorectal and Ovarian cancer screening trial (PLCO), the Italian Screening for Colon and Rectum trial (SCORE), and the Norwegian Colorectal Cancer Prevention trial (NORCCAP)). DATA SOURCES: Aggregated data were pooled from each randomised trial on incidence of colorectal cancer and mortality stratified by sex, age at screening, and colon subsite (distal v proximal). ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Invited individuals aged 55-74 (PLCO), 55-64 (SCORE), and 50-64 (NORCCAP). Individuals were randomised to receive flexible sigmoidoscopy screening once only (SCORE and NORCCAP) or twice (PLCO), or receive usual care (no intervention). RESULTS: 287 928 individuals were included in the pooled analysis; 115 139 randomised to screening and 172 789 to usual care. Compliance rates were 58%, 63%, and 87% in SCORE, NORCCAP, and PLCO, respectively. Median follow-up was 10.5 to 12.1 years. Screening reduced the incidence of colorectal cancer in men (relative risk 0.76; 95% confidence interval 0.70 to 0.83) and women (0.83; 0.75 to 0.92). No difference in the effect of screening was seen between men younger than 60 and those older than 60. Screening reduced the incidence of colorectal cancer in women younger than 60 (relative risk 0.71; 95% confidence interval 0.59 to 0.84), but not significantly in those aged 60 or older (0.90; 0.80 to 1.02). Colorectal cancer mortality was significantly reduced in both younger and older men, and in women younger than 60. Screening reduced colorectal cancer incidence to a similar extent in the distal colon in men and women, but there was no effect of screening in the proximal colon in older women with a significant interaction between sex and age group (P=0.04). CONCLUSION: Flexible sigmoidoscopy is an effective tool for colorectal cancer screening in men and younger women. The benefit is smaller and not statistically significant for women aged over 60; alternative screening methods that more effectively detect proximal tumours should be considered for these women. PMID- 28087511 TI - Invited Commentary: Ambient Environment and the Risk of Preterm Birth. AB - Preterm birth is a common adverse birth outcome known to be associated with increased infant mortality, and it often results in a higher burden of offspring morbidity in both the short and long terms. The potential for environmental factors, particularly air pollution and meteorological parameters, to increase preterm birth risk has received significant attention worldwide, but the findings are generally inconsistent, with variations in study designs and methods across populations and geographic locations. In the current issue of the Journal, Giorgis-Allemand et al. (Am J Epidemiol. 2017;185(4):247-258) take the field a step further than most prior investigations of the ambient environment. They examined the associations of ambient air pollution and meteorological factors with preterm risk among 13 cohorts across 11 European countries. No association with air pollution was observed, but associations with increased preterm birth risk were found for both increased atmospheric pressure and ambient temperature exposures during the first trimester. The study is notable in attempting to address several important issues that challenge the field, including exposure misclassification and defining critical windows of exposure. Their comprehensive evaluation of ambient exposures is to be commended. PMID- 28087513 TI - How Accurate Is a Single Cutpoint to Identify High Blood Pressure in Adolescents? AB - In 2007 the International Diabetes Federation (IDF) proposed single blood pressure (BP) cutpoints (systolic: >=130 mm Hg and diastolic: >=85 mm Hg) for the diagnosis of high blood pressure (HBP) in adolescents. Before this proposal, HBP had been defined as BP at or above the 95th percentile for age, sex, and height percentile (reference standard). In this study, we evaluated the risk for misclassification when using the IDF single-cutpoints criteria. We first applied the IDF criteria to a reconstructed population with the same age, sex, and height distribution as the population used to develop the reference standard. The proposed single cutpoints corresponded to percentiles from the 81.6th to 99.9th for systolic BP and from the 92.9th to 98.9th for diastolic BP in the reconstructed population. Using IDF criteria, there were high false-negative fractions for both systolic and diastolic BP (from 54% to 93%) in 10- to 12-year olds and a false-positive fraction up to 35% in older subjects. We then applied the IDF criteria to 1,162 overweight/obese adolescents recruited during 1998-2000 from pediatric clinical centers in Milano, Varese, and Modena in Italy and in Zaragoza, Spain. Overall false-negative and false-positive fractions were 22% and 2%, respectively; negative predictive values were especially low for 10- to 12 year-old subjects. The use of IDF's single cutpoints carries a high risk of misclassification, mostly due to false negatives in younger subjects. The effort to simplify diagnosis could be overcome by the risk of undiagnosed HBP. PMID- 28087515 TI - H-BLAST: a fast protein sequence alignment toolkit on heterogeneous computers with GPUs. AB - Motivation: The sequence alignment is a fundamental problem in bioinformatics. BLAST is a routinely used tool for this purpose with over 118 000 citations in the past two decades. As the size of bio-sequence databases grows exponentially, the computational speed of alignment softwares must be improved. Results: We develop the heterogeneous BLAST (H-BLAST), a fast parallel search tool for a heterogeneous computer that couples CPUs and GPUs, to accelerate BLASTX and BLASTP-basic tools of NCBI-BLAST. H-BLAST employs a locally decoupled seed extension algorithm for better performance on GPUs, and offers a performance tuning mechanism for better efficiency among various CPUs and GPUs combinations. H-BLAST produces identical alignment results as NCBI-BLAST and its computational speed is much faster than that of NCBI-BLAST. Speedups achieved by H-BLAST over sequential NCBI-BLASTP (resp. NCBI-BLASTX) range mostly from 4 to 10 (resp. 5 to 7.2). With 2 CPU threads and 2 GPUs, H-BLAST can be faster than 16-threaded NCBI BLASTX. Furthermore, H-BLAST is 1.5-4 times faster than GPU-BLAST. Availability and Implementation: https://github.com/Yeyke/H-BLAST.git. Contact: yux06@syr.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28087516 TI - Michael Massam. PMID- 28087514 TI - The Influence of Meteorological Factors and Atmospheric Pollutants on the Risk of Preterm Birth. AB - Atmospheric pollutants and meteorological conditions are suspected to be causes of preterm birth. We aimed to characterize their possible association with the risk of preterm birth (defined as birth occurring before 37 completed gestational weeks). We pooled individual data from 13 birth cohorts in 11 European countries (71,493 births from the period 1994-2011, European Study of Cohorts for Air Pollution Effects (ESCAPE)). City-specific meteorological data from routine monitors were averaged over time windows spanning from 1 week to the whole pregnancy. Atmospheric pollution measurements (nitrogen oxides and particulate matter) were combined with data from permanent monitors and land-use data into seasonally adjusted land-use regression models. Preterm birth risks associated with air pollution and meteorological factors were estimated using adjusted discrete-time Cox models. The frequency of preterm birth was 5.0%. Preterm birth risk tended to increase with first-trimester average atmospheric pressure (odds ratio per 5-mbar increase = 1.06, 95% confidence interval: 1.01, 1.11), which could not be distinguished from altitude. There was also some evidence of an increase in preterm birth risk with first-trimester average temperature in the -5 degrees C to 15 degrees C range, with a plateau afterwards (spline coding, P = 0.08). No evidence of adverse association with atmospheric pollutants was observed. Our study lends support for an increase in preterm birth risk with atmospheric pressure. PMID- 28087517 TI - A story in a tea cup. PMID- 28087518 TI - Cardiovascular function in male and female JCR:LA-cp rats: effect of high fat/high-sucrose diet. AB - Thirty percent of the world population is diagnosed with metabolic syndrome. High fat/high-sucrose (HF/HS) diet (Western diet) correlates with metabolic syndrome prevalence. We characterized effects of the HF/HS diet on vascular (arterial stiffness, vasoreactivity, and coronary collateral development) and cardiac (echocardiography) function, oxidative stress, and inflammation in a rat model of metabolic syndrome (JCR rats). Furthermore, we determined whether male versus female animals were affected differentially by the Western diet. Cardiovascular function in JCR male rats was impaired versus normal Sprague-Dawley (SD) rats. HF/HS diet compromised cardiovascular (dys)function in JCR but not SD male rats. In contrast, cardiovascular function was minimally impaired in JCR female rats on normal chow. However, cardiovascular function in JCR female rats on the HF/HS diet deteriorated to levels comparable to JCR male rats on the HF/HS diet. Similarly, oxidative stress was markedly increased in male but not female JCR rats on normal chow but was equally exacerbated by the HF/HS diet in male and female JCR rats. These results indicate that the Western diet enhances oxidative stress and cardiovascular dysfunction in metabolic syndrome and eliminates the protective effect of female sex on cardiovascular function, implying that both males and females with metabolic syndrome are at equal risk for cardiovascular disease.NEW & NOTEWORTHY Western diet abolished protective effect of sex against cardiovascular disease (CVD) development in premenopausal animals with metabolic syndrome. Western diet accelerates progression of CVD in male and female animals with preexisting metabolic syndrome but not normal animals. Exacerbation of baseline oxidative stress correlates with accelerated progression of CVD in metabolic syndrome animals on Western diet. PMID- 28087521 TI - Trolley waits in England rise sixfold in six years, show latest figures. PMID- 28087519 TI - Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis. AB - The influence of cardiac sympathetic innervation on electrical activation in normal and chronically infarcted ventricular myocardium is not understood. Yorkshire pigs with normal hearts (NL, n = 12) or anterior myocardial infarction (MI, n = 9) underwent high-resolution mapping of the anteroapical left ventricle at baseline and during left and right stellate ganglion stimulation (LSGS and RSGS, respectively). Conduction velocity (CV), activation times (ATs), and directionality of propagation were measured. Myocardial fiber orientation was determined using diffusion tensor imaging and histology. Longitudinal CV (CVL) was increased by RSGS (0.98 +/- 0.11 vs. 1.2 +/- 0.14m/s, P < 0.001) but not transverse CV (CVT). This increase was abrogated by beta-adrenergic receptor and gap junction (GJ) blockade. Neither CVL nor CVT was increased by LSGS. In the peri-infarct region, both RSGS and LSGS shortened ARIs in sinus rhythm (423 +/- 37 vs. 322 +/- 30 ms, P < 0.001, and 423 +/- 36 vs. 398 +/- 36 ms, P = 0.035, respectively) and altered activation patterns in all animals. CV, as estimated by mean ATs, increased in a directionally dependent manner by RSGS (14.6 +/- 1.2 vs. 17.3 +/- 1.6 ms, P = 0.015), associated with GJ lateralization. RSGS and LSGS inhomogeneously modulated AT and induced relative or absolute functional activation delay in parts of the mapped regions in 75 and 67%, respectively, in MI animals, and in 0 and 15%, respectively, in control animals (P < 0.001 for both). In conclusion, sympathoexcitation increases CV in normal myocardium and modulates activation propagation in peri-infarcted ventricular myocardium. These data demonstrate functional control of arrhythmogenic peri-infarct substrates by sympathetic nerves and in part explain the temporal nature of arrhythmogenesis.NEW & NOTEWORTHY This study demonstrates regional control of conduction velocity in normal hearts by sympathetic nerves. In infarcted hearts, however, not only is modulation of propagation heterogeneous, some regions showed paradoxical conduction slowing. Sympathoexcitation altered propagation in all infarcted hearts studied, and we describe the temporal arrhythmogenic potential of these findings.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/sympathetic-nerves-and-cardiac-propagation/. PMID- 28087522 TI - Nicholas Wright. PMID- 28087523 TI - Use of acupuncture in the USA: changes over a decade (2002-2012). AB - BACKGROUND: The use of acupuncture has gained popularity in the USA. The number of acupuncture users and licensed acupuncturists increased by 50% and 100%, respectively, between 2002 and 2012, coinciding with increasing acknowledgement of the importance and efficacy of acupuncture over this time period. METHODS: This paper presents new findings from the complementary health approaches section of the 2012 National Health Interview Survey (n=33 373 respondents). In particular, data on the use of acupuncture and user characteristics were compared against data collected from an earlier survey in 2002. Statistical analyses included weighted distribution, logistical regression and Pearson's chi2 tests. RESULTS: The profile of the most common acupuncture users comprised the following sociodemographics age 41-65 years (47.4%); female gender (69.6%); and non Hispanic (85.3%) and/or white (78.1%) ethnicity. Respondents also tended to be US citizens (92.1%) with some college education (57.1%) and in very good to excellent health (60.8%). The proportion of respondents using acupuncture for treatment of a specific health problem, as opposed to promotion of general wellness, was 84.7% in 2002 and 55.3% in 2012. CONCLUSIONS: Our data suggest a growing development of acupuncture in the USA. We anticipate that the findings of our analysis of the changes in acupuncture use over the 10-year period from 2002 to 2012 will provide information for users, acupuncturists, researchers and the general public to help better understand the status of acupuncture and reasons for its usage, and to anticipate future trends for acupuncture use in the USA. PMID- 28087524 TI - US Senate takes first step to repeal Affordable Care Act. PMID- 28087520 TI - Atheroprotective vaccination with MHC-II-restricted ApoB peptides induces peritoneal IL-10-producing CD4 T cells. AB - Although immunization with major histocompatibility complex (MHC) class II restricted apolipoprotein B (ApoB) peptides has been shown to be atheroprotective, the mechanism is unclear. Here, we investigated CD4+ T cell populations in immunized atherosclerotic mice. Peptides (16-mers) from mouse ApoB, the core protein of low-density lipoprotein (LDL), were screened for binding to I-Ab by computer prediction and confirmed by radiolabeled peptide competition. Three new peptides, P101 (FGKQGFFPDSVNKALY, 5.5 nM IC50), P102 (TLYALSHAVNSYFDVD, 6.8 nM), and P103 (LYYKEDKTSLSASAAS, 95 nM), were tested in an atherosclerosis model (Apoe-/- mice on Western diet). Immunization with each of the three peptides (1 time in complete Freund's adjuvant subcuntaneously and 4 time in incomplete Freund's adjuvant intraperitoneally) but not with adjuvant alone showed significantly reduced atherosclerotic plaques in the aortic root by serial sections and in the whole aorta by en face staining. There were no differences in body weight, LDL cholesterol, or triglycerides. Peritoneal leukocytes from ApoB peptide-immunized mice, but not control mice, secreted significant amounts of IL-10 (150 pg/ml). Flow cytometry showed that peptide immunization induced IL-10 in 10% of peritoneal CD4+ T cells, some of which also expressed chemokine (C-C motif) receptor 5 (CCR5). Vaccination with ApoB peptides expanded peritoneal FoxP3+ regulatory CD4+ T cells and more than tripled the number of CCR5+FoxP3+ cells. Similar trends were also seen in the draining mediastinal lymph nodes but not in the nondraining inguinal lymph nodes. We conclude that vaccination with MHC class II-restricted autologous ApoB peptides induces regulatory T cells (Tregs) and IL-10, suggesting a plausible mechanism for atheroprotection.NEW & NOTEWORTHY Vaccination against apolipoprotein B (ApoB), the protein of LDL, attracts attention as a novel approach to prevent atherosclerosis. We discovered major histocompatibility complex class II restricted ApoB peptides, which reduce atherosclerosis and induce IL-10-producing CD4+ T cells and chemokine (C-C motif) receptor 5 expression on regulatory T cells, suggesting that immunization with ApoB peptides inhibits atherosclerosis by inducing anti-inflammatory cytokines. PMID- 28087525 TI - Capturing Compositional Variation in Denitrifying Communities: a Multiple-Primer Approach That Includes Epsilonproteobacteria. AB - Denitrifying Epsilonproteobacteria may dominate nitrogen loss processes in marine habitats with intense redox gradients, but assessment of their importance is limited by the currently available primers for nitrite reductase genes. Nine new primers targeting the nirS gene of denitrifying Epsilonproteobacteria were designed and tested for use in sequencing and quantitative PCR on two microbial mat samples (vent 2 and vent 4) from the Calypso hydrothermal vent field, Bay of Plenty, New Zealand. Commonly used nirS and nirK primer sets nirS1F/nirS6R, cd3aF/R3cd, nirK1F/nirK5R, and F1aCu/R3Cu were also tested to determine what may be missed by the common single-primer approach to assessing denitrifier diversity. The relative importance of Epsilonproteobacteria in these samples was evaluated by 16S rRNA gene sequencing. Epsilonproteobacteria represented up to 75.6% of 16S rRNA libraries, but nirS genes from this group were not found with commonly used primers. Pairing of the new primer EPSnirS511F with either EPSnirS1100R or EPSnirS1105R recovered nirS sequences from members of the genera Sulfurimonas, Sulfurovum, and Nitratifractor. The new quantitative PCR primers EPSnirS103F/EPSnirS530R showed dominance of denitrifying Epsilonproteobacteria in vent 4 compared to vent 2, which had greater representation by "standard" denitrifiers measured with the cd3aF/R3cd primers. Limited results from commonly used nirK primers suggest biased amplification between primers. Future application of multiple nirS and nirK primers, including the new epsilonproteobacterial nirS primers, will improve the detection of denitrifier diversity and the capability to identify changes in dominant denitrifying communities.IMPORTANCE Estimating the potential for increasing nitrogen limitation in the changing global ocean is reliant on understanding the microbial community that removes nitrogen through the process of denitrification. This process is favored under oxygen limitation, which is a growing global-ocean phenomenon. Current methods use the nitrite reductase genes nirS and nirK to assess denitrifier diversity and abundance using primers that target only a few known denitrifiers and systematically exclude denitrifying Epsilonproteobacteria, a group known to dominate in reducing environments, such as hydrothermal vents and anoxic basins. As oxygen depletion expands in the oceans, it is important to study denitrifier community dynamics within those areas to predict future global ocean changes. This study explores the design and testing of new primers that target epsilonproteobacterial nirS and reveals the varied success of existing primers, leading to the recommendation of a multiple-primer approach to assessing denitrifier diversity. PMID- 28087526 TI - Rapid Enrichment of Dehalococcoides-Like Bacteria by Partial Hydrophobic Separation. AB - Organohalide-respiring bacteria can be difficult to enrich and isolate, which can limit research on these important organisms. The goal of this research was to develop a method to rapidly (minutes to days) enrich these organisms from a mixed community. The method presented is based on the hypothesis that organohalide respiring bacteria would be more hydrophobic than other bacteria as they dehalogenate hydrophobic compounds. The method developed tests this hypothesis by separating a portion of putative organohalide-respiring bacteria, those phylogenetically related to Dehalococcoides mccartyi, at the interface between a hydrophobic organic solvent and an aqueous medium. This novel partial separation technique was tested with a polychlorinated biphenyl-enriched sediment-free culture, a tetrachloroethene-enriched digester sludge culture, and uncontaminated lake sediment. Significantly higher fractions, up to 20.4 times higher, of putative organohalide-respiring bacteria were enriched at the interface between the medium and either hexadecane or trichloroethene. The selective partial separation of these putative organohalide-respiring bacteria occurred after 20 min, strongly suggesting that the separation was a result of physical-chemical interactions between the cell surface and hydrophobic solvent. Dechlorination activity postseparation was verified by the production of cis-dichloroethene when amended with tetrachloroethene. A longer incubation time of 6 days prior to separation with trichloroethene increased the total number of putative organohalide-respiring bacteria. This method provides a way to quickly separate some of the putative organohalide-respiring bacteria from other bacteria, thereby improving our ability to study multiple and different bacteria of potential interest and improving knowledge of these bacteria.IMPORTANCE Organohalide respiring bacteria, bacteria capable of respiring chlorinated contaminants, can be difficult to enrich, which can limit their predictable use for the bioremediation of contaminated sites. This paper describes a method to quickly separate Dehalococcoides-like bacteria, a group of organisms containing organohalide-respiring bacteria, from other bacteria in a mixed community. From this work, Dehalococcoides-like bacteria appear to have a hydrophobic cell surface, facilitating a rapid (20 min) partial separation from a mixed culture at the surface of a hydrophobic liquid. This method was verified in a polychlorinated biphenyl-enriched sediment-free culture, an anaerobic digester sludge, and uncontaminated sediment. The method described can drastically reduce the amount of time required to partially separate Dehalococcoides-like bacteria from a complex mixed culture, improving researchers' ability to study these important bacteria. PMID- 28087527 TI - Floc Formation Reduces the pH Stress Experienced by Microorganisms Living in Alkaline Environments. AB - The survival of microorganisms within a cementitious geological disposal facility for radioactive wastes heavily depends on their ability to survive the calcium dominated, hyperalkaline conditions resulting from the dissolution of the cementitious materials. The results from this study show that the formation of flocs, composed of a complex mixture of extracellular polymeric substances (EPS), provides protection against alkaline pH values up to 13.0. The flocs were dominated by Alishewanella and Dietzia spp., producing a mannose-rich carbohydrate fraction incorporating extracellular DNA, resulting in Ca2+ sequestration. EPS provided a ~10-MUm thick layer around the cells within the center of the flocs, which were capable of growth at pH values of 11.0 and 11.5, maintaining internal pH values of 10.4 and 10.7, respectively. Microorganisms survived at a pH of 12.0, where an internal floc pH of 11.6 was observed, as was a reduced associated biomass. We observed limited floc survival (<2 weeks) at a pH of 13.0. This study demonstrates that flocs maintain lower internal pHs in response to the hyperalkaline conditions expected to occur within a cementitious geological disposal facility for radioactive wastes and indicates that floc communities within such a facility can survive at pHs up to 12.0.IMPORTANCE The role of extracellular polymeric substances (EPS) in the survival of microorganisms in hyperalkaline conditions is poorly understood. Here, we present the taxonomy, morphology, and chemical characteristics of an EPS-based microbial floc, formed by a consortium isolated from an anthropogenic hyperalkaline site. Short-term (<2 weeks) survival of the flocs at a pH of 13 was observed, with indefinite survival observed at a pH of 12.0. Measurements from micro-pH electrodes (10-MUm-diameter tip) demonstrated that flocs maintain lower internal pHs in response to hyperalkaline conditions (pH 11.0, 11.5, and 12.0), demonstrating that floc formation and EPS production are survival strategies under hyperalkaline conditions. The results indicate how microbial communities may survive and propagate within the hyperalkaline environment that is expected to prevail in a cementitious geological disposal facility for radioactive wastes; the results are also relevant to the wider extremophile community. PMID- 28087528 TI - Engineering Mycobacteria for the Production of Self-Assembling Biopolyesters Displaying Mycobacterial Antigens for Use as a Tuberculosis Vaccine. AB - : Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis or Mycobacterium bovis and still remains one of the world's biggest global health burdens. Recently, engineered polyhydroxyalkanoate (PHA) biobeads that were produced in both Escherichia coli and Lactococcus lactis and displayed mycobacterial antigens were found to induce significant cell-mediated immune responses in mice. We observed that such PHA beads contained host cell proteins as impurities, which we hypothesized to have the potential to induce immunity. In this study, we aimed to develop PHA beads produced in mycobacteria (mycobacterial PHA biobeads [MBB]) and test their potential as a TB vaccine in a mouse model. As a model organism, nonpathogenic Mycobacterium smegmatis was engineered to produce MBB or MBB with immobilized mycobacterial antigens Ag85A and ESAT-6 on their surface (A:E-MBB). Three key enzymes involved in the poly(3-hydroxybutyric acid) pathway, namely, beta-ketothiolase (PhaA), acetoacetyl-coenzyme A reductase (PhaB), and PHA synthase (PhaC), were engineered into E. coli-Mycobacterium shuttle plasmids and expressed in trans Immobilization of specific antigens to the surface of the MBB was achieved by creating a fusion with the PHA synthase which remains covalently attached to the polyester core, resulting in PHA biobeads displaying covalently immobilized antigens. MBB, A: E-MBB, and an M. smegmatis vector control (MVC) were used in a mouse immunology trial, with comparison to phosphate-buffered saline (PBS)-vaccinated and Mycobacterium bovis BCG-vaccinated groups. We successfully produced MBB and A:E-MBB and used them as vaccines to induce a cellular immune response to mycobacterial antigens.IMPORTANCE Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis or Mycobacterium bovis and still remains one of the world's biggest global health burdens. In this study, we produced polyhydroxyalkanoate (PHA) biobeads in mycobacteria and used them as vaccines to induce a cellular immune response to mycobacterial antigens. PMID- 28087529 TI - Resilience, Dynamics, and Interactions within a Model Multispecies Exoelectrogenic-Biofilm Community. AB - Anode-associated multispecies exoelectrogenic biofilms are essential for the function of bioelectrochemical systems (BESs). The individual activities of anode associated organisms and physiological responses resulting from coculturing are often hard to assess due to the high microbial diversity in these systems. Therefore, we developed a model multispecies biofilm comprising three exoelectrogenic proteobacteria, Shewanella oneidensis, Geobacter sulfurreducens, and Geobacter metallireducens, with the aim to study in detail the biofilm formation dynamics, the interactions between the organisms, and the overall activity of an exoelectrogenic biofilm as a consequence of the applied anode potential. The experiments revealed that the organisms build a stable biofilm on an electrode surface that is rather resilient to changes in the redox potential of the anode. The community operated at maximum electron transfer rates at electrode potentials that were higher than 0.04 V versus a normal hydrogen electrode. Current densities decreased gradually with lower potentials and reached half-maximal values at -0.08 V. Transcriptomic results point toward a positive interaction among the individual strains. S. oneidensis and G. sulfurreducens upregulated their central metabolisms as a response to cultivation under mixed-species conditions. G. sulfurreducens was detected in the planktonic phase of the bioelectrochemical reactors in mixed-culture experiments but not when it was grown in the absence of the other two organisms.IMPORTANCE In many cases, multispecies communities can convert organic substrates into electric power more efficiently than axenic cultures, a phenomenon that remains unresolved. In this study, we aimed to elucidate the potential mutual effects of multispecies communities in bioelectrochemical systems to understand how microbes interact in the coculture anodic network and to improve the community's conversion efficiency for organic substrates into electrical energy. The results reveal positive interactions that might lead to accelerated electron transfer in mixed-species anode communities. The observations made within this model biofilm might be applicable to a variety of nonaxenic systems in the field. PMID- 28087530 TI - Pgas, a Low-pH-Induced Promoter, as a Tool for Dynamic Control of Gene Expression for Metabolic Engineering of Aspergillus niger. AB - The dynamic control of gene expression is important for adjusting fluxes in order to obtain desired products and achieve appropriate cell growth, particularly when the synthesis of a desired product drains metabolites required for cell growth. For dynamic gene expression, a promoter responsive to a particular environmental stressor is vital. Here, we report a low-pH-inducible promoter, Pgas, which promotes minimal gene expression at pH values above 5.0 but functions efficiently at low pHs, such as pH 2.0. First, we performed a transcriptional analysis of Aspergillus niger, an excellent platform for the production of organic acids, and we found that the promoter Pgas may act efficiently at low pH. Then, a gene for synthetic green fluorescent protein (sGFP) was successfully expressed by Pgas at pH 2.0, verifying the results of the transcriptional analysis. Next, Pgas was used to express the cis-aconitate decarboxylase (cad) gene of Aspergillus terreus in A. niger, allowing the production of itaconic acid at a titer of 4.92 g/liter. Finally, we found that Pgas strength was independent of acid type and acid ion concentration, showing dependence on pH only.IMPORTANCE The promoter Pgas can be used for the dynamic control of gene expression in A. niger for metabolic engineering to produce organic acids. This promoter may also be a candidate tool for genetic engineering. PMID- 28087531 TI - Salivary Gluten Degradation and Oral Microbial Profiles in Healthy Individuals and Celiac Disease Patients. AB - Celiac disease (CD) is a chronic immune-mediated enteropathy induced by dietary gluten in genetically predisposed individuals. Saliva harbors the second highest bacterial load of the gastrointestinal (GI) tract after the colon. We hypothesized that enzymes produced by oral bacteria may be involved in gluten processing in the intestine and susceptibility to celiac disease. The aim of this study was to investigate salivary enzymatic activities and oral microbial profiles in healthy subjects versus patients with classical and refractory CD. Stimulated whole saliva was collected from patients with CD in remission (n = 21) and refractory CD (RCD; n = 8) and was compared to healthy controls (HC; n = 20) and subjects with functional GI complaints (n = 12). Salivary gluten-degrading activities were monitored with the tripeptide substrate Z-Tyr-Pro-Gln-pNA and the alpha-gliadin-derived immunogenic 33-mer peptide. The oral microbiome was profiled by 16S rRNA-based MiSeq analysis. Salivary glutenase activities were higher in CD patients compared to controls, both before and after normalization for protein concentration or bacterial load. The oral microbiomes of CD and RCD patients showed significant differences from that of healthy subjects, e.g., higher salivary levels of lactobacilli (P < 0.05), which may partly explain the observed higher gluten-degrading activities. While the pathophysiological link between the oral and gut microbiomes in CD needs further exploration, the presented data suggest that oral microbe-derived enzyme activities are elevated in subjects with CD, which may impact gluten processing and the presentation of immunogenic gluten epitopes to the immune system in the small intestine.IMPORTANCE Ingested gluten proteins are the triggers of intestinal inflammation in celiac disease (CD). Certain immunogenic gluten domains are resistant to intestinal proteases but can be hydrolyzed by oral microbial enzymes. Very little is known about the endogenous proteolytic processing of gluten proteins in the oral cavity. Given that this occurs prior to gluten reaching the small intestine, such enzymes are likely to contribute to the composition of the gluten digest that ultimately reaches the small intestine and causes CD. We demonstrated that endogenous salivary protease activities are incomplete, likely liberating peptides from larger gluten proteins. The potentially responsible microbes were identified. The study included refractory CD patients, who have been studied less with regard to CD pathogenesis. PMID- 28087532 TI - Establishment and Validation of RNA-Based Predictive Models for Understanding Survival of Vibrio parahaemolyticus in Oysters Stored at Low Temperatures. AB - This study developed RNA-based predictive models describing the survival of Vibrio parahaemolyticus in Eastern oysters (Crassostrea virginica) during storage at 0, 4, and 10 degrees C. Postharvested oysters were inoculated with a cocktail of five V. parahaemolyticus strains and were then stored at 0, 4, and 10 degrees C for 21 or 11 days. A real-time reverse transcription-PCR (RT-PCR) assay targeting expression of the tlh gene was used to evaluate the number of surviving V. parahaemolyticus cells, which was then used to establish primary molecular models (MMs). Before construction of the MMs, consistent expression levels of the tlh gene at 0, 4, and 10 degrees C were confirmed, and this gene was used to monitor the survival of the total V. parahaemolyticus cells. In addition, the tdh and trh genes were used for monitoring the survival of virulent V. parahaemolyticus Traditional models (TMs) were built based on data collected using a plate counting method. From the MMs, V. parahaemolyticus populations had decreased 0.493, 0.362, and 0.238 log10 CFU/g by the end of storage at 0, 4, and 10 degrees C, respectively. Rates of reduction of V. parahaemolyticus shown in the TMs were 2.109, 1.579, and 0.894 log10 CFU/g for storage at 0, 4, and 10 degrees C, respectively. Bacterial inactivation rates (IRs) estimated with the TMs (-0.245, -0.152, and -0.121 log10 CFU/day, respectively) were higher than those estimated with the MMs (-0.134, -0.0887, and -0.0732 log10 CFU/day, respectively) for storage at 0, 4, and 10 degrees C. Higher viable V. parahaemolyticus numbers were predicted using the MMs than using the TMs. On the basis of this study, RNA-based predictive MMs are the more accurate and reliable models and can prevent false-negative results compared to TMs.IMPORTANCE One important method for validating postharvest techniques and for monitoring the behavior of V. parahaemolyticus is to establish predictive models. Unfortunately, previous predictive models established based on plate counting methods or on DNA based PCR can underestimate or overestimate the number of surviving cells. This study developed and validated RNA-based molecular predictive models to describe the survival of V. parahaemolyticus in oysters during low-temperature storage (0, 4, and 10 degrees C). The RNA-based predictive models show the advantage of being able to count all of the culturable, nonculturable, and stressed cells. By using primers targeting the tlh gene and pathogenesis-associated genes (tdh and trh), real-time RT-PCR can evaluate the total surviving V. parahaemolyticus population as well as differentiate the pathogenic ones from the total population. Reliable and accurate predictive models are very important for conducting risk assessment and management of pathogens in food. PMID- 28087533 TI - Polysaccharide Degradation Capability of Actinomycetales Soil Isolates from a Semiarid Grassland of the Colorado Plateau. AB - Among the bacteria, members of the order Actinomycetales are considered quintessential degraders of complex polysaccharides in soils. However, studies examining complex polysaccharide degradation by Actinomycetales (other than Streptomyces spp.) in soils are limited. Here, we examine the lignocellulolytic and chitinolytic potential of 112 Actinomycetales strains, encompassing 13 families, isolated from a semiarid grassland of the Colorado Plateau in Utah. Members of the Streptomycetaceae, Pseudonocardiaceae, Micromonosporaceae, and Promicromonosporaceae families exhibited robust activity against carboxymethyl cellulose, xylan, chitin, and pectin substrates (except for low/no pectinase activity by the Micromonosporaceae). When incubated in a hydrated mixture of blended Stipa and Hilaria grass biomass over a 5-week period, Streptomyces and Saccharothrix (a member of the Pseudonocardiaceae) isolates produced high levels of extracellular enzyme activity, such as endo- and exocellulase, glucosidase, endo- and exoxylosidase, and arabinofuranosidase. These characteristics make them well suited to degrade the cellulose and hemicellulose components of grass cell walls. On the basis of the polysaccharide degradation profiles of the isolates, relative abundance of Actinomycetales sequences in 16S rRNA gene surveys of Colorado Plateau soils, and analysis of genes coding for polysaccharide-degrading enzymes among 237 Actinomycetales genomes in the CAZy database and 5 genomes from our isolates, we posit that Streptomyces spp. and select members of the Pseudonocardiaceae and Micromonosporaceae likely play an important role in the degradation of hemicellulose, cellulose, and chitin substances in dryland soils.IMPORTANCE Shifts in the relative abundance of Actinomycetales taxa have been observed in soil microbial community surveys during large, manipulated climate change field studies. However, our limited understanding of the ecophysiology of diverse Actinomycetales taxa in soil systems undermines attempts to determine the underlying causes of the population shifts or their impact on carbon cycling in soil. This study combines a systematic analysis of the polysaccharide degradation potential of a diverse collection of Actinomycetales isolates from surface soils of a semiarid grassland with analysis of genomes from five of these isolates and publicly available Actinomycetales genomes for genes encoding polysaccharide-active enzymes. The results address an important gap in knowledge of Actinomycetales ecophysiology-identification of key taxa capable of facilitating lignocellulose degradation in dryland soils. Information from this study will benefit future metagenomic studies related to carbon cycling in dryland soils by providing a baseline linkage of Actinomycetales phylogeny with lignocellulolytic functional potential. PMID- 28087534 TI - Mechanisms of Horizontal Cell-to-Cell Transfer of Wolbachia spp. in Drosophila melanogaster. AB - Wolbachia is an intracellular endosymbiont present in most arthropod and filarial nematode species. Transmission between hosts is primarily vertical, taking place exclusively through the female germ line, although horizontal transmission has also been documented. The results of several studies indicate that Wolbachia spp. can undergo transfer between somatic and germ line cells during nematode development and in adult flies. However, the mechanisms underlying horizontal cell-to-cell transfer remain largely unexplored. Here, we establish a tractable system for probing horizontal transfer of Wolbachia cells between Drosophila melanogaster cells in culture using fluorescence in situ hybridization (FISH). First, we show that horizontal transfer is independent of cell-to-cell contact and can efficiently take place through the culture medium within hours. Further, we demonstrate that efficient transfer utilizes host cell phagocytic and clathrin/dynamin-dependent endocytic machinery. Lastly, we provide evidence that this process is conserved between species, showing that horizontal transfer from mosquito to Drosophila cells takes place in a similar fashion. Altogether, our results indicate that Wolbachia utilizes host internalization machinery during infection, and this mechanism is conserved across insect species.IMPORTANCE Our work has broad implications for the control and treatment of tropical diseases. Wolbachia can confer resistance against a variety of human pathogens in mosquito vectors. Elucidating the mechanisms of horizontal transfer will be useful for efforts to more efficiently infect nonnatural insect hosts with Wolbachia as a biological control agent. Further, as Wolbachia is essential for the survival of filarial nematodes, understanding horizontal transfer might provide new approaches to treating human infections by targeting Wolbachia Finally, this work provides a key first step toward the genetic manipulation of Wolbachia. PMID- 28087535 TI - Efficient Low-pH Iron Removal by a Microbial Iron Oxide Mound Ecosystem at Scalp Level Run. AB - Acid mine drainage (AMD) is a major environmental problem affecting tens of thousands of kilometers of waterways worldwide. Passive bioremediation of AMD relies on microbial communities to oxidize and remove iron from the system; however, iron oxidation rates in AMD environments are highly variable among sites. At Scalp Level Run (Cambria County, PA), first-order iron oxidation rates are 10 times greater than at other coal-associated iron mounds in the Appalachians. We examined the bacterial community at Scalp Level Run to determine whether a unique community is responsible for the rapid iron oxidation rate. Despite strong geochemical gradients, including a >10-fold change in the concentration of ferrous iron from 57.3 mg/liter at the emergence to 2.5 mg/liter at the base of the coal tailings pile, the bacterial community composition was nearly constant with distance from the spring outflow. Scalp Level Run contains many of the same taxa present in other AMD sites, but the community is dominated by two strains of Ferrovum myxofaciens, a species that is associated with high rates of Fe(II) oxidation in laboratory studies.IMPORTANCE Acid mine drainage pollutes more than 19,300 km of rivers and streams and 72,000 ha of lakes worldwide. Remediation is frequently ineffective and costly, upwards of $100 billion globally and nearly $5 billion in Pennsylvania alone. Microbial Fe(II) oxidation is more efficient than abiotic Fe(II) oxidation at low pH (P. C. Singer and W. Stumm, Science 167:1121-1123, 1970, https://doi.org/10.1126/science.167.3921.1121). Therefore, AMD bioremediation could harness microbial Fe(II) oxidation to fuel more-cost-effective treatments. Advances will require a deeper understanding of the ecology of Fe(II)-oxidizing microbial communities and the factors that control their distribution and rates of Fe(II) oxidation. We investigated bacterial communities that inhabit an AMD site with rapid Fe(II) oxidation and found that they were dominated by two operational taxonomic units (OTUs) of Ferrovum myxofaciens, a taxon associated with high laboratory rates of iron oxidation. This research represents a step forward in identifying taxa that can be used to enhance cost-effective AMD bioremediation. PMID- 28087536 TI - Lysobacter PilR, the Regulator of Type IV Pilus Synthesis, Controls Antifungal Antibiotic Production via a Cyclic di-GMP Pathway. AB - Lysobacter enzymogenes is a ubiquitous soil gammaproteobacterium that produces a broad-spectrum antifungal antibiotic, known as heat-stable antifungal factor (HSAF). To increase HSAF production for use against fungal crop diseases, it is important to understand how HSAF synthesis is regulated. To gain insights into transcriptional regulation of the HSAF synthesis gene cluster, we generated a library with deletion mutations in the genes predicted to encode response regulators of the two-component signaling systems in L. enzymogenes strain OH11. By quantifying HSAF production levels in the 45 constructed mutants, we identified two strains that produced significantly smaller amounts of HSAF. One of the mutations affected a gene encoding a conserved bacterial response regulator, PilR, which is commonly associated with type IV pilus synthesis. We determined that L. enzymogenes PilR regulates pilus synthesis and twitching motility via a traditional pathway, by binding to the pilA promoter and upregulating pilA expression. Regulation of HSAF production by PilR was found to be independent of pilus formation. We discovered that the pilR mutant contained significantly higher intracellular levels of the second messenger cyclic di-GMP (c-di-GMP) and that this was the inhibitory signal for HSAF production. Therefore, the type IV pilus regulator PilR in L. enzymogenes activates twitching motility while downregulating antibiotic HSAF production by increasing intracellular c-di-GMP levels. This study identifies a new role of a common pilus regulator in proteobacteria and provides guidance for increasing antifungal antibiotic production in L. enzymogenesIMPORTANCE PilR is a widespread response regulator of the two-component system known for regulating type IV pilus synthesis in proteobacteria. Here we report that, in the soil bacterium Lysobacter enzymogenes, PilR regulates pilus synthesis and twitching motility, as expected. Unexpectedly, PilR was also found to control intracellular levels of the second messenger c-di-GMP, which in turn inhibits production of the antifungal antibiotic HSAF. The coordinated production of type IV pili and antifungal antibiotics has not been observed previously. PMID- 28087537 TI - Effects of Lactobacillus plantarum Strain OLL2712 Culture Conditions on the Anti inflammatory Activities for Murine Immune Cells and Obese and Type 2 Diabetic Mice. AB - Studies on the health-promoting effects of lactic acid bacteria (LAB) are numerous, but few provide examples of the relationship between LAB function and culture conditions. We verified the effect of differences in culture conditions on Lactobacillus plantarum OLL2712 functionality; this strain exhibits anti inflammatory activity and preventive effects against metabolic disorders. We measured interleukin-10 (IL-10) and IL-12 production in murine immune cells treated with OLL2712 cells prepared under various culture conditions. The results showed that the IL-10-inducing activities of OLL2712 cells on murine immune cells differed dramatically between OLL2712 groups at different culture phases and using different culture medium components, temperatures, and neutralizing pHs. In particular, exponential-phase cells had much more IL-10-inducing activity than stationary-phase cells. We confirmed that the Toll-like receptor 2 (TLR2) stimulation activity of OLL2712 cells depended on culture conditions in conjunction with IL-10-inducing activity. We also demonstrated functional differences by culture phases in vivo; OLL2712 cells at exponential phase had more anti-inflammatory activity and anti-metabolic-disorder effects on obese and diabetic mice than those by their stationary-phase counterparts. These results suggest that culture conditions affect the functionality of anti-inflammatory LAB.IMPORTANCE While previous studies demonstrated that culture conditions affected the immunomodulatory properties of lactic acid bacteria (LAB), few have comprehensively investigated the relationship between culture conditions and LAB functionality. In this study, we demonstrated several culture conditions of Lactobacillus plantarum OLL2712 for higher anti-inflammatory activity. We also showed that culture conditions concretely influenced the health-promoting functions of OLL2712 in vivo, particularly against metabolic disorders. Further, we characterized a novel mechanism by which changing LAB culture conditions affected immunomodulatory properties. Our results suggest that culture condition optimization is important for the production of LAB with anti-inflammatory activity. PMID- 28087538 TI - BCAP inhibits proliferation and differentiation of myeloid progenitors in the steady state and during demand situations. AB - B-cell adaptor for phosphatidylinositol 3-kinase (BCAP) is a signaling adaptor expressed in mature hematopoietic cells, including monocytes and neutrophils. Here we investigated the role of BCAP in the homeostasis and development of these myeloid lineages. BCAP-/- mice had more bone marrow (BM) monocytes than wild-type (WT) mice, and in mixed WT:BCAP-/- BM chimeras, monocytes and neutrophils skewed toward BCAP-/- origin, showing a competitive advantage for BCAP-/- myeloid cells. BCAP was expressed in BM hematopoietic progenitors, including lineage-Sca-1+c kit+ (LSK), common myeloid progenitor, and granulocyte/macrophage progenitor (GMP) cells. At the steady state, BCAP-/- GMP cells expressed more IRF8 and less C/EBPalpha than did WT GMP cells, which correlated with an increase in monocyte progenitors and a decrease in granulocyte progenitors among GMP cells. Strikingly, BCAP-/- progenitors proliferated and produced more myeloid cells of both neutrophil and monocyte/macrophage lineages than did WT progenitors in myeloid colony-forming unit assays, supporting a cell-intrinsic role of BCAP in inhibiting myeloid proliferation and differentiation. Consistent with these findings, during cyclophosphamide-induced myeloablation or specific monocyte depletion, BCAP-/- mice replenished circulating monocytes and neutrophils earlier than WT mice. During myeloid replenishment after cyclophosphamide-induced myeloablation, BCAP-/- mice had increased LSK proliferation and increased numbers of LSK and GMP cells compared with WT mice. Furthermore, BCAP-/- mice accumulated more monocytes and neutrophils in the spleen than did WT mice during Listeria monocytogenes infection. Together, these data identify BCAP as a novel inhibitor of myelopoiesis in the steady state and of emergency myelopoiesis during demand conditions. PMID- 28087541 TI - This is my house - respect it. PMID- 28087540 TI - International, evidence-based consensus diagnostic criteria for HHV-8 negative/idiopathic multicentric Castleman disease. AB - Human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research. PMID- 28087539 TI - Quantitative stability of hematopoietic stem and progenitor cell clonal output in rhesus macaques receiving transplants. AB - Autologous transplantation of hematopoietic stem and progenitor cells lentivirally labeled with unique oligonucleotide barcodes flanked by sequencing primer targets enables quantitative assessment of the self-renewal and differentiation patterns of these cells in a myeloablative rhesus macaque model. Compared with other approaches to clonal tracking, this approach is highly quantitative and reproducible. We documented stable multipotent long-term hematopoietic clonal output of monocytes, granulocytes, B cells, and T cells from a polyclonal pool of hematopoietic stem and progenitor cells in 4 macaques observed for up to 49 months posttransplantation. A broad range of clonal behaviors characterized by contribution level and biases toward certain cell types were extremely stable over time. Correlations between granulocyte and monocyte clonalities were greatest, followed by correlations between these cell types and B cells. We also detected quantitative expansion of T cell-biased clones consistent with an adaptive immune response. In contrast to recent data from a nonquantitative murine model, there was little evidence for clonal succession after initial hematopoietic reconstitution. These findings have important implications for human hematopoiesis, given the similarities between macaque and human physiologies. PMID- 28087542 TI - NHS in 2017: the long arm of government. PMID- 28087543 TI - Leisure-time sport and overuse injuries of extremities in children age 6-13, a 2.5 years prospective cohort study: the CHAMPS-study DK. AB - OBJECTIVES: It is not known which sports are most likely to cause overuse injuries of the extremities in children. In this study, we report on the incidence of overuse injuries of the upper and lower extremities in children who participate in various leisure-time sports and relate this to the frequency of sport sessions. DESIGN: Natural experiment including a prospective cohort study. SETTING: 10 state schools in 1 Danish municipality: Svendborg. PARTICIPANTS: 1270 children aged 6-13 years participating in the Childhood Health, Activity, and Motor Performance School Study Denmark. OUTCOMES MEASURES: Over 2.5 years, parents answered weekly SMS-track messages (a) on type and frequency of leisure time sports undertaken by their child, and (b) reporting if their child had experienced any musculoskeletal pain. Children with reported pain were examined by a clinician and diagnosed as having an overuse injury of an extremity or not. The incidence of diagnosed overuse injury was calculated for each of the 9 most common sports in relation to 5-week periods. Incidence by frequency of sessions was calculated, and multivariable analysis was performed taking into account age, sex and frequency of physical education classes at school. RESULTS: Incidence of overuse injuries of the lower extremity ranged from 0.2 to 3.3 for the 9 sports, but was near 0 for overuse injuries of the upper extremities. There was no obvious dose-response. The multivariate analysis showed soccer and handball to be the sports most likely to result in an overuse injury. CONCLUSIONS: Among a general population of schoolchildren, overuse injuries of the lower extremities were not common and overuse injuries of the upper extremities were rare. Organised leisure-time sport, as practised in Denmark, can be considered a safe activity for children. PMID- 28087544 TI - Children's experiences of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review and meta-ethnography of qualitative studies. AB - OBJECTIVE: To synthesis the qualitative studies of children's experiences of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). DESIGN: Systematic review and meta-ethnography. BACKGROUND: CFS/ME is an important disabling illness, with uncertain cause and prognosis. As a result, children with CFS/ME can find themselves living with greater uncertainty and stigma, exacerbating the impact of the condition. There is a growing body of qualitative research in CFS/ME, yet there has been no attempt to systematically synthesis the studies involving children. METHODS: Studies exploring the experiences of children diagnosed with CFS/ME, published or unpublished, using qualitative methods were eligible. MEDLINE, EMBASE, PsycINFO and CINAHL databases were searched as well as grey literature, reference lists and contacting authors. Quality assessment was done independently using the Critical Appraisal Skills Programme (CASP) checklist. Studies were synthesised using techniques of meta-ethnography. RESULTS: Ten studies involving 82 children with CFS/ME aged 8-18 were included. Our synthesis describes four third-order constructs within children's experiences: (1) disruption and loss: physical, social and the self; (2) barriers to coping: suspension in uncertainty, problems with diagnosis and disbelief; (3) facilitators to coping: reducing uncertainty, credible illness narratives, diagnosis and supportive relationships and (4) hope, personal growth and recovery. CFS/ME introduces profound biographical disruption through its effects on children's ability to socialise, perform school and therefore how they see their future. Unfamiliarity of the condition, problems with diagnosis and felt stigma prevent children from forming a new illness identity. Children adopt coping strategies such as building credible explanations for their illness. CONCLUSIONS: Physical, social, emotional and self-dimensions of life should be included when treating and measuring outcomes from healthcare in paediatric CFS/ME. There is a need for greater recognition and diagnosis of childhood CFS/ME, specialist advice on activity management and improved communication between health and education providers to help children cope with their condition. PMID- 28087545 TI - Predictors of public support for nutrition-focused policy, systems and environmental change strategies in Los Angeles County, 2013. AB - BACKGROUND: Since 2010, federal and local agencies have invested broadly in a variety of nutrition-focused policy, systems and environmental change (PSE) initiatives in Los Angeles County (LAC). To date, little is known about whether the public supports such efforts. We address this gap in the literature by examining predictors of support for a variety of PSEs. METHODS: Voters residing in LAC (n=1007) were randomly selected to participate in a cross-sectional telephone survey commissioned by the LAC Department of Public Health. The survey asked questions about attitudes towards the obesity epidemic, nutrition knowledge and behaviours, public opinions about changing business practices/government policies related to nutrition, and sociodemographics. A factor analysis informed outcome variable selection (ie, type of PSEs). Multivariable regression analyses were performed to examine predictors of public support. Predictors in the regression models included (primary regressor) community economic hardship; (control variables) political affiliation, sex, age, race and income; and (independent variables) perceptions about obesity, perceived health and weight status, frequency reading nutrition labels, ease of finding healthy and unhealthy foods, and food consumption behaviours (ie, fruit and vegetables, non-diet soda, fast-food and sit-down restaurant meals). RESULTS: 3 types of PSE outcome variables were identified: promotional/incentivising, limiting/restrictive and business practices. Community economic hardship was not found to be a significant predictor of public support for any of the 3 PSE types. However, Republican party affiliation, being female and perceiving obesity as a serious health problem were. CONCLUSIONS: These findings have implications for public health practice and community planning in local health jurisdictions. PMID- 28087546 TI - Association between insomnia symptoms, job strain and burnout syndrome: a cross sectional survey of 1300 financial workers. AB - OBJECTIVES: Professional burnout is closely related to work stress but less frequently associated with disturbed sleep. This study determines whether job strain and sleep disturbances are associated risk factors of burnout among financial workers. DESIGN: Observational study. PARTICIPANTS: 1300 employees (725 female) of a financial company. PRIMARY MEASURES: Self-reported questionnaires (Maslach Burnout Inventory, Job Content Questionnaire, Sleep questionnaire based on ICSD-3 classification), the Epworth sleepiness scale and the Hospital Anxiety and Depression Scale (HADS). RESULT: The prevalence of burnout was 10.2% (9.0% moderate and 1.2% severe). 23.3% of workers were considered with high job strain, and 93.1% had a high level of job satisfaction. 16.8% of individuals had insomnia and 97% reported non-restorative sleep. The bivariate analyses demonstrate a higher risk of burnout in participants with insomnia (OR=14.7, 95% CI 9.8 to 21.9), non-restorative sleep (OR=9.9, 95% CI 5.1 to 19.5) and anxiety (OR=10.2, 95% CI 6.8 to 15.3). High job strain was associated with burnout (OR=1.9, 95% CI 1.1 to 3.6). This association was not maintained after adjustment for sleep parameters. Job satisfaction was another independent risk factor for burnout (OR=124, 95% CI 65 to 237). CONCLUSIONS: In our sample of financial workers, job strain represents a burnout risk factor only if associated with insomnia. Insomnia can be considered as a relevant clinical marker that should be targeted in mental health prevention programmes at the workplace. PMID- 28087547 TI - Risk of pneumonia in patients with isolated minor rib fractures: a nationwide cohort study. AB - OBJECTIVES: Isolated minor rib fractures (IMRFs) after blunt chest traumas are commonly observed in emergency departments. However, the relationship between IMRFs and subsequent pneumonia remains controversial. This nationwide cohort study investigated the association between IMRFs and the risk of pneumonia in patients with blunt chest traumas. DESIGN: Nationwide population-based cohort study. SETTING: Patients with IMRFs were identified between 2010 and 2011 from the Taiwan National Health Insurance Research Database. PARTICIPANTS: Non traumatic patients were matched through 1:8 propensity-score matching according to age, sex, and comorbidities (namely diabetes, hypertension, cardiovascular disease, asthma and chronic obstructive pulmonary disease (COPD)) with the comparison cohort. We estimated the adjusted HRs (aHRs) by using the Cox proportional hazard model. A total of 709 patients with IMRFs and 5672 non traumatic patients were included. MAIN OUTCOME MEASURE: The primary end point was the occurrence of pneumonia within 30 days. RESULTS: The incidence of pneumonia following IMRFs was 1.6% (11/709). The aHR for the risk of pneumonia after IMRFs was 8.94 (95% CI=3.79 to 21.09, p<0.001). Furthermore, old age (>=65 years; aHR=5.60, 95% CI 1.97 to 15.89, p<0.001) and COPD (aHR=5.41, 95% CI 1.02 to 3.59, p<0.001) were risk factors for pneumonia following IMRFs. In the IMRF group, presence of single or two isolated rib fractures was associated with an increased risk of pneumonia with aHRs of 3.97 (95% CI 1.09 to 14.44, p<0.001) and 17.13 (95% CI 6.66 to 44.04, p<0.001), respectively. CONCLUSIONS: Although the incidence of pneumonia following IMRFs is low, patients with two isolated rib fractures were particularly susceptible to pneumonia. Physicians should focus on this complication, particularly in elderly patients and those with COPD. PMID- 28087548 TI - Early lens extraction with intraocular lens implantation for the treatment of primary angle closure glaucoma: an economic evaluation based on data from the EAGLE trial. AB - OBJECTIVE: To investigate the cost-effectiveness of early lens extraction with intraocular lens implantation for the treatment of primary angle closure glaucoma (PACG) compared to standard care. DESIGN: Cost-effectiveness analysis alongside a multicentre pragmatic two-arm randomised controlled trial. Patients were followed up for 36 months, and data on health service usage and health state utility were collected and analysed within the trial time horizon. A Markov model was developed to extrapolate the results over a 5-year and 10-year time horizon. SETTING: 22 hospital eye services in the UK. POPULATION: Males and females aged 50 years or over with newly diagnosed PACG or primary angle closure (PAC). INTERVENTIONS: Lens extraction compared to standard care (ie, laser iridotomy followed by medical therapy and glaucoma surgery). OUTCOME MEASURES: Costs of primary and secondary healthcare usage (UK NHS perspective), quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER) for lens extraction versus standard care. RESULTS: The mean age of participants was 67.5 (8.42), 57.5% were women, 44.6% had both eyes eligible, 1.4% were of Asian ethnicity and 35.4% had PAC. The mean health service costs were higher in patients randomised to lens extraction: L2467 vs L1486. The mean adjusted QALYs were also higher with early lens extraction: 2.602 vs 2.533. The ICER for lens extraction versus standard care was L14 284 per QALY gained at three years. Modelling suggests that the ICER may drop to L7090 per QALY gained by 5 years and that lens extraction may be cost saving by 10 years. Our results are generally robust to changes in the key input parameters and assumptions. CONCLUSIONS: We find that lens extraction has a 67-89% chance of being cost-effective at 3 years and that it may be cost saving by 10 years. TRIAL REGISTRATION NUMBER: ISRCTN44464607; Results. PMID- 28087549 TI - Engaging stakeholders and target groups in prioritising a public health intervention: the Creating Active School Environments (CASE) online Delphi study. AB - OBJECTIVES: Stakeholder engagement and public involvement are considered as integral to developing effective public health interventions and is encouraged across all phases of the research cycle. However, limited guidelines and appropriate tools exist to facilitate stakeholder engagement-especially during the intervention prioritisation phase. We present the findings of an online 'Delphi' study that engaged stakeholders (including young people) in the process of prioritising secondary school environment-focused interventions that aim to increase physical activity. SETTING: Web-based data collection using an online Delphi tool enabling participation of geographically diverse stakeholders. PARTICIPANTS: 37 stakeholders participated, including young people (age 13-16 years), parents, teachers, public health practitioners, academics and commissioners; 33 participants completed both rounds. PRIMARY AND SECONDARY OUTCOME MEASURES: Participants were asked to prioritise a (short-listed) selection of school environment-focused interventions (eg, standing desks, outdoor design changes) based on the criteria of 'reach', 'equality', 'acceptability', 'feasibility', 'effectiveness' and 'cost'. Participants were also asked to rank the criteria and the effectiveness outcomes (eg, physical activity, academic achievement, school enjoyment) from most to least important. Following feedback along with any new information provided, participants completed round 2 4 weeks later. RESULTS: The intervention prioritisation process was feasible to conduct and comments from participants indicated satisfaction with the process. Consensus regarding intervention strategies was achieved among the varied groups of stakeholders, with 'active lessons' being the favoured approach. Participants ranked 'mental health and well-being' as the most important outcome followed by 'enjoyment of school'. The most important criteria was 'effectiveness', followed by 'feasibility'. CONCLUSIONS: This novel approach to engaging a wide variety of stakeholders in the research process was feasible to conduct and acceptable to participants. It also provided insightful information relating to how stakeholders prioritise interventions. The approach could be extended beyond the specific project to be a useful tool for researchers and practitioners. PMID- 28087550 TI - Trends and changes in paediatric tonsil surgery in Sweden 1987-2013: a population based cohort study. AB - OBJECTIVES: The objective of this study was to longitudinally describe the history of tonsil surgery in Swedish children and adolescents regarding incidence, indications for surgery, surgical methods and the age and gender distributions. SETTING: A retrospective longitudinal population-based cohort study based on register data from the Swedish National Patient Register (NPR) and population data from Statistics Sweden. PARTICIPANTS: All Swedish children 1-<18 years registered in the NPR with a tonsil surgery procedure 1987-2013. RESULTS: 167 894 tonsil surgeries were registered in the NPR 1987-2013. An increase in the total incidence rate was observed, from 22/10 000 person years in 1987 to 47/10 000 in 2013. The most marked increase was noted in children 1-3 years of age, increasing from 17 to 73/10 000 person years over the period. The proportion children with obstructive/sleep disordered breathing (SDB) indications increased from 42.4% in 1987 to 73.6% in 2013. Partial tonsillectomy, tonsillotomy (TT), increased since 1996 and in 2013 55.1% of all tonsil procedures were TTs. CONCLUSIONS: There have been considerable changes in clinical practice for tonsil surgery in Swedish children over the past few decades. Overall, a doubling in the total incidence rate was observed. This increase consisted mainly of an increase in surgical procedures due to obstructive/SDB indications, particularly among the youngest age group (1-3 years old). TT has gradually replaced tonsillectomy as the predominant method for tonsil surgery. PMID- 28087551 TI - Cost-effectiveness of superficial femoral artery endovascular interventions in the UK and Germany: a modelling study. AB - OBJECTIVES: To assess the lifetime costs and cost-effectiveness of 5 endovascular interventions to treat superficial femoral arterial disease. DESIGN: A model based health economic evaluation. An existing decision analytical model was used, with updated effectiveness data taken from the literature, and updated costs based on purchasing prices. SETTING: UK and German healthcare perspectives were considered. PARTICIPANTS: Patients with intermittent claudication of the femoropopliteal arteries eligible for endovascular treatment. METHODS: UK and German healthcare perspectives were considered, as were different strategies for re-intervention. INTERVENTIONS: Percutaneous transluminal angioplasty (PTA) with bail-out bare metal stenting (assumed to represent the existing standard of care, and 4 alternatives: primary bare metal stents, drug-eluting stents, drug-eluting balloons (DEBs) and biomimetic stents). PRIMARY OUTCOME MEASURES: The incremental cost-effectiveness ratio between 2 treatments, defined as the incremental costs divided by the incremental quality-adjusted life years (QALYs). RESULTS: Use of a biomimetic stent, BioMimics 3D, was always estimated to dominate the other interventions, having lower lifetime costs and greater effectiveness, as measured by QALYs. Of the remaining interventions, DEBs were always the most effective, and PTA the least effective. There was uncertainty in the cost-effectiveness results, with key drivers being the costs and effectiveness of the biomimetic stent along with the costs of DEBs. CONCLUSIONS: All 4 of the alternatives to PTA were more effective, with the biomimetic stent being the most cost-effective. As there was uncertainty in the results, and all of the interventions have different mechanisms of action, all 4 may be considered to be alternatives to PTA. PMID- 28087552 TI - Screening for Atrial Fibrillation using Economical and accurate TechnologY (SAFETY)-a pilot study. AB - INTRODUCTION: Atrial fibrillation (AF) is a cause of stroke and a marker of atherosclerosis and of all patients with stroke, around 17% have AF. The screening and treatment of AF could prevent about 12% of all strokes. Several relatively low-cost devices with good accuracy now exist which can detect AF including WatchBP and AliveCor. However, they can only measure the ECG or pulse over short time periods. Inexpensive devices such as heart rate monitors, which are widely available, can measure heart rate for prolonged periods and may have potential in screening for AF. This study aims to determine the accuracy of AliveCor and WatchBP along with a bespoke algorithm using a heart rate monitor belt (Polar H7) and a wearable RR interval recorder (Firstbeat Bodyguard 2) for detecting AF during a single screening visit in primary care patients. METHODS/ANALYSIS: A multicentre case-control diagnostic study comparing the four different devices for the detection of AF with a reference standard consisting of a 12-lead ECG in GP surgeries across Hampshire, UK. We aim to recruit 92 participants with AF and 329 without AF aged 65 years and over. We will ask participants to rate comfort and overall impression for each device. We will collect qualitative data from participants capturing their experience of using wearable devices in order to evaluate acceptability. We will collect data from GPs to determine their views on AF screening. ETHICS AND DISSEMINATION: This protocol was approved by the London-City & East Research Ethics Committee in June 2016. The findings of the trial will be disseminated through peer-reviewed journals, national and international conference presentations and the Atrial Fibrillation Association, UK. TRIAL REGISTRATION NUMBER: ISRCTN17495003, Pre results. PMID- 28087553 TI - Prevalence of obesity and overweight in African learners: a protocol for systematic review and meta-analysis. AB - INTRODUCTION: Obesity and overweight are an emerging problem in Africa. Obese children are at increased risk of developing hypertension, high cholesterol, orthopaedic problems and type 2 diabetes as well as increased risk of adult obesity. Prevention of childhood overweight and obesity therefore needs high priority. The review approach is particularly useful in establishing whether research findings are consistent and can be generalised across populations and settings. This systematic review aims to assess the magnitude and distribution of overweight and obesity among primary school learners within populations in Africa. METHODS AND ANALYSIS: A comprehensive search of key bibliographic databases including MEDLINE (PubMed), MEDLINE (EbscoHost), CINAHL (EbscoHost), Academic Search Complete (EbscoHost) and ISI Web of Science (Science Citation Index) will be conducted for published literature. Grey literature will be also be obtained. Full-text articles of eligible studies will be obtained and screened following predefined inclusion criteria. The quality of reporting as well as risk of bias of included studies will be assessed, data extracted and synthesised. The results will be summarised and presented by country and major regional groupings. Meta-analysis will be conducted for identical variables across studies. This review will be reported following the MOOSE Guidelines for Meta-Analysis and Systematic Reviews of Observational Studies. ETHICS AND DISSEMINATION: Ethics is not a requirement since no primary data will be collected. All data that will be presented in this review are based on published articles. The findings of this systematic review will be submitted for publication in peer-reviewed journals and disseminated in national and international conferences and also in policy documents to appropriate bodies for decision-making, where needed. It is expected that the findings will identify some research gaps for further studies. PMID- 28087555 TI - Associations of reallocating sitting time into standing or stepping with glucose, insulin and insulin sensitivity: a cross-sectional analysis of adults at risk of type 2 diabetes. AB - OBJECTIVE: To quantify associations between sitting time and glucose, insulin and insulin sensitivity by considering reallocation of time into standing or stepping. DESIGN: Cross-sectional. SETTING: Leicestershire, UK, 2013. PARTICIPANTS: Adults aged 30-75 years at high risk of impaired glucose regulation (IGR) or type 2 diabetes. 435 adults (age 66.8+/-7.4 years; 61.7% male; 89.2% white European) were included. METHODS: Participants wore an activPAL3 monitor 24 hours/day for 7 days to capture time spent sitting, standing and stepping. Fasting and 2-hour postchallenge glucose and insulin were assessed; insulin sensitivity was calculated by Homeostasis Model Assessment of Insulin Secretion (HOMA-IS) and Matsuda-Insulin Sensitivity Index (Matsuda-ISI). Isotemporal substitution regression modelling was used to quantify associations of substituting 30 min of waking sitting time (accumulated in prolonged (>=30 min) or short (<30 min) bouts) for standing or stepping on glucose regulation and insulin sensitivity. Interaction terms were fitted to assess whether the associations with measures of glucose regulation and insulin sensitivity was modified by sex or IGR status. RESULTS: After adjustment for confounders, including waist circumference, reallocation of prolonged sitting to short sitting time and to standing was associated with 4% lower fasting insulin and 4% higher HOMA-IS; reallocation of prolonged sitting to standing was also associated with a 5% higher Matsuda-ISI. Reallocation to stepping was associated with 5% lower 2 hour glucose, 7% lower fasting insulin, 13% lower 2-hour insulin and a 9% and 16% higher HOMA-IS and Matsuda-ISI, respectively. Reallocation of short sitting time to stepping was associated with 5% and 10% lower 2-hour glucose and 2-hour insulin and 12% higher Matsuda-ISI. Results were not modified by IGR status or sex. CONCLUSIONS: Reallocating a small amount of short or prolonged sitting time with standing or stepping may improve 2-hour glucose, fasting and 2-hour insulin and insulin sensitivity. Findings should be confirmed through prospective and intervention research. TRIAL REGISTRATION NUMBER: ISRCTN31392913, Post-results. PMID- 28087557 TI - A longitudinal comparative study of falls in persons with knee arthroplasty and persons with or at high risk for knee osteoarthritis. PMID- 28087556 TI - AHEAD Study: an observational study of the management of anticoagulated patients who suffer head injury. AB - OBJECTIVES: Management of anticoagulated patients after head injury is unclear due to lack of robust evidence. This study aimed to determine the adverse outcome rate in these patients and identify risk factors associated with poor outcome. DESIGN: Multicentre, observational study using routine patient records. SETTING: 33 emergency departments in England and Scotland. PARTICIPANTS: 3566 adults (aged >=16 years) who had suffered blunt head injury and were currently taking warfarin. MAIN OUTCOME MEASURES: Primary outcome measure was rate of adverse outcome defined as death or neurosurgery following initial injury, clinically significant CT scan finding or reattendance with related complication within 10 weeks of initial hospital attendance. Secondary objectives included identifying risk factors for adverse outcome using univariable and multivariable analyses. RESULTS: Clinical data available for 3534/3566 patients (99.1%), median age 79 years; mean initial international normalised ratio (INR) 2.67 (SD 1.34); 81.2% Glasgow Coma Scale (GCS) 15: 59.8% received a CT scan with significant head injury-related finding in 5.4% (n=208); 0.5% underwent neurosurgery; 1.2% patients suffered a head injury-related death. Overall adverse outcome rate was 5.9% (95% CI 5.2% to 6.7%). Patients with GCS=15 and no associated symptoms had lowest risk of adverse outcome (risk 2.7%; 95% CI 2.1 to 3.6). Patients with GCS=15 multivariable analysis (using imputation) found risk of adverse outcome to increase when reporting at least one associated symptom: vomiting (relative risk (RR) 1.8; 95% CI 1.0 to 3.4), amnesia (RR 3.5; 95% CI 2.1 to 5.7), headache (RR 1.3; 95% CI 0.8 to 2.2), loss of consciousness (RR 1.75; 95% CI 1.0 to 3.0). INR measurement did not predict adverse outcome in patients with GCS=15 (RR 1.1; 95% CI 1.0 to 1.2). CONCLUSIONS: In alert warfarinised patients following head injury, the presence of symptoms is associated with greater risk of adverse outcome. Those with GCS=15 and no symptoms are a substantial group and have a low risk of adverse outcome. TRIAL REGISTRATION NUMBER: NCT02461498. PMID- 28087554 TI - How prepared are UK medical graduates for practice? A rapid review of the literature 2009-2014. AB - OBJECTIVE: To understand how prepared UK medical graduates are for practice and the effectiveness of workplace transition interventions. DESIGN: A rapid review of the literature (registration #CRD42013005305). DATA SOURCES: Nine major databases (and key websites) were searched in two timeframes (July-September 2013; updated May-June 2014): CINAHL, Embase, Educational Resources Information Centre, Health Management Information Consortium, MEDLINE, MEDLINE in Process, PsycINFO, Scopus and Web of Knowledge. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Primary research or studies reporting UK medical graduates' preparedness between 2009 and 2014: manuscripts in English; all study types; participants who are final-year medical students, medical graduates, clinical educators, patients or NHS employers and all outcome measures. DATA EXTRACTION: At time 1, three researchers screened manuscripts (for duplicates, exclusion/inclusion criteria and quality). Remaining 81 manuscripts were coded. At time 2, one researcher repeated the process for 2013-2014 (adding six manuscripts). Data were analysed using a narrative synthesis and mapped against Tomorrow's Doctors (2009) graduate outcomes. RESULTS: Most studies comprised junior doctors' self-reports (65/87, 75%), few defined preparedness and a programmatic approach was lacking. Six themes were highlighted: individual skills/knowledge, interactional competence, systemic/technological competence, personal preparedness, demographic factors and transitional interventions. Graduates appear prepared for history taking, physical examinations and some clinical skills, but unprepared for other aspects, including prescribing, clinical reasoning/diagnoses, emergency management, multidisciplinary team-working, handover, error/safety incidents, understanding ethical/legal issues and ward environment familiarity. Shadowing and induction smooth transition into practice, but there is a paucity of evidence around assistantship efficacy. CONCLUSIONS: Educational interventions are needed to address areas of unpreparedness (eg, multidisciplinary team-working, prescribing and clinical reasoning). Future research in areas we are unsure about should adopt a programmatic and rigorous approach, with clear definitions of preparedness, multiple stakeholder perspectives along with multisite and longitudinal research designs to achieve a joined-up, systematic, approach to understanding future educational requirements for junior doctors. PMID- 28087558 TI - Cross-national comparison of medication use in Australian and Dutch nursing homes. PMID- 28087559 TI - Corrigendum: Dementia-associated mortality and its predictors among older adults in sub-Saharan Africa: results from a 2-year follow-up in Congo (the EPIDEMCA-FU study). PMID- 28087560 TI - Disruptive behaviour may hinder the acquisition of daily living skills for youth with autism spectrum disorder. PMID- 28087561 TI - Mindfulness-based cognitive therapy delays depressive relapse across demographic subgroups. PMID- 28087562 TI - An uncommon diagnosis for a common neonatal presentation. PMID- 28087563 TI - Fascicular Ventricular Arrhythmias: Pathophysiologic Mechanisms, Anatomical Constructs, and Advances in Approaches to Management. PMID- 28087564 TI - Right Ventricular Ejection Fraction Is Incremental to Left Ventricular Ejection Fraction for the Prediction of Future Arrhythmic Events in Patients With Systolic Dysfunction. AB - BACKGROUND: Left ventricular ejection fraction remains the primary risk stratification tool used in the selection of patients for implantable cardioverter defibrillator therapy. However, this solitary marker fails to identify a substantial portion of patients experiencing sudden cardiac arrest. In this study, we examined the incremental value of considering right ventricular ejection fraction for the prediction of future arrhythmic events in patients with systolic dysfunction using the gold standard of cardiovascular magnetic resonance. METHODS AND RESULTS: Three hundred fourteen consecutive patients with ischemic cardiomyopathy or nonischemic dilated cardiomyopathy undergoing cardiovascular magnetic resonance were followed for the primary outcome of sudden cardiac arrest or appropriate implantable cardioverter defibrillator therapy. Blinded quantification of left ventricular and right ventricular (RV) volumes was performed from standard cine imaging. Quantification of fibrosis from late gadolinium enhancement imaging was incrementally performed. RV dysfunction was defined as right ventricular ejection fraction <=45%. Among all patients (164 ischemic cardiomyopathy, 150 nonischemic dilated cardiomyopathy), the mean left ventricular ejection fraction was 32+/-12% (range, 6-54%) with mean right ventricular ejection fraction of 48+/-15% (range, 7-78%). At a median of 773 days, 49 patients (15.6%) experienced the primary outcome (9 sudden cardiac arrest, 40 appropriate implantable cardioverter defibrillator therapies). RV dysfunction was independently predictive of the primary outcome (hazard ratio=2.98; P=0.002). Among those with a left ventricular ejection fraction >35% (N=121; mean left ventricular ejection fraction, 45+/-6%), RV dysfunction provided an adjusted hazard ratio of 4.2 (P=0.02). CONCLUSIONS: RV dysfunction is a strong, independent predictor of arrhythmic events. Among patients with mild to moderate LV dysfunction, a cohort greatly contributing to global sudden cardiac arrest burden, this marker provides robust discrimination of high- versus low risk subjects. PMID- 28087565 TI - Perturbation of Retinoid Homeostasis Increases Malformation Risk in Embryos Exposed to Pregestational Diabetes. AB - Pregestational diabetes is highly associated with an increased risk of birth defects. However, factors that can increase or reduce the expressivity and penetrance of malformations in pregnancies in women with diabetes remain poorly identified. All-trans retinoic acid (RA) plays crucial roles in embryogenesis. Here, we find that Cyp26a1, which encodes a key enzyme for catabolic inactivation of RA required for tight control of local RA concentrations, is significantly downregulated in embryos of diabetic mice. Embryonic tissues expressing Cyp26a1 show reduced efficiency of RA clearance. Embryos exposed to diabetes are thus sensitized to RA and more vulnerable to the deleterious effects of increased RA signaling. Susceptibility to RA teratogenesis is further potentiated in embryos with a preexisting genetic defect of RA metabolism. Increasing RA clearance efficiency using a preconditioning approach can counteract the increased susceptibility to RA teratogenesis in embryos of diabetic mice. Our findings provide new insight into gene-environment interactions that influence individual risk in the manifestation of diabetes-related birth defects and shed light on environmental risk factors and genetic variants for a stratified medicine approach to screening women with diabetes who are of childbearing age and assessing the risk of birth defects during pregnancy. PMID- 28087566 TI - Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults. AB - BACKGROUND: With the advent of high throughput sequencing, the identification of genetic causes of cardiovascular disease (CVD) has become an integral part of medical diagnosis and management and at the forefront of personalized medicine in this field. The use of whole exome sequencing for clinical diagnosis, risk stratification, and management of inherited CVD has not been previously evaluated. METHODS AND RESULTS: We analyzed the results of whole exome sequencing in first 200 adult patients with inherited CVD, who underwent genetic testing at the Yale Program for Cardiovascular Genetics. Genetic diagnosis was reached and reported with a success rate of 26.5% (53 of 200 patients). This compares to 18% (36 of 200) that would have been diagnosed using commercially available genetic panels (P=0.04). Whole exome sequencing was particularly useful for clinical diagnosis in patients with aborted sudden cardiac death, in whom the primary insult for the presence of both depressed cardiac function and prolonged QT had remained unknown. The analysis of the remaining cases using genome annotation and disease segregation led to the discovery of novel candidate genes in another 14% of the cases. CONCLUSIONS: Whole exome sequencing is an exceptionally valuable screening tool for its capability to establish the clinical diagnosis of inherited CVDs, particularly for poorly defined cases of sudden cardiac death. By presenting novel candidate genes and their potential disease associations, we also provide evidence for the use of this genetic tool for the identification of novel CVD genes. Creation and sharing of exome databases across centers of care should facilitate the discovery of unknown CVD genes. PMID- 28087567 TI - Interventions to increase adherence to therapeutic exercise in older adults with low back pain and/or hip/knee osteoarthritis: a systematic review and meta analysis. AB - OBJECTIVE: To evaluate whether interventions aimed at increasing adherence to therapeutic exercise increase adherence greater than a contextually equivalent control among older adults with chronic low back pain and/or hip/knee osteoarthritis. DESIGN: A systematic review and meta-analysis. DATA SOURCES: Five databases (MEDLINE (PubMed), CINAHL, SportDISCUS (EBSCO), Embase (Ovid) and Cochrane Library) were searched until 1 August 2016. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials that isolated the effects of interventions aiming to improve adherence to therapeutic exercise among adults >=45 years of age with chronic low back pain and/or hip/knee osteoarthritis were included. RESULTS: Of 3899 studies identified, nine studies (1045 participants) were eligible. Four studies, evaluating strategies that aimed to increase motivation or using behavioural graded exercise, reported significantly better exercise adherence (d=0.26-1.23). In contrast, behavioural counselling, action coping plans and/or audio/video exercise cues did not improve adherence significantly. Meta-analysis using a random effects model with the two studies evaluating booster sessions with a physiotherapist for people with osteoarthritis revealed a small to medium significant pooled effect in favour of booster sessions (standardised mean difference (SMD) 0.39, 95% CI 0.05 to 0.72, z=2.26, p=0.02, I2=35%). CONCLUSIONS: Meta-analysis provides moderate-quality evidence that booster sessions with a physiotherapist assisted people with hip/knee osteoarthritis to better adhere to therapeutic exercise. Individual high-quality trials supported the use of motivational strategies in people with chronic low back pain and behavioural graded exercise in people with osteoarthritis to improve adherence to exercise. PMID- 28087568 TI - Effect of specific exercise-based football injury prevention programmes on the overall injury rate in football: a systematic review and meta-analysis of the FIFA 11 and 11+ programmes. AB - OBJECTIVE: To investigate the effect of FIFA injury prevention programmes in football (FIFA 11 and FIFA 11+). DESIGN: Systematic review and meta-analysis. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials comparing the FIFA injury prevention programmes with a control (no or sham intervention) among football players. DATA SOURCES: MEDLINE via PubMed, EMBASE via OVID, CINAHL via Ebsco, Web of Science, SportDiscus and Cochrane Central Register of Controlled Trials, from 2004 to 14 March 2016. RESULTS: 6 cluster randomised controlled trials had assessed the effect of FIFA injury prevention programmes compared with controls on the overall football injury incidence in recreational/subelite football. These studies included 2 specific exercise-based injury prevention programmes: FIFA 11 (2 studies) and FIFA 11+ (4 studies). The primary analysis showed a reduction in the overall injury risk ratio of 0.75 (95% CI 0.57 to 0.98), p=0.04, in favour of the FIFA injury prevention programmes. Secondary analyses revealed that when pooling the 4 studies applying the FIFA 11+ prevention programme, a reduction in the overall injury risk ratio (incidence rate ratio (IRR) 0.61; 95% CI 0.48 to 0.77, p<0.001) was present in favour of the FIFA 11+ prevention programme. No reduction was present when pooling the 2 studies including the FIFA 11 prevention programme (IRR 0.99; 95% CI 0.80 to 1.23, p=0.940). CONCLUSIONS: An injury-preventing effect of the FIFA injury prevention programmes compared with controls was shown in football. This effect was induced by the FIFA 11+ prevention programme which has a substantial injury preventing effect by reducing football injuries by 39%, whereas a preventive effect of the FIFA 11 prevention programme could not be documented. TRIAL REGISTRATION NUMBER: PROSPERO CRD42015024120. PMID- 28087569 TI - Exercise as treatment for alcohol use disorders: systematic review and meta analysis. AB - OBJECTIVES: To conduct a systematic review and meta-analysis investigating effects of exercise for people with alcohol use disorders (AUDs) across multiple health outcomes. We also investigated the prevalence and predictors of dropout from exercise studies in AUDs. DESIGN: Systematic review and random effects meta analysis with meta-regression analyses. DATA SOURCES: 3 major electronic databases were searched from inception until April 2016 for exercise intervention studies in adults with AUDs. ELIGIBILITY CRITERIA: Studies of acute exercise in people with AUDs; and randomised and non-randomised trials examining effects of long-term (>=2 weeks) exercise. RESULTS: 21 studies and 1204 unique persons with AUDs (mean age 37.8 years, mean illness duration 4.4 years) were included. Exercise did not reduce daily alcohol consumption (standardised mean difference (SMD) =-0.886, p=0.24), or the Alcohol Use Disorders Identification Test (AUDIT) total scores (SMD=-0.378, p=0.18). For weekly consumption (n=3 studies), a statistically significant difference was observed favouring exercise (SMD=-0.656, p=0.04), but not after adjustment for publication bias (SMD=-0.16, 95% CI -0.88 to 0.55). Exercise significantly reduced depressive symptoms versus control (randomised controlled trials (RCTs) =4; SMD=-0.867, p=0.006, I2=63%) and improved physical fitness (VO2) (RCTs=3; SMD=0.564, p=0.01, I2=46%). The pooled dropout rate was 40.3% (95% CI 23.3% to 60.1%) which was no different to control conditions (OR=0.73, p=0.52). Dropouts were higher among men (beta=0.0622, p<0.0001, R2=0.82). LIMITATIONS: It was not possible to investigate moderating effects of smoking. CONCLUSIONS: Available evidence indicates exercise appears not to reduce alcohol consumption, but has significant improvements in other health outcomes, including depression and physical fitness. Additional long-term controlled studies of exercise for AUDs are required. PMID- 28087577 TI - Umbrella: an innovative integrated sexual health service in Birmingham, UK. PMID- 28087576 TI - Circulating Modified Metabolites and a Risk of ESRD in Patients With Type 1 Diabetes and Chronic Kidney Disease. AB - OBJECTIVE: Patients with type 1 diabetes (T1D) with impaired renal function are at increased risk for end-stage renal disease (ESRD). Although the rate of progression varies, determinants and mechanisms of this variation are unknown. RESEARCH DESIGN AND METHODS: We examined serum metabolomic profiles associated with variation in renal function decline in participants with T1D (the Joslin Kidney Study prospective cohort). One hundred fifty-eight patients with proteinuria and chronic kidney disease stage 3 were followed for a median of 11 years to determine estimated glomerular filtration rate slopes from serial measurements of serum creatinine and to ascertain time to onset of ESRD. Baseline serum samples were subjected to global metabolomic profiling. RESULTS: One hundred ten amino acids and purine and pyrimidine metabolites were detected in at least 80% of participants. Serum levels of seven modified metabolites (C glycosyltryptophan, pseudouridine, O-sulfotyrosine, N-acetylthreonine, N acetylserine, N6-carbamoylthreonyladenosine, and N6-acetyllysine) were associated with renal function decline and time to ESRD (P < 0.001) independent of the relevant clinical covariates. The significant metabolites correlated with one another and with the indices of tubular injury. CONCLUSIONS: This prospective cohort study in participants with T1D, proteinuria, and impaired renal function at baseline demonstrated that patients with increased circulating levels of certain modified metabolites experience faster renal function decline, leading to ESRD. Whether some of these candidate metabolites are risk factors or just prognostic biomarkers of progression to ESRD in T1D needs to be determined. PMID- 28087575 TI - Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms. AB - Practitioners of ancient societies from the time of Hippocrates and earlier recognized and treated the signs of inflammation, heat, redness, swelling, and pain with agents that block or inhibit proinflammatory chemical mediators. More selective drugs are available today, but this therapeutic concept has not changed. Because the acute inflammatory response is host protective to contain foreign invaders, much of today's pharmacopeia can cause serious unwanted side effects, such as immune suppression. Uncontrolled inflammation is now considered pathophysiologic and is associated with many widely occurring diseases such as cardiovascular disease, neurodegenerative diseases, diabetes, obesity, and asthma, as well as classic inflammatory diseases (e.g., arthritis and periodontal diseases). The inflammatory response, when self-limited, produces a superfamily of chemical mediators that stimulate resolution of the response. Specialized proresolving mediators (SPMs), identified in recent years, are endogenous mediators that include the n-3-derived families resolvins, protectins, and maresins, as well as arachidonic acid-derived (n-6) lipoxins, which promote resolution of inflammation, clearance of microbes, reduction of pain, and promotion of tissue regeneration via novel mechanisms. Aspirin and statins have a positive impact on these resolution pathways, producing epimeric forms of specific SPMs, whereas other drugs can disrupt timely resolution. In this article, evidence from recent human and preclinical animal studies is reviewed, indicating that SPMs are physiologic mediators and pharmacologic agonists that stimulate resolution of inflammation and infection. The findings suggest that it is time to challenge current treatment practices-namely, using inhibitors and antagonists alone-and to develop immunoresolvents as agonists to test resolution pharmacology and their role in catabasis for their therapeutic potential.-Serhan, C. N. Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms. PMID- 28087579 TI - Differential Host Plant-Associated Genetic Variation Between Sympatric Mite Species of the Genus Oligonychus (Acari: Tetranychidae). AB - Adaptation to different host plants can lead to host-associated differentiation (HAD). The mites Oligonychus perseae and Oligonychus punicae have a broad range of host plants, but, to date, records of them coexisting sympatrically had only been reported on avocado. However, our field observations showed both species coexisting on host plants other than avocado. The lack of previous records of these mites on the host plants studied here suggests only recent divergence to new host plant species. Previous studies showed that O. punicae had a limited migration capacity compared with O. perseae, suggesting that O. punicae is more likely to develop a close host plant relationship leading to HAD. Adults of both species were collected from trees hosting both mite species. Three genera of host plants considered were Persea, Salix, and Alnus; two species within one genus were Alnus jorullensis and Alnus acuminata; and three varieties within one species were Persea americana var. Fuerte, var. Hass, and var. Criollo, a noncommercial variety. Using sequence data from a segment of the mitochondrial cytochrome oxidase subunit I, the phylogenetic relationships and genetic population structure of both mite species in relation to the host plant were determined. Oligonychus perseae populations showed a significant population structure in relation to host plant at the species and genus level, but there was no effect of variety. In contrast, host plant explained none of the genetic variation among O. punicae populations. The potential role of coexistence mechanisms in the contrasting genetic population structure of both mite species is discussed. PMID- 28087580 TI - Self-regulating ubiquitin ligases. PMID- 28087578 TI - Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies. AB - Diverse neurodegenerative disorders are characterized by deposition of tau fibrils composed of conformers (i.e. strains) unique to each illness. The development of tau imaging agents has enabled visualization of tau lesions in tauopathy patients, but the modes of their binding to different tau strains remain elusive. Here we compared binding of tau positron emission tomography ligands, PBB3 and AV-1451, by fluorescence, autoradiography and homogenate binding assays with homologous and heterologous blockades using tauopathy brain samples. Fluorescence microscopy demonstrated intense labelling of non-ghost and ghost tangles with PBB3 and AV-1451, while dystrophic neurites were more clearly detected by PBB3 in brains of Alzheimer's disease and diffuse neurofibrillary tangles with calcification, characterized by accumulation of all six tau isoforms. Correspondingly, partially distinct distributions of autoradiographic labelling of Alzheimer's disease slices with 11C-PBB3 and 18F-AV-1451 were noted. Neuronal and glial tau lesions comprised of 4-repeat isoforms in brains of progressive supranuclear palsy, corticobasal degeneration and familial tauopathy due to N279K tau mutation and 3-repeat isoforms in brains of Pick's disease and familial tauopathy due to G272V tau mutation were sensitively detected by PBB3 fluorescence in contrast to very weak AV-1451 signals. This was in line with moderate 11C-PBB3 versus faint 18F-AV-1451 autoradiographic labelling of these tissues. Radioligand binding to brain homogenates revealed multiple binding components with differential affinities for 11C-PBB3 and 18F-AV-1451, and higher availability of binding sites on progressive supranuclear palsy tau deposits for 11C-PBB3 than 18F-AV-1451. Our data indicate distinct selectivity of PBB3 compared to AV-1451 for diverse tau fibril strains. This highlights the more robust ability of PBB3 to capture wide-range tau pathologies. PMID- 28087581 TI - Brief encounters of cytochrome c. PMID- 28087582 TI - Driving Under the Influence of Drugs: Looking for Reasonable Blood Cutoffs and Realistic Analytical Values. PMID- 28087583 TI - Retrospective Accuracy Study of Point-of-Care Hemoglobin A1c in Field Conditions. PMID- 28087584 TI - Emergence of Klebsiella variicola positive for NDM-9, a variant of New Delhi metallo-beta-lactamase, in an urban river in South Korea. AB - Objectives: To examine the presence of pathogenic bacteria carrying New Delhi metallo-beta-lactamase in the environment and to characterize the genome structures of these strains. Methods: Phenotypic screening of antimicrobial susceptibility and WGS were conducted on three Klebsiella variicola strains possessing NDM-9 isolated from an urban river. Results: Three carbapenem resistant K. variicola isolated from Gwangju tributary were found to possess bla NDM-9 genes. Antimicrobial susceptibility testing indicated resistance of these strains to aminoglycosides, carbapenems, cephems, folate pathway inhibitors, fosfomycin and penicillins, but susceptibility to fluoroquinolones, phenicols, tetracyclines and miscellaneous agents. WGS revealed that the 108 kb IncFII(Y) like plasmids carry bla NDM-9 sandwiched between IS 15 for the GJ1 strain, IS 26 for the GJ2 strain, IS 15D1 for the GJ3 strain and IS Vsa3 , and further bracketed by IS 26 and Tn AS3 along with the mercury resistance operon upstream and the class 1 integron composed of gene cassettes of aadA2 , dfrA12 and sul1 downstream. An aph(3')-Ia gene conferring resistance to aminoglycosides is located after the integrons. Chromosomally encoded bla LEN-13 , fosA , aqxA and oqxB genes, as well as plasmid-mediated bla TEM-1B and bla CTX-M-65 encoding ESBL, ant(3')-Ia and mph (A) genes, were also identified. Conclusions: The findings of the present study provide us with the information that NDM-9 has been spreading into the environment. Dissemination of NDM-9 in the environment has raised a health risk alarm as this variant of NDM carries MDR genes with highly transferable mobile genetic elements, increasing the possibility of resistance gene transfer among microorganisms in the environment. PMID- 28087585 TI - Standard-based comprehensive detection of adverse drug reaction signals from nursing statements and laboratory results in electronic health records. AB - Objective: We propose 2 Medical Dictionary for Regulatory Activities-enabled pharmacovigilance algorithms, MetaLAB and MetaNurse, powered by a per-year meta analysis technique and improved subject sampling strategy. Matrials and methods: This study developed 2 novel algorithms, MetaLAB for laboratory abnormalities and MetaNurse for standard nursing statements, as significantly improved versions of our previous electronic health record (EHR)-based pharmacovigilance method, called CLEAR. Adverse drug reaction (ADR) signals from 117 laboratory abnormalities and 1357 standard nursing statements for all precautionary drugs ( n = 101) were comprehensively detected and validated against SIDER (Side Effect Resource) by MetaLAB and MetaNurse against 11 817 and 76 457 drug-ADR pairs, respectively. Results: We demonstrate that MetaLAB (area under the curve, AUC = 0.61 +/- 0.18) outperformed CLEAR (AUC = 0.55 +/- 0.06) when we applied the same 470 drug-event pairs as the gold standard, as in our previous research. Receiver operating characteristic curves for 101 precautionary terms in the Medical Dictionary for Regulatory Activities Preferred Terms were obtained for MetaLAB and MetaNurse (0.69 +/- 0.11; 0.62 +/- 0.07), which complemented each other in terms of ADR signal coverage. Novel ADR signals discovered by MetaLAB and MetaNurse were successfully validated against spontaneous reports in the US Food and Drug Administration Adverse Event Reporting System database. Discussion: The present study demonstrates the symbiosis of laboratory test results and nursing statements for ADR signal detection in terms of their system organ class coverage and performance profiles. Conclusion: Systematic discovery and evaluation of the wide spectrum of ADR signals using standard-based observational electronic health record data across many institutions will affect drug development and use, as well as postmarketing surveillance and regulation. PMID- 28087586 TI - Using e-cigarettes in the home to reduce smoking and secondhand smoke: disadvantaged parents' accounts. AB - Electronic cigarettes (e-cigarettes) are subject to considerable public health debate. Most public health experts agree that for smokers who find it particularly challenging to quit, e-cigarettes may reduce harm. E-cigarette use in the home may also reduce children's secondhand smoke (SHS) exposure, although e-cigarette vapour may pose risks. This is the first qualitative study to explore disadvantaged parents' views and experiences of e-cigarettes in relation to reducing SHS exposure in the home. Interviews with 25 disadvantaged parents from Edinburgh who smoked and had children aged 1-3 were conducted in 2013, with 17 re interviewed in 2014. Accounts of e-cigarette perceptions and use were analysed thematically. E-cigarettes were seen by some as potentially valuable in helping quitting or reducing smoking in difficult circumstances, and protecting children from SHS when smoking outside is constrained. However, parents raised concerns about safety issues and continuing their nicotine addiction. In relation to children, concerns included possible health effects of the vapour, children playing with them and role-modelling e-cigarette use. While significant concerns remain about e-cigarettes, for some parents who find it challenging to quit or safely leave their children to smoke outside, e-cigarettes may offer potential for reducing the harm to them and their children. PMID- 28087587 TI - Association between dietary intake and 'school-valued' outcomes: a scoping review. AB - Approximately one in four Australian children aged 5-17 years are overweight or obese. Most of the health effects of overweight and obesity in childhood do not eventuate until into adulthood; therefore, motivation for children to have a healthy diet may be low. This scoping review examined the literature for associations between diet quality in 5-18 year olds and 'school-valued' outcomes including student attendance, academic performance, behaviour at school and mental health. A literature search for studies that assessed dietary intake and at least one 'school-valued' outcome in schoolchildren, in highly developed countries was conducted. After applying selection criteria, 35 studies were included examining academic performance (46%), behaviour (11%), mental health (31%) and 11% examining two of these outcomes each. No relevant studies addressed attendance. In general, dietary factors including consumption of fruit and vegetables, discretionary foods and/or beverages, or overall diet quality, were suggested to be correlates of the 'school-valued' outcomes. However, the evidence is not comprehensive. This review elucidates the extent and nature of available literature, and provides a basis for future research where the potential benefits of diet on 'school-valued' outcomes can be thoroughly explored. PMID- 28087588 TI - Bleeding associated with the management of acute coronary syndromes. PMID- 28087589 TI - Erratum. PMID- 28087590 TI - Medication reconciliation. PMID- 28087591 TI - Clinical trials in antineutrophil cytoplasmic antibody-associated vasculitis: what we have learnt so far, and what we still have to learn. AB - The prognosis of the antineutrophil cytoplasmic antibody associated vasculitides (AAV), microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA), has been fundamentally improved over the last five decades by the use of glucocorticoids and immunosuppressants, turning them from consistently fatal diseases into chronic conditions. The long-term course is now largely determined by the frequency of disease flares and by accruing damage caused by disease activity and treatment-related comorbidities. This review summarizes the evidence derived from clinical trials performed during the last 30 years and the remaining clinical unmet needs that new studies aim to address. In MPA and GPA, ongoing studies assess (i) different strategies to reduce cumulative glucocorticoid doses currently used for induction and maintenance of remission, (ii) the efficacy of new drugs and (iii) the optimal duration of immunosuppression and the use of biomarkers to individualize therapy. Prospective randomized trials also target disease-associated cardiovascular risk and infections. The first prospective controlled trials specifically designed for EGPA have recently been launched and could lead to new therapeutic options for patients diagnosed with this rare disease. This is an exciting time for researchers in the field of AAV, and for patients as collaborative efforts raise the hope of developing new therapies and more individualized approaches to the management of the diseases, maximizing efficacy while minimizing treatment toxicities. PMID- 28087592 TI - A fifth of healthcare spending is wasted, says OECD report. PMID- 28087593 TI - Norovirus-Mediated Modification of the Translational Landscape via Virus and Host Induced Cleavage of Translation Initiation Factors. AB - Noroviruses produce viral RNAs lacking a 5' cap structure and instead use a virus encoded viral protein genome-linked (VPg) protein covalently linked to viral RNA to interact with translation initiation factors and drive viral protein synthesis. Norovirus infection results in the induction of the innate response leading to interferon stimulated gene (ISG) transcription. However, the translation of the induced ISG mRNAs is suppressed. A SILAC-based mass spectrometry approach was employed to analyze changes to protein abundance in both whole cell and m7GTP-enriched samples to demonstrate that diminished host mRNA translation correlates with changes to the composition of the eukaryotic initiation factor complex. The suppression of host ISG translation correlates with the activity of the viral protease (NS6) and the activation of cellular caspases leading to the establishment of an apoptotic environment. These results indicate that noroviruses exploit the differences between viral VPg-dependent and cellular cap-dependent translation in order to diminish the host response to infection. PMID- 28087595 TI - Is epicardial fat depot associated with atrial fibrillation? A systematic review and meta-analysis. AB - Aims: Atrial fibrillation (AF) is the leading rhythm disorder in western countries. A direct relationship between left atrium (LA) enlargement and electromechanical remodelling has been established. A causative link between epicardial fat (EF), visceral adipose tissue deposited around the heart, and AF has been hypothesized. Several reports suggested the association between EF and the presence of AF. The aim of this study was to verify the relationship between AF and EF depot, performing a meta-analysis of observational case series studies. Methods and results: Studies were identified by searching electronic databases by two independent investigators using 'atrial fibrillation' and 'epicardial fat' as keywords. Comparisons between healthy participants and AF cases were performed using a random effect meta-analysis estimating standardized mean difference among comparison groups. Meta regression was used to address the effect given by potential biological and technical confounders. Through a search result of 502 articles, only 7 were selected to conduct the present study. The comparison between all AF with respect to healthy participants resulted in a 32.0 ml of EF difference (95% confidence interval (CI) = 21.5, 42.5) showing that EF volume is higher in AF cases. A statistical significant difference of EF was observed when comparing both persistent and paroxysmal AF subtypes with respect to healthy participants (EF difference 48.0 ml (95% CI = 25.2, 70.8) and 15.7 ml (95% CI = 10.1, 21.4) for persistent and paroxysmal, respectively). A significant EF difference resulted also when comparing persistent to paroxysmal AF subtypes (29.6 ml (95% CI = 12.7, 46.5)). Conclusions: The present work expands the strength of previously reported association between EF amount and atrial arrhythmia. PMID- 28087594 TI - A Human Proteome Array Approach to Identifying Key Host Proteins Targeted by Toxoplasma Kinase ROP18. AB - Toxoplasma kinase ROP18 is a key molecule responsible for the virulence of Toxoplasma gondii; however, the mechanisms by which ROP18 exerts parasite virulence via interaction with host proteins remain limited to a small number of identified substrates. To identify a broader array of ROP18 substrates, we successfully purified bioactive mature ROP18 and used it to probe a human proteome array. Sixty eight new putative host targets were identified. Functional annotation analysis suggested that these proteins have a variety of functions, including metabolic process, kinase activity and phosphorylation, cell growth, apoptosis and cell death, and immunity, indicating a pleiotropic role of ROP18 kinase. Among these proteins, four candidates, p53, p38, UBE2N, and Smad1, were further validated. We demonstrated that ROP18 targets p53, p38, UBE2N, and Smad1 for degradation. Importantly, we demonstrated that ROP18 phosphorylates Smad1 Ser 187 to trigger its proteasome-dependent degradation. Further functional characterization of the substrates of ROP18 may enhance understanding of the pathogenesis of Toxoplasma infection and provide new therapeutic targets. Similar strategies could be used to identify novel host targets for other microbial kinases functioning at the pathogen-host interface. PMID- 28087596 TI - A meta-analysis on the prognostic significance of inferolateral early repolarization pattern in Brugada syndrome. AB - Aims: The early repolarization (ER) pattern has been linked to an increased risk for arrhythmic death in various clinical settings. There are limited and conflicting data regarding the prognostic significance of ER pattern in Brugada syndrome (BS). The aim of this meta-analysis was to provide a detailed analysis of the currently available studies regarding the arrhythmic risk in patients with BS and ER pattern. Methods and results: Current databases were searched until May 2015. A random-effect meta-analysis of the effect of ER pattern on the incidence of arrhythmic events in patients with BS was performed. Five studies were included comprising a total of 1375 patients with BS. An ER pattern was reported in 177 patients (12.8%). During follow-up (44.9-93 months), 143 patients (10.4%) suffered an arrhythmic event. Overall, BS patients with ER pattern displayed an increased risk of arrhythmic events compared to patients without ER (OR 3.29, 95% CI: 2.06 to 5.26, P < 0.00001; Heterogeneity: P = 0.11, I2 = 48%). Three studies provided data regarding ER pattern location. Inferior, lateral, or inferolateral ER pattern location was observed in 20.3%, 32.2%, and 48%, respectively. An inferolateral ER location conferred the higher arrhythmic risk (OR 4.87, 95% CI: 2.64 to 9.01, P< 0.00001; Heterogeneity: P = 0.85, I2 = 0%). Conclusion: This meta-analysis suggests that the ER pattern is associated with a high risk of arrhythmic events in patients with BS. In particular, BS patients with inferolateral ER (global ER pattern) displayed the highest arrhythmic risk. PMID- 28087597 TI - Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses. AB - Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca2+ and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown. However, using cell-based assays and integrated proteomics, phosphoproteomics, and transcriptomics analyses, we identified the downstream signaling events these drugs affect. Changes in plasma membrane depolarization and elevated intracellular Na+, which compromised Na+ dependent nutrient transport, were documented. Deficits in nutrient deficit acted in turn to trigger the unfolded protein response and the amino acid response, leading ultimately to nutrient starvation and GIC cell death. Our results suggest new therapeutic targets to attack aggressive gliomas. Cancer Res; 77(7); 1741-52. (c)2017 AACR. PMID- 28087599 TI - Long Noncoding RNA LINC00092 Acts in Cancer-Associated Fibroblasts to Drive Glycolysis and Progression of Ovarian Cancer. AB - The majority of patients with epithelial ovarian cancer are diagnosed at a late stage when the peritoneal metastases exist; however, there is little knowledge of the metastatic process in this disease setting. In this study, we report the identification of the long noncoding RNA LINC00092 as a nodal driver of metastatic progression mediated by cancer-associated fibroblasts (CAF). Prometastatic properties of CAFs in vitro and in vivo were found to associate with elevated expression of the chemokine CXCL14. In clinical specimens, elevated levels of CXCL14 in CAFs also correlated with poor prognosis. Notably, CXCL14 high CAFs mediated upregulation of LINC00092 in ovarian cancer cells, the levels of which also correlated with poor prognosis in patients. Mechanistic studies showed that LINC00092 bound a glycolytic enzyme, the fructose-2,6-biphosphatase PFKFB2, thereby promoting metastasis by altering glycolysis and sustaining the local supportive function of CAFs. Overall, our study uncovered a positive feedback loop in the metabolism of CXCL14-positive CAFs and ovarian cancer cells that is critical for metastatic progression. Cancer Res; 77(6); 1369-82. (c)2017 AACR. PMID- 28087598 TI - Bayesian Network Inference Modeling Identifies TRIB1 as a Novel Regulator of Cell Cycle Progression and Survival in Cancer Cells. AB - Molecular networks governing responses to targeted therapies in cancer cells are complex dynamic systems that demonstrate nonintuitive behaviors. We applied a novel computational strategy to infer probabilistic causal relationships between network components based on gene expression. We constructed a model comprised of an ensemble of networks using multidimensional data from cell line models of cell cycle arrest caused by inhibition of MEK1/2. Through simulation of a reverse engineered Bayesian network model, we generated predictions of G1-S transition. The model identified known components of the cell-cycle machinery, such as CCND1, CCNE2, and CDC25A, as well as revealed novel regulators of G1-S transition, IER2, TRIB1, TRIM27. Experimental validation of model predictions confirmed 10 of 12 predicted genes to have a role in G1-S progression. Further analysis showed that TRIB1 regulated the cyclin D1 promoter via NFkappaB and AP-1 sites and sensitized cells to TRAIL-induced apoptosis. In clinical specimens of breast cancer, TRIB1 levels correlated with expression of NFkappaB and its target genes (IL8, CSF2), and TRIB1 copy number and expression were predictive of clinical outcome. Together, our results establish a critical role of TRIB1 in cell cycle and survival that is mediated via the modulation of NFkappaB signaling. Cancer Res; 77(7); 1575-85. (c)2017 AACR. PMID- 28087601 TI - An unusual cause of 'dextrocardia'. PMID- 28087600 TI - Sunitinib Stimulates Expression of VEGFC by Tumor Cells and Promotes Lymphangiogenesis in Clear Cell Renal Cell Carcinomas. AB - Sunitinib is an antiangiogenic therapy given as a first-line treatment for renal cell carcinoma (RCC). While treatment improves progression-free survival, most patients relapse. We hypothesized that patient relapse can stem from the development of a lymphatic network driven by the production of the main growth factor for lymphatic endothelial cells, VEGFC. In this study, we found that sunitinib can stimulate vegfc gene transcription and increase VEGFC mRNA half life. In addition, sunitinib activated p38 MAPK, which resulted in the upregulation/activity of HuR and inactivation of tristetraprolin, two AU-rich element-binding proteins. Sunitinib stimulated a VEGFC-dependent development of lymphatic vessels in experimental tumors. This may explain our findings of increased lymph node invasion and new metastatic sites in 30% of sunitinib treated patients and increased lymphatic vessels found in 70% of neoadjuvant treated patients. In summary, a therapy dedicated to destroying tumor blood vessels induced the development of lymphatic vessels, which may have contributed to the treatment failure. Cancer Res; 77(5); 1212-26. (c)2017 AACR. PMID- 28087603 TI - Coronary microvascular reserve and outcome in aortic stenosis: Pathophysiological significance vs. clinical relevance. PMID- 28087604 TI - HIV infection, ACS, PCI and high platelet reactivity: ingredients for a perfect thrombotic storm. PMID- 28087602 TI - Novel application of 3D contrast-enhanced CMR to define fibrotic structure of the human sinoatrial node in vivo. AB - Aims: The adult human sinoatrial node (SAN) has a specialized fibrotic intramural structure (35-55% fibrotic tissue) that provides mechanical and electrical protection from the surrounding atria. We hypothesize that late gadolinium enhanced cardiovascular magnetic resonance (LGE-CMR) can be applied to define the fibrotic human SAN structure in vivo. Methods and results : LGE-CMR atrial scans of healthy volunteers (n olu, 23-52 y.o.) using a 3 Tesla magnetic resonance imaging system with a spatial resolution of 1.0 mm3 or 0.625 * 0.625 * 1.25 mm3 were obtained and analysed. Percent fibrosis of total connective and cardiomyocyte tissue area in segmented atrial regions were measured based on signal intensity differences of fibrotic vs. non-fibrotic cardiomyocyte tissue. A distinct ellipsoidal fibrotic region (length: 23.6 +/- 1.9 mm; width: 7.2 +/- 0.9 mm; depth: 2.9 +/- 0.4 mm) in all hearts was observed along the posterior junction of the crista terminalis and superior vena cava extending towards the interatrial septum, corresponding to the anatomical location of the human SAN. The SAN fibrotic region consisted of 41.9 +/- 5.4% of LGE voxels above an average threshold of 2.7 SD (range 2-3 SD) from the non-fibrotic right atrial free wall tissue. Fibrosis quantification and SAN identification by in vivo LGE-CMR were validated in optically mapped explanted donor hearts ex vivo (n ivo, 19-65 y.o.) by contrast-enhanced CMR (9.4 Tesla; up to 90 um3 resolution) correlated with serial histological sections of the SAN. Conclusion: This is the first study to visualize the 3D human SAN fibrotic structure in vivo using LGE-CMR. Identification of the 3D SAN location and its high fibrotic content by LGE-CMR may provide a new tool to avoid or target SAN structure during ablation. PMID- 28087605 TI - Histopathological Workup of a Hybrid Implanted Melody(r) Valve in Mitral Valve Position. PMID- 28087606 TI - Reinnervation post-heart transplantation. AB - Heart transplantation results in complete denervation of the donor heart with loss of afferent and efferent nerve connections. The majority of patients remain completely denervated during the first 6-12 months following transplantation. Evidence of reinnervation is usually found during the second year after transplantation and involve the myocardial muscle, sinoatrial node, and coronary vessels, but remains incomplete and regionally limited many years post transplant. Restoration of cardiac innervation can improve exercise capacity as well as blood flow regulation in the coronary arteries, and hence improve quality of life. As yet, there is no evidence that the reinnervation process is associated with the occurrence of allograft-related events or survival. PMID- 28087607 TI - Type II Diabetes, Obesity, and Breast Cancer Risk: The Multiethnic Cohort. AB - Background: Obesity has been more consistently associated with breast cancer than type II diabetes. This analysis examined the combination of the two factors in the Multiethnic Cohort (MEC).Methods: Women ages 45-75 years entered the MEC in 1993-1996 by completing a questionnaire. Type II diabetes status was self reported at baseline, two follow-up questionnaires, and confirmed by administrative data. Cancers were identified from tumor registries and deaths through vital records until 2010. Cox regression was applied to estimate HRs and 95% confidence intervals (CI) for BMI and type II diabetes status alone and in combination.Results: Among 103,721 (25,146 white, 20,255 African American, 7,681 Native Hawaiian, 28,012 Japanese American, 22,627 Latina) women with 14,558 type II diabetes cases, 6,692 women developed breast cancer during 14.8 +/- 4.1 years of follow-up. Type II diabetes was significantly associated with breast cancer risk (HR, 1.15; 95% CI, 1.07-1.23), but including body mass index (BMI) lowered the HR to 1.08 (95% CI, 1.00-1.16). Ethnic-specific BMI-adjusted models showed elevated risks for type II diabetes in Latinas only (HR, 1.30; 95% CI, 1.11 1.52). In contrast, obesity predicted statistically significant 21%-46% higher risks, after type II diabetes adjustment, in all ethnic groups except Latinas (HR, 1.17; 95% CI, 0.99-1.38).Conclusions: As reported previously, inclusion of BMI weakened the association of type II diabetes with breast cancer. Type II diabetes status, but not BMI, was primarily associated with higher breast cancer risk in Latinas.Impact: The role of obesity and type II diabetes in breast cancer etiology may differ by ethnicity suggesting metabolic differences related to obesity. Cancer Epidemiol Biomarkers Prev; 26(6); 854-61. (c)2017 AACR. PMID- 28087608 TI - Diabetes, Abnormal Glucose, Dyslipidemia, Hypertension, and Risk of Inflammatory and Other Breast Cancer. AB - Background: Obesity has been associated with substantially higher risk of inflammatory breast cancer (IBC) than other breast cancer. Here, we assess whether comorbidities of obesity, namely diabetes, abnormal glucose, dyslipidemia, and hypertension, are differentially related to risk of IBC and other breast cancers by tumor stage at diagnosis (localized/regional/distant/unstaged).Methods: We used linked SEER-Medicare data, with female breast cancer cases ages 66+ years identified by SEER registries (years 1992-2011). We divided first breast cancers into IBC (N = 2,306), locally advanced non-IBC (LABC; N = 10,347), and other (N = 197,276). We selected female controls (N = 200,000) from a stratified 5% random sample of Medicare recipients alive and breast cancer free. We assessed exposures until 12 months before diagnosis/selection using Medicare claims data. We estimated odds ratios (OR) and 99.9% confidence intervals (CI) using unconditional logistic regression.Results: Diabetes was associated with increased risk of distant IBC (98.5% of IBC cases; OR 1.44; 99.9% CI 1.21-1.71), distant (OR 1.24; 99.9% CI, 1.09-1.40) and regional (OR 1.29 (99.9% CI, 1.14-1.45) LABC, and distant (OR 1.23; 99.9% CI, 1.10-1.39) and unstaged (OR 1.32; 99.9% CI, 1.18-1.47) other breast cancers. Dyslipidemia was associated with reduced risk of IBC (OR 0.80; 95% CI, 0.67-0.94) and other breast cancers except localized disease. Results were similar by tumor estrogen receptor status. Abnormal glucose levels and hypertension had little association with risk of any tumor type.Conclusions: Associations with diabetes and dyslipidemia were similar for distant stage IBC and other advanced tumors.Impact: If confirmed, such findings could suggest avenues for prevention. Cancer Epidemiol Biomarkers Prev; 26(6); 862-8. (c)2017 AACR. PMID- 28087609 TI - Role of attitudes and intentions in predicting adherence to oral diabetes medications. AB - The purpose of this quantitative study was to investigate the extent to which patient attitudes and intentions predict adherence to the use of oral antihyperglycemic regimens in African Americans. This cross-sectional study of 115 participants used correlation analysis to establish relationships among patient attitudes, intentions and adherence. Data analyses showed significant correlations between the variables. Multiple regression analysis was used to establish predictions between the variables. A prediction model containing attitudes, subjective norms and perceived behavioral control (PBC) explained 37% of the variance to behavioral intention. Intentions accounted for 8.5% of the variance to adherence. Attitudes predicted behavioral intentions. The findings support the theory of planned behavior model and identify important correlations between attitudes, intentions and behaviors. In addition, the results underscore the need for promoting positive attitudes and positive intentions in effective adherence to the use of oral antihyperglycemic regimens. Achieving adequate adherence through behavioral counseling can effect positive social change by reducing the mortality and morbidity that are associated with inadequate adherence to the use of oral diabetic agents. PMID- 28087611 TI - Production of N-acyl homoserine lactones by the sponge-associated marine actinobacteria Salinispora arenicola and Salinispora pacifica. AB - The structures of acyl homoserine lactone (AHL) compounds and their quantification were accomplished using an integrated liquid chromatography-mass spectrometry approach. The precursor and product ions, along with retention times of peaks, were searched against an in-house database of AHLs and structures confirmed by accurate mass and by comparison with authentic AHL standards. The two compounds, N-(3-oxodecanoyl)-L-homoserine lactone and N-(3-oxododecanoyl)-L homoserine lactone, were characterised and quantified in Salinispora sp. cultures. PMID- 28087610 TI - Long non-coding RNA exchange during the oocyte-to-embryo transition in mice. AB - The oocyte-to-embryo transition (OET) transforms a differentiated gamete into pluripotent blastomeres. The accompanying maternal-zygotic RNA exchange involves remodeling of the long non-coding RNA (lncRNA) pool. Here, we used next generation sequencing and de novo transcript assembly to define the core population of 1,600 lncRNAs expressed during the OET (lncRNAs). Relative to mRNAs, OET lncRNAs were less expressed and had shorter transcripts, mainly due to fewer exons and shorter 5' terminal exons. Approximately half of OET lncRNA promoters originated in retrotransposons suggesting their recent emergence. Except for a small group of ubiquitous lncRNAs, maternal and zygotic lncRNAs formed two distinct populations. The bulk of maternal lncRNAs was degraded before the zygotic genome activation. Interestingly, maternal lncRNAs seemed to undergo cytoplasmic polyadenylation observed for dormant mRNAs. We also identified lncRNAs giving rise to trans-acting short interfering RNAs, which represent a novel lncRNA category. Altogether, we defined the core OET lncRNA transcriptome and characterized its remodeling during early development. Our results are consistent with the notion that rapidly evolving lncRNAs constitute signatures of cells-of-origin while a minority plays an active role in control of gene expression across OET. Our data presented here provide an excellent source for further OET lncRNA studies. PMID- 28087612 TI - Biofilm formation and antimicrobial resistance genes of coagulase-negative staphylococci isolated from cows with mastitis in Argentina. AB - Mastitis affects the health and welfare of dairy cows worldwide. Coagulase negative staphylococci (CNS) are known to form biofilms and are increasingly recognized as a cause of persistent bovine intramammary infections. A total of 90 CNS isolated from cows with clinical and subclinical mastitis in Argentina from 2008 to 2014 were identified by PCR-RFLP using the gap gene. Standard microtiter plate assays were used to assess CNS biofilm formation, and Staphylococcus haemolyticus species formed the strongest biofilms. The presence of biofilm associated genes icaA, bap and aap was detected in a few isolates, while embP, fbe, atlE and eno were present in the majority of isolates. Genes encoding resistance to beta-lactams were detected among the isolates; blaZ, mecA and mecC were detected in 21, 4 and 1 isolate, respectively. Resistance to macrolides and lincosamides (n = 6) was attributable to ermB, ermC, mphC or mrsA or a combination of those genes. In this study, we identified CNS species involved in mastitis and provide information about pathogenicity and antimicrobial resistance, which is essential to design efficient strategies to control mastitis caused by CNS. PMID- 28087614 TI - Usefulness of FTIR spectroscopy to distinguish rough and smooth variants of Lactobacillus farciminis CNCM-I-3699. AB - In this study, the potential of Fourier transform infrared (FTIR) spectroscopy for assessing putative biochemical and structural differences between the two variants, rough (R) and smooth (S), of Lactobacillus farciminis CNCM-I-3699, a pleomorphic strain, was investigated. The main differences observed were localized in the polysaccharide (1200-900 cm-1) and protein (1700-1500 cm-1) regions. Based on spectral information in these two spectral ranges, clustering resulted in a dendrogram that showed a clear discrimination between both morphotypes. Significant increases in favor of morphotype S compared to R at specific wavenumbers for polysaccharides (22.18% vs. 5.24% at 1068 cm-1) and capsular polysaccharides (16% vs. 13.17% at 1048 cm-1) were recorded. Compared to S, the morphotype R exhibits a 1.27-fold higher signal at the wavenumber of 1637 cm-1 assigned to the amide I beta-sheet and a 2.71-fold higher signal at the wavenumber of 1513 cm-1 assigned to the tyrosine involved in the beta-sheet arrangement of proteins. The FTIR analysis is efficient to separate and give data on mainly surface component differences observed previously between S colony morphotype (ropy and exopolysaccharide positive) and the R colony morphotype (non ropy but highly autoaggregative). PMID- 28087613 TI - Systemic and mucosal pre-administration of recombinant Helicobacter pylori neutrophil-activating protein prevents ovalbumin-induced allergic asthma in mice. AB - PURPOSE: Previous epidemiologic studies have demonstrated an inverse association between Helicobacter pylori infection and the frequency of allergic asthma. The neutrophil-activating protein (NAP) of H. pylori has been identified as a modulator possessing anti-Th2 inflammation activity. Here, we sought to determine whether systemic or mucosal pre-administration of recombinant H. pylori NAP (rNAP) could prevent ovalbumin (OVA)-induced allergic asthma in mice. METHODS: Mice were exposed to purified rNAP through intraperitoneal injection or inhalation and then sensitized with OVA. Following a challenge with aerosolized OVA, the bronchoalveolar lavage fluid (BALF) cell count, lung tissue histology, BALF cytokines and serum IgE were evaluated. RESULTS: Both intraperitoneal injection and inhalation of rNAP prior to OVA sensitization significantly reduced eosinophil accumulation and inflammatory infiltration in lung tissue in OVA induced asthma mice; eosinophils were reduced in the BALF of rNAP-treated mice. In addition, IL-4 and IL-13 levels were lower (P < 0.01), IL-10 and IFN-gamma levels were higher (P < 0.01) and IgE serum levels were lower (P < 0.01) in the treated groups compared to the control group. CONCLUSIONS: Systemic and mucosal pre-administration of rNAP could suppress the development of OVA-induced asthma in mice; rNAP may be utilized as part of novel strategies for the prevention or treatment of allergic diseases. PMID- 28087615 TI - Microbial catabolism of sterols: focus on the enzymes that transform the sterol 3beta-hydroxy-5-en into 3-keto-4-en. AB - An overview on the microbial sterol catabolism is described with a focus on the catabolic step of the 3beta-hydroxy-5-en structure. Cholesterol oxidase transforms this structure into the corresponding 3-keto-4-en feature, and thus initiates the sterol molecule catabolism. The oxidase has been found in a large number of microorganisms, especially in Actinobacteria as species of Rhodococcus and Streptomyces. Other Actinobacteria as species of Mycobacterium and Nocardia possess NAD(P)-dependent dehydrogenase for this catabolic step. In Rhodococcus jostii, oxidation of the C26 of the sterol side chain is the initiating step. The resulting stenone or sterol-C26-oic acid is then catabolized according to two subpathways: cleavage of the sterol side chain and degradation of the steroid nucleus. Divergent items concerned with the enzymes that transform the sterol 3beta-hydroxy-5-en are discussed. PMID- 28087616 TI - Pathways to false-positive diagnoses using molecular genetic detection methods; Phytophthora cinnamomi a case study. AB - Phytophthora cinnamomi is one of the world's most invasive plant pathogens affecting ornamental plants, horticultural crops and natural ecosystems. Accurate diagnosis is very important to determine the presence or absence of this pathogen in diseased and asymptomatic plants. In previous studies, P. cinnamomi species specific primers were designed and tested using various polymerase chain reaction (PCR) techniques including conventional PCR, nested PCR and quantitative real time PCR. In all cases, the primers were stated to be highly specific and sensitive to P. cinnamomi. However, few of these studies tested their primers against closely related Phytophthora species (Phytophthora clade 7). In this study, we tested these purported P. cinnamomi-specific primer sets against 11 other species from clade 7 and determined their specificity; of the eight tested primer sets only three were specific to P. cinnamomi. This study demonstrated the importance of testing primers against closely related species within the same clade, and not just other species within the same genus. The findings of this study are relevant to all species-specific microbial diagnosis. PMID- 28087617 TI - In vitro activity of the antiasthmatic drug zafirlukast against the oral pathogens Porphyromonas gingivalis and Streptococcus mutans. AB - Oral infections are among the most common diseases worldwide. Many protocols for the prevention and treatment of oral infections have been described, yet no golden standard has been developed so far. The antiseptic chlorhexidine and antibiotics are often used in these treatment procedures. However, long-term use of chlorhexidine can lead to side effects and extensive use of antibiotics can promote the development of antibiotic-resistant bacteria, which in turn can compromise the effectiveness of the treatment. Consequently, it remains important to search for new antibacterial agents for the treatment of oral infections. In this study, we report on the antibacterial activity of the antiasthma drug zafirlukast against oral pathogens Porphyromonas gingivalis and Streptococcus mutans. Furthermore, its activity against oral biofilms grown on titanium surfaces was confirmed. In addition, we demonstrated that zafirlukast displays no cytotoxicity against human osteoblasts. Combined, this study paves the way for further research to determine the potential of zafirlukast to be used as a new antibiotic against oral pathogens. PMID- 28087618 TI - Spotlight on... Mariagrazia Pizza. PMID- 28087619 TI - Genome-wide transcription profiling of aerobic and anaerobic Escherichia coli biofilm and planktonic cultures. AB - Many studies have described the response of the facultative anaerobe, Escherichia coli, to anaerobic conditions, yet they all investigated free-living (planktonic) cells because attempts to cultivate anaerobic E. coli biofilm were mostly unsuccessful. We challenged these findings and cultivated E. coli strain MG1655 biofilm under both aerobic and anaerobic conditions, characterizing the mature biofilm architecture and global gene expression profile. We used RNA sequencing technology to compare stationary phase planktonic cells with mature biofilm, cultured with and without oxygen. Our results suggest that gene expression patterns significantly differ between biofilm and planktonic cultures cultivated under the same oxygenic conditions. The anaerobic E. coli biofilms were slow growing and patchy compared to aerobic biofilms, yet some features were unchanged like the production of extracellular polymeric substances. A closer inspection of the mRNA data revealed that essential cell processes were attenuated in anaerobic biofilms, including protein synthesis, information transfer, cell structure, regulation and transport. Our results suggest that lack of oxygen imposes severe stress on mature biofilms thus limiting the cells' activity. We further propose that E. coli does not favor growing in anaerobic biofilms and when forced to do so, the cells prevail by attenuating their activity in order to survive. PMID- 28087620 TI - E152A substitution drastically affects NDM-5 activity. AB - New Delhi Metallo beta-lactamase (NDM) is of significant public health concern due to its enormous potential to hydrolyse all major beta-lactams including carbapenems. Amino acid substitutions outside the active site reportedly affect NDM beta-lactamase activities. Here, the effect of amino acid substitutions in the possible omega-like loop region of NDM-5 has been elucidated. Overall, three substitution mutations near active site of NDM-5 were done, namely, E152A, S191A and D223A and subsequently, the change in antimicrobial resistance was monitored upon expressing each mutant in a suitable host. Among the three mutants, E152A substitution on a loop near the active site resulted in significant reduction in beta-lactam antibiotic resistance as compared to NDM-5 that compelled us to conduct further studies on the E152A-substituted NDM-5. The purified NDM-5 was able to hydrolyse all the beta-lactams tested whereas the E152A mutation suppressed its activities. NDM-5 showed maximum kcat/Km ratio against penicillins and carbapenems and had lower Km as compared to NDM-5_E152A. Though, the amino acid substitution did not affect the overall folding pattern of NDM-5, significant differences in thermal stability between the wild-type and mutated protein were observed. Therefore, we infer that the E152 residue is important in regulating the beta-lactam hydrolysing properties of NDM-5. PMID- 28087621 TI - The HOOK region of voltage-gated Ca2+ channel beta subunits senses and transmits PIP2 signals to the gate. AB - The beta subunit of voltage-gated Ca2+ (CaV) channels plays an important role in regulating gating of the alpha1 pore-forming subunit and its regulation by phosphatidylinositol 4,5-bisphosphate (PIP2). Subcellular localization of the CaV beta subunit is critical for this effect; N-terminal-dependent membrane targeting of the beta subunit slows inactivation and decreases PIP2 sensitivity. Here, we provide evidence that the HOOK region of the beta subunit plays an important role in the regulation of CaV biophysics. Based on amino acid composition, we broadly divide the HOOK region into three domains: S (polyserine), A (polyacidic), and B (polybasic). We show that a beta subunit containing only its A domain in the HOOK region increases inactivation kinetics and channel inhibition by PIP2 depletion, whereas a beta subunit with only a B domain decreases these responses. When both the A and B domains are deleted, or when the entire HOOK region is deleted, the responses are elevated. Using a peptide-to-liposome binding assay and confocal microscopy, we find that the B domain of the HOOK region directly interacts with anionic phospholipids via polybasic and two hydrophobic Phe residues. The beta2c short subunit, which lacks an A domain and contains fewer basic amino acids and no Phe residues in the B domain, neither associates with phospholipids nor affects channel gating dynamically. Together, our data suggest that the flexible HOOK region of the beta subunit acts as an important regulator of CaV channel gating via dynamic electrostatic and hydrophobic interaction with the plasma membrane. PMID- 28087622 TI - Calmodulin limits pathogenic Na+ channel persistent current. AB - Increased "persistent" current, caused by delayed inactivation, through voltage gated Na+ (NaV) channels leads to cardiac arrhythmias or epilepsy. The underlying molecular contributors to these inactivation defects are poorly understood. Here, we show that calmodulin (CaM) binding to multiple sites within NaV channel intracellular C-terminal domains (CTDs) limits persistent Na+ current and accelerates inactivation across the NaV family. Arrhythmia or epilepsy mutations located in NaV1.5 or NaV1.2 channel CTDs, respectively, reduce CaM binding either directly or by interfering with CTD-CTD interchannel interactions. Boosting the availability of CaM, thus shifting its binding equilibrium, restores wild-type (WT)-like inactivation in mutant NaV1.5 and NaV1.2 channels and likewise diminishes the comparatively large persistent Na+ current through WT NaV1.6, whose CTD displays relatively low CaM affinity. In cerebellar Purkinje neurons, in which NaV1.6 promotes a large physiological persistent Na+ current, increased CaM diminishes the persistent Na+ current, suggesting that the endogenous, comparatively weak affinity of NaV1.6 for apoCaM is important for physiological persistent current. PMID- 28087623 TI - A p53-based genetic tracing system to follow postnatal cardiomyocyte expansion in heart regeneration. AB - In the field of heart regeneration, the proliferative potential of cardiomyocytes in postnatal mice is under intense investigation. However, solely relying on immunostaining of proliferation markers, the long-term proliferation dynamics and potential of the cardiomyocytes cannot be readily addressed. Previously, we found that a p53 promoter-driving reporter predominantly marked the proliferating lineages in mice. Here, we established a p53-based genetic tracing system to investigate postnatal cardiomyocyte proliferation and heart regeneration. By selectively tracing proliferative cardiomyocytes, a differential pattern of clonal expansion in p53+ cardiac myocytes was revealed in neonatal, adolescent and adult stages. In addition, the percentage of p53+ lineage cardiomyocytes increased continuously in the first month. Furthermore, these cells rapidly responded to heart injury and greatly contributed to the replenished myocardium. Therefore, this study reveals complex proliferating dynamics in postnatal cardiomyocytes and heart repair, and provides a novel genetic tracing strategy for studying postnatal cardiac turnover and regeneration. PMID- 28087624 TI - Tissue-specific regulation of alternative polyadenylation represses expression of a neuronal ankyrin isoform in C. elegans epidermal development. AB - Differential mRNA polyadenylation plays an important role in shaping the neuronal transcriptome. In C. elegans, several ankyrin isoforms are produced from the unc 44 locus through alternative polyadenylation. Here, we identify a key role for an intronic polyadenylation site (PAS) in temporal- and tissue-specific regulation of UNC-44/ankyrin isoforms. Removing an intronic PAS results in ectopic expression of the neuronal ankyrin isoform in non-neural tissues. This mis expression underlies epidermal developmental defects in mutants of the conserved tumor suppressor death-associated protein kinase dapk-1 We have previously reported that the use of this intronic PAS depends on the nuclear polyadenylation factor SYDN-1, which inhibits the RNA polymerase II CTD phosphatase SSUP-72. Consistent with this, loss of sydn-1 blocks ectopic expression of neuronal ankyrin and suppresses epidermal morphology defects of dapk-1 These effects of sydn-1 are mediated by ssup-72 autonomously in the epidermis. We also show that a peptidyl-prolyl isomerase PINN-1 antagonizes SYDN-1 in the spatiotemporal control of neuronal ankyrin isoform. Moreover, the nuclear localization of PINN-1 is altered in dapk-1 mutants. Our data reveal that tissue and stage-specific expression of ankyrin isoforms relies on differential activity of positive and negative regulators of alternative polyadenylation. PMID- 28087625 TI - Faithful mRNA splicing depends on the Prp19 complex subunit faint sausage and is required for tracheal branching morphogenesis in Drosophila. AB - Morphogenesis requires the dynamic regulation of gene expression, including transcription, mRNA maturation and translation. Dysfunction of the general mRNA splicing machinery can cause surprisingly specific cellular phenotypes, but the basis for these effects is not clear. Here, we show that the Drosophila faint sausage (fas) locus, which is implicated in epithelial morphogenesis and has previously been reported to encode a secreted immunoglobulin domain protein, in fact encodes a subunit of the spliceosome-activating Prp19 complex, which is essential for efficient pre-mRNA splicing. Loss of zygotic fas function globally impairs the efficiency of splicing, and is associated with widespread retention of introns in mRNAs and dramatic changes in gene expression. Surprisingly, despite these general effects, zygotic fas mutants show specific defects in tracheal cell migration during mid-embryogenesis when maternally supplied splicing factors have declined. We propose that tracheal branching, which relies on dynamic changes in gene expression, is particularly sensitive for efficient spliceosome function. Our results reveal an entry point to study requirements of the splicing machinery during organogenesis and provide a better understanding of disease phenotypes associated with mutations in general splicing factors. PMID- 28087626 TI - Snail2 and Zeb2 repress P-cadherin to define embryonic territories in the chick embryo. AB - Snail and Zeb transcription factors induce epithelial-to-mesenchymal transition (EMT) in embryonic and adult tissues by direct repression of E-cadherin transcription. The repression of E-cadherin transcription by the EMT inducers Snail1 and Zeb2 plays a fundamental role in defining embryonic territories in the mouse, as E-cadherin needs to be downregulated in the primitive streak and in the epiblast, concomitant with the formation of mesendodermal precursors and the neural plate, respectively. Here, we show that in the chick embryo, E-cadherin is weakly expressed in the epiblast at pre-primitive streak stages where it is substituted for by P-cadherin We also show that Snail2 and Zeb2 repress P cadherin transcription in the primitive streak and the neural plate, respectively. This indicates that E- and P-cadherin expression patterns evolved differently between chick and mouse. As such, the Snail1/E-cadherin axis described in the early mouse embryo corresponds to Snail2/P-cadherin in the chick, but both Snail factors and Zeb2 fulfil a similar role in chick and mouse in directly repressing ectodermal cadherin genes to contribute to the delamination of mesendodermal precursors at gastrulation and the proper specification of the neural ectoderm during neural induction. PMID- 28087627 TI - The chemical compound bubblin induces stomatal mispatterning in Arabidopsis by disrupting the intrinsic polarity of stomatal lineage cells. AB - Stem cell polarization is a crucial step in asymmetric cell division, which is a universal system for generating cellular diversity in multicellular organisms. Several conventional genetics studies have attempted to elucidate the mechanisms underlying cell polarization in plants, but it remains largely unknown. In plants, stomata, which are valves for gas exchange, are generated through several rounds of asymmetric divisions. In this study, we identified and characterized a chemical compound that affects stomatal stem cell polarity. High-throughput screening for bioactive molecules identified a pyridine-thiazole derivative, named bubblin, which induced stomatal clustering in Arabidopsis epidermis. Bubblin perturbed stomatal asymmetric division, resulting in the generation of two identical daughter cells. Both cells continued to express the stomatal fate determinant SPEECHLESS, and then differentiated into mispatterned stomata. Bubblin-treated cells had a defect in the polarized localization of BREAKING OF ASYMMETRY IN THE STOMATAL LINEAGE (BASL), which is required for asymmetric cell fate determination. Our results suggest that bubblin induces stomatal lineage cells to divide without BASL-dependent pre-mitotic establishment of polarity. Bubblin is a potentially valuable tool for investigating cell polarity establishment in stomatal asymmetric division. PMID- 28087628 TI - ID4 levels dictate the stem cell state in mouse spermatogonia. AB - Spermatogenesis is a classic model of cycling cell lineages that depend on a balance between stem cell self-renewal for continuity and the formation of progenitors as the initial step in the production of differentiated cells. The mechanisms that guide the continuum of spermatogonial stem cell (SSC) to progenitor spermatogonial transition and precise identifiers of subtypes in the process are undefined. Here we used an Id4-eGfp reporter mouse to discover that EGFP intensity is predictive of the subsets, with the ID4-EGFPBright population being mostly, if not purely, SSCs, whereas the ID4-EGFPDim population is in transition to the progenitor state. These subsets are also distinguishable by transcriptome signatures. Moreover, using a conditional overexpression mouse model, we found that transition from the stem cell to the immediate progenitor state requires downregulation of Id4 coincident with a major change in the transcriptome. Collectively, our results demonstrate that the level of ID4 is predictive of stem cell or progenitor capacity in spermatogonia and dictates the interface of transition between the different functional states. PMID- 28087629 TI - Jmjd2c facilitates the assembly of essential enhancer-protein complexes at the onset of embryonic stem cell differentiation. AB - Jmjd2 H3K9 demethylases cooperate in promoting mouse embryonic stem cell (ESC) identity. However, little is known about their importance at the exit of ESC pluripotency. Here, we reveal that Jmjd2c facilitates this process by stabilising the assembly of mediator-cohesin complexes at lineage-specific enhancers. Functionally, we show that Jmjd2c is required in ESCs to initiate appropriate gene expression programs upon somatic multi-lineage differentiation. In the absence of Jmjd2c, differentiation is stalled at an early post-implantation epiblast-like stage, while Jmjd2c-knockout ESCs remain capable of forming extra embryonic endoderm derivatives. Dissection of the underlying molecular basis revealed that Jmjd2c is re-distributed to lineage-specific enhancers during ESC priming for differentiation. Interestingly, Jmjd2c-bound enhancers are co occupied by the H3K9-methyltransferase G9a (also known as Ehmt2), independently of its H3K9-modifying activity. Loss of Jmjd2c abrogates G9a recruitment and further destabilises loading of the mediator and cohesin components Med1 and Smc1a at newly activated and poised enhancers in ESC-derived epiblast-like cells. These findings unveil Jmjd2c and G9a as novel enhancer-associated factors, and implicate Jmjd2c as a molecular scaffold for the assembly of essential enhancer protein complexes with an impact on timely gene activation. PMID- 28087630 TI - Reconstitution of Torso signaling in cultured cells suggests a role for both Trunk and Torso-like in receptor activation. AB - Formation of the Drosophila embryonic termini is controlled by the localized activation of the receptor tyrosine kinase Torso. Both Torso and Torso's presumed ligand, Trunk, are expressed uniformly in the early embryo. Polar activation of Torso requires Torso-like, which is expressed by follicle cells adjacent to the ends of the developing oocyte. We find that Torso expressed at high levels in cultured Drosophila cells is activated by individual application of Trunk, Torso like or another known Torso ligand, Prothoracicotropic Hormone. In addition to assays of downstream signaling activity, Torso dimerization was detected using bimolecular fluorescence complementation. Trunk and Torso-like were active when co-transfected with Torso and when presented to Torso-expressing cells in conditioned medium. Trunk and Torso-like were also taken up from conditioned medium specifically by cells expressing Torso. At low levels of Torso, similar to those present in the embryo, Trunk and Torso-like alone were ineffective but acted synergistically to stimulate Torso signaling. Our results suggest that Torso interacts with both Trunk and Torso-like, which cooperate to mediate dimerization and activation of Torso at the ends of the Drosophila embryo. PMID- 28087631 TI - PAPC couples the segmentation clock to somite morphogenesis by regulating N cadherin-dependent adhesion. AB - Vertebrate segmentation is characterized by the periodic formation of epithelial somites from the mesenchymal presomitic mesoderm (PSM). How the rhythmic signaling pulse delivered by the segmentation clock is translated into the periodic morphogenesis of somites remains poorly understood. Here, we focused on the role of paraxial protocadherin (PAPC/Pcdh8) in this process. We showed that in chicken and mouse embryos, PAPC expression is tightly regulated by the clock and wavefront system in the posterior PSM. We observed that PAPC exhibits a striking complementary pattern to N-cadherin (CDH2), marking the interface of the future somite boundary in the anterior PSM. Gain and loss of function of PAPC in chicken embryos disrupted somite segmentation by altering the CDH2-dependent epithelialization of PSM cells. Our data suggest that clathrin-mediated endocytosis is increased in PAPC-expressing cells, subsequently affecting CDH2 internalization in the anterior compartment of the future somite. This in turn generates a differential adhesion interface, allowing formation of the acellular fissure that defines the somite boundary. Thus, periodic expression of PAPC in the anterior PSM triggers rhythmic endocytosis of CDH2, allowing for segmental de adhesion and individualization of somites. PMID- 28087632 TI - Sequential organogenesis sets two parallel sensory lines in medaka. AB - Animal organs are typically formed during embryogenesis by following one specific developmental programme. Here, we report that neuromast organs are generated by two distinct and sequential programmes that result in parallel sensory lines in medaka embryos. A ventral posterior lateral line (pLL) is composed of neuromasts deposited by collectively migrating cells whereas a midline pLL is formed by individually migrating cells. Despite the variable number of neuromasts among embryos, the sequential programmes that we describe here fix an invariable ratio between ventral and midline neuromasts. Mechanistically, we show that the formation of both types of neuromasts depends on the chemokine receptor genes cxcr4b and cxcr7b, illustrating how common molecules can mediate different morphogenetic processes. Altogether, we reveal a self-organising feature of the lateral line system that ensures a proper distribution of sensory organs along the body axis. PMID- 28087633 TI - The Abl pathway bifurcates to balance Enabled and Rac signaling in axon patterning in Drosophila. AB - The Abl tyrosine kinase signaling network controls cell migration, epithelial organization, axon patterning and other aspects of development. Although individual components are known, the relationships among them remain unresolved. We now use FRET measurements of pathway activity, analysis of protein localization and genetic epistasis to dissect the structure of this network in Drosophila We find that the adaptor protein Disabled stimulates Abl kinase activity. Abl suppresses the actin-regulatory factor Enabled, and we find that Abl also acts through the GEF Trio to stimulate the signaling activity of Rac GTPase: Abl gates the activity of the spectrin repeats of Trio, allowing them to relieve intramolecular repression of Trio GEF activity by the Trio N-terminal domain. Finally, we show that a key target of Abl signaling in axons is the WAVE complex that promotes the formation of branched actin networks. Thus, we show that Abl constitutes a bifurcating network, suppressing Ena activity in parallel with stimulation of WAVE. We suggest that the balancing of linear and branched actin networks by Abl is likely to be central to its regulation of axon patterning. PMID- 28087634 TI - Genome-wide identification of regulatory elements in Sertoli cells. AB - A current goal of molecular biology is to identify transcriptional networks that regulate cell differentiation. However, identifying functional gene regulatory elements has been challenging in the context of developing tissues where material is limited and cell types are mixed. To identify regulatory sites during sex determination, we subjected Sertoli cells from mouse fetal testes to DNaseI-seq and ChIP-seq for H3K27ac. DNaseI-seq identified putative regulatory sites around genes enriched in Sertoli and pregranulosa cells; however, active enhancers marked by H3K27ac were enriched proximal to only Sertoli-enriched genes. Sequence analysis identified putative binding sites of known and novel transcription factors likely controlling Sertoli cell differentiation. As a validation of this approach, we identified a novel Sertoli cell enhancer upstream of Wt1, and used it to drive expression of a transgenic reporter in Sertoli cells. This work furthers our understanding of the complex genetic network that underlies sex determination and identifies regions that potentially harbor non-coding mutations underlying disorders of sexual development. PMID- 28087635 TI - Retinoblastoma protein controls growth, survival and neuronal migration in human cerebral organoids. AB - The tumor suppressor retinoblastoma protein (RB) regulates S-phase cell cycle entry via E2F transcription factors. Knockout (KO) mice have shown that RB plays roles in cell migration, differentiation and apoptosis, in developing and adult brain. In addition, the RB family is required for self-renewal and survival of human embryonic stem cells (hESCs). Since little is known about the role of RB in human brain development, we investigated its function in cerebral organoids differentiated from gene-edited hESCs lacking RB. We show that RB is abundantly expressed in neural stem and progenitor cells in organoids at 15 and 28 days of culture. RB loss promoted S-phase entry in DCX+ cells and increased apoptosis in Sox2+ neural stem and progenitor cells, and in DCX+ and Tuj1+ neurons. Associated with these cell cycle and pro-apoptotic effects, we observed increased CCNA2 and BAX gene expression, respectively. Moreover, we observed aberrant Tuj1+ neuronal migration in RB-KO organoids and upregulation of the gene encoding VLDLR, a receptor important in reelin signaling. Corroborating the results in RB-KO organoids in vitro, we observed ectopically localized Tuj1+ cells in RB-KO teratomas grown in vivo Taken together, these results identify crucial functions for RB in the cerebral organoid model of human brain development. PMID- 28087636 TI - R-spondin 1 is required for specification of hematopoietic stem cells through Wnt16 and Vegfa signaling pathways. AB - Hematopoietic stem cells (HSCs) are the therapeutic component of bone marrow transplants, but finding immune-compatible donors limits treatment availability and efficacy. Recapitulation of endogenous specification during development is a promising approach to directing HSC specification in vitro, but current protocols are not capable of generating authentic HSCs with high efficiency. Across phyla, HSCs arise from hemogenic endothelium in the ventral floor of the dorsal aorta concurrent with arteriovenous specification and intersegmental vessel (ISV) sprouting, processes regulated by Notch and Wnt. We hypothesized that coordination of HSC specification with vessel patterning might involve modulatory regulatory factors such as R-spondin 1 (Rspo1), an extracellular protein that enhances beta-catenin-dependent Wnt signaling and has previously been shown to regulate ISV patterning. We find that Rspo1 is required for HSC specification through control of parallel signaling pathways controlling HSC specification: Wnt16/DeltaC/DeltaD and Vegfa/Tgfbeta1. Our results define Rspo1 as a key upstream regulator of two crucial pathways necessary for HSC specification. PMID- 28087637 TI - Retinoic acid receptor regulation of epimorphic and homeostatic regeneration in the axolotl. AB - Salamanders are capable of regenerating amputated limbs by generating a mass of lineage-restricted cells called a blastema. Blastemas only generate structures distal to their origin unless treated with retinoic acid (RA), which results in proximodistal (PD) limb duplications. Little is known about the transcriptional network that regulates PD duplication. In this study, we target specific retinoic acid receptors (RARs) to either PD duplicate (RA treatment or RARgamma agonist) or truncate (RARbeta antagonist) regenerating limbs. RARE-EGFP reporter axolotls showed divergent reporter activity in limbs undergoing PD duplication versus truncation, suggesting differences in patterning and skeletal regeneration. Transcriptomics identified expression patterns that explain PD duplication, including upregulation of proximal homeobox gene expression and silencing of distal-associated genes, whereas limb truncation was associated with disrupted skeletal differentiation. RARbeta antagonism in uninjured limbs induced a loss of skeletal integrity leading to long bone regression and loss of skeletal turnover. Overall, mechanisms were identified that regulate the multifaceted roles of RARs in the salamander limb including regulation of skeletal patterning during epimorphic regeneration, skeletal tissue differentiation during regeneration, and homeostatic regeneration of intact limbs. PMID- 28087638 TI - Intrinsic properties of limb bud cells can be differentially reset. AB - An intrinsic timing mechanism specifies the positional values of the zeugopod (i.e. radius/ulna) and then autopod (i.e. wrist/digits) segments during limb development. Here, we have addressed whether this timing mechanism ensures that patterning events occur only once by grafting GFP-expressing autopod progenitor cells to the earlier host signalling environment of zeugopod progenitor cells. We show by detecting Hoxa13 expression that early and late autopod progenitors fated for the wrist and phalanges, respectively, both contribute to the entire host autopod, indicating that the autopod positional value is irreversibly determined. We provide evidence that Hoxa13 provides an autopod-specific positional value that correctly allocates cells into the autopod, most likely through the control of cell-surface properties as shown by cell-cell sorting analyses. However, we demonstrate that only the earlier autopod cells can adopt the host proliferation rate to permit normal morphogenesis. Therefore, our findings reveal that the ability of embryonic cells to differentially reset their intrinsic behaviours confers robustness to limb morphogenesis. We speculate that this plasticity could be maintained beyond embryogenesis in limbs with regenerative capacity. PMID- 28087639 TI - Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development. AB - Vascular endothelial growth factors (VEGFs) control angiogenesis and lymphangiogenesis during development and in pathological conditions. In the zebrafish trunk, Vegfa controls the formation of intersegmental arteries by primary angiogenesis and Vegfc is essential for secondary angiogenesis, giving rise to veins and lymphatics. Vegfd has been largely thought of as dispensable for vascular development in vertebrates. Here, we generated a zebrafish vegfd mutant by genome editing. vegfd mutants display significant defects in facial lymphangiogenesis independent of vegfc function. Strikingly, we find that vegfc and vegfd cooperatively control lymphangiogenesis throughout the embryo, including during the formation of the trunk lymphatic vasculature. Interestingly, we find that vegfd and vegfc also redundantly drive artery hyperbranching phenotypes observed upon depletion of Flt1 or Dll4. Epistasis and biochemical binding assays suggest that, during primary angiogenesis, Vegfd influences these phenotypes through Kdr (Vegfr2) rather than Flt4 (Vegfr3). These data demonstrate that, rather than being dispensable during development, Vegfd plays context specific indispensable and also compensatory roles during both blood vessel angiogenesis and lymphangiogenesis. PMID- 28087640 TI - Flexible sigmoidoscopy screening for colorectal cancer. PMID- 28087641 TI - Molecular Pathways: Targeting Protein Tyrosine Phosphatases in Cancer. AB - The aberrant activation of oncogenic signaling pathways is a universal phenomenon in cancer and drives tumorigenesis and malignant transformation. This abnormal activation of signaling pathways in cancer is due to the altered expression of protein kinases and phosphatases. In response to extracellular signals, protein kinases activate downstream signaling pathways through a series of protein phosphorylation events, ultimately producing a signal response. Protein tyrosine phosphatases (PTP) are a family of enzymes that hydrolytically remove phosphate groups from proteins. Initially, PTPs were shown to act as tumor suppressor genes by terminating signal responses through the dephosphorylation of oncogenic kinases. More recently, it has become clear that several PTPs overexpressed in human cancers do not suppress tumor growth; instead, they positively regulate signaling pathways and promote tumor development and progression. In this review, we discuss both types of PTPs: those that have tumor suppressor activities as well as those that act as oncogenes. We also discuss the potential of PTP inhibitors for cancer therapy. Clin Cancer Res; 23(9); 2136-42. (c)2017 AACR. PMID- 28087642 TI - STXBP4 Drives Tumor Growth and Is Associated with Poor Prognosis through PDGF Receptor Signaling in Lung Squamous Cell Carcinoma. AB - Purpose: Expression of the DeltaN isoform of p63 (DeltaNp63) is a diagnostic marker highly specific for lung squamous cell carcinoma (SCC). We previously found that Syntaxin Binding Protein 4 (STXBP4) regulates DeltaNp63 ubiquitination, suggesting that STXBP4 may also be an SCC biomarker. To address this issue, we investigated the role of STXBP4 expression in SCC biology and the impact of STXBP4 expression on SCC prognosis.Experimental Design: We carried out a clinicopathologic analysis of STXBP4 expression in 87 lung SCC patients. Whole transcriptome analysis using RNA-seq was performed in STXBP4-positive and STXBP4 negative tumors of lung SCC. Soft-agar assay and xenograft assay were performed using overexpressing or knockdown SCC cells.Results: Significantly higher levels of STXBP4 expression were correlated with accumulations of DeltaNp63 in clinical lung SCC specimens (Spearman rank correlation rho = 0.219). Notably, STXBP4 positive tumors correlated with three important clinical parameters: T factor (P < 0.001), disease stage (P = 0.030), and pleural involvement (P = 0.028). Whole transcriptome sequencing followed by pathway analysis indicated that STXBP4 is involved in functional gene networks that regulate cell growth, proliferation, cell death, and survival in cancer. Platelet-derived growth factor receptor alpha (PDGFRalpha) was a key downstream mediator of STXBP4 function. In line with this, shRNA mediated STXBP4 and PDGFRA knockdown suppressed tumor growth in soft-agar and xenograft assays.Conclusions: STXBP4 plays a crucial role in driving SCC growth and is an independent prognostic factor for predicting worse outcome in lung SCC. These data suggest that STXBP4 is a relevant therapeutic target for patients with lung SCC. Clin Cancer Res; 23(13); 3442-52. (c)2017 AACR. PMID- 28087643 TI - Tumor BRCA1 Reversion Mutation Arising during Neoadjuvant Platinum-Based Chemotherapy in Triple-Negative Breast Cancer Is Associated with Therapy Resistance. AB - Purpose: In germline BRCA1 or BRCA2 (BRCA1/2) mutation carriers, restoration of tumor BRCA1/2 function by a secondary mutation is recognized as a mechanism of resistance to platinum and PARP inhibitors, primarily in ovarian cancer. We evaluated this mechanism of resistance in newly diagnosed patients with BRCA1/2 mutant breast cancer with poor response to neoadjuvant platinum-based therapy.Experimental Design: PrECOG 0105 was a phase II neoadjuvant study of gemcitabine, carboplatin, and iniparib in patients with stage I-IIIA triple negative or BRCA1/2 mutation-associated breast cancer (n = 80). All patients underwent comprehensive BRCA1/2 genotyping. For mutation carriers with moderate or extensive residual disease after neoadjuvant therapy, BRCA1/2 status was resequenced in the residual surgical breast tumor tissue.Results: Nineteen patients had a deleterious germline BRCA1/2 mutation, and four had moderate residual disease at surgery. BRCA1/2 sequencing of residual tissue was performed on three patients. These patients had BRCA1 1479delAG, 3374insGA, and W1712X mutations, respectively, with LOH at these loci in the pretreatment tumors. In the first case, a new BRCA1 mutation was detected in the residual disease. This resulted in a 14-amino acid deletion and restoration of the BRCA1 reading frame. A local relapse biopsy 4 months later revealed the identical reversion mutation, and the patient subsequently died from metastatic breast cancer.Conclusions: We report a BRCA1 reversion mutation in a patient newly diagnosed with triple negative breast cancer that developed over 18 weeks of platinum-based neoadjuvant therapy. This was associated with poor therapy response, early relapse, and death. Clin Cancer Res; 23(13); 3365-70. (c)2017 AACR. PMID- 28087645 TI - Corrigendum to: HIF-2alpha-mediated induction of pulmonary thrombospondin-1 contributes to hypoxia-driven vascular remodelling and vasoconstriction. PMID- 28087644 TI - U.S. FDA Approval Summary: Nivolumab for Treatment of Unresectable or Metastatic Melanoma Following Progression on Ipilimumab. AB - On December 22, 2014, the FDA granted accelerated approval to nivolumab (OPDIVO; Bristol-Myers Squibb) for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on a clinically meaningful, durable objective response rate (ORR) in a non-comparative analysis of 120 patients who received 3 mg/kg of nivolumab intravenously every 2 weeks with at least 6-month follow-up in an ongoing, randomized, open-label, active controlled clinical trial. The ORR as assessed by a blinded independent review committee per RECIST v1.1 was 31.7% (95% confidence interval, 23.5-40.8). Ongoing responses were observed in 87% of responding patients, ranging from 2.6+ to 10+ months. In 13 patients, the response duration was 6 months or longer. The risks of nivolumab, including clinically significant immune-mediated adverse reactions (imARs), were assessed in 268 patients who received at least one dose of nivolumab. The FDA review considered whether the ORR and durations of responses were reasonably likely to predict clinical benefit, the adequacy of the safety database, and systematic approaches to the identification, description, and patient management for imARs in product labeling. Clin Cancer Res; 23(14); 3484 8. (c)2017 AACR. PMID- 28087646 TI - Wheat Genotypes With Combined Resistance to Wheat Curl Mite, Wheat Streak Mosaic Virus, Wheat Mosaic Virus, and Triticum Mosaic Virus. AB - The wheat curl mite, Aceria tosichella Keifer, (WCM) is a global pest of bread wheat that reduces yields significantly. In addition, WCM carries Wheat streak mosaic virus (WSMV, family Potyviridae, genus Tritimovirus), the most significant wheat virus in North America; High Plains wheat mosaic virus (HPWMoV, genus Emaravirus, formerly High plains virus); and Triticum mosaic virus (TriMV, family Potyviridae, genus Poacevirus). Viruses carried by WCM have reduced wheat yields throughout the U.S. Great Plains for >50 yr, with average yield losses of 2-3% and occasional yield losses of 7-10%. Acaricides are ineffective against WCM, and delayed planting of winter wheat is not feasible. Five wheat breeding lines containing Cmc4, a WCM resistance gene from Aegilops tauschii, and Wsm2, a WSMV resistance gene from wheat germplasm CO960293-2 were selected from the breeding process and assessed for phenotypic reaction to WCM feeding, population increase, and the degree of WSMV, HPWMoV, and TriMV infection. Experiments determined that all five lines are resistant to WCM biotype 1 feeding and population increase, and that two breeding lines contain resistance to WSMV, HPWMoV, and TriMV infection as well. These WCM-, WSMV-, HPWMoV-, and TriMV-resistant genotypes can be used improve management of wheat yield losses from WCM-virus complexes. PMID- 28087647 TI - An Additional Phytosanitary Cold Treatment Against Ceratitis capitata (Diptera: Tephritidae) in 'Oroblanco' Citrus Fruit. AB - For 'Oroblanco' ('Sweetie'), the sweet seedless pummelo-grapefruit hybrid, when exported from Israel to Japan, the standard cold treatment against Ceratitis capitata (Wied.) (Diptera: Tephritidae) is conducted at <= 1.5 degrees C, for 16 d. In recent years, the transportation means of exported citrus was changed from reefer vessels to individual refrigerated containers, where the fruit bulk is relatively small and may be exposed to temperature fluctuations and to the risk of chilling injuries. To reduce this risk, Israel proposed to Japan to increase the treatment temperature and extend its duration to 2.2 degrees C and 18 d, respectively. This study shows that the proposed treatment effectively kills the third instar larva of C. capitata, in Oroblanco. PMID- 28087648 TI - Effect of in vivo neutralization of tumor necrosis alpha on the efficacy of antibiotic treatment in systemic Salmonella enterica infections. AB - Immunity can co-operate with antibiotics, but can also antagonize drug efficacy by segregating the bacteria to areas of the body that are less accessible to antimicrobials, and by selecting for subpopulations with low division rates that are often difficult to eradicate. We studied the effect of an anti inflammatory/immunosuppressive anti-TNFalpha treatment, which accelerates bacterial growth in the tissues and inhibits or reverses the formation of granulomas, on the efficacy of ampicillin and ciprofloxacin during a systemic Salmonella enterica infection of the mouse. The anti-TNFalpha treatment neither precluded nor enhanced the efficacy of antibiotic treatment. However, the anti TNFalpha treatment rendered the animals susceptible to the rapid relapse of the infection seen after cessation of the antibiotic treatment. Reactivation of an established infection, due to late administration of anti-TNFalpha antibodies, could be successfully controlled by antibiotics, but full clearance of the bacterial load from the tissues was not achieved. We conclude that the lack of TNFalpha does not preclude the efficacy of antibiotic treatment and must be monitored with care due to post-treatment relapses. Combinations of anti-cytokine compounds and antibiotic molecules may not be the best way to treat persistent infections with intracellular bacteria like Salmonella. PMID- 28087649 TI - Identification of unique essential proteins from a Mycobacterium tuberculosis F15/LAM4/KZN phage secretome library. AB - Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis disease (TB), the leading cause of death from bacterial infection worldwide. Although treatable, the resurgence of multidrug-resistant and extensively drug-resistant TB is a major setback for the fight against TB globally. Consequently, there is an urgent need for new Mtb-derived biomarkers for use in the design of new drugs and rapid point-of-care diagnostic or prognostic tools for the management of TB transmission. Therefore, the present study aimed to identify unique Mtb-secreted proteins from the extensively drug-resistant Mtb F15/LAM4/KZN phage secretome library. A whole genome library was constructed using genomic DNA fragments of the Mtb F15/LAM4/KZN strain. A phage secretome sub-library of 8 * 103 clones was prepared and phage DNA was sequenced from 120 randomly selected clones. DNA sequence BLAST analysis identified 86 open reading frames. Using bioinformatics tools and databases, 10 proteins essential for in vivo growth and survival of Mtb (Nrp, PssA, MmpL5, SirA, GatB, EspA, TopA, EccCa1, Rv1634 and Rv3103c) were identified. Proteins essential for the growth and survival of Mtb during infection have potential application in the development of diagnostic tools, new drugs and vaccines. Further studies will be conducted to evaluate their potential application in the fight against TB. PMID- 28087651 TI - Frontline Science: Multiple cathepsins promote inflammasome-independent, particle induced cell death during NLRP3-dependent IL-1beta activation. AB - Sterile particles cause several chronic, inflammatory diseases, characterized by repeating cycles of particle phagocytosis and inflammatory cell death. Recent studies have proposed that these processes are driven by the NLRP3 inflammasome, a platform activated by phagocytosed particles, which controls both caspase-1 dependent cell death (pyroptosis) and mature IL-1beta secretion. After phagocytosis, particles can disrupt lysosomes, and inhibitor studies have suggested that the resulting release of a lysosomal protease-cathepsin B-into the cytosol somehow activates NLRP3. However, using primary murine macrophages, we found that particle-induced cell death occurs independent of NLRP3/caspase-1 and depends instead on multiple, redundant cathepsins. In contrast, nigericin, a soluble activator of NLRP3 inflammasomes, induced cell death that was dependent on the NLRP3. Interestingly, nigericin-induced cell death depended partly on a single cathepsin, cathepsin X. By inhibiting or silencing multiple cathepsins in macrophages, several key proinflammatory events induced by sterile particles are blocked, including cell death, pro-IL-1beta production, and IL-1beta secretion. These data suggest that cathepsins might be potential therapeutic targets in particulate-mediated inflammatory disease. In support of this concept, we find that a broad-spectrum cathepsin inhibitor can suppress particle-induced IL-1 dependent peritonitis. PMID- 28087650 TI - Simkania negevensis may produce long-lasting infections in human pneumocytes and endometrial cells. AB - Simkania negevensis is a novel Chlamydia-related bacterium and the founding member of the Simkaniaceae family within the Chlamydiales order. Little is known about the biology and pathogenesis of this bacterium. So far, S. negevensis has been considered as an amoebal symbiont, but its natural host remains unknown. Moreover, evidence of human exposition has been reported worldwide and an association with pneumonia and bronchiolitis is suspected. Here, we evaluated the ability of S. negevensis to replicate in potential environmental reservoirs, namely amoebae and arthropods, as well as in mammalian cells (Vero cells, pneumocytes and endometrial cells) and further evaluated the characteristics of its replicative vacuole. We demonstrated that S. negevensis efficiently replicates in all cell lines tested, with the shortest doubling time and an increased adhesion observed in pneumocytes. Our work highlights the specificities of the Simkania-containing vacuole compared to other Chlamydiales; contrarily to Chlamydia trachomatis, S. negevensis does not disrupt the Golgi apparatus. Importantly, our work suggests that S. negevensis infection is associated with few cytopathic effects and might persist for a prolonged time in infected cells. Further evaluation of its implication in human diseases is required; an implication in chronic or subacute respiratory infections might be suspected. PMID- 28087652 TI - Differential regulation of CD103 (alphaE integrin) expression in human dendritic cells by retinoic acid and Toll-like receptor ligands. AB - CD103 (alphaE integrin) is an important dendritic cell (DC) marker that characterizes functionally distinct DC subsets in mice and humans. However, the mechanism by which CD103 expression is regulated in human DCs and the role of CD103 for DC function are not very well understood. Here, we show that retinoic acid (RA) treatment of human monocyte-derived DCs (MoDCs) increased the ability of the DCs to synthesize RA and induced MoDC expression of CD103 and beta7 at the mRNA and protein level. In contrast, RA was unable to induce the expression of CD103 in primary human DCs isolated from the gastric mucosa. Inhibition of TGF beta signaling in MoDCs down-regulated RA-induced CD103 expression, indicating that TGF-beta-dependent pathways contribute to the induction of CD103. Conversely, when RA-treated MoDCs were stimulated with live Helicobacter pylori, commensal bacteria, LPS, or a TLR2 agonist, the RA-induced up-regulation of CD103 and beta7 integrin expression was completely abrogated. To determine whether CD103 expression impacts DC priming of CD4+ T cells, we next investigated the ability of CD103+ and CD103? DCs to induce mucosal homing and T cell proliferation. Surprisingly, RA treatment of DCs enhanced both alpha4beta7 expression and proliferation in cocultured T cells, but no difference was seen between RA-treated CD103+ and CD103? DCs. In summary, our data demonstrate that RA, bacterial products, and the tissue environment all contribute to the regulation of CD103 on human DCs and that DC induction of mucosal homing in T cells is RA dependent but not CD103 dependent. PMID- 28087654 TI - Effects of external strain on the regulation of microtubule sliding induced by outer arm dynein of sea urchin sperm flagella. AB - Oscillatory bending movement of eukaryotic flagella is powered by orchestrated activity of dynein motor proteins that hydrolyse ATP and produce microtubule sliding. Although the ATP concentration within a flagellum is kept uniform at a few millimoles per litre level, sliding activities of dyneins are dynamically coordinated along the flagellum in accordance with the phase of bending waves. Thus at the organellar level the dynein not only generates force for bending but also modulates its motile activity by responding to bending of the flagellum. Single molecule analyses have suggested that dynein at the molecular level, even if isolated from the axoneme, could alter the modes of motility in response to mechanical strain. However, it still remains unknown whether the coordinated activities of multiple dyneins can be modulated directly by mechanical signals. Here, we studied the effects of externally applied strain on the sliding movement of microtubules interacted with an ensemble of dynein molecules adsorbed on a glass surface. We found that by bending the microtubules with a glass microneedle, three modes of motility that have not been previously characterized without bending can be induced: stoppage, backward sliding and dissociation. Modification in sliding velocities was also induced by imposed bending. These results suggest that the activities of dyneins interacted with a microtubule can be modified and coordinated through external strain in a quite flexible manner, and that such a regulatory mechanism may be the basis of flagellar oscillation. PMID- 28087653 TI - Identification of regulatory networks and hub genes controlling soybean seed set and size using RNA sequencing analysis. AB - To understand the gene expression networks controlling soybean seed set and size, transcriptome analyses were performed in three early seed developmental stages, using two genotypes with contrasting seed size. The two-dimensional data set provides a comprehensive and systems-level view on dynamic gene expression networks underpinning soybean seed set and subsequent development. Using pairwise comparisons and weighted gene coexpression network analyses, we identified modules of coexpressed genes and hub genes for each module. Of particular importance are the discoveries of specific modules for the large seed size variety and for seed developmental stages. A large number of candidate regulators for seed size, including those involved in hormonal signaling pathways and transcription factors, were transiently and specifically induced in the early developmental stages. The soybean homologs of a brassinosteroid signaling receptor kinase, a brassinosteroid-signaling kinase, were identified as hub genes operating in the seed coat network in the early seed maturation stage. Overexpression of a candidate seed size regulatory gene, GmCYP78A5, in transgenic soybean resulted in increased seed size and seed weight. Together, these analyses identified a large number of potential key regulators controlling soybean seed set, seed size, and, consequently, yield potential, thereby providing new insights into the molecular networks underlying soybean seed development. PMID- 28087655 TI - Hagfish Houdinis: biomechanics and behavior of squeezing through small openings. AB - Hagfishes are able to squeeze through small openings to gain entry to crevices, burrows, hagfish traps and carcasses, but little is known about how they do this, or what the limits of this ability are. The purpose of this study was to describe this ability, and to investigate possible mechanisms by which it is accomplished. We investigated the hypothesis that the passive movement of blood within a hagfish's flaccid subcutaneous sinus allows it to squeeze through narrow apertures that it would not be able to if it were turgid. To test this hypothesis, we analyzed videos of Atlantic hagfish (Myxine glutinosa) and Pacific hagfish (Eptatretus stoutii) moving through narrow apertures in the lab. We measured changes in body width as the animals moved through these openings and documented the behaviors associated with this ability. We found that hagfishes are able to pass through narrow slits that are less than one half the width of their bodies. Our results are consistent with the idea that a flaccid subcutaneous sinus allows hagfish to squeeze through narrow apertures by facilitating a rapid redistribution of venous blood. In addition, we describe nine distinct behaviors associated with this ability, including a form of non undulatory locomotion also seen in snakes and lampreys. Our results illuminate a behavior that may be a critical component of the hagfish niche, as a result of its likely importance in feeding and avoiding predators. PMID- 28087656 TI - Conspecific aggregations mitigate the effects of ocean acidification on calcification of the coral Pocillopora verrucosa. AB - In densely populated communities, such as coral reefs, organisms can modify the physical and chemical environment for neighbouring individuals. We tested the hypothesis that colony density (12 colonies each placed ~0.5 cm apart versus ~8 cm apart) can modulate the physiological response (measured through rates of calcification, photosynthesis and respiration in the light and dark) of the coral Pocillopora verrucosa to partial pressure of CO2 (PCO2 ) treatments (~400 MUatm and ~1200 MUatm) by altering the seawater flow regimes experienced by colonies placed in aggregations within a flume at a single flow speed. While light calcification decreased 20% under elevated versus ambient PCO2 for colonies in low-density aggregations, light calcification of high-density aggregations increased 23% at elevated versus ambient PCO2 As a result, densely aggregated corals maintained calcification rates over 24 h that were comparable to those maintained under ambient PCO2 , despite a 45% decrease in dark calcification at elevated versus ambient PCO2 Additionally, densely aggregated corals experienced reduced flow speeds and higher seawater retention times between colonies owing to the formation of eddies. These results support recent indications that neighbouring organisms, such as the conspecific coral colonies in the present example, can create small-scale refugia from the negative effects of ocean acidification. PMID- 28087658 TI - Are winter and summer dormancy symmetrical seasonal adaptive strategies? The case of temperate herbaceous perennials. AB - BACKGROUND: Dormancy in higher plants is an adaptive response enabling plant survival during the harshest seasons and has been more explored in woody species than in herbaceous species. Nevertheless, winter and summer shoot meristem dormancy are adaptive strategies that could play a major role in enhancing seasonal stress tolerance and resilience of widespread herbaceous plant communities. SCOPE: This review outlines the symmetrical aspects of winter and summer dormancy in order to better understand plant adaptation to severe stress, and highlight research priorities in a changing climate. Seasonal dormancy is a good model to explore the growth-stress survival trade-off and unravel the relationships between growth potential and stress hardiness. Although photoperiod and temperature are known to play a crucial, though reversed, role in the induction and release of both types of dormancy, the thresholds and combined effects of these environmental factors remain to be identified. The biochemical compounds involved in induction or release in winter dormancy (abscisic acid, ethylene, sugars, cytokinins and gibberellins) could be a priority research focus for summer dormancy. To address these research priorities, herbaceous species, being more tractable than woody species, are excellent model plants for which both summer and winter dormancy have been clearly identified. CONCLUSIONS: Summer and winter dormancy, although responding to inverse conditions, share many characteristics. This analogous nature can facilitate research as well as lead to insight into plant adaptations to extreme conditions and the evolution of phenological patterns of species and communities under climate change. The development of phenotypes showing reduced winter and/or enhanced summer dormancy may be expected and could improve adaptation to less predictable environmental stresses correlated with future climates. To this end, it is suggested to explore the inter- and intraspecific genotypic variability of dormancy and its plasticity according to environmental conditions to contribute to predicting and mitigating global warming. PMID- 28087657 TI - European consensus conference on faecal microbiota transplantation in clinical practice. AB - Faecal microbiota transplantation (FMT) is an important therapeutic option for Clostridium difficile infection. Promising findings suggest that FMT may play a role also in the management of other disorders associated with the alteration of gut microbiota. Although the health community is assessing FMT with renewed interest and patients are becoming more aware, there are technical and logistical issues in establishing such a non-standardised treatment into the clinical practice with safety and proper governance. In view of this, an evidence-based recommendation is needed to drive the practical implementation of FMT. In this European Consensus Conference, 28 experts from 10 countries collaborated, in separate working groups and through an evidence-based process, to provide statements on the following key issues: FMT indications; donor selection; preparation of faecal material; clinical management and faecal delivery and basic requirements for implementing an FMT centre. Statements developed by each working group were evaluated and voted by all members, first through an electronic Delphi process, and then in a plenary consensus conference. The recommendations were released according to best available evidence, in order to act as guidance for physicians who plan to implement FMT, aiming at supporting the broad availability of the procedure, discussing other issues relevant to FMT and promoting future clinical research in the area of gut microbiota manipulation. This consensus report strongly recommends the implementation of FMT centres for the treatment of C. difficile infection as well as traces the guidelines of technicality, regulatory, administrative and laboratory requirements. PMID- 28087659 TI - Plant-parasitic nematodes: towards understanding molecular players in stress responses. AB - Background: Plant-parasitic nematode interactions occur within a vast molecular plant immunity network. Following initial contact with the host plant roots, plant-parasitic nematodes (PPNs) activate basal immune responses. Defence priming involves the release in the apoplast of toxic molecules derived from reactive species or secondary metabolism. In turn, PPNs must overcome the poisonous and stressful environment at the plant-nematode interface. The ability of PPNs to escape this first line of plant immunity is crucial and will determine its virulence. Scope: Nematodes trigger crucial regulatory cytoprotective mechanisms, including antioxidant and detoxification pathways. Knowledge of the upstream regulatory components that contribute to both of these pathways in PPNs remains elusive. In this review, we discuss how PPNs probably orchestrate cytoprotection to resist plant immune responses, postulating that it may be derived from ancient molecular mechanisms. The review focuses on two transcription factors, DAF-16 and SKN-1 , which are conserved in the animal kingdom and are central regulators of cell homeostasis and immune function. Both regulate the unfolding protein response and the antioxidant and detoxification pathways. DAF-16 and SKN-1 target a broad spectrum of Caenorhabditis elegans genes coding for numerous protein families present in the secretome of PPNs. Moreover, some regulatory elements of DAF-16 and SKN-1 from C. elegans have already been identified as important genes for PPN infection. Conclusion: DAF-16 and SKN-1 genes may play a pivotal role in PPNs during parasitism. In the context of their hub status and mode of regulation, we suggest alternative strategies for control of PPNs through RNAi approaches. PMID- 28087661 TI - Disturbance by an endemic rodent in an arid shrubland is a habitat filter: effects on plant invasion and taxonomical, functional and phylogenetic community structure. AB - Background and Aims: Disturbance often drives plant invasion and may modify community assembly. However, little is known about how these modifications of community patterns occur in terms of taxonomic, functional and phylogenetic structure. This study evaluated in an arid shrubland the influence of disturbance by an endemic rodent on community functional divergence and phylogenetic structure as well as on plant invasion. It was expected that disturbance would operate as a habitat filter favouring exotic species with short life cycles. Methods: Sixteen plots were sampled along a disturbance gradient caused by the endemic fossorial rodent Spalacopus cyanus , measuring community parameters and estimating functional divergence for life history traits (functional dispersion index) and the relative contribution to functional divergence of exotic and native species. The phylogenetic signal (Pagel's lambda) and phylogenetic community structure (mean phylogenetic distance and mean nearest taxon phylogenetic distance) were also estimated. The use of a continuous approach to the disturbance gradient allowed the identification of non-linear relationships between disturbance and community parameters. Key Results: The relationship between disturbance and both species richness and abundance was positive for exotic species and negative for native species. Disturbance modified community composition, and exotic species were associated with more disturbed sites. Disturbance increased trait convergence, which resulted in phylogenetic clustering because traits showed a significant phylogenetic signal. The relative contribution of exotic species to functional divergence increased, while that of natives decreased, with disturbance. Exotic and native species were not phylogenetically distinct. Conclusions: Disturbance by rodents in this arid shrubland constitutes a habitat filter over phylogeny-dependent life history traits, leading to phylogenetic clustering, and drives invasion by favouring species with short life cycles. Results can be explained by high phenotypic and phylogenetic resemblance between exotic and native species. The use of continuous gradients when studying the effects of disturbance on community assembly is advocated. PMID- 28087660 TI - The morphophysiological dormancy in Amborella trichopoda seeds is a pleisiomorphic trait in angiosperms. AB - Background and Aims: Recent parsimony-based reconstructions suggest that seeds of early angiosperms had either morphophysiological or physiological dormancy, with the former considered as more probable. The aim of this study was to determine the class of seed dormancy present in Amborella trichopoda , the sole living representative of the most basal angiosperm lineage Amborellales, with a view to resolving fully the class of dormancy present at the base of the angiosperm clade. Methods: Drupes of A. trichopoda without fleshy parts were germinated and dissected to observe their structure and embryo growth. Pre-treatments including acid scarification, gibberellin treatment and seed excision were tested to determine their influence on dormancy breakage and germination. Character-state mapping by maximum parsimony, incorporating data from the present work and published sources, was then used to determine the likely class of dormancy present in early angiosperms. Key Results: Germination in A. trichopoda requires a warm stratification period of at least approx. 90 d, which is followed by endosperm swelling, causing the water-permeable pericarp-mesocarp envelope to split open. The embryo then grows rapidly within the seed, to radicle emergence some 17 d later and cotyledon emergence after an additional 24 d. Gibberellin treatment, acid scarification and excision of seeds from the surrounding drupe tissues all promoted germination by shortening the initial phase of dormancy, prior to embryo growth. Conclusions: Seeds of A. trichopoda have non-deep simple morphophysiological dormancy, in which mechanical resistance of the pericarp mesocarp envelope plays a key role in the initial physiological phase. Maximum parsimony analyses, including data obtained in the present work, indicate that morphophysiological dormancy is likely to be a pleisiomorphic trait in flowering plants. The significance of this conclusion for studies of early angiosperm evolution is discussed. PMID- 28087662 TI - Terpenoids in plant and arbuscular mycorrhiza-reinforced defence against herbivorous insects. AB - Background: Plants, though sessile, employ various strategies to defend themselves against herbivorous insects and convey signals of an impending herbivore attack to other plant(s). Strategies include the production of volatiles that include terpenoids and the formation of symbiotic associations with fungi, such as arbuscular mycorrhiza (AM). This constitutes a two-pronged above-ground/below-ground attack-defence strategy against insect herbivores. Scope: Terpenoids represent an important constituent of herbivore-induced plant volatiles that deter herbivores and/or attract their predators. Terpenoids serve as airborne signals that can induce defence responses in systemic undamaged parts of the plant and also prime defence responses in neighbouring plants. Colonization of roots by AM fungi is known to influence secondary metabolism in plants; this includes alteration of the concentration and composition of terpenoids, which can boost both direct and indirect plant defence against herbivorous insects. Enhanced nutrient uptake facilitated by AM, changes in plant morphology and physiology and increased transcription levels of certain genes involved in the terpenoid biosynthesis pathway result in alterations in plant terpenoid profiles. The common mycorrhizal networks of external hyphae have added a dimension to the two-pronged plant defence strategy. These act as conduits to transfer defence signals and terpenoids. Conclusion: Improved understanding of the roles of terpenoids in plant and AM defences against herbivory and of interplant signalling in natural communities has significant implications for sustainable management of pests in agricultural ecosystems. PMID- 28087663 TI - Evolution and structural diversification of Nictaba-like lectin genes in food crops with a focus on soybean (Glycine max). AB - Background and Aims: The Nictaba family groups all proteins that show homology to Nictaba, the tobacco lectin. So far, Nictaba and an Arabidopsis thaliana homologue have been shown to be implicated in the plant stress response. The availability of more than 50 sequenced plant genomes provided the opportunity for a genome-wide identification of Nictaba -like genes in 15 species, representing members of the Fabaceae, Poaceae, Solanaceae, Musaceae, Arecaceae, Malvaceae and Rubiaceae. Additionally, phylogenetic relationships between the different species were explored. Furthermore, this study included domain organization analysis, searching for orthologous genes in the legume family and transcript profiling of the Nictaba -like lectin genes in soybean. Methods: Using a combination of BLASTp, InterPro analysis and hidden Markov models, the genomes of Medicago truncatula , Cicer arietinum , Lotus japonicus , Glycine max , Cajanus cajan , Phaseolus vulgaris , Theobroma cacao , Solanum lycopersicum , Solanum tuberosum , Coffea canephora , Oryza sativa , Zea mays, Sorghum bicolor , Musa acuminata and Elaeis guineensis were searched for Nictaba -like genes. Phylogenetic analysis was performed using RAxML and additional protein domains in the Nictaba-like sequences were identified using InterPro. Expression analysis of the soybean Nictaba -like genes was investigated using microarray data. Key Results: Nictaba like genes were identified in all studied species and analysis of the duplication events demonstrated that both tandem and segmental duplication contributed to the expansion of the Nictaba gene family in angiosperms. The single-domain Nictaba protein and the multi-domain F-box Nictaba architectures are ubiquitous among all analysed species and microarray analysis revealed differential expression patterns for all soybean Nictaba-like genes. Conclusions: Taken together, the comparative genomics data contributes to our understanding of the Nictaba -like gene family in species for which the occurrence of Nictaba domains had not yet been investigated. Given the ubiquitous nature of these genes, they have probably acquired new functions over time and are expected to take on various roles in plant development and defence. PMID- 28087664 TI - Human Blood CD1c+ Dendritic Cells Encompass CD5high and CD5low Subsets That Differ Significantly in Phenotype, Gene Expression, and Functions. AB - There are three major dendritic cell (DC) subsets in both humans and mice, that is, plasmacytoid DCs and two types of conventional DCs (cDCs), cDC1s and cDC2s. cDC2s are important for polarizing CD4+ naive T cells into different subsets, including Th1, Th2, Th17, Th22, and regulatory T cells. In mice, cDC2s can be further divided into phenotypically and functionally distinct subgroups. However, subsets of human cDC2s have not been reported. In the present study, we showed that human blood CD1c+ cDCs (cDC2s) can be further separated into two subpopulations according to their CD5 expression status. Comparative transcriptome analyses showed that the CD5high DCs expressed higher levels of cDC2-specific genes, including IFN regulatory factor 4, which is essential for the cDC2 development and its migration to lymph nodes. In contrast, CD5low DCs preferentially expressed monocyte-related genes, including the lineage-specific transcription factor MAFB. Furthermore, compared with the CD5low subpopulation, the CD5high subpopulation showed stronger migration toward CCL21 and overrepresentation among migratory DCs in lymph nodes. Additionally, the CD5high DCs induced naive T cell proliferation more potently than did the CD5low DCs. Moreover, CD5high DCs induced higher levels of IL-10-, IL-22-, and IL-4-producing T cell formation, whereas CD5low DCs induced higher levels of IFN-gamma-producing T cell formation. Thus, we show that human blood CD1c+ cDC2s encompass two subsets that differ significantly in phenotype, that is, gene expression and functions. We propose that these two subsets of human cDC2s could potentially play contrasting roles in immunity or tolerance. PMID- 28087665 TI - NKG2D Promotes B1a Cell Development and Protection against Bacterial Infection. AB - NKG2D is a potent activating receptor that is expressed on cytotoxic immune cells such as CD8 T and NK cells, where it promotes cytotoxicity after binding stress ligands on infected or transformed cells. On NK cell precursors NKG2D modulates proliferation and maturation. Previously, we observed that NKG2D deficiency affects peripheral B cell numbers. In this study, we show that NKG2D regulates B1a cell development and function. We find that mice deficient for NKG2D have a strong reduction of B1a cell numbers. As a result, NKG2D-deficient mice produce significantly less Ag-specific IgM Abs upon immunization with T cell-independent Ags, and they are more susceptible to Gram-negative sepsis. Klrk1-/- B1a cells are also functionally impaired and they fail to provide protection against Francisella novicida upon adoptive transfer. Using mixed bone marrow chimeric mice, we show that the impact of NKG2D deficiency on B1a cell development is cell intrinsic. No changes in homeostatic turnover and homing of B cells were detectable, limiting the effects of NKG2D to modulation of the hematopoietic development of B1a cells. Using conditional ablation, we demonstrate that the effect of NKG2D on B1a cell development occurs at a developmental stage that precedes the common lymphoid progenitor. Our findings reveal an unexpected new role for NKG2D in the regulation of B1a cell development. The protective effects of this activating receptor therefore reach beyond that of cytotoxic cells, stimulating the immune system to fight bacterial infections by promoting development of innate-like B cells. PMID- 28087666 TI - Dysregulation of B Cell Repertoire Formation in Myasthenia Gravis Patients Revealed through Deep Sequencing. AB - Myasthenia gravis (MG) is a prototypical B cell-mediated autoimmune disease affecting 20-50 people per 100,000. The majority of patients fall into two clinically distinguishable types based on whether they produce autoantibodies targeting the acetylcholine receptor (AChR-MG) or muscle specific kinase (MuSK MG). The autoantibodies are pathogenic, but whether their generation is associated with broader defects in the B cell repertoire is unknown. To address this question, we performed deep sequencing of the BCR repertoire of AChR-MG, MuSK-MG, and healthy subjects to generate ~518,000 unique VH and VL sequences from sorted naive and memory B cell populations. AChR-MG and MuSK-MG subjects displayed distinct gene segment usage biases in both VH and VL sequences within the naive and memory compartments. The memory compartment of AChR-MG was further characterized by reduced positive selection of somatic mutations in the VH CDR and altered VH CDR3 physicochemical properties. The VL repertoire of MuSK-MG was specifically characterized by reduced V-J segment distance in recombined sequences, suggesting diminished VL receptor editing during B cell development. Our results identify large-scale abnormalities in both the naive and memory B cell repertoires. Particular abnormalities were unique to either AChR-MG or MuSK MG, indicating that the repertoires reflect the distinct properties of the subtypes. These repertoire abnormalities are consistent with previously observed defects in B cell tolerance checkpoints in MG, thereby offering additional insight regarding the impact of tolerance defects on peripheral autoimmune repertoires. These collective findings point toward a deformed B cell repertoire as a fundamental component of MG. PMID- 28087669 TI - The Role of the p38-MNK-eIF4E Signaling Axis in TNF Production Downstream of the NOD1 Receptor. AB - Activation of nucleotide-binding oligomerization domain (NOD) 1 and NOD2 by muropeptides triggers a complex transcriptional program in innate immune cells. However, little is known about posttranscriptional regulation of NOD1- and NOD2 dependent responses. When stimulated with a prototypic NOD1 agonist, N acetylglucosaminyl-N-acetylmuramyl-l-alanyl-d-isoglutamyl-meso-diaminopimelic acid (GM-triDAP), human monocyte-derived macrophages (MDM) produced an order of magnitude more TNF, IL-6, and pro-IL-1beta than did monocyte-derived dendritic cells (MDDC), despite similar NOD1 expression, similar cytokine mRNA kinetics, and comparable responses to LPS. TNF production by GM-triDAP-activated MDM was independent of autocrine IL-1. However, GM-triDAP-activated MDM translated TNF mRNA more efficiently than did MDDC. As an underlying mechanism, NOD1 triggering in MDM caused a more potent and long-lasting activation of the signaling axis involving p38 MAPK, MAPK-interacting kinase (MNK), and eukaryotic translation initiation factor 4E, which is a critical regulator of translation. Furthermore, MNK controlled TNF mRNA abundance in MDDC and MDM upon NOD1 triggering. NOD1 dependent responses were more sensitive to MNK inhibition than were TLR4 dependent responses. These results demonstrate the importance of the p38-MNK eukaryotic translation initiation factor 4E axis in TNF production downstream of NOD1. PMID- 28087668 TI - The Threshold of Protection from Liver-Stage Malaria Relies on a Fine Balance between the Number of Infected Hepatocytes and Effector CD8+ T Cells Present in the Liver. AB - Since the demonstration of sterile protection afforded by injection of irradiated sporozoites, CD8+ T cells have been shown to play a significant role in protection from liver-stage malaria. This is, however, dependent on the presence of an extremely high number of circulating effector cells, thought to be necessary to scan, locate, and kill infected hepatocytes in the short time that parasites are present in the liver. We used an adoptive transfer model to elucidate the kinetics of the effector CD8+ T cell response in the liver following Plasmodium berghei sporozoite challenge. Although effector CD8+ T cells require <24 h to find, locate, and kill infected hepatocytes, active migration of Ag-specific CD8+ T cells into the liver was not observed during the 2-d liver stage of infection, as divided cells were only detected from day 3 postchallenge. However, the percentage of donor cells recruited into division was shown to indicate the level of Ag presentation from infected hepatocytes. By titrating the number of transferred Ag-specific effector CD8+ T cells and sporozoites, we demonstrate that achieving protection toward liver-stage malaria is reliant on CD8+ T cells being able to locate infected hepatocytes, resulting in a protection threshold dependent on a fine balance between the number of infected hepatocytes and CD8+ T cells present in the liver. With such a fine balance determining protection, achieving a high number of CD8+ T cells will be critical to the success of a cell-mediated vaccine against liver-stage malaria. PMID- 28087670 TI - Plant Lectins Activate the NLRP3 Inflammasome To Promote Inflammatory Disorders. AB - Plant-derived dietary lectins have been reported to be involved in the pathogenesis of several inflammatory diseases, including inflammatory bowel disease, diabetes, rheumatoid arthritis, and celiac disease, but little is known about the molecular mechanisms underlying lectin-induced inflammation. In this study, we showed that plant lectins can induce caspase-1 activation and IL-1beta secretion via the NLRP3 inflammasome. Lectins were internalized and subsequently escaped from the lysosome and then translocated to the endoplasmic reticulum. Endoplasmic reticulum-loaded plant lectins then triggered Ca2+ release and mitochondrial damage, and inhibition of Ca2+ release and mitochondrial reactive oxygen species by chemical inhibitors significantly suppressed NLRP3 inflammasome activation. In vivo, plant lectin-induced inflammation and tissue damage also depended on the NLRP3 inflammasome. Our findings indicate that plant lectins can act as an exogenous "danger signal" that can activate the NLRP3 inflammasome and suggest that dietary lectins might promote inflammatory diseases via the NLRP3 inflammasome. PMID- 28087667 TI - PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis. AB - In the autoimmune disease multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), expansion of pathogenic, myelin-specific Th1 cell populations drives active disease; selectively targeting this process may be the basis for a new therapeutic approach. Previous studies have hinted at a role for protein arginine methylation in immune responses, including T cell-mediated autoimmunity and EAE. However, a conclusive role for the protein arginine methyltransferase (PRMT) enzymes that catalyze these reactions has been lacking. PRMT5 is the main PRMT responsible for symmetric dimethylation of arginine residues of histones and other proteins. PRMT5 drives embryonic development and cancer, but its role in T cells, if any, has not been investigated. In this article, we show that PRMT5 is an important modulator of CD4+ T cell expansion. PRMT5 was transiently upregulated during maximal proliferation of mouse and human memory Th cells. PRMT5 expression was regulated upstream by the NF-kappaB pathway, and it promoted IL-2 production and proliferation. Blocking PRMT5 with novel, highly selective small molecule PRMT5 inhibitors severely blunted memory Th expansion, with preferential suppression of Th1 cells over Th2 cells. In vivo, PRMT5 blockade efficiently suppressed recall T cell responses and reduced inflammation in delayed-type hypersensitivity and clinical disease in EAE mouse models. These data implicate PRMT5 in the regulation of adaptive memory Th cell responses and suggest that PRMT5 inhibitors may be a novel therapeutic approach for T cell-mediated inflammatory disease. PMID- 28087671 TI - Induction and Differentiation of IL-10-Producing Regulatory B Cells from Healthy Blood Donors and Rheumatoid Arthritis Patients. AB - The most important feature of B cells is the production of Abs upon activation; additionally, B cells produce pro- and anti-inflammatory cytokines in response to certain stimuli. IL-10-producing B cells represent a major subset of regulatory B cells (Bregs) that suppress autoimmune and inflammatory responses. B cells play a crucial role in the development and maintenance of the chronic inflammatory autoimmune disease rheumatoid arthritis (RA); however, controversial data are available on IL-10- producing Bregs in RA. Our aim was to identify the optimal conditions that induce IL-10+ Bregs and, furthermore, to shed light on the signaling pathways that are responsible for their expansion. The results show that dual stimulation by CpG and CD40L for 48 h is optimal for IL-10 induction, and this can be synergistically boosted by IL-21. We identified the CD19+CD27+ memory B cell population as the major source of IL-10+ Bregs. We detected significantly fewer CD19+CD27+IL-10+ cells in RA patients compared with healthy controls, and these were functionally defective in suppressing IFN-gamma production by CD4+ T cells in coculture. IL-21 drastically increased the number of IL-10+ Bregs within the CD19+CD27+ and CD19+CD27- populations; furthermore, it induced the appearance of IL-10+Blimp-1+ plasmablasts. Monitoring the phosphorylation of key signaling molecules revealed that activation of ERK, p38, and CREB is indispensable for the induction of IL-10 production, whereas phosphorylation of STAT3 further enhances IL-10 expression in human Bregs. We conclude that CREB and STAT3 are the key transcription factors responsible for the expansion and differentiation of human IL-10-producing Bregs. PMID- 28087673 TI - Ribosomal DNA stability is supported by many 'buffer genes'-introduction to the Yeast rDNA Stability Database. AB - The ribosomal RNA gene (rDNA) is the most abundant gene in yeast and other eukaryotic organisms. Due to its heavy transcription, repetitive structure and programmed replication fork pauses, the rDNA is one of the most unstable regions in the genome. Thus, the rDNA is the best region to study the mechanisms responsible for maintaining genome integrity. Recently, we screened a library of ~4800 budding yeast gene knockout strains to identify mutants defective in the maintenance of rDNA stability. The results of this screen are summarized in the Yeast rDNA Stability (YRS) Database, in which the stability and copy number of rDNA in each mutant are presented. From this screen, we identified ~700 genes that may contribute to the maintenance of rDNA stability. In addition, ~50 mutants had abnormally high or low rDNA copy numbers. Moreover, some mutants with unstable rDNA displayed abnormalities in another chromosome. In this review, we introduce the YRS Database and discuss the roles of newly identified genes that contribute to rDNA maintenance and genome integrity. PMID- 28087672 TI - Elimination of sucrose transport and hydrolysis in Saccharomyces cerevisiae: a platform strain for engineering sucrose metabolism. AB - Many relevant options to improve efficacy and kinetics of sucrose metabolism in Saccharomyces cerevisiae and, thereby, the economics of sucrose-based processes remain to be investigated. An essential first step is to identify all native sucrose-hydrolysing enzymes and sucrose transporters in this yeast, including those that can be activated by suppressor mutations in sucrose-negative strains. A strain in which all known sucrose-transporter genes (MAL11, MAL21, MAL31, MPH2, MPH3) were deleted did not grow on sucrose after 2 months of incubation. In contrast, a strain with deletions in genes encoding sucrose-hydrolysing enzymes (SUC2, MAL12, MAL22, MAL32) still grew on sucrose. Its specific growth rate increased from 0.08 to 0.25 h-1 after sequential batch cultivation. This increase was accompanied by a 3-fold increase of in vitro sucrose-hydrolysis and isomaltase activities, as well as by a 3- to 5-fold upregulation of the isomaltase-encoding genes IMA1 and IMA5. One-step Cas9-mediated deletion of all isomaltase-encoding genes (IMA1-5) completely abolished sucrose hydrolysis. Even after 2 months of incubation, the resulting strain did not grow on sucrose. This sucrose-negative strain can be used as a platform to test metabolic engineering strategies and for fundamental studies into sucrose hydrolysis or transport. PMID- 28087674 TI - Yeast as a tool to express sugar acid transporters with biotechnological interest. AB - Sugar acids can be used as platform chemicals to generate primary building blocks of industrially relevant products. Microbial production of these organic compounds at high yields requires the engineering of the enzymatic machinery and the presence of plasma membrane transporters able to export them outside the cells. In this study, several yeast carboxylic acid transporters belonging to the Jen family were screened for the transport of biotechnologically relevant sugar acids, namely gluconic, saccharic, mucic, xylaric and xylonic acid, and functionally characterised in Saccharomyces cerevisiae. We show that Jen permeases are capable of transporting most of these sugar acids, although with different specificities. Saccharate is a substrate of the transporters ScJen1 S271Q and KlJen2, gluconate of CaJen2 and KlJen2, and xylarate and mucate of CaJen2. A molecular docking approach of these transporters identified the residues that play a major role in the substrate binding of these sugar acids, namely R188 (ScJen1), R122 (CaJen2) and R127 (KlJen2), all equivalent residues (TMS II). The identification of Jen members as sugar acid transporters can contribute to engineering efficient microbial cell factories with increased sugar acid production, as the ScJen1 is able to promote substrate efflux. PMID- 28087675 TI - DNA repair and mutations during quiescence in yeast. AB - Life is maintained through alternating phases of cell division and quiescence. The causes and consequences of spontaneous mutations have been extensively explored in proliferating cells, and the major sources include errors of DNA replication and DNA repair. The foremost consequences are genetic variations within a cell population that can lead to heritable diseases and drive evolution. While most of our knowledge on DNA damage response and repair has been gained through cells actively dividing, it remains essential to also understand how DNA damage is metabolized in cells which are not dividing. In this review, we summarize the current knowledge concerning the type of lesions that arise in non dividing budding and fission yeast cells, as well as the pathways used to repair them. We discuss the contribution of these models to our current understanding of age-related pathologies. PMID- 28087677 TI - Incorporating Persistent Pain in Phenotypic Frailty Measurement and Prediction of Adverse Health Outcomes. AB - BACKGROUND: Frailty, a syndrome of physiological deficits, is prevalent among older adults and predicts elevated risk of adverse health outcomes. Although persistent pain predicts similar risk, it is seldom considered in frailty measurement. This article evaluated the construct and predictive validity of including persistent pain in phenotypic frailty measurement. METHODS: Frailty and persistent pain were operationalized using data from the Health and Retirement Study (2006-2012 waves). Among a subset of adults aged 65 and older (n = 3,652), we used latent class analysis to categorize frailty status and to evaluate construct validity. Using Cox proportional hazards models, we compared time to incident adverse outcomes (death, fall, hospitalization, institutionalization, and functional disability) between frailty classes determined by either including or excluding persistent pain as a frailty component. RESULTS: In latent class models, persistent pain occurred with other frailty components in patterns consistent with a medical syndrome. Frail and intermediately frail classes determined by including persistent pain were more strongly associated with all adverse outcomes compared with frail and intermediately frail classes determined excluding persistent pain. Frail respondents had significantly greater risk of death compared with nonfrail respondents when frailty models included rather than excluded persistent pain (respectively, hazard ratio [HR] = 3.87, 95% confidence interval [CI] = 2.99-5.00 (including pain); HR = 2.10, 95% CI = 1.71-2.59 (excluding pain). CONCLUSIONS: Findings support consideration of persistent pain as a component of the frailty phenotype. Persistent pain assessment may provide an expedient method to enhance frailty measurement and improve prediction of adverse outcomes. PMID- 28087676 TI - The Longitudinal Study of Aging in Human Young Adults: Knowledge Gaps and Research Agenda. AB - BACKGROUND: To prevent onset of age-related diseases and physical and cognitive decline, interventions to slow human aging and extend health span must eventually be applied to people while they are still young and healthy. Yet most human aging research examines older adults, many with chronic disease, and little is known about aging in healthy young humans. METHOD: This article explains how this knowledge gap is a barrier to extending health span and puts forward the case that geroscience should invest in researching the pace of aging in young adults. As one illustrative example, we describe an initial effort to study the pace of aging in a young-adult birth cohort by using repeated waves of biomarkers collected across the third and fourth decades to quantify the pace of coordinated physiological deterioration across multiple organ systems (eg, pulmonary, periodontal, cardiovascular, renal, hepatic, metabolic, and immune function). RESULTS: Findings provided proof of principle that it is possible to quantify individual variation in the pace of aging in young adults still free of age related diseases. CONCLUSIONS: This article articulates research needs to improve longitudinal measurement of the pace of aging in young people, to pinpoint factors that slow or speed the pace of aging, to compare pace of aging against genomic clocks, to explain slow-aging young adults, and to apply pace of aging in preventive clinical trials of antiaging therapies. This article puts forward a research agenda to fill the knowledge gap concerning lifelong causes of aging. PMID- 28087683 TI - Percutaneous Patent Ductus Arteriosus (PDA) Closure During Infancy: A Meta analysis. AB - CONTEXT: Patent ductus arteriosus (PDA) is a precursor to morbidity and mortality. Percutaneous (catheter-based) closure is the procedure of choice for adults and older children with a PDA, but use during infancy (<1 year) is not well characterized. OBJECTIVE: Investigate the technical success and safety of percutaneous PDA closure during infancy. DATA SOURCES: Scopus, Web of Science, Embase, PubMed, and Ovid (Medline) were searched through December 2015 with no language restrictions. STUDY SELECTION: Publications needed to clearly define the intervention as percutaneous PDA closure during infancy (<1 year of age at intervention) and must have reported adverse events (AEs). DATA EXTRACTION: The study was performed according to the Systematic Reviews and Meta-Analysis checklist and registered prospectively. The quality of the selected studies was critically examined. Data extraction and assignment of AE attributability and severity were independently performed by multiple observers. Outcomes were agreed on a priori. Data were pooled by using a random-effects model. RESULTS: Thirty eight studies were included; no randomized controlled trials were found. Technical success of percutaneous PDA closure was 92.2% (95% confidence interval [CI] 88.8-95.0). Overall AE and clinically significant AE incidence was 23.3% (95% CI 16.5-30.8) and 10.1% (95% CI 7.8-12.5), respectively. Significant heterogeneity and publication bias were observed. LIMITATIONS: Limitations include lack of comparative studies, lack of standardized AE reporting strategy, and significant heterogeneity in reporting. CONCLUSIONS: Percutaneous PDA closure during infancy is feasible and associated with few catastrophic AEs; however, the limitations constrain the interpretability and generalizability of the current findings. PMID- 28087684 TI - The Effect of Price Information on the Ordering of Images and Procedures. AB - BACKGROUND AND OBJECTIVES: Ordering rates for imaging studies and procedures may change if clinicians are shown the prices of those tests while they are ordering. We studied the effect of 2 forms of paid price information, single median price and paired internal/external median prices, on how often pediatric-focused and adult-oriented clinicians (most frequently general pediatricians and adult specialists caring for pediatric-aged patients, respectively) order imaging studies and procedures for 0- to 21-year-olds. METHODS: In January 2014, we randomized 227 pediatric-focused and 279 adult-oriented clinicians to 1 of 3 study arms: Control (no price display), Single Median Price, or Paired Internal/External Median Prices (both with price display in the ordering screen of electronic health record). We used 1-way analysis of variance and paired t tests to examine how frequently clinicians (1) placed orders and (2) designated tests to be completed internally within an accountable care organization. RESULTS: For pediatric-focused clinicians, there was no significant difference in the rates at which orders were placed or designated to be completed internally across the study arms. For adult-oriented clinicians caring for children and adolescents, however, those in the Single Price and Paired Price arms placed orders at significantly higher rates than those in the Control group (Control 3.2 [SD 4.8], Single Price 6.2 [SD 6.8], P < .001 and Paired Prices 5.2 [SD 7.9], P = .04). The rate at which adult-oriented clinicians designated tests to be completed internally was not significantly different across arms. CONCLUSIONS: The effect of price information on ordering rates appears to depend on whether the clinician is pediatric-focused or adult-oriented. PMID- 28087685 TI - BST-2 restricts IAV release and is countered by the viral M2 protein. AB - BST-2 (tetherin, CD317, and HM1.24) is induced by interferon and restricts virus release by tethering the enveloped viruses to the cell surface. The effect of BST 2 on influenza A virus (IAV) infection has been inconclusive. In the present study, we report that BST-2 diminishes the production of IAV virus-like particles (VLPs) that are generated by viral neuraminidase and hemagglutinin proteins to a much greater degree than it inhibits the production of wild-type IAV particles. This relatively weaker inhibition of IAV is associated with reduction in BST-2 levels, which is caused by the M2 protein that interacts with BST-2 and leads to down-regulation of cell surface BST-2 via the proteasomal pathway. Similarly to the viral antagonist Vpu, M2 also rescues the production of human immunodeficiency virus-1 VLPs and IAV VLPs in the presence of BST-2. Replication of wild-type and the M2-deleted viruses were both inhibited by BST-2, with the M2 deleted IAV being more restricted. These data reveal one mechanism that IAV employs to counter restriction by BST-2. PMID- 28087686 TI - Amoebozoans Are Secretly but Ancestrally Sexual: Evidence for Sex Genes and Potential Novel Crossover Pathways in Diverse Groups of Amoebae. AB - Sex is beneficial in eukaryotes as it can increase genetic diversity, reshuffle their genomes, and purge deleterious mutations. Yet, its evolution remains a mystery. The eukaryotic clade supergroup Amoebozoa encompasses diverse lineages of polymorphic amoeboid forms, including both free-living and parasitic lineages. The group is generally believed to be asexual, though recent studies show that some of its members are implicated in cryptic forms of sexual cycles. In this study, we conduct a comprehensive inventory and analysis of genes involved in meiosis and related processes, in order to investigate the evolutionary history of sex in the clade. We analyzed genomic and transcriptomic data of 39 amoebozoans representing all major subclades of Amoebozoa. Our results show that Amoebozoa possess most of the genes exclusive to meiosis but lack genes encoding synaptonemal complex (SC). The absence of SC genes is discussed in the context of earlier studies that reported ultrastructural evidence of SC in some amoebae. We also find interclade and intrageneric variation in sex gene distribution, indicating diversity in sexual pathways in the group. Particularly, members of Mycetozoa engage in a novel sexual pathway independent of the universally conserved meiosis initiator gene, SPO11. Our findings strongly suggest that not only do amoebozoans possess sex genes in their genomes, but also, based on the transcriptome evidence, the present sex genes are functional. We conclude that Amoebozoa is ancestrally sexual, contrary to the long held belief that most of its members are asexual. Thus, asexuality in Amoebozoa, if confirmed to be present, is a derived-trait that appeared later in their evolution. PMID- 28087687 TI - Survival Benefits of Invasive Versus Conservative Strategies in Heart Failure in Patients With Reduced Ejection Fraction and Coronary Artery Disease: A Meta Analysis. AB - BACKGROUND: Heart failure with reduced ejection fraction caused by ischemic heart disease is associated with increased morbidity and mortality. It remains unclear whether revascularization by either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) carries benefits or risks in this group of stable patients compared with medical treatment. METHODS AND RESULTS: We performed a meta-analysis of available studies comparing different methods of revascularization (PCI or CABG) against each other or medical treatment in patients with coronary artery disease and left ventricular ejection fraction <=40%. The primary outcome was all-cause mortality; myocardial infarction, revascularization, and stroke were also analyzed. Twenty-one studies involving a total of 16 191 patients were included. Compared with medical treatment, there was a significant mortality reduction with CABG (hazard ratio, 0.66; 95% confidence interval, 0.61-0.72; P<0.001) and PCI (hazard ratio, 0.73; 95% confidence interval, 0.62-0.85; P<0.001). When compared with PCI, CABG still showed a survival benefit (hazard ratio, 0.82; 95% confidence interval, 0.75 0.90; P<0.001). CONCLUSIONS: The present meta-analysis indicates that revascularization strategies are superior to medical treatment in improving survival in patients with ischemic heart disease and reduced ejection fraction. Between the 2 revascularization strategies, CABG seems more favorable compared with PCI in this particular clinical setting. PMID- 28087689 TI - Rethinking Revascularization in Left Ventricular Systolic Dysfunction. PMID- 28087688 TI - Thirty Years of Evidence on the Efficacy of Drug Treatments for Chronic Heart Failure With Reduced Ejection Fraction: A Network Meta-Analysis. AB - BACKGROUND: Treatments that reduce mortality and morbidity in patients with heart failure with reduced ejection fraction, including angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), and angiotensin receptor-neprilysin inhibitors (ARNI), have not been studied in a head-to-head fashion. This network meta-analysis aimed to compare the efficacy of these drugs and their combinations regarding all-cause mortality in patients with heart failure with reduced ejection fraction. METHODS AND RESULTS: A systematic literature review identified 57 randomized controlled trials published between 1987 and 2015, which were compared in terms of study and patient characteristics, baseline risk, outcome definitions, and the observed treatment effects. Despite differences identified in terms of study duration, New York Heart Association class, ejection fraction, and use of background digoxin, a network meta-analysis was considered feasible and all trials were analyzed simultaneously. The random-effects network meta analysis suggested that the combination of ACEI+BB+MRA was associated with a 56% reduction in mortality versus placebo (hazard ratio 0.44, 95% credible interval 0.26-0.66); ARNI+BB+MRA was associated with the greatest reduction in all-cause mortality versus placebo (hazard ratio 0.37, 95% credible interval 0.19-0.65). A sensitivity analysis that did not account for background therapy suggested that ARNI monotherapy is more efficacious than ACEI or ARB monotherapy. CONCLUSIONS: The network meta-analysis showed that treatment with ACEI, ARB, BB, MRA, and ARNI and their combinations were better than the treatment with placebo in reducing all-cause mortality, with the exception of ARB monotherapy and ARB plus ACEI. The combination of ARNI+BB+MRA resulted in the greatest mortality reduction. PMID- 28087690 TI - Editorial: An expanded view of viruses. PMID- 28087692 TI - Underuse of screening in Osler-Weber-Rendu syndrome. PMID- 28087691 TI - Imaging proteins at the single-molecule level. AB - Imaging single proteins has been a long-standing ambition for advancing various fields in natural science, as for instance structural biology, biophysics, and molecular nanotechnology. In particular, revealing the distinct conformations of an individual protein is of utmost importance. Here, we show the imaging of individual proteins and protein complexes by low-energy electron holography. Samples of individual proteins and protein complexes on ultraclean freestanding graphene were prepared by soft-landing electrospray ion beam deposition, which allows chemical- and conformational-specific selection and gentle deposition. Low energy electrons do not induce radiation damage, which enables acquiring subnanometer resolution images of individual proteins (cytochrome C and BSA) as well as of protein complexes (hemoglobin), which are not the result of an averaging process. PMID- 28087693 TI - De Novo Genome and Transcriptome Assembly of the Canadian Beaver (Castor canadensis). AB - The Canadian beaver (Castor canadensis) is the largest indigenous rodent in North America. We report a draft annotated assembly of the beaver genome, the first for a large rodent and the first mammalian genome assembled directly from uncorrected and moderate coverage (< 30 *) long reads generated by single-molecule sequencing. The genome size is 2.7 Gb estimated by k-mer analysis. We assembled the beaver genome using the new Canu assembler optimized for noisy reads. The resulting assembly was refined using Pilon supported by short reads (80 *) and checked for accuracy by congruency against an independent short read assembly. We scaffolded the assembly using the exon-gene models derived from 9805 full-length open reading frames (FL-ORFs) constructed from the beaver leukocyte and muscle transcriptomes. The final assembly comprised 22,515 contigs with an N50 of 278,680 bp and an N50-scaffold of 317,558 bp. Maximum contig and scaffold lengths were 3.3 and 4.2 Mb, respectively, with a combined scaffold length representing 92% of the estimated genome size. The completeness and accuracy of the scaffold assembly was demonstrated by the precise exon placement for 91.1% of the 9805 assembled FL-ORFs and 83.1% of the BUSCO (Benchmarking Universal Single-Copy Orthologs) gene set used to assess the quality of genome assemblies. Well represented were genes involved in dentition and enamel deposition, defining characteristics of rodents with which the beaver is well-endowed. The study provides insights for genome assembly and an important genomics resource for Castoridae and rodent evolutionary biology. PMID- 28087694 TI - Iso-alpha-acids, Bitter Components of Beer, Prevent Inflammation and Cognitive Decline Induced in a Mouse Model of Alzheimer's Disease. AB - Alongside the rapid growth in aging populations worldwide, prevention and therapy for age-related memory decline and dementia are in great demand to maintain a long, healthy life. Here we found that iso-alpha-acids, hop-derived bitter compounds in beer, enhance microglial phagocytosis and suppress inflammation via activation of the peroxisome proliferator-activated receptor gamma. In normal mice, oral administration of iso-alpha-acids led to a significant increase both in CD11b and CD206 double-positive anti-inflammatory type microglia (p < 0.05) and in microglial phagocytosis in the brain. In Alzheimer's model 5xFAD mice, oral administration of iso-alpha-acids resulted in a 21% reduction in amyloid beta in the cerebral cortex as observed by immunohistochemical analysis, a significant reduction in inflammatory cytokines such as IL-1beta and chemokines including macrophage inflammatory protein-1alpha in the cerebral cortex (p < 0.05) and a significant improvement in a novel object recognition test (p < 0.05), as compared with control-fed 5xFAD mice. The differences in iso-alpha-acid fed mice were due to the induction of microglia to an anti-inflammatory phenotype. The present study is the first to report that amyloid beta deposition and inflammation are suppressed in a mouse model of Alzheimer's disease by a single component, iso-alpha-acids, via the regulation of microglial activation. The suppression of neuroinflammation and improvement in cognitive function suggests that iso-alpha-acids contained in beer may be useful for the prevention of dementia. PMID- 28087695 TI - Novel Interconnections in Lipid Metabolism Revealed by Overexpression of Sphingomyelin Synthase-1. AB - This study investigates the consequences of elevating sphingomyelin synthase 1 (SMS1) activity, which generates the main mammalian sphingolipid, sphingomyelin. HepG2 cells stably transfected with SMS1 (HepG2-SMS1) exhibit elevated enzyme activity in vitro and increased sphingomyelin content (mainly C22:0- and C24:0 sphingomyelin) but lower hexosylceramide (Hex-Cer) levels. HepG2-SMS1 cells have fewer triacylglycerols than controls but similar diacylglycerol acyltransferase activity, triacylglycerol secretion, and mitochondrial function. Treatment with 1 mm palmitate increases de novo ceramide synthesis in both cell lines to a similar degree, causing accumulation of C16:0-ceramide (and some C18:0-, C20:0-, and C22:0-ceramides) as well as C16:0- and C18:0-Hex-Cers. In these experiments, the palmitic acid is delivered as a complex with delipidated BSA (2:1, mol/mol) and does not induce significant lipotoxicity. Based on precursor labeling, the flux through SM synthase also increases, which is exacerbated in HepG2-SMS1 cells. In contrast, palmitate-induced lipid droplet formation is significantly reduced in HepG2-SMS1 cells. [14C]Choline and [3H]palmitate tracking shows that SMS1 overexpression apparently affects the partitioning of palmitate-enriched diacylglycerol between the phosphatidylcholine and triacylglycerol pathways, to the benefit of the former. Furthermore, triacylglycerols from HepG2-SMS1 cells are enriched in polyunsaturated fatty acids, which is indicative of active remodeling. Together, these results delineate novel metabolic interactions between glycerolipids and sphingolipids. PMID- 28087696 TI - Genetic and Biochemical Characterization of a Gene Operon for trans-Aconitic Acid, a Novel Nematicide from Bacillus thuringiensis. AB - trans-Aconitic acid (TAA) is an isomer of cis-aconitic acid (CAA), an intermediate of the tricarboxylic acid cycle that is synthesized by aconitase. Although TAA production has been detected in bacteria and plants for many years and is known to be a potent inhibitor of aconitase, its biosynthetic origins and the physiological relevance of its activity have remained unclear. We have serendipitously uncovered key information relevant to both of these questions. Specifically, in a search for novel nematicidal factors from Bacillus thuringiensis, a significant nematode pathogen harboring many protein virulence factors, we discovered a high yielding component that showed activity against the plant-parasitic nematode Meloidogyne incognita and surprisingly identified it as TAA. Comparison with CAA, which displayed a much weaker nematicidal effect, suggested that TAA is specifically synthesized by B. thuringiensis as a virulence factor. Analysis of mutants deficient in plasmids that were anticipated to encode virulence factors allowed us to isolate a TAA biosynthesis-related (tbr) operon consisting of two genes, tbrA and tbrB We expressed the corresponding proteins, TbrA and TbrB, and characterized them as an aconitate isomerase and TAA transporter, respectively. Bioinformatics analysis of the TAA biosynthetic gene cluster revealed the association of the TAA genes with transposable elements relevant for horizontal gene transfer as well as a distribution across B. cereus bacteria and other B. thuringiensis strains, suggesting a general role for TAA in the interactions of B. cereus group bacteria with nematode hosts in the soil environment. This study reveals new bioactivity for TAA and the TAA biosynthetic pathway, improving our understanding of virulence factors employed by B. thuringiensis pathogenesis and providing potential implications for nematode management applications. PMID- 28087697 TI - Development of High Affinity and High Specificity Inhibitors of Matrix Metalloproteinase 14 through Computational Design and Directed Evolution. AB - Degradation of the extracellular matrices in the human body is controlled by matrix metalloproteinases (MMPs), a family of more than 20 homologous enzymes. Imbalance in MMP activity can result in many diseases, such as arthritis, cardiovascular diseases, neurological disorders, fibrosis, and cancers. Thus, MMPs present attractive targets for drug design and have been a focus for inhibitor design for as long as 3 decades. Yet, to date, all MMP inhibitors have failed in clinical trials because of their broad activity against numerous MMP family members and the serious side effects of the proposed treatment. In this study, we integrated a computational method and a yeast surface display technique to obtain highly specific inhibitors of MMP-14 by modifying the natural non specific broad MMP inhibitor protein N-TIMP2 to interact optimally with MMP-14. We identified an N-TIMP2 mutant, with five mutations in its interface, that has an MMP-14 inhibition constant (Ki ) of 0.9 pm, the strongest MMP-14 inhibitor reported so far. Compared with wild-type N-TIMP2, this variant displays ~900-fold improved affinity toward MMP-14 and up to 16,000-fold greater specificity toward MMP-14 relative to other MMPs. In an in vitro and cell-based model of MMP dependent breast cancer cellular invasiveness, this N-TIMP2 mutant acted as a functional inhibitor. Thus, our study demonstrates the enormous potential of a combined computational/directed evolution approach to protein engineering. Furthermore, it offers fundamental clues into the molecular basis of MMP regulation by N-TIMP2 and identifies a promising MMP-14 inhibitor as a starting point for the development of protein-based anticancer therapeutics. PMID- 28087698 TI - Inhibition of Transient Receptor Potential Channel Mucolipin-1 (TRPML1) by Lysosomal Adenosine Involved in Severe Combined Immunodeficiency Diseases. AB - Impaired adenosine homeostasis has been associated with numerous human diseases. Lysosomes are referred to as the cellular recycling centers that generate adenosine by breaking down nucleic acids or ATP. Recent studies have suggested that lysosomal adenosine overload causes lysosome defects that phenocopy patients with mutations in transient receptor potential channel mucolipin-1 (TRPML1), a lysosomal Ca2+ channel, suggesting that lysosomal adenosine overload may impair TRPML1 and then lead to subsequent lysosomal dysfunction. In this study, we demonstrate that lysosomal adenosine is elevated by deleting adenosine deaminase (ADA), an enzyme responsible for adenosine degradation. We also show that lysosomal adenosine accumulation inhibits TRPML1, which is rescued by overexpressing ENT3, the adenosine transporter situated in the lysosome membrane. Moreover, ADA deficiency results in lysosome enlargement, alkalinization, and dysfunction. These are rescued by activating TRPML1. Importantly, ADA-deficient B lymphocytes are more vulnerable to oxidative stress, and this was rescued by TRPML1 activation. Our data suggest that lysosomal adenosine accumulation impairs lysosome function by inhibiting TRPML1 and subsequently leads to cell death in B lymphocytes. Activating TRPML1 could be a new therapeutic strategy for those diseases. PMID- 28087699 TI - Activation of c-Abl Kinase Potentiates the Anti-myeloma Drug Lenalidomide by Promoting DDA1 Protein Recruitment to the CRL4 Ubiquitin Ligase. AB - Cullin-RING ligase 4 (CRL4), a complex of Cul4 and DDB1, regulates the cell cycle, DNA damage repair, and chromatin replication by targeting a variety of substrates for ubiquitination. CRL4 is also hijacked by viral proteins or thalidomide-derived compounds to degrade host restriction factors. Here we report that the c-Abl non-receptor kinase phosphorylates DDB1 at residue Tyr-316 to recruit a small regulatory protein, DDA1, leading to increased substrate ubiquitination. Pharmacological inhibition or genetic ablation of the Abl-DDB1 DDA1 axis decreases the ubiquitination of CRL4 substrates, including IKZF1 and IKZF3, in lenalidomide-treated multiple myeloma cells. Importantly, panobinostat, a recently approved anti-myeloma drug, and dexamethasone enhance lenalidomide induced substrate degradation and cytotoxicity by activating c-Abl, therefore providing a mechanism underlying their combination with lenalidomide to treat multiple myeloma. PMID- 28087702 TI - Aging: It's Personal. PMID- 28087701 TI - The Ubiquitin Ligase Nedd4L Regulates the Na/K/2Cl Co-transporter NKCC1/SLC12A2 in the Colon. AB - The ubiquitin ligase Nedd4-like (Nedd4L, or Nedd4-2) binds to and regulates stability of the epithelial Na+ channel (ENaC) in salt-absorbing epithelia in the kidney, lung, and other tissues. Its role in the distal colon, which also absorbs salt and fluid and expresses ENaC, is unknown. Using a conditional knock-out approach to knock out Nedd4L in mice intestinal epithelium (Nedd4Lf/f ;Vil CreERT2 ) we show here that Nedd4L depletion leads to a higher steady-state short circuit current (Isc) in mouse distal colon tissue relative to controls. This higher Isc was partially reduced by the addition of apical amiloride and strongly reduced by basolateral bumetanide as well as by depletion of basolateral Cl-, suggesting that Na+/K+/2Cl- (NKCC1/SLC12A2) co-transporter and ENaC are targets of Nedd4L in the colon. In accordance, NKCC1 (and gammaENaC) protein abundance in the colon of the Nedd4L knock-out animals was increased, indicating that Nedd4L normally suppresses these proteins. However, we did not observe co immunoprecipitation between Nedd4L and NKCC1, suggesting that Nedd4L indirectly suppresses NKCC1 expression. Low salt diet resulted in a strong increase in beta and gamma (but not alpha) ENaC mRNA and protein expression and ENaC activity. Although salt restriction also increased NKCC1 protein and mRNA abundance, it did not lead to its elevated activity (Isc). These results identify NKCC1 as a novel target for Nedd4L-mediated down-regulation in vivo, which modulates ion and fluid transport in the distal colon together with ENaC. PMID- 28087703 TI - Bedroom Scenes: Filmic Portrayals of Intimacy and Sexuality in Long-Lived Relationships. PMID- 28087700 TI - Two Small Molecules Restore Stability to a Subpopulation of the Cystic Fibrosis Transmembrane Conductance Regulator with the Predominant Disease-causing Mutation. AB - Cystic fibrosis (CF) is caused by mutations that disrupt the plasma membrane expression, stability, and function of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. Two small molecules, the CFTR corrector lumacaftor and the potentiator ivacaftor, are now used clinically to treat CF, although some studies suggest that they have counteracting effects on CFTR stability. Here, we investigated the impact of these compounds on the instability of F508del-CFTR, the most common CF mutation. To study individual CFTR Cl- channels, we performed single-channel recording, whereas to assess entire CFTR populations, we used purified CFTR proteins and macroscopic CFTR Cl- currents. At 37 degrees C, low temperature-rescued F508del-CFTR more rapidly lost function in cell-free membrane patches and showed altered channel gating and current flow through open channels. Compared with purified wild-type CFTR, the full-length F508del-CFTR was about 10 degrees C less thermostable. Lumacaftor partially stabilized purified full-length F508del-CFTR and slightly delayed deactivation of individual F508del-CFTR Cl- channels. By contrast, ivacaftor further destabilized full-length F508del-CFTR and accelerated channel deactivation. Chronic (prolonged) co-incubation of F508del-CFTR-expressing cells with lumacaftor and ivacaftor deactivated macroscopic F508del-CFTR Cl- currents. However, at the single-channel level, chronic co-incubation greatly increased F508del-CFTR channel activity and temporal stability in most, but not all, cell-free membrane patches. We conclude that chronic lumacaftor and ivacaftor co-treatment restores stability in a small subpopulation of F508del-CFTR Cl- channels but that the majority remain destabilized. A fuller understanding of these effects and the characterization of the small F508del-CFTR subpopulation might be crucial for CF therapy development. PMID- 28087704 TI - Transformed by Discovered Shadows. PMID- 28087709 TI - A broad spectrum. PMID- 28087710 TI - Targeting Argonaute to chromatin. AB - In many eukaryotes, siRNAs bound to Argonaute proteins guide chromatin-modifying enzymes to complementary loci, resulting in transcriptional gene silencing. Multiple lines of evidence indicate that siRNAs base-pair with longer RNAs produced at target loci, but the possibility that siRNAs base-pair directly with DNA remains an attractive hypothesis. In a recent study, Shimada et al. (pp. 2571 2580) conducted experiments that address these alternative hypotheses, yielding additional evidence that fission yeast siRNA-Argonaute silencing complexes are recruited to target loci exclusively via interactions with nascent transcripts. PMID- 28087711 TI - CTCF-mediated topological boundaries during development foster appropriate gene regulation. AB - The genome is organized into repeating topologically associated domains (TADs), each of which is spatially isolated from its neighbor by poorly understood boundary elements thought to be conserved across cell types. Here, we show that deletion of CTCF (CCCTC-binding factor)-binding sites at TAD and sub-TAD topological boundaries that form within the HoxA and HoxC clusters during differentiation not only disturbs local chromatin domain organization and regulatory interactions but also results in homeotic transformations typical of Hox gene misregulation. Moreover, our data suggest that CTCF-dependent boundary function can be modulated by competing forces, such as the self-assembly of polycomb domains within the nucleus. Therefore, CTCF boundaries are not merely static structural components of the genome but instead are locally dynamic regulatory structures that control gene expression during development. PMID- 28087712 TI - PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance. AB - Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression. PMID- 28087713 TI - Functional genomics reveals that tumors with activating phosphoinositide 3-kinase mutations are dependent on accelerated protein turnover. AB - Activating mutations in the phosphoinositide 3-kinase (PI3K) signaling pathway are frequently identified in cancer. To identify pathways that support PI3K oncogenesis, we performed a genome-wide RNAi screen in isogenic cell lines harboring wild-type or mutant PIK3CA to search for PI3K synthetic-lethal (SL) genes. A combined analysis of these results with a meta-analysis of two other large-scale RNAi screening data sets in PI3K mutant cancer cell lines converged on ribosomal protein translation and proteasomal protein degradation as critical nononcogene dependencies for PI3K-driven tumors. Genetic or pharmacologic inhibition of either pathway alone, but not together, selectively killed PI3K mutant tumor cells in an mTOR-dependent manner. The expression of ribosomal and proteasomal components was significantly up-regulated in primary human colorectal tumors harboring PI3K pathway activation. Importantly, a PI3K SL gene signature containing the top hits of the SL genes identified in our meta-analysis robustly predicted overall patient survival in colorectal cancer, especially among patients with tumors with an activated PI3K pathway. These results suggest that disruption of protein turnover homeostasis via ribosome or proteasome inhibition may be a novel treatment strategy for PI3K mutant human tumors. PMID- 28087714 TI - DLG5 connects cell polarity and Hippo signaling protein networks by linking PAR-1 with MST1/2. AB - Disruption of apical-basal polarity is implicated in developmental disorders and cancer; however, the mechanisms connecting cell polarity proteins with intracellular signaling pathways are largely unknown. We determined previously that membrane-associated guanylate kinase (MAGUK) protein discs large homolog 5 (DLG5) functions in cell polarity and regulates cellular proliferation and differentiation via undefined mechanisms. We report here that DLG5 functions as an evolutionarily conserved scaffold and negative regulator of Hippo signaling, which controls organ size through the modulation of cell proliferation and differentiation. Affinity purification/mass spectrometry revealed a critical role of DLG5 in the formation of protein assemblies containing core Hippo kinases mammalian ste20 homologs 1/2 (MST1/2) and Par-1 polarity proteins microtubule affinity-regulating kinases 1/2/3 (MARK1/2/3). Consistent with this finding, Hippo signaling is markedly hyperactive in mammalian Dlg5-/- tissues and cells in vivo and ex vivo and in Drosophila upon dlg5 knockdown. Conditional deletion of Mst1/2 fully rescued the phenotypes of brain-specific Dlg5 knockout mice. Dlg5 also interacts genetically with Hippo effectors Yap1/Taz Mechanistically, we show that DLG5 inhibits the association between MST1/2 and large tumor suppressor homologs 1/2 (LATS1/2), uses its scaffolding function to link MST1/2 with MARK3, and inhibits MST1/2 kinase activity. These data reveal a direct connection between cell polarity proteins and Hippo, which is essential for proper development of multicellular organisms. PMID- 28087718 TI - Edwin Thomas Melley. PMID- 28087715 TI - SF3B1/Hsh155 HEAT motif mutations affect interaction with the spliceosomal ATPase Prp5, resulting in altered branch site selectivity in pre-mRNA splicing. AB - Mutations in the U2 snRNP component SF3B1 are prominent in myelodysplastic syndromes (MDSs) and other cancers and have been shown recently to alter branch site (BS) or 3' splice site selection in splicing. However, the molecular mechanism of altered splicing is not known. We show here that hsh155 mutant alleles in Saccharomyces cerevisiae, counterparts of SF3B1 mutations frequently found in cancers, specifically change splicing of suboptimal BS pre-mRNA substrates. We found that Hsh155p interacts directly with Prp5p, the first ATPase that acts during spliceosome assembly, and localized the interacting regions to HEAT (Huntingtin, EF3, PP2A, and TOR1) motifs in SF3B1 associated with disease mutations. Furthermore, we show that mutations in these motifs from both human disease and yeast genetic screens alter the physical interaction with Prp5p, alter branch region specification, and phenocopy mutations in Prp5p. These and other data demonstrate that mutations in Hsh155p and Prp5p alter splicing because they change the direct physical interaction between Hsh155p and Prp5p. This altered physical interaction results in altered loading (i.e., "fidelity") of the BS-U2 duplex into the SF3B complex during prespliceosome formation. These results provide a mechanistic framework to explain the consequences of intron recognition and splicing of SF3B1 mutations found in disease. PMID- 28087719 TI - Genetics insight into the amyotrophic lateral sclerosis/frontotemporal dementia spectrum. AB - Recent genetic discoveries have dramatically changed our understanding of two major neurodegenerative conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are common, devastating diseases of the brain. For decades, ALS and FTD were classified as movement and cognitive disorders, respectively, due to their distinct clinical phenotypes. The recent identification of chromosome 9 open reading frame 72 (C9orf72) as the major gene causative of familial forms of ALS and FTD uncovered a new reality of a continuous FTD/ALS spectrum. The finding that up to 50% of all patients present some degree of ALS and FTD phenotypes supports this ALS/FTD continuum. Now >100 genes are known to contribute to ALS/FTD, with a few major contributors that are reviewed below. The low penetrance of C9orf72 mutations, its contribution to sporadic cases, and its combination with other genes support an oligogenic model where two or more genes contribute to disease risk, onset, progression and phenotype: from 'pure' ALS or FTD to combined ALS/FTD. These advances in the genetics of ALS/FTD will soon lead to a better mechanistic understanding of the pathobiology of the disease, which should result in the development of effective therapies in the near future. PMID- 28087720 TI - A liminal stage after predictive testing for Huntington disease. AB - BACKGROUND: Following predictive testing for Huntington disease (HD), knowledge of one's carrier status may have consequences on disease onset. Our study aimed to address two questions. First, does knowledge of being a carrier of the pathological HD mutation trigger onset of the disease? Second, does this knowledge influence self-awareness and allow carriers to identify signs and symptoms of disease onset? METHODS: Between 2012 and 2015, 75 HD mutation carriers were examined using the Unified Huntington's Disease Rating Scale (UHDRS) motor score. Onset estimation made with the disease burden score was compared with UHDRS findings. We collected qualitative data with questionnaires and semistructured interviews. RESULTS: 38 women and 37 men, aged 43.7 years+/ 10.5 (20-68), were interviewed after a mean delay between test and study interview of 10.5 years+/-4.7 (from 4 to 21 years). Estimation of age at onset was 4.5+/-8.5 years earlier than data-derived age at onset. Participants were categorised according to their motor score: scores <5 were premanifest (n=35), and scores >5 were manifest carriers (n=40). Self-observation was a major preoccupation for all, independent of their clinical status (82% vs 74%, p=0.57). Among manifest carriers, 56% thought they showed symptoms, but only 33% felt ill. Interestingly, this was also observed in those without motor signs (20% and 9%). Being a mutation carrier did not significantly facilitate recognition of motor signs. Interviews with premanifest carriers allowed the burden of self observation to be illustrated despite lack of motor signs. CONCLUSIONS: Estimating age at onset based on disease burden score may not be accurate. The transition to disease was experienced as an ambiguous or liminal experience. The view of mutation carriers is not always concordant with medical onset estimation, highlighting the difficulties involved in the concept of onset and its use as an outcome in future disease-modifying trials. PMID- 28087716 TI - The piggyBac transposon-derived genes TPB1 and TPB6 mediate essential transposon like excision during the developmental rearrangement of key genes in Tetrahymena thermophila. AB - Ciliated protozoans perform extreme forms of programmed somatic DNA rearrangement during development. The model ciliate Tetrahymena thermophila removes 34% of its germline micronuclear genome from somatic macronuclei by excising thousands of internal eliminated sequences (IESs), a process that shares features with transposon excision. Indeed, piggyBac transposon-derived genes are necessary for genome-wide IES excision in both Tetrahymena (TPB2 [Tetrahymena piggyBac-like 2] and LIA5) and Paramecium tetraurelia (PiggyMac). T. thermophila has at least three other piggyBac-derived genes: TPB1, TPB6, and TPB7 Here, we show that TPB1 and TPB6 excise a small, distinct set of 12 unusual IESs that disrupt exons. TPB1 deficient cells complete mating, but their progeny exhibit slow growth, giant vacuoles, and osmotic shock sensitivity due to retention of an IES in the vacuolar gene DOP1 (Dopey domain-containing protein). Unlike most IESs, TPB1 dependent IESs have piggyBac-like terminal inverted motifs that are necessary for excision. Transposon-like excision mediated by TPB1 and TPB6 provides direct evidence for a transposon origin of not only IES excision machinery but also IESs themselves. Our study highlights a division of labor among ciliate piggyBac derived genes, which carry out mutually exclusive categories of excision events mediated by either transposon-like features or RNA-directed heterochromatin. PMID- 28087721 TI - Joubert syndrome: neuroimaging findings in 110 patients in correlation with cognitive function and genetic cause. AB - BACKGROUND: Joubert syndrome is a clinically and genetically heterogeneous ciliopathy. Neuroimaging findings have not been systematically evaluated in a large cohort of patients with Joubert syndrome in correlation with molecular genetic cause and cognitive function. METHODS: Brain MRI of 110 patients with Joubert syndrome was included in this study. A comprehensive evaluation of brain MRI studies for infratentorial and supratentorial morphological abnormalities was performed. Genetic cause was identified by whole-exome sequencing, and cognitive functions were assessed with age-appropriate neurocognitive tests in a subset of patients. RESULTS: The cerebellar hemispheres were enlarged in 18% of the patients, mimicking macrocerebellum. The posterior fossa was enlarged in 42% of the patients, resembling Dandy-Walker malformation. Abnormalities of the brainstem, such as protuberance at the ventral contour of the midbrain, were present in 66% of the patients. Abnormalities of the supratentorial brain were present in approximately one-third of the patients, most commonly malrotation of the hippocampi. Mild ventriculomegaly, which typically did not require shunting, was present in 23% of the patients. No correlation between neuroimaging findings and molecular genetic cause was apparent. A novel predictor of outcome was identified; the more severe the degree of vermis hypoplasia, the worse the neurodevelopmental outcome was. CONCLUSIONS: The spectrum of neuroimaging findings in Joubert syndrome is wide. Neuroimaging does not predict the genetic cause, but may predict the neurodevelopmental outcome. A high degree of vermis hypoplasia correlates with worse neurodevelopmental outcome. This finding is important for prognostic counselling in Joubert syndrome. PMID- 28087722 TI - A systematic review of administrative and clinical databases of infants admitted to neonatal units. AB - OBJECTIVES: High quality information, increasingly captured in clinical databases, is a useful resource for evaluating and improving newborn care. We conducted a systematic review to identify neonatal databases, and define their characteristics. METHODS: We followed a preregistered protocol using MesH terms to search MEDLINE, EMBASE, CINAHL, Web of Science and OVID Maternity and Infant Care Databases for articles identifying patient level databases covering more than one neonatal unit. Full-text articles were reviewed and information extracted on geographical coverage, criteria for inclusion, data source, and maternal and infant characteristics. RESULTS: We identified 82 databases from 2037 publications. Of the country-specific databases there were 39 regional and 39 national. Sixty databases restricted entries to neonatal unit admissions by birth characteristic or insurance cover; 22 had no restrictions. Data were captured specifically for 53 databases; 21 administrative sources; 8 clinical sources. Two clinical databases hold the largest range of data on patient characteristics, USA's Pediatrix BabySteps Clinical Data Warehouse and UK's National Neonatal Research Database. CONCLUSIONS: A number of neonatal databases exist that have potential to contribute to evaluating neonatal care. The majority is created by entering data specifically for the database, duplicating information likely already captured in other administrative and clinical patient records. This repetitive data entry represents an unnecessary burden in an environment where electronic patient records are increasingly used. Standardisation of data items is necessary to facilitate linkage within and between countries. PMID- 28087723 TI - Prophylactic propranolol for prevention of ROP and visual outcome at 1 year (PreROP trial). AB - OBJECTIVE: To evaluate the role of prophylactic propranolol in the prevention of retinopathy of prematurity (ROP) in infants <=32 weeks of gestational age and their visual outcome at 1 year of corrected gestational age. DESIGN: Randomised double blind placebo controlled trial, parallel group nrolment with allocation ratio of 1:1. SETTINGS: Two level III neonatal intensive care units. PARTICIPANTS: 109 preterm neonates of <=32 weeks of gestation with postnatal age <=8 days old. INTERVENTION: Study group: Infants with gestational age between 26 and 32 weeks were started on propranolol prophylaxis (0.5 mg/kg/dose every 12 hours) on seventh completed day of life, till a corrected gestational age of 37 weeks or complete vascularisation of retina whichever was later. Control group infants received a placebo. OUTCOME MEASURES: Primary: ROP of all grades; Secondary: evaluation of complications due to propranolol, ROP needing treatment with laser and/or antivascular endothelial growth factor (anti-VEGF) and visual outcome at 12 months corrected age. RESULTS: Prophylactic propranolol in the prescribed dose of 1 mg/kg/day showed a decreasing trend in the incidence of ROP (56.8% vs 68.6%; p=0.39), need for laser therapy (21.56% vs 31.37%; p=0.37), treatment with anti-VEGF (3.92% vs 15.68%; p=0.09) or visual outcomes at 1 year in the study and control groups, respectively, though these reductions were not statistically significant. Decreasing trends favouring propranolol in all other ROP-related outcomes were also noted in the study group. CONCLUSIONS: Prophylactic propranolol in the prescribed dose of 1 mg/kg/day showed a decreasing trend in all outcomes of ROP though statistically not significant. TRIAL REGISTRATION NUMBER: CTRI/2013/11/004131. PMID- 28087724 TI - What does it mean to be a skinny baby? PMID- 28087725 TI - Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO2 targets: the PHELBI follow-up study. AB - BACKGROUND: Tolerating higher partial pressures of carbon dioxide (PCO2) in mechanically ventilated extremely low birthweight infants to reduce ventilator induced lung injury may have long-term neurodevelopmental side effects. This study analyses the results of neurodevelopmental follow-up of infants enrolled in a randomised multicentre trial. METHODS: Infants (n=359) between 400 and 1000 g birth weight and 23 0/7-28 6/7 weeks gestational age who required endotracheal intubation and mechanical ventilation within 24 hours of birth were randomly assigned to high PCO2 or to a control group with mildly elevated PCO2 targets. Neurodevelopmental follow-up examinations were available for 85% of enrolled infants using the Bayley Scales of Infant Development II, the Gross Motor Function Classification System (GMFCS) and the Child Development Inventory (CDI). RESULTS: There were no differences in body weight, length and head circumference between the two PCO2 target groups. Median Mental Developmental Index (MDI) values were 82 (60-96, high target) and 84 (58-96, p=0.79). Psychomotor Developmental Index (PDI) values were 84 (57-100) and 84 (65-96, p=0.73), respectively. Moreover, there was no difference in the number of infants with MDI or PDI <70 or <85 and the number of infants with a combined outcome of death or MDI<70 and death or PDI<70. No differences were found between results for GMFCS and CDI. The risk factors for MDI<70 or PDI<70 were intracranial haemorrhage, bronchopulmonary dysplasia, periventricular leukomalacia, necrotising enterocolitis and hydrocortisone treatment. CONCLUSIONS: A higher PCO2 target did not influence neurodevelopmental outcomes in mechanically ventilated extremely preterm infants. Adjusting PCO2 targets to optimise short-term outcomes is a safe option. TRIAL REGISTRATION NUMBER: ISRCTN56143743. PMID- 28087727 TI - Bioethics and imagination: towards a narrative bioethics committed to social action and justice. AB - Recently, the involvement of various authors coming from the social sciences and the arts has reinforced the humanistic component of bioethics. Their contributions vary from very theoretical perspectives to rather practical ones. In this paper, Martha Nussbaum's books, The Fragility of Goodness (1986), Love's Knowledge (1990), Cultivating Humanity (1997) and Creating Capabilities (2011) are analysed from the vantage point of narrative bioethics. It is argued that Nussbaum's notions of 'Narrative', 'Imagination' and 'Cultivation' open up the possibility of developing an action-oriented form of narrative bioethics, that is, a bioethics committed to social action and justice. PMID- 28087726 TI - Benefit of Mineralocorticoid Receptor Antagonism in AKI: Role of Vascular Smooth Muscle Rac1. AB - AKI is a frequent complication in hospitalized patients. Unfortunately, there is no effective pharmacologic approach for treating or preventing AKI. In rodents, mineralocorticoid receptor (MR) antagonism prevents AKI induced by ischemia reperfusion (IR). We investigated the specific role of vascular MR in mediating AKI induced by IR. We also assessed the protective effect of MR antagonism in IR induced AKI in the Large White pig, a model of human AKI. In mice, MR deficiency in smooth muscle cells (SMCs) protected against kidney IR injury. MR blockade by the novel nonsteroidal MR antagonist, finerenone, or genetic deletion of MR in SMCs associated with weaker oxidative stress production. Moreover, ischemic kidneys had higher levels of Rac1-GTP, required for NADPH oxidase activation, than sham control kidneys, and genetic deletion of Rac1 in SMCs protected against AKI. Furthermore, genetic deletion of MR in SMCs blunted the production of Rac1 GTP after IR. Pharmacologic inhibition of MR also prevented AKI induced by IR in the Large White pig. Altogether, we show that MR antagonism, or deletion of the MR gene in SMCs, limited the renal injury induced by IR through effects on Rac1 mediated MR signaling. The benefits of MR antagonism in the pig provide a rational basis for future clinical trials assessing the benefits of this approach in patients with IR-mediated AKI. PMID- 28087728 TI - Inside an Angel's mind. PMID- 28087729 TI - Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and PH domain and leucine-rich repeat phosphatase cross-talk (PHLPP) in cancer cells and in transforming growth factor beta-activated stem cells. PMID- 28087730 TI - A novel role of chromodomain protein CBX8 in DNA damage response. PMID- 28087731 TI - Increased NBCn1 expression, Na+/HCO3- co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension. AB - Genome-wide association studies have revealed an association between variation at the SLC4A7 locus and blood pressure. SLC4A7 encodes the electroneutral Na+/HCO3- co-transporter NBCn1 which regulates intracellular pH (pHi). We conducted a functional study of variants at this locus in primary cultures of vascular smooth muscle and endothelial cells. In both cell types, we found genotype-dependent differences for rs13082711 in DNA-nuclear protein interactions, where the risk allele is associated with increased SLC4A7 expression level, NBCn1 availability and function as reflected in elevated steady-state pHi and accelerated recovery from intracellular acidosis. However, in the presence of Na+/H+ exchange activity, the SLC4A7 genotypic effect on net base uptake and steady-state pHi persisted only in vascular smooth muscle cells but not endothelial cells. We found no discernable effect of the missense polymorphism resulting in the amino acid substitution Glu326Lys. The finding of a genotypic influence on SLC4A7 expression and pHi regulation in vascular smooth muscle cells provides an insight into the molecular mechanism underlying the association of variation at the SLC4A7 locus with blood pressure. PMID- 28087732 TI - Novel GNB1 mutations disrupt assembly and function of G protein heterotrimers and cause global developmental delay in humans. AB - Global developmental delay (GDD), often accompanied by intellectual disability, seizures and other features is a severe, clinically and genetically highly heterogeneous childhood-onset disorder. In cases where genetic causes have been identified, de novo mutations in neuronally expressed genes are a common scenario. These mutations can be best identified by exome sequencing of parent offspring trios. De novo mutations in the guanine nucleotide-binding protein, beta 1 (GNB1) gene, encoding the Gbeta1 subunit of heterotrimeric G proteins, have recently been identified as a novel genetic cause of GDD. Using exome sequencing, we identified 14 different novel variants (2 splice site, 2 frameshift and 10 missense changes) in GNB1 in 16 pediatric patients. One mutation (R96L) was recurrently found in three ethnically diverse families with an autosomal dominant mode of inheritance. Ten variants occurred de novo in the patients. Missense changes were functionally tested for their pathogenicity by assaying the impact on complex formation with Ggamma and resultant mutant Gbetagamma with Galpha. Signaling properties of G protein complexes carrying mutant Gbeta1 subunits were further analyzed by their ability to couple to dopamine D1R receptors by real-time bioluminescence resonance energy transfer (BRET) assays. These studies revealed altered functionality of the missense mutations R52G, G64V, A92T, P94S, P96L, A106T and D118G but not for L30F, H91R and K337Q. In conclusion, we demonstrate a pathogenic role of de novo and autosomal dominant mutations in GNB1 as a cause of GDD and provide insights how perturbation in heterotrimeric G protein function contributes to the disease. PMID- 28087733 TI - Metformin restores the mitochondrial network and reverses mitochondrial dysfunction in Down syndrome cells. AB - Alterations in mitochondrial activity and morphology have been demonstrated in human cells and tissues from individuals with Down syndrome (DS), as well as in DS mouse models. An impaired activity of the transcriptional coactivator PGC 1alpha/PPARGC1A due to the overexpression of chromosome 21 genes, such as NRIP1/RIP140, has emerged as an underlying cause of mitochondrial dysfunction in DS. We tested the hypothesis that the activation of the PGC-1alpha pathway might indeed reverse this mitochondrial dysfunction. To this end, we investigated the effects of metformin, a PGC-1alpha-activating drug, on mitochondrial morphology and function in DS foetal fibroblasts. Metformin induced both the expression of PGC-1alpha and an augmentation of its activity, as demonstrated by the increased expression of target genes, strongly promoting mitochondrial biogenesis. Furthermore, metformin enhanced oxygen consumption, ATP production, and overall mitochondrial activity. Most interestingly, this treatment reversed the fragmentation of mitochondria observed in DS and induced the formation of a mitochondrial network with a branched and elongated tubular morphology. Concomitantly, cristae remodelling occurred and the alterations observed by electron microscopy were significantly reduced. We finally demonstrated that the expression of genes of the fission/fusion machinery, namely OPA1 and MFN2, was reduced in trisomic cells and increased by metformin treatment. These results indicate that metformin promotes the formation of a mitochondrial network and corrects the mitochondrial dysfunction in DS cells. We speculate that alterations in the mitochondrial dynamics can be relevant in the pathogenesis of DS and that metformin can efficiently counteract these alterations, thus exerting protective effects against DS-associated pathologies. PMID- 28087735 TI - Relationships linking emotional, motor, cognitive and GABAergic dysfunctions in dystrophin-deficient mdx mice. AB - Alterations in the Duchenne muscular dystrophy (DMD) gene have been associated with enhanced stress reactivity in vertebrate species, suggesting a role for brain dystrophin in fear-related behavioral and cognitive processes. Because the loss of dystrophin (Dp427) reduces clustering of central gamma-aminobutyric acid (GABAA) receptors, it is suspected that local inhibitory tuning and modulation of neuronal excitability are perturbed in a distributed brain circuit that normally controls such critical behavioral functions. In this study, we undertook a large scale behavioral study to evaluate fear-related behavioral disturbances in dystrophin-deficient mdx mice. We first characterized the behavioral determinants of the enhanced fearfulness displayed by mdx mice following mild acute stress and its association with increased anxiety and altered fear memories. We further demonstrated that this enhanced fearfulness induces long-lasting motor inhibition, suggesting that neurobehavioral dysfunctions significantly influence motor outcome measures in this model. We also found that mdx mice are more sensitive to the sedative and hypnotic effects of 4,5,6,7-tetrahydroisoxazolo[5,4 c]pyridin-3-ol hydrochlorid (THIP), a selective pharmacological activator of extrasynaptic GABAA receptors involved in central tonic inhibition. Our results highlight that information on the emotional aspects of mdx mice are important to better understand the bases of intellectual and neuropsychiatric defects in DMD and to better define valuable functional readouts for preclinical studies. Our data also support the hypothesis that altered spatial localization of GABAA receptors due to Dp427 loss is a pathological mechanism associated with brain dysfunction in DMD, suggesting that extrasynaptic GABAA receptors might be candidate targets for future therapeutic developments. PMID- 28087734 TI - Increased mitophagy in the skeletal muscle of spinal and bulbar muscular atrophy patients. AB - Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by polyglutamine expansion in the androgen receptor (AR) and characterized by the loss of lower motor neurons. Here we investigated pathological processes occurring in muscle biopsy specimens derived from SBMA patients and, as controls, age-matched healthy subjects and patients suffering from amyotrophic lateral sclerosis (ALS) and neurogenic atrophy. We detected atrophic fibers in the muscle of SBMA, ALS and neurogenic atrophy patients. In addition, SBMA muscle was characterized by the presence of a large number of hypertrophic fibers, with oxidative fibers having a larger size compared with glycolytic fibers. Polyglutamine-expanded AR expression was decreased in whole muscle, yet enriched in the nucleus, and localized to mitochondria. Ultrastructural analysis revealed myofibrillar disorganization and streaming in zones lacking mitochondria and degenerating mitochondria. Using molecular (mtDNA copy number), biochemical (citrate synthase and respiratory chain enzymes) and morphological (dark blue area in nicotinamide adenine dinucleotide-stained muscle cross-sections) analyses, we found a depletion of the mitochondria associated with enhanced mitophagy. Mass spectrometry analysis revealed an increase of phosphatidylethanolamines and phosphatidylserines in mitochondria isolated from SBMA muscles, as well as a 50% depletion of cardiolipin associated with decreased expression of the cardiolipin synthase gene. These observations suggest a causative link between nuclear polyglutamine-expanded AR accumulation, depletion of mitochondrial mass, increased mitophagy and altered mitochondrial membrane composition in SBMA muscle patients. Given the central role of mitochondria in cell bioenergetics, therapeutic approaches toward improving the mitochondrial network are worth considering to support SBMA patients. PMID- 28087737 TI - A homozygous mutation in TRIM36 causes autosomal recessive anencephaly in an Indian family. AB - Anencephaly (APH) is characterized by the absence of brain tissues and cranium. During primary neurulation stage of the embryo, the rostral part of the neural pore fails to close, leading to APH. APH shows a heterogeneous etiology, ranging from environmental to genetic causes. The autosomal recessive inheritance of APH has been reported in several populations. In this study, we employed whole-exome sequencing and identified a homozygous missense mutation c.1522C > A (p.Pro508Thr) in the TRIM36 gene as the cause of autosomal recessive APH in an Indian family. The TRIM36 gene is expressed in the developing brain, suggesting a role in neurogenesis. In silico analysis showed that proline at codon position 508 is highly conserved in 26 vertebrate species, and the mutation is predicted to affect the conformation of the B30.2/SPRY domain of TRIM36. Both in vitro and in vivo results showed that the mutation renders the TRIM36 protein less stable. TRIM36 is known to associate with microtubules. Transient expression of the mutant TRIM36 in HeLa and LN229 cells resulted in microtubule disruption, disorganized spindles, loosely arranged chromosomes, multiple spindles, abnormal cytokinesis, reduced cell proliferation and increased apoptosis as compared with cells transfected with its wild-type counterpart. The siRNA knock down of TRIM36 in HeLa and LN229 cells also led to reduced cell proliferation and increased apoptosis. We suggest that microtubule disruption and disorganized spindles mediated by mutant TRIM36 affect neural cell proliferation during neural tube formation, leading to APH. PMID- 28087738 TI - Newer vape pens still trigger urge to smoke, study finds. PMID- 28087736 TI - Imputation of orofacial clefting data identifies novel risk loci and sheds light on the genetic background of cleft lip +/- cleft palate and cleft palate only. AB - Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is among the most common human birth defects with multifactorial etiology. Here, we present results from a genome-wide imputation study of nsCL/P in which, after adding replication cohort data, four novel risk loci for nsCL/P are identified (at chromosomal regions 2p21, 14q22, 15q24 and 19p13). On a systematic level, we show that the association signals within this high-density dataset are enriched in functionally relevant genomic regions that are active in both human neural crest cells (hNCC) and mouse embryonic craniofacial tissue. This enrichment is also detectable in hNCC regions primed for later activity. Using GCTA analyses, we suggest that 30% of the estimated variance in risk for nsCL/P in the European population can be attributed to common variants, with 25.5% contributed to by the 24 risk loci known to date. For each of these, we identify credible SNPs using a Bayesian refinement approach, with two loci harbouring only one probable causal variant. Finally, we demonstrate that there is no polygenic component of nsCL/P detectable that is shared with nonsyndromic cleft palate only (nsCPO). Our data suggest that, while common variants are strongly contributing to risk for nsCL/P, they do not seem to be involved in nsCPO which might be more often caused by rare deleterious variants. Our study generates novel insights into both nsCL/P and nsCPO etiology and provides a systematic framework for research into craniofacial development and malformation. PMID- 28087739 TI - TNF Signaling through RIP1 Kinase Enhances SN38-Induced Death in Colon Adenocarcinoma. AB - Elucidation of TNF-directed mechanisms for cell death induction and maintenance of tumor growth has revealed a role for receptor-interacting protein kinases 1 and 3 (RIPK1/RIP1 and RIPK3/RIP3), components of the necrosome complex, as determinants of cell fate. Here, the participation of TNF signaling was analyzed with regard to the cytotoxic action of different DNA-damaging agents in a panel of colon cancer cells. While most of these cell lines were insensitive to TNF, combination with these drugs increased sensitivity by inducing cell death and DNA damage, especially in the case of the topoisomerase inhibitor SN38. Changes in levels of RIP1 and RIP3 occurred following monotherapy with SN38 or in combination with TNF. Downregulation of RIP1 resulted in increased resistance to SN38, implying a requirement for RIP1 in mediating cytotoxicity through the TNF/TNFR signaling pathway. Downregulation of RIP1 in a xenograft model impaired tumor growth inhibition from SN38 treatment, suggesting the potential of RIP1 to determine the clinical outcome of irinotecan treatment. These results indicate that TNF plays a key role in determining the cytotoxic effectiveness of SN38 in colorectal cancer and suggests a re-evaluation of TNF-based interventions to enhance therapeutic efficacy.Implications: The capacity of RIP1 to influence drug sensitivity suggests RIP1 may have biomarker potential. Mol Cancer Res; 15(4); 395-404. (c)2017 AACR. PMID- 28087743 TI - Updates on prevention: obesity, ezetimibe, PCSK9, and HIV infection. PMID- 28087740 TI - Bone Microenvironment Changes in Latexin Expression Promote Chemoresistance. AB - Although docetaxel is the standard of care for advanced prostate cancer, most patients develop resistance to docetaxel. Therefore, elucidating the mechanism that underlies resistance to docetaxel is critical to enhance therapeutic intervention. Mining cDNA microarray from the PC-3 prostate cancer cell line and its docetaxel-resistant derivative (PC3-TxR) revealed decreased latexin (LXN) expression in the resistant cells. LXN expression was inversely correlated with taxane resistance in a panel of prostate cancer cell lines. LXN knockdown conferred docetaxel resistance to prostate cancer cells in vitro and in vivo, whereas LXN overexpression reduced docetaxel resistance in several prostate cancer cell lines. A mouse model of prostate cancer demonstrated that prostate cancer cells developed resistance to docetaxel in the bone microenvironment, but not the soft tissue microenvironment. This was associated with decreased LXN expression in prostate cancer cells in the bone microenvironment compared with the soft tissue microenvironment. It was identified that bone stromal cells decreased LXN expression through methylation and induced chemoresistance in prostate cancer in vitro These findings reveal that a subset of prostate cancer develops docetaxel resistance through loss of LXN expression associated with methylation and that the bone microenvironment promotes this drug resistance phenotype.Implications: This study suggests that the LXN pathway should be further explored as a viable target for preventing or reversing taxane resistance in prostate cancer. Mol Cancer Res; 15(4); 457-66. (c)2017 AACR. PMID- 28087742 TI - Heartbeat: Warfarin therapy for mechanical heart valves. PMID- 28087744 TI - Quality indicators for acute myocardial infarction. PMID- 28087741 TI - 14-3-3sigma Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2. AB - 14-3-3sigma has been implicated in the development of chemo and radiation resistance and in poor prognosis of multiple human cancers. While it has been postulated that 14-3-3sigma contributes to these resistances via inhibiting apoptosis and arresting cells in G2-M phase of the cell cycle, the molecular basis of this regulation is currently unknown. In this study, we tested the hypothesis that 14-3-3sigma causes resistance to DNA-damaging treatments by enhancing DNA repair in cells arrested in G2-M phase following DNA-damaging treatments. We showed that 14-3-3sigma contributed to ionizing radiation (IR) resistance by arresting cancer cells in G2-M phase following IR and by increasing non-homologous end joining (NHEJ) repair of the IR-induced DNA double strand breaks (DSB). The increased NHEJ repair activity was due to 14-3-3sigma-mediated upregulation of PARP1 expression that promoted the recruitment of DNA-PKcs to the DNA damage sites for repair of DSBs. On the other hand, the increased G2-M arrest following IR was due to 14-3-3sigma-induced Chk2 expression.Implications: These findings reveal an important molecular basis of 14-3-3sigma function in cancer cell resistance to chemo/radiation therapy and in poor prognosis of human cancers. Mol Cancer Res; 15(4); 418-28. (c)2017 AACR. PMID- 28087745 TI - The ESC Heart Failure Association postgraduate course in heart failure. PMID- 28087746 TI - Two weeks at Harvard, for two European heart failure trainees. PMID- 28087747 TI - Zurich International Symposium on Arrhythmogenic Right Ventricular Cardiomyopathies. PMID- 28087748 TI - Cardiologists of Tomorrow, Austria. PMID- 28087750 TI - Christmas greetings 2016 from the European Heart Journal. PMID- 28087749 TI - Ron T van Domburg PhD retirement. PMID- 28087751 TI - ODYSSEY ESCAPE: is PCSK9 inhibition the Trojan Horse for the use of lipoprotein apheresis in familial hypercholesterolaemia? PMID- 28087752 TI - Deficient retinoid-driven angiogenesis may contribute to failure of adult human lung regeneration in emphysema. AB - BACKGROUND: Molecular pathways that regulate alveolar development and adult repair represent potential therapeutic targets for emphysema. Signalling via retinoic acid (RA), derived from vitamin A, is required for mammalian alveologenesis, and exogenous RA can induce alveolar regeneration in rodents. Little is known about RA signalling in the human lung and its potential role in lung disease. OBJECTIVES: To examine regulation of human alveolar epithelial and endothelial repair by RA, and characterise RA signalling in human emphysema. METHODS: The role of RA signalling in alveolar epithelial repair was investigated with a scratch assay using an alveolar cell line (A549) and primary human alveolar type 2 (AT2) cells from resected lung, and the role in angiogenesis using a tube formation assay with human lung microvascular endothelial cells (HLMVEC). Localisation of RA synthetic (RALDH-1) and degrading (cytochrome P450 subfamily 26 A1 (CYP26A1)) enzymes in human lung was determined by immunofluorescence. Regulation of RA pathway components was investigated in emphysematous and control human lung tissue by quantitative real-time PCR and Western analysis. RESULTS: RA stimulated HLMVEC angiogenesis in vitro; this was partially reproduced with a RAR-alpha agonist. RA induced mRNA expression of vascular endothelial growth factor A (VEGFA) and VEGFR2. RA did not modulate AT2 repair. CYP26A1 protein was identified in human lung microvasculature, whereas RALDH-1 partially co-localised with vimentin-positive fibroblasts. CYP26A1 mRNA and protein were increased in emphysema. CONCLUSIONS: RA regulates lung microvascular angiogenesis; the endothelium produces CYP26A1 which is increased in emphysema, possibly leading to reduced RA availability. These data highlight a role for RA in maintenance of the human pulmonary microvascular endothelium. PMID- 28087753 TI - Acquired central hypoventilation following Listeria monocytogenes rhombencephalitis. PMID- 28087754 TI - Sore throat test and treat - a L34 million question? PMID- 28087755 TI - ?Pitolisant for narcolepsy. AB - ?Pitolisant (Wakix-Bioprojet Pharma) is a new treatment for adults with narcolepsy with or without cataplexy. It was licensed for use in the EU in March last year and has orphan drug status.1 Here, we consider the evidence for pitolisant for the treatment of narcolepsy in adults and how it fits with current management strategies. PMID- 28087756 TI - Fine-mapping of genes determining extrafusal fiber properties in murine soleus muscle. AB - Muscle fiber cross-sectional area (CSA) and proportion of different fiber types are important determinants of muscle function and overall metabolism. Genetic variation plays a substantial role in phenotypic variation of these traits; however, the underlying genes remain poorly understood. This study aimed to map quantitative trait loci (QTL) affecting differences in soleus muscle fiber traits between the LG/J and SM/J mouse strains. Fiber number, CSA, and proportion of oxidative type I fibers were assessed in the soleus of 334 genotyped female and male mice of the F34 generation of advanced intercross lines (AIL) derived from the LG/J and SM/J strains. To increase the QTL detection power, these data were combined with 94 soleus samples from the F2 intercross of the same strains. Transcriptome of the soleus muscle of LG/J and SM/J females was analyzed by microarray. Genome-wide association analysis mapped four QTL (genome-wide P < 0.05) affecting the properties of muscle fibers to chromosome 2, 3, 4, and 11. A 1.5-LOD QTL support interval ranged between 2.36 and 4.67 Mb. On the basis of the genomic sequence information and functional and transcriptome data, we identified candidate genes for each of these QTL. The combination of analyses in F2 and F34 AIL populations with transcriptome and genomic sequence data in the parental strains is an effective strategy for refining QTL and nomination of the candidate genes. PMID- 28087758 TI - Method for the Determination of Carbonyl Compounds in E-Cigarette Aerosols. AB - Low levels of thermal degradation products such as carbonyls (formaldehyde, acetaldehyde, acrolein, crotonaldehyde) have been reported in e-cigarette aerosols. The collection and analysis of e-cigarette aerosol carbonyls are often adapted from methods developed for tobacco cigarette smoke. These methodologies are often not sensitive enough to detect low carbonyl levels in e-cigarette aerosols. One objective of this work was to develop and validate a rapid, selective and sensitive ultra-performance liquid chromatography with mass spectrometry method optimized for analysis of carbonyls in e-cigarette aerosols. Aerosols were trapped in 20-puff collections, 4-s durations, 55-mL volumes, 30-s intervals, square wave puff profiles. Collection apparatus involved a linear smoking machine with Cambridge filter pad followed by a glass impinger containing acidified 2,4-dinitrophenylhydrazine. This method showed limits of quantitation and detection of 0.016 and 0.003 ug puff-1, respectively, and run time of 4 min. Six e-cigarettes were evaluated (five devices each). All contained measurable levels of carbonyls. Levels were mostly well below those in conventional cigarettes. However, for some e-cigarettes, formaldehyde levels were above those for tobacco cigarettes (highest at 14.1 ug puff-1). Temperatures related to carbonyl yields in e-cigarette aerosols were explored to better understand carbonyl formation: formation of formaldehyde is low at temperatures below 350 degrees C. PMID- 28087759 TI - Separation of Vitamin E on a 100-A Phenogel Column. AB - The effect of pi-electrons and hydroxyl group on the separations of vitamin E on a swelling-controlled polystyrene-divinylbenzene (Phenogel) column using toluene/isooctane as the mobile phase was investigated. The effect of the pi electrons was demonstrated in the baseline separation of alpha-tocopherol and alpha-tocotrienol on a 100-A Phenogel column. In addition, baseline separation of alpha-, (beta- + gamma-)- and delta-tocopherol could be achieved on this column. The separation mechanism of these isomers are due to the difference in the interactions between the hydroxyl group on the chromanol ring of each tocopherol and the gel matrix caused by the steric hindrance of methyl group(s). It was concluded that solutes of the same molecular size but different in the polar groups could be separated on a high performance size-exclusion chromatography by controlling the swelling of the gel matrix via modification of the mobile phase. PMID- 28087757 TI - Alternative transcription of sodium/bicarbonate transporter SLC4A7 gene enhanced by single nucleotide polymorphisms. AB - Genome-wide association studies have identified the single nucleotide polymorphism (SNP) rs3278 in the human SLC4A7 gene as one of the marker loci for addiction vulnerability. This marker is located in an intron of the gene, and its genomic role has been unknown. In this study, we examined rs3278 and three adjacent SNPs prevalent in alcoholics for their effects on an alternative promoter that would lead to the production of the NH2-terminally truncated protein NBCn1DeltaN450, missing the first 450 amino acids. Analysis of the transcription start site database and a promoter prediction algorithm identified a cluster of three promoters in intron 7 and two short CpG-rich sites in intron 6. The promoter closest to rs3278 showed strong transcription activity in luciferase reporter gene assays. Major-to-minor allele substitution at rs3278 resulted in increased transcription activity. Equivalent substitutions at adjacent rs3772723 (intron 7) and rs13077400 (exon 8) had negligible effect; however, the substitution at nonsynonymous rs3755652 (exon 8) increased the activity by more than twofold. The concomitant substitution at rs3278/rs3755652 produced an additive effect. The rs3755652 had more profound effects on the promoter than the upstream regulatory CpG sites. The amino acid change E326K caused by rs3755652 had negligible effect on transporter function. In HEK 293 cells, NBCn1DeltaN450 was expressed in plasma membranes, but at significantly lower levels than the nontruncated NBCn1-E. The pH change mediated by NBCn1DeltaN450 was also low. We conclude that rs3278 and rs3755652 stimulate an alternative transcription of the SLC4A7 gene, increasing the production of a defective transporter. PMID- 28087760 TI - Molecularly Imprinted Solid Phase Extraction using Bismethacryloyl-beta cyclodextrin and Methacrylic Acid as Double Functional Monomers for Selective Analysis of Glycyrrhizic Acid in Aqueous Media. AB - In this work, a new molecularly imprinted solid phase extraction protocol was developed for the selective extraction and purification of glycyrrhizic acid from liquorice roots in aqueous media. The molecularly imprinted polymers (MIPs) for glycyrrhizic acid were prepared by using bismethacryloyl-beta-cyclodextrin and methacrylic acid as double functional monomers and characterized by Fourier transform infrared spectroscopy, scanning electron microscope, thermo gravimetric analysis, nitrogen adsorption and elemental analysis. In aqueous media, the adsorption properties of MIPs including adsorption kinetics, adsorption isotherms and selectivity adsorption were investigated. The characterization of imprinted polymers indicated that the prepared MIPs had good stability and many cavity structures. The results of adsorption experiments illustrated the MIPs had high adsorption capacity of glycyrrhizic acid (69.3 mg g-1) with the imprinting factor 3.77, and it took ~5 min to get adsorption equilibrium. The MIPs could be used as an solid phase extraction sorbent absorbent for enrichment and purification of glycyrrhizic acid from the crude extraction of licorice roots, and the results showed promising practical value. PMID- 28087761 TI - Proteomics: Technologies and Their Applications. AB - Proteomics involves the applications of technologies for the identification and quantification of overall proteins present content of a cell, tissue or an organism. It supplements the other "omics" technologies such as genomic and transcriptomics to expound the identity of proteins of an organism, and to cognize the structure and functions of a particular protein. Proteomics-based technologies are utilized in various capacities for different research settings such as detection of various diagnostic markers, candidates for vaccine production, understanding pathogenicity mechanisms, alteration of expression patterns in response to different signals and interpretation of functional protein pathways in different diseases. Proteomics is practically intricate because it includes the analysis and categorization of overall protein signatures of a genome. Mass spectrometry with LC-MS-MS and MALDI-TOF/TOF being widely used equipment is the central among current proteomics. However, utilization of proteomics facilities including the software for equipment, databases and the requirement of skilled personnel substantially increase the costs, therefore limit their wider use especially in the developing world. Furthermore, the proteome is highly dynamic because of complex regulatory systems that control the expression levels of proteins. This review efforts to describe the various proteomics approaches, the recent developments and their application in research and analysis. PMID- 28087762 TI - A Delay between Motor Cortex Lesions and Neuronal Transplantation Enhances Graft Integration and Improves Repair and Recovery. AB - We previously reported that embryonic motor cortical neurons transplanted immediately after lesions in the adult mouse motor cortex restored damaged motor cortical pathways. A critical barrier hindering the application of transplantation strategies for a wide range of traumatic injuries is the determination of a suitable time window for therapeutic intervention. Here, we report that a 1 week delay between the lesion and transplantation significantly enhances graft vascularization, survival, and proliferation of grafted cells. More importantly, the delay dramatically increases the density of projections developed by grafted neurons and improves functional repair and recovery as assessed by intravital dynamic imaging and behavioral tests. These findings open new avenues in cell transplantation strategies as they indicate successful brain repair may occur following delayed transplantation.SIGNIFICANCE STATEMENT Cell transplantation represents a promising therapy for cortical trauma. We previously reported that embryonic motor cortical neurons transplanted immediately after lesions in the adult mouse motor cortex restored damaged cortical pathways. A critical barrier hindering the application of transplantation strategies for a wide range of traumatic injuries is the determination of a suitable time window for therapeutic intervention. We demonstrate that a 1 week delay between the lesion and transplantation significantly enhances graft vascularization, survival, proliferation, and the density of the projections developed by grafted neurons. More importantly, the delay has a beneficial impact on functional repair and recovery. These results impact the effectiveness of transplantation strategies in a wide range of traumatic injuries for which therapeutic intervention is not immediately feasible. PMID- 28087763 TI - Circadian Kinetics of Cell Cycle Progression in Adult Neurogenic Niches of a Diurnal Vertebrate. AB - The circadian system may regulate adult neurogenesis via intracellular molecular clock mechanisms or by modifying the environment of neurogenic niches, with daily variation in growth factors or nutrients depending on the animal's diurnal or nocturnal lifestyle. In a diurnal vertebrate, zebrafish, we studied circadian distribution of immunohistochemical markers of the cell division cycle (CDC) in 5 of the 16 neurogenic niches of adult brain, the dorsal telencephalon, habenula, preoptic area, hypothalamus, and cerebellum. We find that common to all niches is the morning initiation of G1/S transition and daytime S-phase progression, overnight increase in G2/M, and cycle completion by late night. This is supported by the timing of gene expression for critical cell cycle regulators cyclins D, A2, and B2 and cyclin-dependent kinase inhibitor p20 in brain tissue. The early night peak in p20, limiting G1/S transition, and its phase angle with the expression of core clock genes, Clock1 and Per1, are preserved in constant darkness, suggesting intrinsic circadian patterns of cell cycle progression. The statistical modeling of CDC kinetics reveals the significant circadian variation in cell proliferation rates across all of the examined niches, but interniche differences in the magnitude of circadian variation in CDC, S-phase length, phase angle of entrainment to light or clock, and its dispersion. We conclude that, in neurogenic niches of an adult diurnal vertebrate, the circadian modulation of cell cycle progression involves both systemic and niche-specific factors.SIGNIFICANCE STATEMENT This study establishes that in neurogenic niches of an adult diurnal vertebrate, the cell cycle progression displays a robust circadian pattern. Common to neurogenic niches located in diverse brain regions is daytime progression of DNA replication and nighttime mitosis, suggesting systemic regulation. Differences between neurogenic niches in the phase and degree of S-phase entrainment to the clock suggest additional roles for niche specific regulatory mechanisms. Understanding the circadian regulation of adult neurogenesis can help optimize the timing of therapeutic approaches in patients with brain traumas or neurodegenerative disorders and preserve neural stem cells during cytostatic cancer therapies. PMID- 28087764 TI - Accumulation of Polyribosomes in Dendritic Spine Heads, But Not Bases and Necks, during Memory Consolidation Depends on Cap-Dependent Translation Initiation. AB - Translation in dendrites is believed to support synaptic changes during memory consolidation. Although translational control mechanisms are fundamental mediators of memory, little is known about their role in local translation. We previously found that polyribosomes accumulate in dendritic spines of the adult rat lateral amygdala (LA) during consolidation of aversive pavlovian conditioning and that this memory requires cap-dependent initiation, a primary point of translational control in eukaryotic cells. Here we used serial electron microscopy reconstructions to quantify polyribosomes in LA dendrites when consolidation was blocked by the cap-dependent initiation inhibitor 4EGI-1. We found that 4EGI-1 depleted polyribosomes in dendritic shafts and selectively prevented their upregulation in spine heads, but not bases and necks, during consolidation. Cap-independent upregulation was specific to spines with small, astrocyte-associated synapses. Our results reveal that cap-dependent initiation is involved in local translation during learning and that local translational control varies with synapse type.SIGNIFICANCE STATEMENT Translation initiation is a central regulator of long-term memory formation. Local translation in dendrites supports memory by providing necessary proteins at synaptic sites, but it is unknown whether this requires initiation or bypasses it. We used serial electron microscopy reconstructions to examine polyribosomes in dendrites when memory formation was blocked by an inhibitor of translation initiation. This revealed two major pools of polyribosomes that were upregulated during memory formation: one pool in dendritic spine heads that was initiation dependent and another pool in the bases and necks of small spines that was initiation independent. Thus, translation regulation differs between spine types and locations, and translation that occurs closest to individual synapses during memory formation is initiation dependent. PMID- 28087765 TI - Synapsin II Regulation of GABAergic Synaptic Transmission Is Dependent on Interneuron Subtype. AB - Synapsins are epilepsy susceptibility genes that encode phosphoproteins reversibly associated with synaptic vesicles. Synapsin II (SynII) gene deletion produces a deficit in inhibitory synaptic transmission, and this defect is thought to cause epileptic activity. We systematically investigated how SynII affects synchronous and asynchronous release components of inhibitory transmission in the CA1 region of the mouse hippocampus. We found that the asynchronous GABAergic release component is diminished in SynII-deleted (SynII( )) slices. To investigate this defect at different interneuron subtypes, we selectively blocked either N-type or P/Q-type Ca2+ channels. SynII deletion suppressed the asynchronous release component at synapses dependent on N-type Ca2+ channels but not at synapses dependent on P/Q-type Ca2+ channels. We then performed paired double-patch recordings from inhibitory basket interneurons connected to pyramidal neurons and used cluster analysis to classify interneurons according to their spiking and synaptic parameters. We identified two cell subtypes, presumably parvalbumin (PV) and cholecystokinin (CCK) expressing basket interneurons. To validate our interneuron classification, we took advantage of transgenic animals with fluorescently labeled PV interneurons and confirmed that their spiking and synaptic parameters matched the parameters of presumed PV cells identified by the cluster analysis. The analysis of the release time course at the two interneuron subtypes demonstrated that the asynchronous release component was selectively reduced at SynII(-) CCK interneurons. In contrast, the transmission was desynchronized at SynII(-) PV interneurons. Together, our results demonstrate that SynII regulates the time course of GABAergic release, and that this SynII function is dependent on the interneuron subtype.SIGNIFICANCE STATEMENT Deletion of the neuronal protein synapsin II (SynII) leads to the development of epilepsy, probably due to impairments in inhibitory synaptic transmission. We systematically investigated SynII function at different subtypes of inhibitory neurons in the hippocampus. We discovered that SynII affects the time course of GABA release, and that this effect is interneuron subtype specific. Within one of the subtypes, SynII deficiency synchronizes the release and suppresses the asynchronous release component, while at the other subtype SynII deficiency suppresses the synchronous release component. These results reveal a new SynII function in the regulation of the time course of GABA release and demonstrate that this function is dependent on the interneuron subtype. PMID- 28087767 TI - Trial-by-Trial Motor Cortical Correlates of a Rapidly Adapting Visuomotor Internal Model. AB - Accurate motor control is mediated by internal models of how neural activity generates movement. We examined neural correlates of an adapting internal model of visuomotor gain in motor cortex while two macaques performed a reaching task in which the gain scaling between the hand and a presented cursor was varied. Previous studies of cortical changes during visuomotor adaptation focused on preparatory and perimovement epochs and analyzed trial-averaged neural data. Here, we recorded simultaneous neural population activity using multielectrode arrays and focused our analysis on neural differences in the period before the target appeared. We found that we could estimate the monkey's internal model of the gain using the neural population state during this pretarget epoch. This neural correlate depended on the gain experienced during recent trials and it predicted the speed of the subsequent reach. To explore the utility of this internal model estimate for brain-machine interfaces, we performed an offline analysis showing that it can be used to compensate for upcoming reach extent errors. Together, these results demonstrate that pretarget neural activity in motor cortex reflects the monkey's internal model of visuomotor gain on single trials and can potentially be used to improve neural prostheses.SIGNIFICANCE STATEMENT When generating movement commands, the brain is believed to use internal models of the relationship between neural activity and the body's movement. Visuomotor adaptation tasks have revealed neural correlates of these computations in multiple brain areas during movement preparation and execution. Here, we describe motor cortical changes in a visuomotor gain change task even before a specific movement is cued. We were able to estimate the gain internal model from these pretarget neural correlates and relate it to single-trial behavior. This is an important step toward understanding the sensorimotor system's algorithms for updating its internal models after specific movements and errors. Furthermore, the ability to estimate the internal model before movement could improve motor neural prostheses being developed for people with paralysis. PMID- 28087766 TI - Control of Amygdala Circuits by 5-HT Neurons via 5-HT and Glutamate Cotransmission. AB - The serotonin (5-HT) system and the amygdala are key regulators of emotional behavior. Several lines of evidence suggest that 5-HT transmission in the amygdala is implicated in the susceptibility and drug treatment of mood disorders. Therefore, elucidating the physiological mechanisms through which midbrain 5-HT neurons modulate amygdala circuits could be pivotal in understanding emotional regulation in health and disease. To shed light on these mechanisms, we performed patch-clamp recordings from basal amygdala (BA) neurons in brain slices from mice with channelrhodopsin genetically targeted to 5-HT neurons. Optical stimulation of 5-HT terminals at low frequencies (<=1 Hz) evoked a short-latency excitation of BA interneurons (INs) that was depressed at higher frequencies. Pharmacological analysis revealed that this effect was mediated by glutamate and not 5-HT because it was abolished by ionotropic glutamate receptor antagonists. Optical stimulation of 5-HT terminals at higher frequencies (10-20 Hz) evoked both slow excitation and slow inhibition of INs. These effects were mediated by 5-HT because they were blocked by antagonists of 5-HT2A and 5-HT1A receptors, respectively. These fast glutamate- and slow 5-HT-mediated responses often coexisted in the same neuron. Interestingly, fast-spiking and non-fast spiking INs displayed differential modulation by glutamate and 5-HT. Furthermore, optical stimulation of 5-HT terminals did not evoke glutamate release onto BA principal neurons, but inhibited these cells directly via activation of 5-HT1A receptors and indirectly via enhanced GABA release. Collectively, these findings suggest that 5-HT neurons exert a frequency-dependent, cell-type-specific control over BA circuitry via 5-HT and glutamate co-release to inhibit the BA output.SIGNIFICANCE STATEMENT The modulation of the amygdala by serotonin (5-HT) is important for emotional regulation and is implicated in the pathogenesis and treatment of affective disorders. Therefore, it is essential to determine the physiological mechanisms through which 5-HT neurons in the dorsal raphe nuclei modulate amygdala circuits. Here, we combined optogenetic, electrophysiological, and pharmacological approaches to study the effects of activation of 5-HT axons in the basal nucleus of the amygdala (BA). We found that 5-HT neurons co-release 5-HT and glutamate onto BA neurons in a cell-type-specific and frequency dependent manner. Therefore, we suggest that theories on the contribution of 5-HT neurons to amygdala function should be revised to incorporate the concept of 5 HT/glutamate cotransmission. PMID- 28087771 TI - Genome-Wide Convergence during Evolution of Mangroves from Woody Plants. AB - When living organisms independently invade a new environment, the evolution of similar phenotypic traits is often observed. An interesting but contentious issue is whether the underlying molecular biology also converges in the new habitat. Independent invasions of tropical intertidal zones by woody plants, collectively referred to as mangrove trees, represent some dramatic examples. The high salinity, hypoxia, and other stressors in the new habitat might have affected both genomic features and protein structures. Here, we developed a new method for detecting convergence at conservative Sites (CCS) and applied it to the genomic sequences of mangroves. In simulations, the CCS method drastically reduces random convergence at rapidly evolving sites as well as falsely inferred convergence caused by the misinferences of the ancestral character. In mangrove genomes, we estimated ~400 genes that have experienced convergence over the background level of convergence in the nonmangrove relatives. The convergent genes are enriched in pathways related to stress response and embryo development, which could be important for mangroves' adaptation to the new habitat. PMID- 28087770 TI - Mitochondrial Mutation Rate, Spectrum and Heteroplasmy in Caenorhabditis elegans Spontaneous Mutation Accumulation Lines of Differing Population Size. AB - Mitochondrial genomes of metazoans, given their elevated rates of evolution, have served as pivotal markers for phylogeographic studies and recent phylogenetic events. In order to determine the dynamics of spontaneous mitochondrial mutations in small populations in the absence and presence of selection, we evolved mutation accumulation (MA) lines of Caenorhabditis elegans in parallel over 409 consecutive generations at three varying population sizes of N = 1, 10, and 100 hermaphrodites. The N =1 populations should have a minimal influence of natural selection to provide the spontaneous mutation rate and the expected rate of neutral evolution, whereas larger population sizes should experience increasing intensity of selection. New mutations were identified by Illumina paired-end sequencing of 86 mtDNA genomes across 35 experimental lines and compared with published genomes of natural isolates. The spontaneous mitochondrial mutation rate was estimated at 1.05 * 10-7/site/generation. A strong G/C->A/T mutational bias was observed in both the MA lines and the natural isolates. This suggests that the low G + C content at synonymous sites is the product of mutation bias rather than selection as previously proposed. The mitochondrial effective population size per worm generation was estimated to be 62. Although it was previously concluded that heteroplasmy was rare in C. elegans, the vast majority of mutations in this study were heteroplasmic despite an experimental regime exceeding 400 generations. The frequencies of frameshift and nonsynonymous mutations were negatively correlated with population size, which suggests their deleterious effects on fitness and a potent role for selection in their eradication. PMID- 28087769 TI - Enzyme Efficiency but Not Thermostability Drives Cefotaxime Resistance Evolution in TEM-1 beta-Lactamase. AB - A leading intellectual challenge in evolutionary genetics is to identify the specific phenotypes that drive adaptation. Enzymes offer a particularly promising opportunity to pursue this question, because many enzymes' contributions to organismal fitness depend on a comparatively small number of experimentally accessible properties. Moreover, on first principles the demands of enzyme thermostability stand in opposition to the demands of catalytic activity. This observation, coupled with the fact that enzymes are only marginally thermostable, motivates the widely held hypothesis that mutations conferring functional improvement require compensatory mutations to restore thermostability. Here, we explicitly test this hypothesis for the first time, using four missense mutations in TEM-1 beta-lactamase that jointly increase cefotaxime Minimum Inhibitory Concentration (MIC) ~1500-fold. First, we report enzymatic efficiency (kcat/KM) and thermostability (Tm, and thence DeltaG of folding) for all combinations of these mutations. Next, we fit a quantitative model that predicts MIC as a function of kcat/KM and DeltaG. While kcat/KM explains ~54% of the variance in cefotaxime MIC (~92% after log transformation), DeltaG does not improve explanatory power of the model. We also find that cefotaxime MIC rises more slowly in kcat/KM than predicted. Several explanations for these discrepancies are suggested. Finally, we demonstrate substantial sign epistasis in MIC and kcat/KM, and antagonistic pleiotropy between phenotypes, in spite of near numerical additivity in the system. Thus constraints on selectively accessible trajectories, as well as limitations in our ability to explain such constraints in terms of underlying mechanisms are observed in a comparatively "well-behaved" system. PMID- 28087768 TI - The Rice Paradox: Multiple Origins but Single Domestication in Asian Rice. AB - The origin of domesticated Asian rice (Oryza sativa) has been a contentious topic, with conflicting evidence for either single or multiple domestication of this key crop species. We examined the evolutionary history of domesticated rice by analyzing de novo assembled genomes from domesticated rice and its wild progenitors. Our results indicate multiple origins, where each domesticated rice subpopulation (japonica, indica, and aus) arose separately from progenitor O. rufipogon and/or O. nivara. Coalescence-based modeling of demographic parameters estimate that the first domesticated rice population to split off from O. rufipogon was O. sativa ssp. japonica, occurring at ~13.1-24.1 ka, which is an order of magnitude older then the earliest archeological date of domestication. This date is consistent, however, with the expansion of O. rufipogon populations after the Last Glacial Maximum ~18 ka and archeological evidence for early wild rice management in China. We also show that there is significant gene flow from japonica to both indica (~17%) and aus (~15%), which led to the transfer of domestication alleles from early-domesticated japonica to proto-indica and proto aus populations. Our results provide support for a model in which different rice subspecies had separate origins, but that de novo domestication occurred only once, in O. sativa ssp. japonica, and introgressive hybridization from early japonica to proto-indica and proto-aus led to domesticated indica and aus rice. PMID- 28087772 TI - Possible Roles of New Mutations Shared by Asian and American Zika Viruses. AB - Originating in Africa, the Zika virus (ZIKV) has spread to Asia, Pacific Islands and now to the Americas and beyond. Since the first isolation in 1947, ZIKV strains have been sampled at various times in the last 69 years, but this history has not been reflected in studying the patterns of mutation accumulation in their genomes. Implementing the viral history, we show that the ZIKV ancestor appeared sometime in 1930-1945 and, at that point, its mutation rate was probably less than 0.2 * 10-3/nucleotide site/year and subsequently increased significantly in most of its descendants. Sustaining a high mutation rate of 4 * 10-3/site/year throughout its evolution, the Ancestral Asian strain, which was sampled from a mosquito in Malaysia, accumulated 13 mutations in the 3'-untranslated region of RNA stem-loops prior to 1963, seven of which generate more stable stem-loop structures and are likely to inhibit cellular antiviral activities, including immune and RNA interference (RNAi) pathways. The seven mutations have been maintained in all Asian and American strains and may be responsible for serious medical problems we are facing today and offer testable hypotheses to examine their roles in molecular interactions during brain development. PMID- 28087773 TI - RWTY (R We There Yet): An R Package for Examining Convergence of Bayesian Phylogenetic Analyses. AB - Bayesian inference using Markov chain Monte Carlo (MCMC) has become one of the primary methods used to infer phylogenies from sequence data. Assessing convergence is a crucial component of these analyses, as it establishes the reliability of the posterior distribution estimates of the tree topology and model parameters sampled from the MCMC. Numerous tests and visualizations have been developed for this purpose, but many of the most popular methods are implemented in ways that make them inconvenient to use for large data sets. RWTY is an R package that implements established and new methods for diagnosing phylogenetic MCMC convergence in a single convenient interface. PMID- 28087774 TI - The Origin of Mitochondrial Cristae from Alphaproteobacteria. AB - Mitochondria are the respiratory organelles of eukaryotes and their evolutionary history is deeply intertwined with that of eukaryotes. The compartmentalization of respiration in mitochondria occurs within cristae, whose evolutionary origin has remained unclear. Recent discoveries, however, have revived the old notion that mitochondrial cristae could have had a pre-endosymbiotic origin. Mitochondrial cristae are likely homologous to the intracytoplasmic membranes (ICMs) used by diverse alphaproteobacteria for harnessing energy. Because the Mitochondrial Contact site and Cristae Organizing System (MICOS) that controls the development of cristae evolved from a simplified version that is phylogenetically restricted to Alphaproteobacteria (alphaMICOS), ICMs most probably transformed into cristae during the endosymbiotic origin of mitochondria. This inference is supported by the sequence and structural similarities between MICOS and alphaMICOS, and the expression pattern and cellular localization of alphaMICOS. Given that cristae and ICMs develop similarly, alphaMICOS likely functions analogously to mitochondrial MICOS by culminating ICM development with the creation of tubular connections and membrane contact sites at the alphaproteobacterial envelope. Mitochondria thus inherited a pre-existing ultrastructure adapted to efficient energy transduction from their alphaproteobacterial ancestors. The widespread nature of purple bacteria among alphaproteobacteria raises the possibility that cristae evolved from photosynthetic ICMs. PMID- 28087775 TI - Rapid Expansion of Immune-Related Gene Families in the House Fly, Musca domestica. AB - The house fly, Musca domestica, occupies an unusual diversity of potentially septic niches compared with other sequenced Dipteran insects and is a vector of numerous diseases of humans and livestock. In the present study, we apply whole transcriptome sequencing to identify genes whose expression is regulated in adult flies upon bacterial infection. We then combine the transcriptomic data with analysis of rates of gene duplication and loss to provide insight into the evolutionary dynamics of immune-related genes. Genes up-regulated after bacterial infection are biased toward being evolutionarily recent innovations, suggesting the recruitment of novel immune components in the M. domestica or ancestral Dipteran lineages. In addition, using new models of gene family evolution, we show that several different classes of immune-related genes, particularly those involved in either pathogen recognition or pathogen killing, are duplicating at a significantly accelerated rate on the M. domestica lineage relative to other Dipterans. Taken together, these results suggest that the M. domestica immune response includes an elevated diversity of genes, perhaps as a consequence of its lifestyle in septic environments. PMID- 28087776 TI - Seed Plant-Specific Gene Lineages Involved in Carpel Development. AB - Evolutionary innovations are important drivers of speciation and some are the defining characters of entire phyla. One such major innovation is the carpel, the unifying character and most complex plant organ, composed of many clearly distinct tissue types to ensure reproductive success. The origin of the carpel is unknown, but many components of the gene regulatory network (GRN) governing carpel development and their genetic interactions are known from the core eudicot Arabidopsis thaliana. To unravel the evolution of the carpel GRN and to discriminate between "early" and "late" steps in carpel evolution, we calculated thorough phylogeny reconstructions based on sequenced genomes. The A. thaliana carpel GRN members ALCATRAZ (ALC), CRABS CLAW (CRC), HALF FILLED (HAF), HECATE (HEC), INDEHISCENT (IND), NGATHA (NGA), and SPATULA (SPT) were analyzed in their phylogenetic context. We find that the carpel GRN components are of various ages, but interestingly, we identify especially high retention rates for carpel development genes in Brassicaceae. Our data suggest that genes whose A. thaliana homologs are involved in processes already present in the most recent common ancestor of seed plants, such as reproductive meristem termination or adaxial/abaxial polarity specification, are not retained in duplicates after whole genome duplications (WGD). In contrast, genes involved in processes associated with derived carpel characters in Arabidopsis, such as the transmitting tract or style development show a higher gene retention rate after WGD. This work provides a starting point for analyses of carpel genes in early diverging angiosperms which would be very informative for evolutionary studies. PMID- 28087778 TI - No Evidence for Phylostratigraphic Bias Impacting Inferences on Patterns of Gene Emergence and Evolution. AB - Phylostratigraphy is a computational framework for dating the emergence of DNA and protein sequences in a phylogeny. It has been extensively applied to make inferences on patterns of genome evolution, including patterns of disease gene evolution, ontogeny and de novo gene origination. Phylostratigraphy typically relies on BLAST searches along a species tree, but new simulation studies have raised concerns about the ability of BLAST to detect remote homologues and its impact on phylostratigraphic inferences. Here, we re-assessed these simulations. We found that, even with a possible overall BLAST false negative rate between 11 15%, the large majority of sequences assigned to a recent evolutionary origin by phylostratigraphy is unaffected by technical concerns about BLAST. Where the results of the simulations did cast doubt on previously reported findings, we repeated the original analyses but now excluded all questionable sequences. The originally described patterns remained essentially unchanged. These new analyses strongly support phylostratigraphic inferences, including: genes that emerged after the origin of eukaryotes are more likely to be expressed in the ectoderm than in the endoderm or mesoderm in Drosophila, and the de novo emergence of protein-coding genes from non-genic sequences occurs through proto-gene intermediates in yeast. We conclude that BLAST is an appropriate and sufficiently sensitive tool in phylostratigraphic analysis that does not appear to introduce significant biases into evolutionary pattern inferences. PMID- 28087777 TI - Genome Sequencing Reveals the Origin of the Allotetraploid Arabidopsis suecica. AB - Polyploidy is an example of instantaneous speciation when it involves the formation of a new cytotype that is incompatible with the parental species. Because new polyploid individuals are likely to be rare, establishment of a new species is unlikely unless polyploids are able to reproduce through self fertilization (selfing), or asexually. Conversely, selfing (or asexuality) makes it possible for polyploid species to originate from a single individual-a bona fide speciation event. The extent to which this happens is not known. Here, we consider the origin of Arabidopsis suecica, a selfing allopolyploid between Arabidopsis thaliana and Arabidopsis arenosa, which has hitherto been considered to be an example of a unique origin. Based on whole-genome re-sequencing of 15 natural A. suecica accessions, we identify ubiquitous shared polymorphism with the parental species, and hence conclusively reject a unique origin in favor of multiple founding individuals. We further estimate that the species originated after the last glacial maximum in Eastern Europe or central Eurasia (rather than Sweden, as the name might suggest). Finally, annotation of the self incompatibility loci in A. suecica revealed that both loci carry non-functional alleles. The locus inherited from the selfing A. thaliana is fixed for an ancestral non-functional allele, whereas the locus inherited from the outcrossing A. arenosa is fixed for a novel loss-of-function allele. Furthermore, the allele inherited from A. thaliana is predicted to transcriptionally silence the allele inherited from A. arenosa, suggesting that loss of self-incompatibility may have been instantaneous. PMID- 28087779 TI - Genomics of Parallel Experimental Evolution in Drosophila. AB - What are the genomic foundations of adaptation in sexual populations? We address this question using fitness-character and whole-genome sequence data from 30 Drosophila laboratory populations. These 30 populations are part of a nearly 40 year laboratory radiation featuring 3 selection regimes, each shared by 10 populations for up to 837 generations, with moderately large effective population sizes. Each of 3 sets of the 10 populations that shared a selection regime consists of 5 populations that have long been maintained under that selection regime, paired with 5 populations that had only recently been subjected to that selection regime. We find a high degree of evolutionary parallelism in fitness phenotypes when most-recent selection regimes are shared, as in previous studies from our laboratory. We also find genomic parallelism with respect to the frequencies of single-nucleotide polymorphisms, transposable elements, insertions, and structural variants, which was expected. Entirely unexpected was a high degree of parallelism for linkage disequilibrium. The evolutionary genetic changes among these sexual populations are rapid and genomically extensive. This pattern may be due to segregating functional genetic variation that is abundantly maintained genome-wide by selection, variation that responds immediately to changes of selection regime. PMID- 28087780 TI - Oncogenes without a Neighboring Tumor-Suppressor Gene Are More Prone to Amplification. AB - Focal copy number gains or losses are important genomic hallmarks of cancer. The genomic distribution of oncogenes and tumor-suppressor genes (TSG) in relation to focal copy number aberrations is unclear. Our analysis revealed that the mean distance of TSGs from oncogenes was significantly shorter than that of noncancer genes, suggesting that oncogenes and TSGs tend to be in close physical proximity in the human genome. Such relationship was conserved in mouse and drosophila. Pan cancer analysis using data from The Cancer Genome Atlas indicated that oncogenes without a nearby TSG are more prone to amplification. In conclusion, our study provides evidence for the nonrandom distribution of oncogenes and TSGs across different species. Our data also support that the existence of a neighboring TSG can suppress amplification of an oncogene, shedding new light on a previously unappreciated protective mechanism of TSGs. PMID- 28087781 TI - Deleterious Variants in Asian Rice and the Potential Cost of Domestication. AB - Many SNPs are predicted to encode deleterious amino acid variants. These slightly deleterious mutations can provide unique insights into population history, the dynamics of selection, and the genetic bases of phenotypes. This is especially true for domesticated species, where a history of bottlenecks and selection may affect the frequency of deleterious variants and signal a "cost of domestication". Here, we investigated the numbers and frequencies of deleterious variants in Asian rice (Oryza sativa), focusing on two varieties (japonica and indica) and their wild relative (O. rufipogon). We investigated three signals of a potential cost of domestication in Asian rice relative to O. rufipogon: an increase in the frequency of deleterious SNPs (dSNPs), an enrichment of dSNPs compared with synonymous SNPs (sSNPs), and an increased number of deleterious variants. We found evidence for all three signals, and domesticated individuals contained ~3-4% more deleterious alleles than wild individuals. Deleterious variants were enriched within low recombination regions of the genome and experienced frequency increases similar to sSNPs within regions of putative selective sweeps. A characteristic feature of rice domestication was a shift in mating system from outcrossing to predominantly selfing. Forward simulations suggest that this shift in mating system may have been the dominant factor in shaping both deleterious and neutral diversity in rice. PMID- 28087782 TI - Mutation Supply and Relative Fitness Shape the Genotypes of Ciprofloxacin Resistant Escherichia coli. AB - Ciprofloxacin is an important antibacterial drug targeting Type II topoisomerases, highly active against Gram-negatives including Escherichia coli. The evolution of resistance to ciprofloxacin in E. coli always requires multiple genetic changes, usually including mutations affecting two different drug target genes, gyrA and parC. Resistant mutants selected in vitro or in vivo can have many different mutations in target genes and efflux regulator genes that contribute to resistance. Among resistant clinical isolates the genotype, gyrA S83L D87N, parC S80I is significantly overrepresented suggesting that it has a selective advantage. However, the evolutionary or functional significance of this high frequency resistance genotype is not fully understood. By combining experimental data and mathematical modeling, we addressed the reasons for the predominance of this specific genotype. The experimental data were used to model trajectories of mutational resistance evolution under different conditions of drug exposure and population bottlenecks. We identified the order in which specific mutations are selected in the clinical genotype, showed that the high frequency genotype could be selected over a range of drug selective pressures, and was strongly influenced by the relative fitness of alternative mutations and factors affecting mutation supply. Our data map for the first time the fitness landscape that constrains the evolutionary trajectories taken during the development of clinical resistance to ciprofloxacin and explain the predominance of the most frequently selected genotype. This study provides strong support for the use of in vitro competition assays as a tool to trace evolutionary trajectories, not only in the antibiotic resistance field. PMID- 28087783 TI - Cohort Profile Update: The Janus Serum Bank Cohort in Norway. PMID- 28087784 TI - Interactions between Zinc and Allosteric Modulators of the Glycine Receptor. AB - The glycine receptor is a pentameric ligand-gated ion channel that is involved in fast inhibitory neurotransmission in the central nervous system. Zinc is an allosteric modulator of glycine receptor function, enhancing the effects of glycine at nanomolar to low-micromolar concentrations and inhibiting its effects at higher concentrations. Low-nanomolar concentrations of contaminating zinc in electrophysiological buffers are capable of synergistically enhancing receptor modulation by other compounds, such as ethanol. This suggests that, unless accounted for, previous studies of glycine receptor modulation were measuring the effects of modulator plus comodulation by zinc on receptor function. Since zinc is present in vivo at a variety of concentrations, it will influence glycine receptor modulation by other pharmacologic agents. We investigated the utility of previously described "zinc-enhancement-insensitive" alpha1 glycine receptor mutants D80A, D80G, and W170S to probe for interactions between zinc and other allosteric modulators at the glycine receptor. We found that only the W170S mutation conferred complete abolishment of zinc enhancement across a variety of agonist and zinc concentrations. Using alpha1 W170S receptors, we established that, in addition to ethanol, zinc interacts with inhalants, but not volatile anesthetics, to synergistically enhance channel function. Additionally, we determined that this interaction is abolished at higher zinc concentrations when receptor-enhancing binding sites are saturated, suggesting a mechanism by which modulators such as ethanol and inhalants are capable of increasing receptor affinity for zinc, in addition to enhancing channel function on their own. PMID- 28087791 TI - The Science of Conducting Research With LGBT Older Adults- An Introduction to Aging with Pride: National Health, Aging, and Sexuality/Gender Study (NHAS). PMID- 28087785 TI - Thermolytic Degradation of Synthetic Cannabinoids: Chemical Exposures and Pharmacological Consequences. AB - Synthetic cannabinoids are manufactured clandestinely with little quality control and are distributed as herbal "spice" for smoking or as bulk compound for mixing with a solvent and inhalation via electronic vaporizers. Intoxication with synthetic cannabinoids has been associated with seizure, excited delirium, coma, kidney damage, and other disorders. The chemical alterations produced by heating these structurally novel compounds for consumption are largely unknown. Here, we show that heating synthetic cannabinoids containing tetramethylcyclopropyl-ring substituents produced thermal degradants with pharmacological activity that varied considerably from their parent compounds. Moreover, these degradants were formed under conditions simulating smoking. Some products of combustion retained high affinity at the cannabinoid 1 (CB1) and CB2 receptors, were more efficacious than (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3 hydroxypropyl)cyclohexanol (CP55,940) in stimulating CB1 receptor-mediated guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) binding, and were potent in producing Delta9-tetrahydrocannabinol-like effects in laboratory animals, whereas other compounds had low affinity and efficacy and were devoid of cannabimimetic activity. Degradants that retained affinity and efficacy also substituted in drug discrimination tests for the prototypical synthetic cannabinoid 1-pentyl-3-(1 naphthoyl)indole (JWH-018), and are likely to produce psychotropic effects in humans. Hence, it is important to take into consideration the actual chemical exposures that occur during use of synthetic cannabinoid formulations to better comprehend the relationships between dose and effect. PMID- 28087792 TI - The Unfolding of LGBT Lives: Key Events Associated With Health and Well-being in Later Life. AB - PURPOSE OF THE STUDY: Life events are associated with the health and well-being of older adults. Using the Health Equity Promotion Model, this article explores historical and environmental context as it frames life experiences and adaptation of lesbian, gay, bisexual, and transgender (LGBT) older adults. DESIGN AND METHODS: This was the largest study to date of LGBT older adults to identify life events related to identity development, work, and kin relationships and their associations with health and quality of life (QOL). Using latent profile analysis (LPA), clusters of life events were identified and associations between life event clusters were tested. RESULTS: On average, LGBT older adults first disclosed their identities in their 20s; many experienced job-related discrimination. More had been in opposite-sex marriage than in same-sex marriage. Four clusters emerged: "Retired Survivors" were the oldest and one of the most prevalent groups; "Midlife Bloomers" first disclosed their LGBT identities in mid 40s, on average; "Beleaguered At-Risk" had high rates of job-related discrimination and few social resources; and "Visibly Resourced" had a high degree of identity visibility and were socially and economically advantaged. Clusters differed significantly in mental and physical health and QOL, with the Visibly Resourced faring best and Beleaguered At-Risk faring worst on most indicators; Retired Survivors and Midlife Bloomers showed similar health and QOL. IMPLICATIONS: Historical and environmental contexts frame normative and non normative life events. Future research will benefit from the use of longitudinal data and an assessment of timing and sequencing of key life events in the lives of LGBT older adults. PMID- 28087793 TI - Race/Ethnicity and Health-Related Quality of Life Among LGBT Older Adults. AB - PURPOSE OF THE STUDY: Few existing studies have addressed racial/ethnic differences in the health and quality of life of lesbian, gay, bisexual, and transgender (LGBT) older adults. Guided by the Health Equity Promotion Model, this study examines health-promoting and health risk factors that contribute to racial/ethnic health disparities among LGBT adults aged 50 and older. DESIGN AND METHODS: We utilized weighted survey data from Aging with Pride: National Health, Aging, and Sexuality/Gender Study. By applying multiple mediator models, we analyzed the indirect effects of race/ethnicity on health-related quality of life (HRQOL) via demographics, lifetime LGBT-related discrimination, and victimization, and socioeconomic, identity-related, spiritual, and social resources. RESULTS: Although African Americans and Hispanics, compared with non Hispanic Whites, reported lower physical HRQOL and comparable psychological HRQOL, indirect pathways between race/ethnicity and HRQOL were observed. African Americans and Hispanics had lower income, educational attainment, identity affirmation, and social support, which were associated with a decrease in physical and psychological HRQOL. African Americans had higher lifetime LGBT related discrimination, which was linked to a decrease in their physical and psychological HRQOL. African Americans and Hispanics had higher spirituality, which was associated with an increase in psychological HRQOL. IMPLICATIONS: Findings illustrate the importance of identifying both health-promoting and health risk factors to understand ways to maximize the health potential of racially and ethnically diverse LGBT older adults. Interventions aimed at health equity should be tailored to bolster identity affirmation and social networks of LGBT older adults of color and to support strengths, including spiritual resources. PMID- 28087794 TI - Bouncing Back: Resilience and Mastery Among HIV-Positive Older Gay and Bisexual Men. AB - PURPOSE OF THE STUDY: Adults with HIV infection are living into old age. It is critical we investigate positive constructs such as resilience and mastery to determine factors associated with psychological well-being. We examine HIV related factors, adverse conditions, and psychosocial characteristics that are associated with resilience (the ability to bounce back) and mastery (sense of self-efficacy). DESIGN AND METHODS: We analyzed 2014 data from the longitudinal study Aging with Pride: National Health, Aging, and Sexuality/Gender Study (NHAS), focusing on a subsample of 335 gay and bisexual older men. Multivariate linear regression was used to identify factors that contributed or detracted from resilience and mastery in the sample recruited from 17 sites from across the United States. RESULTS: Resilience and mastery were independently associated with psychological health-related quality of life. In multivariate analysis, adjusting for demographic characteristics, previous diagnosis of depression was negatively associated with resilience. Time since HIV diagnosis was positively associated with mastery whereas victimization was negatively associated with mastery. Social support and community engagement were positively associated with both resilience and mastery. IMPLICATIONS: Individual and structural-environmental characteristics contributed to resilience and mastery. These findings can be used to develop interventions incorporating an increased understanding of factors that are associated with both resilience and mastery. PMID- 28087795 TI - Who Says I Do: The Changing Context of Marriage and Health and Quality of Life for LGBT Older Adults. AB - PURPOSE OF THE STUDY: Until recently, lesbian, gay, bisexual, and transgender (LGBT) adults were excluded from full participation in civil marriage. The purpose of this study is to examine how legal marriage and relationship status are associated with health-promoting and at-risk factors, health, and quality of life of LGBT adults aged 50 and older. DESIGN AND METHODS: We utilized weighted survey data from Aging with Pride: National Health, Aging, and Sexuality/Gender Study (NHAS) participants who resided in states with legalized same-sex marriage in 2014 (N = 1,821). Multinomial logistic regression was conducted to examine differences by relationship status (legally married, unmarried partnered, single) in economic and social resources; LGBT contextual and identity factors; health; and quality of life. RESULTS: We found 24% were legally married, and 26% unmarried partnered; one-half were single. Those legally married reported better quality of life and more economic and social resources than unmarried partnered; physical health indicators were similar between legally married and unmarried partnered. Those single reported poorer health and fewer resources than legally married and unmarried partnered. Among women, being legally married was associated with more LGBT microaggressions. IMPLICATIONS: LGBT older adults, and practitioners serving them, should become educated about how legal same-sex marriage interfaces with the context of LGBT older adults' lives, and policies and protections related to age and sexual and gender identity. Longitudinal research is needed to understand factors contributing to decisions to marry, including short- and long-term economic, social, and health outcomes associated with legal marriage among LGBT older adults. PMID- 28087796 TI - Prior Military Service, Identity Stigma, and Mental Health Among Transgender Older Adults. AB - PURPOSE OF THE STUDY: Converging evidence from large community-based samples, Internet studies, and Veterans Health Administration data suggest that transgender adults have high rates of U.S. military service. However, little is known about the role of prior military service in their mental health later in life, particularly in relation to identity stigma. In this article, we examine relationships between prior military service, identity stigma, and mental health among transgender older adults. DESIGN AND METHODS: We used a subsample of transgender older adults (n = 183) from the 2014 survey of Aging with Pride: National Health, Aging, and Sexuality/Gender Study (NHAS). We employed weighted multivariate linear models to evaluate the relationships between psychological health-related quality of life (HRQOL), depressive symptomatology (Center for Epidemiological Studies Depression Scale [CES-D] scores), identity stigma, and prior military service, controlling for background characteristics. RESULTS: Identity stigma was significantly related with higher depressive symptomatology and lower psychological HRQOL. Having a history of prior military service significantly predicted lower depressive symptomatology and higher psychological HRQOL. The relationships between psychological HRQOL, identity stigma, and prior military service were largely explained by depressive symptomatology. Prior military service significantly attenuated the relationship between identity stigma and depressive symptomatology. IMPLICATIONS: By identifying the role of military service in the mental health of transgender older adults, this study provides insights into how prior military service may contribute to resilience and positive mental health outcomes. Directions for future research are discussed. PMID- 28087797 TI - The Cascading Effects of Marginalization and Pathways of Resilience in Attaining Good Health Among LGBT Older Adults. AB - PURPOSE OF THE STUDY: Lesbian, gay, bisexual, and transgender (LGBT) older adults comprise a diverse and growing health disparate population. In the present study, using the Health Equity Promotion Model, we investigated pathways by which LGBT older adults experience resilience, risk, and marginalization and their relationship to attaining positive health outcomes. DESIGN AND METHODS: Aging with Pride: National Health, Aging, and Sexuality/Gender Study (NHAS) is the first longitudinal research project designed to examine the health, aging, and well-being of LGBT adults aged 50 and older. Using data from 2014 (N = 2,415), we tested a structural equation model linking lifetime marginalization, identity affirmation and management, social and psychological resources, and health behaviors to positive health outcomes. RESULTS: Identity affirmation positively predicted social resources and mental health, and social resources positively predicted mental health. Marginalization was associated with fewer social resources for LGBT older adults with an open identity management style, lower identity affirmation for LGBT older adults who strategically concealed their sexual identity, and poorer mental health. Mental health was associated with better health behaviors, which in turn predicted positive physical health outcomes. IMPLICATIONS: Although a health disparate population, good health among LGBT older adults appears to be attained via multiple resilience and risk pathways. Providers must remain aware of the historical contexts in which LGBT older adults lived and the strengths they developed in order to understand their health and to develop tailored and targeted prevention and intervention services. PMID- 28087798 TI - Social Network Types and Mental Health Among LGBT Older Adults. AB - PURPOSE OF THE STUDY: This study was designed to identify social network types among lesbian, gay, bisexual, and transgender (LGBT) older adults and examine the relationship between social network type and mental health. DESIGN AND METHODS: We analyzed the 2014 survey data of LGBT adults aged 50 and older (N = 2,450) from Aging with Pride: National Health, Aging, and Sexuality/Gender Study. Latent profile analyses were conducted to identify clusters of social network ties based on 11 indicators. Multiple regression analysis was performed to examine the association between social network types and mental health. RESULTS: We found five social network types. Ordered from greatest to least access to family, friend, and other non-family network ties, they were diverse, diverse/no children, immediate family-focused, friend-centered/restricted, and fully restricted. The friend-centered/restricted (33%) and diverse/no children network types (31%) were the most prevalent. Among individuals with the friend centered/restricted type, access to social networks was limited to friends, and across both types children were not present. The least prevalent type was the fully restricted network type (6%). Social network type was significantly associated with mental health, after controlling for background characteristics and total social network size; those with the fully restricted type showed the poorest mental health. IMPLICATIONS: Unique social network types (diverse/no children and friend-centered/restricted) emerge among LGBT older adults. Moreover, individuals with fully restricted social networks are at particular risk due to heightened health needs and limited social resources. This study highlights the importance of understanding heterogeneous social relations and developing tailored interventions to promote social connectedness and mental health in LGBT older adults. PMID- 28087799 TI - Factors Associated With High-Risk Alcohol Consumption Among LGB Older Adults: The Roles of Gender, Social Support, Perceived Stress, Discrimination, and Stigma. AB - PURPOSE OF THE STUDY: Lesbian, gay, and bisexual (LGB) adults have elevated rates of high-risk alcohol consumption compared with heterosexual adults. Although drinking tends to decline with age in the general population, we know little about LGB older adults' drinking. Using 2014 data from Aging with Pride: National Health, Aging, and Sexuality/Gender Study (NHAS), we aimed to identify factors associated with high-risk drinking in LGB older adults. DESIGN AND METHODS: A U.S. sample of 2,351 LGB adults aged 50-98 years completed a survey about personal and social experiences, substance use, and health. Multinomial logistic regression was conducted to identify predictors of past-month high-risk alcohol consumption. RESULTS: Approximately one fifth (20.6%) of LGB older adults reported high-risk drinking, with nonsignificantly different rates between men (22.4%) and women (18.4%). For women, current smoking and greater social support were associated with greater likelihood of high-risk drinking; older age, higher income, recovery from addiction, and greater perceived stress were associated with lower likelihood. For men, higher income, current smoking, and greater day to-day discrimination were associated with greater likelihood of high-risk drinking; transgender identity and recovery from addiction were associated with lower likelihood. IMPLICATIONS: Social contexts and perceived drinking norms may encourage higher levels of alcohol consumption in LGB older women, whereas men's drinking may be linked with discrimination-related stress. Prevention and intervention with this population should take into account gender differences and sexual minority-specific risk factors. With future waves of data, we will be able to examine LGB older adults' drinking trajectories over time. PMID- 28087800 TI - Health Care Engagement Among LGBT Older Adults: The Role of Depression Diagnosis and Symptomatology. AB - PURPOSE OF THE STUDY: Optimal engagement in health care plays a critical role in the success of disease prevention and treatment, particularly for older adults who are often in greater need of health care services. However, to date, there is still limited knowledge about the relationship between depression and health care engagement among lesbian, gay, bisexual, and transgender (LGBT) older adults. DESIGN AND METHODS: This study utilized data from Aging with Pride: National Health, Aging, Sexuality/Gender Study, from the 2014 survey with 2,450 LGBT adults 50 years old and older. Multiple-variable regression was utilized to evaluate relationships between three indicators of health care engagement and four depression groups after controlling for background characteristics and discrimination in health care. Health care engagement indicators were "not using preventive care," "not seeking care when needed," and "difficulty in adhering to treatments." Depression groups were defined by depression diagnosis and symptomatology, including Diagnosed-Symptomatic group (Diag-Sympt), Diagnosed Nonsymptomatic group (Diag-NoSympt), Nondiagnosed-Symptomatic group (NoDiag Sympt), and Nondiagnosed-Nonsymptomatic group (NoDiag-NoSympt). RESULTS: Depression groups displayed different patterns and levels of health care engagement. The Diag-Sympt group displayed the highest "difficulty in adhering to treatments." Diag-NoSympt group displayed the lowest "not using preventive care." The NoDiag-Sympt group reported the highest "not using preventive care" and "not seeking care when needed." The NoDiag-NoSympt group had the lowest "not seeking care when needed" and "difficulty in adhering to treatments." IMPLICATIONS: Depression diagnosis and symptomatology are jointly associated with health care engagement among LGBT older adults. Interventions aiming to promote health care engagement among this population should simultaneously consider both depression diagnosis and symptomatology. PMID- 28087801 TI - Occurrence of similar mycoviruses in pathogenic, saprotrophic and mycorrhizal fungi inhabiting the same forest stand. AB - Fungal viruses (mycoviruses) are considered to be highly host specific, but phylogenetic analysis supports the occasional occurrence of horizontal transmission between species. We used an extensive sampling strategy to investigate whether similar viruses occur in more than one fungal species of the same forest habitat. Mycelial samples were collected from in-growth mesh bags (N = 259), fruiting bodies (N = 173) and cultured isolates (N = 68) at a forest site where the spatial distribution of viral infections in clonal individuals of the wood decay fungus Heterobasidion parviporum was mapped in detail earlier. The investigation revealed previously known Heterobasidion viruses in ~2% of the single or pooled mycorrhizal samples from mesh bags, ~3% of the fruiting body samples and none of the fungal cultures analyzed. Novel virus strains distinct from known Heterobasidion viruses were detected in cultures of ectomycorrhizal fungi (Lactarius tabidus, L. rufus) and saprotrophic fungi (Megacollybia platyphylla, Mucoraceae spp.). Overall, our results support the view that mycoviruses do not readily cross species borders. Regarding potential virocontrol applications, the introduction of Heterobasidion viruses into natural habitats is not expected to cause a major infection pressure towards the indigenous fungal community. However, the ecological consequences of the putative interspecies virus transmission events detected require further investigation. PMID- 28087802 TI - Cytochrome c peroxidase (CcP) is a molecular determinant of the oxidative stress response in the extreme acidophilic Leptospirillum sp. CF-1. AB - Bioleaching processes are used to recover metals from sulfidic ores. Biofilm formation on ores is important for bioleaching because the attached microorganisms start the leaching process by concentrating ferric ions in the extracellular matrix. It has been shown that hydrogen peroxide is spontaneously generated on the surface of ores and that it negatively influences the growth and activity of microorganisms. However, the mechanism by which bioleaching microorganisms tolerate exogenous H2O2 as an adaptive trait remains elusive. Herein, we demonstrate that the gene yhjA, encoding a predicted periplasmic cytochrome c peroxidase (CcP), is important for the response to exogenously generated oxidative stress in the iron-oxidizing acidophilic bacterium Leptospirillum sp. CF-1. Our results show that yhjA is co-transcribed with the genes encoding the peroxide-responsive transcription regulator PerR and peroxiredoxin AhpC. CcP activity, but not yhjA mRNA level, significantly increased in response to hydrogen peroxide and ferric ion exposure, suggesting a post-translational regulation. In agreement with these results, challenging planktonic cells with hydrogen peroxide significantly increased their attachment to pyrite surfaces. In summation, our results suggest that CcP is important to cope with exogenous H2O2, thus favoring the early steps of attachment to mineral substrates. PMID- 28087803 TI - Epiphytic Planctomycetes communities associated with three main groups of macroalgae. AB - Planctomycetes, a unique group of widespread and understudied bacteria, are known to be associated with macroalgae. The temporal dynamics and the host-specific association of planctomycetal communities on Fucus spiralis, Ulva sp. and Chondrus crispus from two locations in the North Coast of Portugal were assessed both by denaturing gradient gel electrophoresis with group-specific primers and 16S rDNA amplicon libraries. The epiphytic planctomycetal communities showed a significant association with the host macroalgal species independently of the geographical location and the season. This pattern was confirmed by clone libraries of winter and summer samples: we obtained 720 16S rRNA gene sequences that represented 44 operational taxonomic units (OTUs) within the phylum Planctomycetes. Most of the OTUs belonged to Blastopirellula, followed by Rhodopirellula, Planctomyces, the Pir4 lineage and the uncultured class OM190 (this last one nearly 30% of the OTUs). Ulva sp. and C. crispus had more diverse planctomycetal communities than F. spiralis. Analysis of beta diversity showed that the planctomycetal microbiome was host specific. We hypothesize that the specific association of Planctomycetes and their macroalgal hosts is likely determined by nutritional molecules provided by the algae and the set of sulfatases inherent to each Planctomycetes species. PMID- 28087804 TI - Clinical Selection Strategies to Identify Ischemic Stroke Patients With Large Anterior Vessel Occlusion: Results From SITS-ISTR (Safe Implementation of Thrombolysis in Stroke International Stroke Thrombolysis Registry). AB - BACKGROUND AND PURPOSE: The National Institutes of Health Stroke Scale (NIHSS) correlates with presence of large anterior vessel occlusion (LAVO). However, the application of the full NIHSS in the prehospital setting to select patients eligible for treatment with thrombectomy is limited. Therefore, we aimed to evaluate the prognostic value of simple clinical selection strategies. METHODS: Data from the Safe Implementation of Thrombolysis in Stroke International Stroke Thrombolysis Registry (January 2012-May 2014) were analyzed retrospectively. Patients with complete breakdown of NIHSS scores and documented vessel status were included. We assessed the association of prehospital stroke scales and NIHSS symptom profiles with LAVO (internal carotid artery, carotid-terminus or M1 segment of the middle cerebral artery). RESULTS: Among 3505 patients, 23.6% (n=827) had LAVO. Pathological finding on the NIHSS item best gaze was strongly associated with LAVO (adjusted odds ratio 4.5, 95% confidence interval 3.8-5.3). All 3 face-arm-speech-time test (FAST) items identified LAVO with high sensitivity. Addition of the item gaze to the original FAST score (G-FAST) or high scores on other simplified stroke scales increased specificity. The NIHSS symptom profiles representing total anterior syndromes showed a 10-fold increased likelihood for LAVO compared with a nonspecific clinical profile. If compared with an NIHSS threshold of >=6, the prehospital stroke scales performed similarly or even better without losing sensitivity. CONCLUSIONS: Simple modification of the face-arm-speech-time score or evaluating the NIHSS symptom profile may help to stratify patients' risk of LAVO and to identify individuals who deserve rapid transfer to comprehensive stroke centers. Prospective validation in the prehospital setting is required. PMID- 28087805 TI - Prehospital Scales for Large Vessel Occlusion: Closing in on a Moving Target. PMID- 28087806 TI - Splenectomy Does Not Improve Long-Term Outcome After Stroke. AB - BACKGROUND AND PURPOSE: Immune responses to brain antigens after stroke contribute to poor outcome. We hypothesized that splenectomy would lessen the development of such responses and improve outcome. METHODS: Male Lewis rats (275 350 g) underwent 2-hour middle cerebral artery occlusion immediately after splenectomy or sham splenectomy. Animals were survived to 4 weeks (672 hrs), and immune responses to myelin basic protein determined at euthanasia. Infarct volume was determined in a subset of animals euthanized at 72 hours. Behavioral outcomes were assessed to 672 hours. RESULTS: Splenectomy was associated with worse neurological scores early after stroke, but infarct size at 72 hours was similar in both groups. Behavioral outcomes and immune responses to myelin basic protein were also similar among splenectomized and sham-operated animals 672 hours after middle cerebral artery occlusion. CONCLUSIONS: Splenectomy did not alter the immune responses to brain antigens or improve outcome after stroke. Differences between this study and other studies of splenectomy and stroke are examined. PMID- 28087808 TI - Identification of a Novel Liver X Receptor Agonist that Regulates the Expression of Key Cholesterol Homeostasis Genes with Distinct Pharmacological Characteristics. AB - Activation of liver X receptor (LXR) is associated with cholesterol metabolism and anti-inflammatory processes, which makes it beneficial to antiatherosclerosis therapy. Nevertheless, existing agonists that target LXR, for example TO901317, are related to unwanted side effects. In the present study, using a screening method we identified IMB-808, which displayed potent dual LXRalpha/beta agonistic activity. In vitro, IMB-808 effectively increased the expressing quantity of genes related to reverse cholesterol transport process as well as those associated with cholesterol metabolism pathway in multiple cell lines. Additionally, IMB-808 remarkably promoted cholesterol efflux from RAW264.7 as well as THP-1 macrophage cells and reduced cellular lipid accumulation accordingly. Interestingly, compared with TO901317, IMB-808 almost did not increase the expressing quantity of genes related to lipogenesis in HepG2 cells, which indicated that IMB-808 could exhibit fewer internal lipogenic side effects with a characteristic of selective LXR agonist. Furthermore, in comparison with the full LXR agonist TO901317, IMB-808 recruits coregulators differently and possesses a distinct predictive binding pattern for the LXR ligand-binding domain. In summary, our study demonstrated that IMB-808 could act as an innovative partial LXR agonist that avoids common lipogenic side effects, providing insight for the design of novel LXR modulators. Our data indicate that this compound might be used as a promising therapeutic agent for the prospective treatment of atherosclerosis in the future. PMID- 28087807 TI - Field Validation of the Los Angeles Motor Scale as a Tool for Paramedic Assessment of Stroke Severity. AB - BACKGROUND AND PURPOSE: The Los Angeles Motor Scale (LAMS) is a 3-item, 0- to 10 point motor stroke-deficit scale developed for prehospital use. We assessed the convergent, divergent, and predictive validity of the LAMS when performed by paramedics in the field at multiple sites in a large and diverse geographic region. METHODS: We analyzed early assessment and outcome data prospectively gathered in the FAST-MAG trial (Field Administration of Stroke Therapy-Magnesium phase 3) among patients with acute cerebrovascular disease (cerebral ischemia and intracranial hemorrhage) within 2 hours of onset, transported by 315 ambulances to 60 receiving hospitals. RESULTS: Among 1632 acute cerebrovascular disease patients (age 70+/-13 years, male 57.5%), time from onset to prehospital LAMS was median 30 minutes (interquartile range 20-50), onset to early postarrival (EPA) LAMS was 145 minutes (interquartile range 119-180), and onset to EPA National Institutes of Health Stroke Scale was 150 minutes (interquartile range 120-180). Between the prehospital and EPA assessments, LAMS scores were stable in 40.5%, improved in 37.6%, and worsened in 21.9%. In tests of convergent validity, against the EPA National Institutes of Health Stroke Scale, correlations were r=0.49 for the prehospital LAMS and r=0.89 for the EPA LAMS. Prehospital LAMS scores did diverge from the prehospital Glasgow Coma Scale, r=-0.22. Predictive accuracy (adjusted C statistics) for nondisabled 3-month outcome was as follows: prehospital LAMS, 0.76 (95% confidence interval 0.74-0.78); EPA LAMS, 0.85 (95% confidence interval 0.83-0.87); and EPA National Institutes of Health Stroke Scale, 0.87 (95% confidence interval 0.85-0.88). CONCLUSIONS: In this multicenter, prospective, prehospital study, the LAMS showed good to excellent convergent, divergent, and predictive validity, further establishing it as a validated instrument to characterize stroke severity in the field. PMID- 28087809 TI - Trim13 Potentiates Toll-Like Receptor 2-Mediated Nuclear Factor kappaB Activation via K29-Linked Polyubiquitination of Tumor Necrosis Factor Receptor-Associated Factor 6. AB - Ubiquitination is a versatile post-translational modification involved in nuclear factor-kappaB (NF-kappaB) activation of Toll-like receptor (TLR) signaling. Here, we demonstrated that Trim13, an E3 ubiquitin ligase, is up-regulated in macrophages upon stimulation with TLR2 ligand. Knockdown of Trim13 attenuated TLR2-mediated production of cytokines/chemokines and formation of foam cells as well as activation of NF-kappaB. Trim13 interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6) and potentiates NF-kappaB activity via ubiquitination of TRAF6. Overexpression of inactive mutant (C10/13A) or really interesting new gene (RING) deletion mutant of Trim13 did not potentiate ubiquitination of TRAF6 or activation of NF-kappaB. These results suggest that the effects of Trim13 are dependent on its E3 ligase activity. Trim13 used K29 linked polyubiquitin chains for TRAF6 ubiquitination to promote NF-kappaB activity and thus potentiated activation of TLR2-mediated immune responses. Our data identify Trim13 as a positive regulator of NF-kappaB activation and suggest that K29-linked polyubiquitination is a specific ubiquitin-linked pattern involved in the control of TLR2 signaling. PMID- 28087811 TI - Twenty years of social capital and health research: a glossary. AB - Research on social capital in public health is approaching its 20th anniversary. Over this period, there have been rich and productive debates on the definition, measurement and importance of social capital for public health research and practice. As a result, the concepts and measures characterising social capital and health research have also evolved, often drawing from research in the social, political and behavioural sciences. The multidisciplinary adaptation of social capital-related concepts to study health has made it challenging for researchers to reach consensus on a common theoretical approach. This glossary thus aims to provide a general overview without recommending any particular approach. Based on our knowledge and research on social capital and health, we have selected key concepts and terms that have gained prominence over the last decade and complement an earlier glossary on social capital and health. PMID- 28087810 TI - AKT1, LKB1, and YAP1 Revealed as MYC Interactors with NanoLuc-Based Protein Fragment Complementation Assay. AB - The c-Myc (MYC) transcription factor is a major cancer driver and a well validated therapeutic target. However, directly targeting MYC has been challenging. Thus, identifying proteins that interact with and regulate MYC may provide alternative strategies to inhibit its oncogenic activity. In this study, we report the development of a NanoLuc-based protein-fragment complementation assay (NanoPCA) and mapping of the MYC protein interaction hub in live mammalian cells. The NanoPCA system was configured to enable detection of protein-protein interactions (PPI) at the endogenous level, as shown with PRAS40 dimerization, and detection of weak interactions, such as PINCH1-NCK2. Importantly, NanoPCA allows the study of PPI dynamics with reversible interactions. To demonstrate its utility for large-scale PPI detection in mammalian intracellular environment, we have used NanoPCA to examine MYC interaction with 83 cancer-associated proteins in live cancer cell lines. Our new MYC PPI data confirmed known MYC-interacting proteins, such as MAX, GSK3A, and SMARCA4, and revealed a panel of novel MYC interaction partners, such as RAC-alpha serine/threonine-protein kinase (AKT)1, liver kinase B (LKB)1, and Yes-associated protein (YAP)1. The MYC interactions with AKT1, LKB1, and YAP1 were confirmed by coimmunoprecipitation of endogenous proteins. Importantly, AKT1, LKB1, and YAP1 were able to activate MYC in a transcriptional reporter assay. Thus, these vital growth control proteins may represent promising MYC regulators, suggesting new mechanisms that couple energetic and metabolic pathways and developmental signaling to MYC-regulated cellular programs. PMID- 28087812 TI - Long-term effects of youth unemployment on mental health: does an economic crisis make a difference? AB - BACKGROUND: Ill health is a risk factor and a consequence of unemployment, which might vary depending on the national rate of unemployment. We investigated the long-term effect of youth unemployment on mental health and explored the possible interaction during periods of high (economic crisis) and low (non-crisis) unemployment rates. METHODS: A register-linked population-based cohort study was conducted including individuals aged 17-24 years. The crisis cohort (n=6410) took part in the Labour Force Survey during the economic crisis (1991-1994) in Sweden and the non-crisis cohort (n=8162) took part in the same survey before the crisis (1983-1986). Follow-up was 19 years. Adjusted HRs and 95% CIs for an inpatient care discharge mental diagnosis with employed people as the reference group were calculated by Cox regressions models. RESULTS: In fully adjusted models, <3 months (HR: 1.69; 95% CI 1.14 to 2.49), 3-6 months (2.19; 1.43 to 3.37) and >6 months (2.70; 1.71 to 4.28) of unemployment were associated with increased risks of getting a mental diagnosis in the crisis cohort. In the non-crisis cohort the risks were: 1.92; 1.40 to 2.63, 2.60; 1.72 to 3.94 and 3.33; 2.00 to 5.57, respectively. No interactions between labour force status and level of unemployment were found. CONCLUSIONS: Youth unemployment is related to mental health problems, independent of the overall national rate of unemployment, which is important as the youth unemployment rates are currently at stable high level. PMID- 28087813 TI - Ethnic differences in anthropometric measures and abdominal fat distribution: a cross-sectional pooled study in Inuit, Africans and Europeans. AB - BACKGROUND: Ethnic variation in abdominal fat distribution may explain differences in cardiometabolic risk between populations. However, the ability of anthropometric measures to quantify abdominal fat is not clearly understood across ethnic groups. The aim of this study was to investigate the associations between anthropometric measures and visceral (VAT) and subcutaneous abdominal adipose tissue (SAT) in Inuit, Africans and Europeans. METHODS: We combined cross sectional data from 3 studies conducted in Greenland, Kenya and Denmark using similar methodology. A total of 5275 individuals (3083 Inuit, 1397 Africans and 795 Europeans) aged 17-95 years with measures of anthropometry and ultrasonography of abdominal fat were included in the study. Multiple regression models with fractional polynomials were used to analyse VAT and SAT as functions of body mass index (BMI), waist circumference, waist-to-hip ratio, waist-to height ratio and body fat percentage. RESULTS: The associations between conventional anthropometric measures and abdominal fat distribution varied by ethnicity in almost all models. Europeans had the highest levels of VAT in adjusted analyses and Africans the lowest with ethnic differences most apparent at higher levels of the anthropometric measures. Similar ethnic differences were seen in the associations with SAT for a given anthropometric measure. CONCLUSIONS: Conventional anthropometric measures like BMI and waist circumference do not reflect the same amount of VAT and SAT across ethnic groups. Thus, the obesity level at which Inuit and Africans are at increased cardiometabolic risk is likely to differ from that of Europeans. PMID- 28087816 TI - Acetazolamide potentiates the afferent drive to prefrontal cortex in vivo. AB - The knowledge on real-time neurophysiological effects of acetazolamide is still far behind the wide clinical use of this drug. Acetazolamide - a carbonic anhydrase inhibitor - has been shown to affect the neuromuscular transmission, implying a pH-mediated influence on the central synaptic transmission. To start filling such a gap, we chose a central substrate: hippocampal-prefrontal cortical projections; and a synaptic phenomenon: paired-pulse facilitation (a form of synaptic plasticity) to probe this drug's effects on interareal brain communication in chronically implanted rats. We observed that systemic acetazolamide potentiates the hippocampal-prefrontal paired-pulse facilitation. In addition to this field electrophysiology data, we found that acetazolamide exerts a net inhibitory effect on prefrontal cortical single-unit firing. We propose that systemic acetazolamide reduces the basal neuronal activity of the prefrontal cortex, whereas increasing the afferent drive it receives from the hippocampus. In addition to being relevant to the clinical and side effects of acetazolamide, these results suggest that exogenous pH regulation can have diverse impacts on afferent signaling across the neocortex. PMID- 28087817 TI - T-cell redeployment and intracellular cytokine expression following exercise: effects of exercise intensity and cytomegalovirus infection. AB - The magnitude of lymphocytosis following exercise is directly related to exercise intensity. Infection with cytomegalovirus (CMV) also augments lymphocytosis after exercise. It is not known if the enhanced T-cell response to exercise due to CMV depends on exercise intensity. Furthermore, exercise-induced changes in T-cell expression of type I and type II cytokines are thought to be intensity dependent, but direct comparisons are lacking. The aim of this experiment was to determine if CMV affects the exercise-induced redistribution of T-cell subsets at varying intensities, and determine the effect of exercise intensity on CD8+ T-cell cytokine expression. Seventeen cyclists (nine CMV seropositive; CMV+) completed three 30 min cycling trials at -5, +5, and +15% of blood lactate threshold (LT). T-cell subsets in blood and intracellular expression of type I (IL-2, interferon(IFN)-gamma) and type II (IL-4, IL-10) cytokines by CD8+ T cells pre, post, and 1-h post-exercise were assessed by flow cytometry. Independently of CMV, T-cell subset redistribution was greater after +15%LT compared to -5%LT (P < 0.05). Independently of intensity, CMV- mobilized more low- (CD27+ CD28+) and medium- (CD27+ CD28-) differentiated T cells than CMV+, whereas CMV+ mobilized more high (CD27- CD28-) differentiated T cells. The numbers of IL-2+, IFN-gamma+, IL-4+, and IL-10+ CD8+ T cells increased after exercise above LT Only type I cytokine expression was influenced by exercise intensity (P < 0.05). In conclusion, T-cell redeployment by exercise is directly related to exercise intensity, as are changes in the number of CD8+ T-cells expressing type I cytokines. Although CMV+ mobilized more high-differentiated T cells than CMV-, this occurred at all intensities. Therefore, the augmenting effect of CMV on T cell mobilization is independent of exercise intensity. PMID- 28087818 TI - Three hours of intermittent hypoxia increases circulating glucose levels in healthy adults. AB - An independent association exists between sleep apnea and diabetes. Animal models suggest exposure to intermittent hypoxia, a consequence of sleep apnea, results in altered glucose metabolism and fasting hyperglycemia. However, it is unknown if acute exposure to intermittent hypoxia increases glucose concentrations in nondiabetic humans. We hypothesized plasma glucose would be increased from baseline following 3 h of intermittent hypoxia in healthy humans independent of any effect on insulin sensitivity. Eight (7M/1F, 21-34 years) healthy subjects completed two study visits randomized to 3 h of intermittent hypoxia or continuous normoxia, followed by an oral glucose tolerance test. Intermittent hypoxia consisted of 25 hypoxic events per hour where oxygen saturation (SpO2) was significantly reduced (Normoxia: 97 +/- 1%, Hypoxia: 90 +/- 2%, P < 0.01). Venous plasma glucose concentrations were measured on both visits before and after the 3 h protocol. No changes in plasma glucose were observed from baseline after 3 h of continuous normoxia (5.1 +/- 0.2 vs. 5.1 +/- 0.1 mmol/L, P > 0.05). In contrast, circulating glucose concentrations were increased after 3 h of intermittent hypoxia when compared to baseline (5.0 +/- 0.2 vs. 5.3 +/- 0.2 mmol/L, P = 0.01). There were no detectable changes in insulin sensitivity following intermittent hypoxia when compared to continuous normoxia, as assessed by the oral glucose tolerance test (P > 0.05). Circulating glucose is increased after 3 h of intermittent hypoxia in healthy humans, independent of any lasting changes in insulin sensitivity. These novel findings could explain, in part, the high prevalence of diabetes in patients with sleep apnea and warrant future studies to identify underlying mechanisms. PMID- 28087819 TI - Electrophysiologic effects of the IK1 inhibitor PA-6 are modulated by extracellular potassium in isolated guinea pig hearts. AB - The pentamidine analog PA-6 was developed as a specific inward rectifier potassium current (IK1) antagonist, because established inhibitors either lack specificity or have side effects that prohibit their use in vivo. We previously demonstrated that BaCl2, an established IK1 inhibitor, could prolong action potential duration (APD) and increase cardiac conduction velocity (CV). However, few studies have addressed whether targeted IK1 inhibition similarly affects ventricular electrophysiology. The aim of this study was to determine the effects of PA-6 on cardiac repolarization and conduction in Langendorff-perfused guinea pig hearts. PA-6 (200 nm) or vehicle was perfused into ex-vivo guinea pig hearts for 60 min. Hearts were optically mapped with di-4-ANEPPS to quantify CV and APD at 90% repolarization (APD90). Ventricular APD90 was significantly prolonged in hearts treated with PA-6 (115 +/- 2% of baseline; P < 0.05), but not vehicle (105 +/- 2% of baseline). PA-6 slightly, but significantly, increased transverse CV by 7%. PA-6 significantly prolonged APD90 during hypokalemia (2 mmol/L [K+]o), although to a lesser degree than observed at 4.56 mmol/L [K+]o In contrast, the effect of PA-6 on CV was more pronounced during hypokalemia, where transverse CV with PA-6 (24 +/- 2 cm/sec) was significantly faster than with vehicle (13 +/- 3 cm/sec, P < 0.05). These results show that under normokalemic conditions, PA-6 significantly prolonged APD90, whereas its effect on CV was modest. During hypokalemia, PA-6 prolonged APD90 to a lesser degree, but profoundly increased CV Thus, in intact guinea pig hearts, the electrophysiologic effects of the IK1 inhibitor, PA-6, are [K+]o-dependent. PMID- 28087820 TI - Emerging functional roles of nuclear receptors in breast cancer. AB - Nuclear receptors (NRs) have been targets of intensive drug development for decades due to their roles as key regulators of multiple developmental, physiological and disease processes. In breast cancer, expression of the estrogen and progesterone receptor remains clinically important in predicting prognosis and determining therapeutic strategies. More recently, there is growing evidence supporting the involvement of multiple nuclear receptors other than the estrogen and progesterone receptors, in the regulation of various processes important to the initiation and progression of breast cancer. We review new insights into the mechanisms of action of NRs made possible by recent advances in genomic technologies and focus on the emerging functional roles of NRs in breast cancer biology, including their involvement in circadian regulation, metabolic reprogramming and breast cancer migration and metastasis. PMID- 28087821 TI - Selection of first-line therapy in multiple sclerosis using risk-benefit decision analysis. AB - OBJECTIVE: To integrate long-term measures of disease-modifying drug efficacy and risk to guide selection of first-line treatment of multiple sclerosis. METHODS: We created a Markov decision model to evaluate disability worsening and progressive multifocal leukoencephalopathy (PML) risk in patients receiving natalizumab (NTZ), fingolimod (FGL), or glatiramer acetate (GA) over 30 years. Leveraging publicly available data, we integrated treatment utility, disability worsening, and risk of PML into quality-adjusted life-years (QALYs). We performed sensitivity analyses varying PML risk, mortality and morbidity, and relative risk of disease worsening across clinically relevant ranges. RESULTS: Over the entire reported range of NTZ-associated PML risk, NTZ as first-line therapy is predicted to provide a greater net benefit (15.06 QALYs) than FGL (13.99 QALYs) or GA (12.71 QALYs) treatment over 30 years, after accounting for loss of QALYs due to PML or death (resulting from all causes). NTZ treatment is associated with delayed worsening to an Expanded Disability Status Scale score >=6.0 vs FGL or GA (22.7, 17.0, and 12.4 years, respectively). Compared to untreated patients, NTZ treated patients have a greater relative risk of death in the early years of treatment that varies according to PML risk profile. CONCLUSIONS: NTZ as a first line treatment is associated with the highest net benefit across full ranges of PML risk, mortality, and morbidity compared to FGL or GA. Integrated modeling of long-term treatment risks and benefits informs stratified clinical decision making and can support patient counseling on selection of first-line treatment options. PMID- 28087822 TI - Amygdala and hippocampus are symptomatogenic zones for central apneic seizures. AB - OBJECTIVE: To identify limbic sites of respiratory control in the human brain, and by extension, the symptomatogenic zone for central apnea. METHODS: We used direct stimulation of anatomically, precisely placed stereotactic EEG electrodes to analyze breathing responses. We prospectively studied 3 patients who were explored with stereotactically implanted depth electrodes. The amygdala and hippocampus, as well as extralimbic sites (orbitofrontal, temporal tip, and temporal neocortex), were investigated. RESULTS: Individual stimulation of the amygdala and hippocampal head consistently elicited central apnea in the expiratory phase, as did exquisitely focal hippocampal seizures. CONCLUSIONS: These findings confirm that hippocampus and amygdala are limbic breathing control sites in humans, as well as the symptomatogenic zone for central apneic seizures. PMID- 28087823 TI - Prognosis of carotid dissecting aneurysms: Results from CADISS and a systematic review. AB - OBJECTIVE: To determine the natural history of dissecting aneurysm (DA) and whether DA is associated with an increased recurrent stroke risk and whether type of antithrombotic drugs (antiplatelets vs anticoagulants) modifies the persistence or development of DA. METHODS: We included 264 patients with extracranial cervical artery dissection (CAD) from the Cervical Artery Dissection in Stroke Study (CADISS), a multicenter prospective study that compared antiplatelet with anticoagulation therapy. Logistic regression was used to estimate age- and sex-adjusted odds ratios. We conducted a systematic review of published studies assessing the natural history of DA and stroke risk in patients with non-surgically-treated extracranial CAD with DA. RESULTS: In CADISS, DA was present in 24 of 264 patients at baseline. In 36 of 248 patients with follow-up neuroimaging at 3 months, 12 of the 24 baseline DAs persisted, and 24 new DA had developed. There was no association between treatment allocation (antiplatelets vs anticoagulants) and whether DA at baseline persisted at follow-up or whether new DA developed. During 12 months of follow-up, stroke occurred in 1 of 48 patients with DA and in 7 of 216 patients without DA (age- and sex-adjusted odds ratio 0.84; 95% confidence interval 0.10-7.31; p = 0.88). Published studies, mainly retrospective, showed a similarly low risk of stroke and no evidence of an increased stroke rate in patients with DA. CONCLUSIONS: The results of CADISS provide evidence suggesting that DAs may have benign prognosis and therefore medical treatment should be considered. PMID- 28087824 TI - Neuropathology of SUDEP: Role of inflammation, blood-brain barrier impairment, and hypoxia. AB - OBJECTIVE: To seek a neuropathologic signature of sudden unexpected death in epilepsy (SUDEP) in a postmortem cohort by use of immunohistochemistry for specific markers of inflammation, gliosis, acute neuronal injury due to hypoxia, and blood-brain barrier (BBB) disruption, enabling the generation of hypotheses about potential mechanisms of death in SUDEP. METHODS: Using immunohistochemistry, we investigated the expression of 6 markers (CD163, human leukocyte antigen-antigen D related, glial fibrillary acid protein, hypoxia inducible factor-1alpha [HIF-1alpha], immunoglobulin G, and albumin) in the hippocampus, amygdala, and medulla in 58 postmortem cases: 28 SUDEP (definite and probable), 12 epilepsy controls, and 18 nonepileptic sudden death controls. A semiquantitative measure of immunoreactivity was scored for all markers used, and quantitative image analysis was carried out for selected markers. RESULTS: Immunoreactivity was observed for all markers used within all studied brain regions and groups. Immunoreactivity for inflammatory reaction, BBB leakage, and HIF-1alpha in SUDEP cases was not different from that seen in control groups. CONCLUSIONS: This study represents a starting point to explore by immunohistochemistry the mechanisms underlying SUDEP in human brain tissue. Our approach highlights the potential and importance of considering immunohistochemical analysis to help identify biomarkers of SUDEP. Our results suggest that with the markers used, there is no clear immunohistochemical signature of SUDEP in human brain. PMID- 28087825 TI - Incidence and predictors of epilepsy after pediatric arterial ischemic stroke. AB - OBJECTIVE: To determine the cumulative incidence and clinical predictors of remote symptomatic seizures and epilepsy after pediatric arterial ischemic stroke (AIS). METHODS: We performed a retrospective analysis of 218 participants with neonatal AIS (NAIS), presumed perinatal AIS (PPAIS), and childhood AIS (CAIS) from a single-center prospective consecutive cohort enrolled from 2006 to 2014. Medical records were reviewed for timing, semiology, and treatment of acute symptomatic seizures, remote symptomatic seizures (RSS), and epilepsy. Cumulative incidence of RSS and epilepsy were assessed using survival analysis. RESULTS: Acute symptomatic seizures occurred in 94% of NAIS (n = 70/74) and 17% of CAIS (n = 18/105). Younger children were more likely to present with seizures at stroke ictus, and acute symptomatic seizures were predictive of later RSS and epilepsy in CAIS. Median follow-up for the entire cohort was 34 months, interquartile range 44.9 months (16.3-61.2). Estimated cumulative incidence of RSS at 2 years was 19% in NAIS, 24% in PPAIS, and 7% in CAIS. Estimated cumulative incidence of epilepsy at 2 years was 11% in NAIS, 19% in PPAIS, and 7% in CAIS. The median time to these outcomes was <2 years in all stroke subtypes. Among participants developing epilepsy (n = 34), seizures were often well-controlled at last follow up with median Engel class of <=2 (<1 seizure/month). CONCLUSIONS: RSS and epilepsy are important neurologic sequelae of pediatric AIS. Children with perinatal stroke and CAIS with acute symptomatic seizures are at increased risk of these outcomes. These cohorts need further study to identify biomarkers and potential therapeutic targets for epileptogenesis. PMID- 28087826 TI - Comparison of brain MRI findings with language and motor function in the dystroglycanopathies. AB - OBJECTIVE: To describe the spectrum of brain MRI findings in a cohort of individuals with dystroglycanopathies (DGs) and relate MRI results to function. METHODS: All available brain MRIs done for clinical indications on individuals enrolled in a DG natural history study (NCT00313677) were reviewed. Reports were reviewed when MRI was not available. MRIs were categorized as follows: (1) cortical, brainstem, and cerebellar malformations; (2) cortical and cerebellar malformations; or (3) normal. Language development was assigned to 1 of 3 categories by a speech pathologist. Maximal motor function and presence of epilepsy were determined by history or examination. RESULTS: Twenty-five MRIs and 9 reports were reviewed. The most common MRI abnormalities were cobblestone cortex or dysgyria with an anterior-posterior gradient and cerebellar hypoplasia. Seven individuals had MRIs in group 1, 8 in group 2, and 19 in group 3. Language was impaired in 100% of those in MRI groups 1 and 2, and degree of language impairment correlated with severity of imaging. Eighty-five percent of the whole group achieved independent walking, but only 33% did in group 1. Epilepsy was present in 8% of the cohort and rose to 37% of those with an abnormal MRI. CONCLUSIONS: Developmental abnormalities of the brain such as cobblestone lissencephaly, cerebellar cysts, pontine hypoplasia, and brainstem bowing are hallmarks of DG and should prompt consideration of these diagnoses. Brain imaging in individuals with DG helps to predict outcomes, especially language development, aiding clinicians in prognostic counseling. PMID- 28087827 TI - Neuropsychological outcome following frontal lobectomy for pharmacoresistant epilepsy in adults. AB - OBJECTIVE: This retrospective cohort study characterized cognitive and motor outcomes in a large sample of adults who underwent frontal lobe resections for treatment of pharmacoresistant epilepsy. METHODS: Ninety patients who underwent unilateral frontal lobe resection for epilepsy (42 language-dominant hemisphere/48 nondominant hemisphere) between 1989 and 2014 completed comprehensive preoperative and postoperative neuropsychological evaluations that included measures of verbal and nonverbal intellectual functioning, attention/working memory, processing speed, language, executive functioning, verbal and visual memory, and motor functioning. Objective methods were used to assess meaningful change across a wide range of abilities and to identify factors associated with neuropsychological decline following frontal lobectomy. Detailed postoperative neuroimaging analysis was conducted to characterize region, extent, and volume of resection. RESULTS: Forty-eight percent of patients did not demonstrate meaningful postoperative declines in cognition and an additional 42% demonstrated decline in 1 or 2 cognitive domains. When cognitive decline was observed, it usually occurred on measures of intelligence, visuomotor processing speed, or executive functioning. Side and site of resection were unrelated to cognitive outcome, but played a role in decline of contralateral manual dexterity following supplementary motor area resection. Higher preoperative ability, older age at surgery, absence of a malformation of cortical development on MRI, and poor seizure outcome were related to cognitive decline on some measures, but had poor sensitivity in identifying at-risk patients. CONCLUSIONS: The vast majority of patients who undergo frontal lobectomy for treatment of pharmacoresistant epilepsy demonstrate good cognitive and motor outcomes. PMID- 28087828 TI - TDP-43 pathology and memory impairment in elders without pathologic diagnoses of AD or FTLD. AB - OBJECTIVE: To investigate the association of TAR DNA-binding protein 43 (TDP-43) pathology with memory, other cognitive domains, and dementia in community dwelling elders without pathologic diagnoses of Alzheimer disease (AD) or frontotemporal lobar degeneration (FTLD). METHODS: Of 1,058 autopsied participants, 343 (32.4%) did not have pathologic diagnoses of AD or FTLD. Diagnosis of dementia was based on clinical evaluation and cognitive performance tests, which were used to create summary measures of global cognition and of 5 cognitive domains. TDP-43 pathology evaluated in 6 brain regions by immunohistochemistry was converted into a summary measure of TDP-43 severity. RESULTS: Of 343 participants, 135 (39.4%) had TDP-43 pathology with a mean TDP-43 severity score of 0.394 (SD 0.490). TDP-43 inclusions were confined to the amygdala (stage 1) in 43.7% of participants, 40% showed additional involvement of the hippocampus or entorhinal cortex (stages 2), while fewer (16.3%) showed additional TDP-43 pathology in the temporal and frontal cortices (stage 3). Severity of TDP-43 pathology was independently related to lower function in global cognition and episodic and semantic memory while increased odds of dementia was only a trend. When participants with hippocampal sclerosis (HS) were excluded from the models, TDP-43 pathology remained associated with lower episodic memory but relationships with global cognition, semantic memory, and dementia were attenuated. CONCLUSIONS: TDP-43 pathology in elders, without pathologic diagnoses of AD or FTLD, is common and independently associated with lower function in episodic memory, while its associations with global cognitive impairment and dementia are difficult to separate from HS. PMID- 28087829 TI - Tracheophytes Contain Conserved Orthologs of a Basic Helix-Loop-Helix Transcription Factor That Modulate ROOT HAIR SPECIFIC Genes. AB - ROOT HAIR SPECIFIC (RHS) genes, which contain the root hair-specific cis-element (RHE) in their regulatory regions, function in root hair morphogenesis. Here, we demonstrate that an Arabidopsis thaliana basic helix-loop-helix transcription factor, ROOT HAIR DEFECTVE SIX-LIKE4 (RSL4), directly binds to the RHE in vitro and in vivo, upregulates RHS genes, and stimulates root hair formation in Arabidopsis. Orthologs of RSL4 from a eudicot (poplar [Populus trichocarpa]), a monocot (rice [Oryza sativa]), and a lycophyte (Selaginella moellendorffii) each restored root hair growth in the Arabidopsis rsl4 mutant. In addition, the rice and S. moellendorffii RSL4 orthologs bound to the RHE in in vitro and in vivo assays. The RSL4 orthologous genes contain RHEs in their promoter regions, and RSL4 was able to bind to its own RHEs in vivo and amplify its own expression. This process likely provides a positive feedback loop for sustainable root hair growth. When RSL4 and its orthologs were expressed in cells in non-root-hair positions, they induced ectopic root hair growth, indicating that these genes are sufficient to specify root hair formation. Our results suggest that RSL4 mediates root hair formation by regulating RHS genes and that this mechanism is conserved throughout the tracheophyte (vascular plant) lineage. PMID- 28087831 TI - A Tale of Two CENPCs: Centromere Localization of KINETOCHORE NULL2 and CENP-C. PMID- 28087830 TI - Recognition of the Magnaporthe oryzae Effector AVR-Pia by the Decoy Domain of the Rice NLR Immune Receptor RGA5. AB - Nucleotide binding domain and leucine-rich repeat proteins (NLRs) are important receptors in plant immunity that allow recognition of pathogen effectors. The rice (Oryza sativa) NLR RGA5 recognizes the Magnaporthe oryzae effector AVR-Pia through direct interaction. Here, we gained detailed insights into the molecular and structural bases of AVR-Pia-RGA5 interaction and the role of the RATX1 decoy domain of RGA5. NMR titration combined with in vitro and in vivo protein-protein interaction analyses identified the AVR-Pia interaction surface that binds to the RATX1 domain. Structure-informed AVR-Pia mutants showed that, although AVR-Pia associates with additional sites in RGA5, binding to the RATX1 domain is necessary for pathogen recognition but can be of moderate affinity. Therefore, RGA5-mediated resistance is highly resilient to mutations in the effector. We propose a model that explains such robust effector recognition as a consequence, and an advantage, of the combination of integrated decoy domains with additional independent effector-NLR interactions. PMID- 28087832 TI - Comparison of cardiovascular risk algorithms in patients with vs without rheumatoid arthritis and the role of C-reactive protein in predicting cardiovascular outcomes in rheumatoid arthritis. AB - Objectives: The aims were to compare the performance of cardiovascular risk calculators, Framingham Risk Score (FRS) and QRISK2, in RA and matched non-RA patients and to evaluate whether their performance could be enhanced by the addition of CRP. Methods: We conducted a retrospective analysis, using a clinical practice data set linked to Hospital Episode Statistics (HES) data from the UK. Patients presenting with at least one RA diagnosis code and no prior cardiovascular events were matched to non-RA patients using disease risk scores. The overall performance of the FRS and QRISK2 was compared between cohorts, and assessed with and without CRP in the RA cohort using C-Index, Akaike Information Criterion (AIC) and the net reclassification index (NRI). Results: Four thousand seven hundred and eighty RA patients met the inclusion criteria and were followed for a mean of 3.8 years. The C-Index for the FRS in the non-RA and RA cohort was 0.783 and 0.754 (P < 0.001) and that of the QRISK2 was 0.770 and 0.744 (P < 0.001), respectively. Log[CRP] was positively associated with cardiovascular events, but improvements in the FRS and QRISK2 C-Indices as a result of inclusion of CRP were small, from 0.764 to 0.767 (P = 0.026) for FRS and from 0.764 to 0.765 (P = 0.250) for QRISK2. The NRI was 3.2% (95% CI: -2.8, 5.7%) for FRS and 2.0% (95% CI: -5.8, 4.5%) for QRISK2. Conclusion: The C-Index for the FRS and QRISK2 was significantly better in the non-RA compared with RA patients. The addition of CRP in both equations was not associated with a significant improvement in reclassification based on NRI. PMID- 28087833 TI - Dysregulation of MAP Kinase Signaling Pathways Including p38MAPK, SAPK/JNK, and ERK1/2 in Cultured Rat Cerebellar Astrocytes Exposed to Diphenylarsinic Acid. AB - Diphenylarsinic acid (DPAA) was a major compound found in the arsenic poisoning incident that occurred in Kamisu, Ibaraki, Japan in 2003. People exposed to DPAA via contaminated well water suffered from several neurological disorders, including cerebellar symptoms. We previously reported that DPAA induces cellular activation in cultured rat cerebellar astrocytes, dose-dependent promotion of cell growth (low DPAA), cell death (high DPAA), and increased phosphorylation of mitogen-activated protein (MAP) kinases (p38MAPK, SAPK/JNK, and ERK1/2). Moreover, DPAA induces up-regulation of oxidative stress-counteracting proteins, activation of CREB phosphorylation, increased protein expression of c-Jun and c Fos, and aberrant secretion of brain-active cytokines (MCP-1, adrenomedullin, FGF2, CXCL1, and IL-6). Here, we explored the role of MAP kinases in DPAA-induced activation of astrocytes using specific MAP kinase signaling inhibitors [SB203580 (p38MAPK), SP600125 (SAPK/JNK), SCH772984 (ERK1/2), and U0126 (MEK1/2, a kinase for ERK1/2)]. DPAA-induced activation of MAP kinases had little contribution to DPAA-induced cell growth and death. On the other hand, a power relationship among MAP kinases was also observed, in which p38MAPK suppressed DPAA-induced SAPK/JNK and ERK1/2 activation, whereas ERK1/2 and MEK1/2 facilitated p38MAPK and SAPK/JNK activation. In addition, SAPK/JNK had minimal effects on the activation of other MAP kinases. DPAA-induced activation of transcription factors and secretion of brain-active cytokines were submissively but intricately dominated by MAP kinases. Collectively, our results indicate that DPAA-induced activation of MAP kinases is neither a cell growth-promoting response nor a cytoprotective one but leads to transcriptional disruption and aberrant secretion of brain-active cytokines in cerebellar astrocytes. PMID- 28087834 TI - Environmental Deflection: The Impact of Toxicant Exposures on the Aging Epigenome. AB - Epigenetic drift and age-related methylation have both been used in the literature to describe changes in DNA methylation that occurs with aging. However, ambiguity remains regarding the exact definition of both of these terms, and neither of these fields of study explicitly considers the impact of environmental factors on the aging epigenome. Recent twin studies have demonstrated longitudinal, pair-specific discordance in DNA methylation patterns, suggesting an effect of the environment on age-related methylation and/or epigenetic drift. Supporting this idea, other new reports have shown clear environment- and toxicant-mediated shifts away from the baseline rates of age related methylation and epigenetic drift within an organism, a process we now term "environmental deflection." By defining and delineating environmental deflection, this contemporary review aims to highlight the effects of specific toxicological factors on the rate of DNA methylation changes that occur over the life course. In an effort to inform future epigenetics-based toxicology studies, a field of research now classified as toxicoepigenetics, we provide clear definitions and examples of "epigenetic drift" and "age-related methylation," summarize the recent evidence for environmental deflection of the aging epigenome, and discuss the potential functional effects of environmental deflection. PMID- 28087835 TI - Study of TiO2 P25 Nanoparticles Genotoxicity on Lung, Blood, and Liver Cells in Lung Overload and Non-Overload Conditions After Repeated Respiratory Exposure in Rats. AB - Inhaled titanium dioxide (TiO2) nanoparticles (NPs) can have negative health effects, and have been shown to cause respiratory tract cancer in rats. Inflammation has been linked to oxidative stress, and both have been described as possible mechanisms for genotoxicity of NPs, but rarely examined side-by-side in animal studies. In the present study, a wide range of complementary endpoints have been performed to study TiO2 P25 NP-induced genotoxicity in lung overload and non-overload conditions. Additionally, lung burden, inflammation, cytotoxicity and oxidative stress have also been evaluated in order to link genotoxicity with these responses. To assess quick and delayed responses after recovery, endpoints were evaluated at two time points: 2 h and 35 days after three repeated instillations. This study confirmed the previously described lung overload threshold at approximately 200-300 cm2 of lung burden for total particle surface area lung deposition or 4.2 ul/kg for volume-based cumulative lung exposure dose, above which lung clearance is impaired and inflammation is induced. Our results went on to show that these overload doses induced delayed genotoxicity in lung, associated with persistent inflammation only at the highest dose. The lowest tested doses had no toxicity or genotoxicity effects in the lung. In blood, no lymphocyte DNA damage, erythrocytes chromosomal damage or gene mutation could be detected. Our data also demonstrated that only overload doses induced liver DNA lesions irrespective of the recovery time. Tested doses of TiO2 P25 NPs did not induce glutathione changes in lung, blood or liver at both recovery times. PMID- 28087837 TI - Editor's Highlight: Off-Target Effects of Neuroleptics and Antidepressants on Saccharomyces cerevisiae. AB - Over the past years, the use of antidepressants and neuroleptics has steadily increased. Although incredibly useful to treat disorders like depression, schizophrenia, epilepsy, or mental retardation, these drugs display many side effects. Toxicogenomic studies aim to limit this problem by trying to identify cellular targets and off-targets of medical compounds. The baker yeast Saccharomyces cerevisiae has been shown to be a key player in this approach, as it represents an incredible toolbox for the dissection of complex biological processes. Moreover, the evolutionary conservation of many pathways allows the translation of yeast data to the human system. In this paper, a better attention was paid to chlorpromazine, as it still is one of the most widely used drug in therapy. The results of a toxicogenomic screening performed on a yeast mutants collection treated with chlorpromazine were instrumental to identify a set of genes for further analyses. For this purpose, a multidisciplinary approach was used based on growth phenotypes identification, Gene Ontology search, and network analysis. Then, the impacts of three antidepressants (imipramine, doxepin, and nortriptyline) and three neuroleptics (promazine, chlorpromazine, and promethazine) on S. cerevisiae were compared through physiological analyses, microscopy characterization, and transcriptomic studies. Data highlight key differences between neuroleptics and antidepressants, but also between the individual molecules. By performing a network analysis on the human homologous genes, it emerged that genes and proteins involved in the Notch pathway are possible off-targets of these molecules, along with key regulatory proteins. PMID- 28087838 TI - From the Cover: Does the Assessment of Nondisjunction Provide a More Sensitive Assay for the Detection of Aneugens? AB - The detection of aneugenic chemicals is important due to the implications of aneuploidy for human health. Aneuploidy can result from chromosome loss or nondisjunction due to chromosome mis-segregation at anaphase. Frequently, aneugens are detected using the in vitro micronucleus assay (IVM), with either centromere or kinetochore labeling. However, this method does not consider nondisjunction, the suggested predominant mechanism of spindle poison induced aneugenicity in primary human lymphocytes. Therefore, the IVM may be relatively insensitive in detecting aneuploidy. To investigate whether chromosome distribution analysis, specifically of nondisjunction, using chromosome-specific centromeric probes provides a more sensitive assay for aneugen detection, six reference aneugens with differing modes of action were tested on human lymphoblastoid TK6 cells. The results show that chromosome loss is a substantial part of the process leading to aneuploidy in TK6 cells. This differs from previous studies on human lymphocytes where nondisjunction has been described as the major mechanism of aneugenicity. However, in the current study more cells and types of aneugenic damage were analyzed. Although compound specific effects on nondisjunction were identified, chromosome distribution analysis did not provide increased sensitivity for the detection of aneugens: For the six reference aneugens examined, chromosome loss was shown at the same concentrations or lower than nondisjunction, even when nondisjunction levels were comparatively high. Therefore, in TK6 cells methods that detect chromosome loss, eg, the IVM, provide a more sensitive technique for the detection of aneugens than the measurement of nondisjunction. PMID- 28087836 TI - Neuropathological Consequences of Gestational Exposure to Concentrated Ambient Fine and Ultrafine Particles in the Mouse. AB - Increasing evidence indicates that the central nervous system (CNS) is a target of air pollution. We previously reported that postnatal exposure of mice to concentrated ambient ultrafine particles (UFP; <=100 nm) via the University of Rochester HUCAPS system during a critical developmental window of CNS development, equivalent to human 3rd trimester, produced male-predominant neuropathological and behavioral characteristics common to multiple neurodevelopmental disorders, including autism spectrum disorder (ASD), in humans. The current study sought to determine whether vulnerability to fine (<=2.5 MUm) and UFP air pollution exposure extends to embryonic periods of brain development in mice, equivalent to human 1st and 2nd trimesters. Pregnant mice were exposed 6 h/day from gestational days (GDs) 0.5-16.5 using the New York University VACES system to concentrated ambient fine/ultrafine particles at an average concentration of 92.69 MUg/m3 over the course of the exposure period. At postnatal days (PNDs) 11-15, neuropathological consequences were characterized. Gestational air pollution exposures produced ventriculomegaly, increased corpus callosum (CC) area and reduced hippocampal area in both sexes. Both sexes demonstrated CC hypermyelination and increased microglial activation and reduced total CC microglia number. Analyses of iron deposition as a critical component of myelination revealed increased iron deposition in the CC of exposed female offspring, but not in males. These findings demonstrate that vulnerability of the brain to air pollution extends to gestation and produces features of several neurodevelopmental disorders in both sexes. Further, they highlight the importance of the commonalities of components of particulate matter exposures as a source of neurotoxicity and common CNS alterations. PMID- 28087839 TI - Understanding the Property-Activity Relationships of Polyhedral Cuprous Oxide Nanocrystals in Terms of Reactive Crystallographic Facets. AB - The property-activity relationship is usually established to understand the toxicity mechanism of nanomaterials. In the present study, different morphological Cu2O nanocrystals, octahedrons, truncated octahedrons, cuboctahedrons, and cubes, were synthesized to precisely tuning the {100} and {111} facet percentages in purpose of systematically investigating the toxicity role of crystallographic facets in BEAS-2B and RAW 264.7 cells. It was found that the toxicity of polyhedral Cu2O nanocrystals was highly dependent on the exposed {100} surface after short-term exposure because {100} facets could produce more reactive oxygen species (ROS) than {111} facets; however, after long-term exposure, their toxicity showed again the correlation with total surface property because toxic copper ions were largely released from the whole nanocrystal surface irrespective of {100} or {111} facet and this copper dissolution caused the collapse of surface crystals and the vanishing of ROS. This study reveals the potential hazard of crystallographic facets based on ROS and metal dissolution mechanism at the different exposure time. PMID- 28087840 TI - Vibrio cholerae Cholix Toxin-Induced HepG2 Cell Death is Enhanced by Tumor Necrosis Factor-Alpha Through ROS and Intracellular Signal-Regulated Kinases. AB - Cholix toxin (Cholix) from Vibrio cholerae is a potent virulence factor exhibiting ADP-ribosyltransferase activity on eukaryotic elongation factor 2 (eEF2) of host cells, resulting in the inhibition of protein synthesis. Administration of Cholix or its homologue Pseudomonas exotoxin A (PEA) to mice causes lethal hepatocyte damage. In this study, we demonstrate cytotoxicity of Cholix on human hepatocytes in the presence of tumor necrosis factor alpha (TNF alpha), which has been reported to play a fatal role in PEA administered to mice. Compared with incubating HepG2 cells with Cholix alone, co-treatment with TNF alpha and Cholix (TNF-alpha/Cholix) significantly enhanced the activation of caspases, cytochrome c release from mitochondria into cytoplasm, and poly-ADP ribose polymerase (PARP) cleavage, while incubation with TNF-alpha alone or co treatment with TNF-alpha/catalytically inactive Cholix did not. In the early stage of cell death, Cholix increased phosphorylation of mitogen-activated protein kinases (e.g., p38, ERK, JNK) and Akt, which was not affected by TNF alpha alone. MAPK inhibitors (SP600125, SB20852, and U0126) suppressed PARP cleavage induced by TNF-alpha/Cholix. Protein kinase inhibitor Go6976 suppressed JNK phosphorylation and PARP cleavage by TNF-alpha/Cholix. In contrast, PKC activator PMA in the absence of TNF-alpha promoted Cholix-induced PARP cleavage. Reactive oxygen species (ROS) inhibitor, N-acetyl cysteine (NAC), suppressed TNF alpha/Cholix-induced JNK and ERK phosphorylation, resulting in inhibition of PARP cleavage. These data suggest that ROS and JNK pathways are important mediators of TNF-alpha/Cholix-induced HepG2 cell death. PMID- 28087843 TI - Recovery of H-Reflex with Transforaminal Epidural Steroid Injection in S1 Radiculopathy. PMID- 28087841 TI - Single-cell transcriptome analysis of fish immune cells provides insight into the evolution of vertebrate immune cell types. AB - The immune system of vertebrate species consists of many different cell types that have distinct functional roles and are subject to different evolutionary pressures. Here, we first analyzed conservation of genes specific for all major immune cell types in human and mouse. Our results revealed higher gene turnover and faster evolution of trans-membrane proteins in NK cells compared with other immune cell types, and especially T cells, but similar conservation of nuclear and cytoplasmic protein coding genes. To validate these findings in a distant vertebrate species, we used single-cell RNA sequencing of lck:GFP cells in zebrafish and obtained the first transcriptome of specific immune cell types in a nonmammalian species. Unsupervised clustering and single-cell TCR locus reconstruction identified three cell populations, T cells, a novel type of NK like cells, and a smaller population of myeloid-like cells. Differential expression analysis uncovered new immune-cell-specific genes, including novel immunoglobulin-like receptors, and neofunctionalization of recently duplicated paralogs. Evolutionary analyses confirmed the higher gene turnover of trans membrane proteins in NK cells compared with T cells in fish species, suggesting that this is a general property of immune cell types across all vertebrates. PMID- 28087844 TI - High Abdominal Wall Pain: An Unusual Radiation in Thoracic Facet Joint Syndrome. PMID- 28087842 TI - Novel determinants of mammalian primary microRNA processing revealed by systematic evaluation of hairpin-containing transcripts and human genetic variation. AB - Mature microRNAs (miRNAs) are processed from hairpin-containing primary miRNAs (pri-miRNAs). However, rules that distinguish pri-miRNAs from other hairpin containing transcripts in the genome are incompletely understood. By developing a computational pipeline to systematically evaluate 30 structural and sequence features of mammalian RNA hairpins, we report several new rules that are preferentially utilized in miRNA hairpins and govern efficient pri-miRNA processing. We propose that a hairpin stem length of 36 +/- 3 nt is optimal for pri-miRNA processing. We identify two bulge-depleted regions on the miRNA stem, located ~16-21 nt and ~28-32 nt from the base of the stem, that are less tolerant of unpaired bases. We further show that the CNNC primary sequence motif selectively enhances the processing of optimal-length hairpins. We predict that a small but significant fraction of human single-nucleotide polymorphisms (SNPs) alter pri-miRNA processing, and confirm several predictions experimentally including a disease-causing mutation. Our study enhances the rules governing mammalian pri-miRNA processing and suggests a diverse impact of human genetic variation on miRNA biogenesis. PMID- 28087845 TI - Waking EEG Cortical Markers of Chronic Pain and Sleepiness. AB - Objective: Spectral power analyses of EEG recordings are reported to distinguish the cortical activity of individuals with chronic pain from those of controls. Further study of these spectral patterns may provide a greater understanding of the processes associated with chronic pain, in addition to providing potential biometric markers of chronic pain for use in both clinical and research settings. However, sleep deprived groups have demonstrated similar characteristics in their spectral power characteristics, particularly in alpha bandwidth power activity. Methods: 103 individuals with chronic pain provided resting awake EEG data in addition to ratings of pain and sleep quality. Two Principal Axis Factor analyses using Promax rotation produced one pain and one sleep factor from relevant questionnaire data provided by participants. These factors were then used to test hypothesized relationships with alpha and theta bandwidth power at the frontal and parietal areas of the cortex. Results: Our findings suggest that reductions in alpha bandwidth power are independently associated with both chronic pain intensity ratings and measures of sleep deficits. Conversely, theta bandwidth power was not found to be associated with either chronic pain or sleep quality measures. Conclusions: This study's findings support that chronic pain intensity and sleep deficits are related to the Alpha spectral bandwidth activity in individuals with chronic pain. PMID- 28087846 TI - Pregabaline as a Rare Cause of Hepatotoxicity. PMID- 28087848 TI - Correction to: "Early Administration of Carvedilol Protected against Doxorubicin Induced Cardiomyopathy." PMID- 28087847 TI - Addressing Disparities in Low Back Pain Care by Developing Culturally Appropriate Information for Aboriginal Australians: "My Back on Track, My Future". AB - Objectives: Addressing disparities in low back pain care (LBP) is an important yet largely unaddressed issue. One avenue to addressing disparities, recommended by clinical guidelines, is to ensure that LBP information is culturally appropriate. Our objectives were, first, to develop LBP information that was culturally appropriate for Aboriginal Australians living in a rural area and, second, to compare this to traditional information. Methods: The overall information development process was guided by a "cultural security" framework and included partnerships between Aboriginal/non-Aboriginal investigators, a synthesis of research evidence, and participation of a project steering group consisting of local Aboriginal people. LBP information (entitled My Back on Track, My Future [MBOT]) was developed as five short audio-visual scenarios, filmed using Aboriginal community actors. A qualitative randomized crossover design compared MBOT with an evidence-based standard (the Back Book [BB]). Twenty Aboriginal adults participated. Qualitatively we ascertained which information participants' preferred and why, perceptions about each resource, and LBP management. Results: Thirteen participants preferred MBOT, four the BB, two both, and one neither. Participants valued seeing "Aboriginal faces," language that was understandable, the visual format, and seeing Aboriginal people undertaking positive changes in MBOT. In contrast, many participants found the language and format of the BB a barrier. Participants who preferred the BB were more comfortable with written information and appreciated the detailed content. Conclusions: The MBOT information was more preferred and addressed important barriers to care, providing support for use in practice. Similar processes are needed to develop pain information for other cultural groups, particularly those underserved by existing approaches to care. PMID- 28087849 TI - Malaria Prevalence and Its Associated Risk Factors among Patients Attending Chichu and Wonago Health Centres, South Ethiopia. AB - BACKGROUND: There were about of 124 to 283 million cases of malaria with 367,000 to 755,000 deaths annually. This study aimed to assess the prevalence of malaria cases and associated risk factors among attendants at Chichu and Wonago health centers, South Ethiopia. METHODS: In this health institution based cross sectional study, 324 subjects, attendants from outpatient department who came for any kind of medical services, were included during May to June 2016. A blood film examination format and structured questionnaire were used for data collection. Peripheral blood samples were collected and the presence of malaria cases was observed microscopically. The collected data were analyzed by SPSS version 20.0. RESULTS: Malaria cases were detected in 91 (28.1%) of the participants with higher infection rate amongst (56.04%). The predominant Plasmodium species detected was P. vivax (52.75%) followed by P. falciparum (35.16%) and mixed malaria infection by both of the species (12.09%). Housing construction and not using of insecticide treated bed nets for the last 6 months were significantly associated with the risk of getting malaria. Individuals who had stagnant water in their compound were more likely to get malaria than those who did not (OR=1.87, 95% CI: 1.20, 2.76). Houses that had been sprayed with insecticide in the past 6 months were protected against malaria infection (OR=0.33, 95% CI: 0.11, 0.92). Moreover, bed net utilization was associated with a significantly lower risk of infection (OR=0.19, 95% CI: 0.09, 0.37). CONCLUSIONS: Type of housing construction, not using bed net, insecticide spraying and residing near stagnant water were associated risk factors with malaria positivity in the study area. PMID- 28087850 TI - A Hybrid ANN-GA Model to Prediction of Bivariate Binary Responses: Application to Joint Prediction of Occurrence of Heart Block and Death in Patients with Myocardial Infarction. AB - BACKGROUND: In medical studies, when the joint prediction about occurrence of two events should be anticipated, a statistical bivariate model is used. Due to the limitations of usual statistical models, other methods such as Artificial Neural Network (ANN) and hybrid models could be used. In this paper, we propose a hybrid Artificial Neural Network-Genetic Algorithm (ANN-GA) model to prediction the occurrence of heart block and death in myocardial infarction (MI) patients simultaneously. METHODS: For fitting and comparing the models, 263 new patients with definite diagnosis of MI hospitalized in Cardiology Ward of Hajar Hospital, Shahrekord, Iran, from March, 2014 to March, 2016 were enrolled. Occurrence of heart block and death were employed as bivariate binary outcomes. Bivariate Logistic Regression (BLR), ANN and hybrid ANN-GA models were fitted to data. Prediction accuracy was used to compare the models. The codes were written in Matlab 2013a and Zelig package in R3.2.2. RESULTS: The prediction accuracy of BLR, ANN and hybrid ANN-GA models was obtained 77.7%, 83.69% and 93.85% for the training and 78.48%, 84.81% and 96.2% for the test data, respectively. In both training and test data set, hybrid ANN-GA model had better accuracy. CONCLUSIONS: ANN model could be a suitable alternative for modeling and predicting bivariate binary responses when the presuppositions of statistical models are not met in actual data. In addition, using optimization methods, such as hybrid ANN-GA model, could improve precision of ANN model. PMID- 28087851 TI - Effect of Educational Intervention on the Fruit and Vegetables Consumption among the Students: Applying Theory of Planned Behavior. AB - BACKGROUND: The importance of consuming fruits and vegetables (F&V) in prevention of chronic diseases is known. Childhood play an important role in formation of healthy eating habits. The purpose of this study was to examine the effect of education, with application of the theory of planned behavior, on improvement of F&V consumption. METHODS: In this quasi-experimental study, 184 fourth, fifth, and sixth-grade students participated were enrolled from Jan 2013 to Jun 2014. The samples were selected from 6 schools in Chalderan County, West Azerbaijan, Iran through cluster random sampling method. Two out of 6 schools were randomly selected and each was employed in either experimental or control group. The data collection instruments included a researcher-made questionnaire and a 24-h F&V recall. Data were collected after verification of the reliability and validity of the questionnaire. RESULTS: Before the intervention, no significant difference was observed between the intervention and control group regarding attitude, subjective norms, perceived behavioral control, behavioral intention and fruits and vegetables consumption (P>0.05). However, after the educational intervention, the mean scores of attitude, subjective norms, perceived behavioral control, behavioral intention variables and fruits and vegetables were significantly higher in the intervention group when compared to the control group(P<0.05). CONCLUSIONS: Increased behavioral intention, attitude, subjective norms, and perceived behavioral control can promote F&V consumption among the students. PMID- 28087852 TI - Comparative Analysis of Lighting Characteristics and Ultraviolet Emissions from Commercial Compact Fluorescent and Incandescent Lamps. AB - BACKGROUND: Some characteristics of lighting sources such as color properties and ultraviolet emissions have important roles on visual and non-visual health effects of lighting. This study aimed to investigate the light emissions of some compact fluorescent lamps (CFLs) and incandescent lamps commercially available to the Iranian consumers. METHODS: Sixty lamps included 48 single envelope CFLs, and 12 incandescent lamps available in the electrical devices markets (in the west of Iran) were randomly selected from famous manufacturers between 2014 and 2015. Lighting characteristics and ultraviolet (UV) emissions were measured using spectroradiometer and calibrated radiometer, respectively. Data analysis was performed using SPSS16 software. RESULTS: Color-rendering indexes of the studied lamps were above 80, which showed good color properties. The daylight CFLs had more desirable and natural color temperature (near to 5000 0k) compared with the other types of the studied lamps. Occupational exposures for periods up 8 h to UVB from the studied lamps at distances up to 0.25 m were more than the recommended limits. Moreover, public exposures for periods up 16 h to UVB from the studied lamps at any distances up to 2 m were more than the recommended limits. CONCLUSIONS: Warm white lamps are suitable for homes usage, while daylight lamps can be used for offices rooms. Occupational exposure to single envelope CFLs near the body at distances of less than 25 cm can result in overexposure to actinic UV. Moreover, CFLs must be used at distances greater than 200 cm for public exposure. PMID- 28087853 TI - A New Microwave Shield Preparation for Super High Frequency Range: Occupational Approach to Radiation Protection. AB - BACKGROUND: Widespread use of X-band frequency (a part of the super high frequency microwave) in the various workplaces would contribute to occupational exposure with potential of adverse health effects. According to limited study on microwave shielding for the workplace, this study tried to prepare a new microwave shielding for this purpose. METHODS: We used EI-403 epoxy thermosetting resin as a matrix and nickel oxide nanoparticle with the diameter of 15-35 nm as filler. The Epoxy/ Nickel oxide composites with 5, 7, 9 and 11 wt% were made in three different thicknesses (2, 4 and 6 mm). According to transmission / reflection method, shielding effectiveness (SE) in the X-band frequency range (8 12.5 GHz) was measured by scattering parameters directly given by the 2-port Vector Network Analyzer. The fabricated composites characterized by X-ray Diffraction and Field Emission Scanning Electron Microscope. RESULTS: The best average of shielding effectiveness in each thickness of fabricated composites obtained by 11%-2 mm, 7%-4 mm and 7%-6 mm composites with SE values of 46.80%, 66.72% and 64.52%, respectively. In addition, the 11%-6 mm, 5%-6 mm and 11%-4 mm fabricated composites were able to attenuate extremely the incident microwave energy at 8.01, 8.51 and 8.53 GHz by SE of 84.14%, 83.57 and 81.30%, respectively. CONCLUSIONS: The 7%-4mm composite could be introduced as a suitable alternative microwave shield in radiation protection topics in order to its proper SE and other preferable properties such as low cost and weight, resistance to corrosion etc. It is necessary to develop and investigate the efficacy of the fabricated composites in the fields by future studies. PMID- 28087854 TI - A Structural Equation Modeling of the Relationships between Depression, Drug Abuse and Social Support with Suicidal Ideation among Soldiers in Iran in 2015. AB - BACKGROUND: Military service is a crucial period in the lives of young people and during this period soldier facing with multiple psychosocial problems. OBJECTIVES: The present study aimed to explore structural analysis of the relationships between depression, drug abuse, social support and the risk of suicidal ideation among Military Medical University soldiers in Iran. METHODS: In the present correlational research, a sample of 176 soldiers, from three units, was selected using randomly stratified sampling. Data were collected through the Social Support Questionnaire (SSQ), the Beck Depression Inventory-II (BDI-II), the Beck Scale for Suicide Ideation (BSS) and the Possibility of Drug Abuse Scale (LDAS). Structural equation modeling was used to test the fit of the model, identify direct and indirect effects of the psychosocial correlates. Data were analyzed using the SPSS and AMOS software (Verson22). RESULTS: out of the whole subjects, 28.4% had suicidal ideation and 65.3% had degrees of depression (mild to severe). A significant reverse relationship was observed between social support and suicidal ideation (p<0.05). The strongest relationship was detected between drug abuse and suicidal ideation. The final structural model indicated that 74% of the variance in suicidal ideation was explained by the three examined variables of depression, social support and drug abuse. CONCLUSIONS: The overall results showed that the risk of suicidal ideation, depression and drug abuse are relatively significant in Military Medical University soldiers requiring taking serious actions by the authorities and other relevant organizations in order to improve the psychosocial health status of these soldiers. PMID- 28087855 TI - Factors Associated with Hookah Use among Male High School Students: The Role of Demographic Characteristics and Hookah User and Non-User Prototypes. AB - BACKGROUND: As students' hookah use has become a widespread problem in the developing countries, it is time to understand the cognitive determinants of students' decisions to do so. This study aimed to investigate the roles of psychological and demographic factors associated with hookah use among male high school students. METHODS: This descriptive-analytical study was performed among 601 high school male students, recruited through multistage sampling method in the Kermanshah City, west of Iran in 2016. The data-gathering tool consisted of a self-administered questionnaire with questions about hookah use behavior and demographic, behavioral and psychological variables. Data were analyzed using SPSS-18 software using chi-square and logistic regression. RESULTS: 36.1% of the participants reported ever hookah use and 17.1% mentioned using hookah in the past month. Pleasure (28.1%) and sensation seeking (22.5%) were common reasons of hookah use. In comparison to non-users, hookah users evaluated a typical hookah user as more clever, less immature, more popular, more attractive, more self confident, more independent, and less selfish (P<0.001). CONCLUSIONS: The results revealed the importance of psychological factors when examining students' hookah use status. Thus, design and implementation of interventions might be effective in prevention of hookah use among students. PMID- 28087856 TI - An Outbreak of Aeromonas hydrophila Food Poisoning in Deptsang Village, Samdrup Jongkhar, Bhutan, 2016. AB - BACKGROUND: An outbreak investigation was carried out to determine the cause and confirm the source of food poisoning in Deptsang village for implementing prevention and control measures. METHODS: We conducted a retrospective cohort study for the outbreak investigation. Stool specimens were collected from cases to perform culture and antibiogram. The team also inspected the environment and hygiene practices in both the construction site and the entire community. The association between the exposure to carcass meat and their outcome of acute gastroenteritis was assessed by risk ratio. P<0.05 was considered statistically significant. RESULTS: Fifty-five villagers consumed the carcass meat during lunch and dinner resulting in 33 cases. Multi-drug resistant Aeromonas hydrophila was isolated from stool specimens of cases, which were susceptible to chloramphenicol only. A risk ratio of 2.1 was found between those people who consumed the carcass meat and those who did not consume the carcass meat (P<0.001). CONCLUSIONS: The current outbreak of food poisoning was caused by the consumption of carcass meat contaminated with A. hydrophila. Provision of health education with emphasis on food hygiene is needed in remote areas to prevent such outbreaks in the future. PMID- 28087857 TI - Predictors of Bone Mineral Density among Asian Indians in Northern Mississippi: A Pilot Study. AB - BACKGROUND: Osteoporosis is a systemic skeletal disorder characterized by low bone mineral density (BMD) that leads to an increase in bone fragility, causing an individual to be at an increased risk for fractures. Asian-Indians are at an increased risk for developing osteoporosis. Considering the number of Asian Indians in the US is rapidly growing, they likely could be an underappreciated population at risk for bone fractures. The aim of this study was to investigate bone health and determine the factors affecting BMD in Asian-Indians living in the US. METHODS: Asian-Indians residing in Northern Mississippi (n = 87) were enrolled in this cross-sectional study from June 2013 to August 2014. Eligible participants completed a self-administered Osteoporosis Risk Factor Assessment questionnaire. BMD and body composition were measured using a dual energy x-ray absorptiometry scan (DXA). RESULTS: Eight-seven Asian-Indians (male: 62.1%) participated, with the average age being 28.49 yr old (SD = 6.62). Overall, 31.0% and 48.3% had low femoral neck BMD and spinal BMD, respectively. Multiple regression analysis revealed that age, percent body fat, and body mass index (BMI) significantly predicted BMD at femur neck (P<0.05). Additionally, percent body fat, BMI, childhood milk consumption, and gender were statistically significant predictors of spinal BMD (P<0.05). CONCLUSIONS: The findings from this study should be beneficial to healthcare providers that work with Asian Indian population groups. Health promotion programs focusing on osteoporosis prevention are needed among Asian-Indians to prevent the risk of fractures. PMID- 28087858 TI - Comment on: "Economic Burden of Thalassemia Major in Iran, 2015". AB - . PMID- 28087859 TI - Timeliness: The authors' vested right but the editors' last concern. AB - . PMID- 28087860 TI - Retraction note: Triptolide contributes to decrease in TLR4 expression by upregulating miR-224-3p to inhibit the inflammatory reaction in diabetic nephropathy. PMID- 28087862 TI - Is the Rx to blame for the patient's weight gain? AB - Avoid prescribing medications that can cause weight gain in overweight and obese patients when possible, use the lowest effective dose when such agents are necessary, and warn patients of this adverse effect so that they can take precautions, such as walking an extra mile a day or giving up that high-calorie latte in the morning. PMID- 28087861 TI - Jolkinolide A and Jolkinolide B Inhibit Proliferation of A549 Cells and Activity of Human Umbilical Vein Endothelial Cells. AB - BACKGROUND Jolkinolide A (JA) and Jolkinolide B (JB) are diterpenoids extracted from the roots of Euphorbia fischeriana Steud and have been shown to have anti tumor activity. However, their effects on the ability of tumor cells to invade blood vessels and metastasize remain largely unknown. Investigations into the effects of JA and JB on the angiogenesis of tumor tissues may facilitate the identification of new natural drugs with anti-tumor growth and metastasis activities. MATERIAL AND METHODS We used different concentrations of JA and JB (20 MUg/ml, 40 MUg/ml, 60 MUg/ml, 80 MUg/ml, and 100 MUg/ml) to stimulate A549 cells and then studied the effects on the growth and metastasis of lung cancers. In addition, we used conditional media from A549 cells (A549-CM) stimulated by either JA or JB in different concentrations to culture human umbilical vein endothelial cells (HUVECs). RESULTS We found that both JA and JB significantly inhibited the Akt-STAT3-mTOR signaling pathway and reduced the expression of VEGF in A549 cells, but JB exhibited more significant inhibitory effects than JA. The JB-stimulated A549 cell conditional media had a greater inhibitory effect on the proliferation and migration of HUVECs than did the conditional media of JA stimulated A549 cells. This effect gradually increased with increasing concentrations of either type of Jolkinolide. CONCLUSIONS Our results suggest that JA and JB inhibited VEGF expression in A549 cells through the inhibition of the Akt-STAT3-mTOR signaling pathway, and directly inhibited the proliferation and migration of HUVECs. These findings are of great significance for the development of new plant-derived chemotherapy agents for the treatment of cancer. PMID- 28087863 TI - HIV update: Which single-tablet regimens, and when. AB - With the approval of single-tablet regimens that contain 3 or 4 drugs, many patients take just one pill a day. So what are the options and what's on the horizon? PMID- 28087864 TI - Drug-induced weight gain: Rethinking our choices. AB - Weight gain secondary to medications is a potentially modifiable risk. Here's how to optimize drug choices for patients with several common conditions. PMID- 28087865 TI - Recreational cannabinoid use: The hazards behind the "high". AB - Marijuana use can cause concerning physical, psychomotor, cognitive, and psychiatric effects, not to mention a near-doubling of car accidents. PMID- 28087866 TI - When can infants and children benefit from probiotics? AB - The latest studies indicate that probiotics can help with colic, eczema, and certain types of diarrhea. They may also help with upper respiratory infections and IBS pain. PMID- 28087867 TI - Persistent fever investigation saves patient's life. AB - A 47-year-old woman had been hospitalized one month earlier for lupus nephritis with a hypertensive emergency that led to a seizure. During this earlier hospitalization, she was given a diagnosis of posterior reversible encephalopathy syndrome. PMID- 28087868 TI - Mildly pruritic palmar rash. AB - After taking azithromycin and prednisone for lower respiratory symptoms, this patient developed a rash. The way it spread provided a diagnostic clue. PMID- 28087869 TI - Clinical Inquiry: Which patients with metabolic syndrome benefit from metformin? AB - In patients with metabolic syndrome who are in the highest-risk quartile for progression to diabetes (predicted mean 3-year risk, 60%), metformin, 850 mg twice daily, reduces the absolute risk by about 20% over a 3-year period. Metformin doesn't reduce the incidence in patients at lower risk of progression. PMID- 28087870 TI - PURLs: Deliver or wait with late preterm membrane rupture? AB - While ACOG recommends delivery for all women with ruptured membranes after 34 weeks' gestation, a new study finds expectant management may be the way to go. PMID- 28087871 TI - Poison ivy: How effective are available treatments? AB - In this study, only one treatment approach significantly reduced pruritus. Three approaches were often associated with recurrences of rash or symptoms. PMID- 28087872 TI - Clinical Inquiry: How do clinical prediction rules compare with joint fluid analysis in diagnosing gout? AB - Clinical prediction rules effectively diagnose gout without joint fluid analysis. The American College of Rheumatology clinical prediction rules, the most accurate rules developed for research purposes, have a sensitivity of 92%, specificity of 89%, positive likelihood ratio of 8.36, and negative likelihood ratio of 0.09. PMID- 28087873 TI - Clinical Inquiry: Which treatments are safe and effective for chronic sinusitis? AB - For adults with chronic rhinosinusitis (CRS), intranasal steroid (INS) therapy is more likely than placebo to improve symptoms. PMID- 28087874 TI - Two cases of asymmetric papules. AB - Both of these young patients presented with rashes that had spread from their abdomen to their arms and legs--but only on one side. PMID- 28087875 TI - What can we do about the Zika virus in the United States? AB - Control measures include using insect repellents, aerial spraying of insecticides, eliminating mosquito breeding sites, covering water tanks, and using mosquito nets or door and window screens. Infection during pregnancy is the greatest concern because of congenital anomalies (including microcephaly) that negatively affect brain development. PMID- 28087876 TI - A tricky interplay, indeed. AB - Despite the lack of evidence, some providers are still prescribing native vitamin D for their patients with chronic kidney disease for reasons unrelated to parathyroid hormone suppression. PMID- 28087877 TI - Erratum. AB - The article incorrectly stated: "Elevations of both fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) lead to hyperphosphatemia and hypocalcemia because of decreased urinary excretion of phosphorus." In fact, FGF23 normally acts to lower blood phosphate levels. Furthermore, an elevated phosphorus level causes an increase in serum calcium levels and not hypocalcemia. This information has been corrected in the online version of the article. PMID- 28087878 TI - Notice of retraction. AB - According to JAMA's retraction statement, the first author of the article admitted to data fabrication following an internal investigation.2 The source article does not provide subgroup analysis to determine how much of an effect the fabricated data may have had on the final reported outcome. PMID- 28087879 TI - Management of Daily Glycemic Fluctuations in Patients With Type 2 Diabetes. AB - Traditional measures of overall glucose control, such as glycated hemoglobin (A1C), may not fully capture short-term, rapid changes in blood glucose. With the availability of multiple options to control A1C, glycemic fluctuations have emerged as an additional therapeutic goal for the management of type 2 diabetes (T2D). PMID- 28087880 TI - Direct Synthesis of Highly Designable Hybrid Metal Hydroxide Nanosheets by Using Tripodal Ligands as One-Size-Fits-All Modifiers. AB - Brucite-type layered metal hydroxides are prepared from diverse metallic elements and have outstanding functions; however, their poor intercalation ability significantly limits their chemical designability and the use of their potentially ultrahigh surface areas and unique properties as two-dimensional nanosheets. Here, we demonstrate that tripodal ligands (RC(CH2 OH)3 , R=NH2 , CH2 OH, or NHC2 H4 SO3 H) are useful as "one-size-fits-all" modifiers for the direct synthesis of hybrid metal hydroxide nanosheets with various constituent metallic elements (M=Mg, Mn, Fe, Co, Ni, or Cu) and surface functional groups. The hybrid nanosheets are formed directly from solution phases, and they are stacked into a turbostratic layered structure. The ligands form tridentate Mg-O-C bonds with brucite layers. The hybrid brucite intercalates various molecules and is exfoliated into nanosheets at room temperature, although the non-modified material does not intercalate any molecules. Consequently, both the constituent metallic elements and surface functional groups are freely designed by the direct synthesis. PMID- 28087882 TI - Cooperatively Interlocked [2+1]-Type pi-System-Anion Complexes. AB - As fascinating examples of closely connected multiple pi-electronic systems involving noncovalent interactions, the cooperatively interlocked [2+1]-type anion complexes of well-designed pi-electronic molecules are reported. The anion responsive pi-electronic molecules investigated in this study are the boron complexes of dipyrrolyldiketones bearing arylethynyl moieties at the pyrrole alpha-positions. Diverse substituents were introduced at the terminal aryl moieties, thus controlling the cooperativity to form [2+1]-type complexes. Theoretical studies showed that this cooperativity was induced by effective interactions between the introduced arylethynyl moieties. The investigations of the anion-binding processes showed that the first and second bindings to the guest anion were energetically almost equivalent, indicating the fundamental and important features of the electronic states of the halide anions. Furthermore, the interlocked anion complexes, whose geometries were distorted from the orthogonal arrangements, had the racemic states of the chiral conformations, either of which was induced by ion pairing with an appropriate chiral pi electronic cation, resulting in the chiroptical property as shown by circular dichroism. PMID- 28087881 TI - Role of STIM2 in cell function and physiopathology. AB - An endoplasmic reticulum (ER)-resident protein that regulates cytosolic and ER free-Ca2+ concentration by induction of store-operated calcium entry: that is the original definition of STIM2 and its function. While its activity strongly depends on the amount of calcium stored in the ER, its function goes further, to intracellular signalling and gene expression. Initially under-studied owing to the prominent function of STIM1, STIM2 came to be regarded as vital in mice, gradually emerging as an important player in the nervous system, and cooperating with STIM1 in the immune system. STIM2 has also been proposed as a relevant player in pathological conditions related to ageing, Alzheimer's and Huntington's diseases, autoimmune disorders and cancer. The discovery of additional functions, together with new splicing forms with opposite roles, has clarified existing controversies about STIM2 function in SOCE. With STIM2 being essential for life, but apparently not for development, newly available data demonstrate a complex and still intriguing behaviour that this review summarizes, updating current knowledge of STIM2 function. PMID- 28087883 TI - Defining genetic and chemical diversity in wheat grain by 1H-NMR spectroscopy of polar metabolites. AB - SCOPE: The application of high-throughput 1H nuclear magnetic resonance (1H-NMR) of unpurified extracts to determine genetic diversity and the contents of polar components in grain of wheat. METHODS AND RESULTS: Milled whole wheat grain was extracted with 80:20 D2 O:CD3 OD containing 0.05% d4 -trimethylsilylpropionate. 1H-NMR spectra were acquired under automation at 300 degrees K using an Avance Spectrometer operating at 600.0528 MHz. Regions for individual metabolites were identified by comparison to a library of known standards run under identical conditions. The individual 1H-NMR peaks or levels of known metabolites were then compared by Principal Component Analysis using SIMCA-P software. CONCLUSIONS: High-throughput 1H-NMR is an excellent tool to compare the extent of genetic diversity within and between wheat species, and to quantify specific components (including glycine betaine, choline, and asparagine) in individual genotypes. It can also be used to monitor changes in composition related to environmental factors and to support comparisons of the substantial equivalence of transgenic lines. PMID- 28087884 TI - The role of immunoglobulin prophylaxis for prevention of cytomegalovirus infection in pediatric hematopoietic stem cell transplantation recipients. AB - BACKGROUND: Following cessation of intravenous immunoglobulin (IVIg) administration for allogeneic hematopoietic stem cell transplantation (HSCT) recipients at our unit, we observed a sharp decline in the incidence of cytomegalovirus (CMV) infection. PROCEDURE: We conducted a retrospective study of the role of IVIg in the prevention of CMV infection in children and young adults who underwent HSCT from matched related donor. RESULTS: We included 109 patients (IVIg+/IVIg- ratio 82/27). Median age was 8.5 years. Patients were transplanted for malignant (59.7%) and nonmalignant diseases (40.3%) with myeloablative, reduced-intensity, and nonmyeloablative conditioning in 76, 22, and 2% of the transplants, respectively. Graft sources were peripheral blood stem cells, bone marrow, and cord blood in 58.7, 39.4, and 2%, respectively. The cumulative incidence of CMV infection at 1 year after HSCT was significantly higher in the cohort that did not receive IVIg compared with the one that did (44.4% vs. 13.4%, respectively, P = 0.001). Significant risk factor for CMV infection in the cohort not receiving IVIg was conditioning with total body irradiation (TBI) (87.5% in TBI+ vs. 26.3% in TBI-, P = 0.003). CONCLUSIONS: We conclude that children and young adults who undergo HSCT with TBI may need a preemptive regimen of anti-CMV treatment, if they do not get IVIg prophylaxis. PMID- 28087885 TI - Absence of intestinal microbiota increases beta-cyclodextrin stimulated reverse cholesterol transport. AB - SCOPE: Non-digestible oligosaccharides are used as prebiotics for perceived health benefits, among these modulating lipid metabolism. However, the mechanisms of action are incompletely understood. The present study characterized the impact of dietary beta-cyclodextrin (betaCD, 10%, w/w), a cyclic oligosaccharide, on sterol metabolism and reverse cholesterol transport (RCT) in conventional and also germ-free mice to establish dependency on metabolism by intestinal bacteria. METHODS AND RESULTS: In conventional betaCD-fed C57BL/6J wild-type mice plasma cholesterol decreased significantly (-40%, p < 0.05), largely within HDL, while fecal neutral sterol excretion increased (3-fold, p < 0.01) and fecal bile acid excretion was unchanged. Hepatic cholesterol levels and biliary cholesterol secretion were unaltered. Changes in cholesterol metabolism translated into increased macrophage-to-feces RCT in betaCD-administered mice (1.5-fold, p < 0.05). In germ-free C57BL/6J mice betaCD similarly lowered plasma cholesterol ( 40%, p < 0.05). However, betaCD increased fecal neutral sterol excretion (7.5 fold, p < 0.01), bile acid excretion (2-fold, p < 0.05) and RCT (2.5-fold, p < 0.01) even more substantially in germ-free mice compared with the effect in conventional mice. CONCLUSION: In summary, this study demonstrates that betaCD lowers plasma cholesterol levels and increases fecal cholesterol excretion from a RCT-relevant pool. Intestinal bacteria decrease the impact of betaCD on RCT. These data suggest that dietary betaCD might have cardiovascular health benefits. PMID- 28087886 TI - d-Chiro inositol ameliorates endothelial dysfunction via inhibition of oxidative stress and mitochondrial fission. AB - SCOPE: d-chiro inositol (DCI), an isomer of inositol, possesses anti-oxidative and endothelial protective properties. The mechanism by which DCI prevents endothelial dysfunction was investigated, with emphasis on oxidative stress. METHODS AND RESULTS: DCI was found to inhibit NOX4 induction and enhance Nrf2 activity in palmitate (PA)-stimulated cells, showing that DCI prevents oxidative stress. DCI suppressed Ser616 phosphorylation and increased Ser637 phosphorylation of Drp1 and inhibited PA-induced mitochondrial fission. Knockdown of Drp1 attenuated NOX4 over-expression and increased the inhibitory effect of DCI. In addition, DCI enhanced AMPK activity through the LKB1-dependent pathway. AMPK knockdown diminished the inhibitory effect of DCI on Drp1/NOX4 induction, indicating that AMPK is essential for Drp1 and NOX4 suppression by DCI. As a result, DCI inhibited cell apoptosis against PA insults. Consistent with the effects observed in cells, DCI reversed endothelial dysfunction in rat aorta rings under lipid-challenged conditions. In high fat-fed mice, oral administration of DCI inhibited Drp1/NOX4 induction and enhanced NO generation in the aortic endothelium, confirming its protective role in endothelial function in vivo. CONCLUSION: Drp1 activation-induced mitochondrial fission and NOX4 over expression are associated with endothelial injury. DCI prevented endothelial dysfunction by inhibiting oxidative stress and mitochondrial fission in an AMPK dependent manner. PMID- 28087887 TI - Evaluation of a standardized ward round in a prenatal inpatient setting. AB - OBJECTIVE: To evaluate the impact of incorporating a standardized ward round (SWR) tool including checklists for communication, safety, and efficiency into ward rounds. METHODS: A prospective non-randomized, before-and-after observational study was conducted at a tertiary maternity hospital in Brisbane, Australia, between October 1, 2014, and October 1, 2015. Obstetric team members performing prenatal ward rounds used role-specific lanyards prompting the structure of each consultation. Rounds were audited before and after the introduction of the SWR for safety checks, hand hygiene, the duration of patient encounters, and plan congruity. Patients completed a paper-based satisfaction survey. Results from before and after the introduction of the SWR were compared. RESULTS: There were 71 conventional ward rounds and 79 SWRs audited, and no difference was found in the mean duration of patient encounters (P=0.566). SWRs were associated with increased rates of each of the five safety checks being performed and of hand hygiene being observed correctly (all P<0.001). SWR was also associated with a greater proportion of patients indicating that they understood their plan of care. CONCLUSION: The use of a structured tool for ward rounds improved communication with patients, increased the frequency of safety checks being performed, and improved hand hygiene without prolonging ward rounds. PMID- 28087888 TI - Simulated microgravity decreases circulating iron in rats: role of inflammation induced hepcidin upregulation. AB - NEW FINDINGS: What is the central question of this study? Although microgravity is well known to reduce circulating iron in astronauts, the underlying mechanism is still unknown. We investigated whether hepcidin, a key hormone regulating iron metabolism, could be involved in this deleterious effect. What is the main finding and its importance? We show that hindlimb suspension, a model of microgravity, stimulates the production of hepcidin in liver of rats. In agreement with the biological role of hepcidin, we found a decrease of circulating iron and an increase of spleen iron content in hindlimb-unloaded rats. Consequently, our study supports the idea that hepcidin could play a role in the alteration of iron metabolism parameters observed during spaceflight. During spaceflight, humans exposed to microgravity exhibit an increase of iron storage and a reduction of circulating iron. Such perturbations could promote oxidative stress and anaemia in astronauts. The mechanism by which microgravity modulates iron metabolism is still unknown. Herein, we hypothesized that microgravity upregulates hepcidin, a hormone produced by the liver that is the main controller of iron homeostasis. To test this hypothesis, rats were submitted to hindlimb unloading (HU), the reference model to mimic the effects of microgravity in rodents. After 7 days, the mRNA level of hepcidin was increased in the liver of HU rats (+74%, P = 0.001). In agreement with the biological role of hepcidin, we found an increase of spleen iron content (+78%, P = 0.030) and a decrease of serum iron concentration (-35%, P = 0.002) and transferrin saturation (-25%, P = 0.011) in HU rats. These findings support a role of hepcidin in microgravity-induced iron metabolism alteration. Furthermore, among the signalling pathways inducing hepcidin mRNA expression, we found that only the interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) axis was activated by HU, as shown by the increase of phospho-STAT3 (+193%, P < 0.001) and of the hepatic mRNA level of haptoglobin (+167%, P < 0.001), a STAT3 inducible gene, in HU rats. Taken together, these data support the idea that microgravity may alter iron metabolism through an inflammatory process upregulating hepcidin. PMID- 28087889 TI - National audit of the quality of pain relief provided in emergency departments in Aotearoa, New Zealand: The PRiZED 1 Study. AB - OBJECTIVE: Pain is a common feature of ED presentations and the timely provision of adequate analgesia is important for patient care. However, there is currently no New Zealand data with respect to this indicator of care quality. The present study aimed to provide a baseline for the quality of care with respect to the provision of timely and adequate analgesia in New Zealand EDs. METHODS: The present study is a secondary analysis of data initially collected for the Shorter Stays in Emergency Department Study, using a retrospective chart review of 1685 randomly selected ED presentations (2006-2012) from 26 New Zealand public hospital EDs. RESULTS: Of the 1685 charts randomly selected, 1547 (91%) were reviewed from 21 EDs. There were 866 ED presentations with painful conditions, of whom 132 (15%) did not have pain recorded, 205 (24%) did not receive pain relief and 19 (2%) did not have time of analgesia documented leaving 510 (59%) for the analysis of time to analgesia. Four hundred and fifty-seven (53%) did not have pain well documented sufficiently to assess adequacy, leaving 277 (32%) for the analysis of adequacy of analgesia. The median (interquartile range) time to analgesia was 62 (30-134) min and the provision of adequate analgesia was 141/277 (51%, 95% CI: 45-57%); however, there was some variation between hospitals for both outcomes. CONCLUSION: Although these outcomes are on a par with other countries, this baseline audit has shown both poor documentation and variation in the provision of timely and adequate pain relief in New Zealand EDs, with room for improvement with respect to this quality indicator. PMID- 28087890 TI - Overview of the benefits and potential issues of the nonavalent HPV vaccine. AB - HPV-related diseases affect anogenital and oropharyngeal regions, heavily affecting the psychosexual dimension of both male and female individuals. HPV vaccination programs based on a bivalent or quadrivalent vaccine have opened broad perspectives for primary prevention. A nonavalent HPV vaccine (9vHPV), covering nine genotypes (HPV6, HPV11, HPV16, HPV18, HPV31, HPV33, HPV45, HPV52, and HPV58), might provide further improvement in terms of direct protection. In the present report, efficacy and safety data from 9vHPV vaccine development programs are examined. Efficacy data come from a pivotal trial, which was conducted among women aged 16-26 years randomly assigned to receive either the 9vHPV or the quadrivalent HPV (4vHPV) vaccine. The 9vHPV vaccine was shown to have potential benefits as compared with 4vHPV, increasing the overall estimated rate of prevention to 90% for cervical cancer and up to 80% for precancerous cervical lesions. For all other HPV-related pre-invasive and invasive lesions, 9vHPV showed potentially greater disease reduction, depending on the anatomic region examined. Thus, the 9vHPV vaccine shows clinical potential for the prevention of HPV-related diseases in both sexes. Future adoption of 9vHPV will depend on factors including market price, cost-effectiveness data, use of a two dose schedule, and safety and efficacy monitoring in real-life programs. PMID- 28087891 TI - Physical activity and exercise for chronic pain in adults: an overview of Cochrane Reviews. AB - BACKGROUND: Chronic pain is defined as pain lasting beyond normal tissue healing time, generally taken to be 12 weeks. It contributes to disability, anxiety, depression, sleep disturbances, poor quality of life, and healthcare costs. Chronic pain has a weighted mean prevalence in adults of 20%.For many years, the treatment choice for chronic pain included recommendations for rest and inactivity. However, exercise may have specific benefits in reducing the severity of chronic pain, as well as more general benefits associated with improved overall physical and mental health, and physical functioning.Physical activity and exercise programmes are increasingly being promoted and offered in various healthcare systems, and for a variety of chronic pain conditions. It is therefore important at this stage to establish the efficacy and safety of these programmes, and furthermore to address the critical factors that determine their success or failure. OBJECTIVES: To provide an overview of Cochrane Reviews of adults with chronic pain to determine (1) the effectiveness of different physical activity and exercise interventions in reducing pain severity and its impact on function, quality of life, and healthcare use; and (2) the evidence for any adverse effects or harm associated with physical activity and exercise interventions. METHODS: We searched theCochrane Database of Systematic Reviews (CDSR) on the Cochrane Library (CDSR 2016, Issue 1) for systematic reviews of randomised controlled trials (RCTs), after which we tracked any included reviews for updates, and tracked protocols in case of full review publication until an arbitrary cut-off date of 21 March 2016 (CDSR 2016, Issue 3). We assessed the methodological quality of the reviews using the AMSTAR tool, and also planned to analyse data for each painful condition based on quality of the evidence.We extracted data for (1) self-reported pain severity, (2) physical function (objectively or subjectively measured), (3) psychological function, (4) quality of life, (5) adherence to the prescribed intervention, (6) healthcare use/attendance, (7) adverse events, and (8) death.Due to the limited data available, we were unable to directly compare and analyse interventions, and have instead reported the evidence qualitatively. MAIN RESULTS: We included 21 reviews with 381 included studies and 37,143 participants. Of these, 264 studies (19,642 participants) examined exercise versus no exercise/minimal intervention in adults with chronic pain and were used in the qualitative analysis.Pain conditions included rheumatoid arthritis, osteoarthritis, fibromyalgia, low back pain, intermittent claudication, dysmenorrhoea, mechanical neck disorder, spinal cord injury, postpolio syndrome, and patellofemoral pain. None of the reviews assessed 'chronic pain' or 'chronic widespread pain' as a general term or specific condition. Interventions included aerobic, strength, flexibility, range of motion, and core or balance training programmes, as well as yoga, Pilates, and tai chi.Reviews were well performed and reported (based on AMSTAR), and included studies had acceptable risk of bias (with inadequate reporting of attrition and reporting biases). However the quality of evidence was low due to participant numbers (most included studies had fewer than 50 participants in total), length of intervention and follow-up (rarely assessed beyond three to six months). We pooled the results from relevant reviews where appropriate, though results should be interpreted with caution due to the low quality evidence. Pain severity: several reviews noted favourable results from exercise: only three reviews that reported pain severity found no statistically significant changes in usual or mean pain from any intervention. However, results were inconsistent across interventions and follow-up, as exercise did not consistently bring about a change (positive or negative) in self-reported pain scores at any single point. Physical function: was the most commonly reported outcome measure. Physical function was significantly improved as a result of the intervention in 14 reviews, though even these statistically significant results had only small-to moderate effect sizes (only one review reported large effect sizes). Psychological function and quality of life: had variable results: results were either favourable to exercise (generally small and moderate effect size, with two reviews reporting significant, large effect sizes for quality of life), or showed no difference between groups. There were no negative effects. Adherence to the prescribed intervention: could not be assessed in any review. However, risk of withdrawal/dropout was slightly higher in the exercising group (82.8/1000 participants versus 81/1000 participants), though the group difference was non significant. Healthcare use/attendance: was not reported in any review. Adverse events, potential harm, and death: only 25% of included studies (across 18 reviews) actively reported adverse events. Based on the available evidence, most adverse events were increased soreness or muscle pain, which reportedly subsided after a few weeks of the intervention. Only one review reported death separately to other adverse events: the intervention was protective against death (based on the available evidence), though did not reach statistical significance. AUTHORS' CONCLUSIONS: The quality of the evidence examining physical activity and exercise for chronic pain is low. This is largely due to small sample sizes and potentially underpowered studies. A number of studies had adequately long interventions, but planned follow-up was limited to less than one year in all but six reviews.There were some favourable effects in reduction in pain severity and improved physical function, though these were mostly of small-to-moderate effect, and were not consistent across the reviews. There were variable effects for psychological function and quality of life.The available evidence suggests physical activity and exercise is an intervention with few adverse events that may improve pain severity and physical function, and consequent quality of life. However, further research is required and should focus on increasing participant numbers, including participants with a broader spectrum of pain severity, and lengthening both the intervention itself, and the follow-up period. PMID- 28087892 TI - Editorial Comment to Clinical characteristics of testicular germ cell tumors in patients aged 50 years and older: A large-scale study from the Cancer Registration Committee of the Japanese Urological Association. PMID- 28087893 TI - Brompheniramine as a novel probe for indirect UV detection and its application for the capillary electrophoresis of adamantane drugs. AB - Brompheniramine, an antihistamine drug, was employed as a novel UV probe for capillary electrophoresis with indirect UV detection of adamantane drugs (memantine, amantadine, and rimantadine). The probe possesses high molar absorptivity of 24 * 103 L/mol cm at 6 mM, which enables the measurement of these nonchromophore analytes without derivatization. The simple background electrolyte (10 mM sodium dihydrogen phosphate (pH 5.0) containing 5 mM brompheniramine and 6 mM beta-cyclodextrin) provided the separation of the analytes in a short time (7.5 min). Under these conditions, brompheniramine had similar mobility to that of the analyte ions resulting in symmetric peaks with minimal electrodispersion. The analytes displace the probe at a one-to-one ratio with transfer values close to unity. beta-Cyclodextrin played a role in the resolution of the structurally similar adamantane derivatives. Method validation showed good linearity (r2 > 0.98), precision (%RSD <= 3.30), and accuracy (recoveries ranging from 98 to 109%). The proposed method was successfully applied to determine the adamantane content in pharmaceutical products. PMID- 28087894 TI - Public cardiopulmonary resuscitation training rates and awareness of hands-only cardiopulmonary resuscitation: a cross-sectional survey of Victorians. AB - OBJECTIVES: To provide contemporary Australian data on the public's training in cardiopulmonary resuscitation (CPR) and awareness of hands-only CPR. METHODS: A cross-sectional telephone survey in April 2016 of adult residents of the Australian state of Victoria was conducted. Primary outcomes were rates of CPR training and awareness of hands-only CPR. RESULTS: Of the 404 adults surveyed (mean age 55 +/- 17 years, 59% female, 73% metropolitan residents), 274 (68%) had undergone CPR training. Only 50% (n = 201) had heard of hands-only CPR, with most citing first-aid courses (41%) and media (36%) as sources of information. Of those who had undergone training, the majority had received training more than 5 years previously (52%) and only 28% had received training or refreshed training in the past 12 months. Most received training in a formal first-aid class (43%), and received training as a requirement for work (67%). The most common reasons for not having training were: they had never thought about it (59%), did not have time (25%) and did not know where to learn (15%). Compared to standard CPR, a greater proportion of respondents were willing to provide hands-only CPR for strangers (67% vs 86%, P < 0.001). CONCLUSION: From an Australian perspective, there is still room for improvement in CPR training rates and awareness of hands only CPR. Further promotion of hands-only CPR and self-instruction (e.g. DVD kits or online) may see further improvements in CPR training and bystander CPR rates. PMID- 28087895 TI - Crohn disease risk prediction-Best practices and pitfalls with exome data. AB - The Critical Assessment of Genome Interpretation (CAGI) experiment is the first attempt to evaluate the state-of-the-art in genetic data interpretation. Among the proposed challenges, Crohn disease (CD) risk prediction has become the most classic problem spanning three editions. The scientific question is very hard: can anybody assess the risk to develop CD given the exome data alone? This is one of the ultimate goals of genetic analysis, which motivated most CAGI participants to look for powerful new methods. In the 2016 CD challenge, we implemented all the best methods proposed in the past editions. This resulted in 10 algorithms, which were evaluated fairly by CAGI organizers. We also used all the data available from CAGI 11 and 13 to maximize the amount of training samples. The most effective algorithms used known genes associated with CD from the literature. No method could evaluate effectively the importance of unannotated variants by using heuristics. As a downside, all CD datasets were strongly affected by sample stratification. This affected the performance reported by assessors. Therefore, we expect that future datasets will be normalized in order to remove population effects. This will improve methods comparison and promote algorithms focused on causal variants discovery. PMID- 28087897 TI - FGFR1 Analyses in Four Patients with Hypogonadotropic Hypogonadism with Split Hand/Foot Malformation: Implications for the Promoter Region. AB - Heterozygous loss-of-function mutations of FGFR1 (fibroblast growth factor receptor 1) cause various disorders including hypogonadotropic hypogonadism with split-hand/foot malformation (HH-SHFM). We examined FGFR1 in four Japanese patients with HH-SHFM (cases 1-4) and the mother of case 4 with HH only. Cases 1 and 2 had heterozygous loss-of-function mutations with no dominant negative effect (c.289G>A, p.[G97S]; and c.2231G>C, p.[R744T]), and case 3 had a splice donor site mutation (c.1663+1G>T). Notably, case 4 had a maternally inherited 8,312 bp microdeletion that involved noncoding exon 1U and impaired FGFR1 expression. Furthermore, consistent with the presence of transcription-related histone marks (e.g., H3K4Me3, H3K4Me1, and H3K27Ac) and multiple transcription factor-binding sites around exon 1U, functional studies demonstrated a marked transactivation function of a 414-bp segment harboring the transcription start site. These results support the relevance of FGFR1 mutations to HH-SHFM, and argue for the presence of the FGFR1 core-promoter elements around exon 1U. PMID- 28087896 TI - EAG channels expressed in microvillar photoreceptors are unsuited to diurnal vision. AB - KEY POINTS: The principles underlying the evolutionary selection of ion channels for expression in sensory neurons are unclear. Photoreceptor depolarization in the diurnal Drosophila melanogaster is predominantly provided by light-activated transient receptor potential (TRP) channels, whereas repolarization is mediated by sustained voltage-gated K+ channels of the Shab family. In the present study, we show that phototransduction in the nocturnal cockroach Periplaneta americana is predominantly mediated by TRP-like channels, whereas membrane repolarization is based on EAG channels. Although bright light stimulates Shab channels in Drosophila, further restricting depolarization and improving membrane bandwidth, it strongly suppresses EAG conductance in Periplaneta. This light-dependent inhibition (LDI) is caused by calcium and is abolished by chelating intracellular calcium or suppressing eag gene expression. LDI increases membrane resistance, augments gain and reduces the signalling bandwidth. This makes EAG unsuitable for light response conditioning during the day and might have resulted in the evolutionary replacement of EAG by other delayed rectifiers in diurnal insects. ABSTRACT: The principles underlying evolutionary selection of ion channels for expression in sensory neurons are unclear. Among species possessing microvillar photoreceptors, the major ionic conductances have only been identified in Drosophila melanogaster. In Drosophila, depolarization is provided by light activated transient receptor potential (TRP) channels with a minor contribution from TRP-like (TRPL) channels, whereas repolarization is mediated by sustained voltage-gated K+ (Kv) channels of the Shab family. Bright light stimulates Shab channels, further restricting depolarization and improving membrane bandwidth. In the present study, data obtained using a combination of electrophysiological, pharmacological and molecular knockdown techniques strongly suggest that in photoreceptors of the nocturnal cockroach Periplaneta americana the major excitatory channel is TRPL, whereas the predominant delayed rectifier is EAG, a ubiquitous but enigmatic Kv channel. By contrast to the diurnal Drosophila, bright light strongly suppresses EAG conductance in Periplaneta. This light dependent inhibition (LDI) is caused by calcium entering the cytosol and is amplified following inhibition of calcium extrusion, and it can also be abolished by chelating intracellular calcium or suppressing eag gene expression by RNA interference. LDI increases membrane resistance, augments gain and reduces the signalling bandwidth, impairing information transfer. LDI is also observed in the nocturnal cricket Gryllus integer, whereas, in the diurnal water strider Gerris lacustris, the delayed rectifier is up-regulated by light. Although LDI is not expected to reduce delayed rectifier current in the normal illumination environment of nocturnal cockroaches and crickets, it makes EAG unsuitable for light response conditioning during the day, and might have resulted in the evolutionary replacement of EAG by other delayed rectifiers in diurnal insects. PMID- 28087898 TI - Editorial Comment to Assessing clinically significant prostate cancer: Diagnostic properties of multiparametric magnetic resonance imaging compared to three dimensional transperineal template mapping histopathology. PMID- 28087901 TI - Response to Re: Role of routine computed tomography scan in the oncological follow up of patients treated by radical cystectomy for bladder cancer. PMID- 28087900 TI - iTRAQ-based quantitative proteomic analysis and bioinformatics study of proteins in pterygia. AB - PURPOSE: To analyze proteins in the tissue of pterygia, and to investigate their potential roles in pterygia, using the comparative proteomic technique of Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) coupled with offline 2DLC-MS/MS, Western-bolt. METHOD: The tissue of pterygia and healthy conjunctiva was collected from 10 pterygia patients (6 females, 4 males; average age was 52 years old; average course of disease was 6 years) in our hospital from September, 2015 to March, 2016. iTRAQ was used to analyze proteins in the patients' pterygia and healthy conjunctiva. Proteins with a fold change of >2. 0 or <0. 5 were considered to be significantly differentially expressed (with corrected p-values of <0. 1). The identified proteins were subjected to subsequent gene ontology analysis using the DAVID database. Then we confirmed the targeted proteins with western-blot. RESULTS: 156 proteins that expressed differently between the pterygia and healthy conjunctiva were identified using iTRAQ analysis. Of these proteins, 18 were down-regulated, and 138 were up-regulated. On the basis of biological processes in gene ontology, the identified proteins were mainly involved in cellular process, metabolic process, developmental process, location, cellular component organization, Among these proteins, matrix Metalloproteinase 10 (MMP-10) and CD34 may have potential roles in the pathogenesis of pterygia. Then we confirmed with Western-bolt that MMP-10 and CD34 were up-regulated in pterygia. CONCLUSION: This study is the first to identify 156 proteins associated with pterygia with iTRAQ technology. Data in our study will aid in providing a better understanding of pterygia. PMID- 28087899 TI - Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats. AB - SCOPE: Studies suggest diets rich in fruit and vegetables reduce bone loss, although the specific compounds responsible are unknown. Substrates for endogenous nitric oxide (NO) production, including organic nitrates and dietary nitrate, may support NO production in age-related conditions, including osteoporosis. We investigated the capability of dietary nitrate to improve NO bioavailability, reduce bone turnover and loss. METHODS AND RESULTS: Six-month old Sprague Dawley rats [30 ovariectomized (OVX) and 10 sham-operated (sham)] were randomized into three groups: (i) vehicle (water) control, (ii) low-dose nitrate (LDN, 0.1 mmol nitrate/kg bw/day), or (iii) high-dose nitrate (HDN, 1.0 mmol nitrate/kg bw/day) for three weeks. The sham received vehicle. Serum bone turnover markers; bone mass, mineral density, and quality; histomorphometric parameters; and fecal microbiome were examined. Three weeks of LDN or HDN improved NO bioavailability in a dose-dependent manner. OVX resulted in cancellous bone loss, increased bone turnover, and fecal microbiome changes. OVX increased relative abundances of Firmicutes and decreased Bacteroideceae and Alcaligenaceae. Nitrate did not affect the skeleton or fecal microbiome. CONCLUSION: These data indicate that OVX affects the fecal microbiome and that the gut microbiome is associated with bone mass. Three weeks of nitrate supplementation does not slow bone loss or alter the fecal microbiome in OVX. PMID- 28087902 TI - A review of the preventability of maternal mortality in one hospital system in Louisiana, USA. AB - OBJECTIVE: To determine preventability of in-hospital maternal mortality in the Ochsner Health System (OHS) in the US state of Louisiana. METHODS: A retrospective study was undertaken of all known cases of in-hospital maternal death (during pregnancy or within 42 days of termination) that occurred within OHS facilities in 1995-2013. Associations between characteristics and mortality and preventability were investigated. Incidence rate ratios (IRRs) were calculated in view of varying reference values. RESULTS: Among 16 eligible deaths, 12 (75%) were deemed potentially preventable. The incidences of overall and preventable maternal death were higher if the patient had late entry to prenatal care (IRR 6.3 [P=0.004] and 8.8 [P=0.004], respectively). Maternal mortality was increased if the patient had required transfer to the OHS (IRR 15.8 [P<0.001] overall and 15.8 [P=0.002] for preventable mortality). Deaths of patients with private insurance were more likely to be not preventable than were those of patients without such insurance (P=0.003). Uninsured patients had the highest MMR, with an IRR of 13.8 (P=0.014) when compared with Medicaid patients. CONCLUSION: The factors most predictive of mortality were late entry to prenatal care, critical status requiring transfer from an outside facility, and non private insurance status. PMID- 28087903 TI - [Interpretation of 2016 asthma management and prevention guideline]. AB - The revision in 2016 asthma management and prevention guideline includes both the diagnosis of asthma and the control-based asthma management. It points out that asthma is a heterogeneous disease, and the diagnosis of asthma should be based on the characteristic pattern of symptoms and evidence of variable airflow limitation, emphasizing the diagnosis of atypical asthma. Besides, the epidemiology of asthma, assessment of asthma, management severe asthma, special type of asthma and asthma in special populations have been added in this version. The revised guideline provides an important reference for the standardized management of asthma. PMID- 28087904 TI - [Protective effect of diosgenin on chondrocytes mediated by JAK2/STAT3 signaling pathway in mice with osteoarthritis]. AB - Objective: To investigate the effect of diosgenin (Dgn) on chondrocytes and its relation to JAK2/STAT3 signaling pathway in mice with osteoarthritis (OA).Methods: Fifteen male C57BL/6 mice were randomly divided into three groups:control group, OA group and OA+Dgn group. After 4 weeks of treatment, the histopathological changes of cartilage tissue were observed by toluidine blue staining under light microscopy and the ultrastructure of chondrocytes was observed under electron microscopy. The primarily cultured chondrocytes of OA mice were randomly divided into 4 groups:(1) OA group, (2) Dgn group, (3) Dgn+AG490 group, (4) AG490 group. The expression of p-JAK2, p-STAT3, Bax, succinate dehydrogenase (SDH) and cytochrome c oxidase (COX) were detected by Western blotting, and superoxide dismutase (SOD) was detected using colorimetric method. Results: The morphological observation showed that the chondrocytes of OA group presented considerable pathological changes, while the chondrocytes in OA+Dgn group maintained intact membrane. Electron microscopy observation found obvious injury in cartilage tissues of OA group, while that in OA+Dgn group remained smooth. Compared with OA group, the expressions of p-JAK2 and p-STAT3 in chondrocytes of Dgn group were increased (all P<0.05), and the expressions of Bax protein, SDH, COX and SOD were decreased (all P<0.05). While compared with Dgn group, the expressions of p-JAK2, p-STAT3, SDH, COX and SOD in chondrocytes of Dgn+AG490 group were decreased (all P<0.05), and the expression of Bax protein was increased (P<0.05). Conclusion: Diosgenin can inhibit apoptosis and increase mitochondrial oxidative stress capacity of chondrocytes in mice with osteoarthritis, which is closely related to the activation of JAK2/STAT3 signaling pathway. PMID- 28087905 TI - [Inflammatory cytokines and oxidative stress markers in the inhibition of osteoarthritis by curcumin]. AB - Objective: To observe the influence of matrix metalloproteinases-2 (MMP-2), monocyte chemoattractant protein-1 (MCP-1), CD47, L-selectin and advanced oxidation proteinproducts (AOPP) in osteoarthritis and the intervention of curcumin. Methods: A total of 20 male C57BL/6 mice (10.05-15.00 g) were randomly divided into control group, OA group, Cur25 group and Cur50 group (intraperitoneal injected 25 MUmol/L or 50 MUmol/L of curcumin everyday after modeling). After 4 weeks treatment, we observed the morphological changes of the gross specimen by immunohistochemical method, and observed the ultrastructure of cartilage tissue under electron microscope. The expression of MMP-2, MCP-1 and CD47 were detected by western blotting, and L-selectin and AOPP were detected by ELISA and spectrophotometer, respectively. Results: In the cartilage tissue morphology, the chondrocytes of OA group showed obvious change, while Cur25 and Cur50 groups maintained the good cartilage cell membrane intact. Compared with control group, the expressions of MMP-2, MCP-1, L-selectin and AOPP in OA group, Cur25 group and Cur50 group were increased (all P<0.05), while CD47 levels were decreased (all P<0.05). Compared with OA group, the expressions of MMP-2, MCP-1, L-selectin and AOPP in Cur25 group and Cur50 group were decreased (all P<0.05), while CD47 levels were increased (all P<0.05), and such changes were more significant in Cur50 group (all P<0.05). Conclusion: The MMP-2, MCP-1, CD47, L selectin and AOPP are closely associated with the pathology course of OA. Curcumin has protection effect on cartilage, which can relieve joint cartilage degeneration, reduce cartilage inflammation and increase the metabolic activity of chondrocytes. PMID- 28087906 TI - [Effect and its molecular mechanisms of curcumin on pulmonary artery smooth muscle cells in rat model with chronic obstructive pulmonary disease]. AB - Objective: To investigate the effects and the underlying molecular mechanisms of curcumin on pulmonary artery smooth muscle cells in rat model with chronic obstructive pulmonary disease (COPD). Methods: A total of 75 male Wistar rats were randomly divided into control group (group CN), model group (group M), low dose curcumin group (group CL), medium-dose curcumin group (group CM) and high dose curcumin group (group CH). HE staining was used to observe the morphology of pulmonary artery. Proliferating cell nuclear antigen (PCNA), apoptosis-related protein Bcl-2 and Bax were detected by immunohistochemical staining. TUNEL kit was used to analyze the effects of curcumin on apoptosis of smooth muscle cells, and the protein expressions of SOCS-3/JAK2/STAT pathway in lung tissues were determined by western blot. Results: Right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVMI) in group M were significantly higher than those in group CN, group CH and group CM (all P<0.05). HE staining and TUNEL kit test showed that the number of pulmonary artery smooth muscle cells had a significant increase in group M, while the pulmonary artery tube became thin, and the smooth muscle cells shrinked in group CM and group CH. Immunohistochemistry showed that PCNA and Bcl-2 in group M were significantly higher than those in group CN (all P<0.05), while Bax expression was significantly lower than that in group CN (P<0.05). PCNA in group CM and group CH were significantly lower than that in group M (all P<0.05), while Bax expression was significantly higher than that in group M (P<0.05). Western blot showed that SOCS-3 protein was significantly decreased in group M, while the p-JAK2, p-STAT1, p-STAT3 were significantly increased (all P<0.05). Compared with group M, SOCS-3 protein in group CM and group CH were significantly increased (all P<0.05), while the p-JAK2, p-STAT3 were significantly reduced (all P<0.05). Conclusion: Curcumin could promote the apoptosis of smooth muscle cells in rats with COPD, and improve the mean pulmonary artery pressure and RVMI through stimulating SOCS-3/JAK2/STAT signaling pathway. PMID- 28087908 TI - [Berberine regulates glycemia via local inhibition of intestinal dipeptidyl peptidase-IV]. AB - Objective: To investigate the effect of berberine on glycemia regulation in rats with diabetes and the related mechanisms. Methods: Diabetic-like rat model was successfully induced by intraperitoneal injection of streptozotocin in 50 out of 60 male SD rats, which were then randomly divided into 5 groups with 10 rats in each:control group (received vehicle only), positive drug control group (sitagliptin 10 mg.kg-1.d-1), low-dose berberine group (30 mg.kg-1.d-1), moderate dose berberine group (60 mg.kg-1.d-1), and high-dose berberine group (120 mg.kg 1.d-1). All animals were fed for 3 d, and fasting blood sampling was performed on day 3 of administration. Rats were given glucose (2 g/kg) by gavage 30 min after the last dose. Blood and intestinal samples were obtained 2 h after glucose loading. Fasting blood glucose (FBG) and 2-h postprandial plasma glucose (2h-PPG) were detected by using biochemical analyzer, and insulin, glucagon-like peptide-1 (GLP-1) and dipeptidyl peptidase-IV(DPP-IV) were measured by using ELISA kit. Results: No significant difference in FBG and serum DPP-IV level were found between berberine groups and control group (all P>0.05). Compared with control group, serum levels of GLP-1 and insulin were increased in high-and moderate-dose berberine groups, while 2h-PPG was decreased (all P<0.05); GLP-1 levels in the intestinal samples were increased, while DPP-IV levels were decreased in all berberine groups (all P<0.05). Conclusions: Short-term berberine administration can decrease 2h-PPG level in streptozotocin-induced diabetic rat model through local inhibition of intestinal DPP-IV. The efficacy of DPP-IV inhibitor may be associated with its intestinal pharmacokinetics. PMID- 28087907 TI - [Effect of methyleugenol on expression of MUC5AC in nasal mucosa of rats with allergic rhinitis]. AB - Objective: To investigate the effect of methyleugenol on expression of MUC5AC in nasal mucosa of rats with allergic rhinitis (AR). Methods: Seventy-two Wistar rats were randomly divided into 6 groups:normal control group, AR group, loratadine group, low-dose methyleugenol group, middle-dose methyleugenol group and high-dose methyleugenol group with 12 rats in each group. AR was induced by intraperitoneal injection of ovalbumin in latter 5 groups. 10 mg loratadine q.d was given to rats in loratadine group by gavage; and 10 mg/kg, 20 mg/kg and 40 mg/kg methyleugenol were given by gavege q.d to rats in low-, middle-and high dose methyleugenol groups, respectively. Nasal mucosa samples were obtained from rats at 1, 2, 4 and 6 weeks after drug intervention. The expression of MUC5AC protein and mRNA in nasal mucosa was detected by immunohistochemistry and real time fluorescence quota PCR (RT-PCR), respectively. Results: Compared with AR, the percentage of cells staining positively for MUC5AC protein and the relative quantity of MUC5AC mRNA in middle-and high-dose methyleugenol groups were significantly decreased after 2 and 4 weeks of drug intervention (P<0.05), but no such decrease was observed in low-dose methyleugenol group at all time points (P>0.05). The percentage of cells with positive expression of MUC5AC protein and mRNA in loratadine group were significantly decreased after 1 week of administration (P<0.05). The percentage of cells with positive MUC5AC protein in middle-dose methyleugenol group was higher than that in loratadine group (P<0.05) after 6 week of drug intervention, but the difference was not seen in high-dose group (P>0.05). There was no significant difference in relative quantities of MUC5AC mRNA after 4 weeks of administration between high-and middle-dose methyeugenol groups and loratadine group (P>0.05). Conclusion: Methyleugenol can attenuate AR through inhibiting the expression of MUC5AC mRNA and protein in nasal mucosa of AR rats. PMID- 28087909 TI - [Tripotolide ameliorates inflammation and apoptosis induced by focal cerebral ischemia/reperfusion in rats]. AB - Objective: To investigate the effects of triptolide on inflammation and apoptosis induced by focal cerebral ischemia/reperfusion in rats. Methods: The rat model of focal cerebral ischemia/reperfusion injury was established according to Longa's method. A total of 80 SD rats were randomly divided into 5 groups:normal control, sham group, DMSO group, middle cerebral artery occlusion (MCAO) group, and MCAO with tripolide treatment group. TTC staining was used to examine the site and volume of cerebral infarction, and Longa score was employed for neurological disorders measurement. Number of astrocytes was measured by fluorescence staining, and neuronal apoptosis was determined by TUNEL staining. The expressions of inducible nitric oxide synthase(iNOS), cyclooxygenase 2(COX-2) and NF-kappaB proteins were detected by immunohistochemistry, and the expression of iNOS, COX-2 mRNA was detected by real-time PCR. Results: Compared with DMSO group and MCAO group, brain edema was improved (80.03+/-0.46)% (P<0.05), infarct volume was reduced (8.3+/-1.4)% (P<0.01), Longa score was decreased (1.38+/-0.20, P<0.05) in triptolide treatment group. Meanwhile triptolide also dramatically reduced the number of GFAP-positive astrocytes (P<0.05), alleviated protein expression of COX-2 (91.67+/-1.31), iNOS (95.24+/-5.07) and NF-kappaB (75.03+/ 2.06) triggered by MCAO (all P<0.05), and induced a down-regulation of cell apoptosis as showed by TUNEL assay (64.15+/-3.52, P<0.05). Conclusion: Triptolide can reduce the cerebral infarction volume, attenuate brain edema and ameliorate the neurological deficits induced by cerebral ischemia-reperfusion injury rats, indicating that it might be used as a potential anti-inflammatory agent. PMID- 28087911 TI - [Aortic stiffness and its influencing factors in patients with chronic kidney disease]. AB - Objective: To investigate the changes of aortic stiffness and its influencing factors in patients with chronic kidney diseases (CKD). Methods: Eightyfour patients with CKD from Department of Nephrology, Zhejiang Provincial People's Hospital were divided into the dialysis group (CKD stage 5, n=48) and non dialysis group (CKD stage 3-5, n=36). Clinical data, biochemical parameters and echocardiography findings were collected. SphygmoCor pulse wave analysis system was used to obtain pulse wave analysis (PWA) parameters including central aortic systolic blood pressure (CSP), central pulse pressure (CPP), augmented pressure (AP), augmentation index (AIX), and heart rate 75-adjusted augmentation index (HR75AIX). The influencing factors of aortic stiffness were analyzed by spearman correlation analysis and multiple regression analysis. Results: CSP, CPP, AP, AIX and HR75AIX in dialysis patients had no significant differences compared with those in non-dialysis group (all P>0.05). Spearman correlation analysis showed that CSP was positively correlated with systolic blood pressure, diastolic blood pressure, cholesterol, low-density lipoprotein cholesterol, left atrial diameter (LA),left ventricular systolic diameter (LVDs), left ventricular diastolic diameter (LVDd), and negatively correlated with calcium and hemoglobin levels. CPP was positively correlated with systolic blood pressure, age, LA, LVDd, and negatively correlated with diastolic blood pressure and hemoglobin levels. AP was positively correlated with systolic blood pressure, age, LA, LVDd, and negatively correlated with hemoglobin levels. AIX was positively correlated with systolic blood pressure, age, sodium, and negatively correlated with phosphorus levels. HR75AIX was positively correlated with systolic blood pressure, sodium, cholesterol, and negatively correlated with hemoglobin and albumin levels. Multiple regression analysis showed that higher systolic blood pressure was the independent risk factor for CSP (beta=0.944, P<0.01); lower diastolic blood pressure (beta=0.939, P<0.01) and higher systolic blood pressure (beta=-1.010, P<0.01) were the independent risk factors for CPP; older age (beta=0.237, P<0.01) and higher systolic blood pressure (beta=0.200, P<0.01) were the independent risk factors for AP; higher systolic blood pressure (beta=0.163 and 0.115, P<0.05 and P<0.01) and higher sodium (beta=0.646 and 0.625, all P<0.05) were independent risk factors for both AIX and HR75AIX. Conclusions: No significant correlation is observed between aortic stiffness and CKD of different stages. Control blood pressure and restrict sodium intake may be effective means of delaying arterial stiffness in patients with CKD. PMID- 28087910 TI - [Progress on anti-tumor molecular mechanisms of dihydroartemisinin]. AB - Artemisinin is an anti-malarial drug with poor water solubility and oral absorption; so a variety of derivatives based on the parent nucleus have been developed. Compared with artemisinin, dihydroartemisinin (DHA) has a stronger anti-malaria activity, and has the advantages of high metabolic rate and better water solubility. Recent studies have discovered that DHA has a good inhibitory effect on tumor cells, which is closely related to the peroxide bridge in its molecular structure. Since tumor cells need more Fe3+ than normal cells, there are a large number of transferrin receptors on the tumor cell membrane. DHA can break the peroxide bridge in the presence of Fe2+, and the free radicals generated can play its lethal effect on tumor cells. In addition, DHA can promote endocytosis of transferrin receptor, and thus prevent cancer cells from taking Fe3+ from microenvironment. This article reviews the anti-tumor molecular mechanism of DHA, including accelerating oxidative damage, inducing apoptosis, inhibiting the growth, proliferation and invasion of tumor cells, reversing tumor multidrug resistance. PMID- 28087912 TI - [T cell receptor beta-chain CDR3 spectratyping and cytomegalovirus activation in allogeneic hematopoietic stem cell transplant recipients]. AB - Objective: To explore the association between T-cell receptor beta variable (TCR BV) complementarity determining region 3 (CDR3) spectratyping and CMV activation in the recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Methods: Fluorescence quantitative PCR melting curve analysis was used to sequence 24 TCR BV families in 7 HSCT recipients and 3 healthy controls. CMV-pp65 antigenemia was measured by immunohistochemical staining. Plasma IgM specific for CMV was identified using ELISA. Relationship between TCR BV families and CMV activation was statistically analyzed.Results: Twenty-four TCR BV families were expressed in 3 healthy controls, while TCR BV CDR3 sequencing results in 7 recipients turned out to be BV9, BV11, BV17, BV20 and so on. Amino acid sequence features were as follows:TCR BV9 contained "QVRGGTDTQ", TCR BV11 contained "VATDEQ" and "LGDEQ", TCR BV17 contained "IGQGNTEA", and TCR BV20 contained "VGLAANEQ". Five recipients suffered from pp65 antigenemia in 3 month after transplantation, and pp65-positive cells ranged from 2 to 15 per 5*104 white blood cells. Three recipients were CMV-IgM positive. No significant differences were found in TCR BV families between pp65-positive recipients and pp65-negative recipients (all P>0.05). But there was statistically significant difference in frequency of TCR BV11 between CMV-IgM negative recipients and CMV-IgM positive recipients (P<0.05).Conclusion: T cell immune response was characterized by special TCR BV CDR3 spectratyping in HSCT recipients, and TCR BV11 expression may be associated with CMV activation. PMID- 28087913 TI - [Cigarette smoking in different manners induces acute lung injury in rats]. AB - Objective: To investigate the effects of cigarette smoking in different manners on acute lung injury in rats. Methods: The commercially available cigarettes with tar of 1,5, 11 mg were smoked in Canada depth smoking (health canada method, HCM) manner, and those with tar of 11 mg were also smoked in international standard (ISO) smoking manner. Rats were fixed and exposed to mainstream in a manner of nose-mouth exposure. After 28 days, the bronchoalveolar lavage fluids from left lung were collected for counting and classification of inflammatory cells and determination of pro-inflammatory cytokines IL-1beta and TNF-alpha. The right lungs were subjected to histological examination and determination of myeloperoxidase (MPO) and superoxide dismutase (SOD) activities and glutathione, reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Results: In both HCM and ISO manners, the degree of lung injury was closely related to the tar content of cigarettes, and significant decrease in the body weight of rats was observed after smoking for one week. In a HCM manner, smoking with cigarette of 11 mg tar resulted in robust infiltration of macrophages, lymphocytes and neutrophils into lungs, significant increase in IL-1beta and TNF-alpha levels and MPO activities, and significant decrease in GSH levels and SOD activities and increase in ROS and MDA levels (all P<0.05). Smoking with cigarette of 5 mg tar led to moderate increase in IL-1beta and TNF-alpha levels, and MPO activities (all P<0.05), and moderate decrease in GSH levels and SOD activities and increase of ROS and MDA levels (all P<0.05). However, smoking with cigarette of 1 mg tar affected neither inflammatory cell infiltration nor IL-1beta and TNF-alpha levels. Conclusion: Cigarette smoking in nose-mouth exposure manner can induce acute lung injury in rats; and the degree of lung injury is closely related to the content of tar and other hazards in cigarettes. PMID- 28087914 TI - [Atorvastatin improves reflow after percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction by decreasing serum uric acid level]. AB - Objective: To investigate the effect of atorvastatin on reflow in patients with acute ST-segment elevation myocardial infarction (STEMI) after percutaneous coronary intervention (PCI) and its relation to serum uric acid levels. Methods: One hundred and fourteen STEMI patients undergoing primary PCI were enrolled and randomly divided into two groups:55 cases received oral atorvastatin 20 mg before PCI (routine dose group) and 59 cases received oral atorvastatin 80 mg before PCI (high dose group). According to the initial serum uric acid level, patients in two groups were further divided into normal uric acid subgroup and hyperuricemia subgroup. The changes of uric acid level and coronary artery blood flow after PCI were observed. Correlations between the decrease of uric acid, the dose of atorvastatin and the blood flow of coronary artery after PCI were analyzed. Results: Serum uric acid levels were decreased after treatment in both groups (all P<0.05), and patients with hyperuricemia showed more significant decrease in serum uric acid level (P<0.05). Compared with the routine dose group, serum uric acid level in patients with hyperuricemia decreased more significantly in the high dose group (P<0.05), but no significant difference was observed between patients with normal serum uric acid levels in two groups (P>0.05). Among 114 patients, there were 19 cases without reflow after PCI (16.7%). In the routine dose group, there were 12 patients without reflow, in which 3 had normal uric acid and 9 had high uric acid levels (P<0.01). In the high dose group, there were 7 patients without reflow, in which 2 had normal uric acid and 5 had high uric acid (P<0.05). Logistic regression analysis showed that hyperuricemia was one of independent risk factors for no-reflow after PCI (OR=1.01, 95% CI:1.01-1.11, P<0.01). The incidence of no-flow after PCI in the routine dose group was 21.8% (12/55), and that in the high dose group was 11.9% (7/59) (P<0.01). Conclusion: High dose atorvastatin can decrease serum uric acid levels and improve reflow after PCI in patients with STEMI. PMID- 28087916 TI - [A case of idiopathic hypertrophic cranial pachymeningitis presenting as chronic subdural hematoma]. AB - A 26-year-old male presented with a 6-day history of paroxysmal headache which was worsen with nausea and vomiting for 1 day. Head CT on admission revealed left chronic subdural hematoma with midline shift. An emergency Burr hole drainage for hematoma was performed. Headache recurred 6 days later. MRI of the brain revealed a diffuse thickening and a gadolinium-enhancement of the falx, cranial dura mater and tentorium cerebelli on the left side with pia mater involved. Lumber puncture showed increased intracranial pressure and elevated IgG level in cerebrospinal fluid. Histological examination of the biopsy specimen showed thickened, fibrotic dura with a sterile chronic inflammation. According to pathological examination, idiopathic hypertrophic cranial pachymeningitis was considered as the final diagnosis. Symptoms were improved with steroid pulse therapy. PMID- 28087915 TI - [Microvascular decompression for hemifacial spasm induced by vertebral artery dissecting aneurysm: one case report]. AB - A 61-year-old female presented with 4 years history of left-sided hemifacial spasm. Head MRI and angiography indicated left vertebral artery dissecting aneurysm which compressed ipsilateral cranial nerves VII and VIII. Microvascular decompression was performed. The dissecting aneurysm was pushed apart and the distal part of the parent artery was adhered to the dura on the petrosum. The compressed nerves were totally decompressed. The symptom of facial spasm was completely resolved immediately after surgery and did not recur during 6 months of follow up. PMID- 28087917 TI - [Reasearch progress on the role of neutrophils in asthma]. AB - Asthma is a phenotypically heterogeneous chronic disease of the airways. Studies have found that neutrophils are crucial to airway inflammation in acute asthma, persistent asthma, particularly in asthma of poor response to glucocorticoid treatment. The role of neutrophils in development of bronchial asthma is complex, as they can release a potent source of cytokines and inflammatory mediators participating in asthma. Differing from eosinophilic inflammatory asthma, neutrophilic inflammatory asthma is not depend on helper T (Th)2 cells, but may be related to Th1 and Th17 cells. This review highlights the role of neutrophils in the development of asthma, and the treatment of neutrophilic asthma with biological agents and novel small molecules. PMID- 28087918 TI - [Research progress on the role of TANK-binding kinase 1 in anti-virus innate immune response]. AB - The innate immune response against viral infection is mainly relies on type I interferon, the production of which is mediated by TANK-binding kinase 1 (TBK1). It is revealed that the downstream TBK1 is activated by viral nucleic acid sensors RIG-I, cGAS and TLR3. The activity of TBK1 is complexly and precisely regulated by different type of protein modifications, including phosphorylation, ubiquitination and Sumolylation. This article focuses on the role of TBK1 in anti viral innate immunity and the regulatory mechanism for the TBK1 activation. PMID- 28087921 TI - Pathogen Characterization of Fresh and Stored Mesophilic Anaerobically Digested Biosolids. AB - Culturable bacterial pathogens (Campylobacter, Salmonella, Listeria, Yersinia) and indicators (E. coli, enterococci, Clostridium perfringens) were quantified at six water resource recovery facilities that land apply anaerobically digested biosolids in Ontario, Canada. Cryptosporidium parvum and Giardia lamblia were also quantified by polymerase chain reaction (PCR). Salmonella and Listeria were frequently detected in sludge and liquid biosolids (70-100% of samples) but less often in fresh dewatered cake biosolids (50-60%); with low levels in fresh cake (<100 cells/g dw). Yersinia were in 20 to 30% of samples, typically at very low levels (<10 cell/g dw). Giardia and Cryptosporidium were detected in 80 and 20% of cake biosolids at geometric means of 270 cysts/g dw and 70 oocysts/g dw, respectively. E. coli reduction was typically >2-log10 while pathogen reduction was variable. "Sudden increase" of pathogens was not observed, however, Salmonella and E. coli showed regrowth (at 1 to 3 orders of magnitude) after 2- to 3-day storage at 30 degrees C. PMID- 28087920 TI - Spatial and Temporal Variation of Water Quality in the Bertam Catchment, Cameron Highlands, Malaysia. AB - The spatio-temporal variability of water quality associated with anthropogenic activities was studied for the Bertam River and its main tributaries within the Bertam Catchment, Cameron Highlands, Malaysia. A number of physico-chemical parameters of collected samples were analyzed to evaluate their spatio-temporal variability. Nonparametric statistical analysis showed significant temporal and spatial differences (p < 0.05) in most of the parameters across the catchment. Parameters except dissolved oxygen and chemical oxygen demand displayed higher values in rainy season. The higher concentration of total suspended solids was caused by massive soil erosion and sedimentation. Seasonal variations in contaminant concentrations are largely affected by precipitation and anthropogenic influences. Untreated domestic wastewater discharge as well as agricultural runoff significantly influenced the water quality. Poor agricultural practices and development activities at slope areas also affected the water quality within the catchment. The analytical results provided a basis for protection of river environments and ecological restoration in mountainous Bertam Catchment. PMID- 28087922 TI - Urogenital Tuberculosis. AB - Urogenital tuberculosis is the second most frequent form of extrapulmonary tuberculosis. Starting with a pulmonary focus, 2 to 20% of patients develop urogenital tuberculosis through hematogenous spread to the kidneys, prostate, and epididymis; through the descending collecting system to the ureters, bladder, and urethra; and through the ejaculatory ducts to the genital organs. Urogenital tuberculosis occurs at all age ranges, but it is predominant in males in their fourth and fifth decades. It is a serious, insidious disease, generally developing symptoms only at a late stage, which leads to a diagnostic delay with consequent urogenital organ destruction; there are reports of patients with renal failure as their initial clinical presentation. Although the condition has been long recognized by nephrologists, urologists, and infectious disease specialists, urogenital tuberculosis is still largely unknown. Even when suggestive findings such as hematuria, sterile pyuria, and recurrent urinary infections are present, we rarely remember this diagnostic possibility. Greater knowledge of the features of urogenital tuberculosis then becomes relevant and should emphasize the importance of an early diagnosis. PMID- 28087923 TI - Enhanced Aerobic Sludge Granulation by Seeding Concentrated Activated Sludge with Ca-Alginate Gel. AB - The present study focuses on the effect of Ca-alginate gel on aerobic sludge granulation. Three sequencing batch reactors (SBRs) seeded with different mixtures of Ca-alginate gel and activated sludge with the fraction (weight/weight of dry biomass) of 0%, 5.5%, and 15.5%, respectively. The granulation time of 14 days was obtained with 5.5% additive, while 32 days were needed to adapt aerobic granules developed with 0% Ca-alginate gel. Full granulation was achieved in the trial with 15.5% additive from the 20th day. Comparing with granules in reactor 1, the granules cultivated with Ca-alginate gel exhibited attributes of much faster settling velocities, higher biomass retention, greater mechanical strength, and better nutrient-removing capability. The alginate-metal gel may be the structural polymer of aerobic granules and offer bacteria the inhabitancy and protection, which is beneficial to retain more biomass and improve the efficiency of wastewater treatment. PMID- 28087924 TI - Clinical Testing of Tuberculosis Vaccine Candidates. AB - It is almost 100 years since the development of bacille Calmette-Guerin (BCG), the only licensed vaccine against tuberculosis (TB). While BCG does confer consistent protection against disseminated disease, there is an urgent need for a more effective vaccine against pulmonary disease. There are several indications for such an improved vaccine, including prevention of infection, prevention of disease, and a therapeutic vaccine to prevent recurrent disease. The two main approaches to TB vaccine development are developing an improved whole mycobacterial priming agent to replace BCG and/or developing a subunit booster vaccine to be administered after a BCG or BCG replacement priming vaccination. In this article we review the status of the current candidate vaccines being evaluated in clinical trials. The critical challenges to successful TB vaccine development are the uncertain predictive value of the preclinical animal models and the lack of a validated immune correlate of protection. While it is relatively simple to evaluate safety and immunogenicity in phase 1/2 studies, the evaluation of efficacy requires complex studies with large numbers of subjects and long periods of follow-up. This article reviews the potential role for human Experimental Medicine studies, in parallel with product development, to help improve the predictive value of the early-stage trials. PMID- 28087925 TI - Host Responses to Urinary Tract Infections and Emerging Therapeutics: Sensation and Pain within the Urinary Tract. AB - Urinary tract infection (UTI) pathogenesis is understood increasingly at the level of the uropathogens and the cellular and molecular mediators of host inflammatory responses. However, little is known about the mediators of symptoms during UTI and what distinguishes symptomatic events from asymptomatic bacteriuria. Here, we review bladder physiology and sensory pathways in the context of an emerging literature from murine models dissecting the host and pathogen factors mediating pain responses during UTI. The bladder urothelium is considered a mediator of sensory responses and appears to play a role in UTI pain responses. Virulence factors of uropathogens induce urothelial damage that could trigger pain due to compromised bladder-barrier function. Instead, bacterial glycolipids are the major determinants of UTI pain independent of urothelial damage, and the O-antigen of lipopolysaccharide modulates pain responses. The extent of pain modulation by O-antigen can have profound effects, from abolishing pain responses to inducing chronic pain that results in central nervous system features reminiscent of neuropathic pain. Although these effects are largely dependent upon Toll-like receptors, pain is independent of inflammation. Surprisingly, some bacteria even possess analgesic properties, suggesting that bacteria exhibit a wide range of pain phenotypes in the bladder. In summary, UTI pain is a complex form of visceral pain that has significant potential to inform our understanding of bacterial pathogenesis and raises the specter of chronic pain resulting from transient infection, as well as novel approaches to treating pain. PMID- 28087926 TI - Urinary Tract Infections in Infants and Children. AB - Urinary tract infections (UTI) are one of the most common infections in children and symptoms may be nonspecific. The risk of renal scarring is highest in children under 1 year of age with febrile UTI and high-grade vesicoureteral reflux (VUR). Although treatment of UTI is usually straightforward, given increased rates of antimicrobial resistance worldwide, the choice of treatment for pediatric UTI should be guided by community resistance patterns whenever feasible. The benefit of antimicrobial prophylaxis after first UTI and/or in the presence of VUR remains controversial, but a recent meta-analysis supports continuous antimicrobial prophylaxis in children with VUR, indicating a need for more research in this area. PMID- 28087927 TI - Genome-Wide Approaches to Defining Macrophage Identity and Function. AB - Macrophages play essential roles in the response to injury and infection and contribute to the development and/or homeostasis of the various tissues they reside in. Conversely, macrophages also influence the pathogenesis of metabolic, neurodegenerative, and neoplastic diseases. Mechanisms that contribute to the phenotypic diversity of macrophages in health and disease remain poorly understood. Here we review the recent application of genome-wide approaches to characterize the transcriptomes and epigenetic landscapes of tissue-resident macrophages. These studies are beginning to provide insights into how distinct tissue environments are interpreted by transcriptional regulatory elements to drive specialized programs of gene expression. PMID- 28087929 TI - Fungal Plant Pathogenesis Mediated by Effectors. AB - The interactions between fungi and plants encompass a spectrum of ecologies ranging from saprotrophy (growth on dead plant material) through pathogenesis (growth of the fungus accompanied by disease on the plant) to symbiosis (growth of the fungus with growth enhancement of the plant). We consider pathogenesis in this article and the key roles played by a range of pathogen-encoded molecules that have collectively become known as effectors. PMID- 28087928 TI - Factors associated with non-completion of follow-up: 33-month latent tuberculous infection treatment trial. AB - SETTING: A post-hoc exploratory analysis of a randomized, open-label clinical trial that enrolled 8053 participants from the United States, Canada, Brazil, and Spain. OBJECTIVE: To assess factors associated with non-completion of study follow-up (NCF) in a 33-month latent tuberculous infection treatment trial, PREVENT TB. DESIGN: Participants were randomized to receive 3 months of weekly directly observed therapy vs. 9 months of daily self-administered therapy. NCF was defined as failing to be followed for at least 993 days (33 months) from enrollment. Possible factors associated with NCF were analyzed using univariate and multivariate regression via Cox proportional hazard model. RESULTS: Of 7061 adults selected for analysis, 841 (11.9%) did not complete study follow-up. Homelessness, young age, low education, history of incarceration, smoking, missing an early clinic visit, receiving isoniazid only, and male sex were significantly associated with NCF. Similar results were found in the North American region (United States and Canada) only. In Brazil and Spain, the only significant factor was missing an early clinic visit. CONCLUSIONS: Study subjects at higher risk for NCF were identified by characteristics known at enrollment or in early follow-up. Evaluation of follow-up in other trials might help determine whether the identified factors consistently correlate with retention. PMID- 28087930 TI - Fungal Ecology: Principles and Mechanisms of Colonization and Competition by Saprotrophic Fungi. AB - Decomposer fungi continually deplete the organic resources they inhabit, so successful colonization of new resources is a crucial part of their ecology. Colonization success can be split into (i) the ability to arrive at, gain entry into, and establish within a resource and (ii) the ability to persist within the resource until reproduction and dissemination. Fungi vary in their life history strategies, the three main drivers of which are stress (S-selected), disturbance (ruderal, or R-selected), and incidence of competitors (C-selected); however, fungi often have combinations of characteristics from different strategies. Arrival at a new resource may occur as spores or mycelium, with successful entry and establishment (primary resource capture) within the resource largely dependent on the enzymatic ability of the fungus. The communities that develop in a newly available resource depend on environmental conditions and, in particular, the levels of abiotic stress present (e.g., high temperature, low water availability). Community change occurs when these initial colonizers are replaced by species that are either more combative (secondary resource capture) or better able to tolerate conditions within the resource, either through changing abiotic conditions or due to modification of the resource by the initial colonizers. Competition for territory may involve highly specialized species-specific interactions such as mycoparasitism or may be more general; in both cases combat involves changes in morphology, metabolism, and reactive oxygen species production, and outcomes of these interactions can be altered under different environmental conditions. In summary, community development is not a simple ordered sequence, but a complex ever-changing mosaic. PMID- 28087933 TI - Ecology of Fungal Plant Pathogens. AB - Fungal plant pathogens are ubiquitous and highly diverse. Key to their success is high host density, which notably is the case in agroecosystems. Several hypotheses related to the effects of plant pathogens on plant diversity (the Janzen-Connell hypothesis, the dilution effect hypothesis) and the phenomenon of higher biomass in plant mixtures (i.e., overyielding) can all be explained by the quantitative interplay between host and pathogen density. In many agroecosystems, fungal plant pathogens cause great losses, since in monocultures diseased plants cannot be replaced by healthy plants. On the other hand, in natural ecosystems fungal plant pathogens shape the succession of vegetation and enhance the biodiversity of forests and grasslands. When pathogens are introduced into areas outside their natural range, they may behave differently, causing severe damage. Once introduced, changes may occur such as hybridization with other closely related pathogens or host shifts, host jumps, or horizontal gene transfer. Such changes can be hazardous for both agricultural and natural ecosystems. PMID- 28087932 TI - The Complexity of Fungal Vision. AB - Life, as we know it, would not be possible without light. Light is not only a primary source of energy, but also an important source of information for many organisms. To sense light, only a few photoreceptor systems have developed during evolution. They are all based on an organic molecule with conjugated double bonds that allows energy transfer from visible (or UV) light to its cognate protein to translate the primary physical photoresponse to cell-biological actions. The three main classes of receptors are flavin-based blue-light, retinal-based green light (such as rhodopsin), and linear tetrapyrrole-based red-light sensors. Light not only controls the behavior of motile organisms, but is also important for many sessile microorganisms including fungi. In fungi, light controls developmental decisions and physiological adaptations as well as the circadian clock. Although all major classes of photoreceptors are found in fungi, a good level of understanding of the signaling processes at the molecular level is limited to some model fungi. However, current knowledge suggests a complex interplay between light perception systems, which goes far beyond the simple sensing of light and dark. In this article we focus on recent results in several fungi, which suggest a strong link between light-sensing and stress-activated mitogen-activated protein kinases. PMID- 28087934 TI - Fungal Cell Cycle: A Unicellular versus Multicellular Comparison. AB - All cells must accurately replicate DNA and partition it to daughter cells. The basic cell cycle machinery is highly conserved among eukaryotes. Most of the mechanisms that control the cell cycle were worked out in fungal cells, taking advantage of their powerful genetics and rapid duplication times. Here we describe the cell cycles of the unicellular budding yeast Saccharomyces cerevisiae and the multicellular filamentous fungus Aspergillus nidulans. We compare and contrast morphological landmarks of G1, S, G2, and M phases, molecular mechanisms that drive cell cycle progression, and checkpoints in these model unicellular and multicellular fungal systems. PMID- 28087935 TI - Diagnosis, Treatment, and Prevention of Urinary Tract Infection. AB - UTI may involve the lower or upper urinary tract and may be uncomplicated or complicated. The emphasis of this chapter is uncomplicated UTI. The diagnosis of uncomplicated cystitis (bladder infection) and pyelonephritis (kidney infection) is usually easily made based on the clinical presentation, whereas the diagnosis in patients with complicated UTI is often more complex. Thus uncomplicated cystitis is usually manifested by dysuria, frequency and/or urgency without fever, and pyelonephritis is usually manifested by fever and back pain/costovertebral angle tenderness. However, pyuria is usually present with UTI, regardless of location, and its absence suggests that another condition may be causing the patient's symptoms. Treatment of cystitis is usually straightforward with one of several effective short-course antimicrobial regimens, although antimicrobial resistance continues to increase and can complicate treatment choices in certain areas. Likewise, antimicrobial resistance has complicated our management of uncomplicated pyelonephritis since resistance of uropathogens to the fluoroquinolone class, the mainstay of oral treatment for pyelonephritis, is increasing worldwide, and some of the other agents used for cystitis are not recommended for pyelonephritis due to low tissue levels. The goal of prevention of recurrent cystitis is to minimize the use of antimicrobials and there are several research efforts in progress to develop effective and safe antimicrobial-sparing preventive approaches for this common condition. PMID- 28087936 TI - Fungal Ligninolytic Enzymes and Their Applications. AB - The global push toward an efficient and economical biobased economy has driven research to develop more cost-effective applications for the entirety of plant biomass, including lignocellulosic crops. As discussed elsewhere (Karlsson M, Atanasova L, Funck Jensen D, Zeilinger S, in Heitman J et al. [ed], Tuberculosis and the Tubercle Bacillus, 2nd ed, in press), significant progress has been made in the use of polysaccharide fractions from lignocellulose, cellulose, and various hemicellulose types. However, developing processes for use of the lignin fraction has been more challenging. In this chapter, we discuss characteristics of lignolytic enzymes and the fungi that produce them as well as potential and current uses of lignin-derived products. PMID- 28087931 TI - Evolution of Cell-Autonomous Effector Mechanisms in Macrophages versus Non-Immune Cells. AB - Specialized adaptations for killing microbes are synonymous with phagocytic cells including macrophages, monocytes, inflammatory neutrophils, and eosinophils. Recent genome sequencing of extant species, however, reveals that analogous antimicrobial machineries exist in certain non-immune cells and also within species that ostensibly lack a well-defined immune system. Here we probe the evolutionary record for clues about the ancient and diverse phylogenetic origins of macrophage killing mechanisms and how some of their properties are shared with cells outside the traditional bounds of immunity in higher vertebrates such as mammals. PMID- 28087937 TI - Myeloid Cell Phenotypes in Susceptibility and Resistance to Helminth Parasite Infections. AB - Many major tropical diseases are caused by long-lived helminth parasites that are able to survive by modulation of the host immune system, including the innate compartment of myeloid cells. In particular, dendritic cells and macrophages show markedly altered phenotypes during parasite infections. In addition, many specialized subsets such as eosinophils and basophils expand dramatically in response to these pathogens. The changes in phenotype and function, and their effects on both immunity to infection and reactivity to bystander antigens such as allergens, are discussed. PMID- 28087939 TI - Dendritic Cells in the Immune System-History, Lineages, Tissues, Tolerance, and Immunity. AB - The aim of this review is to provide a coherent framework for understanding dendritic cells (DCs). It has seven sections. The introduction provides an overview of the immune system and essential concepts, particularly for the nonspecialist reader. Next, the "History" section outlines the early evolution of ideas about DCs and highlights some sources of confusion that still exist today. The "Lineages" section then focuses on five different populations of DCs: two subsets of "classical" DCs, plasmacytoid DCs, monocyte-derived DCs, and Langerhans cells. It highlights some cellular and molecular specializations of each, and also notes other DC subsets that have been proposed. The following "Tissues" section discusses the distribution and behavior of different DC subsets within nonlymphoid and secondary lymphoid tissues that are connected by DC migration pathways between them. In the "Tolerance" section, the role of DCs in central and peripheral tolerance is considered, including their ability to drive the differentiation of different populations of regulatory T cells. In contrast, the "Immunity" section considers the roles of DCs in sensing of infection and tissue damage, the initiation of primary responses, the T-cell effector phase, and the induction of immunological memory. The concluding section provides some speculative ideas about the evolution of DCs. It also revisits earlier concepts of generation of diversity and clonal selection in terms of DCs driving the evolution of T-cell responses. Throughout, this review highlights certain areas of uncertainty and suggests some avenues for future investigation. PMID- 28087940 TI - The Memory Immune Response to Tuberculosis. AB - Immunological memory is a central feature of the adaptive immune system and a prerequisite for generating effective vaccines. Understanding long-term memory responses to Mycobacterium tuberculosis will thus provide us with valuable insights that can guide us in the search for a novel vaccine against tuberculosis (TB). For many years, triggering CD4 T cells and, in particular, those secreting interferon-gamma has been the goal of most TB vaccine research, and numerous data from animals and humans support the key role of this subset in protective immunity. More recently, we have learned that the memory response required for effective control of M. tuberculosis is much more complex, probably involving several phenotypically different CD4 T cell subsets as well as other cell types that are yet to be defined. Herein, we describe recent insights into memory immunity to TB in the context of both animal models and the human infection. With the increasing amount of data generated from clinical testing of novel TB vaccines, we also summarize recent knowledge of vaccine-induced memory immunity. PMID- 28087941 TI - Interplay between Myeloid Cells and Humoral Innate Immunity. AB - The innate immune system represents the first line of defense against pathogens and comprises both a cellular and a humoral arm. Fluid-phase pattern recognition molecules (PRMs), which include collectins, ficolins, and pentraxins, are key components of the humoral arm of innate immunity and are expressed by a variety of cells, including myeloid, epithelial, and endothelial cells, mainly in response to infectious and inflammatory conditions. Soluble PRMs share basic multifunctional properties including activation and regulation of the complement cascade, opsonization of pathogens and apoptotic cells, regulation of leukocyte extravasation, and fine-tuning of inflammation. Therefore, soluble PRMs are part of the immune response and retain antibody-like effector functions. Here, we will review the expression and general function of soluble PRMs, focusing our attention on the long pentraxin PTX3. PMID- 28087942 TI - The Mutualistic Interaction between Plants and Arbuscular Mycorrhizal Fungi. AB - Mycorrhizal fungi belong to several taxa and develop mutualistic symbiotic associations with over 90% of all plant species, from liverworts to angiosperms. While descriptive approaches have dominated the initial studies of these fascinating symbioses, the advent of molecular biology, live cell imaging, and "omics" techniques have provided new and powerful tools to decipher the cellular and molecular mechanisms that rule mutualistic plant-fungus interactions. In this article we focus on the most common mycorrhizal association, arbuscular mycorrhiza (AM), which is formed by a group of soil fungi belonging to Glomeromycota. AM fungi are believed to have assisted the conquest of dry lands by early plants around 450 million years ago and are found today in most land ecosystems. AM fungi have several peculiar biological traits, including obligate biotrophy, intracellular development inside the plant tissues, coenocytic multinucleate hyphae, and spores, as well as unique genetics, such as the putative absence of a sexual cycle, and multiple ecological functions. All of these features make the study of AM fungi as intriguing as it is challenging, and their symbiotic association with most crop plants is currently raising a broad interest in agronomic contexts for the potential use of AM fungi in sustainable production under conditions of low chemical input. PMID- 28087938 TI - The Role and Function of Fcgamma Receptors on Myeloid Cells. AB - A key determinant for the survival of organisms is their capacity to recognize and respond efficiently to foreign antigens. This is largely accomplished by the orchestrated activity of the innate and adaptive branches of the immune system. Antibodies are specifically generated in response to foreign antigens, facilitating thereby the specific recognition of antigens of almost infinite diversity. Receptors specific for the Fc domain of antibodies, Fc receptors, are expressed on the surface of the various myeloid leukocyte populations and mediate the binding and recognition of antibodies by innate leukocytes. By directly linking the innate and the adaptive components of immunity, Fc receptors play a central role in host defense and the maintenance of tissue homeostasis through the induction of diverse proinflammatory, anti-inflammatory, and immunomodulatory processes that are initiated upon engagement by the Fc domain. In this chapter, we discuss the mechanisms that regulate Fc domain binding to the various types of Fc receptors and provide an overview of the astonishing diversity of effector functions that are mediated through Fc-FcR interactions on myeloid cells. Lastly, we discuss the impact of FcR-mediated interactions in the context of IgG-mediated inflammation, autoimmunity, susceptibility to infection, and responsiveness to antibody-based therapeutics. PMID- 28087943 TI - RNA Interference in Fungi: Retention and Loss. AB - RNA interference (RNAi) is a mechanism conserved in eukaryotes, including fungi, that represses gene expression by means of small noncoding RNAs (sRNAs) of about 20 to 30 nucleotides. Its discovery is one of the most important scientific breakthroughs of the past 20 years, and it has revolutionized our perception of the functioning of the cell. Initially described and characterized in Neurospora crassa, the RNAi is widespread in fungi, suggesting that it plays important functions in the fungal kingdom. Several RNAi-related mechanisms for maintenance of genome integrity, particularly protection against exogenous nucleic acids such as mobile elements, have been described in several fungi, suggesting that this is the main function of RNAi in the fungal kingdom. However, an increasing number of fungal sRNAs with regulatory functions generated by specific RNAi pathways have been identified. Several mechanistic aspects of the biogenesis of these sRNAs are known, but their function in fungal development and physiology is scarce, except for remarkable examples such as Mucor circinelloides, in which specific sRNAs clearly regulate responses to environmental and endogenous signals. Despite the retention of RNAi in most species, some fungal groups and species lack an active RNAi mechanism, suggesting that its loss may provide some selective advantage. This article summarizes the current understanding of RNAi functions in the fungal kingdom. PMID- 28087944 TI - Laboratory Diagnosis and Susceptibility Testing for Mycobacterium tuberculosis. AB - The laboratory, which utilizes some of the most sophisticated and rapidly changing technologies, plays a critical role in the diagnosis of tuberculosis. Some of these tools are being employed in resource-challenged countries for the rapid detection and characterization of Mycobacterium tuberculosis. Foremost, the laboratory defines appropriate specimen criteria for optimal test performance. The direct detection of mycobacteria in the clinical specimen, predominantly done by acid-fast staining, may eventually be replaced by rapid-cycle PCR. The widespread use of the Xpert MTB/RIF (Cepheid) assay, which detects both M. tuberculosis and key genetic determinants of rifampin resistance, is important for the early detection of multidrug-resistant strains. Culture, using both broth and solid media, remains the standard for establishing the laboratory-based diagnosis of tuberculosis. Cultured isolates are identified far less commonly by traditional biochemical profiling and more commonly by molecular methods, such as DNA probes and broad-range PCR with DNA sequencing. Non-nucleic acid-based methods of identification, such as high-performance liquid chromatography and, more recently, matrix-assisted laser desorption/ionization-time of flight mass spectrometry, may also be used for identification. Cultured isolates of M. tuberculosis should be submitted for susceptibility testing according to standard guidelines. The use of broth-based susceptibility testing is recommended to significantly decrease the time to result. Cultured isolates may also be submitted for strain typing for epidemiologic purposes. The use of massive parallel sequencing, also known as next-generation sequencing, promises to continue to this molecular revolution in mycobacteriology, as whole-genome sequencing provides identification, susceptibility, and typing information simultaneously. PMID- 28087945 TI - Innate Immune Responses to Tuberculosis. AB - Tuberculosis remains one of the greatest threats to human health. The causative bacterium, Mycobacterium tuberculosis, is acquired by the respiratory route. It is exquisitely adapted to humans and is a prototypic intracellular pathogen of macrophages, with alveolar macrophages being the primary conduit of infection and disease. However, M. tuberculosis bacilli interact with and are affected by several soluble and cellular components of the innate immune system which dictate the outcome of primary infection, most commonly a latently infected healthy human host, in whom the bacteria are held in check by the host immune response within the confines of tissue granuloma, the host histopathologic hallmark. Such individuals can develop active TB later in life with impairment in the immune system. In contrast, in a minority of infected individuals, the early host immune response fails to control bacterial growth, and progressive granulomatous disease develops, facilitating spread of the bacilli via infectious aerosols. The molecular details of the M. tuberculosis-host innate immune system interaction continue to be elucidated, particularly those occurring within the lung. However, it is clear that a number of complex processes are involved at the different stages of infection that may benefit either the bacterium or the host. In this article, we describe a contemporary view of the molecular events underlying the interaction between M. tuberculosis and a variety of cellular and soluble components and processes of the innate immune system. PMID- 28087947 TI - Lichenized Fungi and the Evolution of Symbiotic Organization. AB - Lichen symbioses comprise a fascinating relationship between algae and fungi. The lichen symbiotic lifestyle evolved early in the evolution of ascomycetes and is also known from a few basidiomycetes. The ascomycete lineages have diversified in the lichenized stage to give rise to a tremendous variety of morphologies. Their thalli are often internally complex and stratified for optimized integration of algal and fungal metabolisms. Thalli are frequently colonized by specific nonlichenized fungi and occasionally also by other lichens. Microscopy has revealed various ways these fungi interact with their hosts. Besides the morphologically recognizable diversity of the lichen mycobionts and lichenicolous (lichen-inhabiting) fungi, many other microorganisms including other fungi and bacterial communities are now detected in lichens by culture-dependent and culture-independent approaches. The application of multi-omics approaches, refined microscopic techniques, and physiological studies has added to our knowledge of lichens, not only about the taxa involved in the lichen interactions, but also about their functions. PMID- 28087948 TI - Regulation of Immunity to Tuberculosis. AB - Immunity against Mycobacterium tuberculosis requires a balance between adaptive immune responses to constrain bacterial replication and the prevention of potentially damaging immune activation. Regulatory T (Treg) cells express the transcription factor Foxp3+ and constitute an essential counterbalance of inflammatory Th1 responses and are required to maintain immune homeostasis. The first reports describing the presence of Foxp3-expressing CD4+ Treg cells in tuberculosis (TB) emerged in 2006. Different Treg cell subsets, most likely specialized for different tissues and microenvironments, have been shown to expand in both human TB and animal models of TB. Recently, additional functional roles for Treg cells have been demonstrated during different stages and spectrums of TB disease. Foxp3+ regulatory cells can quickly expand during early infection and impede the onset of cellular immunity and persist during chronic TB infection. Increased frequencies of Treg cells have been associated with a detrimental outcome of active TB, and may be dependent on the M. tuberculosis strain, animal model, local environment, and the stage of infection. Some investigations also suggest that Treg cells are required together with effector T cell responses to obtain reduced pathology and sterilizing immunity. In this review, we will first provide an overview of the regulatory cells and mechanisms that control immune homeostasis. Then, we will review what is known about the phenotype and function of Treg cells from studies in human TB and experimental animal models of TB. We will discuss the potential role of Treg cells in the progression of TB disease and the relevance of this knowledge for future efforts to prevent, modulate, and treat TB. PMID- 28087946 TI - Invasion of Host Cells and Tissues by Uropathogenic Bacteria. AB - Within the mammalian urinary tract uropathogenic bacteria face many challenges, including the shearing flow of urine, numerous antibacterial molecules, the bactericidal effects of phagocytes, and a scarcity of nutrients. These problems may be circumvented in part by the ability of uropathogenic Escherichia coli and several other uropathogens to invade the epithelial cells that line the urinary tract. By entering host cells, uropathogens can gain access to additional nutrients and protection from both host defenses and antibiotic treatments. Translocation through host cells can facilitate bacterial dissemination within the urinary tract, while the establishment of stable intracellular bacterial populations may create reservoirs for relapsing and chronic urinary tract infections. Here we review the mechanisms and consequences of host cell invasion by uropathogenic bacteria, with consideration of the defenses that are brought to bear against facultative intracellular pathogens within the urinary tract. The relevance of host cell invasion to the pathogenesis of urinary tract infections in human patients is also assessed, along with some of the emerging treatment options that build upon our growing understanding of the infectious life cycle of uropathogenic E. coli and other uropathogens. PMID- 28087950 TI - Amyloid Prions in Fungi. AB - Prions are infectious protein polymers that have been found to cause fatal diseases in mammals. Prions have also been identified in fungi (yeast and filamentous fungi), where they behave as cytoplasmic non-Mendelian genetic elements. Fungal prions correspond in most cases to fibrillary beta-sheet-rich protein aggregates termed amyloids. Fungal prion models and, in particular, yeast prions were instrumental in the description of fundamental aspects of prion structure and propagation. These models established the "protein-only" nature of prions, the physical basis of strain variation, and the role of a variety of chaperones in prion propagation and amyloid aggregate handling. Yeast and fungal prions do not necessarily correspond to harmful entities but can have adaptive roles in these organisms. PMID- 28087949 TI - The Vaginal Microbiota and Urinary Tract Infection. AB - The vagina is a key anatomical site in the pathogenesis of urinary tract infection (UTI) in women, serving as a potential reservoir for infecting bacteria and a site at which interventions may decrease the risk of UTI. The vaginal microbiota is a dynamic and often critical factor in this pathogenic interplay, because changes in the characteristics of the vaginal microbiota resulting in the loss of normally protective Lactobacillus spp. increase the risk of UTI. These alterations may result from the influence of estrogen deficiency, antimicrobial therapy, contraceptives, or other causes. Interventions to reduce adverse effects on the vaginal microbiota and/or to restore protective lactobacilli may reduce the risks of UTI. PMID- 28087951 TI - A phase II study of concurrent chemoradiotherapy and erlotinib for inoperable esophageal squamous cell carcinoma. AB - Cisplatin-based concurrent chemoradiotherapy for patients with unresectable, locally advanced esophageal squamous cell carcinoma (ESCC) is associated with significant toxicities that are often intolerable. Prognosis for this subgroup of patients remains poor, and new therapeutic approaches are urgently needed. We investigated the efficacy and safety of paclitaxel combined with erlotinib and concurrent radiotherapy in patients with inoperable ESCC. Erlotinib (150 mg) was administered daily for 60 days beginning at the start of radiotherapy, and paclitaxel (45 mg/m2) was administered weekly along with intensity modulated conformal radiotherapy (60 Gy in 30 fractions). The median follow-up time was 21 months. The associations between EGFR and VEGF expression and treatment outcome were evaluated. Among the 21 patients treated, the overall response rate (CR + PR) was 85.6%. The median LPFS, PFS and OS were: 17.5, 14.3, and 22.9 months, respectively. Treatment-related grade 3 toxicities included esophagitis (two patients) and hypoleukemia (one patient). Grade 4 pulmonary toxicity was observed in one patient. Patients expressing EGFR had longer PFS, while those expressing VEGF or with a history of smoking had worse outcomes. Weekly paclitaxel combined with erlotinib and concurrent radiotherapy shows promise as an effective, tolerated regimen for patients with inoperable ESCC. PMID- 28087953 TI - Tenofovir-induced nephrotoxicity: A retrospective cohort study. AB - BACKGROUND: Tenofovir (TDF) has been associated with renal function deterioration, but local data regarding the incidence and risk factors for this adverse event were lacking. OBJECTIVES: To determine the incidence of nephrotoxicity in HIV-infected patients on tenofovir-based regimens and to evaluate risk factors involved in tenofovir-associated renal function decline. METHODS: This is a single-centre retrospective cohort study of 440 HIV-infected adults who were started on tenofovirbased antiretroviral regimens. Data were extracted from electronic medical and pharmacy records. RESULTS: A decline in eGFR of 25% or more was seen in 67 patients (15.2%) with an estimated incidence rate of 12 per 100 person-years. Among all 440 subjects, 22 discontinued TDF based therapy due to renal complication. From multivariate analysis, the odds of developing >25% decrease in eGFR with tenofovir-containing regimen was three times higher for patients with baseline moderate renal impairment (HR 3.19; 95% CI, 1.43-7.12; p=0.005) and 14 times higher for patients with baseline severe renal impairment (HR 14.2; 95% CI, 11.20-170.7; p=0.036) as compared to those without pre-existing renal insufficiency. Age above 50 years and CD4 cell count of less than 50 were significantly associated with >25% decrement in eGFR. CONCLUSION: The incidence rate of tenofovir-related renal dysfunction was found to be 12 per 100 person-years. Preexisting renal impairment, age 50 and above, and CD4 cell count below 50 as were predictors for renal function decline. Given that the use of tenofovir is escalating in Malaysia, increased awareness about this adverse event is essential. PMID- 28087952 TI - An observational study of trigeminal neuralgia patients taking carbamazepine during the fasting month of Ramadan. AB - INTRODUCTION: Trigeminal neuralgia is an agonising orofacial pain affecting unilaterally the distribution of the trigeminal nerve and it usually occurs in the middle and older age groups. Carbamazepine which is an anti-neuralgic as well as an anti-convulsant medication is the first line drug for treatment of trigeminal neuralgia. It is commonly taken as one tablet (200 mg) three times a day. MATERIALS AND METHODS: This is an observational study carried out from April to September 2014 to determine how Muslim patients on carbamazepine treatment for trigeminal neuralgia cope with their neuralgic pain. The pattern of how the medication was taken during the fasting month of Ramadan was also observed. RESULTS: A total of 29 patients participated in this study and 27(93%) observed the fast. Ten of them adjusted the carbamazepine dose from three times pre Ramadan to twice daily during the fasting month. Three patients continued fasting despite feeling the pain during the daytime while five patients had their pain under control with the newly adjusted dose. CONCLUSION: Medical professionals should advise trigeminal neuralgia patients on how to take and adjust their carbamazepine dose during the fasting month. PMID- 28087954 TI - Functional limitation and health-related quality of life, and associated factors among long term stroke survivors in a Malaysian community. AB - PURPOSE: this study aimed to evaluate function and quality of life (QoL) and associated factors among long term stroke survivors in the Malaysian community. METHODS: A cross-sectional study was conducted involving stroke survivors living in the community at two or more years post-stroke. Eligible participants with the diagnosis of stroke were identified from 2005-2010 case mix database of a tertiary hospital. the patients' medical records were analysed and data on demographic and clinical profiles were collected. telephone interviews were conducted to assess existing stroke-related impairments, comorbidities, stroke recurrences, current level of function and QoL, with the usage of rivermead mobility index (rMI), barthel index (bI) and stroke specific quality of life scale (ssQOL). RESULTS: A total of 203 stroke survivors; mean age 64.5 (standard Deviation(sD) 12.2) years, 45.3% males, stroke duration 44.7 (sD 13.8) months completed the interviews. Mean rMI was 11.7 (sD 3.4) and bI was 89.8 (sD 19.8). Forty three percent and 99% had difficulty in ascending/descending stairs and fast walking, respectively. Up to 20% had limitations in most of the bI subsets. Mean ssQOL was 207.6 (sD 37.2), with domains mostly affected were 'energy' and 'social role'. Function and QOL were both influenced by age (p<0.01) and stroke related impairments (p<0.05), but not by co-morbidities or stroke recurrence. QoL and function (both mobility and ADL) were strongly positively correlated with each other (p<0.01). CONCLUSIONS: It was observed that functional limitations especially mobility, remains post-stroke major problem and were attributed mainly to stroke-related impairments. PMID- 28087955 TI - Water as neutral oral contrast agent in abdominopelvic CT: comparing effectiveness with Gastrografin in the same patient. AB - INTRODUCTION: Positive oral contrast is no longer deemed necessary for abdominopelvic computed tomography (CT) scans. Studies have shown water to be an equally effective oral contrast agent. However, to our knowledge no study has compared effectiveness between gastrografin and water in the same patient, which will provide a more objective evaluation of the two oral contrast agents. We aim to make a head-to-head comparison of water as neutral oral contrast (OC) against gastrografin as positive OC for abdominopelvic CT scans in the same patient. METHODS: A retrospective review of 206 abdominopelvic CT scans of 103 patients was performed. The scans were reviewed in consensus by two blinded radiologists. The ability to visualise each abdominopelvic organ, contrastassociated artefacts and small bowel wall delineation, was qualitatively scored on a 5-point scale. Each patient had two sets of scores, one with water and another with gastrografin as OC. Paired scores from the two OCs were evaluated by Wilcoxon signed rank test to determine any significant difference in performance between the two OCs for visualisation of abdominopelvic anatomy on CT. RESULTS: There was significantly better delineation of duodenal wall (p<0.001) and overall visualisation of the duodenum (p=0.011) using water as OC compared to gastrografin. No statistically significant differences were demonstrated between water and gastrografin for visualisation of the rest of the abdominopelvic organs, walldelineation of the rest small bowel and contrast-associated artefacts. CONCLUSIONS: Water can be used in place of gastrografin as oral contrast in abdominopelvic CT without compromising visualization of abdominopelvic organs. PMID- 28087956 TI - Intralesional Injection of OK-432 in Cystic Hygroma. AB - BACKGROUND: Lymphangiomas are congenital malformations of the lymphatic system with characteristic dilated endothelium-lined spaces. It is vulnerability to infection or chemical irritants cause spontaneous reduction in size and in some cases complete resolution. Intralesional injection of OK-432 or Picibanil (lyophilized incubation mixture of Group A Streptococcus pyogenes of human origin) is slowly gaining recognition as its safety and efficacy standards have shown to avoid complications resulting from surgical interventions. The objective of this study was to evaluate the clinical outcomes of cystic hygroma patients who received OK-432 injections. METHODS: In between 2011 and 2013, six patients with cystic hygroma received intralesional injection of OK-432. All the patients were assessed clinically and radiologically either via ultrasound, computer tomography (CT) or magnetic resonant imaging (MRI) prior to and after receiving the injections. Patients' response towards treatment was classified as total shrinkage, marked shrinkage (greater than 50% reduction in size), slight shrinkage (less than 50% reduction in size) or non-responsive to treatment. RESULTS: Mean duration of follow-up was 12 months. Total shrinkage was achieved in one patient, marked shrinkage in three patients and one patient experienced mild shrinkage. Only one out of the six patients showed no response to treatment. None of the patients in this study experienced serious complications or adverse effects post intralesional injection of OK-432. CONCLUSIONS: Intralesional OK-432 injection is an effective and safe alternative in treating cystic hygroma. PMID- 28087957 TI - Cardiovascular risk assessment between urban and rural population in Malaysia. AB - INTRODUCTION: Cardiovascular disease (CVD) caused significant burden to Malaysia as it accounted for 36% of total deaths. This study aims to evaluate the burden of cardiovascular risk factors among Malaysian adult and assess the difference between urban and rural population in the selected communities. METHODS: This study is part of the ongoing Prospective Urban Rural Epidemiology (PURE) database, whereby the baseline data were collected since June 2008. CVD risk was measured using INTERHEART risk score which comprised of eleven risk factors i.e. age and gender, family history of heart attack, smoking status, exposure to second hand smoke, diabetes mellitus, hypertension status, waist-hip ratio, self reported stress, depression, dietary habits and physical activity status. RESULTS: Majority of the studied participants had low cardiovascular risk (57%). Participants from rural area were generally older, had lower educational status, higher prevalence of smokers, obesity, hypertension, diabetes, and more likely to be depressed. In comparison, urbanites had lower physical activities and more likely to be stressful. Mean INTERHEART score among rural participants were higher, especially for male, in comparison to urbanite (11.5+/-5.83 vs. 10.01+/ 5.74, p<0.001). CONCLUSION: Contradict to common beliefs, participants in rural areas generally have higher cardiovascular risk factors compared to their urban counterparts. The rural population should be targeted for focused preventive interventions, taking account the socioeconomic and cultural context. PMID- 28087958 TI - The teaching of trauma management in undergraduate medical education. AB - BACKGROUND: The teaching of trauma in medical schools faces many educational and logistic challenges. Issues on what to teach, how to teach, when to teach, who will teach and whether medical students with insufficient exposure to clinical medicine can benefit from a trauma course are unclear. MATERIALS AND METHODS: A well-designed one day intensive trauma course concentrating on the primary survey was taught to semester seven and semester eight students by a multi-disciplinary team comprising of surgeons, anaesthetists, emergency physicians and trained medical officers. The course comprised of a pre-test of 30 multiple choice questions followed by three hours of lectures, three hours of skill stations and a post-test. The pre-test and posttest scores were analysed using the paired sample t-test and the independent t-test. RESULTS: The pre- and post-test scores showed significant improvement for both semester seven and semester eight students. Semester seven students, who only had a sevenweek posting in Surgery had pre-test and post-test scores of only 4% less than semester eight students who had an additional six weeks in Orthopaedics and two weeks in Accident and Emergency postings. The use of a multidisciplinary team reduced the logistic burden of finding sufficient surgeons to teach trauma management. CONCLUSION: Trauma education can be taught to undergraduates by a multidisciplinary team as early as year three, in semester seven. However, the mean score of semester eight students is only at 66%, suggesting that a refresher course prior to graduation at semester ten will be useful. KEY WORDS. PMID- 28087959 TI - A study on HLA-DR/DQ typing in adult Malay patients with acute amoebic liver abscess. AB - INTRODUCTION: Amoebiasis is a parasitic disease caused by Entamoeba histolytica that may lead to death in developing countries. Few important risk factors have been identified in the development of amoebic liver abscess (ALA). There are limited reports that suggest an association between antigens of the major histocompatibility complex (MHC) particularly class II antigens and ALA development. This present work aimed at studying the possible association of HLA antigens with ALA and disease severity. Results of the study may serve as a guide for further immunological studies dealing with E. histolytica. METHODS: This preliminary study involved two groups of subjects: 20 ALA patients in the experimental group and 40 healthy individuals in the control group. Cases were selected from adult Malay patients confirmed with ALA based on clinical signs and symptoms, radiological findings, microbiological findings and who were admitted to the medical or surgical ward, Hospital USM, Kelantan. Venous blood was obtained from each patient and HLA typing was then conducted using polymerase chain reaction specific primer sequence. RESULTS: HLA DR12 was most frequently found in the healthy control and ALA groups at 40% and 55% respectively. HLA DQ7 and DQ8 were found to have the highest percentage in the ALA group at 65%. In the control group, HLA DQ8 (57.5%) had the highest percentage. CONCLUSION: HLA antigens play a role in acquisition of ALA and provide understanding of the disease outcome. PMID- 28087960 TI - Retention of Knowledge following training of students in Basic Trauma Life Support. AB - INTRODUCTION: In the course of their undergraduate training at the International Medical University, students receive a Basic Trauma Life Support course. OBJECTIVE: We wanted to test the long-term retention of knowledge (after 16 months) of third year medical students who had received training in Basic Trauma Life Support Method: To assess the retention of knowledge one cohort of students who received the training course were tested again 16 months later using the same 30 question One Best Answer quiz. RESULTS: Seventy-three students who underwent the course sat for the Retention test. The number of students who passed the Retention test was not significantly different from the test taken immediately after the course. The mean scores, 62.5% and 59.5% respectively, were however significantly different. CONCLUSION: Our study involves a relatively long interval between the course and retention of knowledge test shows encouraging results. PMID- 28087961 TI - Treatment of Heavily Pre-treated Metastatic Breast Cancer with Eribulin: First local experience in Sabah. AB - There are many options in the treatment of heavily pretreated metastatic breast cancer however none of the therapeutic agents have shown promising improvement of survival with good toxicity profile. Eribulin is a novel nontaxane microtubule dynamics inhibitor. Two recent clinical trial showed that Eribulin improves progression-free and overall survival in this subset of patients. We report our experience with using Eribulin in five patients with metastatic breast cancer either in second or third-line setting, in our centre. PMID- 28087962 TI - Angry patient with fibromyalgia: Diagnosis and management in primary care. AB - I report a case of 40-year-old lady who presented with symptoms and signs suggestive of fibromyalgia but was disregarded by attending doctor. She was infuriated and lodged a complaint to Family Medicine Specialist (FMS) whereby further assessment confirmed the diagnosis of fibromyalgia and subsequently treated in primary care setting. PMID- 28087963 TI - Vitamin-D-deficiency rickets even with abundant sunlight -A case to highlight emerging problem. AB - We describe a case of vitamin-D-deficiency rickets in a young child to highlight its existence in Malaysia where sunlight is abundant throughout the year. The child presented with deformity of both legs. He came from an educated urban family but remained indoors most of the time. Radiographs of knees and wrists showed changes of florid rickets. Low serum 25-hydoxyvitamin-D, high parathyroid hormone, normal serum phosphate and calcium levels, and normal renal function clinched the diagnosis of vitamin-D-deficiency rickets. He improved remarkably after treatment with oral Vitamin-D. We emphasise the importance of exposure to sunlight to prevent rickets. PMID- 28087965 TI - Hypopharyngeal cancer masquerading as a thyroid mass. AB - Hypopharyngeal cancer (HPC) is generally a rare head and neck malignancy. There are differing clinical presentations depending on the subsite location of primary tumour. Advanced HPC will have neck node metastasis particularly upper jugulodigastric nodes. We report a patient with postcricoid tumour who presented with anterior huge neck swelling mimic thyroid mass. The patient first presented to the General Surgical Unit for management of presumed thyroid lesion. She was diagnosed post-cricoid squamous cell carcinoma when further assessed by otorhinolaryngologist. PMID- 28087964 TI - Arrythmogenic Right Ventricular Dysplasia. AB - A 10-year-old well and asymptomatic female was referred for screening of acute right ventricular dilatation (ARVD) as she had an elder brother diagnosed with ARVD whom died of sudden cardiac death. Electrocardiography (ECG), transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (CMR) were performed. Results of these investigations were suggestive of ARVD. Despite being a rare cardiac disease and largely unrecognised in children and young adult population, ARVD is an important cause of ventricular arrhythmias in this group of patients and is one of the causes of sudden cardiac death (SCD) in this population. PMID- 28087966 TI - Gastric ulcer that turned out to be metastasis of a synovial sarcoma: A case report and literature review. AB - Primary gastrointestinal synovial sarcoma or its metastases to the gastrointestinal tract is rare. Here we present a case of 56-year-old gentleman with left thigh synovial sarcoma and gastric metastases along with the literature review. PMID- 28087967 TI - Periampullary Carcinoma with Penile Metastasis. AB - Periampullary carcinoma metastases are usually located at regional nodes, adjacent organs, liver or lung. On the other hand, metastatic penile cancer is uncommon. Penile metastasis usually originates from pelvic region with prostate and bladder being the most frequent primary location. We present a very rare case of periampullary carcinoma with penile metastasis in a 49-year-old man. He initially presented with early ampullary type periampullary carcinoma and had pyloric preserving pancreatoduodenectomy and adjuvant chemotherapy. However, after six years of uneventful follow up, he presented with a penile lesion which was confirmed to be pancreatic metastasis. He was started on chemotherapy but passed away two months later. Ampullary carcinoma type of periampullary carcinoma usually presents early with favourable prognosis. However, tumour recurrence can present much later after definitive treatment and at a rare site such as penis with generally poor outcome. PMID- 28087968 TI - Thymic carcinoma presenting with an unusual and delayed metastasis to the neural foramen, mimicking thoracic spinal radiculopathy. AB - We report a case of metastatic thymic carcinoma which presented as an enhancing mass located in the neural foramen of the thoracic spine. More common tumours which arise in the neural foramen would include a neurogenic tumour or developmental anomalies such as a foregut duplication cyst. This case is singular firstly because the lesion present as radiculopathy which mimics a neurogenic tumour. Secondly, the presentation was unusually delayed as the patient presented to our centre more than a decade after the resection of the primary tumour in another institution. PMID- 28087969 TI - Axillary accessory breast carcinoma masquerading as axillary abscess: a case report. AB - Accessory breast is a frequently seen developmental breast abnormality, commoner among Asians than Caucasians. This ectopic breast tissue shares many similarities as the normal breast tissue, and although subjected to the same pathological processes, accessory breast carcinoma is rare. As locations of the accessory breast may be variable, detection of pathological lesions through clinical examinations and standard diagnostic tools (i.e., mammogram) can be difficult. Staging and management should be tailored-made according to the location of the accessory breast as well as its known pattern of lymphatic drainage. We report a case of an intra-ductal carcinoma occurring in an axillary accessory breast. PMID- 28087970 TI - Liquid chromatography high resolution mass spectrometry for the determination of baclofen and its metabolites in plasma: Application to therapeutic drug monitoring. AB - Baclofen is used to manage alcohol dependence. This study describes a simple method using liquid chromatography coupled to high-resolution mass spectrometry (LC-HR-MS) developed in plasma samples. This method was optimized to allow quantification of baclofen and determination of metabolic ratio of its metabolites, an oxidative deaminated metabolite of baclofen (M1) and its glucuronide form (M2). The LC-HR-MS method on Exactive(r) apparatus is a newly developed method with all the advantages of high resolution in full-scan mode for the quantification of baclofen and detection of its metabolites in plasma. The present assay provides a protein precipitation method starting with 100 MUL plasma giving a wide polynomial dynamic range (R2 > 0.999) between 10 and 2000 ng/mL and a lower limit of quantitation of 3 ng/mL for baclofen. Intra- and inter day precisions were <8.1% and accuracies were between 91.2 and 103.3% for baclofen. No matrix effect was observed. The assay was successfully applied to 36 patients following baclofen administration. Plasma concentrations of baclofen were determined between 12.2 and 1399.9 ng/mL and metabolic ratios were estimated between 0.4 and 81.8% for M1 metabolite and on the order of 0.3% for M2 in two samples. PMID- 28087971 TI - Structural study of 1-(2', 3'-O-isopropylidene-(alpha-d-allo and -beta-l talofuranosyluron)-5'-cyanohydrin)uracil stereoisomers by NMR spectroscopy and theoretical methods. PMID- 28087972 TI - Lack of effect of oral cabotegravir on the pharmacokinetics of a levonorgestrel/ethinyl oestradiol-containing oral contraceptive in healthy adult women. AB - AIMS: This study aimed to investigate whether cabotegravir (CAB), an integrase inhibitor in development for treatment and prevention of human immunodeficiency virus-1, influences the pharmacokinetics (PK) of a levonorgestrel (LNG) and ethinyl oestradiol (EO)-containing oral contraceptive (OC) in healthy women. METHODS: In this open-label, fixed-sequence crossover study, healthy female subjects received LNG 0.15 mg/EO 0.03 mg tablet once daily Days 1-10 alone and with oral CAB 30 mg once daily Days 11-21. At the end of each treatment period, subjects underwent predose sampling for concentrations of follicle-stimulating hormone, luteinizing hormone, and progesterone and serial PK sampling for plasma LNG, EO, and CAB concentrations. RESULTS: Twenty women were enrolled, and 19 completed the study. One subject was withdrawn due to an adverse event unrelated to study medications. Geometric least squares mean ratios (90% confidence interval) of LNG + CAB vs. LNG alone for LNG area under the plasma concentration time curve over the dosing interval of duration tau and maximum observed plasma concentration were 1.12 (1.07-1.18) and 1.05 (0.96-1.15), respectively. Geometric least squares mean ratio (90% confidence interval) of EO + CAB vs. EO alone for EO area under the plasma concentration-time curve over the dosing interval of duration tau and maximum observed plasma concentration were 1.02 (0.97-1.08) and 0.92 (0.83-1.03), respectively. Steady-state CAB PK parameters were comparable to historical values. There was no apparent difference in mean luteinizing hormone, follicle-stimulating hormone, and progesterone concentrations between periods. No clinically significant trends in laboratory values, vital signs, or electrocardiography values were observed. CONCLUSIONS: Repeat doses of oral CAB had no significant effect on LNG/EO PK or pharmacodynamics, which supports CAB coadministration with LNG/EO OCs in clinical practice. PMID- 28087973 TI - Association of granulomas in mesenteric lymph nodes in Crohn's disease with younger age and transmural inflammation. AB - BACKGROUND AND AIMS: Mesenteric lymph nodes were usually removed during bowel resection surgery for Crohn's disease (CD). Mesenteric lymph node (MLN) granuloma predicted postoperative disease recurrence in patients with CD after ileocolic resection (ICR). This study was aimed to identify factors associated with MLN granulomas in a cohort of CD patients who underwent ICR. METHODS: The study group consisted of 18 patients with CD who underwent the index ICR between 2004 and 2012 and had MLN granulomas. The control group included 32 cases negative for MLN granulomas, which were randomly selected from the same period. Clinicodemographic and histological features were compared in these two groups. RESULTS: The presence of MLN granuloma was associated with younger age, perianal disease, and ileocolic disease. Gender, body mass index, smoking status, disease duration, extraintestinal manifestation, length of bowel resected, total number of nodes examined, medical treatment, and indications for surgery were not significantly different between the groups. The presence of MLN granuloma was associated with mural granuloma, transmural inflammation, mural abscess, hypertrophy of the muscularis propria, fibrosis of the muscularis propria, and serosal fibrosis in the small bowel. The multivariable analysis confirms that MLN granuloma was associated with age and transmural inflammation. CONCLUSIONS: In CD patients who underwent the index ICR, the presence of MLN granuloma was associated with younger age and transmural inflammation. Our current results suggest that the detection of MLN granulomas may be enhanced in patients at higher risk, that is, younger patients or those with transmural inflammation on imaging or histopathology. PMID- 28087974 TI - Application of Z-sinapinic matrix in peptide MALDI-MS analysis. AB - Since introduction of sinapinic acid (SA) and alpha-cyano-4-hydroxycinnamic acid as matrices, successful application of matrix-assisted laser desorption/ionization mass spectrometry started for protein/polypeptides. Both show some limitations in short peptide analysis because matrix clusters are quite abundant. Cinnamics currently used are E-cinnamics. Here, Z-SA as matrix for peptides is studied and compared with E-SA and alpha-cyano-4-hydroxycinnamic acid. Minor number of clusters is always observed in the low m/z region allowing the detection of short peptides. The results here described show that this novel matrix is a tool of choice for direct, rapid and sensitive detection of hydrophilic and hydrophobic peptides. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28087975 TI - Screening and treating Helicobacter pylori infection for gastric cancer prevention on the population level. AB - Helicobacter pylori infection is the major cause of gastric cancer, and removal of H. pylori infection from a population could theoretically decrease the number of cases by about 89%. However, in real-life settings, few studies have reported the effect of screening and treating this pathogen in population-based programs. This is mainly because of the lack of an adequate infrastructure for delivery of systematic screening services to asymptomatic individuals, the lack of standardization to ensure that each subject receives the correct diagnostic testing and antibiotic treatment, and limited resources. We illustrate our method of implementing two population-based screen-and-treat programs in Taiwan, where the epidemiological characteristics of disease burden have changed from the traditionally Eastern pattern towards that of the Western countries. Our first example is a high-risk population that resides on an offshore island, in which a strategy of mass eradication of H. pylori was applied. The other example is an intermediate-risk population, which is representative of the general average-risk population, in which there is integration of the screen-and-treat method with the established framework of colorectal cancer screening using the fecal-occult blood test. The information provided here may be useful for integration of gastric cancer prevention measures into the healthcare priorities of populations with different gastric cancer risks, such as those with limited resources. PMID- 28087976 TI - The role of diode array ultraviolet detection for the identification of synthetic cathinones. AB - The utility of diode array ultraviolet (UV) detection for aiding in the identification of synthetic cathinones, including different sub-classes and positional isomers is presented. For 35 synthetic cathinones, unique UV spectra are obtained for seven sub-classes, including mostly beta ketones, where position and type of substitution on benzene rings give rise to differences in UV maxima and relative intensity of the spectral bands. This aspect is key to distinguishing positional isomers that contain differences in R substitution (mono and di) around the benzene ring, which provides complementary information to electron ionization mass spectrometry, where the latter technique cannot distinguish between these types of positional isomers. In addition, it is possible to ascertain the substitution position based on the UV spectra. For ten sets of positional isomers, it was possible to distinguish most of the positional isomers within a set. For ultra-high performance supercritical fluid chromatography (UHPSFC) versus reversed phase ultra-high performance liquid chromatography (UHPLC), there was at least a 10 nm blue shift in UV maximum (shift to shorter wavelengths). This highlights the importance of taking in account the effect of mobile phase on the UV maximum when performing method development in UHPSFC. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28087977 TI - Fibroblast growth factor 23 in untreated nephrotic syndrome. AB - AIM: Despite its importance in bone and cardiovascular disease in subjects with kidney disease, there are no data on fibroblast growth factor 23 (FGF23) perturbations in nephrotic syndrome. We evaluated FGF23 and markers of mineral bone metabolism in subjects with untreated NS. METHODS: In this cross-sectional study, we measured circulating levels of FGF23, 25-hydroxy vitamin D [25(OH)D], 1,25 di-hydroxy vitamin D [1,25(OH)2 D], serum albumin, serum calcium, phosphorus, creatinine and intact parathyroid hormone (iPTH) in 101 patients with adults onset NS and 40 healthy controls. We examined the correlation between FGF23 and markers of mineral bone metabolism. RESULTS: Compared to healthy controls, subjects with NS showed reduced levels of 25(OH)D (21.76 +/- 10.18 vs 35.74 +/- 40.27 nmol/L, P = 0.001), 1,25(OH)2 D (median; 37.80 vs 73.13 pmol/L, P = 0.0001) and FGF23 (37.81 +/- 20.42 vs 48.20 +/- 11.60 pg/mL, P = 0.004) levels. Serum phosphorus levels were marginally, but significantly higher in subjects with nephrotic syndrome compared to healthy controls (P = 0.004). Serum iPTH levels were significantly higher in subjects with NS compared to healthy controls (52.24 +/- 39.58 vs 37.90 +/- 14.60 pg/mL, P = 0.028). CONCLUSIONS: We conclude that FGF23 is reduced in subjects with NS compared to healthy controls. The reduced levels of Vitamin D, and urinary losses may contribute to lower levels of FGF23 in NS. PMID- 28087978 TI - Identification of gonadotropin-releasing hormone metabolites in greyhound urine. AB - Gonadotropin-releasing hormone (GnRH) is a 10-residue peptide hormone that induces secretion of luteinizing hormone (LH) and follicle-stimulating hormone into the blood from the pituitary gland. In males, LH acts on the testes to produce testosterone. The performance-enhancing potential of testosterone makes administration of exogenous GnRH a concern in sports doping control. Detection of GnRH abuse is challenging owing to its rapid clearance from the body and its degradation in urine. Following recent investigations of GnRH abuse in racing greyhounds in New Zealand, we carried out a GnRH administration study in greyhounds in an attempt to identify GnRH metabolites that might provide more facile detection of GnRH abuse; little information is available on in vivo metabolites of exogenous GnRH in any species and none in dogs. We identified three C-terminal GnRH metabolites in urine: GnRH 5-10, GnRH 6-10, and GnRH 7-10. These metabolites and intact GnRH, which was also detected in urine, were all excreted over a 1-3 h period after GnRH administration. Two of the GnRH metabolites - GnRH 5-10 and GnRH 6-10 - were more stable in urine than intact GnRH offering improved potential to detect GnRH administration. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28087979 TI - Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus. AB - BACKGROUND AND PURPOSE: Astroglia contribute to the pathophysiology of major depression and antidepressant drugs act by modulating synaptic plasticity; therefore, the present study investigated whether the fast antidepressant action of ketamine is reflected in a rapid alteration of the astrocytes' morphology in a genetic animal model of depression. EXPERIMENTAL APPROACH: S-Ketamine (15 mg.kg-1 ) or saline was administered as a single injection to Flinders Line (FSL/ FRL) rats. Twenty-four hours after the treatment, perfusion fixation was carried out and the morphology of glial fibrillary acid protein (GFAP)-positive astrocytes in the CA1 stratum radiatum (CA1.SR) and the molecular layer of the dentate gyrus (GCL) of the hippocampus was investigated by applying stereological techniques and analysis with Imaris software. The depressive-like behaviour of animals was also evaluated using forced swim test. KEY RESULTS: FSL rats treated with ketamine exhibited a significant reduction in immobility time in comparison with the FSL-vehicle group. The volumes of the hippocampal CA1.SR and GCL regions were significantly increased 1 day after ketamine treatment in the FSL rats. The size of astrocytes in the ketamine-treated FSL rats was larger than those in the FSL vehicle group. Additionally, the number and length of the astrocytic processes in the CA1.SR region were significantly increased 1 day following ketamine treatment. CONCLUSIONS AND IMPLICATIONS: Our results support the hypothesis that astroglial atrophy contributes to the pathophysiology of depression and a morphological modification of astrocytes could be one mechanism by which ketamine rapidly improves depressive behaviour. PMID- 28087980 TI - The significance of glypican-3 expression profiling in the tumor cellular origin theoretical system for hepatocellular carcinoma progression. AB - BACKGROUND AND AIM: Glypican-3 (GPC3) expression is correlated with poor prognosis and progression in hepatocellular carcinoma (HCC). HCC progression can be associated with the differentiation status of tumor cell before malignant transformation. Our aim was to investigate the dynamic expression of GPC3 during tumor cells differentiation and to explore the role and theoretical significance of GPC3 in malignant essence of HCC. METHODS: The expressions of tissue GPC3 and alpha fetoprotein (AFP) were detected by immunohistochemical staining. The tumor size, lymph node involvement, and metastasis were determined by pathological and imaging studies. HepG2 cells were induced to differentiate by all-trans retinoic acid (ATRA). Differentiation was evaluated by cytokeratin 19, gamma glutamyl transferase, and AFP through reverse transcription-polymerase chain reaction and real-time polymerase chain reaction. GPC3 staining was analyzed through flow cytometry. RESULTS: Based on the immunohistochemical staining, the enrolled 316 cases were divided into two subtypes, namely, GPC3+ HCC and GPC3- HCC. Significant differences in morphology, histology variations, AFP expression, TNM staging, and overall survival curves were observed between two subtypes. During HCC differentiation induced by ATRA, the mean value of GPC3 expression treated with ATRA was much lower than the ones in placebo. There were significant differences between GPC3+ HCC and GPC3- HCC for cumulative intrahepatic and extrahepatic recurrence in early stage HCC (P = 0.009, P = 0.010). CONCLUSIONS: Glypican-3 is correlated with the clinical malignant behavior of HCC. Moreover, GPC3 phenotype changes from positive to negative during tumor cells differentiation. Meanwhile, GPC3 plays a significant role in tumor cellular origin theoretical system, which can better reflect the malignant essence of tumors. PMID- 28087981 TI - Humanized chondroitinase ABC sensitizes glioblastoma cells to temozolomide. AB - BACKGROUND: Malignant gliomas (glioblastomas; GBMs) are extremely aggressive and have a median survival of approximately 15 months. Current treatment modalities, which include surgical resection, radiation and chemotherapy, have done little to prolong the lives of GBM patients. Chondroitin sulfate proteoglycans (CSPG) are critical for cell-cell and cell-extracellular matrix (ECM) interactions and are implicated in glioma growth and invasion. Chondroitinase (Chase) ABC is a bacterial enzyme that cleaves chondroitin sulfate disaccharide chains from CSPGs in the tumor ECM. Wild-type Chase ABC has limited stability and/or activity in mammalian cells; therefore, we created a mutant humanized version (Chase M) with enhanced function in mammalian cells. METHODS: We hypothesized that disruption of cell-cell and cell-ECM interactions by ChaseM and temozolomide (TMZ) will enhance the chemotherapeutic availability and sensitivity of glioma cells. RESULTS: Utilizing primary patient-derived neurospheres, we found that ChaseM decreases glioma neurosphere aggregation in vitro. Furthermore, an oncolytic HSV-1 virus expressing secreted ChaseM (OV-ChaseM) enhanced viral spread and glioma cell killing compared to OV-Control, in vitro. OV-ChaseM plus TMZ combinatorial treatment resulted in a significant synergistic enhancement of glioma cell killing accompanied by an increase in apoptotic cell death. Intracellular flow cytometric analysis revealed a significant reduction in the phosphorylation of the pro-survival AKT protein following OV-ChaseM plus TMZ treatment. Lastly, in nude mice bearing intracranial GBM30 glioma xenografts, intratumoral OV-ChaseM plus TMZ (10 mg/kg by oral gavage) combination therapy resulted in a significant (p < 0.02) enhancement of survival compared to each individual treatment alone. CONCLUSIONS: These data reveal that OV-ChaseM enhances glioma cell viral susceptibility and sensitivity to TMZ. PMID- 28087983 TI - Erratum. PMID- 28087982 TI - The impact of CES1 genotypes on the pharmacokinetics of methylphenidate in healthy Danish subjects. AB - AIMS: This study investigated the influence of CES1 variations, including the single nucleotide polymorphism (SNP) rs71647871 (G143E) and variation in copy number, on the pharmacokinetics of a single oral dose of 10 mg methylphenidate. METHODS: CES1 genotype was obtained from 200 healthy Danish Caucasian volunteers. Based on the genotype, 44 (19 males and 25 females) were invited to participate in an open, prospective trial involving six predefined genotypes: three groups with two, three and four CES1 copies, respectively; a group of carriers of the CES1 143E allele; a group of individuals homozygous for CES1A1c (CES1VAR); and a group having three CES1 copies, in which the duplication, CES1A2, had increased transcriptional activity. Plasma concentrations of methylphenidate and its primary metabolites were determined at scheduled time points. RESULTS: Median AUC of d-methylphenidate was significantly larger in the group carrying the 143E allele (53.3 ng ml-1 h-1 , range 38.6-93.9) than in the control group (21.4 ng ml-1 h-1 , range 15.7-34.9) (P < 0.0001). Median AUC of d-methylphenidate was significantly larger in the group with four CES1 copies (34.5 ng ml-1 h-1 , range 21.3-62.8) than in the control group (P = 0.01) and the group with three CES1 copies (23.8 ng ml-1 h-1 , range 15.3-32.0, P = 0.03). There was no difference between the groups with two and three copies of CES1. CONCLUSIONS: The 143E allele resulted in an increased AUC, suggesting a significantly decreased CES1 enzyme activity. Surprisingly, this was also the case in subjects with homozygous duplication of CES1, perhaps reflecting an undiscovered mutation affecting the activity of the enzyme. PMID- 28087984 TI - Challenges in detecting substances for equine anti-doping. AB - The artificial increase of the physical capability of horses using drugs is well known in racing and other equine sports. Both illicit and therapeutic substances are regarded as prohibited substances in competition in most countries. Some countries make distinctions for a few, specific drugs which are, however, allowed for use in other countries. The primary objective in the case of doping control is the detection of any trace of drug exposure, either parent drug or any of its metabolites, using the most powerful analytical methods which are generally based on chromatographic/mass spectrometric techniques. Of major concern in horseracing is the absence of a single organization regulating the anti-doping framework; instead of this, individual racing authorities provide rules and regulations often resulting in variations in the applied doping control programmes of different countries. The aim of this paper is to review the recent literature (approximately from 2012 to mid-2016) to highlight the numerous and diverse challenges faced in doping control of racing and equestrian sports, including the detection of designer drugs (anabolic steroids or stimulants) and of other emerging prohibited substances, such as peptides and noble gases in horse urine and plasma. Moreover, the application of 'omics' techniques (especially of metabolomics) deserves attention for establishing possible fingerprints of drug abuse as well as the evolution of instrumental analysis resulting a powerful ally in the fight against doping in equine sports. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28087986 TI - Barriers to access to opioid medicines for patients with opioid dependence: a review of legislation and regulations in eleven central and eastern European countries. AB - BACKGROUND AND AIMS: Barriers linked to drug control systems are considered to contribute to inequitable access to controlled medicines, leaving millions of people in pain and suffering. Most studies focus on access to opioids for the treatment of severe (cancer) pain. This study aims to identify specific access barriers for patients with opioid dependence in legislation and regulations of 11 central and eastern European countries. METHODS: This study builds on a previous analysis of legislation and regulations as part of the EU 7th Framework Access To Opioid Medication in Europe (ATOME) project. An in-depth analysis was undertaken to determine specific barriers for patients with opioid dependence in need of opioid analgesics or opioid agonist therapy (OAT). For each country, the number and nature of specific potential barriers for these patients were assessed according to eight categories: prescribing; dispensing; manufacturing; usage; trade and distribution; affordability; penalties; and other. An additional keyword search was conducted to minimize the omission of barriers. Barriers in an additional category, language, were recorded qualitatively. Countries included Bulgaria, Cyprus, Estonia, Greece, Hungary, Latvia, Lithuania, Serbia, Slovakia, Slovenia and Turkey. RESULTS: Ten of the 11 countries (all except Estonia) showed specific potential barriers in their legislation and regulations. The total number of barriers varied from two (Slovenia) to 46 (Lithuania); the number of categories varied from one (Slovenia) to five (Lithuania). Most specific potential barriers were shown in the categories 'prescribing', 'usage' and 'other'. The total number in a single category varied from one to 18 (Lithuania, prescribing). Individual differences between countries in the same specific potential barrier were shown; for example, variation in minimum age criteria for admission to OAT ranging from 15 (Lithuania, in special cases) to 20 years (Greece). All countries had stigmatizing language in their legislation. CONCLUSIONS: Patients with opioid dependence are likely to experience specific barriers to accessing opioids in addition to those experienced by other non dependent patients. PMID- 28087985 TI - Prophylactic tributyrin treatment mitigates chronic-binge ethanol-induced intestinal barrier and liver injury. AB - BACKGROUND AND AIM: Impaired gut-liver axis is a potential factor contributing to alcoholic liver disease. Ethanol depletes intestinal integrity and causes gut dysbiosis. Butyrate, a fermentation byproduct of gut microbiota, is altered negatively following chronic ethanol exposure. This study aimed to determine whether prophylactic tributyrin could protect the intestinal barrier and liver in mice during combined chronic-binge ethanol exposure. METHODS: C57BL/6J mice exposed to 5% v/v ethanol-containing diet for 10 days received a single ethanol gavage (5 g/kg) 9 h before euthanasia. Control mice were isocalorically pair-fed maltose dextrin for ethanol. Diets were supplemented (5 mM) with tributyrin or glycerol. Intestine and liver disease activity was assessed histologically. Protein and mRNA expression of tight junction (TJ) proteins, toll-like receptors, and tumor necrosis factor-alpha were assessed. Caco-2 monolayers with or without ethanol exposure and/or sodium butyrate were used to test butyrate's direct effects on intestinal integrity. RESULTS: Chronic-binge ethanol feeding impaired intestinal TJ protein co-localization staining; however, tributyrin co-treatment mitigated these effects. Ethanol depleted TJ and transepithelial electrical resistance in Caco-2 monolayers, but butyrate co-treatment reduced these effects. Hepatic toll-like receptor mRNA expression and tumor necrosis factor-alpha protein expression was induced by ethanol; however, the response was significantly dampened in mice co-treated with tributyrin. Tributyrin altered localization of both neutrophils and single hepatocyte death: Leukocytes and apoptotic hepatocytes localized predominantly around the portal tract in ethanol only treated mice, whereas localization predominated around the central vein in ethanol-tributyrin mice. CONCLUSIONS: Prophylactic tributyrin supplementation mitigated effects of combined chronic-binge ethanol exposure on disruption of intestinal TJ localization and intestinal permeability and liver injury. PMID- 28087987 TI - NMR line-fitting quantification of polysaccharide N-acylurea-based modification in glycoconjugates of Salmonella Typhi Vi polysaccharide. AB - The polysaccharides modification via carbodiimide reaction is one of the most applied methods for obtaining conjugated vaccines against Salmonella enterica. However, N-acylurea carbodiimide adduct generated in the process is a critical impurity in carbohydrate-based vaccines. A quantitative NMR method was developed for assessing the N-acylurea carbodiimide adduct impurity. The procedure was based on line-fitting facilities for processing the NMR signals on complex spectra. The method showed good linearity, accuracy and precision under inter operator variation (relative standard deviation <5%). Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28087988 TI - CpG island methylator phenotype is an independent predictor of survival after curative resection for colorectal cancer: A prospective cohort study. AB - BACKGROUND AND AIMS: The CpG island methylator phenotype (CIMP) is found in approximately 30% of colorectal cancer (CRC) cases. However, the role of CIMP status in predicting oncologic outcomes in curatively resected CRC is still unclear. STUDY: Between January 2006 and December 2006, we retrospectively reviewed 157 consecutive patients who underwent curative surgery for CRC. Prognostic significance of CIMP status was evaluated using reverse transcriptase polymerase chain reaction. RESULTS: CIMP-high (H) and CIMP-none/low (N/L) tumors were found in 50 cases (31.8%) and 107 cases (68.2%), respectively. CIMP-H tumors were significantly associated with female sex, colonic location, poorly/mucinous histologic type, higher T category, perineural invasion, and MSI-high status (P = 0.001). During a median of 64.5 months, tumor recurrence developed in 47 (29.9%) patients. The 5-year disease-free survival for CIMP-H and CIMP-N/L was 61.4% and 76.3% (P = 0.018). In addition, multivariate analysis showed that CIMP-H was also a significant prognostic factor (P = 0.042). When analysis was performed according to anatomical location, more marked survival differences were observed in patients with colon cancer (P = 0.026) than in patients with rectal cancer (P = 0.210). Similarly, the role of CIMP status as a prognostic indicator was more prominent in patients with stage I/II (P = 0.006) than in patients with stage III/IV CRC (P = 0.65). CONCLUSIONS: DNA methylation status can be considered as a useful predictor of survival after CRC surgery, particularly for patients with stage I/II disease or colon cancer. PMID- 28087989 TI - Alcohol Consumption and Gastric Cancer Risk: A Meta-Analysis. AB - BACKGROUND We sought to determine by meta-analysis the relationship between drinking alcohol and the risk of gastric cancer. MATERIAL AND METHODS A systematic Medline search was performed to identify all published reports of drinking alcohol and the associated risk of gastric cancer. Initially we retrieved 2,494 studies, but after applying inclusion and exclusion criteria, only ten studies were found to be eligible for our meta-analysis. RESULTS Our meta-analysis showed that alcohol consumption elevated the risk of gastric cancer with an odds ratio (OR) of 1.39 (95% CI 1.20-1.61). Additionally, subgroup analysis showed that only a nested case-control report from Sweden did not support this observation. Subgroup analysis of moderate drinking and heavy drinking also confirmed that drinking alcohol increased the risk of gastric cancer. Publication bias analysis (Begg's and Egger's tests) showed p values were more than 0.05, suggesting that the 10 articles included in our analysis did not have a publication bias. CONCLUSIONS The results from this meta-analysis support the hypothesis that alcohol consumption can increase the risk of gastric cancer; suggesting that effective moderation of alcohol drinking may reduce the risk of gastric cancer. PMID- 28087990 TI - Modification of the Onsager Reaction Field and Its Application on Spectral Parameters. AB - Solvent polarity is an important solvent property. The Onsager's theory of reaction field was the most classic model to describe solvent effects and was widely used in relating dielectric constant and other solvent polarity parameters. In this study, a modified semi-empirical reaction field was presented to relate electron transition energies or hyperfine coupling constants with the dielectric constants of solvents. In previous work, this relationship was well established by traditional Onsager reaction field for nonhydrogen-bonding systems but failed for hydrogen-bonding systems. In this modified reaction field model, the radius of the field was replaced by that of the primary solvation shell or the molecular fragment rather than that of the probe. In this way, the molecular volume of the solvent which contains information of the molecular size and overall interactions is involved in the reaction field. The 154 sets of electron transition energies and 44 sets of nitrogen isotropic hyperfine coupling constants were used to verify the modified model, indicating it works far better than the traditional model for hydrogen-bonding systems. PMID- 28087991 TI - An Exceptionally Selective DNA Cooperatively Binding Two Ca2+ Ions. AB - Ca2+ is a highly important metal ion in biology and in the environment, and thus there is extensive work in developing sensors for Ca2+ detection. Although many Ca2+ -binding proteins are known, few nucleic acids can selectively bind Ca2+ . DNA-based biosensors are attractive for their high stability and excellent programmability. We report a RNA-cleaving DNAzyme, EtNa, cooperatively binding two Ca2+ ions but to only one Mg2+ . Four DNAzymes with known Ca2+ -dependent activity were compared, and the EtNa had the best selectivity for Ca2+ . The EtNa is 90 times more active in Ca2+ than in Mg2+ . Phosphorothioate (PS) modification showed that both non-bridging oxygen atoms at the scissile phosphate contribute equally to Ca2+ binding. The pH-rate profile suggests two concurrent deprotonation reactions. EtNa was further engineered for Ca2+ sensing, and found to have a detection limit of 17 MUm Ca2+ and excellent selectivity. The detection of Ca2+ in tap water was performed, and the result was comparable with that by ICP-MS. This study offers new fundamental insights into Ca2+ binding by nucleic acids and improved metal selectivity by having multiple cooperative metal binding sites. PMID- 28087993 TI - Erratum. PMID- 28087994 TI - Commentary on: Mauf S, Jentzsch T, Laberke PJ, Thali MJ, Bartsch C. Why we need postmortem analysis of cardiac implantable electronic devices. J Forensic Sci 2016;61(4):988-92. PMID- 28087996 TI - Grating lobes suppression by adding virtual receiving subaperture in synthetic aperture imaging. AB - A method of suppression of grating lobes is presented, analyzed, and verified. The method is based on creating a Virtual Receiving Subaperture (VRS) by adding virtual transducer elements not existing in the physical layout of the receiver. The VRS channels are filled with data based on signals from real channels. The analytical model of the synthetic aperture imaging system's impulse response is presented to describe the properties of the VRS. The model shows a reduction of the receiving grating lobes' amplitude (with a comparison to the main lobe's amplitude) by a magnitude equal to the number of receiving transducer elements. It is shown that effective properties of the entire system with a VRS are similar to a system with a pitch in the receiving aperture that is twice as small. The numerical calculations of the impulse response show a doubling of the signal to noise ratio, which results in a reduction of the receiving grating lobes. For experimental validation, the generalized Plane Wave Imaging with and without the VRS is compared with a basic synthetic transmit aperture (STA) imaging. The experiment confirmed that the use of a VRS allows for visualization of the objects in a medium in which they are not imaged without a VRS or are visualized with a lower contrast. The reduction of grating lobes attained using the proposed method is at the level of 15dB in the visualization of the superficial cyst. PMID- 28087997 TI - Experience in action: Moderating care in web-based patient feedback. AB - What does it take to mobilise experiences of care and make them useful for improving services? This article draws on ethnographic fieldwork with a UK-based patient feedback website to develop a critical perspective on patient experience as a contingent accomplishment and a focal point for eliciting, provoking, and respecifying relations of accountability. Following a single posting from the moderation room back to the author and into the wards and offices of the hospital, I show how moderators, carers, and clinical staff respond to and act upon a seemingly stable experience. Drawing on recent work in science studies and ethnomethodology, I suggest that the work of 'capturing the patient experience' is not so much a matter of accurate reporting or incontestable opining, but an exercise in testing versions of reality through the ongoing respecification of objects, audiences, and identities. Attending to the mundane practices of moderating accounts of care highlights the work of ordering alongside technologies of evaluation - the largely invisible labour that sustains the possibility of public patient feedback in the first place. PMID- 28087998 TI - Performance evaluation of PRIDE UNDA system with pyroprocessing feed material. AB - The PRIDE (PyRoprocessing Integrated inactive DEmonstration) is an engineering scale pyroprocessing test-bed facility that utilizes depleted uranium (DU) instead of spent fuel as a process material. As part of the ongoing effort to enhance pyroprocessing safeguardability, UNDA (Unified Non-Destructive Assay), a system integrating three different non-destructive assay techniques, namely, neutron, gamma-ray, and mass measurement, for nuclear material accountancy (NMA) was developed. In the present study, UNDA's NMA capability was evaluated by measurement of the weight, 238U mass, and U enrichment of oxide-reduction-process feed material (i.e., porous pellets). In the 238U mass determination, the total neutron counts for porous pellets of six different weights were measured. The U enrichment of the porous pellets, meanwhile, was determined according to the gamma spectrums acquired using UNDA's NaI-based enrichment measurement system. The results demonstrated that the UNDA system, after appropriate corrections, could be used in PRIDE NMA applications with reasonable uncertainty. It is expected that in the near future, the UNDA system will be tested with next-step materials such as the products of the oxide-reduction and electro-refining processes. PMID- 28087999 TI - Identification of irradiated foodstuffs using ESR microwave saturation. AB - This study aims primarily to investigate the usage of differences in microwave (MW) saturation behaviour of food samples for identification of radiation treatment. Twenty different samples (dry plant, herbal, spice etc.) which do not have radiation specific satellite ESR signal were especially selected. It is not possible to detect radiation treatment on these samples by European standard (EN 1787, 2000). MW saturation studies were performed on all samples in the range of 0.01-160mW. Our experimental results demonstrate that radiation identification can be possible for ten samples and cannot be possible for the other ten samples by performing the MW saturation studies. PMID- 28088000 TI - Efficient degradation of butylparaben by gamma radiolysis. AB - Gamma radiolysis and ozonolysis are two competitive advanced oxidation processes for degradation of organic pollutants present in the ground water. In this paper, the gamma radiolytic degradation of an emerging organic pollutant Butylparaben (BP) in aqueous solution has been investigated for the first time at different absorbed doses. The effect of the absorbed dose rate in the degradation and mineralization of BP has been investigated. About 65% mineralization of BP was observed at absorbed dose of 70kGy and dose rate of 0.7kGyh-1. Interestingly, turbidity appeared in the solution during radiolysis at doses higher than 2kGy, which disappeared again at very higher dose (~90kGy) making the solution again transparent. At lower dose rate of 0.175kGyh-1 the turbidity was appeared at much lower dose about 1kGy. However, the dose rate showed no effect in the dose of the disappearance of the turbidity. The hydrophobic fragments insoluble in water were generated during the initial stage of gamma radiolysis and those were completely mineralized to CO2 and H2O by direct absorption of gamma radiation. About 90kGy dose was required to achieve ~90% mineralization of BP. On the contrary, maximum 50% mineralization was achieved after 5h of ozonation at the O3 flow rate of 0.5Lmin-1 at pH 7.5 and it remained even constant upon prolonged ozonation. The oxygen-equivalent-chemical-oxidation-capacity (OCC) was used as the parameter to compare the % mineralization efficiencies of the two oxidative processes studied here and the gamma radiolysis was found to be more efficient between those processes. The phytotoxicity of the treated BP solution to agricultural seeds showed that the radiolytically generated fragments were less toxic compared to ozonolytically generated fragments. Thus gamma radiolysis is effective for reducing the organic burden and the toxicity of water polluted with emerging pollutants like BP. PMID- 28088001 TI - Improving the sensitivity and accuracy of gamma activation analysis for the rapid determination of gold in mineral ores. AB - Mining companies rely on chemical analysis methods to determine concentrations of gold in mineral ore samples. As gold is often mined commercially at concentrations around 1 part-per-million, it is necessary for any analysis method to provide good sensitivity as well as high absolute accuracy. We describe work to improve both the sensitivity and accuracy of the gamma activation analysis (GAA) method for gold. We present analysis results for several suites of ore samples and discuss the design of a GAA facility designed to replace conventional chemical assay in industrial applications. PMID- 28088002 TI - Radiochemical studies, pre-clinical investigation and preliminary clinical evaluation of 170Tm-EDTMP prepared using in-house freeze-dried EDTMP kit. AB - The objective of the present work is to formulate 170Tm-EDTMP using an in-house freeze-dried EDTMP kit and evaluate its potential as a bone pain palliation agent. Patient dose of 170Tm-EDTMP was prepared with high radiochemical purity using the lyophilized kit at room temperature within 15min. Pre-clinical evaluation in normal Wistar rats revealed selective skeletal accumulation with extended retention. Preliminary clinical investigation in 8 patients with disseminated skeletal metastases exhibited selective uptake in the bone and retention therein for a long duration. PMID- 28088003 TI - The effect of the antioxidant on the properties of thiolated poly(aspartic acid) polymers in aqueous ocular formulations. AB - Thiolated polymers are a promising new group of excipients, but their stability against atmospheric oxidation has not been investigated in detail, and only a few efforts have been made to improve their stability. The oxidation of the thiol groups in solutions of thiolated polymers may result in a decrease of mucoadhesion and unpredictable in situ gelation. The aims of our work were to study the stability of aqueous solutions of thiolated polymers and the effects of stabilizing agents. We investigated thiolated poly(aspartic acid) polymers stabilized with dithiothreitol, glutathione or acetylcysteine. The effects of these antioxidants on the gel structure, mucoadhesion and drug release were determined by means of scanning electron microscopy, swelling, rheology, adhesion and drug release tests. It was concluded that the stability of polymer solutions containing antioxidants is sufficient for one day. Polymers stabilized with dithiotreitol demonstrated fast swelling and drug release, but weaker mucoadhesion as compared with the other samples. Polymers stabilized with glutathione displayed the weakest cohesive properties, resulting in fast and uncontrolled drug release and moderate mucoadhesion. Acetylcysteine-stabilized polymers exhibited an optimum cross-linked structure, with free thiol groups ensuring polymer-mucin interactions, resulting in the best mucoadhesive properties. PMID- 28088004 TI - A catechin nanoformulation inhibits WM266 melanoma cell proliferation, migration and associated neo-angiogenesis. AB - We validated the anticancer potential of a nanoformulation made by (+)-catechin, gelatin and carbon nanotubes in terms of inhibition of cancer cell proliferation, migration and associated neo-angiogenesis. Gelatin was selected to stabilize the catechin without compromising its anti-oxidant potential and the carbon nanotubes were used to increase its intracellular bioavailability. The anticancer potential of the resulting nanohybrid was validated on an aggressive melanoma cell line, in vitro and in zebrafish xenotransplants. The nanohybrid strongly enhances the cytotoxic effect of (+)-catechin. At a concentration of (+)-catechin 50MUg/ml, the nanohybrid inhibited the ability of melanoma cells to proliferate (100% increase of cell doubling time and severe impairment in zebrafish xenotransplants), to migrate (totally inhibition in vitro and 50% reduction of cell motility in zebrafish xenotransplants) and to induce neo-angiogenesis (100% inhibition in zebrafish xenotransplants). Conversely, the free (+)-catechin and carrier (CNT:gel) had no statistically significant effects over the control, at any concentration tested. Our results suggest that the use of the nanohybrid, able to improve the therapeutic efficacy of the catechins, could represent a successful strategy for a future clinical translation. PMID- 28088005 TI - Nicotine hydrogen tartrate loaded chitosan nanoparticles: Formulation, characterization and in vitro delivery from dry powder inhaler formulation. AB - This study reports the development of nanoparticles in the form of inhalable micro-aggregates of biodegradable chitosan (CS) loaded with nicotine hydrogen tartrate (NHT) for potential pulmonary delivery of nicotine from dry powder inhaler (DPI) formulations with prolonged release profile. The NHT-loaded CS particles were prepared using a water-in-oil emulsion crosslinking method. The prepared particles were characterized using scanning electron microscopy (SEM) and transmission electron microscopy (TEM) for morphological studies; Zetasizer and Mastersizer were applied for particle size analysis. The in vitro aerosolization of the formulations was studied using a twin-stage-impinger (TSI) and promising aerosolization characteristics were shown. The nanoparticles were spherical with size ranges between 167 and 411nm while micro-aggregates (3.73 4.73MUm) were formed among nanoparticles. According to differential scanning calorimetry (DSC), X-ray diffraction (XRD) analysis and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, the NHT crystallinity was lost when in the particles, indicating it was uniformly dispersed as a solid solution. On the basis of X-ray photoelectron spectroscopy (XPS) analysis, the amount of NHT loaded on the surface of CS increased proportionally with increasing drug loading in the bulk so there was no surface enhancement. The fine particle doses (FPD) of NHT ranging between 1.7 and 3.2mg from DPI formulations were concentration dependent and increased with increased drug loading. Based on the in vitro release study, NHT released from CS particles with a burst release in the first 8h and subsequent prolonged release of nicotine. PMID- 28088006 TI - Correction. PMID- 28088007 TI - Impairment of Host Liver Repopulation by Transplanted Hepatocytes in Aged Rats and the Release by Short-Term Growth Hormone Treatment. AB - Hepatocyte transplantation is an alternative to whole liver transplantation. Yet, efficient liver repopulation by transplanted hepatocytes is low in livers of old animals. This restraint might be because of the poor proliferative capacity of aged donor hepatocytes or the regenerative impairment of the recipient livers. The age-dependent liver repopulation by transplanted wild-type hepatocytes was investigated in juvenile and senescent rats deficient in dipeptidyl-peptidase IV. Repopulation was quantified by flow cytometry and histochemical estimation of dipeptidyl-peptidase IV enzyme activity of donor cells in the negative host liver. As a potential pathway involved, expression of cell cycle proteins was assessed. Irrespective of the age of the donor hepatocytes, large cell clusters appeared in juvenile, but only small clusters in senescent host livers. Because juvenile and senescent donor hepatocytes were likewise functional, host-derived factor(s) impaired senescent host liver repopulation. Growth hormone levels were significantly higher in juvenile than in senescent rats, suggesting that growth hormone might promote host liver repopulation. Indeed, short-term treatment with growth hormone augmented senescent host liver repopulation involving the growth hormone-mediated release of the transcriptional blockade of genes associated with cell cycle progression. Short-term growth hormone substitution might improve liver repopulation by transplanted hepatocytes, thus augmenting the therapeutic benefit of clinical hepatocyte transplantation in older patients. PMID- 28088008 TI - Instruments evaluating the quality of the clinical learning environment in nursing education: A systematic review of psychometric properties. AB - BACKGROUND: The clinical learning environment is fundamental to nursing education paths, capable of affecting learning processes and outcomes. Several instruments have been developed in nursing education, aimed at evaluating the quality of the clinical learning environments; however, no systematic review of the psychometric properties and methodological quality of these studies has been performed to date. OBJECTIVES: The aims of the study were: 1) to identify validated instruments evaluating the clinical learning environments in nursing education; 2) to evaluate critically the methodological quality of the psychometric property estimation used; and 3) to compare psychometric properties across the instruments available. DESIGN: A systematic review of the literature (using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines) and an evaluation of the methodological quality of psychometric properties (using the COnsensus-based Standards for the selection of health Measurement INstruments guidelines). DATA SOURCES: The Medline and CINAHL databases were searched. Eligible studies were those that satisfied the following criteria: a) validation studies of instruments evaluating the quality of clinical learning environments; b) in nursing education; c) published in English or Italian; d) before April 2016. REVIEW METHODS: The included studies were evaluated for the methodological quality of the psychometric properties measured and then compared in terms of both the psychometric properties and the methodological quality of the processes used. RESULTS: The search strategy yielded a total of 26 studies and eight clinical learning environment evaluation instruments. A variety of psychometric properties have been estimated for each instrument, with differing qualities in the methodology used. Concept and construct validity were poorly assessed in terms of their significance and rarely judged by the target population (nursing students). Some properties were rarely considered (e.g., reliability, measurement error, criterion validity), whereas others were frequently estimated, but using different coefficients and statistical analyses (e.g., internal consistency, structural validity), thus rendering comparison across instruments difficult. Moreover, the methodological quality adopted in the property assessments was poor or fair in most studies, compromising the goodness of the psychometric values estimated. CONCLUSIONS: Clinical learning placements represent the key strategies in educating the future nursing workforce: instruments evaluating the quality of the settings, as well as their capacity to promote significant learning, are strongly recommended. Studies estimating psychometric properties, using an increased quality of research methodologies are needed in order to support nursing educators in the process of clinical placements accreditation and quality improvement. PMID- 28088009 TI - Cardiac output and systemic vascular resistance: Clinical assessment compared with a noninvasive objective measurement in children with shock. AB - PURPOSE: To evaluate physician assessment of cardiac output and systemic vascular resistance in patients with shock compared with an ultrasonic cardiac output monitor (USCOM). To explore potential changes in therapy decisions if USCOM data were available using physician intervention answers. STUDY DESIGN: Double blinded, prospective, observational study in a tertiary hospital pediatric intensive care unit. Forty children (<18years) admitted with shock, requiring ongoing volume resuscitation or inotropic support. Two to 3 physicians clinically assessed cardiac output and systemic vascular resistance, categorizing them as high, normal, or low. An investigator simultaneously measured cardiac index (CI) and systemic vascular resistance index (SVRI) with USCOM categorized as high, normal, or low. RESULTS: Overall agreement between physician and USCOM for CI (48.5% [kappa = 0.18]) and SVRI (45.9% [kappa = 0.16]) was poor. Interobserver agreement was also poor for CI (58.7% [kappa = 0.33]) and SVRI (52.3% [kappa = 0.28]). Comparing theoretical physician interventions to "acceptable" or "unacceptable" clinical interventions, based on USCOM measurement, 56 (21%) physician interventions were found to be "unacceptable." CONCLUSIONS: There is poor agreement between physician-assessed CI and SVRI and USCOM, with significant interobserver variability among physicians. Objective measurement of CI and SVRI may reduce variability and improve diagnostic accuracy. PMID- 28088010 TI - Challenges and opportunities for improving food quality and nutrition through plant biotechnology. AB - Plant biotechnology has been around since the advent of humankind, resulting in tremendous improvements in plant cultivation through crop domestication, breeding and selection. The emergence of transgenic approaches involving the introduction of defined DNA sequences into plants by humans has rapidly changed the surface of our planet by further expanding the gene pool used by plant breeders for plant improvement. Transgenic approaches in food plants have raised concerns on the merits, social implications, ecological risks and true benefits of plant biotechnology. The recently acquired ability to precisely edit plant genomes by modifying native genes without introducing new genetic material offers new opportunities to rapidly exploit natural variation, create new variation and incorporate changes with the goal to generate more productive and nutritious plants. PMID- 28088011 TI - Particulates and noise exposure during bicycle, bus and car commuting: A study in three European cities. AB - BACKGROUND: In order to curb traffic-related air pollution and its impact on the physical environment, contemporary city commuters are encouraged to shift from private car use to active or public transport modes. However, personal exposures to particulate matter (PM), black carbon and noise during commuting may be substantial. Therefore, studies comparing exposures during recommended modes of transport versus car trips are needed. METHODS: We measured personal exposure to various-sized particulates, soot, and noise during commuting by bicycle, bus and car in three European cities: Helsinki in Finland, Rotterdam in the Netherlands and Thessaloniki in Greece using portable monitoring devices. We monitored commonly travelled routes in these cities. RESULTS: The total number of one-way trips yielding data on any of the measured parameters were 84, 72, 94 and 69 for bicycle, bus, closed-window car and open-window car modes, respectively. The highest mean PM2.5 (85ug/m3), PM10 (131ug/m3), black carbon (10.9ug/m3) and noise (75dBA) levels were recorded on the bus, bus (again), open-window car and bicycle modes, respectively, all in Thessaloniki, PM and soot concentrations were generally higher during biking and taking a bus than during a drive in a a car with closed windows. Ratios of bike:car PM10 ranged from 1.1 in Thessaloniki to 2.6 in Helsinki, while bus:car ratios ranged from in 1.0 in Rotterdam to 5.6 in Thessaloniki. Higher noise levels were mostly recorded during bicycle rides. CONCLUSION: Based on our study, active- and public-transport commuters are often at risk of higher air pollution and noise exposure than private car users. This should be taken into account in urban transportation planning. PMID- 28088013 TI - Delineating hierarchy of selenotranscriptome expression and their response to selenium status in chicken central nervous system. AB - Selenium (Se) incorporated in selenoproteins as selenocysteine and supports various important cellular and organismal functions. We recently reported that chicken brain exhibited high priority for Se supply and retention under conditions of dietary Se deficiency and supernutrition Li et al. (2012) . However, the selenotranscriptome expressions and their response to Se status in chicken central nervous system (CNS) are unclear. To better understand the relationship of Se homeostasis and selenoproteins expression in chicken CNS, 1day old HyLine White chickens were fed a low Se diet (Se-L, 0.028mg/g) supplemented with 4 levels of dietary Se (0 to 5.0mgSe/kg) as Na2SeO3 for 8weeks. Then chickens were dissected for getting the CNS, which included cerebral cortex, cerebellum, thalamus, bulbus cinereus and marrow. The expressions of selenoproteome which have 24 selenoproteins were detected by the quantitative real-time PCR array. The concept of a selenoprotein hierarchy was developed and the hierarchy of different regions in chicken CNS was existence, especially cerebral cortex and bulbus cinereus. The expression of selenoproteins has a hierarch while changing Se content, and Selenoprotein T (Selt), Selenoprotein K (Selk), Selenoprotein W (Selw), Selenoprotein U (Selu), Glutathione peroxidase 3 (Gpx3), Glutathione peroxidase 4 (Gpx4), Selenoprotein P (Sepp1), Selenoprotein O (Selo), Selenoprotein 15 (Sel15), Selenoprotein N (Seln), Glutathione peroxidase 2 (Gpx2) and Selenoprotein P 2 (Sepp2) take more necessary function in the chicken CNS. Therefore, we hypothesize that hierarchy of regulated the transcriptions of selenoproteome makes an important role of CNS Se metabolism and transport in birds. PMID- 28088012 TI - New 4'-(4-chlorophenyl)-2,2':6',2"-terpyridine ruthenium(II) complexes: Synthesis, characterization, interaction with DNA/BSA and cytotoxicity studies. AB - In this study, we have developed a series of new monofunctional Ru(II) complexes of the general formula mer-[Ru(Cl-Ph-tpy)(N-N)Cl]Cl in which Cl-Ph-tpy is 4'-(4 chlorophenyl)-2,2':6',2"-terpyridine, N-N is a bidentate chelating ligand (1,2 diaminoethane (en, 1), 1,2-diaminocyclohexane (dach, 2) or 2,2'-bipyridine (bpy, 3)). All complexes were fully characterized by elemental analysis and spectroscopic techniques (IR, UV-Vis, 1D and 2D NMR). Their chemical behavior in aqueous solution was studied by UV-Vis and NMR spectroscopy showing that all compounds are relatively labile leading to the formation of the corresponding aqua species 1aq-3aq. Their DNA binding ability was evaluated by UV-Vis spectroscopy, fluorescence quenching measurements and viscosity measurements. Competitive studies with ethidium bromide (EB) showed that the complexes can displace DNA-bound EB, suggesting strong competition with EB (Ksv=1.1-2.7*104M 1). These experiments show that the ruthenium complexes interact with DNA via intercalation. The complexes bind to serum protein albumin displaying relatively high binding constants (Ksv=104-105M-1). Compound 3 displayed from high to moderate cytotoxicity against two cancer cell lines HeLa and A549 (with IC50ca. 12.7MUM and 53.8MUM, respectively), while complexes 1 and 2 showed only moderate cytotoxicity (with IC50ca. 84.8MUM and 96.3MUM, respectively) against HeLa cells. The cell cycle analysis (by flow cytometry) of HeLa and A549 cells treated with complex 3 shows minor changes on the cell cycle phase distribution. PMID- 28088014 TI - Reduced complexity of force and muscle activity during low level isometric contractions of the ankle in diabetic individuals. AB - BACKGROUND: This study evaluated the structure and amount of variability of surface electromyography (sEMG) patterns and ankle force data during low-level isometric contractions in diabetic subjects with different degrees of neuropathy. METHODS: We assessed 10 control subjects and 38 diabetic patients, classified as absent, mild, moderate, or severe neuropathy, by a fuzzy system based on clinical variables. Multichannel sEMG (64-electrode matrix) of tibialis anterior and gastrocnemius medialis muscles were acquired during isometric contractions at 10%, 20%, and 30% of the maximum voluntary contraction, and force levels during dorsi- and plantarflexion were recorded. Standard deviation and sample entropy of force signals were calculated and root mean square and sample entropy were calculated from sEMG signals. Differences among groups of force and sEMG variables were verified using a multivariate analysis of variance. FINDINGS: Overall, during dorsiflexion contractions, moderate and severe subjects had higher force standard deviation and moderate subjects had lower force sample entropy. During plantarflexion, moderate subjects had higher force standard deviation and all diabetic subjects had lower entropy. Tibialis anterior presented higher root mean square in absent group and lower entropy in mild subjects. For gastrocnemius medialis, entropy was higher in severe and lower in moderate subjects. INTERPRETATION: Diabetic neuropathy affects the complexity of the neuromuscular system during low-level isometric contractions, reducing the system's capacity to adapt to challenging mechanical demands. The observed patterns of neuromuscular complexity were not associated with disease severity, with the majority of alterations recorded in moderate subject. PMID- 28088015 TI - Transferrin gated mesoporous silica nanoparticles for redox-responsive and targeted drug delivery. AB - This work reports on a targeted and controlled drug delivery system based on protein decorated mesoporous silica nanoparticles (MSNs). In this system, transferrin (Tf), a naturally existing protein, is grafted on the surfaces of MSNs via redox-cleavable disulfide bonds, serving as both a capping agent and a targeting ligand simultaneously. The uniform particles with ordered mesoporous structures and the successful construction of the Tf/MSN hybrid nanocarriers can be confirmed through combined techniques. It is found that the model anticancer drug doxorubicin (DOX) can be efficiently encapsulated in the MSNs in the absence of glutathione (GSH), and a burst release of DOX is observed when the system is exposed to GSH, indicating good capping efficiency of Tf and redox-responsive release of DOX. Owing to the biocompatible Tf shell, the hybrid nanocarriers exhibited excellent biocompatibility in a wide concentration range and enhanced intracellular accumulation and targeting capability to tumor cells in vitro. The facile approach and the strategy of integration of multifunctions into one moiety present great potential in site-specific, controlled-release drug delivery system and provide us new ideas in design of MSN-based nanocontainers. PMID- 28088016 TI - Release and cytotoxicity studies of magnetite/Ag/antibiotic nanoparticles: An interdependent relationship. AB - Though the cytotoxic properties of magnetite nanoparticles (NPs) are rather well investigated and known to be dose dependent and rather low, surface functionalization can drastically change their properties. To determine whether the cytotoxicity of magnetite/Ag/antibiotic NPs may be associated, among other things, with iron, silver and antibiotic release, this study investigates the release profiles and cytotoxicity of magnetite/Ag/rifampicin and magnetite/Ag/doxycycline NPs compares it similar profiles from magnetite, magnetite/Ag NPs and antibiotics. It was established that the studied NPs released not only water-soluble substances, such as antibiotics, but also poorly soluble ones, such as iron and silver. The deposition of silver on the magnetite surface promotes the release of iron by the formation of a galvanic couple. Antibiotic adsorbed on the magnetite/Ag surface plays a dual role in the galvanic corrosion processes: as a corrosion inhibitor for iron oxides and as a corrosion promoter for silver. Magnetite/Ag/rifampicin and magnetite/Ag/doxycycline. NPs were found to have greater cytotoxicity towards the HEK293T cell line than magnetite NPs. These results were attributed to the combined toxic action of the released iron, silver ions and antibiotics. Intensive and simultaneous release of the NP components caused cell stress and suppressed their growth. PMID- 28088017 TI - Co-delivery of ibuprofen and gentamicin from nanoporous anodic titanium dioxide layers. AB - Although single-drug therapy may prove insufficient in treating bacterial infections or inflammation after orthopaedic surgeries, complex therapy (using both an antibiotic and an anti-inflammatory drug) is thought to address the problem. Among drug delivery systems (DDSs) with prolonged drug release profiles, nanoporous anodic titanium dioxide (ATO) layers on Ti foil are very promising. In the discussed research, ATO samples were synthesized via a three-step anodization process in an ethylene glycol-based electrolyte with fluoride ions. The third step lasted 2, 5 and 10min in order to obtain different thicknesses of nanoporous layers. Annealing the as-prepared amorphous layers at the temperature of 400 degrees C led to obtaining the anatase phase. In this study, water-insoluble ibuprofen and water-soluble gentamicin were used as model drugs. Three different drug loading procedures were applied. The desorption-desorption-diffusion (DDD) model of the drug release was fitted to the experimental data. The effects of crystalline structure, depth of TiO2 nanopores and loading procedure on the drug release profiles were examined. The duration of the drug release process can be easily altered by changing the drug loading sequence. Water-soluble gentamicin is released for a long period of time if gentamicin is loaded in ATO as the first drug. Additionally, deeper nanopores and anatase phase suppress the initial burst release of drugs. These results confirm that factors such as morphological and crystalline structure of ATO layers, and the procedure of drug loading inside nanopores, allow to alter the drug release performance of nanoporous ATO layers. PMID- 28088018 TI - Antibacterial serine protease from Wrightia tinctoria: Purification and characterization. AB - A serine protease was purified from the leaves of Wrightia tinctoria by sequential flow through method comprising screening, optimization, ammonium sulfate precipitation, gel filtration and ion exchange column chromatography. The yield and purification fold obtained were 11.58% and 9.56 respectively. A single band of serine protease was visualized on SDS-PAGE and 2-D gel electrophoretic analyses were revealed with the molecular mass of 38.5 kDa. Serine protease had an optimum pH of 8.0 and was stable at 45 degrees C with high relative protease activity. The addition of metal ions such as Mg2+ and Mn2+ exhibits a high relative activity. Serine protease had a potent antibacterial activity against both Gram-positive and Gram-negative bacteria. A 10 MUg/ml of serine protease was tested against S. aureus, M. luteus, P. aeruginosa and K. pneumoniae which had 21, 20, 18 and 17 mm of zone of inhibition respectively. Serine protease from W. tinctoria degrades the peptidoglycan layer of bacteria which was visualized by transmission electron microscopic analysis. PMID- 28088019 TI - Melatonin and resveratrol reverse the toxic effect of high boron (B) and modulate biochemical parameters in pepper plants (Capsicum annuum L.). AB - The objectives of this research were to test a possible involvement of melatonin (MEL) and resveratrol (RES) in restoring growth and to control boron (B) toxicity in peppers. The plants were subjected to four different nutrient solution treatments as following: 1) half-strength Hoagland's nutrient solution (Control), 2) half-strength Hoagland's nutrient solution+100 MUM B (100 MUMB), 3) half strength Hoagland's nutrient solution+100 MUM boron+100 MUMresveratrol (100 MUMRES), and 4) half-strength Hoagland's nutrient solution+100 MUM B+1 MUMmelatonin (1 MUM MEL). Pepper plants subjected to B excess (100 MUM) for 68 days (d) exhibited visible B toxicity symptoms, reduced rate of photosynthesis (Pn) and reduced dry weight (DW), while their leaf and fruit had the greatest increase of B concentration. The reduction of photosynthesis was restored, the reduction of DW was prevented, while the B leaf and fruit accumulation was moderated with the application of both 100 MUMresveratrol (RES) and 1 MUMmelatonin (MEL). Moreover, plants exposed to MEL and/or RES displayed no visible B toxicity symptoms. The present study revealed a novel role of MEL and/or RES in the adaptation of pepper plants to B excess based on plant growth, physiological and biochemical criteria. PMID- 28088020 TI - Sulphur alters chromium (VI) toxicity in Solanum melongena seedlings: Role of sulphur assimilation and sulphur-containing antioxidants. AB - The present study investigates modulation in hexavalent chromium [Cr(VI) 25 MUM] toxicity by sulphur (S; 0.5, 1.0 and 1.5 mM S as low (LS), medium (MS) and high sulphur (HS), respectively) in Solanum melongena (eggplant) seedlings. Biomass accumulation (fresh and dry weights), photosynthetic pigments, photosynthetic oxygen evolution and S content were declined by Cr(VI) toxicity. Furthermore, fluorescence characteristics (JIP-test) were also affected by Cr(VI), but Cr(VI) toxicity on photosystem II photochemistry was ameliorated by HS treatment via reducing damaging effect on PS II reaction centre and its reduction side. Enhanced respiration, Cr content and oxidative biomarkers: superoxide radical, hydrogen peroxide, lipid peroxidation and membrane damage were observed under Cr(VI) stress. Though Cr(VI) enhanced adenosine triphasphate sulfurylase (ATPS) and o-acetylserine(thiol)lyase (OASTL), glutathione-S-transferase (GST), glutathione reductase (GR) and ascorbate peroxidase (APX) activity, and content of total glutathione, cysteine and NP-SH, however, their levels/activity were further enhanced by S being maximum with HS treatment. The results show that Cr(VI) toxicity does increase under LS treatment while HS protected Cr(VI) induced damaging effects in brinjal seedlings. Under HS treatment, in mitigating Cr(VI) toxicity, S assimilation and its associated metabolites such as cysteine, glutathione and NP-SH play crucial role. PMID- 28088022 TI - Valorization of aluminum scrap via an acid-washing treatment for reductive removal of toxic bromate from water. AB - Aluminum scrap (AS) is adopted for the first time as a readily available aluminum source to prepare zero-valent aluminum (ZVAl) for removing bromate from water via a reductive reaction. Since aluminum is easily oxidized to aluminum oxide (Al2O3) on exposure to air, an acid-washing pretreatment on AS is developed to remove the layer of Al2O3. HCl is found as the most effective acid to pretreat AS and the HCl-pretreated or acid-washed AS (AWAS) is able to remove bromate from water and convert it to bromide. Factors, such as temperature, pH, co-existing anions, and particle size, which influence the bromate removal using AWAS are also investigated. The mechanism of bromate removal by AWAS can be attributed to both reduction and adsorption. The elevated temperature also significantly improves bromate removal capacity of AWAS as well as the reaction kinetics. The bromate removal capacity of AWAS is substantially improved under acidic conditions. However, the basic conditions and co-existing anions suppress or interfere with the interaction between bromate and AWAS, leading to much lower removal capacities. The recyclability of AWAS is also evaluated and the acid-washing regeneration is necessary to restore its capacity. However, the mass of AWAS can gradually decrease due to multi-cycle acid-washing regeneration. Through this study, the valorization of AS via acid-washing is demonstrated and optimization of acid-washing parameters is presented. Our findings reveal that the acid washing is a useful technique to utilize AS as an inexpensive and efficient material for removing bromate from water. PMID- 28088021 TI - Sanguinarine-induced oxidative stress and apoptosis-like programmed cell death(AL PCD) in root meristem cells of Allium cepa. AB - A vast number of studies on plant cell systems clearly indicate that various biotic and abiotic stresses give rise to the uncontrolled increase in the level of reactive oxygen species (ROS). Excess concentrations of ROS result in damage to proteins, lipids, carbohydrates, and DNA, which may lead, in consequence, to the apoptotic cell death. The current study investigates the effects of sanguinarine (SAN), a natural alkaloid derived from the roots of Sanguinaria canadensis, on root apical meristem cells of Allium cepa. It is shown that SAN treatment generated large amounts of hydrogen peroxide (H2O2) and superoxide anion (O2.-). Oxidative stress induced in SAN-treated cells was correlated with DNA fragmentation, formation of micronuclei (MN), altered and 'degenerated' chromatin structures characteristic of apoptosis-like programmed cell death (AL PCD). The experiments with SAN + MG132 (a proteasome inhibitor engaged in Topo II mediated formation of cleavable complexes) and SAN + ascorbic acid (AA; H2O2 scavenger) seem to suggest, however, that the high level of H2O2 is not the only factor responsible for changes observed at the chromatin level and for the consequent cell death. Our findings imply that Topo II-DNA covalent complexes and 26S proteasomes are also involved in SAN-induced DNA damage. PMID- 28088023 TI - A novel model to predict gas-phase hydroxyl radical oxidation kinetics of polychlorinated compounds. AB - In this study, a novel model based on aromatic meta-substituent grouping was presented to predict the second-order rate constants (k) for OH oxidation of PCBs in gas-phase. Since the oxidation kinetics are dependent on the chlorination degree and position, we hypothesized that it may be more accurate for k value prediction if we group PCB congeners based on substitution positions (i.e., ortho (o), meta (m), and para (p)). To test this hypothesis, we examined the correlation of polarizability (alpha), a quantum chemical based descriptor for k values, with an empirical Hammett constant (sigma+) on each substitution position. Our result shows that alpha is highly linearly correlated to ?sigmao,m,p+ based on aromatic meta-substituents leading to the grouping based predictive model. With the new model, the calculated k values exhibited an excellent agreement with experimental measurements, and greater predictive power than the quantum chemical based quantitative structure activity relationship (QSAR) model. Further, the relationship of alpha and ?sigmao,m,p+ for PCDDs congeners, together with highest occupied molecular orbital (HOMO) distribution, were used to validate the aromatic meta-substituent grouping method. This newly developed model features a combination of good predictability of quantum chemical based QSAR model and simplicity of Hammett relationship, showing a great potential for fast and computational tractable prediction of k values for gas phase OH oxidation of polychlorinated compounds. PMID- 28088024 TI - Multi-year record of atmospheric and snow surface nitrate in the central Antarctic plateau. AB - Continuous all year-round samplings of atmospheric aerosol and surface snow at high (daily to 4-day) resolution were carried out at Dome C since 2004-05 to 2013 and nitrate records are here presented. Basing on a larger statistical data set than previous studies, results confirm that nitrate seasonal pattern is characterized by maxima during austral summer for both aerosol and surface snow, occurring in-phase with solar UV irradiance. This temporal pattern is likely due to a combination of nitrate sources and post-depositional processes whose intensity usually enhances during the summer. Moreover, it should be noted that a case study of the synoptic conditions, which took place during a major nitrate event, showed the occurrence of a stratosphere-troposphere exchange. The sampling of both matrices at the same time with high resolution allowed the detection of a an about one-month long recurring lag of summer maxima in snow with respect to aerosol. This result can be explained by deposition and post-deposition processes occurring at the atmosphere-snow interface, such as a net uptake of gaseous nitric acid and a replenishment of the uppermost surface layers driven by a larger temperature gradient in summer. This hypothesis was preliminarily tested by a comparison with surface layers temperature data in the 2012-13 period. The analysis of the relationship between the nitrate concentration in the gas phase and total nitrate obtained at Dome C (2012-13) showed the major role of gaseous HNO3 to the total nitrate budget suggesting the need to further investigate the gas-to-particle conversion processes. PMID- 28088025 TI - Residues of 2-hydroxy-3-phenylpyrazine, a degradation product of some beta-lactam antibiotics, in environmental water in Vietnam. AB - Antibiotic-resistant bacteria have become a serious problem worldwide, caused in part by the excessive use and discharge of antibiotics into the environment. Ampicillin (ABPC) is a widely used antibiotic. However, this chemical rapidly decomposes in water containing divalent cations like Ca2+ and Mg2+, thus, detection of ABPC in environmental water is difficult. This study was carried out to evaluate the presence of 2-hydroxy-3-phenylpyrazine (HPP), one of the degradation products of ABPC and beta-lactam antibiotics with an ABPC substructure, in environmental water. An analytical method for HPP monitoring in environmental water was developed using liquid chromatography/tandem mass spectrometry. The analyte was extracted from water samples and enriched using a solid-phase extraction cartridge. The quantification limit was 1 ng L-1. The HPP recovery rates from spiked water samples of 25 and 125 ng L-1 were 84.1 and 86.1%, respectively. The method was then used to determine HPP residue levels in 98 environmental water samples from rivers, household ponds, and aquacultural ponds in Vietnam. HPP residues were detected in 60 samples. The HPP detection rates in rivers and household ponds were 42 and 79%, respectively. HPP was not detected in aquacultural ponds. HPP residue concentrations in the samples ranged from 1.3 to 413.3 ng L-1. The residue levels in rivers flowing through city centres were higher than levels in other sampling locations. The findings of this study suggest that HPP is a promising marker for assessing the discharge of ABPC and beta-lactam antibiotics with an ABPC substructure into the environment around sampling sites. PMID- 28088026 TI - Current ambient concentrations of ozone in Panama modulate the leaf chemistry of the tropical tree Ficus insipida. AB - Tropospheric ozone (O3) is a major air pollutant and greenhouse gas, affecting carbon dynamics, ecological interactions, and agricultural productivity across continents and biomes. Elevated [O3] has been documented in tropical evergreen forests, the epicenters of terrestrial primary productivity and plant-consumer interactions. However, the effects of O3 on vegetation have not previously been studied in these forests. In this study, we quantified ambient O3 in a region shared by forests and urban/commercial zones in Panama and found levels two to three times greater than in remote tropical sites. We examined the effects of these ambient O3 levels on the growth and chemistry of seedlings of Ficus insipida, a regionally widespread tree with high stomatal conductance, using open top chambers supplied with ozone-free or ambient air. We evaluated the differences across treatments in biomass and, using UPLC-MS-MS, leaf secondary metabolites and membrane lipids. Mean [O3] in ambient air was below the levels that induce chronic stress in temperate broadleaved trees, and biomass did not differ across treatments. However, leaf secondary metabolites - including phenolics and a terpenoid - were significantly downregulated in the ambient air treatment. Membrane lipids were present at lower concentrations in older leaves grown in ambient air, suggesting accelerated senescence. Thus, in a tree species with high O3 uptake via high stomatal conductance, current ambient [O3] in Panamanian forests are sufficient to induce chronic effects on leaf chemistry. PMID- 28088028 TI - Role of small RNAs in epigenetic reprogramming during plant sexual reproduction. AB - Sexual reproduction, the formation of a new individual from specialized reproductive cells after fertilization, involves the precise orchestration of different developmental and genomic processes. These processes are to a large extent governed by small RNAs (sRNAs) that either belong to the class of micro RNAs (miRNAs) or small-interfering RNAs (siRNAs). The latter are derived from transposable elements (TEs) and involved in genome defense and transgenerational inheritance of heterochromatin identity, ensuring genome stability. Remarkably, male and female gametophytes employ sRNAs to ensure reproductive success, but the underlying processes of their formation and action differ. Here, we review current advances in the field concerning the roles of sRNAs during flowering plant (angiosperm) reproduction and pinpoint where further research is required to solve open questions. PMID- 28088027 TI - An alternative strategy to western blot as a confirmatory diagnostic test for HIV infection. AB - BACKGROUND: In China, western blot (WB) is the recommended procedure for the diagnosis of HIV infection. However, this technique is time consuming and labor intensive, and its complexity restricts wide application in resource-limited regions. OBJECTIVE: The aim of this study was to evaluate the efficacy of a dry blood spots (DBS)-urine paired enzyme-linked immunosorbent assay (ELISA) test, instead of WB, for HIV antibody detection. STUDY DESIGN: Plasma, DBS, and urine samples were collected from 1213 subjects from different populations. Two diagnostic testing strategies were conducted in parallel. The equivalence of the paired ELISA and WB strategies was assessed. RESULTS: A diagnosis of HIV was determined in 250 subjects according to the paired ELISA test, and in 249 according to the WB strategy. The discordant case was judged HIV-positive during follow-up. In total, 18 subjects were diagnosed with possible HIV using the paired ELISA test, among whom, 11 subjects tested negative with WB, and one was confirmed to be HIV-positive during follow-up. For the remaining 945 subjects, both strategies indicated a negative result. The kappa test indicated good conformity (kappa=0.954) between the two diagnostic strategies. CONCLUSION: The DBS-urine paired ELISA could be applied as an alternative to WB in HIV diagnosis, which would be valuable in resource-limited regions owing to the associated affordability and ease of use. PMID- 28088029 TI - An updated meta-analysis of cohort studies: Diabetes and risk of Alzheimer's disease. AB - BACKGROUND: In recently, several large longitudinal population-based studies have shown that the rate of cognitive decline is accelerated in elderly people with diabetes mellitus. But the relation between diabetes and AD is still an area of controversy. The objective of this review was to update the evidence for or against diabetes as a risk factor of AD. METHODS: We searched the literature from their inception to May 2016 without restriction of language. We included all longitudinal population-based studies examining the association between diabetes and risk of AD. The meta-analysis was conducted using Stata software. RESULTS: A total of 17 studies involving 1,746,777 individuals were included. After pooling these 17 studies, subjects with diabetes had significant higher incidence of AD than those without diabetes (RR: 1.53, 95% CI: 1.42-1.63). When stratified by ethnicity, five cohorts were identified as Eastern populations, twelve were identified as Western populations. The Relative risk of AD in Western populations and Eastern populations were 1.36(1.18-1.53) and 1.62(1.49-1.75). CONCLUSION: The risk of AD is higher among people with diabetes than in the general population, especially in Eastern populations. So the necessary treatment measures should be taken in order to decrease the risk of AD. PMID- 28088030 TI - Efficacy and safety of linagliptin/metformin single-pill combination as initial therapy in drug-naive Asian patients with type 2 diabetes. AB - AIM: To assess efficacy/safety of initial linagliptin/metformin single-pill combination (SPC) therapies versus individual drug components over 24weeks in treatment-naive Asian patients with type 2 diabetes mellitus and insufficient glycemic control. METHODS: Patients (initial glycated hemoglobin [HbA1c] ?7.5% to <11.0% [58-97mmol/mol]; main group) were randomized to: linagliptin 5mg once daily (qd); metformin 500mg twice daily (bid); metformin 1000mg bid; linagliptin 2.5mg/metformin 500mg bid; or linagliptin 2.5mg/metformin 1000mg bid. Patients with severe hyperglycemia (HbA1c ?11.0% [97mmol/mol]) received linagliptin 2.5mg/metformin 1000mg bid or linagliptin 5mg qd (switched at week 12 from linagliptin to SPC if HbA1c >8.0% [64mmol/mol]). The main group primary endpoint was HbA1c change from baseline to week 24. RESULTS: At week 24, adjusted mean change from baseline in HbA1c (main group, n=733) was: linagliptin 5mg qd, -1.3%; metformin 500mg bid, -1.6%; metformin 1000mg bid, -2.1%; linagliptin 2.5mg/metformin 500mg bid, -2.2%; linagliptin 2.5mg/metformin 1000mg bid, -2.3%. The first test of primary HbA1c analysis (linagliptin 2.5mg/metformin 1000mg bid vs. metformin 1000mg bid) was borderline non-significant; however, SPCs produced significantly greater reductions in HbA1c from baseline versus respective monotherapies in all but one pre-defined sensitivity analysis. In the severe hyperglycemia group (n=143), linagliptin 2.5mg/metformin 1000mg bid produced a superior HbA1c reduction (-4.7%) versus linagliptin 5mg qd (-3.5%) after 12weeks. Hypoglycemic adverse events were low across groups. CONCLUSIONS: Initial linagliptin/metformin SPC significantly improved glycemic control in this population. PMID- 28088031 TI - The timing of zygotic genome activation. AB - After fertilization, the embryonic genome is inactive until transcription is initiated during the maternal-to-zygotic transition. How the onset of transcription is regulated in a precisely timed manner, however, is a long standing question in biology. Several mechanisms have been shown to contribute to the temporal regulation of genome activation but none of them can fully explain the general absence of transcription as well the gene specific onset that follows. Here we review the work that has been done toward elucidating the mechanisms underlying the temporal regulation of transcription in embryos. PMID- 28088032 TI - Oral cannabidiol does not produce a signal for abuse liability in frequent marijuana smokers. AB - BACKGROUND: Cannabidiol (CBD) is a naturally occurring constituent of the marijuana plant. In the past few years, there has been great interest in the therapeutic effects of isolated CBD and it is currently being explored for numerous disease conditions (e.g., pain, epilepsy, cancer, various drug dependencies). However, CBD remains a Schedule I drug on the U.S. Controlled Substances Act (CSA). Despite its status, there are no well-controlled data available regarding its abuse liability. METHODS: Healthy, frequent marijuana users (n=31) were enrolled in this within subject, randomized, placebo controlled, double-blind, multisite study that administered oral cannabidiol (0, 200, 400, 800mg) alone and in combination with smoked marijuana (0.01%, 5.3-5.8% THC). Participants received one dose combination across 8 once-weekly outpatient sessions (7.5h). The primary findings on the drug interaction effects were previously reported (Haney et al., 2016). The present study is a secondary analysis of the data to examine the abuse liability profile of oral cannabidiol (200, 400, 800mg) in comparison to oral placebo and active smoked marijuana (5.3 5.8% THC). RESULTS: Active marijuana reliably produced abuse-related subjective effects (e.g., high) (p<0.05). However, CBD was placebo-like on all measures collected (p>0.05). CONCLUSIONS: Overall, CBD did not display any signals of abuse liability at the doses tested and these data may help inform U.S. regulatory decisions regarding CBD schedule on the CSA. PMID- 28088033 TI - A Bayesian spatial random parameters Tobit model for analyzing crash rates on roadway segments. AB - This study develops a Bayesian spatial random parameters Tobit model to analyze crash rates on road segments, in which both spatial correlation between adjacent sites and unobserved heterogeneity across observations are accounted for. The crash-rate data for a three-year period on road segments within a road network in Florida, are collected to compare the performance of the proposed model with that of a (fixed parameters) Tobit model and a spatial (fixed parameters) Tobit model in the Bayesian context. Significant spatial effect is found in both spatial models and the results of Deviance Information Criteria (DIC) show that the inclusion of spatial correlation in the Tobit regression considerably improves model fit, which indicates the reasonableness of considering cross-segment spatial correlation. The spatial random parameters Tobit regression has lower DIC value than does the spatial Tobit regression, suggesting that accommodating the unobserved heterogeneity is able to further improve model fit when the spatial correlation has been considered. Moreover, the random parameters Tobit model provides a more comprehensive understanding of the effect of speed limit on crash rates than does its fixed parameters counterpart, which suggests that it could be considered as a good alternative for crash rate analysis. PMID- 28088034 TI - An evaluation of Nova Scotia's alcohol ignition interlock program. AB - Alcohol ignition interlock programs for offenders aim to reduce recidivism among convicted drink drivers. This study presents an evaluation of Nova Scotia's interlock program implemented in 2008 in order to assess its effectiveness to reduce impaired driving and to help identify areas for improvement. Data used include conviction and crash records of individual participants; provincial monthly counts of alcohol-related charges, convictions and fatal and serious crashes; and interlock logged events. Methods used include descriptive statistics, survival analysis, time series and logistic regression analysis. With respect to specific deterrence (i.e., preventing recidivism) there was a 90% reduction in recidivism among voluntary participants since participation in the interlock program and a 79% reduction after these participants exited from the program. With respect to general deterrence (i.e., referring to a preventative effect on the entire population of drivers in Nova Scotia) there were temporary decreases in the numbers of alcohol-related charges (13.32%) and convictions (9.93%) and a small significant decrease in the number of fatal and serious injury alcohol-related crashes, following the implementation of the program. The evidence suggests the interlock program was better at preventing harm due to alcohol-impaired driving than the alternative of not using the interlock program. Recommendations were formulated supporting the continuation of the interlock program in Nova Scotia. PMID- 28088035 TI - Diagnosis, treatment, and outcomes of infantile spasms in the Trisomy 21 population. AB - PURPOSE: To determine if there are differences in the timing of diagnosis and response to treatment between infants with infantile spasms (IS) and Trisomy 21 (T21) and those with idiopathic IS. METHOD: This was a retrospective study evaluating the time from onset of IS to diagnosis, treatment of IS, time from treatment to resolution of IS, and development of epilepsy in children with T21 and IS compared to children with idiopathic IS. RESULTS: Thirteen children with T21 and IS were identified over a 10 year period and compared to 32 children in the control group. There was no significant difference in age of onset, time between onset and diagnosis, or acute response to treatment. However, the children with idiopathic IS were more likely to go on to develop epilepsy than those with T21 and IS (41% vs. 0, p=0.006). CONCLUSION: The children with T21 and IS were diagnosed and treated similarly to those patients with idiopathic IS. There were no significant differences in the age of onset, time between the onset and diagnosis of IS, or acute treatment response of IS between the T21 and control groups. However those with T21 and IS had a lower risk of subsequent epilepsy following IS than those with idiopathic IS. IS in the T21 population appears to be inherently different from IS of unknown etiology. PMID- 28088036 TI - An emotional approach to beef evaluation. AB - The emotions associated with beef consumption, the influence of breeding system information on emotions ("Conventional" - C vs "Only from the Italian Simmental" OIS label) and their relationship with liking were evaluated by 93 meat consumers. Respondents were asked to evaluate the same samples of Italian Simmental meat provided with the two different labels. Liking scores were obtained using a 9-point scale and the emotions from the EsSense25 list were scored on 5-point scale (1="not at all", 5="extremely"). A positive and significant effect of OIS information was highlighted on liking scores. Moreover, the breeding system information significantly affected 22 out of the 25 emotions. OIS label elicited higher positive and lower negative feelings about the meat than did the C label. Providing the same beef with different breeding information led to different emotions being evoked in consumers, and these differences in emotions were associated with different levels of liking for beef. PMID- 28088037 TI - Assessment of the meat quality of lamb M. longissimus thoracis et lumborum and M. triceps brachii following three different Halal slaughter procedures. AB - A total of fifteen male and fifteen female lambs were allocated to three groups of ten animals and subjected to: traditional Halal slaughter without stunning (TNS); slaughter following electric head-only stunning (EHOS) or; post-cut electric head-only stun (PCEHOS) and their meat quality was determined. Instrumental and sensory analyses were carried out on two muscles; M. longissimus thoracis et lumborum (LTL) and M. triceps brachii (TB). Additionally, the effects of sex and muscle type were also assessed. No differences were found among slaughter methods for pH, drip loss and shear force. TB had a higher pHu and was more tender than LTL. Muscles from EHOS and PCEHOS lambs discoloured more quickly than TNS muscles. There were no differences in the measured sensory attributes, with the exception of EHOS meat being tougher than PCEHOS and TNS meat. This study showed that the three slaughter methods had no substantial effect on lamb meat quality. PMID- 28088038 TI - Evidence of functional duplicity of Nestin expression in the adult mouse midbrain. AB - Whether or not neurogenesis occurs in the adult substantia nigra pars compacta (SNc) is an important question relevant for developing better treatments for the motor symptoms of Parkinson's disease (PD). Although controversial, it is generally believed that dividing cells here remain undifferentiated or differentiate into glia, not neurons. However, there is a suggestion that Nestin expressing neural precursor cells (NPCs) in the adult SNc have a propensity to differentiate into neurons, which we sought to confirm in the present study. Adult (>8-weeks old) transgenic NesCreERT2/GtROSA or NesCreERT2/R26eYFP mice were used to permanently label Nestin-expressing cells and their progeny with beta galactosidase (beta-gal) or enhanced yellow fluorescent protein (eYFP), respectively. Most beta-gal+ or eYFP+ cells were found in the ependymal lining of the midbrain aqueduct (Aq) and in the midline ventral to Aq. Smaller but significant numbers were in the periaqueductal gray (PAG), the ventral tegmental area (VTA), and in SNc. Low-level basal proliferation was evidenced by a modest increase in number of beta-gal+ or eYFP+ cells over time, fewer beta-gal+ or eYFP+ cells when mice were administered the anti-mitotic agent Cytarabine, and incorporation of the proliferation marker bromodeoxyuridine (BrdU) in a very small number of beta-gal+ cells. No evidence of migration was found, including no immunoreactivity against the migration markers doublecortin (DCX) or polysialic acid neural cell adhesion molecule (PSA-NCAM), and no dispersal of beta-gal+ or eYFP+ cells through the midbrain parenchyma over time. However, beta-gal+ or eYFP+ cells did increase in size and express higher levels of mature neuronal genes over time, indicating growth and neuronal differentiation. In mice whose SNc dopamine neurons had been depleted with 6-hydroxy-dopamine, a model of PD, there were ~2-fold more beta-gal+ cells in SNc specifically, although the proportion that were also NeuN+ was not affected. Remarkably, as early as 4days following putative Nestin-expression, many beta-gal+ or eYFP+ cells had mature neuronal morphology and were NeuN+. Furthermore, mature neuronal beta-gal+ cells were immunoreactive against the self-renewal or pluripotency marker sex determining region Y-box 2 (Sox2). Overall, our data support the notion that some Nestin-expressing, presumably NPCs, have a limited capacity for proliferation, no capacity for migration, and a propensity to generate new neurons within the microenvironment of the adult midbrain. However, our data also suggest that significant numbers of extant midbrain neurons express Nestin and other classical neurogenesis markers in contexts that are presumably not neurogenic. These findings foreshadow duplicitous roles for Nestin and other molecules that are traditionally associated with neurogenesis in the adult midbrain, which should be considered in future PD research. PMID- 28088039 TI - Read my lips: Visual speech influences word processing in infants. AB - What do infants hear when they read lips? In the present study, twelve-to thirteen-month-old infants viewed a talking face produce familiar and unfamiliar words. The familiar words were of three types: in Experiment 1, they were produced correctly (e.g., "bottle"); in Experiment 2, infants saw and heard mispronunciations in which the altered phoneme either visually resembled the original phoneme (visually consistent, e.g. "pottle"), or did not visually resemble the original phoneme (visually inconsistent, e.g., "dottle"). Infants in the correct and consistent conditions differentiated the familiar and unfamiliar words, but infants in the inconsistent condition did not. Experiment 3 confirms that infants were sensitive to the mispronunciations in the consistent condition with auditory-only words. Thus, although infants recognized the consistent mispronunciations when they saw a face articulating the words, they did not with the auditory information alone. These results provide the first evidence that visual articulatory information affects word processing in infants. PMID- 28088040 TI - Listen up! Developmental differences in the impact of IDS on speech segmentation. AB - While American English infants typically segment words from fluent speech by 7.5 months, studies of infants from other language backgrounds have difficulty replicating this finding. One possible explanation for this cross-linguistic difference is that the input infants from different language backgrounds receive is not as infant-directed as American English infant-directed speech (Floccia et al., 2016). Against this background, the current study investigates whether German 7.5- and 9-month-old infants segment words from fluent speech when the input is prosodically similar to American English IDS. While 9-month-olds showed successful segmentation of words from exaggerated IDS, 7.5-month-olds did not. These findings highlight (a) the beneficial impact of exaggerated IDS on infant speech segmentation, (b) cross-linguistic differences in word segmentation that are based not just on the kind of input available to children and suggest (c) developmental differences in the role of IDS as an attentional spotlight in speech segmentation. PMID- 28088041 TI - The role of the IFG and pSTS in syntactic prediction: Evidence from a parametric study of hierarchical structure in fMRI. AB - Sentences encode hierarchical structural relations among words. Several neuroimaging experiments aiming to localize combinatory operations responsible for creating this structure during sentence comprehension have contrasted short, simple phrases and sentences to unstructured controls. Some of these experiments have revealed activation in the left inferior frontal gyrus (IFG) and posterior superior temporal sulcus (pSTS), associating these regions with basic syntactic combination. However, the wide variability of these effects across studies raises questions about this interpretation. In an fMRI experiment, we provide support for an alternative hypothesis: these regions underlie top-down syntactic predictions that facilitate sentence processing but are not necessary for building syntactic structure. We presented stimuli with three levels of structure: unstructured lists, two-word phrases, and simple, short sentences; and two levels of content: natural stimuli with real words and stimuli with open class items replaced with pseudowords (jabberwocky). While both the phrase and sentence conditions engaged syntactic combination, our experiment only encouraged syntactic prediction in the sentence condition. We found increased activity for both natural and jabberwocky sentences in the left IFG (pars triangularis and pars orbitalis) and pSTS relative to unstructured word lists and two-word phrases, but we did not find any such effects for two-word phrases relative to unstructured word lists in these areas. Our results are most consistent with the hypothesis that increased activity in IFG and pSTS for basic contrasts of structure reflects syntactic prediction. The pars opercularis of the IFG showed a response profile consistent with verbal working memory. We found incremental effects of structure in the anterior temporal lobe (ATL), and increased activation only for sentences in the angular gyrus (AG)/temporal-parietal junction (TPJ) - both regions showed these effects for stimuli with all real words. These findings support a role for the ATL in semantic combination and the AG/TPJ in thematic processing. PMID- 28088042 TI - Strategies for metabolite profiling based on liquid chromatography. AB - This paper aims at covering the principal strategies based on liquid chromatography (LC) for metabolite profiling in the field of drug discovery and development. The identification of metabolites generated in the organism is an important task during the early stages of preclinical research to define the most proper strategy for optimizing, adjusting metabolic clearance and minimizing bioactivation. An early assessment of the metabolite profile may be critical since metabolites can contribute to pharmacological and/or toxicological effects. The study of metabolites first involves their synthesis/generation and their further characterization and structural elucidation. For such a purpose, both in vitro and in vivo methods are commonly used for the generation of the corresponding metabolites. Next, analytical methods are used to tackle identification and characterization studies. Among the arsenal of techniques available in our labs, we will focus on LC, especially coupled to mass spectrometry (LC-MS), as one of the most powerful approaches for metabolite identification, characterization and quantification. Here, the topic of metabolite profiling based on LC will be addressed and representative examples of different possibilities will be discussed. PMID- 28088043 TI - HPLC-UV method for simultaneous determination of MK-1775 and AZD-7762 in both acetonitrile-aqueous solution and mouse plasma. AB - A sensitive and precise method is described for the simultaneous determination of two small molecule kinase inhibitors: MK-1775 (MK) and AZD-7762 (AZD), in acetonitrile (ACN)-aqueous solution and in mouse plasma. A Nova-Pak C18 reversed phase column (3.9mm*150mm, 4MUm, 60A) was utilized in the separation using an isocratic mobile phase of 0.1% v/v triethylamine in phosphate buffer (pH=7.4): acetonitrile (ACN) (60:40, v/v), at a flow rate of 0.8mL/min. Detection wavelength was set at 310nm for both MK and AZD, and 431nm for the internal standard sunitinib (SUN). The developed method was validated following the ICH guidelines and it was shown to be accurate, precise and linear in the range of 41ng/mL to 8333ng/mL for both drugs in the ACN-aqueous solution and from 83ng/mL to 8333ng/mL for both drugs in mouse plasma samples. For the first time, the presented data suggest the suitability of this method for the simultaneous separation and quantification of MK and AZD in both ACN aqueous solution as well as in mouse plasma samples. PMID- 28088044 TI - Dried haematic microsamples and LC-MS/MS for the analysis of natural and synthetic cannabinoids. AB - Synthetic cannabinoids are new psychoactive substances (NPS) with similar effects when compared to natural ones found in Cannabis derivatives. They have rapidly integrated into the illicit market, often sold as alternatives under international control. The need to identify and quantify an unprecedented and growing number of new compounds represents a unique challenge for toxicological, forensic and anti-doping analysis. Dried blood spots have been used within the bioanalytical framework in place of plasma or serum, in order to reduce invasiveness, lower sample size, simplify handling, storage and shipping of samples and to facilitate home-based and on-field applications. However, DBS implementation has been limited mainly by concerns related to haematocrit effect on method accuracy. Volumetric absorptive microsampling (VAMSTM), a second generation dried miniaturized sampling technology, has been developed just in order to eliminate haematocrit effect, thus providing accurate sampling but still granting feasible sample processing. An original LC-MS/MS method was herein developed and validated for the analysis of THC and its 2 main metabolites, together with 10 representative synthetic cannabinoids in both DBS and VAMS dried microsamples. The ultimate goal of this work is to provide highly innovative DBS and VAMS analytical protocols, whose performances were extensively optimized and compared, in order to provide effective and alternative tools that can be applied for natural and synthetic cannabinoid determination, in place of classical analytical strategies. PMID- 28088045 TI - UHPLC-MS/MS method for the quantitation of penicillin G and metabolites in citrus fruit using internal standards. AB - Penicillin G has been applied to citrus trees as a potential treatment in the fight against Huanglongbing (HLB). Here, we have developed and validated a method to identify and quantitate penicillin G and two of its metabolites, penillic acid and penilloic acid, in citrus fruit using ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). This method improves upon a previous method by incorporating isotopically labeled internal standards, namely, penillic acid-D5, and penilloic acid-D5. These standards greatly enhanced the accuracy and precision of our measurements by compensating for recovery losses, degradation, and matrix effects. When 2g of citrus fruit sample is extracted, the limits of detection (LOD) were determined to be 0.1ng/g for penicillin G and penilloic acid, and 0.25ng/g for penillic acid. At fortification levels of 0.1, 0.25, 1, and 10ng/g, absolute recoveries for penillic and penilloic acids were generally between 50-70%. Recoveries corrected with the isotopically labeled standards were approximately 90-110%. This method will be useful for the identification and quantitation of drug residues and their degradation products using isotopically labeled standards and UHPLC-MS/MS. PMID- 28088046 TI - Application of acid modified polyurethane foam surface for detection and removing of organochlorine pesticides from wastewater. AB - The commercial polyurethane foam was acid modified to get an inexpensive adsorbent (AM-PUF) has highly surface polarity and sorption capacity. The elemental analysis, scanning electron microscopy, thermal analysis, ultraviolet/visible/infrared spectroscopies and X-ray diffraction were used for characterization of AM-PUF. The surface of AM-PUF has amorphous character (broadband at 2theta, 21.75 degrees ) and contains several active sites e.g. NH, OH, CO, CC and COC groups. The electrical conductivity (sigma), iodine value and methylene blue index of AM-PUF are 1.7*10-5Omega-1m-1, 208mg/g and 107mg/g. The AM-PUF has a high efficiency for completely removing (99-100%) of Aldrin, DDT, Endrin, Heptachlor, Heptachlor epoxide and Lindane pesticides in both acidic and alkaline solutions. The removing rates of the organochlorine pesticides from wastewater are very rapid (t1/2=22s). The negative value of DeltaG (-10.9kJ/mol) for removing of OCPs using AM-PUF showed that the feasibility of the removing process and its spontaneous nature. PMID- 28088047 TI - Sliding doors: Did drama-based inter-professional education improve the tensions round person-centred nursing and social care delivery for people with dementia: A mixed method exploratory study. AB - This educational intervention takes place when the population of older people with dementia is increasing. Health and Social care professionals must work jointly in increasingly complex contexts. Negative attitudes towards older people are cited as a contributor to poor care delivery, including the use of dismissive and/or patronising language, failing to meet fundamental needs and afford choice. 'Sliding Doors to Personal Futures' is a joint, drama-based, educational initiative between NHS Education Scotland and the Scottish Social Services Council, delivered using interprofessional education (IPE) towards encouraging person-centred health and social care. This paper considers whether 'Sliding Doors' had an impact on social work and nursing students' attitudes to older people, person-centred care and interprofessional collaboration. Two groups of third year students were studied; one from nursing and one from social work. A mixed methods approach was taken and attitudes and attitudinal shifts measured and discussed. Quantitative results demonstrated that social work students made positive attitudinal shifts in some questionnaire items and collectively the social work students were more person-centred than nursing students in their care approaches. The qualitative data however, drawn from focus groups, illuminated these results and highlighted the link between the ability for a professional to be person-centred and the conceptual view of risk within the particular profession. Risk acceptance, the theoretical position of social work, may facilitate person-centred care, whereas the perceived risk-averse nature of the nursing profession may inhibit it. Students' attempts to understand the quantitative results, without understanding the restrictions and parameters of each other's profession, led them to revert to stereotypes and negative views of each other as practitioners. The paper concludes that there is an important difference between nurses' and social workers' frames of reference. It is suggested that IPE in its current form will not impact positively on outcomes for older people, unless both professions can openly acknowledge the reality of their professional contexts and develop an understanding of each other's professional restrictions, opportunities and aspirations. PMID- 28088048 TI - Disclosure management behaviors in Korean adults with well-controlled epilepsy: Their relation to perception of stigma. AB - PURPOSE: In spite of the fact that epilepsy is a concealable stigmatized identity, there is little evidence pertaining to disclosure management in adults living with epilepsy. We determined the factors contributing to disclosure management strategies in adults living with well-controlled epilepsy. METHODS: This was a cross-sectional multicenter study. Korean adults whose seizures had remitted for at least one year participated in this study. Using statistical analyses, we determined whether disclosure management behaviors measured using the Disclosure Management Scale (DMS) were related to demographic, clinical, and psychosocial variables. The Stigma Scale and Hospital Anxiety Depression Scale (HADS) were used. RESULTS: Of a total of 225 participants, 76% stated that they often or sometimes kept their epilepsy a secret, while 24% reported that they never or rarely kept their diagnosis hidden. The mean DMS score was 6.1 (SD=2.4). In univariate analyses, the DMS scores were significantly related to the HADS depression scores (r=0.187, p=0.005) and the presence of perceived stigma (p=0.001). In linear regression analyses, perceived stigma was identified only as an independent factor associated with DMS scores (p=0.031), while HADS depression lost significance (p=0.057). The presence of perceived stigma explained only 4.6% of the variance in DMS scores. CONCLUSIONS: Our study shows that over 70% of Korean adults with well-controlled epilepsy often or sometimes keep their epilepsy a secret. Although perceived stigma is associated with concealment behaviors, it accounts for only a small proportion of the variance in disclosure management. PMID- 28088049 TI - Sudden unexpected death in epilepsy (SUDEP) disclosure in pediatric epilepsy: An Italian survey on "to tell or not to tell". AB - BACKGROUND AND OBJECTIVES: Although there has recently been significant debate regarding the importance of disclosing the risk of SUDEP, professional societies and clinical practice guidelines currently recommend that the risk of SUDEP be disclosed as part of a comprehensive epilepsy education program. Therefore, the primary aim of the present study was to examine whether healthcare providers treating pediatric patients with epilepsy in Italy would disclose the risk of SUDEP to the parents of children with epilepsy. METHODS: The present study assessed data from a questionnaire that collected sociodemographic information and clinicians' attitudes towards SUDEP. The survey was available online from September to December 2015. Chi-squared (chi2) tests and multivariate logistic regression analysis were performed when appropriate, and a qualitative content analysis of open-ended questions was performed. FINDINGS: A total of 114 medical doctors (71 females and 43 males) completed the questionnaire. Of the respondents, 18 (16.2%) stated that all patients should be counseled about SUDEP, 22 (19.8%) thought that the majority should be, 58 (52.3%) said that only a minority should be, and 13 (11.7%) believed none should be. With respect to physicians' experience in counseling about SUDEP, only 2 (1.8%) counseled all their patients. A univariate logistic regression analysis showed that the factors associated with "not counseling about SUDEP at all" were the low number of patients with epilepsy they took care of (p<0.01), fewer years of experience (p=0.03), and the belief that it was safe from a legal point of view (p<0.001), The main reasons for counseling about SUDEP were refractory course of epilepsy (79%) and if the parent/patient requested information (65%). Additionally, the findings of the qualitative analysis highlighted the emotional difficulties that neuropediatricians encounter when dealing with the disclosure of SUDEP. CONCLUSIONS: The present findings showed that a minority of neuropediatricians in Italy counseled all parents of their patients about SUDEP. Educational training may help physicians better communicate with the patient/parents regarding this difficult issue. PMID- 28088050 TI - Pharmacists' knowledge of issues in pharmacotherapy of epilepsy using antiepileptic drugs: A cross-sectional study in Palestinian pharmacy practice. AB - OBJECTIVE: Antiepileptic drugs (AEDs) are mainstay in controlling epileptic seizures. As experts in medications, pharmacists should be able to ensure accuracy of dosing regimens, explain adverse effects, and screen for and alert people with epilepsy (PWE) and their physicians to possible drug-drug interactions (DDIs). The aim of this study was to evaluate pharmacists' knowledge of issues in pharmacotherapy of epilepsy using AEDs. METHODS: This was a cross sectional observational study conducted in the Palestinian pharmacy practice. A 10-item case-based questionnaire was used to determine actions taken by pharmacists in theoretical situations in pharmacotherapy of epilepsy. Demographic and practice details of the study participants were also collected. Scores were calculated as percentage of correct answers for each participant. RESULTS: The number of participants was 394. The majority (approximately 75%) identified themselves as community pharmacists. The median score was 33.4% with an IQR of 33.3. Pharmacists who received training on epilepsy and AEDs during their pharmacy degree program were 4.78-fold (95% C.I. of 1.82-12.60) more likely to score >=50% in the test than those who did not receive training on epilepsy and AEDs. Despite gaps in knowledge, pharmacists tended to perform the necessary action in cases of adverse effects and aggravated seizures associated with AEDs. CONCLUSION: Pharmacists can play a crucial role in providing essential information on AEDs to patients and prescribers. There are many knowledge gaps that need to be filled. Specifically designed pedagogic and/or training interventions might be helpful in filling these gaps. PMID- 28088051 TI - Online recruitment and testing of infants with Mechanical Turk. AB - Testing infants in the laboratory is expensive in time and money; consequently, many studies are underpowered, reducing their reproducibility. We investigated whether the online platform, Amazon Mechanical Turk (MTurk), could be used as a resource to more easily recruit and measure the behavior of infant populations. Using a looking time paradigm, with users' webcams we recorded how long infants aged 5 to 8months attended while viewing children's television programs. We found that infants (N=57) were more reliably engaged by some movies than by others and that the most engaging movies could maintain attention for approximately 70% of a 10- to 13-min period. We then identified the cinematic features within the movies. Faces, singing-and-rhyming, and camera zooms were found to increase infant attention. Together, we established that MTurk can be used as a rapid tool for effectively recruiting and testing infants. PMID- 28088052 TI - Positive and negative life events and reasons for living modulate suicidal ideation in a sample of patients with history of suicide attempts. AB - BACKGROUND: The influence of life events on suicidal behavior remains inconclusive, while reasons for living (RFL) may be protective. OBJECTIVES: To analyze the association between positive and negative life events and suicidal ideation (SI) and the interaction between life events and RFL on SI. METHOD: Patients with history of suicide attempts (n = 338) underwent a comprehensive clinical evaluation, including SI (Beck's Suicidal Ideation scale), RFL (Reasons for Living Inventory, RFLI) and life events (family, school, student or professional, social, health and religion-related and other life events) during the last twelve months. RESULTS: The only negative life events associated with SI were health-related events (OR = 2.01 95%CI[1.04;3.92]). Family-related positive life events and RFL were negatively associated with SI (OR = 0.73 95%CI[0.58;0.91] and OR = 0.98 95%CI[0.97;0.98], respectively). No significant interaction between the number of positive life events and RFLI total score with current SI (p = 0.57) was detected. Family-related positive life events and RFL did not have any additive effect on SI. Positive life events did not moderate the association between health-related negative life events and SI. LIMITATIONS: This was a retrospective study, the presence of axis II disorders was not investigated and results cannot be generalized due to the sample choice (only suicide attempters). CONCLUSIONS: Patients with history of suicide attempts could be less sensitive to negative life events, except for those related to health. Clinicians should pay more attention to somatic problems in patients at risk of suicide. Family support, positive psychology and therapies that strengthen RFL should be developed to prevent suicide. PMID- 28088053 TI - Sensitivity and specificity of the gain short-screener for predicting substance use disorders in a large national sample of emerging adults. AB - BACKGROUND AND OBJECTIVES: Emerging Adults (ages 18-25) have the highest prevalence of substance use disorders and rarely receive treatment from the specialty care system. Thus, it is important to have screening instruments specifically developed for emerging adults for use in Screening, Brief Intervention and Referral to Treatment (SBIRT) models. Optimal cutoffs for the widely-used GAIN Short-Screener's (GAIN-SS) Substance Disorder Screener (SDScrY) are not established specifically for emerging adults. Therefore, this study examined the sensitivity and specificity of the SDScrY in predicting emerging adult (ages 18-25) substance use disorders. METHODS: We analyzed data from emerging adults in a large clinical sample (n=9,808) who completed both the five item SDScrY (alpha=0.85) and the full criteria set for DSM-IV Substance Use Disorders. We estimated the sensitivity, specificity and area under the curve to determine optimal cutoffs. RESULTS: Analyses revealed a high correlation between the SDScrY screener and its longer parent scale (r=0.95, p<0.001). Sensitivity (83%) and specificity (95%) were highest at a cutoff score of two (AUC=94%) on the SDScrY for any past year substance use disorder. Sensitivity (85%) was also high at a cutoff score of two on the SDScrY for any past year alcohol disorder. CONCLUSIONS: The five-item Substance Use Disorder Screener is a sensitive and specific screener for emerging adults, and could be used to identify emerging adults who may benefit from SBIRT interventions. PMID- 28088054 TI - Medicinal versus recreational cannabis use: Patterns of cannabis use, alcohol use, and cued-arousal among veterans who screen positive for PTSD. AB - INTRODUCTION: The present study is the first to test whether veterans who use cannabis specifically for the purposes of self-medication for their reported PTSD symptoms differ from veterans who use cannabis medicinally for other reasons, or recreationally, in terms of patterns of cannabis use, use of alcohol, and reactivity to written combat trauma reminders. METHODS: Assessment measures were administered online to a sample of veterans with a history of cannabis use (n=1971). Cued arousal was assessed pre/post via a prompt about combat experiences. Hypotheses were tested using a series of Bonferroni corrected one way analyses of variance, t-tests, bivariate and partial correlations, and a Chi square test. RESULTS: Compared to recreational users, veterans who identify as medicinal cannabis users reported greater combat exposure (d=0.56), PTSD symptoms (d=1.02), subjective arousal when cued (d=0.25), and cannabis use (dfrequency=0.40; ddensity=0.42), but less alcohol use (d=0.28). Few differences were observed between medicinal users who reported using for PTSD versus those who reported using for other reasons. CONCLUSIONS: Compared to those who use cannabis recreationally, veterans who report that they use cannabis medicinally use more cannabis and endorse significantly more symptoms of arousal following a prompt about combat trauma experiences. PMID- 28088055 TI - Marijuana use disorder symptoms among recent onset marijuana users. AB - BACKGROUND: With recreational marijuana having recently been legalized in a growing number of U.S. states, as well as the increasing support for its legalization among substantial segments of the American public, an understanding of the development of symptoms associated with marijuana use disorders will assist in guiding both education and policy. METHODS: This study examined the prevalence of marijuana use disorder symptoms among a nationally representative sample of recent onset marijuana users ages 12-21 drawn from the National Survey of Drug Use and Health (N=9697). RESULTS: The most frequently reported marijuana use symptoms were "tolerance", and "time occupied acquiring, using or recovering from the effects of marijuana". Logistic regression analyses indicated an expected positive association between marijuana use frequency and each marijuana use disorder symptom. In many cases the positive trend was quadratic or cubic, with greater increases between rates among low and moderate frequency marijuana users (i.e. 1-10days per month) than among those using at a higher frequency (i.e. >10days per month). Relationships between marijuana use frequency and marijuana use symptoms were largely consistent according to age, gender and ethnicity. CONCLUSIONS: Recognizing symptoms of marijuana use disorders among adolescents and young adults using marijuana infrequently may assist in early identification and intervention for those at risk for problem use. PMID- 28088056 TI - The evolving relationship between premorbid intelligence and serious depression across the lifespan - A longitudinal study of 43,540 Swedish men. AB - BACKGROUND: An association between higher intelligence and lower probability of serious depression has previously been established. Yet, to our knowledge, no large prospective study has examined the relationship across the lifespan. METHODS: A cohort of 49,321 Swedish men was followed from conscription in 1969-70 (age 18-20) through to 2008. Odds ratios (OR) for first time hospitalisation for depression (FTHD) were calculated in relation to intelligence for distinct time periods across the lifespan, while controlling for established risk factors for depression. RESULTS: There was a linear association between higher intelligence in youth and lower odds for FTHD during the entire follow-up period, 1973-2008. The association got progressively weaker across the lifespan. During 1973-80, one step down on the stanine scale was associated with an unadjusted increase in OR of 1.34 [95% confidence interval (CI) 1.26-1.42], adjusted OR 1.23 [1.15-1.32]; while, during 2001-2008, the ORs were less than half of the magnitude of the first period, unadjusted 1.14 [1.07-1.21], and adjusted 1.09 [1.01-1.17]. LIMITATIONS: The study includes men only, and the number of available places for in-patient care decreased during the follow-up period. CONCLUSION: For the first time, we have shown that the association between lower intelligence and depression decreases over time. The attenuation of the association in the adjusted models suggests a slower accumulation of depressogenic stressors among people with a higher IQ-score. Further exploration of intelligence's role in the etiology of depression across the lifespan is required in order to facilitate adequate diagnoses and ameliorating interventions. PMID- 28088057 TI - A systematic review of adult attachment and social anxiety. AB - BACKGROUND: Attachment has been implicated in the development of social anxiety. Our aim was to synthesise the extant literature exploring the role of adult attachment in these disorders. METHOD: Search terms relating to social anxiety and attachment were entered into MEDLINE, PsycINFO and Web of Science. Risk of bias of included studies was assessed using and adapted version of the Agency for Healthcare Research and Quality assessment tool. Eligible studies employed validated social anxiety and attachment assessments in adult clinical and analogue samples. The review included cross sectional, interventional and longitudinal research. RESULTS: Of the 30 identified studies, 28 showed a positive association between attachment insecurity and social anxiety. This association was particularly strong when considering attachment anxiety. Cognitive variables and evolutionary behaviours were identified as potential mediators, concordant with psychological theory. LIMITATIONS: Due to a lack of longitudinal research, the direction of effect between attachment and social anxiety variables could not be inferred. There was substantial heterogeneity in the way that attachment was conceptualised and assessed across studies. CONCLUSIONS: The literature indicates that attachment style is associated with social anxiety. Clinicians may wish to consider attachment theory when working clinically with this population. In the future, it may be useful to target the processes that mediate the relationship between attachment and social anxiety. PMID- 28088058 TI - Has the symptom severity inclusion requirement narrowed the definition of major depressive disorder in antidepressant efficacy trials? AB - BACKGROUND: The inclusion criteria of all placebo-controlled studies of antidepressants have required a minimum level of severity on standardized measures of symptoms of depression. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project we examined the association between scores on the Hamilton Depression Rating Scale (HAMD) and the number of criteria met for MDD, as well as the impact of different HAMD cutoff scores on the distribution of the number of DSM-IV criteria met. We speculated that the use of a minimum symptom severity score (MSSS) for inclusion in an antidepressant efficacy trial (AETs) disproportionately excludes patients who are at or just above the diagnostic threshold for MDD, whereas patients who are well above the diagnostic threshold are not excluded. METHODS: Seven hundred forty outpatients with current MDD were evaluated with a semi-structured diagnostic interview. We compared the distribution of DSM-IV MDD criteria scores in patients who scored at or above or below the 3 cutoff scores on the HAMD most commonly used for inclusion in an AET. RESULTS: The distribution of the number of DSM-IV MDD symptom criteria met was significantly associated with HAMD scores. Compared to patients scoring below 18 on the HAMD the patients scoring 18 and above were less likely to report 5 MDD criteria (13.9% vs. 43.7%, chi2=82.2, p<0.001; RR 0.32 [95% C.I. 0.24-0.41]) and more likely to report 9 criteria (9.3% vs. 0.3%, chi2=27.6, p<0.001; RR 28.7 [95% C.I. 4.0-207.5]). The pattern was similar when comparing patients scoring above and below the cutoffs of 20 and 22. At a cutoff of 22 on the HAMD more than 85% of the patients meeting 5 or 6 MDD criteria would be excluded from a trial. In contrast, less than 10% of the patients meeting 8 or 9 criteria would be excluded based on a HAMD cutoff of 18. LIMITATIONS: The present study was conducted in a single outpatient practice in which the majority of patients were white, female, and had health insurance. Although the study was limited to a single site, a strength of the recruitment procedure was that the sample was not selected for participation in a treatment study, and exclusion and inclusion criteria did not reduce the representativeness of the patient groups. CONCLUSIONS: While there is not a perfect relationship between the HAMD score and the number of DSM MDD criteria present, the results of the current study suggest that HAMD scores can be thought of as a proxy for the number of DSM diagnostic criteria. Thus, the recruitment strategy for AETs has increasingly redefined the MDD diagnostic category by requiring a greater number of criteria than that required in the DSM. PMID- 28088059 TI - Infrared analysis of clay bricks incorporated with spent shea waste from the shea butter industry. AB - The peculiar challenge of effective disposing abundant spent shea waste and the excellent compositional variation tolerance of clay material offered an impetus to examine the incorporation of spent shea waste into clay material as an eco friendly disposal route in making clay bricks. For this purpose, the chemical constituent, mineralogical compositions and thermal behavior of both clay material and spent shea waste were initially characterized from which modelled brick specimens incorporating 5-20 wt% of the waste into the clay material were prepared. The clay material showed high proportions of SiO2 (52.97 wt%) and Al2O3 (27.10 wt%) indicating their rich kaolinitic content: whereas, the inert nature of spent shea waste was exhibited by their low oxide content. The striking similarities in infrared absorption bands of pristine clay material and clay materials incorporated with 15 wt% of spent shea waste showed that the waste incorporation had no impact on bond formation of the clay bricks. Potential performance benefits of developing bricks from clay material incorporated with spent shea waste included improved fluxing agents, economic sintering and making of sustainable bricks. Consequently, the analytical results authenticate the incorporation of spent shea waste into clay materials for various desired benefits aside being an environmental correct route of its disposal. PMID- 28088060 TI - Life cycle analysis of mitigation methodologies for railway rolling noise and groundbourne vibration. AB - Negative outcomes such as noise and vibration generated by railways have become a challenge for both industry and academia in order to guarantee that the railway system can accomplish its purposes and at the same time provide comfort for users and people living in the neighbourhood along the railway corridor. The research interest on this field has been increasing and the advancement in noise and vibration mitigation methodologies can be observed using various engineering techniques that are constantly put into test to solve such effects. In contrast, the life cycle analysis of the mitigation measures has not been thoroughly carried out. There is also a lack of detailed evaluation in the efficiency of various mechanisms for controlling rolling noise and ground-borne vibration. This research is thus focussed on the evaluation of materials used, the total cost associated with the maintenance of such the measures and the carbon footprint left for each type of mechanism. The insight into carbon footprint together with life cycle cost will benefit decision making process for the industry in the selection of optimal and suitable mechanism since the environmental impact is a growing concern around the world. PMID- 28088061 TI - Galectins: emerging regulatory checkpoints linking tumor immunity and angiogenesis. AB - Immune checkpoints, a plethora of inhibitory pathways aimed at maintaining immune cell homeostasis, may be co-opted by cancer cells to evade immune destruction. Therapies targeting immune checkpoints have reached a momentum yielding significant clinical benefits in patients with various malignancies by unleashing anti-tumor immunity. Galectins, a family of glycan-binding proteins, have emerged as novel regulatory checkpoints that promote immune evasive programs by inducing T-cell exhaustion, limiting T-cell survival, favoring expansion of regulatory T cells, de-activating natural killer cells and polarizing myeloid cells toward an immunosuppressive phenotype. Concomitantly, galectins can trigger vascular signaling programs, serving as bifunctional messengers that couple tumor immunity and angiogenesis. Thus, targeting galectin-glycan interactions may halt tumor progression by simultaneously augmenting antitumor immunity and suppressing aberrant angiogenesis. PMID- 28088062 TI - A retrospective audit of bacterial culture results of donated human milk in Perth, Western Australia. AB - INTRODUCTION: The bacterial content of donated human milk is either endogenous or introduced via contamination. Defining milk bank bacterial content will allow researchers to devise appropriate tests for significant and commonly encountered organisms. OBJECTIVE: A retrospective audit was conducted on data recorded from the Perron Rotary Express Milk Bank, King Edward Memorial Hospital, Subiaco, Western Australia. This aimed to describe the incidence of bacterial species detected in donated human milk and to identify potentially pathogenic bacteria. MATERIAL AND METHODS: The data comprised of 2890 batches donated by 448 women between 2007 and 2011. RESULTS: Coagulase negative Staphylococcus (CoNS) represented the highest prevalence of bacteria in donated milk, isolated from 85.5% of batches (range: 20 to 650,000CFU/mL) followed by Acinetobacter species in 8.1% of batches (range: 100 to 180,000CFU/mL). Staphylococcus aureus was the most prevalent potentially pathogenic bacteria in 5% of batches (range: 40 to 100,000CFU/mL). CONCLUSION: Further investigation is warranted to better define the risks posed by the presence of toxin-producing S. aureus in raw and pasteurized human milk which may allow minimization of risk to the preterm infants. PMID- 28088063 TI - Verbal and musical short-term memory: Variety of auditory disorders after stroke. AB - Auditory cognitive deficits after stroke may concern language and/or music processing, resulting in aphasia and/or amusia. The aim of the present study was to assess the potential deficits of auditory short-term memory for verbal and musical material after stroke and their underlying cerebral correlates with a Voxel-based Lesion Symptom Mapping approach (VLSM). Patients with an ischemic stroke in the right (N=10) or left (N=10) middle cerebral artery territory and matched control participants (N=14) were tested with a detailed neuropsychological assessment including global cognitive functions, music perception and language tasks. All participants then performed verbal and musical auditory short-term memory (STM) tasks that were implemented in the same way for both materials. Participants had to indicate whether series of four words or four tones presented in pairs, were the same or different. To detect domain-general STM deficits, they also had to perform a visual STM task. Behavioral results showed that patients had lower performance for the STM tasks in comparison with control participants, regardless of the material (words, tones, visual) and the lesion side. The individual patient data showed a double dissociation between some patients exhibiting verbal deficits without musical deficits or the reverse. Exploratory VLSM analyses suggested that dorsal pathways are involved in verbal (phonetic), musical (melodic), and visual STM, while the ventral auditory pathway is involved in musical STM. PMID- 28088064 TI - Improved cognition while cycling in Parkinson's disease patients and healthy adults. AB - Persons with Parkinson's disease (PD) are typically more susceptible than healthy adults to impaired performance when two tasks (dual task interference) are performed simultaneously. This limitation has by many experts been attributed to limitations in cognitive resources. Nearly all studies of dual task performance in PD employ walking or balance-based motor tasks, which are commonly impaired in PD. These tasks can be performed using a combination of one or two executive function tasks. The current study examined whether persons with PD would demonstrate greater dual task effects (DTEs) on cognition compared to healthy older adults (HOAs) during a concurrent cycling task. Participants with and without PD completed a battery of 12 cognitive tasks assessing visual and verbal processing in the following cognitive domains: speed of processing, controlled processing, working memory and executive function. Persons with PD exhibited impairments compared to healthy participants in select tasks (i.e., 0-back, 2 back and operation span). Further, both groups unexpectedly exhibited dual task facilitation of response times in visual tasks across cognitive domains, and improved verbal recall during an executive function task. Only one measure, 2 back, showed a speed-accuracy trade-off in the dual task. These results demonstrate that, when paired with a motor task in which they are not impaired, people with PD exhibit similar DTEs on cognitive tasks as HOAs, even when these task effects are facilitative. More generally, these findings demonstrate that pairing cognitive tasks with cycling may actually improve cognitive performance which may have therapeutic relevance to cognitive decline associated with aging and PD pathology. PMID- 28088065 TI - Methionine enkephalin (MENK) mounts antitumor effect via regulating dendritic cells (DCs). AB - MENK, an endogenous opioid peptide has been reported to have many immunological and antitumor activities. So far the detailed mechanisms of antitumor through regulating DCs by MENK have not been elucidated yet. The aim of this work was to investigate the antitumor mechanisms of MENK via regulating DC. The monitoring methods, such as ELISA, MTS assay, CFSE, Real-time PCR and Western blot were included in our research. We found bone marrow derived dendritic cells (BMDCs) in 36 female C57BL/6 mice treated with MENK enhanced expression of key surface molecules, increased production of critical cytokines reduced endocytosis of FITC dextran, upregulated TLR4 through MyD88/NF-kappaB signaling pathway and mounted higher antitumor activity. These observations were further supported by an enhancement of nuclear translocation of the p65NF-kappaB subunit involved in this process. Surprisingly, mu-opioid receptors were the main participants of this kind of activation, not delta-opioid receptors nor kappa-opioid receptors, and these interactions could be partly blocked by Naltrexone (a kind of opioid antagonist). In vivo study the activated CD4+, CD8+T cells and decreased ability to induce differentiation of Foxp3+ regulatory T cells were detected post treatment of MENK. Thus, it is concluded that MENK could exert antitumor effect through precisely regulating opioid receptor mediated functions of DCs. In addition, MENK treated DCs may serve as a new immunotherapy approach against tumor. PMID- 28088067 TI - Tuning neural circuits by turning the interneuron knob. AB - Interneurons play a critical role in sculpting neuronal circuit activity and their dysfunction can result in neurological and neuropsychiatric disorders. To temporally structure and balance neuronal activity in the adult brain interneurons display a remarkable degree of subclass-specific plasticity, of which the underlying molecular mechanisms have recently begun to be elucidated. Grafting new interneurons to pre-existing neuronal networks allows for amelioration of circuit dysfunction in rodent models of neurological disease and can reopen critical windows for circuit plasticity. The crucial contribution of specific classes of interneurons to circuit homeostasis and plasticity in health and disease underscores their generation as an important objective for emerging strategies of lineage reprogramming in vivo. PMID- 28088066 TI - Activity-dependent development of visual receptive fields. AB - It is widely appreciated that neuronal activity contributes to the development of brain representations of the external world. In the visual system, in particular, it is well known that activity cooperates with molecular cues to establish the topographic organization of visual maps on a macroscopic scale [1,2] (Huberman et al., 2008; Cang and Feldheim, 2013), mapping axons in a retinotopic and eye specific manner. In recent years, significant progress has been made in elucidating the role of activity in driving the finer-scale circuit refinement that shapes the receptive fields of individual cells. In this review, we focus on these recent breakthroughs-primarily in mice, but also in other mammals where noted. PMID- 28088068 TI - Perceived assistance in pursuing personal goals and personal recovery among mental health consumers across housing services. AB - Personal goals/plans play a central role in personal recovery and psychiatric rehabilitation of persons with mental illnesses. Yet, few studies have explored whether perceiving practitioners' assistance towards the pursuit of goals are associated with personal recovery and other favorable rehabilitation outcomes. A total of 2121 mental health consumers, of which 1222 use supported-housing services and 899 use group-home services, completed self-report questionnaires as part of a larger quality-assurance study conducted during the years 2013-2014. Eighty percent of participants living in supported-housing and 72% living in group-homes reported having personal goals/plans for the forthcoming year. Furthermore, their type of goals was different. Irrespective of the type of goal or housing service, participants who reported having goals/plans (compared with those who did not) showed higher levels of personal recovery and more favorable psychosocial outcomes. Regression analyses showed that perceiving professional staff members (but not para-professionals) as assisting in pursuing goals/plans was positively associated with personal recovery. This study empirically validates the value of having personal goals and professionals' assistance in pursuing goals/plans in regards to personal recovery. We propose that recovery oriented services should seek to enhance goal setting and goal-pursuit, and to train practitioners in these areas. PMID- 28088069 TI - Nuclear pore complexes and regulation of gene expression. AB - Nuclear pore complexes (NPCs), are large multiprotein channels that penetrate the nuclear envelope connecting the nucleus to the cytoplasm. Accumulating evidence shows that besides their main role in regulating the exchange of molecules between these two compartments, NPCs and their components also play important transport-independent roles, including gene expression regulation, chromatin organization, DNA repair, RNA processing and quality control, and cell cycle control. Here, we will describe the recent findings about the role of these structures in the regulation of gene expression. PMID- 28088070 TI - Fatigue life of bovine meniscus under longitudinal and transverse tensile loading. AB - The knee meniscus is composed of a fibrous extracellular matrix that is subjected to large and repeated loads. Consequently, the meniscus is frequently torn, and a potential mechanism for failure is fatigue. The objective of this study was to measure the fatigue life of bovine meniscus when applying cyclic tensile loads either longitudinal or transverse to the principal fiber direction. Fatigue experiments consisted of cyclic loads to 60%, 70%, 80% or 90% of the predicted ultimate tensile strength until failure occurred or 20,000 cycles was reached. The fatigue data in each group was fit with a Weibull distribution to generate plots of stress level vs. cycles to failure (S-N curve). Results showed that loading transverse to the principal fiber direction gave a two-fold increase in failure strain, a three-fold increase in creep, and a nearly four-fold increase in cycles to failure (not significant), compared to loading longitudinal to the principal fiber direction. The S-N curves had strong negative correlations between the stress level and the mean cycles to failure for both loading directions, where the slope of the transverse S-N curve was 11% less than the longitudinal S-N curve (longitudinal: S=108-5.9ln(N); transverse: S=112 5.2ln(N)). Collectively, these results suggest that the non-fibrillar matrix is more resistant to fatigue failure than the collagen fibers. Results from this study are relevant to understanding the etiology of atraumatic radial and horizontal meniscal tears, and can be utilized by research groups that are working to develop meniscus implants with fatigue properties that mimic healthy tissue. PMID- 28088072 TI - Microstructural, mechanical and corrosion characteristics of heat-treated Mg 1.2Zn-0.5Ca (wt%) alloy for use as resorbable bone fixation material. AB - Mg-Zn-Ca alloys have grabbed most of the recent attention in research attempting to develop an Mg alloy for bone fixation devices due to their superior biocompatibility. However, early resorption and insufficient strength remain the main problems that hinder their use. Heat treatment has previously been thoroughly studied as a post-shaping process, especially after the fabrication of complex parts (e.g. porous structures) by 3D-printing or powder metallurgy. In this work, the effect of heat treatment on Mg-1.2Zn-0.5Ca (wt%) alloy's microstructural, mechanical and corrosion properties was studied. The surface morphology of samples was characterized by optical microscopy, scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and x-ray diffraction (XRD). Hardness, compression and tensile tests were conducted, while the in vitro corrosion characteristics of the prepared samples were determined using potentiodynamic polarization (PDP) and immersion tests. It was found that increasing the age hardening duration up to 2-5h increased the heat-treated Mg 1.2Zn-0.5Ca alloy's mechanical properties. Further increase in the age hardening duration did not result in further enhancement in mechanical properties. Similarly, heat treatment significantly altered the Mg-1.2Zn-0.5Ca alloy's in vitro corrosion properties. The corrosion rate of the Mg-1.2Zn-0.5Ca alloy after the heat treatment process was reduced to half of that for the as-cast alloy. XRD results showed the formation of biocompatible agglomerations of hydroxyapatite (HA) and magnesium hydroxide (Mg(OH)2) on the corroded surface of the heat treated Mg-1.2Zn-0.5Ca alloy samples. The performed heat treatment process had a significant effect on both mechanical and corrosion properties of the prepared Mg 1.2Zn-0.5Ca alloy. The age hardening duration which caused the greatest increase in mechanical and the most slowed corrosion rate for Mg-1.2Zn-0.5Ca alloy material was between 2 and 5h. PMID- 28088071 TI - Discrete quasi-linear viscoelastic damping analysis of connective tissues, and the biomechanics of stretching. AB - The time- and frequency-dependent properties of connective tissue define their physiological function, but are notoriously difficult to characterize. Well established tools such as linear viscoelasticity and the Fung quasi-linear viscoelastic (QLV) model impose forms on responses that can mask true tissue behavior. Here, we applied a more general discrete quasi-linear viscoelastic (DQLV) model to identify the static and dynamic time- and frequency-dependent behavior of rabbit medial collateral ligaments. Unlike the Fung QLV approach, the DQLV approach revealed that energy dissipation is elevated at a loading period of ~10s. The fitting algorithm was applied to the entire loading history on each specimen, enabling accurate estimation of the material's viscoelastic relaxation spectrum from data gathered from transient rather than only steady states. The application of the DQLV method to cyclically loading regimens has broad applicability for the characterization of biological tissues, and the results suggest a mechanistic basis for the stretching regimens most favored by athletic trainers. PMID- 28088073 TI - Strategies to design clinical studies to identify predictive biomarkers in cancer research. AB - The discovery of reliable biomarkers to predict efficacy and toxicity of anticancer drugs remains one of the key challenges in cancer research. Despite its relevance, no efficient study designs to identify promising candidate biomarkers have been established. This has led to the proliferation of a myriad of exploratory studies using dissimilar strategies, most of which fail to identify any promising targets and are seldom validated. The lack of a proper methodology also determines that many anti-cancer drugs are developed below their potential, due to failure to identify predictive biomarkers. While some drugs will be systematically administered to many patients who will not benefit from them, leading to unnecessary toxicities and costs, others will never reach registration due to our inability to identify the specific patient population in which they are active. Despite these drawbacks, a limited number of outstanding predictive biomarkers have been successfully identified and validated, and have changed the standard practice of oncology. In this manuscript, a multidisciplinary panel reviews how those key biomarkers were identified and, based on those experiences, proposes a methodological framework-the DESIGN guidelines-to standardize the clinical design of biomarker identification studies and to develop future research in this pivotal field. PMID- 28088074 TI - Anti-angiogenic treatment in breast cancer: Facts, successes, failures and future perspectives. AB - Angiogenesis is one of the hallmarks of cancer and a crucial requisite in the development of tumors. Interrupting this process by blocking the vascular endothelial growth factor (VEGF) with the monoclonal antibody bevacizumab has been considered a possible breakthrough in the treatment of various types of cancer, especially for advanced disease. However in breast cancer, studies have shown ambivalent results causing debate about the value of this drug. In this article, we review the evidence for anti-angiogenic treatment options for breast cancer, as well as discuss the possible factors limiting the effectiveness of anti-angiogenic agents and offer a recommendation regarding the future research on these therapies for the treatment of breast cancer. PMID- 28088075 TI - Development of a hypoxia-triggered and hypoxic radiosensitized liposome as a doxorubicin carrier to promote synergetic chemo-/radio-therapy for glioma. AB - The treatment of malignant primary brain tumors is challenging. Concomitant radiochemotherapy has become the standard clinical treatment for malignant glioma, but there are two critical challenges to overcome in order to increase efficacy. First, glioma is known to have increased resistant to radiation due to its intra-tumoral hypoxia. In addition, the blood-brain barrier (BBB) restricts the distribution of the chemotherapeutic agent to the brain. Therefore, we developed a hypoxic radiosensitizer-prodrug liposome (MLP), in order to deliver DOX to the tumor and to overcome the above challenges, achieving a synergistic chemo-/radiotherapy treatment of malignant glioma. In this study, hypoxic radiosensitizer nitroimidazoles were conjugated with lipid molecules with a hydrolysable ester bond to form MDH. MDH was mixed together with DSPE-PEG2000 and cholesterol to make MLP liposomes, which were found to have strong radiosensitivity and to promote cargo release under hypoxic conditions, due to the properties of nitroimidazoles under hypoxic conditions. MLP/DOX was found to have distinct advantages, including precise and stealthy pharmacokinetics and efficient passive uptake by the tumor. Furthermore, the combination of MLP/DOX and radiotherapy (RT) significantly inhibited glioma growth as assessed by in vivo bioluminescence imaging. These findings suggest that MLP is a promising candidate as a DOX delivery system to enhance the antitumor treatment effects on glioma, owing to synergistic chemo-/radiotherapy. PMID- 28088076 TI - In vivo visualization of endogenous miR-21 using hyaluronic acid-coated graphene oxide for targeted cancer therapy. AB - Oncogene-targeted nucleic acid therapy has been spotlighted as a new paradigm for cancer therapeutics. However, in vivo delivery issues and uncertainty of therapeutic antisense drug reactions remain critical hurdles for a successful targeted cancer therapy. In this study, we developed a fluorescence-switchable theranostic nanoplatform using hyaluronic acid (HA)-conjugated graphene oxide (GO), which is capable of both sensing oncogenic miR-21 and inhibiting its tumorigenicity simultaneously. Cy3-labeled antisense miR-21 peptide nucleic acid (PNA) probes loaded onto HA-GO (HGP21) specifically targeted CD44-positive MBA MB231 cells and showed fluorescence recovery by interacting with endogenous miR 21 in the cytoplasm of the MBA-MB231 cells. Knockdown of endogenous miR-21 by HGP21 led to decreased proliferation and reduced migration of cancer cells, as well as the induction of apoptosis, with enhanced PTEN levels. Interestingly, in vivo fluorescence signals markedly recovered 3 h after the intravenous delivery of HGP21 and displayed signals more than 5-fold higher than those observed in the HGPscr-treated group of tumor-bearing mice. These findings demonstrate the possibility of using the HGP nanoplatform as a cancer theranostic tool in miRNA targeted therapy. PMID- 28088078 TI - Genetically tailored magnetosomes used as MRI probe for molecular imaging of brain tumor. AB - We investigate here the potential of single step production of genetically engineered magnetosomes, bacterial biogenic iron-oxide nanoparticles embedded in a lipid vesicle, as a new tailorable magnetic resonance molecular imaging probe. We demonstrate in vitro the specific binding and the significant internalization into U87 cells of magnetosomes decorated with RGD peptide. After injection at the tail vein of glioblastoma-bearing mice, we evidence in the first 2 h the rapid accumulation of both unlabeled and functionalized magnetosomes inside the tumor by Enhanced Permeability and Retention effects. 24 h after the injection, a specific enhancement of the tumor contrast is observed on MR images only for RGD labeled magnetosomes. Post mortem acquisition of histological data confirms MRI results with more magnetosomes found into the tumor treated with functionalized magnetosomes. This work establishes the first proof-of-concept of a successful bio-integrated production of molecular imaging probe for MRI. PMID- 28088077 TI - RhoA knockdown by cationic amphiphilic copolymer/siRhoA polyplexes enhances axonal regeneration in rat spinal cord injury model. AB - Spinal cord injury (SCI) results in permanent loss of motor and sensory function due to developmentally-related and injured-induced changes in the extrinsic microenvironment and intrinsic neuronal biochemistry that limit plasticity and axonal regeneration. Our long term goal is to develop cationic, amphiphilic copolymers (poly (lactide-co-glycolide)-g-polyethylenimine, PgP) for combinatorial delivery of therapeutic nucleic acids (TNAs) and drugs targeting these different barriers. In this study, we evaluated the ability of PgP to deliver siRNA targeting RhoA, a critical signaling pathway activated by multiple extracellular inhibitors of axonal regeneration. After generation of rat compression SCI model, PgP/siRhoA polyplexes were locally injected into the lesion site. Relative to untreated injury only, PgP/siRhoA polyplexes significantly reduced RhoA mRNA and protein expression for up to 4 weeks post injury. Histological analysis at 4 weeks post-injury showed that RhoA knockdown was accompanied by reduced apoptosis, cavity size, and astrogliosis and increased axonal regeneration within the lesion site. These studies demonstrate that PgP is an efficient non-viral delivery carrier for therapeutic siRhoA to the injured spinal cord and may be a promising platform for the development of combinatorial TNA/drug therapy. PMID- 28088079 TI - Geographic determinants of individual obesity risk in Spain: A multilevel approach. AB - This paper seeks to understand the determinants of individual body weight status and obesity risk in Spain by concurrently examining individual and regional characteristics. The data are drawn from the National Health Survey of Spain for the year 2011-2012 (INE-National Statistical Institute of Spain) and contain information for a representative sample of 12,671 adults across 50 provinces in Spain. A multilevel analysis is carried out to examine the determinants of individual weight status and obesity, controlling not only for the individual effects and those of the immediate environment but also for the broader setting to which individuals and their immediate environment belong. Our findings suggest that attributes from all three levels of analysis have an effect on individual weight status and obesity. Lack of green spaces and criminality taken as proxies of the social environment positively affect individual and women's BMI and obesity, respectively. PMID- 28088080 TI - A computer-based simulator for intravascular photoacoustic images. AB - Intravascular photoacoustic (IVPA) is a newly developed catheter-based imaging technique for the diagnosis of arterial atherosclerosis. A framework of simulating IVPA transversal images from a cross-sectional vessel model with given optical and acoustic parameters was presented. The light illumination and transportation in multi-layered wall and atherosclerotic plaque tissues were modeled through Monte Carlo (MC) simulation. The generation and transmission of photoacoustic (PA) waves in the acoustically homogeneous medium were modeled through the PA wave equation, which is solved explicitly with a finite difference time domain (FDTD) algorithm in polar coordinates. Finally, a series of cross sectional gray-scale images displaying the distribution of the deposited optical energy were reconstructed from the time-dependent acoustic pressure series with a time-reversal based algorithm. Experimental results demonstrate a good correlation between the simulated IVPA images and the optical absorption distribution profiles. The simulator provides a powerful tool for generating IVPA image data sets, which are used to improve the imaging catheter and to test the performance of image post-processing algorithms. PMID- 28088081 TI - Lead (Pb2+) and copper (Cu2+) remediation from water using superparamagnetic maghemite (gamma-Fe2O3) nanoparticles synthesized by Flame Spray Pyrolysis (FSP). AB - Superparamagnetic maghemite (gamma-Fe2O3) nanoparticles of controllable morphology were successfully synthesized using a flame spray pyrolysis (FSP) technique. Their physico-chemical properties, size, morphology, and surface chemistries were determined using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), selected area electron diffraction patterns (SAED), SEM-EDX, scanning electron microscopy (SEM), and pHZPC(6.3). Elemental contents before and after adsorption were identified using energy dispersive X-ray fluorescence (ED-XRF), energy dispersive X-ray analysis (EDX) and elemental mapping. Surface area (SBET 79.35m2/g) and size distribution analyses were conducted using a surface area analyzer and dynamic light scattering (DLS), respectively. The magnetic moment (44.5 at 300K and 50.16 at 2K) was determined using a physical properties measurement system (PPMS). The first adsorption study using gamma-Fe2O3 nanoparticles synthesized by FSP to successfully remediate Pb2+ and Cu2+ from water is reported. Batch adsorption studies were carried out. An optimum pH of 5.0 was studied for Pb2+ and Cu2+ removal. Pb2+ and Cu2+ removal mechanisms by these maghemite nanoparticles were presented. The adsorption of Pb2+ and Cu2+ was highly pH dependent. The metal ion uptake was mainly governed by electrostatic attractions. Sorption kinetic data followed the pseudo-second-order model. The Freundlich, Langmuir, Redlich-Peterson, Radke and Sips adsorption isotherm models were applied to interpret equilibrium data. The Freundlich and Langmuir isotherm equations best fit the respective equilibrium data for Pb2+ and Cu2+. The maximum Langmuir adsorption capacities of these maghemite nanoparticles were 68.9mg/g at 45 degrees C for Pb2+ and 34.0mg/g at 25 degrees C for Cu2+. Thus, these maghemite nanoparticles made by FSP were readily prepared, characterized and showed promise for remediating heavy metal ions from aqueous solutions. PMID- 28088082 TI - Nature of phase transitions in ammonium oxofluorovanadates, a vibrational spectroscopy study of (NH4)3VO2F4 and (NH4)3VOF5. AB - Two ammonium oxofluorovanadates, (NH4)3VO2F4 and (NH4)3VOF5, have been investigated by temperature-dependent infrared and Raman spectroscopy methods to determine the nature of phase transitions (PT) in these compounds. Dynamics of quasioctahedral groups was simulated within the framework of semi-empirical approach, which justified the cis-conformation of VO2F43- (C2v) and the C4v geometry of VOF53-. The observed infrared and Raman spectra of both compounds at room temperature (RT) revealed the presence at least of two crystallographically independent octahedral groups. The first order PT at elevated temperatures is connected with a complete dynamic disordering of these groups with only single octahedral state. At lower temperatures, the octahedra are ordered and several octahedral states appear. This PT is the most pronounced in the case of (NH4)3VOF5, when at least seven independent VOF53- octahedra are present in the structure below 50K, in accordance with the Raman spectra. Ammonium groups do not take part in PTs at higher and room temperatures but their reorientational motion freezes at lower temperatures. PMID- 28088083 TI - Specificity and stability of transient protein-protein interactions. AB - Remarkable features that are achieved in a protein-protein complex to precise levels are stability and specificity. Deviation from the normal levels of specificity and stability, which is often caused by mutations, could result in disease conditions. Chemical nature, 3-D arrangement and dynamics of interface residues code for both specificity and stability. This article reviews roles of interfacial residues in transient protein-protein complexes. It is proposed that aside from hotspot residues conferring stability to the complex, a small set of 'rigid' residues at the interface that maintain conformation between complexed and uncomplexed forms, play a major role in conferring specificity. Exceptionally, 'super hotspot' residues, which confer both stability and specificity, are attractive sites for interaction with small molecule inhibitors. PMID- 28088084 TI - Correlates of anti-hepatitis C positivity and use of harm reduction services among people who inject drugs in two cities in Croatia. AB - BACKGROUND: We assessed correlates of anti-hepatitis C (anti-HCV) positivity and utilization of needle and syringe exchange programs (NSEP) and opioid agonist treatment (OAT) among people who inject drugs (PWID) in two Croatian cities. METHODS: We conducted a cross-sectional study using respondent-driven (RDS) sampling among PWID in Rijeka (N=255) and Split (N=399). We used RDS-weighted population estimates and multivariable logistic regression to explore correlates of anti-HCV positivity and NSEP and OAT utilization. RESULTS: Seventy-eight percent (78.0%) of PWID in Rijeka and 61.5% in Split had been tested previously for HCV, while 21.5% and 7.0%, respectively, were tested for HCV in the past 12 months. Among PWID who report being infected with HCV, 24.9% in Rijeka and 11.3% in Split received anti-HCV treatment. In Rijeka, PWID who utilized NSEP and, in Split, those who were ever imprisoned, had higher odds of anti-HCV positivity. In Rijeka, PWID on OAT were more likely to use non-sterile injecting equipment and to inject for longer than 10 years. PWID enrolled in NSEP were more likely to inject opioid agonist medication (OAM) and less likely to use non-sterile injecting equipment. More than half of PWID reported misuse of OAM in the past month, while out of PWID enrolled in OAT, 65.4% in Rijeka and 88.7% in Split injected OAM in the month prior to the survey. CONCLUSIONS: Key findings of the paper point to the need to scale up HCV testing and treatment, improve access to NSEP and the quality of OAT provisions in order to prevent its misuse among PWID. PMID- 28088085 TI - New pyridazinone-4-carboxamides as new cannabinoid receptor type-2 inverse agonists: Synthesis, pharmacological data and molecular docking. AB - In the last few years, cannabinoid type-2 receptor (CB2R) selective ligands have shown a great potential as novel therapeutic drugs in several diseases. With the aim of discovering new selective cannabinoid ligands, a series of pyridazinone-4 carboxamides was designed and synthesized, and the new derivatives tested for their affinity toward the hCB1R and hCB2R. The 6-(4-chloro-3-methylphenyl)-2-(4 fluorobenzyl)-N-(cis-4-methylcyclohexyl)-3-oxo-2,3-dihydropyridazine-4 carboxamide (9) displayed high CB2-affinity (KiCB2 = 2.0 +/- 0.81 nM) and a notable selectivity (KiCB1/KiCB2 > 2000). In addition, 9 and other active new synthesized entities have demonstrated to behave as CB2R inverse agonists in [35S]-GTPgammaS binding assay. ADME predictions of the newly synthesized CB2R ligands suggest a favourable pharmacokinetic profile. Docking studies disclosed the specific pattern of interactions of these derivatives. Our results support that pyridazinone-4-carboxamides represent a new promising scaffold for the development of potent and selective CB2R ligands. PMID- 28088086 TI - Design and synthesis of new RAF kinase-inhibiting antiproliferative quinoline derivatives. Part 2: Diarylurea derivatives. AB - This article describes the design, synthesis, and biological screening of a new series of diarylurea derivatives possessing quinoline nucleus. Nine target compounds were selected by the National Cancer Institute (NCI, Bethesda, Maryland, USA) for in vitro antiproliferative screening against a panel of 58 cancer cell lines of nine cancer types. Following one-dose initial screening, compounds 1d-g and 2b were selected for 5-dose screening in order to calculate their IC50 and total growth inhibition (TGI) values against the cell lines. Compounds 1e and 1g were the most promising analogues. Both compounds showed strong potency and broad-spectrum antiproliferative activity against the different tested cancer types. Their IC50 and TGI values were less than those of the reference drug, sorafenib, against most of the tested cell lines of the nine different cancer types. Furthermore, the most potent compounds 1d-g were tested against C-RAF kinase as a potential molecular target of this series of compounds. All of them showed high potency, and the most potent derivative was compound 1e (IC50 = 0.10 MUM). It was further tested against a panel of another twelve kinases, and it showed selectivity against C-RAF kinase. This could be, at least in part, the possible mechanism of antiproliferative action of this series of compounds at molecular level. The binding modes of compounds 1e and 1g were studied by docking studies, which highlighted the importance of the urea linker compared with the amide linker. PMID- 28088087 TI - Ethylene biosynthesis and perception during ripening of loquat fruit (Eriobotrya japonica Lindl.). AB - In order to gain insights into the controversial ripening behavior of loquat fruits, in the present study we have analyzed the expression of three genes related to ethylene biosynthesis (ACS1, ACO1 and ACO2), two ethylene receptors (ERS1a and ERS1b), one signal transduction component (CTR1) and one transcription factor (EIL1) in peel and pulp of loquat fruit during natural ripening and also in fruits treated with ethylene (10MULL-1) and 1-MCP (10MULL-1), an ethylene action inhibitor. In fruits attached to or detached from the tree, a slight increase in ethylene production was detected at the yellow stage, but the respiration rate declined progressively during ripening. Accumulation of transcripts of ethylene biosynthetic genes did not correlate with changes in ethylene production, since the maximum accumulation of ACS1 and ACO1 mRNA was detected in fully coloured fruits. Expression of ethylene receptor and signaling genes followed a different pattern in peel and pulp tissues. After fruit detachment and incubation at 20 degrees C for up to 6days, ACS1 mRNA slightly increased, ACO1 experienced a substantial increment and ACO2 declined. In the peel, these changes were advanced by exogenous ethylene and partially inhibited by 1-MCP. In the pulp, 1-MCP repressed most of the changes in the expression of biosynthetic genes, while ethylene had almost no effects. Expression of ethylene perception and signaling genes was barely affected by ethylene or 1-MCP. Collectively, a differential transcriptional regulation of ethylene biosynthetic genes operates in peel and pulp, and support the notion of non-climacteric ripening in loquat fruits. Ethylene action, however, appears to be required to sustain or maintain the expression of specific genes. PMID- 28088088 TI - Prevalence of new psychoactive substances in Northeast Asia from 2007 to 2015. AB - The proliferation of new psychoactive substances (NPS) has been a global trend in drug abuse and its regulation has been a worldwide concern. There is no doubt that it is necessary to share information related to these emerging substances between countries and continents for the effective regulation of NPS. With efforts for the efficient regulation of NPS, many studies and information have been published for the prevalence of NPS in the United States and other countries in Europe and Oceania. However, there is lack of information available for the prevalence of NPS in Asian and African countries. Therefore, this research was focused on the investigation of legal status of certain NPS in Northeast Asian countries, including China, Japan, South Korea and Taiwan, in order to provide information on the prevalence and trend of emerging NPS in these countries. The results showed that a total of 940 NPS was reported in 4 Northeast Asian countries from 2007 to 2015. Among 940 NPS, 882 NPS are legally restricted in at least one country (94%) and 96 substances were not currently under control (6%) in these countries. The number of controlled NPS that are currently controlled in all 4 countries was only 25 (or 28%) out of 882 NPS. Each substance was categorized in 9 groups according to the classification proposed by the United Nations Office on Drugs and Crime (UNODC). In Northeast Asia, the most commonly controlled NPS were synthetic cannabinoids, synthetic cathinones, and phenethylamines. It was found that Japan is the most proactive country in terms of the NPS regulation with 41% of the total number of controlled NPS in Northeast Asia, followed by South Korea (21%), China (28%), Taiwan (10%). Comparing the number of NPS newly regulated in each country every year, NPS has been broadly scheduled in 2011 and the number of scheduled NPS has dramatically increased from 2013 to 2015. It was shown that Northeast Asia is also in danger of these emerging NPS and the effective regulation across countries is important for the prevention of NPS. Also, this study will bring attention to local law enforcement in the construction of local drug crime prevention network sharing information for these controlled substances. PMID- 28088089 TI - The traumatic potential of a projectile shot from a sling. AB - Herein, we analyze the energy parameters of stones of various weights and shapes shot from a sling and based on this data evaluate its traumatic potential. Four police officers proficient in the use of a sling participated in the trials. The following projectile types, shot using an overhead technique at a target 100m away were: round steel balls of different sizes and weights (24mm, 57g; 32mm, 135g; 38mm, 227g); different shaped stones weighing 100-150g and 150-200g and a golf ball (47g). Our data indicated that projectiles shot from unconventional weapons such as a sling, have serious traumatic potential for unprotected individuals and can cause blunt trauma of moderate to critical severity such as fractures of the trunk, limb, and facial skull bone, depending on the weight and shape of the projectile and the distance from the source of danger. Asymmetrically shaped projectiles weighing more than 100g were the most dangerous. Projectiles weighing more than 100g can cause bone fractures of the trunk and limbs at distances of up to 60m from the target and may cause serious head injuries to an unprotected person (Abbreviated Injury Scale 4-5) at distances up to 200m from the target. Due to the traumatic potential of projectiles shot from a sling, the police must wear full riot gear and keep at a distance of at least 60m from the source of danger in order to avoid serious injury. Furthermore, given the potential for serious head injuries, wearing a helmet with a visor is mandatory at distances up to 200m from the source of danger. PMID- 28088090 TI - Degradation in forensic trace DNA samples explored by massively parallel sequencing. AB - Routine forensic analysis using STRs will fail if the DNA is too degraded. The DNA degradation process in biological stain material is not well understood. In this study we sequenced old semen and blood stains by massively parallel sequencing. The sequence data coverage was used to measure degradation across the genome. The results supported the contention that degradation is uniform across the genome, showing no evidence of regions with increased or decreased resistance towards degradation. Thus the lack of genetic regions robust to degradation removes the possibility of using such regions to further optimize analysis performance for degraded DNA. PMID- 28088091 TI - Solar-to-chemical and solar-to-fuel production from CO2 by metabolically engineered microorganisms. AB - Recent development of carbon capture utilization (CCU) for reduction of greenhouse gas emission are reviewed. In the case of CO2 utilization, I describe development of solar-to-chemical and solar-to-fuel technology that refers to the use of solar energy to convert CO2 to desired chemicals and fuels. Photoautotrophic cyanobacterial platforms have been extensively developed on this principle, producing a diverse range of alcohols, organic acids, and isoprenoids directly from CO2. Recent breakthroughs in the metabolic engineering of cyanobacteria were reviewed. In addition, adoption of the light harvesting mechanisms from nature, photovoltaics-derived water splitting technologies have recently been integrated with microbial biotechnology to produce desired chemicals. Studies on the integration of electrode material with next-generation microbes are showcased for alternative solar-to-chemical and solar-to-fuel platforms. PMID- 28088092 TI - Aptamer-based environmental biosensors for small molecule contaminants. AB - Aptasensors are promising biosensors, which take advantage of using aptamers as a recognition element. The combination of the excellent characteristics of aptamers and the leading detection platform techniques, such as optical, electrochemical with nanomaterial-integrated, or mass-sensitive techniques with high sensitivity and specificity draws a promising view for the application of the aptasensors for the detection of harmful small toxic chemicals and real-time monitoring in the environments. In spite of attraction of aptasensors, application of them is limited to the complex environment due to the facts that how the immobilization of aptamers onto the surface affects the functions of aptamers and their structures for the detection of environmental contaminants are not clearly known. This review examines the most recent update on the selection of aptamers for small molecules, the development and application of aptasensors in the detection of small molecule contaminants in environment. Additionally, their applications to the real samples as environmental monitoring reported in the publications also are reviewed. PMID- 28088093 TI - Miniaturized and integrated whole cell living bacterial sensors in field applicable autonomous devices. AB - Live-cell based bioreporters are increasingly being deployed in microstructures, which facilitates their handling and permits the development of instruments that could perform autonomous environmental monitoring. Here we review recent developments of on-chip integration of live-cell bioreporters, the coupling of their reporter signal to the devices, their longer term preservation and multi analyte capacity. We show examples of instruments that have attempted to fully integrate bioreporters as their sensing elements. PMID- 28088095 TI - Chemoreceptor-based signal sensing. AB - Chemoreceptors are at the beginning of chemosensory signaling cascades that correspond to a major signal transduction mechanism. Chemoreceptors show a significant structural diversity of their ligand binding domains which present either a mono-modular or bi-modular arrangement. Although the majority of chemoreceptors are of unknown function, significant progress has been made in recent years in their functional annotation, which is reviewed here. In vitro ligand binding studies to recombinant ligand binding domains proved to be an efficient strategy to identify chemoreceptor functions. Obtained information is consistent with the view that a major driving force for the evolution of chemotaxis is to access carbon and nitrogen sources. The use of the newly generated information for the construction of biosensors is discussed. PMID- 28088094 TI - Organ-on-a-chip for assessing environmental toxicants. AB - Man-made xenobiotics, whose potential toxicological effects are not fully understood, are oversaturating the already-contaminated environment. Due to the rate of toxicant accumulation, unmanaged disposal, and unknown adverse effects to the environment and the human population, there is a crucial need to screen for environmental toxicants. Animal models and in vitro models are ineffective models in predicting in vivo responses due to inter-species difference and/or lack of physiologically-relevant 3D tissue environment. Such conventional screening assays possess limitations that prevent dynamic understanding of toxicants and their metabolites produced in the human body. Organ-on-a-chip systems can recapitulate in vivo like environment and subsequently in vivo like responses generating a realistic mock-up of human organs of interest, which can potentially provide human physiology-relevant models for studying environmental toxicology. Feasibility, tunability, and low-maintenance features of organ-on-chips can also make possible to construct an interconnected network of multiple-organs-on-chip toward a realistic human-on-a-chip system. Such interconnected organ-on-a-chip network can be efficiently utilized for toxicological studies by enabling the study of metabolism, collective response, and fate of toxicants through its journey in the human body. Further advancements can address the challenges of this technology, which potentiates high predictive power for environmental toxicology studies. PMID- 28088096 TI - Mycelium transformation of Streptomyces toxytricini into pellet: Role of culture conditions and kinetics. AB - The present study envisages the role of different carbon sources, nitrogen sources, metals, pH, inoculum volume and agitation rate in pellet formation of S. toxytricini at shake-flask level. It was found that galactose, ammonium sulphate, sodium nitrate, Cu2+, Zn2+, higher inoculum volume (5% v/v) and agitation rate at 300rpm caused significant reduction in pellet size (up to the range of 30MUm 0.5mm) but biomass formations was also reduced subsequently. Interestingly diffused type of morphology was obtained in Fe2+ supplemented medium with reduced biomass (1.5gL-1). Rheological study revealed that non-Newtonian behaviour of culture broth. Besides this, kinetics study was also made to understand the growth kinetics (0.39gL-1h-1), oxygen uptake rate (0.1146mgL-1h-1), and production of lipstatin (0.0072gh-1). PMID- 28088097 TI - Ionic-liquid pretreatment of cassava residues for the cogeneration of fermentative hydrogen and methane. AB - An ionic liquid of N-methylmorpholine-N-oxide (NMMO) was used to effectively pretreat cassava residues for the efficient enzymatical hydrolysis and cogeneration of fermentative hydrogen and methane. The reducing sugar yield of enzymolysed cassava residues with NMMO pretreatment improved from 36 to 42g/100g cassava residues. Scanning electron microscopy images revealed the formation of deep grooves (~4MUm wide) and numerous pores in the cassava residues pretreated with NMMO. X-ray diffraction patterns showed that the crystallinity coefficient of NMMO-pretreated cassava residues decreased from 40 to 34. Fourier transform infrared spectra indicated that crystal cellulose I was partially transformed to amorphous cellulose II in the NMMO-pretreated cassava residues. This transformation resulted in a reduced crystallinity index from 0.85 to 0.77. Hydrogen yield from the enzymolysed cassava residues pretreated with NMMO increased from 92.3 to 126mL/gTVS, and the sequential methane yield correspondingly increased from 79.4 to 101.6mL/g TVS. PMID- 28088098 TI - Environmental impact of engineered carbon nanoparticles: from releases to effects on the aquatic biota. AB - Nano-ecotoxicology is an emerging science which aims to assess the environmental effect of nanotechnologies. The development of this particular aspect of ecotoxicology was made necessary in order to evaluate the potential impact of recently produced and used materials: nanoparticles (NPs). Among all the types of NPs, carbon nanoparticles (CNPs) especially draw attention giving the increasing number of applications and integration into consumer products. However the potential impacts of CNPs in the environment remain poorly known. This review aims to point out the critical issues and aspects that will govern the toxicity of CNPs in the environment. PMID- 28088099 TI - Protein-templated synthesis of metal-based nanomaterials. AB - There is currently intense interest in using protein scaffolds to prepare uniform nanometre-sized clusters of metals or other inorganic material for use as sensors, imaging agents, drugs, magnetic materials or catalysts. Non-templated chemical synthesis of such clusters often results in a product of variable size and quality, but protein molecules have proved adept at nucleating and stabilizing precise nanoclusters of various kinds. Although much research has focused on natural proteins, such as the iron-storage protein ferritin, recent developments in protein design have allowed entirely novel, symmetrical proteins to be used as templates for the first time. PMID- 28088100 TI - Exploiting molecular motors as nanomachines: the mechanisms of de novo and re engineered cytoskeletal motors. AB - Cytoskeletal molecular motors provide exciting proof that nanoscale transporters can be highly efficient, moving for microns along filamentous tracks by hydrolyzing ATP to fuel nanometer-size steps. For nanotechnology, such conversion of chemical energy into productive work serves as an enticing platform for re purposing and re-engineering. It also provides a roadmap for successful molecular mechanisms that can be mimicked to create de novo molecular motors for nanotechnology applications. Here we focus specifically on how the mechanisms of molecular motors are being re-engineered for greater control over their transport parameters. We then discuss mechanistic work to create fully synthetic motors de novo and conclude with future directions in creating novel motor systems. PMID- 28088101 TI - Sequenced defined biomolecules for nanomaterial synthesis, functionalization, and assembly. AB - Biomolecules represent an invaluable resource to nanotechnology by providing a large diversity of highly functional biomolecular templates. As a result, these have been extensively used for controlling the synthesis, functionalization, and assembly of nanomaterials, while also creating materials with new properties and structures. In the following, we focus on the use of peptides to achieve these goals and describe their general utility, sequence programmability, and use as templates. Also, we highlight several recent advances in the identification and selection of high affinity nanomaterial-binding peptides, provide a few examples of peptide functionalized surfaces and peptide templated materials, and describe how simple modifications to well characterized nanomaterial-binding peptides can be used to manipulate interactions and physiochemical properties. PMID- 28088102 TI - Effects of photoperiod regimes and ultraviolet-C radiations on biosynthesis of industrially important lignans and neolignans in cell cultures of Linum usitatissimum L. (Flax). AB - Lignans and neolignans are principal bioactive components of Linum usitatissimum L. (Flax), having multiple pharmacological activities. In present study, we are reporting an authoritative abiotic elicitation strategy of photoperiod regimes along with UV-C radiations. Cell cultures were grown in different photoperiod regimes (24h-dark, 24h-light and 16L/8D h photoperiod) either alone or in combination with various doses (1.8-10.8kJ/m2) of ultraviolet-C (UV-C) radiations. Secoisolariciresinol diglucoside (SDG), lariciresinol diglucoside (LDG), dehydrodiconiferyl alcohol glucoside (DCG), and guaiacylglycerol-beta coniferyl alcohol ether glucoside (GGCG) were quantified by using reverse phase high performance liquid chromatography (RP-HPLC). Results showed that the cultures exposed to UV-C radiations, accumulated higher levels of lignans, neolignans and other biochemical markers than cultures grown under different photoperiod regimes. 3.6kJ/m2 dose of UV-C radiations resulted in 1.86-fold (7.1mg/g DW) increase in accumulation of SDG, 2.25-fold (21.6mg/g DW) in LDG, and 1.33-fold (9.2mg/g DW) in GGCG in cell cultures grown under UV+photoperiod than their respective controls. Furthermore, cell cultures grown under UV+dark showed 1.36-fold (60.0mg/g DW) increase in accumulation of DCG in response to 1.8kJ/m2 dose of UV-C radiations. Smilar trends were observed in productivity of SDG, LDG and GGCG. Additionally, 3.6kJ/m2 dose of UV-C radiations also resulted in 2.82 fold (195.65mg/l) increase in total phenolic production, 2.94-fold (98.9mg/l) in total flavonoid production and 1.04-fold (95%) in antioxidant activity of cell cultures grown under UV+photoperiod. These findings open new dimensions for feasible production of biologically active lignans and neolignans by Flax cell cultures. PMID- 28088103 TI - Chemically-enzymatic synthesis of photosensitive DNA. AB - The sensitizing propensity of radio-/photosensitizing nucleoside depends on DNA sequence surrounding a sensitizer. Therefore, in order to compare sensitizers with regard to their ability to induce a DNA damage one has to study the sequence dependence of damage yield. However, chemical synthesis of oligonucleotides labeled with sensitizing nucleosides is hindered due to the fact that a limited number of such nucleoside phosphoramidites are accessible. Here, we report on a chemically-enzymatic method, employing a DNA polymerase and ligase, that enables a modified nucleoside, in the form of its 5'-triphosphate, to be incorporated into DNA fragment in a pre-determined site. Using such a protocol two double stranded DNA fragments - a long one, 75 base pairs (bp), and a short one, 30bp in length - were pin-point labeled with 5-bromodeoxyuridine. Four DNA polymerases together with DHPLC for the inspection of reaction progress were used to optimize the process under consideration. As an ultimate test showing that the product possessing an assumed nucleotide sequence was actually obtained, we irradiated the synthesized oligonucleotide with UVB photons and analyzed its photoreactivity with the LC-MS method. Our results prove that a general approach enabling precise labeling of DNA with any nucleoside modification processed by DNA polymerase and ligase has been worked out. PMID- 28088104 TI - Biofabrication of size controllable silver nanoparticles - A green approach. AB - A facile biosynthetic approach for the size controllable production of silver nanoparticles (AgNPs) using the leaf extract of Cinnamomum tsoi as reducing and capping agent is developed. The polyphenolic functionalities present in the extract are essentially responsible for the synthesis and stabilization of AgNPs. The size and morphology of the AgNPs were effectively tuned by changing the volume of the extract. The availability of oxidized polyphenols play key role in tuning the size and morphology of the prepared NPs. The as prepared AgNPs were characterized by X-ray diffraction (XRD), Ultraviolet-visible spectroscopy (UV visible), Transmission electron microscopy (TEM), Selected area electron diffraction (SAED), Dynamic light scattering (DLS) and Fourier transform infrared (FTIR) techniques. FTIR and Zeta potential measurements have confirmed the decoration of oxidized polyphenols on the surface of synthesized AgNPs. TEM and DLS measurements revealed the size variation of AgNPs with change in the volume of plant extract. The prepared AgNPs showed the significant inhibition of alpha amylase and alpha-glucosidase enzymes and exhibited a dose dependent activity. The enhanced in-vitro antidiabetic activity of the AgNPs may be due to the oxidized polyphenols present on the AgNPs surface which was confirmed by FTIR analysis. In addition, the present method is substitute to the chemical approaches of size controlled AgNPs synthesis that are being used nowadays. PMID- 28088105 TI - Tectona grandis leaf extract, free and associated with nanoemulsions, as a possible photosensitizer of mouse melanoma B16 cell. AB - Over the past six years we have been studying extracts from tropical, specially Amazon, plants, to search for new sensitizers for photodynamic therapy of cancer and infectious diseases. Tectona grandis is a genus of tropical hardwood trees in the mint family, Lamiaceae. That is native to south and southeast Asia, but since the end of the 20th century is also gaining ground in the Amazon. The present work aims to evaluate the photodynamic potential of hydro-alcoholic extract from Tectona grandis LF leaves (TGE) and the same extract prepared as the oil-water nanoemulsion (TGE-NE) against melanoma B16 F10 cells. The method for preparation of a stable nanoemulsion with ~20nm particles associated to the TGE (TGE-NE) was successfully developed. We have shown that both free and nanostructured presentations possess the ability to sensitize B16 F10 cells to red light of the LED in vitro. Photodynamic effect was observed for both TGE and TGE-NE because toxicity increased under illumination with red light. While TGE was highly toxic towards melanoma cells under illumination with red light of the LED, it also possessed significant dark toxicity towards both B16 F10 and murine fibroblast NIH3T3 cells. The TGE-NE showed reasonable photocytotoxicity and was much less toxic towards normal cells in the dark compared to free TGE. PMID- 28088106 TI - UV-A induced delayed development in the larvae of coral Seriatopora caliendrum. AB - Coral reefs are vulnerable to ultraviolet radiation (UVR, 280-400nm). Not only do the fluxes of UVR fluctuate daily, they are also increasing due to global ocean and atmospheric changes. The deleterious effects of UVR on scleractinian corals have been intensively studied, but much less is known about the response of corals in the early pre-settlement phase. In this study, we tested how UVR exposure affects survival and development of Seriatopora caliendrum larvae and examined the photophysiological changes induced in the symbiotic dinoflagellate Symbiodinium. Results showed that the contents of chl c and carotenoids normalized to the number of algae cells in the larvae decreased significantly when larvae were exposed to UVR compared to those protected from UVR, while the cell density of Symbiodinium was higher in UVR-exposed larvae. The effective photochemical efficiency of the symbiotic algae increased when cultured under PAR plus UV-A (here taken as 320-395nm). We further present the novel finding that during the development experiment, presence of UV-A induced a decline in the rates of metamorphosis and settlement, which disappeared when the larvae were also exposed to UV-B (here defined as 295-320nm). However, UVR had no distinguishable effect on the numbers of larvae that either survived, metamorphosed or settled by the end of the culture period. Therefore, it is concluded from this study that UV-A radiation may extend the planktonic duration of coral larvae, but not have an overall inhibitory effect on developmental outcomes. PMID- 28088107 TI - GaAs laser therapy reestablishes the morphology of the NMJ and nAChRs after injury due to bupivacaine. AB - BACKGROUND: Local anesthetics are used to relieve pre- and postoperative pain, acting on both sodium channels and nicotinic acetylcholine receptors (nAChR) at the neuromuscular junction (NMJ). Bupivacaine acts as a non-competitive antagonist and has limitations, such as myotoxicity, neurotoxicity, and inflammation. Low-level laser therapy (LLLT) has anti-inflammatory, regenerative, and analgesic effects. The aim of the present study was to evaluate the effects of a gallium arsenide laser (GaAs) on the morphology of the NMJ and nAChRs after application of bupivacaine in the sternomastoid muscle. METHODS: Thirty-two adult male Wistar rats received injections of bupivacaine 0.5% (Bupi: right antimere) and 0.9% sodium chloride (Cl: left antimere). Next, the animals were divided into a Control group (C) and a Laser group (LLLT). The laser group received LLLT (GaAs 904nm, 50mW, 4,8J) in both antimeres for five consecutive days. After seven days, the animals were euthanized and the surface portion of the sternomastoid muscle was removed, frozen, and subjected to morphological and morphometric analyses of the NMJs (nonspecific esterase reaction), confocal laser scanning, and an ultrastructural analysis. The nAChRs were quantified by Western blotting. RESULTS: In the chloride group, the morphology and morphometry of the NMJs remained stable. The maximum diameters of the NMJs were lower in the Bupi (15.048+/-1.985) and LLLT/Bupi subgroups (15.456+/-1.983) compared to the Cl (18.502+/-2.058) and LLLT/Cl subgroups (19.356+/-2.522) (p<0.05). Ultrastructurally, LLLT reduced myonecrosis observed after application of bupivacaine, with recovery in the junctional folds and active zone. There was an increase in the perimeter of the LLLT/Bupi subgroup (150.33) compared to the Bupi subgroup (74.69) (p<0.01) observed by confocal microscopy. There was also an increase in the relative planar area of the NMJ after LBI (8.75) compared to CBupi (4.80) (p<0.01). An analysis of the protein expression of nAChRalpha1 showed no major differences in the groups studied. There was an increase in protein expression of the epsilon subunit after application of LLLT (13.055) compared to Bupi (0.251) (p<0.01). Taken together, the present experiments indicate that there was a positive association of the alpha and gamma subunits (p<0.05). CONCLUSIONS: These results demonstrate that LLLT at the dose used in this study reduced structural alterations in the NMJ and molecular changes in nAChRs triggered by bupivacaine, providing important data supporting the use of LLLT in therapeutic protocols for injuries triggered by local anesthetics. PMID- 28088108 TI - Hemostatic effect of intrauterine balloon for postpartum hemorrhage with special reference to concomitant use of "holding the cervix" procedure (Matsubara). AB - OBJECTIVE: The intrauterine balloon (Balloon) has recently been widely used to achieve hemostasis for postpartum hemorrhage (PPH). We concomitantly used a novel method, "holding the cervix", with the Balloon to prevent Balloon prolapse and achieve hemostasis. We aimed to clarify the following three factors: 1) hemostatic success rate of Balloon use for PPH, 2) effect of holding the cervix on Balloon prolapse, and, 3) the rate of bleeding after Balloon insertion, possibly predictive of Balloon failure. STUDY DESIGN: We retrospectively examined 80 patients undergoing Balloon application for PPH in our institution. We defined "success" as achieving hemostasis with no requirement of additional invasive procedures, and "failure" as their requirement. Between success vs. failure, several parameters were compared. For statistical analyses, Fisher's exact test and Wilcoxon rank sum test were applied. RESULTS: Excluding "unable to insert" patients, "holding the cervix" was performed in 56 (75%). Prolapse was less likely to occur in patients with than in those without "holding the cervix" (4 vs. 11%, respectively). The success rate in patients with "Balloon+holding the cervix" was 94%. Treatment for atonic bleeding and placenta previa (PP) showed similarly high success rates (97 and 94%, respectively). The rate of bleeding following Balloon insertion was significantly higher in failure than success cases (P=0.03) and all failure cases showed bleeding >250mL/h. CONCLUSIONS: The "Balloon+holding the cervix" strategy achieved hemostasis in over 90% of primary PPH. TREATMENT: for not only atonic bleeding but also PP showed a high success rate. Bleeding >250mL/h after Balloon insertion may indicate the requirement of additional invasive procedures. PMID- 28088109 TI - Carbetocin versus oxytocin for prevention of post-partum haemorrhage at caesarean section in the United Kingdom: An economic impact analysis. AB - OBJECTIVE: To determine the economic impact of the introduction of carbetocin for the prevention of postpartum haemorrhage (PPH) at caesarean section, compared to oxytocin. STUDY DESIGN: The model is a decision tree conducted from a UK National Health Service perspective. 1500 caesarean sections (both elective and emergency) were modelled over a 12 month period. Efficacy data was taken from a published Cochrane meta-analysis, and costs from NHS Reference costs, the British National Formulary and the NHS electronic Medicines Information Tool. A combination of hospital audit data and expert input from an advisory board of clinicians was used to inform resource use estimates. The main outcome measures were the incidence of PPH and total cost over a one year time horizon, as a result of using carbetocin compared to oxytocin for prevention of PPH at caesarean section. RESULTS: The use of carbetocin compared to oxytocin for prevention of PPH at caesarean section was associated with a reduction of 30 (88 vs 58) PPH events (>500ml blood loss), and a cost saving of L27,518. In probabilistic sensitivity analysis, carbetocin had a 91.5% probability of producing better outcomes, and a 69.4% chance of being dominant (both cheaper and more effective) compared to oxytocin. CONCLUSION: At list price, the introduction of carbetocin appears to provide improved clinical outcomes along with cost savings, though this is subject to uncertainty regarding the underlying data in efficacy, resource use, and cost. PMID- 28088110 TI - Highly sensitive detection of cysteine over glutathione and homo-cysteine: New insight into the Michael addition of mercapto group to maleimide. AB - A fluorescence "off-on" probe CMP for thiols was designed with coumarin as the fluorophore and maleimide as the receptor. The fluorescence of the coumarin was quenched through photoinduced electron transfer (PET) from the fluorophore to maleimide group. The Michael addition of the mercapto group toward maleimide formed a thioether with relatively weak fluorescence. The intramolecular nucleophilic substitution of amino group in cysteine (Cys) to alkylthio produced a much stronger fluorescent amino adduct, which was supported by UPLC-MS and NMR titration. The above sensing mechanism ensured CMP a highly sensitive probe toward Cys over GSH and Hcy. The fluorescence intensity at 495nm was linear with Cys concentration over the range of 0-10MUM with a detection limit of 14nM and a rapid response time of 20min. High selectivity and good competition of the probe toward thiols over other biologically relevant species enabled us to monitor mercapto-containing proteins as well as fluorescence imaging Cys in living cells. PMID- 28088111 TI - Psychometric evaluation of the Generalized Anxiety Disorder Screener GAD-7, based on a large German general population sample. AB - BACKGROUND: The Generalized Anxiety Disorder Scales GAD-7 and GAD-2 are instruments for the assessment of anxiety. The aims of this study are to test psychometric properties of these questionnaires, to provide normative values, and to investigate associations with sociodemographic factors, quality of life, psychological variables, and behavioral factors. METHODS: A German community sample (n=9721) with an age range of 18-80 years was surveyed using the GAD-7 and several other questionnaires. RESULTS: Confirmatory factor analyses confirmed the unidimensionality and measurement invariance of the GAD-7 across age and gender. Females were more anxious than males (mean scores: M=4.07 vs. M=3.01; effect size: d=0.33). There was no linear age trend. A total of 5.9% fulfilled the cut off criterion of 10 and above. Anxiety was correlated with low quality of life, fatigue, low habitual optimism, physical complaints, sleep problems, low life satisfaction, low social support, low education, unemployment, and low income. Cigarette smoking and alcohol consumption were also associated with heightened anxiety, especially in women. When comparing the GAD-7 (7 items) with the ultra short GAD-2 (2 items), the GAD-7 instrument was superior to the GAD-2 regarding several psychometric criteria. LIMITATIONS: The response rate (33%) was low. Because of the cross-sectional character of the study, causal conclusions cannot be drawn. A further limitation is the lack of a gold standard for diagnosing anxiety. CONCLUSIONS: The GAD-7 can be recommended for use in clinical research and routine. PMID- 28088112 TI - A current perspective on the oncopreventive and oncolytic properties of selective serotonin reuptake inhibitors. AB - Current cancer research strongly focuses on identifying novel pathways that can be selectively exploited in the clinic and identifying drugs capable of exploiting cancer vulnerabilities. Occasionally, drugs identified to exploit a cancer-specific vulnerability are on the market for clinical indications in another disease area. Rebranding them as anti-cancer drugs is a process commonly referred to as drug repurposing and is typically a faster method than bringing a novel drug to market. Selective serotonin reuptake inhibitors (SSRIs) are primarily used for treating several types of depression, but over the past two decades mounting evidence suggests that drugs in this class have oncolytic properties and reduce the risk of certain cancers. In the current work, we discuss how the secondary mechanisms of action associated with these drugs mediate their oncolytic effect. In particular, sertraline limits tumor growth by abrogating the PI3K/akt signaling pathway, a growth pathway shown to be constitutively active in multiple cancers. Fluoxetine has been shown to activate the AMPA-type glutamate receptor, induce massive calcium influx and mitochondrial calcium overload and induce caspase-9-dependent apoptosis. This receptor being highly overexpressed in cancer stem cells may explain why SSRIs lower the risk of multiple types of cancer. Fluoxetine has also been shown to inhibit multidrug resistance pumps, increasing the efficacy of several standard chemotherapies. Given the vast potential of SSRIs in treating cancer, these drugs should be more heavily used not only in treating cancer-related depression, but in combating cancer and increasing the efficacy of standard of care chemotherapies. PMID- 28088114 TI - Between exposure, access and use: Reconsidering foodscape influences on dietary behaviours. AB - Good accessibility to both healthy and unhealthy food outlets is a greater reality than food deserts. Yet, there is a lack of conceptual insights on the contextual factors that push individuals to opt for healthy or unhealthy food outlets when both options are accessible. Our comprehension of foodscape influences on dietary behaviours would benefit from a better understanding of the decision-making process for food outlet choices. In this paper, we build on the fundamental position that outlet choices are conditioned by how much outlets' attributes accommodate individuals' constraints and preferences. We further argue that food outlets continuously experienced within individuals' daily-path help people re-evaluate food acquisition possibilities, push them to form intentions, and shape their preferences for the choices they will subsequently make. Doing so, we suggest differentiating access, defined as the potential for the foodscape to be used at the time when individuals decide to do so, from exposure, which acts as a constant catalyst for knowledge, intention, preferences and routine tendency. We conclude with implications for future research, and discuss consequences for public policy. PMID- 28088113 TI - Modulatory effect of vanillic acid on antioxidant status in high fat diet-induced changes in diabetic hypertensive rats. AB - The worldwide incidence of diabetes has increased dramatically along with widespread lifestyle and dietary changes. Diets high in fat are strongly associated with the development of obesity and can induce insulin resistance in humans and animals. It is clear that obesity constitutes a risk factor for contributing to the development of type 2 diabetes. In the present study, we investigated the therapeutic potential action of vanillic acid on diabetes associated complications using a rat model. Rats were made diabetic hypertensive by high fat diet (HFD) for 20 weeks and were treated with vanillic acid (50mg/kg bw) for last 8 weeks. The effects of vanillic acid on glucose, plasma insulin, systolic and diastolic blood pressure, thiobarbituric acid reactive substances (TBARS), hydroperoxides as a lipid peroxidation marker, and the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), vitamin C and vitamin E as an antioxidant marker, AST and ALT as a liver function marker, urea, uric acid and creatinine as a kidney function marker were investigated. Histopathology of liver and kidney was also investigated as part of the pathology of diabetes. Treatment of diabetic rats with oral administration of vanillic acid at a dose of 50mgkg/body weight for 8 weeks resulted in a significant decrease in fasting plasma glucose, insulin and blood pressure levels in comparison with diabetic control group. The antioxidant activities were significantly increased and the levels of lipid peroxidation markers were significantly decreased in diabetic hypertensive rats treated with vanillic acid. These results suggest that vanillic acid offer a modulatory effect on control of diabetic hypertension by reduction of blood glucose, insulin and blood pressure, combating oxidative stress by activation of tissue antioxidants. PMID- 28088115 TI - In-situ synthesis of novel Z-scheme SnS(2)/BiOBr photocatalysts with superior photocatalytic efficiency under visible light. AB - In this study, a novel SnS2/BiOBr heterojunction photocatalyst was synthesized via a facile in-situ growth strategy. The heterojunction interface was formed by loading BiOBr nanosheets on the surface of ultrathin hexagonal SnS2 nanoplates. UV/Vis diffuse reflectance spectroscopy (DRS) indicated that SnS2/BiOBr composites possessed stronger visible-light absorption. The as-fabricated SnS2/BiOBr heterojunction nanoplates exhibited considerable improvement in terms of photocatalytic activity for the degradation of rhodamine B (RhB) under visible light irradiation as compared with BiOBr and SnS2. The enhanced photocatalytic activity was attributed to the closely contacted interface between BiOBr and SnS2, thereby resulting in faster transfer of the photoinduced electron-hole pairs through their interface, as shown by the results of photoluminescence spectroscopy (PL) and photocurrent measurements. Radical trapping experiments demonstrated that holes (h+) and superoxide anion radicals (O2-) were the main active species in the photocatalytic oxidation process. The mechanism of the excellent photocatalytic activity of SnS2/BiOBr heterojunction composite was also discussed. PMID- 28088116 TI - Upconversion color tuning in Ce(3+)-doped LiYF(4):Yb(3+)/Ho(3+)@LiYF(4) nanoparticles towards ratiometric fluorescence detection of chromium(III). AB - Ratiometric fluorescence sensor exhibits advantages of sensitive response, high anti-interference ability and naked eye visualization owing to multiple independent emission peaks utilized for results analysis. To achieve such multi emission probe, the traditional methods have involved simple mixing of two emitters or tedious synthesis processes of hybrid material. However, these probes often have problems of inconstant emission strength ratio, low light-stability, and complicated synthetic process, which limit their applications in practical field. Herein, we report a single-structure Ce3+-doped LiYF4:Yb3+/Ho3+@LiYF4 upconversion nanoparticles (UCNPs), which features two emission peaks in the green (at 540nm) and red (at 640nm) region under the excitation of 980nm near infrared laser. Importantly, the red/green intensity ratio can be regulated by changing the doping level of Ce3+ to modulate output colors. Furthermore, a Cr3+ responsive rhodamine derivative (CRD) was modified on the devised UCNPs surface to fabricate the colorimetric probe by luminescent resonance energy transfer (LRET) process. Upon addition of Cr3+ into the probe solution, the absorption peak of CRD at 560nm is significantly enhanced, which greatly reduced the green emission, leading to an obvious color evolution from green to yellow to orange and to red with increasing the concentration of Cr3+. This method is successfully applied to practical detection of Cr3+ ion in industrial waste water. The work reported here demonstrates a useful way to construct color-based visual assays. PMID- 28088117 TI - Adsorption of phosphate from aqueous solution using iron-zirconium modified activated carbon nanofiber: Performance and mechanism. AB - Phosphate (P) removal is significant for the prevention of eutrophication in natural waters. In this paper, a novel adsorbent for the removal of P from aqueous solution was synthesized by loading zirconium oxide and iron oxide onto activated carbon nanofiber (ACF-ZrFe) simultaneously. The adsorbent was characterized by scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy and X-ray photoelectron spectroscopy (XPS). The results showed that P adsorption was highly pH dependent and the optimum pH was found to be 4.0. The isotherm of adsorption could be well described by the Langmuir model and the maximum P adsorption capacity was estimated to be 26.3mgP/g at 25 degrees C. The kinetic data were well fitted to the pseudo-second-order equation, indicating that chemical sorption was the rate-limiting step. Moreover, co existing ions including sulfate (SO42-), chloride (Cl-), nitrate (NO3-) and fluoride (F-) exhibited a distinct effect on P adsorption with the order of F >NO3->Cl->SO42-. Further investigations by FT-IR spectroscopy and pH variations associated with the adsorption process revealed that ligands exchange and electrostatic interactions were the dominant mechanisms for P adsorption. The findings reported in this work highlight the potential of using ACF-ZrFe as an effective adsorbent for the removal of P in natural waters. PMID- 28088118 TI - Histidine-functionalized carbon-based dot-Zinc(II) nanoparticles as a novel stabilizer for Pickering emulsion synthesis of polystyrene microspheres. AB - Carbon-based dots (CDs) are nanoparticles with size-dependent optical and electronic properties that have been widely applied in energy-efficient displays and lighting, photovoltaic devices and biological markers. However, conventional CDs are difficult to be used as ideal stabilizer for Pickering emulsion due to its irrational amphiphilic structure. The study designed and synthesized a new histidine-functionalized carbon dot-Zinc(II) nanoparticles, which is termed as His-CD-Zn. The His-CD was made via one-step hydrothermal treatment of histidine and maleic acid. The His-CD reacted with Zn2+ to form His-CD-Zn. The as-prepared His-CD-Zn was used as a solid particle surfactant for stabilizing styrene-in water emulsion. The Pickering emulsion exhibits high stability and sensitive pH switching behaviour. The introduction of S2O82- triggers the emulsion polymerization of styrene. The resulted polystyrene microsphere was well coated with His-CDs on the surface. It was successfully used as an ideal adsorbent for removal of heavy metallic ions from water with high adsorption capacity. The study also provides a prominent approach for fabrication of amphiphilic carbon based nanoparticles for stabilizing Pickering emulsion. PMID- 28088119 TI - Composite films of metal doped CoS/carbon allotropes; efficient electrocatalyst counter electrodes for high performance quantum dot-sensitized solar cells. AB - This study reports the enhanced catalytic ability of metal ions-doped CoS and CoS/carbon allotrope counter electrodes (CEs) (synthesized using a successive ionic layer adsorption and reaction (SILAR) method) to improve the power conversion efficiency (eta) in quantum dot-sensitized solar cells (QDSSCs). Firstly, doping effects of different metal ions (Mg2+, Ca2+, Sr2+ and Ba2+) in the CoS CE on the QDSSCs performance have been investigated. Overall, among the different metal doped CoS CEs, the best energy conversion efficiency of 2.19%, achieved for Sr, is the highest reported for QDSSCs constructed with metal doped CoS. A sandwich structural Sr- and Ba-CoS/carbon allotrope (graphene sheet (GS), graphene oxide (GO) and carbon nanotube (CNT)) composite CEs have been prepared by repeating electrophoretic deposition (EPD) of carbon materials and deposition of CoS nanoparticles. Dramatic enhancements of eta have been observed with the Sr and Ba-CoS/GO CEs based QDSSCs (~76% and ~41%, respectively), which is higher than that of the bare CoS CE. Because of the large specific surface area and superior electrical conductivity of GS, GO and CNT and the high electrocatalytic activity of CoS, these CEs show an improvement in the photocurrent density in the cells, as revealed from electrochemical and spectral data. PMID- 28088120 TI - 3D architecture of a graphene/CoMoO(4) composite for asymmetric supercapacitors usable at various temperatures. AB - Designing and optimizing the electrode materials and studying the electrochemical performance or cycle life of the supercapacitor under different working conditions are crucial to its practical application. Herein, we proposed a rational design of 3D-graphene/CoMoO4 nanoplates by a facile two-step hydrothermal method. Owing to the high electron transfer rate of graphene and the high activity of the CoMoO4 nanoplates, the three-dimensional electrode architectures achieved remarkable electrochemical performances with high areal specific capacitance (1255.24F/g at 1A/g) and superior cycling stability (91.3% of the original specific capacitance after 3000 cycles at 1A/g). The all-solid state asymmetric supercapacitor composed of 3D-graphene/CoMoO4 and activated carbon (AC) exhibited a specific capacitance of 109F/g at 0.2A/g and an excellent cycling stability with only 12.1% of the initial specific capacitance off after 3000 cycles at 2A/g. The effects of temperature and charge-discharge current densities on the charge storage capacity of the supercapacitor were also investigated in detail for practical applications. PMID- 28088121 TI - Synthesis of CTAB intercalated graphene and its application for the adsorption of AR265 and AO7 dyes from water. AB - Environmental applications of graphene (GN) are limited by the occurrence of aggregation. Herein, graphene oxide (GO) was synthesized, reduced to GN by ascorbic acid, and intercalated with cetyltrimethylammonium bromide (CTAB). GN CTAB was characterized by Boehm's titration, N2 adsorption/desorption, Fourier transform infrared spectroscopy, Raman spectroscopy, Fluorescence spectrophotometry, X-ray diffraction and Scanning electron microscopy. Then, GN CTAB was used for the adsorptive removal of acid red 265 (AR265) and acid orange 7 (AO7) dyes from water both under batch and column operation. Under batch operation, the effect of pH, adsorbent dosage, initial dye concentration, contact time and temperature on dyes adsorption were assessed. Adsorption isotherms, kinetics, and thermodynamics were analyzed systematically. Regarding the fixed bed operation, the effect of both the bed height and flow rate were studied and experimental results fitted to the Thomas and BDST models. Then, the bed loss capacity along five adsorption-regeneration cycles was determined in order to further approach the practical application of GN-CTAB for wastewater treatment, namely for the removal of dyes. PMID- 28088122 TI - A comparative study on the effects of ultrathin luminescent graphene oxide quantum dot (GOQD) and graphene oxide (GO) nanosheets on the interfacial interactions and mechanical properties of an epoxy composite. AB - The reinforcement effect of graphene oxide nanosheets on the mechanical properties of an epoxy coating has been extensively studied. However, the effect of graphene oxide quantum dot (GOQD) as a new unique carbon based nanomaterial (with lateral dimension of 5-6nm and thickness of one carbon atom) on the mechanical properties of epoxy coating has not been reported and compared with GO yet. So this study aims at fabrication of a high-performance polymer composite with unique mechanical properties using GOQD nanosheets. GO and GOQD were obtained through two different strategies of "top-down" synthesis from an expandable graphite by a modified Hummers' method and an easy "bottom-up" method by carbonizing citric acid, respectively. The morphology, size distribution, microstructure and chemistry of the GO and GOQD were compared by utilizing X-ray diffraction (XRD) analysis, atomic force microscopy (AFM), high resolution transmission electron microscopy (HR-TEM), high resolution field-emission scanning electron microscopy (FE-SEM), thermal gravimetric analysis (TGA), Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS). Results obtained from these analyses confirmed successful synthesize of GOQD and GO nanosheets. The reinforcement effect of GO and GOQD nanosheets on the mechanical properties of the epoxy coating was studied by dynamic mechanical thermal analysis (DMTA) and tensile test. It was found that the GOQD could remarkably enhance the energy of break, Young's modulus, tensile stress and interfacial interactions compared to the neat epoxy and the one reinforced with GO nanosheets. GOQD improved the fracture toughness by factor of 175% and 700% compared to the GO/Epoxy and neat epoxy, respectively. PMID- 28088123 TI - Antibody-dependent cellular cytotoxicity and influenza virus. AB - Antibodies are a key defence against influenza infection and disease, but neutralizing antibodies are often strain-specific and of limited utility against divergent or pandemic viruses. There is now considerable evidence that influenza specific antibodies with Fc-mediated effector functions, such as antibody dependent cellular cytotoxicity (ADCC), can assist in the clearance of influenza infection in vitro and in animal models. Further, ADCC-mediating antibodies that recognize a broad array of influenza strains are common in humans, likely as a result of being regularly exposed to influenza infections. The concept that influenza-specific ADCC can assist in the partial control of influenza infections in humans is gaining momentum. This review examines the utility of influenza specific ADCC antibodies. PMID- 28088124 TI - Nipah virus: transmission of a zoonotic paramyxovirus. AB - Nipah virus is a recently-recognised, zoonotic paramyxovirus that causes severe disease and high fatality rates in people. Outbreaks have occurred in Malaysia, Singapore, India and Bangladesh, and a putative Nipah virus was also recently associated with human disease in the Philippines. Worryingly, human-to-human transmission is common in Bangladesh, where outbreaks occur with near-annual frequency. Onward human transmission of Nipah virus in Bangladesh is associated with close contact with clinically-unwell patients or their infectious secretions. While Nipah virus isolates associated with outbreaks of human infection have not resulted in sustained transmission to date, specific exposures carry a high risk of person-to-person transmission, an observation which is supported by recent findings in animal models. Novel paramyxoviruses continue to emerge from wildlife hosts, and represent an ongoing threat to human health globally. PMID- 28088125 TI - Computational methods for analyzing conformational variability of macromolecular complexes from cryo-electron microscopy images. AB - Thanks to latest technical advances in cryo-electron microscopy (cryo-EM), structures of macromolecular complexes (viruses, ribosomes, etc.) are now often obtained at near-atomic resolution. Also, studies of conformational changes of complexes, in connection with their function, are gaining ground. Conformational variability analysis is usually done by classifying images in a number of discrete classes supposedly representing all conformational states present in the specimen. However, discrete classes cannot be meaningfully defined when the conformational change is continuous (the specimen contains a continuum of states instead of a few discrete states). For such cases, first image analysis methods that explicitly consider continuous conformational changes were recently developed. The latest developments in cryo-EM image analysis methods for conformational variability analysis are the focus of this review. PMID- 28088126 TI - Severe hypoalbuminemia and steatohepatitis leading to death in a young vegetarian female, 8 months after mini gastric bypass: A case report. AB - BACKGROUND: Hypoalbuminemia is an important complication after Mini Gastric Bypass (MGB) and is more frequent in vegetarians, diabetic nephropathy, and alcoholic and liver disease patients. The patients must be followed in regular intervals and serum albumin must be checked in every visit after MGB. Hypoalbuminemia must be prevented by good protein regimes. CASE SUMMARY: A 29 years old female was admitted 8 month after Laparoscopic Mini Gastric Bypass with malaise, dyspnea, icter, nausea, vomiting, diarrhea and edema of extremities from 2 weeks before admission. She had become vegetarian autonomously and had not participated in routine postop follow up, and also discontinued her high protein regimen. In para clinictest results, she had severe hypoalbuminemia, anemia, elevated liver enzymes and direct bilirubinemia, metabolic acidosis in Arterial Blood Gas (ABG), and in Core Needle Biopsy (CNB) marked Steatohepatitis was shown. Unfortunately, the patient did not respond to medical care and died. CONCLUSION: Regular follow up after Mini Gastric Bypass is very important for many reasons such as early diagnosis and treatment of hypoalbuminemia. PMID- 28088127 TI - Cerebral laterality for language is related to adult salivary testosterone levels but not digit ratio (2D:4D) in men: A functional transcranial Doppler ultrasound study. AB - The adequacy of three competing theories of hormonal effects on cerebral laterality are compared using functional transcranial Doppler sonography (fTCD). Thirty-three adult males participated in the study (21 left-handers). Cerebral lateralization was measured by fTCD using an extensively validated word generation task. Adult salivary testosterone (T) and cortisol (C) concentrations were measured by luminescence immunoassay and prenatal T exposure was indirectly estimated by the somatic marker of 2nd to 4th digit length ratio (2D:4D). A significant quadratic relationship between degree of cerebral laterality for language and adult T concentrations was observed, with enhanced T levels for strong left hemisphere dominance and strong right hemisphere dominance. No systematic effects on laterality were found for cortisol or 2D:4D. Findings suggest that higher levels of T are associated with a relatively attenuated degree of interhemispheric sharing of linguistic information, providing support for the callosal and the sexual differentiation hypotheses rather than the Geschwind, Behan and Galaburda (GBG) hypothesis. PMID- 28088128 TI - Structure of the O-specific polysaccharide from the lipopolysaccharide of Aeromonas hydrophila strain K691 containing 4-acetamido-4,6-dideoxy-d-glucose. AB - The O-specific polysaccharide (OPS) was isolated from the lipopolysaccharide of Aeromonas hydrophila strain K691 and studied by chemical methods and 1H and 13C NMR spectroscopy, including 2D 1H,1H COSY, TOCSY, NOESY, 1H-detected heteronuclear 1H,13C HSQC, and HMBC experiments. It was found that the O-specific polysaccharide was built up of pentasaccharide repeating units composed of beta GlcpNAc, 2-O-acetylated alpha-Rhap, and beta-Quip4NAc residues. The following structure of the OPS was established: ->3)-alpha-l-Rha2OAc-(1->3)-beta-d-GlcNAc (1->3)-alpha-l-Rha2OAc-(1->3)-beta-d-GlcNAc-(1->2)-beta-d-Qui4NAc-(1->. PMID- 28088129 TI - In vitro eye irritation testing using the open source reconstructed hemicornea - a ring trial. AB - The aim of the present ring trial was to test whether two new methodological approaches for the in vitro classification of eye irritating chemicals can be reliably transferred from the developers' laboratories to other sites. Both test methods are based on the well-established open source reconstructed 3D hemicornea models. In the first approach, the initial depth of injury after chemical treatment in the hemicornea model is derived from the quantitative analysis of histological sections. In the second approach, tissue viability, as a measure for corneal damage after chemical treatment, is analyzed separately for epithelium and stroma of the hemicornea model. The three independent laboratories that participated in the ring trial produced their own hemicornea models according to the test producer's instructions, thus supporting the open source concept. A total of 9 chemicals with different physicochemical and eye-irritating properties were tested to assess the between-laboratory reproducibility (BLR), the predictive performance, as well as possible limitations of the test systems. The BLR was 62.5% for the first and 100% for the second method. Both methods enabled to discriminate Cat. 1 chemicals from all non-Cat. 1 substances, which qualifies them to be used in a top-down approach. However, the selectivity between No Cat. and Cat. 2 chemicals still needs optimization. PMID- 28088131 TI - Study Break: Number Crunching towards Molecular Barcoding PMID- 28088130 TI - Vaccine Candidates against Nontypeable Haemophilus influenzae: a Review AB - Nonencapsulated, nontypeable Hemophilus influenzae (NTHi) remains an important cause of acute otitis and respiratory diseases in children and adults. NTHi bacteria are one of the major causes of respiratory tract infections, including acute otitis media, cystic fibrosis, and community-acquired pneumonia among children, especially in developing countries. The bacteria can also cause chronic diseases such as chronic bronchitis and chronic obstructive pulmonary disease in the lower respiratory tract of adults. Such bacteria express several outer membrane proteins, some of which have been studied as candidates for vaccine development. Due to the lack of effective vaccines as well as the spread and prevalence of NTHi worldwide, there is an urgent need to design and develop effective vaccine candidates against these strains. PMID- 28088132 TI - Expression and Secretion of Cyan Fluorescent Protein (CFP) in B. subtilis using the Chitinase Promoter from Bacillus pumilus SG2 AB - Background: Improved cyan fluorescent protein (ICFP) is a monochromic, green fluorescent protein (GFP) derivative produced by Aequorea macrodactyla in a process similar to GFP. This protein has strong absorption spectra at wavelengths 426-446 nm. ICFP can be used in cell, organelle or intracellular protein labeling, investigating the protein-protein interactions as well as assessing the promoter activities. Methods: In our previous study, the promoters of two chitinases (ChiS and ChiL) from Bacillus pumilus SG2 were assessed in B. subtilis and their regulatory elements were characterized. In the present study, icfp was cloned downstream of several truncated promoters obtained in the former study, and ICFP expression was evaluated in B. subtilis. Results: Extracellular expression and secretion of ICFP were analyzed under the control of different truncated versions of ChiSL promoters grown on different media. Results from SDS PAGE and fluorimetric analyses showed that there were different expression rates of CFP; however, the UPChi-ICFP3 construct exhibited a higher level of expression and secretion in the culture medium. Conclusion: Our presented results revealed that inserting this truncated form of Chi promoter upstream of the ICFP, as a reporter gene, in B. subtilis led to an approximately ten fold increase in ICFP expression. PMID- 28088133 TI - Droplet growth during vapor-liquid transition in a 2D Lennard-Jones fluid. AB - Results for the kinetics of vapor-liquid phase transition have been presented from the molecular dynamics simulations of a single component two-dimensional Lennard-Jones fluid. The phase diagram for the model, primary prerequisite for this purpose, has been obtained via the Monte Carlo simulations. Our focus is on the region very close to the vapor branch of the coexistence curve. Quenches to such region provide morphology that consists of disconnected circular clusters in the vapor background. We identified that these clusters exhibit diffusive motion and grow via sticky collisions among them. The growth follows power-law behavior with time, exponent of which is found to be in nice agreement with a theoretical prediction. PMID- 28088134 TI - Dirac bubble potential for He-He and inadequacies in the continuum: Comparing an analytic model with elastic collision experiments. AB - We focus on the long-pending issue of the inadequacy of the Dirac bubble potential model in the description of He-He interactions in the continuum [L. L. Lohr and S. M. Blinder, Int. J. Quantum Chem. 53, 413 (1995)]. We attribute this failure to the lack of a potential wall to mimic the onset of the repulsive interaction at close range separations. This observation offers the explanation to why this excessively simple model proves incapable of quantitatively reproducing previous experimental findings of glory scattering in He-He, although being notorious for its capability of reproducing several distinctive features of the atomic and isotopic helium dimers and trimers [L. L. Lohr and S. M. Blinder, Int. J. Quantum Chem. 90, 419 (2002)]. Here, we show that an infinitely high, energy-dependent potential wall of properly calculated thickness rc(E) taken as a supplement to the Dirac bubble potential suffices for agreement with variable energy elastic collision cross section experiments for 4He-4He, 3He-4He, and 3He 3He [R. Feltgen et al., J. Chem. Phys. 76, 2360 (1982)]. In the very low energy regime, consistency is found between the Dirac bubble potential (to which our extended model is shown to reduce) and cold collision experiments [J. C. Mester et al., Phys. Rev. Lett. 71, 1343 (1993)]; this consistency, which in this regime lends credence to the Dirac bubble potential, was never noticed by its authors. The revised model being still analytic is of high didactical value while expected to increase in predictive power relative to other appraisals. PMID- 28088135 TI - Isomorphism between the multi-state Hamiltonian and the second-quantized many electron Hamiltonian with only 1-electron interactions. AB - We introduce the isomorphism between an multi-state Hamiltonian and the second quantized many-electron Hamiltonian (with only 1-electron interactions). This suggests that all methods developed for the former can be employed for the latter, and vice versa. The resonant level (Landauer) model for nonequilibrium quantum transport is used as a proof-of-concept example. Such as the classical mapping models for the multi-state Hamiltonian proposed in our previous work [J. Liu, J. Chem. Phys. 145, 204105 (2016)] lead to exact results for this model problem. We further demonstrate how these methods can also be applied to the second-quantized many-electron Hamiltonian even when 2-electron interactions are included. PMID- 28088136 TI - Pressure effects on structure and dynamics of metallic glass-forming liquid. AB - Although the structure and dynamics of metallic glass-forming liquids have been extensively investigated, studies of the pressure effects are rare. In the present study, the structural and dynamical properties of a ternary metallic liquid are systematically studied via extensive molecular dynamics simulations. Our results clearly show that, like isobaric cooling, isothermal compression could also slow down the dynamics of metallic liquid, leading to glass formation. However, the temperature- and pressure-induced glass transitions differ in the formation of local coordination structures and the variation of fragility. The increase of the kinetic fragility with increasing pressure is also accompanied by a monotonic structural fragility change. These findings may suggest a link between dynamics and structure. In addition, with increasing pressure, the dynamics becomes more heterogeneous, as revealed by the non-Gaussian parameter and dynamic correlation length. Here the length scales of both slow and fast domains are examined and discussed by analyzing the four-point dynamic structure factor associated with spatial correlations of atomic mobility. These correlation lengths coexist in the metallic liquids and grow comparatively in the considered temperature and pressure ranges. Finally, the scaling relation between the relaxation times and correlation lengths is discussed, which is found to be consistent with the spirit of Adam-Gibbs and random first-order transition theories. PMID- 28088137 TI - Forces on nuclei moving on autoionizing molecular potential energy surfaces. AB - Autoionization of molecular systems occurs in diatomic molecules and in small biochemical systems. Quantum chemistry packages enable calculation of complex potential energy surfaces (CPESs). The imaginary part of the CPES is associated with the autoionization decay rate, which is a function of the molecular structure. Molecular dynamics simulations, within the framework of the Born Oppenheimer approximation, require the definition of a force field. The ability to calculate the forces on the nuclei in bio-systems when autoionization takes place seems to rely on an understanding of radiative damages in RNA and DNA arising from the release of slow moving electrons which have long de Broglie wavelengths. This work addresses calculation of the real forces on the nuclei moving on the CPES. By using the transformation of the time-dependent Schrodinger equation, previously used by Madelung, we proved that the classical forces on nuclei moving on the CPES correlated with the gradient of the real part of the CPES. It was proved that the force on the nuclei of the metastable molecules is time independent although the probability to detect metastable molecules exponentially decays. The classical force is obtained from the transformed Schrodinger equation when h=0 and the Schrodinger equation is reduced to the classical (Newtonian) equations of motion. The forces on the nuclei regardless on what potential energy surface they move (parent CPES or product real PESs) vary in time due to the autoionization process. PMID- 28088138 TI - Fast simulation of Brownian dynamics in a crowded environment. AB - Brownian dynamics simulations are an increasingly popular tool for understanding spatially extended biochemical reaction systems. Recent improvements in our understanding of the cellular environment show that volume exclusion effects are fundamental to reaction networks inside cells. These systems are frequently studied by incorporating inert hard spheres (crowders) into three-dimensional Brownian dynamics (BD) simulations; however these methods are extremely slow owing to the sheer number of possible collisions between particles. Here we propose a rigorous "crowder-free" method to dramatically increase the simulation speed for crowded biochemical reaction systems by eliminating the need to explicitly simulate the crowders. We consider both the cases where the reactive particles are point particles, and where they themselves occupy a volume. Using simulations of simple chemical reaction networks, we show that the "crowder-free" method is up to three orders of magnitude faster than conventional BD and yet leads to nearly indistinguishable results from the latter. PMID- 28088139 TI - Long-range interactions from the many-pair expansion: A different avenue to dispersion in DFT. AB - One of the several problems that plague majority of density functional theory calculations is their inability to properly account for long-range correlations giving rise to dispersion forces. The recently proposed many-pair expansion (MPE) [T. Zhu et al., Phys. Rev. B 93, 201108(R) (2016)] is a hierarchy of approximations that systematically corrects any deficiencies of an approximate functional to finally converge to the exact energy. This is achieved by decomposing the total density into a sum of two-electron densities and accounting for successive two-, four-, six-,... electron interactions. Here, we show that already low orders of MPE expansion recover the dispersion energy accurately. To this end, we employ the Pariser-Parr-Pople Hamiltonian and study the behavior of long-range interactions in trans-polyacetylene as well as stacks of ethylene and benzene molecules. We also show how convergence of the expansion is affected by electron conjugation and the choice of the density partitioning. PMID- 28088140 TI - Ring-polymer molecular dynamics studies on the rate coefficient of the abstraction channel of hydrogen plus ethane, propane, and dimethyl ether. AB - To accurately compute the rates of the abstraction channels of hydrogen plus ethane (Et), propane (Pr), and dimethyl ether (DME), ring-polymer molecular dynamics (RPMD) method is used in conjunction with the recently constructed local permutation invariant polynomial neural-networks potential energy surface of the parent H + CH4 system [Q. Meng et al., J. Chem. Phys. 144, 154312 (2016)]. For H + Et, one of the H atoms in CH4 of the parent system is replaced by a methyl group, while for the H + DME reaction, it is replaced by the methoxyl group. For the H + Pr reaction, replacing one of the H atoms in CH4 by an ethyl group, the terminal channel is built, meanwhile the middle channel is considered through replacing two H atoms in CH4 by two methyl groups. Since the potential energy barriers of the title reactions must differ from the H + CH4 barrier, the corrections have to be made by computing the ratio of free-energy barriers between H + CH4 and the title reactions at coupled cluster with a full treatment singles and doubles (where the triples contribution is calculated by perturbation theory, that is, CCSD(T)) level. Comparing the present RPMD rates with the previous theoretical and experimental results, good agreement can be found. Moreover, probable reasons for the deviation between the present RPMD rates and the previous experimental ones are discussed. PMID- 28088141 TI - Determination of accurate, mean bond lengths from radial distribution functions. AB - The mean bond length d between a central atom and its nearest neighbors can be estimated from the position of the first peak in the radial distribution function g(r). However, as we demonstrate here, this estimate does not allow one to deduce temperature-induced changes in d. Instead, skewness has to be included into the analysis, which can be achieved, for example, via the skew normal distribution (SND). Fits to the first peak using the SND give bond length in good agreement with direct measurements of nearest-neighbor distribution functions in crystals as well as with a Voronoi-tessellation based detection of nearest-neighbors in liquids. While the location of the first peak in g(r) may shift to smaller values with increasing temperature for three studied liquids-argon, copper, and the bulk metallic-glass (BMG) forming alloy Zr60Cu30Al10-we find our improved estimates of d to systematically increase with temperature in all cases. Recent conclusions on temperature-induced bond contractions in simple metallic or BMG-forming liquids may therefore have arisen from the neglect of skewness effects. PMID- 28088142 TI - Colloidal transport by active filaments. AB - Enhanced colloidal transport beyond the limit imposed by diffusion is usually achieved through external fields. Here, we demonstrate the ballistic transport of a colloidal sphere using internal sources of energy provided by an attached active filament. The latter is modeled as a chain of chemo-mechanically active beads connected by potentials that enforce semi-flexibility and self-avoidance. The fluid flow produced by the active beads and the forces they mediate are explicitly taken into account in the overdamped equations of motion describing the colloid-filament assembly. The speed and efficiency of transport depend on the dynamical conformational states of the filament. We characterize these states using filament writhe as an order parameter and identify ones yielding maxima in speed and efficiency of transport. The transport mechanism reported here has a remarkable resemblance to the flagellar propulsion of microorganisms which suggests its utility in biomimetic systems. PMID- 28088143 TI - Fokker-Planck quantum master equation for mixed quantum-semiclassical dynamics. AB - We revisit Caldeira-Leggett's quantum master equation representing mixed quantum classical theory, but with limited applications. Proposed is a Fokker-Planck quantum master equation theory, with a generic bi-exponential correlation function description on semiclassical Brownian oscillators' environments. The new theory has caustic terms that bridge between the quantum description on primary systems and the semiclassical or quasi-classical description on environments. Various parametrization schemes, both analytical and numerical, for the generic bi-exponential environment bath correlation functions are proposed and scrutinized. The Fokker-Planck quantum master equation theory is of the same numerical cost as the original Caldeira-Leggett's approach but acquires a significantly broadened validity and accuracy range, as illustrated against the exact dynamics on model systems in quantum Brownian oscillators' environments, at moderately low temperatures. PMID- 28088144 TI - More room for microphase separation: An extended study on binary liquids confined in SBA-15 cylindrical pores. AB - The confinement of liquid mixtures in porous channels provides new insight into fluid ordering at the nanoscale. In this study, we address a phenomenon of microphase separation, which appears as a novel fascinating confinement effect for fully miscible binary liquids. We investigate the structure of tert-butanol toluene mixtures confined in the straight and mono-dispersed cylindrical nanochannels of SBA-15 mesoporous silicates (D = 8.3 nm). Small angle neutron scattering experiments on samples with carefully designed isotopic compositions are performed to systematically vary the scattering length density of the different compounds and assess the radial concentration profile of the confined phases. The resulting modulation of the Bragg reflections of SBA-15 is compared with the predictions from different core-shell models, highlighting a molecular scale phase-separated tubular structure with the tert-butanol forming a layer at the pore surface, surrounding a toluene-rich core. The present structural study suggests that the microphase separation phenomenon in confinement, which so far had only been reported for a smaller pore size (D = 3.65 nm) and a unique mixture composition, must be considered as a general phenomenon. It also highlights the strength of neutron scattering method with isotopic substitution, which is a unique experimental approach to reveal this phenomenon. PMID- 28088145 TI - A generalized Ewald decomposition for screened Coulomb interactions. AB - Medium-range interactions occur in a wide range of systems, including charged particle systems with varying screening lengths. We generalize the Ewald method to charged systems described by interactions involving an arbitrary dielectric response function epsilon(??). We provide an error estimate and optimize the generalization to find the break-even parameters that separate a neighbor list only algorithm from the particle-particle particle-mesh algorithm. We examine the implications of different choices of the screening length for the computational cost of computing the dynamic structure factor. We then use our new method in molecular dynamics simulations to compute the dynamic structure factor for a model plasma system and examine the wave-dispersion properties of this system. PMID- 28088147 TI - Hopping charge transport in amorphous semiconductors with the spatially correlated exponential density of states. AB - Hopping charge transport in amorphous semiconductors having spatially correlated exponential density of states has been considered. Average carrier velocity is exactly calculated for the quasi-equilibrium (nondispersive) transport regime. We suggest also a heuristic approach for the consideration of the carrier velocity for the non-equilibrium dispersive regime. PMID- 28088146 TI - Photoinduced C-I bond homolysis of 5-iodouracil: A singlet predissociation pathway. AB - 5-Iodouracil (5-IU) can be integrated into DNA and acts as a UV sensitive chromophore suitable for probing DNA structure and DNA-protein interactions based on the photochemical reactions of 5-IU. Here, we perform joint studies of time resolved Fourier transform infrared (TR-FTIR) spectroscopy and ab initio calculations to examine the state-specific photochemical reaction mechanisms of the 5-IU. The fact that uracil (U) is observed in TR-FTIR spectra after 266 nm irradiation of 5-IU in acetonitrile and ascribed to the product of hydrogen abstraction by the uracil-5-yl radical (U.) provides experimental evidence for the C-I bond homolysis of 5-IU. The excited state potential energy curves are calculated with the complete active space second-order perturbation//complete active space self-consistent field method, from which a singlet predissociation mechanism is elucidated. It is shown that the initially populated 1(pipi*) state crosses with the repulsive 1(pisigma*) or 1(nIsigma*) state, through which 5-IU undergoes dissociation to the fragments of (U.) radical and iodine atom. In addition, the possibility of intersystem crossing (ISC) is evaluated based on the calculated vertical excitation energies. Although a probable ISC from 1(pipi*) state to 3(nOpi*) and then to the lowest triplet 3(pipi*) could occur in principal, there is little possibility for the excited state populations bifurcating to triplet manifold, given that the singlet state predissociation follows repulsive potential and should occur within dozens to hundreds of femtoseconds. Such low population of triplet states means that the contribution of triplet state to photoreactions of 5-IU should be quite minor. These results demonstrate clearly a physical picture of C-I bond homolysis of 5-IU and provide mechanistic illuminations to the interesting applications of 5-IU as photoprobes and in radiotherapy of cancer. PMID- 28088148 TI - Lithium ion micrometer diffusion in a garnet-type cubic Li7La3Zr2O12 (LLZO) studied using 7Li NMR spectroscopy. AB - Mobile lithium ions in a cubic garnet Li7La3Zr2O12 (Al-stabilized) were studied using 7Li NMR spectroscopy for membrane and powder samples, the latter of which was ground from the membrane. Lithium diffusion in a micrometer space was measured using the pulsed-gradient spin-echo 7Li NMR method between 70 and 130 degrees C. When the observation time (Delta) was shorter than 20 ms, the echo attenuation showed diffusive diffraction patterns, indicating that the Li+ diffusing space is not free but restricted. For longer Delta, the values of apparent diffusion constant (Dapparent) became gradually smaller to approach an equilibrated value (close to a tracer diffusion constant). In addition, the Dapparent depends on the pulse field gradient strength (g) and became smaller as g became larger. These experimental results suggest that the lithium ions diffuse through Li+ pathways surrounded by stationary anions and lithium ions, and are affected by collisions and diffractions. One-dimensional profiles of the membrane sample of thickness 0.5 mm were observed from 65 to 110 degrees C and the area intensity, as well as the lithium occurrence near the surface, increased with the increase in temperature. The temperature-dependent area intensity showed a correspondence to the number of Li+ carrier ions estimated from the ionic conductivity and the equilibrated diffusion constant through the Nernst-Einstein relationship. PMID- 28088149 TI - Collective excitations in liquid dimethyl sulfoxide (DMSO): FIR spectrum, low frequency vibrational density of states, and ultrafast dipolar solvation dynamics. AB - Valuable dynamical and structural information about neat liquid DMSO at ambient conditions can be obtained through a study of low frequency vibrations in the far infrared (FIR), that is, terahertz regime. For DMSO, collective excitations as well as single molecule stretches and bends have been measured by different kinds of experiments such as OHD-RIKES and terahertz spectroscopy. In the present work, we investigate the intermolecular vibrational spectrum of DMSO through three different computational techniques namely (i) the far-infrared spectrum obtained through the Fourier transform of total dipole moment auto-time correlation function, (ii) from the Fourier transform of the translational and angular velocity time autocorrelation functions, and (iii) a quenched normal mode analysis of the parent liquid at 300 K. The three spectra, although exhibit differences among each other, reveal similar features which are in good, semi quantitative, agreement with experimental results. The study of participation ratio of the density of states obtained from the normal mode analysis shows that the broad spectrum around 100 cm-1 involves collective oscillations of 300-400 molecules. Dipolar solvation dynamics exhibit ultrafast energy relaxation with an initial time constant around 157 fs which can be attributed to the coupling to the collective excitations. We compare the properties of DMSO with those of water vis-a-vis the existence of the low frequency collective modes. Last, we find that the collective excitation spectrum exhibits strong temperature dependence. PMID- 28088150 TI - Optimal orientation of an asymmetric top molecule with terahertz pulses. AB - Terahertz pulses effects are investigated in an asymmetric top C2v molecule using numerical simulations. The average value of the direction cosine PhiZx is computed solving the time dependent Schrodinger equation for several types of pulses. The H2S molecule taken as a test case is first subject to two short terahertz pulses with a duration smaller than 5 ps, an identical maximum value of the electric field of 2 MV/cm, but a different shape. The thermal average ??PhiZx?? is calculated for several temperatures, and non-periodic time variations are found even for the lowest temperature. For a given temperature, the maximum orientation achieved is shown to be dependent on the overlap between the absorption spectrum of the molecule and the Fourier transform of the pulse. The maximum orientation is also shown to be closely related to the molecular energy increase. In a second step, the optimal control theory is used to build a 14 ps long few-cycle pulse with the same maximum value of the electric field allowing us to reach a large maximum value of ?PhiZx? equal to 0.93. A fairly good understanding of the wavefunction describing the molecule after the pulse was achieved. PMID- 28088151 TI - Phase transition of a symmetric diblock copolymer induced by nanorods with different surface chemistry. AB - We investigate the phase transition of a symmetric diblock copolymer induced by nanorods with different surface chemistry. The results demonstrate that the system occurs the phase transition from a disordered structure to ordered parallel lamellae and then to the tilted layered structure as the number of rods increases. The dynamic evolution of the domain size and the order parameter of the microstructure are also examined. Furthermore, the influence of rod property, rod-phase interaction, rod-rod interaction, rod length, and polymerization degree on the behavior of the polymer system is also investigated systematically. Moreover, longer amphiphilic nanorods tend to make the polymer system form the hexagonal structure. It transforms into a perpendicular lamellar structure as the polymerization degree increases. Our simulations provide an efficient method for determining how to obtain the ordered structure on the nanometer scales and design the functional materials with optical, electronic, and magnetic properties. PMID- 28088152 TI - Theoretical description of circular dichroism in photoelectron angular distributions of randomly oriented chiral molecules after multi-photon photoionization. AB - Photoelectron circular dichroism refers to the forward/backward asymmetry in the photoelectron angular distribution with respect to the propagation axis of circularly polarized light. It has recently been demonstrated in femtosecond multi-photon photoionization experiments with randomly oriented camphor and fenchone molecules [C. Lux et al., Angew. Chem., Int. Ed. 51, 4755 (2012) and C. S. Lehmann et al., J. Chem. Phys. 139, 234307 (2013)]. A theoretical framework describing this process as (2+1) resonantly enhanced multi-photon ionization is constructed, which consists of two-photon photoselection from randomly oriented molecules and successive one-photon ionization of the photoselected molecules. It combines perturbation theory for the light-matter interaction with ab initio calculations for the two-photon absorption and a single-center expansion of the photoelectron wavefunction in terms of hydrogenic continuum functions. It is verified that the model correctly reproduces the basic symmetry behavior expected under exchange of handedness and light helicity. When applied to fenchone and camphor, semi-quantitative agreement with the experimental data is found, for which a sufficient d wave character of the electronically excited intermediate state is crucial. PMID- 28088153 TI - Signatures of spatially correlated noise and non-secular effects in two dimensional electronic spectroscopy. AB - We investigate how correlated fluctuations affect oscillatory features in rephasing and non-rephasing two-dimensional (2D) electronic spectra of a model dimer system. Based on a beating map analysis, we show that non-secular environmental couplings induced by uncorrelated fluctuations lead to oscillations centered at both cross- and diagonal-peaks in rephasing spectra as well as in non rephasing spectra. Using an analytical approach, we provide a quantitative description of the non-secular effects in terms of the Feynman diagrams and show that the environment-induced mixing of different inter-excitonic coherences leads to oscillations in the rephasing diagonal-peaks and non-rephasing cross-peaks. We demonstrate that as correlations in the noise increase, the lifetime of oscillatory 2D signals is enhanced at rephasing cross-peaks and non-rephasing diagonal-peaks, while the other non-secular oscillatory signals are suppressed. We discuss that the asymmetry of 2D lineshapes in the beating map provides information on the degree of correlations in environmental fluctuations. Finally we investigate how the oscillatory features in 2D spectra are affected by inhomogeneous broadening. PMID- 28088154 TI - Vibrational properties of anhydrous and partially hydrated uranyl fluoride. AB - Uranyl fluoride (UO2F2) is a hygroscopic powder with two main structural phases: an anhydrous crystal and a partially hydrated crystal of the same R3-m symmetry. The formally closed-shell electron structure of anhydrous UO2F2 is amenable to density functional theory calculations. We use density functional perturbation theory (DFPT) to calculate the vibrational frequencies of the anhydrous crystal structure and employ complementary inelastic neutron scattering and temperature dependent Raman scattering to validate those frequencies. As a model closed-shell actinide, we investigated the effect of LDA, GGA, and non-local vdW functionals as well as the spherically averaged Hubbard +U correction on vibrational frequencies, electronic structure, and geometry of anhydrous UO2F2. A particular choice of Ueff=5.5 eV yields the correct U-Oyl bond distance and vibrational frequencies for the characteristic Eg and A1g modes that are within the resolution of experiment. Inelastic neutron scattering and Raman scattering suggest a degree of water coupling to the lattice vibrations in the more experimentally accessible partially hydrated UO2F2 system, with the symmetric stretching vibration shifted approximately 47 cm-1 lower in energy compared to the anhydrous structure. Evidence of water interaction with the uranyl ion is present from a two-peak decomposition of the uranyl stretching vibration in the Raman spectra and anion-hydrogen stretching vibrations in the inelastic neutron scattering spectra. A first-order dehydration phase transition temperature is definitively identified to be 125 degrees C using temperature-dependent Raman scattering. PMID- 28088155 TI - Signal replication in a DNA nanostructure. AB - Logic circuits based on DNA strand displacement reaction are the basic building blocks of future nanorobotic systems. The circuits tethered to DNA origami platforms present several advantages over solution-phase versions where couplings are always diffusion-limited. Here we consider a possible implementation of one of the basic operations needed in the design of these circuits, namely, signal replication. We show that with an appropriate preparation of the initial state, signal replication performs in a reproducible way. We also show the existence of side effects concomitant to the high effective concentrations in tethered circuits, such as slow leaky reactions and cross-activation. PMID- 28088156 TI - Path integral approach to the Wigner representation of canonical density operators for discrete systems coupled to harmonic baths. AB - We derive a semi-analytical form for the Wigner transform for the canonical density operator of a discrete system coupled to a harmonic bath based on the path integral expansion of the Boltzmann factor. The introduction of this simple and controllable approach allows for the exact rendering of the canonical distribution and permits systematic convergence of static properties with respect to the number of path integral steps. In addition, the expressions derived here provide an exact and facile interface with quasi- and semi-classical dynamical methods, which enables the direct calculation of equilibrium time correlation functions within a wide array of approaches. We demonstrate that the present method represents a practical path for the calculation of thermodynamic data for the spin-boson and related systems. We illustrate the power of the present approach by detailing the improvement of the quality of Ehrenfest theory for the correlation function Czz(t)=Re?sigmaz(0)sigmaz(t)? for the spin-boson model with systematic convergence to the exact sampling function. Importantly, the numerically exact nature of the scheme presented here and its compatibility with semiclassical methods allows for the systematic testing of commonly used approximations for the Wigner-transformed canonical density. PMID- 28088158 TI - Infrared spectra and band strengths of amorphous and crystalline N2O. AB - Infrared transmission spectra from 4000 to 400 cm-1, and associated band strengths and absorption coefficients, are presented for the first time for both amorphous and crystalline N2O. Changes in the spectra as a function of ice thickness and ice temperature are shown. New measurements of density, refractive index, and specific refraction are reported for amorphous and crystalline N2O. Comparisons are made to published results, and the most-likely reason for some recent disagreements in the literature is discussed. As with CO2, its isoelectronic congener, the formation of amorphous N2O is found to require greater care than the formation of amorphous solids from more-polar molecules. PMID- 28088157 TI - Stochastic thermodynamics of a chemical nanomachine: The channeling enzyme tryptophan synthase. AB - The enzyme tryptophan synthase is characterized by a complex pattern of allosteric interactions that regulate the catalytic activity of its two subunits and opening or closing of their ligand gates. As a single macromolecule, it implements 13 different reaction steps, with an intermediate product directly channeled from one subunit to another. Based on experimental data, a stochastic model for the operation of tryptophan synthase has been earlier constructed [D. Loutchko, D. Gonze, and A. S. Mikhailov, J. Phys. Chem. B 120, 2179 (2016)]. Here, this model is used to consider stochastic thermodynamics of such a chemical nanomachine. The Gibbs energy landscape of the internal molecular states is determined, the production of entropy and its flow within the enzyme are analyzed, and the information exchange between the subunits resulting from allosteric cross-regulations and channeling is discussed. PMID- 28088159 TI - Symmetry and magnetism in Ni9Te6 clusters ligated by CO or phosphine ligands. AB - The removal of a single ligand from the magnetic Ni9Te6(L)8 (L = P(CH3)3, CO) clusters is found to quench the magnetic moment. The reduction in magnetic moment is caused by a geometric deformation of the Ni9Te6 core that breaks the octahedral symmetry of the cluster. This effect is observed in both the CO and phosphine based ligands. The octahedral symmetry bare cluster is also found to have a large magnetic moment. These results highlight the dilemma faced by magnetic ligand protected clusters whose symmetry has been broken: whether to break the spin symmetry as in Hund's rules or to break the spatial symmetry as in the Jahn-Teller effect. The spatial symmetry breaking is found to be an oblate distortion that forms additional Ni-Te bonds resulting in the enhanced stability of the cluster. PMID- 28088160 TI - Photofragment ion imaging from mass-selected Mg+BrCH3 complex: Dissociation mechanism following photoinduced charge transfer. AB - We have observed fragment ion images produced by ultraviolet photodissociation of Mg+BrCH3 complex ions using a reflectron time-of-flight mass spectrometer combined with an imaging detector. The BrCH3+ fragment ion was produced after the 266-nm excitation of Mg+BrCH3. In the image of the BrCH3+ ions, a split distribution was observed parallel to the polarization direction of the photolysis laser. In calculated potential energy curves, we found a repulsive potential correlated with a dissociation limit of Mg + BrCH3+: The calculation results indicate that the dissociation and the charge transfer occurred via non adiabatic process after the 52A' <- 12A' photoexcitation. The obtained energy and angular distributions of BrCH3+ photofragments were consistent with the fast BrCH3+ formation process on the repulsive potential energy curve. PMID- 28088161 TI - Efficient free energy calculations by combining two complementary tempering sampling methods. AB - Although energy barriers can be efficiently crossed in the reaction coordinate (RC) guided sampling, this type of method suffers from identification of the correct RCs or requirements of high dimensionality of the defined RCs for a given system. If only the approximate RCs with significant barriers are used in the simulations, hidden energy barriers with small to medium height would exist in other degrees of freedom (DOFs) relevant to the target process and consequently cause the problem of insufficient sampling. To address the sampling in this so called hidden barrier situation, here we propose an effective approach to combine temperature accelerated molecular dynamics (TAMD), an efficient RC-guided sampling method, with the integrated tempering sampling (ITS), a generalized ensemble sampling method. In this combined ITS-TAMD method, the sampling along the major RCs with high energy barriers is guided by TAMD and the sampling of the rest of the DOFs with lower but not negligible barriers is enhanced by ITS. The performance of ITS-TAMD to three systems in the processes with hidden barriers has been examined. In comparison to the standalone TAMD or ITS approach, the present hybrid method shows three main improvements. (1) Sampling efficiency can be improved at least five times even if in the presence of hidden energy barriers. (2) The canonical distribution can be more accurately recovered, from which the thermodynamic properties along other collective variables can be computed correctly. (3) The robustness of the selection of major RCs suggests that the dimensionality of necessary RCs can be reduced. Our work shows more potential applications of the ITS-TAMD method as the efficient and powerful tool for the investigation of a broad range of interesting cases. PMID- 28088162 TI - Molecular collisions and reactive scattering in external fields: Are field induced couplings important at short range? AB - We use accurate quantum scattering calculations to elucidate the role of short range molecule-field interactions in atom-molecule inelastic collisions and abstraction chemical reactions at low temperatures. We consider two examples: elastic and inelastic scattering of NH(Sigma3) molecules with Mg(S1) atoms in a magnetic field; reactive scattering LiF + H -> Li + HF in an electric field. Our calculations suggest that, for non-reactive collision systems and abstraction chemical reactions, the molecule-field interactions cannot generally be neglected at short range because the atom-molecule potential passes through zero at short range. An important exception occurs for Zeeman transitions in atom-molecule collisions at magnetic fields ?1000 G, for which the molecule-field couplings need only be included at large rho outside the range of the atom-molecule interaction. Our results highlight the importance of an accurate description of rho-dependent molecule-field interactions in quantum scattering calculations on molecular collisions and chemical reactions at low temperatures. PMID- 28088163 TI - Note: Determine entanglement length through monomer mean-square displacement. AB - I present a refined version of the method for determining entanglement length through monomer mean-square displacement. By retrieving a prefactor pi/2 that might be lost in previous derivation, the entanglement length of the standard bead-spring model estimated by this method coincides with the measurements of other methods. PMID- 28088164 TI - Photochemical generation of H2NCNX, H2NNCX, H2NC(NX) (X = O, S) in low temperature matrices. AB - The [NH2, C, N, O] and the [NH2, C, N, S] molecular systems were investigated by computational and matrix-isolation spectroscopic methods. The determination of the equilibrium structures and relative energies by CCSD(T) method was followed by the computation of the harmonic and anharmonic vibrational wavenumbers, infrared intensities, relative Raman activities, and UV excitation energies. These computed data were used to assist the identification of products obtained by UV laser photolysis of 3,4-diaminofurazan and 3,4-diaminothiadiazole in low temperature Ar and Kr matrices. It is shown that two open-chain H2NNCX and H2NCNX and one cyclic H2NC(NX) (X = O, S) isomers are generated in the case of both systems. Except for H2NNCO and H2NCNS, the present study reports the first generation and spectroscopic identification of these compounds. PMID- 28088165 TI - Genomic characterization of Ensifer aridi, a proposed new species of nitrogen fixing rhizobium recovered from Asian, African and American deserts. AB - BACKGROUND: Nitrogen fixing bacteria isolated from hot arid areas in Asia, Africa and America but from diverse leguminous plants have been recently identified as belonging to a possible new species of Ensifer (Sinorhizobium). In this study, 6 strains belonging to this new clade were compared with Ensifer species at the genome-wide level. Their capacities to utilize various carbon sources and to establish a symbiotic interaction with several leguminous plants were examined. RESULTS: Draft genomes of selected strains isolated from Morocco (Merzouga desert), Mexico (Baja California) as well as from India (Thar desert) were produced. Genome based species delineation tools demonstrated that they belong to a new species of Ensifer. Comparison of its core genome with those of E. meliloti, E. medicae and E. fredii enabled the identification of a species conserved gene set. Predicted functions of associated proteins and pathway reconstruction revealed notably the presence of transport systems for octopine/nopaline and inositol phosphates. Phenotypic characterization of this new desert rhizobium species showed that it was capable to utilize malonate, to grow at 48 degrees C or under high pH while NaCl tolerance levels were comparable to other Ensifer species. Analysis of accessory genomes and plasmid profiling demonstrated the presence of large plasmids that varied in size from strain to strain. As symbiotic functions were found in the accessory genomes, the differences in symbiotic interactions between strains may be well related to the difference in plasmid content that could explain the different legumes with which they can develop the symbiosis. CONCLUSIONS: The genomic analysis performed here confirms that the selected rhizobial strains isolated from desert regions in three continents belong to a new species. As until now only recovered from such harsh environment, we propose to name it Ensifer aridi. The presented genomic data offers a good basis to explore adaptations and functionalities that enable them to adapt to alkalinity, low water potential, salt and high temperature stresses. Finally, given the original phylogeographic distribution and the different hosts with which it can develop a beneficial symbiotic interaction, Ensifer aridi may provide new biotechnological opportunities for degraded land restoration initiatives in the future. PMID- 28088166 TI - Impact of home care versus alternative locations of care on elder health outcomes: an overview of systematic reviews. AB - BACKGROUND: Many elders struggle with the decision to remain at home or to move to an alternative location of care. A person's location of care can influence health and wellbeing. Healthcare organizations and policy makers are increasingly challenged to better support elders' dwelling and health care needs. A summary of the evidence that examines home care compared to other care locations can inform decision making. We surveyed and summarized the evidence evaluating the impact of home care versus alternative locations of care on elder health outcomes. METHODS: We conducted an overview of systematic reviews. Data sources included MEDLINE, the Cochrane Library, EMBASE, and CINAHL. Eligible reviews included adults 65+ years, elder home care, alternative care locations, and elder health outcomes. Two independent reviewers screened citations. We extracted data and appraised review quality using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) checklist. Results were synthesized narratively. RESULTS: The search yielded 2575 citations, of which 19 systematic reviews were eligible. Three hundred and forty studies with 271,660 participants were synthesized across the systematic reviews. The categories of comparisons included: home with support versus independent living at home (n = 11 reviews), home care versus institutional care (n = 3 reviews), and rehabilitation at home versus conventional rehabilitation services (n = 7 reviews). Two reviews had data relevant to two categories. Most reviews favoured home with support to independent living at home. Findings comparing home care to institutional care were mixed. Most reviews found no differences in health outcomes between rehabilitation at home versus conventional rehabilitation services. Systematic review quality was moderate, with a median AMSTAR score of 6 (range 4 - 10 out of 11). CONCLUSIONS: The evidence on the impact of home care compared to alternative care locations on elder health outcomes is heterogeneous. Our findings support positive health impacts of home support interventions for community dwelling elders compared to independent living at home. There is insufficient evidence to determine the impact of alternative care locations on elders' health. Additional research targeting housing and care options for the elderly is needed. PMID- 28088167 TI - Randomized, double-blind, placebo-controlled clinical trial to assess the safety and effectiveness of a novel dual-action oral topical formulation against upper respiratory infections. AB - BACKGROUND: Current prevention options for upper respiratory infections (URIs) are not optimal. We conducted a randomized, double-blinded, placebo-controlled pilot clinical trial to evaluate the safety and efficacy of ARMS-ITM (currently marketed as HaloTM) in the prevention of URIs. METHODS: ARMS-I is patented novel formulation for the prevention and treatment of influenza, comprising a broad spectrum antimicrobial agent (cetylpyridinium chloride, CPC) and components (glycerin and xanthan gum) that form a barrier on the host mucosa, thus preventing viral contact and invasion. Healthy adults (18-45 years of age) were randomized into ARMS-I or placebo group (50 subjects each). The drug was sprayed intra-orally (3* daily) for 75 days. The primary objectives were to establish whether ARMS-I decreased the frequency, severity or duration of URIs. Secondary objectives were to evaluate safety, tolerability, rate of virus detection, acceptability and adherence; effect on URI-associated absenteeism and medical visits; and effect of prior influenza vaccination on study outcomes. RESULTS: Of the 94 individuals who completed the study (placebo: n = 44, ARMS-I: n = 50), six presented with confirmed URI (placebo: 4, ARMS-I: 2), representing a 55% relative reduction, albeit this was statistically not significant). Influenza, coronavirus or rhinovirus were detected in three participants; all in the placebo group. Moreover, frequency of post-treatment exit visits was reduced by 55% in ARMS-I compared to the placebo group (N = 4 and 2, respectively). Fever was reported only in the placebo group. ARMS-I significantly reduced the frequency and severity of cough and sore throat, and duration of cough (P <= .019 for all comparisons). ARMS-I was safe, well tolerated, had high acceptability and high adherence to medication use. Medical visits occurred only in the placebo group while absenteeism did not differ between the two arms. Prior influenza vaccination had no effect on study outcome. CONCLUSIONS: This randomized proof-of concept clinical trial demonstrated that ARMS-I tended to provide protection against URIs in the enrolled study participants, while reducing severity and duration of cough and sore throat. A clinical trial with a larger number of study participants is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT02644135 (retrospectively registered). PMID- 28088168 TI - Do nursing staff encourage functional activity among nursing home residents? A cross-sectional study of nursing staff perceived behaviors and associated factors. AB - BACKGROUND: Nursing home residents are mainly inactive. Nursing staff can encourage residents to perform functional activities during daily care activities. This study examines 1) the extent to which nursing staff perceive that they encourage functional activity in nursing home residents and 2) the associations between these nursing behaviors and professional characteristics, contextual factors, and information-seeking behaviors. METHODS: In this cross sectional study, 368 registered nurses and certified nurse assistants, working in somatic and psychogeriatric wards of forty-one nursing homes throughout the Netherlands participated. Self-reported data were collected with a questionnaire, comprising the MAINtAIN-behaviors, which assesses the extent to which nursing staff encourage functional activities, including different activities of daily living (ADL), household activities, and miscellaneous encouraging activities (e.g., discouraging informal caregivers from taking over activities residents can do themselves). Additional data collected included professional characteristics (e.g., age), contextual factors (e.g., ward type), and information-seeking behaviors (e.g., reading professional journals). Descriptive statistics were used to determine the extent to which functional activities were encouraged. Hierarchical linear regression analyses were performed to determine the associations between the encouragement of functional activities and other factors. RESULTS: Nursing staff perceived that household activities (mean 4.1 (scale range 1-9), SD 1.9) were less often encouraged than ADL (mean 6.9, SD 1.2) or miscellaneous activities (mean 6.7, SD 1.5). The percentage of nursing staff stating that different household activities, ADL, or miscellaneous activities were almost always encouraged ranged from 11 to 45%, 41 to 86%, and 50 to 83% per activity, respectively. The extent to which these activities were encouraged differed for some of the professional characteristics, contextual factors, or information-seeking behaviors, but no consistent pattern in associations emerged. CONCLUSIONS: According to nursing staff, household activities are not as often encouraged as ADL or miscellaneous activities. Professional characteristics, contextual factors, and information-seeking behaviors are not consistently associated with the encouragement of functional activity. Nursing staff should also focus on improving the encouragement of household activities. Future research could examine the role of other factors in encouraging functional activity, such as experienced barriers, and assess to what extent the perception of nursing staff corresponds with their actual behavior. PMID- 28088169 TI - Tenosynovitis caused by Scedosporium apiospermum infection misdiagnosed as an Alternaria species: a case report. AB - BACKGROUND: Scedosporium apiospermum, which can usually be isolated from soil, polluted stream water and decaying vegetation, is increasingly recognized as an opportunistic dematiaceous fungus. The mortality rate of infection in immunocompromised hosts is over 50%. S. apiospermum is commonly responsible for dermal and epidermal infections (i.e., mycetoma) after traumatic penetration. CASE PRESENTATION: A 73-year-old woman was admitted to our hospital complaining of painful swelling and tenderness on the dorsum of the proximal left wrist and hand. The symptoms had persisted for approximately 2 months. A physical examination revealed a 4 x 3 cm, poorly defined, erythematous papule, which was fluctuant, with pustules and crusts on the dorsum of the left hand. CONCLUSIONS: We report a very rare case of tenosynovitis caused by S. apiospermum infection. We identified the infectious agent via molecular DNA sequencing. The infectious agent was initially misidentified as an Alternaria species by microscopic examination with lactophenol cotton blue (LPCB) staining. The infection was successfully treated with debridement and adjuvant fluconazole therapy. PMID- 28088170 TI - Application of a Bayesian dominance model improves power in quantitative trait genome-wide association analysis. AB - BACKGROUND: Multi-marker methods, which fit all markers simultaneously, were originally tailored for genomic selection purposes, but have proven to be useful also in association analyses, especially the so-called BayesC Bayesian methods. In a recent study, BayesD extended BayesC towards accounting for dominance effects and improved prediction accuracy and persistence in genomic selection. The current study investigated the power and precision of BayesC and BayesD in genome-wide association studies by means of stochastic simulations and applied these methods to a dairy cattle dataset. METHODS: The simulation protocol was designed to mimic the genetic architecture of quantitative traits as realistically as possible. Special emphasis was put on the joint distribution of the additive and dominance effects of causative mutations. Additive marker effects were estimated by BayesC and additive and dominance effects by BayesD. The dependencies between additive and dominance effects were modelled in BayesD by choosing appropriate priors. A sliding-window approach was used. For each window, the R. Fernando window posterior probability of association was calculated and this was used for inference purpose. The power to map segregating causal effects and the mapping precision were assessed for various marker densities up to full sequence information and various window sizes. RESULTS: Power to map a QTL increased with higher marker densities and larger window sizes. This held true for both methods. Method BayesD had improved power compared to BayesC. The increase in power was between -2 and 8% for causative genes that explained more than 2.5% of the genetic variance. In addition, inspection of the estimates of genomic window dominance variance allowed for inference about the magnitude of dominance at significant associations, which remains hidden in BayesC analysis. Mapping precision was not substantially improved by BayesD. CONCLUSIONS: BayesD improved power, but precision only slightly. Application of BayesD needs large datasets with genotypes and own performance records as phenotypes. Given the current efforts to establish cow reference populations in dairy cattle genomic selection schemes, such datasets are expected to be soon available, which will enable the application of BayesD for association mapping and genomic prediction purposes. PMID- 28088171 TI - Assessing the sustainability of daily chlorhexidine bathing in the intensive care unit of a Veteran's Hospital by examining nurses' perspectives and experiences. AB - BACKGROUND: Daily bathing with chlorhexidine gluconate (CHG) of intensive care unit (ICU) patients has been shown to reduce healthcare-associated infections and colonization by multidrug resistant organisms. The objective of this project was to describe the process of daily CHG bathing and identify the barriers and facilitators that can influence its successful adoption and sustainability in an ICU of a Veterans Administration Hospital. METHODS: We conducted 26 semi structured interviews with a convenience sample of 4 nurse managers (NMs), 13 registered nurses (RNs) and 9 health care technicians (HCTs) working in the ICU. We used qualitative content analysis to code and analyze the data. Dedoose software was used to facilitate data management and coding. Trustworthiness and scientific integrity of the data were ensured by having two authors corroborate the coding process, conducting member checks and keeping an audit trail of all the decisions made. RESULTS: Duration of the interviews was 15 to 39 min (average = 26 min). Five steps of bathing were identified: 1) decision to give a bath; 2) ability to give a bath; 3) decision about which soap to use; 4) delegation of a bath; and 5) getting assistance to do a bath. The bathing process resulted in one of the following three outcomes: 1) complete bath; 2) interrupted bath; and 3) bath not done. The outcome was influenced by a combination of barriers and facilitators at each step. Most barriers were related to perceived workload, patient factors, and scheduling. Facilitators were mainly organizational factors such as the policy of daily CHG bathing, the consistent supply of CHG soap, and support such as reminders to conduct CHG baths by nurse managers. CONCLUSIONS: Patient bathing in ICUs is a complex process that can be hindered and interrupted by numerous factors. The decision to use CHG soap for bathing was only one of 5 steps of bathing and was largely influenced by scheduling/workload and patient factors such as clinical stability, hypersensitivity to CHG, patient refusal, presence of IV lines and general hygiene. Interventions that address the organizational, provider, and patient barriers to bathing could improve adherence to a daily CHG bathing protocol. PMID- 28088172 TI - EcoTILLING by sequencing reveals polymorphisms in genes encoding starch synthases that are associated with low glycemic response in rice. AB - BACKGROUND: Glycemic response, a trait that is tedious to be assayed in cereal staples, has been identified as a factor correlated with alarmingly increasing prevalence of Type II diabetes. Reverse genetics based discovery of allelic variants associated with this nutritional trait gains significance as they can provide scope for genetic improvement of this factor which is otherwise difficult to target through routine screening methods. RESULTS: Through EcoTILLING by sequencing in 512 rice accessions, we report the discovery of six deleterious variants in the genes with potential to increase Resistant Starch (RS) and reduce Hydrolysis Index (HI) of starch. By deconvolution of the variant harbouring EcoTILLING DNA pools, we discovered accessions with a minimum of one to a maximum of three deleterious allelic variants in the candidate genes. CONCLUSIONS: Through biochemical assays, we confirmed the potential role of the discovered alleles alone or in combinations in increasing RS the key factor for reduction in glycemic response. PMID- 28088173 TI - High-risk human papillomavirus infection and abnormal cervical cytology among Nepali and Bhutanese refugee women living in eastern Nepal. AB - BACKGROUND: Cervical cancer is the leading cause of cancer morbidity and mortality among women in Nepal and Bhutan. Data on high-risk human papillomavirus (HR-HPV) infection and cervical abnormalities among Nepali and Bhutanese women are sparse. The objectives of this study were to assess and compare the prevalence of HR-HPV infection and cervical abnormalities among Nepali and Bhutanese women living in Jhapa District in eastern Nepal; and examine the risk factors for HR-HPV infection and cervical abnormalities in those women. METHODS: Study participants were recruited from a women's health camp organized by NFCC International, a Nepal-based non-governmental organization, in 2014. Consenting participants were administered a demographic and health questionnaire and cervico vaginal specimens collected. Both self-collected and clinician-collected cervico vaginal specimens were tested for HR-HPV infection. Cytologic exam was performed on clinician-collected samples and cervical cytology results were categorized according to the Bethesda classification. A participant was classified as a Bhutanese if they were either born in Bhutan or currently lived in one of the United Nations administered Bhutanese refugee camps in Jhapa; otherwise, the participant was classified as a Nepali. RESULTS: Of the 647 study participants, 15.9% were Bhutanese women living in refugee camps and the overall age (+/- standard deviation) was 38.8 +/- 8.2 years. The prevalence of HR-HPV infection was 8.9% and abnormal cervical cytology was 7.1% respectively, with no significant difference in HR-HPV positivity (p = 0.399) or abnormal cervical cytology (p = 0.698) between Nepali and Bhutanese women. Compared to women whose husbands had not migrated for employment, women whose husbands had migrated outside of the district had 3.30 times (95% Confidence Interval [CI]: 1.13-9.64) the odds of being HR-HPV positive and women whose husbands had migrated outside the country had 2.92 times (95% CI: 1.32-6.49) the odds of having abnormal cervical cytology. CONCLUSIONS: HR-HPV positivity and abnormal cervical cytology were similar among Nepali and Bhutanese women. Husbands migrating for employment within or outside the country was a significant risk factor for high-risk HPV infection and cervical cytology, indicating the important role spousal behavior may play in HR-HPV acquisition and cervical abnormalities among these women. PMID- 28088174 TI - Feasibility and safety of dilatational tracheotomy using the rigid endoscope: a multicenter study. AB - BACKGROUND: Fiberoptic tracheo-bronchoscopy is the most commonly used procedure for percutaneous dilational tracheotomy (PDT). However, PDT can be associated with major complications, including death. Furthermore it is unclear, whether the tracheal ring fractures may contribute to the development of tracheal stenosis after PDT nor whether tracheal ring fractures can be prevented by using a rigid endoscope for this procedure. The purpose of this study was to evaluate the feasibility of and the incidence of complications for PDT using the rigid tracheotomy endoscope (TED). METHODS: In a prospective multicenter observational study from 2006 to 2010, 180 adult patients in intensive care and those scheduled for ear, nose and throat surgery underwent PDT using TED. Data collection was performed using a structured protocol. The patients were observed according to PDT phase (phase 1: puncture, phase 2: dilatation and phase 3: cannula insertion). The descriptive data are given as the number (percent) of cases and the mean +/- standard deviation (SD) where appropriate. The relationships between dichotomous and categorical parameters were analyzed using the chi-square test. P values <= 0.05 were considered significant. RESULTS: PDT was performed in 179 patients. The procedure time was 14.8 +/- 6.2 (mean +/- SD) minutes. Pneumothorax or procedure-related lethal complications did not occur. Other adverse events included tracheal ring fractures (17.1%), desaturations (6.8%), special incidents (6.2%), bleeding (5.5%), anesthesia complications (4.5%) and posterior tracheal wall injuries (1.1%). CONCLUSION: The use of TED in PDT is feasible, and the incidence of complications and adverse events was comparable with that of PDT using the flexible endoscope. Tracheal ring fractures in PDT cannot be avoided by the use of a rigid endoscope. With TED, the airway always remains open thus the use of jet ventilation via the TED during PDT is possible. PMID- 28088175 TI - Prevalence and risk factors for cardiovascular disease among chronic kidney disease patients: results from the Chinese cohort study of chronic kidney disease (C-STRIDE). AB - BACKGROUND: Although a high incidence of cardiovascular disease (CVD) is observed among chronic kidney disease (CKD) patients in developed countries, limited information is available about CVD prevalence and risk factors in the Chinese CKD population. The Chinese Cohort of Chronic Kidney Disease (C-STRIDE) was established to investigate the prevalence and risk factors of CVD among Chinese CKD patients. METHODS: Participants with stage 1-4 CKD (18-74 years of age) were recruited at 39 clinical centers located in 28 cities from 22 provinces of China. At entry, the socio-demographic status, medical history, anthropometric measurements and lifestyle behaviors were documented, and blood and urine samples were collected. Estimated glomerular filtration rate (eGFR) was calculated by the CKD-EPI creatinine equation. CVD diagnosis was based on patient self-report and review of medical records by trained staff. A multivariable logistic regression model was used to estimate the association between risk factors and CVD. RESULTS: Three thousand four hundred fifty-nine Chinese patients with pre-stage 5 CKD were enrolled, and 3168 finished all required examinations and were included in the study. In total, 40.8% of the cohort was female, with a mean age of 48.21 +/- 13.70 years. The prevalence of CVD was 9.8%, and in 69.1% of the CVD cases cerebrovascular disease was observed. Multivariable analysis showed that increasing age, lower eGFR, presence of hypertension, abdominal aorta calcification and diabetes were associated with comorbid CVD among CKD patients. The odds ratios and 95% confidence intervals for these risk factors were 3.78 (2.55-5.59) for age 45-64 years and 6.07 (3.89-9.47) for age >=65 years compared with age <45 years; 2.07 (1.28-3.34) for CKD stage 3a, 1.66 (1.00-2.62) for stage 3b, and 2.74 (1.72-4.36) for stage 4 compared with stages 1 and 2; 2.57 (1.50 4.41) for hypertension, 1.82 (1.23-2.70) for abdominal aorta calcification, and 1.70 (1.30-2.23) for diabetes, respectively. CONCLUSIONS: We reported the CVD prevalence among a CKD patient cohort and found age, hypertension, diabetes, abdominal aorta calcification and lower eGFR were independently associated with higher CVD prevalence. Prospective follow-up and longitudinal evaluations of CVD risk among CKD patients are warranted. PMID- 28088176 TI - TTCA: an R package for the identification of differentially expressed genes in time course microarray data. AB - BACKGROUND: The analysis of microarray time series promises a deeper insight into the dynamics of the cellular response following stimulation. A common observation in this type of data is that some genes respond with quick, transient dynamics, while other genes change their expression slowly over time. The existing methods for detecting significant expression dynamics often fail when the expression dynamics show a large heterogeneity. Moreover, these methods often cannot cope with irregular and sparse measurements. RESULTS: The method proposed here is specifically designed for the analysis of perturbation responses. It combines different scores to capture fast and transient dynamics as well as slow expression changes, and performs well in the presence of low replicate numbers and irregular sampling times. The results are given in the form of tables including links to figures showing the expression dynamics of the respective transcript. These allow to quickly recognise the relevance of detection, to identify possible false positives and to discriminate early and late changes in gene expression. An extension of the method allows the analysis of the expression dynamics of functional groups of genes, providing a quick overview of the cellular response. The performance of this package was tested on microarray data derived from lung cancer cells stimulated with epidermal growth factor (EGF). CONCLUSION: Here we describe a new, efficient method for the analysis of sparse and heterogeneous time course data with high detection sensitivity and transparency. It is implemented as R package TTCA (transcript time course analysis) and can be installed from the Comprehensive R Archive Network, CRAN. The source code is provided with the Additional file 1. PMID- 28088177 TI - A novel quantitative PCR detects Babesia infection in patients not identified by currently available non-nucleic acid amplification tests. AB - BACKGROUND: Ticks transmit Babesia microti, the causative agents of babesiosis in North America and Europe. Babesiosis is now endemic in Northeastern USA and affects people of all ages. Babesia species infect erythrocytes and can be transmitted through blood transfusion. Whole blood and blood products, which are not tested for Babesia, can cause transfusion-transmitted babesiosis (TTB) resulting in severe consequences in the immuno-compromised patients. The purpose of this study was epidemiological evaluation of babesiosis in a tick-infested state. RESULTS: We examined blood samples from 192 patients who visited clinics during the active tick-borne diseases season, using a newly developed qPCR assay that uses the specific molecular beacon probe. Due to the absence of clear symptomology, clinical laboratories did not test 131 samples by IFA, FISH or microscopic examination of Giemsa-stained blood smears. Babesia infection was detected in all age groups by FISH and microscopy; notably patients >40 years of age represented 64% of tested samples and 13% were younger patients. We tested all samples using qPCR and found that 38% were positive for Babesia. Of 28 samples that were positive by FISH, 27 (96%) were also positive by qPCR indicating high congruency between nucleic acid based tests. Interestingly, of 78 asymptomatic samples not tested by FISH, 22 were positive by our qPCR. Direct detection of Babesia relies upon microscopic examination of patient blood smears, which is labor intensive, difficult to scale up, requires specific expertise and is hence, often not performed. In fact, a clinical laboratory examined only 23 of 86 blood samples obtained from two different counties by microscopy. By considering individuals positive for Babesia infection when results from currently available microscopy, FISH or serological tests were positive, we found that our qPCR is highly sensitive (96.2%) and showed a specificity of 70.5% for Babesia. CONCLUSION: Robust qPCR using specific probes can be highly useful for efficient and appropriate diagnosis of babesiosis in patients in conjunction with conventional diagnostics, or as a stand-alone test, especially for donated blood screening. The use of a nucleic acid amplification test based screening of blood and blood products could prevent TTB. PMID- 28088178 TI - Health-related quality of life and associated factors in functionally independent older people. AB - BACKGROUND: Health-related quality of life (HRQL) is a key indicator of elderly people's health status that can be affected by different factors. However, little is known about which variables are associated with it in functionally independent elderly people. The aim of this project was to study HRQL and a wide variety of health, lifestyle, social and contextual aspects and their relation to HRQL in a sample of functionally independent, non-cognitively impaired community-dwelling adults, over 65 years of age, from a northern region of Spain. METHODS: A cross sectional study for which data was collected by face-to-face interviews with the selected individuals. HRQL was measured with the EuroQol-5D scale, consisting of a 5 item descriptive system and a visual analogue scale (VAS). VAS values lower than 70 were considered poor HRQL. Binary logistic regression was used to identify factors related to the outcome. RESULTS: Six hundred and thirty-four individuals were included in the study. The mean age was 74.8 (SD 6.7) years, 55% of the participants were women and 46% rated their HRQL as poor. Several variables were found to be significantly associated with a poor HRQL in the multivariate model, adjusted for age and sex: polypharmacy (OR: 2.32, 95% CI: 1.62-3.31), the presence of sensory impairment (OR: 1.83, 95% CI: 1.24-2.69), not being engaged in cognitively stimulating activities (OR: 2.51, 95% CI: 1.03 6.16), or in group social activities (OR: 1.57, 95% CI: 1.11-2.22), low level of social support (OR: 3.12, 95%CI: 1.78-5.46) and the presence of obstacles in the closest home environment (OR: 1.83, 95%CI: 1.11-3.02). CONCLUSIONS: The study identified a set of health, social and contextual variables as strongly related to HRQL in functionally independent community-dwelling older people. The results highlight the multidimensional nature of HRQL. They also reveal the importance of a comprehensive assessment of HRQL when designing adequate health-related programmes aiming to enhance active and healthy ageing and delay the onset of dependence. PMID- 28088179 TI - Chronic constipation diagnosis and treatment evaluation: the "CHRO.CO.DI.T.E." study. AB - BACKGROUND: According to Rome criteria, chronic constipation (CC) includes functional constipation (FC) and irritable bowel syndrome with constipation (IBS C). Some patients do not meet these criteria (No Rome Constipation, NRC). The aim of the study was is to evaluate the various clinical presentation and management of FC, IBS-C and NRC in Italy. METHODS: During a 2-month period, 52 Italian gastroenterologists recorded clinical data of FC, IBS-C and NRC patients, using Bristol scale, PAC-SYM and PAC-QoL questionnaires. In addition, gastroenterologists were also asked to record whether the patients were clinically assessed for CC for the first time or were in follow up. Diagnostic tests and prescribed therapies were also recorded. RESULTS: Eight hundred seventy eight consecutive CC patients (706 F) were enrolled (FC 62.5%, IBS-C 31.3%, NRC 6.2%). PAC-SYM and PAC-QoL scores were higher in IBS-C than in FC and NRC. 49.5% were at their first gastroenterological evaluation for CC. In 48.5% CC duration was longer than 10 years. A specialist consultation was requested in 31.6%, more frequently in IBS-C than in NRC. Digital rectal examination was performed in only 56.4%. Diagnostic tests were prescribed to 80.0%. Faecal calprotectin, thyroid tests, celiac serology, breath tests were more frequently suggested in IBS-C and anorectal manometry in FC. More than 90% had at least one treatment suggested on chronic constipation, most frequently dietary changes, macrogol and fibers. Antispasmodics and psychotherapy were more frequently prescribed in IBS-C, prucalopride and pelvic floor rehabilitation in FC. CONCLUSIONS: Patients with IBS-C reported more severe symptoms and worse quality of life than FC and NRC. Digital rectal examination was often not performed but at least one diagnostic test was prescribed to most patients. Colonoscopy and blood tests were the "first line" diagnostic tools. Macrogol was the most prescribed laxative, and prucalopride and pelvic floor rehabilitation represented a "second line" approach. Diagnostic tests and prescribed therapies increased by increasing CC severity. PMID- 28088180 TI - Nuclear envelope structural proteins facilitate nuclear shape changes accompanying embryonic differentiation and fidelity of gene expression. AB - BACKGROUND: Nuclear size and shape are specific to a cell type, function, and location, and can serve as indicators of disease and development. We previously found that lamin A/C and associated nuclear envelope structural proteins were upregulated when murine embryonic stem (ES) cells differentiated to primitive endoderm cells. Here we further investigated the morphological changes of nuclei that accompany this differentiation. RESULTS: The nuclei of undifferentiated wild type cells were found shaped as flattened, irregular ovals, whereas nuclei of Gata4-positive endoderm cells were more spherical, less flattened, and with a slightly reduced volume. The morphological change was confirmed in the trophectoderm and primitive endoderm lineages of E4.5 blastocysts, compared to larger and more irregularly shaped of the nuclei of the inner cell mass. We established ES cells genetically null for the nuclear lamina proteins lamin A/C or the inner nuclear envelope protein emerin, or compound mutant for both lamin A/C and emerin. ES cells deficient in lamin A/C differentiated to endoderm but less efficiently, and the nuclei remained flattened and failed to condense. The size and shape of emerin-deficient nuclei also remained uncondensed after treatment with RA. The emerin/lamin A/C double knockout ES cells failed to differentiate to endoderm cells, though the nuclei condensed but retained a generally flattened ellipsoid shape. Additionally, ES cells deficient for lamin A/C and/or emerin had compromised ability to undergo endoderm differentiation, where the differentiating cells often exhibited coexpression of pluripotent and differentiation markers, such as Oct3/4 and Gata4, respectively, indicating an infidelity of gene regulation. CONCLUSIONS: The results suggest that changes in nuclear size and shape, which are mediated by nuclear envelope structural proteins lamin A/C and/or emerin, also impact gene regulation and lineage differentiation in early embryos. Nevertheless, mice lacking both lamin A/C and emerin were born at the expected frequency, indicating their embryonic development is completed despite the observed protein deficiency. PMID- 28088181 TI - Acute and chronic kidney disease in elderly patients with hip fracture: prevalence, risk factors and outcome with development and validation of a risk prediction model for acute kidney injury. AB - BACKGROUND: Hip fracture is a common injury in older people with a high rate of postoperative morbidity and mortality. This patient group is also at high risk of acute kidney injury (AKI) and chronic kidney disease (CKD), but little is known of the impact of kidney disease on outcome following hip fracture. METHODS: An observational cohort of consecutive patients with hip fracture in a large UK secondary care hospital. Predictive modelling of outcomes using development and validation datasets. Inclusion: all patients admitted with hip fracture with sufficient serum creatinine measurements to define acute kidney injury. Main outcome measures - development of acute kidney injury during admission; mortality (in hospital, 30-365 day and to follow-up); length of hospital stay. RESULTS: Data were available for 2848 / 2959 consecutive admissions from 2007-2011; 776 (27.2%) male. Acute kidney injury occurs in 24%; development of acute kidney injury is independently associated with male sex (OR 1.48 (1.21 to 1.80), premorbid chronic kidney disease stage 3B or worse (OR 1.52 (1.19 to 1.93)), age (OR 3.4 (2.29 to 5.2) for >85 years) and greater than one major co-morbidities (OR 1.61 (1.34 to 1.93)). Acute kidney injury of any stage is associated with an increased hazard of death, and increased length of stay (Acute kidney injury: 19.1 (IQR 13 to 31) days; no acute kidney injury 15 (11 to 23) days). A simplified predictive model containing Age, CKD stage (3B-5), two or more comorbidities, and male sex had an area under the ROC curve of 0.63 (0.60 to 0.67). CONCLUSIONS: Acute kidney injury following hip fracture is common and associated with worse outcome and greater hospital length of stay. With the number of people experiencing hip fracture predicted to rise, recognition of risk factors and optimal perioperative management of acute kidney injury will become even more important. PMID- 28088183 TI - Incidence, aetiology and outcome of community-acquired acute kidney injury in medical admissions in Malawi. AB - BACKGROUND: Epidemiological data on Acute Kidney Injury (AKI) from low-income countries is sparse. The aim of this study was to establish the incidence, severity, aetiology, and outcomes of community-acquired AKI in Malawi. METHODS: We conducted a prospective observational study of general medical admissions to a tertiary hospital in Blantyre between 27th April and 17th July 2015. All patients were screened on admission with a serum creatinine; those with creatinine above laboratory reference range were managed by the nephrology team. Hospital outcome was recorded in all patients. RESULTS: Eight hundred ninety-two patients were included; 188 (21 . 1%) had kidney disease on admission, including 153 (17 . 2%) with AKI (median age 41 years; 58 . 8% HIV seropositive). 60 . 8% of AKI was stage 3. The primary causes of AKI were sepsis and hypovolaemia in 133 (86 . 9%) cases, most commonly gastroenteritis (n = 29; 19 . 0%) and tuberculosis (n = 18; 11 . 8%). AKI was multifactorial in 117 (76 . 5%) patients; nephrotoxins were implicated in 110 (71 . 9%). Inpatient mortality was 44 . 4% in patients with AKI and 13 . 9% if no kidney disease (p <0.0001). 63 . 2% of patients who recovered kidney function left hospital with persistent kidney injury. CONCLUSION: AKI incidence is 17 . 2% in medical admissions in Malawi, the majority is severe, and AKI leads to significantly increased in-hospital mortality. The predominant causes are infection and toxin related, both potentially avoidable and treatable relatively simply. Effective interventions are urgently required to reduce preventable young deaths from AKI in this part of the world. PMID- 28088182 TI - Overexpression of wheat ferritin gene TaFER-5B enhances tolerance to heat stress and other abiotic stresses associated with the ROS scavenging. AB - BACKGROUND: The yield of wheat (Triticum aestivum L.), an important crop, is adversely affected by heat stress in many regions of the world. However, the molecular mechanisms underlying thermotolerance are largely unknown. RESULTS: A novel ferritin gene, TaFER, was identified from our previous heat stress responsive transcriptome analysis of a heat-tolerant wheat cultivar (TAM107). TaFER was mapped to chromosome 5B and named TaFER-5B. Expression pattern analysis revealed that TaFER-5B was induced by heat, polyethylene glycol (PEG), H2O2 and Fe-ethylenediaminedi(o-hydroxyphenylacetic) acid (Fe-EDDHA). To confirm the function of TaFER-5B in wheat, TaFER-5B was transformed into the wheat cultivar Jimai5265 (JM5265), and the transgenic plants exhibited enhanced thermotolerance. To examine whether the function of ferritin from mono- and dico-species is conserved, TaFER-5B was transformed into Arabidopsis, and overexpression of TaFER 5B functionally complemented the heat stress-sensitive phenotype of a ferritin lacking mutant of Arabidopsis. Moreover, TaFER-5B is essential for protecting cells against heat stress associated with protecting cells against ROS. In addition, TaFER-5B overexpression also enhanced drought, oxidative and excess iron stress tolerance associated with the ROS scavenging. Finally, TaFER-5B transgenic Arabidopsis and wheat plants exhibited improved leaf iron content. CONCLUSIONS: Our results suggest that TaFER-5B plays an important role in enhancing tolerance to heat stress and other abiotic stresses associated with the ROS scavenging. PMID- 28088184 TI - Anti-hepatitis B virus (HBV) response of imiquimod based toll like receptor 7 ligand in hbv-positive human hepatocelluar carcinoma cell line. AB - BACKGROUND: Toll like receptors (TLRs) play an important role in innate immunity and various studies suggest that TLRs play a crucial role in pathogenesis of hepatitis B virus (HBV) infection. The present study aims in looking into the status of crucial host and viral gene expression on inciting TLR7. METHODS: The transcription of TLR7 pathway signaling molecules and HBV DNA viral load were quantified by Real Time-PCR after stimulation of TLR7 with its imiquimod based ligand, R837. Cell cycle analysis was performed using flow-cytometry. Expression of TLR7 and chief cell cycle regulator governing G1/S transition, p53 was also seen in liver biopsysss samples of CHB patients. HBV induced alteration in histone modifications in HepG2 cells and its restoration on TLR7 activation was determined using western blot. RESULTS: The TLR7 expression remains downregulated in HepG2.2.15 cells and in liver biopsy samples from CHB patients. Interestingly HBV DNA viral load showed an inverse relationship with the TLR7 expression in the biopsy samples. We also evaluated the anti-viral activity of R837, an agonist of TLR7. It was observed that there was a suppression of HBV replication and viral protein production upon TLR7 stimulation. R837 triggers the anti-viral action probably through the Jun N-terminal Kinase (JNK) pathway. We also observed a downregulation of histone H3K9Me3 repression mark upon R837 treatment in HBV replicating HepG2.2.15 cells, mimicking that of un-infected HepG2 cells. Additionally, the G1/S cell cycle arrest introduced by HBV in HepG2.2.15 cells was released upon ligand treatment. CONCLUSION: The study thus holds a close insight into the changes in hepatocyte micro-environment on TLR7 stimulation in HBV infection. PMID- 28088185 TI - iGC-an integrated analysis package of gene expression and copy number alteration. AB - BACKGROUND: With the advancement in high-throughput technologies, researchers can simultaneously investigate gene expression and copy number alteration (CNA) data from individual patients at a lower cost. Traditional analysis methods analyze each type of data individually and integrate their results using Venn diagrams. Challenges arise, however, when the results are irreproducible and inconsistent across multiple platforms. To address these issues, one possible approach is to concurrently analyze both gene expression profiling and CNAs in the same individual. RESULTS: We have developed an open-source R/Bioconductor package (iGC). Multiple input formats are supported and users can define their own criteria for identifying differentially expressed genes driven by CNAs. The analysis of two real microarray datasets demonstrated that the CNA-driven genes identified by the iGC package showed significantly higher Pearson correlation coefficients with their gene expression levels and copy numbers than those genes located in a genomic region with CNA. Compared with the Venn diagram approach, the iGC package showed better performance. CONCLUSION: The iGC package is effective and useful for identifying CNA-driven genes. By simultaneously considering both comparative genomic and transcriptomic data, it can provide better understanding of biological and medical questions. The iGC package's source code and manual are freely available at https://www.bioconductor.org/packages/release/bioc/html/iGC.html . PMID- 28088186 TI - Concentration of fine needle aspirates similar to molecular method improves sensitivity of the diagnosis of tuberculous lymphadenitis in Addis Ababa, Ethiopia. AB - BACKGROUND: Tuberculous lymphadenitis (TBLN) diagnosis has been a true challenge solely by clinical evidence in developing countries, due to limited the diagnostic facility on hand. However, the availability and affordability of available diagnostic tools in resource-limited settings like Ethiopia necessitates the quest for other techniques with added value over direct Z-N microscopy. Therefore, we aimed at to assess whether the concentration of lymph node aspirate similarly improves the detection rate of tuberculous lymphadenitis or not. MATERIALS AND METHODS: A cross-sectional study design was conducted on 132 individual subjects presumptive for tuberculous lymphadenitis from February to October 2013 in Addis Ababa, Ethiopia. Fine needle aspirate (FNA) samples were collected from the cases and cultured on Lowenstein-Jensen (LJ) slants. Identification of species and strains of mycobacteria was made by region of difference (RD) based polymerase chain reaction (PCR). Data entry and statistical analyses were performed by SPSS version 20. The confidence level of 95% was used for statistical significance. RESULT: A total of 132 study subjects were included in our study. Of these 56.1% (74/132) were positive for M. tuberculosis on culture. The detection rate of direct smear microscopy and the concentration method were 29.5 and 65.2% respectively. The sensitivity of direct smear microscopy was 43.2%, for concentrated smear microscopy 94.5%, for PCR 93.2% and for cytomorphology 95.4%. The level of agreement of concentrated ZN smear microscopy was 0.62 which was very similar with kappa of 0.58 of molecular (PCR) technique. AFB positivity by the concentration method and molecular method was increased in caseous aspirates as compared to purulent and hemorrhagic aspirates though it was not statistically significant (p-value = 0.18) and (p = 0.62) respectively. CONCLUSION: The concentration of FNA (Fine Needle Aspirate) aspirates for acid-fast smear microscopy similarly improves the sensitivity of acid fast bacilli in diagnosing of TBLN. PMID- 28088187 TI - A double-blind, randomized, placebo-controlled trial of combined calcitriol and ergocalciferol versus ergocalciferol alone in chronic kidney disease with proteinuria. AB - BACKGROUND: KDOQI guideline suggests that nutritional vitamin D should be supplemented in chronic kidney disease (CKD) patients who have vitamin D insufficiency/deficiency. However, there are scarce data regarding the additional benefit of active vitamin D supplement in CKD patients who were receiving nutritional vitamin D supplement. This study was conducted to explore the effect of adding active vitamin D to nutritional vitamin D supplement on proteinuria and kidney function in CKD with vitamin D insufficiency/deficiency. METHODS: This double-blind, randomized placebo-controlled trial was performed to answer the above question. Sixty-eight patients with CKD stage 3-4, urine protein to creatinine ratio (UPCR) > 1 g/g, and serum 25OH-D level < 30 ng/mL were enrolled. Patients were randomly assigned to receive 12-week treatment with oral ergocalciferol plus placebo (n = 36) or oral ergocalciferol plus calcitriol (n = 32). RESULTS: The mean baseline values of UPCR of both groups were comparable (3.6 +/- 3.8 g/g in combined group and 3.5 +/- 3.0 g/g in ergocalciferol group). Following 12-week treatment, there were significant reductions in UPCR from baseline in both groups (2.3 +/- 2.1 g/g in combined group and 2.4 +/- 2.0 g/g in ergocalciferol group). The percentage reductions in UPCR of both groups were not significantly different. The mean eGFR and blood pressure did not differ between baseline and 12-week follow-up and between both groups. No severe hypercalcemia or serious side effects were noted in both groups. CONCLUSIONS: The proteinuria lowering effect of ergocalciferol in CKD patients with vitamin D deficiency was demonstrated. Additional calcitriol supplement did not have more effects on proteinuria. TRIAL REGISTRATION: (Thai Clinical Trials Registry (TCTR) 20140929002 ). Date of registration: September 27, 2014. PMID- 28088188 TI - Incidence and predictors of left ventricular remodeling among elderly Asian women: a community-based cohort study. AB - BACKGROUND: Left ventricular (LV) remodeling is closely linked to the progression of heart failure. There are limited data on the epidemiology of new onset LV remodeling among elderly women, which requires further investigation. METHOD: We examined data from a community-based cohort of women aged > 65 years, who had received > 2 echocardiography scans from 2009 to 2014. Exclusion criteria for patients included prior echocardiographic evidence of left ventricular enlargement (LVE) or hypertrophy (LVH). LVE was defined as the index of left ventricular internal diameter at end-diastole to height, and LVH was defined as the left ventricular mass and thickness index which indicate hypertrophy. RESULTS: Of the 474 subjects (age 71.85 +/- 6.47 years), 49 (10.3%) developed LVH, while 55 (11.6%) developed LVE during the mean follow-up period of 5 years. Independent predictors of LVH included: central blood pressure (CBP, per 10 mmHg) [HR 1.094, 95% CI 1.011-1.202], BMI?25(kg/m 2)[HR 1.306, 95% CI 1.175-1.434], B type natriuretic peptide (BNP) >= 100 (pg/mL) [HR 1.635, 95% CI 1.107-3.311] and brachial-ankle pulse wave velocity (baPWV) >=16 m/s [HR 1.605, 95% CI 1.474 2.039]. Predictors of LVE were CBP (per 10 mmHg) [HR 1.121, 95% CI 1.027-1.238], BMI?25(kg/m 2)[HR 1.302, 95% CI 1.173-1.444], Low-density lipoprotein cholesterol (LDL-C) [HR 1.193, 95%CI 1.013-1.405] and E/e' ratio [HR 1.077, 95% CI 1.017 1.140]. CONCLUSION: CBP and BMI were demonstrated to be independent and robust predictors of left ventricular remodeling among elderly women, including both LVE and LVH. BNP and baPWV were specifically related to the development of LVH, whereas LDL-C and E/e' ratio were related to LVE. PMID- 28088189 TI - MARS: improving multiple circular sequence alignment using refined sequences. AB - BACKGROUND: A fundamental assumption of all widely-used multiple sequence alignment techniques is that the left- and right-most positions of the input sequences are relevant to the alignment. However, the position where a sequence starts or ends can be totally arbitrary due to a number of reasons: arbitrariness in the linearisation (sequencing) of a circular molecular structure; or inconsistencies introduced into sequence databases due to different linearisation standards. These scenarios are relevant, for instance, in the process of multiple sequence alignment of mitochondrial DNA, viroid, viral or other genomes, which have a circular molecular structure. A solution for these inconsistencies would be to identify a suitable rotation (cyclic shift) for each sequence; these refined sequences may in turn lead to improved multiple sequence alignments using the preferred multiple sequence alignment program. RESULTS: We present MARS, a new heuristic method for improving Multiple circular sequence Alignment using Refined Sequences. MARS was implemented in the C++ programming language as a program to compute the rotations (cyclic shifts) required to best align a set of input sequences. Experimental results, using real and synthetic data, show that MARS improves the alignments, with respect to standard genetic measures and the inferred maximum-likelihood-based phylogenies, and outperforms state-of-the-art methods both in terms of accuracy and efficiency. Our results show, among others, that the average pairwise distance in the multiple sequence alignment of a dataset of widely-studied mitochondrial DNA sequences is reduced by around 5% when MARS is applied before a multiple sequence alignment is performed. CONCLUSIONS: Analysing multiple sequences simultaneously is fundamental in biological research and multiple sequence alignment has been found to be a popular method for this task. Conventional alignment techniques cannot be used effectively when the position where sequences start is arbitrary. We present here a method, which can be used in conjunction with any multiple sequence alignment program, to address this problem effectively and efficiently. PMID- 28088190 TI - Total kidney and liver volume is a major risk factor for malnutrition in ambulatory patients with autosomal dominant polycystic kidney disease. AB - BACKGROUND: In patients with autosomal dominant polycystic kidney disease (ADPKD), malnutrition may develop as renal function declines and the abdominal organs become enlarged. We investigated the relationship of intra-abdominal mass with nutritional status. METHODS: This cross-sectional study was performed at a tertiary hospital outpatient clinic. Anthropometric and laboratory data including serum creatinine, albumin, and cholesterol were collected, and kidney and liver volumes were measured. Total kidney and liver volume was defined as the sum of the kidney and liver volumes and adjusted by height (htTKLV). Nutritional status was evaluated by using modified subjective global assessment (SGA). RESULTS: In a total of 288 patients (47.9% female), the mean age was 48.3 +/- 12.2 years and the mean estimated glomerular filtration rate (eGFR) was 65.3 +/- 25.3 mL/min/1.73 m2. Of these patients, 21 (7.3%) were mildly to moderately malnourished (SGA score of 4 and 5) and 63 (21.7%) were at risk of malnutrition (SGA score of 6). Overall, patients with or at risk of malnutrition were older, had a lower body mass index, lower hemoglobin levels, and poorer renal function compared to the well-nourished group. However, statistically significant differences in these parameters were not observed in female patients, except for eGFR. In contrast, a higher htTKLV correlated with a lower SGA score, even in subjects with an eGFR >=45 mL/min/1.73 m2. Subjects with an htTKLV >=2340 mL/m showed an 8.7-fold higher risk of malnutrition, after adjusting for age, hemoglobin, and eGFR. CONCLUSIONS: Nutritional risk was detected in 30% of ambulatory ADPKD patients with relatively good renal function. Intra-abdominal organomegaly was related to nutritional status independently from renal function deterioration. PMID- 28088191 TI - Predicting probable Alzheimer's disease using linguistic deficits and biomarkers. AB - BACKGROUND: The manual diagnosis of neurodegenerative disorders such as Alzheimer's disease (AD) and related Dementias has been a challenge. Currently, these disorders are diagnosed using specific clinical diagnostic criteria and neuropsychological examinations. The use of several Machine Learning algorithms to build automated diagnostic models using low-level linguistic features resulting from verbal utterances could aid diagnosis of patients with probable AD from a large population. For this purpose, we developed different Machine Learning models on the DementiaBank language transcript clinical dataset, consisting of 99 patients with probable AD and 99 healthy controls. RESULTS: Our models learned several syntactic, lexical, and n-gram linguistic biomarkers to distinguish the probable AD group from the healthy group. In contrast to the healthy group, we found that the probable AD patients had significantly less usage of syntactic components and significantly higher usage of lexical components in their language. Also, we observed a significant difference in the use of n-grams as the healthy group were able to identify and make sense of more objects in their n-grams than the probable AD group. As such, our best diagnostic model significantly distinguished the probable AD group from the healthy elderly group with a better Area Under the Receiving Operating Characteristics Curve (AUC) using the Support Vector Machines (SVM). CONCLUSIONS: Experimental and statistical evaluations suggest that using ML algorithms for learning linguistic biomarkers from the verbal utterances of elderly individuals could help the clinical diagnosis of probable AD. We emphasise that the best ML model for predicting the disease group combines significant syntactic, lexical and top n gram features. However, there is a need to train the diagnostic models on larger datasets, which could lead to a better AUC and clinical diagnosis of probable AD. PMID- 28088192 TI - Nucleotide diversity inflation as a genome-wide response to experimental lifespan extension in Drosophila melanogaster. AB - BACKGROUND: Evolutionary theory predicts that antagonistically selected alleles, such as those with divergent pleiotropic effects in early and late life, may often reach intermediate population frequencies due to balancing selection, an elusive process when sought out empirically. Alternatively, genetic diversity may increase as a result of positive frequency-dependent selection and genetic purging in bottlenecked populations. RESULTS: While experimental evolution systems with directional phenotypic selection typically result in at least local heterozygosity loss, we report that selection for increased lifespan in Drosophila melanogaster leads to an extensive genome-wide increase of nucleotide diversity in the selected lines compared to replicate control lines, pronounced in regions with no or low recombination, such as chromosome 4 and centromere neighborhoods. These changes, particularly in coding sequences, are most consistent with the operation of balancing selection and the antagonistic pleiotropy theory of aging and life history traits that tend to be intercorrelated. Genes involved in antioxidant defenses, along with multiple lncRNAs, were among those most affected by balancing selection. Despite the overwhelming genetic diversification and the paucity of selective sweep regions, two genes with functions important for central nervous system and memory, Ptp10D and Ank2, evolved under positive selection in the longevity lines. CONCLUSIONS: Overall, the 'evolve-and-resequence' experimental approach proves successful in providing unique insights into the complex evolutionary dynamics of genomic regions responsible for longevity. PMID- 28088193 TI - Invasive Cardiac Lipoma: a case report and review of literature. AB - BACKGROUND: Cardiac lipomas are rare benign tumors of the heart. They are usually asymptomatic and are thus most often diagnosed on autopsies. Symptoms, when present, depend upon the location within the heart. Typical locations are the endocardium of the right atrium and the left ventricle. Diagnostic modality of choice is cardiac MRI. Treatment guidelines have not yet been established due to the very low prevalence of these tumors and are thus guided by the patient's symptomatology. CASE PRESENTATION: We describe a case of an invasive cardiac lipoma, wherein the initial symptom of the patient was shortness of breath. Although the echocardiogram visualized the tumor in the right atrium, a cardiac MRI was performed for better tissue characterization. The MRI revealed a large, fat containing, septated mass in the right atrium with invasion into the inter atrial septum and inferior cavoatrial junction. There was also invasion of the coronary sinus along the inferior and left lateral aspect of the posterior atrioventricular groove. Although the mass appeared to represent a lipoma by imaging characteristics, the unusual extension into the coronary sinus led to consideration of a low-grade liposarcoma in the differential. Thus a pre operative biopsy was performed along with MDM2 gene amplification to rule out a liposarcoma preceding surgical excision. CONCLUSION: Cardiac lipomas are well characterized on cardiac MRI, which is the diagnostic modality of choice. Typical locations are the right atrium and the left ventricle. However, in those with atypical features such as invasion of the coronary sinus, pre-operative biopsy for histopathologic confirmation is imperative to exclude well-differentiated liposarcoma. Our patient with a simple lipoma underwent partial resection to relieve symptoms. We discuss prognosis and treatment of symptomatic cardiac lipomas. PMID- 28088194 TI - Testing a cognitive model to predict posttraumatic stress disorder following childbirth. AB - BACKGROUND: One third of women describes their childbirth as traumatic and between 0.8 and 6.9% goes on to develop posttraumatic stress disorder (PTSD). The cognitive model of PTSD has been shown to be applicable to a range of trauma samples. However, childbirth is qualitatively different to other trauma types and special consideration needs to be taken when applying it to this population. Previous studies have investigated some cognitive variables in isolation but no study has so far looked at all the key processes described in the cognitive model. This study therefore aimed to investigate whether theoretically-derived variables of the cognitive model explain unique variance in postnatal PTSD symptoms when key demographic, obstetric and clinical risk factors are controlled for. METHOD: One-hundred and fifty-seven women who were between 1 and 12 months post-partum (M = 6.5 months) completed validated questionnaires assessing PTSD and depressive symptoms, childbirth experience, postnatal social support, trauma memory, peritraumatic processing, negative appraisals, dysfunctional cognitive and behavioural strategies and obstetric as well as demographic risk factors in an online survey. RESULTS: A PTSD screening questionnaire suggested that 5.7% of the sample might fulfil diagnostic criteria for PTSD. Overall, risk factors alone predicted 43% of variance in PTSD symptoms and cognitive behavioural factors alone predicted 72.7%. A final model including both risk factors and cognitive behavioural factors explained 73.7% of the variance in PTSD symptoms, 37.1% of which was unique variance predicted by cognitive factors. CONCLUSIONS: All variables derived from Ehlers and Clark's cognitive model significantly explained variance in PTSD symptoms following childbirth, even when clinical, demographic and obstetric were controlled for. Our findings suggest that the CBT model is applicable and useful as a way of understanding and informing the treatment of PTSD following childbirth. PMID- 28088195 TI - Automatic liver segmentation based on appearance and context information. AB - BACKGROUND: Automated image segmentation has benefits for reducing clinicians' workload, quicker diagnosis, and a standardization of the diagnosis. METHODS: This study proposes an automatic liver segmentation approach based on appearance and context information. The relationship between neighboring pixels in blocks is utilized to estimate appearance information, which is used for training the first classifier and obtaining the probability distribution map. The map is used for extracting context information, along with appearance features, to train the next classifier. The prior probability distribution map is achieved after iterations and refined through an improved random walk for liver segmentation without user interaction. RESULTS: The proposed approach is evaluated using CT images with eight contemporary approaches, and it achieves the highest VOE, RVD, ASD, RMSD and MSD. It also achieves a high average score of 76 using the MICCAI-2007 Grand Challenge scoring system. CONCLUSIONS: Experimental results show that the proposed method is superior to eight other state of the art methods. PMID- 28088196 TI - The antibacterial activity and mechanism of ginkgolic acid C15:1. AB - BACKGROUND: The present study investigated the antibacterial activity and underlying mechanisms of ginkgolic acid (GA) C15:1 monomer using green fluorescent protein (GFP)-labeled bacteria strains. RESULTS: GA presented significant antibacterial activity against Gram-positive bacteria but generally did not affect the growth of Gram-negative bacteria. The studies of the antibacterial mechanism indicated that large amounts of GA (C15:1) could penetrate GFP-labeled Bacillus amyloliquefaciens in a short period of time, and as a result, led to the quenching of GFP in bacteria. In vitro results demonstrated that GA (C15:1) could inhibit the activity of multiple proteins including DNA polymerase. In vivo results showed that GA (C15:1) could significantly inhibit the biosynthesis of DNA, RNA and B. amyloliquefaciens proteins. CONCLUSION: We speculated that GA (C15:1) achieved its antibacterial effect through inhibiting the protein activity of B. amyloliquefaciens. GA (C15:1) could not penetrate Gram-negative bacteria in large amounts, and the lipid soluble components in the bacterial cell wall could intercept GA (C15:1), which was one of the primary reasons that GA (C15:1) did not have a significant antibacterial effect on Gram-negative bacteria. PMID- 28088198 TI - Does equity in healthcare spending exist among Indian states? Explaining regional variations from national sample survey data. AB - BACKGROUND: Equity and justice in healthcare payment form an integral part of health policy and planning. In the majority of low and middle-income countries (LMICs), healthcare inequalities are further aggravated by Out of Pocket Expenditure (OOPE). This paper examines the pattern of health equity and regional disparities in healthcare spending among Indian states by applying Andersen's behavioural model of healthcare utilization. METHODS: The present study uses data from the 66th quinquennial round of Consumer Expenditure Survey, of the National Sample Survey Organization (NSSO), conducted in 2009-10 by Ministry of Statistics and Programme Implementation (MoSPI), Government of India (GoI). To measure equity and regional disparities in healthcare expenditure, states have been categorized under three heads on the basis of monthly OOPE i.e., Category A (OOPE > =INR 100); Category B (OOPE between INR 50 to 99) and Category C (OOPE < INR 50). Multiple Generalised Linear Regression Model (GLRM) has been employed to explore the effect of various socio-economic covariates on the level of OOPE. RESULTS: The gap in the ratio of average healthcare spending between the poorest and richest households was maximum in Category A states (richest/poorest = 14.60), followed by Category B (richest/poorest 11.70) and Category C (richest/poorest 11.40). Results also indicate geographical concentration of lower level healthcare spending among Indian states (e.g., Odisha, Chhattisgarh and all the north-eastern states). Results from the multivariate analysis suggest that people residing in urban areas, having higher economic status, belonging to non-Muslim communities, non-Scheduled Tribes (STs), and non-poor households spend more on healthcare than their counterparts. CONCLUSIONS: In spite of various efforts by the government to reduce the burden of healthcare spending, widespread inequalities in healthcare expenditure are prevalent. Households with high healthcare needs (SCs/STs, and the poor) are in a more disadvantaged position in terms of spending on health care. It has also been observed that spending on healthcare was comparatively lower among backward or isolated states. No doubt, the overall social security measures should be enhanced, but at the same time, looking at the regional differences, more priority should be assigned to the disadvantaged states to reduce the burden of OOPE. It is proposed that there is need to increase government spending, especially for the disadvantaged states and population, to minimise the burden of OOPE. PMID- 28088197 TI - Production of human pro-relaxin H2 in the yeast Pichia pastoris. AB - BACKGROUND: Initially known as the reproductive hormone, relaxin was shown to possess other therapeutically useful properties that include extracellular matrix remodeling, anti-inflammatory, anti-ischemic and angiogenic effects. All these findings make relaxin a potential drug for diverse medical applications. Its precursor, pro-relaxin, is an 18 kDa protein, that shows activity in in vitro assays. Since extraction of relaxin from animal tissues raises several issues, prokaryotes and eukaryotes were both used as expression systems for recombinant relaxin production. Most productive results were obtained when using Escherichia coli as a host for human relaxin expression. However, in such host, relaxin precipitated in the form of inclusion bodies and, therefore, required several expensive recovery steps as cell lysis, refolding and reduction. RESULTS: To overcome the issues related to prokaryotic expression here we report the production and purification of secreted human pro-relaxin H2 by using the methylotrophic yeast Pichia pastoris as expression host. The methanol inducible promoter AOX1 was used to drive expression of the native and histidine tagged forms of pro-relaxin H2 in dual phase fed-batch experiments on the 22 L scale. Both protein forms presented the correct structure, as determined by mass spectrometry and western blotting analyses, and demonstrated to be biologically active in immune enzymatic assays. The presence of the tag allowed to simplify pro-relaxin purification obtaining higher purity. CONCLUSIONS: This work presents a strategy for microbial production of recombinant human pro-relaxin H2 in Pichia pastoris that allowed the obtainment of biologically active pro-hormone, with a final concentration in the fermentation broth ranging between 10 and 14 mg/L of product, as determined by densitometric analyses. PMID- 28088199 TI - Strategies to reduce the stigma toward people with mental disorders in Iran: stakeholders' perspectives. AB - BACKGROUND: Stigma affects all aspects of mental disorders, and is the most important risk factor for promoting mental health. The aim of this study was to explore strategies effective in reducing the stigma toward people with mental disorders in Iran. METHODS: This qualitative study was conducted from 2013 to 2016. All participants were recruited by purposive sampling method. The majority of them were stakeholders of mental health in Iran. Data were collected through eight individual interviews, two focus groups, and six written narratives. The data were collected, coded and analyzed simultaneously. Content analysis was employed to analyze the qualitative interview data. RESULTS: The major themes that emerged were: "Emphasis on education and changing attitudes", "Changing the culture", "Promoting supportive services", "Role of various organizations and institutions", "Integrated reform of structures and policies to improve the performance of custodians", and "Evidence-based actions". CONCLUSIONS: This study did not investigate the extent of stigma or its origins, rather it examines strategies appropriate for implementation in Iran. Additional studies are needed to evaluate the effectiveness of strategies for reducing the stigma attached to patients with mental disorders. PMID- 28088200 TI - Vitamin D status among the elderly Chinese population: a cross-sectional analysis of the 2010-2013 China national nutrition and health survey (CNNHS). AB - BACKGROUND: Vitamin D inadequacy is common among the elderly, especially within the Asian population. The vitamin D status among healthy adults in the elderly Chinese population was evaluated. METHODS: A total of 6014 healthy adults aged 60 years or older (2948 men, 3066 women) participated in this descriptive cross sectional analysis. Possible predictors of vitamin D inadequacy were evaluated via multiple logistic regression analyses. RESULTS: The median serum 25 hydroxyvitamin D (25(OH)D) levels were 61.0 nmol/l (interquartile range (IQR) 44.3-80.6, range 5.1-154.5) for men and 53.7 nmol/l (IQR 38.8-71.0, range 6.0 190.0) for women, with 34.1% (95% confidence interval (CI) 32.4-35.8) of men and 44.0% (95% CI 42.2-45.8) of women presenting vitamin D inadequacy (25(OH)D <50 nmol/l). According to the multivariate logistic regression analyses, vitamin D inadequacy was positively correlated with female gender (P <0.0001), underweight (P = 0.0259), the spring season (P <0.0001), low ambient UVB levels (P <0.0001) and living in large cities (P = 0.0026). For men, vitamin D inadequacy was positively correlated with the spring season (P = 0.0015), low ambient UVB levels (P <0.0001) and living in large cities (P = 0.0022); for women, vitamin D inadequacy was positively correlated with the spring season (P = 0.0005) and low ambient UVB levels (P <.0001). CONCLUSIONS: Vitamin D inadequacy is prevalent among the elderly population in China. Because residing in regions with low ambient UVB levels increases the risk of vitamin D inadequacy both for men and women, vitamin D supplementation and sensible sun exposure should be encouraged, especially during the cooler seasons. Further studies are required to determine the optimal vitamin D intake and sun exposure levels to maintain sufficient vitamin D levels in the elderly Chinese population. PMID- 28088201 TI - Anti-allodynic effect of Buja in a rat model of oxaliplatin-induced peripheral neuropathy via spinal astrocytes and pro-inflammatory cytokines suppression. AB - BACKGROUND: Oxaliplatin, a widely used anticancer drug against metastatic colorectal cancer, can induce acute peripheral neuropathy, which is characterized by cold and mechanical allodynia. Activation of glial cells (e.g. astrocytes and microglia) and increase of pro-inflammatory cytokines (e.g. IL-1beta and TNF alpha) in the spinal cord play a crucial role in the pathogenesis of neuropathic pain. Our previous study demonstrated that Gyejigachulbu-Tang (GBT), a herbal complex formula, alleviates oxaliplatin-induced neuropathic pain in rats by suppressing spinal glial activation. However, it remains to be elucidated whether and how Buja (Aconiti Tuber), a major ingredient of GBT, is involved in the efficacy of GBT. METHODS: Cold and mechanical allodynia induced by an oxaliplatin injection (6 mg/kg, i.p.) in Sprauge-Dawley rats were evaluated by a tail immersion test in cold water (4 degrees C) and a von Frey hair test, respectively. Buja (300 mg/kg) was orally administrated for five consecutive days after the oxaliplatin injection. Glial activation in the spinal cord was quantified by immunohistochemical staining using GFAP (for astrocytes) and Iba-1 (for microglia) antibodies. The amount of spinal pro-inflammatory cytokines, IL 1beta and TNF-alpha, were measured by ELISA. RESULTS: Significant behavioral signs of cold and mechanical allodynia were observed 3 days after an oxaliplatin injection. Oral administration of Buja significantly alleviated oxaliplatin induced cold and mechanical allodynia by increasing the tail withdrawal latency to cold stimuli and mechanical threshold. Immunohistochemical analysis showed the activation of astrocytes and microglia and the increase of the IL-1beta and TNF alpha levels in the spinal cord after an oxaliplatin injection. Administration of Buja suppressed the activation of spinal astrocytes without affecting microglial activation and down-regulated both IL-1beta and TNF-alpha levels in the spinal cord. CONCLUSIONS: Our results indicate that Buja has a potent anti-allodynic effect in a rat model of oxaliplatin-induced neuropathic pain, which is associated with the inhibition of activation of astrocytes and release of pro inflammatory cytokines in the spinal cord. Thus, our findings suggest that administration of Buja could be an alternative therapeutic option for the management of peripheral neuropathy, a common side-effect of oxaliplatin. PMID- 28088202 TI - Association between depression and fruit and vegetable consumption among adults in South Asia. AB - BACKGROUND: In recent years there has been a growing research interest regarding the impact of dietary behaviour on mental health outcomes. The present study aimed to investigate the association between fruit and vegetable (F&V) consumption and depression in three south Asian countries- Bangladesh, India and Nepal. METHODS: Cross-sectional data were obtained from World Health Survey of WHO conducted during 2002-04. In total 14,133 adult subjects (Bangladesh 3262, India 7594, Nepal 3277) aged 18 years and above were included in the study. Outcome variables were Self-Reported Depression (SRD) during last 30 days and 12 months. Multivariable regression methods were used to explore the association between F&V consumption and depression. RESULTS: Prevalence of Self-Reported Depression during past 12 months were respectively 39%, 17.7%, and 49.9% for Bangladesh, India and Nepal. In India, those who consumed less than five servings of vegetables were respectively 41% [AOR = 1.41; 95%CI = 0.60-3.33] and 57% [AOR = 1.57; 95%CI = 0.93-2.64] more likely to report severe-extreme and mild-moderate depression during past 30 days compared to those who consumed five servings a day. Regarding fruit consumption, compared to those who consumed five servings a day, the odds of severe-extreme and mild-moderate SRD were respectively 3.5 times [AOR = 3.48; 95%CI = 1.216-10.01] and 45% [AOR = 1.44; 95%CI = 0.89-2.32] higher in Bangladesh, and 2.9 times [AOR = 2.92; 95%CI = 1.12-7.64] and 42% higher [AOR = 1.41; 95%CI = 0.89-2.24] in Nepal compared to those who consumed less than five servings a day during last 30 days. CONCLUSION: Daily intake of less than five servings of F&V was associated with higher odds of depression. Nutrition programs aimed at promoting F&V consumption might prove beneficial to reduce the prevalence of depression in south Asian population. Further studies are required to understand the factors limiting the adequate consumption of F&V. PMID- 28088203 TI - A 3-Arm randomised controlled trial of Communicating Healthy Beginnings Advice by Telephone (CHAT) to mothers with infants to prevent childhood obesity. AB - BACKGROUND: With an increasing prevalence of obesity in young children globally, there is an urgent need for the development of effective early interventions. A previous Healthy Beginnings Trial using a nurse-led home visiting program has demonstrated that providing mothers with evidence-based advice can improve maternal practice regarding obesity prevention, and can reduce Body Mass Index (BMI) in the first few years of life. However, the costs for scale-up of home visiting limit its population reach. This trial aims to determine the efficacy of Communicating Healthy Beginnings Advice by Telephone (CHAT) to mothers with infants in improving infant feeding practices and preventing the early onset of childhood overweight and obesity. METHODS/DESIGN: We propose a 3-arm randomised controlled trial (RCT) with a consecutive sample of 1056 mothers with their newborn children in New South Wales (NSW) Australia. Pregnant women who are between weeks 28 and 34 of their pregnancy will be invited to participate in the CHAT trial. Informed consent will be obtained, and after baseline data collection, participants will be randomly allocated to the telephone intervention, text messaging intervention, or the control group. The intervention comprises telephone consultations or text messages, together with 6 intervention packages being mailed at specific times from the third trimester of pregnancy until 12 months post birth. The main trial outcome measures include a) duration of breastfeeding, b) timing of introduction of solids, c) nutrition behaviours, physical activity and television viewing, and d) weight and BMI z-score at 12 and 24 months, e) cost-effectiveness, as well as f) feasibility and acceptability of the interventions. DISCUSSION: The results will ascertain whether early intervention using telephone consultation or text messaging together with staged mailed intervention resources can be feasible and effective in improving infant feeding practices, physical activity and reducing children's BMI in the early years of life. If proven to be feasible, effective as well as cost-effective, the trial results will inform a series of recommendations for policy and practice related to promoting healthy infant feeding and physical activity in young children in the first years of life. TRIAL REGISTRATION: The CHAT Trial is registered with the Australian Clinical Trial Registry ( ACTRN12616001470482p ). It was registered on October 21, 2016. PMID- 28088204 TI - The ecology of medical care on an isolated island in Okinawa, Japan: a retrospective open cohort study. AB - BACKGROUND: We aimed to describe the ecology of medical care on an isolated island with limited access to secondary care, and to evaluate the gatekeeping function of the island's primary care clinic through comparison with a previous nationwide survey. METHODS: We conducted this retrospective, open cohort study on Iheya, an isolated island in Okinawa Prefecture that has one primary care clinic. We considered Iheya as unique location in which to examine the role of primary care in Japan. Participants were patients who visited the island's clinic between February 1, 2013 and January 31, 2014. We calculated the number of visits to the clinic and referrals to off-island medical facilities using electronic medical records. We also compared data for Iheya with a nationwide survey conducted in 2003. RESULTS: Iheya had 1314 inhabitants in 2013. Of the 5682 visits to the clinic in the 1-year study period, 290 people were referred to off-island medical institutions. There were 64 referrals to emergency departments; of these, 57 people were admitted to hospital. The rate of visits to the clinic per month per 1000 inhabitants was 360.4 visits (95% confidence interval: 351.0-369.7). Of these, 18.4 (16.3-20.5) were referred off-island, with 4.1 (3.1-5.1) referrals to emergency departments and 3.6 (2.6-4.6) hospitalizations. Despite the high incidence of visits to the primary care clinic, the rates of hospital-based outpatient clinic visits, emergency department visits, and hospitalizations were lower than rates reported in a previous Japanese study. CONCLUSIONS: This suggests that several dimensions of primary care, its gatekeeping function in particular, are likely to play important roles in this geographical setting. PMID- 28088205 TI - Quercetin improves macrophage reverse cholesterol transport in apolipoprotein E deficient mice fed a high-fat diet. AB - BACKGROUND: Quercetin, one of the most widely distributed flavonoids in plants, has been demonstrated to reduce hyperlipidaemia and atherosclerotic lesion formation. Reverse cholesterol transport (RCT) plays a crucial role in exporting cholesterol from peripheral cells, which is one mechanism utilized in the prevention and treatment of atherosclerosis. The aim of this study is to investigate whether quercetin reduces lipid accumulation by improving RCT in vivo. METHODS: Apolipoprotein E-deficient mice fed a high-fat diet were used to investigate the effect of quercetin on RCT by an isotope tracing method, and the underlying mechanisms were clarified by molecular techniques. RESULTS: These novel results demonstrated that quercetin significantly improved [3H]-cholesterol transfer from [3H]-cholesterol-loaded macrophages to the plasma (approximately 34% increase), liver (30% increase), and bile (50% increase) and finally to the feces (approximately 40% increase) for excretion in apolipoprotein E-deficient mice fed a high-fat diet. Furthermore, quercetin markedly increased the cholesterol accepting ability of plasma and high-density lipoprotein (HDL) and dramatically decreased the content of malondialdehyde in plasma and oxidized phosphocholine carried by HDL. Therefore, the underlying mechanisms of quercetin in improving RCT may be partially due to the elevated cholesterol accepting ability of HDL, the increased expression levels of proteins related to RCT, such as ATP-binding cassettes (ABC) A1 and G1, and the improved antioxidant activity of HDL . CONCLUSION: Quercetin accelerates RCT in an atherosclerosis model, which is helpful in clarifying the lipid-lowering effect of quercetin. PMID- 28088207 TI - Cytokine and neuropeptide levels are associated with pain relief in patients with chronically painful total knee arthroplasty: a pilot study. AB - BACKGROUND: There are few studies with an assessment of the levels of cytokines or neuropeptides as correlates of pain and pain relief in patients with painful joint diseases. Our objective was to assess whether improvements from baseline to 2-months in serum cytokine, chemokine and substance P levels were associated with clinically meaningful pain relief at 2-months post-injection in patients with painful total knee arthroplasty (TKA). METHODS: Using data from randomized trial of 60 TKAs, we assessed the association of change in cytokine/chemokine/Substance P levels with primary study outcome, clinically important improvement in Western Ontario McMaster Osteoarthritis Index (WOMAC) pain subscale at 2-months post injection using Student's t-tests and Spearman's correlation coefficient (non parametric). Patients were categorized as pain responders (20-point reduction or more on 0-100 WOMAC pain) vs. pain non-responders. Sensitivity analysis used 0-10 daytime pain numeric rating scale (NRS) instead of WOMAC pain subscale. RESULTS: In a pilot study, compared to non-responders (n = 23) on WOMAC pain scale at 2 months, pain responders (n = 12) had significantly greater increase in serum levels of IL-7, IL-10, IL-12, eotaxin, interferon gamma and TNF-alpha from baseline to 2-months post-injection (p < 0.05 for all). Change in several cytokine/chemokine and substance P levels from pre-injection to 2-month follow-up correlated significantly with change in WOMAC pain with correlation coefficients ranging -0.37 to -0.51: IL-2, IL-7, IL-8, IL-9, IL-16, IL-12p, GCSF, IFN gamma, IP-10, MCP, MIP1b, TNF-alpha and VEGF (n = 35). Sensitivity analysis showed that substance P decreased significantly more from baseline to 2-months in the pain responders (0.54 +/- 0.53; n = 10) than in the pain non-responders (0.48 +/- 1.18; n = 9; p = 0.023) and that this change in serum substance P correlated significantly with change in daytime NRS pain, correlation coefficient was 0.53 (p = 0.021; n = 19). Findings should be interpreted with caution, since cytokine analyses were performed for a sub-group of the entire trial population. CONCLUSION: Serum cytokine, chemokine and Substance P levels correlated with pain response in patients with painful TKA after an intra-articular injection in a randomized trial. PMID- 28088206 TI - Comparing accelerometer, pedometer and a questionnaire for measuring physical activity in bronchiectasis: a validity and feasibility study? AB - BACKGROUND: There are challenges for researchers and clinicians to select the most appropriate physical activity tool, and a balance between precision and feasibility is needed. Currently it is unclear which physical activity tool should be used to assess physical activity in Bronchiectasis. The aim of this research is to compare assessment methods (pedometer and IPAQ) to our criterion method (ActiGraph) for the measurement of physical activity dimensions in Bronchiectasis (BE), and to assess their feasibility and acceptability. METHODS: Patients in this analysis were enrolled in a cross-sectional study. The ActiGraph and pedometer were worn for seven consecutive days and the IPAQ was completed for the same period. Statistical analyses were performed using SPSS 20 (IBM). Descriptive statistics were used; the percentage agreement between ActiGraph and the other measures were calculated using limits of agreement. Feedback about the feasibility of the activity monitors and the IPAQ was obtained. RESULTS: There were 55 (22 male) data sets available. For step count there was no significant difference between the ActiGraph and Pedometer, however, total physical activity time (mins) as recorded by the ActiGraph was significantly higher than the pedometer (mean +/- SD, 232 (75) vs. 63 (32)). Levels of agreement between the two devices was very good for step count (97% agreement); and variation in the levels of agreement were within accepted limits of +/-2 standard deviations from the mean value. IPAQ reported more bouted- moderate - vigorous physical activity (MVPA) [mean, SD; 167(170) vs 6(9) mins/day], and significantly less sedentary time than ActiGraph [mean, SD; 362(115) vs 634(76) vmins/day]. There were low levels of agreement between the two tools (57% sedentary behaviour; 0% MVPA10+), with IPAQ under-reporting sedentary behaviour and over-reporting MVPA10+ compared to ActiGraph. The monitors were found to be feasible and acceptable by participants and researchers; while the IPAQ was accepta ble to use, most patients required assistance to complete it. CONCLUSIONS: Accurate measurement of physical activity is feasible in BE and will be valuable for future trials of therapeutic interventions. ActiGraph or pedometer could be used to measure simple daily step counts, but ActiGraph was superior as it measured intensity of physical activity and was a more precise measure of time spent walking. The IPAQ does not appear to represent an accurate measure of physical activity in this population. TRIAL REGISTRATION: Clinical Trials Registration Number NCT01569009 : Physical Activity in Bronchiectasis. PMID- 28088208 TI - Stirring the motivational soup: within-person latent profiles of motivation in exercise. AB - BACKGROUND: The purpose of the present study was to use a person-oriented analytical approach to identify latent motivational profiles, based on the different behavioural regulations for exercise, and to examine differences in satisfaction of basic psychological needs (competence, autonomy and relatedness) and exercise behaviour across these motivational profiles. METHODS: Two samples, consisting of 1084 and 511 adults respectively, completed exercise-related measures of behavioural regulation and psychological need satisfaction as well as exercise behaviour. Latent profile analyses were used to identify motivational profiles. RESULTS: Six profiles, representing different combinations of regulations for exercise, were found to best represent data in both samples. Some profiles were found in both samples (e.g., low motivation profile, self determined motivation profile and self-determined with high introjected regulation profile), whereas others were unique to each sample. In line with the Self-Determination Theory, individuals belonging to more self-determined profiles demonstrated higher scores on need satisfaction. CONCLUSIONS: The results support the notions of motivation being a multidimensional construct and that people have different, sometimes competing, reasons for engaging in exercise. The benefits of using person-oriented analyses to examine within-person interactions of motivation and different regulations are discussed. PMID- 28088209 TI - Pulmonary embolism in non-brain tumor patients after surgery-a retrospective study in China. AB - BACKGROUND: The incidence rate of pulmonary emboli (PE) is high in tumor patients; however, the morbidity and mortality associated with the development of PE after tumor surgery are unknown. We studied the clinical profiles and outcomes of patients with PE after non-brain tumor surgery. METHODS: We retrospectively screened 55,967 patients who underwent non-brain tumor surgery at the Peking University Cancer Hospital from January 2008 to June 2015. Among them, 76 patients who were diagnosed with PE were enrolled in our study. Factors impacting the overall survival at 90 days were analyzed. A Kaplan-Meier curve was plotted for time to death or until day 90. Cox proportional hazard modeling was performed for univariate- and multivariate-adjusted factor analyses. RESULTS: The morbidity rate was approximately 135.8 per 100,000 non-brain tumor surgery patients (possibly underestimated). When treated, seven patients had major bleeding, and 14 patients had clinically relevant non-major bleeding, which represented 9.2 and 18.4% of all the patients, respectively. The 3-month overall mortality rate was 11.8% in our study. The Acute Physiology and Chronic Health Evaluation II (APACHE II) score and platelet distribution width (PDW) were independent risk factors for the prognosis of PE after non-brain surgery (P values of 0.001 and 0.016, respectively). CONCLUSIONS: Treatment of PE in non-brain tumor surgical patients remained a challenge due to the high bleeding rate. The APACHE II score and PDW were independent prognostic factors of survival in patients with PE after non brain tumor surgery; however, the study power was limited. PMID- 28088210 TI - Endothelial function in children with a history of henoch schonlein purpura. AB - BACKGROUND: Although Henoch-Schonlein purpura (HSP) is the most common form of systemic vasculitis in children, the long term effect of HSP on endothelial function is still not clear. The aim of our study was to evaluate the long term effect of HSP on endothelial function in children and adolescents. METHODS: This research was an observational prospective study. The study group comprised of 19 children diagnosed with HSP. The minimum interval between the diagnosis with HSP and endothelial testing was 5 months. Endothelial function evaluation was assessed by a noninvasive technology named peripheral arterial tonometry, using an EndoPATTM device. This method measures blood flow in the limb, in response to arterial occlusion, and calculates a Reactive Hyperemic Index (RHI) as an index of endothelial function. RHI values of the study group were compared to those of a known control group. RESULTS: Nineteen children and adolescents with HSP underwent endothelial function studies. Endothelial function was compared to that of a known control group comprising of 23 healthy children and adolescents. The two groups had similar characteristics, including age, male to female ratio, height, weight and BMI. Mean RHI was 1.81 in the study group, and 1.87 in the control group (p = 0.18). Linear regression of the study group, showed a positive correlation between the time interval from HSP diagnosis to participation in the study, and between the RHI value (r = 0.542, p = 0.016). RHI levels were significantly higher in patients who had endothelial function measured more than 6 years since the diagnosis of HSP compared with those patients with less than 6 years follow up (1.98 + 0.74 vs. 1.38 +/- 0.43 P = 0.037). CONCLUSIONS: These results suggest that HSP causes short term endothelial dysfunction that improves with time. PMID- 28088211 TI - Innovation contests to promote sexual health in China: a qualitative evaluation. AB - BACKGROUND: Innovation contests call on non-experts to help solve problems. While these contests have been used extensively in the private sector to increase engagement between organizations and clients, there is little data on the role of innovation contests to promote health campaigns. We implemented an innovation contest in China to increase sexual health awareness among youth and evaluated community engagement in the contest. METHODS: The sexual health image contest consisted of an open call for sexual health images, contest promotion activities, judging of entries, and celebrating contributions. Contest promotion activities included in-person and social media feedback, classroom didactics, and community driven activities. We conducted 19 semi-structured interviews with a purposive sample to ensure a range of participant scores, experts and non-expert participants, submitters and non-submitters. Transcripts of each interview were coded with Atlas.ti and evaluated by three reviewers. RESULTS: We identified stages of community engagement in the contest which contributed to public health impact. Community engagement progressed across a continuum from passive, moderate, active, and finally strong engagement. Engagement was a dynamic process that appeared to have little relationship with formally submitting an image to the contest. Among non-expert participants, contest engagement increased knowledge, healthy attitudes, and empowered participants to share ideas about safe sex with others outside of the contest. Among experts who helped organize the contest, the process of implementing the contest fostered multi-sectoral collaboration and re-oriented public health leadership towards more patient centered public health campaigns. CONCLUSION: The results of this study suggest that innovation contests may be a useful tool for public health promotion by enhancing community engagement and re-orienting health campaigns to make them more patient-centered. PMID- 28088212 TI - Ultrasensitive detection of oncogenic human papillomavirus in oropharyngeal tissue swabs. AB - BACKGROUND: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) caused by oncogenic human papillomavirus (HPV) is rising worldwide. HPV-OPSCC is commonly diagnosed by RT-qPCR of HPV E6 and E7 oncoproteins or by p16 immunohistochemistry (IHC). Droplet digital PCR (ddPCR) has been recently reported as an ultra-sensitive and highly precise method of nucleic acid quantification for biomarker analysis. To validate the use of a minimally invasive assay for detection of oncogenic HPV based on oropharyngeal swabs using ddPCR. Secondary objectives were to compare the accuracy of ddPCR swabs to fresh tissue p16 IHC and RT-qPCR, and to compare the cost of ddPCR with p16 IHC. METHODS: We prospectively included patients with p16+ oral cavity/oropharyngeal cancer (OC/OPSCC), and two control groups: p16- OC/OPSCC patients, and healthy controls undergoing tonsillectomy. All underwent an oropharyngeal swab with ddPCR for quantitative detection of E6 and E7 mRNA. Surgical specimens had p16 IHC performed. Agreement between ddPCR and p16 IHC was determined for patients with p16 positive and negative OC/OPSCC as well as for healthy control patients. The sensitivity and specificity of ddPCR of oropharyngeal swabs were calculated against p16 IHC for OPSCC. RESULTS: 122 patients were included: 36 patients with p16+OPSCC, 16 patients with p16-OPSCC, 4 patients with p16+OCSCC, 41 patients with p16-OCSCC, and 25 healthy controls. The sensitivity and specificity of ddPCR of oropharyngeal swabs against p16 IHC were 92 and 98% respectively, using 20-50 times less RNA than that required for conventional RT-qPCR. Overall agreement between ddPCR of tissue swabs and p16 of tumor tissue was high at K = 0.826 [0.662-0.989]. CONCLUSION: Oropharyngeal swabs analyzed by ddPCR is a quantitative, rapid, and effective method for minimally invasive oncogenic HPV detection. This assay represents the most sensitive and accurate mode of HPV detection in OPSCC without a tissue biopsy in the available literature. PMID- 28088213 TI - Glycine-alanine dipeptide repeat protein contributes to toxicity in a zebrafish model of C9orf72 associated neurodegeneration. AB - BACKGROUND: The most frequent genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) is the expansion of a GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 (C9orf72) locus. The pathological hallmarks observed in C9orf72 repeat expansion carriers are the formation of RNA foci and deposition of dipeptide repeat (DPR) proteins derived from repeat associated non-ATG (RAN) translation. Currently, it is unclear whether formation of RNA foci, DPR translation products, or partial loss of C9orf72 predominantly drive neurotoxicity in vivo. By using a transgenic approach in zebrafish we address if the most frequently found DPR in human ALS/FTLD brain, the poly-Gly-Ala (poly-GA) protein, is toxic in vivo. METHOD: We generated several transgenic UAS responder lines that express either 80 repeats of GGGGCC alone, or together with a translation initiation ATG codon forcing the translation of GA80-GFP protein upon crossing to a Gal4 driver. The GGGGCC repeat and GA80 were fused to green fluorescent protein (GFP) lacking a start codon to monitor protein translation by GFP fluorescence. RESULTS: Zebrafish transgenic for the GGGGCC repeat lacking an ATG codon showed very mild toxicity in the absence of poly-GA. However, strong toxicity was induced upon ATG initiated expression of poly-GA, which was rescued by injection of an antisense morpholino interfering with start codon dependent poly-GA translation. This morpholino only interferes with GA80-GFP translation without affecting repeat transcription, indicating that the toxicity is derived from GA80-GFP. CONCLUSION: These novel transgenic C9orf72 associated repeat zebrafish models demonstrate poly-GA toxicity in zebrafish. Reduction of poly-GA protein rescues toxicity validating this therapeutic approach to treat C9orf72 repeat expansion carriers. These novel animal models provide a valuable tool for drug discovery to reduce DPR associated toxicity in ALS/FTLD patients with C9orf72 repeat expansions. PMID- 28088214 TI - Determinants and materno-fetal outcomes related to cesarean section delivery in private and public hospitals in low- and middle-income countries: a systematic review and meta-analysis protocol. AB - BACKGROUND: Despite the well-established morbidity, mortality, long-term effects, and unnecessary extra-cost burden associated with cesarean section delivery (CSD) worldwide, its rate has grown exponentially. This has become a great topical challenge for the international healthcare community and individual countries. Estimated at three times the acceptable rate as defined by the World Health Organization in 1985, the continued upward trend has been fuelled by higher income countries. Some low- and middle-income countries (LMICs) have now taken the lead, and the factors contributing to this situation are poorly understood. The expansion of the private healthcare sector may be playing a significant role. Distinguishing between the public and private hospitals' role is critical in this investigation as it has not yet been approached. This review aims to systematically synthesize knowledge on the determinants of the CSD rate rise in private and public hospitals in LMICs and to investigate materno-fetal and materno-infant outcomes of CSD in perinatal period, between private and public hospitals. METHODS/DESIGN: We will include studies published in English, French, Spanish, and Portuguese since 2000, using any experimental design, including randomized controlled trials (RCTs), non-RCTs, quasi-experimental, before and after studies, and interrupted time series. Outcomes of interest are the determinants of CSD and materno-fetal and materno-infant outcomes. We will only include studies carried out in private and public hospitals in LMICs. The literature searches will be conducted in the following databases: MEDLINE, Embase, CINAHL, Cochrane database, LILACS, and HINARI. We will also include unpublished studies in the gray literature (theses and technical reports). Using the two-person approach, two independent review authors will screen eligible articles, extract data, and assess risk of bias. Disagreements will be resolved through discussion with a third author. Results will be presented as structured summaries of the included studies. If possible, a meta-analysis will be conducted and, subsequently, an analysis for heterogeneity will be implemented. DISCUSSION: The proposed systematic review of the CSD rate rise will provide up-to-date evidence in regard to differences in proportions, determinants, and materno-fetal and materno-infant outcomes in perinatal period, between private and public hospitals in LMICs. We believe that this knowledge synthesis will help to shed light on the evidence and support evidence-informed decision-making with a view to addressing the issue in LMICs. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016036871. PMID- 28088215 TI - Non-associative versus associative learning by foraging predatory mites. AB - BACKGROUND: Learning processes can be broadly categorized into associative and non-associative. Associative learning occurs through the pairing of two previously unrelated stimuli, whereas non-associative learning occurs in response to a single stimulus. How these two principal processes compare in the same learning task and how they contribute to the overall behavioural changes brought about by experience is poorly understood. We tackled this issue by scrutinizing associative and non-associative learning of prey, Western flower thrips Frankliniella occidentalis, by the predatory mite, Neoseiulus californicus. We compared the behaviour of thrips-experienced and -naive predators, which, early in life, were exposed to either thrips with feeding (associative learning), thrips without feeding (non-associative learning), thrips traces on the surface (non-associative learning), spider mites with feeding (thrips-naive) or spider mite traces on the surface (thrips-naive). RESULTS: Thrips experience in early life, no matter whether associative or not, resulted in higher predation rates on thrips by adult females. In the no-choice experiment, associative thrips experience increased the predation rate on the first day, but shortened the longevity of food-stressed predators, a cost of learning. In the choice experiment, thrips experience, no matter whether associative or not, increased egg production, an adaptive benefit of learning. CONCLUSIONS: Our study shows that both non-associative and associative learning forms operate in foraging predatory mites, N. californicus. The non-rewarded thrips prey experience produced a slightly weaker, but less costly, learning effect than the rewarded experience. We argue that in foraging predatory mites non-associative learning is an inevitable component of associative learning, rather than a separate process. PMID- 28088216 TI - Immunohistochemical features of giant cell ependymoma of the filum terminale with unusual clinical and radiological presentation. AB - BACKGROUND: Giant cell ependymoma of the filum terminale is a rare variant, generally manifested as a well-circunscribed intradural mass with an indolent biological behavior. CASE PRESENTATION: We describe the case of a 48-year-old Mexican female who non-relevant past medical history, that developed a GCE of the filum terminale. Magnetic resonance imaging and computed tomography revealed the presence of an intra-axial tumor extending from L3 to L5 with extra-medullary invasion. Therefore the tumor was considered unresectable and only incisional biopsy was obtained, establishing the tentative diagnosis of a poorly differentiated neoplasia. A second evaluation of the case revealed the presence of numerous non-cohesive pleomorphic giant cells with intranuclear inclusions and broad eosinophilic cytoplasm, alternating with intermediate size cells with round, hyperchromatic nuclei and forming a perivascular pseudo-rosettes pattern. The ependymal phenotype was supported by light microscopy and corroborated by immunohistochemistry analysis. The patient was subsequently treated with radiotherapy 54Gy. She is alive after a 27-month follow-up, with residual disease, difficulty ambulating and pain. CONCLUSIONS: GCE of filum terminale may have an atypical clinical and radiological presentation, albeit with invasive characteristics and anaplasia on histologic analysis. However, its biological behavior is indolent and associated to longer survival. Due to the presence of giant cells, the differential diagnosis of other primary neoplasias at that site were considered, including paraganglioma, malignant peripheral nerve sheath tumors as well as metastatic malignant melanoma, adrenal carcinoma, thyroid gland carcinoma and urothelial carcinoma, that may all harbor giant cells. PMID- 28088217 TI - Surgical treatment of upper cervical spine metastases: a retrospective study of 39 cases. AB - BACKGROUND: The surgical treatment of upper cervical spine metastases are controversial up to now. By summarizing and analyzing the clinical data of the upper cervical spine involved metastases treated surgically in our center, we mainly aimed to investigate the surgical decisions and outcomes so as to provide more references for the clinical treatment of this special and complex spine metastasis. METHODS: We evaluated the patients' pre- and post-operative neck pain and neurologic function with paired t test, followed by the statistics of the selection of surgical approaches, ways of reconstruction, and related complications. Moreover, the Kaplan-Meier survival analysis was adopted to analyze the patients' survival according to different growth group (rapid, moderate, and slow). RESULTS: There were 39 patients with atlantoaxial metastases in this study. The most common symptom (94.87%) was occipital-cervical pain, which relieved greatly after surgical interventions (p < 0.01). The metastases mainly resulted from lung cancer and nasopharyngeal cancer with an incidence of 38.46 and 10.26%, respectively. As to different growth group, the rapid-growth tumors accounted for 69.23% in all atlantoaxial metastases. Tumor resection and stabilization were performed mainly via the combined anterior and posterior approach (66.67%). The 1-, 2-, and 3-year overall survival rate at the last follow-up was 58.5, 40, and 28.3%, respectively, with a median survival time of 18 months. The rate of complications associated with the surgical intervention was 12.82% (5/39), which is lower than that of the previous reports and generally controllable. CONCLUSIONS: Relatively radical interventions with surgery for upper cervical spine metastases offered satisfactory outcomes with a low mortality. Together with adjuvant therapy, surgical treatment benefits patients with atlantoaxial metastases by relieving regional pain, restoring or improving the neurologic function, stabilizing the quality of life, and prolonging the survival time of such patients. PMID- 28088219 TI - The unhealthy food environment does not modify the association between obesity and participation in the Supplemental Nutrition Assistance Program (SNAP) in Los Angeles County. AB - BACKGROUND: Participation in the Supplemental Nutrition Assistance Program (SNAP) has been linked to an increased risk of obesity, but not much is known about the mechanisms behind this association. The objective of this study was to determine if the neighborhood density of unhealthy food outlets modifies the association between obesity and participation in SNAP. METHODS: Data comes from the first wave of the Los Angeles Family and Neighborhood Survey; included are a subsample of adults (18+ years) who were SNAP participants or eligible non-participants (N = 1,176). We carried out multilevel analyses with obesity (BMI >= 30 Kg/m2), SNAP participation, and the neighborhood density of unhealthy food outlets as dependent, independent and modifying variables, respectively, controlling for age, gender, race/ethnicity, marital status, working status, mental health, and neighborhood poverty. RESULTS: SNAP participants had double the odds of obesity compared to eligible non-participants (OR = 2.02; 95%CI = 1.44-2.83). However, the neighborhood density of unhealthy food outlets did not modify this association. CONCLUSIONS: SNAP participation was associated with higher odds of obesity in our primarily Hispanic sample in Los Angeles County, with no effect modification found for the unhealthy portion of the food environment. More research is needed with additional food environment measures to confirm our null findings. Additional research is needed to elucidate the mechanisms linking SNAP participation and obesity as they remain unclear. PMID- 28088218 TI - Spinal versus general anaesthesia in surgery for inguinodynia (SPINASIA trial): study protocol for a randomised controlled trial. AB - BACKGROUND: Chronic inguinodynia (groin pain) is a common complication following open inguinal hernia repair or a Pfannenstiel incision but may also be experienced after other types of (groin) surgery. If conservative treatments are to no avail, tailored remedial surgery, including a neurectomy and/or a (partial) meshectomy, may be considered. Retrospective studies in patients with chronic inguinodynia suggested that spinal anaesthesia is superior compared to general anaesthesia in terms of pain relief following remedial operations. This randomised controlled trial is designed to study the effect of type of anaesthesia (spinal or general) on pain relief following remedial surgery for inguinodynia. METHODS: A total of 190 adult patients who suffer from unacceptable chronic (more than 3 months) inguinodynia, as subjectively judged by the patients themselves, are included. Only patients scheduled to undergo a neurectomy and/or a meshectomy by an open approach are considered for inclusion and randomised to spinal or general anaesthesia. Patients are excluded if pain is attributable to abdominal causes or if any contraindications for either type of anaesthesia are present. Primary outcome is effect of type of anaesthesia on pain relief. Secondary outcomes include patient satisfaction, quality of life, use of analgesics and (in)direct medical costs. Patient follow-up period is one year. DISCUSSION: The first patient was included in January 2016. The expected trial deadline is December 2019. Potential effects are deemed related to the entire setting of type of anaesthesia. Since any setting is multifactorial, all of these factors may influence the outcome measures. This is the first large randomised controlled trial comparing the two most frequently used anaesthetic techniques in remedial surgery for groin pain. There is a definite need for evidence-based strategies to optimise results of these types of surgery. Besides pain relief, other important patient-related outcome measures are assessed to include patient's perspectives on outcome. TRIAL REGISTRATION: The protocol (protocol number NL54115.015.15 ) is approved by the Medical Ethics Committee of Maxima Medical Centre, Veldhoven, The Netherlands. The study protocol was registered at www.trialregister.nl (NTR registration number: 5586) on 15 January 2016. PMID- 28088220 TI - Anti-inflammatory potential of ellagic acid, gallic acid and punicalagin A&B isolated from Punica granatum. AB - BACKGROUND: Punica granatum (pomegranate), an edible fruit originating in the Middle East, has been used as a traditional medicine for treatment of pain and inflammatory conditions such as peptic ulcer. The numerous risks associated with nonsteroidal anti-inflammatory drugs (NSAIDs) for treatment of pain and inflammation give rise to using medicinal herbs as alternative therapies. This study aimed to evaluate the anti-inflammatory effect of isolated compounds from the ethyl acetate (EtOAc) fraction of P. granatum by determination of their inhibitory effects on lipopolysaccharide (LPS), stimulated nitric oxide (NO), prostaglandin E2 (PGE-2), interleukin-6 (IL-6) and cyclooxxgenase-2 (COX-2) release from RAW264.7 cells. METHODS: The compounds ellagic acid, gallic acid and punicalagin A&B were isolated from EtOAc by high performance liquid chromatography (HPLC) and further identified by mass spectrometry (MS). The inhibitory effect of ellagic acid, gallic acid and punicalagin A&B were evaluated on the production of LPS-induced NO by Griess reagent, PGE-2 and IL-6 by immunoassay kit and prostaglandin E2 competitive ELISA kit, and COX-2 by Western blotting. RESULTS: Ellagic acid, gallic acid and punicalagin A&B potentially inhibited LPS-induced NO, PGE-2 and IL-6 production. CONCLUSION: The results indicate that ellagic acid, gallic acid and punicalagin may be the compounds responsible for the anti-inflammatory potential of P. granatum. PMID- 28088221 TI - Role of pelvic and para-aortic lymphadenectomy in abandoned radical hysterectomy in cervical cancer. AB - BACKGROUND: Cervical cancer (CC) occupies fourth place in cancer incidence and mortality worldwide in women, with 560,505 new cases and 284,923 deaths per year. Approximately, nine of every ten (87%) take place in developing countries. When a macroscopic nodal involvement is discovered during a radical hysterectomy (RH), there is controversy in the literature between resect macroscopic lymph node compromise or abandonment of the surgery and sending the patient for standard chemo-radiotherapy treatment. The objective of this study is to compare the prognosis of patients with CC whom RH was abandoned and bilateral pelvic lymphadenectomy and para-aortic lymphadenectomy was performed with that of patients who were only biopsied or with removal of a suspicious lymph node, treated with concomitant radiotherapy/chemotherapy in the standard manner. METHODS: A descriptive and retrospective study was conducted in two institutions from Mexico and Colombia. Clinical records of patients with early-stage CC programmed for RH with an intraoperative finding of pelvic lymph, para-aortic nodes, or any extracervical involvement that contraindicates the continuation of surgery were obtained. Between January 2007 and December 2012, 42 clinical patients complied with study inclusion criteria and were selected for analysis. RESULTS: In patients with CC whom RH was abandoned due to lymph node affectation, there is no difference in overall survival or in disease-free period between systematic lymphadenectomy and tumor removal or lymph node biopsy, in pelvic lymph nodes as well as in para-aortic lymph nodes, when these patients receive adjuvant treatment with concomitant radiotherapy/chemotherapy. CONCLUSIONS: This is a hypothesis-generator study; thus, the recommendation is made to conduct randomized prospective studies to procure better knowledge on the impact of bilateral pelvic and para-aortic lymphadenectomy on this group of patients. PMID- 28088222 TI - Clinical importance of personality difficulties: diagnostically sub-threshold personality disorders. AB - BACKGROUND: Current categorical classification of personality disorders has been criticized for overlooking the dimensional nature of personality and that it may miss some sub-threshold personality disturbances of clinical significance. We aimed to evaluate the clinical importance of these conditions. For this, we used a simple four-level dimensional categorization based on the severity of personality disturbance. METHODS: The sample consisted of 352 patients admitted to mental health services. All underwent diagnostic assessments (SCID-I and SCID II) and filled in questionnaires concerning their social situation and childhood adversities, and other validated tools, including the Beck Depression Inventory (BDI), Alcohol Use Disorders Identification Test (AUDIT), health-related quality of life (15D), and the five-item Mental Health Index (MHI-5). The patients were categorized into four groups according to the level of personality disturbance: 0 = No personality disturbance, 1 = Personality difficulty (one criterion less than threshold for one or more personality disorders), 2 = Simple personality disorder (one personality disorder), and 3 = Complex/Severe personality disorder (two or more personality disorders or any borderline and antisocial personality disorder). RESULTS: The proportions of the groups were as follows: no personality disturbance 38.4% (n = 135), personality difficulty 14.5% (n = 51), simple personality disorder 19.9% (n = 70), and complex/severe personality disorder 24.4% (n = 86). Patients with no personality disturbance were significantly differentiated (p < 0.05) from the other groups regarding the BDI, 15D, and MHI-5 scores as well as the number of Axis I diagnoses. Patients with complex/severe personality disorders stood out as being worst off. Social dysfunction was related to the severity of the personality disturbance. Patients with a personality difficulty or a simple personality disorder had prominent symptoms and difficulties, but the differences between these groups were mostly non significant. CONCLUSIONS: An elevated severity level of personality disturbance is associated with an increase in psychiatric morbidity and social dysfunction. Diagnostically sub-threshold personality difficulties are of clinical significance and the degree of impairment corresponds to actual personality disorders. Since these two groups did not significantly differ from each other, our findings also highlight the complexity related to the use of diagnostic thresholds for separate personality disorders. PMID- 28088223 TI - Predictors of long term use of psychiatric services of patients with recent-onset schizophrenia: 12 years follow-up. AB - BACKGROUND: The aim of study was to investigate predictors of long term use of psychiatric services of patients with recent-onset schizophrenia. METHODS: A cohort of 50 clinically stable patients with recent-onset schizophrenia was included in a randomized controlled trial comparing early integrated treatment with treatment as usual. Recent onset was defined as emergence of psychotic symptoms for the first time during the preceding 2 years. The follow up period was from the date of randomization and until 12 years after termination of treatment trial, 14 years forward. RESULTS: Score on Brief psychiatric rating scale both at baseline and after 2 years of treatment, suicide attempts during 2 years of treatment and being an inpatient during 2 years of treatment were significant predictors of long term use of services. CONCLUSION: High score on Brief psychiatric rating scale, suicide attempts and being admitted as inpatient early in the course of schizophrenia are possible predictors of long term use of services. TRIAL REGISTRATION: ClinicalTrials.gov NCT00184509 . Registered 15 September 2005. PMID- 28088224 TI - Clinical analysis of Krukenberg tumours in patients with colorectal cancer-a review of 57 cases. AB - BACKGROUND: A Krukenberg tumour (KT) is defined as an ovarian metastasis from a gastrointestinal adenocarcinoma and suggests a terminal condition. This study aimed to identify the prognostic factors affecting the survival of patients with KTs of colorectal origin who receive cytoreductive surgery. METHODS: Medical records of patients who had received cytoreductive surgery and had been pathologically diagnosed with KT of colorectal origin in two centres were reviewed. Information about the patients' clinicopathological features and follow up visit were collected. Factors influencing patient survival were analysed. RESULTS: Fifty-seven patients were included in this study. The median survival time was 35 months. Five-year overall survival was 25%. Patients who had recurrence 2 years after resection of the primary tumour, achieved complete cytoreduction, had metastases confined to the pelvis, had no lymph node involvement, and received systemic chemotherapy had a significantly longer median survival than those who had recurrence at the same time as resection of the primary tumour (P = 0.027), received incomplete cytoreduction (P < 0.001), had metastases beyond the pelvis (P < 0.001), had lymph node involvement (P = 0.011), and did not receive systemic chemotherapy (P = 0.006) on log-rank test. Less extensive metastatic disease, achievement of complete cytoreduction, and use of systemic chemotherapy were significantly associated with improved prognosis on multivariate analysis. CONCLUSIONS: Cytoreductive surgery may confer survival benefits in patients with KTs of colorectal origin who attain complete cytoreduction and whose metastases are confined to the pelvis and when combined with active systemic chemotherapy. PMID- 28088225 TI - Using low-cost drones to map malaria vector habitats. AB - BACKGROUND: There is a growing awareness that if we are to achieve the ambitious goal of malaria elimination, we must compliment indoor-based vector control interventions (such as bednets and indoor spraying) with outdoor-based interventions such as larval source management (LSM). The effectiveness of LSM is limited by our capacity to identify and map mosquito aquatic habitats. This study provides a proof of concept for the use of a low-cost (< $1000) drone (DJI Phantom) for mapping water bodies in seven sites across Zanzibar including natural water bodies, irrigated and non-irrigated rice paddies, peri-urban and urban locations. RESULTS: With flying times of less than 30 min for each site, high-resolution (7 cm) georeferenced images were successfully generated for each of the seven sites, covering areas up to 30 ha. Water bodies were readily identifiable in the imagery, as well as ancillary information for planning LSM activities (access routes to water bodies by road and foot) and public health management (e.g. identification of drinking water sources, mapping individual households and the nature of their construction). CONCLUSION: The drone-based surveys carried out in this study provide a low-cost and flexible solution to mapping water bodies for operational dissemination of LSM initiatives in mosquito vector-borne disease elimination campaigns. Generated orthomosaics can also be used to provide vital information for other public health planning activities. PMID- 28088226 TI - Use of an intraoperative navigation system for retrieving a broken dental instrument in the mandible: a case report. AB - BACKGROUND: A fracture of root canal instruments, with a fractured piece protruding beyond the apex, is a troublesome incident during an endodontic treatment. Locating and retrieving them represents a challenge to maxillofacial surgeons because it is difficult to access due to the proximity between the foreign body and vital structures. Although safe and accurate for surgery, radiographs and electromagnetic devices do not provide a precise three dimensional position. In contrast, computer-aided navigation provides a correlation between preoperatively collected data and intraoperatively encountered anatomy. However, using a navigation system for mandible treatment is difficult as the mobile nature of the mandible complicates its synchronization with the preoperative imaging data during surgery. CASE PRESENTATION: This report describes a case of a dental instrument breakage in the mandible during an endodontic treatment for a restorative dental procedure in a 65-year-old Japanese woman. The broken dental instrument was removed using a minimally invasive approach with a surgical navigation system and an interocclusal splint for a stable, identically repeatable positioning of the mandible. Using the three dimensional position of the navigation probe, a location that best approximated the most anterior extent of the fragment was selected. A minimally invasive vestibular incision was made at this location, a subperiosteal reflection was performed, and the foreign body location was confirmed using a careful navigation system. The instrument was carefully visualized and extruded from the apical to the tooth crown side and was then removed using mosquito forceps through the medullary cavity of the crown side of the tooth. Follow-up was uneventful; her clinical course was good. CONCLUSIONS: The use of a surgical navigation system together with an interocclusal splint enabled the retrieval of a broken dental instrument in a safe and minimally invasive manner without damaging the surrounding vital structures. PMID- 28088227 TI - Simplified Chinese version of the Forgotten Joint Score (FJS) for patients who underwent joint arthroplasty: cross-cultural adaptation and validation. AB - BACKGROUND: The Forgotten Joint Score (FJS) is a newly developed health-related quality of life (HRQoL) questionnaire designed to evaluate the awareness after total knee arthroplasty (TKA). This study cross-culturally adapted and psychometrically validated a simplified Chinese version of the FJS (SC-FJS). METHODS: Cross-cultural adaptation was performed according to the internationally recognized guidelines. One-hundred and fifty participants who underwent primary TKA were recruited in this study. Cronbach's alpha and intra-class correlations were used to determine reliability. Construct validity was analyzed by evaluating the correlations between SC-FJS and the Knee Injury and Osteoarthritis Outcome Score (KOOS) and the short form (36) health survey (SF-36). RESULTS: Each of the 12 items was properly responded and correlated with the total items. SC-FJS had excellent reliability [Cronbach's alpha = 0.907, intra-class correlation coefficient (ICC) = 0.970, 95% CI 0.959-0.978). Elimination of any one item in all did not result in a value of Cronbach's alpha of <0.80. SC-FJS had a high correlation with symptoms (0.67, p < 0.001) and pain (0.60, p < 0.001) domains of KOOS and social functioning (0.66, p < 0.001) domain of SF-36, and it also moderately correlated with function in daily living (0.53, p < 0.001) and function in sport and recreation (0.40, p < 0.001) domains of KOOS, and physical subscale of SF-36 (0.49-0.53, p < 0.001) but had a low (r = 0.20) or not significant (p > 0.05) correlation with mental subscale of SF-36. CONCLUSIONS: SC FJS demonstrated excellent acceptability, internal consistency, reliability, and construct validity, which can be recommended for patients who underwent joint arthroplasty in Mainland China. PMID- 28088228 TI - The loss-of-function mutations and down-regulated expression of ASB3 gene promote the growth and metastasis of colorectal cancer cells. AB - BACKGROUND: Ankyrin repeat and SOCS box protein 3 (ASB3) is a member of ASB family and contains ankyrin repeat sequence and SOCS box domain. Previous studies indicated that it mediates the ubiquitination and degradation of tumor necrosis factor receptor 2 and is likely involved in inflammatory responses. However, its effects on oncogenesis are unclear. This study aimed to investigate the effects of ASB3 on the growth and metastasis of colorectal cancer (CRC). METHODS: We used next-generation sequencing or Sanger sequencing to detect ASB3 mutations in CRC specimens or cell lines, and used real-time quantitative polymerase chain reaction, Western blotting, and immunohistochemical or immunofluorescence assay to determine gene expression. We evaluated cell proliferation by MTT and colony formation assays, tested cell cycle distribution by flow cytometry, and assessed cell migration and invasion by transwell and wound healing assays. We also performed nude mouse experiments to evaluate tumorigenicity and hepatic metastasis potential of tumor cells. RESULTS: We found that ASB3 gene was frequently mutated (5.3%) and down-regulated (70.4%) in CRC cases. Knockdown of endogenous ASB3 expression promoted CRC cell proliferation, migration, and invasion in vitro and facilitated tumorigenicity and hepatic metastasis in vivo. Conversely, the ectopic overexpression of wild-type ASB3, but not that of ASB3 mutants that occurred in clinical CRC tissues, inhibited tumor growth and metastasis. Further analysis showed that ASB3 inhibited CRC metastasis likely by retarding epithelial-mesenchymal transition, which was characterized by the up regulation of beta-catenin and E-cadherin and the down-regulation of transcription factor 8, N-cadherin, and vimentin. CONCLUSION: ASB3 dysfunction resulted from gene mutations or down-regulated expression frequently exists in CRC and likely plays a key role in the pathogenesis and progression of CRC. PMID- 28088229 TI - Clinicopathologic significance of TRAP1 expression in colorectal cancer: a large scale study of human colorectal adenocarcinoma tissues. AB - BACKGROUND: Colorectal cancer is the major cause of cancer mortality, despite development of therapeutic strategies. The novel marker tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial heat shock protein that has been related to drug resistance and protection from apoptosis in colorectal cancer. This study aims to delineate the clinicopathologic significance of TRAP1 expression in colorectal cancer. METHODS: Seven-hundred and fourteen FFPE tissues were collected from colorectal cancer patients who underwent surgery from February 2002 to July 2011 at Dong-A University Medical Center, Busan, South Korea. We performed TRAP1 immunohistochemistry using tissue microarray, and divided into two groups, TRAP1 high expression group and low expression group. Statistical analysis was utilized to evaluate the association of TRAP1 with clinicopathologic characteristics and disease-specific survival of patients. RESULTS: High TRAP1 expression was observed in 564 cases (79%) and low expression was 150 cases (21%). TRAP1 expression was significantly increased in colorectal cancer with advanced pathologic T-stage compared with that in early T-stage (p = 0.008). By univariate survival analysis, high TRAP1 expression was significantly associated with worse disease-specific survival (p = 0.01). But, TRAP1 expression was marginally associated with lymph node involvement and tumor differentiation (p = 0.085, p = 0.082, respectively). Multivariate analysis indicated that TRAP1 expression (hazard ratio, 1.947; 95% CI, 1.270 to 2.984; p = 0.002), and pathologic T stage (hazard ratio, 3.190; 95% CI, 1.275 to 7.983; p = 0.013) were independent prognostic factors for colorectal adenocarcinomas. CONCLUSIONS: Here, we found that overexpression of TRAP1 might contribute to tumor cell local invasion of colorectal cancer. The association between TRAP1 overexpression and worse disease-specific survival also suggested that TRAP1 protein expression might have oncogenic role. Consequently, our data demonstrated that TRAP1 expression was a good prognostic biomarker for depth of invasion and disease specific survival in colorectal cancer. PMID- 28088230 TI - Relationship between the uptake of 18F-borono-L-phenylalanine and L-[methyl-11C] methionine in head and neck tumors and normal organs. AB - BACKGROUND AND PURPOSE: The purpose of this study was to determine the distribution of 4-borono-2-18F-fluoro-phenylalanine (18F-BPA) and L-[methyl-11C] methionine (11C-Met) in normal organs and tumors and to evaluate the usefulness of 11C-Met/PET in screening potential candidates for boron neutron capture therapy (BNCT). MATERIAL METHODS: Seven patients who had at least one histologically confirmed head and neck tumor were included in this study. They underwent both whole-body 18F-BPA-PET/CT and 11C-Met-PET/CT within a span of 6 months. Uptake was evaluated using the maximum standardized uptake value (SUVmax). Regions of interest (ROIs) were placed within the tumors and target organs of brain, thyroid, submandibular gland, lung, liver, esophagus, stomach pancreas, spleen, muscle, and bone marrow. RESULTS: The tumor SUVmax of FBPA and 11C-Met showed strong correlation (r 2 = 0.72, P = 0.015). Although 18F-BPA and 11C-Met showed markedly different uptake in some organs (submandibular gland, liver, heart, stomach pancreas, spleen, and bone marrow), the uptake of 11C-Met was consistently higher than that of 18F-BPA in these cases. CONCLUSION: 11C-Met PET/CT might be used instead of 18F-BPA PET/CT to predict the accumulation of 10B in tumors and to select candidates for BNCT. However, it would not be suitable for evaluating accumulation in some normal organs. Therefore, the 18F-BPA-PET study remains a prerequisite for BNCT. This is the first report of the correlation between 18F-BPA and 11C-Met accumulation. PMID- 28088232 TI - Utilization of mobile phones for accessing menstrual regulation services among low-income women in Bangladesh: a qualitative analysis. AB - BACKGROUND: As many as one-third of all pregnancies in Bangladesh are unplanned, with nearly one-half of these pregnancies ending in either menstrual regulation (MR) or illegal clandestine abortion. Although MR is provided free of charge, or at a nominal cost, through the public sector and various non-profits organizations, many women face barriers in accessing safe, affordable MR and post MR care. Mobile health (mHealth) services present a promising platform for increasing access to MR among low-income women at risk for clandestine abortion. We sought to investigate the knowledge, attitudes and practices regarding mHealth of both MR clients and formal and informal sexual and reproductive healthcare providers in urban and rural low-income settlements in Bangladesh. METHODS: A total of 58 interviews were conducted with MR clients, formal MR providers, and informal MR providers in four low-income settlements in the Dhaka and Sylhet districts of Bangladesh. Interview data was coded and qualitatively analysed for themes using standard qualitative research practices. RESULTS: Our findings suggest that low-income MR clients in Bangladesh have an inadequate understanding of how to use their mobile phones to obtain health service information or counselling related to MR, and correspondingly low levels of formal or informal mHealth service utilization. Few were aware of any formal mHealth services in place in their communities, despite the fact that providers stated that hotlines were available. Overall, MR clients expressed positive opinions of mHealth services as a means of improving women's access to affordable and timely MR. Formal and informal MR providers believed that mobile phones had benefits with respect to information dissemination and making appointments, but emphasized the necessity of in-person consultations for effective sexual and reproductive healthcare. CONCLUSIONS: We report low utilization yet high acceptability of mHealth services among low-income MR clients in Bangladesh. Expanding formal and informal mHealth services targeted towards MR - and increasing publicity of these services in low-income communities - may help increase timely access to accurate MR information and formal providers among women at risk for clandestine abortion. While expanding formal and informal mHealth services for SRHR in Bangladesh may be useful in disseminating information about MR and connecting women with formal providers, in-person visits remain necessary for adequate treatment. PMID- 28088231 TI - Efficacy of gabapentin for prevention of postherpetic neuralgia: study protocol for a randomized controlled clinical trial. AB - BACKGROUND: Postherpetic neuralgia (PHN) is a chronic neuropathic pain that results from alterations of the peripheral nervous system in areas affected by the herpes zoster virus. The symptoms include pain, paresthesia, dysesthesia, hyperalgesia, and allodynia. Despite the availability of pharmacological treatments to control these symptoms, no treatments are available to control the underlying pathophysiology responsible for this disabling condition. METHODS/DESIGN: Patients with herpes zoster who are at least 50 years old and have a pain score of 4 or higher on a visual analogue scale (VAS) will be recruited. The aim is to recruit 134 patients from the practices of general physicians. Participants will be randomized to receive gabapentin to a maximum of 1800 mg/day for 5 weeks or placebo. Both arms will receive 1000-mg caplets of valacyclovir three times daily for 7 days (initiated within 72 h of the onset of symptoms) and analgesics as needed. The primary outcome measure is the percentage of patients with a VAS pain score of 0 at 12 weeks from rash onset. The secondary outcomes measures are changes in quality of life (measured by the SF-12 questionnaire), sleep disturbance (measured by the Medical Outcomes Study Sleep Scale), and percentage of patients with neuropathic pain (measured by the Douleur Neuropathique in 4 Questions). DISCUSSION: Gabapentin is an anticonvulsant type of analgesic that could prevent the onset of PHN by its antihypersensitivity action in dorsal horn neurons. TRIAL REGISTRATION: ISRCTN Registry identifier: ISRCTN79871784 . Registered on 2 May 2013. PMID- 28088233 TI - Successful recovery from a subclavicular ulcer caused by lenvatinib for thyroid cancer: a case report. AB - BACKGROUND: There are currently no effective therapeutic methods for locally recurrent, metastatic, or progressive radioactive iodine (RAI)-refractory differentiated thyroid cancer. However, multitargeted tyrosine kinase inhibitors (TKIs) such as lenvatinib or sorafenib have been approved for patients with RAI refractory differentiated thyroid cancer as a second targeted therapy, and these agents can prolong patient survival. However, several cases have been reported that TKIs have caused fatal complications such as fistula formation or bleeding. CASE PRESENTATION: We report a case of a 53-year-old woman, who underwent repeated neck dissections and RAI therapy after total thyroidectomy in an outside hospital. Pathology revealed a papillary carcinoma of the tall cell variant. Locoregional recurrence was not under control; therefore, she visited our hospital. Although surgery was performed for locoregional recurrences three times in our hospital, they were not under control and distant metastases were found in the lung and bone a year later. Therefore, although sorafenib was initiated, the locoregional recurrence progressed 6 months later and computed tomography (CT) showed a 7-cm mass in the right subclavicular lesion. Lenvatinib was started at a dose of 24 mg daily. However, although tumor was rapidly reduced, an ulcer occurred in the right subclavicular lesion and was gradually increasing in size. The pulsation of subclavicular artery was found in the deep portion of the ulcer. Therefore, a pectoralis major myocutaneous flap was transplanted to cover the ulcer. Lenvatinib was an antiangiogetic TKI; therefore, it was preoperatively discontinued for 8 days and postoperatively for 12 days. The postoperative course was uneventful. CONCLUSIONS: Fistula formation or bleeding is known to be a severe side effect of antiangiogenic TKIs such as lenvatinib or sorafenib. There is a possibility that severe complications can occur when initiating TKIs in patients whose tumor has invaded into the skin, vessels, trachea, esophagus, and other areas. Therefore, it is necessary to use antiangiogenic TKIs very carefully. It is important to determine the appropriate time to start TKIs; however, there is no established protocol for this, and it is a problem that needs urgent attention. PMID- 28088234 TI - Stability-based validation of dietary patterns obtained by cluster analysis. AB - BACKGROUND: Cluster analysis is a data-driven method used to create clusters of individuals sharing similar dietary habits. However, this method requires specific choices from the user which have an influence on the results. Therefore, there is a need of an objective methodology helping researchers in their decisions during cluster analysis. The objective of this study was to use such a methodology based on stability of clustering solutions to select the most appropriate clustering method and number of clusters for describing dietary patterns in the NESCAV study (Nutrition, Environment and Cardiovascular Health), a large population-based cross-sectional study in the Greater Region (N = 2298). METHODS: Clustering solutions were obtained with K-means, K-medians and Ward's method and a number of clusters varying from 2 to 6. Their stability was assessed with three indices: adjusted Rand index, Cramer's V and misclassification rate. RESULTS: The most stable solution was obtained with K-means method and a number of clusters equal to 3. The "Convenient" cluster characterized by the consumption of convenient foods was the most prevalent with 46% of the population having this dietary behaviour. In addition, a "Prudent" and a "Non-Prudent" patterns associated respectively with healthy and non-healthy dietary habits were adopted by 25% and 29% of the population. The "Convenient" and "Non-Prudent" clusters were associated with higher cardiovascular risk whereas the "Prudent" pattern was associated with a decreased cardiovascular risk. Associations with others factors showed that the choice of a specific dietary pattern is part of a wider lifestyle profile. CONCLUSION: This study is of interest for both researchers and public health professionals. From a methodological standpoint, we showed that using stability of clustering solutions could help researchers in their choices. From a public health perspective, this study showed the need of targeted health promotion campaigns describing the benefits of healthy dietary patterns. PMID- 28088236 TI - Economic burden of family caregiving for elderly population in southern Ghana: the case of a peri-urban district. AB - BACKGROUND: Health systems in low and lower-middle income countries, particularly in sub-Sahara Africa, often lack the specialized personnel and infrastructure to provide comprehensive care for elderly/ageing populations. Close-to-client community-based approaches are a low-cost way of providing basic care and social support for elderly populations in such resource-constrained settings and family caregivers play a crucial role in that regard. However, family caregiving duties are often unremunerated and their care-related economic burden is often overlooked though this knowledge is important in designing or scaling up effective interventions. The objective of this study, therefore, was to estimate the economic burden of family caregiving for the elderly in southern Ghana. METHODS: The study was a retrospective cross-sectional cost-of-care study conducted in 2015 among family caregivers for elderly registered for a support group in a peri-urban district in southern Ghana. A simple random sample of 98 respondents representative of the support group members completed an interviewer administered questionnaire. Costs were assessed over a 1-month period. Direct costs of caregiving (including out-of-pocket costs incurred on health care) as well as productivity losses (i.e. indirect cost) to caregivers were analysed. Intangible costs were assessed using the 12-item Zarit burden interview (ZBI) tool and the financial cost dimension of the cost of care index. RESULTS: The estimated average cost of caregiving per month was US$186.18, 66% of which was direct cost. About 78% of the family caregivers in the study reported a high level of caregiving burden (as measured with the ZBI) with females reporting a relatively higher level than males. Further, about 87% of the family caregivers reported a high level of financial stress as a result of caregiving for their elderly relative. CONCLUSION: The study shows that support/caregiving for elderly populations imposes economic burden on families, potentially influencing the economic position of families with attendant implications for equity and future family support for such vulnerable populations. PMID- 28088235 TI - The sense behind retroviral anti-sense transcription. AB - Retroviruses are known to rely extensively on the expression of viral proteins from the sense proviral genomic strand. Yet, the production of regulatory retroviral proteins from antisense-encoded viral genes is gaining research attention, due to their clinical significance. This report will discuss what is known about antisense transcription in Retroviridae, and provide new information about antisense transcriptional regulation through a comparison of Human Immunodeficiency Virus (HIV), Human T-cell Lymphotrophic Virus (HTLV-1) and endogenous retrovirus-K (ERVK) long terminal repeats (LTRs). We will attempt to demonstrate that the potential for antisense transcription is more widespread within retroviruses than has been previously appreciated, with this feature being the rule, rather than the exception. PMID- 28088237 TI - Association between diabetes mellitus and multi-drug-resistant tuberculosis: a protocol for a systematic review and meta-analysis. AB - INTRODUCTION: Multi-drug-resistant tuberculosis (MDR-TB) has emerged as a challenge to global tuberculosis (TB) control and remains a major public health concern in many countries. Diabetes mellitus (DM) is an increasingly recognized comorbidity that can both accelerate TB disease and complicate its treatment. The aim of this study is to summarize available evidence on the association of DM and MDR-TB among TB patients and to provide a pooled estimate of risks. METHODS: All studies published in English before October 2016 will be searched using comprehensive search strings through PubMed, EMBASE, Web of Science, and WHO Global Health Library databases which have reported the association of DM and MDR TB in adults with TB (age > =15). Two authors will independently collect detailed information using structured data abstraction form. The quality of studies will be checked using Newcastle-Ottawa Scale for cohort and case-control studies and the Agency for Healthcare Research and Quality tool for cross-sectional studies. Heterogeneity between included studies will be assessed using the I2 statistic. We will check potential publication bias by visual inspection of the funnel plot and Egger's regression test statistic. We will use the random effects model to compute a pooled estimate. DISCUSSION: Increases in the burden of non communicable diseases and aging populations are changing the importance of different risk factors for TB, and the profile of comorbidities and clinical challenges for people with TB. Although classic risk factors and comorbidities such as overcrowding, under-nutrition, silicosis, and HIV infection are crucial to address, chronic conditions like diabetes are important factors that impair host defenses against TB. Thus, undertaking integrated multifaceted approach is remarkably necessary for reducing the burden of DM and successful TB treatment outcome. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016045692 . PMID- 28088238 TI - Lymph node pooling: a feasible and efficient method of lymph node molecular staging in colorectal carcinoma. AB - BACKGROUND: Pathologic lymph node staging is becoming a deficient method in the demanding molecular era. Nevertheless, the use of more sensitive molecular analysis for nodal staging is hampered by its high costs and extensive time requirements. Our aim is to take a step forward in colon cancer (CC) lymph node (LN) pathology diagnosis by proposing a feasible and efficient molecular method in routine practice using reverse transcription loop-mediated isothermal amplification (RT-LAMP). RESULTS: Molecular detection of tumor cytokeratin 19 (CK19) mRNA with RT-LAMP was performed in 3206 LNs from 188 CC patients using two methods: individual analysis of 1449 LNs from 102 patients (individual cohort), and pooled LN analysis of 1757 LNs from 86 patients (pooling cohort). A median of 13 LNs (IQR 10-18) per patient were harvested in the individual cohort, and 18 LNs (IQR 13-25) per patient in the pooling cohort (p <= 0.001). The median of molecular assays performed in the pooling cohort was 2 per patient (IQR 1-3), saving a median of 16 assays/patient. The number of molecular assays performed in the individual cohort was 13 (IQR 10-18), corresponding to the number of LNs to be analyzed. The sensitivity and specificity of the pooling method for LN involvement (assessed by hematoxylin and eosin) were 88.9% (95% CI 56.5-98.0) and 79.2% (95% CI 68.9-86.8), respectively; concordance, 80.2%; PPV, 33.3%; NPV, 98.4%. The individual method had 100% sensitivity (95% CI 72.2-100), 44.6% specificity (95% CI 34.8-54.7), 50% concordance, 16.4% PPV, and 100% NPV. The amount of tumor burden detected in all LNs of a case, or total tumor load (TTL) was similar in both cohorts (p = 0.228). CONCLUSIONS: LN pooling makes it possible to analyze a high number of LNs from surgical colectomies with few molecular tests per patient. This approach enables a feasible means to integrate LN molecular analysis from CC specimens into pathology diagnosis and provides a more accurate LN pathological staging with potential prognostic implications. PMID- 28088240 TI - Feasibility of an altruistic sperm donation program in Canada: results from a population-based model. AB - BACKGROUND: Stringent donor-screening criteria and legislation prohibiting payment for donor gametes have contributed to the radical decline of donor insemination (DI) using sperm provided by Canadian men. Thus, many individuals rely on imported sperm. This paper examines the feasibility of an altruistic sperm donation (ASD) program to meet the needs of Canadians. METHODS: Using Canadian census data, published literature and expert opinions, two population based, top-down mathematical models were developed to estimate the supply and demand for donor sperm and the feasibility of an ASD program. RESULTS: It was estimated that 63 donors would pass Canadian screening criteria, which would provide 1,575 donations. The demand for DI by women was 7,866 samples (4,319 same sex couples, 1,287 single women and 2,260 heterosexual couples). CONCLUSION: Considerable effort would be necessary to create the required increase in awareness of the program and change in societal behaviour towards sperm donation for an ASD program to be feasible in Canada. PMID- 28088239 TI - Towards interruption of schistosomiasis transmission in sub-Saharan Africa: developing an appropriate environmental surveillance framework to guide and to support 'end game' interventions. AB - Schistosomiasis is a waterborne parasitic disease in sub-Saharan Africa, particularly common in rural populations living in impoverished conditions. With the scale-up of preventive chemotherapy, national campaigns will transition from morbidity- to transmission-focused interventions thus formal investigation of actual or expected declines in environmental transmission is needed as 'end game' scenarios arise. Surprisingly, there are no international or national guidelines to do so in sub-Saharan Africa. Our article therefore provides an introduction to key practicalities and pitfalls in the development of an appropriate environmental surveillance framework. In this context, we discuss how strategies need to be adapted and tailored to the local level to better guide and support future interventions through this transition. As detection of egg-patent infection in people becomes rare, careful sampling of schistosome larvae in freshwater and in aquatic snails with robust species-specific DNA assays will be required. Appropriate metrics, derived from observed prevalence(s) as compared with predetermined thresholds, could each provide a clearer insight into contamination- and exposure-related dynamics. Application could be twofold, first to certify areas currently free from schistosomiasis transmission or second to red-flag recalcitrant locations where extra effort or alternative interventions are needed. PMID- 28088241 TI - Perceptions of mistreatment among trainees vary at different stages of clinical training. AB - BACKGROUND: Mistreatment of trainees remains a frequently reported phenomenon in medical education. One barrier to creating an educational culture of respect and professionalism may be a lack of alignment in the perceptions of mistreatment among different learners. Through the use of clinical vignettes, our aim was to assess the perceptions of trainees toward themes of potential mistreatment at different stages of training. METHODS: Based on observations from external experts embedded in the clinical learning environment, six thematic areas of potential mistreatment were identified: verbal abuse, specialty-choice discrimination, non-educational tasks, withholding/denying learning opportunities, neglect and gender/racial insensitivity. Corresponding clinical vignettes were created and distributed to 1) medical students, 2) incoming interns, 3) residents/fellows. Perceptions of the appropriateness of the interactions depicted in the vignettes were measured on a 5-point Likert scale. Scores were categorized into neutral or appropriate (<=3) or inappropriate (i.e. mistreatment) (>3) and compared using chi-squared tests. RESULTS: Four hundred twenty seven trainees participated (182 students, 120 interns, 125 residents/fellows). Proportions of students perceiving mistreatment differed significantly from those of interns and residents/fellows in domains of verbal abuse, specialty discrimination and gender/racial insensitivity (p < 0.05). In scenarios comparing interns to residents/fellows, no significant differences were noted in perceptions of mistreatment in the domains of non-educational tasks, withholding learning and neglect. CONCLUSIONS: Perceptions of mistreatment differ at different developmental stages of medical training. After exposure to the clinical learning environment, perceptions of incoming interns did not differ from those of residents/fellows, implicating clinical rotations as a key period in indoctrinating students into the prevailing culture. More longitudinal studies are needed to confirm or better examine this phenomenon. PMID- 28088242 TI - Differences in spatial distributions of iron supplementation use among pregnant women and associated factors in Ethiopia: evidence from the 2011 national population based survey. AB - BACKGROUND: Iron supplementation during pregnancy prevents against low birth weight, incidence of prematurity and postpartum hemorrhage. However, the coverage of iron supplementation is still low in Ethiopia. This study aimed to investigate the spatial variations and associated factors of iron supplementation during pregnancy using the 2011 national demographic and health survey data. METHODS: This study used secondary data from the 2011 Ethiopian demographic and health survey. The survey was cross sectional and used a multistage cluster sampling procedure. A logistic regression statistical model using adjusted odds ratio (AOR) and 95% confidence interval (CI) was used to identify the associated factors. Getis-Ord G-statistic was used to identify high and low hotspot areas of iron tablet supplementation during pregnancy. RESULTS: The coverage of iron tablet supplementation was 17.1% [95%CI: (16.3-17.9)] with the highest coverage of 38.9% [95%CI: (32.4--46.1)] in Addis Ababa followed by Tigray regional state with 33.8% [95%CI: (29.9-38.00)]. The lowest coverage was found in Oromiya regional state at 11.9% [95%CI: (10.7-13.0)]. Multivariable analysis showed that mothers who were aware of the Community Conversation Program had 20% [AOR = 1.2; 95% CI: (1.04-1.4)] higher odds of taking iron tablets. The odds of taking iron tablets was 2.9 times [AOR = 2.9; 95% CI: (2.3-3.7)] higher among those who took deworming tablets. Those mothers who attended the minimum four antenatal visits recommended by WHO were 3.9 times [AOR = 3.9; 95% CI: (3.3-4.6)] more likely and those mothers in the age group 31-49 years were 2.9 times [AOR = 2.9; 95% CI: (1.1-7.4)] more likely to use iron tablets as compared to those mothers who did not attend antenatal care and mothers in the age group less than 20 years. Mothers having a family size of 10 and above had 32% [AOR = 0.68; 95% CI: (0.49 0.97)] lower odds of taking iron tablets during pregnancy. The spatial analysis found that only northern, central and eastern parts of Ethiopia were identified as hotspots of iron supplementation. CONCLUSION: Iron supplementation use was not equally distributed in Ethiopia, with relatively higher prevalence in Tigray, Addis Ababa and Harari regional states. Attention should be given to younger age mothers, mothers with large family size and mothers who reside in areas with low coverage of iron tablet distribution. Promotion of antenatal care services based on the WHO standard can be used as an intervention for improving iron supplementation during pregnancy. PMID- 28088243 TI - Reducing sedentary time in adults at risk of type 2 diabetes: process evaluation of the STAND (Sedentary Time ANd Diabetes) RCT. AB - BACKGROUND: Reducing sedentary behaviour may have important health implications. This study evaluated the potential enablers and barriers for outcomes of a randomised controlled trial (RCT) designed to evaluate a pragmatic education based intervention designed to reduce sedentary (sitting) behaviour in young adults at high risk of type 2 diabetes. METHODS: Data were collected from participants in the intervention group immediately after an educational workshop addressing sedentary time and diabetes risk (n = 71), through phone interviews 6 weeks (n = 45) after the workshop, and at the conclusion of the 12-month trial (n = 10). The two education session facilitators were also interviewed about the intervention. RESULTS: The RCT showed no difference in sedentary time at 12 months between intervention and control arms. The lack of behaviour change appeared not to be attributed to the workshops, which were well led and very favourably received according to feedback. However, factors contributing to this lack of behaviour change include lack of perceived health risk from baseline measures feedback; the preference to adopt physically active behaviours rather than to sit less; certain barriers to sitting less; motivational drift after the 3-month follow-up measurements where participants had no contact for a further 9 months; and, for some, unreliability of the self-monitoring tool. CONCLUSIONS: The workshop was well led and well received by the attendees but future interventions need to consider more contact with participants, discuss any specific benefits around simply standing to reduce sitting time, address the barriers to sitting less, and provide a more user-friendly and reliable self monitoring tool. TRIAL REGISTRATION: Current controlled trials ISRCTN08434554 , MRC project 91409. Registered retrospectively on 22 February 2011. PMID- 28088244 TI - Study of the variability of scapular inclination and the glenoid version - considerations for preoperative planning: clinical-radiological study. AB - BACKGROUND: Preoperative planning with the aid of imaging methods is a principal factor in successful surgery on the shoulder. This work aims to evaluate the variability of glenoid version, spiralling twist and scapular inclination in relation to the frontal axis. Studies focusing on measuring the variability of scapular inclination in the standardised rest position are lacking in the literature. METHODS: We evaluated 104 CT scans of the shoulder. We measured the glenoid version with respect to the scapular axis at three levels. We measured the scapular inclination angle in relation to the sagittal plane and we determined scapular inclination in relation to the frontal axis. Statistical evaluation was performed using the marginal linear model and parameters were estimated using the generalised least squares method, which enables the dependency of measurements performed on the same subject to be taken into consideration. RESULTS: The highest values of retroversion are attained by the glenoid in the cranial section (average -9.96 degrees , range -29.7 to +13.2 degrees ). Proof of the spiralling twist is the decline in retroversion at the centre of the glenoid (average -2.09 degrees , range -16.7 to +11.6 degrees ). Retroversion decreases further in the inferior direction (average -0.5 degrees , range -20.9 to +17.5 degrees ). The average thoracoscapular angle is 45.46 degrees , ranging from 13.1 to 69.0 degrees . The average scapular inclination in relation to the frontal plane is 44.54 degrees , ranging from 21.0 to76.9 degrees . CONCLUSIONS: During preoperative planning, the surgeon should take into consideration not only the glenoid version in relation to the scapular axis, but also the value of the scapular inclination so as to eliminate possible surgical errors, optimise prosthesis implantation and thus decrease the risk of functional restrictions of the joint. CLINICAL TRIAL REGISTRATION: Ethics Committee for Multi-Centric Clinical Trials (EK-554/14,29thApril 2014). PMID- 28088245 TI - The value of dynamic contrast-enhanced MRI in characterizing complex ovarian tumors. AB - BACKGROUND: The study aimed to investigate the utility of dynamic contrast enhanced MRI (DCE-MRI) in the differentiation of malignant, borderline, and benign complex ovarian tumors. METHODS: DCE-MRI data of 102 consecutive complex ovarian tumors (benign 15, borderline 16, and malignant 71), confirmed by surgery and histopathology, were analyzed retrospectively. The patterns (I, II, and III) of time-signal intensity curve (TIC) and three semi-quantitative parameters, including enhancement amplitude (EA), maximal slope (MS), and time of half rising (THR), were evaluated and compared among benign, borderline, and malignant ovarian tumors. The types of TIC were compared by Pearson Chi-square chi 2 between malignant and benign, borderline tumors. The mean values of EA, MS, and THR were compared using one-way ANOVA or nonparametric Kruskal-Wallis test. RESULTS: Fifty-nine of 71 (83%) malignant tumors showed a type-III TIC; 9 of 16 (56%) borderline tumors showed a type-II TIC, and 10 of 15 (67%) benign tumors showed a type-II TIC, with a statistically significant difference between malignant and benign tumors (P < 0.001) and between malignant and borderline tumors (P < 0.001). MS was significantly higher in malignant tumors than in benign tumors and in borderline than in benign tumors (P < 0.001, P = 0.013, respectively). THR was significantly lower in malignant tumors than in benign tumors and in borderline than in benign tumors (P < 0.001, P = 0.007, respectively). There was no statistically significant difference between malignant and borderline tumors in MS and THR (P = 0.19, 0.153) or among malignant, borderline, and benign tumors in EA (all P > 0.05). CONCLUSIONS: DCE MRI is helpful for characterizing complex ovarian tumors; however, semi quantitative parameters perform poorly when distinguishing malignant from borderline tumors. PMID- 28088246 TI - Budget impact analysis of vaccination against Haemophilus influenzae type b as a part of a Pentavalent vaccine in the childhood immunization schedule of Iran. AB - BACKGROUND: Health decision makers need to know the impact of the development of a new intervention on the public health and health care costs so that they can plan for economic and financial objectives. The aim of this study was to determine the budget impact of adding Haemophilus influenzae type b (Hib) as a part of a Pentavalent vaccine (Hib-HBV-DTP) to the national childhood immunization schedule of Iran. METHODS: An excel-based model was developed to determine the costs of including the Pentavalent vaccine in the national immunization program (NIP), comparing the present schedule with the previous one (including separate DTP and hepatitis B vaccines). The total annual costs included the cost of vaccination (the vaccine and syringe) and the cost of Hib treatment. The health outcome was the estimated annual cases of the diseases. The net budget impact was the difference in the total annual cost between the two schedules. Uncertainty about the vaccine effectiveness, vaccination coverage, cost of the vaccine, and cost of the diseases were handled through scenario analysis. RESULTS: The total cost of vaccination during 5 years was $18,060,463 in the previous program and $67,774,786 in the present program. Inclusion of the Pentavalent vaccine would increase the vaccination cost about $49 million, but would save approximately $6 million in the healthcare costs due to reduction of disease cases and treatment costs. The introduction of the Pentavalent vaccine resulted in a net increase in the healthcare budget expenditure across all scenarios from $43.4 million to $50.7 million. CONCLUSIONS: The results of this study showed that the inclusion of the Pentavalent vaccine in the NIP of Iran had a significant impact on the health care budget and increased the financial burden on the government. Budget impact of including Pentavalent vaccine in the national immunization schedule of Iran?. PMID- 28088247 TI - First molecular identification of Echinococcus vogeli and Echinococcus granulosus (sensu stricto) G1 revealed in feces of domestic dogs (Canis familiaris) from Acre, Brazil. AB - BACKGROUND: Echinococcus granulosus (sensu lato) (s.l.) and Echinococcus vogeli are causative agents of chronic zoonotic diseases such as cystic and polycystic echinococcosis, respectively. In Brazil, polycystic echinococcosis has a restricted geographical distribution in the North Region, while cystic echinococcosis is observed in the South Region. Domestic dogs (Canis familiaris) fed with raw viscera represent a risk factor for E. granulosus (s.l.) infection in the South Region. Although this practice is frequent, it remains unclear whether domestic dogs are infected with E. vogeli in the state of Acre, located in the Amazon basin in the North Region of Brazil. The aim of this study was to investigate this gap in the polycystic echinococcosis epidemiology. METHODS: Sixty-five fecal samples were collected from the ground in five municipalities (Sena Madureira, n = 14; Rio Branco, n = 06; Bujari, n = 06; Xapuri, n = 30; and Epitaciolandia, n = 09) located in the state of Acre, northern Brazil. The samples were screened for parasites by copro-PCR using the cox1 gene associated with automated sequencing. RESULTS: Echinococcus vogeli was molecularly confirmed in a sample from Sena Madureira and E. granulosus (sensu stricto) (s.s.) (G1) in a sample from Rio Branco. CONCLUSIONS: These findings indicate that molecular assays are useful in typing Echinococcus taxa from fecal samples of dogs in northern Brazil. The present study is the first molecular record of E. vogeli in domestic dogs found in the state of Acre, reinforcing their role as a source of infection for humans. Because E. granulosus (s.s.) (G1) was detected for the first time in the North Region, from the epidemiological standpoint this finding is highly relevant, because it expands the known geographical distribution, which was previously restricted to the South Region of Brazil. PMID- 28088248 TI - The spectrum of rheumatic in-patient diagnoses at a pediatric hospital in Kenya. AB - BACKGROUND: Pediatric rheumatic diseases are chronic illnesses that can cause considerable disease burden to children and their families. There is limited epidemiologic data on these diseases in East Africa. The aim of this study was to assess the spectrum of pediatric rheumatic diagnoses in an in-patient setting and determine the accuracy of ICD-10 codes in identifying these conditions. METHODS: Medical records from Gertrude's Children's Hospital in Kenya were reviewed for patients diagnosed with "diseases of the musculoskeletal system and connective tissue" as per ICD-10 diagnostic codes assigned at discharge between January and December 2011. Cases were classified as "rheumatic" or "non-rheumatic". Accuracy of the assigned ICD-10 code was ascertained. Death records were reviewed. Longitudinal follow-up of "rheumatic" cases was done by chart review up to March 2014. RESULTS: Twenty six patients were classified as having a "rheumatic" condition accounting for 0.32% of patients admitted. Of these, 11 (42.3%) had an acute inflammatory arthropathy, 6 (23.1%) had septic arthritis, 4 (15.4%) had Kawasaki disease, 2 (7.7%) had pyomyositis, and there was one case each of septic bursitis, rheumatic fever, and a non-specific soft tissue disorder. No cases of juvenile idiopathic arthritis (JIA) were identified. One case of systemic lupus erythematosus was documented by death records. The agreement between the treating physician's discharge diagnosis and medical records ICD-10 code assignment was good (Kappa: 0.769). On follow-up, one child had recurrent knee swelling that was suspicious for JIA. CONCLUSIONS: Pediatric rheumatic conditions represented 0.32% of admissions at a pediatric hospital in Kenya. Acute inflammatory arthropathies, septic arthritis and Kawasaki disease were the most frequent in-patient rheumatic diagnoses. Chronic pediatric rheumatic diseases were rare amongst this in-patient population. Despite limitations associated with the use of administrative diagnostic codes, they can be a first step in evaluating the spectrum of pediatric rheumatic conditions in Kenya and other countries in East Africa. PMID- 28088249 TI - Interactions of human microglia cells with Japanese encephalitis virus. AB - BACKGROUND: Japanese encephalitis virus (JEV) is a neurotropic flavivirus causing mortality and morbidity in humans. Severe Japanese encephalitis cases display strong inflammatory responses in the central nervous system and an accumulation of viral particles in specific brain regions. Microglia cells are the unique brain-resident immune cell population with potent migratory functions and have been proposed to act as a viral reservoir for JEV. Animal models suggest that the targeting of microglia by JEV is partially responsible for inflammatory reactions in the brain. Nevertheless, the interactions between human microglia and JEV are poorly documented. METHODS: Using human primary microglia and a new model of human blood monocyte-derived microglia, the present study explores the interaction between human microglia and JEV as well as the role of these cells in viral transmission to susceptible cells. To achieve this work, vaccine-containing inactivated JEV and two live JEV strains were applied on human microglia. RESULTS: Live JEV was non-cytopathogenic to human microglia but increased levels of CCL2, CXCL9 and CXCL10 in such cultures. Furthermore, human microglia up regulated the expression of the fraktalkine receptor CX3CR1 upon exposure to both JEV vaccine and live JEV. Although JEV vaccine enhanced MHC class II on all microglia, live JEV enhanced MHC class II mainly on CX3CR1+ microglia cells. Importantly, human microglia supported JEV replication, but infectivity was only transmitted to neighbouring cells in a contact-dependent manner. CONCLUSION: Our findings suggest that human microglia may be a source of neuronal infection and sustain JEV brain pathogenesis. PMID- 28088250 TI - Pre-hospital treatment of bee and wasp induced anaphylactic reactions: a retrospective study. AB - BACKGROUND: Bee and wasp stings are among the most common triggers of anaphylaxis in adults representing around 20% of fatal anaphylaxis from any cause. Data of pre-hospital treatment of bee and wasp induced anaphylactic reactions are sparse. This study aimed to estimate the incidence of bee and wasp induced anaphylactic reactions, the severity of the reactions and to correlate the pre-hospital treatment with the severity of the anaphylactic reaction. METHODS: Retrospective and descriptive study based on data from the Mobile Emergency Care Units (MECUs) in the Region of Southern Denmark (2008 only for Odense and 2009-2014 for the whole region). Discharge summaries with diagnosis related to anaphylaxis according to the International Classification of Diseases 10 (ICD-10) were reviewed to identify bee and wasp induced anaphylactic reactions. The severity of the anaphylactic reaction was assessed according to Sampson's severity score and Mueller's severity score. Treatment was evaluated in relation to administration of adrenaline, glucocorticoids and antihistamine. RESULTS: We identified 273 cases (Odense 2008 n = 14 and Region of Southern Denmark 2009-2014 n = 259) of bee and wasp induced anaphylaxis. The Incidence Rate was estimated to 35.8 cases per 1,000,000 person year (95% CI 25.9-48.2) in the Region of Southern Denmark during 2009-2014. According to Sampson's severity score, 65% (n = 177) of the cases were graded as moderate to severe anaphylaxis (grade 3-5). Almost one third of cases could not be graded according to Mueller's severity score. Adrenaline was administrated in 54% (96/177) of cases with moderate to severe anaphylaxis according to Sampson's severity score, compared to 88% receiving intravenous glucocorticoids (p < 0.001) and 91% receiving intravenous antihistamines (p < 0.001). Even in severe anaphylaxis (grade 5) adrenaline was administered in only 80% of the cases. CONCLUSION: Treatment with adrenaline is not administered in accordance with international guidelines. However, making an assessment of the severity of the anaphylactic reaction is difficult in retrospective studies. PMID- 28088251 TI - Lucerastat, an iminosugar with potential as substrate reduction therapy for glycolipid storage disorders: safety, tolerability, and pharmacokinetics in healthy subjects. AB - BACKGROUND: Lucerastat, an inhibitor of glucosylceramide synthase, has the potential to restore the balance between synthesis and degradation of glycosphingolipids in glycolipid storage disorders such as Gaucher disease and Fabry disease. The safety, tolerability, and pharmacokinetics of oral lucerastat were evaluated in two separate randomized, double-blind, placebo-controlled, single- and multiple-ascending dose studies (SAD and MAD, respectively) in healthy male subjects. METHODS: In the SAD study, 31 subjects received placebo or a single oral dose of 100, 300, 500, or 1000 mg lucerastat. Eight additional subjects received two doses of 1000 mg lucerastat or placebo separated by 12 h. In the MAD study, 37 subjects received placebo or 200, 500, or 1000 mg b.i.d. lucerastat for 7 consecutive days. Six subjects in the 500 mg cohort received lucerastat in both absence and presence of food. RESULTS: In the SAD study, 15 adverse events (AEs) were reported in ten subjects. Eighteen AEs were reported in 15 subjects in the MAD study, in which the 500 mg dose cohort was repeated because of elevated alanine aminotransferase (ALT) values in 4 subjects, not observed in other dose cohorts. No severe or serious AE was observed. No clinically relevant abnormalities regarding vital signs and 12-lead electrocardiograms were observed. Lucerastat Cmax values were comparable between studies, with geometric mean Cmax 10.5 (95% CI: 7.5, 14.7) and 11.1 (95% CI: 8.7, 14.2) MUg/mL in the SAD and MAD study, respectively, after 1000 mg lucerastat b.i.d. tmax (0.5 - 4 h) and t1/2 (3.6 - 8.1 h) were also within the same range across dose groups in both studies. Using the Gough power model, dose proportionality was confirmed in the SAD study for Cmax and AUC0-infinity, and for AUC0-12 in the MAD study. Fed-to-fasted geometric mean ratio for AUC0-12 was 0.93 (90% CI: 0.80, 1.07) and tmax was the same with or without food, indicating no food effect. CONCLUSIONS: Incidence of drug-related AEs did not increase with dose. No serious AEs were reported for any subject. Overall, lucerastat was well tolerated. These results warrant further investigation of substrate reduction therapy with lucerastat in patients with glycolipid storage disorders. SAD study was registered on clinicaltrials.gov under the identifier NCT02944487 on the 24th of October 2016 (retrospectively registered). MAD study was registered on clinicaltrials.gov under the identifier NCT02944474 on the 25th of October 2016 (retrospectively registered). TRIAL REGISTRATION: A Study to Assess the Safety and Tolerability of Lucerastat in Subjects With Fabry Disease. Clinicaltrials.gov: NCT02930655 . PMID- 28088252 TI - Quantification of Whey Protein Content in Infant Formulas by Sodium Dodecyl Sulfate-Capillary Gel Electrophoresis (SDS-CGE): Single-Laboratory Validation, First Action 2016.15. AB - Protein separation by sodium dodecyl sulfate-capillary gel electrophoresis, followed by UV absorption at 220 nm, allows for the quantification of major proteins in raw milk. In processed dairy samples such as skim milk powder (SMP) and infant formulas, signals from individual proteins are less resolved, but caseins still migrate as one family between two groups of whey proteins. In the first group, alpha-lactalbumin and beta-lactoglobulin migrate as two distinct peaks. Lactosylated adducts show delayed migration times and interfere with peak separation, but both native and modified forms as well as other low-MW whey proteins still elute before the caseins. The second group contains high-MW whey proteins (including bovine serum albumin, lactoferrin, and immunoglobulins) and elutes after the caseins. Caseins and whey proteins can thus be considered two distinct nonoverlapping families whose ratio can be established based on integrated areas without the need for a calibration curve. Because mass-to-area response factors for whey proteins and caseins are different, an area correction factor was determined from experimental measurement using SMP. Method performance assessed on five infant formulas showed RSDs of 0.2-1.2% (within day) and 0.5 1.1% (multiple days), with average recoveries between 97.4 and 106.4% of added whey protein. Forty-three different infant formulas and milk powders were analyzed. Of the 41 samples with manufacturer claims, the measured whey protein content was in close agreement with declared values, falling within 5% of the declared value in 76% of samples and within 10% in 95% of samples. PMID- 28088253 TI - Integration of traditional Chinese medicine and Western medicine in the era of precision medicine. AB - Precision medicine has received growing recognition from clinicians, health systems, and the pharmaceutical industry, as well as patients and policymakers, which will leave a major impact on the practice of medicine. Interestingly, traditional Chinese medicine (TCM) provides personalized medical treatment based on the theory of TCM characterized by holistic concept and pattern differentiation. This, to some extent, is similar to the personalized medical treatment of precision medicine. In China, TCM as well as Western medicine (WM) plays an important role in healthcare. In this article, the authors summarized the influence of precision medicine on current medical directions, the advantages of TCM in disease treatment, further development of precision medicine and the strategies for integration of TCM and WM under this new treatment approach. In addition, the authors discuss the perspective of precise medical diagnosis and treatment, precise prevention, and the complementary advantages of the integration of TCM and WM. Finally, the authors give their perspectives on the challenges and opportunities presented by precision medicine, in the context of further research toward the integration of TCM and WM. PMID- 28088254 TI - Role of dietary and lifestyle modifications in reflex epilepsy based on traditional Persian medicine. PMID- 28088255 TI - A review on different English versions of an ancient classic of Chinese medicine: Huang Di Nei Jing. AB - Huang Di Nei Jing (Nei Jing), one of the most important classical texts of traditional Chinese medicine, is the foundation upon which today's Chinese medicine principles are built. This seminal ancient classic has been translated into English many times by different scholars worldwide. The authors have found thirteen English versions, each of which has its own distinctive features. By reviewing different versions and research achievements of the English translation, the authors try to summarize the translation style, purpose, content and other features of each version, and point out each translation's weaknesses, strengths, or significance. The emerging of so many English versions of Nei Jing, an ancient and sophisticated text, shows that scholars have disparate understanding of its language and concepts. Additionally, different educational backgrounds, professions and goals of the translators will all contribute to different perspectives and approaches in the translation. It is understandable that so many versions of translation exist for such an ancient and important classic. However, to achieve truly accurate translation of ancient classical texts of Chinese medicine, all translators should abide by certain basic requirements and translation principles. PMID- 28088256 TI - Ethnobotanics used in folk medicine of Tamil culture in Sri Lanka: a scientific review. AB - Tamil culture has recognized the potential use of plant herbs for prevention and treatment of different diseases. These folk remedies have been practiced by Sri Lankan Tamils even after modernization. This review focuses on frequently used medicinal plants among Sri Lankan Tamil communities, such as Cuminum cyminum, Azadirechta indica, Coriandrum sativum, Sesamum indicum, Zingiber officinale, Trigonella foenum-graecum, Moringa oleifera, Plectranthus amboinicus, Allium sativum and Curcuma longa, for their documented medicinal properties, which include antimicrobial, antioxidant, antitumor, anti-inflammatory, antihypertensive, hypocholesterolemic, antidiabetic and diuretic effects. PMID- 28088257 TI - Clinical and experimental research in antituberculosis drug-induced hepatotoxicity: a review. AB - Drug-induced liver injury is the common adverse effect seen in patients receiving antituberculosis drugs (ATDs). There are several risk factors associated with the development of hepatotoxicity in such patients. Though there have been appreciable efforts taken by carrying out studies investigating the efficacy of several natural and synthetic compounds in minimising this effect, the only choice available for clinicians is withdrawal of drugs. This review would give a precise idea of ATD-induced hepatotoxicity, its underlying mechanisms and alternative therapies for the same. PMID- 28088258 TI - Comparing outcomes from the two most recognized acupuncturist workforce surveys. AB - OBJECTIVE: To determine the informational consistency produced by the two most recent independent surveys and draw a conclusion whether the data would be sufficient for the National Center for Health Workforce Analysis and Bureau of Labor and Statistics consideration. METHODS: This paper compares workforce outcomes collected by the two most prominent acupuncture entities that have produced the most useful acupuncturist workforce data (California Acupuncture Board 2015 Occupational Analysis and the National Certification Commission of Acupuncture and Oriental Medicine(r) 2013 Job Analysis) at national and state levels. RESULTS: Findings based upon the most compatible survey questions showed the following: more than 70% of acupuncturists work fewer than 40 hours weekly; approximately 76% work in solo practice or in shared space with other acupuncturists; more than 70% of the national sample have been in practice 15 years or less; and median income is between $40 000 and $50 000. A preponderance of acupuncturists is less than 50 years of age, and fewer than 15% of all respondents have been in practice more than 20 years. CONCLUSION: Basic workforce information is a necessary precursor for conducting workforce projections. It is useful to track the expansion or contraction of any given profession. Tracking influences subsequent planning for the profession based upon reliable and valid information about its growth. The ability of the profession to collect its own workforce data is paramount to workforce projection models. Any future survey should be a shared project that follows guidelines supported by the National Center for Health Workforce Analysis. PMID- 28088259 TI - Integration for coexistence? Implementation of intercultural health care policy in Ghana from the perspective of service users and providers. AB - OBJECTIVE: In spite of the World Health Organization's recommendations over the past decades, Ghana features pluralistic rather than truly integrated medical system. Policies about the integration of complementary medicine into the national health care delivery system need to account for individual-level involvement and cultural acceptability of care rendered by health care providers. Studies in Ghana, however, have glossed over the standpoint of the persons of the illness episode about the intercultural health care policy framework. This paper explores the health care users, and providers' experiences and attitudes towards the implementation of intercultural health care policy in Ghana. METHODS: In depth interviews, augmented with informal conversations, were conducted with 16 health service users, 7 traditional healers and 6 health professionals in the Sekyere South District and Kumasi Metropolis in the Ashanti Region of Ghana. Data were thematically analysed and presented based on the a posteriori inductive reduction approach. RESULTS: Findings reveal a widespread positive attitude to, and support for integrative medical care in Ghana. However, inter-provider communication in a form of cross-referrals and collaborative mechanisms between healers and health professionals seldom occurs and remains unofficially sanctioned. Traditional healers and health care professionals are skeptical about intercultural health care policy mainly due to inadequate political commitment for provider education. The medical practitioners have limited opportunity to undergo training for integrative medical practice. We also find a serious mistrust between the practitioners due to the "diversity of healing approaches and techniques." Weak institutional support, lack of training to meet standards of practice, poor registration and regulatory measures as well as negative perception of the integrative medical policy inhibit its implementation in Ghana. CONCLUSION: In order to advance any useful intercultural health care policy in Ghana, the government's total commitment in informed training and provider education, enforcement of regulatory instrument and improved community engagement is needed. Evidence-based incorporation of traditional medical therapies into clinical practice will provide safer, faster and more effective health care for the underserved and resource-poor, particularly in the rural areas. PMID- 28088260 TI - Korean Chungtaejeon tea extract attenuates body weight gain in C57BL/6J-Lep ob/ob mice and regulates adipogenesis and lipolysis in 3T3-L1 adipocytes. AB - OBJECTIVE: Traditional Korean Chungtaejeon (CTJ) tea is a type of fermented tea, which has received increasing attention in recent years because of its purported health benefits. The present study was designed to investigate the effect and mechanism of CTJ tea extract on body weight gain using C57BL/6J-Lep ob/ob mice and 3T3-L1 adipocytes, respectively. METHODS: The effects of CTJ on cell viability, lipid accumulation, and expression of protein and mRNA were measured in 3T3-L1 adipocytes by using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, oil red O staining, Western blotting, and reverse transcriptase-polymerase chain reaction analyses. C57BL6J-Lep ob/ob mice were administered with CTJ (200 or 400 mg/kg body weight) for ten weeks. Then, body weight, food intake, total cholesterol, and triglyceride were measured in ob/ob mice. RESULTS: CTJ tea extract treated at 250 MUg/mL (CTJ250) significantly suppressed lipid accumulation in the differentiated 3T3-L1 adipocytes. Likewise, CTJ250 significantly decreased the protein expression of peroxisome proliferator activated receptorgamma (PPARgamma), CCAAT/enhancer-binding protein alpha, and adipocyte lipid-binding protein, and regulated the mRNA expression of PPARgamma, sterol regulatory element-binding protein-1c gene, fatty acid synthase, adipocyte lipid-binding protein, hormone-sensitive lipase, carnitine palmitoyl transferase 1, cluster of differentiation 36, and acetyl-CoA carboxylase in the differentiated 3T3-L1 adipocytes. Mice administered with CTJ showed dose dependent decrease in body weight gain, starting from week 4 of the experiment. CTJ tea extract administered at 400 mg/kg body weight significantly decreased fat mass, food efficacy ratio, and levels of plasma triglyceride and total cholesterol. CONCLUSION: CTJ attenuated weight gain in ob/ob mice and regulated the activity of the molecules involved in adipogenesis and lipolysis in 3T3-L1 adipocytes. CTJ is a potentially valuable herbal therapy for the prevention of obesity and/or obesity-related disorders. PMID- 28088262 TI - Low rate of early implant failure is confirmed, but smoking and antidepressants are shown to be risk factors. PMID- 28088261 TI - Parquetina nigrescens leaves: chemical profile and influence on the physical and biochemical indices of sexual activity of male Wistar rats. AB - OBJECTIVE: The leaves of Parquetina nigrescens have been claimed in folk medicine to be useful for managing sexual dysfunction, but there is inadequate scientific evidence for this claim. This investigation was conducted to assess the effects of aqueous leaf extract of Parquetina nigrescens (AEPN) in rats induced with sexual dysfunction. METHODS: Male rats were allocated into various groups after being induced into sexual dysfunction with paroxetine hydrochloride. The groups were treated with distilled water, PowMaxM (reference drug), and the AEPN at 20, 40 and 80 mg/kg body weight (BW) respectively for 7 d. Frequencies of mount (MF), intromission (IF), ejaculation (EF), as well as latencies of mount (ML), intromission (IL) and post-ejaculatory interval (PEI) were progressively monitored with receptive female rats on days 1, 3 and 7. The precentage of mounted, intromitted, and ejaculated rats, intromission ratio (IR), copulatory efficiency (CE) and intercopulatory interval (ICI) were also computed. Standard methods were employed to determine the levels of serum luteinizing and follicle stimulating hormones (LH and FSH), testosterone, nitric oxide (NO) and the activity of phosphodiesterase V (PDE5). RESULTS: The plant contained alkaloids, saponins, flavonoids, cardiac glycosides, steroids, tannins, phlobatannins, cardenolides, phenolics, anthraquinones and triterpenes with alkaloids (2.32 mg/g) occurring in greatest quantity while flavonoids, anthraquinones and cardenolides (0.01 mg/g, each) were the least. All the 20 standard amino acids were detected in the plant leaf, with the lowest concentration being 0.30 mg/g for methionine and the highest being 2.12 mg/g for cysteine. Furthermore, P. nigrescens leaves contained Na, K, Fe, Mg, Zn, Ca, Cu, Mn, P, Pb, Cd, Ni, Cr, and Co, with Fe present in the highest and Co the lowest concentrations. Paroxetine significantly (P<0.05) reduced MF, IF, EF, percentage mounted , intromitted, ejaculated, IR, CE, serum testosterone, LH, FSH and NO, while ML, IL, PEI, IF and PDE5 were significantly (P<0.05) increased and/or prolonged. The AEPN significantly reversed these paroxetine-treatment-related alterations with most profound activity at the highest dose of 80 mg/kg BW, similar to that of the PowMaxM-treated animals. CONCLUSION: The AEPN restored both the physical and biochemical indices of male sexual activity/competence via changes in reproductive hormones, NO and PDE5 activity. The pro-sexual activity, attributed to a myriad of mineral, amino acid and secondary metabolite constituents, was best at 80 mg/kg BW of AEPN. PMID- 28088263 TI - Insufficient evidence to claim that more frequent toothbrushing reduces the risk of developing new caries. PMID- 28088264 TI - No evidence of higher rates of implant failure in people with controlled diabetes. PMID- 28088265 TI - Ceramic inlays, onlays, and overlays have a high survival rate and a low rate of complications. PMID- 28088266 TI - Previous bad experience, propensity to anxiety, and pain expectations may be associated with fear and anxiety when undergoing tooth extractions. PMID- 28088267 TI - A meta-analysis of three identified single nucleotide polymorphisms at 1p13.3 and 1q41 and their associations with lipid levels and coronary artery disease. AB - The aim of this meta-analysis was to detect whether three identified single nucleotide polymorphisms (SNPs) (rs646776, rs599839, and rs17465637) at 1p13.3 and 1q41 are associated with lipid levels and the risk of coronary artery disease (CAD). Databases of MEDLINE, EMBASE, the Cochrane Library, and BIOSIS were systematically searched. The pooled effects were expressed as odds ratio or standardized mean difference or mean difference with 95% confidence intervals. A total of 14 studies with 57,916 patients were included in the meta-analysis. Pooled effects showed that the AA group of 1p13.3 rs599839 had higher total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC), and lower high density lipoprotein cholesterol (HDLC) levels than the GA/GG group, and the CAD group had higher AA genotype frequency than the control group. The TT group of 1p13.3 rs646776 had higher TC and LDLC levels and lower HDLC levels than the CT/CC group. The CAD group also had higher CC genotype frequency of 1q41 rs17465637 than the control group. The SNPs of 1p13 rs599839 and rs646776 were associated with serum lipid levels. The genetic variants of 1p13 rs599839 and 1q41 rs17465637 SNPs were prominently related to CAD, and the genetic variants of chromosome 1p13 promote the risk of CAD by increased TC and LDLC levels and decreased HDLC levels. PMID- 28088268 TI - Aberrant beta-catenin expression in urothelial carcinomas in blackfoot disease endemic areas. AB - Arsenic is a well-known toxic element and carcinogenic agent. The aim of this study was to investigate p63, E-cadherin, and beta-catenin proteins in urothelial carcinoma (UC) in both arsenic contaminated areas [so-called blackfoot disease (BFD) area] and non-BFD areas. The expressions of p63, E-cadherin, and beta catenin proteins in 20 UC cases of blackfoot disease and 22 UC cases in non-BFD areas were detected using immunohistochemical methods. The results revealed a high p63 expression in 20 (47.6%) UC cases and high E-cadherin expression in six (14.3%) UC cases. Expressions of p63 and E-cadherin showed no significant correlations with clinicopathologic parameters. However, all 20 BFD cases and 12 of 22 (54.5%) non-BFD cases showed aberrant beta-catenin expression. Ten out of 22 (45.5%) non-BFD cases also had normal membranous immunoreactivity. The beta catenin staining pattern significantly differed between cases in endemic and nonendemic areas of BFD (p=0.001). Tumor sites also significantly correlated with beta-catenin expression (p=0.044). In addition, membranous localization of beta catenin was lower in UC from BFD-endemic areas compared with those from non-BFD endemic areas. In conclusion, it is suggested that relocalization of beta-catenin from membrane to cytoplasm may be involved in the tumorigenesis of UC from BFD endemic areas. PMID- 28088269 TI - Association of MMP-2 and MMP-9 expression with recurrences in primary spontaneous pneumothorax. AB - Primary spontaneous pneumothorax (PSP) is a common benign problem. However, PSP recurrence is still a troublesome complication for most patients. This study intended to determine the role of matrix metalloproteinase-2 (MMP-2) and MMP-9 in type II pneumocytes of patients with PSP and its relation with recurrence. Ninety one patients who had undergone needlescopic video-assisted thoracoscopic surgery wedge resection of lung with identifiable blebs for PSP were included in this study. Immunohistochemical (IHC) staining was used to measure the expression of MMP-2 and MMP-9 in lung tissues of PSP patients. The results were further correlated with clinicopathological parameters and recurrence rates using chi square or Fisher's exact test. The value of MMP-2 and MMP-9 for overall recurrence was analyzed by univariate and multivariable Cox regression model. IHC data revealed that MMP-2 and MMP-9 staining was predominantly observed in type II pneumocytes of patients with PSP. We found that MMP-2 and MMP-9 expression in PSP, especially male PSP patients, was significantly correlated with recurrence. In the univariate and multivariate analyses, MMP-2 and MMP-9 were statistically significant risk factors for overall recurrence in PSP patients. Therefore, high expression levels of MMP-2 and MMP-9 in type II pneumocytes show a positive correlation with PSP recurrence risk. Further studies are needed to validate whether reduction of MMP-2 and MMP-9 expression may be a promising way for decreasing the risk of PSP recurrence in the future. PMID- 28088270 TI - Association of plasminogen activator inhibitor-1 and vitamin D receptor expression with the risk of keloid disease in a Chinese population. AB - Keloid disease (KD) is a benign fibroproliferative scarring condition of unknown etiopathogenesis. Plasminogen activator inhibitor-1 (PAI-1) and vitamin D receptor (VDR) have been shown to play important roles in the progression of tissue fibrosis; therefore, both these genes are potential susceptibility genes for KD. We aimed to determine whether the gene expression levels of PAI-1 and VDR are altered in Chinese KD patients. We measured the expression of PAI and VDR in human peripheral blood lymphocytes in 236 patients with keloid and 219 age- and sex-matched healthy controls by quantitative real-time polymerase chain reaction. We found that PAI-1 expression in peripheral blood lymphocytes was significantly higher in patients with KD than in control individuals (p < 0.0001), while VDR expression was significantly lower in KD patients than in control individuals (p < 0.0001). High levels of PAI-1 and low levels of VDR expression were significantly associated with an increased risk for KD. PAI-1 and VDR might play important roles in keloid development. Gene expression levels of PAI-1 and VDR may, therefore, be used as potential markers for the prediction of keloid development after scarring. PMID- 28088271 TI - ADAMTS-3, -13, -16, and -19 levels in patients with habitual abortion. AB - A disintegrin-like and metalloproteinase domain with thrombospondin-type 1 motifs (ADAMTS) protein superfamily includes 19 secreted metalloproteases. Proteolytic substrates of ADAMTS enzymes have been linked to reproductive function. The aim of this study was to investigate serum ADAMTS-3, -13, -16, and -19 levels in women with habitual abortions compared with those in healthy controls. A total of 86 women were enrolled in this prospective case-control study. ADAMTS-3, -13, 16, and -19 values were recorded and analyzed in association with demographic and clinical parameters. There were no statistically significant differences between the two groups in terms of demographics. No statistically significant differences were observed between the groups with regard to ADAMTS-13 and -19 levels (p>0.05). However, ADAMTS-3 and -16 were significantly higher in the study group than in the control group (p=0.004 and p=0.005, respectively). To estimate habitual abortions using an area under receiver operating characteristic curve analysis, the cutoff values for ADAMTS-3 and -16 were found to be 87.28 ng/mL (sensitivity, 64.44%; specificity 68.29%) and 15.75 ng/mL (sensitivity, 66.67%; specificity 68.29%), respectively. In conclusion, the pregnancy-loss rate seems to be affected by both ADAMTS-3 and -16. PMID- 28088272 TI - Comparison of renal pelvic pressure and postoperative fever incidence between standard- and mini-tract percutaneous nephrolithotomy. AB - This study was proposed to compare the clinical effectiveness of mini-tract percutaneous nephrolithotomy (MPCNL) with standard-tract percutaneous nephrolithotomy (SPCNL) and verify whether MPCNL is associated with both higher renal pelvic pressure (RPP) and incidence of postoperative fever. A total of 228 patients with kidney stone were randomly allocated to the MPCNL group (n=114) and SPCNL group (n=114). Both intraoperative and postoperative indexes along with the incidence of complications were compared between the two treatment groups. RPP was measured using a baroreceptor which was connected to an open-ended ureteric catheter during the operation of percutaneous nephrolithotomy. The MPCNL group exhibited significantly longer average operation time, more average amount of flush water, and lesser average amount of bleeding during the operation than the SPCNL group (p<0.05). Moreover, significantly lesser average amount of postoperative serum creatinine, shorter average hospital stay, and more average amount of postoperative hemoglobin were observed in the MPCNL group than in the SPCNL group (p<0.05). MPCNL were more applicable to clear caliceal stones (p<0.05), whereas SPCNL were more effective for the removal of simple pelvic stones. The difference in the incidence of postoperative fever between the two treatment groups also appeared to be significant (p<0.05). Logistic regression provided solid evidence that both RPP and its accumulation time at which RPP>=30 mmHg significantly affected the incidence of postoperative fever. MPCNL was correlated with both higher RPP and increased likelihood of postoperative fever compared with SPCNL. PMID- 28088273 TI - A real-world impact of cost-effectiveness of pegylated interferon/ribavarin regimens on treatment-naive chronic hepatitis C patients in Taiwan. AB - Treatments with pegylated interferon/ribavirin (PEG-IFN/RBV) has been standard-of care in patients with chronic hepatitis C virus (HCV) (CHC) infection and reimbursed in Taiwan. However, the actual cost-effectiveness remains unclear. We aimed to evaluate a real-world cost-effectiveness for CHC patients treated with PEG-IFN/RBV by using a clinical cohort with linkage to the National Health Insurance Research Database of Taiwan. The total and itemized medical-care expenses of outpatient visits of 117 treatment-naive CHC patients with linkage to the two million sampling of the National Health Insurance Research Database were collected. Four components of costs were assessed, including antiviral agents, nonantiviral agents, laboratory testing and consultation costs. The cost per sustained virological response (SVR) achieved was calculated to evaluate the cost effectiveness. The average cost per treatment in 117 naive Taiwanese CHC patients was $4620. With an overall SVR rate of 78.6%, the average cost per SVR was $5878. The average medical-care cost per treatment for 52 Genotype 1 (G1) patients was $5133, including $4420 for antivirals, $380 for nonantivirals, $302 for laboratory, and $78 for consultation, compared to $4209, $3635, $317, $233, and $56 for 65 Genotype 2 (G2) patients. With an SVR rate at 67.3% for G1 and 87.7% for G2 patients, the cost per SVR achieved was significantly higher in G1 patients than those in G2 patients ($7627 vs. $4799, p = 0.001). In the current study, we provided the real-world cost-effectiveness of PEG-IFN/RBV for treatment naive CHC patients. The genotype-specific cost-effectiveness could enhance decision-making for policy-makers in the coming era of directly acting antiviral therapy. PMID- 28088274 TI - Epstein-Barr virus-positive mucocutaneous ulcer. PMID- 28088275 TI - Late-onset nonlesional nondominant frontal lobe seizures presenting as ictal dyscalculia. PMID- 28088276 TI - Solid supports for extraction and preconcentration of proteins and peptides in microfluidic devices: A review. AB - Determination of proteins and peptides is among the main challenges of today's bioanalytical chemistry. The application of microchip technology in this field is an exhaustively developed concept that aims to create integrated and fully automated analytical devices able to quantify or detect one or several proteins from a complex matrix. Selective extraction and preconcentration of targeted proteins and peptides especially from biological fluids is of the highest importance for a successful realization of these microsystems. Incorporation of solid structures or supports is a convenient solution employed to face these demands. This review presents a critical view on the latest achievements in sample processing techniques for protein determination using solid supports in microfluidics. The study covers the period from 2006 to 2015 and focuses mainly on the strategies based on microbeads, monolithic materials and membranes. Less common approaches are also briefly discussed. The reviewed literature suggests future trends which are discussed in the concluding remarks. PMID- 28088277 TI - Immunoassays of chemically modified polysaccharides, glycans in glycoproteins and ribose in nucleic acids. AB - Glycosylation of proteins plays an important role in health and diseases. At present new simple and inexpensive methods of glycoprotein analysis are sought. We developed a monoclonal antibody Manost 2.1 in mice after immunization with the adduct of mannan with Os(VI)temed complex (temed is N,N,N',N' tetramethylethylenediamine). The specificity of this antibody to different biomolecules treated with Os(VI)temed was tested using dot blot immunoassay. Manost 2.1 showed specificity toward Os(VI)temed-modified polysaccharides, glycoproteins and ribonucleotide at the 3'-end in DNA. The antibody recognized neither the unmodified compounds nor the non-glycosylated proteins treated with Os(VI)temed. We also performed western blotting and Coomassie silver blue staining of mixtures of biomacromolecules treated with Os(VI)temed and identified specifically the modified glycoproteins. The immunochemical method using Manost 2.1 was compared with electrochemical analyses based on redox signals of the Os(VI)temed adducts, with similar results in terms of sensitivity. This new antibody-based approach opens the door for rapid and inexpensive analysis of glycans and glycoproteins in various scientific and medical fields, including cancer research and the future application of glycoprotein detection in clinical practice. PMID- 28088278 TI - Metabolomic analysis of urine samples by UHPLC-QTOF-MS: Impact of normalization strategies. AB - Among the various biological matrices used in metabolomics, urine is a biofluid of major interest because of its non-invasive collection and its availability in large quantities. However, significant sources of variability in urine metabolomics based on UHPLC-MS are related to the analytical drift and variation of the sample concentration, thus requiring normalization. A sequential normalization strategy was developed to remove these detrimental effects, including: (i) pre-acquisition sample normalization by individual dilution factors to narrow the concentration range and to standardize the analytical conditions, (ii) post-acquisition data normalization by quality control-based robust LOESS signal correction (QC-RLSC) to correct for potential analytical drift, and (iii) post-acquisition data normalization by MS total useful signal (MSTUS) or probabilistic quotient normalization (PQN) to prevent the impact of concentration variability. This generic strategy was performed with urine samples from healthy individuals and was further implemented in the context of a clinical study to detect alterations in urine metabolomic profiles due to kidney failure. In the case of kidney failure, the relation between creatinine/osmolality and the sample concentration is modified, and relying only on these measurements for normalization could be highly detrimental. The sequential normalization strategy was demonstrated to significantly improve patient stratification by decreasing the unwanted variability and thus enhancing data quality. PMID- 28088279 TI - Archaeometric analysis of Roman bronze coins from the Magna Mater temple using solid-state voltammetry and electrochemical impedance spectroscopy. AB - Voltammetry of microparticles (VMP) and electrochemical impedance spectroscopy (EIS) techniques, complemented by SEM-EDX and Raman spectroscopy, were applied to a set of 15 Roman bronze coins and one Tessera from the temple of Magna Mater (Rome, Italy). The archaeological site, dated back between the second half and the end of the 4th century A.D., presented a complicated stratigraphic context. Characteristic voltammetric patterns for cuprite and tenorite for sub microsamples of the corrosion layers of the coins deposited onto graphite electrodes in contact with 0.10 M HClO4 aqueous solution yielded a grouping of the coins into three main groups. This grouping was confirmed and refined using EIS experiments of the coins immersed in air-saturated mineral water using the reduction of dissolved oxygen as a redox probe. The electrochemical grouping of coins corroborated the complex stratigraphy of the archaeological site and, above all, the reuse of the coins during the later periods due to the economic issues related to the fall of the Roman Empire. PMID- 28088280 TI - Comparative study of colloidal gold and quantum dots as labels for multiplex screening tests for multi-mycotoxin detection. AB - Quantum dots (QDs) and colloidal gold nanoparticles (CG) were evaluated as labels for multiplex lateral flow immunoassay (LFIA) for determination of mycotoxins deoxynivalenol (DON), zearalenone (ZEN) and T2/HT2-toxin (T2/HT2) in cereal matrices. Both developed assays were based on the same immunoreagents (except for the labels), therefore their analytical characteristics could be objectively compared. For both LFIAs antigens (DON-ovalbumin (OVA), ZEN-OVA and T2-OVA) and rabbit anti-mouse immunoglobulin were immobilized on a nitrocellulose membrane as three test lines and one control line, respectively. Depending on the LFIA, monoclonal antibodies (mAb) against DON, ZEN and T2 were conjugated with CdSeS/ZnS QDs or CG. T2 and HT2 were detected by one test line (T2-OVA) with an anti-T2 mAb which showed 110% cross-reactivity with HT2. Both tests were developed in accordance with the legal limits and were developed in such a way that they had the same cut-off limits of 1000 MUg kg-1, 80 MUg kg-1 and 80 MUg kg 1 for DON, ZEN and T2/HT2, respectively in order to allow a correct comparison. Applicability of these assays was demonstrated by analysis of naturally contaminated wheat samples. The results demonstrate that both the LFIAs can be used as rapid, cost-effective and convenient qualitative tool for on-site screening for simultaneous detection of DON, ZEN and HT2/T2 in wheat without special instrumentation. However, the QD-based LFIA consumed less immunoreagents and was more sensitive and economically beneficial. In addition, the results were easier to interpret, resulting in a lower false negative rate (<5%) which was in good agreement with Commission Decision 2002/657/EC regarding the performance of analytical methods intended for screening purposes. PMID- 28088281 TI - Flow injection microfluidic device with on-line fluorescent derivatization for the determination of Cr(III) and Cr(VI) in water samples after solid phase extraction. AB - In this paper, a rapid and simple method using magnetic multi-walled carbon nanotubes (MWCNTS), as a solid-phase extraction (SPE) sorbent, was successfully developed for extraction and preconcentration trace amounts of Cr(III) in water samples. The synthesized magnetic-MWCNTs nanocomposite was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD). A rhodamine derivative (R1) was synthesized and characterized as a highly selective and sensitive fluorescent derivatizing agent for Cr(III). After SPE procedure, Cr(III) analysis was performed by flow injection microfluidic chip with on-line fluorescent derivatization and laser induced fluorescence (LIF) spectroscopy detection. The parameters, which affected the efficiency of the developed method were investigated and optimized. Under the optimized conditions, the method exhibited a linear dynamic range of 0-10.0 nM, with a detection limit of 0.094 nM and an enrichment factor of 38. Furthermore, real water samples were analyzed and good recoveries were obtained from 91.0 to 101.6%. PMID- 28088282 TI - Conjugation site analysis of antibody-drug-conjugates (ADCs) by signature ion fingerprinting and normalized area quantitation approach using nano-liquid chromatography coupled to high resolution mass spectrometry. AB - Trastuzumab-MCC-DM1 (T-DM1) is an antibody-drug conjugate (ADC) that consists of a monoclonal antibody (mAb) trastuzumab non-cleavably linked to a cytotoxic drug DM1. During production, the DM1 agents were conjugated to the lysine residues of the mAb in a non-specific manner, yielding a heterogeneous mixture of ADC molecules that differ with respect to both the number and the conjugation sites of DM1 per mAb molecule. Since drug conjugation sites of ADC can significantly impact properties such as stability and pharmacokinetic behaviors, a rapid and reliable approach for conjugation site analysis of ADCs is highly demanded. Herein, we have employed a signature ion fingerprinting approach to specifically determine lysine residues with DM1 conjugation, and developed a normalized peak area quantitation method to characterize the percentage of DM1-conjugated lysine for each putative site using a T-DM1 biosimilar as a model drug. With this integrative approach, 38 lysine residues were identified with DM1 conjugation among 90 possible sites. More interestingly, we found that the T-DM1 biosimilar exhibited a specific preference of DM1-conjugation for several lysine residues, and such preference was consistent among three production batches. A molecular modeling approach was subsequently utilized to analyze all the conjugation sites, and revealed an intriguing correlation of the conjugated residue's microenvironment with the conjugation level. In summary, our study introduced an approach that is widely applicable to ADCs of interest for conjugation site analysis. Moreover, it suggests the necessity of performing conjugation site analysis for product and process characterization and also for routine use in lot release and stability testing of manufactured ADCs. PMID- 28088283 TI - Quantification of plasma sulfatides by mass spectrometry: Utility for metachromatic leukodystrophy. AB - Impaired sulfatide catabolism is the primary biochemical insult in patients with the inherited neurodegenerative disease, metachromatic leukodystrophy (MLD), and sulfatide elevation in body fluids is useful in the diagnostic setting. Here we used mass spectrometry to quantify fourteen species of sulfatide, in addition to the deacetylated derivative, lyso-sulfatide, using high pressure liquid chromatography-electrospray ionisation-tandem mass spectrometry in both positive and negative ion mode. A single phase extraction of 0.01 mL of MLD plasma identified all 14 sulfatide species in the positive ion mode but none in the negative ion mode. Interrogation of seven major and seven hydroxylated molecular species, as well as lyso-sulfatide, identified the C18 isoform as the most informative for MLD. The C18 produced a linear response and was below the limit of quantification (<10 pmol mL-1) in control plasma with concentrations in MLD plasma ranging from 12 to 196 pmol mL-1. Serial plasma samples from an MLD patient post-therapeutic bone marrow transplant proved similar to non-disease controls with C18 sulfatide concentrations below the limit of quantification, as did samples from three individuals with an arylsulfatase A pseudodeficiency - a population variant which appears deficient upon enzymatic assay, without manifestation of disease. These findings emphasise the utility of the C18 sulfatide species for the diagnosis of MLD and biochemical monitoring of MLD patients. Extension of this approach to a newborn screening card correctly identified an MLD patient at birth with elevated C18 sulfatide at levels almost double that present in the newborn card from his unaffected sibling, suggesting the methodology may have applicability for newborn screening. PMID- 28088284 TI - Improving accuracy and reproducibility of vibrational spectra for diluted solutions. AB - In what appears to be a trivial operation in which the averaged spectrum of solvent is subtracted from the spectra of solutions, can be a misleading step in improving reproducibility of vibrational spectra. Near-infrared spectra of pure water and glycine solutions were used to quantify instrumental and spectral variations, and examine its influence on the reproducibility of difference spectra over a wide concentration range. Significant improvements were observed (fourfold), in comparison with the most commonly applied technique that uses an averaged spectrum of solvent. We propose a new technique, in which subtraction of the closest spectrum of solvent involves calculating the smallest area under the subtracted curve, to extract the optimal outcome. These results reveal that, contrary to common practice, reproducibility for spectra of diluted solutions can bypass even instrumental baseline shifts and render results that are limited only by the noise originating from the instrument's sensor. PMID- 28088285 TI - Plasmon-enhanced fluorescence imaging with silicon-based silver chips for protein and nucleic acid assay. AB - Metal-enhanced fluorescence shows great potential for improving the sensitivity of fluoroscopy, which has been widely used in protein and nucleic acid detection for biosensor and bioassay applications. In comparison with the traditional glass supported metal nanoparticles (MNPs), the introduction of a silicon substrate has been shown to provide an increased surface-enhanced Raman scattering (SERS) effect due to the coupling between the MNPs and the semiconducting silicon substrate. In this work, we further study the fluorescence-enhanced effect of the silicon-supported silver-island (Ag@Si) plasmonic chips. In particular, we investigate their practical application of improving the traditional immunoassay such as the biotin-streptavidin-based protein assay and the protein-/nucleic acid labeled cell and tissue samples. The protein assay shows a wavelength-dependent enhancement effect of the Ag@Si chip, with an enhancement factor ranging from 1.2 (at 532 nm) to 57.3 (at 800 nm). Moreover, for the protein- and nucleic acid labeled cell and tissue samples, the Ag@Si chip provides a fluorescence enhancement factor of 3.0-4.1 (at 800 nm) and a significant improvement in the signal/background ratio for the microscopy images. Such a ready accommodation of the fluorescence-enhanced effect for the immunoassay samples with simple manipulations indicates broad potential for applications of the Ag@Si chip not only in biological studies but also in the clinical field. PMID- 28088286 TI - Sunshine Has Darkened my Worldview. PMID- 28088287 TI - Insulin-Like Growth Factor Binding Protein-3 Deficiency Leads to Behavior Impairment with Monoaminergic and Synaptic Dysfunction. AB - Insulin-like growth factor binding protein (IGFBP)-3 regulates IGF bioactivity, induces apoptosis, and inhibits cell growth independent of IGFs, but the functional role of IGFBP3 in the brain is not clear. In the present study, we revealed the effect of IGFBP3 on the brain by characterizing the phenotype of Igfbp3-null mice. Compared with wild-type mice, Igfbp3-null mice had significantly decreased IGF-1 content in the brain but no change in weights of brain and body. In Igfbp3-null mice, the number of dendritic spines was significantly reduced, and the dendritic diameter was thickening. In addition, in Igfbp3-null mice, a decrease in phosphorylated Akt and ERK1/2 significantly reduced PSD-95 expression, and GAD65/67 expression was significantly decreased. These results indicate that IGFBP3 deficiency impairs neuronal structure and signaling. In behavioral studies, Igfbp3-null mice were hyperactive, and a Y-maze alternation test revealed impaired spatial working memory but no anxiety-like behavior. Monoaminergic analysis using high-performance liquid chromatography indicated that Igfbp3-null mice had lower levels of dopamine and serotonin compared with wild-type mice, suggesting an abnormal monoaminergic neurotransmission. In conclusion, our studies found that the deletion of IGFBP3 results in behavioral impairments that are associated with abnormal synaptic function and monoaminergic neurotransmission, which helps to characterize the critical role of IGFBP3 in the brain. PMID- 28088288 TI - A Novel Mouse Model of Staphylococcus aureus Vascular Graft Infection: Noninvasive Imaging of Biofilm Development in Vivo. AB - Staphylococcus aureus causes very serious infections of vascular grafts. Knowledge of the molecular mechanisms of this disease is largely lacking because of the absence of representable models. Therefore, the aim of this study was to set up a mouse model of vascular graft infections that closely mimics the human situation. A catheter was inserted into the right carotid artery of mice, which acted as a vascular graft. Mice were infected i.v. using 8 different S. aureus strains, and development of the infection was followed up. Although all strains had varying abilities to form biofilm in vitro and different levels of virulence in mice, they all caused biofilm formation on the grafts. This graft infection was monitored using magnetic resonance imaging (MRI) and 18F-fluordeoxyglucose positron emission tomography (FDG-PET). MRI allowed the quantification of blood flow through the arteries, which was decreased in the catheter after infection. FDG-PET revealed high inflammation levels at the site of the catheter after infection. This model closely resembles the situation in patients, which is characterized by a tight interplay between pathogen and host, and can therefore be used for the testing of novel treatment, diagnosis, and prevention strategies. In addition, combining MRI and PET with microscopic techniques provides an appropriate way to characterize the course of these infections and to precisely analyze biofilm development. PMID- 28088289 TI - Effects of treatment with sucrose in drinking water on liver histology, lipogenesis and lipogenic gene expression in rats fed high-fiber diet. AB - We studied the influence of sucrose in drinking water on liver histology, fatty acid profile and lipogenic genes expression in rats maintained on high-fiber. The experimental groups were: control group (water) and sucrose group (sucrose solution in drinking water, 30% w/v). Liver histology of sucrose treated rats revealed steatosis and increased number of alphaSMA immunoreactive cells without the signs of fibrosis. Sucrose treatment increased de novo lipogenesis, lipid peroxidation and MUFA content and decreased PUFA content, C18:2n6 and C20:4n6 content in total phospholipids and phosphatidylethanolamine and C18:2n6 content in cardiolipin. RT-qPCR revealed increase in Delta-9-desaturase and SREBP1c gene expression and decrease in the Delta-5-desaturase and elongase 5 expression. Treatment with sucrose extensively changes fatty acid composition of hepatic lipid and phospholipid classes including cardiolipin, increases oxidative stress and causes pathological changes in liver in rats maintained on high-fiber diet. PMID- 28088290 TI - Could post-weaning dietary chia seed mitigate the development of dyslipidemia, liver steatosis and altered glucose homeostasis in offspring exposed to a sucrose rich diet from utero to adulthood? AB - The present work analyzes the effects of dietary chia seeds during postnatal life in offspring exposed to a sucrose-rich diet (SRD) from utero to adulthood. At weaning, chia seed (rich in alpha-linolenic acid) replaced corn oil (rich in linoleic acid) in the SRD. At 150 days of offspring life, anthropometrical parameters, blood pressure, plasma metabolites, hepatic lipid metabolism and glucose homeostasis were analyzed. Results showed that chia was able to prevent the development of hypertension, liver steatosis, hypertriglyceridemia and hypercholesterolemia. Normal triacylglycerol secretion and triacylglycerol clearance were accompanied by an improvement of de novo hepatic lipogenic and carnitine-palmitoyl transferase-1 enzymatic activities, associated with an accretion of n-3 polyunsaturated fatty acids in the total composition of liver homogenate. Glucose homeostasis and plasma free fatty acid levels were improved while visceral adiposity was slightly decreased. These results confirm that the incorporation of chia seed in the diet in postnatal life may provide a viable therapeutic option for preventing/mitigating adverse outcomes induced by an SRD from utero to adulthood. PMID- 28088291 TI - BCFA suppresses LPS induced IL-8 mRNA expression in human intestinal epithelial cells. AB - Branched chain fatty acids (BCFA) are components of common food fats and are major constituents of the normal term human newborn GI tract. Polyunsaturated fatty acids (PUFA) have been suggested to reduce the risk and development of inflammatory bowel diseases (IBD); however, little is known about the influence of BCFA on inflammation. We investigated the effect of BCFA on interleukin (IL)-8 and NF-kappaB production in a human intestinal epithelial cell line (Caco-2). Cells were pre-treated with specific BCFA, or DHA, or EPA, and then activated with lipopolysaccharide (LPS). Both anteiso- and iso- BCFA reduce IL-8. Anteiso BCFA more effectively suppressed IL-8 than iso-BCFA in LPS stimulated Caco-2 cells. However BCFA in general were less effective than DHA or EPA. Activated BCFA-treated cells expressed less of the cell surface Toll-like receptor 4 (TLR 4) compared to controls. These are the first data to show the reduction of pro inflammatory markers in human cells mediated by BCFA. PMID- 28088292 TI - Human fetal intestinal epithelial cells metabolize and incorporate branched chain fatty acids in a structure specific manner. AB - BACKGROUND: Branched chain fatty acids (BCFA) are constituents of gastrointestinal (GI) tract in healthy newborn human infants, reduce the incidence of necrotizing enterocolitis (NEC) in a neonatal rat model, and are incorporated into small intestine cellular lipids in vivo. We hypothesize that BCFA are taken up, metabolized and incorporated into human fetal cells in vitro. METHODS: Human H4 cells, a fetal non-transformed primary small intestine cell line, were incubated with albumin-bound non-esterified anteiso-17:0, iso-16:0, iso-18:0 and/or iso-20:0, and FA profiles in lipid fractions were analyzed. RESULTS: All BCFA were readily incorporated as major constituents of cellular lipids. Anteiso-17:0 was preferentially taken up, and was most effective among BCFA tested in displacing normal (n-) FA. The iso BCFA were preferred in reverse order of chain length, with iso-20:0 appearing at lowest level. BCFA incorporation in phospholipids (PL) followed the same order of preference, accumulating 42% of FA as BCFA with no overt morphological signs of cell death. Though cholesterol esters (CE) are at low cellular concentration among lipid classes examined, CE had the greatest affinity for BCFA, accumulating 65% of FA as BCFA. BCFA most effectively displaced lower saturated FA. Iso-16:0, iso-18:0 and anteiso-17:0 were both elongated and chain shortened by +/-C2. Iso-20:0 was chain shortened to iso-18:0 and iso-16:0 but not elongated. CONCLUSIONS: Nontransformed human fetal intestinal epithelial cells incorporate high levels of BCFA when they are available and metabolize them in a structure specific manner. These findings imply that specific pathways for handling BCFA are present in the lumen-facing cells of the human fetal GI tract that is exposed to vernix-derived BCFA in late gestation. PMID- 28088293 TI - The essentiality of arachidonic acid in addition to docosahexaenoic acid for brain growth and function. AB - The essentiality of arachidonic acid (ARA) and docosahexaenoic acid (DHA) for growth and brain function using delta-6-desaturase knockout (D6D-KO) mice and a novel artificial rearing method was investigated. Newborn male wild type (WT) and homozygous D6D-KO pups were separated from their dams within 48h and fed artificial milk containing alpha-linolenic acid and linoleic acid (Cont), or supplemented with ARA, DHA or both (ARA+DHA). After weaning, each group was fed diets similar to artificial milk in fatty acid composition for 7 weeks. KO-Cont showed a lower body weight than WT-Cont. When ARA was added to the control diet, (KO-ARA and KO-ARA+DHA diets) the body weight gain was restored. The KO-DHA group was initially similar to the WT groups for the first 6 weeks, but afterwards their body weight was significantly lower. Brain weight in the 10 week old KO ARA+DHA group was significantly higher within the KO dietary groups. Motor activity of the KO-ARA and KO-ARA+DHA groups was elevated relative to the KO-Cont group but the KO-ARA+DHA group exhibited similar activity to the WT-Cont group. In the motor coordination ability test, the KO-Cont group performed significantly worse compared with the WT-Cont group. KO-ARA mice showed decreased motor coordination in spite of their increased motor activity. The best performance was observed in only KO-ARA+DHA mice. These experiments demonstrated that supplementation with only ARA or only DHA was insufficient for optimal development. ARA was essential for normal growth within the lactation period. In conclusion, only the combination of preformed ARA and DHA was capable of improving the dysfunction caused by D6D deficiency. PMID- 28088294 TI - Suitability of small diagnostic peripheral-blood samples for cell-therapy studies. AB - BACKGROUND AIMS: Primary hematopoietic stem and progenitor cells (HSPCs) are key components of cell-based therapies for blood disorders and are thus the authentic substrate for related research. We propose that ubiquitous small-volume diagnostic samples represent a readily available and as yet untapped resource of primary patient-derived cells for cell- and gene-therapy studies. METHODS: In the present study we compare isolation and storage methods for HSPCs from normal and thalassemic small-volume blood samples, considering genotype, density-gradient versus lysis-based cell isolation and cryostorage media with different serum contents. Downstream analyses include viability, recovery, differentiation in semi-solid media and performance in liquid cultures and viral transductions. RESULTS: We demonstrate that HSPCs isolated either by ammonium-chloride potassium (ACK)-based lysis or by gradient isolation are suitable for functional analyses in clonogenic assays, high-level HSPC expansion and efficient lentiviral transduction. For cryostorage of cells, gradient isolation is superior to ACK lysis, and cryostorage in freezing media containing 50% fetal bovine serum demonstrated good results across all tested criteria. For assays on freshly isolated cells, ACK lysis performed similar to, and for thalassemic samples better than, gradient isolation, at a fraction of the cost and hands-on time. All isolation and storage methods show considerable variation within sample groups, but this is particularly acute for density gradient isolation of thalassemic samples. DISCUSSION: This study demonstrates the suitability of small-volume blood samples for storage and preclinical studies, opening up the research field of HSPC and gene therapy to any blood diagnostic laboratory with corresponding bioethics approval for experimental use of surplus material. PMID- 28088295 TI - Keeping the Momentum: A Reflection on 2016, and a Look Forward to 2017. PMID- 28088296 TI - 9th Congress of Toxicology in Developing Countries and XIX Brazilian Congress of Toxicology. PMID- 28088297 TI - Corrigendum to "Both Immediate and Delayed Intracavernous Injection of Autologous Adipose-derived Stromal Vascular Fraction Enhances Recovery of Erectile Function in a Rat Model of Cavernous Nerve Injury" [Eur Urol 2012;62:720-7]. PMID- 28088298 TI - Retraction notice to "Synthesis and characterization of silver sulfide nanoparticles for photocatalytic and antimicrobial applications" [J. Photochem. Photobiol. B Biol., 141 (2014) 235-240]. PMID- 28088299 TI - Retraction notice to "Influence of humic acid on the stability and bacterial toxicity of zinc oxide nanoparticles in water" [J. Photochem. Photobiol. B Biol., 153 (2015) 289-295]. PMID- 28088301 TI - Methocarbamol use is associated with decreased hospital length of stay in trauma patients with closed rib fractures. AB - BACKGROUND: The objective of this study was to evaluate the effect of methocarbamol on hospital length of stay in patients with closed rib fracture injuries. METHODS: This was a retrospective cohort study conducted in an academic medical center in the United States. Adult trauma patients, who sustained closed rib fractures, were included. Patients were categorized based on whether they received methocarbamol or not during admission. The primary outcome of interest was time to hospital discharge in days (i.e. length of hospital stay). A Cox Proportional Hazards Model was constructed to determine if methocarbamol use was associated with a greater likelihood of earlier discharge. RESULTS: A total of 592 patients were included in the final study cohort. Of these, 329 received methocarbamol and 263 did not receive methocarbamol. In the Cox Proportional Hazards Model methocarbamol use was associated with a greater likelihood of being discharged from the hospital (HR 1.47, 95% CI 1.21 to 1.78, p < 0.001). . CONCLUSIONS: The use of methocarbamol after traumatic rib fractures may result in a reduction in the length of hospital stay. PMID- 28088300 TI - Cytoplasmic RNA-Protein Particles Exhibit Non-Gaussian Subdiffusive Behavior. AB - The cellular cytoplasm is a complex, heterogeneous environment (both spatially and temporally) that exhibits viscoelastic behavior. To further develop our quantitative insight into cellular transport, we analyze data sets of mRNA molecules fluorescently labeled with MS2-GFP tracked in real time in live Escherichia coli and Saccharomyces cerevisiae cells. As shown previously, these RNA-protein particles exhibit subdiffusive behavior that is viscoelastic in its origin. Examining the ensemble of particle displacements reveals a Laplace distribution at all observed timescales rather than the Gaussian distribution predicted by the central limit theorem. This ensemble non-Gaussian behavior is caused by a combination of an exponential distribution in the time-averaged diffusivities and non-Gaussian behavior of individual trajectories. We show that the non-Gaussian behavior is a consequence of significant heterogeneity between trajectories and dynamic heterogeneity along single trajectories. Informed by theory and simulation, our work provides an in-depth analysis of the complex diffusive behavior of RNA-protein particles in live cells. PMID- 28088302 TI - The CYP79A1 catalyzed conversion of tyrosine to (E)-p-hydroxyphenylacetaldoxime unravelled using an improved method for homology modeling. AB - The vast diversity and membrane-bound nature of plant P450s makes it challenging to study the structural characteristics of this class of enzymes especially with respect to accurate intermolecular enzyme-substrate interactions. To address this problem we here apply a modified hybrid structure strategy for homology modeling of plant P450s. This allows for structural elucidation based on conserved motifs in the protein sequence and secondary structure predictions. We modeled the well studied Sorghum bicolor cytochrome P450 CYP79A1 catalyzing the first step in the biosynthesis of the cyanogenic glucoside dhurrin. Docking experiments identified key regions of the active site involved in binding of the substrate and facilitating catalysis. Arginine 152 and threonine 534 were identified as key residues interacting with the substrate. The model was validated experimentally using site-directed mutagenesis. The new CYP79A1 model provides detailed insights into the mechanism of the initial steps in cyanogenic glycoside biosynthesis. The approach could guide functional characterization of other membrane-bound P450s and provide structural guidelines for elucidation of key structure-function relationships of other plant P450s. PMID- 28088303 TI - [Letter to the editor: Spinal subarachnoid hematoma after-spinal anesthesia: case report [Rev Bras Anestesiol 2016]]. PMID- 28088304 TI - Mechanical biomarkers of medial compartment knee osteoarthritis diagnosis and severity grading: Discovery phase. AB - OBJECTIVE: To investigate, as a discovery phase, if 3D knee kinematics assessment parameters can serve as mechanical biomarkers, more specifically as diagnostic biomarker and burden of disease biomarkers, as defined in the Burden of Disease, Investigative, Prognostic, Efficacy of Intervention and Diagnostic classification scheme for osteoarthritis (OA) (Altman et al., 1986). These biomarkers consist of a set of biomechanical parameters discerned from 3D knee kinematic patterns, namely, flexion/extension, abduction/adduction, and tibial internal/external rotation measurements, during gait recording. METHODS: 100 medial compartment knee OA patients and 40 asymptomatic control subjects participated in this study. OA patients were categorized according to disease severity, by the Kellgren and Lawrence grading system. The proposed biomarkers were identified by incremental parameter selection in a regression tree of cross-sectional data. Biomarker effectiveness was evaluated by receiver operating characteristic curve analysis, namely, the area under the curve (AUC), sensitivity and specificity. RESULTS: Diagnostic biomarkers were defined by a set of 3 abduction/adduction kinematics parameters. The performance of these biomarkers reached 85% for the AUC, 80% for sensitivity and 90% for specificity; the likelihood ratio was 8%. Burden of disease biomarkers were defined by a 3-decision tree, with sets of kinematics parameters selected from all 3 movement planes. CONCLUSION: The results demonstrate, as part of a discovery phase, that sets of 3D knee kinematic parameters have the potential to serve as diagnostic and burden of disease biomarkers of medial compartment knee OA. PMID- 28088305 TI - Inertial particle dynamics in large artery flows - Implications for modeling arterial embolisms. AB - The complexity of inertial particle dynamics through swirling chaotic flow structures characteristic of pulsatile large-artery hemodynamics renders significant challenges in predictive understanding of transport of such particles. This is specifically crucial for arterial embolisms, where knowledge of embolus transport to major vascular beds helps in disease diagnosis and surgical planning. Using a computational framework built upon image-based CFD and discrete particle dynamics modeling, a multi-parameter sampling-based study was conducted on embolic particle dynamics and transport. The results highlighted the strong influence of material properties, embolus size, release instance, and embolus source on embolus distribution to the cerebral, renal and mesenteric, and ilio-femoral vasculature beds. The study also isolated the importance of shear gradient lift, and elastohydrodynamic contact, in affecting embolic particle transport. Near-wall particle re-suspension due to lift alters aortogenic embolic particle dynamics significantly as compared to cardiogenic. The observations collectively indicated the complex interplay of particle inertia, fluid-particle density ratio, and wall collisions, with chaotic flow structures, which render the overall motion of the particles to be non-trivially dispersive in nature. PMID- 28088306 TI - Ventricular fibrillation occurring after atrioventricular node ablation despite minimal difference between pre- and post-ablation heart rates. AB - We report the case of an 82-year-old man presenting with ventricular fibrillation (VF) occurring acutely after atrioventricular node (AVN) ablation. This patient had severe valvular cardiomyopathy, chronic atrial fibrillation (AF), and underwent prior to the AVN ablation a biventricular implantable cardiac defibrillator positioning. The VF was successfully cardioverted with one external electrical shock. What makes this presentation original is that the pre-ablation spontaneous heart rate in AF was slow (84 bpm), and that VF occurred after ablation despite a minimal heart rate drop of only 14 bpm. VF is the most feared complication of AVN ablation, but it had previously only been described in case of acute heart rate drop after ablation of at least 30 bpm (and more frequently>50 bpm). This case report highlights the fact that VF may occur after AVN ablation regardless of the heart rate drop, rendering temporary fast ventricular pacing mandatory whatever the pre-ablation heart rate. PMID- 28088307 TI - In-office fabrication of a definitive cast and duplication of an interim implant supported fixed acrylic resin complete denture. AB - The information contained in an interim implant-supported fixed acrylic resin complete denture is a starting point for fabricating the definitive restoration. Duplicating this information in an expedient, precise, and sanitary fashion is desirable so that the interim restoration can be returned to the waiting patient. A technique is described to fabricate an accurate definitive polyvinyl siloxane cast with laboratory analogs bonded to a prepolymerized, dimensionally stable, composite resin baseplate. A screw-retained polyvinyl siloxane duplication of the interim denture is related to this cast. This combination allows for most of the relevant information of the interim denture to be communicated to the dental laboratory. PMID- 28088308 TI - Effect of various polishing systems on the surface roughness and phase transformation of zirconia and the durability of the polishing systems. AB - STATEMENT OF PROBLEM: Although many systems are used to polish zirconia, a comparison of the performance of zirconia and feldspathic porcelain polishing systems is lacking. PURPOSE: The purpose of this in vitro study was to compare the effects of 3 polishing systems on surface roughness, zirconia phase transformation, and durability of the polishing systems when applied to zirconia and feldspathic porcelain. MATERIAL AND METHODS: Three polishing systems were evaluated: Z1, a zirconia polishing system; Z2, a zirconia polishing system, and F1, a feldspathic porcelain polishing system. Three ceramic systems were evaluated: PR and ZM zirconia specimens (diameter 15 mm, height 2 mm; 23 specimens each) and CB feldspathic porcelain specimens of the same size (15 specimens). A rough surface was created on the 3 types of specimens (15 specimens each) to model an occlusal adjustment under the same conditions. Polishing was carried out with the 3 polishing systems for 2 minutes each. Surface roughness was measured with a 3-dimensional (3D) optical profiler. The surface was also observed with a scanning electron microscopy. X-ray diffraction analysis was performed for 8 PR or ZM zirconia specimens polished by using the Z1 and Z2 systems for 8 minutes to evaluate the phase transformation of zirconia before, during, and after polishing. These specimens were compared and analyzed for phase transformation that might have occurred during the polishing of the specimens. After finishing the surface roughness experiment and the phase transformation experiment, the volumes of the polishers were measured with a 3D volume scanner and compared with those before the experiments to evaluate the durability of the polishing system. A statistical analysis of all data was performed using 2-way ANOVA and the Tukey honest significant difference test (alpha=.05). RESULTS: The 2 zirconia polishing systems (Z1, Z2) created a significantly (P<.001) smoother surface, regardless of the type of specimens used for polishing, than the feldspathic porcelain polishing system (F1). When polishing treatment was carried out on zirconia specimens for 8 minutes, the maximum percentages of monoclinic phase increased by 0.03% in the Z1 system and by 0.09% in the Z2 system. The volume change for the durability evaluation of the polishing system was 13.35 and 29.37% in the Z1 system, 2.05 and 5.92% in the Z2 system, and 3.60 and 4.95% in the F1 system, respectively. CONCLUSIONS: Zirconia polishing systems created a smoother surface on zirconia than the feldspathic porcelain polishing system. No significant changes in the phase transformation of zirconia were found before and after polishing. Each polishing system showed different levels of wear resistance. PMID- 28088309 TI - [New therapy outlooks in Hodgkin lymphoma]. AB - Classical Hodgkin lymphoma (HL) is a curable disease in 80% of advanced and 90% of localized stages. An improvement of the HL curability is still possible with the emergence of first-line therapy with a better balance between efficacy and toxicity and early identification patients with high risk of failure requiring specific treatment. 18FDG PET-CT gained a major role in the baseline staging and response assessment to HL treatment. The prognostic value of early PET-CT allowed to develop PET-CT guided therapies able to optimize the balance between efficacy and toxicity including the modulation of the chemotherapy intensity or the omission of radiotherapy for some localized diseases. New drugs emerged in the treatment of relapse or refractory HL (brentuximab vedotine [BV], immunological checkpoint inhibitor anti-PD1). Although their place in the strategies of salvage therapy is still debated several trials have reported relevant efficacy in some unmet medical need: refractory patients or relapses after auto/allograft. This review addresses the questions of PET-CT-based therapeutic strategies in first line and the impact of new drugs targeting the micro-environment (anti-PD1) or the Hodgkin Reed Sternberg cells (BV). PMID- 28088310 TI - Performance limitations of networked control systems with quantization and packet dropouts. AB - This paper investigates the problem of optimal tracking performance of networked control systems (NCSs) with quantization and packet-dropouts. The system under consideration is linear time-invariant (LTI), multi-input multi-output (MIMO), where an H2 norm of error signal between the reference input and the system output is used as the tracking performance index. The impacts of packet-dropouts in the communication channel and the quantized input and output are studied. The goal is to obtain the minimal error in tracking a random signal, by searching through all possible stabilizing two-parameter controllers. It is shown that, the minimum value of tracking error is closely related to the reference input signal direction, the non-minimum phase zeros and unstable poles of the given plant, including the locations and directions. We also demonstrated the quantization error and the packet-dropouts may degrade the tracking performance. A typical example is given to evaluate the theoretical results. PMID- 28088311 TI - Prevalence of preoperative penile abnormalities among voluntary male medical circumcision patients in Swaziland. AB - BACKGROUND: Circumcision has been found to be an effective strategy for lowering the transmission of HIV in Africa. The Luke Commission, a mobile hospital outreach program, has used this information to decrease the rate of HIV in Swaziland by performing voluntary male medical circumcisions throughout the country. During many of these circumcisions, genital medical conditions and penile abnormalities are simultaneously discovered and corrected. PURPOSE: The goal of our study was to evaluate the prevalence of penile abnormalities discovered and treated during voluntary male medical circumcisions performed by The Luke Commission (TLC) throughout rural Swaziland. BASIC PROCEDURES: We completed a retrospective analysis of all male patients who underwent voluntary male medical circumcision performed by TLC during a period from June-August, 2014. The penile abnormalities included: phimosis, paraphimosis, epispadias, hypospadias, ulcers, balanitis, torsion, and foreskin adherent to the glans. MAIN FINDINGS: Of 929 total circumcisions, 771 (83%) patients had at least one pre existing penile abnormality identified during their examinations and procedures, totaling 1110 abnormalities. Three specific abnormalities were detected - phimosis, adherent foreskin, and hypospadias. The 6-12 and 13-19 age groups had adequate sample sizes to yield precise estimates of prevalence (age group 6-12: 87% (95% confidence interval [CI]=84-90%; age group 13-19: 79% (95% CI=74-84%). PRINCIPLE CONCLUSIONS: The Luke Commission is improving the lives of children and adults with limited access to healthcare through regular preoperative evaluations during male circumcision, and the organization is setting an example for other international healthcare groups. LEVEL OF EVIDENCE: Type of Study: Prognostic Study, Level II. PMID- 28088312 TI - Dementia in Parkinson's disease. AB - Dementia can occur in a substantial number of patients with Parkinson's disease with a point prevalence close to 30%. The cognitive profile is characterized by predominant deficits in executive, visuospatial functions, attention and memory. Behavioral symptoms are frequent such as apathy, visual hallucinations and delusions. The most prominent associated pathology is Lewy body-type and biochemical deficit is cholinergic. Placebo-controlled randomized trials with cholinesterase inhibitors demonstrated modest but significant benefits in cognition, behavioral symptoms and global functions. PMID- 28088313 TI - q-Space Myelin Map imaging for longitudinal analysis of demyelination and remyelination in multiple sclerosis patients treated with fingolimod: A preliminary study. AB - BACKGROUND: Fingolimod (FTY) is an oral sphingosine-1-phosphate receptor modulator that reduces relapse and slows brain atrophy in multiple sclerosis (MS) patients. In addition, FTY has been shown to enhance remyelination in certain animal models. OBJECTIVE: To analyze feasibility of a novel q-space Myelin Map imaging to monitor demyelination and remyelination under FTY treatment in MS patients. METHODS: Treatment outcomes of 24 consecutive MS patients treated with FTY were analyzed. A longitudinal analysis of q-space Myelin Map imaging was performed in a subset of these patients. RESULTS: During the treatment course (average of 16.1months), 10 patients (42%) exhibited improvement on the Expanded Disability Status Scale (EDSS) or maintained disability-free state ("optimal responders"). The average baseline age and EDSS score were significantly younger and milder in optimal responders compared to the rest of patients. A pilot longitudinal q-space Myelin Map study in 8 patients (including 4 optimal responders) showed that optimal responders tended to show signs of remyelination while exhibiting no newly evolved demyelinated lesions. CONCLUSION: FTY may improve disability in younger patients with milder MS, and absence of demyelination activity and presence of remyelination activity may in part be associated with such improvement. q-Space Myelin Map imaging is a clinically feasible modality to monitor demyelination and remyelination in MS patients. PMID- 28088314 TI - Is advanced paternal age a health risk for the offspring? AB - In this article we review the epidemiologic evidence for adverse health effects in offspring of fathers of advanced age. First the evidence regarding fetal survival is addressed, and afterward we review the evidence regarding morbidity in children with older fathers. The adverse conditions most consistently associated with increased paternal age are stillbirths, musculo-skeletal syndromes, cleft palate, acute lymphoblastic leukemia and retinoblastoma, and neurodevelopmental disorders in the autism spectrum and schizophrenia. Finally, we consider the public health impact of the increasing paternal age. We conclude that the adverse health effects in children that might be caused by the present increase in paternal age are severe but quantitatively of minor importance. However, identification of morbidities that are more frequent in offspring of older fathers, after having taken any maternal age effects and other confounding into account, may lead to a better understanding of the pathogenesis behind such conditions. PMID- 28088315 TI - Paris saponin-induced autophagy promotes breast cancer cell apoptosis via the Akt/mTOR signaling pathway. AB - Paris saponins possess anticancer, anti-inflammatory, and antiviral effects. However, the anticancer effect of Paris saponins has not been well elucidated and the mechanisms underlying the potential function of Paris saponins in cancer therapy are needed to be further identify. In this study, we report that saponin compounds isolated from Paris polyphylla exhibited antitumor activity against breast cancer cell lines, MCF-7 and MDA-MB-231. Paris saponin XA-2 induced apoptosis in both cell lines, as evidenced by the activation of caspases and cleavage of Poly (ADP-ribose) polymerase. The ability of XA-2 to induce autophagy was confirmed by acridine orange staining, accumulation of autophagosome-bound Long chain 3 (LC3)-II, and measurement of autophagic flux. XA-2-induced autophagy was observed to promote apoptosis by the combined treatment of breast cancer cell lines with XA-2 and autophagy inhibitors 3-methyladenine and bafilomycin A1, respectively. Moreover, we report a decrease in the levels of Akt/mTOR signaling pathway proteins, such as the phosphorylated forms of Akt, mTOR, P70S6K, and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). Taken together, these results provide important insights explaining the anticancer activity of Paris saponins and the potential development of XA-2 as a new therapeutic agent. PMID- 28088316 TI - Individual female differences in chemoattractant production change the scale of sea urchin gamete interactions. AB - Sperm selection by females is an important process influencing fertilization and, particularly in broadcast-spawning organisms, often occurs before sperm reach the egg. Waterborne sperm chemoattractants are one mechanism by which eggs selectively influence conspecific sperm behavior, but it remains an open question whether the eggs from different females produce different amounts of sperm chemoattractant, and how that might influence sperm behavior. Here, we quantify the differences in attractant production between females of the sea urchin species Lytechinus pictus and use computational models and microfluidic sperm chemotaxis assays to determine how differences in chemoattractant production between females affects their ability to attract sperm. Our study demonstrates that there is significant individual female variation in egg chemoattractant production, and that this variation changes the scope and strength of sperm attraction. These results provide evidence for the importance of individual female variability in differential sperm attraction and fertilization success. PMID- 28088317 TI - Neuropeptides-2015, Aberdeen University, Scotland. PMID- 28088318 TI - Correlation of the HPV detection, protein expression and DNA content in cutaneous pre-invasive and invasive carcinoma among Croatian patients. AB - Development of cutaneous carcinomas has been associated with HPV infection. There have been various reports on p16, p53 and pRb expression in cutaneous carcinomas and on its linkage to HPV status. Association of protein expression and HPV infection with DNA content is not clear. The aim of this study was to determine a possible correlation between HPV type, protein expression and DNA content in both pre-invasive and invasive squamous cell carcinoma, as well as differences between studied groups in these parameters. Sections of formalin fixed paraffin-embedded tumor tissue from 54 cases of Morbus Bowen (preinvasive cutaneous carcinoma) and 41 cases of invasive squamous cell carcinoma of the skin were subjected to HPV genotyping using Lipa (Line imuno probe assay), immunohistochemical staining for p16(INK4A), p53, pRb and prepared for flow cytometry DNA content analysis. Obtained data were analyzed in SPSS using Chi square test. Only p16 expression showed statistically significant differences in studied groups. Statistically significant correlations were found only in MB between parameters HPV-p53, p53 pRb and p53-p16. Our results suggest different virus-induced pathobiology pathways for different cutaneous carcinoma groups. PMID- 28088319 TI - ERCC1 and ERCC2 as predictive biomarkers to oxaliplatin-based chemotherapy in colorectal cancer patients from Egypt. AB - BACKGROUND: The impact of Excision repair cross-complementation group 1 (ERCC1) and group 2 (ERCC2) expression levels on the efficacy of oxaliplatin-based chemotherapy is still controversial. The present study was conducted to determine the predictive value of these molecular biomarkers in stage III and IV colorectal cancer (CRC) patients receiving oxaliplatin (OX)-based chemotherapy as first-line treatment. METHODS: The study included 80 CRC patients who received first line oxaliplatin based chemotherapy The expression levels of ERCC1 and ERCC2-mRNA and proteins were determined in the primary tumors by quantitative real time reverse transcription polymerase chain reaction(RT-qPCR) and immunohistochemistry (IHC); respectively. The results of mRNA expression were correlated with patients' characteristics, response to treatment, overall- and event free survival (OS & EFS). RESULTS: Sixty four out of the 80 patients were legible for assessment of ERCC1 and ERCC2 expression. The cut-off levels of ERCC1and ERCC2-RNA were 3.8*10 3& 4.6*10-3; respectively. Reduced ERCC1 and ERCC2 RNA expressions were detected in 50 (78.1%) and 48 (75%) cases, respectively whereas reduced proteins were detected in 48 cases (75%) for ERCC1 and ERCC2. After The median follow up period was 30.5months (range: 7-104months), Patients with low mRNAERCC1levels showed significantly longer OS (p=0.011) and EFS (p?0.001). However, no significant relation was found between ERCC2 levels and OS or EFS. In multivariate analysis performance status (PS), stage of the disease and ERCC1-mRNA expression were independent prognostic factors for EFS whereas tumor histology and stage of the disease were independent factors for OS. CONCLUSIONS: ERCC1 expression levels may help in selecting patients who benefit from oxaliplatin chemotherapy in stage III & IV CRC. Further large trials are needed to validate these data. PMID- 28088322 TI - Failure to rescue and preventability: Striving for the impossible? PMID- 28088321 TI - Surgeon-, pathologist-, and hospital-level variation in suboptimal lymph node examination after colectomy: Compartmentalizing quality improvement strategies. AB - BACKGROUND: The goals of this study were to characterize the variation in suboptimal lymph node examination for patients with colon cancer across individual surgeons, pathologists, and hospitals and to examine if this variation affects 5-year, disease-specific survival. METHODS: A retrospective cohort study was conducted by merging the New York State Cancer Registry with the Statewide Planning & Research Cooperative System, Medicaid, and Medicare claims to identify resections for stages I-III colon cancer from 2004-2011. Multilevel logistic regression models characterized variation in suboptimal lymph node examination (<12 lymph nodes). Multilevel competing-risks Cox models were used for survival analyses. RESULTS: The overall rate of suboptimal lymph node examination was 32% in 12,332 patients treated by 1,503 surgeons and 814 pathologists at 187 hospitals. Patient-level predictors of suboptimal lymph node examination were older age, male sex, nonscheduled admission, lesser stage, and left colectomy procedure. Hospital-level predictors of suboptimal lymph node examination were a nonacademic status, a rural setting, and a low annual number of resections for colon cancer. The percent of the total clustering variance attributed to surgeons, pathologists, and hospitals was 8%, 23%, and 70%, respectively. Increasing the pathologist and hospital-specific rates of suboptimal lymph node examination were associated with worse 5-year, disease-specific survival. CONCLUSION: There was a large variation in suboptimal lymph node examination between surgeons, pathologists, and hospitals. Collaborative efforts that promote optimal examination of lymph nodes may improve prognosis for colon cancer patients. Given that 93% of the variation was attributable to pathologists and hospitals, endeavors in quality improvement should focus on these 2 settings. PMID- 28088323 TI - Vanishing leg ulcers. PMID- 28088320 TI - Quantifying lipid changes in various membrane compartments using lipid binding protein domains. AB - One of the largest challenges in cell biology is to map the lipid composition of the membranes of various organelles and define the exact location of processes that control the synthesis and distribution of lipids between cellular compartments. The critical role of phosphoinositides, low-abundant lipids with rapid metabolism and exceptional regulatory importance in the control of almost all aspects of cellular functions created the need for tools to visualize their localizations and dynamics at the single cell level. However, there is also an increasing need for methods to determine the cellular distribution of other lipids regulatory or structural, such as diacylglycerol, phosphatidic acid, or other phospholipids and cholesterol. This review will summarize recent advances in this research field focusing on the means by which changes can be described in more quantitative terms. PMID- 28088324 TI - Protective effect of sugar cane extract against dextran sulfate sodium-induced colonic inflammation in mice. AB - Sugar cane extract (SCE) exhibits various biological effects and has been reported to enhance animal growth performance. However, the effect of SCE on inflammation in animals is still obscure. To study the effects and underlying mechanism of SCE on dextran sulfate sodium (DSS)-induced colonic inflammation, forty female ICR mice (26.63+/-0.19g, 6-week-old) were assigned into four groups: a control group (Cont), a DSS-challenged group (DSS), a SCE-supplemented group (SCE), and a DSS+SCE group (DSS+SCE). Mice in Cont group and DSS group were fed basic diet and other mice received 1% SCE supplemented in basic diet from 6-week to 8-week-old. Mice in DSS and DSS+SCE groups were also given a 4% DSS solution from 7-week to 8-week-old via drinking water to induce colonic inflammation. After 2 weeks, mice were sacrificed and samples were collected. The results showed that dietary SCE alleviated DSS induced growth suppression, splenic damage, colonic histological changes, colonic inflammation, oxidative stress, and colonic dysfunction of tight junctions. Meanwhile, the DSS exposure activated nuclear transcription factor kappa B p65 and inhibited nuclear factor E2-related factor 2 (Nrf2), while SCE markedly attenuated the DSS-promoted effect on the p65 nuclear accumulation and the DSS-inhibited effect on the Nrf2 nuclear accumulation. In conclusion, SCE conferred a protective role in the DSS-induced inflammation and the mechanism might be associated with the activated signals of the nuclear factor kappa B p65 and Nrf2. PMID- 28088325 TI - Molecular dynamics simulations of ternary lipid bilayers containing plant sterol and glucosylceramide. AB - An atomic-level molecular dynamics simulation was carried out to study the effects of a plant sterol (sitosterol) and glucosylceramide (GlcCer) on a 1,2 dilinoleoylposphocholine (DLiPC) membrane. Initially, a membrane containing 50mol% sitosterol was compared with that containing the same ratio of cholesterol. These simulations showed differential condensing and ordering effects of sitosterol and cholesterol, with cholesterol being slightly more efficient than sitosterol in packing the membrane more tightly to a liquid ordered phase. By incorporation of 9.3% GlcCer on DLiPC/sterol membrane no notable change was observed in terms of area per lipid, bilayer thickness, order parameter and lateral diffusion. Some clusters of GlcCer/sterol were observed at higher ratio of GlcCer (15.5%), supporting the existence of GlcCer/sitosterol enriched Lo-domains on the nanometer scale in the plant lipid mixture. PMID- 28088326 TI - Acute kidney injury due to tropical infectious diseases and animal venoms: a tale of 2 continents. AB - South and Southeast Asia and Latin American together comprise 46 countries and are home to approximately 40% of the world population. The sociopolitical and economic heterogeneity, tropical climate, and malady transitions characteristic of the region strongly influence disease behavior and health care delivery. Acute kidney injury epidemiology mirrors these inequalities. In addition to hospital acquired acute kidney injury in tertiary care centers, these countries face a large preventable burden of community-acquired acute kidney injury secondary to tropical infectious diseases or animal venoms, affecting previously healthy young individuals. This article reviews the epidemiology, clinical picture, prevention, risk factors, and pathophysiology of acute kidney injury associated with tropical diseases (malaria, dengue, leptospirosis, scrub typhus, and yellow fever) and animal venom (snakes, bees, caterpillars, spiders, and scorpions) in tropical regions of Asia and Latin America, and discusses the potential future challenges due to emerging issues. PMID- 28088327 TI - CFTR impairment upregulates c-Src activity through IL-1beta autocrine signaling. AB - Cystic Fibrosis (CF) is a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Previously, we found several genes showing a differential expression in CFDE cells (epithelial cells derived from a CF patient). One corresponded to c-Src; its expression and activity was found increased in CFDE cells, acting as a signaling molecule between the CFTR activity and MUC1 overexpression. Here we report that bronchial IB3-1 cells (CF cells) also showed increased c-Src activity compared to 'CFTR-corrected' S9 cells. In addition, three different Caco-2 cell lines, each stably transfected with a different CFTR-specific shRNAs, displayed increased c-Src activity. The IL 1beta receptor antagonist IL1RN reduced the c-Src activity of Caco-2/pRS26 cells (expressing a CFTR-specific shRNA). In addition, increased mitochondrial and cellular ROS levels were detected in Caco-2/pRS26 cells. ROS levels were partially reduced by incubation with PP2 (c-Src inhibitor) or IL1RN, and further reduced by using the NOX1/4 inhibitor GKT137831. Thus, IL-1beta->c-Src and IL 1beta->NOX signaling pathways appear to be responsible for the production of cellular and mitochondrial ROS in CFTR-KD cells. In conclusion, IL-1beta constitutes a new step in the CFTR signaling pathway, located upstream of c-Src, which is stimulated in cells with impaired CFTR activity. PMID- 28088328 TI - Altered myocyte contractility and calcium homeostasis in alpha-myosin heavy chain point mutations linked to familial dilated cardiomyopathy. AB - Mutations in the human cardiac motor protein beta-myosin heavy chain (betaMHC) have been long recognized as a cause of familial hypertrophic cardiomyopathy. Recently, mutations (P830L and A1004S) in the less abundant but faster isoform alpha-myosin heavy chain (alphaMHC) have been linked to dilated cardiomyopathy (DCM). In this study, we sought to determine the cellular contractile phenotype associated with these point mutations. Ventricular myocytes were isolated from 2 month male Sprague Dawley rats. Cells were cultured in M199 media and infected with recombinant adenovirus containing the P830L or the A1004S mutant human alphaMHC at a MOI of 500 for 18 h. Uninfected cells (UI), human betaMHC (MOI 500, 18 h), and human alphaMHC (MOI 500, 18 h) were used as controls. Cells were loaded with fura-2 (1 MUM, 15 min) after 48 h. Sarcomere shortening and calcium transients were recorded in CO2 buffered M199 media (36 degrees +/-1 C) with and without 10 nM isoproterenol (Iso). The A1004S mutation resulted in decreased peak sarcomere shortening while P830L demonstrated near normal shortening kinetics at baseline. In the presence of Iso, the A1004S sarcomere shortening was identical to the betaMHC shortening while the P830L was identical to the alphaMHC control. All experimental groups had identical calcium transients. Despite a shared association with DCM, the P830L and A1004S alphaMHC mutations alter myocyte contractility in completely different ways while at the same preserving peak intracellular calcium. PMID- 28088329 TI - Introduction for the special issue on the chemistry of redox signaling. PMID- 28088330 TI - Genomic insights in gynecologic cancer. AB - Recent technological advances in DNA sequencing have enabled a remarkably detailed understanding of the molecular changes that define gynecologic and other cancers. Several groups have carried out large-scale genomic analyses of ovarian, uterine, and most recently, cervical cancer. These analyses have led to new insights into the molecular changes characterizing these cancers, which provide insight into clinical outcomes. These molecular characterizations have similarly led to new genomic-based classification schemas, which may better stratify clinical outcomes, help prognosticate and guide treatments. Discovery of characteristic mutations may also provide potential new targets for molecularly targeted chemotherapies, as has been already described with poly-ADP ribose polymerase inhibitors and ovarian cancer. The purpose of this article is to provide an overview of the defining molecular abnormalities and markers in gynecologic cancer, to discuss the clinical implications, and to provide a comprehensive view of the current state of genomic knowledge in gynecologic cancer. PMID- 28088331 TI - Eicosapentaenoic acid ameliorates palmitate-induced lipotoxicity via the AMP kinase/dynamin-related protein-1 signaling pathway in differentiated H9c2 myocytes. AB - BACKGROUND: Emerging evidence suggested the preferable effects of eicosapentaenoic acid (EPA; n-3 polyunsaturated fatty acid) against cardiac lipotoxicity, which worsens cardiac function by means of excessive serum free fatty acids due to chronic adrenergic stimulation under heart failure. Nonetheless, the precise molecular mechanisms remain elusive. In this study, we focused on dynamin-related protein-1 (Drp1) as a possible modulator of the EPA mediated cardiac protection against cardiac lipotoxicity, and investigated the causal relation between AMP-activated protein kinase (AMPK) and Drp1. METHODS AND RESULTS: When differentiated H9c2 myocytes were exposed to palmitate (PAL; saturated fatty acid, 400uM) for 24h, these myocytes showed activation of caspases 3 and 7, enhanced caspase 3 cleavage, depolarized mitochondrial membrane potential, depleted intracellular ATP, and enhanced production of intracellular reactive oxygen species. These changes suggested lipotoxicity due to excessive PAL. PAL enhanced mitochondrial fragmentation with increased Drp1 expression, as well. EPA (50uM) restored the PAL-induced apoptosis, mitochondrial dysfunction, and mitochondrial fragmentation with increased Drp1 expression by PAL. EPA activated phosphorylation of AMPK, and pharmacological activation of AMPK by 5 aminoimidazole-4-carboxamide ribonucleotide ameliorated the PAL-induced apoptosis, mitochondrial dysfunction, and downregulated Drp1. An AMPK knockdown via RNA interference enhanced Drp1 expression and attenuated the protective effects of EPA against the PAL-induced lipotoxicity. CONCLUSION: EPA ameliorates the PAL-induced lipotoxicity via AMPK activation, which subsequently suppresses mitochondrial fragmentation and Drp1 expression. Our findings may provide new insights into the molecular mechanisms of EPA-mediated myocardial protection in heart failure. PMID- 28088332 TI - Manipulation of tumor oxygenation and radiosensitivity through modification of cell respiration. A critical review of approaches and imaging biomarkers for therapeutic guidance. AB - Tumor hypoxia has long been considered as a detrimental factor for the response to irradiation. In order to improve the sensitivity of tumors cells to radiation therapy, tumor hypoxia may theoretically be alleviated by increasing the oxygen delivery or by decreasing the oxygen consumption by tumor cells. Mathematical modelling suggested that decreasing the oxygen consumption should be more efficient than increasing oxygen delivery in order to alleviate tumor hypoxia. In this paper, we review several promising strategies targeting the mitochondrial respiration for which alleviation of tumor hypoxia and increase in sensitivity to irradiation have been demonstrated. Because the translation of these approaches into the clinical arena requires the use of pharmacodynamics biomarkers able to identify shift in oxygen consumption and tumor oxygenation, we also discuss the relative merits of imaging biomarkers (Positron Emission Tomography and Magnetic Resonance) that may be used for therapeutic guidance. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux. PMID- 28088333 TI - Mitochondrial uncoupling in cancer cells: Liabilities and opportunities. AB - Acquisition of the endosymbiotic ancestor of mitochondria was a critical event in eukaryote evolution. Mitochondria offered an unparalleled source of metabolic energy through oxidative phosphorylation and allowed the development of multicellular life. However, as molecular oxygen had become the terminal electron acceptor in most eukaryotic cells, the electron transport chain proved to be the largest intracellular source of superoxide, contributing to macromolecular injury, aging, and cancer. Hence, the 'contract of endosymbiosis' represents a compromise between the possibilities and perils of multicellular life. Uncoupling proteins (UCPs), a group of the solute carrier family of transporters, may remove some of the physiologic constraints that link mitochondrial respiration and ATP synthesis by mediating inducible proton leak and limiting oxidative cell injury. This important property makes UCPs an ancient partner in the metabolic adaptation of cancer cells. Efforts are underway to explore the therapeutic opportunities stemming from the intriguing relationship of UCPs and cancer. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux. PMID- 28088334 TI - Subtype identification of human Blastocystis spp. isolated from Lao People's Democratic Republic. AB - Blastocystis sp. is the most common protist found in the intestinal tract of humans and animals. Blastocystis subtypes (STs) are classified based on the molecular phylogeny of the small subunit rRNA gene (SSU rDNA). At least 17 Blastocystis STs have been reported and, of these, STs 1-9 have been found in humans. This study revealed the presence of human Blastocystis STs in Lao People's Democratic Republic (Lao PDR). Fecal samples were collected from apparently healthy people from the central province of Khammouane and the southern province of Champasak. Fresh fecal samples, found to be positive for Blastocystis using microscopy, were individually cultured in Jones' medium and each sample was used for the amplification and sequencing of a fragment of SSU rDNA. BLAST searches and phylogenetic analysis confirmed the distribution of four Blastocystis STs: ST1 (64%), ST2 (8%), ST3 (24%) and ST7 (4%). This is the first report to provide molecular data revealing the prevalence of Blastocystis STs in apparently healthy people from Lao PDR. PMID- 28088335 TI - Reply. PMID- 28088336 TI - Human basophils may not undergo modulation by DC-SIGN and mannose receptor targeting immunotherapies due to absence of receptors. PMID- 28088337 TI - Stressed brain, stressed heart? PMID- 28088339 TI - Evidence-based management of systemic sclerosis: Navigating recommendations and guidelines. AB - OBJECTIVES: Systemic sclerosis (SSc) is a rare heterogeneous connective tissue disease. Recommendations addressing the major issues in the management of SSc including screening and treatment of organ complications are needed. METHODS: The updated European League Against Rheumatism/European Scleroderma Trial and Research (EULAR/EUSTAR) and the British Society of Rheumatology (BSR) and British Health Professionals in Rheumatology (BHPR) guidelines were compared and contrasted. RESULTS: The updated EULAR/EUSTAR guidelines focus specifically on the management of SSc features and include data on newer therapeutic modalities and mention a research agenda. These recommendations are pharmacologic, with few guidelines regarding investigations and non-pharmacologic management. Recommendations from BSR/BHPR are similar to the organ manifestations mentioned in the EULAR/EUSTAR recommendations, and expand on several domains of treatment, including general measures, non-pharmacologic treatment, cardiac involvement, calcinosis, and musculoskeletal features. The guidelines usually agree with one another. Limitations include the lack of guidance for combination or second-line therapy, algorithmic suggestions, the absence of evidence-based recommendations regarding the treatment of specific complications (i.e., gastric antral ectasia and erectile dysfunction). Consensus for when to treat interstitial lung disease in SSc is lacking. There are differences between Europe and North American experts due to access and indications for certain therapies. CONCLUSIONS: Care gaps in SSc have been demonstrated so the EULAR/EUSTAR and BSR/BHP guidelines can promote best practices. Certain complications warrant active investigation to further improve outcomes in SSc and future updates of these recommendations. Care gaps in SSc have been demonstrated so the EULAR/EUSTAR and BSR/BHP guidelines can promote best practices. Certain complications warrant active investigation to further improve outcomes in SSc. PMID- 28088338 TI - Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study. AB - BACKGROUND: Emotional stress is associated with increased risk of cardiovascular disease. We imaged the amygdala, a brain region involved in stress, to determine whether its resting metabolic activity predicts risk of subsequent cardiovascular events. METHODS: Individuals aged 30 years or older without known cardiovascular disease or active cancer disorders, who underwent 18F-fluorodexoyglucose PET/CT at Massachusetts General Hospital (Boston, MA, USA) between Jan 1, 2005, and Dec 31, 2008, were studied longitudinally. Amygdalar activity, bone-marrow activity, and arterial inflammation were assessed with validated methods. In a separate cross-sectional study we analysed the relation between perceived stress, amygdalar activity, arterial inflammation, and C-reactive protein. Image analyses and cardiovascular disease event adjudication were done by mutually blinded researchers. Relations between amygdalar activity and cardiovascular disease events were assessed with Cox models, log-rank tests, and mediation (path) analyses. FINDINGS: 293 patients (median age 55 years [IQR 45.0-65.5]) were included in the longitudinal study, 22 of whom had a cardiovascular disease event during median follow-up of 3.7 years (IQR 2.7-4.8). Amygdalar activity was associated with increased bone-marrow activity (r=0.47; p<0.0001), arterial inflammation (r=0.49; p<0.0001), and risk of cardiovascular disease events (standardised hazard ratio 1.59, 95% CI 1.27-1.98; p<0.0001), a finding that remained significant after multivariate adjustments. The association between amygdalar activity and cardiovascular disease events seemed to be mediated by increased bone-marrow activity and arterial inflammation in series. In the separate cross-sectional study of patients who underwent psychometric analysis (n=13), amygdalar activity was significantly associated with arterial inflammation (r=0.70; p=0.0083). Perceived stress was associated with amygdalar activity (r=0.56; p=0.0485), arterial inflammation (r=0.59; p=0.0345), and C reactive protein (r=0.83; p=0.0210). INTERPRETATION: In this first study to link regional brain activity to subsequent cardiovascular disease, amygdalar activity independently and robustly predicted cardiovascular disease events. Amygdalar activity is involved partly via a path that includes increased bone-marrow activity and arterial inflammation. These findings provide novel insights into the mechanism through which emotional stressors can lead to cardiovascular disease in human beings. FUNDING: None. PMID- 28088340 TI - The role of magnetic resonance imaging techniques in evaluation and management of the idiopathic inflammatory myopathies. AB - Magnetic resonance imaging (MRI) is an important tool in the evaluation of neuromuscular disorders. MRI accurately demonstrates muscle oedema, atrophy, subcutaneous pathology and fatty infiltration and also highlights the distribution of muscle involvement. This review examines the role of MRI in evaluation of the idiopathic inflammatory myopathies (IIMs), a heterogeneous group of autoimmune conditions characterised by muscle inflammation and a variety of extra-muscular manifestations. MRI has a clear role in aiding diagnosis of these conditions, guiding muscle biopsy, differentiating subtypes of IIM using a pattern-based approach, and monitoring disease activity in a longitudinal fashion. Whole body MRI is an emerging technique that offers several advantages over regional MRI, but is not currently widely available. We will also consider newer MRI techniques which provide detailed information regarding the metabolism, function and structure of muscle, although their use is restricted to research purposes at present. PMID- 28088343 TI - First confirmed report of a bacterial brood disease in stingless bees. AB - Susceptibility to brood pathogens in eusocial stingless bees (Meliponini), alternative pollinators to honey bees, is unknown. Brood losses in managed colonies of the Australian stingless bee, Tetragonula carbonaria, were studied over 20months. We isolated a disease-causing bacterium, Lysinibacillus sphaericus (Firmicutes, Bacillaceae), from worker and queen larvae, brood cell provisions and honey stores. Pathogenicity experiments confirmed this bacterium as the causal organism. It took 22days from infection to first appearance of brood disease symptoms. This is the first confirmed record of a brood pathogen in stingless bees. PMID- 28088341 TI - Evaluation of an In-house indirect ELISA for detection of antibody against haemorrhagic septicemia in Asian elephants. AB - Pasteurella multocida causes haemorrhagic septicemia in livestock and wild animals, including elephants. The disease has been reported in Asian elephants in India and Sri Lanka, but to date there have been no reported cases in Thailand. ELISA or indirect hemagglutination assays (IHA) have been demonstrated to be able to detect the antibody against the disease in cattle, but no data are available for elephants. The present study reports a novel in-house indirect ELISA for antibody detection of haemorrhagic septicemia in Asian elephants, and evaluates the sensitivity and specificity of the method using a Bayesian approach. The characteristics of ELISA and IHA were analyzed using a one population Bayesian model assuming conditional dependence between these two diagnostic tests. The IHA was performed as recommended by the World Organization for Animal Health (OIE) manual for haemorrhagic septicemia. An in-house indirect ELISA was developed with a heat extract antigen of P. multocida strain M-1404 (serovar B:2) as a coating antigen and rabbit anti-immunoglobulin G conjugated with horseradish peroxidase (eIgG-HRP). The checkerboard titration method was done using elephant sera immunized with P. multocida bacterin and negative sera from colostrum-deprived elephant calves. The concentrations of heat extract antigen (160MUg/ml), sample serum (1:100), and eIgG-HRP (1:1000) were optimal for the assay. The calculated cut-off value was 0.103. Of the elephant sera, 50.59% (43/85) were considered seropositive by ELISA. The sensitivity of the ELISA test was higher than that of the IHA test [median=86.5%, 95% posterior probability interval (PPI)=52.5-98.9%] while the specificity was lower (median=54.1%, PPI=43.6-64.7%). The median sensitivity and specificity of IHA were 80.5% (PPI=43.8-98.0%) and 78.4% (PPI=69.0-87.0%), respectively. These findings suggest that our in-house indirect ELISA can be used as a tool to detect the antibody against haemorrhagic septicemia in Asian elephants. PMID- 28088342 TI - Nanoparticle standards for immuno-based quantitation of alpha-synuclein oligomers in diagnostics of Parkinson's disease and other synucleinopathies. AB - Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by symptoms such as rigor, tremor and bradykinesia. A reliable and early diagnosis could improve the development of early therapeutic strategies before death of dopaminergic neurons leads to the first clinical symptoms. The sFIDA (surface based fluorescence intensity distribution analysis) assay is a highly sensitive method to determine the concentration of alpha-synuclein (alpha-syn) oligomers which are presumably the major toxic isoform of alpha-syn and potentially the most direct biomarker for PD. Oligomer-based diagnostic tests require standard molecules that closely mimic the native oligomer. This is particularly important for calibration and assessment of inter-assay variation. In this study, we generated a standard in form of alpha-syn coated silica nanoparticles (alpha-syn SiNaPs) that are in the size range of alpha-syn oligomers and provide a defined number of alpha-syn epitopes. The preparation of the sFIDA assay was realized on an automated platform to allow handling of high number of samples and reduce the effects of human error. The assay outcome was analyzed by determination of coefficient of variation and linearity for the applied alpha-syn-SiNaPs concentrations. Additionally, the limit of detection and lower limit of quantification were determined yielding concentrations in the lower femtomolar range. PMID- 28088344 TI - Design control considerations for biologic-device combination products. AB - Combination products are therapeutic and diagnostic medical products that combine drugs, devices, and/or biological products with one another. Historically, biologics development involved identifying efficacious doses administered to patients intravenously or perhaps by a syringe. Until fairly recently, there has been limited focus on developing an accompanying medical device, such as a prefilled syringe or auto-injector, to enable easy and more efficient delivery. For the last several years, and looking forward, where there may be little to distinguish biologics medicines with relatively similar efficacy profiles, the biotechnology market is beginning to differentiate products by patient-focused, biologic-device based combination products. As innovative as biologic-device combination products are, they can pose considerable development, regulatory, and commercialization challenges due to unique physicochemical properties and special clinical considerations (e.g., dosing volumes, frequency, co-medications, etc.) of the biologic medicine. A biologic-device combination product is a marriage between two partners with "cultural differences," so to speak. There are clear differences in the development, review, and commercialization processes of the biologic and the device. When these two cultures come together in a combination product, developers and reviewers must find ways to address the design controls and risk management processes of both the biologic and device, and knit them into a single entity with supporting product approval documentation. Moreover, digital medicine and connected health trends are pushing the boundaries of combination product development and regulations even further. Despite an admirable cooperation between industry and FDA in recent years, unique product configurations and design features have resulted in review challenges. These challenges have prompted agency reviewers to modernize consultation processes, while at the same time, promoting development of innovative, safe and effective combination products. It remains the manufacturer's responsibility to comply with the relevant requirements and regulations, and develop good business practices that clearly describe how these practices comply with FDA's final rule (21 CFR Part 4) and aligns with the company's already established quality system. PMID- 28088346 TI - Msi1 promotes tumor progression by epithelial-to-mesenchymal transition in cervical cancer. AB - Musashi1 (Msi1) is an RNA-binding protein that has been reported to be a pivotal regulator in tumorigenesis and progression in several cancers. However, its function and mechanism in cervical cancer is still unknown. In this study, Msi1 expression was found elevated in cervical cancers by immunohistochemistry and correlated with poor outcomes. Then, endogenous Msi1 was silenced in cervical cancer cell lines by short hairpin RNA, and its function and mechanism were determined. The results showed that the silencing of Msi1 in SiHa and HeLa cells inhibited the cells' migratory and invasive abilities in vitro and tumor progression in vivo. Epithelial-to-mesenchymal transition (EMT) markers were down regulated, and Wnt activity was inhibited by the silencing of Msi1. In clinical tissues, positive correlations between Msi1 and EMT markers were found. In conclusion, Msi1, a diagnostic marker and potential therapeutic target, promoted the EMT progression through activation of the Wnt signaling pathway in cervical cancers, thereby contributing to poor prognosis. PMID- 28088345 TI - Phenotypic characterization of perivascular myoid cell neoplasms, using myosin 1B, a newly identified human pericyte marker. AB - Our aims were to identify pericyte-specific markers for the analysis of formalin fixed, paraffin-embedded human tissue samples, and to characterize perivascular myoid cell neoplasms phenotypically. Previously identified pericyte markers failed to distinguish pericytes from other cellular types, such as vascular smooth muscle cells (vSMCs) and fibroblasts, in immunohistochemistry analysis. However, we compared gene expression profiles between pericytes, vSMCs, and fibroblasts, and performed human skin vasculature immunohistochemistry analysis, which led to the identification of myosin 1B (MYO1B) as a novel pericyte marker. Afterward, we investigated the expression levels of MYO1B and h-caldesmon (h-CD) in perivascular myoid cell neoplasms, angioleiomyomas (n=28), glomus tumors (n=23), and myopericytomas (n=3). Angioleiomyomas were shown to contain MYO1B negative and h-CD-positive (MYO1B-hCD+) tumor cells, with vSMC features. Glomus tumors were predominantly composed of the MYO1B+hCD+ tumor cells, with the intermediate features between pericytes and vSMCs, whereas MYO1B+hCD- tumor cells with pericytic features and/or the MYO1B-hCD+ tumor cells with vSMC features were frequently found in these tumors. The perivascular concentric pattern of 2 myopericytoma cases was composed of MYO1B+hCD+ tumor cells, whereas that of one myopericytoma contained MYO1B-hCD+ tumor cells. These results indicate that the ability to distinguish between these cell types may allow us to understand the differentiation and origin of perivascular myoid cell neoplasms. This is the first study to identify cell properties of perivascular myoid cell neoplasms by using a pericyte-specific marker with considerably lower expression in vSMCs and fibroblasts. PMID- 28088347 TI - Disparity configuration influences depth discrimination in naive adults, but not in children. AB - We report a series of experiments in which we assess depth discrimination performance in adults and children using a disparity-balanced target configuration to avoid the effects of anticipatory vergence eye movements. In our first study we found that children outperformed adults by a substantial margin, and the adults were consistently near chance. This was surprising given that we initially tested naive adults to provide a benchmark for the children's data, and all observers met the criterion for stereoacuity. In subsequent experiments we recruited groups of inexperienced adult observers and assessed the role of a wide range of spatial and temporal factors in this apparent deficit. We found that the adult performance remained poor in spite of changes to the stimulus layout, exposure duration, and spatial scale. The only manipulations that improved performance were those that limited the binocular disparity to a single sign. We conclude that these data reflect a form of involuntary disparity pooling that makes it difficult for naive observers to judge depth from disparity from multiple targets. The absence of this effect in children likely reflects the late maturation of global processes and depth cue integration. PMID- 28088348 TI - Neuroprotective effects of Kukoamine A against cerebral ischemia via antioxidant and inactivation of apoptosis pathway. AB - Kukoamine A (KuA) is a bioactive compound, which is known for a hypotensive effect. Recent studies have shown that KuA has anti-oxidative effect and anti apoptosis stress in vitro. However, its neuroprotective effect in rats with cerebral ischemia is still unclear. In the study, we investigated whether KuA could attenuate cerebral ischemia induced by permanent middle cerebral artery occlusion (pMCAO) in rats. Results revealed that KuA could significantly reduce infarct volume both pre-treatment and post-treatment, and increase corresponding Garcia neurological scores. Acute KuA postconditioning not only significantly reduced cerebral infarct volume, brain water content and improved neurological deficit scores, but also decreased the number of TUNEL-positive cells. Moreover, it markedly increased the activities of Cu/Zn-SOD and Mn-SOD, reduced levels of MDA and H2O2. Increased expressions of caspase-3, cytochrome c and the ratio of Bax/Bcl-2 were significantly alleviated with KuA treatment. These findings demonstrated that KuA was able to protect the brain against injury induced by pMCAO via mitochondria mediated apoptosis signaling pathway. PMID- 28088349 TI - Stroke biomarkers in clinical practice: A critical appraisal. AB - Biomarkers provide critical mechanistic insights to key biologic processes that occur during cerebral ischemia which, when carefully applied, can improve clinical decision-making in acute stroke management. The translation of a blood based biomarker in ischemic stroke to clinical practice is challenging, in part, due to the complexity of ischemic stroke pathogenesis and the presence of a blood brain barrier that restricts the release of brain-specific markers into the circulation. The pathologic and clinical aspects of ischemic stroke are described in this review, where a non-exhaustive list of biomarkers that interrogate different aspects of ischemic stroke such as oxidative damage, inflammation, thrombus formation, cardiac function and brain injury are described. The potential roles of these biomarkers are further examined under different clinical scenarios aimed at (1) averting the risk of hemorrhagic transformation, (2) identifying individuals at risk of early neurologic deterioration and malignant infarction, (3) aiding in the diagnosis of ischemic stroke and its differentiation from other stroke mimics, (4) guiding the search for stroke etiology, and (5) assessing stroke risk within the community. Researchers should explore the roles of stroke biomarkers to enhance clinical decision-making that is presently largely based on intuition and subjective reasoning. PMID- 28088350 TI - The emotive nature of conflict monitoring in the medial prefrontal cortex. AB - The detection of conflict between incompatible impulses, thoughts, and actions is a ubiquitous source of motivation across theories of goal-directed action. In this overview, we explore the hypothesis that conflict is emotive, integrating perspectives from affective science and cognitive neuroscience. Initially, we review evidence suggesting that the mental and biological processes that monitor for information processing conflict-particularly those generated by the anterior midcingulate cortex-track the affective significance of conflict and use this signal to motivate increased control. In this sense, variation in control resembles a form of affect regulation in which control implementation counteracts the aversive experience of conflict. We also highlight emerging evidence proposing that states and dispositions associated with acceptance facilitate control by tuning individuals to the emotive nature of conflict, before proposing avenues for future research, including investigating the role of affect in reinforcement learning and decision making. PMID- 28088351 TI - Neural activity reveals perceptual grouping in working memory. AB - There is extensive evidence that the contralateral delay activity (CDA), a scalp recorded event-related brain potential, provides a reliable index of the number of objects held in visual working memory. Here we present evidence that the CDA not only indexes visual object working memory, but also the number of locations held in spatial working memory. In addition, we demonstrate that the CDA can be predictably modulated by the type of encoding strategy employed. When individual locations were held in working memory, the pattern of CDA modulation mimicked previous findings for visual object working memory. Specifically, CDA amplitude increased monotonically until working memory capacity was reached. However, when participants were instructed to group individual locations to form a constellation, the CDA was prolonged and reached an asymptote at two locations. This result provides neural evidence for the formation of a unitary representation of multiple spatial locations. PMID- 28088352 TI - Mutations at the Darkener of Apricot locus modulate pheromone production and sex behavior in Drosophila melanogaster. AB - Mutations at the Darkener of Apricot (Doa) locus of Drosophila melanogaster alter sexual differentiation by disrupting sex-specific splicing of doublesex pre-mRNA, a key regulator of sex determination. Here, we study the effect of seven Doa alleles and several trans-heterozygous combinations on pheromones and courtship behavior. The cuticular hydrocarbon (CHC) profile was slightly masculinized in females, with an accumulation of shorter compounds (C23 and C25) and a reduction in longer compounds (C27 and C29). The profile was feminized in males. Female cuticular profiles showed fewer dienes and female pheromones in six alleles and in the trans-heterozygotes and showed more male pheromones (tricosene and pentacosene) in three alleles (DEM, E786 and HD) and in all trans-heterozygotes. Courtship was severely affected in Doa males; in particular, males made fewer copulation attempts and copulated less with both control and Doa females. These results suggest that Doa could modulate pheromone production and sex behavior by altering sexual differentiation in the cuticle and the nervous system. PMID- 28088353 TI - Expansion and differentiation of IgM+ B cells in the rainbow trout peritoneal cavity in response to different antigens. AB - To date, intraperitoneal (i.p.) injection seems to be the most effective vaccination route in aquaculture, as many i.p. administered fish vaccines are capable of conferring strong and long-lasting immune responses. Despite this, how peritoneal leukocytes are regulated upon antigen encounter has only been scarcely studied in fish. Although, in the past, myeloid cells were thought to be the main responders to peritoneal inflammation, a recent study revealed that IgM+ B cells are one of the main cell types in the teleost peritoneal cavity in response to pathogenic bacteria. Thus, in the current work, we have focused on establishing how IgM+ B cells are recruited into the peritoneum in rainbow trout (Oncorhynchus mykiss) comparing different antigens: Escherichia coli as a bacterial model, E. coli-derived lipopolysaccharide (LPS) or viral hemorrhagic septicemia virus (VHSV). In addition to studying their capacity to dominate the peritoneal cavity, we have established how these IgM+ B cells are regulated in response to the different antigens, determining their levels of IgM secretion, surface MHC II expression, cell size and phagocytic abilities. Our results reveal that IgM+ B cells are one of the main cell types amplified in the peritoneum in response to either bacterial or viral antigens and that these immunogenic stimulations provoke a differentiation of some of these cells towards plasmablasts/plasma cells whereas others seem to be implicated in antigen presentation. These findings contribute to a better understanding of the immune processes that regulate peritoneal inflammation in teleost fish. PMID- 28088354 TI - Uncovering oxysterol-binding protein (OSBP) as a target of the anti-enteroviral compound TTP-8307. AB - The genus Enterovirus (e.g. poliovirus, coxsackievirus, rhinovirus) of the Picornaviridae family of positive-strand RNA viruses includes many important pathogens linked to a range of acute and chronic diseases for which no approved antiviral therapy is available. Targeting a step in the life cycle that is highly conserved provides an attractive strategy for developing broad-range inhibitors of enterovirus infection. A step that is currently explored as a target for the development of antivirals is the formation of replication organelles, which support replication of the viral genome. To build replication organelles, enteroviruses rewire cellular machinery and hijack lipid homeostasis pathways. For example, enteroviruses exploit the PI4KIIIbeta-PI4P-OSBP pathway to direct cholesterol to replication organelles. Here, we uncover that TTP-8307, a known enterovirus replication inhibitor, acts through the PI4KIIIbeta-PI4P-OSBP pathway by directly inhibiting OSBP activity. However, despite a shared mechanism of TTP 8307 with established OSBP inhibitors (itraconazole and OSW-1), we identify a number of notable differences between these compounds. The antiviral activity of TTP-8307 extends to other viruses that require OSBP, namely the picornavirus encephalomyocarditis virus and the flavivirus hepatitis C virus. PMID- 28088355 TI - KIR genes and HLA class I ligands in a Caucasian Brazilian population with colorectal cancer. AB - Colorectal cancer (CRC) can occur anywhere in the colon or rectum and represents the third most common cancer in the world in both sexes. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer cell immunoglobulin like receptors (KIR). The aim of our study was to evaluate the association between the KIR genes and HLA ligands in patients with colorectal cancer and healthy controls. We examined the polymorphism of 16 KIR genes and their HLA ligands in 154 caucasoid CRC patients and 216 controls. When both groups were compared, no significant differences were found for HLA ligands and KIR genes after Bonferroni correction. However, the Bx haplotypes (heterozygous and homozygous for the haplotype B) were more frequent in controls, when compared with patients. These findings suggest that individuals with Bx haplotypes could have some protection to colorectal cancer. The hypothesis is not related with the presence of a special KIR gene and HLA ligand related to the disease, but to the presence of several activating genes in the individuals with no better action of one in relation to other. Further studies to confirm this observation are warranted. PMID- 28088356 TI - Advancing the prediction accuracy of protein-protein interactions by utilizing evolutionary information from position-specific scoring matrix and ensemble classifier. AB - Protein-Protein Interactions (PPIs) are essential to most biological processes and play a critical role in most cellular functions. With the development of high throughput biological techniques and in silico methods, a large number of PPI data have been generated for various organisms, but many problems remain unsolved. These factors promoted the development of the in silico methods based on machine learning to predict PPIs. In this study, we propose a novel method by combining ensemble Rotation Forest (RF) classifier and Discrete Cosine Transform (DCT) algorithm to predict the interactions among proteins. Specifically, the protein amino acids sequence is transformed into Position-Specific Scoring Matrix (PSSM) containing biological evolution information, and then the feature vector is extracted to present protein evolutionary information using DCT algorithm; finally, the ensemble rotation forest model is used to predict whether a given protein pair is interacting or not. When performed on Yeast and H. pylori data sets, the proposed method achieved excellent results with an average accuracy of 98.54% and 88.27%. In addition, we achieved good prediction accuracy of 98.08%, 92.75%, 98.87% and 98.72% on independent data sets (C.elegans, E.coli, H.sapiens and M.musculus). In order to further evaluate the performance of our method, we compare it with the state-of-the-art Support Vector Machine (SVM) classifier and get good results. As a web server, the source code and Yeast data sets used in this article are freely available at http://202.119.201.126:8888/DCTRF/. PMID- 28088357 TI - Joint genome-wide prediction in several populations accounting for randomness of genotypes: A hierarchical Bayes approach. II: Multivariate spike and slab priors for marker effects and derivation of approximate Bayes and fractional Bayes factors for the complete family of models. AB - This study corresponds to the second part of a companion paper devoted to the development of Bayesian multiple regression models accounting for randomness of genotypes in across population genome-wide prediction. This family of models considers heterogeneous and correlated marker effects and allelic frequencies across populations, and has the ability of considering records from non-genotyped individuals and individuals with missing genotypes in any subset of loci without the need for previous imputation, taking into account uncertainty about imputed genotypes. This paper extends this family of models by considering multivariate spike and slab conditional priors for marker allele substitution effects and contains derivations of approximate Bayes factors and fractional Bayes factors to compare models from part I and those developed here with their null versions. These null versions correspond to simpler models ignoring heterogeneity of populations, but still accounting for randomness of genotypes. For each marker loci, the spike component of priors corresponded to point mass at 0 in RS, where S is the number of populations, and the slab component was a S-variate Gaussian distribution, independent conditional priors were assumed. For the Gaussian components, covariance matrices were assumed to be either the same for all markers or different for each marker. For null models, the priors were simply univariate versions of these finite mixture distributions. Approximate algebraic expressions for Bayes factors and fractional Bayes factors were found using the Laplace approximation. Using the simulated datasets described in part I, these models were implemented and compared with models derived in part I using measures of predictive performance based on squared Pearson correlations, Deviance Information Criterion, Bayes factors, and fractional Bayes factors. The extensions presented here enlarge our family of genome-wide prediction models making it more flexible in the sense that it now offers more modeling options. PMID- 28088358 TI - The peroxisome proliferator-activated receptor alpha agonist fenofibrate attenuates alcohol self-administration in rats. AB - Fibrates are a class of medications used to treat hypercholesterolemia and dyslipidemia that target nuclear peroxisome proliferator-activated receptors (PPARs). Studies have shown the PPARalpha agonist fenofibrate decreases voluntary EtOH consumption however its impact on the reinforcing and motivational effects of EtOH is unknown. We evaluated the ability of fenofibrate (25, 50 and 100 mg/kg), to alter EtOH (10%, w/v) and sucrose (2%, w/v) operant self administration in rats under a FR2 schedule of reinforcement over four days and under a progressive ratio (PR) schedule on day five of treatment. Results showed fenofibrate dose-dependently decreased EtOH self-administration under both schedules of reinforcement with the greatest effects seen after four to five days of treatment. Fenofibrate decreased responding for sucrose only under the PR schedule of reinforcement and this effect was not dose-dependent. These findings provide further evidence for fenofibrate as a potential treatment for alcohol use disorder in humans. PMID- 28088359 TI - Argentation chromatography coupled to ultrahigh-resolution mass spectrometry for the separation of a heavy crude oil. AB - Simplification of highly complex mixtures such as crude oil by using chromatographic methods makes it possible to get more detailed information about the composition of the analyte. Separation by argentation chromatography can be achieved based on the interaction of different strength between the silver ions (Ag+) immobilized through a spacer on the silica gel surface and the pi-bonds of the analytes. Heavy crude oils contain compounds with a high number of heteroatoms (N, O, S) and a high degree of unsaturation thus making them the perfect analyte for argentation chromatography. The direct coupling of argentation chromatography and ultrahigh-resolution mass spectrometry allows to continuously tracking the separation of the many different compounds by retention time and allows sensitive detection on a molecular level. Direct injection of a heavy crude oil into a ultrahigh-resolution mass spectrometer showed components with DBE of up to 25, whereas analytes with DBE of up to 35 could be detected only after separation with argentation chromatography. The reduced complexity achieved by the separation helps increasing the information depth. PMID- 28088360 TI - Hollow porous ionic liquids composite polymers based solid phase extraction coupled online with high performance liquid chromatography for selective analysis of hydrophilic hydroxybenzoic acids from complex samples. AB - Polar and hydrophilic properties of hydroxybenzoic acids usually made them coelute with interferences in high performance liquid chromatography (HPLC) analysis. Then selective analysis of them was necessary. Herein, hollow porous ionic liquids composite polymers (PILs) based solid phase extraction (SPE) was firstly fabricated and coupled online with HPLC for selective analysis of hydroxybenzoic acids from complex matrices. Hollow porous PILs were firstly synthesized using Mobil Composition of Matter No. 48 (MCM-48) spheres as sacrificial support, 1-vinyl-3-methylimidazolium chloride (VMIM+Cl-) as monomer, and ethylene glycol dimethacrylate (EGDMA) as cross-linker. Various parameters affecting synthesis, adsorption and desorption behaviors were investigated and optimized. Steady-state adsorption studies showed the resulting hollow porous PILs exhibited high adsorption capacity, fast adsorption kinetics, and excellent specific adsorption. Subsequently, the application of online SPE system was studied by selective analysis of protocatechuic acid (PCA), 4-hydroxybenzoic acid (4-HBA), and vanillic acid (VA) from Pollen Typha angustifolia. The obtained limit of detection (LOD) varied from 0.002 to 0.01MUg/mL, the linear range (0.05 5.0MUg/mL) was wide with correlation coefficient (R) from 0.9982 to 0.9994, and the average recoveries at three spiking levels ranged from 82.7 to 102.4%, with column-to-column relative standard deviation (RSD) below 8.1%. The proposed online method showed good accuracy, precision, specificity and convenience, which opened up a universal and efficient route for selective analysis of hydroxybenzoic acids from complex samples. PMID- 28088361 TI - Purification and characterisation of dsRNA using ion pair reverse phase chromatography and mass spectrometry. AB - RNA interference has provided valuable insight into a wide range of biological systems and is a powerful tool for the analysis of gene function. The exploitation of this pathway to block the expression of specific gene targets holds considerable promise for the development of novel RNAi-based insect management strategies. In addition, there are a wide number of future potential applications of RNAi to control agricultural insect pests as well as its use for prevention of diseases in beneficial insects. The potential to synthesise large quantities of dsRNA by in-vitro transcription or in bacterial systems for RNA interference applications has generated significant demand for the development and application of high throughput analytical tools for the rapid extraction, purification and analysis of dsRNA. Here we have developed analytical methods that enable the rapid purification of dsRNA from associated impurities from bacterial cells in conjunction with downstream analyses. We have optimised TRIzol extractions in conjunction with a single step protocol to remove contaminating DNA and ssRNA, using RNase T1/DNase I digestion under high-salt conditions in combination with solid phase extraction to purify the dsRNA. In addition, we have utilised and developed IP RP HPLC for the rapid, high resolution analysis of the dsRNA. Furthermore, we have optimised base-specific cleavage of dsRNA by RNase A and developed a novel method utilising RNase T1 for RNase mass mapping approaches to further characterise the dsRNA using liquid chromatography interfaced with mass spectrometry. PMID- 28088363 TI - Seasonal variations of U.S. mortality rates: Roles of solar ultraviolet-B doses, vitamin D, gene exp ression, and infections. AB - Death rates in the U.S. show a pronounced seasonality. The broad seasonal variation shows about 25% higher death rates in winter than in summer with an additional few percent increase associated with the Christmas and New Year's holidays. A pronounced increase in death rates also starts in mid-September, shortly after the school year begins. The causes of death with large contributions to the observed seasonality include diseases of the circulatory system; the respiratory system; the digestive system; and endocrine, nutritional, and metabolic diseases. Researchers have identified several factors showing seasonal variation that could possibly explain the seasonal variations in mortality rate. These factors include seasonal variations in solar ultraviolet B(UVB) doses and serum 25-hydroxyvitamin D [25(OH)D] concentrations, gene expression, ambient temperature and humidity, UVB effects on environmental pathogen load, environmental pollutants and allergens, and photoperiod (or length of day). The factors with the strongest support in this analysis are seasonal variations in solar UVB doses and 25(OH)D concentrations. In the U.S., population mean 25(OH)D concentrations range from 21ng/mL in March to 28ng/mL in August. Measures to ensure that all people had 25(OH)D concentrations >36ng/mL year round would probably reduce death rates significantly. PMID- 28088362 TI - Molecular characterization of a novel orthomyxovirus from rainbow and steelhead trout (Oncorhynchus mykiss). AB - A novel virus, rainbow trout orthomyxovirus (RbtOV), was isolated in 1997 and again in 2000 from commercially-reared rainbow trout (Oncorhynchus mykiss) in Idaho, USA. The virus grew optimally in the CHSE-214 cell line at 15 degrees C producing a diffuse cytopathic effect; however, juvenile rainbow trout exposed to cell culture-grown virus showed no mortality or gross pathology. Electron microscopy of preparations from infected cell cultures revealed the presence of typical orthomyxovirus particles. The complete genome of RbtOV is comprised of eight linear segments of single-stranded, negative-sense RNA having highly conserved 5' and 3'-terminal nucleotide sequences. Another virus isolated in 2014 from steelhead trout (also O. mykiss) in Wisconsin, USA, and designated SttOV was found to have eight genome segments with high amino acid sequence identities (89 99%) to the corresponding genes of RbtOV, suggesting these new viruses are isolates of the same virus species and may be more widespread than currently realized. The new isolates had the same genome segment order and the closest pairwise amino acid sequence identities of 16-42% with Infectious salmon anemia virus (ISAV), the type species and currently only member of the genus Isavirus in the family Orthomyxoviridae. However, pairwise comparisons of the predicted amino acid sequences of the 10 RbtOV and SttOV proteins with orthologs from representatives of the established orthomyxoviral genera and a phylogenetic analysis using the PB1 protein showed that while RbtOV and SttOV clustered most closely with ISAV, they diverged sufficiently to merit consideration as representatives of a novel genus. A set of PCR primers was designed using conserved regions of the PB1 gene to produce amplicons that may be sequenced for identification of similar fish orthomyxoviruses in the future. PMID- 28088364 TI - Antibodies: From novel repertoires to defining and refining the structure of biologically important targets. AB - Antibodies represent a highly successful class of molecules that bind a wide range of targets in therapeutic-, diagnostic- and research-based applications. The antibody repertoire is composed of the building blocks required to develop an effective adaptive immune response against foreign insults. A number of species have developed novel genetic and structural mechanisms from which they derive these antibody repertoires, however, traditionally antibodies are isolated from human, and rodent sources. Due to their high-value therapeutic, diagnostic, biotechnological and research applications, much innovation has resulted in techniques and approaches to isolate novel antibodies. These approaches are bolstered by advances in our understanding of species immune repertoires, next generation sequencing capacity, combinatorial antibody discovery and high throughput screening. Structural determination of antibodies and antibody-antigen complexes has proven to be pivotal to our current understanding of the immune repertoire for a range of species leading to advances in man-made libraries and fine tuning approaches to develop antibodies from immune-repertoires. Furthermore, the isolation of antibodies directed against antigens of importance in health, disease and developmental processes, has yielded a plethora of structural and functional insights. This review highlights the significant contribution of antibody-based crystallography to our understanding of adaptive immunity and its application to providing critical information on a range of human-health related indications. PMID- 28088365 TI - Stem cells for ALS: An overview of possible therapeutic approaches. AB - Amyotrophic lateral sclerosis (ALS) is an unusual, fatal, neurodegenerative disorder leading to the loss of motor neurons. After diagnosis, the average lifespan ranges from 3 to 5 years, and death usually results from respiratory failure. Although the pathogenesis of ALS remains unclear, multiple factors are thought to contribute to the progression of ALS, such as network interactions between genes, environmental exposure, impaired molecular pathways and many others. The neuroprotective properties of neural stem cells (NSCs) and the paracrine signaling of mesenchymal stem cells (MSCs) have been examined in multiple pre-clinical trials of ALS with promising results. The data from these initial trials indicate a reduction in the rate of disease progression. The mechanism through which stem cells achieve this reduction is of major interest. Here, we review the to-date pre-clinical and clinical therapeutic approaches employing stem cells, and discuss the most promising ones. PMID- 28088366 TI - Serum levels of Glial fibrillary acidic protein in Chinese children with autism spectrum disorders. AB - OBJECTIVE: Glial fibrillary acidic protein (GFAP) has been studied in many neurological diseases. The purpose of this study is to investigate the potential role of GFAP in Chinese children with autism spectrum disorders (ASD) by measuring serum circulating levels of GFAP and comparing them with age and gender matched typical development children. METHODS: A total of one hundred and fifty 2 6 years old Chinese children (75 confirmed autism cases and 75 their age-gender matched typical development children) participated in this study. Serum levels of GFAP were assayed with enzyme-linked immunosorbent assay methods, and severity of ASD was evaluated with the Childhood Autism Rating Scale (CARS) Score. RESULTS: The results indicated that the mean serum GFAP level was significantly (P<0.001) higher in autistic children as compared to controls (1.71+/-0.53ng/ml vs. 0.99+/ 0.25ng/ml). There was a significant positive association between serum GFAP levels and CARS scores (r [Pearson]=0.390, P=0.001). Based on the Receiver operating characteristic (ROC) curve, the optimal cut-off value of serum GFAP levels as an indicator for auxiliary diagnosis of autism was projected to be 1.28ng/ml which yielded a sensitivity of 77.3% and a specificity of 88.4%, the area under the curve was 0.895(95%CI, 0.844-0.947). Further, an increased risk of ASD was associated with GFAP levels >1.28ng/ml (adjusted OR 9.88, 95% CI: 3.32 17.82) in the multivariate logistic analysis model. CONCLUSION: The data indicates that serum GFAP levels may be associated with severity of ASD among Chinese children, suggesting the hypothesis that increased serum levels of GFAP could be implicated in the pathophysiology of autism in Chinese children. PMID- 28088367 TI - Assignment of C1q-binding HLA antibodies as unacceptable HLA antigens avoids positive CDC-crossmatches prior to transplantation of deceased donor organs. AB - Soon, a virtual crossmatch shall replace the complement-dependent cytotoxicity (CDC) allocation crossmatch in the Eurotransplant region. To prevent positive CDC crossmatches in the recipient centre, careful definition of unacceptable antigens is necessary. For highly sensitized patients, this is difficult by CDC alone. Assignment of all antibodies detected by sensitive assays, however, could prevent organ allocation. To assess the usefulness of the Luminex C1q-assay to prevent positive CDC-crossmatches, all CDC-crossmatches performed prior to deceased kidney transplantation in a 16-month-period were reviewed. Sera causing positive crossmatches were investigated by the C1q-assay. 31 out of 1432 crossmatches (2.2%) were positive. Sera involved in 26 positive crossmatches were available. C1q-binding donor-specific antibodies were detected in 19 sera (73.1%). The other sera were from recipients without any HLA antibodies detectable by CDC or common solid phase assays. Three patients had known Non-HLA antibodies causing positive CDC-results. Four crossmatches were only weak positive. Therefore, avoidance of donors with HLA antigens against whom C1q-binding antibodies were detected would have prevented all positive crossmatches due to HLA antibodies. Provided that all HLA specificities against which antibodies are detected by the Luminex C1q-assay are considered as unacceptable antigens, CDC-crossmatches prior to transplantation might safely be omitted in many patients. They should be maintained in highly immunized patients, however, for whom assignment of all C1q positive antibodies as unacceptable antigens could lead to a significant delay or even prevention of transplantation. PMID- 28088368 TI - Pollutants and biomarker responses in two reef fish species (Haemulon aurolineatum and Ocyurus chrysurus) in the Southern Gulf of Mexico. AB - The environmental quality differences between two groups of reefs in the Veracruz Reef System were evaluated. The North group of reefs is very close to Veracruz, an urban and port zone, whereas the South group is more isolated, with minor anthropogenic disturbances. To prove the hypothesis that the North group is more affected by anthropogenic activities, the concentrations of hydrocarbons in liver, metals and metalloids such as Se, As, Ba, Cd, Hg and V in muscle, and PAH metabolites in bile were evaluated, and related to biomarkers (transcript abundance of cytochrome P4501A, Vitellogenin, and Glutathione-S-transferase) in two species of fish: Haemulon aurolineatum and Ocyurus chysurus. H. aurolineatum presents the highest concentrations for many pollutants, but O. chysurus shows the most significant differences in pollutant concentrations and biomarkers between the two reef groups, suggesting that this species could be used as a sentinel in future studies in the Gulf of Mexico. PMID- 28088369 TI - Assessment of human-induced change and biological risk posed by contaminants in estuarine/harbour sediments: Sydney Harbour/estuary (Australia). AB - A rapid, simple yet scientifically sound scheme providing two important types of information used in assessment of estuarine sediments is presented. The mean enrichment quotient (MEQ) (fine contemporary sediment metal concentration/fine fraction background metal concentration) for Cu, Pb and Zn provides the magnitude of human-induced change, (deviation from the pristine condition), while sediment quality guidelines (SQGs) assess the risk posed by sedimentary contaminants to the benthic community. Maximum metal enrichment for sediment in Sydney estuary (Australia) is >100 times for Cu, Pb and Zn and the MEQ is >10 times for most of the estuary. Adverse effect on benthic populations due to Cu, Pb and Zn are expected in 2%, 50% and 36% of the waterway, respectively. SQGs for contaminant mixtures predict ~2% of the estuary has the highest risk of adverse effects, while 25% has intermediate risk. The scheme is well suited to initial assessments of estuarine sediments worldwide. PMID- 28088370 TI - Predator-prey interaction between muricid gastropods and mussels under ocean acidification. AB - Predation of the muricid gastropod Thais clavigera on two-sized groups of the mussel Brachidontes variabilis was studied under three pCO2 levels, 380, 950, and 1250MUatm. At 950MUatm pCO2 level, the prey handling time decreased significantly and large-sized B. variabilis were preferred by T. clavigera. However, the prey consumption rate was independent of pCO2 levels, although the prey searching time increased significantly at elevated pCO2. These findings indicated that the predator-prey interaction between T. clavigera and B. variabilis was altered under ocean acidification, which will have a long-term impact on the population dynamics of the interacting species. PMID- 28088371 TI - A quality by design (QbD) study on enoxaparin sodium loaded polymeric microspheres for colon-specific delivery. AB - The aim of this study was to apply quality by design (QbD) for pharmaceutical development of enoxaparin sodium microspheres for colon-specific delivery. The Process Parameters (CPPs) and Critical Quality Attributes (CQAs) were identified. A central composite experimental design was used in order to develop the design space of microspheres for colon-specific delivery that have the desired Quality Target Product Profile (QTPP). The CPPs studied were Eudragit(r) FS 30D/Eudragit(r) RS-PO ratio, poly(vinyl alcohol) (PVA) concentration and sodium chloride (NaCl) concentration. The encapsulation efficiency increased with NaCl concentration increase, the percentages of enoxaparin sodium reaching 94% for some formulations. Increasing the ratio Eudragit(r) FS-30D/Eudragit(r) RS-PO ensured a relatively complete release of enoxaparin sodium in the environment simulating the colonic pH. Based on these results, the optimum conditions were decided and the optimum formulation was prepared. The results obtained for the latter in terms of in vitro enoxaparin sodium release were good, the microparticles releasing only 9.42% enoxaparin sodium in acidic environment and 15.16% in the medium which simulated duodenal pH, but allowing the release of up to 89.24% in the medium which simulated colonic pH. The in vitro release profile of enoxaparin sodium was close to the ideal one, therefore the system was successfully designed using QbD approach. PMID- 28088372 TI - Nanoformulation of dual bexarotene-tailed phospholipid conjugate with high drug loading. AB - Bexarotene (Bex), a synthetic retinoid X receptor-selective activator, has been proved to be an efficacious chemotherapeutic agent. But, its clinical application is limited due to the poor solubility. In this report, dual bexarotene-tailed phospholipid (DBTP) conjugate based nanovesicles were prepared in order to develop new nanoformulation. DBTP conjugate was first synthesized by conjugating two Bex molecules with glycerophosphorylcholine (GPC) through facial esterification. The amphiphilic DBTP nanovesicles were prepared without any additive by reverse-phase evaporation method. They were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The results revealed that the DBTP nanovesicles have a spherical structure with an average diameter approximately 138.7nm and a negatively charged surface (-33.3+/-2.5mV). The loading efficiency of Bex is 76wt% after a simple calculation. In vitro degradation of DBTP nanovesicles and the release of Bex were further studied in detail. The results demonstrated that DBTP nanovesicles were stable in neutral environment but degraded in a weakly acidic condition and released parent drug Bex effectively. Cellular uptake was investigated by confocal laser scanning microscope (CLSM) and liquid chromatography-mass spectroscopy (LC-MS). The results demonstrated the successful internalization and intracellular release of DBTP nanovesicles. Furthermore, the cytotoxicity analysis and apoptosis of the nanovesicles showed higher antitumor activities compared with free Bex. In a conclusion, DBTP nanovesicles could be an effective nanoformulation of Bex. PMID- 28088373 TI - Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for the prediction of non-union consolidation. AB - INTRODUCTION: Non-union perfusion can be visualized with dynamic contrast enhanced (DCE) MRI. This study evaluated DCE-MRI to predict non-union consolidation after surgery and detect factors that affect bone healing. MATERIALS AND METHODS: Between 2010 and 2015 non-union perfusion was prospectively quantified in 205 patients (mean age, 51.5 years, 129 men, 76 women) before intervention and at 6, 12, 26, 52 and more weeks follow-up. DCE-MRI results were related to the osseous consolidation, the ability to predict successful outcome was estimated by ROC analysis. The relevance of the body mass index (BMI) and the non-union severity score (NUSS) to the healing process was assessed. RESULTS: Tibial (n=99) and femoral (n=76) non-unions were most common. Consolidation could be assessed in 169 patients, of these 103 (61%) showed eventual healing and demonstrated higher perfusion than in failed consolidation at 6 (p=0.0226), 12 (p=0.0252) and 26 (p=0.0088) weeks follow-up. DCE-MRI at 26 weeks follow-up predicted non-union consolidation with a sensitivity of 75% and a specificity of 87% (false classification rate 19%). Higher BMI (p=0.041) and NUSS (p<0.0001) were associated with treatment failure. CONCLUSIONS: DCE-MRI perfusion analysis after non-union surgery predicts successful outcome and could facilitate the decision of early intervention. NUSS and BMI are important prognostic factors concerning consolidation. PMID- 28088374 TI - Fibrinogen in traumatic haemorrhage: A narrative review. AB - Haemorrhage in the setting of severe trauma is associated with significant morbidity and mortality. There is increasing awareness of the important role fibrinogen plays in traumatic haemorrhage. Fibrinogen levels fall precipitously in severe trauma and the resultant hypofibrinogenaemia is associated with poor outcomes. Hence, it has been postulated that early fibrinogen replacement in severe traumatic haemorrhage may improve outcomes, although, to date there is a paucity of high quality evidence to support this hypothesis. In addition there is controversy regarding the optimal method for fibrinogen supplementation. We review the current evidence regarding the role of fibrinogen in trauma, the rationale behind fibrinogen supplementation and discuss current research. PMID- 28088375 TI - Two stage management of Cierny-Mader type IV chronic osteomyelitis of the long bones. AB - INTRODUCTION: Cierny-Mader (C-M) type IV chronic osteomyelitis represents a complex clinical challenge with permeation of extensive bone and soft tissue involvement. Aggressive debridement through viable tissue margin includes en bloc resection improves the odds of eradication of infection, which creates large bone and soft tissue loss in treating this type of osteomyelitis. The potentially large defects increase reconstruction problems with traditional reconstruction technique. The newly staged induced membrane technique presents length independent, potential as an alternative reconstruction method for segmental bone defects due to type IV chronic osteomyelitis. The purpose of this study was to assess the result and related factors of C-M type IV chronic osteomyelitis treated with staged methods of aggressive debridement and induced membrane technique. METHODS: From January 2012 to January 2014, 36 consecutive adult patients of C-M type IV chronic osteomyelitis were treated by this staged method in our clinical center with a minimum of 2-years follow-up. The clinical and imaging results were retrospectively analyzed. RESULTS: Five patients had a second debridement and eight needed a local flap transfer to cover the wound in the first stage. Patients formed a mean of 5.5cm (range: 2-10.9) segmental bone defect; Sixteen patients had autograft and twenty had autograft mixed allograft in the second stage. The mean follow-up time was 29.5 months (range: 24-45). No patients required amputation. Bone union was achieved in all patients. Clinical eradication of osteomyelitis was achieved in 35 (97%) patients, 35 (97%) patients were able to walk independently, and 31patients (86%) returned to work. Patients returned to a mean of 82% (46.3%-100%) lower extremity function. Bone union time was not dependent on the length of bone defect, but associated with the infection site (p=0.005) and age (p=0.005). CONCLUSIONS: Staged methods of aggressive debridement and induced membrane technique seems to be a simple, reliable and effective for the treatment of C-M type IV chronic osteomyelitis. Advanced age and poor soft tissue envelope may have adverse affects and are relative contraindications. The combined assessment and management of such patients with a plastic surgeon are advocated. PMID- 28088376 TI - How early must an acute Achilles tendon rupture be repaired? AB - An acute Achilles tendon rupture is the most common tendon rupture of the lower extremities, yet the optimal timing for an early surgical repair is unclear. To identify the optimal time for an early surgical repair with favorable results, we evaluated the isokinetic muscle strength and clinical outcomes of early surgical repairs of acute Achilles tendon ruptures performed at different time points after injury. Between January 2011 and July 2015, a total of 65 patients underwent an acute Achilles tendon rupture repair within 1 week after injury. To compare the outcomes at different time points post-injury, we divided patients into 3 groups: group 1, surgical treatment at <=24h; group 2, surgery at >=24h and <=48h; and group 3, surgery at >=48 hours and <=1 week. The isokinetic muscle strength in both ankles were measured using a Cybex dynamometer, and the Achilles tendon total rupture score, the modified Tegner scoring system, the visual analog scale was used to assess clinical outcomes. Kruskal-Wallis and Fisher's exact tests were used to compare multiple results in the 3 groups. No significant differences were found among the groups in terms of ankle isokinetic muscle strength or clinical outcome scores (P>0.05). The complication rate was low in all groups. There were no significant differences in isokinetic muscle strength or clinical outcomes following acute Achilles tendon rupture repairs performed within 1 week after injury. PMID- 28088377 TI - Intracapsular hip fractures in the elderly. Do we know what is important? AB - BACKGROUND: Hip fractures in the elderly are a common reason for admission to the department of orthopaedic surgery, this condition asks an important part of health resources and is associated with high levels of co-morbidity and mortality. Many improvements have been introduced in the treatment of these patients, preoperative regional analgesia, intensive physical therapy, interdisciplinary care program; but still remain unresolved gaps. The aim of this study is to document the natural history of early versus delayed surgical intervention in elderly patients with hip fractures and to establish the prognostic factors of mortality and walking ability after discharge. METHODS: A sample of 499 patients admitted in our Institution was prospectively reviewed between February 2008 and February 2013. Preoperatively characteristics and functional data were assessed in relation with time to surgery (focused on mortality and ability to walk at first year). RESULTS: The ability to walk and activities of daily living (functional results) were not associated with surgical delays (surgery before 24h from admission, surgery among 24h and 72h from admission and surgery later than 72h). However, ASA class, Parkinson disease and age were significantly associated with poor functional results. In the same way, mortality at 1year was not associated with time to surgery, but ASA class was associated with significant risk factor of 1 year-mortality. CONCLUSIONS: ASA class, Parkinson disease and age are independent predictor of poor functional outcomes after intracapsular hip fracture. In addition, ASA class is an independent predictor of mortality. Patients with poor functional status before fracture and older than 75 years would benefit from geriatric and rehabilitation intervention immediately after surgery. PMID- 28088378 TI - Antimicrobial coated implants in trauma and orthopaedics-A clinical review and risk-benefit analysis. AB - Implant-associated infections remain a major issue in orthopaedics and antimicrobial functionalization of the implant surface by antibiotics or other anti-infective agents have gained interest. The goal of this article is to identify antimicrobial coatings, for which clinical data are available and to review their clinical need, safety profile, and their efficacy to reduce infection rates. PubMed database of the National Library of Medicine was searched for clinical studies on antimicrobial coated implants for internal fracture fixation devices and endoprostheses for bone surgery, for which study design, level of evidence, biocompatibility, development of resistance, and effectiveness to reduce infection rates were analyzed. Four different coating technologies were identified: gentamicin poly(d, l-lactide) coating for tibia nails, one high (MUTARS(r)) and one low amount silver (Agluna) technology for tumor endoprostheses, and one povidone-iodine coating for titanium implants. There was a total of 9 published studies with 435 patients, of which 7 studies were case series (level IV evidence) and 2 studies were case control studies (level III evidence). All technologies were reported with good systemic and local biocompatibility, except the development of local argyria with blue to bluish grey skin discoloration after the use of silver MUTARS(r) megaendoprostheses. For the local use of gentamicin, there is contradictory data on the risk of emergence of gentamicin-resistance strains, a risk that does not seem to exist for silver and iodine based technologies. Regarding reduction of infection rates, one case control study showed a significant reduction of infection rates by Agluna silver coated tumor endoprostheses. Based on socio-economic data, there is a strong need for improvement of infection prevention and treatment strategies, including implant coatings, in fracture care, primary and revision arthroplasty, and bone tumor surgery. The reviewed gentamicin, silver Agluna, and povidone-iodine technologies have shown a good risk benefit ratio for patients. Further data from randomized control trials are desirable, although this will remain challenging in the context of infection prevention due to the required large sample size of such studies. PMID- 28088379 TI - Outcome following use of the Achillon jig for the repair of acutely ruptured Achilles tendons. AB - We report a series of 143 patients who underwent limited open Achilles tendon repair using the Achillon device at a mean follow-up of 25 months. All patients attending our institution with a diagnosis of acute Achilles tendon rupture were considered for operative repair using the Achillon jig unless they declined surgery or met the exclusion criteria. Following surgery patients were contacted and asked to complete an Achilles Tendon Rupture Score (ATRS). The clinical records were reviewed for evidence of complications, demographic information and evidence of re-rupture. Statistical analysis of subgroups including age at presentation, delay to surgery and patients with complications was carried out using the Kruskal Wallis non-parametric test. We report no re-ruptures at a mean of 25 months (minimum 12 months) following surgery. The mean ATRS score was 84/100 (range 15-100). There was no statistical significance between any of the subgroups analyzed. In conclusion, acute Achilles repair using the Achillon jig is safe, with a low re-rupture rate, excellent ATRS scores at a minimum of 12 months post-operatively and low complications. The incidence of sural nerve injury is much lower than published series of percutaneous Achilles tendon repair without the use of a jig. PMID- 28088380 TI - Aquatic Exercise Therapy for People With Parkinson Disease: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the effects of aquatic exercise therapy on gait variability and disability compared with usual care for people with Parkinson disease (PD). DESIGN: Single-blind randomized controlled trial. SETTING: Community-based hydrotherapy pool. PARTICIPANTS: Individuals with PD (Hoehn-Yahr stages I-III) (N=21). INTERVENTIONS: Participants were randomly assigned to either an aquatic exercise therapy group (45min, twice a week for 6wk) or a group that received usual care. MAIN OUTCOME MEASURES: The primary outcome measure was gait variability as measured using a motion capture system. Secondary outcomes were quality of life measured on the Parkinson's Disease Questionnaire-39 and freezing of gait and motor disability quantified by the Unified Parkinson's Disease Rating Scale. Feasibility was evaluated by measuring safety, adverse events, and participant satisfaction. RESULTS: People in the aquatic therapy group and usual care group showed similar small improvements in gait variability. The aquatic therapy group showed greater improvements in disability than the usual care group (P<.01). No differences between groups or over time were identified for freezing of gait or quality of life. Aquatic therapy sessions were safe and enjoyable with no adverse events. CONCLUSIONS: Aquatic therapy appears feasible and safe for some people in the early stages of PD. PMID- 28088381 TI - Long-Term Neurobehavioral Symptoms and Return to Productivity in Operation Enduring Freedom/Operation Iraqi Freedom Veterans With and Without Traumatic Brain Injury. AB - OBJECTIVE: To describe Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans who underwent the Comprehensive Traumatic Brain Injury Evaluation (CTBIE), differences between the traumatic brain injury (TBI) and non TBI subgroups, and factors associated with return to productivity (RTP). DESIGN: Retrospective medical record review. SETTING: Medical center. PARTICIPANTS: Medical records of OEF/OIF veterans (N=236) who underwent the CTBIE between 2009 and 2013. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Demographic characteristics, injury history, clinical presentation, and factors associated with RTP. RESULTS: Veteran sample included 90.7% men, was 45.3% white and 34.7% black, with half of Hispanic origin, and had a mean age of 33 years. The mean time since injury was approximately 4 years. Reported symptoms were high, with >90% reporting anxiousness, irritability, sleep difficulty, forgetfulness, and headaches. TBI diagnosis was found in 163 veterans (69%). The TBI subgroup was younger (TBI: 32.5y vs non-TBI: 34.9y; P=.02), reported a greater number of injuries (P<.001), and had significantly higher rates of half of the reported symptoms. Greatest differences were noted with forgetfulness (TBI: 95.7% vs non TBI: 79.5%; P<.001), poor concentration (TBI: 90.2% vs non-TBI: 76.7%; P=.007), and headaches (TBI: 93.9% vs non-TBI: 83.6%; P=.014). RTP was 60.6% for the total veteran population. Factors associated with RTP were race (white) (odds ratio [OR], 2.00; 95% confidence interval [CI], 1.13-3.55; P=.018), sensitivity to light (OR, 2.58; 95% CI, 1.17-5.66; P=.018), and fatigue (OR, 3.68; 95% CI, 1.51 8.95; P=.004). Veterans that did RTP were 3 times less likely to report depression (OR, .32; 95% CI, .12-.85; P=.022). CONCLUSIONS: Veterans reported a substantial number of lingering symptoms, with a higher prevalence in veterans with TBI. Veterans with reported depression were less likely to RTP. Future research should focus on the relation between depression and non-RTP and the effectiveness of Department of Veterans Affairs services. PMID- 28088382 TI - Functional Electrical Stimulation for Foot Drop in Multiple Sclerosis: A Systematic Review and Meta-Analysis of the Effect on Gait Speed. AB - OBJECTIVE: To review the efficacy of functional electrical stimulation (FES) used for foot drop in people with multiple sclerosis (pwMS) on gait speed in short and long walking performance tests. DATA SOURCES: Five databases (Cochrane Library, CINAHL, Embase, MEDLINE, and PubMed) and reference lists were searched. STUDY SELECTION: Studies of both observational and experimental design where gait speed data in pwMS could be extracted were included. DATA EXTRACTION: Data were independently extracted and recorded. Methodologic quality was assessed using the Effective Public Health Practice Project tool. DATA SYNTHESIS: Nineteen studies (described in 20 articles) recruiting 490 pwMS were identified and rated as moderate or weak, with none gaining a strong rating. All studies rated weak for blinding. Initial and ongoing orthotic and therapeutic effects were assessed regarding the effect of FES on gait speed in short and long walking tests. Meta analyses of the short walk tests revealed a significant initial orthotic effect (t=2.14, P=.016), with a mean increase in gait speed of .05m/s, and ongoing orthotic effect (t=2.81, P=.003), with a mean increase of .08m/s. There were no initial or ongoing effects on gait speed in long walk tests and no therapeutic effect on gait speed in either short or long walk tests. CONCLUSIONS: FES used for foot drop has a positive initial and ongoing effect on gait speed in short walking tests. Further fully powered randomized controlled trials comparing FES with alternative treatments are required. PMID- 28088383 TI - Evaluating the role of astrocytes on beta-estradiol effect on seizures of Pilocarpine epileptic model. AB - Epilepsy with periodic and unpredictable seizures is associated with hippocampal glutamate toxicity and tissue reorganization. Astrocytes play an important role in mediating the neuroprotective effects of estradiol and reducing seizure severity. Accordingly, the protective effects of low and high doses of estradiol on behavioral, astrocytic involvement and neuronal survival aspects of Pilocarpine-induced epilepsy were investigated. Lithium- Pilocarpine (30mg/kg) model was used to provoke epilepsy. Betaeta-estradiol (2,40MUg/ul) was injected subcutaneously from 48 before to 48h after seizure induction. Behavioral convulsions were then monitored and recorded on the day of induction. Four weeks later, glutamine synthetase (GS) activity and the astrocyte transporter GLT-1 expression of the hippocampus were measured. Moreover, hippocampal glutamate and GABA were evaluated to study excitability changes. Finally, neuronal counting in the hippocampus was also performed using Nissl staining. The latency for generalized clonic (GC) convulsions significantly increased while the rate of GC and death significantly reduced due to beta-estradiol treatment. GS activity and GLT-1 expression increased in the groups receiving the high dose of beta estradiol and Pilocarpine. Furthermore, the amount of both GABA and glutamate content decreased due to high dose of estradiol, while only GABA increased in Pilocarpine treated rats. Finally, administration of beta-estradiol with low and high doses increased and improved the density of nerve cells. It is concluded that chronic administration beta-estradiol has anticonvulsant and neuroprotective properties which are plausibly linked to astrocytic activity. PMID- 28088384 TI - The signalling mechanisms of a novel mitochondrial complex I inhibitor prevent lipid accumulation and attenuate TNF-alpha-induced insulin resistance in vitro. AB - RTC-1 has recently been identified as a member of a new class of anti-diabetic compounds acting through the inhibition of complex I of the mitochondrial respiratory chain (NADH:ubiquinone oxidoreductase) to improve glucose handling and inhibit weight gain in mice fed a high-fat diet (HFD). The exact mechanism by which the reduced activity of NADH:ubiquinone oxidoreductase, in response to RTC 1, promotes these improved metabolic parameters remains to be established. Through extensive in vitro analysis, new molecular insights into these downstream signalling pathways have been obtained. RTC-1-induced inhibition of NADH:ubiquinone oxidoreductase was found to promote glucose uptake in C2C12 myotubes in vitro, through the activation of the Akt substrate of 160kDa (AS160), in response to the increased activity of Akt and AMP-activated protein kinase (AMPK). RTC-1-induced phosphorylation of the AMPK substrate, acetyl-CoA carboxylase (ACC) in vitro, was associated with a decrease in lipid accumulation in 3T3-L1 adipocytes and murine mesenchymal stromal cells (MSC). The novel compound also prevented tumour necrosis factor-alpha (TNF-alpha)-induced insulin resistance and demonstrated insulin sensitising effects in C2C12 myotubes. Taken together, these results present a systematic analysis of the signalling mechanisms responsible for the potent anti-diabetic and anti-obesogenic effects of this modulator of mitochondrial function, strengthening the potential use of such compounds for the treatment of type 2 diabetes mellitus (T2DM). PMID- 28088385 TI - Flavonoid derivative (Fla-CN) inhibited adipocyte differentiation via activating AMPK and up-regulating microRNA-27 in 3T3-L1 cells. AB - Fla-CN (3-O-[(E)-4-(4-cyanophenyl)-2-oxobut-3-en-1-yl] kaempferol) is a semi synthesized flavonoid derivative of tiliroside which exhibited anti-diabetic effect in vivo. Our previous study revealed the role of Fla-CN in anti-obesity and anti-diabetes in vivo, but the underlying mechanism remained to be addressed. The present study aimed to investigate the mechanism of anti-adipogenesis in vitro. Fla-CN markedly inhibited intracellular lipid accumulation in a dose dependent manner, and the inhibitory effect was mainly limited to the early stage of adipocyte differentiation in vitro. Further investigations revealed that Fla CN up-regulated the expression level of miR-27a/b and suppressed its target genes expression including peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein alpha (C/EBPalpha). Furthermore, the phosphorylation of AMP-activated protein kinase (AMPK) was also enhanced by Fla CN in pre-adipocyte differentiation. These effects were abolished when cells were treated with miR-27a/b inhibitor and AMPK inhibitor Compound C. Additionally, Fla CN reduced the expressions of adipocyte-specific genes such as sterol regulatory element-binding transcription factor 1c (SREBP-1c), fatty acid synthase (FAS) and adipocyte fatty acid binding protein (aP2). In conclusion, these results suggested a mechanism of Fla-CN for adipocyte differentiation inhibition of 3T3 L1 cells through miR-27a/b induction and AMPK activation. PMID- 28088386 TI - Trypsin induces biphasic muscle contraction and relaxation via transient receptor potential vanilloid 1 and neurokinin receptors 1/2 in porcine esophageal body. AB - Duodenal reflux of fluids containing trypsin relates to refractory gastroesophageal reflux disease (GERD). Esophageal peristalsis and clearance are important factors in GERD pathogenesis. However, the function of trypsin in esophageal body contractility is not fully understood. In this study, effects of trypsin on circular smooth muscle (CSM) and longitudinal smooth muscle (LSM) of the porcine esophageal body were examined. Trypsin elicited a concentration dependent biphasic response, a major contraction and a subsequent relaxation only in CSM. In CSM, contraction occurred at trypsin concentrations of 100nM and relaxation at 1MUM. A proteinase-activated receptor (PAR)2 activating peptide, SLIGKV-NH2 (1mM), induced a monophasic contraction. Those responses were unaffected by tetrodotoxin though abolished by the gap junction uncouplers carbenoxolone and octanol. They were also partially inhibited by a transient receptor potential vanilloid type 1 (TRPV1) antagonist and abolished by combination of neurokinin receptor 1 (NK1) and NK2 antagonists, but not by an NK3 antagonist, suggesting a PAR2-TRPV1-substance P pathway in sensory neurons. Substance P (100nM), an agonist for various NK receptors (NK1, NK2 and NK3) with differing affinities, induced significant contraction in CSM, but not in LSM. The contraction was also blocked by the combination of NK1 and NK2 antagonists, but not by the NK3 antagonist. Moreover, substance P-induced contractions were unaffected by the TRPV1 antagonist, but inhibited by a gap junction uncoupler. In conclusion, trypsin induced a biphasic response only in CSM and this was mediated by PAR2, TRPV1 and NK1/2. Gap junctions were indispensable in this tachykinin induced response. PMID- 28088387 TI - SIRT2 mediated antitumor effects of shikonin on metastatic colorectal cancer. AB - SIRT2 is involved in the development of a variety of cancers. Shikonin is a natural compound that is known to have antitumor effects. This study aims to assess the effects of shikonin on the development and metastatic progression of colorectal cancer (CRC) through regulation of SIRT2 expression and whether this effect is related to the phosphorylation of extracellular signal-regulated kinases (ERKs). The results demonstrated that SIRT2 is downregulated in CRC biopsy samples (n=31) compared with the adjacent non-cancerous tissues (ANCT, n=26). Furthermore, CRC metastases were positive for SIRT2 despite a lack of expression in the primary tumor. In addition, data from an in vitro assay revealed that overexpression of SIRT2 inhibited the proliferation and metastatic progression of SW480 cells while blocking of SIRT2 expression induced the proliferation and metastatic progression of HT29 cells. Shikonin inhibited the viability, migration and invasion of SW480 cells and it also inhibited the tumor growth in the nude mice model; while AGK2 (a specific inhibitor of SIRT2) reversed these effects. Epidermal growth factor (EGF, an activator of ERK) and ERK-overexpression inhibited the effects of shikonin on SIRT2 expression, proliferation and metastasis in SW480 cells. However, this proliferative effect of EGF was reversed by SIRT2 overexpression. In conclusion, these results suggest that SIRT2 is a new therapeutic target for the treatment of CRC. The antitumor effects of shikonin on CRC seem to be mediated by SIRT2 upregulation via phospho ERK inhibition. PMID- 28088388 TI - Activation of GR but not PXR by dexamethasone attenuated acetaminophen hepatotoxicities via Fgf21 induction. AB - Glucocorticoid receptor (GR) signaling is indispensable for cell growth and development, and plays important roles in drug metabolism. Fibroblast growth factor (Fgf) 21, an important regulator of glucose, lipid, and energy metabolism, plays a cytoprotective role by attenuating toxicities induced by chemicals such as dioxins, acetaminophen (APAP), and alcohols. The present study investigates the impact of dexamethasone (DEX)-activated GR on Fgf21 expression and how it affects the progression of APAP-induced hepatotoxicity. Our results showed that DEX dose/concentration- and time-dependently increased Fgf21 mRNA and protein expression in mouse liver as well as cultured mouse and human hepatoma cells. By using PXR-null mouse model, we demonstrated that DEX induced Fgf21 expression by a PXR-independent mechanism. In cultured mouse and human hepatoma cells, inhibition of GR signaling, by RU486 (Mifepristone) or GR silencing using GR specific siRNA, attenuated DEX-induced Fgf21 expression. In addition, DEX increased luciferase reporter activity driven by the 3.0-kb mouse and human Fgf21/FGF21 gene promoter. Further, ChIP-qPCR assays demonstrated that DEX increased the binding of GR to the specific cis-regulatory elements located in the 3.0-kb mouse and human Fgf21/FGF21 gene promoter. Pretreatment of 2mg/kg DEX ameliorated APAP-induced liver injury in wild-type but not Fgf21-null mice. In conclusion, via GR activation, DEX induced Fgf21 expression in mouse liver and human hepatoma cells. PMID- 28088390 TI - Brodifacoum poisoning: A clear and present danger to public health in the USA. PMID- 28088389 TI - Nalfurafine is a G-protein biased agonist having significantly greater bias at the human than rodent form of the kappa opioid receptor. AB - Nalfurafine is a moderately selective kappa opioid receptor (KOR) analgesic with low incidence of dysphoric side effects in clinical development for the treatment of uremic pruritis. The basis for its reduced dysphoric effect compared to other KOR agonists is not clear, but prior studies suggest that the aversive properties of KOR agonists require p38alpha MAPK activation through an arrestin-dependent mechanism. To determine whether nalfurafine is a functionally selective KOR agonist, we measured its potency to activate the G protein-dependent early phase of Extracellular Signal-Regulated Kinase (ERK1/2) phosphorylation and the arrestin-dependent late phase of p38 MAPK signaling. Nalfurafine was approximately 250 fold more potent for ERK1/2 activation as compared to p38 MAPK activation in human KOR (hKOR) expressing HEK293 cells, and approximately 20 fold more potent for ERK1/2 activation than p38 activation in rodent KOR (rKOR) expressing HEK293 cells. The 10-fold greater G-bias at the hKOR than rKOR was unexpected, however the G protein biased effect of nalfurafine is consistent with its reduced dysphoric effects in human and rodent models. Although nalfurafine is reported to have low receptor selectivity in radioligand binding assays, its antinociceptive effect was blocked by the selective KOR antagonist norbinaltorphimine. Nalfurafine pretreatment also resulted in a KOR-dependent and mu opioid receptor-independent reduction in scratching induced by 5'-GNTI. These findings suggest that nalfurafine is a functionally selective KOR agonist and that KOR agonists able to selectively activate G protein signaling without activating p38alpha MAPK may have therapeutic potential as non-dysphoric antipruritic analgesics. PMID- 28088391 TI - Changes in the cerebellar and cerebro-cerebellar circuit in type 2 diabetes. AB - Currently, 422 million adults suffer from diabetes worldwide, leading to tremendous disabilities and a great burden to families and society. Functional and structural MRIs have demonstrated that patients with type 2 diabetes mellitus (T2DM) exhibit abnormalities in brain regions in the cerebral cortex. However, the changes of cerebellar anatomical connections in diabetic patients remains unclear. In the current study, diffusion tensor imaging deterministic tractography and statistical analysis were employed to investigate abnormal cerebellar anatomical connections in diabetic patients. This is the first study to investigate the altered cerebellar anatomical connectivity in T2DM patients. Decreased anatomical connections were found in the cerebellar and cerebro cerebellar circuits of T2DM patients, providing valuable new insights into the potential neuro-pathophysiology of diabetes-related motor and cognitive deficits. PMID- 28088392 TI - Benefits of Oxygen Saturation Targeting Trials: Oximeter Calibration Software Revision and Infant Saturations. AB - It has been reported in the 3 Benefits of Oxygen Saturation Targeting (BOOST-II) trials that changes in oximeter calibration software resulted in clearer separation between the oxygen saturations in the two trial target groups. A revised analysis of the published BOOST-II data does not support this conclusion. PMID- 28088393 TI - Discoid Skin Rash in a Preterm Infant. PMID- 28088394 TI - Tinea in Tots: Cases and Literature Review of Oral Antifungal Treatment of Tinea Capitis in Children under 2 Years of Age. PMID- 28088395 TI - Lactate and Lactate: Pyruvate Ratio in the Diagnosis and Outcomes of Pediatric Acute Liver Failure. AB - OBJECTIVES: To assess the accuracy of blood lactate and lactate: pyruvate molar ratio (L:P) as a screen for mitochondrial, respiratory chain, or fatty acid oxidation disorders in children with pediatric acute liver failure (PALF); to determine whether serum lactate >= 2.5 mmol/L or L:P >= 25 correlated with biochemical variables of clinical severity; and to determine whether lactate or L:P is associated with clinical outcome at 21 days. STUDY DESIGN: Retrospective review of demographic, clinical, laboratory, and outcome data for PALF study group participants who had lactate and pyruvate levels collected on the same day. RESULTS: Of 986 participants, 110 had lactate and pyruvate levels collected on the same day. Of the 110, the etiology of PALF was a mitochondrial disorder in 8 (7%), indeterminate in 65 (59%), and an alternative diagnosis in 37 (34%). Lactate, pyruvate, and L:P were similar among the 3 etiologic groups. There was no significant association between the initial lactate or L:P and biochemical variables of clinical severity or clinical outcome at 21 days. CONCLUSIONS: A serum lactate >= 2.5 mmol/L and/or elevated L:P was common in all causes of PALF, not limited to those with a mitochondrial etiology, and did not predict 21-day clinical outcome. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00986648. PMID- 28088396 TI - Pulmonary Alveolar Proteinosis in Association with Secondary Hemophagocytic Lymphohistiocytosis. AB - Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease in the pediatric population. There are currently few cases documenting hemophagocytic lymphohistiocytosis as a cause for secondary PAP. We describe an ex-preterm child with secondary hemophagocytic lymphohistiocytosis, complicated by PAP and hypoxemic respiratory failure. PMID- 28088397 TI - Antibiotics in Pregnancy Increase Children's Risk of Otitis Media and Ventilation Tubes. AB - OBJECTIVES: To study the association between antibiotic intake in pregnancy and the development of otitis media and placement of ventilation tubes (VTs) in the offspring under the hypothesis that antibiotics in pregnancy may alter the offspring's propensity for disease. STUDY DESIGN: Data from the 700 children in the Copenhagen Prospective Studies on Asthma in Childhood 2010 unselected birth cohort study were used. Information on maternal antibiotic use and other exposures during pregnancy was collected prospectively from interviews and validated in national registries. Otitis media episodes were registered in a prospective diary for 3 years. Information regarding children's VTs was obtained from national registries. RESULTS: There were 514 children who had diary information and were included in the analysis regarding otitis media episodes. For VTs analysis, 699 children were included. Thirty-seven percent of the mothers received antibiotics during pregnancy, and this was associated with increased risk of otitis media (adjusted hazard ratio 1.30; 95% CI 1.04-1.63; P = .02). The risk of receiving VTs was especially associated with third trimester antibiotics (adjusted hazard ratio 1.60; 95% CI 1.08-2.36, P = .02). The risk of otitis media increased with increasing number of treatments (per-level adjusted hazard ratio 1.20; 95% CI 1.04-1.40; P = .02), but for VTs this association was not significant after adjustment. CONCLUSION: Maternal use of antibiotics during pregnancy is associated with an increased risk of otitis media and VT insertions in the offspring. Antibiotics late in pregnancy mainly contributed to these effects, pointing toward potential transmission of an unfavorable microbiome from mother to child. PMID- 28088399 TI - The Timing of Pertussis Cases in Unvaccinated Children in an Outbreak Year: Oregon 2012. AB - OBJECTIVE: To assess whether, during a 2012 pertussis outbreak, unvaccinated and poorly vaccinated cases occurred earlier on a community level. STUDY DESIGN: Pediatric pertussis among children 2 months to 10 years of age in the Oregon Sentinel Surveillance region during an epidemic starting at the beginning of 2012 were stratified by immunization status, age, zip code, and calendar date of disease onset. Differences in median onset as days between fully or mostly vaccinated, poorly vaccinated, and unvaccinated cases were examined overall and within local zip code areas. Disease clusters also were examined using SatScan analysis. RESULTS: Overall, 351 pertussis cases occurred among children aged 2 months to 10 years of age residing in 72 distinct zipcodes. Among unvaccinated or poorly vaccinated cases, their median date of onset was at calendar day 117 (April 26, 2012), whereas for those who were fully or mostly vaccinated the median date of onset was 41 days later, at day 158 (June 6, 2012). Within each local zip code area, the unvaccinated cases were 3.2 times more likely than vaccinated cases to have earlier median dates of onset (95% CI 2.9-3.6). CONCLUSION: In this outbreak, pertussis cases among unvaccinated children represented an earlier spread of disease across local areas. Controlling outbreaks may require attention to the composition and location of the unvaccinated. PMID- 28088398 TI - Mindfulness-Based Stress Reduction for Adolescents with Functional Somatic Syndromes: A Pilot Cohort Study. AB - OBJECTIVE: To assess the feasibility of a mindfulness-based stress reduction (MBSR) program for adolescents with widespread chronic pain and other functional somatic symptoms and to make preliminary assessments of its clinical utility. STUDY DESIGN: Three cohorts of subjects completed an 8-week MBSR program. Child- and parent-completed measures were collected at baseline and 8 and 12 weeks later. Measures included the Functional Disability Inventory (FDI), the Fibromyalgia/Symptom Impact Questionnaire-Revised (FIQR/SIQR), the Pediatric Quality of Life Inventory, the Multidimensional Anxiety Scale (MASC2), and the Perceived Stress Scale. Subjects and parents were interviewed following the program to assess feasibility. RESULTS: Fifteen of 18 subjects (83%) completed the 8-week program. No adverse events occurred. Compared with baseline scores, significant changes were found in mean scores on the FDI (33% improvement, P = .026), FIQR/SIQR (26% improvement, P = .03), and MASC2 (child: 12% improvement, P = .02; parent report: 17% improvement, P = .03) at 8 weeks. MASC2 scores (child and parent) and Perceived Stress Scale scores were significantly improved at 12 weeks. More time spent doing home practice was associated with better outcomes in the FDI and FIQR/SIQR (44% and 26% improvement, respectively). Qualitative interviews indicated that subjects and parents reported social support as a benefit of the MBSR class, as well as a positive impact of MBSR on activities of daily living, and on pain and anxiety. CONCLUSIONS: MBSR is a feasible and acceptable intervention in adolescents with functional somatic syndromes and has preliminary evidence for improving functional disability, symptom impact, and anxiety, with consistency between parent and child measures. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02190474. PMID- 28088400 TI - Hospitalizations for Respiratory Syncytial Virus and Vaccine-Preventable Infections in the First 2 Years After Pediatric Liver Transplant. AB - OBJECTIVES: To examine in liver transplant recipients at centers participating in the Pediatric Health Information System dataset the number of hospitalizations for respiratory syncytial virus (RSV) and vaccine-preventable infections (VPIs) in the first 2 years after transplantation, morbidity and mortality associated with these hospitalizations, and costs associated with these hospitalizations. STUDY DESIGN: A retrospective cohort study of patients <18 years of age who underwent liver transplantation at a Pediatric Health Information System center between January 1, 2004, and December 31, 2012. Hospitalizations for RSV/VPIs during the first 2 years post-transplant were ascertained using International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. Data were collected on clinical care, outcomes, and costs during these hospitalizations. RESULTS: There were 2554 liver transplant recipients identified; 415 patients (16.3%) had 544 cases of RSV/VPIs. RSV, rotavirus, and influenza were the most common infections resulting in hospitalization. Ninety two patients (3.6%) had RSV/VPI during their transplant hospitalization. Transplant hospitalizations complicated by RSV/VPI were longer (44 days vs. 21 days; P < .001), had higher rejection rates (37% vs. 26%; P = .02), and were more expensive ($259 697 vs. $190 860; P < .001). Multivariate analyses identified age <2 years at transplant (P < .001) and multivisceral recipient (P = .04) as predictors of a hospitalization for RSV. CONCLUSIONS: VPIs occurred in 1 of 6 liver transplant recipients in the first 2 years post-transplant, a significantly higher rate than in the general pediatric population. These hospitalizations had substantial morbidity, mortality, and costs, demonstrating the importance of vaccinating patients before transplantation. PMID- 28088401 TI - Pharmacological rescue of adult hippocampal neurogenesis in a mouse model of X linked intellectual disability. AB - Oligophrenin-1 (OPHN1) is a Rho GTPase activating protein whose mutations cause X linked intellectual disability (XLID). How loss of function of Ophn1 affects neuronal development is only partly understood. Here we have exploited adult hippocampal neurogenesis to dissect the steps of neuronal differentiation that are affected by Ophn1 deletion. We found that mice lacking Ophn1 display a reduction in the number of newborn neurons in the dentate gyrus. A significant fraction of the Ophn1-deficient newly generated neurons failed to extend an axon towards CA3, and showed an altered density of dendritic protrusions. Since Ophn1 deficient mice display overactivation of Rho-associated protein kinase (ROCK) and protein kinase A (PKA) signaling, we administered a clinically approved ROCK/PKA inhibitor (fasudil) to correct the neurogenesis defects. While administration of fasudil was not effective in rescuing axon formation, the same treatment completely restored spine density to control levels, and enhanced the long-term survival of adult-born neurons in mice lacking Ophn1. These results identify specific neurodevelopmental steps that are impacted by Ophn1 deletion, and indicate that they may be at least partially corrected by pharmacological treatment. PMID- 28088402 TI - Historical relationships of three enigmatic phasianid genera (Aves: Galliformes) inferred using phylogenomic and mitogenomic data. AB - The phylogeny of the Phasianidae (pheasants, partridges, and allies) has been studied extensively. However, these studies have largely ignored three enigmatic genera because of scarce DNA source material and limited overlapping phylogenetic data: blood pheasants (Ithaginis), snow partridges (Lerwa), and long-billed partridges (Rhizothera). Thus, phylogenetic positions of these three genera remain uncertain in what is otherwise a well-resolved phylogeny. Previous studies using different data types place Lerwa and Ithaginis in similar positions, but the absence of overlapping data means the relationship between them could not be inferred. Rhizothera was originally described in the genus Perdix (true partridges), although a partial cytochrome b (CYB) sequence suggests it is sister to Pucrasia (koklass pheasant). To identify robust relationships among Ithaginis, Lerwa, Rhizothera, and their phasianid relatives, we used 3692 ultra-conserved element (UCE) loci and complete mitogenomes from 19 species including previously hypothesized relatives of the three focal genera and representatives from all major phasianid clades. We used DNA extracted from historical specimen toepads for species that lacked fresh tissue in museum collections. Maximum likelihood and multispecies coalescent UCE analyses strongly supported Lerwa sister to a large clade which included Ithaginis at its base, and also including turkey, grouse, typical pheasants, tragopans, Pucrasia, and Perdix. Rhizothera was also in this clade, sister to a diverse group comprising Perdix, typical pheasants, Pucrasia, turkey and grouse. Mitogenomic genealogies differed from UCEs topologies, supporting a sister relationship between Ithaginis and Lerwa rather than a grade. The position of Rhizothera using mitogenomes depended on analytical choices. Unpartitioned and codon-based analyses placed Rhizothera sister to a tragopan clade, whereas a partitioned DNA model of the mitogenome was congruent with UCE results. In all mitogenome analyses, Pucrasia was sister to a clade including Perdix and the typical pheasants with high support, in contrast to UCEs and published nuclear intron data. Due to the strong support and consistent topology provided by all UCE analyses, we have identified phylogenetic relationships of these three enigmatic, poorly-studied, phasianid taxa. PMID- 28088403 TI - Ginkgo fruit extract as an additive to modify rumen microbiota and fermentation and to mitigate methane production. AB - Ginkgo fruit, an unused byproduct of the ginkgo nut industry, contains antimicrobial compounds known as anacardic acids. Two major cultivars of ginkgo, Kyuju (K) and Tokuro (T), were evaluated for their potential as a feed additive for ruminants. In batch culture, we incubated a mixture of hay and concentrate in diluted rumen fluid with or without 1.6% (fruit equivalent) ginkgo fruit extract. We conducted another series of batch culture studies to determine the dose response of fermentation. We also conducted continuous culture using the rumen simulation technique (RUSITEC) with cultivar K and carried out a pure culture study to monitor the sensitivity of 17 representative rumen bacterial species to ginkgo extract and component phenolics. Although both K and T extracts led to decreased methane and increased propionate production, changes were more apparent with K extract, and were dose-dependent. Total gas production was depressed at doses >=3.2%, suggesting that 1.6% was the optimal supplementation level. In RUSITEC fermentation supplemented with 1.6% ginkgo K, methane decreased by 53% without affecting total gas or total VFA production, but with decreased acetate and increased propionate. Disappearance of dry matter, neutral detergent fiber, and acid detergent fiber were not affected by ginkgo, but ammonia levels were decreased. Quantitative PCR indicated that the abundance of protozoa, fungi, methanogens, and bacteria related to hydrogen and formate production decreased, but the abundance of bacteria related to propionate production increased. MiSeq analysis (Illumina Inc., San Diego, CA) confirmed these bacterial changes and identified archaeal community changes, including a decrease in Methanobrevibacter and Methanomassiliicoccaceae and an increase in Methanoplanus. Pure culture study results supported the findings for the above bacterial community changes. These results demonstrate that ginkgo fruit can modulate rumen fermentation toward methane mitigation and propionate enhancement via microbial selection. PMID- 28088404 TI - Variation in fat globule size in bovine milk and its prediction using mid infrared spectroscopy. AB - The objectives of this study were to investigate the sources of variation in milk fat globule (MFG) size in bovine milk and its prediction using mid-infrared (MIR) spectroscopy. Mean MFG size was measured in 2,076 milk samples from 399 Ayrshire, Brown Swiss, Holstein, and Jersey cows, and expressed as volume moment mean (D[4,3]) and surface moment mean (D[3,2]). The mid-infrared spectra of the samples and milk performance data were also recorded during routine milk recording and testing. The effects of breed, herd nested within breed, days in milk, season, milking period, age at calving, parity, and individual animal on the variation observed in MFG size were investigated. Breed, herd nested within breed, days in milk, season, and milking period significantly affected mean MFG size. Milk fat globule size was the largest at the beginning of lactation and subsequently decreased. Milk samples with the smallest MFG on average came from Holstein cows, and those with the largest were from Jersey and Brown Swiss cows. Partial least squares regression was used to predict MFG size from MIR spectra of samples with a calibration data set containing 2,034 and 2,032 samples for D[4,3] and D[3,2], respectively. Coefficients of determination of cross validation for D[4,3] and D[3,2] prediction models were 0.51 and 0.54, respectively. The associated ratio of performance deviation values were 1.43 and 1.48 for D[4,3] and D[3,2], respectively. With these models, individual mean MFG size could not be accurately predicted, but results may be sufficient to screen samples for having either small or large MFG on average. Significant but low correlations of D[4,3] and D[3,2] with milk fat yield were estimated (0.16 and 0.21, respectively). Significant and moderate Pearson correlation coefficients for fat percent with D[4,3] and D[3,2] were assessed (0.34 and 0.36, respectively). This correlation was greater between milk fat percentage and predicted MFG size than with measured MFG size with coefficients of 0.47 and 0.49 for D[4,3] and D[3,2], respectively. The MIR prediction equations are potentially overusing the correlation between fat and MFG size and exploiting the strong relationship between the MIR spectra and total milk fat. However, the predictions of MFG size are able to determine variation in mean globule size beyond what would be achieved just by looking at the correlation with fat production. PMID- 28088405 TI - Evaluation of factors associated with immunoglobulin G, fat, protein, and lactose concentrations in bovine colostrum and colostrum management practices in grassland-based dairy systems in Northern Ireland. AB - The objectives of this study were to investigate colostrum feeding practices and colostrum quality on commercial grassland-based dairy farms, and to identify factors associated with colostrum quality that could help inform the development of colostrum management protocols. Over 1 yr, background information associated with dairy calvings and colostrum management practices were recorded on 21 commercial dairy farms. Colostrum samples (n = 1,239) were analyzed for fat, protein, lactose, and IgG concentration. A subset was analyzed for somatic cell count and total viable bacteria count. Factors associated with nutritional and IgG concentrations were determined using both univariate and multivariate models. This study found that 51% of calves were administered their first feed of colostrum via esophageal tube, and the majority of calves (80%) were fed >2 L of colostrum at their first feed (mean = 2.9 L, SD = 0.79), at a mean time of 3.2 h (SD 4.36) after birth, but this ranged across farms. The mean colostral fat, protein, and lactose percentages and IgG concentrations were 6.4%, 14%, 2.7%, and 55 mg/mL, respectively. The mean somatic cell count and total viable count were 6.3 log10 and 6.1 log10, respectively. Overall, 44% of colostrum samples contained <50 mg/mL IgG, and almost 81% were in excess of industry guidelines (<100,000 cfu/mL) for bacterial contamination. In the multivariate model, IgG concentration was associated with parity and time from parturition to colostrum collection. The nutritional properties of colostrum were associated with parity, prepartum vaccination, season of calving, and dry cow nutrition. The large variation in colostrum quality found in the current study highlights the importance of routine colostrum testing, and now that factors associated with lower-quality colostrum on grassland-based dairy farms have been identified, producers and advisers are better informed and able to develop risk-based colostrum management protocols. PMID- 28088406 TI - Short communication: Effects of vacuum freeze-drying on inactivation of Cronobacter sakazakii ATCC29544 in liquid media with different initial inoculum levels. AB - Vacuum freeze-drying is an important food-processing technology for valid retention of nutrients and bioactive compounds. Cronobacter sakazakii has been reported to be associated with severe infections in neonates through consumption of contaminated powdered infant formula. In this study, effects of vacuum freeze drying treatment for 12, 24, and 36 h on inactivation of C. sakazakii with different initial inoculum levels in sterile water, tryptic soy broth (TSB), skim milk, and whole milk were determined. Results indicated that the lethality rate of C. sakazakii in each sample increased with the extension of vacuum freeze drying time. With initial inoculum levels of 102 and 103 cfu/mL, the survival of C. sakazakii in different liquid media was significantly affected by vacuum freeze-drying for 12, 24, and 36 h. In addition, the lethality rates of C. sakazakii in whole milk, skim milk, and TSB was significantly reduced compared with those in sterile water. Furthermore, whole milk showed the strongest protective role for C. sakazakii cells, followed by skim milk and TSB medium. Using the scanning electron microscope, the intracellular damage and obvious distortion of C. sakazakii cells were observed after vacuum freeze-drying for 24 and 36 h compared with the untreated sample, and the injured cells increased with the extension of vacuum-drying time. We concluded that inactivation of vacuum freeze-drying on C. sakazakii cells is related to the food matrix, and a combination with other methods for inactivating C. sakazakii is required for ensuring microbial safety of powdered infant formula. PMID- 28088407 TI - Far-off and close-up dry matter intake modulate indicators of immunometabolic adaptations to lactation in subcutaneous adipose tissue of pasture-based transition dairy cows. AB - The common practice of increasing dietary energy density during the close-up dry period (last ~3 wk prepartum) has been recently associated with a higher incidence of metabolic disorders after calving. Despite these reports, over feeding of metabolizable energy (ME) during the far-off, nonlactating period is a common management policy aimed at achieving optimum calving body condition score (BCS) in pasture-based systems, as cows are generally thinner than total mixed ration cows at the end of lactation. Our hypothesis was that both far-off and close-up overfeeding influence the peripartum adipose tissue changes associated with energy balance and inflammatory state. Sixty mid-lactation, grazing dairy cows of mixed age and breed were randomly allocated to 1 of 2 groups that were managed through late lactation to achieve a low and high BCS (approximately 4.25 and 5.0 on a 10-point scale) at dry-off. The low BCS cows were then overfed ME to ensure that they achieved the same BCS as the higher BCS group by calving. Within each rate of BCS gain treatment, cows were offered 65, 90, or 120% of their pre calving ME requirements for 3 wk pre-calving in a 2 * 3 factorial arrangement of treatments (i.e., 10 cows/treatment). Subcutaneous adipose tissue was collected via biopsy at -1, 1, and 4 wk relative to parturition. Quantitative PCR was used to measure mRNA and microRNA expression of targets related to adipogenesis and inflammation. Cows overfed in the far-off period had increased expression of miR 143 and miR-378 prepartum (-1 wk) indicating greater adipogenesis, consistent with their rapid gain in BCS following dry-off. Furthermore, the lower postpartum expression of IL6, TNF, TLR4, TLR9, and miR-145, and a higher abundance of miR 99a indicated lower body fat mobilization in early lactation in the same group. In the close-up period, feeding either 65 or 120% of ME requirements caused changes in FASN, IL1B, IL6R, TLR9, and the microRNA miR-143, miR-155, and miR 378. Their respective expression patterns indicate a tentative negative-feedback mechanism in metabolically compromised, feed-restricted cows, and a possible immune-related stimulation of lipolysis in apparently static adipocytes in overfed cows. Data from cows fed 90% of ME requirements indicate the existence of a balance between lipolytic (inflammatory-related) and anti-lipolytic signals, to prime the mobilization machinery in light of imminent lactation. Overall, results indicate that far-off dry cow nutrition influences peripartum adipose tissue metabolism, with neither strategy negatively affecting the physiological adaptation to lactation. Furthermore, to ensure a favorable transition, cows should be subjected to a small feed restriction in the close-up period, irrespective of far-off nutritional management. PMID- 28088408 TI - The effects of adding fat to diets of lactating dairy cows on total-tract neutral detergent fiber digestibility: A meta-analysis. AB - The objective of this meta-analysis was to determine the effects of supplemental fat on fiber digestibility in lactating dairy cattle. Published papers that evaluated the effects of adding fat to the diets of lactating dairy cattle on total-tract neutral detergent fiber digestibility (ttNDFd) and dry matter intake (DMI) were compiled. The final data set included 108 fat-supplemented treatment means, not including low-fat controls, from 38 publications. The fat-supplemented treatment means exhibited a wide range of ttNDFd (49.4% +/- 9.3, mean +/- standard deviation) and DMI (21.3 kg/d +/- 3.5). Observations were summarized as the difference between the treatment means for fat-supplemented diets minus their respective low-fat control means. Additionally, those differences were divided by the difference in diet fatty acid (FA) concentration between the treatment and control diets. Treatment means were categorized by the type of fat supplement. Supplementing 3% FA in the diet as medium-chain fats (containing predominately 12 and 14-carbon saturated FA) or unsaturated vegetable oil decreased ttNDFd by 8.0 and 1.2 percentage units, respectively. Adding 3% calcium salts of long-chain FA or saturated fats increased ttNDFd by 3.2 and 1.3 percentage units, respectively. No other fat supplement type affected ttNDFd. Except for saturated fats and animal-vegetable fats, supplementing dietary fat decreased DMI. When the values for changes in ttNDFd are regressed on changes in DMI there was a positive relationship, though the coefficient of determination is only 0.20. When changes in ttNDFd were regressed on changes in DMI, within individual fat supplement types, there was no relationship within calcium salt supplements. There was a positive relationship between changes in ttNDFd and changes in DMI for saturated fats. Neither relationship suggested that the increased ttNDFd with calcium salts or saturated FA was due to decreased DMI for these fat sources. A subset of the means included measured ruminal neutral detergent fiber digestion. Analysis of this smaller data set did not suggest that ruminal neutral detergent fiber digestibility is depressed by fat supplementation more than ttNDFd. Adding fats, other than those with medium-chain FA, consistently increased digestible energy density of the diet. However, due to reduced DMI, this increased energy density may not result in increased digestible nutrient intake. PMID- 28088409 TI - Genome-wide association analysis and pathways enrichment for lactation persistency in Canadian Holstein cattle. AB - Lactation persistency (LP), defined as the rate of declining milk yield after milk peak, is an economically important trait for dairy cattle. Improving LP is considered a good alternative method for increasing overall milk production because it does not cause the negative energy balance and other health issues that cows experience during peak milk production. However, little is known about the biology of LP. A genome-wide association study (GWAS) and pathway enrichment were used to explore the genetic mechanisms underlying LP. The GWAS was performed using a univariate regression mixed linear model on LP data of 3,796 cows and 44,100 single nucleotide polymorphisms (SNP). Eight and 47 SNP were significantly and suggestively associated with LP, respectively. The 2 most important quantitative trait loci regions for LP were (1) a region from 106 to 108 Mb on Bos taurus autosome (BTA) 5, where the most significant SNP (ARS-BFGL-NGS-2399) was located and also formed a linkage disequilibrium block with 3 other SNP; and (2) a region from 29.3 to 31.3 Mb on BTA 20, which contained 3 significant SNP. Based on physical positions, MAN1C1, MAP3K5, HCN1, TSPAN9, MRPS30, TEX14, and CCL28 are potential candidate genes for LP because the significant SNP were located in their intronic regions. Enrichment analyses of a list of 536 genes in 0.5-Mb flanking regions of significant and suggestive SNP indicates that synthesis of milk components, regulation of cell apoptosis processes and insulin, and prolactin signaling pathways are important for LP. Upstream regulators relevant for LP positional candidate genes were prolactin (PRL), peroxisome proliferator-activated receptor gamma (PPARG), and Erb-B2 receptor tyrosine kinase 2 (ERBB2). Several networks related to cellular development, proliferation and death were significantly enriched for LP positional candidate genes. In conclusion, this study detected several SNP, genes, and interesting regions for fine mapping and validation of candidate genes and SNP for potential use in selection for improved LP. This study also provided further insights on the biology of LP which will help to prioritize selected candidate genes for functional validation and application. PMID- 28088410 TI - Short communication: Sodium salicylate negatively affects rumen fermentation in vitro and in situ. AB - Administration of sodium salicylate (SS) to cows in early lactation has a positive effect on whole-lactation milk production but a negative effect on metabolism in some cases. The objective of this trial was to determine whether SS directly affects rumen fermentation. Experiment 1 was designed to investigate the effects of direct inclusion of SS in a 24-h batch culture, and experiment 2 was designed to test the fermentative ability of rumen fluid from heifers who had received SS. In experiment 1, we combined strained and pooled rumen fluid from 3 heifers in a 2:1 ratio with McDougall's buffer, and added 150 mL of the inoculum to each flask (n = 5/treatment) with 2.5 g of fermentation substrate similar to a lactating cow ration, ground to 1 mm. We then added premixed treatments (1-mL volume) to achieve the desired final amount of SS (CON1 = 0 mg, LOW = 125 mg, MED = 250 mg, HI = 375 mg). In experiment 2, 6 heifers (n = 3/treatment) were drenched daily for 3 d, either with 62.5 g of SS dissolved in water (SAL) or an equal volume of water (CON2). Rumen fluid was collected from each heifer and was not pooled. After the fluid was mixed 2:1 with McDougall's buffer, 150 mL of inoculum was added to the fermentation flasks (n = 4/heifer) with 2.5 g of fermentation substrate. This experiment was performed the day before SS treatment began and repeated 1, 13, and 35 d after the end of the treatment period. We also performed an in situ experiment at each of these time points. In the first experiment, inclusion of SS resulted in a decrease in dry matter disappearance (DMD) over 24 h, as well as an increase in final pH. We detected no difference between treatments for gas production asymptotic volume, rate, or lag. In the second experiment, we detected a significant treatment * day interaction for DMD: we observed no difference between groups during a 24-h batch culture on the day following treatment, but SAL resulted in lower DMD on d 13 and d 35. We detected no treatment effect on the final pH of the batch culture or on any gas-production parameters. We observed a tendency for SAL to decrease the DMD rate in situ on the day after treatment. These results indicate that SS administration has a negative effect on rumen microorganisms. PMID- 28088411 TI - Standardization of milk infrared spectra for the retroactive application of calibration models. AB - The objective of this study was to standardize the infrared spectra obtained over time and across 2 milk laboratories of Canada to create a uniform historical database and allow (1) the retroactive application of calibration models for prediction of fine milk composition; and (2) the direct use of spectral information for the development of indicators of animal health and efficiency. Spectral variation across laboratories and over time was inspected by principal components analysis (PCA). Shifts in the PCA scores were detected over time, leading to the definition of different subsets of spectra having homogeneous infrared signal. To evaluate the possibility of using common equations on spectra collected by the 2 instruments and over time, we developed a standardization (STD) method. For each subset of data having homogeneous infrared signal, a total of 99 spectra corresponding to the percentiles of the distribution of the absorbance at each wavenumber were created and used to build the STD matrices. Equations predicting contents of saturated fatty acids, short-chain fatty acids, and C18:0 were created and applied on different subsets of spectra, before and after STD. After STD, bias and root mean squared error of prediction decreased by 66% and 32%, respectively. When calibration equations were applied to the historical nonstandardized database of spectra, shifts in the predictions could be observed over time for all investigated traits. Shifts in the distribution of the predictions over time corresponded to the shifts identified by the inspection of the PCA scores. After STD, shifts in the predicted fatty acid contents were greatly reduced. Standardization reduced spectral variability between instruments and over time, allowing the merging of milk spectra data from different instruments into a common database, the retroactive use of calibrations equations, or the direct use of the spectral data without restrictions. PMID- 28088412 TI - Short communication: Urea hydrolysis in dairy cattle manure under different temperature, urea, and pH conditions. AB - The objective of the study was to quantify the rate of urea hydrolysis in dairy cattle manure under different initial urea concentration, temperature, and pH conditions. In particular, by varying all 3 factors simultaneously, the interactions between them could also be determined. Fresh feces and artificial urine solutions were combined into a slurry to characterize the rate of urea hydrolysis under 2 temperatures (15 degrees C and 35 degrees C), 3 urea concentrations in urine solutions (500, 1,000, and 1,500 mg of urea-N/dL), and 3 pH levels (6, 7, and 8). Urea N concentration in slurry was analyzed at 0.0167, 1, 2, 4, 6, 8, 12, 16, 20, and 24 h after initial mixing. A nonlinear mixed effects model was used to determine the effects of urea concentration, pH, and temperature treatments on the exponential rate of urea hydrolysis and to predict the hydrolysis rate for each treatment combination. We detected a significant interaction between pH and initial urea level. Increasing urea concentration from 1,000 to 1,500 mg of urea-N/dL decreased the rate of urea hydrolysis across all pH levels. Across all pH and initial urea levels, the rate of urea hydrolysis increased with temperature, but the effect of pH was only observed for pH 6 versus pH 8 at the intermediate initial urea concentration. The fast rates of urea hydrolysis indicate that urea was almost completely hydrolyzed within a few hours of urine mixing with feces. The estimated urea hydrolysis rates from this study are likely maximum rates because of the thorough mixing before each sampling. Although considerable mixing of feces and urine occurs on the barn floor of commercial dairy operations from cattle walking through the manure, such mixing may be not as quick and thorough as in this study. Consequently, the urea hydrolysis rates from this study indicate the maximum loss of urea and should be accounted for in management aimed at mitigating ammonia emissions from dairy cattle manure under similar urea concentration, pH, and temperature conditions reported in this experiment. PMID- 28088413 TI - Short communication: Associations between feed push-up frequency, feeding and lying behavior, and milk yield and composition of dairy cows. AB - Feeding management factors have great potential to influence activity patterns and feeding behavior of dairy cows, which may have implications for performance. The objectives of this study were to assess the effects of feed push-up frequency on the behavioral patterns of dairy cows, and to determine associations between behavior and milk yield and composition. Lactating Holstein dairy cows (n = 28, parity = 1.9 +/- 1.1; mean +/- SD) were housed in tiestalls, milked twice per day, and offered ad libitum access to water and a total mixed ration (containing, on a dry matter basis: 25% corn silage, 25% grass/alfalfa haylage, 30% high moisture corn, and 20% protein/mineral supplement), provided twice per day. Cows were divided into 2 groups of 14 (balanced by days in milk, milk production, and parity) and individually exposed to each of 2 treatments in a crossover design with 21-d periods; treatment 1 had infrequent feed push-up (3*/d), whereas treatment 2 had frequent feed push-up (5*/d). During the last 7 d of each period, dry matter intake and milk production were recorded and lying behavior was monitored using electronic data loggers. During the last 2 d of each period, milk samples were collected for analysis of protein and fat content and feed samples of fresh feed and orts were collected for particle size analysis. The particle size separator had 3 screens (19, 8, and 1.18 mm) and a bottom pan, resulting in 4 fractions (long, medium, short, fine). Sorting was calculated as the actual intake of each particle size fraction expressed as a percentage of the predicted intake of that fraction. Feed push-up frequency had no effect on lying time [11.4 +/- 0.37 h/d; mean +/- standard error (SE)], milk production (40.2 +/- 1.28 kg/d) and composition (milk protein: 3.30 +/- 0.048%; milk fat: 3.81 +/- 0.077%), or feed sorting. Cows sorted against long particles (78.0 +/- 2.2%) and for short (102.6 +/- 0.6%) and fine (108.4 +/- 0.9%) particles. Milk fat content decreased by 0.1 percentage points for every 10% increase in sorting against long particles and was not associated with lying behavior or other cow-level factors. Milk protein content decreased by 0.03 percentage points for every hour decrease in lying time and by 0.04 percentage points for every 10% increase in sorting against long particles. These results suggest that sorting against long ration particles may negatively affect milk composition. Additionally, we did not find that altering feed push-up frequency affected feed sorting or cow standing and lying patterns. PMID- 28088414 TI - Social dominance in prepubertal dairy heifers allocated in continuous competitive dyads: Effects on body growth, metabolic status, and reproductive development. AB - The objective of this study was to compare the body weight (BW) and size, metabolic status, and reproductive development of dominant and subordinate prepubertal dairy heifers allocated in competitive dyads. Sixteen Holstein and Jersey * Holstein prepubertal heifers (means +/- SEM; 250.8 +/- 9.8 d; 208.5 +/- 13.9 kg of BW) were assigned to 8 homogeneous dyads according to breed, age, and BW. Dyads were housed in pens separated 1 m from each other during 120 d, receiving a total mixed ration on a 5% restriction of their potential dry matter intake, and had access to the same feeder (60 cm) throughout the experiment. Dominant and subordinate heifers were defined based on the winning agonistic interactions in each dyad. Body development was recorded every 20 d in all heifers, and blood samples were collected on the same days to determine endocrine and metabolic status. The maximum follicle diameter, number of follicles >6 mm, and the presence of corpus luteum were observed weekly by ultrasound. Heifer BW (269.3 vs. 265.3 +/- 1.5 kg) and average daily gains (0.858 vs. 0.770 +/- 0.02 kg/d) were greater in dominant than subordinate heifers. On d 30, 37, and 53, dominant heifers had more follicles than subordinate heifers, and maximum follicle diameter was greater in dominant than in subordinate heifers (10.0 vs. 9.0 +/- 0.3 mm). Dominant heifers achieved puberty earlier than subordinate heifers (313.9 +/- 4.9 vs. 329.6 +/- 5.7 d) with similar BW (279.4 +/- 2.6 vs. 277.4 +/- 5.8 kg). Glucose concentrations were greater in dominant than subordinate heifers (89.2 vs. 86.8 +/- 1.2 mg/dL), but cholesterol concentrations were greater in subordinate than dominant heifers (86.1 vs. 90.2 +/- 2.6 mg/dL). We concluded that, under continuous competitive situations, dominant heifers were more precocious than subordinate ones, achieving an earlier puberty. Dominant heifers had greater body growth and glucose concentrations than subordinate heifers, which may be responsible, at least in part, for the differences on reproductive development between heifers of different social status. PMID- 28088415 TI - Qualitative and quantitative identification of adulteration of milk powder using DNA extracted with a novel method. AB - The extraction of high-quality DNA from processed dairy products is often the crucial step in an authentication process by PCR-based methods. In this study, we optimized a novel DNA extraction method for milk powder and used the extracted DNA for identification of milk powder based on PCR analysis. The DNA quality was assessed by amplifying target sequences from mitochondrial genes, as well as by monitoring the yield, purity, and integrity of the extracted DNA. In addition, a laboratory adulteration model of milk powder was detected by PCR-based methods (PCR and real-time PCR) using primers targeting the mitochondrial 12S rRNA gene. Results showed that a sufficient amount and quality of DNA could be isolated from milk powder with this method. Both PCR and real-time PCR detection of cow milk compositions in goat milk powder further confirmed the DNA extracted with this extraction method could be widely used in addressing milk powder adulterant by a PCR-based method. PMID- 28088416 TI - Space allowance influences individually housed Holstein bull calf innate immune measures and standing behaviors after castration at 3 weeks of age. AB - Dairy calves in the Southwest regions of the United States are typically raised individually in wooden hutches with 1.23 m2 of space. The objective of the study was to determine if increased space allowance in wooden hutches influences measures of innate immunity and behaviors of Holstein bull calves pre- and postcastration. Calves were randomly assigned at 4 d of age to conventional (CONV; 1.23 m2 of space; n = 18), moderate (MOD; 1.85 m2 space; n = 17), or maximized space allowance (MAX; 3.71 m2 space; n = 19) in hutches. Calves were surgically castrated at 24 d of age. Peripheral whole blood samples were collected at -1, +1, +5, and +12 d of castration. Accelerometer loggers (n = 16 calves per treatment) were used from -3 to +5 d of castration to assess standing behaviors. All calves decreased total standing duration the day of castration versus precastration. Overall, MAX spent the most time in the stand position postcastration versus CONV and MOD. Within treatments, MOD and MAX had increased plasma cortisol 1 d postcastration versus precastration. A treatment * time tendency was observed for cortisol at 12 d postcastration; MAX had the least circulating cortisol. A treatment * time tendency for circulating haptoglobin (Hp) was observed and Hp was greatest among CONV 1 d pre- and 12 d postcastration. Compared with precastration, CONV had increased Hp at 1, 5, and 12 d, whereas MOD had increased Hp at 5 d, and Hp remained similar within MAX. A treatment * time tendency for tumor necrosis factor-alpha (TNF-alpha) from lipopolysaccharide-stimulated whole blood was observed; at 1 d postcastration, MOD had the most TNF-alpha, whereas MAX had the least. Within MAX, calves had increased TNF-alpha from precastration to 5 d postcastration. A treatment * time interaction was observed for whole blood bactericidal activity against Escherichia coli (WB anti-E). The CONV tended to have the greatest WB anti-E at d -1, but at d 1 and 5 postcastration, CONV had the least WB anti-E. Overall, MAX had less intensity of neutrophil oxidative burst versus CONV and MOD. The lower response of neutrophil oxidative burst and slower Hp secretion after castration is indicative that the wound site likely had less microbial exposure. The findings of this study suggest that calves housed with more space are potentially at less risk of too much inflammation after castration, which may likely be due to the effects of increased space on hide cleanliness and increased standing time. PMID- 28088417 TI - Milk fat threshold determination and the effect of milk fat content on consumer preference for fluid milk. AB - Milk consumption in the United States has been in decline since the 1960s. Milk fat plays a critical role in sensory properties of fluid milk. The first objective of this study was to determine the change in percent milk fat needed to produce a detectable or just noticeable difference (JND) to consumers in skim, 1%, 2%, and whole milks. The second objective was to evaluate how milk fat affected consumer preferences for fluid milk. Threshold tests were conducted to determine the JND for each reference milk (skim, 1%, 2%, and whole milk), with a minimum of 60 consumers for each JND. The JND was determined for milks by visual appearance without tasting and tasting without visual cues. Serving temperature effect (4, 8, or 15 degrees C) on tasting JND values were also investigated. The established JND values were then used to conduct ascending forced-choice preference tests with milks. Consumers were assigned to 3 groups based on self reported milk consumption: skim milk drinkers (n = 59), low-fat milk drinkers (consumed 1% or 2% milk, n = 64), and whole milk drinkers (n = 49). Follow-up interviews were conducted where consumers were asked to taste and explain their preference between milks that showed the most polarization within each consumer segment. Descriptive sensory analysis was performed on the milks used in the follow-up interviews to quantify sensory differences. Visual-only JND were lower than tasting-only JND values. Preference testing revealed 3 distinct preference curves among the consumer segments. Skim milk drinkers preferred skim milk and up to 2% milk fat, but disliked milk higher in fat due to it being "too thick," "too heavy," "flavor and texture like cream," "too fatty," and "looks like half and half." Low-fat milk drinkers preferred 2% milk up to 3.25% (whole milk), but then disliked higher milk fat content. Whole milk drinkers preferred whichever milk was higher in milk fat regardless of how high the fat content was, distinct from skim and low-fat milk drinkers. The findings of this study provide insights on sensory characteristics of milk fat in fluid milk and consumer sensory perception of these properties. These results also provide insights on how the industry might adjust milk fat references for adjusting milk sensory properties to increase milk preference and remain within the standards of identity of milk. PMID- 28088418 TI - Laboratory silo type and inoculation effects on nutritional composition, fermentation, and bacterial and fungal communities of oat silage. AB - The objectives were to evaluate (1) the use of 2 types of experimental silos (S) to characterize whole-crop oat (Avena sativa L.) silage with or without addition of an inoculant (I), and (2) the effect of inoculation on the microbial community structure of oats ensiled using only plastic bucket silos (BKT). From each of 6 sections in a field, oats were harvested, treated (INO) or not (CON) with inoculant, packed into 19-L BKT or vacuum bags (BG), and ensiled for 217 d. The inoculant added contained Lactobacillus buchneri and Pediococcus pentosaceus (4 * 105 and 1 * 105 cfu/g of fresh oats, respectively). The experimental design was a complete randomized design replicated 6 times. Treatment design was the factorial combination of 2 S * 2 I. Some differences existed between BG versus BKT at silo opening (217 d), including a decreased CP (7.73 vs. 7.04 +/- 0.247% of DM) and ethanol (1.93 vs. 1.55 +/- 0.155) and increased lactic acid (4.28 vs. 3.65 +/- 0.241), respectively. Also, WSC and mold counts were reduced in BG versus BKT for CON (1.78 vs. 2.70 +/- 0.162% of DM and 0.8 vs. 2.82 +/- 0.409 log cfu/fresh g) but not for INO (~1.53 and 1.55), respectively. Application of INO increased DM recovery (96.1 vs. 92.9 +/- 0.63%), aerobic stability (565 vs. 133 +/- 29.2 h), acetic acid (2.38 vs. 1.22 +/- 0.116% of DM), and reduced NDF (65.0 vs. 67.0 +/- 0.57), ADF (36.7 vs. 38.1 +/- 0.60), ethanol (0.63 vs. 2.85 +/- 0.155), and yeast counts (1.10 vs. 4.13 +/- 0.484 log cfu/fresh g) in INO versus CON, respectively. At d 0, no differences were found for S and I on the nutritional composition and background microbial counts. Leuconostocaceae (82.9 +/- 4.27%) and Enterobacteriaceae (15.2 +/- 3.52) were the predominant bacterial families and unidentified sequences were predominant for fungi. A higher relative abundance of the Davidiellaceae fungal family (34.3 vs. 19.6 +/- 4.47) was observed in INO versus CON. At opening (217 d), INO had a lower relative abundance of Leuconostocaceae (42.3 vs. 95.8 +/- 4.64) and higher Lactobacillaceae (57.4 vs. 3.9 +/- 4.65) versus CON. Despite several differences were found between BKT and BG, both techniques can be comparable for characterizing effects of INO on the most basic measures used in silage evaluation. The use of inoculant improved oat silage quality partially by a shift in the bacterial community composition during ensiling, which mainly consisted of an increased relative abundance of Lactobacillaceae and reduction of Leuconostocaceae relative to CON. PMID- 28088419 TI - Hexanal as biomarker for milk oxidative stress induced by copper ions. AB - Milk flavor varies greatly due to oxidative stress during storage. Several studies have documented the use of volatile biomarkers for determining milk oxidation, but only a few have focused on the development of inline procedures enabling the monitoring of milk oxidative stress. In this work, oxidative stress was induced in pasteurized milk samples by spiking increasing concentrations of copper ions (from 0 to 32 mg.L-1). During storage (4 degrees C), hexanal evolution was monitored by a proton transfer reaction mass spectrometer. The mass fragment m/z 83 was selected as a biomarker for hexanal determination. Its intensity evolved with a sigmoidal trend, showing a maximum rate proportional to the Cu2+ content in milk. The proposed approach is simple, fast (up to 120 sample/h), sensitive (8.8 MUg.m-3 per MUM hexanal in the sample), with low limit of detection (0.5 MUM, determined as 3 times the standard deviation divided by the slope of a calibration line), precise (<6%), with good recovery (99-104%), and noninvasive. The method can be used for laboratory screening of milk susceptibility toward oxidation or for quality control in the processing line. PMID- 28088420 TI - Exploring expert opinion on the practicality and effectiveness of biosecurity measures on dairy farms in the United Kingdom using choice modeling. AB - Biosecurity, defined as a series of measures aiming to stop disease-causing agents entering or leaving an area where farm animals are present, is very important for the continuing economic viability of the United Kingdom dairy sector, and for animal welfare. This study gathered expert opinion from farmers, veterinarians, consultants, academics, and government and industry representatives on the practicality and effectiveness of different biosecurity measures on dairy farms. The study used best-worst scaling, a technique that allows for greater discrimination between choices and avoids the variability in interpretation associated with other methods, such as Likert scales and ranking methods. Keeping a closed herd was rated as the most effective measure overall, and maintaining regular contact with the veterinarian was the most practical measure. Measures relating to knowledge, planning, and veterinary involvement; buying-in practices; and quarantine and treatment scored highly for effectiveness overall. Measures relating to visitors, equipment, pest control, and hygiene scored much lower for effectiveness. Overall, measures relating to direct animal to-animal contact scored much higher for effectiveness than measures relating to indirect disease transmission. Some of the most effective measures were also rated as the least practical, such as keeping a closed herd and avoiding nose-to nose contact between contiguous animals, suggesting that real barriers exist for farmers when implementing biosecurity measures on dairy farms. We observed heterogeneity in expert opinion on biosecurity measures; for example, veterinarians rated the effectiveness of consulting the veterinarian on biosecurity significantly more highly than dairy farmers, suggesting a greater need for veterinarians to promote their services on-farm. Still, both groups rated it as a practical measure, suggesting that the farmer-veterinarian relationship holds some advantages for the promotion of biosecurity. PMID- 28088421 TI - The influence of ultra-pasteurization by indirect heating versus direct steam injection on skim and 2% fat milks. AB - Fluid milk is traditionally pasteurized by high temperature, short time (HTST) pasteurization, which requires heating to at least 72 degrees C for 15 s. Ultra pasteurization (UP) extends milk shelf life and is defined as heating to at least 138 degrees C for 2 s. The UP process can be done by indirect heating (IND) or by direct steam injection (DSI). The influence of these 2 UP methods on milk flavor has not been widely investigated. The objective of this study was to compare the effect of HTST, IND-UP, and DSI-UP on sensory perception of fluid milk. Raw skim and standardized 2% milks were pasteurized at 140 degrees C for 2.3 s by IND or DSI or by HTST (78 degrees C, 15 s) and homogenized at 20.7 MPa. The processed milks were stored in light-shielded opaque high-density polyethylene containers at 4 degrees C and examined by descriptive analysis and microbial analysis on d 3, 7, and 14. Furosine and serum protein denaturation analyses were performed on d 0 and 14 as an indicator of heat treatment. Last, consumer acceptance testing was conducted at d 10, with adults (n = 250) and children (ages 8 to13 y, n = 100) who were self-reported consumers of skim or 2% milk; consumers only received samples for either skim or 2% milk. The entire experiment was repeated in triplicate. Milks treated by HTST had lower cooked flavor than either UP milk. Milks heated by DSI-UP were characterized by sulfur or eggy and cooked flavors, whereas IND-UP milks had higher sweet aromatic and sweet taste compared with DSI UP milk. Aromatic flavor intensities of all milks decreased across 14 d of storage. Furosine concentrations and serum protein denaturation were highest for the IND treatments, followed by DSI and HTST. Furosine content in both skim and 2% milk increased with time, but the increase was faster in IND-UP skim milk. Adult and child consumers preferred HTST milk over either UP milk, regardless of fat content. Ultra-pasteurization by IND or DSI did not affect consumer acceptance at 10 d postprocessing, but traditional HTST milks were preferred by consumers of all ages. PMID- 28088422 TI - Effects of clay after an aflatoxin challenge on aflatoxin clearance, milk production, and metabolism of Holstein cows. AB - Oral supplementation of clay to dairy cattle has been reported to reduce toxicity of aflatoxin (AF) in contaminated feed. The objective of this study was to determine the effects of 3 concentrations of dietary clay supplementation in response to an AF challenge. Ten multiparous rumen-cannulated Holstein cows [body weight (mean +/- SD) = 669 +/- 20 kg and 146 +/- 69 d in milk], were assigned to 1 of 5 treatments in a randomized replicated 5 * 5 Latin square design balanced to measure carryover effects. Periods (21 d) were divided in an adaptation phase (d 1 to 14) and a measurement phase (d 15 to 21). From d 15 to 17, cows received an AF challenge. The challenge consisted of 100 MUg of aflatoxin B1 (AFB1)/kg of dietary dry matter intake (DMI). The material was fitted into 10-mL gelatin capsules and administered into the rumen through a rumen-cannula based on the average DMI obtained on d 12 to 14. Treatments were no clay plus an AF challenge (POS); 3 different concentrations of clay (0.5, 1, or 2% of dietary DMI) plus an AF challenge; and a control consisting of no clay and no AF challenge (C). Statistical analysis was performed using the MIXED procedure of SAS (SAS Institute Inc., Cary, NC). Two contrasts, CONT1 (POS vs. C) and CONT2 (POS vs. the average of 0.5, 1, and 2% clay), were compared along with the linear and quadratic treatment effects (POS, 0.5%, 1%, 2%). Cows supplemented with clay had lower AF excretion in milk as aflatoxin M1 (AFM1; 0.5% = 20.83 MUg/d, 1% = 22.82 MUg/d, and 2% = 16.51 MUg/d) and AF transfer from rumen fluid to milk (AFM1; 0.5% = 1.01%, 1% = 0.98%, and 2% = 0.74%) compared with cows in POS (AFM1 = 27.81 MUg/d and AF transfer = 1.37%, CONT2). Similarly, concentrations of AFM1 in milk (0.5% = 0.35 MUg/kg, 1% = 0.30 MUg/kg, 2% = 0.25 MUg/kg), AFB1 in feces (0.5% = 1.79 MUg/g, 1% = 1.52 MUg/kg, 2% = 1.48 MUg/kg), and AFB1 in rumen fluid (0.5% = 0.05 MUg/kg, 1% = 0.02 MUg/kg, 2% = 0.02 MUg/kg) were reduced in cows fed clay compared with POS (0.43 MUg/kg, 2.78 MUg/kg, and 0.10 MUg/kg, respectively, CONT2). Cows supplemented with clay tended to have lower 3.5% fat-corrected milk [0.5% = 38.2 kg, 1% = 39.3 kg, 2% = 38.4 kg, standard error of the mean (SEM) = 1.8] than cows in POS (41.3 kg; SEM = 1.8; CONT2). Plasma superoxide dismutase (SOD) concentration tended to be lower for cows fed clay in the diet (0.5% = 2.16 U/mL, 1% = 1.90 U/mL, 2% = 2.3 U/mL; SEM = 0.3) than for cows in POS (2.72 U/mL; CONT2). Additionally, when cows were exposed to AF without clay in the diet, plasma concentrations of aspartate aminotransferase (AST) decreased from 84.23 (C) to 79.17 (POS) and glutamate dehydrogenase (GLDH) decreased from 91.02 (C) to 75.81 (POS). In conclusion, oral supplementation of clay reduced the transfer of AF from the rumen to milk and feces. PMID- 28088423 TI - Effects of rumen-protected Capsicum oleoresin on productivity and responses to a glucose tolerance test in lactating dairy cows. AB - The objective of this experiment was to investigate the effects of rumen protected Capsicum oleoresin (RPC) supplementation on feed intake, milk yield and composition, nutrient utilization, fecal microbial ecology, and responses to a glucose tolerance test in lactating dairy cows. Nine multiparous Holstein cows were used in a replicated 3 * 3 Latin square design balanced for residual effects with three 28-d periods. Each period consisted of 14 d for adaptation and 14 d for data collection and sampling. Treatments were 0 (control), 100, and 200 mg of RPC/cow per day. They were mixed with a small portion of the total mixed ration and top-dressed. Glucose tolerance test was conducted once during each experimental period by intravenous administration of glucose at a rate of 0.3 g/kg of body weight. Dry matter intake was not affected by RPC. Milk yield tended to increase for RPC treatments compared to the control. Feed efficiency was linearly increased by RPC supplementation. Concentrations of fat, true protein, and lactose in milk were not affected by RPC. Apparent total-tract digestibility of dry matter, organic matter, and crude protein was linearly increased, and fecal nitrogen excretion was linearly decreased by RPC supplementation. Rumen protected Capsicum oleoresin did not affect the composition of fecal bacteria. Glucose concentration in serum was not affected by RPC supplementation post glucose challenge. However, compared to the control, RPC decreased serum insulin concentration at 5, 10, and 40 min post glucose challenge. The area under the insulin concentration curve was also decreased 25% by RPC. Concentration of nonesterified fatty acids and beta-hydroxybutyrate in serum were not affected by RPC following glucose administration. In this study, RPC tended to increase milk production and increased feed efficiency in dairy cows. In addition, RPC decreased serum insulin concentration during the glucose tolerance test, but glucose concentration was not affected by treatment. PMID- 28088424 TI - Comparison between conjugated linoleic acid and essential fatty acids in preventing oxidative stress in bovine mammary epithelial cells. AB - Some in vitro and in vivo studies have demonstrated protective effects of conjugated linoleic acid (CLA) isomers against oxidative stress and lipid peroxidation. However, only a few and conflicting studies have been conducted showing the antioxidant potential of essential fatty acids. The objectives of the study were to compare the effects of CLA to other essential fatty acids on the thiol redox status of bovine mammary epithelia cells (BME-UV1) and their protective role against oxidative damage on the mammary gland by an in vitro study. The BME-UV1 cells were treated with complete medium containing 50 MUM of cis-9,trans-11 CLA, trans-10,cis-12 CLA, alpha-linolenic acid, gamma-linolenic acid, and linoleic acid. To assess the cellular antioxidant response, glutathione, NADPH, and gamma-glutamyl-cysteine ligase activity were measured 48 h after addition of fatty acids (FA). Intracellular reactive oxygen species and malondialdehyde production were also assessed in cells supplemented with FA. Reactive oxygen species production after 3 h of H2O2 exposure was assessed to evaluate and to compare the potential protection of different FA against H2O2 induced oxidative stress. All FA treatments induced an intracellular GSH increase, matched by high concentrations of NADPH and an increase of gamma glutamyl-cysteine ligase activity. Cells supplemented with FA showed a reduction in intracellular malondialdehyde levels. In particular, CLA isomers and linoleic acid supplementation showed a better antioxidant cellular response against oxidative damage induced by H2O2 compared with other FA. PMID- 28088425 TI - Short communication: Staphylococcus aureus infection modulates expression of drug transporters and inflammatory biomarkers in mouse mammary gland. AB - Mastitis is the most common disease in dairy herds worldwide and is often caused by Staphylococcus aureus. Little is known about the effect of mastitis on transporters in the mammary gland and the effect on transporter-mediated secretion of drugs into milk. We studied gene expressions of ATP-binding cassette and solute carrier transporters in S. aureus-infected mammary glands of mice. On d 7 of lactation, NMRI mice were inoculated with 1,000 cfu of S. aureus in 2 mammary glands and with a saline vehicle in 2 control glands. Gene expression of the transporters, Bcrp, Mdr1, Mrp1, Oatp1a5, Octn1, and Oct1, and of Csn2, the gene encoding beta-casein, were determined in mammary glands at 72 h after treatment. As biomarkers of the inflammatory response gene, expressions of the cytokines Il6, Tnfalpha, and the chemokine Cxcl2 were measured. Despite a high individual variation between the 6 animals, some characteristic patterns were evident. The 3 inflammatory biomarkers were upregulated in all animals; Csn2 was downregulated compared with controls in all animals, although not statistically significantly. Both Mrp1 and Oatp1a5 were statistically significantly upregulated and Bcrp was downregulated. Gene expression of Bcrp followed the expression of Csn2 in each of the animals, indicating a possible co-regulation. The findings demonstrate that S. aureus infection has an effect on expression of drug transporters in the mammary gland, which may affect secretion of drugs into milk and efficacy of drug therapy. PMID- 28088426 TI - Propensity-matched comparison of video-assisted thoracoscopic with thoracotomy lobectomy for locally advanced non-small cell lung cancer. AB - OBJECTIVE: We evaluated whether video-assisted thoracoscopic lobectomy for locally advanced non-small cell lung cancer could be performed safely and with acceptable long-term outcomes by our improved technique and compared with standard thoracotomy lobectomy in a well-balanced population. METHODS: Patients with clinical stage II and III A non-small cell lung cancers who received lobectomy were reviewed. Video-assisted thoracoscopic lobectomies were all performed with Wang's technique by the surgeons who had overcome the learning curve and achieved proficiency. By using propensity-matched analysis, perioperative outcomes and long-term survival were compared. RESULTS: Matching based on propensity scores produced 120 patients in each group. Conversion rate to thoracotomy was 11.7%. After thoracoscopic lobectomy, hospital length of stay was shorter compared with thoracotomy (9.2 vs 12 days; P = .014) despite similar rates of postoperative complications (30/125 [25%] vs 34/125 [28.3%]; P = .56). Disease-free survival (49.1% vs 42.2%; P = .40) and overall survival (55.0% vs 57.1%; P = .73) at 5 years were similar between groups. Although advanced pathologic stage (hazard ratio [HR], 2.018; 95% confidence interval [CI], 1.330 3.062) and no postoperative chemotherapy (HR, 1.880; 95% CI, 1.236-2.858) were independently associated with increased hazard of death in multivariable Cox regression at each time point in follow-up, thoracoscopic lobectomy was not (HR, 1.075; 95% CI, 0.714-1.620; P = .73). CONCLUSIONS: With continued experience and optimized technique, video-assisted thoracoscopic lobectomy can be performed in the majority of cases without compromising perioperative outcomes and oncologic efficacy. PMID- 28088427 TI - Temperature during operations on the aortic arch: How low should we go? PMID- 28088428 TI - Aortic floating thrombus detected by computed tomography angiography incidentally: Five cases and a literature review. AB - OBJECTIVE: To analyze the findings of aortic floating thrombus (AFT) on computed tomography angiography (CTA) for a definitive, timely diagnosis and to select a reasonable management course to improve prognosis. METHOD: We retrospectively analyzed imaging findings of 5 patients with AFT detected by CTA, including location, morphology, size, involved aortic segment, concomitant embolism, stent, and dynamic changes during the follow-up. RESULTS: Seven lesions were detected in the initial CTA studies of the 5 patients: 5 aortic intraluminal floating thrombi (3 patients) and 2 aortic in-stents floating thrombi (ASFTs; 2 patients). One aortic intraluminal floating thrombus was located in the right anterior wall of the ascending aorta and 2 in the aortic isthmus. Interval increasing in size of the splenic embolism and a new renal segmental artery embolism were noted in 1 patient after 7 days anticoagulation therapy. One ASFT was located in the original narrowing part of the aortic stent and another in the overlap of the stents. During the follow-up, some lesions disappeared, whereas the morphology and size varied in others. Four new ASFTs occurred. All the lesions were attached to the focal thickened inner walls of the stents with the free-floating portions along the direction of blood flow. CONCLUSIONS: AFT is a rare, life-threatening disease. Abnormal coagulation function, aortic disease, and history of aortic stent implantation are the potential predictors for AFT. CTA scanning can depict the lesions clearly and evaluate curative efficacy. The therapeutic strategy should be based on the etiology and the patient's physical condition, whereas the preferred treatment is conservative medication. PMID- 28088429 TI - Discussion. PMID- 28088430 TI - Flipping the classroom: Case-based learning, accountability, assessment, and feedback leads to a favorable change in culture. AB - OBJECTIVE: The 88-week Thoracic Surgery Curriculum is challenging to implement because of the large content in a traditional lecture format. This study investigates flipping the classroom by using a case-based format designed to stimulate resident preparation and engagement. METHODS: The didactic conference format was altered. Curricular reading assignments, case review, and conference participation prepared residents for novel formative assessment quizzes. Ten residents participated, and faculty served as controls. Scores were compared with the use of linear regression adjusted for clustering of responses for each person. A survey was administered to determine impressions of this educational technique. RESULTS: A majority of residents completed curricular readings (82%) and reviewed case presentations (79%). Resident performance initially lagged behind faculty but exceeded faculty performance by the conclusion (interaction P = .047). Junior resident overall performance was superior to senior residents over the entire analysis (P = .026); however, both groups improved over time similarly (P = .34) Increased reading from the curriculum (5% increase per level, P = .001) and case presentation review (6% increase per level, P < .0001) were associated with improved quiz performance. Residents presenting cases at their session performed no better than other quiz-takers for the same session (P = .38). The majority of residents viewed this method favorably. CONCLUSIONS: This method stimulated increased resident participation and engagement in this pilot study. Assessment scores increased at both resident levels, and resident performance exceeded faculty performance with time. By using experiential learning principles, flipping the classroom in this manner may improve educational culture by enhancing accountability, assessment, and feedback. PMID- 28088431 TI - Author Reply. PMID- 28088432 TI - Detection of Upper Tract Urothelial Malignancies by Computed Tomography Urography in Patients Referred for Hematuria at a Large Tertiary Referral Center. AB - OBJECTIVE: To evaluate the age-stratified prevalence of upper tract urothelial malignancies diagnosed on computed tomography urography in a large cohort of patients referred for initial evaluation of hematuria. MATERIALS AND METHODS: A total of 1123 consecutive adults without a history of urothelial cancer underwent initial computed tomography urography for gross hematuria (n = 652), microscopic hematuria (n = 457), or unspecified hematuria (n = 14) at a single institution from October 2006 to October 2012. Imaging findings suggestive of urothelial lesions were correlated with clinical information, including cystoscopy, cytology, and surgical pathology reports. Patients subsequently diagnosed with urothelial cancer following a normal radiographic evaluation were identified and analyzed. Age, gender, smoking history, and location and type of malignancy were analyzed. RESULTS: Upper tract urothelial cancer was detected in 4 (0.36%) patients, with a mean age of 66.5 years. All 4 patients presented with gross hematuria and were current or former smokers. None of the 535 patients under age 55 who underwent computed tomography urography were diagnosed with upper tract disease regardless of age, smoking history, or degree of hematuria. Likewise, no upper tract cancers were detected in patients referred for microscopic hematuria, regardless of age. CONCLUSION: Detection of upper tract urothelial cancer by computed tomography urography is exceedingly rare in patients presenting at a tertiary referral center with hematuria, particularly in the lower risk strata (younger age, microscopic hematuria). Further investigation into risk-stratified approaches to imaging for hematuria workup is warranted to minimize unnecessary costs and radiation exposure. PMID- 28088433 TI - Author Reply. PMID- 28088434 TI - Editorial Comment. PMID- 28088435 TI - Editorial Comment. PMID- 28088436 TI - Injury severity, sex, and transfusion volume, but not transfusion ratio, predict inflammatory complications after traumatic injury. AB - BACKGROUND: Blood component (packed red blood cells [PRBC], fresh frozen plasma [FFP], platelets [PLT]) ratios transfused in a 1:1:1 fashion are associated with survival after trauma; the relationship among blood component ratios and inflammatory complications after trauma is not fully understood. OBJECTIVES: To evaluate the relationship among blood component ratios (1:1 vs other for PRBC:FFP and PRBC:PLT) and inflammatory complications (primary outcome) in patients with major trauma. METHODS: Secondary analysis of a multi-institution database (N = 1538). Survival methods were used to determine the relationship among blood component ratios and inflammatory complications. RESULTS: Patients were primarily male (68%), Caucasians (89%), aged 39 +/- 14 years, involved in a motor vehicle collision (53%). Eighty-six percent of patients developed an inflammatory complication; 76% developed organ failure, 27% ventilator-associated pneumonia, and 24% acute respiratory distress syndrome. Injury severity, sex, and total PRBC transfusion volume, not blood component ratio, predicted inflammatory complications. CONCLUSIONS: Increased understanding of factors associated with inflammation after trauma and PRBC transfusion is needed. PMID- 28088437 TI - Safety and feasibility of PCI in patients undergoing TAVR: A systematic review and meta-analysis. AB - We aimed to evaluate the safety and feasibility of PCI (percutaneous coronary intervention) for coronary artery disease (CAD) in patients undergoing transcatheter aortic valve replacement (TAVR) by performing a meta-analysis. A systemic search of the database was performed. Studies were included comparing TAVR versus TAVR with PCI for significant CAD in patients undergoing TAVR for severe aortic stenosis. The primary outcome was 30 day mortality and secondary outcomes were myocardial infarction, stroke, life threatening bleeding, major access site vascular complications and renal failure. There were no significant differences in 30 day and six months-one year mortality between TAVR and TAVR with PCI group. There were also no significant differences in myocardial infarction, stroke, and life threatening bleeding and major access site vascular complications between the two groups. PCI in addition to TAVR in patients with concomitant severe aortic stenosis and CAD is safe and feasible and does not increase procedural risk. PMID- 28088438 TI - A Snapshot of Urban Adolescent Women's Contraceptive Knowledge at the Onset of a Community Long-Acting Reversible Contraceptive Promotion Initiative. AB - STUDY OBJECTIVE: To contextualize young women's knowledge and attitudes regarding contraception at the outset of an intervention promoting long-acting reversible contraceptive (LARC) use for teen pregnancy prevention. DESIGN AND SETTING: Our intervention was on the basis of diffusion of innovation theory, and at the outset we were interested in likely early adopters' existing knowledge and attitudes toward contraception. This mixed methods study consisted of focus groups within positive youth development programs in Rochester, New York; we discussed young women's knowledge and sources of information for all US Food and Drug Administration-approved contraceptive methods. PARTICIPANTS: Seven focus groups and 24 female adolescent participants aged 15-19 years. INTERVENTIONS AND MAIN OUTCOME MEASURES: Quantitative ranking of all contraceptive methods; qualitative themes from focus group discussions. RESULTS: Our findings showed a high level of knowledge about a select group of methods, which included LARC methods, and that participants received contraceptive information from peers and family. Participants had more concerns than positive impressions regarding the effectiveness, safety, practicality, and partner reception of the contraceptive methods, with the exception of the condom. Quantitatively, the condom received the highest average rating. CONCLUSION: The importance of personal anecdotes in our findings supports the use of outreach and information campaigns; providing medically accurate information and spreading positive personal anecdotes will be key to improving young women's impressions of the safety and acceptability of LARC use. This snapshot of contraceptive knowledge indicates that young women can be mature, informed consumers of sexual and reproductive health care, and through diffusion of innovation could be key players in promoting the most effective means of pregnancy prevention. PMID- 28088439 TI - Antimicrobial activity of photodynamic therapy in combination with colistin against a pan-drug resistant Acinetobacter baumannii isolated from burn patient. AB - Nosocomially-acquired multi-, extensively-, and pandrug resistant (MDR, XDR, and PDR) strains of microorganisms such as Acinetobacter baumannii remain a serious cause of infection and septic mortality in burn patients. Treatment of patients with nosocomial burn wound infections is often complicated by drug-resistant strains of A. baumannii. Today, many researchers are focusing on the investigation of novel non-antibiotic strategies such as photodynamic therapy (PDT). We report a new PDT strategy that suppresses colistin resistance in PDR A. baumannii by interfering with the expression of a pmrA/pmrB two-component system. In the current study, A. baumannii with a PDR feature isolated from a burn patient was used as a test strain. PDT was carried out using toluidine blue O (TBO) and light-emitting diode (LED) as a photosensitizer and radiation source, respectively. The antimicrobial susceptibility profiles were assessed for cells surviving PDT. The effects of sub-lethal PDT (sPDT) on the expression of the pmrA/pmrB two-component signal transduction system were evaluated by real-time quantitative reverse transcription PCR. Results of drug susceptibly testing (DST) in LED and TBO groups separately showed that the bacteria were resistant to all tested antibiotics, while the DST result of the LED+TBO group showed highly declining bacterial growth when compared with the control group. Reduction in the expression of pmrA and pmrB was observed in the treated strains after sPDT. This represents the first conclusive example of a direct role for the PDT in breaking antibiotic resistance by directly modulating two-component system activity. PMID- 28088442 TI - The in vivo fate of nanocrystals. AB - There has been significant research interest in, and development of, nanocrystals in recent years for the delivery of poorly water-soluble drugs via various routes. However, there is a common misinterpretation of nanocrystallization as an approach to modulate, and more specifically to enhance, the dissolution of drug crystals. Nevertheless, it is possible for nanocrystals to interact with biological tissues because nanocrystals can survive for a longer duration in vivo compared with solution counterparts. Therefore, understanding the in vivo fate of nanocrystals and determining its contribution to efficacy is of tremendous significance for optimizing the performance of nanocrystals. Here, we critically review the general hypotheses related to the in vivo fate of nanocrystals. PMID- 28088440 TI - Intersections of post-transcriptional gene regulatory mechanisms with intermediary metabolism. AB - Intermediary metabolism studies have typically concentrated on four major regulatory mechanisms-substrate availability, allosteric enzyme regulation, post translational enzyme modification, and regulated enzyme synthesis. Although transcriptional control has been a big focus, it is becoming increasingly evident that many post-transcriptional events are deeply embedded within the core regulatory circuits of enzyme synthesis/breakdown that maintain metabolic homeostasis. The prominent post-transcriptional mechanisms affecting intermediary metabolism include alternative pre-mRNA processing, mRNA stability and translation control, and the more recently discovered regulation by noncoding RNAs. In this review, we discuss the latest advances in our understanding of these diverse mechanisms at the cell-, tissue- and organismal-level. We also highlight the dynamics, complexity and non-linear nature of their regulatory roles in metabolic decision making, and deliberate some of the outstanding questions and challenges in this rapidly expanding field. PMID- 28088441 TI - Resveratrol limits epithelial to mesenchymal transition through modulation of KHSRP/hnRNPA1-dependent alternative splicing in mammary gland cells. AB - Resveratrol (RESV) is a natural polyphenolic compound endowed with anti inflammatory, anti-proliferative, as well as pro-apoptotic activities that make it a potential anti-tumor compound. Here we show that RESV counteracts the TGF beta-induced Epithelial to Mesenchymal Transition (EMT) phenotype in mammary gland cells and affects the alternative exon usage of pre-mRNAs that encode crucial factors in adhesion and migration -including CD44, ENAH, and FGFR2- in a panel of immortalized and transformed mammary gland cells. RESV causes a shift from the mesenchymal-specific forms of these factors to the respective epithelial forms and increases the expression of the RNA-binding proteins KHSRP and hnRNPA1. From a mechanistic point of view, we show that the combined silencing of KHSRP and hnRNPA1 prevents the RESV-dependent inclusion of the epithelial-type exons in the Cd44 pre-mRNA. Our findings support an unexpected regulatory mechanism where RESV limits EMT by controlling gene expression at post-transcriptional level. PMID- 28088443 TI - Quantifying confidence in the reporting of metabolic biotransformations. AB - How confident can we be in the assignment of metabolite structures? Are the analytical techniques used sufficient to support hypotheses about what is being formed? In this Feature, we discuss the results of an extensive survey into the analytical techniques used, and their value in the characterisation of metabolites. The survey covers the structures of over 16000 metabolites formed from 1732 query compounds, covering over 35 years of the literature and a variety of journals. The value of different characterisation techniques is considered, alongside or in the absence of synthetic standards. The changes in analytical techniques used over time are briefly considered, and a metric for the confidence that a claimed metabolite has been confirmed is proposed. PMID- 28088444 TI - Feeding recombinant E. coli with GST-mBmKTX fusion protein increases the fecundity and lifespan of Caenorhabditis elegans. AB - Scorpion venom could be a useful treatment for a variety of diseases, such as cancer, epilepsy and analgesia. BmKTX is a polypeptide extracts from scorpion venom (PESV), which have attracted much attention from researchers in recent years. mBmKTX is a mutant polypeptide according to the amino acid sequence of BmKTX. We expressed it with the vector pGEX-4T-1 in Escherichia coli, and Caenorhabditis elegans were used as the animal model and fed with the strains. In this study, the expression of pGEX-mBmKTX was analyzed by SDS-PAGE, and GST mBmKTX purified from pGEX-mBmKTX as a glutathione S-transferase (GST)-tagged fusion protein is approximately 30kDa. The secondary structure prediction shows that mBmKTX is mainly composed of approximately 13% beta-sheet and 86% loop. A food clearance assay and brood size assay indicated that the worms fed pGEX mBmKTX ate more and had greater fecundity than those fed the empty vector. A lifespan analysis demonstrated that mBmKTX could significantly prolong the lifespan of C. elegans, with an increase of 22.5% compared with the control. Behavioral assays confirmed that mBmKTX had no influence on the locomotion of C. elegans. In addition, microarray analysis and quantitative real-time PCR demonstrated that there are 320 differentially expressed genes, 182 of which are related to reproduction, growth and lifespan. In conclusion, the data suggested that mBmKTX has potential utility for increasing fecundity and animal survival. PMID- 28088445 TI - Synthesis and exploration of novel radiolabeled bombesin peptides for targeting receptor positive tumor. AB - Increasing evidence of peptide receptor overexpression in various cancer cells, warrant the development of receptor specific radiolabeled peptides for molecular imaging and therapy in nuclear medicine. Gastrin-releasing-peptide (GRP) receptor, are overexpressed in a variety of human cancer cells. The present study report the synthesis and biological evaluation of new bombesin (BBN) analogs, HYNIC-Asp-[Phe13]BBN(7-13)-NH-CH2-CH2-CH3:BA1, HYNIC-Pro-[Tyr13Met14]BBN(7 14)NH2:BA2 as prospective tumor imaging agent with compare to BBN(7-14)NH2:BS as standard. The pharmacophores were radiolabeled in high yields with 99mTc, characterized for their stability in serum and saline, cysteine/histidine and were found to be substantially stable. Internalization/externalization and receptor binding studies were assessed using MDA-MB-231 cells and showed high receptor binding-affinity and favourable internalization. Fluorescence studies revealed that BA1 changed the morphology of the cells and could localize in the nucleus more effectively than BA2/BS. Cell-viability studies displayed substantial antagonistic and nuclear-internalization effect of BA1. BA1 also exhibited antiproliferative effect on MDA-MB-231 cell by inducing apoptosis. In vivo behaviour of the radiopeptides was evaluated in GRP receptor positive tumor bearing mice. The 99mTc-BA1/99mTc-BA2 demonstrated rapid blood/urinary clearance through the renal pathway and comparatively more significant tumor uptake image and favourable tumor-to-non-target ratios provided by 99mTc-BA1. The specificity of the in vivo uptake was confirmed by co-injection with BS. Moreover, 99mTc-BA1 provided a much clearer tumor image in scintigraphic studies than others. Thus the combination of favourable in vitro and in vivo properties renders BA1 as more potential antagonist bombesin-peptide for targeting GRP-receptor positive tumor. These properties are encouraging to carry out further experiments for non invasive receptor targeting potential diagnostinc and therapeutic agent for tumors. PMID- 28088446 TI - Identification and characterization of cell-bound membrane vesicles. AB - In contrast to the released/circulating membrane vesicles (extracellular vesicles), cell-bound membrane vesicles are poorly identified and characterized. In this study, cell-bound membrane vesicles on human umbilical vein endothelial cells (HUVECs) and human hepatoma HepG-2 cells were investigated. We identified that cell-bound membrane vesicles are not co-localized with the major markers for extracellular vesicles (e.g. phosphatidylserine, CD63, CD107alpha, CD31, and DNA fragments for the three well-known types of extracellular vesicles) and for intracellular organelles with similar sizes (e.g. MitoTracker and LAMP1/LAMP3 for mitochondria and multivesicular bodies or lysosomes, respectively). The data imply that cell-bound membrane vesicles are neither the precursors of extracellular vesicles nor a false structure pushed up by an intracellular organelle but probably a novel unknown structure in the plasma membrane. Moreover, we revealed that cell-bound membrane vesicles are resistant to various detergents including but probably not limited to Triton X-100, SDS, and saponin. We further characterized that these unique vesicles are soluble in organic solvents (e.g. chloroform-methanol mixture and ethanol) which can be prevented by a lipid-stabilizing fixative (e.g. OsO4) and that they are co-localized with, but do not monopolize, the major markers (e.g. caveolin-1 and GM1) for lipid rafts (a nano-sized detergent-resistant domains in the plasma membrane). The data imply that cell-bound membrane vesicles contain the lipid component and lipid rafts. Involvement of other specific unknown components might explain the detergent resistance of cell-bound membrane vesicles. Further research will mainly depend on the establishment of an effective approach for isolation/purification of these vesicles from the plasma membrane. PMID- 28088447 TI - Differential binding of monovalent cations to KcsA: Deciphering the mechanisms of potassium channel selectivity. AB - This work explores whether the ion selectivity and permeation properties of a model potassium channel, KcsA, could be explained based on ion binding features. Non-permeant Na+ or Li+ bind with low affinity (millimolar KD's) to a single set of sites contributed by the S1 and S4 sites seen at the selectivity filter in the KcsA crystal structure. Conversely, permeant K+, Rb+, Tl+ and even Cs+ bind to two different sets of sites as their concentration increases, consistent with crystallographic evidence on the ability of permeant species to induce concentration-dependent transitions between conformational states (non-conductive and conductive) of the channel's selectivity filter. The first set of such sites, assigned also to the crystallographic S1 and S4 sites, shows similarly high affinities for all permeant species (micromolar KD's), thus, securing displacement of potentially competing non-permeant cations. The second set of sites, available only to permeant cations upon the transition to the conductive filter conformation, shows low affinity (millimolar KD's), thus, favoring cation dissociation and permeation and results from the contribution of all S1 through S4 crystallographic sites. The differences in affinities between permeant and non permeant cations and the similarities in binding behavior within each of these two groups, correlate fully with their permeabilities relative to K+, suggesting that binding is an important determinant of the channel's ion selectivity. Conversely, the complexity observed in permeation features cannot be explained just in terms of binding and likely relates to reported differences in the occupancy of the S2 and S3 sites by the permeant cations. PMID- 28088448 TI - Fast formation of low-defect-density tethered bilayers by fusion of multilamellar vesicles. AB - A facile and reproducible preparation of surface-supported lipid bilayers is essential for fundamental membrane research and biotechnological applications. We demonstrate that multilamellar vesicles fuse to molecular-anchor-grafted surfaces yielding low-defect-density, tethered bilayer membranes. Continuous bilayers are formed within 10min, while the electrically insulating bilayers with <0.1MUm-2 defect density can be accomplished within 60min. Surface plasmon resonance spectroscopy indicates that an amount of lipid material transferred from vesicles to a surface is inversely proportional to the density of an anchor, while the total amount of lipid that includes tethered and transferred lipid remains constant within 5% standard error. This attests for the formation of intact bilayers independent of the tethering agent density. Neutron reflectometry (NR) revealed the atomic level structural details of the tethered bilayer showing, among other things, that the total thickness of the hydrophobic slab of the construct was 3.2nm and that the molar fraction of cholesterol in lipid content is essentially the same as the molar fraction of cholesterol in the multilamellar liposomes. NR also indicated the formation of an overlayer with an effective thickness of 1.9nm. These overlayers may be easily removed by a single rinse of the tethered construct with 30% ethanol solution. Fast assembly and low residual defect density achievable within an hour of fusion makes our tethered bilayer methodology an attractive platform for biosensing of membrane damaging agents, such as pore forming toxins. PMID- 28088449 TI - The role of SUMOylation in ageing and senescent decline. AB - Posttranslational protein modifications are playing crucial roles in essential cellular mechanisms. SUMOylation is a reversible posttranslational modification of specific target proteins by the attachment of a small ubiquitin-like protein. Although the mechanism of conjugation of SUMO to proteins is analogous to ubiquitination, it requires its own, specific set of enzymes. The consequences of SUMOylation are widely variable, depending on the physiological state of the cell and the attached SUMO isoform. Accumulating recent findings have revealed a prominent role of SUMOylation in molecular pathways that govern senescence and ageing. Here, we review the link between SUMO attachment events and cellular processes that influence senescence and ageing, including promyelocytic leukaemia (PML) nuclear body and telomere function, autophagy, reactive oxygen species (ROS) homeostasis and growth factor signalling. PMID- 28088450 TI - Assessment of ganglioside age-related and topographic specificity in human brain by Orbitrap mass spectrometry. AB - The gangliosides (GGs) of the central nervous system (CNS) exhibit age and topographic specificity and these patterns may correlate with the functions and pathologies of the brain regions. Here, chloroform extraction, nanoelectrospray (nanoESI) negative ionization, together with Orbitrap high resolution mass spectrometry (MS) determined the topographic and age-related GG specificity in normal adult human brain. Mapping of GG mixtures extracted from 20 to 82 year old frontal and occipital lobes revealed besides a decrease in the GG number with age, a variability of sialylation degree within the brain regions. From the 111 species identified, 105 were distinguished in the FL20, 74 in OL20, 46 in FL82 and 56 in OL82. The results emphasize that within the juvenile brain, GG species exhibit a higher expression in the FL than in OL, while in the aged brain the number of GG species is higher in the OL. By applying MS/MS analysis, the generated fragment ions confirmed the incidence of GT1c (d18:1/18:0) and GT1c (d18:1/20:0) in the investigated samples. The present findings are of major value for further clinical studies carried out using Orbitrap MS in order to correlate gangliosides with CNS disorders. PMID- 28088451 TI - Efficient sortase-mediated N-terminal labeling of TEV protease cleaved recombinant proteins. AB - A major challenge in attaching fluorophores or other handles to proteins is the availability of a site-specific labeling strategy that provides stoichiometric modification without compromising protein integrity. We developed a simple approach that combines TEV protease cleavage, sortase modification and affinity purification to N-terminally label proteins. To achieve stoichiometrically labeled protein, we included a short affinity tag in the fluorophore-containing peptide for post-labeling purification of the modified protein. This strategy can be easily applied to any recombinant protein with a TEV site and we demonstrate this on Epidermal Growth Factor Receptor (EGFR) and Membrane Scaffold Protein (MSP) constructs. PMID- 28088452 TI - Treatment of rheumatoid arthritis with combination of methotrexate and Tripterygium wilfordii: A meta-analysis. AB - AIMS: Extracts of Tripterygium wilfordii Hook F (TwHF), a traditional Chinese herbal medicine, have been widely used for treating rheumatoid arthritis (RA) in combination with methotrexate (MTX) in China for several decades. However, the efficacy and safety of MTX plus TwHF treatment remain unclear. MAIN METHODS: A comprehensive search of databases in both Chinese and English was performed. Data from the selected studies were extracted and analyzed independently by two authors. KEY FINDINGS: Six randomized controlled trials were included in the final analysis with a total of 643 patients. All trials added TwHF (in the form of Tripterygium glycosides) to the MTX-based therapy. For efficacy, the addition of TwHF increased 50% responder rates (RR) (RR 1.337, 95% confidence interval [CI]: 1.188-1.505, P<0.001), and it reduced swollen and tender joint counts, shortened the duration of morning stiffness, decreased the erythrocyte sedimentation rate, and decreased the level of C-reactive protein and rheumatoid factor. For safety, the addition of TwHF did not increase the rate of adverse events (RR 0.824, 95% CI: 0.635-1.068, P=0.143). SIGNIFICANCE: MTX plus TwHF therapy may be a more effective and similar safe strategy for treating RA compared to MTX monotherapy. Further large clinical trials to investigate the TwHF add-on therapy are warranted. PMID- 28088453 TI - Improving the translation of novel biomarkers to clinical practice: The story of cystatin C implementation in Canada: A professional practice column. PMID- 28088454 TI - Alpha-l-iduronidase and arylsulfatase B in dried blood spots on filter paper: Biochemical parameters and time stability. AB - BACKGROUND: The goal of this study was to assess the biochemical parameters of the enzymes alpha-l-iduronidase (IDUA) and arylsulfatase B (ASB), which are deficient in mucopolysaccharidosis (MPS) I and VI, respectively, in dried blood spot (DBS) samples impregnated on filter paper. METHODS AND RESULTS: The optimal pH, Km, and Vmax of IDUA and ASB in DBS are hereby presented. After these analyses, the reference values for the activities of these enzymes in DBS with cutoff of 3.65nmol/h/mL for IDUA and 6.80nmol/h/mL for ASB were established. The research also showed that the stability (21days) of the IDUA activity is lower than ASB, which maintained its enzymatic activity stable up until 60days of analysis, after impregnating the filter paper with blood. CONCLUSION: Currently, DBS ensures important advantages in handling storage and transportation of samples with respect to neonatal screening programs. This study contributes to characterizing and differentiating the biochemistry of deficient enzymes in MPSs I and VI of DBS samples. PMID- 28088455 TI - Statistical Considerations Concerning Dissimilar Regulatory Requirements for Dissolution Similarity Assessment. The Example of Immediate-Release Dosage Forms. AB - When performing in vitro dissolution testing, especially in the area of biowaivers, it is necessary to follow regulatory guidelines to minimize the risk of an unsafe or ineffective product being approved. The present study examines model-independent and model-dependent methods of comparing dissolution profiles based on various compared and contrasted international guidelines. Dissolution profiles for immediate release solid oral dosage forms were generated. The test material comprised tablets containing several substances, with at least 85% of the labeled amount dissolved within 15 min, 20-30 min, or 45 min. Dissolution profile similarity can vary with regard to the following criteria: time point selection (including the last time point), coefficient of variation, and statistical method selection. Variation between regulatory guidance and statistical methods can raise methodological questions and result potentially in a different outcome when reporting dissolution profile testing. The harmonization of existing guidelines would address existing problems concerning the interpretation of regulatory recommendations and research findings. PMID- 28088456 TI - Development of a Predictive Model for the Long-Term Stability Assessment of Drug In-Adhesive Transdermal Films Using Polar Pressure-Sensitive Adhesives as Carrier/Matrix. AB - Drug crystallization in transdermal drug delivery systems is a critical quality defect. The impact of drug load and hydration on the physical stability of polar (acrylic) drug-in-adhesive (DIA) films was investigated with the objective to identify predictive formulation parameters with respect to drug solubility and long-term stability. Medicated acrylic films were prepared over a range of drug concentrations below and above saturation solubility and were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, polarized microscopy, and dynamic vapor sorption (DVS) analysis. Physical stability of medicated films was monitored over 4 months under different storage conditions and was dependent on solubility parameters, Gibbs free energy for drug phase transition from the amorphous to the crystalline state, and relative humidity. DVS data, for assessing H-bonding capacity experimentally, were essential to predict physical stability at different humidities and were used together with Gibbs free energy change and the Hoffman equation to develop a new predictive thermodynamic model to estimate drug solubility and stability in DIA films taking into account relative humidity. PMID- 28088457 TI - Preformulation Characterization, Stabilization, and Formulation Design for the Acrylodan-Labeled Glucose-Binding Protein SM4-AC. AB - This study describes the physicochemical characterization, stabilization, and formulation design of SM4-AC, an acrylodan-labeled glucose/galactose-binding protein for use in a continuous glucose monitoring device. The physical stability profile of SM4-AC as a function of pH and temperature was monitored using a combination of biophysical techniques and the resulting physical stability profile was visualized using an empirical phase diagram. Forced degradation chemical stability studies (Asn deamidation, Met oxidation) of SM4-AC were performed using a combination of capillary isoelectric focusing, peptide mapping, and reversed-phase HPLC. Differential scanning fluorimetry was then employed to screen various pharmaceutical excipients for their ability to physically stabilize SM4-AC. An optimized formulation of 20% sucrose and 2.5 mM calcium chloride in 10 mM MES buffer, 150 mM NaCl at pH 6.0 increased the conformational stability of SM4-AC by 15 degrees C. Accelerated and real-time stability studies were setup to compare the SM4-AC protein's physicochemical stability and glucose binding activity in 2 formulations for up to 12 months. SM4-AC in an optimized formulation (vs the original formulation) showed improved physical stability, and similar chemical stability and glucose binding activity profiles during storage up to 52 weeks at various temperatures. PMID- 28088458 TI - Non-thermal atmospheric pressure plasma functionalized dental implant for enhancement of bacterial resistance and osseointegration. AB - OBJECTIVE: Even though roughened titanium (Ti) and Ti alloys have been clinically used as dental implant, they encourage bacterial adhesion, leading to failure of the initial stability. Here, the non-thermal atmospheric pressure plasma jet (NTAPPJ) functionalized Ti and Ti alloy were investigated to promote cellular activities but inhibit the initial attachment of the adherent pioneer bacterium, Streptococcus sanguinis, without topographical changes. METHODS: After the produced radicals from NTAPPJ were characterized, bacterial adhesion to specimens was assessed by PrestoBlue assay and live-dead staining with or without the NTAPPJ functionalizing. After the surface was characterized using optical profilometry, X-ray photoelectron spectroscopy and contact angle analysis, the ions released from the specimens were investigated. In vitro initial cell attachment (4h or 24h) with adhesion images and alkaline phosphatase activity (ALP, 14 days) measurements were performed using rat bone marrow-derived mesenchymal stem cells. RESULTS: The initial bacterial adhesion to the Ti and Ti alloy was significantly inhibited after NTAPPJ functionalizing (p<0.05) compared to those without NTAPPJ functionalizing. The bacterial adhesion-resistance effect was induced by carbon cleaning, which was dependent on the working gas used on the Ti specimens (nitrogen>ammonia and air, p<0.05). The initial cell adhesion with well-developed vinculin localization and consequent ALP activity at 14days to the NTAPPJ-functionalized specimens were superior to the non-treated specimens. SIGNIFICANCE: For the promising success of dental implants, NTAPPJ functionalizing is suggested as a novel surface modification technique; this technique can help ensure the success of integration between the dental implants and bone tissues with less concern of inflammation. PMID- 28088459 TI - Strain development in bulk-filled cavities of different depths characterized using a non-destructive acoustic emission approach. AB - OBJECTIVES: (1) To evaluate the effect of cavity depth and composite type on the interfacial debonding in bulk-filled cavities. (2) To correlate the theoretical shrinkage stress and the level of interfacial debonding determined by acoustic emission (AE). METHODS: 80 sound molars were divided in two groups to receive a Class-I cavity (3.5*3.5mm) with 2.5- or 4.0-mm depth. The cavities were restored with either a conventional paste-like (Filtek Z100, 3M ESPE), a conventional flowable (G-aenial Universal Flo, GC), a bulk-fill paste-like (Tetric EvoCeram Bulk Fill, Ivoclar Vivadent) or a bulk-fill flowable (SDR, Dentsply) composite (n=10). AE signals were recorded from the start of curing for 20min. The cumulative number of AE events was correlated with the theoretical maximum shrinkage stress induced by each composite. Two samples from each group were scanned using micro-computed tomography (MUCT) and qualitatively evaluated. RESULTS: Both composite type and cavity depth had a significant influence on the number of AE. The conventional paste-like composite generated significantly more AE than the other composites. The AE number increased sigmoidally in function of time, with a more rapid increase after a few seconds for the conventional composites than for the bulk-fill composites. A strong linear correlation was found between the predicted shrinkage stress values and the total number of AE events for both cavities depth. Representative MUCT images showed larger de bonding areas for 4.0-mm cavities and for conventional composites. SIGNIFICANCE: Premature interfacial or cohesive cracks can already develop during placement/curing of the composite. This might compromise the restoration integrity and in turn affect its survival in the long term. The amount AE events increased linearly with the theoretical maximum shrinkage stress of the composites. PMID- 28088460 TI - Ultrasound-Mediated Delivery of RNA to Colonic Mucosa of Live Mice. AB - BACKGROUND & AIMS: It is a challenge to deliver nucleic acids to gastrointestinal (GI) tissues due to their size and need for intracellular delivery. They are also extremely susceptible to degradation by nucleases, which are ubiquitous in the GI tract. We investigated whether ultrasound, which can permeabilize tissue through a phenomenon known as transient cavitation, can be used to deliver RNA to the colonic mucosa of living mice. METHODS: We investigated delivery of fluorescently labeled permeants to colon tissues of Yorkshire pigs ex vivo and mice in vivo. Colon tissues were collected and fluorescence was measured by confocal microscopy. We then evaluated whether ultrasound is effective in delivering small interfering (si)RNA to C57BL/6 mice with dextran sodium sulfate-induced colitis. Some mice were given siRNA against tumor necrosis factor (Tnf) mRNA for 6 days; colon tissues were collected and analyzed histologically and TNF protein levels measured by enzyme-linked immunosorbent assay. Feces were collected and assessed for consistency and occult bleeding. We delivered mRNA encoding firefly luciferase to colons of healthy C57BL/6 mice. RESULTS: Exposure of ex vivo pig colon tissues to 20 kHz ultrasound for 1 minute increased the level of delivery of 3 kDa dextran 7-fold compared with passive diffusion (P = .037); 40 kHz ultrasound application for 0.5 seconds increased the delivery 3.3-fold in living mice (P = .041). Confocal microscopy analyses of colon tissues from pigs revealed regions of punctuated fluorescent dextran signal, indicating intracellular delivery of macromolecules. In mice with colitis, ultrasound delivery of unencapsulated siRNA against Tnf mRNA reduced protein levels of TNF in colon tissues, compared with mice with colitis given siRNA against Tnf mRNA without ultrasound (P <= .014), and reduced features of inflammation (P <= 4.1 * 10-5). Separately, colons of mice administered an mRNA encoding firefly luciferase with ultrasound and the D-luciferin substrate had levels of bioluminescence 11-fold greater than colons of mice given the mRNA alone (P = .0025). Ultrasound exposures of 40 kHz ultrasound for 0.5 seconds were well tolerated, even in mice with acute colitis. CONCLUSIONS: Ultrasound can be used to deliver mRNAs and siRNAs to the colonic mucosa of mice and knock down expression of target mRNAs. PMID- 28088461 TI - Changes in the Prevalence of Hepatitis C Virus Infection, Nonalcoholic Steatohepatitis, and Alcoholic Liver Disease Among Patients With Cirrhosis or Liver Failure on the Waitlist for Liver Transplantation. AB - BACKGROUND & AIMS: Concurrent to development of more effective drugs for treatment of hepatitis C virus (HCV) infection, there has been an increase in the incidence of nonalcoholic fatty liver disease. Data indicate that liver transplantation prolongs survival times of patient with acute hepatitis associated with alcoholic liver disease (ALD). We compared data on disease prevalence in the population with data from liver transplantation waitlists to evaluate changes in the burden of liver disease in the United States. METHODS: We collected data on the prevalence of HCV from the 2010 and 2013-2014 cycles of the National Health and Nutrition Examination Survey. We also collected data from the HealthCore Integrated Research Database on patients with cirrhosis and chronic liver failure (CLF) from 2006 through 2014, and data on patients who received transplants from the United Network for Organ Sharing from 2003 through 2015. We determined percentages of new waitlist members and transplant recipients with HCV infection, stratified by indication for transplantation, modeling each calendar year as a continuous variable using the Spearman rank correlation, nonparametric test of trends, and linear regression models. RESULTS: In an analysis of data from the National Health and Nutrition Examination Survey (2013-2014), we found that the proportion of patients with a positive HCV antibody who had a positive HCV RNA was 0.5 (95% confidence interval, 0.42-0.55); this value was significantly lower than in 2010 (0.64; 95% confidence interval, 0.59-0.73) (P = .03). Data from the HealthCore database revealed significant changes (P < .05 for all) over time in percentages of patients with compensated cirrhosis (decreases in percentages of patients with cirrhosis from HCV or ALD, but increase in percentages of patients with cirrhosis from nonalcoholic steatohepatitis [NASH]), CLF (decreases in percentages of patients with CLF from HCV or ALD, with an almost 3-fold increase in percentage of patients with CLF from NASH), and hepatocellular carcinoma (HCC) (decreases in percentages of patients with HCC from HCV or ALD and a small increase in HCC among persons with NASH). Data from the United Network for Organ Sharing revealed that among patients new to the liver transplant waitlist, or undergoing liver transplantation, for CLF, there was a significant decrease in the percentage with HCV infection and increases in percentages of patients with nonalcoholic fatty liver disease or ALD. Among patients new to the liver transplant waitlist or undergoing liver transplantation for HCC, proportions of those with HCV infection, nonalcoholic fatty liver disease, or ALD did not change between 2003 and 2015. CONCLUSIONS: In an analysis of 3 different databases (National Health and Nutrition Examination Survey, HealthCore, and United Network for Organ Sharing), we found the proportion of patients on the liver transplant waitlist or undergoing liver transplantation for chronic HCV infection to be decreasing and fewer patients to have cirrhosis or CLF. However, the percentages of patients on the waitlist or receiving liver transplants for NASH or ALD are increasing, despite different relative burdens of disease among the entire population of patients with cirrhosis. PMID- 28088462 TI - Activation of the Hypoxia Inducible Factor 1alpha Subunit Pathway in Steatotic Liver Contributes to Formation of Cholesterol Gallstones. AB - BACKGROUND & AIMS: Hypoxia-inducible factor 1alpha subunit (HIF1A) is a transcription factor that controls the cellular response to hypoxia and is activated in hepatocytes of patients with nonalcoholic fatty liver disease (NAFLD). NAFLD increases the risk for cholesterol gallstone disease by unclear mechanisms. We studied the relationship between HIF1A and gallstone formation associated with liver steatosis. METHODS: We performed studies with mice with inducible disruption of Hif1a in hepatocytes via a Cre adenoviral vector (inducible hepatocyte-selective HIF1A knockout [iH-HIFKO] mice), and mice without disruption of Hif1a (control mice). Mice were fed a diet rich in cholesterol and cholate for 1 or 2 weeks; gallbladders were collected and the number of gallstones was determined. Livers and biliary tissues were analyzed by histology, quantitative reverse-transcription polymerase chain reaction, immunohistochemistry, and immunoblots. We measured concentrations of bile acid, cholesterol, and phospholipid in bile and rates of bile flow. Primary hepatocytes and cholangiocytes were isolated and analyzed. HIF1A was knocked down in Hepa1-6 cells with small interfering RNAs. Liver biopsy samples from patients with NAFLD, with or without gallstones, were analyzed by quantitative reverse-transcription polymerase chain reaction. RESULTS: Control mice fed a diet rich in cholesterol and cholate developed liver steatosis with hypoxia; levels of HIF1A protein were increased in hepatocytes around central veins and 90% of mice developed cholesterol gallstones. Only 20% of the iH-HIFKO mice developed cholesterol gallstones. In iH-HIFKO mice, the biliary lipid concentration was reduced by 36%, compared with control mice, and bile flow was increased by 35%. We observed increased water secretion from hepatocytes into bile canaliculi to mediate these effects, resulting in suppression of cholelithogenesis. Hepatic expression of aquaporin 8 (AQP8) protein was 1.5-fold higher in iH-HIFKO mice than in control mice. Under hypoxic conditions, cultured hepatocytes increased expression of Hif1a, Hmox1, and Vegfa messenger RNAs (mRNAs), and down-regulated expression of AQP8 mRNA and protein; AQP8 down-regulation was not observed in cells with knockdown of HIF1A. iH-HIFKO mice had reduced inflammation and mucin deposition in the gallbladder compared with control mice. Liver tissues from patients with NAFLD with gallstones had increased levels of HIF1A, HMOX1, and VEGFA mRNAs, compared with livers from patients with NAFLD without gallstones. CONCLUSIONS: In steatotic livers of mice, hypoxia up-regulates expression of HIF1A, which reduces expression of AQP8 and concentrates biliary lipids via suppression of water secretion from hepatocytes. This promotes cholesterol gallstone formation. Livers from patients with NAFLD and gallstones express higher levels of HIF1A than livers from patients with NAFLD without gallstones. PMID- 28088463 TI - Stress-induced EGF receptor signaling through STAT3 and tumor progression in triple-negative breast cancer. AB - Elevated STAT3 activity is a hallmark of many epithelial carcinomas particularly in breast cancers where it is known to contribute to tumor progression through a variety of context-dependent biological responses. However, its role downstream of stress-exposed EGF receptors (EGFR) that are transactivated in endosomes independent of exogenous ligand has not been studied. This review discusses how STAT3 signaling induced by therapeutic stress in EGFR-driven triple-negative breast cancers (TNBC) might override normal epithelial homeostatic mechanisms and provide a survival advantage for tumor cells before they leave the primary tumor and spread to distant sites. Despite continued improvements in breast cancer treatment strategies, TNBC is still associated with poor prognosis and high risk of distant recurrence and death. Understanding EGFR-STAT3 signaling mechanisms regulating the earliest steps of tumor progression is a key to discovery of new targeted therapies against TNBC. PMID- 28088464 TI - Microparticles: Inflammatory and haemostatic biomarkers in Polycystic Ovary Syndrome. AB - Polycystic Ovary Syndrome (PCOS) is associated with a chronic low-grade inflammation and predisposition to hemostatic and atherosclerotic complications. This case-control study evaluated the microparticles (MPs) profile in patients with the PCOS and related these MPs to clinical and biochemical parameters. MPs derived from platelets (PMPs), leuckocytes (LMPs) and endothelial cells (EMPs) were evaluated, as well as MPs expressing tissue factor (TFMPs), by flow cytometry, comparing women with PCOS (n = 50) and a healthy control group (n = 50). PCOS women presented increased total MPs, PMPs, LMPs and EMPs levels when compared to control group (all p < 0.05). TFMPs was similar between the groups (p = 0.379). In conclusion, these MPs populations could be useful biomarkers for association with thrombosis and cardiovascular disease in PCOS women. PMID- 28088465 TI - Neuronal effects of thyroid hormone metabolites. AB - Thyroid hormones and their metabolites are active regulators of gene expression, mitochondrial function and various other physiological actions in different organs and tissues. These actions are mediated by a spatio-temporal regulation of thyroid hormones and metabolites within a target cell. This spatio-temporal resolution as well as classical and non-classical actions of thyroid hormones and metabolites is accomplished and regulated on multiple levels as uptake, local activation and signaling of thyroid hormones. In this review, we will give an overview of the systems involved in regulating the presence and activity of thyroid hormones and their metabolites within the brain, specifically in neurons. While a wealth of data on thyroxin (T4) and 3,5,3'-triiodothyronine (T3) in the brain has been generated, research into the presence of action of other thyroid hormone metabolites is still sparse and requires further investigations. PMID- 28088466 TI - Teneurin-2 (TENM2) deficiency induces UCP1 expression in differentiating human fat cells. AB - Under certain conditions UCP1 expressing adipocytes arise in white adipose tissue depots of both mice and humans. It is still not fully understood whether these cells differentiate de novo from specific progenitor cells or if they transdifferentiate from mature white adipocytes. Performing expression pattern analysis comparing adipocyte progenitor cells from deep and subcutaneous neck adipose tissue, we recently identified teneurin-2 (TENM2) enriched in white adipocyte progenitor cells. Here we tested whether TENM2 deficiency in adipocyte progenitor cells would lead to a brown adipocyte phenotype. By targeting TENM2 in SGBS preadipocytes using siRNA, we demonstrate that TENM2 knockdown induces both UCP1 mRNA and protein expression upon adipogenic differentiation without affecting mitochondrial mass. Furthermore, TENM2 knockdown in human SGBS adipocytes resulted in increased basal and leak mitochondrial respiration. In line with our previous observation these data suggest that TENM2 deficiency in human adipocyte precursors leads to induction of brown adipocyte marker genes upon adipogenic differentiation. PMID- 28088467 TI - STAT3 signaling mediates tumour resistance to EGFR targeted therapeutics. AB - Several EGFR inhibitors are currently undergoing clinical assessment or are approved for the clinical management of patients with varying tumour types. However, treatment often results in a lack of response in many patients. The majority of patients that initially respond eventually present with tumours that display acquired resistance to the original therapy. A large number of receptor tyrosine and intracellular kinases have been implicated in driving signaling that mediates this tumour resistance to anti-EGFR targeted therapy, and in a few cases these discoveries have led to overall changes in prospective tumour screening and clinical practice (K-RAS in mCRC and EGFR T790M in NSCLC). In this mini-review, we specifically focus on the role of the STAT3 signaling axis in providing both intrinsic and acquired resistance to inhibitors of the EGFR. We also focus on STAT3 pathway targeting in an attempt to overcome resistance to anti-EGFR therapeutics. PMID- 28088468 TI - Hypothalamic effects of thyroid hormone. AB - Thyroid hormone (TH) is a key driver of metabolism in mammals. Plasma concentrations of TH are kept within a narrow range by negative feedback regulation in the hypothalamus-pituitary-thyroid (HPT) axis. Plasma TH concentrations are an important determinant of metabolic processes in liver and brown adipose tissue (BAT). In addition to endocrine effects of TH derived from the circulation, recent studies have demonstrated additional neural routes for intrahypothalamic thyroid hormone to regulate metabolism in liver and BAT via the sympathetic and parasympathetic branch of the autonomic nervous system (ANS). This review provides an overview of studies reporting metabolic effects of selective administration of T3 within hypothalamic nuclei including the paraventricular nucleus (PVN), the ventromedial nucleus (VMH), the arcuate nucleus (Arc), and the anterior hypothalamic area (AHA). This overview of the literature suggests that intrahypothalamic T3 can have profound effects on hepatic glucose production and insulin sensitivity, energy expenditure in BAT, cardiovascular function and feeding behavior. As the experiments have been performed in experimental animals exclusively, and the timing and route of T3 administration may be an important determinant of effect size, the clinical relevance of these metabolic effects in the chronic setting remains to be established. PMID- 28088469 TI - Estrogen induced expression of tissue factor pathway inhibitor-2 in MCF7 cells involves lysine-specific demethylase 1. AB - Hormone-sensitive cancers can be influenced by estrogens, a process usually mediated through the estrogen receptor (ER). Tissue factor pathway inhibitor type 2 (TFPI-2) is a Kunitz-type serine protease inhibitor involved in regulating the extracellular matrix. The present study demonstrates that the expression of TFPI 2 can be induced by estrogens. Breast cancer data from GOBO displayed increased levels of TFPI-2 and increased survival in patients with ERalpha+ tumors. Treatment of MCF7 cells (ERalpha+) with 17beta-estradiol (E2) or 17alpha-ethinyl estradiol (EE2) increased TFPI-2 mRNA and protein levels. This effect was mitigated with fulvestrant and by knocking down ERalpha, indicating that estrogen mediated TFPI-2 induction was through ERalpha. Upon knock down of DNA cytosine-5 methyltransferase 1 (DNMT1) or lysine-specific demethylase 1 (LSD1) in MCF7 cells, reduced effect of E2 on TFPI-2 mRNA levels was observed. Our data thus suggest that estrogen induced TFPI-2 expression in MCF7 cells is mediated by ERalpha and also by the action of LSD1. PMID- 28088470 TI - The effects of dietary kefir and low molecular weight sodium alginate on serum immune parameters, resistance against Streptococcus agalactiae and growth performance in Nile tilapia (Oreochromis niloticus). AB - The present study evaluates the effects of dietary kefir and low molecular weight sodium alginate (LWMSA) (singular or combined) on non-specific immune response, disease resistance and growth performance of Nile tilapia (Oreochromis niloticus). Fish with average weight of 18.60 +/- 0.04 g were supplied and randomly stocked in sixteen glass tanks (150 L) at density of 20 fish per tank. Fish were fed experimental diets as follows: 0 g kg-1 LMWSA (Control, Diet 1), 10 g kg-1 LMWSA (Diet 2), 40 g kg-1 kefir (Diet 3), and 10 g kg-1 LMWSA + 40 g kg-1 kefir (Diet 4) for 50 days. At the end of the feeding trial, serum lysozyme (SL), phagocytosis (PI), respiratory burst (RB), and alternative complement (ACH50) activities as well as growth performance were measured. Singular and combined administration of kefir and low molecular weight sodium alginate (LMWSA) significantly increased serum SL, PI, RB, and ACH50 activities compared control group (P < 0.05); the highest innate immune responses were observed in fish fed combinational diet (kefir + LMWSA) (P < 0.05). The results of experimental challenge revealed significantly higher resistance against Streptococcus agalactiae in fish fed supplemented diets and the highest post challenge survival rate was observed in synbiotic diet (P < 0.05). Similar results obtained in case of growth parameters. Feeding on supplemented diet significantly improved SGR and FCR and the highest growth parameters was observed in fish fed synbiotic diet (P < 0.05). These finding revealed that combined administration of dietary kefir and LMWSA can be considered for improving immune response, disease resistance and growth performance of Nile tilapia. PMID- 28088471 TI - Effects of Group I metabotropic glutamate receptor antagonists on sensitivity to reinforcer magnitude and delayed reinforcement in a delay-discounting task in rats: Contribution of delay presentation order. AB - Metabotropic glutamate receptor 1 (mGluR1) blockade has been shown to decrease impulsive choice, as measured in delay discounting. However, several variables are known to influence an animal's discounting, including sensitivity to delayed reinforcement and sensitivity to reinforcer magnitude. The goal of this experiment was to determine the effects of mGluR1, as well as mGluR5, antagonism on these parameters. Forty Sprague Dawley rats were trained in delay discounting, in which consistently choosing a small, immediate reward reflects impulsive choice. For half of the rats, the delay to the large reinforcer increased across blocks of trials, whereas the delay decreased across the session for half of the rats. Following training, half of the rats received injections of the mGluR1 antagonist JNJ 16259685 (JNJ; 0, 0.1, 0.3, or 1.0mg/kg; i.p), and half received injections of the mGluR5 antagonist MPEP (0, 1.0, 3.0, or 10.0mg/kg; i.p.). Administration of JNJ increased sensitivity to delayed reinforcement (i.e., promoted impulsive choice), regardless of which schedule was used. However, the order in which delays were presented modulated the effects of JNJ on sensitivity to reinforcer magnitude. Specifically, JNJ decreased sensitivity to reinforcer magnitude in rats trained on the descending schedule only. MPEP did not alter sensitivity to reinforcer magnitude or sensitivity to delayed reinforcement. These results show that mGluR1 is an important mediator of impulsive choice, and they provide further evidence that delay order presentation is an important variable that influences drug effects in delay discounting. PMID- 28088472 TI - Cholesterol and ergosterol affect the activity of Staphylococcus aureus antibiotic efflux pumps. AB - The aim of this study is to evaluate the effect of ergosterol on steroids and cholesterol efflux pumps in multidrug resistant strains of S. aureus. Were used RN4220 harboring plasmid pUL5054, which carries the gene encoding the MsrA macrolide efflux protein; and IS-58, which possesses the TetK tetracycline efflux protein; 1199B resists hydrophilic fluoroquinolones via a NorA-mediated mechanism and wild strain 1199B. The Minimal Inhibitory Concentration (MIC) was determined and the evaluation of possible inhibition of efflux pumps by reduction of MIC. Some of the detrimental effects on bacterial cells can be attributed to the detergent properties of cholesterol and ergosterol on account of their amphipathic structure. Besides the cholesterol did not affect directly the pump structure, a synergism was observed, maybe due the interaction with the cell membrane and interference in the lipid bilayer. PMID- 28088473 TI - Endothelium adhesion molecules ICAM-1, ICAM-2, VCAM-1 and VLA-4 expression in leprosy. AB - Leprosy triggers a complex relationship between the pathogen and host immune response. Endothelium plays an important role in this immune response by directly influencing cell migration to infected tissues. The objective of this work is to investigate the possible role of endothelium in M. leprae infection, correlating the characteristics of endothelial markers with the expression pattern of cytokines. Thirty-six skin biopsy samples were cut into 5-MUm thick sections and stained with hematoxylin-eosin and Ziehl-Neelsen for morphological analysis and then submitted to immunohistochemical analysis using monoclonal antibodies against ICAM-1, ICAM-2, VCAM-1, and VLA-4. Immunostaining for ICAM-1 showed a significantly larger number of stained endothelial cells in the tuberculoid leprosy (9.92 +/- 1.11 cells/mm2) when compared to lepromatous samples (5.87 +/- 1.01 cells/mm2) and ICAM-2 revealed no significant difference in the number of endothelial cells expressing this marker between the tuberculoid (13.21 +/- 1.27 cells/mm2) and lepromatous leprosy (14.3 +/- 1.02 cells/mm2). VCAM-1 immunostained showed 18.28 +/- 1.46/mm2 cells in tuberculoid leprosy and 10.67 +/ 1.25 cells/mm2 in the lepromatous leprosy. VLA-4 exhibited 22.46 +/- 1.38 cells/mm2 in the tuberculoid leprosy 16.04 +/- 1.56 cells/mm2 in the lepromatous leprosy. Samples with characteristics of the tuberculoid leprosy exhibited a larger number of cells stained with ICAM-1, VCAM-1 and VLA-4, demonstrating the importance of these molecules in the migration and selection of cells that reach the inflamed tissue. PMID- 28088474 TI - Diagnostic accuracy of fractional exhaled nitric oxide measurement in predicting cough-variant asthma and eosinophilic bronchitis in adults with chronic cough: A systematic review and meta-analysis. AB - BACKGROUND: Individual studies have suggested the utility of fractional exhaled nitric oxide (Feno) measurement in detecting cough-variant asthma (CVA) and eosinophilic bronchitis (EB) in patients with chronic cough. OBJECTIVE: We sought to obtain summary estimates of diagnostic test accuracy of Feno measurement in predicting CVA, EB, or both in adults with chronic cough. METHODS: Electronic databases were searched for studies published until January 2016, without language restriction. Cross-sectional studies that reported the diagnostic accuracy of Feno measurement for detecting CVA or EB were included. Risk of bias was assessed with Quality Assessment of Diagnostic Accuracy Studies 2. Random effects meta-analyses were performed to obtain summary estimates of the diagnostic accuracy of Feno measurement. RESULTS: A total of 15 studies involving 2187 adults with chronic cough were identified. Feno measurement had a moderate diagnostic accuracy in predicting CVA in patients with chronic cough, showing the summary area under the curve to be 0.87 (95% CI, 0.83-0.89). Specificity was higher and more consistent than sensitivity (0.85 [95% CI, 0.81-0.88] and 0.72 [95% CI, 0.61-0.81], respectively). However, in the nonasthmatic population with chronic cough, the diagnostic accuracy to predict EB was found to be relatively lower (summary area under the curve, 0.81 [95% CI, 0.77-0.84]), and specificity was inconsistent. CONCLUSIONS: The present meta-analyses indicated the diagnostic potential of Feno measurement as a rule-in test for detecting CVA in adult patients with chronic cough. However, Feno measurement may not be useful to predict EB in nonasthmatic subjects with chronic cough. These findings warrant further studies to validate the roles of Feno measurement in clinical practice of patients with chronic cough. PMID- 28088475 TI - Role of some vasoactive mediators in scorpion envenomed children: Possible relation to envenoming outcome. AB - Scorpion envenomation causes an autonomic storm resulting in changes in the vasoactive mediators' levels which lead to myocardial damage, cardiovascular disturbances, peripheral circulatory failure, pulmonary edema, multi-system-organ failure and death. The study aimed to determine the circulating levels of adrenaline, noradrenaline, angiotensin converting enzyme (ACE), Angiotensin II (Ang II), kallikrein enzyme, nitric oxide (NO), aldosterone, and electrolytes Na+, K+ and Ca+2 in scorpion envenomed children and to evaluate the potential relation between these vasoactive mediators, the severity of scorpion envenoming and the clinical outcome of envenomed children. Forty envenomed children (22 mild and 18 severe cases) along with 10 healthy control children were enrolled in the study. The circulating levels of adrenaline, noradrenaline, Ang II, ACE, kallikrein enzyme, and NO were determined by ELISA, and spectrophotometric assays on admission and 24 h later. On admission, serum aldosterone, and electrolytes; Na+, K+ and Ca+2 were determined by RIA, Flame photometer and Flame atomic absorption respectively. All envenomed children showed significant surge of adrenaline, noradrenaline, ACE, Ang II, aldosterone, NO and Na+, that concomitantly faced by significant reduction in kallikrein, K+ and Ca+2 on admission. Twenty four hours later, all envenomed children continued to show significant elevation of ACE, Ang II and NO. The severely envenomed children showed considerable reduction in circulating levels of adrenaline, noradrenaline, ACE and Ang II, while dramatic increase in kallikrein activity was reported in comparison to mildly envenomed children after 24 h of medical care. Also, NO exhibited considerable accumulation in non survivors, on admission, that was persistent for the subsequent 24 h and was accompanied by high kallikrein, low catecholamines and Ang II levels compared to survivors. Finally, the hypertensive cases showed substantial higher levels of catecholamine, ACE and Ang II, 24 h after admission. These findings indicated that, disturbances of the studied vasoactive mediators were common in scorpion envenomed children and may account for several inflammatory manifestations and clinical outcome. ACE inhibitors could be considered as possible therapeutic agent in victims with prominent increase in ACE and Ang II while kallikrein inhibitor and antioxidants may be effective in the treatment of late hypotensive ones. PMID- 28088476 TI - A chimeric protein of abrin and Abrus precatorius agglutinin that neutralizes abrin mediated lethality in mice. AB - Abrin, a type II ribosome inactivating protein from the Abrus precatorius plant, is extremely toxic. It has been shown to be 75 times more potent than its infamous sister toxin, ricin and their potential use in bio-warfare is a cause of major concern. Although several vaccine candidates are under clinical trials for ricin, none are available against abrin. The present study proposes a chimeric protein, comprising of 1-123 amino acids taken from the A chain of abrin and 124 175 amino acids from Abrus precatorius agglutinin A chain, as a vaccine candidate against abrin intoxication. The design was based on the inclusion of the immunogenic region of the full length protein and the minimal essential folding domains required for inducing neutralizing antibody response. The chimera also contains the epitope for the only two neutralizing antibodies; D6F10 and A7C4, reported against abrin till now. Active immunization with the chimera protected all the mice challenged with 45 X LD50 of abrin. Also, passive transfer of antibodies raised against the chimera rescued all mice challenged with 50 X LD50 of toxin. Hence the chimeric protein appears to be a promising vaccine candidate against abrin induced lethality. PMID- 28088477 TI - Selected scorpion toxin exposures induce cytokine release in human peripheral blood mononuclear cells. AB - A cytokine screening on human peripheral blood mononuclear cells (PBMCs) stimulated with selected scorpion toxins (ScTx's) was performed in order to evaluate their effect on human immune cells. The ScTx's chosen for this report were three typical buthid scorpion venom peptides, one with lethal effects on mammals Centruroides suffussus suffusus toxin II (CssII), another, with lethal effects on insects and crustaceans Centruroides noxius toxin 5 (Cn5), and one more without lethal effects Tityus discrepans toxin (Discrepin). A Luminex multiplex analysis was performed in order to determine the amounts chemokines and cytokines IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12-p40, IL-13, interferon alpha (IFN-alpha), interferon gamma (IFN-gamma), tumor necrosis factor alpha TNF alpha, and interferon-inducible protein-10 (IP-10) secreted from human PBMCs exposed to these toxins. Although, the ScTx Cn5 is not lethal for mammals, it was able to induce the secretion of cytokines IL-1beta, IL-6, and TNF-alpha, IL-10 and IP-10 in comparison to the lethal CssII, which was able to induce only IP-10 secretion. Discrepin also was able to induce only IP-10. Interestingly, only low amounts of interferons alpha and beta were induced in the presence of the ScTx's assayed. In a synergic experiment, the combination of Discrepin and Cn5 displayed considerable reverse effects on induction of IL-1beta, IL-6, IL-10 and TNF-alpha, but they had a slight synergic effect on IP-10 cytokine production in comparison with the single effect obtained with the Cn5 alone. Thus, the results obtained suggest that the profile of secreted cytokines promoted by ScTx Cn5 is highly related with a cytokine storm event, and also it suggests that the mammalian lethal neurotoxins are not solely responsible of the scorpion envenomation symptomatology. PMID- 28088478 TI - Comparison of the adjuvant activity of emulsions with different physicochemical properties on the antibody response towards the venom of West African carpet viper (Echis ocellatus). AB - Adjuvant emulsions are widely used to enhance the antibody response of the animals used as immunoglobulin source for producing antivenoms. Usually, the adjuvant activity of emulsions is attributed both to their ability to trigger "danger" signals from cells in which they induce death, and to form depots from which immunogens are slowly released. However, there is contradictory evidence suggesting that adjuvant activity of emulsions is independent of the dispersion type and the rate of immunogen release. In order to test how physical properties of emulsions, composed of mineral oil and water, affect their ability to enhance the antibody response towards snake venoms, we compared water-in-oil (W/O) emulsions prepared at volume ratios of 70/30, 50/50 or 30/70, a 50/50 oil-in water (O/W) emulsion, and a water-in-oil-in-water (W/O/W) multiple emulsion. Comparison included their droplet-size, viscosity, rate of immunogen release and ability to enhance the antibody response of mice immunized with the venom of the African viperid snake Echis ocellatus. It was found that all emulsions released a low amount of venom, and that the 50/50 (W/O) and the multiple emulsion (W/O/W) were those that induced the higher anti-venom antibody response. Our results suggest that the ability of emulsions to enhance the anti-venom response is not associated to their ability to form depots from which the venom is slowly released. PMID- 28088479 TI - Three-Dimensional Structure of Full-Length NtrX, an Unusual Member of the NtrC Family of Response Regulators. AB - Bacteria sense and adapt to environmental changes using two-component systems. These signaling pathways are formed by a histidine kinase that phosphorylates a response regulator (RR), which finally modulates the transcription of target genes. The bacterium Brucella abortus codes for a two-component system formed by the histidine kinase NtrY and the RR NtrX that participates in sensing low oxygen tension and generating an adaptive response. NtrX is a modular protein with REC, AAA+, and DNA-binding domains, an architecture that classifies it among the NtrC subfamily of RRs. However, it lacks the signature GAFTGA motif that is essential for activating transcription by the mechanism proposed for canonical members of this subfamily. In this article, we present the first crystal structure of full length NtrX, which is also the first structure of a full-length NtrC-like RR with all the domains solved, showing that the protein is structurally similar to other members of the subfamily. We also report that NtrX binds nucleotides and the structures of the protein bound to ATP and ADP. Despite binding ATP, NtrX does not have ATPase activity and does not form oligomers in response to phosphorylation or nucleotide binding. We also identify a nucleotide sequence recognized by NtrX that allows it to bind to a promoter region that regulates its own transcription and to establish a negative feedback mechanism to modulate its expression. Overall, this article provides a detailed description of the NtrX RR and supports that it functions by a mechanism different to classical NtrC-like RRs. PMID- 28088481 TI - SAXS Structural Studies of Dps from Deinococcus radiodurans Highlights the Conformation of the Mobile N-Terminal Extensions. AB - The radiation-resistant bacterium Deinococcus radiodurans contains two DNA binding proteins from starved cells (Dps): Dps1 (DR2263) and Dps2 (DRB0092). These are suggested to play a role in DNA interaction and manganese and iron storage. The proteins assemble as a conserved dodecameric structure with structurally uncharacterised N-terminal extensions. In the case of DrDps1, these extensions have been proposed to be involved in DNA interactions, while in DrDps2, their function has yet to be established. The reported data reveal the relative position of the N-terminal extensions to the dodecameric sphere in solution for both Dps. The low-resolution small angle X-ray scattering (SAXS) results show that the N-terminal extensions protrude from the spherical shell of both proteins. The SAXS envelope of a truncated form of DrDps1 without the N terminal extensions appears as a dodecameric sphere, contrasting strongly with the protrusions observed in the full-length models. The effect of iron incorporation into DrDps2 was investigated by static and stopped-flow SAXS measurements, revealing dynamic structural changes upon iron binding and core formation, as reflected by a quick alteration of its radius of gyration. The truncated and full-length versions of DrDps were also compared on the basis of their interaction with DNA to analyse functional roles of the N-terminal extensions. DrDps1 N-terminal protrusions appear to be directly involved with DNA, whilst those from DrDps2 are indirectly associated with DNA binding. Furthermore, detection of DrDps2 in the D. radiodurans membrane fraction suggests that the N-terminus of the protein interacts with the membrane. PMID- 28088480 TI - Sensing Membrane Curvature in Macroautophagy. AB - In response to intracellular stress events ranging from starvation to pathogen invasion, the cell activates one or more forms of macroautophagy. The key event in these related pathways is the de novo formation of a new organelle called the autophagosome, which either surrounds and sequesters random portions of the cytoplasm or selectively targets individual intracellular challenges. Thus, the autophagosome is a flexible membrane platform with dimensions that ultimately depend upon the target cargo. The intermediate membrane, termed the phagophore or isolation membrane, is a cup-like structure with a clear concave face and a highly curved rim. The phagophore is largely devoid of integral membrane proteins; thus, its shape and size are governed by peripherally associated membrane proteins and possibly by the lipid composition of the membrane itself. Growth along the phagophore rim marks the progress of both organelle expansion and ultimately organelle closure around a particular cargo. These two properties, a reliance on peripheral membrane proteins and a structurally distinct membrane architecture, suggest that the ability to target or manipulate membrane curvature might be an essential activity of proteins functioning in this pathway. In this review, we discuss the extent to which membranes are naturally curved at each of the cellular sites believed to engage in autophagosome formation, review basic mechanisms used to sense this curvature, and then summarize the existing literature concerning which autophagy proteins are capable of curvature recognition. PMID- 28088482 TI - Combined spatiotemporal ICA (stICA) for continuous and dynamic lag structure analysis of MREG data. AB - This study investigated lag structure in the resting-state fMRI by applying a novel independent component (ICA) method to magnetic resonance encephalography (MREG) data. Briefly, the spatial ICA (sICA) was used for defining the frontal and back nodes of the default mode network (DMN), and the temporal ICA (tICA), which is enabled by the high temporal resolution of MREG (TR=100ms), was used to separate both neuronal and physiological components of these two spatial map regions. Subsequently, lag structure was investigated between the frontal (DMNvmpf) and posterior (DMNpcc) DMN nodes using both conventional method with all-time points and a sliding-window approach. A rigorous noise exclusion criterion was applied for tICs to remove physiological pulsations, motion and system artefacts. All the de-noised tICs were used to calculate the null distributions both for expected lag variability over time and over subjects. Lag analysis was done for the three highest correlating denoised tICA pairs. Mean time lag of 0.6s (+/- 0.5 std) and mean absolute correlation of 0.69 (+/- 0.08) between the highest correlating tICA pairs of DMN nodes was observed throughout the whole analyzed period. In dynamic 2min window analysis, there was large variability over subjects as ranging between 1-10sec. Directionality varied between these highly correlating sources an average 28.8% of the possible number of direction changes. The null models show highly consistent correlation and lag structure between DMN nodes both in continuous and dynamic analysis. The mean time lag of a null-model over time between all denoised DMN nodes was 0.0s and, thus the probability of having either DMNpcc or DMNvmpf as a preceding component is near equal. All the lag values of highest correlating tICA pairs over subjects lie within the standard deviation range of a null-model in whole time window analysis, supporting the earlier findings that there is a consistent temporal lag structure across groups of individuals. However, in dynamic analysis, there are lag values exceeding the threshold of significance of a null-model meaning that there might be biologically meaningful variation in this measure. Taken together the variability in lag and the presence of high activity peaks during strong connectivity indicate that individual avalanches may play an important role in defining dynamic independence in resting state connectivity within networks. PMID- 28088483 TI - Physiology recording with magnetic field probes for fMRI denoising. AB - Physiological noise originating in cardiovascular and respiratory processes is a substantial confound in BOLD fMRI. When unaccounted for it reduces the temporal SNR and causes error in inferred brain activity and connectivity. Physiology correction typically relies on auxiliary measurements with peripheral devices such as ECG, pulse oximeters, and breathing belts. These require direct skin contact or at least a tight fit, impairing subject comfort and adding to the setup time. In this work, we explore a touch-free alternative for physiology recording, using magnetic detection with NMR field probes. Placed close to the chest such probes offer high sensitivity to cardiovascular and respiratory dynamics without mechanical contact. This is demonstrated by physiology regression in a typical fMRI scenario at 7T, including validation against standard devices. The study confirms essentially equivalent performance of noise models based on conventional recordings and on field probes. It is shown that the field probes may be positioned in the subject's back such that they could be readily integrated in the patient table. PMID- 28088485 TI - Semantic attributes are encoded in human electrocorticographic signals during visual object recognition. AB - Non-invasive neuroimaging studies have shown that semantic category and attribute information are encoded in neural population activity. Electrocorticography (ECoG) offers several advantages over non-invasive approaches, but the degree to which semantic attribute information is encoded in ECoG responses is not known. We recorded ECoG while patients named objects from 12 semantic categories and then trained high-dimensional encoding models to map semantic attributes to spectral-temporal features of the task-related neural responses. Using these semantic attribute encoding models, untrained objects were decoded with accuracies comparable to whole-brain functional Magnetic Resonance Imaging (fMRI), and we observed that high-gamma activity (70-110Hz) at basal occipitotemporal electrodes was associated with specific semantic dimensions (manmade-animate, canonically large-small, and places-tools). Individual patient results were in close agreement with reports from other imaging modalities on the time course and functional organization of semantic processing along the ventral visual pathway during object recognition. The semantic attribute encoding model approach is critical for decoding objects absent from a training set, as well as for studying complex semantic encodings without artificially restricting stimuli to a small number of semantic categories. PMID- 28088484 TI - Optimal trajectories of brain state transitions. AB - The complexity of neural dynamics stems in part from the complexity of the underlying anatomy. Yet how white matter structure constrains how the brain transitions from one cognitive state to another remains unknown. Here we address this question by drawing on recent advances in network control theory to model the underlying mechanisms of brain state transitions as elicited by the collective control of region sets. We find that previously identified attention and executive control systems are poised to affect a broad array of state transitions that cannot easily be classified by traditional engineering-based notions of control. This theoretical versatility comes with a vulnerability to injury. In patients with mild traumatic brain injury, we observe a loss of specificity in putative control processes, suggesting greater susceptibility to neurophysiological noise. These results offer fundamental insights into the mechanisms driving brain state transitions in healthy cognition and their alteration following injury. PMID- 28088486 TI - Pharmacological targeting of adenosine receptor signaling. AB - Adenosine receptor signaling plays important roles in normal physiology, but is also known to modulate the development or progression of several different diseases. The design of new, efficient, and safe pharmacological approaches to target the adenosine system may have considerable therapeutic potential, but is also associated with many challenges. This review summarizes the main challenges of adenosine receptor targeted treatment including tolerance, disease stage, cell type-specific effects, caffeine intake, adenosine level assessment and receptor distribution in vivo. Moreover, we discuss several potential ways to overcome these obstacles (i.e., the use of partial agonists, indirect receptor targeting, allosteric enhancers, prodrugs, non-receptor-mediated effects, neoreceptors, conditional knockouts). It is important to address these concerns during development of new and successful therapeutic approaches targeting the adenosine system. PMID- 28088488 TI - Average activity, but not variability, is the dominant factor in the representation of object categories in the brain. AB - To categorize the perceived objects, brain utilizes a broad set of its resources and encoding strategies. Yet, it remains elusive how the category information is encoded in the brain. While many classical studies have sought the category information in the across-trial-averaged activity of neurons/neural populations, several recent studies have observed category information also in the within trial correlated variability of activities between neural populations (i.e. dependent variability). Moreover, other studies have observed that independent variability of activity, which is the variability of the measured neural activity without any influence from correlated variability with other neurons/populations, could also be modulated for improved categorization. However, it was unknown how important each of the three factors (i.e. average activity, dependent and independent variability of activities) was in category encoding. Therefore, we designed an EEG experiment in which human subjects viewed a set of object exemplars from four categories. Using a computational model, we evaluated the contribution of each factor separately in category encoding. Results showed that the average activity played a significant role while the independent variability, although effective, contributed moderately to the category encoding. The inter channel dependent variability showed an ignorable effect on the encoding. We also investigated the role of those factors in the encoding of variations which showed similar effects. These results imply that the brain, rather than variability, seems to use the average activity to convey information on the category of the perceived objects. PMID- 28088489 TI - Does MHC Class I Chain-Related Gene A Matter? AB - In this issue of Biology of Blood and Marrow Transplantation, Askar et al. evaluate the association of MHC class I chain-related gene A (MICA) polymorphisms with the development of graft-versus host-disease (GVHD) after unrelated donor hematopoietic stem cell transplantation (HCT) [1]. Prior reports have provided conflicting results, leaving the effect of MICA donor-recipient mismatch in HCT unanswered. PMID- 28088487 TI - Adenosine receptors and caffeine in retinopathy of prematurity. AB - Retinopathy of prematurity (ROP) is a major cause of childhood blindness in the world and is caused by oxygen-induced damage to the developing retinal vasculature, resulting in hyperoxia-induced vaso-obliteration and subsequent delayed retinal vascularization and hypoxia-induced pathological neovascularization driven by vascular endothelial growth factor (VEGF) signaling pathway in retina. Current anti-VEGF therapy has shown some effective in a clinical trial, but is associated with the unintended effects on delayed eye growth and retinal vasculature development of preterm infants. Notably, cellular responses to hypoxia are characterized by robust increases in extracellular adenosine production and the markedly induced adenosine receptors, which provide a novel target for preferential control of pathological angiogenesis without affecting normal vascular development. Here, we review the experimental evidence in support of adenosine receptor-based therapeutic strategy for ROP, including the aberrant adenosine signaling in oxygen-induced retinopathy and the role of three adenosine receptor subtypes (A1R, A2AR, A2BR) in development and treatment of ROP using oxygen-induced retinopathy models. The clinical and initial animal evidence that implicate the therapeutic effect of caffeine (a non-selective adenosine receptor antagonist) in treatment of ROP are highlighted. Lastly, we discussed the translational potential as well therapeutic advantage of adenosine receptor- and caffeine-based therapy for ROR and possibly other proliferative retinopathy. PMID- 28088490 TI - Microwave-based treatments of wheat kernels do not abolish gluten epitopes implicated in celiac disease. AB - Microwave based treatment (MWT) of wet wheat kernels induced a striking reduction of gluten, up to <20 ppm as determined by R5-antibodybased ELISA, so that wheat could be labeled as gluten-free. In contrast, analysis of gluten peptides by G12 antibody-based ELISA, mass spectrometry-based proteomics and in vitro assay with T cells of celiac subjects, indicated no difference of antigenicity before and after MWT. SDS-PAGE analysis and Raman spectroscopy demonstrated that MWT simply induced conformational modifications, reducing alcohol solubility of gliadins and altering the access of R5-antibody to the gluten epitopes. Thus, MWT neither destroys gluten nor modifies chemically the toxic epitopes, contradicting the preliminary claims that MWT of wheat kernels detoxifies gluten. This study provides evidence that R5-antibody ELISA alone is not effective to determine gluten in thermally treated wheat products. Gluten epitopes in processed wheat should be monitored using strategies based on combined immunoassays with T cells from celiacs, G12-antibody ELISA after proteolysis and proper molecular characterization. PMID- 28088491 TI - Toxicogenetic study of Persea americana fruit pulp oil and its effect on genomic instability. AB - Persea americana Mill., commonly known as avocado, is a tree native to Central America that is widely used as a food source and for the treatment of diseases. This plant has various biological properties such as analgesic, anti-inflammatory and total cholesterol-lowering activity. In view of its pharmacological potential, we conducted a toxicogenetic study of the fruit pulp oil of P. americana (PAO) and investigated its influence on genotoxicity induced by methyl methanesulfonate (MMS) and doxorubicin. V79 cells and Swiss mice were used for the assays. The results showed no genotoxic effects of PAO in the in vitro or in vivo test systems. However, the highest PAO dose tested led to an increase in the levels of aspartate aminotransferase, indicating hepatic/tissue damage. This effect may be related to high concentrations of palmitic acid, the main component of PAO. Furthermore, PAO was effective in reducing the chromosome damage induced by MMS and doxorubicin. These results contribute to the safety assessment of PAO as a medicinal plant for human use. PMID- 28088493 TI - Apoptosis induced by the methanol extract of Salvia miltiorrhiza Bunge in non small cell lung cancer through PTEN-mediated inhibition of PI3K/Akt pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bunge, a well-known traditional Chinese medicinal (TCM) plant, has been used to treat cardiovascular diseases since thousands of years. Many studies reported that the active component tanshinones displayed a variety of biological activities: anti thrombous, anti-allergic, anti-inflammatory, antioxidant and anti-tumor promoting. But the mechanism of how the active components working still need to be clarified. The anti-tumor effect of compounds of tanshinone (CTN), the methanol extract of Salvia miltiorrhiza Bunge roots, was investigated. The aim of this study was to investigate the effects of CTN on the growth inhibition, apoptosis and molecular targets of human non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: CTN-induced cytotoxicity was determined by MTT assay. The cell survival was evaluated using clonogenic survival assay. The morphology of Glc-82 cells after treatment with CTN was determined by fluorescence microscopy. Cell cycle distribution was revealed by flow cytometry. The apoptotic cells were quantified with annexin V-FITC/PI staining and flow cytometry, and observed using Hoechst 33258 staining and TUNEL assays. The expression levels of proteins were analyzed using western blot. Tumor growth was assessed by subcutaneous inoculation of cells into BALB/c nude mice. RESULTS: CTN inhibited the proliferation of NSCLC in a dose-dependent manner and induced both early and late apoptosis. Treatment of Glc-82 cells with CTN (5-80MUg/ml) significantly (p<0.05) suppressed the cell proliferation in a concentration and time-dependent manner. CTN induced significant (p<0.05) and dose-dependent apoptosis of Glc-82 cells. Cell cycle assay showed that CTN induced a G2/M phase arrest, and significantly (p<0.05) increased expression of p53 and p21, actived caspase-3/9 and PARP1, which suggest the involvement of the mitochondria in the apoptotic signals. In addition, CTN decreased expression of the anti-apoptotic protein Bcl-2, Bcl-xl and increased expression of the pro-apoptotic protein Bax. Result also showed that CTN could increase expression levels of PTEN, and reduce the phosphorylated levels of Akt (protein kinase B) on Thr 308 and Ser 473 domain. In vivo assay showed that the antitumor effect of CTN was significantly augmented without increasing toxicity in nude mice bearing Glc-82 xenograft. CONCLUSION: The PTEN/Akt signaling axis is defined as a critical pathway regulated by PTEN in NSCLC. CTN, the methanol extract of Salvia miltiorrhiza Bunge, are the active compounds as shown by their ability to induce apoptosis through the mitochondrial pathway of apoptosis and PTEN-mediated inhibition of PI3K/Akt pathway. CTN could inhibit tumor growth more efficiently, which supports the ethno-medicinal use of this herb as an alternative or complementary therapy for NSCLC. PMID- 28088492 TI - Pikuni-Blackfeet traditional medicine: Neuroprotective activities of medicinal plants used to treat Parkinson's disease-related symptoms. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Parkinson's disease (PD) is a multifactorial neurodegenerative disorder affecting 5% of the population over the age of 85 years. Current treatments primarily involve dopamine replacement therapy, which leads to temporary relief of motor symptoms but fails to slow the underlying neurodegeneration. Thus, there is a need for safe PD therapies with neuroprotective activity. In this study, we analyzed contemporary herbal medicinal practices used by members of the Pikuni-Blackfeet tribe from Western Montana to treat PD-related symptoms, in an effort to identify medicinal plants that are affordable to traditional communities and accessible to larger populations. AIM OF THE STUDY: The aims of this study were to (i) identify medicinal plants used by the Pikuni-Blackfeet tribe to treat individuals with symptoms related to PD or other CNS disorders, and (ii) characterize a subset of the identified plants in terms of antioxidant and neuroprotective activities in cellular models of PD. MATERIALS AND METHODS: Interviews of healers and local people were carried out on the Blackfeet Indian reservation. Plant samples were collected, and water extracts were produced for subsequent analysis. A subset of botanical extracts was tested for the ability to induce activation of the Nrf2 mediated transcriptional response and to protect against neurotoxicity elicited by the PD-related toxins rotenone and paraquat. RESULTS: The ethnopharmacological interviews resulted in the documentation of 26 medicinal plants used to treat various ailments and diseases, including symptoms related to PD. Seven botanical extracts (out of a total of 10 extracts tested) showed activation of Nrf2 mediated transcriptional activity in primary cortical astrocytes. Extracts prepared from Allium sativum cloves, Trifolium pratense flowers, and Amelanchier arborea berries exhibited neuroprotective activity against toxicity elicited by rotenone, whereas only the extracts prepared from Allium sativum and Amelanchier arborea alleviated PQ-induced dopaminergic cell death. CONCLUSIONS: Our findings highlight the potential clinical utility of plants used for medicinal purposes over generations by the Pikuni-Blackfeet people, and they shed light on mechanisms by which the plant extracts could slow neurodegeneration in PD. PMID- 28088494 TI - The N-butyl alcohol extract from Hibiscus rosa-sinensis L. flowers enhances healing potential on rat excisional wounds. AB - ETHNO-PHARMACOLOGICAL RELEVANCE: Hibiscus rosa-sinensis L. (HRS), a folk medicine named Zhujin in China, possess anti-tumor, antioxidant, antibacterial, low density lipoprotein oxidation prevention and macrophage death prevention effects. The leaves and red flowers of HRS have been traditionally used to treat with furuncle and ulceration. AIM OF THE STUDY: To investigate the efficacy and possible mechanism of the N-butyl alcohol extract of HRS (NHRS) red flowers in wound healing by analyzing the collagen fiber deposition, angiogenic activity and macrophages action of the NHRS. MATERIALS AND METHODS: In an excisional wound healing model in rats, different concentrations of NHRS, or recombinant bovine basic fibroblast growth factor (rbFGF), were respectively applied twice daily for 9 days. Histopathology was assessed on day 9 via hematoxylin and eosin (HE) and Masson's trichrome (MT) staining, and immunohistochemistry for vascular endothelial growth factor (VEGF), transforming growth factor-beta1 (TGF-beta1) and CD68. Immunomodulation by NHRS was evaluated by a carbon clearance test in mice. RESULTS: Wound healing post-surgery was greater in the rbFGF-control, NHRS M and MHRS-H groups than in the model and 5% dimethylsulfoxide (DMSO)-control groups after the third day. By the sixth day the wound contraction of NHRS-M and MHRS-H groups was much higher than the rbFGF-control group. HE and MT staining revealed that epithelialization, fibroblast distribution, collagen deposition of NHRS-M- and NHRS-H-control groups were significantly higher than the model group. Moreover, immunohistochemistry showed more intense staining of VEGF, TGF-beta1 and CD68 in the rbFGF- and NHRS-control groups, compared to that in model and 5% DMSO-control groups. The clearance and phagocytic indices of NHRS-M- and NHRS-H control groups were significantly higher than that of the carboxyl methyl cellulose (CMC) group in mice. CONCLUSION: NHRS accelerates wound repair via enhancing the macrophages activity, accelerating angiogenesis and collagen fiber deposition response mediated by VEGF and TGF-beta1. PMID- 28088495 TI - Interaction strength between different grazers and macroalgae mediated by ocean acidification over warming gradients. AB - Since the past century, rising CO2 levels have led to global changes (ocean warming and acidification) with subsequent effects on marine ecosystems and organisms. Macroalgae-herbivore interactions have a main role in the regulation of marine community structure (top-down control). Gradients of warming prompt complex non-linear effects on organism metabolism, cascading into altered trophic interactions and community dynamics. However, not much is known on how will acidification and grazer assemblage composition shape these effects. Within this context, we aimed to assess the combined effects of warming gradients and acidification on macroalgae-herbivore interactions, using three cosmopolitan species, abundant in the Iberian Peninsula and closely associated in nature: the amphipod Melita palmata, the gastropod Gibbula umbilicalis, and the green macroalga Ulva rigida. Under two CO2 treatments (DeltaCO2 ? 450 MUatm) across a temperature gradient (13.5, 16.6, 19.9 and 22.1 degrees C), two mesocosm experiments were performed to assess grazer consumption rates and macroalgae herbivore interaction, respectively. Warming (Experiment I and II) and acidification (Experiment II) prompted negative effects in grazer's survival and species-specific differences in consumption rates. M. palmata was shown to be the stronger grazer per biomass (but not per capita), and also the most affected by climate stressors. Macroalgae-herbivore interaction strength was markedly shaped by the temperature gradient, while simultaneous acidification lowered thermal optimal threshold. In the near future, warming and acidification are likely to strengthen top-down control, but further increases in disturbances may lead to bottom-up regulated communities. Finally, our results suggest that grazer assemblage composition may modulate future macroalgae-herbivore interactions. PMID- 28088496 TI - Endogenous thrombin potential changes during the first cycle of oral contraceptive use. AB - OBJECTIVES: Venous thromboembolism (VTE) risk increases within months of combination oral contraceptive (COC) initiation. Because elevated endogenous thrombin potential (ETP) has been found in several studies to be a VTE risk factor, we evaluated the extent of ETP changes during the initial cycle of an ethinyl estradiol (EE) and levonorgestrel (LNG) COC. We also assessed the relationship between ETP changes and systemic EE and LNG concentrations. STUDY DESIGN: Participants provided multiple blood samples during a first 21-day cycle of a 30-mcg EE/150-mcg LNG COC and after a further 7 days without an active COC. Thrombin generation measured with and without addition of activated protein C (APC) yielded ETP+APC and ETP-APC and the normalized APC sensitivity ratio (nAPCsr). EE and LNG pharmacokinetic analyses were conducted over 24 h after the first COC tablet and again at steady state. RESULTS: Thrombin generation was determined in 16 of the 17 women who completed the study. Mean ETP-APC increased steadily to 21% above baseline at 24 h after the 6th COC tablet (COC624; p<.001) and to 28% above baseline at steady state (COC21; p<.001). The percentage increase in mean ETP+APC was considerably more - 54% at COC624 and 79% at steady state. Mean nAPCsr increased by 28% at COC624 and by 41% at steady state. Higher concentrations of EE or LNG were not correlated with greater increases in ETP. CONCLUSIONS: ETP increases during the first COC cycle were substantial. IMPLICATIONS: The early increases in ETP may provide biological support for the rapid increase in VTE risk during initial COC use. The lack of association between this clotting system perturbation and the systemic EE concentration is surprising and deserves further study. PMID- 28088497 TI - Offering the full range of contraceptive options: a survey of interest in vasectomy training in the US family planning community. AB - OBJECTIVE: To assess current practices regarding female and male sterilization counseling and provision, as well as determine interest in providing vasectomy among family planning specialists. METHODS: Members of the US-based network of family planning fellowship physicians (current fellows, graduates and faculty) received a Web-based survey from November 2015 through January 2016 regarding current sterilization preferences and practices, as well as interest in obtaining training in vasectomy counseling and procedure. RESULTS: Nearly 60% (n=178/302) of family planning fellowship providers responded to the survey. While 62% (111/178) of respondents reported counseling their patients about vasectomy at least most of the time and 57% (102/178) recommended vasectomy over female sterilization, few (8/178; 4 trained in family medicine and 4 trained in obstetrics and gynecology) had performed a vasectomy in the last year. Nearly 90% (158/178) of respondents were somewhat or very interested in receiving training on vasectomy counseling; 58% (103/178) desired procedural training. Desire for training was associated with being male and receiving residency training in family medicine. CONCLUSIONS: Few family planning fellowship physicians provide vasectomy, and the majority expressed being at least somewhat interested in receiving further training. IMPLICATIONS: Vasectomy is more effective, safer and less expensive than female sterilization but is less common than female sterilization. One barrier to vasectomy access is the low number of vasectomy providers. Creating a structured vasectomy training program through the family planning fellowship may help to increase the number of vasectomy providers. PMID- 28088498 TI - Vaginal misoprostol prior to intrauterine device insertion in women delivered only by elective cesarean section: a randomized double-blind clinical trial. AB - OBJECTIVE: The current study aims to evaluate if vaginal misoprostol (400 mcg) administered prior to intrauterine device (IUD) insertion increases the ease and success of insertion among women who had delivered only by elective cesarean delivery (CD). STUDY DESIGN: The current study was a randomized, double-blind, placebo-controlled trial conducted in Assiut Women's Health Hospital, Egypt, between the 1st of April 2015 and the 31st of March 2016 and included women who delivered only by elective CD. One hundred forty women were randomized into two groups; misoprostol group received two misoprostol 400-mcg tablets vaginally, and placebo group received two placebo tablets 3 h before a copper T380A IUD insertion. The primary outcome measure was the difference in the ease of insertion score using a 10-cm visual analog scale between both groups with 0=very easy insertion, and 10=terribly difficult insertion. RESULTS: The ease of insertion score was lower in the misoprostol group (2.2+/-0.5 vs. 4.2+/-0.5, p=.0001) with higher number of successful IUD insertions than the placebo group (69 [98.6%] vs. 61 [87.1%], p=.009). The mean pain score reported by the women was lower in misoprostol group (2.7+/-0.6 vs. 4.3+/-0.8) with higher level of satisfaction from the whole procedure (8.9+/-0.4 vs. 7.9+/-0.2) with p=.001 for both. CONCLUSIONS: Misoprostol 400 mcg vaginally prior to IUD insertion eases and increase the success of insertion with reduction of pain among women who had delivered only by elective CD. IMPLICATIONS: The use of vaginal misoprostol before IUD insertion in women who had never delivered vaginally before may increase the ease and success of insertion. Moreover, it may reduce the pain felt by women during the procedure. PMID- 28088499 TI - Initial uncertainty impacts statistical learning in sound sequence processing. AB - This paper features two studies confirming a lasting impact of first learning on how subsequent experience is weighted in early relevance-filtering processes. In both studies participants were exposed to sequences of sound that contained a regular pattern on two different timescales. Regular patterning in sound is readily detected by the auditory system and used to form "prediction models" that define the most likely properties of sound to be encountered in a given context. The presence and strength of these prediction models is inferred from changes in automatically elicited components of auditory evoked potentials. Both studies employed sound sequences that contained both a local and longer-term pattern. The local pattern was defined by a regular repeating pure tone occasionally interrupted by a rare deviating tone (p=0.125) that was physically different (a 30msvs. 60ms duration difference in one condition and a 1000Hz vs. 1500Hz frequency difference in the other). The longer-term pattern was defined by the rate at which the two tones alternated probabilities (i.e., the tone that was first rare became common and the tone that was first common became rare). There was no task related to the tones and participants were asked to ignore them while focussing attention on a movie with subtitles. Auditory-evoked potentials revealed long lasting modulatory influences based on whether the tone was initially encountered as rare and unpredictable or common and predictable. The results are interpreted as evidence that probability (or indeed predictability) assigns a differential information-value to the two tones that in turn affects the extent to which prediction models are updated and imposed. These effects are exposed for both common and rare occurrences of the tones. The studies contribute to a body of work that reveals that probabilistic information is not faithfully represented in these early evoked potentials and instead exposes that predictability (or conversely uncertainty) may trigger value-based learning modulations even in task-irrelevant incidental learning. PMID- 28088501 TI - A review of reproductive and developmental toxicity of silver nanoparticles in laboratory animals. AB - We summarized significant effects reported in the literature on the reproductive and developmental toxicity of silver nanoparticles (AgNPs) in laboratory animals. AgNPs showed testicular/sperm toxicity in males and ovarian and embryonic toxicity in females. Maternal injection of AgNPs delayed physical development and impaired cognitive behavior in offspring. Ag was accumulated in the testes after administration of AgNPs. AgNPs were identified in the visceral yolk sac after administration during early gestation in mice. Radiolabeled AgNPs were detected in placenta, breast milk, and pre- and postnatal offspring after injection during late gestation in rats. Ag in the ionic form, and possibly also particles, was suggested to be bioavailable. Although this review provides initial information on the potential reproductive and developmental toxicity of AgNPs, data is still very limited. Further studies using state-of-the-art methodologies and the relevant routes and doses for human exposure are required. PMID- 28088500 TI - Voice emotion perception and production in cochlear implant users. AB - Voice emotion is a fundamental component of human social interaction and social development. Unfortunately, cochlear implant users are often forced to interface with highly degraded prosodic cues as a result of device constraints in extraction, processing, and transmission. As such, individuals with cochlear implants frequently demonstrate significant difficulty in recognizing voice emotions in comparison to their normal hearing counterparts. Cochlear implant mediated perception and production of voice emotion is an important but relatively understudied area of research. However, a rich understanding of the voice emotion auditory processing offers opportunities to improve upon CI biomedical design and to develop training programs benefiting CI performance. In this review, we will address the issues, current literature, and future directions for improved voice emotion processing in cochlear implant users. PMID- 28088503 TI - Evidence for splice transcript variants of TMEM165, a gene involved in CDG. AB - BACKGROUND: Defects in TMEM165 gene cause a type-II Congenital Disorder of Glycosylation affecting Golgi glycosylation processes. TMEM165 patients exhibit psychomotor retardation, important osteoporosis, scoliosis, irregular epiphyses and thin bone cortex. TMEM165 protein is highly conserved in evolution and belongs to the family of UPF0016 membrane proteins which could be an unique group of Ca2+/H+ antiporters regulating Ca2+ and pH homeostasis and mainly localized in the Golgi apparatus. METHODS: RT-PCR from human brain tissues revealed TMEM165 splice-transcript variants. mRNA expression was analyzed by RT-Q-PCR. Expression plasmids allowed us to visualize isoform proteins and their subcellular localization. Their functions on glycosylation were achieved by looking at the gel mobility of highly glycosylated proteins in cells overexpressing isoforms. RESULTS: In this study, we highlight, as previously shown for other ion channels, the existence of TMEM165 splice-transcripts isoforms, in particular the Short Form (SF) and the Long-Form (LF) transcripts, leading to a 129 aa and 259 aa protein isoform, respectively. These proteins both localize in the endoplasmic reticulum and have different effects on glycosylation compared to the wild-type protein (324 aa). We also point out that the SF is expressed at low levels in all human cells and tissues checked, excepted in brain, and forms homodimer. The LF was only expressed in the temporal lobe of human brain. GENERAL SIGNIFICANCE: The finding of numerous splice variants could lead to a family of TMEM165 isoforms. This family of TMEM165 splice transcripts could participate in the fine regulation of TMEM165 isoforms' functions and localizations. PMID- 28088502 TI - The nucleotide changes within HBV core promoter/precore during the first 12weeks of nucleos(t)ide treatment might be associated with a better virological response. AB - OBJECTIVES: We aimed to study the dynamic changes of hepatitis B virus (HBV) core promoter/precore (CP/preC) sequences during antiviral treatment and their associations with virological responses. MATERIALS AND METHODS: The baseline and 12-week CP/preC sequences (nts 1655-2014) were obtained from 52 chronic hepatitis B patients with positive hepatitis B e antigen (HBeAg), who received a 104-week lamivudine and adefovir dipivoxil combination therapy. The mutations within the CP/preC were analyzed against genotype specific reference sequences. The nucleotide change rates in individuals during therapy were analyzed in a pairwise comparison manner. RESULTS: There was no significant difference of the mutation rate at each nucleotide site between baseline and week 12 of treatment (P>0.05). The mutation rates of A1762T/G1764A and G1896A were found to decrease from 46.2% (24/52) at baseline to 36.5% (19/52) at week 12 (P=0.426) and from 28.8% (15/52) to 21.2% (11/52) (P=0.497), respectively. The nucleotide change rates varied from 0.0% - 7.8% in individuals [0.0% in Group 1 (N=26); 0.3% - 7.8% in Group 2 (N=26)] during the first 12-week treatment. HBV DNA levels in Group 2 were significantly lower than those in Group 1 throughout therapy (P<0.01) (e.g., 1.5+/-1.3log10 IU/ml vs. 2.6+/-1.0log10 IU/ml at week 104, P=0.001). At week 104 the rates of HBV DNA undetectable and HBeAg loss in Group 2 were significantly higher than those in Group 1 (P<0.05). Along with the increased nucleotide change rates, the rate of HBV DNA undetectable at week 104 tended to increase (odds ratio=0.323, 95% confidence interval=0.138-0.758, P<0.001). CONCLUSION: Our findings suggested that the nucleotide changes within HBV CP/preC region during the first 12-week treatment might be associated with a better virological response. PMID- 28088504 TI - Novel insights into the transport mechanism of the human amino acid transporter LAT1 (SLC7A5). Probing critical residues for substrate translocation. AB - BACKGROUND: LAT1 (SLC7A5) is the transport competent unit of the heterodimer formed with the glycoprotein CD98 (SLC3A2). It catalyzes antiport of His and some neutral amino acids such as Ile, Leu, Val, Cys, Met, Gln and Phe thus being involved in amino acid metabolism. Interestingly, LAT1 is over-expressed in many human cancers that are characterized by increased demand of amino acids. Therefore LAT1 was recently acknowledged as a novel target for cancer therapy. However, knowledge on molecular mechanism of LAT1 transport is still scarce. METHODS: Combined approaches of bioinformatics, site-directed mutagenesis, chemical modification, and transport assay in proteoliposomes, have been adopted to unravel dark sides of human LAT1 structure/function relationships. RESULTS: It has been demonstrated that residues F252, S342, C335 are crucial for substrate recognition and C407 plays a minor role. C335 and C407 cannot be targeted by SH reagents. The transporter has a preferential dimeric structure and catalyzes an antiport reaction which follows a simultaneous random mechanism. CONCLUSIONS: Critical residues of the substrate binding site of LAT1 have been probed. This site is not freely accessible by molecules other than substrate. Similarly to LeuT, K+ has some regulatory properties on LAT1. GENERAL SIGNIFICANCE: The collected data represent a solid basis for deciphering molecular mechanism underlying LAT1 function. PMID- 28088505 TI - Gaps in the Public's Knowledge About Chronic Pain: Representative Sample of Hispanic Residents From 5 States. AB - : Educating the general public about chronic pain and its care is a national health priority. We evaluated knowledge, attitudes, and beliefs (KAB) of a 5 state, population-based sample of Hispanic individuals aged 35 to 75 years without chronic pain, representing more than 8.8 million persons. A Web-based survey assessed KAB using an adapted version of the Survey of Pain Attitudes Brief and self-reported knowledge about chronic pain (nothing, a little, a lot). In unweighted analyses of participants (N = 349), the mean age was 52.0 (+/-10.6) years, 54% were women, 53% preferred Spanish, and 39% did not graduate from high school. More participants reported knowing nothing about chronic pain (24%) than a lot (12%). In weighted logistic models with knowing nothing as the reference, knowing a lot was associated with greater KAB for chronic pain-related emotions, functioning, and cure (all P < .01) but poorer KAB about pain medications (P < .001). Associations were similar for those knowing a little. Men and women preferring Spanish had poorer KAB about pain medications than men preferring English (both P < .001). In view of Hispanic individuals' disparities in chronic pain care, these data underscore the need for effective public educational campaigns about chronic pain. PERSPECTIVE: In this 5-state representative sample of Hispanic individuals without chronic pain, one-quarter reported knowing nothing about chronic pain and had poorer KAB about multiple aspects of this disease. This study reinforces the need to evaluate and address gaps in the general public's knowledge about chronic pain. PMID- 28088506 TI - Linguistic Indicators of Pain Catastrophizing in Patients With Chronic Musculoskeletal Pain. AB - : The present study examined markers of pain catastrophizing in the word use of patients with chronic pain. Patients (N = 71) completed the Pain Catastrophizing Scale and wrote about their life with pain. Quantitative word count analysis examined whether the essays contained linguistic indicators of catastrophizing. Bivariate correlations showed that catastrophizing was associated with greater use of first person singular pronouns, such as "I" (r = .27, P <= .05) and pronouns referencing other people (r = .28, P <= .05). Catastrophizing was further significantly associated with greater use of sadness (r = .35, P <= .01) and anger (r = .30, P <= .05) words. No significant relationships with positive emotion and cognitive process words were evident. Controlling for patients' engagement in the writing task, gender, age, pain intensity, and neuroticism in multiple regression, the linguistic categories together uniquely explained 13.6% of the variance in catastrophizing (P <= .001). First person singular pronouns (beta = .24, P <= .05) and words relating to sadness (beta = .25, P <= .05) were significant, and pronouns referencing other people (beta = .19, P <= .10) were trending. The results suggest that pain catastrophizing is associated with a "linguistic fingerprint" that can be discerned from patients' natural word use. PERSPECTIVE: Quantitative word count analysis examined whether pain catastrophizing is reflected in patients' written essays about living with pain. Catastrophizing was associated with more first person singular pronouns, more pronouns referencing other people, and more expressions of sadness and anger. The results can help understand how catastrophizing translates into communicative behaviors. PMID- 28088507 TI - Patient-Reported Outcomes and Opioid Use in Outpatients With Chronic Pain. AB - : The Weill Cornell Medical College Pain Registry database contains patient characteristics, treatments, and outcomes for a prospective cohort of 1,159 chronic pain patients who were seen at the Weill Cornell Medical College Pain Medicine outpatient clinic from July 8, 2011 to December 10, 2014. Patients aged 45 to 64 years comprised 43% followed by age >= 65 years at 37%. Fifty-eight percent were female. Average pain intensity (Brief Pain Inventory) was reported as mild by 22.3% of patients, moderate by 34.7%, and severe by 43.0%. For each pain intensity category, patient's report of average percent pain relief and health state (EuroQOL 5 Dimensions) was inversely related to average pain intensity category, whereas measures of pain interference, number of worst pain locations, and physical and psychological distress were directly related to pain intensity category. Seventy-seven percent of patients received an opioid at 1 or more clinic encounters. Median daily opioid dose in morphine equivalents was 55 with a range from 2 to 1,145 morphine equivalents. Regression analysis revealed that being male was associated with greater likelihood of an opioid ordered and higher average dosage than being female. The registry can identify patient characteristics and treatments that provide new insights into chronic pain management. PERSPECTIVE: This article describes results of analyses of patient reported outcomes and patient-related electronic health record data collected under standard of care from a prospective cohort of chronic pain outpatients at a New York City pain management clinic. The registry provides an opportunity to learn how to improve individualized chronic pain management. PMID- 28088508 TI - Relationship Between Central Retinal Vessel Trunk Location and Visual Field Loss in Glaucoma. AB - PURPOSE: To study the relationship between horizontal central retinal vessel trunk location (CRVTL) on glaucomatous optic discs and sector-specific visual field (VF) loss. DESIGN: Retrospective cross-sectional study. METHODS: CRVTL of 421 eyes from 421 patients was manually tracked on the horizontal optic disc axis on fundus images. Focal circumpapillary retinal nerve fiber layer thickness (cpRNFLT) measurements were extracted from optical coherence tomography (OCT). The relationship between focal visual field (VF) loss and CRVTL and focal cpRNFLT was studied by linear regression models. Furthermore, we related central VF loss to CRVTL and focal cpRNFLT separately for mild (VF mean deviation [MD] >=-6 dB), moderate (-12 dB <= MD <-6 dB), and severe (MD <-12 dB) glaucoma. RESULTS: CRVTL nasalization was significantly correlated only to central VF loss (Garway-Heath scheme [central 6 locations, C6]: correlation: r = -0.16, P < .001; macular vulnerability zone [central 2 locations, C2]: r = -0.14, P = .003; central 4 locations [C4]: r = -0.17, P < .001). While focal cpRNFLT at the sectors corresponding to C2 and C6 was significantly correlated to the respective VF sectors as well (C2: r = 0.15, P = .002; C6: r = 0.10, P = .03), multivariate models combining cpRNFLT and CRVTL substantially improved structure-function models compared with cpRNFLT alone (likelihood ratio tests, C2 and C6: P < .001). The correlations between CRVTL and central VF loss of C4 were -0.11 (P = .04), 0.39 (P = .01), and -0.63 (P = .002) for mild, moderate, and severe glaucoma, respectively. CONCLUSIONS: CRVTL nasalization is significantly and exclusively correlated to central VF loss for all glaucoma severities independent of cpRNFLT, and thus might be a structural biomarker of central VF loss. PMID- 28088509 TI - Choroidal Neovascularization in Malattia Leventinese Diagnosed Using Optical Coherence Tomography Angiography. AB - PURPOSE: To compare optical coherence tomography angiography (OCT-A) with traditional multimodal imaging in patients with Malattia Leventinese. DESIGN: Retrospective case series. METHODS: Eight eyes of 4 consecutive patients with Malattia Leventinese were retrospectively studied. All patients underwent a complete ophthalmologic examination including color fundus photography, fluorescein and indocyanine green angiographies, spectral-domain optical coherence tomography, and optical coherence tomography angiography. RESULTS: The choriocapillaris segmentation of OCT-A revealed the presence of a hyperflow signal corresponding to active choroidal neovascularization in 3 eyes and inactive choroidal neovascularization in 1 eye. Traditional multimodal imaging did not show each vascular layer and any leakage in these cases. CONCLUSION: OCT A, unlike traditional multimodal imaging, helps diagnose choroidal neovascularization in patients with Malattia Leventinese suffering from metamorphopsia and reduced visual acuity. PMID- 28088510 TI - Association Between Nocturnal Blood Pressure Dips and Optic Disc Hemorrhage in Patients With Normal-Tension Glaucoma. AB - PURPOSE: To investigate the effect of nocturnal blood pressure (BP) dips on the occurrence of optic disc hemorrhage (ODH) in normal-tension glaucoma (NTG) patients and determine whether ODH is associated with greater likelihood of visual field progression (VFP). DESIGN: Prospective case-control study. METHODS: This study enrolled 698 eyes of 349 consecutive NTG patients who were >=40 years old, underwent 24-hour intraocular pressure and ambulatory BP monitoring in the habitual position, were examined for ODH every 4-6 months with optic disc photography, and had >=5 reliable visual field tests with minimum follow-up of 3 years. NTG patients were classified into 2 groups: "nonphysiologic" dippers, including nondippers and overdippers, and "physiologic" dippers. Odds ratios for the association between the "nonphysiologic" group and ODH were calculated using logistic regression models. Kaplan-Meier analyses were performed to compare outcomes with reference to the presence of ODH for VFP. RESULTS: Overall, ODH and VFP were detected in 107 (15.3%) eyes and 60 (8.6%) eyes among total 698 eyes, respectively. Overdippers showed a significantly greater frequency of ODH than nondippers or dippers. Being an overdipper was a significant and an independent risk factor for ODH occurrence during follow-up. The rates of VFP were 6%, 7%, and 24% for dippers, nondippers, and overdippers, respectively. Eyes with ODH were associated with greater likelihoods of subsequent VFP than those without. VFP occurred only in eyes with ODH. CONCLUSIONS: Being an overdipper is a significant risk factor for ODH in NTG eyes. The detection of ODH during follow up is a potent predictor of future VFP. PMID- 28088511 TI - EGFR L858M/L861Q cis Mutations Confer Selective Sensitivity to Afatinib. AB - INTRODUCTION: Tyrosine kinase inhibitors (TKIs) have been developed to treat patients with EGFR-mutant lung cancers. However, the therapeutic efficacy of TKIs in patients with uncommon EGFR mutations remains unclear. METHODS: Next generation sequencing was performed on a patient's lung adenocarcinoma tumor sample, revealing rare combined in cis (on the same allele) EGFR mutations. Stable Ba/F3 and NIH-3T3 cell lines harboring the mutations were established to investigate the effect of first-, second-, and third-generation EGFR TKIs on cell proliferation by MTS assay and EGFR phosphorylation by Western blotting. RESULTS: EGFR L858M/L861Q mutations in cis were detected in the tumor of a patient with NSCLC. The patient demonstrated primary resistance to erlotinib and was subsequently treated with afatinib, which caused tumor regression. In in vitro studies, first- and third-generation TKIs exhibited a decreased capacity to prevent EGFR phosphorylation and inhibit cell proliferation in EGFR L858M/L861Q cells compared with cells harboring the common EGFR L858R point mutation. In contrast, afatinib treatment reduced proliferation and inhibited EGFR phosphorylation in L858M/L861Q- and L858R-mutant cells at similar concentrations. CONCLUSIONS: Afatinib may be a beneficial therapeutic option for a subset of patients with lung cancer who harbor rare EGFR mutations in their tumors. Understanding how uncommon mutations affect protein structure and TKI binding will be important for identifying effective targeted therapies for these patients. PMID- 28088512 TI - ROS1 Fusions Rarely Overlap with Other Oncogenic Drivers in Non-Small Cell Lung Cancer. AB - INTRODUCTION: Chromosomal rearrangements involving the gene ROS1 define a distinct molecular subset of NSCLCs with sensitivity to ROS1 inhibitors. Recent reports have suggested a significant overlap between ROS1 fusions and other oncogenic driver alterations, including mutations in EGFR and KRAS. METHODS: We identified patients at our institution with ROS1-rearranged NSCLC who had undergone testing for genetic alterations in additional oncogenes, including EGFR, KRAS, and anaplastic lymphoma receptor tyrosine kinase gene (ALK). Clinicopathologic features and genetic testing results were reviewed. We also examined a separate database of ROS1-rearranged NSCLCs identified through the commercial FoundationOne assay (Foundation Medicine, Cambridge, MA). RESULTS: Among 62 patients with ROS1-rearranged NSCLC evaluated at our institution, none harbored concurrent ALK fusions (0%) or EGFR activating mutations (0%). KRAS mutations were detected in two cases (3.2%), one of which harbored a concurrent noncanonical KRAS I24N mutation of unknown biological significance. In a separate ROS1 fluorescence in situ hybridization-positive case, targeted sequencing failed to confirm a ROS1 fusion but instead identified a KRAS G13D mutation. No concurrent mutations in B-Raf proto-oncogene, serine/threonine kinase gene (BRAF), erb-b2 receptor tyrosine kinase 2 gene (ERBB2), phosphatidylinositol-4,5 bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA), AKT/serine threonine kinase 1 gene (AKT1), or mitogen-activated protein kinase kinase 1 gene (MAP2K1) were detected. Analysis of an independent data set of 166 ROS1-rearranged NSCLCs identified by FoundationOne demonstrated rare cases with co-occurring driver mutations in EGFR (one of 166) and KRAS (three of 166) and no cases with co occurring ROS1 and ALK rearrangements. CONCLUSIONS: ROS1 rearrangements rarely overlap with alterations in EGFR, KRAS, ALK, or other targetable oncogenes in NSCLC. PMID- 28088513 TI - An Immunogram for the Cancer-Immunity Cycle: Towards Personalized Immunotherapy of Lung Cancer. AB - INTRODUCTION: The interaction of immune cells and cancer cells shapes the immunosuppressive tumor microenvironment. For successful cancer immunotherapy, comprehensive knowledge of antitumor immunity as a dynamic spatiotemporal process is required for each individual patient. To this end, we developed an immunogram for the cancer-immunity cycle by using next-generation sequencing. METHODS: Whole exome sequencing and RNA sequencing were performed in 20 patients with NSCLC (12 with adenocarcinoma, seven with squamous cell carcinoma, and one with large cell neuroendocrine carcinoma). Mutated neoantigens and cancer germline antigens expressed in the tumor were assessed for predicted binding to patients' human leukocyte antigen molecules. The expression of genes related to cancer immunity was assessed and normalized to construct a radar chart composed of eight axes reflecting seven steps in the cancer-immunity cycle. RESULTS: Three immunogram patterns were observed in patients with lung cancer: T-cell-rich, T-cell-poor, and intermediate. The T-cell-rich pattern was characterized by gene signatures of abundant T cells, regulatory T cells, myeloid-derived suppressor cells, checkpoint molecules, and immune-inhibitory molecules in the tumor, suggesting the presence of antitumor immunity dampened by an immunosuppressive microenvironment. The T-cell-poor phenotype reflected lack of antitumor immunity, inadequate dendritic cell activation, and insufficient antigen presentation in the tumor. Immunograms for both the patients with adenocarcinoma and the patients with nonadenocarcinoma tumors included both T-cell-rich and T-cell-poor phenotypes, suggesting that histologic type does not necessarily reflect the cancer immunity status of the tumor. CONCLUSIONS: The patient-specific landscape of the tumor microenvironment can be appreciated by using immunograms as integrated biomarkers, which may thus become a valuable resource for optimal personalized immunotherapy. PMID- 28088514 TI - Assessing the feasibility, acceptability and potential effectiveness of an integrated approach to smoking cessation for new and expectant fathers: The Dads in Gear study protocol. AB - BACKGROUND: Evidence related to the effects of tobacco exposure in pregnancy and on infant and child health have focused on women's smoking cessation. Less often addressed is men's smoking, which when continued in fatherhood, reduces the chances of female partners' cessation and can negatively impact children's health as well as men's health. Dads in Gear (DIG) is an innovative program designed specifically for new fathers who want to reduce and quit smoking that includes three components: smoking cessation, fathering, and physical activity. The over arching purpose of this study is to evaluate the feasibility of the DIG program and provide estimates of program efficacy. The purpose of this article is to describe the rationale and protocol for evaluating the DIG program's feasibility, acceptability and potential effectiveness. METHODS: Using a prospective, non comparative design, the DIG program will be implemented and evaluated in six communities. The program will be offered by trained facilitators to fathers who currently smoke and want to quit. The RE-AIM framework will guide the evaluation. Open-ended questions in participant surveys, and semi-structured interviews and weekly telephone de-briefs with facilitators will provide data for a process evaluation. Estimates of effectiveness include smoking behavior, fathering and physical activity measures at baseline, end of program, and 3-month follow up. CONCLUSION: The DIG program could support positive changes with respect to smoking cessation, physical activity and overall health for men. These effects could also promote family health. The program might also provide an effective model for engaging men in other health behavior change. PMID- 28088515 TI - The membrane-tethered NAC transcription factor, AtNTL7, contributes to ER-stress resistance in Arabidopsis. AB - We screened for endoplasmic reticulum (ER) stress-resistant mutants among 25 mutants of the Arabidopsis NTL (NAC with Transmembrane motif 1-Like) family. We identified a novel mutant, SALK_044777, showing strong resistance to ER stress. RT-PCR and genomic DNA sequence analyses identified the mutant as atntl7, which harbors a T-DNA insertion in the fourth exon of AtNTL7. Two other atntl7-mutant alleles, in which T-DNA was inserted in the second exon and third intron of AtNTL7, respectively, showed ER-stress sensitive phenotypes, suggesting that SALK_044777 is a gain-of-function mutant. Arabidopsis plants overexpressing AtNTL7 showed strong ER-stress resistance. Our findings suggest that AtNTL7 fragment is cleaved from the ER membrane under ER stress and translocates into the nucleus to induce downstream ER-stress responsive genes. PMID- 28088516 TI - Structural study of the effects of mutations in proteins to identify the molecular basis of the loss of local structural fluidity leading to the onset of autoimmune diseases. AB - Protein-Protein Interactions (PPIs) are crucial in most of the biological processes and PPI dysfunctions are known to be associated with the onsets of various diseases. One of such diseases is the auto-immune disease. Auto-immune diseases are one among the less studied group of diseases with very high mortality rates. Thus, we tried to correlate the appearances of mutations with their probable biochemical basis of the molecular mechanisms leading to the onset of the disease phenotypes. We compared the effects of the Single Amino Acid Variants (SAVs) in the wild type and mutated proteins to identify any structural deformities that might lead to altered PPIs leading ultimately to disease onset. For this we used Relative Solvent Accessibility (RSA) as a spatial parameter to compare the structural perturbation in mutated and wild type proteins. We observed that the mutations were capable to increase intra-chain PPIs whereas inter-chain PPIs would remain mostly unaltered. This might lead to more intra molecular friction causing a deleterious alteration of protein's normal function. A Lyapunov exponent analysis, using the altered RSA values due to polymorphic and disease causing mutations, revealed polymorphic mutations have a positive mean value for the Lyapunov exponent while disease causing mutations have a negative mean value. Thus, local spatial stochasticity has been lost due to disease causing mutations, indicating a loss of structural fluidity. The amino acid conversion plot also showed a clear tendency of altered surface patch residue conversion propensity than polymorphic conversions. So far, this is the first report that compares the effects of different kinds of mutations (disease and non disease causing polymorphic mutations) in the onset of autoimmune diseases. PMID- 28088517 TI - Osborne-Mendel rats simultaneously develop cardiac and renal dysfunction, left atrial thrombosis, peripheral artery occlusion, and ascending aortic dissection. AB - Although chronic kidney disease (CKD) is strongly associated with onsets of cardiovascular disease (CVD), the pathogenic mechanism between these diseases has not been fully understood. To develop and validate new therapeutic strategies for this complication, appropriate experimental models that reflect the complexity of the underlying pathophysiology are needed. The Osborne-Mendel (OM) rat was identified as an atherosclerosis-prone and a premature-death rat strain among 16 inbred rat strains when fed high-cholesterol containing diet. When fed high cholesterol diet, OM rats showed simultaneous occurrence of aortic aneurysm, aortic dissection, peripheral artery occlusion, and left atrial thrombosis. OM rats had significantly lower max dP/dt and higher min dP/dt than F344 rats did, indicating impaired left ventricle contractility and relaxation. OM rats developed renal dysfunction, showing increased urinary albumin excretion. OM rats also showed mild hypertension, decreased endothelial function, and enhanced coagulation and platelet aggregation, compared with F344 rats. We now report that OM rat would be a novel spontaneous animal model which simultaneously demonstrates cardiac and renal dysfunction, and CVD events. This model could be a useful model for the pre-clinical testing of pharmacological therapies and could provide new insight into potential targets and pathways for the treatment of CKD and CVD. PMID- 28088518 TI - S100A8 protein attenuates airway hyperresponsiveness by suppressing the contraction of airway smooth muscle. AB - Airway hyperresponsiveness (AHR) is a major clinical problem in allergic asthma mainly caused by the hypercontractility of airway smooth muscles (ASM). S100A8 is an important member of the S100 calcium-binding protein family with a potential to regulate cell contractility. Here, we analyze the potential of S100A8 to regulate allergen-induced AHR and ASM contraction. Treatment with recombinant S100A8 (rS100A8) diminished airway hyperresponsiveness in OVA-sensitized rats. ASM contraction assays showed that rS100A8 reduced hypercontractility in both isolated tracheal rings and primary ASM cells treated by acetylcholine. rS100A8 markedly rescued the phosphorylation level of myosin light chain induced by acetylcholine in ASM cells. These results show that rS100A8 plays a protective role in regulating AHR in asthma by inhibiting ASM contraction. These results support S100A8 as a novel therapeutic target to control ASM contraction in asthma. PMID- 28088519 TI - Phytochemicals as multi-target inhibitors of the inflammatory pathway- A modeling and experimental study. AB - The arachidonic acid pathway consists of several enzymes and targeting them is favored for developing anti-inflammatory drugs. However, till date the current drugs are generally active against a single target, leading to undesirable side effects. Phytochemicals are known to inhibit multiple targets simultaneously and hence, an attempt is made here to investigate their suitability. A pharmacophore based study is performed with three sets of reported phytochemicals namely, dual 5-LOX/mPGES1, alkaloids and FLAP inhibitors. The analysis indicated that phenylpropanoids (including ferulic acid) and benzoic acids derivatives, and berberine mapped onto these pharmacophores with three hydrophobic centroids and an acceptor feature. 2,4,5-trimethoxy (7) and 3,4-dimethoxy cinnamic acids (8) mapped onto all the three pharmacophores. Experimental studies indicated that berberine inhibited 5-LOX (100 MUM) and PGE2 (50 MUM) production by 72.2 and 72.0% and ferulic acid by 74.3 and 54.4% respectively. This approach offers a promising theoretical combined with experimental strategy for designing novel molecules against inflammatory enzymes. PMID- 28088520 TI - Palmitic acid increases invasiveness of pancreatic cancer cells AsPC-1 through TLR4/ROS/NF-kappaB/MMP-9 signaling pathway. AB - Pancreatic cancer (PC) is an aggressive malady with proclivity for early metastasis. Overexpression of toll-like receptor 4 (TLR4) in pancreatic ductal adenocarcinoma, the most common type of pancreatic malignancy, correlates to tumor size, lymph node involvement, venous invasion and pathological stage. Lipopolysaccharides (LPS) are natural TLR4 ligands that have been shown to increase the invasive ability of PC cells. However, rapid inactivation of circulating LPS and low systemic absorption of inhaled LPS from the bronchoalveolar compartment make other agonists such as saturated fatty acids more suitable to be considered for TLR4-related cell invasiveness. Interestingly, PC risk was strongly associated to intake of saturated fat from animal food sources, in particular to consumption of saturated palmitic acid (PA). In the present study, we investigated the influence of PA on the invasive capacity of human PC cells AsPC-1. Using specific inhibitors, we found that PA stimulation of these tumor cells induced a TLR4-mediated cell invasion. Our results also indicate that the signaling events downstream of TLR4 involved generation of reactive oxygen species, activation of nuclear factor-kappa beta, and secretion and activation of matrix metalloproteinase 9 (MMP-9). Furthermore, PA stimulation decreased the levels of the micro RNA 29c (miR-29c). Of note, while inhibition of miR-29c increased MMP-9 mRNA levels, MMP-9 secretion and activation, and invasiveness, miR-29c mimic abrogated all these PA-stimulated effects. These results strongly suggest that miR-29c could be an attractive potential pharmacological agent for antitumoral therapy in PC. PMID- 28088521 TI - Signal peptidase I processed secretory signal sequences: Selection for and against specific amino acids at the second position of mature protein. AB - Signal peptides direct proteins from the cytoplasm to the periplasm. These N terminal peptides are cleaved upon entry to the periplasm by either signal peptidase I, or signal peptidase II for lipoproteins. Signal peptidase I is a serine protease that has either a serine-lysine or serine-histidine catalytic dyad present in the active site. The recognition site for signal peptide cleavage by signal peptidase I has been defined primarily by an Ala-X-Ala motif at the C terminal end of the signal peptide, one amino acid away from the cleavage site. We used a verified set of signal peptidase I cleaved proteins from E. coli to look for novel conserved features, focusing on the N-terminus of the mature protein. We observed a striking bias for the presence of acidic residues at second position of the mature protein (P2'), and a complete absence of aromatic amino acids at the same position. Whole genome analysis of the predicted set of all E. coli and B. subtilis secreted proteins confirmed the same strong bias for acidic residues at P2' of the mature protein, and against aromatic amino acids at the same position. When these studies were extended to archaeal genomes (M. voltae and S. tokodaii) and the yeast genome from S. cerevisiae, this bias was not observed. E. coli and B. subtilis primarily express a signal peptidase I contains a serine-lysine catalytic dyad, whilst those of archaeal and eukaryotic origin generally have a serine-histidine catalytic dyad. This difference may explain the differential bias for acidic residues and against aromatic residues at P2'. These observations suggest additional key residues that may favor or prevent signal sequence recognition or cleavage by signal peptidase I, and thereby facilitate more accurate in silico prediction of signal peptidase I cleavage sites. PMID- 28088522 TI - Down-regulation of GJA3 is associated with lens epithelial cell apoptosis and age related cataract. AB - Lens epithelial cell apoptosis is regarded as the common molecular basis of the initiation and subsequent progression of cataract. Recent studies have shown that Oxidative radicals derived from H2O2 causes lens epithelial cell apoptosis, While much work still needs to be done to elucidate this important mechanism of lens epithelial cell apoptosis induced by H2O2. The present study investigated the effect of human lens epithelial cell (SRA01/04) apoptosis induced by H2O2 and the possible molecular mechanism involved. Our data in this report has validated that H2O2 is an effective inducer of lens epithelial cells apoptosis, with the concentrations of H2O2 (100 MUM). Moreover, we revealed that the down regulation of the GJA3 gene was associated with H2O2-induced lens epithelial cells apoptosis. Over-expression of GJA3 gene restrained the lens epithelial cells apoptosis induced by H2O2. Furthermore, GJA3 V44 M mutation partly inhibited the capacity of GJA3 to suppress apoptosis induced by H2O2 in SRA01/04 cells, eliciting the critical role of GJA3 in H2O2-induced lens epithelial cells apoptosis. The in vivo results indicated that down-regulation of GJA3 in lens epithelial cells was associated with age-related cataract genesis. Data from this study established the association of GJA3 down regulation with lens epithelial cells apoptosis and age-related cataract genesis. PMID- 28088523 TI - The selective cysteinyl leukotriene receptor 1 (CysLT1R) antagonist montelukast regulates extracellular matrix remodeling. AB - Scar formation after filtration surgery of glaucoma is mainly caused by excessive synthesis of new extracellular matrix (ECM) and contraction of subconjunctival tissue mediated by human Tenon fibroblasts (HTFs) and the transforming growth factor (TGF-beta1). Montelukast, a potent and specific cysteinyl leukotriene receptor 1 (cysLT1R) antagonist, is a licensed drug clinically used for the treatment of bronchial asthma. In this study, we investigated the effects of montelukast on the contractility of HTFs cultured in a three-dimensional collagen gel. We found that cysLT1R was expressed in HTFs. Interestingly, the expression of cysLT1R was increased in response to TGF-beta1 in a dose dependent manner, suggesting its potential role in TGF-beta1 induced fibrosis. Importantly, we found that montelukast inhibited TGF-beta1-induced collagen gel contraction mediated by HTFs in a concentration- and time-dependent manner. In addition, TGF beta1-induced expression of MMP-1 and MMP-3, generation of fibronectin and type I collagen production, focal adhesion kinase (FAK) and paxillin phosphorylation in HTFs were also ameliorated by montelukast in a dose dependent manner. These results suggested that montelukast might provide therapeutic possibilities for inhibition of scar formation after such surgery. PMID- 28088524 TI - Possible roles of the transcription factor Nrf1 (NFE2L1) in neural homeostasis by regulating the gene expression of deubiquitinating enzymes. AB - The transcription factor Nrf1 (NFE2L1) maintains protein homeostasis (proteostasis) by regulating the gene expression of proteasome subunits in response to proteasome inhibition. The deletion of the Nrf1 gene in neural stem/progenitor cells causes severe neurodegeneration due to the accumulation of ubiquitinated proteins in Purkinje cells and motor neurons (Nrf1 NKO mice). However, the molecular mechanisms governing this neurodegenerative process remain unclear. We demonstrate herein that the loss of Nrf1 leads to the reduced gene expression of the deubiquitinating enzymes (DUBs) but not proteasome subunits in Nrf1 NKO mice between P7 and P18. First, we show that K48-linked polyubiquitinated proteins accumulate in Nrf1-deficient Purkinje cells and cerebral cortex neurons. Nevertheless, loss of Nrf1 does not alter the expression and proteolytic activity of proteasome. A significantly reduced expression of deubiquitinating enzymes was also demonstrated in Nrf1-deficient cerebellar tissue using microarray analysis. The genome database further reveals species conserved ARE, a Nrf1 recognition element, in the regulatory region of certain DUB genes. Furthermore, we show that Nrf1 can activate Usp9x gene expression related to neurodegeneration. Altogether these findings suggest that neurodegeneration in Nrf1 NKO mice may stem from the dysfunction of the ubiquitin mediated regulation of neuronal proteins. PMID- 28088525 TI - Miles Away Milestones: A Framework for Assessment of Pediatric Residents During Global Health Rotations. PMID- 28088526 TI - Subcutaneous immunization with Streptococcus pneumoniae GAPDH confers effective protection in mice via TLR2 and TLR4. AB - The surface localized Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of Streptococcus pneumoniae is best known as housekeeping protein. Currently, GAPDH has been recognized as moonlighting protein and virulent factor. Therefore, we investigate whether GAPDH can act as a suitable vaccine candidate protein to prevent pneumococcal infection. In this study, mice received subcutaneous vaccination with recombinant GAPDH followed by challenge with D39 and 19F showing higher survival rate and lower bacterial loads in nasal washes and lung homogenates than control. Meanwhile, high titers of rGAPDH specific antibody and elevated titers of IgG subtype indicated that rGAPDH could elicit immune response in mice. Then, we investigated the mechanism that immunization with rGAPDH conferred protection against Streptococcus pneumoniae in host. In vitro experiments, rGAPDH induced phenotypic and functional maturation of BMDCs, because the high expression of CD40, CD86 and MHC II and the production of IL 12p70, IL-6 and TNF-alpha were observed after treatment with rGAPDH. However, the costimulatory molecules and cytokines declined significantly in TLR2-/- and TLR4 /- mice, indicating rGAPDH can be a potential ligand for both TLR2 and TLR4. Subsequent investigations suggested that rGAPDH could also activate the phosphorylation of MAPKs, PI3K-Akt and NF-kappaB. Meantime, upregulation of mir 146a and downregulation of mir-27a in BMDCs were observed. Taken together, our findings confirm that rGAPDH, a housekeeping protein, is also qualified as a vaccine candidate protein and rGAPDH activates BMDCs in a TLR2 and TLR4 dependent manner. PMID- 28088527 TI - Navigation in the electronic health record: A review of the safety and usability literature. AB - OBJECTIVE: Inefficient navigation in electronic health records has been shown to increase users' cognitive load, which may increase potential for errors, reduce efficiency, and increase fatigue. However, navigation has received insufficient recognition and attention in the electronic health record (EHR) literature as an independent construct and contributor to overall usability. Our aims in this literature review were to (1) assess the prevalence of navigation-related topics within the EHR usability and safety research literature, (2) categorize types of navigation actions within the EHR, (3) capture relationships between these navigation actions and usability principles, and (4) collect terms and concepts related to EHR navigation. Our goal was to improve access to navigation-related research in usability. MATERIALS AND METHODS: We applied scoping literature review search methods with the assistance of a reference librarian to identify articles published since 1996 that reported evaluation of the usability or safety of an EHR user interface via user test, analytic methods, or inspection methods. The 4336 references collected from MEDLINE, EMBASE, Engineering Village, and expert referrals were de-duplicated and screened for relevance, and navigation related concepts were abstracted from the 21 articles eligible for review using a standard abstraction form. RESULTS: Of the 21 eligible articles, 20 (95%) mentioned navigation in results and discussion of usability evaluations. Navigation between pages of the EHR was the more frequently documented type of navigation (86%) compared to navigation within a single page (14%). Navigation actions (e.g., scrolling through a medication list) were frequently linked to specific usability heuristic violations, among which flexibility and efficiency of use, recognition rather than recall, and error prevention were most common. DISCUSSION: Discussion of navigation was prevalent in results across all types of evaluation methods among the articles reviewed. Navigating between multiple screens was frequently identified as a usability barrier. The lack of standard terminology created some challenges to identifying and comparing articles. CONCLUSION: We observed that usability researchers are frequently capturing navigation-related issues even in articles that did not explicitly state navigation as a focus. Capturing and synthesizing the literature on navigation is challenging because of the lack of uniform vocabulary. Navigation is a potential target for normative recommendations for improved interaction design for safer systems. Future research in this domain, including development of normative recommendations for usability design and evaluation, will be facilitated by development of a standard terminology for describing EHR navigation. PMID- 28088528 TI - Study of the involved sorption mechanisms of Cr(VI) and Cr(III) species onto dried Salvinia auriculata biomass. AB - Removal of Cr(VI) species by dried biomass of the aquatic macrophyte Salvinia auriculata was studied in order to understand the involved sorption mechanisms. Kinetic tests were carried out under the conditions such as concentration range of Cr(VI) from 50 to 250 mg L-1 and a temperature of 30 degrees C. Modification of the biosorbent by the presence of Cr(VI) species was assessed by analysis of its porosity, density and infrared molecular absorption spectrum. A series of experimental approaches involving directed chemical modifications on the biosorbent surface was performed. The main functional groups involved in the sorption mechanisms were identified. The gas sorption analyser was applied and proved that a strong chemical effect of Cr(VI) species on the surface took place, resulting in a leaching organic matter with an obvious and significant increase in the porosity parameters. The intra-particle diffusion model revealed different mass transfer zones into the adsorbent during Cr(VI) removal. New combined Langmuir and Dubinin-Radushkevich isotherm was the best to fit the equilibrium data of Cr(VI) species removal. Finally, Cr(VI) removal was mainly mediated by a redox process where Cr(III) species were formed. PMID- 28088529 TI - Effect of water chemistry on disinfection by-product formation in the complex surface water system. AB - The relationship between the disinfection by-products (DBPs) formed with chlorination and chloramination techniques and the water chemistry of Haihe River was compared. Samples were collected at 28 different points within the mainstream and tributaries of the river. The DBPs investigated include trihalomethanes (THMs), haloacetic acids (HAAs), haloacetonitriles (HANs), haloketones (HKs), and trichloronitromethane. THMs formed when the samples were chlorinated mostly exceeded 100 and 600 MUg/L in the mainstream and tributaries and in the estuary, respectively. A similar trend was obtained for HAAs whose concentrations exceeded 150 MUg/L in almost all samples. The amounts of DBPs formed when the samples were chloraminated were much lower than when chlorination was used. The concentrations and species of THMs and HAAs in samples collected from sites near the estuary were different from those in samples collected from the mainstream, which may be due to high concentrations of Cl- and Br-. Although natural organic matter is the major cause of DBP formation during water disinfection, this study shows that other water chemistry factors such as salt composition and concentrations may also considerably affect the formation of DBPs in natural aquatic systems. PMID- 28088530 TI - Distribution of antibiotic resistance in the effluents of ten municipal wastewater treatment plants in China and the effect of treatment processes. AB - Municipal wastewater treatment plant (WWTP) effluents represent an important contamination source of antibiotic resistance, threatening the ecological safety of receiving environments. In this study, the release of antibiotic resistance to sulfonamides and tetracyclines in the effluents of ten WWTPs in China was investigated. Results indicate that the concentrations of antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) ranged from 1.1 * 101 to 8.9 * 103 CFU mL-1 and 3.6 * 101 (tetW) to 5.4 * 106 (tetX) copies mL-1, respectively. There were insignificant correlations of the concentrations of ARB and ARGs with those of corresponding antibiotics. Strong correlations were observed between the total concentrations of tetracycline resistance genes and sulfonamide resistance genes, and both of which were significantly correlated with intI1 concentrations. Statistical analysis of the effluent ARG concentrations in different WWTPs revealed an important role of disinfection in eliminating antibiotic resistance. The release rates of ARB and ARGs through the effluents of ten WWTPs ranged from 5.9 * 1012 to 4.8 * 1015 CFU d-1 and 6.4 * 1012 (tetW) to 1.7 * 1018 (sul1) copies d-1, respectively. This study helps the effective assessment and scientific management of ecological risks induced by antibiotic resistance discharged from WWTPs. PMID- 28088532 TI - Comparison of an anaerobic feed and split anaerobic-aerobic feed on granular sludge development, performance and ecology. AB - The retrofitting of existing wastewater sequencing batch reactors (SBRs) to select for rapid-settling aerobic granular sludge (AGS) over floc-based conventional activated sludge (CAS), could be a viable option to decrease reactor cycle time and increase hydraulic capacity. Successful CAS-to-AGS conversion has previously been shown to be highly dependent on having a dedicated anaerobic feed, which presents additional engineering challenges when retrofitting SBRs. In this study we compared the performance of a split anaerobic-aerobic (An-Aer) feed with that of a traditional dedicated anaerobic feed regarding AGS formation and stability, nitrogen removal performance and microbial ecology. Using pilot trials, we showed that AGS could be established and maintained when using a split An-Aer feed at low organic loading rates analogous to that of a parallel full scale conventional SBR. Additionally, we showed that AGS start-up time and nitrogen removal performance were comparable under a split An-Aer feed and dedicated anaerobic feed. Microbial ecology characterisations based on whole-of community 16S rRNA profiles and targeted analysis of functional genes specific for nitrifying and denitrifying microorganisms, showed that the two different feed strategies had only subtle impacts on both the overall community composition and functional ecology. A much greater divergence in microbial ecology was seen when comparing AGS with CAS. Data presented here will be of value to those planning to retrofit existing CAS-based SBRs to operate with AGS and demonstrates the viability of using a more cost-effective split An-Aer feed configuration over a dedicated anaerobic feed. PMID- 28088531 TI - The effect of dissolved organic matter on soybean peroxidase-mediated removal of triclosan in water. AB - Dissolved organic matter (DOM) is ubiquitous in water and involved in numerous important chemical processes in aqueous systems, enabling it a unique challenge for a variety of water treatment processes. Soybean peroxidase (SBP)-based enzymatic process, as a promising treatment technique, has been successfully applied to remove pollutants in wastewaters such as coal-tar and refinery wastewater. In this study, the effect of DOM on the removal of polychlorinated aromatic antimicrobials triclosan (TCS) by SBP was investigated. Our results suggested that DOM significantly suppressed the catalytic performance of SBP to TCS, presumably resulting from the competition of the phenolic moiety in DOM structure as the active substrate of SBP via the analysis of excitation emission matrix (EEM) spectra of DOM. Although the product species of TCS in SBP-mediated system with DOM has no change compared with the system without DOM, the yields of self-coupling products relative to total transformed TCS were remarkably reduced in the presence of DOM, suggesting that DOM participated in the oxidative coupling reactions. Cross-coupling between TCS and DOM was also verified using guaiacol as a model DOM constituent. Moreover, the products including self coupling products and co-polymers in SBP-mediated TCS reaction system with DOM were innocuous through growth inhibition assay of S. obliquus. PMID- 28088533 TI - Anti-HMGCR and anti-DFS70 antibodies immunofluorescence patterns. PMID- 28088534 TI - The social transmission of metacontrol policies: Mechanisms underlying the interpersonal transfer of persistence and flexibility. AB - Humans often face binary cognitive-control dilemmas, with the choice between persistence and flexibility being a crucial one. Tackling these dilemmas requires metacontrol, i.e., the control of the current cognitive-control policy. As predicted from functional, psychometric, neuroscientific, and modeling approaches, interindividual variability in metacontrol biases towards persistence or flexibility could be demonstrated in metacontrol-sensitive tasks. These biases covary systematically with genetic predispositions regarding mesofrontal and nigrostriatal dopaminergic functioning and the individualistic or collectivistic nature of the cultural background. However, there is also evidence for mood- and meditation-induced intraindividual variability (with negative mood and focused attention meditation being associated with a bias towards persistence, and positive mood and open-monitoring meditation being associated with a bias towards flexibility), suggesting that genetic and cultural factors do not determine metacontrol settings entirely. We suggest a theoretical framework that explains how genetic predisposition and cultural learning can lead to the implementation of metacontrol defaults, which however can be shifted towards persistence or flexibility by situational factors. PMID- 28088535 TI - Neurobiological consequences of juvenile stress: A GABAergic perspective on risk and resilience. AB - ALBRECHT, A., MULLER, I., ARDI, Z., CALISKAN, G., GRUBER, D., IVENS, S., SEGAL, M., BEHR, J., HEINEMANN, U., STORK, O., and RICHTER-LEVIN, G. Neurobiological consequences of juvenile stress: A GABAergic perspective on risk and resilience. NEUROSCI BIOBEHAV REV XXX-XXX, 2016.- Childhood adversity is among the most potent risk factors for developing mood and anxiety disorders later in life. Therefore, understanding how stress during childhood shapes and rewires the brain may optimize preventive and therapeutic strategies for these disorders. To this end, animal models of stress exposure in rodents during their post-weaning and pre-pubertal life phase have been developed. Such 'juvenile stress' has a long lasting impact on mood and anxiety-like behavior and on stress coping in adulthood, accompanied by alterations of the GABAergic system within core regions for the stress processing such as the amygdala, prefrontal cortex and hippocampus. While many regionally diverse molecular and electrophysiological changes are observed, not all of them correlate with juvenile stress-induced behavioral disturbances. It rather seems that certain juvenile stress-induced alterations reflect the system's attempts to maintain homeostasis and thus promote stress resilience. Analysis tools such as individual behavioral profiling may allow the association of behavioral and neurobiological alterations more clearly and the dissection of alterations related to the pathology from those related to resilience. PMID- 28088536 TI - Targeting sonic hedgehog signaling in neurological disorders. AB - Sonic hedgehog (Shh) signaling influences neurogenesis and neural patterning during the development of central nervous system. Dysregulation of Shh signaling in brain leads to neurological disorders like autism spectrum disorder, depression, dementia, stroke, Parkinson's diseases, Huntington's disease, locomotor deficit, epilepsy, demyelinating disease, neuropathies as well as brain tumors. The synthesis, processing and transport of Shh ligand as well as the localization of its receptors and signal transduction in the central nervous system has been carefully reviewed. Further, we summarize the regulation of small molecule modulators of Shh pathway with potential in neurological disorders. In conclusion, further studies are warranted to demonstrate the potential of positive and negative regulators of the Shh pathway in neurological disorders. PMID- 28088537 TI - Mouse models of frontotemporal dementia: A comparison of phenotypes with clinical symptomatology. AB - Frontotemporal dementia (FTD) is the second most common cause of young onset dementia. It is increasingly recognized that there is a clinical continuum between FTD and amyotrophic lateral sclerosis (ALS). At a clinical, pathological and genetic level there is much heterogeneity in FTD, meaning that our understanding of this condition, pathophysiology and development of treatments has been limited. A number of mouse models focusing predominantly on recapitulating neuropathological and molecular changes of disease have been developed, with most transgenic lines expressing a single specific protein or genetic mutation. Together with the species-typical presentation of functional deficits, this makes the direct translation of results from these models to humans difficult. However, understanding the phenotypical presentations in mice and how they relate to clinical symptomology in humans is essential for advancing translation. Here we review current mouse models in FTD and compare their phenotype to the clinical presentation in patients. PMID- 28088538 TI - Perceived parental alcohol problems and drinking patterns in youth: A cross sectional study of 69,030 secondary education students in Denmark. AB - The aim of the study was to examine whether young people with parental alcohol problems have different drinking patterns than those without parental alcohol problems. Further, we examined whether the association between parental alcohol problems and young people's drinking patterns differed depending on the gender of the child and the parent, and whether more severe parental alcohol problems and cohabitation with the parent with alcohol problems was associated with earlier and heavier drinking patterns. Data came from the Danish National Youth Study 2014, a web-based national survey. 75,025 high school and vocational school students (15-25years) participated. Drinking patterns were investigated by the following outcomes: non-drinking, weekly alcohol consumption, frequent binge drinking, and early intoxication debut age. The main predictor variables were perceived parental alcohol problems, gender of the parent with alcohol problems, cohabitation with a parent with alcohol problems and severity of the parents' alcohol problems. Young people with parental alcohol problems had a higher weekly alcohol consumption (boys: 15.2 vs. 13.9 drinks per week; girls: 11.6 vs. 10.2 drinks per week), higher odds of early intoxication debut age (boys: OR=1.68 [95% CI 1.50-1.89]; girls: OR 1.95 [95% CI 1.79-2.14]), and more frequent binge drinking (boys, OR=1.16 [95% CI 1.04-1.29]; girls, OR=1.21 [95% CI 1.11-1.32]) compared to young people without parental alcohol problems. In conclusion, this study shows that young people with perceived parental alcohol problems have an earlier intoxication debut age, binge drink more frequently, and drink larger quantities per week than young people without perceived parental alcohol problems. PMID- 28088539 TI - The DNA damage response of C. elegans affected by gravity sensing and radiosensitivity during the Shenzhou-8 spaceflight. AB - Space radiation and microgravity are recognized as primary and inevitable risk factors for humans traveling in space, but the reports regarding their synergistic effects remain inconclusive and vary across studies due to differences in the environmental conditions and intrinsic biological sensitivity. Thus, we studied the synergistic effects on transcriptional changes in the global genome and DNA damage response (DDR) by using dys-1 mutant and ced-1 mutant of C. elegans, which respectively presented microgravity-insensitivity and radiosensitivity when exposure to spaceflight condition (SF) and space radiation (SR). The dys-1 mutation induced similar transcriptional changes under both conditions, including the transcriptional distribution and function of altered genes. The majority of alterations were related to metabolic shift under both conditions, including transmembrane transport, lipid metabolic processes and proteolysis. Under SF and SR conditions, 12/14 and 10/13 altered pathways, respectively, were both grouped in the metabolism category. Out of the 778 genes involved in DDR, except eya-1 and ceh-34, 28 altered genes in dys-1 mutant showed no predicted protein interactions, or anti-correlated miRNAs during spaceflight. The ced-1 mutation induced similar changes under SF and SR; however, these effects were stronger than those of the dys-1 mutant. The additional genes identified were related to phosphorous/phosphate metabolic processes and growth rather than, metabolism, especially for environmental information processing under SR. Although the DDR profiles were significantly changed under both conditions, the ced-1 mutation favored DNA repair under SF and apoptosis under SR. Notably, 37 miRNAs were predicted to be involved in the DDR. Our study indicates that, the dys-1 mutation reduced the transcriptional response to SF, and the ced-1 mutation increased the response to SR, when compared with the wild type C. elegans. Although some effects were due to radiosensitivity, microgravity, depending on the dystrophin, exerts predominant effects on transcription in C. elegans during short-duration spaceflight. PMID- 28088540 TI - Multiplexed site-specific genome engineering for overproducing bioactive secondary metabolites in actinomycetes. AB - Actinomycetes produce a large variety of pharmaceutically active compounds, yet production titers often require to be improved for discovery, development and large-scale manufacturing. Here, we describe a new technique, multiplexed site specific genome engineering (MSGE) via the 'one integrase-multiple attB sites' concept, for the stable integration of secondary metabolite biosynthetic gene clusters (BGCs). Using MSGE, we achieved five-copy chromosomal integration of the pristinamycin II (PII) BGC in Streptomyces pristinaespiralis, resulting in the highest reported PII titers in flask and batch fermentations (2.2 and 2g/L, respectively). Furthermore, MSGE was successfully extended to develop a panel of powerful Streptomyces coelicolor heterologous hosts, in which up to four copies of the BGCs for chloramphenicol or anti-tumour compound YM-216391 were efficiently integrated in a single step, leading to significantly elevated productivity (2-23 times). Our multiplexed approach holds great potential for robust genome engineering of industrial actinomycetes and novel drug discovery by genome mining. PMID- 28088541 TI - Secretory pathway optimization of CHO producer cells by co-engineering of the mitosRNA-1978 target genes CerS2 and Tbc1D20. AB - Chinese Hamster Ovary (CHO) cells are the most commonly used host for the production of biopharmaceuticals. Although transcription and translation engineering strategies have been employed to generate high-producer cell clones, the secretory pathway still remains a bottleneck in cellular productivity. In this study we show that ectopic expression of a human mitochondrial genome encoded small RNA (mitosRNA-1978) in an IgG expressing CHO cell line strongly improved specific productivity by functioning in a microRNA-like fashion. By next generation sequencing we identified two endoplasmic reticulum (ER)-localized proteins, Ceramide Synthase 2 (CerS2) and the Rab1 GAP Tbc domain family member 20 (Tbc1D20), as target genes of mitosRNA-1978. Combined transient siRNA-mediated knockdown of CerS2 and Tbc1D20 resulted in increased specific productivity of CHO IgG cells, thus recapitulating the mitosRNA-1978 phenotype. In support of a function in vesicular trafficking at the level of the ER, we provide evidence for altered cellular ceramide composition upon CerS2 knockdown and increased activity of Rab1 in CHO-IgG cells depleted of Tbc1D20. Importantly, in a fed-batch process, the combined stable knockdown of CerS2 and Tbc1D20 in CHO-IgG cells resulted in dramatically increased antibody production which was accompanied by enhanced cell growth. Thus, by identifying mitosRNA-1978 target genes in combination with an informed shRNA-mediated co-engineering approach we successfully optimized the secretory capacity of CHO producer cells used for the manufacturing of therapeutic proteins. PMID- 28088542 TI - Interaction of earthworms-microbe facilitating biofilm dewaterability performance during wasted activated sludge reduction and stabilization. AB - Sludge dewaterability was chemically and morphologically explored during sewage sludge treatment by vermifiltration. The results, with a conventional biofilter (BF, no earthworms) as a control, demonstrated that the capillary suction time(CST) and specific resistance of filtration(SRF) of vermifilter (VF, with earthworms) treated sludge were 64.9+/-1.7s and (23.1+/-1.3)*1012m/kg,16.8% and 36.0% lower than that of the BF, respectively. Additionally, the VF could efficiently decompose loosely bound extracellular polymeric substances (LB-EPS), releasing more water trapped inside biofilm. Furthermore, the VF enable to reduce the electrostatic repulsive forces between particles, verified by 9.61+/-0.19mV of the absolute value of zeta potential, 19.6% lower than that of the BF. Notably, based on scanning electron microscopy (SEM) analysis, the fractal dimension (Df) of sludge floc structure stated that more small and loose sludge flocs tended to aggregate into bigger inorganic particles. Therefore sludge flocs with highly compacted structure and smooth surface can transform part of vicinal water and water of hydration into easier-removed interstitial water, improving the dewaterability. PMID- 28088543 TI - Transformation of terrestrial organic matter along thermokarst-affected permafrost coasts in the Arctic. AB - The changing climate in the Arctic has a profound impact on permafrost coasts, which are subject to intensified thermokarst formation and erosion. Consequently, terrestrial organic matter (OM) is mobilized and transported into the nearshore zone. Yet, little is known about the fate of mobilized OM before and after entering the ocean. In this study we investigated a retrogressive thaw slump (RTS) on Qikiqtaruk - Herschel Island (Yukon coast, Canada). The RTS was classified into an undisturbed, a disturbed (thermokarst-affected) and a nearshore zone and sampled systematically along transects. Samples were analyzed for total and dissolved organic carbon and nitrogen (TOC, DOC, TN, DN), stable carbon isotopes (delta13C-TOC, delta13C-DOC), and dissolved inorganic nitrogen (DIN), which were compared between the zones. C/N-ratios, delta13C signatures, and ammonium (NH4-N) concentrations were used as indicators for OM degradation along with biomarkers (n-alkanes, n-fatty acids, n-alcohols). Our results show that OM significantly decreases after disturbance with a TOC and DOC loss of 77 and 55% and a TN and DN loss of 53 and 48%, respectively. C/N-ratios decrease significantly, whereas NH4-N concentrations slightly increase in freshly thawed material. In the nearshore zone, OM contents are comparable to the disturbed zone. We suggest that the strong decrease in OM is caused by initial dilution with melted massive ice and immediate offshore transport via the thaw stream. In the mudpool and thaw stream, OM is subject to degradation, whereas in the slump floor the nitrogen decrease is caused by recolonizing vegetation. Within the nearshore zone of the ocean, heavier portions of OM are directly buried in marine sediments close to shore. We conclude that RTS have profound impacts on coastal environments in the Arctic. They mobilize nutrients from permafrost, substantially decrease OM contents and provide fresh water and nutrients at a point source. PMID- 28088544 TI - Off-site impacts of wildfires on aquatic systems - Biomarker responses of the mosquitofish Gambusia holbrooki. AB - The number of wildfires has markedly increased in Mediterranean Europe, including in Portugal. Wildfires are environmentally concerning, not only due to the loss of biodiversity and forest area, but also as a consequence of environmental contamination by specific compounds including metals and polycyclic aromatic compounds (PAHs). These contaminants, mostly bound to ashes, can reach downstream water bodies, namely through surface runoff, being ultimately dispersed by vast areas and contacting with aquatic biota. Being toxicologically noteworthy, the potential toxic outcomes of the input of such chemicals across the aquatic compartment must be characterized. In this context, the present study used a biomarker-based approach to find early-warning signals of toxicity triggered by the exposure of the mosquitofish, Gambusia holbrooki, to affected aqueous runoff and stream water samples collected from a forest burnt area. The chemical analysis revealed concerning levels of metals and polycyclic aromatic hydrocarbons in both runoff and stream water samples. Biological responses elicited by the collected samples showed the occurrence of pro-oxidative modifications, specifically driven by enzymatic forms involved in the metabolism of glutathione. Despite these effects, no further signs of involvement of metals and PAHs were elicited in terms of neurotoxicity. The overall set of data implicates chemicals resulting from wildfires in clear deleterious effects in exposed fish. PMID- 28088545 TI - How do people's perceptions and climatic disaster experiences influence their daily behaviors regarding adaptation to climate change? - A case study among young generations. AB - Adaptation is a commonly applied strategy used to address individual behavior changes, in response to climate change. However, in-depth, evidence-based investigations of the relationships among individual perceptions, climatic disaster experiences, and daily behaviors regarding adaptation to climate change remain to be conducted. We obtained survey data from 488 respondents in southwestern China, a region prone to frequent and severe droughts, to assess factors that influence adaptive behaviors and to identify their pathways. We applied Construal Level Theory (CLT) and the Theory of Planned Behavior (TPB) to differentiate between respondents' high-level abstract construals and their low level concrete construals. We analyzed the influences of these two levels of perception, combined with drought experiences on water-saving behaviors. We developed a structural equation model to estimate the correlation coefficients of the latent and observed variables in the structural process linked to the respondents' adaptive behaviors. The results found that a concrete perception of saving water plays a more significant part than an abstract perception of climate change in prompting specific adaptive behaviors. Improving public perceptions of climate change might increase the desirability of adaptation, whereas improving perceptions of water saving might increase the feasibility of implementing adaptive measures. Experience influenced individual behaviors, but that influence was indirect through its effects on perceptions. PMID- 28088546 TI - Product vs corporate carbon footprint: Some methodological issues. A case study and review on the wine sector. AB - Carbon footprint (CF) is nowadays one of the most widely used environmental indicators. The scope of the CF assessment could be corporate (when all production processes of a company are evaluated, together with upstream and downstream processes following a life cycle approach) or product (when one of the products is evaluated throughout its life cycle). Our hypothesis was that usually product CF studies (PCF) collect corporate data, because it is easier for companies to obtain them than product data. Six main methodological issues to take into account when collecting corporate data to be used for PCF studies were postulated and discussed in the present paper: fugitive emissions, credits from waste recycling, use of "equivalent factors", reference flow definition, accumulation and allocation of corporate values to minor products. A big project with 18 wineries, being wine one of the most important agri-food products assessed through CF methodologies, was used to study and to exemplify these 6 methodological issues. One of the main conclusions was that indeed, it is possible to collect corporate inventory data in a per year basis to perform a PCF, but having in mind the 6 methodological issues described here. In the literature, most of the papers are presenting their results as a PCF, while they collected company data and obtained, in fact, a "key performance indicator" (ie., CO2eq emissions per unit of product produced), which is then used as a product environmental impact figure. The methodology discussed in this paper for the wine case study is widely applicable to any other product or industrial activity. PMID- 28088547 TI - Traffic-related trace elements in soils along six highway segments on the Tibetan Plateau: Influence factors and spatial variation. AB - The accumulation of traffic-related trace elements in soil as the result of anthropogenic activities raises serious concerns about environmental pollution and public health. Traffic is the main source of trace elements in roadside soil on the Tibetan Plateau, an area otherwise devoid of industrial emissions. Indeed, the rapid development of tourism and transportation in this region means it is becoming increasingly important to identify the accumulation levels, influence distance, spatial distribution, and other relevant factors influencing trace elements. In this study, 229 soil samples along six segments of the major transportation routes on the Tibetan Plateau (highways G214, S308, and G109), were collected for analysis of eight trace elements (Cr, Co, Ni, As, Cu, Zn, Cd, and Pb). The results of statistical analyses showed that of the eight trace elements in soils, Cu, Zn, Cd, and Pb were primarily derived from traffic. The relationship between the trace element accumulation levels and the distance from the roadside followed an exponential decline, with the exception of Segment 3, the only unpaved gravel road studied. In addition, the distance of influence from the roadside varied by trace element and segment, ranging from 16m to 144m. Background values for each segment were different because of soil heterogeneity, while a number of other potential influencing factors (including traffic volume, road surface material, roadside distance, land cover, terrain, and altitude) all had significant effects on trace-element concentrations. Overall, however, concentrations along most of the road segments investigated were at, or below, levels defined as low on the Nemero Synthesis index. PMID- 28088548 TI - Soil carbon dioxide emissions from a rubber plantation on tropical peat. AB - Land-use change in tropical peatland potentially results in a large amount of carbon dioxide (CO2) emissions owing to drainage, which lowers groundwater level (GWL) and consequently enhances oxidative peat decomposition. However, field information on carbon balance is lacking for rubber plantations, which are expanding into Indonesia's peatlands. To assess soil CO2 emissions from an eight year-old rubber plantation established on peat after compaction, soil CO2 efflux was measured monthly using a closed chamber system from December 2014 to December 2015, in which a strong El Nino event occurred, and consequently GWL lowered deeply. Total soil respiration (SR) and oxidative peat decomposition (PD) were separately quantified by trenching. In addition, peat surface elevation was measured to determine annual subsidence along with GWL. With GWL, SR showed a negative logarithmic relationship (p<0.01), whereas PD showed a strong negative linearity (p<0.001). Using the significant relationships, annual SR and PD were calculated from hourly GWL data to be 3293+/-1039 and 1408+/-214gCm-2yr-1 (mean+/ 1 standard deviation), respectively. PD accounted for 43% of SR on an annual basis. SR showed no significant difference between near and far positions from rubber trees (p>0.05). Peat surface elevation varied seasonally in almost parallel with GWL. After correcting for GWL difference, annual total subsidence was determined at 5.64+/-3.20 and 5.96+/-0.43cmyr-1 outside and inside the trenching, respectively. Annual subsidence only through peat oxidation that was calculated from the annual PD, peat bulk density and peat carbon content was 1.50cmyr-1. As a result, oxidative peat decomposition accounted for 25% of total subsidence (5.96cmyr-1) on average on an annual basis. The contribution of peat oxidation was lower than those of previous studies probably because of compaction through land preparation. PMID- 28088549 TI - Redistribution of elements between wastes and organic-bearing material in the dispersion train of gold-bearing sulfide tailings: Part I. Geochemistry and mineralogy. AB - Migration and redistribution of elements during prolonged interaction of cyanide wastes with the underlying natural organic-bearing material have been studied in two ~40cm deep cores that sample primary ores and their weathering profile (wastes I and II, respectively) in the dispersion train of gold-bearing sulfide tailings in Siberia. Analytical results of SR-XRF, whole-rock XRF, AAS, CHNS, and SEM measurements of core samples show high K, Sr, Ti, and Fe enrichments and correlation of P2O5 and Mn with LOI and Corg. Organic material interlayered or mixed with the wastes accumulates Cu, Zn, Se, Cd, Ag, Au, and Hg. The peat that contacts wastes II bears up to 3wt.% Zn, 1000g/t Se, 100g/t Cd, and 8000g/t Hg. New phases of Zn and Hg sulfides and Hg selenides occur as abundant sheaths over bacterial cells suggesting microbial mediation in sorption of elements. Organic bearing material in the cores contains 10-30g/t Au in 2-5cm thick intervals, both within and outside the intervals rich in sulfides and selenides. Most of gold is invisible but reaches 345g/t and forms 50nm to 1.5MUm Au0 particles in a thin 2 3cm interval of organic remnants mixed with wastes I. Vertical and lateral infiltration of AMD waters in peat and oxidative dissolution of wastes within the dispersion train of the Ursk tailings lead to redistribution of elements and their accumulation by combined physical (material's permeability, direction AMD), chemical (complexing, sorption by organic matter and Fe(III) hydroxides) and biochemical (metabolism of sulfate-reducing bacteria) processes. The accumulated elements form secondary sulfates, and Hg and Zn selenides. The results provide insights into accumulation of elements in the early history of coal and black shale deposits and have implications for remediation of polluted areas and for secondary enrichment technologies. PMID- 28088551 TI - Individual and sex differences in high and low responder phenotypes. AB - Individual differences in responses to a novel environment are an important tool to predict predisposition to neuropsychiatric disorders. One way to examine individual differences involves classifying animals based on locomotion in a novel context. In this study we focused on individual and sex differences by categorizing female and male mice as high (HR) or low responders (LR) on the basis of open field locomotion. We then assessed whether groups differed on behavioral measures of spontaneous alternations, anxiety, depression and contextual fear conditioning. In the Y-maze, we observed no differences across HR/LR or sex on spontaneous alternations, but HR displayed more locomotion. HR male mice showed less anxiety-like behavior in the light-dark test but not the elevated plus maze. We observed no differences in the forced swim test across HR/LR, although males exhibited greater depression-like behavior overall. HR mice exhibited less contextual fear memory compared to LR regardless of sex. Principal component analyses suggested sex-specific patterns of behaviors across tests, with female responses within individual tests tending to load together. In females anxiety- and depression-like behaviors explained a large part of the variance observed across tests in our battery, whereas male behavior was primarily explained by variables related to locomotion. PMID- 28088550 TI - Novel involvement of miR-522-3p in high-mobility group box 1-induced prostaglandin reductase 1 expression and reduction of phagocytosis. AB - Resolution of inflammation is important for physiological homeostasis. Chronic inflammatory diseases may be caused by abnormal resolution of inflammation. However, what causes a failure of inflammatory resolution is unclear. Here we investigated the involvement of high mobility group box 1 (HMGB1) protein in the control of inflammatory resolution as an 'anti-resolution factor'. We first confirmed the increased expression of HMGB1 and prostaglandin reductase 1 (PTGR1) in inflammatory conditions and HMGB1-mediated regulation of the expression of PTGR1. The inhibition of phagocytosis by HMGB1 was abrogated by PTGR1 silencing. PTGR1 was a direct target of miR522-3p and its expression was regulated by miRNA 522-3p inhibitor or mimic. Finally, miR-522-3p had an important role in the regulation of PTGR1 expression by HMGB1. The data indicates that HMGB1-miR-522-3p PTGR1 axis may be involved in the abnormal resolution of inflammation and suggests that this mechanism might be a target for modulation of chronic inflammatory disorder. PMID- 28088552 TI - Antipredator tactics are largely maternally controlled in goitered gazelle, a hider ungulate. AB - Predation is usually the primary cause of infant death among ungulate species, with the annual variation in the survival of neonates over their first summer a major factor in the population dynamics of many ungulates. Consequently, the maternal rearing strategy of a species is crucial for its reproductive success. Since the roles mothers and fawns play in the implementation of antipredator strategies in hider species have been poorly understood until now, this paper considers this behavior in the goitered gazelle, which is a typical hider species. I found that within the first month after birth goitered gazelle mothers largely controlled the behavior of their fawns both during the active period (determining the timing of separation and reunion with fawns, movement direction and speed, and bed site location) and the hiding period (keeping the hiding fawns under continuous watch from a distance, especially right after birth). With age the fawns' mobility increased and cases of independent behavior of fawns apart from their mothers were found more often, though females continued to control their fawns' behaviors. The main elements of the goitered gazelles' maternal care strategy - generally related to protecting fawns from potential predator attack - are very similar to other hider species in both bovids and cervids, which demonstrates a standard set of maternal care behaviors, irrespective of predator type or its behavioral peculiarities. Such maternal behaviors, however, likely only decrease the predation losses to a certain extent. PMID- 28088554 TI - WITHDRAWN: MicroRNA-99a Suppresses Proliferation, Migration, Invasion and Induces G1-phase Cell Cycle Arrest via Targeting Insulin-like Growth Factor 1 Receptor Pathway in Renal Cell Carcinoma 786-0 and OS-RC-2 Cells. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 28088553 TI - The influence of landmark stability on control by occasion setters. AB - In an operant serial feature-positive procedure, an occasion setter (OSX) signals that a response will be reinforced in the presence of a second stimulus (e.g., a discriminative stimulus, A). During a transfer test, the OS is paired with a different discriminative stimulus. Experiment 1a tested transfer effects in a touchscreen-based spatial occasion setting task with pigeons. During training, four OSs (OSW, OSX, OSY, and OSZ) were paired on separate trials with landmark A (LMA) or B (LMB) and the opportunity for a reinforced response at one location to the immediate left (R1) or right (R2) of the LM (OSW->LMA:R1, OSX->LMA:R2, OSY >LMB:R1, OSZ->LMB:R2). Training also included non-reinforced trials of LMA and LMB alone (LMA- and LMB-) and trials of a non-modulated LM with R1 and R2 reinforced across separate trials (LMC:R1 and LMC:R2). After training, the number and spatial location of responses during test trials of a LM paired with the same OS as in training did not differ reliably from transfer tests of an OS paired with a different, modulated LM (OSW->LMB and OSY->LMA), but did differ from transfer to the non-modulated LM (OSX->LMC). Experiment 1b utilized the same pigeons and training with LMB to test the degree to which the spatial stability of a LM influenced transfer. Retraining with LMA was intended to establish it as a non-modulated, stable LM (LMA:R2). Subsequent tests with LMA revealed reduced modulation by the formerly trained OS (OSW), and complete disruption of modulation of spatial location during transfer with a different OS (OSY). These findings further our understanding of the conditions under which OSs may develop and transfer modulation. PMID- 28088555 TI - Injury in Pelvic Fracture Urethral Injury Is Membranobulbar: Fact or Myth. AB - Pelvic fracture urethral injuries commonly result from motor vehicle collisions, and the mechanism of injury conventionally thought was a shearing injury at the membranous urethra, which would destroy the striated sphincter. Continence would therefore depend on the bladder neck. Striated sphincter and the site of injury have not been shown clearly on preoperative imaging. We demonstrate our protocol of performing magnetic resonance imaging whereby the membranous sphincter is seen intact and the injury is shown to be at the membranobulbar junction contrary to conventional belief. This suggests that surgical reconstruction can be undertaken, preserving both sphincter mechanisms and improving postoperative continence. PMID- 28088556 TI - Regulation of Docetaxel Sensitivity in Prostate Cancer Cells by hsa-miR-125a-3p via Modulation of Metastasis-Associated Protein 1 Signaling. AB - OBJECTIVE: To identify the potential downstream targets of hsa-miR-125a-3p, a mature form of miR-125a, during the pathogenesis of chemoresistance in prostate cancer (PCa). MATERIALS AND METHODS: The expression levels of hsa-miR-125a-3p were assessed in chemoresistant PCa tissues and experimentally established chemoresistant cells using quantitative reverse transcription-polymerase chain reaction. The effect of hsa-miR-125a-3p knockdown or hsa-miR-125a-3p overexpression on the Dox-induced cell death was evaluated using apoptosis ELISA in chemosensitive PC-3 cells or in chemoresistant PC-3 cells (PC-3R). Finally, using multiple assays, the regulation of metastasis-associated protein 1 (MTA1), an essential component of the Mi-2-nucleosome remodeling deacetylation complex, by hsa-miR-125a-3p was studied at both molecular and functional levels. RESULTS: The expression of hsa-miR-125a-3p was significantly downregulated in chemoresistant PCa tissues and cells. Inhibition of hsa-miR-125a-3p significantly increased docetaxel (Dox) resistance in PC-3 cells, whereas upregulation of hsa miR-125a-3p effectively reduced Dox resistance in PC-3R, suggesting that this microRNA (miRNA) may act as a tumor suppressor along the pathogenesis of drug resistance. Mechanistically, hsa-miR-125a-3p induced apoptosis and Dox sensitivity in PCa cells through regulating MTA1. CONCLUSION: Our results collectively indicate that miRNA-MTA1 can form a delicate regulatory loop to maintain a bistable state in the Dox chemosensitivity, and future endeavor in this filed should provide important clues to develop miRNA-based therapies that benefit advanced PCa patients through modulating the functional status of MTA1. PMID- 28088557 TI - Meta-analysis of organizational skills interventions for children and adolescents with Attention-Deficit/Hyperactivity Disorder. AB - BACKGROUND: In addition to problems with attention and hyperactivity, children with ADHD present with poor organizational skills required for managing time and materials in academic projects. Organizational skills training (OST) has been increasingly used to address these deficits. We conducted a systematic review and meta-analysis of OST in children with ADHD. OBJECTIVES: The objective of this study was to systematically review the evidence of the effects of OST for children with ADHD for organizational skills, attention, and academic performance. METHODS: We searched 3 electronic databases to locate randomized controlled trials published in English in peer-reviewed journals comparing OST with parent education, treatment-as-usual, or waitlist control conditions. Standardized mean difference effect sizes from the studies were statistically combined using a random-effects meta-analyses across six outcomes: teacher- and parent-rated organizational skills, teacher- and parent-rated inattention, teacher-rated academic performance, and Grade Point Average (GPA). Risk of bias was assessed for randomization, allocation concealment, blinding of participants and treatment personnel, blinding of outcome assessors, incomplete outcome data, and selective outcome reporting. RESULTS: Twelve studies involving 1054 children (576 treatment, 478 control) were included in the meta-analyses. Weighted mean effect sizes for teacher- and parent-rated outcome measures of organizational skills were g=0.54 (95% CI 0.17 to 0.91) and g=0.83 (95% CI 0.32 to 1.34), respectively. Weighted mean effect sizes of teacher- and parent-rated symptoms of inattention were g=0.26 (95% CI 0.01 to 0.52) and g=0.56 (95% CI 0.38 to 0.74), respectively. Weighted standardized mean effect size for teacher-rated academic performance and GPA were g=0.33 (95% CI 0.14 to 0.51) and g=0.29 (95% CI 0.07 to 0.51), respectively. CONCLUSIONS: OST leads to moderate improvements in organizational skills of children with ADHD as rated by teachers and large improvements as rated by parents. More modest improvements were observed on the ratings of symptoms of inattention and academic performance. PROTOCOL REGISTRATION: PROSPERO (CRD42015019261). PMID- 28088558 TI - The effects of upper body exercise across different levels of blood flow restriction on arterial occlusion pressure and perceptual responses. AB - Recent studies have investigated relative pressures that are applied during blood flow restriction exercise ranging from 40%-90% of resting arterial occlusion pressure; however, no studies have investigated relative pressures below 40% arterial occlusion pressure. The purpose of this study was to characterize the cardiovascular and perceptual responses to different levels of pressures. Twenty six resistance trained participants performed four sets of unilateral elbow flexion exercise using 30% of their 1RM in combination with blood flow restriction inflated to one of six relative applied pressures (0%, 10%, 20%, 30%, 50%, 90% arterial occlusion pressure). Arterial occlusion pressure was measured before (pre) and immediately after the last set of exercise at the radial artery. RPE and discomfort were taken prior to (pre) and following each set of exercise. Data presented as mean (95% CI) except for perceptual responses represented as the median (25th, 75th percentile). Arterial occlusion pressure increased from pre to post (p<0.001) in all conditions but was augmented further with higher pressures [e.g. 0%: 36 (30-42) mmHg vs. 10%: 39 (34-44) mmHg vs. 90% 46 (41-52) mmHg]. For RPE and discomfort, there were significant differences across conditions for all sets of exercise (p<0.01) with the ratings of RPE [e.g. 0%: 14.5 (13, 17) vs. 10%: 13.5 (12, 17) vs. 90%: 17 (14.75, 19) during last set] and discomfort [e.g. 0%: 3.5 (1.5, 6.25) vs. 10%: 3 (1, 6) vs. 90%: 7 (4.5, 9) during last set] generally being greater at the higher restriction pressures. All of these differences at the higher restriction pressures occurred despite completing a lower total volume of exercise. Applying higher relative pressures results in the greatest cardiovascular response, higher perceptual ratings, and greater decrease in exercise volume compared to lower restriction pressures. Therefore, the perceptual responses from lower relative pressures may be more appealing and provide a safer and more tolerable stimulus for individuals. PMID- 28088559 TI - Increased expression of carbon monoxide-producing enzymes in the MPOA after sexual experience in male rats. AB - The hypothalamus contains numerous nuclei involved in the regulation of reproductive, stress, circadian, and homeostatic behaviors, with many of these nuclei concentrated within the preoptic and anterior regions. The gaseous neurotransmitter, nitric oxide (NO), has already been shown to have an important regulatory role within the medial preoptic area (MPOA) of the anterior hypothalamus, where it facilitates sexual behaviors. However, little is known about the role of other gaseous neurotransmitters in this area. Here, we report that the carbon monoxide (CO) producing enzymes HO-1 and HO-2 are present in the MPOA and are differentially influenced by sexual experience in a manner similar to that previously reported for NO enzymes. Immunohistochemical staining of brains collected after 0, 1, or 7 sexual experiences reveals that HO-1 is expressed transiently after the first sexual experience, while HO-2 increases only with repeated experience. This increase appears to be specific to the MPOA, as nearby brain areas do not exhibit this degree or pattern of expression. We observed a transient increase in HO-2 colocalization with neuronal nitric oxide synthase (nNOS) after a single sexual experience, but these cells appear to be otherwise disparate, despite the fact that both express within the central nucleus of the MPOA. Together, these findings suggest that endogenous CO may be behaviorally relevant within the MPOA and that CO and NO may be differentially regulated there. PMID- 28088560 TI - Role of comorbidities and in-hospital complications in short-term status epilepticus outcome. AB - OBJECTIVE: pre-morbid patient conditions and hospitalization complications possibly play a role in status epilepticus short-term outcome, although evidence is incomplete and non-conclusive. The study's aim was to define whether comorbidities and in-hospital complications arising after status epilepticus affect its prognosis. METHODS: A retrospective single center study was carried out. All selected patients were adults presenting an EEG-proven status epilepticus episode between 2003 and 2014. Medical charts were comprehensively reviewed. In-hospital mortality and length of hospital stay represented study outcomes. RESULTS: One hundred seventy-three subjects met the inclusion criteria. Seventy-one cases (41%) developed infections and 59 (34%) non-infectious complications. Median hospital stay was 16days and overall in-hospital mortality was 44%. Multivariate analysis revealed the association between in-hospital mortality and the following comorbidities: history of diabetes mellitus (Odds ratio=7.89, p=0.002) and evidence of extracranial malignancy (Odds ratio=10.28, p=0.009). Complications were not associated to death after multivariate statistics, which instead displayed systemic inflammatory response syndrome significance (Odds ratio=12.90, p<0.001). Infections and non-infectious complications were associated with longer hospital stay (p=0.025 and p=0.01 respectively). CONCLUSIONS: status epilepticus management is a multifaceted problem. RESULTS: suggest that some pre-morbid patient conditions and in-hospital adverse events play an unfavorable prognostic role. This preliminary information may help clinicians optimize preventive and therapeutic strategies to guarantee patients the best chances of survival. PMID- 28088561 TI - Mutant DD genotype of NFKB1 gene is associated with the susceptibility and severity of coronary artery disease. AB - Nuclear factor kappaappa B (NF-kappaB) is an important transcription factor in the development and progression of coronary artery disease (CAD). Recent evidence suggests that -94 ATTG ins/del mutant in the promoter of NFKB1 gene is an essential functional mutant. The present study demonstrated the frequencies of the del/del (DD) genotype and del (D) allele were significantly higher in CAD patients than in controls. CAD patients carrying mutant DD genotype had worse stenosis of diseased coronary arteries compared to those carrying ins/ins (II) or ins/del (ID) genotype. Plasma levels of endothelial nitric oxide synthase (eNOS) were lower, while inflammatory cytokine incnterlukin-6 (IL-6) was higher in CAD patients with DD genotype than those with II or ID genotype (both P<0.05). In vitro study showed that mutant human umbilical vein endothelial cells (DD genotype HUVECs) were more susceptible to H2O2-induced apoptosis, which was accompanied with a decreased Bcl-2 expression. Further, mutant HUVECs had lower eNOS but higher IL-6 mRNA levels and decreased phosphorylation of eNOS under H2O2 stimulation (both P<0.05). Compared to wild type cells (II genotype), significantly downregulated protein expression of total NF-kappaB p50 subunit were observed in mutant HUVECs with or without oxidative stress, and a lower expression of unclear p50 was associated with a decreased p50 nuclear translocation in mutant HUVECs versus wild type cells under H2O2-stimulation (both P<0.05). In conclusion, mutant DD genotype of NFKB1 gene is associated with the risk and severity of CAD. Dwonregulation of NF-kappaB p50 subunit leads to exacerbated endothelial dysfunction and apoptosis and enhanced inflammatory response that is the potential underlying mechanism. PMID- 28088562 TI - The effect of high temperature sol-gel polymerization parameters on the microstructure and properties of hydrophobic phenol-formaldehyde/silica hybrid aerogels. AB - Phenol-formaldehyde/silica hybrid aerogels with different degree of hydrophobicity were successfully synthesized via high temperature sol-gel polymerization. Tetraethoxysilane (TEOS) and methyltriethoxysilane (MTES) were used as precursor and co-precursor of the hydrophobic silica-based phase, respectively. The hydrolysis step of silica based sols were conducted by acid catalyzed reactions and HCl was used as hydrolysis catalyst. The chemical structure of prepared hybrid aerogels was characterized by Fourier Transform Infrared spectroscopy (FT-IR). The effect of MTES/TEOS proportion and catalyst content on the morphology and microstructure of samples were investigated by FE SEM and C, Si mapping analysis. The acid catalyzed hydrolysis of TEOS and MTES sols leads to formation of a sol with primarily silica particles in the organic inorganic hybrid sol and varying colloid growth mechanisms were occurred with change in MTES and HCl molar ratio. With the increasing of MTES content, the microstructure of samples changed from uniform colloidal network, core-shell structure to polymeric structure with a huge phase separation. The increasing of HCl mole fraction leads to smaller particle size. Moreover, the shrinkage of samples was decreased and water contact angles of the resulted aerogels were increased from 40 to 156.8 degrees with the increases of MTES content. PMID- 28088563 TI - A novel fabrication of a high performance SiO(2)-graphene oxide (GO) nanohybrids: Characterization of thermal properties of epoxy nanocomposites filled with SiO(2) GO nanohybrids. AB - In this study it has been aimed to enhance the thermal resistance of epoxy coating through incorporation of SiO2-GO nanohybrids. SiO2-GO nanohybrids were synthesized through one-step sol-gel route using a mixture of Tetraethylorthosilane (TEOS) and 3-Aminopropyl triethoxysilane (APTES) silanes. The SiO2-GO nanohybrids were prepared at various hydrolysis times of 24, 48 and 72h. Then 0.2wt.% of GO and SiO2-GO nanohybrids were separately incorporated into the epoxy coating. Results revealed that amino functionalized SiO2 nanoparticles with particle size around 20-30nm successfully synthesized on the basal plane of GO. Results showed significant improvement of dispersion and interfacial interactions between nanohybrids and epoxy composite arising from covalent bonding between the SiO2-GO and the epoxy matrix. It was found that the thermal resistance of SiO2-GO nanohybrids and SiO2-GO/Epoxy nanocomposite was noticeably higher than GO and epoxy matrix, respectively. PMID- 28088564 TI - Doping and vacancy effects of graphyne on SO2 adsorption. AB - The adsorption of sulfur dioxide (SO2) on pristine and modified graphyne (including boron- or nitrogen- doping and introducing a single carbon atom defect) was investigated by density functional theory calculations. The structural, electronic, and magnetic properties of graphyne were changed according to the dopant atom site of doping and vacancy. SO2 adsorption was obviously affected by modification of graphyne. SO2 weakly interacted with pristine and nitrogen-doped graphynes. Boron doping at the sp-hybridized carbon site and introducing a single carbon atom vacancy in graphyne brought about a dramatic enhancement in SO2 adsorption. The strongly chemisorbed SO2 at these active sites caused deformation of the graphyne structure and electron redistribution, which induced changes in the conductivity and magnetism of graphynes. PMID- 28088565 TI - Rapid microwave-assisted growth of silver nanoparticles on 3D graphene networks for supercapacitor application. AB - Silver nanoparticles (AgNPs) grown on a three dimensional (3d) graphene networks (GNs) has been successfully prepared by an efficient and rapid microwave-assisted growth process to form GNs/AgNPs nanocomposite electrode materials for supercapacitor application. The 3d nature of the used GNs offers a unique architecture, which creates an efficient conduction networks and maximum utilization of space and interface, and acts as a conductive layer for the deposited AgNPs. The electrochemical performances of the fabricated electrode were evaluated by cyclic voltammetry (CV), galvanostatic charge/discharge and electrochemical impedance spectroscopy (EIS) tests. Specifically, the optimal GNs/AgNPs nanocomposite exhibits remarkable performances with a high specific capacitance of 528Fg-1 at a current density of 1Ag-1 and excellent capacitance retention of ~93% after 3000cycles. Moreover, this microwave-assisted growth strategy of AgNPs is simple and effective, which could be extended to the construction of other three dimensional graphene based metallic composites for energy storage and conversion applications. PMID- 28088567 TI - Simple fabrication of zeolitic imidazolate framework ZIF-8/polymer composite beads by phase inversion method for efficient oil sorption. AB - Zeolitic imidazolate framework ZIF-8 beads of 2-3mm in diameter were prepared using a simple one-step phase inversion method. The beads were fabricated by different amounts of ZIF-8 to polyether sulfone (PES) ratios. ZIF-8 played the role of an adsorbent while PES acted as a binder in the composite matrix to keep the ZIF-8 particles. Since ZIF-8 is highly hydrophobic, the beads floated on water and adsorbed oil droplets successfully. This efficient oil adsorption is attributed to the hydrophobicity and high surface area of ZIF-8 particles which can effectively adsorb oil droplets. Different characterization techniques were used to understand the textural properties of the composite beads. The FESEM analysis showed that ZIF-8 particles were well coated and dispersed into the polymer bead composites and some pores are created on the beads surface at higher loadings which facilitated high oil sorption. The nitrogen adsorption-desorption indicated that ZIF-8/PES beads had very high surface area which makes them suitable for adsorption applications. The ZIF-8/PES beads demonstrate easy handling and recycling compared to ZIF-8 powder and showed superior buoyancy and oil sorption capacity compared with natural sorbents like activated carbon. This study shows the phase inversion method can be applied to produce a variety of functional composite bead materials for specific applications like adsorption. PMID- 28088566 TI - Removal of salicylic acid as an emerging contaminant by a polar nano-dendritic adsorbent from aqueous media. AB - A polar nano-dendritic adsorbent containing amine groups (SAPAMAA) was synthesized onto the nanoparticles of SiO2Al2O3 and its uptake of salicylic acid (SA) from the synthetic and real water was investigated. The synthesized nanomaterials were fully studied by nuclear magnetic resonance spectrum (1H NMR and 13C NMR), Fourier transform infrared spectroscopy (FT-IR), zeta potential (zeta), inductively coupled plasma atomic emission spectroscopy (ICP-AES), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Brunauer-Emmett-Teller (BET) and elemental analysis. Various parameters such as the effect of the contact time, adsorbent dosage, initial SA concentrations, effect of solution's temperature, interfering ions, the hydrophobicity of the nanoadsorbent and initial pH were assessed. The contact time to approach equilibrium for higher adsorption was 15min (252.8mgg-1). The isotherms could be fitted by Sips model (with the average relative error of 6.6) and the kinetic data could be characterized by pseudo-second-order rate equation (with the average relative error of 13.0), implying chemical adsorption as the ratelimiting step of uptake process which was supported by the experimental data from the effect of interfering ions, zeta potential, and altering of the adsorbent's hydrophobicity. The uptake capacities decreased with temperature increasing, and showed that the uptake of SA was chemically exothermic in nature between 15 and 80 degrees C. In addition, the spent SAPAMAA could be regenerated by the removal of adsorbed SA with NaOH and ethanol to regain the original SAPAMAA, the regenerated SAPAMAA also exhibited the high adsorption capacity after 10 runs. Moreover, SAPAMAA could also be applied to uptake SA from a real water (Anzali lagoon water). We envisage that the prepared nano-dendritic with remarkable characteristics such as environmentally friendly, low-cost, easy preparation in large quantity, high mechanical and chemical stability will play a significant role in developing a new generation of emerging contaminants adsorbent. PMID- 28088568 TI - Nanostructured tin oxide films: Physical synthesis, characterization, and gas sensing properties. AB - Nanostructured tin oxide (SnO2) films are synthesized using physical method i.e. thermal evaporation and are further characterized with X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, transmission electron microscopy, and atomic force microscopy measurement techniques for confirming its structure and morphology. The chemiresistive properties of SnO2 films are studied towards different oxidizing and reducing gases where these films have demonstrated considerable selectivity towards oxidizing nitrogen dioxide (NO2) gas with a maximum response of 403% to 100ppm @200 degrees C, and fast response and recovery times of 4s and 210s, respectively, than other test gases. In addition, SnO2 films are enabling to detect as low as 1ppm NO2 gas concentration @200 degrees C with 23% response enhancement. Chemiresistive performances of SnO2 films are carried out in the range of 1-100ppm and reported. Finally, plausible adsorption and desorption reaction mechanism of NO2 gas molecules with SnO2 film surface has been thoroughly discussed by means of an impedance spectroscopy analysis. PMID- 28088569 TI - Design of beta-cyclodextrin modified TiO(2) nanotubes for the adsorption of Cu(II): Isotherms and kinetics study. AB - This paper builds on previous literature showing the interesting adsorptive properties of TiO2 nanotubes. It further explores the positive effect of beta cyclodextrin on these properties. Hence, beta-cyclodextrin modified TiO2 nanotubes were successfully prepared and characterized by XRD, N2 physisorption at 77K, Raman, FTIR-ATR, 1H NMR, TEM and EPR. The adsorptive interaction of Cu(II) with materials was investigated in aqueous solution at pH 9.25 (NH4+/NH3). The main conclusion is that copper(II)-ammonia complexation equilibria play an important role in the adsorption process. The beta-cyclodextrin was found to improve the Cu(NH3)42+ adsorption mainly by retarding its precipitation to high concentrations values (>400mgL-1). Adsorption experimental data showed good fit with the pseudo-second-order model and the Langmuir isotherm model. PMID- 28088570 TI - Achillea millefolium L. extract mediated green synthesis of waste peach kernel shell supported silver nanoparticles: Application of the nanoparticles for catalytic reduction of a variety of dyes in water. AB - In this paper, silver nanoparticles (Ag NPs) are synthesized using Achillea millefolium L. extract as reducing and stabilizing agents and peach kernel shell as an environmentally benign support. FT-IR spectroscopy, UV-Vis spectroscopy, X ray Diffraction (XRD), Field emission scanning electron microscopy (FESEM), Energy Dispersive X-ray Spectroscopy (EDS), Thermo gravimetric-differential thermal analysis (TG-DTA) and Transmission Electron Microscopy (TEM) were used to characterize peach kernel shell, Ag NPs, and Ag NPs/peach kernel shell. The catalytic activity of the Ag NPs/peach kernel shell was investigated for the reduction of 4-nitrophenol (4-NP), Methyl Orange (MO), and Methylene Blue (MB) at room temperature. Ag NPs/peach kernel shell was found to be a highly active catalyst. In addition, Ag NPs/peach kernel shell can be recovered and reused several times with no significant loss of its catalytic activity. PMID- 28088571 TI - Theophylline-assisted, eco-friendly synthesis of PtAu nanospheres at reduced graphene oxide with enhanced catalytic activity towards Cr(VI) reduction. AB - Theophylline as a naturally alkaloid is commonly employed to treat asthma and chronic obstructive pulmonary disorder. Herein, a facile theophylline-assisted green approach was firstly developed for synthesis of PtAu nanospheres/reduced graphene oxide (PtAu NSs/rGO), without any surfactant, polymer, or seed involved. The obtained nanocomposites were applied for the catalytic reduction and removal of highly toxic chromium (VI) using formic acid as a model reductant at 50 degrees C, showing the significantly enhanced catalytic activity and improved recyclability when compared with commercial Pt/C (50%) and home-made Au nanocrystals supported rGO (Au NCs/rGO). It demonstrates great potential applications of the catalyst in wastewater treatment and environmental protection. The eco-friendly route provides a new platform to fabricate other catalysts with enhanced catalytic activity. PMID- 28088572 TI - BCS class IV drugs: Highly notorious candidates for formulation development. AB - BCS class IV drugs (e.g., amphotericin B, furosemide, acetazolamide, ritonavir, paclitaxel) exhibit many characteristics that are problematic for effective oral and per oral delivery. Some of the problems associated include low aqueous solubility, poor permeability, erratic and poor absorption, inter and intra subject variability and significant positive food effect which leads to low and variable bioavailability. Also, most of the class IV drugs are substrate for P glycoprotein (low permeability) and substrate for CYP3A4 (extensive pre systemic metabolism) which further potentiates the problem of poor therapeutic potential of these drugs. A decade back, extreme examples of class IV compounds were an exception rather than the rule, yet today many drug candidates under development pipeline fall into this category. Formulation and development of an efficacious delivery system for BCS class IV drugs are herculean tasks for any formulator. The inherent hurdles posed by these drugs hamper their translation to actual market. The importance of the formulation composition and design to successful drug development is especially illustrated by the BCS class IV case. To be clinically effective these drugs require the development of a proper delivery system for both oral and per oral delivery. Ideal oral dosage forms should produce both a reasonably high bioavailability and low inter and intra subject variability in absorption. Also, ideal systems for BCS class IV should produce a therapeutic concentration of the drug at reasonable dose volumes for intravenous administration. This article highlights the various techniques and upcoming strategies which can be employed for the development of highly notorious BCS class IV drugs. Some of the techniques employed are lipid based delivery systems, polymer based nanocarriers, crystal engineering (nanocrystals and co-crystals), liquisolid technology, self-emulsifying solid dispersions and miscellaneous techniques addressing the P-gp efflux problem. The review also focuses on the roadblocks in the clinical development of the aforementioned strategies such as problems in scale up, manufacturing under cGMP guidelines, appropriate quality control tests, validation of various processes and variable therein etc. It also brings to forefront the current lack of regulatory guidelines which poses difficulties during preclinical and clinical testing for submission of NDA and subsequent marketing. Today, the pharmaceutical industry has as its disposal a series of reliable and scalable formulation strategies for BCS Class IV drugs. However, due to lack of understanding of the basic physical chemistry behind these strategies formulation development is still driven by trial and error. PMID- 28088573 TI - Heat shock proteins and cancer: How can nanomedicine be harnessed? AB - Heat shock protein (hsp90) is an interesting target for cancer therapy because it is involved in the folding and stabilization of numerous proteins, including many that contribute to the development of cancer. It is part of the chaperone machinery that includes other heat shock proteins (hsp70, hsp27, hsp40) and is mainly localized in the cytosol, although many analogues or isoforms can be found in mitochondrion, endoplasmic reticulum and the cell membrane. Many potential inhibitors of hsp90 have been tested for cancer therapy but their usefulness is limited by their poor solubility in water and their ability to reach the target cells and the correct intracellular compartment. Nanomedicine, the incorporation of active molecules into an appropriate delivery system, could provide a solution to these drawbacks. In this review, we explain the rationale for using nanomedicine for this sort of cancer therapy, considering the properties of the chaperone machinery and of the different hsp90 analogues. We present some results that have already been obtained and put forward some strategies for delivery of hsp90 analogues to specific organelles. PMID- 28088574 TI - Time dependence of the enhancement effect of chemical enhancers: Molecular mechanisms of enhancing kinetics. AB - Chemical enhancers are widely used for facilitating drug penetration in transdermal drug delivery system (TDDS). However, there is a lack of knowledge about how the enhancement effect changes over time. In this study, on the basis of kinetic parameters of enhancement effect, molecular details of the dynamic enhancement process was described and a new hypothesis of the recovery mechanism of the skin barrier function was proposed. Using pretreated skin and flurbiprofen patch, the effects of Azone (AZ) and menthyl decanoate (MT-10) were evaluated with in vitro permeation experiment and further confirmed by confocal laser scanning microscopy (CLSM) and TEWL. The results showed that the enhancement ratio (ER) increased firstly, then reached a plateau and finally decreased. The enhancement effect of MT-10 was slower (Tonset, MT-10>Tonset, AZ), weaker (ERmax, MT-10=60years old (53.8% vs. 82.0%, p<0.001), and was thus more suitable as screening test. FibroMeter with vibration controlled transient elastography (VCTE) was the most accurate among the eight fibrosis tests evaluated. The sensitivity of the eLIFT-FMVCTE algorithm (first-line eLIFT, second-line FibroMeterVCTE) was 76.1% for advanced fibrosis and 92.1% for cirrhosis. Prognostic study: patients diagnosed as having "no/mild fibrosis" by the algorithm had excellent liver-related prognosis with thus no need for referral to a hepatologist. CONCLUSION: The eLIFT-FMVCTE algorithm extends the detection of advanced liver fibrosis to all CLD patients and reduces unnecessary referrals of patients without significant CLD to hepatologists. LAY SUMMARY: Blood fibrosis tests and transient elastography accurately diagnose advanced liver fibrosis in the large population of patients having chronic liver disease, but these non-invasive tests are only currently available in specialized centers. We have developed an algorithm including the easy liver fibrosis test (eLIFT), a new simple and widely available blood test. It is used as a first-line procedure that selects at-risk patients who need further evaluation with the FibroMeterVCTE, an accurate fibrosis test combining blood markers and transient elastography result. This new algorithm, called the eLIFT-FMVCTE, accurately identifies the patients with advanced chronic liver disease who need referral to a specialist, and those with no or mild liver lesions who can remain under the care of their usual physician. CLINICAL TRIAL REGISTRATION: No registration (analysis of pooled data from previously published diagnostic studies). PMID- 28088583 TI - Environmental carcinogenesis and pH homeostasis: Not only a matter of dysregulated metabolism. AB - According to the World Health Organization, around 20% of all cancers would be due to environmental factors. Among these factors, several chemicals are indeed well recognized carcinogens. The widespread contaminant benzo[a]pyrene (B[a]P), an often used model carcinogen of the polycyclic aromatic hydrocarbons' family, has been suggested to target most, if not all, cancer hallmarks described by Hanahan and Weinberg. It is classified as a group I carcinogen by the International Agency for Research on Cancer; however, the precise intracellular mechanisms underlying its carcinogenic properties remain yet to be thoroughly defined. Recently, the pH homeostasis, a well known regulator of carcinogenic processes, was suggested to be a key actor in both cell death and Warburg-like metabolic reprogramming induced upon B[a]P exposure. The present review will highlight those data with the aim of favoring research on the role of H+ dynamics in environmental carcinogenesis. PMID- 28088584 TI - Proton pump inhibition and cancer therapeutics: A specific tumor targeting or it is a phenomenon secondary to a systemic buffering? AB - One of the unsolved mysteries in oncology includes the strategies that cancer cells adopt to cope with an adverse microenvironment. However, we knew, from the Warburg's discovery that through their metabolism based on sugar fermentation, cancer cells acidify their microenvironment and this progressive acidification induces a selective pressure, leading to the development of very malignant cells entirely armed to survive in the hostile microenvironment generated by their own metabolism. In the last decades a primordial role for proton exchangers has been supported as a key tumor advantage in facing off the acidic milieu. Proton exchangers do not allow intracellular acidification through a continuous elimination of H+ either outside the cells or within the internal vacuoles. This article wants to comment a translational process through that led to the preclinical demonstration that a class of proton pump inhibitors (PPI) exploited worldwide for peptic ulcer treatment and gastroprotection are indeed powerful chemosensitizers as well. In this process we achieved the clinical proof of concept that PPI may well be included in new anti-cancer strategies with a solid background and rationale. PMID- 28088585 TI - Nocardiosis in the south of France over a 10-years period, 2004-2014. AB - BACKGROUND: Nocardiosis is a rare disease with polymorphic presentations. The epidemiology and clinical presentation could change with the increasing number of immunocompromised patients. METHODS: The medical records and microbiological data of patients affected by nocardiosis and treated at the university hospitals of Marseille between 2004 and 2014 were analyzed retrospectively. RESULTS: The cases of 34 patients infected by Nocardia spp during this period were analyzed. The main underlying conditions were transplantation (n=15), malignancy (n=9), cystic fibrosis (n=4), and immune disease (n=3); no immunodeficiency condition was observed for three patients. No case of AIDS was observed. At diagnosis, 61.8% had received steroids for over 3 months. Four clinical presentations were identified, depending on the underlying condition: the disseminated form (50.0%) and the visceral isolated form (26.5%) in severely immunocompromised patients, the bronchial form (14.7%) in patients with chronic lung disease, and the cutaneous isolated form (8.8%) in immunocompetent patients. Nocardia farcinica was the main species identified (26.5%). Trimethoprim-sulfamethoxazole was prescribed in 68.0% of patients, and 38.0% underwent surgery. Mortality was 11.7%, and the patients who died had disseminated or visceral nocardiosis. CONCLUSIONS: The clinical presentation and outcome of nocardiosis depend on the patient's initial immune status and underlying pulmonary condition. Severe forms were all iatrogenic, occurring after treatments altering the immune system. PMID- 28088586 TI - A Case-control Study of Risk Sources for Severe Fever with Thrombocytopenia Syndrome in Hubei Province, China. AB - BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS), an emerging infectious disease caused by a novel bunyavirus, was discovered in rural areas of Central China in 2009. METHODS: A case-control study based on hospital data was applied to detect the potential risk sources for SFTS in SFTS-endemic counties in Hubei Province. Cases were defined as hospitalized SFTSV confirmed patients. Controls were randomly selected from non-SFTSV patients in the same hospital ward within 2 weeks of inclusion of the cases, and they were matched by age (+/- 5 years) and gender according to 1:2 matching condition. RESULTS: 68 cases and 136 controls participated in this study. In multivariate analysis, "Contact with cattle tick" was the major risk source (Conditional Logistic Regression OR MH=8.62, 95% CI=1.79-41.51), outdoor activities and working in weeds or hillside fields could increase risk of cattle tick contact and SFTS infection (Conditional Logistic Regression OR-MH=8.82, 95% CI=1.69-46.05, P value=0.01). CONCLUSION: Our results suggested cattle might be dominant hosts in SFTS-endemic regions in Hubei Province, which provided clues to transmission mechanism of "vectors, host animals, and humans", thus more effectively preventing and controlling the disease. PMID- 28088587 TI - Late-onset neonatal sepsis in Arab states in the Gulf region: two-year prospective study. AB - OBJECTIVES: This study aimed to investigate the incidence of late-onset sepsis (LOS) in neonatal intensive care units (NICUs) in Arab states in the Gulf region and to describe the main causative organisms and their antibiotic resistance. METHODS: This observational prospective cohort study was conducted over a 2-year period in five NICUs in Kuwait, Saudi Arabia, and the United Arab Emirates. LOS was defined as the growth of a single potentially pathogenic organism from blood or cerebrospinal fluid in infants >3days of age with clinical and laboratory findings consistent with infection. RESULTS: Seven hundred and eighty-five cases of LOS occurred among 67 474 live births. The overall incidence of LOS was 11.63 (95% confidence interval (CI) 10.84-12.47) per 1000 live births, or 56.14 (95% CI 52.38-60.08) per 1000 admissions. Coagulase-negative staphylococci and Klebsiella spp were the most common organisms, causing 272 (34.65%) and 179 (22.80%) of LOS cases, respectively. No evidence of a seasonal variation in the incidence of Klebsiella spp or in the incidence of all Gram-negative organisms was found. More than half of the Klebsiella spp were resistant to third-generation cephalosporins. CONCLUSION: LOS poses a major burden in this area, which could be due to the increasing care of premature babies. Gram-negative organisms, particularly Klebsiella spp, are having an increasing role in LOS in this region, with high levels of resistance to third-generation cephalosporins. NICUs in the area should create a platform through which to share experience in reducing neonatal sepsis and contribute to a common antibiotic stewardship program. PMID- 28088588 TI - Dengue infection in pregnancy and its impact on the placenta. AB - A histopathological and immunohistochemical study was conducted in placental tissues and retained products of conception from 24 patients with confirmed dengue infection during pregnancy. The immunohistochemical assay was positive for dengue virus in 19 placental and three ovular remnants analyzed. The light microscopic findings were signs of hypoxia, choriodeciduitis, deciduitis and intervillositis and the viral antigens were found in cytoplasmic of the trophoblast, villous stroma and decidua. Our results suggest that immunohistochemistry could be used as a laboratory confirmation method for dengue in pregnant women, especially in endemic areas when embedded material is the only material available. PMID- 28088589 TI - Analysis of laboratory testing results for Chlamydia trachomatis infection in an STI clinic in India: Need for extragenital screening. AB - BACKGROUND: Extragenital sites are believed to serve as hidden reservoirs for ongoing transmission of infection. In addition, treatment for rectal Chlamydia infection is different from that of genital Chlamydia infection. Many cases may be missed if only genital testing is performed. METHODS: Between September 2015 and August 2016, all male and female attendees at an STI clinic of a tertiary care hospital with genital and or extragenital discharge were screened for CT infection. Samples included endocervical swabs in women, urethral swabs and urine samples in men. Rectal and pharyngeal samples were collected wherever indicated. RESULTS: Of total of 439 samples collected from 417 patients (245 women and 172 men), samples from women had a high positivity rate than men. (13.6% and 11%). High rates of rectal CT was detected nearly 30.43%. All rectal positive cases except one had no concomitant genital infection. CONCLUSIONS: Prevalence of extragenital Chlamydia is increasing in men as well as women. What needs to be stressed on is the sexual behaviour of an individual and not the sexual identity. Further studies are needed to help formulate guidelines and recommendations for extragenital screening in a population. PMID- 28088590 TI - Human papillomavirus genotypes 68 and 58 are the most prevalent genotypes in women from quilombo communities in the state of Maranhao, Brazil. AB - OBJECTIVES: To determine the frequency of human papillomavirus (HPV) types and behavioral characteristics related to cytological abnormalities in women descendants of slaves, who live in isolated communities known as quilombos in the state of Maranhao, Brazil. METHODS: Cervicovaginal specimens of 353 women were analyzed by conventional cytology and genotyping. HPV detection and genotyping was performed using a linear array HPV genotyping test kit. Behavioral factors and their association with cytological abnormalities were analyzed, as well as the association between cytological abnormalities and HPV infection. RESULTS: The frequency of HPV infection was 13%, and infection with high-risk HPV types was more frequent than with low-risk types (10.2% vs. 2.8%). The most prevalent genotypes were HPV 68 (3.1%) and HPV 58 (2.6%). HPV-positive women were 6.5 times more likely than HPV-negative women to be diagnosed with cytological abnormalities. There was a significant association between HPV infection and the presence of cytological abnormalities in women 31-40 years of age and in women 51 60 years of age. CONCLUSIONS: A distinct profile of high-risk HPV genotypes was detected, with predominance of types 68 and 58. It is possible that the results of the present study are due to specific characteristics of the population, which is geographically isolated and maintains conservative sexual habits. PMID- 28088591 TI - Specific agreement on dichotomous outcomes can be calculated for more than two raters. AB - OBJECTIVE: For assessing interrater agreement, the concepts of observed agreement and specific agreement have been proposed. The situation of two raters and dichotomous outcomes has been described, whereas often, multiple raters are involved. We aim to extend it for more than two raters and examine how to calculate agreement estimates and 95% confidence intervals (CIs). STUDY DESIGN AND SETTING: As an illustration, we used a reliability study that includes the scores of four plastic surgeons classifying photographs of breasts of 50 women after breast reconstruction into "satisfied" or "not satisfied." In a simulation study, we checked the hypothesized sample size for calculation of 95% CIs. RESULTS: For m raters, all pairwise tables [ie, m (m - 1)/2] were summed. Then, the discordant cells were averaged before observed and specific agreements were calculated. The total number (N) in the summed table is m (m - 1)/2 times larger than the number of subjects (n), in the example, N = 300 compared to n = 50 subjects times m = 4 raters. A correction of n?(m - 1) was appropriate to find 95% CIs comparable to bootstrapped CIs. CONCLUSION: The concept of observed agreement and specific agreement can be extended to more than two raters with a valid estimation of the 95% CIs. PMID- 28088592 TI - A systematic review found that deviations from intention-to-treat are common in randomized trials and systematic reviews. AB - OBJECTIVES: To describe the characteristics, and estimate the incidence, of trials included in systematic reviews deviating from the intention-to-treat (ITT) principle. STUDY DESIGN AND SETTING: A 5% random sample of reviews were selected (Medline 2006-2010). Trials from reviews were classified based on the ITT: (1) ITT trials (trials reporting standard ITT analyses); (2) modified ITT (mITT) trials (modified ITT; trials deviating from standard ITT); or (3) no ITT trials. RESULTS: Of 222 reviews, 81 (36%) included at least one mITT trial. Reviews with mITT trials were more likely to contain trials that used placebo, that investigated drugs, and that reported favorable results. The incidence of reviews with mITT trial ranged from 29% (17/58) to 48% (23/48). Of the 2,349 trials, 597 (25.4%) were classified as ITT trials, 323 (13.8%) as mITT trials, and 1,429 (60.8%) as no ITT trials. The mITT trials were more likely to have reported exclusions compared to studies classified as ITT trials and to have received funding. CONCLUSION: The reporting of the type of ITT may differ according to the clinical area and the type of intervention. Deviation from ITT in randomized controlled trials is a widespread phenomenon that significantly affects systematic reviews. PMID- 28088593 TI - Additional considerations are required when preparing a protocol for a systematic review with multiple interventions. AB - OBJECTIVES: The number of systematic reviews that aim to compare multiple interventions using network meta-analysis is increasing. In this study, we highlight aspects of a standard systematic review protocol that may need modification when multiple interventions are to be compared. STUDY DESIGN AND SETTING: We take the protocol format suggested by Cochrane for a standard systematic review as our reference and compare the considerations for a pairwise review with those required for a valid comparison of multiple interventions. We suggest new sections for protocols of systematic reviews including network meta analyses with a focus on how to evaluate their assumptions. We provide example text from published protocols to exemplify the considerations. CONCLUSION: Standard systematic review protocols for pairwise meta-analyses need extensions to accommodate the increased complexity of network meta-analysis. Our suggested modifications are widely applicable to both Cochrane and non-Cochrane systematic reviews involving network meta-analyses. PMID- 28088594 TI - The number of primary events per variable affects estimation of the subdistribution hazard competing risks model. AB - OBJECTIVES: To examine the effect of the number of events per variable (EPV) on the accuracy of estimated regression coefficients, standard errors, empirical coverage rates of estimated confidence intervals, and empirical estimates of statistical power when using the Fine-Gray subdistribution hazard regression model to assess the effect of covariates on the incidence of events that occur over time in the presence of competing risks. STUDY DESIGN AND SETTING: Monte Carlo simulations were used. We considered two different definitions of the number of EPV. One included events of any type that occurred (both primary events and competing events), whereas the other included only the number of primary events that occurred. RESULTS: The definition of EPV that included only the number of primary events was preferable to the alternative definition, as the number of competing events had minimal impact on estimation. In general, 40-50 EPV were necessary to ensure accurate estimation of regression coefficients and associated quantities. However, if all of the covariates are continuous or are binary with moderate prevalence, then 10 EPV are sufficient to ensure accurate estimation. CONCLUSION: Analysts must base the number of EPV on the number of primary events that occurred. PMID- 28088595 TI - Clinical trial registration was not an indicator for low risk of bias. AB - OBJECTIVES: To determine the prevalence of registered trials and to evaluate the risk of bias between registered and unregistered clinical trials. STUDY DESIGN AND SETTING: The Cochrane Gynecology and Fertility Group's specialized register was searched on November 5, 2015, for randomized controlled trials published from 2010 to 2014. Studies were selected if they had randomized women or men for fertility treatments, were published in full text and written in English. Two reviewers then independently assessed trial registration status for each trial, by searching the publication, trial registries, and by contacting the original authors. RESULTS: Of 693 eligible randomized controlled trials, only 44% were found to be registered. Unregistered clinical trials had smaller sample sizes than registered trials (P < 0.001). A random subsample of 125 registered and 125 unregistered trials was assessed for risk of bias using five of the Cochrane Risk of Bias "domains." Registered and unregistered trials differed in their risk of bias for random sequence generation (P = 0.001), allocation concealment (P = 0.003), and selective reporting (P < 0.001) but not blinding or incomplete outcome data (P > 0.05) domains. Only 54 (43.2%) of the 125 registered trials were registered prospectively. This study has the following limitations. Only English language trials were included in this review. We were unable to obtain protocols for the unregistered trials and therefore were unable to assess the risk of bias in the selective reporting domain. CONCLUSIONS: All available trials should be included in systematic reviews and assessed for risk of bias as there are both registered trials with high risk of bias and unregistered trials with low risk of bias and by excluding unregistered trials more than half of the available evidence will be lost. PMID- 28088596 TI - Indirect evidence of reporting biases was found in a survey of medical research studies. AB - OBJECTIVES: To explore indirect evidence of reporting biases by examining the distribution of P-values reported in published medical articles and to compare P values distributions across different contexts. STUDY DESIGN AND SETTING: We selected a random sample (N = 1,500) of articles published in PubMed in March 2014. We extracted information on study type, design, medical discipline, and P values for the first reported outcome and primary outcome (if specified) from each article. We plotted the P-values transformed to the z-score scale and used caliper tests to investigate threshold effects. RESULTS: Out of the 1,500 randomly selected records, 758 (50.5%) were included. We retrieved or calculated 758 P-values for first reported outcomes and 389 for primary outcomes (specified in only 51% of included studies). The first reported and the primary outcome differed in 28% (110/389) of the included studies. The distributions of P-values for first reported outcomes and primary outcomes showed a notable discontinuity at the common thresholds of statistical significance (P-value = 0.05 and P-value = 0.01). We also found marked discontinuities in the distributions of z-scores across various medical disciplines, study designs, and types. CONCLUSION: Reporting biases are still common in medical research. We discuss their implications, strategies to detect them, and recommended practices to avoid them. PMID- 28088597 TI - Phase II Randomized Trial of Negative-Pressure Wound Therapy to Decrease Surgical Site Infection in Patients Undergoing Laparotomy for Gastrointestinal, Pancreatic, and Peritoneal Surface Malignancies. AB - BACKGROUND: Surgical site infections (SSIs) remain a major source of morbidity and cost after resection of intra-abdominal malignancies. Negative-pressure wound therapy (NPWT) has been reported to significantly reduce SSIs when applied to the closed laparotomy incision. This article reports the results of a randomized clinical trial examining the effect of NPWT on SSI rates in surgical oncology patients with increased risk for infectious complications. STUDY DESIGN: From 2012 to 2016, two hundred and sixty-five patients who underwent open resection of intra-abdominal neoplasms were stratified into 3 groups: gastrointestinal (n = 57), pancreas (n = 73), or peritoneal surface (n = 135) malignancy. They were randomized to receive NPWT or standard surgical dressing (SSD) applied to the incision from postoperative days 1 through 4. Primary outcomes of combined incisional (superficial and deep) SSI rates were assessed up to 30 days after surgery. RESULTS: There were no significant differences in superficial SSIs (12.8% vs 12.9%; p > 0.99) or deep SSI (3.0% vs 3.0%; p > 0.99) rates between the SSD and NPWT groups, respectively. When stratified by type of surgery, there were still no differences in combined incisional SSI rates for gastrointestinal (25% vs 24%; p > 0.99), pancreas (22% vs 22%; p > 0.99), and peritoneal surface malignancy (9% vs 9%; p > 0.99) patients. When performing univariate and multivariate logistic regression analysis of demographic and operative factors for the development of combined incisional SSI, the only independent predictors were preoperative albumin (p = 0.0031) and type of operation (p = 0.018). CONCLUSIONS: Use of NPWT did not significantly reduce incisional SSI rates in patients having open resection of gastrointestinal, pancreatic, or peritoneal surface malignancies. Based on these results, at this time NPWT cannot be recommended as a therapeutic intervention to decrease infectious complications in these patient populations. PMID- 28088598 TI - Are the Current Guidelines for the Surgical Management of Intraductal Papillary Mucinous Neoplasms of the Pancreas Adequate? A Multi-Institutional Study. AB - BACKGROUND: Controversy persists regarding the management of patients with intraductal papillary mucinous neoplasms (IPMN). International consensus guidelines stratify patients into high-risk, worrisome, and low risk categories. STUDY DESIGN: The medical records of 7 institutions were reviewed for patients who underwent surgical management of IPMN between 2000 and 2015. RESULTS: There were 324 patients included in the analysis; 60.4% of patients had main-duct/mixed type, and 39.7% had branch-duct IPMN. The median cyst size was 2.65 cm, invasive cancer (IC) or high-grade dysplasia (HGD) was present in 42% (n = 136); 68.9% of patients with high-risk, 40.0% of patients with worrisome, and 24.6% of patients with low risk features exhibited HGD/IC. Multivariate analysis demonstrated that only 1 of 3 high-risk features and 2 of 7 worrisome features predicted the presence of HGD/IC. Positive predictive values for HGD/ IC in patients with obstructive jaundice and lymphadenopathy were 0.83 (95% CI 0.65 to 0.94) and 0.69 (95% CI 0.39 to 0.91), respectively. In the absence of high-risk features, HGD/IC was still present in 57.4% of patients with 2 or more worrisome features. Regression analysis demonstrated that each additional worrisome factor present was additive in predicting HGD/IC in a linear fashion (odds ratio 1.39; 95% CI 1.08 to 1.80; p < 0.01). CONCLUSIONS: These data demonstrate that the current consensus guidelines for surgical resection of IPMN may not adequately stratify and identify patients at risk for having HGD or invasive cancer. Patients with multiple worrisome features, in the absence of high-risk factors, should be considered for resection. PMID- 28088599 TI - Southern Surgical Association: A Tradition of Mentorship in Translational Research. PMID- 28088600 TI - Development and Validation of a Methodology to Reduce Mortality Using the Veterans Affairs Surgical Quality Improvement Program Risk Calculator. AB - BACKGROUND: To identify patients with a high risk of 30-day mortality after elective surgery, who may benefit from referral for tertiary care, an institution specific process using the Veterans Affairs Surgical Quality Improvement Program (VASQIP) Risk Calculator was developed. The goal was to develop and validate the methodology. Our hypothesis was that the process could optimize referrals and reduce mortality. STUDY DESIGN: A VASQIP risk score was calculated for all patients undergoing elective noncardiac surgery at a single Veterans Affairs (VA) facility. After statistical analysis, a VASQIP risk score of 3.3% predicted mortality was selected as the institutional threshold for referral to a tertiary care center. The model predicted that 16% of patients would require referral, and 30-day mortality would be reduced by 73% at the referring institution. The main outcomes measures were the actual vs predicted referrals and mortality rates at the referring and receiving facilities. RESULTS: The validation included 565 patients; 90 (16%) had VASQIP risk scores greater than 3.3% and were identified for referral; 60 consented. In these patients, there were 16 (27%) predicted mortalities, but only 4 actual deaths (p = 0.007) at the receiving institution. When referral was not indicated, the model predicted 4 mortalities (1%), but no actual deaths (p = 0.1241). CONCLUSIONS: These data validate this methodology to identify patients for referral to a higher level of care, reducing mortality at the referring institutions and significantly improving patient outcomes. This methodology can help guide decisions on referrals and optimize patient care. Further application and studies are warranted. PMID- 28088601 TI - Mid-Term Outcomes in Patients with Congenitally Corrected Transposition of the Great Arteries: A Single Center Experience. AB - BACKGROUND: Optimal management of patients with congenitally corrected transposition of the great arteries (ccTGA) is unclear. The goal of this study was to compare the outcomes in patients with ccTGA undergoing different management strategies. STUDY DESIGN: Patients with ccTGA believed suitable for biventricular circulation, treated between 1995 and 2016, were included. The cohort was divided into 4 groups: systemic right ventricle (RV) (patients without surgical intervention or with a classic repair), anatomic repair, Fontan palliation, and patients receiving only a pulmonary artery band (PAB) or a shunt. Transplant-free survival from presentation was calculated for each group. RESULTS: The cohort included 97 patients: 45 (46%) systemic RV, 26 (27%) anatomic repair, 9 (9%) Fontan, and 17 (18%) PAB/shunt. Median age at presentation was 2 months (range 0 days to 69 years) and median follow-up was 10 years (1 month to 28 years). At initial presentation, 10 (11%) patients had any RV dysfunction (8 mild, 2 severe), and 16 (18%) patients had moderate or severe tricuspid regurgitation (TR). During the study, 10 (10%) patients died, and 3 (3%) patients underwent transplantation. At last follow-up, 11 (11%) patients were in New York Heart Association class III/IV, 5 (5%) had moderate or severe systemic ventricle dysfunction, and 16 (16%) had moderate or severe systemic atrioventricular valve regurgitation. Transplant-free survivals at 10 years were 93%, 86%, 100%, and 79% for systemic RV, anatomic repair, Fontan palliation, and PAB/shunt, respectively (p = 0.33). On multivariate analysis, only systemic RV dysfunction was associated with a higher risk for death or transplant (p = 0.001). CONCLUSIONS: Transplant free survival in ccTGA appears to be similar between patients with a systemic RV, anatomic repair, and Fontan procedure. Systemic RV dysfunction is a risk factor for death and transplant. PMID- 28088602 TI - Aggressive Surgical Approach to the Management of Neuroendocrine Tumors: A Report of 1,000 Surgical Cytoreductions by a Single Institution. AB - BACKGROUND: Neuroendocrine tumors (NETs) are rare neoplasms. Our group has treated more than 2,000 NET patients and has performed more than 1,000 surgical cytoreductive procedures. STUDY DESIGN: Records of 834 NET patients who underwent surgical cytoreduction at our institution were reviewed. Demographic information, intraoperative findings, extent of disease, complications, and survival rates were calculated. RESULTS: Eight hundred patients underwent 1,001 cytoreductive operations. Sixty-five percent had small bowel primaries. One hundred and thirty eight patients presented with an unknown primary site, which was localized intraoperatively in 89% of these cases. The intraoperative complication rate was 9%. The incidence of intraoperative carcinoid crisis was 1%. Mean +/- SD operative time was 368 +/- 146 minutes. Mean +/- SD hospital stay was 9 +/- 10 days. Minor postoperative complications occurred after 43% of procedures and major postoperative complications were noted after 19% of procedures. The 30-day postoperative mortality rate was 2%. Median overall survival (OS) for patients with pancreatic NETs was 124 months. The 5-, 10-, and 20-year OS rates for patients with pancreatic NETs were 67%, 51%, and 36%, respectively. The life expectancy difference (between OS and actuarial survival) after surgical cytoreduction for patients with pancreatic NETs was 16.6 years. Median OS for patients with small bowel NETs was 161 months. The 5-, 10-, and 20-year OS rates for patients with small bowel NETs were 84%, 67% and 31%, respectively. The life expectancy difference after surgical cytoreduction for patients with small bowel NETs was 11.7 years. CONCLUSIONS: Surgical cytoreduction in NET patients has low morbidity and mortality rates and results in prolonged survival. We believe that surgical cytoreduction should play a major role in the care of patients with NETs. PMID- 28088603 TI - Hospital Readmissions after Surgery: How Important Are Hospital and Specialty Factors? AB - BACKGROUND: Hospital readmission rates after surgery can represent an overall hospital effect or a combination of specialty and patient effects. We hypothesized that hospital readmission rates for procedures within specialties were more strongly correlated than rates across specialties within the same hospital. STUDY DESIGN: For general, orthopaedic, and vascular specialties at Veterans Affairs hospitals during 2008 to 2014, 30-day risk-adjusted readmission rates were estimated for 6 high-volume procedures and each specialty. Relationships were assessed using the Pearson correlation coefficient. RESULTS: At 84 hospitals, 64,724 orthopaedic, 24,963 general, and 10,399 vascular inpatient procedures were performed; mean readmission rates were 6.3%, 13.6%, and 16.4%, respectively. There was no correlation between specialty-specific adjusted hospital readmission rates: general and orthopaedic (r = 0.21; p = 0.06), general and vascular (r = 0.15; p = 0.19), and vascular and orthopaedic surgery (r = 0.07; p = 0.55). Within specialties, we found modest correlations between knee and hip arthroplasty readmission rates (r = 0.39; p < 0.01) and colectomy and ventral hernia repair (r = 0.24; p = 0.03), but not between lower-extremity bypass and endovascular aortic repair (r = 0.13; p = 0.26). Overall, controlling for patient-level factors, 1.9% of the variation in readmissions was attributable to specialty-level factors; only 0.6% was attributable to hospital-level factors. CONCLUSIONS: Hospital readmission rates for orthopaedic, vascular, and general surgery were not correlated between specialties; within each of the 3 specialties, modest correlations were found between 2 procedures within 2 of these specialties. These findings suggest that hospital surgical readmission rates are primarily explained by patient- and procedure-specific factors and less by broader specialty and/or hospital effects. PMID- 28088604 TI - ALBA Screening Instrument (ASI): A brief screening tool for Lewy Body Dementia. AB - BACKGROUND: Early detection of neurodegenerative diseases is essential for treatment and proper care of these patients. Screening tools available today are effective for several types of dementia. However, there is no one specific for Lewy Body Dementia (LBD). OBJECTIVES: The aim of this paper is to present a tool for early detection of LBD, accessible even for non-medical staff. METHODS: We stratified subjects (MMSE>20) into four groups: health controls (HC), Mild Cognitive Impairment (MCI), LBD and other dementias (Alzheimer and vascular). All subjects (age range 50-90) were examined with a comprehensive neuropsychological and neuropsychiatric evaluation, as well as neuroimaging to differentiate diagnosis between groups, fulfilling corresponding criteria. Both neurologists and neuropsychologists were blind to the performance on clinical evaluations and ASI, respectively. The sensitivity and specificity of the instrument were determined to differentiate LBD from other groups. RESULTS: We evaluated 427 subjects, 91 HC, 140 with MCI and 196 with dementia. In the dementia group, 75 were diagnosed with LBD and 121 with other dementias. ASI total score was 12.7+/ 0.4 for LBD, 2.9+/-0.2 for HC, 5+/-0.7 for MCI, and 5.4+/-2.6 for other causes of dementia. ROC curve analysis showed a sensitivity of 90.7% and a specificity of 93.6% stands, with 9 as the cutoff with better test performance compared against other groups. CONCLUSION: ASI is a brief screening tool for LBD with high sensitivity and specificity and useful even for non-medical staff. PMID- 28088605 TI - Comparison of the anterior chamber angle structure between children and adults. AB - PURPOSE: To investigate the anterior chamber structure in children and adults with a similar axial length (AL). METHODS: A total of 50 children (mean age, 7.1 +/- 3.3 years; range, 3-16) with mainly refractive error and 50 adults (mean age, 73.7 +/- 7.8 years; range, 50-85) with short AL were included. The mean AL was 22.21 +/- 0.88 mm (range, 20.67-23.97 mm) in children; 22.34 +/- 0.53 mm (range, 20.50-22.96 mm), in adults. The corneal curvature, spherical equivalent, AL, central corneal thickness (CCT), inter-scleral spur distance, perpendicular distance, anterior chamber depth (ACD), angle opening distance (AOD), and lens vault were measured. An independent t test and a stepwise regression analysis were used to analyze the data. RESULTS: There were no significant differences between groups in AL, spherical equivalent, and perpendicular distance. By comparison, the children had larger corneal curvature (children:adults = 7.70:7.40 mm), longer inter-scleral spur distance (11.65:11.20 mm), greater CCT (560:522 MUm), deeper anterior chamber (3.05:2.53 mm), and larger AOD (0.56:0.37 mm) than adults (all P < 0.01). The lens vault was smaller in the children than in the adults (0.04:0.54, P < 0.01). The predictive factors for lens vault were the ACD (coefficient = -0.407), inter-scleral spur distance (0.307), AOD ( 0.650), group (children, -0.108) and corneal curvature (-0.214). The predictive factors for the AOD were the lens vault (-0.310), inter-scleral spur distance (0.140), and corneal curvature (-0.143). CONCLUSIONS: In our cohort, the anterior chamber angle (the semicircle structure of the anterior segment) in children was larger than in adults. This may partially explain why, despite having a short AL, children rarely develop primary angle closure. PMID- 28088606 TI - Choice of factor VIII/IX regimen in adolescents and young adults with severe or moderately severe haemophilia. A French national observational study (ORTHem 15 25). AB - INTRODUCTION: The value and challenges of long-term prophylaxis (LTP) in adolescents and young adults need further characterisation. AIM: To determine the proportions of adolescents and young adults with severe or moderately severe haemophilia in France under LTP and treatment on demand (OD). METHODS: Patients 15 to 25years old with haemophilia A or B, factor VIII/IX <=2% and no current inhibitor could be included if they had been under factor VIII/IX treatment at least 12months and kept a treatment and bleeding diary. RESULTS: LTP was administered to 169/212 patients (79.7%) and OD treatment to 40/212 patients (18.9%). The most frequent reasons for initiating LTP were joint bleeding, target joints and frequent bleeds; whereas OD treatment was most often selected on the basis of mild bleeding phenotype or because of constraints on LTP. The mean annual bleed rate (ABR) in the OD group (6.33) was higher than in the LTP group (3.07, p<0.001). Mean ABR did not differ significantly between age strata (15-18, >18-21 and >21-25years), but was significantly higher for patients with severe haemophilia (4.02) as compared to those with moderate haemophilia (1.97, p=0.002). No significant difference was observed in mean ABR for joint bleeds between the LTP and OD groups. Physician reported LTP compliance was good or excellent in 97.0% of patients. CONCLUSION: LTP is the predominant factor VIII/IX treatment among adolescents and young adults with severe or moderately severe haemophilia in France. LTP was associated with low ABR and high compliance. PMID- 28088607 TI - Transcatheter aortic valve implantation leads to a restoration of von Willebrand factor (VWF) abnormalities in patients with severe aortic stenosis - Incidence and relevance of clinical and subclinical VWF dysfunction in patients undergoing transfemoral TAVI. AB - BACKGROUND: In this study, we sought to analyze the incidence and relevance of von Willebrand factor (VWF) abnormalities in patients undergoing transcatheter aortic valve implantation (TAVI), especially on perioperative bleeding. Furthermore, we hypothesized that, similar to aortic valve surgery, TAVI results in a restoration of VWF abnormalities. METHODS AND RESULTS: We performed a prospective analysis of periinterventional VWF parameters in 74 patients (80+/ 7years, female in 37.5%) undergoing transfemoral TAVI for severe symptomatic aortic valve stenosis. At baseline, VWF:Ag was 210+/-90IU/dl with a mean VWF activity of 166+/-106IU/dl; activity-to-antigen ratio was 0.85+/-0.45. Heyde's syndrome (severe aortic stenosis plus GI bleeding from angiodyplasia) was observed in 2/74 (2.7%). Whereas preprocedural loss of high-molecular-weight (HMW) VWF multimers was found in thirty-six patients (48.6%), none of the patients fulfilled criteria for possible acquired VW syndrome. After TAVI, an increase of both VWF:Ag and activity compared to baseline was observed (p<0.01). In patients with HMW multimer loss, post-interventional recovery of multimers occurred in all cases. In the two patients with Heyde's syndrome, a trend towards reduced VWF:Ag was seen, with loss of HMW multimers in one patient. Of interest, all patients suffering from periprocedural major bleeding (5/74; 6.8%) exhibited activity-to-antigen ratios <0.7, indicating subclinical VWF dysfunction. CONCLUSION: Whereas clinically relevant VWF dysfunction is rare, loss of HMW VWF multimers is common in TAVI patients. Similar to surgery, TAVI leads to a restoration of this loss. Furthermore, VWF parameters may be useful parameter to evaluate risk of periprocedural bleeding. PMID- 28088608 TI - Gene analysis of six cases of congenital protein S deficiency and functional analysis of protein S mutations (A139V, C449F, R451Q, C475F, A525V and D599TfsTer13). AB - Congenital deficiency of protein S (PS), an anticoagulant factor, leads to venous thrombosis, with onset predominantly beginning in adolescence. In the present study, gene analysis of six unrelated Japanese families diagnosed with congenital PS deficiency identified five missense mutations in the PROS1 gene - c.757C>T (Ala139Val; A139V), c.1346 G>T (Cys449Phe; C449F), c.1352G>A (Arg451Gln; R451Q), c.1424G>T (Cys475Phe; C475F) and c.1574C>T (Ala525Val; A525V) - and one frameshift mutation, c.2135delA (Asp599ThrfsTer13; D599TfsTer13). C449F, R451Q, A525V and D599TfsTer13 are novel mutations. Results from ELISA to measure PS antigen levels in culture supernatant showed that the A139V variant was similar to wild-type, but other variants showed reductions when compared with wild-type. Results from pulse-chase analysis confirmed that the A139V variant exhibited secretion equivalent to wild-type, but for the other variants, there was no extracellular secretion, and it had nearly all been degraded inside the cell within six hours. Results from pulse-chase analysis using proteasome inhibitors also showed that intracellular degradation of mutant protein was inhibited. Activity of the A139V variant was decreased to 71% of wild-type, and the phospholipid binding capacity fell to as low as 45%. These results suggest that although the A139V variant has normal secretion, it has abnormal phospholipid binding capacity, and therefore causes type II PS deficiency, in which PS activity is decreased. It is also thought that with the other variants, misfolding due to amino acid mutations causes nearly all PS to be degraded intracellularly, therefore leading to type I PS deficiency. PMID- 28088609 TI - Leukemia inhibitory factor impairs structural and neurochemical development of rat visual cortex in vivo. AB - Minipump infusions into visual cortex in vivo at the onset of the critical period have revealed that the proinflammatory cytokine leukemia inhibitory factor (LIF) delays the maturation of thalamocortical projection neurons of the lateral geniculate nucleus, and tecto-thalamic projection neurons of the superior colliculus, and cortical layer IV spiny stellates and layer VI pyramidal neurons. Here, we report that P12-20 LIF infusion inhibits somatic maturation of pyramidal neurons and of all interneuron types in vivo. Likewise, DIV 12-20 LIF treatment in organotypic cultures prevents somatic growth GABA-ergic neurons. Further, while NPY expression is increased in the LIF-infused hemispheres, the expression of parvalbumin mRNA and protein, Kv3.1 mRNA, calbindin D-28k protein, and GAD-65 mRNA, but not of GAD-67 mRNA or calretinin protein is substantially reduced. Also, LIF treatment decreases parvalbumin, Kv3.1, Kv3.2 and GAD-65, but not GAD 67 mRNA expression in OTC. Developing cortical neurons are known to depend on neurotrophins. Indeed, LIF alters neurotrophin mRNA expression, and prevents the growth promoting action of neurotophin-4 in GABA-ergic neurons. The results imply that LIF, by altering neurotrophin expression and/or signaling, could counteract neurotrophin-dependent growth and neurochemical differentiation of cortical neurons. PMID- 28088610 TI - The effects of voluntary wheel running on neuroinflammatory status: Role of monocyte chemoattractant protein-1. AB - The health benefits of exercise and physical activity (PA) have been well researched and it is widely accepted that PA is crucial for maintaining health. One of the mechanisms by which exercise and PA exert their beneficial effects is through peripheral immune system adaptations. To date, very few studies have looked at the regulation of neuroimmune reactions in response to PA. We studied the effect of voluntary wheel running (VWR) on pro- and anti-inflammatory cytokine levels, patterns of glial cell activation and expression of immune receptors in the brains of female C57BL/6 mice. By using homozygous monocyte chemoattractant protein (MCP)-1 null mice, we investigated the role of this key immunoregulatory cytokine in mediating VWR-induced neuroinflammatory responses. We demonstrated that, compared to their sedentary counterparts, C57BL/6 mice exposed for seven weeks to VWR had increased levels of pro- and anti-inflammatory cytokines, markers of glial cell activation and a trend towards increased expression of toll-like receptor (TLR) 4 in the brain. Measurements of serum cytokines revealed that the alterations in brain cytokine levels could not be explained by the effects of PA on peripheral cytokine levels. We propose that the modified neuroimmune status observed in the VWR group represents an activated immune system, as opposed to a less activated immune system in the sedentary group. Since MCP-1 knockout mice displayed differing patterns of pro- and anti inflammatory brain cytokine expression and glial activation when compared to their wild-type counterparts, we concluded that the effects of VWR on neuroimmune reactions may be modulated by MCP-1. These identified immunomodulatory effects of PA in the brain could contribute to the observed positive relationship between physically active lifestyles and a reduced risk for a number of neurodegenerative diseases that possess a significant neuroinflammatory component. PMID- 28088611 TI - Lactobacillus paracasei modulates LPS-induced inflammatory cytokine release by monocyte-macrophages via the up-regulation of negative regulators of NF-kappaB signaling in a TLR2-dependent manner. AB - The application of the probiotic lactobacillus is suggested in the treatment of some inflammatory diseases of intestines due to its potential ability to attenuate inflammation. However, the mechanism is not completely understood. In PBMCs, Lactobacillus paracasei (L. Paracasei) down-regulated the LPS-induced production of TNF-alpha and IL-6. Using a macrophage-like differentiated THP-1 cell line induced by PMA, we investigated the effect of L. paracasei on the production of pro-inflammatory cytokines by monocyte-macrophages. Treatment of the differentiated THP-1 cells with L. paracasei either concurrently with or before LPS challenge attenuated the LPS-induced secretion of TNF-alpha and IL 1beta. This effect was due to a decrease in IkappaB phosphorylation and NF-kappaB nuclear translocation. Furthermore, treatment of the differentiated THP-1 cells with L. paracasei induced the expression of negative regulators of the NF-kappaB signaling pathway, including the deubiquitinating enzyme A20, suppressor of cytokine signaling (SOCS) 1, SOCS3, and IL-1 receptor-associated kinase (IRAK) 3. Pretreatment with an IRAK4 inhibitor suppressed the L. paracasei-induced expression of these negative regulators and further increased the LPS-mediated expressions of TNF-alpha and IL-1beta. Moreover, treatment with an antibody against Toll-like receptor (TLR) 2 reversed the effect of L. paracasei on inducing negative regulators and inhibiting TNF-alpha and IL-1beta productions. Our findings suggest that L. paracasei inhibits the production of pro inflammatory cytokines by monocyte-macrophages via the induction of negative regulators of the NF-kappaB signaling pathway in a TLR2-IRAK4-dependent manner. PMID- 28088612 TI - Alterations in cytokine gene expression profile in colon mucosa of Inflammatory Bowel Disease patients on different therapeutic regimens. AB - Inflammatory bowel disease (IBD) is assumed to be caused by genetic and environmental factors that interact together in promoting intestinal immune dysregulation where cytokines have validated role. However, the underlying intimate mechanisms in the human IBD involving cytokines still needs to be supplemented especially in the clinical context. The aim of this study was to investigate the expression of some inflammatory and regulatory cytokines (IL-17A, IL-23, IL-6, TGFbeta1, and IL-10) as well as of the transcription factor FoxP3 in mucosal samples of IBD and non-IBD patients. We assessed the mRNA relative quantities (RQ) of the above-mentioned cytokines and the transcription factor FoxP3 in paired colonic samples (inflamed and adjacent normal mucosa) from 37 patients with IBD and in normal mucosal tissue in 12 persons without IBD by performing a qRT-PCR assay and tested the protein levels of target cytokines in serum samples. The patients were divided into three groups: without any therapy (n=10), on 5-ASA (n=11) and on immunosuppressants (Azathioprine+/-5 ASA/corticosteroids) (n=16) in order to compare the RQ values for each therapeutic group. All investigated genes were found upregulated in the inflamed mucosa of IBD patients in the following order: IL-6>FoxP3>TGFbeta1>IL-23>IL 17A>IL-10. We also observed that the gene expression of FoxP3 and IL-6 were substantially higher in the inflamed mucosal tissue of the IBD patients than the adjacent normal mucosa (p=0.035, p=0.03 respectively). Differences between higher mRNA expression of FoxP3 and IL-6 in inflamed tissue were considered significant in patients with ulcerative colitis (UC) (p=0.011, p=0.000 respectively) and with Crohn's disease (CD) (p=0.008, p=0.000 respectively) in comparison to the normal mucosa of non-IBD persons and we found increased TGFbeta1 in CD patients alone (p=0.041). Furthermore, IL-6 and TGFbeta1 were overexpressed (RQ>10) in non inflamed mucosa from IBD patients compared to the normal mucosa from the controls. When we compared the gene expression for paired mucosa in the immunosuppressive treated group with the 5-ASA treated group we observed opposite changes in IL-6 and TGFbeta1 expression. Additionally, we found higher serum levels of IL-23 (p=0.008), TGFbeta1 and IL-6 in IBD patients compared to non-IBD patients. The obtained specific expression profile consisting of IL-6, TGFbeta1, IL-10 and FoxP3 may represent a transcriptional hallmark for IBD. Furthermore, we found that treatment with immunosuppressive therapy was more beneficial for driving cytokine expression to restore immune regulation in patients with IBD, unlike the 5-ASA therapy. PMID- 28088613 TI - Adipocyte and epidermal fatty acid-binding protein serum concentrations in patients with lipodystrophy. AB - OBJECTIVE: Lipodystrophy (LD) syndromes are associated with diabetes mellitus, hypertriglyceridemia, and coronary artery disease. One pathogenetic factor of LD is dysregulation of several adipokines. However, the insulin resistance- and dyslipidemia-promoting adipokines adipocyte (AFABP) and epidermal (EFABP) fatty acid-binding protein have not been investigated in non-HIV-associated LD so far. MATERIAL AND METHODS: We performed a cross-sectional analysis of AFABP and EFABP serum concentrations in 37 LD patients and 37 age-, gender-, and body mass index matched healthy controls. Moreover, AFABP and EFABP were correlated to clinical and biochemical parameters of inflammation, glucose control, and lipid metabolism. RESULTS: There was no significant difference in median circulating AFABP and EFABP levels between LD patients (21.7MUg/l and 7.5MUg/l, respectively) and healthy controls (24.5MUg/l and 8.6MUg/l, respectively). Neither AFABP nor EFABP were related to markers of impaired glucose control or lipid metabolism. Multiple linear regression analysis showed a positive and independent association of AFABP with gender, serum leptin levels, and body mass index. CONCLUSIONS: Circulating levels of AFABP and EFABP are not decreased in LD despite adipose tissue loss in contrast to other adipokines including leptin and adiponectin. PMID- 28088615 TI - Cloning, heterologous expression and biochemical characterization of a non specific endoglucanase family 12 from Aspergillus terreus NIH2624. AB - The cellulases from Glycoside Hydrolyses family 12 (GH12) play an important role in cellulose degradation and plant cell wall deconstruction being widely used in a number of bioindustrial processes. Aiming to contribute toward better comprehension of these class of the enzymes, here we describe a high-yield secretion of a endoglucanase GH12 from Aspegillus terreus (AtGH12), which was cloned and expressed in Aspergillus nidulans strain A773. The purified protein was used for complete biochemical and functional characterization. The optimal temperature and pH of the enzyme were 55 degrees C and 5.0 respectively, which has high activity against beta-glucan and xyloglucan and also is active toward glucomannan and CMC. The enzyme retained activity up to 60 degrees C. AtGH12 is strongly inhibited by Cu2+, Fe2+, Cd2+, Mn2+, Ca2+, Zn2+ and EDTA, whereas K+, Tween, Cs+, DMSO, Triton X-100 and Mg2+ enhanced the enzyme activity. Furthermore, SAXS data reveal that the enzyme has a globular shape and CD analysis demonstrated a prevalence of a beta-strand structure corroborating with typical beta-sheets fold commonly found for other endoglucanases from GH12 family. PMID- 28088614 TI - CCAAT/Enhancer-binding protein beta promotes pathogenesis of EAE. AB - The CCAAT/Enhancer Binding Protein beta (C/EBPbeta) transcription factor is activated by multiple inflammatory stimuli, including IL-17 and LPS, and C/EBPbeta itself regulates numerous genes involved in inflammation. However, the role of C/EBPbeta in driving autoimmunity is not well understood. Here, we demonstrate that Cebpb-/- mice are resistant to EAE. Cebpb-/- mice exhibited reduced lymphocyte and APC infiltration into CNS following EAE induction. Furthermore, MOG-induced Th17 cytokine production was impaired in draining LN, indicating defects in Th17 cell priming. In vitro Th17 polarization studies indicated that T cell responses are not inherently defective, instead supporting the known roles for C/EBPbeta in myeloid lineage cell activation as the likely mechanism for defective Th17 priming in vivo. However, we did uncover an unexpected role for C/EBPbeta in regulating ll23r expression in APCs. ChIP assays confirmed that C/EBPbeta binds directly to the Il23r gene promoter in dendritic cells and Th17 cells. These data establish C/EBPbeta as a key driver of autoimmune inflammation in EAE, and propose a novel role for C/EBPbeta in regulation of IL-23R expression. PMID- 28088616 TI - Patient agency and contested notions of disability in social assistance applications in South Africa. AB - Problems in fairly allocating welfare and health resources are very often located in the spaces where citizens interact directly with state workers. This study draws on observations of doctor-patient encounters in disability assessments for the South African disability grant (DG) to examine how doctor-patient interactions and patient agency shape social welfare allocation in a context of high poverty and inequality. Data were gathered via interviews with healthcare workers and observations of doctor-patient interactions in twelve clinics and three hospitals in the Western Cape province between October 2013 and August 2014. Twenty-four doctors were interviewed, of whom seventeen were observed conducting a total of 216 consultations with patients. Two training sessions of DG assessors were also observed. Findings show that interactions between doctors and patients are sites of negotiation and contestation over rights to social assistance. Claimants' understanding of disability differed from biomedical and bureaucratic definitions. Patients attempted to influence doctors' decisions through narratives of suffering and performances of disability. Others used verbal or physical abuse as a form of protest against perceived unfair treatment. To defend themselves from these pressures and maintain authority in these interactions, doctors employed coping strategies that distanced and objectified claimants. This resulted in strained doctor-patient relationships and made the DG system confusing to the public. This demonstrates the importance of considering trust, power dynamics and the exercise of agency by both patients and providers in understanding policy implementation. PMID- 28088617 TI - Assessing physician productivity following Norwegian hospital reform: A panel and data envelopment analysis. AB - BACKGROUND: Although health care reforms may improve efficiency at the macro level, less is known regarding their effects on the utilization of health care personnel. Following the 2002 Norwegian hospital reform, we studied the productivity of the physician workforce and the effect of personnel mix on this measure in all nineteen Norwegian hospitals from 2001 to 2013. METHODS: We used panel analysis and non-parametric data envelopment analysis (DEA) to study physician productivity defined as patient treatments per full-time equivalent (FTE) physician. Resource variables were FTE and salary costs of physicians, nurses, secretaries, and other personnel. Patient metrics were number of patients treated by hospitalization, daycare, and outpatient treatments, as well as corresponding diagnosis-related group (DRG) scores accounting for differences in patient mix. Research publications and the fraction of residents/FTE physicians were used as proxies for research and physician training. RESULTS: The number of patients treated increased by 47% and the DRG scores by 35%, but there were no significant increases in any of the activity measures per FTE physician. Total DRG per FTE physician declined by 6% (p < 0.05). In the panel analysis, more nurses and secretaries per FTE physician correlated positively with physician productivity, whereas physician salary was neutral. In 2013, there was a 12%-80% difference between the hospitals with the highest and lowest physician productivity in the differing treatment modalities. In the DEA, cost efficiency did not change in the study period, but allocative efficiency decreased significantly. Bootstrapped estimates indicated that the use of physicians was too high and the use of auxiliary nurses and secretaries was too low. CONCLUSIONS: Our measures of physician productivity declined from 2001 to 2013. More support staff was a significant variable for predicting physician productivity. Personnel mix developments in the study period were unfavorable with respect to physician productivity. PMID- 28088618 TI - Modelling possible causality in the associations between unemployment, cannabis use, and alcohol misuse. AB - BACKGROUND: There has been considerable interest in the extent to which substance use and unemployment may be related, particularly the causal pathways that may be involved in these associations. It has been argued that these associations may reflect social causation, in which unemployment influences substance use, or that they may reflect social selection, in which substance use increases the risk of becoming and remaining unemployed. The present study sought to test these competing explanations. METHODS: Data from the Christchurch Health and Development Study, featuring a longitudinal birth cohort, were used to model the associations between unemployment and both cannabis and alcohol. Data on patterns of unemployment, involvement with cannabis, and symptoms of alcohol use disorder were examined from ages 18-35 years. The associations between unemployment and both cannabis dependence and alcohol use disorder (AUD) were modelled using conditional fixed-effects regression models, augmented by time-dynamic covariate factors. RESULTS: The analyses showed evidence of possible reciprocal causal processes in the association between unemployment and cannabis dependence, in which unemployment of at least three months' duration significantly (p < 0.0001) increased the risk of cannabis dependence, and cannabis dependence significantly (p < 0.0001) increased the risk of being unemployed. Similar evidence was found for the associations between unemployment and AUD, although these associations were smaller in magnitude. CONCLUSIONS: The present findings support both social causation and social selection arguments, by indicating that unemployment plays a causal role in substance misuse, and that it is also likely that a reverse causal process whereby substance misuse increases the risk of unemployment. PMID- 28088619 TI - Pappa Ante Portas: The effect of the husband's retirement on the wife's mental health in Japan. AB - The "Retired Husband Syndrome", that affects the mental health of wives of retired men around the world, has been anecdotally documented but never formally investigated. Using Japanese micro-data and the exogenous variation across cohorts in the maximum age of guaranteed employment induced by a 2006 Japanese reform, we estimate that the husband's earlier retirement significantly increases the probability that the wife reports symptoms related to the syndrome. We also find that retirement has a negative effect both on the household's economic situation and on the husband's own mental health, and that the higher economic distress contributes to reducing the wife's mental health. PMID- 28088620 TI - Relations between neighbourhood socioeconomic status and birth outcomes are mediated by maternal weight. AB - Lower neighbourhood-level socioeconomic status (SES) has been repeatedly associated with an increased risk of adverse birth outcomes, even after controlling for individual-level SES. Few studies have empirically assessed potential mechanisms underlying the associations. The objectives of this study were to (1) examine relations between neighbourhood SES and birth outcomes, and (2) explore if maternal weight variables mediated these relations. Data came from a provincial prospective pregnancy cohort study in Canada. Census data was used to create a continuous measure of neighbourhood SES. Using information from maternal questionnaires and medical records, two mediators (pre-pregnancy body mass index (BMI), and gestational weight gain (GWG)) and five birth outcomes (preterm birth, low birth weight, macrosomia, small for gestational age (SGA), large for gestational age (LGA)) were examined. After adjusting for individual level covariates, mediation analyses supported significant associations between lower neighbourhood SES and increased risk of macrosomia (b = 0.1183, 95% BCa CI: 0.0607-0.1896) and LGA (b = 0.0565, 95% BCa CI: 0.0040-0.1186) through higher pre pregnancy BMI. Significant associations were also observed between neighbourhood SES and macrosomia, LGA, and preterm birth (b = 0.0105, 95% BCa CI: 0.0014 0.0246) through pre-pregnancy BMI and GWG in tandem; pairwise comparisons suggested that associations with macrosomia and LGA through pre-pregnancy BMI alone were significant over associations through pre-pregnancy BMI and GWG together. These findings add to a growing body of literature assessing potential mechanisms underlying relations between neighbourhood SES and adverse birth outcomes, and suggest that neighbourhood-level SES may influence birth outcomes through maternal weight. PMID- 28088621 TI - 4-hydroxynonenal causes impairment of human subcutaneous adipogenesis and induction of adipocyte insulin resistance. AB - OBJECTIVE: Increased adipose production of 4-hydroxynonenal (4-HNE), a bioreactive aldehyde, directly correlates with obesity and insulin resistance. The aim of this study was to elucidate the impact of 4-HNE in mediating adipocyte differentiation and function in two metabolically distinct obese groups; the insulin sensitive (IS) and the insulin resistant (IR). METHODS: Subcutaneous (SC) adipose tissues were obtained from eighteen clinically well characterized obese premenopausal women undergoing weight reduction surgery. Cellular distribution of 4-HNE in the form of protein adducts was determined by immunohistochemistry in addition to its effect on oxidative stress, cell growth, adipogenic capacity and insulin signaling in preadipocytes derived from the IS and IR participants. RESULTS: 4-HNE was detected in the SC adipose tissue in different cell types with the highest level detected in adipocytes and blood vessels. Short and long-term in vitro treatment of SC preadipocytes with 4-HNE caused inhibition of their growth and increased production of reactive oxygen species (ROS) and antioxidant enzymes. Repeated 4-HNE treatment led to a greater reduction in the adipogenic capacity of preadipocytes from IS subjects compared to IR and caused dephosphorylation of IRS-1 and p70S6K while activating GSK3alpha/beta and BAD, triggering an IR phenotype. CONCLUSION: These data suggest that 4-HNE-induced oxidative stress plays a role in the regulation of preadipocyte growth, differentiation and insulin signaling and may therefore contribute to adipose tissue metabolic dysfunction associated with insulin resistance. PMID- 28088622 TI - Reactive oxygen species and cancer paradox: To promote or to suppress? AB - Reactive oxygen species (ROS), a group of highly reactive ions and molecules, are increasingly being appreciated as powerful signaling molecules involved in the regulation of a variety of biological processes. Indeed, their role is continuously being delineated in a variety of pathophysiological conditions. For instance, cancer cells are shown to have increased ROS levels in comparison to their normal counterparts. This is partly due to an enhanced metabolism and mitochondrial dysfunction in cancer cells. The escalated ROS generation in cancer cells contributes to the biochemical and molecular changes necessary for the tumor initiation, promotion and progression, as well as, tumor resistance to chemotherapy. Therefore, increased ROS in cancer cells may provide a unique opportunity to eliminate cancer cells via elevating ROS to highly toxic levels intracellularly, thereby, activating various ROS-induced cell death pathways, or inhibiting cancer cell resistance to chemotherapy. Such results can be achieved by using agents that either increase ROS generation, or inhibit antioxidant defense, or even a combination of both. In fact, a large variety of anticancer drugs, and some of those currently under clinical trials, effectively kill cancer cells and overcome drug resistance via enhancing ROS generation and/or impeding the antioxidant defense mechanism. This review focuses on our current understanding of the tumor promoting (tumorigenesis, angiogenesis, invasion and metastasis, and chemoresistance) and the tumor suppressive (apoptosis, autophagy, and necroptosis) functions of ROS, and highlights the potential mechanism(s) involved. It also sheds light on a very novel and an actively growing field of ROS-dependent cell death mechanism referred to as ferroptosis. PMID- 28088623 TI - A novel role of topical iodine in skin: Activation of the Nrf2 pathway. AB - For a long time iodine has been used as an active dermal agent in the treatment of inflammatory, immune-mediated and infectious diseases. Moreover, topical iodine application has been reported to provide protection against sulfur-mustard induced skin lesions, heat-induced and acid-induced skin burns in both haired guinea-pigs and mouse ear swelling models. However, the exact mechanism of action underlying these benefits of iodine has not yet been elucidated. In the current study, a novel mechanism of action by which iodine provides skin protection and relief, based on its electrophilic nature, is suggested. This study demonstrates that both iodine and iodide are capable of activating the Nrf2 pathway in human skin. As a result, skin protection against UVB-induced damage was acquired and the secretion of pro-inflammatory cytokines (IL-6, IL-8) from LPS-challenged skin was reduced. Iodide role in the enhanced activation of this pathway is demonstrated. The mode of action by which iodine and iodide activate the Nrf2 pathway is discussed. PMID- 28088624 TI - Oxidative Phospholipidomics in health and disease: Achievements, challenges and hopes. AB - Phospholipid peroxidation products are recognized as important bioactive lipid mediators playing an active role as modulators in signalling events in inflammation, immunity and infection. The biochemical responses are determined by the oxidation structural features present in oxPL modulating biophysical and biological properties in model membranes and lipoproteins. In spite of the extensive work conducted with model systems over the last 20 years, the study of oxPL in biological systems has virtually stagnated. In fact, very little is known concerning the predominant oxPL in fluids and tissues, their basal levels, and any variations introduced with age, gender and ethnicity in health and disease. In consequence, knowledge on oxPL has not yet translated into clinical diagnostic, in the early and timely diagnosis of "silent" diseases such as atherosclerosis and cardiovascular diseases, or as prognosis tools in disease stratification and particularly useful in the context of multimorbidities. Their use as therapeutic solutions or the development of innovative functional biomaterials remains to be explored. This review summarizes the achievements made in the identification of oxPL revealing an enormous structural diversity. A brief overview of the challenges associated with the analysis of such diverse array of products is given and a critical evaluation on key aspects in the analysis pipeline that need to be addressed. Once these issues are addressed, Oxidative Phospholipidomics will hopefully lead to major breakthrough discoveries in biochemistry, pharmaceutical, and clinical areas for the upcoming 20 years. This article is part of Special Issue entitled 4-Hydroxynonenal and Related Lipid Oxidation Products. PMID- 28088626 TI - Characterization and source apportionment of PM2.5 based on error estimation from EPA PMF 5.0 model at a medium city in China. AB - Heze city, a medium-size city in Shandong province, Eastern China. Ambient PM2.5 samples were collected in urban area of Heze from August 2015 to April 2016, and chemical species and sources of PM2.5 were investigated in this paper. The results indicated that the average concentration of PM2.5 was 100.9 MUg/m3 during the sampling period, and the water-soluble ions, carbonaceous species included elemental carbon (EC) and organic carbon (OC), as well as elements contributed 32.7-51.7%, 16.3% and 12.5%, respectively, to PM2.5. Pearson's correlation analysis showed that the existing form of NH4+ was more complex and diverse in spring/summer, and ammonium nitrate, ammonium sulfate and ammonium hydrogen sulfate might be major form of NH4+ in autumn/winter. Correlation analysis between PM2.5 and SO42-/NO3-, PM2.5 and OC/EC during different seasons suggested that mobile sources might make an important impact on the increase of PM2.5 concentrations in spring/summer, and stationary sources might play a critical role on the increase of PM2.5 concentrations in autumn/winter. Seven factors were selected in Positive Matrix Factorization (PMF) models analysis based on the Error Estimation (EE) diagnostics during different seasons. Secondary source had the highest contribution to PM2.5 in Heze for the whole year, and followed by coal combustion, vehicle exhaust, soil dust, construction dust, biomass burning and metal manufacturing, and their annual contributions to PM2.5 were 26.5%, 17.2%, 16.5%, 11.5%, 7.7%, 7.0% and 3.8%, respectively. The air masses that were originated from Mongolia reflected the features of large-scale and long-distance air transport; while the air masses that began in Jiangsu, Shandong and Henan showed the features of small-scale and short-distance. Shandong, Henan and Jiangsu were identified as the major potential sources-areas of PM2.5 by using potential source contribution function (PSCF) and concentration-weighted trajectory (CWT) models. PMID- 28088625 TI - Absence of DJ-1 causes age-related retinal abnormalities in association with increased oxidative stress. AB - Oxidative stress alters physiological function in most biological tissues and can lead to cell death. In the retina, oxidative stress initiates a cascade of events leading to focal loss of RPE and photoreceptors, which is thought to be a major contributing factor to geographic atrophy. Despite these implications, the molecular regulation of RPE oxidative stress under normal and pathological conditions remains largely unknown. A better understanding of the mechanisms involved in regulating RPE and photoreceptors oxidative stress response is greatly needed. To this end we evaluated photoreceptor and RPE changes in mice deficient in DJ-1, a protein that is thought to be important in protecting cells from oxidative stress. Young (3 months) and aged (18 months) DJ-1 knockout (DJ-1 KO) and age-matched wild-type mice were examined. In both group of aged mice, scanning laser ophthalmoscopy (SLO) showed the presence of a few autofluorescent foci. The 18 month-old DJ-1 KO retinas were also characterized by a noticeable increase in RPE fluorescence to wild-type. Optical coherence tomography (OCT) imaging demonstrated that all retinal layers were present in the eyes of both DJ 1 KO groups. ERG comparisons showed that older DJ-1 KO mice had reduced sensitivity under dark- and light-adapted conditions compared to age-matched control. Histologically, the RPE contained prominent vacuoles in young DJ-1 KO group with the appearance of enlarged irregularly shaped RPE cells in the older group. These were also evident in OCT and in whole mount RPE/choroid preparations labeled with phalloidin. Photoreceptors in the older DJ-1 KO mice displayed decreased immunoreactivity to rhodopsin and localized reduction in cone markers compared to the wild-type control group. Lower levels of activated Nrf2 were evident in retina/RPE lysates in both young and old DJ-1 KO mouse groups compared to wild-type control levels. Conversely, higher levels of protein carbonyl derivatives and iNOS immunoreactivity were detected in retina/RPE lysates from both young and old DJ-1 KO mice. These results demonstrate that DJ-1 KO mice display progressive signs of retinal/RPE degeneration in association with higher levels of oxidative stress markers. Collectively this analysis indicates that DJ 1 plays an important role in protecting photoreceptors and RPE from oxidative damage during aging. PMID- 28088627 TI - The telomere-binding protein TRF2 is required for metronomic therapeutic effects of gemcitabine and capecitabine. AB - Gemcitabine and capecitabine are two effective anticancer agents against solid tumors. The pharmacological mechanisms have been known as incorporation into DNA and thereby inhibition of DNA synthesis. When used as metronomic chemotherapy, they may inhibit angiogenesis and induce immunity. In our previous study, we showed that low-dose gemcitabine caused telomere shortening by stabilizing TRF2 that was required for XPF-dependent telomere loss. In this report, we established a SKOV3.ip1 ascites cell model. Tumor-bearing mice were treated with low-dose gemcitabine (GEM) or capecitabine (CAP). Both GEM and CAP caused telomere shortening and increased expression of TRF2 with improved ascites in nude mice and decreased in vitro clonogenic activity. TRF2 knockdown altered telomeres to a shortened but new status that may evade XPF-dependent telomere loss and conferred resistance of SKOV3.ip1 ascites cells to low-dose GEM and CAP. Our study provides a new mechanism of metronomic chemotherapy i.e. TRF2 is required for metronomic therapeutic effects of gemcitabine and capecitabine. PMID- 28088628 TI - Methods needed to measure predictive accuracy: A study of diabetic patients. AB - Diabetes is one of the leading causes of morbidity and mortality and it can result in several complications such as kidney failure, heart failure, stroke, and blindness making it a major medical and public health concern in the United States. Statistical methods are important to detect risk factors and identify the best sampling plan to determine predictive bounds for diabetic patients' data. The main objective of this paper is to identify the best fit bootstrapping sampling method and to draw the predictive bound considering diabetes patient data. A random sample was used from the National Health and Nutritional Examination Survey (NHANES) for this study. We found that there were significant relationships between age, marital status, and race/ethnicity with diabetes status (p<0.001) and no relationship was observed between gender and diabetes status. We ran the logistic regression to identify the risk factors from the data. We identified that the significant risk factors are age (p<0.001), total protein (p<0.001), fast food (p<0.0339), and direct HDL (p<0.001). This study provides evidence that the parametric bootstrapping method is the best fit method compared with other methods to estimate the predictive error bounds. These findings will be of great significance for identifying the best sampling methods, which can increase the statistical accuracy of laboratory clinical research of diabetes. This will also allow for the determination of precise risk factors that will best represent the data by detecting mild and extreme outliers from disease observations. Therefore, these results will be useful for researchers and clinicians to select the best sampling methods to study diabetes and other diseases in order to maximize the accuracy of their results. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy. PMID- 28088629 TI - Induction of hypothyroidism during early postnatal stages triggers a decrease in cognitive performance by decreasing hippocampal synaptic plasticity. AB - Thyroid hormones are vital in the control of multiple body functions, including the correct performance of the brain. Multiple diseases are associated with thyroid gland functioning, including hypothyroidism. To date, little is known regarding the effects of the establishment of this condition at a young age on brain function. Here, we evaluated the effect of hypothyroidism in an early postnatal stage in cognitive abilities with focus on the hippocampus. In our model, hypothyroidism was induced in young rats at 21days of age using 0.05% 6 propyl-2-thiouracil (PTU) for 4weeks reaching significantly lower levels of fT4 (control: 1.337ng/dL+/-0.115, PTU: 0.050ng/dL+/-0.001). Following the induction of hypothyroidism, several cognitive tasks were assessed to investigate the effects of hypothyroidism on cognition performance. We determined that hypothyroidism triggers a significant dysfunction in learning and memory processes observed in the Morris Water Maze were the latency times were higher in PTU rats (controls: 37s; PTU: 57s). The cognitive impairment was correlated with a reduction in hippocampal plasticity with respect to both long-term potentiation (LTP) (control: 1.45, PTU: 1.00) and depression (LTD) (control: 0.71, PTU: 1.01). Furthermore, a decrease in the rate of glucose utilization (control: 223nmol*mg of protein, PTU:148nmol*mg of protein) was observed, along with an increase in oxidative stress and a decrease in MAP2 marker in the hippocampus. Our findings suggest that the induction of hypothyroidism in a young rat model alters numerous functions at the level of the hippocampus. PMID- 28088630 TI - Support-dependent active species formation for CuO catalysts: Leading to efficient pollutant degradation in alkaline conditions. AB - Redox metal ions play the crucial role in versatile advanced oxidation technologies, in which controlling the active species formation through catalyst design is one of the key challenges in oxidant utilization. This work describes an example of different active species formations in CuO-mediated degradation just because of supporting material differences. Although three CuO catalysts were prepared by similar procedures, it was found that CuO-MgO catalyst demonstrated high efficiency in phenol degradation with bicarbonate activated H2O2, in which the superoxide radical is crucial, while hydroxyl radical and singlet oxygen are ignorable. For the CuO-MgO-Al2O3 and CuO-Al2O3 catalysts, the degradation proceeds by popular hydroxyl radical based process, however, the efficiency was poor. The EPR experiments also confirmed the absence of hydroxyl radical in CuO-MgO system but its presence in CuO-MgO-Al2O3 and CuO-Al2O3 system. The high catalytic efficiency with ignorable hydroxyl radical in the CuO-MgO system leads us to propose that an alternative Cu(III) species dominates the degradation. The basic MgO support may facilitate the formation of the Cu(III) species, whereas the neutral MgO-Al2O3 and acidic Al2O3 supports are unable to stabilize the high valent Cu(III) species, leading to the common hydroxyl radical mechanism with low efficiency of H2O2 in alkaline conditions. PMID- 28088631 TI - An ESIPT-based two-photon fluorescent probe detection of hydrogen peroxide in live cells and tissues. AB - A variety of diseases associated with human aging, which have a strong oxidative stress, but connecting age-related diseases and oxidative stress of the basic molecular mechanisms still insufficiently understood. Oxidative stress origins from the unregulated production of reactive oxygen species (ROS), and oxidative damaging to tissues and organs from subsequent oxidation-reduction chemistry by cellular mismanagement. In particular, H2O2 is a major by-product of ROS in live organisms and a common marker for oxidative stress, and its dynamic equilibrium can have various physiological and pathological consequences. H2O2 is a small molecule, but it is an essential oxygen metabolite in living systems and acts as an important compound in cellular signal transduction by reversible oxidation of proteins. To quantitatively detect of H2O2 in biosystems, herein, we adopted a 2 (2'-hydroxyphenyl)-4(3H)-quinazolinone (HPQ), a small organic fluorophore known for its luminescence mechanism through excited-state intramolecular proton transfer (ESIPT). HPQ was employed as a precursor to develop a turn-on probe (HPQ H) for bioimaging applications. After cleavaging the boronic ester moiety by H2O2, HPQ-H releases a HPQ fluorophore which shows a 45-fold fluorescence intensity enhancement with high sensitivity and selectivity over other reactive oxygen species (ROS), and a high resolution imaging and large tissue-imaging depth (70-170MUm) in living cells and tissues images under two-photon excitation (720nm). PMID- 28088632 TI - Nanosized complexation assemblies housed inside reverse micelles churn out monocytic delivery cores for bendamustine hydrochloride. AB - OBJECTIVE: We explore a plausible method of targeting bendamustine hydrochloride (BM) to circulatory monocytes by exploiting their intrinsic endocytic/phagocytic capability. METHODS: We do so by complexation of sodium alginate and chitosan inside dioctyl sulfo succinate sodium (AOT) reverse micelles to form bendamustine hydrochloride loaded nanoparticles (CANPs). Dynamic light scattering, electrophoretic mobility and UV spectroscopy were used to detail intra-micellar complexation dynamics and to prove that drug was co-captured during interaction of carbohydrate polymers. A fluorescent conjugate of drug (RBM) was used to trace its intracellular fate after its loading into nanoparticles. RESULTS: CANPs were sized below 150nm, had 75% drug entrapment and negative zeta potential (-30mV). Confocal microscopy demonstrated that developed chitosan alginate nanoparticles had the unique capability to carry BM specifically to its site of action. Quantitative and mechanism based cell uptake studies revealed that monocytes had voracious capacity to internalize CANPs via simultaneous scavenger receptor based endocytic and phagocytic mechanism. Comparative in vitro pharmacokinetic studies revealed obtainment of significantly greater intracellular drug levels when cells were treated with CANPs. This caused reduction in IC50 (22.5+/-2.1MUg/mL), enhancement in G2M cell cycle arrest, greater intracellular reactive oxygen species generation, and increased apopotic potential of bendamustine hydrochloride in THP-1 cells. CONCLUSION: Selective monocytic targeting of bendamustine hydrochloride using carbohydrate constructs can prove advantageous in case of leukemic disorders displaying overabundance of such cells. PMID- 28088633 TI - Quantitative analysis of lab-to-lab variability in Caco-2 permeability assays. AB - In this study, Caco-2 permeability results from different laboratories were compared. Six different sets of apparent permeability coefficient (Papp) values reported in the literature were compared to experimental Papp obtained in our laboratory. The differences were assessed by determining the root mean square error (RMSE) values between the datasets, which reached levels as high as 0.581 for the training set compounds, i.e. ten compounds with known effective human permeability (Peff). The consequences of these differences in Papp for prediction of oral drug absorption were demonstrated by introducing the Papp into the absorption and pharmacokinetics simulation software application GastroPlusTM for prediction of the fraction absorbed (Fa) in humans using calibrated "user-defined permeability models". The RMSE were calculated to assess the differences between the simulated Fa and experimental values reported in the literature. The RMSE for Fa simulated with the permeability model calibrated using experimental Papp from our laboratory was 0.128. When the calibration was performed using Papp from literature datasets, the RMSE values for Fa were higher in all cases except one. This study shows quantitative lab-to-lab variability of Caco-2 permeability results and the potential consequences this can have in the use of these results for predicting intestinal absorption of drugs. PMID- 28088634 TI - Chitosan-g-poly(N-isopropylacrylamide) copolymers as delivery carriers for intracameral pilocarpine administration. AB - This study reports, for the first time, the development of a chitosan-g-poly(N isopropylacrylamide) (Chi-PN) biodegradable in situ gelling delivery system for ocular pilocarpine administration through intracameral injection. The number of thermo-responsive polymer segments grafted onto the chitosan via carbodiimide mediated formation of amide linkages was greatly affected by varying the feeding amount of carboxyl-terminated poly(N-isopropylacrylamide) in the synthesis, thereby determining the phase transition temperature and enzymatic degradability of Chi-PN materials. The increase in grafting ratio facilitated temperature triggered gelation and drug encapsulation at physiological conditions. Additionally, the slow biodegradation process of delivery carriers was responsible for the delayed pilocarpine release, which allowed that the drug concentration could reach minimum therapeutic level for treating glaucoma during 42days of the study. All of the synthesized Chi-PN carriers demonstrated good ocular biocompatibility with lens epithelial cell cultures. In a rabbit model of experimental glaucoma, the intraocular pressure-lowering and miotic as well as corneal endothelial preservation responses to pilocarpine strongly depended on the drug release profiles. It is concluded that injectable biodegradable chitosan based thermogels can be potentially utilized as intracameral biomaterials for extended release of antiglaucoma medications and improved performance of delivery carriers. PMID- 28088635 TI - Mucoadhesive amorphous solid dispersions for sustained release of poorly water soluble drugs. AB - The oral delivery of mucoadhesive patches has been shown to enhance the absorption of large molecules such as peptides. We hypothesized that this mechanism could have utility for poorly soluble small molecules by utilizing a mucoadhesive polymer as the matrix for an amorphous solid dispersion. Binary dispersions of itraconazole and carbomer (Carbopol 71G) were prepared utilizing a thermokinetic mixing process (KinetiSol Dispersing) and the physicochemical properties were investigated by powder X-ray diffraction, calorimetry, and liquid chromatography. Adhesion of the dispersions to freshly excised porcine intestine was investigated with a texture analyzer. Minitablets were compressed from the optimal dispersion and further investigated in vitro and in vivo in rats. Thermokinetic mixing successfully processed amorphous dispersions up to 30% drug loading and each dispersion exhibited works of adhesion that were approximately an order of magnitude greater than a negative control in vitro. Ethylcellulose (EC) coated and uncoated minitablets prepared with the 30% drug load dispersion were delivered orally to rats and exhibited sustained release characteristics, with overall bioavailability greater for the uncoated minitablets compared to the EC-coated minitablets, similar to the rank order observed in our in vitro dissolution experiments. Necropsy studies showed that minitablets delivered with enteric-coated capsules targeted release to the distal small intestine and adhered to the intestinal mucosa, but the rat model presented limitations with respect to evaluating the overall performance. Based on the in vitro and in vivo results, further investigations in larger animals are a logical next step where fluid volumes, pH, and transit times are more favorable for the evaluated dosage forms. PMID- 28088636 TI - Comparison of mucoadhesive and cohesive features of poly(acrylic acid)-conjugates respective their molecular mass. AB - OBJECTIVES: This study aimed to assess the impact of molecular mass as well as the differences between poly(acrylic acid)-thiol-conjugates (PAA100,250,450KDa) on their mucoadhesive and cohesive qualities. METHODS: Covalent attachment of cysteine (CYS), cysteamine (CYSM) and l-gluthathione (GSH) to poly(acrylic acid) was achieved by formation of amide bonds between primary amino group of the amino acid (in the case of cysteine and glutathione), respectively the amino group of the aminothiol cysteamine and carboxylic acid group of the polymer. Obtained polymer conjugates were evaluated in regard to their safety profile, mucoadhesive properties on the buccal mucosa by rotating cylinder, tensile strength and rheological investigations, respectively. Furthermore, stability, cohesive and water uptake studies were performed. KEY FINDINGS: Mucoadhesive studies revealed that maximum detachment force of PAACYS450 was 24.3-fold higher in comparison to the respective controls. Stability studies revealed for PAACYS450 a 50.2-fold higher stability compared to controls. CONCLUSION: Taken together, among all polymers tested, PAACYS450 evinced the most favorable qualities regarding mucoadhesion and cohesion, followed by PAACYSM450 and PAACYS250. PMID- 28088637 TI - Multi-scale control influences sense of agency: Investigating intentional binding using event-control approach. AB - Control exercised by humans through interactions with the environment is critical for sense of agency. Here, we investigate how control at multiple levels influence implicit sense of agency measured using intentional binding. Participants are asked to hit a moving target using a joystick with noisy control followed by an intentional binding task initiated by the target hitting action. Perceptual-motor level control was manipulated through noise in the joystick controller (experiment 1) and goal-level control in terms of feedback about successful hit (experiments 2a and 2b). In the first experiment, intentional binding increased with amount of joystick control only when goal was not achieved and independent otherwise suggesting that the two levels interact hierarchically. In the second experiment, the estimated duration was dependent on when participants knew about goal completion. The results are similar to those obtained with explicit measures of sense of agency indicating that multi-scale event control influences agency. PMID- 28088638 TI - The DLNO/DLCO ratio: Physiological significance and clinical implications. AB - DLNO/DLCO directly measures the ratio of the diffusing capacities of the lung for nitric oxide (NO) and carbon monoxide (CO). In terms of the Roughton and Forster (1957) equation, 1/DL=1/Dm+1/thetaVc, where Dm is the membrane (Dm) and thetaVc is the red cell component of the overall diffusing conductance (DL); DLNO mostly reflects the Dm component and DLCO the thetaVc red cell component. The DLNO/DLCO ratio is positively related to the DmCO/Vc ratio and the CO red cell resistance (1/thetaCOVc) as a percentage of the total resistance (1/DLCO), independent of the absolute values of DLNO or DLCO. In clinical studies, a raised DLNO/DLCO ratio (>=110% predicted versus a control group), plus a low DLNO and DLCO (<67% pred), predicts pulmonary vascular disease, while a low DLNO/DLCO ratio, with similarly reduced DLNO and DLCO, is associated with interstitial lung disease with fibrosis. More clinical studies are needed, and reference values need to be better defined. PMID- 28088639 TI - Docosahexaenoic acid loaded lipid nanoparticles with bactericidal activity against Helicobacter pylori. AB - Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid present in fish oil, has been described as a promising molecule to the treatment of Helicobacter pylori gastric infection. However, due to its highly unsaturated structure, DHA can be easily oxidized loosing part of its bioactivity. This work aims the nanoencapsulation of DHA to improve its bactericidal efficacy against H. pylori. DHA was loaded into nanostructured lipid carriers (NLC) produced by hot homogenization and ultrasonication using a blend of lipids (Precirol ATO5(r), Miglyol-812(r)) and a surfactant (Tween 60(r)). Homogeneous NLC with 302+/-14nm diameter, -28+/-3mV surface charge (dynamic and electrophoretic light scattering) and containing 66+/-7% DHA (UV/VIS spectroscopy) were successfully produced. Bacterial growth curves, performed over 24h in the presence of different DHA concentrations (free or loaded into NLC), demonstrated that nanoencapsulation enhanced DHA bactericidal effect, since DHA-loaded NLC were able to inhibit H. pylori growth in a much lower concentrations (25MUM) than free DHA (>100MUM). Bioimaging studies, using scanning and transmission electron microscopy and also imaging flow cytometry, demonstrated that DHA-loaded NLC interact with H. pylori membrane, increasing their periplasmic space and disrupting membrane and allowing the leakage of cytoplasmic content. Furthermore, the developed nanoparticles are not cytotoxic to human gastric adenocarcinoma cells at bactericidal concentrations. DHA-loaded NLC should, therefore, be envisaged as an alternative to the current treatments for H. pylori infection. PMID- 28088640 TI - Bioethanol production from cellulosic hydrolysates by engineered industrial Saccharomyces cerevisiae. AB - Even though industrial yeast strains exhibit numerous advantageous traits for the production of bioethanol, their genetic manipulation has been limited. This study demonstrates that an industrial polyploidy Saccharomyces cerevisiae JHS200 can be engineered through Cas9 (CRISPR associated protein 9)-based genome editing. Specifically, we generated auxotrophic mutants and introduced a xylose metabolic pathway into the auxotrophic mutants. As expected, the engineered strain (JX123) enhanced ethanol production from cellulosic hydrolysates as compared to other engineered haploid strains. However, the JX123 strain produced substantial amounts of xylitol as a by-product during xylose fermentation. Hypothesizing that the xylitol accumulation might be caused by intracellular redox imbalance from cofactor difference, the NADH oxidase from Lactococcus lactis was introduced into the JX123 strain. The resulting strain (JX123_noxE) not only produced more ethanol, but also produced xylitol less than the JX123 strain. These results suggest that industrial polyploidy yeast can be modified for producing biofuels and chemicals. PMID- 28088641 TI - Pathophysiological and behavioral effects of systemic inflammation in aged and diseased rodents with relevance to delirium: A systematic review. AB - Delirium is a frequent outcome for aged and demented patients that suffer a systemic inflammatory insult. Animal models that reconstruct these etiological processes have potential to provide a better understanding of the pathophysiology of delirium. Therefore, we systematically reviewed animal studies in which systemic inflammation was superimposed on aged or diseased animal models. In total, 77 studies were identified. Aged animals were challenged with a bacterial endotoxin in 29 studies, 25 studies superimposed surgery on aged animals, and in 6 studies a bacterial infection, Escherichia coli (E. coli), was used. Diseased animals were challenged with a bacterial endotoxin in 15 studies, two studies examined effects of the cytokine IL-1beta, and one study used polyinosinic:polycytidilic acid (poly I:C). This systematic review analyzed the impact of systemic inflammation on the production of inflammatory and neurotoxic mediators in peripheral blood, cerebrospinal fluid (CSF), and on the central nervous system (CNS). Moreover, concomitant behavioral and cognitive symptoms were also evaluated. Finally, outcomes of behavioral and cognitive tests from animal studies were compared to features and symptoms present in delirious patients. PMID- 28088642 TI - Anti-RAGE antibody selectively blocks acute systemic inflammatory responses to LPS in serum, liver, CSF and striatum. AB - Systemic inflammation induces transient or permanent dysfunction in the brain by exposing it to soluble inflammatory mediators. The receptor for advanced glycation endproducts (RAGE) binds to distinct ligands mediating and increasing inflammatory processes. In this study we used an LPS-induced systemic inflammation model in rats to investigate the effect of blocking RAGE in serum, liver, cerebrospinal fluid (CSF) and brain (striatum, prefrontal cortex, ventral tegmental area and substantia nigra). Intraperitoneal injection of RAGE antibody (50MUg/kg) was followed after 1h by a single LPS (5mg/kg) intraperitoneal injection. Twenty-four hours later, tissues were isolated for analysis. RAGE antibody reduced LPS-induced inflammatory effects in both serum and liver; the levels of proinflammatory cytokines (TNF-alpha, IL-1beta) were decreased and the phosphorylation/activation of RAGE downstream targets (ERK1/2, IkappaB and p65) in liver were significantly attenuated. RAGE antibody prevented LPS-induced effects on TNF-alpha and IL-1beta in CSF. In striatum, RAGE antibody inhibited increases in IL-1beta, Iba-1, GFAP, phospho-ERK1/2 and phospho-tau (ser202), as well as the decrease in synaptophysin levels. These effects were caused by systemic RAGE inhibition, as RAGE antibody did not cross the blood-brain barrier. RAGE antibody also prevented striatal lipoperoxidation and activation of mitochondrial complex II. In conclusion, blockade of RAGE is able to inhibit inflammatory responses induced by LPS in serum, liver, CSF and brain. PMID- 28088643 TI - Molecular mechanisms of bio-catalysis of heme extraction from hemoglobin. AB - Red blood cell hemolysis in sickle cell disease (SCD) releases free hemoglobin. Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. We propose an approach that helps to eliminate extracellular hemoglobin toxicity in SCD by employing a bacterial protein system that evolved to extract heme from extracellular hemoglobin. NEAr heme Transporter (NEAT) domains from iron-regulated surface determinant proteins from Staphylococcus aureus specifically bind free heme as well as facilitate its extraction from hemoglobin. We demonstrate that a purified NEAT domain fused with human haptoglobin beta-chain is able to remove heme from hemoglobin and reduce heme content and peroxidase activity of hemoglobin. We further use molecular dynamics (MD) simulations to resolve molecular pathway of heme transfer from hemoglobin to NEAT, and to elucidate molecular mechanism of such heme transferring process. Our study is the first of its kind, in which simulations are employed to characterize the process of heme leaving hemoglobin and subsequent rebinding with a NEAT domain. Our MD results highlight important amino acid residues that facilitate heme transfer and will guide further studies for the selection of best NEAT candidate to attenuate free hemoglobin toxicity. PMID- 28088645 TI - Towards solving the hard problem of consciousness: The varieties of brain resonances and the conscious experiences that they support. AB - The hard problem of consciousness is the problem of explaining how we experience qualia or phenomenal experiences, such as seeing, hearing, and feeling, and knowing what they are. To solve this problem, a theory of consciousness needs to link brain to mind by modeling how emergent properties of several brain mechanisms interacting together embody detailed properties of individual conscious psychological experiences. This article summarizes evidence that Adaptive Resonance Theory, or ART, accomplishes this goal. ART is a cognitive and neural theory of how advanced brains autonomously learn to attend, recognize, and predict objects and events in a changing world. ART has predicted that "all conscious states are resonant states" as part of its specification of mechanistic links between processes of consciousness, learning, expectation, attention, resonance, and synchrony. It hereby provides functional and mechanistic explanations of data ranging from individual spikes and their synchronization to the dynamics of conscious perceptual, cognitive, and cognitive-emotional experiences. ART has reached sufficient maturity to begin classifying the brain resonances that support conscious experiences of seeing, hearing, feeling, and knowing. Psychological and neurobiological data in both normal individuals and clinical patients are clarified by this classification. This analysis also explains why not all resonances become conscious, and why not all brain dynamics are resonant. The global organization of the brain into computationally complementary cortical processing streams (complementary computing), and the organization of the cerebral cortex into characteristic layers of cells (laminar computing), figure prominently in these explanations of conscious and unconscious processes. Alternative models of consciousness are also discussed. PMID- 28088644 TI - Tert-butyl hydroperoxide (t-BHP) induced apoptosis and necroptosis in endothelial cells: Roles of NOX4 and mitochondrion. AB - Oxidative stress causes endothelial death while underlying mechanisms remain elusive. Herein, the pro-death effect of tert-butyl hydroperoxide (t-BHP) was investigated with low concentration (50MUM) of t-BHP (t-BHPL) and high concentration (500MUM) of t-BHP (t-BHPH). Both t-BHPL and t-BHPH induced endothelial cell death was determined. T-BHPL induced caspase-dependent apoptosis and reactive oxygen species (ROS) generation, which was inhibited by N-acetyl-L cysteine (NAC). Furthermore, NADPH oxidase inhibitor diphenyleneiodonium (DPI), NOX4 siRNA, and NOX4 inhibitor GKT137831 reduced t-BHPL-induced ROS generation while mitochondrial respiratory chain inhibitors rotenone (Rot), 2 thenoyltrifluoroacetone (TTFA), and antimycin A (AA) failed to do so. NOX4 overexpression resulted in increased ROS generation and Akt expression but decreased sensitivity to t-BHPL. In contrast, T-BHPH induced LDH release, PI uptake, and cell translucent cytoplasm. RIP1 inhibitor necrostatin-1 (Nec-1), MLKL inhibitor necrosulfonamide (NSA) and silencing RIP1, RIP3, and MLKL inhibited t-BHPH-induced cell death while pan-caspase inhibitor Z-VAD-FMK showed no effect. T-BHPH-induced ROS production was inhibited by TTFA, AA and Rot while DPI showed no effect. T-BHPH induced RIP1/RIP3 interaction, which was decreased by Rot, TTFA, and AA. Silence RIP1 and RIP3 but not MLKL inhibited t-BHPH-induced mitochondrial membrane potential (MMP) decrease and ROS production. Moreover, P38MAPK inhibitor SB203580 reversed both t-BHPL and t-BHPH-induced cell death while inhibitors for ERKs and JNKs showed no obvious effect. These data suggested that t-BHP induced both apoptosis and necroptosis in endothelial cells which was mediated by ROS and p38MAPK. ROS derived from NADPH oxidase and mitochondria contributed to t-BHPL and t-BHPH-induced apoptosis and necroptosis, respectively. PMID- 28088646 TI - Bone microarchitecture in adolescent boys with autism spectrum disorder. AB - BACKGROUND: Boys with autism spectrum disorder (ASD) have lower areal bone mineral density (aBMD) than typically developing controls (TDC). Studies of volumetric BMD (vBMD) and bone microarchitecture provide information about fracture risk beyond that provided by aBMD but are currently lacking in ASD. OBJECTIVES: To assess ultradistal radius and distal tibia vBMD, bone microarchitecture and strength estimates in adolescent boys with ASD compared to TDC. DESIGN/METHODS: Cross-sectional study of 34 boys (16 ASD, 18 TDC) that assessed (i) aBMD at the whole body (WB), WB less head (WBLH), hip and spine using dual X-ray absorptiometry (DXA), (ii) vBMD and bone microarchitecture at the ultradistal radius and distal tibia using high-resolution peripheral quantitative CT (HRpQCT), and (iii) bone strength estimates (stiffness and failure load) using micro-finite element analysis (FEA). We controlled for age in all groupwise comparisons of HRpQCT and FEA measures. Activity questionnaires, food records, physical exam, and fasting levels of 25(OH) vitamin D and bone markers (C-terminal collagen crosslinks and N-terminal telopeptide (CTX and NTX) for bone resorption, N-terminal propeptide of Type 1 procollagen (P1NP) for bone formation) were obtained. RESULTS: ASD participants were slightly younger than TDC participants (13.6 vs. 14.2years, p=0.44). Tanner stage, height Z-scores and fasting serum bone marker levels did not differ between groups. ASD participants had higher BMI Z-scores, percent body fat, IGF-1 Z-scores, and lower lean mass and aBMD Z-scores than TDC at the WB, WBLH, and femoral neck (P<0.1). At the radius, ASD participants had lower trabecular thickness (0.063 vs. 0.070mm, p=0.004), compressive stiffness (56.7 vs. 69.7kN/mm, p=0.030) and failure load (3.0 vs. 3.7kN, p=0.031) than TDC. ASD participants also had 61% smaller cortical area (6.6 vs. 16.4mm2, p=0.051) and thickness (0.08 vs. 0.22mm, p=0.054) compared to TDC. At the tibia, ASD participants had lower compressive stiffness (183 vs. 210kN/mm, p=0.048) and failure load (9.4 vs. 10.8kN, p=0.043) and 23% smaller cortical area (60.3 vs. 81.5mm2, p=0.078) compared to TDC. A lower proportion of ASD participants were categorized as "very physically active" (20% vs. 72%, p=0.005). Differences in physical activity, calcium intake and IGF-1 responsiveness may contribute to group differences in stiffness and failure load. CONCLUSION: Bone microarchitectural parameters are impaired in ASD, with reductions in bone strength estimates (stiffness and failure load) at the ultradistal radius and distal tibia. This may result from lower physical activity and calcium intake, and decreased IGF-1 responsiveness. PMID- 28088647 TI - The developmental relationship between specific cognitive domains and grey matter in the cerebellum. AB - There is growing evidence that the cerebellum is involved in cognition and cognitive development, yet little is known about the developmental relationship between cerebellar structure and cognitive subdomains in children. We used voxel based morphometry to assess the relationship between cerebellar grey matter (GM) and language, reading, working memory, executive function, and processing speed in 110 individuals aged 8-17 years from the Pediatric Imaging, Neurocognition, and Genetics (PING) Study. Further, we examined the effect of age on the relationships between cerebellar GM and cognition. Higher scores on vocabulary, reading, working memory, and set-shifting were associated with increased GM in the posterior cerebellum (lobules VI-IX), in regions which are typically engaged during cognitive tasks in healthy adults. For reading, working memory, and processing speed, the relationship between cerebellar GM and cognitive performance changed with age in specific cerebellar subregions. As in adults, posterior lobe cerebellar GM was associated with cognitive performance in a pediatric population, and this relationship mirrored the known developmental trajectory of posterior cerebellar GM. These findings provide further evidence that specific regions of the cerebellum support cognition and cognitive development, and suggest that the strength of this relationship depends on developmental stage. PMID- 28088649 TI - Fumarate reductase superfamily: A diverse group of enzymes whose evolution is correlated to the establishment of different metabolic pathways. AB - Fumarate and succinate are known to be present in prebiotic systems essential for the origin of life. The fumarate and succinate interconversion reactions have been conserved throughout evolution and are found in all living organisms. The fumarate and succinate interconversion is catalyzed by the enzymes succinate dehydrogenase (SDH) and fumarate reductase (FRD). In this work we show that SDH and FRD are part of a group of enzymes that we propose to designate "fumarate reductase superfamily". Our results demonstrate that these enzymes emerged from a common ancestor and were essential in the development of metabolic pathways involved in energy transduction. PMID- 28088648 TI - The influence of 5-HTTLPR transporter genotype on amygdala-subgenual anterior cingulate cortex connectivity in autism spectrum disorder. AB - Social deficits in autism spectrum disorder (ASD) are linked to amygdala functioning and functional connection between the amygdala and subgenual anterior cingulate cortex (sACC) is involved in the modulation of amygdala activity. Impairments in behavioral symptoms and amygdala activation and connectivity with the sACC seem to vary by serotonin transporter-linked polymorphic region (5 HTTLPR) variant genotype in diverse populations. The current preliminary investigation examines whether amygdala-sACC connectivity differs by 5-HTTLPR genotype and relates to social functioning in ASD. A sample of 108 children and adolescents (44 ASD) completed an fMRI face-processing task. Youth with ASD and low expressing 5-HTTLPR genotypes showed significantly greater connectivity than youth with ASD and higher expressing genotypes as well as typically developing (TD) individuals with both low and higher expressing genotypes, in the comparison of happy vs. baseline faces and happy vs. neutral faces. Moreover, individuals with ASD and higher expressing genotypes exhibit a negative relationship between amygdala-sACC connectivity and social dysfunction. Altered amygdala-sACC coupling based on 5-HTTLPR genotype may help explain some of the heterogeneity in neural and social function observed in ASD. This is the first ASD study to combine genetic polymorphism analyses and functional connectivity in the context of a social task. PMID- 28088651 TI - Limitations in biexponential fitting of NMR inversion-recovery curves. AB - NMR relaxation agents have long been employed as contrast agents in MRI. In many cases, the contrast agent is confined to either (i) the vascular and/or extracellular compartment (EC), as is the case with gadolinium(III)-based agents, or (ii) the intracellular compartment (IC), as is the case with manganese(II) ions. The compartmentalization of contrast agents often results in tissue-water 1H relaxation profiles that are well modeled as biexponential. It has long been recognized that water exchange between compartments modifies the biexponential relaxation parameters (amplitudes and rate constants) from those that would be found in the absence of exchange. Nevertheless, interpretation in terms of an "apparent" two-compartment biophysical model, apparent EC vs. apparent IC, can provide insight into tissue structure and function, and changes therein, in the face of physiologic challenge. The accuracy of modeling biexponential data is highly dependent upon the amplitudes, rate constants, and signal-to-noise characterizing the data. Herein, simulated (in silico) inversion-recovery relaxation data are modeled by standard, nonlinear-least-squares analysis and the error in parameter values assessed for a range of amplitudes and rate constants characteristic of in vivo systems following administration of contrast agent. The findings provide guidance for laboratories seeking to exploit contrast-agent driven, biexponential relaxation to differentiate MRI-based compartmental properties, including the apparent diffusion coefficient. PMID- 28088650 TI - Assessing the identity and expression level of the cytochrome P450 20A1 (CYP20A1) gene in the BPA-, BDE-47, and WAF-exposed copepods Tigriopus japonicus and Paracyclopina nana. AB - CYP20A1 is a member of the cytochrome P450 (CYP) superfamily, identified as an orphan P450 without any assigned biological function; hence, its continued status as an "orphan" gene. In order to address this shortcoming in our understanding of this superfamily, we sought to characterize the CYP20A1 gene in the copepods Tigriopus japonicus (Tj-CYP20A1) and Paracyclopina nana (Pn-CYP20A1) at their mRNA transcriptional level. We assessed the response of this gene's expression in various developmental stages and in response to treatment with bisphenol A (BPA), 2, 2', 4, 4'-tetrabromodiphenyl ether (BDE-47), and water accommodated fractions (WAFs) of crude oil. As shown in the vertebrate CYP20A1, both Tj-CYP20A1 and Pn CYP20A1 contained characteristic conserved motifs and domain regions (I helix, K helix and heme-binding motifs) with unusual amino acid sequences apparent in their gene structure. Also molecular characterization of the putative responsive elements in the promoter regions was performed. We observed transcriptional up regulation of these genes during post-embryonic developmental stages including sex-specific up-regulation in adults. In addition, concentration- and time dependent mRNA transcripts in response to xenobiotics (BPA, BDE-47, and WAFs) were seen. This study focuses on the molecular elucidation of CYP20A1 genes and their interactions with xenobiotics in the copepods T. japonicus and P. nana that provides important insight into the biological importance of CYP20A1 in invertebrates. PMID- 28088652 TI - Convergence of interoception, emotion, and social cognition: A twofold fMRI meta analysis and lesion approach. AB - Guided by indirect evidence, recent approaches propose a tripartite crosstalk among interoceptive signaling, emotional regulation, and low-level social cognition. Here we examined the neurocognitive convergence of such domains. First, we performed three meta-analyses of functional magnetic resonance imaging studies to identify which areas are consistently coactivated by these three systems. Multi-level Kernel Density Analysis (MKDA) revealed major overlaps in the right anterior insular and frontotemporal regions (viz., the orbitofrontal and inferior frontal gyri, the amygdala, and mid temporal lobe/subcortical structures). Second, we explored such domains in patients with fronto-insulo temporal damage. Relative to controls, the patients showed behavioral impairments of interoception, emotional processing, and social cognition, with preservation of other cognitive functions. Convergent results from both studies offer direct support for a model of insular-frontotemporal regions integrating interoception, emotion, and social cognition. PMID- 28088654 TI - Transcriptional response of skeletal muscle to a low protein perinatal diet in rat offspring at different ages: The role of key enzymes of glucose-fatty acid oxidation. AB - Skeletal muscle is a plastic tissue during development with distinctive acute and chronic response to maternal protein restriction. This study evaluated gene and protein expression of key-enzymes of glycolytic pathway (HK2, PFK, PDK4 and CS), and fatty acid oxidation (CPT1 and beta-HAD) of two different types of skeletal muscle [soleus and extensor digitorium longus (EDL)] from offspring rats at 30 and 90 days of age, exposed to maternal isoenergetic low protein diet throughout gestation and lactation. Pups from dams fed 17% protein diet (n=5, normal protein, Np), and low protein pups from dams fed 8% casein diet (low protein, Lp, n=5) were evaluated. Offspring were sacrificed either 30 or 90 days old. Soleus and EDL were analyzed for mRNA and protein expression by quantitative PCR and western blotting, respectively. Soleus was more affected by Lp maternal diet at 90 days by down-regulation of key enzymes of glycolytic pathway, in particular HK2 and PDK4 with a concomitant reduction of beta-HAD mRNA. For EDL, the effects of Lp maternal diet were more pronounced at 30 days, as the transcriptional key enzymes of glycolytic pathway were down-regulated. One important finding was that the observed acute (30 days) transcriptional changes did not remain in adult Lp rats (90 days), except for PDK4. The robust PDK4 mRNA down-regulation, observed in both soleus and EDL, and at both ages, and the consequent down-regulation of the PDK4 protein expression can be responsible for a state of reduced metabolic flexibility of skeletal muscle in response to maternal low protein diet. PMID- 28088653 TI - Immune stimulation during chemotherapy increases incidence of acute graft versus host disease in acute myeloid leukemia: A study on behalf of SFGM-TC and ALFA. AB - 60-70% of AML patients have an indication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) during their treatment. Graft versus host disease (GvHD), the major cause of mortality and comorbidities post-transplantation, develops by immunological mechanism and decides greatly prognosis and quality of life (QoL) of graft recipient. Current GvHD prophylaxis is not personalized. Infections, toxicities and leukemic infiltration complicate the first chemotherapy phases prior to allo-HSCT. They, to certain extent, induce local immune stimulation. Impact of immune stimulation of this period on incidence of GvHD has not been evaluated. We retrospectively studied 238 AML patients transplanted at first remission from 21 French centers in the ALFA-0702 protocol and found that cutaneous and digestive immune stimulation during induction increases the incidence of skin and gut aGVHD, respectively. Furthermore, prolonged febrile duration correlates with elevated incidence of grade II-IV aGvHD. Thus, we identified a group of patients with higher risk of aGvHD. The benefit of personalized GvHD prophylaxis should be explored in a prospective cohort to decrease incidence of aGvHD in these patients and improve their QoLs. PMID- 28088655 TI - Insurance based lie detection: Enhancing the verifiability approach with a model statement component. AB - PURPOSE: The Verifiability Approach (VA) is verbal lie detection tool that has shown promise when applied to insurance claims settings. This study examined the effectiveness of incorporating a Model Statement comprised of checkable information to the VA protocol for enhancing the verbal differences between liars and truth tellers. METHOD: The study experimentally manipulated supplementing (or withholding) the VA with a Model Statement. It was hypothesised that such a manipulation would (i) encourage truth tellers to provide more verifiable details than liars and (ii) encourage liars to report more unverifiable details than truth tellers (compared to the no model statement control). As a result, it was hypothesized that (iii) the model statement would improve classificatory accuracy of the VA. Participants reported 40 genuine and 40 fabricated insurance claim statements, in which half the liars and truth tellers where provided with a model statement as part of the VA procedure, and half where provide no model statement. RESULTS: All three hypotheses were supported. In terms of accuracy, the model statement increased classificatory rates by the VA considerably from 65.0% to 90.0%. CONCLUSION: Providing interviewee's with a model statement prime consisting of checkable detail appears to be a useful refinement to the VA procedure. PMID- 28088656 TI - Low-dose aspirin use and survival in breast cancer patients: A nationwide cohort study. AB - BACKGROUND: Preclinical evidence from breast cancer cell lines and animal models suggest that aspirin could have anti-cancer properties. In a large breast cancer patient cohort, we investigated whether post-diagnostic low-dose aspirin use was associated with a reduction in the risk of breast cancer-specific mortality. METHODS: We identified 15,140 newly diagnosed breast cancer patients within the Scottish Cancer Registry. Linkages to the Scottish Prescribing Information System provided data on dispensed medications and breast cancer-specific deaths were identified from National Records of Scotland Death Records. Time-dependent Cox regression models were used to calculate hazard ratios (HR) and 95% CIs for breast cancer-specific and all-cause mortality by post-diagnostic low-dose aspirin use. HRs were adjusted for a range of potential confounders including age at diagnosis, year of diagnosis, cancer stage, grade, cancer treatments received, comorbidities, socioeconomic status and use of statins. Secondary analysis investigated the association between pre-diagnostic low-dose aspirin use and breast cancer-specific and all-cause mortality. RESULTS: Post-diagnostic users of low-dose aspirin appeared to have increased breast cancer-specific mortality compared with non-users (HR 1.44, 95% CI 1.26, 1.65) but this association was entirely attenuated after adjustment for potential confounders (adjusted HR 0.92, 95% CI 0.75, 1.14). Findings were similar in analysis by increasing duration of use and in analysis of pre-diagnostic low-dose aspirin use. CONCLUSION: In this large nationwide study of breast cancer patients, we found little evidence of an association between post-diagnostic low-dose aspirin use and cancer-specific mortality. PMID- 28088657 TI - Early adulthood body mass index, cumulative smoking, and esophageal adenocarcinoma survival. AB - BACKGROUND: Smoking and obesity are esophageal adenocarcinoma (EAC) risk factors. However, the same risk factors may also affect biological aggressiveness and cancer outcomes. Our study evaluated the combined effects of early-adulthood obesity and cumulative smoking on the EAC survival. PATIENTS AND METHODS: In two EAC cohorts, Toronto (TO; N=235) and Boston (BO; N=329), associations between early adulthood body mass index (EA-BMI), BMI at 1year prior to diagnosis (BMI 1), and smoking with overall survival (OS) were assessed using Cox proportional hazard models, adjusted for relevant covariates. RESULTS: Both cohorts were predominantly Caucasian (89%), male (88%), ever-smokers (73%) with locally advanced/metastatic EAC (78%), and good ECOG performance status (90%); median packyears was 34; median EA-BMI, 24; median BMI-1, 25. No relationships with survival were found with BMI-1. For smoking and EA-BMI, TO, BO, and combined TO BO analyses showed similar associations: smoking conferred worse OS in the combined TO-BO cohort, with adjusted hazard ratios (aHR) of 1.22 (95%CI: 1.15 1.43;p<0.0001) for each 20 pack-year increase. Likewise, EA-BMI >=25 was associated with worse OS (EA-BMI of 25-<30, aHR=1.84,95%CI: 1.37-2.48; and EA BMI>30, aHR=2.78, 95%CI: 1.94-3.99). Risk of death was also increased in remotely underweight patients with EA-BMI<18.5 (aHR=2.03,95%CI: 1.27-3.24), when compared to normal-EA-BMI (18<=EA-BMI<25). CONCLUSIONS: Two key modifiable behaviors, elevated BMI in early adulthood and heavy cumulative smoking history are independently associated with increased mortality risk in two North American cohorts of EAC patients. PMID- 28088659 TI - Altered cerebral insulin response in transgenic mice expressing the epsilon-4 allele of the human apolipoprotein E gene. AB - Apolipoprotein E epsilon-4 (APOEepsilon4 or APOE4), an allelic variation of the APOE gene, not only increases the risk of developing the late-onset form of Alzheimer's disease (AD), but also influences the outcome of treatment. Indeed, data from clinical studies show that the beneficial effect of insulin on cognition is blunted in APOE4 carriers. To investigate how APOE impacts insulin response, we assessed the effects of an acute insulin injection in APOE3- and APOE4-targeted replacement mice that respectively express the human APOE3 or APOE4 isoform instead of the endogenous murine ApoE protein. We evaluated cognition, insulin signaling and proteins implicated in Abeta transport and tau phosphorylation in the cortex and brain capillaries. We found that a single acute insulin injection increased Akt pSer473 in APOE4 compared to APOE3 mice (+113% versus +78.5%), indicating that APOE4 carriage potentiates activation of insulin upstream signaling pathway in the brain. Insulin also led to decreased concentrations of the receptor for advanced glycation endproducts (RAGE) in brain capillaries in both groups of mice. Moreover, higher phosphorylation of tau at Ser202, one of the key markers of AD neuropathology, was observed in insulin injected APOE4 mice (+44%), consistent with findings in human APOE4 carriers (+400% compared to non-carriers). Therefore, our data suggest that APOE4 carriage leads to an increased insulin-induced activation of cerebral Akt pathway, associated with higher AD-like tau neuropathology. Our results provide evidence of altered insulin signaling in APOE4 carriers as well as a possible mechanism to explain the absence of cognitive benefit from insulin therapy in these individuals. PMID- 28088658 TI - Exposure to chronic early-life stress lastingly alters the adipose tissue, the leptin system and changes the vulnerability to western-style diet later in life in mice. AB - Early-life stress (ES) increases the vulnerability to develop psychopathologies and cognitive decline in adulthood. Interestingly, this is often comorbid with metabolic disorders, such as obesity. However, it is unclear whether ES leads to lasting metabolic changes and to what extent this is associated with the ES induced cognitive impairments. Here, we used an established chronic ES mouse model (from postnatal day (P) 2 to P9) to investigate the short- and long-term effects of ES exposure on parameters of the adipose tissue and the leptin system (i.e. circulating levels and gene expression of leptin and its receptor) in both sexes. Immediately following ES, the offspring exhibited reductions in white adipose tissue (WAT) mass, plasma leptin levels and in leptin mRNA expression in WAT. Furthermore, ES exposure led to increased brown adipose tissue and browning of WAT, which was evident by a drastic increase in uncoupling protein 1 mRNA expression in the inguinal WAT at P9. Notably, the ES-induced reductions in WAT mass, plasma leptin and leptin expression in WAT were sustained into adulthood and were accompanied by changes in body fat distribution, such as a higher ratio between mesenteric WAT and other WATs. Interestingly, while ES exposure increased leptin receptor mRNA expression in the choroid plexus, it was unaltered in the hippocampus. This suggests an adaptation to maintain central leptin homeostasis following ES exposure. In addition, chronic ES exposure resulted in the well established cognitive impairment in object recognition performance during adulthood, which correlated positively with reductions in WAT mass observed in male, but not in female mice. Finally, to assess if ES leads to a different metabolic phenotype in a moderate obesogenic environment, we measured body fat accumulation of control and ES-exposed mice in response to a moderate western style diet (WSD) that was provided during adulthood. ES-exposed mice subjected to WSD exhibit a higher increase in adiposity when compared to controls, suggesting that ES exposure might result in a higher vulnerability to develop obesity in a moderate obesogenic environment. To conclude, chronic ES exposure alters parameters of the adipose tissue, leads to central adaptations in leptin regulation and results in higher fat accumulations when exposed to a WSD challenge later in life. A better understanding of these metabolic effects induced by ES might open up new avenues for therapeutic (e.g. nutritional) interventions. PMID- 28088660 TI - Processes of anticipatory postural adjustment and step movement of gait initiation. AB - The purpose of this study was to elucidate whether the anticipatory postural adjustment (APA) and focal step movement of gait initiation are produced as a single process or different processes and whether the APA receives an inhibitory drive from the ongoing stop process of gait initiation. Healthy humans initiated gait in response to a first visual cue that instructed the initial swing leg. In some trials, a switch or stop cue was also provided after the first cue. When the stop cue was provided, participants withheld gait initiation. When the switch cue was provided, participants immediately switched the initial swing leg. In both the stop and switch tasks, the APA in response to the first cue, represented by the S1 period of the displacement of the center of pressure, appeared in more than half of the trials in which the withholding of gait initiation or switching of the initial swing leg was successfully completed. These findings indicate that the APA and focal step movement of gait initiation are produced as a dual process. In trials in which the APA in response to the first cue appeared, the amplitude and duration of the APA were decreased when the participants switched the initial swing leg or withheld gait initiation. This finding indicates that the ongoing stop process of gait initiation produces an inhibitory drive over the APA. The decreases in the amplitude and duration of the APA during the switching of the initial swing leg were similar to those during the withholding of gait initiation; moreover, the decreases during the switching of the initial swing leg were positively correlated with the decreases during the withholding of gait initiation. Thus, the stop processes during switching the initial swing leg and withholding gait initiation likely share a common inhibitory mechanism over the APA. PMID- 28088661 TI - Reduced cortical voluntary activation during bilateral knee extension. AB - INTRODUCTION: Reduced neural drive is mainly thought to explain the bilateral deficit phenomenon, i.e. the difference in maximal isometric voluntary contraction (MVC) between unilateral and bilateral contractions. The aim of the present study was to further document if bilateral knee extension is associated with changes in voluntary activation level assessed by both peripheral nerve electrical stimulation and transcranial magnetic stimulation. METHODS: Fourteen subjects performed unilateral and bilateral knee extensions with both superimposed femoral electrical nerve stimulation and transcranial magnetic stimulation in order to assess voluntary activation (VAFNES) and cortical voluntary activation (VATMS), respectively. RESULTS: There was no difference in MVC force of the tested leg when involved in unilateral and bilateral knee extensions (p=0.87). However, a significantly reduced VAFNES (-2.1+/-2.4%; p=0.01) and VATMS (-1.6+/-2.7%; p=0.04) have been evidenced during bilateral knee extension. DISCUSSION: It is hypothesized that counterbalances could have masked the decrease of voluntary activation during bilateral contraction. PMID- 28088662 TI - Metabolic profiles of exudates from chronic leg ulcerations. AB - Chronic leg ulceration is a disease usually associated with other comorbidities, and significantly reduces patient quality of life. Infected leg ulcers can lead to limb-threatening sequelae or mortality. Leg ulcerations are colonized by a number of microbes that are able to cause life-threating infections in susceptible patients. Wound exudate is a body fluid that collects metabolites from patient eukaryotic cells and from prokaryotic bacterial communities inhabiting the wound. This study aimed at identification of metabolites in exudates collected from chronic leg ulcers, and correlation of this metabolome with patient comorbidities and microbiological status of the wound. By means of NMR spectroscopy we detected 42 metabolites of microbial or patient origin. The metabolites that were in abundance in exudates analyzed were lactate, lysine, and leucine. Metabolites were associated with the presence of neutrophils in wounds and destruction of high quantities of microbes, but also with hypoxia typical for venous insufficiency. The combination of nuclear magnetic resonance spectroscopy technique and partial least squares discriminant analysis allowed us to further discriminate groups of metabolites with regards to potential clinical meaning. For example, to discriminate between S.aureus versus all other isolated microbial species, or between patients suffering from type I or II diabetes versus patients without diabetes. Therefore, wound exudate seems to be highly applicable material for discriminant analysis performed with the use of NMR technique to provide for rapid metabolomics of chronic wound status. PMID- 28088663 TI - Development and validation of a sensitive and fast UPLC-MS/MS method for simultaneous determination of seven bioactive compounds in rat plasma after oral administration of Guizhi-gancao decoction. AB - Rapid, sensitive, selective and accurate UPLC-MS/MS method was developed and fully validated for simultaneous determination of cinnamaldehyde, cinnamic acid, 2-methoxy cinnamic acid, glycyrrhizic acid, glycyrrhetinic acid, liquiritigenin and isoliquiritin in rat plasma after oral administration of Guizhi-gancao decoction. Plasma samples were processed with a simple protein precipitation technique using acetonitrile, followed by chromatographic separation using a Thermo Hypersil GOLD C18 column. A 11.0min linear gradient elution was used at a flow rate of 0.2mL/min with a mobile phase of 0.1% acetic acid containing 0.2mM ammonium acetate in water and acetonitrile. The analytes and internal standard, schisandrin, were detected using both positive and negative ion electrospray ionization in multiple reaction monitoring mode. The developed method was validated for intra-day and inter-day accuracy and precision whose values fell in the acceptable limits. Matrix effect was found to be minimal. Recovery efficiency of all the analytes was found to be >60%. Stability results showed that the analytes were stable at all the conditions. This validated method was successfully used to study the pharmacokinetics of multiple compounds in rat plasma after oral administration of Guizhi-gancao decoction. PMID- 28088664 TI - Powerful combination of analytical and chemometric methods for the photodegradation of 5-Fluorouracil. AB - The photodegradation of the antineoplastic drug 5-fluorouracil (5-FU) under the action of UV light was studied using UV-vis spectroscopy and High Performance Liquid Chromatography coupled to Diode Array Detector and High Resolution Mass Spectrometry (HPLC-DAD-HRMS). To analyze, integrate and interpret the degradation kinetics, the Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) chemometric method has been applied. The high complexity of the photodegradation process of this drug involving up to seven different photoproducts showed the advantages of the proposed approach which provides simultaneously mechanistic and structural information explaining the 5-FU photodegradability. Moreover, this study provides a new tool to be used for elucidating the photodegradation kinetics at real time. PMID- 28088665 TI - Influenza A(H1N1)pdm 2009 and influenza B virus co-infection in hospitalized and non-hospitalized patients during the 2015-2016 epidemic season in Israel. AB - BACKGROUND: Influenza A and B viruses co-infections are rare events and mainly occurred in immunocompromised patients. OBJECTIVES: In this study we report an unusually high occurrence of influenza A (H1N1)pdm 2009 and influenza B virus co infections during the epidemic year 2015-2016. STUDY DESIGN: Nasopharyngeal swabs were collected from 1919 patients visiting 26 outpatient clinics distributed throughout Israel and presenting with influenza-like illness. In addition, hospitalized patient tested for influenza viruses were also included in the study. Patients samples collected between October 2015 and April 2016 were tested for the presence of influenza viruses by real-time PCR. RESULTS: Of the 1919 patient samples tested, 11 (0.6%) were co-infected with both influenza A(H1N1)pdm 2009 and influenza B/Victoria viruses. Similar observation was noted in four hospitalized patients during the same period. Patients at ages 1-72 years, and their clinical symptoms were similar to that of patients infected with either influenza A or B viruses. Of all patients, only one hospitalized patient was immunocompromised. IN CONCLUSION: Co-infection of influenza A(H1N1)pdm 2009 and influenza B viruses is an increasingly recognized phenomenon. This co-infection can occur not only in immunocompromised individuals, but also in immunocompetent patients. Although co-infection appears to be a rare event, it may still play a role in the epidemiology, pathogenicity and evolution of influenza viruses. PMID- 28088666 TI - Vocal emotion decoding in the subthalamic nucleus: An intracranial ERP study in Parkinson's disease. AB - Using intracranial local field potential (LFP) recordings in patients with Parkinson's disease (PD) undergoing deep brain stimulation (DBS), we explored the electrophysiological activity of the subthalamic nucleus (STN) in response to emotional stimuli in the auditory modality. Previous studies focused on the influence of visual stimuli. To this end, we recorded LFPs within the STN in response to angry, happy, and neutral prosodies in 13 patients with PD who had just undergone implantation of DBS electrodes. We observed specific modulation of the right STN in response to anger and happiness, as opposed to neutral prosody, occurring at around 200-300ms post-onset, and later at around 850-950ms post onset for anger and at around 3250-3350ms post-onset for happiness. Taken together with previous reports of modulated STN activity in response to emotional visual stimuli, the present results appear to confirm that the STN is involved in emotion processing irrespective of stimulus valence and sensory modality. PMID- 28088668 TI - Near-infrared light triggered drug delivery system for higher efficacy of combined chemo-photothermal treatment. AB - : The combination of chemotherapy and photothermal therapy is a promising strategy for cancer treatment. In the present study, indocyanine green (ICG), a widely used near-infrared (NIR) dye in photothermal therapy, and chemotherapeutic drug-doxorubicin (DOX) were loaded within the nanoparticles of novel designed arylboronic ester and cholesterol modified hyaluronic acid (PPE-Chol1-HA), denoted as PCH-DI. We take advantage of reactive oxygen species (ROS) production capability of ICG and ROS-sensitivity of arylboronic ester to realize controllable drug release. It was confirmed that PCH-DI exhibited remarkable photothermal effect and light-triggered faster release of DOX with NIR laser irradiation. DOX in PCH-DI/Laser group exhibited the most efficient nucleus binding toward HCT-116 colon cells in vitro. Furthermore, enhanced cytotoxicity and promoted tumor growth suppression effect of PCH-DI on HCT-116 tumor xenograft nude mice and AOM-induced murine orthotopic colorectal cancer model was achieved under NIR laser irradiation. Thus, the co-delivery system based on PCH appears to be a promising platform for the combined chemo-photothermal therapy in tumor treatment. STATEMENT OF SIGNIFICANCE: In case of chemo-photothermal combination therapy, the synchronism of treatments plays an important role in achieving expected antitumor efficiency. In this study, a light triggered ROS mediated drug delivery system was developed with the help of ROS-sensitive moieties of arylboronic ester and ROS producer of ICG. We innovatively make use of the ROS production capability of ICG under NIR laser irradiation to promote a faster release of DOX resulting from swelling of PCH-DI due to the presence of arylboronic ester. Intracellular ROS detection demonstrated that ROS level of PCH I increased under irradiation. Moreover, the faster release behavior of DOX from PCH-DI with NIR laser irradiation was confirmed by the in vitro drug release and cellular uptake study. Meanwhile, local hyperthermia was verified by photothermal effect tests. Therefore, the synchronism of the combination therapy was achieved via light triggered faster release of DOX (chemo-therapy) and local hyperthermia (thermal-therapy) using PCH-DI under irradiation. It was reasonable to attribute the efficient anti-tumor efficiency of PCH-DI both in vitro and in vivo to the enhanced synergistic effect of chemo-photothermal combination therapy with realization of synchronism. To this end, this novel co-delivery system has provided a promising solution for achieving the synchronism of treatment to strengthen the efficiency of combination therapy. PMID- 28088669 TI - Micro-mechanical properties of the tendon-to-bone attachment. AB - : The tendon-to-bone attachment (enthesis) is a complex hierarchical tissue that connects stiff bone to compliant tendon. The attachment site at the micrometer scale exhibits gradients in mineral content and collagen orientation, which likely act to minimize stress concentrations. The physiological micromechanics of the attachment thus define resultant performance, but difficulties in sample preparation and mechanical testing at this scale have restricted understanding of structure-mechanical function. Here, microscale beams from entheses of wild type mice and mice with mineral defects were prepared using cryo-focused ion beam milling and pulled to failure using a modified atomic force microscopy system. Micromechanical behavior of tendon-to-bone structures, including elastic modulus, strength, resilience, and toughness, were obtained. Results demonstrated considerably higher mechanical performance at the micrometer length scale compared to the millimeter tissue length scale, describing enthesis material properties without the influence of higher order structural effects such as defects. Micromechanical investigation revealed a decrease in strength in entheses with mineral defects. To further examine structure-mechanical function relationships, local deformation behavior along the tendon-to-bone attachment was determined using local image correlation. A high compliance zone near the mineralized gradient of the attachment was clearly identified and highlighted the lack of correlation between mineral distribution and strain on the low-mineral end of the attachment. This compliant region is proposed to act as an energy absorbing component, limiting catastrophic failure within the tendon-to-bone attachment through higher local deformation. This understanding of tendon-to-bone micromechanics demonstrates the critical role of micrometer scale features in the mechanics of the tissue. STATEMENT OF SIGNIFICANCE: The tendon-to-bone attachment (enthesis) is a complex hierarchical tissue with features at a numerous scales that dissipate stress concentrations between compliant tendon and stiff bone. At the micrometer scale, the enthesis exhibits gradients in collagen and mineral composition and organization. However, the physiological mechanics of the enthesis at this scale remained unknown due to difficulty in preparing and testing micrometer scale samples. This study is the first to measure the tensile mechanical properties of the enthesis at the micrometer scale. Results demonstrated considerably enhanced mechanical performance at the micrometer length scale compared to the millimeter tissue length scale and identified a high compliance zone near the mineralized gradient of the attachment. This understanding of tendon-to-bone micromechanics demonstrates the critical role of micrometer scale features in the mechanics of the tissue. PMID- 28088670 TI - Fibrin hydrogels induce mixed dorsal/ventral spinal neuron identities during differentiation of human induced pluripotent stem cells. AB - : We hypothesized that generating spinal motor neurons (sMNs) from human induced pluripotent stem cell (hiPSC)-derived neural aggregates (NAs) using a chemically defined differentiation protocol would be more effective inside of 3D fibrin hydrogels compared to 2D poly-L-ornithine(PLO)/laminin-coated tissue culture plastic surfaces. We performed targeted RNA-Seq using next generation sequencing to determine the substrate-specific differences in gene expression that regulate cell phenotype. Cells cultured on both substrates expressed sMN genes CHAT and MNX1, though persistent WNT signaling contributed to a higher expression of genes associated with interneurons in NAs cultured in 3D fibrin scaffolds. Cells in fibrin also expressed lower levels of astrocyte progenitor genes and higher levels of the neuronal-specific gene TUBB3, suggesting a purer population of neurons compared to 2D cultures. STATEMENT OF SIGNIFICANCE: Fibrin scaffolds can support the neuronal differentiation of pluripotent stem cells. This study provides insight into how fibrin hydrogels affect neuronal induction by analyzing of the signaling pathways activated during the differentiation process. These insights can then be used to tailor the properties of these hydrogels to optimize the generation of sMNs for regenerative medicine applications. PMID- 28088671 TI - Melatonin attenuates titanium particle-induced osteolysis via activation of Wnt/beta-catenin signaling pathway. AB - : Wear debris-induced inhibition of bone regeneration and extensive bone resorption were common features in peri-prosthetic osteolysis (PPO). Here, we investigated the effect of melatonin on titanium particle-stimulated osteolysis in a murine calvariae model and mouse-mesenchymal-stem cells (mMSCs) culture system. Melatonin inhibited titanium particle-induced osteolysis and increased bone formation at osteolytic sites, confirmed by radiological and histomorphometric data. Furthermore, osteoclast numbers decreased dramatically in the low- and high-melatonin administration mice, as respectively, compared with the untreated animals. Melatonin alleviated titanium particle-induced depression of osteoblastic differentiation and mineralization in mMSCs. Mechanistically, melatonin was found to reduce the degradation of beta-catenin, levels of which were decreased in presence of titanium particles both in vivo and in vitro. To further ensure whether the protective effect of melatonin was mediated by the Wnt/beta-catenin signaling pathway, ICG-001, a selective beta-catenin inhibitor, was added to the melatonin-treated groups and was found to attenuate the effect of melatonin on mMSC mineralization. We also demonstrated that melatonin modulated the balance between receptor activator of nuclear factor kappa-B ligand and osteoprotegerin via activation of Wnt/beta-catenin signaling pathway. These findings strongly suggest that melatonin represents a promising candidate in the treatment of PPO. STATEMENT OF SIGNIFICANCE: Peri-prosthetic osteolysis, initiated by wear debris-induced inhibition of bone regeneration and extensive bone resorption, is the leading cause for implant failure and reason for revision surgery. In the current study, we demonstrated for the first time that melatonin can induce bone regeneration and reduce bone resorption at osteolytic sites caused by titanium-particle stimulation. These effects might be mediated by activating Wnt/beta-catenin signaling pathway and enhancing osteogenic differentiation. Meanwhile, the ability of melatonin to modulate the balance between receptor activator of nuclear factor kappa-B ligand and osteoprotegerin mediated by Wnt/beta-catenin signaling pathway, thereby suppressing osteoclastogenesis, may be implicated in the protective effects of melatonin on titanium-particle-induced bone resorption. These results suggested that melatonin can be considered as a promising therapeutic agent for the prevention and treatment of peri-prosthetic osteolysis. PMID- 28088672 TI - Using discrete multi-physics for detailed exploration of hydrodynamics in an in vitro colon system. AB - We developed a mathematical model that describes the motion of viscous fluids in the partially-filled colon caused by the periodic contractions of flexible walls (peristalsis). In-vitro data are used to validate the model. The model is then used to identify two fundamental mechanisms of mass transport: the surfing mode and the pouring mode. The first mechanism is faster, but only involves the surface of the liquid. The second mechanism causes deeper mixing, and appears to be the main transport mechanism. Based on the gained understanding, we propose a series of measures that can improve the reliability of in-vitro models. The tracer in PET-like experiments, in particular, should not be injected in the first pocket, and its viscosity should be as close as possible to that of the fluid. If these conditions are not met, the dynamics of the tracer and the fluid diverge, compromising the accuracy of the in-vitro data. PMID- 28088667 TI - Cell-laden hydrogels for osteochondral and cartilage tissue engineering. AB - : Despite tremendous advances in the field of regenerative medicine, it still remains challenging to repair the osteochondral interface and full-thickness articular cartilage defects. This inefficiency largely originates from the lack of appropriate tissue-engineered artificial matrices that can replace the damaged regions and promote tissue regeneration. Hydrogels are emerging as a promising class of biomaterials for both soft and hard tissue regeneration. Many critical properties of hydrogels, such as mechanical stiffness, elasticity, water content, bioactivity, and degradation, can be rationally designed and conveniently tuned by proper selection of the material and chemistry. Particularly, advances in the development of cell-laden hydrogels have opened up new possibilities for cell therapy. In this article, we describe the problems encountered in this field and review recent progress in designing cell-hydrogel hybrid constructs for promoting the reestablishment of osteochondral/cartilage tissues. Our focus centers on the effects of hydrogel type, cell type, and growth factor delivery on achieving efficient chondrogenesis and osteogenesis. We give our perspective on developing next-generation matrices with improved physical and biological properties for osteochondral/cartilage tissue engineering. We also highlight recent advances in biomanufacturing technologies (e.g. molding, bioprinting, and assembly) for fabrication of hydrogel-based osteochondral and cartilage constructs with complex compositions and microarchitectures to mimic their native counterparts. STATEMENT OF SIGNIFICANCE: Despite tremendous advances in the field of regenerative medicine, it still remains challenging to repair the osteochondral interface and full-thickness articular cartilage defects. This inefficiency largely originates from the lack of appropriate tissue-engineered biomaterials that replace the damaged regions and promote tissue regeneration. Cell-laden hydrogel systems have emerged as a promising tissue-engineering platform to address this issue. In this article, we describe the fundamental problems encountered in this field and review recent progress in designing cell-hydrogel constructs for promoting the reestablishment of osteochondral/cartilage tissues. Our focus centers on the effects of hydrogel composition, cell type, and growth factor delivery on achieving efficient chondrogenesis and osteogenesis. We give our perspective on developing next-generation hydrogel/inorganic particle/stem cell hybrid composites with improved physical and biological properties for osteochondral/cartilage tissue engineering. We also highlight recent advances in biomanufacturing and bioengineering technologies (e.g. 3D bioprinting) for fabrication of hydrogel-based osteochondral and cartilage constructs. PMID- 28088673 TI - Relationship between neonatal gastroschisis and maternal body mass index in a United Kingdom population. AB - OBJECTIVE: It has been reported that gastroschisis is associated with low maternal body mass index (BMI). We tested this hypothesis in the UK. STUDY DESIGN: We studied cases of gastroschisis ascertained from the regional fetal congenital anomaly register. We compared each affected mother with two controls from the birth register and maternity database. The first control was the next mother to deliver in the hospital, representing the normal population of mothers. The second control was the next mother to deliver an unaffected child whose age was within one year of that of the index case controlling for maternal age. RESULTS: There was a strong inverse association between maternal age and gastroschisis. An inverse association between gastroschisis and birth order was eliminated by adjustment for maternal age. The average age of mothers of affected children was 22.1 years; of the next delivery control was 28.8 years, and of the age matched control was 22.2 years. A weak non-statistically significant negative association between BMI and gastroschisis was further weakened by adjustment for maternal age. CONCLUSION: Our results confirm the previously reported association between low maternal age and gastroschisis but suggest that within our UK population the link between low BMI and gastroschisis reported elsewhere is explained by younger mothers being thinner. PMID- 28088674 TI - People's reasons for wanting to complete probation: Use and predictive validity in an e-health intervention. AB - The criminal justice system tends to emphasize external contingencies (e.g., fees, jail time) to motivate offender compliance. However, people's reasons for desistance vary considerably. This study evaluated the acceptability, utility, and predictive validity of questions that ask about people's reasons for wanting to successfully complete probation. Substance-using probationers (N=113) participated in a web-based computer intervention that targeted substance use and treatment initiation. Questions around seven dimensions of reasons for completing probation were developed to provide tailored feedback during the web-based program. A principle components factor analysis found that survey items loaded onto two distinct factors. Factor one, "Tangible Loss" focused on external and present-focused reasons. Factor two, "Better Life" focused on internal and future focused reasons. There was a significant negative association between Better Life scores and days of substance use after two months (beta=-0.31, SE=0.13, p<0.05). There was a significant positive association with Better Life scores and days of treatment attendance (beta=1.46, SE=0.26, p<0.001). Tangible Loss scores were no associated with substance use and treatment attendance. These findings may help to create more effective motivational tracks in e-health interventions, and may complement traditional motivation measures with an explicit focus on people's stated reasons for wanting to complete probation. PMID- 28088675 TI - Involvement of water channel Aquaporin 5 in H2S-induced pulmonary edema. AB - Acute exposure to hydrogen sulfide (H2S) poses a significant threat to life, and the lung is one of the primary target organs of H2S. However, the mechanisms involved in H2S-induced acute pulmonary edema are poorly understood. This study aims to investigate the effects of H2S on the expression of water channel aquaporin 5 (AQP5) and to elucidate the signaling pathways involved in AQP5 regulation. In an in vivo study, C57BL6 mice were exposed to sub-lethal concentrations of inhaled H2S, and histological injury of the lungs and ultrastructure injury of the epithelial cells were evaluated. With real-time PCR and western blot assays, we found that H2S exposure contributed to a significant decrease in AQP5 expression both in murine lung tissue and the A549 cell line, and the ERK1/2 and p38 MAPK signaling pathways were demonstrated to be implicated in AQP5 regulation. Therefore, adjusting AQP5 protein levels could be considered a therapeutic strategy for the treatment of APE induced by H2S and other hazardous gases. PMID- 28088676 TI - Structure of O-specific polysaccharide of Oligotropha carboxidovorans OM5 - a wastewater bacterium. AB - Oligotropha carboxidovorans strain OM5 (previously known as Pseudomonas carboxydovorans OM5) is a rod-shaped Gram-negative bacterium isolated from wastewater. This bacterium is able to live in aerobic and, facultatively, in autotrophic conditions. For autotrophic growth, the bacteria can utilize carbon monoxide or hydrogen as a source of energy. The O-specific polysaccharide isolated from O. carboxidovorans OM5 lipopolysaccharide was structurally characterized using chemical analyses, 1D and 2D NMR spectroscopy, and MALDI-TOF mass spectrometry techniques. The polysaccharide was found to be a homopolymer built up of 3-O-methyl-alpha-d-mannose residues linked by (1 -> 2)-glycosidic bonds. The degree of polymerization of high-molecular-weight polysaccharide was estimated at approximately 35-40 units. The structure of the homopolymer is depicted below: [Formula: see text]. PMID- 28088677 TI - The relationship between children's sensitivity to dominant and non-dominant patterns of lexical stress and reading accuracy. AB - This study reports on a new task for assessing children's sensitivity to lexical stress for words with different stress patterns and demonstrates that this task is useful in examining predictors of reading accuracy during the elementary years. In English, polysyllabic words beginning with a strong syllable exhibit the most common or dominant pattern of lexical stress (e.g., "coconut"), whereas polysyllabic words beginning with a weak syllable exhibit a less common non dominant pattern (e.g., "banana"). The new Aliens Talking Underwater task assesses children's ability to match low-pass filtered recordings of words to pictures of objects. Via filtering, phonetic detail is removed but prosodic contour information relating to lexical stress is retained. In a series of two alternative forced choice trials, participants see a picture and are asked to choose which of two filtered recordings matches the name of that picture; one recording exhibits the correct lexical stress of the target word, and the other recording reverses the pattern of stress over the initial two syllables of the target word rendering it incorrect. Target words exhibit either dominant stress or non-dominant stress. Analysis of data collected from 192 typically developing children aged 5 to 12years revealed that sensitivity to non dominant lexical stress was a significant predictor of reading accuracy even when age and phonological awareness were taken into account. A total of 76.3% of variance in children's reading accuracy was explained by these variables. PMID- 28088679 TI - Post-event processing in social anxiety disorder: Examining the mediating roles of positive metacognitive beliefs and perceptions of performance. AB - BACKGROUND: Post-event processing (PEP) is defined as repetitive negative thinking following anxiety provoking social events. PEP is thought to maintain anxiety symptoms in Social Anxiety Disorder (SAD) but little is known about the specific factors that contribute to the maintenance of PEP. AIMS: The current study investigated how perceptions of performance and positive metacognitive beliefs might contribute to the persistence of PEP. METHOD: Participants with SAD (n = 24) as well as anxious (n = 24) and healthy (n = 25) control participants completed a standardized social performance task in the lab. Their engagement in PEP and perceptions of performance were assessed in the week that followed. RESULTS: Immediately following the social task, individuals with SAD rated their performance more negatively and endorsed a greater number of positive metacognitive beliefs about PEP than did participants in both control groups. Importantly, both metacognitive beliefs and initial negative self-ratings of performance mediated the relationship between group status and PEP in the days following the event. CONCLUSIONS: These results are consistent with cognitive and metacognitive models of SAD and enhance our understanding of the cognitive processes which may function to initiate and maintain negative thinking patterns in SAD. PMID- 28088678 TI - Three-dimensional lumbar segment movement characteristics during paediatric cerebral palsy gait. AB - Kinematic analysis of the trunk during cerebral palsy (CP) gait has been well described. In contrast, movement of the lumbar spine is generally ignored. This is most likely due to the complex nature of the spine. As an alternative to using complex sensor protocols, this study modelled the lumbar region as a single segment and investigated characteristic patterns of movement during CP gait. In addition, the impact of functional level of impairment and the relationship with lower lumbar spinal loading were examined. Fifty-two children with CP (26 GMFCS I and 26 GMFCS II) and 26 controls were recruited. A full barefoot 3-dimensional kinematic and kinetic analysis were conducted. Lumbar segment movement demonstrated increased forward flexion for CP children. This movement became more pronounced according to GMFCS level with GMFCS II children demonstrating increases of up to 8 degrees . In addition, a moderate correlation was present between lumbar flexion/extension and L5/S1 sagittal moments (r=0.427 in the global frame and r=0.448 with respect to the pelvis, p<0.01). Children with CP demonstrated increased movement of the lumbar region compared to TD, with movement becoming more excessive as GMFCS level increased. Excessive forward flexion and loading at the lumbar spine were linked. However, the moderate correlation suggests other contributors to increased loading were present. In conclusion, this study is a first step at identifying how lumbar segment movement is altered during CP gait. PMID- 28088680 TI - The influence of patient, caregiver, and family factors on symptoms of anxiety and depression in children and adolescents with intractable epilepsy. AB - OBJECTIVE: The objective was to evaluate the association of caregiver and family factors with symptoms of anxiety and depression in children and adolescents with medically refractory localization-related epilepsy (i.e., failed at least two epilepsy medications). METHOD: Forty-four children (ages 6-11years) and 65 adolescents (ages 12-18years) and their parents participated in this multicentered, observational, cross-sectional study. Univariable and multivariable linear regressions were used to evaluate the influence of multiple patient, caregiver, and family characteristics on self-reported symptoms of anxiety and depression in the children and adolescents. RESULTS: Among children, depressive symptoms were associated with a lower proportion of life with seizures (beta=.344, p=.022), caregiver depression (beta=.462, p=.002), poorer family relationships (beta=.384, p=.010), and poorer family mastery and social support (beta=.337, p=.025); in multivariable analysis, proportion of life with epilepsy and parental depression remained significant. No significant predictors of anxiety were found among children. Among adolescents, depressive symptoms were associated with caregiver unemployment (beta=.345, p=.005) and anxiety (beta=.359, p=.003), low household income (beta=.321, p=.012), poorer family mastery and social support (beta=.334, p=.007), and greater family demands (beta=.326, p=.008); in multivariable analysis, caregiver unemployment and anxiety remained significant. Greater anxiety symptoms among adolescents were associated with females (beta=.320, p=.009) and caregiver depression (beta=.246, p=.048) and anxiety (beta=.392, p=.001) and poorer family mastery and social support (beta=.247, p=.047); in multivariable analysis, female sex and caregiver anxiety remained significant. SIGNIFICANCE: These findings highlight the central role of caregiver psychopathology, which is amenable to intervention, on children and adolescents' symptoms of anxiety and depression. Addressing caregiver psychopathology may improve children and adolescents' quality of life even if seizure control is not attained. PMID- 28088681 TI - Maintenance effects of working memory intervention (Cogmed) in children with symptomatic epilepsy. AB - PURPOSE: To extend previous research documenting the benefits of working memory (WM) intervention (Cogmed) immediately post-intervention in children with epilepsy by assessing the 3-month maintenance effects. METHODS: Participants involved in a previous randomized clinical trial (RCT) were invited to participate if they completed Cogmed within the last 3months (n=15) and additional participants (n=13) were prospectively recruited. Standardized assessments of near-transfer effects (i.e., visual and auditory attention and WM) were completed prior to and immediately after intervention and at 3-month follow up. An additional measure assessing the far-transfer effect of fluid reasoning was administered prior to intervention and at 3-month follow-up. RESULTS: Participants exhibited gains in auditory and visual attention and WM immediately following intervention and gains were generally sustained at 3-month follow-up. Intervention did not improve visual-verbal WM or fluid reasoning. The clinical variables studied (i.e., age of seizure onset, seizure frequency, epilepsy duration, and overall intellectual functioning) did not elucidate reliable relationships with intervention. CONCLUSIONS: Working memory training is possibly efficacious in improving related skills which are maintained for 3months in children with active epilepsy. No transfer to fluid reasoning was documented. Further investigation by means of a large-scale RCT which includes a placebo and both objective and subjective measures of the impact of training on daily functioning is warranted. PMID- 28088682 TI - Female sexual function mediates the effects of medication adherence on quality of life in people with epilepsy. AB - PURPOSE: The purpose of this study was to understand the mediating effects of female sexual functioning in the association between medication adherence and quality of life (QoL) in Iranian women with epilepsy (WWE). METHODS: Women's sexual functioning was measured using Female Sexual Function Index; QoL using Quality of Life in Epilepsy; epilepsy severity using Liverpool Seizure Severity Scale; subjective medication adherence using Medication Adherence Report Scale; and objective medication adherence using serum level for antiepileptic drugs in 567 WWE. Medication adherence was measured at baseline, while women's sexual functioning, QoL, and epilepsy severity were measured at the 6-month follow-up. Structural equation modeling and regression models were conducted to examine the mediating role of women's sexual functioning. RESULTS: The mediating effects of sexual functioning in the relationship between medication adherence (including subjective and objective measures) and QoL were supported in the total score of Female Sexual Function Index (coefficient=0.415, SE=0.117, p<0.001 for subjective medication adherence; coefficient=1.980, SE=0.446, p<0.001 for objective medication adherence). Seizure severity was significantly associated with QoL but only when objective medication adherence was measured (coefficient=-0.094, SE=0.036, p=0.009). CONCLUSION: Our results extended the importance of medication adherence from symptom reduction to the beneficial effects of women's sexual functioning and QoL. Health care providers should be aware of these additional benefits of medication adherence and use these arguments to encourage female patients to take their medication, which can eventually increase their sexual satisfaction and overall QoL. PMID- 28088683 TI - Effects of protease-activated receptor 1 inhibition on anxiety and fear following status epilepticus. AB - Protease-activated receptor 1 (PAR1) is an important contributor to the pathogenesis of a variety of brain disorders associated with a risk of epilepsy development. Using the lithium-pilocarpine model of temporal lobe epilepsy (TLE), we recently showed that inhibition of this receptor during the first ten days after pilocarpine-induced status epilepticus (SE) results in substantial anti epileptogenic and neuroprotective effects. As PAR1 is expressed in the central nervous system regions of importance for processing emotional reactions, including amygdala and hippocampus, and TLE is frequently associated with a chronic alteration of the functions of these regions, we tested the hypothesis that PAR1 inhibition could modulate emotionally driven behavioral responses of rats experiencing SE. We showed that SE induces a chronic decrease in the animals' anxiety-related behavior and an increase of locomotor activity. PAR1 inhibition after SE abolished the alteration of the anxiety level but does not affect the increase of locomotor activity in the open field and elevated plus maze tests. Moreover, while PAR1 inhibition produces an impairment of memory recall in the context fear conditioning paradigm in the control group, it substantially improves contextual and cued fear learning in rats experiencing SE. These data suggest that PAR1-dependent signaling is involved in the mechanisms underlying emotional disorders in epilepsy. PMID- 28088684 TI - Changes in electroencephalographic characteristics and blood-brain barrier permeability in WAG/Rij rats with cortical dysplasia. AB - PURPOSE: This study investigated the effects of cortical dysplasia (CD) on electrophysiology and blood-brain barrier (BBB) permeability in WAG/Rij rats with genetic absence epilepsy. METHODS: Pregnant WAG/Rij rats were exposed to 145cGy of gamma-irradiation on embryonic day 17 to induce CD. An electroencephalogram was recorded from cortices subdurally in the offspring of the pregnant animals. Horseradish peroxidase (HRP) was used as determinant of BBB permeability. RESULTS: A massive tissue loss in the cerebral cortex was seen in WAG/Rij rats with CD (p<0.05). There was a significant decrease in the number and duration of spike-and-wave discharges (SWDs) and an increase in the frequency of SWDs in the WAG/Rij rats with CD when compared with the properties of SWDs in intact WAG/Rij rats (p<0.01). Ultrastructurally, the accumulation of HRP reaction products in the cerebral cortex and thalamus of WAG/Rij rats was significantly higher than that of control values (p<0.01). The accumulation of HRP reaction products in the cerebral cortex and thalamus regions of WAG/Rij rats with CD increased and was higher than that of the control and WAG/Rij animals (p<0.01). CONCLUSION: In our study, we showed that number and duration of SWDs decreased and SWD frequency increased in WAG/Rij rats with CD, suggesting a shift in seizure pattern. The association of these alterations with significant loss of cortical thickness and increased BBB permeability to HRP tracer may represent a causal relation of the EEG abnormalities with cerebral structural changes in these animals. PMID- 28088685 TI - A semi-interpenetrating network of polyacrylamide and recombinant basement membrane allows pluripotent cell culture in a soft, ligand-rich microenvironment. AB - The physical properties of the extracellular matrix play an essential role in guiding stem cell differentiation and tissue morphogenesis both in vivo and in vitro. Existing work to investigate the role of matrix mechanics in directing stem cell proliferation, self-renewal, and differentiation has been limited by the poor attachment and survival of human pluripotent cells cultured on soft matrices (Young's modulus E ? 1000 Pa). To address this limitation we developed a protocol for generating semi-interpenetrating networks of polyacrylamide and recombinant basement membrane. Using these materials, we found that human embryonic stem cells (hESCs) remained proliferative and pluripotent even when grown in small colonies and on surfaces ranging in stiffness from 150 to 12000 Pa, spanning the range of tissue stiffnesses likely to be encountered in the embryo. Considerable recent attention has focused on the role of the transcriptional coactivator and Hippo effector YAP in regulating differentiation and cell proliferation both in the early embryo and in vitro. We found that while YAP localized to the nucleus on substrates of E ? 1000 Pa, its localization was heterogeneous on substrates of moduli ? 450 Pa, with predominantly nuclear localization at the colony periphery and mixed cytoplasmic and nuclear localization for cells in the colony interior, a pattern reminiscent of YAP subcellular localization in the inner cell mass (ICM) of the early embryo. In addition, hESC colony dynamics were highly responsive to substrate stiffness, with cells assembling into monolayers, multilayer structures, and transient, hollow rosettes in response to decreasing substrate stiffnesses in the range of 12000 to 150 Pa. We suggest that soft, ligand-rich substrates such as are described here provide a promising means of recapitulating aspects of early mammalian development that are otherwise inaccessible, and more broadly may be useful in the derivation of complex tissues from pluripotent cells in an in vitro setting. PMID- 28088686 TI - Immune history and influenza virus susceptibility. AB - Antibody responses to influenza viruses are critical for protection, but the ways in which repeated viral exposures shape antibody evolution and effectiveness over time remain controversial. Early observations demonstrated that viral exposure history has a profound effect on the specificity and magnitude of antibody responses to a new viral strain, a phenomenon called 'original antigenic sin.' Although 'sin' might suppress some aspects of the immune response, so far there is little indication that hosts with pre-existing immunity are more susceptible to viral infections compared to naive hosts. However, the tendency of the immune response to focus on previously recognized conserved epitopes when encountering new viral strains can create an opportunity cost when mutations arise in these conserved epitopes. Hosts with different exposure histories may continue to experience distinct patterns of infection over time, which may influence influenza viruses' continued antigenic evolution. Understanding the dynamics of B cell competition that underlie the development of antibody responses might help explain the low effectiveness of current influenza vaccines and lead to better vaccination strategies. PMID- 28088687 TI - Whole-Genome DNA Methylation Profiling Identifies Epigenetic Signatures of Uterine Carcinosarcoma. AB - Uterine carcinosarcoma (UCS) is a form of endometrial cancer simultaneously exhibiting carcinomatous and sarcomatous elements, but the underlying molecular and epigenetic basis of this disease is poorly understood. We generated complete DNA methylomes for both the carcinomatous and the sarcomatous components of three UCS samples separated by laser capture microdissection and compared DNA methylomes of UCS with those of normal endometrium as well as methylomes derived from endometrioid carcinoma, serous endometrial carcinoma, and endometrial stromal sarcoma. We identified epigenetic lesions specific to carcinosarcoma and specific to its two components. Hallmarks of DNA methylation abnormalities in UCS included global hypomethylation, especially in repetitive elements, and hypermethylation of tumor suppressor gene promoters. Among these, aberrant DNA methylation of MIR200 genes is a key feature of UCS. The carcinoma component of UCS was characterized by hypermethylation of promoters of EMILIN1, NEFM, and CLEC14A, genes that are associated with tumor vascularization. In contrast, DNA methylation changes of PKP3, FAM83F, and TCP11 were more characteristic of the sarcoma components. Our findings highlight the epigenetic signatures that distinguish the two components of UCS, providing a valuable resource for investigation of this disease. PMID- 28088688 TI - Randomized Phase III Study to Assess Efficacy and Safety of Adjuvant CAPOX with or without Bevacizumab in Patients after Resection of Colorectal Liver Metastases: HEPATICA study. AB - Bevacizumab is a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF). Recurrence after resection of colorectal liver metastases (CRLMs), presumably caused by VEGF-mediated outgrowth of micrometastases, might decrease when VEGF is inhibited. This study examines the efficacy and safety of adding bevacizumab to an adjuvant regimen of CAPOX in patients undergoing radical resection for their CRLMs. Patients with resected CRLMs were randomized after surgery to receive CAPOX and bevacizumab (arm A) or CAPOX alone (arm B) as adjuvant treatment. CAPOX was given in both arms for a total of eight cycles. Bevacizumab was administered for 16 cycles. The primary end point was disease free survival (DFS). Secondary outcomes were overall survival (OS), toxicity, and quality of life (QoL). In total, 79 patients were randomized. At the time of analysis, 23 events were encountered in arm A and 20 in arm B. One-year DFS rate was 79% [95% confidence interval (CI): 68%-93%] and 68% (95% CI: 55%-85%) for arm A and B, respectively (P=.89). Toxicity was evaluated for 75 patients. No significant differences in toxicity between the two arms were found. QoL scores were higher in arm A, of which emotional functioning and global QoL scores were significant. Adding bevacizumab to a CAPOX regimen in patients undergoing a resection for their CLM is safe and showed higher QoL scores compared with CAPOX alone. Because of premature closure of the study, conclusions about the effect on DFS of additional VEGF inhibition in this setting could not yet be made. PMID- 28088689 TI - Syntheses, structures and fluorescence properties of three rare-earth containing docosatungstates. AB - Three rare-earth containing docosatungstates Na3H2[RE(H2O)4][RE(H2O)5]2[W22O74H2].36H2O [RE=DyIII (1), HoIII (2), YIII (3)] have been synthesized by reaction of Na2WO4.2H2O, dimethylamine hydrochloride (DMAHC) and RE(NO3)3.6H2O in the aqueous solution and characterized by elemental analyses, IR spectra, thermogravimetric (TG) analysis, powder X-ray diffraction (PXRD) and single-crystal X-ray diffraction. 1-3 are isomorphous and each molecular unit consists of a S-shaped docosatungstate [W22O74H2]14- polyoxoanion with two supporting [RE(H2O)5]3+ cations and one disordered [RE(H2O)4]3+ cation. The [W22O74H2]14- polyoxoanion can be viewed as combination of two hendecatungstate [W11O38H]9- subunits in the staggered fashion by sharing two MU2 O atoms. The TG curves of 1-3 reveal the one-step weight loss between 25 degrees C to 700 degrees C. Moreover, both 1 and 2 demonstrate the characteristic luminescence emission behaviors of the corresponding RE3+ ions and their lifetime decay curves can be well fitted to the double exponential function. In addition, the CIE chromaticity coordinates of 1 and 2 have been obtained based on their corresponding emission spectra, and their dominant wavelengths and color purities have been also calculated. PMID- 28088690 TI - Electrochemical studies of DNA interaction and antimicrobial activities of MnII, FeIII, CoII and NiII Schiff base tetraazamacrocyclic complexes. AB - Tetraazamacrocyclic complexes of MnII, FeIII, CoII and NiII have been synthesized by template method. These tetraazamacrocycles have been analyzed with various techniques like molar conductance, IR, UV-vis, mass spectral and cyclic voltammetric studies. On the basis of all these studies, octahedral geometry has been assigned to these tetraazamacrocyclic complexes. The DNA binding properties of these macrocyclic complexes have been investigated by electronic absorption spectra, fluorescence spectra, cyclic voltammetric and differential pulse voltammetric studies. The cyclic voltammetric data showed that ipc and ipa were effectively decreased in the presence of calf thymus DNA, which is a strong evidence for the interaction of these macrocyclic complexes with the calf thymus DNA (ct-DNA). The heterogeneous electron transfer rate constant found in the order: KCoII>KNiII>KMnII which indicates that CoII macrocyclic complex has formed a strong intercalated intermediate. The Stern-Volmer quenching constant (KSV) and voltammetric binding constant were found in the order KSV(CoII)>KSV(NiII)>KSV(MnII) and K+(CoII)>K+(NiII)>K+(MnII) which shows that CoII macrocyclic complex exhibits the high interaction affinity towards ct-DNA by the intercalation binding. Biological studies of the macrocyclic complexes compared with the standard drug like Gentamycin, have shown antibacterial activities against E. coli, P. aeruginosa, B. cereus, S. aureus and antifungal activity against C. albicans. PMID- 28088691 TI - Stability effect of cholesterol-poly(acrylic acid) in a stimuli-responsive polymer-liposome complex obtained from soybean lecithin for controlled drug delivery. AB - The development of polymer-liposome complexes (PLCs), in particular for biomedical applications, has grown significantly in the last decades. The importance of these studies comes from the emerging need in finding intelligent controlled release systems, more predictable, effective and selective, for applications in several areas, such as treatment and/or diagnosis of cancer, neurological, dermatological, ophthalmic and orthopedic diseases, gene therapy, cosmetic treatments, and food engineering. This work reports the development and characterization of a pH sensitive system for controlled release based on PLCs. The selected hydrophilic polymer was poly(acrylic acid) (PAA) synthesized by atom transfer radical polymerization (ATRP) with a cholesterol (CHO) end-group to improve the anchoring of the polymer into the lipid bilayer. The polymer was incorporated into liposomes formulated from soybean lecithin and stearylamine, with different stearylamine/phospholipid and polymer/phospholipid ratios (5, 10 and 20%). The developed PLCs were characterized in terms of particle size, polydispersity, zeta potential, release profiles, and encapsulation efficiency. Cell viability studies were performed to assess the cytotoxic potential of PLCs. The results showed that the liposomal formulation with 5% of stearylamine and 10% of polymer positively contribute to the stabilization of the complexes. Afterwards, the carboxylic acid groups of the polymer present at the surface of the liposomes were crosslinked and the same parameters analyzed. The crosslinked complexes showed to be more stable at physiologic conditions. In addition, the release profiles at different pHs (2-12) revealed that the obtained complexes released all their content at acidic conditions. In summary, the main accomplishments of this work are: (i) innovative synthesis of cholesterol poly(acrylic acid) (CHO-PAA) by ATRP; (ii) stabilization of the liposomal formulation by incorporation of stearylamine and CHO-PAA; (iii) new approach for CHO-PAA crosslinking, resulting in more stable PLCs at physiological conditions; (iv) destabilization of PLCs upon slight changes of pH, showing their pH sensitivity; and (v) the PLCs do not exhibit cellular toxicity. PMID- 28088692 TI - Evaluation of motor and cognitive development among infants exposed to HIV. AB - This study of a prospective and cross-sectional nature compared the motor and cognitive development of HIV-exposed and unexposed infants in their first 18months of age. 40 infants exposed to HIV and antiretroviral therapy (Experimental Group - EG) and 40 unexposed infants (Control Group - CG) participated in the study. They were divided into four age groups of 4, 8, 12 and 18months old, with 10 infants from EG and 10 from CG in each group. The infants were evaluated once on motor and cognitive development by the Bayley Scale of Infant and Toddler Development. Performance category grading and comparisons among scaled score, composite score and percentile rank were held. There was significant group effect for scores in motor and cognitive domains showing lower scores for EG regardless of age. In comparison to the CG, the EG presented lower scores for cognitive domain at 8 and 18months. In the performance categories, all infants were classified at or above the average for motor and cognitive development, except of one EG-18month old infant classified as borderline for motor development. Infants exposed to HIV and antiretroviral therapy own adequate cognitive and motor development in the first 18months. However, the lower scores found, particularly on the 8th and 18th month for cognitive development, may indicate future problems, highlighting the need for systematic follow-up of this population. PMID- 28088693 TI - Reinforcement of a PMMA resin for interim fixed prostheses with silica nanoparticles. AB - PURPOSE: Fractures in long span provisional/interim restorations are a common complication. Adequate fracture toughness is necessary to resist occlusal forces and crack propagation, so these restorations should be constructed with materials of improved mechanical properties. The aim of this study was to investigate the possible reinforcement of neat silica nanoparticles and trietoxyvinylsilane modified silica nanoparticles in a PMMA resin for fixed interim restorations. MATERIALS AND METHODS: Composite PMMA-Silica nanoparticles powders were mixed with PMMA liquid and compact bar shaped specimens were fabricated according to the British standard BS EN ISO 127337:2005. The single-edge notched method was used to evaluate fracture toughness (three-point bending test), while the dynamic thermomechanical properties (Storage Modulus, Loss Modulus, tandelta) of a series of nanocomposites with different amounts of nanoparticles (0.25%, 0.50%, 0.75%, 1% w.t.) were evaluated. Statistical analysis was performed and the statistically significant level was set to p<0.05. RESULTS: The fracture toughness of all experimental composites was remarkably higher compared to control. There was a tendency to decrease of fracture toughness, by increasing the concentration of the filler. No statistically significant differences were detected among the modified/unmodified silica nanoparticles. Dynamic mechanical properties were also affected. By increasing the silica nanoparticles content an increase in Storage Modulus was recorded, while Glass Transition Temperature was shifted at higher temperatures. CONCLUSIONS: Under the limitations of this in-vitro study, it can be suggested that both neat silica nanoparticles and trietoxyvinylsilane-modified silica nanoparticles, especially at low concentrations, may enhance the overall performance of fixed interim prostheses, as can effectively increase the fracture toughness, the elastic modulus and the Glass Transition Temperature of PMMA resins used in fixed provisional restorations. PMID- 28088695 TI - Deep metabolome annotation in natural products research: towards a virtuous cycle in metabolite identification. AB - Natural products (NPs) research is changing and rapidly adopting cutting-edge tools, which radically transform the way to characterize extracts and small molecules. With the innovations in metabolomics, early integration of deep metabolome annotation information allows to efficiently guide the isolation of valuable NPs only and, in parallel, to generate massive metadata sets for the study of given extracts under various perspectives. This is the case for chemotaxonomy studies where common biosynthetic traits among species can be evidenced, but also for drug discovery purpose where such traits, in combination with bioactivity studies on extracts, may evidence bioactive molecules even before their isolation. One of the major bottlenecks of such studies remains the level of accuracy at which NPs can be identified. We discuss here the advancements in LC-MS and associated mining methods by addressing what would be ideal and what is achieved today. We propose future developments for reinforcing generic NPs databases both in the spectral and structural dimensions by heading towards a virtuous metabolite identification cycle allowing annotation of both known and unreported metabolites in an iterative manner. Such approaches could significantly accelerate and improve our knowledge of the huge chemodiversity found in nature. PMID- 28088694 TI - Metabolic network modeling with model organisms. AB - Flux balance analysis (FBA) with genome-scale metabolic network models (GSMNM) allows systems level predictions of metabolism in a variety of organisms. Different types of predictions with different accuracy levels can be made depending on the applied experimental constraints ranging from measurement of exchange fluxes to the integration of gene expression data. Metabolic network modeling with model organisms has pioneered method development in this field. In addition, model organism GSMNMs are useful for basic understanding of metabolism, and in the case of animal models, for the study of metabolic human diseases. Here, we discuss GSMNMs of most highly used model organisms with the emphasis on recent reconstructions. PMID- 28088697 TI - Vertical distribution of 236U in the North Pacific Ocean. AB - The first extensive study on 236U in the North Pacific Ocean has been conducted. The vertical distribution of 236U/238U isotopic ratios and the 236U concentrations were analysed on seven depth profiles, and large variations with depth were found. The range of 236U/238U isotopic ratios was from (0.09 +/- 0.03) * 10-10 to (14.1 +/- 2.2) * 10-10, which corresponds to 236U concentrations of (0.69 +/- 0.24) * 105 atoms/kg and (119 +/- 21) * 105 atoms/kg, respectively. The variations in 236U concentrations could mainly be attributed to the different water masses in the North Pacific Ocean and their formation processes. Uranium 236 inventories on the water column of each sampling station were calculated and varied between (3.89 +/- 0.08) * 1012 atoms/m2 and (7.03 +/- 0.50) * 1012 atoms/m2, which is lower than in former studies on comparable latitudes in the North Atlantic Ocean and the Sea of Japan. The low inventories of 236U found for the North Pacific Ocean in this study can be explained by the lack of additional input sources of artificial radionuclides, apart from global and regional/local fallout. This study expands the use of 236U as oceanographic circulation tracer to yet another ocean basin and shows that this isotope can be used for tracing circulation patterns of water masses in the Pacific Ocean. PMID- 28088696 TI - Cell-selective proteomics for biological discovery. AB - Cells alter the proteome to respond to environmental and developmental cues. Global analysis of proteomic responses is of limited value in heterogeneous environments, where there is no 'average' cell. Advances in sequencing, protein labeling, mass spectrometry, and data analysis have fueled recent progress in the investigation of specific subpopulations of cells in complex systems. Here we highlight recently developed chemical tools that enable cell-selective proteomic analysis of complex biological systems, from bacterial pathogens to whole animals. PMID- 28088698 TI - Metformin enhancing the antitumor efficacy of carboplatin against Ehrlich solid carcinoma grown in diabetic mice: Effect on IGF-1 and tumoral expression of IGF-1 receptors. AB - Diabetes has been listed as a risk factor for various types of cancer. Cancer cell development can be promoted by increased levels of IGF-1 and hyperinsulinemia that are associated with diabetes type II. Metformin is an anti diabetic agent and its potential antitumor impact has become the objective of numerous studies. In this vein, we hypothesize that using metformin in diabetes type II mice may synergistic with carboplatin for reducing the risk of cancer. Therefore, the study aimed to evaluate the in vivo antitumor activity of metformin against solid EAC tumor growth in female diabetic mice and its potential pro-apoptotic and anti-proliferative effects with clarification of its inconclusive biological mechanisms. Mice were assigned into nine groups; normal control, diabetic control, diabetic plus EAC control, EAC control, and treated groups received carboplatin and/or metformin (100, 200mg/kg). Metformin administration especially with high dose potentiated the antitumor activity of carboplatin displayed by increased pro-apoptotic activators "caspase-3 and bax" and reduced anti-apoptotic protein bcl-2. This was confirmed by the histopathological scores. Moreover, the combination therapy was effective in attenuating the expression of the pro-angiogenic mediator "VEGF" and the microvessel density as revealed by the CD34. Additionally, this combination down regulated the high levels of the mutagenic element "IGF-1" and its receptor expression, and attenuated the intensity of inflammatory mediators. In conclusion, it was found that metformin therapy could enhance apoptotic marker, and suppress the neovascularization and proliferation process. This clarified the ability of metformin to support carboplatin activity in reducing tumor progression in type II diabetes. PMID- 28088699 TI - Procyanidin B2 gallates inhibit IFN-gamma and IL-17 production in T cells by suppressing T-bet and RORgammat expression. AB - Procyanidins are widely found in plants and have anti-inflammatory activities. Procyanidin B2 (PCB2) inhibits production of proinflammatory cytokines in macrophages. However, there has been no study that has attempted to determine the effects of PCB2 gallates on T cell functions. In the present study, murine splenocytes were isolated and treated with PCB2 or PCB2 gallates in the presence of an anti-CD3 monoclonal antibody (mAb). PCB2 gallates, but not PCB2, inhibited proliferation and T cell activation of splenocytes after stimulation with the anti-CD3 mAb. In addition, PCB2 gallates, particularly 3,3"-di-O-gallate (3,3"-di OG), significantly inhibited production of interferon (IFN)-gamma, interleukin (IL)-12p40, and IL-17 in splenocytes, but did not suppress IL-10 production. Intracellular staining revealed that the expression of IFN-gamma and IL-17 in both CD4+ and CD8+ T cells was obviously decreased by PCB2 3,3"-di-OG compared with PCB2, PCB2 3-OG, and PCB2 3"-OG. Treatment of isolated CD4+ and CD8+ T cells with procyanidins in the presence of the anti-CD3 mAb led to significant inhibition of IFN-gamma production by PCB2 3,3"-di-OG in both cell types. Furthermore, PCB2 3,3"-di-OG suppressed the expression of transcription factors T bet and RORgammat that regulate IFN-gamma and IL-17, respectively. In conclusion, we revealed a new mechanism through which PCB2 gallates inhibit IFN-gamma and IL 17 production in T cells by down-regulation of T-bet and RORgammat expression. Our results suggest that PCB2 gallates have a potential role in Th1/Th17-mediated diseases such as inflammatory and autoimmune diseases. PMID- 28088700 TI - Chlorogenic acid ameliorated concanavalin A-induced hepatitis by suppression of Toll-like receptor 4 signaling in mice. AB - Chlorogenic acid (CGA), one of the most abundant dietary polyphenolic compounds, has been reported to exhibit anti-inflammatory ability. However, the hepatoprotective effects and molecular mechanisms of CGA on concanavalin A (Con A)-induced hepatitis have not been explored. In the present study, we found that pretreatment with CGA dose-dependently inhibited the elevation of plasma aminotransferases and alleviated hepatic pathological damage as well as hepatocyte apoptosis in Con A-exposed mice. Additionally, CGA markedly suppressed the production of serum tumor necrosis factor (TNF)-alpha and interferon (IFN) gamma, alleviated the infiltration of hepatic macrophages, neutrophils, and activated CD4+ T lymphocytes in Con A-primed mice. Moreover, CGA downregulated Con A-induced hepatic expression of adhesion molecules (ICAM-1, VCAM-1 and ELAM 1) mRNA and protein, and inhibited Con A-activated Toll-like receptor (TLR) 4 signal molecules including TLR4, p-IRAK1, p-IkappaB, and p-p38. Finally, our results also showed that CGA exhibited a therapeutic effect, which CGA posttreatment improved hepatic damage at 1, 3, and 6h after Con A. Taken together, these data suggested that CGA could effectively prevent mice from Con A induced hepatitis, which might be through suppressing the activation of TLR4 signaling, downregulating the expression of adhesion molecules, and alleviating the infiltration and activation of hepatic leukocytes and the production of pro inflammatory cytokines. PMID- 28088701 TI - Testing the causal theory of reference. AB - Theories of reference are a crucial research topic in analytic philosophy. Since the publication of Kripke's Naming and Necessity, most philosophers have endorsed the causal/historical theory of reference. The goal of this paper is twofold: (i) to discuss a method for testing experimentally the causal theory of reference for proper names by investigating linguistic usage and (ii) to present the results from two experiments conducted with that method. Data collected in our experiments confirm the causal theory of reference for people proper names and for geographical proper names. A secondary but interesting result is that the semantic domain affects reference assignment: while with people proper names speakers tend to assign the semantic reference, with geographical proper names they are prompted to assign the speaker's reference. PMID- 28088702 TI - The social nature of overimitation: Insights from Autism and Williams syndrome. AB - When imitating novel actions, typically developing preschoolers often copy components of the demonstration that are unrelated to the modeled action's goal, a phenomenon known as 'overimitation'. According to the social motivation account, overimitation fulfills social affiliation motives (i.e., the imitator's drive to experience social connectedness with the demonstrator and the social context). Conversely, according to the social-cognitive account, overimitation reflects overattribution of causal relevance (i.e., the imitator's failure to appreciate that some components of the demonstration are not relevant to the action's outcome). Autism Spectrum Disorder (ASD) and William syndrome (WS) are characterized by reduced and enhanced spontaneous social motivation, respectively, as well as similar impairments in social-cognition, thus providing helpful test cases to understand the nature of overimitation. Using a novel eye tracking paradigm, we examined overimitation in 31 preschoolers with ASD, 18 age- and IQ-matched peers with WS, and 19 age-matched typically developing children. We found that children with WS and typically developing children were more likely to overimitate, and to increase their attention to the model's face during demonstration of causally irrelevant actions, compared to those with ASD. These findings will be discussed in the context of support for the social-motivational account of overimitation. PMID- 28088703 TI - Dopaminergic rules of engagement for memory in Drosophila. AB - Dopamine is associated with a variety of conserved responses across species including locomotion, sleep, food consumption, aggression, courtship, addiction and several forms of appetitive and aversive memory. Historically, dopamine has been most prominently associated with dynamics underlying reward, punishment, or salience. Recent emerging evidence from Drosophila supports a role in all of these functions, as well as additional roles in the interplay between external sensation and internal states and forgetting of the very memories dopamine helped encode. We discuss how cell-specific resolution and manipulation are elucidating the rules of dopamine's involvement in encoding valence and memory. PMID- 28088704 TI - An examination of the anxiolytic effects of exercise for people with anxiety and stress-related disorders: A meta-analysis. AB - The literature regarding exercise for people with established anxiety disorders is equivocal. To address this issue, we conducted a systematic review and meta analysis investigating the benefits of exercise compared to usual treatment or control conditions in people with an anxiety and/or stress-related disorders. Major electronic databases were searched from inception until December/2015 and a random effect meta-analysis conducted. Altogether, six randomized control trials (RCTs) including 262 adults (exercise n=132, 34.74 [9.6] years; control n=130, 37.34 [10.0] years) were included. Exercise significantly decreased anxiety symptoms more than control conditions, with a moderate effect size (Standardized Mean Difference=-0.582, 95%CI -1.0 to -0.76, p=0.02). Our data suggest that exercise is effective in improving anxiety symptoms in people with a current diagnosis of anxiety and/ or stress-related disorders. Taken together with the wider benefits of exercise on wellbeing and cardiovascular health, these findings reinforce exercise as an important treatment option in people with anxiety/stress disorders. PMID- 28088705 TI - Ultrasonic compaction of granular geological materials. AB - It has been shown that the compaction of granular materials for applications such as pharmaceutical tableting and plastic moulding can be enhanced by ultrasonic vibration of the compaction die. Ultrasonic vibrations can reduce the compaction pressure and increase particle fusion, leading to higher strength products. In this paper, the potential benefits of ultrasonics in the compaction of geological granular materials in downhole applications are explored, to gain insight into the effects of ultrasonic vibrations on compaction of different materials commonly encountered in sub-sea drilling. Ultrasonic vibrations are applied, using a resonant 20kHz compactor, to the compaction of loose sand and drill waste cuttings derived from oolitic limestone, clean quartz sandstone, and slate phyllite. For each material, a higher strain for a given compaction pressure was achieved, with higher sample density compared to that in the case of an absence of ultrasonics. The relationships between the operational parameters of ultrasonic vibration amplitude and true strain rate are explored and shown to be dependent on the physical characteristics of the compacting materials. PMID- 28088706 TI - Topological imaging in bounded elastic media. AB - Detecting, imaging and sizing defects in a bounded elastic medium is still a difficult task, especially when access is complex. Adjoint methods simplify the task as they take advantage of prior information such as the geometry and material properties. However, they still reveal a number of important limitations. Artifacts observed on the conventional topological energy image result from wave interactions with the boundaries of the inspected medium. The paper describes a method for addressing these artifacts, which involves forward and adjoint fields specified in terms of the boundary conditions. Modified topological energies are then defined according to the type of analyzed flaw (open slit or inclusion). Comparison of the numerical results with the experimental data confirms the relevance of the approach. PMID- 28088707 TI - DNA sensing and immune responses in cancer therapy. AB - The identification of critical DNA sensors and their pathways has led to revealing the central role of DNA sensing in immune system. It has been initially demonstrated that DNA sensing and immune responses have high impacts on the development and prevention of infection and inflammatory. In addition to toll like receptor pathways, there is now also emerging evidence that cytosolic enzyme cyclic GMP-AMP synthase (cGAS) is essential for the recognition of not only pathogen-derived DNA but also tumor DNA for innate sensing. The strategies through activating DNA sensing pathways toward enhancing antitumor immunity have shown promise and are further tested in clinical studies. Here, we highlight recent progresses in understanding mechanisms activated by DNA sensing mediated immune responses in cancer therapy. PMID- 28088708 TI - Germinal centers: programmed for affinity maturation and antibody diversification. AB - The seminal discovery by Eisen that antibodies undergo improvements in antigen binding affinity over the course of an immune response led to a long running search for the underlying mechanism. Germinal centers in lymphoid organs are now recognized to be critically involved in this phenomenon, known as antibody affinity maturation. As well as improving in affinity for specific epitopes, some antibody responses maintain or even increase their breadth of antigen-recognition over time. This has led to another intense line of research aimed at understanding how broadly neutralizing anti-pathogen responses are generated. Recent work indicates that germinal centers also play an important role in the diversification process. We discuss current understanding of how germinal centers are programmed to support both affinity maturation and antibody diversification. PMID- 28088709 TI - Characterization of smokeless powders using multiplexed collision-induced dissociation mass spectrometry and chemometric procedures. AB - This work demonstrates a non-targeted mass spectrometry approach for identification of organic compounds in smokeless powders. Unburned powders were removed from various commercial ammunitions of different brand, primer composition, caliber, and age. The unburned powders and corresponding fired residues were analyzed by liquid chromatography-atmospheric pressure chemical ionization-time-of-flight mass spectrometry (LC-APCI-TOFMS). Multiplexed collision-induced dissociation was performed at increasing collision potentials resulting in successive fragmentation that provided structural information for compound identification in a non-targeted manner. Nine compounds were identified in the powders, including akardite II, ethyl centralite, diphenylamine, N nitrosodiphenylamine, and dibutyl phthalate. Multivariate statistical procedures were performed to first investigate association and discrimination of the unburned powders. Principal components analysis (PCA) of the chemical profiles suggested nine distinct groups of powders, according to the dominant organic compounds present. The clusters formed in hierarchical cluster analysis (HCA) were mostly in agreement with PCA groupings although HCA provided a metric to quantify the similarity. Finally, association of the fired residue to the corresponding unburned powder was possible although the success was highly dependent on the composition of the unburned powder and the extent of compound depletion as a result of firing. PMID- 28088710 TI - Short range shooting distance estimation using variable pressure SEM images of the surroundings of bullet holes in textiles. AB - Modifications of cotton and polyester textiles due to shots fired at short range were analyzed with a variable pressure scanning electron microscope (VP-SEM). Different mechanisms of fiber rupture as a function of fiber type and shooting distance were detected, namely fusing, melting, scorching, and mechanical breakage. To estimate the firing distance, the approximately exponential decay of GSR coverage as a function of radial distance from the entrance hole was determined from image analysis, instead of relying on chemical analysis with EDX, which is problematic in the VP-SEM. A set of backscattered electron images, with sufficient magnification to discriminate micrometer wide GSR particles, was acquired at different radial distances from the entrance hole. The atomic number contrast between the GSR particles and the organic fibers allowed to find a robust procedure to segment the micrographs into binary images, in which the white pixel count was attributed to GSR coverage. The decrease of the white pixel count followed an exponential decay, and it was found that the reciprocal of the decay constant, obtained from the least-square fitting of the coverage data, showed a linear dependence on the shooting distance. PMID- 28088711 TI - Surgery for chronic mesh infection occurred 10 years after sacrectomy - Mesh resection and mesentric leaf repair: A case report. AB - INTRODUCTION: Sacrectomy to treat malignant tumors is often results in large pelvic defects to require reconstruction, using a prosthetic mesh. Importance is to avoid its direct contact of mesh with intestine to prevent adhesion between them. PRESENTATION OF CASE: An 83-year old woman who was diagnosed with a mesh infection caused by a small bowel penetration 10 years after sacrectomy combined with mesh reconstruction for chordoma. In the first operation, because of incomplete re-peritonealization due to a large defect in the retroperitoneum, a mesh unavoidably was compelled to contact with the small intestine. We subtotally removed the mesh and performed mesentric leaf repair of the pelvic defect. The postoperative course was complicated by infection of the pelvis. She was discharged 59days after surgery with a little purulent discharge from perineal wound, which was persisted for two years after operation. DISCUSSION/CONCLUSION: We used the mesenteric leaf to repair the pelvic defect at the operation. This procedure might be the best alternative, when the use of mesh has to be avoided like present case. To our knowledge, this is the first report of mesh infection after sacrectomy, so we report herein. PMID- 28088712 TI - A referential theory of the repetition-induced truth effect. AB - People are more likely to judge repeated statements as true compared to new statements, a phenomenon known as the illusory truth effect. The currently dominant explanation is an increase in processing fluency caused by prior presentation. We present a new theory to explain this effect. We assume that people judge truth based on coherent references for statements in memory. Due to prior presentation, repeated statements have more coherently linked references; thus, a repetition-induced truth effect follows. Five experiments test this theory. Experiment 1-3 show that both the amount and the coherence of references for a repeated statement influence judged truth. Experiment 4 shows that people also judge new statements more likely "true" when they share references with previously presented statements. Experiment 5 realizes theoretically predicted conditions under which repetition should not influence judged truth. Based on these data, we discuss how the theory relates to other explanations of repetition induced truth and how it may integrate other truth-related phenomena and belief biases. PMID- 28088713 TI - The effects of utterance timing and stimulation of left prefrontal cortex on the production of referential expressions. AB - We examined the relationship between the timing of utterance initiation and the choice of referring expressions, e.g., pronouns (it), zeros (...and went down), or descriptive NPs (the pink pentagon). We examined language production in healthy adults, and used anodal transcranial direct current stimulation (tDCS) to test the involvement of the left prefrontal cortex (PFC) in the timing of utterance production and the selection of reference forms in a discourse context. Twenty-two subjects (11 anodal, 11sham) described fast-paced actions, e.g. The gray oval flashes, then it moves right 2 blocks. We only examined trials in contexts that supported pronoun/zero use. For sham participants, pronouns/zeros increased on trials with longer latencies to initiate the target utterance, and trials where the previous trial was short. We argue that both of these conditions enabled greater message pre-planning and greater discourse connectedness: The strongest predictor of pronoun/zero usage was the presence of a connector word like and or then, which was also tended to occur on trials with longer latencies. For the anodal participants, the latency effect disappeared. PFC stimulation appeared to enable participants to produce utterances with greater discourse connectedness, even while planning incrementally. PMID- 28088714 TI - Children's and adults' use of verbal information to visually anticipate others' actions: A study on explicit and implicit social-cognitive processing. AB - According to recent theories, social cognition is based on two different types of information-processing; an implicit or action-based one and an explicit or verbal one. The present study examined whether implicit and explicit social-cognitive information processing interact with each other by investigating young children's and adults' use of verbal (i.e., explicit) information to predict others' actions. Employing eye-tracking to measure anticipatory eye-movements as a measure of implicit processing, Experiment 1 presented 1.5-, 2.5-, and 3.5-year old children as well as adults with agents who announced to move to either of two possible targets. The results show that only the 3.5-year-old children and adults, but not the 1.5- and 2.5-year-old children were able to use verbal information to correctly anticipate others' actions. Yet, Experiments 2 and 3 showed that 2.5-year-old children were able to use explicit information to give a correct explicit answer (Experiment 2) and that they were able to use statistical information to anticipate the other's actions (Experiment 3). Overall, the study is in line with theoretical claims that two types of information-processing underlie human social cognition. It shows that these two inform each other by 3years of age. PMID- 28088715 TI - Micropollutant-induced tolerance of in situ periphyton: Establishing causality in wastewater-impacted streams. AB - The overarching aim of this field study was to examine causal links between in situ exposure to complex mixtures of micropollutants from wastewater treatment plants and effects on freshwater microbial communities in the receiving streams. To reach this goal, we assessed the toxicity of serial dilutions of micropollutant mixtures, extracted from deployed passive samplers at the discharge sites of four Swiss wastewater treatment plants, to in situ periphyton from upstream and downstream of the effluents. On the one hand, comparison of the sensitivities of upstream and downstream periphyton to the micropollutant mixtures indicated that algal and bacterial communities composing the periphyton displayed higher tolerance towards these micropollutants downstream than upstream. On the other hand, molecular analyses of the algal and bacterial structure showed a clear separation between upstream and downstream periphyton across the sites. This finding provides an additional line of evidence that micropollutants from the wastewater discharges were directly responsible for the change in the community structure at the sampling sites by eliminating the micropollutant-sensitive species and favouring the tolerant ones. What is more, the fold increase of algal and bacterial tolerance from upstream to downstream locations was variable among sampling sites and was strongly correlated to the intensity of contamination by micropollutants at the respective sites. Overall, our study highlights the sensitivity of the proposed approach to disentangle effects of micropollutant mixtures from other environmental factors occurring in the field and, thus, establishing a causal link between exposure and the observed ecological effects on freshwater microbial communities. PMID- 28088716 TI - Unveiling the transformation and bioavailability of dissolved organic matter in contrasting hydrothermal vents using fluorescence EEM-PARAFAC. AB - The submarine hydrothermal systems are extreme environments where active cycling of dissolved organic matter (DOM) may occur. However, little is known about the optical properties and bioavailability of hydrothermal DOM, which could provide valuable insights into its transformation processes and biogeochemical reactivity. The quantity, quality, and bioavailability of DOM were investigated for four very different hydrothermal vents east of Taiwan, using dissolved organic carbon (DOC), absorption spectroscopy, and fluorescence excitation emission matrices-parallel factor analysis (EEM-PARAFAC). The DOC and absorption coefficient a280 were both lower in the two hydrothermal vents off the Orchid Island and on the Green Island than in the surrounding seawater and the two vents off the Kueishantao Island, indicating effective removals of DOM in the former two hydrothermal systems owing to possible adsorption/co-precipitation and thermal degradation respectively. The four hydrothermal DOM showed notable differences in the absorption spectral slope S275-295, humification index HIX, biological index BIX, EEM spectra, and the relative distributions of seven PARAFAC components. The results demonstrated a high diversity of chemical composition and transformation history of DOM under contrasting hydrothermal conditions. The little change in the hydrothermal DOC after 28-day microbial incubations indicated a low bioavailability of the bulk DOM, and different PARAFAC components showed contrasting bioavailability. The results have profound implications for understanding the biogeochemical cycling and environmental effects of hydrothermal DOM in the marine environments. PMID- 28088717 TI - Removal of antibiotic resistance genes from wastewater treatment plant effluent by coagulation. AB - Antibiotic resistance genes (ARGs), as emerging environmental contaminants, have become a threat to human health. Recent studies have demonstrated that the effluent from wastewater treatment plants is a significant point source of ARGs released into the environment. In this study, we investigated the effectiveness of coagulation technology in the removal of ARGs from treated wastewater. Specifically, we measured the removal of five ARGs (two sulfonamide resistance genes, sulI and sulII, and three tetracycline resistance genes, tetO, tetW and tetQ) and the class 1 integron intI1 gene via the application of two coagulants: FeCl3 and polyferric chloride (PFC). Moreover, the removal of dissolved organic carbon (DOC), NH3N and total phosphorus (TP) in the coagulation process was investigated. The coagulation process effectively removed ARGs from the effluent with 0.5-log to 3.1-log reductions. Significant removal correlations were observed between dissolved NH3N and DOC, intI1 and sulI, sulII and tetO, sulII and tetW, and tetO and tetW, implying that the co-removal of DOC, dissolved NH3N, the intI1 gene and different ARGs played an important role in ARG loss during coagulation with Fe-based coagulants. These results indicate that coagulation may play a promising role in ARG reduction in wastewater treatment plants. PMID- 28088718 TI - Highly efficient inactivation of bacteria found in drinking water using chitosan bentonite composites: Modelling and breakthrough curve analysis. AB - Disinfection of bacterially-contaminated drinking water requires a robust and effective technique and can be achieved by using an appropriate disinfectant material. The advanced use of nanomaterials is observed as an alternative and effective way for the disinfection process and water treatment as a whole. Hence, the inactivation of Escherichia coli (E. coli) using chitosan-Bentonite (Cts Bent) composites was studied in a fixed bed column. Cts-Bent composites were synthesized using in situ cross-linking method using Bent-supported silver and zinc oxide nanoparticles. These composites were characterized by Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, and energy dispersive spectroscopy. The effect of the composite bed mass, initial concentration of bacteria, and flow rate on the bacterial inactivation was investigated. The characterization results revealed that the composites were successfully prepared and confirmed the presence of both silver and zinc oxide nanoparticles in the chitosan matrix. The growth curves of E. coli were expressed as breakthrough curves, based on the logistic, Gompertz, and Boltzmann models. The breakthrough time and processed volume of treated water at breakthrough were used as performance indicators, which revealed that the composites performed best at low bacterial concentration and flow rate and with substantial bed mass. The chitosan composites were found to be highly effective, which was demonstrated when no bacteria were observed in the effluent sample within the first 27 h of analysing river water. All the models were suitable for adequately describing and reproducing the experimental data with a sigmoidal pattern. Therefore, the prepared composite is showing potential to work as a disinfectant and provide an alternative solution for water disinfection; hence this study should propel further research of the same or similar materials. PMID- 28088719 TI - Low temperature MBBR nitrification: Microbiome analysis. AB - This study aims to investigate post carbon removal moving bed biofilm reactor (MBBR) nitrification through the transition from 20 degrees C to 1 degrees C and during through long term operation at 1 degrees C. Four pilot nitrifying MBBR reactors were operated at various ammonia loading rates to elucidate the temperature effects on ammonia removal rates, cell viability and bacterial communities. The transition from 20 degrees C to 1 degrees C and during long term operation at 1 degrees C were modeled using Arrhenius temperature correction coefficients. Specifically, the steady state removal rates at 1 degrees C on average were 22.8% of the maximum ammonia removal rate at 20 degrees C, which corresponds to an Arrhenius temperature correction of 1.086 during steady operation at 1 degrees C. The microbial communities of the nitrifying MBBR biofilm were shown to be significantly more diverse at 20 degrees C as compared to 1 degrees C operation. Although less diverse at 1 degrees C, 2000 species of bacteria were identified in the nitrifying biofilm during operation at this low temperature. Nitrosomonads were shown to be the dominant ammonia oxidizing bacteria (AOB) and Nitrospira was shown to be the dominant nitrite oxidizing bacteria (NOB) in all the pilot MBBR reactors at all temperatures. The performance of the post carbon removal nitrifying MBBR systems were shown to be enhanced at 1 degrees C by an increase in the viable embedded biomass as well as thicker biofilm. This effectively increases the number of viable cell present during low temperature operation, which partially compensates for the significant decrease in rate of ammonia removal per nitrifying cell. Operation at the highest loading conditions tested in this study at 1 degrees C were shown to reduce the ammonia removal rate compared to lower loading conditions at 1 degrees C. The lower performance at higher loading conditions at 1 degrees C demonstrated an enrichment in the stress response metagenomics pathways of the system. PMID- 28088720 TI - Role of dissolved Mn(III) in transformation of organic contaminants: Non oxidative versus oxidative mechanisms. AB - Mn(III) is a strong oxidant for one electron transfer, which may be important in the transformation of organic contaminants during water/wastewater treatment and biogeochemical redox processes. This study explored the reaction mechanisms of dissolved Mn(III) with organics. The role of dissolved Mn(III) either as a catalyst or an oxidant in reactions with organics was recognized. Aquo and/or hydroxo (or free) Mn(III), generated from the bisulfite activated permanganate process, facilitated efficient N-dealkylation of atrazine via a beta-elimination mechanism, resulting no net redox reaction. In contrast, free Mn(III) degraded 4 chlorophenol via intramolecular redox processes, the same as hydroxyl radical (OH), resulting in dechlorination,OH substitution, ring-opening and mineralization. Mn(III)-pyrophosphate compounds did not react with atrazine because complexation by pyrophosphate rendered Mn(III) unable to bond with atrazine, thus the electron and proton transfers between the reactants couldn't occur. However, it degraded 4-chlorophenol at a slower rate compared to free Mn(III), due to its reduced oxidation potential. These results showed two distinct mechanisms on the degradation of organic contaminants and the insights may be applied in natural manganese-rich environments and water treatment processes with manganese compounds. PMID- 28088721 TI - Modeling biosolids drying through a laminated hydrophobic membrane. AB - The adaptation of the membrane distillation process as a low-cost and sustainable approach to biosolids drying and stabilization is investigated, which may have application in container-based sanitation systems proposed in low-income urban regions. Three-layer laminated, breathable, hydrophobic membranes enclose the biosolids, facilitating drying but preventing transport of contaminants. The membranes used in this process are non-wetting with pore spaces that only allow vapor transport. Water vapor can be expelled due to a moderate vapor pressure gradient. Other constituents, including both particulate and dissolved matter are retained. The permeate, therefore, is expected to be of high purity and pathogen free. This study presents experimental results showing usable rates of moisture transfer through the laminated hydrophobic membranes with temperature gradients, DeltaT = -2 degrees C, corresponding to the condition that biosolids do not receive external heating in which laminate-enclosed biosolids are 2 degrees C cooler than outside, as well as conditions that samples are 2 degrees C and 10 degrees C warmer than the ambient temperature (DeltaT = 2 and 10 degrees C, respectively). The conditions result in reduction in the moisture content of the laminate-enclosed biosolids from about 97% to 12-30% and the permeate is observed to be free of fecal coliforms, indicator organisms for pathogens. The initial constant-rate drying period is described well with a stagnant film model that accounts for different temperature gradients, laminate surface area, and ambient relative humidity. The proposed model may be used to assess the feasibility of incorporating laminated hydrophobic membranes to enhance biosolids drying in container-based sanitation systems as well as other applications. PMID- 28088722 TI - In situ denitrification and DNRA rates in groundwater beneath an integrated constructed wetland. AB - Evaluation of the environmental benefits of constructed wetlands (CWs) requires an understanding of their impacts on the groundwater quality under the wetlands. Empirical mass-balance (nitrogen in/nitrogen out) approaches for estimating nitrogen (N) removal in CWs do not characterise the final fate of N; where nitrate (NO3--N) could be reduced to either ammonium (NH4+-N) or N2 with the potential for significant production of N2O. Herein, in situ denitrification and DNRA (dissimilatory nitrate reduction to ammonium) rates were measured in groundwater beneath cells of an earthen lined integrated constructed wetland (ICW, used to remove the nutrients from municipal wastewater) using the 15N enriched NO3--N push-pull method. Experiments were conducted utilising replicated (n = 3) shallow (1 m depth) and deep (4 m depth) piezometers installed along two control planes. These control planes allowed for the assessment of groundwater underlying high (Cell 2, septic tank waste) and low (Cell 3) load cells of the ICW. Background piezometers were also installed off-site. Results showed that denitrification (N2O-N + N2-N) and DNRA were major NO3--N consumption processes accounting together for 54-79% of the total biochemical consumption of the applied NO3--N. Of which 14-16% and 40-63% were consumed by denitrification and DNRA, respectively. Both processes differed significantly across ICW cells indicating that N transformation depends on nutrient loading rates and were significantly higher in shallow compared to the deep groundwater. In such a reduced environment (low dissolved oxygen and low redox potential), higher DNRA over the denitrification rate can be attributed to the high C concentration and high TC/NO3--N ratio. Low pH (6.5-7.1) in this system might have limited denitrification to some extent to an incomplete state, evidenced by a high N2O N/(N2O-N+N2-N) ratio (0.35 +/- 0.17, SE). A relatively higher N2O-N/(N2O-N+N2-N) ratio and higher DNRA rate over denitrification, suggest that the end products of N transformations are reactive. This N2O can be consumed to N2 and/or emitted to the atmosphere. The DNRA rate and accumulation of NH4+-N indicated that the ICW created a suitable groundwater biogeochemical environment that enhanced NO3--N reduction to NH4+-N. This study showed that CWs significantly influence NO3--N attenuation to reactive forms of N in the groundwater beneath them and that solely focusing on within wetland NO3--N attenuation can underestimate the environmental benefits of wetlands. PMID- 28088723 TI - Discovery and metagenomic analysis of an anammox bacterial enrichment related to Candidatus "Brocadia caroliniensis" in a full-scale glycerol-fed nitritation denitritation separate centrate treatment process. AB - A distinctive red biofilm was observed in a glycerol-fed digester liquid effluent treatment process coupling partial nitrification (nitritation) and partial denitrification (denitritation) processes. Based on initial phylogenetic screening using 16S rRNA clone libraries and quantitative polymerase chain reaction, the biofilm was enriched in novel anaerobic ammonium oxidizing bacteria (AMX/anammox) closely related to Candidatus "Brocadia caroliniensis". The metabolic functionality of the C. "Brocadia caroliniensis" enrichment was further explored using high-throughput sequencing and de novo metagenome assembly. The population anammox genome that was binned from the metagenome consisted of 209 contigs with a total of 3.73 Mbp consensus sequences having 43.3% GC content, and 27.4 average coverage depth. The assembled metagenome bin was comprised of 3582 open reading frames (ORFs). Based on 16S rRNA similarity the binned metagenome was closely related with Candidatus "Brocadia caroliniensis", Candidatus "Brocadia fulgida", planctomycete KSU-1, and Candidatus "Kuenenia stuttgartiensis" with 99%, 96%, 92% and 93% similarity, respectively. Essential genes in anammox metabolic functions including ammonium and nitrite transport, hydrazine synthesis, electron transfer for catabolism, and inorganic carbon fixation, among several other anabolic pathways, were also observed in the population genome of the C. "Brocadia caroliniensis" related enrichment. Our results demonstrate the wider profusion of anammox bacteria in engineered nitrogen removal systems than expected. The utility of metagenomics approaches to deciphering such novel functionality in these systems is also highlighted. PMID- 28088724 TI - The effect of urban growth on landscape-scale restoration for a fire-dependent songbird. AB - A landscape-scale perspective on restoration ecology has been advocated, but few studies have informed restoration with landscape metrics or addressed broad-scale threats. Threats such as urban growth may affect restoration effectiveness in a landscape context. Here, we studied longleaf pine savanna in the rapidly urbanizing southeastern United States where a habitat-specialist bird, Bachman's sparrow (Peucaea aestivalis), is closely associated with savanna vegetation structure and frequent fire. Our objectives were to construct a species distribution model for Bachman's sparrow, determine the relationship between fire and urbanization, quantify the urban growth effect (2010-2090), identify potential restoration areas, and determine the interaction between restoration potential and urban growth by 2050. Number of patches, patch size, and isolation metrics were used to evaluate scenarios. The species distribution model was 88% accurate and emphasized multiscale canopy cover characteristics, fire, and percent habitat. Fires were less common <600 m from urban areas, and this fire suppression effect exacerbated urban growth effects. For restoration scenarios, canopy cover reduction by 30% resulted in nearly double the amount of habitat compared to the prescribed fire scenario; canopy cover reduction resulted in larger patch sizes and less patch isolation compared to current conditions. The effect of urban growth on restoration scenarios was unequal. Seventy-four percent of restoration areas from the prescribed fire scenario overlapped with projected urban growth, whereas the canopy cover reduction scenario only overlapped by 9%. We emphasize the benefits of simultaneously considering the effects of urban growth and landscape-scale restoration potential to promote a landscape with greater patch sizes and less isolation. PMID- 28088725 TI - Risk management, financial evaluation and funding for wastewater and stormwater reuse projects. AB - This paper has considered risk management, financial evaluation and funding in seven Australian wastewater and stormwater reuse projects. From the investigated case studies it can be seen that responsible parties have generally been well equipped to identify potential risks. In relation to financial evaluation methods some serious discrepancies, such as time periods for analysis, and how stormwater benefits are valued, have been identified. Most of the projects have required external, often National Government, funding to proceed. As National funding is likely to become less common in the future, future reuse projects may need to be funded internally by the water industry. In order to enable this the authors propose that the industry requires (1) a standard project evaluation process, and (2) an infrastructure funders' forum (or committee) with representation from both utilities and regulators, in order to compare and prioritise future reuse projects against each other. PMID- 28088726 TI - Fabrication of highly hydrophilic filter using natural and hydrothermally treated mica nanoparticles for efficient waste oil-water separation. AB - For the effective oil/water separation, a novel superhydrophilic (underwater superoleophobic) filter is fabricated with the naturally and hydrothermally treated mica particles. To fabricate a double layered filter, hydrothermally treated mica particles were initially electrodeposited on a stainless steel mesh and a natural mica particles were sprayed on the first hydrothermally deposited mica layer. The double layered mica coated membrane showed superamphiphilic and superhydrophilic/superoleophobic (contact angle >159 degrees ) characteristics in air and underwater respectively. The membrane can separate range of oil-water mixtures with oil/water separation efficiency over ~99%. Properties of double layered mica membrane were investigated and noted that the surface adhesion properties of mica is enhanced by the hydrothermal treatment of mica and the higher roughness of the mica layer is maintained by the natural mica. PMID- 28088727 TI - Representativeness of clinical PET study participants with schizophrenia: A systematic review. AB - While positron emission tomography (PET) studies have provided invaluable data on antipsychotic effects, selection bias remains a serious concern. A systematic review of PET studies that measured dopamine D2 receptor blockade with antipsychotics was conducted to examine their inclusion/exclusion criteria, using PubMed, EMBASE, and ClinicalTrials.gov (last search, September 2016). PET studies were included if they measured D2 receptor occupancy in patients with schizophrenia and included introduction of antipsychotic treatment or antipsychotic regimen change in a systematic manner. Twenty-six studies were identified. Age limit was included in 13 studies; one study solely included geriatric patients while others targeted younger adults. Eleven, 6, and 3 studies specifically targeted clinically stable patients, patients with severe psychopathology, and antipsychotic-free patients, respectively. Nineteen and 18 studies excluded patients with physical comorbidity and substance abuse, respectively. As a result, the mean age of subjects ranged from 23 to 42 years when one study that targeted geriatric patients was excluded. Mean Positive and Negative Syndrome Scale total scores ranged from 54 to 95. No comparison active drug or placebo arm was employed in 24 studies. Blind assessment of symptomatology was performed in 5 studies. In general, subjects participating in clinical PET studies were relatively young, presented with mild symptomatology, and were free from substance abuse or physical comorbidities. These characteristics need to be taken into account when clinical PET data are interpreted. On the other hand, it should also be noted that this study was only qualitative and conservative interpretation is necessary for possibility of subjective bias. PMID- 28088729 TI - New insights into AOX2 transcriptional regulation in Chlamydomonas reinhardtii. AB - A feature of the mitochondrial electron transport chain in plants, some protists and many fungi is the presence of two terminal oxidases, the energy-conserving cytochrome oxidase and another termed alternative oxidase (AOX). AOX branches from the main respiratory chain, directly coupling the oxidation of ubiquinol with reduction of oxygen to water. The AOX genes can be divided into two discrete subfamilies, AOX1 and AOX2. Although AOX has been proposed to play essential roles in stress tolerance of organisms, the role of subfamily AOX2 is largely unknown. In the model green alga Chlamydomonas reinhardtii, two genes have been identified that encode for AOX, AOX1 and AOX2. To test AOX2 transcriptional regulation in this alga, we used a real-time PCR analysis and an artificial microRNA approach. The C. reinhardtii AOX2 gene is up-regulated by oxygen or copper deprivation. Moreover, in dark-adapted unstressed cells, AOX2 is induced. Together, our results imply that the AOX2 gene is a stress-inducible and is regulated by the copper response regulator 1 (CRR1), probably together with yet unknown regulatory factor(s). PMID- 28088728 TI - The association between insomnia-related sleep disruptions and cognitive dysfunction during the inter-episode phase of bipolar disorder. AB - Sleep disturbance and cognitive dysfunction are two domains of impairment during inter-episode bipolar disorder. Despite evidence demonstrating the importance of sleep for cognition in healthy and sleep-disordered samples, this link has been minimally examined in bipolar disorder. The present study tested the association between insomnia-related sleep disruptions and cognitive dysfunction during inter episode bipolar disorder. Forty-seven participants with bipolar disorder and a comorbid insomnia diagnosis (BD-Insomnia) and 19 participants with bipolar disorder without sleep disturbance in the last six months (BD-Control) participated in the study. Two domains of cognition were assessed: working memory and verbal learning. Insomnia-related sleep disruptions were assessed both categorically (i.e., insomnia diagnosis) and dimensionally (i.e., total wake time, total sleep time, total wake time variability, and total sleep time variability). Hierarchical linear regressions, adjusting for participant age, demonstrated that insomnia diagnosis did not have an independent or interactive effect on cognition. However, regardless of insomnia diagnosis, greater total sleep time variability predicted poorer working memory and verbal learning performance. Further, following sleep treatment, a reduction in total wake time predicted improved working memory performance and a reduction in total sleep time variability predicted improved verbal learning performance. These findings raise the possibility that sleep disturbance may contribute to cognitive dysfunction in bipolar disorder and highlight the importance of treating sleep disturbance in bipolar disorder. PMID- 28088730 TI - Dramatic response to pyridoxine in a girl with absence epilepsy with ataxia caused by a de novo CACNA1A mutation. PMID- 28088731 TI - Biological properties of citral and its potential protective effects against cytotoxicity caused by aspirin in the IEC-6 cells. AB - Citral, 3,7-dimethyl-2,6-octadienal, is a key component of several essential oils extracted from lemon-scented herbal plants. The present study was designed to investigate the antioxidant activities of citral and assess its possible protective effects against aspirin-induced toxicity in vitro. We used IEC-6 cells (rat small intestine epithelial cells). The antioxidant activities were determined by 1,1-diphenyl-2-picrylhydrazyl (DPPH), beta-carotene/linoleic acid and Ferric reducing antioxidant power (FRAP). Cytotoxicity was evaluated by cell viability, anti-oxidant enzyme activities, malondialdehyde (MDA) production and by the expression of MAPKs (Mitogen-Activated Protein Kinases) pathways. According to results, citral showed an important antioxidant activity. It inhibited the oxidation of linoleic acid, a moderate DPPH was found and it showed a Ferric reducing antioxidant potential with an EC50 value of 125+/-28.86MUg/mL. Then, the co-treatment of aspirin with citral significantly decreased the aspirin induced cell death, and the MDA level. It modulated the superoxide dismutase (SOD) and glutathione (GSH) activities. Also, the activation of MAPKs was attenuated by citral. These findings suggest that citral can protect IEC-6 cells against aspirin-induced oxidative stress that may help to discover new chemicals out of natural antioxidant substances. PMID- 28088732 TI - Apelin-13 protects rat primary cortical glia-neuron co-culture against pentylenetetrazole-induced toxicity. AB - In spite of recent advances in the treatment of epilepsy, up to 35% of people living with the condition do not respond to accessible anti-epileptic drugs (AEDs) and continue to experience regular, devastating and potentially life threatening seizures. Neuronal death is a significant feature of epilepsy in humans and experimental models. It has been reported that apelin, an endogenous ligand for the angiotensin-1-like receptor (APJ), has anticonvulsive as well as protective effects in some neurodegenerative situations. In the current study, we investigated the effects of apelin-13 on pentylenetetrazole (PTZ)-induced neurotoxicity in rat's brain primary culture. Cell injury was induced by 20mM PTZ and the cells viability was examined by MTT assay. Intracellular calcium, reactive oxygen species (ROS) and mitochondrial membrane potential were determined by fluorescence spectrophotometry methods. Markers of apoptosis were determined by immunohistochemistry. The data showed that PTZ caused a loss of cell viability and mitochondrial membrane potential. In addition, intracellular reactive oxygen species, intracellular calcium, COX-2 and caspase-3 positive cells were increased in PTZ-treated cells. Incubation of the cells with aplein-13 (10MUM) elicited protective effect and reduced markers of cell damage and death. The results suggest that apelin-13 has protective effects against PTZ-induced toxicity and such effects are accompanied by its calcium blocking, antioxidant and, anti-inflammatory and anti-apoptotic properties. PMID- 28088733 TI - Long non-coding RNA UC001kfo promotes hepatocellular carcinoma proliferation and metastasis by targeting alpha-SMA. AB - Several long non-coding RNAs (lncRNAs) have been investigated and found to be correlated with the behaviours and prognosis of hepatocellular carcinoma (HCC); Specifically, we revealed that the lncRNA UC001kfo was differentially expressed in HCC tissues compared with normal liver tissues using lncRNA microarrays, but its functional role in cancers, including HCC, has not yet been elucidated. The present study found that the expression of UC001kfo was upregulated in HCC tissues and cell lines in comparison with tumour-adjacent tissues and normal hepatocytes, respectively. In addition, a high UC001kfo level was determined to be correlated with macro-vascular invasion and TNM stage of HCC. Specifically, patients with high UC001kfo expression displayed a significantly lower overall survival rate and progression-free survival rate. Moreover, both univariate and multivariate COX regression analyses identified TNM stage and high UC001kfo expression as risk factors for poor prognosis in HCC patients. In addition, UC001kfo was verified to promote the proliferation, metastasis and epithelial mesenchymal transition (EMT) in HCC cells in both in vitro and in vivo assays. Mechanistically, alpha-SMA was indicated as a potential target gene of UC001kfo in mediating HCC metastasis. In conclusion, UC001kfo promotes HCC proliferation and metastasis by targeting alpha-SMA, and UC001kfo may potentially serve as a prognostic marker and a therapeutic target for treatment of HCC. PMID- 28088734 TI - In vivo and in silico sedative-hypnotic like activity of 7-methyljuglone isolated from Diospyros lotus L. AB - Diospyros lotus L. possesses different therapeutic activities such as antioxidant, anti-proliferative, anti-microbial and sedative. However, no studies on the sedative-hypnotic activity of 7-methyljuglone are reported. In the present study, we have evaluated in vivo the anxiolytic-hypnotic like effects of 7 methyljuglone in mice with open field and phenobarbitone-induced sleeping time tests. We have also assessed in silico the involvement of GABAA, GABAB and 5HT1 neurotransmission in its mechanism of action. The intraperitoneal administration of 7-methyljuglone (2.5-10mg/kg) reduce significantly the number of crossed lines in mice open field test and concomitantly it shown a significant activity in term of onset of sleeping time and also in its duration. Moreover, 7-methyljuglone demonstrated in silico an interesting interaction with GABAA but not GABAB and 5HT1binding sites. All of these results, taken together, 7-methyljuglone may be an innovative candidate for designing new pharmaceutical and therapeutic applications. PMID- 28088735 TI - Long non-coding RNA CCAT1 promotes human retinoblastoma SO-RB50 and Y79 cells through negative regulation of miR-218-5p. AB - OBJECTIVE: To investigate the regulatory role and potential mechanism of long non coding RNAs (lncRNA) in human retinoblastoma (RB). METHODS: The lncRNA profile in RB tissues were analyzed by microarray and quantitative reverse transcription PCR (qRT-PCR). One of the identified lncRNAs (LncRNA CCAT1) was selected for further experiments. SO-RB50 and Y79 cells were transfected with negative control, siRNA targeting lncRNA CCAT1 (si-CCAT1) and si-CCAT1+miR218-5p inhibitor, respectively. lncRNA CCAT1 expression was measured by qRT-PCR. Cell proliferation, migration and invasion were detected by CCK8, wound scratching, and transwell assay, respectively. Apoptosis and cell cycle distribution were assessed by flow cytometry. Apoptosis- (cle-caspase-3, cle-caspase-9, Bax and Bcl-2) and cell cycle-related protein expression (cyclin B1, CDC2 and p-CDC2 (Thr161)) were analyzed by Western blot. RESULTS: lncRNA CCAT1 expression in SO-RB50 and Y79 cells was significantly inhibited after si-CCAT1 transfection (P<0.01). Both RB cells exhibited significantly reduced proliferation, migration and invasion abilities, but markedly increased apoptosis at 48h after si-CCAT1 transfection (P<0.05 or 0.01). RB cells in si-CCAT1+miR218-5p inhibitor group had significantly higher proliferation, migration and invasion, but notably lower apoptosis compared with si-CCAT1 group at 24 and 48h after transfection (all P<0.05 or 0.01). si-CCAT1 significantly increased the expression of cle-caspase 3, cle-caspase-9, Bax, but decreased Bcl-2 expression (P<0.01). The proportion of G2/M SO-RB50 and Y79 cells in siCCAT1 group was significantly increased compared with negative control group (P<0.01). LncRNA CCAT1 interference significantly reduced the expression of cyclin B1, CDC2 and p-CDC2 (Thr161) (P<0.01). CONCLUSION: LncRNA CCAT1 promotes the proliferation migration and invasion, and reduces cell apoptosis of SO-RB50 and Y79 cells, probably through negative modulation of miR-218-5p. Our study suggested lncRNA CCAT1 as a potential biomarker and therapeutic target for RB. PMID- 28088736 TI - LncRNA CCAT2 promotes tumorigenesis by over-expressed Pokemon in non-small cell lung cancer. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) remains one of the most important death-related diseases, with poor effective diagnosis and less therapeutic biomarkers. LncRNA colon cancer-associated transcript 2 (CCAT2) was identified as an oncogenic lncRNA and over-expressed in many tumor cells. The aims of this study were to detect the correlation between CCAT2 and its regulatory genes and then explore the potential mechanism between them in NSCLC. METHODS: In this study, qRT-PCR was used to detect CCAT2, Pokemon and p21 expression. Western-blot was used to detect protein levels of Pokemon and p21. CCK-8 assay and Transwell chambers were used to assess cell viability and invasion. RESULTS: CCAT2 and Pokemon were over-expressed in NSCLC tissue and cells. In NSCLC cells, CCAT2 knockdown significantly decreased cell viability and invasion as well as Pokemon expression, but increased the expression of p21; then CCAT2 overexpression revealed an opposite result. In addition, over-expressed Pokemon reversed the results that induced by si-CCAT2, while down-regulation of Pokemon significantly reversed the results that induced by CCAT2 overexpression. CONCLUSION: The results indicated that CCAT2 promotes tumorigenesis by over-expression of Pokemon, and the potential mechanism might relate to the Pokemon related gene p21. PMID- 28088737 TI - The hemostatic effect study of Cirsium setosum on regulating alpha1-ARs via mediating norepinephrine synthesis by enzyme catalysis. AB - BACKGROUND: Cirsium setosum (CS) is the aboveground part of Cephalanoplos segetum Kitam. Although it has been used as a hemostatic treatment for thousands of years and is still in use today, the mechanism of CS on regulating ARs is still not clear. PURPOSE: In this study, we aimed to clarify the mechanism of CS on regulating ARs. METHODS: We developed a simple method based on UPLC/Q-TOF MS combined adrenergic receptor dual-luciferase reporter assay systems for the rapid determination of active constituents in CS. The mechanism of tyramine, the main active component for regulating ARs, was further investigated by an in vitro norepinephrine biotransformation test and in vivo vaso activity tests. RESULTS: Two phenethylamine ARs regulators (tyramine and N-methyltyramine) in CS were characterized, and it was found that tyramine could induce vasoconstriction via regulation of alpha1-ARs by mediating norepinephrine synthesis. CONCLUSION: The hemostatic effect of CS is associated with tyramine and N-methyltyramine, via regulation of alpha1-ARs, and the mechanism of tyramine is related to mediating norepinephrine synthesis by enzyme catalysis. PMID- 28088738 TI - Piperine modulates isoproterenol induced myocardial ischemia through antioxidant and anti-dyslipidemic effect in male Wistar rats. AB - Myocardial infarction due to ischemia accounts for majority of deaths among cardiovascular disorders. Isoproterenol (ISO) induced myocardial infarction and the protection offered by piperine was investigated in the present report. Lipid profile analysis by determining the levels of cholesterol, phospholipids, triglycerides and lipoproteins in serum and heart tissues showed anti dyslipidemic action of piperine against ISO induced myocardial injury by modulating the ISO induced altered lipid profiles, maintaining to near control values. ISO treatment increased TBARS levels, PCC, serum markers of heart, depleted antioxidant status (GSH, SOD, CAT, GPx and GST) in tissues and, total, protein- and non-protein-sulfhydryl levels in serum and heart tissues. Piperine pre-treatment decreased the levels of serum markers, lipid peroxidation and PCC with increased antioxidant status in the heart tissues of ISO administered rats. Increased levels of the glycoprotein components in serum and decreased levels in heart tissues upon ISO administration were restored to near normal levels by piperine pre-treatment. Our present reports also showed the modulatory effect of piperine on membrane bound ATPase's showing protection against ISO induced changes in membrane fluidity. The present study proved piperine as a potent therapeutic agent with its antioxidant and anti-dyslipidemic action against ISO induced myocardial infarction. PMID- 28088739 TI - The effects of rurality on substance use disorder diagnosis: A multiple-groups latent class analysis. AB - BACKGROUND: Rates of accidental overdose mortality from substance use disorder (SUD) have risen dramatically in the United States since 1990. Between 1999 and 2004 alone rates increased 62% nationwide, with rural overdose mortality increasing at a rate 3 times that seen in urban populations. Cultural differences between rural and urban populations (e.g., educational attainment, unemployment rates, social characteristics, etc.) affect the nature of SUD, leading to disparate risk of overdose across these communities. METHODS: Multiple-groups latent class analysis with covariates was applied to data from the 2011 and 2012 National Survey on Drug Use and Health (n=12.140) to examine potential differences in latent classifications of SUD between rural and urban adult (aged 18years and older) populations. Nine drug categories were used to identify latent classes of SUD defined by probability of diagnosis within these categories. Once the class structures were established for rural and urban samples, posterior membership probabilities were entered into a multinomial regression analysis of socio-demographic predictors' association with the likelihood of SUD latent class membership. RESULTS: Latent class structures differed across the sub-groups, with the rural sample fitting a 3-class structure (Bootstrap Likelihood Ratio Test P value=0.03) and the urban fitting a 6-class model (Bootstrap Likelihood Ratio Test P value<0.0001). Overall the rural class structure exhibited less diversity in class structure and lower prevalence of SUD in multiple drug categories (e.g. cocaine, hallucinogens, and stimulants). CONCLUSIONS: This result supports the hypothesis that different underlying elements exist in the two populations that affect SUD patterns, and thus can inform the development of surveillance instruments, clinical services, and prevention programming tailored to specific communities. PMID- 28088740 TI - Associations between adverse childhood experiences, student-teacher relationships, and non-medical use of prescription medications among adolescents. AB - OBJECTIVE: Few studies have investigated associations between adverse childhood experiences (ACE) and nonmedical use of prescription medication (NMUPM) in population-based samples of adolescents, and even fewer have examined whether promotive factors might buffer these effects. The present study assesses the direct effects of ACE and positive student-teacher relationships on NUMPD and whether positive student-teacher relationships moderate this association. DESIGN: Data were from the 2013 Minnesota Student Survey (MSS), an in-school survey administered every three years to students throughout Minnesota. The analytic sample (n=104,332) was comprised of 8th, 9th, and 11th graders. RESULTS: Approximately 3% of students acknowledged past year NMUPM, the majority of whom reported at least one ACE. The most frequently used prescription drug was Ritalin/ADHD medications (1.71%) followed by opiate-based painkillers (1.67%), tranquilizers (0.92%), and stimulants (0.75%). Students who reported any use tended to use more than one medication. For every additional ACE, there was a 56%, 51%, 47%, and 52% increase in the odds of past year stimulant use, ADHD medication, pain reliever, and tranquilizer use, respectively. The estimated rate of the number of prescription drugs used increased by 62% for every additional ACE. Positive student- teacher relationships buffered the association between ACE and NMUPD, especially at higher levels of ACEs. CONCLUSION: Our findings have important implications for prevention work. Training educators to recognize trauma symptomology and cultivating strong student-teacher relationships are important considerations for future school-based substance use prevention initiatives. PMID- 28088741 TI - Prevalence and correlates of fentanyl-contaminated heroin exposure among young adults who use prescription opioids non-medically. AB - BACKGROUND: The rate of overdose deaths caused by fentanyl-contaminated heroin (FCH) use is increasing rapidly in the United States. We examined risk factors for exposure to FCH and experiences with FCH use among young adult non-medical prescription opioids (NMPO) users. METHODS: We analyzed data from the Rhode Island Young Adult Prescription Drug Study (RAPiDS), which enrolled young adults aged 18 to 29 reporting prior 30day NMPO use between January 2015 and February 2016. Participants completed questionnaires ascertaining drug use patterns and risk behaviors, including FCH exposure. Logistic regression was used to assess factors associated with known or suspected FCH exposure. RESULTS: Of 199 participants, the median age was 25 (IQR: 22, 27), 130 (65.3%) were male, and 122 (61.3%) were of White, non-Hispanic race/ethnicity. In total, 22 (11%) reported known or suspected FCH exposure in the prior six months. Several drug use patterns and risk behaviors were associated with FCH exposure, including: regular heroin and cocaine use; diverted pharmaceutical fentanyl use in the prior six months; NMPO use to avoid withdrawal symptoms; longer duration of NMPO use; regular injection drug use; and prior overdose (all p<0.001). Among participants who reported FCH exposure, 59% were unaware that their heroin was contaminated with fentanyl prior to last use, 59% reported that FCH provides a better high, and all recognized that fentanyl increases overdose risk. CONCLUSIONS: Exposure to fentanyl-contaminated heroin is an emerging trend among young adult NMPO users in Rhode Island. Overdose prevention programs addressing FCH use are urgently needed. PMID- 28088742 TI - Patterns of drug use and HIV infection among adults in a nationally representative sample. AB - BACKGROUND: Little is known about drug use patterns among people living with HIV in comparison to an uninfected group in the general population. The aim of this study was to investigate the association between legal and illegal drug use and HIV infection in a nationally representative sample of adults in the United States. METHODS: Public use data files (2005-2014) from the National Survey on Drug Use and Health (NSDUH) were used. Respondents were asked whether a medical professional had ever told them that they had HIV/AIDS. Ever (lifetime), past year, and past month use of cigarettes, alcohol, marijuana, cocaine, heroin, hallucinogens, inhalants, and nonmedical use of psychotherapeutics was assessed. Logistic regression was used to estimate adjusted odds ratios (aOR) of the relationship between drug use and HIV infection, adjusting for demographics. RESULTS: Of 377,787 respondents age 18 and older, 548 (0.19%) were categorized as HIV-infected. Ever use of cigarettes, tobacco, marijuana, cocaine, heroin, hallucinogens, inhalants, and psychotherapeutics was higher in HIV-infected individuals compared to HIV-uninfected individuals after adjustment for sex, age, race/ethnicity, education, total family income, and marital status. Past year and past month use was also higher for HIV-infected individuals for all substances aside from alcohol. CONCLUSIONS: In a nationally representative sample, there are higher levels of drug use and DSM-IV dependence among the HIV-infected population compared to the HIV-uninfected population. This is of concern because drug use and dependence can impede engagement in HIV care and adherence to antiretroviral therapy. PMID- 28088743 TI - Socioeconomic differences in adolescent substance abuse treatment participation and long-term outcomes. AB - Socioeconomic status (SES) has been consistently linked to poorer access, utilization and outcomes of health care services, but this relationship has been understudied in adolescent substance abuse treatment research. This study examined SES differences in adolescent's treatment participation and long-term outcomes of abstinence and 12-step attendance over five years after treatment. Data are from 358 adolescents (ages 13-18) who were recruited at intake to substance abuse treatment between 2000 and 2002 at four Kaiser Permanente Northern California outpatient treatment programs. Follow-up interviews of adolescents and their parents were conducted at 1, 3, and 5years, with over 80% response rates across time points. Using parent SES as a proxy for adolescent SES, no socioeconomic differences were found in treatment initiation, treatment retention, or long-term abstinence from alcohol or drugs. Parent education, but not parent income, was significantly associated with 12-step attendance post treatment such that adolescents with higher parent education were more likely to attend than those with lower parent education. Findings suggest a lack of socioeconomic disparities in substance abuse treatment participation in adolescence, but potential disparities in post-treatment 12-step attendance during the transition from adolescence to young adulthood. PMID- 28088744 TI - Self-concept mediate the relationship between childhood maltreatment and abstinence motivation as well as self-efficacy among drug addicts. AB - OBJECTIVE: Childhood maltreatment is widely accepted as a risk factor for drug addiction from adolescence to adulthood. However, the influence of childhood maltreatment on drug treatment related variables, such as drug abstinence motivation and self-concept, as well as self-efficacy, remains unclear. This study aims at exploring whether self-concept mediates the relationship between childhood maltreatment and abstinence motivation, as well as self-efficacy, among drug addicts. METHODS: This study involves 816 (550 males, 226 females, mean age=34.59, range=16-58 years) drug addicts from compulsory detoxification units. Participants completed questionnaires, including the childhood trauma questionnaire 28 - item short form (CTQ - SF), Tennessee self-concept scale (TSCS), general self-efficacy scale (GSES), and drug abstinence motivation questionnaire (DAMQ). RESULTS: The structural equation model (SEM) analysis, including total and specific forms of maltreatment scores, showed that childhood maltreatment was negatively associated with self-concept, self-efficacy, and abstinence motivation. Self-concept was positively associated with self-efficacy and abstinence motivation. Conversely, significant association between self efficacy and abstinence motivation did not exist. An indirect analysis showed that self-concept mediated the relationship between childhood maltreatment and self-efficacy. Critically, self-concept arbitrated the relationship between childhood maltreatment and abstinence motivation. The indirect effect of self concept between childhood maltreatment and abstinence motivation still existed when the total scores of maltreatment were replaced by the scores of specific forms of maltreatment. CONCLUSIONS: These results demonstrated that self-concept is a critical factor in understanding the relationship between childhood maltreatment and abstinence motivation, as well as self-efficacy, among drug addicts. Improving the sense of self-worth may be an effective intervention therapy among drug addicts with childhood maltreatment history. PMID- 28088745 TI - Health-compromising practices of undergraduate college students: Examining racial/ethnic and gender differences in characteristics of prescription stimulant misuse. PMID- 28088746 TI - Development of a screening questionnaire for DSM-5 intermittent explosive disorder (IED-SQ). AB - OBJECTIVE: This study was designed to develop and test a screening approach to identify individuals with DSM-5 Intermittent Explosive Disorder (IED), a disorder of recurrent, problematic, impulsive aggression. METHODS: A screening approach to diagnose DSM-5 IED (IED-SQ) was developed by combining items related to life history of aggression and items related to the DSM-5 diagnostic criteria for IED. In study 1, the IED-SQ was studied in 72 adult participants; 33 that met DSM-5 criteria for lifetime IED and 39 that did not. In study 2, the IED-SQ was given to 740 undergraduates at a US university. Measures of aggression and anger expression and anger control were assessed in both studies. RESULTS: In study 1, the IED-SQ demonstrated strong concordance with the best estimate diagnoses (Kappa =.80) for lifetime IED by DSM-5 criteria and good test-retest reliability (kappa =0.71). In study 2, the IED-SQ identified 4.3% of the undergraduate sample as meeting DSM-5 criteria for lifetime IED, a rate comparable to that in recent epidemiological studies. Participants identified as meeting DSM-5 criteria for lifetime IED, in both studies, had higher aggression scores, and higher anger expression, and lower anger control scores, compared to participants that did not meet DSM-5 criteria for lifetime IED. CONCLUSIONS: These data suggest that the IED-SQ is a useful screening tool that can quickly identify the presence of IED by DSM-5 criteria in adults. PMID- 28088747 TI - Decreased S100B serum levels after treatment in bipolar patients in a manic phase. AB - BACKGROUND: Previous studies have suggested that patients with bipolar disorder might have brain damage. The aim of this study was to investigate the serum levels of brain injury biomarkers and S100A10 in bipolar patients in a manic phase, and evaluate the changes in S100B, neuron specific enolase (NSE), heat shock protein 70 (HSP70) and S100A10 after treatment. METHOD: We consecutively enrolled 17 bipolar inpatients in a manic phase and 30 healthy subjects. Serum brain injury biomarkers and S100A10 were measured with assay kits. All patients were evaluated by examining the correlation between brain injury biomarkers and Young Mania Rating Scale (YMRS) scores. RESULT: We found significantly decreased S100B levels only in bipolar manic patients after treatment (p=0.002), but S100B levels were not significantly different from those in healthy controls (p>0.05). CONCLUSION: Our results indicate there were decreased S100B serum levels in bipolar patients in a manic phase after treatment and that increased serum S100B levels might be a possible indicator of transient disruption of the blood-brain barrier in bipolar patients in a manic phase. PMID- 28088748 TI - A DNA probe based on phosphorescent resonance energy transfer for detection of transgenic 35S promoter DNA. AB - A QDs-DNA nano-probe was made by combining Mn-doped ZnS room-temperature phosphorescence (RTP) quantum dots (QDs) and DNA. Then an RTP sensor for quantitative detection of genetically-modified mark sequence cauliflower mosaic virus 35S promoter (Ca MV 35S) DNA was built on basis of phosphorescent resonance energy transfer (PRET). The underlying principles were that a QDs-DNA water soluble nano-probe was built by connecting single-strand DNA to the surfaces of QDs via a ligand exchange method. This probe had good RTP performance and could well identify Ca MV 35S. Thereby, the simple, rapid and efficient detection of genetically-modified organisms was realized. With the increase of target DNA sequence, the phosphorescent intensity of QDs was gradually reduced due to the energy transfer between QDs and the organic quencher BHQ2. This sensor had a detection limit of 4.03nM and a detection range of 12-300nM. Moreover, this sensor had high selectivity. This sensor could effectively detect the target DNA compared with mismatched and random sequences. Thus, this method is very promising for biological analysis. PMID- 28088749 TI - Dual-channel probe of carbon dots cooperating with gold nanoclusters employed for assaying multiple targets. AB - Herein, carbon dots (CD@Papain) from papain have been originally synthesized in aqueous solution along with a quantum yield of 6.2%, and showed cyan fluorescence at 435nm. Meanwhile, papain-templated Au nanoclusters (AuNCs@Papain) were prepared with the same precursor. On the basis of the two types of nanomaterials, CD@Papain and AuNCs@Papain have been designed to assemble as one nanosensor (termed as CD-AuNCs@Papain) through a typical cross-linking reaction. Significantly, it not only emitted the dual-emission fluorescent signals with the same excitation, but also can assay multiple targets through exhibiting cyan, yellow, and red emission respectively. Thereby, H2O2, doxycycline and I- can be detected by CD-AuNCs@Papain. The mechanism of the fluorescence variations of CD AuNCs@Papain: Au(0) of CD-AuNCs@Papain oxidized as Au(I) by H2O2, the formation of hydrogen bonds between the CD-AuNCs@Papain and I-, the inner filter effect (IFE) occurring caused by tetracyclines. Meanwhile, the detection limits of H2O2, doxycycline and I- were obtained as 0.3nM, 0.2nM, and 0.6nM at a signal-to-ratio of 3, respectively. These results suggested that the nanoprobe here has provided the possibility for rapidly assaying multiple targets with the acceptable selectivity. PMID- 28088750 TI - Continuous minimally-invasive alcohol monitoring using microneedle sensor arrays. AB - The present work describes an attractive skin-worn microneedle sensing device for the minimally invasive electrochemical monitoring of subcutaneous alcohol. The device consists of an assembly of pyramidal microneedle structures integrated with Pt and Ag wires, each with a microcavity opening. The microneedle aperture was modified by electropolymerizing o-phenylene diamine onto the Pt wire microtransducer, followed by the immobilization of alcohol oxidase (AOx) in an intermediate chitosan layer, along with an outer Nafion layer. The resulting microneedle-based enzyme electrode displays an interference-free ethanol detection in artificial interstitial fluid without compromising its sensitivity, stability and response time. The skin penetration ability and the efficaciousness of the biosensor performance towards subcutaneous alcohol monitoring was substantiated by the ex vivo mice skin model analysis. Our results reveal that the new microneedle sensor holds considerable promise for continuous non-invasive alcohol monitoring in real-life situations. PMID- 28088751 TI - Chip-based digital surface plasmon resonance sensing platform for ultrasensitive biomolecular detection. AB - A chip-based ultrasensitive surface plasmon resonance (SPR) sensor in a checkerboard nanostructure on plastic substrates is presented for digital detection. The sensing elements on the checkerboard are composed of silver-capped nanoslit arrays, which were fabricated using the thermal-embossing nanoimprint method, to meet the demand for low-cost and rapid fabrication. Sharp Fano resonances in the optimized nanoslit arrays provide high-intensity sensitivities (20,000% per refractive index unit), with an element size of 12.5um. The polarization-dependent transmission in the checkerboard pattern produces optical isolation between sensing elements and results in a crosstalk lower than 1%. Protein-antibody experiments demonstrated that the digital detection limit was up to 1pg/mL, which is approximately 1000 times lower than that of conventional analog detection. For a 140um*140um checkerboard pattern, the dynamic range was approximately 100 times higher than that of conventional surface plasmon resonance measurements. This new digital detection method is very useful for detecting ultralow concentrations of analytes with a nonuniform distribution on the sensor surface. PMID- 28088754 TI - Top considerations for creating bioinformatics software documentation. AB - Investing in documenting your bioinformatics software well can increase its impact and save your time. To maximize the effectiveness of your documentation, we suggest following a few guidelines we propose here. We recommend providing multiple avenues for users to use your research software, including a navigable HTML interface with a quick start, useful help messages with detailed explanation and thorough examples for each feature of your software. By following these guidelines, you can assure that your hard work maximally benefits yourself and others. PMID- 28088752 TI - Microfluidic approaches for isolation, detection, and characterization of extracellular vesicles: Current status and future directions. AB - Extracellular vesicles (EVs) are cell-derived vesicles present in body fluids that play an essential role in various cellular processes, such as intercellular communication, inflammation, cellular homeostasis, survival, transport, and regeneration. Their isolation and analysis from body fluids have a great clinical potential to provide information on a variety of disease states such as cancer, cardiovascular complications and inflammatory disorders. Despite increasing scientific and clinical interest in this field, there are still no standardized procedures available for the purification, detection, and characterization of EVs. Advances in microfluidics allow for chemical sampling with increasingly high spatial resolution and under precise manipulation down to single molecule level. In this review, our objective is to give a brief overview on the working principle and examples of the isolation and detection methods with the potential to be used for extracellular vesicles. This review will also highlight the integrated on-chip systems for isolation and characterization of EVs. PMID- 28088755 TI - Hispanic mothers' beliefs regarding HPV vaccine series completion in their adolescent daughters. AB - Rates of human papillomavirus (HPV) vaccine series completion among adolescent Hispanic females in Texas in 2014 (~39%) lag behind the Healthy People 2020 goal (80%). This qualitative study identifies Hispanic mothers' salient behavioral, normative and control beliefs regarding having their adolescent daughters complete the vaccine series. Thirty-two mothers of girls (aged 11-17) that had received at least one dose of the HPV vaccine, completed in-depth interviews. Six girls had received one dose of the HPV vaccine, 10 girls had received two doses, and 16 girls had received all three doses. The questions elicited salient: (i) experiential and instrumental attitudes (behavioral beliefs); (ii) supporters and non-supporters (normative beliefs) and (iii) facilitators and barriers (control beliefs). Directed content analysis was employed to select the most salient beliefs. Mothers: (i) expressed salient positive feelings (e.g. good, secure, happy and satisfied); (ii) believed that completing the series resulted in positive effects (e.g. protection, prevention); (iii) believed that the main supporters were themselves, their daughter's father and doctor with some of their friends not supporting series completion and (iv) believed that vaccine affordability, information, transportation, ease of scheduling and keeping vaccination appointments and taking their daughter's immunization card to appointments were facilitators. This study represents the first step in building theory-based framework of vaccine series completion for this population. The beliefs identified provide guidance for health care providers and intervention developers. PMID- 28088756 TI - Super-refractory Status Epilepticus with Hemophagocytic Syndrome in a Child with HIV Infection. PMID- 28088753 TI - Mitochondrial redox plays a critical role in the paradoxical effects of NAPDH oxidase-derived ROS on coronary endothelium. AB - AIMS: There are conflicting reports on the role of reactive oxygen species (ROS) i.e. beneficial vs. harmful, in vascular endothelium. Here, we aim to examine whether duration of exposure to ROS and/or subcellular ROS levels are responsible for the apparently paradoxical effects of oxidants on endothelium. METHODS AND RESULTS: We have recently generated binary (Tet-ON/OFF) conditional transgenic mice (Tet-Nox2:VE-Cad-tTA) that can induce 1.8 +/- 0.42-fold increase in NADPH oxidase (NOX)-derived ROS specifically in vascular endothelium upon withdrawal of tetracycline from the drinking water. Animals were divided in two groups: one exposed to high endogenous ROS levels for 8 weeks (short-term) and the other for 20 weeks (long-term). Using endothelial cells (EC) isolated from mouse hearts (MHEC), we demonstrate that both short-term and long-term increase in NOX-ROS induced AMPK-mediated activation of eNOS. Interestingly, although endothelium dependent nitric oxide (NO)-mediated coronary vasodilation was significantly increased after short-term increase in NOX-ROS, coronary vasodilation was drastically reduced after long-term increase in ROS. We also show that short-term ROS increase induced proliferation in EC and angiogenic sprouting in the aorta. In contrast, long-term increase in cytosolic ROS resulted in nitrotyrosine mediated inactivation of mitochondrial (mito) antioxidant MnSOD, increase in mito ROS, loss of mitochondrial membrane potential (Deltapsim), decreased EC proliferation and angiogenesis. CONCLUSION: The findings suggest that NOX-derived ROS results in increased mito-ROS. Whereas short-term increase in mito-ROS was counteracted by MnSOD, long-term increase in ROS resulted in nitrotyrosine mediated inactivation of MnSOD, leading to unchecked increase in mito-ROS and loss of Deltapsim followed by inhibition of endothelial function and proliferation. PMID- 28088757 TI - Challenges in neonatal transport in Jamaica: A resource-limited setting. AB - Aim: This study aimed to determine challenges associated with neonatal transport in Jamaica, a resource-limited setting. Methods: This was a prospective descriptive study of neonates transported to the University Hospital of the West Indies (UHWI) over a 15 month period. Data on the clinical status of the neonates before, during and at the end of transport, as well as on accompanying staff and equipment, were collected. Neonatal demographics, reason for transfer and outcome at 48 h and at discharge were also collected. Descriptive analyses were performed. Results: Fifty neonates were transferred to the UHWI; the most common reason for transfer was for respiratory support [30 (60%)]. The most common mode of transport was by road ambulance [42 (84%)]. Seventeen (34%) neonates experienced at least one adverse event during transport. On arrival, 27 (54%) neonates required warming, 42 (84%) fluid resuscitation and 14 (28%) cardiopulmonary resuscitation (CPR). Eighteen (36%) neonates died. The need for CPR on arrival predicted mortality (odds ratio: 2.3, confidence interval: 0.01 0.75, p = 0.02). A lack of appropriate equipment and adequately trained personnel was also noted. Conclusion: Ensuring pre-transport stabilization of neonates, the availability of adequately trained staff and the provision of appropriate equipment must be urgently addressed to improve the outcome of neonatal transport in resource-limited settings like Jamaica. PMID- 28088758 TI - C5-substituents of uridines and 2-thiouridines present at the wobble position of tRNA determine the formation of their keto-enol or zwitterionic forms - a factor important for accuracy of reading of guanosine at the 3?-end of the mRNA codons. AB - Modified nucleosides present in the wobble position of the tRNA anticodons regulate protein translation through tuning the reading of mRNA codons. Among 40 of such nucleosides, there are modified uridines containing either a sulfur atom at the C2 position and/or a substituent at the C5 position of the nucleobase ring. It is already evidenced that tRNAs with 2-thiouridines at the wobble position preferentially read NNA codons, while the reading mode of the NNG codons by R5U/R5S2U-containing anticodons is still elusive. For a series of 18 modified uridines and 2-thiouridines, we determined the pKa values and demonstrated that both modifying elements alter the electron density of the uracil ring and modulate the acidity of their N3H proton. In aqueous solutions at physiological pH the 2-thiouridines containing aminoalkyl C5-substituents are ionized in ca. 50%. The results, confirmed also by theoretical calculations, indicate that the preferential binding of the modified units bearing non-ionizable 5-substituents to guanosine in the NNG codons may obey the alternative C-G-like (Watson-Crick) mode, while binding of those bearing aminoalkyl C5-substituents (protonated under physiological conditions) and especially those with a sulfur atom at the C2 position, adopt a zwitterionic form and interact with guanosine via a 'new wobble' pattern. PMID- 28088759 TI - How accurate are accurate force-fields for B-DNA? AB - Last generation of force-fields are raising expectations on the quality of molecular dynamics (MD) simulations of DNA, as well as to the belief that theoretical models can substitute experimental ones in several cases. However these claims are based on limited benchmarks, where MD simulations have shown the ability to reproduce already existing 'experimental models', which in turn, have an unclear accuracy to represent DNA conformation in solution. In this work we explore the ability of different force-fields to predict the structure of two new B-DNA dodecamers, determined herein by means of 1H nuclear magnetic resonance (NMR). The study allowed us to check directly for experimental NMR observables on duplexes previously not solved, and also to assess the reliability of 'experimental structures'. We observed that technical details in the annealing procedures can induce non-negligible local changes in the final structures. We also found that while not all theoretical simulations are equally reliable, those obtained using last generation of AMBER force-fields (BSC1 and BSC0OL15) show predictive power in the multi-microsecond timescale and can be safely used to reproduce global structure of DNA duplexes and fine sequence-dependent details. PMID- 28088760 TI - USP15 regulates dynamic protein-protein interactions of the spliceosome through deubiquitination of PRP31. AB - Post-translational modifications contribute to the spliceosome dynamics by facilitating the physical rearrangements of the spliceosome. Here, we report USP15, a deubiquitinating enzyme, as a regulator of protein-protein interactions for the spliceosome dynamics. We show that PRP31, a component of U4 snRNP, is modified with K63-linked ubiquitin chains by the PRP19 complex and deubiquitinated by USP15 and its substrate targeting factor SART3. USP15SART3 makes a complex with USP4 and this ternary complex serves as a platform to deubiquitinate PRP31 and PRP3. The ubiquitination and deubiquitination status of PRP31 regulates its interaction with the U5 snRNP component PRP8, which is required for the efficient splicing of chromosome segregation related genes, probably by stabilizing the U4/U6.U5 tri-snRNP complex. Collectively, our data suggest that USP15 plays a key role in the regulation of dynamic protein-protein interactions of the spliceosome. PMID- 28088762 TI - The super-n-motifs model: a novel alignment-free approach for representing and comparing RNA secondary structures. AB - Motivation: Comparing ribonucleic acid (RNA) secondary structures of arbitrary size uncovers structural patterns that can provide a better understanding of RNA functions. However, performing fast and accurate secondary structure comparisons is challenging when we take into account the RNA configuration (i.e. linear or circular), the presence of pseudoknot and G-quadruplex (G4) motifs and the increasing number of secondary structures generated by high-throughput probing techniques. To address this challenge, we propose the super-n-motifs model based on a latent analysis of enhanced motifs comprising not only basic motifs but also adjacency relations. The super-n-motifs model computes a vector representation of secondary structures as linear combinations of these motifs. Results: We demonstrate the accuracy of our model for comparison of secondary structures from linear and circular RNA while also considering pseudoknot and G4 motifs. We show that the super-n-motifs representation effectively captures the most important structural features of secondary structures, as compared to other representations such as ordered tree, arc-annotated and string representations. Finally, we demonstrate the time efficiency of our model, which is alignment free and capable of performing large-scale comparisons of 10 000 secondary structures with an efficiency up to 4 orders of magnitude faster than existing approaches. Availability and Implementation: The super-n-motifs model was implemented in C ++. Source code and Linux binary are freely available at http://jpsglouzon.github.io/supernmotifs/ . Contact: Shengrui.Wang@Usherbrooke.ca. Supplementary information: Supplementary data are available at Bioinformatics o nline. PMID- 28088761 TI - Amplification of unscheduled DNA synthesis signal enables fluorescence-based single cell quantification of transcription-coupled nucleotide excision repair. AB - Nucleotide excision repair (NER) comprises two damage recognition pathways: global genome NER (GG-NER) and transcription-coupled NER (TC-NER), which remove a wide variety of helix-distorting lesions including UV-induced damage. During NER, a short stretch of single-stranded DNA containing damage is excised and the resulting gap is filled by DNA synthesis in a process called unscheduled DNA synthesis (UDS). UDS is measured by quantifying the incorporation of nucleotide analogues into repair patches to provide a measure of NER activity. However, this assay is unable to quantitatively determine TC-NER activity due to the low contribution of TC-NER to the overall NER activity. Therefore, we developed a user-friendly, fluorescence-based single-cell assay to measure TC-NER activity. We combined the UDS assay with tyramide-based signal amplification to greatly increase the UDS signal, thereby allowing UDS to be quantified at low UV doses, as well as DNA-repair synthesis of other excision-based repair mechanisms such as base excision repair and mismatch repair. Importantly, we demonstrated that the amplified UDS is sufficiently sensitive to quantify TC-NER-derived repair synthesis in GG-NER-deficient cells. This assay is important as a diagnostic tool for NER-related disorders and as a research tool for obtaining new insights into the mechanism and regulation of excision repair. PMID- 28088763 TI - Scater: pre-processing, quality control, normalization and visualization of single-cell RNA-seq data in R. AB - Motivation: Single-cell RNA sequencing (scRNA-seq) is increasingly used to study gene expression at the level of individual cells. However, preparing raw sequence data for further analysis is not a straightforward process. Biases, artifacts and other sources of unwanted variation are present in the data, requiring substantial time and effort to be spent on pre-processing, quality control (QC) and normalization. Results: We have developed the R/Bioconductor package scater to facilitate rigorous pre-processing, quality control, normalization and visualization of scRNA-seq data. The package provides a convenient, flexible workflow to process raw sequencing reads into a high-quality expression dataset ready for downstream analysis. scater provides a rich suite of plotting tools for single-cell data and a flexible data structure that is compatible with existing tools and can be used as infrastructure for future software development. Availability and Implementation: The open-source code, along with installation instructions, vignettes and case studies, is available through Bioconductor at http://bioconductor.org/packages/scater . Contact: davis@ebi.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28088764 TI - Prevalence and long-term prognosis of patients with 'narrower than normal' QRS complexes. AB - Aims: Very narrow QRS have been reported in sudden death survivors but prevalence and prognosis role of narrow QRS is unknown. Methods and results: 546 healthy men between 50 and 60 years (group 1) and 373 similar patients with coronary artery disease (368 men, group 2) underwent signal averaged ECG (SA-ECG) allowing precise measurement of QRS duration. All cause-mortality was determined after 18 +/- 3 years follow-up. Mean QRS duration was 97 +/- 13 ms in group 1 and 103 +/- 16 ms in group 2. Tenth percentile was 84 ms in group 1 and 85 ms in group 2. All cause-mortality in group 1 was 10.4% (57/546): 6/85 in case of QRS <85 ms (7%) and 2/23 (9%) in case of QRS >120 ms (ns). HR for all-cause mortality was 0.75 (95% CI 0.32-1.76, P = 0.52) for QRS <85 ms and 0.86 (95% CI 0.21-3.53, P = 0.84) for QRS >120 ms. All cause mortality in group 2 was 29% (109/373): 7/44 in case of QRS <85 ms (16%) and 22/44 (50%) in case of QRS >120 ms (P = 0.002). HR for all-cause mortality was 0.65 (95% CI 0.29-1.45, P = 0.29) for QRS <85 ms and 1.73 (95% CI 1.02-2.94, P = 0.05) for QRS >120 ms. Conclusion: QRS duration <80-85 ms can be observed in a significant proportion of middle-aged healthy males and in similar patients with ischemic heart disease. Narrow QRS were not linked to prognosis in any group. PMID- 28088765 TI - Allo-allo-triploid Sphagnum * falcatulum: single individuals contain most of the Holantarctic diversity for ancestrally indicative markers. AB - Background and Aims: Allopolyploids exhibit both different levels and different patterns of genetic variation than are typical of diploids. However, scant attention has been given to the partitioning of allelic information and diversity in allopolyploids, particularly that among homeologous monoploid components of the hologenome. Sphagnum * falcatulum is a double allopolyploid peat moss that spans a considerable portion of the Holantarctic. With monoploid genomes from three ancestral species, this organism exhibits a complex evolutionary history involving serial inter-subgeneric allopolyploidizations. Methods: Studying populations from three disjunct regions [South Island (New Zealand); Tierra de Fuego archipelago (Chile, Argentina); Tasmania (Australia)], allelic information for five highly stable microsatellite markers that differed among the three (ancestral) monoploid genomes was examined. Using Shannon information and diversity measures, the holoploid information, as well as the information within and among the three component monoploid genomes, was partitioned into separate components for individuals within and among populations and regions, and those information components were then converted into corresponding diversity measures. Key Results: The majority (76 %) of alleles detected across these five markers are most likely to have been captured by hybridization, but the information within each of the three monoploid genomes varied, suggesting a history of recurrent allopolyploidization between ancestral species containing different levels of genetic diversity. Information within individuals, equivalent to the information among monoploid genomes (for this dataset), was relatively stable, and represented 83 % of the grand total information across the Holantarctic, with both inter-regional and inter-population diversification each accounting for about 5 % of the total information. Conclusions: Sphagnum * falcatulum probably inherited the great majority of its genetic diversity at these markers by reticulation, rather than by subsequent evolutionary radiation. However, some post-hybridization genetic diversification has become fixed in at least one regional population. Methodology allowing statistical analysis of any ploidy level is presented. PMID- 28088766 TI - Staphylococcus aureus CC395 harbours a novel composite staphylococcal cassette chromosome mec element. AB - Background: CoNS species are likely reservoirs of the staphylococcal cassette chromosome mec (SCC mec ) in Staphylococcus aureus . S . aureus CC395 is unique as it is capable of exchanging DNA with CoNS via bacteriophages, which are also known to mediate transfer of SCC mec . Objectives: To analyse the structure and putative origin of the SCC mec element in S . aureus CC395. Methods: The only MRSA CC395 strain described in the literature, JS395, was subjected to WGS, and its SCC mec element was compared with those found in CoNS species and other S. aureus strains. Results: JS395 was found to carry an unusually large 88 kb composite SCC mec element. The 33 kb region downstream of orfX harboured a type V SCC mec element and a CRISPR locus, which was most similar to those found in the CoNS species Staphylococcus capitis and Staphylococcus schleiferi . A 55 kb SCC element was identified downstream of the type V SCC mec element and contained a mercury resistance region found in the composite SCC element of some Staphylococcus epidermidis and S . aureus strains, an integrated S . aureus plasmid containing genes for the detoxification of cadmium and arsenic, and a stretch of genes that was partially similar to the type IVg SCC mec element found in a bovine S . aureus strain. Conclusions: The size and complexity of the SCC mec element support the idea that CC395 is highly prone to DNA uptake from CoNS. Thus CC395 may serve as an entry point for SCC mec and SCC structures into S . aureus . PMID- 28088767 TI - Pharmacokinetic study of anidulafungin in ICU patients with intra-abdominal candidiasis. AB - Background: Only limited pharmacokinetic data are available for anidulafungin in ICU patients, especially in patients treated for severe intra-abdominal infection (IAI). Methods: This was a prospective multicentre observational study in ICU patients with suspected yeast IAI. All patients received an intravenous loading dose of 200 mg of anidulafungin, followed by 100 mg/day. Thirteen blood samples were drawn between day 1 and day 5 for pharmacokinetic analysis. Samples were analysed by an HPLC-tandem MS method. Demographics and SAPS2 and SOFA scores were recorded. Results: Fourteen patients with a median age (IQR) of 62 years (48-70) and with a mean BMI of 30.5 kg/m 2 were included from three centres; 57.1% were women. Their median (IQR) SAPS2 score was 54 (45-67) and their median (IQR) SOFA score was 8 (7-12). Six patients with community-acquired IAI and eight patients with nosocomial-acquired IAI were included. Twelve yeasts were isolated: six Candida albicans , two Candida glabrata , two Candida tropicalis , one Candida parapsilosis and one Candida krusei . Pharmacokinetic parameters were as follows [mean (% coefficient of variation)]: C max (mg/L) = 6.0 (29%); T max (h) = 1.6 (25.8%); C min (mg/L) = 3.2 (36.8%); AUC 0-24 (mg.h/L) = 88.9 (38.6%); t 1/2 (h) = 42.1 (68.2%); CL (L/h) = 1.2 (42.3%); and V (L) = 72.8 (87.8%). A two compartment model best described the anidulafungin concentrations in the population pharmacokinetic study. Conclusions: The pharmacokinetic parameters of anidulafungin in critically ill ICU patients with complicated IAI are similar to those observed in the literature. However, an increased V and a longer t 1/2 were observed in this study. (EudraCT No. 2010-018695-25). PMID- 28088768 TI - In vitro activity of ceftazidime/avibactam against urinary isolates from patients in a Phase 3 clinical trial programme for the treatment of complicated urinary tract infections. AB - Objectives: To evaluate the in vitro activity of ceftazidime/avibactam relative to comparator agents against Gram-negative isolates from a Phase 3 clinical trial programme for complicated urinary tract infections (RECAPTURE). Methods: The in vitro activity of ceftazidime/avibactam was evaluated against 840 Gram-negative pathogens isolated at baseline from 1033 randomized patients in two pivotal Phase 3 clinical trials for the treatment of complicated urinary tract infections. The trials were conducted in 160 institutions from 25 countries worldwide. Susceptibility testing was performed by broth microdilution at a central laboratory according to CLSI methodologies. Results: Overall, ceftazidime/avibactam showed significant activity against the Enterobacteriaceae and Pseudomonas aeruginosa with MIC 90 values of 0.5 and 8 mg/L, respectively. Against the most common Enterobacteriaceae, MIC 90 values were 0.25 mg/L for Escherichia coli , 1 mg/L for Klebsiella pneumoniae , 0.06 mg/L for Proteus mirabilis and 2 mg/L for Enterobacter cloacae . The ceftazidime/avibactam MIC 90 for 154 ceftazidime-non-susceptible isolates of Enterobacteriaceae was 1 mg/L and the ceftazidime/avibactam MIC 90 for 15 non-susceptible isolates of P. aeruginosa was 64 mg/L. There was a significant reduction in the ceftazidime/avibactam MIC relative to ceftazidime alone for most of the Enterobacteriaceae isolates. Conclusions: The ceftazidime/avibactam in vitro activity against these clinical urinary tract isolates demonstrates the potential utility of the drug in complicated urinary tract infections. PMID- 28088769 TI - Ultradeep sequencing detection of the R263K integrase inhibitor drug resistance mutation. PMID- 28088770 TI - A novel disrupted mcr-1 gene and a lysogenized phage P1-like sequence detected from a large conjugative plasmid, cultured from a human atypical enteropathogenic Escherichia coli (aEPEC) recovered in China. PMID- 28088771 TI - Do we still need cross-sectional studies in Nephrology? Yes we do! AB - Cross-sectional studies represent the second line of evidence (after case reports) in the ladder of evidence aimed at defining disease aetiology. This study design is used to generate hypotheses about the determinants of a given disease but also to investigate the accuracy of diagnostic tests and to assess the burden of a given disease in a population. The intrinsic limitation of cross sectional studies, when applied to generate aetiological hypotheses, is that both the exposure under investigation and the disease of interest are measured at the same point in time. For this reason, generally the cross-sectional design does not provide definitive proofs about cause-and-effect relationships. An advantage of cross-sectional studies in aetiological and diagnostic research is that they allow researchers to consider many different putative risk factors/diagnostic markers at the same time. For example, in a hypothetical study aimed at generating hypotheses about the risk factors for left ventricular hypertrophy (LVH) in patients with chronic kidney disease, investigators could look at several risk factors as potential determinants of LVH (age, gender, cholesterol, blood pressure, inflammation, etc.) with minimal or no additional costs. In this article, we make examples derived from the nephrology literature to show the usefulness of cross-sectional studies in clinical and epidemiological research. PMID- 28088772 TI - Thrombospondin immune regulation and the kidney. AB - Most therapeutic attempts to prevent the progression of kidney diseases have been based on interventions to inhibit the production of transforming growth factor beta (TGF-beta). Thrombospondins (TSPs) play an important role in activating TGF beta. In the healthy kidney, two TSPs are expressed, TSP1 and TSP2, which exert contrasting effects. While TSP1 is a major activator of TGF-beta in renal cells and exerts pro-inflammatory effects both in vitro and in vivo, TSP2 lacks the ability for TGF-beta activation but regulates matrix remodeling and inflammation in experimental kidney disease. The effects of TSPs in the kidney have been mostly investigated by using the murine model of unilateral ureteral obstruction. In this model, TSP1 expression is increased along with the development of interstitial fibrosis and TGF-beta. Relief of the obstruction gradually improves renal function and decreases the expression in TSP1 and TGF-beta1. Several inhibitors of TSP1 prevented progressive interstitial fibrosis in murine models of ureteral obstruction, suggesting that control of latent TGF-beta activation by inhibiting TSP1 might represent a novel potential target for preventing renal interstitial fibrosis. However, further studies are needed to assess whether TSP1 mediated TGF-beta activation can be safely used in humans. In fact, TSPs normally act to suppress tumors in vivo. Moreover, TGF-beta can exert a pivotal function in the immune system, as it may induce the production of regulatory T cells and suppress B cell responses. Knowledge of the molecular mechanisms involved in TGF beta regulation may help in finding effective treatments of tissue fibrosis, cancer and autoimmune disease. PMID- 28088773 TI - Epidemiology and outcome of acute pancreatitis in end-stage renal disease dialysis patients: a 10-year national cohort study. AB - Background: The objective of this study is to determine the incidence and severity of acute pancreatitis (AP) in patients with end-stage renal disease (ESRD) on dialysis and whether the dialysis modality [hemodialysis (HD) versus peritoneal dialysis (PD)] confers a higher risk for AP as well as complications or mortality related to AP. Methods: We analyzed national health insurance claims data of 67 078 ESRD patients initiating dialysis between 1999 and 2007 in Taiwan. All patients were followed up from the start of their dialysis to first AP diagnosis, death, end of dialysis or 31 December 2008. Cox proportional hazards models were used to identify risk factors. Results: The cumulative incidence rates of AP were 0.6, 1.7, 2.6, 3.4 and 4% at 1, 3, 5, 7 and 9 years, respectively. ESRD patients on HD and PD had an AP incidence of 5.11 and 5.86 per 1000 person-years, respectively. Independent risk factors for AP in this population were being elderly, being female, having biliary stones or liver disease, and being on PD. Severe AP occurred in 44.9% of the HD patients and in 36% of the PD patients. Patients with AP on HD had a higher incidence of upper gastrointestinal (UGI) bleeding than those on PD (P = 0.002). In contrast, those with AP on PD had a higher incidence of need for total parenteral nutrition (TPN) support than those on HD (P = 0.072). Overall in-hospital mortality was 8.1%. The risk factors for mortality after an AP attack were male gender, increased age, AP severity, and the presence of diabetes mellitus or liver disease. Conclusions: ESRD patients on PD were at higher risk for AP than those on HD. HD patients with AP attacks had a greater incidence of UGI bleeding and PD patients with AP attacks a more frequent need for TPN support. PMID- 28088774 TI - Association between e-alert implementation for detection of acute kidney injury and outcomes: a systematic review. AB - Background: Electronic alerts (e-alerts) for acute kidney injury (AKI) in hospitalized patients are increasingly being implemented; however, their impact on outcomes remains uncertain. Methods: We performed a systematic review. Electronic databases and grey literature were searched for original studies published between 1990 and 2016. Randomized, quasi-randomized, observational and before-and-after studies that included hospitalized patients, implemented e alerts for AKI and described their impact on one of care processes, patient centred outcomes or resource utilization measures were included. Results: Our search yielded six studies ( n = 10 165 patients). E-alerts were generally automated, triggered through electronic health records and not linked to clinical decision support. In pooled analysis, e-alerts did not improve mortality [odds ratio (OR) 1.05; 95% confidence intervals (CI), 0.84-1.31; n = 3 studies; n = 3425 patients; I 2 = 0%] or reduce renal replacement therapy (RRT) use (OR 1.20; 95% CI, 0.91-1.57; n = 2 studies; n = 3236 patients; I 2 = 0%). Isolated studies reported improvements in selected care processes. Pooled analysis found no significant differences in prescribed fluid therapy. Conclusions: In the available studies, e-alerts for AKI do not improve survival or reduce RRT utilization. The impact of e-alerts on processes of care was variable. Additional research is needed to understand those aspects of e-alerts that are most likely to improve care processes and outcomes. PMID- 28088775 TI - Diagnostic accuracy of glycated hemoglobin for post-transplantation diabetes mellitus after kidney transplantation: systematic review and meta-analysis. AB - Background: Early detection of post-transplantation diabetes mellitus (PTDM) allows prompt clinical and pharmacological interventions, reducing the chance of adverse outcomes. We conducted a systematic review and meta-analysis to determine the overall diagnostic accuracy of glycated hemoglobin (HbA1c) for the diagnosis of renal PTDM. Methods: We searched MEDLINE, Embase and SCOPUS up to June 2016. Studies that included adults without previous diabetes were selected if they reported an oral glucose tolerance test as a reference test, HbA1c levels measured by standardized methods and data necessary for drawing 2 * 2 tables. A bivariate model was used to calculate the pooled estimates. Results: Based on 2057 kidney recipients from six studies, an HbA1c cut-off point of 6.5% in early months after transplant resulted in sensitivity of 0.48 [95% confidence interval (95% CI) 0.31-0.65], specificity of 0.96 (95% CI 0.95-0.97), positive likelihood ratio (PLR) of 12.0 (95% CI 7.4-19.5) and negative likelihood ratio (NLR) of 0.54 (95% CI 0.38-0.77). Based on 1888 kidney recipients from four studies, an HbA1c cut-off point of 6.2% early after transplant resulted in sensitivity of 0.76 (95% CI 0.49-0.91), specificity of 0.89 (95% CI 0.86-0.92), PLR of 7.18 (95% CI 5.29 9.75) and NLR of 0.27 (95% CI 0.11-0.65). Conclusion: HbA1c cut-off points of 6.5% and 6.2% presented high specificity but low/moderate sensitivity to diagnose PTDM. PMID- 28088776 TI - Prognostic utility of estimated albumin excretion rate in chronic kidney disease: results from the Study of Heart and Renal Protection. AB - Background: Estimated albumin excretion rate (eAER) provides a better estimate of 24-h albuminuria than albumin:creatinine ratio (ACR). However, whether eAER is superior to ACR in predicting end-stage renal disease (ESRD), vascular events (VEs) or death is uncertain. Methods: The prognostic utility of ACR and eAER (estimated from ACR, sex, age and race) to predict mortality, ESRD and VEs was compared using Cox proportional hazards regression among 5552 participants with chronic kidney disease in the Study of Heart and Renal Protection, who were not on dialysis at baseline. Results: During a median follow-up of 4.8 years, 1959 participants developed ESRD, 1204 had a VE and 1130 died (641 from a non vascular, 369 from a vascular and 120 from an unknown cause). After adjustment for age, sex and eGFR, both ACR and eAER were strongly and similarly associated with ESRD risk. The average relative risk (RR) per 10-fold higher level was 2.70 (95% confidence interval 2.45-2.98) for ACR and 2.67 (2.43-2.94) for eAER. Neither ACR nor eAER provided any additional prognostic information for ESRD risk over and above the other. For VEs, there were modest positive associations between both ACR and eAER and risk [adjusted RR per 10-fold higher level 1.37 (1.22-1.53) for ACR and 1.36 (1.22-1.52) for eAER]. Again, neither measure added prognostic information over and above the other. Similar results were observed when ACR and eAER were related to vascular mortality [RR per 10-fold higher level: 1.64 (1.33-2.03) and 1.62 (1.32-2.00), respectively] or to non-vascular mortality [1.53 (1.31-1.79) and 1.50 (1.29-1.76), respectively]. Conclusions: In this study, eAER did not improve risk prediction of ESRD, VEs or mortality. PMID- 28088777 TI - Causes and characteristics of medical student referrals to a professional behaviour board. AB - Objectives: To describe the nature of unprofessional behaviour displayed by medical students, as well as the characteristics of students referred to the professional behaviour board. Methods: A descriptive mixed methods approach was taken, in which qualitative data on unprofessional behaviour, as well as quantitative data on the demographics of referred students were collected during the study period between June 1, 2009 and January 1, 2014. In order to compare the referred students with the total student population, data on gender, nationality and phase in the curriculum of the total student population, collected from the student administration desk, were also used. Results: In the study period, a total of 107 referrals were reported, concerning 93 different students (3% of the total student population). Sixty-five of the 107 referrals (61%) concerned male students. Thirty referrals (28%) concerned non-Dutch students. Most referrals (71%) occurred during clinical rotations. The referrals were equally distributed over three professional behaviour domains: dealing with oneself, dealing with others, and dealing with tasks/work. 'Withdrawn behaviour' was reported 17 times, 'insufficient Dutch language proficiency' 14 times, 'impertinent emails' 9 times and 'placing privacy-sensitive photos on the internet' 3 times. Conclusions: Although only a minority of students are referred to a professional behaviour board, this study shows that student characteristics such as gender and nationality may correlate to a higher incidence of unprofessional behaviour. Further explanatory and exploratory research is needed to unravel this relationship, and to study the influence of curriculum reforms on these relationships, respectively. PMID- 28088778 TI - Implementing and tailoring a western-developed communication skills training program for graduate medical trainees in Qatar. PMID- 28088779 TI - Comprehensive proteome analysis of lysosomes reveals the diverse function of macrophages in immune responses. AB - Phagocytosis and autophagy in macrophages have been shown to be essential to both innate and adaptive immunity. Lysosomes are the main catabolic subcellular organelles responsible for degradation and recycling of both extracellular and intracellular material, which are the final steps in phagocytosis and autophagy. However, the molecular mechanisms underlying lysosomal functions after infection remain obscure. In this study, we conducted a quantitative proteomics analysis of the changes in constitution and glycosylation of proteins in lysosomes derived from murine RAW 264.7 macrophage cells treated with different types of pathogens comprising examples of bacteria (Listeria monocytogenes, L. m), DNA viruses (herpes simplex virus type-1, HSV-1) and RNA viruses (vesicular stomatitis virus, VSV). In total, 3,704 lysosome-related proteins and 300 potential glycosylation sites on 193 proteins were identified. Comparative analysis showed that the aforementioned pathogens induced distinct alterations in the proteome of the lysosome, which is closely associated with the immune functions of macrophages, such as toll-like receptor activation, inflammation and antigen-presentation. The most significant changes in proteins and fluctuations in glycosylation were also determined. Furthermore, Western blot analysis showed that the changes in expression of these proteins were undetectable at the whole cell level. Thus, our study provides unique insights into the function of lysosomes in macrophage activation and immune responses. PMID- 28088780 TI - National survey of China's oncologists' knowledge, attitudes, and clinical practice patterns on complementary and alternative medicine. AB - It is common for cancer patients to use complementary and alternative medicine (CAM). This study was designed to explore China's oncologists' knowledge, attitudes and clinical practices regarding CAM use by their patients. An online survey was conducted of China's oncologists. Among 11,270 participants who completed the online survey, 6,007 (53.3%) were identified as oncologists. Most were men (75.2%), with a mean age of 33.4 (standard deviation: 6.5) years. The 6,007 oncologists discussed with 36.5% of their patients about CAM. Most of them (75.6%) did not want to initiate discussions due to lack of knowledge on CAM. Oncologists estimated that 40.0% of their patients used CAM treatments. Oncologists reported that 28.7% of their patients underwent anticancer therapy with the concurrent use of CAM. Four out of five of the responding oncologists self-reported inadequate knowledge and only 22.0% reported receiving professional education on CAM. Nearly half (44.9%) of the oncologists believed CAM treatment was effective for symptoms and treatment of cancer. Physician factors associated with initiating discussions with patients about CAM use included sex, age (>= 33 years), medical license for traditional Chinese medicine, enough knowledge and professional education experience. China's oncologists infrequently discussed with their patients about CAM due to lack of knowledge. Most of the oncologists did not encourage CAM use. PMID- 28088781 TI - MiR-30c-5p ameliorates hepatic steatosis in leptin receptor-deficient (db/db) mice via down-regulating FASN. AB - Approximately 15-40% of the general adult population suffers from non-alcoholic fatty liver disease (NAFLD) worldwide. However, no drug is currently licensed for its treatment. In this study, we observed a significant reduction of miR-30c-5p in the liver of leptin receptor-deficient (db/db) mice. Remarkably, recombinant adeno-associated virus (rAAV)-mediated delivery of miR-30c-5p was sufficient to attenuate triglyceride accumulation and hepatic steatosis in db/db mice. Through computational prediction, KEGG analysis and Ago2 co-immunoprecipitation, we identified that miR-30c-5p directly targeted fatty acid synthase, a key enzyme in fatty acid biosynthesis. Moreover, down-regulation of FASN by siRNA attenuated some key features of NAFLD, including decreased triglyceride accumulate and lipid deposition. Our findings reveal a new role of miR-30c-5p in counterbalancing fatty acid biosynthesis, which is sufficient to attenuate triglyceride accumulation and hepatic steatosis in db/db mice. PMID- 28088782 TI - PDE5 inhibitors enhance the lethality of [pemetrexed + sorafenib]. AB - The combination of pemetrexed and sorafenib has significant clinical activity against a wide variety of tumor types in patients and the present studies were performed to determine whether sildenafil enhances the killing potential of [pemetrexed + sorafenib]. In multiple genetically diverse lung cancer cell lines, sildenafil enhanced the lethality of [pemetrexed + sorafenib]. The three-drug combination reduced the activities of AKT, mTOR and STAT transcription factors; increased the activities of eIF2alpha and ULK-1; lowered the expression of MCL-1, BCL-XL, thioredoxin and SOD2; and increased the expression of Beclin1. Enhanced cell killing by sildenafil was blocked by inhibition of death receptor signaling and autophagosome formation. Enforced activation of STAT3 and AKT or inhibition of JNK significantly reduced cell killing. The enhanced cell killing caused by sildenafil was more reliant on increased PKG signaling than on the generation of nitric oxide. In vivo sildenafil enhanced the anti-tumor properties of [pemetrexed + sorafenib]. Based on our data we argue that additional clinical studies combining pemetrexed, sorafenib and sildenafil are warranted. PMID- 28088784 TI - A phase I clinical study of autologous dendritic cell therapy in patients with relapsed or refractory multiple myeloma. AB - Cellular immunotherapy is emerging as a potential immunotherapeutic modality in multiple myeloma (MM). We have developed potent immunotherapeutic agent (VAX DC/MM) generated by dendritic cells (DCs) loaded with autologous myeloma cells irradiated with ultraviolet B. In this study, we evaluated the safety and efficacy of VAX-DC/MM in patients with relapsed or refractory MM. This trial enrolled relapsed or refractory MM patients who had received both thalidomide- and bortezomib-based therapies. Patients received the intradermal VAX-DC/MM injection every week for 4 weeks. Patients were treated with 5 * 106 or 10 * 106 cells, with nine patients treated at a higher dose. The median time from diagnosis to VAX-DC/MM therapy was 56.6 months (range, 28.5-130.5). Patients had received a median of five prior treatments, and 75% had received autologous stem cell transplantation. VAX-DC therapy was well-tolerated, and the most frequent adverse events were local reactions at the injection site and infusion-related reactions. In seven of nine patients who received 10*106 cells, an immunological response (77.8%) was observed by interferon-gamma ELISPOT assay or a mixed lymphocyte reaction assay for T-cell proliferation. The clinical benefit rate was 66.7% including one (11.1%) with minor response and five (55.6%) with stable disease; three (33.3%) patients showed disease progression. In conclusion, VAX DC/MM therapy was well-tolerated, and had disease-stabilizing activity in heavily pretreated MM cases. Further studies are needed to increase the efficacy of VAX DC/MM in patients with MM. PMID- 28088783 TI - alpha-Asarone blocks 7beta-hydroxycholesterol-exposed macrophage injury through blocking elF2alpha phosphorylation and prompting beclin-1-dependent autophagy. AB - Macrophage apoptosis is salient in advanced atherosclerotic lesions and is induced by several stimuli including endoplasmic reticulum (ER) stress. This study examined that alpha-asarone present in purple perilla abrogated macrophage injury caused by oxysterols via ER stress- and autophagy-mediated mechanisms. Nontoxic alpha-asarone at 1-20 MUM attenuated 7beta-hydroxycholesterol-induced activation of eukaryotic initiation factor 2alpha in macrophages leading to C/EBP homologous protein (CHOP) expression and apoptosis due to sustained ER stress. The alpha-asarone treatment increased the formation of autophagolysosomes localizing in perinuclear regions of 7beta-hydroxycholesterol-exposed macrophages. Consistently, this compound promoted the induction of the key autophagic proteins of beclin-1, vacuolar protein sorting 34 and p150 responsible for vesicle nucleation, and prompted the conversion of microtubule-associated protein 1A/1B-light chain 3 and the induction of p62, neighbor of BRCA1 and autophagy-related (Atg) 12-Atg5-Atg16L conjugate involved in phagophore expansion and autophagosome formation. Additionally, alpha-asarone increased ER phosphorylation of bcl-2 facilitating beclin-1 entry to autophagic process. Furthermore, the deletion of Atg5 or beclin-1 gene enhanced apoptotic CHOP induction. Collectively, alpha-asarone-stimulated autophagy may be potential multi-targeted therapeutic avenues in treating ER stress-associated macrophage apoptosis. PMID- 28088785 TI - The IgH locus 3' cis-regulatory super-enhancer co-opts AID for allelic transvection. AB - Immunoglobulin heavy chain (IgH) alleles have ambivalent relationships: they feature both allelic exclusion, ensuring monoallelic expression of a single immunoglobulin (Ig) allele, and frequent inter-allelic class-switch recombination (CSR) reassembling genes from both alleles. The IgH locus 3' regulatory region (3'RR) includes several transcriptional cis-enhancers promoting activation induced cytidine deaminase (AID)-dependent somatic hypermutation (SHM) and CSR, and altogether behaves as a strong super-enhancer. It can also promote deregulated expression of translocated oncogenes during lymphomagenesis. Besides these rare, illegitimate and pathogenic interactions, we now show that under physiological conditions, the 3'RR super-enhancer supports not only legitimate cis- , but also trans-recruitment of AID, contributing to IgH inter-allelic proximity and enabling the super-enhancer on one allele to stimulate biallelic SHM and CSR. Such inter-allelic activating interactions define transvection, a phenomenon well-known in drosophila but rarely observed in mammalian cells, now appearing as a unique feature of the IgH 3'RR super-enhancer. PMID- 28088786 TI - EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis. AB - EZH2 inhibition and reactivation of tumor suppressor microRNAs (miRNAs) represent attractive anti-cancer therapeutic strategies. We found that EZH2-suppressed let 7b and miR-361, two likely tumor suppressors, inhibited endometrial cancer (EC) cell proliferation and invasion, and abrogated cancer stem cell-like properties. In EC cells, EZH2 induced and functioned together with YY1 to epigenetically suppress miR-361, which upregulated Twist, a direct target of miR-361. Treating EC cells with GSK343, a specific EZH2 inhibitor, mimicked the effects of siRNA mediated EZH2 knockdown, upregulating miR-361 and downregulating Twist expression. Combining GSK343 with 5 AZA-2'-deoxycytidine synergistically suppressed cell proliferation and invasion in vitro, and decreased tumor size and weight in EC cell xenografted mice. Quantitative real-time PCR analysis of 24 primary EC tissues showed that lower let-7b and miR-361 levels were associated with worse patient outcomes. These results were validated in a larger EC patient dataset from The Cancer Genome Atlas. Our findings suggest that EZH2 drives EC progression by regulating miR-361/Twist signaling, and support EZH2 inhibition as a promising anti-EC therapeutic strategy. PMID- 28088787 TI - HINT2 downregulation promotes colorectal carcinoma migration and metastasis. AB - Histidine triad nucleotide-binding 2 (HINT2), a member of the histidine triad proteins family, sensitizes cells to apoptosis in hepatocellular carcinoma. Here, we showed that HINT2 expression is lower in primary colorectal cancer (CRC) and metastasis tissues than in normal colorectal tissues, and that HINT2 abundance is inversely correlated with CRC tumor stage. Treating CRC cells with 5-aza-2' deoxycytidine, a demethylating agent, upregulated HINT2, suggesting HINT2 downregulation is caused by methylation of the gene promoter. HINT2 downregulation increased tumor migration and invasion in vitro, promoted CRC cell metastasis in vivo, and increased expression of epithelial-to-mesenchymal transition (EMT) markers. Furthermore, HINT2 downregulation depended on hypoxia inducible factor (HIF)-2alpha-mediated transcriptional activation of zinc finger E-box-binding homeobox 1 (ZEB1). These results suggest that HINT2 downregulation promotes HIF-2alpha expression, which induces EMT and enhances CRC cell migration and invasion. HINT2 may thus a useful clinical indicator of CRC progression and metastasis risk. PMID- 28088788 TI - Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic leukemia: Cerdulatinib, but not ibrutinib, induces apoptosis of tumor cells protected by the microenvironment. AB - Ibrutinib (BTK inhibitor) has generated remarkable responses in CLL. However, the drug, to a large extent, does not cause cell death directly and does not eradicate CLL malignant clones. Inability to eradicate CLL has fostered resistance generation. Once patients become resistant, they do poorly with a median survival of 3-4 months. Novel therapeutic strategies are needed to prevent resistance, improve treatment outcome and ultimately cure the disease. Herein, we explore dual targeting of the BCR and JAK-STAT pathways with a novel single agent, cerdulatinib, which selectively inhibits both SYK (a BCR component) and JAK kinases. We demonstrated that cerdulatinib delivered potent tumor inhibition in 60 primary CLL patient samples, especially in those with poor prognostic indicators. Importantly, cerdulatinib, but not ibrutinib, is able to overcome the support of microenvironment and induces CLL cell death at clinically achievable concentrations. Notably, cerdulatinib blocked proliferation of ibrutinib resistant primary CLL cells and of BTKC481S-transfected/ibrutinib-resistant lymphoma cells. These anti-tumor effects are well correlated with the inhibition of BCR and JAK-STAT signaling and downstream inhibition of the functions of AKT, ERK and NFkappaB. Collectively, our results show that simultaneous targeting of BCR and JAK-STAT pathways is a more effective strategy relative to single BTK inhibition. PMID- 28088789 TI - Gprc5a-knockout mouse lung epithelial cells predicts ceruloplasmin, lipocalin 2 and periostin as potential biomarkers at early stages of lung tumorigenesis. AB - Lung cancer is the leading cause of cancer death. As most of lung cancer patients were diagnosed with the advanced stage, early detection is considered as the most effective strategy to reduce high mortality. Thus, it is desirable to identify specific biomarkers at early stages of lung tumorigenesis. GPRC5A is a lung tumor suppressor gene. GPRC5A deficiency is linked to lung cancer development. We hyposthesized that, dysregulated gene expression that results from Gprc5a deficiency may provide potential biomarkers at early stages of lung tumorigenesis. By analysis of top 20 upregulated genes in mouse tracheal epithelial cells (MTEC) of Gprc5a knockout (KO) vs wild-type (WT), we found that ceruloplasmin, lipocalin-2, and periostin are not only upregulated in lung epithelial cells of Gprc5a-ko mice, but also expressed at high levels in lung tumor tissues of Gprc5a-ko mice. This suggests that increased expression of these genes is associated with lung tumorigenesis. Importantly, expression of ceruloplasmin, lipocalin-2, and periostin has also been found to be significantly increased, both at mRNA and protein levels, in the lung tissues from NSCLC patients, which is correlated with repressed GPRC5A. Thus, dysregulated ceruloplasmin, lipocalin-2, and periostin may be used as potential biomarkers at early stages of lung tumorigenesis. PMID- 28088790 TI - Intraperitoneal immunotherapy with T cells stably and transiently expressing anti EpCAM CAR in xenograft models of peritoneal carcinomatosis. AB - The epithelial cell adhesion molecule (EpCAM) is overexpressed in a wide variety of tumor types, including peritoneal carcinomatosis (PC) from gastrointestinal and gynecological malignancies. To develop a chimeric antigen receptor T (CART) cell therapy approach to treat patients with end-stage PC, we constructed third generation CARs specific to EpCAM using the 4D5MOC-B single chain variable fragment. CART cells were generated with lentiviral transduction and exhibited specific in vitro killing activity against EpCAM-positive human ovarian and colorectal cancer cells. A single intraperitoneal injection of the CART cells eradicated established ovarian xenografts and resulted in significantly prolonged animal survival. Since EpCAM is also expressed on normal epithelium, anti-EpCAM CART cells were generated by mRNA electroporation that display a controlled cytolytic activity with a limited CAR expression duration. Multiple repeated infusions of these RNA CAR-modified T cells delayed disease progression in immunodeficient mice bearing well-established peritoneal ovarian and colorectal xenografts. Thus, our study demonstrates the effectiveness of using anti-EpCAM CAR-expressing T cells for local treatment of PC in mice. The possibility of using this approach for clinical treatment of EpCAM-positive gastrointestinal and gynecological malignancies warrants further validation. PMID- 28088791 TI - Sinomenine hydrochloride inhibits breast cancer metastasis by attenuating inflammation-related epithelial-mesenchymal transition and cancer stemness. AB - Sinomenine hydrochloride (SH) has been investigated for its anti-tumor growth effect. We have previously reported that SH inhibited breast cancer cell proliferation via MAPKs signaling. However, whether SH could inhibit tumor metastasis has not been fully explored. In this study, we found that SH suppressed the metastasis potential of breast cancer cells. The wound healing and transwell assays showed that SH inhibited the migration and invasion ability of both 4T1 and MDA-MB-231 breast cancer cells. The orthotopic mouse model of 4T1 and the experimental mouse model of MDA-MB-231-luc (MDA-MB-231 cell line expressing firefly luciferase) demonstrated that SH treatment inhibited breast cancer metastasis by inhibiting epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties without obvious hepatotoxicity and renal toxicity. We also found that SH decreased spleen volume and weight in both mouse models, especially in the 4T1 mouse model. IL-6, a strong inflammatory factor causing EMT, was remarkably reduced. Overall, this anti-metastasis effect of SH could be possibly caused by attenuating inflammatory reaction, which led to inhibition of EMT and CSC characteristics of breast cancer cells. This study, together with our previous one, provides more evidence of SH as a potential drug for breast cancer therapy. PMID- 28088792 TI - Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose. AB - Thiopurines are widely used as anticancer and immunosuppressive agents. However, life-threatening myelotoxicity has been noticed and largely explained by genetic variations, including NUDT15 polymorphisms (e.g., rs116855232). In this study, we conduct a meta-analysis to investigate the impact of rs116855232 on thiopurines induced myelotoxicity susceptibility (1752 patients from 7 independent cohorts), as well as on thiopurines intolerance dose (2745 patients from 13 cohorts). Variant allele of rs116855232 contributes 7.86-fold (P < 0.00001, 95% CI: 6.13 10.08) higher risk to develop leucopenia with high specificity (91.74%) and sensitivity (43.19%), and lower thiopurines intolerance dose (P < 0.00001). Through bioinformatics prediction, amino acid changes induced by genetic variants are considered to reduce the stability, and break an alpha helix of NUDT15, which is part of the thiopurine binding pocket. Additionally, we conduct an expression quantitative trait loci (eQTL) analysis for NUDT15, and find a promoter-located eQTL signal (rs554405994), which may act as a potential marker to predict thiopurines-induced myelotoxicity. In conclusion, genetic polymorphisms in NUDT15 are strongly associated with adverse drug reaction (ADR) of thiopurines, although more evidences are needed to determine values of all functional NUDT15 polymorphisms for clinical regimen, rs116855232 should be considered as a highly credible pharmacogenetic indicator for thiopurines using espcially is Asians. PMID- 28088793 TI - HnRNP-L mediates bladder cancer progression by inhibiting apoptotic signaling and enhancing MAPK signaling pathways. AB - Heterogeneous nuclear ribonucleoprotein L (hnRNP-L) is a promoter of various kinds of cancers, but its actions in bladder cancer (BC) are unclear. In this study, we investigated the function and the underlying mechanism of hnRNP-L in bladder carcinogenesis. Our results demonstrated that enhanced hnRNP-L expression in BC tissues was associated with poor overall survival of BC patients. Depletion of hnRNP-L significantly suppressed cell proliferation in vitro and inhibited xenograft tumor growth in vivo. Furthermore, downregulation of hnRNP-L resulted in G1-phase cell cycle arrest and enhanced apoptosis accompanied by inhibition of EMT and cell migration. All these cellular changes were reversed by ectopic expression of hnRNP-L. Deletion of hnRNP-L resulted in decreased expression of Bcl-2, enhanced expression of caspases-3, -6 and -9 and inhibition of the MAPK signaling pathway. These findings demonstrate that hnRNP-L contributes to poor prognosis and tumor progression of BC by inhibiting the intrinsic apoptotic signaling and enhancing MAPK signaling pathways. PMID- 28088794 TI - The Lack of Association between FCN2 Gene Promoter Region Polymorphisms and Dental Caries in Polish Children. AB - The aim of this study was to examine the association of single-nucleotide polymorphisms (SNPs) in the gene encoding ficolin-2 protein (FCN2 gene) at positions -986 (rs17514136), -602 (rs3124953), and -4 (rs3124952) with dental caries in Polish children. Two hundred and sixty Polish Caucasian children aged 15 years were enrolled in this study: 82 with "higher" caries experience (DMFT >5) and 178 with "lower" caries experience (DMFT <=5). In addition, subjects with caries experience (DMFT >=1) and caries-free subjects (DMFT = 0) were compared. FCN2 SNPs were genotyped with PCR-RFLP methods. There were no significant differences in the genotype, allele, or haplotype distributions in 3 analyzed SNPs of the FCN2 gene between children with "higher" and those with "lower" caries experience as well as between children with caries experience and caries free children. In conclusion, we did not find any association of FCN2 promoter polymorphisms at positions -986, -602, and -4 with dental caries in Polish children. PMID- 28088795 TI - Influence of Intracranial Air on Electrode Position and Clinical Outcomes following Deep Brain Stimulation for Parkinson's Disease. AB - BACKGROUND: The introduction of intracranial air during deep brain stimulation (DBS) surgery is believed to negatively impact targeting accuracy and clinical outcomes. OBJECTIVE: To quantify the relationship between intracranial air (ICA) volumes, targeting accuracy, and clinical outcomes in patients undergoing subthalamic nucleus (STN) DBS for Parkinson's disease. METHODS: ICA in 73 consecutive STN DBS cases (146 leads) was measured by high-resolution CT and correlated with proximal lead bowing, electrode displacement, targeting accuracy, and clinical outcomes at 6 and 12 months. RESULTS: There was a statistically significant correlation of ICA volume (mean +/- SEM: 21.3 +/- 13.7 cm3) and proximal lead bowing (2.8 +/- 1.4 mm, r = 0.34, p = 0.01). There was no significant correlation of ICA with targeting error (2.0 +/- 1.2 mm), distal contact deviation (1.2 +/- 0.7 mm), motor Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III improvement at 6 months (42.3 +/- 4.5%) or 12 months (30.3 +/- 7.7%), or dopaminergic medication reduction at 6 months (44.7+/- 4.2%) or 12 months (32.9 +/- 5.9%). Comparison of top and bottom ICA quintile extremes also revealed no differences in these measures. CONCLUSIONS: Though the proximal DBS lead bends in association with ICA, movement of the distal contact, targeting error, and clinical outcomes are not affected by ICA. This unexpected finding is maintained at ICA quintile extremes. PMID- 28088796 TI - Lung Ultrasound and Chest X-Rays: Together to Improve the Diagnosis. PMID- 28088797 TI - Automated Interpretation of Pulmonary Function Tests in Adults with Respiratory Complaints. AB - BACKGROUND: The use of pulmonary function tests is primarily based on expert opinion and international guidelines. Current interpretation strategies are using predefined cutoffs for the description of a typical pattern. OBJECTIVES: We aimed to explore the predicted disease outcome based on the American Thoracic Society/European Respiratory Society (ATS/ERS) interpreting strategy. Subsequently, we investigated whether an unbiased machine learning framework integrating lung function with clinical variables may provide alternative decision trees resulting in a more accurate diagnosis. METHODS: Our study included data from 968 subjects admitted for the first time to a pulmonary practice. The final clinical diagnosis was based on the combination of complete pulmonary function with the investigations that were decided at the physician's discretion. Clinical diagnoses were separated into 10 different groups and validated by an expert panel. RESULTS: The ATS/ERS algorithm resulted in a correct diagnostic label in 38% of the subjects. Chronic obstructive pulmonary disease (COPD) was detected with an acceptable accuracy (74%), whereas all other diseases were poorly identified. The new data-based decision tree improved the general accuracy to 68% after 10-fold cross-validation when detecting the most common lung diseases, with a significantly higher positive predictive value and sensitivity for COPD, asthma, interstitial lung disease, and neuromuscular disorder (83/78, 66/82, 52/59, and 100/54%, respectively). CONCLUSIONS: Our data show that the current algorithms for lung function interpretation can be improved by a computer-based choice of lung function and clinical variables and their decision-making thresholds. PMID- 28088798 TI - The Intracranial-B2LEED3S Score and the Risk of Intracranial Hemorrhage in Ischemic Stroke Patients Under Antiplatelet Treatment. AB - BACKGROUND: Chronic antiplatelet therapy in the post-acute phase of non cardioembolic ischemic stroke is limited by the risk of intracranial hemorrhage (ICH) complications. METHODS: We developed an ICH risk score based on the PERFORM trial cohort (n = 19,100), which included patients with a non-cardioembolic ischemic stroke or transient ischemic attack, and externally validated this score in one contemporary trial of very similar size and inclusion criteria, the PRoFESS trial (n = 20,332 patients). Outcome was ICH over 2 years. A Cox proportional-hazard regression analysis identified risk factors. Discrimination was quantified with c-statistics and calibration was assessed by comparing predicted and observed ICH risk in PERFORM and PRoFESS. RESULTS: ICH occurred within 2 years in 263 (1.4%) patients in PERFORM trial and in 246 (1.2%) patients in PRoFESS trial. A 13-point score based on 9 items (Intracranial-B2LEED3S score low body mass index, blood pressure, lacune, elderly, Asian ethnicity, coronary artery or cerebrovascular disease history, dual antithrombotic agent or oral anticoagulant, gender) was derived from the PERFORM trial. In PERFORM, the observed 2-year ICH risk varied from 0.75% in low-risk (score <=2) to 2.44% in high-risk patients (score >=5) with an acceptable calibration but a low discrimination both in PERFORM (c-statistic 0.64, 95% CI 0.61-0.68) and on external validation in PRoFESS (0.58, 95% CI 0.55-0.62). CONCLUSION: The Intracranial-B2LEED3S score helps identify patients who are at a high risk of bleeding. However, other variables need to be identified to improve the score (e.g., microbleeds) (Clinical Trial Registration Information ISRCTN66157730). URL: http://www.isrctn.com/ISRCTN66157730?totalResults=5&pageSize=10&page=1&searchType basic search&offset=3&q=&filters=conditionCategory%3ACirculatory+System%2CrecruitmentCo ntry%3ATaiwan%2CrecruitmentCountry%3AAustria&sort=. PMID- 28088799 TI - Use of Spinal Cord Diffusion Tensor Imaging to Quantify Neural Ablation and Evaluate Outcome after Percutaneous Cordotomy for Intractable Cancer Pain. AB - BACKGROUND: Up to 20% of patients experience only partial pain relief after percutaneous cordotomy for cancer pain. OBJECTIVE: To determine whether diffusion tensor imaging (DTI) can quantify neural ablation and help evaluate early postoperative outcomes after cordotomy. METHODS: Patients undergoing percutaneous CT-guided cordotomy for intractable cancer pain were prospectively studied. Pre- and postoperative assessment was made using the visual analog scale (VAS) on pain and the pain severity scores of the Brief Pain Inventory Short Form. On postoperative day 1, DTI images of the high cervical spinal cord were obtained. DTI metrics were correlated with the number of ablations as well as early postoperative pain outcomes. RESULTS: Seven patients (4 male, mean age 53.8 +/- 4.6 years) were studied. Fractional anisotropy of the hemicord was significantly lower on the side of the lesion as compared to the contralateral side (0.54 +/- 0.03 vs. 0.63 +/- 0.03, p < 0.001). Mean diffusivity correlated with the improvement in the VAS score at 1 week (r = 0.88, 95% CI = 0.34-1.00, p = 0.008), as well as the change in pain severity scores at 1 week (r = 0.99, 95% CI = 0.82 1.00, p < 0.001). CONCLUSION: DTI metrics are sensitive to the number of ablations as well as early improvement in pain scores after cordotomy. DTI of the cervical spinal cord is a potential biomarker of neural ablation after percutaneous cordotomy for intractable cancer pain. PMID- 28088800 TI - Repeatability and Reproducibility of Foveal Avascular Zone Area Measurements Using AngioPlex Spectral Domain Optical Coherence Tomography Angiography in Healthy Subjects. AB - PURPOSE: The aim of this study was to evaluate the repeatability and reproducibility of foveal avascular zone (FAZ) area measurements using AngioPlex spectral domain optical coherence tomography (OCT) angiography in normal subjects. METHODS: Twenty-two healthy subjects (25 eyes) underwent FAZ area measurements with AngioPlex OCT. Each volunteer was separately examined 3 consecutive times by the 2 experienced observers. The FAZ area was measured using ImageJ software. Intraobserver repeatability was evaluated by calculating the coefficient of variation (CoV) and intraclass correlation coefficient (ICC). Interobserver reproducibility was also assessed using the Bland-Altman test and concordance correlation coefficient (CCC). RESULTS: The FAZ areas were measured as 0.373 +/- 0.109 and 0.377 +/- 0.112 mm2 by observers 1 and 2, respectively. The repeatability assessment of the FAZ area measurements yielded CoV values of 0.029 and 0.034 and ICC values of 0.997 and 0.996 by observers 1 and 2, respectively. The mean difference between the 2 observers was 0.004. CCC values ranged from 0.9705 to 0.9844. CONCLUSIONS: The FAZ area measurements obtained using AngioPlex OCT showed a good repeatability and reproducibility in healthy subjects. Excellent reliability makes AngioPlex OCT a valid device for measuring the FAZ area. PMID- 28088801 TI - Natural History of Untreated Hemifacial Spasm: A Study of 104 Consecutive Patients over 5 Years. AB - BACKGROUND: The natural history without treatment of a large series of hemifacial spasm (HFS) patients has not been well-documented. OBJECTIVE: The purpose of this study was to characterize the natural history and clinical outcome in patients with HFS. METHODS: The initial visits of all 2,155 patients and the diagnosis of HFS took place between 2001 and 2010. In 1,775 of the patients, compressing vessels were identified on magnetic resonance imaging. Of these, we excluded 1,469 patients (82.8%) who received microvascular decompression, 101 (5.7%) who continued to visit the clinic for botulinum toxin injections, and 9 (0.5%) who died or suffered from other diseases. Ninety-two (5.2%) of the patients were lost to follow-up; the remaining 104 were followed up for 5-42 years (mean 12 years) after the onset of the symptoms of HFS. RESULTS: The condition was aggravated in 11 (10.6%) of the 104 patients and stationary in 40 (38.5%) for 6-42 years (mean 13 years). Ten (9.6%) improved partially for 7-18 years (mean 11 years). Forty three (41.3%) were in remission for between 2 months and 23 years (mean 6.4 years) after onset and required no further treatment for 5 months to 13 years (mean 5.7 years). CONCLUSION: This study provides useful information to HFS patients for understanding the disease and determining treatment. PMID- 28088802 TI - Interplay between Cortical Spreading Depolarization and Seizures. AB - Cortical spreading depolarization (CSD) is an electrophysiologic phenomenon found mostly in the setting of neurologic injury resulting in the disturbance of ion homeostasis and leading to changes in the local vascular response. The bioelectric etiology of CSD shares similarities to those in epileptic disorders, yet the relationship between seizures and CSD is unclear, with several studies observing cortical depression before, during, and after seizure activity, thus obscuring our understanding of whether CSD activity potentiates or limits seizures and vice versa. Cortical sampling has exhibited how the redistribution of ion concentrations in the intra- and extracellular environments interplay between the excitation of seizures and the electrical depression of CSD. Modeling of both environments has suggested that CSD synchronizes the affected tissue, creating a favorable environment for seizure activity; however, other studies have demonstrated the opposite: epileptiform activity initiating waves of CSD. Further studies have underscored the role of the vascular response and subsequent ischemia in CSD that contributes to epileptogenesis. Investigations in migraine, traumatic brain injury, and other neurologic injuries suggest that several drugs may target CSD. Manipulations in the occurrence and nature of CSD can potentially alter the threshold for seizure activity, and perhaps minimize immediate and long term sequelae associated with epilepsy. PMID- 28088803 TI - Small versus Large Ruptured Intracranial Aneurysm: Concerns with the Site of Aneurysm. AB - BACKGROUND: Although size is one of the strongest predictors, small aneurysms often rupture. We compared the characteristics of small and large ruptured intracranial aneurysms (RIAs) according to their location to find the factors associated with small RIAs in each location. METHODS: Patients with subarachnoid hemorrhage due to saccular RIAs were consecutively enrolled. The sizes were dichotomized as small (<5 mm) or large, and the location was classified as paraclinoid-distal internal carotid artery, sidewalls of anterior or middle cerebral artery (MCA; sidewall), MCA-bifurcation, anterior or posterior communicating artery (Acom or Pcom, respectively), and posterior circulation RIAs. Independent factors associated with small RIAs compared to large RIAs were investigated in each location. RESULTS: Small RIAs were observed in 384 of 791 patients (48.5%), and were most commonly located at Acom (17.1%) followed by Pcom (9.0%) and sidewalls (7.2%). Female sex (OR 3.038; 95% CI 2.099-4.395), young age (OR 0.971; 95% CI 0.958-0.985), hypertension (OR 1.412; 95% CI 1.033-1.930) and multiple aneurysms (OR 1.942; 95% CI 1.335-2.824) were associated with small RIAs. By location, sidewall aneurysms (OR 2.183; 95% CI 1.049-4.542) were associated with small RIAs, whereas MCA-bifurcation (OR 0.318; 95% CI 0.168 0.599) and Pcom aneurysms (OR 0.511; 95% CI 0.277-0.944) were associated with large RIAs. The presence of multiple aneurysms (OR 4.69; 95% CI 1.45-21.19) was associated with small RIAs at sidewalls, and young age, female sex, hypertension and the presence of bilateral A1 (OR 1.85; 95% CI 1.09-3.13) were associated with small RIAs at Acom. Acom RIAs with bilateral A1 was smaller than those with unilateral A1 (4.7 +/- 2.1 vs. 5.8 +/- 2.6 mm; p < 0.001). CONCLUSIONS: Intracranial aneurysms which rupture below 5 mm are not uncommon, and the factors associated with small-sized RIAs differ according to location. Sidewall aneurysms, with multiple aneurysms and Acom aneurysms with bilateral A1 may rupture even at small size. PMID- 28088804 TI - Monitoring Noninvasive Ventilation in Patients with Obesity Hypoventilation Syndrome: Comparison between Ventilator Built-in Software and Respiratory Polygraphy. AB - BACKGROUND: Polygraphy (PG) remains the standard method of assessing noninvasive ventilation (NIV) effectiveness. Built-in software (BIS) of recent NIV equipment provides estimates of some ventilator parameters, but their usefulness is unclear. OBJECTIVES: To assess the reliability of BIS compared with PG in a cohort of obesity hypoventilation syndrome (OHS) patients on NIV. METHODS: Thirty stable OHS patients on NIV were evaluated in an outpatient setting with simultaneous PG and BIS recordings. The automated apnea-hypopnea event index (EIAUT) provided by Rescan and manual scoring based on available traces obtained from the software (EIBIS) were compared with manual PG scoring (EIPG). Each manual scoring was separately performed by 2 trained operators. Agreement between the 2 operators was assessed using the kappa coefficient. Pearson correlation and Bland-Altman plots were used to evaluate agreement between EIAUT, EIBIS, and EIPG. RESULTS: Twenty-six cases were valid for analysis (age +/-61 years, 17 men). All patients were ventilated in the spontaneous/timed mode (mean inspiratory positive airway pressure 17 +/- 3 cm H2O, mean expiratory positive airway pressure 10 +/- 3 cm H2O). Cohen's kappa agreement between the operators was 0.7 for EIBIS and 0.84 for EIPG. EIBIS showed good correlation with EIPG (r2 = 0.79 p < 0.001), better than scoring provided by the automated analysis (r2 = 0.71, p < 0.006 for EIAUT vs. EIPG). CONCLUSIONS: In stable OHS patients on NIV, unattended home-based monitoring using Rescan is reproducible and reliable to assess quality of ventilation when compared with PG. In addition, manual scoring of events using data obtained with this device is more consistent than software based automated analysis. PMID- 28088806 TI - Effects of Aloe Sterol Supplementation on Skin Elasticity, Hydration, and Collagen Score: A 12-Week Double-Blind, Randomized, Controlled Trial. AB - BACKGROUND/AIMS: Our previous study confirmed that Aloe sterol stimulates collagen and hyaluronic acid production in human dermal fibroblasts. This study aims to investigate whether Aloe sterol intake affects skin conditions. METHODS: We performed a 12-week, randomized, double-blind, placebo-controlled study to evaluate the effects of oral Aloe sterol supplementation on skin elasticity, hydration, and the collagen score in 64 healthy women (age range 30-59 years; average 44.3 years) who were randomly assigned to receive either a placebo or an Aloe sterol-supplemented yogurt. Skin parameters were measured and ultrasound analysis of the forearm was performed. RESULTS: ANCOVA revealed statistical differences in skin moisture, transepidermal water loss, skin elasticity, and collagen score between the Aloe sterol and placebo groups. The gross elasticity (R2), net elasticity (R5), and biological elasticity (R7) scores of the Aloe sterol group significantly increased with time. In addition, skin fatigue area F3, which is known to decrease with age and fatigue, also increased with Aloe sterol intake. Ultrasound echogenicity revealed that the collagen content in the dermis increased with Aloe sterol intake. CONCLUSION: The results suggest that continued Aloe sterol ingestion contributes to maintaining healthy skin. PMID- 28088805 TI - A Retrospective Analysis of Stereoelectroencephalography and Subdural Electroencephalography for Preoperative Evaluation of Intractable Epilepsy. AB - BACKGROUND: Different methods for intracranial electrode recording have various advantages and disadvantages, and controversy exists regarding the complications of stereoelectroencephalography (SEEG) and subdural EEG. OBJECTIVE: The purpose of this study was to determine the efficacy and safety of SEEG by comparing it with subdural EEG. METHODS: Data from 100 patients who underwent SEEG (n = 48) and subdural EEG (n = 52) to evaluate the epileptogenic zone were collected from June 2011 to June 2015. The evaluation results, surgical outcomes, and complications were compared. RESULTS: No significant differences were noted between the SEEG and subdural EEG groups in identifying the epileptogenic zone or undergoing epileptic surgery. Of the 88 patients who underwent epilepsy surgery after assessment, 59.5% in the SEEG group and 52.2% in the subdural EEG group became seizure free. No significant differences in postoperative seizure control or intelligence improvement were noted. The overall complication rate in SEEG patients (8/48; 16.7%) was lower than that in subdural EEG patients (13/52; 25%), particularly for hemorrhage and infection (4.2 vs. 17.3%, p < 0.05). CONCLUSIONS: This retrospective review indicates that SEEG has low associated complications, particularly regarding hemorrhage and infection. SEEG is a safe and effective method for intracranial monitoring. PMID- 28088807 TI - Posterior versus Anterior Circulation Stroke in Young Adults: A Comparative Study of Stroke Aetiologies and Risk Factors in Stroke among Young Fabry Patients (sifap1). AB - BACKGROUND: Although 20-30% of all strokes occur in the posterior circulation, few studies have explored the characteristics of patients with strokes in the posterior compared to the anterior circulation so far. Especially data on young patients is missing. METHODS: In this secondary analysis of data of the prospective multi-centre European sifap1 study that investigated stroke and transient ischemic attack (TIA) patients aged 18-55 years, we compared vascular risk factors, stroke aetiology, presence of white matter hyperintensities (WMH) and cerebral microbleeds (CMB) between patients with ischaemic posterior circulation stroke (PCS) and those having suffered from anterior circulation stroke (ACS) based on cerebral MRI. RESULTS: We diagnosed PCS in 612 patients (29.1%, 407 men, 205 women) and ACS in 1,489 patients (70.9%). Their age (median 46 vs. 47 years, p = 0.205) and stroke severity (modified Rankin Scale: both 2, p = 0.375, Barthel Index 90 vs. 85, p = 0.412) were similar. PCS was found to be more frequent among the male gender (66.5 vs. 60.1% with ACS, p = 0.003). Vertebral artery (VA) dissection was more often the cause of PCS (16.8%) than was carotid artery dissection of ACS (7.9%, p < 0.001). Likewise, small vessel disease (Trial of Org 10172 in Acute Stroke Treatment [TOAST] = 3, PCS: 14.7%, ACS: 11.8%) and stroke of other determined aetiology (TOAST = 4, PCS: 24.5%, ACS: 16.0%) were more frequent in those with PCS. Furthermore, patent foramen ovale (PFO; PCS: 31.1%, ACS: 25.4%, p = 0.029) was more often detected in patients with PCS. In contrast, large-artery atherosclerosis (TOAST = 1, PCS: 15.4%, ACS: 22.2%) and cardio-embolic stroke (TOAST = 2, PCS: 15.6%, ACS: 18.0%) were less frequent in those with PCS (p < 0.001) as were preceding cerebrovascular events (10.1 vs. 14.1%, p = 0.014), TIA (4.8 vs. 7.7%, p = 0.016) and smoking (53.2 vs. 61.0%, p = 0.001). The presence, extent, and location of WMH and CMB did not differ between the 2 groups. CONCLUSIONS: Our data suggested a different pattern of aetiology and risk factors in young patients with PCS compared to those with ACS. These findings especially call for a higher awareness of VA dissection and potentially for more weight of a PFO as a risk factor in young patients with PCS. Clinical trial registration-URL: http://www.clinicaltrials.gov; NCT00414583. PMID- 28088808 TI - Shunt Surgery in Idiopathic Intracranial Hypertension Aided by Electromagnetic Navigation. AB - BACKGROUND: Idiopathic intracranial hypertension (IIH) is characterized by increased cerebrospinal fluid (CSF) pressure and normal or slit ventricles. Lumboperitoneal shunting had been favored by many investigators for CSF diversion in IIH for decades; however, it has been associated with various side effects. Because of the small ventricular size adequate positioning of a ventricular catheter is challenging. OBJECTIVES: Here, we investigated the usefulness of electromagnetic (EM)-guided ventricular catheter placement for ventriculoperitoneal shunting in IIH. METHODS: Eighteen patients with IIH were included in this study. The age of patients ranged from 5 to 58 years at the time of surgery (mean age: 31.8 years; median: 29 years). There were 2 children (5 and 11 years old) and 16 adults. Inclusion criteria for the study were an established clinical diagnosis of IIH, lack of improvement with medication, and the presence of small ventricles. In all patients EM-navigated placement of the ventricular catheter was performed using real-time tracking of the catheter tip for exact positioning close to the foramen of Monro. Postoperative CT scans were correlated with intraoperative screen shots to validate the position of the catheter. RESULTS: In all patients EM-navigated ventricular catheter placement was achieved with a single pass. There were no intraoperative or postoperative complications. Postoperative imaging confirmed satisfactory positioning of the ventricular catheter. No proximal shunt failure was observed during the follow-up at a mean of 41.5 months (range: 7-90 months, median: 40.5 months). CONCLUSIONS: EM navigated ventricular catheter placement in shunting for IIH is a safe and straightforward technique. It obviates the need for sharp head fixation, the head of the patient can be moved during surgery, and it may reduce the revision rate during follow-up. PMID- 28088809 TI - Fibroblast Growth Factor Receptor 1 (FGFR1), Partly Related to Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) and Microvessel Density, is an Independent Prognostic Factor for Non-Small Cell Lung Cancer. AB - BACKGROUND This study aimed to explore the correlation between FGFR1 and clinical features, including survival analysis and the promotion of angiogenesis by fibroblast growth factor receptor 1 (FGFR1) and vascular endothelial growth factor receptor 2 (VEGFR2). FGFR1 gene amplification has been found in non-small cell lung cancer (NSCLC). However, the prognostic value of FGFR1 and the correlation between FGFR1 and clinical features are still controversial. MATERIAL AND METHODS A total of 92 patients with NSCLC who underwent R0 resection between July 2006 and July 2008 were enrolled in the study. The expression of FGFR1, VEGFR2, and CD34 was detected by immunohistochemistry. The correlations between the aforementioned markers and the patients' clinical features were analyzed by the chi-square test. The impact factors of prognosis were evaluated by Cox regression analyses. RESULTS The expression ratios of FGFR1 and VEGFR2 were 26.1% and 43.4%, respectively. The intensity of FGFR1 expression was related to VEGFR2 and histopathology. To some extent, the average microvessel density (MVD) had correlation to the expression of FGFR1 and VGEFR2. The pathological stages III-IV and high expression of FGFR1 were found to be independent prognostic factors. CONCLUSIONS The expression intensity of FGFR1 and VEGFR2 was associated with MVD, and the expression of FGFR1 is one of the independent prognostic indicators for NSCLC. PMID- 28088810 TI - Leptin Influences Healing in the Sprague Dawley Rat Fracture Model. AB - BACKGROUND Leptin plays a crucial role in bone metabolism, and its level is related to bone callus formation in the fracture repair process. The objective of this study was to evaluate the effect of recombinant leptin on the healing process of femoral fractures in rats. MATERIAL AND METHODS Forty-eight male Sprague Dawley (SD) rats with an average body weight of 389 g (range: 376-398 g) and an average age of 10 weeks were included in this animal research, and all rats were randomly divided into two major groups. Then standardized femur fracture models were implemented in all SD rats. Rats in the control group were treated with only 0.5 mL of physiological saline, and rats in the experimental group were treated with recombinant leptin 5 MUg/kg/d along with the same 0.5 mL of physiological saline for 42 days intraperitoneally. At the same time, each major group was evenly divided into three parallel subgroups for each parallel bone evaluation separately at the second, fourth, and sixth weeks. Each subgroup included eight rats. RESULTS The total radiological evaluation results showed that the healing progress of femoral fracture in the experimental group was superior to that in the control group from the fourth week. At the sixth week, experimental group rats began to present significantly better femoral fracture healing progress than that of the control group rats. Results of biomechanics show the ultimate load (N) and deflection ultimate load (mm) of the experimental group rats was significantly increased compared with that of the control group rats from the fourth week. CONCLUSIONS Our results suggest that leptin may have a positive effect on SD rat femur fracture healing. PMID- 28088811 TI - Secondary Hypertension, Erythrocytosis, and Unilateral Renal Cystic Disease in a Submariner: A Case Report. AB - Erythrocytosis, or increased red blood cell mass, may be primary as in the case of polycythemia vera (PV), or secondary due to a variety of causes related to erythropoietin (EPO) secretion and hypoxia. Chronic pulmonary disease and certain EPO-secreting tumors should be addressed and excluded early during the course of evaluation for a patient presenting with increased red blood cell mass. Inclusion of the JAK2 V617F gene mutation in the recent World Health Organization criteria for the diagnosis of PV allows for facilitated diagnosis and guides therapy. EPO levels can be helpful in diagnosis and guiding therapy, but in the case of cystic renal diseases, EPO levels are often not elevated, creating diagnostic uncertainty. This report describes a case of symptoms directly attributable to erythrocytosis in the setting of negative JAK2 mutation and normal EPO levels. The subsequent discovery of a large cystic renal kidney and PV were the leading diagnostic considerations. PMID- 28088812 TI - Learning Curves of Emergency Tourniquet Use Exploring for Utility in Training. AB - BACKGROUND: Emergency tourniquet use to control hemorrhage from limb wounds is associated with improved survival and control of shock. In 2013, we introduced a way to measure learning curves of tourniquet users. With a dataset from an unrelated study, we had an opportunity to explore learning in detail. The study aim was to generate hypotheses about measurement methods in the learning of tourniquet users. METHODS: We gathered data from a previous experiment that yielded a convenient sample of repeated tourniquet applications used as a marker of learning. Data on consecutive applications on a manikin were used in the current report and were associated with two users, three models of tourniquet, and six metrics (i.e., effectiveness, pulse cessation, blood loss, time to effectiveness, windlass turn number, and pressure applied). There were 840 tests (140 tests per user, two users, three models). RESULTS: Unique characteristics of learning were associated with each user. Hypotheses generated included the following: trainee learning curves can vary in shape (e.g., flat, curved) by which metric of learning is chosen; some metrics may show much learning, whereas others show almost none; use of more than one metric may assess more comprehensively than using only one metric but may require more assessment time; number of uses required can vary by instructional goal (e.g., expertise, competence); awareness of the utility of specific metrics may vary by instructor; and some, but not all, increases in experience are associated with improved performance. CONCLUSIONS: This first-aid study generated hypotheses about caregiver learning for further study of tourniquet education and standards. PMID- 28088813 TI - Significant Pressure Loss Occurs Under Tourniquets Within Minutes of Application. AB - BACKGROUND: Pressure decreases occur after tourniquet application, risking arterial occlusion loss. Our hypothesis was that the decreases could be mathematically described, allowing creation of evidence-based, tourniquet reassessment- time recommendations. METHODS: Four tourniquets with width (3.8cm, 3.8cm, 13.7cm, 10.4cm), elasticity (none, none, mixed elastic/nonelastic, elastic), and mechanical advantage differences (windlass, ratchet, inflation, recoil) were applied to 57.5cm-circumference 10% and 20% ballistic gels for 600 seconds and a 57.5cmcircumference thigh and 31.5cm-circumference arm for 300 seconds. Time 0 target completion-pressures were 262mmHg and 362mmHg. RESULTS: Two-phase decay equations fit the pressure-loss curves. Tourniquet type, gel or limb composition, circumference, and completionpressure affected the curves. Curves were clinically significant with the nonelastic Combat Application Tourniquet (C-A-T), nonelastic Ratcheting Medical Tourniquet (RMT), and mixed elastic/nonelastic blood pressure cuff (BPC), and much less with the elastic Stretch Wrap And Tuck-Tourniquet (SWATT). At both completion-pressures, pressure loss was faster on 10% than 20% gel, and even faster and greater on the thigh. The 362mmHg completion-pressure had the most pressure loss. Arm curves were different from thigh but still approached plateau pressure losses (maximal calculated losses at infinity) in similar times. With the 362mmHg completion pressure, thigh curve plateaus were -68mmHg C-A-T, -62mmHg RMT, -34mmHg BPC, and 13mmHg SWATT. The losses would be within 5mmHg of plateau by 4.67 minutes C-A-T, 6.00 minutes RMT, 4.98 minutes BPC, and 6.40 minutes SWATT and within 1mmHg of plateau by 8.18 minutes C-A-T, 10.52 minutes RMT, 10.07 minutes BPC, and 17.68 minutes SWATT. Timesequenced images did not show visual changes during the completion to 300 or 600 seconds pressure-drop interval. CONCLUSION: Proper initial tourniquet application does not guarantee maintenance of arterial occlusion. Tourniquet applications should be reassessed for arterial occlusion 5 or 10 minutes after application to be within 5mmHg or 1mmHg of maximal pressure loss. Elastic tourniquets have the least pressure loss. PMID- 28088814 TI - Postural Stability of Special Warfare Combatant-Craft Crewmen With Tactical Gear. AB - BACKGROUND: The US Naval Special Warfare's Special Warfare Combatant-Craft Crewmen (SWCC) operate on small, high-speed boats while wearing tactical gear (TG). The TG increases mission safety and success but may affect postural stability, potentially increasing risk for musculoskeletal injury. Therefore, the purpose of this study was to examine the effects of TG on postural stability during the Sensory Organization Test (SOT). METHODS: Eight SWCC performed the SOT on NeuroCom's Balance Manager with TG and with no tactical gear (NTG). The status of gear was performed in randomized order. The SOT consisted of six different conditions that challenge sensory systems responsible for postural stability. Each condition was performed for three trials, resulting in a total of 18 trials. RESULTS: Overall performance, each individual condition, and sensory system analysis (somatosensory, visual, vestibular, preference) were scored. Data were not normally distributed therefore Wilcoxon signed-rank tests were used to compare each variable (rho = .05). No significant differences were found between NTG and TG tests. No statistically significant differences were detected under the two TG conditions. This may be due to low statistical power, or potentially insensitivity of the assessment. Also, the amount and distribution of weight worn during the TG conditions, and the SWCC's unstable occupational platform, may have contributed to the findings. The data from this sample will be used in future research to better understand how TG affects SWCC. CONCLUSION: The data show that the addition of TG used in our study did not affect postural stability of SWCC during the SOT. Although no statistically significant differences were observed, there are clinical reasons for continued study of the effect of increased load on postural stability, using more challenging conditions, greater surface perturbations, dynamic tasks, and heavier loads. PMID- 28088815 TI - Trigger-Point Dry Needling for the SOF Medic. AB - We propose that trigger-point dry needle (TrP-DN) therapy is an effective low risk treatment for pain associated with myofascial trigger points (MTrP), and should be incorporated into the Special Operations Forces (SOF) Medic's scope of practice. Furthermore, TrP-DN therapy can be used as a treatment adjunct on the SOF continuum of care, providing analgesia and increased tolerance for rehabilitative therapy, thereby facilitating improved patient outcomes and faster return to operational readiness. The incidence of musculoskeletal injuries in the SOF community is discussed, as are available treatment options TrP-DN methods, a case study of a Soldier deployed to Afghanistan, the science behind the subject of MTrP and TrP-DN, and the risks associated with TrP-DN and how we can mitigate them effectively. Caution should be used in the interpretation of a body of literature based largely on case studies. Although the amount of published evidence in support of the potential benefits of TrP-DN is growing, larger, randomized, placebo-controlled trials and studies that evaluate the effects of TrP-DN in a methodologically rigorous and statistically significant way are needed. Based on anecdotal evidence of and personal experience with the success of the therapy, as well as its growing use within both civilian and military medicine, the possible therapeutic benefit of TrP-DN is relevant for the SOF community. PMID- 28088816 TI - Continuous One-Arm Kettlebell Swing Training on Physiological Parameters in US Air Force Personnel: A Pilot Study. AB - BACKGROUND: The primary aim of this study was to investigate the effects of continuous one-arm kettlebell (KB) swing training on various US Air Force physical fitness testing components. Thirty trained male (n = 15) and female (n = 15) US Air Force (USAF) personnel volunteered and were sequentially assigned to one of three groups based on 1.5-mile run time: (1) KB one-arm swing training, (2) KB one-arm swing training plus highintensity running (KB + run), and (3) traditional USAF physical training (PT) according to Air Force Instruction 36 2905. METHODS: The following measurements were made before and after 10 weeks of training: 1.5-mile run, 1-minute maximal push-ups, 1-minute maximal situps, maximal grip strength, pro agility, vertical jump, 40-yard dash, bodyweight, and percent body fat. Subjects attended three supervised exercise sessions per week for 10 weeks. During each exercise session, all groups performed a 10-minute dynamic warm-up followed by either (1) 10 minutes of continuous KB swings, (2) 10 minutes of continuous kettlebell swings plus 10 minutes of high-intensity running, or (3) 20 minutes of moderate intensity running plus push-ups and sit ups. Average and peak heart rate were recorded for each subject after all sessions. Paired t tests were conducted to detect changes from pretesting to posttesting within each group and analysis of variance was used to compare between-group variability (rho <= .05). RESULTS: Twenty subjects completed the study. There were no statistically significant changes in 1.5-mile run time between or within groups. The 40- yard dash significantly improved within the KB swing (rho <= .05) and KB + run group (rho <= .05); however, there were no significant differences in the traditional PT group (rho <= .05) or between groups. Maximal push-ups significantly improved in the KB + run group (rho <= .05) and trends toward significant improvements in maximal push-ups were found in both the KB (rho = .057) and traditional PT (rho = .067) groups. CONCLUSIONS: This study suggests that continuous KB swing training may be used by airmen as a high-intensity, low-impact alternative to traditional USAF PT to maintain aerobic fitness and improve speed and maximal push-ups. PMID- 28088817 TI - Mitigating Exertional Heat Illness in Military Personnel: The Science Behind a Rice-Based Electrolyte and Rehydration Drink. AB - BACKGROUND: Exertional heat illness continues to be prevalent among members of active duty personnel, especially those in specific military occupational specialties such as loadmasters, flight crew, flight maintainers, and Special Operations Forces. Therefore, the primary objective of this article was to elucidate the various oral rehydration solutions (ORSs) on the market that are used to mitigate exertional heat illness (EHI) in military personnel, and to focus on the science behind a ricebased electrolyte drink, CeraSport(r), currently used by US military personnel in mitigating EHI during sustained training operations in high-heat environments. METHODS: A search of the literature (through March 2016) was performed using PubMed and ProQuest, in addition to searching bibliographies and text books. We reviewed 63 articles and three texts. Articles were limited to those published in English and to studies that used only carbohydrates (e.g., no amino acids) and drinks reported to be used by the military in field training and deployment. CONCLUSION: Heat illness is prevalent among military personnel operating in high-heat environments and a variety of ORSs and sports drinks are available to help mitigate this. However, CeraSport, compared with other ORSs and sports drinks, may offer benefits such as faster gastric emptying rates and improved absorption from the gastrointestinal tract, which can provide rapidly available carbohydrate substrates for energy needs, and increased water retention for maintenance of blood plasma volume. PMID- 28088818 TI - Red-Green Versus Blue Tactical Light: A Direct, Objective Comparison. AB - BACKGROUND: Success in Special Operations Forces medicine (SOFMED) depends on maximizing visual capability without compromising the provider or casualty when under fire. There is no single light that has been deemed "ideal" for all SOFMED environments. METHODS: We used the Farnsworth-Munsell (FM) hue test to determine color vision of normal subjects under white, red-green, and blue flashlights to determine color discrimination. Then we used a timed color-determination visual test to determine how quickly normal subjects can identify color correctly. We had subjects perform a simulated surgery illuminated by a normal white-light source, then by red-green or blue light-emitting diode (LED) tactical light. RESULTS: The total error score for white light was 49.714, 272.923 for red/green light, and 531.4 for blue light. The subjective perception of simulated trauma wounds was not substantially different with red-green LED tactical light when compared with white LED light. However, simulated surgery under the blue LED was more difficult compared with simulated surgery under the red-green LED light. CONCLUSION: Red-green was a superior light source for SOFMED and military first responders in this study, especially, where light was required to allow accurate and efficient application of Tactical Combat Casualty Care to injured personnel. PMID- 28088819 TI - Pretrauma Interventions in Force Health Protection: Introducing the "Left of Bang" Paradigm. PMID- 28088820 TI - Caffeine and Performance. AB - The role of caffeine in enhancing performance has been studied for years, and there is no doubt that caffeine can be performance enhancing. Also, a wealth of information allows for an interesting distinction between physical and cognitive performance. Most adults in America consume moderate doses of caffeine in various forms on a daily basis as caffeine is typically found in coffee, tea, soft drinks, dietary supplements, energy drinks, energy shots, and chocolate, as well as over-the-counter pills and gums. Although caffeine is readily available and widely consumed, when using it to enhance performance, a few factors should be considered. The authors discuss caffeine use among Servicemembers, its properties and effects on physical and cognitive performance, how to use it to optimize performance, and, finally, some of safety and regulatory considerations. The bottom line is that all individuals do not respond the same way to caffeine and their response depends on how the body uses and breaks down caffeine. Thus, as a user, you should monitor your own responses and performance changes when using caffeine based on the general recommendations provided. PMID- 28088821 TI - Tularemia. PMID- 28088822 TI - Load Carriage-Related Paresthesias: Part 1: Rucksack Palsy and Digitalgia Paresthetica. AB - This is the first of a two-part article discussing loadcarriage- related paresthesias, including brachial plexus lesions (rucksack palsy), digitalgia paresthetica, and meralgia paresthetica. Paresthesias are sensations of numbness, burning, and/or tingling, usually experienced as a result of nerve injury, compression, traction, or irritation. Rucksack palsy is a traction or compression injury to the brachial plexus, caused by the shoulder straps of the rucksack. The patient presents with paresthesia, paralysis, cramping with pain, and muscle weakness of the upper limb. Muscle-strength losses appear to be greater in those carrying heavier loads. Hypothetical risk factors for rucksack palsy include improper load distribution, longer carriage distances, and load weight. Nerve traction, compression, and symptoms may be reduced by use of a rucksack hip belt; wider, better-padded, and proper adjustment of the shoulder straps; reduction of weight in the rucksack; a more symmetric distribution of the load; and resistance training to improve the strength and hypertrophy of the shoulder muscles. Assessment and neck joint and nerve mobilization may relieve brachial plexus tension and reduce symptoms. Another load-carriage-related disorder is digitalgia paresthetica, likely caused by compression of the sensory digital nerves in the foot during load carriage. Patients have paresthesia in the toes. Although no studies have demonstrated effective prevention measures for digitalgia paresthetica, reducing loads and march distances may help by decreasing the forces and repetitive stress on the foot and lower leg. Specialty evaluations by a physical therapist, podiatrist, or other healthcare provider are important to rule out entrapment neuropathies such as tarsal tunnel syndrome. Part 2 of this article will discuss meralgia paresthetica. PMID- 28088823 TI - Garlic Burn to the Face. AB - Topical burns from the use of garlic have been reported rarely in the medical literature. Most cases have resulted from the use of naturopathic or home remedy treatments. A 20-year-old male military Servicemember presented to a military wound care clinic 7 days after applying a homemade topical preparation of garlic to the zygomatic region of the right side of his face. The patient had consulted the Internet for treatment of a minor skin lesion in that area. He created a garlic paste, applied it to the affected area, and covered it with a dressing. Twelve hours later, he noted an intense burning sensation where he had applied the garlic paste. After the initial blistering, the patient recovered without any additional treatment. Second-degree burns were an unintended consequence of the use of garlic as a home remedy. PMID- 28088825 TI - Prolonged Field Care for the Winter 2016 Edition. PMID- 28088824 TI - The Hidden Complexity of Biological "Dirty Bombs": Implications for Special Operations Medical Personnel. AB - The recent capture of a terrorist in Belgium carrying explosives, fecal matter, and animal tissue may indicate a shift from conventional weapons to crude bacteriological preparations as instruments of terror. It is important to note that although such weapons lack technological sophistication, bacteria are inherently complex, unpredictable, and undetectable in the field. Therefore, it is important that Special Operations medical personnel understand the complications that such seemingly simple devices can add to the treatment of casualties in the field and subsequent evaluation in the clinic. PMID- 28088826 TI - Management of Burn Wounds Under Prolonged Field Care. PMID- 28088827 TI - Prolonged Field Care of a Casualty With Penetrating Chest Trauma. AB - As Special Operations mission sets shift to regions with less coalition medical infrastructure, the need for quality long-term field care has increased. More and more, Special Operations Medics will be expected to maintain casualties in the field well past the "golden hour" with limited resources and other tactical limitations. This case report describes an extended-care scenario (>12 hours) of a casualty with a chest wound, from point of injury to eventual casualty evacuation and hand off at a Role II facility. This case demonstrates the importance of long-term tactical medical considerations and the effectiveness of minimal fluid resuscitation in treating penetrating thoracic trauma. PMID- 28088828 TI - Telemedicine to Reduce Medical Risk in Austere Medical Environments: The Virtual Critical Care Consultation (VC3) Service. AB - One of the core capabilities of prolonged field care is telemedicine. We developed the Virtual Critical Care Consult (VC3) Service to provide Special Operations Forces (SOF) medics with on-demand, virtual consultation with experienced critical care physicians to optimize management and improve outcomes of complicated, critically injured or ill patients. Intensive-care doctors staff VC3 continuously. SOF medics access this service via phone or e-mail. A single phone call reaches an intensivist immediately. An e-mail distribution list is used to share information such as casualty images, vital signs flowsheet data, and short video clips, and helps maintain situational awareness among the VC3 critical care providers and other key SOF medical leaders. This real-time support enables direct communication between the remote provider and the clinical subject matter expert, thus facilitating expert management from near the point of injury until definitive care can be administered. The VC3 pilot program has been extensively tested in field training exercises and validated in several real world encounters. It is an immediately available capability that can reduce medical risk and is scalable to all Special Operations Command forces. PMID- 28088829 TI - Case of a 5-Year-Old Foreign National Who Sustained Penetrating Abdominal Trauma. AB - OBJECTIVE: Review application of telemedicine support for penetrating trauma. Clinical context: Special Operations Resuscitation Team (SORT) deployed in Africa Area of Responsibility (AOR) Organic expertise: Internal Medicine physician, two Special Operations Combat medics (SOCMs), and one radiology technician Closest surgical support: Non-US surgical support 20km away; a nonsurgeon who will perform surgeries; neighboring country partner-force surgeon 2 hours by fixedwing flight. Earliest evacuation: Evacuated 4 days after presentation to a neighboring country with surgical capability. PMID- 28088830 TI - Embedded Fragment Removal and Wound Debridement in a Non-US Partner Force Soldier. AB - OBJECTIVE: Review application of telemedicine support for removal of fragment and wound management. Clinical context: Special Forces Operational Detachment- Alpha deployed in Central Command area of responsibility operating out of a small aid station ("house" phase of prolonged field care) Organic expertise: 18D Special Operations Combat medic Closest medical support: Combined Joint Special Operations Task Force (CJSOTF) surgeon located in another country; thus, all consults were either via telephone or over Secret Internet Protocol Router e mail. Earliest evacuation: NA. PMID- 28088831 TI - Ultrasound-Guided Triage. PMID- 28088832 TI - From the Trails of Afghanistan to the Streets of America: COL (Ret) Andy Pennardt on Frontline Medical Care. PMID- 28088833 TI - Portuguese 2nd Parachute Battalion. PMID- 28088834 TI - Committee on Tactical Combat Casualty Care 7-8 September 2016: Meeting Highlights. PMID- 28088835 TI - National TEMS Initiative and Council NTIC Competency Domains/The TACMED Challenge! PMID- 28088836 TI - Upregulation of long noncoding RNA TUG1 promotes cervical cancer cell proliferation and migration. AB - Long noncoding RNAs (lncRNAs), a novel class of transcripts that have critical roles in carcinogenesis and progression, have emerged as important gene expression modulators. Recent evidence indicates that lncRNA taurine-upregulated gene 1 (TUG1) functions as an oncogene in numerous types of human cancers. However, its function in the development of cervical cancer remains unknown. The aim of this research was to investigate the clinical significance and biological functions of TUG1 in cervical cancer. TUG1 was found to be significantly upregulated in cervical cancer tissues and four cervical cancer cell lines by quantitative real-time polymerase chain reaction (qRT-PCR). Elevated TUG1 expression was correlated with larger tumor size, advanced international federation of gynecology and obstetrics (FIGO) stage, poor differentiation, and lymph node metastasis. Furthermore, knockdown of TUG1 suppressed cell proliferation with activation of apoptosis, in part by regulating the expression of Bcl-2 and caspase-3. Silencing of TUG1 inhibited cell migration and invasion via the progression of epithelial-mesenchymal transition (EMT). Taken together, our findings indicate that TUG1 acts as an oncogene in cervical cancer and may represent a novel therapeutic target. PMID- 28088837 TI - Disease severity classification using quantitative magnetic resonance imaging data of cartilage in femoroacetabular impingement. AB - Femoroacetabular impingement (FAI) is a condition in which subtle deformities of the femoral head and acetabulum (hip socket) result in pathological abutment during hip motion. FAI is a common cause of hip pain and can lead to acetabular cartilage damage and osteoarthritis. For some patients with FAI, surgical intervention is indicated, and it can improve quality of life and potentially delay the onset of osteoarthritis. For other patients, however, surgery is contraindicated because significant cartilage damage has already occurred. Unfortunately, current imaging modalities (X-rays and conventional MRI) are subjective and lack the sensitivity to distinguish these two groups reliably. In this paper, we describe the pairing of T2* mapping data (an investigational, objective MRI sequence) and a spatial proportional odds model for surgically obtained ordinal outcomes (Beck's scale of cartilage damage). Each hip in the study is assigned its own spatial dependence parameter, and a Dirichlet process prior distribution permits clustering of said parameters. Using the fitted model, we produce a six-color, patient-specific predictive map of the entire acetabular cartilage. Such maps will facilitate patient education and clinical decision making. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28088838 TI - Re-evaluation of Phenotypic Expression in Differentiated-type Early Adenocarcinoma of the Stomach. AB - A total of 313 cases of differentiated-type early gastric adenocarcinomas, including 113 cases of small-sized carcinoma (5< * <=10 mm) and 121 cases of microcarcinoma (0< * <=5 mm), were examined immunohistochemically to clarify the phenotypic expressions. They were classified into four categories (gastric phenotype (G-type), intestinal phenotype, gastrointestinal phenotype, and null phenotype) by a two-step process: the phenotype based on an immunoprofile of mucin core proteins (MUCs) with CDX2 (w/.CDX2-assessment); and the phenotype of MUCs only (w/o.CDX2-assessment). CDX2 expression was observed in 89.1% (279/313); it was highly expressed in 87.6% (106/121) of microcarcinomas. MUC2 expression increased as tumor size increased (P < 0.05). Compared with w/o.CDX2-assessment, w/.CDX2-assessment showed significantly fewer G-type carcinomas (P < 0.05). Each phenotype marker was less expressed in the submucosal part than in the mucosal part. In conclusion, CDX2 was a sensitive marker for assessing intestinal phenotype. A large portion of the early differentiated-type adenocarcinomas expressed CDX2 from the very early stage of carcinogenesis, and the proportion of G-type was unexpectedly low. Lower expression of each phenotype marker was considered the cause of phenotype alteration during submucosal invasion. PMID- 28088839 TI - Pharmacokinetic/Pharmacodynamic Modeling of the PDE4 Inhibitor TAK-648 in Type 2 Diabetes: Early Translational Approaches for Human Dose Prediction. AB - TAK-648 is a PDE4 inhibitor with demonstrated preclinical antidiabetic properties. Our objective was to develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for human type 2 diabetes (T2D) dose prediction using HbA1c results from a db/db mouse study. Estimated parameters in combination with tPDE4i values calculated for the clinical roflumilast dose of 500 MUg were used to translate preclinical effects of TAK-648 to required exposure in humans. A first-in-human study with single TAK-648 doses of 0.05-0.85 mg in healthy volunteers yielded mean maximum TAK-648 concentrations (Cmax) and area under the curve (AUC) values from 0.62-11.9 MUg/L and 4.58-93.8 MUg*h/L, respectively. Based on the performed pharmacokinetic/pharmacodynamic analysis and clinical PK results, clinical efficacy would be expected at a daily dose of 0.1 mg, which is well within the investigated clinical dose range. This result significantly enhanced the confidence in TAK-648 for type 2 diabetes treatment and underlines the necessity of translational approaches in early preclinical phases. PMID- 28088840 TI - Evaluation of a Short-term Training Program in Bedside Emergency Ultrasound in Southwestern Tanzania. AB - OBJECTIVES: To evaluate the effect of a short-term training program in emergency ultrasound on physician skills and attitudes in southwestern Tanzania. METHODS: Eight registrar physicians at Mbeya Zonal Referral Hospital (Mbeya, Tanzania) underwent a 5-day course in bedside emergency ultrasound, focusing primarily on the focused assessment with sonography for trauma examination, including didactic sessions, practical sessions, and on-job training. The impact on ultrasound knowledge was assessed by pretest and posttest evaluations. Provider skill was evaluated by a standardized observed simulated patient encounter. Attitudes toward ultrasound training, utility, and self-confidence were assessed by a post training questionnaire. RESULTS: All 8 physicians who began the training completed the course and successfully passed their objective structured clinical examination. There was a statistically significant improvement in written ultrasound test scores from 31% to 66% (P < .01) after the course. Most trainees felt confident performing and interpreting a basic focused assessment with sonography for trauma examination at the end of the course, and 7 of 8 stated that they would consider paying tuition for similar courses in the future. Main concerns with the course revolved around insufficient time dedicated to practicing under supervision. CONCLUSIONS: Registrar physicians in Tanzania can effectively learn basic emergency ultrasound skills in a short-term training program. Similar future programs may consider heavier emphasis on practical hands on training with experts. Ongoing data collection is required to understand the true impact of such training on long-term ultrasound use and patient outcomes. PMID- 28088842 TI - Unbiased split variable selection for random survival forests using maximally selected rank statistics. AB - The most popular approach for analyzing survival data is the Cox regression model. The Cox model may, however, be misspecified, and its proportionality assumption may not always be fulfilled. An alternative approach for survival prediction is random forests for survival outcomes. The standard split criterion for random survival forests is the log-rank test statistic, which favors splitting variables with many possible split points. Conditional inference forests avoid this split variable selection bias. However, linear rank statistics are utilized by default in conditional inference forests to select the optimal splitting variable, which cannot detect non-linear effects in the independent variables. An alternative is to use maximally selected rank statistics for the split point selection. As in conditional inference forests, splitting variables are compared on the p-value scale. However, instead of the conditional Monte Carlo approach used in conditional inference forests, p-value approximations are employed. We describe several p-value approximations and the implementation of the proposed random forest approach. A simulation study demonstrates that unbiased split variable selection is possible. However, there is a trade-off between unbiased split variable selection and runtime. In benchmark studies of prediction performance on simulated and real datasets, the new method performs better than random survival forests if informative dichotomous variables are combined with uninformative variables with more categories and better than conditional inference forests if non-linear covariate effects are included. In a runtime comparison, the method proves to be computationally faster than both alternatives, if a simple p-value approximation is used. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28088841 TI - Intracellular fate of Ureaplasma parvum entrapped by host cellular autophagy. AB - Genital mycoplasmas, including Ureaplasma spp., are among the smallest human pathogenic bacteria and are associated with preterm birth. Electron microscopic observation of U. parvum showed that these prokaryotes have a regular, spherical shape with a mean diameter of 146 nm. U. parvum was internalized into HeLa cells by clathrin-mediated endocytosis and survived for at least 14 days around the perinuclear region. Intracellular U. parvum reached endosomes in HeLa cells labeled with EEA1, Rab7, and LAMP-1 within 1 to 3 hr. After 3 hr of infection, U. parvum induced the cytosolic accumulation of galectin-3 and was subsequently entrapped by the autophagy marker LC3. However, when using atg7-/- MEF cells, autophagy was inadequate for the complete elimination of U. parvum in HeLa cells. U. parvum also colocalized with the recycling endosome marker Rab11. Furthermore, the exosomes purified from infected HeLa cell culture medium included U. parvum. In these purified exosomes ureaplasma lipoprotein multiple banded antigen, host cellular annexin A2, CD9, and CD63 were detected. This research has successfully shown that Ureaplasma spp. utilize the host cellular membrane compartments possibly to evade the host immune system. PMID- 28088843 TI - Evaluating surrogate marker information using censored data. AB - Given the long follow-up periods that are often required for treatment or intervention studies, the potential to use surrogate markers to decrease the required follow-up time is a very attractive goal. However, previous studies have shown that using inadequate markers or making inappropriate assumptions about the relationship between the primary outcome and surrogate marker can lead to inaccurate conclusions regarding the treatment effect. Currently available methods for identifying and validating surrogate markers tend to rely on restrictive model assumptions and/or focus on uncensored outcomes. The ability to use such methods in practice when the primary outcome of interest is a time-to event outcome is difficult because of censoring and missing surrogate information among those who experience the primary outcome before surrogate marker measurement. In this paper, we propose a novel definition of the proportion of treatment effect explained by surrogate information collected up to a specified time in the setting of a time-to-event primary outcome. Our proposed approach accommodates a setting where individuals may experience the primary outcome before the surrogate marker is measured. We propose a robust non-parametric procedure to estimate the defined quantity using censored data and use a perturbation-resampling procedure for variance estimation. Simulation studies demonstrate that the proposed procedures perform well in finite samples. We illustrate the proposed procedures by investigating two potential surrogate markers for diabetes using data from the Diabetes Prevention Program. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28088844 TI - Role of contrast CT for the diagnosis and the prognosis of suspected LVAD thrombosis. AB - BACKGROUND: There is an urgent need for further studies evaluating the role of imaging modalities in the management of left ventricular assist device (LVAD) thrombosis. This study reviews the role of computed tomography (CT) in the diagnosis of suspected LVAD thrombosis. METHODS: All contrast chest CTs performed in patients with suspected LVAD thrombosis at the University of Minnesota between January 2008 and April 2014 were reviewed. Significant CT findings were identified, operative notes were reviewed, and patient outcomes were reported. RESULTS: A total of 32 contrast chest CT examinations were performed in 24 patients with suspected LVAD thrombosis. LVAD thrombus was identified on CT in two patients (one in the outflow graft and one in the inflow cannula), and complications were found in two patients (one with inflow cannula malposition and one with outflow graft stenosis at aortic anastomosis site). Thirteen patients (67%) underwent LVAD explantation for clinically presumed LVAD thrombosis (LVAD exchange in seven, orthotopic heart transplant in six). LVAD thrombus was confirmed at the time of surgery in eight patients (62%; six in the motor, two in the outflow graft). CONCLUSIONS: CT has a low sensitivity but high specificity for detecting LVAD thrombus. The sensitivity is higher, but still modest for the detection of thrombus in the outflow cannula. PMID- 28088845 TI - '...it shows that there's no limits': the psychological impact of co-production for experts by experience working in youth mental health. AB - Co-production is commonly conceptualised as a more equal sharing of power and decision-making between a dichotomy of service user and service provider, each bringing valuable and different assets to the process. Experts by experience lie in the overlap between this conceptually created duality, providing the services they now do by virtue of having once used services themselves. Previous related studies suggest that their involvement in co-production could impact positively on their social capital, self-esteem, self-efficacy and life skills. However, no studies have been explicitly psychological or phenomenological in nature, and the theoretical basis for such outcomes remains under-developed. This phenomenological study explored the psychological impact of co-production for young people who were paid experts by experience for a young person's mental health charity in a large and diverse urban area in the UK, looking at the what of psychological impact, as well as the theoretical why and how. Semi-structured interviews were conducted with a convenience sample of five males, with a mean age of 25 years. Interpretative phenomenological analysis yielded three master themes: the co-production approach, I'm a professional and identities in transition. Participants valued a collegiate organisational approach that prioritised empowerment, agency and equality between experts by experience and 'experts by qualification', leading to a positive impact on their self-efficacy and self-esteem. Co-production impacted fundamentally on their identity structure, enabling them to explore a new identity as a 'professional'. The results are framed within identity process theory and point to the potential benefits of this model to co-production. PMID- 28088846 TI - Fermi Level Pinning at Electrical Metal Contacts of Monolayer Molybdenum Dichalcogenides. AB - Electrical metal contacts to two-dimensional (2D) semiconducting transition metal dichalcogenides (TMDCs) are found to be the key bottleneck to the realization of high device performance due to strong Fermi level pinning and high contact resistances (Rc). Until now, Fermi level pinning of monolayer TMDCs has been reported only theoretically, although that of bulk TMDCs has been reported experimentally. Here, we report the experimental study on Fermi level pinning of monolayer MoS2 and MoTe2 by interpreting the thermionic emission results. We also quantitatively compared our results with the theoretical simulation results of the monolayer structure as well as the experimental results of the bulk structure. We measured the pinning factor S to be 0.11 and -0.07 for monolayer MoS2 and MoTe2, respectively, suggesting a much stronger Fermi level pinning effect, a Schottky barrier height (SBH) lower than that by theoretical prediction, and interestingly similar pinning energy levels between monolayer and bulk MoS2. Our results further imply that metal work functions have very little influence on contact properties of 2D-material-based devices. Moreover, we found that Rc is exponentially proportional to SBH, and these processing parameters can be controlled sensitively upon chemical doping into the 2D materials. These findings provide a practical guideline for depinning Fermi level at the 2D interfaces so that polarity control of TMDC-based semiconductors can be achieved efficiently. PMID- 28088847 TI - Vapor and Gas-Bubble Growth Dynamics around Laser-Irradiated, Water-Immersed Plasmonic Nanoparticles. AB - Microbubbles produced by exposing water-immersed metallic nanoparticles to resonant light play an important role in emerging and efficient plasmonic enhanced processes for catalytic conversion, solar energy harvesting, biomedical imaging, and cancer therapy. How do these bubbles form, and what is their gas composition? In this paper, the growth dynamics of nucleating bubbles around laser-irradiated, water-immersed Au plasmonic nanoparticles are studied to determine the exact origin of the occurrence and growth of these bubbles. The microbubbles' contact angle, footprint diameter, and radius of curvature were measured in air-equilibrated water (AEW) and degassed water (DGW) with fast imaging. Our experimental data reveals that the growth dynamics can be divided into two regimes: an initial bubble nucleation phase (regime I, < 10 ms) and, subsequently a bubble growth phase (regime II). The explosive growth in regime I is identical for AEW and DGW due to the vaporization of water. However, the slower growth in regime II is distinctly different for AEW and DGW, which is attributed to the uptake of dissolved gas expelled from the water around the hot nanoparticle. Our scaling analysis reveals that the bubble radius scales with time as R(t) ? t1/6 for both AEW and DGW in the initial regime I, whereas in the later regime II it scales as R(t) ? t1/3 for AEW and is constant for perfectly degassed water. These scaling relations are consistent with the experiments. PMID- 28088848 TI - Mercury Bioaccumulation in Estuarine Fishes: Novel Insights from Sulfur Stable Isotopes. AB - Estuaries are transitional habitats characterized by complex biogeochemical and ecological gradients that result in substantial variation in fish total mercury concentrations (THg). We leveraged these gradients and used carbon (delta13C), nitrogen (delta15N), and sulfur (delta34S) stable isotopes to examine the ecological and biogeochemical processes underlying THg bioaccumulation in fishes from the San Francisco Bay Estuary. We employed a tiered approach that first examined processes influencing variation in fish THg among wetlands, and subsequently examined the roles of habitat and within-wetland processes in generating larger-scale patterns in fish THg. We found that delta34S, an indicator of sulfate reduction and habitat specific-foraging, was correlated with fish THg at all three spatial scales. Over the observed ranges of delta34S, THg concentrations in fish increased by up to 860% within wetlands, 560% among wetlands, and 291% within specific impounded wetland habitats. In contrast, delta13C and delta15N were not correlated with THg among wetlands and were only important in low salinity impounded wetlands, possibly reflecting more diverse food webs in this habitat. Together, our results highlight the key roles of sulfur biogeochemistry and ecology in influencing estuarine fish THg, as well as the importance of fish ecology and habitat in modulating the relationships between biogeochemical processes and Hg bioaccumulation. PMID- 28088849 TI - Effect of Gallium Exposure in Arabidopsis thaliana is Similar to Aluminum Stress. AB - Although gallium (Ga) is a rare element, it is widely used in semiconductor devices. Ga contamination of the environment has been found in semiconductor producing countries. Here, the physiological and molecular impacts of Ga in the model plant Arabidopsis thaliana were investigated in medium culture. The primary symptom of Ga toxicity is inhibition of root growth. The increased production of malondialdehyde (MDA) suggests that Ga stress could cause oxidative damage in plants. Roots were the main Ga accumulating sites. The distinctive Ga granules were deposited within the intercellular space in roots. The granules are Ga(OH)3 precipitation, which indicates immobilization or limited translocation of Ga in A. thaliana. Ga stress induces root secretion of organic acids such as citrate and malate. The expression of the transporters AtALMT and AtMATE, responsible for citrate and malate secretion, respectively, were elevated under Ga stress, so the secretion may play a role in the resistance. Indeed, supplying exogenous citrate significantly enhanced Ga tolerance. The overall response to Ga exposure in A. thaliana is highly similar to that with aluminum stress. Our findings provide information for risk assessment in Ga-contaminated soil. PMID- 28088850 TI - Importance of Interlayer Equivalent Pores for Anion Diffusion in Clay-Rich Sedimentary Rocks. AB - The anion exclusion behavior in two different clay stones, Opalinus Clay (OPA) and Helvetic Marl (HM), was studied using a well-established experimental through diffusion technique. The ionic strength of the pore water was varied between 0.01 and 5 M to evaluate its effect on the diffusion of HTO and 36Cl-. The total porosity determined by HTO-diffusion was independent of the ionic strength, while the anion accessible porosity varies with the ionic strength of the pore water. In the case of Opalinus Clay, the anion accessible porosity increases from 3% at low ionic strength (0.01 M) up to 8.4% at high ionic strength (5 M), whereas the anion accessible porosity of Helvetic Marl increases from 0.6% up to only 1.1%. The anion exclusion effect in HM is thus more pronounced than that in OPA, even at high ionic strength. This observation can be correlated to differences in mineralogy and to the fact that HM has a larger fraction of interlayer equivalent pores. Interlayer equivalent pores are small pores in compressed clay stones that are small enough to have, because of overlapping electric double layers, properties similar to those of interlayers and are therefore rather inaccessible for anions. PMID- 28088851 TI - Monitoring the Reaction Process During the S2 -> S3 Transition in Photosynthetic Water Oxidation Using Time-Resolved Infrared Spectroscopy. AB - Photosynthetic water oxidation performed at the Mn4CaO5 cluster in photosystem II plays a crucial role in energy production as electron and proton sources necessary for CO2 fixation. Molecular oxygen, a byproduct, is a source of the oxygenic atmosphere that sustains life on earth. However, the molecular mechanism of water oxidation is not yet well-understood. In the reaction cycle of intermediates called S states, the S2 -> S3 transition is particularly important; it consists of multiple processes of electron transfer, proton release, and water insertion, and generates an intermediate leading to O-O bond formation. In this study, we monitored the reaction process during the S2 -> S3 transition using time-resolved infrared spectroscopy to clarify its molecular mechanism. A change in the hydrogen-bond interaction of the oxidized YZ* radical, an immediate electron acceptor of the Mn4CaO5 cluster, was clearly observed as a ~100 MUs phase before the electron-transfer phase with a time constant of ~350 MUs. This observation provides strong experimental evidence that rearrangement of the hydrogen-bond network around YZ*, possibly due to the movement of a water molecule located near YZ* to the Mn site, takes place before the electron transfer. The electron transfer was coupled with proton release, as revealed by a relatively high deuterium kinetic isotope effect of 1.9. This proton release, which decreases the redox potential of the Mn4CaO5 cluster to facilitate electron transfer to YZ*, was proposed to determine, as a rate-limiting step, the relatively slow electron-transfer rate of the S2 -> S3 transition. PMID- 28088852 TI - Plasmonic Imaging of Surface Electrochemical Reactions of Single Gold Nanowires. AB - Nanomaterials have been widely used in energy and sensing applications because of their unique chemical and physical properties, especially their surface reactions. Measuring the local reactions of individual nanomaterials, however, has been an experimental challenge. Here we report on plasmonic imaging of surface electrochemical reactions of individual gold nanowires (AuNWs). We coated a gold thin film (plasmonic sensing layer) with a dielectric layer (Cytop) with refractive index close to that of water, and then a graphene layer for electrical contact. This design removed the interference from the sensing layer while preserving sharp surface plasmon resonance, which allowed us to obtain cyclic voltammograms of surface electrochemistry of individual AuNWs for the first time. We also investigated the difference in the electrochemical reactions of AuNWs and Au surfaces, and local distribution of electrochemical activities within a single AuNW. PMID- 28088853 TI - The Formation of Ti-H Species at Interface Is Lethal to the Efficiency of TiO2 Based Dye-Sensitized Devices. AB - TiO2-based dye-sensitization cycle is one of the basic strategies for the development of solar energy applications. Although the power conversion efficiency (PCE) of dye-sensitized devices has been improved through constant attempts, the intrinsically fatal factor that leads to the complete failure of the PCE of TiO2-mediated dye-sensitized devices has not yet been determined. Here, by using isotopically labeled MAS-1H NMR, ATR-FTIR spectroscopy (separate H/D and 48Ti/49Ti experiments), and ESR, we revealed that the accumulative formation of Ti-H species on the TiO2 surface is the intrinsic cause of the PCE failure of TiO2-based dye-sensitization devices. Such a Ti-H species is generated from the reduction of hydrogen ions (mostly released from dye carboxyl groups or organic electrolyte) accompanied by electron injection on the surface of TiO2, which deteriorates the PCE mainly by reducing the electrical conductivity of the TiO2 (by a maximum of ~80%) and the hydrophilic nature of the TiO2 surface (contact angle increased). PMID- 28088854 TI - Conjugated Covalent Organic Frameworks via Michael Addition-Elimination. AB - Dynamic covalent chemistry enables self-assembly of reactive building blocks into structurally complex yet robust materials, such as covalent organic frameworks (COFs). However, the synthetic toolbox used to prepare such materials, and thus the spectrum of attainable properties, is very limited. For pi-conjugated COFs, the Schiff base condensation of aldehydes and amines is the only general dynamic reaction, but the resulting imine-linked COFs display only a moderate electron delocalization and are susceptible to hydrolysis, particularly in acidic conditions. Here we report a new dynamic polymerization based on Michael addition elimination reaction of structurally diverse beta-ketoenols with amines, and use it to prepare novel two-dimensional (2D) pi-conjugated COFs, as crystalline powders and exfoliated micron-size sheets. pi-Conjugation is manifested in these COFs in significantly reduced band gap (1.8-2.2 eV), solid state luminescence and reversible electrochemical doping creating midgap (NIR absorbing) polaronic states. The beta-ketoenamine moiety enables protonation control of electron delocalization through the 2D COF sheets. It also gives rise to direct sensing of triacetone triperoxide (TATP) explosive through fluorescence quenching. PMID- 28088855 TI - Atom-Economic Synthesis of Pentaleno[2,1-b]indoles via Tandem Cyclization of Alkynones Initiated by Aminopalladation. AB - An atom-economic Pd(OAc)2-catalyzed tandem cyclization of alkynones to synthesize pentaleno[2,1-b]indoles was developed efficiently. In the formed tetracyclic indole framework, two neighboring stereocenters, one being all-carbon quaternary, are being constructed in a single process with excellent diastereoselectivity. This reaction was initiated by aminopalladation of alkynes and quenched by addition to the intramolecular carbonyl groups. PMID- 28088856 TI - Hollow Carbon Spheres with Abundant Micropores for Enhanced CO2 Adsorption. AB - The interest in the design and controllable fabrication of hollow carbon spheres (HCSs) emanates from their tremendous potential applications in adsorption, energy conversion and storage, and catalysis. However, the effective synthesis of uniform HCSs with high surface area and abundant micropores remains a challenge. In this work, HCSs with tunable microporous shells were rationally synthesized via the hard-template method using resorcinol (R) and formaldehyde (F) as a carbon precursor. HCSs with a very high surface area (1369 m2/g) and abundant micropores (0.53 cm3/g) can be obtained with the assistance of additional inorganic silanes (TEOS) simultaneously with the carbon source (RF). Interestingly, the extra-abundant micropores showed favorable adsorption for CO2, resulting in a 1.5 times increase in the CO2 adsorption capacity compared to that of normal HCSs under the same conditions. Meanwhile, these HCSs hold potential for use in the separation of gases such as CO2 and N2. PMID- 28088857 TI - Methane Activation by Tantalum Carbide Cluster Anions Ta2C4. AB - Methane activation by transition metals is of fundamental interest and practical importance, as this process is extensively involved in the natural gas conversion to fuels and value-added chemicals. While single-metal centers have been well recognized as active sites for methane activation, the active center composed of two or more metal atoms is rarely addressed and the detailed reaction mechanism remains unclear. Here, by using state-of-the-art time-of-flight mass spectrometry, cryogenic anion photoelectron imaging spectroscopy, and quantum chemical calculations, the cooperation of the two Ta atoms in a dinuclear carbide cluster Ta2C4- for methane activation has been identified. The C-H bond activation takes place predominantly around one Ta atom in the initial stage of the reaction and the second Ta atom accepts the delivered H atom from the C-H bond cleavage. The well-resolved vibrational spectra of the cryogenically cooled anions agree well with theoretical simulations, allowing the clear characterization of the structure of Ta2C4- cluster. The reactivity comparison between Ta2C4- cluster and the carbon-less analogues (Ta2C3- and Ta2C2-) demonstrated that the cooperative effect of the two metal atoms can be well tuned by the carbon ligands in terms of methane activation and transformation. PMID- 28088858 TI - From Blue to Green: Fine-Tuning of Photoluminescence and Electrochemiluminescence in Bifunctional Organic Dyes. AB - We describe the synthesis, computational analysis, photophysics, electrochemistry and electrochemiluminescence (ECL) of a series of compounds formed of two triphenylamines linked by a fluorene or spirobifluorene bridge. The phenylamine moieties were modified at the para-position of the two external rings by electron withdrawing or electron-donating substituents. These modifications allowed for fine-tuning of the photoluminescence (PL) and ECL emission from blue to green, with an overall wavelength span of 73 (PL) and 67 (ECL) nm, respectively. For all compounds, we observed a very high PL quantum yield (79-89%) and formation of stable radical ions. The ECL properties were investigated by direct annihilation of the electrogenerated radical anion and radical cation. The radical-ion annihilation process is very efficient and causes an intense greenish-blue ECL emission, easily observable even by naked eye, with quantum yield higher than the standard 9,10-diphenylanthracene. The ECL spectra show one single band that almost matches the PL band. Because the energy of the annihilation reaction is higher than that required to form the singlet excited state, the S-route is considered the favored pathway followed by the ECL process in these molecules. All these features point to this type of molecular system as promising for ECL applications. PMID- 28088859 TI - Determination of the Geographical Origin of All Commercial Hake Species by Stable Isotope Ratio (SIR) Analysis. AB - The determination of the geographical origin of food products is relevant to comply with the legal regulations of traceability, to avoid food fraud, and to guarantee food quality and safety to the consumers. For these reasons, stable isotope ratio (SIR) analysis using an isotope ratio mass spectrometry (IRMS) instrument is one of the most useful techniques for evaluating food traceability and authenticity. The present study was aimed to determine, for the first time, the geographical origin for all commercial fish species belonging to the Merlucciidae family using SIR analysis of carbon (delta13C) and nitrogen (delta15N). The specific results enabled their clear classification according to the FAO (Food and Agriculture Organization of the United Nations) fishing areas, latitude, and geographical origin in the following six different clusters: European, North African, South African, North American, South American, and Australian hake species. PMID- 28088860 TI - Combined Experimental and Computational Study on the Unimolecular Decomposition of JP-8 Jet Fuel Surrogates. I. n-Decane (n-C10H22). AB - Exploiting a high temperature chemical reactor, we explored the pyrolysis of helium-seeded n-decane as a surrogate of the n-alkane fraction of Jet Propellant 8 (JP-8) over a temperature range of 1100-1600 K at a pressure of 600 Torr. The nascent products were identified in situ in a supersonic molecular beam via single photon vacuum ultraviolet (VUV) photoionization coupled with a mass spectroscopic analysis of the ions in a reflectron time-of-flight mass spectrometer (ReTOF). Our studies probe, for the first time, the initial reaction products formed in the decomposition of n-decane-including radicals and thermally labile closed-shell species effectively excluding mass growth processes. The present study identified 18 products: molecular hydrogen (H2), C2 to C7 1-alkenes [ethylene (C2H4) to 1-heptene (C7H14)], C1-C3 radicals [methyl (CH3), vinyl (C2H3), ethyl (C2H5), propargyl (C3H3), allyl (C3H5)], small C1-C3 hydrocarbons [methane (CH4), acetylene (C2H2), allene (C3H4), methylacetylene (C3H4)], along with higher-order reaction products [1,3-butadiene (C4H6), 2-butene (C4H8)]. On the basis of electronic structure calculations, n-decane decomposes initially by C-C bond cleavage (excluding the terminal C-C bonds) producing a mixture of alkyl radicals from ethyl to octyl. These alkyl radicals are unstable under the experimental conditions and rapidly dissociate by C-C bond beta-scission to split ethylene (C2H4) plus a 1-alkyl radical with the number of carbon atoms reduced by two and 1,4-, 1,5-, 1,6-, or 1,7-H shifts followed by C-C beta-scission producing alkenes from propene to 1-octene in combination with smaller 1-alkyl radicals. The higher alkenes become increasingly unstable with rising temperature. When the C-C beta-scission continues all the way to the propyl radical (C3H7), it dissociates producing methyl (CH3) plus ethylene (C2H4). Also, at higher temperatures, hydrogen atoms can abstract hydrogen from C10H22 to yield n-decyl radicals, while methyl (CH3) can also abstract hydrogen or recombine with hydrogen to form methane. These n-decyl radicals can decompose via C-C-bond beta scission to C3 to C9 alkenes. PMID- 28088861 TI - Ultrasensitive Label-Free Nanosensing and High-Speed Tracking of Single Proteins. AB - Label-free detection, analysis, and rapid tracking of nanoparticles is crucial for future ultrasensitive sensing applications, ranging from understanding of biological interactions to the study of size-dependent classical-quantum transitions. Yet optical techniques to distinguish nanoparticles directly among their background remain challenging. Here we present amplified interferometric scattering microscopy (a-iSCAT) as a new all-optical method capable of detecting individual nanoparticles as small as 15 kDa proteins that is equivalent to half a GFP. By balancing scattering and reflection amplitudes the interference contrast of the nanoparticle signal is amplified 1 to 2 orders of magnitude. Beyond high sensitivity, a-iSCAT allows high-speed image acquisition exceeding several hundreds of frames-per-second. We showcase the performance of our approach by detecting single Streptavidin binding events and by tracking single Ferritin proteins at 400 frames-per-second with 12 nm localization precision over seconds. Moreover, due to its extremely simple experimental realization, this advancement finally enables a cheap and routine implementation of label-free all-optical single nanoparticle detection platforms with sensitivity operating at the single protein level. PMID- 28088863 TI - Detection of Multiconfigurational States of Hydrogen-Passivated Silicene Nanoclusters. AB - Utilizing density functional theory (DFT) and a complete active space self consistent field (CASSCF) approach,we study the electronic properties of rectangular silicene nano clusters with hydrogen passivated edges denoted by H SiNCs (nz,na), with nz and na representing the zigzag and armchair directions, respectively. The results show that in the nz direction, the H-SiNCs prefer to be in a singlet (S = 0) ground state for nz > na. However, a transition from a singlet (S = 0) to a triplet (S = 1) ground state is revealed for na > nz. Through the calculated Raman spectrum, the S = 0 and S = 1 ground states can be observed by the E2g (G) and A (D) Raman modes. Furthermore, H-SiNC clusters are shown to have HOMO-LUMO (HL) energy gaps, which decrease as a function of na and nz for S = 0 and S = 1 states. The H-SiNC with a S = 1 ground state can be potentially used for silicene-based spintronic devices. PMID- 28088862 TI - Self-Assembling Peptide Epitopes as Novel Platform for Anticancer Vaccination. AB - The aim of the present study was to improve the immunogenicity of peptide epitope vaccines using novel nanocarriers based on self-assembling materials. Several studies demonstrated that peptide antigens in nanoparticulate form induce stronger immune responses than their soluble forms. However, several issues such as poor loading and risk of inducing T cell anergy due to premature release of antigenic epitopes have challenged the clinical success of such systems. In the present study, we developed two vaccine delivery systems by appending a self assembling peptide (Ac-AAVVLLLW-COOH) or a thermosensitive polymer poly(N isopropylacrylamide (pNIPAm) to the N-terminus of different peptide antigens (OVA250-264, HPV-E743-57) to generate self-assembling peptide epitopes (SAPEs). The obtained results showed that the SAPEs were able to form nanostructures with a diameter from 20 to 200 nm. The SAPEs adjuvanted with CpG induced and expanded antigen-specific CD8+ T cells in mice. Furthermore, tumor-bearing mice vaccinated with SAPEs harboring the HPV E743-57 peptide showed a delayed tumor growth and an increased survival compared to sham-treated mice. In conclusion, self-assembling peptide based systems increase the immunogenicity of peptide epitope vaccines and therefore warrants further development toward clinical use. PMID- 28088864 TI - Integrated, High-Throughput, Multiomics Platform Enables Data-Driven Construction of Cellular Responses and Reveals Global Drug Mechanisms of Action. AB - An understanding of how cells respond to perturbation is essential for biological applications; however, most approaches for profiling cellular response are limited in scope to pre-established targets. Global analysis of molecular mechanism will advance our understanding of the complex networks constituting cellular perturbation and lead to advancements in areas, such as infectious disease pathogenesis, developmental biology, pathophysiology, pharmacology, and toxicology. We have developed a high-throughput multiomics platform for comprehensive, de novo characterization of cellular mechanisms of action. Platform validation using cisplatin as a test compound demonstrates quantification of over 10 000 unique, significant molecular changes in less than 30 days. These data provide excellent coverage of known cisplatin-induced molecular changes and previously unrecognized insights into cisplatin resistance. This proof-of-principle study demonstrates the value of this platform as a resource to understand complex cellular responses in a high-throughput manner. PMID- 28088865 TI - Mass Spectrometry of Intact Proteins Reveals +98 u Chemical Artifacts Following Precipitation in Acetone. AB - Protein precipitation in acetone is frequently employed ahead of mass spectrometry for sample preconcentration and purification. Unfortunately, acetone is not chemically inert; mass artifacts have previously been observed on glycine containing peptides when exposed to acetone under acidic conditions. We herein report a distinct chemical modification occurring at the level of intact proteins when incubated in acetone. This artifact manifests as one or more satellite peaks in the MS spectrum of intact protein, spaced 98 u above the mass of the unmodified protein. Other artifacts (+84, +112 u) also appear upon incubation of proteins or peptides in acetone. The reaction is pH-sensitive, being suppressed when proteins are exposed to acetone under acidic conditions. The +98 u artifact is speculated to originate through an intermediate product of aldol condensation of acetone to form diacetone alcohol and mesityl oxide. A +98 u product could originate from nucleophilic attack on mesityl oxide or through condensation with diacetone alcohol. Given the extent of modification possible upon exposure of proteins to acetone, particularly following overnight solvent exposure or incubation at room temperature, an awareness of the variables influencing this novel modification is valued by proteomics researchers who employ acetone precipitation for protein purification. PMID- 28088866 TI - Combined Experimental and Computational Study on the Unimolecular Decomposition of JP-8 Jet Fuel Surrogates. II: n-Dodecane (n-C12H26). AB - We investigated temperature-dependent products in the pyrolysis of helium-seeded n-dodecane, which represents a surrogate of the n-alkane fraction of Jet Propellant-8 (JP-8) aviation fuel. The experiments were performed in a high temperature chemical reactor over a temperature range of 1200 K to 1600 K at a pressure of 600 Torr, with in situ identification of the nascent products in a supersonic molecular beam using single photon vacuum ultraviolet (VUV) photoionization coupled with the analysis of the ions in a reflectron time-of flight mass spectrometer (ReTOF). For the first time, the initial decomposition products of n-dodecane-including radicals and thermally labile closed-shell species-were probed in experiments, which effectively exclude mass growth processes. A total of 15 different products were identified, such as molecular hydrogen (H2), C2 to C7 1-alkenes [ethylene (C2H4) to 1-heptene (C7H14)], C1-C3 radicals [methyl (CH3), ethyl (C2H5), allyl (C3H5)], small C1-C3 hydrocarbons [acetylene (C2H2), allene (C3H4), methylacetylene (C3H4)], as well as the reaction products [1,3-butadiene (C4H6), 2-butene (C4H8)] attributed to higher order processes. Electronic structure calculations carried out at the G3(CCSD,MP2)//B3LYP/6-311G(d,p) level of theory combined with RRKM/master equation of rate constants for relevant reaction steps showed that n-dodecane decomposes initially by a nonterminal C-C bond cleavage and producing a mixture of alkyl radicals from ethyl to decyl with approximately equal branching ratios. The alkyl radicals appear to be unstable under the experimental conditions and to rapidly dissociate either directly by C-C bond beta-scission to produce ethylene (C2H4) plus a smaller 1-alkyl radical with the number of carbon atoms diminished by two or via 1,5-, 1,6-, or 1,7- 1,4-, 1,9-, or 1,8-H shifts followed by C-C beta-scission producing alkenes from propene to 1-nonene together with smaller 1 alkyl radicals. The stability and hence the branching ratios of higher alkenes decrease as temperature increases. The C-C beta-scission continues all the way to the propyl radical (C3H7), which dissociates to methyl (CH3) plus ethylene (C2H4). In addition, at higher temperatures, another mechanism can contribute, in which hydrogen atoms abstract hydrogen from C12H26 producing various n-dodecyl radicals and these radicals then decompose by C-C bond beta-scission to C3 to C11 alkenes. PMID- 28088867 TI - The political use of psychiatry: A comparison between totalitarian regimes. AB - BACKGROUND: After the end of Second World War, the recent experience of the Nazi horrors stimulated a debate about the political use of psychiatry. Over the years, the focus shifted on major dictatorships of the time and especially on Soviet Union. AIMS: This article aims to provide a critical review of the ways in which psychiatry was used by totalitarian regimes of the 20th century. METHODS: We summarized relevant literature about political use of psychiatry in totalitarian regimes of the 20th century, with particular focus on Fascism, Nazism, Argentina dictatorship, Soviet Union and China. RESULTS: One of the features that are common to most of the dictatorships is that the use of psychiatry has become more prominent when the regimes have had the need to make more acceptable the imprisonment of enemies in the eyes of the world. This for example happened in the Nazi regime when sterilization and killing of psychiatric patients was explained as a kind of euthanasia, or in the Soviet Union after the formal closure of the corrective labor camps and the slow resumption of relations with the capitalistic world, or in China to justify persecution of religious minorities and preserve economic relations with Western countries. CONCLUSION: Psychiatry has been variously used by totalitarian regimes as a means of political persecution and especially when it was necessary to make acceptable to public opinion the imprisonment of political opponents. PMID- 28088868 TI - Prognostic values of Ki-67 in neoadjuvant setting for breast cancer: a systematic review and meta-analysis. AB - AIM: To assess the prognostic values of Ki-67 in neoadjuvant setting for breast cancer patients. METHODS: PubMed and EMBASE were searched. Revman software was used to conduct random-effect model meta-analysis. RESULTS: 49 studies (14,076 patients) were included. High Ki-67 before and after neoadjuvant chemotherapy were associated with worse overall survival (OS; before: hazard ratio [HR]: 2.29; 95% CI: 1.42-3.69; after: HR: 2.24; 95% CI: 1.82-2.75) and disease-free survival (DFS; before: HR: 1.54; 95% CI: 1.23-1.95; after: HR: 2.08; 95% CI: 1.83-2.37). Low/no reduction or increase might be associated with worse DFS (HR: 2.13; 95% CI: 1.51-3.02) and OS. CONCLUSION: Ki-67 before and after neoadjuvant chemotherapy, as well as the change could predict the prognosis for breast cancer patients. PMID- 28088869 TI - Moving from Public Health Failure to Opportunity. PMID- 28088870 TI - Fatal Relapse of Myelodysplastic Syndrome in a Patient with HIV/Hepatitis C Coinfection Treated with Simeprevir/Sofosbuvir. AB - Registrational studies and observational cohorts clearly suggest sustained virologic response (SVR) rates in HIV-/hepatitis C-coinfected patients are similar to monoinfected patients when utilizing interferon-free regimens, and this can be accomplished with agents that are well tolerated with minimal adverse events. These randomized trials that led to the approval of several of our new direct-acting antiviral agents, however, specifically excluded patients who had significant comorbidities and none to our knowledge accepted patients with a history of cancer. Therefore, the effect of treatment of active hepatitis C in such patients and the effect on preexisting neoplasia are relatively unknown. We prospectively followed a 62-year-old male coinfected with HIV/hepatitis C who had a history of anal squamous cell carcinoma, prostate carcinoma, renal cell carcinoma all clinically cured and a myelodysplastic syndrome that was in remission. The patient achieved an SVR of hepatitis C with simeprevir/sofosbuvir without ribavirin and died shortly thereafter of a fatal relapse of his previously clinically controlled myelodysplastic syndrome. PMID- 28088871 TI - Herbal Medicine Practices of Patients With Liver Cancer in Peru: A Comprehensive Study Toward Integrative Cancer Management. AB - RATIONALE: The highest burden of liver cancer occurs in developing countries, where the use of herbal medicine (HM) is still widespread. Despite this trend, few studies have been conducted to report HM practices of patients with a hepatic tumor in the developing world. Hence, this study aimed to document the use of HM among patients with liver cancer in Peru. STUDY DESIGN AND METHODS: A comparative behavioral epidemiological survey was conducted among liver cancer patients attending the National Cancer Institute of Peru. Information was obtained by direct interviews based on a semistructured questionnaire. The use of HM in Peruvian liver cancer patients was reported, first, regarding general consumption prior to the onset of disease, and second, after the appearance of symptoms that patients would relate to their tumor. In parallel, general consumption of HM in noncancerous people was assessed as a comparative figure. A correspondence analysis was performed to reveal potential associations between the symptoms of cancer and the specific use of HM. RESULTS: Eighty-eight patients and 117 noncancerous individuals participated in the survey. Overall, 68.3% of the people interviewed claimed to use HM on a regular basis for general health preservation. Furthermore, 56.8% of the patients turned to plants first to treat the disorders for which they later came to the cancer care center. When compared with the number of plant species used routinely (n = 78), a selection of plants was made by patients in response to the symptoms of cancer (n = 46). At least 2 plant species, Aloe vera and Morinda citrifolia, were significantly associated with the treatment of liver cancer-related symptoms in the patient group. CONCLUSIONS: The present study is the first survey on the HM practices of patients with liver cancer in Latin America and, more broadly, in the developing world. Our findings confirm that HM remains one of the principal primary health care resources in Peru, even for a severe disease like liver cancer. These traditional, complementary and alternative medicine practices should be taken into consideration in Peruvian health programs aiming to educate the population in cancer prevention and treatment, as well as integrative cancer management. PMID- 28088872 TI - Prognostic prediction by liver tissue proteomic profiling in patients with colorectal liver metastases. AB - AIM: To obtain proteomic profiles in patients with colorectal liver metastases (CRLM) and identify the relationship between profiles and the prognosis of CRLM patients. MATERIALS & METHODS: Prognosis prediction (favorable or unfavorable according to Fong's score) by a classification and regression tree algorithm of surface-enhanced laser desorption/ionization TOF-MS proteomic profiles from cryopreserved CRLM (patients) and normal liver tissue (controls). RESULTS: The protein peak 7371 m/z showed the clearest differences between CRLM and control groups (94.1% sensitivity, 100% specificity, p < 0.001). The algorithm that best differentiated favorable and unfavorable groups combined 2970 and 2871 m/z protein peaks (100% sensitivity, 90% specificity). CONCLUSION: Proteomic profiling in liver samples using classification and regression tree algorithms is a promising technique to differentiate healthy subjects from CRLM patients and to classify the severity of CRLM patients. PMID- 28088873 TI - Developmental Changes in Ultradian Sleep Cycles across Early Childhood. AB - Nocturnal human sleep is composed of cycles between rapid eye movement (REM) sleep and non-REM (NREM) sleep. In adults, the structure of ultradian cycles between NREM and REM sleep is well characterized; however, less is known about the developmental trajectories of ultradian sleep cycles across early childhood. Cross-sectional studies indicate that the rapid ultradian cycling of active-quiet sleep in infancy shifts to a more adult-like pattern of NREM-REM sleep cycling by the school-age years, yet longitudinal studies elucidating the details of this transition are scarce. To address this gap, we examined ultradian cycling during nocturnal sleep following 13 h of prior wakefulness in 8 healthy children at 3 longitudinal points: 2Y (2.5-3.0 years of age), 3Y (3.5-4.0 years of age), and 5Y (5.5-6.0 years of age). We found that the length of ultradian cycles increased with age as a result of increased NREM sleep episode duration. In addition, we observed a significant decrease in the number of NREM sleep episodes as well as a nonsignificant trend for a decrease in the number of cycles with increasing age. Together, these findings suggest a concurrent change in which cycle duration increases and the number of cycles decreases across development. We also found that, consistent with data from adolescents and adults, the duration of NREM sleep episodes decreased with time since lights-off whereas the duration of REM sleep episodes increased over this time period. These results indicate the presence of circadian modulation of nocturnal sleep in preschool children. In addition to characterizing changes in ultradian cycling in healthy children ages 2 to 5 years, this work describes a developmental model that may provide insights into the emergence of normal adult REM sleep regulatory circuitry as well as potential trajectories of dysregulated ultradian cycles such as those associated with affective disorders. PMID- 28088875 TI - Goldstein et al.'s Secondary Analysis of Progesterone Clinical Trial for Traumatic Brain Injury Can Only Reflect the Same Trial Design Flaws: A Response to "Very Early Administration of Progesterone Does Not Improve Neuropsychological Outcomes in Subjects with Moderate to Severe Traumatic Brain Injury". PMID- 28088876 TI - Desolventizing of Jatropha curcas oil from azeotropes of solvents using ceramic membranes. AB - The separation of Jatropha curcas oil from azeotropes of ethyl alcohol-n-hexane and isopropyl alcohol-n-hexane using ceramic membranes with different cutoffs (5, 10 and 20 kDa) is presented. The mass ratios of oil:azeotropes (O:S) studied were 1:3 for feeding pressures of 0.1, 0.2 and 0.3 MPa, and 1:1 for the feeding pressure of 0.1 MPa. Isopropyl alcohol was the best solvent for the membranes conditioning to permeate n-hexane (240 kg/m2 h). In the separation of J. curcas oil and azeotropes of solvents, both membranes showed oil retention and total flux decreases with time. Overall, the lowest decrease in the retentions was reached in the 5 kDa membrane, while the lowest decrease in the total flux was reached in the 20 kDa. In the separation of oil and ethyl alcohol-n-hexane azeotrope, the best retention at 60 min of the process was equal to 17.3 wt% in the 20 kDa membrane at 0.3 MPa and O:S ratio equalled to 1:3. In this condition, the total permeate flux was 17.5 kg/m2 h. Different retentions and permeabilities are provided when changing the O:S ratio, the feeding pressure and the molecular weight cutoff of membranes. PMID- 28088874 TI - A Clinical Validation of Self-Reported Periodontitis Among Participants in the Black Women's Health Study. AB - BACKGROUND: There is a paucity of data on the validity of self-report of periodontal disease in African Americans. The Black Women's Health Study (BWHS), a United States national cohort study of 59,000 black women followed via mailed questionnaires since 1995, offered the opportunity to clinically validate self reported periodontitis among a sample of participants. METHODS: Oral health questionnaires were sent to study participants residing in Massachusetts. Respondents living in the Boston metro area were invited for clinical examination. Self-reports were compared with clinical data obtained from the 77 women (mean age: 59 years) who were examined. The authors examined the predictive ability of individual and combined questionnaire items with respect to clinical periodontal disease severity. Validation parameters were calculated for each question, and receiver operating characteristic statistics were generated to compare questionnaire items. RESULTS: Periodontitis prevalence in the validation sample was 24% for severe periodontitis and 61% for moderate disease. Performance of individual questionnaire items with respect to predicting periodontitis was better for severe compared with moderate disease. Combinations of questionnaire items improved the predictive ability with respect to severe disease beyond that of individual questionnaire items. CONCLUSIONS: Prevalence of severe periodontitis was similar to other age-comparable populations, without regard for race or sex, whereas prevalence of total periodontitis (moderate and severe) among women of similar age and/or race was much higher. Predictive ability of questionnaire items assessed in the BWHS was similar to that in other studies. PMID- 28088877 TI - The Concerted Action of Type 2 and Type 3 Deiodinases Regulates the Cell Cycle and Survival of Basal Cell Carcinoma Cells. AB - BACKGROUND: Thyroid hormones (THs) mediate pleiotropic cellular processes involved in metabolism, cellular proliferation, and differentiation. The intracellular hormonal environment can be tailored by the type 1 and 2 deiodinase enzymes D2 and D3, which catalyze TH activation and inactivation respectively. In many cellular systems, THs exert well-documented stimulatory or inhibitory effects on cell proliferation; however, the molecular mechanisms by which they control rates of cell cycle progression have not yet been entirely clarified. We previously showed that D3 depletion or TH treatment influences the proliferation and survival of basal cell carcinoma (BCC) cells. Surprisingly, we also found that BCC cells express not only sustained levels of D3 but also robust levels of D2. The aim of the present study was to dissect the contribution of D2 to TH metabolism in the BCC context, and to identify the molecular changes associated with cell proliferation and survival induced by TH and mediated by D2 and D3. METHODS: We used the CRISPR/Cas9 technology to genetically deplete D2 and D3 in BCC cells and studied the consequences of depletion on cell cycle progression and on cell death. Cell cycle progression was analyzed by fluorescence activated cell sorting analysis of synchronized cells, and the apoptosis rate by annexin V incorporation. RESULTS: Mechanistic investigations revealed that D2 inactivation accelerates cell cycle progression thereby enhancing the proportion of S-phase cells and cyclin D1 expression. Conversely, D3 mutagenesis drastically suppressed cell proliferation and enhanced apoptosis of BCC cells. Furthermore, the basal apoptotic rate was oppositely regulated in D2- and D3-depleted cells. CONCLUSION: Our results indicate that BCC cells constitute an example in which the TH signal is finely tuned by the concerted expression of opposite-acting deiodinases. The dual regulation of D2 and D3 expression plays a critical role in cell cycle progression and cell death by influencing cyclin D1-mediated entry into the G1-S phase. These findings reinforce the concept that TH is a potential therapeutic target in human BCC. PMID- 28088878 TI - What potential do aptamers hold in therapeutic delivery? PMID- 28088879 TI - The biopharmaceutical classification system of excipients. AB - The increasing number of new chemical entities is bringing new challenges to the field of drug delivery. These drugs present bioavailability issues that are frequently associated with intestinal metabolism or efflux mechanisms. Some excipients, particularly surfactants, have demonstrated a capacity to interfere with these mechanisms, improving drug bioavailability. Consequently, these excipients can no longer be considered as inert and should be subject to special considerations from a regulatory perspective. In the present manuscript, the state-of-the-art research related to these abilities of excipients to interfere with intestinal metabolism and efflux mechanisms are presented and discussed. Here, a biopharmaceutical classification system of excipients is proposed for the first time as a tool in the development of new products and for regulatory purposes. PMID- 28088881 TI - An industry update: the latest developments in therapeutic delivery. AB - This Industry Update covers the period from 1 October through to 31 October 2016, and is based on information sourced from company press releases, scientific literature, patents and various news websites. The month saw several news items covering drug-delivery devices, including a new sensor to monitor and support the use of inhalers; launch in the UK of a new autoinjector for Cimzia(r), UCB's rheumatoid arthritis drug; and approval of Roche's Lucentis(r) in a prefilled syringe. Research was also published to show the value of continuous blood pressure monitoring in dementia management. Astellas announced the acquisition of German pharmaceutical company Ganymed while Sunovion completed its purchase of Cynapsus. A new EU-funded collaboration was announced looking at the value of PET based biomarkers in Alzheimer's disease. GSK gained USA approval for its shingles vaccine, but Novo Nordisk and Sanofi received complete response letters from the US FDA, requiring further information before regulatory review of their drug submissions can be completed. The UK's NICE concluded that a drug marketed by BMS to treat a common type of lung cancer was not cost-effective and Cornell University announced results showing that its nanoparticle technology, originally developed as a tumor biomarker, could be effective in directly treating the disease. PMID- 28088880 TI - Recent advances in light-responsive on-demand drug-delivery systems. AB - The convergence of wearable sensors and personalized medicine enhance the ability to sense and control the drug composition and dosage, as well as location and timing of administration. To date, numerous stimuli-triggered smart drug-delivery systems have been developed to detect changes in light, pH, temperature, biomolecules, electric field, magnetic field, ultrasound and mechanical forces. This review examines the major advances within the last 5 years for the three most common light-responsive drug delivery-on-demand strategies: photochemical, photoisomerization and photothermal. Examples are highlighted to illustrate progress of each strategy in drug delivery applications, and key limitations are identified to motivate future research to advance this important field. PMID- 28088882 TI - Diabetes management strategies: can nanoparticles be used to therapeutically deliver insulin? PMID- 28088883 TI - Candesartan cilexetil loaded nanodelivery systems for improved oral bioavailability. AB - Candesartan cilexetil (CC), an antihypertensive drug, has low oral bioavailability due to poor solubility and hepatic first-pass metabolism. These are major limitations in oral delivery of CC. Several approaches are known to reduce the problems of solubility and improve the bioavailability of CC. Among various approaches, nanotechnology-based delivery of CC has potential to overcome the challenges associated with the oral administration. This review focuses on various nano-based delivery systems available and tried for improving the aqueous solubility, dissolution and consequently bioavailability of CC upon oral administration. Of all, solid lipid nanoparticles appear to be promising delivery system, based on current reported results, for delivery of CC, as this system improved the oral bioavailability and possessed prolonged pharmacodynamic effect. PMID- 28088884 TI - Dual Raltegravir-Etravirine Combination as Maintenance Regimen in Virologically Suppressed HIV-1-Infected Patients. AB - Nucleoside reverse transcriptase inhibitor (NRTI)- and protease inhibitor (PI) sparing antiretroviral regimens may be useful in selected human immune deficiency virus (HIV)-infected patients with resistance or intolerance to these drug classes. This was an observational prospective study of patients on suppressive antiretroviral therapy containing two NRTIs plus one ritonavir-boosted PI who switched to a dual regimen containing raltegravir plus etravirine. Patients were required not to have prior virological failure to raltegravir and to have efficacy of etravirine shown through the genotypic resistance assay in case of prior non-nucleoside reverse transcriptase inhibitor (NNRTI) virological failure. As a whole, 38 patients were enrolled. The mean duration of current regimen was 4.3 years, and the reason for simplification was toxicity in 29 patients and resistance to NRTIs in 9 patients. After switching, the percentage of patients with HIV RNA <20 copies/ml at week 48 was 81.6% in the intent-to-treat-exposed analysis. The switch led to a significant reduction in the mean serum triglyceride levels (-81.2 mg/dl), in the mean total cholesterol levels (-44.3 mg/dl), and in the prevalence of tubular proteinuria (-30.2%), with a significant increase in the mean phosphoremia (+0.52 mg/dl) and in both mean lumbar and femoral neck bone mineral density (+6.5% and +4.7%, respectively). Two patients (5.2%) had virological failure due to suboptimal adherence, and five subjects (13.1%) discontinued treatment due to adverse events. In our study, simplification to the dual-therapy raltegravir plus etravirine was associated with a good efficacy and tolerability, in addition to a favorable effect on kidney, bone, and serum lipids. PMID- 28088885 TI - [Androgen receptor-mediated processes in castrate-resistant metastatic prostate cancer]. AB - In the past six years, five new drugs have been approved by the FDA for the treatment of metastatic castrate-resistant prostate cancer. While the disease itself still remains incurable, the sequential use of these drugs can significantly prolong survival while maintaining good quality of life. Research from the past decade made it clear that androgen receptor-mediated processes play a central part in the progression of the disease. Hormonal mechanisms related to androgen-receptors can remain active until late stages of the disease. A deeper understanding of these mechanisms has led to the introduction of new endocrine therapies, which resulted in a change of the nomenclature. The identification and remodelling of androgen receptor mutations that are responsible for primary and secondary resistance developing during the new therapies can pave the way to new and more efficient androgen receptor inhibitor treatments. The aim of the review is to present the pathophysiology of the androgen receptor signaling axis at the receptor level, to review FDA-approved drugs and to draw attention to the most promising developments in the treatment of this disease. Orv. Hetil., 2017, 158(2), 42-49. PMID- 28088886 TI - [Tongue necrosis as an uncommon manifestation of temporal arteritis]. AB - Authors present a rare manifestation of the temporal arteritis, wich caused initial diagnostic difficulties, but it responded well for corticosteroid treatment. The features of the disease, pathogenesis, possible therapy are briefly summarized beside the description of clinical course. Orv. Hetil., 2017, 158(2), 77-80. PMID- 28088887 TI - [Improvement of lumbal motor control and trunkmuscle conditions with a novel low back pain prevention exercise program]. AB - INTRODUCTION: Ballet dancers often suffer from low back pain. AIM: Low back pain can be reduced by strengthening the core muscles with the help of a special exercise program. MATERIALS AND METHODS: In the study 62 ballet dancer women (average age: 14.89 +/- 1.21 years) were included. Intervention group: n = 30 participant, average age: 14.86 +/- 1.00 years, control group: n = 32 participant, average age: 14.91 +/- 1.37 years. We examined the pain intensity that occurs during training with visual analog scale, the habitual posture with photogrammetry, the abdominal muscle strength with Kraus-Weber test, the static muscle strength of the trunk muscles with core test and the lumbar motor control with leg lowering test. The intervention group did a trunk prevented exercise program during 3 months, and then we examined them again. RESULTS: In the intervention group the intensity of pain significantly decreased (VAS1: p = 0.012; VAS2: p = 0.021), the abdominal muscle strength significantly improved (K W. B: p=0.025; K-W. C: p<0.001), the static muscle strength of trunk muscles significantly increased (Core-test: p<0.001) and the lumbar motor control significantly improved in both legs (Leg low. R.: p<0.001; Leg low. L.: p<0.001). Also, the habitual posture greatly improved (frontal view: 34.78%, side view: 52.17%). CONCLUSION: In ballet dancers with a special exercise program, which improves the conditions of trunk muscles, the motor control of lumbar regions can be improved and the lower back pain and the incidence of injuries can be reduced. Orv., Hetil., 2017, 158(2), 58-66. PMID- 28088888 TI - [Smoking trajectories among Hungarian adolescents]. AB - INTRODUCTION: Understanding adolescent smoking trajectories is necessary for tailored prevention programs. AIM: To identify adolescent cigarette use patterns and risk factors of smoking trajectories by a longitudinal study. METHOD: We conducted a three-year prospective survey in two age cohorts (6th and 9th school grades) of metropolitan adolescents (n = 1,092) with yearly data collection by self-administered questionnaires. Five smoking trajectory groups were defined by cigarette smoking data. RESULTS: 67.5% of the sample remained nonsmoker, 11.3% smoked all the time, 14.3% were initiators, 3.3% quitters and 3.7% experimenters. Members of smoking trajectory groups differed significantly from each other according to number of smoking friends, parental smoking, family structure, academic achievement and weekly allowance at baseline. CONCLUSIONS: Concerning tobacco prevention programs, adolescents are not homogenous population, because distinct set of risk factors are highlighted in their different smoking behavior groups. Orv. Hetil., 2017, 158(2), 67-76. PMID- 28088889 TI - [Spontaneous bacterial peritonitis]. AB - Spontaneous bacterial peritonitis occurs most commonly in cirrhotic patients with ascites. Pathogens get into the circulation by intestinal translocation and colonize in peritoneal fluid. Diagnosis of spontaneous bacterial peritonitis is based on elevated polymorphonuclear leukocyte count in the ascites (>0,25 G/L). Ascites culture is often negative but aids to get information about antibiotic sensitivity in positive cases. Treatment in stable patient can be intravenous then orally administrated ciprofloxacin or amoxicillin/clavulanic acid, while in severe cases intravenous III. generation cephalosporin. Nosocomial spontaneous bacterial peritonitis often caused by Gram-positive bacteria and multi-resistant pathogens can also be expected thus carbapenem should be the choice of the empiric treatment. Antibiotic prophylaxis should be considered. Norfloxacin is used most commonly, but changes are expected due to increase in quinolone resistance. As a primary prophylaxis, a short-term antibiotic treatment is recommended after gastrointestinal bleeding for 5 days, while long-term prophylaxis is for patients with low ascites protein, and advanced disease (400 mg/day). Secondary prophylaxis is recommended for all patients recovered from spontaneous bacterial peritonitis. Due to increasing antibiotic use of antibiotics prophylaxis is debated to some degree. Orv. Hetil., 2017, 158(2), 50 57. PMID- 28088890 TI - Nanoparticles as a Carrier System for Drug Delivery Across Blood Brain Barrier. AB - Brain, the centre of the nervous system and an integral part the body, is protected by two anatomical and physiological barriers- Blood-Brain Barrier (BBB) and Blood-Cerebrospinal Fluid Barrier (BCSFB). Blood-Brain Barrier is a very complex and highly organized multicellular structure that shields the brain from harmful substances and invading organisms from the bloodstream and thus offering protection against various brain diseases and injuries. However, it also impede the effective delivery of drug to the brain, thus, preventing treatment of numerous neurological disorders. Even though various traditional approaches such as Intra-Cerebro-Ventricular (ICV) injection, use of implants, disruption of BBB and use of prodrugs have achieved some success in overcoming these barriers, researchers are continuously working for promising alternatives for improved brain drug delivery. Recent breakthroughs in the field of nanotechnology provide an appropriate solution to problems associated with these delivery approaches and thus can be effectively used to treat a wide variety of brain diseases. Thus, nanotechnology promises to bring a great future to the individuals with various brain disorders. This review provides a brief overview of various brain drug delivery approaches along with limitations. In addition, the significance of nanoparticles as drug carrier systems for effective brain specific drug delivery has been highlighted. To show the complexity of the problems to be overcome for improved brain drug delivery, a concise intercellular classification of the BBB along with general transport routes across it is also included. PMID- 28088891 TI - Recent Advances in Developing Photosensitizers for Photodynamic Cancer Therapy. AB - BACKGROUND & AIM: Photosensitizers are key molecules used in photodynamic cancer therapy (PDT), which is an effective therapeutic modality option for several diseases and nononcological disorders. Due to its lower systemic toxicity and its ability to destroy tumors selectively, PDT has been considered as clinical avenue for the treatment of several cancers. METHODS & RESULTS: Three essential elements are involved in a PDT procedure: a photosensitizer, light of a specific wavelength, and singlet oxygen. However, the properties of conventional photosensitizers exhibit some drawbacks that may limit their use. Nanoparticles can provide significant benefits that counter these drawbacks and enable higher efficiency and biosafety. With the development of nanotechnology, nanoparticles have been used to encapsulate photosensitizers to enhance the phototoxic and pharmacokinetic properties of these agents. CONCLUSION: Here, the main motivation for this review is to summarize recent progress in the development of photosensitizers, in particular, photosensitizers with nanoparticle modifications. In addition, we reviewed the clinical treatment of several diseases using photosensitizers formulated with nanoparticles, with the overall goal of aiding the design and development of novel photosensitizers. PMID- 28088892 TI - Interventions to Reduce Cardiovascular Risk in Children with Type 1 Diabetes. AB - BACKGROUND: Despite recent advances in improved glycemic control, the magnitude of lifetime risk from premature cardiovascular disease in individuals with type 1 diabetes remains at least 10 fold higher than in the general population. The availability of lipoprotein fractionation has allowed the spotlight for this increased risk to shift from dysglycemia to diabetes-induced dyslipidemia associated with insulin resistance. Interventions designed to simultaneously improve both factors can have distinct and additive effects on slowing the initiation and progression of atherosclerotic lesions. As fullblown cardiovascular disease is not evident during childhood, there is a critical need to identify the most predictable surrogate markers that could assign elevated risk, as well as the design of safe and targeted interventions that could improve outcomes in this population. CONCLUSION: This review will examine the evidence supporting the notion that cardiovascular disease in type 1 diabetes is associated with significant insulin resistance and it begins in childhood, making it necessary to design rational clinical trials that will significantly reduce risk in this population. PMID- 28088893 TI - Intervention for Cardiac Repair: A Clinical Perspective. AB - Cardiovascular disease remains the leading cause of death worldwide. Damage to the heart resulting from cardiovascular disease leads to gradual loss of function and reduced quality of life. Cardiac injury is particularly debilitating, more so than injury to any other organ, given our current inability to either generate new and functional cardiac tissue or to mimic the actions of the heart using external devices. Advances in the field of stem cells and genetics have paved the way for the development of a variety of novel therapies. A number of these therapies have shown great promise in regenerating cardiac tissue in non-human disease models and some have progressed towards clinical trials. Given the rapid progress and emergence of novel targets for therapy, it is perhaps timely that we assess the practicality of these techniques and their potential for translation to bedside. Hence, this review aims to outline the major therapies in development and to provide insight into the feasibility of the respective techniques with the hope that research can be steered towards developing therapies with greater potential of being employed at the bedside. PMID- 28088894 TI - Clinical Significance of the Sympathetic Nervous System in the Development and Progression of Pulmonary Arterial Hypertension. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is defined as a complex disease of clinically characterized by elevated pulmonary pressure eventually resulting in right heart failure and premature death. To date, PAH still remains a life threatening disease. Published evidence suggests that patients with PAH present profound sympathetic nervous system abnormalities and sympathetic activity has been shown to be increased. The mechanism of PAH is still complex and poorly understood. RESULTS: Some data have showed that adrenoceptors are involved in the process of the pathology and have different functions in the progression of PAH followed by heart failure. Alpha-adrenergic receptors mediate most excitatory effects and induce growth of smooth muscle cells and adventitial fibroblasts via complex cellular and molecular mechanisms. However, beta-adrenergic receptor mainly detected in endothelial layer commonly exerts relaxation effects on pulmonary artery. In addition, G protein-coupled receptor kinase 2, the primary G protein-coupled receptor kinase expressed in the heart, has been shown to be increased, resulting in the distinctive loss of inotropic reserve and functional capacity of the failing heart according to the activation of sympathetic nervous system. CONCLUSION: Here, we summarize the relevant available studies describing the roles of sympathetic nervous system in the progression of PAH. PMID- 28088895 TI - Investigating Physical, Psychological and Social Well-being of Older Persons in Jordan. AB - BACKGROUND: Older persons are overwhelmed with psychological stressors due to requirements related to the management of their health problems. The purpose of this study was to investigate physical, psychological and social wellbeing of older persons. METHOD: Cross-sectional explorative design used convenience sample of 1058 older persons in Jordan. Data was collected in regard to physical, psychological and social wellbeing using selfreported format. RESULTS: The three most bothered physical symptoms are; pain in arms, legs, or joints; feeling tired or having low energy; and back pain with percentages of 71.5% (n=756), 69.6% (n=737), and 62.2% (n=754), respectively. Older persons had slight to mild level of depression (M = 17.9, SD = 7.7), moderate to high level of life satisfaction (M=24.1, SD=5.6), moderate level perception of social support, and mild to moderate level psychological distress (M = 39.1 (SD = 11.3). Depression among participants has significant and positive association with sleep disturbance (r = .21, p < .001), psychological distress level (r =.50, p <.001). There was a significant difference between males and females in depression (t = -4.40, p <.001), psychological distress (t = -3.38, p <.001), life satisfaction (t = 2.09, p = .04) and sleep disturbances (t = -2.16, p = .03). CONCLUSION: Older persons are in need for periodic assessment for their psychosocial wellbeing in their routine checkups and visits to outpatients units. Research is needed to investigate impact of psychological and social wellbeing on other biological and health care related issues such as access and utilization of care and quality of life among older persons. PMID- 28088896 TI - Formulation and Optimization of Lansoprazole Pellets Using Factorial Design Prepared by Extrusion-Spheronization Technique Using Carboxymethyl Tamarind Kernel Powder. AB - BACKGROUND: In the present study, Lansoprazole pellets were prepared employing a novel excipient Carboxymethyl tamarind kernel powder (CMTKP) using extrusion spheronization technique. Various research studies including patents have been carried out on this polymer. Pellet formulation was optimized for formulation parameters (concentration of microcrystalline cellulose, CMTKP, croscarmellose sodium and isopropyl alcohol). METHODS: Process parameters (speed and duration of spheronization) were optimized using factorial design. The pellets were evaluated for yield, bulk and tapped density, particle size, hardness, drug content, disintegration time and drug release. RESULTS: The optimized batch showed 93.53% yield, 0.307 kg/cm2 hardness, 2.15 mm average particle size, 292 sec disintegration time and 90.46% drug content. CONCLUSION: Drug release of the optimized batch (2F7) and marketed formulation (LANZOL cap) was found to be 82.33% and 80.07%, respectively. An accelerated study indicated that optimized formulation was stable. PMID- 28088897 TI - Multiplex-PCR As a Rapid and Sensitive Method for Identification of Meat Species in Halal-Meat Products. AB - BACKGROUND: Species identification and authentication in meat products are important subjects for ensuring the health of consumers. The multiplex-PCR amplification and species- specific primer set were used for the identification of horse, donkey, pig and other ruminants in raw and processed meat products. METHODS: Oligonucleotid primers were designed and patented for amplification of species-specific mitochondrial DNA sequences of each species and samples were prepared from binary meat mixtures. RESULTS: The results showed that meat species were accurately determined in all combinations by multiplex-PCR, and the sensitivity of this method was 0.001 ng, rendering this technique open to and suitable for use in industrial meat products. It is concluded that more fraud is seen in lower percentage industrial meat products than in higher percentage ones. There was also more fraud found in processed products than in raw ones. CONCLUSION: This rapid and useful test is recommended for quality control firms for applying more rigorous controls over industrial meat products, for the benefit of target consumers. PMID- 28088898 TI - Metabolomic Shifts Following Play-Based Activity in Overweight Preadolescents. AB - BACKGROUND: Play-based activities can be a positive intervention to increase participation of overweight children. Metabolomics can reveal elemental shifts in the metabolome, lending to potential mechanistic explanations behind improvements in physiological systems. OBJECTIVE: To elucidate dose-response urinary metabolomic signature shifts in overweight preadolescents following four or eight weeks of supervised play-based activity versus a typical summer break control group. We hypothesized that eight weeks of activity would cause the greatest shift in the metabolites. STUDY DESIGN: Twenty-two recreationally active preadolescents (12 males, 10 females) were randomly assigned to a four-week (4w) or eight-week (8w) activity group or to a control group (C). Participants reported to the laboratory on two separate occasions during which descriptive characteristics were recorded and urine samples were obtained. Children in the 4w and 8w cohort were tested at the beginning and end of the four and eight weeks of a supervised play-based physical activity program where they were active for 6 hours a day, 5 days a week. Children in the C group were tested before and after eight weeks of an unsupervised summer break. RESULTS: A valid supervised partial least squares discriminant analysis model was obtained between post-exercise subjects in 8w and C (3 components, R2X = 0.332, R2Y = 0.976, Q2 = 0.091). The eight week intervention yielded significant metabolomic changes in several identified compounds. CONCLUSION: When compared to a typical unsupervised summer break, a supervised play-based intervention provides enough of a stimulus for a shift in the metabolome. PMID- 28088899 TI - Editorial: Molecular Imaging in Dementia: From the State of the Art to the New Perspectives. PMID- 28088900 TI - Synaptic Plasticity, Dementia and Alzheimer Disease. AB - Neuroplasticity is not only shaped by learning and memory but is also a mediator of responses to neuron attrition and injury (compensatory plasticity). As an ongoing process it reacts to neuronal cell activity and injury, death, and genesis, which encompasses the modulation of structural and functional processes of axons, dendrites, and synapses. The range of structural elements that comprise plasticity includes long-term potentiation (a cellular correlate of learning and memory), synaptic efficacy and remodelling, synaptogenesis, axonal sprouting and dendritic remodelling, and neurogenesis and recruitment. Degenerative diseases of the human brain continue to pose one of biomedicine's most intractable problems. Research on human neurodegeneration is now moving from descriptive to mechanistic analyses. At the same time, it is increasing apparently that morphological lesions traditionally used by neuropathologists to confirm post-mortem clinical diagnosis might furnish us with an experimentally tractable handle to understand causative pathways. Consider the aging-dependent neurodegenerative disorder Alzheimer's disease (AD) which is characterised at the neuropathological level by deposits of insoluble amyloid beta-peptide (Abeta) in extracellular plaques and aggregated tau protein, which is found largely in the intracellular neurofibrillary tangles. We now appreciate that mild cognitive impairment in early AD may be due to synaptic dysfunction caused by accumulation of non fibrillar, oligomeric Abeta, occurring well in advance of evident widespread synaptic loss and neurodegeneration. Soluble Abeta oligomers can adversely affect synaptic structure and plasticity at extremely low concentrations, although the molecular substrates by which synaptic memory mechanisms are disrupted remain to be fully elucidated. The dendritic spine constitutes a primary locus of excitatory synaptic transmission in the mammalian central nervous system. These structures protruding from dendritic shafts undergo dynamic changes in number, size and shape in response to variations in hormonal status, developmental stage, and changes in afferent input. It is perhaps not unexpected that loss of spine density may be linked to cognitive and memory impairment in AD, although the underlying mechanism(s) remain uncertain. This article aims to present a critical overview of current knowledge on the bases of synaptic dysfunction in neurodegenerative diseases, with a focus on AD, and will cover amyloid- and nonamyloid- driven mechanisms. We will consider also emerging data dealing with potential therapeutic approaches for ameliorating the cognitive and memory deficits associated with these disorders. PMID- 28088901 TI - Advanced Structure-activity Relationships Applied to Mentha spicata L. Subsp. spicata Essential Oil Compounds as AChE and NMDA Ligands, in Comparison with Donepezil, Galantamine and Memantine - New Approach in Brain Disorders Pharmacology. AB - BACKGROUND: Alzheimer's disease (AD) therapy is based on several natural and synthetic compounds that act as acetylcholinesterase (AChE) and N-methyl-D aspartate receptor (NMDA) ligands that have limited efficiency in relieving AD symptoms. Recent studies show that inhibitors isolated from Mentha spicata L. subsp. spicata are promising for AD therapy. OBJECTIVE: We aimed to identify novel and more potent phytopharmaceutical compounds for AD treatment by taking into account the compounds from Mentha spicata L. subsp. spicata essential oil. METHOD: We generated structure-activity relationship (SAR) models that predict the biological activities of 14 Mentha spicata L. subsp. spicata compounds on AChE and NMDA by comparing their molecular features with those of the three conventional ligands: donepezil, galantamine and memantine. RESULTS: The most relevant descriptors for predicting the biological activities of considered compounds are solvent accessible area and their subdivided, hydrophobicity, energy of frontier molecular orbitals and counts of the aromatic ring and rotatable bounds. 1,8-cineole, the main compound from Mentha spicata L. subsp. spicata essential oil, resulted to be similar with memantine and dissimilar with donepezil in respect to hidrophobicity (logP1,8-cineole=2.95, logPmemantine=2.81, logPdonepezil=4.11), the energy of LUMO (eLUMO1,8-cineole=3.01 eV, eLUMOmemantine=3.35 eV, eLUMOdonepezil=-0.35 eV) and the solvent accessible surface areas over all hydrophobic (SA_H1,8-cineole= 350 A2, SA_Hmemantine= 358 A2, SA_Hdonepezil= 655 A2) or polar atoms (SA_P1,8-cineole= 4 A2, SA_Pmemantine=10 A2, SA_Pdonepezil=44.62 A2). CONCLUSION: Our results point towards 1,8-cineole as a good candidate for NMDA antagonism, with a weaker AChE inhibitory effect. Our results may be useful in establishing new therapeutic strategies for neurological disorders. PMID- 28088902 TI - Brain Tumor Segmentation Using Deep Belief Networks and Pathological Knowledge. AB - In this paper, we propose an automatic brain tumor segmentation method based on Deep Belief Networks (DBNs) and pathological knowledge. The proposed method is targeted against gliomas (both low and high grade) obtained in multi-sequence magnetic resonance images (MRIs). Firstly, a novel deep architecture is proposed to combine the multi-sequences intensities feature extraction with classification to get the classification probabilities of each voxel. Then, graph cut based optimization is executed on the classification probabilities to strengthen the spatial relationships of voxels. At last, pathological knowledge of gliomas is applied to remove some false positives. Our method was validated in the Brain Tumor Segmentation Challenge 2012 and 2013 databases (BRATS 2012, 2013). The performance of segmentation results demonstrates our proposal providing a competitive solution with stateof- the-art methods. PMID- 28088903 TI - Antitubercular Marine Natural Products. AB - Due to the importance of nature as a source of new drug candidates, the purpose of this article is to emphasize the marine natural products, which exhibit antitubercular activity, published between January 2000 and May 2016, with 138 quotations to 250 compounds obtained from marine resources. These metabolites are organized by chemical constitution and named as simple alkyl lipids derivatives, aromatics derivatives, peptides, alkaloids, terpenoids, steroids, macrolides, and polycyclic polyketides. PMID- 28088904 TI - Fc-fusion Proteins in Therapy: An Updated View. AB - Fc-fusion proteins are composed of Fc region of IgG antibody (Hinge-CH2-CH3) and a desired linked protein. Fc region of Fc-fusion proteins can bind to neonatal Fc receptor (FcRn) thereby rescuing it from degradation. The first therapeutic Fc fusion protein was introduced for the treatment of AIDS. The molecular designing is the first stage in production of Fc-fusion proteins. The amino acid residues in the Fc region and linked protein are very important in the bioactivity and affinity of the fusion proteins. Although, therapeutic monoclonal antibodies are the top selling biologics but the application of therapeutic Fc-fusion proteins in clinic is in progress and among these medications Etanercept is the most effective in therapy. At present, eleven Fc-fusion proteins have been approved by FDA. There are novel Fc-fusion proteins which are in pre-clinical and clinical development. In this article, we review the molecular and biological characteristics of Fc-fusion proteins and then further discuss the features of novel therapeutic Fc-fusion proteins. PMID- 28088905 TI - Update on Recent Developments in Small Molecular HIV-1 RNase H Inhibitors (2013 2016): Opportunities and Challenges. AB - Combinations of antiretroviral drugs are successfully used to treat HIV-infected patients. However, drug resistance is a major problem that makes discovery of new antiretroviral drugs an ongoing priority. The ribonuclease H (RNase H) activity of the HIV-1 reverse transcriptase catalyzes the selective hydrolysis of the RNA strand of RNA:DNA heteroduplex replication intermediates, and represents an attractive unexploited target for drug development. This review reports on recent progress in the characterization of HIV-1 RNase H inhibitors from 2013 to 2016, describing their chemical structures, structureactivity relationship and binding modes. Focus is given to emerging medicinal chemistry principles and insights into the discovery and development of RNase H inhibitors. PMID- 28088906 TI - Epratuzumab and Blinatumomab as Therapeutic Antibodies for Treatment of Pediatric Acute Lymphoblastic Leukemia: Current Status and Future Perspectives. AB - BACKGROUND: More than 85% of children affected by acute lymphoblastic leukemia (ALL) are successfully treated; however relapse remains a remarkable clinical concern, with 50-60% of relapsing patients facing a fatal outcome. Management of relapsed patients includes standardized intensive risk-adapted regimens based on conventional drugs, and hematopoietic stem cells transplantation for patients with unfavourable features. Biological drugs, in particular the monoclonal antibody epratuzumab and the bi-functional recombinant single chain peptide blinatumomab, have been recently recognized as novel potential agents to be integrated in salvage ALL therapy to further improve rescue outcome. METHODS: A systematic search of peer-reviewed scientific literature and clinical trials in public databases has been carried out. Both clinical and pre-clinical studies have been included to summarize recent evidence on epratuzumab and blinatumomab for salvage ALL therapy. RESULTS: Sixty-two papers and 25 clinical trials were included. Although not all patients responded properly to these agents, their use in relapsed and refractory pediatric ALL seems promising. CONCLUSION: Phase 3 studies have recently begun and more consistent results about epratuzumab and blinatumomab safety and efficacy in comparison to conventional therapies are expected in the next years. Epratuzumab seems safe in the dosing scheme proposed in ALL, but its efficacy over the conventional chemotherapy is still questionable. Blinatumomab has shown promising results in high risk cases such as elder adult patients and conclusive studies on pediatric ALL are needed. Patient inter-individual variability to these agents has not been investigated in depth, but this issue needs to be addressed, in particular for blinatumomab. PMID- 28088908 TI - Editorial: From Current Diagnostic Tools and Therapeutics for Alzheimer's Disease Towards Earlier Diagnostic Markers and Treatment Targets. PMID- 28088907 TI - Tofacitinib, an Oral Janus Kinase Inhibitor: Perspectives in Dermatology. AB - BACKGROUND: Tofacitinib (formerly known as CP-690,550, CP690550, tasocitinib), a novel selective immunosuppressant, is a small molecule classified as Janus kinase inhibitor. The aim of this review article is to present updated data summary on the tofacitinib in the field of dermatology. METHOD: We undertook a structured search of bibliographic databases for peer-reviewed scientific articles, including review articles, original research articles as well as case report articles based on inclusion/exclusion criteria. Technical reports on tofacitinib from U.S. Food and Drug Administration and European Medical Agency were also included. RESULTS: Forty-three papers were included in this review. We report current data on tofacitinib chemical properties, pharmacology, non-clinical toxicity, as well as efficacy and safety in potential new indications in dermatology: psoriasis, alopecia areata, vitiligo, atopic dermatitis and nail dystrophy associated with alopecia areata. CONCLUSION: JAK/STAT pathway has an important role in the pathogenesis of psoriasis, alopecia areata, atopic dermatitis, and vitiligo. Despite encouraging efficacy, due to concerns about the overall safety profile of tofacitinib, additional studies will have to determine the adequate risk-to-benefit ratio. PMID- 28088909 TI - Synergistic Interaction Between Heme Oxygenase (HO) and Nuclear-Factor E2- Related Factor-2 (Nrf2) against Oxidative Stress in Cardiovascular Related Diseases. AB - BACKGROUND: Nuclear factor-erythroid related factor-2 (Nrf2) is a master regulator of transcriptional activation of anti-oxidants in cells. Similarly, heme oxygenase (HO) is a cytoprotective protein with anti-oxidant effects. This review article will shed more light on the interaction between Nrf2 and HO. METHODS AND RESULTS: A PubMed search was done for recent articles on Nrf2 and HO. These studies suggested that under normal physiological conditions, Nrf2 is bound within the cytoplasm to its repressor, Kelch-like ECHassociated protein (Keap1), an oxidative stress sensor. Upon activation, Nrf2 translocates to the nucleus and binds to the antioxidant-response-element located at the promoter region of some anti-oxidants including the cytoprotective protein HO. Since the HO-1 gene harbors binding site for Nrf2, mutual stimulatory and regulatory effects between Nrf2 and HO-1 have been reported. Accordingly, the interaction between Nrf2 and HO-1 has been implicated in the regulation of many physiological anti-oxidants including superoxide dismutases, catalase, glutathione S-transferase, peroxidase, NAD(P)H quinone oxidoreductase, and thioredoxin. CONCLUSION: Although an overwhelming body of evidence has underscored unique anti-oxidant attributes of HO- 1 and Nrf2, emerging evidence suggests that the cytoprotective activities of Nrf2 and HO-1 may be attributed, at least in part, to the potentiation of different anti-oxidants in physiological mileu. Since Nrf2 binds to the antioxidant responsive element of HO-1, the coordinated regulation of Nrf2 and keap1 by the HO-system may constitute the basis of many physiological effects of HO-1 including its effects against oxidative stress and inflammation in a wide spectrum of cardiovascular, cardio-metabolic and other related diseases. PMID- 28088910 TI - Sodium-glucose Cotransporter 2 Inhibitors (SGLT2i): Their Role in Cardiometabolic Risk Management. AB - BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel category of oral antidiabetic drugs that inhibit renal glucose reabsorption and increase renal glucose excretion, thus lowering plasma glucose levels. This unique mechanism of SGLT2i action is insulin independent, thus improving glycemic control without promoting hypoglycemia in the absence of exogenously administered insulin. METHODS: The present narrative review addresses the putative associations between SGLT2i and several cardiovascular (CV) and microvascular risk factors, as well as their effects on cardiac and renal function. RESULTS: SGLT2i improve several CV risk factors, including fasting and postprandial plasma glucose levels, lipids, blood pressure, body weight, serum uric acid and arterial stiffness. These drugs may also favorably modulate cardiac and renal function via their effects on inflammation, oxidative stress, diuresis, fluid and sodium retention, myocardial function, vascular resistance and 'fuel' metabolism. In the EMPA-REG OUTCOME study, the first published large CV outcome SGLT2i trial, empagliflozin significantly reduced the primary composite outcome (i.e. CV death, nonfatal myocardial infarction or stroke) and all-cause death as well as hospitalization for heart failure. In addition, empagliflozin was associated with a slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care in patients at high CV risk. CONCLUSION: Multiple metabolic benefits may account for the positive clinical outcomes in the EMPA-REG OUTCOME study. Ongoing CV outcome trials involving other SGLT2i will help establish whether the reported CV and microvascular risk benefits are compound-specific or drug class effects. PMID- 28088911 TI - Microbubbles: A Novel Strategy for Chemotherapy. AB - BACKGROUND: Ultrasound microbubbles have conventionally been used for diagnostic purposes. In recent years, however, new types of microbubbles have emerged as important carriers for drug delivery. Moreover, studies have shown that ultrasound microbubbles can serve as valuable and noninvasive tools in cancer therapy; thus the use of ultrasound microbubbles to deliver chemotherapeutic drugs to malignant tissues is a promising possibility. METHODS: In this review, we briefly describe the status of ultrasound microbubbles in clinical practice and then discuss the development of targeted microbubbles. Finally, we consider novel strategies for the use of microbubbles in cancer therapy. RESULTS: Many different kinds of microbubbles are emerged. Novel strategies of ultrasound microbubble have been shown to be effective in cancer therapy. CONCLUSION: Although many problems need to be solved in the future, the ultrasound drugs loaded microbubbles still have strong potential for the use in clinical cancer therapy. PMID- 28088912 TI - Melatonin as a Therapeutic Resource for Inflammatory Visual Diseases. AB - BACKGROUND: Uveitis and optic neuritis are prevalent ocular inflammatory diseases, and highly damaging ocular conditions. Both diseases are currently treated with corticosteroids, but they do not have adequate efficacy and are often associated with severe side effects. Thus, uveitis and optic neuritis remain a challenging field to ophthalmologists and a significant public health concern. OBJECTIVE: This review summarizes findings showing the benefits of a treatment with melatonin in experimental models of these inflammatory ocular diseases. RESULTS: Oxidative and nitrosative damage, tumor necrosis factor, and prostaglandin production have been involved in the pathogeny of uveitis and optic neuritis. Melatonin is an efficient antioxidant and antinitridergic, and has the ability to reduce prostaglandin and tumor necrosis factor levels both in the retina and optic nerve. Moreover, melatonin not only prevents functional and structural consequences of experimental uveitis and optic neuritis, but it is also capable of suppressing the actively ongoing ocular inflammatory response. CONCLUSIONS: Since melatonin protects ocular tissues against inflammation, it could be a potentially useful anti-inflammatory therapy in ophthalmology. PMID- 28088913 TI - A Comparative Study of Short Term Efficacy of Aripiprazole and Risperidone in Schizophrenia. AB - OBJECTIVE: To compare the short term anti-schizophrenic efficacy and side effect profile of aripiprazole with risperidone. METHODOLOGY: The study was a non randomized, naturalistic, rater blinded, prospective, 8-12 weeks, comparative trial between the risperidone and aripiprazole in patients with schizophrenia. Patients already getting treatment with aripiprazole (10 to 30 mg/day) or risperidone (3 to 8mg/day) were recruited. Mini International Neuropsychiatric Interview (MINI) Plus, Positive and Negative Syndrome Scale (PANSS), Abnormal Involuntary Movement Scale (AIMS), Simpson Angus Scale (SAS), Udvalg for Klinske Undersogelser (UKU) Scale, Clinical Global Impression-severity scales were administered by principal investigator on the day of recruitment. Anthropometric measurements (height, weight, BMI, waist, hip, waist circumference) blood pressure and pulse rate were measured on day 1 and during follow up. All tests except MINI plus were administered again after 8-12weeks. RESULTS: Both aripiprazole and risperidone treated patients have shown significant improvement on positive and negative symptoms but there was no statistically significant difference between the two groups. Mean improvement in patient rated improvement scale score showed a trend towards significance favoring aripiprazole. Common adverse events (seen in >= 5% of patients) as assessed by the UKU Scale occurred more frequently in the risperidone group than in the aripiprazole group. Drug induced extra pyramidal symptoms were more common in risperidone treated patients. Aripiprazole showed less treatment emerged weight gain. CONCLUSION: Aripiprazole is equally efficacious and better tolerated than risperidone in patients with schizophrenia over a short-term period of eight weeks. Aripiprazole showed better patient satisfaction and side effect profile. PMID- 28088915 TI - Evaluation of microRNA Stability in Plasma and Serum from Healthy Dogs. AB - BACKGROUND: Early and specific detection of cancer is of great importance for successful treatment of the disease. New biomarkers, such as microRNAs, could improve treatment efficiency and survival ratio. In human medicine, deregulation of microRNA profiles in circulation has shown great potential as a new type of biomarker for cancer diagnostics. There are, however, few studies of circulating microRNAs in dogs. Extracellular circulating microRNAs have shown a high level of stability in human blood and other body fluids. Nevertheless, there are still important issues to be solved before microRNAs can be applied routinely as a clinical tool, one of them being their stability over time in media commonly used for blood sampling. OBJECTIVE: Evaluation of the stability of microRNA levels in plasma and serum from healthy dogs after storage at room temperature for different time points before being processed. METHODS: The levels of four microRNAs (cfa-let-7a, cfa-miR-16, cfa-miR-23a and cfa-miR-26a) known to be stably expressed from other canine studies, have been measured by quantitative real-time PCR (qPCR). RESULTS: MicroRNA levels were found sufficiently stable for gene profiling in serum- and plasma stored at room temperature for 1 hour but not for samples stored at room temperature for 24 hours. CONCLUSION: Storage at room temperature of serum and plasma samples intended for microRNA profiling should be kept for a minimum period of time before proceeding with RNA isolation. For the four microRNAs investigated in the present study, we did not find significant differences in microRNA levels between serum and plasma samples from the same time point. PMID- 28088916 TI - An Increasing Threat in an Iranian Referral Children's Hospital: Multidrug Resistant Acinetobacter baumannii. AB - INTRODUCTION: Acinetobacter baumannii has emerged as an important nosocomial pathogen in the past decades. Due to the prevalence of A. baumannii across the world, suitable typing methods to investigate the epidemiological distribution of the organism have been developed. The aim of this study was to investigate the epidemiological and molecular diversity of A. baumannii strains isolated from nosocomial infections of hospitalized children in Children Medical Center Hospital (CMC), an Iranian referral hospital, in Tehran, Iran. MATERIAL AND METHODS: A total of 27 non-duplicate clinical A. baumannii isolates were collected during October 2013 to March 2014 and tested for antimicrobial resistance to several antibiotic agents. The genetic similarity of the strains was investigated by amplification of Random amplified polymorphic DNA-polymerase chain reaction (RAPD-PCR) method. RESULTS: One predominant RAPD profile (type B) was identified in 15 strains (56% of all typed isolates). Other clusters depicted in the dendrogram, namely A, C, and D comprised 6 (22%), 5 (19%) and 1 (3%) isolates, respectively. All A. baumannii strains were resistant to all antibiotics except colistin. CONCLUSION: This study highlights the clonal spread of multidrug-resistant A. baumannii in our hospital. Therefore, the factors responsible for dissemination of such isolates need to be identified, controlled, and prevented to avoid major outbreaks. PMID- 28088914 TI - Diverse Functions and Mechanisms of Pericytes in Ischemic Stroke. AB - BACKGROUND: Every year, strokes take millions of lives and leave millions of individuals living with permanent disabilities. Recently more researchers embrace the concept of the neurovascular unit (NVU), which encompasses neurons, endothelial cells (ECs), pericytes, astrocyte, microglia, and the extracellular matrix. It has been well-documented that NVU emerged as a new paradigm for the exploration of mechanisms and therapies in ischemic stroke. To better understand the complex NVU and broaden therapeutic targets, we must probe the roles of multiple cell types in ischemic stroke. The aims of this paper are to introduce the biological characteristics of brain pericytes and the available evidence on the diverse functions and mechanisms involving the pericytes in the context of ischemic stroke. METHODS: Research and online content related to the biological characteristics and pathophysiological roles of pericytes is review. The new research direction on the Pericytes in ischemic stroke, and the potential therapeutic targets are provided. RESULTS: During the different stages of ischemic stroke, pericytes play different roles: 1) On the hyperacute phase of stroke, pericytes constriction and death may be a cause of the no-reflow phenomenon in brain capillaries; 2) During the acute phase, pericytes detach from microvessels and participate in inflammatory-immunological response, resulting in the BBB damage and brain edema. Pericytes also provide benefit for neuroprotection by protecting endothelium, stabilizing BBB and releasing neurotrophins; 3) Similarly, during the later recovery phase of stroke, pericytes also contribute to angiogenesis, neurogenesis, and thereby promote neurological recovery. CONCLUSION: This emphasis on the NVU concept has shifted the focus of ischemic stroke research from neuro-centric views to the complex interactions within NVU. With this new perspective, pericytes that are centrally positioned in the NVU have been widely studied in ischemic stroke. More work is needed to elucidate the beneficial and detrimental roles of brain pericytes in ischemic stroke that may serve as a basis for potential therapeutic targets. PMID- 28088917 TI - Effects of heart valve prostheses on phase contrast flow measurements in Cardiovascular Magnetic Resonance - a phantom study. AB - BACKGROUND: Cardiovascular Magnetic Resonance is often used to evaluate patients after heart valve replacement. This study systematically analyses the influence of heart valve prostheses on phase contrast measurements in a phantom trial. METHODS: Two biological and one mechanical aortic valve prostheses were integrated in a flow phantom. B0 maps and phase contrast measurements were acquired at a 1.5 T MR scanner using conventional gradient-echo sequences in predefined distances to the prostheses. Results were compared to measurements with a synthetic metal-free aortic valve. RESULTS: The flow results at the level of the prosthesis differed significantly from the reference flow acquired before the level of the prosthesis. The maximum flow miscalculation was 154 ml/s for one of the biological prostheses and 140 ml/s for the mechanical prosthesis. Measurements with the synthetic aortic valve did not show significant deviations. Flow values measured approximately 20 mm distal to the level of the prosthesis agreed with the reference flow for all tested all prostheses. CONCLUSIONS: The tested heart valve prostheses lead to a significant deviation of the measured flow rates compared to a reference. A distance of 20 mm was effective in our setting to avoid this influence. PMID- 28088918 TI - Direct bladder hernia after indirect hernia repair in extremely low birth weight babies: two case reports and a review of the literature. AB - BACKGROUND: Inguinal hernia repair is the most common surgical procedure in babies. Despite a meticulous technique, relapses may occur. The occurrence of a direct bladder wall hernia in relapses has never before been reported in the literature. CASE PRESENTATION: Here, we report two cases of direct bladder herniation: a white baby boy born after 25 weeks of gestation and a white baby boy born after 26 weeks of gestation. Both of the formerly extremely low birth weight babies were affected after open bilateral hernia repair. Recurrent hernias developed on the right side, and direct bladder herniation was identified intraoperatively. In one case, laparoscopy was applied to identify a supravesical type of hernia. Immaturity and a difficult postnatal course might have contributed to hernia relapse in these cases. CONCLUSIONS: Misinterpretation of bladder herniation might have disastrous consequences. Laparoscopy is a helpful tool in comparable cases. PMID- 28088919 TI - The Journal Impact Factor is under attack - use the CAPCI factor instead. AB - The uses and misuses of the Journal Impact Factor (JIF) have been thoroughly discussed in the literature. A few years ago, I predicted that JIF would soon be replaced, while another colleague argued the opposite. Over the past few months, attacks on JIF have intensified, with some publishing organizations gradually removing the indicator from their journals' websites. Here, I argue that most, if not all of the misuses of JIF are related to its name. The word "impact" should be removed, since it implies an influential attribute, either for the journals, their published papers, or their authors. I propose instead the use of a new name, the "CAPCI factor", standing for Citation Average Per Citable Item, which accurately describes what is represented by this measure. PMID- 28088920 TI - Cardiac strain findings in children with latent rheumatic heart disease detected by echocardiographic screening. AB - BACKGROUND: Identification of patients with latent rheumatic heart disease by echocardiography presents a unique opportunity to prevent disease progression. Myocardial strain is a more sensitive indicator of cardiac performance than traditional measures of systolic function. OBJECTIVE: The objective of this study was to test the hypothesis that abnormalities in myocardial strain may be present in children with latent rheumatic heart disease. METHODS: Standard echocardiography images with electrocardiogram gating were obtained from Ugandan children found to have latent rheumatic heart disease as well as control subjects. Traditional echocardiography measures of systolic function were obtained, and offline global longitudinal strain analysis was performed. Comparison between groups was performed using strain as a continuous (Mann Whitney U-test) and categorical (cut-off 5th percentile for age) variable. RESULTS: Our study included 14 subjects with definite rheumatic heart disease, 13 with borderline rheumatic heart disease, and 112 control subjects. None of the subjects had abnormal left ventricular size or ejection fraction. Global longitudinal strain was lower than the 5th percentile in 44% of the subjects with any rheumatic heart disease (p=0.002 versus controls) and 57% of the subjects with definite rheumatic heart disease (p=0.03). The mean absolute strain values were significantly lower when comparing subjects with any rheumatic heart disease with controls (20.4+/-3.95 versus 22.4+/-4.35, p=0.025) and subjects with definite rheumatic heart disease with controls (19.9+/-4.25 versus 22.4+/-4.35, p=0.033). CONCLUSION: Global longitudinal strain is decreased in subjects with rheumatic heart disease in the absence of abnormal systolic function. Larger studies with longer-term follow-up are required to determine whether there is a role for strain to help better understand the pathophysiology of latent rheumatic heart disease. PMID- 28088921 TI - Red flags: a case series of clinician-family communication challenges in the context of CHD. AB - We describe three cases of newborns with complex CHD characterised by communication challenges. These communication challenges were categorised as patient, family, or system-related red flags. Strategies for addressing these red flags were proposed, for the goal of optimising care and improving quality of life in this vulnerable population. PMID- 28088922 TI - Restricting the marketing of foods and non-alcoholic beverages to children in South Africa: are all nutrient profiling models the same? AB - The WHO has called for governments to improve children's food environment by implementing restrictions on the marketing of 'unhealthy' foods to children. Nutrient profiling (NP) models are used to define 'unhealthy' foods and support child-directed food marketing regulations. The aim of the present study was to assess the suitability of the South African NP model (SANPM), developed and validated for health claim regulations, for child-directed food marketing regulations. The SANPM was compared with four NP models specifically developed for such regulations. A representative list of 197 foods was compiled by including all foods advertised on South African free-to-air television channels in 2014 and foods commonly consumed by South African children. The nutritional information of the foods was sourced from food packaging, company websites and a food composition table. Each individual food was classified by each of the five NP models. The percentage of foods that would be allowed according to the different NP models ranged from 6 to 45 %; the models also varied considerably with regard to the type of foods allowed for marketing to children. The majority of the pairwise comparisons between the NP models yielded kappa statistics >0.4, indicating a moderate agreement between the models. An almost perfect pairwise agreement (kappa=0.948) existed between the SANPM and the UK Food Standards Agency model (United Kingdom Office of Communication nutrient profiling model), a model extensively tested and validated for such regulations. The SANPM is considered appropriate for child-directed food marketing regulations in South Africa. PMID- 28088923 TI - An assessment of the influence of macronutrients on growth performance and nutrient utilisation in broiler chickens by nutritional geometry. AB - The right-angled triangle mixture experiment was designed to include fourteen diets with different concentrations of starch, protein and lipid. Experimental diets were offered to male Ross 308 broiler chickens from 10 to 23 d after hatching, and response curves and surfaces were generated to illustrate the influence of macronutrients on growth performance and nutrient utilisations. Despite the primary function of macronutrients, especially protein, may not be providing energy, macronutrients were expressed as energy derived from starch, protein and fat for statistical purposes in the mixture design. Energy derived from lipid had a greater impact on feed intake than energy derived from starch and protein. When we compared the influence of starch and protein on feed intake, 'equal distance rule' was observed, which means the animal consumes feed to the point on its respective nutritional rails where the shortage of starch exactly equals the surplus of consumed protein. Increasing the protein-derived energy intake increased weight gain in broiler chickens, whereas energy intake derived from starch and lipid had little impact on weight gain. Feed conversion ratio (FCR) may be reduced by either increasing protein energy intake or decreasing starch energy intake. As the slope of the contours was less than 1, the influence of starch energy intakes on FCR exceeded that of protein energy intakes. In conclusion, energy derived from protein is more important than non-protein energy in terms of weight gain, and a balance between protein and energy supplies is required for efficient muscle protein deposition. PMID- 28088924 TI - Microbiology of otitis media in Indigenous Australian children: review. AB - OBJECTIVES: To review research addressing the polymicrobial aetiology of otitis media in Indigenous Australian children in order to identify research gaps and inform best practice in effective prevention strategies and therapeutic interventions. METHODS: Literature review. RESULTS: Studies of aspirated middle ear fluid represented a minor component of the literature reviewed. Most studies relied upon specimens from middle-ear discharge or the nasopharynx. Culture-based middle-ear discharge studies have found that non-typeable Haemophilus influenzae and Streptococcus pneumoniae predominate, with Moraxella catarrhalis, Staphylococcus aureus and Streptococcus pyogenes isolated in a lower proportion of samples. Alloiococcus otitidis was detected in a number of studies; however, its role in otitis media pathogenesis remains controversial. Nasopharyngeal colonisation is a risk factor for otitis media in Indigenous infants, and bacterial load of otopathogens in the nasopharynx can predict the ear state of Indigenous children. CONCLUSION: Most studies have used culture-based methods and specimens from middle-ear discharge or the nasopharynx. Findings from these studies are consistent with international literature, but reliance on culture may incorrectly characterise the microbiology of this condition. Advances in genomic technologies are now providing microbiologists with the ability to analyse the entire mixed bacterial communities ('microbiomes') of samples obtained from Indigenous children with otitis media. PMID- 28088925 TI - A randomized controlled trial of Kundalini yoga in mild cognitive impairment. AB - BACKGROUND: Global population aging will result in increasing rates of cognitive decline and dementia. Thus, effective, low-cost, and low side-effect interventions for the treatment and prevention of cognitive decline are urgently needed. Our study is the first to investigate the effects of Kundalini yoga (KY) training on mild cognitive impairment (MCI). METHODS: Older participants (>=55 years of age) with MCI were randomized to either a 12-week KY intervention or memory enhancement training (MET; gold-standard, active control). Cognitive (i.e. memory and executive functioning) and mood (i.e. depression, apathy, and resilience) assessments were administered at baseline, 12 weeks and 24 weeks. RESULTS: At baseline, 81 participants had no significant baseline group differences in clinical or demographic characteristics. At 12 weeks and 24 weeks, both KY and MET groups showed significant improvement in memory; however, only KY showed significant improvement in executive functioning. Only the KY group showed significant improvement in depressive symptoms and resilience at week 12. CONCLUSION: KY group showed short- and long-term improvements in executive functioning as compared to MET, and broader effects on depressed mood and resilience. This observation should be confirmed in future clinical trials of yoga intervention for treatment and prevention of cognitive decline (NCT01983930). PMID- 28088926 TI - Proxy rated quality of life of care home residents with dementia: a systematic review. AB - BACKGROUND: Quality of life (QoL) is an important outcome for people with dementia living in care homes but usually needs to be rated by a proxy. We do not know if relative or paid carer proxy reports differ. We conducted the first systematic review and meta-analysis of data investigating whether and how these proxy reports of QoL differ. METHODS: We searched four databases: Medline, Embase, PsychInfo, and CINAHL in October 2015 with the terms: dementia, QoL, proxy, and care home. Included studies either compared proxy QoL ratings or investigated the factors associated with them. We meta-analyzed data comparing staff and family proxy rated QoL. RESULTS: We included 17/105 papers identified. We found no difference between global proxy ratings of QoL (n = 1,290; pooled effect size 0.06 (95% CI = -0.08 to 0.19)). Studies investigating factors associated with ratings (n = 3,537) found family and staff ratings correlated with the resident's physical and mental health. Staff who were more distressed rated resident QoL lower. Relatives rated it lower when the resident had lived in the care home for longer, when they observed more restraint, or contributed more to fees. CONCLUSIONS: Relatives and staff proxy QoL ratings share a clear relationship to resident health and overall ratings were similar. Rater-specific factors were, however, also associated with scores. Understanding why different raters consider the QoL of the same person differently is an important consideration when evaluating the meaning of proxy rated QoL. Proxy raters' backgrounds may affect their rating of QoL. PMID- 28088927 TI - Assessing understanding of relative clauses: a comparison of multiple-choice comprehension versus sentence repetition. AB - Although sentence repetition is considered a reliable measure of children's grammatical knowledge, few studies have directly compared children's sentence repetition performance with their understanding of grammatical structures. The current study aimed to compare children's performance on these two assessment measures, using a multiple-choice picture-matching sentence comprehension task and a sentence repetition task. Thirty-three typically developing children completed both assessments, which included relative clauses representing a range of syntactic roles. Results revealed a similar order of difficulty of constructions on both measures but little agreement between them when evaluating individual differences. Interestingly, repetition was the easier of the two measures, with children showing the ability to repeat sentences they did not understand. This discrepancy is primarily attributed to the additional processing load resulting from the design of multiple-choice comprehension tasks, and highlights the fact that these assessments are invoking skills beyond those of linguistic competence. PMID- 28088929 TI - Morphologic analysis of sperm from two neotropical primate species: comparisons between the squirrel monkeys Saimiri collinsi and Saimiri vanzolinii. AB - Sperm morphometry can be applied to identify different animal groups and species and to evaluate sperm quality. Furthermore, knowledge on species-specific differences will help to enhance biological information, as well as to develop efficient reproductive technologies. The aims in the present study were to describe sperm morphometry from the recently characterized species S. collinsi and S. vanzolinii, to verify if the morphometric sperm patterns are similar or different between both species, and to determine if the sperm morphometry is affected by the levels of sperm defects using the S. collinsi as a model. Semen was collected from S. collinsi (n = 10) and S. vanzolinii (n = 2) monkeys, and sperm was submitted to morphological analysis. From the 10 samples from S. collinsi, five presented sperm of poor quality and two subgroups were formed for this species, i.e. high and poor quality sperm. Data on sperm motility and vigour were analysed, as well morphometric parameters on sperm head and tail. It was observed the normal morphometry was correlated with high quality sperm. Poor quality sperm presented smaller and 7% more ellipticity in their head, when compared with high quality sperm. Sperm from S. vanzolinii presented larger head than those from S. collinsi, but tail lengths were similar. Sperm morphometry can be used as a complementary tool to predict sperm motility and vigour for the S. collinsi species, and S. collinsi appear as a suitable model for S. vanzolinii. PMID- 28088928 TI - Multi-modal MRI investigation of volumetric and microstructural changes in the hippocampus and its subfields in mild cognitive impairment, Alzheimer's disease, and dementia with Lewy bodies. AB - BACKGROUND: Volumetric atrophy and microstructural alterations in diffusion tensor imaging (DTI) measures of the hippocampus have been reported in people with Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, no study to date has jointly investigated concomitant microstructural and volumetric changes of the hippocampus in dementia with Lewy bodies (DLB). METHODS: A total of 84 subjects (23 MCI, 17 DLB, 14 AD, and 30 healthy controls) were recruited for a multi-modal imaging (3T MRI and DTI) study that included neuropsychological evaluation. Freesurfer was used to segment the total hippocampus and delineate its subfields. The hippocampal segmentations were co-registered to the mean diffusivity (MD) and fractional anisotropy (FA) maps obtained from the DTI images. RESULTS: Both AD and MCI groups showed significantly smaller hippocampal volumes compared to DLB and controls, predominantly in the CA1 and subiculum subfields. Compared to controls, hippocampal MD was elevated in AD, but not in MCI. DLB was characterized by both volumetric and microstructural preservation of the hippocampus. In MCI, higher hippocampal MD was associated with greater atrophy of the hippocampus and CA1 region. Hippocampal volume was a stronger predictor of memory scores compared to MD within the MCI group. CONCLUSIONS: Through a multi-modal integration, we report novel evidence that the hippocampus in DLB is characterized by both macrostructural and microstructural preservation. Contrary to recent suggestions, our findings do not support the view that DTI measurements of the hippocampus are superior to volumetric changes in characterizing group differences, particularly between MCI and controls. PMID- 28088930 TI - Adherence of older people with instability in vestibular rehabilitation programmes: prediction criteria. AB - OBJECTIVE: To determine whether demographic characteristics or balance examination findings can predict the adherence of older people with instability to a vestibular rehabilitation programme. METHODS: A prospective case-control study was conducted of 120 patients aged 65 years or more (mean age, 77.3 +/- 6.33 years). Two groups were classified according to patients' adherence with the follow-up post-rehabilitation protocol. Analysed variables included: age, sex, body mass index, Timed Up and Go test findings, computerised dynamic posturography, Dizziness Handicap Inventory scores and Short Falls Efficacy Scale - International questionnaire results, number of falls, and type of vestibular rehabilitation. RESULTS: Two groups were established: adherents (99 individuals) and non-adherents (21 individuals). There were differences between the groups regarding: sex (female-to-male ratio of 4.8:1 in adherents and 1.63:1 in non adherents), age (higher in non-adherents) and voluntary movement posturographic test results (non-adherents had poorer scores). CONCLUSION: The patients most likely to abandon a vestibular rehabilitation programme are very elderly males with low scores for centre of gravity balancing and limits of stability. PMID- 28088931 TI - Development of medical treatment for eye injuries in the mainland of China over the past decade. AB - In the article, the development of medical treatment for eye injuries in the mainland of China was reviewed. According to the data provided in Eye Injury Vitrectomy Study (EIVS), 27% of 72 eyes with no light perception (NLP) gained recovery in term of antomy and visual function. Vitrectomy initiated at more than 4 weeks after open eye injury is an independent risk factor for developing PVR. Prognosis of anatomy and visual function of the injured eye with PVR is markedly worse than that without PVR. Serious injuries of ciliary body, choroid and retina are three key parts of the eye with NLP. The concept that the treatment of the eye injury gradually focus on the whole globe is embodied. The data from 13575 in patients with traumatic eyes in 14 hospitals revealed that the rate of immediate enucleation was remarkable reduced with comparison of 20 years ago. PMID- 28088932 TI - Trauma of the globe: State of art in global and in China. AB - Current states of traumatic eye injury are reviewed in terms of epidemiology in the developing countries and developed countries, causes of the trauma, eye injury types, traumatic eye injury diagnostic methods and treatments. Trauma caused vision-threatening conditions such as open global injury, traumatic optic neuropathy and proliferative vitreoretinopathy are particularly discussed. Also the most updated clinic research in China as Eye Injury Vitrectomy Study is discussed. At the end, the current achievements and research in traumatic eye injury in the world are summerized. PMID- 28088933 TI - New classification of ocular foreign bodies. AB - Foreign bodies (FBs) in the eye are usually classified as intraocular (IOFB) or extraocular (EOFB). In IOFB the FB is within the eye ball and in EOFB it is outside. This classification seems oversimplified. Hence a new classification is proposed on the basis of FB locations, in which adnexal FBs (in orbit, lids, con- junctiva and lacrimal apparatus) are also included. These are further classified according to their exact location. FBs can also be classified in many other ways. Besides IOFB and EOFB, another condition IMFB (intramural foreign body) is also described. The FBs are situated within cornea or sclera and are neither IOFB nor EOFB. Ocular trauma also includes trauma to ocular adnexa and hence the terms IOFB and EOFB have been replaced by IGFB (intraglobal foreign body) and EGFB (extraglobal foreign body). PMID- 28088934 TI - Clinical diagnosis and treatment of intraorbital wooden foreign bodies. AB - PURPOSE: The intraorbital wooden foreign body is often misdiagnosed or missed on computed tomog- raphy (CT) scan, due to the invisible or unclear images. The residual foreign bodies often occur during surgical removal. The clinical manifestations, imaging features and treatment of intraorbital wooden foreign bodies were discussed in this study. METHOD: We retrospectively analyzed 14 cases of intraorbital wooden foreign bodies managed at our hospital between January 2007 and May 2015. All patients underwent orbital CT examination before surgery, and surgery was performed under general anesthesia with orbital wound debridement and suture, as well as exploration and removal of wooden foreign bodies. RESULTS: At first, 11 cases underwent removal of foreign bodies, including 1 case with incomplete removal and then receiving a secondary surgery. Foreign bodies were not found in three cases with preoperative misdiagnosis and orbital MRI found residual foreign bodies in the orbit. Operations were performed via primary wound approach in eight cases, conjunctival approach in two cases, and anterior orbitotomy in four cases. Postoperatively, one case was complicated with eye injuries, three cases with ocular muscle injuries, eight cases with visual loss, and eight cases with orbital abscess. The length of foreign bodies ranged from 1.8 cm to 11.0 cm. The maximum of four foreign bodies were removed at the same time. CONCLUSION: Because the imaging of orbital wooden foreign bodies is complex and varied, MRI should be combined when they are invisible on CT scan. At the same time injuries trajectory and clinical mani- festations of patients should be taken into account. Surgical exploration should be extensive and thor- ough, and foreign bodies and orbital abscess must be cleared. PMID- 28088935 TI - Status of ocular trauma in hospitalized patients in Kashan, 2011: As a sample of industrial city. AB - PURPOSE: Ocular trauma is the third leading cause of hospitalization in ophthalmology patients, imposing direct and indirect physical and psychological costs on society. This study aims to investigate the status of ocular trauma in hospitalized patients in the industrialized city of Kashan in 2011. METHODS: This cross-sectional descriptive applied study was conducted in 2012 on patients hospitalized for ocular trauma. Data, including age, gender, occupation, education, timing of admission following accident, location of accident, type of injury, damaging instrument, and type of trauma, were collected using a questionnaire designed by a trained nurse, and analyzed using SPSS-16 software by means of means +/- standard deviation, frequency, and percentage for descriptive data and t-test, one-way analysis of variance, Chi-square and Fisher exact test for analysis at significance level of p < 0.05. RESULTS: In total, 82 patients were hospitalized due to ocular traumas. The majority of patients were male (65 patients, 79.3%). Their mean age was (25.4 +/- 21.4) years, with an age range of 20-40 years (30 patients, 36.6%). Hyphema was the most common injury (26 patients, 25.5%), home was the most frequent incident location (32 patients, 39%), and knife or other cutting tools were mostly responsible for injuries (18 patients, 21.9%). Patients were hospitalized for 1e6 days, and the average length of stay in hospital was 2.63 days. Frequency distribution of injuries based on whether or not ruptures differed significantly among different age groups. CONCLUSION: The majority of ocular trauma occurred in young males. Knife was the principle culprit for eye injuries, followed by vehicles. To reduce such incidents, it is recommended that people be trained to avoid high-risk behaviors when using knives and to better heed driving rules and regulations. PMID- 28088936 TI - Endoscopic decompression of the optic canal for traumatic optic neuropathy. AB - PURPOSE: Traumatic optic neuropathy (TON) is a serious complication of head trauma with the incidence rate of 0.5%-5%. The aim of this study was to investigate the therapeutic efficacy of endoscopic decompression of the optic canal for optic nerve injuries. METHODS: In this study, 11 patients treated in our hospital from January 2009 to January 2015 with the visual loss resulting from TON were retrospectively reviewed for preoperative vision, visual evoked potential (VEP) scan, surgical approach, postoperative visual acuity, complications, and follow-up results. RESULTS: All these patients received endoscopic decompression of the optic canal. At the 3-month follow- up, the visual acuity improvement rate of the 11 patients was 45.5%. The vision acuity of 2 cases improved from hand movement to 0.08 and 0.3 after operation. Another patient's vision acuity returned to 0.05 compared to light sensation preoperatively. Two cases had finger counting before surgery but they had a vision acuity of 0.4 and light sensation respectively after surgery. However, the other 6 cases' vision did not improve after surgery. CONCLUSION: Endoscopic decompression of the optic canal is an effective way to cure TON. VEP could be used as an important reference for preoperative and prognosis evaluation. Operative time after trauma is only a relative condition that may affect the therapeutic effect of optic canal decompression. Poor results of this procedure may be related to the severity of the optic nerve injury. PMID- 28088937 TI - Traumatic cardiac injury: Experience from a level-1 trauma centre. AB - PURPOSE: Traumatic cardiac injury (TCI) is a challenge for trauma surgeons as it provides a short thera- peutic window and the management is often dictated by the underlying mechanism and hemodynamic status. The current study is to evaluate the factors influencing the outcome of TCI. METHODS: Prospectively maintained database of TCI cases admitted at a Level-1 trauma center from July 2008 to June 2013 was retrospectively analyzed. Hospital records were reviewed and statistical analysis was performed using the SPSS version 15. RESULTS: Out of 21 cases of TCI, 6 (28.6%) had isolated and 15 (71.4%) had associated injuries. Ratio be- tween blunt and penetrating injuries was 2:1 with male preponderance. Mean ISS was 31.95. Thirteen patients (62%) presented with features suggestive of shock. Cardiac tamponade was present in 12 (57%) cases and pericardiocentesis was done in only 6 cases of them. Overall 19 patients underwent surgery. Perioperatively 8 (38.1%) patients developed cardiac arrest and 7 developed cardiac arrhythmia. Overall survival rate was 71.4%. Mortality was related to cardiac arrest (p = 0.014), arrhythmia (p = 0.014), and hemorrhagic shock (p =0.04). The diagnostic accuracy of focused assessment by sonography in trauma (FAST) was 95.24%. CONCLUSION: High index of clinical suspicion based on the mechanism of injury, meticulous examination by FAST and early intervention could improve the overall outcome. PMID- 28088938 TI - Clinical analysis of 54 cases of large area soft tissue avulsion in the lower limb. AB - OBJECTIVE: To assess the clinical curative effect of different treatment methods for large area avulsion injury in the lower limb. METHODS: Between January 2010 and December 2013, 54 patients with large area avulsion injury in the lower limb were treated in the trauma center of our hospital, including 34 males and 20 females with a mean age of 35.7 years (range, 16-65 years). The injury mechanism was traffic accident in 44 cases, hitting by heavy objects in 8 cases, and fall from height in 2 cases, involving 31 thighs, 19 legs and 4 feet involved. The sizes of the avulsed wounds ranged from 10 cm *15 cm to 50 cm *30 cm. There were 16 cases combined with hemorrhagic shock, 5 with femoral fractures, and 7 with tibiofibula fractures. Averagely the patients were sent to our hospital within 3.5 h (range, 1.5-10 h) after injury. For the 54 patients, three different surgical strategies were performed based on the wound area and condition of the avulsed skin: in Group A, 24 patients were treated by debridement and preservation of subcutaneous vascular network + vertical mattress suture of full thickness skin flap + tube drainage; in Group B, 25 patients were treated by split-thickness skin flap meshing and grafting + vacuum sealing drainage (VSD); and in Group C, the other 5 patients were treated by debridement and VSD at stage I + reattachment of autologous reserved frozen split-thickness skin graft at stage II. RESULTS: All the 54 patients recovered and were discharged eventually, without any deaths or amputees. In each group, there were no statistical differences (all p > 0.05) among different injury sites in terms of survival rate and length of hospital stay, except for the infection rate, which was much higher (p =0.000) at the leg area than that at the thigh (32.54% +/- 2.97% vs. 2.32% +/- 2.34% in Group A and 50.00% +/- 0.00% vs. 0 in Group C) or the foot (50.00% +/- 0.00% vs. 0 in Group C). Moreover comparison of the three surgical methods showed a significant different (all p < 0.05) between each other for all the three assessed parameters, i.e. flap survival rate, length of hospital stay, and infection rate. CONCLUSION: Treatment choices for skin avulsion on the lower limb should be based on the viability of the avulsed skin flap and the location of the wound. Proper choice can not only reduce the economic burden caused by using VSD, but also shorten the long hospital stay due to repeated wound dressing change or second stage surgery. PMID- 28088939 TI - Complications in the management of closed high-energy proximal tibial plateau fractures. AB - PURPOSE: To report complications in the management of complex closed proximal tibial fractures. METHOD: A retrospective study was conducted to analyze the infectious and noninfectious complications encountered in the management of high energy Schatzker type V and VI tibial plateau fractures. All patients were treated at the level 1 trauma centre between January 2011 and March 2014. Sixty two patients were included in the study. The mean patient age was (43.16 +/- 11.59) years with 60 males and 2 females. Infectious complications like superficial and deep infection, wound dehiscence, malalignment in the immediate postoperative period and in follow-up period were noted. RESULTS: The overall complication rate was 30.65% (19 out of 62). Infectious complications were noted in 20.97% cases (13/62). In majority of the cases (8/13), superficial infection was seen which managed with regular dressing and antibiotic administration. The patients (5/13) who had developed deep-seated infection were subjected to repeated debridements, flap coverage, implant removal or amputation depending upon the host response. Thirteen patients had experienced noninfectious complications. Hardware related complications were noticed in six patients and four among them received a secondary procedure. Malalignment was observed in seven patients but only single patient underwent subsequent operative intervention. CONCLUSION: Proximal tibial plateau fractures especially Shatzker type V and VI are associated with extensive soft tissue damage even in closed injuries. The complications encountered in the management of these fractures can be minimized with appropriate patient selection and minimal soft tissue dissection. PMID- 28088940 TI - Indirect reduction technique using a distraction support in minimally invasive percutaneous plate osteosynthesis of tibial shaft fractures. AB - PURPOSE: To describe an indirect reduction technique during minimally invasive percutaneous plate osteosynthesis (MIPPO) of tibial shaft fractures with the use of a distraction support. METHODS: Between March 2011 and October 2014, 52 patients with a mean age of 48 years (16-72 years) sustaining tibial shaft fractures were included. All the patients underwent MIPPO for the fractures using a distraction support prior to insertion of the plate. Fracture angular deformity was assessed by goni- ometer measurement on preoperative and postoperative images. RESULTS: Preoperative radiographs revealed a mean of 7.6 degrees (1.2 degrees -28 degrees ) angulation in coronal plane and a mean of 6.8 degrees (0.5 degrees -19 degrees ) angulation in sagittal plane. Postoperative anteroposterior and lateral radio- graphs showed a mean of 0.8 degrees (0 degrees -4.0 degrees ) and 0.6 degrees (0 degrees -3.6 degrees ) of varus/valgus and apex anterior/posterior angulation, respectively. No intraoperative or postoperative complications were noted. CONCLUSIONS: This study suggests that the distraction support during MIPPO of tibial shaft fractures is an effective and safe method with no associated complications. PMID- 28088941 TI - Fracture union in percutaneous Kirschner wire fixation in paediatric tibial shaft fractures. AB - PURPOSE: To evaluate the efficacy of intramedullary Kirschner wires for the treatment of unstable tibial shaft fractures in children. METHODS: This prospective study was conducted at the Department of Orthopaedic Surgery in Maharishi Markandeshwar Medical College from June 2005 to June 2010. Sixty-six children having closed fracture of the tibial shaft with a mean age of 7.7 years (range, 2-14 years) were recruited from emergency and outpatient department. They were treated with percutaneous intramedullary Kirschner wires. The clinical results of our study were rated on the basis of the criteria of union, nonunion, delayed union or malunion. All children were followed for one year. RESULTS: Children achieved union in a mean time of 8 weeks (range, 6-10 weeks). Postoperatively, three children (4.55%) had delayed union, one (1.52%) valgus deformity of lower leg, three (4.55%) post- operative knee pain and twelve (18.18%) skin irritation at pin site.Wires were removed after 8-22 weeks without any complications. No patient was lost to follow-up. The results were excellent in 95.45% and good in 4.55% children. CONCLUSION: This technique is cost effective, simple, quick to perform, safe and reliable and avoids pro- longed hospitalization with good results. PMID- 28088942 TI - A distal-lock electromagnetic targeting device for intramedullary nailing: Suggestions and clinical experience. AB - PURPOSE: To describe our clinical experience with a system named SureShot? Distal Targeting (Smith & Nephew, Memphis, USA) based on magnetic field presence and discuss our suggestions on this technique. METHODS: We analysed prospectively 47 patients affected by humeral, tibial or femoral fractures, treated in our institution during a 3-year period of time (August 2010 to September 2013). We considered the following parameters: the time to set up, the time to position a single screw, the effectiveness of the system (drilling ad screwing), the irradiation exposure time during distal locking procedure and surgical complications. RESULTS: A total number of 96 screws were inserted. The mean preparation time of the device was 5.1 min +/- 2 min (range 3-10 min). The mean time for single screw targeting was 5.8 min +/- 2.3 min (range 4-18 min). No major complications occurred. Only a few locking procedures were needed to be practiced in order to obtain the required expertise with this targeting device. CONCLUSION: According to our results, this device is reliable and valid whenever the correct technique is followed. It is also user friendly, exposes to lower radiation and needs less surgical time compared to relative data from the literature. However, the surgeon should always be aware of how to use the free hand technique in case of malfunctioning of the system. PMID- 28088944 TI - Gastroduodenal artery aneurysm - A rare complication of traumatic pancreatic injury. AB - Aneurysm of gastroduodenal artery (GDA) is rare. Most reported cases are due to pancreatitis and atherosclerosis; however, those following pancreatic trauma have not been reported. We encoun- tered GDA aneurysm in a patient of blunt abdominal trauma, who had pancreatic contusion and retroduodenal air on contrast enhanced computed tomography of abdomen. Emergency laparotomy for suspected duodenal injury revealed duodenal wall and pancreatic head contusion, mild hemo- peritoneum and no evidence of duodenal perforation. In the postoperative period, the patient developed upper gastrointestinal hemorrhage on day 5. Repeat imaging revealed GDA aneurysm, which was managed successfully by angioembolization. This case highlights, one, delayed presen- tation of GDA aneurysm after blunt pancreatic trauma and two, its successful management using endovascular technique. PMID- 28088943 TI - Percutaneous poking reduction and fixation versus open reduction and fixation in the treatment of displaced calcaneal fractures for Chinese patients: A systematic review and meta-analysis. AB - PURPOSE: To compare the efficacy of percutaneous poking reduction and fixationwith open reduction and fixation in the treatment of displaced calcaneal fractures. METHODS: Reports of studies using case-controlled trials (CCT) to compare the percutaneous poking reduction and fixation with the open reduction and fixation in the management of calcaneal fractures were retrieved from the Cochrane Library, PubMed Database, CNKI, Chinese Biomedical Database, Wanfang Data (from January of 2005 to August of 2015). Methodological quality of the trials was critically assessed, and relevant data were extracted. Statistical software Revman 5.0 was used for data-analysis. RESULTS: Fifteen articles were included in the meta-analysis. Comparison of the efficacy of percutaneous poking reduction and fixation with open reduction and fixation in the treatment of calcaneal fractures revealed statistical significance in the incidence of complications after operation [RR = 0.32, 95% CI (0.20, 0.5), p < 0.05]. However, there were neither statistical significance in the degrees of recovery for calcaneal Bohler angle [WMD = -1.65, 95% CI (-3.43, 0.14), p > 0.05] and calcaneal Gissane angle [WMD = -3.21, 95% CI (-6.75, 0.33), p > 0.05], nor statistical significance in the rate of good foot function after operation [RR= 0.95, 95% CI (0.90, 1.00), p > 0.05]. CONCLUSION: For the treatment of calcaneal fractures, percutaneous poking reduction and fixation is su- perior to open reduction and fixation in terms of the incidence of postoperative complications. But both techniques can obtain satisfactory clinical function. PMID- 28088945 TI - Clinical analysis of thoracoscopic surgery combined with intraoperative autologous blood transfusion in the treatment of traumatic hemothorax. AB - From January 2013 to January 2015, 19 patients of traumatic hemothorax with hemorrhagic shock were treated in our department by thoracoscopic surgery combined with autologous blood transfusion. This study retrospectively analyzed the therapeutic effect and shared our experience. The average amount of blood transfused back was 662.41 ml +/- 269.15 ml. None of the patients developed transfusion reaction and were all discharged uneventfully. Thoracoscopic surgery combined with autologous blood trans- fusion is effective in the rescue of patients with progressive hemothorax and hemorrhagic shock. When corresponding indications are well managed, treatment for these patients is quicker, safer, and more effective. PMID- 28088946 TI - Effects of chlorogenic acid on intracellular calcium regulation in lysophosphatidylcholine-treated endothelial cells. AB - Lysophosphatidylcholine (LPC) is a major phospholipid component of oxidized low density lipoprotein (ox-LDL) and is implicated in its atherogenic activity. This study investigated the effects of LPC on cell viability, intracellular calcium homeostasis, and the protective mechanisms of chlorogenic acid (CGA) in human umbilical vein endothelial cells (HUVECs). LPC increased intracellular calcium ([Ca2+]i) by releasing Ca2+ from intracellular stores and via Ca2+ influx through store-operated channels (SOCs). LPC also increased the generation of reactive oxygen species (ROS) and decreased cell viability. The mRNA expression of Transient receptor potential canonical (TRPC) channel 1 was increased significantly by LPC treatment and suppressed by CGA. CGA inhibited LPC-induced Ca2+ influx and ROS generation, and restored cell viability. These results suggested that CGA inhibits SOC-mediated Ca2+ influx and ROS generation by attenuating TRPC1 expression in LPC-treated HUVECs. Therefore, CGA might protect endothelial cells against LPC injury, thereby inhibiting atherosclerosis. [BMB Reports 2017; 50(6): 323-328]. PMID- 28088947 TI - Heme oxygenase-1 (HO-1)/carbon monoxide (CO) axis suppresses RANKL-induced osteoclastic differentiation by inhibiting redox-sensitive NF-kappaB activation. AB - Heme oxygenase (HO-1) catalyzes heme to carbon monoxide (CO), biliverdin/bilirubin, and iron and is known to prevent the pathogenesis of several human diseases. We assessed the beneficial effect of heme degradation products on osteoclastogenesis induced by receptor activator of NF-kappaB ligand (RANKL). Treatment of RAW264.7 cells with CORM-2 (a CO donor) and bilirubin, but not with iron, decreased RANKL-induced osteoclastogenesis, with CORM-2 having a more potent anti-osteogenic effect. CORM-2 also inhibited RANKLinduced osteoclastogenesis and osteoclastic resorption activity in marrow-derived macrophages. Treatment with hemin, a HO-1 inducer, strongly inhibited RANKL induced osteoclastogenesis in wild-type macrophages, but was ineffective in HO 1+/- cells. CORM-2 reduced RANKL-induced NFATc1 expression by inhibiting IKK dependent NF-kappaB activation and reactive oxygen species production. These results suggest that CO potently inhibits RANKL-induced osteoclastogenesis by inhibiting redox-sensitive NF-kappaB-mediated NFATc1 expression. Our findings indicate that HO-1/CO can act as an antiresorption agent and reduce bone loss by blocking osteoclast differentiation. [BMB Reports 2017; 50(2): 103-108]. PMID- 28088949 TI - [Recent advancement of renal transplantation at home and abroad]. PMID- 28088948 TI - Translation initiation mediated by nuclear cap-binding protein complex. AB - In mammals, cap-dependent translation of mRNAs is initiated by two distinct mechanisms: cap-binding complex (CBC; a heterodimer of CBP80 and 20)-dependent translation (CT) and eIF4E-dependent translation (ET). Both translation initiation mechanisms share common features in driving cap- dependent translation; nevertheless, they can be distinguished from each other based on their molecular features and biological roles. CT is largely associated with mRNA surveillance such as nonsense-mediated mRNA decay (NMD), whereas ET is predominantly involved in the bulk of protein synthesis. However, several recent studies have demonstrated that CT and ET have similar roles in protein synthesis and mRNA surveillance. In a subset of mRNAs, CT preferentially drives the cap dependent translation, as ET does, and ET is responsible for mRNA surveillance, as CT does. In this review, we summarize and compare the molecular features of CT and ET with a focus on the emerging roles of CT in translation. [BMB Reports 2017; 50(4): 186-193]. PMID- 28088950 TI - [Risk factors for acute rejection in living-donor kidney transplant recipients in China: a subgroup analysis of a multi-center, registry study]. AB - Objective: To evaluate pre-and early post-transplantation risk factors for acute rejection(AR) in kidney recipients. Methods: This subgroup analysis of a multi center registry study was conducted on living-donor kidney transplant recipients in China with 10 years of follow-up. This study analyzed 1 255 recipients including 921 males(73.4%) and with a mean age of (33+/-10)years. Data from patients were first analyzed with univariate analysis and then multivariate analysis was used for finding out the potential risk factors of AR. Results: A total of 106(8.4%) patients were suspected with AR after kidney transplantation, while 1 149 patients were considered as non-AR. Multivariable analysis demonstrated a significant influence of recipient age and cold ischemia time(CIT) on the occurrence of AR(OR: 0.956, 95% CI: 0.923-0.990; OR: 1.006, 95% CI: 1.002 1.011, respectively). The frequency of severe infection was significantly higher in the AR group than non-AR group(38.7% vs 10.8%; P<0.000 1). The occurrence of new-onset diabetes mellitus and tumors was similar in the two groups. Conclusions: Recipient age and CIT are risk factors for AR after living-donor kidney transplantation. Reducing CIT and intensive management of younger recipient could benefit kidney transplant patients. PMID- 28088951 TI - [Noninvasive diagnostic and predictive value in renal transplant recipients with acute rejection by measurement of urine Fractalkine]. AB - Objective: To investigate the relationship between early-stage renal acute rejection(AR) and the level of Fractalkine in urine, explore the diagnostic and noninvasive monitoring value in early stage after transplantation by measurement of urine Fractalkine. Methods: Urine samples were examined from renal transplant patients between January 2006 and October 2009. A total of 155 patients were enrolled, including 49 with biopsy-proved AR, 58 patients with stable renal function and no abnormal histological findings, 10 patients with subclinical rejection in protocol biopsy, 9 patients with biopsy-proven acute tubular necrosis and 29 patients with biopsy-proven chronic allograft nephropathy. Additionally, urine samples were also collected from 40 healthy controls. Fractalkine was measured in urine samples using a commercial human Fractalkine enzyme-linked immunosorbent assay (ELISA) kit. Immunohistochemistry for Fractalkine expression was performed on biopsies from renal transplant patients with AR and non-AR. Results: Forty-nine patients with AR excreted urinary Fractalkine at a significantly higher level than levels in patients with stable renal function and healthy controls[(429.1+/-56.1)vs (94.6+/-8.4), (84.5+/ 8.9)ng/mmol creatine, both P<0.001]. Patients with AR excreted urinary Fractalkine at a significantly higher level than levels in patients with acute tubular necrosis and chronic allograft nephropathy[(429.1+/-56.1)vs(133.0+/-9.8), (183.0+/-18.9)ng/mmol creatine, both P<0.001]. Receiver operating characteristic(ROC)curve was constructed to determine the discriminatory power of Fractalkine levels for diagnosis of AR. The area under ROC curve was 0.920(95% CI: 0.875-0.969, P<0.001), which showed that Fractalkine was a suitable marker for the diagnosis of AR. At a cut-off point of 157.5 ng/mmol creatinine, the sensitivity was 83.7% and the specificity was 84.5% (P<0.001). The dynamic level of urinary Fractalkine in AR patients within 3 weeks after transplantation fluctuated above 300 ng/mmol creatine, which is remarkably higher than patients with stable renal function (below 200 ng/mmol creatinine). Conclusions: As a noninvasive monitoring method, Fractalkine in urine may be a new approach for detection of AR as well as useful to predict response to antirejection therapy. It has good sensitivity and specificity. Besides, measurement of Fractalkine in urine is a simple, inexpensive method for the routine clinical monitoring after kidney transplantation. PMID- 28088952 TI - [Comparison of clinical outcomes between antithymocyte globulin and basiliximab in renal transplantation from donation after citizen death: a matched pair study]. AB - Objective: To compare the safety and effectiveness between antithymocyte globulin (ATG) and basiliximab in deceased donor renal transplantation within matched groups where paired recipients received graft donations from same donors. Methods: A total of 124 cases of deceased donor kidney transplantation performed at Wuhan Tongji Hospital from January 2013 to November 2015 were retrospectively analyzed. Based upon their induction therapies, the recipients receiving graft donations from same donors were divided into two groups, namely ATG group (n=62) and basiliximab group (n=62). Clinical data were gathered and comparisons were made between the two groups. Results: Delayed graft function (DGF) implicated less patients in the ATG group (11, 17.7%) compared with basiliximab group (21, 33.9%) (P=0.040). Duration of DGF was also significantly shorter in the ATG group than in the basiliximab group[(14.92+/-6.23) vs(20.26+/-7.89)days, P=0.048]. The rates of DGF were 5/18 in the ATG group and 10/15 in the basiliximab group (P=0.025), when subgrouping the patients with elevated risk factors (donor age >50 or a history of hypertension or graft cold ischemia time >24 h) for DGF. The acute rejection rates did not differ between the two groups significantly; comparable one-year graft and patient survival were observed between the ATG and basiliximab groups(all P>0.05). Conclusions: The duration of DGF and DGF rate after deceased donor renal transplantation is reduced by ATG, when compared with basiliximab. Moreover, in recipients with elevated risk factors for DGF, ATG diminishes DGF incidence significantly. PMID- 28088953 TI - [Research of mHLA-G and the receptor expression with kidney rejection and CMV active infection following kidney transplantation]. AB - Objective: To study the expression of membrane HLA-G (mHLA-G) and the receptor immunoglobulin-like transcript 2(ILT2) on lymphocyte and find their association with rejection and cytomegalovirus (CMV) infection after renal transplantation. Methods: A total of 88 cases of renal transplant recipients for the first time from February 2014 to February 2016 were studied in this work. Recipients can be divided into rejection group (n=12) and stable renal function group (n=41) according to whether rejection occurred. Recipients only infected CMV not developed rejection were included in the CMV positive group (n=24). CMV negative group (n=11) including CMV negative recipients once infected CMV.The expression of mHLA-G and ILT2 on lymphocytes were detected by flow cytometry, and the differences among different groups were analyzed. Results: The data showed that after renal transplantation, T and B lymphocytes mHLA-G expression rate was the lowest in the rejection group (0.42%+/-0.35%, 0.88%+/-0.47%), having significant difference with renal function stable group and CMV positive group (all P<0.01). In CMV positive group the expression of mHLA-G on T and B lymphocytes was the highest (1.31%+/-0.69%, 2.01%+/-0.91%), having significant difference with rejection group (P<0.001). The expression of mHLA-G on B cell was statistically significantly different between CMV positive group and CMV negative group (P<0.05). There was no significant difference in ILT2 expression on B cell among the four groups (P>0.05). The expression rate of ILT2 on T cells was higher in the CMV positive group (36.91%+/-14.91%), having significant difference with the other three groups (P<0.01). Conclusions: Low expression of mHLA-G on T and B lymphocytes may predict rejection after renal transplantation. High expression of mHLA-G and ILT2 on lymphocytes is prone to CMV infection after renal transplantation . PMID- 28088954 TI - [Experiences of rescuing infective arterial hemorrhage and pseudoaneurysm in DCD kidney transplantation]. AB - Objective: To summarize experiences of rescuing arterial hemorrhage and pseudoaneurysm caused by infection in donation after cardiac death (DCD) kidney transplantation. Methods: A total of 198 consecutive DCD kidney transplantations between 1 June 2013 and 30 July 2016 in the Third Affiliated Hospital of Sun Yat sen University were retrospectively analyzed. The means of rescuing infective arterial hemorrhage and pseudoaneurysm after operation and their therapeutic effects were summarized. Results: A total of 5 infective arterial hemorrhage, 2 infective pseudoaneurysm with hemorrhage, and 1 infective pseudoaneurysm developed in 198 DCD kidney transplantation recipients with total morbidity of 4.0%, and the morbidity of fungal infection accounted for 2.5%. One case received open surgical therapy. Two cases were treated with endovascular interventional therapy. Five cases received combined treatments of open surgery and endovascular intervention. Selective antibiotics were used based on drug sensitivity test postoperation. The wound was drained, and the drainage was repeatedly cultured to monitor the pathogen till the results turned to negative. Five patients received graft nephrectomy and were restored to hemodialysis. Two patients were successfully rescued with stable graft function. One case died. The mortality of patient was 1/8. Graft loss rate was 5/8. Both patients with stable graft function were mainly treated by intervention. Conclusions: Infective arterial hemorrhage and pseudoaneurysm were primary risk factors causing patient/graft death postoperation in DCD kidney transplantation. Endovascular therapy can be used as an effective rescuing method under the circumstance of infection. The measure allows opportunity of successfully rescuing kidney graft and deserves recommendation. PMID- 28088955 TI - [Effect of Kruppel like zinc finger transcription factor 2 on gamma glutamylcysteine synthetase in bronchial epithelial cells of chronic obstructive pulmonary disease]. AB - Objective: To research the regulation effects of Kruppel like zinc finger transcription factor 2 (KLF2) on gamma-glutamylcysteine synthetase (gamma-GCS) in airway epithelial cells of chronic obstructive pulmonary disease (COPD). Methods: (1) Human specimen experiment: lung tissue of pulmonary lobectomy patients with lung cancer with or without COPD was collected from Department of Thoracic Surgery of Hunan Cancer Hospital from December 2008 to December 2009. The patients were divided into COPD group and control group without COPD. The levels of KLF2, gamma-GCS mRNA and protein expression in lung tissues were measured by immunohistochemistry and in situ hybridization (ISH). Then, the correlation between KLF2 and gamma-GCS mRNA and protein expression levels were analyzed, as well as the correlation between KLF2 or gamma-GCS protein and smoking index, percentage of forced expiratory volume in one second to predicted value (FEV1%), percentage of forced expiratory volume in one second to forced vital capacity (FVC/FEV1). (2) Animal experiment: the primary bronchial epithelial cells of rats were extracted by enzyme digestion. After 6 hours of incubation with 10% tobacco smoke extract (TSE), cellular glutathione (GSH) was measured by enzyme linked immunosorbent assay (ELISA) method. The cells were transfected by specific inhibitor of KLF2 through the liposom, which inhibited the protein expression of KLF2. Then, the cells were divided into KB group (blank control group without any treatment), KB+ TSE group (treated with TSE), NC group (control group transfected with miRNA), NC+ TSE group (treated with miRNA and TSE), 92a group (transfected with KLF2 inhibitor), 92a+ TSE group (treated with KLF2 inhibitor transfection and TSE) based in the treatment. After that, the changes of KLF2 and gamma-GCS mRNA and protein expression in the cells of each group were measured by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot method. Results: (1) Human specimen experiment: The expressions of KLF2 mRNA, protein and gamma-GCS mRNA, protein in the lung tissue of COPD patients were strong positive and higher than those in control group (0.32+/-0.04 vs 0.19+/-0.03, 0.35+/-0.05 vs 0.22+/-0.03; 0.28+/-0.03 vs 0.16+/-0.03, 0.31+/-0.05 vs 0.21+/-0.03; all P<0.01). Linear correlation analysis showed that KLF2 mRNA and protein were positively correlated with gamma-GCS mRNA and protein (r=0.705, 0.722; both P<0.01). The KLF2 and gamma-GCS protein were positively correlated with smoking index, FEV1% and FEV1/FVC (r=0.552, 0.728, 0.670, and r=0.631, 0.727, 0.657; all P<0.01). (2) Animal experiment: The level of GSH in KB+ TSE group was significantly higher than that in KB group[(28.05+/-2.04) vs (7.27+/-0.33) nmol/mg, P<0.01]. The KLF2 mRNA, protein and gamma-GCS mRNA, protein in KB+ TSE group (1.715+/-0.026, 1.842+/-0.028 and 2.117+/-0.067, 1.879+/-0.065) were higher than those in KB group (1.130+/-0.017, 1.177+/-0.033 and 1.378+/-0.053, 1.177+/ 0.042; all P<0.05), and those in 92a group (0.472+/-0.028, 0.634+/-0.025 and 0.582+/-0.025, 0.554+/-0.021) were significantly lower than those in KB group, NC group (1.047+/-0.056, 1.092+/-0.045 and 1.303+/-0.037, 1.252+/-0.037), and those in TSE+ 92a group (0.262+/-0.017, 0.288+/-0.017 and 0.337+/-0.022, 0.321+/-0.022) were significantly lower than those in KB+ TSE group, 92a group and NC+ TSE group (1.576+/-0.036, 1.646+/-0.066 and 1.948+/-0.093, 1.843+/-0.078) (all P<0.05). Conclusion: KLF2 exerts antioxidative effect by regulating the expression of gamma-GCS in the bronchial epithelial cells of chronic obstructive pulmonary disease. PMID- 28088956 TI - [Thoracic paravertebral block in the PACU for immediate postoperative pain relief after video-assisted thoracoscopic surgery]. AB - Objective: To investigate the effectiveness and safety of the thoracic paravertebral block(TPVB) in the post postanesthesia care unit(PACU) for patients suffered moderate to severe pain after Video-Assisted Thoracoscopic Surgery(VATS). Methods: 78 atients who complained moderate to severe pain on arrival to PACU after VATS were randomly assigned into two groups: thoracic paravertebral block treatment group(P group) and sufentanil treatment group(S group). The VAS Pain score at rest and movement, heart rate, blood pressure, and pulse oximetry 1 hour after treatment and duration of patients staying in the PACU after treatment were recorded. VAS Pain score at rest and on coughing at 8, 24 and 48 hours after treatment were closely monitored. Sufentanil comsumption, patient satisfaction and related complications were also recorded. Results: A successful TPVB was achieved in all patients in P group without puncture related complications. The VAS pain scores at rest and on coughing 1 hour, 8 hours, 24 hours and 48 hours after treatment in P group were significantly lower than the patients in S group. Systolic blood pressure 1 hour after treatment in P group was also lower than the patients in S group(118mmHg+/-14mmHg vs 128 mmHg+/-14 mmHg, P=0.021). SPO2 1 hour after treatment in P group was much higher than the patients in S group(95%+/-3% vs 92%+/-4%, P=0.015). The duration of patients staying in the PACU after treatment in both groups were similar. Sufentanil comsumption, rate of vomiting and nausea was significantly less and satisfaction was better in P group than thoses in S group. Conclusion: In the postanesthesia care unit, TPVB could provide effective and safe analgesia therapy for patients suffered from moderate to severe pain after VATS. PMID- 28088957 TI - [Application of lymph node labeling with carbon nanoparticles by preoperative endoscopic subserosal injection in laparoscopic radical gastrectomy]. AB - Objective: To evaluate the application value of carbon lymph node tracing technique by preoperative endoscopic subserosal injection in laparoscopic radical gastrectomy. Methods: From June 2013 to February 2015, seventy eight patients with gastric cancer were enrolled and randomly divided into trial group and control group. Subserosal injection of carbon nanoparticles around the tumor was performed by preoperative endoscopic subserosal injection one day before the operation in trial group, while the patients routinely underwent laparoscopic gastrectomy in control group. Results of harvested lymph nodes, postoperative complications were compared between the two groups. Carbon nanoparticle-related side effect was also evaluated. Results: The average number of harvested lymph node in trial group was significantly higher than that in control group (35.5+/ 8.5 vs 29.5+/-6.5, P<0.05). The rate of overall black-dyed harvested lymph node was 74.7% (1 035/1 386) in trial group, the black-dyed lymph node rate in D1 lymph node was 80.1%, which was significantly higher than that in D2 lymph node (69.8%, chi2=19.38, P<0.01). When comparing the lymph node with and without black dyed in trial group, the rate of metastasis lymph node was significantly higher in lymph node with black-dyed (17.3% vs 4.0%, chi2=38.67, P<0.01). There was no significant difference in postoperative complications rate between two group (trial group 10.2%; control group 12.8%, chi2=0.00, P>0.05), and no carbon nanoparticle-related side effect was observed. Conclusion: Given a higher harvested lymph node number and a similar rate of complications, preoperative endoscopic subserosal injection of carbon nanoparticles was safe and feasible. PMID- 28088958 TI - [Clinical effect analysis of endovascular repair for aortic pseudoaneurysms in 13 cases]. AB - Objective: To discuss the clinical safety and efficacyof endovascular aneurysm repair (EVAR) for aortic pseudoaneurysms. Methods: From October 2008 to October 2015, 13 patients (11 male, 2 female, with a mean age of 55.6) with aortic pseudoaneurysms treated by EVAR wereenrolled. All the 13 casesunderwentcomputed tomographic arteriography (CTA). The etiology diagnosis withdescendingaortic pseudoaneurysms, infected abdominal aortic pseudoaneurysms, abdominal aortic pseudoaneurysmsin Behcet's syndrome, and uncertain reasons were 4, 4, 4, and 1 case, respectively. Results: In this group, 14 stentswere planted.All the patients hadno accidents and complications in perioperative period.Twelve patients were successfully followed up, 1 patient died of recurrent abdominal aortic pseudoaneurysmsin Behcet's syndrome, and 1 patient with recurrent infected abdominal aortic pseudoaneurysm wascured by pseudoaneurysm resection and extra anatomic bypass grafting. Concluson: EVAR is a safe and effective option for aortic pseudoaneurysms. PMID- 28088959 TI - [Effect of exendin-4 on lipid deposition in skeletal muscle of diet-induced obese mice and its underlying mechanism]. AB - Objective: To investigate the effect of exendin-4, a glucagon-like peptide-1 (GLP 1) receptor agonist, on reducing lipid deposition and improving insulin resistance in skeletal muscle and the underlying mechanisms in high-fat diet (HFD)-induced obese mice. Methods: Twelve male C57BL/6J mice were challenged with HFD for 12 weeks to induce obesity and then randomly divided into two groups: exendin-4 group (intraperitoneal injection of 24 nmol.kg-1.d-1 exendin-4 for 4 weeks) and HFD group (intraperitoneal injection of normal saline for 4 weeks), with 6 mice in each group. Additional 6 mice were also selected as control group. Body weight, fasting blood glucose were recorded. Serum triglyceride (TG), total cholesterol (TC), insulin and skeletal muscle triglyceride levels were measured by enzyme-linked immunosobent assay (ELISA). Oil red O staining was used for morphologic changes of frozen sections from skeletal muscle. The protein levels of lipid metabolic pathway mediated by AMP-activated protein kinase (AMPK) and insulin signailing pathway were determined by Western blot. Results: Compared with mice in HFD group, exendin-4 significantly decreased body weight[(37.68+/ 1.80) vs (46.03+/-5.00) g, P<0.025], fasting blood glucose[(5.40+/-0.33) vs (7.65+/-1.92) mmol/L, P<0.025], serum TG[(37.78+/-7.14) vs (80.76+/-34.22) mg/dl, P<0.025], TC[(180.13+/-18.75) vs (217.57+/-22.52) mg/dl, P<0.025], insulin[(0.58+/-0.01) vs (1.67+/-1.23) ng/ml, P<0.025]and skeletal muscle TG levels[(9.84+/-1.08) vs (19.35+/-7.44) mg/g, P<0.025]of obese mice. Oil red O staining revealed that exendin-4 alleviated the accumulation of larger lipid droplets in skeletal muscle. The protein expressions of lipolysis and lipid oxidation mediated by AMPK and insulin signailing pathway were up-regulated, and the protein expressions of lipogenesis mediated by AMPK were down-regulated after intervention of exendin-4. Conclusion: Exendin-4 reduces lipid deposition and insulin resistance in skeletal muscle of HFD-induced obese mice via activating AMPK and up-regulating insulin signailing pathway. PMID- 28088960 TI - [Role and mechanism of hydrogen sulfide in cigarette smoke induced chronic obstructive pulmonary disease related pulmonary vascular remodeling in rats]. AB - Objective: To investigate the role and mechanism of hydrogen sulfide (H2S) in rats with chronic obstructive pulmonary disease (COPD) related pulmonary vascular remodeling. Methods: Twenty four healthy male Sprague-Dawley rats were randomly divided into 4 groups: control group, cigarette smoke (CS) group, CS+ Sodium hydrosulfide (NaHS) group and CS+ DL-propargylglycine (PPG) group. Rats in control group were fed normally and breathed clear air, and for the rest groups, passive cigarette smoke inhalation method were adopted to establish COPD model. After 8 weeks, the rats in corresponding groups were treated by NaHS or PPG. After 16 weeks, the markers of pulmonary vascular remodeling in all groups were measured. Proliferation marker proliferative cell nuclear antigen (PCNA) and oxidative stress marker 3-neurotrophin (3-NT) in all groups were measured by immunohistochemistry (IHC). Results: Compared with control group, the airway resistance was increased (0.859+/-0.283 vs 0.578+/-0.088, P<0.05) and the pathological scores was much higher in CS group, which suggested that the COPD model was successful. The degree of small resistance pulmonary artery medial wall thickness and full vascular muscularization of CS group were much higher (0.54+/ 0.20 vs 0.37+/-0.12, 0.39+/-0.08; 0.61+/-0.16 vs 0.20+/-0.12, 0.34+/-0.13, all P<0.01)than control group and CS+ NaHS group, there was no significant difference between CS+ PPG group and CS group. In accordance with the results of morphometric analysis, the proliferation marker PCNA was more in CS group when compared with control group and CS+ NaHS group (0.27+/-0.08 vs 0.12+/-0.06, 0.14+/-0.06, both P<0.05), there was no significant difference between CS+ PPG group and CS group. Furthermore, the IHC also showed that 3-NT significantly increased in CS group compared with control group and CS+ NaHS group (0.26+/-0.08 vs 0.18+/-0.04, 0.19+/-0.06, both P<0.01), there was no significant difference between CS+ PPG group and CS group as well. In addition, the small resistance pulmonary artery medial wall thickness had strong correlation with the expression level of oxidative stress marker 3-NT (r=0.906, P<0.001). Conclusion: H2S significantly attenuates cigarette smoke induced COPD related pulmonary vascular remodeling, which could be related to its ability to decrease oxidative stress. PMID- 28088961 TI - [The clinical and prognostic significance of acute myeloid leukemia with FLT3 ITD]. AB - Objective: To investigate the clinical significance and prognosis factors of acute myeloid leukemia (AML) with FLT3 mutation-internal tandem duplication (FLT3 ITD) and provide more evidence for prognosis evaluation in AML with FLT3-ITD. Methods: The clinical characteristics and outcomes of 98 AML with FLT3-ITD were analyzed. Results: In patients with FLT3-ITD positive AML, the median of WBC and peripheral blood blast at initial diagnosis were 58.2 (0.3-461.8) *109/L and 42.2 (0-397.1) *109/L, respectively. The complete remission (CR) rate after one course induction therapy was 60.6% in 71 patients with intermediate or adverse risk. The primary refractory rate was 26.8% in 71 patients with intermediate or adverse risk. The lower number of peripheral blood blast was a favorable factor to achieve CR after one course induction therapy (P=0.009). CR after one course (HR=0.395, 95% CI 0.183-0.85, P=0.001) and allo-transplantation in CR1 (HR=0.180, 95% CI 0.043-0.752, P=0.018) favored longer relapse-free survival (RFS). CR after one course (HR=0.251, 95% CI 0.121-0.523, P< 0.001) and lower number of peripheral blood blast (HR=0.219, 95% CI 0.088-0.545, P=0.003) favored longer overall survival (OS) in AML with FLT3-ITD. Conclusion: FLT3-ITD positive AML with lower number of peripheral blood blast has a relative favorable prognosis. CR after one course and allotransplantation in CR1 are important strategy to improve prognosis in AML with FLT3-ITD. PMID- 28088962 TI - [Efficacy and safety of Sorafenib as monotherapy to FLT3-ITD positive acute myeloid leukemia]. AB - Objective: To explore the efficacy and safety of Sorafenib as monotherapy to FLT3 positive acute myeloid leukemia (AML). Methods: From April 2014 to December 2015, fourteen AML patients with FLT3 positive, 7 males and 7 females with a median age of 42 (range: 14-81) years old, were enrolled in this study. Of the 14 cases, 4 were de novo cases, 9 refractory cases and 1 relapsed case, including 78.6% patients with severe complications and 57.1% patients with KPS score less than 60 [the median KPS score was 45 (20-70) ]. The administration of Sorafenib was 400 mg twice daily and Sorafenib was continued if tolerated. The treatment response was evaluated by MICM and the data were analyzed by paired samples t test before and after Sorafenib treatment. Results: The peripheral blood WBC count [4.2 (0.9 11.8) *109/L vs 39.6 (2.3-209.5) *109/L, P<0.001 ], the percentage of peripheral blast cell [0.07 (0-0.54) vs 0.53 (0-0.94), P<0.001] and the percentage of bone marrow blast cell [0.266 (0.020-0.880) vs 0.604 (0.180-0.900), P=0.003] were significantly decreased after Sorafenib monotherapy compared with before. The overall response rate was 57.1% (8/14), including 5 cases (35.7%) with complete remission (CR). Of 4 de novo cases, 2 achieved CR, 1 with PR, 1 with NR; 3 of 10 refractory and relapsed patients achieved CR and 2 cases achieved PR, 5 cases NR. The median duration of achieving molecular remission (FLT3-ITD negative) after Sorafenib was 46(33-72) days, and the median progression free survival (PFS) was 53 (28-175) days. Conclusion: Sorafenib shows activity in FLT3-ITD mutation positive AML patients. Sorafenib monotherapy could be used as a treatment option for elderly patients or patients with severe complications, and refractory and relapsed patients with not suitable for intensive chemotherapy. PMID- 28088963 TI - [Clinical characteristics and prognosis in 12 patients with adult T cell leukemia/lymphoma confirmed by HTLV-1 provirus gene detection]. AB - Objective: To analyze the clinical characteristics and prognosis of adult T cell leukemia/lymphoma (ATLL). Methods: Peripheral blood samples from patients who were suspected as ATLL from March, 2013 to July, 2015, were collected for HTLV-1 provirus genes detection in genomic DNA extraction by PCR. Cases showing positive results were confirmed as ATLL. Clinical and laboratory characteristics, therapeutic outcomes and survival evaluation were collected. Results: 12 out of 23 suspected patients were confirmedly diagnosed as ATLL through HTLV-1 provirus genes detection by PCR. Eight patients were male and four patients were female. Median age was 51 (range 28-66) years old. All of those patients came from coastal cities of Fujian province where a HTLV-1 epidemic area locates. In the subtype classification of these 12 ATLL, 11 patients were classified as acute type and one case as lymphoma type ATLL. As one of the clinical characteristics of ATLL, ' flower cells ', with typical or atypical morphology had been observed in a high rate (81.8%). Clinical symptom such as hepatomegaly, splenomegaly and lymphadenectasis were detected in most of patients, and hypercalcemia and elevated LDH were also noted commonly. The ATLL cells immunophenotype were typical, and the major subtype was CD4+ CD8- type. Confection of hepatitis B virus was detected in a high rate (54.5%). Ten patients received chemotherapy, and 2 cases in complete remission after chemotherapy received allogeneic hematopoietic stem cell transplantation. At the end of the follow-up, 7 cases died, 4 cases survived, 1 case was lost, and the median survival was 2.8 (0.9 10.8) months. We found a case had HTLV-1 provirus negative after transplantation. Conclusion: In the coastal area of Fujian Province, ATLL is not rare. Characteristics of those ATLL are typical. But prognosis is still unsatisfactory. PMID- 28088964 TI - [The influence of depression degree on regulatory T cells in patients with non-M3 acute myeloid leukemia]. AB - Objective: To investigate the influence of depression levels on regulatory T cells (Tregs) in patients with non-M3 acute myeloid leukemia (AML). Methods: A total of 63 patients with primarily diagnostic non-M3 AML and 25 healthy controls were enrolled, and the levels of depression by using HADM score and the percentages of Tregs by flow cytometry were evaluated in pre-treatment and post treatment, respectively. Results: After every course of chemotherapy, the percentages of Tregs of PBMNC in AML showed the higher level of (6.48+/-1.81)% than those of (4.99+/-1.29)% in control (P= 0.001). There was no difference among different levels of depression groups after the first cycle. However, the percentages of Tregs increased with the worse of depression after the second and third cycles. Partial correlation analysis after adjusting age indicated that the percentages of Tregs showed no correlation with the levels of depression after the first cycle (correlation coefficient, 0.120, P=0.345), and showed the positive correlation with depression levels after the second and third cycles (correlation coefficient, 0.619 and 0.614, all P values <0.05). Conclusion: The depression levels showed an association with the percentages of Tregs in patients with non-M3 AML, which could be observed only after the second cycles of chemotherapy. PMID- 28088965 TI - [Hepatitis B complicated with thrombotic thrombocytopenic purpura after interferon treatment: a case report]. PMID- 28088966 TI - [Delayed hematologic response to immunosuppressive therapy in severe aplastic anemia]. AB - Objective: To explore the characteristics of delayed hematologic response in very/severe aplastic anemia (V/SAA) patients who were treated with immunosuppressive treatment (IST) as first-line approach, and investigate the rationality of early salvage treatment in refractory patients. Methods: The data of V/SAA patients front-line treated with IST were retrospectively analyzed. Delayed response was defined as acquiring hematologic response between 6 and 12 months after 1 course of IST. The clinical as well as hematologic characteristics of the delayed responded patients were investigated. Results: Of the 533 patients, 45 (8.44%, 45/533) were delayed hematologic responders, which accounted for 29.03% (45/155) of the whole non-responders at 6 months. The quality of response in delayed responders analyzed at 12 months (chi2=62.616, P <0.001) and at the end of follow-up (chi2=6.299, P=0.043) was significantly worse than that of robust response group. There were more VSAA patients in delayed response group compared with robust response group (57.8% vs 38.3%, P=0.013), and all the baseline absolute reticulocyte (ARC) count, ARC proportion and absolute neutrophil count (ANC) were much lower than that in delayed response group. Multivariate analysis about the above 2 groups showed that the baseline ARC count <10*109/L significanty reduced the chance of hematologic response within 6 months [OR=3.641(95% CI 1.718-7.719) , P=0.001], and not any factor was found to predict delayed hematologic response in non-responders at 6 months. The 5-year overall survival of 76.50% (95% CI 71.6%-81.4%) and event free survival of 29.10%(95% CI 25.2%-33.0% ) in non-responders at 6 months, both were worse than 97.6% (95% CI 96.6%-98.6% ) and 84.0% (95% CI 81.1%-86.9% ) (P <0.001) of robust response group. Conclusion: The incidence of delayed hematologic response in V/SAA patients by IST is low. The quality of delayed response is not satisfactory and there is no effective means to predict the delayed response. It is reasonable to carry out salvage treatment as early as possible. PMID- 28088967 TI - [A phase I dose-escalating trial of pegylated liposomal doxorubicin in combination with cyclophosphamide, vincristine and prednisone for aggressive non Hodgkin lymphoma]. AB - Objective: To explore the maximum tolerated dose of pegylated liposomal doxorubicin (PLD) in combination with cyclophosphamide, vincristine and prednisone as a modified CHOP regimen for aggressive non-Hodgkin lymphoma. Methods: Patients with newly diagnosed aggressive non-Hodgkin lymphoma were eligible for this trial. PLD was administered in cycle 1 and categorized into 4 dose level (30 mg/m2, 35 mg/m2, 40 mg/m2, 45 mg/m2 D1) according to a 3 + 3 approach for dose-escalation. Doxorubin was used in cycles 2-6. In this combination regimen, the doses of cyclophosphamide (750 mg/m2 D1), vincristine (1.4 mg/m2 D1, maximum dose of 2 mg) and prednisone (100 mg D1-5) were fixed. Toxicities of cycle 1 were documented. Results: Totally, 21 patients were enrolled in this trial. Among them, 15 patients had T-cell lymphoma and 6 had B cell lymphoma. When the dose of PLD was escalated to the level of 45 mg/m2, 2 of 3 patients developed grade 3 mucositis, which met the criteria of dose-limiting toxicity. Therefore, the dose was de-escalated for one level. At the level of 40 mg/m2, only one among 12 patients had pneumonia and grade 4 neutropenia. In all dose levels, the grade 3/4 toxicities observed were neutropenia (13 cases, 61.9% ), mucositis (2 cases, 9.5% ), thrombocytopenia (1 case, 4.8%) and pneumonia (1 case, 4.8%). Conclusion: When combined with cyclophosphamide, vincristine and prednisone as a combination regimen, the maximum tolerated dose of PLD was 40 mg/m2. PMID- 28088968 TI - [Para-neoplastic autoimmune multi-organ syndrome associated with follicular lymphoma: a case report and literature review]. AB - Objective: To broaden our knowledge of para-neoplastic autoimmune multi-organ syndrome (PAMS). Methods: A patient with PAMS associated with follicular lymphoma and bronchiolitis obliterans treated in our hospital was retrospectively analyzed and the clinical features of PAMS were reviewed. Results: A 49-year-old female patient suffered from painful ulcers in the oral cavity and vagina, dry cough and dyspnea. Imaging examinations suggested multiple lymph node enlargements. Inguinal lymph node biopsy revealed follicular lymphoma. Although the oral and vaginal ulcers went into remission with glucocorticoid and thalidomide therapy and follicular lymphoma gained partial remission with six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy, respiratory failure still progressed. Conclusion: PAMS should be considered in patients with unexplained oral mucosa ulcers and dyspnea, which didn't match with the chest image manifestations. Extensive work-up should be performed to find out the potential tumor after diagnosis of PAMS. Early diagnosis and complete removal of tumor were essential to PAMS treatment. PMID- 28088969 TI - [The clinical features of patients with lymphoplasmacytic diseases harboring MyD88 L265P mutation]. AB - Objective: To explore the clinical features of lymphoplasmacytic diseases with MyD88 L265P mutation. Methods: To analyze the distribution of MYD88 L265P mutation in patients with lymphoplasmacytic diseases by using of ARMS PCR-CE. Results: There were 25(30.9%) MyD88 L265P mutated patients in 81 patients. The mutation was frequently observed in 14 patients with WM (77.8%, 14/18), 2 patients with lymphoplasmacytic lymphoma (66.7%, 2/3), 1 acute lymphocytic leukemia patient (50.0%, 1/2), 3 multiple myeloma patients (30.0%, 3/10), 1 patient with monoclonal gammopathy of undetermined significance (25%, 1/4), 3 patients with chronic lymphocytic leukemia (13.0%, 3/23) and 1 lymphoma patient (4.8%, 1/21). 20 (80%, 20/25) patients were identified with IgM subtype. Compared with wild-type group of 56 cases, mutated patients were older (median age: 67 years vs 55 years, P< 0.001), with lower WBC count (median count: 5.23 * 109/L vs 10.80 * 109/L, P=0.001), lower HGB level (median count: 85 g/L vs 119 g/L, P<0.001). Conclusion: MyD88 L265P mutation was mainly observed in patients with IgM subtype lymphoplasmacytic diseases, and Waldenstrom' s macroglobulinemia was the most common disease. Compared with the wild-type group, patients with MyD88 L265P mutation were older and had lower WBC count, lower level of HGB. However, further studies were needed to test the prognostic value of MyD88 L265P mutation. PMID- 28088970 TI - [TNFAIP3 deletion status in classical Hodgkin lymphoma and its relation to Epstein-Barr virus]. AB - Objective: To investigate the TNFAIP3/A20 abnormalities and its association with Epstein-Barr virus (EBV) in classical Hodgkin lymphoma (CHL). Methods: Formalin fixed, paraffinembedded tissue blocks of 54 CHL patients were collected and subjected to the construction of tissue microarray (TMA) for further analyses. EBV status was evaluated by in situ hybridization (ISH) for EBER1/2 and immunohistochemistry (IHC) with anti-LMP-1 antibody. Fluorescence in situ hybridization (FISH) and IHC were performed to determine the copy number alterations of TNFAIP3 and A20 protein expression respectively. Results: The concordance rate of IHC for LMP-1 and ISH for EBER1/2 was100%, and 25.9% (14/54) cases were identified with EBV infection. Immunohistochemistry analysis demonstrated 27.8% (15/54) cases with A20 expression deficiency. Of the 54 cases tested for A20 expression, 49 cases were simultaneously analyzed by FISH, which showed 10 (20.4% ) cases harboring TNFAIP3 deletion. However, discrepancy was observed between the results of A20 by IHC and TNFAIP3 deletion by FISH. Only 1 case with TNFAIP3 deletion demonstrated complete loss of A20 immunoreactivity. In addition, comparison of the frequency of either A20 expression loss or TNFAIP3 deletion between EBV-positive and-negative cases did not reveal any significance (P>0.05). Conclusion: TNFAIP3 deletion could be observed in both EBV-positive and - negative CHL cases. A20 expression by IHC could not confirm TNFAIP3 deletion by FISH, which might be related to the technical issues. PMID- 28088971 TI - [Eltrombopag for refractory thrombocytopenia in patients with allogeneic hematopoietic stem cell transplantation]. AB - Objective: To evaluate the efficacy and safety of eltrombopag in post-HSCT thrombocytopenia. Methods: A total of 10 patients who underwent post-HSCT thrombocytopenia at Peking University center, who had been treated with eltrombopag, were retrospectively evaluated. Results: Of the 10 cases, 5 males and 5 females with a median of 34 years old (range, 17-54 years), 5 patients were acute myeloid leukemia, 3 with acute lymphoid leukemia and 2 with severe aplastic anemia. Nine patients had undergone haplo-identical donor transplantation, and one patient was a matched related recipient. All patients had failed prior treatment for thrombocytopenia before eltrombopag started. The median time when eltrombopag started was 221 days (range, 73-917 days) after transplantation. Five patients (50%) had achieved CR. The cumulative incidence of 30-day CR was 35.7%. The median time to platelet recovery >= 50 * 109/L without transfusion support was 16 days (range, 10-56 days). At the last follow-up, three of the patients with CR had withdrawal eltrombopag and remained normal platelet counts. No patients experienced drug-related adverse events. Conclusion: Eltrombopag is effective and well tolerated in patients with refractory post-HSCT thrombocytopenia. PMID- 28088972 TI - [Critical roles of matrix metalloproteinases secreted by leukemic cells in the pathogenesis of central nervous system leukemia]. AB - Objective: To observe the effects of matrix metalloproteinases (MMP)-2 and MMP-9 secreted by leukemic cells on tight junction proteins ZO-1, claudin-5 and occluding and the permeability of the blood-brain barrier (BBB) and explore the mechanisms of MMP-2 and MMP-9 in leukemic cell infiltration of the central nervous system (CNS). Methods: The mRNA expressions of MMP-2 and MMP-9 in leukemic cell lines SHI-1, HL-60 and U937 were detected by quantitative RT-PCR. The MMP inhibitor GM6001 was used to inhibit the secretion of MMP-2 and MMP-9. RNA interference (RNAi) was used to knock down the expression of MMP-2 and MMP-9. Zymography was used to analyze the secretion of MMP-2 and MMP-9 in the supernatant of different leukemia cell lines treated or untreated with drugs, as well as the RNAi-treated cells. An in vitro BBB model composed of human brain microvascular endothelial cells (BMVECs) was developed on a Matrigel-based insert. Cell invasion through a barrier of Matrigel-based human basement membrane and the BMVECs-based human BBB barrier was assayed to measure the invasive capacity and the capacity to breakdown the BBB of different leukemia cell lines treated or untreated with drugs, as well as the RNAi-treated cells. The morphologic changes of BMVECs after co-culture with different leukemia cell lines treated or untreated with drugs, as well as the RNAi-treated cells in vitro BBB models were observed by invert microscopy and tight junction proteins in these BMVECs were analyzed with a laser-scanning confocal microscope. Results: 1The mRNA expression in different leukemic cell lines shown a pronounced transcription of MMP-2 and - 9, and the transcriptional level in SHI-1 cells was the highest among all leukemic cell lines tested (P<0.01). The data of activities of MMP-2 and -9 were consistent with the results of mRNA expression and SHI-1 displayed higher capacity of invasion (P<0.01). 2After incubation 24h with different leukemic cells, the BMVECs disrupted to loss cell-cell contacts and grew in single cell. Confocal imaging showed down-regulations of ZO-1, claudin-5 and occluding accompanied by the disruption of BBB in vitro models. SHI-1 cells had stronger alterations to BMVECs, tight junction proteins and the permeability of the BBB than HL-60 and U937 cells. However, GM6001 and the knock-down of MMP-2 and MMP-9 altered the responses of BBB. They reduced the degradation of three tight junction proteins with a decreased permeability of BBB. Conclusion: MMP-2 and MMP-9 secreted by leukemic cells could disrupt the BBB by degrading the tight junction proteins ZO-1, claudin-5 and occluding, which contributed the infiltration of leukemic cell into CNS. PMID- 28088973 TI - [Clinical characteristics of HIV-negative plasmablastic lymphoma]. PMID- 28088974 TI - [Bortezomib, rituximab combined with chemotherapy for mantle cell lymphoma: two cases report and literature review]. PMID- 28088975 TI - [Palliative radiotherapy for AIDS related diffuse large B cell lymphoma: a report of six cases with literature review]. PMID- 28088976 TI - [Effects of omega-3 polyunsaturated fatty acids on multiple myeloma growth inhibition and enhanced sensitivity of dexamethasone]. PMID- 28088977 TI - [Osteonecrosis of the jaw associated with long time withdrawal of bisphosphonates in multiple myeloma: one case report]. PMID- 28088978 TI - [Advances in genes mutation and pathophysiology of congenital sideroblastic anemia]. PMID- 28088979 TI - [Value of PET-CT clinical application in extranodal NK/T cell lymphoma]. PMID- 28088980 TI - Indicators for continuous quality improvement for otitis media in primary health care for Aboriginal and Torres Strait Islander children. AB - Otitis media is a common, generally self-limiting childhood illness that can progress to severe disease and have lifelong sequelae, including hearing loss and developmental delays. Severe disease is disproportionately prevalent among Aboriginal and Torres Strait Islander children. Primary health care is at the frontline of appropriate prevention and treatment. Continuous quality improvement in the prevention and management of important causes of morbidity in client populations is accepted best practice in primary health care and now a requirement of Australian Government funding to services providing care for Aboriginal and Torres Strait Islander children. To date, there have been no indicators for continuous quality improvement in the prevention and management of otitis media and its sequelae in primary health care. Through an expert group consensus process, seven evidence-based indicators, potentially extractable from electronic health records, have been developed. The development process and indicators are described. PMID- 28088981 TI - Hematopoiesis in aging: Current concepts and challenges. PMID- 28088982 TI - Accumulation of DNA damage in the aged hematopoietic stem cell compartment. AB - Aging is associated with loss of functional potential of multiple tissue systems, and there has been significant interest in understanding how tissue-specific cells contribute to this decline. DNA damage accumulation has been widely associated with aging in differentiated cell types. However, tissue-specific stem cells were once thought to be a geno-protected population, as damage accrued in a stem cell population has the potential to be inherited by differentiated progeny, as well as propagated within the stem cell compartment through self-renewal divisions. This review will discuss the evidence for DNA damage accumulation in the aged HSC compartment, potential drivers, and finally the consequences of the acquired damage. PMID- 28088983 TI - The epigenetic basis of hematopoietic stem cell aging. AB - Highly proliferative tissues such as the gut, skin, and bone marrow lose millions of cells each day to normal attrition and challenge from different biological adversities. To achieve a lifespan beyond the longevity of individual cell types, tissue-specific stem cells sustain these tissues throughout the life of a human. For example, the lifespan of erythrocytes is about 100 days and adults make about two million new erythrocytes every second. A small pool of hematopoietic stem cells (HSCs) in the bone marrow is responsible for the lifetime maintenance of these populations. However, there are changes that occur within the HSC pool during aging. Biologically, these changes manifest as blunted immune responses, decreased bone marrow cellularity, and increased risk of myeloid diseases. Understanding the molecular mechanisms underlying dysfunction of aging HSCs is an important focus of biomedical research. With advances in modern health care, the average age of the general population is ever increasing. If molecular or pharmacological interventions could be discovered that rejuvenate aging HSCs, it could reduce the burden of age related immune system compromise as well as open up new opportunities for treatment of hematological disorders with regenerative therapy. PMID- 28088985 TI - Lymphocyte generation and population homeostasis throughout life. AB - Immune aging is a multi-faceted process that manifests as reduced competence to fight infections and malignant cells, as well as diminished tissue repair, unprovoked inflammation, and increased autoreactivity. The aging adaptive immune system, with its high complexity in functional cell subpopulations and diversity of B- and T-cell receptors, has to cope with the challenge of maintaining homeostasis while responding to exogenous stimuli and compensating for reduced generative capacity. With thymic involution, naive T cells begin to function as quasi-stem cells and maintain the compartment through peripheral homeostatic proliferation that shapes the T-cell repertoire through peripheral selection and the activation of differentiation pathways. Similarly, reduced generation of early B-cell progenitors alters the composition of the peripheral B-cell compartment with the emergence of a unique, auto-inflammatory B-cell subset, termed age-associated B cells (ABCs). These changes in T- and B-cell composition and function are core manifestations of immune aging. PMID- 28088986 TI - Age-associated changes in human hematopoietic stem cells. AB - Aging has a broad impact on the function of the human hematopoietic system. This review will focus primarily on the effect of aging on the human hematopoietic stem cell (HSC) population. With age, even though human HSCs increase in number, they have decreased self-renewal capacity and reconstitution potential upon transplantation. As a population, human HSCs become more myeloid-biased in their differentiation potential. This is likely due to the human HSC population becoming more clonal with age, selecting for myeloid-biased HSC clones. The HSC clones that come to predominate with age may also contain disease-causing genetic and epigenetic changes that confer an increased risk of developing into an age associated clonal hematopoietic disease, such as myelodysplastic syndrome, myeloproliferative disorders, or leukemia. The selection of these aged human HSC clones may be in part due to changes in the aging bone marrow microenvironment. While there have been significant advances in the understanding of the effect of aging on mouse hematopoiesis and mouse HSCs, we have comparatively less detailed analyses of the effect of aging on human HSCs. Continued evaluation of human HSCs in the context of aging will be important to determine how applicable the findings in mice and other model organisms are to the human clinical setting. PMID- 28088984 TI - The aging hematopoietic stem cell niche: Phenotypic and functional changes and mechanisms that contribute to hematopoietic aging. AB - The hematopoietic system has the remarkable ability to provide a lifelong supply of mature cells that make up the entire blood and immune system. However, similar to other adult stem cell niches, the hematopoietic system is vulnerable to the detrimental effects of aging. This is a substantial health concern as the trend for population aging continues to increase. Identifying mechanisms that underlie hematopoietic aging is vital for understanding hematopoietic-related diseases. In this review, we first discuss the cellular hierarchy of the hematopoietic system and the components that make up the surrounding hematopoietic niche. We then provide an overview of the major phenotypes associated with hematopoietic aging and discuss recent research investigating cell-intrinsic and cell-extrinsic mechanisms of hematopoietic stem cell (HSCs) aging. We end by discussing the exciting new concept of possibly reversing the HSC aging process along with outstanding questions that remain to be answered. PMID- 28088987 TI - Molecular mechanisms underlying lineage bias in aging hematopoiesis. AB - Although hematopoietic stem cells (HSCs) have traditionally been thought to possess the ability to give rise to all the mature cell types in the hematopoietic system, this conception of hematopoiesis was based on evaluation of hematopoietic output from large numbers of HSCs using transplantation models. More recent studies evaluating HSCs at the clonal or near-clonal level, both in transplantation studies and during in situ hematopoiesis, have established that individual HSCs can exhibit lineage bias, giving rise to myeloid-biased, lymphoid biased, or more balanced differentiation, with the proportion of myeloid-biased HSCs increasing with age. This age-associated shift in lineage potential is associated with decreased cellular immunity and increased incidence of diseases with prominent inflammatory components including atherosclerosis, autoimmunity, neurodegenerative disease, and carcinogenesis. Understanding the molecular mechanisms that regulate this shift in linage bias therefore represents an important area of investigation in numerous human diseases. In this review, we summarize our current understanding of the cell-intrinsic (autonomous) and cell extrinsic factors that regulate HSC lineage fate bias during aging. In addition, we have attempted to bring attention to important caveats and unanswered questions related to the issue of HSC lineage bias to encourage explorations of these important lines of inquiry. Ultimately, we expect a comprehensive understanding of HSC lineage bias during aging to have important implications for human health, since strategies to alter lineage bias in old HSCs not only has the potential to restore immune function in the elderly, but also to reduce the incidence of inflammation-associated diseases, many for which there is a current unmet need for novel and more effective treatments. PMID- 28088988 TI - Clonal hematopoiesis. AB - Cancer results from multistep pathogenesis, yet the pre-malignant states that precede the development of many hematologic malignancies have been difficult to identify. Recent genomic studies of blood DNA from tens of thousands of people have revealed the presence of remarkably common, age-associated somatic mutations in genes associated with hematologic malignancies. These somatic mutations drive the expansion from a single founding cell to a detectable hematopoietic clone. Owing to the admixed nature of blood that provides a sampling of blood cell production throughout the body, clonal hematopoiesis is a rare view into the biology of pre-malignancy and the direct effects of pre-cancerous lesions on organ dysfunction. Indeed, clonal hematopoiesis is associated not only with increased risk of hematologic malignancy, but also with cardiovascular disease and overall mortality. Here we review rapid advances in the genetic understanding of clonal hematopoiesis and nascent evidence implicating clonal hematopoiesis in malignant and non-malignant age-related disease. PMID- 28088989 TI - Rejuvenation of aged hematopoietic stem cells. AB - Until recently, there was broad consensus in the stem cell aging field that the phenotype of aged hematopoietic stem cells (HSCs) is fixed-dominated by cell intrinsic regulatory mechanisms that cannot be altered by pharmacological or genetic means. The conventional thinking was that HSC aging could not be reverted by therapeutic intervention. This paradigm has started to shift dramatically, primarily because hallmarks of aged HSCs have been successfully reverted by distinct experimental approaches by multiple laboratories. We will discuss in this review these hallmarks of HSCs aging and the novel approaches that successfully ameliorated or even reverted aging-associated hallmarks of aged HSCs. PMID- 28088990 TI - Prevention and management of glucocorticoid-induced side effects: A comprehensive review: Infectious complications and vaccination recommendations. AB - Part 3 of this 4-part continuing medical education series reviews several important infectious complications of corticosteroid use, including a focus on pneumocystis pneumonia (PCP) prophylaxis, tuberculosis, viral hepatitis, and other infections, followed by a discussion of vaccination recommendations in immunosuppressed patients. PMID- 28088991 TI - Prevention and management of glucocorticoid-induced side effects: A comprehensive review: Ocular, cardiovascular, muscular, and psychiatric side effects and issues unique to pediatric patients. AB - The final article in this 4-part continuing medical education series reviews the ocular, cardiovascular, muscular, and psychiatric side effects of glucocorticoids and discusses side effects unique to pediatric patients. PMID- 28088992 TI - Prevalence of hormonal and endocrine dysfunction in patients with lichen planopilaris (LPP): A retrospective data analysis of 168 patients. AB - BACKGROUND: Studies on the pathophysiology and comorbidities associated with lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are limited. OBJECTIVE: The purpose of this study was to determine the prevalence of androgen excess in the postmenopausal LPP population, in relation to demographics and comorbidities. METHODS: A retrospective data analysis of 413 patients with LPP, FFA, and LPP/FFA seen in the Department of Dermatology at the Cleveland Clinic Foundation in Ohio between 2005 and 2015 was conducted. Of this cohort, 168 patients met the inclusion criteria. RESULTS: Androgen excess was identified in 31.5% (n = 53) of the 168 patients with LPP and all subtypes (P < .001). Androgen deficiency was identified in 32.1% (n = 17) of the 53 patients with FFA (P < .001). The androgen excess group was significantly more likely to present with hirsutism, seborrheic dermatitis, polycystic ovary syndrome, ovarian cysts, or a combination of these (P < .001). LIMITATIONS: This study was limited by being retrospective. CONCLUSION: Our study demonstrated that LPP is associated with androgen excess, and FFA is associated with androgen deficiency. PMID- 28088993 TI - Treatment of recalcitrant port-wine stains (PWS) using a combined pulsed dye laser (PDL) and radiofrequency (RF) energy device. AB - BACKGROUND: Pulsed dye laser (PDL) is the treatment of choice for port-wine stains (PWS). Some PWS are recalcitrant to this modality. A number of reasons for PDL treatment resistance have been described, including inadequate heat generation. OBJECTIVE: We evaluated PDL combined with radiofrequency (RF) energy into a single device to target larger and deeper blood vessels and overcome PDL resistance. METHOD: This was an open-label, prospective, single-center investigation of a novel device combining RF energy with PDL conducted to treat recalcitrant PWS. Ten patients with 11 recalcitrant PWS were enrolled. Each PWS was divided into 5 treatment areas: PDL alone, RF alone, PDL+RF, RF+PDL, and untreated control. Patients underwent a maximum of 6 treatments, scheduled 4 to 6 weeks apart with follow-up evaluation at 4 and 12 weeks after the final treatment. Colorimetry and standardized digital photography were performed at all visits. Lesional biopsy specimens were collected for selected patients. RESULTS: Areas treated with RF followed by PDL and PDL followed by RF showed the greatest improvement based on blinded review of digital photographs, reaching statistical significance (P value < .05) at the 12-week follow-up evaluation when compared with baseline. Adverse events, including purpura, erythema, edema, scabbing, crusting, and blistering, resolved without sequelae; a small residual scar was noted in 1 patient. LIMITATIONS: Small sample size and short follow-up period are limitations. CONCLUSION: Combined RF/PDL technology is promising for the treatment of recalcitrant PWS. PMID- 28088994 TI - Impact of dermoscopy on an internet-based skin cancer triage system: Interim results of a randomized study. PMID- 28088995 TI - Frequency of total body skin examinations among US dermatologists. PMID- 28088996 TI - A systematic review of comorbidity indices used in the nonmelanoma skin cancer population. PMID- 28088997 TI - Predictors of actinic keratosis count in patients with multiple keratinocyte carcinomas: A cross-sectional study. PMID- 28088998 TI - Successful treatment of actinic keratoses using nonthermal atmospheric pressure plasma: A case series. PMID- 28088999 TI - Standard step sectioning of skin biopsy specimens diagnosed as superficial basal cell carcinoma frequently yields deeper and more aggressive subtypes. PMID- 28089000 TI - Incidence ratio of basal cell carcinoma to squamous cell carcinoma equalizes with age. PMID- 28089001 TI - The detection of human papillomavirus-16 in squamous cell carcinoma of the nail unit: A case series. PMID- 28089002 TI - Segmental hemangioma of the head and neck: High prevalence of PHACE syndrome. PMID- 28089003 TI - Treatment of myxoid cysts with intralesional photodynamic therapy: A case series. PMID- 28089004 TI - Elder mistreatment training gaps among dermatology resident physicians and opportunity to improve care of a vulnerable population: A cross-sectional study. PMID- 28089005 TI - Knowledge of dermatologic abbreviations: A survey of patients and physicians who are not dermatologists. PMID- 28089006 TI - Ethical dilemma in missed melanoma: What to tell the patient and other providers. PMID- 28089007 TI - Biomechanics in dermatology: Recent advances and future directions. AB - Biomechanics is increasingly being recognized as an important research area in dermatology. To highlight only a few examples, biomechanics has contributed to the development of novel topical therapies for aesthetic and medical purposes, enhanced our understanding of the pathogenesis of plantar melanoma, and provided insight into the epidemiology of psoriatic disease. This article summarizes the findings from recent studies to demonstrate the important role that biomechanics may have in dermatologic disease and therapy and places these biomechanical findings in a clinical context for the practicing physician. In addition, areas for future biomechanics research and development in dermatology are discussed. PMID- 28089012 TI - Multiple junctional nevi on the buttocks: An indicator of tanning bed use. PMID- 28089013 TI - Brimonidine tartrate 0.33% gel for the management of posttreatment erythema induced by laser skin resurfacing. PMID- 28089014 TI - The wingman flap: Bilateral closure of a supra-tip defect of the nose. PMID- 28089015 TI - Time and cost savings of the forceps tie. PMID- 28089016 TI - WITHDRAWN: Reporting adverse events related to cosmetic products. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published in Dermatitis, 27 (2016) 236-237, doi: 10.1097/DER.0000000000000195. The duplicate article has therefore been withdrawn.The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 28089017 TI - Reply to "Clusters of CD123+ plasmacytoid dendritic cells help distinguish lupus alopecia from lichen planopilaris": Plasmacytoid dendritic cell content, clustering, and distribution pattern are useful parameters in differentiating lupus alopecia from lichen planopilaris. PMID- 28089018 TI - Reply to: "Plasmacytoid dendritic cell content, clustering, and distribution pattern are useful parameters in differentiating lupus alopecia from lichen planopilaris". PMID- 28089019 TI - Indoor tanning among New Jersey high school students before and after the enactment of youth access restrictions. PMID- 28089020 TI - Reply to: "Indoor tanning among New Jersey high school students before and after the enactment of youth access restrictions". PMID- 28089021 TI - Limitations and challenges of nail unit dermoscopy in longitudinal melanonychia. PMID- 28089022 TI - Reply to: "Limitations and challenges of nail unit dermoscopy in longitudinal melanonychia". PMID- 28089023 TI - Comparative Transcriptomic Analysis of the Effects of Antidepressant Drugs in Stress-Susceptible Mice. PMID- 28089024 TI - A New Hope for Biological Insights Into Depression. PMID- 28089025 TI - Brain-Derived Neurotrophic Factor and the Orbitofrontal Regulation of Behavior. PMID- 28089026 TI - The Habenula: Darkness, Disappointment, and Depression. PMID- 28089027 TI - Neurocognitive Markers of Depression. PMID- 28089028 TI - Editorial: The Central and Eastern European Proteomics Conferences: 10 Years Anniversary. PMID- 28089029 TI - Guidelines for privileging, credentialing, and proctoring to perform GI endoscopy. PMID- 28089030 TI - Negative result of capsule endoscopy in obscure GI bleeding: searching in the dark despite bright lights. PMID- 28089031 TI - Role of radiofrequency ablation in esophageal squamous dysplasia and early neoplasia. PMID- 28089032 TI - Rule of three for esophageal dilation: like the tortoise versus the rabbit, low and slow is our friend and our patients' win. PMID- 28089033 TI - What we don't know. PMID- 28089034 TI - Echoing concerns related to endoscope reprocessing. PMID- 28089035 TI - Duodenal endoscopic interventions for obesity and diabetes. PMID- 28089036 TI - Biliary bypass redux: lessons for the therapeutic endoscopist from the archives of surgery. PMID- 28089037 TI - The magnets are coming! Are we ready to swallow our capsules? PMID- 28089038 TI - Response. PMID- 28089039 TI - Helicobacter pylori-related metabolic syndrome as predictor of progression to esophageal carcinoma in a subpopulation-based Barrett's esophagus cohort. PMID- 28089040 TI - Antireflux stent for distal malignant biliary obstruction: some inspiration from a randomized controlled trial. PMID- 28089041 TI - Response. PMID- 28089042 TI - Molecular screening of xerophilic Aspergillus strains producing mycophenolic acid. AB - Mycophenolic acid (MPA) is the fungal secondary metabolite displaying several biological properties. Up to now, screening of fungal strains producing MPA has mainly been the result of the search of this molecule in their culture medium by chemical methods. Here we developed a molecular approach by targeting the expression level of the MpaC gene encoding the polyketide synthase, one of the key enzymes involved in the MPA synthesis. Thirty xerophilic Aspergillus strains were identified using the RNA polymerase II subunit and the beta-tubulin genes. Seven Aspergillus species were evidenced. The expression level of the MpaC gene was quantified and compared to the MPA production rate. Only Aspergillus pseudoglaucus and all the eight strains of this species produced MPA. While the MpaC gene was not expressed or weakly expressed in the MPA non-producing strains, all the A. pseudoglaucus strains presented a high level of expression of this gene. The highest expression level of the MpaC gene among the MPA non-producing strains was significantly lower than the lowest expression level of this gene in the MPA producing strains. To our knowledge, this is the first study that demonstrates the effectiveness of molecular approach for the screening of MPA producing species. PMID- 28089043 TI - Contrasting microsatellite diversity in the evolutionary lineages of Phytophthora lateralis. AB - Following recent discovery of Phytophthora lateralis on native Chamaecyparis obtusa in Taiwan, four phenotypically distinct lineages were discriminated: the Taiwan J (TWJ) and Taiwan K (TWK) in Taiwan, the Pacific Northwest (PNW) in North America and Europe and the UK in west Scotland. Across the four lineages, we analysed 88 isolates from multiple sites for microsatellite diversity. Twenty-one multilocus genotypes (MLGs) were resolved with high levels of diversity of the TWK and PNW lineages. No alleles were shared between the PNW and the Taiwanese lineages. TWK was heterozygous at three loci, whereas TWJ isolates were homozygous apart from one isolate, which exhibited a unique allele also present in the TWK lineage. PNW lineage was heterozygous at three loci. The evidence suggests its origin may be a yet unknown Asian source. North American and European PNW isolates shared all their alleles and also a dominant MLG, consistent with a previous proposal that this lineage is a recent introduction into Europe from North America. The UK lineage was monomorphic and homozygous at all loci. It shared its alleles with the PNW and the TWJ and TWK lineages, hence a possible origin in a recent hybridisation event between a Taiwan lineage and PNW cannot be ruled out. PMID- 28089044 TI - Cytological analysis of the effect of reactive oxygen species on sclerotia formation in Sclerotinia minor. AB - The Sclerotium is one of the most persistent organs in filamentous fungi. Control of sclerotial formation is promising in the prevention of sclerotial disease. In this study, cytological analyses of sclerotial development were conducted in Sclerotinia minor. Number and size of sclerotia were correlated with nutrient concentration of the media. Interruption of aeration by sealing with parafilm completely suppressed sclerotial formation. We also found that reactive oxygen species (ROS) generated two phases, i.e., hydrogen peroxide at sclerotial initial (SI) stage and O2- at outer layer of sclerotial development/mature stages, during sclerotial formation. Ultrastructural analyses revealed that ROS was prominently produced at the outer layer of sclerotia in sclerotial mature (SM) phase. Although most of the inhibitors for ROS generation enzymes were ineffective for sclerotial formation, ascorbic acid, one of the scavengers of hydrogen peroxide, inhibited melanin biosynthesis during sclerotial maturation stage. The mycelia sealed with parafilm, when exogenously sprayed with hydrogen peroxide, could not produce sclerotium. These results indicated that ROS generation during sclerotial formation is mainly involved in the production of melanin layer. PMID- 28089045 TI - Biotransformation of limonene by an endophytic fungus using synthetic and orange residue-based media. AB - Aroma and fragrances have high commercial value for use in food, cosmetics and perfumes. The biotransformation of terpenes by microorganisms represents an attractive alternative method for production of flavourings. Endophytic fungi offer a great potential for the production of several groups of compounds; however, few studies have evaluated the biotransformation of limonene. Following preliminary studies on the biotransformation of limonene, submerged fermentation was carried out using an endophytic fungus isolated from Pinus taeda and identified as Phomopsis sp. The presence of several biotransformation products was detected and identified by mass spectrometry (GC-MS). The studied strain showed a divergent metabolic behaviour, as compounds of interest such as alpha terpineol, carvone, and limoneno-1,2-diol were produced under different conditions. In addition to the minor metabolites terpinen-4-ol, menthol and carveol, this strain also produced major metabolites, including 0.536 g L-1 carvone and 2.08 g L-1 limonene-1,2-diol in synthetic medium and 2.10 g L-1 limonene-1,2-diol in a natural orange extract medium with single fed-batch, while the cyclic fed-batch resulted in concentrations less than 1 g L-1. Therefore, our study produced a wide variety of limonene derivatives at a high concentration using a natural medium and a newly isolated endophytic fungal strain. PMID- 28089046 TI - Deception Island, Antarctica, harbors a diverse assemblage of wood decay fungi. AB - Very little is known about fungal diversity in Antarctica as compared to other biomes and how these important organisms function in this unusual ecosystem. Perhaps one of the most unusual ecosystems is that of Deception Island; an active volcanic island part of the South Shetland Islands of the Antarctic Peninsula. Here we describe the fungal diversity associated with historic wood from structures on the island, which reveals a diverse fungal assemblage of known wood decay fungi as well as the discovery of undescribed species. The major group of wood decay fungi identified were species of Cadophora and as shown in previous studies in other geographic regions of Antarctica, they caused a soft-rot type of decay in the introduced woods. Additionally, unlike other areas of Antarctica that have been studied, filamentous basidiomycetes (Hypochniciellum spp. and Pholiota spp.) were also identified that have different modes of degradation including brown and white rot. Matches of fungal sequences to known species in temperate regions likely introduced on building materials indicates human influences and volcanic activity have greatly impacted fungal diversity. Lahars (mudslides from volcanic activity) have partially buried many of the structures and the buried environment as well as the moist, warm soils provided conditions conducive for fungal growth that are not found in other regions of Antarctica. The diverse assemblage of decay fungi and different forms of wood decomposition add to the difficulty of conserving wooden structures at these important polar heritage sites. PMID- 28089047 TI - CYPome of the conifer pathogen Heterobasidion irregulare: Inventory, phylogeny, and transcriptional analysis of the response to biocontrol. AB - The molecular mechanisms underlying the interaction of the pathogen, Heterobasidion annosum s.l., the conifer tree and the biocontrol fungus, Phlebiopsis gigantea have not been fully elucidated. Members of the cytochrome P450 (CYP) protein family may contribute to the detoxification of components of chemical defence of conifer trees by H. annosum during infection. Additionally, they may also be involved in the interaction between H. annosum and P. gigantea. A genome-wide analysis of CYPs in Heterobasidion irregulare was carried out alongside gene expression studies. According to the Standardized CYP Nomenclature criteria, the H. irregulare genome has 121 CYP genes and 17 CYP pseudogenes classified into 11 clans, 35 families, and 64 subfamilies. Tandem CYP arrays originating from gene duplications and belonging to the same family and subfamily were found. Phylogenetic analysis showed that all the families of H. irregulare CYPs were monophyletic groups except for the family CYP5144. Microarray analysis revealed the transcriptional pattern for 130 transcripts of CYP-encoding genes during growth on culture filtrate produced by P. gigantea. The high level of P450 gene diversity identified in this study could result from extensive gene duplications presumably caused by the high metabolic demands of H. irregulare in its ecological niches. PMID- 28089048 TI - Identification of A. arborescens, A. grandis, and A. protenta as new members of the European Alternaria population on potato. AB - Alternaria species, primarily the small-spored Alternaria alternata and the large spored Alternaria solani, are considered a serious threat to potato cultivation. To develop control strategies, it is important to gain insight into the Alternaria population. Based on the sequence analyses of the internal transcribed spacer region (ITS) and the glyceraldehyde-3-phosphate dehydrogenase gene, the small-spored and large-spored Alternaria isolates could be separated from each other. Sequence analyses of the calmodulin gene and the RNA polymerase second largest subunit showed that besides A. solani also A. grandis and A. protenta were present in the large-spored Alternaria population. Sequence analyses of the Alternaria major allergen gene Alt a 1 and the elongation factor-alpha revealed that both A. alternata and species belonging to the Alternaria arborescens species complex were present in the small-spored Alternaria population. Furthermore, according to the histone h3 sequence the members of the A. arborescens species complex could be subdivided into two groups. Concerning the fitness, it was concluded that the mycelium growth rate of the large-spored isolates was significantly lower compared to the growth rate of the small-spored isolates. In contrast, the spore-germinating capacity and early growth of the large-spored isolates was greater compared to those of the small-spored isolates. Within the groups of small-spored and large-spored isolates there were no significant differences in fitness between the species. PMID- 28089049 TI - Variation in virulence of Beauveria bassiana and B. pseudobassiana to the pine weevil Pissodes nemorensis in relation to mycelium characteristics and virulence genes. AB - Entomopathogenic fungi such as Beauveria spp. have potential applications in the biocontrol of insect pests but little is known regarding their infectivity to the pine weevil Pissodes nemorensis. In this study, five isolates of Beauveria pseudobassiana and five isolates of Beauveria bassiana were tested for characteristics correlating with virulence on P. nemorensis. Isolate UAMH301 had the lowest mean lethal concentration value whereas the highest value was obtained with isolate LRC137. Growth rate was negatively correlated with virulence in B. bassiana, because isolate LRC137, the least virulent isolate, grew much more rapidly than the other B. bassiana isolates on SDYA. In contrast, its growth on a hyperosmotic medium was the slowest. Sporulation rate and conidial area were not correlated with virulence. Mycelial cell density was positively correlated with virulence in both species, and the four tested genes appear to be one-copy genes. Bbchit1 and Bbhog1, genes respectively encoding a chitinase and a protein kinase, induced relative expression levels were positively correlated with virulence in B. pseudobassiana. We discuss in terms of previous morphological, physiological and genetic parameters related to virulence in Beauveria and the importance of testing the expression of putative virulence genes in comparison with their basal transcript levels. PMID- 28089050 TI - Burns Open journal. PMID- 28089051 TI - Individualized Medicine in Ovarian Cancer: Are We There Yet? PMID- 28089052 TI - Corrigendum to 'Equivalency challenge: evaluation of Lipodox(r) as the generic equivalent for Doxil(r) in a human ovarian cancer orthotropic mouse model' [Gynecol. Oncol. 141 (2016) 357-363]. PMID- 28089053 TI - Advances in neuromodulation in children: Current experience and future directions. PMID- 28089054 TI - The Perfect Resume. PMID- 28089057 TI - 25th Critical Care Transport Medicine Conference. PMID- 28089055 TI - Articles That May Change Your Practice: Prehospital Ultrasound. PMID- 28089058 TI - Inferior Wall Acute Myocardial Infarction: Not as Preload Dependent as Once Thought? PMID- 28089059 TI - Management of Hospitalized Asthmatic Children Before Transport. AB - Asthmatic children are at risk for respiratory failure and should be appropriately treated before transport. The objectives were to find out if the Pediatric Advanced Life Support guidelines for asthma treatment were followed in the emergency department (ED); to determine if additional treatment during transport or within the first 2 hours of admission was needed; and to compare the management of intubated asthmatics by the ED, transport team, and the intensive care unit (ICU) physician. The records for children diagnosed with acute asthma over 7 years who were transported by the intensive care transport team were reviewed. The use of albuterol, steroids, oxygen, heliox, continuous positive airway pressure or bilevel positive airway pressure, and ventilator settings was recorded. Two hundred seventy-nine children were 7 years (age, 5 mo-17 y), and 62% were male. Eighty percent received oxygen, albuterol, and steroids in the ED. Heliox was initiated more often by the transport team when compared with the ED or hospital physician (77% vs. 7.7% vs. 15.3%, P < .0001). Forty-five were mechanically ventilated and were more likely to receive volume control (P < .0001) and higher rates (P = .007) in the ED than the ICU. We conclude that most children with acute asthma were treated with oxygen, albuterol, and steroids in the ED. If used, heliox was most likely started during transport. Intubated children were more likely to receive volume control with higher rates compared with lower rates and pressure control in the ICU. PMID- 28089060 TI - Evaluating Services at a Major Trauma Center Before Helipad Construction. AB - INTRODUCTION: Two of the 4 hospitals designated as major trauma centers in London, UK, currently operate on-site helicopter landing pads. King's College Hospital (KCH) is constructing a third. We evaluate current trauma services at King's College Hospital, before the helipad entering service, establishing baseline workload and mortality measures. METHODS: We retrospectively analyzed data from patients admitted January 1, 2014, to December 31, 2015, to KCH after major trauma with on-scene helicopter emergency medical services involvement (N = 427) using the Trauma Audit and Research Network database. RESULTS: The median Injury Severity Score of the cohort was 22 (interquartile range [IQR], 13-30). The median length of stay was 11 days (IQR, 5-24). Fifty-seven percent of the patients received intensive care unit (ICU) admission, with a median ICU length of stay (LOS) of 5 days (IQR, 2-12) in this subgroup. There was no significant difference in Injury Severity Score, LOS, or ICU LOS between 2014 and 2015. One hundred ninety-three patients (45.2%) underwent >= 1 operation, accounting for 1,276.5 hours of operating room time in total. Cox proportional hazards regression showed no difference in survival outcomes between 2014 and 2015. CONCLUSION: Baseline workload and mortality measures were obtained, forming the basis of future service evaluation to assess the impact of helipad construction. PMID- 28089061 TI - Erratum to 'A Case Review: In-Flight Births Over a 4-Year Period in the Northern Territory, Australia' [Air Medical Journal 35(5):317-320]. PMID- 28089063 TI - 16-Year-Old Female Near Hanging With Negative Pressure Pulmonary Edema. PMID- 28089064 TI - Toward Zero Preventable Deaths. PMID- 28089066 TI - Evaluation and prevention of the negative matrix effect of terpenoids on pesticides in apples quantification by gas chromatography-tandem mass spectrometry. AB - The sample matrix can enhance the gas chromatography signal of pesticide residues relative to that obtained with the same concentration of pesticide in solvent. This paper is related to negative matrix effects observed in coupled gas chromatography-mass spectrometry ion trap (GC/MS2) quantification of pesticides in concentrated extracts of apple peel prepared by the Quick Easy Cheap Effective Rugged and Safe (QuEChERS) method. It is focused on the pesticides most frequently used on the apple varieties studied, throughout the crop cycle, right up to harvest, to combat pests and diseases and to improve fruit storage properties. Extracts from the fleshy receptacle (flesh), the epiderm (peel) and fruit of three apple varieties were studied by high-performance thin-layer chromatography hyphenated with UV-vis light detection (HPTLC/UV visible). The peel extracts had high concentrations of triterpenic acids (oleanolic and ursolic acids), reaching 25mgkg-1, whereas these compounds were not detected in the flesh extracts (<0.05mgkg-1). A significant relationship has been found between the levels of these molecules and negative matrix effects in GC/MS2. The differences in the behavior of pesticides with respect to matrix effects can be accounted for by the physicochemical characteristics of the molecules (lone pairs, labile hydrogen, conjugation). The HPTLC/UV visible method developed here for the characterization of QuEChERS extracts acts as a complementary clean-up method, aimed to decrease the negative matrix effects of such extracts. PMID- 28089067 TI - Effect of mobile phase additives on solute retention at low aqueous pH in hydrophilic interaction liquid chromatography. AB - Trifluoracetic acid (TFA) added to the aqueous acetonitrile mobile phase induces some unexpected changes in the ionic component of retention in hydrophilic interaction separations when using Type B silica and amide-bonded silica columns. TFA use results in anion exchange properties which contrast with the cation exchange typically found with ammonium salt buffers. The significant cation exchange properties of silica hydride columns are also moderated by TFA. Similar behaviour was shown in a metal- free amide column operated on a system washed with a metal complexing agent, suggesting that adsorbed metal cations were not responsible for this anion exchange behaviour. Both suppression of silanol ionisation at low pH and ion pairing of bases with TFA could contribute to this effect. It is also possible that the column surface acquires some positive charges at the low pH of TFA. A surprising reversal of the properties of the columns back to predominately cation exchange behaviour was shown using methanesulfonic acid (MSA), which appears to be a stronger acid than TFA in high concentrations of acetonitrile. MSA maintains sufficient ionic strength in the mobile phase even at low concentrations, giving good peak shape, which could be useful for mass spectrometry detection. Besides giving different selectivity to TFA, MSA also gives different selectivity to that of ammonium salt buffers, suggesting it may be useful in manipulating the selectivity of a separation. Similar changes to the selectivity with TFA could be achieved by adding neutral methylsulfonate salts to the TFA mobile phase. While it is possible that methylsulfonate ions are retained on the stationary phase surface, experiments using ion pair reagents of opposite charge yielded the same results as MSA salts. It therefore seems more likely that the higher ionic strength of these solutions negates the influence of charges that may be formed in TFA solutions. Ion pairing effects with MSA are expected to be limited. PMID- 28089068 TI - The experimental design approach to eluotropic strength of 20 solvents in thin layer chromatography on silica gel. AB - The eluotropic strength on thin-layer silica plates was investigated for 20 chromatographic grade solvents available in current market. 35 model compounds were used as test subjects in the investigation. The use of modern mixture screening design allowed to estimate each solvent as a separate elution coefficient with an acceptable error of estimation (0.0913 of RM value). Additional bootstrapping technique was used to check the distribution and uncertainty of eluotropic estimates, proving very similar confidence intervals to linear regression. Principal component analysis proved that the only one parameter (mean eluotropic strength) is satisfactory to describe the solvent property, as it explains almost 90% of variance of retention. The obtained eluotropic data can be good appendix to earlier published results and their values can be interpreted in context of RM differences. PMID- 28089069 TI - A sensitive gas chromatography detector based on atmospheric pressure chemical ionization by a dielectric barrier discharge. AB - In this work, we present a novel concept for a gas chromatography detector utilizing an atmospheric pressure chemical ionization which is initialized by a dielectric barrier discharge. In general, such a detector can be simple and low cost, while achieving extremely good limits of detection. However, it is non selective apart from the use of chemical dopants. Here, a demonstrator manufactured entirely from fused silica capillaries and printed circuit boards is shown. It has a size of 75*60*25mm3 and utilizes only 2W of power in total. Unlike other known discharge detectors, which require high-purity helium, this detector can theoretically be operated using any gas able to form stable ion species. Here, purified air is used. With this setup, limits of detection in the low parts-per-billion range have been obtained for acetone. PMID- 28089070 TI - Steric exclusion chromatography for purification of cell culture-derived influenza A virus using regenerated cellulose membranes and polyethylene glycol. AB - Steric exclusion chromatography has been used for the purification of proteins and bacteriophages using monoliths. The operation is carried out by mixing a crude sample containing the target species with a predetermined concentration and molecular weight of polyethylene glycol (PEG) and loading it onto a non-reactive hydrophilic surface. Product capture occurs by the mutual steric exclusion of PEG between the product and the matrix. Selectivity is significantly influenced by target product size. Product elution is achieved by decreasing the PEG concentration. In this study, a 75cm2 cellulose membrane adsorber was used for the purification of a clarified and inactivated influenza A virus broth produced in a 5L bioreactor using suspension Madin Darby canine kidney cells. Product recovery was above 95% based on hemagglutination activity and single radial immunodiffusion assays. Maximum depletion of double stranded host cell DNA and total protein was 99.7% and 92.4%, respectively. Purified virus particles showed no aggregation with a monodisperse peak around 84nm. 250mL of the clarified inactivated virus broth was purified within 40min. The surface area productivity based on the recovery of the viral hemagglutinin antigen was 28-50mgm-2h-1 depending on the feed and loading conditions. PMID- 28089071 TI - Lead, cadmium and mercury in cerebrospinal fluid and risk of amyotrophic lateral sclerosis: A case-control study. AB - Exposure to neurotoxic chemicals such as pesticides, selenium, and heavy metals have been suggested to play a role in the etiology of amyotrophic lateral sclerosis (ALS). We assessed exposure to lead, cadmium, and mercury in 38 ALS patients (16 men and 22 females) and 38 hospital-admitted controls by using their cerebrospinal fluid (CSF) content as biomarker. We determined CSF heavy metal levels with inductively coupled plasma sector field mass spectrometry, according to a methodology specifically developed for this biological matrix. ALS patients had higher median values for Pb (155 vs. 132ng/L) but lower levels for Cd (36 vs. 72ng/L) and Hg (196 vs. 217ng/L). In the highest tertile of exposure, ALS odds ratio was 1.39 (95% CI 0.48-4.25) for Pb, 0.29 (0.08-1.04) for Cd and 3.03 (0.52 17.55) for Hg; however, no dose-response relation emerged. Results were substantially confirmed after conducting various sensitivity analyses, and after stratification for age and sex. Though interpretation of these results is limited by the statistical imprecision of the estimates, and by the possibility that CSF heavy metal content may not reflect long-term antecedent exposure, they do not lend support to a role of the heavy metals cadmium, lead and mercury in ALS etiology. PMID- 28089072 TI - The role of implantable cardioverter defibrillators in patients bridged to transplantation with a continuous-flow left ventricular assist device: A propensity score matched analysis. AB - BACKGROUND: Implantable cardioverter defibrillators (ICDs) provide a significant mortality benefit for appropriately selected patients with advanced heart failure. ICDs are associated with a mortality benefit when used in patients with a pulsatile left ventricular assist device (LVAD). It is unclear whether patients with a continuous-flow LVAD (CF-LVAD) derive the same benefit. We sought to determine if the presence of an ICD provided a mortality benefit during CF-LVAD support as a bridge to transplantation. METHODS: Patients were identified in the United Network for Organ Sharing (UNOS) registry who underwent LVAD implantation as bridge to transplantation between May 2004 and April 2014, with follow-up through June 2014. Primary outcome was freedom from death while on CF-LVAD support with adjustment for complications requiring UNOS listing status upgrade. Secondary end-points included freedom from delisting while on CF-LVAD support and incidence of transplantation. RESULTS: The study cohort comprised 2,990 patients, and propensity score matching identified 1,012 patients with similar propensity scores. There was no difference in survival during device support between patients with and without an ICD (hazard ratio [HR] = 1.20; 95% confidence interval [CI], 0.66-2.17; p = 0.55). Adjusting for device complications requiring a UNOS listing status upgrade had minimal influence (HR = 1.11; 95% CI, 0.60 2.05; p = 0.74). There was no increased risk of delisting owing to being too sick for patients with an ICD (HR = 1.08; 95% CI, 0.63-1.86; p = 0.78). Likewise, the probability of transplantation was similar (HR = 1.05; 95% CI, 0.87-1.27; p = 0.62). CONCLUSIONS: Among patients bridged to transplantation with a CF-LVAD, the presence of an ICD did not reduce mortality. PMID- 28089073 TI - The H Index in Perspective. PMID- 28089074 TI - Does teaching of robotic partial nephrectomy affect renal function and perioperative outcomes? AB - PURPOSE: Partial nephrectomy (PN) represents the treatment of choice for localized renal tumor<7cm. Minimally invasive approaches are considered standard of care in many institutions. Maintaining acceptable warm ischemic time (WIT) while teaching robotic PN (RPN) remains challenging. The goal of the present study was to assess the effect of teaching RPN on WIT and renal function in patients undergoing RPN. METHODS: Patients undergoing RPN for cT1-T2 renal tumors were included. RENAL nephrometry score was used to adjust for tumor complexity. Glomerular filtration rates (GFR) were determined preoperatively, at day 2 and at >=3-month follow-up. Patients in whom the attending surgeon (staff) performed tumorectomy and renorraphy were compared with those in whom the fellow performed these steps. Primary outcomes were WIT and GFR decrease at follow-up visit. Morbidity and margin positivity represented secondary outcomes. RESULTS: Overall, 69 patients (46 "staff" vs. 23 "fellow") were included. Patient's characteristics did not differ significantly between the 2 groups. In particular, RENAL score and preoperative GFR were similar between both groups. Mean WIT was 22+/-9 in the staff and 24+/-7 in the fellow group (P = 0.09). At follow-up, a GFR reduction of 9% was observed in the staff group vs. 13% in the fellow group (P = 0.38). Complication rates (13% vs. 17%, P = 0.63) and positive margins (9% vs. 4%, P = 0.47) did not differ significantly between staff and fellow. CONCLUSIONS: In our experience, teaching RPN with a strict supervision and stepwise standardized procedure was oncologically and functionally safe after 3 to 6 months of follow up. PMID- 28089075 TI - Conjunctival impression cytology evaluation of patients with dry eye disease using scleral contact lenses. AB - PURPOSE: To evaluate conjunctival impression cytology and HLADR expression changes after wearing scleral contact lenses (ScCLs) for moderate to severe dry eye disease (DED). DESIGN: Prospective interventional case series. METHODS: Forty one eyes from 25 patients with moderate to severe DED were evaluated for Esclera ScCL treatment. Best-corrected visual acuity (BCVA) and slit-lamp findings were assessed. Impression cytology specimens were obtained from DED patients at the baseline and after wearing ScCLs for 12 months. The impression cytology specimens were analyzed using morphological results score, and HLA-DR positive cells were detected and quantified. The values were compared to assess the IC changes after wearing ScCLs. RESULTS: Forty-one eyes from 25 patients were fitted with ScCLs to manage DED. The underlying diseases were Stevens-Johnson syndrome (22 eyes), Sjogren's syndrome (11 eyes), graft-versus-host disease (2 eyes), dry eye after keratomileusis (2 eyes) and undifferentiated ocular surface disease (4 eyes). The HE-PAS impression cytology score did not differ significantly before and after wearing ScCLs for 12 months in DED patients (p>0.05). The percentage of eyes expressing the HLA-DR antigen in the temporal conjunctiva after wearing ScCL for 12 months significantly increased in patients with Sjogren's syndrome (11.11% to 66.66%; p=0.0498). In groups with Stevens Johnson syndrome and other ocular surface disorders, we did not observe statistically significant differences (p>0.05). CONCLUSIONS: The ScCLs did not change the parameters used to evaluate inflammatory processes, which were measured using conjunctival impression cytology and HLA-DR expression, except in Sjogren syndrome, in which there was an unexpected increase in HLA expression. PMID- 28089076 TI - Comparative analyses of secreted proteins in plant pathogenic smut fungi and related basidiomycetes. AB - In the ten years since the genome sequence of the basidiomycete corn smut fungus Ustilago maydis was published, additional genomes of smut species infecting different hosts became available. In addition, the genomes of related Malassezia species causing skin diseases and of Pseudozyma species not known to infect plants were determined. As secreted proteins are critical virulence determinants in U. maydis we compare here the secretomes of 12 basidiomycete species to gain information about their composition and conservation. For this we classify secreted proteins into those with and without domains using InterPro scans. Homology among proteins is inferred by building clusters based on pairwise similarities and cluster presence is then assessed in the different species. We detect in particular a strong correspondence between the secretomes of Pseudozyma species and plant infecting smuts. Furthermore, we identify a high proportion of secreted proteins to be part of gene families and present an advancement of the CRISPR-Cas9 technology for simultaneous disruption of multiple genes in U. maydis using five genes of the eff1 family as example. PMID- 28089077 TI - The changing pattern of uterine contractions before and after fresh embryo transfer and its relation to clinical outcome. AB - In this prospective cohort study of 286 women undergoing fresh embryo transfer after IVF, uterine contraction frequency and direction were measured before (-5 min), 5 min after (+5 min) and 60 min after (+60 min) embryo transfer. Mean +/- SD uterine contraction frequency at -5 min was 1.8 +/- 1.1 contractions per min, increasing significantly (P < 0.05) to 2.0 +/- 1.1 at +5 min, and returning back to baseline 1.8 +/- 1.1 at +60 min. At -5 min, the proportion of women the with retrograde, antegrade, indeterminate direction and absent contractions were 33%, 44%, 17% and 6%; at +5 min, 40%, 42%, 13% and 5%, and at +60 min, 42%, 38%, 14% and 6%. No significant change was observed in the proportion of direction at these three time points. Logistic regression analysis showed live birth rate was significantly reduced in older women (P = 0.035) and in those with higher uterine contraction frequency at +5 min (P = 0.006). Frequency of uterine contraction immediately after embryo transfer (+5 min) seemed to be a significant predictor of IVF outcome and may help to identify women who could benefit from the use of muscle relaxant therapy to improve outcome. PMID- 28089078 TI - hucMSC Exosome-Derived GPX1 Is Required for the Recovery of Hepatic Oxidant Injury. AB - Exosomes are small biological membrane vesicles secreted by various cells, including mesenchymal stem cells (MSCs). We previously reported that MSC-derived exosomes (MSC-Ex) can elicit hepatoprotective effects against toxicant-induced injury. However, the success of MSC-Ex-based therapy for treatment of liver diseases and the underlying mechanisms have not been well characterized. We used human umbilical cord MSC-derived exosome (hucMSC-Ex) administrated by tail vein or oral gavage at different doses and, in engrafted liver mouse models, noted antioxidant and anti-apoptotic effects and rescue from liver failure. A single systemic administration of hucMSC-Ex (16 mg/kg) effectively rescued the recipient mice from carbon tetrachloride (CCl4)-induced liver failure. Moreover, hucMSC-Ex derived glutathione peroxidase1 (GPX1), which detoxifies CCl4 and H2O2, reduced oxidative stress and apoptosis. Knockdown of GPX1 in hucMSCs abrogated antioxidant and anti-apoptotic abilities of hucMSC-Ex and diminished the hepatoprotective effects of hucMSC-Ex in vitro and in vivo. Thus, hucMSC-Ex promote the recovery of hepatic oxidant injury through the delivery of GPX1. PMID- 28089079 TI - Repeated subarachnoid administrations of autologous mesenchymal stromal cells supported in autologous plasma improve quality of life in patients suffering incomplete spinal cord injury. AB - BACKGROUND AIMS: Cell therapy with mesenchymal stromal cells (MSCs) offers new hope for patients suffering from spinal cord injury (SCI). METHODS: Ten patients with established incomplete SCI received four subarachnoid administrations of 30 * 106 autologous bone marrow MSCs, supported in autologous plasma, at months 1, 4, 7 and 10 of the study, and were followed until the month 12. Urodynamic, neurophysiological and neuroimaging studies were performed at months 6 and 12, and compared with basal studies. RESULTS: Variable improvement was found in the patients of the series. All of them showed some degree of improvement in sensitivity and motor function. Sexual function improved in two of the eight male patients. Neuropathic pain was present in four patients before treatment; it disappeared in two of them and decreased in another. Clear improvement in bladder and bowel control were found in all patients suffering previous dysfunction. Before treatment, seven patients suffered spasms, and two improved. Before cell therapy, nine patients suffered variable degree of spasticity, and 3 of them showed clear decrease at the end of follow-up. At this time, nine patients showed infra-lesional electromyographic recordings suggesting active muscle reinnervation, and eight patients showed improvement in bladder compliance. After three administrations of MSCs, mean values of brain-derived neurotrophic factor, glial-derived neurotrophic factor, ciliary neurotrophic factor, and neurotrophin 3 and 4 showed slight increases compared with basal levels, but without statistically significant difference. CONCLUSIONS: Administration of repeated doses of MSCs by subarachnoid route is a well-tolerated procedure that is able to achieve progressive and significant improvement in the quality of life of patients suffering incomplete SCI. PMID- 28089080 TI - Salba-chia (Salvia hispanica L.) in the treatment of overweight and obese patients with type 2 diabetes: A double-blind randomized controlled trial. AB - BACKGROUND AND AIM: Preliminary findings indicate that consumption of Salba-chia (Salvia hispanica L.), an ancient seed, improves management of type 2 diabetes and suppresses appetite. The aim of this study was to assesse the effect of Salba chia on body weight, visceral obesity and obesity-related risk factors in overweight and obese adults with type 2 diabetes. METHODS: A double-blind, randomized, controlled trial with two parallel groups involved 77 overweight or obese patients with type 2 diabetes (HbA1c: 6.5-8.0%; BMI: 25-40 kg/m2). Both groups followed a 6-month calorie-restricted diet; one group received 30 g/1000 kcal/day of Salba-chia, the other 36 g/1000 kcal/day of an oat bran-based control. Primary endpoint was change in body weight over 6-months. Secondary endpoints included changes in waist circumference, body composition, glycemic control, C-reactive protein, and obesity-related satiety hormones. RESULTS: At 6 months, participants on Salba-chia had lost more weight than those on control (1.9 +/- 0.5 kg and 0.3 +/- 0.4 kg, respectively; P = 0.020), accompanied by a greater reduction in waist circumference (3.5 +/- 0.7 cm and 1.1 +/- 0.7 cm, respectively; P = 0.027). C-reactive protein was reduced by 1.1 +/- 0.5 mg/L (39 +/- 17%) on Salba-chia, compared to 0.2 +/- 0.4 mg/L (7 +/- 20%) on control (P = 0.045). Plasma adiponectin on the test intervention increased by 6.5 +/- 0.7%, with no change observed on control (P = 0.022). CONCLUSIONS: The results of this study, support the beneficial role of Salba-chia seeds in promoting weight loss and improvements of obesity related risk factors, while maintaining good glycemic control. Supplementation of Salba-chia may be a useful dietary addition to conventional therapy in the management of obesity in diabetes. REGISTRATION: clinicaltrials.gov identifier: NCT01403571. PMID- 28089081 TI - Asthma-chronic obstructive pulmonary disease overlap syndrome - Literature review and contributions towards a Portuguese consensus. AB - INTRODUCTION: Phenotypic overlap between the two main chronic airway pulmonary diseases, asthma and chronic obstructive pulmonary disease (COPD), has been the subject of debate for decades, and recently the nomenclature of asthma-COPD overlap syndrome (ACOS) was adopted for this condition. The definition of this entity in the literature is, however, very heterogeneous, it is therefore important to define how it applies to Portugal. METHODS: A literature review of ACOS was made in a first phase resulting in the drawing up of a document that was later submitted for discussion among a panel of chronic lung diseases experts, resulting in reflexions about diagnosis, treatment and clinical guidance for ACOS patients. RESULTS: There was a consensus among the experts that the diagnosis of ACOS should be considered in the concomitant presence of: clinical manifestations characteristic of both asthma and COPD, persistent airway obstruction (post bronchodilator FEV1/FVC<0.7), positive response to bronchodilator test (increase in FEV1 of >=200mL and >=12% from baseline) and current or past history of smoking or biomass exposure. In reaching diagnosis, the presence of peripheral eosinophilia (>300eosinophils/MUL or >5% of leukocytes) and previous history of atopy should also be considered. The recommended first line pharmacological treatment in these patients is the ICS/LABA association; if symptomatic control is not achieved or in case of clinical severity, triple therapy with ICS/LABA/LAMA may be used. An effective control of the exposure to risk factors, vaccination, respiratory rehabilitation and treatment of comorbidities is also important. CONCLUSIONS: The creation of initial guidelines on ACOS, which can be applied in the Portuguese context, has an important role in the generation of a broad nationwide consensus. This will give, in the near future, a far better clinical, functional and epidemiological characterization of ACOS patients, with the ultimate goal of achieving better therapeutic guidance. PMID- 28089082 TI - Backcasting to identify food waste prevention and mitigation opportunities for infant feeding in maternity services. AB - Food waste in hospitals is of major concern for two reasons: one, healthcare needs to move toward preventative and demand led models for sustainability and two, food system sustainability needs to seek preventative measures such as diet adaptation and waste prevention. The impact of breast-milk substitute use on health services are well established in literature in terms of healthcare implications, cost and resourcing, however as a food demand and waste management issue little has been published to date. This paper presents the use of a desk based backcasting method to analyse food waste prevention, mitigation and management options within the Irish Maternity Service. Best practice in healthcare provision and waste management regulations are used to frame solutions. Strategic problem orientation revealed that 61% of the volume of ready to use breast-milk substitutes purchased by maternity services remains unconsumed and ends up as waste. Thirteen viable strategies to prevent and manage this waste were identified. Significant opportunities exist to prevent waste and also decrease food demand leading to both positive health and environmental outcomes. Backcasting methods display great promise in delivering food waste management strategies in healthcare settings, especially where evidenced best practice policies exist to inform solution forming processes. In terms of food waste prevention and management, difficulties arise in distinguishing between demand reduction, waste prevention and waste reduction measures under the current Waste Management Hierarchy definitions. Ultimately demand reduction at source requires prioritisation, a strategy which is complimentary to health policy on infant feeding. PMID- 28089083 TI - Bile-ated Cell Death Decreases Aortic Aneurysm Formation. PMID- 28089084 TI - Predicting the Need for Intra-operative Large Volume Blood Transfusions During Thoraco-abdominal Aortic Aneurysm Repair. AB - OBJECTIVE: Thoraco-abdominal aortic aneurysm (TAAA) repair is a complex procedure performed in patients at high cardiovascular risk. High volume intra-operative bleeding is often recorded, and the amount of intra-operative blood product transfusion is associated with relevant morbidity and mortality. The aim of the study was to identify pre-operative predictors of intra-operative large volume blood transfusions (LVBT) to stratify patients pre-operatively. METHODS: This was a retrospective analysis of prospectively collected data of all patients who underwent open TAAA surgery at San Raffaele Scientific Institute from January 2009 to December 2015. Intra-operative red blood cell (RBC) transfusions were administered to maintain a hematocrit of at least 30%. A LVBT was defined as a transfusion of at least four RBC units, corresponding to 1000 mL. RESULTS: The study population included 428 patients: 260 (61%) received fewer than 4 RBC units, and 168 (39%) were transfused with at least 4 RBC units. In patients who underwent LVBT, higher mortality was observed after surgery (p=.003), longer intensive care unit admission (p=.004), and longer mechanical ventilation compared with less transfused patients (p=.0002). The patients who received fewer units were administered a higher dose of heparin during the surgical operation compared with patients of the LVBT group: 3400+/-1100 vs. 2900+/-1300 IU (international units) (p=.0004). Pre-operative chronic renal failure (OR 1.8), the pre-operative haemoglobin value (OR 0.8), and the need for urgent or emergent surgery (OR 3.15) were independent predictors of LVBT on multivariate analysis. CONCLUSIONS: The identification of patients at risk of intra-operative LVBT during TAAA surgery is critical as these patients experience a worse outcome. Nevertheless, only few independent predictors are available for clinical practice. PMID- 28089085 TI - The timing of bone SPECT to predict osteonecrosis after internal fixation of femur neck fractures. AB - BACKGROUND: Bone SPECT can be used after a femur neck fracture to assess the circulation of the femoral head in the immediate postoperative period because the blood supply is one of the major factors affecting bone uptake of radiotracer on bone scintigraphy. The purpose of our present study was to investigate whether osteonecrosis of the femoral head (OFH) after internal fixation of femoral neck fracture could be predicted by early and late bone SPECT. METHODS: This retrospective cohort study enrolled 44 patients (33 women; mean age, 66.9 years) who underwent surgical fixation for femoral neck fractures. Early and late bone SPECT images were obtained within 2 weeks postoperatively and at 3 months postoperatively. Patients were followed up for a minimum of 24 months (average, 34 months). RESULTS: OFH developed in 9 out of 44 patients but no patient showed nonunion. Seventeen patients with normal femoral head uptake on early bone SPECT were healed. Of 27 patients with decreased femoral head uptake on early bone SPECT, 2 patients developed OFH on radiography before 3 months postoperatively, 18 patients recovered to normal uptake on the late SPECT, and the remaining 7 patients still showed decreased uptake on the late SPECT at 3 months postoperatively. All of these 7 cases finally developed OFH on radiography. CONCLUSION: Bone SPECT can reliably predict the possibility of OFH with after femoral neck fracture at least 3 months after surgery, while early bone SPECT showed low specificity. STUDY DESIGN: Clinical. PMID- 28089086 TI - Improved pressurized Marinelli beaker measurements of radioactive xenon in air. AB - INL has shown that a Marinelli beaker geometry can be used for the measurement of radioactive xenon in air using an aluminum Marinelli. A carbon fiber Marinelli was designed and constructed to improve overall performance. This composite Marinelli can withstand sample pressures of 276bar and achieve approximately a 4x performance improvement in the minimum detectable concentrations (MDCs) and concentration uncertainties. The MDCs obtained during a 24h assay for 133Xe, 131mXe, and 135Xe are: 1.4, 13, and 0.35Bq/m3. PMID- 28089087 TI - Prevalence profile of odontogenic cysts and tumors on Brazilian sample after the reclassification of odontogenic keratocyst. AB - PURPOSE: The aim of this study was to evaluate the impact of the reclassification of odontogenic keratocyst (OKC) as a tumor on the prevalence profile of odontogenic cysts (OCs) and odontogenic tumors (OTs). STUDY DESIGN: Two referral Oral and Maxillofacial Pathology services in Brazil were evaluated. All cases diagnosed as OCs or OTs were selected and classified according to the 1992 WHO classification (cases before 2005 WHO classification of tumors excluding OKC) and the 2005 WHO classification of tumors, going forward including cases of odontogenic keratocyst tumor (KCOT). The frequency and prevalence of OCs and OTs were compared before and after the reclassification. RESULTS: Among 27,854 oral biopsies, 4920 (17.66%) were OCs and 992 (3.56%) were OTs. The prevalence of OTs before 2005 WHO classification of tumors was 2.04%, while the prevalence after 2005 WHO classification was 11.51% (p < 0.0001). Before 2006, the most frequent tumor diagnosed was odontoma with 194 cases (39.67%), and after 2005 WHO classification of tumors the KCOT was the most frequent with 207 cases (41.07%). CONCLUSIONS: The increase in the prevalence of OTs after 2005 WHO is related to the improvement of pathology services and to the inclusion of KCOT in the OTs group. PMID- 28089088 TI - Synovial chondromatosis of the temporomandibular joint: Immunohistochemical examinations regarding the role of insulin-like growth factors and their binding proteins in the etiology of this disease. AB - Synovial chondromatosis (SC) is a benign disease of the joints without a known cause. It sometimes affects the temporomandibular joint (TMJ) and is accompanied by pain, swelling, malocclusion, and crepitation. It has been divided into three stages by Milgram and is supposed to originate from the synovia and cartilage of a joint (Milgram, 1977b). The aim of this study was to examine an involvement of the insulin-like growth factors (IGF-I/-II) and their binding proteins (IGFBP-1 to -6) in the etiology of this disease. Therefore 23 specimen of SC from 16 patients were immunohistochemically stained and microscopically examined. Staining was assessed semiquantitatively: negative (-), weakly positive ((+)), moderately positive (+), strongly positive (++) and very strongly positive (+++). It could be seen that especially the chondro- and fibrocytes and the synovia showed positive staining for almost all IGFs and IGFBPs. The underlying tissue, consisting of connective tissue or chondroid matrix, was stained as well but more weakly so. We conclude that the IGF/IGFBP system seems to contribute to the pathogenesis of SC, especially IGF-I and -II, and their effects enhancing binding protein 5. PMID- 28089089 TI - 27Al-27Al double-quantum single-quantum MAS NMR: Applications to the structural characterization of microporous materials. AB - In this paper, we review and illustrate applications, reported in the literature or used in our group, of 27Al-27Al double-quantum single-quantum (DQ-SQ) MAS NMR experiments for the structural characterization of Al-containing microporous solids, namely zeolites, aluminophosphates and metal-organic frameworks. Information regarding the periodic frameworks or the localization of the various aluminum species in the materials are obtained from the analysis of the two dimensional NMR spectra, which allows getting local structural details sometimes inaccessible from other characterization technique. An application of 27Al-27Al of the DQ-SQ experiment for the detection of aluminum pairing in zeolite is shown. PMID- 28089090 TI - Non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus: Effects of statins and antidiabetic drugs. PMID- 28089091 TI - Characteristics and processing of Pol IV-dependent transcripts in Arabidopsis. AB - RNAi is a highly conserved machinery in eukaryotes for transcriptional or post transcriptional silencing. In plants, RNA-directed DNA Methylation (RdDM) pathway deploys small interfering RNAs (siRNAs) to target DNA methylation. This process is initiated by the plant-specific RNA polymerase IV (Pol IV) to produce RNA precursors that are later processed into siRNAs. Until recently, characterization of Pol IV transcript had been difficult due to its presumed rapid turnover. This review summarizes five recent reports on Pol IV-dependent RNAs that explore the biogenesis and features of Pol IV transcripts, as well as alternative dicer independent processing of Pol IV products. PMID- 28089092 TI - Treatment of de novo hepatitis C virus-related fibrosing cholestatic hepatitis after orthotopic heart transplantation by ledipasvir and sofosbuvir. PMID- 28089093 TI - Minimally Invasive Surgery for Evacuating the Intracerebral Hematoma in Early Stages Decreased Secondary Damages to the Internal Capsule in Dog Model of ICH Observed by Diffusion Tensor Imaging. AB - BACKGROUND: Diffusion tensor imaging was used to observe the effects of performing early minimally invasive surgery (MIS) on internal capsule in dog model of intracerebral hemorrhage (ICH). METHODS: Twenty-five male dogs were selected to prepare an ICH model, and then they were randomly distributed into a model control (MC) group (5 dogs) or an MIS group (20 dogs). In the MIS group, the intracerebral hematoma was evacuated by stereotactic minimally invasive procedures over 6 hours (5 dogs), 12 hours (5 dogs), 18 hours (5 dogs), or 24 hours (5 dogs) after successful induction of ICH. The same procedure was performed in the MC group but without evacuating the hematoma. All the animals were sacrificed within 2 weeks after the hematoma was surgically evacuated. The neurologic deficit score and diffusion tensor imaging (DTI) were observed before and after the MIS. The perihematomal blood-brain barrier (BBB) permeability and the brain water content (BWC) were measured 2 weeks after the hematoma was surgically evacuated. RESULTS: The DTI demonstrated that integrity of the internal capsule restored largely after surgery and the fractional anisotropy (FA) values of the internal capsule on the hematoma side increased significantly as compared with those in the MC group or those before surgery in the same group. The postoperative ratios of FA values of each MIS subgroup increased compared with the MC group and those before surgery in the same subgroup before operation. The neurologic deficit score, the perihematomal BBB permeability, and the BWC of each MIS subgroup decreased significantly compared with those of the MC group. The 6-12-hour group displayed a more favorable result. CONCLUSIONS: Performing the MIS in the early stage (6-12 hours) after ICH could decrease the secondary damages to the internal capsule so as to promote the recovery of motor function. The optimal time window for MIS should be within 6-12 hours after onset of ICH. PMID- 28089094 TI - Postprandial Clearance of Oxidized Low-Density Lipoprotein in Patients with Stroke Due to Atherosclerosis. AB - BACKGROUND: Oxidized low-density lipoprotein (OxLDL) is a contributor to atherosclerosis development. OxLDL formation increases in the postprandial state due to oxidative stress in subjects with coronary artery disease (CAD) and diabetes, but has not been studied in patients with atherosclerotic stroke. We aimed to determine differences in postprandial OxLDL in patients with atherosclerotic stroke compared to stroke from other causes. METHODS: Patients with ischemic stroke but no history of CAD (n = 42) were enrolled and categorized by stroke subtype as extracranial atherosclerosis (EC), n = 12; intracranial atherosclerosis (IC), n = 16; or other cause, n = 14. After fasting overnight, subjects consumed a standardized fat meal. OxLDL levels were measured at t = 0 and t = 4 hours postprandial using enzyme-linked immunosorbent assay. Comparisons between the mean changes in OxLDL between the groups were performed using the analysis of variance procedure. RESULTS: The IC group had the highest mean baseline level of OxLDL and the greatest decline during the postprandial period. There was a trend toward a difference in the mean change in OxLDL between the 3 groups (P = .0553). Subjects with atherosclerotic stroke (EC and IC groups) had higher fasting OxLDL and had a significant decline in OxLDL compared to those with stroke from other causes (P = .0164). CONCLUSIONS: Subjects with stroke due to atherosclerosis, particularly intracranially, demonstrated high fasting OxLDL and a decline in OxLDL during the postprandial period. This decline in OxLDL may indicate an accelerated clearance of OxLDL resulting from meal-induced oxidative stress. PMID- 28089095 TI - Characteristics of Anatomy and Function of the Left Atrial Appendage and Their Relationships in Patients with Cardioembolic Stroke: A 3-Dimensional Transesophageal Echocardiography Study. AB - BACKGROUND: Increasing attention is being paid to the left atrial appendage (LAA) in the context of risk stratification in cardioembolic stroke (CES) and the requirement for meticulous planning of percutaneous closure device implantation. However, detailed systematic assessment of the LAA remains limited. METHODS: This study evaluated the anatomy and function of LAA using 3-dimensional transesophageal echocardiography (3D-TEE) on 194 consecutive patients older than 50 years old hospitalized exclusively for CES. Patients were stratified into 3 groups on the basis of cardiac rhythm: (1) chronic atrial fibrillation (AF), n = 53; (2) paroxysmal AF, n = 26; and (3) no detected AF, n = 115. RESULTS: Significant differences between the groups were observed for anatomical (orifice area [OA], depth, diastolic volume) and functional parameters (ejection fraction [EF], flow velocity [FV]), as measured by 3D-TEE. The anatomical parameters were consistently the greatest, and functional parameters were the poorest, in the group with chronic AF. There were significant inverse correlations between them (r = -.33, P = .0003 for depth and EF; r = -.27, P = .0020 for depth and FV; r = .22, P = .016 for OA and EF; and r = -.38, P < .0001 for OA and FV). CONCLUSIONS: LAA morphology and function were strongly affected by cardiac rhythm disturbances. Patients with chronic AF had the greatest LAA dimensions, areas, and volumes as well as the lowest LAA functions. An inverse correlation was observed between LAA size and function. PMID- 28089096 TI - The international development of second degree graduate entry nursing. PMID- 28089097 TI - A systematic approach for the chromatographic fractionation and purification of major steroid saponins in commercial extracts of Yucca schidigera Roezl. AB - Yucca schidigera Roezl. (yucca) is one of the major industrial sources of steroid saponins used as animal and human food additives. This work describes a new, systematic and reproducible three-step method by medium and high-pressure liquid chromatography (under RP, NP and RP conditions), for the isolation and purification of three groups of saponins, which were further purified in six sub fractions, and finally into twelve individual steroid saponins previously reported in Y. schidigera. In accordance to the increasing applications of yucca extracts, further analytical, biological and physicochemical studies are still required. The presented method is applicable to the preparation of steroids saponins previously reported in commercial extracts of Y. schidigera, both as highly purified mixtures of defined composition, including twelve pure components. PMID- 28089098 TI - Toward a collaborative model of pandemic preparedness and response: Taiwan's changing approach to pandemics. AB - BACKGROUND: Over time, as newly emerging infectious diseases have become increasingly common and more easily spread, it has become clear that traditional response mechanisms have proven inadequate to the task of prevention and control. PURPOSE: To explore whether enhanced cooperation with local government and community institutions can effectively supplement traditional state-centric public health epidemic responses. METHODS: Drawing on Taiwan as a case study, we assess the role of the whole-of-society approach to epidemic response as arises from the collaborative governance literature. The approach calls for enhanced cooperation, trust building, resource sharing and consensus-oriented decision making among multiple levels of government, business, non-profits, and the public in general. RESULTS: The Taiwan case illustrates the benefits of the whole-of society approach. Enhanced cooperation between state, local government and non state institutions, particularly neighborhood committees, has resulted in a strengthened, holistic epidemic preparedness and response infrastructure. CONCLUSION: The Taiwan case provides evidence that by implementing the whole-of society approach to pandemic preparedness and response governments can enhance their ability to manage future outbreaks. We recommend that governments beyond Taiwan's borders seriously consider adopting this approach. PMID- 28089099 TI - Clinical characteristics and outcome of invasive fungal infections in pediatric acute myeloid leukemia patients in a medical center in Taiwan. AB - BACKGROUND: Invasive fungal infection (IFI) causes significant morbidity and mortality in patients with hematological malignancies, especially those with acute myeloid leukemia (AML), recurrent acute leukemia, high-risk acute lymphoblastic leukemia, and after allogeneic hematopoietic stem cell transplantation. The study aimed to investigate the clinical characteristics and outcome of IFIs in pediatric AML patients in a medical center in Taiwan. METHODS: We performed retrospective chart reviews. We enrolled pediatric AML patients who were admitted to National Taiwan University Hospital between January 2005 and December 2014. IFI was defined according to the European Organization for Research and Treatment of Cancer/Mycosis Study Group 2008 consensus criteria. RESULTS: In total, 78 patients were included for analysis. Twenty two episodes of IFIs were identified in 16 patients. The incidence for IFIs was 20.5% (16/78), and no specific trend of increase or decrease was observed through the study period (p=0.374). Candida species caused the majority (59.1%) of IFIs. Prolonged neutropenia and elevated alanine aminotransferase and creatinine values were factors associated with IFIs (p<0.001, p<0.001, and p=0.001, respectively). Patients with endotracheal intubation or inotropes usage had a higher probability of developing IFIs (p<0.001 and p=0.001, respectively). The overall mortality of IFIs was 53% (8/15) over 10 years, and patients with pulmonary aspergillosis had the highest mortality (80%). CONCLUSION: IFIs continue to pose significant morbidity and mortality in pediatric AML patients, and patients with other hematology-oncology cancers. Recognition of factors associated with IFIs may help us early identify IFIs and promptly initiate antifungal therapy. PMID- 28089100 TI - Community-onset Clostridium difficile infection at a tertiary medical center in southern Taiwan, 2007-2015. AB - BACKGROUND: Clostridium difficile infection (CDI) is well-known as the major cause of infectious diarrhea in hospitalized patients. Community-onset CDI (CO CDI) is an emerging threat. However, clinical information of CO-CDI in Taiwan remains scarce. METHODS: A retrospective study was conducted at a medical center in southern Taiwan. Symptomatic patients between 2007 and 2015 with C. difficile toxin or tcdB detected in stool were identified as CDI, and were classified as CO CDI [including community-associated CDI (CA-CDI) and community-onset health care facility-associated CDI (CO-HCFA-CDI)] and health care facility-onset CDI (HCFO CDI). RESULTS: Of 427 patients, 15 (3.5%) were CA-CDI, 49 (11.5%) CO-HCFA-CDI, and 363 (85.0%) HCFO-CDI. Despite major involvement of the elderly (mean age: 66.1 years vs. 69.9 years, p = 0.46), no significant differences were noted between CA-CDI and CO-HCFA-CDI groups, except that solid organ cancer was more common in the CO-HCFA-CDI group. The CO-CDI group more often presented with abdominal pain but had shorter hospital stays and less exposure of proton-pump inhibitors or broad-spectrum antibiotics than the HCFO-CDI group did. The mortality rate related to CDI was 4.7% (3 patients) in the CO-CDI group. Despite a lower in-hospital mortality rate in the CO-CDI group (10.9% vs. 22.0%; p = 0.04), the recurrence rate was similar (10.9% vs. 7.2%; p = 0.3). CONCLUSIONS: CO CDI is not common but associated with substantial morbidity and mortality. Physicians should put CDI into consideration among patients who present community onset fever, diarrhea, or abdominal pain alone or in combination. PMID- 28089101 TI - Reply to the letter regarding "early dual drainage combining transpapillary endotherapy and percutaneous catheter drainage in patients with pancreatic fistula associated with severe acute pancreatitis". PMID- 28089102 TI - Comparison of corticosteroid, autologous blood or sclerosant injections for chronic tennis elbow. AB - OBJECTIVES: To compare three different ultrasound-guided injections for chronic tennis elbow. DESIGN: Assessor-blinded, randomized controlled comparative trial. METHODS: 44 patients with clinically diagnosed tennis elbow, confirmed by Doppler ultrasound, received under ultrasound guidance, a single corticosteroid injection (n=14), or two injections (separated by 4 weeks) of either autologous blood (n=14) or polidocanol (n=16). Clinical and ultrasound examination was performed at baseline, 4, 12 and 26 weeks. RESULTS: Complete recovery or much improvement was greater for corticosteroid injection than autologous blood and polidocanol at 4 weeks (p<0.001, number needed to treat 1 (95% CI 1-2)). In contrast, at 26 weeks corticosteroid was significantly worse than polidocanol (p=0.004, number needed to harm 2 (1-6)). Recurrence after corticosteroid injection was significantly higher than autologous blood or polidocanol (p=0.007, number needed to harm 2 (1-4)). Corticosteroid injection produced greater reduction in tendon thickness and vascularity than autologous blood at 4 weeks only. Compared to autologous blood, polidocanol reduced tendon thickness at 4 and 12 weeks and reduced echogenicity and hyperaemia after 12 or 26 weeks respectively. CONCLUSIONS: Injections of corticosteroid cannot be recommended over polidocanol or autologous blood, because despite beneficial short-term effect there were inferior long-term effects. Whether polidocanol or autologous blood injections are effective is unknown, especially as their global effect profiles are not unlike previously reported for wait-and-see. PMID- 28089103 TI - Pioglitazone with imatinib in CML may reduce residual disease. PMID- 28089104 TI - ImmunoScore predicts gastric cancer postsurgical outcome. PMID- 28089105 TI - Selumetinib for children with plexiform neurofibromas. PMID- 28089106 TI - "Edge-on" MOSkin detector for stereotactic beam measurement and verification. AB - Dosimetry in small radiation field is challenging and complicated because of dose volume averaging and beam perturbations in a detector. We evaluated the suitability of the "Edge-on" MOSkin (MOSFET) detector in small radiation field measurement. We also tested the feasibility for dosimetric verification in stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT). "Edge-on" MOSkin detector was calibrated and the reproducibility and linearity were determined. Lateral dose profiles and output factors were measured using the "Edge-on" MOSkin detector, ionization chamber, SRS diode and EBT2 film. Dosimetric verification was carried out on two SRS and five SRT plans. In dose profile measurements, the "Edge-on" MOSkin measurements concurred with EBT2 film measurements. It showed full width at half maximum of the dose profile with average difference of 0.11mm and penumbral width with difference of +/-0.2mm for all SRS cones as compared to EBT2 film measurement. For output factor measurements, a 1.1% difference was observed between the "Edge-on" MOSkin detector and EBT2 film for 4mm SRS cone. The "Edge-on" MOSkin detector provided reproducible measurements for dose verification in real-time. The measured doses concurred with the calculated dose for SRS (within 1%) and SRT (within 3%). A set of output correction factors for the "Edge-on" MOSkin detector for small radiation fields were derived from EBT2 film measurement and presented. This study showed that the "Edge-on" MOSkin detector is a suitable tool for dose verification in small radiation field. PMID- 28089107 TI - Radiologist Contribution to Improved Nasogastric Tube Placement for Hospitalized Neurological Patients. PMID- 28089108 TI - Knowledge and attitudes of primary care nurses about the management of patients with insomnia. AB - OBJECTIVE: To describe the knowledge, attitudes, and performance of primary care nurses in the management of patients with insomnia. METHODS: Descriptive study. An online questionnaire was sent to all primary care nurses of the Majorca Primary Care Department between June-July 2014. MEASUREMENTS: sociodemographic variables, professional characteristics, tuition, usual clinical practice in the management of patients with insomnia. RESULTS: 138 nurses answered the questionnaire (47%). Most of them were women (92.8%), 50.42 years old (DE=8.9). The majority considered insomnia an important health problem. Only 11% had received some formative activity on insomnia in the last 5 years. Nearly half declares to ask patients about consequences of insomnia in their jobs and about habits that alter their sleep quality. 79.7% considered the possible adverse effects of insomnia drugs and take into consideration the age of patient (80.4%). The usual treatments were sleep hygiene (76%), phytotherapy (44.9%) and 22.4% cognitive behavioral therapy (CBT). This therapy is considered effective and applicable by nurses (63.7%) and doctors (58%). Those nurses who attended courses in the last 5 years apply CBT more frequently. CONCLUSIONS: Nurses conduct a correct anamnesis and evaluation of patients with insomnia. However some therapies of known effectiveness, such as CBT, are still scarcely applied. PMID- 28089109 TI - A cross-sectional study of physical activity and arterial compliance: the effects of age and artery size. AB - Our study examined the relationship between habitual high levels of vigorous physical activity on large and small artery compliance via radial artery pulse wave analysis. Eighty-three healthy men (n = 44) and women (n = 39), aged 18-78 years, were recruited as habitually less active (light-to-moderate exercise <=3 times/wk) or habitually highly active (vigorous exercise >=5 times/wk). A multivariate analysis of variance revealed a significant interaction of age and activity level; habitual vigorous activity was associated with greater compliance in large and small arteries in older adults (40-78 years) and younger adults (18 22 years). In the large and small arteries, we observed an age-associated decrease in arterial compliance (aged >= 40 years), though it appears to be less pronounced in the large artery among habitually highly active subjects. This study suggests that aging may be associated with declines in large and small artery compliance that can be attenuated by habitual vigorous activity. PMID- 28089110 TI - Recurrence after management of meatal balanitis xerotica obliterans. AB - INTRODUCTION: We review outcomes after management of meatal balanitis xerotica obliterans (BXO). The primary outcome was recurrent meatal BXO. METHODS: A database comprising mostly hypospadias patients was queried for meatal BXO. The disease was confirmed histologically in all cases. Management included topical steroids and/or immunosuppressants, and/or surgical excision of BXO with two stage oral mucosa graft circumferential replacement urethroplasty. RESULTS: A total of 12 patients had meatal BXO (8 boys and 4 adults). Of these, 10 had hypospadias, two presenting without prior surgery and eight returning 5-30 years after one or multiple (n = 2) repairs. Another two boys did not have hypospadias: one developing BXO 10 years after newborn circumcision and the other having persistent meatal BXO following therapeutic circumcision. Topical and intraluminal steroids (1% betamethasone or clobetasol) and tacrolimus were used for >=12 weeks each as primary therapy or for meatal recurrence in a total of six cases. Complete response with resolution of white discoloration and relief of stranguria only occurred in two of the three receiving clobetasol, with follow up <=12 weeks. BXO excision and urethroplasty was done in 11 patients, 10 using oral mucosa grafts; one with a focal lesion and a negative frozen section had reoperative TIP. Of the 10 undergoing excision with two-stage replacement urethroplasty, six remain disease free at a mean follow-up of 23 months (8-48 months), and four had recurrent stranguria and visible meatal BXO at a median of 26 months (22-105 months). Three of the four with recurrences had additional treatment and one was lost to follow-up. All initially had topical steroids, and two also used tacrolimus, without clinical resolution. These three then underwent a second BXO excision and two-stage oral graft replacement urethroplasty. In two recurrences, BXO was found invading from the meatus proximally within oral mucosa (Figure). Of these three with secondary urethroplasties, two are free of disease at 6 and 18 months, and the third had another meatal recurrence 6 months after the second stage. DISCUSSION: We found topical steroids and immunosuppressants to have limited efficacy, with two clinical complete responses achieved only with clobetasol in patients with short follow-up. Forty percent of patients recurred at 2-9 years after visually complete BXO excision and two-stage oral mucosa graft replacement urethroplasty, and in two cases disease invaded into oral mucosa, the first well-documented cases of this occurrence. PMID- 28089111 TI - The molecular landscape of colitis-associated carcinogenesis. AB - In spite of the well-established histopathological phenotyping of IBD-associated preneoplastic and neoplastic lesions, their molecular landscape remains to be fully elucidated. Several studies have pinpointed the initiating role of longstanding/relapsing inflammatory insult on the intestinal mucosa, with the activation of different pro-inflammatory cytokines (TNF-alpha, IL-6, IL-10, IFN gamma), chemokines and metabolites of arachidonic acid resulting in the activation of key transcription factors such as NF-kappaB. Longstanding inflammation may also modify the intestinal microbiota, prompting the overgrowth of genotoxic microorganisms, which may act as further cancer promoters. Most of the molecular dysregulation occurring in sporadic colorectal carcinogenesis is documented in colitis-associated adenocarcinoma too, but marked differences have been established in both their timing and prevalence. Unlike sporadic cancers, TP53 alterations occur early in IBD-related carcinogenesis, while APC dysregulation emerges mainly in the most advanced stages of the oncogenic cascade. From the therapeutic standpoint, colitis-associated cancers are associated with a lower prevalence of KRAS mutations than the sporadic variant. Epigenetic changes, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs, are significantly involved in colitis-associated cancer development and progression. The focus now is on identifying diagnostic and prognostic biomarkers, with a view to ultimately designing patient-tailored therapies. PMID- 28089112 TI - Predictive Utility of the Total Glasgow Coma Scale Versus the Motor Component of the Glasgow Coma Scale for Identification of Patients With Serious Traumatic Injuries. AB - STUDY OBJECTIVE: The motor component of the Glasgow Coma Scale (mGCS) has been proposed as an easier-to-use alternative to the total GCS (tGCS) for field assessment of trauma patients by emergency medical services. We perform a systematic review and meta-analysis to compare the predictive utility of the tGCS versus the mGCS or Simplified Motor Scale in field triage of trauma for identifying patients with adverse outcomes (inhospital mortality or severe brain injury) or who underwent procedures (neurosurgical intervention or emergency intubation) indicating need for high-level trauma care. METHODS: Ovid MEDLINE, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Health and Psychosocial Instruments, and the Cochrane databases were searched through June 2016 for English-language cohort studies. We included studies that compared the area under the receiver operating characteristic curve (AUROC) of the tGCS versus the mGCS or Simplified Motor Scale assessed in the field or shortly after arrival in the emergency department for predicting the outcomes described above. Meta analyses were performed with a random-effects model, and subgroup and sensitivity analyses were conducted. RESULTS: We included 18 head-to-head studies of predictive utility (n=1,703,388). For inhospital mortality, the tGCS was associated with slightly greater discrimination than the mGCS (pooled mean difference in [AUROC] 0.015; 95% confidence interval [CI] 0.009 to 0.022; I2=85%; 12 studies) or the Simplified Motor Scale (pooled mean difference in AUROC 0.030; 95% CI 0.024 to 0.036; I2=0%; 5 studies). The tGCS was also associated with greater discrimination than the mGCS or Simplified Motor Scale for nonmortality outcomes (differences in AUROC from 0.03 to 0.05). Findings were robust in subgroup and sensitivity analyses. CONCLUSION: The tGCS is associated with slightly greater discrimination than the mGCS or Simplified Motor Scale for identifying severe trauma. The small differences in discrimination are likely to be clinically unimportant and could be offset by factors such as convenience and ease of use. PMID- 28089113 TI - [Calcium supplements and cardiovascular disease risk: End of the controversy?] PMID- 28089115 TI - Correlation of antimuscarinic acetylcholine receptor antibody titers and antidesmoglein antibody titers with the severity of disease in patients with pemphigus. AB - BACKGROUND: Acetylcholine receptor (AchR) antibody levels significantly correlate with disease severity at initial pemphigus diagnosis and during follow-up. However, it is not clear if they are just an epiphenomenon or a potential trigger of the known pathogenic process in pemphigus vulgaris. OBJECTIVE: We sought to assess the changes in anti-muscarinic (M3) AchR and anti-desmoglein (Dsg) antibody titers with therapy. METHODS: This was a hospital-based cohort study involving 45 patients with active pemphigus. Disease was graded clinically using Pemphigus Disease Area Index. Antibody titers were estimated using enzyme-linked immunosorbent assay at baseline, 3 months, and 15 months. RESULTS: All patients with pemphigus had significantly higher anti-M3 AchR titers when compared with a control group. Only 95.5% of patients had anti-Dsg1 antibodies and 84.4% of patients had anti-Dsg3 antibodies. A statistically significant reduction in all 3 antibody titers from baseline to follow-up with treatment was observed. There was a good correlation between all 3 antibody titer and Pemphigus Disease Area Index score at baseline and after therapy and between anti-M3 AchR and anti-Dsg1 antibody titers. LIMITATIONS: Sample size was small and follow-up period was short. CONCLUSIONS: Anti-M3 AchR antibodies are strongly associated with pemphigus. They significantly correlate with disease activity and their titers decline with therapy along with anti-Dsg antibodies. PMID- 28089114 TI - Genetic epidemiology of motor neuron disease-associated variants in the Scottish population. AB - Genetic understanding of motor neuron disease (MND) has evolved greatly in the past 10 years, including the recent identification of association between MND and variants in TBK1 and NEK1. Our aim was to determine the frequency of pathogenic variants in known MND genes and to assess whether variants in TBK1 and NEK1 contribute to the burden of MND in the Scottish population. SOD1, TARDBP, OPTN, TBK1, and NEK1 were sequenced in 441 cases and 400 controls. In addition to 44 cases known to carry a C9orf72 hexanucleotide repeat expansion, we identified 31 cases and 2 controls that carried a loss-of-function or pathogenic variant. Loss of-function variants were found in TBK1 in 3 cases and no controls and, separately, in NEK1 in 3 cases and no controls. This study provides an accurate description of the genetic epidemiology of MND in Scotland and provides support for the contribution of both TBK1 and NEK1 to MND susceptibility in the Scottish population. PMID- 28089116 TI - Bullying and Sexual Discrimination in the Greek Health Care System. AB - INTRODUCTION: Modern medicine is based on teamwork and communication. Bullying and discrimination can have a serious effect on these, affecting the standard of medical training and patient care. AIM: To determine the incidence of bullying and sex discrimination in the Greek health care system. METHODS: An online questionnaire was designed and circulated among Greek medical professionals. RESULTS: We received 1349 completed questionnaires with a response rate of 48% and with 45% of them being female. Equal opportunities in specialty training were reported by 55% of the participants. Female doctors in medicine and in surgery reported no equal opportunities at an incidence of 15% and 30%, respectively (p < 0.001). Family obligations and lack of family support were considered as the main obstacles in female doctors' professional development by 92% and 59% of the participants, respectively. Both sexes appeared to have suffered from various forms of abusive behavior with characteristics that vary between them. Verbal abuse, threatening behavior, and sexual harassment were reported by 50%, 38%, and 20%, respectively, with women being 3 times more likely to be victims of sexual harassment (34% vs. 9%, p < 0.001). Finally, the availability of official support mechanisms was reported in only 15% of the cases, whereas friends and colleagues were the main support for 46.17% of the cases. CONCLUSION: This is the first study attempting to preliminary describe the extent of bullying and sexual discrimination in the Greek national health care system. Despite the limitations of this study, it is imperative that more research is performed on this issue from the appropriate national authorities. PMID- 28089117 TI - Respiratory diseases in the marginal labour sectors: a call to action. PMID- 28089119 TI - Not outsider artists-just artists. PMID- 28089118 TI - Occupational lung diseases: from old and novel exposures to effective preventive strategies. AB - Occupational exposure is an important, global cause of respiratory disease. Unlike many other non-communicable lung diseases, the proximal causes of many occupational lung diseases are well understood and they should be amenable to control with use of established and effective approaches. Therefore, the risks arising from exposure to silica and asbestos are well known, as are the means of their prevention. Although the incidence of occupational lung disease has decreased in many countries, in parts of the world undergoing rapid economic transition and population growth-often with large informal and unregulated workforces-occupational exposures continue to impose a heavy burden of disease. The incidence of interstitial and malignant lung diseases remains unacceptably high because control measures are not implemented or exposures arise in novel ways. With the advent of innovative technologies, new threats are continually introduced to the workplace (eg, indium compounds and vicinal diketones). In developed countries, work-related asthma is the commonest occupational lung disease of short latency. Although generic control measures to reduce the risk of developing or exacerbating asthma are well recognised, there is still uncertainty, for example, with regards to the management of workers who develop asthma but remain in the same job. In this Review, we provide recommendations for research, surveillance, and other action for reducing the burden of occupational lung diseases. PMID- 28089120 TI - Population Genetics and Demography Unite Ecology and Evolution. AB - The interplay of ecology and evolution has been a rich area of research for decades. A surge of interest in this area was catalyzed by the observation that evolution by natural selection can operate at the same contemporary timescales as ecological dynamics. Specifically, recent eco-evolutionary research focuses on how rapid adaptation influences ecology, and vice versa. Evolution by non adaptive forces also occurs quickly, with ecological consequences, but understanding the full scope of ecology-evolution (eco-evo) interactions requires explicitly addressing population-level processes - genetic and demographic. We show the strong ecological effects of non-adaptive evolutionary forces and, more broadly, the value of population-level research for gaining a mechanistic understanding of eco-evo interactions. The breadth of eco-evolutionary research should expand to incorporate the breadth of evolution itself. PMID- 28089121 TI - Remarks about "A pediatric patient of hemorrhagic acute transverse myelitis". PMID- 28089122 TI - Reply to the remarks about "A pediatric patient of hemorrhagic acute transverse myelitis". PMID- 28089123 TI - Ticks and Borrelia in urban and peri-urban green space habitats in a city in southern England. AB - Ticks are becoming increasingly recognised as important vectors of pathogens in urban and peri-urban areas, including green space used for recreational activities. In the UK, the risk posed by ticks in such areas is largely unknown. In order to begin to assess the risk of ticks in urban/peri-urban areas in southern England, questing ticks were collected from five different habitat types (grassland, hedge, park, woodland and woodland edge) in a city during the spring, summer and autumn of 2013/2014 and screened for Borrelia burgdorferi sensu lato. In addition, seasonal differences in B. burgdorferi s.l. prevalence were also investigated at a single site during 2015. Ixodes ricinus presence and activity were significantly higher in woodland edge habitat and during spring surveys. DNA of Borrelia burgdorferi s.l. was detected in 18.1% of nymphs collected across the 25 sites during 2013 and 2014 and two nymphs also tested positive for the newly emerging tick-borne pathogen B. miyamotoi. Borrelia burgdorferi s.l. prevalence at a single site surveyed in 2015 were found to be significantly higher during spring and summer than in autumn, with B. garinii and B. valaisiana most commonly detected. These data indicate that a range of habitats within an urban area in southern England support ticks and that urban Borrelia transmission cycles may exist in some of the urban green spaces included in this study. Sites surveyed were frequently used by humans for recreational activities, providing opportunity for exposure to Borrelia infected ticks in an urban/peri-urban space that might not be typically associated with tick-borne disease transmission. PMID- 28089124 TI - Local-scale spatio-temporal distribution of questing Ixodes ricinus L. (Acari: Ixodidae)-A case study from a riparian urban forest in Wroclaw, SW Poland. AB - This paper presents the distribution of questing Ixodes ricinus ticks in suburban forest intensively visited by people. The local-scale observations conducted during a 4-year study at 99 plots (of 100m2 each) located throughout the entire area of a riparian urban forest, showed a high variation in the density of ticks from year to year. Although I. ricinus is generally permanent in the study area, spatial distribution of sample plots harbouring I. ricinus is variable, i.e. mainly random for adults and larvae, and random or clustered for nymphs. Among the most common plant species in the herb layer, there were not any species which had a statistically significant and constant impact on the occurrence of any of the development stages of I. ricinus. Also relations between the density of tick development stages and vegetation variables, including cover of the herb layer, total species number, species number of the herb layer, and percentage coverage of particular species, as well as ecological indices for light, soil moisture, reaction, and nutrients, did not show any constant and predictable pattern in subsequent years of the study. Only tree and shrub layers were found as variables positively affecting the density of ticks. Although small, suburban forests can be considered as tick-borne risk areas, it is impossible to determine in details areas of tick-borne risk. PMID- 28089125 TI - Long-Term Outcomes of Permanent Cement Spacers in the Infected Foot. AB - When osteomyelitis occurs in the infected foot, cement spacers have been used as a limb salvage tool. The aim of the present study was to assess the longevity and outcomes in high-risk, low-demand patients who have undergone resection of bone and subsequent placement of permanent antibiotic-eluting cement spacers in the foot. A retrospective review case series of 30 patients who had undergone placement of a permanent antibiotic-eluting cement spacer in the foot were evaluated for retention, spacer exchange, removal, amputation, and functional status. The minimum follow-up time for inclusion was 12 months. Two thirds of all patients had successful spacers (n = 20) that were either retained (n = 14) or successfully exchanged (n = 6). One third of all patients experienced spacer failure (n = 10) and required removal. Of the 10 patients requiring spacer removal, 4 underwent removal with subsequent arthrodesis and 6 underwent removal with subsequent pseudoarthrosis. Also, 8 of these patients (26.7%) required partial foot amputation of the ipsilateral foot. These amputations were not directly related to the use or removal of the spacer. The average time to spacer removal or partial amputation was 20.9 (range 0.2 to 60.9) months. The longest retained spacer in the foot was 76 months at the last follow-up visit. The longest exchanged spacer at the last follow-up visit was 111 months. All surviving patients were ambulatory at the last follow-up visit. PMID- 28089126 TI - The "All-Inside" Arthroscopic Brostrom Procedure Augmented With a Proximal Suture Anchor: An Innovative Technique. AB - Arthroscopic treatments of chronic lateral ankle stability have been reported in the literature. The authors report on an innovative technique augmenting the "All Inside" Arthroscopic Brostrom procedure with an additional suture anchor. PMID- 28089127 TI - Mini-Invasive Treatment for Brachymetatarsia of the Fourth Ray in Females: Percutaneous Osteotomy With Mini-Burr and External Fixation-A Case Series. AB - Brachymetatarsia is a rare disease defined by metatarsal shortening and characterized by aesthetic dissatisfaction with or without pain. The aim of our study was to evaluate the outcomes of fourth ray brachymetatarsia treated with percutaneous osteotomy using a mini-burr and gradual lengthening with external fixation. A total of 7 females were recruited for the study; 6 (85.71%) of whom had a bilateral deformity, for a total of 13 feet affected by fourth ray brachymetatarsia. Percutaneous diaphysis osteotomy with a mini-burr followed by metatarsal elongation was performed. Metatarsal lengthening was measured as the difference between the preoperative and postoperative length at external fixator removal. The American Orthopaedic Foot and Ankle Society lesser toe metatarsophalangeal-interphalangeal score, patient satisfaction, restoration of Lelievre parabola, and treatment time were evaluated. Numerical data are reported as the mean +/- standard deviation and 95% confidence intervals. The Mann-Whitney U test was used to compare the changes in the AOFAS score with a level of significance of p < .05. The mean metatarsal lengthening was 17.46 +/- 4.89 (95% confidence interval [CI] 14.8 to 20.12) mm and the mean treatment time was 99.23 +/- 8.53 (95% CI 94.59 to 103.87) days. The mean American Orthopaedic Foot and Ankle Society lesser toe metatarsophalangeal-interphalangeal score improved significantly from 76.38 +/- 2.66 (95% CI 74.77 to 78.03) preoperatively to 86.46 +/- 1.45 (95% CI 84.85 to 88.07) postoperatively (p < .01). In 12 of 13 feet (92.31%), the Lelievre parabola was restored, and the patients were satisfied with the clinical outcomes. The results of our study demonstrate that percutaneous osteotomy with the mini-burr and external fixation is an effective treatment for lengthening of fourth ray brachymetatarsia. Furthermore, we found good clinical and functional outcomes, high patient satisfaction, and a similar duration of treatment compared with other gradual lengthening procedures. PMID- 28089128 TI - Management of Paget's Disease of the Calcaneum. AB - The calcaneum is not the most common site for Paget's disease of bone, with only a few reports of monostotic involvement. We present 2 cases of Paget's disease of bone affecting the calcaneus, present an overview of the published data, and describe our management of these interesting cases. PMID- 28089129 TI - Kinematic Magnetic Resonance Imaging of Peroneal Tendon Subluxation with Intraoperative Correlation. AB - Magnetic resonance imaging (MRI) is a noninvasive modality of choice for the detection of static peroneal tendon pathologic features. The depiction of peroneal tendon subluxation using real-time kinematic MRI has not been previously reported. We describe the MRI and intraoperative correlation of peroneal tendon and retinacular pathologic findings, and the novel use of kinematic MRI in the illustration of peroneal tendon subluxation. PMID- 28089130 TI - Trends in Nutrient Content of Children's Menu Items in U.S. Chain Restaurants. AB - INTRODUCTION: Restaurant food is widely consumed by children and is associated with poor diet quality. Although many restaurants have made voluntary commitments to improve the nutritional quality of children's menus, it is unclear whether this has led to meaningful changes. METHODS: Nutrients in children's menu items (n=4,016) from 45 chain restaurants were extracted from the nutrition information database MenuStat. Bootstrapped mixed linear models estimated changes in mean calories, saturated fat, and sodium in children's menu items between 2012 and 2013, 2014, and 2015. Changes in nutrient content of these items over time were compared among restaurants participating in the Kids LiveWell initiative and non participating restaurants. Types of available children's beverages were also examined. Data were analyzed in 2016. RESULTS: There was a significant increase in mean beverage calories from 2012 to 2013 (6, 95% CI=0.8, 10.6) and from 2012 to 2014 (11, 95% CI=3.7, 18.3), but no change between 2012 and 2015, and no differences in nutrient content of other items over time. Restaurants participating in Kids LiveWell reduced entree calories between 2012 and 2013 ( 24, 95% CI= -40.4, -7.2) and between 2012 and 2014 (-40, 95% CI= -68.1, -11.4) and increased side dish calories between 2012 and 2015 (49, 95% CI=4.6, 92.7) versus non-participating restaurants. Sugar-sweetened beverages consistently constituted 80% of children's beverages, with soda declining and flavored milks increasing between 2012 and 2015. CONCLUSIONS: Results suggest little progress toward improving nutrition in children's menu items. Efforts are needed to engage restaurants in offering healthful children's meals. PMID- 28089131 TI - Transcriptome-wide identification and functional investigation of circular RNA in the teleost large yellow croaker (Larimichthys crocea). AB - Circular RNA (circRNA) was first reported over thirty years ago. With the development of high-throughput sequencing technologies, circRNA has been identified in an increasing number of species. However, few studies on circRNA have been reported in teleost fish. Accumulating transcriptome and phenotype data enable us to probe the biological functions of circRNA in fish species. Here, we report the identification of circRNAs from RNA sequencing (RNA-seq) data in large yellow croaker (Larimichthys crocea), a commercially important marine fish in China and East Asia. Using the computational identification, 975 circular RNAs were detected, of which three were validated by experiments. GO and KEGG analyses revealed the biological functions of genes hosting the circRNAs were enriched in the progression of translation initiation, macromolecule metabolism and binding. Notably, we found that many circRNAs in large yellow croaker had abundant microRNA-binding sites. A total of 363 the identified circRNAs had more than five miRNA-binding sites, among which twenty-two had more than ten binding sites for the miRNA-430 and the let-7 family. Our study confirmed the presence of circRNAs in large yellow croaker for the first time, providing a valuable reference for circRNA identification in fish species. Meanwhile, this work confirmed that the RNA-seq data from the traditional linear transcriptome library could be used for preliminary circRNA identification, which may offer an important reference for preliminary circRNA investigations in other species. PMID- 28089132 TI - Trajectories of mental and physical functioning among spouse caregivers of cancer survivors over the first five years following the diagnosis. AB - OBJECTIVE: Identify the trajectories of physical and mental functioning among spouse caregivers of patients with cancer over the first five years post diagnosis and variables associated with low or deteriorating functioning. METHODS: Caregivers completed a survey at 6 months and 1, 2, 3.5, and 5 years post-patient diagnosis, including the SF-12 for quality of life (QOL). SF-12 Mental Component Summary (MCS, n=299) and Physical Component Summary (PCS, n=300) scores were analyzed using SAS. RESULTS: Five trajectories for PCS were identified, the top three were: (a) high PCS (53.0%); (b) steady decline in PCS (17.0%); and (c) steady increase, but remaining below population norm (16.7%). Five trajectories for MCS were also identified, the top two being: (a) high MCS (45.8%) and (b) MCS comparable to population norm (27.8%). Variables associated with low or deteriorating QOL included depression, social support, coping, burden, and/or unmet needs. CONCLUSIONS: This is the first study to document spouse caregivers' QOL over the first five years post-patient diagnosis. Although many participants experienced high functioning, almost a third reported low or deteriorating mental or physical functioning. PRACTICE IMPLICATIONS: Variables associated with low or deteriorating mental and physical functioning can be targeted in future interventions. PMID- 28089133 TI - 'You have a swelling': The language of cancer diagnosis and implications for cancer management in Kenya. AB - OBJECTIVE: To examine the ramifications of language as a vehicle of communication in the Kenyan healthcare system. METHODS: (1) A review of literature search on language access and health care in Kenya, using Scopus, Web of Science, Ebscohost, ProQuest and Google Scholar electronic databases. (2) Two illustrative case studies from a Nairobi based qualitative research project on family cancer caregivers' experiences. RESULTS: Evidence from the case studies shows that language barriers may hinder understanding of cancer diagnoses and consequently, the nature of interventions sought by family members as informal caregivers of cancer patients. CONCLUSION: Findings demonstrate the significance of language in understanding cancer diagnosis as a basis for treatment seeking behaviour and specifically in light of the critical role played by informal caregivers in under resourced health care contexts. PRACTICE IMPLICATIONS: (1) The assumption that English and Swahili are adequate in communication in Kenyan health care contexts ought to be reviewed. (2) Further research and assessment of language needs as a basis for training of language interpreters in the Kenyan health care system is a necessity. PMID- 28089134 TI - Extended (alternate day) antipsychotic dosing and dopamine supersensitivity psychosis: A case report. PMID- 28089135 TI - Phenotypic continuum between autism and schizophrenia: Evidence from the Movie for the Assessment of Social Cognition (MASC). AB - Schizophrenic (SCZ) and autism (ASD) spectrum disorders share several features including social cognition impairments. In SCZ, the link between symptomatic dimensions and social cognition deficits remains unclear. The Movie for the Assessment of Social Cognition (MASC) test, available in several languages including English, investigates mental state attribution capabilities in complex interpersonal situations. After its translation into French, we used MASC to direct compare social cognition in 36 young participants with SCZ to 19 with ASD and 20 healthy controls (HC) matched for gender, age (18-25y.o.) and level of education. The MASC discriminated each group from the others, patients with SCZ exhibiting difficulties compared to ASD (MASC total score 28.1 (4) and 24.2 (6.6), respectively; p<.001). In the whole sample, MASC scores were inversely correlated with autistic traits, evaluated by autism quotient, and with disorganization symptoms. Finally, in SCZ, over-mentalizing difficulties were correlated with age at disease onset. Our results demonstrate the validity of the French version of the MASC and bring direct evidence supporting the hypothesis of a phenotypic continuum between autism and schizophrenia. PMID- 28089136 TI - Recent insights into biohydrogen production by microalgae - From biophotolysis to dark fermentation. AB - One of the best options to alleviate the problems associated with global warming and climate change is to reduce burning of fossil fuels and search for new alternative energy resources. In case of biodiesel and bioethanol production, the choice of feedstock and the process design influences the GHG emissions and appropriate methods need to be adapted. Hydrogen is a zero-carbon and energy dense alternative energy carrier with clean burning properties and biohydrogen production by microalgae can reduce production associated GHG emissions to a great extent. Biohydrogen can be produced through dark fermentation using sugars, starch, or cellulosic materials. Microalgae-based biohydrogen production is recently regarded as a promising pathway for biohydrogen production via photolysis or being a substrate for anaerobic fermentation. This review lists the methods of hydrogen production by microalgae. The enzymes involved and the factors affecting the biohydrogen production process are discussed. The bottlenecks in microalgae-based biohydrogen production are critically reviewed and future research areas in hydrogen production are presented. PMID- 28089137 TI - A comparison of cangrelor, prasugrel, ticagrelor, and clopidogrel in patients undergoing percutaneous coronary intervention: A network meta-analysis. AB - BACKGROUND: Newer P2Y12 inhibitors have more rapid onset of platelet inhibition compared with clopidogrel, especially the intravenous P2Y12 inhibitor cangrelor. Direct comparisons between cangrelor and oral P2Y12 inhibitors ticagrelor and prasugrel do not exist. Thus, we performed a network meta-analysis to directly and indirectly compare different P2Y12 inhibitors in patients undergoing percutaneous coronary intervention (PCI). METHODS: MEDLINE/PubMed and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) that compared at least two P2Y12 inhibitors including cangrelor, clopidogrel, prasugrel, and ticagrelor. Network meta-analysis with a Bayesian approach was performed to directly and indirectly compare the effects of the aforementioned P2Y12 inhibitors on clinical outcomes. Odds ratios with credible intervals (OR [CrIs]) were generated with random-effects models to compare outcomes. RESULTS: This analysis included 15 RCTs with 54,025 patients randomized to cangrelor (n=12,475), clopidogrel (n=26,903), prasugrel (n=7455), or ticagrelor (n=7192) at time of PCI. Patients had a mean age of 63+/-10, 74% were male, and 82% underwent PCI for acute coronary syndrome. No significant differences between cangrelor and clopidogrel were found with respect to cardiovascular death (OR 1.01 [CrI 0.23 4.39]), myocardial infarction (OR 0.94 [CrI 0.69-1.25]), major adverse cardiac events (OR 0.91 [CrI 0.69-1.18]), stent thrombosis (OR 0.66 [CrI 0.37-1.19]), or major bleeding (OR 1.52 [CrI 0.79-2.98]). Rank probability data suggested that ticagrelor and prasugrel were better than cangrelor for reducing ischemic events, though these differences were not significant. CONCLUSION: Despite rapid platelet inhibition provided by cangrelor, newer oral P2Y12 inhibitors such as ticagrelor and prasugrel have comparable clinical outcomes. PMID- 28089138 TI - Bloodstream infections in children caused by carbapenem-resistant versus carbapenem-susceptible gram-negative microorganisms: Risk factors and outcome. AB - Carbapenems are often considered the last resort agents reserved for treatment of infections due to highly antimicrobial resistant organisms such as A. baumannii and P. aeruginosa. However, carbapenem-resistant Gram-negative (CRGN) pathogens have become much more prevalent in the last decade. The objective of this study was to determine risk factors for and outcome of bacteremia caused by Gram negative microorganisms in a pediatric tertiary-care hospital. Among 97 patients with hospital-acquired Gram-negative bacteremia, 66 patients with carbapenem susceptible Gram-negative pathogens (CSGN) were compared with the remaining 31 with CRGN isolates. The overall clinical response and microbiological response rates were 83.3% and 43.9% in CSGN group, and 54.8% and 32.3% in CRGN group, respectively (P=0.002 and P=0.004, respectively). The treatment failure and relapse rates were 18.2% and 6.1% in CSGN group, and 38.7% and 6.5% in CRGN group, respectively (P=0.03 in each). The infection-related mortality rates were 10.8% in the CSGN group and 32.3% in the CRGN group (P=0.01). The total length of stay in hospital before infection was longer in patients with CRGN bacteremia than that of the CSGN bacteremia (P=0.002). The extended spectrum antibiotic usage prior to infection was significantly different between the groups (P=0.008). Infections due to CRGN are generally associated with poorer patient outcomes. Longer hospital stay and extended spectrum antibiotic usage prior to infection are the most important risk factors for CRGN bacteremia in our cohort. PMID- 28089139 TI - Cannabidiol Claims and Misconceptions. AB - Once a widely ignored phytocannabinoid, cannabidiol now attracts great therapeutic interest, especially in epilepsy and cancer. As with many rising trends, various myths and misconceptions have accompanied this heightened public interest and intrigue. This forum article examines and attempts to clarify some areas of contention. PMID- 28089140 TI - Identifying Actionable, Evidence-Based Practices to Guide Adolescents' Eating. PMID- 28089141 TI - Stable emulsion (SE) alone is an effective adjuvant for a recombinant, baculovirus-expressed H5 influenza vaccine in healthy adults: A Phase 2 trial. AB - BACKGROUND: Influenza A viruses of the H5 subtype have been identified as important targets for development of vaccines. Achievement of potentially protective antibody responses against pandemic strains has usually required the use of adjuvants. OBJECTIVES: We evaluated a candidate A/Indonesia/05/2005 (H5) vaccine generated by baculovirus expression of recombinant hemagglutinin (HA) protein with or without stable emulsion (SE) as an adjuvant. METHODS: Healthy subjects 18-49years old were randomized (1:1:1:1) to receive two doses of rHA at 7.5ug per dose (no adjuvant), or 3.8ug, 7.5ug, or 15ug per dose formulated with 2% SE separated by 21days, and serum from day 0, 21, 42, and 201 assessed by hemagglutination-inhibition. RESULTS: 341 subjects were enrolled in the study and 321 received two doses of vaccine. Vaccination was well tolerated in all groups. After two doses, seroconversion was noted in only 9% (95% confidence interval 4%, 17%) of recipients of unadjuvanted vaccine at 7.5ug, but in 70% (59%, 80%), 76% (65%, 85%), and 83% (73%, 91%) of those receiving adjuvanted vaccine at 3.8ug, 7.5ug, or 15ug respectively. CONCLUSIONS: Stable emulsion alone is an effective adjuvant for rH5 vaccine in healthy adults. All three adjuvanted dose groups met the current criterion for seroconversion rate for pandemic vaccines. This dose ranging study also identified a group (15ug per dose formulated with 2% SE) that met the criteria for both seroconversion and percentage of subjects achieving an HI antibody titer?40. These Phase 2 data support the further clinical development of SE adjuvanted Panblok H5. CLINICAL TRIAL REGISTRATION: NCT01612000. The protocol was approved by the relevant Institutional Review Board for each study site, and the study was conducted in accordance with the Declaration of Helsinki, International Conference of Harmonisation - Good Clinical Practice, and all applicable laws and regulations. All participants provided written informed consent before study procedures. PMID- 28089142 TI - Bedside Monitoring of Cerebral Energy State During Cardiac Surgery-A Novel Approach Utilizing Intravenous Microdialysis. AB - OBJECTIVES: This study investigated whether the lactate-to-pyruvate (LP) ratio obtained by microdialysis (MD) of the cerebral venous outflow reflected a derangement of global cerebral energy state during cardiopulmonary bypass (CPB). DESIGN: Interventional, prospective, randomized study. SETTING: Single-center, university teaching hospital. PARTICIPANTS: The study included 10 patients undergoing primary, elective coronary artery bypass grafting. INTERVENTIONS: Patients were randomized blindly to low mean arterial pressure (MAP) (40-60 mmHg; n = 5) or high MAP (60-80 mmHg; n = 5) during CPB. The MD catheters were positioned in a retrograde direction into the jugular bulb, and a reference catheter was inserted into the brachial artery. The correlations among LP ratio, MAP, data obtained from bifrontal near-infrared spectroscopy (NIRS), and postoperative neurologic outcome measures were assessed. MEASUREMENTS AND MAIN RESULTS: The correlated difference between pooled LP ratio (low and high MAP) of the jugular venous and the arterial blood was significant (LParterial 17 [15-20] v LPvenous 26 [23-27]; p = 0.0001). No cerebral desaturations (decrease in rSO2>20% from baseline) were observed in either group during CPB. In each group, 50% of the patients showed significant cognitive decline (mini-mental state examination, 3 points) 2 days after surgery. CONCLUSION: The LP ratio of cerebral venous blood increased significantly during CPB, indicating compromised cerebral oxidative metabolism. Conventional monitoring of rSO2 by NIRS did not show a corresponding decrease in cerebral oxygenation. As the patients exhibited decreased cognitive functions after CPB, increases in jugular venous LP ratio may be a sensitive indicator of impending cerebral damage. PMID- 28089143 TI - Long-term mortality following Pseudomonas aeruginosa bloodstream infection. AB - BACKGROUND: Pseudomonas aeruginosa bloodstream infections (BSI) are associated with substantial short-term mortality. There is little data on long-term mortality associated with this BSI. AIM: To describe mortality rates up to one year post infection and the significant factors associated with death. METHODS: Positive blood cultures for P. aeruginosa were identified retrospectively from January 2008 to January 2011 at seven tertiary care hospitals. Extensive epidemiological, clinical and outcome data were obtained. FINDINGS: Three hundred and eighty-eight BSI episodes were included in the analysis. The majority of infections were hospital acquired. The most common patient comorbidities were haematological or oncological. Seventy-eight percent of the cohort had a medical device in situ in the preceding seven days. Sixty-one percent of the cohort received adequate empirical therapy. All-cause mortality was 4% at 48 h, 19% at one month and 38% at one year. Forty-eight-hour mortality was associated with non hospital-acquired infection, pulmonary comorbidity, recent corticosteroid therapy, and a Pitt bacteraemia score >2. Comorbidities became significantly associated with mortality from seven days post infection. Long-term mortality (defined as mortality at one year) was associated with female sex, haematological or oncological comorbidity, a Charlson comorbidity index >2 and recent corticosteroid therapy. CONCLUSION: The exact role of infection, from this highly virulent pathogen, in the cause of death over time needs to be studied further. It is not clear if patients are dying from or with P. aeruginosa BSI. PMID- 28089145 TI - Effect of exercise training on endothelial function in heart failure patients: A systematic review meta-analysis. AB - OBJECTIVE: Endothelial dysfunction contributes to the development and progression of cardiovascular disease and heart failure (HF) and is associated with an increased risk of mortality. Flow-mediated dilation (FMD) is widely utilised to assess endothelial function and is improved with exercise training in heart failure patients. The aim of this meta-analysis is to quantify the effect of exercise training in patients with heart failure. BACKGROUND: A large number of studies now exist that have examined endothelial function in patients with heart failure. We sought to add to the current literature by quantifying the effect of exercise training on endothelial function. METHODS: We conducted database searches (PubMed, EMBASE, PROQUEST and Cochrane Trials Register to June 2016) for exercise based rehabilitation trials in heart failure, using search terms exercise training, endothelial function, flow-mediated dilation (FMD) and endothelial progenitor cells (EPCs). RESULTS: The 16 included studies provided a total of 529 participants, 293 in an intervention and 236 in controls groups. FMD was improved with exercise training in exercise vs. control, SMD of 1.08 (95%CI 0.70 to 1.46, p<0.00001). CONCLUSION: Overall exercise training improved endothelial function, assessed via FMD, and endothelial progenitor cells in heart failure patients. PMID- 28089144 TI - Essential role of ICAM-1 in aldosterone-induced atherosclerosis. AB - OBJECTIVE: Elevated aldosterone is associated with increased risk of atherosclerosis complications, whereas treatment with mineralocorticoid receptor (MR) antagonists decreases the rate of cardiovascular events. Here we test the hypothesis that aldosterone promotes early atherosclerosis by modulating intercellular adhesion molecule-1 (ICAM-1) expression and investigate the molecular mechanisms by which aldosterone regulates ICAM-1 expression. METHODS AND RESULTS: Apolipoprotein-E (ApoE)-/- mice fed an atherogenic diet and treated with aldosterone for 4weeks showed increased vascular expression of ICAM-1, paralleled by enhanced atherosclerotic plaque size in the aortic root. Moreover, aldosterone treatment resulted in increased plaque lipid and inflammatory cell content, consistent with an unstable plaque phenotype. ApoE/ICAM-1 double knockout (ApoE-/-/ICAM-1-/-) littermates were protected from the aldosterone induced increase in plaque size, lipid content and macrophage infiltration. Since aldosterone is known to regulate ICAM-1 transcription via MR in human endothelial cells, we explored MR regulation of the ICAM-1 promoter. Luciferase reporter assays performed in HUVECs using deletion constructs of the human ICAM-1 gene promoter showed that a region containing a predicted MR-responsive element (MRE) is required for MR-dependent transcriptional regulation of ICAM-1. CONCLUSIONS: Pro-atherogenic effects of aldosterone are mediated by increased ICAM-1 expression, through transcriptional regulation by endothelial MR. These data enhance our understanding of the molecular mechanism by which MR activation promotes atherosclerosis complications. PMID- 28089146 TI - Factors associated with development of coronary artery aneurysms after Kawasaki disease are similar for those treated promptly and those with delayed or no treatment. AB - BACKGROUND: While the risk is reduced, patients may develop coronary artery (CA) aneurysms after Kawasaki disease (KD) despite receiving intravenous immunoglobulin (IVIG) within 10days of symptom onset. Risk factors for CA aneurysms may differ compared to those patients with delayed or no treatment. METHODS: Patients diagnosed with KD between 1990 and 2013 were included. Patients with maximum coronary artery z-scores>5 were classified as having CA aneurysms. Separate multivariable regression models were used to determine factors associated with CA aneurysms for those with versus without prompt treatment. RESULTS: Of 1358 patients included, 83% (n=1126) were treated with IVIG within 10days and 5% (n=53) developed CA aneurysms. Patients who had delayed (>10days) or no IVIG treatment were at increased odds of developing CA aneurysms (OR: 3.1,95% CI: 1.9-5.1, p<0.001). For patients with prompt treatment with IVIG, factors associated with increased odds of CA aneurysms were: longer duration of fever prior to treatment (OR: 1.2/day, p=0.04), age<1year (OR: 3.9, p=0.001), higher pre-IVIG white blood cell count (OR: 1.05/*109/L, p=0.007), lower hemoglobin (OR: 1.4/g/L, p=0.004) and non-response to initial IVIG treatment (OR: 2.5, p<0.001). For patients with delayed or no treatment, factors associated with increased odds of CA aneurysms were: males (OR: 5.4, p=0.009), age<1year (OR: 29.9, p<0.001), and higher platelet count (OR: 1.4/100*1012/L, p=0.001). Delayed treatment with IVIG did not reduce the risk of CA aneurysms (OR: 1.9, p=0.28), and total duration of fever was not associated with CA aneurysms for this group (OR: 1.04/day, p=0.16). CONCLUSIONS: Factors associated with the development of CA aneurysms are generally similar for those treated promptly versus those with delayed or no treatment. For those with delayed diagnosis, treatment with IVIG does not appear to be effective to prevent CA aneurysms. PMID- 28089147 TI - SeQuent Please vs. Pantera Lux drug coated balloon angioplasty in real life: Results from the Dusseldorf DCB registry. AB - BACKGROUND: In-stent restenosis (ISR) is still a major concern in interventional cardiology. Drug coated balloon (DCB) angioplasty has been shown to be a promising option in treatment of ISR. However heterogeneity of different DCBs in suppression of neointimal growth has been described in a porcine model of coronary ISR. Therefore, in this registry analysis, we compared two frequently used paclitaxel eluting DCBs, the SeQuent Please and the Pantera Lux DCB. METHODS: 571 patients were treated with DCB angioplasty at the Heinrich-Heine University Dusseldorf between 2009 and 2012. Follow-up was conducted during ambulatory care at our department. Major adverse cardiac events (death, myocardial infarction [MI] and target lesion revascularization) were registered during hospitalization and follow-up. RESULTS: Patient characteristics, prior diseases, clinical presentation, ejection fraction, procedural success and lost for-follow-up did not differ between patients treated with the SeQuent Please and. The Pantera Lux DCB. MACE during hospital course were similar as well (Pantera Lux: 6 patients [1.6%] vs. SeQuent(r)Please: 3 patients [1.5%], relative risk 1.06, 95% confidence interval 0.3-4.2, P=0.93). Event free survival was significantly longer in patients treated with the Pantera Lux DCB as compared to SeQuent Please DCB (Hazard ratio: 0.65, 95% confidence interval 0.43-0.98; P value of log-rank test: 0.0405). CONCLUSION: MACE free survival was longer in Pantera Lux DCB treated patients as compared to SeQuent Please treated patients. This finding has to be confirmed in future clinical trials. PMID- 28089148 TI - Percutaneous revascularization of chronic total occlusions: Rationale, indications, techniques, and the cardiac surgeon's point of view. AB - Chronic total occlusions (CTO) are frequently found in clinical practice, yet they are still undertreated, despite the frequent presence of clinical indications for revascularization. The presence of a CTO is a frequent cause of incomplete revascularization, which has been associated with worse long-term outcomes (including mortality), compared to complete revascularization. Such low rates of attempted revascularization can be attributed to a common misconception about the lack of benefit of CTO revascularization, combined with historically lower success rates and higher complication rates of CTO percutaneous coronary intervention. However, modern percutaneous techniques, devices and algorithms now allow successful CTO revascularization in approximately 90% of cases. Additionally, state-of-the-art surgical techniques offer complete revascularization and provide excellent long-term patency rates. The present review provides a critical appraisal of the literature supporting the rationale, indications, modalities and state-of-the-art techniques of CTO revascularization by both percutaneous and surgical approaches. PMID- 28089149 TI - Fasting glucose, NT-proBNP, treatment with eptifibatide, and outcomes in non-ST segment elevation acute coronary syndromes: An analysis from EARLY ACS. AB - BACKGROUND: Higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels have been linked to a more favorable glucometabolic profile. Little is known about the interaction of NT-proBNP and fasting glucose in non-ST-segment elevation acute coronary syndrome (NSTE ACS). METHODS: Fasting glucose and NT proBNP were measured in 2240 patients enrolled in the EARLY ACS trial. Multivariable Cox models were used to assess associations between fasting glucose and NT-proBNP and a 96-hour composite of death, myocardial infarction (MI), recurrent ischemia, or thrombotic bailout; 30-day death or MI; and 1-year mortality. RESULTS: In adjusted Cox models, neither NT-proBNP nor fasting glucose was associated with the 96-hour endpoint (p=0.95 and p=0.87). NT-proBNP was associated with 30-day death or MI (hazard ratio [HR] 1.11, 95% confidence interval [CI] 1.02-1.22, p=0.02) and 1-year mortality (HR 1.63, 95% CI 1.42-1.89, p<0.0001), but fasting glucose was associated only with 1-year death (HR 1.53, 95% CI 1.08-2.16, p=0.02). NT-proBNP*glucose interaction terms were non significant in all models. As fasting glucose levels increased, the risk of 96 hour and 30-day endpoints increased among patients who received early eptifibatide but not delayed, provisional use (pint=0.035 and pint=0.029). Higher NT-proBNP levels were associated with greater 30-day death or MI among patients who received early eptifibatide but not delayed, provisional use (pint=0.045). CONCLUSION: NT-proBNP and fasting glucose concentrations were associated with intermediate-term ischemic outcomes and may identify differential response to treatment with eptifibatide. CLINICALTRIALS. GOV IDENTIFIER: NCT00089895. PMID- 28089150 TI - Anticoagulant bridging in left-sided mechanical heart valve patients. AB - BACKGROUND: In preparation for an invasive procedure with a high bleeding risk, patients with a mechanical heart valve temporarily have to discontinue their anticoagulant therapy and are usually bridged with either intravenous unfractionated heparin (UFH) or subcutaneous low-molecular-weight heparin (LMWH). In this study we retrospectively analyzed the safety of UFH versus LMWH as bridging strategy in left-sided mechanical heart valve patients. METHODS: We performed a retrospective multicenter study in four surgical centers in The Netherlands. Patients with a mechanical heart valve implantation bridged from January 2010 until January 2015 were included. The cumulative incidence of adverse events in the 30days following the procedure was recorded. Main outcomes were major bleeding according to International Society on Thrombosis and Haemostasis (ISTH) criteria, symptomatic thromboembolism, and mortality. RESULTS: In total, 238 (174 aortic, 42 mitral, 22 aortic+mitral) bridging episodes were included. The incidence of major bleeding was 16 (19%) events in the UFH group versus 29 (19%) events in the LMWH group (p=0.97). Incidences of thromboembolism were 2 (2.4%) versus 1 (0.6%). The incidence of death was 1 (1.2%) patient in the UFH group versus 3 (1.9%) patients in the LMWH group. More than 50% of all bleeding complications were categorized as a major bleeding. CONCLUSIONS: Bridging anticoagulation in patients with aortic and mitral mechanical valves is associated with considerable risk, but no difference was apparent between UFH and LMWH strategy. The rate of thromboembolism and death was low with either strategy and the vast majority of adverse events were bleedings. PMID- 28089151 TI - Influenza vaccination reduces hemorrhagic stroke risk in patients with atrial fibrillation: A population-based cohort study. AB - PURPOSE: The risk of hemorrhagic stroke in patients with atrial fibrillation (AF) is low but the consequences of its occurrence are extremely severe. In this study, we investigated the association of influenza vaccination with the risk of hemorrhagic stroke to develop an efficient strategy for reducing this risk in patients with AF. METHODS: In this study, data were retrieved from the Taiwan National Health Insurance Research Database. The study cohort comprised all patients who received a diagnosis of AF (n=14,454) before January 1, 2005 (index date) and were followed until December 31, 2012. Propensity scores were calculated using a logistic regression model to determine the effects of vaccination by accounting for covariates that predict receiving the intervention (vaccine). A time-dependent Cox proportional hazard model was used to calculate the hazard ratios (HRs) for hemorrhagic stroke in vaccinated and unvaccinated patients with AF. RESULTS: The study population comprised 6570 patients who did (2547 [38.77%]) and did not receive (4023 [61.23%]) influenza vaccination. The adjusted HRs (aHRs) for hemorrhagic stroke were lower in the vaccinated patients than in the unvaccinated patients (influenza season, noninfluenza season, and all seasons: aHRs=0.97 [0.59-1.60], 0.51 [0.30-0.87], and 0.72 [0.50-1.03], respectively). CONCLUSIONS: Influenza vaccination exerts dose-response and synergistic protective effects against hemorrhagic stroke in patients with AF who have a high risk of hemorrhagic stroke (i.e., male sex, age>=75years, Charlson comorbidity index >=3, and hypertension) and reduces the incidence of hemorrhagic stroke. PMID- 28089152 TI - Autonomic function in Takotsubo syndrome long after the acute phase. AB - OBJECTIVES: Although it is well documented that an exaggerated sympathetic stimulation plays a role in the development of Takotsubo Syndrome (TS) during the acute phase, only few studies have focused on autonomic adaptations in stress induced cardiomyopathy long after the acute phase. Aim of the study was to investigate whether an impairment of the autonomic function is still present long after a TS event. This was done by comparing the response to a maximal exercise test in TS patients after apparent recovery (>1-year after the acute event) with that obtained in healthy subjects and in post-myocardial infarction (post-MI) patients. METHODS: To assess heart rate recovery (HRR) and chronotropic response (CR), 24 TS patients, 25 healthy subjects and 22 post-MI patients underwent maximal exercise test, after at least 3 days of beta-blockers wash-out. RESULTS: HRR in TS patients (19.2+/-9.7bpm) was lower than in healthy subjects (27.7+/ 8.3, p=0.003), and similar to post-MI patients (19.3+/-8.4; p=0.99). A decreasing CR trend (p=0.06), higher in healthy subjects (72+/-13%) than in TS (65+/-22%) and post-MI (57+/-21%) patients, was also found. CONCLUSION: Compared to healthy subjects, TS patients showed a blunted parasympathetic reactivation after exercise, similar to that observed in post-MI patients, thereby suggesting that vagal control of heart rate after exercise is abnormal long after the acute presentation of TS. PMID- 28089153 TI - Temporal trends in management and outcomes of patients with acute coronary syndrome according to renal function. AB - INTRODUCTION: Recent new therapeutic options have improved outcomes of acute coronary syndrome (ACS) patients. However, data regarding the incremental effect of the improved treatment on patients with renal dysfunction are limited. We sought to evaluate temporal trends in management and outcome of ACS patients according to renal function. METHODS: The study population consisted of all ACS patients enrolled in the Acute Coronary Syndromes Israeli Survey (ACSIS) during 2002-2013. Patients were categorized as normal renal function, mild to moderate and severe renal insufficiency. Patient's characteristics, clinical data and outcomes were compared in each group between 2 time frames - early (2002-2006) vs. late (2008-2013). RESULTS: The study population included 11,234 patients. Regardless of renal function, patients enrolled in the recent surveys were more frequently selected for an invasive approach and were more commonly treated with guideline-based therapy. Among patients with normal renal function or mild to moderate renal dysfunction the improvement in treatment was associated with a significant reduction in 5-year mortality (10.1% vs. 12.6%, p=0.004, and 36% vs. 41.9%, p=0.01, respectively). On the other hand, outcomes of patients with severe renal insufficiency were unchanged. Multivariate analysis showed that reperfusion was associated with 41% mortality reduction in patients with mild to moderate renal insufficiency (HR=0.59 CI 95 0.48-0.72, p<0.01%). CONCLUSIONS: Treatment of ACS patients has improved over the past decade. Treatment improvement was associated with a significant mortality reduction in patients with normal renal function and mild to moderate renal dysfunction but not in patients with severe renal dysfunction. PMID- 28089154 TI - Pre-hospital electrocardiogram triage with telemedicine near halves time to treatment in STEMI: A meta-analysis and meta-regression analysis of non randomized studies. AB - BACKGROUND: A shorter time to treatment has been shown to be associated with lower mortality rates in acute myocardial infarction (AMI). Several strategies have been adopted with the aim to reduce any delay in diagnosis of AMI: pre hospital triage with telemedicine is one of such strategies. We therefore aimed to measure the real effect of pre-hospital triage with telemedicine in case of AMI in a meta-analysis study. METHODS: We performed a meta-analysis of non randomized studies with the aim to quantify the exact reduction of time to treatment achieved by pre-hospital triage with telemedicine. Data were pooled and compared by relative time reduction and 95% C.I.s. A meta-regression analysis was performed in order to find possible predictors of shorter time to treatment. RESULTS: Eleven studies were selected and finally evaluated in the study. The overall relative reduction of time to treatment with pre-hospital triage and telemedicine was -38/-40% (p<0.001). Absolute time reduction was significantly correlated to time to treatment in the control groups (p<0.001), while relative time reduction was independent. A non-significant trend toward shorter relative time reductions was observed over years. CONCLUSIONS: Pre-hospital triage with telemedicine is associated with a near halved time to treatment in AMI. The benefit is larger in terms of absolute time to treatment reduction in populations with larger delays to treatment. PMID- 28089155 TI - Prognostic value of body mass index in transcatheter aortic valve implantation: A "J"-shaped curve. AB - OBJECTIVES: We aimed to determine whether body mass index (BMI) is a prognostic indicator for long-term, all-cause mortality in patients undergoing transcatheter aortic valve implantation (TAVI). BACKGROUND: Obesity in patients with established cardiovascular disease has previously been identified as an indicator of good prognosis, a phenomenon known as the "obesity paradox". The prognostic significance of BMI in patients with severe aortic stenosis (AoS) undergoing TAVI is a matter of current debate, as published studies are scarce and their results conflicting. METHODS: This is an observational, retrospective study involving 770 patients who underwent TAVI for AoS. The cohort was divided into three groups based on their BMI: normal weight (>=18.5 to <25kg/m2), overweight (>=25 to <30kg/m2) and obese (>=30kg/m2). The predictive effect of BMI on all-cause mortality 3years following TAVI intervention was analysed using a Cox regression. RESULTS: 155 patients died during follow-up. The overweight group (n=302, 38.97%), experienced a lower mortality rate compared to the normal weight and obese groups (15.9% vs 25.7% and 21.0%, respectively [log-rank p-value=0.036]). After adjustment by logistic EuroSCORE, being overweight was found to be an independent protective factor against mortality (HR: 0.63 [95% CI: 0.42 to 0.94], p=0.024). This was not the case for obesity (HR: 0.92 [95% CI: 0.63 to 1.35], p=0.664). We therefore describe for the first time, a "J-shaped" regression curve describing the relationship between BMI and mortality. CONCLUSIONS: BMI is a predictive factor of all-cause mortality in AoS patients undergoing TAVI. This relationship takes the form of a "J-shaped" curve in which overweight patients are associated with the lowest mortality rate at follow-up. PMID- 28089156 TI - Letter to the editor. PMID- 28089157 TI - Genomic Profiling of Circulating Tumor DNA in Relapsed EGFR-mutated Lung Adenocarcinoma Reveals an Acquired FGFR3-TACC3 Fusion. PMID- 28089158 TI - Cardiac Dose and Survival After Stereotactic Body Radiotherapy for Early-stage Non-Small-cell Lung Cancer. AB - INTRODUCTION: Recent analyses have identified cardiac dose as an important predictor of overall survival (OS) after chemoradiation for locally advanced non small-cell lung cancer (NSCLC). However, the survival influence of the cardiac dose after stereotactic body radiotherapy (SBRT) is unknown. We performed a dose volume histogram (DVH) analysis of patients treated with SBRT for early stage NSCLC to examine survival and cardiac toxicity. MATERIALS AND METHODS: We reviewed the medical records of patients who had undergone SBRT for early-stage NSCLC from June 2007 to June 2015 and documented the cardiac DVH parameters, including the maximum and mean dose and percentage of volume receiving >5, >10, >20, and >30 Gy (V5, V10, V20, and V30, respectively). The biologically effective doses and 2-Gy equivalent doses were also calculated. The DVH parameters were assessed as predictors of OS using Cox regression analysis. RESULTS: We identified 102 patients with 118 treated tumors. At a median follow-up period of 27.2 months (range, 9.8-72.5 months), the 2-year OS estimate was 70.4%. The cardiac DVH parameters were as follows: maximum dose, median, 14.2 Gy (range, 0.3 77.8 Gy); mean dose, median, 1.6 Gy (range, 0-12.6 Gy); and V5, median, 8.7% (range, 0%-96.4%). We identified no correlation between OS and any cardiac dose parameter. No patient developed acute (within 3 months) cardiac toxicity. Four patients died of cardiac causes; all had had preexisting heart disease. CONCLUSION: In our cohort, cardiac dose was not a predictor of OS after lung SBRT, despite a subset of patients receiving high maximum cardiac doses. The findings from our limited cohort showed that high doses to small volumes of the heart appear safe. Analyses of larger patient cohorts with longer follow-up durations are needed to better delineate the safe cardiac DVH constraints for SBRT. PMID- 28089159 TI - Immunohistochemistry for EGFR Mutation Detection in Non-Small-Cell Lung Cancer. AB - INTRODUCTION: The sensitivity and specificity of immunohistochemistry (IHC) was compared with the standard polymerase chain reaction (PCR)-based method for detecting common activating epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC). Additionally, we evaluated predictive value of IHC EGFR mutation-positive status for EGFR tyrosine kinase inhibitor (TKI) treatment outcome and estimated cost-effectiveness for the upfront IHC testing. METHODS: The trial included 79 consecutive EGFR mutation-positive and 29 EGFR mutation-negative NSCLC cases diagnosed with reflex PCR-based testing. Two mutation-specific antibodies against the most common exon 19 deletion, namely E746-A750del (clone SP111) and L858R mutation (clone SP125) were tested by using automated immunostainer. Sixty of 79 EGFR mutation-positive cases were treated with EGFR TKIs for advanced disease and included in treatment outcome analysis. A decision tree was used for the cost-effectiveness analysis. RESULTS: The overall sensitivity and specificity of the IHC-based method compared with the PCR-based method were 84.8% (95% confidence interval [CI] 74.6-91.6) and 100% (95% CI 85.4 100), respectively. The median progression-free survival (PFS) and overall survival (OS) of patients with IHC-positive EGFR mutation status were highly comparable to the total cohort (PFS: 14.3 vs. 14.0 months; OS: 34.4 vs. 34.4 months). The PCR and IHC cost ratio needs to be approximately 8-to-1 and 4-to-1 in White and Asian populations, respectively, to economically justify upfront use of IHC. CONCLUSION: The trial confirmed an excellent specificity with fairly good sensitivity of IHC with mutation-specific antibodies for common EGFR mutations and the accuracy of IHC testing for predicting response to EGFR TKIs. The use of upfront IHC depends mainly on the population EGFR mutation positivity probability. PMID- 28089160 TI - Investigation of hexavalent chromium sorption in serpentine sediments. AB - In this study the removal of hexavalent chromium (Cr6+) by serpentine sediments was investigated in order to delineate Cr6+ sorption behavior in aquifers with ultramafic geologic background. Batch experiments were conducted in order to determine the influence of several parameters on Cr6+ removal, including the pH of the sediment solution, mineralogy, sediment's particle size and Cr6+ initial concentration. The results showed that Cr6+ removal was due to both adsorption and reduction phenomena. Reduction was attributed to the presence of a magnetic fraction in the sediment, mostly related to magnetite, which contributed almost 50% of the total removal in the pH range 3-7. Adsorption behavior was dominated by the finer sediment fraction (d<0.075mm). The amount of Cr6+ adsorbed was constant in the pH range 3-7, while it decreased sharply in the range 7-8.5. Cr6+ adsorption was found to increase and decrease proportionally with increasing initial Cr6+ concentration of and particle size, respectively. The linear Langmuir and Freundlich adsorption isotherms were used to describe the experimental data, with Freundlich providing a better fit to determine distribution factors for transport modeling. PMID- 28089161 TI - Genome-wide gene expression patterns in dikaryon of the basidiomycete fungus Pleurotus ostreatus. AB - Dikarya is a subkingdom of fungi that includes Ascomycota and Basidiomycota. The gene expression patterns of dikaryon are poorly understood. In this study, we bred a dikaryon DK13*3 by mating monokaryons MK13 and MK3, which were from the basidiospores of Pleurotus ostreatus TD300. Using RNA-Seq, we obtained the transcriptomes of the three strains. We found that the total transcript numbers in the transcriptomes of the three strains were all more than ten thousand, and the expression profile in DK13*3 was more similar to MK13 than MK3. However, the genes involved in macromolecule utilization, cellular material synthesis, stress resistance and signal transduction were much more up-regulated in the dikaryon than its constituent monokaryons. All possible modes of differential gene expression, when compared to constituent monokaryons, including the presence/absence variation, and additivity/nonadditivity gene expression in the dikaryon may contribute to heterosis. By sequencing the urease gene poure sequences and mRNA sequences, we identified the monoallelic expression of the poure gene in the dikaryon, and its transcript was from the parental monokaryon MK13. Furthermore, we discovered RNA editing in the poure gene mRNA of the three strains. These results suggest that the gene expression patterns in dikaryons should be similar to that of diploids during vegetative growth. PMID- 28089162 TI - The Abductor Pollicis Longus Tendon as an Alternative Graft in Hand Surgery. AB - Initial treatment of damaged tendons after soft tissue trauma of the hand can be performed with primary tendon reconstruction or with tendon grafts if indicated. The most frequently used tendons are from the palmaris longus and plantaris muscles. Nonetheless, these muscles may not be present or their anatomic characteristics might not suitable for reconstructive procedures. Here, we present an alternative surgical technique for tendon reconstruction of the hand using abductor pollicis longus accessory tendons as grafts. The abductor pollicis longus can be considered an excellent choice of graft for tendon reconstruction of the hand because of its multiple bellies, ease of extraction, and limited donor site morbidity and the frequent absence of the palmaris longus tendon. PMID- 28089163 TI - Fragment-Specific Fixation Versus Volar Locking Plates in Primarily Nonreducible or Secondarily Redisplaced Distal Radius Fractures: A Randomized Controlled Study. AB - PURPOSE: To compare the patient-reported, clinical, and radiographic outcome of 2 methods of internal fixation in distal radius fractures. METHODS: Fifty patients, mean age 56 years (range, 21-69 years) with primarily nonreducible or secondarily redisplaced distal radius fractures were randomized to open reduction internal fixation using volar locking plates (n = 25) or fragment-specific fixation (n = 25). The patients were assessed on grip strength, range of motion, patient reported outcome (Quick Disabilities of the Arm, Shoulder, and Hand), pain (visual analog scale), health-related quality of life (Short Form-12 [SF-12]), and radiographic evaluation. Grip strength at 12 months was the primary outcome measure. RESULTS: At 12 months, no difference was found in grip strength, which was 90% of the uninjured side in the volar plate group and 87% in the fragment specific fixation group. No differences were found in range of motion and the median Quick Disabilities of the Arm, Shoulder, and Hand score was 5 in both groups. The overall complication rate was significant, 21% in the volar locking plate group, compared with 52% in the fragment-specific group. CONCLUSIONS: In treatment of primarily nonreducible or secondarily redisplaced distal radius fractures, volar locking plates and fragment-specific fixation both achieve good and similar patient-reported outcomes, although more complications were recorded in the fragment-specific group. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 28089164 TI - Low Median Nerve Palsy as Initial Manifestation of Churg-Strauss Syndrome. AB - Anterior interosseous nerve (AIN) syndrome is typically characterized by forearm pain and partial or complete dysfunction of the AIN-innervated muscles. Although the exact etiology and pathophysiology of the disorder remain unclear, AIN syndrome is increasingly thought to be an inflammatory condition of the nerve rather than a compressive neuropathy because the symptoms often resolve spontaneously following prolonged observation. However, peripheral neuropathy can be 1 of the first symptoms of systemic vasculitis that needs early systemic immunotherapy to prevent extensive nerve damage. Churg-Strauss syndrome (CSS; eosinophilic granulomatosis with polyangiitis) is 1 type of primary systemic vasculitis that frequently damages the peripheral nervous system. CSS-associated neuropathy usually involves nerves of the lower limb, and few studies have reported on the involvement of the upper limb alone. We report on a rare case of low median nerve palsy as the initial manifestation of CSS. The patient recovered well with early steroid treatment for primary systemic vasculitis. PMID- 28089165 TI - High-flow nasal cannula oxygen for reverting severe acute exacerbation of chronic obstructive pulmonary disease: A case report. PMID- 28089166 TI - Pediatric donation after controlled cardiac death (Maastricht type III donors). PMID- 28089167 TI - Diabetic self care practices in rural Mysuru, Southern Karnataka, India - A need for Diabetes Self Management Educational (DSME) program. AB - CONTEXT: Diabetes and its complications are the leading cause of morbidity and mortality in the world. Self care has emerged as a crucial element in the management of diabetes and a key factor associated with the quality of diabetic care. AIMS: The purpose of the study was to assess the self care activities of patients with Type II diabetes mellitus in a rural area of Mysuru district. SETTINGS AND DESIGN: A community based cross sectional descriptive study was carried out among 400 diabetic patients in rural Mysore. METHODS AND MATERIAL: Self care Activities (Diet, exercise, self blood glucose monitoring, medication, foot care, smoking) were assessed using a pre designed and tested questionnaire. STATISTICAL ANALYSIS USED: Relevant descriptive analysis like percentages is carried out using SPSS version 22.0. RESULTS: Most of the diabetic patients had good compliance for medication (92.5%), followed by 72% for diabetic diet. Only 27.75% of the diabetic patients participated in walking, 24.25% practised foot care, blood glucose monitoring by 24.75% and only 25.5% of them were current smokers. CONCLUSIONS: The rural diabetic patients are more adherent and compliant to medication and diabetic diet and less compliant to physical activity, foot care and self glucose monitoring. PMID- 28089168 TI - The relationship between dietary intake and other cardiovascular risk factors with blood pressure in individuals without a history of a cardiovascular event: Evidence based study with 5670 subjects. AB - BACKGROUND AND AIM: Raised blood pressure is a leading cause of morbidity and mortality worldwide; improved nutritional approaches to population-wide prevention are required.We aimed to investigate the relationship between dietary intake and other cardiovascular risk factors with blood pressure in individuals without a history of a cardiovascular event in an Iranian cohort. MATERIAL AND METHOD: A cross-sectional study of 5670 healthy subjects [approximately 40% (n=2179) males and 60% (n=3491) females] was undertaken in a sample from northeastern Iran. Subjects were recruited from an urban population, using a stratified-cluster method and derived from the Mashhad Stroke Heart Atherosclerosis Disorder (MASHAD) study, Mashhad, Iran. The age of the subjects was between 35 and 64 years. None of the subjects had a past history of major disease. RESULTS: The mean ages for the male and female subgroups were 50.1+/- 8.1years and 48.2 +/-7.8 y respectively. Not unexpectedly, subjects without hypertension (HTN) were younger than those with established HTN. Individuals with HTN were significantly more adipose than those without (p<0.01). We found no significant differences in crude or total energy adjusted intake of nutrients between the three groups (p>0.05), except for crude and energy adjusted phosphorus intake (p<0.05) and crude intake of the cholesterol (p<0.05). There was a significant correlation between the dietary intake of total fatty acids, phosphorus and vitamin E with both systolic blood pressure (SBP) and diastolic blood pressure (DBP). PUFA (odds ratio [OR] [95% confidence interval (CI)], 1.56 [1.05-1.06]; P<0.01), sodium (OR [95% CI], 1.00 [(1.00-1.01)]; P<0.01) and phosphorus (OR [95% CI], 1.00 [(1.00-1.01)]; P<0.01)were significant independent predictors of HTN after adjustment for energy intake. CONCLUSION: In our representative population from North-Eastern Iran, it appears that in adults without a history of cardiovascular disease, crude or energy adjusted intake of phosphorus and total fatty acid intake were significant determinants of BP, however we found no association between sodium and potassium intake with BP. PMID- 28089169 TI - The role of n-3 polyunsaturated fatty acids (n-3PUFAs) in affective disorders. AB - BACKGROUND: Among emerging treatments for depressive disorders several studies suggested that n-3 polyunsaturated fatty acids (n-3PUFAs) supplementation can be used. However, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) differ in terms of biochemistry, metabolism and therapeutic effects. Therefore, a clear picture of their specific and different role on affective disorders has not yet emerged. OBJECTIVES: To investigate the effects of n-3PUFAs on affective disorders including major depression, bipolar disorder and perinatal depression. METHODS: a comprehensive search on PUBMED, Medline and PsychINFO of all RCTs using n-3PUFAs patients with depressive symptoms published up to April 2016 was performed. We included trials that examined unipolar or bipolar disorder and trials that investigated depressive symptoms in relation to pregnancy. Trials were excluded if the depressive symptomatology was related to other primary organic diseases. RESULTS: 264 RCT studies were identified but only 36 met the inclusion criteria. First, it has been reported that n-3PUFAs supplementation might have clinical benefits on depressive symptoms. Second, EPA supplement, rather than DHA, seems to be more effective in treating major depression. Third, n-3PUFAs can have beneficial effects in bipolar depression but not in perinatal depression. CONCLUSIONS: there are only some evidence on the efficacy of n-3PUFAs in affective disorders especially to unipolar and bipolar depression not powered enough to confirm a therapeutic effect for affective disorder. Therefore, further studies with larger and more homogeneous samples, are required to confirm these effects. PMID- 28089170 TI - Iliolumbar artery: a useful pedicle for the iliac crest free flap in maxillofacial reconstruction. AB - The iliac crest free flap is commonly used in maxillofacial reconstruction, and is typically supplied by the deep circumflex iliac artery (DCIA). However, the iliolumbar artery is an alternative blood supply that can potentially be used in such reconstructions. We describe the anatomy of the iliolumbar artery and review publications about its clinical use. We raised four cadaveric iliac crest free flaps using both the DCIA and the iliolumbar artery to illustrate its use in reconstructing maxillofacial defects. It provided a longer pedicle for microvascular anastomosis than the DCIA, was more versatile in orientation of the flap, and allowed the chance of anastomosing both pedicles to "super-charge" the flap's blood supply. We describe a patient in whom this flap was used successfully, which shows that the iliolumbar artery is a suitable pedicle to augment (or replace) the DCIA in an iliac crest free flap. PMID- 28089171 TI - Protease Inhibitors of Parasitic Flukes: Emerging Roles in Parasite Survival and Immune Defence. AB - Protease inhibitors play crucial roles in parasite development and survival, counteracting the potentially damaging immune responses of their vertebrate hosts. However, limited information is currently available on protease inhibitors from schistosomes and food-borne trematodes. Future characterization of these molecules is important not only to expand knowledge on parasitic fluke biology but also to determine whether they represent novel vaccine and/or drug targets. Moreover, protease inhibitors from flukes may represent lead compounds for the development of a new range of therapeutic agents against inflammatory disorders and cancer. This review discusses already identified protease inhibitors of fluke origin, emphasizing their biological function and their possible future development as new intervention targets. PMID- 28089172 TI - Metal oxide nanoparticles as antimicrobial agents: a promise for the future. AB - Microbial infectious diseases are a global threat to human health. Excess and improper use of antibiotics has created antimicrobial-resistant microbes that can defy clinical treatment. The hunt for safe and alternate antimicrobial agents is on in order to overcome such resistant micro-organisms, and the birth of nanotechnology offers promise to combat infectious organisms. Over the past two decades, metal oxide nanoparticles (MeO-NPs) have become an attractive alternative source to combat microbes that are highly resistant to various classes of antibiotics. Their vast array of physicochemical properties enables MeO-NPs to act as antimicrobial agents through various mechanisms. Apart from exhibiting antimicrobial properties, MeO-NPs also serve as carriers of drugs, thus barely providing a chance for micro-organisms to develop resistance. These immense multiple properties exhibited by MeO-NPs will have an impact on the treatment of deadly infectious diseases. This review discusses the mechanisms of action of MeO-NPs against micro-organisms, safety concerns, challenges and future perspectives. PMID- 28089173 TI - Use of interactive iBooks for patient education in otology. AB - INTRODUCTION: Physicians in the ambulatory setting face challenges in adequately educating patients in a brief office encounter. OBJECTIVE: To evaluate the efficacy of an iPad-based interactive educational module (iBook) in various otologic pathologies. METHODS: Patients presenting with symptoms of tinnitus, dizziness, hearing loss, or cochlear implant evaluation were included. In total, 44 patients received the iBook and 22 patients served as controls. Prior to viewing the iBook, patients completed a pre-survey to assess baseline knowledge. After viewing the iBook, patients completed a post-survey to assess changes in perception and knowledge of their disease. Results were compared to that of the control group who did not receive iBook supplementation prior to being seen by the physician. RESULTS: Paired t-test analysis showed significant improvements (p<0.01) in both self-reported perception and concrete understanding in various concepts when compared to pre-iBook results. This was further compared to the control group, which showed a significant gain in factual knowledge (p=0.02). CONCLUSION: Patients who viewed the iBook, personalized to their diagnosis, displayed significantly improved understanding of their condition. Increased use of interactive educational modalities, such as the iBook, can be of benefit to an otologic practice in improving patient education and satisfaction. PMID- 28089174 TI - Neonatal acute kidney injury - Severity and recovery prediction and the role of serum and urinary biomarkers. AB - Neonatal acute kidney injury is common, in part due to incomplete renal maturation and also due to frequent exposure to risk factors for acute kidney injury such as perinatal asphyxia, extracorporeal-membrane-oxygenation, cardiac surgery, sepsis, prematurity and nephrotoxicity. However the current method by which acute kidney injury is diagnosed is sub-optimal and not universally accepted which impairs the accurate estimation of the true incidence of neonatal acute kidney injury. Serum Cystatin-C, urinary NGAL, KIM-1 and IL-18 are promising neonatal acute kidney injury biomarkers however the diagnosis of acute kidney injury remains serum creatinine/urine output-based in many studies. Emerging biomarkers which require further study in the neonatal population include netrin-1 and EGF. Increased awareness amongst clinicians of nephrotoxic medications being a modifiable risk factor for the development of neonatal acute kidney injury is imperative. The burden of chronic kidney failure following neonatal acute kidney injury is unclear and requires further study. PMID- 28089175 TI - Reduction of carcinomatosis risk using icodextrin as a carrier solution of intraperitoneal oxaliplatin chemotherapy. AB - There is no standard treatment in patients with high risk metachronous peritoneal carcinomatosis (PC) in colonic cancer, as perforated tumour or synchronous ovarian metastasis. Icodextrin 4% (ICDX), presently used to prevent postoperative abdominal adhesions, could inhibit the coactivation of the tumour cells and the microenvironment cells, associated with the development of PC. The aim of this study was to inhibit the formation of the PC in a murine model mimicking surgical situation using ICDX and intraperitoneal (IP) prophylactic chemotherapy. We created a model of growing PC in mice using cells of murine colonic cancer CT26. Cells and treatments were injected simultaneously. Five groups were created: CT26 (control group), CT26 + ICDX (ICDX group), CT26 + chemotherapy (oxaliplatin and 5FU) (chemo group), CT26 + chemotherapy + ICDX (ICDX chemo group), ICDX (toxicity group). At day 15, PC was evaluated with rodents PCI. In the chemo group, PCI was significantly lower than in the control group (3.2 versus 8.4, p = 0.02). ICDX had a synergetic effect on PC with chemotherapy; indeed PCI in ICDX chemo group was lower than in chemo group (1.4 versus 3.2, p = 0.04). There was no morbidity linked to ICDX in toxicity group. Safety of ICDX needs to be verified, particularly on colonic anastomosis before ICDX associated to IP chemotherapy could be used as a preventive treatment of PC in high risk patients. This prophylactic treatment is easy to use and would be administrated at the end of a curative surgery for a colonic cancer. PMID- 28089176 TI - Inflammatory myofibroblastic tumor: An unusual hepatic tumor mimicking liver abscess. PMID- 28089177 TI - Cell cycle-dependent positive and negative functions of Fun30 chromatin remodeler in DNA damage response. AB - The evolutionally conserved Fun30 chromatin remodeler in Saccharomyces cerevisiae has been shown to contribute to cellular resistance to genotoxic stress inflicted by camptothecin (CPT), methyl methanesulfonate (MMS) and hydroxyurea (HU). Fun30 aids in extensive DNA resection of DNA double stranded break (DSB) ends, which is thought to underlie its role in CPT-resistance. How Fun30 promotes MMS- or HU resistance has not been resolved. Interestingly, we have recently found Fun30 to also play a negative role in cellular tolerance to MMS and HU in the absence of the Rad5-dependent DNA damage tolerance pathway. In this report, we show that Fun30 acts to down regulate Rad9-dependent DNA damage checkpoint triggered by CPT or MMS, but does not affect Rad9-independent intra-S phase replication checkpoint induced by MMS or HU. These results support the notion that Fun30 contributes to cellular response to DSBs by preventing excessive DNA damage checkpoint activation in addition to its role in facilitating DNA end resection. On the other hand, we present evidence suggesting that Fun30's negative function in MMS- and HU-tolerance in the absence of Rad5 is not related to its regulation of checkpoint activity. Moreover, we find Fun30 to be cell cycle regulated with its abundance peaking in G2/M phase of the cell cycle. Importantly, we demonstrate that artificially restricting Fun30 expression to G2/M does not affect its positive or negative function in genotoxin-resistance, but confining Fun30 to S phase abolishes its functions. These results indicate that both positive and negative functions of Fun30 in DNA damage response occur mainly in G2/M phase. PMID- 28089178 TI - Hatchery workers' IgG antibody profiles to airborne bacteria. AB - Occupational exposure to high concentrations of airborne bacteria in poultry production is related to an increased risk of respiratory disorders. However, etiology and in particular microorganisms' potential role in pathogenesis still needs to be elucidated. Thus, detection of specific antibodies against occupational microbial antigens may lead to identification of potentially harmful species. For the purpose of IgG titer determination, indirect immunofluorescence on various bacterial isolates from duck hatchery air was combined with image based quantification of fluorescence intensity. Moreover, in addition to established assays with pure bacterial cultures, a new approach utilized complex bioaerosol samples for detection of anti-microbial antibodies in human sera by determination of percentages of antibody-bound cells in different serum dilutions. Mean titers in sera from hatchery workers and a non-exposed control group did not display significant differences for most tested isolates and application of comprehensive cluster analysis to entire titer data revealed no structure reflecting workers and controls group. Furthermore, determination of immunoreactivity to the complete microbial community in workplace air displayed similar proportions of antibody-bound cells in both groups. Although no general differences in immunoreaction patterns were observed, mean titers to a Proteus mirabilis isolate and to 3 of 4 distinct Acinetobacter baumannii isolates were higher in the group of hatchery workers than in the reference group indicating a potential applicability as exposure markers. We conclude, despite long term bioaerosol exposure, hatchery workers' IgG antibody profiles to tested antigens did not differ substantially from those of the control group. However, increased workers' titers to A. baumannii and clinical relevance of this species should lead to further investigations regarding potential involvement in pathogenesis of occupational respiratory disorders. PMID- 28089179 TI - Type 2 Diabetes, Obesity, and Aspirin Responsiveness. PMID- 28089180 TI - Enteric Coating and Aspirin Nonresponsiveness in Patients With Type 2 Diabetes Mellitus. AB - BACKGROUND: A limitation of aspirin is that some patients, particularly those with diabetes, may not have an optimal antiplatelet effect. OBJECTIVES: The goal of this study was to determine if oral bioavailability mediates nonresponsiveness. METHODS: The rate and extent of serum thromboxane generation and aspirin pharmacokinetics were measured in 40 patients with diabetes in a randomized, single-blind, triple-crossover study. Patients were exposed to three 325-mg aspirin formulations: plain aspirin, PL2200 (a modified-release lipid based aspirin), and a delayed-release enteric-coated (EC) aspirin. Onset of antiplatelet activity was determined by the rate and extent of inhibition of serum thromboxane B2 (TXB2) generation. Aspirin nonresponsiveness was defined as a level of residual serum TXB2 associated with elevated thrombotic risk (<99.0% inhibition or TXB2 >3.1 ng/ml) within 72 h after 3 daily aspirin doses. RESULTS: The rate of aspirin nonresponsiveness was 15.8%, 8.1%, and 52.8% for plain aspirin, PL2200, and EC aspirin, respectively (p < 0.001 for both comparisons vs. EC aspirin; p = 0.30 for comparison between plain aspirin and PL2200). Similarly, 56% of EC aspirin-treated subjects had serum TXB2 levels >3.1 ng/ml, compared with 18% and 11% of subjects after administration of plain aspirin and PL2200 (p < 0.0001). Compared with findings for plain aspirin and PL2200, this high rate of nonresponsiveness with EC aspirin was associated with lower exposure to acetylsalicylic acid (63% and 70% lower geometric mean maximum plasma concentration [Cmax] and 77% and 82% lower AUC0-t [area under the curve from time 0 to the last time measured]) and 66% and 72% lower maximum decrease of TXB2, with marked interindividual variability. CONCLUSIONS: A high proportion of patients treated with EC aspirin failed to achieve complete inhibition of TXB2 generation due to incomplete absorption. Reduced bioavailability may contribute to "aspirin resistance" in patients with diabetes. (Pharmacodynamic Evaluation of PL2200 Versus Enteric-Coated and Immediate Release Aspirin in Diabetic Patients; NCT01515657). PMID- 28089181 TI - Dynamic MR defecography of the posterior compartment: Comparison with conventional X-ray defecography. AB - PURPOSE: The goal of this study was to compare conventional X-ray defecography and dynamic magnetic resonance (MR) defecography in the diagnosis of pelvic floor prolapse of the posterior compartment. MATERIAL AND METHODS: Fifty women with a mean age of 65.5 years (range: 53-72 years) who underwent X-ray defecography and MR defecography for clinical suspicion of posterior compartment dysfunction, were included in this retrospective study. X-ray defecography and dynamic MR defecography were reviewed separately for the presence of pelvic organ prolapse. The results of the combination of X-ray defecography and MR defecography were used as the standard of reference. Differences in sensitivities between X-ray defecography and MR defecography were compared using the McNemar test. RESULTS: With the gold standard, we evidenced a total of 22 cases of peritoneocele (17 elytroceles, 3 hedroceles and 2 elytroceles+hedroceles), including 15 cases of enterocele, 28 patients with rectocele including 16 that retained contrast, 37 cases of rectal prolapse, and 11 cases of anismus. The sensitivities of X-ray defecography were 90.9% for the diagnosis of peritoneocele, 71.4% for rectocele, 81.1% for rectal prolapse and 63.6% for anismus. The sensitivities of MR defecography for the same diagnoses were 86.4%, 78.6%, 62.2% and 63.6%, respectively. For all these pathologies, no significant differences between X-ray defecography and MR defecography were found. CONCLUSION: Dynamic MR defecography is equivalent to X-ray defecography for the diagnosis of abnormalities of the posterior compartment of the pelvic floor. PMID- 28089182 TI - More perfect? PMID- 28089183 TI - One patch or more? Defining success in treatment of post-dural puncture headache. PMID- 28089184 TI - Bone Wax Is Effective in Reducing Blood Loss After Total Knee Arthroplasty. AB - BACKGROUND: Total knee arthroplasty (TKA) is associated with major blood loss and blood transfusion is often required. This study aimed to evaluate the efficacy of bone wax in reducing blood loss and transfusion rates after TKA. METHODS: A prospective randomized controlled study that included 100 patients undergoing primary unilateral TKA with cement was conducted in a tertiary center between March 2014 and June 2014. The bone wax group received 2.5 g of bone wax, applied onto the uncovered bone around the prostheses and the nail holes before the tourniquet was released, whereas the control group had hemostasis achieved using electrocautery only. Total blood loss was calculated using the hemoglobin balance method. RESULTS: There were no demographic differences between the 2 groups. The preoperative serum hemoglobin levels were comparable between the 2 groups. The drop in serum hemoglobin levels at 24 h post-TKA was 1.6 +/- 0.9 and 2.1 +/- 1.1 g/dL in the bone wax and control groups respectively (P = .021), while the drop in serum hemoglobin levels at 72 h post-TKA was 2.7 +/- 1.1 and 3.6 +/- 1.2 g/dL respectively (P = .013). Total blood loss at 72 h post-TKA was 987.9 and 1183.5 mL for the bone wax and control groups respectively (P = .017). There was no adverse event associated with the use of bone wax at the 3-month follow-up. CONCLUSION: The application of bone wax in TKA was safe and effective for reducing total blood loss and maintaining higher hemoglobin levels. PMID- 28089185 TI - Joint Replacement Volume Positively Correlates With Improved Hospital Performance on Centers for Medicare and Medicaid Services Quality Metrics. AB - BACKGROUND: The Center for Medicare and Medicaid Services (CMS) is transitioning Medicare from a fee-for-service program into a value-based pay-for-performance program. In order to accomplish this goal, CMS initiated 3 programs that attempt to define quality and seek to reward high-performing hospitals and penalize poor performing hospitals. These programs include (1) penalties for hospital-acquired conditions (HACs), (2) penalties for excess readmissions for certain conditions, and (3) performance on value-based purchasing (VBP). The objective of this study was to determine whether high-volume total joint hospitals perform better in these programs than their lower-volume counterparts. METHODS: We analyzed data from the New York Statewide Planning and Research Cooperative System database on total New York State hospital discharges from 2013 to 2015 for total knee and total hip arthroplasty. This was compared to data from Hospital Compare on HAC's, excess readmissions, and VBP. From these databases, we identified 123 hospitals in New York, which participated in all 3 Medicare pay-for-performance programs and performed total joint replacements. RESULTS: Over the 3-year period spanning 2013-2015, hospitals in New York State performed an average of 1136.59 total joint replacement surgeries and achieved a mean readmission penalty of 0.005909. The correlation coefficient between surgery volume and combined performance score was 0.277. Of these correlations, surgery volume and VBP performance, and surgery volume and combined performance showed statistical significance (P < .01). CONCLUSION: Our study demonstrates that there is a positive association between joint replacement volumes and overall hospital quality, as well as joint replacement volumes and VBP performance, specifically. These findings are consistent with previously reported associations between patient outcomes and procedure volumes. However, a relationship between joint replacement volume and HAC scores or readmission penalties could not be demonstrated. PMID- 28089186 TI - Predictors of Same-Day Discharge in Primary Total Joint Arthroplasty Patients and Risk Factors for Post-Discharge Complications. AB - BACKGROUND: Same-day (<24 h) discharge total joint arthroplasty (TJA) may be a safe and effective option for certain patients with end-stage osteoarthritis. Given the growing pressure to improve quality and lower TJA episode costs, surgeons must identify which TJA patients can be appropriately discharged home quickly and safely. This study identifies characteristics associated with same day discharge post-TJA as well as assesses risk factors for complications in this select patient population. METHODS: Bivariate and multivariate analyses were performed using perioperative variables from the 2011 to 2014 National Surgical Quality Improvement Program database. RESULTS: In total, 7474 primary TJAs among 120,847 TJA patients were discharged within 24 h post-surgery. These patients were more likely to be younger (<50 years), male sex, American Society of Anesthesiologists class 1 or 2, and less likely to be obese or taking steroids (P < .05 for all). They were also less likely to have co-morbidities. Rates of severe adverse event (SAE) or unplanned readmission post-discharge were 1.3% and 1.9%, respectively. Multivariate analysis identified age >80 (odds ratio [OR] 4.16, P = .001), smoking (OR 1.61, P = .03), bleeding-causing disorders (OR 2.56, P = .01), American Society of Anesthesiologists class 3 or 4 (OR 1.42, P < .05), and SAE pre-discharge (OR 13.13, P < .0001) as independent predictors for adverse events or readmission in this population. CONCLUSION: Patient characteristics, co morbidities, and SAEs pre-discharge can be used to assess potential for discharge within 24 h. The results of our analysis may be used to develop risk stratification tools for identification of patients that are truly appropriate for same-day discharge TJA. PMID- 28089187 TI - Effect of Periarticular Morphine Injection for Total Knee Arthroplasty: A Randomized, Double-Blind Trial. AB - BACKGROUND: The periarticular multimodal cocktail injection including morphine is currently commonly used to treat postoperative pain after total knee arthroplasty (TKA). Despite its analgesic effect, it is frequently reported to cause nausea and vomiting, which are adverse effects of opioids. This study aimed to assess the efficacy of morphine as a component of a multimodal cocktail injection for providing postoperative analgesia and alleviating swelling in patients who underwent TKA. METHODS: This is a prospective, single-center, randomized controlled trial involving 102 patients scheduled for unilateral TKA. A mixture of steroids, local anesthetics, nonsteroidal anti-inflammatory drugs, and epinephrine with or without morphine (10 mg) was injected to randomly assigned patients. Postoperative assessment was performed with all attending personnel and patients blinded to group assignment. Visual analog scale of pain, range of motion, nausea numerical rating scale, number of patients with vomiting, total dose of antiemetic drugs used, thigh swelling, the Western Ontario and McMaster Universities Osteoarthritis Index score, and adverse outcomes were compared between groups on postoperative days. RESULTS: Visual analog scale scores did not differ between the 2 groups at any postoperative time point. The nausea numerical rating scale scores during the postoperative period from 30 min to 9 h, the number of vomiting episodes, and the total dose of antiemetic drugs administered were significantly higher in the morphine group. The thigh girth, Western Ontario and McMaster Universities Osteoarthritis Index, and the incidence of complications were not different between groups. CONCLUSION: The results of this study suggested that addition of morphine to the multimodal cocktail injection is not effective for relieving postoperative pain, alleviating swelling, or improving range of motion, and results in nausea and vomiting. PMID- 28089188 TI - Barriers to providing maternity care to women with physical disabilities: Perspectives from health care practitioners. AB - BACKGROUND: Women with physical disabilities are known to experience disparities in maternity care access and quality, and communication gaps with maternity care providers, however there is little research exploring the maternity care experiences of women with physical disabilities from the perspective of their health care practitioners. OBJECTIVE: This study explored health care practitioners' experiences and needs around providing perinatal care to women with physical disabilities in order to identify potential drivers of these disparities. METHODS: We conducted semi-structured telephone interviews with 14 health care practitioners in the United States who provide maternity care to women with physical disabilities, as identified by affiliation with disability related organizations, publications and snowball sampling. Descriptive coding and content analysis techniques were used to develop an iterative code book related to barriers to caring for this population. Public health theory regarding levels of barriers was applied to generate broad barrier categories, which were then analyzed using content analysis. RESULTS: Participant-reported barriers to providing optimal maternity care to women with physical disabilities were grouped into four levels: practitioner level (e.g., unwillingness to provide care), clinical practice level (e.g., accessible office equipment like adjustable exam tables), system level (e.g., time limits, reimbursement policies), and barriers relating to lack of scientific evidence (e.g., lack of disability-specific clinical data). CONCLUSION: Participants endorsed barriers to providing optimal maternity care to women with physical disabilities. Our findings highlight the needs for maternity care practice guidelines for women with physical disabilities, and for training and education regarding the maternity care needs of this population. PMID- 28089189 TI - Exploring the brain bases of dreaming. Commentary on "Beyond the neuropsychology of dreaming: Insights into the neural basis of dreaming with new techniques of sleep recording and analysis." Sleep Medicine Reviews. PMID- 28089190 TI - Positron emission tomography in the management of documented or suspected recurrent ovarian cancer. AB - BACKGROUND: To prospectively evaluate the value of positron emission tomography (PET) or integrated computed tomography (CT) and PET (PET/CT) in the management of documented or suspected recurrent ovarian cancer. METHODS: Patients with ovarian cancer who had completed primary cytoreductive surgery and standard adjuvant chemotherapy were studied to evaluate the following indications: (1) CA125 elevation after complete remission with negative CT or magnetic resonance imaging (MRI) result; (2) post-therapy surveillance CT/MRI-detected suspicious lesions that guided biopsy was not feasible; (3) documented relapse for restaging prior to or after curative salvage therapy. The clinical impact of PET, as compared with those of CT/MRI, was determined on a per scan basis. RESULTS: From 2002 to 2009, 73 patients were recruited, and 92 PET scans were performed. Up to June 2015, 53 patients had died of disease, four were alive with disease, and the remaining 16 were alive without disease. Among the 92 scans, PET had positive impacts in 72.8%, no clinical impacts in 21.7%, and negative impacts in 5.4%. For indication 1, the sensitivity and positive predictive value of PET in detecting recurrence were 80.0% and 92.3%, respectively. For indication 2, the sensitivity, specificity, positive predictive value, and negative predictive value of PET were 91.2%, 62.5%, 91.2%, and 62.5%, respectively. For indication 3, PET provided positive impact in 85.3% and negative impact in 2.9% of the 34 scans. CONCLUSION: PET has value in the management of suspected or documented recurrent ovarian cancer, with positive impacts on confirming recurrent status and offering a better treatment plan. PMID- 28089191 TI - Object shape dependency of in-plane resolution for iterative reconstruction of computed tomography. AB - The present study aimed to investigate whether the in-plane resolution property of iterative reconstruction (IR) of computed tomography (CT) data is object shape dependent by testing columnar shapes with diameters of 3, 7, and 10cm (circular edge method) and a cubic shape with 5-cm side lengths (linear edge method). For each shape, objects were constructed of acrylic (contrast in Hounsfield units [DeltaHU]=120) as well as a soft tissue equivalent material (DeltaHU=50). For each shape, we measured the modulation transfer functions (MTFs) of IR and filtered back projection (FBP) using two multi-slice CT scanners at scan doses of 5 and 10mGy. In addition, we evaluated a thin metal wire using the conventional method at 10mGy. For FBP images, the MTF results of the tested objects and the wire method showed substantial agreement, thus demonstrating the validity of our analysis technique. For IR images, the MTF results of different shapes were nearly identical for each object contrast and dose combination, and we did not observe shape-dependent effects of the resolution properties of either tested IR. We conclude that both the circular edge method and linear edge method are equally useful for evaluating the resolution properties of IRs. PMID- 28089192 TI - Commissioning Monte Carlo algorithm for robotic radiosurgery using cylindrical 3D array with variable density inserts. AB - INTRODUCTION: To commission the Monte Carlo (MC) algorithm based model of CyberKnife robotic stereotactic system (CK) and evaluate the feasibility of patient specific QA using the ArcCHECK cylindrical 3D-array (AC) with Multiplug inserts (MP). RESULTS: Four configurations were used for simple beam setup and two for patient QA, replacing water equivalent inserts by lung. For twelve collimators (5-60mm) in simple setup, mean (SD) differences between MC and RayTracing algorithm (RT) of the number of points failing the 3%/1mmgamma criteria were 1(1), 1(3), 1(2) and 1(2) for the four MP configurations. Tracking fiducials were placed within AC for patient QA. Single lung insert setup resulted in mean gamma-index 2%/2mm of 90.5% (range [74.3-95.9]) and 82.3% ([66.8-94.5]) for MC and RT respectively, while 93.5% ([86.8-98.2]) and 86.2% ([68.7-95.4]) in presence of largest inhomogeneities, showing significant differences (p<0.05). DISCUSSION: After evaluating the potential effects, 1.12g/cc PMMA and 0.09g/cc lung material assignment showed the best results. Overall, MC-based model showed superior results compared to RT for simple and patient specific testing, using a 2%/2mm criteria. Results are comparable with other reported commissionings for flattening filter free (FFF) delivery. Further improvement of MC calculation might be challenging as Multiplan has limited material library. CONCLUSIONS: The AC with Multiplug allowed for comprehensive commissioning of CyberKnife MC algorithm and is useful for patient specific QA for stereotactic body radiation therapy. MC calculation accuracy might be limited due to Multiplan's insufficient material library; still results are comparable with other reported commissioning measurements using FFF beams. PMID- 28089193 TI - Brake Reaction Time After Hip Arthroscopy for Femoroacetabular Impingement and Labral Tear. AB - PURPOSE: To determine if a difference exists in brake reaction time (BRT) before and after hip arthroscopy for femoroacetabular impingement (FAI) and labral tear compared with age- and gender-matched controls. METHODS: Consecutive adult subjects undergoing primary hip arthroscopy were eligible for this prospective investigation. Individuals with symptomatic FAI and labral tear that underwent hip arthroscopy with minimum 8 weeks follow-up were included. BRT was measured using the RT-2S reaction time tester a maximum of 6 weeks preoperatively and every 2 weeks postoperatively for 8 weeks. Sit-to-stand test (STST) was measured at each BRT testing session. An age- and gender-matched control group without hip or lower extremity symptoms were selected and completed both BRT and STST. Continuous pre- and postoperative BRT values were compared with Mann-Whitney and analyses of variance. Association of BRT and STST tests was performed with Spearman correlation. An a priori sample size calculation determined that minimally 18 subjects per group (surgery group vs control group) were necessary to detect, with 80% power (difference of 0.2 seconds in BRT). RESULTS: Nineteen subjects (age 37.1 +/- 12.7 years, 10 women, 11 right hip) were analyzed. All subjects underwent arthroscopic labral repair and FAI correction. There was no difference between preoperative (604 +/- 148 milliseconds [ms]) and postoperative (608 ms 2 weeks; 566 ms 4 weeks; 559 ms 6 weeks; 595 ms 8 weeks) BRT. There was no difference between controls and subjects at any time point. There was a strong negative correlation between BRT and STST preoperatively and at 4 and 6 weeks postoperatively and a moderate negative correlation at 2 weeks postoperatively. CONCLUSIONS: After hip arthroscopy for FAI and labral tear, BRT is not different from preoperative values or that of controls. In addition, BRT had a significant correlation with STST in the first 6 weeks after surgery. LEVEL OF EVIDENCE: Level II, diagnostic, prospective. PMID- 28089194 TI - Left ventricular global longitudinal strain predicts major adverse cardiac events and all-cause mortality in heart transplant patients. AB - BACKGROUND: Left ventricular global longitudinal strain (LVGLS) is a robust longitudinal myocardial deformation marker that is strongly affected by cardiac allograft vasculopathy (CAV), microvascular dysfunction, and acute cellular rejection (ACR). We evaluated graft deformation for risk stratification in long term heart transplant (HTx) patients. METHODS: The study included 196 patients who underwent HTx between 2011 and 2013. Patients underwent comprehensive echocardiography and coronary angiography. Previous rejection burden was assessed, and ACR grades were calculated. Patients were prospectively followed until February 24, 2016. Major adverse cardiac events (MACE), including coronary event, heart failure, treated rejection, and cardiovascular death, and all-cause mortality were recorded. RESULTS: During follow-up, 57 patients experienced MACE. Median follow-up was 1,035 (interquartile range [IQR] 856-1,124) days. Median time to first event was 534 (IQR 276-763) days. LVGLS was a strong predictor of MACE (hazard ratio [HR] 4.9, 95% confidence interval [CI] 2.7-8.9, p < 0.0001) in patients with and without CAV. LVGLS was a strong predictor of all-cause mortality (HR 4.9, 95% CI 2.2-10.8, p < 0.0001). Left ventricular ejection fraction (LVEF) also predicted MACE, but only in patients with CAV. No relationship between LVEF and all-cause mortality was seen. We obtained a strong MACE (HR 6.3, 95% CI 2.8-14.1, p < 0.0001) and all-cause mortality (HR 6.6, 95% CI 2.3-19.2, p < 0.0001) predictive model by combining LVGLS and restrictive left ventricular filling pattern (LVFP), which remained strong after adjustment for CAV, ACR score, hemoglobin, creatinine, and time since transplantation. CONCLUSIONS: Measurement of LVGLS strongly predicts MACE and mortality in long term HTx patients. Predictive ability was seen in patients with and without CAV. A combined model of left ventricular systolic deformation by LVGLS and diastolic graft performance by LVFP was a stronger model for prediction of MACE and all cause mortality. PMID- 28089195 TI - Cumulative volumetric analysis as a key criterion for the treatment of brain metastases. AB - BACKGROUND: Recent studies have demonstrated diminished cognitive function, worse quality of life, and no overall survival benefit from the addition of adjuvant whole brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) in the management of brain metastases. This study analyzes the treatment outcome of SRS, specifically CyberKnife Radiosurgery, based on the total tumor volume compared to the absolute number of lesions. METHODS: A retrospective analysis of hospital records at Virginia Hospital Center for patients with brain metastases who underwent CyberKnife Radiosurgery between June 2008 and June 2014 was performed. Previous treatment history, metastatic tumor dimensions, and outcomes were recorded. Predictors of neurological defects, local tumor progression, and overall survival were assessed with univariate and multivariate analysis. RESULTS: We identified 130 adult patients with a median age of 61.5years and a median follow-up of 7.1months. Unfavorable outcomes such as death, tumor progression, or neurological defect showed correlation with cumulative tumor volume greater than the median volume of 7cc (p<0.05). Worsening neurological defects showed an association with an increased number of lesions (p<0.02) and age (p<0.05). For local tumor progression, patients who have received WBRT were less likely to progress (.74, 95% CI, .48, 1.10), while those who received chemotherapy (1.48 95% CI, .98, 2.26), or surgery (1.56 95%, CI .98, 2.47) without WBRT were more likely to progress. CONCLUSIONS: Our data suggest that a cumulative tumor volume greater than 7cc correlates with worse outcomes following CyberKnife Radiosurgery. In addition, WBRT appears to have a role in improved survival for patients with increased tumor burden. A prospective study is warranted to validate these findings. PMID- 28089196 TI - Descriptive analysis of unplanned readmission and reoperation rates after intradural spinal tumor resection. AB - INTRODUCTION: Spinal cord tumors (SCT) are relatively uncommon and usually require surgical treatment. Readmission within 30days after discharge is an important indicator of health care quality. The aim of this study was to investigate the rates and causes of unplanned readmissions and reoperations after SCT surgery. METHODS: A retrospective analysis of patients' charts at a single center from May 2007 to September 2015 was completed. INCLUSION CRITERIA: history of laminectomy with excision of neoplasm in the spinal cord. EXCLUSION CRITERIA: (1) surgery outside the timeframe; (2) less than 19years old; (3) non-neoplastic intramural pathologies; (4) previous resection at the same location; (5) metastatic lesions. RESULTS: We found 131 patients that met criteria. Six patients (4.5%) were readmitted within 30days and two within 90days (1.5%). Four underwent reoperation: one for a cerebrospinal fluid leak, two for pseudomenigoceles, and one for repeat laminectomy. Resection of intramedullary tumors resulted in twice the risk of having one or more complications compared to extramedullary tumors (RR 2.0; 95% CI: 1.0-4.2; p=0.057), and nearly four times the risk of having a neurological complication (RR 3.8; 95% CI 1.5-9.5; p=0.005). CONCLUSION: This study analyzes readmission, reoperation and complication rates for the surgical care of SCT highlighting how SCT surgery is still involved with morbidity in experienced and specialized centers. This information is useful both for health care enhancement projects and for evidence-based patient counseling. PMID- 28089197 TI - Long-term follow-up analysis of microsurgical clip ligation and endovascular coil embolization for dorsal wall blister aneurysms of the internal carotid artery. AB - : Blister aneurysms at non-branching sites of the dorsal internal carotid artery (dICA) are fragile, rare, and often difficult to treat. The purpose of this study is to address the demographics, treatment modalities, and long-term outcome of patients treated for dICA blister aneurysms. A retrospective review of medical records identified all consecutive patients who presented with a blister aneurysm from 2002 to 2011 at our institution. Eighteen patients (M=7, F=11; mean age: 48.4+/-15.1years; range: 15-65years) harbored a total of 43 aneurysms, 25 of which were dorsal wall blister aneurysms of the ICA. Eleven (61.1%) patients presented with aneurysmal subarachnoid hemorrhage (aSAH), and 10 (55.6%) patients had multiple aneurysms at admission. Twelve patients had 18 aneurysms that were treated microsurgically. Five (41.7%) of these patients had a single recurrence that was retreated with subsequent repeat clip ligation. Six patients had 7 blister aneurysms that were treated with endovascularly. One (16.7%) of these patients had a single recurrence that was retreated with subsequent coil embolization. Postoperative vasospasm occurred in 8 (44.4%) patients, one of whom suffered from a stroke. This is one of the largest single-institution dICA blister aneurysm studies to date. There was no detected significant difference between microsurgical clip ligation and endovascular coil embolization in terms of surgical outcome. These blister aneurysms demonstrate a propensity to be associated with multiple cerebral aneurysms. Strict clinical and angiographic long-term follow-up may be warranted. STATEMENT OF SIGNIFICANCE: Blister aneurysms are focal wall defects covered by a thin layer of fibrous tissue and adventitia, lacking the usual collagenous layer. Due to their pathologically thin vessel wall, blister aneurysms are prone to rupture. The management of these rare and fragile aneurysms presents a number of challenges. Here, we address the long term outcome of patients treated for blister aneurysms at non-branching sites of the dICA. The presented data and analysis is imperative to determine the necessary strict long-term clinical and angiographic follow-up. PMID- 28089198 TI - Point-of-Care Detection Devices for Food Safety Monitoring: Proactive Disease Prevention. AB - Food safety has become an increasingly significant public concern in both developed and under-developed nations around the world; it increases morbidity, mortality, human suffering, and economic burden. This Opinion focuses on (i) examining the influence of pathogens and chemicals (e.g., food additives and pesticide residue) on food-borne illnesses, (ii) summarizing food hazards that are present in Asia, and (iii) summarizing the array of current point-of-care (POC) detection devices that have potential applications in food safety monitoring. In addition, we provide insight into global healthcare issues in both developing and under-developed nations with a focus on bridging the gap between food safety issues in the public sector (associated with relevant clinical cases) and the use of POC detection devices for food safety monitoring. PMID- 28089199 TI - Bioelectronic Nose: An Emerging Tool for Odor Standardization. AB - Odors are perceived differently as a function of individual human experience, and communicating about odors between individuals is therefore very difficult. There is a need to classify and standardize odors, but appropriate tools have not yet been developed. A bioelectronic nose mimics human olfaction and detects target molecules with high sensitivity and selectivity. This new tool has great potential in many applications and is expected to accelerate odor classification and standardization. In particular, a multiplexed bioelectronic nose can provide complex odor information using pattern recognition techniques, and could even reproduce odors via an integrated olfactory display system. We expect that a bioelectronic nose will be a useful tool for odor standardization by providing codes for odors that enable us to communicate odor information. PMID- 28089200 TI - Limitations of the Current Standards of Care for Treating Gout and Crystal Deposition in the Primary Care Setting: A Review. AB - PURPOSE: This article outlines several important issues regarding the management of patients with gout. The topics discussed include best practices for gout based on the most current guidelines, opportunities for improving gout management, and current and emerging therapies for gout. METHODS: [PubMed and Google Scholar databases] were search for all articles and trials published before 2016, using the key terms [hyperuricemia, gout, tophi, joint erosion, joint damage, treatment guidelines, American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), flare, comorbidity, epidemiology, adherence, serum uric acid (sUA), monosodium urate (MSU), <6 mg/dL, MSU crystal formation, as well as individual drug names and classes of treatments of interest (allopurinol, febuxostat, colchicine, non-steroidal anti-inflammatories (NSAIDs)]. Studies were selected that presented data on gout treatment, including drugs under development, and on the management of gout from both the physician and patient perspectives. The reference lists of identified articles were searched manually for additional publications. FINDINGS: Gout, a progressive debilitating form of inflammatory arthritis, is caused by factors that elevate serum uric acid (sUA) levels, leading to hyperuricemia. Continued elevated sUA can result in monosodium urate crystal deposition in joints and soft tissues, causing acute and chronic inflammation. Crystal deposition can lead to chronic gout, with an increased number of flares, tophi development, and structural joint damage. The aims of gout treatment are to reduce the sUA level to <6 mg/dL, to inhibit the formation of new crystals, and to promote the dissolution of existing crystals. Gout is often poorly managed for several reasons, including a lack of adherence to treatment guidelines by health care providers, patients' poor adherence to therapy, and differences between a provider's and patient's perspectives regarding treatment. IMPLICATIONS: Patients need to be educated about their diagnosis and management of the disease, such as the importance of compliance with long-term treatment. Gout treatment may also confounded by contraindications to current standards of therapy and the limitations of current treatment paradigms. Recently approved medications, as well as drugs under development, may provide new ways for reaching the sUA target and also "curing" the disease. PMID- 28089201 TI - Recent Advances in Melanoma and Melanocyte Biology. PMID- 28089202 TI - Cryoballoon ablation versus radiofrequency ablation for atrial fibrillation. AB - Catheter ablation (CA) provides the most effective treatment option for patients suffering from symptomatic atrial fibrillation (AF). The procedural cornerstone of all ablation strategies and for all entities of AF is the electrical isolation of the pulmonary veins (PV). CA with the use of radiofrequency (RF) in conjunction with a 3-dimensional electroanatomical mapping system is the most established ablation approach, but it demands a long learning curve and recurrences of AF are commonly the result of recovered PV conduction. As a consequence, novel ablation systems such as the Cryoballoon (CB) have been evolved aiming at facilitation and increased efficacy of pulmonary vein isolation (PVI). CB ablation is characterized by a short learning curve as well as short procedure times and demonstrated non-inferiority with regard to safety and efficacy when being directly compared to RF ablation for treatment of paroxysmal AF. However, RF ablation is first choice for treatment of persistent AF, in particular when expanded ablation strategies beyond PVI are intended in order to improve clinical outcomes. PMID- 28089203 TI - Carbon footprint and energy use of food waste management options for fresh fruit and vegetables from supermarkets. AB - Food waste is a problem with economic, environmental and social implications, making it both important and complex. Previous studies have addressed food waste management options at the less prioritised end of the waste hierarchy, but information on more prioritised levels is also needed when selecting the best available waste management options. Investigating the global warming potential and primary energy use of different waste management options offers a limited perspective, but is still important for validating impacts from the waste hierarchy in a local context. This study compared the effect on greenhouse gas emissions and primary energy use of different food waste management scenarios in the city of Vaxjo, Sweden. A life cycle assessment was performed for four waste management scenarios (incineration, anaerobic digestion, conversion and donation), using five food products (bananas, tomatoes, apples, oranges and sweet peppers) from the fresh fruit and vegetables department in two supermarkets as examples when treated as individual waste streams. For all five waste streams, the established waste hierarchy was a useful tool for prioritising the various options, since the re-use options (conversion and donation) reduced the greenhouse gas emissions and the primary energy use to a significantly higher degree than the energy recovery options (incineration and anaerobic digestion). The substitution of other products and services had a major impact on the results in all scenarios. Re-use scenarios where food was replaced therefore had much higher potential to reduce environmental impact than the energy recovery scenarios where fossil fuel was replaced. This is due to the high level of resources needed to produce food compared with production of fossil fuels, but also to fresh fruit and vegetables having a high water content, making them inefficient as energy carriers. Waste valorisation measures should therefore focus on directing each type of food to the waste management system that can substitute the most resource-demanding products or services, even when the whole waste flow cannot be treated with the same method. PMID- 28089204 TI - Effect of low aeration rate on simultaneous nitrification and denitrification in an intermittent aeration aged refuse bioreactor treating leachate. AB - Three intermittent aeration aged refuse bioreactors (ARBs), A, B, and C, with aeration rates of 670, 1340, and 2010L/m3 aged refuse.d in stage 1, and 670, 503, and 335L/m3 aged refuse.d in stage 2 were constructed to evaluate the effect of low aeration rate on leachate treatment by simultaneous nitrification and denitrification (SND). Results show that SND can be achieved and improved by reasonably adjusting the aeration rate of the ARB. In stage 1, the average chemical oxygen demand (COD) removal rates of ARBs A, B, and C were 91%, 92%, and 93%, respectively. The ammonia nitrogen (NH4+-N) removal rate of the three ARBs approached 100%. The total nitrogen (TN) average removal rates were 68%, 59%, and 57%. The average SND efficiency values were 73%, 66%, and 65%. In stage 2, the COD removal rates of ARBs A, B, and C decreased from the original values of 85%, 92%, and 93% to 84%, 81%, and 80%. The NH4+-N removal rate decreased from above 99% to 90%-92% in ARB B and from above 99% to 87%-91% in ARB C. The TN removal rates of ARBs B and C increased to 59% and 53% on day 15 from the initial values of 49% and 43% and were maintained at 49%-61% and 50%-60%. The SND efficiency of ARBs B and C improved, and the average values were 68% and 70% after day 15. These values were higher than the 66% of ARB A during the same period. Comprehensively considering the COD, NH4+-N, TN removal rate, and SND efficiency, the optimal aeration rate of 670L/m3 aged refuse.d is therefore suggested in this study. PMID- 28089205 TI - On the power profiles of contact lenses measured with NIMO TR1504. PMID- 28089206 TI - [Detecting unknown geriatric problems in the elderly of Nuevo Leon]. PMID- 28089207 TI - Delivery dilemmas: How drug cryptomarket users identify and seek to reduce their risk of detection by law enforcement. AB - BACKGROUND: Cryptomarkets represent an important drug market innovation by bringing buyers and sellers of illegal drugs together in a 'hidden' yet public online marketplace. We ask: How do cryptomarket drug sellers and buyers perceive the risks of detection and arrest, and attempt to limit them? METHODS: We analyse selected texts produced by vendors operating on the first major drug cryptomarket, Silk Road (N=600) alongside data extracted from the marketplace discussion forum that include buyer perspectives. We apply Fader's (2016) framework for understanding how drug dealers operating 'offline' attempt to reduce the risk of detection and arrest: visibility reduction, charge reduction and risk distribution. RESULTS: We characterize drug transactions on cryptomarkets as 'stretched' across time, virtual and physical space, and handlers, changing the location and nature of risks faced by cryptomarket users. The key locations of risk of detection and arrest by law enforcement were found in 'offline' activities of cryptomarket vendors (packaging and delivery drop offs) and buyers (receiving deliveries). Strategies in response involved either creating or disrupting routine activities in line with a non-offending identity. Use of encrypted communication was seen as 'good practice' but often not employed. 'Drop shipping' allowed some Silk Road vendors to sell illegal drugs without the necessity of handling them. CONCLUSION: Silk Road participants neither viewed themselves as immune to, nor passively accepting of, the risk of detection and arrest. Rational choice theorists have viewed offending decisions as constrained by limited access to relevant information. Cryptomarkets as 'illicit capital' sharing communities provide expanded and low-cost access to information enabling drug market participants to make more accurate assessments of the risk of apprehension. The abundance of drug market intelligence available to those on both sides of the law may function to speed up innovation in illegal drug markets, as well as necessitate and facilitate the development of law enforcement responses. PMID- 28089208 TI - The reconstructive options for oropharyngeal defects in the transoral robotic surgery framework. AB - Transoral robotic surgery (TORS) is a fascinating new technique that has been proved to be a safe and feasible for selected oropharyngeal cancers. Furthermore, TORS offers several advantages in the treatment of locoregionally advanced cancers. Nevertheless, the careful selection of patients is the keypoint for a successful application of this therapeutic modality. However, the reconstruction of large oropharyngeal defects is challenging due to the restoration of velopharyngeal competency and swallowing. Moreover, the absence of mandibular splitting increases the difficulties faced by reconstructive surgeons. The paradigm for oropharyngeal reconstruction has undergone changes reflecting the overall change in the trend of the treatment alternatives over the last few decades. The flap choice and harvesting should be tailored in order to obtain significant advantages both in terms of function and should be easy to inset. In this review, we analysed the strengths and weaknesses of the various flaps used in the TORS framework. PMID- 28089209 TI - Assessment of seasonal variations in persistent organic pollutants across the region of Tuscany using passive air samplers. AB - Concentrations of persistent organic pollutants (POPs) were measured for an entire year in the region of Tuscany, Italy. Passive air samplers consisting of polyurethane foam (PUF) disks were deployed over four sampling periods of 3-5 months from April 2008 to July 2009 in urban (n = 6) and rural (n = 4) sites. The aim of the study was to characterize the spatial and seasonal variations in selected POPs. The POP concentrations (pg m-3) in the air were dominated by dichlorodiphenyltrichloroethane and metabolites (DDTs) and polychlorinated biphenyls (?7PCBs). DDTs, and ?7PCBs showed a clear decreasing urban > rural gradient. The concentrations of DDTs and PCBs were up to 10 and 6 times higher, respectively, in urban sites than in rural sites. ?7PCBs showed a significant correlation with the urbanized areas located <5 km around the sampling sites. For hexachlorocyclohexanes (HCHs), alpha-HCH concentrations were similar at both sampling sites and were found to be quite uniform during the four sampling periods. Seasonal fluctuations were observed for DDTs, and ?7PCBs, with the highest concentrations observed during period 4 (summer-spring); this is most likely due to a temperature-driven re-emission from local sources. These findings were also supported by an air back trajectory analysis in the study area. This study contributes new information about POP levels in the Italian atmosphere and demonstrates the feasibility of using PUF disks to simultaneously assess seasonal concentrations at different sampling sites. PMID- 28089210 TI - PM10 and PM2.5 chemical source profiles with optical attenuation and health risk indicators of paved and unpaved road dust in Bhopal, India. AB - Size classified (PM10 and PM2.5) paved and unpaved road dust chemical source profiles, optical attenuation and potential health risk from exposure to these sources are reported in this study. A total of 45 samples from 9 paved road and 6 unpaved road sites located in and around Bhopal were re-suspended in the laboratory, collected onto filter substrates and subjected to a variety of chemical analyses. In general, road dust was enriched (compared to upper continental crustal abundance) in anthropogenic pollutants including Sb, Cu, Zn, Co, and Pb. Organic and elemental carbon (OC/EC) in PM10 and PM2.5 size fractions were 50-75% higher in paved road dust compared to their counterparts in unpaved road dust. Further, the results suggest that when it is not possible to include carbon fractions in source profiles, the inclusion of optical attenuation is likely to enhance the source resolution of receptor models. Additionally, profiles obtained in this study were not very similar to the US EPA SPECIATE composite profiles for PM10 and PM2.5, for both sources. Specifically, the mass fractions of Si, Fe, OC, and EC were most different between SPECIATE composite profiles and Bhopal composite profiles. An estimate of health indicators for Bhopal road dust revealed that although Cr was only marginally enriched, its inhalation may pose a health risk. The estimates of potential lifetime incremental cancer risk induced by the inhalation of Cr in paved and unpaved road dust (PM10 and PM2.5) for both adults and children were higher than the baseline values of acceptable risk. These results suggest that road dust Cr induced carcinogenic risk should be further investigated. PMID- 28089211 TI - Toxicity effects of an environmental realistic herbicide mixture on the seagrass Zostera noltei. AB - Worldwide seagrass declines have been observed due to multiple stressors. One of them is the mixture of pesticides used in intensive agriculture and boat antifouling paints in coastal areas. Effects of mixture toxicity are complex and poorly understood. However, consideration of mixture toxicity is more realistic and ecologically relevant for environmental risk assessment (ERA). The first aim of this study was to determine short-term effects of realistic herbicide mixture exposure on physiological endpoints of Zostera noltei. The second aim was to assess the environmental risks of this mixture, by comparing the results to previously published data. Z. noltei was exposed to a mixture of four herbicides: atrazine, diuron, irgarol and S-metolachlor, simulating the composition of typical cocktail of contaminants in the Arcachon bay (Atlantic coast, France). Three stress biomarkers were measured: enzymatic activity of glutathione reductase, effective quantum yield (EQY) and photosynthetic pigment composition after 6, 24 and 96 h. Short term exposure to realistic herbicide mixtures affected EQY, with almost 100% inhibition for the two highest concentrations, and photosynthetic pigments. Effect on pigment composition was detected after 6 h with a no observed effect concentration (NOEC) of 1 MUg/L total mixture concentration. The lowest EQY effect concentration at 10% (EC10) (2 MUg/L) and pigment composition NOEC with an assessment factor of 10 were above the maximal field concentrations along the French Atlantic coast, suggesting that there are no potential short term adverse effects of this particular mixture on Z. noltei. However, chronic effects on photosynthesis may lead to reduced energy reserves, which could thus lead to effects at whole plant and population level. Understanding the consequences of chemical mixtures could help to improve ERA and enhance management strategies to prevent further declines of seagrass meadows worldwide. PMID- 28089212 TI - Does particulate matter along roadsides interfere with plant reproduction? A comparison of effects of different road types on Cichorium intybus pollen deposition and germination. AB - The roadside habitat can be challenging for plants, which must maintain normal biological processes despite an influx of airborne pollutants. While the effects of many gases on plants have been quantified, the impacts of particulate pollutants have been relatively less studied. This is especially true of field experiments where particle dispersion may be influenced by meteorology and roadway use. We examined chicory (Cichorium intybus L.) along roadsides in the Cincinnati, Ohio metropolitan area to assess particulate influence on plant pollination through stigmatic clogging. We compared flowers collected from plants situated along interstates, U.S. highways, state highways, and county roads as these different road-types vary in motor vehicle usage and thus should have varying levels of particulate deposition on flowers. We examined floral stigmas for total particulates, total pollen, and percentage of pollen tube germination to determine whether particulates may interfere with early reproductive processes. Our results suggest that there was minimal variation of particulate matter found on chicory stigmas among road-types. Furthermore, the deposition of particulates on stigmas based on road-type did not show a strong link to variation in pollen deposition and pollen germination. There was also no significant relationship between total particulate levels and pollen germination rates across all road types. Future studies should investigate other plant species that may be more sensitive to roadside pollution, such as economically important crops. Locations in which vehicle use is increasing and where pollutants are not regulated strictly should also be examined as the effects of airborne particulates in early plant reproduction would be expected to be more substantial in these areas. PMID- 28089213 TI - A genome-wide profiling of brain DNA hydroxymethylation in Alzheimer's disease. AB - INTRODUCTION: DNA methylation is a key epigenetic mechanism in brain aging and Alzheimer's disease (AD). The newly discovered 5-hydroxymethylcytosine mediates DNA demethylation, is highly abundant in the brain, and is dynamically regulated by life experiences. However, little is known about its genome-wide patterns and potential role in AD. METHODS: Using a genome-wide capture followed by high throughput sequencing, we studied the genome-wide distribution of 5 hydroxymethylcytosine at specific genomic loci in human AD brain and identified differentially hydroxymethylated regions (DhMRs) associated with AD pathology. RESULTS: We identified 517 DhMRs significantly associated with neuritic plaques and 60 DhMRs associated with neurofibrillary tangles. DNA hydroxymethylation in gene bodies was predominantly positively correlated with cis-acting gene expression. Moreover, genes showing differential hydroxymethylation were significantly enriched in neurobiological processes and clustered in functional gene ontology categories. DISCUSSION: Our results reveal a critical role of DNA hydroxymethylation in AD pathology and provide mechanistic insight into the molecular mechanisms underlying AD. PMID- 28089215 TI - Radiation-induced liver disease secondary to adjuvant therapy for extra-hepatic cholangiocarcinoma. PMID- 28089214 TI - Prevalence of chronic pancreatitis: Results of a primary care physician-based population study. AB - BACKGROUND: Data on chronic pancreatitis prevalence are scanty and usually limited to hospital-based studies. AIM: Investigating chronic pancreatitis prevalence in primary care. METHODS: Participating primary care physicians reported the prevalence of chronic pancreatitis among their registered patients, environmental factors and disease characteristics. The data were centrally reviewed and chronic pancreatitis cases defined according to M-ANNHEIM criteria for diagnosis and severity and TIGAR-O classification for etiology. RESULTS: Twenty-three primary care physicians participated in the study. According to their judgment, 51 of 36.401 patients had chronic pancreatitis. After reviewing each patient data, 11 turned out to have definite, 5 probable, 19 borderline and 16 uncertain disease. Prevalence was 30.2/100.000 for definite cases and 44.0/100.000 for definite plus probable cases. Of the 16 patients with definite/probable diagnosis, 8 were male, with mean age of 55.6 (+/-16.7). Four patients had alcoholic etiology, 5 post-acute/recurrent pancreatitis, 6 were deemed to be idiopathic. Four had pancreatic exocrine insufficiency, 10 were receiving pancreatic enzymes, and six had pain. Most patients had initial stage and non-severe disease. CONCLUSIONS: This is the first study investigating the prevalence of chronic pancreatitis in primary care. Results suggest that the prevalence in this context is higher than in hospital-based studies, with specific features, possibly representing an earlier disease stage. PMID- 28089216 TI - Diabetes is Associated with Severe Adverse Events in Multidrug-Resistant Tuberculosis. AB - INTRODUCTION: Diabetes mellitus (DM), a very common disease in Mexico, is a well known risk factor for tuberculosis (TB). However, it is not known by which extent DM predisposes to adverse events (AE) to anti-TB drugs and/or to worse outcomes in patients with multidrug-resistant (MDR-TB) and extensively drug-resistant TB (XDR-TB). The main objective of this study was to describe the outcomes of TB treatment, the impact of DM and the prevalence of AE in a cohort of patients with MDR-/XDR pulmonary TB treated at the national TB referral centre in Mexico City. RESULTS: Ninety patients were enrolled between 2010 and 2015: 73 with MDR-TB (81.1%), 11 with pre-XDR-TB (12.2%) and 6 (6.7%) with XDR-TB, including 49 (54.4%) with DM, and 3 with Human Immunodeficiency Virus (HIV) co-infection (3.3%). In 98% of patients, diagnosis was made by culture and drug susceptibility testing, while in a single case the diagnosis was made by a molecular test. The presence of DM was associated with an increased risk of serious drug-related AEs, such as nephrotoxicity (Odds Ratio [OR]=6.5; 95% Confidence Interval [95% CI]: 1.9-21.8) and hypothyroidism (OR=8.8; 95% CI: 1.8-54.2), but not for a worse outcome. CONCLUSIONS: Our data suggest that DM does not impact second-line TB treatment outcomes, but patients with DM have a higher risk of developing serious AEs to drug-resistant TB treatment, such as nephrotoxicity and hypothyroidism. PMID- 28089217 TI - The impact of inadequate health literacy on patient satisfaction, healthcare utilization, and expenditures among older adults. AB - Inadequate health literacy (HL) is associated with impaired healthcare choices leading to poor quality-of-care. Our primary purpose was to estimate the prevalence of inadequate HL among two populations of AARP(r) Medicare Supplement insureds: sicker and healthier populations; to identify characteristics of inadequate HL; and to describe the impact on patient satisfaction, preventive services, healthcare utilization, and expenditures. Surveys were mailed to insureds in 10 states. Multivariate regression models were used to identify characteristics and adjust outcomes. Among respondents (N = 7334), 23% and 16% of sicker and healthier insureds, respectively, indicated inadequate HL. Characteristics of inadequate HL included male gender, older age, more comorbidities, and lower education. Inadequate HL was associated with lower patient satisfaction, lower preventive service compliance, higher healthcare utilization and expenditures. Inadequate HL is more common among older adults in poorer health, further compromising their health outcomes; thus they may benefit from expanded educational or additional care coordination interventions. PMID- 28089218 TI - NKG2D Signaling: The Immune Subversive Side of HDAC3. AB - Natural killer (NK) cells are alerted to infected and transformed cells by local upregulation of ligands for the NK-activating receptor NKG2D. In a recent report, Greene et al. unveil a new mechanism that induces the expression of the NKG2D ligand retinoic acid early-inducible (RAE-1) in response to murine cytomegalovirus (MCMV) infection through inhibition of casein kinase 2 (CK2), an activator of the repressor histone deacetylase HDAC3. PMID- 28089219 TI - Prognostic factors of epiretinal membranes: A systematic review. AB - INTRODUCTION: Epiretinal membranes (ERM) have been increasingly characterized with the advent of new optical coherence tomographies (OCTs). We intended to perform a systematic review regarding prognostic factors (PF) of ERM after surgery. MATERIALS AND METHODS: Systematic review of electronic databases was performed (last date of search was 10 August 2015): Medline, Scopus, Google Scholar, clinicaltrials.gov and current controlled trials. Search queries included: "membrane", "pucker", "prognosis", "prognostic", "epiretinal", "epiretinienne". Inclusion criteria were: (1) primary purpose was to identify a PF of ERM; (2) prospective or retrospective study, case series (more than 10 patients), or clinical trials; (3) follow-up of at least 3 months; (4) complete ophthalmological evaluation in each patient with visual acuity and OCT, preoperative and>=3months after surgery; (5) vitrectomy with ERM peeling performed in each patient. Eligibility criteria verification, data extraction and evaluation of risk of bias were performed according to Cochrane's recommendations. RESULTS: From 817 studies found, 21 were included (9 prospective, 12 retrospective, 0 trials). In all studies, there was significant visual acuity improvement after surgery. The majority of the studies included pars plana vitrectomy (PPV) combined with phacoemulsification. DISCUSSION AND CONCLUSION: PF for visual acuity (VA) improvement after ERM surgery included: shorter duration of symptoms before surgery, lesser central foveal thickness at baseline identified by the OCT, good integrity of the inter segment/outer segment photoreceptor junction at baseline, and thinner ganglion cell inner plexiform layer at baseline. To avoid bias, studies should analyze VA separately if phacoemulsification is also performed. The knowledge of these PF may assist in planning surgery. PMID- 28089220 TI - [Paracentral acute middle maculopathy: Case report]. PMID- 28089221 TI - [Sickle cell retinopathy]. PMID- 28089222 TI - [Etiology and prognosis of the eye traumas by war weapons in the Senegalese army]. AB - INTRODUCTION: The aim of this work is to identify the main weapons causing eye injuries during the campaigns of the Senegalese army in the south of the country, as well as the prognosis of these traumas. PATIENTS AND METHODS: This study is retrospective and concerns soldiers wounded by the weapons of war during the exercise of their mission within the Senegalese armed forces of 1991 in 2005. They are mainly soldiers affected in the south of the country during a war, clashes with the rebels or in Guinea-Bissau during operation Gabou in 1998. And they were evacuated to the ophthalmology department of the Principal Hospital in Dakar, which is a level 3. RESULTS: Thirty-seven military all male, with an average age of 30.5 years. Forty-six eyes including 9 bilateral cases. The trauma agent is a burst of RPG7 shells in 62% of cases, mine explosion in 13.5%, offensive grenade 10.8%, assault rifle 5.7% and flame lance-roquette anti-char (LRAC) accounts for 8%. We noted a phthisis of the globe for 14 eyes (30.43%) and for 15 eyes (32.60%) a functional loss of the affected globe. Inability to fight was decided by 29 wounded soldiers (78.37% of the cases), sedentary employment in 27 cases (72.97%) and 10 cases (27.03%) of reformed soldiers. DISCUSSION: In the conflict in southern Senegal, the RPG7 shell burst causes 62% of eye injuries. This RPG7 shell called "rebel weapon" is frequently used in conflicts in Africa. The prognosis of trauma with these types of weapons is severe. CONCLUSIONS: The combat goggles systematically integrated in the equipment of the Senegalese combatant, would be an invaluable contribution on the prevention of the traumatisms of the eye. PMID- 28089223 TI - [Spectral-Domain Optical Coherence Tomography appearance of a papillomacular retinal fold in a case of posterior microphthalmos]. PMID- 28089225 TI - [Effectiveness of an individualised physiotherapy program versus group therapy on neck pain and disability in patients with acute and subacute mechanical neck pain]. AB - OBJECTIVE: To compare the efficacy in reducing neck pain and disability in an individualised physiotherapy treatment with group treatment in acute and subacute mechanical neck pain. DESIGN: Randomised clinical trial. LOCATION: Health Area of University Hospital Virgen del Rocio, Seville, Spain. PARTICIPANTS: A total of 90 patients diagnosed with mechanical neck pain of up to one month onset, distributed randomly into two groups: (i)individualised treatment; (ii)group treatment. INTERVENTION: The treatment consisted of 15 sessions of about 60minutes for both groups. Individual treatment consisted of 15minutes of infrared heat therapy, 17minutes of massage, and analytical passive stretching of the trapezius muscles and angle of the scapula. The group treatment consisted of a program of active mobilisation, isometric contractions, self-stretching, and postural recommendations. MAIN MEASURES: Pain was measured at the beginning and end of treatment pain using a Visual Analogue Scale (VAS) and an algometer applied on the trapezius muscles and angle of the scapula, and neck disability using the Neck Disability Index. RESULTS: Both treatments were statistically significant (P<.001) in improving all variables. Statistically significant differences (P<.001) were found for all of them in favour of individualised treatment compared to group treatment. CONCLUSIONS: Patients with acute or subacute mechanical neck pain experienced an improvement in pain and neck disability after receiving either of the physiotherapy treatments used in our study, with the individual treatment being more effective than collective. PMID- 28089226 TI - [Coping and subjective burden in primary caregivers of dependent elderly relatives in Andalusia, Spain]. AB - PURPOSE: To analyse the relationship between the type of coping and subjective burden in caregivers of dependent elderly relatives in Andalusia (Spain). DESIGN: Cross-sectional study. LOCATION: Primary Health Care (autonomous community of Andalusia, Spain). PARTICIPANTS: A convenience sample of 198 primary caregivers of dependent elderly relatives. KEY MEASUREMENTS: Coping (Brief COPE), subjective burden (caregiver stress index), objective burden (functional capacity [Barthel Index], cognitive impairment [Pfeiffer Test], behavioural problems of the care recipient [Neuropsychiatric Inventory], and caregivers' dedication to caring), gender and kinship. RESULTS: Most caregivers were women (89.4%), daughters of the care recipient (57.1%), and shared home with him/her (69.7%). On controlling for objective burden, gender and kinship, it was found that subjective burden was positively associated with dysfunctional coping (beta=0.28; P<.001) and negatively with emotion-focused coping (beta=-0.25; P=.001), while no association was found with problem-focused coping. CONCLUSIONS: Dysfunctional coping may be a risk factor for subjective burden, and emotion-focused coping may be a protective factor for that subjective burden regardless of the objective burden, and gender and kinship of the caregivers. PMID- 28089224 TI - Loading of the medial meniscus in the ACL deficient knee: A multibody computational study. AB - The menisci of the knee reduce tibiofemoral contact pressures and aid in knee lubrication and nourishment. Meniscal injury occurs in half of knees sustaining anterior cruciate ligament injury and the vast majority of tears in the medial meniscus transpire in the posterior horn region. In this study, computational multibody models of the knee were derived from medical images and passive leg motion for two female subjects. The models were validated against experimental measures available in the literature and then used to evaluate medial meniscus contact force and internal hoop tension. The models predicted that the loss of anterior cruciate ligament (ACL) constraint increased contact and hoop forces in the medial menisci by a factor of 4 when a 100N anterior tibial force was applied. Contact forces were concentrated in the posterior horn and hoop forces were also greater in this region. No differences were found in contact or hoop tension between the intact and ACL deficient (ACLd) knees when only a 5Nm external tibial torque was applied about the long axis of the tibia. Combining a 100N anterior tibial force and a 5Nm external tibial torque increased posterior horn contact and hoop forces, even in the intact knee. The results of this study show that the posterior horn region of the medial meniscus experiences higher contact forces and hoop tension, making this region more susceptible to injury, especially with the loss of anterior tibia motion constraint provided by the ACL. The contribution of the dMCL in constraining posterior medial meniscus motion, at the cost of higher posterior horn hoop tension, is also demonstrated. PMID- 28089227 TI - [Towards a multimorbidity care model in Primary Care]. PMID- 28089228 TI - Intraplantar injection of sialidase reduces mechanical allodynia during inflammatory pain. AB - Sialic acids are highly charged glycoresidues that are attached to glycoproteins or glycosphingolipids, and they are associated with various biological functions. Gangliosides, sialic acid-containing glycosphingolipids, are abundant in neural tissues and play important roles in the nervous system. Previous studies revealed that peripheral gangliosides are involved in nociceptive behavior and hyperalgesia. These observations prompted us to determine whether the sialic acid cleaving enzyme sialidase affects pain signaling. Intraplantar injection of sialidase reduced mechanical allodynia during complete Freund's adjuvant-induced inflammation. We also found that ganglioside induces mechanical allodynia in naive mice. These results suggest that sialyl conjugates in subcutaneous tissues modify allodynia. PMID- 28089229 TI - Immune checkpoint inhibition in malignant mesothelioma: Does it have a future? PMID- 28089230 TI - Metastatic fractures of long limb bones. AB - The diagnosis of pathological fracture should be considered routinely in patients with long limb-bone fractures. Investigations must be performed to establish the diagnosis of pathological fracture then to determine that the bone lesion is a metastasis. In over 85% of cases, the clinical evaluation combined with a detailed analysis of the radiographs is sufficient to determine that the fracture occurred at a tumour site. Aetiological investigations establish that the tumour is a metastasis. In some patients, the diagnosis of metastatic cancer antedates the fracture. When this is not the case, a diagnostic strategy should be devised, with first- to third-line investigations. When these fail to provide the definitive diagnosis, a surgical biopsy should be performed. The primaries most often responsible for metastatic bone disease are those of the breast, lung, kidney, prostate, and thyroid gland. However, the survival gains provided by newly introduced treatments translate into an increased frequency of bone metastases from other cancers. The optimal treatment of a pathological fracture is preventive. The Mirels score is helpful for determining whether preventive measures are indicated. When selecting a treatment for a pathological fracture, important considerations are the type of tumour, availability of effective adjuvant treatments, and general health of the patient. Metastatic fractures are best managed by a multidisciplinary team. The emergent treatment should start with optimisation of the patient's general condition, in particular by identifying and treating metabolic disorders (e.g., hypercalcaemia) and haematological disorders. Treatment decisions also depend on the above-listed general factors, location of the tumour, and size of the bony defect. Prosthetic reconstruction is preferred for epiphyseal fractures and internal fixation for diaphyseal fractures. PMID- 28089231 TI - [Mother-to-child transmission of hepatitis B virus despite postexposure prophylaxis: A review of the literature and description of 11 observations]. AB - Chronic hepatitis B virus (HBV) infection leads to a risk of developing cirrhosis and hepatocellular carcinoma. In France, where the prevalence of HBV is low, mother-to-child transmission is the cause of chronic infection in more than one third of cases. After exposure, the risk of chronic infection is the highest for newborns (90 %). The World Health Organization implemented a global immunization program in 1991, applied in France in 1994. A significant number of children are infected each year, however, and failure of postexposure prophylaxis is reported in 4-10 % of newborns. We report 11 children with chronic HBV infection due to failure of serovaccination, followed up in two centers between 1993 and 2015. We discuss maternal screening, serovaccination, and follow-up conditions, as well as the role of maternal viral load, amniocentesis, and mode of delivery as risk factors. These observations confirm that serovaccination failures are related to the nonobservance of recommendations for maternal screening or postexposure prophylaxis, and to a high maternal viral load (>106 copies/mL). We therefore recommend improving the screening strategy, with control of the hepatitis B antigen in early pregnancy, and discussion of treatment with a nucleoside analog during the last trimester of pregnancy. Serovaccination should be enforced. Its efficacy should be controlled when the child reaches 9 months of age, in order to organize the follow-up if infection occurs. PMID- 28089233 TI - Epicardial adipose tissue and myocardial ischemia assessed by computed tomography perfusion imaging and invasive fractional flow reserve. AB - BACKGROUND: Epicardial adipose tissue (EAT) is a metabolically active fat depot that is associated with incident coronary artery disease (CAD) and major adverse cardiovascular events. The relationship between EAT and myocardial ischemia remains unclear. This study investigated the relationship between EAT volume and the presence of perfusion defects on myocardial computed tomographic perfusion imaging (CTP) and functional stenoses on invasive fractional flow-reserve (FFR). METHODS: Data were obtained from a previous prospective cross-sectional study in patients with suspected CAD. Patients underwent combined coronary computed tomography angiography (coronary CTA) and CTP followed by invasive coronary angiogram (ICA) and FFR within 14 days. FFR was performed in all major epicardial vessels unless they were angiographically smooth or occluded, with a threshold of <0.8 considered significant. EAT volume was quantified semi-automatically on coronary CTA. RESULTS: There were 38 patients included for analysis, mean age 62.5 +/- 10.0 years, 68.4% male. Median EAT volume was 82.8 mL (interquartile range (IQR) 49.3 mL). FFR was interrogated in 73/114 (64%) vessels. There was no difference in EAT volumes in patients with and without CTP defects (84.4 mL, IQR: 35.6 mL vs 81.1 mL, IQR: 53.1 mL, p = 0.7). There was also no difference in EAT volumes in patients with and without FFR-significant vessels (86.5 mL IQR: 36.6 mL vs 79.1 mL IQR: 54.5 mL, p = 0.7) and no difference when analysed by number of CTP positive territories or FFR-significant vessels (p = 0.4 and p = 0.8 respectively). CONCLUSION: This study demonstrated no observable relationship between EAT volume and perfusion defects on myocardial CT perfusion imaging or functional stenosis on invasive FFR. PMID- 28089236 TI - Letter to the Editor of Tanner, Philbin, Duval, Ellen, Kapogiannis, and Fortenberry (2016). PMID- 28089235 TI - Targeting Cutaneous Cannabinoid Signaling in Inflammation - A "High"-way to Heal? PMID- 28089237 TI - CLL: when the target of treatment is disease-related symptoms. PMID- 28089239 TI - Comparison of direct and optical laryngoscopy during simulated cardiopulmonary resuscitation. PMID- 28089238 TI - Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial. AB - BACKGROUND: Disease-related symptoms impair the quality of life of patients with chronic lymphocytic leukaemia (CLL) who do not require systemic therapy. Available therapies are not specifically aimed at symptom control. Because stimulation of the B-cell receptor activates JAK2 in CLL cells and the JAK2 inhibitor ruxolitinib improves symptoms in patients with myelofibrosis, we postulated that ruxolitinib would improve disease-related symptoms in patients with CLL. We did a phase 2 trial of ruxolitinib to test this hypothesis. METHODS: Symptomatic patients with CLL who did not require systemic therapy were enrolled at MD Anderson Cancer Center (Houston, TX, USA) between Sept 15, 2014, and Sept 20, 2015. Participants were given 10 mg ruxolitinib orally twice a day. Scores on the Brief Fatigue Inventory (BFI), CLL module of the MD Anderson Symptom Inventory (MDASI) and symptom-associated interference in daily activities, were assessed before treatment and after 3 months. This trial is ongoing and is registered at ClinicalTrials.gov (NCT02131584). FINDINGS: 41 patients (25 previously untreated for CLL and 16 previously treated) were enrolled. At 3 months, the mean percentage change from baseline in BFI score was 44.3% (SD 35.0, p<0.0001), in symptom interference score was 43.4% (51.5, p<0.0001), and in MDASI score was 42.1% (37.4, p<0.0001). 32 (78%) of the patients experienced 20% or greater reduction in the mean BFI, and 24 (59%) had a reduction of two units or more in worst fatigue score in past 24 hours as assessed by the BFI. The most comment grade 3-4 adverse events were neutropenia (n=2 [5%]), hypertension (n=2 [5%]), insomnia (n=1 [2%]), tinnitus and dizziness (n=1 [2%]), and thrombocytopenia (n=1 [2%]). INTERPRETATION: In patients with CLL, ruxolitinib was associated with significant improvements in disease-related symptoms as measured by BFI, MDASI, and symptom interference scores. Further studies to test the therapeutic efficacy of ruxolitinib in CLL are warranted. FUNDING: Incyte, National Cancer Institute. PMID- 28089240 TI - Comparison of PaO2 and PaCO2 in arterial blood gas analysis between EcoLiteTM and conventional medium concentration face mask. PMID- 28089241 TI - Dynamic T-wave inversions in the setting of left bundle branch block. AB - We illustrate the case a patient with left bundle branch block (LBBB) and electrocardiogram (ECG) changes consistent with those described in Wellens' syndrome. The characteristic ECG findings of Wellens' syndrome identify patients who have a particularly high rate of important coronary events in the near future, however these findings have previously been described only in the setting of normal conduction. A review of Wellens' syndrome, its criteria and pathophysiology, and its proposed appearance in the setting of LBBB is presented. PMID- 28089242 TI - The impact of working as a medical scribe. PMID- 28089243 TI - The relation between GAD1 and PTSD symptoms: Shared risk for depressive symptoms. PMID- 28089244 TI - Synchronous Ipsilateral High Submuscular Placement of Prosthetic Balloons and Reservoirs. AB - INTRODUCTION: Synchronous ipsilateral high submuscular placement of artificial urinary sphincter (AUS) pressure-regulating balloons (PRBs) and inflatable penile prosthesis (IPP) reservoirs in a single submuscular tunnel is a novel strategy that could be advantageous for patients who have had major pelvic surgery. AIM: To report our initial experience with synchronous ipsilateral vs bilateral placement of AUS PRBs and IPP reservoirs in men undergoing implant surgery. METHODS: We retrospectively reviewed all patients undergoing synchronous AUS and IPP placement from 2007 through 2015 by a single surgeon at our tertiary center. Patients were stratified according to ipsilateral vs bilateral placement of the AUS PRB and IPP reservoir. MAIN OUTCOME MEASURES: Reoperation rates because of infectious or erosive complications and mechanical failure were assessed. RESULTS: Of the 968 implant surgeries during the study period, 47 men had synchronous device placement, of whom 17 (36%) underwent ipsilateral placement of the PRB and reservoir. During a median follow-up of 19 months (range = 1-84 months), reoperations were necessary in 12 of 47 (26%) and were similar between groups (ipsilateral, 5 of 17, 29%; bilateral, 7 of 30, 23%; P = .73). Most reoperations were due to AUS-related complications (10 of 12, 83%) and nearly all patients with reoperation (10 of 12, 83%) had compromised urethras (ie, prior urethral surgery, radiation, or prior AUS implantation). The most common indication for reintervention was cuff erosion (4 of 47, 9%), with no difference between groups (ipsilateral, 3 of 17, 18%; bilateral, 1 of 30, 3%; P = .13). CONCLUSION: Synchronous ipsilateral high submuscular placement of urologic prosthetic balloons could safely facilitate prosthetic surgery in patients with a history of major pelvic and inguinal surgery. PMID- 28089245 TI - Diagnostic accuracy of postmortem imaging vs autopsy-A systematic review. AB - Background Postmortem imaging has been used for more than a century as a complement to medico-legal autopsies. The technique has also emerged as a possible alternative to compensate for the continuous decline in the number of clinical autopsies. To evaluate the diagnostic accuracy of postmortem imaging for various types of findings, we performed this systematic literature review. Data sources The literature search was performed in the databases PubMed, Embase and Cochrane Library through January 7, 2015. Relevant publications were assessed for risk of bias using the QUADAS tool and were classified as low, moderate or high risk of bias according to pre-defined criteria. Autopsy and/or histopathology were used as reference standard. Findings The search generated 2600 abstracts, of which 340 were assessed as possibly relevant and read in full-text. After further evaluation 71 studies were finally included, of which 49 were assessed as having high risk of bias and 22 as moderate risk of bias. Due to considerable heterogeneity - in populations, techniques, analyses and reporting - of included studies it was impossible to combine data to get a summary estimate of the diagnostic accuracy of the various findings. Individual studies indicate, however, that imaging techniques might be useful for determining organ weights, and that the techniques seem superior to autopsy for detecting gas Conclusions and Implications In general, based on the current scientific literature, it was not possible to determine the diagnostic accuracy of postmortem imaging and its usefulness in conjunction with, or as an alternative to autopsy. To correctly determine the usefulness of postmortem imaging, future studies need improved planning, improved methodological quality and larger materials, preferentially obtained from multi-center studies. PMID- 28089246 TI - Identification and characterization of L-lysine decarboxylase from Huperzia serrata and its role in the metabolic pathway of lycopodium alkaloid. AB - Lysine decarboxylation is the first biosynthetic step of Huperzine A (HupA). Six cDNAs encoding lysine decarboxylases (LDCs) were cloned from Huperzia serrata by degenerate PCR and rapid amplification of cDNA ends (RACE). One HsLDC isoform was functionally characterized as lysine decarboxylase. The HsLDC exhibited greatest catalytic efficiency (kcat/Km, 2.11 s-1 mM-1) toward L-lysine in vitro among all reported plant-LDCs. Moreover, transient expression of the HsLDC in tobacco leaves specifically increased cadaverine content from zero to 0.75 mg per gram of dry mass. Additionally, a convenient and reliable method used to detect the two catalytic products was developed. With the novel method, the enzymatic products of HsLDC and HsCAO, namely cadaverine and 5-aminopentanal, respectively, were detected simultaneously both in assay with purified enzymes and in transgenic tobacco leaves. This work not only provides direct evidence of the first two-step in biosynthetic pathway of HupA in Huperzia serrata and paves the way for further elucidation of the pathway, but also enables engineering heterologous production of HupA. PMID- 28089247 TI - [Mid gut neuroendocrine tumors: News on medical treatment]. AB - CONTEXT: Mid gut neuroendocrine tumors (NET) are rare tumors whose incidence is increasing. Curative surgery remains the gold standard for the treatment of NETs of the small intestine. Surgery should be considered as soon as possible even if a metastatic stage is diagnosed. The management of unresectable well differentiated metastatic NETs of the small intestine recently changed with the publication of trials demonstrating the benefit of targeted therapies and metabolic radiotherapy, leading to a change of practices and update of French and international recommendations. OBJECTIVE: The objective of this review is to present the recent data consisting of three phase III studies, which modify the management of well-differentiated metastatic midgut NETs and make an inventory of the available treatment options. DOCUMENTARY SOURCES: The documentary sources used were gathered through the PubMed website using keyword searching (neurendocrine tumor, mid gut, treatment). We also referred to recommendations of the European Society of neuroendocrine tumors (ENETS) trials presented at ESMO Congress 2015 (European Society for Medical Oncology). STUDY SELECTION: We excluded studies of exclusive extra-digestive NETs, poorly differentiated NETs, surgical treatments and phase I studies. RESULTS: We discussed three randomized phase III trials: CLARINET, RADIANT and NETTER studies. These studies demonstrated the efficacy of respectively somatostatin analogues, mTOR inhibitors and metabolic radiotherapy. CONCLUSION: This review highlights the validation by randomized studies of an mTOR inhibitor and metabolic radiotherapy in metastatic non-pancreatic digestive NETs unresectable well-differentiated grade of G1/2 in progression under somatostatin analogues. PMID- 28089248 TI - Triggering receptor expressed on myeloid cells-1 (TREM-1) deficiency augments BAFF production to promote lupus progression. AB - Sensing of nucleic acids by pattern recognition receptors is the key for the initiation and development of systemic lupus erythematosus (SLE). Triggering receptor expressed on myeloid cells-1 (TREM-1) is a novel innate immune receptor, which can amplify Toll-like receptor (TLR)-induced inflammatory responses. Although patients with lupus exhibit increased serum levels of soluble TREM-1 (sTREM-1), the role of TREM-1 in SLE remains unknown. In current study, we found serum sTREM-1 levels were significantly increased in lupus patients and positively correlated with disease activity. Additionally, diseased B6.lpr mice had elevated TREM-1 in the serum, spleen, and lymph nodes. To investigate the role of TREM-1 in lupus, we established Trem-1-/-.lpr mice. Trem-1-/-.lpr mice exhibited lower survival rates and more severe lupus symptoms, including elevated proteinuria, serum anti-dsDNA antibody levels, renal immune complex depositions and lymphocyte subpopulation expansions in both the spleen and lymph nodes. Besides, Trem-1-/-.lpr mice expressed higher serum B cell-activating factor (BAFF) levels and lymph node dendritic cells (DCs) were the major source of increased BAFF. Activation of membrane-bound TREM-1 could suppress TLR9-induced BAFF expression in bone marrow-derived DCs of B6.lpr mice. Moreover, levels of sTREM-1, which could act as an antagonist of membrane-bound TREM-1, were positively correlated with levels of BAFF in the sera of lupus patients. Our findings suggest a novel modulatory role of TREM-1 in the pathogenesis of SLE. sTREM-1 production is a useful diagnostic marker and a molecular target for combination therapy of lupus. PMID- 28089249 TI - Redundant and fault-tolerant algorithms for real-time measurement and control systems for weapon equipment. AB - Because of the high availability requirements from weapon equipment, an in-depth study has been conducted on the real-time fault-tolerance of the widely applied Compact PCI (CPCI) bus measurement and control system. A redundancy design method that uses heartbeat detection to connect the primary and alternate devices has been developed. To address the low successful execution rate and relatively large waste of time slices in the primary version of the task software, an improved algorithm for real-time fault-tolerant scheduling is proposed based on the Basic Checking available time Elimination idle time (BCE) algorithm, applying a single neuron self-adaptive proportion sum differential (PSD) controller. The experimental validation results indicate that this system has excellent redundancy and fault-tolerance, and the newly developed method can effectively improve the system availability. PMID- 28089250 TI - Pathology of behavior in PD: What is known and what is not? AB - Abnormal behavior in Parkinson's disease (PD) stems from a complex orchestration of impaired neural networks that result from PD-related neurodegeneration across multiple levels. Typically, cellular and tissue abnormalities generate neurochemical changes and disrupt specific regions of the brain, in turn creating impaired neural circuits and dysfunctional global networks. The objective of this chapter is to provide an overview of the array of pathological changes that have been linked to different behavioral symptoms of PD such as depression, anxiety, apathy, fatigue, impulse control disorders, psychosis, sleep disorders and dementia. PMID- 28089251 TI - Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis. AB - Nephronophthisis (NPH), an autosomal-recessive tubulointerstitial nephritis, is the most common cause of hereditary end-stage renal disease in the first three decades of life. Since most NPH gene products (NPHP) function at the primary cilium, NPH is classified as a ciliopathy. We identified mutations in a candidate gene in eight individuals from five families presenting late-onset NPH with massive renal fibrosis. This gene encodes MAPKBP1, a poorly characterized scaffolding protein for JNK signaling. Immunofluorescence analyses showed that MAPKBP1 is not present at the primary cilium and that fibroblasts from affected individuals did not display ciliogenesis defects, indicating that MAPKBP1 may represent a new family of NPHP not involved in cilia-associated functions. Instead, MAPKBP1 is recruited to mitotic spindle poles (MSPs) during the early phases of mitosis where it colocalizes with its paralog WDR62, which plays a key role at MSP. Detected mutations compromise recruitment of MAPKBP1 to the MSP and/or its interaction with JNK2 or WDR62. Additionally, we show increased DNA damage response signaling in fibroblasts from affected individuals and upon knockdown of Mapkbp1 in murine cell lines, a phenotype previously associated with NPH. In conclusion, we identified mutations in MAPKBP1 as a genetic cause of juvenile or late-onset and cilia-independent NPH. PMID- 28089254 TI - Volumetric Analysis of Carotid Plaque Components and Cerebral Microbleeds: A Correlative Study. AB - PURPOSE: The purpose of this work was to explore the association between carotid plaque volume (total and the subcomponents) and cerebral microbleeds (CMBs). MATERIALS AND METHODS: Seventy-two consecutive (male 53; median age 64) patients were retrospectively analyzed. Carotid arteries were studied by using a 16 detector-row computed tomography scanner whereas brain was explored with a 1.5 Tesla system. CMBs were studied using a T2*-weighted gradient-recalled echo sequence. CMBs were classified as from absent (grade 1) to severe (grade 4). Component types of the carotid plaque were defined according to the following Hounsfield unit (HU) ranges: lipid less than 60 HU; fibrous tissue from 60 to 130 HU; calcification greater than 130 HU, and plaque volumes of each component were calculated. Each carotid artery was analyzed by 2 observers. RESULTS: The prevalence of CMBs was 35.3%. A statistically significant difference was observed between symptomatic (40%) and asymptomatic (11%) patients (P value = .001; OR = 6.07). Linear regression analysis demonstrated an association between the number of CMBs and the symptoms (P = .0018). Receiver operating characteristics curve analysis found an association between the carotid plaque subcomponents and CMBs (Az = .608, .621, and .615 for calcified, lipid, and mixed components, respectively), and Mann-Whitney test confirmed this association in particular for the lipid components (P value = .0267). CONCLUSIONS: Results of this study confirm the association between CMBs and symptoms and that there is an increased number of CMBs in symptomatic patients. Moreover, we found that an increased volume of the fatty component is associated with the presence and number of CMBs. PMID- 28089253 TI - Progressive Bilateral Vertebral Artery Dissection in a Case of Osteogenesis Imperfecta. AB - A 32-year-old woman with osteogenesis imperfecta (OI) was admitted to the hospital because of a right-sided occipital headache and facial paresthesia. She was diagnosed with lateral medullary syndrome due to right vertebral artery (VA) dissection. She was treated conservatively without antithrombotic therapy. She developed subarachnoid hemorrhage because of contralateral VA dissection 18 days later. This clinical course may reflect the underlying weakness of the vessel wall in OI. In patients with OI, occlusion of a unilateral VA could cause dissection and subsequent rupture of the contralateral VA. Early surgical treatment for lesions of the VA is required in such cases. PMID- 28089252 TI - Practical Approaches for Whole-Genome Sequence Analysis of Heart- and Blood Related Traits. AB - Whole-genome sequencing (WGS) allows for a comprehensive view of the sequence of the human genome. We present and apply integrated methodologic steps for interrogating WGS data to characterize the genetic architecture of 10 heart- and blood-related traits in a sample of 1,860 African Americans. In order to evaluate the contribution of regulatory and non-protein coding regions of the genome, we conducted aggregate tests of rare variation across the entire genomic landscape using a sliding window, complemented by an annotation-based assessment of the genome using predefined regulatory elements and within the first intron of all genes. These tests were performed treating all variants equally as well as with individual variants weighted by a measure of predicted functional consequence. Significant findings were assessed in 1,705 individuals of European ancestry. After these steps, we identified and replicated components of the genomic landscape significantly associated with heart- and blood-related traits. For two traits, lipoprotein(a) levels and neutrophil count, aggregate tests of low frequency and rare variation were significantly associated across multiple motifs. For a third trait, cardiac troponin T, investigation of regulatory domains identified a locus on chromosome 9. These practical approaches for WGS analysis led to the identification of informative genomic regions and also showed that defined non-coding regions, such as first introns of genes and regulatory domains, are associated with important risk factor phenotypes. This study illustrates the tractable nature of WGS data and outlines an approach for characterizing the genetic architecture of complex traits. PMID- 28089255 TI - Characterization of the Walch B3 glenoid in primary osteoarthritis. AB - BACKGROUND: The type B3 glenoid is an addition to the Walch classification. A potential etiologic theory is that it is a progression of the B2. It is characterized by uniconcavity, absent paleoglenoid, medialization, retroversion, and subluxation. The purpose of this study was to describe the morphology of B3 glenoids. METHODS: Fifty-two patients with B3 glenoids underwent 3-dimensional analysis of computed tomography data. Glenoid measurements (retroversion, inclination, medialization) and humeral head subluxation according to the scapular and glenoid planes were determined. The measured variables were compared between male and female patients. RESULTS: The mean B3 retroversion, inclination, and medialization were 24 degrees +/- 7 degrees , 8 degrees +/- 6 degrees superior, and 14 +/- 4 mm, respectively. The mean posterior subluxation was 80% +/- 8% and 54% +/- 6% according to the scapular and glenoid planes, respectively. There were no differences in B3 characteristics between sexes (P > .05). A significant correlation existed between glenoid retroversion and humeral head subluxation relative to the scapular plane, with every 1 degrees increase in retroversion translating to a 1% increase in subluxation (P < .001). In contrast, when referencing the glenoid plane, the humeral head remained concentric to the erosion. CONCLUSIONS: The B3 is uniconcave and retroverted. As glenoid retroversion increases, posterior humeral head subluxation significantly increases as referenced to the scapular plane; however, when referenced to the glenoid plane, the head remains concentric to the erosion. This appearance of "concentricity" is acquired secondary to the wear pattern, creating a uniconcave glenoid. Therefore, surgeons should be aware that the visualized concentricity is a product of the erosion pattern and thus may conceal a greater amount of subluxation potential. PMID- 28089256 TI - A comparative analysis of work-related outcomes after humeral hemiarthroplasty and reverse total shoulder arthroplasty. AB - BACKGROUND: The return to work of young patients undergoing shoulder arthroplasty is increasingly important. Whereas studies have shown superior outcomes of reverse total shoulder arthroplasty (RTSA) compared with humeral hemiarthroplasty (HHA), no prior literature has compared RTSA with HHA in regard to return to work. METHODS: A retrospective review of a prospectively collected shoulder arthroplasty registry was performed to analyze all patients who underwent RTSA or HHA at a single institution. A validated questionnaire evaluating return to work postoperatively was administered at baseline and at follow-up in addition to the American Shoulder and Elbow Surgeons and visual analog scale (VAS) pain surveys. RESULTS: The study included 40 RTSA and 41 HHA patients. The average age at surgery was 68.6 years in the RTSA group and 60.8 years in the HHA group (P < .001). Postoperatively, 65% of RTSA patients returned to work compared with 70.7% of HHA patients (P = .64). There was no significant difference in the time to return to work between the RTSA (2.3 months) and HHA (3.1 months) groups (P = .46). Both groups had statistically significant improvements in both the American Shoulder and Elbow Surgeons and VAS scores. The improvement in pain on the VAS for patients undergoing RTSA (-5.6) trended toward significance compared with HHA (-4.2) (P = .056). CONCLUSION: Roughly two-thirds of patients undergoing either HHA or RTSA were able to return to work postoperatively, with no significant difference found between the 2 groups in terms of time to return to work, despite that patients undergoing RTSA were significantly older. PMID- 28089257 TI - The natural course of nonoperatively treated rotator cuff tears: an 8.8-year follow-up of tear anatomy and clinical outcome in 49 patients. AB - BACKGROUND: The natural course of nonoperatively treated rotator cuff tears is not fully understood. We explored the long-term development of tear anatomy and assessed functional outcomes. METHODS: Eighty-nine small to medium-sized full thickness tears of the rotator cuff, all primarily treated by physiotherapy, were identified retrospectively. Twenty-three tears needed surgical treatment later on, and 17 patients were unable to meet for follow-up. The remaining 49 still unrepaired tears were re-examined after 8.8 (8.2-11.0) years with sonography. Re examination by magnetic resonance imaging was possible for 37 patients. Shoulder function was assessed with shoulder scores. Primary outcome measures were progression of tear size, muscle atrophy, and fatty degeneration and the Constant score (CS). RESULTS: Mean tear size increased by 8.3 mm in the anterior-posterior plane (P = .001) and by 4.5 mm in the medial-lateral plane (P = .001). Increase of tear size was -5 to +9.9 mm in 33 patients, 10 to 19.9 mm in 8 patients, and >=20 mm in 8 patients. The CS was 81 points for tear increases <20 mm and 58.5 points for increases >=20 mm (P = .008). Muscle atrophy and fatty degeneration progressed in 18 and 15 of the 37 patients, respectively. In tears with no progression of atrophy, the CS was 82 points compared with 75.5 points in tears with progression (P = .04). CONCLUSIONS: Anatomic tear deterioration was found in the majority of patients, but it was often moderate. Large tear size increases and progression of muscle atrophy were correlated to a poorer functional outcome. PMID- 28089258 TI - The effect of scapular position on subacromial contact behavior: a cadaver study. AB - BACKGROUND: Patients with subacromial impingement were reported to show abnormal scapular positions during shoulder elevation. However, the relationship between the scapular positions and subacromial impingement is unclear. The purpose of this study was to biomechanically determine the effect of scapular position on subacromial contact behavior by using fresh frozen cadavers. METHODS: The peak contact pressure on the coracoacromial arch was measured with a flexible tactile force sensor in 9 fresh frozen cadaver shoulders. The measurement was performed during passive glenohumeral elevation in the scapular plane ranging from 30 degrees to 75 degrees . The scapular downward and internal rotations and anterior tilt were simulated by tilting the scapula in 5 degrees increments up to 20 degrees . The measurement was also performed with combination of scapular downward and internal rotations and anterior tilt positions. RESULTS: The peak contact pressure decreased linearly with anterior tilt, and a significant difference between neutral scapular position (1.06 +/- 0.89 MPa) and anterior tilt by 20 degrees (0.46 +/- 0.18 MPa) was observed (P < .05). However, the scapular positioning in the other directions did not change the peak contact pressure significantly. Furthermore, any combination of abnormal scapular positions did not affect peak contact pressure significantly. CONCLUSION: Scapular anterior tilt decreased peak contact pressure during passive shoulder elevation. In addition, scapular downward and internal rotations had little effect on peak contact pressure. The abnormal scapular motion reported in previous studies might not be directly related to symptoms caused by subacromial impingement. PMID- 28089259 TI - Prosthetic replacement for coronoid deficiency: report of three cases. AB - BACKGROUND: Persistent elbow instability associated with coronoid deficiency is a difficult condition to treat. Several surgical techniques have been described for coronoid reconstruction, but the resulting outcomes have been unpredictable. We hypothesized that a coronoid prosthesis could restore elbow stability. METHODS: A nonanatomically shaped metallic coronoid prosthesis was custom designed for each of 3 patients. Each had a chronic fracture-subluxation with persistent instability, deficiencies of the coronoid, and compromise of the radial head. Each patient had undergone 2 to 4 prior failed operations. RESULTS: At a mean follow-up of 11 years (range, 10-12), 2 of the 3 patients were completely pain free; the third had a visual analog scale pain score not greater than 3/10. All 3 maintained a stable joint, although a functional range of motion was not able to be maintained in any. Two patients rated themselves "improved" and 1 patient rated himself "almost normal" on the Summary Outcome Determination scale. All radiographic follow-up showed the coronoid prosthesis in proper position without loosening. CONCLUSION: Prosthetic replacement of the coronoid appears successful in restoring stability in chronically unstable elbows with coronoid deficiency. PMID- 28089260 TI - Are degenerative rotator cuff disorders a cause of shoulder pain? Comparison of prevalence of degenerative rotator cuff disease to prevalence of nontraumatic shoulder pain through three systematic and critical reviews. AB - HYPOTHESIS AND BACKGROUND: The role of degeneration is not well understood for rotator cuff pain. If age-related degenerative changes would be the cause of symptoms, degeneration would precede or concur with self-reported pain. We performed 3 systematic literature reviews. Our objectives were to determine the prevalence estimates for rotator cuff partial or complete tears (1) in cadavers and (2) in the general population and (3) to estimate the incidence/prevalence of self-reported nontraumatic shoulder pain in the general population in order to compare their respective age-related profiles. METHODS: We searched PubMed and ScienceDirect, including 2015, for cadaveric studies and transverse and longitudinal studies of the general population reporting the incidence/prevalence of rotator cuff disorders or nontraumatic shoulder pain, or both, according to age. The review process followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Results were interpreted visually. RESULTS: We found 6 cadaveric studies, 2 studies from the general population reporting complete tears, and 10 articles on nontraumatic shoulder pain in the general population that met our criteria. The profiles of degeneration vs. pain were very similar in early years. Although degenerative rotators cuff lesions increased gradually after 50 years, the incidence/prevalence of nontraumatic shoulder pain decreased after 65 years. CONCLUSION: The profile of age-related degenerative rotator cuff disorders fails to correlate systematically with self reported nontraumatic shoulder pain, particularly in older age; thus, it appears that degeneration should not be considered the primary source of the pain. Physical activity may play an important role in the production of the pain, a theory that warrants further study. PMID- 28089261 TI - Is previous nonarthroplasty surgery a risk factor for periprosthetic infection in primary shoulder arthroplasty? AB - BACKGROUND: The purpose of this study was to determine the risk of periprosthetic infection after primary shoulder arthroplasty (SA) in patients undergoing previous nonarthroplasty shoulder surgery compared with those without previous surgery. MATERIALS AND METHODS: All patients undergoing primary SA at our institution between 1970 and 2012 were included in this study. The cohort consisted of 4577 patients treated with 2890 total SAs, 1233 hemiarthroplasties, and 454 reverse SAs; 813 (18%) patients had undergone prior nonarthroplasty shoulder surgery on the operative side. Patients with and without previous surgery were compared for postoperative periprosthetic infection. Univariate and multivariable analyses were used. RESULTS: Deep postoperative infection of the shoulder was diagnosed in 68 patients (1.49%). Of the 813 patients who had undergone previous surgery, 20 (2.46%) developed a deep postoperative infection. However, of the 3764 patients who did not have previous shoulder surgery, 48 patients (1.28%) sustained deep shoulder infection. This difference was significant in both the univariate (P = .0094) and multivariate analyses (P = .0390). In addition, older age and female gender were significantly associated with a lower risk of deep postoperative infection (P = .0150 and P = .0074, respectively). A higher number of previous surgeries was also significantly associated with an increased risk of deep postoperative infection (P = .0272). CONCLUSIONS: The risk of infection after primary SA is significantly higher in patients with a history of prior non-arthroplasty-related surgery. This finding should be discussed with the patients before their surgery, and potential preoperative and intraoperative workup should be undertaken to identify at-risk patients. PMID- 28089263 TI - Adiponectin, orexin A and orexin B concentrations in the serum and uterine luminal fluid during early pregnancy of pigs. AB - Adiponectin is the most abundant adipose-released protein that circulates in human plasma at high concentrations. The neuropeptides orexin A (OXA, hypocretin 1) and orexin B (OXB, hypocretin-2) are derived from a common precursor peptide, prepro-orexin and are produced mainly by neurons located in the lateral hypothalamus. It has been demonstrated that the peptides such as adiponectin and orexins have an important role in the regulation of energy metabolism and neuroendocrine functions. These hormones appear to be implicated in both normal and disturbed pregnancy. The objectives of this study were to determine adiponectin and orexin concentrations in the plasma and uterine luminal fluid (ULF) of pigs during early gestation and to explore the relationships between hormone concentrations and stages of pregnancy. The greatest plasma concentrations of adiponectin were observed on days 15-16 and 27-28 of pregnancy, and the least concentrations were on days 30-32 of gestation and on days 10-11 of the oestrous cycle. In ULF, adiponectin concentrations were greater on days 15-16 of pregnancy and on days 10-11 of the oestrous cycle than on days 10-11 and days 12-13 of pregnancy. The greatest OXA concentrations in the blood plasma were noted on days 10-16 of gestation, and the least OXA concentrations were on days 27-32 of pregnancy and on days 10-11 of the oestrous cycle. Orexin A concentrations in ULF were greater on days 10-11 of the cycle than throughout pregnancy. Serum OXB concentrations were greatest on days 10-11 and 30-32 of pregnancy, and least on days 12-28 of gestation. The greatest OXB concentrations in ULF were on days 10-13 of gestation, and the least OXB concentrations were on days 15-16 of pregnancy. This is first study to demonstrate the presence of adiponectin and orexins in the serum and ULF during early pregnancy of pigs as well as the relationships between adiponectin and orexin concentrations and the stage of pregnancy. The fluctuations in adiponectin and orexin concentrations in the plasma and ULF suggest that the hormones present in ULF are mostly of local origin and that these hormones participate in the processes that accompany early pregnancy. PMID- 28089264 TI - Development and validation of the deep brain stimulation impairment scale (DBS IS). AB - BACKGROUND: Bilateral deep brain stimulation of the subthalamic nucleus (STN-DBS) has considerable influence on motor and non-motor symptoms in Parkinson's disease (PD). While improvements in motor functioning can be easily assessed with general quality of life questionnaires, the measurement of specific STN-DBS-associated impairments often remains insufficient. Hence, we aimed to develop a questionnaire that measures STN-DBS-related impairments. METHODS: The development of the (STN-)DBS Impairment Scale (DBS-IS) consisted of four steps. First, 30 semi-structured interviews before, three and twelve months after STN-DBS-surgery were performed to create 76 items that relate to motor and non-motor functioning in STN-DBS PD patients. Second, pilot-testing led to a rewording of the questions for better understanding. Third, a first multicentre survey was performed to reduce items by applying principal component analysis (PCA). Fourth, a second multicentre survey was conducted to examine factor structure, reliability (internal consistency) and validity. RESULTS: After the first survey (N = 215), the PCA lead to a reduction of 54 items. After the second survey (N = 391), exploratory factor analysis determined six factors with 22 items: 1. Postural instability and gait difficulties (5 items), 2. Cognitive impairment (5 items), 3. Speaking problems (3 items), 4. Apathy (3 items), 5. Impulsivity (3 items), and 6. Difficulties related to the DBS device (3 items). High reliability was reported for all subscales (Cronbach's alpha 0.71-0.90). Similarly, construct validity was high (r > 0.50, p < 0.001). CONCLUSIONS: With this new questionnaire patients can be followed-up and STN-DBS-specific problems might be adequately measured. Also, comparisons between patients with and without STN-DBS might be possible. PMID- 28089265 TI - Gender differences in Parkinson's disease depression. AB - INTRODUCTION: 30-40% of patients with Parkinson's disease (PD) experience depression during their illness; identifying subtypes of depression and groups at risk remains a challenge in routine clinical care. One avenue that remains underexplored is the gender-specific profiles manifested in PD depression. We sought to explore this in a large sample of clinical PD patients. METHODS: 307 patient records at a tertiary referral centre were reviewed for clinical and demographic factors. We used recursive partitioning to determine which items on the Beck Depression Inventory (BDI) were most useful in differentiating patients who scored in the depressed range (>=14) from those who scored in the non depressed range (<=13). We also used recursive partitioning to identify those BDI items that were most effective in differentiating depressed from non-depressed patients in both genders. RESULTS: We were able to identify a subset of items on the BDI that were most useful in partitioning depressed from non-depressed in the entire cohort. Partitioning of men and women with PD depression relied on different key BDI items, melancholy featuring prominently in women, while the more classical factors associated with depression in PD (apathy and loss of libido) featured more prominently in men. CONCLUSION: Unique factors not previously identified as core features of depression in PD were found most useful in partitioning depressed women from non-depressed women. This raises the possibility that a female-specific depressive profile has been under-appreciated in past work. Additional studies are required to discern how this may impact future research, diagnosis and treatment. PMID- 28089266 TI - TRPC1, Orai1, and STIM1 in SOCE: Friends in tight spaces. AB - Store-operated calcium entry (SOCE) is a ubiquitous Ca2+ entry pathway that is activated in response to depletion of ER-Ca2+ stores and critically controls the regulation of physiological functions in miscellaneous cell types. The transient receptor potential canonical 1 (TRPC1) is the first member of the TRPC channel subfamily to be identified as a molecular component of SOCE. While TRPC1 has been shown to contribute to SOCE and regulate various functions in many cells, none of the reported TRPC1-mediated currents resembled ICRAC, the highly Ca2+-selective store-dependent current first identified in lymphocytes and mast cells. Almost a decade after the cloning of TRPC1 two proteins were identified as the primary components of the CRAC channel. The first, STIM1, is an ER-Ca2+ sensor protein involved in activating SOCE. The second, Orai1 is the pore-forming component of the CRAC channel. Co-expression of STIM1 and Orai1 generated robust ICRAC. Importantly, STIM1 was shown to also activate TRPC1 via its C-terminal polybasic domain, which is distinct from its Orai1-activating domain, SOAR. In addition, TRPC1 function critically depends on Orai1-mediated Ca2+ entry which triggers recruitment of TRPC1 into the plasma membrane where it is then activated by STIM1. TRPC1 and Orai1 form discrete STIM1-gated channels that generate distinct Ca2+ signals and regulate specific cellular functions. Surface expression of TRPC1 can be modulated by trafficking of the channel to and from the plasma membrane, resulting in changes to the phenotype of TRPC1-mediated current and [Ca2+]i signals. Thus, TRPC1 is activated downstream of Orai1 and modifies the initial [Ca2+]i signal generated by Orai1 following store depletion. This review will summarize the important findings that underlie the current concepts for activation and regulation of TRPC1, as well as its impact on cell function. PMID- 28089268 TI - Analysis of radioxenon and Krypton-85 at the BfS noble gas laboratory. AB - Proportional counters and a beta-gamma coincidence system and their performance characteristics are described, with emphasis on internal and external quality controls. Typical limits of detection (LD) are 8mBqm-3 for 85Kr and 4mBqm-3 for 133Xe for the proportional counters, while for similar xenon volumes the LD for 133Xe in the beta-gamma system is approximately 4 times lower. Results of comparative analyses agree above the limit of quantification. Xenon-133 levels in southern Germany are presently at or below the LD of the proportional counters, but above the LD of the beta-gamma system, which is now routinely used for analysis of environmental samples. PMID- 28089267 TI - Probes for monitoring regulated exocytosis. AB - Regulated secretion is a fundamental cellular process that serves diverse functions in neurobiology, endocrinology, immunology, and numerous other aspects of animal physiology. In response to environmental or biological cues, cells release contents of secretory granules into an extracellular medium to communicate with or impact neighboring or distant cells through paracrine or endocrine signaling. To investigate mechanisms governing stimulus-secretion coupling, to better understand how cells maintain or regulate their secretory activity, and to characterize secretion defects in human diseases, probes for tracking various exocytotic events at the cellular or sub-cellular level have been developed over the years. This review summarizes different strategies and recent progress in developing optical probes for monitoring regulated secretion in mammalian cells. PMID- 28089269 TI - Reference materials for neptunium determination. PMID- 28089270 TI - Coordinated underground measurements of gamma-ray emitting radionuclides for plasma physics research. AB - Forty-eight samples made of CaF2, LiF and YVO4 were placed inside the KSTAR Tokamak and irradiated by neutrons and charged particles from eight plasma pulses. The aim was to provide information for plasma diagnostics. Due to the short pulse durations, the activities induced in the samples were low and therefore measurements were performed in five low-background underground laboratories. Details of the underground measurements, together with data on the quality control amongst the radiometric laboratories, are presented. PMID- 28089271 TI - Seizure-European Journal of Epilepsy at age 25: Where are we now and where we are going? PMID- 28089272 TI - Retention behavior of isomeric polycyclic aromatic sulfur heterocycles in gas chromatography on stationary phases of different selectivity. AB - Retention indices for 48 polycyclic aromatic sulfur heterocycles (PASHs) were determined using gas chromatography with three different stationary phases: a 50% phenyl phase, a 50% liquid crystalline dimethylpolysiloxane (LC-DMPS) phase, and an ionic liquid (IL) phase. Correlations between the retention behavior on the three stationary phases and PASH geometry (L/B and T, i.e., length-to-breadth ratio and thickness, respectively) were investigated for the following four isomer sets: (1) 4 three-ring molecular mass (MM) 184Da PASHs, (2) 13 four-ring MM 234Da PASHs, (3) 10 five-ring MM 258Da PASHs, and (4) 20 five-ring MM 284Da PASHs. Correlation coefficients for retention on the 50% LC-DMPS vs L/B ranged from r=0.50 (MM 284Da) to r=0.77 (MM 234Da). Correlation coefficients for retention on the IL phase vs L/B ranged from r=0.31 (MM 234Da) to r=0.54 (MM 284Da). Correlation coefficients for retention on the 50% phenyl vs L/B ranged from r=0.14 (MM 258Da) to r=0.59 (MM 284Da). Several correlation trends are discussed in detail for the retention behavior of PASH on the three stationary phases. PMID- 28089273 TI - High performance liquid chromatography analysis of 100-nm liposomal nanoparticles using polymer-coated, silica monolithic columns with aqueous mobile phase. AB - Recently, nanoparticles have garnered considerable attention, and the demand for a rapid and simple method for their analysis has increased accordingly. The bimodal pores (few MUm- and few tens nm-sized pores) of monolithic columns were thought to be suitable for the separation of nanoparticles and small molecules; however, the residual silanol groups on the column surface resulted in the strong adsorption of liposomes and hindered their analysis. To overcome this problem, we modified the surface of the silica monolith via a two-step process and developed three silica monolithic columns coated with three different polymers: glycidyl methacrylate (GMA), 2-hydroxyethyl methacrylate (HEMA), and N-vinylpyrrolidone (VP). These were used for the analysis of 100-nm liposomal nanoparticles. Since 15% polymer coating prevented the nanoparticle adsorption, liposomes (AmBisome(r)) and pegylated liposomes (DOXIL(r)) were eluted rapidly (within 1min) using these columns, without using organic solvents in the mobile phase. Molecular leaching from the liposomes, as well as protein adsorption to the liposomes (corona formation) could be evaluated using the polymer-coated columns, thus illustrating their utility in the rapid and simple analysis of 100-nm liposomal nanoparticles. PMID- 28089274 TI - Retention behavior of alkyl-substituted polycyclic aromatic sulfur heterocycle isomers in gas chromatography on stationary phases of different selectivity. AB - Retention indices for 10 sets of alkyl-substituted polycyclic aromatic sulfur heterocycles (PASHs) isomers (total of 80 PASHs) were determined using gas chromatography with three different stationary phases: a 50% phenyl phase, a 50% liquid crystalline dimethylpolysiloxane (LC-DMPS) phase, and an ionic liquid (IL) phase. Correlations between the retention behavior on the three stationary phases and PASH geometry [length-to-breadth (L/B) and thickness (T)] were investigated for the following PASHs: 4 methyl-substituted dibenzothiophenes (DBTs), 3 ethyl substituted DBTs, 15 dimethyl-substituted DBTs, 8 trimethyl-substituted DBTs, 15 methyl-substituted naphthothiophenes, 30 methyl-substituted benzonaphthothiophenes, and 5 methyl-substituted tetrapheno[1,12-bcd]thiophene. Correlation coefficients for retention on the 50% phenyl phase vs L/B ranged from r=-0.28 (MeBbN23Ts) to r=0.92 (EtDBTs). Correlation coefficients for retention on the IL phase vs L/B ranged from r=0.13 (MeN12Ts) to r=0.83 (EtDBTs). Correlation coefficients for retention on the 50% LC-DMPS phase vs L/B ranged from r=0.22 (MeDBTs) to r=0.84 (TriMeDBTs). PMID- 28089275 TI - Microfluidic membrane suppressor module design and evaluation for capillary ion chromatography. AB - A microfluidic ion-suppression module for use in ion-exchange chromatography has been developed and evaluated. The device consists of an ion-exchange membrane clamped between two polymer chips featuring a 200*100MUm (width*depth) eluent channel (l=60mm), and a 300*150MUm regenerant channel (60mm), respectively. The suppression efficacy using a Nafion membrane was compared with that of a styrene sulfonate grafted fluorinated ethylene propylene (FEP) membrane. The latter was found to outperform Nafion in terms of lowest attainable background signal (suppression efficacy) and dynamic suppression range. Increasing the suppressor temperature or the sulfuric acid regenerant concentration led to an extension of the operational suppression range, this however at the cost of an increased background signal due to enhanced diffusion, inducing sulfate bleed. Under optimized operating conditions, the microfluidic suppressor provided a dynamic capacity of 0.35MUEq./min, being compatible with gradient separations applying up to 70mM KOH in combination with 400MUm i.d. capillary columns operated at the optimal flow velocity. The applicability of the miniaturized suppressor is demonstrated for both isocratic and gradient separations of mixtures of inorganic anions. Band-broadening characteristics of the suppressor were optimized with respect to a commercial capillary hollow-fiber suppressor, yielding comparable overall system efficiency, e.g., 8500 plates for nitrate recorded on a 150mm long capillary column. A second chip device was also constructed, featuring suppression at both sides of the eluent flow path. This double-sided suppressor allowed to increase sample throughput and operate at eluent flow rates of 10MUL/min, while maintaining efficient suppression characteristics. PMID- 28089276 TI - Simultaneous separation of neutral and cationic analytes by one dimensional open tubular capillary electrochromatography using zeolitic imidazolate framework-8 as stationary phase. AB - Developing simple methods for separation of analytes that belong to different classes is of great importance. Herein, we developed a simple one-dimensional (1 D) capillary electrochromatography method to demonstrate the simultaneous separation of target fractions that belong to two different classes (i.e., cationic and neutral analytes) without switching buffer solution by a zeolitic imidazolate framework ZIF-8 coated capillary column. Owing to the difference of charge-to-mass ratio of the cationic analytes, the interaction of the cationic analytes and coating material ZIF-8 and the hydrophobic interactions between the neutral analytes and the microporous framework of ZIF-8, six cationic analytes and four neutral analytes were simultaneously separated in a single run by 1-D capillary electrochromatography. The relative standard deviations (RSDs) of the analytes migration time for intra-day, inter-day and column-to-column were in the range of 0.11-0.87%, 0.54-2.04% and 2.00-6.89% and the RSDs of the analytes peak area for intra-day, inter-day and column-to-column were in the range of 0.70 4.45%, 1.33-6.20% and 2.27-11.88%. Additionally, the developed method was employed in the analysis of urine samples with satisfactory recoveries. PMID- 28089277 TI - Accurate determination of residual acrylic acid in superabsorbent polymer of hygiene products by headspace gas chromatography. AB - This work reports on a method for the determination of residual acrylic acid (AA) in the superabsorbent polymers for hygiene products by headspace analysis. It was based on water extraction for the polymer sample at a room temperature for 50min. Then, the AA in the extractant reacted with bicarbonate solution in a closed headspace sample vial, from which the carbon dioxide generated from the reaction (within 20min at 70 degrees C) was detected by gas chromatography (GC). It was found that there is adsorption partition equilibrium of AA between solid-liquid phases. Therefore, an equation for calculating the total AA content in the original polymers sample was derived based on the above phase equilibrium. The results show that the HS-GC method has good precision (RSD<2.51%) and good accuracy (recoveries from 93 to 105%); the limit of quantification (LOQ) was 373mg/kg. The present method is rapid, accurate, and suitable for determining total residual acrylic acid in a wide variety of applications from processing of superabsorbent polymer to commercial products quality control. PMID- 28089278 TI - Estimating uptake of phthalate ester metabolites into the human nail plate using pharmacokinetic modelling. AB - There is a lack of knowledge regarding uptake of phthalate esters (PEs) and other chemicals into the human nail plate and thus, clarity concerning the suitability of human nails as a valid alternative matrix for monitoring long-term exposure. In particular, the relative importance of internal uptake of phthalate metabolites (from e.g. blood) compared to external uptake pathways is unknown. This study provides first insights into the partitioning of phthalate-metabolites between blood and nail using pharmacokinetic (PK) modelling and biomonitoring data from a Norwegian cohort. A previously published PK model (Lorber PK model) was used in combination with measured urine data to predict serum concentrations of DEHP and DnBP/DiBP metabolites at steady state. Then, partitioning between blood and nail was assessed assuming equilibrium conditions and treating the nail plate as a tissue, assuming a fixed lipid and water content. Although calculated as a worst-case scenario at equilibrium, the predicted nail concentrations of metabolites were lower than the biomonitoring data by factors of 44 to 1300 depending on the metabolite. It is therefore concluded that internal uptake of phthalate metabolites from blood into nail is a negligible pathway and does not explain the observed nail concentrations. Instead, external uptake pathways are more likely to dominate, possibly through deposition of phthalates onto the skin/nail and subsequent metabolism. Modelling gaseous diffusive uptake of PEs from air to nail revealed that this pathway is unlikely to be important. Experimental quantification of internal and external uptake pathways of phthalates and their metabolites into the human nail plate is needed to verify these modelling results. However, based on this model, human nails are not a good indicator of internal human exposure for the phthalate esters studied. PMID- 28089279 TI - Perspective on pre- and post-natal agro-food exposure to persistent organic pollutants and their effects on quality of life. AB - BACKGROUND: Adipose tissue constitutes a continual source of internal exposure to organic pollutants (OPs). When fats mobilize during pregnancy and breastfeeding, OPs could affect foetal and neonatal development, respectively. SCOPE AND APPROACH: The main aim of this review is to deal with pre- and post-natal external exposure to organic pollutants and their effects on health, proposing prevention measures to reduce their risk. The goal is the development of a biomonitoring framework program to estimate their impact on human health, and prevent exposure by recommending some changes in personal lifestyle habits. KEY FINDINGS AND CONCLUSIONS: It has been shown that new studies should be developed taking into account their cumulative effect and the factors affecting their body burden. In conclusion, several programs should continuously be developed by different health agencies to have a better understanding of the effect of these substances and to develop a unified public policy. PMID- 28089280 TI - Financial hardship on the path to Universal Health Coverage in the Gulf States. AB - BACKGROUND: Countries globally are pursuing universal health coverage to ensure better healthcare for their populations and prevent households from catastrophic expenditure. The countries of the Gulf Cooperation Council (GCC) have and continue to implement reforms to strengthen their health systems. A common theme between the countries is their pursuit of universal health coverage to provide access to necessary health care without exposing people to financial hardship. METHODS: Using nationally representative data from the Global Findex study, we sought to analyze the hardship faced by individuals from four high-income countries in the GCC. We estimated the weighted proportion of individuals borrowing for medical reasons and those who are not able to obtain emergency funds. We further examined variations in these outcomes by key socioeconomic factors. RESULTS: We found up to 11% of respondents borrowed money for medical purposes, double of that reported in other high-income countries. In contrast to affluent respondents, we found that respondents from deprived background were more likely to borrow money for medical purposes (adjusted odds ratio: 1.81, P<0.001) and expected to fail in obtaining emergency funds (adjusted odds ratio: 4.03, P<0.001). CONCLUSION: In moving forward with their reforms, GCC countries should adopt a financing strategy that addresses the health needs of poorer groups in their pursuit of universal health coverage. PMID- 28089281 TI - Features of public healthcare services provided to migrant patients in the Eastern Macedonia and Thrace Region (Greece). AB - BACKGROUND: The influx of migrants, refugees and asylum-seekers into European Union (EU) countries, especially into Greece, in the last 20 years is an issue of growing concern and requires a rational approach. The aim of this study is to chart the use of public health services by the migrants of the Eastern Macedonia and Thrace Region, which forms the northeastern border of Greece. METHODS: We collected data from five of the six public hospitals in the specified region, and we carried out a per clinic cross tabulation analysis of admission diagnosis and citizenship variables in order to establish the frequency at which the various diagnoses emerge per distinct group of migrant and non-migrant patients in each clinic. The main limitation of the study was the lack of age-standardised data. An additional analysis of frequencies per clinic focusing on migrant patients yielded hospitalisation frequencies per country of origin. We also performed a t test to compare the average length of stay per clinic between the two groups. Finally, we utilised our available data to map the insurance status of migrant patients. RESULTS: The results have indicated that the hospitalisation rate of migrant patients due to chronic medical conditions is statistically significantly lower compared to non-migrant patients, while the opposite is true when looking at accident-related diagnoses, certain infectious diseases and medical conditions pertaining to depression and alcohol abuse. The comparisons of the average length of stay showed no overall differences between migrants and non-migrants. Only 2.04% of the migrant patients were uninsured. CONCLUSIONS: One of the key issues raised by the influx of migrants settling in host countries is concerned with health policy. The knowledge afforded by the medical parameters that characterise the provision of healthcare to them and the findings of relevant studies can lead to a more efficient identification of health risk factors and more effective prevention and treatment. This knowledge also constitutes a particularly crucial and useful tool to help authorities shape their healthcare policies and modify national health systems, which are currently based on the size and characteristics of indigenous populations, to take into account the different conditions with regard to both the number of patients treated and the epidemiological characteristics of the migrants. A greater appreciation of the particular current and potential roles of non-governmental organisations (NGOs) can help to provide appropriate healthcare services to migrants, refugees and asylum-seekers, especially when these groups are excluded from the public health system. PMID- 28089282 TI - The likely effects of employer-mandated complementary health insurance on health coverage in France. AB - In France, access to health care greatly depends on having a complementary health insurance coverage (CHI). Thus, the generalisation of CHI became a core factor in the national health strategy created by the government in 2013. The first measure has been to compulsorily extend employer-sponsored CHI to all private sector employees on January 1st, 2016 and improve its portability coverage for unemployed former employees for up to 12 months. Based on data from the 2012 Health, Health Care and Insurance survey, this article provides a simulation of the likely effects of this mandate on CHI coverage and related inequalities in the general population by age, health status, socio-economic characteristics and time and risk preferences. We show that the non-coverage rate that was estimated to be 5% in 2012 will drop to 4% following the generalisation of employer sponsored CHI and to 3.7% after accounting for portability coverage. The most vulnerable populations are expected to remain more often without CHI whereas non coverage will significantly decrease among the less risk averse and the more present oriented. With its focus on private sector employees, the policy is thus likely to do little for populations that would benefit most from additional insurance coverage while expanding coverage for other populations that appear to place little value on CHI. PMID- 28089283 TI - MYC Amplification as a Predictive Factor of Complete Pathologic Response to Docetaxel-based Neoadjuvant Chemotherapy for Breast Cancer. AB - BACKGROUND: Neoadjuvant chemotherapy is a standard treatment for stage II and III breast cancer. The identification of biomarkers that may help in the prediction of response to neoadjuvant therapies is necessary for a more precise definition of the best drug or drug combination to induce a better response. MATERIAL AND METHODS: We assessed the role of Ki67, hormone receptors expression, HER2, MYC genes and their protein status, and KRAS codon 12 mutations as predictor factors of pathologic response to anthracycline-cyclophosphamide (AC) followed by taxane docetaxel (T) neoadjuvant chemotherapy (AC+T regimen) in 51 patients with invasive ductal breast cancer. RESULTS: After neoadjuvant chemotherapy, 82.4% of patients showed pathologic partial response, with only 9.8% showing pathologic complete response. In multivariate analysis, MYC immunoreactivity and high MYC gain defined as MYC/nucleus >= 5 were significant predictor factors for pathologic partial response. Using the receiver operating characteristic curve analysis, the ratio of 2.5 MYC/CEP8 (sensitivity of 80% and specificity of 89.1%) or 7 MYC/nuclei copies (sensitivity of 80% and specificity of 73.9%) as the best cutoff in predicting a pathologic complete response was identified. Thus, MYC may have a role in chemosensitivity to AC and/or docetaxel drugs. Additionally, MYC amplification may be a predictor factor of pathologic response to the AC+T regimen in patients with breast cancer. Moreover, patients with an increased number of MYC copies showed pathologic complete response to this neoadjuvant treatment more frequently. CONCLUSION: The analysis of MYC amplification may help in the identification of patients that may have a better response to AC+T treatment. PMID- 28089284 TI - [Bilateral congenital aniridia in ureteropelvic junction syndrome]. PMID- 28089285 TI - Thick keratoconic cornea associated with posterior polymorphous corneal dystrophy. AB - INTRODUCTION: We herein report a case of bilateral unusually thick non-edematous keratoconic corneas with associated endothelial features of posterior polymorphous corneal dystrophy (PPCD). CASE REPORT: We report the case of a 27 year-old myopic woman who presented for refractive surgery. Slit lamp exam showed bilateral corneal protrusion with diffuse deep stromal and endothelial vesicular opacities and small paracentral bands. Topography showed generalized advanced corneal steepening in both eyes with increased anterior and posterior central corneal elevations in comparison to the best fit sphere. Ultrasound pachymetry showed central corneal thickness of 605MUm (RE) and 612MUm (LE). On specular biomicroscopy, cell density of 2503 cells/mm2 RE and 1526 cells/mm2 LE with significant cellular pleomorphism and polymegathism were noted. DISCUSSION: Clinical and paraclinical findings together suggest the presence of simultaneous keratoconus and PPCD. The literature has suggested an association between PPCD and steep cornea. Moreover, many reports have also described cases of associated PPCD and keratoconus with characteristic thinning and ectasia, in comparison to the unusual thick corneas noted in our patient, despite the absence of edema. Identification of genetics factors is further needed to clarify this association. CONCLUSION: This case describes a patient whose corneas present features of both keratoconus and PPCD and is unique due to the presence of increased corneal thickness despite the absence of edema. PMID- 28089286 TI - Historical perspective on the medical use of cannabis for epilepsy: Ancient times to the 1980s. AB - There has been a dramatic surge in the interest of utilizing cannabis for epilepsy treatment in the US. Yet, access to cannabis for research and therapy is mired in conflicting regulatory policies and shifting public opinion. Understanding the current state of affairs in the medical cannabis debate requires an examination of the history of medical cannabis use. From ancient Chinese pharmacopeias to the current Phase III trials of pharmaceutical grade cannabidiol, this review covers the time span of cannabis use for epilepsy therapy so as to better assess the issues surrounding the modern medical opinion of cannabis use. This article is part of a Special Issue titled Cannabinoids and Epilepsy. PMID- 28089287 TI - External ear melanoma: A 10 year assessment of management and outcomes. PMID- 28089288 TI - The Role of Reactive Oxygen Species in Antibiotic-Mediated Killing of Bacteria. AB - Recently, it was proposed that there is a common mechanism behind the activity of bactericidal antibiotics, involving the production of reactive oxygen species (ROS). However, the involvement of ROS in antibiotic-mediated killing has become the subject of much debate. In the present review, we provide an overview of the data supporting the ROS hypothesis; we also present data that explain the contradictory results often obtained when studying antibiotic-induced ROS production. For this latter aspect we will focus on the importance of taking the experimental setup into consideration and on the importance of some technical aspects of the assays typically used. Finally, we discuss the link between ROS production and toxin-antitoxin modules, and present an overview of implications for treatment. PMID- 28089289 TI - Evaluation of five serologic assays for bovine tuberculosis surveillance in domestic free-range pigs from southern Spain. AB - In countries where bovine tuberculosis (bTB) is still prevalent the contact among different animal species in extensive systems contributes to the circulation of Mycobacterium bovis (M. bovis) and other members of the Mycobacterium tuberculosis complex (MTC). Thus, free-range pigs can develop subclinical infections and may contribute to disease spread to bovine and wildlife. Serodiagnosis has been proposed as a screening tool for detecting infected pig herds; however, the value of this method to obtain an accurate diagnosis in this species is still not clear. In this study, sensitivity (Se) and specificity (Sp) estimates of four ELISAs and a lateral flow immunochromatographic antibody assay based on different M. bovis antigens, including MPB70 and MPB83 proteins, were evaluated in naturally infected domestic free-range pigs. For this purpose, submandibular lymph nodes and blood samples from 217 pigs from both TB-infected and historically negative farms were sampled at slaughterhouse and analysed by gross examination, histopathology, bacteriological culture and qPCR. Se and Sp estimates of the 5 evaluated assays ranged from 66.1% to 78% (CI95 from 52.6 to 87.7%) and from 98.9% to 100% (CI95 from 93.8 to 100%), respectively. Results of our study suggest that all the evaluated assays could be used as a first screening tool to conduct bTB surveillance in domestic pigs at population level; however, animals from seropositive herds should later be surveyed by other methods in order to reduce false negative results. PMID- 28089290 TI - Assessing circumstances and causes of dairy cow death in Italian dairy farms through a veterinary practice survey (2013-2014). AB - A questionnaire survey about on farm dairy cow mortality was carried out among veterinary practitioners in Italy between January 2013 and May 2014. The study aimed at investigating the main circumstances of death in dairy cows (euthanasia, emergency slaughter or unassisted death), the primary causes and the risk factors of death. Out of 251 dead cows involved (across 137 farms), 54.6% died assisted and 45.4% were found dead. The main causes of death were metabolic/digestive disorders (22.3%) and mastitis/udder problems (17.1%), while in 14.7% of all cases, reasons of death were unknown. From the univariable generalised linear mixed models, dry cows showed a significantly higher odds to die unassisted compared to lactating cows (OR=3.2); dry cows also had higher odds of dying from unknown reasons (OR=11.7). Season was not significantly related to the risk of dying unassisted and for unknown reasons, but during the summer (characterised by hot and muggy weather in Northern Italy) cows died mostly for problems at calving. 54.2% of cows died during the first 30days in milk (DIM). Half of the multiparous cows that died, died in the first 29.5 DIM, while half of the primiparous cows that died, died in the first 50 DIM. Results pointed out that, especially in dry cows, around calving and during the summer, some failure in management practices and daily inspections may occur. Improvements should be done in monitoring activities and in recognising early symptoms of diseases among stockperson. In addition, in case of diagnosed diseases with poor prognosis, euthanasia procedures should be implemented to prevent cows from dying unassisted. PMID- 28089291 TI - Repair of stenosed neourethra using the proximal neourethral diverticulum - A technique in redo hypospadias surgery. AB - Neourethral diverticulum secondary to distal neourethral stenosis is not uncommon after proximal hypospadias repair. We describe a technique using the neo urethral diverticular roof and overlying skin as a composite flap to reconstruct the urethral stenosis distal to the diverticulum. The composite flap is advanced distally for reconstruction of the stenosed urethra either as a tube or as an onlay. Urethra at the diverticular bed is tubularized to reduce its caliber. This technique has yielded excellent results in three children. The tissue expansion caused by the obstructed urinary stream has been utilized to correct both neourethral diverticulum and stenosis. PMID- 28089292 TI - Assessing quality of life of patients with hypospadias: A systematic review of validated patient-reported outcome instruments. AB - BACKGROUND: Patient-reported outcomes have the potential to provide invaluable information for evaluation of hypospadias patients, aid in decision-making, performance assessment, and improvement in quality of care. To appropriately measure patient-relevant outcomes, well-developed and validated patient-reported outcome (PRO) instruments are essential. OBJECTIVE: To identify and evaluate existing PRO instruments designed to measure quality of life and/or satisfaction of individuals with hypospadias that have been developed and validated in a hypospadias population. METHODS: A systematic search of MEDLINE, EMBASE, PsycINFO, CINAHL and Health and Psychosocial Instruments was conducted in April 2016. Two reviewers independently assessed studies and identified PRO instruments for inclusion. Data were extracted on study characteristics, instrument development and validation, and content domains. RESULTS: A total of 32 studies were included that used or described five PRO instruments: Hypospadias Objective Scoring Evaluation (HOSE), Pediatric Penile Perception Score (PPPS), Penile Perception Score (PPS), Genital Perception Scale (GPS) for adults, and GPS for children/adolescents. Instrument development and validation was limited. The majority of identified instruments focused on postoperative cosmetic satisfaction, with only one instrument considering urinary function, and no instruments evaluating sexual function and psychosocial sequelae. CONCLUSIONS: While many hypospadias studies have acknowledged the necessity of a patient reported element, few have used validated PRO instruments developed in a hypospadias population. Existing instruments to measure patient-reported outcomes in hypospadias require improvement in both the breadth of content and in their development and validation methodology. PMID- 28089293 TI - Response to commentary to 'Bleeding after circumcision is more likely in children with Lichen Sclerosus (Balanitis Xerotica Obliterans)'. PMID- 28089294 TI - The American Academy of Pediatrics Workforce Survey for the Section on Urology 2015. AB - INTRODUCTION: In 2013, the American Academy of Pediatrics (AAP) Division of Workforce and Medical Education Policy assumed the task of organizing the updated AAP Workforce Survey, which was modeled after the Future of Pediatric Education II study. OBJECTIVE: The objective of the present study was to evaluate changes in practice patterns of all pediatric medical and surgical specialists over time, to facilitate advocacy work by the Academy at federal and state levels. STUDY DESIGN: The survey was sent to members of the AAP Section on Urology and the Society for Pediatric Urology between June and November 2014. The survey included general and sub-specialty-specific questions. Data analysis was performed using SPSS 18.0. Descriptive statistics, including frequency distributions and measures of central tendency, were used to summarize all responses. RESULTS: A total of 255 pediatric urologists returned the survey, giving a response rate of 56.4%. The specialty remained vibrant, and members remained content in their career choice. About two-thirds practiced in a full-time clinical setting, and had research, teaching, and/or administrative duties. About 75% reported no change in clinical volume or case complexity, although 50% reported an increase in their referral base. A 50% increase in minor cases and a 43.3% decrease in open cases were reported. Only 13% planned to retire within the next 3-6 years. The current job market for fellows was unrestricted for 51.3%, significantly restricted for location for 23.1%, and restricted with regard to practice type for 25.6%. Overall, 51%, 37%, and 13% of the respondents expressed the opinions that over the next 5 years, too many specialists in pediatric urology were currently being trained, just the right number, and too few, respectively. Medical student interest remained encouraging. DISCUSSION: One of the primary objectives of the survey was to gain insights into whether there was concordance between the number of trainees and the current and future job opportunities. Unfortunately, the main limitations of the survey were the questions on retirement and adding a partner. Since the survey was anonymous, there was a missed opportunity to direct fellows to specific job openings. In addition, every member of a large group may have individually responded, inflating the responses or, in some cases, negating the responses if the partners did not agree. CONCLUSION: Pediatric urologists have an overall sense of contentment of career choice, despite shifts in complex open surgical volume and increasing competition. Surveys that are not anonymous would provide specific geographical manpower needs. PMID- 28089295 TI - Inter-rater reliability of distal ureteral diameter ratio compared to grade of VUR. AB - INTRODUCTION AND OBJECTIVE: Management of vesicoureteral reflux (VUR) remains controversial, and reflux grade constitutes an important prognostic factor. Recent work has suggested that distal ureteral diameter ratio (UDR) is a predictive factor relative to clinical outcome independent of grade. Previous studies have noted significant inter-rater variability with grading of VUR. The present study compared inter-rater reliability of reflux grade and UDR in children with primary VUR. STUDY DESIGN: Four pediatric urologists independently reviewed, in a blinded fashion, voiding cystourethrograms. For each renal unit, grade was assigned according to the standardized international scale. The UDR was calculated by dividing the largest ureteral diameter within the false pelvis by the distance between L1-L3 vertebral bodies. Correlation within each rater was determined using Pearson's correlation coefficient. Reliability of VUR grade and UDR were calculated using two-way ANOVA model inter-rater agreement. RESULTS: Four independent raters reliably measured VUR grade (ICC = 0.87, 95% CI = 0.78 0.93) and UDR (ICC = 0.95, 95% CI = 0.92-0.97). While UDR and grade were equally reliable measures, UDR had a tighter confidence interval. For each rater, grade and UDR were well correlated (r = 0.73-0.84; P < 0.0001). For higher-grade reflux, grade was more variable than UDR (Summary Figure). Using empirical thresholds, the increased variability of grade compared with UDR may lead to significant differences in clinical decision-making among physicians (P = 0.022). DISCUSSION: Known discordance with grading reflux emphasizes the need for a more objective VUR measurement, as clinicians and parents often opt for clinical intervention based on both clinical course and the likelihood of spontaneous resolution. While ICC for UDR and grade were not significantly different, the confidence intervals for grade were wider due to greater variability among grade measurements. This suggests that using UDR measurements may lead to more accurate characterization of VUR and ultimately more consistent clinical decision-making across providers. CONCLUSIONS: Ureteral diameter ratio has good inter-rater reliability among pediatric urologists, with less clinically relevant variability than VUR grade. Ureteral diameter ratio is a more objective and reliable measure than grade, and may be more useful in clinical decision-making. PMID- 28089296 TI - Commentary to "Prospective assessment of cosmesis before and after genital surgery". PMID- 28089297 TI - Time since discharge of 9mm cartridges by headspace analysis, part 1: Comprehensive optimisation and validation of a headspace sorptive extraction (HSSE) method. AB - Estimating the time since discharge of spent cartridges can be a valuable tool in the forensic investigation of firearm-related crimes. To reach this aim, it was previously proposed that the decrease of volatile organic compounds released during discharge is monitored over time using non-destructive headspace extraction techniques. While promising results were obtained for large-calibre cartridges (e.g., shotgun shells), handgun calibres yielded unsatisfying results. In addition to the natural complexity of the specimen itself, these can also be attributed to some selective choices in the methods development. Thus, the present series of paper aimed to more systematically evaluate the potential of headspace analysis to estimate the time since discharge of cartridges through the use of more comprehensive analytical and interpretative techniques. Specifically, in this first part, a method based on headspace sorptive extraction (HSSE) was comprehensively optimised and validated, as the latter recently proved to be a more efficient alternative than previous approaches. For this purpose, 29 volatile organic compounds were preliminary selected on the basis of previous works. A multivariate statistical approach based on design of experiments (DOE) was used to optimise variables potentially involved in interaction effects. Introduction of deuterated analogues in sampling vials was also investigated as strategy to account for analytical variations. Analysis was carried out by selected ion mode, gas chromatography coupled to mass spectrometry (GC-MS). Results showed good chromatographic resolution as well as detection limits and peak area repeatability. Application to 9mm spent cartridges confirmed that the use of co-extracted internal standards allowed for improved reproducibility of the measured signals. The validated method will be applied in the second part of this work to estimate the time since discharge of 9mm spent cartridges using multivariate models. PMID- 28089298 TI - Gunshot wound trajectory analysis using forensic animation to establish relative positions of shooter and victim. AB - Forensic pathologists who autopsy the victims of gun violence are often called upon to answer questions in both criminal and civil proceedings about the relative position of the shooter and the victim. In this case report of an officer-involved shooting incident, the statement of the police officer appeared to be in direct contradiction to the statements of other eyewitnesses, the evidence at the scene, and the final resting position of the decedent's body. Trajectory analysis of two gunshot wound pathways (only one of which was instantaneously incapacitating) was performed to assess the veracity of the officer's statement and forensic animation was used to create a court exhibit. A discussion of the current peer-reviewed literature is included. PMID- 28089299 TI - The (non)sense of routinely analysing beta-hydroxybutyric acid in forensic toxicology casework. AB - Beta-hydroxybutyric acid (BHB) is a ketone body which is generated from fatty acids as an alternative energy source when glucose is not available. Determination of this compound may be relevant in the forensic laboratory as ketoacidosis - an elevated level of ketone bodies - may contribute to the cause of death. In this study, we aimed at determining the relevance of routinely implementing BHB analysis in the forensic toxicological laboratory, as BHB analysis typically requires an additional workload. We therefore performed an unbiased retrospective analysis of BHB in 599 cases, comprising 553 blood, 232 urine and 62 vitreous humour samples. Cases with BHB concentrations above 100mg/L (in blood, urine and/or vitreous humour) were invariably associated with elevated levels of acetone, another ketone body, the detection of which is already implemented in most forensic laboratories using the gas chromatographic procedure for ethanol quantification. Our retrospective analysis did not reveal any positive case that had been missed initially and confirms that BHB analysis can be limited to acetone positive cases. PMID- 28089300 TI - Mitragynine concentrations in two fatalities. AB - Two cases of fatalities are reported of which the recreational use of Mitragyna speciosa ("kratom") could be confirmed. One of these cases presents with one of the highest postmortem mitragynine concentrations published to date. Our results show that even extremely high mitragynine blood concentrations following the consumption of kratom do not necessarily have to be the direct cause of death in such fatalities as a result of an acute overdose. The two cases are compared with regard to the differences in mitragynine concentrations detected and the role of mitragynine in the death of the subjects. Irrespective of the big differences in mitragynine concentrations in the postmortem blood samples, mitragynine was not the primary cause of death in either of the two cases reported here. Additionally, by rough estimation, a significant difference in ratio of mitragynine to its diastereomers in the blood and urine samples between the two cases could be seen. PMID- 28089301 TI - Time since discharge of 9mm cartridges by headspace analysis, part 2: Ageing study and estimation of the time since discharge using multivariate regression. AB - Estimating the time since discharge of spent cartridges can be a valuable tool in the forensic investigation of firearm-related crimes. To reach this aim, it was previously proposed that the decrease of volatile organic compounds released during discharge is monitored over time using non-destructive headspace extraction techniques. While promising results were obtained for large-calibre cartridges (e.g., shotgun shells), handgun calibres yielded unsatisfying results. In addition to the natural complexity of the specimen itself, these can also be attributed to some selective choices in the methods development. Thus, the present series of papers aimed to systematically evaluate the potential of headspace analysis to estimate the time since discharge of cartridges through the use of more comprehensive analytical and interpretative techniques. Following the comprehensive optimisation and validation of an exhaustive headspace sorptive extraction (HSSE) method in the first part of this work, the present paper addresses the application of chemometric tools in order to systematically evaluate the potential of applying headspace analysis to estimate the time since discharge of 9mm Geco cartridges. Several multivariate regression and pre treatment methods were tested and compared to univariate models based on non linear regression. Random forests (RF) and partial least squares (PLS) proceeded by pairwise log-ratios normalisation (PLR) showed the best results, and allowed to estimate time since discharge up to 48h of ageing and to differentiate recently fired from older cartridges (e.g., less than 5h compared to more than 1 2 days). The proposed multivariate approaches showed significant improvement compared to univariate models. The effects of storage conditions were also tested and results demonstrated that temperature, humidity and cartridge position should be taken into account when estimating the time since discharge. PMID- 28089302 TI - Germinal Center Lymphocyte Ratios and Successful HIV Vaccines. AB - Current HIV vaccines are poor inducers of neutralizing antibodies (nAbs). A recent study in Cell Reports used serial fine-needle aspirates from rhesus macaque lymph nodes following HIV-1 surface envelope glycoprotein (Env) trimer immunization, generating a substantial production of HIV-1 nAbs. A remarkable correlation was found between antibody titers and a high frequency and ratio of germinal center B and T follicular helper (TFH) lymphocytes. PMID- 28089303 TI - Practical Polling for Prostate Cancer: AR-V7-based Treatment Selection. PMID- 28089305 TI - Reply to Thomas Zilli, Gilles Crehange and Olivier Chapet's Letter to the Editor re: Pascal Rischmann, Albert Gelet, Benjamin Riche, et al. Focal High Intensity Focused Ultrasound of Unilateral Localized Prostate Cancer: A Prospective Multicentric Hemiablation Study of 111 Patients. Eur Urol 2017;71:267-73. PMID- 28089304 TI - Management of Prostate Cancer in Elderly Patients: Recommendations of a Task Force of the International Society of Geriatric Oncology. AB - CONTEXT: Prostate cancer is the most frequent male cancer. Since the median age of diagnosis is 66 yr, many patients require both geriatric and urologic evaluation if treatment is to be tailored to individual circumstances including comorbidities and frailty. OBJECTIVE: To update the 2014 International Society of Geriatric Oncology (SIOG) guidelines on prostate cancer in men aged >70 yr. The update includes new material on health status evaluation and the treatment of localised, advanced, and castrate-resistant disease. DATA ACQUISITION: A multidisciplinary SIOG task force reviewed pertinent articles published during 2013-2016 using search terms relevant to prostate cancer, the elderly, geriatric evaluation, local treatments, and castration-refractory/resistant disease. Each member of the group proposed modifications to the previous guidelines. These were collated and circulated. The final manuscript reflects the expert consensus. DATA SYNTHESIS: Elderly patients should be managed according to their individual health status and not according to age. Fit elderly patients should receive the same treatment as younger patients on the basis of international recommendations. At the initial evaluation, screening for cognitive impairment is mandatory to establish patient competence in making decisions. Initial evaluation of health status should use the validated G8 screening tool. Abnormal scores on the G8 should lead to a simplified geriatric assessment that evaluates comorbid conditions (using the Cumulative Illness Score Rating-Geriatrics scale), dependence (Activities of Daily Living) and nutritional status (via estimation of weight loss). When patients are frail or disabled or have severe comorbidities, a comprehensive geriatric assessment is needed. This may suggest additional geriatric interventions. CONCLUSIONS: Advances in geriatric evaluation and treatments for localised and advanced disease are contributing to more appropriate management of elderly patients with prostate cancer. A better understanding of the role of active surveillance for less aggressive disease is also contributing to the individualisation of care. PATIENT SUMMARY: Many men with prostate cancer are elderly. In the physically fit, treatment should be the same as in younger patients. However, some elderly prostate cancer patients are frail and have other medical problems. Treatment in the individual patient should be based on health status and patient preference. PMID- 28089306 TI - Effects of dynamic diffraction conditions on magnetic parameter determination in a double perovskite Sr2FeMoO6 using electron energy-loss magnetic chiral dichroism. AB - Electron energy-loss magnetic chiral dichroism (EMCD) spectroscopy, which is similar to the well-established X-ray magnetic circular dichroism spectroscopy (XMCD), can determine the quantitative magnetic parameters of materials with high spatial resolution. One of the major obstacles in quantitative analysis using the EMCD technique is the relatively poor signal-to-noise ratio (SNR), compared to XMCD. Here, in the example of a double perovskite Sr2FeMoO6, we predicted the optimal dynamical diffraction conditions such as sample thickness, crystallographic orientation and detection aperture position by theoretical simulations. By using the optimized conditions, we showed that the SNR of experimental EMCD spectra can be significantly improved and the error of quantitative magnetic parameter determined by EMCD technique can be remarkably lowered. Our results demonstrate that, with enhanced SNR, the EMCD technique can be a unique tool to understand the structure-property relationship of magnetic materials particularly in the high-density magnetic recording and spintronic devices by quantitatively determining magnetic structure and properties at the nanometer scale. PMID- 28089307 TI - Corrigendum to "Beneficial effects of 5-fluorouracil and heparin-based portal infusion chemotherapy combined with mitomycin C and cisplatin after curative resection of pancreatic cancer" [Pancreatology 10 (2010) 250-258]. PMID- 28089308 TI - Physicians' views and experiences of discussing weight management within routine clinical consultations: A thematic synthesis. AB - OBJECTIVE: To systematically search and synthesise qualitative studies of physicians' views and experiences of discussing weight management within a routine consultation. METHODS: A systematic search of four electronic databases identified 11,169 articles of which 16 studies met inclusion criteria. Quality was appraised using the Critical Appraisal Skills Programme tool and a thematic synthesis conducted of extracted data. RESULTS: Four analytical themes were found: (1) physicians' pessimism about patients' weight loss success (2) physicians' feel hopeless and frustrated (3) the dual nature of the physician patient relationship (4) who should take responsibility for weight management. CONCLUSION: Despite clinical recommendations barriers remain during consultations between physicians and patients about weight management. Many of these barriers are potentially modifiable. PRACTICE IMPLICATIONS: Improving training, providing clearer guidelines and placing a greater emphasis on collaboration within and between clinicians will help reduce barriers for both physicians and patients. In particular, there is an urgent need for more specialised training for physicians about weight management to promote knowledge and skills in behaviour change techniques and ways to broach sensitive topics without damaging patient relationships. PMID- 28089309 TI - Does patient coaching make a difference in patient-physician communication during specialist consultations? A systematic review. AB - OBJECTIVE: To systematically review the literature on the effectiveness of a patient coach intervention on patient - physician communication in specialists consultations. METHODS: PubMed, Cochrane, PsycInfo, Cinahl and Embase were searched until November 2015. Included were papers describing interventions directed at adult outpatients in secondary care with a variety of somatic diseases. Outcomes had to be measured in communication effectivity from a patient's perspective. RESULTS: Seventeen publications met the inclusion criteria (involving 3787 patients), describing 13 unique interventions. Most interventions were single one-on-one sessions taking between 20 and 40min before consultation. Research quality in ten studies was high. These studies showed significant improvement on immediate, intermediate and long term patient - physician communication. CONCLUSION: We found limited evidence suggesting an improvement of patient - physician communication by having multiple patient coaching encounters during which questions are prepared and rehearsed and consultations are evaluated and reflected upon, sometimes supported by audio recording the consultation. PRACTICE IMPLICATIONS: The results of this review contribute to the (re-)design of an effective model for patient coaching, a profile and training approach of patient coaches. Future research should aim at determining which patients will benefit most from coaching interventions. PMID- 28089310 TI - Take the HEAT: A pilot study on improving communication with angry families. AB - OBJECTIVE: Our objective was to evaluate the utility of an educational program consisting of a workshop based on the Take the HEAT communication strategy, designed specifically for addressing patients who are angry, using a novel tool to evaluate residents' skills in employing this method. METHODS: 33 first-year pediatric and internal medicine-pediatrics residents participated in the study. The workshop presented the Take the HEAT (Hear, Empathize, Apologize, Take action) strategy of communication. Communication skills were assessed through standardized patient encounters at baseline and post-workshop. Encounters were scored using a novel assessment tool. RESULTS: After the workshop, residents' Take the HEAT communication improved from baseline total average score 23.15 to total average score 25.36 (Z=-3.428, p<0.001). At baseline, empathy skills were the lowest. Intraclass Correlation Coefficient demonstrated substantial agreement (0.60 and 0.61) among raters using the tool. CONCLUSION: First-year pediatric trainees' communication with angry families improved with education focused on the Take the HEAT strategy. Poor performance by residents in demonstrating empathy should be explored further. PRACTICE IMPLICATIONS: This study demonstrates the utility of a brief communications curriculum aimed at improving pediatric residents' ability to communicate with angry families. PMID- 28089312 TI - Hunting down an evidence base for adolescent mental health. PMID- 28089311 TI - Sustaining program effectiveness after implementation: The case of the self management of well-being group intervention for older adults. AB - OBJECTIVE: The Self-Management of Well-being (SMW) group intervention for older women was implemented in health and social care. Our aim was to assess whether effects of the SMW intervention were comparable with the original randomized controlled trial (RCT). Furthermore, we investigated threats to effectiveness, such as participant adherence, group reached, and program fidelity. METHODS: In the implementation study (IMP) 287 and RCT 142 women participated. We compared scores on self-management ability and well-being of the IMP and RCT. For adherence, drop-out rates and session attendance were compared. Regarding reach, we compared participants' baseline characteristics. Professionals completed questions regarding program fidelity. RESULTS: No significant differences were found on effect outcomes and adherence between IMP and RCT (all p>=0.135). Intervention effect sizes were equal (0.47-0.59). IMP participants were significantly less lonely and more likely to be married, but had lower well being. Most professionals followed the protocol, with only minimal deviations. CONCLUSION: The effectiveness of the SMW group intervention was reproduced after implementation, with similar participant adherence, minimal changes in the group reached, and high program fidelity. PRACTICE IMPLICATIONS: The SMW group intervention can be transferred to health and social care without loss of effectiveness. Implementation at a larger scale is warranted. PMID- 28089313 TI - Optimism, Pessimism, and Pragmatism: Musings on the Cost of Medical Innovation. PMID- 28089314 TI - Heart Failure Complicated by Atrial Fibrillation: Don't Bury the Beta-Blockers Just Yet. PMID- 28089315 TI - Racial Tension in Hypertension: Divergent Effects of African and European Ancestry on Cardiac Remodeling. PMID- 28089316 TI - Decreased Mortality With Beta-Blockers in Patients With Heart Failure and Coexisting Atrial Fibrillation: An AF-CHF Substudy. AB - OBJECTIVES: The impact of beta-blockers on mortality and hospitalizations was assessed in the largest randomized trial of patients with both atrial fibrillation (AF) and heart failure with a reduced ejection fraction (HFrEF): the Atrial Fibrillation-Congestive Heart Failure trial. BACKGROUND: Although beta blockers are the cornerstone of therapy for HFrEF, a recent patient-level meta analysis cast doubt on their efficacy in patients with coexisting AF. METHODS: From a total of 1,376 subjects randomized in the AF-CHF trial, those without beta blockers at baseline were propensity matched to a maximum of 2 exposed patients. All absolute standardized differences after matching were <=10%. Primary analyses respected the intention-to-treat principle. In on-treatment sensitivity analyses, beta-blocker status was modeled as a time-dependent covariate. RESULTS: Baseline characteristics were comparable among the matched cohorts (mean age 70 +/- 11 years, 81% male, and mean left ventricular ejection fraction 27 +/- 6%). During a median follow-up of 37 months, beta-blockers were associated with significantly lower all-cause mortality (hazard ratio [HR]: 0.721, 95% confidence interval [CI]: 0.549 to 0.945; p = 0.0180) but not hospitalizations (HR: 0.886; 95% CI: 0.715 to 1.100; p = 0.2232). Similar results were obtained in sensitivity analyses that modeled beta-blockers as a time-dependent variable (HR: 0.668 for all-cause mortality; 95% CI: 0.511 to 0.874; p = 0.0032; HR: 0.814 for hospitalizations; 95% CI: 0.653 to 1.014; p = 0.0658). There were no significant interactions between beta-blockers and patterns (i.e., persistent vs. paroxysmal) or burden of AF with respect to mortality or hospitalizations. CONCLUSIONS: In propensity-matched analyses, beta-blockers were associated with significantly lower mortality but not hospitalizations in patients with HFrEF and AF, irrespective of the pattern or burden of AF. These results support current evidence-based recommendations for beta-blockers in patients with HFrEF, whether or not they have associated AF. PMID- 28089317 TI - Attitudes, perceptions and experiences of mealtimes among residents and staff in care homes for older adults: A systematic review of the qualitative literature. AB - Addressing problems associated with malnutrition in care home residents has been prioritized by researchers and decision-makers. This review aimed to better understand factors that may contribute to malnutrition by examining the attitudes, perceptions and experiences of mealtimes among care home residents and staff. Five databases were searched from inception to November 2015: Medline, Embase, PsychINFO, AMED, and the Cochrane Database. Forward and backward citation checking of included articles was conducted. Titles, abstracts, and full texts were screened independently by two reviewers and quality was assessed using the Wallace criteria. Thematic analysis of extracted data was undertaken. Fifteen studies were included in the review, encompassing the views and opinions of a total of 580 participants set in nine different countries. Four main themes were identified: (1) organizational and staff support, (2) resident agency, (3) mealtime culture, and (4) meal quality and enjoyment. Organizational and staff support was an over-arching theme, impacting all aspects of the mealtime experience. Mealtimes are a pivotal part of care home life, providing structure to the day and generating opportunities for conversation and companionship. Enhancing the mealtime experience for care home residents needs to take account of the complex needs of residents while also creating an environment in which individual care can be provided in a communal setting. PROSPERO Registration: CRD42015025890. PMID- 28089318 TI - Analysis and evaluation of the effectiveness of epidural analgesia and its relationship with eutocic or dystocic delivery. AB - OBJECTIVE: Numerous studies have demonstrated the difference in the verbal rating scale with regard to obstructed labour and induced labour, so that obstructed labour and foetal macrosomia have been related to a greater sensation of pain during labour, particularly in the first stage. Even the epidural analgesia is linked to the need for instrumented or caesarean section due to foetal obstruction. The goal of the study is to analyze and evaluate the effectiveness of epidural analgesia in normal versus obstructed labour. PATIENTS AND METHODS: One hundred and eighty pregnant women were included in an observational, analytical, longitudinal and prospective study, that was performed in the Obstetrics Department of the Hospital Universitario Dexeus. All the nulliparous or multiparous over 36 weeks of pregnancy, after 3cm of cervical dilatation in spontaneous or induced labor were included. All the patients were given epidural analgesia according to protocol. RESULTS: The basic descriptive methods were used for the univariate statistical analysis of the sample and the Mann-Whitney U test was used for the comparison of means between both groups. The correlations between variables were studied by means of the Spearman coefficient of correlation. The differences regarded as statistically significant are those whose P<.05. CONCLUSION: In our population there were no statistically significant differences in the effectiveness of epidural analgesia in normal versus obstructed labour. Patients who got epidural analgesia and had obstructed labors have the same degree of verbal rating scale as patients that do not had obstructed labors (P>.05). PMID- 28089319 TI - Anesthesia management of accidental extubation in the prone position. PMID- 28089320 TI - Advances in operating room management. The role of operating room director. PMID- 28089321 TI - A single session of prefrontal cortex transcranial direct current stimulation does not modulate implicit task sequence learning and consolidation. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is assumed to affect cortical excitability and dependent on the specific stimulation conditions either to increase or decrease learning. OBJECTIVE: The purpose of this study was to modulate implicit task sequence learning with tDCS. METHODS: As cortico-striatal loops are critically involved in implicit task sequence learning, tDCS was applied above the dorsolateral prefrontal cortex (DLPFC). In Experiment 1, anodal, cathodal, or sham tDCS was applied before the start of the sequence learning task. In Experiment 2, stimulation was applied during the sequence learning task. Consolidation of learning was assessed after 24 h. RESULTS: The results of both experiments showed that implicit task sequence learning occurred consistently but it was not modulated by different tDCS conditions. Similarly, consolidation measured after a 24 h-interval including sleep was also not affected by stimulation. CONCLUSIONS: These results indicate that a single session of DLPFC tDCS is not sufficient to modulate implicit task sequence learning. This study adds to the accumulating evidence that tDCS may not be as effective as originally thought. PMID- 28089322 TI - A central giant cell granuloma in posterior part of maxilla-A case report. AB - INTRODUCTION: Central Giant Cell Granuloma (CGCG) is an intraosseous lesion consisting of cellular fibrous tissue that contains multiple foci of hemorrhage, aggregations of multinucleated giant cells and occasionally trabeculae of woven bone1. PRESENTATION OF CASE: we are presenting a case of Central Giant Cell Granuloma on Maxilla. Extra oral examination revealed a diffuse swelling on the left side of face causing slight obliteration of nasio - nasolabial labial fold resulting in facial asymmetry & Intraoral examination shows a purple expansile mass in the region of upper left 26, 27 and 28 edentulous areas. DISCUSSION: Giant Cell Granuloma is a rare bony lesion in the Head and Neck region. It is a non-odontogenic tumor never seen in any other bone of the skeleton. It most commonly affects maxilla followed by the mandible. CONCLUSION: There is no recurrence after a long follow up period. We concluded that conventional excision is to be considered as a best method to treat central giant cell granuloma. PMID- 28089323 TI - Neurophysiological monitoring of lumbar spinal nerve roots: A case report of postoperative deficit and literature review. AB - INTRODUCTION: Intraoperative neurophysiological monitoring (IONM) has proven to help reduce the probability of postoperative neurological deficit for spinal deformity correctional surgeries. However, in rare cases new deficits may still happen. We report a surgical case in which the patient had postoperative paralysis. We would like to call for more case reports with postoperative neurological deficits as they present difficult clinical cases. PRESENTATION OF CASE: A 61-year-old male patient with severe thoracolumbar kyphoscoliosis underwent posterior spinal correction and fusion with segmental T10-L5 pedicle screws and rods instrumentation with IONM. The only intraoperative event was a pedicle breach at left L3 which was detected by triggered electromyography (EMG) testing, and the pedicle screw was repositioned. Left lower extremity paralysis was observed upon patient awakening. He received rehabilitation treatment and had limited recovery of muscle strength. Partial lumbar nerve root injury was likely the cause of the paralysis. DISCUSSION: This is a case with new lumbar nerve root deficit, with positive EMG signal change, but negative somatosensory evoked potential (SSEP) and motor evoked potential (MEP) findings. We discuss the different neurophysiological modalities for monitoring lumbar spinal nerve root function. We review journal articles from the past two decades which reported lumbar root deficits, and list neuromonitoring events during the surgeries. CONCLUSION: Multimodality monitoring with spontaneous and electrically triggered EMG combined with SSEP and MEP may provide the best chance to detect lumbar nerve root injuries. PMID- 28089324 TI - The Peculiar Functions of the Bacterial Extracellular Matrix. AB - A biofilm is a common life form where bacterial cells crowd together surrounded by an extracellular matrix (ECM). Traditionally, the ECM is considered as a structural material that glues and shields the biofilm cells. Here we describe alternative functions of the ECM, highlighting how it benefits microbes beyond the biofilms. Next to protecting free-living cells, the ECM participates in signaling, migration, and genetic exchange either being freely shared with other species or being exclusive to siblings. Considering the structural and recently discovered functions of the ECM, we also attempt to revise its role in sociomicrobiology. In the light of recent findings, the canonical view on ECM as a passive structural material of biofilms should be revisited. PMID- 28089326 TI - Mechanical response of common millet (Panicum miliaceum) seeds under quasi-static compression: Experiments and modeling. AB - The common millet (Panicum miliaceum) seedcoat has a fascinating complex microstructure, with jigsaw puzzle-like epidermis cells articulated via wavy intercellular sutures to form a compact layer to protect the kernel inside. However, little research has been conducted on linking the microstructure details with the overall mechanical response of this interesting biological composite. To this end, an integrated experimental-numerical-analytical investigation was conducted to both characterize the microstructure and ascertain the microscale mechanical properties and to test the overall response of kernels and full seeds under macroscale quasi-static compression. Scanning electron microscopy (SEM) was utilized to examine the microstructure of the outer seedcoat and nanoindentation was performed to obtain the material properties of the seedcoat hard phase material. A multiscale computational strategy was applied to link the microstructure to the macroscale response of the seed. First, the effective anisotropic mechanical properties of the seedcoat were obtained from finite element (FE) simulations of a microscale representative volume element (RVE), which were further verified from sophisticated analytical models. Then, macroscale FE models of the individual kernel and full seed were developed. Good agreement between the compression experiments and FE simulations were obtained for both the kernel and the full seed. The results revealed the anisotropic property and the protective function of the seedcoat, and showed that the sutures of the seedcoat play an important role in transmitting and distributing loads in responding to external compression. PMID- 28089325 TI - Ecology of the Oral Microbiome: Beyond Bacteria. AB - Although great strides have been made in understanding the complex bacterial community inhabiting the human oral cavity, for a variety of (mainly technical) reasons the ecological contributions of oral fungi, viruses, phages, and the candidate phyla radiation (CPR) group of ultrasmall bacteria have remained understudied. Several recent reports have illustrated the diversity and importance of these organisms in the oral cavity, while TM7x and Candida albicans have served as crucial paradigms for CPR species and oral fungi, respectively. A comprehensive understanding of the oral microbiota and its influence on host health and disease will require a holistic view that emphasizes interactions among different residents within the oral community, as well as their interaction with the host. PMID- 28089327 TI - Ceruloplasmin gene expression profile changes in the rat mammary gland during pregnancy, lactation and involution. AB - Copper metabolism disturbances in mammary gland (MG) cells have severe consequences in newborns. The mechanism that controls the balance of copper in the MG has not been thoroughly characterized. Four primary copper homeostasis genes in mammals: (1) ceruloplasmin (Cp) encoding multifunction multicopper blue (ferr)oxidase; (2) CTR1 encoding high affinity copper importer 1; and (3 and 4) two similar genes encoding Cu(I)/Cu(II)-ATPases P1 type (ATP7A and ATP7B) responsible for copper efflux from the cells and metallation of cuproenzymes formed in the Golgi complex are expressed in MG. This study aimed to characterize expression of these genes during pregnancy, lactation and forced involution in the rat MG. We found that Cp anchored to the plasma membrane and ATP7A were expressed during pregnancy and lactation. Soluble Cp and ATP7B were highly expressed in lactating MG decreasing to its ending. CTR1 activity increased during MG growth and reached its maximum at postpartum and then it decreased until the end of lactation. During early forced MG involution, Cp gene expression persisted; while a form of Cp that lacked exon 18 appeared. We suggest that Cp gene expressional changes at the transcriptional and posttranscriptional level reflect various physiological functions of Cp proteins during MG remodeling. PMID- 28089328 TI - Usefulness of Three-dimensional Transthoracic Echocardiograhy in the Localization of the Micra Leadless Pacemaker. PMID- 28089329 TI - In Morocco, the elimination of trachoma as a public health problem becomes a reality. PMID- 28089330 TI - Finite element analysis of implant-assisted removable partial dentures: Framework design considerations. AB - STATEMENT OF PROBLEM: Connecting an acrylic resin base to both a metal framework and a rigidly fixed implant may affect the rotational displacement of the prosthesis during loading. PURPOSE: The purpose of this finite element analysis study was to analyze the effect of connecting a denture base metal framework to an implant with the aim of decreasing the rotational movement of an implant assisted removable partial denture. MATERIAL AND METHODS: A mesial occlusal rest direct retainer and a distal occlusal rest direct retainer were modeled and adapted to incorporate a modified denture base metal framework in the connection area for each model. The stress and deformation patterns of the prosthesis structure were determined using finite element analysis and compared for both situations. RESULTS: A maximum von Mises stress of 923 MPa was observed on the metal framework of the prosthesis with a mesial occlusal rest, and the maximum value was 1478 MPa for the distal occlusal rest. A maximum von Mises stress of 17 MPa occurred on the acrylic resin denture base for the mesial occlusal rest, and a maximum von Mises stress of 29 MPa occurred for the distal occlusal rest. CONCLUSIONS: The distal occlusal rest direct retainer is stiffer than the mesial design and undergoes approximately 66% less deformation. The modified denture base framework with an I-bar and distal occlusal rest design provides more effective support to the acrylic resin structure. PMID- 28089331 TI - Evaluation of marginal and internal adaptation of hybrid and nanoceramic systems with microcomputed tomography: An in vitro study. AB - STATEMENT OF PROBLEM: The accuracy of recently introduced chairside computer aided design and computer-aided manufacturing (CAD-CAM) blocks is not well established, and marginal integrity and internal adaptation are not known. PURPOSE: The purpose of this in vitro study was to evaluate the marginal and internal adaptation of hybrid and nanoceramics using microcomputed tomography (MU CT). MATERIAL AND METHODS: The marginal and internal adaptation of 3 polymer infiltrated ceramic-network (PICN) materials (Vita Enamic [VE]; Lava Ultimate [LU]; Vita Suprinity [VS]) were compared with lithium disilicate (IPS e.max.CAD, IPS). Ninety-six specimens (48 dies and 48 crowns) were prepared (n=12 each group) using a chairside CAD-CAM system. The restorations were scanned with MU CT, with 160 measurements made for each crown, and used in 2-dimensional (2D) analysis. The marginal adaptation of marginal discrepancy (MD), absolute marginal discrepancy (AMD), internal adaptation of shoulder area (SA), axial space (AS), and occlusal space (OS) were compared using appropriate statistical analysis methods (alpha=.05). Cement volumes were compared using 3D analysis. RESULTS: The IPS blocks showed higher MD (130 MUm), AMD (156 MUm), SA (111 MUm) (P<.05), AS (52 MUm), and OS (192 MUm) than the other blocks (P<.01). The adaptation values of VS were significantly lower than those of the IPS block (P<.05). The adaption values of the LU and VE blocks were significantly lower than those of others (P<.01) but were statistically similar to one another (P>.05). IPS had the largest cement space at 18 mm3 (P<.01). CONCLUSIONS: The marginal and internal adaptation values were within a clinically acceptable range for all 3 hybrids and nanoceramics tested. PMID- 28089332 TI - Lithium silicate endocrown fabricated with a CAD-CAM system: A functional and esthetic protocol. AB - An endocrown restoration is an alternative approach to complete crowns with intraradicular cores or dowels for the restoration of endodontically treated teeth. Endocrowns conserve tooth structure and require fewer dental visits. This approach has been widely used, and various materials and techniques have been reported. Computer-aided design and computer-aided manufacturing (CAD-CAM) systems can generate and store libraries of teeth with various anatomies in their database, and diagnostic tooth waxing may not be required. However, occlusal adjustments after the cementation of indirect restorations are often frustrating. Thus, a rapid and efficient way of addressing this challenge is necessary. This clinical report presents a protocol for the fabrication and delivery of an endocrown by using the biogeneric design mode with lithium silicate-based ceramic adjusted before its complete sintering. PMID- 28089333 TI - Fit of interim crowns fabricated using photopolymer-jetting 3D printing. AB - STATEMENT OF PROBLEM: The fit of interim crowns fabricated using 3-dimensional (3D) printing is unknown. PURPOSE: The purpose of this in vitro study was to evaluate the fit of interim crowns fabricated using photopolymer-jetting 3D printing and to compare it with that of milling and compression molding methods. MATERIAL AND METHODS: Twelve study models were fabricated by making an impression of a metal master model of the mandibular first molar. On each study model, interim crowns (N=36) were fabricated using compression molding (molding group, n=12), milling (milling group, n=12), and 3D polymer-jetting methods. The crowns were prepared as follows: molding group, overimpression technique; milling group, a 5-axis dental milling machine; and polymer-jetting group using a 3D printer. The fit of interim crowns was evaluated in the proximal, marginal, internal axial, and internal occlusal regions by using the image-superimposition and silicone-replica techniques. The Mann-Whitney U test and Kruskal-Wallis tests were used to compare the results among groups (alpha=.05). RESULTS: Compared with the molding group, the milling and polymer-jetting groups showed more accurate results in the proximal and marginal regions (P<.001). In the axial regions, even though the mean discrepancy was smallest in the molding group, the data showed large deviations. In the occlusal region, the polymer-jetting group was the most accurate, and compared with the other groups, the milling group showed larger internal discrepancies (P<.001). CONCLUSIONS: Polymer-jet 3D printing significantly enhanced the fit of interim crowns, particularly in the occlusal region. PMID- 28089334 TI - Masticatory function and oral health-related quality of life in patients after partial maxillectomies with closed or open defects. AB - STATEMENT OF PROBLEM: The healing pattern after surgical resection of tumors of the oral cavity involving the maxilla may vary from one patient to another. The result may be open communication between the oral and nasal cavities (open defect) or complete oronasal separation after healing of the defect area (closed defect). PURPOSE: The purpose of this clinical study was to compare masticatory function and oral health-related quality of life (OHRQoL) between patients with closed and open defects who had undergone a partial maxillectomy and were wearing dentomaxillary prostheses. MATERIAL AND METHODS: Thirty-eight participants who had undergone a partial maxillectomy and who were wearing dentomaxillary prostheses were enrolled between September 2014 and April 2016. Participants were assigned to 2 groups according to the type of defect after healing: 19 participants had a closed defect, and 19 participants had an open defect. Masticatory function was evaluated objectively and subjectively. The objective measurement was food-mixing ability, which was assessed using color-changeable chewing gum. The subjective measurement was perceived mastication ability, rated as a masticatory score based on the patient's responses to a 35-item food intake questionnaire. OHRQoL was assessed using the Geriatric Oral Health Assessment Index (GOHAI). The GOHAI questionnaire consists of 12 items reflecting 3 hypothesized domains of the impact of oral disease: physical function, psychosocial function, and pain or discomfort. Differences in the scores obtained by the 3 measurements were compared between the 2 groups, using the Wilcoxon rank sum test (alpha=.05). RESULTS: No significant differences were seen between the 2 groups in objective mixing ability, subjective masticatory score, or GOHAI (P>.05). Regarding the GOHAI physical function domain, only the swallowing item was significantly lower (P=.025) in participants with an open defect than in participants with a closed defect. Regarding the GOHAI psychological function domain, the item related to patients' psychological worries or concerns about their teeth, gingival tissue, or dentures was significantly lower (P=.045) in patients with an open defect than in those with a closed defect. Other items related to physical function, psychological function, and pain or discomfort were not significantly different (P>.05) between the 2 groups. CONCLUSIONS: The closed or open defect in patients who had undergone a partial maxillectomy may not influence patients' masticatory function and overall OHRQoL if they have adequate prosthetic rehabilitation. However, special consideration should be given to patients with an open defect with regard to swallowing function and psychological concerns in order to improve their OHRQoL. PMID- 28089335 TI - Intrusion of maxillary molar using mini-implants: A clinical report and follow-up at 5 years. AB - This clinical report describes a straightforward alternative treatment for adult patients with extruded maxillary molars, who are reluctant to use fixed appliances and complex mechanics. The maxillary molar supereruption of a 57-year old woman was treated using buttons bonded to the buccal and palatal surfaces of the molars, 2 mini-implants, and elastomeric chains. The intrusion was achieved in 5 months. The treatment stability was observed for 5 years after treatment. PMID- 28089336 TI - A comparative study of additive and subtractive manufacturing for dental restorations. AB - STATEMENT OF PROBLEM: Digital systems have recently found widespread application in the fabrication of dental restorations. For the clinical assessment of dental restorations fabricated digitally, it is necessary to evaluate their accuracy. However, studies of the accuracy of inlay restorations fabricated with additive manufacturing are lacking. PURPOSE: The purpose of this in vitro study was to evaluate and compare the accuracy of inlay restorations fabricated by using recently introduced additive manufacturing with the accuracy of subtractive methods. MATERIAL AND METHODS: The inlay (distal occlusal cavity) shape was fabricated using 3-dimensional image (reference data) software. Specimens were fabricated using 4 different methods (each n=10, total N=40), including 2 additive manufacturing methods, stereolithography apparatus and selective laser sintering; and 2 subtractive methods, wax and zirconia milling. Fabricated specimens were scanned using a dental scanner and then compared by overlapping reference data. The results were statistically analyzed using a 1-way analysis of variance (alpha=.05). Additionally, the surface morphology of 1 randomly (the first of each specimen) selected specimen from each group was evaluated using a digital microscope. RESULTS: The results of the overlap analysis of the dental restorations indicated that the root mean square (RMS) deviation observed in the restorations fabricated using the additive manufacturing methods were significantly different from those fabricated using the subtractive methods (P<.05). However, no significant differences were found between restorations fabricated using stereolithography apparatus and selective laser sintering, the additive manufacturing methods (P=.466). Similarly, no significant differences were found between wax and zirconia, the subtractive methods (P=.986). The observed RMS values were 106 MUm for stereolithography apparatus, 113 MUm for selective laser sintering, 116 MUm for wax, and 119 MUm for zirconia. Microscopic evaluation of the surface revealed a fine linear gap between the layers of restorations fabricated using stereolithography apparatus and a grooved hole with inconsistent weak scratches when fabricated using selective laser sintering. In the wax and zirconia restorations, possible traces of milling bur passes were observed. CONCLUSIONS: The results indicate that the accuracy of dental restorations fabricated using the additive manufacturing methods is higher than that of subtractive methods. Therefore, additive manufacturing methods are a viable alternative to subtractive methods. PMID- 28089337 TI - A procedure for directly measuring the physiologic rest position and occlusal vertical dimension. PMID- 28089338 TI - Lymphangitis From Scolopendra heros Envenomation: The Texas Redheaded Centipede. AB - Envenomation by Scolopendra heros, the Texas redheaded centipede, can present variably. Although transient pain and erythema are often treated conservatively, complications may include cellulitis, necrosis, myocardial infarction, and rhabdomyolysis. We present a case of an elderly man who came to the emergency department with lymphangitis and dermatitis secondary to a centipede sting that awoke him from sleep. It is important to recognize the potential of centipede envenomation to have severe local and systemic manifestations. PMID- 28089339 TI - Discovery of a murine model of clinical PAH: Mission impossible? AB - Pulmonary arterial hypertension (PAH) is a lung vascular disease characterized with a progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling resulting in right heart failure and premature death. In this brief review, we document the recent advances in identifying genetically modified murine models of PH, with a focus on the recent discovery of the mouse model of Tie2 Cre-mediated deletion of prolyl hydroxylase 2, which exhibits progressive obliterative vascular remodeling, severe PAH, and right heart failure, thus recapitulating many of the features of clinical PAH. We will also discuss the translational potential of recent findings arising from experimental studies of murine PH models. PMID- 28089340 TI - Activation of NK cell cytotoxicity by aerosolized CpG-ODN/poly(I:C) against lung melanoma metastases is mediated by alveolar macrophages. AB - Controversies remain about NK cells direct responsiveness to Toll-like receptor (TLR) agonists or dependence on macrophages. In a melanoma lung metastasis model, aerosolized TLR9 and TLR3 agonists have been reported to induce antitumor immunity through NK cells activation. In the current study, we demonstrated that in vitro TLR9/TLR3 stimulation induced IFN-gamma secretion by NK cells, but an increase in their cytotoxicity was detected only after NK cells co-culture with in vitro TLR9/TLR3 agonists pretreated alveolar macrophages. Alveolar macrophages from melanoma lung metastases-bearing mice, treated with aerosolized TLR agonists, also promoted NK cell cytotoxicity. Activated NK cells from lungs of melanoma metastases-bearing mice that were given aerosolized TLR9/TLR3 agonists were able to polarize naive alveolar macrophages toward a M1-like phenotype. Our results demonstrate that activation of NK cells in the lung after TLR engagement is mediated by alveolar macrophages and that activated NK cells shape macrophage behavior. PMID- 28089341 TI - Neoadjuvant external beam radiation is associated with No benefit in overall survival for early stage pancreatic cancer. AB - OBJECTIVE: Neoadjuvant protocols for early stage pancreatic adenocarcinoma (PDAC) frequently involve external beam radiation used in combination with systemic chemotherapy. The benefit of radiation in these protocols has not been determined. METHODS: We examined patients with stage I and II PDAC within the National Cancer Data Base between 2006 and 2012. Propensity score matching was used to compare patients receiving neoadjuvant chemotherapy including radiation (NCRT) to those receiving neoadjuvant chemotherapy without radiation (NCT) prior to pancreaticoduodenectomy. RESULTS: Prior to matching, NCRT patients had higher rates of T3 tumors (P = 0.046) and vascular abutment (P < 0.001). Propensity score matching (1:1) yielded 397 patients per group. Patients treated with NCRT were more likely to have node negative resections (P < 0.001) but had increased rates of 90-day mortality (P = 0.015) and demonstrated a trend towards shorter overall survival (P = 0.0502) than those receiving NCT. CONCLUSION: In early stage PDAC, the addition of radiation to NCT is often utilized with more advanced disease and is associated with higher perioperative mortality and no long-term overall survival benefit. PMID- 28089342 TI - A Simulation-based, cognitive assessment of resident decision making during complex urinary catheterization scenarios. AB - BACKGROUND: This study explores general surgery residents' decision making skills in uncommon, complex urinary catheter scenarios. METHODS: 40 residents were presented with two scenarios. Scenario A was a male with traumatic urethral injury and scenario B was a male with complete urinary blockage. Residents verbalized whether they would catheterize the patient and described the workup and management of suspected pathologies. Residents' decision paths were documented and analyzed. RESULTS: In scenario A, 45% of participants chose to immediately consult Urology. 47.5% named five diagnostic tests to decide if catheterization was safe. In scenario B, 27% chose to catheterize with a 16 French Coude. When faced with catheterization failure, participants randomly upsized or downsized catheters. Chi-square analysis revealed no measurable consensus amongst participants. CONCLUSIONS: Residents need more training in complex decision making for urinary catheterization. The decision trees generated in this study provide a useful blueprint of residents' learning needs. SUMMARY: Exploration of general surgery residents' decision making skills in uncommon, complex urinary catheter scenarios revealed major deficiencies. The resulting decision trees reveal residents' learning needs. PMID- 28089343 TI - Assessment of microvascular endothelial function in type 1 diabetes using laser speckle contrast imaging. AB - OBJECTIVE: To test whether laser speckle contrast imaging (LSCI) coupled with physiological post-occlusive reactive hyperemia (PORH) and pharmacological iontophoresis of acetylcholine (ACh) as local vasodilator stimuli could distinguish between cutaneous microvascular responses of Type 1 Diabetes (T1DM)'s patients with endothelial dysfunction and that of healthy controls. METHODS: Patients with T1DM aged >=12years completed a clinical-epidemiological questionnaire. Data detailing patients' such as daily insulin dose, duration of diabetes, and use of pharmaceuticals such as antihypertensive drugs and statins that could interfere with endothelial function were obtained. Vascular reactivity was assessed in the forearm by LSCI and PORH at baseline and during iontophoresis of ACh using increasing anodic currents of 30, 60, 90, 120, 150 and 180MUA in 10second intervals. RESULTS: This study included 50 patients with T1DM and 30 control subjects. The mean resting flux did not differ between patients and control subjects. T1DM patients exhibited endothelial dysfunction upon challenge with physiological or pharmacological stimuli. The microvascular response to both ACh and PORH (i.e., maximum response at peak and amplitude) were significantly reduced in patients with diabetes compared with control subjects (p<0.001). CONCLUSION: We demonstrated that endothelium-dependent skin microvascular vasodilator responses are significantly impaired in patients with T1DM compared to healthy subjects investigated using LSCI coupled with ACh iontophoresis and PORH. Additionally, we find that LSCI is a promising methodology for studying physiological vascular reactivity in T1DM. PMID- 28089344 TI - Heparan sulfate storage in the cardiac conduction system triggers atrioventricular block. AB - OBJECTIVE: To elucidate the novel biological functions of heparan sulfate (HS) by clinic-pathologically studying a patient with paroxysmal atrioventricular (AV) block. PATIENT: A long-surviving male patient with Sanfilippo syndrome type A presented with paroxysmal AV block at age 33years. He then survived another 2.5years after the onset of paroxysmal AV block and pacemaker implantation. METHODS AND RESULTS: His cardiac histopathological examination at autopsy showed HS storage in the cardiac conduction system (CCS), especially in the atrioventricular node (AVN)-His bundle branches. CONCLUSION: HS storage in the CCS might trigger AV block, arising from below the AVN-His bundle branches. This is the first description to indicate that HS might be an essential constituent of life-long CCS plasticity and that its storage in the CCS results in AV block. PMID- 28089345 TI - The insect spermatheca: an overview. AB - In the female insect, the spermatheca is an ectodermal organ responsible for receiving, maintaining, and releasing sperm to fertilize eggs. The number and morphology of spermathecae vary according to species. Within the spermathecal lumen, substances in the semen and secretions from the spermathecal gland nourish the sperm. Thus, the spermatheca provides an appropriate environment that ensures the long-term viability of sperm. Maintaining sperm viability for long periods within the spermatheca is crucial for insect reproductive success; however, the details of this process remain poorly understood. This review examines several aspects of and gaps in the current understanding of spermatheca biology, including morphology, function, reservoir filling, development, and biochemistry. Despite the importance of the spermatheca in insects, there is little information on the gland secretions and their role in the maintenance and protection of male gametes. Furthermore, in this review, we highlight the current information on spermathecal gland secretions and the likely roles they play in the maintenance and protection of sperm. PMID- 28089346 TI - Detection of unusual very-long-chain fatty acid and ether lipid derivatives in the fibroblasts and plasma of patients with peroxisomal diseases using liquid chromatography-mass spectrometry. AB - Metabolic changes occur in patients with peroxisomal diseases owing to impairments in the genes involved in peroxisome function. For diagnostic purposes, saturated very-long-chain fatty acids (VLCFAs) such as C24:0 and C26:0, phytanic acid, pristanic acid, and plasmalogens are often measured as metabolic hallmarks. As the direct pathology of peroxisomal disease is yet to be fully elucidated, we sought to explore the fatty acid species that accumulate in patients with peroxisomal diseases. We developed a method for detecting a range of fatty acids implicated in peroxisomal diseases such as Zellweger syndrome (ZS) and X-linked adrenoleukodystrophy (X-ALD). To this end, we employed an ultra performance liquid chromatography-mass spectrometry (LC-MS) coupled with negatively charged electrospray ionization. Fatty acids from patients and control subjects were extracted from total lipids by acid-hydrolysis and compared. In accordance with previous results, the amounts of VLCFAs, phytanic acid, and pristanic acid differed between the two groups. We identified extremely long and highly polyunsaturated VLCFAs (ultra-VLC-PUFAs) such as C44:12 in ZS samples. Moreover, three unknown molecules were prominent in control samples but scarcely detectable in ZS samples. LC-MS/MS analysis identified these as 1-alkyl-sn glycerol 3-phosphates derived from ether lipids containing fatty alcohols such as C16:0, C18:0, or C18:1. Our method provides an approach to observing a wide range of lipid-derived fatty acids and related molecules in order to understand the metabolic changes involved in peroxisomal diseases. This technique can therefore be used in identifying metabolic markers and potential clinical targets for future treatment. PMID- 28089347 TI - Virtual screening and experimental validation identify novel modulators of nuclear receptor RXRalpha from Drugbank database. AB - Retinoid X receptor alpha (RXRalpha), an important ligand-dependent transcription factor, plays a critical role in the development of various cancers and metabolic and neurodegenerative diseases. Therefore, RXRalpha represents one of the most important targets in modern drug discovery. In this study, Drugbank 2.0 with 1280 old drugs were virtually screened by Glide according to the crystal structure of ligand-binding domain (LBP) of RXRalpha. 15 compounds selected were tested for their binding and transcriptional activity toward RXRalpha by Biacore and reporter gene assay, respectively. The identified new scafford ligand of RXRalpha, Pitavastatin (1), was chemically optimized. Our results demonstrated that statin compounds Pitavastatin (1) and Fluvastatin (4) could bind to the LBP of RXRalpha (KD=13.30MUM and 11.04MUM, respectively) and serve as transcriptional antagonists of RXRalpha. On the contrary, compound (12) (domperidone) and (13) (rosiglitazone maleate) could bind to the LBP of RXRalpha (KD=8.80MUM and 15.01MUM, respectively) but serve as transcriptional agonists of RXRalpha. PMID- 28089348 TI - Shape-based virtual screening, synthesis and evaluation of novel pyrrolone derivatives as antiviral agents against HCV. AB - A ligand-based approach was applied to screen in silico a library of commercially available compounds, with the aim to find novel inhibitors of the HCV replication starting from the study of the viral NS3 helicase. Six structures were selected for evaluation in the HCV subgenomic replicon assay and one hit was found to inhibit the HCV replicon replication in the low micromolar range. A small series of new pyrrolone compounds was designed and synthesised, and novel structures were identified with improved antiviral activity. PMID- 28089349 TI - Development of new PTK7-targeting aptamer-fluorescent and -radiolabelled probes for evaluation as molecular imaging agents: Lymphoma and melanoma in vivo proof of concept. AB - Aptamers are single-stranded oligonucleotides that recognize molecular targets with high affinity and specificity. Aptamer that selectively bind to the protein tyrosine kinase-7 (PTK7) receptor, overexpressed on many cancers, has been labelled as probes for molecular imaging of cancer. Two new PTK7-targeting aptamer probes were developed by coupling frameworks from the fluorescent dye AlexaFluor647 or the 6-hydrazinonicotinamide (HYNIC) chelator-labelled to 99mTc. The derivatizations via a 5'-aminohexyl terminal linker were done at room temperature and under mild buffer conditions. Physicochemical and biological controls for both imaging agents were performed verifying the integrity of the aptamer-conjugates by HPLC. Recognition of melanoma (B16F1) and lymphoma (A20) mouse cell lines by the aptamer was studied using cell binding, flow cytometry and confocal microscopy. Finally, in vivo imaging studies in tumour-bearing mice were performed. The new probes were able to bind to melanoma and lymphoma cell lines in vitro, the in vivo imaging in tumour-bearing mice showed different uptake behaviours showing for the fluorescent conjugate good uptake by B cell lymphoma while the radiolabelled conjugate did not display tumour uptake due to its high extravascular distribution, and both showed rapid clearance properties in tumour-bearing mice. PMID- 28089350 TI - Rickettsia prowazekii methionine aminopeptidase as a promising target for the development of antibacterial agents. AB - Methionine aminopeptidase (MetAP) is a class of ubiquitous enzymes essential for the survival of numerous bacterial species. These enzymes are responsible for the cleavage of N-terminal formyl-methionine initiators from nascent proteins to initiate post-translational modifications that are often essential to proper protein function. Thus, inhibition of MetAP activity has been implicated as a novel antibacterial target. We tested this idea in the present study by targeting the MetAP enzyme in the obligate intracellular pathogen Rickettsia prowazekii. We first identified potent RpMetAP inhibitory species by employing an in vitro enzymatic activity assay. The molecular docking program AutoDock was then utilized to compare published crystal structures of inhibited MetAP species to docked poses of RpMetAP. Based on these in silico and in vitro screens, a subset of 17 compounds was tested for inhibition of R. prowazekii growth in a pulmonary vascular endothelial cell (EC) culture infection model system. All compounds were tested over concentration ranges that were determined to be non-toxic to the ECs and 8 of the 17 compounds displayed substantial inhibition of R. prowazekii growth. These data highlight the therapeutic potential for inhibiting RpMetAP as a novel antimicrobial strategy and set the stage for future studies in pre clinical animal models of infection. PMID- 28089351 TI - Longitudinal association between hippocampus atrophy and episodic-memory decline. AB - There is marked variability in both onset and rate of episodic-memory decline in aging. Structural magnetic resonance imaging studies have revealed that the extent of age-related brain changes varies markedly across individuals. Past studies of whether regional atrophy accounts for episodic-memory decline in aging have yielded inconclusive findings. Here we related 15-year changes in episodic memory to 4-year changes in cortical and subcortical gray matter volume and in white-matter connectivity and lesions. In addition, changes in word fluency, fluid IQ (Block Design), and processing speed were estimated and related to structural brain changes. Significant negative change over time was observed for all cognitive and brain measures. A robust brain-cognition change-change association was observed for episodic-memory decline and atrophy in the hippocampus. This association was significant for older (65-80 years) but not middle-aged (55-60 years) participants and not sensitive to the assumption of ignorable attrition. Thus, these longitudinal findings highlight medial-temporal lobe system integrity as particularly crucial for maintaining episodic-memory functioning in older age. PMID- 28089352 TI - Downregulation of miR-132/212 impairs S-nitrosylation balance and induces tau phosphorylation in Alzheimer's disease. AB - MicroRNA-132 is markedly downregulated in Alzheimer's disease (AD) and related tauopathies, and its levels are closely associated with tau pathology in AD. Whether and how miR-132 contributes to pathology in these neurodegenerative diseases remains unclear. Here, we show that miR-132 and its paralogue miR-212 directly regulate the expression of neuronal nitric oxide synthase (NOS1) through the primate-specific binding site. Inhibition of miR-132 in primary human neurons and neural cells leads to increased NOS1 levels and triggers excessive production of nitric oxide, followed by aberrant S-nitrosylation (SNO) of specific proteins associated with neurodegeneration and tau pathology, such as cyclin-dependent kinase 5, dynamin-related protein 1, and glyceraldehyde-3-phosphate dehydrogenase. This, in turn, increases tau phosphorylation at disease associated Ser396, Ser404, and Ser202 sites, and impairs neural viability. Our findings indicate that downregulation of miR-132/212 disturbs the balance of S nitrosylation and induces tau phosphorylation in a NOS1-dependent way, and thereby may contribute to the pathogenesis of AD and other tauopathies. PMID- 28089353 TI - Cerebrospinal fluid mitochondrial DNA in the Alzheimer's disease continuum. AB - Low levels of cell-free mitochondrial DNA (mtDNA) in the cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients have been identified and proposed as a novel biomarker for the disease. The lack of validation studies of previous results prompted us to replicate this finding in a comprehensive series of patients and controls. We applied droplet digital polymerase chain reaction in CSF specimens from 124 patients representing the AD spectrum and 140 neurologically healthy controls. The following preanalytical and analytical parameters were evaluated: the effect of freeze-thaw cycles on mtDNA, the linearity of mtDNA load across serial dilutions, and the mtDNA levels in the diagnostic groups. We found a wide range of mtDNA copies, which resulted in a high degree of overlap between groups. Although the AD group presented significantly higher mtDNA counts, the receiver-operating characteristic analysis disclosed an area under the curve of 0.715 to distinguish AD patients from controls. MtDNA was highly stable with low analytical variability. In conclusion, mtDNA levels in CSF show a high interindividual variability, with great overlap within phenotypes and presents low sensitivity for AD. PMID- 28089354 TI - Primary biliary cholangitis-primary sclerosing cholangitis in an evolving overlap syndrome: A case report. PMID- 28089355 TI - Lymphocytic esophagitis: A rare finding in adult patients with dysphagia and food impaction. PMID- 28089356 TI - Insertions and Deletions Target Lineage-Defining Genes in Human Cancers. AB - Certain cell types function as factories, secreting large quantities of one or more proteins that are central to the physiology of the respective organ. Examples include surfactant proteins in lung alveoli, albumin in liver parenchyma, and lipase in the stomach lining. Whole-genome sequencing analysis of lung adenocarcinomas revealed noncoding somatic mutational hotspots near VMP1/MIR21 and indel hotspots in surfactant protein genes (SFTPA1, SFTPB, and SFTPC). Extrapolation to other solid cancers demonstrated highly recurrent and tumor-type-specific indel hotspots targeting the noncoding regions of highly expressed genes defining certain secretory cellular lineages: albumin (ALB) in liver carcinoma, gastric lipase (LIPF) in stomach carcinoma, and thyroglobulin (TG) in thyroid carcinoma. The sequence contexts of indels targeting lineage defining genes were significantly enriched in the AATAATD DNA motif and specific chromatin contexts, including H3K27ac and H3K36me3. Our findings illuminate a prevalent and hitherto unrecognized mutational process linking cellular lineage and cancer. PMID- 28089357 TI - Localization of Toll-like Receptor (TLR) 2 and TLR4 mRNA in the Colorectal Mucosa of Miniature Dachshunds with Inflammatory Colorectal Polyps. AB - Inflammatory colorectal polyps (ICRPs) are characterized by the formation of multiple or solitary polyps with marked neutrophil infiltration in the colorectal area, and are speculated to be a novel form of breed-specific canine idiopathic inflammatory bowel disease (IBD). In human IBD, toll-like receptor (TLR) 2 and TLR4 have been reported to be involved in the pathogenesis of the disease. The aim of this study was to evaluate the expression of TLR2 and TLR4 mRNA in the colorectal mucosa of dogs with ICRPs by in-situ hybridization using an RNAscope assay. Samples of inflamed colorectal mucosa (n = 5) and non-inflamed mucosa (n = 5) from miniature dachshunds (MDs) with ICRPs and colonic mucosa from healthy beagles (n = 5) were examined. TLR2 and TLR4 hybridization signals were localized to the colorectal epithelium, inflammatory cells and fibroblasts in the inflamed colorectal mucosa of affected dogs. The signals were significantly greater in inflamed colorectal epithelium compared with non-inflamed epithelium of MDs with ICRPs and healthy beagles (P <0.05). These results suggest that increased expression of TLR2 and TLR4 mRNA in the inflamed colorectal mucosa results from not only inflammatory cell infiltration, but also the upregulation of TLR2 and TLR4 mRNA in the colonic epithelium. PMID- 28089358 TI - Complex febrile seizures-A systematic review. PMID- 28089359 TI - Transient and long-time kinetic responses of the cadaveric leg during internal and external foot rotation. AB - The purpose of this study was to determine the long-time and transient characteristics of the moment generated by external (ER) and internal (IR) rotation of the calcaneus with respect to the tibia. Two human cadaver legs were disarticulated at the knee joint while maintaining the connective tissue between the tibia and fibula. An axial rotation of 21 degrees was applied to the proximal tibia to generate either ER or IR while the fibula was unconstrained and the calcaneus was permitted to translate in the transverse plane. These boundary conditions were intended to allow natural motion of the fibula and for the effective applied axis of rotation to move relative to the ankle and subtalar joints based on natural articular motions among the tibia, fibula, talus, and calcaneus. A load cell at the proximal tibia measured all components of force and moment. A quasi-linear model of the moment along the tibia axis was developed to determine the transient and long-time loads generated by this ER/IR. Initially neutral, everted, inverted, dorsiflexed, and plantarflexed foot orientations were tested. For the neutral position, the transient elastic moment was 16.5N-m for one specimen and 30.3N-m for the other in ER with 26.3 and 32.1N-m in IR. The long-time moments were 5.5 and 13.2N-m (ER) and 9.0 and 9.5N-m (IR). These loads were found to be transient over time similar to previous studies on other biological structures where the moment relaxed as time progressed after the initial ramp in rotation. PMID- 28089360 TI - Renal aspergillosis after liver transplant: Report of an unusual case. PMID- 28089361 TI - Solitary fibrous tumor of the gastroesophageal junction. PMID- 28089362 TI - Clinical pharmacokinetics of oral levofloxacin and sitafloxacin in epididymal tissue. AB - OBJECTIVES: This study aimed to investigate the penetration of fluoroquinolones into human epididymal tissue. METHODS: The penetration of levofloxacin (LVFX) 500 mg or sitafloxacin (STFX) 100 mg into epididymal tissue was examined. Patients with prostate cancer who were referred for orchiectomy were included. LVFX 500 mg (n = 9) or STFX 100 mg (n = 9) was administered orally 1 h before orchiectomy, and 0.5 g of epididymal tissue and blood samples were collected simultaneously during surgery. Drug concentrations were measured by high-performance liquid chromatography, and patient characteristics and adverse events were analyzed. RESULTS: The mean ratio of the epididymal concentration to the serum concentration was 1.48 +/- 0.45 for LVFX and 1.54 +/- 0.81 for STFX. For LVFX, the simulated curves estimated the following: maximum concentrations (Cmax) of 8.84 MUg/ml in serum and 14.1 MUg/g in epididymal tissue and area under the concentration-time curve for 24 h (AUC24) of 68.5 MUg h/ml in serum and 108.9 MUg h/g in epididymal tissue. For STFX, the Cmax was 1.22 MUg/ml in serum and 1.66 MUg/g in epididymal tissue, and the AUC24 was 9.58 MUg h/ml in serum and 13.1 MUg h/g in epididymal tissue. Neither treatment-related adverse events nor postoperative urogenital infections were observed. CONCLUSIONS: The results of this study suggest that oral administration of LVFX 500 mg or STFX 100 mg achieves effective epididymal concentrations for treatment of epididymitis. PMID- 28089363 TI - Pertussis toxin targets the innate immunity through DAP12, FcRgamma, and MyD88 adaptor proteins. AB - Activation of the innate immunity by adjuvants, such as pertussis toxin (PTX), in the presence of autoreactive lymphocytes and antigen mimicry is sufficient to trigger autoimmunity. Toll-like, C-type lectin, and immunglobulin-like receptors play an important role in the innate immunity by sensing a variety of microbial products through several adaptor proteins, including MyD88, DAP12, and FcRgamma. This study investigated the interaction between PTX and innate immune components. The direct interactions between coated PTX and receptor-fusion proteins were examined using ELISA-based binding assays. Functionally, PTX-binding receptors could be classified into two groups: inhibition (DAP12-coupled TREM2, ITIM bearing SIRPalpha, SIGNR1/SIGNR3/DCSIGN) and activation (MyD88-associated TLR4, DAP12-coupled LMIR5/CD300b, FcRgamma-coupled LMIR8/CD300c, CLEC9A, MGL-1). DAP12, MyD88, and FcRgamma were selected for further investigation. A comprehensive analysis of gene transcription showed that PTX up-regulated the expression of various inflammatory mediators. DAP12 deficiency resulted in reduction or enhancement of inflammatory responses in a cytokine-specific manner. PTX was able to activate the TREM2-DAP12 signalling pathway. PTX induced lower expression of inflammatory mediators in the absence of FcRgamma alone and substantially lost its inflammatory capacity in the absence of both FcRgamma and MyD88. PTX was able to activate the MyD88-NF-kappaB signalling pathway in the presence of TLR2 or TLR4. The inflammatory activity of PTX was completely lost by heating. These results demonstrate that PTX targets the innate immunity through DAP12, FcRgamma, and MyD88 providing new insights into the immunobiology of PTX. PMID- 28089364 TI - The impact of neoadjuvant chemotherapy on skeletal muscle depletion and preoperative sarcopenia in patients with resectable colorectal liver metastases. AB - BACKGROUND: Preoperative skeletal muscle depletion or sarcopenia has been suggested to predict worse outcome after resection of colorectal liver metastases. The aim of the present study was to investigate the impact of neoadjuvant chemotherapy on preoperative skeletal muscle mass prior to liver resection. METHODS: Patients operated with liver resection for colorectal liver metastases between 2010 and 2014 were retrospectively reviewed. Muscle mass was evaluated by measuring muscle area on a cross-sectional computed tomography image at the level of the third lumbar vertebra, and normalized for patient height, presenting a skeletal muscle index. RESULTS: Preoperative skeletal muscle mass was analysed in 225 patients, of whom 97 underwent neoadjuvant chemotherapy. In total 147 patients (65%) were categorized as sarcopenic preoperatively. Patients receiving neoadjuvant chemotherapy decreased in skeletal muscle mass (decrease by 5.5 (-1.1 to 11) % in skeletal muscle index, p < 0.001). Patients with muscle loss >5% during neoadjuvant chemotherapy were less likely to undergo adjuvant chemotherapy than others (68% vs 85%, p = 0.048). A >5% muscle loss did not result in worse overall (p = 0.131) or recurrence-free survival (p = 0.105). CONCLUSION: Skeletal muscle mass decreases during neoadjuvant chemotherapy. Skeletal muscle loss during neoadjuvant chemotherapy impairs the conditions for adjuvant chemotherapy. PMID- 28089365 TI - Gastric bleeding risk following spleen preserving distal pancreatectomy with excision of the splenic vessels: a long-term follow-up. AB - BACKGROUND: Spleen-preserving distal pancreatectomy with resection of the splenic vessels (VR-SPDP) is an effective procedure. However, hemodynamic changes in splenogastric circulation may lead to the development of gastric varices (GV) with a risk of gastrointestinal (GI) bleeding. This retrospective study aimed to assess the long-term postoperative clinical follow-up of patients and review the late postoperative abdominal computed tomography (CT) or endoscopic examination. METHODS: From 1988 to 2015, 48 consecutive VR-SPDP for benign or low-grade malignant disease were included. Late postoperative follow-up was undertaken with the use of a prospective database and assessment undertaken by CT and/or endoscopy. RESULTS: The median follow-up was 76 months (range: 12-334 months). Two patients were lost to follow-up. Gastrointestinal hemorrhage occurred in one patient. Endoscopy and abdominal CT showed submucosal GV in five patients. Ten patients had perigastric varices (27%), but none developed clinical complications from their varices. All varices occurred within one year after distal pancreatectomy and remained stable during follow-up. DISCUSSION: Asymptomatic varices frequently occurred in patients who underwent VR-SPDP, but bleeding risk seemed low. Abdominal CT could identify GV and distinguish submucosal varices with a higher risk of gastric bleeding. PMID- 28089366 TI - Limited reduction in uremic solute concentrations with increased dialysis frequency and time in the Frequent Hemodialysis Network Daily Trial. AB - The Frequent Hemodialysis Network Daily Trial compared conventional three-times weekly treatment to more frequent treatment with a longer weekly treatment time in patients receiving in-center hemodialysis. Evaluation at one year showed favorable effects of more intensive treatment on left ventricular mass, blood pressure, and phosphate control, but modest or no effects on physical or cognitive performance. The current study compared plasma concentrations of uremic solutes in stored samples from 53 trial patients who received three-times weekly in-center hemodialysis for an average weekly time of 10.9 hours and 30 trial patients who received six-times weekly in-center hemodialysis for an average of 14.6 hours. Metabolomic analysis revealed that increased treatment frequency and time resulted in an average reduction of only 15 percent in the levels of 107 uremic solutes. Quantitative assays confirmed that increased treatment did not significantly reduce levels of the putative uremic toxins p-cresol sulfate or indoxyl sulfate. Kinetic modeling suggested that our ability to lower solute concentrations by increasing hemodialysis frequency and duration may be limited by the presence of non-dialytic solute clearances and/or changes in solute production. Thus, failure to achieve larger reductions in uremic solute concentrations may account, in part, for the limited benefits observed with increasing frequency and weekly treatment time in Frequent Hemodialysis Daily Trial participants. PMID- 28089367 TI - A career in epilepsy. PMID- 28089368 TI - The transition from pediatric to adult care for youth with epilepsy: Basic biological, sociological, and psychological issues. AB - Transition from pediatric to adult health care for adolescents with epilepsy is challenging for the patient, family, and health care workers. This paper is the first of three that summarize the main findings from the 2nd Symposium on Transition in Epilepsies, held in Paris from June 14-25, 2016. In this paper we describe five basic themes that have an important effect on transition. First, there are important brain changes in adolescence that leave an imbalance between risk taking and pleasure seeking behaviors and frontal executive function compared with adults. Second, puberty is a major change during the transition age. The three most important but separate neuroendocrine axes involved in puberty are gonadarche (activation of the gonads), adrenarche (activation of adrenal androgen production), and activation of the growth hormone-insulin like growth factor. Third, sexual debut occurs during the transition years, and at an earlier age in adolescents with epilepsy than controls. Adult sexual performance is often unsatisfactory. Although AED-induced alterations in sexual hormones and temporal lobe epilepsy may play a role in hyposexuality, depression, anxiety, and other social factors appear most important. Fourth, psychological development is very important with an evolution from an early stage (ages 10-13years) with concrete thinking, to a middle stage (ages 14-17) with analytic and more abstract introspective thinking, and then to a late stage (ages 18-21) with at least the beginnings of adult reasoning. Epilepsy may derail this relatively orderly progression. Adolescents with autistic spectrum disorder may present with severe behavior problems that are sometimes related to undiagnosed epilepsy. Fifth, bone health in adolescence is critical to establish adequate mineralization for all of adult life. While AED interference with Vitamin D metabolism is important, there is evidence that the effects of AEDs on bone are more complex and involve changes in remodeling. Hence, some non-inducing AEDs may have a significant effect on bone health. All five of these themes lead to recommendations for how to approach adolescents and young adults during transition and some specific interventions to achieve maximum long-term adult independence and quality of life. PMID- 28089369 TI - Deciphering the Fringe-Mediated Notch Code: Identification of Activating and Inhibiting Sites Allowing Discrimination between Ligands. AB - Fringe proteins are beta3-N-acetylglucosaminyltransferases that modulate Notch activity by modifying O-fucose residues on epidermal growth factor-like (EGF) repeats of Notch. Mammals have three Fringes: Lunatic, Manic, and Radical. While Lunatic and Manic Fringe inhibit Notch1 activation from Jagged1 and enhance activation from Delta-like 1, Radical Fringe enhances signaling from both. We used a mass spectrometry approach to determine whether the variable effects of Fringes on Notch1 result from generation of unique glycosylation patterns on Notch1. We found that Lunatic and Manic Fringe modified similar sites on Notch1, while Radical Fringe modified a subset. Fringe modifications at EGF8 and EGF12 enhanced Notch1 binding to and activation from Delta-like 1, while modifications at EGF6 and EGF36 (added by Manic and Lunatic but not Radical) inhibited Notch1 activation from Jagged1. Combined, these results suggest that Fringe modifications "mark" different regions in the Notch1 extracellular domain for activation or inhibition. PMID- 28089371 TI - Branched-chain amino acids are associated with odd-chain fatty acids in normoglycaemic individuals. PMID- 28089370 TI - Single-Cell Multiomics: Multiple Measurements from Single Cells. AB - Single-cell sequencing provides information that is not confounded by genotypic or phenotypic heterogeneity of bulk samples. Sequencing of one molecular type (RNA, methylated DNA or open chromatin) in a single cell, furthermore, provides insights into the cell's phenotype and links to its genotype. Nevertheless, only by taking measurements of these phenotypes and genotypes from the same single cells can such inferences be made unambiguously. In this review, we survey the first experimental approaches that assay, in parallel, multiple molecular types from the same single cell, before considering the challenges and opportunities afforded by these and future technologies. PMID- 28089372 TI - Inhibition or deletion of 11beta-HSD1 does not increase angiogenesis in ischemic retinopathy. PMID- 28089373 TI - Clinical parameters affecting dapagliflozin response in patients with type 2 diabetes. PMID- 28089374 TI - Epigenetic information in gametes: Gaming from before fertilization: Comment on "Epigenetic game theory: How to compute the epigenetic control of maternal-to zygotic transition" by Qian Wang et al. PMID- 28089375 TI - Viewpoints of high migratory tuna species ecology: Comment on "Physics of metabolic organization" by M. Jusup et al. PMID- 28089376 TI - Chemotherapy completion in elderly women with ovarian, primary peritoneal or fallopian tube cancer - An NRG oncology/Gynecologic Oncology Group study. AB - PURPOSE: A simple measure to predict chemotherapy tolerance in elderly patients would be useful. We prospectively tested the association of baseline Instrumental Activities of Daily Living (IADL) score with ability to complete 4 cycles of first line chemotherapy without dose reductions or >7days delay in elderly ovarian cancer patients. PATIENTS AND METHODS: Patients' age >=70 along with their physicians chose between two regimens: CP (Carboplatin AUC 5, Paclitaxel 135mg/m2) or C (Carboplatin AUC 5), both given every 3weeks either after primary surgery or as neoadjuvant chemotherapy (NACT) with IADL and quality of life assessments performed at baseline, pre-cycle 3, and post-cycle 4. RESULTS: Two hundred-twelve women were enrolled, 152 selecting CP and 60 selecting C. Those who selected CP had higher baseline IADL scores (p<0.001). After adjusting for age and PS, baseline IADL was independently associated with the choice of regimen (p=0.035). The baseline IADL score was not found to be associated with completion of 4 cycles of chemotherapy without dose reduction or delays (p=0.21), but was associated with completion of 4 cycles of chemotherapy regardless of dose reduction and delay (p=0.008) and toxicity, with the odds ratio (OR) of grade 3+ toxicity decreasing 17% (OR: 0.83; 95%CI: 0.72-0.96; p=0.013) for each additional activity in which the patient was independent. After adjustment for chemotherapy regimen, IADL was also associated with overall survival (p=0.019) for patients receiving CP. CONCLUSION: Patients with a higher baseline IADL score (more independent) were more likely to complete 4 cycles of chemotherapy and less likely to experience grade 3 or higher toxicity. PMID- 28089377 TI - Phase II trial of albumin-bound paclitaxel and granulocyte macrophage colony stimulating factor as an immune modulator in recurrent platinum resistant ovarian cancer. AB - BACKGROUND: Granulocyte macrophage colony-stimulating factor (GM-CSF) stimulates immunity via recruitment of antigen presenting cells and tumor specific T-cell stimulation. Albumin-bound paclitaxel (nab-paclitaxel) followed by GM-CSF may enhance antitumor responses and prolong remissions in ovarian cancer. Immune phenotypes present before treatment may identify responders to chemo immunotherapy. METHODS: Recurrent platinum-resistant ovarian, peritoneal, or fallopian tube cancer patients received nab-paclitaxel, 100mg/m2 days 1, 8, 15 followed by GM-CSF 250MUg days 16-26 every 28days for 6 planned cycles. The primary endpoint was remission duration compared to immediate prior remission. Peripheral blood was evaluated by flow cytometry and interferon-gamma ELISPOT. RESULTS: Twenty-one patients were enrolled. Six patients (29%) achieved a biochemical complete response and 9 (43%) a partial response for an overall response rate of 72%. Median time to progression was 4months and 10% of patients achieved longer remissions than the immediate prior regimen. Median overall survival (OS) was 16.8months. Fewer myeloid derived suppressor cells (MDSC) at enrollment significantly associated with complete response (p=0.05). T-cell responses to IGF1R-p1332-1346 (r=0.827, p=0.0003) and IGF1R-p1242-1256 (r=0.850, p=0.0001) during treatment correlated with time to progression. CONCLUSIONS: Nab paclitaxel combined with GM-CSF demonstrated biochemical responses in a majority of patients, although responses were not sustained. This combination did not demonstrate an advantage in OS over prior studies of nab-paclitaxel monotherapy. Agents that modulate MDSC should be studied as potential adjuvants to therapy. Strategies to expand T cells recognizing tumor-associated antigens biologically significant in ovarian cancer should also continue to be investigated. PMID- 28089379 TI - Characterization of a novel DyP-type peroxidase from Streptomyces avermitilis. AB - DyP-type peroxidases are a heme peroxidase family with unique properties whose members are widely distributed from prokaryotes to eukaryotes. DyP-type peroxidases are subdivided into class P, I and V based on structure-based sequence alignment. Class V enzymes possess degradation activities for anthraquinone dyes, and include extra sequences compared with class P and I. Class V enzymes are mainly found in fungi, with only two such proteins, AnaPX and DyP2, reported in bacteria. Here, we heterologously expressed, purified and biochemically characterized SaDyP2 protein, predicted to belong to class V. SaDyP2 was purified as a ~50 kDa enzyme containing a heme cofactor and was found to oxidize the typical peroxidase substrates, ABTS and DMP. SaDyP2 was generally thermostable and exhibited a lower optimal pH, a feature typical of DyP-type peroxidases. It also degraded anthraquinone dyes, a specific substrate of DyP type peroxidases, although the kcat for SaDyP2 was lower than that for other class V enzymes. The Km value of SaDyP2 for anthraquinone dye was similar to that of other enzymes of this class. Homology modeling revealed that the structure of SaDyP2 best fit that of class V enzymes. PMID- 28089378 TI - Butyrate production under aerobic growth conditions by engineered Escherichia coli. AB - Butyrate is an important industrial platform chemical. Although several groups have reported butyrate production under oxygen-limited conditions by a native producer, Clostridium tyrobutylicum, and by a metabolically engineered Escherichia coli, efforts to produce butyrate under aerobic growth conditions have met limited success. Here, we constructed a novel butyrate synthetic pathway that functions under aerobic growth conditions in E. coli, by modifying the 1 butanol synthetic pathway reported previously. The pathway consists of phaA (acetyltransferase) and phaB (NADPH-dependent acetoacetyl-CoA reductase) from Ralstonia eutropha, phaJ ((R)-specific enoyl-CoA hydratase) from Aeromonas caviae, ter (trans-enoyl-CoA reductase) from Treponema denticola, and endogenous thioesterase(s) of E. coli. To evaluate the potential of this pathway for butyrate production, culture conditions, including pH, oxygen supply, and concentration of inorganic nitrogen sources, were optimized in a mini-jar fermentor. Under the optimal conditions, butyrate was produced at a concentration of up to 140 mM (12.3 g/L in terms of butyric acid) after 54 h of fed-batch culture. PMID- 28089381 TI - PET/CT: underlying physics, instrumentation, and advances. AB - Since it was first introduced, the main goal of PET/CT has been to provide both PET and CT images with high clinical quality and to present them to radiologists and specialists in nuclear medicine as a fused, perfectly aligned image. The use of fused PET and CT images quickly became routine in clinical practice, showing the great potential of these hybrid scanners. Thanks to this success, manufacturers have gone beyond considering CT as a mere attenuation corrector for PET, concentrating instead on design high performance PET and CT scanners with more interesting features. Since the first commercial PET/CT scanner became available in 2001, both the PET component and the CT component have improved immensely. In the case of PET, faster scintillation crystals with high stopping power such as LYSO crystals have enabled more sensitive devices to be built, making it possible to reduce the number of undesired coincidence events and to use time of flight (TOF) techniques. All these advances have improved lesion detection, especially in situations with very noisy backgrounds. Iterative reconstruction methods, together with the corrections carried out during the reconstruction and the use of the point-spread function, have improved image quality. In parallel, CT instrumentation has also improved significantly, and 64- and 128-row detectors have been incorporated into the most modern PET/CT scanners. This makes it possible to obtain high quality diagnostic anatomic images in a few seconds that both enable the correction of PET attenuation and provide information for diagnosis. Furthermore, nowadays nearly all PET/CT scanners have a system that modulates the dose of radiation that the patient is exposed to in the CT study in function of the region scanned. This article reviews the underlying physics of PET and CT imaging separately, describes the changes in the instrumentation and standard protocols in a combined PET/CT system, and finally points out the most important advances in this hybrid imaging modality. PMID- 28089380 TI - Biotic Host-Pathogen Interactions As Major Drivers of Plastid Endosymbiosis. AB - The plastid originated 1.5 billion years ago through a primary endosymbiosis involving a heterotrophic eukaryote and an ancient cyanobacterium. Phylogenetic and biochemical evidence suggests that the incipient endosymbiont interacted with an obligate intracellular chlamydial pathogen that housed it in an inclusion. This aspect of the menage-a-trois hypothesis (MATH) posits that Chlamydiales provided critical novel transporters and enzymes secreted by the pathogens in the host cytosol. This initiated the efflux of photosynthate to both the inclusion lumen and host cytosol. Here we review the experimental evidence supporting the MATH and focus on chlamydial genes that replaced existing cyanobacterial functions. The picture emerging from these studies underlines the importance of chlamydial host-pathogen interactions in the metabolic integration of the primary plastid. PMID- 28089383 TI - [Long-term psychiatric hospitalizations]. AB - BACKGROUND: Long-term hospitalizations in psychiatry raise the question of desocialisation of the patients and the inherent costs. METHODS: Individual indicators were extracted from a medical administrative database containing full time psychiatric hospitalizations for the period 2011-2013 of people over 16 years old living in the French region of Nord-Pas-de-Calais. We calculated the proportion of people who had experienced a hospitalization with a duration of 292 days or more during the study period. A bivariate analysis was conducted, then ecological data (level of health-care offer, the deprivation index and the size of the municipalities of residence) were included into a multilevel regression model in order to identify the factors significantly related to variability of long-term hospitalization rates. RESULTS: Among hospitalized individuals in psychiatry, 2.6% had had at least one hospitalization of 292 days or more during the observation period; the number of days in long-term hospitalization represented 22.5% of the total of days of full-time hospitalization in psychiatry. The bivariate analysis revealed that seniority in the psychiatric system was strongly correlated with long hospitalization rates. In the multivariate analysis, the individual indicators the most related to an increased risk of long-term hospitalization were: total lack of autonomy (OR=9.0; 95% CI: 6.7-12.2; P<001); diagnoses of psychological development disorders (OR=9.7; CI95%: 4.5-20.6; P<.001); mental retardation (OR=4.5; CI95%: 2.5-8.2; P<.001): schizophrenia (OR=3.0; CI95%: 1.7-5.2; P<.001); compulsory hospitalization (OR=1.7; CI95%: 1.4-2.1; P<.001); having experienced therapeutic isolation (OR=1.8; CI95%: 1.5-2.1; P<.001). Variations of long-term hospitalization rates depending on the type of establishment were very high, but the density of hospital beds or intensity of ambulatory activity services were not significantly linked to long-term hospitalization. The inhabitants of small urban units had significantly less risk of long-term hospitalization than those of large cities. We found no influence of material and social deprivation in the long-term hospitalizations. CONCLUSION: Long-term hospitalization in psychiatry only concerns a minority of patients but represents the fifth of the total number of days of full-time hospitalization. The recent patients were significantly less exposed to the risk of having a long-term hospitalization. PMID- 28089382 TI - [Systematic revue of the tools for multiprofessional primary care teams assessment]. AB - BACKGROUND: Multiprofessionnal teams in primary care are developing in many countries including France. These groups appear very heterogeneous regarding the level of integration and interprofessional cooperation. A systematic review of the literature was performed to screen the instruments which assess the organizational development of primary care groups. METHODS: Scientific literature was searched in the Pubmed database, gray literature was searched for on the Internet. The documents were selected by two independent investigators. The collected data included information on assessment instruments: origin, content, method of use, and validation process. RESULTS: Sixty-five documents involving 16 assessment instruments were selected for the study. Twelve instruments have been developed in North America and 4 in Europe. Four instruments were evaluation questionnaires, 4 accreditation tools and 8 were maturity matrices. The maturity matrices were structured by levels of organizational development. Their use were effected by an individual self-assessment of each professional and then by consensus of the group in the presence of an external facilitator. The questionnaire and accreditation tools have organizations and use patterns variable. The number of questions ranged from 25 to 200 with a median of 80. The instruments were organized into 4 to 16 dimensions with a median of 7. Six common themes were identified: practice and staff management, quality development, data patient management, interprofessional cooperation, accessibility and continuity of care, and formation. The validation process of tools were variable and often incomplete. CONCLUSION: The set of assessment tools for primary care group is heterogeneous in purpose, content and mode of use. However, common themes were found for all tools. An evaluation questionnaire, in French, would be useful to monitor over time and evaluate the organizational development of centers and health houses in France. PMID- 28089384 TI - [Trends in social inequities in diabetes care in the Provence-Alpes-Cote-d'Azur region of France between 2008 and 2011]. AB - BACKGROUND: Social inequities in healthcare are known to exist for the management of many chronic diseases in France, including diabetes. The recession that began in 2008 has led to increased income disparities but has it also exacerbated health inequities. The aim of this study was to describe trends in inequities in diabetes-related healthcare between 2008 and 2011 in the PACA region (Provence Alpes-Cote-d'Azur). METHODS: This analysis used two sources of data: the regional national health insurance fund (PACA region) reimbursement database and the socio demographic databases of the national statistics office (INSEE) for four full years (2008 to 2011). It included individuals who had been reimbursed for three purchases of oral diabetes drugs during the previous year and assessed the association between the median household income (weighted by number and age of household members) of each patient's municipality of residence and seven indicators of diabetes monitoring and care. Using adjusted mixed logistic models, including an interaction term between time (number of years) and the median household income of the municipality, we examined the performance of the indicators for each year. RESULTS: The total number of patients with diabetes in the 941 municipalities of the PACA region varied by year from 142,055 to 164,929. Models showed that living in a town with a high or intermediate household income was significantly associated with better performance of the seven indicators and that the interaction term was significant for six of them. The effect of the municipal median income decreased significantly between 2008 and 2011 for five indicators: HbA1c, LDL-cholesterol, microalbuminuria, ophthalmoscopy and diabetes specialist visit. CONCLUSION: Social inequities in diabetes-related healthcare persisted between 2008 and 2011 but appeared to be decreasing, despite the recession. PMID- 28089385 TI - Tailored telephone counselling to increase participation of underusers in a population-based colorectal cancer-screening programme with faecal occult blood test: A randomized controlled trial. AB - BACKGROUND: Despite the involvement of general practitioners, the mailing of several recall letters and of the faecal occult blood test (FOBT) kit, the uptake remains insufficient in the French colorectal cancer-screening programme. Some studies have demonstrated a greater efficacy of tailored telephone counselling over usual care, untailored invitation mailing and FOBT kit mailing. We evaluated the feasibility and the effectiveness of telephone counselling on participation in the population-based FOBT colorectal cancer-screening programme implemented in Alsace (France). METHODS: Underusers were randomized into a control group with untailored invitation and FOBT kit mailing (n=19,756) and two intervention groups for either a computer-assisted telephone interview (n=9367), system for tailored promotion of colorectal cancer screening, or a telephone-based motivational interview (n=9374). RESULTS: Only 5691 (19.9%) people were actually counseled, so that there was no difference in participation between the intervention groups taken together (13.9%, 95% confidence interval [CI] [13.5-14.4]) and the control group (13.9%, 95% CI [13.4-14.4]) (P=1.0) in intent-to-treat analysis. However, in per-protocol analysis, participation was significantly higher in the two intervention groups than in the control group (12.9%, 95% CI [12.6-13.2]) (P<0.01), with no difference between computer-assisted telephone interview (24.6%, 95% CI [22.7-26.4]) and motivational interview (23.6%, 95% CI [21.8 25.4]) (P=0.44). CONCLUSION: There was no difference of effectiveness between tailored telephone counselling and untailored invitation and FOBT kit mailing on participation of underusers in an organized population-based colorectal cancer screening programme. A greater efficacy of telephone counselling, around twice that of invitation and FOBT kit mailing, was observed only in people who could actually be counseled, without difference between computer-assisted telephone interview and motivational interview. However, technical failures hampered telephone counselling, so that there was no difference in intent-to-treat analysis. The rate of technical success of telephone interviews should be evaluated, and enhanced if insufficient, before implementation of telephone counselling in population-based cancer screening programmes. PMID- 28089386 TI - Detection of urinary cell-free miR-210 as a potential tool of liquid biopsy for clear cell renal cell carcinoma. AB - BACKGROUND: Recent findings show that cell-free miRNAs are stable in biological fluid. Urine provides an alternative to blood serum or plasma as a potential source of tumor biomarkers. MiR-210 is proven to be overexpressed in patients with a clear cell renal cell carcinoma (ccRCC). The purpose of this pilot study was to examine the urinary cell-free miR-210 as a potential tool of liquid biopsy for ccRCC. METHODS: Overall, 75 patients with a ccRCC and 45 control subjects without a cancer were included in this study. Urine samples were centrifuged twice and the cell-free urine supernanants were stored in -80 degrees C until use. A total of 350ul cell-free urine was used for the extraction of total RNA. The expression levels of these miRNAs were performed by using quantitative RT PCR. RESULTS: The level of urinary cell-free miR-210 was significantly higher in patients with ccRCC than in control subjects (P<0.001). The urinary cell-free miR 210 yielded the areas under the receiver operating characteristics curve of 0.76 in discriminating the patients with ccRCC from the control subjects with a sensitivity of 57.8% and a specificity of 80.0%. Moreover, the expression level of urinary cell-free miRNA-210 was significantly decreased in the patients a week after surgery (P<0.001). CONCLUSION: Urinary cell-free miR-210 may be used as a potential tool of liquid biopsy for ccRCC diagnosis. Further studies are needed to confirm our results. PMID- 28089388 TI - Cortical bone thickness of the mandibular canal and implications for bilateral sagittal split osteotomy: a cadaveric study. AB - Preoperative delineation of the mandibular canal and surrounding cortical bone thickness is mandatory prior to bilateral sagittal split osteotomy (BSSO). The cortical bone thickness of 101 cadaveric mandibles was measured to define the mandibular canal. The mandibles were cut at the anterior ramus, at the third, second, and first molar, and at the premolar. The cortical bone thickness was measured between the mandibular canal and inferior border, buccal cortex, and lingual cortex at each cutting point. No difference was found between the right and left sides of the mandible, or between males and females, with one exception: males were found to have thicker inferior cortical bone at the premolar site than females. The implications for BSSO are: (1) for sagittal bone cutting, the maximum cutting depth of the buccal cortex at the ramus is 4.5mm, at the second and third molars is 6.5mm, and at the first molar is 5mm; (2) for vertical bone cutting at the first molar, the maximum cutting depth from the inferior border is 7.5mm. The measurement of cortical bone thickness from cadaveric mandibles provides useful preoperative information and confirms the results of computed tomography. PMID- 28089387 TI - Treatment of men with high-risk prostate cancer based on race, insurance coverage, and access to advanced technology. AB - PURPOSE: We characterized factors related to nondefinitive management (NDM) of patients with high-risk prostate cancer and assessed impact from race, insurance status, and facility-level volume of technologically advanced prostate cancer treatments (i.e., intensity-modulated radiation therapy, robotic-assisted laparoscopic radical prostatectomy) on this outcome. METHODS: We identified men with high-risk localized prostate cancer (based on D'Amico criteria) in the National Cancer Database (2010-2012). Primary outcome was NDM (i.e., delayed/no treatment with prostatectomy/radiation therapy or androgen-deprivation monotherapy). Treating facilities were classified by quartiles of proportions of patients treated with advanced technology. Multivariable regression estimated odds of primary outcome based on race, insurance status, and facility-level technology use, and evaluated for interactions between these covariates. RESULTS: Among 60,300 patients, 9,265 (15.4%) received NDM. This was more common among non White men (P<0.001), Medicaid/uninsured patients (P<0.001), and those managed at facilities in the lowest quartile of technology use (25.1% vs. 11.0% highest, P<0.001). Though NDM was common among non-White men with Medicaid/no insurance treated at low-technology centers (43% vs. 10% White, private/Medicare, high-tech facility; adjusted odds ratios = 7.18, P<0.001), this was less likely if this group was managed at a high-tech hospital (22% vs. 43% low-tech, P<0.001). CONCLUSIONS: Technology use at a facility correlates with high-quality prostate cancer care and is associated with diminished disparities based on insurance status and patient race. More research is required to characterize other facility level factors explaining these findings. PMID- 28089389 TI - Three-dimensional finite element model to predict patterns of pterygomaxillary dysjunction during Le Fort I osteotomy. AB - The aim of this study was to determine whether non-linear three-dimensional finite element analysis (3D-FEA) can be applied to simulate pterygomaxillary dysjunction during Le Fort I osteotomy (LFI) not involving a curved osteotome (LFI-non-COSep), and to predict potential changes in the fracture pattern associated with extending the cutting line. Computed tomography (CT) image data (100 snapshots) after LFI were converted to 3D-CT images. 3D-FEA models were built using preoperative CT matrix data and used to simulate pterygomaxillary dysjunction. The pterygomaxillary dysjunction patterns predicted by the 3D-FEA models of pterygomaxillary dysjunction were classified into three categories and compared to the pterygomaxillary dysjunction patterns observed in the postoperative 3D-CT images. Extension of the cutting line was also simulated using the 3D-FEA models to predict the risk and position of pterygoid process fracture. The rate of agreement between the predicted pterygomaxillary dysjunction patterns and those observed in the postoperative 3D-CT images was 87.0% (kappa coefficient 0.79). The predicted incidence of pterygoid process fracture was higher for cutting lines that extended to the pterygomaxillary junction than for conventional cutting lines (odds ratio 4.75; P<0.0001). 3D-FEA can be used to predict pterygomaxillary dysjunction patterns during LFI-non-COSep and provides useful information for selecting safer procedures during LFI-non COSep. PMID- 28089390 TI - Quantitative Evaluation of the In Vivo Vocal Fold Medial Surface Shape. AB - OBJECTIVES/HYPOTHESIS: Glottal insufficiency is a common clinical problem in otolaryngology and medialization laryngoplasty (ML) procedures remain the primary treatment modality. Although the goal of ML is to restore physiologic glottal posture and achieve optimal phonation, this posture has not been directly measured. In this study, we assessed glottal medial surface contour changes with selective activation of the intrinsic laryngeal muscles (ILMs). STUDY DESIGN: Basic science study using an in vivo canine hemilarynx model. METHODS: In an in vivo canine hemilarynx, India ink was used to mark fleshpoints in a grid-like fashion along the medial surface of the vocal fold and ILMs were activated in a graded manner. A right-angled prism provided two views of the medial surface, which were recorded using a high-speed camera and used to reconstruct the 3D posture deformations of the medial surface. RESULTS: Thyroarytenoid (TA) muscle activation results in initial inferomedial bulging and increased glottal channel thickness and then glottal adduction with a final rectangular glottal channel shape. Lateral cricoarytenoid (LCA) activation closes the posterior glottis but final posture remains slightly convergent. Together, TA + LCA forms a rectangular glottis with an increased glottal vertical thickness. Posterior cricoarytenoid activation results in abduction and a slightly divergent glottis, whereas cricothyroid activation elongates the glottis and reduces the glottal channel vertical thickness. CONCLUSIONS: A quantitative analysis of in vivo canine vocal fold medial surface upon activation of selective ILMs is provided. This may guide our therapeutic efforts during medialization laryngoplasty, as well as computational modeling of laryngeal physiology. PMID- 28089391 TI - CAMSAP3-dependent microtubule dynamics regulates Golgi assembly in epithelial cells. AB - The Golgi assembly pattern varies among cell types. In fibroblast cells, the Golgi apparatus concentrates around the centrosome that radiates microtubules; whereas in epithelial cells, whose microtubules are mainly noncentrosomal, the Golgi apparatus accumulates around the nucleus independently of centrosome. Little is known about the mechanisms behind such cell type-specific Golgi and microtubule organization. Here, we show that the microtubule minus-end binding protein Nezha/CAMSAP3 (calmodulin-regulated spectrin-associated protein 3) plays a role in translocation of Golgi vesicles in epithelial cells. This function of CAMSAP3 is supported by CG-NAP (centrosome and Golgi localized PKN-associated protein) through their binding. Depletion of either one of these proteins similarly induces fragmentation of Golgi membranes. Furthermore, we find that stathmin-dependent microtubule dynamics is graded along the radial axis of cells with highest activity at the perinuclear region, and inhibition of this gradient disrupts perinuclear distribution of the Golgi apparatus. We propose that the assembly of the Golgi apparatus in epithelial cells is induced by a multi-step process, which includes CAMSAP3-dependent Golgi vesicle clustering and graded microtubule dynamics. PMID- 28089392 TI - [Views of the Spanish Paediatric Association Bioethics Committee on the refusal of essential and non-essential treatment in minors]. AB - The conflicts that arise when minors or their legal representatives refuse to receive medical treatment considered necessary by the paediatrician pose a serious ethical dilemma and also have a considerable emotional impact. In order to adequately tackle this rejection of medical treatment, there is to identify and attempt to understand the arguments of the people involved, to consider the context in each individual case and be conversant with the procedure to follow in life-threatening scenarios, taking into account bioethical considerations and the legal framework. PMID- 28089393 TI - Poverty and private health expenditures in Italian households during the recent crisis. AB - The global financial crisis that began in 2008 had an overall effect on the health behaviours of Italian households. Aggregate private health expenditures have decreased while the citizens have increasingly been asked to share health costs. The reduction of households' health expenditure could have serious consequences for health, especially if it concerns the most vulnerable people. The aim of this paper is to analyse the relation between poverty and household health expenditure, considering regional and social group variations. The data used stem from the "Family Expenditure Survey" collected by the Italian Statistical Institute (ISTAT) from 1997 to 2013. Results of multivariate analysis controlling for potential socio-demographic confounders show that the propensity to spend for poor families is decreased in the last years compared to not poor households. Meanwhile, among the households who spend, the average expenditure in euro seems to have been more stable over time. This is an alarming signal for the health of the most vulnerable households. These conditions could result in a gradual deterioration of health in poor families, which is likely to increase the burden on health systems in future. Hence, at this moment public intervention does not seem able to alleviate this situation. PMID- 28089394 TI - Grinding damage assessment for CAD-CAM restorative materials. AB - OBJECTIVES: To assess surface/subsurface damage after grinding with diamond discs on five CAD-CAM restorative materials and to estimate potential losses in strength based on crack size measurements of the generated damage. METHODS: The materials tested were: Lithium disilicate (LIT) glass-ceramic (e.max CAD), leucite glass-ceramic (LEU) (Empress CAD), feldspar ceramic (VM2) (Vita Mark II), feldspar ceramic-resin infiltrated (EN) (Enamic) and a composite reinforced with nano ceramics (LU) (Lava Ultimate). Specimens were cut from CAD-CAM blocs and pair-wise mirror polished for the bonded interface technique. Top surfaces were ground with diamond discs of respectively 75, 54 and 18MUm. Chip damage was measured on the bonded interface using SEM. Fracture mechanics relationships were used to estimate fracture stresses based on average and maximum chip depths assuming these to represent strength limiting flaws subjected to tension and to calculate potential losses in strength compared to manufacturer's data. RESULTS: Grinding with a 75MUm diamond disc induced on a bonded interface critical chips averaging 100MUm with a potential strength loss estimated between 33% and 54% for all three glass-ceramics (LIT, LEU, VM2). The softer materials EN and LU were little damage susceptible with chips averaging respectively 26MUm and 17MUm with no loss in strength. Grinding with 18MUm diamond discs was still quite detrimental for LIT with average chip sizes of 43MUm and a potential strength loss of 42%. SIGNIFICANCE: It is essential to understand that when grinding glass ceramics or feldspar ceramics with diamond discs surface and subsurface damage are induced which have the potential of lowering the strength of the ceramic. Careful polishing steps should be carried out after grinding especially when dealing with glass-ceramics. PMID- 28089395 TI - Royal jelly ameliorates diet-induced obesity and glucose intolerance by promoting brown adipose tissue thermogenesis in mice. AB - INTRODUCTION: Identification of thermogenic food ingredients is potentially a useful strategy for the prevention of obesity and related metabolic disorders. It has been reported that royal jelly (RJ) supplementation improves insulin sensitivity; however, its impacts on energy expenditure and adiposity remain elusive. We investigated anti-obesity effects of RJ supplementation and their relation to physical activity levels and thermogenic capacities of brown (BAT) and white adipose tissue (WAT). METHODS: C57BL/6J mice were fed under four different experimental conditions for 17 weeks: normal diet (ND), high fat diet (HFD), HFD with 5% RJ, and HFD with 5% honey bee larva powder (BL). Spontaneous locomotor activity, hepatic triglyceride (TG) content, and blood parameters were examined. Gene and protein expressions of thermogenic uncoupling protein 1 (UCP1) and mitochondrial cytochrome c oxidase subunit IV (COX-IV) in BAT and WAT were investigated by qPCR and Western blotting analysis, respectively. RESULTS: Dietary RJ, but not BL, suppressed HFD-induced accumulations of WAT and hepatic TG without modifying food intake. Consistently, RJ improved hyperglycemia and the homeostasis model assessment-insulin resistance (HOMA-IR). Although dietary RJ and BL unchanged locomotor activity, gene and protein expressions of UCP1 and COX IV in BAT were increased in the RJ group compared to the other experimental groups. Neither the RJ nor BL treatment induced browning of WAT. CONCLUSION: Our results indicate that dietary RJ ameliorates diet-induced obesity, hyperglycemia, and hepatic steatosis by promoting metabolic thermogenesis in BAT in mice. RJ may be a novel promising food ingredient to combat obesity and metabolic disorders. PMID- 28089396 TI - Comparison between measured and perceived weight status in a nationally representative sample of Australian adults. AB - BACKGROUND: Many individuals may not accurately perceive whether their weight status poses a health risk. This paper aimed to determine how accurately Australians perceived their weight status compared to objective measurements, and to determine what factors were associated with underestimating weight status. METHODS: Participants were 7947 non-pregnant adults from the 2011 to 2012 Australian National Nutrition and Physical Activity Survey, with complete data for self-reported and measured weight status. Multivariate logistic regression was used to examine associations between individual characteristics and accuracy of perceived weight status. RESULTS: Overall, 25.5% of the sample underestimated and 3.8% overestimated their weight status. Men were almost twice as likely as women to underestimate (34.0% vs 17.7%, p<0.001). In both sexes, underestimating weight status was strongly associated with higher waist circumference, satisfaction with weight and older age. In men, underestimation was associated with low education levels and being on a diet, and in women, underestimating weight status was associated with being born overseas and area-level disadvantage. CONCLUSIONS: At least a quarter of the adult population misperceives their weight status as healthy when in fact they are at increased risk of morbidity and mortality due to overweight and obesity. This may present a major barrier to prevention efforts. PMID- 28089397 TI - Challenges for critical raw material recovery from WEEE - The case study of gallium. AB - Gallium and gallium compounds are more frequently used in future oriented technologies such as photovoltaics, light diodes and semiconductor technology. In the long term the supply risk is estimated to be critical. Germany is one of the major primary gallium producer, recycler of gallium from new scrap and GaAs wafer producer. Therefore, new concepts for a resource saving handling of gallium and appropriate recycling strategies have to be designed. This study focus on options for a possible recycling of gallium from waste electric and electronic equipment. To identify first starting points, a substance flow analysis was carried out for gallium applied in integrated circuits applied on printed circuit boards and for LEDs used for background lighting in Germany in 2012. Moreover, integrated circuits (radio amplifier chips) were investigated in detail to deduce first approaches for a recycling of such components. An analysis of recycling barriers was carried out in order to investigate general opportunities and risks for the recycling of gallium from chips and LEDs. Results show, that significant gallium losses arose in primary production and in waste management. 93+/-11%, equivalent to 43,000+/-4700kg of the total gallium potential was lost over the whole primary production process until applied in electronic goods. The largest share of 14,000+/-2300kggallium was lost in the production process of primary raw materials. The subsequent refining process was related to additional 6900+/ 3700kg and the chip and wafer production to 21,700+/-3200kg lost gallium. Results for the waste management revealed only low collection rates for related end-of life devices. Not collected devices held 300 +/- 200 kg gallium. Due to the fact, that current waste management processes do not recover gallium, further 80 +/- 10 kg gallium were lost. A thermal pre-treatment of the chips, followed by a manual separation allowed an isolation of gallium rich fractions, with gallium mass fractions up to 35%. Here, gallium loads per chip were between 0.9 and 1.3mg. Copper, gold and arsenic were determined as well. Further treatment options for this gallium rich fraction were assessed. The conventional pyrometallurgical copper route might be feasible. A recovery of gold and gallium in combination with copper is possible due to a compatibility with this base-metal. But, a selective separation prior to this process is necessary. Diluted with other materials, the gallium content would be too low. The recycling of gallium from chips applied on printed circuit boards and LEDs used for background lighting is technically complex. Recycling barriers exist over the whole recycling chain. A forthcoming commercial implementation is not expected in nearer future. This applies in particular for chips carrying gallium. PMID- 28089398 TI - High temperature investigations on optimising the recovery of copper from waste printed circuit boards. AB - High temperature pyrolysis investigations were carried out on waste printed circuit boards (PCBs) in the temperature range 800-1000 degrees C under inert conditions, with an aim to determine optimal operating conditions for the recovery of copper. Pyrolysis residues were characterized using ICP-OES analysis, SEM/EDS and XRD investigations. Copper foils were successfully recovered after pyrolysis at 800 degrees C for 10-20 min; the levels of Pb and Sn present were found to be quite low and these were generally present near the foil edges. The relative proportions of Pb and Sn became progressively higher at longer heating times due to enhanced diffusion of these molten metals in solid copper. While a similar behaviour was observed at 900 degrees C, the pyrolysis at 1000 degrees C resulted in copper forming Cu-Sn-Pb alloys; copper foils could no longer be recovered. Optimal conditions were identified for the direct recovery of copper from waste PCBs with minimal processing. This approach is expected to make significant contributions towards enhancing material recovery, process efficiency and the environmental sustainability of recycling e-waste. Pyrolysis at lower temperatures, short heating times, coupled with reductions in process steps are expected to significantly reduce energy consumption and pollution associated with the handling and processing of waste PCBs. PMID- 28089399 TI - A mass balance model to estimate the rate of composting, methane oxidation and anaerobic digestion in soil covers and shallow waste layers. AB - Although CH4 oxidation in landfill soil covers is widely studied, the extent of composting and CH4 oxidation in underlying waste layers has been speculated but not measured. The objective of this study was to develop and validate a mass balance model to estimate the simultaneous rates of anaerobic digestion (rAD), CH4 oxidation (rOX) and composting (rCOM) in environments where O2 penetration is variable and zones of aerobic and anaerobic activity are intermingled. The modelled domain could include, as an example, a soil cover and the underlying shallow waste to a nominated depth. The proposed model was demonstrated on a blend of biogas from three separate known sources of gas representing the three reaction processes: (i) a bottle of laboratory grade 50:50% CH4:CO2 gas representing anaerobic digestion biogas; (ii) an aerated 250mL bottle containing food waste that represented composting activity; and (iii) an aerated 250mL bottle containing non-degradable graphite granules inoculated with methanotrophs and incubated with CH4 and O2 to represent methanotrophic activity. CO2, CH4, O2 and the stable isotope 13C-CO2 were chosen as the components for the mass balance model. The three reaction rates, r (=rAD, rOX, rCOM) were calculated as fitting parameters to the overdetermined set of 4mass balance equations with the net flux of these components from the bottles q (= [Formula: see text] , [Formula: see text] , [Formula: see text] and [Formula: see text] ) as inputs to the model. The coefficient of determination (r2) for observed versus modelled values of r were 1.00, 0.97, 0.98 when the stoichiometry of each reaction was based on gas yields measured in the individual bottles and q was calculated by summing yields from the three bottles. r2 deteriorated to 0.95, 0.96, 0.87 when using an average stoichiometry from 11 incubations of each of the composting and methane oxidation processes. The significant deterioration in the estimation of rCOM showed that this output is highly sensitive to the evaluated stoichiometry coefficients for the reactions. r2 deteriorated further to 0.86, 0.77, 0.74 when using the average stoichiometry and experimental measurement of the composition and volume of the blended biogas to determine q. This was primarily attributed to average errors of 8%, 7%, 11% and 14% in the measurement of [Formula: see text] , [Formula: see text] , [Formula: see text] and [Formula: see text] relative to the measurement of the same quantities from the individual bottles. PMID- 28089400 TI - Selective sequential separation of ABS/HIPS and PVC from automobile and electronic waste shredder residue by hybrid nano-Fe/Ca/CaO assisted ozonisation process. AB - The separation of plastics containing brominated flame retardants (BFR) like (acrylonitrile-butadiene-styrene (ABS), high-impact polystyrene (HIPS), and polyvinyl chloride (PVC)) from automobile and electronic waste shredder residue (ASR/ESR) are a major concern for thermal recycling. In laboratory scale tests using a hybrid nano-Fe/Ca/CaO assisted ozonation treatment has been found to selectively hydrophilize the surface of ABS/HIPS and PVC plastics, enhancing ABS wettability and thereby promoting its separation from ASR/ESR by means of froth flotation. The water contact angles, of ABS/HIPS and PVC decreased, about 18.7 degrees , 18.3 degrees , and 17.9 degrees in ASR and about 21.2 degrees , 20.7 degrees , and 20.0 degrees in ESR respectively. SEM-EDS, FT-IR, and XPS analyses demonstrated a marked decrease in [Cl] and a significant increase in the number of hydrophilic groups, such as CO, CO, and (CO)O, on the PVC or ABS surface. Under froth flotation conditions at 50rpm, about 99.1% of combined fraction of ABS/HIPS in ASR samples and 99.6% of ABS/HIPS in ESR samples were separated as settled fraction. After separation, the purity of the recovered combined ABS/HIPS fraction was 96.5% and 97.6% in ASR and ESR samples respectively. Furthermore, at 150rpm a 100% PVC separation in the settled fraction, with 98% and 99% purity in ASR and ESR plastics, respectively. Total recovery of non-ABS/HIPS and PVC plastics reached nearly 100% in the floating fraction. Further, this process improved the quality of recycled ASR/ESR plastics by removing surface contaminants or impurities. PMID- 28089401 TI - Recycling organic wastes to agricultural land as a way to improve its quality: A field study to evaluate benefits and risks. AB - A field study was established to assess the effects of a sewage sludge (SS), a mixed municipal solid waste compost (MMSWC) and a compost produced from agricultural wastes (AWC), in a Vertisol, using Lolium multiflorum L. The amendments were applied for two consecutive years: 6, 12 and 24t dry matter ha-1 for SS, and the amendment doses for MMSWC and AWC were calculated to deliver the same amount of organic matter (OM) per unit area. The amendments had significant beneficial effects on some soil properties (e.g. soil OM, NKjeldahl, extractable P and K), and on plant productivity parameters (e.g. biomass yield, chlorophyll, foliar area). For instance, soil OM increased from 0.78% to 1.71, 2.48 and 2.51%, after two consecutive years of application of 24t dry matter ha-1 of SS, MMSWC and AWC, respectively, while the plant biomass obtained increased from 7.75tha-1 to 152.41, 78.14 and 29.26tha-1, for the same amendments. On the plant, effects were more pronounced for SS than for both compost applications, a consequence of its higher capacity to provide N to the plant in a readily available form. However, after two years of application, the effects on soil properties were more noticeable for both composts, as their OM is more resistant to mineralization, which endures their beneficial effects on soil. Cadmium, Cr, Ni and Pb pseudo total concentrations, were not affected significantly by the application of the organic wastes to soil, in all tested doses, neither their extractability by 0.01M CaCl2. On the contrary, Cu and Zn pseudo-total concentrations increased significantly in the second year of the experiment, following the application of the higher rate of MMSWC and AWC, although their extractability remained very low (<0.5% of their pseudo-total fraction). Trace elements concentrations in the aboveground plant material were lower than their maximum tolerable levels for cattle, used as an indicator of risk of their entry into the human food chain. Despite these results, it is interesting to note that the SS promoted a significant increase in the foliar concentrations of Cu, Ni and Zn that did not happen in composts application, which can be explained by the reduction of the soil pH, as a consequence of SS degradation in soil. Concluding, if this type of organic wastes were to be used in a single application, the rate could be as high as 12 or even 24tha-1, however, if they are to be applied in an annual basis, the application rates should be lowered to assure their safe application (e.g. to 6tha-1). Moreover, it is advisable to use more stable and mature organic wastes, which have longer lasting positive effects on soil characteristics. PMID- 28089402 TI - Aerobic composting of digested residue eluted from dry methane fermentation to develop a zero-emission process. AB - Digested residue remained at the end of a process for the production of fuel ethanol and methane from kitchen garbage. To develop a zero-emission process, the compostability of the digested residue was assessed to obtain an added-value fertilizer. Composting of the digested residue by adding matured compost and a bulking agent was performed using a lab-scale composting reactor. The composting process showed that volatile total solid (VTS) degradation mainly occurred during the first 13days, and the highest VTS degradation efficiency was about 27% at the end. The raw material was not suitable as a fertilizer due to its high NH4+ and volatile fatty acids (VFAs) concentration. However, the composting process produced remarkable results; the physicochemical properties indicated that highly matured compost was obtained within 62days of the composting process, and the final N concentration, NO3- concentration, and the germination index (GI) at the end of the composting process was 16.4gkg-1-TS, 9.7gkg-1-TS, and 151%, respectively. Real-time quantitative PCR (qPCR) analysis of ammonia oxidizers indicated that the occurrence of nitrification during the composting of digested residue was attributed to the activity of ammonia-oxidizing bacteria (AOB). PMID- 28089403 TI - Consensus statement on the management of dyslipidaemias in adults. PMID- 28089404 TI - The SCHHS hip fracture clinical network experience-Improving care and outcomes through an interprofessional approach. AB - BACKGROUND: Hip fractures are a major global health care issue, with the 1.26 million estimated cases in 1990 predicted to increase to 4.5 million by 2050. Varying models of care have been developed to improve outcomes following fragility hip fractures. Most of these care models embrace an interprofessional approach to care. Specialist orthopedic nurses play an important role in the management of fragility hip fracture patients and their contribution to the interprofessional health care team is an important predictor of patient outcomes. ASSESSMENT OF THE PROBLEM: The Sunshine Coast Hospital and Health Service (SCHHS) is compromised of four hospitals in South East Queensland, Australia however only one large regional hospital provides specialist hip fracture services. Approximately, 350 older hip fracture patients present to the Sunshine Coast Hospital & Health Service (SCHHS) each year. We used Hospital Health round table (HHRT) data to identify and assess key performance care and management of hip fracture patient and outcomes at SCHHS. The HHRT is a nonprofit membership organisation of health services across Australia and New Zealand that aims to provide opportunity for Health Services to achieve best practice, collect analyse and publish information, identify ways to improve and promote collaboration and networking. Exemplars of best practice are also identified in the data so that organizations can adopt similar models of care. HHRT data identified underperformance in management of hip fracture patients in a number of quality indicators at the study site, including length of stay (LOS), time to surgery and relative stay index (RSI). STRATEGIES FOR QUALITY IMPROVEMENT: Following review of HHRT data key stakeholders undertook a quality improvement project and formed the Hip Fracture Clinical Network Group (HFCNG). This was established in 2013 with the aim of improving outcomes and achieving key performance indicators for all elderly patients who sustain a hip fracture through active collaboration and regular communication between a broad group of key clinical stakeholders. RESULTS OF THE QUALITY IMPROVEMENT PROJECT: Following the implementation of the initiative the Relative Stay Index reduced from 88% in 2012/13 to 78% in 2014/15, and the average LOS reduced from 10.4 days to 8.6 days. The percentage of patients receiving surgery within 2 days rose from 85% to 96%; demonstrating consistent outperformance of the time to surgery key performance indicator of 80%. The percentage of patients discharged to their place of usual residence increased from 45% to 54%. The rate of complications reduced slightly from 69% to 66%. Rates of hospital acquired anaemia reduced from 20.7% to 15%. Detection of delirium rose over the reporting period from 22% to 34%, enabling rapid management. We noted during this period that there was no corresponding increase in readmission rates for this group of patients. These data reflect improvement to clinical documentation and the appropriate identification of cognitive changes. CONCLUSION: In this quality improvement report, we describe how key stakeholders were engaged to improve communication and collaboration, and how the use of a national benchmarking dataset enabled health care providers to identify care gaps and inconsistencies in clinical practice. This quality improvement project markedly improved collaboration, clinical practice and patient outcomes. PMID- 28089406 TI - Intervention Should not be the Thermopylae to Avoid Amputation: Commentary on "Not All Patients with Critical Limb Ischaemia Require Revascularisation". PMID- 28089405 TI - Use of Essential Oils Following Traumatic Burn Injury: A Case Study. AB - Hospital admissions related to burn injury reach 40,000 annually. Patients who experience extensive burns require longer hospital stays and are at increased risk for infection and hospital acquired conditions. This comparative case study is a two patient matched case control design that follows the hospital course of two children who experienced burn injuries. For one of these patients, with the consent of the child's parents, the grandmother treated her granddaughter with essential oils. Essential oils have the potential to inhibit microbial growth, support treatment of wounds, and facilitate healing. However, there have been no large scale studies on essential oils. Data for the two cases were retrieved from the electronic medical record at a Midwestern Pediatric Hospital. Retrieved data included burn site description, treatment for burns, number of days on the ventilator, white blood cell count, length of hospital stay, number of ICU days, infections diagnosed by positive culture and pain ratings. While the goals for treatment were the same for both children, the child who received only standard care was diagnosed with two blood stream infections and four hospital acquired conditions while the child who received supplemental treatment with essential oils did not develop any blood stream infections, was diagnosed with one hospital acquired condition, was in the PICU one day less, and had a four day shorter length of hospital stay. While these case findings are intriguing, research is needed to expand understanding of the role of essential oils in the treatment of burns. PMID- 28089407 TI - THE WORLD APHERESIS ASSOCIATION REGISTRY. PMID- 28089408 TI - The various assays for measuring activity states of factor VIIa in plasma and therapeutic products: Diagnostic value and analytical usefulness in various pathophysiological states. AB - The key coagulation factor FVII, and its activated form FVIIa, present a major interest for their role at the initiation phase of blood coagulation, and because they can activate all blood coagulation cascade, through the extrinsic, but also the intrinsic pathway. Blood activation initiated through FVII is first presented, as it is understood nowadays. Measurement of FVII and FVIIa were of main interest for epidemiological studies, but FVIIa contribution to assay results was only deduced. The introduction of specific FVIIa assays, functional or immunoassays, allowed measuring directly FVIIa without any interference of non activated FVII, or other coagulation factors or their activated forms. The various methods available, and their characteristics are presented, with a special focus on two assays developed by our group for FVIIa (a clotting one and a chromogenic one). The FVIIa clotting assay shows evident superiority for measuring its activity in plasma, in pathophysiological conditions. The normal range is <2.5ng/ml, which represents less than 0.5% of the FVII protein. FVIIa is elevated in some pathological states. The chromogenic assay is of interest for assigning the potency of FVIIa concentrates, as it has a higher dynamic range. Both assays are fully automatable on laboratory instruments, and standardized in a satisfactory manner thanks to the use of the FVIIa concentrate WHO International Standard (NIBSC). The various applications and usefulness of FVIIa laboratory assays are discussed, for the measurement of therapeutic products, or for following recoveries in treated patients, including hemophiliacs with inhibitors, patients with severe bleeding risk (liver diseases, surgery, trauma, ...), and lastly for measurement of its activity in therapeutic products. PMID- 28089409 TI - The Italian registry of therapeutic apheresis - 2015. AB - Data collection on apheresis activities in Italy throughout 2015 including techniques, clinical indications and adverse effects was performed by means of a SidEM model questionnaire (aggregate data). These data provided by 67 Apheresis Units from 17 Italian regions, albeit rough, are sufficiently informative, mainly in comparison with previous surveys on these statistics. PEx has been the most frequent technique for plasma removal/treatment (11787 procedures) followed by LDL-apheresis (927 procedures). ECP/photopheresis has been the most frequent cytapheresis procedure: 6,606 session, mainlyby using the off-line technique.Main indications for therapeutic apheresis are neurologic diseases, thrombotic microangiopathy and solid organ transplantation humoral rejection.The apheresis support activity to haematopoietic stem cell transplantation , the PBSC collection has been documented by 53 center: 3254 procedures in 2259 patients. Over all results have been positive: over 80% get better with therapy. Adverse effects, predominantly mild ones (i.e., paresthesia due to citrate-induced hypocalcemia), occurred in 7.9% of therapeutic sessions, of wich only 83 have been classified as severe (0.4%). PMID- 28089410 TI - Microparticle detection to guide platelet management for the reduction of platelet refractoriness in children - A study proposal. AB - Microparticles have been shown to shed from a variety of viable cells as a consequence of inflammatory processes, activation or physical stress. Seventy to 90% of circulating microparticles are thought to be platelet-derived. The content of microparticles in blood collected from normal blood donors is highly variable and transfers into the final blood component. Elevated microparticle content (MPC) in donor blood might indicate an asymptomatic clinical condition of the donor which might affect the transfusion recipient, particularly pediatric patients. ThromboLUX is a new technology designed to routinely test biological samples for microparticle content. We compared MPC in platelet-rich plasma (PRP) of apheresis donors and the corresponding INTERCEPT-treated apheresis products (N=24). The MPCs in donor and product samples were correlated (r=0.74, P<0.001). Microparticles were significantly reduced after plasma replacement and INTERCEPT treatment. These findings are supported by phase contrast microscopy. Platelet transfusions given to patients with fever or systemic inflammation are less efficacious. In addition, transfusing heterogeneous platelets - concentrates with high MPC and activated platelets - to patients whose immune systems are activated might tip them over a threshold and cause platelet refractoriness. Restricting prophylactic platelet transfusions to homogeneous products - concentrates with resting platelets and therefore low MPC - may reduce the risk of refractoriness in cancer patients, especially children with immature immunity. To test this hypothesis we introduce an evaluation protocol for platelet management, i.e., keeping a split inventory of homogeneous and heterogeneous platelets, and using only homogeneous platelets for prophylaxis as a strategy to reduce refractoriness. PMID- 28089411 TI - Apheresis Medicine education in the United States of America: State of the discipline. AB - Apheresis Medicine is a medical discipline that involves a variety of procedures (based on the targeted component to be removed or collected), indications (therapeutic vs. donation), and personnel (operators, management, and medical oversight). Apheresis services are accredited and/or regulated by a number of agencies and organizations. Given the complexity and the heterogeneity of apheresis services, it has been particularly challenging to formulate educational goals and define curriculums that easily cover all aspects of Apheresis Medicine. This review summarizes the current state of the discipline in the United States of America, and some of the challenges, strategies, and resources that Apheresis Medicine educators have used to ensure that Apheresis Medicine educational programs meet the health care needs of the relevant population within regulatory and accrediting entity frameworks. PMID- 28089412 TI - Whaddaya Know: A Guide to Uncertainty and Subjectivity in Structural Biology. AB - The methods of structural biology, while powerful, are technically complex. Although the Protein Data Bank (PDB) provides a repository that allows anyone to download any structure, many users would not appreciate the caveats that should be considered when examining a structure. Here, we describe several key uncertainties associated with the application of X-ray crystallography, NMR spectroscopy, single-particle electron microscopy (SPEM), and small-angle scattering (SAS) to biological macromolecules. The take-home message is that structures are not absolute truths - they are models that fit the experimental data and therefore have uncertainty and subjectivity associated with them. These uncertainties must be appreciated - careful reading of the associated paper, and any validation report provided by the structure database, is highly recommended. PMID- 28089413 TI - Relation of ST-Segment Elevation Myocardial Infarction to Daily Ambient Temperature and Air Pollutant Levels in a Japanese Nationwide Percutaneous Coronary Intervention Registry. AB - Effects of daily fluctuation of ambient temperature and concentrations of air pollutants on acute cardiovascular events have not been well studied. From January 2011 to December 2012, a total of 56,863 consecutive ST-segment elevation myocardial infarction (STEMI) patients who underwent primary percutaneous coronary intervention were registered from 929 institutes with median interinstitutional distance of 2.6 km. We constructed generalized linear mixed models in which the presence or absence of patients with STEMI per day per institute was included as a binomial response variable, with daily meteorologic and environmental data obtained from their respective observatories nearest to the institutes (median distance of 9.7 and 5.6 km) as the explanatory variables. Both lower mean temperature and increase in maximum temperature from the previous day were independently associated with the STEMI occurrence throughout the year (odds ratio [OR] 0.925, 95% confidence interval [CI] 0.915 to 0.935, per 10 degrees C, p <0.001; and OR 1.012, 95% CI 1.009 to 1.015, per degrees C, p <0.001, respectively). Decrement in minimum temperature from -4 days to -3 days before the event date was marginally associated with the STEMI occurrence, only during the wintertime (OR 0.991, 95% CI 0.982 to 0.999, per degrees C, p = 0.03). As for the air pollutants, nitrogen oxides and suspended particle matter were not correlated with the occurrence of STEMI after adjusting for the meteorologic and livelihood variables. Both the absolute value and relative change in the ambient temperature were associated with the occurrence of STEMI; the associations with the air pollutant levels were less clear after adjustment for these meteorologic variables in Japan. PMID- 28089414 TI - Acupressure effect on sleep quality: A systematic review and meta-analysis. AB - Acupressure is a non-invasive treatment in which pressure is applied to specific body points. Following public health concerns about poor sleep quality and increasing interest in alternative treatments, a systematic review and a meta analysis were designed to evaluate the effects of acupressure on the quality of sleep. Ten English (PubMed, CENTRAL, CINAHL etc.) and five Chinese (CNKI, WANFANG etc.) databases were searched and the validity of the eligible studies was critically appraised. Thirty-two eligible randomized controlled trials of moderate to high quality which employed polysomnography, actigraphy, or self assessment sleep quality tools were included. We conducted a meta-analysis using a random effects model with the Pittsburgh sleep quality index (PSQI) as the primary outcome measure (968 adult patients, 13 trials) for trials investigating the effects of traditional Chinese medicine acupressure compared with standard and sham treatments. We performed subgroup analyses to detect sources of heterogeneity, identify the use of acupoints in different populations and explore the contributions of PSQI domains to the total score change. Comparison with the sham group (7 trials with 385 patients) yielded low heterogeneity and an overall effect of 13%-19% improvement in the PSQI score (MD = -3.41, 95% CI -4.08, -2.75; I2 = 12%). Based on data from four trials (n = 250), sleep latency and sleep duration were most affected. No adverse effects were reported in any of the reviewed trials. Within the limitations of clinical heterogeneity, the results showed that even fragile populations such as the elderly and dialysis patients can benefit from acupressure. Standardized treatment protocols involved 3-5 kg of pressure for one to five minutes per acupoint, delivered three to seven times a week for three to four weeks with the HT7 (Shenmen) acupoint used in most procedures. A high risk of bias due to absence of blinding of patients and personnel remains a serious methodological challenge for acupressure trials and poses a main limitation to presented results. This review has been registered in PROSPERO (registration number CRD42015025013). PMID- 28089415 TI - Antimicrobial stewardship in the Federal Bureau of Prisons: Approaches from the national and local levels. AB - OBJECTIVES: To determine the impact of national and local antimicrobial stewardship measures on overall antibiotic prescribing in the Federal Bureau of Prisons (BOP). SETTING: Care was delivered to more than 160,000 inmates in 122 BOP facilities in the United States and Puerto Rico. PRACTICE DESCRIPTION: Medical centers and health services clinics staffed by in-house medical staff, consultants, and specialists. Staffs include a variety of disciplines, including physicians, pharmacists, dentists, nurses, infection control personnel, therapists, health services administrators, and institution executive staff. PRACTICE INNOVATION: Innovations occurred on 2 levels: local components were used to reinforce national initiatives. Local institutions used a multidisciplinary team approach including education and focused evaluations of all antibiotic prescriptions before dispensing. National initiatives included the development of a closed formulary, clinical practice guidelines, an antimicrobial stewardship group led by pharmacy, development of tools and strategies for institutions, inclusion in the BOP strategic plan, and a drug utilization evaluation. EVALUATION: This was a study of antimicrobial stewardship within BOP and the resultant impact on antibiotic prescriptions. In addition, one institution's antimicrobial stewardship methods were reviewed to determine the impact on antibiotic prescribing practices. RESULTS: The total number of antibiotic prescriptions in BOP-managed institutions in fiscal year (FY) 2010 (October 2009 to September 2010) was 142,907 and progressively decreased to 105,832 in FY2015. The number of antibiotic prescriptions per 1000 inmates correspondingly decreased from 829 in FY2010 to 625 in FY2015. The overall number of antibiotic prescriptions as a percentage of total prescriptions decreased from 7.64% in FY2010 to 5.84% in FY2015. CONCLUSION: A robust multidisciplinary antimicrobial stewardship program has likely contributed to a decrease in both the total number and the rate of antibiotic prescriptions on a per-1000-patient basis in BOP. PMID- 28089417 TI - Venous sinus compromise after pre-sigmoid, transpetrosal approach for skull base tumors: A study on the asymptomatic incidence and report of a rare dural arteriovenous fistula as symptomatic manifestation. AB - The sigmoid sinus is routinely exposed and manipulated during pre-sigmoid, transpetrosal approaches to the skull base, but there is scant data available on the incidence of venous sinus compromise after surgery. We encountered a dural arteriovenous fistula as a result of sigmoid sinus occlusion and examined the incidence of venous sinus thrombosis or narrowing after transpetrosal surgeries. We performed a retrospective analysis of a series of patients treated by the senior surgeons (WCJ, MH, HJK), who underwent either a posterior petrosectomy or translabyrinthine approach for various skull base tumors. All available clinical and radiographic data were thoroughly examined in each patient to determine the post-operative fate of the venous sinuses. Of the 52 available patients, five patients were discovered post-operatively to have a narrowed or constricted sigmoid sinus ipsilateral to the surgery, whereas another five patients were diagnosed with asymptomatic sinus thrombosis either in the transverse or sigmoid or both. None of these patients experienced symptoms, nor were there any instance of ischemic or hemorrhagic complications. However, there was one additional patient who presented with pulsatile tinnitus 2years after surgery. His angiogram showed an occlusion of the ipsilateral sigmoid sinus and a posterior fossa dural arteriovenous fistula. A two-stage transvenous and transarterial embolization was successful in eliminating the fistula. Technical considerations to avoid sinus injuries during pre-sigmoid, transpetrosal surgery are discussed. PMID- 28089418 TI - Distant spread of a supratentorial glioblastoma to the spinal cord. AB - Extracranial spread from a glioblastoma is rare. We present a case of a 48year old man with a previously radiologically-stable left temporal lobe glioblastoma presenting with symptoms referrable to the spinal cord. MRI revealed a spinal cord lesion, with the differential including transverse myelitis and tumour. Open surgical biopsy revealed high-grade astrocytoma. Genetic analysis of both the supratentorial and spinal tumours revealed R132H IDH1 mutations, providing evidence that the spinal cord lesion had spread from the supratentorial tumour. PMID- 28089416 TI - Strategies to overcome therapeutic resistance in renal cell carcinoma. AB - BACKGROUND: Renal cell cancer (RCC) is a prevalent and lethal disease. At time of diagnosis, most patients present with localized disease. For these patients, the standard of care includes nephrectomy with close monitoring thereafter. While many patients will be cured, 5-year recurrence rates range from 30% to 60%. Furthermore, nearly one-third of patients present with metastatic disease at time of diagnosis. Metastatic disease is rarely curable and typically lethal. Cytotoxic chemotherapy and radiation alone are incapable of controlling the disease. Extensive effort was expended in the development of cytokine therapies but response rates remain low. Newer agents targeting angiogenesis and mTOR signaling emerged in the 2000s and revolutionized patient care. While these agents improve progression free survival, the development of resistance is nearly universal. A new era of immunotherapy is now emerging, led by the checkpoint inhibitors. However, therapeutic resistance remains a complex issue that is likely to persist. METHODS AND PURPOSE: In this review, we systematically evaluate preclinical research and clinical trials that address resistance to the primary RCC therapies, including anti-angiogenesis agents, mTOR inhibitors, and immunotherapies. As clear cell RCC is the most common adult kidney cancer and has been the focus of most studies, it will be the focus of this review. PMID- 28089419 TI - Risk factors for respiratory failure of motor neuron disease in a multiracial Asian population. AB - BACKGROUND: Motor neuron disease (MND) is a devastating degenerative disorder. Amyotrophic Lateral Sclerosis (ALS) is the most common and severe form of MND. Respiratory failure arising from ventilator musculature atrophy is the most common cause of death for ALS patients. Exploring the factors correlated with respiratory failure can contribute to disease management. PURPOSE: To characterize the clinical features of MND and determine the factors that may affect respiratory failure of MND patients. METHODS: The case records of all MND patients seen in Singapore General Hospital (SGH) between January 2004 and December 2014 were examined. Demographic, clinical information were collected by reviewing case records. Mortality data, if not available from records, were obtained via phone call interview of family members. Demographic data and clinical treatments were compared between Respiratory support group and Non respiratory support group. RESULTS: There were 73 patients included in our study. 49 (67.1%) patients died during follow-up. The mean age of onset was 58+/ 11.1years. With regard to treatment, 63% needed feeding support, and 42.5% required ventilation aid. The median overall survival was 36months from symptom onset. Chi-square tests showed there was significantly higher percentage of respiratory support needed in Chinese than in other races (P=0.016). Compared with non-feeding support patients, patients with feeding support were more likely to require assisted ventilation (P=0.001). CONCLUSIONS: We report for the first time that the need of feeding support is significantly associated with assisted ventilation. Chinese MND patients may be more inclined to require respiratory support. PMID- 28089421 TI - Microbiology and treatment of brain abscess. AB - Brain abscess is a focal pyogenic infection of the brain's parenchyma. The most frequent intracranial locations (in descending order of frequency) are: frontal temporal, frontal-parietal, partial, cerebellar, and occipital lobes. The major predisposing factors are: an associated contiguous focus of infection, trauma, and hematogenous spread from a distant focus. The microbial etiology depends on the site of the primary infection; the patient's age, underlying condition, and immune status; and the geographic location. The organisms most commonly isolated are anaerobic bacteria, aerobic and microaerophilic streptococci, Enterobacteriaceae, and Staphylococcus aureus. Specimens obtained during surgery or stereotactic computerized axial tomography (CT) guided aspiration should be sent for aerobic, anaerobic, mycobacterial and fungal culture and, when indicated, for protozoa. Before abscess encapsulation and localization, antimicrobial therapy, accompanied by measures to control increasing intracranial pressure, are essential. Once an abscess has formed, surgical excision or drainage combined with prolonged antibiotics (usually 4-8weeks) remains the treatment of choice. PMID- 28089420 TI - Regression of intracranial meningioma following treatment with nivolumab: Case report and review of the literature. AB - The treatment of refractory meningiomas remains a challenge for both neurosurgeons and neuro-oncologists. There have been no clinical reports of the use or effects of anti-PD-1 therapy in patients with meningioma. We describe a patient whose intracranial meningioma decreased significantly in size after treatment with nivolumab, a monoclonal antibody targeting PD-1, for a concomitant advanced lung cancer. This is the first clinical report suggesting that antibodies targeting PD-1 are effective in treating meningioma. It should encourage further research into the use of checkpoint inhibitors in meningioma. PMID- 28089422 TI - Low-magnitude mechanical signals and the spine: A review of current and future applications. AB - Animal and human studies demonstrate the anabolic properties of low-magnitude mechanical stimulation (LMMS) in its ability to improve bone formation by enhancing the proliferation of mesenchymal stem cells and their subsequent commitment down an osteoblastic lineage. Response to mechanical strains as low as 10MUE have been seen, illustrating the sensitivity of mechanosensory cells to mechanotransduction pathways. Applications to the spine include treatment of osteoporosis in preparation for instrumented fusion, fracture reduction in spinal cord injury patients to slow bone mineral density loss, and bone tissue engineering and enhancement of bone-implant osseointegration for pseudarthrosis and hardware failure. This review provides an overview of the fundamentals of LMMS, highlights the cellular basis and biomechanics of how mechanical strain is translated into bone formation, and then discusses current and potential applications of these concepts to spinal disorders. Mechanical signals represent a key regulatory mechanism in the maintenance and formation of bone. Developing practical clinical applications of these mechanotransduction pathways continues to be an important area of investigation in its relation to spinal pathology. PMID- 28089423 TI - Crossed cheiro-oral syndrome: A warning sign for medullary involvement and neurological deterioration. AB - Crossed cheiro-oral syndrome (CCOS) is characterized by crossed sensory disturbance confined to the unilateral perioral area and contralateral hand/finger(s). Although a few classical crossed sensory syndromes accurately predict brainstem or spinal involvement, the clinical significance of CCOS remains unclear. In this study, we analyzed the etiology, localization and outcome of CCOS patients. The results showed that ischemic stroke is the exclusive cause of CCOS. The location of responsible stroke is pertinent to the middle or upper level of the lateral medulla oblongata medial to the lateral sulcus. The vascular supply is from the vertebral artery or the posterior inferior cerebellar artery. Half of the CCOS patients progressed to Wallenberg's syndrome and complicated with disabled daily living. However, no patient died during the follow-up period. A larger size and dorsal extension of the infarction correlated with neurological deterioration. Therefore, CCOS is an independent clinical sign of medullary involvement. It strongly predicts involvement at the lateral medulla oblongata, especially the ischemic stroke, and neurological deterioration. A rapid evaluation of the infarction location and vascular status is suggested in cases of CCOS. PMID- 28089424 TI - High-sensitivity troponins and prognosis of heart failure. PMID- 28089425 TI - [A comparison of various supraglottic airway devices for fiberoptical guided tracheal intubation]. AB - BACKGROUND: Fiberoptical assisted intubation via placed supraglottic airway devices has been described as safe and easy procedure to manage difficult airways. However visualization of the glottis aperture is essential for fiberoptical assisted intubation. Various different supraglottic airway devices are commercially available and might offer different conditions for fiberoptical assisted intubation. The aim of this study was to compare the best obtainable view of the glottic aperture using different supraglottic airway devices. METHODS: With approval of the local ethics committee 52 adult patients undergoing elective anesthesia were randomly assigned to a supraglottic airway device (Laryngeal Tube, Laryngeal Mask Airway I-Gel, Laryngeal Mask Airway Unique, Laryngeal Mask Airway Supreme, Laryngeal Mask Airway Aura-once). After standardized induction of anaesthesia the supraglottic airway device was placed according to the manufacturers recommendations. After successful ventilation the position of the supraglottic airway device in regard to the glottic opening was examined with a flexible fiberscope. A fully or partially visible glottic aperture was considered as suitable for fiberoptical assisted intubation. Suitability for fiberoptical assisted intubation was compared between the groups (H-test, U-test; p<0.05). RESULTS: Demographic data was not different between the groups. Placement of the supraglottic airway device and adequate ventilation was successful in all attempts. Glottic view suitable for fiberoptical assisted intubation differed between the devices ranging from 40% for the laringeal tube (LT), 66% for the laryngeal mask airway Supreme, 70% for the Laryngeal Mask Airway I-Gel and 90% for both the Laryngeal Mask Airway Unique and the Laryngeal Mask Airway Aura-once. CONCLUSION: None of the used supraglottic airway devices offered a full or partial glottic view in all cases. However the Laryngeal Mask Airway Unique and the Laryngeal Mask Airway Aura-once seem to be more suitable for fiberoptical assisted intubation compared to other devices. PMID- 28089426 TI - Exchange of a HeartWare HVAD to a HeartMate 3 left ventricular assist device. PMID- 28089427 TI - Right-to-left inverted living-donor lobar lung transplantation combined with sparing of native right upper lobe. PMID- 28089428 TI - New Uses for Old Biomarkers in chronic obstructive pulmonar disease and Obstructive Sleep Apnea? PMID- 28089429 TI - Diagnosis and quantification of fibrosis, steatosis, and hepatic siderosis through multiparametric magnetic resonance imaging. AB - BACKGROUND: The presence of liver fibrosis is the common denominator in numerous chronic liver diseases that can progress to fibrosis and hepatocellular carcinoma. Most important, with respect to frequency, are viral hepatitis and non alcoholic fatty liver disease, the prevalence of which is increasing in epidemic proportions. Liver biopsy, albeit imperfect, continues to be the criterion standard, but in many clinical situations tends to be replaced with noninvasive imaging methods. OBJECTIVES: The aim of the present article was to describe our imaging department experience with magnetic resonance elastography and to analyze and discuss recently published results in gastroenterology, hepatology, and radiology from other authors in the literature, complemented with a PubMed search covering the last 10 years. RESULTS AND CONCLUSIONS: Magnetic resonance elastography is an efficacious, noninvasive method with results that are concordant with liver biopsy. It is superior to ultrasound elastography because it evaluates a much greater volume of hepatic tissue and shows the often heterogeneous lesion distribution. The greatest advantage of the magnetic resonance protocol described is the fact that it quantifies fibrosis, fat content, and iron content in the same 25min examination specifically directed for that purpose, resulting in a favorable cost-benefit ratio for the patient and/or institution. PMID- 28089430 TI - High variability of expression profiles of homeologous genes for Wnt, Hh, Notch, and Hippo signaling pathways in Xenopus laevis. AB - Cell signaling pathways, such as Wnt, Hedgehog (Hh), Notch, and Hippo, are essential for embryogenesis, organogenesis, and tissue homeostasis. In this study, we analyzed 415 genes involved in these pathways in the allotetraploid frog, Xenopus laevis. Most genes are retained in two subgenomes called L and S (193 homeologous gene pairs and 29 singletons). This conservation rate of homeologs is much higher than that of all genes in the X. laevis genome (86.9% vs 60.2%). Among singletons, 24 genes are retained in the L subgenome, a rate similar to the average for all genes (82.8% vs 74.6%). In addition, as general components of signal transduction, we also analyzed 32 heparan sulfate proteoglycan (HSPG)-related genes and eight TLE/Groucho transcriptional corepressors-related genes. In these gene sets, all homeologous pairs have been retained. Transcriptome analysis using RNA-seq data from developmental stages and adult tissues demonstrated that most homeologous pairs of signaling components have variable expression patterns, in contrast to the conservative expression profiles of homeologs for transcription factors. Our results indicate that homeologous gene pairs for cell signaling regulation have tended to become subfunctionalized after allotetraploidization. Diversification of signaling pathways by subfunctionalization of homeologs may enhance environmental adaptability. These results provide insights into the evolution of signaling pathways after polyploidization. PMID- 28089431 TI - Adults with developmental dyslexia show selective impairments in time-based and self-initiated prospective memory: Self-report and clinical evidence. AB - BACKGROUND: Prospective memory (PM; memory for delayed intentions) would seem to be impaired in dyslexia but evidence is currently limited in scope. AIMS: There is a need, therefore, firstly, to explore PM under controlled conditions using a broader range of PM tasks than used previously and, secondly, to determine whether objectively measured and self-reported PM problems can be found in the same individuals with dyslexia. METHODS AND PROCEDURES: The responses of 30 adults with dyslexia were compared with those of 30 IQ-matched adults without dyslexia on a self-report and a clinical measure of PM. OUTCOMES AND RESULTS: Dyslexia-related deficits were shown on the clinical measure overall and, more particularly, when PM responses had to be made to cues based on time rather than environmental events. Adults with dyslexia were also more likely to forget to carry out an intention under naturalistic conditions 24h later. On the self report questionnaire, the group with dyslexia reported significantly more frequent problems with PM overall, despite using more techniques to aid their memory. In particular, problems were identified with longer-term PM tasks and PM which had to be self-initiated. CONCLUSIONS AND IMPLICATIONS: Dyslexia-related PM deficits were found under both laboratory and everyday conditions in the same participants; the first time that this has been demonstrated. These findings support previous experimental research which has highlighted dyslexia-related deficits in PM when the enacting of intentions is based on time cues and/or has to be self-initiated rather than being in prompted by environmental events. PMID- 28089432 TI - Daily living pain assessment in children with autism: Exploratory study. AB - This study aims to broaden knowledge about pain expression and assessment in daily life situations in children with Autism Spectrum Disorder (ASD). The goals are to provide a description of the responses of the GED-DI, the French version of the NCCPC, and to test the internal structure validity of this scale. Thirty five children with ASD were included in this study (mean age=58months; mean developmental age=32months). The French version of the NCCPC was filled in by parents. Descriptive analysis of responses shows that children with ASD express pain through varied and common behaviours, related to different expressive markers (vocal, facial, activity, etc.). Behaviours more specific to the symptomology and disturbances of ASD are also displayed. A four-factor solution (negative emotional reaction, idiosyncratic expression, hyper-vigilance reaction, pain expression) emerges from an exploratory factor analysis that explains 54.4% of the total variance. Correlation coefficients show good psychometric qualities in terms of internal consistency, factorial validity and discriminant validity. This study provides new data about pain expression in daily life situations and shows that the French version of NCCPC adjusted to ASD children is relevant to assess pain in daily life situations. PMID- 28089433 TI - Derivation and validation of a scoring system for predicting nonalcoholic steatohepatitis in Taiwanese patients with severe obesity. AB - BACKGROUND: Nonalcoholic steatohepatitis (NASH) is common in severely obese Asians and may progress to advanced liver disease. Although invasive, liver biopsy is the gold standard for NASH diagnosis. Scoring systems for predicting NASH in obese Asians are scarce. OBJECTIVES: To develop and validate a scoring system to predict NASH in Taiwanese patients with severe obesity. SETTING: University hospital, Taiwan. METHODS: Preoperative clinical and laboratory data were obtained from 180 severely obese patients who underwent bariatric surgery. NASH was evaluated by liver histopathology. Patients were divided into 2 groups: a derivation cohort (n = 120) and a validation cohort (n = 60). RESULTS: Of the 180 patients, 91 (50.6%) had NASH. Multivariate analysis identified body mass index (BMI), alanine aminotransferase (ALT), and triglyceride as independent predictors for NASH in the derivation group. A weighted sum of the score was: [(1 for presence of 45 kg/m2 ? BMI>40 kg/m2) or (2 for presence of BMI>45 kg/m2)+(2 for presence of ALT>40 IU/L)+(1 for presence of triglyceride>140 mg/L)]. The area under the receiver operating characteristic curve of this model was .80 and .82 in derivation and validation cohort, respectively. Patients were further divided into low- and high-risk for NASH by using a cutoff score of 3. Diagnostic accuracy was 74% and 80% in derivation and validation cohorts, respectively. CONCLUSION: We developed and subsequently validated a simple clinical scoring system incorporating BMI, ALT, and triglyceride to predict NASH in Taiwanese patients with severe obesity. PMID- 28089434 TI - Gastroesophageal reflux disease and Barrett's esophagus after laparoscopic sleeve gastrectomy: a possible, underestimated long-term complication. AB - BACKGROUND: Morbidly obese patients are affected by gastroesophageal reflux disease (GERD) and hiatal hernia (HH) more frequently than lean patients. Because of conflicting results, the indication to sleeve gastrectomy (SG) in patients with GERD is still debated. OBJECTIVES: To evaluate the incidence of GERD on the basis of clinical, endoscopic, and histologic data in patients undergoing SG. SETTINGS: University hospital, Rome, Italy. METHODS: From July 2007 to January 2010, 162 patients underwent primary SG. Preoperatively all patients underwent visual analogue scale (VAS) evaluation of GERD symptoms, proton pump inhibitors (PPIs) consumption recording, and esophagogastroduodenoscopy (EGD). Stomach resection started 6 cm from pylorus on a 48Fr bougie. Staple line was reinforced by an oversewing suture. A postoperative clinical control with VAS evaluation, PPI consumption, and EGD was proposed to all patients. Three patients were excluded because of the occurrence of major postoperative complications. RESULTS: A total of 110 patients accepted to take part in the study (follow-up rate: 69.1%). At a mean 58 months of follow-up, incidence of GERD symptoms, VAS mean score, and PPI intake significantly increased compared with preoperative values (68.1% versus 33.6%: P<.0001; 3 versus 1.8: P = .018; 57.2% versus 19.1%: P<.0001) At EGD, an upward migration of the "Z" line and a biliary-like esophageal reflux was found in 73.6% and 74.5% of cases, respectively. A significant increase in the incidence and in the severity of erosive esophagitis (EE) was evidenced, whereas nondysplastic Barrett's esophagus (BE) was newly diagnosed in 19 patients (17.2%). No significant correlations were found between GERD symptoms and endoscopic findings. CONCLUSION: In the present series the incidence of EE and of BE in SG patients was considerably higher than that reported in the current literature, and it was not related to GERD symptoms. Endoscopic surveillance after SG should be advocated irrespective of the presence of GERD symptoms. PMID- 28089435 TI - Jejunal gluconeogenesis associated with insulin resistance level and its evolution after Roux-en-Y gastric bypass. AB - BACKGROUND: Intestinal gluconeogenesis (GNG) may play an important role in glucose homeostasis, but there is little information about the condition in humans. OBJECTIVES: To study the relationship between intestinal GNG and insulin resistance, its association with the evolution of morbidly obese patients after bariatric surgery, and the effect of insulin and or leptin. SETTING: Regional university hospital, Malaga (Spain). METHODS: Jejunal mRNA expression of genes involved in GNG was analyzed in 3 groups of morbidly obese patients who underwent Roux-en-Y gastric bypass: with low insulin resistance (MO-low-IR), with high insulin resistance (MO-high-IR), and with type 2 diabetes treated with metformin (MO-metf-T2D). Also, intestinal epithelial cells (IEC) from MO-low-IR were incubated with different doses of insulin and or leptin. RESULTS: In MO-high-IR, glutaminase, phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6 Pase), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC 1 alpha), and sterol regulatory element-binding proteins 1 c (SREBP-1 c) expressions were significantly higher than in MO-low-IR. In MO-metf-T2 D, only PEPCK was significantly lower than in MO-high-IR. In IEC, an incubation with a high glucose and insulin dose produced an increase of PEPCK and SREBP-1 c, and a decrease of glutaminase, fructose 1,6-bisphosphatase (FBPase), and PGC-1 alpha expression. At high doses of leptin, G6 Pase and FBPase were significantly increased. The improvement of insulin resistance 3 months after bariatric surgery was positively associated with high G6 Pase and FBPase expression. CONCLUSION: mRNA expression of genes involved in GNG is increased in the jejunum of MO-high IR, and regulated by insulin and or leptin. High mRNA expression of genes involved in GNG is associated with a better evolution of insulin resistance after bariatric surgery. PMID- 28089436 TI - The significance of histologic examination of gastrectomy specimens: a clinicopathologic study of 511 cases. AB - BACKGROUND: Sleeve gastrectomy (SG) is quickly becoming the preferred procedure for bariatric surgery. According to the American Society for Metabolic and Bariatric Surgery guidelines, routine preoperative upper gastrointestinal endoscopies are not recommended universally for bariatric surgery. Some studies have shown that the histologic examination of SG specimens is insignificant and not a cost-effective practice. However, some speculate SG examination may unveil pertinent findings and prevent further progression of precursor lesions. OBJECTIVES: This study aims to explore the clinically significant or actionable lesions that can be revealed with SG examination. SETTING: Tufts Medical Center, Boston, USA. RESULTS: We analyzed 511 SG specimens obtained during bariatric surgery. Incidental findings were grouped in 2 categories: clinically significant/actionable and minor lesions. The clinically significant lesions accounted for 5.8%. This category included 5 cases of gastrointestinal stromal tumor; one case of MALT lymphoma; 4 cases of autoimmune gastritis with concomitant pancreatic metaplasia or neuroendocrine dysplasia. Intestinal metaplasia without dysplasia was identified in 3 cases; 14 cases of Helicobacter pylori associated active gastritis; 1 case of iron pill induced gastritis and 1 case of gastric glandular siderosis. The minor lesions accounted for 6.3%, showing findings other than chronic gastritis. This category included 19 cases of fundic polyps and 1 case of hyperplastic polyp; one case of leiomyoma; 11 cases of H pylori negative active gastritis. CONCLUSIONS: The majority of histopathology results after SG showed no significant changes. However, a few cases had clinically significant lesions in seemingly healthy patients, altering patient's postoperative management. PMID- 28089437 TI - Systems innovation model: an integrated interdisciplinary team approach pre- and post-bariatric surgery at a veterans affairs (VA) medical center. AB - BACKGROUND: Provision of bariatric surgery in the Veterans Health Administration must account for obese veterans' co-morbidity burden and the geographically dispersed location of patients relative to Veterans Affairs (VA) bariatric centers. OBJECTIVES: To evaluate a collaborative, integrated, interdisciplinary bariatric team of surgeons, bariatricians, psychologists, dieticians, and physical therapists working in a hub-and-spokes care model, for pre- and post bariatric surgery assessment and management. METHODS: This is a description of an interdisciplinary clinic and bariatric program at a VA healthcare system and a report on program evaluation findings. Retrospective data of a prospective database was abstracted. For program evaluation, we abstracted charts to characterize patient data and conducted a patient survey. RESULTS: Since 2009, 181 veterans have undergone bariatric surgery. Referrals came from 7 western U.S. states. Mean preoperative body mass index was 46 kg/m2 (maximum 71). Mean age was 53 years, with 33% aged>60 years; 79% were male. Medical co-morbidity included diabetes (70%), hypertension (85%), and lower back or extremity joint pain (84%). A psychiatric diagnosis was present in 58%. At 12 months, follow-up was 81% and percent excess body mass index loss was 50.5%. Among 54 sequential clinic patients completing anonymous surveys, overall satisfaction with the interdisciplinary team approach and improved quality of life were high (98% and 94%, respectively). CONCLUSION: The integrated, interdisciplinary team approach using a hub-and-spokes model is well suited to the VA bariatric surgery population, with its heavy burden of medical and mental health co-morbidity and its system of geographically dispersed patients receiving treatment at specialty centers. As the VA seeks to expand the use of bariatric surgery as an option for obese veterans, interdisciplinary models crafted to address case complexity, care coordination, and long-term outcomes should be part of policy planning efforts. PMID- 28089438 TI - A retrospective comparison of biliopancreatic diversion with duodenal switch with single anastomosis duodenal switch (SIPS-stomach intestinal pylorus sparing surgery) at a single institution with two year follow-up. AB - BACKGROUND: The traditional duodenal switch is performed using a Roux-en-Y configuration. This procedure has proven to be the most effective procedure for long-term weight loss and co-morbidity reduction. Recently, stomach intestinal pylorus sparing surgery (SIPS) has been introduced as a simpler and potentially safer variation of the duodenal switch (DS). It is a single anastomosis end-to side proximal duodeno-ileal bypass with a sleeve gastrectomy. In this study, we compare our outcomes between biliopancreatic diversion with duodenal switch (BPD DS) and SIPS at 2 years. SETTING: This is a retrospective analysis from a single surgeon at a single private institution. METHODS: We analyzed data from 182 patients retrospectively, 62 patients underwent BPD-DS while 120 other patients underwent SIPS between September 2011 and March 2015. A subset analysis was performed comparing data from both procedures to evaluate weight loss and complications. RESULTS: Of 182 patients, 156 patients were beyond 1 year postoperative mark and 99 patients were beyond 2 year postoperative mark. Five patients were lost to follow-up. None of our patients had complications resulting in death. BPD-DS and SIPS had statistically similar weight loss at 3 months but percent excess weight loss (%EWL) was more with BPD-DS than SIPS at 6, 9, 12, 18, and 24 months. Patient lost a mean body mass index (BMI) of 23.3 (follow-up: 69%) and 20.3 kg/m2 (follow-up: 71%) at 2 years from the BPD-DS and SIPS surgery, respectively. However, patients who had undergone SIPS procedure had significantly shorter operative time, shorter length of stay, fewer perioperative and postoperative complications than BPD-DS (P<.001). Interestingly, even though BPD-DS patients lost slightly more weight, the actual final BMI for SIPS group was lower than BPD-DS group (25.6 versus 26.9) (P<.05). There was no statistical difference between 2 groups for postoperative nutritional data such as vitamins D, B1, B12, serum calcium, fasting blood glucose, glycosylated hemoglobin (HbA1C), insulin, serum albumin, serum total protein, and lipid panel. CONCLUSION: The SIPS is a simplified DS procedure. The SIPS eliminates one anastomosis and compared with BPD-DS has fewer perioperative and postoperative complications, shorter operative time and length of stay, and similar nutritional results at 2 years. However, weight loss was more with BPD-DS. A fair criticism is that the vast majority of BPD-DS cases were done before the SIPS cases. As a result, experience and learning curve cannot be completely dismissed when viewing postoperative complications. PMID- 28089439 TI - Evaluating the effect of operative technique on leaks after laparoscopic sleeve gastrectomy: a case-control study. AB - OBJECTIVE: To assess the effect of operative technique on staple line leaks after laparoscopic sleeve gastrectomy (LSG). BACKGROUND: Staple-line leaks after LSG are a major source of morbidity and mortality. Variations in operative technique exist; however, their effect on leaks is poorly understood. METHODS: We analyzed data from the Michigan Bariatric Surgery Collaborative (MBSC) to perform a case control study comparing patients who had a clinically significant leak after undergoing a primary LSG to those who did not. A total of 45 patients with leaks were identified between January 2007 and December 2013. The leak group was matched 1:2 to a control group based on procedure type, age, body mass index, sex, and year the procedure was performed. Technique-specific factors were assessed by reviewing operative notes from all primary bariatric procedures in our study population. Conditional logistic regression was used to identify techniques associated with leaks. To increase the power of our analysis, we used a significance level of .10. RESULTS: Leak rates with LSG have decreased over the past 5 years (1.18% to .36%) as annual case volume has increased (846 cases/yr to 4435 cases/yr). Surgeons who performed 43 or more cases per year had a leak rate<1%. Leaks were more common among cases requiring a blood transfusion (26.2% versus 1.08%, P = .0031) and when cases were converted to open surgery (7.14% versus 0%, P = .0741). However, there was no significant difference in operative time between cases involving a leak and their matched controls (95.4 min versus 87.1 min, P = .1197). Oversewing of the staple line was the only technique associated with less leaks after controlling for confounding factors (OR .397 CI .174, .909, P = .0665). Notably, surgeons who oversewed routinely were also found to have higher case volume (307 versus 140, P = .0216) and less overall complication rates (4.81% versus 7.95%, P = .0027). Furthermore, oversewing technique varied widely as only 22.6% of cases involved oversewing of the entire staple line. CONCLUSION: Despite considerable variation in operative technique, leak rates with laparoscopic sleeve gastrectomy have decreased over time as operative volume has increased. Oversewing of the staple line was associated with fewer leaks, but specific suturing technique was not uniform and oversewing was performed routinely by more experienced surgeons with higher case volumes and less complication rates overall. Before standardizing surgical technique one must take into account variations in surgeon skill and experience. PMID- 28089440 TI - Taiji Train the Trainers Curriculum: Increasing the Work Force to Decrease Falls in the Elderly. PMID- 28089441 TI - Prognostic Implications of Monosomies in Patients With Multiple Myeloma. AB - BACKGROUND: Cytogenetic analysis aides in risk stratification for patients with multiple myeloma (MM). Although several cytogenetic aberrations have been reported to be prognostic, less is known about the association between the presence of monosomies and prognosis. The present study evaluated the prevalence and prognostic implications of monosomies in patients with MM. MATERIALS AND METHODS: Karyotypes were determined using conventional cytogenetics and fluorescence in situ hybridization (FISH). The prognostic effect of monosomies was evaluated by comparison with the clinical factors in MM patients with normal karyotypes. RESULTS: Karyotypes were successfully determined in 167 of the 170 patients with MM. Of these 167 patients, 52 (31.1%) had abnormal karyotypes. Univariable analyses showed that a normal karyotype, hypodiploidy, monosomies of chromosomes 13 and 16, deletion or monosomy of 13q14, and loss of X detected by metaphase analysis were each associated with reduced progression-free survival (P < .05 for each). Univariable analyses showed that a normal karyotype, hypodiploidy, monosomies of chromosomes 13 and 16, deletion or monosomy of 13q14 detected by metaphase analysis and FISH-determined RB1 (13q)/TP53 (17p) deletion were each associated with reduced overall survival (P < .05 for each). Multivariable analysis showed that hypodiploidy detected by metaphase analysis was independently prognostic of shorter progression-free survival (P < .05 for each) and that hypodiploidy, monosomy 16, and loss of Y chromosome and FISH determined TP53 (17p) deletion were associated with reduced overall survival (P < .05 for each). CONCLUSION: In addition to known cytogenetic abnormalities, such as monosomy 13, hypodiploidy, and TP53 (17p) deletion, monosomy 16 and loss of the Y chromosome have adverse prognostic implications in patients with MM. PMID- 28089443 TI - Prevention of paediatric nosocomial infections: adapting before acting. PMID- 28089444 TI - Health-care-associated infections in neonates, children, and adolescents: an analysis of paediatric data from the European Centre for Disease Prevention and Control point-prevalence survey. AB - BACKGROUND: In 2011-12, the European Centre for Disease Prevention and Control (ECDC) held the first Europe-wide point-prevalence survey of health-care associated infections in acute care hospitals. We analysed paediatric data from this survey, aiming to calculate the prevalence and type of health-care associated infections in children and adolescents in Europe and to determine risk factors for infection in this population. METHODS: Point-prevalence surveys took place from May, 2011, to November, 2012, in 1149 hospitals in EU Member States, Iceland, Norway, and Croatia. Patients present on the ward at 0800 h on the day of the survey and who were not discharged at the time of the survey were included. Data were collected by locally trained health-care workers according to patient-based or unit-based protocols. We extracted data from the ECDC database for all paediatric patients (age 0-18 years). We report adjusted prevalence for health-care-associated infections by clustering at the hospital and country level. We also calculated risk factors for development of health-care-associated infections with use of a generalised linear mixed-effects model. FINDINGS: We analysed data for 17 273 children and adolescents from 29 countries. 770 health care-associated infections were reported in 726 children and adolescents, corresponding to a prevalence of 4.2% (95% CI 3.7-4.8). Bloodstream infections were the most common type of infection (343 [45%] infections), followed by lower respiratory tract infections (171 [22%]), gastrointestinal infections (64 [8%]), eye, ear, nose, and throat infections (55 [7%]), urinary tract infections (37 [5%]), and surgical-site infections (34 [4%]). The prevalence of infections was highest in paediatric intensive care units (15.5%, 95% CI 11.6-20.3) and neonatal intensive care units (10.7%, 9.0-12.7). Independent risk factors for infection were age younger than 12 months, fatal disease (via ultimately and rapidly fatal McCabe scores), prolonged length of stay, and the use of invasive medical devices. 392 microorganisms were reported for 342 health-care-associated infections, with Enterobacteriaceae being the most frequently found (113 [15%]). INTERPRETATION: Infection prevention and control strategies in children should focus on prevention of bloodstream infections, particularly among neonates and infants. FUNDING: None. PMID- 28089445 TI - Traumatic arteriovenous fistula of the vertebral artery. PMID- 28089446 TI - STK40 Is a Pseudokinase that Binds the E3 Ubiquitin Ligase COP1. AB - Serine/threonine kinase 40 (STK40) was originally identified as a distant homolog of Tribbles-family proteins. Despite accumulating data attesting to the importance of STK40 in a variety of different physiologic processes, little is known about its biological activity or mechanism of action. Here, we show that STK40 interacts with Constitutive Photomorphogenic Protein 1 (COP1), relying primarily on a C-terminal sequence analogous to the motif found in Tribbles proteins. In order to further elucidate structure-function relationships in STK40, we determined the crystal structure of the STK40 kinase homology domain at 2.5 A resolution. The structure, together with ATP-binding assay results, show that STK40 is a pseudokinase, in which substitutions of conserved residues within the kinase domain prevent ATP binding. Although the structure of the kinase homology domain diverges from the analogous region of Trib1, the results reported here suggest functional parallels between STK40 and Tribbles-family proteins as COP1 adaptors. PMID- 28089447 TI - Networks of Dynamic Allostery Regulate Enzyme Function. AB - Many protein systems rely on coupled dynamic networks to allosterically regulate function. However, the broad conformational space sampled by non-coherently dynamic systems has precluded detailed analysis of their communication mechanisms. Here, we have developed a methodology that combines the high sensitivity afforded by nuclear magnetic resonance relaxation techniques and single-site multiple mutations, termed RASSMM, to identify two allosterically coupled dynamic networks within the non-coherently dynamic enzyme cyclophilin A. Using this methodology, we discovered two key hotspot residues, Val6 and Val29, that communicate through these networks, the mutation of which altered active site dynamics, modulating enzymatic turnover of multiple substrates. Finally, we utilized molecular dynamics simulations to identify the mechanism by which one of these hotspots is coupled to the larger dynamic networks. These studies confirm a link between enzyme dynamics and the catalytic cycle of cyclophilin A and demonstrate how dynamic allostery may be engineered to tune enzyme function. PMID- 28089448 TI - Structural Basis for the Interaction of a Human Small Heat Shock Protein with the 14-3-3 Universal Signaling Regulator. AB - By interacting with hundreds of protein partners, 14-3-3 proteins coordinate vital cellular processes. Phosphorylation of the small heat shock protein, HSPB6, within its intrinsically disordered N-terminal domain activates its interaction with 14-3-3, ultimately triggering smooth muscle relaxation. After analyzing the binding of an HSPB6-derived phosphopeptide to 14-3-3 using isothermal calorimetry and X-ray crystallography, we have determined the crystal structure of the complete assembly consisting of the 14-3-3 dimer and full-length HSPB6 dimer and further characterized this complex in solution using fluorescence spectroscopy, small-angle X-ray scattering, and limited proteolysis. We show that selected intrinsically disordered regions of HSPB6 are transformed into well-defined conformations upon the interaction, whereby an unexpectedly asymmetric structure is formed. This structure provides the first atomic resolution snapshot of a human small HSP in functional state, explains how 14-3-3 proteins sequester their regulatory partners, and can inform the design of small-molecule interaction modifiers to be used as myorelaxants. PMID- 28089449 TI - Transferase Versus Hydrolase: The Role of Conformational Flexibility in Reaction Specificity. AB - Active in the aqueous cellular environment where a massive excess of water is perpetually present, enzymes that catalyze the transfer of an electrophile to a non-water nucleophile (transferases) require specific strategies to inhibit mechanistically related hydrolysis reactions. To identify principles that confer transferase versus hydrolase reaction specificity, we exploited two enzymes that use highly similar catalytic apparatuses to catalyze the transglycosylation (a transferase reaction) or hydrolysis of alpha-1,3-glucan linkages in the cyclic tetrasaccharide cycloalternan (CA). We show that substrate binding to non catalytic domains and a conformationally stable active site promote CA transglycosylation, whereas a distinct pattern of active site conformational change is associated with CA hydrolysis. These findings defy the classic view of induced-fit conformational change and illustrate a mechanism by which a stable hydrophobic binding site can favor transferase activity and disfavor hydrolysis. Application of these principles could facilitate the rational reengineering of transferases with desired catalytic properties. PMID- 28089450 TI - A Structural Model for Vinculin Insertion into PIP2-Containing Membranes and the Effect of Insertion on Vinculin Activation and Localization. AB - Vinculin, a scaffolding protein that localizes to focal adhesions (FAs) and adherens junctions, links the actin cytoskeleton to the adhesive super-structure. While vinculin binds to a number of cytoskeletal proteins, it can also associate with phosphatidylinositol 4,5-bisphosphate (PIP2) to drive membrane association. To generate a structural model for PIP2-dependent interaction of vinculin with the lipid bilayer, we conducted lipid-association, nuclear magnetic resonance, and computational modeling experiments. We find that two basic patches on the vinculin tail drive membrane association: the basic collar specifically recognizes PIP2, while the basic ladder drives association with the lipid bilayer. Vinculin mutants with defects in PIP2-dependent liposome association were then expressed in vinculin knockout murine embryonic fibroblasts. Results from these analyses indicate that PIP2 binding is not required for localization of vinculin to FAs or FA strengthening, but is required for vinculin activation and turnover at FAs to promote its association with the force transduction FA nanodomain. PMID- 28089451 TI - Crystallogenesis of Membrane Proteins Mediated by Polymer-Bounded Lipid Nanodiscs. AB - For some membrane proteins, detergent-mediated solubilization compromises protein stability and functionality, often impairing biophysical and structural analyses. Hence, membrane-protein structure determination is a continuing bottleneck in the field of protein crystallography. Here, as an alternative to approaches mediated by conventional detergents, we report the crystallogenesis of a recombinantly produced membrane protein that never left a lipid bilayer environment. We used styrene-maleic acid (SMA) copolymers to solubilize lipid-embedded proteins into SMA nanodiscs, purified these discs by affinity and size-exclusion chromatography, and transferred proteins into the lipidic cubic phase (LCP) for in meso crystallization. The 2.0-A structure of an alpha-helical seven transmembrane microbial rhodopsin thus obtained is of high quality and virtually identical to the 2.2-A structure obtained from traditional detergent-based purification and subsequent LCP crystallization. PMID- 28089453 TI - Serum uromodulin is a predictive biomarker for cardiovascular events and overall mortality in coronary patients. AB - BACKGROUND: Uromodulin is a protein produced exclusively by the kidneys and present in urine and blood. In contrast to weak and in part contradictory study data on uromodulin in urine samples, the analysis of serum samples recently proved uromodulin's value as superior biomarker for ongoing kidney disease. Whether serum uromodulin is associated with cardiovascular event risk and whether it has predictive power for overall mortality is still unknown and has been evaluated in the present study. METHODS: We measured uromodulin in a series of 529 patients without acute coronary syndrome undergoing coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD) and prospectively recorded mortality as well as cardiovascular events in our patients during a follow-up of up to 8years. RESULTS: We recorded 95 deaths and 145 cardiovascular events over 8years. Serum uromodulin proved protective for overall mortality (HR=0.56 [95%CI 0.43-0.72]; p<0.001), even after full adjustment including eGFR, current smoking, diabetes, and CAD status (adj. HR=0.57 [95%CI 0.37-0.89]; p=0.014). Patients in the lowest tertile of serum uromodulin had a significantly higher cardiovascular event risk compared to patients in the medium and highest tertile (HR=of 1.45 (95%CI 1.04-2.02, p=0.027). The ratio between creatinine and uromodulin was significantly associated with kidney function (r=-0.322; p<0.001) and significantly predicted the incidence of cardiovascular events (HR of 1.26 [95%CI 1.12-1.41], p<0.001) and major cardiovascular events (HR of 1.37 [95%CI 1.21-1.56], p<0.001). CONCLUSION: We conclude that serum uromodulin is a valuable biomarker to predict overall mortality and cardiovascular events. PMID- 28089452 TI - Co-Folding of a FliF-FliG Split Domain Forms the Basis of the MS:C Ring Interface within the Bacterial Flagellar Motor. AB - The interface between the membrane (MS) and cytoplasmic (C) rings of the bacterial flagellar motor couples torque generation to rotation within the membrane. The structure of the C-terminal helices of the integral membrane protein FliF (FliFC) bound to the N terminal domain of the switch complex protein FliG (FliGN) reveals that FliGN folds around FliFC to produce a topology that closely resembles both the middle and C-terminal domains of FliG. The interface is consistent with solution-state nuclear magnetic resonance, small-angle X-ray scattering, in vivo interaction studies, and cellular motility assays. Co-folding with FliFC induces substantial conformational changes in FliGN and suggests that FliF and FliG have the same stoichiometry within the rotor. Modeling the FliFC:FliGN complex into cryo-electron microscopy rotor density updates the architecture of the middle and upper switch complex and shows how domain shuffling of a conserved interaction module anchors the cytoplasmic rotor to the membrane. PMID- 28089454 TI - The role of adenosine challenge in catheter ablation for atrial fibrillation: A systematic review and meta-analysis. AB - AIMS: Adenosine may unmask dormant PV conduction and facilitate consolidation of PV isolation. We performed a meta-analysis to determine the impact of adenosine administration on clinical outcomes in patients undergoing PVI. METHODS: References and electronic databases reporting AF ablation and adenosine following PVI were searched through to 22nd November 2015. The impact of adenosine on freedom from AF was assessed in twenty publications after radiofrequency ablation (RFA), and in four publications after cryoablation to achieve PVI. Relative risks were calculated and combined in a meta-analysis using random effects modeling. RESULTS: In patients undergoing RFA with adenosine challenge, there was a significant reduction in freedom from AF in patients with versus without adenosine induced reconnection (RR 0.86; 95%CI 0.77-0.98; p=0.02) particularly if no further ablation was performed (RR 0.66; 95%CI 0.50-0.87; p<0.01). There was no difference when comparing outcomes in studies of routine adenosine challenge vs no adenosine (RR 1.07; 95%CI 0.93-1.22; p=0.36). There was a non-significant trend to an increase in freedom from AF in patients receiving routine adenosine challenge (RR 1.18 95%CI 0.99-1.42; p=0.07) in non-randomized studies using cryoablation. CONCLUSION: Adenosine induced PV reconnection following PVI is associated with a significant increase in AF recurrence, particularly if the reconnection sites are not targeted for ablation. The routine use of adenosine may be beneficial in AF ablation if given early post-PVI, at sufficient dose and reconnection is ablated. PMID- 28089455 TI - Comparison of transcatheter aortic valve implantation with the newest-generation Sapien 3 vs. Direct Flow Medical valve in a single center cohort. AB - BACKGROUND: The latest generation transcatheter heart valves including Edwards Sapien 3 (ES3) and Direct Flow Medical (DFM) were designed to allow precise implantation at the intended position and to minimize prosthesis dysfunction as well as procedural complications. Our aim was to compare short-term functional and clinical outcomes of these 2 transcatheter aortic valve systems. METHODS: Of 174 patients undergoing transfemoral transcatheter aortic valve implantation (TAVI) at our institution between August 2013 and June 2015, 113 were treated with ES3 and 61 with DFM. Device success, residual aortic regurgitation and early safety endpoints were defined according to the updated VARC-2 criteria and prespecified as primary endpoints. RESULTS: Patients treated with ES3 had a significantly higher rate of procedural success (ES3 94% vs. DFM 79%, p=0.005), mainly driven by lower postprocedural gradients (ES3 8.6+/-0.5mmHg vs. DFM 14.6+/ 1.4mmHg by invasive recordings; p=0.00012) and no incidence of more than mild aortic regurgitation. The occurrence of safety endpoints at 30days was low and comparable in the DFM vs. ES3 group (ES3 88% vs. DFM 95% of patients without endpoints, p=0.26). No significant differences were observed in 30day mortality, stroke or the incidence of new permanent pacemaker implantation. CONCLUSIONS: These single-center experience data show a higher rate of device success for ES3 treated patients, while 30day safety outcome was similar in both groups. Long term follow-up and larger scale multicenter experience will have to assess possible effects of these observations on long-term clinical outcomes. PMID- 28089456 TI - Protective effects of exercise training on endothelial dysfunction induced by total sleep deprivation in healthy subjects. AB - BACKGROUND: Sleep loss is a risk factor for cardiovascular events mediated through endothelial dysfunction. AIMS: To determine if 7weeks of exercise training can limit cardiovascular dysfunction induced by total sleep deprivation (TSD) in healthy young men. METHODS: 16 subjects were examined during 40-h TSD, both before and after 7weeks of interval exercise training. Vasodilatation induced by ACh, insulin and heat (42 degrees C) and pulse wave velocity (PWV), blood pressure and heart rate (HR) were assessed before TSD (controlday), during TSD, and after one night of sleep recovery. Biomarkers of endothelial activation, inflammation, and hormones were measured from morning blood samples. RESULTS: Before training, ACh-, insulin- and heat-induced vasodilatations were significantly decreased during TSD and recovery as compared with the control day, with no difference after training. Training prevented the decrease of ACh-induced vasodilation related to TSD after sleep recovery, as well as the PWV increase after TSD. A global lowering effect of training was found on HR values during TSD, but not on blood pressure. Training induces the decrease of TNF-alpha concentration after TSD and prevents the increase of MCP-1 after sleep recovery. Before training, IL-6 concentrations increased. Cortisol and testosterone decreased after TSD as compared with the control day, while insulin and E selectin increased after sleep recovery. No effect of TSD or training was found on CRP and sICAM-1. CONCLUSIONS: In healthy young men, a moderate to high intensity interval training is effective at improving aerobic fitness and limiting vascular dysfunction induced by TSD, possibly through pro-inflammatory cytokine responses.(ClinicalTrial:NCT02820649). PMID- 28089457 TI - A meta-analysis of add-on use of spironolactone in patients with resistant hypertension. AB - OBJECTIVE: The efficacy of add-on use of spironolactone in patients with resistant hypertension has been investigated in several small studies. We performed this meta-analysis evaluating the efficacy of add-on use of spironolactone in these patients. METHODS: We searched Pubmed, Web of Science, and Cochrane Central for all published studies evaluating add-on use of spironolactone in patients with resistant hypertension. Only randomized controlled trials determining antihypertensive effects of spironolactone were considered. RESULTS: The antihypertensive effects were assessed in 869 patients included in 4 trials with a mean follow-up of 12+/-3weeks. The reduction of systolic blood pressure (SBP) and diastolic BP (DBP) in patients treated with spironolactone was greater than placebo (weighted mean differences (WMD) for SBP 16.67mmHg (95% confidence interval (CI), -27.54, -5.80), p<0.01; WMD for DBP 6.11mmHg (95% CI, -9.34, -2.88), p<0.001), respectively. The rates of serious adverse effects or patient withdrawals from the trials tended to be higher in patients treated with spironolactone than placebo (WMD for odds ratio 2.11 (95% CI, 0.98, 4.53), p=0.05). CONCLUSIONS: This meta-analysis provides the evidence that add-on use of spironolactone in patients with resistant hypertension is effective in lowering SBP and DBP, suggesting an add-on use of spironolactone as fourth line therapy in patients with resistant hypertension. PMID- 28089458 TI - Impact of interaction of diabetes mellitus and impaired renal function on prognosis and the incidence of acute kidney injury in patients undergoing transcatheter aortic valve replacement (TAVR). AB - BACKGROUND: In high-risk patients with severe aortic stenosis undergoing transcatheter aortic valve replacement (TAVR) diabetes mellitus (DM) is a common comorbidity. It is known to increase the risk of arteriosclerosis and adversely affect morbidity, mortality for all types of cardiovascular disease, and post procedural outcome after percutaneous and surgical procedures. Moreover, DM is known to facilitate the genesis of renal failure (RF). Pre-existing RF seems to increase the rate of acute kidney injury (AKI), which is a powerful short- and midterm predictor of mortality in patients undergoing TAVR. Therefore, the aim of the present study was to investigate the impact of DM on AKI, short- and midterm prognosis after TAVR, especially in patients with pre-existing RF. METHODS AND RESULTS: In 337(30%) of 1109 patients DM was documented. The incidence of RF at baseline (GFR <60mL/min) was statistically similar in both patient groups (no DM vs. DM: 54% vs. 61%; p=0.057). Also, the incidence of AKI stage 3 was similar in all patients (no DM vs. DM: 1.6% vs. 1.8%; p=0.799). There were no significant differences regarding the procedure-related complications according to VARC-2 and mortality between patients neither with nor without DM. Even after differentiating patients according to baseline renal function, similar incidence of AKI and midterm mortality were documented. CONCLUSION: In patients undergoing TAVR, neither in case of preserved nor impaired renal function, we couldn't find any evidence for influence of DM on overall acute and midterm prognosis nor the incidence of AKI. PMID- 28089460 TI - Idiopathic gingival papillokeratosis with crypt formation, a report of 7 cases of a previously undescribed entity: possible unusual oral epithelial nevus? AB - We report 7 cases of hitherto undescribed keratotic papillary plaques of uncertain etiology involving the gingiva. All 7 cases presented on the anterior maxillary attached gingiva of patients in the second decade. The lesions were asymptomatic and 86% (6 of 7 cases) presented in a bilateral symmetric distribution. Microscopically, the lesions exhibited parakeratosis and papillary acanthosis with parakeratin-filled crypts. No specific etiology such as a factitial habit or a common exogenous agent has been identified. The possibility of a developmental etiology such as an oral epithelial nevus cannot be entirely excluded. We propose the descriptive term idiopathic gingival papillokeratosis with crypt formation (IGPC) for this condition. PMID- 28089459 TI - Effect of renal denervation on kidney function in patients with chronic kidney disease. AB - AIMS: Renal denervation (RDN) can reduce blood pressure (BP) and slow the decline of renal function in chronic kidney disease (CKD) up to one year. Whether this effect is maintained beyond 12months and whether the magnitude of BP reduction affects estimated glomerular filtration rate (eGFR) is unknown. METHODS AND RESULTS: We examined eGFR in 46 CKD patients (baseline eGFR <=60mL/min/1.73m2) on a yearly basis from 60months before to 3, 6, 12 and 24months after RDN. Ambulatory BP was measured before and after RDN. Linear mixed models analysis demonstrated a significant progressive decline in eGFR from months 60 to 12months (-15.47+/-1.98mL/min/1.73m2, P<0.0001) and from 12months to baseline prior to RDN (-3.41+/-1.64mL/min/1.73m2, P=0.038). Compared to baseline, RDN was associated with improved eGFR at 3months (+3.73+/-1.64mL/min/1.73m2, P=0.02) and no significant changes at 6 (+2.54+/-1.66mL/min/1.73m2, P=0.13), 12 (+1.78+/ 1.64mL/min/1.73m2, P=0.28), and 24 (-0.24+/-2.24mL/min/1.73m2, P=0.91) months post procedure were observed. RDN significantly reduced daytime SBP from baseline to 24months post procedure (148+/-19 vs 136+/-17mmHg, P=0.03) for the entire cohort. Changes in SBP were unrelated to the eGFR changes at 6 (r=0.033, P=0.84), 12 (r=0.01, P=0.93) and 24months (r=-0.42, P=0.17) follow-up. CONCLUSION: RDN can slow further deterioration of renal function irrespective of BP lowering effects in CKD. RDN-induced inhibition of sympathetic outflow to the renal vascular bed may account for improved eGFR via alterations of intrarenal and glomerular hemodynamics. PMID- 28089461 TI - Chronic lymphocytic leukemia in association with a ranula: a report and review of the literature. AB - Chronic lymphocytic leukemia (CLL), an indolent neoplasm of B lymphocytes, is the most common adult leukemia in the Western Hemisphere. Despite this, however, the intraoral presentation of CLL is quite rare. We report the case of an 83-year-old woman with CLL incidentally involving minor salivary glands in association with a ranula (floor-of-mouth mucocele). PMID- 28089462 TI - Destructive soft tissue mass in the maxilla/maxillary sinus. PMID- 28089463 TI - Anti-inflammatory effects of the selective phosphodiesterase 3 inhibitor, cilostazol, and antioxidants, enzymatically-modified isoquercitrin and alpha lipoic acid, reduce dextran sulphate sodium-induced colorectal mucosal injury in mice. AB - Developing effective treatments and preventing inflammatory bowel disease (IBD) are urgent challenges in improving patients' health. It has been suggested that platelet activation and reactive oxidative species generation are involved in the pathogenesis of IBD. We examined the inhibitory effects of a selective phosphodiesterase-3 inhibitor, cilostazol (CZ), and two antioxidants, enzymatically modified isoquercitrin (EMIQ) and alpha-lipoic acid (ALA), against dextran sulphate sodium (DSS)-induced colitis. BALB/c mice were treated with 0.3% CZ, 1.5% EMIQ, and 0.2% ALA in their feed. Colitis was induced by administering 5% DSS in drinking water for 8days. The inhibitory effects of these substances were evaluated by measuring relevant clinical symptoms (faecal blood, diarrhoea, and body weight loss), colon length, plasma cytokine and chemokine levels, whole genome gene expression, and histopathology. Diarrhoea was suppressed by each treatment, while CZ prevented shortening of the colon length. All treatment groups exhibited decreased plasma levels of interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha compared with the DSS group. Microarray analysis showed that cell adhesion, cytoskeleton regulation, cell proliferation, and apoptosis, which might be related to inflammatory cell infiltration and mucosal healing, were affected in all the groups. DSS-induced mucosal injuries such as mucosal loss, submucosal oedema, and inflammatory cell infiltration in the distal colon were prevented by CZ or antioxidant treatment. These results suggest that anti-inflammatory effects of these agents reduced DSS-induced mucosal injuries in mice and, therefore, may provide therapeutic benefits in IBD. PMID- 28089464 TI - Temperature-dependent conformational variation of chromophoric dissolved organic matter and its consequent interaction with phenanthrene. AB - Temperature variation caused by climate change, seasonal variation and geographic locations affects the physicochemical compositions of chromophoric dissolved organic matter (CDOM), resulting in difference in the fates of CDOM-related environmental pollutants. Exploration into the thermal induced structural transition of CDOM can help to better understand their environmental impacts, but information on this aspect is still lacking. Through integrating fluorescence excitation-emission matrix coupled parallel factor analysis with synchronous fluorescence two-dimensional correlation spectroscopy, this study provides an in depth insight into the temperature-dependent conformational transitions of CDOM and their impact on its hydrophobic interaction with persistent organic pollutants (with phenanthrene as an example) in water. The fluorescence components in CDOM change linearly to water temperature with different extents and different temperature regions. The thermal induced transition priority in CDOM is protein-like component -> fulvic-like component -> humic-like component. Furthermore, the impact of thermal-induced conformational transition of CDOM on its hydrophobic interaction with phenanthrene is observed and explored. The fluorescence-based analytic results reveal that the conjugation degree of the aromatic groups in the fulvic- and humic-like substances, and the unfolding of the secondary structure in the protein-like substances with aromatic structure, contribute to the conformation variation. This integrated approach jointly enhances the characterization of temperature-dependent conformational variation of CDOM, and provides a promising way to elucidate the environmental behaviours of CDOM. PMID- 28089465 TI - Differential bioaccumulation patterns of nanosized and dissolved silver in a land snail Achatina fulica. AB - With the increasing application in antimicrobial products, silver nanoparticles (AgNP) are inevitably released into the terrestrial environment, and pose potential risks to invertebrates such as land snails Achatina fulica, which take up AgNP from food and water. Here we differentiate Ag uptake biodynamic between Ag forms (i.e., PVP-AgNP vs. AgNO3) and between exposure pathways. Snails assimilated Ag efficiently from lettuce leaves pre-exposed to AgNP, with assimilation efficiencies (AEs) averaging 62-85% and food ingestion rates of 0.11 +/- 0.03 g g-1 d-1. Dietary Ag bioavailability was independent on Ag forms, as revealed by comparable AEs between AgNP and AgNO3. However, the uptake rate constant from water was much lower for AgNP relative to AgNO3 (2 * 10-4 vs. 0.12 L g-1 d-1). The elimination rate constants were 0.0093 +/- 0.0037 d-1 for AgNP and 0.019 +/- 0.0077 d-1 for AgNO3. Biodynamic modeling further showed that dietary exposure was the dominant uptake pathway for AgNP in most circumstances, while for AgNO3 the relative importance of waterborne and dietary exposure depended on Ag concentrations in food and water. Our findings highlight the importance of dietary uptake of AgNP during bioaccumulation, which should be considered in the risk assessment of these nanoparticles. PMID- 28089466 TI - Contaminants of emerging concern in Caspian tern compared to herring gull eggs from Michigan colonies in the Great Lakes of North America. AB - A broad suite of 87 contaminants of emerging concern (CECs), including 26 polybrominated diphenyl ethers (PBDEs), 23 non-PBDEs halogenated FRs (NPHFRs), 16 organophosphate esters (OPEs), 4 perfluorinated sulfonates (PFSAs), 13 perfluorinated carboxylic acids (PFCAs) and 5 emerging perfluoroalkyl acids (PFAAs) or precursors, were determined in 30 individual Caspian tern (listed as a threatened species in the U.S. State of Michigan) eggs collected in 2013 and 2014 from Michigan nesting sites on Two Tree Island (St, Mary's River), Charity Reef (Saginaw Bay) and Channel-Shelter Island (a Confined Disposal Facility (CDF) in Saginaw Bay). The same CEC suite was determined in 10 herring gull eggs on the Pipe Island Twins in the lower St. Mary's River. In tern eggs, the order of concentrations were SigmaPFSA (mean: 793 ng/g wet weight (ww); range: 116-4690 ng/g ww) > SigmaPFCAs (131; 30.4-506 ng/g ww) ~ SigmaPBDEs (86.7; 32.4-189 ng/g ww) " SigmaNPHFRs (0.67; ND-4.3 ng/g ww) ~ SigmaOPEs (0.46; ND-2.89 ng/g ww). Compared to gull eggs collected from the same area, tern egg exposure contained significantly lower concentrations of SigmaPBDE, but with up to 10 times greater mean concentrations of SigmaPFSAs and SigmaPFCAs. This study highlights the importance of consistent monitoring in eggs of different Great Lakes birds of PBDEs, perfluorooctane sulfonate (PFOS) and perfluoro-4-ethylcyclohexane sulfonate (PFEtCHxS) given that: 1) PBDE concentrations in all analyzed avian eggs exceeded or approached a concentration of 29 ng/g ww, which for birds is the current Canadian FEQG (Federal Environmental Quality Guideline); 2) SigmaPBDE concentrations were comparable to lowest observed effect concentration (LOEC) values reported in the literature; 3) PFOS concentrations in Caspian tern eggs were extremely high with many eggs across sites exceeding 1 ppm, and with the greatest being up to 4.7 ppm; and 4) PFEtCHxS, a potentially persistent and bioaccumulative substance, showed a detection frequency of 100% in 40 of the analyzed eggs. PMID- 28089467 TI - The Evolution of Implant Design Decreases the Incidence of Lateral Release in Primary Total Knee Arthroplasty. AB - BACKGROUND: Appropriate balancing of the patellofemoral joint (PFJ) using a lateral release can help to prevent patellar instability in total knee arthroplasty (TKA). Contemporary total knee implant designs are characterized by enhanced trochlear geometry more similar to native knee anatomy to minimize instability and reduce utilization of a lateral release. METHODS: We retrospectively reviewed consecutive TKA cases from a single senior surgeon's practice with 3 successive total knee designs: the Press-Fit Condylar (PFC), the Sigma, and the ATTUNE (DePuy, Warsaw, IN). We evaluated the use of lateral release with each implant type to determine if design changes have improved patellar stability, reducing the need for lateral release. We used multivariate analysis to determine the association between implant type and lateral release, adjusting for age, sex, preoperative alignment, and bearing type. RESULTS: We evaluated 1991 records of primary TKAs performed from 1980-2015. As compared with the ATTUNE, the adjusted odds of lateral release were greater for patients receiving PFC implants (Odds ratio [OR] 6.35, 95% confidence interval [CI] 3.85,10.49) and Sigma implants (OR 2.02, 95% CI 1.26, 3.23). In addition, fixed bearing implants were associated with greater adjusted odds of lateral release (OR 1.80, 95% CI 1.24, 2.62). CONCLUSION: We found that older knee implants were associated with higher use of lateral release, with successive designs the need for lateral release to balance the PFJ decreased. Continued design improvements to match the native knee anatomy may further improve the stability of the PFJ in future designs. PMID- 28089468 TI - OBTAIN A: Outcome Benefits of Tranexamic Acid in Hip Arthroplasty. A Randomized Double-Blinded Controlled Trial. AB - BACKGROUND: We examined whether the blood conserving effect of tranexamic acid (TXA) in total hip arthroplasty using the direct anterior approach, translates to an effect on functional outcomes in the perioperative period. METHODS: We conducted a single-center, randomized, double-blinded, placebo-controlled trial. One hundred one patients were randomized to receive either TXA or an equivalent volume of normal saline. The primary outcome measure was thigh swelling. Secondary outcome measures included, visual analogue pain score, timed up and go test, a 10 meter walk test, and length of stay. Blood loss and the incidence of blood transfusions were also recorded. RESULTS: There were no statistically significant differences between the primary outcome of thigh swelling or the secondary outcome measures of postoperative pain nor mobility. There was a significant reduction in length of stay for those that received TXA 3.58 days (0.84) compared with the control group 4.27 days (0.98) (P < .001). There was significantly less intraoperative blood loss observed in the TXA group (0.460L SD 0.228) compared with the control group (0.687L SD 0.283L) (P < .001). The estimated blood loss was also significantly less in the TXA group (1.084L SD 0.440) compared with the control group (1.394 L SD 0.426). CONCLUSION: TXA is an effective agent in reducing blood loss in total hip arthroplasty using the anterior approach. The blood conserving effect of TXA was not associated with improved postoperative recovery across the measures of pain and mobility. Administration of TXA may have a positive effect on reducing the duration of inpatient stays. PMID- 28089469 TI - Does Barbed Suture Lower Cost and Improve Outcome in Total Knee Arthroplasty? A Randomized Controlled Trial. AB - BACKGROUND: Wound closure is key to prevent infection, facilitate immediate rehabilitation, and improve efficiency of total knee arthroplasty (TKA). Continuous knotless suturing with barbed suture can potentially save time and distribute tension more evenly. However, its role in TKA in terms of cost effectiveness and wound complications is not clear. This study aims at comparing barbed and traditional sutures' wound closure time and cost in primary TKA. METHODS: One hundred nine knees were randomized into either barbed or traditional group. Synthetic absorbable sutures (Vicryl, Ethicon Inc) and bidirectional barbed sutures (Stratafix, Ethicon Inc) were used. Arthrotomy and subcutaneous wound closure time, wound complications, and rehabilitation parameters in terms of range of motion and Knee Society Score were compared. Patients were followed up to 3 months. RESULTS: Traditional sutures had significantly more positive leak tests (10 vs 2, P value <.05) and wound complications (11 vs 2, P value <.05). No differences in range of motion and Knee Society Score were noted. Arthrotomy and subcutaneous closure time were significantly shorter with barbed sutures (arthrotomy 325 seconds vs 491 seconds; subcutaneous 306 seconds vs 381 seconds, P value <.05). Concerning cost of suture material and operation time, barbed suture on average saved USD 48.7 per TKA in our local institute. CONCLUSION: Bidirectional barbed suture improves the cost-effectiveness of TKA through reducing wound closure time and wound complications. PMID- 28089470 TI - Conversion Hip Arthroplasty in Failed Fixation of Intertrochanteric Fracture: A Propensity Score Matching Study. AB - BACKGROUND: Conversion hip arthroplasty is a salvage procedure for failed internal fixation of intertrochanteric fractures. However, the technical difficulties and perioperative morbidity of conversion arthroplasty are uncertain. METHODS: We compared the type of arthroplasty (total hip arthroplasty or hemiarthroplasty), operative parameters, perioperative morbidity, 1-year mortality, implant stability, and clinical results of 33 conversion hip arthroplasties due to a failed internal fixation of intertrochanteric fracture with those of a matched control group of 33 primary hip arthroplasties due to the same fracture. Propensity score was used for the control matching of gender, age, and body mass index. RESULTS: Total hip arthroplasty was more frequently performed in the conversion group (10/33) compared to the primary group (3/33) (P = .016). The operation time, perioperative blood loss, amount of transfusion, and risk of femoral fracture during the operation were increased in the conversion group. The overall 1-year mortality was 3% (1 patient) in the conversion group and 9% (3 patients) in the primary group (P = .307). At a mean of 3-year follow up, there was no significant difference in clinical results and none of the implants were loose in both groups. CONCLUSION: In patients with failed internal fixation of intertrochanteric fracture, conversion hip arthroplasty should be planned and executed, bearing in mind the increased operative morbidities corresponding to operation time, perioperative blood loss, requirement of transfusion, and intraoperative femoral fracture. PMID- 28089471 TI - Infantile haemangioma. AB - With a prevalence of 4.5%, infantile haemangiomas are the most common benign tumours of infancy, arising in the first few weeks of life and exhibiting a characteristic sequence of growth and spontaneous involution. Most infantile haemangiomas do not require therapy. However, to identify at-risk haemangiomas, close follow-up is crucial in the first weeks of life; 80% of all haemangiomas reach their final size by 3 months of age. The main indications for treatment are life-threatening infantile haemangioma (causing heart failure or respiratory distress), tumours posing functional risks (eg, visual obstruction, amblyopia, or feeding difficulties), ulceration, and severe anatomic distortion, especially on the face. Oral propranolol is now the first-line treatment, which should be administered as early as possible to avoid potential complications. Haemangioma shrinkage is rapidly observed with oral propranolol, but a minimum of 6 months of therapy is recommended. PMID- 28089472 TI - Department of Error. PMID- 28089473 TI - Box- or Virtual-Reality Trainer: Which Tool Results in Better Transfer of Laparoscopic Basic Skills?-A Prospective Randomized Trial. AB - OBJECTIVE: Simulation training improves laparoscopic performance. Laparoscopic basic skills can be learned in simulators as box- or virtual-reality (VR) trainers. However, there is no clear recommendation for either box or VR trainers as the most appropriate tool for the transfer of acquired laparoscopic basic skills into a surgical procedure. DESIGN: Both training tools were compared, using validated and well-established curricula in the acquirement of basic skills, in a prospective randomized trial in a 5-day structured laparoscopic training course. Participants completed either a box- or VR-trainer curriculum and then applied the learned skills performing an ex situ laparoscopic cholecystectomy on a pig liver. The performance was recorded on video and evaluated offline by 4 blinded observers using the Global Operative Assessment of Laparoscopic Skills (GOALS) score. Learning curves of the various exercises included in the training course were compared and the improvement in each exercise was analyzed. SETTING: Surgical Skills Lab of the Department of General and Visceral Surgery, University Hospital Muenster. PARTICIPANTS: Surgical novices without prior surgical experience (medical students, n = 36). RESULTS: Posttraining evaluation showed significant improvement compared with baseline in both groups, indicating acquisition of laparoscopic basic skills. Learning curves showed almost the same progression with no significant differences. In simulated laparoscopic cholecystectomy, total GOALS score was significantly higher for the box-trained group than the VR-trained group (box: 15.31 +/- 3.61 vs. VR: 12.92 +/ 3.06; p = 0.039; Hedge's g* = 0.699), indicating higher technical skill levels. CONCLUSIONS: Despite both systems having advantages and disadvantages, they can both be used for simulation training for laparoscopic skills. In the setting with 2 structured, validated and almost identical curricula, the box-trained group appears to be superior in the better transfer of basic skills into an experimental but structured surgical procedure. PMID- 28089474 TI - What Happened to the Complication? The Importance of ACS NSQIP Pediatric in Optimizing Quality Improvement Initiatives for Resident Education. AB - OBJECTIVE: Morbidity and Mortality (M&M) conference is considered the golden hour of surgical education. Most training programs lack standardized methods to evaluate self-reported outcomes and contributions to resident education. The purpose of this study was to determine whether residents underreport pediatric postoperative complications thereby limiting a comprehensive educational opportunity and the ability to adequately perform quality improvement during M&M conference. DESIGN: A retrospective analysis of resident reports submitted to the M&M committee at an academic medical center was conducted over 1 year. All complications were compared to the American College of Surgeons (ACS) Pediatric National Surgical Quality Improvement Program (NSQIP) data abstracted over the same period. A descriptive analysis of perioperative events was performed. SETTING: This study was conducted at the Medical University of South Carolina Medical Center and MUSC Children's Hospital, an academic tertiary care center located in Charleston, South Carolina. RESULTS: Overall, 81 complications were captured. Resident and NSQIP databases captured 27 (33%) and 68 (84%) complications, respectively. Residents were more likely to report major complications. More common sources of postoperative morbidity, including surgical site infection and transfusion, were underreported at 20% and 5%, respectively. CONCLUSIONS: Resident reporting inadequately captures the full complement of pediatric perioperative complications. NSQIP-abstracted data serve as a useful adjunct to traditional M&M reporting in capturing complications underreported by trainees. PMID- 28089475 TI - Desensitization to acetazolamide in a patient with previous antimicrobial sulfonamide allergy. PMID- 28089476 TI - Serum Asymmetric and Symmetric Dimethylarginine and Morbidity and Mortality in Hemodialysis Patients. AB - BACKGROUND: Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are putative uremic toxins that may exert toxicity by a number of mechanisms, including impaired nitric oxide synthesis and generation of reactive oxygen species. The study goal was to determine the association between these metabolites and cardiovascular outcomes in hemodialysis patients. STUDY DESIGN: Post hoc analysis of the Hemodialysis (HEMO) Study. SETTING & PARTICIPANTS: 1,276 prevalent hemodialysis patients with available samples 3 to 6 months after randomization. PREDICTOR: ADMA and SDMA measured in stored specimens. OUTCOMES: Cardiac death, sudden cardiac death, first cardiovascular event, and any-cause death. Association with predictors analyzed using Cox regression adjusted for potential confounders (including demographics, clinical characteristics, comorbid conditions, albumin level, and residual kidney function). RESULTS: Mean age of patients was 57+/-14 (SD) years, 63% were black, and 57% were women. Mean ADMA (0.9+/-0.2MUmol/L) and SDMA levels (4.3+/-1.4MUmol/L) were moderately correlated (r=0.418). Higher dialysis dose or longer session length were not associated with lower predialysis ADMA or SDMA concentrations. In fully adjusted models, each doubling of ADMA level was associated with higher risk (HR per 2-fold higher concentration; 95% CI) of cardiac death (1.83; 1.29-2.58), sudden cardiac death (1.79; 1.19-2.69), first cardiovascular event (1.50; 1.20-1.87), and any-cause death (1.44; 1.13-1.83). Compared to the lowest ADMA quintile (<0.745 MUmol/L), the highest ADMA quintile (>=1.07MUmol/L) was associated with higher risk (HR; 95% CI) of cardiac death (2.10; 1.44-3.05), sudden cardiac death (2.06; 1.46 2.90), first cardiovascular event (1.75; 1.35-2.27), and any-cause death (1.56; 1.21-2.00). SDMA level was associated with higher risk for cardiac death (HR, 1.40; 95% CI, 1.03-1.92), but this was no longer statistically significant after adjusting for ADMA level (HR, 1.20; 95% CI, 0.86-1.68). LIMITATIONS: Single time point measurement of ADMA and SDMA. CONCLUSIONS: ADMA and, to a lesser extent, SDMA levels are associated with cardiovascular outcomes in hemodialysis patients. PMID- 28089477 TI - Bioimpedance and Fluid Status in Children and Adolescents Treated With Dialysis. AB - BACKGROUND: Assessment of hydration status in patients with chronic kidney failure treated by dialysis is crucial for clinical management decisions. Dilution techniques are considered the gold standard for measurement of body fluid volumes, but they are unfit for day-to-day care. Multifrequency bioimpedance has been shown to be of help in clinical practice in adults and its use in children and adolescents has been advocated. We investigated whether application of multifrequency bioimpedance is appropriate for total-body water (TBW) and extracellular water (ECW) measurement in children and adolescents on dialysis therapy. STUDY DESIGN: A study of diagnostic test accuracy. SETTING & PARTICIPANTS: 16 young dialysis patients (before a hemodialysis session or after peritoneal dialysis treatment) from the Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy, and the Emma Children's Hospital-Academic Medical Center, Amsterdam, the Netherlands. INDEX TEST: TBW and ECW volumes assessed by multifrequency bioimpedance. REFERENCE TESTS: TBW and ECW volumes measured by deuterium and bromide dilution, respectively. RESULTS: Mean TBW volumes determined by multifrequency bioimpedance and deuterium dilution were 19.2+/-8.7 (SD) and 19.3+/-8.3L, respectively; Bland-Altman analysis showed a mean bias between the 2 methods of -0.09 (95% limits of agreement, -2.1 to 1.9) L. Mean ECW volumes were 8.9+/-4.0 and 8.3+/-3.3L measured by multifrequency bioimpedance and bromide dilution, respectively; mean bias between the 2 ECW measurements was +0.6 (95% limits of agreement, -2.3 to 3.5). LIMITATIONS: Participants ingested the deuterated water at home without direct supervision by investigators, small number of patients, repeated measurements in individual patients were not performed. CONCLUSIONS: Multifrequency bioimpedance measurements were unbiased but imprecise in comparison to dilution techniques. We conclude that multifrequency bioimpedance measurements cannot precisely estimate TBW and ECW in children receiving dialysis. PMID- 28089478 TI - The Clinical Course of Minimal Change Nephrotic Syndrome With Onset in Adulthood or Late Adolescence: A Case Series. AB - BACKGROUND: Few studies have examined the treatment and outcome of adult-onset minimal change nephrotic syndrome (MCNS). We retrospectively studied 125 patients who had MCNS with onset in either adulthood or late adolescence. Presenting characteristics, duration of initial treatment and response to treatment, relapse patterns, complications, and long-term outcome were studied. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Patients with new-onset nephrotic syndrome 16 years or older and a histologic diagnosis of MCNS in 1985 to 2011 were identified from pathology records of 10 participating centers. OUTCOMES: Partial and complete remission, treatment resistance, relapse, complications, renal survival. RESULTS: Corticosteroids were given as initial treatment in 105 (84%) patients. After 16 weeks of corticosteroid treatment, 92 (88%) of these patients had reached remission. Median time to remission was 4 (IQR, 2-7) weeks. 7 (6%) patients initially received cyclophosphamide with or without corticosteroids, and all attained remission after a median of 4 (IQR, 3-11) weeks. 13 (10%) patients reached remission without immunosuppressive treatment. One or more relapses were observed in 57 (54%) patients who received initial corticosteroid treatment. Second-line cyclophosphamide resulted in stable remission in 57% of patients with relapsing MCNS. Acute kidney injury was observed in 50 (40%) patients. Recovery of kidney function occurred almost without exception. Arterial or venous thrombosis occurred in 11 (9%) patients. At the last follow-up, 113 (90%) patients were in remission and had preserved kidney function. 3 patients with steroid-resistant MCNS progressed to end-stage renal disease, which was associated with focal segmental glomerulosclerosis lesions on repeat biopsy. LIMITATIONS: Retrospective design, variable treatment protocols. CONCLUSIONS: The large majority of patients who had MCNS with onset in adulthood or late adolescence were treated with corticosteroids and reached remission, but many had relapses. Cyclophosphamide resulted in stable remission in many patients with relapses. Significant morbidity was observed due to acute kidney injury and other complications. Progression to end-stage renal disease occurred in a few patients and was explained by focal segmental glomerulosclerosis. PMID- 28089479 TI - Estimation of radiation-induced secondary cancer risks for early-stage non-small cell lung cancer patients after stereotactic body radiation therapy. AB - PURPOSE: In this study, we evaluated radiation-induced secondary lung cancer risks for the lung and the breast from stereotactic body radiation therapy treatment of early-stage non-small cell lung cancer with different radiation therapy treatment modalities. METHODS AND MATERIALS: Ten patients (5 men and 5 women) with early-stage non-small cell lung cancer who received definitive stereotactic body radiation therapy treatments were retrospectively selected. For each patient, two 3-dimensional conformal radiation therapy (3D-CRT) plans using 6- and 10-MV photons, respectively; a helical tomotherapy (HT) plan; and 2 volumetric modulated arc therapy (VMAT) plans using 1 and 2 arcs, respectively, were generated. The excess absolute risk (EAR) for secondary cancer occurrence was calculated using 3 organ equivalent dose models: the linear-exponential model, the plateau model, and the linear model for prescription dose range of 30 to 70 Gy. RESULTS: The 3D-CRT plans showed significantly lower monitor units compared with the rotational intensity modulate radiation therapy plans. Based on each of the 3 organ equivalent dose models, HT and VMAT plans showed comparable average EARs to both the lung and the breast compared with the 3D-CRT plans in the prescription dose range of 30 to 70 Gy. At a prescription dose of 50 Gy and using the linear-exponential model, the average lung EAR estimation ranged from 15.7 +/- 5.3 to 16.0 +/- 6.5 per 10,000 patients per year with the 5 delivery techniques, and the average EAR estimation for the breast ranged from 18.0 +/- 14.0 to 21.0 +/- 15.0 per 10,000 patients per year. The secondary cancer risk increased approximately linearly with mean organ dose. The 3D-CRT plans showed significantly higher secondary cancer risk for the ipsilateral lung and lower risk for the contralateral lung compared with the HT and VMAT plans. CONCLUSIONS: Rotational intensity modulate radiation therapy techniques including helical tomotherapy and VMAT do not increase secondary cancer risks for the lung or the breast compared with 3D-CRT techniques, despite higher monitor units used. PMID- 28089480 TI - Deep inspiration breath-hold produces a clinically meaningful reduction in ipsilateral lung dose during locoregional radiation therapy for some women with right-sided breast cancer. AB - PURPOSE: The goal of the work described here was to determine whether deep inspiration breath-hold (DIBH) produces a clinically meaningful reduction in pulmonary dose compared with free breathing (FB) during locoregional radiation for right-sided breast cancer. METHODS AND MATERIALS: Four-field, modified-wide tangent plans with full nodal coverage were developed for 30 consecutive patients on paired DIBH and FB CT scans. Nodes were contoured according to European Society for Radiotherapy and Oncology guidelines. Plan metrics were compared using Wilcoxon signed-rank testing. RESULTS: In 21 patients (70%), there was a >=5% reduction in ipsilateral lung V20Gy with DIBH compared with FB. The mean decrease in ipsilateral lung V20Gy was 7.8% (0%-20%, P < .001). The mean lung dose decreased on average by 3.4 Gy with DIBH (-0.2 to 9.1, P < .001). The mean reduction in liver volume receiving 50% of the prescribed dose was 42.3 cm3 (0 178.9 cm3, P < .001). CONCLUSIONS: DIBH reduced ipsilateral lung V20Gy by >=5% in the majority of patients. For some patients, the volume of liver receiving a potentially toxic dose decreased with DIBH. DIBH should be available as a treatment strategy to reduce ipsilateral lung V20Gy prior to compromising internal mammary chain nodal coverage for patients with right-sided breast cancer during locoregional radiation therapy if the V20Gy on FB exceeds 30%. PMID- 28089481 TI - Recommendations for MRI-based contouring of gross tumor volume and organs at risk for radiation therapy of pancreatic cancer. AB - PURPOSE: Local recurrence is a common and morbid event in patients with unresectable pancreatic adenocarcinoma. A more conformal and targeted radiation dose to the macroscopic tumor in nonmetastatic pancreatic cancer is likely to reduce acute toxicity and improve local control. Optimal soft tissue contrast is required to facilitate delineation of a target and creation of a planning target volume with margin reduction and motion management. Magnetic resonance imaging (MRI) offers considerable advantages in optimizing soft tissue delineation and is an ideal modality for imaging and delineating a gross tumor volume (GTV) within the pancreas, particularly as it relates to conformal radiation planning. Currently, no guidelines have been defined for the delineation of pancreatic tumors for radiation therapy treatment planning. Moreover, abdominal MRI sequences are complex and the anatomy relevant to the radiation oncologist can be challenging. The purpose of this study is to provide recommendations for delineation of GTV and organs at risk (OARs) using MRI and incorporating multiple MRI sequences. METHODS AND MATERIALS: Five patients with pancreatic cancer and 1 healthy subject were imaged with MRI scans either on 1.5T or on 3T magnets in 2 separate institutes. The GTV and OARs were contoured for all patients in a consensus meeting. RESULTS: An overview of MRI-based anatomy of the GTV and OARs is provided. Practical contouring instructions for the GTV and the OARs with the aid of MRI were developed and included in these recommendations. In addition, practical suggestions for implementation of MRI in pancreatic radiation treatment planning are provided. CONCLUSIONS: With this report, we attempt to provide recommendations for MRI-based contouring of pancreatic tumors and OARs. This could lead to better uniformity in defining the GTV and OARs for clinical trials and in radiation therapy treatment planning, with the ultimate goal of improving local control while minimizing morbidity. PMID- 28089482 TI - Efficacy of multiple fraction conventional radiation therapy for painful uncomplicated bone metastases: A systematic review. AB - BACKGROUND: Radiation therapy is effective for painful uncomplicated bone metastases, with multiple fraction radiation therapy (MFRT) administered frequently. The optimal dose for MFRT to yield maximum pain relief remains unclear. The aim of this systematic review was to determine pain response across MFRT doses. METHODS: A literature search was conducted in Ovid MEDLINE(R) <1946 to July Week 3 2016>, Embase Classic & Embase <1947 to 2016Week 30> and Cochrane Central Register of Controlled Trials . Pain response rates and the side effects for MFRT doses were extracted. RESULTS: From the 3719 articles identified from the search, 17 were included for quantitative synthesis. 22.5Gy/5 had the highest overall response (OR) rate, 30Gy/15 had better complete response (CR) rate and 20Gy/2 had better partial response (PR) rate. Only 4 of the 17 included studies directly compared MFRT doses with each other - one reported marginally-better OR for 24Gy/6 over 20Gy/2; another found 20Gy/10 to be slightly more efficacious than 30Gy/15 and 22.5Gy/5 for OR. Two randomized trials compared 20Gy/5 and 30Gy/10 - one favored 20Gy/5 while the other concluded 30Gy/10 to be the better option. The overall rate of GI toxicities, nausea, and vomiting did not differ greatly between MFRT doses. CONCLUSION: No major difference exists between the schedules and toxic events studied in these trials. This is consistent with the wealth of randomized data which show no dose response for pain relief after radiotherapy for metastatic bone pain. PMID- 28089483 TI - Patterns of failure after radiotherapy for pediatric patients with intracranial ependymoma. AB - PURPOSE: To investigate the patterns of failure after radiotherapy for pediatric intracranial ependymoma and their correlation with dose parameters. METHODS: Between 2000 and 2013, 206 patients were treated in France. MRI scans at relapse were registered to the original planning CTs for topographic analysis of failure patterns. To compare relapse patients (RP) with non relapse patients (NRP), several dose parameters were derived from dose volume histograms. RESULTS: Over a median follow-up of 53.8months, 84 patients presented with relapse. Topographic analysis showed 50 patients with local relapse in the radiation field, 6 in the edge of field, 6 locoregional outside the field, 10 in the spine, 5 supratentorial and 7 local and distant. The median coverage, target coverage and homogeneity indices did not differ significantly between RP and NRP. The median volume of in-field relapse was 1.25cc [0.11, 27], with a median dose of 57.83Gy [50.04, 61.69]. CONCLUSIONS: Local relapse in the tumor bed and the higher dose regions was the predominant pattern of failure. Improving coverage of the target volume and increasing the dose to the high radioresistant regions, taking into consideration other clinical and biological pronostic factors, may be an effective way of reducing local failures. PMID- 28089484 TI - Dosimetric parameters correlate with duodenal histopathologic damage after stereotactic body radiotherapy for pancreatic cancer: Secondary analysis of a prospective clinical trial. AB - PURPOSE: Prospectively assess relationships between dosimetric parameters and histopathologic/clinical duodenal toxicities in patients on a phase I trial for pancreatic cancer. METHODS: Forty-six borderline resectable/unresectable patients were enrolled on a prospective trial testing neoadjuvant gemcitabine/5 fluorouracil followed by SBRT (5 daily fractions of 5-8Gy) and concurrent nelfinavir. Post-SBRT surgery was performed in 13 resectable patients, which constituted the patient population herein. Pathologic duodenal damage was assessed using predetermined criteria: 1, no/minimal; 2, moderate; and 3, marked damage. Clinical toxicities were assessed per the Clinical Terminology Criteria for Adverse Events (CTCAE). Duodenal dosimetric parameters included V5-V40 and mean/maximum doses. Spearman correlation and linear regression evaluated associations between dosimetric parameters and clinical/pathologic duodenal toxicity. RESULTS: The median duodenal mean and maximum doses were 20 and 37Gy. Median duodenal V5-V40 were 64, 62, 52, 39, 27, 14, 5 and 0cc, respectively. The median duodenal damage score was 2 (four 1, eight 2, and one 3). Higher duodenal damage scores correlated with higher duodenal mean doses (r=0.75, p=0.003), V35 (r=0.61, p=0.03), V30 (r=0.67, p=0.01), V25 (r=0.68, p=0.01), V20 (r=0.56, p=0.05), and the planning target volume (PTV) mean (r=0.59, p=0.03) and maximum (r=0.61, p=0.03) doses. Clinical toxicities did not correlate with dosimetric parameters or duodenal pathologic damage. CONCLUSIONS: Duodenal histologic damage correlates with mean duodenal dose, V20-V35, and PTV mean/maximum doses. PMID- 28089485 TI - Perceptual Error Analysis of Human and Synthesized Voices. AB - OBJECTIVE/HYPOTHESIS: To assess the quality of synthesized voices through listeners' skills in discriminating human and synthesized voices. STUDY DESIGN: Prospective study. METHODS: Eighteen human voices with different types and degrees of deviation (roughness, breathiness, and strain, with three degrees of deviation: mild, moderate, and severe) were selected by three voice specialists. Synthesized samples with the same deviations of human voices were produced by the VoiceSim system. The manipulated parameters were vocal frequency perturbation (roughness), additive noise (breathiness), increasing tension, subglottal pressure, and decreasing vocal folds separation (strain). Two hundred sixty-nine listeners were divided in three groups: voice specialist speech language pathologists (V-SLPs), general clinician SLPs (G-SLPs), and naive listeners (NLs). The SLP listeners also indicated the type and degree of deviation. RESULTS: The listeners misclassified 39.3% of the voices, both synthesized (42.3%) and human (36.4%) samples (P = 0.001). V-SLPs presented the lowest error percentage considering the voice nature (34.6%); G-SLPs and NLs identified almost half of the synthesized samples as human (46.9%, 45.6%). The male voices were more susceptible for misidentification. The synthesized breathy samples generated a greater perceptual confusion. The samples with severe deviation seemed to be more susceptible for errors. The synthesized female deviations were correctly classified. The male breathiness and strain were identified as roughness. CONCLUSION: VoiceSim produced stimuli very similar to the voices of patients with dysphonia. V-SLPs had a better ability to classify human and synthesized voices. VoiceSim is better to simulate vocal breathiness and female deviations; the male samples need adjustment. PMID- 28089486 TI - Molecular genetics of human obesity: A comprehensive review. AB - Obesity and its related health complications is a major problem worldwide. Hypothalamus and their signalling molecules play a critical role in the intervening and coordination with energy balance and homeostasis. Genetic factors play a crucial role in determining an individual's predisposition to the weight gain and being obese. In the past few years, several genetic variants were identified as monogenic forms of human obesity having success over common polygenic forms. In the context of molecular genetics, genome-wide association studies (GWAS) approach and their findings signified a number of genetic variants predisposing to obesity. However, the last couple of years, it has also been noticed that alterations in the environmental and epigenetic factors are one of the key causes of obesity. Hence, this review might be helpful in the current scenario of molecular genetics of human obesity, obesity-related health complications (ORHC), and energy homeostasis. Future work based on the clinical discoveries may play a role in the molecular dissection of genetic approaches to find more obesity-susceptible gene loci. PMID- 28089488 TI - High global prevalence of alcohol use during pregnancy and fetal alcohol syndrome indicates need for urgent action. PMID- 28089487 TI - Estimation of national, regional, and global prevalence of alcohol use during pregnancy and fetal alcohol syndrome: a systematic review and meta-analysis. AB - BACKGROUND: Alcohol use during pregnancy is the direct cause of fetal alcohol syndrome (FAS). We aimed to estimate the prevalence of alcohol use during pregnancy and FAS in the general population and, by linking these two indicators, estimate the number of pregnant women that consumed alcohol during pregnancy per one case of FAS. METHODS: We began by doing two independent comprehensive systematic literature searches using multiple electronic databases for original quantitative studies that reported the prevalence in the general population of the respective country of alcohol use during pregnancy published from Jan 1, 1984, to June 30, 2014, or the prevalence of FAS published from Nov 1, 1973, to June 30, 2015, in a peer-reviewed journal or scholarly report. Each study on the prevalence of alcohol use during pregnancy was critically appraised using a checklist for observational studies, and each study on the prevalence of FAS was critically appraised by use of a method specifically designed for systematic reviews addressing questions of prevalence. Studies on the prevalence of alcohol use during pregnancy and/or FAS were omitted if they used a sample population not generalisable to the general population of the respective country, reported a pooled estimate by combining several studies, or were published in iteration. Studies that excluded abstainers were also omitted for the prevalence of alcohol use during pregnancy. We then did country-specific random-effects meta-analyses to estimate the pooled prevalence of these indicators. For countries with one or no empirical studies, we predicted prevalence of alcohol use during pregnancy using fractional response regression modelling and prevalence of FAS using a quotient of the average number of women who consumed alcohol during pregnancy per one case of FAS. We used Monte Carlo simulations to derive confidence intervals for the country-specific point estimates of the prevalence of FAS. We estimated WHO regional and global averages of the prevalence of alcohol use during pregnancy and FAS, weighted by the number of livebirths per country. The review protocols for the prevalence of alcohol use during pregnancy (CRD42016033835) and FAS (CRD42016033837) are available on PROSPERO. FINDINGS: Of 23 470 studies identified for the prevalence of alcohol use, 328 studies were retained for systematic review and meta-analysis; the search strategy for the prevalence of FAS yielded 11 110 studies, of which 62 were used in our analysis. The global prevalence of alcohol use during pregnancy was estimated to be 9.8% (95% CI 8.9 11.1) and the estimated prevalence of FAS in the general population was 14.6 per 10 000 people (95% CI 9.4-23.3). We also estimated that one in every 67 women who consumed alcohol during pregnancy would deliver a child with FAS, which translates to about 119 000 children born with FAS in the world every year. INTERPRETATION: Alcohol use during pregnancy is common in many countries and as such, FAS is a relatively prevalent alcohol-related birth defect. More effective prevention strategies targeting alcohol use during pregnancy and surveillance of FAS are urgently needed. FUNDING: Centre for Addiction and Mental Health (no external funding was sought). PMID- 28089489 TI - Long non-coding RNAs are associated with spatiotemporal gene expression profiles in the marine gastropod Tegula atra. AB - Increasing evidence suggests that long non-coding RNAs (lncRNAs) play diverse roles in cellular processes, including in the regulation of embryogenesis and growth. However, little is known about the role of lncRNAs in marine invertebrates inhabiting changing environments. Therefore, the aim of this study was to present the first characterization of lncRNAs in an intertidal marine gastropod. Specifically, Tegula atra individuals were sampled in four sites of the central-northern Chilean coastline (28-31 degrees ) during summer and winter. A pipeline was constructed, and 3524 putative lncRNAs were identified from transcriptome databases specific to T. atra. These lncRNAs exhibited characteristics common to known lncRNAs, including a length shorter than coding sequences, low GC-content, and low sequence conservation. Expression analyses revealed that lncRNAs varied more in the summer. Furthermore, a majority of the differentially expressed lncRNAs were found in the southernmost population, the seasonal temperatures of which varied the greatest among all groups. Additionally, co-expression analysis found some lncRNAs strongly correlated with coding genes involved in the environmental stress response, such as heat shock proteins and metalloproteins. In contrast, other lncRNA expressions were strongly uncorrelated with genes involved in lipid/carbohydrates metabolism and cell-cell communication. This study provides the first large-scale characterization of lncRNAs in a marine gastropod, with results suggesting a putative role of lncRNAs in thermal tolerance, as well as an association with molecular mechanisms involved in the local adaptations of marine invertebrate populations. PMID- 28089490 TI - Dynamic Plant-Plant-Herbivore Interactions Govern Plant Growth-Defence Integration. AB - Plants downregulate their defences against insect herbivores upon impending competition for light. This has long been considered a resource trade-off, but recent advances in plant physiology and ecology suggest this mechanism is more complex. Here we propose that to understand why plants regulate and balance growth and defence, the complex dynamics in plant-plant competition and plant herbivore interactions needs to be considered. Induced growth-defence responses affect plant competition and herbivore colonisation in space and time, which has consequences for the adaptive value of these responses. Assessing these complex interactions strongly benefits from advanced modelling tools that can model multitrophic interactions in space and time. Such an exercise will allow a critical re-evaluation why and how plants integrate defence and competition for light. PMID- 28089491 TI - Satellite and central transitions selective 1H/{27Al} D-HMQC experiments at very fast MAS for quadrupolar couplings determination. AB - Recent study has demonstrated the application of the proton-detected heteronuclear multi-quantum coherence (HMQC) at ultrafast Magic Angle Spinning (MAS) to probe quadrupolar nuclei including 14N and 35Cl. In addition, for half integer quadrupolar nucleus like 35Cl, the quadrupolar product can be calculated based on the shift difference between the center band of satellite transition (ST) and the central transition (CT) peaks. The applicability of this technique is further investigated on spin I=5/2, namely 27Al nucleus, and kaolin is chosen as the testing sample. However this study is not straightforward owing to a spin quantum number I=5/2 of 27Al nucleus and a small quadrupolar coupling of kaolin. Furthermore, very fast MAS, which is mandatory for proton-detected experiment to suppress 1H-1H homonuclear dipolar interactions, introduces additional complexities. It induces the partial overlap of CT and the center band of inner ST (ST1) resonance in addition to the insufficiency of CT-selective excitation by soft-pulse irradiation. In the current work, we employ the constant-time D-HMQC experiment, in which the duration between two recoupling blocks is fixed to a constant value and the arbitrary t1 increment can be used within this duration. This constant-time D-HMQC enables the precise determination of CT and ST resonance shifts through CT- and ST-selective observations by the indirect spectral width (i) with asynchronized sampling to the top of rotational-echoes for STs and (ii) three times larger than the spinning frequency, respectively. We also numerically and experimentally develop a satellite-selective excitation technique, in which the radio frequency field is applied to the first spinning sideband of ST1 resonance. The satellite-selective 1D single pulse and 2D conventional D-HMQC experiments are demonstrated. The quadrupolar product of 27Al nucleus extracted from the resulting spectra is in good agreement with the literature. PMID- 28089492 TI - A Safer, Healthier U.S.: The Centers for Disease Control and Prevention, 2009 2016. PMID- 28089493 TI - Recent advances of stroke thrombolysis in Taiwan: A successful interaction between physicians, regulators, and National Health Insurance Administration. PMID- 28089494 TI - Downregulation of miR-1 enhances tumorigenicity and invasiveness in oral squamous cell carcinomas. AB - BACKGROUND/PURPOSE: Cumulative evidence suggest that microRNAs (miRNAs) function as biosignatures of oral squamous cell carcinomas (OSCC). However, the functional roles of miR-1 as well as its downstream targets in the regulation of tumorigenicity in OSCC remain unclear. METHODS: miRNAs RT-PCR analysis was performed to identify miR-1 as a putative candidate on mediating invasiveness of OSCC cells. Consequently, we elucidated the tumorigenicity of OSCC cells with miR 1 downregulation or overexpression, respectively. Finally, miR-1 on OSCC tumor tissues was examined. RESULTS: miR-1 levels were significantly downregulated in the malignant OSCC cells. Overexpression of miR-1 significantly reduced migration/invasiveness of OSCC cells. In addition, overexpression of miR-1 decreased cancer stem cells properties. Conversely, downregulation of miR-1 promotes migration and invasiveness in OSCC cells. We have shown that miR-1 is able to target Slug, suppressing their expression. Clinically, lower miR-1 expression was found in patients with advanced nodal metastasis OSCC. CONCLUSION: miR-1 as novel biosignatures in OSCC lymph node metastatic patients, supporting the development of novel strategies for OSCC treatment. PMID- 28089495 TI - Assessment of the Isometry of the Anterolateral Ligament in a 3-Dimensional Weight-Bearing Computed Tomography Simulation. AB - PURPOSE: To simulate the most isometric insertion points of the anterolateral ligament (ALL) in a weight-bearing 3-dimensional computed tomography (CT) model using previously published anatomic landmarks and to define radiographic landmarks, which make for an easier identification of the optimal insertion points. METHODS: The most isometric femoral insertion points were analyzed for 10 individuals, using data of weight-bearing CT scans in increasing knee flexion positions. An automatic string generation algorithm helped identify isometrically optimal points using an isometric score (0 indicating optimal isometry). Subsequently, a general femoral insertion point was determined, which preserved the isometry in all tested individuals. Based on the femoral insertion point, we assessed the influence of varying tibial insertion points on the isometric behavior of the ALL. RESULTS: The defined femoral insertion point, which preserved the isometry in all analyzed individuals, had a median isometric score between 0.167 * 10-3 and 0.559 * 10-3. The average distance from the most prominent point of the lateral epicondyle was 9.7 mm (standard deviation [SD], 1.6) in a straight superior direction. In a straight lateral radiographic view, this point is located exactly at the intersection of a tangent set between the posterior cortex of the femur and a second perpendicular line intersecting at the level of the most (superior-) posterior point of the Blumensaat line. The best isometric behavior was found on the anatomically defined mean tibial insertion point, located at 37% of the width of the tibial plateau, which worsened gradually if corrected to anterior or posterior. CONCLUSIONS: We determined femoral and tibial insertion points as well as radiographic landmarks for the reconstruction of the ALL that are based on published anatomic descriptions and preserve isometry in all analyzed individuals in this study. CLINICAL RELEVANCE: This study provides new information, which might be helpful to define isometrically optimal insertion points for ALL reconstruction. PMID- 28089496 TI - Cell Toxicity in Fibroblasts, Tenocytes, and Human Mesenchymal Stem Cells-A Comparison of Necrosis and Apoptosis-Inducing Ability in Ropivacaine, Bupivacaine, and Triamcinolone. AB - PURPOSE: To analyze the ability of ropivacaine, bupivacaine, and triamcinolone to induce apoptosis and necrosis in fibroblasts, tenocytes, and human mesenchymal stem cells. METHODS: Human dermal fibroblasts, adipose-derived human mesenchymal stem cells (hMSCs), and tenocytes gained from the rotator cuff tendon were seeded with a cell density of 0.5 * 104/cm2. One specimen of ropivacaine, bupivacaine, and triamcinolone was tested separately on the cells with separate concentrations of 0.5%, 0.25%, and 0.125% for each specimen. The negative control received no agent, only a change of medium. The incubation period for each agent was 30 minutes. After a change of medium and 1 hour, 24 hours, and 7 days of incubation, 104 cells were harvested and analyzed via fluorescence-activated cell sorting with double-staining with annexin V and propidium iodide. Statistical analysis to determine significant difference (P < .05) between the groups with SPSS statistics 23 through one-way analysis of variance with a univariate general linear model was performed. RESULTS: Bupivacaine showed necrosis-inducing effects on fibroblasts and tenocytes, with the necrotic effect peaking at 0.5% and 0.25%. Ropivacaine and triamcinolone caused no significant necrosis. Compared with fibroblasts and tenocytes, hMSCs did not show significant necrotic or apoptotic effects after exposure to bupivacaine. Overall, no significant differences in apoptosis were detected between different cell lines, varying concentrations, or time measurements. CONCLUSIONS: Bupivacaine 0.5% and 0.25% have the most necrosis inducing effects on fibroblasts and tenocytes. Ropivacaine caused less necrosis than bupivaine. Compared with fibroblasts and tenocytes, hMSCs were not affected by necrosis using any of the tested agents. A significant apoptosis-inducing effect could not be detected for the different cell lines. CLINICAL RELEVANCE: Possible cell toxicity raises questions of concern for intra-articular injections using local anesthetics and corticosteroids. The present study demonstrates the necrotic and apoptotic effects of ropivacaine, bupivacaine, and triamcinolone and may give recommendations for intra-articular use of local anesthetics and corticosteroids. PMID- 28089497 TI - Biomechanical Comparison of Standard and Linked Single-Row Rotator Cuff Repairs in a Human Cadaver Model. AB - PURPOSE: The purpose of this study was to evaluate the time zero cyclic and failure loading properties of a linked single-row rotator cuff repair compared with a standard simple suture single-row repair using triple-loaded suture anchors. METHODS: Eighteen human cadaveric shoulders from 9 matched pairs were dissected, and full-thickness supraspinatus tears were created. The tendon cross sectional area was recorded. In each pair, one side was repaired with a linked single-row construct and the other with a simple suture single-row construct, both using 2 triple-loaded suture anchors. After preloading, specimens were cycled to 1 MPa of effective stress at 1 Hz for 500 cycles, and gap formation was recorded with a digital video system. Samples were then loaded to failure, and modes of failure were recorded. RESULTS: There was no statistical difference in peak gap formation between the control and linked constructs (3.6 +/- 0.9 mm and 3.6 +/- 1.2 mm, respectively; P = .697). Both constructs averaged below a 5-mm cyclic failure threshold. There was no statistical difference in ultimate load to failure between the control and linked repair (511.1 +/- 139.0 N and 561.2 +/- 131.8 N, respectively; P = .164), and both groups reached failure at loads similar to previous studies. Constructs failed predominantly via tissue tearing parallel to the medial suture line. CONCLUSIONS: The linked repair performed similarly to the simple single-row repair. Both constructs demonstrated high ultimate load to failure and good resistance to gap formation with cyclic loading, validating the time zero strength of both constructs in a human cadaveric model. CLINICAL RELEVANCE: The linked repair provided equivalent resistance to gap formation and failure loads compared with simple suture single row repairs with triple-loaded suture anchors. This suggests that the linked repair is a simplified rip-stop configuration using the existing suture that may perform similarly to current rotator cuff repair techniques. PMID- 28089498 TI - Anticoagulants in ischemia-guided management of non-ST-elevation acute coronary syndromes. AB - BACKGROUND: The most recent joint guidelines from the American Heart Association (AHA) and American College of Cardiology (ACC) on the management of non-ST elevation acute coronary syndromes (NSTE-ACS) are a result of a substantial and considered undertaking, and those involved deserve much recognition for their efforts. However, the handling of anticoagulants seems somewhat inadequate, and this is a highly-relevant matter when managing NSTE-ACS. OBJECTIVE OF THE REVIEW: Among areas of potential uncertainty, emergency medicine professionals might still be left wondering about the particulars of anticoagulant therapy when pursuing ischemia-guided management of NSTE-ACS (that is, managing NSTE-ACS without an intent for early invasive measures, such as coronary angiography and revascularization). This review seeks to provide insight into this question. DISCUSSION: Relevant clinical trials are appraised and translated into clinical context for emergency medicine professionals, including the implications of noteworthy advancements in the management of NSTE-ACS. CONCLUSIONS: Although current guidelines from the AHA and ACC suggest enoxaparin has better evidence than other anticoagulants in the setting of NSTE-ACS management, careful review of the evidence shows this is not actually clearly supported by the available evidence in the era of contemporary management. Unless and until better contemporary data emerge, emergency medicine professionals must carefully weigh the available evidence, its limitations, and the possible clinical implications of the various anticoagulant options when managing NSTE-ACS. PMID- 28089499 TI - The stability of gadolinium-based contrast agents in human serum: A reanalysis of literature data and association with clinical outcomes. AB - PURPOSE: To reanalyze literature data of gadolinium (Gd)-based contrast agents (GBCAs) in plasma with a kinetic model of dissociation to provide a comprehensive assessment of equilibrium conditions for linear GBCAs. METHODS: Data for the release of Gd from GBCAs in human serum was extracted from a previous report in the literature and fit to a kinetic dissociation/association model. The conditional stabilities (logKcond) and percent intact over time were calculated using the model rate constants. The correlations between clinical outcomes and logKcond or other stability indices were determined. RESULTS: The release curves for Omniscan(r), gadodiamide, OptiMARK(r), gadoversetamide Magnevist(r) and Multihance(r) were extracted and all fit well to the kinetic model. The logKconds calculated from the rate constants were on the order of ~4-6, and were not significantly altered by excess ligand or phosphate. The stability constant based on the amount intact by the initial elimination half-life of GBCAs in plasma provided good correlation with outcomes observed in patients. CONCLUSIONS: Estimation of the kinetic constants for GBCA dissociation/association revealed that their stability in physiological fluid is much lower than previous approaches would suggest, which correlates well with deposition and pharmacokinetic observations of GBCAs in human patients. PMID- 28089500 TI - C-reactive Protein may Predict the Recurrence of Appendicitis in Children Formerly with Appendiceal Mass after Successful Non-operative Treatment. AB - BACKGROUND: This study identified factors associated with the recurrence of appendicitis in children with appendiceal masses after successful nonsurgical treatment. METHODS: In this retrospective study, children who were diagnosed as having appendiceal masses after undergoing conservative treatment between 2000 and 2014 were enrolled and the medical records of those who did not undergo an interval appendectomy were reviewed. The clinical features and outcomes of patients with and those without recurrent appendicitis were compared. Regression analysis was used to identify risk factors of appendicitis recurrence. RESULTS: Seventy patients were included and successfully discharged after receiving nonsurgical treatment for appendiceal masses. Of the patients, 35 (50.0%) developed recurrent appendicitis and 85.7% (30/35) recurrences developed within 3 months. Multivariate analyses showed that patients with a higher serum C-reactive protein (CRP) level and peritonitis more frequently developed recurrence. The appendicitis recurrence rate was significantly higher in the patients with CRP levels of >=103 mg/L with an odds ratio of 16.9 or in those with peritonitis with an odds ratio of 4.9. CONCLUSION: Children with appendiceal masses who develop peritonitis or have CRP levels of >=103 mg/L have a higher recurrence rate of appendicitis and should undergo an interval appendectomy. PMID- 28089501 TI - Effectiveness of conventional disease-modifying antirheumatic drugs in psoriatic arthritis: A systematic review. AB - BACKGROUND: Due to the clinical heterogeneity of psoriatic arthritis (PsA), recommendations have been developed by international groups to guide therapeutic decisions of the rheumatologist. The objective of the current systematic review (RS) was to evaluate the evidence of efficacy of disease-modifying antirheumatic drugs (DMARDs) in PsA. METHODS: Literature search in Medline, EMBASE, Cochrane Library, from 2008 to 2014. We included RS, randomized clinical trials and observational studies, in patients with PsA and an evaluation of efficiency of conventional DMARDs (methotrexate, sulfasalazine, leflunomide), according to the following outcomes: peripheral and axial symptoms; peripheral radiological damage; enthesitis according to power Doppler ultrasound or magnetic resonance imaging (enthesitis count before and after therapy); dactylitis; uveitis. RESULTS: Title and abstract were used to retrieve 1,662 documents for this review (Medline, n=433; EMBASE n=1,132; Cochrane, n=97), and 48 studies were selected for detailed reading; finally, 8 studies were included. CONCLUSIONS: Since the studies included are not robust, and there are arguments to support the effectiveness of methotrexate, the evidence observed with the treatment of DMARDs in PsA is not conclusive. PMID- 28089502 TI - An extended fatty liver index to predict non-alcoholic fatty liver disease. AB - BACKGROUND: In clinical practice, there is a strong interest in non-invasive markers of non-alcoholic fatty liver disease (NAFLD). Our hypothesis was that the fold-change in plasma triglycerides (TG) during a 2-h oral glucose tolerance test (fold-change TGOGTT) in concert with blood glucose and lipid parameters, and the rs738409 C>G single nucleotide polymorphism (SNP) in PNPLA3 might improve the power of the widely used fatty liver index (FLI) to predict NAFLD. METHODS: The liver fat content of 330 subjects was quantified by 1H-magnetic resonance spectroscopy. Blood parameters were measured during fasting and after a 2-h OGTT. A subgroup of 213 subjects underwent these measurements before and after 9 months of a lifestyle intervention. RESULTS: The fold-change TGOGTT was closely associated with liver fat content (r=0.51, P<0.0001), but had less power to predict NAFLD (AUROC=0.75) than the FLI (AUROC=0.79). Not only was the fold change TGOGTT independently associated with liver fat content and NAFLD, but so also were the 2-h blood glucose level and rs738409 C>G SNP in PNPLA3. In fact, a novel index (extended FLI) generated from these and the usual FLI parameters considerably increased its power to predict NAFLD (AUROC=0.79-0.86). The extended FLI also increased the power to predict changes in liver fat content with a lifestyle intervention (n=213; standardized beta coefficient: 0.23-0.29). CONCLUSION: This study has provided novel data confirming that the OGTT-derived fold-change TGOGTT and 2-h glucose level, together with the rs738409 C>G SNP in PNPLA3, allow calculation of an extended FLI that considerably improves its power to predict NAFLD. PMID- 28089503 TI - Comparison of two techniques of adiponectin assay, ELISA and immunoturbidimetry: Should we move towards standardization? PMID- 28089504 TI - Review: Nutrient sulfate supply from mother to fetus: Placental adaptive responses during human and animal gestation. AB - Nutrient sulfate has numerous roles in mammalian physiology and is essential for healthy fetal growth and development. The fetus has limited capacity to generate sulfate and relies on sulfate supplied from the maternal circulation via placental sulfate transporters. The placenta also has a high sulfate requirement for numerous molecular and cellular functions, including sulfate conjugation (sulfonation) to estrogen and thyroid hormone which leads to their inactivation. Accordingly, the ratio of sulfonated (inactive) to unconjugated (active) hormones modulates endocrine function in fetal, placental and maternal tissues. During pregnancy, there is a marked increase in the expression of genes involved in transport and generation of sulfate in the mouse placenta, in line with increasing fetal and placental demands for sulfate. The maternal circulation also provides a vital reservoir of sulfate for the placenta and fetus, with maternal circulating sulfate levels increasing by 2-fold from mid-gestation. However, despite evidence from animal studies showing the requirement of maternal sulfate supply for placental and fetal physiology, there are no routine clinical measurements of sulfate or consideration of dietary sulfate intake in pregnant women. This is also relevant to certain xenobiotics or pharmacological drugs which when taken by the mother use significant quantities of circulating sulfate for detoxification and clearance, and thereby have the potential to decrease sulfonation capacity in the placenta and fetus. This article will review the physiological adaptations of the placenta for maintaining sulfate homeostasis in the fetus and placenta, with a focus on pathophysiological outcomes in animal models of disturbed sulfate homeostasis. PMID- 28089505 TI - Corrigendum to "Maternal plasma antioxidant status in the first trimester of pregnancy and development of obstetric complications" [YPLAC (47C) (2016) 37-45]. PMID- 28089506 TI - Evaluation of the predictive value of placental vascularisation indices derived from 3-Dimensional power Doppler whole placental volume scanning for prediction of pre-eclampsia: A systematic review and meta-analysis. AB - Pre-eclampsia remains a leading cause of maternal and fetal morbidity and mortality. This systematic review aims to evaluate the ability of placental vascularisation indices (PVIs) derived from 3D power Doppler whole placental volume scanning to predict early, late and any-onset pre-eclampsia (PE). The following databases were searched: MEDLINE, EMBASE and Web of Science. Studies selected for inclusion measured PVIs: Vascularisation Index (%) (VI) and/or Flow Index (FI) and/or Vascularisation Flow Index (VFI) derived from 3D power Doppler whole placental volume scanning via Virtual Organ Computer-aided Analysis (VOCAL) technique prior to diagnosis of PE. A total of 667 records were screened with five eligible studies included. A narrative review of all studies was undertaken and three studies with sufficient data were included in a meta-analysis. This review, the first of its kind to evaluate the predictive value of PVIs for PE, reports significantly lower first trimester PVIs across a range of studies in women who develop PE. Mean differences in vascularisation indices in PE and non PE pregnancies were: VI -2.93% (95% CI -5.84,-0.01), FR -2.83 (95% CI -3.97, 1.69) and VFI -0.93 (95% CI -1.6,-0.25), respectively. While only two studies reported sensitivity and specificity data, VI and VFI most accurately predicted early onset PE, and VFI predicted PE in high risk women. Further research is required to validate these findings in different study populations and to examine the performance of PVIs within combined screening models for PE. PMID- 28089507 TI - Gastrointestinal Perforation and Fistula Formation in 5 Patients With Colorectal Cancer During Treatment With Regorafenib. PMID- 28089508 TI - A reply to Douze and Delagnes's 'The pattern of emergence of a Middle Stone Age tradition at Gademotta and Kulkuletti (Ethiopia) through convergent tool and point technologies' [J. Hum. Evol. 91 (2016) 93-121]. AB - Douze and Delagnes (2016) revisit Middle Stone Age (MSA) lithic assemblages from the Gademotta Formation (Fm.), Ethiopia. Their analysis of selected assemblages from three of the 1972 excavations expands the original typo-technological interpretations by Wendorf and Schild (1974). We particularly welcome their evaluation of our recent inferences about the function of pointed artifacts and technological patterns in the Gademotta Fm. (Sahle et al., 2013, 2014). However, we find several arguments and conclusions in Douze and Delagnes (2016) to be rather unconvincing and irreconcilable with results from analyses of whole assemblages (Wendorf and Schild, 1974; Sahle et al., 2013, 2014). Specifically, their summary attribution of all early MSA burin-like fractures on the distal tips of pointed artifacts to intentional resharpening blows, and their use of this pattern as a technological "chrono-marker" unique to the region are untenable. Here, we highlight these issues in the hopes of a clearer understanding of the evident technological patterns in the Gademotta Fm. PMID- 28089509 TI - Occult external iliac vein injury after anterior dislocation of the sacroiliac joint in adult patient. AB - Anterior dislocation of the sacroiliac joint, characterized by dislocation of the ilium anterior to the sacrum, is a subtype of complete posterior pelvic ring disruption. This injury occurs mostly in children. We present an adult patient with anterior dislocation of the sacroiliac joint. It was associated with numerous complications. To the best of our knowledge, it is only the second case reported in the literature. PMID- 28089510 TI - A novel computer-based method for measuring the acetabular angle on hip radiographs. AB - OBJECTIVE: The aim of this study was to propose a new computer based method for measuring acetabular angles on hip radiographs and to assess its practicality, sensitivity and reliability for acetabular angle measurement. METHODS: A total of 314 acetabulum were assessed on 157 pelvic X-ray images. Acetabular angles were measured with both the conventional method (Method 1) and our proposed method (Method 2). All the Acetabular Index (AI) angle, Acetabular Angle (AA) and Acetabular Center (ACM) angle were measured with both methods. RESULTS: The mean AI angle for Method 1 is 11.02 degrees +/- 2.7 degrees and the mean AI angle for Method 2 is 10.08 degrees +/- 1.88 degrees , the mean AA angle for Method 1 is 39.5 degrees +/- 5.3 degrees and the mean AA angle for Method 2 is 39.36 degrees +/- 4.68 degrees , the mean ACM angle for Method 1 is 50.5 degrees +/- 6.01 degrees and the mean ACM angle for Method 2 is 55.42 degrees +/- 12.43 degrees . CONCLUSION: Our novel automated method appear to be reliable and practical for acetabular angle measurement on hip radiographs. LEVEL OF EVIDENCE: Level III, Diagnostic study. PMID- 28089511 TI - The Descending Diencephalic Dopamine System Is Tuned to Sensory Stimuli. AB - The vertebrate diencephalic A11 system provides the sole dopaminergic innervation of hindbrain and spinal cord and has been implicated in modulation of locomotion and sensory processes. However, the exact contributions of sensory stimuli and motor behavior to A11 dopaminergic activity remain unclear. We recorded cellular calcium activity in four anatomically distinct posterior tubercular A11-type dopaminergic subgroups and two adjacent hypothalamic dopaminergic groups in GCaMP7a-transgenic, semi-restrained zebrafish larvae. Our analyses reveal the contributions of different sensory modalities and motor states to dopaminergic activity. Each posterior tubercular and hypothalamic subgroup showed distinct activity patterns, while activity was synchronous within individual subgroups. Caudal and dorsomedial hypothalamic dopaminergic neurons are activated following vigorous tail movements and stay active for about 10 s, revealing predominantly post-motor activity. In contrast, posterior tubercular dopaminergic neurons are predominantly sensory driven, with subgroups differentially responding to different tactile or visual sensory modalities. In the anterior subgroups, neuronal response magnitudes are tuned to tactile stimulus intensities, revealing features similar to sensory systems. We identify the lateral line system as source for this tactile tuning. In contrast, the posterior subgroup is responsive to distinct moving visual stimuli. Specifically, translational forward stimuli, which may indicate insufficient rheotaxis and drift, induce dopaminergic activity, but backward or rotational stimuli not. The activation of posterior tubercular dopaminergic neurons by sensory stimuli, and their projections onto peripheral mechanosensory systems, suggests a participation of A11-type neurons in the feedback regulation of sensory systems. Together with the adjacent hypothalamic neurons, they may serve to set basic behavioral states. PMID- 28089512 TI - Paleozoic Nymphal Wing Pads Support Dual Model of Insect Wing Origins. AB - The appearance of wings in insects, early in their evolution [1], has been one of the more critical innovations contributing to their extraordinary diversity. Despite the conspicuousness and importance of wings, the origin of these structures has been difficult to resolve and represented one of the "abominable mysteries" in evolutionary biology [2]. More than a century of debate has boiled the matter down to two competing alternatives-one of wings representing an extension of the thoracic notum, the other stating that they are appendicular derivations from the lateral body wall. Recently, a dual model has been supported by genomic and developmental data [3-6], representing an amalgamation of elements from both the notal and pleural hypotheses. Here, we reveal crucial information from the wing pad joints of Carboniferous palaeodictyopteran insect nymphs using classical and high-tech techniques. These nymphs had three pairs of wing pads that were medially articulated to the thorax but also broadly contiguous with the notum anteriorly and posteriorly (details unobservable in modern insects), supporting their overall origin from the thoracic notum as well as the expected medial, pleural series of axillary sclerites. Our study provides support for the formation of the insect wing from the thoracic notum as well as the already known pleural elements of the arthropodan leg. These results support the unique, dual model for insect wing origins and the convergent reduction of notal fusion in more derived clades, presumably due to wing rotation during development, and they help to bring resolution to this long-standing debate. PMID- 28089513 TI - Human Disruption of Coral Reef Trophic Structure. AB - The distribution of biomass among trophic levels provides a theoretical basis for understanding energy flow and the hierarchical structure of animal communities. In the absence of energy subsidies [1], bottom-heavy trophic pyramids are expected to predominate, based on energy transfer efficiency [2] and empirical evidence from multiple ecosystems [3]. However, the predicted pyramid of biomass distribution among trophic levels may be disrupted through trophic replacement by alternative organisms in the ecosystem, trophic cascades, and humans preferentially impacting specific trophic levels [4-6]. Using empirical data spanning >250 coral reefs, we show how trophic pyramid shape varies given human mediated gradients along two orders of magnitude in reef fish biomass. Mean trophic level of the assemblage increased modestly with decreasing biomass, contrary to predictions of fishing down the food web [7]. The mean trophic level pattern is explained by trophic replacement of herbivorous fish by sea urchins at low biomass and the accumulation of slow-growing, large-bodied, herbivorous fish at high biomass. Further, at high biomass, particularly where fishers are not selectively removing higher trophic level individuals, a concave trophic distribution emerges. The concave trophic distribution implies a more direct link between lower and upper trophic levels, which may confer greater energy efficiency. This trophic distribution emerges when community biomass exceeds ~650 kg/ha, suggesting that fisheries for upper trophic level species will only be supported under lightly fished scenarios. PMID- 28089514 TI - Reproductive Conflict and the Evolution of Menopause in Killer Whales. AB - Why females of some species cease ovulation prior to the end of their natural lifespan is a long-standing evolutionary puzzle [1-4]. The fitness benefits of post-reproductive helping could in principle select for menopause [1, 2, 5], but the magnitude of these benefits appears insufficient to explain the timing of menopause [6-8]. Recent theory suggests that the cost of inter-generational reproductive conflict between younger and older females of the same social unit is a critical missing term in classical inclusive fitness calculations (the "reproductive conflict hypothesis" [6, 9]). Using a unique long-term dataset on wild resident killer whales, where females can live decades after their final parturition, we provide the first test of this hypothesis in a non-human animal. First, we confirm previous theoretical predictions that local relatedness increases with female age up to the end of reproduction. Second, we construct a new evolutionary model and show that given these kinship dynamics, selection will favor younger females that invest more in competition, and thus have greater reproductive success, than older females (their mothers) when breeding at the same time. Third, we test this prediction using 43 years of individual-based demographic data in resident killer whales and show that when mothers and daughters co-breed, the mortality hazard of calves from older-generation females is 1.7 times that of calves from younger-generation females. Intergenerational conflict combined with the known benefits conveyed to kin by post-reproductive females can explain why killer whales have evolved the longest post-reproductive lifespan of all non-human animals. PMID- 28089515 TI - Navigation through the Plasma Membrane Molecular Landscape Shapes Random Organelle Movement. AB - Eukaryotic plasma membrane organization theory has long been controversial, in part due to a dearth of suitably high-resolution techniques to probe molecular architecture in situ and integrate information from diverse data streams [1]. Notably, clustered patterning of membrane proteins is a commonly conserved feature across diverse protein families (reviewed in [2]), including the SNAREs [3], SM proteins [4, 5], ion channels [6, 7], and receptors (e.g., [8]). Much effort has gone into analyzing the behavior of secretory organelles [9-13], and understanding the relationship between the membrane and proximal organelles [4, 5, 12, 14] is an essential goal for cell biology as broad concepts or rules may be established. Here we explore the generally accepted model that vesicles at the plasmalemma are guided by cytoskeletal tracks to specific sites on the membrane that have clustered molecular machinery for secretion [15], organized in part by the local lipid composition [16]. To increase our understanding of these fundamental processes, we integrated nanoscopy and spectroscopy of the secretory machinery with organelle tracking data in a mathematical model, iterating with knockdown cell models. We find that repeated routes followed by successive vesicles, the re-use of similar fusion sites, and the apparently distinct vesicle "pools" are all fashioned by the Brownian behavior of organelles overlaid on navigation between non-reactive secretory protein molecular depots patterned at the plasma membrane. PMID- 28089516 TI - Environmental Geometry Aligns the Hippocampal Map during Spatial Reorientation. AB - When a navigator's internal sense of direction is disrupted, she must rely on external cues to regain her bearings, a process termed spatial reorientation. Extensive research has demonstrated that the geometric shape of the environment exerts powerful control over reorientation behavior, but the neural and cognitive mechanisms underlying this phenomenon are not well understood. Whereas some theories claim that geometry controls behavior through an allocentric mechanism potentially tied to the hippocampus, others postulate that disoriented navigators reach their goals by using an egocentric view-matching strategy. To resolve this debate, we characterized hippocampal representations during reorientation. We first recorded from CA1 cells as disoriented mice foraged in chambers of various shapes. We found that the alignment of the recovered hippocampal map was determined by the geometry of the chamber, but not by nongeometric cues, even when these cues could be used to disambiguate geometric ambiguities. We then recorded hippocampal activity as disoriented mice performed a classical goal directed spatial memory task in a rectangular chamber. Again, we found that the recovered hippocampal map aligned solely to the chamber geometry. Critically, we also found a strong correspondence between the hippocampal map alignment and the animal's behavior, making it possible to predict the search location of the animal from neural responses on a trial-by-trial basis. Together, these results demonstrate that spatial reorientation involves the alignment of the hippocampal map to local geometry. We hypothesize that geometry may be an especially salient cue for reorientation because it is an inherently stable aspect of the environment. PMID- 28089517 TI - Hypoxia Induces a HIF-1-Dependent Transition from Collective-to-Amoeboid Dissemination in Epithelial Cancer Cells. AB - Cancer metastases arise from a multi-step process that requires metastasizing tumor cells to adapt to signaling input from varying tissue environments [1]. As an early metastatic event, cancer cell dissemination occurs through different migration programs, including multicellular, collective, and single-cell mesenchymal or amoeboid migration [2-4]. Migration modes can interconvert based on changes in cell adhesion, cytoskeletal mechanotransduction [5], and/or proteolysis [6], most likely under the control of transcriptional programs such as the epithelial-to-mesenchymal transition (EMT) [7, 8]. However, how plasticity of tumor cell migration and EMT is spatiotemporally controlled and connected upon challenge by the tumor microenvironment remains unclear. Using 3D cultures of collectively invading breast and head and neck cancer spheroids, here we identify hypoxia, a hallmark of solid tumors [9], as an inducer of the collective-to amoeboid transition (CAT), promoting the dissemination of amoeboid-moving single cells from collective invasion strands. Hypoxia-induced amoeboid detachment was driven by hypoxia-inducible factor 1 (HIF-1), followed the downregulation of E cadherin, and produced heterogeneous cell subsets whose phenotype and migration were dependent (~30%) or independent (~70%) of Twist-mediated EMT. EMT-like and EMT-independent amoeboid cell subsets showed stable amoeboid movement over hours as well as leukocyte-like traits, including rounded morphology, matrix metalloproteinase (MMP)-independent migration, and nuclear deformation. Cancer cells undergoing pharmacological stabilization of HIFs retained their constitutive ability for early metastatic seeding in an experimental model of lung metastasis, indicating that hypoxia-induced CAT enhances cell release rather than early organ colonization. Induced by metabolic challenge, amoeboid movement may thus constitute a common endpoint of both EMT-dependent and EMT-independent cancer dissemination programs. PMID- 28089518 TI - Transcriptional Pre-patterning of Drosophila Gastrulation. AB - Gastrulation of the Drosophila embryo is one of the most intensively studied morphogenetic processes in animal development [1-4]. Particular efforts have focused on the formation of the ventral furrow, whereby ~1,000 presumptive mesoderm cells exhibit coordinated apical constrictions that mediate invagination [5, 6]. Apical constriction depends on a Rho GTPase signaling pathway (T48/Fog) that is deployed by the developmental regulatory genes twist and snail [7-10]. It is thought that coordinate mesoderm constriction depends on high levels of myosin along the ventral midline, although the basis for this localization is uncertain. Here, we employ newly developed quantitative imaging methods to visualize the transcriptional dynamics of two key components of the Rho signaling pathway in living embryos, T48 and Fog. Both genes display dorsoventral (DV) gradients of expression due to differential timing of transcription activation. Transcription begins as a narrow stripe of two or three cells along the ventral midline, followed by progressive expansions into more lateral regions. Quantitative image analyses suggest that these temporal gradients produce differential spatial accumulations of t48 and fog mRNAs along the DV axis, similar to the distribution of myosin activity. We therefore propose that the transcriptional dynamics of t48 and fog expression foreshadow the coordinated invagination of the mesoderm at the onset of gastrulation. PMID- 28089520 TI - The association between family caregivers' involvement in managing older adults' medications and caregivers' information-seeking behavior. AB - OBJECTIVES: 1) To explore the association between family caregivers' involvement in managing care recipients' medications and their information-seeking behavior related to caregiving; and 2) to examine the sources used by caregivers when seeking information. METHODS: A retrospective analysis of cross-sectional data from 2 national studies, the 2011 National Health and Aging Trends Study (NHATS) and its supplement, the National Study of Caregiving (NSOC), was conducted. A nationally representative sample of community-dwelling adults (>=65 years of age) completed NHATS interviews, and a sample of their family caregivers participated in NSOC. Caregiver involvement in medication management was assessed with the use of 2 items asking caregivers if they helped keep track of care recipients' medications or helped with injecting medications. Information seeking was assessed with the use of an item asking caregivers if they ever looked for caregiving-related information. RESULTS: Out of 1367 caregivers interviewed, 54% reported helping to keep track of care recipients' medications and 8.7% assisting with injecting medications. Approximately 10.2% (n = 149) of caregivers reported seeking information to help them care for their care recipients. Caregivers sought information primarily on their own either through online resources or asking friends or relatives (73.3%). Sixty-four percent also sought information from medical providers or social workers. Adult children of caregivers were more likely to seek information for their older adult parents, based on bivariate analysis (P <0.01). In multivariable-adjusted models, caregivers who helped to keep track of medications had 2.30 (95% confidence interval [CI] 1.18 to 4.51) times higher odds of seeking information to help them to provide care for their care recipients. Caregivers helping with injecting medications were less likely to seek information (odds ratio 0.32, 95% CI 0.14 to 0.76). CONCLUSION: Specific caregiver responsibilities, such as assisting with medication management activities, are associated with caregivers' information-seeking behavior related to care recipients' health. Health care providers, including pharmacists, can play an important role in helping caregivers to identify proper resources for information and in educating them about medication management. PMID- 28089519 TI - Role of Nhp6 and Hmo1 in SWI/SNF occupancy and nucleosome landscape at gene regulatory regions. AB - Diverse chromatin modifiers are involved in regulation of gene expression at the level of transcriptional regulation. Among these modifiers are ATP-dependent chromatin remodelers, where the SWI/SNF complex is the founding member. It has been observed that High Mobility Group (HMG) proteins can influence the activity of a number of these chromatin remodelers. In this context, we have previously demonstrated that the yeast HMG proteins Nhp6 and Hmo1 can stimulate SWI/SNF activity. Here, we studied the genome-wide binding patterns of Nhp6, Hmo1 and the SWI/SNF complex, finding that most of gene promoters presenting high occupancy of this complex also display high enrichment of these HMG proteins. Using deletion mutant strains we demonstrate that binding of SWI/SNF is significantly reduced at numerous genomic locations by deletion of NHP6 and/or deletion of HMO1. Moreover, alterations in the nucleosome landscape take place at gene promoters undergoing reduced SWI/SNF binding. Additional analyses show that these effects also correlate with alterations in transcriptional activity. Our results suggest that, besides the ability to stimulate SWI/SNF activity, these HMG proteins are able to assist the loading of this complex onto gene regulatory regions. PMID- 28089521 TI - Trends in naloxone prescriptions prescribed after implementation of a National Academic Detailing Service in the Veterans Health Administration: A preliminary analysis. AB - OBJECTIVES: To evaluate the effects of the U.S. Veterans Health Administration (VA) National Academic Detailing Service alongside the Opioid Overdose Education and Naloxone Distribution (OEND) program on naloxone prescriptions prescribed from October 2014 to September 2016. METHODS: A retrospective, repeated measures cohort study was conducted to evaluate the effectiveness of a real-world application of academic detailing (AD) alongside OEND on providers' outpatient naloxone prescribing from October 2014 to September 2016. Outcome was the number of naloxone prescriptions prescribed per month per provider. During the study period, VA providers were aware of OEND, but may not have been exposed to academic detailing. Therefore, providers were categorized as exposed when the first OEND-specific academic detailing session was provided during the study period. Generalized estimating equations were used to estimate the association between exposure to academic detailing and monthly naloxone prescriptions prescribed while taking into account the correlation within each provider. Incident rate ratios with 95% CIs were reported. RESULTS: Seven hundred fifty (22.6%) of 3313 providers received at least 1 OEND-specific academic detailing visit. At 1 year, the average number of naloxone prescriptions per month was 3 times greater in AD-exposed providers compared with AD-unexposed providers (95% CI 2.0-5.3); and at 2 years, the average number of naloxone prescriptions was 7 times greater (95% CI 3.0-17.9). Moreover, the average difference in naloxone prescribing from baseline to 2 years was 7.1% greater in AD-exposed providers compared with AD-unexposed providers (95% CI 2.0%-12.5%). CONCLUSIONS: This preliminary analysis provides the first evidence that academic detailing influenced naloxone prescribing rates in a large, integrated health care system at 1 and 2 years. In addition, AD-exposed providers had a higher average difference in naloxone prescribing rate compared with AD-unexposed providers after 2 years of follow-up. PMID- 28089522 TI - The impact of medication synchronization on quality care criteria in an independent community pharmacy. AB - OBJECTIVES: To determine the impact of a comprehensive medication synchronization program in an independent community pharmacy by (1) evaluating changes in Electronic Quality Improvement Platform for Plans and Pharmacies (EQuIPP) scores and (2) examining the change in monthly prescription volume. SETTING: Independent community pharmacy in Morgantown, WV. PRACTICE DESCRIPTION: Waterfront Family Pharmacy is a single-location independent community pharmacy located in Morgantown, WV. The pharmacy consists of four full-time pharmacists and is the primary practice site for one community pharmacy PGY-1 resident. The pharmacy provides a variety of clinical services, including vaccine administration, medication therapy management, and diabetes education services. PRACTICE INNOVATION: In September 2014, Waterfront Family Pharmacy started a comprehensive medication synchronization program. EVALUATION: Change in Electronic Quality Improvement Platform for Plans and Pharmacies (EQuIPP) scores and change in monthly prescription volume. RESULTS: At the end of 6 months there was improvement in all targeted EQuIPP scores. There was a 7% improvement in proportion of days covered (PDC) for cholesterol-reducing agents, a 9.5% improvement in PDC for oral glycemic agents, a 1.2% improvement in PDC for renin angiotensin system antagonists, and a 1.8% reduction in the use of high-risk medications in the elderly. There was also an average increase in monthly prescription volume of 4.8% over the first 6 months after the implementation of the comprehensive medication synchronization program. CONCLUSION: The implementation of a comprehensive medication synchronization program in an independent community pharmacy may result in benefits including improved EQuIPP scores and increased prescription volume. PMID- 28089523 TI - Corrigendum to "Inflammation and frailty in the elderly: A systematic review and meta-analysis" [Ageing Res Rev. 31 (2016) 1-8]. PMID- 28089524 TI - How Oral Contraceptives Impact Social-Emotional Behavior and Brain Function. AB - Millions of women worldwide use oral contraceptives ('the pill'; OCs), often starting at a pubertal age when their brains are in a crucial developmental stage. Research into the social-emotional effects of OCs is of utmost importance. In this review, we provide an overview of studies that have emerged over the past decade investigating how OCs, and their main ingredients estradiol (E) and progesterone (P), influence social-emotional behaviors and underlying brain functions. Based on this overview, we present a heuristic model that postulates that OCs modulate core social-emotional behaviors and brain systems. Research domains and challenges for the future, as well as implications, are discussed. PMID- 28089525 TI - Radiotherapeutic management of vestibular schwannomas using size- and location adapted fractionation regimens to maximize the therapeutic ratio. AB - BACKGROUND: We evaluated and compared the radiographic and clinical outcomes of patients with vestibular schwannomas treated with single fraction stereotactic radiosurgery (SRS), 5 fractions of hypofractionated stereotactic radiation therapy (hSRT), or 25 to 30 fractions of conventionally fractionated stereotactic radiation therapy (cfSRT). METHODS AND MATERIALS: Fifty-six patients treated with LINAC-based SRS (median, 12.5 Gy), hSRT (25 Gy), or cfSRT (median, 54 Gy) were retrospectively reviewed. Fractionation was based on the size of the tumor, proximity to the brainstem, and potential risk of neurological sequelae. Median follow-up time was 55.2 months. RESULTS: The pretreatment median tumor diameter was significantly smaller for SRS (1.14 cm) compared with hSRT (1.7 cm) (P = .03) and cfSRT (2.0 cm) (P < .001). The overall local tumor control was 96.4%: 100% SRS, 100% hSRT, and 90% cfSRT (P = .19). Tumor regression was observed in 53.3% of SRS, 76.2% of hSRT, and 90% of cfSRT (P = .05). There was less transient expansion of tumors treated with cfSRT (5%) than with SRS (53.3%) or hSRT (28.6%) (P = .005). The median time to regression was 13.8 months for SRS, 14.2 months for hSRT, and 5.5 months for cfSRT (P = .34). There was a 3.6% incidence of grade 3 trigeminal neuropathy, but there was no grade 3 facial neuropathy. CONCLUSIONS: All 3 regimens demonstrated similar excellent local control with minimal toxicity; however, the ability of hSRT to treat larger tumors with comparable outcomes to SRS and greater patient convenience when compared with cfSRT suggest that hSRT may offer the optimal treatment approach. PMID- 28089526 TI - A feasibility study of 2-mm bolus for postmastectomy radiation therapy. AB - PURPOSE: The purpose of this study was to prospectively evaluate the use of daily 2-mm bolus in patients undergoing postmastectomy radiation without reconstruction using optically stimulated luminescence dosimetry and weekly assessment of skin toxicity. METHODS AND MATERIALS: We prospectively collected data from the first 49 women treated with a daily 2-mm Superflab bolus during their postmastectomy radiation therapy from 2013 to 2016 at The University of Chicago Comprehensive Cancer Center at Silver Cross. Within the first 3 days of starting radiation therapy, we measured the surface dose in vivo at 5 anatomical locations under the 2-mm bolus on the chest wall. We assessed weekly the acute skin toxicity during radiation using the National Cancer Institute Common Toxicity Criteria. Patients with reconstruction before radiation therapy were excluded. RESULTS: Forty-nine women with a mean age of 54.3 years were treated with daily 2-mm bolus to the chest wall following mastectomy. Median follow-up was 32.7 weeks. The mean percentages of prescribed dose (standard deviation) for the median, central, lateral, superior, and inferior optically stimulated luminescence dosimeters were 100.1% (5.6%), 108.1% (6.7%), 98.1% (6.5%), 102.6% (8.9%), and 106.3% (6.6%), respectively. The majority (71.4%) of women experienced a maximum acute National Cancer Institute Common Toxicity Criteria skin toxicity score of 2, with only 12.2% experiencing a score of 3. There were no grade 4 toxicities. There were no local recurrences during our follow-up period. CONCLUSIONS: A daily 2-mm bolus is a feasible regimen for chest wall bolus during postmastectomy radiation therapy with acceptable dose buildup and skin toxicity. PMID- 28089527 TI - MRI in radiotherapy for lung cancer: A free-breathing protocol at 3T. AB - Imaging plays a significant role in radiation therapy. Improvements in treatment delivery require sophisticated imaging technologies to define tumor volume accurately. Magnetic resonance imaging scans can provide morphological and functional information and are increasingly being used in imaging for radiation therapy; however, for lung cancer, most protocols are based on breath-hold imaging and noncompliance to breath-hold maneuver can lead to significant artifacts. For patients presenting for lung cancer radiation therapy, maintaining a breath hold can be impossible. This paper describes a completely free-breathing lung magnetic resonance imaging protocol for use in radiation therapy for lung cancer. PMID- 28089528 TI - Hydrogel spacer distribution within the perirectal space in patients undergoing radiotherapy for prostate cancer: Impact of spacer symmetry on rectal dose reduction and the clinical consequences of hydrogel infiltration into the rectal wall. AB - PURPOSE: Hydrogel prostate-rectum spacers, biomaterials placed between the prostate and rectum, continue to gain interest as a method to reduce or limit rectal dose during dose escalated prostate cancer radiation therapy. Because the spacer is initially injected into the perirectal space as a liquid, the final distribution can vary. The purpose of this study was to evaluate hydrogel spacer (SpaceOAR system) implantation and distribution from a recent prospective randomized control trial and correlate spacer symmetry with rectal dose reduction as well as rectal wall infiltration (RWI) to acute and late toxicity. METHODS AND MATERIALS: T2-weighted magnetic resonance imaging sets of 149 patients enrolled in a prospective clinical trial who received transperineal spacer injection were assessed for hydrogel spacer midline symmetry and RWI using a semiqualitative scoring system. Symmetry was then correlated to rectal dose reduction using a Student t test (1-tailed, paired), whereas a Fisher exact test was used to correlate RWI with acute and late rectal toxicity. All patients had control treatment plans created before spacer injection. RESULTS: Hydrogel spacer was symmetrically placed at midline for 71 (47.7%) patients at the prostate midgland as well as 1 cm superior and inferior to midgland. The remaining 78 (50.9%) patients had some level of asymmetry, with only 2 (1.3%) having far lateral distribution (ie, >2 cm) of hydrogel spacer. As the hydrogel spacer became more asymmetric, the level of rectal dose reduction relative to their control plans decreased. However, all but the most asymmetrical 1.3% had significant rectal dose reduction (P < .05). Rectal wall hydrogel spacer infiltration was seen in 9 (6.0%) patients. There was no correlation between RWI and procedure-related adverse events or acute/late rectal toxicity. CONCLUSIONS: Significant reduction of rectal dose can still be achieved even in the setting of asymmetric hydrogel spacer placement. RWI does not correlate with patient complications. PMID- 28089529 TI - Material characterization of the MSWI bottom ash as a function of particle size. Effects of glass recycling over time. AB - Differences during the last 15years in materials' composition in Municipal Solid Waste Incineration (MSWI) regarding bottom ash (BA) were assessed as a function of particle size (>16, 8-16, 4-8, 2-4, 1-2 and 0-1mm). After sieving, fractions >2mm were carefully washed in order to separate fine particles adhering to bigger particles. The characterization took into account five types of materials: glass (primary and secondary), ceramics (natural and synthetic), non-ferrous metals, ferrous metals and unburned organic matter. The evaluation was performed through a visual (>2mm) and chemical (0-2mm) classification. Results showed that total weight of glass in the particles over 16mm has decreased with respect to 1999. Moreover, the content of glass (primary and secondary) in BA was estimated to be 60.8wt%, with 26.4wt% corresponding to primary glass in >2mm size fractions. Unlike 1999, in which glass was the predominant material, ceramics are currently the major phase in bottom ash (BA) coarse fractions. As for the metals, respect to 1999, results showed a slight increase in all size fractions. The greatest content (>22wt%) of ferromagnetic was observed for the 2-4mm size fraction while the non-ferrous type was almost non-existent in particles over 16mm, remaining below 10wt% for the rest fractions. In the finest fractions (<2mm), about 60 to 95% of non-ferrous metals corresponded to metallic aluminium. The results from the chemical characterization also indicated that the finest fractions contributed significantly to the total heavy metals content, especially for Pb, Zn, Cu, Mn and Ti. PMID- 28089530 TI - Algae-mediated removal of selected pharmaceutical and personal care products (PPCPs) from Lake Mead water. AB - The persistence and fate of pharmaceutical and personal care products (PPCPs) in the Lake Mead ecosystem are particularly important considering the potential ecological risks and human health impacts. This study evaluated the removal of five common PPCPs (i.e., trimethoprim, sulfamethoxazole, carbamazepine, ciprofloxacin, and triclosan) from Lake Mead water mediated by the green alga Nannochloris sp. The results from the incubation studies showed that trimethoprim and carbamazepine were highly resistant to uptake in the algal cultural medium and were measured at approximately 90%-100% of the applied dose after 14days of incubation. Sulfamethoxazole was found relatively persistent, with >60% of the applied dose remaining in the water after 14days, and its removal was mainly caused by algae-mediated photolysis. However, ciprofloxacin and triclosan dissipated significantly and nearly 100% of the compounds were removed from the water after 7days of incubation under 24h of light. Ciprofloxacin and triclosan were highly susceptible to light, and their estimated half-lives were 12.7hours for ciprofloxacin and 31.2hours for triclosan. Algae-mediated sorption contributed to 11% of the removal of trimethoprim and sulfamethoxazole, 13% of the removal of carbamazepine, and 27% of the removal of triclosan from the lake water. This research showed that 1) trimethoprim, sulfamethoxazole, and carbamazepine are quite persistent in aquatic environments and may potentially affect human health via drinking water intake; 2) photolysis is the dominant pathway to remove ciprofloxacin from aquatic ecosystems, which indicates that ciprofloxacin may have lower ecological risks compared with other PPCPs; and 3) triclosan can undergo photolysis as well as algae-mediated uptake and it may potentially affect the food web because of its high toxicity to aquatic species. PMID- 28089531 TI - Predicting the particle size distribution of eroded sediment using artificial neural networks. AB - Water erosion causes soil degradation and nonpoint pollution. Pollutants are primarily transported on the surfaces of fine soil and sediment particles. Several soil loss models and empirical equations have been developed for the size distribution estimation of the sediment leaving the field, including the physically-based models and empirical equations. Usually, physically-based models require a large amount of data, sometimes exceeding the amount of available data in the modeled area. Conversely, empirical equations do not always predict the sediment composition associated with individual events and may require data that are not always available. Therefore, the objective of this study was to develop a model to predict the particle size distribution (PSD) of eroded soil. A total of 41 erosion events from 21 soils were used. These data were compiled from previous studies. Correlation and multiple regression analyses were used to identify the main variables controlling sediment PSD. These variables were the particle size distribution in the soil matrix, the antecedent soil moisture condition, soil erodibility, and hillslope geometry. With these variables, an artificial neural network was calibrated using data from 29 events (r2=0.98, 0.97, and 0.86; for sand, silt, and clay in the sediment, respectively) and then validated and tested on 12 events (r2=0.74, 0.85, and 0.75; for sand, silt, and clay in the sediment, respectively). The artificial neural network was compared with three empirical models. The network presented better performance in predicting sediment PSD and differentiating rain-runoff events in the same soil. In addition to the quality of the particle distribution estimates, this model requires a small number of easily obtained variables, providing a convenient routine for predicting PSD in eroded sediment in other pollutant transport models. PMID- 28089532 TI - Refining health risk assessment by incorporating site-specific background concentration and bioaccessibility data of Nickel in soil. AB - Risk assessment of Nickel (Ni) in a brownfield site contaminated was refined by incorporating the site-specific background level (SSBL) derived using multiple lines of evidence technology and bioaccessibility measured by the Unified Bioaccessibility Method (UBM) and Inhalation Bioaccessibility Method (IBM). The results revealed that the SSBL was 80mg/kg, which was much higher than the general soil screening value (GSSL) (50mg/kg) and more than two times regional background level reported for Tianjing (33mg/kg). The average bioaccessibility for the gastric and intestinal phases was 24.2% (8.6%-54.4%) and 12.6% (7.7% 17.1%), respectively. In simulated lung fluid, only 2.1% (1.0%-4.6%) of Ni in the soil particle was bioaccessible. The amount of samples exceeding the acceptable level was reduced by 50% when SSBL, other than GSSL, was used as the screening value. Moreover, the site-specific target level (SSTL) under acceptable risk level was increased from 94mg/kg to 283mg/kg when bioaccessibility was considered, and the amount of samples above SSTL was reduced to 10%. The study indicated that incorporating site-specific background levels and bioaccessibility data of contaminants in a given site has the potential to support health risk assessment decisions and can reduce the remediation cost greatly. PMID- 28089533 TI - Bias and association of sediment organic matter source apportionment indicators: A case study in a eutrophic Lake Chaohu, China. AB - The sources of sediment organic matter (SOM) could be explained by various indicators. To test their biases and associations, the present study determined multiple indicators for SOM source apportionment, including elemental analysis (carbon and nitrogen, and their stable isotope delta13C and delta15N), n-alkanes compositions as well as derivative indicators (e.g., terrigenous to aquatic ratio), and carbon isotopes of n-alkane in Lake Chaohu, a eutrophic lake. The spatial variation of anthropogenic effects could be revealed by SOM elemental variations. The n-alkanes of all samples had a bimodal distribution with the 1st peak at n-alkane with 17 carbons (C17) and the 2nd predominant peak at C29. The parity advantage index of n-alkanes indicated that the sediments had mixed characteristics of both endogenous and terrigenous sources. Some n-alkanes indicators also revealed eutrophication characteristics of dominant algae in Lake Chaohu. SOM received a mixed contribution of plankton (I), low-latitude terrestrial high-grade plants (II) and microbial material (III) as indicated by isotopic compositions of long-chain n-alkane. Multiport element model (MEM) showed the contribution of self-generated sources of organic matter in Lake Chaohu is >50%, indicating the historic serious eutrophication in Lake Chaohu. The main sources of SOM in the eastern part of the lake were algae and terrestrial input, with little input from microbes, and the contribution from algae decreased from west to east. The multiple indicators' judgment by MEM and principle component analysis (PCA) was of ecological significance and proposed because they offered scientific tools for disclosing the historic variations of SOM as well as their sources. PMID- 28089534 TI - In-situ measurements of light-absorbing impurities in snow of glacier on Mt. Yulong and implications for radiative forcing estimates. AB - The Tibetan Plateau (TP) or the third polar cryosphere borders geographical hotspots for discharges of black carbon (BC). BC and dust play important roles in climate system and Earth's energy budget, particularly after they are deposited on snow and glacial surfaces. BC and dust are two kinds of main light-absorbing impurities (LAIs) in snow and glaciers. Estimating concentrations and distribution of LAIs in snow and glacier ice in the TP is of great interest because this region is a global hotspot in geophysical research. Various snow samples, including surface aged-snow, superimposed ice and snow meltwater samples were collected from a typical temperate glacier on Mt. Yulong in the snow melt season in 2015. The samples were determined for BC, Organic Carbon (OC) concentrations using an improved thermal/optical reflectance (DRI Model 2001) method and gravimetric method for dust concentrations. Results indicated that the LAIs concentrations were highly elevation-dependent in the study area. Higher contents and probably greater deposition at relative lower elevations (generally <5000masl) of the glacier was observed. Temporal difference of LAIs contents demonstrated that LAIs in snow of glacier gradually increased as snow melting progressed. Evaluations of the relative absorption of BC and dust displayed that the impact of dust on snow albedo and radiative forcing (RF) is substantially larger than BC, particularly when dust contents are higher. This was verified by the absorption factor, which was <1.0. In addition, we found the BC-induced albedo reduction to be in the range of 2% to nearly 10% during the snow melting season, and the mean snow albedo reduction was 4.63%, hence for BC contents ranging from 281 to 894ngg-1 in snow of a typical temperate glacier on Mt. Yulong, the associated instantaneous RF will be 76.38-146.96Wm-2. Further research is needed to partition LAIs induced glacial melt, modeling researches in combination with long-term in-situ observations of LAIs in glaciers is also urgent needed in the future work. PMID- 28089535 TI - Farmer attitudes and perceptions to the re-use of fertiliser products from resource-oriented sanitation systems - The case of Vellore, South India. AB - Relatively little research has been conducted to date on farmer attitudes towards the use of fertilisers from resource-oriented sanitation systems. This study employed a psycho-sociological approach to identify factors that encourage, or discourage, negative and positive attitudes to human waste recycling among farmers in southern India. A survey involving face-to-face interviews was performed with 120 randomly sampled farmers, taking into account the following factors: gender, age, religion, caste, type of farming, farm size, annual income and farming history. Variations in variables (chi2 and ANOVA) were considered statistically significant if p-value was <0.05. When asked whether they thought human wastes could be used as fertiliser, of the farmers who expressed an opinion 59% were positive to re-use of urine and 46% to re-use of human faeces. Farmers in Vellore appeared to display what we term, a 'not-in-my-circle' syndrome, as they would prefer their neighbours to use human urine rather than their friends, family and colleagues. The main factors that motivated farmers to respond positively to re-use of urine were improved soil quality and potential cost savings from reduced use of chemical fertilisers. Fear of crop die-off, fear of being ridiculed and uncertainty over consumer marketplace behaviour were significant factors among farmers with a negative attitude. Furthermore, the survey responses indicated that besides socio-demographic factors, other factors such as 'trust' might have to be taken into consideration when planning and implementing nutrient recycling programmes. Early dialogue, continuous interaction and integration of user stakeholders (producers and consumers) in conceptualisation, design and implementation of nutrient recycling programmes are essential to ensure future success and wider adoption. PMID- 28089536 TI - Out of Sight, out of Mind; Subcutaneous, Visceral, and Epicardial Adipose Tissue. PMID- 28089537 TI - Correction to the Article by Dalama et al. "New Oral Hypoglycemic Agents and Cardiovascular Risk. Crossing the Metabolic Border". Rev Esp Cardiol. 2016;69:1088-1097. PMID- 28089538 TI - Carotid artery dissection secondary to carotid artery trauma caused by giant C1 transverse process. PMID- 28089539 TI - Reperfusion therapy in patients with acute ischaemic stroke caused by cervical artery dissection. AB - INTRODUCTION: Cervical artery dissection (CAD) is responsible for up to 20% of all ischaemic strokes in patients younger than 45. The benefits of acute-phase reperfusion therapy in these patients have yet to be confirmed. METHODS: We conducted a retrospective review of patients with CAD admitted to a comprehensive stroke centre between 2010 and 2015. We recorded baseline clinical characteristics, treatments, functional outcomes, and mortality. RESULTS: We identified 35 cases of CAD (23 carotid/12 vertebral); mean age was 43.5 +/- 9.5 years and 67.7% were men. Ten patients (32.3%) had a history of trauma. The most frequent risk factors were arterial hypertension (29%) and smoking (35.5%). The most common clinical presentation was ischaemic stroke (29 patients, 93.5%). The median baseline National Institute of Health Stroke Scale score was 6 (range, 0 41). The most frequently used diagnostic method was CT angiography (74.2%), followed by MRI (64.5%) and digital subtraction angiography (45.6%). Seven patients (22.6%) were treated with intravenous fibrinolysis and 11 (35.5%) with endovascular treatment plus intravenous fibrinolysis; at 3 months, functional independence (modified Rankin Scale scores 0-2) was achieved by 57.1% and 63.6% of these cases, respectively. One patient died (3.2%). CONCLUSIONS: In our sample, the most common form of presentation of CAD was ischaemic stroke. Reperfusion therapy seems to be a safe and effective option for these patients, and outcomes resemble those of other patients with ischaemic stroke. Larger comparative studies are necessary to better assess response to reperfusion therapy in acute ischaemic stroke. PMID- 28089540 TI - Aberrant CDX2 expression in hepatocellular carcinomas: an important diagnostic pitfall. AB - CDX2 is a sensitive and specific marker of intestinal differentiation. It is routinely used in surgical pathology, as its expression within a tumor favors an origin within the gastrointestinal tract. We had anecdotally encountered occasional hepatocellular carcinomas (HCCs) that were CDX2 positive. CDX2 expression in HCC has not yet been reported, but it has also not been examined in detail. Therefore, we evaluated CDX2 expression in a large number of resected HCCs. Full tumor sections from 172 resected HCCs and 6 resected fibrolamellar carcinomas (FLCs) were stained for CDX2. Nine (5.2%) of 172 HCCs were positive for CDX2, whereas all 6 FLCs were negative. CDX2 expression in HCCs was more commonly seen in poorly differentiated tumors (5 of 16 cases, 31%) than well and moderately differentiated tumors (4 of 156 cases, 2.5%), P = .0004. No other statistically significant correlations were observed (P>.05). Results of our study show that a small subset (5%) of HCCs can be CDX2 positive. Awareness of this phenomenon is important because CDX2 expression in a liver tumor does not completely exclude a diagnosis of HCC. PMID- 28089541 TI - Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is a marker that predicts presence of invasion in papillary biliary tumors. AB - Biliary tumors showing intraductal papillary growth (Pap-BTs) include intraductal papillary neoplasm of the bile duct (IPNB) and papillary cholangiocarcinoma (CC). A differential diagnosis between IPNB and papillary CC currently remains challenging. The aim of the present study is to identify histological features and immunohistochemical markers of malignant potential such as tumor invasion in Pap-BTs. Subjects comprised 37 patients with Pap-BT (intrahepatic and perihilar [proximal], 27: 17 noninvasive and 10 invasive; distal, 10: all invasive). We examined histological features and the expression of p53, enhancer of zeste homolog 2, insulin-like growth factor II mRNA-binding protein 3 (IMP3), and DNA methyltransferase-1 in the intraductal area in Pap-BTs. Noninvasive Pap-BT was characterized by the presence of a low-grade dysplastic area, edematous stroma, and the absence of necrosis. The expression of p53, enhancer of zeste homolog 2, IMP3, and DNA methyltransferase-1 was significantly weaker in noninvasive Pap-BTs than in invasive Pap-BTs (P<.01). Diffuse cytoplasmic IMP3 expression was absent in noninvasive Pap-BTs. IMP3 showed the greatest specificity to predict a presence of invasion. A heatmap demonstrated that proximal noninvasive Pap-BTs and distal Pap-BTs may be completely different. In bile duct biopsies, the expression of IMP3 was the most precise predictor of invasion in Pap-BTs. In conclusion, Pap-BTs may be separated into 3 subgroups: (1) proximal noninvasive Pap-BT, corresponding to IPNB; (2) distal invasive Pap-BT, corresponding to papillary CC; and (3) the remaining Pap-BT including IPNB with associated adenocarcinomas, based on histological and immunohistochemical features. IMP3 may be a useful marker for predicting invasion in Pap-BT. PMID- 28089542 TI - Parallelization and High-Performance Computing Enables Automated Statistical Inference of Multi-scale Models. AB - Mechanistic understanding of multi-scale biological processes, such as cell proliferation in a changing biological tissue, is readily facilitated by computational models. While tools exist to construct and simulate multi-scale models, the statistical inference of the unknown model parameters remains an open problem. Here, we present and benchmark a parallel approximate Bayesian computation sequential Monte Carlo (pABC SMC) algorithm, tailored for high performance computing clusters. pABC SMC is fully automated and returns reliable parameter estimates and confidence intervals. By running the pABC SMC algorithm for ~106 hr, we parameterize multi-scale models that accurately describe quantitative growth curves and histological data obtained in vivo from individual tumor spheroid growth in media droplets. The models capture the hybrid deterministic-stochastic behaviors of 105-106 of cells growing in a 3D dynamically changing nutrient environment. The pABC SMC algorithm reliably converges to a consistent set of parameters. Our study demonstrates a proof of principle for robust, data-driven modeling of multi-scale biological systems and the feasibility of multi-scale model parameterization through statistical inference. PMID- 28089543 TI - Optimal Regulatory Circuit Topologies for Fold-Change Detection. AB - Evolution repeatedly converges on only a few regulatory circuit designs that achieve a given function. This simplicity helps us understand biological networks. However, why so few circuits are rediscovered by evolution is unclear. We address this question for the case of fold-change detection (FCD): a response to relative changes of input rather than absolute changes. Two types of FCD circuits recur in biological systems-the incoherent feedforward and non-linear integral-feedback loops. We performed an analytical screen of all three-node circuits in a class comprising ~500,000 topologies. We find that FCD is rare, but still there are hundreds of FCD topologies. The two experimentally observed circuits are among the very few minimal circuits that optimally trade off speed, noise resistance, and response amplitude. This suggests a way to understand why evolution converges on only few topologies for a given function and provides FCD designs for synthetic construction and future discovery. PMID- 28089544 TI - Effects of delivery mode and sociodemographic factors on postpartum stress urinary incontinency in primipara women: A prospective cohort study. AB - BACKGROUND: To determine the frequency of postpartum stress urinary incontinence (SUI) in women undergoing vaginal delivery or elective cesarean section and to investigate the sociodemographic determinants of SUI in a sample of Iranian patients. METHODS: This prospective cohort study was performed during a 1-year period from 2014 to 2015 including 286 healthy nulliparous women in the third trimester of pregnancy without prepregnancy urinary incontinence. Participants were categorized based on the mode of delivery, i.e., vaginal delivery (n=148) and elective cesarean section (n=138). SUI was evaluated in all the participants before delivery and at 1 month, 6 months, and 12 months after delivery using a previously validated Persian questionnaire. The frequency of postpartum SUI was recorded in both study groups and was compared between them. We also determined the sociodemographic determinants of SUI. RESULTS: Baseline characteristics were comparable. The frequency of postpartum SUI was significantly higher in vaginal delivery than in cesarean section after a 1-month (p<0.001), 6-month (p<0.001), and 12-month (p<0.001) period. Age was found to be associated with increased frequency of postpartum SUI in both vaginal delivery (p=0.021, r=0.286) and cesarean section groups (p=0.043, r=0.125). SUI was associated with tool-assisted vaginal delivery (p<0.001) and episiotomy (p<0.001). The birth weight was positively correlated with increased frequency of postpartum SUI in both vaginal delivery (p=0.011, r=0.546) and cesarean section (p=0.034, r=0.311). Patients with SUI had a significantly higher body mass index than the normal individuals (p=0.038). SUI was associated with lower income (p=0.028) and lower neighborhood residence (p=0.033). CONCLUSION: Vaginal delivery is associated with a twofold increased risk of postpartum SUI in primipara women compared with elective cesarean section. Age and birth weight are the main risk factors of postpartum SUI in both modes of delivery. Tool-assisted delivery and episiotomy were determined as the risk factors of postpartum SUI in vaginal delivery. PMID- 28089545 TI - The risk factors and prognostic factors of intrahepatic cholangiocarcinoma. PMID- 28089546 TI - Expression of interleukin-6 by a recombinant rabies virus enhances its immunogenicity as a potential vaccine. AB - Several studies have confirmed that interleukin-6 (IL6) mediates multiple biological effects that enhance immune responses when used as an adjuvant. In the present study, recombinant rabies virus (RABV) expressing canine IL6 (rHEP-CaIL6) was rescued and its pathogenicity and immunogenicity were investigated in mice. We demonstrated that mice received a single intramuscular immunization with rHEP CaIL6 showed an earlier increase and higher maximum titres of virus-neutralizing antibody (VNA) as well as anti-RABV antibodies compared with mice immunized with the parent strain. Moreover, survival rates of mice immunized with rHEP-CaIL6 were higher compared with mice immunized with parent HEP-Flury according to the challenge assay. Flow cytometry further confirmed that immunization with rHEP CaIL6 induced the strong recruitment of mature B cells and CD8+ T cells to lymph nodes, which may partially explain the high levels of VNA and enhanced cellular immunity. Quantitative real-time PCR indicated that rHEP-CaIL6 induced stronger inflammatory and immune responses in the central nervous system, which might have allowed virus clearance in the early infection phase. Furthermore, mice infected intranasally with rHEP-CaIL6 developed no clinical symptoms while mice infected with HEP-Flury showed piloerection. In summary, these data indicate that rHEP CaIL6 induces a strong, protective immune response with a good safety profile. Therefore, a recombinant RABV strain expressing canine IL6 may aid the development of an effective, safe attenuated rabies vaccine. PMID- 28089547 TI - Antibody profiles to wheat germ cell-free system synthesized Plasmodium falciparum proteins correlate with protection from symptomatic malaria in Uganda. AB - The key targets of protective antibodies against Plasmodium falciparum remain largely unknown. In this study, we determined immunoreactivity to 1827 recombinant proteins derived from 1565 genes representing ~30% of the entire P. falciparum genome, for identification of novel malaria vaccine candidates. The recombinant proteins were expressed by wheat germ cell-free system, a platform that can synthesize quality plasmodial proteins that elicit biologically active antibodies in animals. Sera were obtained from indigenous residents of a malaria endemic region in Northern Uganda who were enrolled at the start of a rainy season and prospectively monitored for symptomatic malaria episodes for a year. Immunoreactivity to sera was determined by AlphaScreen; a homogeneous high throughput system that detects protein interactions. Our analysis revealed antibody responses to 128 proteins that significantly associated with protection from symptomatic malaria. From 128 proteins, 53 were down-selected as the most plausible targets of host protective immune response by virtue of having a predicted signal peptide and/or transmembrane domain(s), or confirmed localization on the parasite surface. The 53 proteins comprised of not only previously characterized vaccine candidates but also uncharacterized proteins. Proteins involved in erythrocyte invasion; RON4, RON2 and CLAG3.1 and pre erythrocytic proteins; SIAP-2, TRAP and CelTOS, were recommended for prioritization for further evaluation as vaccine candidates. The findings clearly demonstrate that generation of the protein library using the wheat germ cell-free system coupled with high throughput immunoscreening with AlphaScreen offers new options for rational discovery and selection of potential malaria vaccine candidates. PMID- 28089550 TI - Assessment of microplastic-sorbed contaminant bioavailability through analysis of biomarker gene expression in larval zebrafish. AB - Microplastics (MPs) are prevalent in marine ecosystems. Because toxicants (termed here "co-contaminants") can sorb to MPs, there is potential for MPs to alter co contaminant bioavailability. Our objective was to demonstrate sorption of two co contaminants with different physicochemistries [phenanthrene (Phe), log10Kow=4.57; and 17alpha-ethinylestradiol (EE2), log10Kow=3.67] to MPs; and assess whether co-contaminant bioavailability was increased after MP settlement. Bioavailability was indicated by gene expression in larval zebrafish. Both Phe and EE2 sorbed to MPs, which reduced bioavailability by a maximum of 33% and 48% respectively. Sorption occurred, but was not consistent with predictions based on co-contaminant physicochemistry (Phe having higher log10Kow was expected to have higher sorption). Contaminated MPs settled to the bottom of the exposures did not lead to increased bioavailability of Phe or EE2. Phe was 48% more bioavailable than predicted by a linear sorption model, organism-based measurements therefore contribute unique insight into MP co-contaminant bioavailability. PMID- 28089548 TI - Nanoformulation of synergistic TLR ligands to enhance vaccination against Entamoeba histolytica. AB - Diarrheal infectious diseases represent a major cause of global morbidity and mortality. There is an urgent need for vaccines against diarrheal pathogens, especially parasites. Modern subunit vaccines rely on combining a highly purified antigen with an adjuvant to increase their efficacy. In the present study, we evaluated the ability of a nanoliposome adjuvant system to trigger a strong mucosal immune response to the Entamoeba histolytica Gal/GalNAc lectin LecA antigen. CBA/J mice were immunized with alum, emulsion or liposome based formulations containing synthetic TLR agonists. A liposome formulation containing TLR4 and TLR7/8 agonists was selected based on its ability to generate intestinal IgA, plasma IgG2a/IgG1, IFN-gamma and IL-17A. Immunization with a mucosal prime followed by a parenteral boost generated a high mucosal IgA response that inhibited adherence of parasites to mammalian cells. Inclusion of the immune potentiator all-trans retinoic acid in the regimen further improved the mucosal IgA response. Immunization protected from infection with up to 55% efficacy. Our results show that a nanoliposome delivery system containing TLR agonists is a promising prospect for the development of vaccines against enteric pathogens, especially when a multifaceted immune response is desired. PMID- 28089549 TI - Modified live infectious bursal disease virus (IBDV) vaccine delays infection of neonatal broiler chickens with variant IBDV compared to turkey herpesvirus (HVT) IBDV vectored vaccine. AB - Chickens are commonly processed around 35-45days of age in broiler chicken industry hence; diseases that occur at a young age are of paramount economic importance. Early age infection with infectious bursal disease virus (IBDV) results in long-lasting immunosuppression and profound economic losses. To our knowledge, this is the first study comparing the protection efficacy of modified live (MdLV) IBDV and herpesvirus turkey (HVT)-IBDV vaccines against early age variant IBDV (varIBDV) infection in chicks. Experiments were carried out in IBDV maternal antibody (MtAb) positive chicks (n=330), divided into 6 groups (n=50 60/group), namely Group 1 (saline), Group 2 (saline+varIBDV), Group 3 (HVT-IBDV), Group 4 (HVT-IBDV+varIBDV), Group 5 (MdLV) and Group 6 (MdLV+varIBDV). HVT-IBDV vaccination was given via the in ovo route to 18-day-old embryonated eggs. MdLV was administered via the subcutaneous route in day-old broilers. Group 2, Group 4 and Group 6 were orally challenged with varIBDV (SK-09, 3*103 EID50) at day 6 post-hatch. IBDV seroconversion, bursal weight to body weight ratio (BBW) and bursal histopathology were assessed at 19 and 35days of age. Histopathological examination at day 19 revealed that varIBDV-SK09 challenge caused severe bursal atrophy and lower BBW in HVT-IBDV but not in MdLV vaccinated chicks. However by day 35, all challenged groups showed bursal atrophy and seroconversion. Interestingly, RT-qPCR analysis after varIBDV-SK09 challenge demonstrated an early (9days of age) and significantly high viral load (~5744 folds) in HVT-IBDV vaccinated group vs unvaccinated challenged group (~2.25 folds). Furthermore, flow cytometry analysis revealed inhibition of cytotoxic CD8+ T-cell response (CD44-downregulation) and decreased splenic lymphocytes counts in chicks after HVT-IBDV vaccination. Overall, our data suggest that MdLV delays varIBDV pathogenesis, whereas, HVT-IBDV vaccine is potentially immunosuppressive, which may increase the risk of early age varIBDV infection in broilers. PMID- 28089551 TI - Seasonal circulation assessments of the Northern Arabian/Persian Gulf. AB - Due to the continuous human activities linked to economic expansion in the Arabian Gulf area (also known as Persian Gulf), various activities have had an adverse impact on the coastal environment. Furthermore, reduction of precipitation and river flows has resulted in alterations to the hydro environment regime at various levels. The current study uses a detailed numerical model that was validated with recent field measurements to determine the comprehensive seasonal circulations of the Northern Arabian/Persian Gulf (NAG). The seasons were studied individually using a three-dimensional setup and by considering the baroclinic effects and meteorological forcing. It was found that the NAG exhibits distinctive circulation characteristics each season. In winter, a dense water mass that forms near Kuwait flows toward the southeast near-bed, whereas relatively weak Indian Ocean Surface Waters (IOSW) flow along the Iranian coast and, to a lesser extent, oppose these currents. In spring, the southeast near bed circulations are weaker, while the IOSW is in highest conditions reaching the northern latitudes of the Gulf without being significantly diluted. In summer, a thermocline develops, particularly at the main axis of the NAG, and increases the chances of upwelling. The surface water during this season is significantly controlled by wind. Most distinctive, a non-uniform flow is evident at the offshore regions along the Arabian coast due to strong density gradients. In the fall, the circulations are relatively weaker compared to other seasons; however, cyclonic features are evident at the southeast of the estuary. Well known counter clockwise circulations NAG are evident throughout the season, but at various strengths; summer is the most active season, while fall is the least active season. In a similar manner, the along shore current varied spatially and temporally throughout the seasons. PMID- 28089552 TI - Plankton resting stages in recent sediments of Haifa port, Israel (Eastern Mediterranean) - Distribution, viability and potential environmental consequences. AB - Resting stages of plankton were sampled in the surficial sediments in the port of Haifa, Israel, on the eve of a major port enlargement project. We recorded the structure of the assemblages and examined their relationship with different environments within the port. Our findings reveal a remarkably high diversity coupled with low density and the highest number of oligotrich ciliate cyst types recorded from marine sediments. Near the eutrophic and highly polluted zone of the Kishon estuary ciliates were more abundant than elsewhere in the port, whereas dinoflagellates' abundance was reduced, and these trends held true both for full and empty cysts. Some harmful or potentially toxic species, such as Scrippsiella acuminata, were widespread in the port. The toxigenic species include Alexandrium minutum, Gymnodinium uncatenatum and Lingulodinium polyedrum. Active cells of the unarmoured, bloom-forming Akashiwo sanguinea were identified in the cultures obtained from the incubated sediments. PMID- 28089553 TI - Plastic debris straps on threatened blue shark Prionace glauca. AB - Juveniles of blue shark Prionace glauca caught in pelagic longlines targeting tuna and swordfish in the Atlantic Ocean and the Mediterranean Sea were found entangled with plastic straps around their gill region. The plastic debris were identified as strapping bands and caused several degrees of injuries on the dorsal musculature and pectoral fins. They were also obstructing the gill slits probably causing breathing issues. These records were uploaded in the web site seawatchers.org, and highlight the potential of citizen science in revealing the occurrence of such problems which could help to measure the effects of plastic debris on marine life. PMID- 28089554 TI - Synthesis, antioxidant and antimelanogenic activities of PEGylated alpha tocopheryl lipoate conjugates. PMID- 28089555 TI - Epstein-Barr virus and renal transplantation. AB - Epstein-Barr virus (EBV) is a gamma herpesvirus associated with diseases ranging from asymptomatic viremia to post-transplant malignancies in kidney transplant recipients. EBV specifically is associated with post-transplantation lymphoproliferative disorder (PTLD), in kidney transplant recipients, with increased risk in EBV seronegative patients with EBV seropositive donors on intensified immunosuppression. The diagnosis of PTLD relies on clinical suspicion plus tissue biopsy with polymerase chain reaction (PCR) testing of blood currently used for risk determination in high-risk recipients. Therapeutic strategies for PTLD include reduction of immunosuppression, chemotherapy and rituximab, and consideration of sirolimus-based immunosuppression. Antivirals such as ganciclovir are used to prevent reactivation of cytomegalovirus and other herpes viruses but are not onco-therapeutic. Radiation therapy or surgery is indicated for bulky, disseminated or recalcitrant disease. Prognosis varies depending on the type of malignancy identified and stage of disease. PMID- 28089556 TI - Larval stages of Neoplagioporus elongatus (Goto and Ozaki, 1930) (Opecoelidae: Plagioporinae), with notes on potential second intermediate hosts. AB - The morphology of sporocysts and cercariae of Neoplagioporus elongatus (Goto and Ozaki, 1930) is described for the first time. A cotylomicrocercous cercaria obtained from the sorbeoconch snail Semisulcospira nakasekoae was confirmed to be the cercaria of N. elongatus, based on the degree of sequence identity of the COI gene to that of adult worms. Freshwater annelids (oligochaetes and leeches) and some aquatic insects (odonates) were demonstrated experimentally to be potential second intermediate hosts. PMID- 28089558 TI - Startle suppression after mild traumatic brain injury is associated with an increase in pro-inflammatory cytokines, reactive gliosis and neuronal loss in the caudal pontine reticular nucleus. AB - Mild traumatic brain injury (mTBI) can produce somatic symptoms such as headache, dizziness, fatigue, sleep disturbances and sensorimotor dysfunction. Sensorimotor function can be measured by tests such as the acoustic startle reflex (ASR), an evolutionarily conserved defensive response to a brief yet sharp acoustic stimulus. mTBI produces a long-lasting suppression of ASR in rodents and humans; however, the mechanism of this suppression is unknown. The present study examined whether inflammatory processes in the brainstem (particularly the caudal pontine reticular nucleus, PnC) could account for the suppression of ASR after mTBI, because the PnC is an essential nucleus of the ASR circuit. Furthermore, while inflammation after mTBI is commonly observed in brain regions proximal to the site of impact (cortex and hippocampus), the effects of mTBI in brainstem structures remains largely understudied. The present study demonstrated a suppression of ASR one day after injury and lasting at least three weeks after an mTBI, replicating previous findings. Within the PnC, transient elevations of IL 1beta and TNF-alpha mRNA were observed at one day after injury, while IL-1alpha mRNA exhibited a delayed increase at three weeks after injury. Reactive gliosis (via IBA-1-ir for microglia and GFAP-ir for astrocytes) were also observed in the PnC, at one day and seven days after injury, respectively. Finally, the number of giant neurons (the major functional cell population in the PnC) was decreased three weeks after injury. The results indicate that glial activation precedes neuronal loss in the PnC, and correlates with the behavioral suppression of the ASR. The results also raise implications for brainstem involvement in the development of post-traumatic symptoms. PMID- 28089557 TI - Lower total and regional grey matter brain volumes in youth with perinatally acquired HIV infection: Associations with HIV disease severity, substance use, and cognition. AB - Despite improved survival due to combination antiretroviral therapy (cART), youth with perinatally-acquired HIV (PHIV) show cognitive deficits and developmental delay at increased rates. HIV affects the brain during critical periods of development, and the brain may be a persistent reservoir for HIV due to suboptimal blood brain barrier penetration of cART. We conducted structural magnetic resonance imaging (sMRI) and cognitive testing in 40 PHIV youth (mean age=16.7years) recruited from the NIH Pediatric HIV/AIDS Cohort Study (PHACS) who are part of the first generation of PHIV youth surviving into adulthood. Historical and current HIV disease severity and substance use measures were also collected. Total and regional cortical grey matter brain volumes were compared to a group of 334 typically-developing, HIV-unexposed and uninfected youth (frequency-matched for age and sex) from the Pediatric Imaging, Neurocognition, and Genetics (PING) study (mean age=16.1years). PHIV youth had smaller (2.8-5.1%) total and regional grey matter volumes than HIV-unexposed and uninfected youth, with smallest volumes seen among PHIV youth with higher past peak viral load (VL) and recent unsuppressed VL. In PHIV youth, worse cognitive performance correlated with smaller volumes. This pattern of smaller grey matter volumes suggests that PHIV infection may influence brain development and underlie cognitive dysfunction seen in this population. Among PHIV youth, smaller volumes were also linked to substance use (alcohol use: 9.0-13.4%; marijuana use: 10.1-16.0%). In this study, collection of substance use information was limited to the PHIV cohort; future studies should also collect substance use information in controls to further address interactions between HIV and substance use on brain volume. PMID- 28089559 TI - Microglia-derived neuregulin expression in psychiatric disorders. AB - Several studies have revealed that neuregulins (NRGs) are involved in brain function and psychiatric disorders. While NRGs have been regarded as neuron- or astrocyte-derived molecules, our research has revealed that microglia also express NRGs, levels of which are markedly increased in activated microglia. Previous studies have indicated that microglia are activated in the brains of individuals with autism spectrum disorder (ASD). Therefore, we investigated microglial NRG mRNA expression in multiple lines of mice considered models of ASD. Intriguingly, microglial NRG expression significantly increased in BTBR and socially-isolated mice, while maternal immune activation (MIA) mice exhibited identical NRG expression to controls. Furthermore, we observed a positive correlation between NRG expression in microglia and peripheral blood mononuclear cells (PBMCs) in mice, suggesting that NRG expression in human PBMCs may mirror microglia-derived NRG expression in the human brain. To translate these findings for application in clinical psychiatry, we measured levels of NRG1 splice-variant expression in clinically available PBMCs of patients with ASD. Levels of NRG1 type III expression in PBMCs were positively correlated with impairments in social interaction in children with ASD (as assessed using the Autistic Diagnostic Interview-Revised test: ADI-R). These findings suggest that immune cell-derived NRGs may be implicated in the pathobiology of psychiatric disorders such as ASD. PMID- 28089560 TI - Critical role of P2X7 receptors in the neuroinflammation and cognitive dysfunction after surgery. AB - Postoperative cognitive dysfunction worsens patient outcome after surgery. Neuroinflammation is a critical neuropathological process for it. We determined the role of P2X7 receptors, proteins that participate in inflammatory response, in the neuroinflammation induction after surgery, and whether the choice of volatile anesthetics affects its occurrence. Eight-week old C57BL/6J or P2X7 receptor knockout male mice were subjected to right carotid arterial exposure under anesthesia with 1.8% isoflurane, 2.5% sevoflurane or 10% desflurane. They were tested by Barnes maze and fear conditioning from 2weeks after the surgery. Hippocampus was harvested 6h, 24h and 7days after the surgery for immunohistochemical staining and Western blotting. Mice with surgery under anesthesia with isoflurane, sevoflurane or desflurane took longer than control mice to identify the target box 1 or 8days after the training sessions in Barnes maze. Mice anesthetized by isoflurane or sevoflurane, but not by desflurane, had less freezing behavior than control mice in fear conditioning test. Mice with surgery and anesthesia had increased ionized calcium binding adapter molecule 1 and interleukin 1beta in the hippocampus but this increase was smaller in mice anesthetized with desflurane than mice anesthetized with isoflurane. Mice with surgery had increased P2X7 receptors and its downstream molecule caspase 1. Inhibition or knockout of P2X7 receptors attenuated surgery and anesthesia induced neuroinflammation and cognitive impairment. We conclude that surgery under desflurane anesthesia may have reduced neuroinflammation and cognitive impairment compared with surgery under isoflurane anesthesia. P2X7 receptors may mediate the neuroinflammation and cognitive impairment after surgery. PMID- 28089561 TI - Characterizing Deep White Matter Hyperintensities in Patients with Symptomatic Isolated Cortical Superficial Siderosis. AB - BACKGROUND: In patient with cerebral amyloid angiopathy (CAA) presenting with lobar hemorrhage (LH), magnetic resonance imaging (MRI) white matter hyperintensities (WMH) tend to be predominant in posterior regions with the "multiple subcortical spots" WMH pattern as the most frequent topographical WMH pattern. Our aim was to analyze WMH severity and topographical distribution in patients with cortical superficial siderosis (CSS). METHODS: We retrospectively analyzed MRIs from consecutive symptomatic isolated (i.e., without LH) CSS and LH CAA (with or without associated CSS) patients. We analyzed baseline clinical characteristics including age, history of hypertension, diabetes, hypercholesterolemia, and pre-existing cognitive deficit. The presence of lobar microbleeds (MB) was scored on T2*. FLAIR (fluid-attenuated inversion recovery) WMH severity (using the Fazekas scale) and topographical distribution (using [slightly modified] earlier described WMH patterns) were analyzed and compared between both groups. RESULTS: Twenty CSS and 63 LH-CAA patients were analyzed. Baseline clinical characteristics were similar between both groups, except for hypercholesterolemia less frequently present in the CSS group (P = .026). Lobar MB were significantly less frequently present in the CSS group (P < .01), and CSS was more frequently focal in the CSS group compared with LH-CAA patients with associated CSS (P = .03). Mean Fazekas scale was significantly lower in CSS patients (P = .011). WMH patterns did not differ between both groups, with the multiple subcortical spots pattern as the most frequently observed pattern. CONCLUSIONS: Relative severe WMH scores and similar topographical distribution in CSS patients argue for WMH as a CAA-related feature in these patients with isolated CSS, adding level of evidence that isolated CSS could correspond to early manifestations of CAA. PMID- 28089562 TI - Sequential Multiple Assignment Randomized Trials: An Opportunity for Improved Design of Stroke Reperfusion Trials. AB - BACKGROUND: Modern clinical trials in stroke reperfusion fall into 2 categories: alternative systemic pharmacological regimens to alteplase and "rescue" endovascular approaches using targeted thrombectomy devices and/or medications delivered directly for persistently occluded vessels. Clinical trials in stroke have not evaluated how initial pharmacological thrombolytic management might influence subsequent rescue strategy. A sequential multiple assignment randomized trial (SMART) is a novel trial design that can test these dynamic treatment regimens and lead to treatment guidelines that more closely mimic practice. AIM: To characterize a SMART design in comparison to traditional approaches for stroke reperfusion trials. METHODS: We conducted a numerical simulation study that evaluated the performance of contrasting acute stroke clinical trial designs of both initial reperfusion and rescue therapy. We compare a SMART design where the same patients are followed through initial reperfusion and rescue therapy within 1 trial to a standard phase III design comparing 2 reperfusion treatments and a separate phase II futility design of rescue therapy in terms of sample size, power, and ability to address particular research questions. RESULTS: Traditional trial designs can be well powered and have optimal design characteristics for independent treatment effects. When treatments, such as the reperfusion and rescue therapies, may interact, commonly used designs fail to detect this. A SMART design, with similar sample size to standard designs, can detect treatment interactions. CONCLUSIONS: The use of SMART designs to investigate effective and realistic dynamic treatment regimens is a promising way to accelerate the discovery of new, effective treatments for stroke. PMID- 28089563 TI - Diagnostic and Prognostic Relevance of Magnetic Resonance Imaging and Electrophysiological Findings in Acute Spinal Ischemia. AB - OBJECTIVE: Our purpose was to classify the rare entity of spontaneous spinal ischemia with clinical, magnetic resonance-tomographic, and electrophysiological parameters to determine criteria for outcome prediction. METHODS: We analyzed the stroke registry database of the University Hospital Mannheim, Germany, from 2004 to 2010 for patients with a diagnosis of vascular spinal cord ischemia. RESULTS: Ten patients were identified (mean age 65 years [range 50-83], 5 women). In 5 patients an etiology was found. Spinal diffusion-weighted magnetic resonance imaging revealed acute ischemia in 7 patients at initial imaging and this diagnosis was confirmed during the first week in the remaining 3 patients. Electrophysiological studies showed abnormal motor evoked potentials (MEPs) in 8 patients and abnormal somatosensory evoked potentials (SSEPs) in 7 patients. After rehabilitation, 5 patients had regained walking ability, whereas 5 patients stayed wheelchair bound. All patients with unfavorable outcome (American Spinal Injury Association (ASIA) Impairment score [AIS] score of <=C) showed severe pyramidal tract lesions in MEPs during the first week. All patients with normal MEPs had an excellent outcome (AIS of E, P < .05). CONCLUSIONS: Diffusion weighted imaging (DWI) is a useful tool to confirm acute spinal ischemia suspected in patients within the first days after symptom onset. Poor outcome was associated with severe electrophysiological abnormalities in MEPs and SSEPs. Normal MEPs were significantly predictive of an excellent prognosis. A multimodal diagnostic approach combining DWI and electrophysiological evaluation facilitates the prediction of the individual clinical outcome. PMID- 28089564 TI - Cardiorespiratory Fitness after Transient Ischemic Attack and Minor Ischemic Stroke: Baseline Data of the MoveIT Study. AB - BACKGROUND: Cardiorespiratory fitness (CRF) is reduced in patients with stroke. It is unclear whether it is also reduced in patients with a transient ischemic attack (TIA) or minor stroke. We investigated the CRF in patients with a recent TIA or minor stroke and explored which determinants are associated with a lower fitness. METHODS: In 113 patients with a recent TIA or minor ischemic stroke (64 (SD = 10) years of age; 49 (IQR 27-86) days post TIA or stroke), the peak oxygen consumption (VO2peak) was determined in a symptom-limited ramp exercise test. Physical activity level, vascular risk factors, history of vascular or pulmonary disease, and stroke characteristics were recorded at inclusion and related to the VO2peak. RESULTS: Mean VO2peak was 22 mL/kg/min (SD = 6), which is the fifth percentile of age- and sex-related normative values. Increasing age and female sex were associated with a lower VO2peak (B (95% CI): per 10 years -2.57 mL/kg/min (-3.75; -1.40) and female sex -5.84 mL/kg/min (-8.06; -3.62)). Age- and sex-adjusted linear regression analyses showed that a history of cardiovascular disease and pulmonary disease was associated with a lower VO2peak. In addition, a lower level of physical activity, hypertension, smoking, and overweight were associated with a lower VO2peak. History of stroke and stroke characteristics were not related to VO2peak. CONCLUSION: The majority of patients with a recent TIA or minor ischemic stroke have a poor CRF. Our findings suggest that premorbid cardiovascular and pulmonary disease and vascular risk factors, but not TIA- or stroke-related factors, contribute to a reduced CRF. PMID- 28089565 TI - FGF21 Is an Exocrine Pancreas Secretagogue. AB - The metabolic stress hormone FGF21 is highly expressed in exocrine pancreas, where its levels are increased by refeeding and chemically induced pancreatitis. However, its function in the exocrine pancreas remains unknown. Here, we show that FGF21 stimulates digestive enzyme secretion from pancreatic acinar cells through an autocrine/paracrine mechanism that requires signaling through a tyrosine kinase receptor complex composed of an FGF receptor and beta-Klotho. Mice lacking FGF21 accumulate zymogen granules and are susceptible to pancreatic ER stress, an effect that is reversed by administration of recombinant FGF21. Mice carrying an acinar cell-specific deletion of beta-Klotho also accumulate zymogen granules but are refractory to FGF21-stimulated secretion. Like the classical post-prandial secretagogue, cholecystokinin (CCK), FGF21 triggers intracellular calcium release via PLC-IP3R signaling. However, unlike CCK, FGF21 does not induce protein synthesis, thereby preventing protein accumulation. Thus, pancreatic FGF21 is a digestive enzyme secretagogue whose physiologic function is to maintain acinar cell proteostasis. PMID- 28089566 TI - Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex. AB - Metformin is the most widely prescribed drug for the treatment of type 2 diabetes. However, knowledge of the full effects of metformin on biochemical pathways and processes in its primary target tissue, the liver, is limited. One established effect of metformin is to decrease cellular energy levels. The AMP activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) are key regulators of metabolism that are respectively activated and inhibited in acute response to cellular energy depletion. Here we show that metformin robustly inhibits mTORC1 in mouse liver tissue and primary hepatocytes. Using mouse genetics, we find that at the lowest concentrations of metformin that inhibit hepatic mTORC1 signaling, this inhibition is dependent on AMPK and the tuberous sclerosis complex (TSC) protein complex (TSC complex). Finally, we show that metformin profoundly inhibits hepatocyte protein synthesis in a manner that is largely dependent on its ability to suppress mTORC1 signaling. PMID- 28089567 TI - Adipose Tissue CLK2 Promotes Energy Expenditure during High-Fat Diet Intermittent Fasting. AB - A promising approach to treating obesity is to increase diet-induced thermogenesis in brown adipose tissue (BAT), but the regulation of this process remains unclear. Here we find that CDC-like kinase 2 (CLK2) is expressed in BAT and upregulated upon refeeding. Mice lacking CLK2 in adipose tissue exhibit exacerbated obesity and decreased energy expenditure during high-fat diet intermittent fasting. Additionally, tissue oxygen consumption and protein levels of UCP1 are reduced in CLK2-deficient BAT. Phosphorylation of CREB, a transcriptional activator of UCP1, is markedly decreased in BAT cells lacking CLK2 due to enhanced CREB dephosphorylation. Mechanistically, CREB dephosphorylation is rescued by the inhibition of PP2A, a phosphatase that targets CREB. Our results suggest that CLK2 is a regulatory component of diet induced thermogenesis in BAT through increased CREB-dependent expression of UCP1. PMID- 28089568 TI - Inhibition of Intracellular Triglyceride Lipolysis Suppresses Cold-Induced Brown Adipose Tissue Metabolism and Increases Shivering in Humans. AB - Indirect evidence from human studies suggests that brown adipose tissue (BAT) thermogenesis is fueled predominantly by fatty acids hydrolyzed from intracellular triglycerides (TGs). However, no direct experimental evidence to support this assumption currently exists in humans. The aim of this study was to determine the role of intracellular TG in BAT thermogenesis, in cold-exposed men. Using positron emission tomography with 11C-acetate and 18F-fluorodeoxyglucose, we showed that oral nicotinic acid (NiAc) administration, an inhibitor of intracellular TG lipolysis, suppressed the cold-induced increase in BAT oxidative metabolism and glucose uptake, despite no difference in BAT blood flow. There was a commensurate increase in shivering intensity and shift toward a greater reliance on glycolytic muscle fibers without modifying total heat production. Together, these findings show that intracellular TG lipolysis is critical for BAT thermogenesis and provides experimental evidence for a reciprocal role of BAT thermogenesis and shivering in cold-induced thermogenesis in humans. PMID- 28089570 TI - Use of augmented reality in laparoscopic gynecology to visualize myomas. AB - OBJECTIVE: To report the use of augmented reality (AR) in gynecology. DESIGN: AR is a surgical guidance technology that enables important hidden surface structures to be visualized in endoscopic images. AR has been used for other organs, but never in gynecology and never with a very mobile organ like the uterus. We have developed a new AR approach specifically for uterine surgery and demonstrated its use for myomectomy. SETTING: Tertiary university hospital. PATIENT(S): Three patients with one, two, and multiple myomas, respectively. INTERVENTION(S): AR was used during laparoscopy to localize the myomas. MAIN OUTCOME MEASURE(S): Three-dimensional (3D) models of the patient's uterus and myomas were constructed before surgery from T2-weighted magnetic resonance imaging. The intraoperative 3D shape of the uterus was determined. These models were automatically aligned and "fused" with the laparoscopic video in real time. RESULT(S): The live fused video made the uterus appear semitransparent, and the surgeon can see the location of the myoma in real time while moving the laparoscope and the uterus. With this information, the surgeon can easily and quickly decide on how best to access the myoma. CONCLUSION(S): We developed an AR system for gynecologic surgery and have used it to improve laparoscopic myomectomy. Technically, the software we developed is very different to approaches tried for other organs, and it can handle significant challenges, including image blur, fast motion, and partial views of the organ. PMID- 28089569 TI - Prevention of Dietary-Fat-Fueled Ketogenesis Attenuates BRAF V600E Tumor Growth. AB - Lifestyle factors, including diet, play an important role in the survival of cancer patients. However, the molecular mechanisms underlying pathogenic links between diet and particular oncogenic mutations in human cancers remain unclear. We recently reported that the ketone body acetoacetate selectively enhances BRAF V600E mutant-dependent MEK1 activation in human cancers. Here we show that a high fat ketogenic diet increased serum levels of acetoacetate, leading to enhanced tumor growth potential of BRAF V600E-expressing human melanoma cells in xenograft mice. Treatment with hypolipidemic agents to lower circulating acetoacetate levels or an inhibitory homolog of acetoacetate, dehydroacetic acid, to antagonize acetoacetate-BRAF V600E binding attenuated BRAF V600E tumor growth. These findings reveal a signaling basis underlying a pathogenic role of dietary fat in BRAF V600E-expressing melanoma, providing insights into the design of conceptualized "precision diets" that may prevent or delay tumor progression based on an individual's specific oncogenic mutation profile. PMID- 28089572 TI - Morphology matters: are all euploid blastocysts created equal? PMID- 28089571 TI - Normo- and hyperandrogenic women with polycystic ovary syndrome exhibit an adverse metabolic profile through life. AB - OBJECTIVE: To compare the metabolic profiles of normo- and hyperandrogenic women with polycystic ovary syndrome (PCOS) with those of control women at different ages during reproductive life. DESIGN: Case-control study. SETTING: Not applicable. PATIENT(S): In all, 1,550 women with normoandrogenic (n = 686) or hyperandrogenic (n = 842) PCOS and 447 control women were divided into three age groups: <30, 30-39, and >39 years). INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): Body mass index (BMI), waist circumference, blood pressure, glucose, insulin, cholesterol, lipoproteins, triglycerides and high-sensitivity C-reactive protein. RESULT(S): Both normo- and hyperandrogenic women with PCOS were more obese, especially abdominally. They had increased serum levels of insulin (fasting and in oral glucose tolerance tests), triglycerides, low-density lipoprotein, and total cholesterol, higher blood pressure, and lower high-density lipoprotein levels independently from BMI compared with the control population as early as from young adulthood until menopause. The prevalence of metabolic syndrome was two- to fivefold higher in women with PCOS compared with control women, depending on age and phenotype, and the highest prevalence was observed in hyperandrogenic women with PCOS at late reproductive age. CONCLUSION(S): When evaluating metabolic risks in women with PCOS, androgenic status, especially abdominal obesity and age, should be taken into account, which would allow tailored management of the syndrome from early adulthood on. PMID- 28089573 TI - What is a difficult transfer? Analysis of 7,714 embryo transfers: the impact of maneuvers during embryo transfers on pregnancy rate and a proposal of objective assessment. AB - OBJECTIVE: To establish the relationship between the degree of difficulty of ET and pregnancy rate (PR), with a view to proposing an algorithm for the objective assessment of ET. DESIGN: Retrospective, observational study. SETTING: In vitro fertilization unit. PATIENT(S): Women undergoing assisted reproductive technology (ART) with ET after IVF/intracytoplasmic sperm injection, in whom fresh embryo transfer or frozen-thawed embryo transfer was performed. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate (CPR). RESULT(S): A total of 7,714 ETs were analyzed. The CPR was significantly higher in the cases of easy ET compared with difficult ET (38.2% vs. 27.1%). Each instrumentation needed to successfully deposit the embryos in the fundus involves a progressive reduction in the CPR: use of outer catheter sheath (odds ratio [OR] 0.89; 95% confidence interval [CI] 0.79-1.01), use of Wallace stylet (OR 0.71; 95% CI 0.62-0.81), use of tenaculum (OR 0.54; 95% CI 0.36-0.79). Poor ultrasound visualization significantly diminish the CPR. CONCLUSION(S): The CPR decreases progressively with the use of additional maneuvers during ET. An objective classification of the instrumentation applied during ET is proposed. PMID- 28089574 TI - Does preoperative antimullerian hormone level influence postoperative pregnancy rate in women undergoing surgery for severe endometriosis? AB - OBJECTIVE: To compare postoperative pregnancy rates as they relate to presurgery antimullerian hormone (AMH) level in patients with stage 3 and 4 endometriosis. DESIGN: Retrospective comparative study using data prospectively recorded in the North-West Inter-Regional Female Cohort for Patients with Endometriosis (CIRENDO) database. SETTING: University tertiary referral center. PATIENT(S): One hundred eighty patients with stage 3 and 4 endometriosis and pregnancy intention, managed from June 2010 to March 2015, were divided into two groups according to their preoperative AMH levels: group A (AMH >=2 ng/mL) and group B (AMH <2 ng/mL). INTERVENTION(S): Surgical procedure involved ovarian endometrioma ablation by plasma energy along with resection of various localizations of the disease. Postoperative conception was either spontaneous or used assisted reproductive technology, depending on patient characteristics. MAIN OUTCOME MEASURE(S): Patient characteristics, preoperative symptoms, infertility history, intraoperative findings, and probability of pregnancy were recorded and compared between the two groups. RESULT(S): Among 180 women enrolled in the study, 134 (74.4%) were assigned to group A and 46 (25.6%) to group B. The women's ages were, respectively, 30 +/- 3.8 and 32 +/- 4.6 years. Pregnancy was achieved by 134 (74.4%) patients, and conception was spontaneous in 74 of them (55.2%). Pregnancy rates in groups A and B were, respectively, 74.6% (100 women) and 73.9% (34 women), while spontaneous conception represented 54% (54 women) and 58.8% (20 women). The probability of pregnancy at 12, 24, and 36 months after surgery in groups A and B was comparable, respectively, 65% (95% confidence interval [CI], 55%-75%), 77% (95% CI, 86%-68%), and 83% (95% CI, 90%-75%) versus 50% (95% CI, 69%-34%), 77% (95% CI, 90%-61%), and 83% (95% CI, 94%-68%). Supplementary analysis in women with normal (>=2 ng/mL), low (1-1.99 ng/mL), and very low (<1 ng/mL) AMH level showed an inverse relationship between AMH level, age, and antecedents of miscarriage; however, postoperative pregnancy rates were comparable among the three groups at 12 and 24 months, respectively, 59.5% (95% CI, 49.3%-70%) and 77.4% (95% CI, 68%-85.4%); 57.1% (95% CI, 34%-83%) and 78.6% (95% CI, 55.2%-94.8%); and 46.7% (95% CI, 25.6%-73.7%) and 73.3% (95% CI, 50.4% 91.7%). CONCLUSION(S): The probability of postoperative pregnancy was comparable between women with low and normal AMH level who were managed for stage 3 and 4 endometriosis and who were a mean age of 30 years. However, the small sample size might have been unable to detect differences in pregnancy and live-birth rates between the two groups. As the majority of pregnancies were spontaneous, our results suggest that surgical management may be offered to young patients with severe endometriosis and reduced ovarian reserve with good fertility outcomes. PMID- 28089575 TI - Association of uterine fibroids and pregnancy outcomes after ovarian stimulation intrauterine insemination for unexplained infertility. AB - OBJECTIVE: To investigate the association of non-cavity-distorting uterine fibroids and pregnancy outcomes after ovarian stimulation-intrauterine insemination (OS-IUI) in couples with unexplained infertility. DESIGN: Secondary analysis from a prospective, randomized, multicenter clinical trial investigating fertility outcomes after OS-IUI. SETTING: Reproductive Medicine Network clinical sites. PATIENT(S): Nine hundred couples with unexplained infertility who participated in the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial. INTERVENTION(S): Participants were randomized to one of three arms (clomiphene citrate, letrozole, or gonadotropins), and treatment was continued for up to four cycles or until pregnancy was achieved. MAIN OUTCOMES MEASURE(S): Conception (serum hCG increase), clinical pregnancy (fetal cardiac activity), and live birth rates. RESULT(S): A total of 102/900 participants (11.3%) had at least one documented fibroid and a normal uterine cavity. Women with fibroids were older, more likely to be African American, had a greater uterine volume, lower serum antimullerian hormone levels, and fewer antral follicles than women without fibroids. In conception cycles, clinical pregnancy rates were significantly lower in participants with fibroids than in those without uterine fibroids. Pregnancy loss before 12 weeks was more likely in African American women with fibroids compared with non-African American women with fibroids. There was no difference in conception and live birth rates in subjects with and without fibroids. CONCLUSION(S): No differences were observed in conception and live birth rates in women with non-cavity-distorting fibroids and those without fibroids. These findings provide reassurance that pregnancy success is not impacted in couples with non-cavity-distorting fibroids undergoing OS-IUI for unexplained infertility. CLINICAL TRIAL REGISTRATION NUMBER: NCT01044862. PMID- 28089576 TI - Conditional deletion of pejvakin in adult outer hair cells causes progressive hearing loss in mice. AB - Mutations in the Pejvakin (Pjvk) gene cause autosomal recessive hearing loss DFNB59 with audiological features of auditory neuropathy spectrum disorder (ANSD) or cochlear dysfunction. The precise mechanisms underlying the variable clinical phenotypes of DFNB59 remain unclear. Here, we demonstrate that mice with conditional ablation of the Pjvk gene in all sensory hair cells or only in outer hair cells (OHCs) show similar auditory phenotypes with early-onset profound hearing loss. By contrast, loss of Pjvk in adult OHCs causes a slowly progressive hearing loss associated with OHC degeneration and delayed loss of inner hair cells (IHCs), indicating a primary role for pejvakin in regulating OHC function and survival. Consistent with this model, synaptic transmission at the IHC ribbon synapse is largely unaffected in sirtaki mice that carry a C-terminal deletion mutation in Pjvk. Using the C-terminal domain of pejvakin as bait, we identified in a cochlear cDNA library ROCK2, an effector for the small GTPase Rho, and the scaffold protein IQGAP1, involved in modulating actin dynamics. Both ROCK2 and IQGAP1 associate via their coiled-coil domains with pejvakin. We conclude that pejvakin is required to sustain OHC activity and survival in a cell-autonomous manner likely involving regulation of Rho signaling. PMID- 28089578 TI - Dual influences of early-life maternal deprivation on histone deacetylase activity and recognition memory in rats. AB - Exposure to stress early in life may negatively impact nervous system functioning, including increasing the proneness to learning and memory impairments later in life. Maternal deprivation, a model of early-life stress, hinders memory in adult rats and lessens brain-derived neurotrophic factor (BDNF) levels in the hippocampus in a very heterogeneous way among individuals. The main goal of the present study was to investigate the possible epigenetic modulation underlying recognition memory impairment and reduced BDNF levels in the hippocampus of adult maternally deprived rats. We also evaluated the potential ameliorating properties of the histone deacetylase (HDAC) inhibitor, sodium butyrate, on memory deficits and BDNF changes related to maternal deprivation. Maternally deprived animals were categorized as 'inferior learners' and 'superior learners' according to their performance in object recognition memory task in comparison to controls. Results indicated that HDAC activity was higher in individuals submitted to maternal deprivation with the worst cognitive performance (inferior learners). Acute administration of sodium butyrate increased histone H3 acetylation and BDNF levels, and restored recognition memory in maternally deprived animals with the worst cognitive performance. Moreover, we also showed that there is a positive correlation between BDNF levels and memory performance. Taken together, the results indicated that HDAC inhibitors could be considered as a possible therapeutic agent to improve cognitive performance in inferior learners. Further studies need to be conducted for a better comprehension of the mechanisms related to persistent alterations observed in adult life induced by early stressful circumstances and those leading to resilience. PMID- 28089577 TI - Neutralizing anti-interleukin-1beta antibodies reduce ischemia-related interleukin-1beta transport across the blood-brain barrier in fetal sheep. AB - Hypoxic ischemic insults predispose to perinatal brain injury. Pro-inflammatory cytokines are important in the evolution of this injury. Interleukin-1beta (IL 1beta) is a key mediator of inflammatory responses and elevated IL-1beta levels in brain correlate with adverse neurodevelopmental outcomes after brain injury. Impaired blood-brain barrier (BBB) function represents an important component of hypoxic-ischemic brain injury in the fetus. In addition, ischemia-reperfusion increases cytokine transport across the BBB of the ovine fetus. Reducing pro inflammatory cytokine entry into brain could represent a novel approach to attenuate ischemia-related brain injury. We hypothesized that infusions of neutralizing IL-1beta monoclonal antibody (mAb) reduce IL-1beta transport across the BBB after ischemia in the fetus. Fetal sheep were studied 24-h after 30-min of carotid artery occlusion. Fetuses were treated with placebo- or anti-IL-1beta mAb intravenously 15-min and 4-h after ischemia. Ovine IL-1beta protein expressed from IL-1beta pGEX-2T vectors in Escherichia coli (E. coli) BL-21 cells was produced, purified, and radiolabeled with 125I. BBB permeability was quantified using the blood-to-brain transfer constant (Ki) with 125I-radiolabeled-IL-1beta. Increases in anti-IL-1beta mAb were observed in the brain of the mAb-treated group (P<0.001). Blood-to-brain transport of 125I-IL-1beta was lower (P<0.04) across brain regions in the anti-IL-1beta mAb-treated than placebo-treated ischemic fetuses. Plasma 125I-IL-1beta counts were higher (P<0.001) in the anti IL-1beta mAb- than placebo-treated ischemic fetuses. Systemic infusions of anti IL-1beta mAb reduce IL-1beta transport across the BBB after ischemia in the ovine fetus. Our findings suggest that conditions associated with increases in systemic pro-inflammatory cytokines and neurodevelopmental impairment could benefit from an anti-cytokine therapeutic strategy. PMID- 28089579 TI - Information Architecture for Perinatal Registration in the Netherlands. AB - In the Netherlands, the perinatal registry has undergone significant changes in the past decades. The purpose of this article is to describe the current health care information architecture for the national perinatal registry, including how the national data set is arranged and how electronic messages are used to submit data. We provide implications for women's health care providers based on the creation and implementation of the Dutch perinatal registry system. PMID- 28089580 TI - Medium optimization based on yeast's elemental composition for glutathione production in Saccharomyces cerevisiae. AB - The production of glutathione (GSH) or GSH enriched yeast is still in the focus of research driven by a high industrial interest. In this study, an optimal growth rate for GSH production via Saccharomyces cerevisiae Sa-07346 was investigated. To further improve the fermentation process in a way that it is independent of lots, the influence of different WMIX medium compositions on biomass and GSH production was studied. Thereby, the fermentation medium was adjusted based on yeast's elemental composition. The resulting chemically defined fermentation medium led to high cell densities in fed-batches. Therefore, it has the potential to be applied successfully for other high cell density yeast fermentation processes. As cysteine is the key component for GSH production, different cysteine addition strategies were studied and finally, a continuous cysteine feeding was applied in the late stage of fermentation. Thereby, a GSH concentration of 1459 +/- 57 mg/l was reached by continuously feeding cysteine, which meant an increase to 253% compared to the control without cysteine addition (577 mg/l GSH). PMID- 28089581 TI - Accountability studies of air pollution and health effects: lessons learned and recommendations for future natural experiment opportunities. AB - To address limitations of observational epidemiology studies of air pollution and health effects, including residual confounding by temporal and spatial factors, several studies have taken advantage of 'natural experiments', where an environmental policy or air quality intervention has resulted in reductions in ambient air pollution concentrations. Researchers have examined whether the population impacted by these air quality improvements, also experienced improvements in various health indices (e.g. reduced morbidity/mortality). In this paper, I review key accountability studies done previously and new studies done over the past several years in Beijing, Atlanta, London, Ireland, and other locations, describing study design and analysis strengths and limitations of each. As new 'natural experiment' opportunities arise, several lessons learned from these studies should be applied when planning a new accountability study. Comparison of health outcomes during the intervention to both before and after the intervention in the population of interest, as well as use of a control population to assess whether any temporal changes in the population of interest were also seen in populations not impacted by air quality improvements, should aid in minimizing residual confounding by these long term time trends. Use of either detailed health records for a population, or prospectively collected data on relevant mechanistic biomarkers coupled with such morbidity/mortality data may provide a more thorough assessment of if the intervention beneficially impacted the health of the community, and if so by what mechanism(s). Further, prospective measurement of a large suite of air pollutants may allow a more thorough understanding of what pollutant source(s) is/are responsible for any health benefit observed. The importance of using multiple statistical analysis methods in each paper and the difference in how the timing of the air pollution/outcome association may impact which of these design features is most important is also discussed. Based on these and other lessons learned, researchers may provide a more epidemiologically rigorous evaluation of cause-specific health impacts of an air quality intervention or action. PMID- 28089582 TI - A model for screening and prioritizing consumer nanoproduct risks: A case study from South Africa. AB - The potential risks of the increasing variety and volume of engineered nanomaterials (ENMs) entering into the ecosystem remain poorly quantified. In recent years, information essential to evaluate the ecological risks of ENMs has increased. However, the data are highly fragmented, limited, or severely lacking. This limits the usefulness of the information to support holistic screening and prioritization of potentially harmful ENMs. To screen and prioritize ENMs risks, we adopted a two-phased approach. First, a holistic framework model was developed to integrate a diverse set of factors aimed to assess the potential hazard, exposure, and in turn, risk to the ecosystem of ENMs from a given consumer nanoproduct. Secondly, using published literature we created a database of consumer nanoproduct categories, and types based on embedded ENMs type. The database consisted of eight consumer product categories, eleven different types of ENMs, and twenty-three nanoproduct types. The model results indicates the largest quantities of ENMs were released from sunscreens, textiles, cosmetics and paints with dominant ENMs quantities in descending order (based on quantity) as nTiO2>nZnO>nSiO2>nAg, and nFe2O3. In addition, according to the results from this study, nAg from washing machine were found to likely the highest risk to the environment. Overall, our model-derived results based on the case study illustrated: (i) the holistic framework's ability to screen, prioritize, rank, and compare ENMs potential exposure and risks among different nanoproducts categories and types, (ii) the derived risk estimations could support nanowastes classification with likelihood of non-uniformity of nanowastes classes even from the same nanoproduct category (e.g. cosmetics), and (iii) the lack of a mass based criteria specific for EMNs impedes realistic exposure and risk evaluation in the ecological systems. PMID- 28089583 TI - Association of prenatal and childhood PBDE exposure with timing of puberty in boys and girls. AB - BACKGROUND: Polybrominated diphenyl ether (PBDE) flame retardants are endocrine disrupting chemicals that exhibit estrogenic and androgenic properties and may affect pubertal timing. METHODS: Study subjects were participants between 1999 and 2013 in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a longitudinal cohort study of predominantly Mexican origin families in Northern California. We measured serum concentrations of four PBDEs (BDE-47, -99, -100, -153) in blood collected from mothers during pregnancy (N=263) and their children at age 9years (N=522). We determined timing of pubertal onset in 309 boys and 314 girls using clinical Tanner staging every 9months between 9 and 13years of age, and timing of menarche by self-report. We used Poisson regression for relative risk (RR) of earlier puberty and parametric survival analysis for time ratios (TR) of pubertal milestones. RESULTS: Prenatal concentrations of all 4 congeners and ?PBDEs were associated with later menarche in girls (RRearlier menarche=0.5, 95% confidence interval (CI): 0.3, 0.9 for ?PBDEs) but earlier pubic hair development in boys (RRearlier pubarche=2.0, 95% CI: 1.3, 3.3 for ?PBDEs). No associations were seen between prenatal exposure and girls' breast or pubic hair development or boys' genital development. Childhood PBDE exposure was not associated with any measure of pubertal timing, except for an association of BDE-153 with later menarche. CONCLUSIONS: We found that prenatal PBDE exposure was associated with later menarche in girls but earlier pubarche in boys, suggesting opposite pubertal effects in girls and boys. PMID- 28089584 TI - Pterostilbene attenuates high glucose-induced oxidative injury in hippocampal neuronal cells by activating nuclear factor erythroid 2-related factor 2. AB - In the present study, neuroblastoma (SH-SY5Y) cells were used to investigate the mechanisms mediating the potential protective effects of pterostilbene (PTE) against mitochondrial metabolic impairment and oxidative stress induced by hyperglycemia for mimicking the diabetic encephalopathy. High glucose medium (100mM) decreased cellular viability after 24h incubation which was evidenced by: (i) reduced mitochondrial complex I and III activities; (ii) reduced mitochondrial cytochrome C; (iii) increased reactive oxygen species (ROS) generation; (iv) decreased mitochondrial membrane potential (DeltaPsim); and (v) increased lactate dehydrogenase (LDH) levels. PTE (2.5, 5, and 10MUM for 24h) was nontoxic and induced the nuclear transition of Nrf2. Pretreatment of PTE (2.5, 5, and 10MUM for 2h) displayed a dose-dependently neuroprotective effect, as indicated by significantly prevented high glucose-induced loss of cellular viability, generation of ROS, reduced mitochondrial complex I and III activities, reduced mitochondrial cytochrome C, decreased DeltaPsim, and increased LDH levels. Moreover, the levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and glutathione S-transferase (GST) were elevated after PTE treatment. In addition, the elevation of nuclear Nrf2 by PTE treatment (10MUM for 2h) was abolished by Nrf2 siRNA. Importantly, Nrf2 siRNA induced the opposite changes in mitochondrial complex I and III activities, mitochondrial cytochrome C, reactive species generation, DeltaPsim, and LDH. Overall, the present findings were the first to show that pterostilbene attenuated high glucose-induced central nervous system injury in vitro through the activation of Nrf2 signaling, displaying protective effects against mitochondrial dysfunction derived oxidative stress. PMID- 28089585 TI - The impact of intelligence on memory and executive functions of children with temporal lobe epilepsy: Methodological concerns with clinical relevance. AB - PURPOSE: Patients with TLE are prone to have lower IQ scores than healthy controls. Nevertheless, the impact of IQ differences is not usually considered in studies that compared the cognitive functioning of children with and without epilepsy. This study aimed to determine the effect of using IQ as a covariate on memory and attentional/executive functions of children with TLE. METHODS: Thirty eight children and adolescents with TLE and 28 healthy controls paired as to age, gender, and sociodemographic factors were evaluated with a comprehensive neuropsychological battery for memory and executive functions. The authors conducted three analyses to verify the impact of IQ scores on the other cognitive domains. First, we compared performance on cognitive tests without controlling for IQ differences between groups. Second, we performed the same analyses, but we included IQ as a confounding factor. Finally, we evaluated the predictive value of IQ on cognitive functioning. RESULTS: Although patients had IQ score in the normal range, they showed lower IQ scores than controls (p = 0.001). When we did not consider IQ in the analyses, patients had worse performance in verbal and visual memory (short and long-term), semantic memory, sustained, divided and selective attention, mental flexibility and mental tracking for semantic information. By using IQ as a covariate, patients showed worse performance only in verbal memory (long-term), semantic memory, sustained and divided attention and in mental flexibility. IQ was a predictor factor of verbal and visual memory (immediate and delayed), working memory, mental flexibility and mental tracking for semantic information. CONCLUSION: Intelligence level had a significant impact on memory and executive functioning of children and adolescents with TLE without intellectual disability. This finding opens the discussion of whether IQ scores should be considered when interpreting the results of differences in cognitive performance of patients with epilepsy compared to healthy volunteers. PMID- 28089586 TI - Natural uranium impairs the differentiation and the resorbing function of osteoclasts. AB - BACKGROUND: Uranium is a naturally occurring radionuclide ubiquitously present in the environment. The skeleton is the main site of uranium long-term accumulation. While it has been shown that natural uranium is able to perturb bone metabolism through its chemical toxicity, its impact on bone resorption by osteoclasts has been poorly explored. Here, we examined for the first time in vitro effects of natural uranium on osteoclasts. METHODS: The effects of uranium on the RAW 264.7 monocyte/macrophage mouse cell line and primary murine osteoclastic cells were characterized by biochemical, molecular and functional analyses. RESULTS: We observed a cytotoxicity effect of uranium on osteoclast precursors. Uranium concentrations in the MUM range are able to inhibit osteoclast formation, mature osteoclast survival and mineral resorption but don't affect the expression of the osteoclast gene markers Nfatc1, Dc-stamp, Ctsk, Acp5, Atp6v0a3 or Atp6v0d2 in RAW 274.7 cells. Instead, we observed that uranium induces a dose-dependent accumulation of SQSTM1/p62 during osteoclastogenesis. CONCLUSIONS: We show here that uranium impairs osteoclast formation and function in vitro. The decrease in available precursor cells, as well as the reduced viability of mature osteoclasts appears to account for these effects of uranium. The SQSTM1/p62 level increase observed in response to uranium exposure is of particular interest since this protein is a known regulator of osteoclast formation. A tempting hypothesis discussed herein is that SQSTM1/p62 dysregulation contributes to uranium effects on osteoclastogenesis. GENERAL SIGNIFICANCE: We describe cellular and molecular effects of uranium that potentially affect bone homeostasis. PMID- 28089587 TI - Development of 111In-labeled exendin(9-39) derivatives for single-photon emission computed tomography imaging of insulinoma. AB - Insulinoma is a tumor derived from pancreatic beta-cells, and the resulting hyperinsulinemia leads to characteristic hypoglycemia. Recent studies have reported the frequent overexpression of glucagon-like peptide-1 receptor (GLP-1R) in human insulinomas, suggesting that the binding of a radiolabeled compound to GLP-1R is useful for the imaging of such tumors. Exendin(9-39), a fragment peptide of exendin-3 and -4, binds GLP-1R with high affinity and acts as an antagonist. Accordingly, radiolabeled exendin(9-39) derivatives have also been investigated as insulinoma imaging probes that might be less likely to induce hypoglycemia. In this study, we synthesized a novel indium-111 (111In)-benzyl diethylenetriaminepentaacetic acid (111In-BnDTPA)-conjugated exendin(9-39), 111In BnDTPA-exendin(9-39), and evaluated its utility as a probe for the SPECT imaging of insulinoma. natIn-BnDTPA-exendin(9-39) exhibited a high affinity for GLP-1R (IC50=2.5nM), stability in plasma, and a specific activity that improved following reactions with a solvent and solubilizer. Regarding the in vivo biodistribution of 111In-BnDTPA-exendin(9-39) in INS-1 tumor-bearing mice, high uptake levels were observed in tumors (14.6%ID/g at 15min), with corresponding high tumor-to-blood (T/B), tumor-to-muscle (T/M), and tumor-to-pancreas (T/P) ratios (T/B=2.55, T/M=22.7, T/P=2.7 at 1h). The pre-administration of excess nonradioactive exendin(9-39) significantly reduced accumulation in both the tumor and pancreas (76% and 68% inhibition, respectively) at 1h after 111In-BnDTPA exendin(9-39) injection, indicating that the GLP-1R mediated a majority of 111In BnDTPA-exendin(9-39) uptake in the tumor and pancreas. Finally, 111In-BnDTPA exendin(9-39) SPECT/CT studies in mice yielded clear images of tumors at 30min post-injection. These results suggest that 111In-BnDTPA-exendin(9-39) could be a useful SPECT molecular imaging probe for the detection and exact localization of insulinomas. PMID- 28089588 TI - Discovery of a novel series of N-hydroxypyridone derivatives protecting astrocytes against hydrogen peroxide-induced toxicity via improved mitochondrial functionality. AB - Astrocytes play a key role in brain homeostasis, protecting neurons against neurotoxic stimuli such as oxidative stress. Therefore, the neuroprotective therapeutics that enhance astrocytic functionality has been regarded as a promising strategy to reduce brain damage. We previously reported that ciclopirox, a well-known antifungal N-hydroxypyridone compound, protects astrocytes from oxidative stress by enhancing mitochondrial function. Using the N hydroxypyridone scaffold, we have synthesized a series of cytoprotective derivatives. Mitochondrial activity assay showed that N-hydroxypyridone derivatives with biphenyl group have comparable to better protective effects than ciclopirox in astrocytes exposed to H2O2. N-hydroxypyridone derivatives, especially 11g, inhibited H2O2-induced deterioration of mitochondrial membrane potential and oxygen consumption rate, and significantly improved cell viability of astrocytes. The results indicate that the N-hydroxypyridone motif can provide a novel cytoprotective scaffold for astrocytes via enhancing mitochondrial functionality. PMID- 28089589 TI - Synthesis, anticholinesterase activity and molecular modeling study of novel carbamate-substituted thymol/carvacrol derivatives. AB - New thymol and carvacrol derivatives with the carbamate moiety were synthesized and their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. 5-isopropyl-2-methylphenyl(3 fluorophenyl)carbamate (29) was found to be the most potent AChE inhibitor with IC50 values of 2.22MUM, and 5-isopropyl-2-methylphenyl (4-fluorophenyl)carbamate (30) exhibited the strongest inhibition against BuChE with IC50 value of 0.02MUM. Additionally, the result of H4IIE hepatoma cell toxicity assay for compounds 18, 20, 29, 30 and 35 showed negligible cell death at 0.07-10MUM. Moreover in order to better understand the inhibitory profiles of these molecules, molecular modeling studies were applied. Binding poses of studied compounds at the binding pockets of AChE and BuChE targets were determined. Predicted binding energies of these compounds as well as structural and dynamical profiles of molecules at the target sites were estimated using induced fit docking (IFD) algorithms and post processing molecular dynamics (MD) simulations methods (i.e., Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) approaches). PMID- 28089590 TI - Using the presurgical psychological evaluation to predict 5-year weight loss outcomes in bariatric surgery patients. AB - BACKGROUND: Psychosocial factors contribute to poorer weight loss outcomes following bariatric surgery; however, findings on associations between preoperative psychiatric diagnoses, psychological testing, and weight loss are inconsistent. OBJECTIVES: Examine associations between presurgical psychiatric diagnoses derived from a semi-structured clinical interview and test scores from the Minnesota Multiphasic Personality-Inventory-2 - Restructured Form (MMPI-2-RF) and 5-year Body Mass Index (BMI) outcomes. SETTING: Cleveland Clinic Bariatric and Metabolic Institute METHODS: 446 consecutively consented patients who underwent a Roux-en-Y gastric bypass (RYGB) at least 5 years prior were included in the study. A majority were women (74.2%) and Caucasian (66.2%). Patients' mean presurgical BMI was 49.14 kg/m2 [SD = 9.50 kg/m2]. Psychiatric diagnoses were obtained from a presurgical, semi-structured clinical interview and all participants were administered the MMPI-2-RF at their presurgical evaluations. BMIs were collected at 4 postoperative time points across a 5-year trajectory. This prospective design utilized latent growth curve modeling. RESULTS: Older patients evidenced a slower rate of BMI reduction over time. A presurgical diagnosis of Binge Eating Disorder predicted higher BMIs at the 5-year outcome. Scores on MMPI-2-RF measures of emotional and behavioral dysfunction domains incrementally predicted poorer weight loss outcomes. CONCLUSION: Preoperative indicators of psychopathology, notably indicators that are dimensional in nature, are important in predicting postoperative outcomes. Closer follow-up with patients who evidence presurgical psychological factors, both before and after surgery, may help improve outcomes. PMID- 28089591 TI - Evaluation of incidence of cholelithiasis after bariatric surgery in subjects treated or not treated with ursodeoxycholic acid. AB - BACKGROUND: The use of ursodeoxycholic acid (UDCA) to prevent gallstone formation after gastric bypass (RYGB) is still debated. Furthermore, only 1 study has assessed the effectiveness of UDCA after sleeve gastrectomy (SG) with mitigated results. OBJECTIVES: To compare the incidence of cholelithiasis (CL) between patients treated or not treated with UDCA after RYGB and SG. SETTING: University hospital, France. METHODS: Since January 2008, a postoperative ultrasound monitoring was scheduled for all patients without previous cholecystectomy who underwent bariatric surgery in our institution. Patients who underwent at least 1 ultrasound in the first postoperative year (+/-6 months) were included. We started to systematically prescribe UDCA (500 mg/d) for 6 months postoperatively, in February 2012 for RYGB (once or twice daily) and in October 2013 for SG (once daily). RESULTS: Mean follow-up was 13.0+/-3.4 months. The incidence of CL was 32.5% in the 117 nontreated RYGB and 25.5% in the 51 nontreated SG. It was reduced to 2.4% in the 42 SG treated once daily (P = .005), to 5.7% in the 87 RYGB with 250 mg twice daily (P<.001), but only to 18.6% in the 102 RYGB with 500 mg once daily (P = .03). CONCLUSION: UDCA 500 mg once daily for 6 months is efficient to prevent CL 1 year after SG, but the twice-daily doses seem to be more effective after RYGB. The effectiveness of UDCA once daily after SG and the superiority of the twice-daily doses after RYGB should be confirmed with more patients and longer follow-up. PMID- 28089592 TI - Stapleless laparoscopic sleeve gastrectomy. Preliminary report. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (SG) as a single-stage procedure for the treatment of morbid obesity is becoming increasingly popular. In undeveloped countries, the linear staples required to create the sleeve are not always available because of their high cost. As an alternative to the staples, the bipolar vessel sealer device could be used in bariatric surgery to divide and temporarily seal the stomach. SETTINGS: Universidad Central de Venezuela, Caracas, Venezuela. METHODS: Between May 2015 and July 2016, 9 patients with a mean body mass index of 38.2 kg/m2 were submitted to a stapleless laparoscopic SG using the bipolar vessel sealer for the gastric division. The sleeve was performed over a 42 French bougie and closed with 2 layers of running sutures. Surgical time, morbidity, hospital stay, and excess weight loss were prospectively collected. RESULTS: Mean operative time and hospital stay were 117 min and 2.3 days. There was no major morbidity but 2 patients presented a basal atelectasis, which was solved by medical treatment without consequences. After a mean follow up of 6.8 months the mean excess weight loss was 78.4%. CONCLUSION: The technique of stapleless laparoscopic SG presented in this report is a valid alternative when these devices are not available. Large series with long-term follow-up are necessary to make definitive conclusions. PMID- 28089593 TI - Physician Knowledge and Attitudes About Hepatitis A and Current Practices Regarding Hepatitis A Vaccination Delivery. AB - OBJECTIVE: To assess physicians': 1) knowledge and attitudes about hepatitis A disease and hepatitis A (HepA) vaccine, 2) child care and school HepA vaccine mandates, 3) practices related to HepA vaccine delivery, 4) factors associated with strongly recommending HepA vaccine to all 1- to 2-year-olds, and 5) feasibility of implementing HepA catch-up vaccination at health maintenance visits. METHODS: A national survey was conducted among representative networks of pediatricians and family medicine physicians (FMs) from March to June, 2014 via e mail or mail on the basis of provider preference. RESULTS: Response rates were 81% (356 of 440) among pediatricians and 75% (348 of 464) among FMs. Less than 50% correctly identified that hepatitis A virus (HAV) infection is usually asymptomatic in young children and that morbidity from HAV disease increases with age. Ninety-two percent of pediatricians and 59% of FMs strongly recommend HepA vaccine for all 1- to 2-year-olds. In addition to practice specialty, belief that HepA vaccine is required for kindergarten enrollment was the most robust predictor of strong physician recommendation. CONCLUSIONS: Gaps in knowledge regarding HAV infection and hepatitis A recommendations and lack of a strong recommendation for routine HepA vaccination of young children among FMs likely contribute to suboptimal coverage. Closing knowledge gaps and addressing barriers that prevent all physicians from strongly recommending HepA vaccine to 1- to 2 year-olds could help increase HepA vaccine coverage and ultimately improve population protection against HAV infection. PMID- 28089594 TI - Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor-sensitive Exon 19 Insertion and Exon 20 Insertion in Patients With Advanced Non-Small-cell Lung Cancer. AB - BACKGROUND: The clinical responsiveness to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) patients with exon 19 insertion and the specific exon 20 insertion (A763_Y764 insFQEA) are still not well known. MATERIALS AND METHODS: We analyzed cancer specimens taken from NSCLC patients for EGFR mutations using RNA reverse transcription polymerase chain reaction or direct DNA sequencing. The clinical course and responsiveness to an EGFR TKI in patients with EGFR exon 19 insertion or exon 20 insertion (A763_Y764 insFQEA) were recorded. The published data regarding these mutations were also reviewed. RESULTS: From September 1995 to May 2015, we found 4 patients with an EGFR exon 19 insertion and 6 patients with an EGFR exon 20 insertion (A763_Y764 insFQEA) at the National Taiwan University Hospital. Among patients with an exon 19 insertion, 3 received an EGFR TKI. Of the 3 patients, 1 had a partial response, 1 had stable disease, and 1 had progressive disease. Of the 6 patients with the exon 20 insertion (A763_Y764 insFQEA), 3 received an EGFR TKI. Of those 3 patients, 2 had a partial response and 1 had progressive disease. A review of the published data, together with the data from our patients, patients with an exon 19 insertion and treated with an EGFR TKI (n = 18) had a response rate of 56% and a median time to progression of 10.4 months. Patients with the exon 20 insertion (A763_Y764 insFQEA) and treated with an EGFR TKI (n = 11) had a response rate of 73% and a median time to progression of 5.0 months. CONCLUSIONS: Advanced NSCLC bearing the EGFR exon 19 insertion or exon 20 insertion (A763_Y764 insFQEA) is sensitive to EGFR TKIs. PMID- 28089595 TI - Percutaneous Plating of Weber B Fibular Fractures. AB - The purpose of the present study was to describe a minimally invasive percutaneous technique for plating Weber B distal fibular fractures and to evaluate its efficacy by measuring patient outcomes and hardware removal rates. The data from 17 patients undergoing percutaneous plating of a distal fibular (Weber B) fracture were prospectively studied. A 4- to 6-hole semitubular plate with 3 screws was used for percutaneously plating. The Roles and Maudsley score was used to assess the patients' activity level. All fibular fractures had healed clinically and radiographically by 8 weeks after surgery. The postoperative Roles and Maudsley scores had improved significantly. The time required to return to activity was 4.3 +/- 2.0 months. Hardware removal was required in 3 patients during the study period, which had an average of almost 4 years postoperatively. The results of the present study have demonstrated that percutaneous plating is an effective surgical option for treating Weber B distal fibular fractures. PMID- 28089596 TI - Processing of metacaspase 2 from Trypanosoma brucei (TbMCA2) broadens its substrate specificity. AB - Metacaspases are members of the cysteine peptidase family and may be implicated in programmed cell death in plants and lower eukaryotes. These proteases exhibit calcium-dependent activity and specificity for arginine residues at P1. In contrast to caspases, they do not require processing or dimerization for activity. Indeed, unprocessed metacaspase-2 of Trypanosoma brucei (TbMCA2) is active; however, it has been shown that cleavages at Lys55 and Lys268 increase TbMCA2 hydrolytic activity on synthetic substrates. The processed TbMCA2 comprises 3 polypeptide chains that remain attached by non-covalent bonds. Replacement of Lys55 and Lys268 with Gly via site-directed mutagenesis results in non-processed but enzymatically active mutant, TbMCA2 K55/268G. To investigate the importance of this processing for the activity and specificity of TbMCA2, we performed activity assays comparing the non-processed mutant (TbMCA2 K55/268G) with the processed TbMCA2 form. Significant differences between TbMCA2 WT (processed form) and TbMCA2 K55/268G (non-processed form) were observed. Specifically, we verified that although non-processed TbMCA2 is active when assayed with small synthetic substrates, the TbMCA2 form does not exhibit hydrolytic activity on large substrates such as azocasein, while processed TbMCA2 is able to readily digest this protein. Such differences can be relevant for understanding the physiological regulation and function of TbMCA2. PMID- 28089597 TI - Magnesium and calcium ions differentially affect human serine racemase activity and modulate its quaternary equilibrium toward a tetrameric form. AB - Serine racemase is the pyridoxal 5'-phosphate dependent enzyme that catalyzes both production and catabolism of d-serine, a co-agonist of the NMDA glutamate receptors. Mg2+, or, alternatively, Ca2+, activate human serine racemase by binding both at a specific site and - as ATP-metal complexes - at a distinct ATP binding site. We show that Mg2+ and Ca2+ bind at the metal binding site with a 4.5-fold difference in affinity, producing a similar thermal stabilization and partially shifting the dimer-tetramer equilibrium in favour of the latter. The ATP-Ca2+ complex produces a 2-fold lower maximal activation in comparison to the ATP-Mg2+ complex and exhibits a 3-fold higher EC50. The co-presence of ATP and metals further stabilizes the tetramer. In consideration of the cellular concentrations of Mg2+ and Ca2+, even taking into account the fluctuations of the latter, these results point to Mg2+ as the sole physiologically relevant ligand both at the metal binding site and at the ATP binding site. The stabilization of the tetramer by both metals and ATP-metal complexes suggests a quaternary activation mechanism mediated by 5'-phosphonucleotides similar to that observed in the distantly related prokaryotic threonine deaminases. This allosteric mechanism has never been observed before in mammalian fold type II pyridoxal 5' phosphate dependent enzymes. PMID- 28089598 TI - Impact of Focused Intraoperative Transthoracic Echocardiography by Anesthesiologists on Management in Hemodynamically Unstable High-Risk Noncardiac Surgery Patients. AB - OBJECTIVES: Focused transthoracic echocardiography (TTE) is used perioperatively for surgical patients. Intraoperative application of TTE is feasible, but its benefits remain unclear. The intention of this study was to investigate the effect of intraoperative TTE on the management of high-risk noncardiac surgery patients. DESIGN: A prospective interventional study. SETTING: Single-center university hospital. PARTICIPANTS: Fifty consecutive hemodynamically unstable high-risk patients anesthetized for noncardiac surgery. INTERVENTIONS: Focused TTE was performed on hemodynamically unstable anesthetized patients whenever circulatory instability (defined as hypotension or low cardiac output) occurred intraoperatively. A cardiac output monitoring system using pulse contour analysis was established before induction of anesthesia. The intended therapy for stabilizing the patient was documented; however, the management actually administered was guided by the results of the TTE. Differences between the 2 lines of management were documented and analyzed. MEASUREMENTS AND MAIN RESULTS: Intraoperative TTE was applied successfully in all 50 unstable patients. In 33 patients (66%, 95% confidence interval, 52.11-77.61) TTE led to a change of management. Altogether, 82 episodes of hemodynamic instability were recorded, including 38 episodes (46.34%, 95% confidence interval, 35.95-57.06) in which TTE led to a change of treatment. The most common pathologic finding was hypovolemia (66%); in contrast, in 22%, right-heart overload or right-heart failure (4%) was detected. CONCLUSIONS: Focused TTE by anesthesiologists can provide new information that may alter the hemodynamic management of unstable high-risk noncardiac surgery patients in the operating room. PMID- 28089599 TI - Impact of Oral Chlorhexidine on Bloodstream Infection in Critically Ill Patients: Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVES: Oropharyngeal overgrowth of microorganisms in the critically ill is a risk factor for lower respiratory tract infection and subsequent invasion of the bloodstream. Oral chlorhexidine has been used to prevent pneumonia, but its effect on bloodstream infection never has been assessed in meta-analyses. The authors explored the effect of oral chlorhexidine on the incidence of bloodstream infection, the causative microorganism, and on all-cause mortality in critically ill patients. DESIGN: Systematic review and meta-analysis of published studies. SETTING: Intensive care unit. PARTICIPANTS: The study comprised critically ill patients receiving oral chlorhexidine (test group) and placebo or standard oral care (control group). INTERVENTIONS: PubMed and the Cochrane Register of Controlled Trials were searched. Odds ratios (ORs) were pooled using the random effects model. MEASUREMENTS AND MAIN RESULTS: Five studies including 1,655 patients (832 chlorhexidine and 823 control patients) were identified. The majority of information was from studies at low or unclear risk bias; 1 study was at high risk of bias. Bloodstream infection and mortality were not reduced significantly by chlorhexidine (OR 0.74; 95% confidence interval [CI] 0.37-1.50 and OR 0.69; 95% CI 0.31-1.53, respectively). In the subgroup of surgical, mainly cardiac, patients, chlorhexidine reduced bloodstream infection (OR 0.47; 95% CI 0.22-0.97). Chlorhexidine did not affect any microorganism significantly. CONCLUSION: In critically ill patients, oropharyngeal chlorhexidine did not reduce bloodstream infection and mortality significantly and did not affect any microorganism involved. The presence of a high risk of bias in 1 study and unclear risk of bias in others may have affected the robustness of these findings. PMID- 28089600 TI - Perioperative Aspirin in Cardiac and Noncardiac Surgery. PMID- 28089601 TI - Corrigendum to "Behavioural and neurochemical consequences of chronic gut microbiota depletion during adulthood in the rat" [Neuroscience 339 (2016) 463 477]. PMID- 28089602 TI - Particle swarm optimizer for weighting factor selection in intensity-modulated radiation therapy optimization algorithms. AB - In inverse treatment planning of intensity-modulated radiation therapy (IMRT), the objective function is typically the sum of the weighted sub-scores, where the weights indicate the importance of the sub-scores. To obtain a high-quality treatment plan, the planner manually adjusts the objective weights using a trial and-error procedure until an acceptable plan is reached. In this work, a new particle swarm optimization (PSO) method which can adjust the weighting factors automatically was investigated to overcome the requirement of manual adjustment, thereby reducing the workload of the human planner and contributing to the development of a fully automated planning process. The proposed optimization method consists of three steps. (i) First, a swarm of weighting factors (i.e., particles) is initialized randomly in the search space, where each particle corresponds to a global objective function. (ii) Then, a plan optimization solver is employed to obtain the optimal solution for each particle, and the values of the evaluation functions used to determine the particle's location and the population global location for the PSO are calculated based on these results. (iii) Next, the weighting factors are updated based on the particle's location and the population global location. Step (ii) is performed alternately with step (iii) until the termination condition is reached. In this method, the evaluation function is a combination of several key points on the dose volume histograms. Furthermore, a perturbation strategy - the crossover and mutation operator hybrid approach - is employed to enhance the population diversity, and two arguments are applied to the evaluation function to improve the flexibility of the algorithm. In this study, the proposed method was used to develop IMRT treatment plans involving five unequally spaced 6MV photon beams for 10 prostate cancer cases. The proposed optimization algorithm yielded high-quality plans for all of the cases, without human planner intervention. A comparison of the results with the optimized solution obtained using a similar optimization model but with human planner intervention revealed that the proposed algorithm produced optimized plans superior to that developed using the manual plan. The proposed algorithm can generate admissible solutions within reasonable computational times and can be used to develop fully automated IMRT treatment planning methods, thus reducing human planners' workloads during iterative processes. PMID- 28089603 TI - Melatonin inhibits snake venom and antivenom induced oxidative stress and augments treatment efficacy. AB - Snakebite is a neglected health hazard. Its patho-physiology has largely been focused on systemic and local toxicities; whereas, venom and antivenom induced oxidative stress has long been ignored. Antivenom therapy although neutralizes venom lethality and saves many lives, remains ineffective against oxidative stress. This prompted us to complement antivenom with an antioxidant molecule melatonin that would protect against oxidative stress and increase the efficacy of the existing snakebite therapy. Here we show that D. russelli and E. carinatus venoms induce strong oxidative stress that persists even after antivenom administration in mice model. Additionally, antivenoms also induce oxidative stress. Polyvalent antivenom induce more oxidative stress than monovalent antivenom. Strikingly, antivenom and melatonin together not only inhibit venom and antivenom induced oxidative stress but also significantly reduce the neutralizing antivenom dose. This study provides a therapeutic potential for enhancing the existing snakebite therapy. The combined treatment of antivenom+melatonin would prevent the upsurge of oxidative stress as well as minimize the antivenom load. Thus the investigation offers immense scope for physicians and toxinologists to reinvestigate, design new strategies and think beyond the conventional mode of antivenom therapy. PMID- 28089604 TI - Clonality and resistance features of Acinetobacter baumannii isolates: Comparison of ICU and burn-ward isolates. PMID- 28089605 TI - Commentary to "Urinary continence outcome following vaginoplasty in patients with congenital adrenal hyperplasia". PMID- 28089606 TI - Parasacral transcutaneous electrical neural stimulation (PTENS) once a week for the treatment of overactive bladder in children: A randomized controlled trial. AB - INTRODUCTION: Overactive bladder (OAB) is the most prevalent voiding disorder in childhood, and its main manifestation is urinary urgency. In general, urotherapy and anticholinergics are the first choices of treatment. Parasacral Transcutaneous Electrical Neural Stimulation (PTENS) was introduced as an alternative for the treatment of detrusor overactivity in children, but treatment protocols described to date require several sessions per week or long-lasting sessions, making it difficult for the child to adhere to the treatment. Thus, this study aims to evaluate the effectiveness of PTENS in single weekly sessions in the treatment of OAB in children. STUDY DESIGN: This prospective, randomized controlled trial included 16 children with OAB. Children were divided into two groups: CG (urotherapy and electrical stimulation placebo) and EG (urotherapy and PTENS). For both groups, therapy was delivered in 20 weekly sessions, of duration 20 min each. Placebo electrical stimulation was done in the scapular area. The children were evaluated prior to treatment (T1), at the end of the 20 sessions (T2), and 60 days after the completion of treatment (T3), with a 3-day voiding diary, visual analogue scale (VAS), Rome III diagnostic criteria, and the Bristol Scale. RESULTS: The groups were similar in age, gender, and ethnicity. In the initial assessment, all children, in both groups, had urgency and incontinence, 50% in each group had constipation, and enuresis was present in seven children (87.5%) in the EG and six (75%) in the CG. No differences were found between the groups regarding the volumetric measurements made in the voiding diary, urinary frequency and constipation evaluated by the Rome III criteria and the Bristol Scale. Sixty days after treatment, a significant improvement was found in the EG group (p = 0.03) regarding urgency (Table), as well as an increase in dry nights in those presenting with enuresis (p = 0.03). No difference was noted regarding urinary incontinence (Table). At the end of 20 sessions and after 60 days of treatment, those responsible for the children in the EG perceived greater improvement in symptoms measured by the VAS (p = 0.05 and 0.04, respectively). CONCLUSIONS: Our preliminary results demonstrate that PTENS performed in single weekly sessions is effective in treating the bladder for symptoms of urinary urgency and enuresis, and in the perception of those responsible for the children. Further studies with larger populations are needed to corroborate these results. PMID- 28089607 TI - Estimates of nasal airflow at the nasal cycle mid-point improve the correlation between objective and subjective measures of nasal patency. AB - INTRODUCTION: The nasal cycle represents a significant challenge when comparing pre- and post-surgery objective measures of nasal airflow. METHODS: Computational fluid dynamics (CFD) simulations of nasal airflow were conducted in 12 nasal airway obstruction patients showing significant nasal cycling between pre- and post-surgery computed tomography scans. To correct for the nasal cycle, mid-cycle models were created virtually. Subjective scores of nasal patency were obtained via the Nasal Obstruction Symptom Evaluation (NOSE) and unilateral visual analog scale (VAS). RESULTS: The correlation between objective and subjective measures of nasal patency increased after correcting for the nasal cycle. In contrast to biophysical variables in individual patients, cohort averages were not significantly affected by the nasal cycle correction. CONCLUSIONS: The ability to correct for the confounding effect of the nasal cycle is a key element that future virtual surgery planning software for nasal airway obstruction will need to account for when using anatomic models based on single instantaneous imaging. PMID- 28089608 TI - Piloting the United Kingdom 'Prescribing Safety Assessment' with pharmacist prescribers in Scotland. AB - BACKGROUND: Prescribing is a complex task requiring considerable knowledge and skills. The Prescribing Safety Assessment (PSA) was developed by the British Pharmacological Society and the United Kingdom (UK) Medical Schools Council. Between February and June 2014, over 7000 final year medical students undertook the PSA, with an overall pass rate of 94%. Independent prescribing for suitably trained pharmacists was introduced in the UK in 2006. To date there has been little focus on any objective measures of prescribing safety. OBJECTIVE: To determine the PSA performance of a pilot group of pharmacist prescribers in Scotland relative to medical students and to test the feasibility and acceptability of running the PSA. METHODS: A group of 59 pharmacist prescribers took part in ten events. The PSA consisted of 30 questions to be completed over 60 min. All questions had been used in the 2014 assessments for final year medical students. The PSA was undertaken online under invigilated conditions, mirroring the medical student assessment. One month later, participants were invited to complete an online evaluation questionnaire. RESULTS: The mean overall PSA scores (+/-SD) were 87.5% +/- 8.7 (range 52-98) compared to a 88.5% for medical students. Based on an Angoff passmark of 76.0%, 53 pharmacists (89.8%) passed compared to an overall pass rate in PSA 2014 of 94%. Pharmacists performed equivalently to medical students in all assessment areas, with a slightly lower performance in the prescribing, drug monitoring and data interpretation questions offset by better performance in prescription review and adverse drug reactions. Feedback was positive in relation to appropriateness, relevance and level of difficulty of the PSA although several commented that they were practicing in very specific clinical areas. CONCLUSION: These pilot events have benchmarked the PSA performance of pharmacist prescribers with final year medical students, and feedback confirmed feasibility and acceptability. PMID- 28089610 TI - Epidemiology of Physical Activity and Exercise Training in the United States. AB - The purpose of this review was to provide an overview of the descriptive epidemiology of physical activity (PA) and exercise training in the United States. Overall, there is a low prevalence of meeting the current PA guidelines in all age, sex and race/ethnic groups. Among adults the prevalence of meeting the aerobic component of the guidelines is approximately 51%, whereas the prevalence of meeting both the aerobic and muscle-strengthening guidelines is approximately 23%. Approximately 27% of high school students meet the aerobic component of the pediatric guidelines (60 minutes of daily moderate-to-vigorous activity), and the proportion of youth meeting the guidelines decreases with advancing age. Further research is required to promote physically active lifestyles across the age spectrum in order to achieve optimal health benefits for the overall population. PMID- 28089609 TI - De-immunized and Functional Therapeutic (DeFT) versions of a long lasting recombinant alpha interferon for antiviral therapy. AB - Interferon alpha (IFN-alpha) exerts potent antiviral, immunomodulatory, and antiproliferative activity and have proven clinical utility in chronic hepatitis B and C virus infections. However, repeated IFN-alpha administration induces neutralizing antibodies (NAb) against the therapeutic in a significant number of patients. Associations between IFN-alpha immunogenicity and loss of efficacy have been described. So as to improve the in vivo biological efficacy of IFN-alpha, a long lasting hyperglycosylated protein (4N-IFN) derived from IFN-alpha2b wild type (WT-IFN) was developed. However, in silico analysis performed using established in silico methods revealed that 4N-IFN had more T cell epitopes than WT-IFN. In order to develop a safer and more efficient IFN therapy, we applied the DeFT (De-immunization of Functional Therapeutics) approach to producing functional, de-immunized versions of 4N-IFN. Using the OptiMatrix in silico tool in ISPRI, the 4N-IFN sequence was modified to reduce HLA binding potential of specific T cell epitopes. Following verification of predictions by HLA binding assays, eight modifications were selected and integrated in three variants: 4N IFN(VAR1), (VAR2) and (VAR3). Two of the three variants (VAR1 and VAR3) retained anti-viral function and demonstrated reduced T-cell immunogenicity in terms of T cell proliferation and Th1 and Th2 cytokine levels, when compared to controls (commercial NG-IFN (non-glycosylated), PEG-IFN, WT-IFN and 4N-IFN). It was previously demonstrated that N-glycosylation improved IFN-alpha pharmacokinetic properties. Here, we further reduce immunogenicity as measured in vitro using T cell assays and cytokine profiling by modifying the T cell epitope content of a protein (de-immunizing). Taking into consideration the present results and previously reported immunogenicity data for commercial IFN-alpha2b variants, 4N IFN(VAR1) and 4N-IFN-4N(VAR3) appear to be promising candidates for improved IFN alpha therapy of HCV and HBV. PMID- 28089611 TI - Government's Role in Promoting Healthy Living. AB - Worldwide, poor lifestyle behaviors, including obesity, physical inactivity, and low diet quality, are creating an unstainable burden of chronic disease with disparities across geography, race, income, education, and sex. Government plays an important role in addressing lifestyle behaviors and population health, reducing health disparities and chronic disease. Areas for government involvement include surveillance, research, programming, access to health care, quality assurance and guidelines for diet and physical activity (PA). Some view government as paternalistic and favor individual choice; however, there is opportunity to unite diverse approaches with government working across sectors and engaging the private sector. The paper will conclude with specific evidence based policy approaches to address obesity, nutrition, PA and tobacco use. PMID- 28089612 TI - Growth kinetic models of five species of Lactobacilli and lactose consumption in batch submerged culture. AB - Kinetic behaviors of five Lactobacillus strains were investigated with Contois and Exponential models. Awareness of kinetic behavior of microorganisms is essential for their industrial process design and scale up. The consistency of experimental data was evaluated using Excel software. L. bulgaricus was introduced as the most efficient strain with the highest biomass and lactic acid yield of 0.119 and 0.602gg-1 consumed lactose, respectively. The biomass and carbohydrate yield of L. fermentum and L. lactis were slightly less and close to L. bulgaricus. Biomass and lactic acid production yield of 0.117 and 0.358 for L. fermentum and 0.114 and 0.437gg-1 for L.actobacillus lactis were obtained. L. casei and L. delbrueckii had the less biomass yield, nearly 11.8 and 22.7% less than L. bulgaricus, respectively. L. bulgaricus (R2=0.9500 and 0.9156) and L. casei (R2=0.9552 and 0.8401) showed acceptable consistency with both models. The investigation revealed that the above mentioned models are not suitable to describe the kinetic behavior of L. fermentum (R2=0.9367 and 0.6991), L. delbrueckii (R2=0.9493 and 0.7724) and L. lactis (R2=0.8730 and 0.6451). Contois rate equation is a suitable model to describe the kinetic of Lactobacilli. Specific cell growth rate for L. bulgaricus, L. casei, L. fermentum, L. delbrueckii and L. lactis with Contois model in order 3.2, 3.9, 67.6, 10.4 and 9.8-fold of Exponential model. PMID- 28089613 TI - High frequency of hepatitis E virus infection in swine from South Brazil and close similarity to human HEV isolates. AB - Hepatitis E virus is responsible for acute and chronic liver infections worldwide. Swine hepatitis E virus has been isolated in Brazil, and a probable zoonotic transmission has been described, although data are still scarce. The aim of this study was to investigate the frequency of hepatitis E virus infection in pigs from a small-scale farm in the rural area of Parana State, South Brazil. Fecal samples were collected from 170 pigs and screened for hepatitis E virus RNA using a duplex real-time RT-PCR targeting a highly conserved 70nt long sequence within overlapping parts of ORF2 and ORF3 as well as a 113nt sequence of ORF2. Positive samples with high viral loads were subjected to direct sequencing and phylogenetic analysis. hepatitis E virus RNA was detected in 34 (20.0%) of the 170 pigs following positive results in at least one set of screening real-time RT PCR primers and probes. The swine hepatitis E virus strains clustered with the genotype hepatitis E virus-3b reference sequences in the phylogenetic analysis and showed close similarity to human hepatitis E virus isolates previously reported in Brazil. PMID- 28089614 TI - Dark septate endophyte decreases stress on rice plants. AB - Abiotic stress is one of the major limiting factors for plant development and productivity, which makes it important to identify microorganisms capable of increasing plant tolerance to stress. Dark septate endophytes can be symbionts of plants. In the present study, we evaluated the ability of dark septate endophytes isolates to reduce the effects of water stress in the rice varieties Nipponbare and Piaui. The experiments were performed under gnotobiotic conditions, and the water stress was induced with PEG. Four dark septate endophytes were isolated from the roots of wild rice (Oryza glumaepatula) collected from the Brazilian Amazon. Plant height as well as shoot and root fresh and dry matter were measured. Leaf protein concentrations and antioxidant enzyme activity were also estimated. The dark septate endophytes were grown in vitro in Petri dishes containing culture medium; they exhibited different levels of tolerance to salinity and water stress. The two rice varieties tested responded differently to inoculation with dark septate endophytes. Endophytes promoted rice plant growth both in the presence and in the absence of a water deficit. Decreased oxidative stress in plants in response to inoculation was observed in nearly all inoculated treatments, as indicated by the decrease in antioxidant enzyme activity. Dark septate endophytes fungi were shown to increase the tolerance of rice plants to stress caused by water deficiency. PMID- 28089615 TI - Commentary: Pediatric Psychopharmacology for the Primary Care Clinician. PMID- 28089616 TI - Foreword: Pediatric Psychopharmacology for Primary Care Clinicians. PMID- 28089617 TI - Validity of a population-specific BMR predictive equation for adults from an urban tropical setting. AB - BACKGROUND & AIMS: Basal metabolic rate (BMR) is an important physiologic measure in nutrition research. In many instances it is not measured but estimated by predictive equations. The purpose of this study was to compare measured BMR (BMRm) with estimated BMR (BMRe) obtained by different equations. METHODS: A convenient sample of 148 (89 women) 20-60 year-old subjects from the metropolitan area of Rio de Janeiro, Brazil participated in the study. BMRm values were measured by an indirect calorimeter and predicted by different equations (Schofield, Henry and Rees, Mifflin-St. Jeor and Anjos. All subjects had their body composition and anthropometric variables also measured. Accuracy of the estimations was established by the percentage of BMRe falling within +/-10% of BMRm and bias when the 95% CI of the difference of BMRe and BMRm means did not include zero. RESULTS: Mean BMRm values were 4833.5 (SD 583.3) and 6278.8 (SD 724.0) kJ*day-1 for women and men, respectively. BMRe values were both biased and inaccurate except for values predicted by the Anjos equation. BMR overestimation was approximately 20% for the Schofield equation which was higher comparatively to the Henry and Rees (14.5% and 9.6% for women and men, respectively) and the Mifflin-St. Jeor (approximately 14.0%) equations. BMR estimated by the Anjos equation was unbiased (95% CI = -78.1; 96.3 kJ day-1 for women and -282.6; 30.7 kJ*day-1 for men). CONCLUSIONS: Population-specific BMR predictive equations yield unbiased and accurate BMR values in adults from an urban tropical setting. PMID- 28089619 TI - Water soluble vitamins and peritoneal dialysis - State of the art. AB - This review presents the results of a systematic literature search concerning water soluble vitamins and peritoneal dialysis modality. We provide an overview of the data available on vitamin requirements, dietary intake, dialysis related losses, metabolism and the benefits of supplementation. We also summarise the current recommendations concerning the supplementation of vitamins in peritoneal dialysis and discuss the safety of an administration of vitamins in pharmacological doses. PMID- 28089618 TI - 24-Hour protein, arginine and citrulline metabolism in fed critically ill children - A stable isotope tracer study. AB - BACKGROUND & AIMS: The reference method to study protein and arginine metabolism in critically ill children is measuring plasma amino acid appearances with stable isotopes during a short (4-8 h) time period and extrapolate results to 24-h. However, 24-h measurements may be variable due to critical illness related factors and a circadian rhythm could be present. Since only short duration stable isotope studies in critically ill children have been conducted before, the aim of this study was to investigate 24-h appearance of specific amino acids representing protein and arginine metabolism, with stable isotope techniques in continuously fed critically ill children. METHODS: In eight critically ill children, admitted to the pediatric (n = 4) or cardiovascular (n = 4) intensive care unit, aged 0-10 years, receiving continuous (par)enteral nutrition with protein intake 1.0-3.7 g/kg/day, a 24-h stable isotope tracer protocol was carried out. L-[ring-2H5]-phenylalanine, L-[3,3-2H2]-tyrosine, L-[5,5,5-2H3] leucine, L-[guanido-15N2]-arginine and L-[5-13C-3,3,4,4-2H4]-citrulline were infused intravenously and L-[15N]-phenylalanine and L-[1-13C]leucine enterally. Arterial blood was sampled every hour. RESULTS: Coefficients of variation, representing intra-individual variability, of the amino acid appearances of phenylalanine, tyrosine, leucine, arginine and citrulline were high, on average 14-19% for intravenous tracers and 23-26% for enteral tracers. No evident circadian rhythm was present. The pattern and overall 24-h level of whole body protein balance differed per individual. CONCLUSIONS: In continuously fed stable critically ill children, the amino acid appearances of phenylalanine, tyrosine, leucine, arginine and citrulline show high variability. This should be kept in mind when performing stable isotope studies in this population. There was no apparent circadian rhythm. CLINICAL TRIAL REGISTER: NCT01511354 on clinicaltrials.gov. PMID- 28089620 TI - The use of information theory for the evaluation of biomarkers of aging and physiological age. AB - The present work explores the application of information theoretical measures, such as entropy and normalized mutual information, for research of biomarkers of aging. The use of information theory affords unique methodological advantages for the study of aging processes, as it allows evaluating non-linear relations between biological parameters, providing the precise quantitative strength of those relations, both for individual and multiple parameters, showing cumulative or synergistic effect. Here we illustrate those capabilities utilizing a dataset on heart disease, including diagnostic parameters routinely available to physicians. The use of information-theoretical methods, utilizing normalized mutual information, revealed the exact amount of information that various diagnostic parameters or their combinations contained about the persons' age. Based on those exact informative values for the correlation of measured parameters with age, we constructed a diagnostic rule (a decision tree) to evaluate physiological age, as compared to chronological age. The present data illustrated that younger subjects suffering from heart disease showed characteristics of people of higher age (higher physiological age). Utilizing information-theoretical measures, with additional data, it may be possible to create further clinically applicable information-theory-based markers and models for the evaluation of physiological age, its relation to age-related diseases and its potential modifications by therapeutic interventions. PMID- 28089621 TI - Exaptation, serendipity and aging. AB - The paper shows the importance of serendipity and exaptation in selected key moments of ageing research and argue that rationalistic dominant models in scientific research have masked the importance of reverse models of discovery based on serendipity and exaptation. I ask why this is the case and analyze three contributing factors: unprestatability of the functions of technologies, multidimensionality and astronomical complexity of the space over which biological reactions occurs and role of scientific paradigms in channeling research toward incrementalism. Empirical evidence of the limits of the rationalistic models are presented next. I close the paper by discussing the implications for aging research. PMID- 28089622 TI - Serum procalcitonin correlates with colonoscopy findings and can guide therapeutic decisions in postoperative ischemic colitis. AB - BACKGROUND: Postoperative ischaemic colitis (POIC) is a life-threatening vascular gastrointestinal condition. Serum procalcitonin (PCT) levels be of value in the detection of necrosis. AIMS: To evaluate the correlation between serum PCT levels and the colonoscopic assessment of the severity of POIC. METHODS: Between January 2007 and November 2014, 150 patients with POIC and PCT data were included in the study. The main outcome measure was the correlation between serum PCT and the colonoscopy-based assessment of the severity of POIC (according to Favier's classification: stage 1/2 without multi-organ failure vs. stage 2/3 with multi organ failure). RESULTS: Eighty-five percent of the stage 1 cases (n=22) had a serum PCT level <=2MUg/L; 63% (n=19) of the stage 2 cases with multi-organ failure had a PCT level between 4 and 8MUg/L, and 70% (n=52) of the stage 3 cases had a PCT level >=8MUg/L. The PCT level was strongly correlated with the Favier stage (Spearman's rho: 0.701; p<0.0001). PCT levels were similar in stage 2 cases with multi-organ failure and in stage 3 cases (16.06MUg/L vs. 7.79MUg/L, respectively; p=0.35). CONCLUSION AND RELEVANCE: Serum PCT is correlated with stage 2/3 POIC requiring surgery. If PCT >=5MUg/L, surgery should be considered. PMID- 28089623 TI - Which treatment for type 2 diabetes associated with non-alcoholic fatty liver disease? AB - Type 2 diabetes (T2DM) and nonalcoholic fatty liver disease (NAFLD) are highly prevalent in the community, and share common pathogenic mechanisms. There is also evidence that T2DM may be favored by hepatic fat accumulation; in turn the presence of T2DM is a risk factor for liver disease progression. The treatment of T2DM has considerably changed in the past few years; new drug classes, promoting glucose-lowering through mechanisms different from classical insulin-sensitizing or insulin-secreting action, have been added to continuing lifestyle intervention. Metformin and pioglitazone may be safely used in the presence of liver fat, whereas sulfonylureas and insulin itself have been associated with NAFLD progression and adverse outcome. Drugs acting on the incretin axis and on Na-glucose co-transport at renal tubular level offer new hopes for a tailored treatment able to reduce the burden of hepatic triglyceride accumulation and liver disease progression. PMID- 28089624 TI - Screening for colorectal cancer in France: How to improve adhesion and participation? PMID- 28089625 TI - Azathioprine for refractory ulcerative proctitis: A retrospective multicenter study. AB - BACKGROUND: Efficacy of azathioprine (AZA) in refractory ulcerative proctitis (UP) is unknown. METHODS: All patients treated with AZA for refractory UP in three referral centers between 2002 and 2012 were included. "Treatment success" in the long-term was defined as the absence of colectomy during follow-up, no need for anti-TNF during follow-up, no ongoing systemic steroids use, no adverse event leading to AZA withdrawal, and clinically quiescent disease at last follow up. RESULTS: Of the 1279 adult patients with ulcerative colitis, 25 patients were treated with AZA for refractory UP (median disease duration 4.9 years). Of these, 4 had no short-term clinical assessment. Of the remaining 21, 4 were primary non responders to AZA, 7 discontinued AZA for adverse events and 10 showed clinical improvement. At the long-term assessment at last follow up after a median of 46 months, 5 patients had treatment success and were still on AZA treatment, the remaining 20 were treatment failures. Of these, 5 discontinued AZA for adverse events and 15 were treated with infliximab (clinical response in 11 patients, primary non-response in one patient, and 3 underwent colectomy). CONCLUSION: AZA may be efficacious in maintaining clinical response in one-fifth of patients with refractory UP in a real-life setting. PMID- 28089626 TI - Cisplatin Induces Apoptosis Through the Endoplasmic Reticulum-mediated, Calpain 1 Pathway in Triple-negative Breast Cancer Cells. AB - BACKGROUND: Breast cancer is the most common cancer in women worldwide. Triple negative breast cancer (TNBC) is an aggressive type that can be treated using platinum-based chemotherapy such as cisplatin (cis-diamminedichloroplatinum II). Although the calpain protein is essential in many cellular processes, including apoptosis, cell signaling, and proliferation, its role in cisplatin-induced apoptosis in TNBC cells is not fully understood. The present study assessed calpain 1-dependent, cisplatin-induced apoptosis in TNBC cells. MATERIALS AND METHODS: MDA-MB231 cells were treated with different concentrations of cisplatin (0, 20, and 40 MUM). The cisplatin deposit and its effect on endoplasmic reticulum and, subsequently, calcium release were detected using transmission electron microscopy and Von Koss staining, respectively. Calpain 1 messenger RNA, protein content, and apoptosis was measured using reverse transcriptase polymerase chain reaction, Western blotting, and Hoechst stain, respectively. In addition, calpain modulation, by either activation or inhibition, and its effect on cisplatin-induced apoptosis were assessed. RESULTS: Our results showed that cisplatin induced endoplasmic reticulum stress, indicated by an increase in calcium staining and protein expression of glucose-regulated protein 78 and calmodulin, followed by cleavage of alpha-fodrin and caspase-12 and, eventually, apoptosis. Cyclopiazonic acid showed a similar effect and enhanced the sensitivity of these cells to cisplatin treatment. In contrast, calpain 1 inhibition by both specific small interfering RNA and exogenous inhibitor (calpeptin) attenuated cisplatin-induced apoptosis in these cells. CONCLUSION: Altogether, these findings suggest, for the first time, that calpain 1 activation by endoplasmic reticulum plays an essential role in sensitizing TNBC cells to cisplatin-induced apoptosis. This finding will allow exploration of new insights for the treatment of TNBC by overcoming its resistance to apoptosis. PMID- 28089627 TI - The Relationship Between Tamoxifen-associated Nonalcoholic Fatty Liver Disease and the Prognosis of Patients With Early-stage Breast Cancer. AB - PURPOSE: To investigate the relationship between tamoxifen-associated nonalcoholic fatty liver disease (NAFLD) and survival outcomes in patients with breast cancer. METHODS: Patients with early-stage invasive breast cancer after curative resection from January 2009 to June 2011 were selected. A total of 646 patients who were treated with tamoxifen were included. Patients diagnosed with NAFLD on ultrasonography were classified into the NAFLD and non-NAFLD groups. RESULTS: The NAFLD group included 221 patients, and the non-NAFLD group included 425 patients. Patients in the NAFLD group had significantly higher body mass index than those in the non-NAFLD group (P < .001). Disease-free survival was significantly longer in the non-NAFLD group than the NAFLD group (P = .006). However, there were no significant statistical differences between these 2 groups on overall survival (P = .387). With regard to body mass index, total cholesterol, triglyceride, low-density lipoprotein cholesterol, alanine aminotransferase, and high-density lipoprotein cholesterol, the optimal cutoff points were 21.06, 4.28, 1.22, 3.13, 27.50 and 1.29, respectively, which can be identified as risk factors for distinguishing patients who developed NAFLD from those who did not (P < .05). Moreover, a risk score >= 3 indicated a high risk of development of NAFLD (odds ratio, 3.03; 95% confidence interval, 1.11-8.28; P = .037). CONCLUSION: NAFLD development had a negative effect on survival outcomes of patients with breast cancer. The risk score created >= 3 had a high-level risk of developing NAFLD, and it might be used for physicians to evaluate each patient and give instructive advice for further treatment. PMID- 28089628 TI - CRF1 but not glucocorticoid receptor antagonists reduce separation-induced distress vocalizations in guinea pig pups and CRF overexpressing mouse pups. A combination study with paroxetine. AB - RATIONALE: Given the large number of patients that does not respond sufficiently to currently available treatment for anxiety disorders, there is a need for improved treatment. OBJECTIVES: We evaluated the anxiolytic effects of corticotropin releasing factor (CRF)1 receptor antagonists and glucocorticoid receptor (GR) antagonists in the separation-induced vocalization test in guinea pigs and transgenic mice with central CRF overexpression. Furthermore, we explored effects of these drugs when given in combination with a suboptimal dose of a selective serotonin re-uptake inhibitor (SSRI). METHODS: In guinea pig pups, the CRF1 receptor antagonists CP-154,526 and DMP695, and the GR antagonists mifepristone and Org34517 (all at 2.5, 10 and 40mg/kg intraperitoneally (IP)) were tested alone or in combination with 0.63mg/kg paroxetine IP. In CRF overexpressing mouse pups and wild type littermates, effects of CP-154,526 (10, 20 and 40mg/kg subcutaneously (SC)) and mifepristone (5, 15, 45mg/kg SC) were studied alone or in combination with 0.03mg/kg paroxetine SC. RESULTS: CRF1 but not GR antagonists reduced the number of calls relative to vehicle in guinea pigs and mice, independent of genotype. Treatment of CRF1 receptor or GR antagonists with paroxetine had no combined effect in guinea pigs, wild type or CRF overexpressing mice. CONCLUSIONS: Current results indicate robust anxiolytic properties of CRF1 receptor antagonists in guinea pigs and mice overexpressing CRF, and lack thereof of GR antagonists. Although no combined treatment effects were observed, it would be interesting to study combined treatment of CRF1 receptor antagonists with SSRIs following chronic drug administration. PMID- 28089629 TI - A RACK1-like protein regulates hyphal morphogenesis, root entry and in vivo virulence in Verticillium dahliae. AB - To identify key genes expressed in Verticillium dahliae in early stages of infection of cotton roots, spore suspensions of eight V. dahliae isolates with different virulence levels were induced by cotton roots and genes expressed in these isolates during the early stages of infection were profiled. A gene that was differentially expressed between highly and less virulent strains was identified. Cloning and bioinformatics analysis of the gene suggested that it belongs to the putative Gbeta-like/RACK1 protein family, and has seven WD40 domains. Targeted deletion of the gene revealed that it controls a number of growth-related phenotypes, including conidia and microsclerotia production, normal spore germination and hyphal development. RACK1 is a component of eukaryotic ribosomes, and here we found by qRT-PCR that disruption of RACK1 in V. dahliae (designated VdRACK1) significantly altered the transcriptional levels of other ribosomal proteins, suggesting possible global effects of VdRACK1 deletion on the protein translation of other genes. VdRACK1-null mutants lost the ability to penetrate intact cotton roots. However, the mutant strain was able to infect root-wounded cotton plants and, intriguingly, resulted in a hypervirulent phenotype, implicating a role for VdRACK1 in the restriction of rampant growth within the plant. PMID- 28089631 TI - Chronic lymphocytic leukaemia: a step ahead in the journey toward eradication. PMID- 28089630 TI - The Aspergillus nidulans Pbp1 homolog is required for normal sexual development and secondary metabolism. AB - P bodies and stress granules are RNA-containing structures governing mRNA degradation and translational arrest, respectively. Saccharomyces cerevisiae Pbp1 protein localizes to stress granules and promotes their formation and is involved in proper polyadenylation, suppression of RNA-DNA hybrids, and preventing aberrant rDNA recombination. A genetic screen for Aspergillus nidulans mutants aberrant in secondary metabolism identified the Pbp1 homolog, PbpA. Using Dcp1 (mRNA decapping) as a marker for P-body formation and FabM (Pab1, poly-A binding protein) to track stress granule accumulation, we examine the dynamics of RNA granule formation in A. nidulans cells lacking pub1, edc3, and pbpA. Although PbpA acts as a functional homolog of yeast PBP1, PbpA had little impact on either P-body or stress granule formation in A. nidulans in contrast to Pub1 and Edc3. However, we find that PbpA is critical for sexual development and its loss increases the production of some secondary metabolites including the carcinogen sterigmatocystin. PMID- 28089632 TI - Long interval zoledronic acid use in bone metastases. PMID- 28089633 TI - Definitions of oesophageal cancer. PMID- 28089634 TI - Adjuvant chemotherapy for upper tract urothelial cancer. PMID- 28089636 TI - Influence of perioperative nonsteroidal anti-inflammatory drugs on complications after gastrointestinal surgery: A meta-analysis. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are a key part of multimodal perioperative analgesia. This study aimed to evaluate the influence of perioperative NSAIDs application on complications after gastrointestinal surgery by using meta-analysis. METHODS: A systematic review of published literature was conducted by searching computerized databases including PubMed, CBM, Springer, Chinese Academic Journals, and China Info since the databases were published until June 2015. The articles and retrospective references regarding complications after gastrointestinal surgery were collected to compare postoperative complications associated with NSAIDs or other analgesics. After they were assessed by randomized controlled trials and extracted by the standard of the Jadad systematic review, the homogeneous studies were pooled using RevMan 5.3 software. The meta-analysis was performed on five postoperative complications: postoperative anastomotic leak, cardiovascular events, surgical site infection, nausea and vomiting, and intestinal obstruction. RESULTS: Twelve randomized controlled trials involving 3829 patients met the inclusion criteria. The results of meta-analyses showed the following: (1) postoperative anastomotic leak: NSAIDs (including selective and nonselective NSAIDs) increased the incidence of anastomotic leak [odds ratio (OR)=3.02, 95% confidence interval (CI): 2.16-4.23, p=0.00001]. Further results showed that nonselective NSAIDs significantly increased the incidence of anastomotic leak (OR=2.96, 95% CI: 1.99 4.42, p<0.00001), and selective NSAIDs had no significant difference as compared with the control group using other analgesics (OR=2.27, 95% CI: 0.68-7.56, p=0.18); (2) postoperative cardiovascular events: NSAIDs (selective and nonselective NSAIDs) had no difference when compared with other analgesics (OR=0.50, 95% CI: 0.23-1.12, p=0.09); (3) postoperative surgical site infection: NSAIDs (selective and nonselective NSAIDs) and other analgesics had no difference in surgical site infection (OR=0.77, 95% CI: 0.52-1.15, p=0.20); (4) postoperative nausea and vomiting: NSAIDs (selective and nonselective NSAIDs) decreased the incidence of nausea and vomiting (OR=0.53, 95% CI: 0.34-0.81, p=0.003); (5) postoperative intestinal obstruction: NSAIDs (selective and nonselective NSAIDs) decreased the incidence of intestinal obstruction (OR=0.35, 95% CI: 0.13-0.89, p=0.03). CONCLUSIONS: The meta-analysis suggests that postoperative NSAIDs, especially nonselective NSAIDs, could increase the incidence of anastomotic leak. NSAIDs could decrease postoperative nausea and vomiting and intestinal obstruction, but showed no difference in cardiovascular events and surgical site infection as compared with other analgesics. PMID- 28089635 TI - Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. AB - BACKGROUND: Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab. METHODS: Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200-600 mg) and then monthly rituximab commenced (375 mg/m2 in month 1 and 500 mg/m2 in months 2-6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov, number NCT01682616. FINDINGS: Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1-2 toxicities included upper respiratory tract infections (in 28 [57%] of 49 patients), diarrhoea (27 [55%]), and nausea (25 [51%]). Grade 3-4 adverse events occurred in 37 (76%) of 49 patients; most common were neutropenia (26 [53%]), thrombocytopenia (eight [16%]), anaemia (seven [14%]), febrile neutropenia (six [12%]), and leucopenia (six [12%]). The most common serious adverse events were pyrexia (six [12%]), febrile neutropenia (five [10%]), lower respiratory tract infection, and pneumonia (each three [6%]). Clinical tumour lysis syndrome occurred in two patients (resulting in one death) who initiated venetoclax at 50 mg. After enhancing tumour lysis syndrome prophylaxis measures and commencing venetoclax at 20 mg, clinical tumour lysis syndrome did not occur. The maximum tolerated dose was not identified; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Overall, 42 (86%) of 49 patients achieved a response, including a complete response in 25 (51%) of 49 patients. 2 year estimates for progression-free survival and ongoing response were 82% (95% CI 66-91) and 89% (95% CI 72-96), respectively. Negative marrow minimal residual disease was attained in 20 (80%) of 25 complete responders and 28 (57%) of 49 patients overall. 13 responders ceased all therapy; among these all 11 minimal residual disease-negative responders remain progression-free off therapy. Two with minimal residual disease-positive complete response progressed after 24 months off therapy and re-attained response after re-initiation of venetoclax. INTERPRETATION: A substantial proportion of patients achieved an overall response with the combination of venetoclax and rituximab including 25 (51%) of 49 patients who achieved a complete response and 28 (57%) of 49 patients who achieved negative marrow minimal residual disease with acceptable safety. The depth and durability of responses observed with the combination offers an attractive potential treatment option for patients with relapsed or refractory chronic lymphocytic leukaemia and could allow some patients to maintain response after discontinuing therapy, a strategy that warrants further investigation in randomised studies. FUNDING: AbbVie Inc and Genentech Inc. PMID- 28089637 TI - Postoperative nausea and vomiting free for all: A solution from propofol? PMID- 28089640 TI - Catecholamines are produced by ascidian immune cells: The involvement of PKA and PKC in the adrenergic signaling pathway. AB - The stress response is a complex mechanism, which includes changes in the immune system to enable organisms to maintain homeostasis. The neurohormones dopamine, noradrenaline (NA) and adrenalin are responsible for the physiological modulations that occur during acute stress. In the present study, we analyzed the effects of NA on the immune system specific to nitric-oxide (NO) production by subpopulations of immune cells (hemocytes) of the ascidian Phallusia nigra. We also investigated the capability of immune cells to produce catecholamine (CA). Finally, we tested the involvement of protein kinase A (PKA) and C (PKC) in the NA downstream signaling pathway. The results revealed that NA can reduce NO production by P. nigra hemocytes threefold, and that signet-ring cells, univacuolar refractile granulocytes and morula cells are the cell types most involved in this event. A challenge effected with Zymosan A induced CA production, and co-incubation with both inhibitors of the second messengers PKA and PKC revealed the involvement of these molecules in the adrenergic pathway of P. nigra hemocytes. Taken together, these results suggest that NO production can be down-regulated by NA through alpha- and beta-adrenoceptors via the second messengers PKA and PKC. PMID- 28089641 TI - Current outcomes of one-stage surgical correction for Berry syndrome. AB - OBJECTIVES: Berry syndrome is a combination of distal aortopulmonary window (APW), aortic origin of the right pulmonary artery (RPA), intact ventricular septum, and interrupted aortic arch. We present here our current experience of primary repair of this syndrome with the goal of optimizing treatment for this rare condition. METHODS: From January 2003 through December 2015, 16 infants with Berry syndrome underwent one-stage repair at Shanghai Children's Medical Center. Three different surgical correction techniques were used to repair the APW and aortic origin of the RPA, including intra-aortic baffle in 5, RPA detachment in 6, and RPA angioplasty with aortic cuff in 5 patients. RESULTS: The median age at repair was 90.5 days (range, 8-170 days). The interrupted aortic arch morphology was type A in 14 and type B in 2 patients. The APW morphology was type IIa in 4, type IIb in 10, and type III in 2 patients. Hospital death occurred in 2 patients, and death at follow-up occurred in one other patient. Three patients who previously underwent RPA angioplasty with aortic cuff required reoperation for aortic or RPA stenosis. Freedom from reoperation was 84.8%, 75.4%, and 75.4%, respectively at 1, 5, and 10 years after surgery. CONCLUSIONS: One-stage repair of Berry syndrome has achieved acceptable outcomes. Reoperations mainly are related to aortic or RPA stenosis, and the reoperation rate is higher when RPA arterioplasty is performed with an aortic cuff. PMID- 28089639 TI - A systematic review of the association between fatigue and genetic polymorphisms. AB - Fatigue is one of the most common and distressing symptoms, leading to markedly decreased quality of life among a large subset of patients with a variety of disorders. Susceptibility to fatigue may be influenced by genetic factors including single nucleotide polymorphisms (SNPs), especially in the regulatory regions, of relevant genes. To further investigate the association of SNPs with fatigue in various patient populations, a systematic search was conducted on Pubmed, CINAHL, PsycINFO, and Sociological Abstracts Database for fatigue related terms in combination with polymorphisms or genetic variation-related terms. Fifty papers in total met the inclusion and exclusion criteria for this analysis. These 50 papers were further classified into three subgroups for evaluation: chronic fatigue syndrome (CFS), cancer-related fatigue (CRF) and other disease-related fatigue. SNPs in regulatory pathways of immune and neurotransmitter systems were found to play important roles in the etiologies of CFS, CRF and other disease related fatigue. Evidence for associations between elevated fatigue and specific polymorphisms in TNFalpha, IL1b, IL4 and IL6 genes was revealed for all three subgroups of fatigue. We also found CFS shared a series of polymorphisms in HLA, IFN-gamma, 5-HT and NR3C1 genes with other disease-related fatigue, however these SNPs (excluding IFN-gamma) were not found to be adequately investigated in CRF. Gaps in knowledge related to fatigue etiology and recommendations for future research are further discussed. PMID- 28089642 TI - Mitochondria "muscle in" as a potential adjunct therapy in cardiothoracic surgery. PMID- 28089643 TI - Advancing the science of predicting air leaks. PMID- 28089638 TI - The effects of acute psychological stress on circulating and stimulated inflammatory markers: A systematic review and meta-analysis. AB - Inflammatory reactivity to acute laboratory stress is thought to reflect individual differences in responsivity to environmental stressors and may confer future health risk. To characterize this response, we conducted a meta-analysis of 34 studies that measured circulating inflammatory markers and 15 studies that measured stimulated production of inflammatory markers before and after exposure to laboratory challenge. Results showed significant stress-related increases in circulating interleukin (IL)-1beta (d=0.66, p<0.001), IL-6 (d=0.35, p<0.001), IL 10 (d=0.69, p<0.001), and tumor necrosis factor(TNF)-alpha (d=0.28, p<0.001), but not IL-1ra, IL-2, interferon-gamma, or C-reactive protein. There were sufficient data to assess the time course of IL-6, IL-1beta, and TNF-alpha reactivity. IL-6 increased from baseline to measures taken 40-50, 60-75, 90, and 120min following stress, with the largest effect at 90min post-stress (d=0.70, p<0.001). IL-1beta increased from baseline to 20-30, 40-50, and 60-70min following stress, with the largest effect between 40 and 50min post-stress (d=0.73, p=0.02). For TNF-alpha, there was a significant increase from baseline to 31-50min post stress (d=0.44, p=0.01), but not at later times. There was no difference in magnitude of IL-6 reactivity as a function of type of stress (social-evaluative versus other). For stimulated inflammatory markers, results showed stress-related increases in IL 1beta when measured 20-120min post-stress (d=1.09, p<0.001), and in IL-4 and interferon-gamma when measured 0-10min post stressor (d=-0.42, p<0.001 and d=0.47, p<0.001). These results extend findings from a prior meta-analysis (Steptoe et al., 2007) to show reliable increases in circulating IL-6, IL-1beta, IL-10 and TNF-alpha and stimulated IL-1beta, IL-4 and interferon-gamma in response to acute stress. It is possible that these responses contribute to associations between exposure to life challenges and vulnerability to inflammatory disease. PMID- 28089644 TI - Discussion. PMID- 28089645 TI - Pulmonary and atrial resection and reconstruction for sarcoma with intracardiac extension. PMID- 28089646 TI - A risk score to predict the incidence of prolonged air leak after video-assisted thoracoscopic lobectomy: An analysis from the European Society of Thoracic Surgeons database. AB - OBJECTIVE: The study objective was to develop an aggregate risk score for predicting the occurrence of prolonged air leak after video-assisted thoracoscopic lobectomy from patients registered in the European Society of Thoracic Surgeons database. METHODS: A total of 5069 patients who underwent video assisted thoracoscopic lobectomy (July 2007 to August 2015) were analyzed. Exclusion criteria included sublobar resections or pneumonectomies, lung resection associated with chest wall or diaphragm resections, sleeve resections, and need for postoperative assisted mechanical ventilation. Prolonged air leak was defined as an air leak more than 5 days. Several baseline and surgical variables were tested for a possible association with prolonged air leak using univariable and logistic regression analyses, determined by bootstrap resampling. Predictors were proportionally weighed according to their regression estimates (assigning 1 point to the smallest coefficient). RESULTS: Prolonged air leak was observed in 504 patients (9.9%). Three variables were found associated with prolonged air leak after logistic regression: male gender (P < .0001, score = 1), forced expiratory volume in 1 second less than 80% (P < .0001, score = 1), and body mass index less than 18.5 kg/m2 (P < .0001, score = 2). The aggregate prolonged air leak risk score was calculated for each patient by summing the individual scores assigned to each variable (range, 0-4). Patients were then grouped into 4 classes with an incremental risk of prolonged air leak (P < .0001): class A (score 0 points, 1493 patients) 6.3% with prolonged air leak, class B (score 1 point, 2240 patients) 10% with prolonged air leak, class C (score 2 points, 1219 patients) 13% with prolonged air leak, and class D (score >2 points, 117 patients) 25% with prolonged air leak. CONCLUSIONS: An aggregate risk score was created to stratify the incidence of prolonged air leak after video-assisted thoracoscopic lobectomy. The score can be used for patient counseling and to identify those patients who can benefit from additional intraoperative preventative measures. PMID- 28089647 TI - Hear! Hear! Against alLODDS, we might have a LiNeaR predictive model for prognosis of non-small cell lung cancer from pN+ nodal status. PMID- 28089648 TI - Diabetes and cardiorenal syndrome: Understanding the "Triple Threat". AB - OBJECTIVE: Diabetes is known to be associated with chronic kidney disease (CKD) and cardiovascular disease (CVD) independently. Type 2 cardiorenal syndrome (CRS), a recently defined syndrome, is characterized by primary renal failure that progressively leads to cardiac dysfunction. The effect of diabetes on cardiorenal syndrome has not been explored in a multi-ethnic population. In this retrospective secondary analysis, the hypothesis that diabetes modifies the effect of CVD on CKD was tested. METHODS: The National Health and Nutrition Examination Survey (NHANES) is a cross-sectional survey that was performed on the non-institutionalized population in the United States. All patients from the NHANES study, who were 20 years and older between the years 1999 and 2010, were included in the analysis. CKD was determined using the Cockcroft-Gault equation. The analysis was performed using a complex samples logistic regression to determine the relationship between diabetes and CRS. RESULTS: The prevalence of CKD among the population was 9.6% in Non-Hispanic Whites, 8.9% in African Americans, and 4.5% in Hispanics. The overall unadjusted odds ratio for CKD to no CKD was 6.89 (95% confidence interval [CI], 6.13-7.75, p < 0.001). The adjusted OR was elevated, 2.25 (CI 1.56-3.23, p < 0.001), among individuals with diabetes but was approximately 1.0 (1.43 CI 1.16-1.76, p < 0.05) among patients without diabetes after controlling for medical risk factors and demographic risk factors. CONCLUSION: Diabetes is strongly associated with Type 2 CRS in a nationally representative multi-ethnic population and must be considered when treating patients. Longitudinal studies should further examine this association. PMID- 28089649 TI - Magnetic resonance imaging-conditional devices: Luxury or real clinical need? AB - Although the risk of MRI scanning on patients with conventional devices is lower than initially thought, the patient's safety can only be guaranteed when using MRI-conditional devices. The most important modifications in MRI-conditional devices include a) Reduction in ferromagnetic components to reduce magnetic attraction and susceptibility artifacts; b) Replacement of the reed switch by a Hall sensor in order to avoid unpredictable reed switch behavior; c) Lead coil design to minimize lead heating and electrical current induction; d) Filter circuitry to prevent damage to the internal power supply; and e) Dedicated pacemaker programming to prevent inappropriate pacemaker inhibition and competing rhythms. Although many companies claim to have MRI-conditional devices, adoption in clinical practice is limited because a) Not all companies have MRI-conditional devices approved for both 1.5 and 3T; b) Not all companies offer the option of unlimited MRI scanning (without an exclusion zone in the thorax); c) Certain companies allow only a 30-min MRI scanning and only in afebrile patients; and d) Despite having MRI-conditional pacemakers, certain companies do not have MRI conditional defibrillators and CRT systems. It is clear that this new technology opens the door for MRI to a growing number of patients; however, the widespread adoption of MRI-conditional devices will depend on real-life issues, such as cost, clinical indications for such a device and the permanent education of health care professionals. PMID- 28089650 TI - Neither quantification by qPCR nor quantitative Elisa can be used to discriminate Angus cattle for resistance/susceptibility to Babesia bovis. AB - With the aim of finding quantitative phenotypic traits that can be used to discriminate the levels of resistance/susceptibility to Babesia bovis, we estimated the repeatability and correlation between the level of infection, determined by the number of copies of a fragment of the gene that encodes cytochrome B (NC mt-cyB) of B. bovis, and the levels of the anti-B. bovis antibodies, in blood samples collected from 51 Angus cattle on two different occasions. Samples with the anticoagulant EDTA were used for DNA extraction and without anticoagulant for separation of the blood serum. The quantification of the NC mt-cyB of B. bovis was carried out by the quantitative PCR technique (qPCR), while the anti-B. bovis IgG antibody titers (S/P) were quantified by the ELISA method. The NC and S/P data were log10-transformed to improve the approximation to the normal distribution and were analyzed using mixed models. The correlations between NC mt-cyB and S/P were estimated, as well as the repeatability values for each trait. The results obtained showed the high sensitivity of the techniques, with 100% of the animals being positive for B. bovis, detected by both the serological and molecular tests. The correlations estimated between NC and S/P were low, 0.10 and 0.12, in the first and second collection, respectively. The repeatability estimated for NC was 0.06, whereas for the S/P it was 0.42. The low correlations between S/P and NC in the two collections demonstrated that the variation in the NC value is independent of the level of antibodies. This results indicated that animals with a higher levels of antibodies against B. bovis in the first collection continued to have a higher levels in the second one. However, the very low values for the repeatability value of NC, and for the correlations between S/P and NC, demonstrates that neither NC or S/P could be used to discriminate animals for resistance/susceptibility to B. bovis. PMID- 28089652 TI - Hippocampal-prefrontal connectivity as a translational phenotype for schizophrenia. AB - Finding novel biological targets in psychiatry has been difficult, partly because current diagnostic categories are not defined by pathophysiology and difficult to model in animals. The study of species-conserved systems-level mechanisms implicated in psychiatric disease could be a promising strategy to address some of these difficulties. Altered hippocampal-prefrontal (HC-PFC) connectivity during working memory (WM) processing is a candidate for such a translational phenotype as it has been repeatedly associated with impaired cognition in schizophrenia patients and animal models for psychiatric risk factors. Specifically, persistent hippocampus-dorsolateral prefrontal cortex (HC-DLPFC) coupling during WM is an intermediate phenotype for schizophrenia that has been observed in patients, healthy relatives and carriers of two different risk polymorphisms identified in genome-wide association studies. Rodent studies report reduced coherence between HC and PFC during anesthesia, sleep and task performance in both genetic, environmental and neurodevelopmental models for schizophrenia. We discuss several challenges for translation including differences in anatomy, recording modalities and WM paradigms and suggest that a better understanding of HC-PFC coupling across species can be achieved if translational neuroimaging is used to control for task differences. The evidence for potential neurobiological substrates underlying HC-PFC dysconnectivity is evaluated and research strategies are proposed that aim to bridge the gap between findings from large-scale association studies and disease mechanisms. PMID- 28089651 TI - Canine tick-borne pathogens in Cyprus and a unique canine case of multiple co infections. AB - Canine tick-borne pathogens such as Ehrlichia canis and Hepatozoon canis are widespread in the Mediterranean basin but have never been reported or investigated in Cyprus. We describe herein the presence of canine tick-borne pathogens in three dogs with clinical signs compatible with vector-borne diseases from Paphos area of Cyprus. Molecular and phylogenetic analysis revealed the presence of E. canis, Anaplasma platys, H. canis, Babesia vogeli and Mycoplasma haemocanis in Cyprus. One dog co-infected with E. canis, H. canis, B. vogeli and M. haemocanis is, to the best of our knowledge, the first report of this multiple co-infection in dogs. The tick-borne pathogens reported in the current study should be considered in the differential diagnoses in dogs exposed to ticks in Cyprus. PMID- 28089653 TI - Priming theta burst stimulation enhances motor cortex plasticity in young but not old adults. AB - BACKGROUND: Primary motor cortex neuroplasticity is reduced in old adults, which may contribute to the motor deficits commonly observed in the elderly. Previous research in young subjects suggests that the neuroplastic response can be enhanced using non-invasive brain stimulation (NIBS), with a larger plastic response observed following priming with both long-term potentiation (LTP) and depression (LTD)-like protocols. However, it is not known if priming stimulation can also modulate plasticity in older adults. OBJECTIVE: To investigate if priming NIBS can be used to modulate motor cortical plasticity in old subjects. METHODS: In 16 young (22.3 +/- 1.0 years) and 16 old (70.2 +/- 1.7 years) subjects, we investigated the response to intermittent theta burst stimulation (iTBS; LTP-like) when applied 10 min after sham stimulation, continuous TBS (cTBS; LTD-like) or an identical block of iTBS. Corticospinal plasticity was assessed by recording changes in motor evoked potential (MEP) amplitude. RESULTS: In young subjects, priming with cTBS (cTBS + iTBS) resulted in larger MEPs than priming with either iTBS (iTBS + iTBS; P = 0.001) or sham (sham + iTBS; P < 0.0001), while larger MEPs were seen following iTBS + iTBS than sham + iTBS (P < 0.0001). In old subjects, the response to iTBS + iTBS was not different to sham + iTBS (P > 0.9), whereas the response to cTBS + iTBS was reduced relative to iTBS + iTBS (P = 0.02) and sham + iTBS (P = 0.04). CONCLUSIONS: Priming TBS is ineffective for modifying M1 plasticity in older adults, which may limit the therapeutic use of priming stimulation in neurological conditions common in the elderly. PMID- 28089654 TI - Statins in prevention of venous thromboembolism. PMID- 28089655 TI - Statins and primary prevention of venous thromboembolism: a systematic review and meta-analysis. AB - BACKGROUND: Statins have been suggested to have a protective effect on venous thromboembolism (which includes deep vein thrombosis and pulmonary embolism), but the evidence is uncertain. We sought to evaluate the extent to which statins are associated with first venous thromboembolism events. METHODS: We did a systematic review and meta-analysis of observational cohort studies and randomised controlled trials (RCTs). Relevant studies that reported associations between statins and first venous thromboembolism outcomes were identified from MEDLINE, Embase, Web of Science, Cochrane Library, and a manual search of bibliographies for studies published up until July 18, 2016, and from email correspondence with investigators. Observational cohorts that assessed the association of statin use with venous thromboembolism, deep vein thrombosis, or pulmonary embolism in adults were included, as were intervention studies that assessed the effects of statin therapy compared with a placebo or no treatment and collected data on venous thromboembolism, deep vein thrombosis, or pulmonary embolism outcomes. Studies that compared statins with another statin or lipid-lowering agent were excluded. Study specific relative risks (RRs) were aggregated using random effects models and were grouped by study-level characteristics. The review has been registered with PROSPERO, number CRD42016035622. FINDINGS: 36 eligible studies (13 cohort studies comprising 3 148 259 participants and 23 RCTs of statins vs placebo or no treatment comprising 118 464 participants) were included. In observational studies, the pooled RR for venous thromboembolism was 0.75 (95% CI 0.65-0.87; p<0.0001) when statin use was compared with no statin use. This association remained consistent when grouped by various study-level characteristics. In RCTs, the RR for venous thromboembolism was 0.85 (0.73-0.99; p=0.038) when statin therapy was compared with placebo or no treatment. Subgroup analyses suggested significant differences in the effect of statins by type of statin, with rosuvastatin having the lowest risk on venous thromboembolism compared with other statins 0.57 (0.42-0.75; p=0.015). There was no evidence of an effect of statin use on pulmonary embolism. Statin use was associated with a significant reduction in risk of the specific endpoint of deep vein thrombosis compared with no statin use (RR 0.77, 95% CI 0.69-0.86; p<0.0001). INTERPRETATION: Available evidence from observational and intervention studies suggest a beneficial effect of statin use on venous thromboembolism. In intervention studies, therapy with rosuvastatin significantly reduced venous thromboembolism compared with other statins. Further evidence is however needed to validate these findings. FUNDING: None. PMID- 28089656 TI - How do antidepressants influence the BOLD signal in the developing brain? AB - Depression is a highly prevalent life-threatening disorder, with its first onset commonly occurring during adolescence. Adolescent depression is increasingly being treated with antidepressants, such as fluoxetine. The use of medication during this sensitive period of physiological and cognitive brain development produces neurobiological changes, some of which may outlast the course of treatment. In this review, we look at how antidepressant treatment in adolescence is likely to alter neurovascular coupling and brain energy use and how these changes, in turn, affect our ability to identify neuronal activity changes between participant groups. BOLD (blood oxygen level dependent) fMRI (functional magnetic resonance imaging), the method most commonly used to record brain activity in humans, is an indirect measure of neuronal activity. This means that between-group comparisons - adolescent versus adult, depressed versus healthy, medicated versus non-medicated - rely upon a stable relationship existing between neuronal activity and the BOLD response across these groups. We use data from animal studies to detail the ways in which fluoxetine may alter this relationship, and explore how these alterations may influence the interpretation of BOLD signal differences between groups that have been treated with fluoxetine and those that have not. PMID- 28089658 TI - Utility of Body Mass Index, Waist-to-Height-Ratio and cardiorespiratory fitness thresholds for identifying cardiometabolic risk in 10.4-17.6-year-old children. AB - OBJECTIVE: To examine the utility of Body Mass Index (BMI), Waist-to-Height-Ratio (WHtR) and cardiorespiratory fitness thresholds to identify cardiometabolic risk in youth. METHODS: Cross-sectional cardiometabolic risk factor variables on 534 children aged 10.4-17.6 years of age (52% boys) from the United Kingdom were used. Binary logistic regression and receiver operating characteristic curves were used to examine the utility of established age and gender specific thresholds for BMI, WHtR and cardiorespiratory fitness to identify individuals with increased cardiometabolic risk (increased clustered triglycerides, HDL cholesterol, systolic blood pressure and glucose). RESULTS: A WHtR>=0.5 increased the odds by 11.4 (95% confidence interval 4.7, 27.4, P<0.001) of having increased cardiometabolic risk in boys and by 2.5 (1.2, 5.3, P=0.020) for girls. Similar associations were observed for BMI and cardiorespiratory fitness in both boys and girls with increased cardiometabolic risk. BMI-z, WHtR and cardiorespiratory fitness all showed a significant ability in identifying individuals for increased cardiometabolic risk in boys and girls (P<0.05) despite poor area under the curve (AUC) values (<0.70). Combining anthropometrical variables did improve the diagnostic accuracy for identifying cardiometabolic risk in boys, evidenced by an increased AUC of 0.74 (0.64, 0.85, P<0.001), but not in girls. CONCLUSION: The magnitude of associations was broadly similar for BMI, WHtR and cardiorespiratory fitness in identifying individuals at increased cardiometabolic risk. Yet, combining BMI with WHtR in boys may provide a more accurate method for identifying those at increased cardiometabolic risk. PMID- 28089657 TI - Autism spectrum disorder in the scope of tactile processing. AB - Sensory processing abnormalities are among the most common behavioral phenotypes seen in autism spectrum disorder (ASD), typically characterized by either over- or under-responsiveness to stimulation. In this review, we focus on tactile processing dysfunction in ASD. We firstly review clinical studies wherein sensitivity to tactile stimuli has traditionally been assessed by self-, parent- and experimenter-reports. We also discuss recent investigations using psychophysical paradigms that gauge individual tactile thresholds. These more experimentally rigorous studies allow for more objective assessments of tactile abnormalities in ASD. However, little is understood about the neurobiological mechanisms underlying these abnormalities, or the link between tactile abnormalities and ASD symptoms. Neurobiological research that has been conducted has pointed toward dysfunction in the excitation/inhibition balance of the central nervous system of those with ASD. This review covers recent efforts that have investigated tactile dysfunction in ASD from clinical and behavioral perspectives, and some of the efforts to link these to neurobiology. On the whole, findings are inconsistent, which can be ascribed to the subjectivity of clinical assessments, the heterogeneity of ASD cohorts, and the diversity of tactile sensitivity measures. Future endeavors into understanding tactile processing differences in ASD will greatly benefit from controlled experiments driven by neurobiological hypotheses. PMID- 28089659 TI - Corrigendum to "Unambiguous determination of Plasmodium vivax reticulocyte invasion by flow cytometry" [Int. J. Parasitol. 46 (2016) 31-39]. PMID- 28089660 TI - Characterization, pharmacokinetics and tissue distribution of chlorogenic acid loaded self-microemulsifying drug delivery system. AB - The purpose of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) to improve the oral bioavailability of Chlorogenic acid (CA), an important bioactive compound from Lonicerae Japonicae Flos with poor permeability. SMEDDS was prepared and characterized by self-emulsifying rate, morphological observation, droplet size determination, stability, in vitro release, in vivo bioavailability and tissue distribution experiments. Results shown that the SMEDDS of CA has a high self-emulsifying rate (>98%) in the dissolution media, and its microemulsion exhibits small droplet size (16.37nm) and good stability. In vitro release test showed a complete release of CA from SMEDDS in 480min. After oral administration in mice, significantly enhanced bioavailability of CA was achieved through SMEDDS (249.4% relative to the CA suspension). Interestingly, SMEDDS significantly changed the tissue distribution of CA and showed a better targeting property to the kidney (2.79 of the relative intake efficiency). It is suggested that SMEDDS improves the oral bioavailability of CA may mainly through increasing its absorption and slowing the metabolism of absorbed CA via changing its distribution from the liver to the kidney. In conclusion, it is indicated that SMEDDS is a promising carrier for the oral delivery of CA. PMID- 28089661 TI - Studying the influence of formulation and process variables on Vancomycin-loaded polymeric nanoparticles as potential carrier for enhanced ophthalmic delivery. AB - Ocular topically applied Vancomycin (VCM) suffers poor bioavailability due to its high molecular weight and hydrophilicity. In the present investigation, VCM loaded polymeric nanoparticles (PNPs) were developed aiming to enhance its ocular bioavailability through prolonging its release pattern and ophthalmic residence. PNPs were prepared utilizing double emulsion (W/O/O), solvent evaporation technique. 23*41 full factorial design was applied to evaluate individual and combined influences of polymer type, Eudragit(r) RS100, sonication time, and Span(r)80 concentration on PNPs particle size, encapsulation efficiency, and zeta potential. Further, the optimized formulae were incorporated in 1% Carbopol(r) based gel. In-vivo evaluation of the optimized formulae was performed via Draize test followed by microbiological susceptibility testing on albino rabbits. Results revealed successful formulation of VCM-loaded PNPs was achieved with particle sizes reaching 155nm and up to 88% encapsulation. Draize test confirmed the optimized formulae as non-irritating and safe for ophthalmic administration. Microbiological susceptibility testing confirmed prolonged residence, higher Cmax. with more than two folds increment in the AUC(0.25-24) of VCM-PNPs over control groups. Thus, VCM-loaded PNPs represent promising carriers with superior achievements for enhanced Vancomycin ophthalmic delivery over the traditional use of commercially available VCM parenteral powder after constitution into a solution by the ophthalmologists. PMID- 28089662 TI - Electroacupuncture pretreatment attenuates spinal cord ischemia-reperfusion injury via inhibition of high-mobility group box 1 production in a LXA4 receptor dependent manner. AB - Paraplegia caused by spinal cord ischemia is a severe complication following surgeries in the thoracic aneurysm. HMGB1 has been recognized as a key mediator in spinal inflammatory response after spinal cord injury. Electroacupuncture (EA) pretreatment could provide neuroprotection against cerebral ischemic injury through inhibition of HMGB1 release. Therefore, the present study aims to test the hypothesis that EA pretreatment protects against spinal cord ischemia reperfusion (I/R) injury via inhibition of HMGB1 release. Animals were pre treated with EA stimulations 30min daily for 4 successive days, followed by 20 min spinal cord ischemia induced by using a balloon catheter placed into the aorta. We found that spinal I/R significantly increased mRNA and cytosolic protein levels of HMGB1 after reperfusion in the spinal cord. The EA-pretreated animals displayed better motor performance after reperfusion along with the decrease of apoptosis, HMGB1, TNF-alpha and IL-1beta expressions in the spinal cord, whereas these effects by EA pretreatment was reversed by rHMGB1 administration. Furthermore, EA pretreatment attenuated the down-regulation of LXA4 receptor (ALX) expression induced by I/R injury, while the decrease of HMGB1 release in EA-pretreated rats was reversed by the combined BOC-2 (an inhibitor of LXA4 receptor) treatment. In conclusion, EA pretreatment may promote spinal I/R injury through the inhibition of HMGB1 release in a LXA4 receptor-dependent manner. Our data may represent a new therapeutic technique for treating spinal cord ischemia-reperfusion injury. PMID- 28089663 TI - Phase-dependent activity of neurons in the rostral part of the thalamic reticular nucleus with saccharin intake in a cue-guided lever-manipulation task. AB - Neurons in the rostral part of the thalamic reticular nucleus (rTRN) receive somatosensory and motor information and regulate neural activities of the thalamic nuclei. Previous studies showed that when activity in visual TRN neurons is suppressed prior to the visual stimuli in a visual detection task, the performance of the task improves. However, little is known about such changes in the rTRN preceding certain events. In the present study, we performed unit recordings in the rTRN in alert rats during a cue-guided lever-manipulation task in which saccharin was provided as a reward. Changes in neural activity during saccharin intake were observed in 56% (51 of 91) of the recorded neurons; the firing rates increased in 21 neurons and decreased in 23 neurons. Seven neurons both increased and decreased their firing rates during saccharin intake. Changes in firing rates during the reward-waiting stage between task termination and saccharin intake were also observed in 73% (37 of 51) of the neurons that responded to saccharin intake. Increased activity during saccharin intake did not correlate with increased activity during lever-manipulation or activity during the reward-waiting stage. However, decreased activity during saccharin intake was correlated with activity during the reward-waiting stage. These results suggest that rTRN neurons have phase-dependent changes in their activity and regulate the thalamic activities. Furthermore, the decreased activity of rTRN neurons before reward may contribute to refine somatosensory and motor information processing in the thalamic nuclei depending on the status of mind such as expectation and attention. PMID- 28089664 TI - Neurotensin NTS1 and NTS2 receptor agonists produce anxiolytic-like effects in the 22-kHz ultrasonic vocalization model in rats. AB - Neurotensin is a neuropeptide neurotransmitter that interacts with multiple neurotransmitter systems, including those regulating amygdalar function, via NTS1 and NTS2 receptors. Both receptors are expressed in the amygdala and agonists for NTS1 or NTS2 receptors have exhibited anxiolytic effects in animal models. Systemic adminstration of NTS1 receptor agonist PD149163 was recently shown to reduce footshock conditioned 22-kHz ultrasonic vocalizations in rats, suggesting that PD149163 produced an anxiolytic effect. The effects that neurotensin may have or a selective NTS2 receptor agonist may have on 22-kHz vocalizations has yet to be examined. The current study evaluated the effects of intracerebroventricularly administered neurotensin (0.1-10.0MUg), PD149163 (0.1 10.0ng), or the NTS2 receptor agonist JMV-431 (0.1-1.0MUg) on footshock conditioned 22-kHz vocalizations in male Wistar rats. Neurotensin, PD149163, and JMV-431 all significantly reduced the number 22-kHz calls. No changes in call duration were found, suggesting that non-specific drug effects do not account for the reductions in 22-kHz calls. These data support anxiolytic effects produced by activation of NTS1 or NTS2 receptors, and suggest that neurotensin plays a natural role in the expression of conditioned USVs. These data suggest that both receptor subtypes are putative pharmacologic targets. PMID- 28089665 TI - Dissociation of morphine analgesic effects in the sensory and affective components of formalin-induced spontaneous pain in male and female rats. AB - Sex differences in the analgesic effects of morphine have been previously reported in various models that represent the sensory component of pain. However, pain sensation is a complex process that consists of both sensory and affective components. It is presently unclear whether the analgesic effects of morphine between the sensory and affective components of pain are sexually dimorphic. Moreover, differences in morphine dose-response in the two components of pain have not been examined in male and female rats. Therefore, we examined the analgesic effects of morphine on the sensory and affective components of formalin induced pain behaviors in male and female rats. To discern the sensory component, rats were pretreated with varying doses of morphine and then intraplantar formalin-induced paw flinches were measured. Morphine reduced the number of formalin-induced paw flinches at a treatment dose of 4.0mg/kg. Morphine analgesia was similar across the sexes in the early (phase 1) and late phase (phase 2) of the formalin test. To examine the affective component, rats were pretreated with varying doses of morphine, and then intraplantar formalin-induced conditioned place aversion (CPA) was examined. Formalin produced CPA, which was blocked by morphine at doses of 1.0mg/kg and higher in male and female rats. Lastly, formalin-induced cFos expression and the effects of systemic morphine were examined in the superficial dorsal horn of the spinal cord. Intraplantar formalin produced robust expression of cFos; however, morphine did not attenuate the cFos expression. These results demonstrate a notable dissociation of the analgesic effects of morphine by detecting a fourfold shift in the minimum effective dose between the sensory and affective components of formalin-induced spontaneous pain, that were similar between male and female rats. The findings further suggest disparate mechanisms involved in systemic morphine-induced analgesia in the two components of formalin-induced pain. PMID- 28089666 TI - Mini-open oblique lumbar interbody fusion (OLIF) approach for multi-level discectomy and fusion involving L5-S1: Preliminary experience. AB - STUDY DESIGN: Technical description and single institution retrospective case series. OBJECTIVE: Evaluate technical feasibility and evaluate complications of mini-open retroperitoneal oblique lumbar interbody fusion (OLIF) at the L5-S1 level. SUMMARY OF BACKGROUND: The mini-open retroperitoneal oblique lumbar interbody fusion (OLIF) approach was first described in 2012 as a surgical approach to achieve spinal fusion while limiting invasiveness of the exposure to the anterior lumbar spine. Surgeons who use this approach, along with those who described it in cadaveric studies describe it as a feasible approach in targeting the L2 down to the L5 level and recommend alternative approaches to the L5-S1 level due to the vascular challenges and possible complications. METHODS: Technical description and single institution case series of patients treated with the OLIF between 2013 and 2015 at the L5-S1 level. The previously described surgical approach was modified by identifying and ligating the iliolumbar vein before retracting the iliac artery and vein anteriorly instead of passing between the vessels. RESULTS: Six patients (3 males, 3 females, mean age 62 years) were operated between 2013 and 2015. There were no vascular injuries or peripheral nerve trauma associated with the surgical procedure. Complications associated with the procedure included: cage displacement immediately postoperative requiring re-operation in one patient, transient psoas weakness in one patient, extended hospital stay for pain control in one patient, and transfusion was required in one patient. CONCLUSIONS: Mini-open retroperitoneal oblique lumbar interbody fusion is feasible at the L5-S1 level with limited vascular complications through a technical modification for safe mobilization of the iliac vessels by first ligating the iliolumbar vein. PMID- 28089667 TI - Periprosthetic fractures of the distal femur after total knee arthroplasty : Plate versus nail fixation. AB - : The incidence of periprosthetic fractures about a TKA is increasing. Traditionally, these fractures are classified by their location and prosthesis integrity. In the setting of a supracondyar fracture about a well-fixed prosthesis, both plate and nail fixation of the fracture present themselves as options, each with unique benefits and pitfalls. Through review and discussion of the literature, we aim to describe some of the patient, fracture, and implant related factors that should be considered when planning fixation of periprosthetic fractures about a TKA. Additionally, we present several technical pearls that may be useful in the successful treatment of these difficult injuries. LEVEL OF EVIDENCE: 4. PMID- 28089668 TI - EBIO Does Not Induce Cardiomyogenesis in Human Pluripotent Stem Cells but Modulates Cardiac Subtype Enrichment by Lineage-Selective Survival. AB - Subtype-specific human cardiomyocytes (CMs) are valuable for basic and applied research. Induction of cardiomyogenesis and enrichment of nodal-like CMs was described for mouse pluripotent stem cells (mPSCs) in response to 1-ethyl-2 benzimidazolinone (EBIO), a chemical modulator of small-/intermediate-conductance Ca2+-activated potassium channels (SKs 1-4). Investigating EBIO in human pluripotent stem cells (PSCs), we have applied three independent differentiation protocols of low to high cardiomyogenic efficiency. Equivalent to mPSCs, timed EBIO supplementation during hPSC differentiation resulted in dose-dependent enrichment of up to 80% CMs, including an increase in nodal- and atrial-like phenotypes. However, our study revealed extensive EBIO-triggered cell loss favoring cardiac progenitor preservation and, subsequently, CMs with shortened action potentials. Proliferative cells were generally more sensitive to EBIO, presumably via an SK-independent mechanism. Together, EBIO did not promote cardiogenic differentiation of PSCs, opposing previous findings, but triggered lineage-selective survival at a cardiac progenitor stage, which we propose as a pharmacological strategy to modulate CM subtype composition. PMID- 28089669 TI - Exposure to GDNF Enhances the Ability of Enteric Neural Progenitors to Generate an Enteric Nervous System. AB - Cell therapy is a promising approach to generate an enteric nervous system (ENS) and treat enteric neuropathies. However, for translation to the clinic, it is highly likely that enteric neural progenitors will require manipulation prior to transplantation to enhance their ability to migrate and generate an ENS. In this study, we examine the effects of exposure to several factors on the ability of ENS progenitors, grown as enteric neurospheres, to migrate and generate an ENS. Exposure to glial-cell-line-derived neurotrophic factor (GDNF) resulted in a 14 fold increase in neurosphere volume and a 12-fold increase in cell number. Following co-culture with embryonic gut or transplantation into the colon of postnatal mice in vivo, cells derived from GDNF-treated neurospheres showed a 2 fold increase in the distance migrated compared with controls. Our data show that the ability of enteric neurospheres to generate an ENS can be enhanced by exposure to appropriate factors. PMID- 28089670 TI - In Vitro Propagation and Branching Morphogenesis from Single Ureteric Bud Cells. AB - A method to maintain and rebuild ureteric bud (UB)-like structures from UB cells in vitro could provide a useful tool for kidney regeneration. We aimed in our present study to establish a serum-free culture system that enables the expansion of UB progenitor cells, i.e., UB tip cells, and reconstruction of UB-like structures. We found that fibroblast growth factors or retinoic acid (RA) was sufficient for the survival of UB cells in serum-free condition, while the proliferation and maintenance of UB tip cells required glial cell-derived neurotrophic factor together with signaling from either WNT-beta-catenin pathway or RA. The activation of WNT-beta-catenin signaling in UB cells by endogenous WNT proteins required R-spondins. Together with Rho kinase inhibitor, our culture system facilitated the expansion of UB tip cells to form UB-like structures from dispersed single cells. The UB-like structures thus formed retained the original UB characteristics and integrated into the native embryonic kidneys. PMID- 28089671 TI - PDGFRalpha+ Cells in Embryonic Stem Cell Cultures Represent the In Vitro Equivalent of the Pre-implantation Primitive Endoderm Precursors. AB - In early mouse pre-implantation development, primitive endoderm (PrE) precursors are platelet-derived growth factor receptor alpha (PDGFRalpha) positive. Here, we demonstrated that cultured mouse embryonic stem cells (mESCs) express PDGFRalpha heterogeneously, fluctuating between a PDGFRalpha+ (PrE-primed) and a platelet endothelial cell adhesion molecule 1 (PECAM1)-positive state (epiblast-primed). The two surface markers can be co-detected on a third subpopulation, expressing epiblast and PrE determinants (double-positive). In vitro, these subpopulations differ in their self-renewal and differentiation capability, transcriptional and epigenetic states. In vivo, double-positive cells contributed to epiblast and PrE, while PrE-primed cells exclusively contributed to PrE derivatives. The transcriptome of PDGFRalpha+ subpopulations differs from previously described subpopulations and shows similarities with early/mid blastocyst cells. The heterogeneity did not depend on PDGFRalpha but on leukemia inhibitory factor and fibroblast growth factor signaling and DNA methylation. Thus, PDGFRalpha+ cells represent the in vitro counterpart of in vivo PrE precursors, and their selection from cultured mESCs yields pure PrE precursors. PMID- 28089673 TI - The value of participatory development to support antimicrobial stewardship with a clinical decision support system. AB - BACKGROUND: Current clinical decision support systems (CDSSs) for antimicrobial stewardship programs (ASPs) are guideline- or expert-driven. They are focused on (clinical) content, not on supporting real-time workflow. Thus, CDSSs fail to optimally support prudent antimicrobial prescribing in daily practice. Our aim was to demonstrate why and how participatory development (involving end-users and other stakeholders) can contribute to the success of CDSSs in ASPs. METHODS: A mixed-methods approach was applied, combining scenario-based prototype evaluations (to support verbalization of work processes and out-of-the-box thinking) among 6 medical resident physicians with an online questionnaire (to cross-reference findings of the prototype evaluations) among 54 Dutch physicians. RESULTS: The prototype evaluations resulted in insight into the end-users and their way of working, as well as their needs and expectations. The online questionnaire that was distributed among a larger group of medical specialists, including lung and infection experts, complemented the findings of the prototype evaluations. It revealed a say/do problem concerning the unrecognized need of support for selecting diagnostic tests. CONCLUSIONS: Low-fidelity prototypes of a technology allow researchers to get to know the end-users, their way of working, and their work context. Involving experts allows technology developers to continuously check the fit between technology and clinical practice. The combination enables the participatory development of technology to successfully support ASPs. PMID- 28089672 TI - Isopropyl alcohol is as efficient as chlorhexidine to prevent contamination of blood cultures. AB - BACKGROUND: False-positive blood cultures can lead to unnecessary risks and misuse of antibiotics; to reduce rates of false-positives, it would be useful to determine whether use of an antiseptic with a prolonged effect is required. METHODS: Clinical study of efficacy (blinded and randomized) to compare the rate of blood culture contamination when skin antisepsis was performed with 70% isopropyl alcohol or 2% chlorhexidine gluconate in 70% isopropyl alcohol in 2 hospitals. Patients aged 16 years or older with suspected bloodstream infection who were allocated in the emergency room, internal medicine ward, or intensive care unit were included. RESULTS: Five of 563 (0.9%) blood cultures from the isopropyl arm and 10 of 539 (1.9%) from the chlorhexidine arm were contaminated. No significant differences were observed among the rate of contamination (chi2=1.27; P = .3) or the relative risk of contamination (relative risk = 2.09; 95% confidence interval, 0.72-6.07; P = .2). CONCLUSIONS: The rates of blood contamination were not different when isopropyl alcohol and chlorhexidine were compared. Isopropyl alcohol could be used for skin antisepsis before blood collection. PMID- 28089674 TI - Assessment of ventilator-associated events using the geometric distribution. AB - Hospital-acquired rare events, such as nosocomial infections and other low occurring incidents, in the clinical environment are difficult to monitor using traditional quality indicators. Using the Centers for Disease Control and Prevention definition of ventilator-associated events, we demonstrate an alternative method for assessment of rare events. PMID- 28089675 TI - Burden of Clostridium difficile infection: Associated hospitalization in a cohort of middle-aged and older adults. AB - BACKGROUND: Clostridium difficile is the principal cause of infectious diarrhea in hospitalized patients. The aim of this study was to describe and compare length of stay (LOS), costs, and in-hospital deaths for C difficile infection (CDI) and non-CDI hospitalizations, in a cohort of middle-aged and older Australians. METHODS: We used survey data from the 45 and Up Study, linked to hospitalization and death data. We calculated the average LOS and costs per hospitalization, and the proportion of in-hospital deaths for CDI and non-CDI hospitalizations. We then compared hospitalizations with CDI as a secondary diagnosis to non-CDI hospitalizations by stratifying hospitalizations based on principal diagnosis and then using generalized linear models to compare LOS and in-hospital costs, and logistic regression for in-hospital deaths, adjusting for age and sex. RESULTS: There were 641 CDI hospitalizations during 2006-2012. The average LOS was 17 days; the average cost per hospitalization was AUD 12,704; and in 7.3% of admissions (47 out of 641) the patient died. After adjusting for age and sex, hospitalizations with CDI were associated with longer LOS, higher costs, and a greater proportion of in-hospital deaths compared with hospitalizations with similar principal diagnosis but without CDI. CONCLUSIONS: CDI places additional burden on the Australian hospital system, with CDI patients having relatively lengthy hospital stays and high costs. PMID- 28089677 TI - Global signal regression acts as a temporal downweighting process in resting state fMRI. AB - In resting-state functional MRI (rsfMRI), the correlation between blood oxygenation level dependent (BOLD) signals across different brain regions is used to estimate the functional connectivity of the brain. This approach has led to the identification of a number of resting-state networks, including the default mode network (DMN) and the task positive network (TPN). Global signal regression (GSR) is a widely used pre-processing step in rsfMRI that has been shown to improve the spatial specificity of the estimated resting-state networks. In GSR, a whole brain average time series, known as the global signal (GS), is regressed out of each voxel time series prior to the computation of the correlations. However, the use of GSR is controversial because it can introduce artifactual negative correlations. For example, it has been argued that anticorrelations observed between the DMN and TPN are primarily an artifact of GSR. Despite the concerns about GSR, there is currently no consensus regarding its use. In this paper, we introduce a new framework for understanding the effects of GSR. In particular, we show that the main effects of GSR can be well approximated as a temporal downweighting process in which the data from time points with relatively large GS magnitudes are greatly attenuated while data from time points with relatively small GS magnitudes are largely unaffected. Furthermore, we show that a limiting case of this downweighting process in which data from time points with large GS magnitudes are censored can also approximate the effects of GSR. In other words, the correlation maps obtained after GSR show a high degree of spatial similarity (including the presence of anticorrelations between the DMN and TPN) with maps obtained using only the uncensored (i.e. retained) time points. Since the data from these retained time points are unaffected by the censoring process, this finding suggests that the observed anticorrelations inherently exist in the data from time points with small GS magnitudes and are not simply an artifact of GSR. PMID- 28089676 TI - Multimodal evaluation of the amygdala's functional connectivity. AB - The amygdala is one of the most extensively studied human brain regions and undisputedly plays a central role in many psychiatric disorders. However, an outstanding question is whether connectivity of amygdala subregions, specifically the centromedial (CM), laterobasal (LB) and superficial (SF) nuclei, are modulated by brain state (i.e., task vs. rest). Here, using a multimodal approach, we directly compared meta-analytic connectivity modeling (MACM) and specific co-activation likelihood estimation (SCALE)-derived estimates of CM, LB and SF task-based co-activation to the functional connectivity of these nuclei as assessed by resting state fmri (rs-fmri). Finally, using a preexisting resting state functional connectivity-derived cortical parcellation, we examined both MACM and rs-fmri amygdala subregion connectivity with 17 large-scale networks, to explicitly address how the amygdala interacts with other large-scale neural networks. Analyses revealed strong differentiation of CM, LB and SF connectivity patterns with other brain regions, both in task-dependent and task-independent contexts. All three regions, however, showed convergent connectivity with the right ventrolateral prefrontal cortex (VLPFC) that was not driven by high base rate levels of activation. Similar patterns of connectivity across rs-fmri and MACM were observed for each subregion, suggesting a similar network architecture of amygdala connectivity with the rest of the brain across tasks and resting state for each subregion, that may be modified in the context of specific task demands. These findings support animal models that posit a parallel model of amygdala functioning, but importantly, also modify this position to suggest integrative processing in the amygdala. PMID- 28089678 TI - Reduced effects of age on dopamine D2 receptor levels in physically active adults. AB - Physical activity has been shown to ameliorate dopaminergic degeneration in non human animal models. However, the effects of regular physical activity on normal age-related changes in dopamine function in humans are unknown. Here we present cross-sectional data from forty-four healthy human subjects between 23 and 80 years old, showing that typical age-related dopamine D2 receptor loss, assessed with PET [18F]fallypride, was significantly reduced in physically active adults compared to less active adults. PMID- 28089679 TI - Efficacy and Toxicity of Intravitreous Chemotherapy for Retinoblastoma: Four-Year Experience. AB - PURPOSE: To investigate the efficacy and toxicity of intravitreous melphalan for treatment of retinoblastoma, as a single agent or with concomitant topotecan. PARTICIPANTS: A total of 130 eyes of 120 patients with retinoblastoma receiving 630 intravitreous (melphalan, topotecan) or topotecan periocular injections. A total of 83 (64%) of these eyes were treated with concomitant ophthalmic artery chemosurgery (OAC). DESIGN: Retrospective cohort study. METHODS: Indirect ophthalmoscopy and clinical imaging were used to evaluate clinical response. Ocular survival and disease-free survival were estimated using Kaplan-Meier methods in 130 eyes. Ocular toxicity was evaluated by clinical findings and electroretinography (ERG) on 244 evaluable injections in 63 patients using 30-Hz flicker responses. Analysis was performed using linear mixed effects models with a random intercept and slope for each patient and a fixed effect for number of injections, in addition to any other fixed effect of interest. MAIN OUTCOME MEASURES: Ocular survival, disease-free survival, ERG: peak-to-peak ERG amplitudes in response to 30-Hz photopic flicker stimulation. RESULTS: There were no disease- or treatment-related deaths, and no patient developed externalization of tumor or metastatic disease. Two-year Kaplan-Meier estimates of ocular survival and disease-free survival were 94.2% (95% confidence interval, 89.2 99.4) and 86.2% (95% confidence interval, 78.7-94.5), respectively. There was a significant association between the number of injections and diminished ERG responses, such that on average each intravitreous melphalan injection was associated with a 5.3-MUV decrease in ERG amplitude (P < 0.001). Concomitant intra-arterial chemotherapy (P = 0.01) and greater inherent ocular pigment also were significantly associated with a reduction in ERG (P = 0.045). Patient age and weight, new injection site location, addition of topotecan, concomitant focal treatment, and time interval between injections were not significantly associated with toxicity. CONCLUSIONS: Intravitreous melphalan is an effective treatment for vitreous seeding in retinoblastoma, resulting in high rates of ocular survival and disease-free survival. However, in this study, each injection of melphalan was associated, on average, with a decrement in ERG response. The findings suggest increased toxicity (1) when OAC is given within 1 week of the intravitreous injection and (2) in more deeply pigmented eyes. PMID- 28089680 TI - Peripheral Retinal Changes Associated with Age-Related Macular Degeneration in the Age-Related Eye Disease Study 2: Age-Related Eye Disease Study 2 Report Number 12 by the Age-Related Eye Disease Study 2 Optos PEripheral RetinA (OPERA) Study Research Group. AB - PURPOSE: To compare rates of peripheral retinal changes in Age-Related Eye Disease Study 2 (AREDS2) participants with at least intermediate age-related macular degeneration (AMD) with control subjects without intermediate age-related changes (large drusen). DESIGN: Cross-sectional evaluation of clinic-based patients enrolled in AREDS2 and a prospective study. PARTICIPANTS: Participants from prospective studies. METHODS: The 200 degrees pseudocolor and fundus autofluorescence (FAF) images were captured on the Optos 200 Tx Ultrawide-field device (Optos, Dunfermline, Scotland) by centering on the fovea and then steering superiorly and inferiorly. The montaged images were graded at a reading center with the images divided into 3 zones (zone 1 [posterior pole], zone 2 [midperiphery], and zone 3 [far periphery]) to document the presence of peripheral lesions. MAIN OUTCOME MEASURES: Peripheral retinal lesions: drusen, hypopigmentary/hyperpigmentary changes, reticular pseudodrusen, senile reticular pigmentary changes, cobblestone degeneration, and FAF abnormalities. RESULTS: A total of 484 (951 eyes) AREDS2 participants with AMD (cases) and 89 (163 eyes) controls without AMD had gradable color and FAF images. In zones 2 and 3, neovascularization and geographic atrophy (GA) were present, ranging from 0.4% to 6% in eyes of cases, respectively, and GA was present in 1% of eyes of controls. Drusen were detected in 97%, 78%, and 64% of eyes of cases and 48%, 21%, and 9% of eyes of controls in zones 2 and 3 superior and 3 inferior, respectively (P < 0.001 for all). Peripheral reticular pseudodrusen were seen in 15%. Senile reticular pigmentary change was the predominant peripheral change seen in 48% of cases and 16% of controls in zone 2 (P < 0.001). Nonreticular pigment changes were less frequent in the periphery than in the posterior pole (46% vs. 76%) and negligible in controls. CONCLUSIONS: Peripheral retinal changes are more prevalent in eyes with AMD than in control eyes. Drusen are seen in a majority of eyes with AMD in both the mid and far periphery, whereas pigment changes and features of advanced AMD are less frequent. Age-related macular degeneration may be more than a "macular" condition but one that involves the entire retina. Future longitudinal studies of peripheral changes in AMD and their impact on visual function may contribute to understanding AMD pathogenesis. PMID- 28089681 TI - Steatorrhea and Hyperoxaluria in Severely Obese Patients Before and After Roux-en Y Gastric Bypass. AB - BACKGROUND AND AIMS: Hyperoxaluria after Roux-en-Y gastric bypass (RYGB) is generally attributed to fat malabsorption. If hyperoxaluria is indeed caused by fat malabsorption, magnitudes of hyperoxaluria and steatorrhea should correlate. Severely obese patients, prior to bypass, ingest excess dietary fat that can produce hyperphagic steatorrhea. The primary objective of the study was to determine whether urine oxalate excretion correlates with elements of fat balance in severely obese patients before and after RYGB. METHODS: Fat balance and urine oxalate excretion were measured simultaneously in 26 severely obese patients before and 1 year after RYGB, while patients consumed their usual diet. At these time points, stool and urine samples were collected. Steatorrhea and hyperoxaluria were defined as fecal fat >7 g/day and urine oxalate >40 mg/day. Differences were evaluated using paired 2-tailed t tests. RESULTS: Prior to RYGB, 12 of 26 patients had mild to moderate steatorrhea. Average urine oxalate excretion was 61 mg/day; there was no correlation between fecal fat and urine oxalate excretion. After RYGB, 24 of 26 patients had steatorrhea and urine oxalate excretion averaged 69 mg/day, with a positive correlation between fecal fat and urine oxalate excretions (r = 0.71, P < .001). For each 10 g/day increase in fecal fat output, fecal water excretion increased only 46 mL/day. CONCLUSIONS: Steatorrhea and hyperoxaluria were common in obese patients before bypass, but hyperoxaluria was not caused by excess unabsorbed fatty acids. Hyperphagia, obesity, or metabolic syndrome could have produced this previously unrecognized hyperoxaluric state by stimulating absorption or endogenous synthesis of oxalate. Hyperoxaluria after RYGB correlated with steatorrhea and was presumably caused by excess fatty acids in the intestinal lumen. Because post-bypass steatorrhea caused little increase in fecal water excretion, most patients with steatorrhea did not consider themselves to have diarrhea. Before and after RYGB, high oxalate intake contributed to the severity of hyperoxaluria. PMID- 28089682 TI - Prevalence and Risk of Inflammatory Bowel Disease in Patients with Hidradenitis Suppurativa. AB - Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease. In small studies, inflammatory bowel disease has been associated with the increased prevalence of HS, but the data on the concurrence of inflammatory bowel disease in patients with HS are limited. We therefore investigated the prevalence and risk of inflammatory bowel disease in patients with HS compared with the general population. The study linked all Danish individuals aged >=18 years in nationwide registers. Adjusted odds ratios and adjusted hazard ratios were estimated by logistic regression and Cox regression, respectively. The study comprised 7,732 patients with HS and 4,354,137 subjects from the general population. The prevalence (HS vs. general population) was 0.8% and 0.3% (odds ratio 2.04; 1.59 2.62) for Crohn's disease and 1.3% and 0.7% (odds ratio 1.75; 1.44-2.13) for ulcerative colitis. The risk of new-onset Crohn's disease (hazard ratio 2.19; 1.44-3.34) and ulcerative colitis (hazard ratio 1.63; 1.18-2.27) was significantly increased among patients with HS. In conclusion, HS was significantly associated with the presence and risk of new-onset inflammatory bowel disease, although the prevalence remained low. Gastrointestinal complaints in patients with HS should warrant further clinical examination. PMID- 28089683 TI - Coupling of Homologous Recombination and the Checkpoint by ATR. AB - ATR is a key regulator of cell-cycle checkpoints and homologous recombination (HR). Paradoxically, ATR inhibits CDKs during checkpoint responses, but CDK activity is required for efficient HR. Here, we show that ATR promotes HR after CDK-driven DNA end resection. ATR stimulates the BRCA1-PALB2 interaction after DNA damage and promotes PALB2 localization to DNA damage sites. ATR enhances BRCA1-PALB2 binding at least in part by inhibiting CDKs. The optimal interaction of BRCA1 and PALB2 requires phosphorylation of PALB2 at S59, an ATR site, and hypo-phosphorylation of S64, a CDK site. The PALB2-S59A/S64E mutant is defective for localization to DNA damage sites and HR, whereas the PALB2-S59E/S64A mutant partially bypasses ATR for its localization. Thus, HR is a biphasic process requiring both high-CDK and low-CDK periods. As exemplified by the regulation of PALB2 by ATR, ATR promotes HR by orchestrating a "CDK-to-ATR switch" post resection, directly coupling the checkpoint to HR. PMID- 28089685 TI - Evaluation of Drug-Drug Interaction Potential Between Sacubitril/Valsartan (LCZ696) and Statins Using a Physiologically Based Pharmacokinetic Model. AB - Sacubitril/valsartan (LCZ696) has been approved for the treatment of heart failure. Sacubitril is an in vitro inhibitor of organic anion-transporting polypeptides (OATPs). In clinical studies, LCZ696 increased atorvastatin Cmax by 1.7-fold and area under the plasma concentration-time curve by 1.3-fold, but had little or no effect on simvastatin or simvastatin acid exposure. A physiologically based pharmacokinetics modeling approach was applied to explore the underlying mechanisms behind the statin-specific LCZ696 drug interaction observations. The model incorporated OATP-mediated clearance (CLint,T) for simvastatin and simvastatin acid to successfully describe the pharmacokinetic profiles of either analyte in the absence or presence of LCZ696. Moreover, the model successfully described the clinically observed drug effect with atorvastatin. The simulations clarified the critical parameters responsible for the observation of a low, yet clinically relevant, drug-drug interaction DDI between sacubitril and atorvastatin and the lack of effect with simvastatin acid. Atorvastatin is administered in its active form and rapidly achieves Cmax that coincide with the low Cmax of sacubitril. In contrast, simvastatin requires a hydrolysis step to the acid form and therefore is not present at the site of interactions at sacubitril concentrations that are inhibitory. Similar models were used to evaluate the drug-drug interaction risk for additional OATP transported statins which predicted to maximally result in a 1.5-fold exposure increase. PMID- 28089684 TI - Impact of Cystectomy on Ovarian Reserve: Review of the Literature. AB - Ovarian cysts are common in the reproductive age. Pathologic cysts such as endometriomas and dermoids often require surgical intervention if symptomatic. Laparoscopic cystectomy is the first-line treatment for these cysts and is associated with better pain control and less recurrence than drainage or cyst ablation procedures. There has been an emerging concern about the effect of ovarian cystectomy on ovarian reserve with some evidence of short-term and long term reduction in ovarian reserve. Certain cyst characteristics (endometrioma pathology, large cyst size, bilateral presentation) are associated with a greater decline in ovarian reserve after cystectomy. The impact of surgery on ovarian reserve can be minimized by selecting the appropriate surgery for the patient, careful tissue handling, and limited use of electrosurgery. Patients should be counseled on the risks of surgery on reproductive potential, and the management plan should be individualized to the patient's symptoms and reproductive goals. PMID- 28089686 TI - Simulations of Cytochrome P450 3A4-Mediated Drug-Drug Interactions by Simple Two Compartment Model-Assisted Static Method. AB - In order to predict cytochrome P450 3A4 (CYP3A4)-mediated drug-drug interactions (DDIs), a simple 2-compartment model-assisted, overall inhibition activity (Ai,overall) method was derived based on 2 concepts. One concept was that the increase in blood victim level and fold increase in the area under the blood victim level curve produced by DDI are determined entirely by Ai,overall, the hepatic availability of the victim and fraction of urinary excreted unchanged victim, where Ai,overall is determined by the perpetrator-specific CYP isoform inhibition activities (Ai,CYPs, DDI predictor-1) and victim-specific fractional CYP isoform contributions (fm,CYPs, predictor-2). The other concept was that a DDI can be bridged to other DDIs, so that any possible DDI produced by a given victim or a given perpetrator can be predicted by using these predictors. The Ai,CYP3A4s of 12 common CYP3A4 inhibitors were able to be determined and shown to be useful for the prediction of CYP3A4-mediated DDIs wherein victims were metabolized by multiple CYP isoforms. Additionally, it was demonstrated that fm,CYP values with high confidence can be estimated by bridging DDIs produced by the same victim and different perpetrators. This bridging approach will accelerate prediction of DDIs produced by new chemical entities from the existing DDI database. PMID- 28089687 TI - Stabilizing Effects for Antibody Formulations and Safety Profiles of Cyclodextrin Polypseudorotaxane Hydrogels. AB - Antibodies often have poor physicochemical stability during storage and transport, which is a serious drawback for the development of antibody-based drugs. In this study, we prepared polypseudorotaxane (PPRX) hydrogels consisting of cyclodextrins (CyDs) and polyethylene glycol, and evaluated them as stabilizers for commercially available antibody-based drugs. alpha-CyD and gamma CyD formed PPRX hydrogels with polyethylene glycol (molecular weight 20,000 Da) in the presence of antibody-based drugs such as omalizumab, palivizumab, panitumumab, and ranibizumab. Importantly, both alpha- and gamma-CyD PPRX hydrogel formulations provided high stabilizing effects (ca. 100%) to the all antibody-based drugs used in this study. Furthermore, approximately 100% of the binding activity of omalizumab to the immunoglobulin E receptor was retained after the release from the hydrogels. Plasma levels of omalizumab after subcutaneous injection of the gamma-CyD PPRX hydrogel to rats were equivalent to those of omalizumab alone. According to the results of blood chemistry tests, the weights of organs and histological observations alpha- and gamma-CyD PPRX hydrogels induced no serious adverse effects. These results suggest that CyD PPRX hydrogels are useful as safe and promising stabilizing formulations for antibody based drugs. PMID- 28089688 TI - Functional Identification of Plasma Membrane Monoamine Transporter (PMAT/SLC29A4) as an Atenolol Transporter Sensitive to Flavonoids Contained in Apple Juice. AB - The intestinal absorption of atenolol has recently been reported to be reduced by simultaneous ingestion of fruit juices, such as apple juice. This finding implies a possibility that an unidentified carrier-mediated transport system, which could be interfered by some components of those juices, might be involved in atenolol absorption. In an attempt to explore that possibility, we successfully identified plasma membrane monoamine transporter (PMAT/SLC29A4) as a transporter that can operate for cellular atenolol uptake in the intestine, using Madin-Darby canine kidney II cells stably expressing PMAT. The specific uptake of atenolol by PMAT was greatest at around pH 6.0 and decreased with an increase in pH. At pH 6.0, the PMAT-specific uptake of atenolol was saturable with a Michaelis constant of 0.907 mM. Moreover, PMAT-specific atenolol uptake was extensively inhibited by phloretin and quercetin, which are the major flavonoids contained in apple juice, with the half maximal inhibitory concentrations of 33.3 and 116.3 MUM, respectively. PMAT-specific atenolol uptake was also inhibited by several beta blockers, suggesting that they may also be recognized and transported by PMAT. These results suggest that PMAT is an atenolol transporter that may be involved in intestinal atenolol absorption and sensitive to flavonoids contained in apple juice. PMID- 28089690 TI - MRI Evaluation of Rectal Cancer: Staging and Restaging. AB - Magnetic resonance imaging (MRI) plays an important role in the staging and restaging of rectal cancer. Multiplanar high-resolution (<=3-mm section thickness) T2-weighted images are the primary sequences used for rectal cancer staging. No preprocedural bowel cleansing regimen, intravenous contrast material, nor endorectal coil is necessary. MRI is highly accurate for differentiating T1 T2 disease from T3 and T4 disease, an important distinction as patients with T3 and T4 tumors typically undergo preoperative neoadjuvant chemoradiation before resection. At MRI, the muscularis propria appears as a thin black line encircling the outer wall of the rectum, and tumor extension through this line indicates T3 disease. Further tumor extension into adjacent organs indicates T4 disease. Endorectal ultrasound is generally preferred to differentiate T1 (submucosal involvement) from T2 (extension into but no disruption of muscularis propria) disease. MRI is also accurate in the assessment of tumor involvement of the mesorectal fascia. Tumor involvement of the mesorectal fascia increases the likelihood of recurrence following resection. MRI is less accurate for determination of lymph node status, though heterogeneous signal intensity and irregular margins are suggestive of node positive disease. Approximately 10%-30% of patients who undergo preoperative chemoradiation experience a complete pathologic response that is defined as no residual tumor found at histopathologic analysis of the resected specimen. The addition of diffusion-weighted images to T2-weighted images improves the accuracy of restaging examinations for determination of complete pathologic responders. PMID- 28089691 TI - Orcokinin neuropeptides regulate ecdysis in the hemimetabolous insect Rhodnius prolixus. AB - To grow and develop insects must undergo ecdysis. During this process, the individual sheds the old cuticle to emerge as the following developmental stage. During ecdysis, different programed behaviors are regulated by neuropeptidergic pathways. In general, components of these pathways are better characterized in crustacean and holometabolous insects than in hemimetabola. In insects, the orkoninin gene produces two different neuropeptide precursors by alternative splicing: orcokinin A and orcokinin B. Although orcokinins are well conserved in insect species, their physiological role remains elusive. Here we describe a new splicing variant of the orcokinin gene in the hemimetabolous triatomine Rhodnius prolixus. We further analyze the expression pattern and the function of the alternatively spliced RhoprOK transcripts by means of immunohistochemistry and RNAi-mediated gene silencing. Our results indicate that orkoninis play an essential role in the peptidergic signaling pathway regulating ecdysis in the hemimetabolous insect Rhodnius prolixus. PMID- 28089692 TI - In vitro bioaccessibility of the marine biotoxins okadaic acid, dinophysistoxin-2 and their 7-O-acyl fatty acid ester derivatives in raw and steamed shellfish. AB - Okadaic acid (OA), Dinophysistoxins (DTX1 and DTX2) and their acyl-derivatives (DTX3) are marine toxins responsible for the human diarrhetic shellfish poisoning. To date the amount of toxins ingested from consumption of shellfish has been considered equal to the amount of toxins available for uptake by the human body. The aim of this study is to assess the OA, DTX2 and DTX3 fractions released from raw and steamed mussels and cockles into the digestive fluids (bioaccessibility) using a static in vitro digestion model. Higher bioaccessibility was found in mussels (86 +/- 4%) than in cockles (59 +/- 9%). A significant reduction of ester derivatives of OA and an increase of OA were observed in the bioaccessible fraction of mussel samples, suggesting that DTX3 undergo conversion into their more toxic parent compounds during human digestion. However, similar increase of DTX2 and reduction of the respective acyl derivatives was not observed. Steaming lead to significant reduction of OA and analogues bioaccessibility in both species even though increased concentrations of toxins are obtained after this treatment. Risk assessment based solely on DSP toxins occurrence in seafood can conduct to an overestimation of the exposure and lead to more conservative regulatory measures. PMID- 28089689 TI - Piecing it together: Unraveling the elusive structure-function relationship in single-pass membrane receptors. AB - The challenge of crystallizing single-pass plasma membrane receptors has remained an obstacle to understanding the structural mechanisms that connect extracellular ligand binding to cytosolic activation. For example, the complex interplay between receptor oligomerization and conformational dynamics has been, historically, only inferred from static structures of isolated receptor domains. A fundamental challenge in the field of membrane receptor biology, then, has been to integrate experimentally observable dynamics of full-length receptors (e.g. diffusion and conformational flexibility) into static structural models of the disparate domains. In certain receptor families, e.g. the ErbB receptors, structures have led somewhat linearly to a putative model of activation. In other families, e.g. the tumor necrosis factor (TNF) receptors, structures have produced divergent hypothetical mechanisms of activation and transduction. Here, we discuss in detail these and other related receptors, with the goal of illuminating the current challenges and opportunities in building comprehensive models of single-pass receptor activation. The deepening understanding of these receptors has recently been accelerated by new experimental and computational tools that offer orthogonal perspectives on both structure and dynamics. As such, this review aims to contextualize those technological developments as we highlight the elegant and complex conformational communication between receptor domains. This article is part of a Special Issue entitled: Interactions between membrane receptors in cellular membranes edited by Kalina Hristova. PMID- 28089693 TI - Effects of six priority controlled phthalate esters with long-term low-dose integrated exposure on male reproductive toxicity in rats. AB - Human beings are inevitably exposed to ubiquitous phthalate esters (PEs) surroundings. The purposes of this study were to investigate the effects of long term low-dose exposure to the mixture of six priority controlled phthalate esters (MIXPs): dimethyl phthalate (DMP), diethyl phthalate (DEP), di(n-butyl) phthalate (DBP), butyl benzyl phthalate (BBP), di(2-ethyhexyl) phthalate (DEHP) and di-n octyl phthalate (DNOP), on male rat reproductive system and further to explore the underlying mechanisms of the reproductive toxicity. The male rats were orally exposed to either sodium carboxymethyl cellulose as controls or MIXPs at three different low-doses by gavage for 15 weeks. Testosterone and luteinizing hormone (LH) in serum were analyzed, and pathological examinations were performed for toxicity evaluation. Steroidogenic proteins (StAR, P450scc, CYP17A1 and 17beta HSD), cell cycle and apoptosis-related proteins (p53, Chk1, Cdc2, CDK6, Bcl-2 and Bax) were measured for mechanisms exploration. MIXPs with long-term low-dose exposure could cause male reproductive toxicity to the rats, including the decrease of both serum and testicular testosterone, and the constructional damage of testis. These effects were related to down-regulated steroidogenic proteins, arresting cell cycle progression and promoting apoptosis in rat testicular cells. The results indicate that MIXPs with long-term low-dose exposure may pose male reproductive toxicity in human. PMID- 28089694 TI - Affective and cognitive correlates of PTSD: Electrocortical processing of threat and perseverative errors on the WCST in combat-related PTSD. AB - PTSD is characterized by both affective and cognitive dysfunction. Affectively, PTSD is associated with both heightened emotional reactivity and disengagement. Cognitively, perseverative thinking is a core feature of the disorder. In order to assess the interactive effects of affective and cognitive correlates of PTSD symptoms, 47 OEF/OIF/OND veterans completed an emotional faces matching task while EEG (i.e., late positive potential; LPP) was recorded, and separately completed the Wisconsin Card Sorting Test (WCST) to assess perseverative errors. There was no relationship between PTSD symptoms and either perseverative errors or EEG reactivity to faces. However, an interaction was found such that high perseverative errors on the WCST and a relatively enhanced LPP to angry faces was associated with greater PTSD symptoms, while low errors on the WCST and a relatively blunted LPP to angry faces also related to greater PTSD symptoms. These findings suggest that emotion-cognition interactions are important for understanding PTSD, and that distinct emotion-cognition constellations interact with symptoms. PMID- 28089696 TI - Differential sensory cortical involvement in auditory and visual sensorimotor temporal recalibration: Evidence from transcranial direct current stimulation (tDCS). AB - Adaptation to delayed sensory feedback following an action produces a subjective time compression between the action and the feedback (temporal recalibration effect, TRE). TRE is important for sensory delay compensation to maintain a relationship between causally related events. It is unclear whether TRE is a sensory modality-specific phenomenon. In 3 experiments employing a sensorimotor synchronization task, we investigated this question using cathodal transcranial direct-current stimulation (tDCS). We found that cathodal tDCS over the visual cortex, and to a lesser extent over the auditory cortex, produced decreased visual TRE. However, both auditory and visual cortex tDCS did not produce any measurable effects on auditory TRE. Our study revealed different nature of TRE in auditory and visual domains. Visual-motor TRE, which is more variable than auditory TRE, is a sensory modality-specific phenomenon, modulated by the auditory cortex. The robustness of auditory-motor TRE, unaffected by tDCS, suggests the dominance of the auditory system in temporal processing, by providing a frame of reference in the realignment of sensorimotor timing signals. PMID- 28089695 TI - The pharmacology of tacrine at N-methyl-d-aspartate receptors. AB - The mechanism of tacrine as a precognitive drug has been considered to be complex and not fully understood. It has been reported to involve a wide spectrum of targets involving cholinergic, gabaergic, nitrinergic and glutamatergic pathways. Here, we review the effect of tacrine and its derivatives on the NMDA receptors (NMDAR) with a focus on the mechanism of action and biological consequences related to the Alzheimer's disease treatment. Our findings indicate that effect of tacrine on glutamatergic neurons is both direct and indirect. Direct NMDAR antagonistic effect is often reported by in vitro studies; however, it is achieved by high tacrine concentrations which are not likely to occur under clinical conditions. The impact on memory and behavioral testing can be ascribed to indirect effects of tacrine caused by influencing the NMDAR-mediated currents via M1 receptor activation, which leads to inhibition of Ca2+-activated potassium channels. Such inhibition prevents membrane repolarization leading to prolonged NMDAR activation and subsequently to long term potentiation. Considering these findings, we can conclude that tacrine-derivatives with dual cholinesterase and NMDARs modulating activity may represent a promising approach in the drug development for diseases associated with cognitive dysfunction, such as the Alzheimer disease. PMID- 28089697 TI - Effects of mild cognitive impairment on emotional scene memory. AB - Young and older adults experience benefits in attention and memory for emotional compared to neutral information, but this memory benefit is greatly diminished in Alzheimer's disease (AD). Little is known about whether this impairment arises early or late in the time course between healthy aging and AD. This study compared memory for positive, negative, and neutral items with neutral backgrounds between patients with mild cognitive impairment (MCI) and healthy older adults. We also used a divided attention condition in older adults as a possible model for the deficits observed in MCI patients. Results showed a similar pattern of selective memory for emotional items while forgetting their backgrounds in older adults and MCI patients, but MCI patients had poorer memory overall. Dividing attention during encoding disproportionately reduced memory for backgrounds (versus items) relative to a full attention condition. Participants performing in the lower half on the divided attention task qualitatively and quantitatively mirrored the results in MCI patients. Exploratory analyses comparing lower- and higher-performing MCI patients showed that only higher performing MCI patients had the characteristic scene memory pattern observed in healthy older adults. Together, these results suggest that the effects of emotion on memory are relatively well preserved for patients with MCI, although emotional memory patterns may start to be altered once memory deficits become more pronounced. PMID- 28089698 TI - Novel 2,4-dichlorophenoxy acetic acid substituted thiazolidin-4-ones as anti inflammatory agents: Design, synthesis and biological screening. AB - A library of fourteen 2-imino-4-thiazolidinone derivatives (1a-1n) has been synthesized and evaluated for in vivo anti-inflammatory activity and effect on ex vivo COX-2 and TNF-alpha expression. Compounds 1k (5-(2,4-dichloro-phenooxy) acetic acid (3-benzyl-4-oxo-thiazolidin-2-ylidene)-hydrazide) and 1m (5-(2,4 dichloro-phenooxy)-acetic acid (3-cyclohexyl-4-oxo-thiazolidin-2-ylidene) hydrazide) exhibited in vivo inhibition of 81.14% and 78.80% respectively after 5h in comparison to indomethacin which showed 76.36% inhibition of inflammation without causing any damage to the stomach. Compound 1k showed a reduction of 68.32% in the level of COX-2 as compared to the indomethacin which exhibited 66.23% inhibition of COX-2. The selectivity index of compound 1k was found to be 29.00 in comparison to indomethacin showing selectivity index of 0.476. Compounds 1k and 1m were also found to significantly suppress TNF-alpha concentration to 70.10% and 68.43% in comparison to indomethacin which exhibited 66.45% suppression. PMID- 28089699 TI - Investigation of piperazine benzamides as human beta3 adrenergic receptor agonists for the treatment of overactive bladder. AB - The synthesis of a novel class of piperazine benzamide (reverse amides) targeting the human beta3-adrenergic receptor for the treatment of overactive bladder (OAB) is described. The SAR studies directed towards maintaining well established beta3 potency and selectivities while improving the overall pharmacokinetic profile in the reverse amide class will be evaluated. The results and consequences associated with functional activity at the norepinephrine transporter (NET) will also be discussed. PMID- 28089700 TI - New synthetic route to ethynyl-dUTP: A means to avoid formation of acetyl and chloro vinyl base-modified triphosphates that could poison SELEX experiments. AB - 5-Ethynyl-2'-deoxyuridine is a common base-modified nucleoside analogue that has served in various applications including selection experiments for potent aptamers and in biosensing. The synthesis of the corresponding triphosphates involves a mild acidic deprotection step. Herein, we show that this deprotection leads to the formation of other nucleoside analogs which are easily converted to triphosphates. The modified nucleoside triphosphates are excellent substrates for numerous DNA polymerases under both primer extension and PCR conditions and could thus poison selection experiments by blocking sites that need to be further modified. The formation of these nucleoside analogs can be circumvented by application of a new synthetic route that is described herein. PMID- 28089701 TI - Functionalized triazines as potent HCV entry inhibitors. AB - A series of potent and novel acylsulfonamide-bearing triazines were synthesized and the structure-activity relationships (SARs) as HCV entry inhibitors were evaluated. This acylsulfonamide series was derived from an early lead, 4-(4-(1-(4 chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2 ylamino)benzoic acid wherein the carboxylic acid was replaced with an acylsulfonamide moiety. This structural modification provided a class of compounds which projected an additional vector off the terminus of the acylsulfonamide functionality as a means to drive activity. This effort led to the discovery of potent analogues within this series that demonstrated sub nanomolar EC50 values in the HCV pseudotype particle (HCVpp) assay. PMID- 28089702 TI - The visible burrow system: A view from across the hall. AB - The visible burrow system (VBS) is an ethologically relevant social stress model that creates a distinct dominance hierarchy in rats. Randall Sakai's laboratory performed an impressive series of studies documenting the very different impact of VBS exposure on the brain and behavior of dominants (DOM) and subordinates (SUBs). Hierarchy formation causes pronounced changes in metabolism in SUBs relative to both DOMs and unstressed controls, resulting in marked weight loss and metabolic imbalance. Stress testing revealed multiple phenotypes in the VBS, including DOMs, stress-responsive SUBs and stress-non-responsive SUBs. Stress responsive SUBs have adrenal hypertrophy and elevated baseline corticosterone, consistent with prolonged HPA axis activation; however, peak acute stress responses are not sensitized. In contrast, stress non-responsive individuals do not mount a response to an acute stress, suggesting HPA axis hypofunction. In brain, SUBs exhibit a pattern of gene regulation consistent with impaired stress inhibition (e.g., hippocampal adrenocorticosteroid receptor down-regulation and dendritic retraction) and drive of stress pathways (e.g., increased locus coeruleus tyrosine hydroxylase expression). The non-responsive phenotype is distinguished by down-regulation of paraventricular nucleus corticotropin releasing hormone expression and enhanced neuropeptide Y expression in amygdala. The brain 'signature' created by VBS hierarchy formation differed substantially from that of another well-studied chronic stress model (chronic variable stress). Thus, the impact of VBS is mediated by neurocircuit mechanisms at least in part distinct that of other chronic stress modalities, and suggests that the nature of the stressor may be an essential consideration in development of treatment strategies for stress-related diseases. PMID- 28089703 TI - To each its own? Gender differences in affective, autonomic, and behavioral responses to same-sex and opposite-sex visual sexual stimuli. AB - A large body of research on gender differences in response to erotic stimuli has focused on genital and/or subjective sexual arousal. On the other hand, studies assessing gender differences in emotional psychophysiological responding to sexual stimuli have only employed erotic pictures of male-female couples or female/male nudes. The present study aimed at investigating differences between gynephilic men and androphilic women in emotional responding to visual sexual stimuli depicting female-male, female-female and male-male couples. Affective responses were explored in multiple response systems, including autonomic indices of emotional activation, i.e., heart rate and skin conductance, along with standardized measures of valence and arousal. Blood pressure was measured as an index of autonomic activation associated with sexual arousal, and free viewing times as an index of interest/avoidance. Overall, men showed gender-specific activation characterized by clearly appetitive reactions to the target of their sexual attraction (i.e., women), with physiological arousal discriminating female female stimuli as the most effective sexual cues. In contrast, women's emotional activation to sexual stimuli was clearly non-specific in most of the considered variables, with the notable exception of the self-report measures. Overall, affective responses replicate patterns of gender-specific and gender-nonspecific sexual responses in gynephilic men and androphilic women. PMID- 28089704 TI - Brain mineralocorticoid receptor function in control of salt balance and stress adaptation. AB - We will highlight in honor of Randall Sakai the peculiar characteristics of the brain mineralocorticoid receptor (MR) in its response pattern to the classical mineralocorticoid aldosterone and the naturally occurring glucocorticoids corticosterone and cortisol. Neurons in the nucleus tractus solitarii (NTS) and circumventricular organs express MR, which mediate selectively the action of aldosterone on salt appetite, sympathetic outflow and volume regulation. The MR containing NTS neurons innervate limbic-forebrain circuits enabling aldosterone to also modulate reciprocally arousal, motivation, fear and reward. MR expressed in abundance in this limbic-forebrain circuitry, is target of cortisol and corticosterone in modulation of appraisal processes, memory performance and selection of coping strategy. Complementary to this role of limbic MR is the action mediated by the lower affinity glucocorticoid receptors (GR), which promote subsequently memory storage of the experience and facilitate behavioral adaptation. Current evidence supports the hypothesis that an imbalance between MR and GR-mediated actions compromises resilience and adaptation to stress. PMID- 28089705 TI - So as we worry we weigh: Visible burrow system stress and visceral adiposity. AB - The visible borrow system (VBS) simulates a natural rodent habitat that supports genuine stress provoking social interactions. This model allows investigation of behavioral, neural and endocrine alterations caused by chronic stress. The Sakai lab further used this model to investigate metabolic outcomes of stress in relation to dominance hierarchies formed within the VBS. Communal social conflict occurs among all VBS rats, but only the SUB rats succumb to the redistribution of lipids in the visceral cavity and consequent metabolic dysregulation, such as hyper-insulinemia. These increases in visceral adipose tissue occur after two cycles of VBS stress and recovery bouts and are associated with decreases in subcutaneous adipose tissue. Traditionally, distribution shift in lipid deposition is predominately thought to occur by characteristics specific to the visceral depot, but evidence supports that decreased subcutaneous adipose tissue deposition may be linked to enhanced visceral adipose expansion. This review will discuss VBS stress and redirection of adipose tissue in SUB rats. There will be specific focus on the enhanced adipogenic capacity of visceral adipose tissue as driven by glucocorticoid receptor density, 11-hydroxysteroid dehydrogenase type 1 (11-HSD1) and lipoprotein lipase (LPL). Additionally, the proposed contribution of decreased subcutaneous adipose expansion via stress-induced inhibition of lipid uptake, storage and cellularity will be discussed. Overall, this review will summarize how stress-induced visceral obesity may result from a combination of maladaptive responses within the visceral and subcutaneous depot. PMID- 28089707 TI - Understanding infant eating behaviour - Lessons learned from observation. AB - Observations of human infants during feeding presents a rich source of data to identify the ways in which hunger, appetite and satiety are communicated in early life. Infants signal appetite through their interest or disinterest in food using a series of communication cues from rapid and transient facial expressions to subtle or potent gestures and bodily movements through to vocalisations and eventually speech. Even in the first days of life facial expressions in response to basic tastes are clearly demonstrated and shared between human infants, other primates and the rat. These sensory typical reactions are said to have biological significance since the positive affective response to sweet taste secures a safe and useful source of energy whilst an aversive response to bitter may protect against toxicity. However, beyond these shared responses to basic tastes, the human infant has a sophisticated communication system to demonstrate readiness to eat, avid or waning appetite and satiety. Video capture and behavioural coding of infant communication and caregiver responses during meals reveal the dynamic nature of mealtime interactions. Responsiveness to infant cues is influenced by maternal characteristics and mode of feeding. Breastfeeding facilitates communication by enhancing maternal responsiveness and increasing the frequency of engagement and disengagement cues of the infant. This demonstrates the bi directionality and interdependence of infant communication during a feed, namely that more responsive feeding for example, through breastfeeding, is associated with more proficient communication by the infant. Overall, observational methods have revealed the complex ways in which infants signal energy needs to their caregivers, and in turn these same methods have captured on film the ways in which carers recognise and react to these signals as part of responsive feeding. Potential applications of these methods includes developing interventions to facilitate infant self-regulation through responsive feeding. PMID- 28089706 TI - A sipometer for measuring motivation to consume and reward value of foods and beverages in humans: Description and proof of principle. AB - New methods, derived from animal work, for measuring food reward value (i.e. reinforcing value of food), and motivation (i.e. strength of desire) to consume, in humans are described and validated. A sipping device (sipometer) was developed that permits access to a liquid food or beverage on two reward schedules: continuous reinforcement (CR) and progressively increasing time spent exerting pressure on a straw (PR-schedule). In addition, a pictorial scale showing a cup, from which the 'amount wanted' could be marked was used to pre-test potential consumption. Intake, time spent sipping, breakpoint, and pressure exerted were the main dependent variables measured. Three pilot experiments were conducted. In Experiment 1, participants (n=8) consumed yogurt shakes after a 1-h or 21-h food deprivation period on both schedules. In Experiment 2, participants (n=8) sham consumed (i.e. spit out) sweet and non-sweet beverages, utilizing both schedules. In Experiment 3, sham-consuming sweet and non-sweet beverages on both schedules and working for shake on the PR schedule were repeated, after three nights of either habitual sleep or short sleep duration (n=7) in a crossover design. In Experiment 1, participants sipped longer after 21-h vs. 1-h of food deprivation (13+/-3.0 vs. 8.0+/-2.1s; p=0.04), on the PR schedule. In Experiment 2, sham intake (p=0.01) and sipping time (p=0.04) were greater for sweet than non-sweet beverages on the PR schedule and a similar, though not conventionally significant, effect was observed for exerted pressure (p=0.09). In both Experiment 2 and Experiment 3 after habitual sleep, on the PR schedule, cumulative pressure difference between sweet and non-sweet beverage increased with difference in amount wanted in the taste test. In contrast, after short sleep participants were less willing to work for sweet taste as their wanting increased, suggesting that sleep deprivation raises desire, but lowers behavioral output. Taken together these results demonstrate that the sipometer and associated ratings are reliable and useful measures of motivation to consume and reward value in humans. Participants were more motivated to obtain access to sweet beverages, especially when these were better liked than to obtain access to non-sweet beverages. PMID- 28089708 TI - Hair corticosterone measurement in mouse models of type 1 and type 2 diabetes mellitus. AB - In diabetes, glucocorticoid secretion increases secondary to hyperglycemia and is associated with an extensive list of disease complications. Levels of cortisol in humans, or corticosterone in rodents, are usually measured as transitory biomarkers of stress in blood or saliva. Glucocorticoid concentrations accumulate in human or animal hair over weeks and could more accurately measure the cumulative stress burden of diseases like chronic diabetes. In this study, corticosterone levels were measured in hair in verified rodent models of diabetes mellitus. To induce type 1 diabetes, C57BL/6J mice were injected with streptozotocin and blood and hair samples were collected 28days following induction. Leptin receptor deficient (db/db) mice were used as a spontaneous model of type 2 diabetes and blood and hair samples were collected at 8weeks of age, after the development of hyperglycemia and obesity. Corticosterone levels from serum, new growth hair and total growth hair were analyzed using an enzyme immunoassay. Corticosterone levels in new growth hair and serum were significantly elevated in both models of diabetes compared to controls. In contrast, corticosterone levels in old hair growth did not differ significantly between diabetic and non-diabetic animals. Thus, hair removal and sampling of new hair growth was a more sensitive procedure for detecting changes in hair corticosterone levels induced by periods of hyperglycemia lasting for 4weeks in mice. These results validate the use of hair to measure long-term changes in corticosterone induced by diabetes in rodent models. Further studies are now needed to validate the utility of hair cortisol as a tool for measuring the stress burden of individuals with diabetes and for following the effects of long term medical treatments. PMID- 28089710 TI - One (small) step towards precision nutrition by use of metabolomics. PMID- 28089709 TI - Objective assessment of dietary patterns by use of metabolic phenotyping: a randomised, controlled, crossover trial. AB - BACKGROUND: Accurate monitoring of changes in dietary patterns in response to food policy implementation is challenging. Metabolic profiling allows simultaneous measurement of hundreds of metabolites in urine, the concentrations of which can be affected by food intake. We hypothesised that metabolic profiles of urine samples developed under controlled feeding conditions reflect dietary intake and can be used to model and classify dietary patterns of free-living populations. METHODS: In this randomised, controlled, crossover trial, we recruited healthy volunteers (aged 21-65 years, BMI 20-35 kg/m2) from a database of a clinical research unit in the UK. We developed four dietary interventions with a stepwise variance in concordance with the WHO healthy eating guidelines that aim to prevent non-communicable diseases (increase fruits, vegetables, whole grains, and dietary fibre; decrease fats, sugars, and salt). Participants attended four inpatient stays (72 h each, separated by at least 5 days), during which they were given one dietary intervention. The order of diets was randomly assigned across study visits. Randomisation was done by an independent investigator, with the use of opaque, sealed, sequentially numbered envelopes that each contained one of the four dietary interventions in a random order. Participants and investigators were not masked from the dietary intervention, but investigators analysing the data were masked from the randomisation order. During each inpatient period, urine was collected daily over three timed periods: morning (0900-1300 h), afternoon (1300-1800 h), and evening and overnight (1800 0900 h); 24 h urine samples were obtained by pooling these samples. Urine samples were assessed by proton nuclear magnetic resonance (1H-NMR) spectroscopy, and diet-discriminatory metabolites were identified. We developed urinary metabolite models for each diet and identified the associated metabolic profiles, and then validated the models using data and samples from the INTERMAP UK cohort (n=225) and a healthy-eating Danish cohort (n=66). This study is registered with ISRCTN, number ISRCTN43087333. FINDINGS: Between Aug 13, 2013, and May 18, 2014, we contacted 300 people with a letter of invitation. 78 responded, of whom 26 were eligible and invited to attend a health screening. Of 20 eligible participants who were randomised, 19 completed all four 72 h study stays between Oct 2, 2013, and July 29, 2014, and consumed all the food provided. Analysis of 1H-NMR spectroscopy data indicated that urinary metabolic profiles of the four diets were distinct. Significant stepwise differences in metabolite concentrations were seen between diets with the lowest and highest metabolic risks. Application of the derived metabolite models to the validation datasets confirmed the association between urinary metabolic and dietary profiles in the INTERMAP UK cohort (p<0.0001) and the Danish cohort (p<0.0001). INTERPRETATION: Urinary metabolite models developed in a highly controlled environment can classify groups of free-living people into consumers of diets associated with lower or higher non-communicable disease risk on the basis of multivariate metabolite patterns. This approach enables objective monitoring of dietary patterns in population settings and enhances the validity of dietary reporting. FUNDING: UK National Institute for Health Research and UK Medical Research Council. PMID- 28089712 TI - Effect of heme oxygenase-1 on ochratoxin A-induced nephrotoxicity in mice. AB - Heme oxygenase-1 (HO-1), a heme-degrading enzyme, is suggested to play an important role in kidney pathophysiology, mostly due to its anti-fibrotic, anti apoptotic and anti-oxidant properties. One of the mycotoxin, ochratoxin A (OTA) was previously shown to affect HO-1 expression, however, the mechanisms of OTA induced nephrotoxicity during HO-1 deficiency are unknown. We have shown that OTA regulates the number of pro-fibrotic, pro-inflammatory, anti-oxidative and pro apoptotic factors in HO-1 dependent manner, as the lack of HO-1 accelerates whereas the induction of HO-1 expression by cobalt protoporphyrin (CoPP) attenuates nephrotoxic effect of OTA. The down-regulation of the nuclear factor erythroid-2- related factor 2 (Nrf2) transcription factor by OTA, observed in HO 1 knock-out animals, might be another mechanism of OTA toxicity. Moreover, HO-1 level and OTA treatment influences the expression of microRNAs. Namely, p53 regulated miR-34a and pro-fibrotic miR-21 were already increased in HO-1-/- kidneys and were further induced by OTA administration, whereas anti-fibrotic miR 29c was down-regulated by this mycotoxin. Our study indicates that complex mechanisms of OTA nephrotoxicity may be partially overcome by HO-1 induction. PMID- 28089711 TI - Regulation of Expression of Hyperalgesic Priming by Estrogen Receptor alpha in the Rat. AB - : Hyperalgesic priming, a sexually dimorphic model of transition to chronic pain, is expressed as prolongation of prostaglandin E2-induced hyperalgesia by the activation of an additional pathway including an autocrine mechanism at the plasma membrane. The autocrine mechanism involves the transport of cyclic adenosine monophosphate (AMP) to the extracellular space, and its conversion to AMP and adenosine, by ecto-5'phosphodiesterase and ecto-5'nucleotidase, respectively. The end product, adenosine, activates A1 receptors, producing delayed onset prolongation of prostaglandin E2 hyperalgesia. We tested the hypothesis that the previously reported, estrogen-dependent, sexual dimorphism observed in the induction of priming is present in the mechanisms involved in its expression, as a regulatory effect on ecto-5'nucleotidase by estrogen receptor alpha (EsRalpha), in female rats. In the primed paw AMP hyperalgesia was dependent on conversion to adenosine, being prevented by ecto-5'nucleotidase inhibitor alpha,beta-methyleneadenosine 5'-diphosphate sodium salt and A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. To investigate an interaction between EsRalpha and ecto-5'nucleotidase, we treated primed female rats with oligodeoxynucleotide antisense or mismatch against EsRalpha messenger RNA. Whereas in rats treated with antisense AMP-induced hyperalgesia was abolished, the A1 receptor agonist N6-cyclopentiladenosine still produced hyperalgesia. Thus, EsRalpha interacts with this autocrine pathway at the level of ecto-5'nucleotidase. These results demonstrate a sexually dimorphic mechanism for the expression of priming. PERSPECTIVE: This study presents evidence of an estrogen-dependent mechanism of expression of chronic pain in female rats, supporting the suggestion that differential targets must be considered when establishing protocols for the treatment of painful conditions in men and women. PMID- 28089713 TI - Cortisol increases in response to brief social exchanges with opposite sex partners. AB - Researchers recently demonstrated that cortisol increases in response to mating relevant social interactions. An important next step is investigating factors that explain individual differences in cortisol reactivity within these contexts. The current study examined demographic, situational, and individual difference predictors of cortisol reactivity following brief, non-face-to-face interactions with potential dating partners. College students made a video introducing themselves to another participant. During another appointment, they watched a short video of an opposite-sex confederate introducing himself/herself, and believed the other person was watching their video. Participants were told they would get to know the confederate more during a web-chat, which never took place. Participants received either rejection, acceptance, or no feedback from the confederate. Cortisol levels increased over baseline in all feedback conditions. Cortisol increases were particularly strong for participants who perceived the confederate as a more desirable dating partner, participants who were independently rated as a less desirable partner, and men. PMID- 28089714 TI - Effects of touch on emotional face processing: A study of event-related potentials, facial EMG and cardiac activity. AB - Being touched is known to affect emotion, and even a casual touch can elicit positive feelings and affinity. Psychophysiological studies have recently shown that tactile primes affect visual evoked potentials to emotional stimuli, suggesting altered affective stimulus processing. As, however, these studies approached emotion from a purely unidimensional perspective, it remains unclear whether touch biases emotional evaluation or a more general feature such as salience. Here, we investigated how simple tactile primes modulate event related potentials (ERPs), facial EMG and cardiac response to pictures of facial expressions of emotion. All measures replicated known effects of emotional face processing: Disgust and fear modulated early ERPs, anger increased the cardiac orienting response, and expressions elicited emotion-congruent facial EMG activity. Tactile primes also affected these measures, but priming never interacted with the type of emotional expression. Thus, touch may additively affect general stimulus processing, but it does not bias or modulate immediate affective evaluation. PMID- 28089715 TI - Ameliorating effects of herbal formula hemomine on experimental subacute hemorrhagic anemia in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hemomine (HM) is an herbal mixture consisting of 5 varieties of the hematopoietic herbal extracts (Angelica gigas Nakai, Cnidium officinale Makino, Paeonia lactiflora Pall., Rehmannia glutinosa Liboschitz ex Stueudel, Glycyrrhiza uralensis Fischer). AIM OF THE STUDY: Anemia has been treated with iron supplements, whereas it could cause adverse side effects such as digestive discomfort. In the present study, HM was applied to SHA rats to test for several activities so as to verify its therapeutic potentials on anemia and digestive discomfort. MATERIALS AND METHODS: Sprague-Dawley rats were assigned to seven groups: (Two controls, two references (ferric hydroxide polymatose (FM) and ferritin extract glycerin hydrate (FA)), three different concentrations of HM, n=8 per groups), and induced subacute hemorrhagic anemia (SHA) through blood exsanguinations once a day for 7 days. RESULTS: The SHA animal model showed changes in the markers related to classic iron-deficient and regenerative anemia in this experiment. However, the SHA related anemic signs were dose-dependently inhibited by the administration of HM 2, 1, and 0.5ml/kg for 7 days, and more favorably than the equal dosages of FM and FA. In addition, FM and FA showed the typical constipation signs, including reduction of in thickness of the colonic mucosa, in contrast, HM 2, 1, and 0.5ml/kg groups had no effects on the gastrointestinal motilities and the colonic mucous components when compared to the controls. The results suggested that the HM significantly showed to have therapeutic effects in the experimental SHA in rats, and is more potent than the commercial iron supplement through the proliferation of hematopoietic stem cells with reduced digestive discomfort. CONCLUSIONS: Therefore, Hemomine may prove to be a promising hematopoietic and therapeutic agent for anemia. PMID- 28089716 TI - A characterization of the antimalarial activity of the bark of Cylicodiscus gabunensis Harms. AB - ETHNOPHARMACOLOGICAL RELEVANCE AND AIM: A decoction of the bark of Cylicodiscus gabunensis Harms is used as a traditional medicine in the treatment of malaria in Nigeria. This study aims to validate the antimalarial potency of this decoction in vitro against Plasmodium falciparum and define potential bioactive constituents within the C. gabunensis bark. MATERIALS AND METHODS: A bioassay guided separation and fractionation protocol was applied to C. gabunensis extracts, exploiting the use of a Malaria Sybr Green I Fluorescence assay method to monitor antiproliferative effects on parasites as well as define 50% inhibition concentrations. Spectroscopic techniques, including GC-MS, TOF LC-MS and 1H NMR were used to identify phytochemicals present in bioactive fractions. Analogues of gallic acid were synthesized de novo to support the demonstration of the antimalarial action of phenolic acids identified in C. gabunensis bark. In vitro cytotoxicity of plant extracts, fractions and gallate analogues was evaluated against the HepG2 cell line. RESULTS: The antimalarial activity of ethanolic extracts of C. gabunensis bark was confirmed in vitro, with evidence for phenolic acids, primarily gallic acid and close analogues such as ethyl gallate, likely providing this effect. Further fractionation produced the most potent fraction with a 50% inhibitory concentration of 4.7ug/ml. Spectroscopic analysis, including 1H NMR, LC-MS and GC-MS analysis of this fraction and its acid hydrolyzed products, indicated the presence of conjugates of gallic acid with oligosaccharides. The extracts/fractions and synthetic alkyl and alkenyl gallates showed moderate selectivity against P. falciparum. CONCLUSIONS: These results support the use of the bark of C. gabunensis as a traditional medicine in the treatment of human malaria, with phenolic acid oligosaccharide complexes evident in the most bioactive fractions. PMID- 28089717 TI - Persistent organic pollutants (POPs) in human follicular fluid and in vitro fertilization outcomes, a pilot study. AB - Persistent organic pollutants (POPs) are ubiquitously distributed among the U.S. population and adversely impact human reproduction. These compounds have been detected in human ovarian follicular fluid (FF), where they directly contact a developing oocyte. As a pilot investigation, we measured 43 polychlorinated biphenyl (PCB) congeners, p,p'-dichlorodiphenyltrichloroethane (DDT), and its persistent metabolite p,p'-dichlorodiphenyldichloroethylene (DDE) in residual FF collected from 32 women undergoing in vitro fertilization (IVF). We identified significant inverse associations between higher levels of PCB congeners and indicators of ovarian reserve (e.g., antral follicle count), follicular response to administered gonadotropins (e.g., peak estradiol, number of oocytes retrieved, endometrial thickness), intermediate IVF endpoints (e.g., oocyte fertilization and embryo quality), and clinical IVF outcomes (e.g., embryo implantation and live birth), after adjusting for body mass index, cigarette smoking, race, and age. Our results suggest that ongoing exposure to POPs impacts IVF and merit confirmation in a larger and more definitive future study. PMID- 28089718 TI - Cathelicidin antimicrobial peptide from Alligator mississippiensis has antibacterial activity against multi-drug resistant Acinetobacter baumanii and Klebsiella pneumoniae. AB - Alligator mississippiensis (American alligator), a member of order Crocodilia, lives in bacteria-laden environments but is not often known to succumb to bacterial infections. Their serum has been shown to have antibacterial activity beyond that of human serum, and it is believed that this activity is partially due to cationic antimicrobial peptides (CAMPs). CAMPs are produced by many organisms as part of the innate immune system. CAMPs are attractive possible therapies against multi-drug resistant bacteria, such as those found in biofilm infected war wounds, because they seldom cause genetic resistance in bacteria and are effective against antibiotic resistant bacteria. In this work, we identified, synthesized, and characterized a cathelicidin and two shorter fragments from the American alligator. We discovered the cathelicidin using Basic Local Alignment Search Tool (BLAST) alignment and by comparing A. mississippiensis expressed sequence tags (ESTs) with propeptide cathelicidins of other reptiles. We analyzed the structure using bioinformatics tools and circular dichroism and predicted that the full-length cathelicidin peptide has a mixed structure, with an N terminal alpha-helix and a center Pro hinge. In minimal inhibitory concentration (MIC) assays, it was determined that the cathelicidin and the two shorter fragments have strong activity against multiple Gram-negative bacteria, including clinical isolates of multi-drug resistant (MDR) Acinetobacter baumannii and carbapenem-resistant Klebsiella pneumoniae. Using the ethidium bromide uptake assay, it was found that these peptides permeabilize the bacterial membrane and are less sensitive to salt inhibition than many other known CAMPs. The alligator cathelicidin peptides were not hemolytic against sheep red blood cells at 300 MUg/ml and were not significantly cytotoxic against A549 human lung epithelial cells after 24 h exposure in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. These alligator cathelicidin peptides have activity similar to other CAMPs from reptiles such as NA-CATH. It is possible that the alligator cathelicidins play an important role in the innate immune response of A. mississippiensis, similar to LL-37 in humans. In addition, due to their activities against MDR bacteria and lack of cytotoxicity, the AM-CATH peptides could be an attractive platform for further development as a potential therapeutic. PMID- 28089719 TI - 220th ENMC workshop: Dystroglycan and the dystroglycanopathies Naarden, The Netherlands, 27-29 May 2016. PMID- 28089720 TI - Condyloma Acuminatum of Urinary Bladder in a Male Renal Transplant Recipient - A Diagnostic and Therapeutic Challenge. PMID- 28089721 TI - Angiotensin Inhibitors as Treatment of Sunitinib/Pazopanib-induced Hypertension in Metastatic Renal Cell Carcinoma. AB - BACKGROUND: Research suggests that baseline use of angiotensin system inhibitors (ASIs) improves outcome in patients with metastatic renal cell carcinoma (mRCC), but it remains unknown whether the type of antihypertensive medication used to initiate management at onset of treatment-induced hypertension (HTN) is associated with outcome. We evaluated the association of ASIs and outcome among patients with mRCC treated with first-line tyrosine kinase inhibitors (TKIs). PATIENTS AND METHODS: We identified 303 consecutive patients with mRCC who were treated with sunitinib or pazopanib in a single university hospital cancer center. Statistical analyses were performed using the Kaplan-Meier method and Cox regression adjusted for known risk factors. RESULTS: Progression-free survival (PFS) and overall survival (OS) were similar among patients with baseline HTN (n = 197; 65%) versus patients with no baseline HTN (n = 106; 35%) (PFS; P = .72) (OS; P = .54). There was a significant difference between patients with treatment induced HTN (n = 110) versus patients with no treatment-induced HTN (n = 193) for PFS (15.6 vs. 6.4 months, respectively; P < .001) and OS (34.9 vs. 13.9 months, respectively; P < .001). Use of ASIs at baseline (n = 126; 41.6%) had no impact on outcome as compared with patients receiving other antihypertensive medication (n = 71; 23.4%) or with patients with no baseline antihypertensive medication (n = 106; 35.0%). Among patients with TKI-induced HTN (n = 110), however, ASI users (n = 91) demonstrated improved OS (37.5 vs. 18.1 months; P = .001) and PFS (17.1 vs. 7.2 months; P = .004) versus ASI nonusers (n = 19), respectively. CONCLUSION: Our results demonstrate survival benefit for ASI users among patients with TKI induced HTN. These results, however, require further validation in a prospective setting. PMID- 28089722 TI - Perioperative Allogenic Blood Transfusion in Renal Cell Carcinoma: Risk Factors and Effect on Long-term Outcomes. AB - BACKGROUND: We sought to create a preoperative model to predict the risk of perioperative blood transfusion (PBT) in patients with renal cell carcinoma (RCC) undergoing nephrectomy and to evaluate the effect of PBT on long-term outcomes. PATIENTS AND METHODS: The present retrospective study included 648 consecutive patients who had undergone radical or partial nephrectomy for RCC at a single institution. The risk factors for PBT were analyzed using logistic regression analysis. Cox proportional hazards models addressed the effect of PBT on overall and RCC-specific mortality. RESULTS: A total of 62 patients (10%) received a median of 2 red blood cell units (interquartile range, 2-3; range 1-20). On multivariable logistic regression analysis, 2 preoperative factors were independently associated with receipt of PBT: preoperative anemia (odds ratio, 6.28; P < .001) and open surgery (odds ratio, 3.40; P < .001). The risk of receiving PBT was high with both risk factors present (34%), intermediate with 1 risk factor present (7%-12%), and low with 0 risk factors present (2%). Within a median follow-up period of 63 months (interquartile range, 32-91), 108 patients (17%) had died of RCC and 177 (27%) had died of any cause. In the multivariable Cox models, PBT remained independently associated with overall mortality (hazard ratio [HR], 1.86; P = .004) and RCC-specific mortality (HR, 1.79; P = .007). A dose-dependent association of PBT with RCC-specific mortality was observed (HR, 1.14; P = .01). CONCLUSION: In patients undergoing surgery for RCC, PBT was associated with adverse overall and RCC-specific mortality. Patients with preoperative anemia and those scheduled to undergo open surgery are at an increased risk of PBT and could be candidates for perioperative optimization techniques. PMID- 28089723 TI - Cost-effectiveness of the Decipher Genomic Classifier to Guide Individualized Decisions for Early Radiation Therapy After Prostatectomy for Prostate Cancer. AB - BACKGROUND: Controversy exists regarding the effectiveness of early adjuvant versus salvage radiation therapy after prostatectomy for prostate cancer. Estimates of prostate cancer progression from the Decipher genomic classifier (GC) could guide informed decision-making and improve the outcomes for patients. MATERIALS AND METHODS: We developed a Markov model to compare the costs and quality-adjusted life years (QALYs) associated with GC-based treatment decisions regarding adjuvant therapy after prostatectomy with those of 2 control strategies: usual care (determined from patterns of care studies) and the alternative of 100% adjuvant radiation therapy. Using the bootstrapping method of sampling with replacement, the cases of 10,000 patients were simulated during a 10-year time horizon, with each subject having individual estimates for cancer progression (according to GC findings) and noncancer mortality (according to age). RESULTS: GC-based care was more effective and less costly than 100% adjuvant radiation therapy and resulted in cost savings up to an assay cost of $11,402. Compared with usual care, GC-based care resulted in more QALYs. Assuming a $4000 assay cost, the incremental cost-effectiveness ratio was $90,833 per QALY, assuming a 7% usage rate of adjuvant radiation therapy. GC-based care was also associated with a 16% reduction in the percentage of patients with distant metastasis at 5 years compared with usual care. CONCLUSION: The Decipher GC could be a cost-effective approach for genomics-driven cancer treatment decisions after prostatectomy, with improvements in estimated clinical outcomes compared with usual care. The individualized decision analytic framework applied in the present study offers a flexible approach to estimate the potential utility of genomic assays for personalized cancer medicine. PMID- 28089724 TI - Potential applications of lipid peroxidation products - F4-neuroprostanes, F3 neuroprostanesn-6 DPA, F2-dihomo-isoprostanes and F2-isoprostanes - in the evaluation of the allograft function in renal transplantation. AB - F4-neuroprostanes, F3-neuroprostanesn-6 DPA, and F2-dihomo-isoprostanes, metabolites of non-enzymatic lipid peroxidation of polyunsaturated fatty acids [docosahexaenoic acid, n-6 docosapentanoic acid, and adrenic acid respectively], have become important biomarkers for oxidative stress in several diseases like epilepsy and alzheimer. These biomarkers and the 15-F2t-isoprostane (also known as 8-iso-PGF2alpha), a F2-isoprostane isomer measured as reference oxidative marker at systemic level, were analyzed by UHPLC-QqQ-MS/MS in the urine of 60 renal recipients from cadaveric donors of the Nephrology Unit of the University Hospital Virgen de la Arrixaca, at six different times during the first six months after renal transplantation, and were compared with a control group of 60 healthy subjects from the same hospital. A total of 11 metabolites were analyzed and different patterns were observed. A tendency to decrease was observed in three metabolites (4-epi-4-F3t- NeuroPn-6 DPA, ent-7(RS)-7-F2t-dihomo-IsoP, and ent-7(S)-7-F2t-dihomo-IsoP) and in our reference oxidative marker (15-F2t-IsoP) when kidney function improved and the excretion of urine proteins decreased. These results suggest that these three biomarkers of oxidative stress could be useful to assess renal function in the postransplant phase. Unfortunately, little is known about this kind of biomarker in this cohort of patients, so further investigation would be required in the clinical field to clarify the relationship between oxidative stress and the graft function, as well as the usefulness of these biomarkers as rejection markers. PMID- 28089726 TI - HNE and cholesterol oxidation products in colorectal inflammation and carcinogenesis. AB - Consistent experimental data suggest the importance of inflammation-associated oxidative stress in colorectal cancer (CRC) pathogenesis. Inflammatory bowel disease with chronic intestinal inflammation is now considered a precancerous condition. Oxidative stress is an essential feature of inflammation. Activation of redox-sensitive pro-inflammatory cell signals and inflammatory mediators concur to establish a pro-tumoral environment. In this frame, lipid oxidation products, namely 4-hydroxynonenal and oxysterols, can be produced in big quantity so as to be able to exert their function as inducers of cell signaling pathways of proliferation and survival. Notably, an important source of these two compounds is represented by a high fat diet, which is undoubtedly a risk factor for inflammation and CRC development. Current evidence for the emerging implication of these two oxidized lipids in inflammation and CRC development is discussed in this review. PMID- 28089725 TI - High concentration of branched-chain amino acids promotes oxidative stress, inflammation and migration of human peripheral blood mononuclear cells via mTORC1 activation. AB - Leucine, isoleucine and valine are essential aminoacids termed branched-chain amino acids (BCAA) due to its aliphatic side-chain. In several pathological and physiological conditions increased BCAA plasma concentrations have been described. Elevated BCAA levels predict insulin resistance development. Moreover, BCAA levels higher than 2mmol/L are neurotoxic by inducing microglial activation in maple syrup urine disease. However, there are no studies about the direct effects of BCAA in circulating cells. We have explored whether BCAA could promote oxidative stress and pro-inflammatory status in peripheral blood mononuclear cells (PBMCs) obtained from healthy donors. In cultured PBMCs, 10mmol/L BCAA increased the production of reactive oxygen species (ROS) via both NADPH oxidase and the mitochondria, and activated Akt-mTOR signalling. By using several inhibitors and activators of these molecular pathways we have described that mTOR activation by BCAA is linked to ROS production and mitochondrial dysfunction. BCAA stimulated the activation of the redox-sensitive transcription factor NF kappaB, which resulted in the release of pro-inflammatory molecules, such as interleukin-6, tumor necrosis factor-alpha, intracellular adhesion molecule-1 or CD40L, and the migration of PBMCs. In conclusion, elevated BCAA blood levels can promote the activation of circulating PBMCs, by a mechanism that involving ROS production and NF-kappaB pathway activation. These data suggest that high concentrations of BCAA could exert deleterious effects on circulating blood cells and therefore contribute to the pro-inflammatory and oxidative status observed in several pathophysiological conditions. PMID- 28089727 TI - Clinical characteristics associated with days to discharge among patients admitted with a primary diagnosis of lower limb cellulitis. AB - BACKGROUND: Clinicians have limited ability to classify risk of prolonged hospitalization among patients with lower limb cellulitis. OBJECTIVE: We sought to identify characteristics associated with days to discharge and prolonged stay. METHODS: We conducted retrospective cohort analysis including patients admitted with a primary diagnosis of lower limb cellulitis at community and tertiary hospitals. RESULTS: There were 4224 admissions for lower limb cellulitis among 3692 patients. Mean age of the cohort was 64.4 years. Frequencies of tobacco smoking, obesity, and diabetes mellitus were 25.1%, 44.9%, and 19.3%, respectively. Patients having decreased likelihood of discharge included those with the following: 10-year age increments 0.90 (95% confidence interval [CI] 0.88-0.92), obesity 0.90 (95% CI 0.83-0.97), diabetes mellitus 0.90 (95% CI 0.82 0.98), tachycardia 0.76 (95% CI 0.67-0.85), hypotension 0.77 (95% CI 0.65-0.90), leukocytosis 0.86 (95% CI 0.79-0.93), neutrophilia 0.80 (95% CI 0.73-0.87), elevated serum creatinine 0.74 (95% CI 0.68-0.81), and low serum bicarbonate 0.84 (95% CI 0.75-0.95). LIMITATIONS: This analysis is retrospective and based on coded data. Unknown confounding variables may also influence prolonged stay. CONCLUSIONS: Patients with lower limb cellulitis and prolonged stay have a number of clinical characteristics which may be used to classify risk for prolonged stay. PMID- 28089728 TI - Internet-based skin cancer screening using clinical images alone or in conjunction with dermoscopic images: A randomized teledermoscopy trial. AB - BACKGROUND: Teledermoscopy involves the use of dermoscopic images for remote consultation and decision-making in skin cancer screening. OBJECTIVE: We sought to analyze the potential benefits gained from the addition of dermoscopic images to an internet-based skin cancer screening system. METHODS: A randomized clinical trial assessed the diagnostic performance and cost-effectiveness of clinical teleconsultations (CTC) and clinical with dermoscopic teleconsultations. RESULTS: A total of 454 patients were enrolled in the trial (nCTC = 226, nclinical with dermoscopic teleconsultation = 228). Teledermoscopy improved sensitivity and specificity (92.86% and 96.24%, respectively) compared with CTC (86.57% and 72.33%, respectively). Correct decisions were made in 94.30% of patients through clinical with dermoscopic teleconsultations and in 79.20% in CTC (P < .001). The only variable associated with an increased likelihood of correct diagnosis was management using teledermoscopy (odds ratio 4.04; 95% confidence interval 2.02 8.09; P < .0001). The cost-effectiveness analysis showed teledermoscopy as the dominant strategy, with a lower cost-effectiveness ratio (65.13 vs 80.84). LIMITATIONS: Potentially, a limitation is the establishment of an experienced dermatologist as the gold standard for the in-person evaluation. CONCLUSIONS: The addition of dermoscopic images significantly improves the results of an internet based skin cancer screening system, compared with screening systems based on clinical images alone. PMID- 28089730 TI - Chronic Prostate Inflammation Predicts Symptom Progression in Patients with Chronic Prostatitis/Chronic Pelvic Pain. AB - PURPOSE: We examined the 4-year longitudinal association between histological prostate inflammation and chronic prostatitis/chronic pelvic pain syndrome. We also studied the development of new and progressing existing chronic prostatitis/chronic pelvic pain syndrome in men randomized to placebo in the REDUCE (REduction by DUtasteride of prostate Cancer Events) population. MATERIALS AND METHODS: At multiple time points during 4 years univariable and multivariable analyses were performed between acute and chronic inflammation detected on baseline biopsies and the incidence of chronic pelvic pain syndrome-like symptoms, defined as a positive response to CPSI (Chronic Prostatitis Symptom Index) question 1a-perineal pain and/or question 2b-ejaculatory pain and a total pain subscore of at least 4, and progression of chronic prostatitis/chronic pelvic pain syndrome, defined as a 4-point or greater increase from baseline in total CPSI score, in patients with a baseline categorization of chronic prostatitis/chronic pelvic pain syndrome. RESULTS: Of the 4,109 men in the study acute and chronic inflammation was detected in 641 (15.6%) and 3,216 (78.3%), respectively. Chronic prostatitis/chronic pelvic pain syndrome symptom status was available for 2,816 at baseline. Chronic prostatitis/chronic pelvic pain syndrome like symptoms developed in 317 of 2,150 men without the condition at baseline who had followup data. Acute and chronic inflammation was not associated with the incidence of the symptoms (p >0.1). At a median followup of 12.0 months 109 of 145 men with baseline chronic prostatitis/chronic pelvic pain syndrome and followup data showed symptomatic progression. Chronic but not acute inflammation was significantly associated with shorter time to progression on univariable and multivariable analyses (p = 0.029 and 0.018, respectively). CONCLUSIONS: Inflammation is not associated with an increased risk of chronic prostatitis/chronic pelvic pain syndrome. However, chronic inflammation predicts the risk of symptomatic progression in men in whom chronic prostatitis/chronic pelvic pain syndrome symptoms have been identified. PMID- 28089729 TI - Urinary Biomarkers in Women with Refractory Urgency Urinary Incontinence Randomized to Sacral Neuromodulation versus OnabotulinumtoxinA Compared to Controls. AB - PURPOSE: We measured urinary biomarker levels in women with refractory urgency urinary incontinence and controls at baseline and 6 months after treatment with sacral neuromodulation or intradetrusor injection of onabotulinumtoxinA. We also assessed the association of baseline biomarkers with posttreatment urgency urinary incontinence episodes and overactive bladder symptom bother outcomes. MATERIALS AND METHODS: First morning urine samples were collected from consented trial participants and age matched women without urgency urinary incontinence. Biomarkers reflecting general inflammation, neuroinflammation, afferent neurotransmitters and tissue remodeling were measured using standardized enzyme linked immunosorbent assay and activity assays as appropriate. Symptom bother was assessed by the overactive bladder questionnaire and urgency urinary incontinence episodes were determined by bladder diary. Linear models were used to examine differences in mean biomarker levels and the change in urgency urinary incontinence episodes and symptom bother between baseline and 6 months. Modest evidence of a potential association was represented by p <=0.01 and p <=0.004 represented moderate evidence of an association with outcomes. RESULTS: Baseline biomarker levels differed little between cases and controls except tropoelastin (p = 0.001) and N-terminal telopeptide collagen type 1 (p <0.001). Changes in biomarker levels 6 months after intervention included decreases in collagenase (p <0.001) in both treatment groups and increases in interleukin-8 (p = 0.002) and matrix metalloprotease-9 (p <0.001) in the onabotulinumtoxinA group. Higher baseline calcitonin gene-related peptide across both treatments (p = 0.007) and nerve growth factor in the onabotulinumtoxinA arm (p = 0.007) were associated with less reduction in overactive bladder symptom bother. CONCLUSIONS: Refractory urgency urinary incontinence is a complex condition. These data suggest that matrix remodeling and neuropeptide mediation may be involved in its pathophysiological mechanisms and response to treatment. PMID- 28089731 TI - Investigation of polymorphisms in genes involved in estrogen metabolism in menstrual migraine. AB - Migraine is a common, disabling headache disorder, which is influenced by multiple genes and environmental triggers. After puberty, the prevalence of migraine in women is three times higher than in men and >50% of females suffering from migraine report a menstrual association, suggesting hormonal fluctuations can influence the risk of migraine attacks. It has been hypothesized that the drop in estrogen during menses is an important trigger for menstrual migraine. Catechol-O-methyltransferase (COMT) and Cytochrome P450 (CYP) enzymes are involved in estrogen synthesis and metabolism. Functional polymorphisms in these genes can influence estrogen levels and therefore may be associated with risk of menstrual migraine. In this study we investigated four single nucleotide polymorphisms in three genes involved in estrogen metabolism that have been reported to impact enzyme levels or function, in a specific menstrual migraine cohort. 268 menstrual migraine cases and 142 controls were genotyped for rs4680 in COMT (Val158Met), rs4646903 and rs1048943 in CYP1A1 (T3801C and Ile462Val) and rs700519 in CYP19A1 (Cys264Arg). Neither genotype nor allele frequencies for the COMT and CYP SNPs genotyped were found to be significantly different between menstrual migraineurs and controls by chi-square analysis (P>0.05). Therefore we did not find association of functional polymorphisms in the estrogen metabolism genes COMT, CYP1A1 or CYP19A1 with menstrual migraine. Further studies are required to assess whether menstrual migraine is genetically distinct from the common migraine subtypes and identify genes that influence risk. PMID- 28089733 TI - Antimicrobial peptide gene cecropin-2 and defensin respond to peptidoglycan infection in the female adult of oriental fruit fly, Bactrocera dorsalis (Hendel). AB - Cecropins and defensins are important antimicrobial peptides in insects and are inducible after injection of immune triggers. In this study, we cloned the cDNAs of two antimicrobial peptides (AMPs), cecropin-2 (BdCec-2) and defensin (BdDef) from Bactrocera dorsalis (Hendel), a serious pest causing great economic losses to fruits and vegetables. The BdCec-2 sequence of 192bp encodes a protein of 63 amino acids residues with a predicted molecular weight of 6.78kD. The 282bp cDNA of BdDef encodes a protein of 93 residues with a predicted molecular weight of 9.81kD. Quantitative real-time PCR analyses showed that BdCec-2 and BdDef had similar expression profiles among development stages, the highest mRNA levels of these two AMP genes were observed in the adult stage. Among different adult body segments and tissues, both genes had similar transcriptional profiles, the highest mRNA levels appeared in abdomen and fat body, which was consistent with the reported fact that fat body was the main organ synthesizing AMPs in insects. The expression of BdCec-2 and BdDef were up-regulated after challenge with peptidoglycans from Escherichia coli (PGN-EB) and Staphylococcus aureus (PGN-SA), respectively, suggesting their antimicrobial activity against Gram-negative and Gram-positive microorganisms. These results describe for the first time the basic properties of the cecropin-2 and defensin genes from B. dorsalis that probably play an important role in the defense response against invading microbes. PMID- 28089732 TI - ALOX15 as a suppressor of inflammation and cancer: Lost in the link. AB - Mounting evidence supports a mechanistic link between inflammation and cancer, especially colon cancer. ALOX15 (15-lipoxygenase-1) plays an important role in the formation of key lipid mediators (e.g., lipoxins and resolvins) to terminate inflammation. ALOX15 expression is downregulated in colorectal cancer (CRC). Intestinally-targeted transgenic expression of ALOX15 in mice inhibited dextran sodium sulfate-induced colitis from promoting azoxymethane- induced colorectal tumorigenesis, demonstrating that ALOX15 can suppress inflammation-driven promotion of carcinogen-induced colorectal tumorigenesis and therefore ALOX15 downregulation during tumorigenesis is likely to enhance the link between colitis and colorectal tumorigenesis. ALOX15 suppressed the TNF-alpha, IL-1beta/NF kappaB, and IL-6/STAT3 signaling pathways, which play major roles in promotion of colorectal cancer by chronic inflammation. Defining ALOX15's regulatory role in colitis-associated colorectal cancer could identify important molecular regulatory events that could be targeted to suppress promotion of tumorigenesis by chronic inflammation. PMID- 28089734 TI - Broadening the phenotype of DFNB28: Mutations in TRIOBP are associated with moderate, stable hereditary hearing impairment. AB - DFNB28 is characterized by prelingual, severe to profound sensorineural hearing impairment (HI). It is associated with mutations in exon 6 and 7 of TRIOBP and has not been reported in the European population. Here, we describe two isolated cases of Dutch origin with congenital, moderate HI and compound heterozygous mutations in TRIOBP. Three of the mutations are novel, one nonsense mutation (c.5014G>T (p.Gly1672*)) and two frameshift mutations (c.2653del (p.Arg885Alafs*120) and c.3460_3461del (p.Leu1154Alafs*29)). The fourth mutation is the known c.3232dup (p.Arg1078Profs*6) mutation. Longitudinal audiometric analyses in one of the subjects revealed that HI was stable over a period of 15 years. Vestibular function was normal. Predicted effects of the mutations do not explain the relatively mild phenotype in the presented subjects, whereas location of the mutation might well contribute to the milder HI in one of the subjects. It is known that isoform classes TRIOBP-4 and TRIOBP-5 are important for stereocilia stability and rigidity. To our knowledge, p.Gly1672* is the first pathogenic variant identified in DFNB28 that does not affect isoform class TRIOBP-4. This suggests that a single TRIOBP copy to encode wildtype TRIOBP-4 is insufficient for normal hearing, and that at least one TRIOBP copy to encode TRIOBP-5 is indispensable for normal inner ear function. Furthermore, this study demonstrates that DFNB28 can be milder than reported so far and that mutations in TRIOBP are thus associated with a heterogeneous phenotype. PMID- 28089735 TI - Effects of simvastatin on CAT-1-mediated arginine transport and NO level under high glucose conditions in conditionally immortalized rat inner blood-retinal barrier cell lines (TR-iBRB). AB - OBJECTIVE: Hyperglycemia causes the breakdown of the blood-retinal barrier by impairing endothelial nitric oxide synthase (eNOS) function. Statins have many pleiotropic effects such as improving endothelial barrier permeability and increasing eNOS mRNA stability. The objective of this study was to determine effect of simvastatin on l-arginine transport and NO production under high glucose conditions in conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB). METHODS: Changes in l-arginine transport uptake and, expression levels of cationic amino acid transporter 1 (CAT-1) and eNOS mRNA were investigated after pre-treatment with simvastatin and NOS inhibitors (l-NMMA and l-NAME) under high-glucose conditions using TR-iBRB, an in vitro model of iBRB. The NO level released from TR-iBRB cells was examined using Griess reagents. RESULTS: Under high glucose conditions, [3H]l-arginine uptake was decreased in TR-iBRB cells. Simvastatin pretreatment elevated [3H]l-arginine uptake, the expression levels of CAT-1 and eNOS mRNA, and NO production under high-glucose conditions. Moreover, the co-treatment with simvastatin and NOS inhibitors reduced [3H]l-arginine uptake compared to pretreatment with simvastatin alone. CONCLUSION: Our results suggest that, in the presence of high glucose levels, increased l-arginine uptake due to simvastatin treatment was associated with increased CAT-1 and eNOS mRNA levels, leading to higher NO production in TR-iBRB cells. Thus, simvastatin might be a good modulator for diabetic retinopathy therapy by increasing of the l-arginine uptake and improving endothelial function in retinal capillary endothelial cells. PMID- 28089736 TI - Antibacterial activity of Limonium brasiliense (Baicuru) against multidrug resistant bacteria using a statistical mixture design. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Limonium brasiliense (Boiss.) Kuntze (Plumbaginaceae) is commonly known as "baicuru" or "guaicuru" and preparations of its dried rhizomes have been popularly used in the treatment of premenstrual syndrome and menstrual disorder, and as an antiseptic in genito-urinary infections. This study evaluated the potential antibacterial activity of rhizome extracts against multidrug-resistant bacterial strains using statistical mixture design. MATERIALS AND METHODS: The statistical design of four components (water, methanol, acetone, and ethanol) produced 15 different extracts and also a confirmatory experiment, which was performed using water:acetone (3:7, v/v). The crude extracts and their ethyl-acetate fractions were tested against vancomycin resistant Enterococcus faecium (VREfm), methicillin-resistant Staphylococcus aureus (MRSA) and Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae, all of which have been implicated in hospital and community-acquired infections. The dry residue, total polyphenol, gallocatechin and epigallocatechin contents of the extracts were also tested and statistical analysis was applied in order to define the fit models to predict the result of each parameter for any mixture of components. The principal component and hierarchical clustering analyses (PCA and HCA) of chromatographic data, as well as mass spectrometry (MS) analysis were performanced to determine the main compounds present in the extracts. RESULTS: The Gram-positive bacteria were susceptible to inhibition of bacterial growth, in special the ethyl-acetate fraction of ternary extracts from water:acetone:ethanol and methanol:acetone:ethanol against, respectively, VREfm (MIC=19ug/mL) and MRSA (MIC=39ug/mL). On the other hand, moderate activity of the ethyl-acetate fractions from primary (except water), secondary and ternary extracts (MIC=625ug/mL) was noted against KPC. The quadratic and special cubic models were significant for polyphenols and gallocatechin contents, respectively. Fit models to dry residue and epigallocatechin contents were not possible. PCA and HCA of the chromatographic fingerprints were disturbed by displacement retention time of some peaks, but the ultraviolet spectra indicated the homogeneous presence of flavan-3-ols characteristic of tannins. The MS confirmed the presence of gallic acid, gallocatechin, and epigallocatechin in extracts, and suggested the presence of monomers and dimers of B- and A-type prodelphinidins gallate, as well as a methyl gallate. CONCLUSION: Our results showed the antibacterial potential of L. brasiliense extracts against multidrug-resistant Gram-positive bacteria, such as VREfm and MRSA. The statistical design was a important tool to evaluate the biological activity by optimized form. The presence of some phenolic compounds was also demonstrated in extracts. PMID- 28089737 TI - Browplasminin, a condensed tannin with anti-plasmin activity isolated from an aqueous extract of Brownea grandiceps Jacq. flowers. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Following Venezuelan traditional medicine, females with heavy menstrual blood loss (menorrhagia) drink Brownea grandiceps Jacq. flowers (BG) decoctions to reduce the bleeding. In a previous study, we demonstrated that BG aqueous extract (E) possesses a potent anti-fibrinolytic activity capable of inhibiting plasmin, the main serine-protease that degrades fibrin. It is widely known that plasmin inhibitors are often used as anti fibrinolytics to reduce bleeding during surgeries with high risk of blood loss such as cardiac, liver, vascular, tooth extraction and large orthopedic procedures, as well as for menorrhagia treatments. The aim of this work was to isolate and characterize from BGE the compound responsible for the reported anti fibrinolytic activity. MATERIALS AND METHODS: A decoction of BG was prepared; then it was homogenized, centrifuged and lyophilized to obtain BGE. Subsequently the extract was fractionated by gel filtration and reverse phase using HPLC and the active compound was characterized by MALDI-ToF MS. The kinetic parameters of anti-plasmin activity were evaluated by an amidolytic assay using a chromogenic substrate; also the anti-plasmin activity was estimated by fibrin plate method. Data were analyzed by nonparametric statistics. RESULTS: The active compound was a condensed tannin denominated Browplasminin, which is capable of inhibiting the plasmin activity in a dose-dependent manner when measured in fibrin plates or by the amidolytic activity method; it also has a minor effect on the FXa activity. However, it does not affect the activity of other serine-proteases such as trypsin, t-PA or u-PA. Browplasminin consists predominately of heteroflavan-3-ols of catechin with B-type linkages, and extents up to heptadecamers (~ 5000Da), with hexose residues attached to the polymer that presents a high degree of galloylation. Its IC50 for plasmin was 47.80MUg/mL and for FXa was 237.08MUg/mL, while the Ki were 0.76 and 61.61MUg/mL for plasmin and FXa, respectively. CONCLUSIONS: The overall outcome of this study suggests that Browplasminin could be responsible for reducing heavy menstrual bleeding in women because its kinetic parameters showed that is a good plasmin inhibitor. PMID- 28089738 TI - Evaluation of the diuretic activity of the aqueous and 80% methanol extracts of the root of Euclea divinorum Hiern (Ebenaceae) in Sprague Dawley rats. AB - BACKGROUND: Diuretics are drugs that increase the formation of urine and are important for the treatment of various diseases including hypertension and edema. The root decoction of Euclea divinorum has been used as a diuretic agent in the traditional medicine. Therefore, this study was aimed to evaluate the diuretic activity of the crude extracts of the roots of Euclea divinorum in Sprague Dawley rats. METHODS: The aqueous extract (AE) and 80% methanol extract (80ME) of the plant were prepared using decoction and maceration, respectively. Vehicle (distilled water, 10ml/kg), standard drug (hydrochlorothiazide, 10mg/kg) and three doses (100mg/kg, 200mg/kg and 400mg/kg) of the AE and 80ME were given to male rats by oral gavage. Parameters like urine volume (for 5h), electrolyte concentration and pH were measured (at 5th h) and analyzed. Data were analyzed using one way analysis of variance (ANOVA) followed by Tukey post hoc test. Linear regression was also applied to show the dose dependency nature of the diuretic effect. RESULTS: The result indicated that the 80ME of the plant significantly (p<0.05) produced diuresis at 200mg/kg and 400mg/kg. Furthermore, the AE produced significant diuresis (p<0.05) at all doses. With regard to the electrolyte excretion, the AE produced significant natriuresis and kaliuresis at all tested doses (p<0.001), while the 80ME showed significant natriuresis and kaliuresis at 200mg/kg (p<0.01) and 400mg/kg (p<0.001). Preliminary phytochemical screening revealed the presence of secondary metabolites, including saponins, flavonoids, glycosides, steroids, tannins and terpinoids in both extracts. These constituents might be responsible for the diuretic activity of Euclea divinorum. Both extracts were also found to be safe at 2000mg/kg on the acute toxicity study. CONCLUSION: This finding provides a scientific support for the acclaimed traditional use of the roots of Euclea divinorum as a diuretic agent. PMID- 28089739 TI - The influence of seasonality on the content of goyazensolide and on anti inflammatory and anti-hyperuricemic effects of the ethanolic extract of Lychnophora passerina (Brazilian arnica). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Lychnophora passerina (Mart ex DC) Gardn (Asteraceae), popularly known as Brazilian arnica, is used in Brazilian folk medicine to treat pain, rheumatism, bruises, inflammatory diseases and insect bites. AIM OF THE STUDY: Investigate the influence of the seasons on the anti inflammatory and anti-hyperuricemic activities of ethanolic extract of L. passerina and the ratio of the goyazensolide content, main chemical constituent of the ethanolic extract, with these activities. MATERIALS AND METHODS: Ethanolic extracts of aerial parts of L. passerina were obtained from seasons: summer (ES), autumn (EA), winter (EW) and spring (EP). The sesquiterpene lactone goyazensolide, major metabolite, was quantified in ES, EA, EW and EP by a developed and validated HPLC-DAD method. The in vivo anti-hyperuricemic and anti inflammatory effects of the ethanolic extracts from L. passerina and goyazensolide were assayed on experimental model of oxonate-induced hyperuricemia in mice, liver xanthine oxidase (XOD) inhibition and on carrageenan-induced paw edema in mice. RESULTS: HPLC method using aqueous solution of acetic acid 0.01% (v/v) and acetonitrile with acetic acid 0.01% (v/v) as a mobile phase in a gradient system, with coumarin as an internal standard and DAD detection at 270nm was developed. The validation parameters showed linearity in a range within 10.0 150.0ug/ml, with intraday and interday precisions a range of 0.61-3.82. The accuracy values of intraday and interday analysis within 87.58-100.95%. EA showed the highest goyazensolide content. From the third to the sixth hour after injection of carrageenan, treatments with all extracts at the dose of 125mg/kg were able to reduce edema. Goyazensolide (10mg/kg) showed significant reduction of paw swelling from the second hour assay. This sesquiterpene lactone was more active than extracts and presented similar effect to indomethacin. Treatments with ES, EA and EP (125mg/kg) and goyazensolide (10mg/kg) reduced serum urate levels compared to hyperuricemic control group and were able to inhibit liver XOD activity. One of the mechanisms by which ES, EA, EP and goyazensolide exercise their anti-hyperuricemic effect is by the inhibition of liver XOD activity. Goyazensolide was identified as the main compound present in ES, EA, EW and EP and it is shown to be one of the chemical constituents responsible for the anti inflammatory and anti-hyperuricemic effects of the ethanolic extracts. CONCLUSION: The anti-inflammatory and anti-hyperuricemic activities of the ethanolic extracts from L. passerina were not proportionally influenced by the variation of goyazensolide content throughout the seasons. The involvement of goyazensolide on in vivo anti-inflammatory and anti-hyperuricemic activities of L.passerina extracts was confirmed, as well as the possibility of participation of other constituents on these effects. This study demonstrated that the aerial parts of L. passerina may be collected in any season for use as anti-inflammatory agent. For use in hyperuricemia, the best seasons for the collection are summer, autumn and spring. The ethanolic extract of L. passerina and goyazensolide can be considered promising agents in the therapeutic of inflammation, hyperuricemia and gout. PMID- 28089741 TI - Inflammatory myopathy in a patient with Aicardi-Goutieres syndrome. AB - Aicardi-Goutieres syndrome (AGS) is an inflammatory disorder belonging to the recently characterized group of type I interferonopathies. The most consistently affected tissues in AGS are the central nervous system and skin, but various organ systems and tissues have been reported to be affected, pointing to the systemic nature of the disease. Here we describe a patient with AGS due to a homozygous p.Arg114His mutation in the TREX1 gene. The histologically proven inflammatory myopathy in our patient expands the range of clinical features of AGS. Histological signs of muscle biopsies in the proband, and in two other AGS patients described earlier, are similar to those seen in various autoimmune myositises and could be ascribed to inapproapriate IFN I activation. In view of signs of possible mitochondrial damage in AGS, we propose that mitochondrial DNA could be a trigger of autoimmune responses in AGS. PMID- 28089740 TI - Early remodeling of repolarizing K+ currents in the alphaMHC403/+ mouse model of familial hypertrophic cardiomyopathy. AB - Familial hypertrophic cardiomyopathy (HCM), linked to mutations in myosin, myosin binding proteins and other sarcolemmal proteins, is associated with increased risk of life threatening ventricular arrhythmias, and a number of animal models have been developed to facilitate analysis of disease progression and mechanisms. In the experiments here, we use the alphaMHC403/+ mouse line in which one alphaMHC allele harbors a common HCM mutation (in betaMHC, Arg403 Gln). Here, we demonstrate marked prolongation of QT intervals in young adult (10-12week) male alphaMHC403/+ mice, well in advance of the onset of measurable left ventricular hypertrophy. Electrophysiological recordings from myocytes isolated from the interventricular septum of these animals revealed significantly (P<0.001) lower peak repolarizing voltage-gated K+ (Kv) current (IK,peak) amplitudes, compared with cells isolated from wild type (WT) littermate controls. Analysis of Kv current waveforms revealed that the amplitudes of the inactivating components of the total outward Kv current, Ito,f, Ito,s and IK,slow, were significantly lower in alphaMHC403/+, compared with WT, septum cells, whereas Iss amplitudes were similar. The amplitudes/densities of IK,peak and IK,slow were also lower in alphaMHC403/+, compared with WT, LV wall and LV apex myocytes, whereas Ito,f was attenuated in alphaMHC403/+ LV wall, but not LV apex, cells. These regional differences in the remodeling of repolarizing Kv currents in the alphaMHC403/+ mice would be expected to increase the dispersion of ventricular repolarization and be proarrhythmic. Quantitative RT-PCR analysis revealed reductions in the expression of transcripts encoding several K+ channel subunits in the interventricular septum, LV free wall and LV apex of (10-12week) alphaMHC403/+ mice, although this transcriptional remodeling was not correlated with the observed decreases in K+ current amplitudes. PMID- 28089742 TI - Multiple HABP2 variants in familial papillary thyroid carcinoma: Contribution of a group of "thyroid-checked" controls. AB - A heterozygous germline variant in the HABP2 gene c.1601G > A (p.Gly534Glu), which negatively impacts its tumor suppressive activity in vitro, has been described in 4-14% of kindreds of European-American ancestry with familial papillary thyroid carcinoma (fPTC). But it is also found in ~4% of Europeans and European/Americans from public databases that, however, did not provide information on the thyroid function of the controls. To get unbiased results, we decided to compare HABP2 genotypes of patients with fPTC with those of "thyroid checked" controls. A control group consisting of 136 European patients who were thyroidectomised for medullary thyroid carcinoma and devoid of any histologically detectable PTC or follicular-deriving carcinoma was built. In parallel we recruited 20 patients with fPTC from eleven independent European kindreds. The entire coding region of HABP2 was analyzed by Sanger sequencing the germline DNAs of patients. Nucleotide variants were searched for by Snap Shot analysis in the controls. Two variants, c.1601G > A (p.Gly534Glu) and c.364C > T (p.Arg122Trp), were found in 2 and 3 patients at the heterozygous level respectively (minor allele frequency (MAF): 5.0% and 7.5%, respectively). In controls, the MAF was either similar for the c.1601G > A HABP2 variant (2.94%, ns) or significantly lower for the c.364C > T variant (0.73%, p = 0.016). The Arg122 residue lies in the EGF-3 domain of HABP2 which is important for its activation but, however, superposition of the predicted 3D structures of the wild type and mutated proteins suggests that this variant is tolerated at the protein level. In conclusion, our data do not support the pathogenicity of the HABP2 c.1601G > A variant but highlight the existence of a new one that should be more extensively searched for in fPTC patients and its pathogenicity more carefully evaluated. PMID- 28089743 TI - Multichannel visual evoked potentials in the assessment of visual pathways in children with marked brain abnormalities. AB - PURPOSE: To demonstrate how multichannel visual evoked potentials (VEPs) can provide quantitative measures of visual function in children with marked cortical anatomy abnormalities. METHODS: Four children with marked brain pathology (2 holoprosencephaly, 2 giant interhemispheric cysts with hydrocephalus) underwent pattern reversal and flash VEP recordings from 16 equally distributed electrodes. Voltage maps of the major VEP components were constructed, and their distributions were compared to the magnetic resonance imaging (MRI) findings. RESULTS: No reproducible responses were evident in 1 case, and responses were present, but, as expected based on the MRI finding, not over the occipital electrodes in 3 cases. Thus, the standard clinical VEP electrode placement would not have detected responses. The distribution of responses during monocular testing obtained in 2 cases suggested normal decussation of the visual pathways at the chiasm, and voltage mapping indicated which part of the abnormally positioned brain tissue is functional visual cortex. CONCLUSIONS: In children with markedly abnormal brain anatomy, multichannel VEP recordings can provide quantifiable measures of visual pathway function detected in atypical locations. VEPs provide a quantifiable measure of visual function that could be used to assist in determining visual acuity levels, and offered a baseline for monitoring in the context of raised intracranial pressure. These recordings were also able to identify functional anatomical structures that were not apparent on MRI. In a clinical setting, the use of additional recordings from nonstandard electrode placement based on the MRI findings is suggested. PMID- 28089744 TI - Predictors of surgical success in patients with intermittent exotropia. AB - BACKGROUND: In patients with moderate- to large-angle exotropic deviations, surgical correction remains the definitive treatment. The purpose of this study was to identify preoperative factors that correlate with surgical success and to produce a binomial model that predicts success based on preoperative factors. METHODS: We performed a retrospective review of patients with intermittent exotropia who underwent uniocular recession-resection surgery. Success was defined as ocular deviation <=10Delta exotropia and <=5Delta esotropia at distance at last follow-up (at least 3 months' postoperatively). Preoperative factors such as age at surgery, sex, visual acuity, spherical equivalent, prism fusion range, stereopsis, and ocular deviation were analyzed for correlation with success using binomial logistic regression. RESULTS: A total of 82 patients were identified (average age, 33 years; range, 3.7-81.6 years). Average prismatic deviation was 35Delta at near and 34Delta at distance. Average stereopsis was 167". The average success rate was 58.5%. Univariate binomial regression revealed that patients with smaller angle of deviation at near (OR = 0.96, P = 0.013) or distance (OR = 0.96, P = 0.005), larger myopic refractive errors in terms of mean spherical equivalent (OR = 0.71, P = 0.022) and spherical equivalent in the more myopic eye (OR = 0.75, P = 0.029) contributed to success. A multivariate regression model was able to predict success with an accuracy of 72% (sensitivity, 81%; specificity, 58%; negative predictive value, 67%; positive predictive value, 74%). CONCLUSIONS: A smaller preoperative angle of deviation and larger myopic refractive error correlated with success in uniocular intermittent exotropia surgery in our cohort. Larger deviations and more hyperopia correlated with lower success rates. PMID- 28089745 TI - Dermoid cysts: clinical predictors of complex lesions and surgical complications. AB - PURPOSE: To evaluate the clinical characteristics and role of imaging in the evaluation of dermoid cysts and to determine predictors of cyst rupture during surgical excision of dermoid cysts. METHODS: In this single-center, consecutive, nonrandomized comparative case series, the records of consecutive patients with suspected dermoid cysts who underwent surgery between January 1, 2000, and December 31, 2014, were reviewed retrospectively for demographic information, clinical findings, preoperative imaging, surgical details, and pathology reports. RESULTS: A total of 100 patients were included. Cyst volume was similar between superomedial and superotemporal lesions (P = 0.61) but greater in patients >10 years of age (P < 0.001). Immobility of the cyst was present in all complex dermoids (4/4), but there was no difference in the mobility of superotemporal or superomedial cysts (P = 0.69). Forty-two patients underwent imaging; superomedial lesions were more likely to be imaged than superotemporal lesions (P = 0.073). All 4 patients with complex dermoids presented with orbital signs and underwent preoperative imaging. None of the remaining 38 patients who underwent imaging had orbital signs, and the results of imaging had no effect on surgical planning. Intraoperative cyst rupture occurred in 18 patients. There was no significant difference in cyst rupture between superotemporal and superomedial cysts (P = 0.452). Smaller cyst volume was associated more often with intraoperative cyst rupture (P < 0.001). CONCLUSIONS: Preoperative imaging of superomedial and superolateral dermoid cysts is likely unnecessary unless associated with orbital signs. Intraoperative cyst rupture is not influenced by cyst location but does appear to be more likely in smaller cysts. PMID- 28089746 TI - Congenital entropion and hypotropia secondary to duplication of the inferior rectus muscle. AB - Congenital anomalies of the extraocular muscles apart from congenital fibrosis are relatively rare. Duplication of extraocular muscles is a particularly rare congenital anomaly that has been rarely reported in the literature. We present a case of unilateral congenital entropion and hypotropia resulting from duplication of the inferior rectus muscle. PMID- 28089747 TI - Metabolic engineering of a diazotrophic bacterium improves ammonium release and biofertilization of plants and microalgae. AB - The biological nitrogen fixation carried out by some Bacteria and Archaea is one of the most attractive alternatives to synthetic nitrogen fertilizers. However, with the exception of the symbiotic rhizobia-legumes system, progress towards a more extensive realization of this goal has been slow. In this study we manipulated the endogenous regulation of both nitrogen fixation and assimilation in the aerobic bacterium Azotobacter vinelandii. Substituting an exogenously inducible promoter for the native promoter of glutamine synthetase produced conditional lethal mutant strains unable to grow diazotrophically in the absence of the inducer. This mutant phenotype could be reverted in a double mutant strain bearing a deletion in the nifL gene that resulted in constitutive expression of nif genes and increased production of ammonium. Under GS non-inducing conditions both the single and the double mutant strains consistently released very high levels of ammonium (>20mM) into the growth medium. The double mutant strain grew and excreted high levels of ammonium under a wider range of concentrations of the inducer than the single mutant strain. Induced mutant cells could be loaded with glutamine synthetase at different levels, which resulted in different patterns of extracellular ammonium accumulation afterwards. Inoculation of the engineered bacteria into a microalgal culture in the absence of sources of C and N other than N2 and CO2 from the air, resulted in a strong proliferation of microalgae that was suppressed upon addition of the inducer. Both single and double mutant strains also promoted growth of cucumber plants in the absence of added N fertilizer, while this property was only marginal in the parental strain. This study provides a simple synthetic genetic circuit that might inspire engineering of optimized inoculants that efficiently channel N2 from the air into crops. PMID- 28089748 TI - Bioaccumulation of lead and non-specific immune responses in white shrimp (Litopenaeus vannamei) to Pb exposure. AB - In this study, we investigated organ accumulation and nonspecific immune response in white shrimp (Litopenaeus vannamei) that were exposed to various concentrations of lead (Pb) solution. The concentrations of Pb in the hepatopancreas, haemolymph, and muscle were measured moreover the total heamocyte count, phenoloxidase activity, O2- and physiological factors such as glutamic oxaloacetate transaminase (GOT), glutamic pyruvic transaminase (GPT), and haemolymph glucose were detected. The results showed that the hepatopancreas was the main organ of accumulation of Pb in white shrimp and the cumulative concentration of each organ was positively correlated with the experimental Pb concentration and immersion time. By observing GOT and GPT, Pb was found to inhibit phenoloxidase and O2- activity and to induce organ injury. Thus, the heavy metal Pb accumulates in the hepatopancreas and haemolymph and affects the crustacean metabolic organ injury (rising of GOT and GPT) further to inhibit nonspecific immune responses. PMID- 28089749 TI - Pyroglutamate (5-oxoproline) measured with hydrophilic interaction chromatography (HILIC) tandem mass spectrometry in acutely ill patients. AB - BACKGROUND: Pyroglutamic acid (PGA) is challenging to quantify in plasma and is a rare cause of metabolic acidosis that is associated with inherited disorders or acquired after exposure to drugs. METHOD: We developed a hydrophilic interaction liquid chromatography tandem mass spectrometry method with a short analysis time. We established a reference interval and then measured PGA in acutely ill patients to investigate associations with clinical, pharmaceutical and laboratory parameters. RESULTS: The assay limit of the blank was 0.14MUmol/L and was linear to 5000MUmol/L with good precision. In-source formation of PGA from glutamate and glutamine was avoided by chromatographic separation. The PGA in controls had a reference interval of 22.6 to 47.8MUmol/L. The median PGA concentration in acutely ill patients was similar (P=0.21), but 18 individuals were above the reference interval with concentrations up to 250MUmol/L. We detected an association between PGA concentration and antibiotic and acetaminophen administration as well as renal impairment and severity of illness. Elevations of PGA in this unselected cohort were small compared to those reported in patients with pyroglutamic acidosis. CONCLUSION: The method is suitable for routine clinical use. We confirmed several expected associations with PGA in an acutely ill population. PMID- 28089750 TI - Long noncoding RNA CCAT2 can predict metastasis and poor prognosis: A meta analysis. AB - BACKGROUND: It has been reported that Colon cancer-associated transcript 2 (CCAT2) is dysregulated in various cancers. We performed this meta-analysis to clarify its promising functions as a prognosis marker in malignant tumors. METHODS: Electronic databases, including PubMed, Medline, OVID, Cochrane Library, and Web of Science, were searched from inception to October 20, 2016. The hazard ratio (HR) and 95% confidence interval (CI) were calculated to explore the relationship between CCAT2 expression and survival, which were extracted from the eligible studies. The odds ratio (OR) was calculated to assess the association between CCAT2 expression and pathological parameters using RevMan5.3 software. RESULTS: Six original studies were included in this meta-analysis including 725 cancer patients. The pooled HR suggested that high CCAT2 expression was significantly correlated with overall survival (OS) (HR=2.30, 95% CI: 1.62-3.25, p<0.00001) in cancer patients. Subgroup analysis revealed a significant association between CCAT2 and OS in urogenital system (HR=1.70, 95% CI: 1.27 2.26, p<0.003) and non-urogenital system cancer patients (HR=3.18, 95% CI: 2.09 4.83, p<0.0001). A significant association was observed between high CCAT2 expression and poor progression-free survival (PFS) in cancer patients (pooled HR=2.76, 95% CI: 1.74-4.37). CCAT2 expression was significantly related to lymph node metastasis (LNM) (OR=4.33, 95% CI 2.03-9.22), distant metastasis (DM) (OR=11.66, 95% CI: 5.36-25.37) and tumor stage (OR=2.58, 95% CI 1.86-3.57). CONCLUSIONS: This meta-analysis demonstrated that high CCAT2 expression significantly predicts poor OS, poor PFS, LNM, DM and tumor stage, suggesting that high CCAT2 expression may serve as a novel biomarker for poor prognosis and metastasis in cancers. PMID- 28089751 TI - Reduced serum milk fat globule-epidermal growth factor 8 (MFG-E8) concentrations are associated with an increased risk of microvascular complications in patients with type 2 diabetes. AB - BACKGROUND: The association between serum milk fat globule-epidermal growth factor 8 (MFG-E8) concentrations and vascular complications in T2DM remains unclear. METHODS: A total of 149 patients with T2DM were included. The serum concentrations of MFG-E8, glycosylated hemoglobin (HbA1c), and high-sensitivity C reactive protein (hs-CRP) were measured. RESULTS: There was no significant difference in serum MFG-E8 concentrations between the T2DM group and the T2DM with subclinical atherosclerosis (AS) group (615.49+/-143.54 vs. 596.22+/ 79.46ng/ml, P=0.365), while the serum concentrations of MFG-E8 in the T2DM with microvascular complications group (446.70+/-61.53ng/ml) and the T2DM with subclinical AS and microvascular complications group (200.87+/-38.86ng/ml) were significantly lower than those in the T2DM group (P=0.000 for both). In addition, hs-CRP and HbAlc concentrations were independently associated with serum MFG-E8 concentrations (P=0.024 and P=0.01, respectively), and low serum MFG-E8 concentrations were significantly associated with an increased risk of microvascular complications in T2DM patients. CONCLUSIONS: Serum concentrations of MFG-E8 were negatively associated with the risk of microvascular complications in patients with T2DM. Thus, it might be a potential candidate biomarker for diabetic microvascular complications. PMID- 28089752 TI - Three novel mutations of ARG1 identified in Chinese patients with argininemia detected by newborn screening. AB - Argininemia is a rare autosomal recessive genetic disorder caused by deficiency of arginase Iota, resulting from mutations in the ARG1 gene. Few genetic studies of ARG1 mutations in Chinese patients have been reported. In this study, two argininemia patients were initially diagnosed by tandem mass spectrometry in newborn screening. Mutation analysis of the ARG1 gene was performed by direct sequencing. Three novel mutations were identified and in silico methods were used to predict the impact of these mutations on the activity of enzyme. Two missense mutations, p.D100N and p.R71T, in Patient-1 were predicted to lower the stability of arginase Iota by analysis of 3D crystal structure, while two nonsense mutations, p.G12X and p.E42X, in Patient-2 were predicted to lead to truncated protein. Neonatal screening combined with genetic analysis is important for timely diagnosis and initiation of interventions of a potential genetic metabolic disease such as argininemia. PMID- 28089753 TI - Simultaneous quantitation of sphingoid bases by UPLC-ESI-MS/MS with identical 13C encoded internal standards. AB - Free sphingoid bases (lysosphingolipids) of primary storage sphingolipids are increased in tissues and plasma of several sphingolipidoses. As shown earlier by us, sphingoid bases can be accurately quantified using UPLC-ESI-MS/MS, particularly in combination with identical 13C-encoded internal standards. The feasibility of simultaneous quantitation of sphingoid bases in plasma specimens spiked with a mixture of such standards is here described. The sensitivity and linearity of detection is excellent for all examined sphingoid bases (sphingosine, sphinganine, hexosyl-sphingosine (glucosylsphingosine), hexosyl2 sphingosine (lactosylsphingosine), hexosyl3-sphingosine (globotriaosylsphingosine), phosphorylcholine-sphingosine) in the relevant concentration range and the measurements show very acceptable intra- and inter assay variation (<10% average). Plasma samples of a series of male and female Gaucher Disease and Fabry Disease patients were analyzed with the multiplex assay. The obtained data compare well to those earlier determined for plasma globotriaosylsphingosine and glucosylsphingosine in GD and FD patients. The same approach can be also applied to measure sphingolipids in the same sample. Following extraction of sphingolipids from the same sample these can be converted to sphingoid bases by microwave exposure and subsequently quantified using 13C encoded internal standards. PMID- 28089754 TI - Stem cell therapy: An emerging modality in glomerular diseases. AB - The kidney has been considered a highly terminally differentiated organ with low proliferative potential and thus unlikely to undergo regeneration. Glomerular disease progresses to end-stage renal disease (ESRD), which requires dialysis or renal transplantation for better quality of life for patients with ESRD. Because of the shortage of implantable kidneys and complications such as immune rejection, septicemia and toxicity of immunosuppression, kidney transplantation remains a challenge. Therapeutic options available for glomerular disease include symptomatic treatment and strategies to delay progression. In an attempt to develop innovative treatments by promoting the limited capability of regeneration and repair after kidney injury and overcome the progressive pathological process that is uncontrolled with conventional treatment modalities, stem cell-based therapy has emerged as novel intervention due to its ability to inhibit inflammation and promote regeneration. Recent developments in cell therapy have demonstrated promising therapeutic outcomes in terms of restoration of renal structure and function. This review focuses on stem cell therapy approaches for the treatment of glomerular disease, including the various cell sources used and recent advances in preclinical and clinical studies. PMID- 28089755 TI - Biodistribution and retention of locally administered human mesenchymal stromal cells: Quantitative polymerase chain reaction-based detection of human DNA in murine organs. AB - BACKGROUND: Determining the distributive fate and retention of a cell therapy product after administration is an essential part of characterizing it's biosafety profile. Therefore, regulatory guidelines stipulate that biodistribution assays are a requirement prior to advancing a cell therapy to the clinic. Here the development of a highly sensitive quantitative polymerase chain reaction (qPCR)-based method of tracking the biodistribution and retention of human mesenchymal stromal cells (hMSCs) in mice, rats or rabbits is described. METHODS: A primer-probe-based qPCR assay was developed to detect and quantify human Alu sequences in a heterogeneous sample of human DNA (hDNA) and murine DNA from whole organ genomic DNA extracts. The assay measures the amount of genomic hDNA by amplifying a 31-base pair sequence of the human Alu (hAlu) repeat sequence, thus enabling the detection of 0.1 human cells in 1.5 * 106 heterogeneous cells. RESULTS: Using this assay we investigated the biodistribution of 3 * 105 intramuscularly injected hMSCs in Balb/c nude mice. Genomic DNA was extracted from murine organs and hAlu sequences were quantified using qPCR analysis. After 3 months, hDNA ranging from 0.07%-0.58% was detected only at the injection sites and not in the distal tissues of the mice. DISCUSSION: This assay represents a reproducible, sensitive a method of detecting hDNA in rodent and lapine models. This manuscript describes the method employed to generate preclinical biodistribution data that was accepted by regulatory bodies in support of a clinical trial application. PMID- 28089757 TI - Disorazoles Block Group A Streptococcal Invasion into Epithelial Cells Via Interference with the Host Factor Ezrin. AB - Bacterial pathogens use invasion into human cells as a strategy to escape not only the host's immune response, but also anti-bacterial treatment. This often leads to persistence and enables reinitiation of the infection process at a later time point. Here, we show that a family of myxobacterial metabolites, disorazoles, block invasion of group A Streptococcus (GAS) into human epithelial cells. Mechanistically, disorazoles target ezrin, a host protein involved in linking microfilaments to the membrane, and affect invasion most likely by interfering with dynamic phosphorylation of ezrin. Overall, our study suggests ezrin as a new factor in two different GAS invasion pathways, independent of the already known CD44 pathway, and that disorazoles are promising "pathoblocker" compounds aimed at this additional invasion mechanism. PMID- 28089756 TI - Glycan Alteration Imparts Cellular Resistance to a Membrane-Lytic Anticancer Peptide. AB - Although resistance toward small-molecule chemotherapeutics has been well studied, the potential of tumor cells to avoid destruction by membrane-lytic compounds remains unexplored. Anticancer peptides (ACPs) are a class of such agents that disrupt tumor cell membranes through rapid and non-stereospecific mechanisms, encouraging the perception that cellular resistance toward ACPs is unlikely to occur. We demonstrate that eukaryotic cells can, indeed, develop resistance to the model oncolytic peptide SVS-1, which preferentially disrupts the membranes of cancer cells. Utilizing fission yeast as a model organism, we show that ACP resistance is largely controlled through the loss of cell-surface anionic saccharides. A similar mechanism was discovered in mammalian cancer cells where removal of negatively charged sialic acid residues directly transformed SVS 1-sensitive cell lines into resistant phenotypes. These results demonstrate that changes in cell-surface glycosylation play a major role in tumor cell resistance toward oncolytic peptides. PMID- 28089758 TI - Pupil responses and pain ratings to heat stimuli: Reliability and effects of expectations and a conditioning pain stimulus. AB - BACKGROUND: The locus coeruleus (LC) signals salience to sensory stimuli and these responses can modulate the experience of pain stimuli. The pupil dilation response (PDR) to noxious stimuli is thought to be a surrogate for LC responses, but PDR response to Peltier-controlled noxious heat stimuli, the most commonly used method in experimental pain research, has not been described. NEW METHOD: Healthy volunteers were presented with randomly presented heat stimuli of 5 sec duration and provided pain intensity ratings to each stimulus. Pupillometry was performed and a method developed to quantify the PDR relevant to these stimuli. The stimulus response, reliability, and effect of commonly used manipulations on pain experience were explored. RESULTS: A method of artifact removal and adjusting for lag from stimulus initiation to PDR response was developed, resulting in a close correlation between pain intensity rating and PDR across a large range of heat stimuli. A reliable assessment of PDR within an individual was achieved with fewer presentations as heat stimulus intensity increased. The correlation between pain rating and PDR was disrupted when cognitive load is increased by manipulating expectations or presenting a second pain stimulus. COMPARISON WITH EXISTING METHODS: The PDR began later after skin heating than electrical stimuli and this is the first examination of the PDR using standard nociceptive testing and manipulations of expectations and competing noxious stimulation. CONCLUSIONS: A method is described applying PDR to standard heat nociceptive testing, demonstrating stimulus response, reliability, and disruption by cognitive manipulation. PMID- 28089759 TI - Using pupil size and heart rate to infer affective states during behavioral neurophysiology and neuropsychology experiments. AB - BACKGROUND: Nonhuman primates (NHPs) are a valuable research model because of their behavioral, physiological and neuroanatomical similarities to humans. In the absence of language, autonomic activity can provide crucial information about cognitive and affective states during single-unit recording, inactivation and lesion studies. Methods standardized for use in humans are not easily adapted to NHPs and detailed guidance has been lacking. NEW METHOD: We provide guidance for monitoring heart rate and pupil size in the behavioral neurophysiology setting by addressing the methodological issues, pitfalls and solutions for NHP studies. The methods are based on comparative physiology to establish a rationale for each solution. We include examples from both electrophysiological and lesion studies. RESULTS: Single-unit recording, pupil responses and heart rate changes represent a range of decreasing temporal resolution, a characteristic that impacts experimental design and analysis. We demonstrate the unexpected result that autonomic measures acquired before and after amygdala lesions are comparable despite disruption of normal autonomic function. COMPARISON WITH EXISTING METHODS: Species and study design differences can render standard techniques used in human studies inappropriate for NHP studies. We show how to manage data from small groups typical of NHP studies, data from the short behavioral trials typical of neurophysiological studies, issues associated with longitudinal studies, and differences in anatomy and physiology. CONCLUSIONS: Autonomic measurement to infer cognitive and affective states in NHP is neither off-the shelf nor onerous. Familiarity with the issues and solutions will broaden the use of autonomic signals in NHP single unit and lesion studies. PMID- 28089761 TI - Transfusion Medicine in China Comes of Age. PMID- 28089760 TI - Enhanced Long-Term Brain Magnetic Resonance Imaging Evaluation of Children with Sickle Cell Disease after Hematopoietic Cell Transplantation. AB - Progressive neurovasculopathy in children with sickle cell disease (SCD) results in decreased cognitive function and quality of life (QoL). Hematopoietic cell transplantation (HCT) is believed to halt progression of neurovasculopathy. Quantitative analysis of T2-weighted fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) for white matter hyperintensity (WMH) burden provides a meaningful estimate of small vessel cerebrovascular disease. We asked if quantitative analysis of WMH could complement standardized clinical assessment of MRI/magnetic resonance angiography (MRA) for assessing SCD central nervous system vasculopathy before and after HCT. Retrospective longitudinal clinical examination of scheduled annual MRI/MRA and quantitative analysis of WMH were performed before and 1 to 7 years after HCT at scheduled annual intervals, along with QoL measurements, in children who had engrafted after HCT. Of 18 patients alive and persistently engrafted (median age, 9.1 years), pretransplantation MRI demonstrated that 9 and 5 had sickle-related stroke and/or small infarcts, respectively. Patients were divided into WMH severity tertiles based on pretransplantation WMH volumes. MRI and WMH were assessed 1 to 7 years after HCT. MRI/MRA and WMH volume were stable or slightly better in 17 of 18 patients. By parent- and self-report, post-HCT QoL improved for children in the lowest WMH tertile significantly more than in the other groups. Based on this single institution retrospective sample, we report that WMH appears to quantitatively support MRI-based findings that HCT stabilizes long-term small and large vessel cerebrovascular changes and is associated with the degree of improved QoL. While confirmation in larger prospective studies and evaluation by neurocognitive testing are needed, these findings suggest that WMH is a useful biomarker of neurovasculopathy after transplantation for SCD. PMID- 28089763 TI - Comparison of multi-arm multi-stage design and adaptive randomization in platform clinical trials. AB - Platforms trials are clinical trials that allow for concurrent evaluations of multiple treatments, thus allowing for more efficient and ethical studies compared to traditional two-arm trials. Conventional group-sequential multi-arm multi-stage (MAMS) designs use pre-specified stopping boundaries and treatment selection rules to determine if experimental treatments should be dropped. Flexible MAMS designs allow for interim modifications to the design plan without compromising error rates. Bayesian response adaptive randomization (BRAR) designs increase patient allocation to treatment arms that are performing well during the course of the trial. In this paper, we compare these two major methods and their extensions under several scenarios in the platform trials setting. Results show that BRAR and flexible MAMS designs have comparable power and type 1 error rate under varying simulated scenarios, allowing for addition of flexible treatment selection. BRAR outperforms flexible MAMS when there is a single effective treatment. Flexible MAMS designs are more efficient compared to BRAR when there are no effective treatments. BRAR performance increases as the probability of a treatment arm being dropped increases. PMID- 28089762 TI - Long-Term Results of a Trial of Concurrent Chemotherapy and Escalating Doses of Radiation for Unresectable Non-Small Cell Lung Cancer: NCCTG N0028 (Alliance). AB - INTRODUCTION: This phase I/II trial was designed to determine the maximally tolerated dose of thoracic radiotherapy as part of a combined modality approach. This report includes the long-term outcomes of patients treated on this study. The phase II portion was never completed, as RTOG-0617 opened before it was concluded. METHODS: In this study, the maximally tolerated dose was defined as 74 Gy of radiation in 37 fractions. Twenty-five patients with unresectable NSCLC were treated with 2-Gy daily fractions and concurrent weekly carboplatin and paclitaxel. Of these patients, 20 had stage III disease and five had stage I or II disease. RESULTS: Patients were followed until death or for a minimum of 5 years in the case of survivors. The median and 5-year survivals were 42.5 months and 20% for all patients, 52.9 months and 40% in patients with stages I or II disease, and 39.8 months and 15% in patients with stage III disease. CONCLUSIONS: The median survival of the stage III patients was quite favorable. We believe that this may have been due to a robust central review program of radiotherapy plans before treatment, ensuring compliance with protocol guidelines along with very low exposure of the heart to radiotherapy. Further improvements in 5-year survival will likely require research on both systemic therapy and thoracic radiotherapy. Potential therapeutic modalities that may aid in these efforts include immunotherapy, targeted therapy, improved imaging, adaptive radiotherapy, simultaneous integrated boost techniques, novel dose fractionation regimens, and charged particle therapy. PMID- 28089764 TI - Promoting weight maintenance with electronic health record tools in a primary care setting: Baseline results from the MAINTAIN-pc trial. AB - Maintaining weight loss is a significant challenge in combating obesity. The goal of Maintaining Activity and Nutrition through Technology-Assisted Innovation in Primary Care (MAINTAIN-pc) is to evaluate the use of tools delivered through an electronic health record (EHR) and patient portal, with or without health coach support, to help primary care patients maintain weight loss. EHR tools include flowsheets, standardized surveys, and secure patient messaging. Inclusion criteria were age 18-75years, voluntary 5% weight loss in the past 2years with prior BMI>=25kg/m2, and no bariatric procedures in past 5years. Participants were randomized 1:1 to tailored online coaching with EHR tracking tools (CC) or EHR tracking tools alone (TO). We screened 721 individuals between October 2013 and February 2015; 194 participants enrolled (98 CC; 96 TO). The most common reasons for not enrolling included lack of interest (56%), not meeting age or weight loss criteria (17%), and no verified prior weight loss (10%). At baseline, participants were 53.4 (SD 12.2) years old, 74% female, and 88% White; 95% reported moderate physical activity. Average weight and BMI at baseline were 189.1 (SD 42.1) lbs and 30.4 (5.9) kg/m2, respectively. Pre-weight loss BMI was 34.4 (SD 6.5) kg/m2. Participants lost an average of 11.3% (SD 6.6) of their body weight before enrolling. Demographic and clinical characteristics did not differ by randomized group. The study successfully identified and recruited primary care patients with recent voluntary weight loss for participation in a weight maintenance program that uses EHR-based tools. PMID- 28089765 TI - Intracerebroventricular Delivery as a Safe, Long-Term Route of Drug Administration. AB - Intrathecal delivery methods have been used for many decades to treat a broad range of central nervous system disorders. A literature review demonstrated that intracerebroventricular route is an established and well-tolerated method for prolonged central nervous system drug delivery in pediatric and adult populations. Intracerebroventricular devices were present in patients from one to 7156 days. The number of punctures per device ranged from 2 to 280. Noninfectious complication rates per patient (range, 1.0% to 33.0%) were similar to infectious complication rates (0.0% to 27.0%). Clinician experience and training and the use of strict aseptic techniques have been shown to reduce the frequency of complications. PMID- 28089766 TI - Males With MECP2 C-terminal-Related Atypical Rett Syndromes and Their Carrier Mothers. AB - BACKGROUND: This communication examines the expanding phenotypes of the MECP2 C terminal atypical Rett syndromes in males and their affected carrier mothers. DESCRIPTIONS: We describe three males with normal karyotypes who presented with congenital evolving complex neurodevelopmental encephalopathies with multifaceted symptomatology of hypotonia, epilepsy, ataxia, spasticity, movement disorders, behavioral issues, severe intellectual impairment, and communication skills, and a protracted regression phase followed by stabilization. These phenotypes did not prompt us to identify atypical Rett syndrome early in childhood. RESULTS: Genetic analysis identified the two brothers with C-terminal truncation and the third male with C-terminal missense mutations. These mutations were inherited from their mothers, both of whom had incompletely characterized modest intellectual, mental health, social, and gastrointestinal impairments. Neither was independently able to care properly for their son(s). CONCLUSIONS: Mutations of the MECP2 gene should be considered early in males with hypotonia, developmental delay, profound intellectual impairment, and seizures, associated with a mother with psychosocial, cognitive, and gastrointestinal impairments. Counseling and supporting mildly affected mothers requires both medical and social efforts. PMID- 28089767 TI - The Correlation Between a Short-term Conventional Electroencephalography in the First Day of Life and Brain Magnetic Resonance Imaging in Newborns Undergoing Hypothermia for Hypoxic-Ischemic Encephalopathy. AB - OBJECTIVE: Electroencephalograph recorded in the first day of life in newborns treated with hypothermia for hypoxic-ischemic encephalopathy could be utilized as a predictive tool for the severity of brain injury on magnetic resonance imaging and mortality. STUDY DESIGN: We analyzed newborns who were admitted for therapeutic hypothermia due to hypoxic-ischemic encephalopathy. All enrolled infants underwent encephalography within the first 24 hours of life and underwent brain magnetic resonance imaging after rewarming. All encephalographs were independently reviewed for background amplitude, continuity, and variability. Brain injury determined by magnetic resonance imaging was scored using methods described by Bonifacio et al. RESULTS: Forty-one newborns were included in the study. Each encephalograph variable correlated significantly with the severity of injury on brain magnetic resonance imaging (P < 0.001 for each). The overall encephalograph severity estimated as mild, moderate, and severe also correlated with injury (P < 0.001). Each encephalograph variable correlated with mortality (P < 0.001 for each) and also the overall encephalograph severity (P < 0.001). CONCLUSION: Severity of electrographic findings on encephalograph in the first day of life during therapeutic hypothermia for hypoxic-ischemic encephalopathy correlated with the extent of injury on brain magnetic resonance imaging. This information may be useful for families and aid guide clinical decision making. PMID- 28089768 TI - Sleep Problems in Children With Agenesis of the Corpus Callosum. AB - BACKGROUND: Very little is known about sleep habits in children with agenesis of the corpus callosum (ACC). The purpose of this investigation was to evaluate sleep problems in children with ACC and examine the association with quality of life. METHODS: We performed a cross-sectional, anonymous, internet-based survey offered to parents of children with ACC, aged five to 18 years. The Children's Sleep Habits Questionnaire (CSHQ) and pediatric quality of life (PedsQL) were used to assess sleep habits and quality of life, respectively. Associations between the total and all subdomains of CSHQ and PedsQL were tested. RESULTS: The final sample included 66 parents of children with ACC. Overall, 78% of the children had clinically significant sleep problems, using a cutoff score of 41 on the CSHQ. Compared with a prior national sample of typically developing children, children with ACC scored significantly higher overall and in all subdomains of the CSHQ. The overall CSHQ and PedsQL were moderately correlated (r = -0.485, P < 0.001), indicating that children with more sleep problems had worse quality of life. In addition, the total CSHQ correlated with all subdomains of the pediatric quality of life, including emotional (r = -0.515, P < 0.01), social (r = -0.394, P < 0.01), physical (r = -0.263, P < 0.01), and school (r = -0.362, P < 0.01). These associations remained statistically significant in multivariable regression models controlling for age and gender. CONCLUSIONS: Sleep problems are common and associated with lower quality of life in children with ACC. PMID- 28089769 TI - Nuclear translocation of STAT3 and NF-kappaB are independent of each other but NF kappaB supports expression and activation of STAT3. AB - NF-kappaB and STAT3 are essential transcription factors in immunity and act at the interface of the transition from chronic inflammation to cancer. Different functional crosstalks between NF-kappaB and STAT3 have been recently described arguing for a direct interaction of both proteins. During a systematic analysis of NF-kappaB/STAT3 crosstalk we observed that appearance of the subcellular distribution of NF-kappaB and STAT3 in immunofluorescence heavily depends on the fixation procedure. Therefore, we established an optimized fixation protocol for the reliable simultaneous analysis of the subcellular distributions of both transcription factors. Using this protocol we found that cytokine-induced nuclear accumulation of NF-kappaB or STAT3 did not alter the subcellular distribution of the other transcription factor. Both knockout and overexpression of STAT3 does not have any major effect on canonical TNFalpha-NF-kappaB signalling in MEF or HeLa cells. Similarly, knockout of p65 did not alter nuclear accumulation of STAT3 in response to IL-6. However, p65 expression correlates with elevated total cellular levels of STAT3 and STAT1 and supports activation of these transcription factors. Our findings in MEF cells argue against a direct physical interaction of free cellular NF-kappaB and STAT3 but point to more intricate functional interactions. PMID- 28089770 TI - Structural pierce into molecular mechanism underlying Clostridium perfringens Epsilon toxin function. AB - Epsilon toxin of the Clostridium perfringens garnered a lot of attention due to its potential for toxicity in humans, extreme potency for cytotoxicity in mice and lack of any approved therapeutics prescribed for human. However, the intricacies of the Epsilon toxin action mechanism are yet to be understood. In this regard, various in silico tools have been exploited to model and refine the 3D structure of the toxin and its two receptors. The receptor proteins were embedded into designed lipid membranes within an aqueous and ionized environment. Thereafter, the modeled structures subjected to series of consecutive molecular dynamics runs to achieve the most natural like coordination for each model. Ultimately, protein-protein interaction analyses were performed to understand the probable action mechanism. The obtained results successfully confirmed the accuracy of employed methods to achieve high quality models for the toxin and its receptors within their lipid bilayers. Molecular dynamics analyses lead the structures to a more native like coordination. Moreover, the results of previous empirical studies were confirmed, while new insights for action mechanisms including the detailed roles of Hepatitis A virus cellular receptor 1 (HAVCR1) and Myelin and lymphocyte protein (MAL) proteins were achieved. In light of previous and our observations, we suggested novel models which elucidated the existing interplay between potential players of Epsilon toxin action mechanism with detailed structural evidences. These models would pave the way to have more robust understanding of the Epsilon toxin biology, more precise vaccine construction and more successful drug (inhibitor) design. PMID- 28089771 TI - Extended therapeutic window for post-exposure treatment of ricin intoxication conferred by the use of high-affinity antibodies. AB - The plant toxin ricin is considered a potential bioterror agent against which there is no available antidote. To date, neutralizing antibodies are the most promising post-exposure treatment for ricin intoxication, yet so far they were shown to be effective only when given within several hours post exposure. As part of an ongoing effort to develop efficient ricin-countermeasures, we tested whether high-affinity antibodies that were previously isolated from immunized non human primates, may confer effective post-exposure therapy for ricin-intoxicated mice treated at late time-points after exposure. While each antibody is capable of providing high protection rate by itself, a formulation consisting of three neutralizing antibodies that target different epitopes was tested to provide therapeutic coverage against different variants of the malicious pathogen. Indeed, the tri-antibody based cocktail was highly effective, its administration resulting in very high survival rates (>70%) when animals were treated as late as 48 h post exposure and significant protection (>30%) even at 72 h. This study establishes for the first time that anti-ricin antibodies can serve as a highly effective antidote at such late time-points after exposure. From the clinical point of view, the extended therapeutic window documented here is of high importance allowing adequate time to accurately identify the causative agent and may permit initiation of life-saving treatment with these antibodies even after the onset of clinical signs. PMID- 28089772 TI - Anxiety like behavior due to perinatal exposure to Bisphenol-A is associated with decrease in excitatory to inhibitory synaptic density of male mouse brain. AB - Bisphenol-A (BPA) is a synthetic endocrine disruptor which causes anxiety like behavior in rodents, though the underlying mechanism is not clearly understood. As excitatory-inhibitory synaptic proteins are the key regulators of anxiety, we have examined the effect of perinatal exposure to BPA on this behavior and the expression of excitatory (PSD95), inhibitory (gephyrin) and presynaptic density marker (synaptophysin) proteins in cerebral cortex and hippocampus of 3 and 8 weeks postnatal male mice. In open field (OF) test, BPA exposure reduced the time spent, number of entries and distance travelled in the central zone as compared to control in 8 weeks mice. On the other hand, elevated plus maze (EPM) results showed decrease in time spent and number of entries to the open arms. Immunoblotting and immunofluorescence analysis showed significant downregulation of PSD95 and synaptophysin, but upregulation of gephyrin, leading to reduction in excitatory to inhibitory protein ratio and synaptic density in postnatal 3 and 8 weeks mice. Thus, our findings show that the anxiety like behavior due to perinatal exposure to BPA is associated with decrease in excitatory to inhibitory synaptic density in postnatal male mice. PMID- 28089773 TI - Mitochondrial diseases: Yeast as a model for the study of suppressors. AB - Mitochondrial (mt) tRNA gene mutations are an important cause of human morbidity and are associated with different syndromes. We have previously shown that the mitochondrial protein synthesis elongation factor EF-Tu and isolated sequences from the carboxy-terminal domain of yeast and human mt leucyl-tRNA synthetases (LeuRS), have a wide range of suppression capability among different yeast mt tRNA mutants having defective respiratory phenotype. Here we show that the rescuing capability can be restricted to a specific sequence of six amino acids from the carboxy-terminal domain of mt LeuRS. On the other hand by overexpressing a mutated version of mt EF-Tu in a yeast strain deleted for the endogenous nuclear gene we identified the specific region involved in suppression. Results support the possibility that a small peptide could correct defects associated with many mt tRNA mutations, suggesting a novel therapy for mitochondrial diseases treatment. The involvement of the mt EF-Tu in cellular heat stress response has also been suggested. PMID- 28089774 TI - Rootletin prevents Cep68 from VHL-mediated proteasomal degradation to maintain centrosome cohesion. AB - Centrosome cohesion, mostly regarded as a proteinaceous linker between parental centrioles, ensures the interphase centrosome(s) to function as a single microtubule-organizing center. Maintenance of centrosome cohesion counts on a number of centrosomal linker proteins because depletion of any of those leads to premature centrosome separation in interphase, termed centrosome splitting. However, the underlying mechanisms of the dependence are unknown. Here, we show that absence of Rootletin triggers the von Hippel-Lindau tumour suppressor protein (VHL)-mediated proteasomal degradation of Cep68 and, in turn, results in centrosome splitting. The VHL E3 ligase complex ubiquitinates Cep68 in vitro and in vivo. Co-silencing of Rootletin and VHL reverts Cep68 loss and centrosome splitting. Expression of a stable mutant of Cep68, either diminishing its polyubiquitylation or eliminating binding to beta-domain of VHL, also suppresses centrosome splitting provoked by Rootletin depletion. We propose that the archetypal linker protein Rootletin maintains centrosome cohesion in part through inhibition of VHL-mediated Cep68 degradation. PMID- 28089775 TI - Degenerative effects of cobalt-chloride treatment on neurons and microglia in a porcine retina organ culture model. AB - In order to understand the pathological processes of retinal diseases, experimental models are necessary. Cobalt, as part of the vitamin B12 complex, is important for neuronal integrity. However, it is known that high quantities of cobalt induce cytotoxic mechanisms via hypoxia mimicry. Therefore, we tested the degenerative effect of cobalt chloride (CoCl2) on neurons and microglia in a porcine retina organ culture model. Organotypic cultures of porcine retinas were cultured and treated with different concentrations of CoCl2 (0, 100, 300 and 500 MUM) for 48 h. After four and eight days, CoCl2 induced a strong degeneration of the porcine retina, starting at 300 MUM. A loss of retinal ganglion cells (RGCs, Brn-3a), amacrine cells (calretinin) and bipolar cells (PKCalpha) was observed. Additionally, a high expression of hypoxia induced factor-1a (HIF-1a) and heat shock protein 70 (HSP70) was noted at both points in time. Also, the Caspase 3 protein was activated and P21 expression was induced. However, only at day four, the Bax/Bcl-2 ratio was increased. The effect of CoCl2 was not restricted to neurons. CoCl2 concentrations reduced the microglia amount (Iba1) and activity (Iba1 + Fcgamma-Receptor) at both points in time. These damaging effects on microglia were surprising, since CoCl2 causes hypoxia and a pro-inflammatory environment. However, high concentrations of CoCl2 also seem to be toxic to these cells. Similar degenerative mechanisms as in comparison to retinal ischemia animal models were observed. In summary, an effective and reproducible hypoxia mimicking organotypic model for retinal degeneration was established, which is easy to handle and ready for drug studies. PMID- 28089776 TI - Predictors of same day discharge after percutaneous coronary interventions. AB - OBJECTIVES: The aim of this study is to identify possible predictors for same day discharge (SDD) after percutaneous coronary interventions (PCI). BACKGROUND: Same day discharge after PCI is becoming more and more appealing and patient's selection criteria are being formulated. METHODS: A retrospective analysis was performed in all PCI procedures from January 2013 until December 2015. Patients were discharged the same day (SDD group) or had at least one overnight stay (non SDD group). The decision of SDD or not was on treating physician discretion. We evaluated predictors of SDD decision by a logistic regression analysis. RESULTS: One thousand one hundred sixty eight procedures were performed from our department during the study period: 308 patients (26.4%) were discharged the same day (SDD group) and the rest 860 procedures (73.6%) had at least one overnight stay (non-SDD group). Multivariate analysis revealed that forearm approach (OR=5.498, CI: 2.067-14.629; p=<0.001), patient's residency proximal to the hospital (OR=4.543, CI: 2.406-8.580; p<0.001), completion of the procedure before 13,00p.m. (OR=3.437, CI: 1.789-0.6.601; p<0.001) and the success of the performed procedure (OR=1.125, CI 1.043-2.135; p=0.044) were positive predictors of SDD, while presentation with non-ST elevation myocardial infarction or unstable angina (OR=0.542, CI: 0.268-0.872; p<0.010) and amount of contrast used (OR=0.910, CI: 0.852-0.969; p<0.030) were negative predictors of SDD. CONCLUSION: In retrospect, both procedural and demographic details play a crucial role in patient selection for same day discharge post coronary percutaneous intervention. PMID- 28089777 TI - Bioresorbable vascular scaffold to treat malignant in-stent restenosis in a patient with nickel allergy. AB - Nickel is the most frequent allergen in patients with allergic contact dermatitis and nickel allergy has been associated with recurrent in-stent restenosis. However, it is often misdiagnosed because of a low suspicion threshold. It should be discarded in patients with recurrent in-stent restenosis, especially if their medical history reveals prior contact dermatitis. It is also noteworthy and rarely specified that even newer generation stents that use novel metal alloys also contain low amounts of nickel. To avoid the implantation of new stents containing this metal, when percutaneous coronary intervention is indicated, drug eluting balloons or bioresorbable vascular scaffolds associated with small doses of steroids could provide good alternatives of treatment. To the best of our knowledge, this is the first description of this therapeutic alternative in such an exceedingly rare clinical scenario. PMID- 28089778 TI - Image noise reduction technology reduces radiation in a radial-first cardiac catheterization laboratory. AB - BACKGROUND: Transradial coronary angiography (TRA) has been associated with increased radiation doses. We hypothesized that contemporary image noise reduction technology would reduce radiation doses in the cardiac catheterization laboratory in a typical clinical setting. METHODS AND RESULTS: We performed a single-center, retrospective analysis of 400 consecutive patients who underwent diagnostic and interventional cardiac catheterizations in a predominantly TRA laboratory with traditional fluoroscopy (N=200) and a new image noise reduction fluoroscopy system (N=200). The primary endpoint was radiation dose (mGy cm2). Secondary endpoints were contrast dose, fluoroscopy times, number of cineangiograms, and radiation dose by operator between the two study periods. Radiation was reduced by 44.7% between the old and new cardiac catheterization laboratory (75.8mGycm2+/-74.0 vs. 41.9mGycm2+/-40.7, p<0.0001). Radiation was reduced for both diagnostic procedures (45.9%, p<0.0001) and interventional procedures (37.7%, p<0.0001). There was no statistically significant difference in radiation dose between individual operators (p=0.84). In multivariate analysis, radiation dose remained significantly decreased with the use of the new system (p<0.0001) and was associated with weight (p<0.0001), previous coronary artery bypass grafting (p<0.0007) and greater than 3 stents used (p<0.0004). TRA was used in 90% of all cases in both periods. Compared with a transfemoral approach (TFA), TRA was not associated with higher radiation doses (p=0.20). CONCLUSIONS: Image noise reduction technology significantly reduces radiation dose in a contemporary radial-first cardiac catheterization clinical practice. PMID- 28089779 TI - Percutaneous coronary intervention of chronically occluded saphenous vein grafts using excimer laser atherectomy as an adjuvant therapy. AB - We present two cases with chronic total occlusion of the saphenous vein graft in two patients with a history of previous bypass surgery with unfavorable anatomic features for recanalization of the native coronary artery. In the first case, two dedicated attempts for recanalization of chronic total occlusion of the native artery failed and in the second case there was not an adequate visualization of the native vessel beyond the occlusion point, not even by contralateral injection. Excimer laser atherectomy was used in both cases as an adjuvant therapy during recanalization of the saphenous vein graft in combination with a distal protection device in order to reduce distal embolization. The procedures proved successful after stent implantation in the whole length of the saphenous vein grafts and the patients suffered no remarkable events during hospitalization. PMID- 28089780 TI - Co-feeding transmission facilitates strain coexistence in Borrelia burgdorferi, the Lyme disease agent. AB - Coexistence of multiple tick-borne pathogens or strains is common in natural hosts and can be facilitated by resource partitioning of the host species, within host localization, or by different transmission pathways. Most vector-borne pathogens are transmitted horizontally via systemic host infection, but transmission may occur in the absence of systemic infection between two vectors feeding in close proximity, enabling pathogens to minimize competition and escape the host immune response. In a laboratory study, we demonstrated that co-feeding transmission can occur for a rapidly-cleared strain of Borrelia burgdorferi, the Lyme disease agent, between two stages of the tick vector Ixodes scapularis while feeding on their dominant host, Peromyscus leucopus. In contrast, infections rapidly became systemic for the persistently infecting strain. In a field study, we assessed opportunities for co-feeding transmission by measuring co-occurrence of two tick stages on ears of small mammals over two years at multiple sites. Finally, in a modeling study, we assessed the importance of co-feeding on R0, the basic reproductive number. The model indicated that co-feeding increases the fitness of rapidly-cleared strains in regions with synchronous immature tick feeding. Our results are consistent with increased diversity of B. burgdorferi in areas of higher synchrony in immature feeding - such as the midwestern United States. A higher relative proportion of rapidly-cleared strains, which are less human pathogenic, would also explain lower Lyme disease incidence in this region. Finally, if co-feeding transmission also occurs on refractory hosts, it may facilitate the emergence and persistence of new pathogens with a more limited host range. PMID- 28089781 TI - Genotoxic effect and rat hepatocyte death occurred after oxidative stress induction and antioxidant gene downregulation caused by long term fluoride exposure. AB - Studies focusing on possible genotoxic effects of excess fluoride are contradictory and inconclusive. Currently, studies have reported a probable link to oxidative stress, DNA damage and apoptosis induced by fluoride in rat hepatocytes. We developed an in vivo study administering three doses of fluoride by gavage given to rats for 60 day. Micronucleus test was applied to investigate genotoxic potential of fluoride. The TUNEL method determined DNA fragmentation and apoptosis. Biochemical parameters to investigate mitochondrial swelling and oxidative stress. Semi-quantitative RT-PCR and immunostaining to determine mRNA and protein expression of antioxidant enzymes. Analyses of the hepatic function and morphology were performed. Our results revealed the genotoxic potential of fluoride but did not confirm mitochondrial swelling nor an increase of positive TUNEL labelling induced by fluoride, indicating absence of apoptosis. Oxidative stress induction was confirmed and is probably associated to DNA damage. Cell death events such as empty nuclear spaces, cytoplasm degeneration, nuclear pyknosis, karyorrhexis and karyorrhexis followed by karyolysis were observed. Hepatic function did not appear to be significantly modified makes no evidence of necrosis and suggesting other cell death pathway, the autophagic. In conclusion, prolonged fluoride intake at chosen concentrations caused imbalance of the cellular oxidative state, affected DNA and disrupted cellular homeostasis. It is recommended that fluoride supplementation requires a fresh consideration in light of the current study. PMID- 28089782 TI - Hepatic co-cultures in vitro reveal suitable to detect Nrf2-mediated oxidative stress responses on the bladder carcinogen o-anisidine. AB - The azo dye o-anisidine is known as an industrial and environmental pollutant. Metabolites of o-anisidine remain in the liver for >24h. However, the toxicological impact of o-anisidine on the liver and its individual cell types, e.g., hepatocytes and immune cells, is currently poorly understood. A novel co culture system, composed of HepG2 or Huh-7 cells, and differentiated THP-1 cells was used to study the metabolic capacity towards o-anisidine, and compared to primary murine hepatocytes which express high enzyme activities. As model compounds the carcinogenic arylamine o-anisidine and its non-carcinogenic isomer, p-anisidine, as well as caffeine were used. Global proteome analysis revealed an activation of eIF2 and Nrf2-mediated oxidative stress response pathways only in co-cultures after treatment with o-anisidine. This was confirmed via detection of reactive oxygen species. In addition, the mitochondrial membrane potential decreased already after 3h treatment of cells, which correlated with a decrease of ATP levels (R2>0.92). In the supernatant of co-cultured, but not single cultured HepG2 and Huh-7 cells, o-anisidine caused increases of damage-associated proteins, such as HMGB1 (high mobility group box-1) protein. In summary, only co cultures of HepG2 and THP-1 cells predict o-anisidine induced stress responsive pathways, since the system has a higher sensitivity compared to single cultured cells. PMID- 28089783 TI - Characterization of rat or human hepatocytes cultured in microphysiological systems (MPS) to identify hepatotoxicity. AB - The liver is the main site for drug and xenobiotics metabolism, including inactivation or bioactivation. In order to improve the predictability of drug safety and efficacy in clinical development, and to facilitate the evaluation of the potential human health effects from exposure to environmental contaminants, there is a critical need to accurately model human organ systems such as the liver in vitro. We are developing a microphysiological system (MPS) based on a new commercial microfluidic platform (Nortis, Inc.) that can utilize primary liver cells from multiple species (e.g., rat and human). Compared to conventional monolayer cell culture, which typically survives for 5-7days or less, primary rat or human hepatocytes in an MPS exhibited higher viability and improved hepatic functions, such as albumin production, expression of hepatocyte marker HNF4alpha and canaliculi structure, for up to 14days. Additionally, induction of Cytochrome P450 (CYP) 1A and 3A4 in cryopreserved human hepatocytes was observed in the MPS. The acute cytotoxicity of the potent hepatotoxic and hepatocarcinogen, aflatoxin B1, was evaluated in human hepatocytes cultured in an MPS, demonstrating the utility of this model for acute hepatotoxicity assessment. These results indicate that MPS-cultured hepatocytes provide a promising approach for evaluating chemical toxicity in vitro. PMID- 28089785 TI - Mechanistic modelling of infrared mediated energy transfer during the primary drying step of a continuous freeze-drying process. AB - Conventional pharmaceutical freeze-drying is an inefficient and expensive batch wise process, associated with several disadvantages leading to an uncontrolled end product variability. The proposed continuous alternative, based on spinning the vials during freezing and on optimal energy supply during drying, strongly increases process efficiency and improves product quality (uniformity). The heat transfer during continuous drying of the spin frozen vials is provided via non contact infrared (IR) radiation. The energy transfer to the spin frozen vials should be optimised to maximise the drying efficiency while avoiding cake collapse. Therefore, a mechanistic model was developed which allows computing the optimal, dynamic IR heater temperature in function of the primary drying progress and which, hence, also allows predicting the primary drying endpoint based on the applied dynamic IR heater temperature. The model was validated by drying spin frozen vials containing the model formulation (3.9mL in 10R vials) according to the computed IR heater temperature profile. In total, 6 validation experiments were conducted. The primary drying endpoint was experimentally determined via in line near-infrared (NIR) spectroscopy and compared with the endpoint predicted by the model (50min). The mean ratio of the experimental drying time to the predicted value was 0.91, indicating a good agreement between the model predictions and the experimental data. The end product had an elegant product appearance (visual inspection) and an acceptable residual moisture content (Karl Fischer). PMID- 28089784 TI - Axillary Management of Stage II/III Breast Cancer in Patients Treated with Neoadjuvant Systemic Therapy: Results of CALGB 40601 (HER2-Positive) and CALGB 40603 (Triple-Negative). AB - BACKGROUND: Management of the axilla in stage II/III breast cancer undergoing neoadjuvant systemic therapy (NST) is controversial. To understand current patterns of care, we collected axillary data from 2 NST trials: HER2-positive (Cancer and Leukemia Group B [CALGB] 40601) and triple-negative (CALGB 40603). STUDY DESIGN: Axillary evaluation pre- and post-NST was per the treating surgeon and could include sentinel node biopsy. Post-NST, node-positive patients were recommended to undergo axillary lymph node dissection (ALND). We report pre-NST histopathologic nodal evaluation and post-NST axillary surgical procedures with correlation to clinical and pathologic nodal status. RESULTS: Seven hundred and forty-two patients were treated, 704 had complete nodal data pre-NST and post NST. Pre-NST, 422 (60%) of 704 patients underwent at least 1 procedure for axillary node evaluation (total of 468 procedures): fine needle aspiration (n = 234; 74% positive), core needle biopsy (n = 138; 72% positive), and sentinel node biopsy (n = 96; 33% positive). Pre-NST, 304 patients were considered node positive. Post-NST, 304 of 704 patients (43%) underwent sentinel node biopsy; 44 were positive and 259 were negative (29 and 36 patients, respectively, had subsequent ALND). Three hundred and ninety-one (56%) patients went directly to post-NST ALND and 9 (1%) pre-NST node-positive patients had no post-NST axillary procedure. Post-NST, 170 (24%) of the 704 patients had residual axillary disease. Agreement between post-NST clinical and radiologic staging and post-NST histologic staging was strongest for node-negative (81%) and weaker for node positive (N1 31%, N2 29%), with more than half of the clinically node-positive patients found to be pathologic negative (p < 0.001). CONCLUSIONS: Our results suggest there is no widely accepted standard for axillary nodal evaluation pre NST. Post-NST staging was highly concordant in patients with N0 disease, but poorly so in node-positive disease. Accurate methods are needed to identify post NST patients without residual axillary disease to potentially spare ALND. PMID- 28089786 TI - 3-Carboxyphenylboronic acid-modified carboxymethyl chitosan nanoparticles for improved tumor targeting and inhibitory. AB - Carboxymethyl chitosan-based nanoparticles (CM NPs) were prepared, and were further modified with a tumor-homing ligand (3-carboxyphenylboronic acid, 3-CPBA) to give tumor-targeting nanoparticles (CB NPs). Particle sizes were measured by dynamic light scattering, while the morphology was observed via transmission electron microscopy and scanning electronic microscope. The results show that CM and CB NPs are spherical-like, and kinetically stable in various conditions. Doxorubicin (DOX) as a model drug was successfully encapsulated to give CM-DOX and CB-DOX NPs. The biological effect of these DOX-loaded NPs was then investigated by monolayer cell model and three-dimensional multicellular spheroids (MCS). The results demonstrate that 3-CPBA modification can improve NPs' accumulation and penetration ability. In vivo antitumor effect was evaluated by H22 lung metastasis tumor-bearing mice. CB-DOX NPs can deliver more drug than CM-DOX NPs, and retain for a long time in lung tissue, thus remarkably reducing the size of tumor mass of H22 metastasis lung tumor. All results demonstrate that the obtained NPs would be potentially useful as nano-scaled drug carriers in chemotherapy. PMID- 28089787 TI - Antituberculosis drugs: reducing efflux=increasing activity. AB - In mycobacteria, it was assumed that efflux pumps only had a marginal role in drug resistance. In recent years, owing to the need to find novel drugs against multidrug-resistant tuberculosis, it has become clear that efflux should not be ignored. Although efflux inhibitors have been very useful for characterizing in vitro the properties of efflux pumps, their usefulness in vivo is limited because of their toxicity. Alternatively, programs aimed at discovering novel drugs for treating tuberculosis should implement strategies to characterize efflux liability of candidate drugs. Here, we present an experimental approach for studying efflux of compounds selected under the More Medicines for Tuberculosis research project, and a few examples of how, for tuberculosis drug discovery, efflux matters. PMID- 28089788 TI - Cardiovascular Disease Risk Assessment in Australian Community Pharmacy. AB - BACKGROUND: Population screening and monitoring of cardiovascular risk is suboptimal in Australian primary care. The role of community pharmacy has increased considerably, but without any policy framework for development. The aim of this study was to explore the nature of community pharmacy-based screening models in Australia, capacity to increase delivery of pharmacy screening, and barriers and enablers to increasing capacity. METHODS: An online survey weblink was emailed to pharmacy managers at every quality-accredited pharmacy in Australia by the Quality Pharmacy Care Program. The 122-item survey explored the nature of screening services, pharmacy capacity to deliver services, and barriers and enablers to service delivery in considerable detail. Adaptive questioning was used extensively to reduce the participant burden. Pharmacy location details were requested to facilitate geo-coding and removal of duplicate entries. A descriptive analysis of responses was undertaken. RESULTS: There were 294 valid responses from 4890 emails, a 6% response rate. Most pharmacies (79%) had private counselling areas. Blood pressure assessment was nearly universal (96%), but other common risk factor assessments were offered by a minority. Most did not charge for assessments, and 59% indicated capacity to provide multiple risk factor assessments. Fewer than one in five (19%) reported any formal arrangements with general practice for care coordination. Financial viability was perceived as a key barrier to service expansion, amid concerns of patient willingness to pay. Support from government and non-governmental organisations for their role was seen as necessary. CONCLUSION: There appears to be a critical mass of pharmacies engaging in evidence-based and professional services. Considerable additional support appears required to optimise performance across the profession. PMID- 28089790 TI - Shirtfront Myocardial Infarction: Traumatic Coronary Plaque Disruption Secondary to a Football Tackle. PMID- 28089789 TI - Differing Clinical Characteristics Between Young and Older Patients Presenting with Myocardial Infarction. AB - BACKGROUND: To date, there has been no detailed study of the risk factors and clinical characteristics of patients presenting with myocardial infarction (MI) at a young age in our region. The purpose of this study was to assess the rate and clinical profile of those presenting with young MI in New Zealand. METHODS: We identified a cohort of 1199 patients presenting with acute MI between January 2012 and November 2015 from the Wellington Acute Coronary Syndrome Registry. We compared those presenting with young MI, defined as presentation with MI aged 50 years or younger, to those aged over 50 years. RESULTS: Myocardial infarction at a young age occurred in 154 (12.8%) patients. Compared to those in the older MI group, the young MI group were more likely to be male (80% vs. 71%, p=0.026), of Maori or Pacific Island ethnicity (21% vs. 10%, p<0.0001), have a higher BMI (31kg/m2 vs. 29kg/m2, p<0.0001), have a family history of premature coronary artery disease (49% vs. 34%, p<0.0001) and to be current smokers (47% vs. 20%, p<0.001). Young MI patients were less likely to have hypertension, dyslipidaemia and diabetes than the older MI patient population. Within the young MI group 36% had none or only one traditional risk factor for MI, and would have been classified as low risk prior to their index event. CONCLUSION: Those with young MI accounted for 12.8% of our cohort and had a different risk factor profile to the older MI group with smoking and obesity being particularly prevalent. PMID- 28089791 TI - Supplement CT-Guided Microcoil Placement for Localising Ground-glass Opacity (GGO) Lesions at "Blind Areas" of the Conventional Hook-Wire Technique. AB - BACKGROUND: In the conventional hook-wire technique of pulmonary nodular localisations there are several "blind areas", including the mediastinum-vicinity region, interlobar fissure-neighbouring areas and scapulae-shadowed areas. The present study aims to summarise the experiences of CT-guided microcoil placement as an alternative method for localising pulmonary ground-glass opacity (GGO) lesions before thoracoscopic wedge resections. METHODS: Sixteen GGO lesions at "blind areas" in 16 patients were localised with platinum-fibered microcoils under CT assistance before undergoing video-assisted thoracoscopic surgical resections. Information regarding coil placement, operations and complications was recorded. RESULTS: Of all lesions, 1 was in the mediastinum-vicinity region, 8 were covered by the scapulae, and 7 were close to interlobar fissures (3 horizontal fissures, 4 oblique fissures). All 16 (100%) lesions had been successfully marked with microcoils. No major complications of the puncture procedure occurred; there were only minor pneumothorax (n=2) and haemoptysis (n=1) complications, which required no intervention before operations. All GGO lesions and microcoils were successfully removed by initial wedge resections. Of the 16 lesions in "blind areas", 8 were adenocarcinoma in situ (AIS), 4 were minimally invasive adenocarcinoma (MIA), 3 were atypical adenomatous hyperplasia (AAH), and 1 was interstitial fibrous tissue proliferation. No major complications occurred postoperatively. CONCLUSIONS: For the "blind areas" of the hook-wire technique, CT-guided microcoil placement is an effective method of marking GGO lesions that makes thoracoscopic wedge resection easier. PMID- 28089793 TI - Eggshell palaeogenomics: Palaeognath evolutionary history revealed through ancient nuclear and mitochondrial DNA from Madagascan elephant bird (Aepyornis sp.) eggshell. AB - Palaeognaths, the sister group of all other living birds (neognaths), were once considered to be vicariant relics from the breakup of the Gondwanan supercontinent. However, recent molecular studies instead argue for dispersal of volant ancestors across marine barriers. Resolving this debate hinges upon accurately reconstructing their evolutionary relationships and dating their divergences, which often relies on phylogenetic information from extinct relatives and nuclear genomes. Mitogenomes from the extinct elephant birds of Madagascar have helped inform the palaeognath phylogeny; however, nuclear information has remained unavailable. Here, we use ancient DNA (aDNA) extracted from fossil eggshell, together with target enrichment and next-generation sequencing techniques, to reconstruct an additional new mitogenome from Aepyornis sp. with 33.5X coverage. We also recover the first elephant bird nuclear aDNA, represented by 12,500bp of exonic information. While we confirm that elephant birds are sister taxa to the kiwi, our data suggests that, like neognaths, palaeognaths underwent an explosive radiation between 69 and 52Ma-well after the break-up of Gondwana, and more rapidly than previously estimated from mitochondrial data alone. These results further support the idea that ratites primarily diversified immediately following the Cretaceous-Palaeogene mass extinction and convergently evolved flightlessness. Our study reinforces the importance of including information from the nuclear genome of extinct taxa for recovering deep evolutionary relationships. Furthermore, with approximately 3% endogenous aDNA retrieved, avian eggshell can be a valuable substrate for recovering high quality aDNA. We suggest that elephant bird whole genome recovery is ultimately achievable, and will provide future insights into the evolution these birds. PMID- 28089792 TI - Pharmacological Inhibition of PKCtheta Counteracts Muscle Disease in a Mouse Model of Duchenne Muscular Dystrophy. AB - : Inflammation plays a considerable role in the progression of Duchenne Muscular Dystrophy (DMD), a severe muscle disease caused by a mutation in the dystrophin gene. We previously showed that genetic ablation of Protein Kinase C theta (PKCtheta) in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation. To establish whether pharmacological targeting of PKCtheta in DMD can be proposed as a therapeutic option, in this study we treated young mdx mice with the PKCtheta inhibitor Compound 20 (C20). We show that C20 treatment led to a significant reduction in muscle damage associated with reduced immune cells infiltration, reduced inflammatory pathways activation, and maintained muscle regeneration. Importantly, C20 treatment is efficient in recovering muscle performance in mdx mice, by preserving muscle integrity. Together, these results provide proof of principle that pharmacological inhibition of PKCtheta in DMD can be considered an attractive strategy to modulate immune response and prevent the progression of the disease. RESEARCH IN CONTEXT: Duchenne muscular dystrophy (DMD) is a severe muscle disease affecting 1:3500 male births. DMD is caused by a mutation in dystrophin gene, coding for a protein required for skeletal and cardiac muscle integrity. Lack of a functional dystrophin is primarily responsible for the muscle eccentric contraction-induced muscle damage, observed in dystrophic muscle. However, inflammation plays a considerable role in the progression of DMD. Glucocorticoids, which have anti-inflammatory properties, are being used to treat DMD with some success; however, long term treatment with these drugs induces muscle atrophy and wasting, outweighing their benefit. The identification of specific targets for anti-inflammatory therapies is one of the ongoing therapeutic options. Although blunting inflammation would not be a "cure" for the disease, the emerging clue is that multiple strategies, addressing different aspects of the pathology, which may eventually converge, may be successful. In this context, we previously showed that genetic ablation of Protein Kinase C theta (PKCtheta), an enzyme known to be involved in immune response, in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation. To establish whether pharmacological targeting of PKCtheta in DMD can be proposed as a therapeutic option, in this study we treated young mdx mice with the PKCtheta inhibitor Compound 20 (C20). We show that C20 treatment led to a significant reduction in muscle damage associated with reduced immune cells infiltration, reduced inflammatory pathways activation, and maintained muscle regeneration. Importantly, C20 treatment is efficient in recovering muscle performance in mdx mice, by preserving muscle integrity. Together, these results provide proof of principle that pharmacological inhibition of PKCtheta in DMD can be considered an attractive strategy to modulate immune response and prevent the progression of the disease. PMID- 28089794 TI - A molecular phylogeny reveals the Cuban enigmatic genus Behaimia as a new piece in the Brongniartieae puzzle of papilionoid legumes. AB - The papilionoid legume tribe Brongniartieae comprises a collection of 15 genera with disparate morphologies that were previously positioned in at least four remotely related tribes. The Brongniartieae displays a wide geographical disjunction between Australia and the New World and previous phylogenetic studies had provided conflicting results about the relationships between the American and Australian genera. We carry out phylogenetic analyses of (1) a plastid matK dataset extensively sampled across legumes to solve the enigmatic relationship of the Cuban-endemic monospecific genus Behaimia; and (2) multilocus datasets with focus on all genera ever referred to Brongniartieae. These analyses resulted in a well-resolved and strongly-supported phylogenetic tree of the Brongniartieae. The monophyly of all American genera of Brongniartieae is strongly supported. The doubtful position of the Australian genus Plagiocarpus is resolved within a clade comprising all Australian genera. Behaimia has been traditionally classified in tribe Millettieae, but our new molecular data and re-assessment of morphological traits have resolved the genus within the early-branching papilionoid tribe Brongniartieae. Characters including the pinnately multifoliolate (vs. unifoliolate) leaves, a sessile (vs. stipitate) ovary, and an indehiscent or late dehiscent one-seeded pod distinguish Behaimia from its closer relatives, the South American genera Cyclolobium and Limadendron. PMID- 28089795 TI - Comparison of postoperative biomechanical function between anatomic double-bundle and single-bundle ACL reconstructions using calcium phosphate-hybridized tendon grafts in goats. AB - BACKGROUND: Calcium phosphate (CaP)-hybridized tendon grafts improved biomechanical function compared with untreated grafts after single-bundle (SB) anterior cruciate ligament (ACL) reconstruction. The purpose of this study was to compare the biomechanical function between anatomic double-bundle (DB) and single bundle (SB) ACL reconstructions using CaP-hybridized tendon grafts at 6 months postoperatively in goats. HYPOTHESIS: We hypothesized that the postoperative biomechanical function in the DB group will be better than that in the SB group. MATERIALS AND METHODS: Knee kinematics and in situ forces in the grafts under applied anterior tibial load (ATL) of 50N and internal tibial torque (ITT) of 2.0 Nm at full extension, and 60 degrees and 90 degrees of knee flexion, and the histology of the tendon-bone interface were compared between the DB group (n=6) and SB group (n=6). RESULTS: The in situ forces under ATL in the DB group at full extension and 90 degrees of knee flexion were greater than those in the SB group. The in situ forces under ITT in the DB group at full extension and 60 degrees of knee flexion were greater than those in the SB group. The in situ forces on the posterolateral bundle of the grafts under ATL and ITT in the DB group at full knee extension were greater than those on the posterior half of the grafts in the SB group. The histology did not differ significantly between the groups. CONCLUSIONS: Although CaP-hybridized tendon grafts were used in both groups, the in situ forces under ATL and ITT in the DB group were greater than those in the SB group at 6 months postoperatively. The posterolateral bundle of the grafts in the DB group acted effectively against both ATL and ITT at full extension. The tendon-to-bone healing was similar in both groups. STUDY DESIGN: Controlled laboratory study. Level 2. PMID- 28089796 TI - Correlation between obesity and severity of distal radius fractures. AB - INTRODUCTION: The incidence of obesity has increased significantly worldwide. Our hypothesis was that patients with obesity have a more severe distal radius fracture and we realized a study to evaluate this correlation between obesity and severity of distal radius fractures caused by low-energy injuries. MATERIALS AND METHODS: A total of 114 patients with distal radius fracture were examined in a cross-sectional, observational study. Fractures were classified according to the international AO-Muller/Orthopedic Trauma Association (AO/OTA) classification in order to determine the severity. The patient's Body Mass Index (BMI) was calculated and a Pearson correlation was performed. RESULTS: The patients were predominantly female, and left side was more frequently affected. Most of the fractures were AO/OTA type A (71 patients). The majority of the involved patients in our study were overweighed or obese. We do not observe a direct correlation between grade of obesity and distal radius fracture severity. CONCLUSIONS: Based on the results of this study obesity and severity of distal radius fractures do not correlate. LEVEL OF EVIDENCE: Prognostic. Level IV. CASE SERIES: PMID- 28089797 TI - Distal femoral hemiepiphysiodesis using screw and non-absorbable filament for the treatment of idiopathic genu valgum. Preliminary results of 12 knees. AB - INTRODUCTION: Different techniques for gradual correction of angular deformities of lower limbs exist. Screws and nonabsorbable filament has been described as an effective alternative for transitory hemiepiphysiodesis in New Zealand rabbits. HYPOTHESIS: Hemiepiphysiodesis using screws and non-absorbable filament is effective in pediatric population, for correction of genu valgum. METHODS: Retrospective evaluation, 12 knees in 6 patients younger than 15 years (3 female), operated because of genu valgum. An anchoring system with two 4.0mm cancellous screw with metal washer joined by FiberWire #2.0 filament. Initial and final intermalleolar distance (IMD) and mechanical lateral distal femoral angle were compared, recording complications. Mann-Whitney test was used for statistics, with significance value <0.05. RESULTS: All patients achieved the expected correction. IMD and mLDFA were significatively improved. Only one patient presents a minor perioperative complication. DISCUSSION: Lateral distal femoral hemiepiphysiodesis with screws and nonabsorbable filament resulted to be an effective alternative for genu valgum gradual correction in pediatric population. This is the first article that proposes this model, as an efficient and simple alternative for the treatment of genu valgum in pediatric patients. LEVEL OF EVIDENCE: Retrospective study, Level IV. PMID- 28089798 TI - A meta-analysis of external fixation versus open reduction and internal fixation for complex tibial plateau fractures. AB - PURPOSE: Both external fixation (ExFx) and open reduction and internal fixation(ORIF) were used to treat complex tibial plateau fractures, but it was not sure which one was better. So we did this meta-analysis to evaluate the outcomes of ExFx and ORIF in managing complex tibial plateau fractures. METHODS: Articles published before August 5, 2016 were selected from PubMed, Cochrane library, and some other electronic database. Relevant journals were also searched manually with no language limited. Two independent reviewers searched and assessed the literature. A fixed effect model was initially used for meta analyses with RevMan 5.3. RESULTS: When compared with ORIF, cases undergoing ExFx were more likely to return to the preinjury state at the early stage, but no difference in the later period of follow-up. However, ExFx group had higher infection rate (OR 1.98, 95% CI 1.08-3.63, P = 0.03), higher venous thromboembolism rate (OR 1.56, 95% CI 0.49-4.96, P = 0.45), higher re-operation rate (OR 0.87, 95% CI 0.47-1.62, P = 0.66) and lower compartment syndrome rate (OR 0.61, 95% CI 0.12-3.22, P = 0.56), lower TKA rate (OR 0.51, 95% CI 0.20-1.34, P = 0.17). There were no statistically significant differences in the rate of deep infection, venous thromboembolism, compartment syndrome and VTE between the two groups. CONCLUSION: Although external fixation may offer some advantages, both were acceptable strategies in managing complex tibial plateau fractures. According to our analysis results, we strongly recommend that selection of definitive fixators should base on the fracture patterns, soft-tissue condition as well as the injury stages in clinical practice. More important, further multicentered, randomized controlled studies should be implemented to get a more reliable and clear result. PMID- 28089800 TI - Osteopathic Manipulation in Treatment of Musculoskeletal Chest Pain. PMID- 28089799 TI - Positive Airway Pressure Therapies and Hospitalization in Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Hospitalization of patients with chronic obstructive pulmonary disease creates a huge healthcare burden. Positive airway pressure therapy is sometimes used in patients with chronic obstructive pulmonary disease, but the possible impact on hospitalization risk remains controversial. We studied the hospitalization risk of patients with chronic obstructive pulmonary disease before and after initiation of various positive airway pressure therapies in a "real-world" bioinformatics study. METHODS: We performed a retrospective analysis of administrative claims data of hospitalizations in patients with chronic obstructive pulmonary disease who received or did not receive positive airway pressure therapy: continuous positive airway pressure, bilevel positive airway pressure, and noninvasive positive pressure ventilation using a home ventilator. RESULTS: The majority of 1,881,652 patients with chronic obstructive pulmonary disease (92.5%) were not receiving any form of positive airway pressure therapy. Prescription of bilevel positive airway pressure (1.5%), continuous positive airway pressure (5.6%), and noninvasive positive pressure ventilation (<1%) in patients with chronic obstructive pulmonary disease demonstrated geographic-, sex , and age-related variability. After adjusting for confounders and propensity score, noninvasive positive pressure ventilation (odds ratio [OR], 0.19; 95% confidence interval [CI], 0.13-0.27), bilevel positive airway pressure (OR, 0.42; 95% CI, 0.39-0.45), and continuous positive airway pressure (OR, 0.70; 95% CI, 0.67-0.72) were individually associated with lower hospitalization risk in the 6 months post-treatment when compared with the 6 months pretreatment but not when compared with the baseline period between 12 and 6 months before treatment initiation. Stratified analysis suggests that comorbid sleep-disordered breathing, chronic respiratory failure, heart failure, and age less than 65 years were associated with greater benefits from positive airway pressure therapy. CONCLUSION: Initiation of positive airway pressure therapy was associated with reduction in hospitalization among patients with chronic obstructive pulmonary disease, but the causality needs to be determined by randomized controlled trials. PMID- 28089801 TI - Physician Exposure to Direct-to-Consumer Pharmaceutical Marketing: Potential for Creating Prescribing Bias. PMID- 28089802 TI - Incorporating Formal Nutrition Education into a Medical School Curriculum: A Student-Initiated Lecture Series. PMID- 28089803 TI - Statins and Diabetes: Current Perspectives and Implications for Clinicians. PMID- 28089804 TI - Multicentric Spinal Cord Glioblastoma. AB - A 40-year-old man was referred to our center with a 4-month history of progressive quadriparesis. Previous brain imaging revealed no abnormality. Magnetic resonance imaging (MRI) with contrast of the cervicothoracic spine revealed 2 heterogeneously enhancing lesions at the level of C3-C5 and T2-T4 (A); T1- and T2-weighted MRI showed hypointense and hyperintense lesions, respectively, which is characteristic of spinal cord astrocytoma (B and C). Intraoperative biopsies supported the diagnosis of glioblastoma (hypercellularity, vascular proliferation, and tumor cell palisading around necrosis) (D). Though resection was attempted, surgery was aborted due to hemodynamic instability and signal changes in neuromonitoring. The patient stabilized in the intensive care unit and experienced slight improvement in upper extremity strength. After discharge without further complications, the patient was expected to return for further adjuvant therapy/surgical planning but unfortunately passed away 1.5 months after his operation, most likely to rapid disease progression. PMID- 28089805 TI - Surgical Outcomes of Endoscopic Endonasal Skull Base Surgery of Craniopharyngiomas Evaluated According to the Degree of Hypothalamic Extension. AB - OBJECTIVE: Sparing the hypothalamus after craniopharyngioma treatment is a prerequisite to ensure a good quality of life. In this study, the functional prognosis of craniopharyngioma after endoscopic endonasal skull base surgery (EES) was examined in function of the degree of hypothalamic extension. METHODS: Twenty cases of craniopharyngioma treated by EES were categorized according to the Puget classification using preoperative and postoperative magnetic resonance imaging. The degree of resection rates, amelioration of symptoms, and endocrinologic and hypothalamic functions were evaluated during the postoperative follow-up period. RESULTS: All cases were preoperatively classified into grades 0 (n = 8), 1 (n = 7), and 2 (n = 5). Near total resection was achieved in half of the cases. Moreover, visual improvement was observed in 75% of the cases. The incidence rate of additional endocrinologic dysfunction was not related to the preoperative grade or intraoperative stalk preservation. Postoperative magnetic resonance imaging indicated hypothalamic preservation for all grades. After an average of 60 months follow-up of 11 patients with primary tumors, 4 patients showed tumor regrowth controlled by stereotactic radiation therapy. All patients recorded more than 80% on the Karnofsky Performance Scale and showed no additional obesity at follow-up. CONCLUSIONS: EES provides optimal resection rate and limited complications because of the preservation of the hypothalamus, regardless of the degree of preoperative hypothalamic involvement. Consequently, the rate of obesity occurrence is also decreased. This study indicates that EES protects hypothalamus function and improves tumor removal rate, and that it will become the first choice of surgical procedure for managing craniopharyngiomas. PMID- 28089806 TI - Analysis of Radiation Doses and Dose Reduction Strategies During Cerebral Digital Subtraction Angiography. AB - OBJECTIVE: Adverse effects of increased use of cerebral digital subtraction angiography (DSA) include radiation-induced skin reactions and increased risk of malignancy. This study aimed to identify a method for reducing radiation exposure during routine cerebral DSA. METHODS: A retrospective review of 138 consecutive adult patients who underwent DSA with a biplane angiography system (Artis Zee, Siemens, Germany) from September 2015 to February 2016 was performed. In January 2016, the dose parameter was reset by the manufacturer from 2.4 MUGy to 1.2 MUGy. Predose (group 1) and postdose parameter reduction (group 2) groups were established. Angiograms and procedure examination protocols were reviewed according to patient age, gender, and diagnosis and angiography techniques were reviewed on the basis of the following radiation dose parameters: fluoroscopy time, reference point air kerma (Ka,r; in mGy), and kerma-area product (PKA; in MUGym2). RESULTS: The mean Ka,r values in groups 1 and 2 were 1841.5 mGy and 1274.8 mGy, respectively. The mean PKA values in groups 1 and 2 were 23212.5 MUGym2 and 14854.0 MUGym2, respectively. Ka,r and PKA values were significantly lower in group 2 compared with group 1 (P < 0.001). Among individual factors, young age was a determining factor for reduced fluoroscopy time (P < 0.001), Ka,r (P = 0.047), and PKA (P = 0.022). CONCLUSIONS: Increased awareness of radiation risks, as well as the establishment of strategies to reduce radiation dose, led to lower radiation doses for DSA. The use of appropriate examinations and low dose parameters in fluoroscopy contributed significantly to the radiation dose reductions. PMID- 28089807 TI - Ultrasonography Detects Ulnar Nerve Dislocation Despite Normal Electrophysiology and Magnetic Resonance Imaging. AB - BACKGROUND: Dislocation of the ulnar nerve (UN) occurs in a subset of patients with ulnar neuropathy. Electrodiagnostic and magnetic resonance imaging (MRI) studies are performed to support the clinical diagnosis. We report the case of a patient with ulnar neuropathy with normal electrodiagnostic and MRI studies but with ultrasonography (US) showing UN dislocation, which prompted successful treatment by UN submuscular transposition. CASE DESCRIPTION: A healthy 15-year old female softball player presented with right medial elbow pain and paresthesias of the fourth and fifth digits. She had 4+/5 strength in the right hand intrinsic muscles and a Tinel sign at the right elbow. A snap was palpated at the elbow upon flexion. MRI showed mild common flexor tendonitis, and electrodiagnostic studies showed normal motor responses and no conduction block at the elbow. High-resolution US showed dislocation of the UN over the medial epicondyle. UN dislocation was confirmed intraoperatively, and, after UN submuscular transposition, the patient reported complete resolution of her preoperative symptoms at 6-week follow-up and continued resolution at 1 year. CONCLUSIONS: Normal findings on electrodiagnostic or MRI studies should not immediately dissuade surgeons from operating on a symptomatic patient with a clinical examination supporting ulnar neuropathy and with US evidence of UN dislocation, because such a patient may experience postoperative symptom relief. Furthermore, the dynamic capability of US imaging complements data obtained from electrodiagnostic and MRI studies, especially when these tests are normal, and it should be considered by clinicians when evaluating patients with medial elbow pain or signs of ulnar neuropathy. PMID- 28089808 TI - Stress-Induced Hyperglycemia After Spontaneous Subarachnoid Hemorrhage and Its Role in Predicting Cerebrospinal Fluid Diversion. AB - BACKGROUND: Stress-induced hyperglycemia (SIH) after acute cerebrovascular disease is common and is associated with adverse clinical outcomes. The incidence of SIH after spontaneous subarachnoid hemorrhage (SAH) and its role in shunt placement have not been systematically investigated. The present study is designed to investigate the incidence of SIH after spontaneous SAH and its determinants. The role of SIH and premorbid hyperglycemia (using glycated hemoglobin [HbA1c]) in predicting external ventricular drainage (EVD) and ventriculoperitoneal shunt (VPS) placement is also investigated. METHODS: This study defined SIH using the glycemic gap (GG) and admission glucose:HbA1c ratio. The receiver operating characteristic curve determined threshold values for GG and the ratio that best predicted incidence of adverse clinical outcomes, including in-hospital mortality. RESULTS: We defined SIH using thresholds of 26.7 mg/dL for GG and 26 mg/dL for admission glucose:HbA1c ratio. The incidence of SIH was higher in patients with aneurysmal SAH (aSAH) (99/200 [49.5%]) than in those with nonaneurysmal SAH (16/50 [32.0%]; P = 0.03). Among 200 patients with aSAH, diabetics had higher mortality than nondiabetics (10/24 [41.7%] vs. 39/137 [21.2%]; P = 0.045). SIH among nonhydrocephalic aSAH was more likely to have EVD placed than those without (42/64 [65.6%] vs. 38/79 [48.1%]; P = 0.043). Among 143 patients with aSAH without hydrocephalus, EVD was placed more often in those with HbA1c level >=6.4% (15/19 [78.9%] vs. 65/124 [52.4%]; P = 0.045). Neither SIH nor HbA1c level could predict VPS placement among aSAH survivors. CONCLUSIONS: SIH is common after aSAH. In nonhydrocephalic aSAH, both SIH and premorbid uncontrolled hyperglycemia determine EVD but not VPS placement. PMID- 28089809 TI - Sensitivity and Specificity of Intraoperative Neuromonitoring for Identifying Safety and Duration of Temporary Aneurysm Clipping Based on Vascular Territory, a Multimodal Strategy. AB - BACKGROUND: Patients who undergo clipping of cerebral aneurysms face an inherent risk for new postoperative neurologic deficits. Intraoperative neuromonitoring (IONM) is used often for early detection of ischemic changes, while it is still potentially reversible. However, the value, safety, and efficacy of temporary clipping and multimodal IONM to minimize risks are debated. Our retrospective series examined the sensitivity and specificity of IONM using transcranial motor evoked potentials and somatosensory evoked potentials and quantified the safety of temporary clipping by duration and vascular territory. METHODS: Our prospectively collected database (2010-2013) included 123 consecutive patients who underwent clipping of 133 cerebral aneurysms with use of IONM. We determined postoperative deficit rate and sensitivity and specificity of monitoring to predict these changes intraoperatively. The rate of permanent deficit after temporary clipping was correlated with duration, vascular territory, and IONM findings. RESULTS: Of 133 clipped aneurysms, 15 instances of IONM changes occurred, including 12 temporary without new postoperative deficit and 3 permanent with new postoperative deficit. Somatosensory evoked potential monitoring predicted one of the permanent deficits and transcranial motor evoked potentials predicted the other 2 deficits. CONCLUSIONS: Multimodal IONM was highly specific and sensitive for detecting new deficits. Three patients with new deficits had temporary clipping, including 2 patients with IONM changes not temporally associated with clip placement. Our 1.1% rate of permanent neurologic deficit attributed to temporary clipping support its safety. Differences in patterns of IONM changes among vascular territories warrant further investigation. PMID- 28089810 TI - Laparoscopic Management of Ureteral Endometriosis and Hydronephrosis Associated With Endometriosis. AB - : STUDY OBJECTIVE: To evaluate if laparoscopic treatment of ureteral endometriosis is feasible, safe, and effective and to determine if ureteral dilatation and/or the number of incisions increases complications. DESIGN: An institutional review board-approved retrospective cohort study of consecutive patients who underwent surgery for deep infiltrating endometriosis involving the ureter with hydronephrosis (Canadian Task Force classification III). SETTING: A university hospital. PATIENTS: Of 658 patients who had surgery for deep infiltrating endometriosis between November 2004 and December 2013, 198 of the 658 patients had ureteral endometriosis and required ureterolysis, and 28 of the 198 patients were identified with ureteral dilatation and hydronephrosis associated with endometriosis. INTERVENTIONS: Of these 28 cases, 15 ureterolyses, 12 reanastomoses, and 1 reimplantation were performed. MEASUREMENTS AND MAIN RESULTS: Medical, operative, and pathological data on the evolution of pain, urinary complaints, fertility, complications, and recurrences were collected from clinical records. Additionally, telephone interviews were performed for the follow-up of long-term outcomes. All 28 patients had concomitant surgical procedures because of endometriosis elsewhere in the pelvis or abdomen; 12 (42.9%) underwent surgery of the bowel, whereas 5 (17.9%) had bladder surgery. The evolution of pain after surgery showed a positive response (mean dysmenorrhea evaluation measured by the Numeric Pain Rating Scale from 0-10 preoperatively at the short-term follow-up and the long-term follow-up: 7.25-1.73 and 0.25, respectively). Three complications were noted in the group of 28 patients with ureterohydronephrosis; 1 required surgical reintervention. Logistic regression analyses found vaginal incision (odds ratio = 2.08; 95% CI 0.92-4.73), bladder incision (odds ratio = 8.77; 95% CI 3.25-23.63), number of incisions (odds ratio = 2.12; 95% CI 1.29-3.47), and number of previous surgeries (odds ratio = 1.26; 95% CI 0.93-1.71) as independent risk factors for complications in the group of 198 patients. Three patients underwent reoperation in the group of 28 patients: 1 for ureterovaginal fistula, 1 for persistent ureter dilatation and hydronephrosis, and 1 for persistent pain. CONCLUSION: Laparoscopically assisted ureterolyses, ureteral reanastomoses, and ureteral reimplantation are feasible, safe, and effective treatments for ureteral endometriosis. Complete laparoscopic excision is possible with minimal complications, which seem to be associated with the number of incisions. Ureteral endometriosis should be suspected in all cases of deep infiltrating endometriosis. PMID- 28089811 TI - Large Aberrant External Iliac Vein: Incidental Laparoscopic Finding. PMID- 28089812 TI - Clinical Manifestations and Outcomes in Surgically Managed Gartner Duct Cysts. AB - STUDY OBJECTIVE: Gartner duct cysts (GDCs) are rare embryological remnants of the mesonephric duct with the majority of cases discovered incidentally in asymptomatic patients. The largest prior published series evaluating the surgical management of GDCs included 4 patients. The present study aimed to determine the manifestations and outcomes of surgically managed patients with GDCs with important implications for surveillance, monitoring, and management. DESIGN: A retrospective chart review (Canadian Task Force classification III). SETTING: A tertiary care center. PATIENTS: All women diagnosed with GDCs from January 1994 to April 2014 at our institution were identified. Patients were included if they underwent surgical management and had GDCs confirmed by pathology. One hundred twenty-four charts were manually reviewed, and 29 patients were included in the analysis. INTERVENTIONS: All patients underwent surgical management, which included vaginal excision or marsupialization. MEASUREMENTS AND MAIN RESULTS: A total of 29 patients met the inclusion criteria for this study. The median age of the patients included in the analysis was 36 years old. Eleven patients were asymptomatic at the time of diagnosis (37.9%). The reason for surgical intervention was not available in 9 of these patients. Surgical intervention was performed in 2 of the 11 asymptomatic patients because of an increasing size of the lesion during observation. Presenting symptoms included dyspareunia or pain with tampon placement (37.9%), pelvic pain or pressure (24.1%), pelvic mass or bulge (17.2%), and urinary incontinence (6.9%). Preoperative imaging studies were obtained in 62% of patients; ultrasound was used in 44.4%, computed tomographic scanning in 22.2%, magnetic resonance imaging in 16.7%, and multiple modalities in 16.7%. Approximately 10% were found to have other genitourinary anomalies, including a bladder cyst, urethral diverticulum, and a solitary right kidney with uterine didelphis and septate vagina. The average cyst size was 3.5 cm (+/-1.8 cm). Surgical excision of GDCs was performed in all except for 3 cases of marsupialization. No intraoperative complications occurred. The median follow-up was 82 months (range, 0-246 months). One patient had possible recurrence with dyspareunia and protruding tissue diagnosed 14 months postoperatively. There were no other postoperative complications in the follow-up period. CONCLUSION: GDCs are rare pelvic masses that are often asymptomatic but may present with dyspareunia, pelvic pain or pressure, pelvic mass or bulge, or urinary symptoms. Excision or marsupialization is successful in the majority of cases without significant morbidity. PMID- 28089813 TI - Parasciadicleithrum octofasciatum n. gen., n. sp. (Monogenoidea: Dactylogyridae), parasite of Rocio octofasciata (Regan) (Cichlidae: Perciformes) from Mexico characterised by morphological and molecular evidence. AB - Based on an integrative taxonomic approach, combining morphological characters and partial sequences of the 28S rRNA gene, a new genus and species, Parasciadicleithrum octofasciatum, is proposed to accommodate dactylogyrids infecting the gills of Rocio octofasciata (Cichlidae) from a tributary of the Lacantun River basin, Chiapas State, southern Mexico. Morphologically, the new genus resembles members of Sciadicleithrum (Dactylogyridae) in the presence of membranes on the anterior margins of both ventral and dorsal haptoral bars. However, Parasciadicleithrum octofasciatum n. sp. shows morphological differences with respect to a subset of species of Sciadicleithrum occurring in the same host group and geographic area, such as the body size and gonad dimensions (length and width of germarium and testis, respectively, smaller in the new genus). Phylogenetic analyses performed herein based on Maximum Likelihood and Bayesian Inference criteria, showed that Parasciadicleithrum octofasciatum n. sp. represents an undescribed taxon morphologically very similar to species of Sciadicleithrum from which it can be consistently distinguished on the basis of molecular data. P. octofasciatum n. sp. appeared genetically distant from Sciadicleithrum spp. and nested with dactylogyrid parasites of African cichlids. Parasciadicleithrum n. gen. showed divergence levels in the 28S rDNA sequences of 25-26% with respect to Sciadicleithrum spp. Therefore, on the basis of molecular evidence mainly, and morphological differences highlighted above, the erection of the new genus is proposed. The evolutionary and ecological factors that may have influenced the associations between Neotropical cichlids and their dactylogyrid parasites are briefly discussed. PMID- 28089814 TI - Prospects and problems for standardizing model validation in systems biology. AB - There are currently no widely shared criteria by which to assess the validity of computational models in systems biology. Here we discuss the feasibility and desirability of implementing validation standards for modeling. Having such a standard would facilitate journal review, interdisciplinary collaboration, model exchange, and be especially relevant for applications close to medical practice. However, even though the production of predictively valid models is considered a central goal, in practice modeling in systems biology employs a variety of model structures and model-building practices. These serve a variety of purposes, many of which are heuristic and do not seem to require strict validation criteria and may even be restricted by them. Moreover, given the current situation in systems biology, implementing a validation standard would face serious technical obstacles mostly due to the quality of available empirical data. We advocate a cautious approach to standardization. However even though rigorous standardization seems premature at this point, raising the issue helps us develop better insights into the practices of systems biology and the technical problems modelers face validating models. Further it allows us to identify certain technical validation issues which hold regardless of modeling context and purpose. Informal guidelines could in fact play a role in the field by helping modelers handle these. PMID- 28089815 TI - Do Patients Hospitalized With COPD Have Airflow Obstruction? AB - BACKGROUND: Guidelines recommend the confirmation of a COPD diagnosis with spirometry. International Classification of Diseases, Ninth Revision, Clinical Modification, diagnostic codes are frequently used to identify patients with COPD for administrative purposes. However, coding the diagnosis of COPD does not require confirmation using spirometry. The purpose of this study was to determine how often the discharge diagnosis of COPD is supported by spirometric measurements in the Veterans Affairs (VA) health system. METHODS: We reviewed records of patients hospitalized for COPD in a VA teaching hospital between 2005 and 2015. Individuals were counted once; rehospitalizations for COPD in the same time frame were excluded. Patient records were assessed for the presence of spirometric measurements and for spirometric evidence of COPD. RESULTS: There were 1,278 discharges with the principal diagnosis of COPD and allied conditions in the time frame. A total of 826 discharged patients were included. Among them, 21% had no spirometric measurements, 12% were unable to perform the breathing maneuvers correctly, 56% had spirometric evidence of airways obstruction, and 11% had normal prebronchodilator or postbronchodilator FEV1/FVC measurements. Older patients were more likely to fail the spirometry test or have no documented spirometry. Younger patients were more likely to have the first spirometry conducted after their COPD hospitalizations. CONCLUSIONS: Caution must be taken when using the discharge diagnosis database to measure health-care outcomes and determine resource management. Efforts are needed to assure that patients clinically suspected of having COPD are tested with spirometry to improve the accuracy of a COPD diagnosis. PMID- 28089816 TI - Can High-flow Nasal Cannula Reduce the Rate of Endotracheal Intubation in Adult Patients With Acute Respiratory Failure Compared With Conventional Oxygen Therapy and Noninvasive Positive Pressure Ventilation?: A Systematic Review and Meta analysis. AB - BACKGROUND: The effects of high-flow nasal cannula (HFNC) on adult patients with acute respiratory failure (ARF) are controversial. We aimed to further determine the effectiveness of HFNC in reducing the rate of endotracheal intubation in adult patients with ARF by comparison to noninvasive positive pressure ventilation (NIPPV) and conventional oxygen therapy (COT). METHODS: The PubMed, Embase, Medline, and the Cochrane Central Register of Controlled Trials databases, as well as the Information Sciences Institute Web of Science, were searched for all controlled studies that compared HFNC with NIPPV and COT in adult patients with ARF. The primary outcome was the rate of endotracheal intubation; the secondary outcomes were ICU mortality and length of ICU stay. RESULTS: Eighteen trials with a total of 3,881 patients were pooled in our final studies. Except for ICU mortality (I2 = 67%, chi2 = 12.21, P = .02) and rate of endotracheal intubation (I2 = 63%, chi2 = 13.51, P = .02) between HFNC and NIPPV, no significant heterogeneity was found in outcome measures. Compared with COT, HFNC was associated with a lower rate of endotracheal intubation (z = 2.55, P = .01) while no significant difference was found in the comparison with NIPPV (z = 1.40, P = .16). As for ICU mortality and length of ICU stay, HFNC did not exhibit any advantage over either COT or NIPPV. CONCLUSIONS: In patients with ARF, HFNC is a more reliable alternative than NIPPV to reduce the rate of endotracheal intubation than COT. PMID- 28089817 TI - Patient-Centered Specialty Practice: Defining the Role of Specialists in Value Based Health Care. AB - Health care is at a crossroads and under pressure to add value by improving patient experience and health outcomes and reducing costs to the system. Efforts to improve the care model in primary care, such as the patient-centered medical home, have enjoyed some success. However, primary care accounts for only a small portion of total health-care spending, and there is a need for policies and frameworks to support high-quality, cost-efficient care in specialty practices of the medical neighborhood. The Patient-Centered Specialty Practice (PCSP) model offers ambulatory-based specialty practices one such framework, supported by a formal recognition program through the National Committee for Quality Assurance. The key elements of the PCSP model include processes to support timely access to referral requests, improved communication and coordination with patients and referring clinicians, reduced unnecessary and duplicative testing, and an emphasis on continuous measurement of quality, safety, and performance improvement for a population of patients. Evidence to support the model remains limited, and estimates of net costs and value to practices are not fully understood. The PCSP model holds promise for promoting value-based health care in specialty practices. The continued development of appropriate incentives is required to ensure widespread adoption. PMID- 28089818 TI - Notochordal cell-derived conditioned medium protects human nucleus pulposus cells from stress-induced apoptosis. AB - BACKGROUND CONTEXT: Degenerative disc disease (DDD) remains without an effective therapy and presents a costly burden to society. PURPOSE: Based upon prior reports concerning the effects of notochordal cell-conditioned medium (NCCM) on disc cells, we performed a proof of principle study to determine whether NCCM could reduce cytotoxic stress-induced apoptosis in human disc nucleus pulposus (NP) cells. STUDY DESIGN/SETTING: This is an "in vitro" fundamental or basic science study. METHODS: Nucleus pulpous cells derived from 15 patients undergoing spinal surgery were treated with interleukin (IL)-1beta and Fas ligand or etoposide in the presence of NCCM. We determined pro- or antiapoptotic events using activated caspase assays and determined genomic regulation of apoptosis using polymerase chain reaction arrays validated using Western blotting methods. We interrogated cellular apoptotic regulation using JC-1 dye and flow cytometry and performed enzyme-linked immunosorbent assays to evaluate NP inflammatory cytokine secretion. RESULTS: Notochordal cell-conditioned medium inhibits cytotoxic stress-induced caspase-9 and -3/7 activities and maintains the mitochondrial membrane potential in human NP cells, thereby suppressing the intrinsic apoptotic pathway. Gene expression analysis revealed the X-linked inhibitor of apoptosis protein as a key player responsible for evading etoposide induced apoptosis in the presence of NCCM, and we verified these data using Western blotting. Enzyme-linked immunosorbent assay results revealed distinct differences in IL-6 and IL-8 secretions by NP cells in response to etoposide in the presence of NCCM. CONCLUSIONS: Here we demonstrate for the first time that NCCM reduces cytotoxic stress-induced apoptosis in human NP cells. Soluble factors present in NCCM could be harnessed for the development of novel therapeutics for the treatment of DDD. PMID- 28089819 TI - Lentivirus-mediated silencing of the CTGF gene suppresses the formation of glial scar tissue in a rat model of spinal cord injury. AB - BACKGROUND CONTEXT: One of the many reactive changes following a spinal cord injury (SCI) is the formation of a glial scar, a reactive cellular process whereby glial cells accumulate and surround the central nervous system injury sites to seal in the wound. Thus, the inhibition of glial scar is of great importance for SCI recovery. PURPOSE: This study aimed to explore the effect of lentivirus-mediated silencing of the CTGF gene on the formation of glial scar tissue in a rat model of SCI. STUDY DESIGN: This is a prospective study. STUDY SAMPLE: A total of 56 Wistar female rats aged 8 weeks were randomly selected for this study. OUTCOME MEASURES: The motor function of the rats was assessed using the Basso, Beattie, and Bresnahan (BBB) functional scale, footprint analysis of gait, and the Basso Mouse Scale (BMS). Quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry were performed to detect the mRNA and protein expressions of glial fibrillary acidic protein (GFAP), vimentin, fibronectin, and laminin in the spinal cord tissues. METHODS: A rat model of SCI was successfully established. Fifty-six male Wistar rats were randomly selected and assigned into four groups (14 rats in each group): the sham operation group, the SCI model group, the negative control (NC) group (SCI rats transfected with empty vector plasmids), and the siRNA-CTGF group (SCI rats transfected with lentivirus CTGF siRNA). RESULTS: The SCI rats showed decreased activity and were dragging their bodies while moving. Compared with the sham operation group, the BBB and BMS scores in the SCI model, NC, and siRNA-CTGF groups significantly decreased. However, the BBB and BMS scores in the siRNA-CTGF group were higher than those in the SCI model and NC groups. The mRNA and protein expressions of GFAP, vimentin, fibronectin, and laminin significantly increased in the SCI model, NC, and siRNA-CTGF groups in comparison with those in the sham operation group. Furthermore, the mRNA and protein expressions of GFAP, vimentin, fibronectin, and laminin in the siRNA-CTGF group were lower than those in the SCI model and NC groups 28 days after transfection. CONCLUSIONS: These findings indicate that lentivirus-mediated silencing of the CTGF gene can suppress the formation of glial scar tissue after SCI. PMID- 28089821 TI - The role of STAT3 in glioblastoma progression through dual influences on tumor cells and the immune microenvironment. AB - Glioblastoma multiforme (GBM) is the most aggressive form of cancer that begins within the brain; generally, the patient has a dismal prognosis and limited therapeutic options. Signal transducer and activator of transcription 3 (STAT3) is a critical mediator of tumorigenesis, tumor progression, and suppression of anti-tumor immunity in GBM. In a high percentage of GBM cells and tumor microenvironments, persistent activation of STAT3 induces cell proliferation, anti-apoptosis, glioma stem cell maintenance, tumor invasion, angiogenesis, and immune evasion. This makes STAT3 an attractive therapeutic target and a prognostic indicator in GBM. Targeting STAT3 affords an opportunity to disrupt multiple pro-oncogenic pathways at a single molecular hub. Unfortunately, there are no successful STAT3 inhibitors currently in clinical trials. However, strong clinical evidence implicating STAT3 as a major factor in GBM justifies the identification of safe and effective strategies for inhibiting STAT3. PMID- 28089820 TI - Deregulated expression of VHL mRNA variants in papillary thyroid cancer. AB - Recent findings demonstrated that a subset of papillary thyroid cancers (PTCs) is characterized by reduced expression of the von Hippel-Lindau (VHL) tumor suppressor gene, and that lowest levels associated with more aggressive PTCs. In the present study, the levels of the two VHL mRNA splicing variants, VHL-213 (V1) and VHL-172 (V2), were measured in a series of 96 PTC and corresponding normal matched tissues by means of quantitative RT-PCR. Variations in the mRNA levels were correlated with patients' clinicopathological parameters and disease-free interval (DFI). The analysis of VHL mRNA in tumor tissues, compared to normal matched tissues, revealed that its expression was either up- or down-regulated in the majority of PTC. In particular, V1 and V2 mRNA levels were altered, respectively, in 78 (81.3%) and 65 (67.7%) out of the 96 PTCs analyzed. A significant positive correlation between the two mRNA variants was observed (p < 0.001). Univariate analysis documented the lack of association between each variant and clinicopathological parameters such as age, tumor size, histology, TNM stage, lymph node metastases, and BRAF mutational status. However, a strong correlation was found between altered V1 or V2 mRNA levels and DFI. Multivariate regression analysis indicated higher V1 mRNA values, along with lymph node metastases at diagnosis, as independent prognostic factors predicting DFI. In conclusion, the data reported demonstrate that VHL gene expression is deregulated in the majority of PTC tissues. Of particular interest is the apparent protective role exerted by VHL transcripts against PTC recurrences. PMID- 28089822 TI - MicroRNAs in pituitary tumors. AB - Since the presence of microRNAs was first observed in normal pituitary, the majority of scientific publications addressing their role and the function of microRNAs in the pituitary have been based on pituitary tumor studies. In this review, we briefly describe the involvement of microRNAs in the synthesis of pituitary hormones and we present a comprehensive inventory of microRNA suppressors and inducers of pituitary tumors. Finally, we summarize the functional role of microRNAs in tumorigenesis, progression and aggressiveness of pituitary tumors, mechanisms contributing to the regulation (transcription factors, genomic modifications or epigenetic) or modulation (pharmacological treatment) of microRNAs in these tumors, and the interest of thoroughly studying the expression of miRNAs in body fluids. PMID- 28089823 TI - Thyroid hormones and browning of adipose tissue. AB - Thyroid hormone (TH) disorders are associated with profound changes in whole body energy metabolism. A major TH target is thermogenic brown adipose tissue (BAT), which can be stimulated directly through thyroid hormone receptors (TRs) expressed in brown adipocytes and indirectly, through TRs expressed in hypothalamic neurons. White adipose tissue (WAT) adopts BAT characteristics by a diverse range of stimuli in a process referred to as browning. It is now understood that TH also induce WAT browning through peripheral and central mechanisms. In this review, we discuss evidence from animal and human studies that TH disorders are associated with changes in both BAT thermogenesis and WAT browning, thereby influencing body temperature and body weight regulation. PMID- 28089824 TI - Mitochondrial Uncoupling Protein 2 in human cumulus cells is associated with regulating autophagy and apoptosis, maintaining gap junction integrity and progesterone synthesis. AB - To explore the roles of mitochondrial Uncoupling Protein 2 (UCP2) in cumulus cells (CCs), human CCs were cultured in vitro, and the UCP2 was inhibited by treatment with Genipin, a special UCP inhibitor, or by RNA interference targeting UCP2. No significant differences in adenosine triphosphate levels and the ratio of ADP/ATP were observed after UCP2 inhibition. UCP2 inhibition caused a significant increase in cellular oxidative damage, which was reflected in alterations to several key parameters, including reactive oxygen species (ROS) and lipid peroxidation levels and the ratio of reduced GSH to GSSG. UCP2 blocking resulted in an obvious increase in active Caspase-3, accompanied by the decline of proactive Caspase-3 and a significant increase in the LC3-II/LC3-I ratio, suggesting that UCP2 inhibition triggered cellular apoptosis and autophagy. The mRNA and protein expression of connexin 43 (Cx43), a gap junction channel protein, were significantly reduced after treatment with Genipin or siRNA. The progesterone level in the culture medium was also significantly decreased after UCP2 inhibition. Our data indicated that UCP2 plays highly important roles in mediating ROS production and regulating apoptosis and autophagy, as well as maintaining gap junction integrity and progesterone synthesis, which suggests that UCP2 is involved in the regulation of follicle development and early embryo implantation and implies that it might serve as a potential biomarker for oocyte quality and competency. PMID- 28089825 TI - Clinical and radiographic outcome of revision surgery of total elbow prosthesis: midterm results in 19 cases. AB - BACKGROUND: The aim of this study is to report on the midterm outcomes and complications of revision surgery of total elbow arthroplasty. METHODS: All patients who had undergone total elbow arthroplasty revision surgery between 2009 and 2014 with semiconstrained total elbow prostheses were prospectively enrolled in the study. Records were reviewed for demographic data; baseline measurements; and several follow-up assessments including the Mayo Elbow Performance Score (MEPS), visual analog scale (VAS) score for pain, Oxford Elbow Score, range of motion, satisfaction, and radiographs. RESULTS: A total of 19 revision arthroplasties were included. At a mean follow-up of 57 months, there had been 1 rerevision and 2 removals. One patient was excluded from follow-up because of confounding comorbidity. At last follow-up, MEPS values and VAS pain scores both improved (P < .01). The rate of combined good and excellent results on the MEPS was 53%. The mean VAS scores for pain at rest and with activity were 2 and 4, respectively. Fair results for the Oxford Elbow Score were reported, with a mean score of 28 points. Range of motion improved to an average flexion-extension arc of 108 degrees (P < .01), and the pronation-supination arc improved to an average of 123 degrees (P < .01). All elbows were stable at last follow-up (P < .01). Radiographs showed nonprogressive osteolysis around the prosthesis in 3 cases (19%) and suspicion of loosening in 1 (6%). In 11 patients postoperative complications occurred. Of 15 patients, 13 (87%) were satisfied with the result of the revision procedure. CONCLUSION: Revision of total elbow prostheses leads to satisfactory results, less pain, and better elbow function. This procedure is related to a relatively high complication rate. PMID- 28089826 TI - Comparison of histologic healing and biomechanical characteristics between repair techniques for a delaminated rotator cuff tear in rabbits. AB - BACKGROUND: The purpose of this study was to compare histologic healing and biomechanical characteristics between 2 repair techniques (layer by layer, repair of each layer to bone separately; and whole layer, repair of each layer to the bone en masse) for delaminated rotator cuff tear. MATERIALS AND METHODS: Rabbits were used as subjects and classified into 2 groups: group A, right side, the layer-by-layer repair group; and group B, left side, the whole-layer repair group. Histologic evaluations were done at 3 weeks (n = 7) and 6 weeks (n = 4) after operation. Biomechanical tests to evaluate the tensile property were done at time 0 (n = 5) and 3 weeks (n = 5) after operation. RESULTS: Histologic healing improved in all groups. A smaller cleft was found between layers in group B compared with the cleft in group A at 3 weeks after operation. At time 0, group A showed a higher yield load and ultimate failure load (67 +/- 10.5 N and 80 +/- 7.8 N, respectively). However, at 3 weeks after operation, group B showed a higher yield load (48 +/- 7.6 N). CONCLUSIONS: In the delaminated rotator cuff tear model in the rabbit, the whole-layer repair showed a narrow gap between layers and a higher yield load at 3 weeks after operation. Surgical techniques that unite the cleft in a delaminated tear could improve biomechanical strength after operation. PMID- 28089827 TI - Plication of the posterior capsule for intraoperative posterior instability during anatomic total shoulder arthroplasty. AB - BACKGROUND: Restoration of soft tissue balance for intraoperative posterior instability during anatomic total shoulder arthroplasty (TSA) is particularly difficult. The effectiveness of posterior capsular plication (PCP) in restoring soft tissue balance is largely unknown. The purpose of this study was to report the outcomes, complications, and reoperations of primary TSA in which a PCP was performed to correct excessive intraoperative posterior subluxation. METHODS: Thirty-eight shoulders (37 patients) underwent PCP for intraoperative posterior instability during anatomic TSA. The mean (standard deviation) age was 68 (10) years, and the median (range) clinical and radiographic follow-up periods were 60 (10-154) and 48 (1.5-154) months, respectively. A retrospective chart review was conducted to obtain clinical and radiographic data. RESULTS: TSA resulted in significant improvements in pain and range of motion. The mean (standard deviation) Simple Shoulder Test and American Shoulder and Elbow Surgeons scores were 9.4 (2.7) and 81.1 (19.8), respectively. PCP resulted in restoration of soft tissue balance in 27 shoulders (71%). The remaining 11 shoulders had evidence of posterior subluxation, including posterior dislocation in 2 shoulders. Revision surgery was performed in only 3 shoulders (7.9%), all for instability. However, there was a high rate of radiographic glenoid component loosening (12 shoulders, 32%). Overall results were excellent in 24 (63.2%), satisfactory in 10 (26.3%), and unsatisfactory in 4 (10.5%) shoulders. Recurrence of posterior subluxation was associated with worse motion and strength as well as with a higher rate of glenoid loosening. CONCLUSIONS: PCP seems to correct excessive intraoperative posterior subluxation in approximately two-thirds of the shoulders undergoing anatomic TSA. However, posterior subluxation does recur in the remaining third, and the overall rate of radiographic glenoid loosening is of concern. PMID- 28089828 TI - Nitrite increases glucose-stimulated insulin secretion and islet insulin content in obese type 2 diabetic male rats. AB - PURPOSE: Reduced bioavailability of nitric oxide (NO) is associated with pathogenesis of type 2 diabetes. Nitrite can act as a substrate for generation of systemic NO. The aim of this study was to examine the effects of nitrite administration on glucose-stimulated insulin secretion (GSIS) and islet insulin content in obese type 2 diabetic rats. METHODS: Male rats were divided into 4 groups: Control, control + nitrite, diabetes, and diabetes + nitrite. Sodium nitrite (50 mg/L in drinking water) was administered for 8 weeks. Diabetes was induced using high-fat diet and low-dose of streptozotocine. Serum levels of fasting glucose, insulin, and lipid profile were measured and the insulin resistance/sensitivity indices were calculated every 2 weeks. Glycated hemoglobin (HbA1C) was measured every month. At the end of the study, tissue levels of glucose transporter 4 (GLUT4) protein and serum interleukin-1 beta (IL-1beta) were measured as well as glucose and insulin tolerance test were done. GSIS from isolated pancreatic islets and islet insulin content were also determined. RESULTS: Nitrite administration significantly increased insulin secretion in both control and diabetic rats in presence of 16.7 mM glucose. Nitrite also significantly increased islet insulin content by 27% and 39% in both control and diabetic rats, respectively. Nitrite decreased elevated serum IL-1beta in diabetic rats (4.0 +/- 0.2 vs. 2.9 +/- 0.2 pg/mL, P = 0.001). In diabetic rats, nitrite also significantly increased tissue levels of GLUT4 by 22% and 26% in soleus muscle and epididymal adipose tissue, respectively. In addition, nitrite significantly improved glucose and insulin tolerance, insulin sensitivity, lipid profile, and decreased fasting glucose and insulin, but had no effect on HbA1C. CONCLUSIONS: Long-term nitrite administration increased both insulin secretion and insulin content in obese type 2 diabetic rats. In addition, nitrite therapy had favorable effects on glucose tolerance, insulin resistance, inflammation, and dyslipidemia in type 2 diabetic rats. PMID- 28089829 TI - Resveratrol and capsaicin used together as food complements reduce tumor growth and rescue full efficiency of low dose gemcitabine in a pancreatic cancer model. AB - Pancreatic adenocarcinoma, highly resistant to all current anti-cancer treatments, necessitates new approaches promoting cell death. We hypothesized that combined actions of several Bioactive Food Components (BFCs) might provide specific lethal effect towards tumor cells, sparing healthy cells. Human tumor pancreatic cell lines were tested in vitro for sensitivity to resveratrol, capsaicin, piceatannol, and sulforaphane cytotoxic effects. Combination of two or three components showed striking synergetic effect with gemcitabine in vitro. Each BFC used alone did not affect pancreatic tumor growth in a preclinical in vivo model, whereas couples of BFCs had anti-tumor activity. In addition, tumor toxicity was similar using gemcitabine alone or a combination of BFCs and two thirds of gemcitabine dose. Moreover, BFCs enhanced fibrotic response as compared to gemcitabine treatment alone. Reactive oxygen species (ROS) and apoptosis increases were observed, while cell cycle was very mildly affected. This study raises the possibility to use BFCs as beneficial food complements in the therapy of pancreatic adenocarcinoma, especially for patients unable to receive full doses of chemotherapy. PMID- 28089830 TI - Tumor suppressor SPOP ubiquitinates and degrades EglN2 to compromise growth of prostate cancer cells. AB - EglN prolyl hydroxylases, a family of oxygen-sensing enzymes, hydroxylate distinct proteins to modulate diverse physiopathological signals. Aberrant regulations of EglNs result in multiple human diseases, including cancer. Different from EglN1 which function largely depends on the role of hypoxia-induce factor alpha (HIFalpha) in tumors, the functional significance and the upstream regulatory mechanisms of EglN2, especially in prostate cancer setting, remain largely unclear. Here, we demonstrated that dysregulation of EglN2 facilitated prostate cancer growth both in cells and in vivo. Notably, EglN2 was identified highly expressed in human prostate cancer tissues. Mechanically, Cullin 3-based E3 ubiquitin ligase SPOP, a well-characterized tumor suppressor in prostate cancer, could recognize and destruct EglN2. Meanwhile, androgen receptor (AR), playing a pivotal role in progression and development of prostate cancer, could transcriptionally up-regulate EglN2. Pathologically, SPOP loss-of-function mutations or AR amplification, frequently occurring in prostate cancers, could significantly accumulate EglN2 abundance. Therefore, our study not only underlines an oncogenic role of EglN2 in prostate cancer, but also highlights SPOP as a tumor suppressor to down-regulate EglN2 in prostate cancer. PMID- 28089831 TI - Monomethyltransferase SETD8 regulates breast cancer metabolism via stabilizing hypoxia-inducible factor 1alpha. AB - SETD8 is a methyltransferase that specifically catalyzes the monomethylation of lysine 20 on histone H4. Previous studies have demonstrated that SETD8 is associated with proper cell cycle progression, DNA damage response, and transcriptional regulation. A recent study revealed that SETD8 played an important role in epithelial-mesenchymal transition (EMT) in association with TWIST and enhanced metastatic potential of breast cancer cells. However, the contribution of SETD8 to metabolism reprogramming, one hallmark of cancer, has never been reported. In this study, we report that SETD8 was a positive regulator of anabolic metabolism. SETD8 reprograms breast cancer cell metabolism through hypoxia-inducible factor 1alpha (HIF1alpha) mediated process. Mechanistic studies indicated that SETD8 stabilized HIF1alpha protein level through post transcriptional regulation. Moreover, we demonstrated that SETD8 was a HIF1alpha transcription target. In clinical breast cancer patient tissues, we observed a positive correlation of SETD8 with HIF1alpha and HIF1alpha target genes. Taken together, we validated SETD8 as a novel metabolic reprogramming regulator, and our mechanistic studies shed light on a novel function of SETD8 in breast cancer malignant properties maintenance. PMID- 28089832 TI - Androgen receptor (AR) promotes clear cell renal cell carcinoma (ccRCC) migration and invasion via altering the circHIAT1/miR-195-5p/29a-3p/29c-3p/CDC42 signals. AB - Increasing evidence has demonstrated that the androgen receptor (AR) plays important roles to promote the metastasis of clear cell renal cell carcinoma (ccRCC). The detailed mechanisms, especially how AR functions via altering the circular RNAs (circRNAs) remain unclear. Here we identified a new circRNA (named as circHIAT1) whose expression was lower in ccRCCs than adjacent normal tissues. Targeting AR could suppress ccRCC cell progression via increasing circHIAT1 expression. ChIP assay and luciferase assay demonstrated that AR suppressed circHIAT1 expression via regulating its host gene, Hippocampus Abundant Transcript 1 (HIAT1) expression at the transcriptional level. The consequences of AR-suppressed circHIAT1 resulted in deregulating miR-195-5p/29a-3p/29c-3p expressions, which increased CDC42 expression to enhance ccRCC cell migration and invasion. Increasing this newly identified signal via circHIAT1 suppressed AR enhanced ccRCC cell migration and invasion. Together, these results suggested that circHIAT1 functioned as a metastatic inhibitor to suppress AR-enhanced ccRCC cell migration and invasion. Targeting this newly identified AR-circHIAT1 mediated miR-195-5p/29a-3p/29c-3p/CDC42 signals may help us develop potential new therapies to better suppress ccRCC metastasis. PMID- 28089834 TI - Recent clinical trials utilizing chimeric antigen receptor T cells therapies against solid tumors. AB - Chimeric antigen receptors (CARs) are a series of manufactured receptors that have the capacity of binding to specific antigens expressed on surface of tumor cells. A CAR normally has an extracellular antigen recognition domain derived from single variable chain of a monoclonal antibody, a transmembrane domain and an intracellular T cell activation domain. During the last decade, CAR-T cells were demonstrated to possess great therapeutic effects on hematological malignancies. However, strategies using CAR-T cells to treat solid tumors have been hindered by considerable obstacles including "on tissue off target" effects and cytokine storm syndrome. This review will summarize the current understanding of CAR-T cell therapies and briefly describe the currently enrolled clinical trials in solid tumors. PMID- 28089833 TI - Rufy3 promotes metastasis through epithelial-mesenchymal transition in colorectal cancer. AB - Rufy3 is a RUN domain-containing protein that has been associated with gastric cancers; however, the role of Rufy3 in the progression of colorectal cancer (CRC) remains unknown. We demonstrated that Rufy3 expression was higher in 11/12 fresh CRC tissues than in adjacent normal tissues. Rufy3 induced elevated expression and transactivity of four major oncogenes in CRC. Moreover, siRNA-mediated repression of Rufy3 induced G0/G1 cell cycle arrest, and Rufy3 overexpression enhanced CRC cell proliferation in vitro and in vivo. Furthermore, Rufy3 up regulation promoted epithelial-mesenchymal transition (EMT) and metastatic phenotypes. Using an established in vitro cell model of 5-fluorouracil-resistant (5-FU) CRC cells, we assessed cellular morphology, molecular changes, and invasion and found that these characteristics were consistent with EMT. Silencing of Rufy3 by siRNA reversed EMT and greatly diminished the invasion of 5-FU treated cells. In addition, TGF-beta1 induced Rufy3 expression in a dose dependent manner, and Rufy3 knockdown inhibited TGF-beta1-induced EMT. In vivo, higher expression of Rufy3 promoted CRC cell invasion and metastasis and induced EMT. Taken together, this work identified that Rufy3 promoted cancer metastasis in CRC cells through EMT induction. PMID- 28089835 TI - Supplementary Tests in Idiopathic Normal Pressure Hydrocephalus: A Single-Center Experience with a Combined Lumbar Infusion Test and Tap Test. AB - BACKGROUND: The lumbar infusion test (LIT) and tap test (TT) have previously been described for the diagnosis and selection of appropriate surgical candidates in idiopathic normal pressure hydrocephalus (iNPH). METHODS: We retrospectively reviewed 81 consecutive patients with a clinical diagnosis of iNPH selected for supplementary testing. Clinical evaluation was scored with the Japanese Grading Scale for Normal Pressure Hydrocephalus, the Global Deterioration Score, and the modified Rankin Scale (mRS). The test protocol included a cerebrospinal fluid pressure monitoring (PMi), an LIT, and a TT. Patients were selected for surgery if outflow resistance was >=14 mm Hg/mL/minute or if a clinical improvement was recorded after TT. RESULTS: Sixty-eight patients were selected for ventriculoperitoneal shunting; 72.8% had a positive PMi or LIT, 74.1% had a positive TT, and 63.0% were positive to both tests. Complications were all transient. Clinical evaluation at 12 months after shunting showed a global improvement in 60 patients (88.2%). Overall, 75.0% of patients had no significant disability (mRS score, 1 and 2), 20.6% had an mRS score of 3 or 4, and 4.4% had severe disability after surgery. The positive predictive value of PMi/LIT, TT, or both combined was similar (89.8, 90.0, and 88.2%); however, 21.7% of patients who improved after surgery were selected with either a positive LIT or TT alone. CONCLUSIONS: LIT and TT are complementary and they can easily be combined in sequence with a low complication rate and high probability of selecting patients with iNPH who may benefit from ventriculoperitoneal shunt surgery. PMID- 28089836 TI - Delayed Cerebrospinal Fluid Rhinorrhea After Gamma Knife Radiosurgery with or without Preceding Transsphenoidal Resection for Pituitary Pathology. AB - BACKGROUND: Skull base cerebrospinal fluid (CSF) leak after gamma knife radiosurgery (GKRS) is a very rare complication. In patients who were treated with both GKRS and transsphenoidal resection (TSR) for pituitary lesions, early CSF leak occurs at a comparable rate with the general TSR population (4%). Delayed CSF leak occurring more than a year after TSR, GKRS, or dual therapy is exceedingly rare. METHODS: Retrospective chart review and review of the literature. RESULTS: We present 2 cases of delayed CSF leak after GKRS to treat pituitary adenoma. One patient developed CSF rhinorrhea 16 years after GKRS for growth hormone-producing pituitary adenoma. The patient had previously undergone TSR surgery 7 years prior to GKRS without complication. Additionally, a second patient developed high-flow CSF rhinorrhea 2 years after GKRS for a prolactinoma that failed dopamine agonist therapy. Both patients underwent a complicated clinical course after presentation, requiring multiple revisions for definitive CSF leak repair. CONCLUSIONS: Delayed CSF leak is a rare but serious complication after GKRS independent of TSR status; urgent repair is the treatment of choice. Based on our experience, these leaks have the potential to be refractory, and we recommend aggressive reconstruction, preferably with a vascularized flap, and potentially supplemented by placement of a lumbar drain and acetazolamide. Current evidence is scant and provides little insight regarding an underlying mechanism, which may include bony destruction by the tumor, delayed radiation necrosis, or a secondary empty sella syndrome. PMID- 28089837 TI - Direct Midline Posterior Corpectomy and Fusion of a Lumbar Burst Fracture with Retrospondyloptosis. AB - BACKGROUND: Traumatic burst fractures of the lumbar spine can result in significant neurologic injury and mechanical instability. The ideal surgical approach for the treatment of unstable lumbar spine burst fractures remains debatable. CASE DESCRIPTION: A 37-year-old man presented with severe neurologic injury including loss of motor function below the level of the iliopsoas muscles bilaterally, saddle anesthesia, and absent rectal tone, after a fall from 18.28 m (60 ft). Computed tomography showed an L4 vertebral body comminuted burst fracture with complete posterior translation of L4 over L5. The patient was taken to the operating room for an L4 corpectomy and L2-S1 posterior fusion. The L4 vertebral body was visualized posterior to the posterior elements of L5 and resected in a piecemeal fashion. Because the thecal sac had been completely transected, a visible path down the L3-L4 and L4-L5 disk spaces was apparent, allowing direct posterior discectomies at these levels and completion of the L4 segment resection. The use of a direct posterior approach resulted in minimal blood loss, correction of sagittal alignment, and satisfactory outcomes comparable with the standard posterior transpedicular approach. Construct stability and solid bony fusion have been maintained for 4 years postoperatively. CONCLUSIONS: The use of a direct midline posterior corpectomy approach may be considered for patients with lumbar burst fractures, high-grade neurologic injury, and transection of the thecal sac. PMID- 28089838 TI - Quality of Reporting Randomized Controlled Trials in Five Leading Neurology Journals in 2008 and 2013 Using the Modified "Risk of Bias" Tool. AB - BACKGROUND: To examine the risk of bias of methodological quality of reporting randomized clinical trials (RCTs) in major neurology journals before and after the update (2011) of Cochrane risk of bias tool. METHODS: RCTs in 5 leading neurology journals in 2008 and 2013 were searched systematically. Characteristics were extracted based on the list of the modified Cochrane Collaboration's tool. Country, number of patients, type of intervention, and funding source also were examined for further analysis. RESULTS: A total of 138 RCTs were enrolled in this study. The rates of following a trial plan were 61.6% for the allocation generation, 52.9% for the allocation concealment, 84.8% for the blinding of the participants or the personnel, 34.8% for the blinding of outcome assessment, 78.3% for the incomplete outcome data, and 67.4% for the selective reporting. A significant setback was found in "the selective reporting" in 2013 than that in 2008. Trials performed by multi-centers and on a large scale had significantly more "low risk of bias" trials. Not only the number of surgical trials (5.8%) was much less than that of trials using drugs (73.9%), but also the reporting quality of surgical trials were worse (P = 0.008). Finally, only 17.4% trials met the criterion of "low risk of bias." CONCLUSIONS: The modified "risk of bias" tool is an improved version for assessment. Methodological quality of reporting RCTs in the 5neurology journals is unsatisfactory, especially that for surgical RCTs, and it could be further improved. PMID- 28089839 TI - Maxillary Artery to Middle Cerebral Artery Bypass: A Novel Technique for Exposure of the Maxillary Artery. AB - OBJECTIVE: To define the maxillary artery (MaxA) anatomy and present a novel technique for exposing and preparing this vessel as a bypass donor. METHODS: Cadaveric and radiologic studies were used to define the MaxA anatomy and show a novel method for harvesting and preparing it for extracranial to intracranial bypass. RESULTS: The MaxA runs parallel to the frontal branch of the superficial temporal artery and is located on average 24.8 +/- 3.8 mm inferior to the midpoint of the zygomatic arch. The pterygoid segment of the MaxA is most appropriate for bypass with a maximal diameter of 2.5 +/- 0.4 mm. The pterygoid segment can be divided into a main trunk and terminal part based on anatomic features and use in the bypass procedure. The main trunk of the pterygoid segment can be reached extracranially, either by following the deep temporal arteries downward toward their origin from the MaxA or by following the sphenoid groove downward to the terminal part of the pterygoid segment, which can be followed proximally to expose the entire MaxA. In comparison, the prebifurcation diameter of the superficial temporal artery is 1.9 +/- 0.5 mm. The average lengths of the mandibular and pterygoid MaxA segments are 6.3 +/- 2.4 and 6.7 +/- 3.3 mm, respectively. CONCLUSIONS: The MaxA can be exposed without zygomatic osteotomies or resection of the middle fossa floor. Anatomic landmarks for exposing the MaxA include the anterior and posterior deep temporal arteries and the pterygomaxillary fissure. PMID- 28089840 TI - Biogeography and diversification dynamics of the African woodpeckers. AB - The dynamics of species accumulation of African terrestrial vertebrates over time remains underexplored in comparison with those in the New World, despite Africa hosting about 25% of the world's avian diversity. This lack of knowledge hampers our understanding of the fundamental processes that drive biodiversity and the dynamics of speciation. To begin to address this gap, we reconstructed species level phylogenies of two unrelated clades of African woodpeckers (12 species of Geocolaptes/Campethera and 13 species of Chloropicus/Mesopicos/Dendropicos/Ipophilus) that diverged from their closest Indo-Malayan relatives at similar times. Our results demonstrate that the current taxonomy is misleading: three (Campethera, Dendropicos and Mesopicos) out of four polytpic genera/subgenera are not monophyletic. Our results also show that current estimates of diversity at the species level are significantly understated, as up to 18 species for the 'Campethera clade' and 19 for the 'Dendropicos clade' could be recognized. The first splits within both clades involve species that are largely restricted to the Guineo-Congolian biogeographic regions, followed by later adaptations to particular habitats (forest versus savannah) and colonization of other regions (e.g. Southern Africa), each of which occurred multiple times in both clades. Assuming a conservative species delimitation scheme, our results indicate that diversification rates are decreasing through time for both clades. Applying a more extreme species recognition scheme (18 and 19 species for the Campethera and Dendropicos clades, respectively), our results support a decrease in diversification rates only for the Dendropicos clade and thus underline the importance of the number of species included in our diversification analyses. Greater ecological diversity of the Campethera clade where multiple species exhibit either an arboreal or terrestrial foraging strategy might explain the constant diversification rates through time we found under the eighteen species scheme. PMID- 28089841 TI - The birth of aposematism: High phenotypic divergence and low genetic diversity in a young clade of poison frogs. AB - Rapid radiation coupled with low genetic divergence often hinders species delimitation and phylogeny estimation even if putative species are phenotypically distinct. Some aposematic species, such as poison frogs (Dendrobatidae), have high levels of intraspecific color polymorphism, which can lead to overestimation of species when phenotypic divergence primarily guides species delimitation. We explored this possibility in the youngest origin of aposematism (3-7 MYA) in poison frogs, Epipedobates, by comparing genetic divergence with color and acoustic divergence. We found low genetic divergence (2.6% in the 16S gene) despite substantial differences in color and acoustic signals. While chemical defense is inferred to have evolved in the ancestor of Epipedobates, aposematic coloration evolved at least twice or was lost once in Epipedobates, suggesting that it is evolutionarily labile. We inferred at least one event of introgression between two cryptically colored species with adjacent ranges (E. boulengeri and E. machalilla). We also find evidence for peripheral isolation resulting in phenotypic divergence and potential speciation of the aposematic E. tricolor from the non-aposematic E. machalilla. However, we were unable to estimate a well supported species tree or delimit species using multispecies coalescent models. We attribute this failure to factors associated with recent speciation including mitochondrial introgression, incomplete lineage sorting, and too few informative molecular characters. We suggest that species delimitation within young aposematic lineages such as Epipedobates will require genome-level molecular studies. We caution against relying solely on DNA barcoding for species delimitation or identification and highlight the value of phenotypic divergence and natural history in delimiting species. PMID- 28089842 TI - Curbing tumorigenesis and malignant progression through the pharmacological control of the wound healing process. AB - The prevention of cancer development and its progression is an urgent unmet medical need. Novel knowledge on the biology of cancer has evidenced that genetic changes occurring within cancer cells contribute, but are not sufficient, for tumor promotion and progression. The results of clinical studies and experimental animal models have suggested pursuing new avenues for the prevention of cancer development in the early stages, by using drugs that modulate platelet responses and those interfering with the synthesis and action of the mediators of inflammation. In fact, malignant tumors often develop at sites of chronic injury associated with platelet activation and chronic inflammation. In this review, we cover the evidence supporting this hypothesis and the rationale for the pharmacological treatment with antiplatelet agents, including low-dose aspirin, and antiinflammatory drugs to curb tumorigenesis and malignant progression. The evidence for a chemopreventive effect of low-dose aspirin against colorectal cancer (CRC) has been recently found appropriate by the U.S. Preventive Services Task Force, which recommends the use of the drug for primary prevention of cardiovascular disease and CRC. PMID- 28089843 TI - Early chronic low-level Pb exposure alters global exploratory behaviors but does not impair spatial and object memory retrieval in an object-in-place task in pre adolescent C57BL/6J mice. AB - The mechanisms by which early chronic low-level lead (Pb) exposure disrupts the developing brain are not yet understood. Rodent models have provided promising results however behavioral tests sensitive to effects at lowest levels of exposure during development are needed. Preadolescent animals (N=52) exposed to low and higher levels of Pb via lactation from birth to PND 28 completed the Object-in-Place Task of visual spatial and visual object memory retrieval (at PND 28). Generalized linear mixed models were used, controlling for sex and litter as a random effect. As compared with controls, global vertical exploratory behavior (rearing) markedly increased during memory retrieval. The findings suggested that early chronic Pb exposure altered the development of critical exploratory functions needed for learning and survival. Behaviors exhibited in novel spatial and novel object zone perimeters suggested that the Object-in-Place task is a valid measure of visual spatial and visual object memory in pre-adolescent C57BL/6J mice. Additional studies are needed to understand how early chronic low level lead exposure disrupts the trajectory and possible linkages of critical exploratory and perceptual systems during development. PMID- 28089844 TI - Familial cluster of exposure to a confirmed rabid dog in travelers to Algeria. AB - A 10 person-family originating from Algeria traveled in rural Algeria for the purpose of visiting friends and relatives without seeking pre-travel advice, did not received pre-travel rabies immunization, and were exposed to a confirmed rabid dog including 8 within less than 4 days of arrival. Three received suckling mouse brain rabies vaccine although WHO strongly recommends that its production and administration be discontinued and seven received insufficient doses of equine rabies immune globulin abroad. Rabies treatment was completed on returning to France. This reports underline the fact that travelers visiting friends and relatives in dog rabies endemic country are at high risk of rabies exposure and unaware of such a risk in most instances. Rabies risk warning should be reinforced and rabies pre-exposure vaccination should be considered in all individuals traveling to North Africa (and to sub-Saharan Africa) whatever the duration of stay. PMID- 28089845 TI - Therapeutic hypothermia: Turning humans into cold-blooded ectotherms via adenosine receptors. PMID- 28089846 TI - Modulation of neuroinflammation and pathology in the 5XFAD mouse model of Alzheimer's disease using a biased and selective beta-1 adrenergic receptor partial agonist. AB - Degeneration of noradrenergic neurons occurs at an early stage of Alzheimer's Disease (AD). The noradrenergic system regulates arousal and learning and memory, and has been implicated in regulating neuroinflammation. Loss of noradrenergic tone may underlie AD progression at many levels. We have previously shown that acute administration of a partial agonist of the beta-1 adrenergic receptor (ADRB1), xamoterol, restores behavioral deficits in a mouse model of AD. The current studies examined the effects of chronic low dose xamoterol on neuroinflammation, pathology, and behavior in the pathologically aggressive 5XFAD transgenic mouse model of AD. In vitro experiments in cells expressing human beta adrenergic receptors demonstrate that xamoterol is highly selective for ADRB1 and functionally biased for the cAMP over the beta-arrestin pathway. Data demonstrate ADRB1-mediated attenuation of TNF-alpha production with xamoterol in primary rat microglia culture following LPS challenge. Finally, two independent cohorts of 5XFAD and control mice were administered xamoterol from approximately 4.0-6.5 or 7.0-9.5 months, were tested in an array of behavioral tasks, and brains were examined for evidence of neuroinflammation, and amyloid beta and tau pathology. Xamoterol reduced mRNA expression of neuroinflammatory markers (Iba1, CD74, CD14 and TGFbeta) and immunohistochemical evidence for microgliosis and astrogliosis. Xamoterol reduced amyloid beta and tau pathology as measured by regional immunohistochemistry. Behavioral deficits were not observed for 5XFAD mice. In conclusion, chronic administration of a selective, functionally biased, partial agonist of ADRB1 is effective in reducing neuroinflammation and amyloid beta and tau pathology in the 5XFAD model of AD. PMID- 28089847 TI - The binding orientation of epibatidine at alpha7 nACh receptors. AB - Epibatidine is an alkaloid toxin that binds with high affinity to nicotinic and muscarinic acetylcholine receptors, and has been extensively used as a research tool. To examine binding interactions at the nicotinic receptor, it has been co crystallised with the structural homologue acetylcholine binding protein (AChBP; PDB ID 2BYQ), and with an AChBP chimaera (3SQ6) that shares 64% sequence identity with the alpha7 nACh receptor. However, the binding orientations revealed by AChBP co-crystal structures may not precisely represent their receptor homologues and experimental evidence is needed to verify the ligand poses. Here we identify potential binding site interactions between epibatidine and AChBP residues, and substitute equivalent positions in the alpha7 nACh receptor. The effects of these are probed by [3H]epibatidine binding following the expression alpha7 nACh receptor cysteine mutants in HEK 293 cells. Of the sixteen mutants created, the affinity of epibatidine was unaffected by the substitutions Q55C, L106C, L116C, T146C, D160C and S162C, reduced by C186A and C187A, increased by Q114C and S144C, and abolished by W53C, Y91C, N104C, W145C, Y184C and Y191C. These results are consistent with the predicted orientations in AChBP and suggest that epibatidine is likely to occupy a similar location at alpha7 nACh receptors. We speculate that steric constraints placed upon the C-5 position of the pyridine ring in 3SQ6 may account for the relatively poor affinities of epibatidine derivatives that are substituted at this position. PMID- 28089848 TI - SPARC preserves follicular epithelium integrity in insect ovaries. AB - The importance of juvenile hormone regulating insect oogenesis suggests looking for genes whose expression is regulated by this hormone. SPARC is a calcium binding glycoprotein that forms part of the extracellular membranes, which in vertebrates participates in bones mineralization or regulating cell proliferation in some cancer types. This large number of functions described for SPARC in different species might be related to the significant differences in its structure observed when comparing different species-groups. Indeed, these structural differences allow characterizing the different clades. In the cockroach Blattella germanica, a SPARC homolog emerged from ovarian transcriptomes that were constructed to find genes responding to juvenile hormone. In insects, SPARC functions have been studied in oogenesis and in embryo development of Drosophila melanogaster. In the present work, using RNAi approaches, novel functions for SPARC in the B. germanica panoistic ovaries are described. We found that depletion of SPARC does not allow to the follicular cells to complete mitosis, resulting in giant follicular cells nuclei and in a great alteration of the ovarian follicle cytoskeleton. The SPARC contribution to B. germanica oogenesis occurs stabilizing the follicular cell program and helping to maintain the nuclear divisions. Moreover, SPARC is necessary to maintain the cytoskeleton of the follicular cells. Any modification of these key processes disables females for oviposition. PMID- 28089849 TI - Gastrointestinal Bleeding With Oral Anticoagulation: Understanding the Scope of the Problem. PMID- 28089850 TI - Radiofrequency Ablation of Barrett's Esophagus Reduces Esophageal Adenocarcinoma Incidence and Mortality in a Comparative Modeling Analysis. PMID- 28089851 TI - Neuregulin-1 mutant mice indicate motor and sensory deficits, indeed few references for schizophrenia endophenotype model. AB - Neuregulins (Nrg) are a gene family that binds to tyrosine kinase receptors of the ErbB family. The protein of Nrg1 is to be involved in heart formation, migration of neurons, axonal pathfinding and synaptic function. A relation between Nrg1 and schizophrenia is assumed. Chronic impairment in schizophrenia is characterized by different positive and negative symptoms. Detectable markers of this disease in human and in animal models are activity, social behavior and sensory processing. In this study we compared heterozygous Nrg1 mutant mice in behavior and quantification of dopaminergic and serotoninergic neurons with wild type-like littermates. In the Nrg1 mutant mice the epidermal growth factor-like domain is replaced by the neomycin resistance gene. We found significant differences in locomotor and pain perception behavior. No differences were found in specific schizophrenia social interaction and prepulse inhibition behavior. The number of dopaminergic and serotoninergic neurons did not differ in the investigated regions ventral tegmental area, substantia nigra, periaqueductal grey and raphe nuclei. In conclusion, this analyzed Nrg1 mutant mice model did not serve as a complete schizophrenia model. Particular aspects of schizophrenia disease in locomotor and sensory behavior deficits could represent in this Nrg1 mutant mice. Beside several different models could Nrg1 deficiency represent an endophenotype of schizophrenia disease. PMID- 28089852 TI - Dopamine D1 receptor agonist treatment attenuates extinction of morphine conditioned place preference while increasing dendritic complexity in the nucleus accumbens core. AB - The dopamine D1 receptor (D1R) has a role in opioid reward and conditioned place preference (CPP), but its role in CPP extinction is undetermined. We examined the effect of D1R agonist SKF81297 on the extinction of opioid CPP and associated dendritic morphology in the nucleus accumbens (NAc), a region involved with reward integration and its extinction. During the acquisition of morphine CPP, mice received morphine and saline on alternate days; injections were given immediately before each of eight daily conditioning sessions. Mice subsequently underwent six days of extinction training designed to diminish the previously learned association. Mice were treated with either 0.5mg/kg SKF81297, 0.8mg/kg SKF81297, or saline immediately after each extinction session. There was a dose dependent effect, with the highest dose of SKF81297 attenuating extinction, as mice treated with this dose had significantly higher CPP scores than controls. Analysis of medium spiny neuron morphology revealed that in the NAc core, but not in the shell, dendritic arbors were significantly more complex in the morphine conditioned, SKF81297-treated mice compared to controls. In separate experiments using mice conditioned with only saline, SKF81297 administration after extinction sessions had no effect on CPP and produced differing effects on dendritic morphology. At the doses used in our experiments, SKF81297 appears to maintain previously learned opioid conditioned behavior, even in the face of new information. The D1R agonist's differential, rather than unidirectional, effects on dendritic morphology in the NAc core suggests that it may be involved in encoding reward information depending on previously learned behavior. PMID- 28089853 TI - Region-specific increases in FosB/DeltaFosB immunoreactivity in the rat brain in response to chronic sleep restriction. AB - Using a rat model of chronic sleep restriction (CSR) featuring periodic sleep deprivation with slowly rotating wheels (3h on/1h off), we previously observed that 99h of this protocol induced both homeostatic and allostatic (adaptive) changes in physiological and behavioural measures. Notably, the initial changes in sleep intensity and attention performance gradually adapted during CSR despite accumulating sleep loss. To identify brain regions involved in these responses, we used FosB/DeltaFosB immunohistochemistry as a marker of chronic neuronal activation. Adult male rats were housed in motorized activity wheels and underwent the 3/1 CSR protocol for 99h, or 99h followed by 6 or 12days of recovery. Control rats were housed in home cages, locked activity wheels, or unlocked activity wheels that the animals could turn freely. Immunohistochemistry was conducted using an antibody that recognized both FosB and DeltaFosB, and 24 brain regions involved in sleep/wake, autonomic, and limbic functions were examined. The number of darkly-stained FosB/DeltaFosB-immunoreactive cells was increased immediately following 99h of CSR in 8/24 brain regions, including the medial preoptic and perifornical lateral hypothalamic areas, dorsomedial and paraventricular hypothalamic nuclei, and paraventricular thalamic nucleus. FosB/DeltaFosB labeling was at control levels in all 8 brain areas following 6 or 12 recovery days, suggesting that most of the immunoreactivity immediately after CSR reflected FosB, the more transient marker of chronic neuronal activation. This region-specific induction of FosB/DeltaFosB following CSR may be involved in the mechanisms underlying the allostatic changes in behavioural and physiological responses to CSR. PMID- 28089855 TI - Peripheral electrical stimulation increases corticomotor excitability and enhances the rate of visuomotor adaptation. AB - Peripheral electrical stimulation (PES) modulates corticomotor excitability but its effect on motor performance has not been thoroughly investigated. The purpose of this study was to assess whether increases and/or decreases in corticomotor excitability, induced by PES, influenced motor performance using a visuomotor adaptation task. Three PES interventions (motor stimulation, sensory stimulation or sham) were delivered to the first dorsal interosseous (FDI) in 30 healthy participants matched for age, gender and handedness. Motor stimulation was applied to increase corticomotor excitability, sensory stimulation to decrease corticomotor excitability, while sham stimulation acted as a control. Corticomotor excitability was assessed using the amplitude of motor evoked potentials to transcranial magnetic stimulation recorded from FDI before and after each intervention. Following PES, participants completed a visuomotor adaptation task. This required participants to move a cursor accurately towards virtual targets with index finger movements when the cursor trajectory was rotated 30 degrees counter clockwise. Performance was assessed as angular error (a measure of movement accuracy) and reaction time. The rate of visuomotor adaptation was greater following motor PES compared to sham, but not sensory, with no difference observed between sensory and sham. However, visuomotor adaptation performance overall (the total change in performance from beginning to end) was similar across intervention groups. These findings suggest that motor PES applied prior to task acquisition can facilitate the speed of adaptation. PMID- 28089854 TI - Effects of adolescent methamphetamine and nicotine exposure on behavioral performance and MAP-2 immunoreactivity in the nucleus accumbens of adolescent mice. AB - The neurotoxic effects of methamphetamine (MA) exposure in the developing and adult brain can lead to behavioral alterations and cognitive deficits in adults. Previous increases in the rates of adolescent MA use necessitate that we understand the behavioral and cognitive effects of MA exposure during adolescence on the adolescent brain. Adolescents using MA exhibit high rates of nicotine (NIC) use, but the effects of concurrent MA and NIC in the adolescent brain have not been examined, and it is unknown if NIC mediates any of the effects of MA in the adolescent. In this study, the long-term effects of a neurotoxic dose of MA with or without NIC exposure during early adolescence (postnatal day 30-31) were examined later in adolescence (postnatal day 41-50) in male C57BL/6J mice. Effects on behavioral performance in the open field, Porsolt forced swim test, and conditioned place preference test, and cognitive performance in the novel object recognition test and Morris water maze were assessed. Additionally, the effects of MA and/or NIC on levels of microtubule associated-2 (MAP-2) protein in the nucleus accumbens and plasma corticosterone were examined. MA and NIC exposure during early adolescence separately decreased anxiety-like behavior in the open field test, which was not seen following co-administration of MA/NIC. There was no significant effect of early adolescent MA and/or NIC exposure on the intensity of MAP-2 immunoreactivity in the nucleus accumbens or on plasma corticosterone levels. These results show that early adolescent MA and NIC exposure separately decrease anxiety-like behavior in the open field, and that concurrent MA and NIC exposure does not induce the same behavioral change as either drug alone. PMID- 28089856 TI - Erythrocyte heat shock protein responses to chronic (in vivo) and acute (in vitro) temperature challenge in diploid and triploid salmonids. AB - This research investigated how ploidy level (diploid versus triploid) affects the heat shock protein (HSP) response in erythrocytes under different thermal stress regimes, both in vivo and in vitro, in Atlantic salmon (Salmo salar) and brook charr (Salvelinus fontinalis) in order to address the question of why triploids typically have reduced thermal tolerance. A preliminary study confirmed that identical volumes of diploid and triploid erythrocytes (which equates to a smaller number of larger cells for triploids compared to diploids) did not differ in total protein synthesis rates. After chronic (100d) acclimation of fish to 5, 15 and 25 degrees C, triploid erythrocytes had lower HSP70, HSP90, heat shock factor 1 (HSF1) and ubiquitin (free and total) levels than diploids in both species. Furthermore, Atlantic salmon erythrocytes showed significantly higher protein breakdown (based on conjugated ubiquitin levels) in triploids than diploids after acute heat stress in vitro, but no significant difference was detected between ploidies after acute cold stress. These results indicate that: 1) triploid erythrocytes synthesize more total protein per cell than diploids as a result of increased cell size; 2) triploids have sufficient total HSP levels for survival under low stress conditions; and 3) the lower basal titres of HSPs in triploids may be a handicap when combating acute stress. Taken together, this suggests that triploids are limited in their ability to withstand thermal stress because of a reduced ability to maintain proteostasis under stressful conditions. PMID- 28089857 TI - Na+/K+-ATPase activity in the anoxic turtle (Trachemys scripta) brain at different acclimation temperature. AB - Survival of prolonged anoxia requires a balance between cellular ATP demand and anaerobic ATP supply from glycolysis, especially in critical tissues such as the brain. To add insight into the ATP demand of the brain of the anoxia-tolerant red eared slider turtle (Trachemys scripta) during prolonged periods of anoxic submergence, we quantified and compared the number of Na+-K+-ATPase units and their molecular activity in brain tissue from turtles acclimated to either 21 degrees C or 5 degrees C and exposed to either normoxia or anoxia (6h 21 degrees C; 14days at 5 degrees C). Na+-K+-ATPase activity and density per g tissue were similar at 21 degrees C and 5 degrees C in normoxic turtles. Likewise, anoxia exposure at 21 degrees C did not induce any change in Na+-K+-ATPase activity or density. In contrast, prolonged anoxia at 5 degrees C significantly reduced Na+ K+-ATPase activity by 55%, which was largely driven by a 50% reduction of the number of Na+-K+-ATPase units without a change in the activity of existing Na+-K+ ATPase pumps or alpha-subunit composition. These findings are consistent with the "channel arrest" hypothesis to reduce turtle brain Na+-K+-ATPase activity during prolonged, but not short-term anoxia, a change that likely helps them overwinter under low temperature, anoxic conditions. PMID- 28089858 TI - Glucose, amino acids and fatty acids directly regulate ghrelin and NUCB2/nesfatin 1 in the intestine and hepatopancreas of goldfish (Carassius auratus) in vitro. AB - Ghrelin and nesfatin-1 are two peptidyl hormones primarily involved in food intake regulation. We previously reported that the amount of dietary carbohydrates, protein and lipids modulates the expression of these peptides in goldfish in vivo. In the present work, we aimed to characterize the effects of single nutrients on ghrelin and nesfatin-1 in the intestine and hepatopancreas. First, immunolocalization of ghrelin and NUCB2/nesfatin-1 in goldfish hepatopancreas cells was studied by immunohistochemistry. Second, the effects of 2 and 4hour-long exposures of cultured intestine and hepatopancreas sections to glucose, l-tryptophan, oleic acid, linolenic acid (LNA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on ghrelin and nesfatin-1 gene and protein expression were studied. Co-localization of ghrelin and NUCB2/nesfatin-1 in the cytoplasm of goldfish hepatocytes was found. Exposure to glucose led to an upregulation of preproghrelin and a downregulation of nucb2/nesfatin-1 in the intestine. l-Tryptophan mainly decreased the expression of both peptides in the intestine and hepatopancreas. Fatty acids, in general, downregulated NUCB2/nesfatin-1 in the intestine, but only the longer and highly unsaturated fatty acids inhibited preproghrelin. EPA exposure led to a decrease in preproghrelin, and an increase in nucb2/nesfatin-1 expression in hepatopancreas after 2h. These results show that macronutrients exert a dose- and time dependent, direct regulation of ghrelin and nesfatin-1 in the intestine and hepatopancreas, and suggest a role for these hormones in the digestive process and nutrient metabolism. PMID- 28089859 TI - The perfusion code of DIEP and ms-TRAM flaps is a hard nut to crack. PMID- 28089860 TI - Comment on: "Improved healthcare economic outcomes after liposomal bupivacaine administration in first-stage breast reconstruction". PMID- 28089861 TI - Reply to Letter to the Editor regarding article by Miranda et al. PMID- 28089862 TI - Response to letter, which comments on 'Beard Reconstruction - a Surgical Algorithm'. PMID- 28089863 TI - Prevention of thrombosis in hypercoagulable patients undergoing microsurgery: A novel anticoagulation protocol. AB - BACKGROUND: Hypercoagulable conditions are often considered relative contraindications to free flap reconstruction. This paper presents and critically examines a novel anticoagulation regimen developed to address this disease state. METHODS: Hypercoagulable patients who underwent free tissue transfer between 2007 and 2015 were identified. From 2011, all such patients were subjected to a novel anticoagulation protocol involving an intravenous bolus of 2000 U of unfractionated heparin prior to microvascular pedicle anastomosis, followed by a heparin infusion at 500 U/h, which was postoperatively increased to therapeutic levels. Patients were discharged on full anticoagulation for 1 month. Patients prior to 2011 received only subcutaneous heparin. Outcomes in patients receiving this novel anticoagulation protocol were compared to those of patients receiving standard therapy (postoperative subcutaneous heparin). RESULTS: Twenty-three hypercoagulable patients underwent reconstruction with 32 flaps. Eleven patients were administered the novel protocol. No thromboses were noted in the novel protocol cohort, while three thrombotic events occurred in the control cohort (0% vs. 17.6%, p = 0.23). No flaps were salvaged after thrombosis. All losses occurred in the control cohort (0% vs. 17.6%, p = 0.23). The novel protocol cohort was more likely to have postoperative red blood cell transfusions (72.6% vs. 16.7%, p = 0.007), hematomas (26.7% vs. 0%, p = 0.04), and lower mean hemoglobin nadirs [6.9 (1.0) vs. 8.9 +/- 1.8 g/dL, p = 0.01]. CONCLUSION: The key approach to hypercoagulable patients is likely prevention over treatment. Patients who received prophylactic heparin infusions had clinically lower rates of thrombotic events and flap loss. However, this encouraging finding must be balanced with the increased risk for postoperative bleeding complications. PMID- 28089864 TI - Draft genome sequence of an O25:H4-ST131 Escherichia coli harbouring blaNDM-1 on an IncHI3 plasmid: A first report. AB - Carbapenem resistance conferred by New Delhi metallo-beta-lactamases is mediated by plasmids of diverse incompatibility types harboured by different lineages of Enterobacteriaceae. In this study, we report the draft genome sequence of a ST131 Escherichia coli harbouring the blaNDM gene on an IncHI3 plasmid. PMID- 28089865 TI - Pathogens and epidemiologic feature of severe fever with thrombocytopenia syndrome in Hubei province, China. AB - To evaluate the aetiological agents and epidemiologic features of severe fever with thrombocytopenia syndrome (SFTS) in Hubei province, China, sera from patients were collected from January to December 2011. All cases occurred from April to December, and the epidemic peaked from May to August. The ages of patients ranged from 10 to 86 years (median=55years), and the incidence of SFTS increased with age. The female:male ratio of cases was 1.008:1, and 54.6% (77/141) and 1.4% (2/141) of the cases were confirmed by qPCR to be SFTSV and Hantavirus (HV) infection, respectively. No case of simultaneous infection with two or more pathogens was found. The research in this paper showed that some suspected SFTS cases are confused with HV infection due to similar symptoms. The analysis showed that the distribution of SFTSV has a marked regional aggregation in Hubei province. PMID- 28089866 TI - Inhibition of chaperone-mediated autophagy prevents glucotoxicity in the Caenorhabditis elegans mev-1 mutant by activation of the proteasome. AB - Chronic hyperglycemia is a hallmark of diabetes mellitus and the main cause of diabetes-associated complications. Increased intracellular glucose levels lead to damaged proteins and in consequence disturb cellular proteostasis. As an important contributor to the maintenance and restoration of proteostasis, autophagy mediates the lysosomal degradation of damaged proteins or entire cellular organelles. In the present study we used the stress-sensitive mev-1 mutant of the nematode Caenorhabditis elegans in order to assess the role of lmp 2, a homologue of the lysosome associated membrane protein type 2A, in the context of glucotoxicity, which was achieved by feeding glucose in a liquid medium. Knockdown of lmp-2 by RNA interference completely prevented the survival reduction caused by glucose under heat stress. Those effects were associated with the prevention of (1) increased lysosome formation and (2) reduction of proteasomal activity, which were observed under glucose feeding. Finally, the survival reduction due to knockdown of ubiquitin remained unaffected by the additional lmp-2 knockdown in the absence or presence of glucose. In conclusion, our study provides evidence that lmp-2, a key player in chaperone-mediated autophagy, is functional in C. elegans, too. Inhibition of lmp-2 prevents the reduction of proteasomal activity by glucose and thereby prevents also glucotoxicity. PMID- 28089867 TI - Attenuation of obesity-induced inflammation in mice orally administered with salmon cartilage proteoglycan, a prophylactic agent. AB - Obesity is associated with chronic inflammation of adipose tissue and causes development of type 2 diabetes. M1 macrophage population was increased in adipose tissue of obese mouse. M1 macrophages induce insulin resistance through the secretion of proinflammatory cytokines. Our previous studies demonstrated that salmon cartilage proteoglycan (PG) suppresses excess inflammation in various mouse inflammatory diseases. In this study, we examined the effect of PG on type 2 diabetes using high-fat-diet (HFD) induced obese mouse model. Oral PG administration enhanced the population of small adipocytes (area less than 1000 MUm2) without body and tissue weight gain. In addition, PG administration suppressed mRNA expression of TNF-alpha, IL-6 and CXCL2 in adipose tissue. The proportion of M1 macrophages was decreased by PG administration. In addition, PG administration suppressed hyperglycemia after intraperitoneal glucose injection. Fasted serum insulin level was decreased in PG-administered mice. Moreover, insulin-stimulated phosphorylation of Akt was enhanced in the liver and gastrocnemius skeletal muscle of PG-administered mice. These data suggested that PG administration improves hyperglycemia and insulin sensitivity in obese mice by modulation of M1 macrophages which secrete proinflammatory cytokines in adipose tissue and activation of Akt in liver and skeletal muscle. PMID- 28089868 TI - Novel calcium recognition constructions in proteins: Calcium blade and EF-hand zone. AB - Metal ions can regulate various cell processes being first, second or third messengers, and some of them, especially transition metal ions, take part in catalysis in many enzymes. As an intracellular ion, Ca2+ is involved in many cellular functions from fertilization and contraction, cell differentiation and proliferation, to apoptosis and cancer. Here, we have identified and described two novel calcium recognition environments in proteins: the calcium blade zone and the EF-hand zone, common to 12 and 8 different protein families, respectively. Each of the two environments contains three distinct structural elements: (a) the well-known characteristic Dx[DN]xDG motif; (b) an adjacent structurally identical segment, which binds metal ion in the same way between the calcium blade zone and the EF-hand zone; and (c) the following structurally variable segment, which distinguishes the calcium blade zone from the EF-hand zone. Both zones have sequence insertions between the last residue of the zone and calcium-binding residues in positions V or VI. The long insertion often connects the active and the calcium-binding sites in proteins. Using the structurally identical segments as an anchor, we were able to construct the classical calmodulin type EF-hand calcium-binding site out of two different calcium-binding motifs from two unrelated proteins. PMID- 28089869 TI - The molecular and morphogenetic basis of pancreas organogenesis. AB - The pancreas is an essential endoderm-derived organ that ensures nutrient metabolism via its endocrine and exocrine functions. Here we review the essential processes governing the embryonic and early postnatal development of the pancreas discussing both the mechanisms and molecules controlling progenitor specification, expansion and differentiation. We elaborate on how these processes are orchestrated in space and coordinated with morphogenesis. We draw mainly from experiments conducted in the mouse model but also from investigations in other model organisms, complementing a recent comprehensive review of human pancreas development (Jennings et al., 2015) [1]. The understanding of pancreas development in model organisms provides a framework to interpret how human mutations lead to neonatal diabetes and may contribute to other forms of diabetes and to guide the production of desired pancreatic cell types from pluripotent stem cells for therapeutic purposes. PMID- 28089870 TI - Large dense-core vesicle exocytosis from mouse dorsal root ganglion neurons is regulated by neuropeptide Y. AB - Peptidergic dorsal root ganglion (DRG) neurons transmit sensory and nociceptive information from the periphery to the central nervous system. Their synaptic activity is profoundly affected by neuromodulatory peptides stored and released from large dense-core vesicles (LDCVs). However, the mechanism of peptide secretion from DRG neurons is poorly understood. Using total internal reflection fluorescence microscopy (TIRFM), we visualized individual LDCVs loaded with fluorescent neuropeptide Y (NPY) and analyzed their stimulation-dependent release. We tested several protocols and found an overall low stimulation secretion coupling that increased after raising intracellular Ca2+ concentration by applying a weak pre-stimulus. Interestingly, the stimulation protocol also influenced the mechanism of LDCV fusion. Depolarization of DRG neurons with a solution containing 60mM KCl triggered full fusion, kiss-and-run, and kiss-and stay exocytosis with equal frequency. In contrast, field electrode stimulation primarily induced full fusion exocytosis. Finally, our results indicate that NPY can promote LDCV secretion. These results shed new light on the mechanism of NPY action during modulation of DRG neuron activity, an important pathway in the treatment of chronic pain. PMID- 28089871 TI - Parents' childhood socioeconomic circumstances are associated with their children's asthma outcomes. AB - BACKGROUND: Previous literature documents associations between low socioeconomic status (SES) and poor health outcomes, including asthma. However, this literature has largely focused on the effects of current family circumstances. OBJECTIVE: We sought to test an intergenerational hypothesis, that the childhood SES that parents experience will be associated with asthma outcomes in their children, independent of effects of current family SES. Second, we aimed to test whether this association is in part due to difficulties in current parent-child relationships. METHODS: This was an observational study, whereby 150 parents were interviewed about their childhood SES and their children (physician-diagnosed asthma, ages 9-17 years) were interviewed about current family stress. Asthma control was assessed by parent report and child report (primary outcome), and blood was collected from children to measure cytokine production relevant to asthma (secondary outcomes). RESULTS: To the degree that parents had lower childhood SES, their offspring showed worse asthma outcomes across multiple indicators. This included lower asthma control scores (parent and child report, Ps < .05), and greater stimulated production of TH2 and TH1 cytokines by PBMCs (Ps < .05). These associations were independent of current family SES. Mediation analyses were consistent with a scenario wherein parents with low childhood SES had current family relationships that were more stressful, and these difficulties, in turn, related to worse asthma control and greater cytokine production in children. CONCLUSIONS: These results suggest the potential "long reach" of low SES across generations, and the importance of expanding theories of how the social environment can affect childhood asthma to include characteristics of earlier generations. PMID- 28089872 TI - Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients. AB - BACKGROUND: The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects. OBJECTIVE: We explored this data set to define type 2 inflammation based on airway mucosal IL-13-driven gene expression and how this related to clinically accessible biomarkers. METHODS: IL-13-driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (Feno) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression. RESULTS: Expression of airway mucosal CCL26, periostin, and IL-13-IVS all facilitated segregation of subjects into type 2-high and type 2-low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had Feno values (>=35 ppb) and/or high bEOS counts (>=300 cells/mm3) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of Feno values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26-high status. Clinical variables did not differ between subjects with type 2-high and type 2-low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression. CONCLUSION: A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13-IVS gene expression. Use of Feno values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics. PMID- 28089874 TI - Mathematical modelling of cell layer growth in a hollow fibre bioreactor. AB - Generating autologous tissue grafts of a clinically useful volume requires efficient and controlled expansion of cell populations harvested from patients. Hollow fibre bioreactors show promise as cell expansion devices, owing to their potential for scale-up. However, further research is required to establish how to specify appropriate hollow fibre bioreactor operating conditions for expanding different cell types. In this study we develop a simple model for the growth of a cell layer seeded on the outer surface of a single fibre in a perfused hollow fibre bioreactor. Nutrient-rich culture medium is pumped through the fibre lumen and leaves the bioreactor via the lumen outlet or passes through the porous fibre walls and cell layer, and out via ports on the outer wall of the extra-capillary space. Stokes and Darcy equations for fluid flow in the fibre lumen, fibre wall, cell layer and extra-capillary space are coupled to reaction-advection-diffusion equations for oxygen and lactate transport through the bioreactor, and to a simple growth law for the evolution of the free boundary of the cell layer. Cells at the free boundary are assumed to proliferate at a rate that increases with the local oxygen concentration, and to die and detach from the layer if the local fluid shear stress or lactate concentration exceed critical thresholds. We use the model to predict operating conditions that maximise the cell layer growth for different cell types. In particular, we predict the optimal flow rate of culture medium into the fibre lumen and fluid pressure imposed at the lumen outlet for cell types with different oxygen demands and fluid shear stress tolerances, and compare the growth of the cell layer when the exit ports on the outside of the bioreactor are open with that when they are closed. Model simulations reveal that increasing the inlet flow rate and outlet fluid pressure increases oxygen delivery to the cell layer and, therefore, the growth rate of cells that are tolerant to high shear stresses, but may be detrimental for shear-sensitive cells. The cell layer growth rate is predicted to increase, and be less sensitive to the lactate tolerance of the cells, when the exit ports are opened, as the radial flow through the bioreactor is enhanced and the lactate produced by the cells cleared more rapidly from the cell layer. PMID- 28089873 TI - Patterns of immune development in urban preschoolers with recurrent wheeze and/or atopy. AB - BACKGROUND: Disadvantaged urban children have high rates of allergic diseases and wheezing, which are diseases associated with type 2-biased immunity. OBJECTIVE: We sought to determine whether environmental exposures in early life influence cytokine responses that affect the development of recurrent wheezing illnesses and allergic sensitization. METHODS: A birth cohort of 560 urban families was recruited from neighborhoods with high rates of poverty, and 467 (83%) children were followed until 3 years of age. Cytokine responses were measured in blood cell samples obtained at birth (cord blood) and ages 1 and 3 years. Cytokine responses were examined in relation to personal characteristics and environmental exposures to allergens and endotoxin and to the development of allergic sensitization and recurrent wheeze assessed at age 3 years. RESULTS: Cytokine responses generally increased with age, but responses at birth were poorly predictive for those at ages 1 and 3 years. Exposure to certain allergens (cockroach, mouse, dust mite) was significantly associated with enhanced cytokine responses at age 3 years, including IFN-alpha and IL-10 responses to certain stimulants and responses to phytohemagglutinin. Regarding the clinical outcomes, reduced LPS-induced IL-10 responses at birth were associated with recurrent wheeze. In contrast, reduced respiratory syncytial virus-induced IL-8 responses and increased 5'-cytosine-phosphate-guanine-3' (CpG)-induced IL-12p40 and allergen-induced IL-4 responses were associated with atopy. CONCLUSIONS: These findings suggest that diverse biologic exposures, including allergens and endotoxin, in urban homes stimulate the development of cytokine responses in early life, and that cytokine responses to specific microbial and viral stimuli are associated with the development of allergic sensitization and recurrent wheeze. PMID- 28089875 TI - End points for catheter ablation of persistent atrial fibrillation. PMID- 28089876 TI - Antiarrhythmic drug therapy in patients with arrhythmogenic dysplasia/cardiomyopathy: Is there a role for flecainide? PMID- 28089877 TI - Permanent pacemaker implantation in octogenarians with unexplained syncope and positive electrophysiologic testing. AB - BACKGROUND: Syncope is a common problem in the elderly, and a permanent pacemaker is a therapeutic option when a bradycardic etiology is revealed. However, the benefit of pacing when no association of symptoms to bradycardia has been shown is not clear, especially in the elderly. OBJECTIVE: The aim of this study was to evaluate the effect of pacing on syncope-free mortality in patients aged 80 years or older with unexplained syncope and "positive" invasive electrophysiologic testing (EPT). METHODS: This was an observational study. A positive EPT for the purposes of this study was defined by at least 1 of the following: a corrected sinus node recovery time of >525 ms, a basic HV interval of >55 ms, detection of infra-Hisian block, or appearance of second-degree atrioventricular block on atrial decremental pacing at a paced cycle length of >400 ms. RESULTS: Among the 2435 screened patients, 228 eligible patients were identified, 145 of whom were implanted with a pacemaker. Kaplan-Meier analysis determined that time to event (syncope or death) was 50.1 months (95% confidence interval 45.4-54.8 months) with a pacemaker vs 37.8 months (95% confidence interval 31.3-44.4 months) without a pacemaker (log-rank test, P = .001). The 4-year time-dependent estimate of the rate of syncope was 12% vs 44% (P < .001) and that of any-cause death was 41% vs 56% (P = .023), respectively. The multivariable odds ratio was 0.25 (95% confidence interval 0.15-0.40) after adjustment for potential confounders. CONCLUSION: In patients with unexplained syncope and signs of sinus node dysfunction or impaired atrioventricular conduction on invasive EPT, pacemaker implantation was independently associated with longer syncope-free survival. Significant differences were also shown in the individual components of the primary outcome measure (syncope and death from any cause). PMID- 28089878 TI - Pretransplant Absolute Lymphocyte Counts Impact the Pharmacokinetics of Alemtuzumab. AB - Alemtuzumab is frequently used as part of reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplantation (HCT) in pediatric patients with nonmalignant diseases. We previously suggested an optimal day 0 targeted range of alemtuzumab, but there are no pediatric data regarding the pharmacokinetics (PK) of subcutaneous alemtuzumab to guide precision dosing trials. The goal of this study was to prospectively characterize alemtuzumab PK and to explore absolute lymphocyte count (ALC) as a predictor of interindividual variability. We prospectively enrolled 23 patients who received an alemtuzumab, fludarabine, and melphalan RIC regimen. Seventeen patients completed study and received 1 mg/kg alemtuzumab divided over 5 days subcutaneously, starting on day 14. The median age was 7 years (range, .5 to 18). Blood sampling for PK measurements and descriptive PK analyses were performed. The median maximum alemtuzumab concentration was 2.39 ug/mL (interquartile range, 1.98 to 2.92). The median terminal half-life was 5.2 days (interquartile range, 2.7 to 7.8). The median concentration at day 0 was 1.27 ug/mL (interquartile range, .35 to 1.51). Importantly, day 0 alemtuzumab levels and area under the curve negatively correlated with predose ALC and ALC area-time, respectively. In conclusion, we reported the PK of subcutaneous alemtuzumab given to pediatric allogeneic HCT patients and observed that almost all patients have persistence of lytic levels of alemtuzumab beyond day 0, at levels in excess of that needed to reduce the risk of acute graft-versus-host disease. Additionally, levels correlate with pretransplant ALC. These results will allow the development of population PK models for precision dosing trials. PMID- 28089879 TI - Clinical Outcome of Autologous Hematopoietic Cell Transplantation in Adult Patients with Acute Myeloid Leukemia: Who May Benefit from Autologous Hematopoietic Cell Transplantation? AB - The role of autologous hematopoietic cell transplantation (auto-HCT) for postremission therapy of acute myeloid leukemia is yet to be elucidated. We retrospectively analyzed 240 patients treated with auto-HCT in first remission. All patients were treated with standard induction chemotherapy, and CD34+ stem cells were collected at each cycle of consolidation. Stem cells were infused after total body irradiation (1200 cGy), cytarabine (9 g/m2), and melphalan (100 mg/m2). Estimated 5-year overall survival, disease-free survival (DFS), cumulative incidence of relapse (CIR), and nonrelapse mortality were 58.4%, 55.3%, 38.8%, and 5.9%, respectively. We identified that poor-risk karyotype showed very poor outcome after auto-HCT, and then analyzed 85 patients with good to intermediate-risk molecular cytogenetics with available molecular study results and markers for minimal residual disease (MRD) such as WT1 and core binding factor (CBF) associated MRD (ie, AML1/ETO and CBFbeta/MYH11). Our data identified that old age, pre-HCT markers for MRD, and high post-HCT WT1, high dose of CD34+ stem cell (>=4.5 * 106/kg) infusion, and c-kit or FLT3-ITD mutations were associated with higher relapse rate and poor DFS. Using pre-HCT parameters, except for post-HCT WT1, multivariate analysis revealed that patients with young age (<40 years old), no adverse mutations, and limited dose of CD34+ stem cells might be good candidate for auto-HCT (3-year DFS and CIR were 83.4% and 16.6%, respectively). Young patients with good- to intermediate-risk molecular cytogenetics may benefit from auto-HCT if stem cell dose is limited. PMID- 28089881 TI - Two-step chromatographic purification of glutathione S-transferase-tagged human papillomavirus type 16 E6 protein and its application for serology. AB - Human papillomavirus (HPV) E6 protein is an oncoprotein with a pivotal role in cervical carcinogenesis. Expression and purification of HPV E6 from Escherichia coli (E. coli) has been difficult because of its strong hydrophobicity even when expressed as a fusion protein with glutathione S-transferase (GST). There has been no protocol suggested for purifying GST-tagged HPV E6 protein with high purity so far. Herein, we provide efficient protocol for purifying GST-HPV16 E6 protein for the first time. In the current study, the GST-tagged protein was expressed in E. coli and a purification method was designed using cation-exchange chromatography followed by GST-affinity chromatography. Using physiological pH buffer during cell lysis and first cation-exchange chromatography significantly reduced yield of full-length GST-HPV16 E6 protein. It was found that using an alkaline buffer during cation-exchange chromatography was needed to obtain full length GST-HPV16 E6 protein. GST-HPV16 E6 protein recovered from the purification using alkaline condition retained its inherent p53-binding ability. Moreover, we were able to detect anti-HPV16 E6 antibodies with high sensitivity in sera from patients with cervical cancer using the GST-HPV16 E6 protein. It was found that the GST-HPV16 E6 protein could be used as a coating agent to enhance the sensitivity of detection of serum anti-HPV16 E6 antibodies when treated with ethylene glycol-bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). These results indicate that the two-step chromatographic purification allows obtaining high purity of GST-HPV16 E6 protein and the GST-HPV16 E6 is suitable to be used as an antigen of serology assay. PMID- 28089880 TI - A combined approach for enhancing the stability of recombinant cis-dihydrodiol naphthalene dehydrogenase from Pseudomonas putida G7 allowed for the structural and kinetic characterization of the enzyme. AB - The second enzyme of the naphthalene degradation pathway in Pseudomonas putida G7 is NahB, a dehydrogenase that converts cis-1,2-dihydroxy-1,2-dihydronaphthalene to 1,2-dihydroxynaphthalene. We report the cloning, optimization of expression, purification, kinetic studies and preliminary structural characterization of the recombinant NahB. The nahB gene was cloned into a T7 expression vector and the enzyme was overexpressed in Escherichia coli Rosetta (DE3) as an N-terminal hexa histidine-tagged protein (6xHis-NahB). Using methods of enhancing protein stability in solution, we tested different expression, cell lysis, and purification protocols with and without ligand supplementation. The protein stability was evaluated by dynamic light scattering and circular dichroism spectroscopy assays. Best-derived protocols (expression at 18 degrees C, cell lysis with homogenizer, and three purification steps) were used to produce 20 mg of homogeneous 6xHis-NahB per liter of culture. The secondary and quaternary structures of 6xHis-NahB were assessed by circular dichroism and size-exclusion chromatography experiments, respectively. The enzyme was NAD+-dependent and active at pH 7.0 and 9.4 for the oxidation of the substrate. The Michaelis-Menten parameters determined at pH 7.0 and 25 degrees C for the substrate and cofactor, presented respective Km values of 6 and 350 MUM, and a kcat value of 8.3 s-1. Furthermore, we identified conditions for the crystallization of 6xHis-NahB. X ray diffraction data were collected from a single 6xHis-NahB crystal which diffracted to 2.21 A. The crystal belongs to space group I222, with unit-cell parameters a = 63.62, b = 69.50, and c = 117.47 A. The tertiary structure of 6xHis-NahB was determined using the molecular replacement method. Further structural refinement is currently underway. PMID- 28089882 TI - A highly efficient modified human serum albumin signal peptide to secrete proteins in cells derived from different mammalian species. AB - Signal peptides (SPs) are key elements in the production of recombinant proteins; however, little information is available concerning different SP in mammalian cells other than CHO. In order to study the efficiency of different SPs to direct the traffic along the secretory pathway of the green fluorescence protein (GFP) and a scFv-Fc fusion protein; CHO-K1, HEK293 and NS0 cell lines were transfected in a transient and stable way. SP of human azurocidin (AZ), modified human albumin (mSA), modified Cricetulus griseus Ig kappa chain V III region MOPC 63 like (mIgkappa C) and modified human Ig kappa chain V III region VG (mIgkappa H) were evaluated. The efficiency of SPs to translocate a propeptide across the ER membrane was evaluated by fluorescence microscopy and flow cytometry for the GFP inside the secretory pathway, and by antigen-specific indirect ELISA for the scFv Fc outside the cell. The mSA SP was successful in directing the secretion of the active proteins in these different types of mammalian cells, regardless of the transgene copy number. The goal of this work was to demonstrate that a modified version of SA SP might be used in different mammalian cells employing the same expression vector. PMID- 28089883 TI - Identification and characterization of a pyridoxal 5'-phosphate phosphatase in the silkworm (Bombyx mori). AB - Vitamin B6 comprises six interconvertible pyridine compounds, among which pyridoxal 5'-phosphate (PLP) is a coenzyme for over 140 enzymes. PLP is also a very reactive aldehyde. The most well established mechanism for maintaining low levels of free PLP is its dephosphorylation by phosphatases. A human PLP-specific phosphatase has been identified and characterized. However, very little is known about the phosphatase in other living organisms. In this study, a cDNA clone of putative PLP phosphatase was identified from B. mori and characterized. The cDNA encodes a polypeptide of 343 amino acid residues, and the recombinant enzyme purified from E. coli exhibited properties similar to that of human PLP phosphatase. B. mori has a single copy of the PLPP gene, which is located on 11th chromosome, spans a 5.7kb region and contains five exons and four introns. PLP phosphatase transcript was detected in every larva tissue except hemolymph, and was most highly represented in Malpighian tube. We further down-regulated the gene expression of the PLP phosphatase in 5th instar larvae with the RNA interference. However, no significant changes in the gene expression of PLP biosynthetic enzymes and composition of B6 vitamers were detected as compared with the control. PMID- 28089884 TI - Understanding natural scenes: Contributions of image statistics. AB - Visual processing of natural scenes is carried out in a hierarchical sequence of stages that involve the analysis of progressively more complex features of the visual input. Recent studies have suggested that the semantic content of natural stimuli (e.g., real world photos) can be categorized based on statistical regularities in their appearance, which can be detected early in the visual processing stream. Here we review the studies which have investigated the role of scene statistics in the perception of natural scenes, focusing on both basic visual processing and specific tasks (visual search, expert categorization, emotional picture viewing). Visual processing seems to be adapted to visual regularities in the visual input, such as the amplitude-frequency relationship. Moreover, scene statistics can aid performance in specific tasks such as distinguishing animals from artifactual scenes, possibly by modulating early visual processing stages. PMID- 28089885 TI - Variable Pulse Duration From a New Holmium:YAG Laser: The Effect on Stone Comminution, Fiber Tip Degradation, and Retropulsion in a Dusting Model. AB - OBJECTIVE: To more clearly define the efficiency and potential benefits of variable pulse-width laser technology for ureteroscopic lithotripsy, we performed comparative in vitro evaluations assessing stone comminution, laser fiber tip degradation, and stone retropulsion. METHODS: All experiments were conducted using a Swiss LaserClast Holmium:YAG laser (Electro Medical Systems, Nyon, Switzerland) with adjustable pulse duration (300 us-1500 us). To assess comminution efficiency and fiber tip degradation, a "dusting" model was employed; the laser fiber tip was moved by a 3-dimensional positioning system in a spiral motion across a flat BegoStone surface submerged in water. Comminution efficiency was measured as the loss of stone mass while fiber tip degradation was measured simultaneously. The same laser and fiber were used in a pendulum model to measure stone retropulsion with a high-speed resolution camera. RESULTS: In our dusting model, comminution was significantly greater at high energy (2 J/5 Hz). At the high energy setting, comminution was significantly greater with long pulse duration than short pulse, although this difference was not seen at the high frequency setting (1 J/10 Hz). Tip degradation was increased at high energy settings and was even more pronounced with short pulse duration than long pulse. Short pulse duration caused far more retropulsion than the long pulse setting. CONCLUSION: In an in vitro dusting model, a longer laser pulse duration provides effective stone comminution with the advantage of reducing laser fiber tip degradation and stone retropulsion. PMID- 28089886 TI - Commentary on: Adjuvant Sunitinib in High-risk Renal-cell Carcinoma After Nephrectomy. PMID- 28089887 TI - Ureteral Stone Diameter on Computerized Tomography Coronal Reconstructions Is Clinically Important and Under-reported. AB - OBJECTIVE: To compare the maximum stone diameter of ureteral stones in the coronal plane to that of stones in the axial plane and to determine the clinical significance of the coronal diameter. MATERIALS AND METHODS: A retrospective chart review was performed on patients seen in the clinic between September 2013 and November 2015. Patients were included if they had a history of ureteral stone noted on computerized tomography (CT) performed with coronal reconstructions. Patients were excluded if they had multiple ureteral stones, a history of upper urinary tract abnormalities, a need for urgent intervention, or no follow-up. Management of the ureteral stone and pertinent medical history related to patients' stone disease, including stone diameter on axial and coronal CT imaging, were captured. Multivariate regression was performed to identify predictive factors for stone passage. RESULTS: A total of 150 patients met inclusion criteria. Fifty-four patients spontaneously passed stones and 96 required surgery. The reading radiologist reported the stone measurement in the coronal dimension in 17% of the cases. In 75% of the cases, the coronal diameter was larger than the axial diameter by an average of 1.2 mm. On univariate analysis, stone passage was associated with axial diameter (P <.001), coronal diameter (P <.001), stone location (P = .001), age (P <.001), and medical expulsive therapy (P = .008). On multivariate analysis, only coronal diameter (P <.001), stone location (P = .01), and age (P = .03) remained significant factors associated with spontaneous passage. CONCLUSION: In the current series, only stone size as measured in the coronal diameter was associated with stone passage vs need for surgical intervention on multivariate analysis. We strongly recommend obtaining coronal reconstructions when CT is performed for ureteral stone to guide management decisions and appropriately counsel patients on the probability of stone passage. PMID- 28089888 TI - Evaluation of the Effectiveness of a Short-term Treatment and Repeat Treatment of Nocturnal Enuresis Using an Enuresis Alarm. AB - OBJECTIVE: To evaluate the effectiveness of a 3-month enuresis alarm (EA) treatment and repeat EA treatment among pediatric patients with nocturnal enuresis, and to compare patient characteristics among "responders" and "nonresponders" to treatment. MATERIALS AND METHODS: Clinical outcomes were retrospectively evaluated for 137 children (94 boys and 43 girls, mean age, 10.1 years). Effectiveness was evaluated after an initial 3-month treatment, using the International Children's Continence Society criteria. Among children in the no response group at 3 months, those who continued the EA treatment for >=4 months were subclassified into group 1, whereas children who repeated the EA treatment at an interval >=6 months were subclassified into group 2. RESULTS: Among our 137 cases, 19 achieved complete response and 47 achieved partial response at 3 months, for an overall treatment effectiveness rate of 48%. Among the no-response group, treatment was extended in 17 cases (group 1), with 3 (18%) achieving a successful outcome. Treatment was repeated in 18 cases (group 2). In group 2, 8 (44%) achieved successful outcome at 3-month time point. Daytime urinary incontinence did not modify treatment effectiveness. CONCLUSION: EA treatment should be given for a short period of time and should not be continued without a definite purpose or clear response. Suspending and then repeating this treatment after an appropriate interval is effective for patients who do not respond to the initial course of treatment. PMID- 28089889 TI - MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition. AB - Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low "variant" subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which, combined with chemotherapy, strongly suppresses tumor progression and increases survival. These data identify molecular features for patient stratification and uncover a potential targeted treatment approach for MYC-driven SCLC. PMID- 28089891 TI - Which treatment for obstructive airway disease: The inhaled bronchodilators. PMID- 28089890 TI - Single-chromosome Gains Commonly Function as Tumor Suppressors. AB - Aneuploidy is a hallmark of cancer, although its effects on tumorigenesis are unclear. Here, we investigated the relationship between aneuploidy and cancer development using cells engineered to harbor single extra chromosomes. We found that nearly all trisomic cell lines grew poorly in vitro and as xenografts, relative to genetically matched euploid cells. Moreover, the activation of several oncogenic pathways failed to alleviate the fitness defect induced by aneuploidy. However, following prolonged growth, trisomic cells acquired additional chromosomal alterations that were largely absent from their euploid counterparts and that correlated with improved fitness. Thus, while single chromosome gains can suppress transformation, the genome-destabilizing effects of aneuploidy confer an evolutionary flexibility that may contribute to the aggressive growth of advanced malignancies with complex karyotypes. PMID- 28089892 TI - Algerian propolis extracts: Chemical composition, bactericidal activity and in vitro effects on gilthead seabream innate immune responses. AB - Propolis has been used as a medicinal agent for centuries. The chemical composition of four propolis samples collected from four locations of the Setif region, Algeria, using gas chromatography-mass spectrometry was determined. More than 20 compounds and from 30 to 35 compounds were identified in the aqueous and ethanolic extracts, respectively. Furthermore, the antimicrobial activity of the propolis extracts against two marine pathogenic bacteria was evaluated. Finally, the in vitro effects of propolis on gilthead seabream (Sparus aurata L.) leucocyte activities were measured. The bactericidal activity of ethanolic extracts was very high against Shewanella putrefaciens, average against Photobacterium damselae and very low against Vibrio harveyi. The lowest bactericidal activity was always that found for the aqueous extracts. When the viability of gilthead seabream head-kidney leucocytes was measured after 30 min' incubation with the different extracts, both the ethanolic and aqueous extracts of one of the propolis samples (from Babor) and the aqueous extract of another (from Ain-Abbassa) provoked a significant decrease in cell viability when used at concentrations of 100 and 200 MUg ml-1. Furthermore, significant inhibitory effects were recorded on leucocyte respiratory burst activity when isolated leucocytes where preincubated with the extracts. This effect was dose-dependent in all cases except when extracts from a third propolis sample (from Boutaleb) were used. Our findings suggest that some of Algerian propolis extracts have bactericidal activity against important bacterial pathogens in seabream and significantly modulate in vitro leucocyte activities, confirming their potential as a source of new natural biocides and/or immunomodulators in aquaculture practice. PMID- 28089893 TI - Proteomic characterization of the interactions between fish serum proteins and waterborne bacteria reveals the suppression of anti-oxidative defense as a serum mediated antimicrobial mechanism. AB - Fish blood is one of the crucial tissues of innate immune system, but the full repertoire of fish serum components involved in antibacterial defense is not fully identified. In this study, we demonstrated that turbot serum, but not the heat-inactivated control, significantly reduced the number of Edwardsiella tarda (E. tarda). By conjugating serum proteins with fluorescent dyes, we showed that E. tarda were coated with multiple fish proteins. In order to identify these proteins, we used E. tarda to capture turbot serum proteins and subjected the samples to shotgun proteomic analysis. A total of 76 fish proteins were identified in high confidence, including known antimicrobial proteins such as immunoglobins and complement components. 34 proteins with no previously known immunological functions were also identified. The expression of one of these proteins, IQ motif containing H (IQCH), was exclusively in fish brain and gonads and was induced during bacterial infection. This approach also allowed the study of the corresponding proteomic changes in E. tarda exposed to turbot serum, which is a general decrease of bacterial protein expression except for an upregulation of membrane components after serum treatment. Interestingly, while most other known stresses stimulate bacterial antioxidant enzymes, fish serum induced a rapid suppression of antioxidant proteins and led to an accumulation of reactive oxygen species. Heat treatment of fish serum eliminated this effect, suggesting that heat labile factors in the fish serum overrode bacterial antioxidant defenses. Taken together, this work offers a comprehensive view of the interactions between fish serum proteins and bacteria, and reveals previously unknown factors and mechanisms in fish innate immunity. PMID- 28089894 TI - Determining the cleavage site for the mature antimicrobial peptide of Nile tilapia beta-defensin using 2D electrophoresis, western blot, and mass spectrometry analysis. AB - Several proteomic techniques were used to determine the cleavage site of the mature antimicrobial peptide of Nile tilapia beta-defensin. The computer predicted Nile tilapia beta-defensin (25ASFPWSCLSLSGVCRKVCLPTELFFGPLGCGKGSLCCVSHFL66) composed of 42 amino acids was chemically synthesized and prepared to produce an antibody for Western blotting. Total proteins from the skin of the Nile tilapia were separated on two dimensional electrophoresis, and the spot of Nile tilapia beta-defensin was recognized using Western blot analysis. It was then excised and extracted from the gel. The precise molecular mass of this spot was determined by LC-MS/MS spectrometry. Four major peptides were discovered, with molecular weights of 4293.2 Da, 4306.5 Da, 4678.9 Da, and 4715.0 Da. The calculated mass of the 40 amino-acid sequence (27FPWSCLSLSGVCRKVCLPTELFFGPLGCGKGSLCCVSHFL66) of Nile tilapia beta-defensin starting from Phe27 and ending with Leu66 was 4293.18 Da, which completely matched the 4293.2 Da peptide that was obtained from the mass spectrometry analysis. This result confirmed that the cleavage site for the mature C-terminal Nile tilapia beta-defensin is at residue Ser26-Phe27, not at Ala24-25 as predicted by computer analysis. This study provides a simple but reliable model to determine the cleavage site for a mature antimicrobial peptide. PMID- 28089895 TI - Effects of fulvic acid on growth performance and intestinal health of juvenile loach Paramisgurnus dabryanus (Sauvage). AB - A 60-day feeding trial was conducted to determine the effect of dietary fulvic acid supplements on intestinal digestive activity (enzymatic analysis), antioxidant activity, immune enzyme activity and microflora composition of juvenile loach (initial weight of 6.2 +/- 0.1 g) reared in experimental aquaria. Five test diets containing 0, 0.5, 1.0, 1.5, and 2% fulvic acid were randomly assigned to three aquaria, respectively. Elevated growth performance including final weight, weight gain (WG), specific growth rate (SGR) and feed conversion ratio (FCR) was observed in loaches that were fed fulvic acid. Maximal weight gain rates and specific growth rates occurred at the 1.5% additive level. The optimal dietary fulvic requirement for maximal growth of juvenile loach is 16.4 g per kg of the diet based on the quadratic regression analysis of specific growth rate against dietary fulvic acid levels. Furthermore, intestinal protease activity, antioxidant activity, lysozyme activity (LZM), complement 3 (C3) content, immunoglobulin M (IgM) content, acid phosphatase activity (ACP) and alkaline phosphatase activity (AKP) were significantly elevated with concomitant increasing levels of dietary fulvic acid. Following a deep sequencing analysis, a total of 42,058 valid reads and 609 OTUs (operational taxonomic units) obtained from the control group and the group displaying the most optimal growth rate were analyzed. Fulvic acid supplementation resulted in an abundance of Firmicute and Actinobacteria sequences, with a concomitant reduction in the abundance of Proteobacteria. Results indicated that fulvic acid supplementation resulted in a reduction in the relative abundance of Serratia, Acinetobacter, Aeromonas and Edwardsiella, and a relative increase in the abundance of Lactobacillus in the intestine. In conclusion, these results suggest that fulvic acid improves growth performance and intestinal health condition of loach, indicates that fulvic acid could be used as an immunoenhancer in loach culture. PMID- 28089896 TI - Characterization and expression analysis of a chitinase gene (PmChi-4) from black tiger shrimp (Penaeus monodon) under pathogen infection and ambient ammonia nitrogen stress. AB - Chitinase is a multi-gene family, which play important physiological roles in crustaceans, involved in several biological processes, including digestion, molting and defense against viruses. In the present study, a chitinase-4 gene (PmChi-4) was cloned from Penaeus monodon by rapid amplification of cDNA ends (RACE). The full length of PmChi-4 cDNA was 2178 bp, including an 1815 bp open reading frame (ORF) which encoded 604 amino acid residues. The predicted PmChi-4 protein was 67.7 kDa and shared 61%-88% identity with the type of Chi-4s from other crustaceans. Quantitative real-time (qRT-PCR) analysis indicated that PmChi 4 was expressed ubiquitously with the high expression level in hepatopancreas. PmChi-4 was expressed throughout the whole larvae stages, and the highest level of PmChi-4 transcripts was detected at Mysis3 stage, which indicated that PmChi-4 may be involved in larval metamorphosis. In order to know whether PmChi-4 was related to the immune response of shrimp, Streptococcus agalactiae and Vibrio harveyi were chosen to challenge the shrimp, PmChi-4 transcripts were significantly increased and reached to the maximum at 6 h in hepatopancreas and at 12 h in gill, respectively. The results suggested that PmChi-4 participated in the immune defenses to pathogen infection. Besides, the ammonia nitrogen stress treatment was also carried out, PmChi-4 transcripts were significantly decreased in hepatopancreas and gill and the result showed that PmChi-4 may be involved in ammonia nitrogen stress in P. monodon. Overall, our present study lay a foundation for further research into the biological function and regulation of chitinase in P. monodon. PMID- 28089897 TI - Crustacean hyperglycemic hormones directly modulate the immune response of hemocytes in shrimp Litopenaeus vannamei. AB - A robust immune response against invading pathogens is crucial for host to survive, which depends greatly on the well balance of metabolism. Increasing evidence has indicated that some metabolic hormones, such as insulin, could modulate immune responses directly. Crustacean hyperglycemic hormone (CHH) family is a group of ecdysozoans-specific peptide hormone involved in glucose metabolism and other biological events. In the present study, two members of CHH family (designated as LvCHH I and LvCHH II) in shrimp Litopenaeus vannamei with one and two crustacean neurohormone domains respectively were chosen to investigate their putative modulatory roles in both glucose metabolism and immune response. LvCHH I and LvCHH II were both expressed in the sinus gland and lamina ganglionalis of eyestalks and were significantly induced after white spot syndrome virus (WSSV) infection. Meanwhile, significant increases of hemolymph glucose levels were observed in shrimp at 12 and 24 h after WSSV infection while the glucose inside the hemocytes decreased at 6 h and then increased at 12 h. Gain-of-function of rLvCHHs was subsequently conducted in vivo by injecting the recombinant proteins (rLvCHH I and rLvCHH II). The hemolymph glucose increased significantly from 0.5 h to 3 h after the shrimps received an injection of rLvCHH I, while it decreased at 0.5 h and increased afterward at 3 h post rLvCHH II injection. At the meantime, significant decreases of reactive oxygen species level in hemocytes were observed at 3 h and 6 h post rLvCHH I injection, while it remained unchanged in rLvCHH II injection group. rLvCHH I and rLvCHH II could bind to the cytomembrane of primary shrimp hemocytes in vitro, and the expressions of superoxide dismutase and LvRelish increased when the hemocytes were incubated with rLvCHH I for 3 h. Meanwhile, the expression of antimicrobial peptides, crustin and penaeidin-4, were also induced by rLvCHH I and rLvCHH II. These results demonstrated that host immune response, in addition to glucose metabolism, could be directly modulated by LvCHH family, and the present study provided new insights into the immunomodulation role of metabolic hormones in invertebrate. PMID- 28089898 TI - Exercise Guidelines to Promote Cardiometabolic Health in Spinal Cord Injured Humans: Time to Raise the Intensity? AB - Spinal cord injury (SCI) is a life-changing event that, as a result of paralysis, negatively influences habitual levels of physical activity and hence cardiometabolic health. Performing regular structured exercise therefore appears extremely important in persons with SCI. However, exercise options are mainly limited to the upper body, which involves a smaller activated muscle mass compared with the mainly leg-based activities commonly performed by nondisabled individuals. Current exercise guidelines for SCI focus predominantly on relative short durations of moderate-intensity aerobic upper-body exercise, yet contemporary evidence suggests this is not sufficient to induce meaningful improvements in risk factors for the prevention of cardiometabolic disease in this population. As such, these guidelines and their physiological basis require reappraisal. In this special communication, we propose that high-intensity interval training (HIIT) may be a viable alternative exercise strategy to promote vigorous-intensity exercise and prevent cardiometabolic disease in persons with SCI. Supplementing the limited data from SCI cohorts with consistent findings from studies in nondisabled populations, we present strong evidence to suggest that HIIT is superior to moderate-intensity aerobic exercise for improving cardiorespiratory fitness, insulin sensitivity, and vascular function. The potential application and safety of HIIT in this population is also discussed. We conclude that increasing exercise intensity could offer a simple, readily available, time-efficient solution to improve cardiometabolic health in persons with SCI. We call for high-quality randomized controlled trials to examine the efficacy and safety of HIIT in this population. PMID- 28089899 TI - Progression, incidence, and risk factors for intervertebral disc degeneration in a longitudinal population-based cohort: the Wakayama Spine Study. AB - OBJECTIVE: The present study examined the progression, incidence, and risk factors for intervertebral disc degeneration (DD) throughout the lumbar spine using magnetic resonance imaging (MRI) in a large population-based cohort. METHODS: We followed up 617 subjects for more than 4 years as part of the Wakayama Spine Study. 1) "Progression of DD" in each of the entire, upper (L1/2 to L3/4) and lower (L4/5 and L5/S1) lumbar spine was defined as Pfirrmann grade progression at follow-up in at least one disc in the affected region. 2) "Incidence of DD" in each of these regions was defined if all discs were grade 3 or lower (white disc) at baseline, and at least one disc had progressed to grade 4 or higher (black disc) at follow-up. Logistic regression analyses were used to determine the risk factors for progression and incidence of DD. RESULTS: DD progression and incidence in the entire lumbar spine were 52.0% and 31.6% in men, and 60.4% and 44.7% in women, respectively. Women was associated with DD progression in the upper lumbar spine (odds ratio [OR] = 1.68, 95% confidence interval [CI] = 1.18-2.42). Aging was associated with the incidence of DD in each region (entire: OR = 1.14, CI = 1.06-1.14; upper: OR = 1.10, CI = 1.05-1.15; lower: OR = 1.11, CI = 1.05-1.19). Diabetes mellitus (DM) was associated with the incidence of DD in the upper lumbar spine (OR = 6.83, CI = 1.07-133.7). CONCLUSION: This 4-year longitudinal study is the first to demonstrate DD progression and incidence in the lumbar spine and their risk factors in a large population-based cohort. PMID- 28089900 TI - The rs4238326 polymorphism in ALDH1A2 gene potentially associated with non-post traumatic knee osteoarthritis susceptibility: a two-stage population-based study. AB - OBJECTIVE: A recent genome-wide association study reported significant associations of genetic variants within the ALDH1A2 gene with osteoarthritis (OA) of the hand in European populations. However, these findings have not been well generalized to other joints, or to other populations. METHODS: We performed a two stage population-based case-control study including 196 non-post traumatic knee OA cases and 442 controls in the first stage and independent 143 non-post traumatic knee OA cases and 238 controls in the second stage in a Chinese population by genotyping eight tagging polymorphisms in ALDH1A2. RESULTS: In the first stage, the single nucleotide polymorphism (SNP) rs4238326 was found to be potentially associated with knee OA risk (additive model: odds ratio [OR] = 0.70; 95% confidence interval [95% CI] = 0.49-1.01; P = 0.055), which was further confirmed in the second stage with similar effect (additive model: OR = 0.60; 95% CI = 0.38-0.95; P = 0.029). After combining the two stages, we found that the variant C allele of rs4238326 was probably associated with decreased risk of knee OA (additive model: OR = 0.65; 95% CI = 0.49-0.86; P = 0.003). Furthermore, interaction analyses showed that rs4238326 interacted multiplicatively with age to contribute to knee OA risk (interaction P = 0.041). CONCLUSIONS: These findings indicate that the SNP rs4238326 in ALDH1A2 gene may potentially modify individual susceptibility to knee OA in the Chinese population. Beyond that, further studies are warranted to validate and extend our findings, and future functional studies are required to clarify the possible mechanisms. PMID- 28089901 TI - Over expression of proteins that alter the intracellular signaling pathways in the cytoplasm of the liver cells forming Mallory-Denk bodies. AB - In this study, liver biopsy sections fixed in formalin and embedded in paraffin (FFPE) from patients with alcoholic hepatitis (AH) were used. The results showed that the expression of the SYK protein was up regulated by RNA-seq and real time PCR analyses in the alcoholic hepatitis patients compared to controls. The results were supported by using the IHC fluorescent antibody staining intensity morphometric quantitation. Morphometric quantification of fluorescent intensity measurement showed a two fold increase in SYK protein in the cytoplasm of the cells forming MDBs compared to surrounding normal hepatocytes. The expression of AKT1 was also analyzed. AKT1 is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration. The AKT protein was also increased in hepatocyte balloon cells forming MDBs. This observation demonstrates the role of SYK and its subsequent effect on the internal signaling pathways such as PI3K/AKT as well as p70S6K, as a potential multifunctional target in protein quality control mechanisms of hepatocytes when ER stress is activated. PMID- 28089902 TI - Olmesartan with azelnidipine versus with trichlormethiazide on home blood pressure variability in patients with type II diabetes mellitus. AB - The aim of the present study was to compare the effects of olmesartan combined with azelnidipine versus olmesartan combined with trichlormethiazide, on home blood pressure (BP) and pressure variability in type II diabetes mellitus patients using home BP telemonitoring system. We performed an open-label cross over pilot study of 28 patients with type II diabetes mellitus. Patients received combination treatment with either olmesartan 20 mg plus azelnidipine 16 mg or olmesartan 20 mg plus trichlormethiazide 1 mg for more than 6 weeks each in a cross-over method. The coefficient of morning systolic BP variability in the olmesartan plus azelnidipine group was significantly lower than that in the olmesartan plus trichlormethiazide group (6.4 +/- 1.9 vs. 7.5 +/- 2.6, P = .004). There were no significant differences in mean morning systolic BP between the two groups. Using home BP telemonitoring for hypertensive patients with type II diabetes, this study revealed for the first time that the olmesartan with azelnidipine combination is superior to the olmesartan with trichlormethiazide combination in reducing home BP variability. PMID- 28089903 TI - Advances in MR angiography with 7T MRI: From microvascular imaging to functional angiography. AB - Over the past few decades, vascular flow-dependent imaging techniques have proven to be effective for the visualization of large vessel diseases. However, these approaches are unlikely to be efficacious for small vessels because the affected small vessels cannot always be visualized directly, owing to a lack of detection sensitivity. Recently, many researchers have introduced state-of-the-art imaging techniques to visualize cerebral microvessels using ultra-high-field (UHF) magnetic resonance angiography (MRA). They have demonstrated the superiority of UHF MRA, especially for visualization of the microvasculature compared with clinical MRA images using 1.5T or 3T magnetic resonance imaging (MRI). Thus, UHF MRA may become an important investigative tool for research, facilitating examinations of vascular mechanisms for small vessel diseases and contributing to the early detection of cerebrovascular diseases in clinics. Furthermore, new imaging methods for visualizing vascular dynamics or flow effects may help investigate brain functions, especially in conjunction with blood oxygenation level-dependent contrast functional MRI modalities, as well as situations in which small vessel abnormalities are clinically important. The present article reviews recent technological advances in UHF MRA, especially 7T MRA, and discusses the potential benefits and future directions of UHF MRA. PMID- 28089904 TI - Retuning brain circuitry to treat mental illness: The role of functional neuroimaging. Commentary for the special issue: Mechanisms of change. PMID- 28089905 TI - Nudix-type motif 2 contributes to cancer proliferation through the regulation of Rag GTPase-mediated mammalian target of rapamycin complex 1 localization. AB - Lysosomal localization of mammalian target of rapamycin complex 1 (mTORC1) is a critical step for activation of the molecule. Rag GTPases are essential for this translocation. Here, we demonstrate that Nudix-type motif 2 (NUDT2) is a novel positive regulator of mTORC1 activation. Activation of mTORC1 is impaired in NUDT2-silenced cells. Mechanistically, NUDT2 binds to Rag GTPase and controls mTORC1 translocation to the lysosomal membrane. Furthermore, NUDT2-dependent mTORC1 regulation is critical for proliferation of breast cancer cells, as NUDT2 silenced cells arrest in G0/G1 phases. Taken together, these results show that NUDT2 is a novel complex formation enhancing factor regulating mTORC1-Rag GTPase signaling that is crucial for cell growth control. PMID- 28089906 TI - Adenosine signaling in diabetes mellitus and associated cardiovascular and renal complications. AB - Diabetes mellitus is characterized by abnormal glucose and lipid metabolism, and subsequent hyperglycemia and dyslipidemia, which results from defects in pancreatic islet beta-cells insulin secretion and/or decreased insulin sensitivity in metabolically active organs (i.e. liver, skeletal muscle and adipose tissue). Accumulating evidence highlights a critical role for the adenosine system in the regulation of insulin and glucose homeostasis and the pathophysiology of type 2 diabetes (T2D). Adenosine is a key diverse extracellular signaling molecule that regulates several aspects of tissue function by activating four G-protein-coupled receptors (i.e. A1, A2A, A2B and A3 receptors). Moreover, adenosine receptor signaling plays a critical role in inflammation, immune system, and oxidative stress, factors that are also important in metabolic disorders. This review discusses the role of the adenosine receptor system in the development or progression of diabetes mellitus, with specific focus on T2D, and associated complications linked to the cardiovascular and renal systems. PMID- 28089907 TI - Adenosine and preeclampsia. AB - Adenosine is an endogenous nucleoside with pleiotropic effects in different physiological processes including circulation, renal blood flow, immune function, or glucose homeostasis. Changes in adenosine membrane transporters, adenosine receptors, and corresponding intracellular signalling network associate with development of pathologies of pregnancy, including preeclampsia. Preeclampsia is a cause of maternal and perinatal morbidity and mortality affecting 3-5% of pregnancies. Since the proposed mechanisms of preeclampsia development include adenosine-dependent biological effects, adenosine membrane transporters and receptors, and the associated signalling mechanisms might play a role in the pathophysiology of preeclampsia. Preeclampsia associates with increased adenosine concentration in the maternal blood and placental tissue, likely due to local hypoxia and ischemia (although not directly demonstrated), microthrombosis, increased catecholamine release, and platelet activation. In addition, abnormal expression and function of equilibrative nucleoside transporters is described in foetoplacental tissues from preeclampsia; however, the role of adenosine receptors in the aetiology of this disease is not well understood. Adenosine receptors activation may be related to abnormal trophoblast invasion, angiogenesis, and ischemia/reperfusion mechanisms in the placenta from preeclampsia. These mechanisms may explain only a low fraction of the associated abnormal transformation of spiral arteries in preeclampsia, triggering cellular stress and inflammatory mediators release from the placenta to the maternal circulation. Although increased adenosine concentration in preeclampsia may be a compensatory or adaptive mechanism favouring placental angiogenesis, a poor angiogenic state is found in preeclampsia. Thus, preeclampsia-associated complications might affect the cell response to adenosine due to altered expression and activity of adenosine receptors, membrane transporters, or cell signalling mechanisms. This review summarizes the evidence available on the potential involvement of the adenosine in the clinical, pathophysiology, and therapeutic features of preeclampsia. PMID- 28089908 TI - Human AML-iPSCs Reacquire Leukemic Properties after Differentiation and Model Clonal Variation of Disease. AB - Understanding the relative contributions of genetic and epigenetic abnormalities to acute myeloid leukemia (AML) should assist integrated design of targeted therapies. In this study, we generated induced pluripotent stem cells (iPSCs) from AML patient samples harboring MLL rearrangements and found that they retained leukemic mutations but reset leukemic DNA methylation/gene expression patterns. AML-iPSCs lacked leukemic potential, but when differentiated into hematopoietic cells, they reacquired the ability to give rise to leukemia in vivo and reestablished leukemic DNA methylation/gene expression patterns, including an aberrant MLL signature. Epigenetic reprogramming was therefore not sufficient to eliminate leukemic behavior. This approach also allowed us to study the properties of distinct AML subclones, including differential drug susceptibilities of KRAS mutant and wild-type cells, and predict relapse based on increased cytarabine resistance of a KRAS wild-type subclone. Overall, our findings illustrate the value of AML-iPSCs for investigating the mechanistic basis and clonal properties of human AML. PMID- 28089909 TI - Immunosuppression via Loss of IL2rgamma Enhances Long-Term Functional Integration of hESC-Derived Photoreceptors in the Mouse Retina. AB - Loss of photoreceptors is a common endpoint in degenerative retinal diseases. Human pluripotent stem cells provide a potential source for photoreceptor replacement, but, even in mouse models, the efficiency and efficacy of transplantation-based repair remains poor. In this study, we examined the degree to which immune rejection contributes to these disappointing outcomes using an immunodeficient IL2 receptor gamma (IL2rgamma)-null mouse model. Our results show that prevention of cell rejection in the normal and degenerating retinal environment significantly improves long-term survival and integration of hESC derived donor retinal cells. Transplanted cells are able to differentiate into mature photoreceptors expressing various opsins and can functionally integrate into congenitally blind mice. Our work suggests that even though the retina is often considered immune-privileged, suppression of host immune-mediated cell rejection may well be a useful approach for improving long-term integration of transplanted cells with a view to successful clinical outcomes. PMID- 28089912 TI - Hiding clinical information in medical images: A new high capacity and reversible data hiding technique. AB - A new high capacity and reversible data hiding scheme for e-healthcare applications has been presented in this paper. Pixel to Block (PTB) conversion technique has been used as an effective and computationally efficient alternative to interpolation for the cover image generation to ensure reversibility of medical images. A fragile watermark and Block Checksum (computed for each 4*4 block) have been embedded in the cover image for facilitating tamper detection and tamper localization, and hence content authentication at receiver. The EPR, watermark data and checksum data has been embedded using Intermediate Significant Bit Substitution (ISBS) to avoid commonly used LSB removal/replacement attack. Non-linear dynamics of chaos have been put to use for encrypting the Electronic Patient Record (EPR)/clinical data and watermark data for improving the security of data embedded. The scheme has been evaluated for perceptual imperceptibility and tamper detection capability by subjecting it to various image processing and geometric attacks. Experimental results reveal that the proposed system besides being completely reversible is capable of providing high quality watermarked images for fairly high payload. Further, it has been observed that the proposed technique is able to detect and localise the tamper. A comparison of the observed results with that of some state-of-art schemes show that our scheme performs better. PMID- 28089911 TI - Atypical composition and structure of the mitochondrial dimeric ATP synthase from Euglena gracilis. AB - Mitochondrial respiratory-chain complexes from Euglenozoa comprise classical subunits described in other eukaryotes (i.e. mammals and fungi) and subunits that are restricted to Euglenozoa (e.g. Euglena gracilis and Trypanosoma brucei). Here we studied the mitochondrial F1FO-ATP synthase (or Complex V) from the photosynthetic eukaryote E. gracilis in detail. The enzyme was purified by a two step chromatographic procedure and its subunit composition was resolved by a three-dimensional gel electrophoresis (BN/SDS/SDS). Twenty-two different subunits were identified by mass-spectrometry analyses among which the canonical alpha, beta, gamma, delta, epsilon, and OSCP subunits, and at least seven subunits previously found in Trypanosoma. The ADP/ATP carrier was also associated to the ATP synthase into a dimeric ATP synthasome. Single-particle analysis by transmission electron microscopy of the dimeric ATP synthase indicated that the structures of both the catalytic and central rotor parts are conserved while other structural features are original. These new features include a large membrane-spanning region joining the monomers, an external peripheral stalk and a structure that goes through the membrane and reaches the inter membrane space below the c-ring, the latter having not been reported for any mitochondrial F ATPase. PMID- 28089910 TI - Glioblastoma Cancer Stem Cells Evade Innate Immune Suppression of Self-Renewal through Reduced TLR4 Expression. AB - Tumors contain hostile inflammatory signals generated by aberrant proliferation, necrosis, and hypoxia. These signals are sensed and acted upon acutely by the Toll-like receptors (TLRs) to halt proliferation and activate an immune response. Despite the presence of TLR ligands within the microenvironment, tumors progress, and the mechanisms that permit this growth remain largely unknown. We report that self-renewing cancer stem cells (CSCs) in glioblastoma have low TLR4 expression that allows them to survive by disregarding inflammatory signals. Non-CSCs express high levels of TLR4 and respond to ligands. TLR4 signaling suppresses CSC properties by reducing retinoblastoma binding protein 5 (RBBP5), which is elevated in CSCs. RBBP5 activates core stem cell transcription factors, is necessary and sufficient for self-renewal, and is suppressed by TLR4 overexpression in CSCs. Our findings provide a mechanism through which CSCs persist in hostile environments because of an inability to respond to inflammatory signals. PMID- 28089913 TI - Physicians' perception of alternative displays of clinical research evidence for clinical decision support - A study with case vignettes. AB - OBJECTIVE: To design alternate information displays that present summaries of clinical trial results to clinicians to support decision-making; and to compare the displays according to efficacy and acceptability. METHODS: A 6-between (information display presentation order) by 3-within (display type) factorial design. Two alternate displays were designed based on Information Foraging theory: a narrative summary that reduces the content to a few sentences; and a table format that structures the display according to the PICO (Population, Intervention, Comparison, Outcome) framework. The designs were compared with the summary display format available in PubMed. Physicians were asked to review five clinical studies retrieved for a case vignette; and were presented with the three display formats. Participants were asked to rate their experience with each of the information displays according to a Likert scale questionnaire. RESULTS: Twenty physicians completed the study. Overall, participants rated the table display more highly than either the text summary or PubMed's summary format (5.9vs. 5.4vs. 3.9 on a scale between 1 [strongly disagree] and 7 [strongly agree]). Usefulness ratings of seven pieces of information, i.e. patient population, patient age range, sample size, study arm, primary outcome, results of primary outcome, and conclusion, were high (average across all items=4.71 on a 1 to 5 scale, with 1=not at all useful and 5=very useful). Study arm, primary outcome, and conclusion scored the highest (4.9, 4.85, and 4.85 respectively). Participants suggested additional details such as rate of adverse effects. CONCLUSION: The table format reduced physicians' perceived cognitive effort when quickly reviewing clinical trial information and was more favorably received by physicians than the narrative summary or PubMed's summary format display. PMID- 28089914 TI - Arachidonic acid with taurine enhances pulmonary absorption of macromolecules without any serious histopathological damages. AB - Therapeutic peptides and protein are being used in several indications; however, their poor permeability still remains to be solved. This study focused on the pulmonary route of macromolecules. First, the effects of arachidonic acid (AA) as an absorption enhancer on drug serum concentration, after intratracheal administration, were investigated in rats. Second, the safety of AA was assessed in rats in an acute toxicity study for 7days. AA enhanced the exposure of both interferon-alpha (IFN-alpha) and fluorescein isothiocyanate 4000 (FD-4). In addition, the histopathological analysis indicated that AA caused alveolitis and bronchitis in rats. In combination with Taurine (Tau), these lung injuries were prevented through the histopathological analysis. The combined use of Tau with AA did not show any changes in the pharmacokinetics of FD-4. From these results, we suggest the combined use of AA with Tau as a novel formulation on the pulmonary route of macromolecule drugs. This formulation could improve the bioavailability of macromolecule drugs without any serious local damage to the lungs. PMID- 28089915 TI - Dendrimers as nanocarriers for nucleoside analogues. AB - Dendrimers constitute a class of hyperbranched macromolecules with several potential applications due to their unique properties such as a well-defined structure, multivalency and biocompatibility. These polymers became one of the most promising drug nanocarriers, providing improved solubility of therapeutics, high loading capacity and controllable biodistribution pattern. In addition, the use of dendrimers as drug delivery devices in cancer therapies may help to overcome the resistance mechanisms by transporting activated drug molecules directly to cancer cells. In the recent years, dendrimers were intensively studied for delivery of nucleoside analogues (NAs), essential elements of antiviral therapies, as well as treatments of leukemia, lymphoma and various types of solid tumors. These agents act as antimetabolites, competing with physiological nucleosides, and interacting with intracellular enzymes and nuclear acids to induce cytotoxicity. However, efficiency of NAs-based therapies is often limited by factors like fast metabolism, disadvantageous biodistribution, low solubility and various side effects. In case of treatment of leukemia, target cells usually develop drug resistance, which reduces the activity of nucleoside analogues even further. Thus, drug carrier systems are studied to improve the efficacy and specificity of action of these compounds. In this review, we summarize available data concerning the possibility of application of dendrimers as delivery devices for nucleoside analogues and their active, triphosphate forms. PMID- 28089916 TI - Stable curcumin-loaded polymeric micellar formulation for enhancing cellular uptake and cytotoxicity to FLT3 overexpressing EoL-1 leukemic cells. AB - The present study aims to develop a stable polymeric micellar formulation of curcumin (CM) with improved solubility and stability, and that is suitable for clinical applications in leukemia patients. CM-loaded polymeric micelles (CM micelles) were prepared using poloxamers. The chemical structure of the polymers influenced micellar properties. The best formulation of CM-micelles, namely CM P407, was obtained from poloxamer 407 at drug to polymer ratio of 1:30 and rehydrated with phosphate buffer solution pH 7.4. CM-P407 exhibited the smallest size of 30.3+/-1.3nm and highest entrapment efficiency of 88.4+/-4.1%. When stored at -80 degrees C for 60days, CM-P407 retained high protection of CM and had no significant size change. In comparison with CM solution in dimethyl sulfoxide (CM-DMSO), CM kinetic degradation in both formulations followed a pseudo-first-order reaction, but the half-life of CM in CM-P407 was approx. 200 times longer than in CM-DMSO. Regarding the activity against FLT3 overexpressing EoL-1 leukemic cells, CM-P407 showed higher cytotoxicity than CM-DMSO. Moreover, intracellular uptake to leukemic cells of CM-P407 was 2-3 times greater than that of CM-DMSO. These promising results for CM-P407 will be further investigated in rodents and in clinical studies for leukemia treatment. PMID- 28089918 TI - Cardiovascular and respiratory activity of PK20, opioid and neurotensin hybrid peptide in anesthetized and awake rats. AB - AIM: Chimeric compound - PK20 despite its therapeutic activity on nociceptive and inflammatory processes may affect respiration and blood pressure. Our objective was to evaluate influence of the hybrid composed of endomorphin-2 and neurotensin fragments on ventilation, heart rate and blood pressure in anesthetized and awake rats. METHODS: The effects of PK20 (1mg/kg) were studied either after its intravenous administration in anesthetized rats or intraperitoneal injection in awake state. Tidal volume and the timing components of the breathing pattern, arterial blood pressure, and heart rate were recorded. RESULTS: Intravenous administration of PK20 in the neurally intact rats evoked a dose-dependent apnoea followed by a transient insignificant increase in tidal volume and breathing rate. The blood pressure changes were biphasic: transient increase was replaced by prolonged hypotension. Midcervical vagotomy abrogated all post-PK20 respiratory effects. Hypotension was eliminated after blockade of neurotensin NTS1 receptor, while respiratory changes were reduced by blockade of both: NTS1 and MU opioid receptors. After PK20 intraperitoneal injection awake rats did not show any significant changes in ventilation and blood pressure. CONCLUSION: This chimeric peptide should be used with care via intravenous administration in anesthetized animals since PK20 may evoke respiratory apnoea and hypotension. Nevertheless, applied intraperitoneally in the same dose in conscious rats induced no adverse effects. PMID- 28089917 TI - microRNAs and DICER1 are regulated by 1,25-dihydroxyvitamin D in prostate stroma. AB - Vitamin D deficiency increases the risk of lethal prostate adenocarcinomas (PCa) and the majority of older men are deficient. Although PCa arises from the epithelium, the surrounding stroma has hormonal regulatory control over the epithelium and contributes to carcinogenesis. Herein, we describe regulation of microRNAs (miRs) by the active hormone dihydroxyvitamin D (1,25(OH)2D) in human prostate stroma. 1,25(OH)2D binds the vitamin D receptor (VDR) transcription factor to regulate gene expression, including miRs, which have emerged as potent regulators of protein expression. 1,25(OH)2D-regulated miRs were identified by profiling in primary human prostatic stromal cells (PrS) and three miRs, miR-126 3p, miR 154-5p and miR-21-5p were subsequently validated in laser-capture micro dissected prostate stromal tissue from a vitamin D3 clinical trial (N=45). Regulation of these miRs by 1,25(OH)2D was VDR-dependent. Network analysis of known and putative mRNA targets of these miRs was enriched with cancer and inflammation pathways, consistent with known roles of stroma and of vitamin D in carcinogenesis. Expression of the miR processing ribonuclease, DICER1, positively correlated with vitamin D metabolite levels in the clinical trial specimens. High epithelial/stromal ratios of DICER1 were significantly associated biochemical recurrence (OR 3.1, p=0.03) in a tissue microarray of 170 matched PCa patients. In summary, these results underscore the role of the prostate stroma in regulating responses to the hormone 1,25(OH)2D and identified miRs and DICER1 as being regulated in human prostate stroma. Regulation of stromal DICER1 by 1,25(OH)2D may also have clinical relevance in protection against aggressive PCa. PMID- 28089919 TI - An orally active geranyl acetophenone attenuates airway remodeling in a murine model of chronic asthma. AB - 2,4,6-Trihydroxy-3-geranyl acetophenone (tHGA) is a synthetic compound that is naturally found in Melicope ptelefolia. We had previously demonstrated that parenteral administration of tHGA reduces pulmonary inflammation in OVA sensitized mice. In this study, we evaluated the effect of orally administered tHGA upon airway remodeling in a murine model of chronic asthma. Female BALB/C mice were sensitized intraperitoneally with ovalbumin (OVA) on day 0, 7 and 14, followed by aerosolized 1% OVA 3 times per week for 6 weeks. Control groups were sensitized with saline. OVA sensitized animals were either treated orally with vehicle (saline with 1% DMSO and Tween 80), tHGA (80, 40, 20mg/kg) or zileuton (30mg/kg) 1h prior to each aerosolized OVA sensitization. On day 61, mice underwent methacholine challenge to determine airway hyperresponsiveness prior to collection of bronchoalveolar lavage (BAL) fluid and lung samples. BAL fluid inflammatory cell counts and cytokine concentrations were evaluated while histological analysis and extracellular matrix protein concentrations were determined on collected lung samples. Oral tHGA treatment attenuated airway hyperresponsiveness and inhibited airway remodeling in a dose-dependent fashion. tHGA's effect on airway remodeling could be attributed to the reduction of inflammatory cell infiltration and decreased expression of cytokines associated with airway remodeling. Oral administration of tHGA attenuates airway hyperresponsiveness and remodeling in OVA-induced BALB/c mice. tHGA is an interesting compound that should be evaluated further for its possible role as an alternative non-steroidal pharmacological approach in the management of asthma. PMID- 28089920 TI - G-protein coupled estrogen receptor-mediated non-genomic facilitatory effect of estrogen on cooling-induced reduction of skin blood flow in mice. AB - An enhanced vasoconstrictor activity of cutaneous arteries participates in the reduction of skin blood flow induced by cooling stimulation. Raynaud's phenomenon, which is characterized by intense cooling-induced constriction of cutaneous arteries, is more common in women during the period from menarche to menopause. We thus investigated the effect of 17beta-estradiol (E2) on cooling induced reduction of plantar skin blood flow (PSBF) in mouse in vivo. Ovariectomized female ddY mice, anaesthetized with pentobarbital, were treated with tetrodotoxin for eliminating the sympathetic nerve tone and artificially ventilated. The PSBF was measured by laser Doppler flowmetry. Cooling air temperature around the foot from 25 to 20, 15, or 10 degrees C decreased the PSBF in a temperature-dependent manner, which was suppressed by the specific alpha2C adrenoceptor antagonist MK-912. When E2 was intravenously administered as a bolus followed by a constant infusion for 10min just before the cooling stimulation, the cooling-induced reduction of PSBF was facilitated by E2 in a dose-dependent manner. The facilitatory effect of E2 was not induced after the treatment with MK 912. Similar facilitatory effect was induced by an intravenous application of G 1, an agonist of G protein-coupled estrogen receptor (GPER, also termed GPR30). Moreover, the facilitatory effect of E2 was abolished by the GPER antagonist G15. These results suggest that acute administration of E2 leads to the facilitation of cooling-induced, alpha2C-adrenoceptor-mediated reduction of skin blood flow via the activation of the non-genomic estrogen receptor GPER. PMID- 28089921 TI - Penehyclidine hydrochloride prevents anoxia/reoxygenation injury and induces H9c2 cardiomyocyte apoptosis via a mitochondrial pathway. AB - Penehyclidine hydrochloride (PHC) is an anticholinergic drug that has been widely used in the clinic for years, evaluating for anesthetic premedication, anti muscarinic, or improving microcirculation. However, very little is known about its protective effects against anoxia/reoxygenation (A/R) injury in myocardiocytes. The aim of our study was to investigate the protective effects of PHC pretreatment on A/R injury, as well as the underlying mechanisms involved. To investigate apoptosis, we used the cell viability assay, Annexin-V/PI assay, and lactate dehydrogenase (LDH) and creatine kinase (CK) activity measurements. Intracellular Ca2+ concentrations, reactive oxygen species (ROS), malonaldehyde (MDA), superoxide dismutase (SOD), and mitochondrial membrane potential were also measured. To analyze the molecular mechanisms, mitochondrial permeability transition pore (MPTP) activity and mRNA expressions of Bcl-2, Bax, cytochrome C (Cyt-C), caspase-3, and voltage-dependent anion channel (VDAC) were assessed. Pretreatment with PHC significantly increased cell viability and decreased the percentage of apoptotic cells, as well as LDH and CK activity, which was accompanied by a reduction in intracellular Ca2+ concentration, ROS, and MDA, as well as an increase in SOD levels. PHC pretreatment also restored mitochondrial membrane potential. Moreover, pre-incubation with PHC significantly attenuated MPTP activity and mRNA expressions of Bax, Cyt-C, caspase-3, and VDAC. Our results showed that PHC pretreatment protected H9c2 cells against A/R injury by modulating the mitochondrial apoptosis pathway. PMID- 28089922 TI - X-linked elliptocytosis with impaired growth is related to mutated AMMECR1. AB - In this study, we report a family with X-linked recessive syndrome caused by mutated AMMECR1 and characterized by elliptocytosis with or without anemia, midface hypoplasia, proportionate short stature and hearing loss. Recently, mutations in AMMECR1 were reported in two maternal half-brothers, presenting with nephrocalcinosis, midface hypoplasia and, in one of the siblings, deafness and elliptocytosis. AMMECR1 gene is localized in the critical region of contiguous deletion syndrome on Xq22.3 implicated in Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis (AMME complex). Interestingly, alternative splicing of exon 2, the same exon harboring the truncating mutation, was observed in the proband and in his unaffected mother. Alternative splicing of this exon is predicted to lead to an in-frame deletion. We provide further evidence that mutated AMMECR1 gene is responsible for this clinically recognizable X-linked condition with variable expressivity. PMID- 28089923 TI - Nursing care management of photodynamic therapy in digestive tract carcinomas at a single cancer center. AB - The primary goal of nursing care in cases of endoscopic photodynamic therapy (PDT) for digestive tract carcinoma is to prevent phototoxicity by the intravenous administration of photosensitizers. The adequate protocol and management of patients should be conducted under the instruction of expert physicians. Our experiences of administering porfimer sodium and talaporfin sodium during clinical PDT provide insight regarding the specific management protocol of each photosensitizer during an in-hospital stay. We herein report our nursing protocol based on 15 years of experience. Under adequate management, PDT can be safely performed. PMID- 28089924 TI - Water, juice, or soda? Mothers and grandmothers of preschoolers discuss the acceptability and accessibility of beverages. AB - Intake of sugary beverages is strongly associated with weight gain and obesity among children; however, differences between mothers' and grandmothers' attitudes and practices concerning young children's beverage consumption remain unclear. This is notable since about a quarter of families in the US and the UK rely on grandparents as the main providers of informal childcare. The aim of this study is to examine mothers' and maternal grandmothers' attitudes, knowledge, and practices regarding preschool aged children's beverage consumption. The analysis focuses on identifying intergenerational similarities and differences, given the potential impact that such differences might have on young children's beverage consumption habits. Twenty-two semi-structured interviews, representing eleven families, were analyzed using thematic analysis. The sample included all mother - maternal grandmother dyads from The Grandparents Study, which took place in Eugene, Oregon, USA. More than half of mothers and grandmothers met overweight/obesity criteria. Among the children (mean age 4.7 years; five girls and six boys), seven met overweight/obesity criteria. Most mothers and grandmothers were unemployed, and most reported an annual household income below 30,000 USD. The analysis identified three thematic categories: 1) mothers and grandmothers agree about the hierarchy of healthiness between and within beverages, though juice occupies an ambivalent position; 2) mothers and grandmothers cite role modeling and the home environment as important in regulating preschoolers' beverage intake; 3) mothers and grandmothers balance between restricting sugary beverages and using these beverages as treats. The results suggest that when mothers and grandmothers use soda, juice, and juice drinks as treats, they do so within a wider dynamic of balancing practices, and within two intersecting domains: the hierarchy of beverages, including the still ambivalent status of juice as healthy or unhealthy, and the definition of 'special occasion'. PMID- 28089925 TI - Food portion size area mediates energy effects on expected anxiety in anorexia nervosa. AB - A study in which adolescent patients with anorexia nervosa (n = 24) rated their expected food-anxiety in response to images of portions of food (potatoes, rice pizza, and M&Ms) showed that lower energy-dense foods elicited higher expected anxiety per kilocalorie than higher energy-dense foods. However, the area of the portion sizes could be an unmeasured variable driving the anxiety response. To test the hypothesis that area mediates the effects of energy content on expected anxiety, the same images of portions were measured in area (cm2), and standardized values of expected anxiety were regressed from standardized values of energy and area of portions. With regression of expected anxiety from portion size in area, M&Ms, which had the highest energy density of the four foods, elicited the highest expected anxiety slope (beta = 1.75), which was significantly different from the expected anxiety slopes of the other three foods (beta range = 0.67 - 0.96). Area was confirmed as a mediator of energy effects from loss of significance of the slopes when area was added to the regression of expected anxiety from energy x food. When expected anxiety was regressed from food, area, energy and area by energy interaction, area accounted for 5.7 times more variance than energy, and beta for area (0.7) was significantly larger (by 0.52, SE = 0.15, t = 3.4, p = 0.0007) than beta for energy (0.19). Area could be a learned cue for the energy content of food portions, and thus, for weight gain potential, which triggers anxiety in patients with anorexia nervosa. PMID- 28089926 TI - Sensory-specific satiety is intact in rats made obese on a high-fat high-sugar choice diet. AB - Sensory-specific satiety (SSS) is the temporary decreased pleasantness of a recently eaten food, which inhibits further eating. Evidence is currently mixed whether SSS is weaker in obese people, and whether such difference precedes or follows from the obese state. Animal models allow testing whether diet-induced obesity causes SSS impairment. Female rats (n = 24) were randomly assigned to an obesogenic high-fat, high-sugar choice diet or chow-only control. Tests of SSS involved pre-feeding a single palatable, distinctively-flavored food (cheese- or cocoa-flavored) prior to free choice between both foods. Rats were tested for short-term SSS (2 h pre-feeding immediately followed by 2 h choice) and long-term SSS (3 day pre-feeding prior to choice on day 4). In both short- and long-term tests rats exhibited SSS by shifting preference towards the food not recently eaten. SSS was not impaired in obese rats. On the contrary, in the long-term tests they showed stronger SSS than controls. This demonstrates that neither the obese state nor a history of excess energy consumption fundamentally causes impaired SSS in rats. The putative impaired SSS in obese people may instead reflect a specific predisposition, properties of the obesogenic diet, or history of restrictive dieting and bingeing. PMID- 28089927 TI - Metabolism of selective 20-epi-vitamin D3 analogs in rat osteosarcoma UMR-106 cells: Isolation and identification of four novel C-1 fatty acid esters of 1alpha,25-dihydroxy-16-ene-20-epi-vitamin D3. AB - Analogs of 1alpha,25-dihydroxyvitamin D3 (S1) with 20-epi modification (20-epi analogs) possess unique biological properties. We previously reported that 1alpha,25-dihydroxy-20-epi-vitamin D3 (S2), the basic 20-epi analog is metabolized into less polar metabolites (LPMs) in rat osteosarcoma cells (UMR 106) but not in a perfused rat kidney. Furthermore, we also noted that only selective 20-epi analogs are metabolized into LPMs. For example, 1alpha,25 dihydroxy-16-ene-20-epi-vitamin D3 (S4), but not 1alpha,25-dihydroxy-16-ene-23 yne-20-epi-vitamin D3 (S5) is metabolized into LPMs. In spite of these novel findings, the unequivocal identification of LPMs has not been achieved to date. We report here on a thorough investigation of the metabolism of S4 in UMR-106 cells and isolated two major LPMs produced directly from the substrate S4 itself and two minor LPMs produced from 3-epi-S4, a metabolite of S4 produced through C 3 epimerization pathway. Using GC/MS, ESI-MS and 1H NMR analysis, we identified all the four LPMs of S4 as 25-hydroxy-16-ene-20-epi-vitamin D3-1-stearate and 25 hydroxy-16-ene-20-epi-vitamin D3-1-oleate and their respective C-3 epimers. We report here for the first time the elucidation of a novel pathway of metabolism in UMR-106 cells in which both 1alpha,25(OH)2-16-ene-20-epi-D3 and 1alpha,25(OH)2 16-ene-20-epi-3-epi-D3 undergo C-1 esterification into stearic and oleic acid esters. PMID- 28089928 TI - Improved catalytic properties of Penicillium notatum lipase immobilized in nanoscale silicone polymeric films. AB - Lipases are one of the most proficient biocatalysts having enormous biotechnological prospective. Immobilization offers a potential solution to improve the stability and recycling characteristics of lipases. An extracellular lipase from Penicillium notatum (PNL) was immobilized in silicon polymers (SiP) through entrapment, and subsequently coated this matrix on the network of fibers in the sponges. The silicone polymers-immobilized lipase (SiP-lipase) displayed highest apparent activity and entrapment efficiency of 1.19Ug-1 polymers and 92.3%, respectively. It also exhibited greater catalytic activity in broad working pHs and higher temperature than equivalent free-state of enzyme. Immobilization caused an improvement in thermo-stability of the lipase with an increase in energy of activation. The recycling potential of SiP-lipase was investigated. After reusing the sponge pieces for ten reaction cycles, the SiP preserved its structure without leakage of enzyme, and retained around 90% of its original activity. The SiP surface analysis was envisaged by scanning electron microscopy that further confirmed the recycling efficiency of SiP-lipase. Overall, SiP-lipase displayed a number of useful properties that make it a promising candidate for future applications in different chemical processes. PMID- 28089929 TI - Impact of immobilizing of low molecular weight hyaluronic acid within gelatin based hydrogel through enzymatic reaction on behavior of enclosed endothelial cells. AB - The hydrogels having the ability to promote migration and morphogenesis of endothelial cells (ECs) are useful for fabricating vascularized dense tissues in vitro. The present study explores the immobilization of low molecular weight hyaluronic acid (LMWHA) derivative within gelatin-based hydrogel to stimulate migration of ECs. The LMWHA derivative possessing phenolic hydroxyl moieties (LMWHA-Ph) was bound to gelatin-based derivative hydrogel through the horseradish peroxidase-catalyzed reaction. The motility of ECs was analyzed by scratch migration assay and microparticle-based cell migration assay. The incorporated LMWHA-Ph molecules within hydrogel was found to be preserved stably through covalent bonds during incubation. The free and immobilized LMWHA-Ph did not lose an inherent stimulatory effect on human umbilical vein endothelial cells (HUVECs). The immobilized LMWHA-Ph within gelatin-based hydrogel induced the high motility of HUVECs, accompanied by robust cytoskeleton extension, and cell subpopulation expressing CD44 cell receptor. In the presence of immobilized LMWHA Ph, the migration distance and the number of existing HUVECs were demonstrated to be encouraged in dose-dependent and time-dependent manners. Based on the results obtained in this work, it was concluded that the enzymatic immobilization of LMWHA-Ph within gelatin-based hydrogel represents a promising approach to promote ECs' motility and further exploitation for vascular tissue engineering applications. PMID- 28089930 TI - Scaffolds containing chitosan, gelatin and graphene oxide for bone tissue regeneration in vitro and in vivo. AB - Critical-sized bone defects are augmented with cell free and cell loaded constructs to bridge bone defects. Improving the properties of three-dimensional scaffolds with multiple polymers and others is of growing interest in recent decades. Chitosan (CS), a natural biopolymer has limitations for its use in bone regeneration, and its properties can be enhanced with other materials. In the present study, the composite scaffolds containing CS, gelatin (Gn) and graphene oxide (GO) were fabricated through freeze-drying. These scaffolds (GO/CS/Gn) were characterized by the SEM, Raman spectra, FT-IR, EDS, swelling, biodegradation, protein adsorption and biomineralization studies. The inclusion of GO in the CS/Gn scaffolds showed better physico-chemical properties. The GO/CS/Gn scaffolds were cyto-friendly to rat osteoprogenitor cells, and they promoted differentiation of mouse mesenchymal stem cells into osteoblasts. The scaffolds also accelerated bridging of the rat tibial bone defect with increased collagen deposition in vivo. Hence, these results strongly suggested the potential nature of GO/CS/Gn scaffolds for their application in bone tissue regeneration. PMID- 28089931 TI - A novel polysaccharide with antioxidant, HIV protease inhibiting and HIV integrase inhibiting activities from Fomitiporia punctata (P. karst.) murrill (Basidiomycota, hymenochaetales). AB - A novel polysaccharide fraction (G1) was obtained from the fungus Fomitiporia punctata (P. Karst.) Murrill. G1 exhibited a molecular weight of approximately 151kDa. The FT-IR results suggested that the monosaccharide components of G1 possessed furanoid rings and there were beta-glycosidic bonds between the sugar units. The1H NMR results showed that G1 was composed of arabinose, fructose, galactose and glucose in the molar ratio of 1.6:3.8:19.7:19.7, as determined by gas chromatography-mass spectrometry (GC-MS) and high performance liquid chromatography (HPLC). G1 produced significant antioxidant effects as evidenced by its potency in inhibiting erythrocyte hemolysis, and in scavenging hydroxyl radicals and superoxide radicals. The highest rates of inhibition achieved were 73.58%, 36.55% and 50.98% respectively. In addition, G1 brought about 19.6% inhibition of HIV-1 protease activity at the concentration of 50MUg/mL. G1 displayed inhibitory activity toward HIV-1 integrase in the concentration range of 100-1000MUg/mL. The present study indicates that G1 from Fomitiporia punctate (P. Karst.) Murrill is a novel natural antioxidant. PMID- 28089932 TI - Selenizing Hericium erinaceus polysaccharides induces dendritic cells maturation through MAPK and NF-kappaB signaling pathways. AB - In this study, polysaccharides extracted from Hericium erinaceus were modified to obtain its nine selenium derivatives, sHEP1-sHEP9. Their structures were identified, yields and selenium contents were determined, the phenotypic and functional maturation of murine bone marrow-derived dendritic cells (DCs) and relevant mechanisms were compared taking unmodified HEP as control. The results revealed that the selenylation were successful. sHEP1, sHEP2 and sHEP8 treatment of DCs increased their surface expression of MHC-II and CD86 and indicated that sHEP1, sHEP2 and sHEP8 induced DC maturation. Furthermore, sHEP2 and sHEP8 also significantly decreased DCs endocytosis and significantly enhanced cytokine (IL 12 and IFN-gamma) production. In line with TLR4 activation, sHEP2 increased the phosphorylation of ERK, p38, and JNK, and the nuclear translocation of p-c-Jun, p CREB, and c-Fos. sHEP2 also activated NF-kappaB signaling, as evidenced by degradation of IkappaBalpha/beta and nuclear translocation of p65 and p50. Together, these results suggest that sHEP is a strong immunostimulant. PMID- 28089933 TI - HFB7 - A novel orphan hydrophobin of the Harzianum and Virens clades of Trichoderma, is involved in response to biotic and abiotic stresses. AB - Hydrophobins are small secreted cysteine-rich proteins exclusively found in fungi. They are able to self-assemble in single molecular layers at hydrophobic hydrophilic interfaces and can therefore be directly involved in establishment of fungi in their habitat. The genomes of filamentous mycotrophic fungi Trichoderma encode a rich diversity of hydrophobins, which are divided in several groups based on their structure and evolution. Here we describe a new member of class II hydrophobins, HFB7, that has a taxonomically restricted occurrence in Harzianum and Virens clades of Trichoderma. Evolutionary analysis reveals that HFB7 proteins form a separate clade distinct from other Trichoderma class II hydrophobins and that genes encoding them evolve under positive selection pressure. Homology modelling of HFB7 structure in comparison to T. reesei HFB2 reveals that the two large hydrophobic patches on the surface of the protein are remarkably conserved between the two hydrophobins despite significant difference in their primary structures. Expression of hfb7 gene in T. virens increases at interactions with other fungi and a plant and in response to a diversity of abiotic stress conditions, and is also upregulated during formation of aerial mycelium in a standing liquid culture. This upregulation significantly exceeds that of expression of hfb7 under a strong constitutive promoter, and T. virens strains overexpressing hfb7 thus display only changes in traits characterized by low hfb7 expression, i.e. faster growth in submerged liquid culture. The hfb7 gene is not expressed in conidia. Our data allow to conclude that this protein is involved in defence of Trichoderma against a diversity of stress factors related to the oxidative stress. Moreover, HFB7 likely helps in the establishment of the fungus in wetlands or other conditions related to high humidity. PMID- 28089934 TI - Evaluation of aggregate and silicone-oil counts in pre-filled siliconized syringes: An orthogonal study characterising the entire subvisible size range. AB - Characterisation of particulates in therapeutic monoclonal antibody (mAb) formulations is routinely extended to the sub-visible size-range (0.1-10MUm). Additionally, with the increased use of pre-filled syringes (PFS), particle differentiation is required between proteinaceous and non-proteinaceous particles such as silicone-oil droplets. Here, three orthogonal techniques: Raster Image Correlation Spectroscopy (RICS), Resonance Mass Measurements (RMM) and Micro-Flow Imaging (MFI), were evaluated with respect to their sub-visible particle measurement and characterisation capabilities. Particle formation in mAb PFS solutions was evaluated with increasing polysorbate-20 (PS-20) concentrations. All three techniques provided complementary but distinct information on protein aggregate and silicone-oil droplet presence. PS-20 limited the generation of mAb aggregates during agitation, while increasing the number of silicone-oil droplets (PS-20 concentration dependant). MFI and RMM revealed PS-20 lead to the formation of larger micron-sized droplets, with RICS revealing an increase in smaller sub micron droplets. Subtle differences in data sets complicate the apparent correlation between silicone-oil sloughing and mAb aggregates' generation. RICS (though the use of a specific dye) demonstrates an improved selectivity for mAb aggregates, a broader measurement size-range and smaller sample volume requirement. Thus, RICS is proposed to add value to the currently available particle measurement techniques and enable informed decisions during mAb formulation development. PMID- 28089935 TI - Synergistic antimicrobial potential of essential oils in combination with nanoparticles: Emerging trends and future perspectives. AB - The development of resistance to different antimicrobial agents by bacteria, fungi, viruses, parasites, etc. is a great challenge to the medical field for the treatment of infections caused by them, and therefore, there is a pressing need to search for new and novel antimicrobials. The antimicrobial activity of essential oils and biogenic nanoparticles is well known. Recent studies have demonstrated that nanoparticles functionalized with essential oils have significant antimicrobial potential against multidrug- resistant pathogens. The aim of the present review is to discuss various studies on the broad-spectrum antimicrobial activity of essential oils used singly and in combination with nanoparticles. The brief explanation of their mechanism has also been discussed. PMID- 28089936 TI - Biodegradable lipid nanoparticles induce a prolonged RNA interference-mediated protein knockdown and show rapid hepatic clearance in mice and nonhuman primates. AB - Lipid nanoparticles based on ionizable lipids have been clinically validated as a means of delivery for RNA interference (RNAi) therapeutics. The ideal properties of RNAi carriers are efficient delivery of oligonucleotides into target cells and rapid elimination after the function is performed. Here, we report that degradable lipid nanoparticles are effective carriers of small interfering RNA (siRNA) and have a high therapeutic index. The newly developed degradable lipid nanoparticles carrying siRNA showed potent gene-silencing activity in mouse hepatocytes (ED50~0.02mg/kg siRNA). The ester bond in the lipid tail was hydrolyzed in the liver, resulting in rapid metabolism of the lipid. Toxicity assays showed that the degradable lipid was well-tolerated at siRNA doses of up to 16mg/kg in rats (over 800-fold higher than ED50). A single intravenous injection of siRNA targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) in cynomolgus monkeys resulted in more than 90% protein silencing, and a 50% decrease in plasma low-density lipoprotein (LDL) cholesterol, with a measurable reduction for 2 months. Moreover, quantification of lipids in liver biopsies revealed rapid hepatic clearance of the degradable lipid in nonhuman primates. These degradable lipid nanoparticles with a high therapeutic index hold promise for RNA-based treatments. PMID- 28089937 TI - Surgical outcomes of unilateral recession-resection for vertical strabismus in patients with thyroid eye disease. AB - PURPOSE: To present the surgical outcomes of vertical muscle resection in patients with thyroid eye disease (TED). METHODS: The medical records of 6 patients who underwent unilateral vertical muscle recession-resection to correct vertical strabismus in TED were reviewed retrospectively for postoperative angle of vertical deviation on days 1 and 7 and at months 1, 3, 6, and 12. Surgery was considered successful if the vertical deviation was <=4Delta. Reoperation rates and complications were also noted. RESULTS: The mean preoperative angle of vertical deviation was 39.2Delta +/- 3.8Delta, and the mean final ocular deviation at 12 months postoperatively was 3.8Delta +/- 5.9Delta. There was significant reduction in postoperative vertical deviation (paired t test, P < 0.001). Surgery was successful in 4 patients (67%). There was neither unusual postoperative inflammation nor increased restriction of the resected muscle postoperatively in any patient. CONCLUSIONS: Based on careful assessment and appropriate patient selection, vertical muscle resection can be considered an effective option that provides satisfactory surgical outcomes with regard to vertical deviation correction in TED. PMID- 28089938 TI - WITHDRAWN: 3D-printed RF probeheads for low-cost, high-throughput NMR. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 28089939 TI - Chemical exchange saturation transfer imaging: Advances and applications by Michael T. McMahon, Assaf A. Gild, Jeff W. M. Bulte, and Peter C.M. van Zijl Publisher: Pan Stanford Publishing Pte. Ltd., Singapore. PMID- 28089940 TI - Assessing the effect of football play on knee articular cartilage using delayed gadolinium-enhanced MRI of cartilage (dGEMRIC). AB - The prevalence of cartilage lesions is much higher in football athletes than in the general population. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) has been shown to quantify regional variations of glycosaminoglycan (GAG) concentrations which is an indicator of early cartilage degeneration. The goal of this study is to determine whether dGEMRIC can be used to assess the influence in cartilage GAG concentration due to college level football play. Thirteen collegiate football players with one to four years of collegiate football play experience were recruited and both knee joints were scanned using a dedicated 8 channel phased array knee coil on a 3T MRI system. The contrast concentrations within cartilage were calculated based on the T1 values from dGEMRIC scans. No substantial differences were found in the contrast concentrations between the pre and post-season across all the cartilage compartments. One year collegiate football players presented an average contrast concentration at the pre-season of 0.116+/-0.011mM and post-season of 0.116+/-0.011mM. In players with multiple years of football play, contrast uptake was elevated to 0.141+/-0.012mM at the pre-season and 0.139+/-0.012mM at the post-season. The pre-season 0.023+/-0.016mM and post-season 0.025+/-0.016mM increase in contrast concentration within the group with multiple years of experience presented with a >20% increase in contrast uptake. This may indicate the gradual, cumulative damage of football play to the articular cartilage over years, even though the effect may not be noticeable after a season of play. Playing collegiate football for a longer period of time may lead to cartilage microstructural alterations, which may be linked to early knee cartilage degeneration. PMID- 28089941 TI - Laparoscopic peritoneal lavage or surgical resection for acute perforated sigmoid diverticulitis: A systematic review and meta-analysis. AB - BACKGROUND: Laparoscopic peritoneal lavage (LPL) has been proposed as an alternative, less invasive technique in the treatment of acute perforated sigmoid diverticulitis (APSD). The aim of this meta-analysis is to compare the effectiveness of LPL versus surgical resection (SR) in terms of morbidity and mortality in the management of APSD. METHODS: A comprehensive search was conducted for randomised controlled trials (RCTs) comparing LPL versus SR in the treatment of APSD. The end points included peri-operative mortality, severe adverse events, overall mortality, post-operative abscess, percutaneous reinterventions, reoperation, operative time, postoperative stay, and readmissions. RESULTS: Three RCTs with a total of 372 patients, randomised to either LPL or SR were included. There was no significant difference in peri operative mortality between LPL and SR (OR 1.356, 95% CI 0.365 to 5.032, p = 0.649), or serious adverse events (OR = 1.866, 95% CI = 0.680 to 5.120, p = 0.226). The LPL required significantly less time to complete than SR (WMD = 72.105, 95% CI = -88.335 to -55.876, p < 0.0001). The LPL group was associated with a significantly higher rate of postoperative abscess formation (OR = 4.121, 95% CI = 1.890 to 8.986, p = 0.0004) and subsequent percutaneous interventions (OR = 5.414, 95% CI 1.618 to 18.118, p = 0.006). CONCLUSION: Laparoscopic peritoneal lavage is a safe and quick alternative in the management of APSD. In comparison to SR, LPL results in higher rates of postoperative abscess formation requiring more percutaneous drainage interventions without any difference in perioperative mortality and serious morbidity. PMID- 28089942 TI - Targeting EGFR T790M mutation in NSCLC: From biology to evaluation and treatment. AB - The identification of EGFR mutations and their respectively tyrosine kinase inhibitors (TKIs), changed dramatically treatment and survival of patients with EGFR-positive lung cancer. Nowadays, different EGFR TKIs as afatinib, erlotinib and gefitinib are approved worldwide for the treatment of NSCLC harbouring EGFR mutations, in particular exon 19 deletions or exon 21 (Leu858Arg) substitution EGFR mutations. In first-line setting, when comparing with platinum-based chemotherapy, these target drugs improves progression-free survival, response rate and quality of life. Unfortunately, the development of different mechanism of resistance, limits the long term efficacy of these agents. The most clear mechanism of resistance is the development of EGFR Thr790Met mutation. Against this new target, different third-generation EGFR-mutant-selective TKIs, such as osimertinib, rociletinib and olmutinib, showed a great activity. In this review, we summarize the scientific evidences about biology, evaluation and treatment on NSCLC with EGFR T790M mutation. PMID- 28089943 TI - Resveratrol supplementation and plasma adipokines concentrations? A systematic review and meta-analysis of randomized controlled trials. AB - The results of human clinical trials have revealed that the effects of resveratrol on adipokines are inconsistent. Our objective was to elucidate the role of resveratrol supplementation on adipokines through a systematic review and a meta-analysis of available randomized placebo-controlled trials (RCTs).1 The search included PubMed-MEDLINE, SCOPUS and ISI web of sciences database till up to 6th November 2016. Weight mean differences (WMD)2 were calculated for net changes in adipokines using fixed-effects or random-effects models; meta regression analysis and publication bias were conducted in accordance with standard methods. Nine RCTs with 11 treatment arms were eligible for inclusion in this systematic review and meta-analysis. Meta-analysis of data from 10 treatment arms showed a significant change in plasma adiponectin concentrations following resveratrol supplementation (WMD: 1.10MUg/ml, 95%CI: 0.88, 1.33, p<0.001); Q=11.43, I2=21.29%, p=0.247). There was a significant greater adiponectin reducing effect in trials with higher than or equal to 100mg/day (WMD: 1.11MUg/ml, 95%CI: 0.88, 1.34, p<0.001), versus those with less than 100 mg/day dosage (WMD: 0.84MUg/ml, 95%CI: -0.62, 2.31, p=0.260). Meta-analysis of data from 5 treatment arms did not find any significant change in plasma leptin concentrations following resveratrol supplementation (WMD: 3.77ng/ml, 95% CI: 2.28, 9.83, p=0.222; Q=8.00, I2=50.01%). Resveratrol significantly improves adiponectin but does not affect leptin concentrations. Additional studies are required to further evaluate the potential benefits of resveratrol on adipokines in humans. PMID- 28089944 TI - RSM22, mtYsxC and PNKD-like proteins are required for mitochondrial translation in Trypanosoma brucei. AB - Mitochondrial ribosomes evolved from prokaryotic ribosomes, with which they therefore share more common features than with their counterparts in the cytosol. Yet, mitochondrial ribosomes are highly diverse in structure and composition, having undergone considerable changes, including reduction of their RNA component and varying degree of acquisition of novel proteins in various phylogenetic lineages. Here, we present functional analysis of three putative mitochondrial ribosome-associated proteins (RSM22, mtYsxC and PNKD-like) in Trypanosoma brucei, originally identified by database mining. While in other systems the homologs of RSM22 are known as components of mitochondrial ribosomes, YsxC was linked with ribosomes only in bacteria. The PNKD-like protein shows similarity to a human protein, the defects of which cause PNKD (paroxysmal non-kinesigenic dyskinesia). Here we show that all three proteins are important for the growth of T. brucei. They play an important function in mitochondrial translation, as their ablation by RNAi rapidly and severely affected the de novo synthesis of mitochondrial proteins. Moreover, following the RNAi-mediated depletion of RSM22, structure of the small subunit of mitochondrial ribosome becomes severely compromised, suggesting a role of RSM22 in ribosomal assembly and/or stability. PMID- 28089946 TI - Identification by PCR signature-tagged mutagenesis of attenuated Salmonella Pullorum mutants and corresponding genes in a chicken embryo model. AB - A key feature of the fowl-specific pathogen Salmonella Pullorum is its vertical transmission to progeny via the egg. In this study, PCR signature-tagged mutagenesis identified nine genes of a strain of S. Pullorum that contributed to survival in the chicken embryo during incubation. The genes were involved in invasion, cell division, metabolism and bacterial defence. The competition index in vivo and in vitro together with a virulence evaluation for chicken embryos of all nine mutant strains confirmed their attenuation. PMID- 28089945 TI - Zearalenone exposure impairs ovarian primordial follicle formation via down regulation of Lhx8 expression in vitro. AB - Zearalenone (ZEA) is an estrogenic mycotoxin mainly produced as a secondary metabolite by numerous species of Fusarium. Previous work showed that ZEA had a negative impact on domestic animals with regard to reproduction. The adverse effects and the mechanisms of ZEA on mammalian ovarian folliculogenesis remain largely unknown, particularly its effect on primordial follicle formation. Thus, we investigated the biological effects of ZEA exposure on murine ovarian germ cell cyst breakdown and primordial follicle assembly. Our results demonstrated that newborn mouse ovaries exposed to 10 or 30MUM ZEA in vitro had significantly less germ cell numbers compared to the control group. Moreover, the presence of ZEA in vitro increased the numbers of TUNEL and gammaH2AX positive cells within mouse ovaries and the ratio of mRNA levels of the apoptotic genes Bax/Bcl-2. Furthermore, ZEA exposure reduced the mRNA of oocyte specific genes such as LIM homeobox 8 (Lhx8), newborn ovary homeobox (Nobox), spermatogenesis and oogenesis helix-loop-helix (Sohlh2), and factor in the germline alpha (Figlalpha) in a dose dependent manner. Exposure to ZEA led to remarkable changes in the Lhx8 3'-UTR DNA methylation dynamics in oocytes and severely impaired folliculogenesis in ovaries after transplantation under the kidney capsules of immunodeficient mice. In conclusion, ZEA exposure impairs mouse primordial follicle formation in vitro. PMID- 28089947 TI - Hepatic xanthine oxidase activity and purine nucleosides levels as physiological mediators to analyze a subcutaneous treatment with (PhSe)2 in mice infected by Toxoplasma gondii. AB - The aim of this study was to evaluate the levels of purine nucleosides and xanthine oxidase (XO) activity in the liver of mice chronically infected by Toxoplasma gondii and treated with diphenyl diselenide (PhSe)2. For this experiment, forty Swiss mice were used. Twenty animals were orally infected by approximately 50 bradizoites of a cystogenic ME-49 strain of T. gondii, and the same number of uninfected mice was used as a control group. Ten infected and ten uninfected mice were subcutaneously treated twice (days 1 and 20 post-infection (PI)) with 5 MUmol kg-1 of (PhSe)2. On day 30 PI, liver samples were collected to measure the levels of hypoxanthine (HYPO), xanthine (XAN), uric acid (UA), and XO activity. Infected animals showed increased (P < 0.05) levels of hepatic XAN and UA, as well as XO activity compared to uninfected animals. The use of (PhSe)2 in healthy mice increased the levels of all nucleosides, but decreased XO activity compared to healthy untreated animals. The group of infected and treated animals showed increased XAN and UA levels, and XO activity compared to the healthy control group, however infected and treated mice showed a decrease in the XO activity compared to the infected untreated group. We conclude that chronic infection caused by T. gondii can induce hepatic changes, such as increased UA levels and XO activity, that can increase the pro-oxidative profile. The (PhSe)2 treatment of healthy animals altered the levels of nucleosides, possibly due to low XO activity that decreased nucleoside degradation. Finally, (PhSe)2 treatment decreased XO activity in the infected group and increased nucleoside levels; however it was unable to reduce the UA levels found during the infection. PMID- 28089948 TI - Antifungal activity of umbelliferone derivatives: Synthesis and structure activity relationships. AB - Umbelliferone was an important allelochemical with a wide spectrum bioactivity. In our previous study, C7 hydroxy in the backbone of umbelliferone was identified to be responsible for its phytotoxicity and the targeted modification of the above site could lead to the phytotoxicity loss. In view of this, a series of hydroxycoumarins and C7 O-substituted umbelliferone derivatives were efficiently synthesized to evaluate their antifungal activity against four phytopathogenic fungi. Most of them, as we predicted, exhibited improved fungicidal activity. The phytotoxicity of effective compounds was also assayed by Lactuca sativa to investigate their side effects on plant growth. Compounds 9 and 17 were identified to show strong antifungal activity with low phytotoxicity. A brief investigation on structure-activity relationships revealed that the modification at the C7 hydroxy of umbelliferone could be a promising way to enhance the antifungal activity with decreasing the phytotoxicity. PMID- 28089949 TI - Melaleuca alternifolia nanoparticles against Candida species biofilms. AB - Candida infection is an important cause of morbidity and mortality on immunosuppressed patients. This growing trend has been associated with resistance to the antimicrobial therapy and the ability of microorganism to form biofilms. TTO oil is used as antimicrobial which shows antibiofilm activity against Candida species. However, it presents problems due to its poor solubility and high volatility. The present study aimed to evaluate in vitro antibiofilm activity of TTO nanoparticles against many Candida species. It was performed the characterization of the oil and nanoparticles. The levels of exopolysaccharides, proteins, and the biomass of biofilms were measured. The chromatographic profile demonstrated that the TTO oil is in accordance with ISO 4730 with major constituents of 41.9% Terpinen-4-ol, 20.1% of gamma-Terpinene, 9,8% of alpha Terpinene, and 6,0% of 1,8-Cineole. The TTO nanoparticles showed pH of 6.3, mean diameter of 158.2 +/- 2 nm, polydispersion index of 0.213 +/- 0.017, and zeta potential of -8.69 +/- 0.80 mV. The addition of TTO and its nanoparticles represented a significant reduction of biofilm formed by all Candida species, as well as a reduction of proteins and exopolysaccharides levels. It was possible to visualize the reduction of biofilm in presence of TTO nanoparticles by Calcofluor White method. PMID- 28089950 TI - CRISPR-P 2.0: An Improved CRISPR-Cas9 Tool for Genome Editing in Plants. PMID- 28089951 TI - BZR1 Positively Regulates Freezing Tolerance via CBF-Dependent and CBF Independent Pathways in Arabidopsis. AB - Cold stress is a major environmental factor that adversely affects plant growth and development. The C-repeat binding factor/DRE binding factor 1 (CBF/DREB1) transcriptional regulatory cascade has been shown to play important roles in plant response to cold. Here we demonstrate that two key components of brassinosteroid (BR) signaling modulate freezing tolerance of Arabidopsis plants. The loss-of-function mutant of the GSK3-like kinases involved in BR signaling, bin2-3 bil1 bil2, showed increased freezing tolerance, whereas overexpression of BIN2 resulted in hypersensitivity to freezing stress under both non-acclimated and acclimated conditions. By contrast, gain-of-function mutants of the transcription factors BZR1 and BES1 displayed enhanced freezing tolerance, and consistently cold treatment could induce the accumulation of dephosphorylated BZR1. Biochemical and genetic analyses showed that BZR1 acts upstream of CBF1 and CBF2 to directly regulate their expression. Moreover, we found that BZR1 also regulated other COR genes uncoupled with CBFs, such as WKRY6, PYL6, SOC1, JMT, and SAG21, to modulate plant response to cold stress. Consistently, wrky6 mutants showed decreased freezing tolerance. Taken together, our results indicate that BZR1 positively modulates plant freezing tolerance through CBF-dependent and CBF independent pathways. PMID- 28089952 TI - Impact of tricuspid valve regurgitation in surgical high-risk patients undergoing MitraClip implantation: results from the TRAMI registry. AB - AIMS: We sought to assess the impact of tricuspid regurgitation (TR) severity on patient outcome in a collective with relevant mitral regurgitation undergoing MitraClip implantation.. METHODS AND RESULTS: From August 2010 to July 2013, 766 patients (age 75.3+/-8.5 years, 61% male, median EuroSCORE 24.3%+/-18.4) were prospectively enrolled in the TRAMI registry and stratified by echocardiography into no/mild, moderate and severe TR. Overall, the mean number of implanted MitraClips was higher in patients with severe TR but increasing TR severity was not associated with procedural success. In-hospital and one-year mortality as well as MACE and MACCE (death, myocardial infarction+/-stroke) rates were higher with increasing TR severity. Kaplan-Meier curves indicated a significant difference for mortality (p<0.0001), but not for rehospitalisation for heart failure. After multivariate Cox regression, severe TR proved to be a predictor for one-year mortality (HR 2.01, 95% CI: 1.25-3.26, p=0.004). Higher rates of severe bleeding were more frequent with increasing TR grades. CONCLUSIONS: In patients with MitraClip implantation, increasing TR severity is associated with adverse outcome, higher bleeding rates and decreased survival rates. PMID- 28089953 TI - Transcatheter treatment of severe tricuspid regurgitation using the edge-to-edge repair technique. AB - AIMS: The aim of this study was to investigate the procedural feasibility and short-term durability of the transcatheter tricuspid valve edge-to-edge repair technique in highly symptomatic patients with severe tricuspid regurgitation (TR). METHODS AND RESULTS: Eighteen consecutive patients suffering from severe right-sided heart failure (NYHA Class III-IV), primarily due to moderate to severe tricuspid regurgitation, were included in the study. Applying a modified steering technique for the clip delivery system, six patients were treated for isolated severe TR, while 12 patients were treated for moderate to severe TR and concomitant severe mitral regurgitation. The primary objectives were procedural success, defined as reduction of at least one TR grade, and 30-day echocardiographic and clinical outcomes. A total of 41 clips (2.3+/-0.7 per patient) were placed into the tricuspid valve of high surgical risk patients (EuroSCORE II: 10+/-8%). Procedural success was achieved in all patients; no MACCE occurred in hospital. The presence of a TR grade >=3 was reduced from 94% (17 patients) before the procedure to 33% (six patients) at 30-day follow-up (p<0.001). Sixteen patients (89%) reported an improvement in NYHA functional class at 30 days. CONCLUSIONS: Applying a modified steering technique, the edge to-edge repair technique can be successfully used for the treatment of TR. At 30 day follow-up, the short-term durability of TR reduction appeared promising and the majority of patients improved clinically. Further studies with larger patient populations and longer follow-up have to define the role of this novel treatment option for patients with right-sided heart failure and severe TR. PMID- 28089954 TI - Solid pseudopapillary neoplasm of the pancreas: CT imaging features and radiologic-pathologic correlation. AB - PURPOSE: We aimed to evaluate the imaging features of solid pseudopapillary neoplasm (SPN) of the pancreas with an emphasis on radiologic-pathologic correlation. METHODS: Ten patients (all female; mean age, 32 years) with histologic or cytologic diagnosis of SPN encountered between January 2007 and December 2013 were included in this study. Preoperative computed tomography (CT) images were reviewed for location, attenuation, enhancement pattern, margin, shape, size, morphology, presence of capsule and calcification. CT appearances were correlated with histopathologic findings. RESULTS: Tumors in the distal pancreatic body and tail had a tendency to be larger (mean size 12.6 cm vs. 4.0 cm). Six of the nine tumors that were resected had a fibrous pseudocapsule at histology, five of which could be identified on CT scan. Eight lesions had mixed hypoenhancing solid components and cystic areas corresponding to tumor necrosis and hemorrhage. The two smallest lesions were purely solid and nonencapsulated. Varied patterns of calcification were seen in four tumors. Three of the four pancreatic tail tumors invaded the spleen. At a median follow-up of 53 months, there was no evidence of recurrence in the nine patients who underwent surgical resection of the tumor. CONCLUSION: A mixed solid and cystic pancreatic mass in a young woman is suggestive of SPN. However, smaller lesions may be completely solid. Splenic invasion can occur in pancreatic tail SPNs; however, in this series it did not adversely affect the long-term outcome. PMID- 28089955 TI - Is integrated 18F-FDG PET/MRI superior to 18F-FDG PET/CT in the differentiation of incidental tracer uptake in the head and neck area? AB - PURPOSE: We aimed to investigate the accuracy of 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) compared with contrast-enhanced 18F-FDG PET/computed tomography (PET/CT) for the characterization of incidental tracer uptake in examinations of the head and neck. METHODS: A retrospective analysis of 81 oncologic patients who underwent contrast-enhanced 18F-FDG PET/CT and subsequent PET/MRI was performed by two readers for incidental tracer uptake. In a consensus reading, discrepancies were resolved. Each finding was either characterized as most likely benign, most likely malignant, or indeterminate. Using all available clinical information including results from histopathologic sampling and follow-up examinations, an expert reader classified each finding as benign or malignant. McNemar's test was used to compare the performance of both imaging modalities in characterizing incidental tracer uptake. RESULTS: Forty-six lesions were detected by both modalities. On PET/CT, 27 lesions were classified as most likely benign, one as most likely malignant, and 18 as indeterminate; on PET/MRI, 31 lesions were classified as most likely benign, one lesion as most likely malignant, and 14 as indeterminate. Forty-three lesions were benign and one lesion was malignant according to the reference standard. In two lesions, a definite diagnosis was not possible. McNemar's test detected no differences concerning the correct classification of incidental tracer uptake between PET/CT and PET/MRI (P = 0.125). CONCLUSION: In examinations of the head and neck area, incidental tracer uptake cannot be classified more accurately by PET/MRI than by PET/CT. PMID- 28089956 TI - Robust causal inference using directed acyclic graphs: the R package 'dagitty'. AB - Directed acyclic graphs (DAGs), which offer systematic representations of causal relationships, have become an established framework for the analysis of causal inference in epidemiology, often being used to determine covariate adjustment sets for minimizing confounding bias. DAGitty is a popular web application for drawing and analysing DAGs. Here we introduce the R package 'dagitty', which provides access to all of the capabilities of the DAGitty web application within the R platform for statistical computing, and also offers several new functions. We describe how the R package 'dagitty' can be used to: evaluate whether a DAG is consistent with the dataset it is intended to represent; enumerate 'statistically equivalent' but causally different DAGs; and identify exposure-outcome adjustment sets that are valid for causally different but statistically equivalent DAGs. This functionality enables epidemiologists to detect causal misspecifications in DAGs and make robust inferences that remain valid for a range of different DAGs. The R package 'dagitty' is available through the comprehensive R archive network (CRAN) at [https://cran.r-project.org/web/packages/dagitty/]. The source code is available on github at [https://github.com/jtextor/dagitty]. The web application 'DAGitty' is free software, licensed under the GNU general public licence (GPL) version 2 and is available at [http://dagitty.net/]. PMID- 28089958 TI - Heredity and environment: a warning to eugenists. PMID- 28089957 TI - The epigenetic clock and physical development during childhood and adolescence: longitudinal analysis from a UK birth cohort. AB - Background: Statistical models that use an individual's DNA methylation levels to estimate their age (known as epigenetic clocks) have recently been developed, with 96% correlation found between epigenetic and chronological age. We postulate that differences between estimated and actual age [age acceleration (AA)] can be used as a measure of developmental age in early life. Methods: We obtained DNA methylation measures at three time points (birth, age 7 years and age 17 years) in 1018 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). Using an online calculator, we estimated epigenetic age, and thus AA, for each child at each time point. We then investigated whether AA was prospectively associated with repeated measures of height, weight, body mass index (BMI), bone mineral density, bone mass, fat mass, lean mass and Tanner stage. Results: Positive AA at birth was associated with higher average fat mass [1321 g per year of AA, 95% confidence interval (CI) 386, 2256 g] from birth to adolescence (i.e. from age 0-17 years) and AA at age 7 was associated with higher average height (0.23 cm per year of AA, 95% CI 0.04, 0.41 cm). Conflicting evidence for the role of AA (at birth and in childhood) on changes during development was also found, with higher AA being positively associated with changes in weight, BMI and Tanner stage, but negatively with changes in height and fat mass. Conclusions: We found evidence that being ahead of one's epigenetic age acceleration is related to developmental characteristics during childhood and adolescence. This demonstrates the potential for using AA as a measure of development in future research. PMID- 28089959 TI - Data Resource Profile: IPUMS-International. PMID- 28089960 TI - Cohort Profile: The ENVIRonmental influence ON early AGEing (ENVIRONAGE): a birth cohort study. PMID- 28089961 TI - Cohort Profile: Stress in Pregnancy (SIP) Study. PMID- 28089962 TI - Mycoplasma Clearance and Risk Analysis in a Model Bioprocess. AB - Mycoplasmas are a type of bacteria that lack cell walls and are occasional cell culture contaminants. In a biotechnology setting, because they can pass through 0.2 MUm filters, mycoplasmas could pose a potential patient safety hazard if undetected contaminants from the production culture were not completely removed by downstream biotechnology manufacturing. In this study we investigated the ability of typical commercial monoclonal antibody purification operations to clear and kill mycoplasmas, using Acholeplasma laidlawii as a model organism. Our spike/removal studies have shown that protein A column chromatography clears about 4-5 log10 Column regeneration effectively prevents A. laidlawii column carryover between chromatography runs. Moreover, low-pH hold steps, typically implemented after protein A purification, effectively kill A. laidlawii using either pH 3.8 glycine or acetate solutions (LRV >=5.30 and >=4.57, respectively). Solvent/detergent treatment, used in some processes instead of low-pH hold, also completely kills highly concentrated A. laidlawii (LRV >=5.95).LAY ABSTRACT: Biotechnology medicines need to be free from contaminating microorganisms such as mycoplasmas, a type of bacteria that can cause disease in humans (e.g., walking pneumonia). Here we show that some monoclonal antibody manufacturing steps can effectively clear and/or kill Acholeplasma laidlawii, a model mycoplasma species used in our study. This provides an additional level of safety assurance of biotechnology medicines for patients. PMID- 28089963 TI - PDA Points To Consider: Technical Product Lifecycle Management: Communication and Knowledge Exchange between Marketing Authorization Holders and Health Authorities. PMID- 28089964 TI - Increasing Patient Safety by Closing the Sterile Production Gap-Part 1. Introduction. AB - Terminal sterilization is considered the preferred means for the production of sterile drug products because it affords enhanced safety for the patient as the formulation is filled into its final container, sealed, and sterilized. Despite the obvious patient benefits, the use of terminal sterilization is artificially constrained by unreasonable expectations for the minimum time-temperature process to be used. The core misunderstanding with terminal sterilization is a fixation that destruction of a high population of a resistant biological indicator is required. The origin of this misconception is unclear, but it has resulted in sterilization conditions that are extremely harsh (15 min at 121 degrees C, of F0 > 8 min), which limit the use of terminal sterilization to extremely heat stable formulations. These articles outline the artificial nature of the process constraints and describe a scientifically sound means to expand the use of terminal sterilization by identifying the correct process goal-destruction of the bioburden present in the container prior to sterilization. Recognition that the true intention is bioburden destruction in routine products allows for the use of reduced conditions (lower temperatures, shorter process dwell, or both) without added patient risk. By focusing attention on the correct process target, lower time-temperature conditions can be used to expand the use of terminal sterilization to products unable to withstand the harsh conditions that have been mistakenly applied. The first article provides the background and describes the benefits to patient, producer, and regulator. The second article includes validation and operational advice that can be used in the implementation.LAY ABSTRACT: Terminal sterilization is considered the preferred means for the production of sterile drug products because it affords enhanced safety for the patient as the formulation is filled into its final container, sealed, and sterilized. Despite the obvious patient benefits, the use of terminal sterilization is artificially constrained by unreasonable expectations for the minimum time-temperature process to be used. These articles outline the artificial nature of the process constraints and describe a scientifically sound means to expand the use of terminal sterilization by identifying the correct process goal-destruction of the bioburden present in the container prior to sterilization. By focusing attention on the correct process target, lower time temperature conditions can be used to expand the use of terminal sterilization to products unable to withstand the harsh conditions that have been mistakenly applied. The first article provides the background, and describes the benefits to patient, producer, and regulator. The second article includes validation and operational advice that can be used in the implementation. PMID- 28089965 TI - Increasing Patient Safety by Closing the Sterile Production Gap-Part 2. Implementation. AB - Terminal sterilization is considered the preferred means for the production of sterile drug products because it affords enhanced safety for the patient as the formulation is filled into its final container, sealed, and sterilized. Despite the obvious patient benefits, the use of terminal sterilization is artificially constrained by unreasonable expectations for the minimum time-temperature process to be used. The core misunderstanding with terminal sterilization is a fixation that destruction of a high concentration of a resistant biological indicator is required. The origin of this misconception is unclear, but it has resulted in sterilization conditions that are extremely harsh (15 min at 121 degrees C, of F0 >8 min), which limit the use of terminal sterilization to extremely heat stable formulations. These articles outline the artificial nature of the process constraints and describe a scientifically sound means to expand the use of terminal sterilization by identifying the correct process goal-the destruction of the bioburden present in the container prior to sterilization. Recognition that the true intention is bioburden destruction in routine products allows for the use of reduced conditions (lower temperatures, shorter process dwell, or both) without added patient risk. By focusing attention on the correct process target, lower time-temperature conditions can be used to expand the use of terminal sterilization to products unable to withstand the harsh conditions that have been mistakenly applied. The first article provides the background, and describes the benefits to patient, producer, and regulator. The second article includes validation and operational advice that can be used in the implementation.LAY ABSTRACT: Terminal sterilization is considered the preferred means for the production of sterile drug products because it affords enhanced safety for the patient as the formulation is filled into its final container, sealed, and sterilized. Despite the obvious patient benefits, the use of terminal sterilization is artificially constrained by unreasonable expectations for the minimum time-temperature process to be used. These articles outline the artificial nature of the process constraints and describe a scientifically sound means to expand the use of terminal sterilization by identifying the correct process goal-the destruction of the bioburden present in the container prior to sterilization. By focusing attention on the correct process target, lower time temperature conditions can be used to expand the use of terminal sterilization to products unable to withstand the harsh conditions that have been mistakenly applied. The first article provides the background, and describes the benefits to patient, producer, and regulator. The article manuscript includes validation and operational advice that can be used in the implementation. PMID- 28089966 TI - Revision of Viable Environmental Monitoring in a Development Pilot Plant Based on Quality Risk Assessment: A Case Study. AB - In this case study, the principles of quality risk management were applied to review sampling points and monitoring frequencies in the hormonal tableting unit of a formulation development pilot plant. In the cleanroom area, premises of different functions are located. Therefore a general method was established for risk evaluation based on the Hazard Analysis and Critical Control Points (HACCP) method to evaluate these premises (i.e., production area itself and ancillary clean areas) from the point of view of microbial load and state in order to observe whether the existing monitoring program met the emerged advanced monitoring practice.LAY ABSTRACT: In pharmaceutical production, cleanrooms are needed for the manufacturing of final dosage forms of drugs-intended for human or veterinary use-in order to protect the patient's weakened body from further infections. Cleanrooms are premises with a controlled level of contamination that is specified by the number of particles per cubic meter at a specified particle size or number of microorganisms (i.e. microbial count) per surface area. To ensure a low microbial count over time, microorganisms are detected and counted by environmental monitoring methods regularly. It is reasonable to find the easily infected places by risk analysis to make sure the obtained results really represent the state of the whole room. This paper presents a risk analysis method for the optimization of environmental monitoring and verification of the suitability of the method. PMID- 28089967 TI - Clinical Orofacial Examination in Juvenile Idiopathic Arthritis: International Consensus-based Recommendations for Monitoring Patients in Clinical Practice and Research Studies. AB - OBJECTIVE: To develop international consensus-based recommendations for the orofacial examination of patients with juvenile idiopathic arthritis (JIA), for use in clinical practice and research. METHODS: Using a sequential phased approach, a multidisciplinary task force developed and evaluated a set of recommendations for the orofacial examination of patients with JIA. Phase 1: A Delphi survey was conducted among 40 expert physicians and dentists with the aim of identifying and ranking the importance of items for inclusion. Phase 2: The task force developed consensus about the domains and items to be included in the recommendations. Phase 3: A systematic literature review was performed to assess the evidence supporting the consensus-based recommendations. Phase 4: An independent group of orofacial and JIA experts were invited to assess the content validity of the task force's recommendations. RESULTS: Five recommendations were developed to assess the following 5 domains: medical history, orofacial symptoms, muscle and temporomandibular joint function, orofacial function, and dentofacial growth. After application of data search criteria, 56 articles were included in the systematic review. The level of evidence for the 5 recommendations was derived primarily from descriptive studies, such as cross-sectional and case control studies. CONCLUSION: Five recommendations are proposed for the orofacial examination of patients with JIA to improve the clinical practice and aid standardized data collection for future studies. The task force has formulated a future research program based on the proposed recommendations. PMID- 28089969 TI - Changes in Treatment Patterns in Patients with Psoriatic Arthritis Initiating Biologic and Nonbiologic Therapy in a Clinical Registry. AB - OBJECTIVE: Treatment options for psoriatic arthritis (PsA) have increased and improved in the past decade; treatment patterns in PsA remain poorly understood. Understanding current practices would aid in treatment management of patients with PsA. METHODS: This observational study was based on data from the Corrona registry of adult patients with PsA in North America collected between January 1, 2004, and December 31, 2012. Patients were divided among 3 therapy cohorts: tumor necrosis factor inhibitor (TNFi) monotherapy, methotrexate (MTX) monotherapy, and TNFi and MTX combination therapy. Patients were further divided among 3 study periods to understand changes over time: 2004-2006, 2007-2009, and 2010-2012. Data were collected on persistence, discontinuation, restarting, switching, adding/dropping therapy, and dose stretching. RESULTS: This study included 520 patients: 190 TNFi monotherapy, 217 MTX monotherapy, and 113 combination therapy; 110 from 2004 to 2006, 192 from 2007 to 2009, and 218 from 2010 to 2012. Over time, the proportion of patients initiating TNFi monotherapy decreased, while the proportion initiating combination therapy remained constant. The percentage of patients who were persistent decreased over time across all therapy cohorts, but remained higher in TNFi monotherapy than in other cohorts. Duration of persistence decreased over time. Patients initiating MTX monotherapy were more likely than their TNFi counterparts to add therapy. CONCLUSION: Treatment patterns in patients with PsA have changed from 2004 to 2012. Physicians are not more likely to initiate TNFi monotherapy, although clinical evidence supporting its effectiveness has increased over this study period, and patients remain more persistent with it. PMID- 28089968 TI - Prevalence of Anti-infliximab Antibodies and Their Associated Co-factors in Children with Refractory Arthritis and/or Uveitis: A Retrospective Longitudinal Cohort Study. AB - OBJECTIVE: Infliximab (IFX) is a monoclonal tumor necrosis factor-alpha inhibiting antibody used in children with refractory arthritis and uveitis. Immunogenicity is associated with a lack of clinical response and infusion reactions in adults; data on immunogenicity in children treated with IFX for rheumatic diseases are scarce. We aimed to describe the prevalence of anti-IFX antibodies and determine co-factors associated with anti-IFX antibodies in children with inflammatory rheumatic and ocular diseases. METHODS: Consecutive children treated between August 2009 and August 2012 with IFX at our department were included. Blood samples were collected every 6 months before IFX infusion and tested for anti-IFX antibodies by radioimmunoassay. Patients' charts were retrospectively reviewed for clinical features and analyzed for associations with anti-IFX antibodies. RESULTS: Anti-IFX antibodies occurred in 14/62 children (23%) and 32/253 blood samples (12.6%) after a mean treatment time of 1084 days (range 73-3498). Infusion reactions occurred in 10/62 (16%) children during the treatment period. With continuation of IFX, anti-IFX antibodies disappeared in 7/14 children. In the bivariate analysis, the occurrence of anti-IFX antibodies was associated with younger age at IFX treatment start (mean age 7.01 vs 9.88 yrs, p = 0.003) and infusion reactions (OR 15.0), while uveitis as treatment indication was protective against development of anti-IFX antibodies (OR 0.17), likely because of higher IFX doses. In the multivariate logistic regression, all 3 covariates remained highly significant. CONCLUSION: Anti-IFX antibodies occurred commonly at any time during IFX treatment. Anti-IFX antibodies were associated with younger age at IFX start, infusion reactions, and arthritis as treatment indication. PMID- 28089970 TI - Spatial Working Memory Impairment in Patients with Non-neuropsychiatric Systemic Lupus Erythematosus: A Blood-oxygen-level Dependent Functional Magnetic Resonance Imaging Study. AB - OBJECTIVE: Using ethology and functional magnetic resonance imaging (fMRI) to explore mild cognitive dysfunction and spatial working memory (WM) impairment in patients with systemic lupus erythematosus (SLE) without overt neuropsychiatric symptoms (non-NPSLE) and to study whether any clinical biomarkers could serve as predictors of brain dysfunction in this disease. METHODS: Eighteen non-NPSLE patients and 18 matched subjects were all tested using the Montreal cognitive assessment scale test and scanned using blood-oxygen-level dependent fMRI while performing the n-back task to investigate the activation intensity of some cognition-related areas. RESULTS: Ethology results showed that non-NPSLE patients had mild cognitive dysfunction and memory dysfunction (p < 0.05). The fMRI scan confirmed a neural network consisting of bilateral dorsolateral prefrontal cortex (DLPFC), premotor area, parietal lobe, and supplementary motor area (SMA)/anterior cingulate cortex (ACC) that was activated during the n-back task, with right hemisphere dominance. However, only the right SMA/ACC showed a load effect in the non-NPSLE group; the activation intensity of most WM-related brain areas for the non-NPSLE group was lower than for the control group under 3 memory loads. Further, we found that the activation intensity of some cognition-related areas, including the bilateral caudate nucleus/insula and hippocampus/parahippocampal gyrus were lower than the control group under the memory loads. An inverse correlation existed between individual activation intensity and disease duration. CONCLUSION: Non-NPSLE-related brain damage with right DLPFC-posterior parietal lobe and parahippocampal gyrus default network causes impairment of spatial WM and mild cognitive dysfunction. Patients with longer disease duration would be expected to exhibit increased central nervous system damage. PMID- 28089971 TI - Incidence of Malignancy Prior to Antineutrophil Cytoplasmic Antibody-associated Vasculitis Compared to the General Population. AB - OBJECTIVE: Previous studies have reported an increased malignancy risk preceding antineutrophil cytoplasmic antibody-associated vasculitis (AAV), suggesting common pathogenic pathways in these 2 entities. However, the study results were conflicting and often limited to patients with granulomatosis with polyangiitis (GPA). Here, we study the malignancy risk prior to AAV diagnosis [either GPA or microscopic polyangiitis (MPA)] to elaborate on the putative association between malignancy and AAV. METHODS: A total of 203 patients were selected for the current study. Malignancies prior to AAV diagnosis were identified using a nationwide pathology database, and their occurrence was verified by reviewing the medical files of 145 patients (71.4%). The malignancy incidence was compared to the general population by calculation of standardized incidence ratios (SIR), matching for sex, age, and time period. SIR were calculated for 2 intervals: < 2 years and >= 2 years prior to AAV diagnosis. Separate analyses were performed for GPA and MPA. RESULTS: The overall risk for malignancy prior to AAV diagnosis was similar to that of the general population (SIR 0.96, 95% CI 0.55-1.57), as was true when risks were analyzed by malignancy type, including skin, bladder, kidney, lung, stomach, rectum, and uterus (SIR ranged from 1.64 to 4.14). We found no significant difference in malignancy risk between patients with GPA and MPA. CONCLUSION: Our findings do not support the hypothesis that preceding malignancies and AAV have a causal relationship or shared pathogenic pathways. PMID- 28089972 TI - A Preliminary Core Domain Set for Clinical Trials of Shoulder Disorders: A Report from the OMERACT 2016 Shoulder Core Outcome Set Special Interest Group. AB - OBJECTIVE: The Outcome Measures in Rheumatology (OMERACT) Shoulder Core Outcome Set Special Interest Group (SIG) was established to develop a core outcome set (COS) for clinical trials of shoulder disorders. METHODS: In preparation for OMERACT 2016, we systematically examined all outcome domains and measurement instruments reported in 409 randomized trials of interventions for shoulder disorders published between 1954 and 2015. Informed by these data, we conducted an international Delphi consensus study including shoulder trial experts, clinicians, and patients to identify key domains that should be included in a shoulder disorder COS. Findings were discussed at a stakeholder premeeting of OMERACT. At OMERACT 2016, we sought consensus on a preliminary core domain set and input into next steps. RESULTS: There were 13 and 15 participants at the premeeting and the OMERACT 2016 SIG meeting, respectively (9 attended both meetings). Consensus was reached on a preliminary core domain set consisting of an inner core of 4 domains: pain, physical function/activity, global perceived effect, and adverse events including death. A middle core consisted of 3 domains: emotional well-being, sleep, and participation (recreation and work). An outer core of research required to inform the final COS was also formulated. CONCLUSION: Our next steps are to (1) analyze whether participation (recreation and work) should be in the inner core, (2) conduct a third Delphi round to finalize definitions and wording of domains and reach final endorsement for the domains, and (3) determine which instruments fulfill the OMERACT criteria for measuring each domain. PMID- 28089973 TI - Malignancies in Patients with Anti-RNA Polymerase III Antibodies and Systemic Sclerosis: Analysis of the EULAR Scleroderma Trials and Research Cohort and Possible Recommendations for Screening. AB - OBJECTIVE: To analyze the characteristics of anti-RNA polymerase III antibodies (anti-RNAP3)- positive patients with systemic sclerosis (SSc) in the European League Against Rheumatism Scleroderma Trials and Research group (EUSTAR) registry with a focus on the risk of cancer and the characteristics of malignancies, and the aim to provide guidelines about potential cancer screening in these patients. METHODS: (1) Analysis of the EUSTAR database: 4986 patients with information on their anti-RNAP3 status were included. (2) Case-control study: additional retrospective data, including malignancy history, were queried in 13 participating EUSTAR centers; 158 anti-RNAP3+ cases were compared with 199 local anti-RNAP3- controls, matched for sex, cutaneous subset, disease duration, and age at SSc onset. (3) A Delphi exercise was performed by 82 experts to reach consensus for cancer screening in anti-RNAP3+ patients. RESULTS: In the EUSTAR registry, anti-RNAP3 were associated in multivariable analysis with renal crisis and diffuse cutaneous involvement. In the case-control study, anti-RNAP3 were associated with gastric antral vascular ectasia, rapid progression of skin involvement, and malignancies concomitant to SSc onset (OR 7.38, 95% CI 1.61 33.8). When compared with other anti-RNAP3+ patients, those with concomitant malignancies had older age (p < 0.001) and more frequent diffuse cutaneous involvement (p = 0.008). The Delphi exercise highlighted the need for malignancy screening at the time of diagnosis for anti-RNAP3+ patients and tight followup in the following years. CONCLUSION: Anti-RNAP3+ patients with SSc have a high risk of concomitant malignancy. These results have implications for clinical practice and suggest regular screening for cancer in anti-RNAP3+ patients. PMID- 28089974 TI - Cardiopulmonary Disease Development in Anti-RNA Polymerase III-positive Systemic Sclerosis: Comparative Analyses from an Unselected, Prospective Patient Cohort. AB - OBJECTIVE: Extensive skin disease and renal crisis are hallmarks of anti-RNA polymerase III (RNAP)-positive systemic sclerosis (SSc), while lung and heart involvement data are conflicting. Here, the aims were to perform time-course analyses of interstitial lung disease (ILD) and pulmonary hypertension (PH) in the RNAP subset of a prospective unselected SSc cohort and to use the other autoantibody subsets as comparators. METHODS: The study cohort included 279 patients with SSc from the observational Oslo University Hospital cohort with complete data on (1) SSc-related autoantibodies, (2) paired, serial analyses of lung function and fibrosis by computed tomography, and (3) PH verified by right heart catheterization. RESULTS: RNAP was positive in 33 patients (12%), 79% of which had diffuse cutaneous SSc. Pulmonary findings were heterogeneous; 49% had no signs of fibrosis while 18% had > 20% fibrosis at followup. Forced vital capacity at followup was < 80% in 39% of the RNAP subset, comparable to the antitopoisomerase subset (ATA; 47%), but higher than anticentromere (ACA; 13%). Accumulated frequency of PH in the RNAP subset (12%) was lower than in ACA (18%). At 93% and 78%, the 5- and 10-year survival rates in RNAP were comparable to the ATA and ACA subsets. CONCLUSION: In this cohort, the RNAP subset was marked by cardiopulmonary heterogeneity, ranging from mild ILD to development of severe ILD in 18%, and PH development in 12%. These data indicate that cardiopulmonary risk stratification early in the disease course is particularly important in RNAP positive SSc. PMID- 28089975 TI - In Vitro Fertilization in 37 Women with Systemic Lupus Erythematosus or Antiphospholipid Syndrome: A Series of 97 Procedures. AB - OBJECTIVE: To compile and assess data about complication and success rates for in vitro fertilization (IVF) of women with systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). To date, such data are sparse. METHODS: This retrospective study described women with SLE and/or APS who have had at least 1 IVF cycle. RESULTS: Thirty-seven women with SLE (n = 23, including 8 with antiphospholipid antibodies), SLE with APS (n = 4), or primary APS (n = 10) underwent 97 IVF procedures. For 43% of cases, the infertility was female in origin, for 19% male, 14% mixed, and 24% unexplained. No women had premature ovarian insufficiency because of cyclophosphamide. Median age at IVF was 34 years (range 26-46). The median number of IVF cycles was 2.6 (1-8). Patients were treated with hydroxychloroquine (72%), steroids (70%), azathioprine (3%), aspirin (92%), and/or low molecular weight heparin (62%). There were 27 (28%) pregnancies, 23 live births among 26 neonates (3 twin pregnancies), 2 miscarriages, and 2 terminations for trisomy 13 and 21. Six spontaneous pregnancies occurred during the followup. Finally, 26 women (70%) delivered at least 1 healthy child. Complications occurred in or after 8 IVF cycles (8%): SLE flares in 4 (polyarthritis in 3 and lupus enteritis in 1) and thromboembolic events in 4 others. One SLE flare was the first sign of previously undiagnosed SLE. Poor treatment adherence was obvious in 2 other flares and 2 thromboses. No ovarian hyperstimulation syndrome was reported. CONCLUSION: These preliminary results confirm that IVF can be safely and successfully performed in women with SLE and/or APS. PMID- 28089976 TI - Disease Characteristics and Rheumatoid Arthritis Development in Patients with Early Undifferentiated Arthritis: A 2-year Followup Study. AB - OBJECTIVE: To examine the 2-year disease course in patients with undifferentiated arthritis (UA) focusing on fulfillment of the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) rheumatoid arthritis (RA) classification criteria. METHODS: Data were provided by the Norwegian Very Early Arthritis Clinic study, which included patients presenting with >= 1 swollen joint of <= 16 weeks' duration. UA was defined as patients not fulfilling the 2010 ACR/EULAR RA criteria and who did not have a clinical diagnosis other than RA at baseline. The main outcome was fulfillment of the 2010 RA criteria. Secondary outcomes were disease-modifying antirheumatic drug (DMARD) use, resolution of synovitis without use of DMARD during followup, and final clinical diagnosis. RESULTS: We included 477 patients with UA of whom 47 fulfilled the 2010 ACR/EULAR RA criteria during followup (UA-RA) and 430 did not (UA-non-RA). Of the UA-RA patients, 70% fulfilled the criteria within the first 6 months. UA RA patients were older, more often positive for rheumatoid factor and anticitrullinated protein antibodies, female, and ever smokers, and they more often presented with polyarticular arthritis, small joint involvement, and a swollen shoulder joint. During followup, 53% of UA-RA patients vs 13% of UA-non RA patients used DMARD (p < 0.001). Overall, 71% of patients with UA achieved absence of clinical synovitis at final followup without use of DMARD. The most frequent final clinical diagnosis was UA (61%). CONCLUSION: Only 9.8% of patients with UA fulfilled the 2010 RA criteria during 2-year followup. Small joint involvement and swollen shoulder joint were among the factors associated with RA development. In two-thirds of patients with UA, the arthritis resolved without use of DMARD. PMID- 28089977 TI - Antimelanoma Differentiation-associated Gene 5 Antibody: Expanding the Clinical Spectrum in North American Patients with Dermatomyositis. AB - OBJECTIVE: To determine the clinical features associated with the antimelanoma differentiation-associated gene 5 antibody (anti-MDA5) in US patients with clinically amyopathic dermatomyositis (CADM) and classic DM. METHODS: Patients with CADM were consecutively selected from the University of Pittsburgh Myositis Database from 1985 to 2013. CADM was defined by a typical DM rash without objective muscle weakness and no or minimal abnormalities of muscle enzymes, electromyography, or muscle biopsy. DM was defined by Bohan and Peter criteria and was 1:1 matched (sex and age +/- 5 yrs) to patients with CADM. Anti-MDA5 autoAb levels were determined using ELISA. Clinical features were compared between CADM and DM and between MDA5-positive and MDA5-negative subjects, using chi-squared and/or Mann-Whitney U tests as appropriate. RESULTS: We identified 61 patients with CADM who were matched to 61 DM controls (female 62% vs 64%; mean age 44.8 yrs vs 48.2, p < 0.5). Anti-MDA5 frequency was the same in both cohorts (13.1%), and anti-MDA5 was significantly associated with a higher likelihood of cutaneous ulcers, digital tip ulcerations, and puffy fingers as well as interstitial lung disease (ILD). Most patients with ILD had rapidly progressive ILD (RPILD) leading to early death. Patients with CADM were more likely to have dysphagia, but there were no other clinical differences seen associated with CADM as compared to classic DM. CONCLUSION: Anti-MDA5 positivity had a similar frequency in US patients with CADM and DM and is associated with ILD, RPILD, cutaneous ulcers, digital tip ulceration, and poor survival. PMID- 28089978 TI - Rituximab Retreatment in Rheumatoid Arthritis in a Real-life Cohort: Data from the CERERRA Collaboration. AB - OBJECTIVE: Several aspects of rituximab (RTX) retreatment in rheumatoid arthritis (RA) need to be further elucidated. The aim of this study was to describe the effect of repeated courses of RTX on disease activity and to compare 2 retreatment strategies, fixed-interval versus on-flare retreatment, in a large international, observational, collaborative study. METHODS: In the first analysis, patients with RA who received at least 4 cycles with RTX were included. In the second analysis, patients who received at least 1 RTX retreatment and for whom information about the strategy for retreatment was available were identified. Two retreatment strategies (fixed-interval vs on-flare) were compared by fitting-adjusted, mixed-effects models of 28-joint Disease Activity Score (DAS28) over time for first and second retreatment. RESULTS: A total of 1530 patients met the eligibility criteria for the first analysis. Significant reductions of mean DAS28 between the starts of subsequent treatment cycles were observed (at start of first treatment cycle: 5.5; second: 4.3; third: 3.8; and fourth: 3.5), suggesting improved response after each additional cycle (p < 0.0001 for all pairwise comparisons). A total of 800 patients qualified for the second analysis: 616 were retreated on flare and 184 at fixed interval. For the first retreatment, the fixed-interval retreatment group yielded significantly better results than the on-flare group (estimated marginal mean DAS28 = 3.8, 95% CI 3.6-4.1 vs 4.6, 95% CI 4.5-4.7, p < 0.0001). Similar results were found for the second retreatment. CONCLUSION: Repeated treatment with RTX leads to further clinical improvement after the first course of RTX. A fixed-interval retreatment strategy seems to be more effective than on-flare retreatment. PMID- 28089979 TI - Quality of Care for Systemic Lupus Erythematosus: Mind the Knowledge Gap. AB - Systemic lupus erythematosus (SLE) is a prototypical chronic multiorgan autoimmune disorder that can lead to significant burden of disease and loss of life expectancy. The disease burden is the result of a complex interplay between genetic, biologic, socioeconomic, and health system variables affecting the individual. Recent advances in biological understanding of SLE are yet to translate to transformative therapies, and genetic and socioeconomic variables are not readily amenable to intervention. In contrast, healthcare quality, a variable readily amenable to change, has been inadequately addressed in SLE, despite evidence in other chronic diseases that quality of care is strongly associated with patient outcomes. This article will analyze the available literature on the quality of care relevant to SLE, identify knowledge gaps, and suggest ways to address this in future research. PMID- 28089980 TI - Sex-specific Relationship of Serum Uric Acid with All-cause Mortality in Adults with Normal Kidney Function: An Observational Study. AB - OBJECTIVE: To explain the clinical effect of serum uric acid (SUA) levels as a risk factor for mortality, considering exclusion of kidney function. METHODS: Participants aged over 40 years who underwent health checkups were recruited. Individuals with estimated glomerular filtrations rates < 60 ml/min/1.73 m2 and who received laboratory study and colonoscopy on the same day were excluded. RESULTS: SUA levels were higher in men than in women (5.7 +/- 1.2 mg/dl for men and 4.2 +/- 0.9 mg/dl for women, p < 0.001). During 12.3 +/- 3.6 years of followup, 1402 deaths occurred among 27,490 participants. About 6.9% of men and 3.1% of women died. The overall mortality rate had a U-shaped association with SUA levels, a U-shaped association in men, and no association in women. There was a significant interaction of sex for the SUA-mortality association (p for interaction = 0.049); therefore, survival analysis was conducted by sex. In men, the lower SUA group had a higher mortality rate after adjustment (SUA <= 4.0 mg/dl, adjusted HR 1.413, 95% CI 1.158-1.724, p = 0.001) compared with the reference group (SUA 4.1-6.0 mg/dl). A higher SUA contributed to an insignificant increased mortality in men (> 8.0 mg/dl, adjusted HR 1.140, 95% CI 0.794-1.636, p = 0.479). Women failed to show any significant association between SUA and mortality. CONCLUSION: This study provided novel evidence that SUA-mortality association differed by sex. We demonstrated that a lower SUA was an independent risk factor for all-cause mortality in men with normal kidney function. PMID- 28089981 TI - Sleep Disturbances and Neurobehavioral Performance in Juvenile Idiopathic Arthritis. AB - OBJECTIVE: To examine the extent of polysomnographic (PSG) sleep disturbances [obstructive apnea hypopnea index (OAHI), number of wake bouts, arousals, periodic limb movements] and the effect of OAHI on neurobehavioral performance in juvenile idiopathic arthritis (JIA) with obstructive sleep apnea (OSA), JIA without OSA, and controls without OSA, adjusting for intelligence quotient (IQ), pain, medications, daytime sleepiness, and wake bouts. METHODS: Children 6-11 years, 68 with JIA and 67 controls, underwent 1 night of PSG and completed self reported daytime sleepiness surveys, multiple sleep latency tests for physiological sleepiness, and neurobehavioral performance tests the next day. RESULTS: Compared with JIA and controls without OSA, mean OAHI and arousals were significantly higher in JIA with OSA (p < 0.001, respectively). In comparison with JIA and controls without OSA, mean simple reaction time and sustained attention were significantly slower in JIA with OSA, adjusting for IQ, pain, any medication, daytime sleepiness, and wake bouts. CONCLUSION: Elevated OAHI is suggestive of obstructive sleep apnea and a comorbidity in JIA that may predispose children with JIA to daytime sleepiness and impaired neurobehavioral performance. PMID- 28089983 TI - Detailed Analysis of the Articular Domain in Patients with Primary Sjogren Syndrome. AB - OBJECTIVE: We used the 28-joint Disease Activity Score (DAS28) and the European League Against Rheumatism Sjogren's Syndrome Disease Activity Index (ESSDAI) articular domain to assess the effect of rituximab (RTX) and abatacept (ABA) on articular involvement in primary Sjogren syndrome (pSS). METHODS: Patients with pSS treated with RTX (n = 18) or ABA (n = 13) and having a DAS28 erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) level >= 3.2 at baseline were selected. Generalized estimating equations were used to analyze the DAS28 and ESSDAI articular domain over time. RESULTS: In the RTX group, DAS28-ESR/CRP decreased significantly up to 48 weeks. In the ABA group, DAS28-ESR/CRP decreased significantly up to 24 weeks. DAS28 correlated significantly with ESSDAI articular domain. CONCLUSION: DAS28 is useful to evaluate the effect of biologicals on articular involvement in patients with pSS. PMID- 28089982 TI - Fragility Fractures Are Associated with an Increased Risk for Cardiovascular Events in Women and Men with Rheumatoid Arthritis: A Population-based Study. AB - OBJECTIVE: Women and men with rheumatoid arthritis (RA) have an increased risk for fragility fractures and cardiovascular disease (CVD), each of which has been reported to contribute to excess morbidity and mortality in these patients. Fragility fractures share similar risk factors for CVD but may occur at relatively younger ages in patients with RA. We aimed to determine whether a fragility fracture predicts the development of CVD in women and men with RA. METHODS: We studied a population-based cohort with incident RA from 1955 to 2007 and compared it with age- and sex-matched non-RA subjects. We identified fragility fractures and CVD events following the RA incidence/index date, along with relevant risk factors. We used Cox models to examine the association between fractures and the development of CVD, in which fractures and CVD risk factors were modeled as time-dependent covariates. RESULTS: There were 1171 subjects (822 women; 349 men) in each of the RA and non-RA cohorts. Over followup, there were 406 and 346 fragility fractures and 286 and 225 CVD events, respectively. The overall CVD risk was increased significantly for RA subjects following a fragility fracture (HR 1.81, 95% CI 1.38-2.37) but not for non-RA subjects (HR 1.18, 95% CI 0.85-1.63). Results were similar for women and men with RA. CONCLUSION: Fragility fractures in both women and men with RA are associated with an increased risk for CVD events and should raise an alert to clinicians to target these individuals for further screening and preventive strategies for CVD. PMID- 28089984 TI - Achieving Consensus on Total Joint Replacement Trial Outcome Reporting Using the OMERACT Filter: Endorsement of the Final Core Domain Set for Total Hip and Total Knee Replacement Trials for Endstage Arthritis. AB - OBJECTIVE: Discussion and endorsement of the OMERACT total joint replacement (TJR) core domain set for total hip replacement (THR) and total knee replacement (TKR) for endstage arthritis; and next steps for selection of instruments. METHODS: The OMERACT TJR working group met at the 2016 meeting at Whistler, British Columbia, Canada. We summarized the previous systematic reviews, the preliminary OMERACT TJR core domain set and results from previous surveys. We discussed preliminary core domains for TJR clinical trials, made modifications, and identified challenges with domain measurement. RESULTS: Working group participants (n = 26) reviewed, clarified, and endorsed each of the inner and middle circle domains and added a range of motion domain to the research agenda. TJR were limited to THR and TKR but included all endstage hip and knee arthritis refractory to medical treatment. Participants overwhelmingly endorsed identification and evaluation of top instruments mapping to the core domains (100%) and use of subscales of validated multidimensional instruments to measure core domains for the TJR clinical trial core measurement set (92%). CONCLUSION: An OMERACT core domain set for hip/knee TJR trials has been defined and we are selecting instruments to develop the TJR clinical trial core measurement set to serve as a common foundation for harmonizing measures in TJR clinical trials. PMID- 28089985 TI - Giant Cell Arteritis-related Stroke: A Retrospective Multicenter Case-control Study. AB - OBJECTIVE: Our aim was to describe patients with giant cell arteritis (GCA) related stroke and to compare them with a control group of GCA patients without stroke. METHODS: We created a retrospective multicenter cohort of patients with (1) GCA diagnosed according to the American College of Rheumatology criteria between 1995 and 2015, and (2) stroke occurring at the time of GCA diagnosis or occurring within 4 weeks of starting GCA therapy. The control group consisted of GCA patients without stroke. RESULTS: Forty patients [21 women (53%), median age 78 (60-91) yrs] with GCA-related stroke were included and were compared with 200 control patients. Stroke occurred at GCA diagnosis in 29 patients (73%), whereas it occurred after diagnosis in 11 patients. Vertebrobasilar territory was involved in 29 patients (73%). Seven patients died within a few hours or days following stroke. Compared with the control group, stroke patients had more ophthalmic ischemic symptoms [25 (63%) vs 50 (25%), p < 0.001]. Conversely, they demonstrated lower biological inflammatory variables [C-reactive protein: 61 (28 185) mg/l vs 99 (6-400) mg/l, p = 0.04] and less anemia [22/37 (59%) vs 137/167 (79%), p = 0.03] than patients without stroke. Multivariate logistic regression revealed that the best predictors for the occurrence of stroke were the presence of ophthalmic ischemic symptoms at diagnosis (OR 5, 95% CI 2.14-12.33, p = 0.0002) and the absence of anemia (OR 0.39, 95% CI 0.16-0.99, p = 0.04). CONCLUSION: Stroke, especially in the vertebrobasilar territory, is more likely to occur in patients with GCA who experience recent ophthalmic ischemic symptoms and who exhibit low inflammatory variables. PMID- 28089986 TI - Estimating glomerular filtration rate for the full age spectrum from serum creatinine and cystatin C. AB - Background: We recently published and validated the new serum creatinine (Scr) based full-age-spectrum equation (FAS crea ) for estimating the glomerular filtration rate (GFR) for healthy and kidney-diseased subjects of all ages. The equation was based on the concept of normalized Scr and shows equivalent to superior prediction performance to the currently recommended equations for children, adolescents, adults and older adults. Methods: Based on an evaluation of the serum cystatin C (ScysC) distribution, we defined normalization constants for ScysC ( Q cysC = 0.82 mg/L for ages <70 years and Q cysC = 0.95 mg/L for ages >=70 years). By replacing Scr/ Q crea in the FAS crea equation with ScysC/ Q cysC , or with the average of both normalized biomarkers, we obtained new ScysC-based (FAS cysC ) and combined Scr-/ScysC-based FAS equations (FAS combi ). To validate the new FAS cysC and FAS combi we collected data on measured GFR, Scr, ScysC, age, gender, height and weight from 11 different cohorts including n = 6132 unique white subjects (368 children, aged <=18 years, 4295 adults and 1469 older adults, aged >=70 years). Results: In children and adolescents, the new FAS cysC equation showed significantly better performance [percentage of patients within 30% of mGFR (P30) = 86.1%] than the Caucasian Asian Paediatric Adult Cohort equation (P30 = 76.6%; P < 0.0001), or the ScysC based Schwartz equation (P30 = 68.8%; P < 0.0001) and the FAS combi equation outperformed all equations with P30 = 92.1% (P < 0.0001). In adults, the FAS cysC equation (P30 = 82.6%) performed equally as well as the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI cysC ) (P30 = 80.4%) and the FAS combi equation (P30 = 89.9%) was also equal to the combined CKD-EPI equation (P30 = 88.2%). In older adults, FAS cysC was superior (P30 = 88.2%) to CKD-EPI cysC (P30 = 84.4%; P < 0.0001) and the FAS combi equation (P30 = 91.2%) showed significantly higher performance than the combined CKD-EPI equation (P30 = 85.6%) (P < 0.0001). Conclusion: The FAS equation is not only applicable to all ages, but also for all recommended renal biomarkers and their combinations. PMID- 28089987 TI - New Editor on Journal of Cell Science. PMID- 28089989 TI - RhoA regulates actin network dynamics during apical surface emergence in multiciliated epithelial cells. AB - Homeostatic replacement of epithelial cells from basal precursors is a multistep process involving progenitor cell specification, radial intercalation and, finally, apical surface emergence. Recent data demonstrate that actin-based pushing under the control of the formin protein Fmn1 drives apical emergence in nascent multiciliated epithelial cells (MCCs), but little else is known about this actin network or the control of Fmn1. Here, we explore the role of the small GTPase RhoA in MCC apical emergence. Disruption of RhoA function reduced the rate of apical surface expansion and decreased the final size of the apical domain. Analysis of cell shapes suggests that RhoA alters the balance of forces exerted on the MCC apical surface. Finally, quantitative time-lapse imaging and fluorescence recovery after photobleaching studies argue that RhoA works in concert with Fmn1 to control assembly of the specialized apical actin network in MCCs. These data provide new molecular insights into epithelial apical surface assembly and could also shed light on mechanisms of apical lumen formation. PMID- 28089995 TI - Systematic evaluation of markers used for the identification of human induced pluripotent stem cells. AB - Low efficiency of somatic cell reprogramming and heterogeneity among human induced pluripotent stem cells (hiPSCs) demand extensive characterization of isolated clones before their use in downstream applications. By monitoring human fibroblasts undergoing reprogramming for their morphological changes and expression of fibroblast (CD13), pluripotency markers (SSEA-4 and TRA-1-60) and a retrovirally expressed red fluorescent protein (RV-RFP), we compared the efficiency of these features to identify bona fide hiPSC colonies. The co expression kinetics of fibroblast and pluripotency markers in the cells being reprogrammed and the emerging colonies revealed the heterogeneity within SSEA-4+ and TRA-1-60+ cells, and the inadequacy of these commonly used pluripotency markers for the identification of bona fide hiPSC colonies. The characteristic morphological changes in the emerging hiPSC colonies derived from fibroblasts expressing RV-RFP showed a good correlation between hiPSC morphology acquisition and silencing of RV-RFP and facilitated the easy identification of hiPSCs. The kinetics of retroviral silencing and pluripotency marker expression in emerging colonies suggested that combining both these markers could demarcate the stages of reprogramming with better precision than with pluripotency markers alone. Our results clearly demonstrate that the pluripotency markers that are routinely analyzed for the characterization of established iPSC colonies are not suitable for the isolation of pluripotent cells in the early stages of reprogramming, and silencing of retrovirally expressed reporter genes helps in the identification of colonies that have attained a pluripotent state and the morphology of human embryonic stem cells (hESCs). PMID- 28089996 TI - A comparison of lobectomy and total thyroidectomy in patients with papillary thyroid microcarcinoma: a retrospective individual risk factor-matched cohort study. AB - OBJECTIVE: Papillary thyroid microcarcinoma (PTMC) accounts for most of the increase in thyroid cancer in recent decades. We compared clinical outcomes and surgical complications of lobectomy and total thyroidectomy (TT) in PTMC patients. DESIGN AND METHODS: In this retrospective individual risk factor matched cohort study, 2031 patients with PTMC were initially included. Patients who underwent lobectomy or TT were one-to-one matched according to individual risk factors, including age, sex, primary tumor size, extrathyroidal extension, multifocality and cervical lymph node (LN) metastasis. RESULTS: In total, 688 patients were assigned to each group. During the median 8.5 years of follow-up, 26 patients (3.8%) in the lobectomy group and 11 patients (1.6%) in the TT group had recurrences. The relative risk of recurrence was significantly less in the TT than that in the lobectomy group (hazard ratio (HR) 0.41; 95% confidence interval (CI) 0.21-0.81; P = 0.01). Most recurrences (84.6%) in the lobectomy group occurred in the contralateral lobe, and all patients were disease-free after completion of thyroidectomy. There were no significant differences in recurrence free survival between the two groups after exclusion of contralateral lobe recurrences (HR, 2.75; 95% CI, 0.08-8.79; P = 0.08). There were significantly more patients with transient and permanent hypoparathyroidism in the TT than that in the lobectomy group (P < 0.001). CONCLUSIONS: Lobectomy could be appropriate for most patients with PTMC when there is no evidence of extrathyroidal disease in the preoperative work-up. Preoperative and postoperative imaging studies are important for patients who undergo lobectomy for PTMC, because most recurrences are in the contralateral lobe. PMID- 28089998 TI - First Clinical Experience With Targeted REnal Nerve Demodulation (TREND-1) Using a Neurotropic Agent for the Treatment of Sympathetic Hypertension. AB - AIMS: To evaluate the feasibility and safety of a novel targeted neuromodulatory treatment for sympathetic hypertension involving a one-time local injection of neurotropic agents near renal nerves. METHODS AND RESULTS: Seven patients suffering from uncontrolled hypertension per ESH-ESC guidelines were treated using a single dose of NW2013, a neurotropic Na+/K+ ATPase antagonist. A microneedle catheter was used to administer 1.2 mL of NW2013 (0.6 mL per artery) to the perivascular space surrounding renal arteries using percutaneous endovascular procedures under fluoroscopic guidance. All patients were successfully treated without any procedural complications. Patients were followed for 12 months post procedure, and office and 24-hour ambulatory blood pressure measurements were made. Both office and ambulatory blood pressures were lower at 24 hours, 1 month, and 3 months after treatment. The decrease in office blood pressure was greater than the decrease in ambulatory blood pressure. A reduction in medication regimen was also observed in 2 patients. One patient suffered a cerebrovascular event after 6-month follow-up and died from stroke, unrelated to the treatment. Overall, the reduction in office and ambulatory blood pressure was sustained over the course of 12 months. CONCLUSIONS: Treatment of hypertension using local administration of NW2013 near renal nerves appears to be feasible and safe. Large, controlled, randomized, and blinded clinical studies with monitoring of patient compliance to daily oral medication are recommended to further establish the efficacy of this novel treatment. PMID- 28089997 TI - The Impact of Age and Sex on In-Hospital Outcomes of Chronic Total Occlusion Percutaneous Coronary Intervention. AB - OBJECTIVES: We sought to determine the effect of age and sex on procedural outcomes and efficiency of chronic total occlusion (CTO) percutaneous coronary intervention (PCI). METHODS: We examined the clinical and angiographic characteristics and outcomes of 1675 CTO-PCIs performed in 1644 patients between 2012 and 2016 at 15 United States centers. RESULTS: Mean age was 65.3 +/- 10 years and 1408 (86%) were men. Overall technical and procedural success rates were 88% and 87%, respectively. Increasing age was associated with more comorbidities (dyslipidemia, hypertension, prior coronary artery bypass graft surgery, prior stroke, peripheral arterial disease, and chronic lung disease) and more lesion calcification. As compared with the reference age of <65 years, age >75 years was independently associated with technical failure (odds ratio [OR], 2.28; 95% confidence interval [CI], 1.20-4.28). Increasing age was also independently associated with the incidence of major adverse cardiovascular events (MACEs; OR, 2.93; 95% CI, 1.10-9.23 for 65-75 years and OR, 5.71; 95% CI, 1.89-19.60 for >75 years). Compared with men, women (n = 236; 14%) were older (66.8 +/- 11.1 years vs 65.0 +/- 9.8 years; P=.02), but had similar clinical characteristics and lower J-CTO scores (2.3 +/- 1.3 vs 2.5 +/- 1.2; P=.02). Although crude technical success rate was higher in women compared with men (92% vs 87%; P=.04), multivariable analysis did not show independent association between sex and technical failure (OR, men/women, 1.66; 95% CI, 0.86-3.50) or MACE (OR, 0.61; 95% CI, 0.25-1.73). CONCLUSIONS: Older age, but not sex, is associated with lower technical success and higher in-hospital complication rate for CTO-PCI. CTO-PCI is relatively infrequently attempted in women, despite high technical success and acceptable complication rates. PMID- 28089999 TI - Impact of Impaired Renal Function in Patients With Severely Calcified Coronary Lesions Treated With Orbital Atherectomy. AB - OBJECTIVES: We evaluated the clinical outcomes of patients with chronic kidney disease (CKD) who underwent orbital atherectomy for severe coronary artery calcification (CAC) prior to stent implantation. BACKGROUND: Percutaneous coronary intervention (PCI) of lesions with severe CAC is associated with increased rates of adverse clinical events. Patients with CKD are at increased risk for atherosclerotic cardiovascular disease, including vascular calcification, and have worse outcomes after PCI. METHODS: Of the 456 consecutive real-world patients in our retrospective multicenter registry with severe CAC who underwent orbital atherectomy, 88 patients (19.3%) had CKD (creatinine >=1.5 mg/dL). The primary endpoint was the 30-day rate of major adverse cardiac and cerebrovascular event (MACCE), defined as death, myocardial infarction (MI), target-vessel revascularization (TVR), and stroke. RESULTS: The CKD group had a higher prevalence of diabetes mellitus and hypertension as well as a lower mean left ventricular ejection fraction. The primary endpoint was similar in the CKD and non-CKD groups (3.4% vs 1.9%; P=.40), as were 30-day rates of death (2.2% vs 1.1%; P=.30), MI (1.1% vs 0.5%; P=.40), TVR (0% vs 0%; P>.99), and stroke (0% vs 0.3%; P>.99). Angiographic complications and stent thrombosis rates were low and did not differ between the two groups. CONCLUSION: Despite higher-risk baseline characteristics, patients with CKD had no significant differences in MACCE. Orbital atherectomy represents a reasonable treatment strategy for the treatment of severe CAC in patients with CKD. A prospective randomized trial with long-term follow-up is needed to identify the optimal treatment for these patients. PMID- 28090000 TI - Neoatherosclerosis in the Iliac Artery Stent - Insights From Optical Coherence Tomography and Intravascular Ultrasound. PMID- 28090001 TI - Assessment of Atherosclerosis - Vascular Imaging Tests and Vascular Function Tests. PMID- 28090002 TI - Easy detection of hormone secretion from LbetaT2 cells by using Gaussia luciferase. AB - Reproduction is regulated by gonadotropins secreted from gonadotrophs. The production and secretion of gonadotropins are mainly regulated by gonadotropin releasing hormone (GnRH). Agonists or antagonists that influence GnRH action on gonadotrophs are important to regulate reproduction; however, these factors have not been fully characterized due to the lack of simple and easy-to-use techniques to detect gonadotropin secretion from gonadotropin-producing cells. In the present study, we found that Gaussia luciferase (Gluc), which was expressed in LbetaT2 cells, can be secreted like a luteinizing-hormone (LH) upon stimulation with GnRH. The Gluc secreted into the medium was easily monitored as luminescence signals. The detection range of the GnRH-induced Gluc activity was comparable to that of the enzyme-linked immunosorbent assay for LH. In addition, when the Gluc was expressed in AtT20 cells, which produce adrenocorticotropic hormone (ACTH), the Gluc activity in the medium increased in parallel with the ACTH secretion upon stimulation with corticotropin-releasing hormone. Thus, the Gluc assay in the present study can be easily used for high-throughput screening of factors that influence LH or ACTH secretion from LbetaT2 or AtT20 cells, respectively. PMID- 28090004 TI - Difference in Dynamic Body Balance between Forward and Lateral Single-Leg Hop Landing. AB - Since the loss of balance can result in falls or lower extremity injuries during sports or daily activities, quantitative evaluation of one's ability to maintain balance with changes in the direction of motion is crucial. The present study aimed to assess whether the trajectory length of the center of pressure (COP) and peak values of the ground reaction force (GRF) following a single-leg hop landing differ when hopping forward or laterally, and to ascertain disparities in balance characteristics due to differences in hop direction. Twenty-four young volunteers (mean age, 22.1 years) were asked to stand on one foot on a level floor, take a half step in the forward and lateral directions, and land on one foot, repeating this task ten times on each leg. Data measured in this study included COP trajectory length up to 200 ms (200msCOP) and 1 s (1sCOP), the peak value of the frontal GRF (pFML), the peak value of the sagittal GRF (pFAP), and the peak value of the vertical GRF (pFV). Means were calculated from the measured values of ten attempts. 200msCOP reflects postural sway immediately after landing, and pFML and pFV reflect the force of impact upon landing. 200msCOP, pFML, and pFV were significantly higher with lateral hopping versus forward hopping (p<0.01, p<0.05, and p<0.05), and hop direction yielded differences in dynamic balance. PMID- 28090003 TI - Primary Hinged External Fixation of Terrible Triad Injuries and Olecranon Fracture-Dislocations of the Elbow. AB - This study aimed to introduce a new treatment that apples primary hinged external fixation for complex fracture-dislocations of the elbow in 12 cases. We retrospectively assessed the functional outcomes of eight patients with terrible triad injuries and three patients with an olecranon fracture-dislocation of the elbow, who were treated at our hospital using a primary hinged external fixator between June 2012 and December 2014. Ten patients underwent repair or replacement of the radial head, while three underwent repair of the olecranon. In principle, they were treated without reconstruction of the coronoid fracture and collateral ligament injury. The patients were evaluated for a mean follow-up period of 16 months after the initial surgery. Early mobilization was encouraged while the hinged external fixator was in place. At the follow-up, the mean Mayo Elbow Performance Score was 93 points; the results were "excellent" in six cases and "good" in five. No patients had recurrent elbow instability. Only one patient needed an additional procedure after the initial operation. These results suggested that primary hinged external fixation without repair of the ligament and soft tissue is an effective minimally invasive surgery for the management of terrible triad injuries and olecranon fracture-dislocations of the elbow. PMID- 28090005 TI - Unstable Angina Pectoris in a 22-year-old Female Patient. AB - Because of the protective effect of estrogen for atherosclerosis, the prevalence of acute coronary syndrome in women before menopause is low. We report a rare case of unstable angina in a young Japanese female who had a history of cigarette smoking and contraceptive use. Her coronary stenosis was successfully treated by percutaneous coronary intervention. PMID- 28090006 TI - Expression of apical junction complex proteins in colorectal mucosa of miniature dachshunds with inflammatory colorectal polyps. AB - We examine the expression of tight junction and adherence junction proteins in the colorectal mucosa of miniature dachshunds (MDs) with inflammatory colorectal polyps (ICRPs). Colorectal mucosa samples were endoscopically obtained from 8 MDs with ICRPs and 8 control dogs for immunoblotting. Paraffin-embedded tissues of surgically resected inflamed lesions from another 5 MDs with ICRPs and full thickness colorectal specimens from 5 healthy beagles were obtained for immunohistochemistry. The expression patterns of claudin-1, -2, -3, -4, -5, -7 and -8, E-cadherin and beta-catenin were analyzed in the non-inflamed mucosa and inflamed mucosa of ICRPs and colorectal mucosa of control dogs by immunoblotting. The localization of these proteins in the inflamed lesions was analyzed by immunohistochemistry. The expressions of each of claudin, E-cadherin and beta catenin were not significantly different between control dogs and non-inflamed colonic mucosa from MDs with ICRPs. In contrast, only E-cadherin and beta-catenin were detected in the inflamed lesions of MDs with ICRPs. By immunohistochemistry, claudin-2, -3, -4, -5 and -7, E-cadherin and beta-catenin were expressed in the colorectal epithelium within the inflamed mucosa, but not in granulation tissue. Distributions of claudin-2, -3, -4, -5, and -7, E-cadherin and beta-catenin in the colonic epithelium were not different between MDs with ICRPs and control dogs. These results indicated that no significant alteration was detected in several tight junction or adherence junction proteins expression in the colorectal epithelium of ICRPs. PMID- 28090008 TI - Characterization of the Growth of Deep and Subcortical White Matter Hyperintensity on MR Imaging: A Retrospective Cohort Study. AB - PURPOSE: In elderly patients, deep and subcortical white matter hyperintense lesions are frequently observed on MRI; however, the growth process of these lesions is unclear. The aims of this retrospective cohort study were to elucidate the growth characteristics of deep and subcortical white matter hyperintense lesions, and to insight their etiology. MATERIALS AND METHODS: We enrolled 103 patients (1610 lesions) whose deep and subcortical white matter hyperintense lesions were monitored for 3 or more years by MRI examination. The area of each hyperintense lesion was measured using a tracing method in the first and last MRI examinations. The annual rate of increase in the area of each lesion was calculated, and using the Pearson product-moment correlation coefficient the correlation between the annual rate of increase in area and the interval between the first and last MRI examinations was determined. RESULTS: The paired t-test showed a significant increase in the mean area of all the deep and subcortical white matter hyperintense lesions between the first and last MRI examinations (P < 0.001). However, hyperintense lesions had decreased in the area or disappeared in 227 (14.1%) lesions in the last MRI examination, particularly in patients with diabetes. The mean annual rate of increase in area of all hyperintense lesions was 0.013 +/- 0.021 cm2 per year. The annual rate of increase in area and the interval between the first and last MRI examinations showed a weak negative correlation (r = -0.121; P < 0.01). CONCLUSION: Decrease in the area and the disappearance of the subcortical white matter hyperintense lesions, and a decline in the annual rate of increase in the lesion area with time suggest that the interstitial fluid accumulation associated with dysfunctional drainage around the vessels may be involved in the possible etiologies of deep and subcortical white matter hyperintense lesions. PMID- 28090007 TI - Ductal Carcinoma in situ Detected during Prospective MR Imaging Screening of a Woman with a BRCA2 Mutation: The First Case Report in Japan. AB - The present case is the first report in Japan in which a breast cancer was discovered as a result of prospective magnetic resonance imaging (MRI) screening study for BRCA1/2 mutation carriers who were free of breast or ovarian cancer. This case is significant and it verifies the importance of MRI screening in breast or ovarian cancer-free BRCA1/2 mutation carriers who do not exhibit positive mammographic or ultrasonographic findings. PMID- 28090009 TI - Prognostic Impact of Atrial Fibrillation and New Risk Score of Its Onset in Patients at High Risk of Heart Failure - A Report From the CHART-2 Study. AB - BACKGROUND: The prognostic impact of atrial fibrillation (AF) among patients at high risk for heart failure (HF) remains unclear. In addition, there is no risk estimation model for AF development in these patients.Methods and Results:The present study included 5,382 consecutive patients at high risk of HF enrolled in the CHART-2 Study (n=10,219). At enrollment, 1,217 (22.6%) had AF, and were characterized, as compared with non-AF patients, by higher age, lower estimated glomerular filtration rate, higher B-type natriuretic peptide (BNP) level and lower left ventricular ejection fraction. A total of 116 non-AF patients (2.8%) newly developed AF (new AF) during the median 3.1-year follow-up. AF at enrollment was associated with worse prognosis for both all-cause death and HF hospitalization (adjusted hazard ratio (aHR) 1.31, P=0.027 and aHR 1.74, P=0.001, for all-cause death and HF hospitalization, respectively) and new AF was associated with HF hospitalization (aHR 4.54, P<0.001). We developed a risk score with higher age, smoking, pulse pressure, lower eGFR, higher BNP, aortic valvular regurgitation, LV hypertrophy, and left atrial and ventricular dilatation on echocardiography, which effectively stratified the risk of AF development with excellent accuracy (AUC 0.76). CONCLUSIONS: These results indicated that AF is associated with worse prognosis in patients at high risk of HF, and our new risk score may be useful to identify patients at high risk for AF onset. PMID- 28090010 TI - Long-Term Outcomes After Percutaneous Lower Extremity Arterial Interventions With Atherectomy vs. Balloon Angioplasty - Propensity Score-Matched Registry. AB - BACKGROUND: The impact of endovascular revascularization of the lower extremity arteries with atherectomy (AT) compared with percutaneous transluminal angioplasty (PTA) is still unclear. Therefore, the aim of the study was to compare long-term outcomes after percutaneous PTA and AT in patients requiring endovascular revascularization.Methods and Results:This was a single-center, retrospective registry of obstructive and symptomatic PAD patients who underwent endovascular revascularization. PTA was performed in 215 patients, and AT in 204 (Silver Hawk, EV3, n=125; CSI 360 degrees , n=66; Pathway Medical Technologies, n=13). There were no significant between-group differences in baseline characteristics except for increased CAD, dialysis and CLI prevalence in the PTA group. Following propensity score analysis 131 well-matched pairs were included in analysis. Bail-out stenting was more frequent in the reference group (PTA, 6.1% vs. AT, 0%; P=0.004). At 6- and 12-month follow-up there were no differences in TLR between the groups (PTA, 8.3% vs. AT, 5.3%; P=0.47; and PTA, 16.7% vs. AT, 13.7%; P=0.73, respectively). The difference was in favor of AT at 24-month follow-up (PTA, 29.0% vs. AT, 16.7%; P=0.05). No difference was observed in amputation rate (PTA, 0.7% vs AT, 1.5%; P=0.62). On Kaplan-Meier analysis there were no significant differences between groups in time to TLR, amputation or death. CONCLUSIONS: AT was associated with lower risk of TLR, and this should be confirmed in randomized controlled trials. PMID- 28090012 TI - ? PMID- 28090011 TI - Cardiac Amyloidosis Associated With Amyloidogenic Transthyretin V122I Variant in an Elderly Japanese Woman. PMID- 28090013 TI - Significance of monitoring trough plasma concentration levels for invasive fungal infection prophylaxis with itraconazole oral solution in patients with hematological malignancies: a prospective study. AB - In this prospective study, we examined the prophylactic effect of itraconazole oral solution (ITCZ-OS) against invasive fungal disease in hematologic malignancy patients. The participants were 36 patients, at least 16 years of age, with hematologic malignancies treated at our hospital. ITCZ-OS 200 mg/day was administered orally twice a day with a target trough plasma concentration of 350 ng/ml. If the patient did not achieve the target trough plasma concentration, the dose was increased. The success rate of achieving the target trough plasma concentration of ITCZ with a dose of 200 mg/day was 63.9%. During the observation period, 2 patients (5.6%) were diagnosed with possible invasive fungal disease according to the EORTC/MSG 2008 criteria. Adverse events were observed in 2 patients (5.6%). The results showed administration of ITCZ-OS while monitoring ITCZ trough plasma concentrations to be effective for preventing invasive fungal disease, and no serious adverse events occurred. Since predicting trough levels in response to ITCZ administrations is difficult, its measurement is necessary to maintain the prophylactic effect of ITCZ. PMID- 28090014 TI - Retrospective analysis of clinical outcomes of the patients with chronic myeloid leukemia who stopped administration of tyrosine kinase inhibitors: a single institution experience. AB - We describe herein the clinical outcomes of 16 patients with chronic myeloid leukemia in the chronic phase who stopped the administration of tyrosine kinase inhibitors (TKI) after maintaining undetectable levels of major BCR-ABL1, based on real-time quantitative polymerase chain reaction, for prolonged periods (undetectable MR for a median of 2,100 days (822-4,068). The reasons for discontinuing TKI were enrollments in a clinical trial testing discontinuation of these agents (n=9), adverse effects (n=2) or financial problems (n=5). After TKI discontinuation, patients were followed for a median of 551 days (154-2,446). A total of 8 patients (50%) experienced molecular relapse after a median of 119 days (28-171). Among them, 6 patients who lost major molecular response (MMR) were treated with imatinib (n=2) or dasatinib (n=4), while 2 patients who lost undetectable MR after discontinuing TKI (1 each had taken bostinib and imatinib) but maintained MMR were carefully monitored without re-administration of TKI. Of 6 patients who re-started TKI, 4 (67%) achieved undetectable MR but the other 2 achieved only MMR. The results of this small, retrospective study may support the current understanding of treatment discontinuation, possibly leading to a sustained deep molecular response in some patients. PMID- 28090015 TI - TAFRO syndrome showing cholangitis on liver biopsy. AB - TAFRO syndrome is a systemic inflammatory disorder. TAFRO is an acronym that stands for thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, lymphadenopathy and hepatosplenomegaly. There are no reports of TAFRO syndrome describing cholangitis on liver biopsy. Herein, we report the first case of TAFRO syndrome with cholangitis. The patient was a 56-year-old man who presented with sudden onset abdominal pain and fever. His symptoms progressed to generalized edema, thrombocytopenia, hepatomegaly, and acute renal failure. Biopsies taken from the mediastinal lymph nodes and bone marrow showed the mixed type of multicentric Castleman's disease and mild reticulin fibrosis, respectively, compatible with TAFRO syndrome. His symptoms were temporarily relieved by steroid pulse therapy and tocilizumab. Fever and anasarca relapsed in a few weeks, however. He was then administered rituximab which resolved his symptoms almost completely. PMID- 28090016 TI - Gastrointestinal post-transplant lymphoproliferative disorder with rapidly forming characteristic lesions after cord blood transplantation: a report of two cases. AB - Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disorder (PTLD) frequently involves the gastrointestinal tract, but the endoscopic characteristics of this condition have not been discussed in detail. We report two cases of EBV-related PTLD involving rapidly forming characteristic lesions. Case 1 was a 60-year-old man with acute myeloid leukemia who underwent cord blood transplantation (CBT) after which he initially achieved complete remission (CR). He developed nausea and vomiting on day 99. Gastrointestinal endoscopy showed no tumor-like lesions in his stomach. However, a second endoscopic evaluation, which was performed 7 days after the first, revealed multiple raised lesions in his stomach, and a histopathological examination of the biopsy specimen resulted in a diagnosis of EBV-related PTLD. Case 2 was a 36-year-old man with acute myeloid leukemia who underwent CBT after achieving his second CR. He suffered nausea and pharyngalgia on day 309. Although the initial gastrointestinal endoscopic examination showed only multiple erosive or small ulcerative lesions, a second endoscopic evaluation, which was performed 10 days after the first, revealed a raised lesion with a central ulcer in the duodenum. Histopathological examination of the biopsy specimen yielded a diagnosis of EBV-related PTLD. Both patients were successfully treated by reducing the dose of immunosuppressive agents and administering rituximab. PMID- 28090017 TI - Quincke's edema and hypersensitivity pneumonitis induced by lenalidomide for multiple myeloma. AB - A 64-year-old man with recurrent multiple myeloma (BJP-kappa type) was treated with 15 mg of lenalidomide (LEN) and dexamethasone. He developed Quincke's edema on his eyelid on day 4. Since the edema improved after withdrawal of LEN, the drug was subsequently re-administered at a decreased dose. However, the edema developed again on day 4. After withdrawal of LEN, the drug was administered again with gradually dose escalation, while confirming the absence of eyelid edema. Although edema did not develop, eosinophils and basophils were increased, and the CRP level was elevated. During the third course of LEN administration, his chest CT showed bilateral ground-glass opacity, and LEN-induced hypersensitivity pneumonitis was diagnosed. The pneumonitis resolved after LEN withdrawal and prednisolone administration. These observations suggested that Quincke's edema, eosinophilia and basophilia, CRP elevation, and hypersensitivity pneumonitis might occur due to the immunological effects of LEN, which is classified as an immunomodulatory drug. PMID- 28090019 TI - Simultaneous occurrence of autoimmune hemolytic anemia and pure red cell aplasia. AB - Simultaneous onset of autoimmune hemolytic anemia (AIHA) and pure red cell aplasia (PRCA) is rare and any possible association between these two disorders remains obscure. A 46-year-old previously healthy woman was diagnosed as having AIHA based on severe anemia, positive direct and indirect Coomb's tests, decreased serum haptoglobin, elevated serum LDH, and indirect bilirubin-dominant hyperbilirubinemia. Oral steroid administration (1 mg/kg) and subsequent half pulse steroid therapy ameliorated the AIHA, but the anemia was unexpectedly prolonged with the low peripheral blood reticulocyte count further decreasing to 0.11%. Bone marrow aspiration revealed a marked decrease in erythroblasts with an M/E ratio of 69.5. Anti-parvovirus B19 IgM antibody and serum B19 viral DNA (109 copy/ml) were detected but no other distinct abnormalities which might have caused acquired PRCA were detected. Therefore, she was considered likely to have idiopathic AIHA and acquired PRCA simultaneously. AIHA-mediated erythroblastosis probably raised the parvovirus B19 DNA level to an extraordinary degree and thereby led to severe aplastic crisis, subsequently causing prolonged anemia. Parvovirus B19 infection should be considered in AIHA patients showing unexpectedly low reticulocyte counts. PMID- 28090018 TI - Congenital haptoglobin deficiency discovered on the occasion of anaphylaxis induced by platelet concentrate transfusion. AB - A 77-year-old man with myelodysplastic syndrome suffered from duodenal perforation after undergoing endoscopic submucosal dissection (ESD) for treatment of duodenal cancer. He presented with hemorrhagic shock, peritonitis and disseminated intravascular coagulation (DIC), and received transfusions of red blood cells (RBC), fresh frozen plasma (FFP), gamma-globulin and albumin (Alb). One month after the last RBC transfusion, prolonged thrombocytopenia was observed, and platelet concentrate (PC) was transfused. However, immediately after starting PC transfusion, he developed dyspnea, hypotension and rash, and was thus diagnosed as being in anaphylactic shock. Analysis of the patient's serum revealed absence of haptoglobin (Hp) and the presence of anti-Hp antibody. Further studies, using PCR detected Hpdel, yielded a diagnosis of congenital Hp deficiency. Thus, the anaphylactic shock was considered to have been induced by Hp in the transfused PC reacting with pre-existing anti-Hp antibodies. Thereafter, transfusions were safely carried out with the use of washed PC. Congenital Hp deficiency is relatively prevalent, and in such cases transfusions should be carried out using washed RBC, washed PC and congenital Hp deficiency donor derived FFP to avoid anaphylactic transfusion reactions. Transfusions would be even safer if production of congenital Hp deficiency donor derived PC were to be made available in the future. PMID- 28090020 TI - Overview. PMID- 28090021 TI - Gene mutations in bone marrow failure syndromes. AB - Acquired bone marrow failure syndromes consist of aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH), and myelodysplastic syndromes (MDS). Clonal hematopoiesis is frequently observed in non-neoplastic disorders, aplastic anemia and PNH as well as a neoplastic phenotype, MDS. However, the significance of such clonal hematopoiesis, particularly in aplastic anemia, remains to be elucidated. Recent advancements in next generation sequencing technology have revealed a diverse clonal structure in these bone marrow failure syndromes, as well as in age-related clonal hematopoiesis in healthy people. In this review article, we describe gene mutations in bone marrow failure syndromes, together with those detected in healthy people. PMID- 28090022 TI - Gene mutations in myeloproliferative neoplasms. AB - This review outlines recent advances in the understanding of gene alterations and the genetic background associated with myeloproliferative neoplasms (MPNs), as well as describing the roles of these genetic factors in the development of MPNs. JAK2, CALR, and MPL mutations that are specifically found in patients with MPNs have been shown to constitutively activate cytokine receptors. Other mutations that are commonly found in hematopoietic malignancies have been demonstrated to synergize with disease-specific mutations and to accelerate the development of MPN, or to define the disease subtype. However, some of these mutations are found in healthy elderly persons, such that the mechanism of MPN development remains elusive. Further analyses including those for genetic factors associated with the occurrence of MPN will lead to a complete understanding of MPN development. PMID- 28090023 TI - Gene mutations in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a heterogeneous disease, the onset of which involves a variety of chromosomal abnormalities and gene mutations. In recent years, the use of next-generation sequencers has facilitated intensive exploration of gene mutations resulting in the discovery of many AML-related gene mutations, and in clarifying the clonal evolution process of relapse. Epigenetic regulatory gene mutations have occurred in pre-leukemic cells with normal differentiation potential, and the acquisition of numerous genetic mutations was found to be strongly associated with AML onset, with further co-mutations contributing to clonal diversity and leading to the generation of treatment resistant clones. As a result of these fruitful findings, the gene mutations of AML are becoming useful as not only prognostic factors but also the targets of molecular medicines such as FLT3 and IDH inhibitors. Most notably, several guidelines have proposed a prognostic classification that groups FLT3ITD, NPM1 mutation, and CEBPA mutation together under conventional chromosomal aberrations. This review outlines recent findings pertaining to the gene mutations in AML. PMID- 28090024 TI - Gene mutations in myelodysplastic syndromes. AB - Recent progress in next generation sequencing technologies has enabled us to investigate somatic mutations throughout the coding regions of myelodysplastic syndromes (MDS), and have likely provided us with almost the entire spectrum of driver mutations responsible for this disease. As shown by numerous recent studies, such frequent mutations play an important role in the leukemogenesis of MDS. In the first part of this review, we comprehensively describe the characteristics and frequencies of the most prevalent mutations already confirmed as drivers in MDS. Second, we focus on the associations between karyotypic abnormalities and somatic mutations involving chromosomes 5 and 7. In particular, CSNK1A1 mutations are the most recently identified among the 5q- syndromes. Finally, we summarize recently reported findings on the functional effects of frequent splice factor mutations on splicing defects, which have been clarified by multiple institutions. PMID- 28090025 TI - Gene mutations in malignant lymphoma. AB - Information on the cancer genome has accumulated rapidly, since approximately 2009, with the use of second-generation sequencing technology. Malignant lymphoma is no exception. In mature B-cell lymphomas, which constitute the vast majority of non-Hodgkin lymphomas, frequent mutations are identified in genes involved in signaling pathways, histone-modifying molecules, the DNA damage-response pathway, etc. The signaling pathways in which multiple genes are mutated include immune cell-specific pathways such as the B-cell receptor, the Toll-like receptor, and their downstream NF-kappaB signaling pathways, as well as the NOTCH signaling pathway. In mature T/NK-cell lymphomas, mutations accumulate in genes involved in the T-cell receptor pathway and its downstream NF-kappaB signaling pathway, regulators of DNA methylation, the JAK-STAT pathway, etc. Many of these mutations are found in multiple types of lymphomas but the frequencies of each gene mutation differ among diseases, demonstrating characteristic profiles. This cumulative and growing fund of knowledge provides an important basis for the development of new molecular-targeted drugs. PMID- 28090026 TI - ? PMID- 28090028 TI - ? PMID- 28090027 TI - ? PMID- 28090029 TI - Erratum. PMID- 28090030 TI - Effect of polymerization cycles on flexural strengths and microhardness of different denture base materials. AB - The purpose of this study was to evaluate the effect of different polymerization cycles on the flexural strengths and microhardness of two denture base materials (Meliodent and Paladent). Heat-polymerized acrylic resin specimens (65.0 mm long*10.0 mm wide*2.5 mm in height) were prepared using different short and long polymerization cycles. After the specimens had been polymerized, they were stored in distilled water at 37+/-1 degrees C for 24 h. Flexural strength test was performed at a cross-head speed of 5 mm/min and Vickers microhardness was measured. Data were analyzed with a 1-way analysis of variance followed by Tukey test, and Student t-test (alpha=0.05). The flexural strengths and microhardness were significantly different between Meliodent and Paladent (p<0.05). Significant differences were found among the polymerization cycles in terms of flexural strengths and microhardness (p<0.05). Polymerization with G cycle may be suggested for Meliodent and H cycle may be suggested for Paladent. PMID- 28090031 TI - Differentiation behavior of iPS cells cultured on PLGA with osteoinduction medium. AB - In the present report, we have generated osteoblast-like cells derived from mouse induced-pluripotent stem (iPS) cells on PLGA with osteoinduction medium in vitro and in vivo. The cell culture period was 2 weeks. At 2 weeks, mRNA level of type I collagen was significantly higher than at 1 week. Osteocalcin mRNA level at 2 weeks was tendency to increase compared with at 1 week. And the cells cultured on PLGA were positive for immunofluorescent staining of osteocalcin and alizarin red S staining. The scaffold and osteogenic-like cells induced in vitro were implanted subcutaneously into SCID mice. In resected teratoma, hard tissues resembling bone were observed mixed with other tissues on the scaffold. The sum of these findings suggests that PLGA does not disturb the osteogenesis of iPS cells. PMID- 28090032 TI - The influence of elastic moduli of core materials on shear stress distributions at the adhesive interface in resin built-up teeth. AB - This study aimed to investigate shear stress distributions in resin built-up teeth using resin composites of varying elastic moduli (E), with or without fiber posts. Three-dimensional mathematical models of a root-filled mandibular premolar tooth were constructed. Resin post and cores were built-up with resin composites of three different E: 12,000, 18,000 and 24,000 MPa, with or without fiber posts. Finite element linear analysis was performed to calculate shear stress distributions at bonding interface between resin core and dentin. Regardless of fiber post insertion, the shear stress on the cervical surface of resin core decreased as the E of resin composites increased. Insertion of fiber posts increased the shear stress on the post surface of resin core, with increases in the E of resin composites. In conclusion, using resin core materials with higher E decreased the shear stress at cervical interface between resin core and dentin regardless of fiber post insertion. PMID- 28090033 TI - The effect of surface sealant application and accelerated aging on posterior restorative surfaces: An SEM and AFM study. AB - The purpose of this study was to evaluate the effect of surface sealant application and 10,000 thermocycles on the surface roughness and microhardness of different resin composite systems. A micro-hybrid (G Aenial Posterior), a nano hybrid (Clearfil Majesty Posterior), a nano-fill (Filtek Ultimate Universal Restorative, Enamel Shade), and a bulk-fill resin composite (Filtek Bulk Fill Posterior Restorative) were used for the study. Specimens were evaluated at 24 h, after application of the surface sealant Fortify Plus, and after thermocycling. Data were analyzed using two-way repeated measures of analysis of variance (ANOVA) and a posthoc Bonferroni test (p<0.05). Surface roughness values of G Aenial Posterior and Filtek Ultimate Universal Restorative increased significantly after surface sealant application. However, neither surface sealant application nor thermocycling had a significant effect on composite microhardness values except Filtek Ultimate Universal Restorative (p>0.05). PMID- 28090034 TI - Evaluation of sub-surface penetration and bonding durability of self-etching primer systems to Er:YAG laser treated cervical dentin. AB - This study aimed to investigate self-etching bonding systems penetrating in sub surface dentin layer after Er:YAG laser irradiation and micro-shear bonding durability over a period of 1 year. Dentin slices obtained from extracted human third molars were prepared. Two self-etching adhesive systems were evaluated: Clearfil SE Bond and Clearfil Tri-S Bond. Specimens were tested for micro-shear bond strength with one of the following treatments: Er:YAG laser irradiation and 600-grit silicon paper polishing at 24 h, 7 days, 6 months and 1 year. The adhesive interfaces between bonding agents and lased cervical dentin were studied. No hybrid layer could be observed for lased dentin. The slim resin tags could be seen penetrating through the lased subsurface layer. Bond strength to lased dentin after 6 months and 1 year were significantly decreased (p<0.05). PMID- 28090035 TI - Effect of ice-quenching on the change in hardness of a Pd-Au-Zn alloy during porcelain firing simulation. AB - This study examined the effect of ice-quenching after degassing on the change in hardness of a Pd-Au-Zn alloy during porcelain firing simulations. By ice quenching after degassing, the specimens were softened due to homogenization without the need for an additional softening heat treatment. The lowered hardness by ice-quenching after degassing was recovered greatly from the first stage of porcelain firing process by controlling the cooling rate. The increase in hardness during cooling after porcelain firing was attributed to the precipitation of the f.c.t. PdZn phase containing Au, which caused severe lattice strain in the interphase boundary between the precipitates and matrix of the f.c.c. structure. The final hardness was slightly higher in the ice-quenched specimen than in the specimen cooled at stage 0 (the most effective cooling rate for alloy hardening) after degassing. This was attributed to the more active grain interior precipitation during cooling in the ice-quenched specimen after degassing. PMID- 28090036 TI - Fabrication and Functionalization of Inorganic Materials Using Amphiphilic Molecules. AB - In this review, the synthesis of inorganic materials with various properties using amphiphilic molecules is examined. Amphiphilic molecules are used for the formation of highly ordered mesostructures and the surface modification. Two examples of the mesostructures are crystalline mesoporous titania (TiO2) and the novel visible light responsive mesostuructured titania modified with dye in the pores, which can be fabricated using the molecular self-assemblies of amphiphiles as templates. Surface modification using amphiphilic molecules enables the construction of self-assembled arrays of silica particles and the preparation of a film that can control adsorption/desorption behavior of bovine serum albumin (BSA) by light irradiation. PMID- 28090037 TI - Expression of (Pro)renin Receptor During Rapamycin-Induced Erythropoiesis in K562 Erythroleukemia Cells and Its Possible Dual Actions on Erythropoiesis. AB - (Pro)renin receptor ((P)RR), a specific receptor for renin and prorenin, is expressed in erythroblastic cells. (P)RR has multiple biological actions: prorenin activation, stimulation of the intracellular signaling including extracellular signal-regulated kinases, and functional complex formation with vacuolar H+-ATPase (v-ATPase). However, the functional implication of (P)RR in erythroblast cells has not been clarified. The aim of the present study was to clarify changes of (P)RR expression during erythropoiesis and a role of (P)RR in the heme synthesis. (P)RR expression was studied during rapamycin-induced erythropoiesis in a human erythroleukemia cell line, K562. Treatment with rapamycin (100 nM) for 48 hours significantly increased %number of hemoglobin producing cells, gamma-globin mRNA levels, erythroid specific 5-aminolevulinate synthase (ALAS2) mRNA levels, and heme content in K562 cells. Both (P)RR protein and mRNA levels increased about 1.4-fold during rapamycin-induced erythropoiesis. Suppression of (P)RR expression by (P)RR-specific small interference RNA increased ALAS2 mRNA levels about 1.6-fold in K562 cells, compared to control using scramble RNA, suggesting that (P)RR may down-regulate ALAS2 expression. By contrast, treatment with bafilomycin A1, an inhibitor of v-ATPase, decreased greatly % number of hemoglobin-producing cells and heme content in K562 cells, indicating that the v-ATPase function is essential for hemoglobinization and erythropoiesis. Treatment with bafilomycin A1 increased (P)RR protein and mRNA levels. In conclusion, we propose that (P)RR has dual actions on erythropoiesis: the promotion of erythropoiesis via v-ATPase function and the down-regulation of ALAS2 mRNA expression. Thus, (P)RR may contribute to the homeostatic control of erythropoiesis. PMID- 28090039 TI - Interaction between the RGS6 gene and psychosocial stress on obesity-related traits. AB - Obesity is a major risk factor for chronic diseases and arises from the interactions between environmental factors and multiple genes. Psychosocial stress may affect the risk for obesity, modifying food intake and choice. A recent study suggested regulator of G-protein signaling 6 (RGS6) as a novel candidate gene for obesity in terms of reward-related feeding under stress. In this study, we tried to verify the unidentified connection between RGS6 and human obesity with psychosocial stress in a Korean population. A total of 1,462 adult subjects, who participated in the Korean Association Resource cohort project, were included for this analysis. Obesity-related traits including waist circumference, body mass index, and visceral adipose tissue were recorded. A total of 4 intronic SNPs for the RGS6 gene were used for this study. We found that interactions between SNP rs2239219 and psychosocial stress are significantly associated with abdominal obesity (p = 0.007). As risk allele of this SNP increased, prevalence of abdominal obesity under high-stress conditions gradually increased (p = 0.013). However, we found no SNPs-by-stress interaction effect on other adiposity phenotypes. This study suggests that RGS6 is closely linked to stress-induced abdominal obesity in Korean adults. PMID- 28090038 TI - Combination Therapy with Ombitasvir/Paritaprevir/Ritonavir for Dialysis Patients Infected with Hepatitis C Virus: A Prospective Multi-Institutional Study. AB - Hepatitis C virus (HCV) infection is common in dialysis patients worldwide and nosocomial HCV spread within dialysis facilities continues to develop. Combination therapy with daclatasvir and asunaprevir (DCV/ASV) that has proven efficacy for dialysis patients infected with genotype 1b HCV (HCV/1b) has several concerns in Japan. The recently available combination therapy with ombitasvir, paritaprevir, and ritonavir (OBV/PTV/r) is not contraindicated in patients with chronic renal failure and has more safety profile and shorter treatment period than that with DCV/ASV. We evaluated the effects of combination therapy with OBV/PTV/r in four dialysis patients infected with HCV/1b, who were eligible for our study. On-treatment assessments included standard laboratory testing, serum HCV RNA and symptom-directed physical examinations. Three patients had a sustained virological response at 12 weeks after treatment, but one remaining patient had viral breakthrough. Notably, the patient with viral breakthrough had been coinfected with HCV/1b and HCV/2b; namely, HCV/2b with resistance-associated variations was not eradicated by the combination therapy. Among the three patients responsive to the combination therapy, one patient complained of appetite loss and itching, while in another patient the therapy was discontinued due to itching, exacerbation of wamble, and a falling tendency probably due to interaction with valsartan. These AEs were ameliorated or disappeared after the completion of the therapy. The significance of our study is persuasive virological evaluation associated to the combination therapy and reasonable interpretation of AEs. In conclusion, combination therapy with OBV/PTV/r may have promise as an efficacious therapy, but caution regarding AEs should be practiced. PMID- 28090040 TI - Outcomes of Brugada Syndrome Patients with Coronary Artery Vasospasm. AB - Objective To evaluate the outcomes of patients with concomitant Brugada syndrome and coronary artery vasospasm. Methods Patients diagnosed with Brugada syndrome with an implantable cardiac defibrillator were retrospectively investigated, and the coexistence of vasospasm was evaluated. The clinical features and outcomes were evaluated, especially in patients with coexistent vasospasm. A provocation test using acetylcholine was performed in patients confirmed to have no organic stenosis on percutaneous coronary angiography to confirm the presence of vasospasm. Implantable cardiac defibrillator shock status was checked every three months. Statistical comparisons of the groups with and without vasospasm were performed. A univariate analysis was also performed, and the odds ratio for the risk of implantable cardiac defibrillator shock was calculated. Patients Thirty five patients with Brugada syndrome, of whom six had coexistent vasospasm. Results There were no significant differences in the laboratory data, echocardiogram findings, disease, or the history of taking any drugs between patients with and without vasospasm. There were significant differences in the clinical features of Brugada syndrome, i.e. cardiac events such as resuscitation from ventricular fibrillation or appropriate implantable cardiac defibrillator shock. Four patients with vasospasm had cardiac events such as resuscitation from ventricular fibrillation and/or appropriate defibrillator shock; three of them had no cardiac events with calcium channel blocker therapy to prevent vasospasm. The coexistence of vasospasm was a potential risk factor for an appropriate implantable cardiac defibrillator shock (odds ratio: 13.5, confidence interval: 1.572-115.940, p value: 0.035) on a univariate analysis. Conclusion Coronary artery vasospasm could be a risk factor for cardiac events in patients with Brugada syndrome. PMID- 28090041 TI - Clinical Characteristics of Stenotrophomonas maltophilia Bacteremia: A Regional Report and a Review of a Japanese Case Series. AB - Objective Stenotrophomonas maltophilia is an emerging nosocomial pathogen that causes fatal infections in critically ill or immunocompromised patients. S. maltophilia bacteremia (SMB) is a rare condition, and its clinical characteristics in Japanese settings are not well known. Methods The medical charts of patients with SMB were retrospectively reviewed at two medical facilities (Okayama University Hospital and Tsuyama Chuo Hospital) for seven years. The data were analyzed along with those previously reported from other Japanese facilities. Result A total of 181 patients (110 men and 71 women) were evaluated. The major underlying diseases included hematologic malignancy (36.5%), solid organ malignancy (25.4%), and neutropenia (31.5%). The recent use of carbapenem was seen in 56.9% of the cases in total, and more than one-third of the patients in our hospitals were treated with carbapenem at the onset of SMB. Of 28 (63.6%) of 44 cases treated for S. maltophilia, those who did not survive were more likely to have been treated with broad-spectrum antibiotics. A multivariate analysis revealed that a higher updated Charlson Comorbidity Index [odds ratio (95% confidence interval), 1.75 (1.11-2.75); p=0.015] and intubation [odds ratio (95% confidence interval), 12.6 (1.62-97.9); p=0.016] were associated with mortality in our cases. Pathogens were often resistant to ceftazidime but susceptible to minocycline, trimethoprim/sulfamethoxazole, and fluoroquinolones. The overall mortality rates within 30 and 90 days were 37.5% and 62.5%, respectively. Conclusion The clinical characteristics of SMB in Japanese cases were similar to those reported from other countries. Clinicians should be aware that breakthrough infection by S. maltophilia may occur during administration of carbapenem. PMID- 28090042 TI - Autoimmune Hepatitis Associated with Immune Thrombocytopenic Purpura. AB - Although autoimmune hepatitis (AIH) is frequently complicated with chronic thyroiditis or other autoimmune disorders, reports on its association with immune thrombocytopenic purpura (ITP) are scarce. We herein describe a case of AIH associated with ITP. A 75-year-old Japanese woman was admitted to our hospital due to increased aminotransferase levels and severe thrombocytopenia. Elevated serum immunoglobulin G (IgG) was detected, and tests for platelet-associated IgG and anti-nuclear antibody were positive. Following the diagnosis of AIH associated ITP, prednisolone treatment of 0.6 mg/kg/day resulted in a decrease in the aminotransferase levels and an increased platelet count. PMID- 28090043 TI - Pheochromocytoma Multisystem Crisis Behaving Like Interstitial Pneumonia: An Autopsy Case. AB - Pheochromocytoma multisystem crisis is a rare and life-threatening disease that is associated with numerous symptoms and which is also difficult to diagnose. We herein report an autopsy case of a 61-year-old man who died due to pheochromocytoma multisystem crisis. The patient complained of vomiting and breathlessness. Computed tomography showed a shadow-like region with a similar appearance to interstitial pneumonia. The patient was diagnosed with takotsubo cardiomyopathy induced by severe lung disease based on the results of echocardiography and coronary angiography. The patient was treated for interstitial pneumonia. However, his condition rapidly deteriorated and he died 6 hours after arrival. We were later informed of his extremely high catecholamine serum levels. We found pheochromocytoma with hemorrhage at autopsy. The patient's lungs showed acute passive congestion with edema and extravasation. PMID- 28090044 TI - Acute Multiple Cerebral Infarction in a Patient with an Accessory Mitral Valve. AB - A 96-year-old woman developed hemiparesis 2 weeks after orthopedic surgery. Magnetic resonance imaging revealed multiple cerebral infarctions in the bilateral hemisphere. Transthoracic echocardiography revealed a mobile structure attached to the anterior mitral leaflet that protruded toward the left ventricular outflow tract. The structure was identified as an accessory mitral valve. Doppler echocardiography showed that there was no significant left ventricular outflow obstruction. This is a rare case of a silent accessory mitral valve that was detected after multiple cerebral infarctions. PMID- 28090045 TI - A Pitfall in the Diagnosis of Eosinophilic Myocarditis in a Patient who Received Steroid Therapy. AB - Eosinophilic myocarditis is a rare form of myocardial inflammation that is characterized by the infiltration of eosinophilic cells into the myocardium. The clinical symptoms of eosinophilic myocarditis are similar to those of acute coronary syndrome, and eosinophilic myocarditis sometimes occurs in combination with bronchial asthma. We herein present a case of eosinophilic myocarditis in which additional time was required to make a definitive diagnosis because the patient received steroid therapy. The diagnosis of eosinophilic myocarditis is challenging, especially when a patient has other inflammatory diseases, such as bronchial asthma. We should pay attention to the possibility that steroid therapy may mask the presentation of eosinophilic myocarditis. PMID- 28090046 TI - An Isolated Case of Late-onset Amyloidogenic Transthyretin Type Familial Amyloid Polyneuropathy Associated with a Mutant Transthyretin Substituting Methionine for Valine at Position 30 Showing Latent Progressive Cardiac Involvement Confirmed by Serial Annual Electrocardiograms. AB - Late-onset amyloidogenic transthyretin (ATTR) type familial amyloid polyneuropathy (FAP) shows features distinct from those of early-onset hereditary ATTR type FAP. We herein describe an asymptomatic 68-year-old man with late-onset ATTR type FAP whose serial annual electrocardiograms demonstrated progressive left bundle branch block. Latent but severe cardiac involvement seems to be one feature of late-onset ATTR type FAP, similar to senile systemic amyloidosis (SSA). Early differential diagnosis of late-onset ATTR type FAP from SSA is important because, currently, only the former has new therapeutic options available in Japan. The present case report, therefore, highlights the necessity of careful observation for periodic electrocardiograms. PMID- 28090047 TI - Platypnea-orthodeoxia Syndrome in a Patient with an Atrial Septal Defect: The Diagnosis and Choice of Treatment. AB - A 77-year-old woman developed dyspnea over three years which occurred during sitting, standing or walking. Her physical examination, chest X-ray, ECG and cardiac catheterization results were all normal. A marked fall in arterial oxygen saturation was observed on sitting or standing. Transesophageal echocardiography showed an increase of right to left shunt flow on sitting. The patient was diagnosed with platypnea-orthodeoxia syndrome and underwent the surgical closure of an atrial septal defect of 19 mm in diameter. After the surgery, the patient's POS symptoms were completely resolved. She was discharged and followed at the outpatient clinic. Her post-treatment course was uneventful. PMID- 28090048 TI - Hyponatremia in an Elderly Patient due to Isolated Hypoaldosteronism Occurring after Licorice Withdrawal. AB - Hyponatremia is one of the most common electrolyte disorders encountered in the elderly. We present the case of an 81-year-old man who developed hyponatremia due to isolated hypoaldosteronism occurring after licorice withdrawal. He had severe hypokalemia with hypertension and was diagnosed with pseudoaldosteronism. He had been taking a very small dose of licorice as a mouth refresher since his early adulthood. Five months after licorice withdrawal, he developed hypovolemic hyponatremia, which was resolved with administration of fludrocortisone acetate. Our experience with this case suggests that isolated hypoaldosteronism occurring after licorice withdrawal should be considered as a potential cause of hyponatremia in elderly patients. PMID- 28090049 TI - Thyroid Storm Precipitated by Diabetic Ketoacidosis and Influenza A: A Case Report and Literature Review. AB - A 46-year-old woman with a history of Graves' disease presented with the chief complaints of appetite loss, weight loss, fatigue, nausea, and sweating. She was diagnosed with diabetic ketoacidosis (DKA), thyroid storm, and influenza A. She was treated with an intravenous insulin drip, intravenous fluid therapy, intravenous hydrocortisone, oral potassium iodine, and oral methimazole. As methimazole-induced neutropenia was suspected, the patient underwent thyroidectomy. It is important to maintain awareness that thyroid storm and DKA can coexist. Furthermore, even patients who have relatively preserved insulin secretion can develop DKA if thyroid storm and infection develop simultaneously. PMID- 28090050 TI - Euglycemic Diabetic Ketoacidosis with Persistent Diuresis Treated with Canagliflozin. AB - Diabetic ketoacidosis is characterized by hyperglycemia, anion-gap acidosis, and increased plasma ketones. After the resolution of hyperglycemia, persistent diuresis is rare. We herein report the case of a 27-year-old Asian woman with type 2 diabetes who was treated with a sodium-glucose cotransporter 2 (SGLT2) inhibitor (canagliflozin) who developed euglycemic diabetic ketoacidosis and persistent diuresis in the absence of hyperglycemia. Physicians should consider euglycemic diabetic ketoacidosis in the differential diagnosis of patients treated with SGLT2 inhibitors. PMID- 28090051 TI - Different Effects of Tolvaptan in Patients with Idiopathic Membranous Nephropathy with Nephrotic Syndrome. AB - This case report discusses the clinical indication for immunosuppressants in patients with idiopathic membranous nephropathy (IMN). Because this disease occasionally shows spontaneous remission, it is necessary to determine the predictive values for a therapeutic effect in order to provide appropriate treatment. Two distinct cases described herein illustrate the different effects of tolvaptan in responders and non-responders, according to the pre-treatment levels of AQP-2 immunostaining in the samples from renal biopsy and urinary levels of AQP-2 and osmolality, suggesting that these values may be useful predictors of response to tolvaptan in patients with nephrotic IMN. PMID- 28090052 TI - Interstitial Pneumonia Associated with the Influenza Vaccine: A Report of Two Cases. AB - Although the influenza vaccine is relatively safe and effective, serious complications can develop in rare cases. We encountered two cases of interstitial pneumonia that developed after vaccination during the 2014-2015 influenza season. Overall, nine cases, including the two presented here, have been recorded in PubMed and the Cochrane library; eight patients were treated with corticosteroids, and all nine survived, suggesting a good prognosis. Interstitial pneumonia is rare; however, we found an increase in its incidence after 2009. Therefore, clinicians must be aware of the possibility of this complication and duly educate all patients in advance. PMID- 28090053 TI - A Suspected Case of an Alveolar Haemorrhage Caused by Dasatinib. AB - A 39-year-old man treated with dasatinib for chronic myelogenous leukaemia presented to our hospital with haemoptysis, coughing, and dyspnoea. Chest radiography and computed tomography revealed ground-glass opacities and a crazy paving pattern. Bronchoalveolar lavage was not performed due to serious hypoxemia and bleeding. Significant bleeding from the peripheral bronchi led to a diagnosis of an alveolar haemorrhage. Dasatinib-induced alveolar haemorrhaging was suspected based on the clinical findings. His condition improved immediately after dasatinib withdrawal and initiation of steroid therapy. Reports of alveolar haemorrhaging induced by dasatinib are rare. As such, this is considered an important case. PMID- 28090054 TI - Hemoglobin Kansas as a Rare Cause of Cyanosis: A Case Report and Review of the Literature. AB - Hemoglobin (Hb) Kansas is an inherited Hb variant with a low oxygen affinity that is associated with low oxygen saturation on pulse oximetry (SpO2). It leads to asymptomatic cyanosis. Patients with Hb Kansas do not require any specific treatment and the prognosis is good. In patients with unexplained cyanosis, we should thus consider Hb variants, including Hb Kansas and avoid unnecessary investigations and managements. We herein report the case of 65-year-old woman with Hb Kansas and review five other cases (three lineages) that have been reported in Japan. PMID- 28090055 TI - Natalizumab is Effective for the Treatment of Relapsing-remitting Tumefactive Multiple Sclerosis. AB - We herein report the case of a 57-year-old woman presenting with a biopsy-proven tumefactive demyelinating lesion as her first clinical event. Subsequently, she displayed a relapsing-remitting course with recurrence of large demyelinating lesions exceeding 2 cm in diameter rather than the small ovoid lesions characteristic of multiple sclerosis. Administration of interferon beta did not suppress the disease activity. Finally, treatment with natalizumab, which is a humanized monoclonal antibody against the cell-adhesion molecule alpha4-integrin, was initiated, resulting in clinical and radiological stabilization. Our experience here suggests that natalizumab may be an effective therapeutic option for relapsing-remitting tumefactive multiple sclerosis with high disease activity. PMID- 28090056 TI - Suspected Pulmonary Infection with Trichoderma longibrachiatum after Allogeneic Stem Cell Transplantation. AB - Aspergillus and Candida species are the main causative agents of invasive fungal infections in immunocompromised human hosts. However, saprophytic fungi are now increasingly being recognized as serious pathogens. Trichoderma longibrachiatum has recently been described as an emerging pathogen in immunocompromised patients. We herein report a case of isolated suspected invasive pulmonary infection with T. longibrachiatum in a 29-year-old man with severe aplastic anemia who underwent allogeneic stem cell transplantation. A direct microscopic examination of sputum, bronchoaspiration, and bronchoalveolar lavage fluid samples revealed the presence of fungal septate hyphae. The infection was successfully treated with 1 mg/kg/day liposomal amphotericin B. PMID- 28090057 TI - The First Case Report of Acute Cholangitis and Bacteremia Due to Neisseria subflava. AB - We herein report a case of acute cholangitis and bacteremia caused by a commensal Neisseria species, Neisseria subflava, in an 82-year-old man with cholangiocarcinoma. Emergency endoscopic nasobiliary drainage and cefoperazone/sulbactam therapy were effective. Gram negative coccobacilli were isolated from both blood and bile cultures on 5% sheep blood agar. The isolate was identified as N.subflava biovar perflava by mass spectrometry, a sequence analysis of the 16S rRNA, and biochemical testing. Although biliary infections due to commensal Neisseria are extremely rare, this case demonstrates the possibility of its occurrence in patients undergoing bile duct treatment. PMID- 28090058 TI - Herpes Simplex Encephalitis Complicated by Cerebral Hemorrhage during Acyclovir Therapy. AB - Herpes simplex encephalitis (HSE) can be complicated by adverse events in the acute phase. We herein present the case of a 71-year-old woman with HSE complicated by cerebral hemorrhage. She presented with acute deterioration of consciousness and fever and was diagnosed with HSE based on the detection of herpes simplex virus-1 in the cerebrospinal fluid by a polymerase chain reaction. The cerebral hemorrhage developed during acyclovir therapy; however, its diagnosis was delayed for 2 days. After the conservative treatment of the cerebral hemorrhage, the patient made a near-complete recovery. Cerebral hemorrhage should be considered as an acute-phase complication of HSE. PMID- 28090059 TI - Isolated Bilateral Coronary Ostial Stenosis in Behcet's Disease. PMID- 28090060 TI - Medullary Nephrocalcinosis in a Furosemide Abuser. PMID- 28090061 TI - Umbilical Plaque in Psoriatic Arthritis. PMID- 28090062 TI - Ankylosis of the Finger in Erosive Osteoarthritis. PMID- 28090063 TI - Mycotic Aneurysm of a Persistent Sciatic Artery. PMID- 28090064 TI - Purpura Fulminans Associated with Overwhelming Postsplenectomy Infection. PMID- 28090065 TI - Assessment of workplace air concentrations of formaldehyde during and before working hours in medical facilities. AB - Workplace air concentrations of formaldehyde (FA) in medical facilities where FA and FA-treated organs were stored and handled were measured before and during working hours and assessed by the official method specified by Work Environment Measurement Law. Sixty-percent of the total facilities examined were judged as inappropriately controlled work environment. The concentrations of FA before working hours by spot sampling were found to exceed 0.1 ppm in some facilities, and tended to increase with increasing volume of containers storing FA and FA treated materials. Regression analysis revealed that logarithmic concentrations of FA during working hours by the Law-specified analytical method were highly correlated with those before working hours by spot sampling, suggesting the importance for appropriate storing methods of FA and FA-treated materials. The concentrations of FA during working hours are considered to be lowered by effective ventilation of FA-contaminated workplace air and appropriate storage of FA and FA-treated materials in plastic containers in the medical facilities. In particular, such improvement by a local exhaust ventilation system and tightly sealed containment of FA-treated material were urgently needed for the dissecting room where FA-treated cadavers were prepared and handled for a gross anatomy course in a medical school. PMID- 28090066 TI - Trapezius muscle activity and body movement at the beginning and the end of a workday and during the lunch period in female office employees. AB - The aim of this study was to analyze the activity of the trapezius muscle and the arm acceleration during the course of a workday in office employees. It was examined if there are significant changes in trapezius muscle activity in the afternoon compared to the morning work period and relationships to the level of arm acceleration during lunchtime. Nineteen female office employees were recruited. A one hour period of the work in the morning, afternoon, and lunchtime were compared. The measures of the trapezius muscle activity and muscle rest time (TR) did not significantly differ between working in the morning (TR: median 10%; range 1%-49) or working in the afternoon (TR: median 18%; range 2%-34%). The 90th percentile of arm acceleration during lunch time significantly correlated with less trapezius muscle activity in the afternoon compared to the morning values (RT: Spearman R=0.80; p<0.01). Differences in the duration and level of trapezius muscle activity were bigger between the subjects than between different work periods or between lunchtime and work. Furthermore it seems that higher arm accelerations during lunch may be beneficial in reducing trapezius activity in the afternoon compared to the morning values. PMID- 28090067 TI - Discovery and Synthesis of Amino Acids Modified Deoxycholic Acid Derivatives and in Vitro Antiproliferative Evaluation. AB - A series of deoxycholic acid (DCA) derivatives bearing amino acid moiety has been synthesized and investigated for their potential antiproliferative activities. DCA derivative compounds were synthesized by a two or three step synthetic approach. Their bioactivities were evaluated using 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) method and Western blotting analysis on three tumor cell lines A549 (human lung cancer cell line), MCF-7 (human breast cancer cell line) and HeLa (human cervical carcinoma cell). The novel derivatives DCA3d, DCA5a, DCA5b, DCA5c, and DCA5d were found to be promising antiproliferative agents. Furthermore, DCA5b showed the greatest cytotoxic activity by induction of apoptosis. These compounds show potentiality for further optimization as antitumor drugs. PMID- 28090068 TI - Relationship between Physicochemical Properties of Medical Supplies and Serious Adverse Drug Reactions Listed in the Package Inserts. AB - We sought to clarify the relationship between the physicochemical properties of each medical supply and serious adverse drug reactions listed in the package inserts, by reviewing new information. We investigated 1) 1078 medicines currently available on the domestic Japanese market by using physicochemical data, such as cLogD, molecular weight (MW), and pKa and 2) the serious adverse drug reactions stated in the package inserts and the presence or absence of serious renal and liver disorders, as well as mental, extrapyramidal, and skin disorders. The renal disorders data showed: cLogD<0, adjusted odds ratio (aOR)=2.00; MW values >=500, aOR=2.28; and pKa<7.4, aOR=1.95-2.06. The liver disorders data showed: pKa<8.4, aOR=1.83-1.95, and MW values >=300, aOR=1.47 1.87. The mental disorders data showed: cLogD>=0, aOR=2.12, and MW values<400, aOR=2.46-2.85. The extrapyramidal disorders data showed: pKa>=6.4, aOR=4.50 11.32; cLogD>=0, aOR=4.71; and MW values<500, aOR=7.95-15.08. The skin disorders data showed: cLogD<0, aOR=1.46; MW values >=500, aOR=1.69; and pKa<6.4, aOR=1.65 or<7.4-8.4, aOR=1.59. This information will be useful for investigating the relationships between new drugs entering the market and their potential future adverse drug reactions, and for establishing both precautionary and medical observational standards. PMID- 28090069 TI - Fabrication of Janus particles composed of poly (lactic-co-glycolic) acid and hard fat using a solvent evaporation method. AB - The feasibility of fabricating Janus particles based on phase separation between a hard fat and a biocompatible polymer was investigated. The solvent evaporation method used involved preparing an oil-in-water (o/w) emulsion with a mixture of poly (lactic-co-glycolic) acid (PLGA), hard fat, and an organic solvent as the oil phase and a polyvinyl alcohol aqueous solution as the water phase. The Janus particles were formed when the solvent was evaporated to obtain certain concentrations of PLGA and hard fat in the oil phase, at which phase separation was estimated to occur based on the phase diagram analysis. The hard fat hemisphere was proven to be the oil phase using a lipophilic dye Oil Red O. When the solvent evaporation process was performed maintaining a specific volume during the emulsification process; Janus particles were formed within 1.5 h. However, the formed Janus particles were destroyed by stirring for over 6 h. In contrast, a few Janus particles were formed when enough water to dissolve the oil phase solvent was added to the emulsion immediately after the emulsification process. The optimized volume of the solvent evaporation medium dominantly formed Janus particles and maintained the conformation for over 6 h with stirring. These results indicate that the formation and stability of Janus particles depend on the rate of solvent evaporation. Therefore, optimization of the solvent evaporation rate is critical to obtaining stable PLGA and hard fat Janus particles. PMID- 28090070 TI - Biotin treatment causing erroneous immunoassay results: A word of caution for clinicians. AB - Biotin or vitamin B7 when ingested in high doses may cause immunoassay interference leading to false potentially misleading results. It is important that clinicians should always interpret laboratory results in the context of patient's clinical state as erroneous results may lead to misdiagnosis and injudicious treatment with adverse patient outcome. PMID- 28090071 TI - Impact of Morning Onset on the Incidence of Recurrent Acute Coronary Syndrome and Progression of Coronary Atherosclerosis in Acute Myocardial Infarction. AB - BACKGROUND: The relationship between time of onset of acute myocardial infarction (MI) and long-term clinical outcome has not been completely understood. We hypothesized that morning onset acute MI may be associated with adverse cardiac events.Methods and Results:This study involved 663 patients who underwent primary percutaneous coronary intervention (PCI). The main outcome measures were cardiac death, recurrent acute coronary syndrome (ACS), and re-hospitalization for heart failure. Major adverse cardiac events (MACE) were defined as a composite of individual adverse outcomes. Morning onset acute MI occurred in 212 patients (32.0%); they had higher rates of recurrent ACS (13% vs. 8%, P=0.03) and MACE (21% vs. 14%, P=0.012) than the patients with other times of onset. The PCI rate for progressive lesions was also higher than for patients with other times of onset (23% vs. 14%, P=0.013). On multivariate Cox regression analysis, morning onset was an independent predictor of recurrent ACS, MACE, and PCI for progressive lesions, with adjusted hazard ratios of 1.34 (95% CI: 1.06-2.92, P=0.030), 1.51 (95% CI: 1.02-2.23, P=0.038), and 1.58 (95% CI: 1.03-2.42, P=0.037), respectively. CONCLUSIONS: Morning onset may be associated with increased risk of recurrent ACS and coronary atherosclerosis progression. PMID- 28090072 TI - Reconsideration of Inferior Vena Cava Parameters for Estimating Right Atrial Pressure in an East Asian Population - Comparative Simultaneous Ultrasound Catheterization Study. AB - BACKGROUND: Ultrasound measurements of the inferior vena cava (IVC) diameter (IVCD), together with its respiratory variation, provide a noninvasive estimate of right atrial pressure (RAP). However, there is a paucity of studies that have compared this technique with simultaneous catheterization. We explored the best cut-off values of IVC parameters for elevated RAP in comparison with RAP measured by catheterization.Methods and Results:We prospectively enrolled 120 East Asian patients who were scheduled for catheterization. The IVCD and IVC collapsibility index (IVCCI) were measured according to the current guidelines. The optimal maximum IVCD (IVCDmax) and IVCCI cut-offs for detecting elevated RAP (RAP >=10 mmHg) were 17 mm and 40%, respectively. When we combined both in proportion to the guidelines, the sensitivity and specificity for detecting elevated RAP were 75% and 94%, respectively. When the cut-off values from the current guidelines (>21 mm and <50%) were applied, the respective sensitivity and specificity were 42% and 99%. Interestingly, the cut-off value of the optimal IVCDmax indexed by body surface area (11 mm/m2) was similar to previous Western population data. When we combined both cut-off values (11 mm/m2and 40%), the sensitivity and specificity were 75% and 95%, respectively. CONCLUSIONS: The optimal absolute IVCDmax and IVCCI cut-offs to detect elevated RAP were smaller than those in the current guidelines. Indexed IVCDmax may be an IVC parameter that can be used internationally. PMID- 28090073 TI - A Case of Miller Fisher Syndrome, Thromboembolic Disease, and Angioedema: Association or Coincidence? AB - BACKGROUND Miller Fisher Syndrome is characterized by the clinical triad of ophthalmoplegia, ataxia, and areflexia, and is considered to be a variant of Guillain-Barre Syndrome. Miller Fisher Syndrome is observed in approximately 1-5% of all Guillain-Barre cases in Western countries. Patients with Miller Fisher Syndrome usually have good recovery without residual deficits. Venous thromboembolism is a common complication of Guillain-Barre Syndrome and has also been reported in Miller Fisher Syndrome, but it has generally been reported in the presence of at least one prothrombotic risk factor such as immobility. A direct correlation between venous thromboembolism and Miller Fisher Syndrome or Guillain-Barre Syndrome has not been previously described. CASE REPORT We report the case of a 32-year-old Hispanic male who presented with acute, severe thromboembolic disease and concurrently demonstrated characteristic clinical features of Miller Fisher Syndrome including ophthalmoplegia, ataxia, and areflexia. Past medical and family history were negative for thromboembolic disease, and subsequent hypercoagulability workup was unremarkable. During the course of hospitalization, the patient also developed angioedema. CONCLUSIONS We describe a possible association between Miller Fisher Syndrome, thromboembolic disease, and angioedema. PMID- 28090074 TI - Targeting of Wnt/beta-Catenin by Anthelmintic Drug Pyrvinium Enhances Sensitivity of Ovarian Cancer Cells to Chemotherapy. AB - BACKGROUND Aberrant activation of Wnt/beta-catenin has been shown to promote ovarian cancer proliferation and chemoresistance. Pyrvinium, an FDA-approved anthelmintic drug, has been identified as a potent Wnt inhibitor. Pyrvinium may sensitize ovarian cancer cells to chemotherapy. MATERIAL AND METHODS The effect of pyrvinium alone and its combination with paclitaxel in ovarian cancer was investigated using an in vitro culture system and in vivo xenograft models. The mechanisms of its action were also analyzed, focusing on the Wnt/beta-catenin pathway. RESULTS Pyrvinium inhibited growth and induced apoptosis of paclitaxel- and cisplatin-resistant epithelial ovarian cancer cell lines A2278/PTX and SK-OV 3. Its combination with paclitaxel was synergistic in targeting ovarian cancer cells in vitro. In 3 independent ovarian xenograft mouse models, pyrvinium alone inhibited tumor growth. More importantly, we observed significant inhibition of tumor growth throughout the treatment when using pyrvinium and paclitaxel combined. Mechanistically, pyrvinium increased the Wnt-negative regulator axin and decreased the b-catenin levels in ovarian cancer cells. In addition, pyrvinium suppressed Wnt/b-catenin-mediated transcription, as shown by the decreased mRNA levels of MYC, cyclin D, and BCL-9. In contrast, the inhibitory effects of pyrvinium were reversed by beta-catenin stabilization or overexpression, demonstrating that pyrvinium acted on ovarian cancer cells via targeting the Wnt/beta-catenin signaling pathway. CONCLUSIONS We demonstrated that the anthelmintic drug pyrvinium targets ovarian cancer cells through suppressing Wnt/beta-catenin signaling. Our work highlights the therapeutic value of inhibiting Wnt/beta-catenin in ovarian cancer. PMID- 28090075 TI - Virus-host interactions and their roles in coral reef health and disease. AB - Coral reefs occur in nutrient-poor shallow waters, constitute biodiversity and productivity hotspots, and are threatened by anthropogenic disturbance. This Review provides an introduction to coral reef virology and emphasizes the links between viruses, coral mortality and reef ecosystem decline. We describe the distinctive benthic-associated and water-column- associated viromes that are unique to coral reefs, which have received less attention than viruses in open ocean systems. We hypothesize that viruses of bacteria and eukaryotes dynamically interact with their hosts in the water column and with scleractinian (stony) corals to influence microbial community dynamics, coral bleaching and disease, and reef biogeochemical cycling. Last, we outline how marine viruses are an integral part of the reef system and suggest that the influence of viruses on reef function is an essential component of these globally important environments. PMID- 28090076 TI - A journey into the brain: insight into how bacterial pathogens cross blood-brain barriers. AB - The blood-brain barrier, which is one of the tightest barriers in the body, protects the brain from insults, such as infections. Indeed, only a few of the numerous blood-borne bacteria can cross the blood-brain barrier to cause meningitis. In this Review, we focus on invasive extracellular pathogens, such as Neisseria meningitidis, Streptococcus pneumoniae, group B Streptococcus and Escherichia coli, to review the obstacles that bacteria have to overcome in order to invade the meninges from the bloodstream, and the specific skills they have developed to bypass the blood-brain barrier. The medical importance of understanding how these barriers can be circumvented is underlined by the fact that we need to improve drug delivery into the brain. PMID- 28090079 TI - Archaeal evolution: Evolutionary insights from the Vikings. PMID- 28090078 TI - Interfacing broadband photonic qubits to on-chip cavity-protected rare-earth ensembles. AB - Ensembles of solid-state optical emitters enable broadband quantum storage and transduction of photonic qubits, with applications in high-rate quantum networks for secure communications and interconnecting future quantum computers. To transfer quantum states using ensembles, rephasing techniques are used to mitigate fast decoherence resulting from inhomogeneous broadening, but these techniques generally limit the bandwidth, efficiency and active times of the quantum interface. Here, we use a dense ensemble of neodymium rare-earth ions strongly coupled to a nanophotonic resonator to demonstrate a significant cavity protection effect at the single-photon level-a technique to suppress ensemble decoherence due to inhomogeneous broadening. The protected Rabi oscillations between the cavity field and the atomic super-radiant state enable ultra-fast transfer of photonic frequency qubits to the ions (~50 GHz bandwidth) followed by retrieval with 98.7% fidelity. With the prospect of coupling to other long-lived rare-earth spin states, this technique opens the possibilities for broadband, always-ready quantum memories and fast optical-to-microwave transducers. PMID- 28090077 TI - Clinical and biological insights from viral genome sequencing. AB - Whole-genome sequencing (WGS) of pathogens is becoming increasingly important not only for basic research but also for clinical science and practice. In virology, WGS is important for the development of novel treatments and vaccines, and for increasing the power of molecular epidemiology and evolutionary genomics. In this Opinion article, we suggest that WGS of viruses in a clinical setting will become increasingly important for patient care. We give an overview of different WGS methods that are used in virology and summarize their advantages and disadvantages. Although there are only partially addressed technical, financial and ethical issues in regard to the clinical application of viral WGS, this technique provides important insights into virus transmission, evolution and pathogenesis. PMID- 28090080 TI - You are where you live. AB - This month's Genome Watch discusses how whole-genome sequencing of bacteria from several body sites has provided insights into the spatial diversity of bacteria within patients. PMID- 28090082 TI - Polycystic kidney disease: Autophagy boost to treat ADPKD? PMID- 28090081 TI - Metabolic reprogramming and tolerance during sepsis-induced AKI. AB - The host defence against infection is an adaptive response in which several mechanisms are deployed to decrease the pathogen load, limit tissue injury and restore homeostasis. In the past few years new evidence has suggested that the ability of the immune system to limit the microbial burden - termed resistance - might not be the only defence mechanism. In fact, the capacity of the host to decrease its own susceptibility to inflammation- induced tissue damage - termed tolerance - might be as important as resistance in determining the outcome of the infection. Metabolic adaptations are central to the function of the cellular immune response. Coordinated reprogramming of metabolic signalling enables cells to execute resistance and tolerance pathways, withstand injury, steer tissue repair and promote organ recovery. During sepsis-induced acute kidney injury, early reprogramming of metabolism can determine the extent of organ dysfunction, progression to fibrosis, and the development of chronic kidney disease. Here we discuss the mechanisms of tolerance that act in the kidney during sepsis, with particular attention to the role of metabolic responses in coordinating these adaptive strategies. We suggest a novel conceptual model of the cellular and organic response to sepsis that might lead to new avenues for targeted, organ protective therapies. PMID- 28090083 TI - Kidney disease and obesity: epidemiology, mechanisms and treatment. AB - The theme of World Kidney Day 2017 is 'kidney disease and obesity: healthy lifestyle for healthy kidneys'. To mark this event, Nature Reviews Nephrology invited five leading researchers to describe changes in the epidemiology of obesity-related kidney disease, advances in current understanding of the mechanisms and current approaches to the management of affected patients. The researchers also highlight new advances that could lead to the development of novel treatments and identify areas in which further basic and clinical studies are needed. PMID- 28090084 TI - Limiting parental feedback disrupts vocal development in marmoset monkeys. AB - Vocalizations of human infants undergo dramatic changes across the first year by becoming increasingly mature and speech-like. Human vocal development is partially dependent on learning by imitation through social feedback between infants and caregivers. Recent studies revealed similar developmental processes being influenced by parental feedback in marmoset monkeys for apparently innate vocalizations. Marmosets produce infant-specific vocalizations that disappear after the first postnatal months. However, it is yet unclear whether parental feedback is an obligate requirement for proper vocal development. Using quantitative measures to compare call parameters and vocal sequence structure we show that, in contrast to normally raised marmosets, marmosets that were separated from parents after the third postnatal month still produced infant specific vocal behaviour at subadult stages. These findings suggest a significant role of social feedback on primate vocal development until the subadult stages and further show that marmoset monkeys are a compelling model system for early human vocal development. PMID- 28090085 TI - Prediction and real-time compensation of qubit decoherence via machine learning. AB - The wide-ranging adoption of quantum technologies requires practical, high performance advances in our ability to maintain quantum coherence while facing the challenge of state collapse under measurement. Here we use techniques from control theory and machine learning to predict the future evolution of a qubit's state; we deploy this information to suppress stochastic, semiclassical decoherence, even when access to measurements is limited. First, we implement a time-division multiplexed approach, interleaving measurement periods with periods of unsupervised but stabilised operation during which qubits are available, for example, in quantum information experiments. Second, we employ predictive feedback during sequential but time delayed measurements to reduce the Dick effect as encountered in passive frequency standards. Both experiments demonstrate significant improvements in qubit-phase stability over 'traditional' measurement-based feedback approaches by exploiting time domain correlations in the noise processes. This technique requires no additional hardware and is applicable to all two-level quantum systems where projective measurements are possible. PMID- 28090086 TI - Centrality in the host-pathogen interactome is associated with pathogen fitness during infection. AB - To perform their functions proteins must interact with each other, but how these interactions influence bacterial infection remains elusive. Here we demonstrate that connectivity in the host-pathogen interactome is directly related to pathogen fitness during infection. Using Y. pestis as a model organism, we show that the centrality-lethality rule holds for pathogen fitness during infection but only when the host-pathogen interactome is considered. Our results suggest that the importance of pathogen proteins during infection is directly related to their number of interactions with the host. We also show that pathogen proteins causing an extensive rewiring of the host interactome have a higher impact in pathogen fitness during infection. Hence, we conclude that hubs in the host pathogen interactome should be explored as promising targets for antimicrobial drug design. PMID- 28090087 TI - A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis. AB - T helper 9 (Th9) cells contribute to lung inflammation and allergy as sources of interleukin-9 (IL-9). However, the mechanisms by which IL-9/Th9 mediate immunopathology in the lung are unknown. Here we report an IL-9-driven positive feedback loop that reinforces allergic inflammation. We show that IL-9 increases IL-2 production by mast cells, which leads to expansion of CD25+ type 2 innate lymphoid cells (ILC2) and subsequent activation of Th9 cells. Blocking IL-9 or inhibiting CD117 (c-Kit) signalling counteracts the pathogenic effect of the described IL-9-mast cell-IL-2 signalling axis. Overproduction of IL-9 is observed in expectorates from cystic fibrosis (CF) patients, and a sex-specific variant of IL-9 is predictive of allergic reactions in female patients. Our results suggest that blocking IL-9 may be a therapeutic strategy to ameliorate inflammation associated with microbial colonization in the lung, and offers a plausible explanation for gender differences in clinical outcomes of patients with CF. PMID- 28090088 TI - The beta-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor. AB - beta-TrCP and SKP2 are two well-studied F-box proteins, which often act as oncogenes. Whether and how they communicate with each other is unknown. Here we report that FBXW2, a poorly characterized F-box, is a substrate of beta-TrCP1 and an E3 ligase for SKP2. While beta-TrCP1 promotes FBXW2 ubiquitylation and shortens its half-life, FBXW2 does the same to SKP2. FBXW2 has tumour suppressor activity against lung cancer cells and blocks oncogenic function of both beta TrCP1 and SKP2. The levels of beta-TrCP1-FBXW2-SKP2 are inversely correlated during cell cycle with FBXW2 and beta-TrCP/SKP2 being high or low, respectively, in arrested cells, whereas the opposite is true in proliferating cells. Consistently, FBXW2 predicts a better patient survival, whereas beta-TrCP1 and SKP2 predict a worse survival. Finally, the gain- and loss-of-function mutations of FBXW2 are found in various human cancers. Collectively, our data show that the beta-TrCP-FBXW2-SKP2 axis forms an oncogene-tumour suppressor-oncogene cascade to control cancer cell growth with FBXW2 acting as a tumour suppressor by promoting SKP2 degradation. PMID- 28090089 TI - Transfer of minimally manipulated CMV-specific T cells from stem cell or third party donors to treat CMV infection after allo-HSCT. AB - Cytomegalovirus (CMV) infection is a common, potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo HSCT). We assessed prospectively the safety and efficacy of stem cell-donor- or third-party-donor-derived CMV-specific T cells for the treatment of persistent CMV infections after allo-HSCT in a phase I/IIa trial. Allo-HSCT patients with drug-refractory CMV infection and lacking virus-specific T cells were treated with a single dose of ex vivo major histocompatibility complex-Streptamer isolated CMV epitope-specific donor T cells. Forty-four allo-HSCT patients receiving a T-cell-replete (D+ repl; n=28) or T-cell-depleted (D+ depl; n=16) graft from a CMV-seropositive donor were screened for CMV-specific T-cell immunity. Eight D+ depl recipients received adoptive T-cell therapy from their stem cell donor. CMV epitope-specific T cells were well supported and became detectable in all treated patients. Complete and partial virological response rates were 62.5% and 25%, respectively. Owing to longsome third-party donor (TPD) identification, only 8 of the 57 CMV patients transplanted from CMV-seronegative donors (D-) received antigen-specific T cells from partially human leukocyte antigen (HLA)-matched TPDs. In all but one, TPD-derived CMV-specific T cells remained undetectable. In summary, adoptive transfer correlated with functional virus-specific T-cell reconstitution in D+ depl patients. Suboptimal HLA match may counteract expansion of TPD-derived virus-specific T cells in D- patients. PMID- 28090090 TI - Incidence and prognostic impact of ASXL2 mutations in adult acute myeloid leukemia patients with t(8;21)(q22;q22): a study of the German-Austrian AML Study Group. PMID- 28090091 TI - Proposed diagnostic criteria and classification of basophilic leukemias and related disorders. AB - Basophils form a distinct cell lineage within the hematopoietic cell family. In various myeloid neoplasms, including chronic myeloid leukemia, basophilia is frequently seen. Acute and chronic basophilic leukemias, albeit rare, have also been described. However, no generally accepted criteria and classification of basophilic leukemias have been presented to date. To address this unmet need, a series of Working Conferences and other meetings were organized between March 2015 and March 2016. The current article provides a summary of consensus statements from these meetings, together with proposed criteria to delineate acute basophilic leukemia (ABL) from chronic basophilic leukemia (CBL) and primary forms of the disease where no preceding myeloid malignancy is detected, from the more common 'secondary' variants. Moreover, the term hyperbasophilia (HB) is proposed for cases with a persistent peripheral basophil count ?1000 per MUl of blood. This condition, HB, is highly indicative of the presence of an underlying myeloid neoplasm. Therefore, HB is an important checkpoint in the diagnostic algorithm and requires a detailed hematologic investigation. In these patients, an underlying myeloid malignancy is often found and is then labeled with the appendix -baso, whereas primary cases of ABL or CBL are very rare. The criteria and classification proposed in this article should facilitate the diagnosis and management of patients with unexplained basophilia and basophil neoplasms in routine practice, and in clinical studies. PMID- 28090094 TI - Doing Your Part to Advance Pharmacy Education Scholarship. PMID- 28090092 TI - The clonal origins of leukemic progression of myelodysplasia. AB - The genetics behind the progression of myelodysplasia to secondary acute myeloid leukemia (sAML) is poorly understood. In this study, we profiled somatic mutations and their dynamics using next generation sequencing on serial samples from a total of 124 patients, consisting of a 31 patient discovery cohort and 93 patients from two validation cohorts. Whole-exome analysis on the discovery cohort revealed that 29 of 31 patients carry mutations related to at least one of eight commonly mutated pathways in AML. Mutations in genes related to DNA methylation and splicing machinery were found in T-cell samples, which expand at the initial diagnosis of the myelodysplasia, suggesting their importance as early disease events. On the other hand, somatic variants associated with signaling pathways arise or their allelic burdens expand significantly during progression. Our results indicate a strong association between mutations in activated signaling pathways and sAML progression. Overall, we demonstrate that distinct categories of genetic lesions play roles at different stages of sAML in a generally fixed order. PMID- 28090093 TI - uPAR promotes tumor-like biologic behaviors of fibroblast-like synoviocytes through PI3K/Akt signaling pathway in patients with rheumatoid arthritis. AB - Urokinase-type plasminogen activator receptor (uPAR), is a multifunctional receptor on cell surface, widely present in endothelial cells, fibroblasts, and a variety of malignant cells. Current studies have suggested that uPAR overexpressed on synovial tissues or in synovial fluid or plasma in patients with rheumatoid arthritis (RA). However, there are limited researches regarding the role of uPAR on fibroblast-like synoviocytes of rheumatoid arthritis (RA-FLSs) and its underlying mechanisms. Here, our studies show that the expression of uPAR protein was significantly higher in fibroblast-like synoviocytes (FLSs) from RA than those from osteoarthritis or traumatic injury patients. uPAR gene silencing significantly inhibited RA-FLSs cell proliferation, restrained cell transformation from the G0/G1 phase to S phase, aggravated cell apoptosis, interfered with RA-FLSs cell migration and invasion, and reduced activation of the PI3K/Akt signaling pathway, which may be associated with beta1-integrin. Cell supernatants from uPAR gene-silenced RA-FLSs markedly inhibited the migration and tubule formation ability of the HUVECs (a human endothelial cell line). Therefore, we demonstrate that uPAR changes the biological characteristics of RA FLSs, and affects neoangiogenesis of synovial tissues in patients with RA. All of these may be associated with the beta1-integrin/PI3K/Akt signaling pathway. These results imply that targeting uPAR and its downstream signal pathway may provide therapeutic effects in RA. PMID- 28090095 TI - Academic Freedom Should Be Redefined: Point and Counterpoint. AB - As part of the 2014-15 Academic Leadership Fellows Program, the cohort teams presented debates on topics relevant to academic pharmacy at a public forum during the 2015 American Association of Colleges of Pharmacy Interim Meeting. The topic of one of the debates was "Academic Freedom Should Be Redefined." The "point" of the debate focused on important issues such as the fundamental definition of academic freedom as it was written in the 1940 American Association of University Professors' Statement and the need for redefinition as a consequence of many misunderstandings and misinterpretations that have arisen over time. The "counterpoint" received the greatest support, and it asserted that redefinition is not necessary, but rather the need is to clearly articulate the intended meaning of academic freedom through education, discussion, and by not supporting inappropriate behaviors in the name of "academic freedom." Reinforced clarity and operational guidance from the academy and academic institutions may add further clarification and may be the best approach to address the concerns related to academic freedom. PMID- 28090096 TI - A Bioinformatics Practicum to Develop Student Understanding of Immunological Rejection of Protein Drugs. AB - Objectives. To design and implement a bioinformatics exercise that applies immunological principles to predicting rejection of protein drugs based upon patient genotype. Design. Doctor of pharmacy (PharmD) students used the Immune Epitope Database, a freely available bioinformatics tool. Over a 2-week laboratory, students interrogated whether a protein drug would be predicted to induce an immune response based upon patient genotype. Results were presented at the last laboratory session, and students completed reports discussing their findings. Assessment. Pre-lab quizzes and a final report were graded. Students answered questionnaires assessing perceived learning gains. To determine the impact on student understanding of immunity against protein drugs, the quality of student data analysis and comparisons to class data were graded. Independent measures of student learning demonstrated that students developed a greater understanding of how patient genotype could contribute to treatment failure with protein drugs. Conclusions. This study indicates that questions related to clinical immunology can be posed using bioinformatics tools. PMID- 28090097 TI - Impact of the Birkman Method Assessment on Pharmacy Student Self-Confidence, Self Perceptions, and Self-Awareness. AB - Objective. To identify changes in pharmacy student self-confidence, self perceptions, and self-awareness after completing the Birkman Method assessment and training program. Methods. Survey tools were developed to evaluate students at baseline and following the co-curricular Birkman Method program. Following IRB approval, students participating in the Birkman Method program were recruited for enrollment in this survey-based study. Results. Student self-confidence was high at baseline (mean=4 out of 5) and did not significantly change after Birkman Method testing and training. Self-perceptions regarding usual and stressed communication style and behaviors and behavioral needs under stress changed significantly after Birkman Method testing and training for these endpoints. The Birkman Method intervention resulted in a significant improvement in self awareness, as indicated by a mean self-perception accuracy score increase of 1.6 points (95% CI: 1.3-1.9). Conclusions. A Birkman Method assessment and training program is an effective self-assessment tool for students, and may be useful for accomplishing Accreditation Council for Pharmacy Education (ACPE) 2016 Standard 4 affective domain elements, particularly self-awareness. PMID- 28090098 TI - Evaluation of a Teaching Assistant Program for Third-Year Pharmacy Students. AB - Objectives. To determine if a teaching assistant (TA) program for third-year pharmacy students (PY3s) improves confidence in teaching abilities. Additionally, 3 assessment methods (faculty, student, and TA self-evaluations) were compared for similarities and correlations. Methods. An application and interview process was used to select 21 pharmacy students to serve as TAs for the Pharmaceutical Care Laboratory course for 2 semesters. Participants' self-perceived confidence in teaching abilities was assessed at the start, midpoint, and conclusion of the program. The relationships between the scores were analyzed using 3 assessment methods. Results. All 21 TAs agreed to participate in the study and completed the 2 teaching semesters. The TAs confidence in overall teaching abilities increased significantly (80.7 vs 91.4, p<0.001). There was a significant difference between the three assessment scores in the fall (p=0.027) and spring (p<0.001) semesters. However, no correlation was found among the assessment scores. Conclusions. The TA program was effective in improving confidence in teaching abilities. The lack of correlation among the assessment methods highlights the importance of various forms of feedback. PMID- 28090099 TI - First-Year Pharmacy Students' Views on Their Chosen Professional Career. AB - Objective. To investigate what factors influenced students to study pharmacy and determine in which sector they hoped to gain employment, both in the short and longer term. Methods. First-year pharmacy students (n=124) were invited to complete a paper-based, self-administered questionnaire consisting of 4 sections. Descriptive statistics and nonparametric tests were conducted. Results. One hundred (96.8% response rate) students completed the questionnaire (22.5% male; 77.5% female). Key influential factors for choosing pharmacy included: enjoyment of science at school, a desire to improve people's health and wellbeing, and to work in health care. Career aspirations were to work in a hospital or in community practice rather than in industry or academia. Conclusions. Students choose pharmacy as a career primarily for altruistic and clinical reasons. This research provides information for pharmacy schools about the career aspirations of students and data from future pharmacists is potentially helpful to pharmacy professional organizations and potential employers. PMID- 28090100 TI - Description and Evaluation of an MPharm Practice-based Experience Pilot Program. AB - Objective. To determine the level of support among pharmacists in central Scotland to serve as mentors and provide practice-based experience to students enrolled in a master of pharmacy degree program. Methods. A study was conducted during the 2011-2012 academic year in which first-year MPharm students in Scotland were paired with practicing pharmacists for 2 half-day visits per month. The students were integrated into the pharmacy workflow and engaged in activities ranging from date checking to counseling patients. The pharmacists and students who participated were asked to complete a survey in spring 2012 regarding their experiences and, in addition, the students were asked to maintain diary entries describing their experiences. Results. Thirty-nine students were paired successfully with 38 pharmacists. Every pharmacist stated their student was welcome to return in the 2012-2013 academic year and 29 agreed to accept a second student. Nine of 12 participating chain community pharmacies asked for program expansion and 11 chain community pharmacies and one other community pharmacy that did not participate in 2011-2012 asked to join in 2012-2013. Conclusion. Large numbers of pharmacists in central Scotland are willing to mentor and provide practice-based pharmacy education for students in a manner consistent with General Pharmaceutical Council accreditation standards for the master of pharmacy degree curriculum. PMID- 28090101 TI - A Novel Mathematical Model for Determining Faculty Workload. AB - Objective. To develop a mathematical model for determining faculty workload at a college of pharmacy with a team-based learning curriculum. Methods. Using faculty provided data, our model calculated activity and weighted means in teaching, scholarship and service. Subsequently, these data were used to develop departmental and institutional workload models. Results. For the pharmaceutical and biomedical sciences department, percent faculty activity mean values were greatest for service followed by teaching and scholarship. These values in the clinical sciences department were greatest for teaching followed by service and scholarship. Overall, the institutional workload model had the largest maximum faculty activity value for teaching, followed by service and then scholarship. Conclusions. A novel faculty workload model proved to be effective in optimizing faculty workload within a college of pharmacy. Since the workload analysis, the faculty service commitment has been substantially changed, by reducing the number of committees at our institution. This type of workload analysis may particularly benefit colleges of pharmacy that employ a team based learning curriculum, with a large time commitment to teaching. PMID- 28090102 TI - Virtual Patient Case Sharing Across Two Schools of Pharmacy. AB - Objective. To expand the use of virtual patients at 2 schools of pharmacy through virtual patient case sharing. Design. Faculty members at two schools of pharmacy collaborated to expand the use of virtual patients. Two simulation programs, vpSim and DecisionSim (Decision Simulation, LLC, Chadsford, PA), were used to create interactive patient cases for a required course and an elective course at the different schools. Each school developed cases for their own use and then shared the cases with the other school. Assessment. The development, sharing, and subsequent modification of cases were examined using a standardized data collection form completed by both schools. Survey instruments were used to gather data regarding faculty perception and student satisfaction. Pre- and post-tests were administered to assess student learning. Five cases were developed and shared between the institutions. The time spent constructing new cases (22 hours/case) was significantly longer than the time spent modifying the shared cases (1.2 hours/case). Faculty members and students were largely satisfied with case sharing and the use of virtual patient cases, respectively. Virtual patients significantly enhanced student learning of material (mean score: 3.2 vs 3.6 on a 5-point scale). Conclusions. The sharing of virtual patient cases may allow institutions to overcome barriers to implementation of virtual patient programs, namely faculty resources, while improving student learning and satisfaction. PMID- 28090103 TI - A Critical Care Hybrid Online Elective Course for Third-Year Pharmacy Students. AB - Objective. To assess the impact of a four-week hybrid online elective course in critical care on student learning attitudes and outcomes compared to that achieved when the same course was taught using a traditional lecture-based approach. Design. A hybrid online elective course was created that featured video recorded lectures and in-class skills laboratories. Course evaluations were used to assess student perceptions of learning methods, and examination scores were used to assess learning outcomes. Assessment. One hundred five students enrolled in the critical care elective course from 2011-2014. Fifty-four students completed the traditional lecture course, and 51 completed the hybrid online elective course. The examination scores of students who completed the hybrid course were significantly higher than those of students who completed the traditional lecture course. The majority of students enrolled in the hybrid online elective course stated they preferred that format over a traditional course format and would recommend the elective course to a peer. Conclusion. Students preferred the format used for an online hybrid elective course in critical care over a traditional course format, and performed better on examinations than did students who had completed the course when it was offered in a traditional lecture format. PMID- 28090104 TI - Interprofessional Online Global Health Course. AB - Objective. The design and evaluation of an online global health course targeted for pharmacy and other undergraduates is presented. Design. Enrolled students represented nursing, health education, pharmacy and a variety of other disciplines. The course was designed as an entirely online one with no class meetings. The course consisted of eight modules addressing global health competencies and interprofessional education competencies. Readings, quizzes, study question and team projects were tailored to the goals of each module. Students worked in interprofessional teams for their team projects. Assessment. Assessments consisted of pre and post course perceptions and course evaluation. Rubrics were designed to evaluate team assignments and peer assessment of team participation. Conclusion. Course was successful in enhancing perceptions of global health knowledge and understanding of roles and responsibilities of various health disciplines in addressing challenges of global health. No changes in teamwork perceptions were documented after completing the course. The overall course structure was successful in meeting course goals. PMID- 28090105 TI - Student Knowledge, Skills, and Self-Efficacy Gains After Completing an Advanced Pharmacy Practice Experience in Geriatrics. AB - Objective. To assess changes in pharmacy students' knowledge, skills, and self efficacy after completing an advanced pharmacy practice experience (APPE) in geriatrics. Design. During the 2013-2014 academic year, 30 Virginia Commonwealth University (VCU) School of Pharmacy students were required to complete a 5-week Geriatrics APPE at Plaza Professional Pharmacy in Richmond, Virginia. All students completed a 25-point knowledge-based pre- and post-assessment to measure students' self-efficacy. The average time required to accurately fill one unit dose prescription card before and after completing the APPE was also evaluated. Assessment. Students' average score on the knowledge component improved significantly from 54% to 88% after completing the APPE. The average time required to fill one prescription decreased significantly from 4.0 minutes to 2.5 minutes. Students reported an increase in self-efficacy in the following areas: communication, immunizations, geriatrics-specific pharmacotherapy knowledge, and the ability to fill and check monthly unit dose prescription cards. Conclusion. Requiring fourth-year pharmacy students to complete a geriatrics APPE as a capstone experience to the integrated geriatrics content covered in the first through third years of the doctor of pharmacy (PharmD) curriculum provides an important opportunity to improve students' knowledge, skills, and self-efficacy in providing care to older adults. PMID- 28090106 TI - An Interprofessional Simulation Using the SBAR Communication Tool. AB - Objective. To determine the impact of an interprofessional simulation using the SBAR (situation-background-assessment-recommendation/request) communication tool on pharmacy students' self-perception of interprofessional competence and reactions towards interprofessional collaboration. Design. Ninety-six pharmacy students participated in an interprofessional simulation within a required applications-based capstone course. Pharmacy students collaborated with nursing students on multiple patient cases in various settings using the SBAR communication tool over the telephone. Assessment. Pharmacy students' responses to all 20 items on the Interprofessional Collaborative Competency Attainment Survey (ICCAS) completed after participating in the simulation indicated significant positive changes. The themes identified in students' reflection papers indicated the simulation was beneficial and student responses on satisfaction surveys were positive with a mean score of 4.2 on a 5-point Likert scale. Conclusion. Implementation of an interprofessional simulation using the SBAR communication tool improved pharmacy students' self-perception of interprofessional competence and attitudes toward interprofessional collaboration. PMID- 28090107 TI - Developing a Framework for Objective Structured Clinical Examinations Using the Nominal Group Technique. AB - Objective. To use the nominal group technique to develop a framework to improve existing and develop new objective structured clinical examinations (OSCEs) within a four-year bachelor of pharmacy course. Design. Using the nominal group technique, a unique method of group interview that combines qualitative and quantitative data collection, focus groups were conducted with faculty members, practicing pharmacists, and undergraduate pharmacy students. Five draft OSCEs frameworks were suggested and participants were asked to generate new framework ideas. Assessment. Two focus groups (n=9 and n=7) generated nine extra frameworks. Two of these frameworks, one from each focus group, ranked highest (mean scores of 4.4 and 4.1 on a 5-point scale) and were similar in nature. The project team used these two frameworks to produce the final framework, which includes an OSCE in every year of the course, earlier implementation of teaching OSCEs, and the use of independent simulated patients who are not examiners. Conclusions. The new OSCE framework provides a consistent structure from course entry to exit and ensures graduates meet internship requirements. PMID- 28090108 TI - A Process for Curricular Improvement Based on Evaluation of Student Performance on Milestone Examinations. AB - Objective. To identify and address areas for curricular improvement by evaluating student achievement of expected learning outcomes and competencies on annual milestone examinations. Design. Students were tested each professional year with a comprehensive milestone examination designed to evaluate student achievement of learning outcomes and professional competencies using a combination of multiple choice questions, standardized patient assessments (SPAs), and objective structured clinical examination (OSCE) questions. Assessment. Based on student performance on milestone examinations, curricular changes were instituted, including an increased emphasis on graded comprehensive cases, OSCE skills days, and use of patient simulation in lecture and laboratory courses. After making these changes, significant improvements were observed in second and third-year pharmacy students' grades for the therapeutic case and physician interaction/errors and omissions components of the milestone examinations. Conclusion. Results from milestone examinations can be used to identify specific areas in which curricular improvements are needed to foster student achievement of learning outcomes and professional competencies. PMID- 28090109 TI - Substance Use Attitudes, Behaviors, Education and Prevention in Colleges of Pharmacy in the United States. AB - This review describes and summarizes student pharmacists' substance use behavior in the United States. Current literature indicates that there are problems with alcohol and other drug use among student pharmacists. Although researchers have found variations in the type and rate of reported substance use, significant proportions of student pharmacists were identified as being at high risk for substance use disorders (SUDs). Findings from this review suggest that pharmacy schools should encourage and stimulate more research in order to implement effective screening and early intervention programs in an effort to address this important student health issue. PMID- 28090110 TI - Entrustable Professional Activities: Personalization and Expansion for Pharmacy Graduates? PMID- 28090111 TI - Aligning Aspirations with Inspirations: Address of the 2015-2016 President to the Opening General Session at the AACP Annual Meeting. PMID- 28090112 TI - Demystifying Advocacy: Moving Faculty and Students Toward Citizen Engagement: Report of the 2015-2016 AACP Standing Committee on Advocacy. PMID- 28090113 TI - Examining the Foundation of AACP: Report of the 2015-16 Argus Commission. PMID- 28090114 TI - Priming the Preceptor Pipeline: Collaboration, Resources, and Recognition: The Report of the 2015-2016 Professional Affairs Standing Committee. PMID- 28090115 TI - Report of the 2015-2016 Academic Affairs Standing Committee. PMID- 28090116 TI - Report of the 2014-2016 AACP Research and Graduate Affairs Committee. PMID- 28090117 TI - Generation of Shear Waves by Laser in Soft Media in the Ablative and Thermoelastic Regimes. AB - This article describes the generation of elastic shear waves in a soft medium using a laser beam. Our experiments show two different regimes depending on laser energy. Physical modeling of the underlying phenomena reveals a thermoelastic regime caused by a local dilatation resulting from temperature increase, and an ablative regime caused by a partial vaporization of the medium by the laser. Computed theoretical displacements are close to experimental measurements. A numerical study based on the physical modeling gives propagation patterns comparable to those generated experimentally. These results provide a physical basis for the feasibility of a shear wave elastography technique (a technique which measures a soft solid stiffness from shear wave propagation) by using a laser beam. PMID- 28090118 TI - Thermochemistry and kinetics of graphite oxide exothermic decomposition for safety in large-scale storage and processing. AB - The success of graphene technologies will require the development of safe and cost-effective nano-manufacturing methods. Special safety issues arise for manufacturing routes based on graphite oxide (GO) as an intermediate due to its energetic behavior. This article presents a detailed thermochemical and kinetic study of GO exothermic decomposition designed to identify the conditions and material compositions that avoid explosive events during storage and processing at large scale. It is shown that GO becomes more reactive for thermal decomposition when it is pretreated with OH- in suspension and the effect is reversible by back-titration to low pH. This OH- effect can lower the decomposition reaction exotherm onset temperature by up to 50 degrees of Celsius, causing overlap with common drying operations (100-120 degrees C) and possible self-heating and thermal runaway during processing. Spectroscopic and modeling evidence suggest epoxide groups are primarily responsible for the energetic behavior, and epoxy ring opening/closing reactions are offered as an explanation for the reversible effects of pH on decomposition kinetics and enthalpies. A quantitative kinetic model is developed for GO thermal decomposition and used in a series of case studies to predict the storage conditions under which spontaneous self-heating, thermal runaway, and explosions can be avoided. PMID- 28090119 TI - Redefinition of the Genus Typhlocypris Vejdovsky, 1882 (Ostracoda, Candonidae). AB - The taxonomy of the genus Typhlocypris Vejdovsky, 1882 is reviewed. New morphological information on Typhlocypris eremita (Vejdovsky, 1882), the type species of the genus, is provided, and a new reference material is presented. The generic diagnosis is emended with details derived from the developmental trajectory of the valves, from the juvenile stage A-3 to the adult. Those criteria clearly differentiate Typhlocypris from the related genus Pseudocandona Kaufmann, 1900. As here redefined, Typhlocypris is a phylogentic lineage of the subfamily Candoninae containing extant species presently living in aquatic subterranean habitats and fossil species recovered from non-marine Late Palaeogene to Neogene and Quaternary deposits in Europe and western Asia. The type species of Typhlocypris is considered a metaspecies, taxonomically treated as T. eremita (sensu lato), which includes populations resembling the newly designated reference material. The homeomorphic triangular valve shape of the Candoninae is discussed. Careful examination of the valve morphology of Typhlocypris combined with the analysis of limb traits helps to distinguish representatives of this genus from unrelated phylogenetic groups presenting similar triangularly shaped valves. It is emphasised that for a useful description of Typhlocypris taxa both transmitted light and scanning electron microscopy are necessary. PMID- 28090120 TI - Morphotypes of Cytheridella Ilosvayi (Ostracoda) Detected by Soft and Hard Part Analyses. AB - Quantitative approaches dealing with soft- and hard-part morphological variability of ostracods are very rare for most species. Here we present intraspecific limb and shell variability of the Neotropical freshwater ostracod species assumed as Cytheridella ilosvayi. For the first time such an analysis considered adult females and males, as well as juveniles. Variability of the appendages included the antennule, second antenna as well as the first and second thoracopod and was analysed in terms of ratios of podomeres, setae and limbs. Limb variability of adult and juvenile individuals (down to A-3) is generally low. The highest variation is shown in podomere proportions of the antennas, while thoracopods and setae provide minor and/or non-significant influence on the variability. Based on discrimination analyses shell parameters (i.e., shell length, position of the transversal sulcus) emerge to be more important for differentiation of groups than limb ratios. Adult females exhibit a large size range in which two clearly separated morphotypes exist. Although differences in limbs are small their existence can be proven also on the basis of proportions between podomeres of the antennas. Males and juveniles, however, do not display a separation into corresponding subgroups or morphotypes. The presence of two morphologically similar females and only one type of males indicates the coexistence of female morphotypes which may represent either two (cryptic) species or a mixed reproduction population in which parthenogenetic and sexual reproduction coexists. PMID- 28090122 TI - Effect of static vs. dynamic imaging on particle transport in CT-based numerical models of human central airways. AB - Advances in quantitative computed tomography (CT) has provided methods to assess the detailed structure of the pulmonary airways and parenchyma, providing the means of applying computational fluid dynamics-based modeling to better understand subject-specific differences in structure-to-function relationships. Most of the previous numerical studies, seeking to predict patterns of inhaled particle deposition, have considered airway geometry and regional ventilation derived from static images. Because geometric alterations of the airway and parenchyma associated with regional ventilation may greatly affect particle transport, we have sought to investigate the effect of rigid vs. deforming airways, linear vs. nonlinear airway deformations, and step-wise static vs. dynamic imaging on particle deposition with varying numbers of intermediate lung volume increments. Airway geometry and regional ventilation at different time points were defined by four-dimensional (space and time) dynamic or static CT images. Laminar, transitional, and turbulent air flows were reproduced with a three-dimensional eddy-resolving computational fluid dynamics model. Finally, trajectories of particles were computed with the Lagrangian tracking algorithm. The results demonstrated that static-imaging-based models can contribute 7% uncertainty to overall particle distribution and deposition primarily due to regional flow rate (ventilation) differences as opposed to geometric alterations. The effect of rigid vs. deforming airways on serial distribution of particles over generations was significantly smaller than reported in a previous study that used the symmetric Weibel geometric model with smaller flow rate. Rigid vs. deforming airways were also shown to affect parallel particle distribution over lobes by 8% and the differences associated with use of static vs. dynamic imaging was 18%. These differences demonstrate that estimates derived from static vs. dynamic imaging can significantly affect the assessment of particle distribution heterogeneity. The effect of linear vs. nonlinear airway deformations was within the uncertainty due to mesh size. PMID- 28090123 TI - Transfer Standard Uncertainty Can Cause Inconclusive Inter-Laboratory Comparisons. AB - Inter-laboratory comparisons use the best available transfer standards to check the participants' uncertainty analyses, identify underestimated uncertainty claims or unknown measurement biases, and improve the global measurement system. For some measurands, instability of the transfer standard can lead to an inconclusive comparison result. If the transfer standard uncertainty is large relative to a participating laboratory's uncertainty, the commonly used standardized degree of equivalence <= 1 criterion does not always correctly assess whether a participant is working within their uncertainty claims. We show comparison results that demonstrate this issue and propose several criteria for assessing a comparison result as passing, failing, or inconclusive. We investigate the behavior of the standardized degree of equivalence and alternative comparison measures for a range of values of the transfer standard uncertainty relative to the individual laboratory uncertainty values. The proposed alternative criteria successfully discerned between passing, failing, and inconclusive comparison results for the cases we examined. PMID- 28090121 TI - Redox Signaling through DNA. AB - Biological electron transfer reactions between metal cofactors are critical to many essential processes within the cell. Duplex DNA is, moreover, capable of mediating the transport of charge through its pi-stacked nitrogenous bases. Increasingly, [4Fe4S] clusters, generally redox-active cofactors, have been found to be associated with enzymes involved in DNA processing. DNA-binding enzymes containing [4Fe4S] clusters can thus utilize DNA charge transport (DNA CT) for redox signaling to coordinate reactions over long molecular distances. In particular, DNA CT signaling may represent the first step in the search for DNA lesions by proteins containing [4Fe4S] clusters that are involved in DNA repair. Here we describe research carried out to examine the chemical characteristics and biological consequences of DNA CT. We are finding that DNA CT among metalloproteins represents powerful chemistry for redox signaling at long range within the cell. PMID- 28090124 TI - Practical Synthetic Procedures for the Iron-Catalyzed Intermolecular Olefin Aminohydroxylation Using Functionalized Hydroxylamines. AB - A set of practical synthetic procedures for the iron-catalyzed intermolecular olefin aminohydroxylation reactions in gram scale is reported. In these transformations, a bench-stable functionalized hydroxylamine is applied as the amination reagent. This method is compatible with a broad range of synthetically valuable olefins including those that are incompatible with the existing aminohydroxylation methods. It also provides valuable amino alcohol building blocks with regio- and stereo-chemical arrays that are complementary to known methods. PMID- 28090125 TI - A multi-physics model for ultrasonically activated soft tissue. AB - A multi-physics model has been developed to investigate the effects of cellular level mechanisms on the thermomechanical response of ultrasonically activated soft tissue. Cellular level cavitation effects have been incorporated in the tissue level continuum model to accurately determine the thermodynamic states such as temperature and pressure. A viscoelastic material model is assumed for the macromechanical response of the tissue. The cavitation model based equation of-state provides the additional pressure arising from evaporation of intracellular and cellular water by absorbing heat due to structural and viscoelastic heating in the tissue, and temperature to the continuum level thermomechanical model. The thermomechanical response of soft tissue is studied for the operational range of frequencies of oscillations and applied loads for typical ultrasonically activated surgical instruments. The model is shown to capture characteristics of ultrasonically activated soft tissue deformation and temperature evolution. At the cellular level, evaporation of water below the boiling temperature under ambient conditions is indicative of protein denaturation around the temperature threshold for coagulation of tissues. Further, with increasing operating frequency (or loading), the temperature rises faster leading to rapid evaporation of tissue cavity water, which may lead to accelerated protein denaturation and coagulation. PMID- 28090126 TI - Fourier Transform Infrared Absorption Spectroscopy for Quantitative Analysis of Gas Mixtures at Low Temperatures for Homeland Security Applications. AB - Performance standard specifications for point chemical vapor detectors are established in ASTM E 2885-13 and ASTM E 2933-13. The performance evaluation of the detectors requires the accurate delivery of known concentrations of the chemical target to the system under test. Referee methods enable the analyte test concentration and associated uncertainties in the analyte test concentration to be validated by independent analysis, which is especially important for reactive analytes. This work extends the capability of a previously demonstrated method for using Fourier transform infrared (FT-IR) absorption spectroscopy for quantitatively evaluating the composition of vapor streams containing hazardous materials at Acute Exposure Guideline Levels (AEGL) to include test conditions colder than laboratory ambient temperatures. The described method covers the use of primary reference spectra to establish analyte concentrations, the generation of secondary reference spectra suitable for measuring analyte concentrations under specified testing environments, and the use of additional reference spectra and spectral profile strategies to mitigate the uncertainties due to impurities and water condensation within the low-temperature (7 degrees C, -5 degrees C) test cell. Important benefits of this approach include verification of the test analyte concentration with characterized uncertainties by in situ measurements co located with the detector under test, near-real-time feedback, and broad applicability to toxic industrial chemicals. PMID- 28090127 TI - Parametrization of white matter manifold-like structures using principal surfaces. AB - In this manuscript, we are concerned with data generated from a diffusion tensor imaging (DTI) experiment. The goal is to parameterize manifold-like white matter tracts, such as the corpus callosum, using principal surfaces. The problem is approached by finding a geometrically motivated surface-based representation of the corpus callosum and visualized fractional anisotropy (FA) values projected onto the surface. The method also applies to any other diffusion summary. An algorithm is proposed that 1) constructs the principal surface of a corpus callosum; 2) flattens the surface into a parametric 2D map; 3) projects associated FA values on the map. The algorithm is applied to a longitudinal study containing 466 diffusion tensor images of 176 multiple sclerosis (MS) patients observed at multiple visits. For each subject and visit the study contains a registered DTI scan of the corpus callosum at roughly 20,000 voxels. Extensive simulation studies demonstrate fast convergence and robust performance of the algorithm under a variety of challenging scenarios. PMID- 28090128 TI - ASSOCIATION OF TOTAL AND DIFFERENTIAL WHITE BLOOD CELL COUNTS TO DEVELOPMENT OF TYPE 2 DIABETES IN MEXICAN AMERICANS IN CAMERON COUNTY HISPANIC COHORT. AB - OBJECTIVE: To evaluate the relationship between total and differential White Blood Cell (WBC) counts with time to transition to type 2 diabetes in Mexican Americans using prospective data from the Cameron County Hispanic Cohort (CCHC). RESULTS: Multivariable Cox proportional hazards regression models revealed that obese Mexican-American cohort participants whose total WBC or granulocyte count increased over time had 1.39 and 1.35 times higher risk respectively of transition to type 2 diabetes when compared to overweight participants. The granulocyte or total WBC count in participants with BMI>=35 were significant risk factors for transition to type 2 diabetes. CONCLUSIONS: Increased total WBC and WBC differential counts, particularly lymphocytes and granulocytes, are associated with risk of transition to type 2 diabetes in obese Mexican Americans, after adjusting for other potential confounders. Screening and monitoring the WBC counts, including lymphocytes and granulocytes can help with monitoring potential transition to type 2 diabetes. PMID- 28090129 TI - Work Stress and Alcohol Use: Developing and Testing a Biphasic Self-Medication Model. AB - This study developed and tested a moderated-mediation model of work stress and alcohol use, based on the biphasic (stimulant and sedative) effects of alcohol and the self-medication and stress-vulnerability models of alcohol use. The model proposes that exposure to work stressors can increase both negative affect and work fatigue, and that these two sources of strain can subsequently motivate the use of alcohol. However, the relations of negative affect and work fatigue to alcohol use are conditional on the joint moderating effects of alcohol outcome expectancies and gender. Data were collected from a national probability sample of 2,808 U.S. workers. Supporting the model, the results indicated that work stressor exposure was conditionally related via negative affect to heavy alcohol use among both men and women holding strong tension reduction alcohol expectancies and to after work alcohol use among men holding strong tension reduction alcohol expectancies. Also, work stressor exposure was conditionally related via work fatigue to both heavy alcohol use and workday alcohol use among men holding strong fatigue reduction alcohol expectancies. The results have application in the identification of individuals at higher risk of problematic alcohol use and are relevant to workplace safety and to the design of appropriate interventions. PMID- 28090130 TI - Parent predictors of adolescents' explanatory style. AB - The current study tested the prospective relations (six month lag) between three aspects of the parent-child relationship at Time 1 (T1) and adolescents' explanatory styles at Time 2 (T2): caregiving behaviors, parents' explanatory style for their own negative events, and parents' explanatory style for their children's negative events. The sample included 129 adolescents aged 11 to 14 years at baseline and their parents. Adolescents reported on their own explanatory style and their parents' caregiving behaviors; parents self-reported on their caregiving behaviors and their explanatory style for their own and their children's events. Regression analyses identified maternal acceptance as a significant predictor of T2 adolescents' explanatory style. Marginal effects emerged for fathers' psychological control and fathers' explanatory style for their children's events. Findings suggest that the ways parents - especially mothers - interact with their children may play a role in adolescents' cognitive vulnerability to depression. PMID- 28090131 TI - Can't afford a baby? Debt and young Americans. AB - This article explores the role of personal debt in the transition to parenthood. We analyze data from the National Longitudinal Study of Youth-1997 cohort and find that for the generation coming of age in the 2000s, student loans delay fertility for women, particularly at very high levels of debt. Home mortgages and credit card debt, in contrast, appear to be precursors to parenthood. These results indicate that different forms of debt have different implications for early adulthood transitions: whereas consumer loans or home mortgages immediately increase access to consumption goods, there is often a significant delay between the accrual and realization of benefits for student loans. The double-edged nature of debt as both barrier and facilitator to life transitions highlights the importance of looking at debt both as a monetary issue and also as a carrier of social meanings. PMID- 28090132 TI - Asymptotic Normality of Quadratic Estimators. AB - We prove conditional asymptotic normality of a class of quadratic U-statistics that are dominated by their degenerate second order part and have kernels that change with the number of observations. These statistics arise in the construction of estimators in high-dimensional semi- and non-parametric models, and in the construction of nonparametric confidence sets. This is illustrated by estimation of the integral of a square of a density or regression function, and estimation of the mean response with missing data. We show that estimators are asymptotically normal even in the case that the rate is slower than the square root of the observations. PMID- 28090133 TI - Impacts of Changes of Indoor Air Pressure and Air Exchange Rate in Vapor Intrusion Scenarios. AB - There has, in recent years, been increasing interest in understanding the transport processes of relevance in vapor intrusion of volatile organic compounds (VOCs) into buildings on contaminated sites. These studies have included fate and transport modeling. Most such models have simplified the prediction of indoor air contaminant vapor concentrations by employing a steady state assumption, which often results in difficulties in reconciling these results with field measurements. This paper focuses on two major factors that may be subject to significant transients in vapor intrusion situations, including the indoor air pressure and the air exchange rate in the subject building. A three-dimensional finite element model was employed with consideration of daily and seasonal variations in these factors. From the results, the variations of indoor air pressure and air exchange rate are seen to contribute to significant variations in indoor air contaminant vapor concentrations. Depending upon the assumptions regarding the variations in these parameters, the results are only sometimes consistent with the reports of several orders of magnitude in indoor air concentration variations from field studies. The results point to the need to examine more carefully the interplay of these factors in order to quantitatively understand the variations in potential indoor air exposures. PMID- 28090134 TI - Outcome-Dependent Sampling Design and Inference for Cox's Proportional Hazards Model. AB - We propose a cost-effective outcome-dependent sampling design for the failure time data and develop an efficient inference procedure for data collected with this design. To account for the biased sampling scheme, we derive estimators from a weighted partial likelihood estimating equation. The proposed estimators for regression parameters are shown to be consistent and asymptotically normally distributed. A criteria that can be used to optimally implement the ODS design in practice is proposed and studied. The small sample performance of the proposed method is evaluated by simulation studies. The proposed design and inference procedure is shown to be statistically more powerful than existing alternative designs with the same sample sizes. We illustrate the proposed method with an existing real data from the Cancer Incidence and Mortality of Uranium Miners Study. PMID- 28090135 TI - [Pax Narcotica : The Open-Air Drug Markets of Philadelphia's Puerto Rican Inner City]. PMID- 28090137 TI - Echocardiographic assessment of right ventricle adaptation to endurance training in young rowers - speckle tracking echocardiography. AB - The aim of this study was to determine the relationship between the degree of cardiorespiratory fitness and the function of the right ventricle (RV). 117 rowers, age 17.5+/-1.5 years. All subjects underwent cardiopulmonary exercise. Standard echocardiography and 2D speckle tracking echocardiography with evaluation of longitudinal strain in each segment of the RV (basal - RVLS-B; mid RVLS-M, apical - RVLS-A) and global RV free-wall strain (RVLS-G) were performed. RVLS-B values were lower compared to the RVLS-M (-25.8+/-4.4 vs -29.3+/-3.5; p<0.001) and RVLS-A values (-25.8+/-4.4 vs -26.2+/-3.4; p=0.85). Correlations between VO2max and RVLS were observed in men: RVLS-G strain (r = 0.43; p <0.001); RVLS-B (r = 0.30; p = 0.02); RVLS-M (r = 0.38; p = 0.02). A similar relationship was not observed in the group of women. The strongest predictors corresponding to a change in global and basal strain were VO2max and training time: RVLS-G (VO2max: beta = 0.18, p = 0.003; training time: beta = -0.39; p = 0.02) and RVLS B (VO2max: beta = 0.23; p = 0.0001 training time: beta = -1.16; p = 0.0001). The global and regional reduction of RV systolic function positively correlates with the level of fitness, and this relationship is observed already in young athletes. The character of the relationship between RV deformation parameters and the variables that determine the physical performance depend on gender. The dependencies apply to the proximal fragment of the RV inflow tract, which may be a response to the type of flow during exercise in endurance athletes. PMID- 28090138 TI - Agility training in young elite soccer players: promising results compared to change of direction drills. AB - The aim of this study was to compare the effect of two different training programmes - change of direction (COD) vs. agility (AG) - on straight sprint (SS), COD and AG test performances in young elite soccer players. Thirty-two soccer players (age: 14.5+/-0.9 years; height: 171.2+/-5.1 cm; body mass: 56.4+/ 7.1 kg, body fat: 10.3+/-2.3%) participated in a short-term (6 weeks) training study. Players were randomly assigned to two experimental groups - training with change of direction drills (COD-G, n=11) or using agility training (AG-G, n= 11) and to a control group (CON-G, n=10). All players completed the following tests before and after training: straight sprint (15m SS), 15 m agility run with (15m AR-B) and without a ball (15m-AR), 5-0-5 agility test, reactive agility test (RAT), and RAT test with ball (RAT-B). A significant group effect was observed for all tests (p<0.001; eta2=large). In 15m SS, COD-G and AG-G improved significantly (2.21; ES=0.57 and 2.18%; ES=0.89 respectively) more than CON-G (0.59%; ES=0.14). In the 15m-AR and 5-0-5 agility test, COD-G improved significantly more (5.41%; ES=1.15 and 3.41; ES=0.55 respectively) than AG-G (3.65%; ES=1.05 and 2.24; ES=0.35 respectively) and CON-G (1.62%; ES=0.96 and 0.97; ES=0.19 respectively). Improvements in RAT and RAT-B were larger (9.37%; ES=2.28 and 7.73%; ES=2.99 respectively) in RAT-G than the other groups. In conclusion, agility performance amongst young elite soccer could be improved using COD training. Nevertheless, including a conditioning programme for agility may allow a high level of athletic performance to be achieved. PMID- 28090136 TI - The impact of duration on effectiveness of exercise, the implication for periodization of training and goal setting for individuals who are overfat, a meta-analysis. AB - Given the assumption that all methods of exercise, e.g., endurance (ET), resistance (RT), or combination of both (E+R), can induce a beneficial effect size (ES) for changes in body composition and health status of individuals who are overfat. Thus the aim and purpose of this study is to evaluate the current body of knowledge to address the question as to the impact that the duration of exercise has on its relative effectiveness for inducing health and body compositional changes in individuals who are overfat to assist with developing periodized exercise protocols and establishing short and long term goals. A tiered meta-analysis of 92-studies and 200-exercise groupings were used for establishing pooled ES within and between groupings based on the increments of 4 week of duration and study designs of <=8, 9-16, 17-23, 24-36, and >=36 weeks. Analysis based on random-effect of response indicates a continuum of effectiveness within and between ET, RT and E+R based on duration. Where beneficial effectiveness is not indicated for any measures until after 8-weeks of continuous training with progressive effectiveness being noted in changes to cardiorespiratory fitness, inflammatory cytokines, and alteration of metabolic status from 12-weeks through 32-weeks of continuous training. Results indicate a greater ES for RT and E+R versus ET early in intervention that equalizes with longer durations. Supporting the use of RT and E+R within a periodized program. And secondarily, goals should be established first on performance gains and second body composition or health status modifications for the individual who is overfat. PMID- 28090139 TI - The blood antioxidant defence capacity during intermittent hypoxic training in elite swimmers. AB - The main objective of this study was to examine the chronic effect of simulated intermittent normobaric hypoxia on blood antioxidant defence capacity in swimmers. The study included 14 male and 14 female competitive swimmers performing part of land training under simulated intermittent normobaric hypoxia (O2 = 15.5%) or in normoxia. Land interval training took place twice per week, with a total of 8 training units during the study, performed with individualized intensity. The activities of blood antioxidant enzymes did not change significantly during the first and last training unit in the hypoxic and normoxic group. However, when comparing individual variables a significant effect of exercise was observed on GPx an CAT activities, whereas training units significantly differentiated GPx and GR activities. The oxygen conditions and gender had a significant influence on CAT activity. The total antioxidant capacity was not significantly affected. Only in male swimmers from the hypoxic group did the training significantly increase resting levels of MDA. In conclusion, training in normobaric hypoxia was not an adequate stimulus for the excessive response of the antioxidant defence system, despite increased oxidative stress in these conditions. PMID- 28090140 TI - Influence of warm-up duration and recovery interval prior to exercise on anaerobic performance. AB - The purpose of the study was to determine the impact of different active warm-up (AWU) durations and the rest interval separating it from exercise on anaerobic performance. Eleven male physical education students (22.6 +/- 2.52 years; 179.2 +/- 4.3 cm; 82.5 +/- 9.7 kg; mean +/- SD) participated in a cross-over randomized study, and they all underwent the Wingate test after three AWU durations: 5 min (AWU5), 15 min (AWU15) and 20 min (AWU20), with recovery (WREC) or without a recovery interval (NREC) separating the AWU and anaerobic exercise performance. All the AWUs consisted of pedalling at a constant pace of 60 rpm at 50% of the maximal aerobic power. The rest interval between the end of warm-up and the beginning of exercise was set at 5 min. During the Wingate test, peak power (PP), mean power (MP) and the fatigue index (FI) were recorded and analysed. Oral temperature was recorded at rest and at the end of the warm-up. Likewise, rest, post-warm-up and post-Wingate heart rate (HR) and rating of perceived exertion (RPE) were recorded during each session. The ANOVA showed a significant effect of recovery interval, warm-up duration and measurement point on RPE scores (P<0.001). Although the effect of AWU duration on MP and PP was significant (P<0.05), the effect of the recovery interval on both parameters was not significant (P>0.05). Moreover, the analyses showed a significant interaction between recovery interval and AWU duration (P<0.001 and P<0.05 for MP and PP respectively). The AWU15 duration improves the MP and PP when associated with a recovery interval prior to exercise of 5 min. However, the AWU5 duration allows better improvement of power output when the exercise is applied immediately after the warm-up. Consequently, physically active males, as well as educators and researchers interested in anaerobic exercise, must take into account the duration of warm-up and the following recovery interval when practising or assessing activities requiring powerful lower limb muscle contractions. PMID- 28090141 TI - Do maximal aerobic power and blood lactate concentration affect Specific Judo Fitness Test performance in female judo athletes? AB - The Special Judo Fitness Test (SJFT) has become the test most widely used by coaches and physical trainers for assessment of competitors' judo-specific physical aptitude and training programme prescription. The aim of this study was to investigate the relationship between the SJFT performance indices and both maximal aerobic power and the level of blood lactate concentrations in female judo athletes. Seventeen female judokas (age: 21.9+/-1.6 years, body mass: 74.6+/ 27.4 kg, height: 164.5+/-8.6 cm; BMI: 27.1+/-8.0 kg . m-2) took part in this study. All participants performed the SJFT, 20 m multi-stage shuttle run test (MSRT), and 30 m straight sprint test (SST), from which we calculated both acceleration (10 m) and the maximal anaerobic speed (MAnS: flying 20 m sprint). A blood sample was taken 3 min after the SJFT. The number of throws was significantly correlated with estimated VO2max (r=0.795, p=0.0001) and both acceleration (r=0.63, p =0.006) and MAnS (r=0.76, p=0.0004). Peak blood lactate recorded after the SJFT was 13.90+/-1.39 mmol . l-1. No significant correlation was found between blood lactate concentration and the SJFT performance indices. The lack of significant correlation between blood lactate and SJFT performance suggests that lactic anaerobic metabolism has no effect on this type of judo specific supra-maximal exercise. The observed results can provide coaches and strength and conditioning professionals with relevant information for the interpretation of SJFT performance and the prescription of specific training programmes for female judo athletes. PMID- 28090144 TI - Maximal power training induced different improvement in throwing velocity and muscle strength according to playing positions in elite male handball players. AB - This study was designed to assess the effect of strength and power training on throwing velocity and muscle strength in handball players according to their playing positions. Twenty-two male handball players were assigned to either an experimental group (n=11) or a control group (n=11) (age: 22.1 +/- 3.0 years). They were asked to complete (i) the ball throwing velocity test and (ii) the one repetition maximum (1-RM) tests for the half-back squat, the pull-over, the bench press, the developed neck, and the print exercises before and after 12 weeks of maximal power training. The training was designed to improve strength and power with an intensity of 85-95% of the 1RM. In addition to their usual routine handball training sessions, participants performed two sessions per week. During each session, they performed 3-5 sets of 3-8 repetitions with 3 min of rest in between. Then, they performed specific shots (i.e., 12 to 40). Ball-throwing velocity (p<0.001) was higher after the training period in rear line players (RL). The training programme resulted in an improvement of 1RM bench press (p<0.001), 1RM developed neck (p<0.001) and 1RM print (p<0.001) in both front line (FL) and RL. The control group showed a significant improvement only in ball throwing velocity (p<0.01) and 1RM bench press (p<0.01) in RL. A significantly greater improvement was found in ball-throwing velocity (p<0.001), 1RM bench press (p<0.001), and 1RM half-back squat exercises in players of the central axis (CA) compared to the lateral axis (LA) (p<0.01). The power training programme induced significantly greater increases in ball-throwing velocity and muscle strength in FL than RL and in CA than LA axis players. PMID- 28090142 TI - The midpoint between ventilatory thresholds approaches maximal lactate steady state intensity in amateur cyclists. AB - The aim was to determine whether the midpoint between ventilatory thresholds (MPVT) corresponds to maximal lactate steady state (MLSS). Twelve amateur cyclists (21.0 +/- 2.6 years old; 72.2 +/- 9.0 kg; 179.8 +/- 7.5 cm) performed an incremental test (25 W.min-1) until exhaustion and several constant load tests of 30 minutes to determine MLSS, on different occasions. Using MLSS determination as the reference method, the agreement with five other parameters (MPVT; first and second ventilatory thresholds: VT1 and VT2; respiratory exchange ratio equal to 1: RER = 1.00; and Maximum) was analysed by the Bland-Altman method. The difference between workload at MLSS and VT1, VT2, RER=1.00 and Maximum was 31.1 +/- 20.0, -86.0 +/- 18.3, -63.6 +/- 26.3 and -192.3 +/- 48.6 W, respectively. MLSS was underestimated from VT1 and overestimated from VT2, RER = 1.00 and Maximum. The smallest difference (-27.5 +/- 15.1 W) between workload at MLSS and MPVT was in better agreement than other analysed parameters of intensity in cycling. The main finding is that MPVT approached the workload at MLSS in amateur cyclists, and can be used to estimate maximal steady state. PMID- 28090143 TI - Acute exercise regulates adipogenic gene expression in white adipose tissue. AB - White adipose tissue expansion is associated with both hypertrophy and hyperplasia of adipocytes. Exercise training results in adipocyte hypotrophy by activating lipolysis, but it is poorly understood whether exercise regulates adipogenesis by altering adipogenic gene expression. The purpose of this study was to evaluate the effect of a single bout of swimming exercise on adipogenic gene expression in white adipose tissue (WAT). Male C57BL/6J mice were divided into two groups: a sedentary control group and a 120-minute swimming exercise group. Immediately after acute exercise, adipogenic gene expression in WAT was analysed by RT-PCR, and tdTomato positive cells in WAT from UCP1-cre-tdTomato mice were observed under a confocal microscope. In epididymal white adipose tissue (eWAT), PPARgamma2 and C/EBPalpha expression at the mRNA level was significantly decreased with high induction of Wnt10b and KLFs (KLF2, KLF3, KLF7, KLF6, KLF9 and KLF15), whereas PPARgamma2, not C/EBPalpha, was decreased with high induction of Wnt6 and KLFs (KLF2, KLF3, KLF7, KLF6 and KLF9) in inguinal white adipose tissue (iWAT) after acute exercise. The expression of C/EBPbeta and C/EBPdelta was upregulated in both WATs with a high level of PGC-1alpha expression. Expression level of UCP1 was increased only in adipocytes of eWAT, while beige cell specific gene expression was comparable between groups and tdTomato positive cells were not found in WAT of UCP1-cre-tdTomato reporter mouse immediately after acute exercise. These results suggest that acute exercise suppresses adipogenic gene expression and may regulate thermogenesis by activating C/EBPbeta, PGC-1alpha and UCP1 in WAT. PMID- 28090145 TI - Total body composition estimated by standing-posture 8-electrode bioelectrical impedance analysis in male wrestlers. AB - Standing-posture 8-electrode bioelectrical impedance analysis is a fast and practical method for evaluating body composition in clinical settings, which can be used to estimate percentage body fat (BF%) and skeletal muscle mass in a subject's total body and body segments. In this study, dual-energy X-ray absorptiometry (DXA) was used as a reference method for validating the standing 8 electrode bioelectrical impedance analysis device BC-418 (BIA8, Tanita Corp., Tokyo, Japan). Forty-eight Taiwanese male wrestlers aged from 17.9 to 22.3 years volunteered to participate in this study. The lean soft tissue (LST) and BF% in the total body and body segments were measured in each subject by the BIA8 and DXA. The correlation coefficients between total body, arm, leg segments impedance index (BI, ht2/Z) and lean soft tissue mass measured from DXA were r = 0.902, 0.453, 0.885, respectively (p < 0.01). In addition, the total body and segmental LST estimated by the BIA8 were highly correlated with the DXA data (r = 0.936, 0.466, 0.886, p < 0.01). The estimation of total body and segmental BF% measured by BIA8 and DXA also showed a significant correlation (r > 0.820, p < 0.01). The estimated LST and BF% from BIA8 in the total body and body segments were highly correlated with the DXA results, which indicated that the standing-posture 8 electrode bioelectrical impedance analysis may be used to derive reference measures of LST and BF% in Taiwanese male wrestlers. PMID- 28090146 TI - Rapid weight loss in the context of Ramadan observance: recommendations for judokas. AB - Judo is a weight-classified combat sport, and many athletes seek to compete at the lightest possible weight category to gain an advantage from competing against shorter/smaller, and supposedly weaker opponents. To achieve a desired weight, most judokas opt for rapid weight loss techniques. Short-duration maximal efforts are not greatly affected by "making weight", but prolonged and/or repeated exercise is significantly impaired. Negative effects on mood, ratings of perceived exertion, and cognitive function are also reported. Moreover, rapid weight loss reduces maximal cardiac output and glycogen stores, and impairs thermo-regulation. Limited empirical data suggest that Ramadan reduces judokas' performance, and this is likely to be exacerbated by attempts at rapid weight loss. Weight reduction during Ramadan tends to be counterproductive, and judokas who aim for a lower weight category are advised to attempt any desired reduction of body mass during the weeks leading up to Ramadan, rather than during the holy month. PMID- 28090147 TI - Regression shrinkage and neural models in predicting the results of 400-metres hurdles races. AB - This study presents the application of regression shrinkage and artificial neural networks in predicting the results of 400-metres hurdles races. The regression models predict the results for suggested training loads in the selected three month training period. The material of the research was based on training data of 21 Polish hurdlers from the Polish National Athletics Team Association. The athletes were characterized by a high level of performance. To assess the predictive ability of the constructed models a method of leave-one-out cross validation was used. The analysis showed that the method generating the smallest prediction error was the LASSO regression extended by quadratic terms. The optimal model generated the prediction error of 0.59 s. Otherwise the optimal set of input variables (by reducing 8 of the 27 predictors) was defined. The results obtained justify the use of regression shrinkage in predicting sports outcomes. The resulting model can be used as a tool to assist the coach in planning training loads in a selected training period. PMID- 28090149 TI - Multiplexed and fully automated detection of metabolic biomarkers using microdialysis probe. AB - We report here, the design and development of an automated near real-time continuous detection system for lactate, glutamate, pyruvate and glucose using microdialysis probe. The system developed can automatically push perfusate through microdialysis probe (20, 100 and 1000 kDa MWCO cutoff probe) at low to medium flow rate of 0.5-2 MUL/min with almost 100% fluid recovery. The microdialysate collected from the probe is analyzed automatically for these four metabolite biomarkers. It operates in a continuous mode with measurements of all four biomarkers once every 20 min. The dynamic range for these different markers covers the entire clinical range of traumatic brain injury. The prototype shows a low variation of ~ 7-10% across the entire clinical range for all the biomarkers with fairly good accuracy of ~95%. The instrument canrun continuously for 24 h without user intervention. With a long tubing of 1 m to and from the microdialysis probe and associated dead volume, the total lag time for actual event at the probe site versusreported concentration is roughly 1 h. PMID- 28090148 TI - Early Identification of Autism: Early Characteristics, Onset of Symptoms, and Diagnostic Stability. AB - In the first year of life, infants who later go on to develop autistic spectrum disorders (ASD) may exhibit subtle disruptions in social interest and attention, communication, temperament, and head circumference growth that occur prior to the onset of clinical symptoms. These disruptions may reflect the early course of ASD development and may also contribute to the later development of clinical symptoms through alterations in the child's experience of his or her environment. By age 2, developmental precursors of autism symptoms can be used to diagnose children reliably, and by age 3, the diagnosis is thought to be relatively stable. The downward extension of the autism diagnosis poses important questions for therapists in designing interventions that are applicable for infants who demonstrate early risk factors. We review current knowledge of the early signs of ASD in the infancy period (0-12 months) and the manifestation of symptoms in toddlerhood (12- 36 months), noting the importance of considering the variability in onset and trajectory of ASD. Finally, we consider the implications of this emerging research for those who work or interact with young children, including the importance of early monitoring and the development and evaluation of age appropriate interventions. PMID- 28090150 TI - M1 and M2 Functional Imprinting of Primary Microglia: Role of P2X7 Activation and miR-125b. AB - Amyotrophic lateral sclerosis (ALS) is a most frequently occurring and severe form of motor neuron disease, causing death within 3-5 years from diagnosis and with a worldwide incidence of about 2 per 100,000 person-years. Mutations in over twenty genes associated with familial forms of ALS have provided insights into the mechanisms leading to motor neuron death. Moreover, mutations in two RNA binding proteins, TAR DNA binding protein 43 and fused in sarcoma, have raised the intriguing possibility that perturbations of RNA metabolism, including that of the small endogenous RNA molecules that repress target genes at the posttranscriptional level, that is, microRNAs, may contribute to disease pathogenesis. At present, the mechanisms by which microglia actively participate to both toxic and neuroprotective actions in ALS constitute an important matter of research. Among the pathways involved in ALS-altered microglia responses, in previous works we have uncovered the hyperactivation of P2X7 receptor by extracellular ATP and the overexpression of miR-125b, both leading to uncontrolled toxic M1 reactions. In order to shed further light on the complexity of these processes, in this short review we will describe the M1/M2 functional imprinting of primary microglia and a role played by P2X7 and miR-125b in ALS microglia activation. PMID- 28090151 TI - Cytokine Changes following Acute Ethanol Intoxication in Healthy Men: A Crossover Study. AB - Alcohol is a known modulator of the innate immune system. Owing to the absence of human studies, alcohol's effect on circulating cytokine profile remains unclear. We investigated the effect of acute high dose alcohol consumption on systemic cytokine release. After an overnight fasting, alcohol-experienced healthy male volunteers (N = 20) aged 25-45 years were given oral ethanol in the form of vodka (4.28 mL/kg) which they drank over a period of 30 minutes reaching peak blood alcohol concentration of 0.12% (SD 0.028). Blood samples were obtained prior to alcohol intake as well as 2, 7, and 12 hours thereafter. Serum levels of the inflammatory cytokines IL-1beta, IL-1Ra, IL-6, IL-10, IL-17, IFN-gamma, MCP-1, and TNF-alpha were determined by the multibead-based assay. Baseline cytokine levels were not related to BMI, hepatic parameters, electrolytes, glucose, or morning cortisol levels. Within 2 hours of alcohol intake, levels of IL-1Ra were elevated and remained so throughout the assessment period (p for trend = 0.015). In contrast, the levels of the chemokine MCP-1 dropped acutely followed by steadily increasing levels during the observation period (p < 0.001). The impact of sustained elevated levels of MCP-1 even after the clearance of blood alcohol content deserves attention. PMID- 28090154 TI - Unresolved Disrespectful Behavior in Health Care: Practitioners Speak Up (Again) Part 1. AB - Survey reveals widespread health workplace intimidation. PMID- 28090152 TI - New Role of Adult Lung c-kit+ Cells in a Mouse Model of Airway Hyperresponsiveness. AB - Structural changes contribute to airway hyperresponsiveness and airflow obstruction in asthma. Emerging evidence points to the involvement of c-kit+ cells in lung homeostasis, although their potential role in asthma is unknown. Our aim was to isolate c-kit+ cells from normal mouse lungs and to test whether these cells can interfere with hallmarks of asthma in an animal model. Adult mouse GFP-tagged c-kit+ cells, intratracheally delivered in the ovalbumin-induced airway hyperresponsiveness, positively affected airway remodeling and improved airway function. In bronchoalveolar lavage fluid of cell-treated animals, a reduction in the number of inflammatory cells and in IL-4, IL-5, and IL-13 release, along with an increase of IL-10, was observed. In MSC-treated mice, the macrophage polarization to M2-like subset may explain, at least in part, the increment in the level of anti-inflammatory cytokine IL-10. After in vitro stimulation of c-kit+ cells with proinflammatory cytokines, the indoleamine 2,3 dioxygenase and TGFbeta were upregulated. These data, together with the increased apoptosis of inflammatory cells in vivo, indicate that c-kit+ cells downregulate immune response in asthma by influencing local environment, possibly by cell-to cell contact combined to paracrine action. In conclusion, intratracheally administered c-kit+ cells reduce inflammation, positively modulate airway remodeling, and improve function. These data document previously unrecognized properties of c-kit+ cells, able to impede pathophysiological features of experimental airway hyperresponsiveness. PMID- 28090153 TI - Bounding the HL-index of a graph: a majorization approach. AB - In mathematical chemistry, the median eigenvalues of the adjacency matrix of a molecular graph are strictly related to orbital energies and molecular orbitals. In this regard, the difference between the occupied orbital of highest energy (HOMO) and the unoccupied orbital of lowest energy (LUMO) has been investigated (see Fowler and Pisansky in Acta Chim. Slov. 57:513-517, 2010). Motivated by the HOMO-LUMO separation problem, Jaklic et al. in (Ars Math. Contemp. 5:99-115, 2012) proposed the notion of HL-index that measures how large in absolute value are the median eigenvalues of the adjacency matrix. Several bounds for this index have been provided in the literature. The aim of the paper is to derive alternative inequalities to bound the HL-index. By applying majorization techniques and making use of some known relations, we derive new and sharper upper bounds for this index. Analytical and numerical results show the performance of these bounds on different classes of graphs. PMID- 28090155 TI - Plan to Settle 340B Disputes Elicits Dispute: Roadblocks Remain to Quieting Drug Pricing Controversies. AB - Plan to settle 340B disputes is itself the focus of a dispute. PMID- 28090156 TI - Drug and Device News. AB - Approvals, new indications, regulatory activities, and more. PMID- 28090157 TI - Pharmaceutical Approval Update. AB - Olaratumab (Lartruvo) for the treatment of soft tissue sarcoma; bezlotoxumab (Zinplava) for use with an antibiotic to reduce recurrence of C. difficile infection; and doxylamine succinate/pyridoxine hydrochloride (Bonjesta) for the treatment of nausea and vomiting during pregnancy. PMID- 28090158 TI - Zarxio (Filgrastim-sndz): The First Biosimilar Approved by the FDA. AB - Zarxio (filgrastim-sndz), a biosimilar for the treatment of severe chronic neutropenia. PMID- 28090159 TI - Transition From Paper to Computerized Pharmacist Clinical Decision Support. PMID- 28090161 TI - 2017 Presages Dramatic Change For Federal Health Care Policies: Republicans Are Likely to Face Hiccups Along the Way. AB - President-elect Donald Trump campaigned on a promise to repeal Obamacare. We review what effect the incoming administration may have on U.S. health care policy. PMID- 28090160 TI - Extending Patents With New Indications. PMID- 28090162 TI - Systemic Market and Organizational Changes: Impact on P&T Committees. AB - The authors consider market stakeholder consolidation, market-driven efficiency demands, consumerism, and legal enforcement of patient rights related to access to appropriate drugs and posit how future P&T committees may approach these issues. PMID- 28090163 TI - Branko Furst's Radical Alternative: Is the Heart Moved by the Blood, Rather Than Vice Versa? AB - We examine key evidence against the standard cardiac function model and describe Branco Furst's alternative model with its implications for therapy and further exploration. PMID- 28090164 TI - A Comparison of Medication Histories Obtained by a Pharmacy Technician Versus Nurses in the Emergency Department. AB - PURPOSE: To compare the medication history error rate of the emergency department (ED) pharmacy technician with that of nursing staff and to describe the workflow environment. METHODS: Fifty medication histories performed by an ED nurse followed by the pharmacy technician were evaluated for discrepancies (RN-PT group). A separate 50 medication histories performed by the pharmacy technician and observed with necessary intervention by the ED pharmacist were evaluated for discrepancies (PT-RPh group). Discrepancies were totaled and categorized by type of error and therapeutic category of the medication. The workflow description was obtained by observation and staff interview. RESULTS: A total of 474 medications in the RN-PT group and 521 in the PT-RPh group were evaluated. Nurses made at least one error in all 50 medication histories (100%), compared to 18 medication histories for the pharmacy technician (36%). In the RN-PT group, 408 medications had at least one error, corresponding to an accuracy rate of 14% for nurses. In the PT-RPh group, 30 medications had an error, corresponding to an accuracy rate of 94.4% for the pharmacy technician (P < 0.0001). The most common error made by nurses was a missing medication (n = 109), while the most common error for the pharmacy technician was a wrong medication frequency (n = 19). The most common drug class with documented errors for ED nurses was cardiovascular medications (n = 100), while the pharmacy technician made the most errors in gastrointestinal medications (n = 11). CONCLUSION: Medication histories obtained by the pharmacy technician were significantly more accurate than those obtained by nurses in the emergency department. PMID- 28090166 TI - Society for Immunotherapy of Cancer And American Heart Association. AB - We review key sessions from the Society for Immunotherapy of Cancer and the American Heart Association annual meetings. PMID- 28090165 TI - Challenges and Solutions in Reducing Opioid Misuse and Abuse. AB - We present some of the approaches to and challenges of the opioid crisis that emerged from thought-leaders at an Academy of Managed Care Pharmacy symposium. PMID- 28090167 TI - Novel Screening Test Sparks New Ideas About Old Drugs. PMID- 28090168 TI - Psychiatric symptoms and mental health court engagement. AB - People with mental illnesses are overrepresented in the criminal justice system. Many interventions have been implemented to treat the underlying causes of criminal justice involvement and prevent people with mental illnesses from recidivating. Mental health courts (MHC) are one of these programs. This analysis examines the relationship between psychiatric symptoms and MHC engagement. Eighty MHC participants from two Midwestern MHCs were interviewed. Symptom severity was assessed at baseline using the Brief Psychiatric Rating Scale. MHC engagement was estimated by treatment adherence, substance use, days spent in jail, probation violations, and MHC retention during a six month follow-up period. Using nonparametric statistical tests and logistic regression, results indicate symptoms of depression, anxiety, and guilt are more severe at baseline for those people who are incarcerated during the follow-up period. Symptoms of anxiety are more severe for people who are terminated or went missing during the follow-up period. Further research is needed to determine the directionality and causality of these relationships. MHCs professionals should be aware of the relationship between symptom severity and MHC engagement and attempt to connect participants with treatment and services as early as possible and individualize treatment plans based on current symptoms and need. PMID- 28090169 TI - Contextualized theory-based predictors of intention to practice monogamy among adolescents in Botswana junior secondary schools: Results of focus group sessions and a cross-sectional study. AB - Culture and tradition influences behaviour. Multiple partner and concurrent relationships are made responsible for the increase of HIV infection in Sub Saharan Africa. A contextualized "Theory of Planned Behaviour" was used to identify predictors of intention to practice monogamy. A mixed method design using qualitative data from focus groups, stories and a survey were analyzed for quantitative data. The qualitative data added to the behavioural beliefs a socio cultural belief domain as well as attitudes, subjective norms, and perceived behavioural control predicted the intention to practice monogamy. The adolescents showed a tendency towards having more than one sexual partner. The normative beliefs and the socio cultural beliefs also predicted intentions while hedonistic belief and partner reaction did not. In contextualizing theory-based interventions, it is important to draw from stories and the langauage that circulate in a community about a given behaviour. More studies are needed on ways to combine qualitative approaches with quantitative approaches to inform the development of theory based culturally appropriate and context specific intervention strategies to reduce the risk of HIV. PMID- 28090170 TI - Gender's role in misperceptions of peers' sexual motives. AB - The sexual double standard influences men's and women's sexual attitudes and behavior, leading men and women to consider distinct sexual motives, or reasons whether or not to engage in sexual intercourse (Crawford & Popp 2003; Reiss 1964). The goal of the present paper was to document how the sexual double standard shapes perceptions of peers' sexual motives. We build on past research by using open-ended questions and measuring perceptions of both same-gender and other-gender peers. The sample included 154 heterosexual college students (50% female, 49% European American, 25% Latino American, 26% African American) recruited via probability sampling. When we compared perceptions of men's and women's sexual motives, we found that participants seemed to rely on the sexual double standard. Participants were more likely to attribute a female-stereotyped motive (e.g., romantic relationship characteristics, feeling "ready", emotional investment) and less likely to attribute a male-stereotyped motive ("easy", arousal, physical appearance) to female peers than to male peers. However, when we compared participants' own motives to perceptions of their peers' motives, participants overestimated male-stereotyped motives and underestimated female stereotyped motives in peers, regardless of peer gender, possibly in congruence with stereotypes of hookup culture. These findings demonstrate that, although individuals sometimes rely on the sexual double standard to attribute sexual motives to others, misperceptions of peers' sexual motives may also be influenced by stereotypes of hookup culture. These misperceptions contribute to pluralistic ignorance that may influence college students' sexual behaviors. PMID- 28090171 TI - Aberrant expression of cyclin D1 in cancer. AB - Cyclin D1 binds and activates cyclin-dependent kinases 4/6 (Cdk4/6) to phosphorylate the retinoblastoma (RB) family proteins, relieving E2F/DPs from the negative restraint of RB proteins and histone deacetylases. The cyclin D-Cdk4/6 complexes activate cyclin E/Cdk2 through titration of the Cdk inhibitors p21Cip1/p27Kip1. Cyclin E/Cdk2 further phosphorylates RBs, thereby activating E2F/DPs, and cells enter the S phase of the cell cycle. Cyclin D-Cdk4/6 also phosphorylates MEP50 subunit of the protein arginine methyltransferase 5 (PRMT5), which cooperates with cyclin D1 to drive lymphomagenesis in vivo. Activated PRMPT5 causes arginine methylation of p53 to suppress expression of pro-apoptotic and anti-proliferative target genes, explaining the molecular mechanism for tumorigenesis. Cyclin D1 physically interacts with transcription factors such as estrogen receptor, androgen receptor, and Myb family proteins to regulate gene expression in Cdk-independent fashion. Dmp1 is a Myb-like protein that quenches the oncogenic signals from activated Ras or HER2 by inducing Arf/p53-dependent cell cycle arrest. Cyclin D1 binds to Dmp1alpha to activate both Arf and Ink4a promoters to induce cell cycle arrest or apoptosis in non-transformed cells to prevent them from neoplastic transformation. Dmp1-deficiency significantly accelerates mouse mammary tumorigenesis with reduced apoptosis and increased metastasis. Cyclin D1 interferes with ligand activation of PPARgamma involved in cellular differentiation; it also physically interacts with histone deacetylases (HDACs) and p300 to repress gene expression. It has also been shown that cyclin D1 accelerates tumorigenesis through transcriptional activation of miR-17/20 and Dicer1 which, in turn, represses cyclin D1 expression. Identification of cyclin D1-binding proteins/promoters will be essential for further clarification of its biological activities. PMID- 28090173 TI - On the Evolutionary Biology of Elpidium Ostracods (Limnocytheridae, Timiriaseviinae): A Proposal for Pluridisciplinary Studies. AB - The present essay reviews the history of the research on Elpidium ostracods (Timiriaseviinae), a group exclusively known to live in micro-aquaria of phytotelmata from Neotropical bromeliaceans. A new species, E. martensi n. sp., is described and aspects dealing with functional morphology and taxonomy of the genus are presented. Related to these topics an evolutionary hypothesis and a programme of pluridisciplinary research are proposed. This should allow further improvement of our knowledge on the origin and evolution of the subfamily Timiriaseviinae, one of the most diverse cytheroid ostracod groups in inland waters since the beginning of the Mesozoic. Specifically, the following aspects are treated in-depth in the essay: (1) morphologic traits of the valves, useful for characterisation of Timiriaseviinae taxa; (2) the reversal of the valve overlap and hinge elements; (3) the diverse development of the posterior half of the female carapace, a quasi-independent morphological trait; (4) the morphological shapes of the male copulatory process; (5) the functional significance of the antero-ventral segment of the valve selvage for the life of Elpidium ostracods in the micro-aquaria of the bromeliaceans; (6) the necessary improvement of comparative descriptions of the limbs-chaetotaxy for Timiriaseviinae. PMID- 28090172 TI - THE RETINOBLASTOMA PROTEIN: A MASTER TUMOR SUPPRESSOR ACTS AS A LINK BETWEEN CELL CYCLE AND CELL ADHESION. AB - RB1 was the first tumor suppressor gene discovered. Over four decades of work have revealed that the Rb protein (pRb) is a master regulator of biological pathways influencing virtually every aspect of intrinsic cell fate including cell growth, cell-cycle checkpoints, differentiation, senescence, self-renewal, replication, genomic stability and apoptosis. While these many processes may account for a significant portion of RB1's potency as a tumor suppressor, a small, but growing stream of evidence suggests that RB1 also significantly influences how a cell interacts with its environment, including cell-to-cell and cell-to-extracellular matrix interactions. This review will highlight pRb's role in the control of cell adhesion and how alterations in the adhesive properties of tumor cells may drive the deadly process of metastasis. PMID- 28090174 TI - Can We Improve Training for Health Professionals to Sustain Local Health Development? AB - Can we improve training for health professionals? We explore specific variables that need to be accounted for to achieve sustainable local health development through training. A problem-based approach with appreciation of the need for making changes is suggested as the only authentic basis for training. PMID- 28090175 TI - Adiponectin, Leptin and Objectively Measured Physical Activity in Adults: A Narrative Review. AB - The objective of this study was to compile and analyse existing scientific evidences reporting the effects of objectively measured physical activity on the levels of adiponectin and leptin. Articles related to the effects of objectively measured physical activity on the levels of adiponectin and leptin were searched from the Medline and PubMed databases. The search was limited to 'objectively measured' physical activity, and studies that did not objectively measure the physical activity were excluded. Only English articles were included in the search and review. A total of 18 articles encompassing 2,026 respondents met the inclusion criteria. The eligible articles included all forms of evidence (e.g., cross-sectional and intervention). Seventeen and 11 studies showed the effects of objectively measured physical activity on adiponectin and leptin, respectively. Five and four cross-sectional studies showed the effects of objectively measured physical activity on adiponectin and leptin, respectively. Two out of five studies showed a weak to moderate positive association between adiponectin and objectively measured physical activity, while three out of four studies showed a weak to moderate inverse association between leptin and objectively measured physical activity. For intervention studies, six out of 12 studies involving adiponectin and five out of seven studies involving leptin showed a significant effect between the proteins and objectively measured physical activity. However, a definitive conclusion could not be drawn due to several methodological flaws in the existing articles and the acute lack of additional research in this area. In conclusion, the existing evidences are encouraging but yet not compelling. Hence, further well-designed large trials are needed before the effectiveness of objectively measured physical activity in elevating adiponectin levels and in decreasing leptin levels could be strongly confirmed. PMID- 28090176 TI - Updates on Knowledge, Attitude and Preventive Practices on Tuberculosis among Healthcare Workers. AB - Ranking as the most communicable disease killer worldwide, tuberculosis, has accounted with a total of 9.6 million new tuberculosis cases with 1.5 million tuberculosis-related deaths reported globally in 2014. Tuberculosis has remain as an occupational hazard for healthcare workers since 1920s and due to several tuberculosis outbreaks in healthcare settings in the early 1990s, the concern about the transmission to both patients and healthcare workers has been raised. Healthcare workers have two to three folds greater the risk of active tuberculosis than the general population. Several studies on knowledge, attitude and practices on tuberculosis among healthcare workers worldwide have revealed that majority of the participated healthcare workers had good knowledge on tuberculosis. Most of the healthcare workers from South India and South Africa also reported to have positive attitude whereas a study in Thailand reported that most of the healthcare providers have negative attitude towards tuberculosis patients. Nevertheless, majority of the healthcare workers have low level of practice on tuberculosis prevention. An improved communication between healthcare workers and the patients as well as their families is the key to better therapeutic outcomes with good knowledge, attitude and preventive practice towards tuberculosis. PMID- 28090178 TI - Median Survival Time of Endometrial Cancer Patients with Lymphovascular Invasion at the Hospital Universiti Sains Malaysia. AB - BACKGROUND: Endometrial cancer is the most common gynaecologic malignancy among females worldwide. The purpose of this study was to determine the median survival time of endometrial cancer patients at the Hospital Universiti Sains Malaysia (USM). METHODS: A list of 121 endometrial cancer cases registered at Hospital USM between 2000 until 2011 was retrospectively reviewed. The survival time of the endometrial cancer patients was estimated by Kaplan-Meier survival analysis. Log rank tests were performed to compare the survival of the patients based on socio demographics and clinical presentation. RESULTS: Only 108 patients, 87.0%, were included who were of Malay ethnicity. Previous history included menopause in 67.6% of patients and diabetes mellitus in 39.8% of patients; additionally, 63.4% of patients were nulliparous. Tumour staging was as follows: 24.5% stage I, 10.8% stage II, 26.5% stage III and 38.2% stage IV. The overall median survival time of the endometrial cancer patients was 70.20 months (95% confidence interval (CI): 51.79, 88.61). The significant factors were age, the presence of lymphovascular invasion and treatment received. CONCLUSION: The overall survival of endometrial cancer was low. A prospective study needs to be carried out to discover more effective and accurate tests for the early detection of endometrial cancer. PMID- 28090177 TI - The Effects of Crocin on 6-OHDA-Induced Oxidative/Nitrosative Damage and Motor Behaviour in Hemiparkinsonian Rats. AB - BACKGROUND: Crocin is considered to prevent oxidative stress-related diseases, such as ischemia and Alzheimer's. The aim of the present investigation was to evaluate the effects of crocin on motor behaviour and 6-OHDA-induced oxidative/nitrosative damage to the striatum in an experimental model of Parkinson's disease. METHODS: Left medial forebrain bundle was lesioned by microinjection of 6-OHDA (16MUg in 0.2% ascorbate-saline). Crocin (30 and 60 mg/kg) was injected intraperitoneally three days before surgery until six weeks. Rotational behaviour and biochemical analysis were used to evaluate the effect of crocin in a unilateral 6-OHDA-induced model of Parkinson's disease. RESULTS: The contralateral rotations induced by apomorphine in 6-OHDA lesioned group were highly significant (P < 0.001) as compared to the sham group. Moreover, chronic administration of crocin at doses of 30 and 60 mg/kg over six weeks did not change the rotations. The TBARS and nitrite levels in the striatum were also significantly (P < 0.05) increased in lesioned group. Treatment with crocin at a dose of 60 mg/kg significantly decreased the nitrite levels (P < 0.05) in the striatum. CONCLUSION: Crocin at a dose of 60 mg/kg could be effective in preventing the nitrosative damage in the striatum. Further investigations using higher doses of crocin is suggested to get the full neuroprotective effects of crocin in Parkinson's disease. PMID- 28090179 TI - Correlation of Demographic and Clinical Characteristics with Rheumatoid Factor Seropositivity in Rheumatoid Arthritis Patients. AB - BACKGROUND: The rheumatoid factor (RF) blood test is the most commonly adopted test for the diagnosis of rheumatoid arthritis (RA). RA patients who are seropositive for RF might face a greater likelihood of developing more aggressive symptoms. METHODS: Our goal was to study the demographic and clinical characteristics, as well as their correlation with RF seropositivity, among a series of 80 RA patients aged >= 18 years who attend Hospital Universiti Sains Malaysia (HUSM). RESULTS: Of the 80 RA patients included in this study, 66 (82.5%) were female and 14 (17.5%) were male. No significant associations between RF seropositivity and demographic and/or clinical characteristics or other laboratory investigations were observed, including gender, morning stiffness, individual joint involvement (from multiple sites of the body), and erythrocyte sedimentation rate (ESR) measurement. However, a significant association between RF seropositivity and patients aged >= 50 was found (P = 0.032). CONCLUSION: RF seropositivity was found to be more common in much older RA patients. PMID- 28090180 TI - A Randomised, Placebo-Controlled Trial of Neurodynamic Sliders on Hamstring Responses in Footballers with Hamstring Tightness. AB - BACKGROUND: Neurodynamics intervention is known to increase apparent muscle extensibility, but information regarding hamstring responses after a neurodynamic sliders (NS) technique is scarce. The aim of this study was to evaluate the effects of NS on apparent hamstring extensibility and activity in footballers with hamstring tightness. METHODS: Forty eligible healthy male footballers with hamstring tightness were each randomly allocated to either a 4-week NS technique or a control group (CG) receiving placebo shortwave intervention. Knee extension angles were measured with the passive knee extension test, and maximal voluntary isometric contraction (MVIC) of hamstrings was measured by a surface electromyography at baseline and after intervention sessions. RESULTS: The results showed that NS produced a statistically and clinically significant increase in knee extension angle compared to CG (P < 0.001); however, there was no difference between the groups receiving MVIC of hamstrings. Within group comparison, NS also provided a significant increase in knee extension angle (P < 0.001), whereas the control group did not. There was no change in hamstring MVIC in either group after intervention. CONCLUSIONS: The findings of this study reveal that four weeks of NS technique improved apparent hamstring extensibility but did not change the hamstring activity in footballers with hamstring tightness. PMID- 28090181 TI - How Much We Think of Ourselves and How Little We Think of Others: An Investigation of the Neuronal Signature of Self-Consciousness between Different Personality Traits through an Event-Related Potential Study. AB - BACKGROUND: Previous studies have revealed that self-related tasks (items) receive more attention than non-self-related, and that they elicit event-related potential (ERP) components with larger amplitudes. Since personality has been reported as one of the biological correlates influencing these components, as well as our behavioural differences, it is important to examine how it affects our self-consciousness in relation to tasks of varied relevance and the neurological basis. METHODS: A total of 33 male and female undergraduate Malaysian medical students of Universiti Sains Malaysia (USM) participated in the study. The participants were divided into two groups, Ambivert (n = 18) and Extravert (n = 15) groups, using the USM personality inventory questionnaire. In the ERP experiment, squares containing standard stimuli of any word other than self and non-self-related nouns (e.g., Bola, Gigi, Anak, etc.; in English: Ball, Teeth, Kids, etc., respectively), those containing self-related pronouns (Saya, Kami or Kita; in English: I, Us or We, respectively), and non-self-related pronouns (Dia, Anda or Mereka; in English: He/She, You or They, respectively), were shown 58%, 21% and 21% of the time, respectively, in a three-stimulus visual oddball paradigm. All words were presented in Bahasa Melayu. The participants were instructed to press 1 for self and 2 for non-self, and ignore standard stimuli. RESULTS: Comparison of both N200 and P300 amplitudes for self-related and non-self-related pronouns in the Extravert group revealed significant differences at seven electrode sites, with self-related having larger amplitude at anterior electrodes and less at posterior. This was not seen in the Ambivert group. CONCLUSION: The present study suggests that self-relevant pronouns are psychologically more important to extraverts than to ambiverts; hence, they have more self-awareness. This may be due to large amount of dopamine in the brains of extraverts, which is more concentrated in the frontal lobe. PMID- 28090182 TI - Supervised Versus Home Exercise Training Programs on Functional Balance in Older Subjects. AB - BACKGROUND: Aging is associated with a progressive decline in physical capabilities and a disturbance of both postural control and daily living activities. The aim of this study was to evaluate the effects of supervised versus home exercise programs on muscle strength, balance and functional activities in older participants. METHODS: Forty older participants were equally assigned to a supervised exercise program (group-I) or a home exercise program (group-II). Each participant performed the exercise program for 35-45 minutes, two times per week for four months. Balance indices and isometric muscle strength were measured with the Biodex Balance System and Hand-Held Dynamometer. Functional activities were evaluated by the Berg Balance Scale (BBS) and the timed get-up-and-go test (TUG). RESULTS: The mean values of the Biodex balance indices and the BBS improved significantly after both the supervised and home exercise programs (P < 0.05). However, the mean values of the TUG and muscle strength at the ankle, knee and hip improved significantly only after the supervised program. A comparison between the supervised and home exercise programs revealed there were only significant differences in the BBS, TUG and muscle strength. CONCLUSIONS: Both the supervised and home exercise training programs significantly increased balance performance. The supervised program was superior to the home program in restoring functional activities and isometric muscle strength in older participants. PMID- 28090183 TI - Sleep Patterns and Predictors of Poor Sleep Quality among Medical Students in King Khalid University, Saudi Arabia. AB - BACKGROUND: Sleep problems and poor sleep quality are important issues for medical students. This study aimed to investigate the sleep patterns, measure the prevalence of poor sleep quality, and identify the predictors of poor sleep among medical students in King Khalid University (KKU), Saudi Arabia. METHODS: This cross-sectional study enrolled 318 medical students during October-November, 2015. Participants were selected by convenience sampling and data were collected using self-administered questionnaires to obtain information regarding socio demographic variables and indicators of sleep quality. RESULTS: The overall mean sleep quality score was 6.79 with a standard deviation of 3.06. Poor sleep quality was reported by 74.2% students. Significantly high mean sleep quality scores (Pittsburgh Sleep Quality Index) were observed for students with very poor subjective sleep quality (mean = 10.50, SD = 2.58), least sleep efficiency (mean = 11.21, SD = 2.23), shorter sleep duration (mean = 7.83, SD = 2.88), sleep onset latency more than 30 minutes (mean = 7.82, SD = 2.53), sleeping after midnight (mean = 7.53, SD = 2.95), and use of sleep aiding medication (mean = 8.78, SD = 3.5). Significant differences were observed between good sleepers and poor sleepers regarding these sleep characteristics. Poor sleep was predicted by sleep behaviours such as going to sleep after midnight (AOR = 2.18, 95% CI: 1.20, 3.94) and sleep duration of less than seven hours (AOR = 7.49, 95% CI: 4.24, 13.22). CONCLUSION: Medical students of KKU have poor sleep quality. Longer sleep latency, going to sleep after midnight, and shorter sleep duration are important problems in this group. PMID- 28090184 TI - Radiographic Evaluation of the Status of Third Molars in Sriganganagar Population - A Digital Panoramic Study. AB - BACKGROUND: Third molar (M3) agenesis and impaction are associated with evolution, changed dietary habits, and human jaw growth. The aim of the study was to radiographically evaluate the prevalence of M3s agenesis, impacted M3s with different impaction patterns, and the approximation of Inferior Dental Canal (IDC) with impacted mandibular M3s roots among the Sriganganagar population. METHODS: The study included 700 randomly selected subjects from OPD with an age range of 25-45 years. Digital OPGs were taken for all subjects using Kodak 8000C digital OPG machine. The M3 impaction patterns were evaluated using Winter's classification. RESULTS: The prevalence of subjects with at least one M3 agenesis was found to be 34.1% and with 95% confidence interval was 30.6% to 37.6%. The overall M3s agenesis was 16.8% with more prevalence in the males. The patients with agenesis of one M3, two M3s, three M3s, and four M3s were 14.4%, 11.3%, 3.7% and 4.7%, respectively. M3 agenesis was more in the upper jaw and on the left side. The total impacted M3s were 21.11% with more prevalence in mixed diet subjects. Mesioangular was most common impaction pattern, and notching was most prevalent IDC relationship with impacted mandibular M3s roots. CONCLUSION: This study highlighted the evolutionary increasing M3 agenesis and the importance of diagnostic OPG for seeing the status of M3s in jaws. PMID- 28090185 TI - Characteristics and Outcomes of Patients with Anterior Circulation Intracranial Aneurysm Managed with Clipping in Hospital Sungai Buloh. AB - INTRODUCTION: The annual incidence of intracranial aneurysm in Malaysia is estimated to be 1.1-1.7 per 100,000 population based on a study done conducted in 1988. Since then, little epidemiological research has been conducted in Malaysia, and the real incidence is therefore probably unreported despite advancements in the diagnosis and treatment of this disorder. Intracranial aneurysm may be treated by microsurgical clipping or embolisation depending on its location and the surgeon's preference. This study aims to report the characteristics and outcomes of patients with a clipped anterior circulation aneurysm in Hospital Sungai Buloh. METHODS: We retrospectively collected the data of patients with anterior circulation aneurysms who underwent clipping from 1 January 2013 until 30 June 2014 in Hospital Sungai Buloh. RESULTS: The mean age of the patients was 48.9 years old, and 56.7% of the study population were male and 63.3% were Malay. There were almost equal numbers of patients with (46.7%) and without (53.3%) co morbidities such as hypertension and ischaemic heart disease. Half of the study population fell under Fisher grade 3 (50.0%), whereas 46.7% were Fisher grade 4. With respect to the Navarro score, 20% of patients scored 10, 16.7% scored 5 or 7, 13.3% scored 11, 10% scored 9, 6.7% scored 1 and 3.3% scored 2, 3 or 8. Most of the patients fell under grade I (33.3%) of the World Federation of Neurological Societies grading (WFNS), and the fewest number of patients were grade III (3.3%). Most (56.7%) patients had an intracranial aneurysm located at the anterior communicating artery (ACOM), followed by the anterior cerebral artery (ACA) and the middle cerebral artery (MCA) (16.7% each), the posterior communicating artery (PCOM) (6.7%) and, finally, the internal carotid artery (ICA) (3.3%). Neurological outcomes at three and six months were assessed using the Modified Rankin Scale (mRS). At three months follow-up, the majority of the participants (33.3%) scored 0 or 6, whereas at six months follow-up, the majority scored 0 (43.3%). CONCLUSION: The main characteristics of patients in Hospital Sungai Buloh were that they were in their 40s and mostly Malays without any known comorbidities. Although the majority of patients had high Fisher grades, their outcomes post intervention were promising. However, as data collected from Hospital Sungai Buloh may not be representative of the whole country, a larger scale data collection is necessary to create our own database and to identify the risks factors that are exclusive to our country, if present. PMID- 28090186 TI - Calcitriol-mediated Reversible Hypercalcemia in a Patient with Primary Adrenal Lymphoma. AB - Primary adrenal lymphomas (PAL) are rare occurrences with only less than 150 cases reported in the literature. Two-thirds of these cases were reported in the last decade due to the advancements in imaging techniques and immunohistochemistry. The non-specific signs and symptoms have resulted in a delayed onset of symptoms and diagnosis of these tumors. Reports of the results of chemotherapy are not gratifying, and most patients die within one year of the diagnosis. We report a 65-year-old male with adrenal non-Hodgkin's lymphoma (NHL), who presented with hypercalcemia and renal failure. We reviewed all adrenal NHL cases presented with hypercalcemia and attempted to comprehend its etiology and overall survival effect. PMID- 28090187 TI - Recurrent Intestinal Obstruction in a Patient with Selective IgA Deficiency. AB - A 32 year old woman presented with acute onset of abdominal pain and fever. An urgent computerised tomography (CT) of the whole abdomen showed dilated loop at the terminal ileum in the right lower abdomen with thickening of the wall and oedema. The CT was suggestive of distal small bowel obstruction at the ileum with surrounding wall oedema. Multiple biopsies taken from the terminal ileum and colon on colonoscopy were all unremarkable. She represented one-year later with a recurrence of intestinal obstruction. CT enteroclysis showed collapse at the distal 3 cm segment of the terminal ileum. There was no associated wall thickening, active inflammatory changes or ileitis. This was suspicious of post inflammatory change or fibrosis. She was subsequently found to have selective IgA deficiency with recurrent infection in the terminal ileum resulting in intestinal obstruction. In conclusion, selective IgA deficiency should be considered in patients with recurrent intestinal obstruction without anatomical obstructions. PMID- 28090188 TI - Enantioselective Synthesis of Caprolactam and Enone Precursors to the Heterocyclic DEFG Ring System of Zoanthenol. AB - The enantioselective synthesis of both caprolactam and enone synthons for the DEFG ring system of zoanthenol are described. The evolution of this synthetic approach proceeds first through a synthesis using the chiral pool as a starting point. Challenges in protecting group strategy led to the modification of this approach beginning with (+/-)-glycidol. Ultimately, an efficient approach was developed by employing an asymmetric hetero-Diels-Alder reaction. The caprolactam building block can be converted by an interesting selective Grignard addition to the corresponding enone synthon. Addition of a model alkyne provides support for the late-stage addition of a hindered alkyne into the caprolactam building block. PMID- 28090189 TI - On the Leptocytheridae Ostracods of the Long-Lived Lake Ohrid: A Reappraisal of their Taxonomic Assignment and Biogeographic Origin. AB - Leptocythere karamani Klie, one of few non-marine species of the family Leptocytheridae (Ostracoda), is redescribed from specimens recently collected from the long-lived Lake Ohrid on the Albanian-Macedonian border. Detailed morphologies of valves and limbs of this species were compared with those of other Ohrid-Prespa leptocytherids, of some recent marine representatives of the genera Leptocythere Sars and Callistocythere Ruggieri from the Mediterranean, Irish and Baltic seas as well as with that of fossil non-marine species from the Miocene palaeo-Lake Pannon belonging to the genera Amnicythere Devoto and Euxinocythere Stancheva. Comparison with other species of Leptocytheridae inhabiting fresh to brackish waters of the Black-Azov, Caspian and Aral seas were also carried out using descriptions provided in the literature. Based on the comparative morphological studies it is shown that L. karamani and other Ohrid leptocytherids have a number of characters distinguishing them from other members of the genus Leptocythere but demonstrating a relationship with species of the genus Amnicythere. The most reliable of these characters are: a) anterior valve vestibulum from where mostly uni-ramified pore canals start, b) the entomodont hinge type with a strong anterior anti-slip tooth, a smooth posterior anti-slip bar on the left valve, and c) the hemipenis with underdeveloped lateral lobe and reduced clasping organ. From this strong evidence, the Ohrid leptocytherid species are allocated to the genus Amnicythere. Finally, a biogeographic scenario on the origin of the Ohrid leptocytherids is proposed which matches the "Lake Pannon derivate hypothesis". Close relationship of the Ohrid Amnicythere species with the non-marine leptocytherid taxa from the Neogene lakes of Central and Eastern Europe and with extant taxa from the Black and Caspian seas may indicate that the Ohrid Amnicythere derived from Lake Pannon species which were able to colonise lakes in Southern Europe through a stepping-stone process and subsequently to adapt to freshwater environment. PMID- 28090190 TI - Expression of the receptor activator of nuclear factor-kB ligand in peripheral blood mononuclear cells in patients with acute Charcot neuroarthropathy. AB - Introduction. The receptor activator of nuclear factor-kB (RANK), ligand (RANK-L) and osteoprotegerin (OPG) are implicated in the pathogenesis of acute Charcot neuroarthropathy (CN). Materials and Methods. This study aimed to investigate the expression of RANK-L and OPG in peripheral blood mononuclear cells (PBMC) from patients with acute CN. Results. We found that the expression of RANK-L was lower in patients with acute CN as compared with diabetic control subjects and healthy control participants; whereas OPG expression was not detected in patients and in both control groups. RANK-L expression at the onset of disease was inversely correlated with the index of polyunsaturation (PUI), a bone marrow MRS-derived measurable index that allows evaluation of disease activity in acute CN, and recovery time. Finally, the expression of RANK-L increased at the time of healing compared with the values found during the acute phase. Conclusions. In conclusion, our preliminary data provide a first step in applying analysis of RANK-L expression in peripheral blood cells to the diagnosis of acute CN. Based on our data we also suggest that analysis of RANK-L expression could be a complementary tool that can be employed to obtain quantitative parameters that may help clinicians to monitor disease activity in patients with acute CN. PMID- 28090191 TI - Blockage of epithelial to mesenchymal transition and upregulation of let 7b are critically involved in ursolic acid induced apoptosis in malignant mesothelioma cell. AB - Malignant pleural mesothelioma (MPN), which is caused by asbestos exposure, is one of aggressive lung tumors. In the present study, we elucidated the anti-tumor mechanism of ursolic acid in malignant mesotheliomas. Ursolic acid significantly exerted cytotoxicity in a time and dose dependent manner in H28, H2452 and MSTO 211H mesothelioma cells and inhibited cell proliferation by colony formation assay in a dose-dependent fashion. Also, ursolic acid treatment accumulated the sub-G1 population, attenuated the expression of procapase 9, cyclin D1, pAKT, p glycogen synthase kinase 3-alpha/beta (pGSK3alpha/beta), beta-catenin and nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) and also cleaved caspase 3 and poly (ADP-ribose) polymerase (PARP) in mesothelioma cells. Furthermore, ursolic acid treatment blocked epithelial and mesenchymal transition (EMT) molecules by activating E-cadherin as an epithelial marker and attenuating Vimentin, and Twist as mesenchymal molecules. Interestingly, miRNA array revealed that 23 miRNAs (>2 folds) including let-7b and miRNA3613-5p, miRNA134 and miRNA196b were significantly upregulated while 33 miRNAs were downregulated in ursolic acid treated H2452 cells. Furthermore, overexpression of let 7b using let 7b mimics enhanced the antitumor effect of ursolic acid to attenuate the expression of procaspases 3, pro-PARP, pAKT, beta-catenin and Twist and increase sub-G1 accumulation in H2452 mesothelioma cells. Overall, our findings suggest that ursolic acid induces apoptosis via inhibition of EMT and activation of let7b in mesothelioma cells as a potent chemotherapeutic agent for treatment of malignant mesotheliomas. PMID- 28090193 TI - Recruiting Participants into Pilot Trials: Techniques for Researchers with Shoestring Budgets. AB - Limited research has focused on recruitment strategies for health promotion researchers conducting small-scale pilot studies. Such research is important because small studies often have limited funding streams and personnel resources. Accordingly, many techniques implemented by large-scale studies are of limited use to smaller research projects. This article provides an overview effective participant recruitment techniques for pilot studies with limited funds and personnel resources. Recruitment techniques were derived from the first author's experience in recruiting participants during his doctoral and postdoctoral studies, the over 25 years of research experience of each of the co-authors, and an extensive review of the literature. Five key recruitment techniques are discussed: 1) leverage existing social networks and personal contacts, 2) identify and foster collaborations with community gatekeepers, 3) develop a comprehensive list of potential recruitment platforms and venues, 4) create recruitment materials that succinctly describe the purpose of the study, and 5) build respectful and trusting relationships with potential participants. Implementation of the proposed techniques can lead to enhanced recruitment, as well as retention among study participants. PMID- 28090192 TI - Spinal rehabilitative exercise or manual treatment for the prevention of cervicogenic headache in adults. AB - This is the protocol for a review and there is no abstract. The objectives are as follows: To quantify and compare the short- and long-term effects of manual treatment and spinal rehabilitative exercise for cervicogenic headache, classified according to the International Headache Society's (IHS) diagnostic criteria, with an active or placebo/sham comparison or wait-list control. PMID- 28090194 TI - Supporting shared decision making beyond consumer-prescriber interactions: Initial development of the CommonGround fidelity scale. AB - Shared decision-making has become a central tenet of recovery-oriented, person centered mental health care, yet the practice is not always transferred to the routine psychiatric visit. Supporting the practice at the system level, beyond the interactions of consumers and medication prescribers, is needed for successful adoption of shared decision-making. CommonGround is a systemic approach, intended to be part of a larger integration of shared decision-making tools and practices at the system level. We discuss the organizational components that CommonGround uses to facilitate shared decision-making, and we present a fidelity scale to assess how well the system is being implemented. PMID- 28090196 TI - How and why to achieve greater objectivity in taxonomy, exemplified by a fossil ostracod (Amplocypris abscissa) from the Miocene Lake Pannon. AB - A project on fossil ostracods from Hennersdorf (Vienna Basin, Middle Pannonian "E" stage) documents the non-marine ostracod Amplocypris abscissa (Reuss 1850) as a polymorphic taxon. The high morphological variability of the valves belonging to this species and its geographic distribution in the Lake Pannon point to a widely spread fossil taxon. This traditional view emerges from the fact that A. abscissa displays few homologous "landmarks" (morphological reference points) which makes it difficult to compare morphotypes within and among populations. The present contribution offers arguments for the need of objective criteria when describing ostracods with few visible morphological traits. It is demonstrated that using a composite algorithmic approach which combines information implemented in the computer programme MORPHOMATICA for different variables, measured on interval and ratio scales, is able to define morphological traits objectively. The data analysed with multivariate statistics are further used for diagnostic profiles of clearly delineated morphotypes. The potential taxonomic value of three morphotypes here identified for Amplocypris abscissa is discussed. It is argued that this taxon represents a phylogenetic lineage within which a cluster of species with discrete morphological traits exists. Finally, it is proposed to apply similar algorithms for the necessary revision of the whole group of Amplocypris species from Lake Pannon. PMID- 28090195 TI - Complex Surgical Strategies to Improve Resectability in Borderline-Resectable Disease. AB - Colorectal cancer is the third most common malignancy in the USA and continues to pose a significant epidemiologic problem, despite major advances in the treatment of patients with advanced disease. Up to 50 % of patients will develop metastatic disease at some point during the course of their disease, with the liver being the most common site of metastatic disease. In this review, we address the relatively poorly defined entity of borderline-resectable colorectal liver metastases. The workup and staging of borderline-resectable disease are discussed. We then discuss management strategies, including surgical techniques and medical therapies, which are currently utilized in order to improve resectability. PMID- 28090197 TI - Biological and biochemical characterization of venom from the broad-banded copperhead (Agkistrodon contortrix laticinctus): isolation of two new dimeric disintegrins. AB - Disintegrins represent a family of effective cell-cell and cell-matrix inhibitors by binding to integrin receptors. Integrins are heterodimeric, transmembrane receptors that are the bridges for these cell interactions. Disintegrins have been shown to have many therapeutic implications for the treatment of strokes, heart attacks, and cancer. Two novel heterodimeric disintegrins were isolated from the venom of the broad-banded copperhead (Agkistrodon contortrix laticinctus). Crude venom separated by cation-exchange chromatography resulted in several fractions possessing hemorrhagic, fibrinolytic, gelatinase, and platelet activities. Venom fractions 2-3 and 17-19 showed fibrinolytic activity. Fractions 2-6, 8-11, and 16-21 had hemorrhagic activity. Gelatinase activity was found in fractions 3, 11, and 19. The isolation of laticinstatins 1 and 2 was accomplished by fractionating crude venom using reverse phase chromatography. Data from both SDS-PAGE and N-terminal sequencing determined that laticinstatins 1 and 2 were heterodimeric disintegrins, and both were assayed for their ability to inhibit platelet aggregation in human whole blood. Future functional evaluation of snake venom disintegrins shows considerable promise for elucidating the biochemical mechanisms of integrin-ligand interactions that will allow the development of adequate medications for hemostatic pathologies such as thrombosis, stroke, and cerebral and cardiac accidents. In this study, we are presenting the first report of the purification, and partial characterization of two new dimeric disintegrins isolated from the venom of broad-banded copperhead snakes. PMID- 28090198 TI - Computational tools and workflows in metabolomics: An international survey highlights the opportunity for harmonisation through Galaxy. PMID- 28090199 TI - MASTR-MS: a web-based collaborative laboratory information management system (LIMS) for metabolomics. AB - BACKGROUND: An increasing number of research laboratories and core analytical facilities around the world are developing high throughput metabolomic analytical and data processing pipelines that are capable of handling hundreds to thousands of individual samples per year, often over multiple projects, collaborations and sample types. At present, there are no Laboratory Information Management Systems (LIMS) that are specifically tailored for metabolomics laboratories that are capable of tracking samples and associated metadata from the beginning to the end of an experiment, including data processing and archiving, and which are also suitable for use in large institutional core facilities or multi-laboratory consortia as well as single laboratory environments. RESULTS: Here we present MASTR-MS, a downloadable and installable LIMS solution that can be deployed either within a single laboratory or used to link workflows across a multisite network. It comprises a Node Management System that can be used to link and manage projects across one or multiple collaborating laboratories; a User Management System which defines different user groups and privileges of users; a Quote Management System where client quotes are managed; a Project Management System in which metadata is stored and all aspects of project management, including experimental setup, sample tracking and instrument analysis, are defined, and a Data Management System that allows the automatic capture and storage of raw and processed data from the analytical instruments to the LIMS. CONCLUSION: MASTR-MS is a comprehensive LIMS solution specifically designed for metabolomics. It captures the entire lifecycle of a sample starting from project and experiment design to sample analysis, data capture and storage. It acts as an electronic notebook, facilitating project management within a single laboratory or a multi-node collaborative environment. This software is being developed in close consultation with members of the metabolomics research community. It is freely available under the GNU GPL v3 licence and can be accessed from, https://muccg.github.io/mastr-ms/. PMID- 28090200 TI - Nonmedical use of prescription drugs in emerging adulthood: differentiating sex from gender. AB - Male-female variations in health-behavior continue to be of national and international significance with men generally being more likely to be engaged in behaviors that enhance risk across an array of preventable diseases and injuries as well as premature deaths. The literature has identified non-medical use of prescription drugs (NMUPD) as a developing and particularly dangerous substance use behavior among college students. The literature has reported sex differences (male; female) in NMUPD but has yet to explain how gender-orientation (e.g., masculine, feminine) might impact NMUPD. The purpose of this study is to address this gap by examining the influence of gender-orientation on NMUPD. Using survey data collected during the 2013-2014 academic year from a convenience sample of college students at a mid-sized Midwestern university, we examine the association of gender-orientation with NMUPD (N=796). To do this, we separate masculine and feminine scales from the BEM Sex Role Inventory and use logistic regression to test whether masculine or feminine gender characteristics influence the likelihood of NMUPD (lifetime measure of any use and by category). This analysis shows that self-identified characteristics associated with masculinity increase the odds of NMUPD while femininity is associated with lower odds of NMUPD. Findings from this study increase our knowledge of gender-orientation and sex interactions as factors that might influence NMUPD thus demonstrating the importance of differentiating sex from gender-orientation. PMID- 28090201 TI - The Inorganic Side of NGF: Copper(II) and Zinc(II) Affect the NGF Mimicking Signaling of the N-Terminus Peptides Encompassing the Recognition Domain of TrkA Receptor. AB - The nerve growth factor (NGF) N-terminus peptide, NGF(1-14), and its acetylated form, Ac-NGF(1-14), were investigated to scrutinize the ability of this neurotrophin domain to mimic the whole protein. Theoretical calculations demonstrated that non-covalent forces assist the molecular recognition of TrkA receptor by both peptides. Combined parallel tempering/docking simulations discriminated the effect of the N-terminal acetylation on the recognition of NGF(1-14) by the domain 5 of TrkA (TrkA-D5). Experimental findings demonstrated that both NGF(1-14) and Ac-NGF(1-14) activate TrkA signaling pathways essential for neuronal survival. The NGF-induced TrkA internalization was slightly inhibited in the presence of Cu2+ and Zn2+ ions, whereas the metal ions elicited the NGF(1-14)-induced internalization of TrkA and no significant differences were found in the weak Ac-NGF(1-14)-induced receptor internalization. The crucial role of the metals was confirmed by experiments with the metal-chelator bathocuproine disulfonic acid, which showed different inhibitory effects in the signaling cascade, due to different metal affinity of NGF, NGF(1-14) and Ac-NGF(1-14). The NGF signaling cascade, activated by the two peptides, induced CREB phosphorylation, but the copper addition further stimulated the Akt, ERK and CREB phosphorylation in the presence of NGF and NGF(1-14) only. A dynamic and quick influx of both peptides into PC12 cells was tracked by live cell imaging with confocal microscopy. A significant role of copper ions was found in the modulation of peptide sub-cellular localization, especially at the nuclear level. Furthermore, a strong copper ionophoric ability of NGF(1-14) was measured. The Ac NGF(1-14) peptide, which binds copper ions with a lower stability constant than NGF(1-14), exhibited a lower nuclear localization with respect to the total cellular uptake. These findings were correlated to the metal-induced increase of CREB and BDNF expression caused by NGF(1-14) stimulation. In summary, we here validated NGF(1-14) and Ac-NGF(1-14) as first examples of monomer and linear peptides able to activate the NGF-TrkA signaling cascade. Metal ions modulated the activity of both NGF protein and the NGF-mimicking peptides. Such findings demonstrated that NGF(1-14) sequence can reproduce the signal transduction of whole protein, therefore representing a very promising drug candidate for further pre-clinical studies. PMID- 28090202 TI - Stigma in Practice: Barriers to Health for Fat Women. AB - In this paper, we explore barriers to health for fat people. By shifting the focus from what fat people do or do not do, neoliberal principles are replaced by a focus instead on structural and institutional policies, attitudes, and practices. This includes the impact of stigma on the health treatment and health seeking behavior of fat people. For example, we consider the role that provider anti-fat attitudes and confirmation bias play in the failure to provide evidenced based healthcare to fat patients. This is an autoethnographic paper, which provides the opportunity to read research from the perspective of fat scholars, framed by questions such as: can fat people have health? Is health itself a state of being, a set of behaviors, a commodity, a performance; perhaps the new social contract? As a co-written autoethnographic paper, one aspect of the evidence provided is the recorded experiences of the two fat authors. This includes writing from notes, journals, compiled and repeated experiences with medical professionals, family, and the community. Framed by feminist standpoint and supported by literature drawn from Fat Studies, Public Health, Obesity Research, and other interdisciplinary fields, this is a valuable opportunity to present an extended account of fat discrimination and the impact of the stigma fat people face through the medical profession and other sectors of the community, written by fat individuals. The paper concludes by considering the health pathways available to fat people. Special attention is paid to whether Bacon and Aphramor's Health at Every Size paradigm provides a path to health for fat individuals. PMID- 28090203 TI - Herbal Extracts That Reduce Ocular Oxidative Stress May Enhance Attentive Performance in Humans. AB - We used herbal extracts in this study to investigate the effects of blue-light induced oxidative stress on subjects' attentive performance, which is also associated with work performance. We employed an attention network test (ANT) to measure the subjects' work performance indirectly and used herbal extracts to reduce ocular oxidative stress. Thirty-two subjects participated in either an experimental group (wearing glasses containing herbal extracts) or a control group (wearing glasses without herbal extracts). During the ANT experiment, we collected electroencephalography (EEG) and electrooculography (EOG) data and measured button responses. In addition, electrocardiogram (ECG) data were collected before and after the experiments. The EOG results showed that the experimental group exhibited a reduced number of eye blinks per second during the experiment and faster button responses with a smaller variation than did the control group; this group also showed relatively more sustained tension in their ECG results. In the EEG analysis, the experimental group had significantly greater cognitive processing, with larger P300 and parietal 2-6 Hz activity, an orienting effect with neural processing of frontal area, high beta activity in the occipital area, and an alpha and beta recovery process after the button response. We concluded that reducing blue-light-induced oxidative stress with herbal extracts may be associated with reducing the number of eye blinks and enhancing attentive performance. PMID- 28090204 TI - A "Tuned" Mask Learnt Approach Based on Gravitational Search Algorithm. AB - Texture image classification is an important topic in many applications in machine vision and image analysis. Texture feature extracted from the original texture image by using "Tuned" mask is one of the simplest and most effective methods. However, hill climbing based training methods could not acquire the satisfying mask at a time; on the other hand, some commonly used evolutionary algorithms like genetic algorithm (GA) and particle swarm optimization (PSO) easily fall into the local optimum. A novel approach for texture image classification exemplified with recognition of residential area is detailed in the paper. In the proposed approach, "Tuned" mask is viewed as a constrained optimization problem and the optimal "Tuned" mask is acquired by maximizing the texture energy via a newly proposed gravitational search algorithm (GSA). The optimal "Tuned" mask is achieved through the convergence of GSA. The proposed approach has been, respectively, tested on some public texture and remote sensing images. The results are then compared with that of GA, PSO, honey-bee mating optimization (HBMO), and artificial immune algorithm (AIA). Moreover, feature extracted by Gabor wavelet is also utilized to make a further comparison. Experimental results show that the proposed method is robust and adaptive and exhibits better performance than other methods involved in the paper in terms of fitness value and classification accuracy. PMID- 28090205 TI - Main Trend Extraction Based on Irregular Sampling Estimation and Its Application in Storage Volume of Internet Data Center. AB - The storage volume of internet data center is one of the classical time series. It is very valuable to predict the storage volume of a data center for the business value. However, the storage volume series from a data center is always "dirty," which contains the noise, missing data, and outliers, so it is necessary to extract the main trend of storage volume series for the future prediction processing. In this paper, we propose an irregular sampling estimation method to extract the main trend of the time series, in which the Kalman filter is used to remove the "dirty" data; then the cubic spline interpolation and average method are used to reconstruct the main trend. The developed method is applied in the storage volume series of internet data center. The experiment results show that the developed method can estimate the main trend of storage volume series accurately and make great contribution to predict the future volume value. ?. PMID- 28090206 TI - The Relationship between Inflammatory Marker Levels and Hepatitis C Virus Severity. AB - Background. Red cell distribution width (RDW) and platelet-lymphocyte ratio (PLR) have been studied in a variety of etiological diseases. We aim to investigate the relationship between RDW and PLR and the severity of hepatitis C virus- (HCV-) related liver disease. Methods. We included fifty-two chronic HCV and 42 HCV related cirrhosis patients and 84 healthy controls. Hematological and virological parameters and liver function biomarkers of HCV-related patients at admission were recorded. Results. RDW, RDW-to-platelet (RPR), and 1/PLR values in HCV related cirrhosis patients were significantly higher than in chronic HCV patients and healthy controls (all P < 0.001). The aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (AAR), AST-to-platelet ratio index (APRI), and fibrosis index based on the four factors (FIB-4) scores in HCV related cirrhosis patients were significantly higher than in chronic HCV patients (all P < 0.001). The areas under the curve of the RDW, RPR, and 1/PLR for predicting cirrhosis were 0.791, 0.960, and 0.713, respectively. Bivariate logistic regression analysis showed that RDW could independently predict the presence of cirrhosis in chronic HCV patients. Conclusions. RDW, RPR, and PLR may be potential markers for estimating HCV severity. PMID- 28090207 TI - Role of Bioadsorbents in Reducing Toxic Metals. AB - Industrialization and urbanization have led to the release of increasing amounts of heavy metals into the environment. Metal ion contamination of drinking water and waste water is a serious ongoing problem especially with high toxic metals such as lead and cadmium and less toxic metals such as copper and zinc. Several biological materials have attracted many researchers and scientists as they offer both cheap and effective removal of heavy metals from waste water. Therefore it is urgent to study and explore all possible sources of agrobased inexpensive adsorbents for their feasibility in the removal of heavy metals. The objective was to study inexpensive adsorbents like various agricultural wastes such as sugarcane bagasse, rice husk, oil palm shell, coconut shell, and coconut husk in eliminating heavy metals from waste water and their utilization possibilities based on our research and literature survey. It also shows the significance of developing and evaluating new potential biosorbents in the near future with higher adsorption capacity and greater reusable options. PMID- 28090208 TI - Three-Dimensional Bioprinting Nanotechnologies towards Clinical Application of Stem Cells and Their Secretome in Salivary Gland Regeneration. AB - Salivary gland (SG) functional damage and severe dry mouth (or xerostomia) are commonly observed in a wide range of medical conditions from autoimmune to metabolic disorders as well as after radiotherapy to treat specific head and neck cancers. No effective therapy has been developed to completely restore the SG functional damage on the long-term and reverse the poor quality of life of xerostomia patients. Cell- and secretome-based strategies are currently being tested in vitro and in vivo for the repair and/or regeneration of the damaged SG using (1) epithelial SG stem/progenitor cells from salispheres or explant cultures as well as (2) nonepithelial stem cell types and/or their bioactive secretome. These strategies will be the focus of our review. Herein, innovative 3D bioprinting nanotechnologies for the generation of organotypic cultures and SG organoids/mini-glands will also be discussed. These bioprinting technologies will allow researchers to analyze the secretome components and extracellular matrix production, as well as their biofunctional effects in 3D mini-glands ex vivo. Improving our understanding of the SG secretome is critical to develop effective secretome-based therapies towards the regeneration and/or repair of all SG compartments for proper restoration of saliva secretion and flow into the oral cavity. PMID- 28090209 TI - Prospect of Human Pluripotent Stem Cell-Derived Neural Crest Stem Cells in Clinical Application. AB - Neural crest stem cells (NCSCs) represent a transient and multipotent cell population that contributes to numerous anatomical structures such as peripheral nervous system, teeth, and cornea. NCSC maldevelopment is related to various human diseases including pigmentation abnormalities, disorders affecting autonomic nervous system, and malformations of teeth, eyes, and hearts. As human pluripotent stem cells including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) can serve as an unlimited cell source to generate NCSCs, hESC/hiPSC-derived NCSCs can be a valuable tool to study the underlying mechanisms of NCSC-associated diseases, which paves the way for future therapies for these abnormalities. In addition, hESC/hiPSC-derived NCSCs with the capability of differentiating to various cell types are highly promising for clinical organ repair and regeneration. In this review, we first discuss NCSC generation methods from human pluripotent stem cells and differentiation mechanism of NCSCs. Then we focus on the clinical application potential of hESC/hiPSC-derived NCSCs on peripheral nerve injuries, corneal blindness, tooth regeneration, pathological melanogenesis, Hirschsprung disease, and cardiac repair and regeneration. PMID- 28090210 TI - Pivotal Cytoprotective Mediators and Promising Therapeutic Strategies for Endothelial Progenitor Cell-Based Cardiovascular Regeneration. AB - Cardiovascular diseases (CVDs), including atherosclerosis, stroke, and myocardial infarction, is a major cause of death worldwide. In aspects of cell therapy against CVD, it is generally accepted that endothelial progenitor cells (EPCs) are potent neovascular modulators in ischemic tissues. In response to ischemic injury signals, EPCs located in a bone marrow niche migrate to injury sites and form new vessels by secreting various vasculogenic factors including VEGF, SDF-1, and FGF, as well as by directly differentiating into endothelial cells. Nonetheless, in ischemic tissues, most of engrafted EPCs do not survive under harsh ischemic conditions and nutrient depletion. Therefore, an understanding of diverse EPC-related cytoprotective mediators underlying EPC homeostasis in ischemic tissues may help to overcome current obstacles for EPC-mediated cell therapy for CVDs. Additionally, to enhance EPC's functional capacity at ischemic sites, multiple strategies for cell survival should be considered, that is, preconditioning of EPCs with function-targeting drugs including natural compounds and hormones, virus mediated genetic modification, combined therapy with other stem/progenitor cells, and conglomeration with biomaterials. In this review, we discuss multiple cytoprotective mediators of EPC-based cardiovascular repair and propose promising therapeutic strategies for the treatment of CVDs. PMID- 28090212 TI - Effects of Morinda officinalis Polysaccharide on Experimental Varicocele Rats. AB - Morinda officinalis is a traditional Chinese herbal medicine, which has been used to tonify the kidney and strengthen yang for a long time in China. In this study, the effects of M. officinalis Polysaccharide (MOP) on experimental varicocele adolescent rats were investigated. The result showed that varicocele destroyed the structure of the seminiferous epithelium and decreased the TJ protein expression (Occludin, Claudin-11, and ZO-1), testosterone (T) concentration in the left testicular tissue and serum, and serum levels of inhibin B (INHB), while increasing the levels of cytokines (TGF-beta3 and TNF-alpha) in the left testicular tissue, as well as serum levels of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and antisperm antibody (AsAb). MOP repaired the damaged seminiferous epithelium and TJ and reduced the levels of cytokines (TGF-beta3 and TNF-alpha) as well as serum levels of GnRH, FSH, LH, and AsAb, while upregulating TJ protein expression, T level in the left testicular tissue and serum, and serum INHB levels. In summary, we conclude that MOP promotes spermatogenesis and counteracts the varicocele induced damage to the seminiferous epithelium and TJ, probably via decreasing cytokines (TGF-beta3 and TNF-alpha) levels and regulating the abnormal sex hormones levels in experimental varicocele rats. PMID- 28090211 TI - Antimicrobial Properties of Plant Essential Oils against Human Pathogens and Their Mode of Action: An Updated Review. AB - A wide range of medicinal and aromatic plants (MAPs) have been explored for their essential oils in the past few decades. Essential oils are complex volatile compounds, synthesized naturally in different plant parts during the process of secondary metabolism. Essential oils have great potential in the field of biomedicine as they effectively destroy several bacterial, fungal, and viral pathogens. The presence of different types of aldehydes, phenolics, terpenes, and other antimicrobial compounds means that the essential oils are effective against a diverse range of pathogens. The reactivity of essential oil depends upon the nature, composition, and orientation of its functional groups. The aim of this article is to review the antimicrobial potential of essential oils secreted from MAPs and their possible mechanisms of action against human pathogens. This comprehensive review will benefit researchers who wish to explore the potential of essential oils in the development of novel broad-spectrum key molecules against a broad range of drug-resistant pathogenic microbes. PMID- 28090213 TI - Germinated and Ungerminated Seeds Extract from Two Lupinus Species: Biological Compounds Characterization and In Vitro and In Vivo Evaluations. AB - In recent years, nutraceuticals attracted a great amount of attention in the biomedical research due to their significant contribution as natural agents for prevention of various health issues. Ethanolic extracts from the ungerminated and germinated seeds of Lupinus albus L. and Lupinus angustifolius L. were analyzed for the content in isoflavones (genistein) and cinnamic acid derivatives. Additionally, the extracts were evaluated for antimicrobial, antiproliferative, and anti-inflammatory properties, using in vitro and in vivo tests. Germination proved to be a method of choice in increasing the amount of genistein and cinnamic acid derivatives in both Lupinus albus L. and Lupinus angustifolius L. seeds. Biological evaluation of all vegetal extracts revealed a weak therapeutic potential for both ungerminated and germinated seeds. PMID- 28090215 TI - Multiple Linear Regressions by Maximizing the Likelihood under Assumption of Generalized Gauss-Laplace Distribution of the Error. AB - Multiple linear regression analysis is widely used to link an outcome with predictors for better understanding of the behaviour of the outcome of interest. Usually, under the assumption that the errors follow a normal distribution, the coefficients of the model are estimated by minimizing the sum of squared deviations. A new approach based on maximum likelihood estimation is proposed for finding the coefficients on linear models with two predictors without any constrictive assumptions on the distribution of the errors. The algorithm was developed, implemented, and tested as proof-of-concept using fourteen sets of compounds by investigating the link between activity/property (as outcome) and structural feature information incorporated by molecular descriptors (as predictors). The results on real data demonstrated that in all investigated cases the power of the error is significantly different by the convenient value of two when the Gauss-Laplace distribution was used to relax the constrictive assumption of the normal distribution of the error. Therefore, the Gauss-Laplace distribution of the error could not be rejected while the hypothesis that the power of the error from Gauss-Laplace distribution is normal distributed also failed to be rejected. PMID- 28090216 TI - ChemEngine: harvesting 3D chemical structures of supplementary data from PDF files. AB - Digital access to chemical journals resulted in a vast array of molecular information that is now available in the supplementary material files in PDF format. However, extracting this molecular information, generally from a PDF document format is a daunting task. Here we present an approach to harvest 3D molecular data from the supporting information of scientific research articles that are normally available from publisher's resources. In order to demonstrate the feasibility of extracting truly computable molecules from PDF file formats in a fast and efficient manner, we have developed a Java based application, namely ChemEngine. This program recognizes textual patterns from the supplementary data and generates standard molecular structure data (bond matrix, atomic coordinates) that can be subjected to a multitude of computational processes automatically. The methodology has been demonstrated via several case studies on different formats of coordinates data stored in supplementary information files, wherein ChemEngine selectively harvested the atomic coordinates and interpreted them as molecules with high accuracy. The reusability of extracted molecular coordinate data was demonstrated by computing Single Point Energies that were in close agreement with the original computed data provided with the articles. It is envisaged that the methodology will enable large scale conversion of molecular information from supplementary files available in the PDF format into a collection of ready- to- compute molecular data to create an automated workflow for advanced computational processes. Software along with source codes and instructions available at https://sourceforge.net/projects/chemengine/files/?source=navbar.Graphical abstract. PMID- 28090214 TI - Challenges of corneal infections. AB - INTRODUCTION: Ocular infections remain an important cause of blindness worldwide and represent a challenging public health concern. In this regard, microbial keratitis due to fungal, bacterial, or viral infection can result in significant vision loss secondary to corneal scarring or surface irregularity. Left untreated corneal perforation and endophthalmitis can result, leading to loss of the eye. Rigorously studied animal models of disease pathogenesis have provided novel information that suggests new modes of treatment that may be efficacious clinically and emerging clinical data is supportive of some of these discoveries. AREAS COVERED: This review focuses on advances in our understanding of disease pathogenesis in animal models and clinical studies and how these relate to improved clinical treatment. We also discuss a novel approach to treatment of microbial keratitis due to infection with these bacterial pathogens using PACK CXL and recommend increased basic and clinical studies to address and refine the efficacy of this procedure. EXPERT COMMENTARY: Because resistance to antibiotics has developed over time to these bacterial pathogens, caution must be exercised in treatment. Attractive novel modes of treatment that hold new promise for further investigation include lipid based therapy, as well as use of small molecules that bind deleterious specific host responsive molecules and use of microRNA based therapies. PMID- 28090217 TI - Scaffold analysis of PubChem database as background for hierarchical scaffold based visualization. AB - BACKGROUND: Visualization of large molecular datasets is a challenging yet important topic utilised in diverse fields of chemistry ranging from material engineering to drug design. Especially in drug design, modern methods of high throughput screening generate large amounts of molecular data that call for methods enabling their analysis. One such method is classification of compounds based on their molecular scaffolds, a concept widely used by medicinal chemists to group molecules of similar properties. This classification can then be utilized for intuitive visualization of compounds. RESULTS: In this paper, we propose a scaffold hierarchy as a result of large-scale analysis of the PubChem Compound database. The analysis not only provided insights into scaffold diversity of the PubChem Compound database, but also enables scaffold-based hierarchical visualization of user compound data sets on the background of empirical chemical space, as defined by the PubChem data, or on the background of any other user-defined data set. The visualization is performed by a web based client-server application called Scaffvis. It provides an interactive zoomable tree map visualization of data sets up to hundreds of thousands molecules. Scaffvis is free to use and its source codes have been published under an open source license.Graphical abstract. PMID- 28090218 TI - Role of T1 Mapping in Inherited Cardiomyopathies. AB - T1 mapping by cardiovascular magnetic resonance is a rapidly evolving method for the quantitative assessment of tissue characteristics in cardiac disease. The myocardial T1 time can be measured without contrast (native T1) or following the administration of intravenous gadolinium-based contrast agent (post-contrast T1). By combining both of these measures, the myocardial extracellular volume fraction can be approximated. This value has been validated histologically in various inherited cardiomyopathies. Due to overlapping phenotypes, the diagnosis of inherited cardiomyopathy can at times be challenging. In this article we discuss when T1 mapping may be a useful tool in the differential diagnosis of cardiomyopathy. We also present evidence of when T1 mapping provides incremental risk stratification over other biomarkers. PMID- 28090219 TI - Integrated Microfluidic Aptasensor for Mass Spectrometric Detection of Vasopressin in Human Plasma Ultrafiltrate. AB - We present a microfluidic aptamer-based biosensor for detection of low-molecular weight biomarkers in patient samples. Using a microfluidic device that integrates aptamer-based specific analyte extraction, isocratic elution, and detection by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, we demonstrate rapid, sensitive and label-free detection of arginine vasopressin (AVP) in human plasma ultrafiltrate. AVP molecules in complex matrices are specifically captured by an aptamer that is immobilized on microbeads via affinity binding in a microchamber. After the removal of unbound, contaminating molecules through washing, aptamer-AVP complexes are thermally disrupted via on-chip temperature control. Released AVP molecules are eluted with purified water and transferred to a separate microchamber, and deposited onto a single spot on a MALDI plate via repeated, piezoelectrically actuated ejection, which enriches AVP molecules over the spot area. This integrated on-chip sample processing enables the quantitative detection of low-abundance AVP by MALDI-TOF mass spectrometry in a rapid and label-free manner. Our experimental results show the detection of AVP in human plasma ultrafiltrate as low as physiologically relevant picomolar concentrations via aptamer-based selective preconcentration, demonstrating the potential of our approach as a rapid (~ 1hr), sensitive clinical AVP assay. PMID- 28090220 TI - UTILIZATION OF HEALTH CARE SERVICES AMONG INTERNAL MIGRANTS IN HANOI AND ITS CORRELATION WITH HEALTH INSURANCE: A CROSS-SECTIONAL STUDY. AB - BACKGROUND: Economic transition (DoiMoi) in the 1980s in Viet Nam has led to internal migration, particularly rural-to-urban migration. Many studies suggested that there is a difference between non-migrants and migrants in using health care services. Current studies have mostly focused on migrants working in industrial zones (IZs) but migrants working in private small enterprises (PSEs) and seasonal migrants seem to be ignored. However, these two groups of migrants are more vulnerable in health care access than others because they usually work without labor contracts and have no health insurance. The study aims to compare the utilization of health care services and explore its correlated factors among these three groups. METHODS: This cross-sectional study included 1800 non migrants and migrants aged 18-55 who were selected through stratified sampling in Long Bien and Ba Dinh districts, Hanoi. These study sites consist of large industrial zones and many slums where most seasonal migrants live in. A structured questionnaire was used to collect information on health service utilization in the last 6 months before the study. Utilization of heath care services was identified as "an ill person who goes to health care centers to seek any treatment (i.e. both private and public health care centers)". RESULTS: 644 of 1800 participants reported having a health problem in the last 6 months before the study. Among these 644 people, 335 people used health care services. The percentage of non-migrants using health care service was the highest (67.6%), followed by migrants working in IZ (53.7%), migrants working in PSE (44%), and seasonal migrants (42%). Multivariate logistic regression showed migrants, especially seasonal migrants and migrants working in PSE, were less likely to use health care services (OR=0.35, p=0.016 and 0.38, p= 0.004, respectively), compared to non-migrants. The study also found that having no health insurance was a risk factor of the utilization (OR=0.29, p<0.001). Other factors such as gender, age, marital status, socioeconomic status, and monthly income were not related to the utilization of health care services. CONCLUSION: Seasonal migrants have the worst utilization of health care services, followed by migrants working in PSE, migrants working in IZ, and non-migrants. Health insurance is an important factor relating to the utilization. Accordingly, health insurance coverage needs to be increased if utilization of health care services for the whole population, particularly migrant population, is to be improved. PMID- 28090221 TI - Nutrition and Other Protective Behaviors Motivated by Environmental Health Risk Awareness. AB - BACKGROUND: Research findings have suggested that exposure to environmental pollutants contributes to increased health risks, which may be modulated by certain nutrition and other protective health behaviors. Nutrition professionals play an important role in effectively disseminating this information and in devising specific community-based nutrition education programs for audiences located in areas with environmental health issues. OBJECTIVE: To assess awareness of environmental health problems and motivation to adopt protective health behaviors for use in planning nutrition education programs for communities exposed to environmental pollutants. METHOD: Data were collected from a modified, validated Environmental Health Engagement Profile (EHEP) survey instrument administered to adults (n=774) participating in community events in Kentucky based on location relative to hazardous waste sites. RESULTS: The modified EHEP survey instrument showed good internal consistency reliability, and demographic characteristics were evaluated. Correlation analyses revealed significant positive correlations in all groups, separately and combined, between awareness of environmental pollution in an individual's surroundings and the extent of concern that pollutants cause adverse health effects (P < 0.01) and between concern that pollutants cause adverse health effects and taking personal actions to protect against such environmental insults (P < 0.01). The groups having the highest level of awareness posed by pollution are those residing near federally designated hazardous waste sites. CONCLUSION: These results suggest that determining and expanding an audience's knowledge and perceptions of environmental health risks will enhance effective nutrition education program planning. PMID- 28090222 TI - Does Bilingual Language Control Decline in Older Age? AB - We investigated age-related decline of bilingual language control. Thirteen older and 13 younger bilinguals performed a verbal fluency task (completing the same letter and semantic categories in each language and switching languages after every category), and a non-linguistic flanker task. In letter fluency, bilinguals produced fewer correct responses after switching languages, suggesting inhibition of the previously-used language. However, this testing-order effect did not differ between groups and older bilinguals produced few wrong-language intrusions, implying intact ability to apply inhibition in older age. In contrast, age-related deficits in the flanker task were robust, implying dissociations between language control and domain-general executive control. In semantic fluency, there were no testing-order effects but older bilinguals produced more intrusions than younger bilinguals, and more intrusions than in letter fluency. Thus, bilinguals may flexibly modulate the degree of inhibition when they can benefit from semantic priming between languages, but less efficiently so in older age. PMID- 28090223 TI - To Resect or Not to Resect Extrahepatic Bile Duct in Gallbladder Cancer? AB - The indications for and limitations of extrahepatic bile duct resection (EHBDR) in the context of gallbladder (GB) cancer are unclear. The purpose of this review was to examine the current literature to determine the impact of EHBDR on loco regional recurrence and survival in GB cancer. The EMBASE and Medline databases were searched up to February 2016 using the terms: extrahepatic bile duct resection and gallbladder cancer. Studies published in the last 20 years were eligible for inclusion. Given the heterogeneity of the population and the study methodologies employed, qualitative data synthesis in the form of meta-analysis was deemed implausible. Twenty-four studies fulfilled the inclusion criteria. The selected studies include 6,722 (55%) EHBDRs in a total of 12,251 GB cancer operations. The 25 studies were categorized into seven groups: 1) cancer survival all stages; 2) hepatoduodenal ligament invasion; 3) outcome in EHBDR and EHBDNR; 4) pT1b tumors; 5) pT2 tumors; 6) pT3/T4 tumors; and 7) incidental GB cancer. Radical cholecystectomy with EHBDR should be used as a standard operation for tumors involving the neck or the cystic duct of the GB (either macroscopically or microscopically). In all other cases, operative strategy should be individualized to the patient. PMID- 28090224 TI - Computerized Tomography-Guided Paracentesis: An Effective Alternative to Bedside Paracentesis? AB - BACKGROUND: Ascites remains the most common cause of hospitalization among patients with decompensated cirrhosis. Paracentesis is a relatively safe procedure with low complication rates. Computerized tomography (CT)-guided therapeutic paracentesis could be a safe and effective alternative to unaided or aided (ultrasonogram-guided) bedside paracentesis. In this retrospective study, we aimed to compare the efficacy, safety, and cost-effectiveness of CT-guided paracentesis with bedside paracentesis. METHODS: The period of study was from 2002 to 2012. All patients with cirrhosis who underwent therapeutic paracentesis were included in the study. These patients were divided into two groups. Group I consisted of patients who underwent CT-guided pigtail catheter insertion with ascitic fluid drainage. Group II consisted of patients who underwent beside therapeutic paracentesis after localization of fluid either by physical examination or sonographic localization. We measured the efficacy of CT-guided paracentesis and bedside paracentesis in terms of volume of fluid removed, length of stay, discharge doses of diuretics (spironolactone and furosemide) and number of days to readmission for symptomatic ascites. We also computed the cost effectiveness of CT-guided therapeutic paracentesis when compared to a bedside procedure. Fischer exact test was used to analyze the distribution of categorical data and unpaired t-test was used for comparison of means. RESULTS: There were a total of 546 unique patients with diagnosed cirrhosis who were admitted to the hospital with symptomatic ascites and underwent therapeutic paracentesis. Two hundred and forty-seven patients underwent CT-guided paracentesis, while 272 patients underwent bedside paracentesis. There was significant inverse correlation between the amount of ascitic fluid removed and total length of stay in the hospital. We found that the volume of fluid removed via a CT-guided pigtail insertion and drainage (2.72 +/- 2.02 L) is significantly higher when compared to fluid removed via bedside paracentesis (1.94 +/- 1.69). We also found that the interval time period between two successive therapeutic paracenteses was significantly longer for CT group (106.56 +/- 75.2 days) when compared to the bedside group (25.57 +/- 7.68 days). CONCLUSION: CT-guided paracentesis with pigtail catheter insertion and drainage is a clinically effective, cheap and safe alternative to conventional bedside paracentesis. PMID- 28090225 TI - Efficacy and Safety of Combination Therapy Consisting of Angiotensin II Type 1 Receptor Blocker, Calcium Channel Blocker and Hydrochlorothiazide in Patients With Hypertension. AB - BACKGROUND: Many patients continue to have high blood pressure (BP) even after treatment with high-dose (H)-angiotensin II type 1 receptor blocker (ARB)/calcium channel blocker (CCB) or middle-dose (M)-ARB/CCB/hydrochlorothiazide (HCTZ). METHODS: Thirty-two hypertensive patients who had the use of H-ARB/CCB or M ARB/CCB/HCTZ were enrolled in this study. We applied a changeover with a switch to H-ARB (telmisartan 80 mg/day)/CCB (amlodipine 5 mg/day or nifedipine CR 40 mg/day)/HCTZ (12.5 mg/day). RESULTS: Systolic BP (SBP) and diastolic BP (DBP) were significantly decreased in all patients and in the H-ARB/CCB and M ARB/CCB/HCTZ groups after 3 months. Percentage (%) of patients who reached the target BP after 3 months (72%) in all patients was significantly higher than that at 0 months (19%). There were no serious adverse effects in any of the patients. CONCLUSIONS: Combination therapy with H-ARB/CCB/HCTZ was associated with a significant reduction of BP. PMID- 28090226 TI - More Use of Peritoneal Dialysis Gives Significant Savings: A Systematic Review and Health Economic Decision Model. AB - BACKGROUND: Patients with end-stage renal disease (ESRD) are in need of renal replacement therapy as dialysis and/or transplantation. The prevalence of ESRD and, thus, the need for dialysis are constantly growing. The dialysis modalities are either peritoneal performed at home or hemodialysis (HD) performed in-center (hospital or satellite) or home. We examined effectiveness and cost-effectiveness of HD performed at different locations (hospital, satellite, and home) and peritoneal dialysis (PD) at home in the Norwegian setting. METHODS: We conducted a systematic review for patients above 18 years with end-stage renal failure requiring dialysis in several databases and performed several meta-analyses of existing literature. Mortality and major complications that required were our main clinical outcomes. The quality of the evidence for each outcome was evaluated using GRADE. Cost-effectiveness was assessed by developing a probabilistic Markov model. The analysis was carried out from a societal perspective, and effects were expressed in quality-adjusted life-years. Uncertainties in the base-case parameter values were explored with a probabilistic sensitivity analysis. Scenario analyses were conducted by increasing the proportion of patients receiving PD with a corresponding reduction in HD patients in-center both for Norway and Europian Union. We assumed an annual growth rate of 4% in the number of dialysis patients, and a relative distribution between PD and HD in-center of 30% and 70%, respectively. RESULTS: From a societal perspective and over a 5-year time horizon, PD was the most cost effective dialysis alternative. We found no significant difference in mortality between peritoneal and HD modalities. Our scenario analyses showed that a shift toward more patients on PD (as a first choice) with a corresponding reduction in HD in-center gave a saving over a 5-year period of 32 and 10,623 million EURO, respectively, for Norway and the European Union. CONCLUSIONS: PD was the most cost-effective dialysis alternative and was comparable with HD regarding efficacy outcomes. There are significant saving potentials if more end-stage renal patients are started on PD instead of HD. PMID- 28090227 TI - Symptomatic Gallstones in the Young: Changing Trends of the Gallstone Disease Related Hospitalization in the State of New York: 1996 - 2010. AB - BACKGROUND: The aim of the study was to evaluate if the gallstone-related hospitalizations in the young (< 20 years of age) have increased over time in both the Bronx County and New York State as a whole. METHODS: We retrospectively reviewed 15 years (1996 - 2010) of Statewide Planning and Research Cooperative System (SPARCS) data of New York State Department of Health. Patients with ICD-9 code diagnosis of 574 (cholelithiasis) among the first three discharge diagnoses were reviewed. RESULTS: Total number of all cause admissions to hospitals had increased from 2.44 million to 2.77 million (1996 - 2010). However, gallstone related hospitalizations had decreased from 1.7% to 1.2%. It was noted that there was a 30% increment in the proportion of those below 20 years of age with gallstone disease requiring hospitalization over the same period. This young patient population contributed only 2.04% to all gallstone-related hospitalizations in 1996, whereas it had increased to 2.96% in 2010. This trend was more pronounced in women, Hispanics and in those who were residing in the Bronx County as compared to all other New York counties combined. CONCLUSION: The gallstone-related hospitalizations in the young (< 20 years of age) have increased over time in both the Bronx County and New York State as a whole. This could be due to increasing prevalence of risk factors such as obesity, physical inactivity, diabetes and early pregnancy. PMID- 28090228 TI - Evaluation of Radiation Dose Received by Premature Neonates Admitted to Neonatal Intensive Care Unit. AB - BACKGROUND: This study aimed to evaluate the radiation dose received by premature neonates using diagnostic radiographies. METHODS: This cross-sectional study was conducted on 116 premature neonates with gestational age from 25 to 37 weeks; with the diagnosis of neonatal respiratory distress syndrome (NRDS) and tachypnea, they were admitted to a neonatal intensive care unit (NICU) at Ahvaz Imam Khomeini Hospital in 2015. For assessing the dose received, the model GR-200 thermoluminescent dosimeter (TLD) was used. For each premature neonate under radiation, three TLDs separately (one for each) were placed on surfaces of Ch1, T1, and G1 (chest, thyroid, and gonad of first newborn, respectively). Moreover, for the adjacent neonate at a distance of 60 - 100 cm, two TLDs were laid in the surfaces of T2 and G2 (thyroid and gonad of second newborn, respectively). The dose received by TLDs for any baby and the adjacent neonate under the entrance surface dose (ESD) was estimated. RESULTS: The mean of neonates' weight under study was 1,950.78 +/- 484.9 g. During the hospitalization period, minimum one and maximum three radiographies were done for any premature neonate. The doses received in the premature neonates to Ch1, T1 and G1 were 0.08 +/- 0.01, 0.06 +/- 0.01, and 0.05 +/- 0.01 mSv, respectively and for adjacent infants for T2 and G2 were 0.003 +/- 0.001 and 0.002 +/- 0.0009 mSv, respectively. CONCLUSIONS: In the study, radiation dose received by organs at risk of premature neonates was lower than the international criteria and standards, therefore, also due to the lack of radiation damage threshold, to limit collimator, and the use of the proper filtration, kilovoltage and time during radiography of premature neonates are recommended. PMID- 28090229 TI - The Impact Exerted on Clinical Outcomes of Patients With Chronic Heart Failure by Aldosterone Receptor Antagonists: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Aldosterone receptor antagonists (ARAs) have been associated with improved clinical outcomes in patients with heart failure with reduced left ventricular ejection fraction (HFREF), but not in those with heart failure with preserved left ventricular ejection fraction (HFpEF). With the aim to study this topic more deeply, we carried out a meta-analysis of selective and non-selective ARAs in HFREF and HFpEF. METHODS: We searched PubMed and Scopus databases. We decided to incorporate in the meta-analysis only randomized controlled trials (RCTs) of ARAs in patients with chronic heart failure (CHF) if they met the following criteria: experimental groups included patients with CHF treated with ARAs in addition to the conventional therapy; control groups included patients with CHF receiving conventional therapy without ARAs. Outcomes of interest were all-cause death, hospitalizations from cardiovascular cause, hyperkalemia, or gynecomastia. RESULTS: We detected 15 studies representing 15,671 patients. ARAs were associated with a reduced odds of all-cause death (odds ratio (OR): 0.79; 95% confidence interval (CI): 0.73 - 0.87) and hospitalizations from cardiovascular cause (OR: 0.73; 95% CI: 0.61 - 0.89). However, subgroup analysis showed that these advantages were limited to HFREF (all-cause death: OR: 0.77, 95% CI: 0.69 - 0.84; hospitalizations from cardiovascular cause: OR: 0.66, 95% CI: 0.51 - 0.85), but they did not affect the HFpEF group (all-cause death: OR: 0.91, 95% CI: 0.76 - 1.1; hospitalizations from cardiovascular cause: OR: 0.85, 95% CI: 0.7 - 1.09). ARAs increased the risk of hyperkalemia (OR: 2.17; 95% CI: 1.88 - 2.5). Non-selective ARAs, but not selective ARAs, increased the risk of gynecomastia (OR: 8.22, 95% CI: 4.9 - 13.81 vs. OR: 0.74, 95% CI: 0.43 - 1.27). CONCLUSIONS: ARAs reduced the risk of adverse cardiac events in HFREF but not HFpEF. In particular, ARA use in HFpEF patients is questionable, since in this CHF type, no significant improvement in all-cause death and cardiovascular hospitalizations was demonstrated with ARA treatment, in the face of the well known risks of hyperkalemia and/or gynecomastia that chronic ARA therapy entails. Selective ARAs were equally effective as non-selective ARAs, without the risk of gynecomastia. PMID- 28090230 TI - Epidemiology of Pregnancy-Associated ICU Utilization in Texas: 2001 - 2010. AB - BACKGROUND: ICU admission is uncommon among obstetric patients. Nevertheless, the epidemiology of ICU utilization is considered to be a useful proxy for study of severe maternal morbidity and near-miss events. However, there is paucity of population-level studies in obstetric patients in the United States. METHODS: The Texas Inpatient Public Use Data File and state-based reports were used to identify pregnancy-associated hospitalizations and those involving admission to ICU (n = 158,410) for the years 2001 - 2010. The clinical characteristics, outcomes, and the overall incidence and temporal trends of ICU admission were examined and stratified analyses of pregnancy outcomes were performed in specific categories of pregnancy-associated hospitalizations. In addition, ICU utilization among hospitalizations with maternal complications and organ dysfunction was evaluated. RESULTS: Chronic comorbidities (9.7%) and presence of organ dysfunction (6.2%) were uncommon among ICU admissions, with 26.5% having high severity of illness. The incidence of ICU admission was 39.0 per 1,000 pregnancy associated hospitalizations-years. Marked variability was found in ICU admission both across pregnancy outcomes (ranging from 0.6 per 1,000 abortions-years to 85.9 per 1,000 stillbirths-years) and categories of pregnancy-associated hospitalizations (ranging from 32.1 per 1,000 delivery hospitalizations-years to 144.8 per 1,000 postpartum hospitalizations-years). The incidence of ICU admission rose 68% among pregnancy-associated hospitalizations and for all examined subgroups, except abortion. Preeclampsia/eclampsia (23.3%) and obstetric hemorrhage (6.9%) were the most common maternal complications among ICU admissions. Four hundred fourteen women (0.3%) died, while 97.6% were discharged home. CONCLUSIONS: This study documents the highest incidence of ICU utilization in obstetric patients in the US to date. The findings suggest low threshold for obstetric ICU admissions in the state and do not support comparative use of ICU utilization as surrogate measure for populations' burden of severe maternal morbidity and near-miss events. Nevertheless, the demonstrated tremendous heterogeneity in ICU utilization across examined subgroups identifies new high risk groups of obstetric patients that would benefit from heightened clinician vigilance and timely ICU triage and care. Further studies are needed to inform reduction in avoidable variability in ICU utilization to both enhance maternal, fetal, and neonatal outcomes and to improve resource allocation. PMID- 28090231 TI - Effects of Ipragliflozin on Diabetic Nephropathy and Blood Pressure in Patients With Type 2 Diabetes: An Open-Label Study. AB - BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are novel agents used to treat type 2 diabetic patients. We investigated the efficacy of the SGLT2 inhibitor ipragliflozin on diabetic nephropathy in Japanese patients with type 2 diabetes. METHODS: A 50 mg dose of ipragliflozin was administered for 24 weeks to 50 patients with type 2 diabetes who were concomitantly managed with diet and exercise therapy alone or antidiabetic medications other than SGLT2 inhibitors. RESULTS: At the end of the 24-week ipragliflozin treatment, significant decreases in mean glycated hemoglobin (HbA1c) (1.0+/-1.2%) and body weight (2.7 +/- 2.5 kg) were observed; in addition, median urinary albumin-to-creatinine ratio (UACR) significantly decreased from 15.5 (8.0 - 85.7) to 12.9 (7.4 - 36.3) mg/gCr. Sub analysis by renal function at baseline revealed that median UACR in patients with estimated glomerular filtration rate (eGFR) >= 90 mL/min/1.73 m2 decreased significantly from 12.3 (7.5 - 89.6) to 10.6 (5.8 - 27.3) mg/gCr. Furthermore, mean eGFR decreased significantly from 102.4 +/- 8.6 to 93.6 +/- 10.5 mL/min/1.73 m2 in these patients. In contrast, UACR and eGFR did not change significantly in patients with eGFR < 90. In addition, analysis of the relationship between the amount of change in UACR and blood pressure at 24 weeks revealed a significant positive correlation between UACR and SBP values, independently of the presence of diabetic nephropathy. CONCLUSIONS: Our results indicate that ipragliflozin may facilitate HbA1c control and body weight reduction. Furthermore, our results also raise the possibility that ipragliflozin significantly reduces urinary albumin levels and improves glomerular hyperfiltration in a subset of patients with type 2 diabetes. PMID- 28090232 TI - Efficacy and Safety of Thrombolytic Therapy in Acute Submassive Pulmonary Embolism: Follow-Up Study. AB - BACKGROUND: Thrombolysis in acute submassive pulmonary embolism (PE) remains controversial. So we studied impact of thrombolytic therapy in acute submassive PE in terms of mortality, hemodynamic status, improvement in right ventricular function, and safety in terms of major and minor bleeding. METHOD: A single center, prospective, randomized study of 86 patients was conducted at LPS Institute of Cardiology, G.S.V.M. Medical College, Kanpur, India. Patients received thrombolysis (single bolus of tenecteplase) with unfractionated heparin (UFH, group I) or placebo with UFH (group II). RESULT: Mean age of patients was 54.35 +/- 12.8 years with male dominance (M:F = 70%:30%). Smoking was the most common risk factor seen in 29% of all patients, followed by recent history of immobilization (25%), history of surgery or major trauma within past 1 month (15%), dyslipidemia (10%) and diabetes mellitus (10%). Dyspnea was the most common symptom in 80% of all patients, followed by chest pain in 55% and syncope in 6%. Primary efficacy outcome occurred significantly better in group I vs. group II (4.5% vs. 20%; P = 0.04), and significant difference was also found in hemodynamic decompensation (4.5% vs. 20%; P = 0.04), the fall in mean pulmonary artery systolic pressure (PASP) (28.8% vs. 22.5%; P = 0.03), improvement in right ventricular (RV) function (70% vs. 40%; P = 0.001) and mean hospital stay (8.1 +/ 2.5 vs. 11.1 +/- 2.14 days; P = 0.001). There was no difference in mortality and major bleeding as safety outcome but increased minor bleeding occurred in group I patients (16% vs. 12%; P = 0.04). CONCLUSION: Patients with acute submassive PE do not derive overall mortality benefit, recurrent PE and rehospitalization with thrombolytic therapy but had improved clinical outcome in form of decrease in hemodynamic decompensation, mean hospital stay, PASP and improvement of RV function with similar risk of major bleed but at cost of increased minor bleeding. PMID- 28090234 TI - Increased Hematocrit During Sodium-Glucose Cotransporter-2 Inhibitor Therapy. PMID- 28090233 TI - Hispanic Patient Perspectives of the Physician's Role in Obesity Management. AB - BACKGROUND: Little is known concerning Hispanic patients' perceptions about the role of the physician in obesity management. This study seeks to describe the perspectives of Hispanic patients toward weight loss, and what they believe their doctor's role should be in the management of obesity. METHODS: A cross-sectional study utilizing semi-structured interviews was conducted in a university-based family medicine clinic. Open-ended questions explored beliefs about the relationship between weight and health, previous weight loss experience, perceptions about the role of the physician in weight loss, past experiences with their physician, and preferences for how a physician could help facilitate weight loss. The free recall listing technique was used to elicit responses. Common themes were identified by a group coding process. RESULTS: Patients were open to discussion from physicians concerning weight loss but many had not been approached. They wanted assistance from their doctors in the form of dietician referrals, specific weight loss goals, and encouragement. Patients' knowledge about the implications of excess weight on health was lacking. CONCLUSION: Hispanic patients want more help and advice from their doctors. General knowledge of the health implications of obesity was lacking, indicating a need for more health education by the healthcare team. PMID- 28090235 TI - A Possible Mechanism for Renoprotective Effect of Sodium-Glucose Cotransporter 2 Inhibitor: Elevation of Erythropoietin Production. PMID- 28090236 TI - Optimal Pre-Pregnancy Body Mass Index Cut-Offs for Obesity in Japan. PMID- 28090237 TI - Positive Criminology and Rethinking the Response to Adolescent Addiction: Evidence on the Role of Social Support, Religiosity, and Service to Others. AB - Adolescent addiction has emerged as a major public health problem. The greatest increase in alcohol and other drug use disorders can be found among youth. Concurrently, technological advances in policing coupled with aggressive prosecuting and sentencing practices have contributed to the growth of America's correctional system. The assertive response of policing, courts, and corrections, however, have not prevented the dramatic rise of adolescent addiction. Unfortunately, there is no national data tracking addicted youth in the criminal justice system to evaluate what works when it comes to youth with addiction. This article reviews justice system responses to adolescent offenders with addiction, and promising approaches engaging juveniles in programmatic components of Alcoholics Anonymous (AA). This study highlights the role of spirituality, service to others, and social support in maintaining sobriety, reducing arrests, and lowering recidivism for adolescents court-referred to treatment. Recommendations for improving the response to adolescent offenders with addiction are offered. PMID- 28090239 TI - THE SCREENING AND RANKING ALGORITHM FOR CHANGE-POINTS DETECTION IN MULTIPLE SAMPLES. AB - The chromosome copy number variation (CNV) is the deviation of genomic regions from their normal copy number states, which may associate with many human diseases. Current genetic studies usually collect hundreds to thousands of samples to study the association between CNV and diseases. CNVs can be called by detecting the change-points in mean for sequences of array-based intensity measurements. Although multiple samples are of interest, the majority of the available CNV calling methods are single sample based. Only a few multiple sample methods have been proposed using scan statistics that are computationally intensive and designed toward either common or rare change-points detection. In this paper, we propose a novel multiple sample method by adaptively combining the scan statistic of the screening and ranking algorithm (SaRa), which is computationally efficient and is able to detect both common and rare change points. We prove that asymptotically this method can find the true change-points with almost certainty and show in theory that multiple sample methods are superior to single sample methods when shared change-points are of interest. Additionally, we report extensive simulation studies to examine the performance of our proposed method. Finally, using our proposed method as well as two competing approaches, we attempt to detect CNVs in the data from the Primary Open Angle Glaucoma Genes and Environment study, and conclude that our method is faster and requires less information while our ability to detect the CNVs is comparable or better. PMID- 28090240 TI - Coccygeal Pad With an Anterior Flexed Coccyx: A Case Report. AB - Objective: A coccygeal pad is a nodular lesion in the sacrococcygeal area. It is a rare disease characterized by corneal thickening, the proliferation of collagen bundles, and an anterior flexed coccyx. In the English literature, 42 patients have been reported. Methods: We present a young male case of a typical coccygeal pad with an anterior flexed coccyx. Results: After resection of the nodule and coccygectomy, there has been no recurrence during the 6-month postoperative follow-up. Conclusions: Plastic surgeons should recognize this as a disease to be differentiated from gluteal skin tumors. PMID- 28090238 TI - Red blood cell dynamics in biomimetic microfluidic networks of pulmonary alveolar capillaries. AB - The pulmonary capillary networks (PCNs) embody organ-specific microvasculatures, where blood vessels form dense meshes that maximize the surface area available for gas exchange in the lungs. With characteristic capillary lengths and diameters similar to the size of red blood cells (RBCs), seminal descriptions coined the term "sheet flow" nearly half a century ago to differentiate PCNs from the usual notion of Poiseuille flow in long straight tubes. Here, we revisit in true-scale experiments the original "sheet flow" model and devise for the first time biomimetic microfluidic platforms of organ-specific PCN structures perfused with RBC suspensions at near-physiological hematocrit levels. By implementing RBC tracking velocimetry, our measurements reveal a wide range of heterogonous RBC pathways that coexist synchronously within the PCN; a phenomenon that persists across the broad range of pressure drops and capillary segment sizes investigated. Interestingly, in spite of the intrinsic complexity of the PCN structure and the heterogeneity in RBC dynamics observed at the microscale, the macroscale bulk flow rate versus pressure drop relationship retains its linearity, where the hydrodynamic resistance of the PCN is to a first order captured by the characteristic capillary segment size. To the best of our knowledge, our in vitro efforts constitute a first, yet significant, step in exploring systematically the transport dynamics of blood in morphologically inspired capillary networks. PMID- 28090241 TI - Reverse Adipofascial Radial Forearm Flap Surgery for Soft-Tissue Reconstruction of Hand Defects. AB - Objective: The reverse radial forearm flap has been used for soft-tissue hand defect surgical procedures worldwide. One of the major drawbacks of this flap, however, is donor site morbidity, as the donor site is closed with a skin graft. Problems with skin graft donor areas include adhesion, contracture, and wound healing complications. In this study, only the adipofascial component of a reverse radial forearm flap was used to prevent these problems; in addition, a skin graft was applied over the flap instead of over the donor site. Methods: Between January 2011 and December 2013, a total of 13 hand defects were reconstructed with a reverse adipofascial radial forearm flap. Patients were evaluated for functional results using total active motion criteria and disability of the arm, shoulder, and hand scores, operation time, hospitalization time, and patient satisfaction. Results: All flaps and grafts placed on flaps survived completely and donor sites healed without complications. The total active motion criteria and the disability of the arm, shoulder, and hand score demonstrated that the functional outcomes were successful. Patient satisfaction scores using the visual analog scale had a mean of 88.3 (SD = 2.95) mm. Operation time for the flap surgery was 126.1 (SD = 21.80) minutes, and patients were discharged at an average of 6.3 (SD = 1.44) days. Conclusion: Use of an adipofascial component in reverse radial forearm flap surgery is appropriate for reducing problems with donor site skin grafts. Patients' functional outcomes denoted that the reverse adipofascial radial forearm flap is a reliable and effective method to cover soft-tissue defects of the hand. Level of Evidence: IV. PMID- 28090242 TI - Reconstructing Defects of the Lower Lip: An Emphasis on the Estlander Flap. PMID- 28090243 TI - Management of Lumbosacral Myelomeningocele. PMID- 28090246 TI - Bayesian Covariate Selection in Mixed-Effects Models For Longitudinal Shape Analysis. AB - The goal of longitudinal shape analysis is to understand how anatomical shape changes over time, in response to biological processes, including growth, aging, or disease. In many imaging studies, it is also critical to understand how these shape changes are affected by other factors, such as sex, disease diagnosis, IQ, etc. Current approaches to longitudinal shape analysis have focused on modeling age-related shape changes, but have not included the ability to handle covariates. In this paper, we present a novel Bayesian mixed-effects shape model that incorporates simultaneous relationships between longitudinal shape data and multiple predictors or covariates to the model. Moreover, we place an Automatic Relevance Determination (ARD) prior on the parameters, that lets us automatically select which covariates are most relevant to the model based on observed data. We evaluate our proposed model and inference procedure on a longitudinal study of Huntington's disease from PREDICT-HD. We first show the utility of the ARD prior for model selection in a univariate modeling of striatal volume, and next we apply the full high-dimensional longitudinal shape model to putamen shapes. PMID- 28090244 TI - Neurodegeneration and Glial Response after Acute Striatal Stroke: Histological Basis for Neuroprotective Studies. AB - Stroke is a leading cause of death and neurological disability worldwide and striatal ischemic stroke is frequent in humans due to obstruction of middle cerebral artery. Several pathological events underlie damage progression and a comprehensive description of the pathological features following experimental stroke in both acute and chronic survival times is a necessary step for further functional studies. Here, we explored the patterns of microglial activation, astrocytosis, oligodendrocyte damage, myelin impairment, and Nogo-A immunoreactivity between 3 and 30 postlesion days (PLDs) after experimental striatal stroke in adult rats induced by microinjections of endothelin-1 (ET-1). The focal ischemia induced tissue loss concomitant with intense microglia activation between 3 and 14 PLDs (maximum at 7 PLDs), decreasing afterward. Astrocytosis was maximum around 7 PLDs. Oligodendrocyte damage and Nogo-A upregulation were higher at 3 PLDs. Myelin impairment was maximum between 7 and 14 PLDs. Nogo-A expression was higher in the first week in comparison to control. The results add important histopathological features of ET-1 induced stroke in subacute and chronic survival times. In addition, the establishment of the temporal evolution of these neuropathological events is an important step for future studies seeking suitable neuroprotective drugs targeting neuroinflammation and white matter damage. PMID- 28090247 TI - OPTIMAL PARAMETER MAP ESTIMATION FOR SHAPE REPRESENTATION: A GENERATIVE APPROACH. AB - Probabilistic label maps are a useful tool for important medical image analysis tasks such as segmentation, shape analysis, and atlas building. Existing methods typically rely on blurred signed distance maps or smoothed label maps to model uncertainties and shape variabilities, which do not conform to any generative model or estimation process, and are therefore suboptimal. In this paper, we propose to learn probabilistic label maps using a generative model on given set of binary label maps. The proposed approach generalizes well on unseen data while simultaneously capturing the variability in the training samples. Efficiency of the proposed approach is demonstrated for consensus generation and shape-based clustering using synthetic datasets as well as left atrial segmentations from late-gadolinium enhancement MRI. PMID- 28090245 TI - Chlorinated Phospholipids and Fatty Acids: (Patho)physiological Relevance, Potential Toxicity, and Analysis of Lipid Chlorohydrins. AB - Chlorinated phospholipids are formed by the reaction of hypochlorous acid (HOCl), generated by the enzyme myeloperoxidase under inflammatory conditions, and the unsaturated fatty acyl residues or the head group. In the first case the generated chlorohydrins are both proinflammatory and cytotoxic, thus having a significant impact on the structures of biomembranes. The latter case leads to chloramines, the properties of which are by far less well understood. Since HOCl is also widely used as a disinfecting and antibacterial agent in medicinal, industrial, and domestic applications, it may represent an additional source of danger in the case of abuse or mishandling. This review discusses the reaction behavior of in vivo generated HOCl and biomolecules like DNA, proteins, and carbohydrates but will focus on phospholipids. Not only the beneficial and pathological (toxic) effects of chlorinated lipids but also the importance of these chlorinated species is discussed. Some selected cleavage products of (chlorinated) phospholipids and plasmalogens such as lysophospholipids, (chlorinated) free fatty acids and alpha-chloro fatty aldehydes, which are all well known to massively contribute to inflammatory diseases associated with oxidative stress, will be also discussed. Finally, common analytical methods to study these compounds will be reviewed with focus on mass spectrometric techniques. PMID- 28090248 TI - Just change the channel? Studying effects of age on emotion regulation using a TV watching paradigm. AB - Older adults are theorized to benefit from proactive forms of emotion regulation that allow them to avoid negative stimuli (Charles, 2010). To test this, we examined choices as a form of emotion regulation. In two studies investigating age differences, participants selected affective stimuli using a cable television interface, while choices and mood were recorded. In lab-based Study 1, older adults spent more time watching neutral channels, but younger adults spent more time watching positive ones. Older adults also watched more low-arousal content, while younger adults watched more high-arousal content. Lagged analyses revealed that younger adults' choices were directed toward increasing positive affect and arousal. Study 2 replicated these findings in a community-based adult lifespan sample at a local museum. These findings suggest that arousal plays an important role in motivating emotion regulation behavior in the context of selections, and this differs by age. PMID- 28090249 TI - Multimodality Imaging for Left Ventricular Hypertrophy Severity Grading: A Methodological Review. AB - Left ventricular hypertrophy (LVH), defined by an increase in left ventricular mass (LVM), is a common cardiac finding generally caused by an increase in pressure or volume load. Assessing severity of LVH is of great clinical value in terms of prognosis and treatment choices, as LVH severity grades correlate with the risk for presenting cardiovascular events. The three main cardiac parameters for the assessment of LVH are wall thickness, LVM, and LV geometry. Echocardiography, with large availability and low cost, is the technique of choice for their assessment. Consequently, reference values for LVH severity in clinical guidelines are based on this technique. However, cardiac magnetic resonance (CMR) and computed tomography (CT) are increasingly used in clinical practice, providing excellent image quality. Nevertheless, there is no extensive data to support reference values based on these techniques, while comparative studies between the three techniques show different results in wall thickness and LVM measurements. In this paper, we provide an overview of the different methodologies used to assess LVH severity with echocardiography, CMR and CT. We argue that establishing reference values per imaging modality, and possibly indexed to body surface area and classified per gender, ethnicity and age-group, might be essential for the correct classification of LVH severity. PMID- 28090250 TI - Early Detection for Right Ventricular Dysfunction in Bronchopulmonary Dysplasia without Pulmonary Hypertension. PMID- 28090251 TI - Two-Dimensional Speckle-Tracking Echocardiography in Normal Korean Population: Is Now to Start Using in Routine Clinical Practice? PMID- 28090252 TI - The Relation of Epicardial Fat Thickness, Neutrophil to Lymphocyte Ratio and Circadian Rhythm of Blood Pressure. PMID- 28090253 TI - The Incremental Effect of Obesity on Myocardial Fibrosis In Patients with Aortic Stenosis. PMID- 28090254 TI - The Importance of Echocardiographic Screening for Pulmonary Arterial Hypertension in Korean Patients with Systemic Sclerosis. PMID- 28090255 TI - Clinical Utility of Echocardiography for the Diagnosis and Prognosis in Children with Bronchopulmonary Dsyplasia. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) may result in chronic pulmonary artery hypertension and right ventricular (RV) dysfunction. Various echocardiographic assessments of RV dysfunction have been used to determine whether echocardiographic measurements of premature infants with BPD could provide sensitive measures of RV function that correlates with BPD severity. METHODS: Twenty-eight control subjects without BPD (non BPD group), 28 patients with mild BPD, 11 patients with moderate BPD, and six patients with severe BPD underwent echocardiograms with standard measurement such as ejection fraction by M-mode, tricuspid regurgitation pressure gradient, myocardial performance index (MPI) derived from pulse Doppler, and tissue Doppler imaging (TDI) measurements. BPD severity was classified by the NICHD/NHLBI/ORD workshop rating scale. Twenty eight control subjects without BPD (non BPD group), 28 patients with mild BPD, 11 patients with moderate BPD, and six patients with severe BPD underwent echocardiograms with standard measurement such as ejection fraction by M-mode, tricuspid regurgitation pressure gradient, myocardial performance index (MPI) derived from pulse Doppler, and TDI measurements. BPD severity was classified by the NICHD/NHLBI/ORD workshop rating scale. RESULTS: None of the standard echocardiographic findings was significantly different between the control group and BPD groups. However, mean septal TDI-MPI of the severe BPD group (0.68 +/- 0.06) was significantly (p < 0.01) higher than that of the non-BPD (0.58 +/- 0.10) or the mild BPD group (0.59 +/- 0.12). In addition, mean RV TDI-MPI of the severe BPD group (0.71 +/- 0.13) was significantly (p < 0.05) higher than that of the non-BPD group (0.56 +/- 0.08) or the mild BPD group (0.60 +/- 0.125). Linear regression showed a good correlation between the severity of BPD and RV TDI-MPI (p = 0.01, R = 0.30) or septal TDI-MPI (p = 0.04, R = 0.24). CONCLUSION: Echocardiographic evaluation of RV function based on an assessment of RV TDI-MPI can provide RV dysfunction parameter in premature infants with BPD. PMID- 28090256 TI - Normal 2-Dimensional Strain Values of the Left Ventricle: A Substudy of the Normal Echocardiographic Measurements in Korean Population Study. AB - BACKGROUND: It is important to understand the distribution of 2-dimensional strain values in normal population. We performed a multicenter trial to measure normal echocardiographic values in the Korean population. METHODS: This was a substudy of the Normal echOcardiogRaphic Measurements in KoreAn popuLation (NORMAL) study. Echocardiographic specialists measured frequently used echocardiographic indices in healthy people according to a standardized method at 23 different university hospitals. The strain values were analyzed from digitally stored images. RESULTS: Of a total of 1003 healthy participants in NORMAL study, 2-dimensional strain values were measured in 501 subjects (265 females, mean age 47 +/- 15 years old) with echocardiographic images only by GE echocardiographic machines. Interventricular septal thickness, left ventricular (LV) posterior wall thickness, systolic and diastolic LV dimensions, and LV ejection fraction were 7.5 +/- 1.0 mm, 7.4 +/- 1.0 mm, 29.9 +/- 2.8 mm, 48.9 +/- 3.6 mm, and 62 +/- 4%, respectively. LV longitudinal systolic strain (LS) values of apical 4-chamber (A4C) view, apical 3-chamber (A3C) view, apical 2-chamber (A2C) view, and LV global LS (LVGLS) were -20.1 +/- 2.3, -19.9 +/- 2.7, -21.2 +/- 2.6, and -20.4 +/- 2.2%, respectively. LV longitudinal systolic strain rate (LVLSR) values of the A4C view, A3C view, A2C view, and LV global LSR (LVGLSR) were -1.18 +/- 0.18, 1.20 +/- 0.21, -1.25 +/- 0.21, and -1.21 +/- 0.21-s, respectively. Females had lower LVGLS (-21.2 +/- 2.2% vs. -19.5 +/- 1.9%, p < 0.001) and LVGLSR (-1.25 +/- 0.18-s vs. -1.17 +/- 0.15-s, p < 0.001) values than males. CONCLUSION: We measured LV longitudinal strain and strain rate values in the normal Korean population. Since considerable gender differences were observed, normal echocardiographic cutoff values should be differentially applied based on sex. PMID- 28090257 TI - Epicardial Fat Thickness and Neutrophil to Lymphocyte Ratio are Increased in Non Dipper Hypertensive Patients. AB - BACKGROUND: In this study, we aimed to investigate the relationship between echocardiographic epicardial fat thickness (EFT), neutrophil to lymphocyte ratio (NLR; an important inflammatory marker), and diurnal blood pressure (BP) changes in patients with recently diagnosed essential hypertension. METHODS: A total of 647 patients underwent echocardiography and 24 hours of ambulatory BP monitoring. EFT was measured by echocardiography, while NLR was measured by dividing the neutrophil count by the lymphocyte count. Patients were categorized into three groups according to BP pattern: the normotensive group, the dipper group, and the non-dipper group. RESULTS: The mean EFT was highest in the non-dipper group (non dipper group, 7.3 +/- 3.0 mm; dipper group, 6.1 +/- 2.0 mm; control group, 5.6 +/ 2.0 mm; p < 0.001). NLR was also highest in the non-dipper group (non-dipper, 2.75 +/- 2.81; dipper, 2.01 +/- 1.32; control, 1.92 +/- 1.11; p < 0.001). EFT was significantly correlated with age (r = 0.160, p < 0.001) and NLR (r = 0.353, p < 0.001). Furthermore, an EFT >= 7.0 mm was associated with the non-dipper BP pattern with 51.3% sensitivity and 71.6% specificity [95% confidence interval (CI) = 0.56-0.65, p < 0.001]. In a multivariate analysis, EFT [adjusted odds ratio (OR) = 3.99, 95% CI = 1.22-13.10, p = 0.022] and NLR (OR = 1.34, 95% CI = 1.05-1.71, p = 0.018) were independent parameters that distinguished a non-dipper pattern after adjustment for cardiovascular risk factors. CONCLUSION: EFT and NLR are independently associated with impaired diurnal BP profiles in hypertensive individuals. EFT (as measured by echocardiography) and NLR appear to be helpful in stratifying cardiometabolic risk. PMID- 28090259 TI - Prevalence of Pulmonary Arterial Hypertension in Korean Adult Patients with Systemic Sclerosis: Result of a Pilot Echocardiographic Screening Study. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality among patients with systemic sclerosis (SSc). Early detection and prompt treatment of PAH associated with SSc (SSc-PAH) result in better prognosis. We conducted echocardiographic study to presume the prevalence of PAH in Korean adult SSc patients and to diagnose SSc-PAH in their early stages with right heart catheterization (RHC). METHODS: We performed free of charge echocardiographic study including 37 adult SSc patients at the Chungnam National University Hospital. The possibility of PAH is determined by the estimation of pulmonary arterial pressure by peak tricuspid regurgitation velocity of > 3.0 m/s. Patients with possible PAH were recommended to undergo RHC to confirm the diagnosis. RESULTS: In 37 patients, 8 patients were suspected with PAH. Among them, 6 patients agreed to be examined with RHC, and 4 were confirmed with PAH. The prevalence of possible PAH was 21.6% (8 of 37 patients), and that of confirmed PAH was 10.8% (4 of 37 patients). Four patients who were confirmed with SSc-PAH through RHC have been treated with specific pulmonary vasodilators and maintained stable. CONCLUSION: Eight patients (21.6%) were possible PAH and 4 (10.8%) were diagnosed as SSc-PAH by RHC after the echocardiographic screening study of 37 adult SSc patients. PMID- 28090258 TI - Echocardiographic and Histologic Correlations in Patients with Severe Aortic Stenosis: Influence of Overweight and Obesity. AB - BACKGROUND: Severe aortic stenosis (AS), leads to pathological left ventricular remodeling that may worsen with concomitant overweight and obesity (OW/O). METHODS: We aimed to prospectively analyze the impact of OW/O on ventricular remodeling in severe AS, by evaluating the percentage of intraendomyocardial fibrosis (PIEF) and the percentage of infiltrating intraendocardial lipid vacuoles (PIELV) and its relationship to global longitudinal strain (GLS) in patients with OW/O. RESULTS: 44 patients with severe AS were included, 13 non obese (29%) and 31 OW/O (71%), all of them with left ventricular ejection fraction >= 55%. GLS was evaluated with 2D speckle tracking. During valve replacement, an endocardial biopsy was obtained, where PIEF and PIELV were analyzed. Patients with higher PIEF and PIELV had greater body mass index (p < 0.0001) and worse GLS (p < 0.0053). A GLS cut-off point < -14% had a sensitivity of 75%, and a specificity of 92.8% to detect important PIEF (AUC: 0.928, 95% confidence interval: 0.798-1.00). On multivariate analysis, OW/O and PIELV were independently associated to the PIEF, and OW/O and PIEF were independently associated to GLS. A high correlation between the amount of PIELV and PIEF were found. CONCLUSION: Patients with severe AS and OW/O have greater PIEF and PIELV, suggesting more pathological remodeling. GLS is useful to detect subclinical myocardial injury and is potentially useful for endomyocardial fibrosis detection. The presence of higher PIELF may be a trigger factor for the development of intraendomyocardial fibrosis. PMID- 28090260 TI - Redefining Effusive-Constrictive Pericarditis with Echocardiography. AB - BACKGROUND: Effusive-constrictive pericarditis (ECP) is traditionally diagnosed by using the expensive and invasive technique of direct pressure measurements in the pericardial space and the right atrium. The aim of this study was to assess the diagnostic role of echocardiography in tuberculous ECP. METHODS: Intrapericardial and right atrial pressures were measured pre- and post pericardiocentesis, and right ventricular and left ventricular pressures were measured post-pericardiocentesis in patients with tuberculous pericardial effusions. Echocardiography was performed post-pericardiocentesis. Traditional, pressure-based diagnostic criteria were compared with post-pericardiocentesis systolic discordance and echocardiographic evidence of constriction. RESULTS: Thirty-two patients with tuberculous pericardial disease were included. Sixteen had ventricular discordance (invasively measured), 16 had ECP as measured by intrapericardial and right atrial invasive pressure measurements and 17 had ECP determined echocardiographically. The sensitivity and specificity of pressure guided measurements (compared with discordance) for the diagnosis of ECP were both 56%. The positive and negative predictive values were both 56%. The sensitivity of echocardiography (compared with discordance) for the diagnosis of ECP was 81% and the specificity 75%, while the positive and the negative predictive values were 76% and 80%, respectively. CONCLUSION: Echocardiography shows a better diagnostic performance than invasive, pressure-based measurements for the diagnosis of ECP when both these techniques are compared with the gold standard of invasively measured systolic discordance. PMID- 28090261 TI - Fabry Disease Presenting with Hypertrophic Cardiomyopathy and Tricuspid Regurgitation. AB - A 71-year-old female who was diagnosed with nonobstructive hypertrophic cardiomyopathy since 1999 presented with dyspnea and severe edema on both legs. For the management of her symptom, cardiac surgery including tricuspid annuloplasty, Maze operation and right atrial reduction plasty was performed. During follow-up after cardiac surgery, a plasma alpha-galactosidase activity was checked for the screening of Fabry disease and the result was around lower normal limit. DNA analysis was implemented for confirmation and it revealed a heterozygote alpha-galactosidase mutation at exon 6 [c.901C>T (p.Arg301Ter)]. This case suggests that Fabry disease might be easily undetected, and clinical suspicion is critical. PMID- 28090262 TI - Rapidly Growing Right Ventricular Outflow Tract Mass in Patient with Sarcomatoid Renal Cell Carcinoma. AB - Cardiac metastasis from renal cell carcinoma (RCC) without inferior vena cava (IVC) involvements is extremely rare with few reported cases. Sarcomatoid RCC with rhabdoid feature is a rare pathologic type of RCC having aggressive behavior due to great metastatic potential. Here, we report a case of rapidly growing cardiac metastasis of RCC which brought on right ventricular outflow tract (RVOT) obstruction without IVC and right atrial involvement in a 61-year-old woman. Cardiac arrest occurred during radical nephrectomy and echocardiography revealed mass nearly obstructing the RVOT which was not recognized by preoperative echocardiography 1 month ago. Postoperative immunohistochemical evaluation of renal mass revealed sarcomatoid RCC with rhabdoid feature. PMID- 28090263 TI - Right Atrial Paraganglioma: An Extremely Rare Primary Cardiac Neoplasm Mimicking Myxoma. AB - In this report, we present a case of 35-year-old lady who had presented with atypical chest pain and exertional breathlessness for past six months. Transthoracic and transesophageal echocardiograms showed a well-circumscribed, echo-dense mass in the right atrium, attached to the interatrial septum at the level of atrioventricular junction and in the vicinity of coronary sinus ostium. She underwent successful resection of the cardiac mass. Histopathology revealed paraganglioma, which was reconfirmed by immunohistochemistry study. This represents an extremely rare presentation as primary cardiac tumors are 20-times less common than metastatic tumors and paraganglioma is one of the rarest primary cardiac tumors, accounting for < 1% of all cases. PMID- 28090264 TI - Drought stress-induced changes of microRNAs in diploid and autotetraploid Paulownia tomentosa. AB - Drought stress adversely affects plant productivity. Growth and timber production of Paulownia trees are limited under drought stress. Changes in gene expression patterns and miRNA in different ploidy of Paulownia tomentosa have been investigated. However, the responses of P. tomentosa to drought stress at the microRNA (miRNA) level have not been reported so far. To identify miRNA candidates and their target genes involved in the drought stress response in diploid and tetraploid P. tomentosa, four small RNA and four degradome libraries from diploid and autotetraploid P. tomentosa under normal and drought stress conditions were constructed and sequenced. A total of 41 conserved and 90 novel miRNAs were identified. Among these miRNAs, 67 (26 conserved and 41 novel) and 53 (six conserved and 47 novel) were significantly differentially expressed in response to drought stress in diploid and autotetraploid P. tomentosa, respectively. Degradome analysis identified 356 candidate miRNA target genes that encoded proteins with functions that included plant defense, transcriptional regulation, and hormone metabolism. In particular, miR4 and miR156 were identified only in autotetraploid P. tomentosa under drought stress. These results will help us build a foundation for future studies of the biological functions of miRNA-mediated gene regulation in P. tomentosa. PMID- 28090265 TI - Identification and monitoring of Korean medicines derived from Cinnamomum spp. by using ITS and DNA marker. AB - In this study, we identified and evaluated the genetic relationships among Cinnamomum plants, which are used in traditional medicine. We also attempted to monitor the distribution of traditional medicines derived from Cinnamomum cassia by using DNA barcoding and a species-specific DNA marker. Plants of the genus Cinnamomum, and in particular C. cassia, are commonly used as medicinal herbs in the form of Cinnamomi Ramulus, Cinnamomi Cortex, and Cassiae Cortex Interior. However, it is difficult to distinguish among different Cinnamomum species based on morphological features, and so to overcome this limitation, nucleotide sequences of the internal transcribed spacer (ITS) region of Cinnamomum DNA were determined and compared. On the basis of the discrepancy in determined ITS sequences, a 408-bp product, amplified by the primer pair CC F1/CC R3, was developed as a C. cassia-specific DNA marker. Using the developed DNA marker in combination with the ITS 2 nucleotide sequence, we monitored imported and commercially supplied medicinal products derived from Cinnamomum plants in markets in Korean, China, and Japan. The results revealed that most of the specimens monitored were derived from C. cassia. PMID- 28090266 TI - Reconstruction of a composite comparative map composed of ten legume genomes. AB - The Fabaceae (legume family) is the third largest and the second of agricultural importance among flowering plant groups. In this study, we report the reconstruction of a composite comparative map composed of ten legume genomes, including seven species from the galegoid clade (Medicago truncatula, Medicago sativa, Lens culinaris, Pisum sativum, Lotus japonicus, Cicer arietinum, Vicia faba) and three species from the phaseoloid clade (Vigna radiata, Phaseolus vulgaris, Glycine max). To accomplish this comparison, a total of 209 cross species gene-derived markers were employed. The comparative analysis resulted in a single extensive genetic/genomic network composed of 93 chromosomes or linkage groups, from which 110 synteny blocks and other evolutionary events (e.g., 13 inversions) were identified. This comparative map also allowed us to deduce several large scale evolutionary events, such as chromosome fusion/fission, with which might explain differences in chromosome numbers among compared species or between the two clades. As a result, useful properties of cross-species genic markers were re-verified as an efficient tool for cross-species translation of genomic information, and similar approaches, combined with a high throughput bioinformatic marker design program, should be effective for applying the knowledge of trait-associated genes to other important crop species for breeding purposes. Here, we provide a basic comparative framework for the ten legume species, and expect to be usefully applied towards the crop improvement in legume breeding. PMID- 28090267 TI - Complications of Hot Turmeric Use in Acute Trauma. AB - The use of hot Tumeric paste for treatment of musculoskeletal injuries is a home remedy commonly used in Oman. This practice occasionally leads to skin burns complicating an already injured extremity. This case report discusses the uses of Tumeric as a medicine as well as the management of the complication arising from its improper use as illustrated in this case. PMID- 28090268 TI - Post Traumatic Buccal Fat Pad Injury in a Child: A missed entity in ER. AB - Maxillofacial injuries in the paediatric age group is common and traumatic herniation of buccal fat pad represents one of the few sequel to facial injuries which can easily be missed during primary or secondary survey in the emergency department, especially in young patients. The uncommon occurrence and thus lack of knowledge, often alarms the parents and/or attending physian alike with the presence of a tumor like lesion within the oral cavity in the post-traumatic period. The following case report describes one such incidence of traumatic extrusion of the buccal fat pad into the oral cavity while addressing the need to reinforce the practice of thorough clinical examination before managing any patient. PMID- 28090269 TI - Primary Tuberculosis of the Appendix. AB - Primary (isolated) tuberculosis of the appendix is a clinical rarity, its reported incidence being 0.1 to 0.3%. Diagnosis is often made only after histopathological examination of resected specimen. This report describes two patients with clinical diagnosis of acute appendicitis and appendicular mass respectively, who were finally diagnosed to have tuberculosis of the appendix on histopathological examination. This article stresses the importance of histopathological examination of resected appendix. PMID- 28090270 TI - Coronary Artery Fistula with Heart Failure in Early Infancy. AB - Heart failure in early infancy is commonly caused by lesions leading to pulmonary over circulation secondary to left-to-right shunt. This case report describes an unusual cause of significant left-to-right shunt in a 2 months old infant presenting with congestive heart failure, which was diagnosed with transthoracic echocardiography. In this infant, transthoracic echocardiography with Doppler color flow mapping allowed direct visualization of a large right coronary artery to right ventricular fistula that was surgically corrected successfully. PMID- 28090271 TI - Rupture of Pseudo aneurysm of Popliteal vessels due to pin migration of External Fixator- A Rare Case Report. AB - External fixators for fracture stabilization or limb lengthening cause complications such as pseudoaneurysm, acute ischemia, bleeding, compartment syndrome, and arterio venous fistula. This is a report of a patient who sustained open fracture of both bones of the right leg and the recovery period was complicated by a rare complication where migration of the proximal pin of external fixator into the popliteal vessels and caused rupture of pseudoaneurysm with popliteal vessels injury after a trivial trauma. PMID- 28090272 TI - Research in Iran: Hopes and Disappointments. PMID- 28090273 TI - The Effects of Berberine and Palmatine on Efflux Pumps Inhibition with Different Gene Patterns in Pseudomonas aeruginosa Isolated from Burn Infections. AB - BACKGROUND: Related Multidrug Resistance (MDR) to efflux pumps is a significant problem in treating infections caused by Pseudomonas aeruginosa (P. aeruginosa). Plant compounds have been identified as Pump Inhibitors (EPIs). In the current study, the potential effect of Berberine and Palmatine as EPIs were investigated on efflux pump inhibition through focusing on different gene patterns in P. aeruginosa isolated from burn infections. METHODS: All isolates were collected and identified using the standard biochemical tests. Antimicrobial sensitivity was performed based on disk agar diffusion method for 12 antibiotics. MIC-MBC tests were also performed based on the broth microdilution method to detect synergistic relationship between ciprofloxacin, Berberine and Palmatine. Detection of mexA, mexB, mexC, mexD, mexE, mexF and mexX was conducted by PCR assay. Fisher's Exact test and Logistic Regression were used as statistical tools. RESULTS: A total of 60 P. aeruginosa isolates were collected. The highest and lowest levels of resistance were found to be respectively against clindamycin and tigecycline. Comparing the MIC with MBC distribution, it was found that Berberine and Palmatine lower the MIC-MBC level of ciprofloxacin. The PCR results indicated that the highest frequency is about MexAB-OprM operon. The statistical analysis among different gene patterns of efflux pumps showed that there were no significant relationships between the effectiveness of Berberine and Palmatine (p>0.05). CONCLUSION: It can be speculated that Berberine and Palmatine both act as EPIs and can be used as auxiliary treatments with the purpose of increasing the effect of available antibiotics as well as decreasing the emergence of MDR bacteria. The efficiency of these combinations should be studied further under in vivo conditions to have a more comprehensive conclusion regarding this issue. PMID- 28090274 TI - The Role of M2000 as an Anti-inflammatory Agent in Toll-Like Receptor 2/microRNA 155 Pathway. AB - BACKGROUND: M2000 is a newly designed and safe Non-Steroidal Anti-Inflammatory Drug (NSAID). The aim of this study was to assess the effects of M2000 on expression levels of Suppressor of Cytokine Signaling-1 (SOCS-1) and Src Homology 2 domain-containing inositol-5'-phosphatase 1 (SHIP1) proteins via Toll-Like Receptor (TLR) 2/microRNA-155 pathway. METHODS: HEK293 TLR2 cell line and Peripheral Blood Mononuclear Cells (PBMCs) were treated by different concentrations of M2000 in MTT assay. RNA was extracted by miRNeasy Mini kit. Then, cDNA was synthesized and the expression levels of SOCS1, SHIP1 and miRNA155 were evaluated by Quantitative Real time PCR. RESULTS: Our results showed that M2000 significantly increased the expression levels of SOCS1 and SHIP-1 in Lipopolysachride (LPS)-treated and non-treated cells. Moreover, M2000 decreased expression level of miR-155 in LPS treated PBMCs. CONCLUSION: M2000 can be used as NSAID in LPS induced inflammation and decrease inflammatory cytokines production by targeting SOCS1, SHIP1 and miR-155 in auto-immune and inflammatory diseases. PMID- 28090275 TI - Induction of Epigenetic Alteration by CPUK02, An Ent- kaurenoid Derivative of Stevioside. AB - BACKGROUND: Dietary polyphenols, such as those found in green tea and red wine, are linked to antitumor activity. They are known to influence many signaling pathways epigenetically within the human body. In this regard, CPUK02 (15 Oxosteviol benzyl ester) is a new ent-kaurenoid derivative of stevioside and exhibits strong anti-cancer activity in vitro and in vivo. Nowadays, the role of epigenetics in cancer has been the subject of intensive study and DNA methylation targeting represents a relevant strategy for cancer treatment. There are no reports regarding the effects of CPUK02 on epigenetic alterations in colorectal cancer cell line. This study was an attempt to compare CPUK02 with 5-AZA as DNMT inhibitor agent and evaluate whether it can induce its anti-cancer effects via altering the level of DNMT3b mRNA, MGMT and SFRP2 methylation pattern in HCT 116 cell line. METHODS: To evaluate DNMT3b expression, DNMT3B mRNA levels in HCT116 CRC cell line were quantified by real-time reverse-transcriptase Polymerase Chain Reaction (PCR) assay after 24 hr of incubation time with CPUK02 and 5-AZA. In addition, the methylation patterns of 2 CpG islands in this cell line were examined by methylation-specific PCR methods. RESULTS: CPUK02 surprisingly, decreased the DNMT3b mRNA level. The average expression levels of DNMT3b in HCT116 treated with CPUK02 and 5-AZA relative to the GAPDH expression level in control were 0.16 and 0.5%, respectively. Furthermore, CPUK02 could decrease the methylated allele of MGMT and SFRP2 genes in HCT 116 after 24 hr. CONCLUSION: In this study, positive correlation was found between mRNA expression of DNMT3b and gene promoter hypermethylation after treatment with CPUK02 and 5-AZA. Our data confirmed that CPUK02 like 5-AZA exhibits demethylating properties. PMID- 28090276 TI - Overexpression of Recombinant Human Teriparatide, rhPTH (1-34) in Escherichia coli : An Innovative Gene Fusion Approach. AB - BACKGROUND: Parathyroid hormone is an 84-amino acid peptide secreted by the parathyroid glands. Its physiological role is maintenance of normal serum calcium level and bone remodeling. Biological activity of this hormone is related to N terminal 1-34 amino acids. The recombinant form of hormone (1-34) has been approved for treatment of osteoporosis from 2002. In this study, a novel fusion partner has been developed for preparation of high yield recombinant 1-34 amino acids of hPTH. METHODS: Novel nucleotide cassette designed encoding a chimeric fusion protein comprising of a fusion partner consisting of a His-tag in N terminal, 53 amino acids belong to Escherichia coli (E. coli) beta-galactosidase (LacZ) gene, a linker sequence for increasing of expression and protection of target peptide structure from fusion tag effect, an Enteropeptidase cleavage site, rhPTH (1-34) gene fragment. Optimized fusion gene was synthesized and ligated into pET-28a vector under control of T7 promoter, and then transformed in E. coli (DH5alpha) cells. Positive clones containing this gene were double digested with NcoI and-BamHI and also approved by sequencing. Gene overexpression was observed in SDS-PAGE after induction with 0.2 mM IPTG. Confirmation of gene expression was performed by western blotting using anti-His-tag antibody conjugated with peroxidase. RESULTS: By this fusion gene design approach, we achieved a high level expression of the rhPTH, where it represented at least 43.7% of the total protein as determined by SDS-PAGE and confirmed by western blotting. CONCLUSION: In addition to high level expression of the designed gene in this work, specific amino acid sequence of bacterial beta-galactosidase was selected as major part of carrier tag for protection of this hormone as important step of recombinant rhPTH with relevant isoelectronic point (pI). This innovation resulted in recombinant production of hPTH very well and the gene construct could be applied as a pattern for similar recombinant peptides where recombinant protein degradation is a critical issue. PMID- 28090277 TI - Anti-Quorum Sensing Activity of Substances Isolated from Wild Berry Associated Bacteria. AB - BACKGROUND: Quorum Sensing (QS) is a mechanism used by bacteria to determine their physiological activities and coordinate gene expression based on cell to cell signaling. Many bacterial physiological functions are under the regulation of quorum sensing such as virulence, luminescence, motility, sporulation and biofilm formation. The aim of the present study was to isolate and characterize Quorum Sensing Inhibitory (QSI) substances from epiphytic bacteria residing on wild berries surfaces. METHODS: Fifty nine bacterial isolates out of 600 screened bacteria were successfully isolated. These bacteria were obtained from berry surfaces of different plants in the wild forests of Ajloun-Jordan. Screening for QSI activity using Chromobacterium violaceum ATCC 12472 monitor strain, resulted in isolating 6 isolates exhibiting QSI activity only, 11 isolates with QSI and antibacterial activity, and 42 isolates with antibacterial activity only. Three potential isolates S 130, S 153, and S 664, were gram positive rods and spore formers, catalase positive and oxidase negative. These were chosen for further testing and characterization. RESULTS: Different solvent extraction of the QSI substances based on polarity indicated that the activity of S 130 was in the butanol extract, S 153 activity in both chloroform and butanol; and for S 664, the activity was detected in the hexane extract. The chloroform extract of S 153 and hexane extract of S 664 were proteinaceous in nature while QSI substances of the butanol extract of S 130 and S 153 were non-proteinaceous. All the tested QSI substances showed a marked thermal stability when subjected at several time intervals to 70 degrees C, with the highest stability observed for the butanol extract of S 153. Assessing the QSI substances using violacein quantification assay revealed varying degrees of activity depending upon the extracting solvent, type of the producer bacteria and the concentration of the substances. CONCLUSION: This study highlighted the potential of untapped reservoirs in nature to be used as a source of unique metabolite that may be further developed for therapy. The potential QSI substances included in this study are just one aspect to be further analyzed for use as biopharmaceutical agents. PMID- 28090278 TI - Isolation and Identification of Phyllospheric Bacteria Possessing Antimicrobial Activity from Astragalus obtusifolius, Prosopis juliflora, Xanthium strumarium and Hippocrepis unisiliqousa. AB - BACKGROUND: The widespread utilization of antimicrobial compounds has caused emergence of resistant microorganisms in the world. Hence, the research to probe the products with antimicrobial features has led to finding natural habitats and discovering new pharmaceutical products. METHODS: In this study, an attempt was made to explore the niche of novel habitat to isolate pyllospheric bacteria from the above ground parts (stems and leaves) of Astragalus obtusifolius, Prosopis juliflora, Xanthium strumarium, and Hippocrepis unisiliqousa to evaluate their antimicrobial features. The inhibitory effects of these strains on the growth of two fungi (Aspergillus niger, Aspergillus fumigatus), two yeasts (Saccharomyces cerevisiae, Candida albicans) and six bacteria (Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, Salmonella typhi, Streptococcus pyogenes) were tested. RESULTS: In total, 113 bacterial strains were isolated. Twenty five bacterial strains (B-1 to B-25) indicated promising antimicrobial (antibacterial and antifungal) activities against aforementioned pathogens. The identification of the bacterial strains was ascertained by morphological, physiological, biochemical tests and two strains with the strongest antimicrobial activities were further characterized based on 16s rRNA sequencing. These two strains were identified as Bacillus amyloliquefaciens. CONCLUSION: Our results provide evidence that phyllospheric microorganisms are capable of producing some compounds with antimicrobial properties. PMID- 28090279 TI - Association of ATP-Binding Cassette Transporter A1 (ABCA1)-565 C/T Gene Polymorphism with Hypoalphalipoproteinemia and Serum Lipids, IL-6 and CRP Levels. AB - BACKGROUND: ATP-binding cassette transporter A1 (ABCA1) is a membrane integral protein which plays a vital role in High Density Lipoprotein (HDL) metabolism and exerts a protective effect against Hypoalphalipoproteinemia (HA) by mediation of rate-limiting step in HDL biogenesis. In addition, this protein possesses anti inflammatory effects by inhibiting the production of some inflammatory cytokines in macrophages. This study investigated the association of ABCA1-565 C/T gene polymorphism with HA and serum lipids, IL-6 and CRP levels. METHODS: A population which consisted of 101 HA and 95 normal subjects were genotyped for ABCA1-565C/T polymorphism by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). The serum concentrations of lipids, IL-6 and high sensitive-CRP (hs-CRP) were measured by the relevant methods. RESULTS: The frequency of T allele was significantly higher in the HA group than the controls (31.7 vs. 19.5%, p=0.002). Thus, carriers of the T allele (CT and TT genotypes) had a higher risk for HA (p=0.016, OR=2.04, 95% CI=1.14-3.63). T allele carriers demonstrated decreased HDL-C and increased triglyceride, IL-6 and CRP levels than those with the CC genotype. CONCLUSION: This study suggests that the-565 C/T polymorphism of ABCA1 gene is associated with an increased risk of HA, decreased HDL-C and increased TG, IL-6 and CRP. PMID- 28090280 TI - In vitro Activity of Linezolid in Combination with Photodynamic Inactivation Against Staphylococcus aureus Biofilms. AB - BACKGROUND: Biofilm infections are a major challenge in medical practice. Bacteria that live in a biofilm phenotype are more resistant to both antimicrobial therapy and host immune responses compared to their planktonic counterparts. So, there is need for new therapeutic strategies to combat these infections. A promising approach [known as Photodynamic Inactivation (PDI)] to kill bacteria growing as biofilms uses light in combination with a photosensitizer to induce a phototoxic reaction which produces reactive oxygen species that can destroy lipids and proteins causing cell death. PDI does not always guarantee full success, so, combination of PDI with antibiotics may give increased efficiency. This study aimed to determine if PDI was effective in the eradication of Staphylococcus aureus (S. aureus) biofilms in combination with linezolid. METHODS: The susceptibility of biofilm cultures of three S. aureus strains to Methylene Blue (MB) and Toluidine Blue O (TBO)-mediated PDI was determined alone and in combination with linezolid. RESULTS: Bactericidal activity (>=3 log10 reduction in viable cell count) was not achieved with MB/TBO PDI or antibiotic treatment alone. When antibiotic treatment was combined with TBO-PDI, a greater reduction in viable count than antibiotic alone was observed for two strains. CONCLUSION: This study showed that although TBO-PDI did not have good bactericidal activity against S. aureus biofilms; it increased the antimicrobial activity of linezolid against these bacteria. PMID- 28090281 TI - Successful Treatment of immune Reconstitution Inflammatory syndrome-related Hemophagocytic Syndrome in an HIV Patient with Primary Effusion Lymphoma. AB - Although the connection of [secondary hemophagocytic syndrome (sHS)] with HIV has been well documented, optimal treatment regimen is not well established. This is due not only to the rarity of the syndrome, but also to the heterogeneity of the involved population. Most cases are related to opportunistic infections or malignancies in advanced stage, but many cases are also related to seroconversion, in the primary infection setting. Moreover, in the [antiretroviral treatment (ART)] era, rare cases of ART-related sHS have been reported. In these, often fatal cases, an [immune reconstitution inflammatory syndrome (IRIS)] process is involved, posing a serious challenge to the treating physician. We hereby report a case of successful treatment of an HIV patient with primary effusion lymphoma who experienced sHS shortly after ART onset. Our patient, treated with high dose dexamethasone and gamma globulin, achieved complete remission. This case might hint possible therapeutic insights in the treatment of IRIS-related sHS. PMID- 28090282 TI - Traceless Solid-Phase alpha-Hydroxytropolone Synthesis. AB - alpha-Hydroxytropolones are established inhibitors of several therapeutically relevant binuclear metalloenzymes, and thus lead drug targets for various human diseases. We have leveraged a recently-disclosed three-component oxidopyrylium cycloaddition in the first solid-phase synthesis of alpha-hydroxytropolones. We also showed that, while minor impurities exist after cleavage and aqueous wash, the semi-crude products display activity in HIV RT-associated RNaseH enzymatic and cell-based assays consistent with pure molecules made in solution phase. These proof-of-principle studies demonstrate the feasibility of solid-phase alpha hydroxytropolone synthesis and its potential to serve as a powerful platform for alpha-hydroxytropolone-based drug discovery and development. PMID- 28090283 TI - Optical control of neuronal activity using a light-operated GIRK channel opener (LOGO). AB - G-protein coupled inwardly rectifying potassium channels (GIRKs) are ubiquitously expressed throughout the human body and are an integral part of inhibitory signal transduction pathways. Upon binding of Gbetagamma subunits released from G protein coupled receptors (GPCRs), GIRK channels open and reduce the activity of excitable cells via hyperpolarization. As such, they play a role in cardiac output, the coordination of movement and cognition. Due to their involvement in a multitude of pathways, the precision control of GIRK channels is an important endeavour. Here, we describe the development of the photoswitchable agonist LOGO (the Light Operated GIRK-channel Opener), which activates GIRK channels in the dark and is rapidly deactivated upon exposure to long wavelength UV irradiation. LOGO is the first K+ channel opener and selectively targets channels that contain the GIRK1 subunit. It can be used to optically silence action potential firing in dissociated hippocampal neurons and LOGO exhibits activity in vivo, controlling the motility of zebrafish larvae in a light dependent fashion. We envisage that LOGO will be a valuable research tool to dissect the function of GIRK channels from other GPCR dependent signalling pathways. PMID- 28090284 TI - Our readership grows by leaps and bounds. PMID- 28090285 TI - Pulmonary vascular and ventricular dysfunction in the susceptible patient (2015 Grover Conference series). AB - Pulmonary blood vessel structure and tone are maintained by a complex interplay between endogenous vasoactive factors and oxygen-sensing intermediaries. Under physiological conditions, these signaling networks function as an adaptive interface between the pulmonary circulation and environmental or acquired perturbations to preserve oxygenation and maintain systemic delivery of oxygen rich hemoglobin. Chronic exposure to hypoxia, however, triggers a range of pathogenetic mechanisms that include hypoxia-inducible factor 1alpha (HIF-1alpha) dependent upregulation of the vasoconstrictor peptide endothelin 1 in pulmonary endothelial cells. In pulmonary arterial smooth muscle cells, chronic hypoxia induces HIF-1alpha-mediated upregulation of canonical transient receptor potential proteins, as well as increased Rho kinase-Ca2+ signaling and pulmonary arteriole synthesis of the profibrotic hormone aldosterone. Collectively, these mechanisms contribute to a contractile or hypertrophic pulmonary vascular phenotype. Genetically inherited disorders in hemoglobin structure are also an important etiology of abnormal pulmonary vasoreactivity. In sickle cell anemia, for example, consumption of the vasodilator and antimitogenic molecule nitric oxide by cell-free hemoglobin is an important mechanism underpinning pulmonary hypertension. Contemporary genomic and transcriptomic analytic methods have also allowed for the discovery of novel risk factors relevant to sickle cell disease, including GALNT13 gene variants. In this report, we review cutting-edge observations characterizing these and other pathobiological mechanisms that contribute to pulmonary vascular and right ventricular vulnerability. PMID- 28090286 TI - Novel methods in pulmonary hypertension phenotyping in the age of precision medicine (2015 Grover Conference series). AB - Among pulmonary vascular diseases, pulmonary hypertension (PH) is the best studied and has been the focus of our work. The current classification of PH is based on a relatively simple combination of patient characteristics and hemodynamics. This leads to inherent limitations, including the inability to customize treatment and the lack of clarity from a more granular identification based on individual patient phenotypes. Accurate phenotyping of PH can be used in the clinic to select therapies and determine prognosis and in research to increase the homogeneity of study cohorts. Rapid advances in the mechanistic understanding of the disease, improved imaging methods, and innovative biomarkers now provide an opportunity to define novel PH phenotypes. We have recently shown that altered metabolism may affect nitric oxide levels and protein glycosylation, the peripheral circulation (which may provide insights into the response to therapy), and exhaled-breath analysis (which may be useful in disease evaluation). This review is based on a talk presented during the 2015 Grover Conference and highlights the relevant literature describing novel methods to phenotype pulmonary arterial hypertension patients by using approaches that involve the pulmonary and systemic (peripheral) vasculature. In particular, abnormalities in metabolism, the pulmonary and peripheral circulation, and exhaled breath in PH may help identify phenotypes that can be the basis for a precision-medicine approach to PH management. These approaches may also have a broader scope and may contribute to a better understanding of other diseases, such as asthma, diabetes, and cancer. PMID- 28090287 TI - Transcription factors, transcriptional coregulators, and epigenetic modulation in the control of pulmonary vascular cell phenotype: therapeutic implications for pulmonary hypertension (2015 Grover Conference series). AB - Pulmonary hypertension (PH) is a complex and multifactorial disease involving genetic, epigenetic, and environmental factors. Numerous stimuli and pathological conditions facilitate severe vascular remodeling in PH by activation of a complex cascade of signaling pathways involving vascular cell proliferation, differentiation, and inflammation. Multiple signaling cascades modulate the activity of certain sequence-specific DNA-binding transcription factors (TFs) and coregulators that are critical for the transcriptional regulation of gene expression that facilitates PH-associated vascular cell phenotypes, as demonstrated by several studies summarized in this review. Past studies have largely focused on the role of the genetic component in the development of PH, while the presence of epigenetic alterations such as microRNAs, DNA methylation, histone levels, and histone deacetylases in PH is now also receiving increasing attention. Epigenetic regulation of chromatin structure is also recognized to influence gene expression in development or disease states. Therefore, a complete understanding of the mechanisms involved in altered gene expression in diseased cells is vital for the design of novel therapeutic strategies. Recent technological advances in DNA sequencing will provide a comprehensive improvement in our understanding of mechanisms involved in the development of PH. This review summarizes current concepts in TF and epigenetic control of cell phenotype in pulmonary vascular disease and discusses the current issues and possibilities in employing potential epigenetic or TF-based therapies for achieving complete reversal of PH. PMID- 28090288 TI - Expression profiling elucidates a molecular gene signature for pulmonary hypertension in sarcoidosis. AB - Pulmonary hypertension (PH), when it complicates sarcoidosis, carries a poor prognosis, in part because it is difficult to detect early in patients with worsening respiratory symptoms. Pathogenesis of sarcoidosis occurs via incompletely characterized mechanisms that are distinct from the mechanisms of pulmonary vascular remodeling well known to occur in conjunction with other chronic lung diseases. To address the need for a biomarker to aid in early detection as well as the gap in knowledge regarding the mechanisms of PH in sarcoidosis, we used genome-wide peripheral blood gene expression analysis and identified an 18-gene signature capable of distinguishing sarcoidosis patients with PH (n = 8), sarcoidosis patients without PH (n = 17), and healthy controls (n = 45). The discriminative accuracy of this 18-gene signature was 100% in separating sarcoidosis patients with PH from those without it. If validated in a large replicate cohort, this signature could potentially be used as a diagnostic molecular biomarker for sarcoidosis-associated PH. PMID- 28090289 TI - An international physician survey of chronic thromboembolic pulmonary hypertension management. AB - We conducted an international study to evaluate practices in the diagnosis and management of patients with chronic thromboembolic pulmonary hypertension (CTEPH) globally across different regions. Between August and October 2012, CTEPH treating physicians completed a 15-minute online questionnaire and provided patient record data for their 2-5 most recent patients with CTEPH. Overall, 496 physicians (Europe: 260; United States: 152; Argentina: 52; Japan: 32) completed the questionnaire and provided patient record data for 1,748 patients. The proportion of physicians who described themselves as working in or affiliated with a specialized pulmonary hypertension (PH) center ranged from 38% in France and Italy to 83% in the United States. A large proportion of patients did not undergo ventilation/perfusion scanning (46%-67%) or right heart catheterization (24%-57%) for the diagnosis of CTEPH. Referral rates for pulmonary endarterectomy evaluation ranged from 25% in Japan to 44% in Europe, with higher referral rates in PH centers; the main reasons for lack of referral were that surgery was not considered unless medical treatment was failing and patient refusal. Other variations in management included greater use of phosphodiesterase 5 inhibitors in the United States than in Europe and Japan and greater use of combination treatment in the United States than in Europe. Physicians' perceptions of their treatment strategy were generally consistent with patient record data. Results from this study, which includes a global aspect of CTEPH care, demonstrate not only regional differences in CTEPH management but, more importantly, considerable nonadherence to the diagnosis and treatment guidelines for CTEPH, even in PH centers. PMID- 28090290 TI - Shared gene expression patterns in mesenchymal progenitors derived from lung and epidermis in pulmonary arterial hypertension: identifying key pathways in pulmonary vascular disease. AB - Rapid access to lung-derived cells from stable subjects is a major challenge in the pulmonary hypertension field, given the relative contraindication of lung biopsy. In these studies, we sought to demonstrate the importance of evaluating a cell type that actively participates in disease processes, as well as the potential to translate these findings to vascular beds in other nonlung tissues, in this instance perivascular skin mesenchymal cells (MCs). We utilized posttransplant or autopsy lung explant-derived cells (ABCG2-expressing mesenchymal progenitor cells [MPCs], fibroblasts) and skin-derived MCs to test the hypothesis that perivascular ABCG2 MPCs derived from pulmonary arterial hypertension (PAH) patient lung and skin would express a gene profile reflective of ongoing vascular dysfunction. By analyzing the genetic signatures and pathways associated with abnormal ABCG2 lung MPC phenotypes during PAH and evaluating them in lung- and skin-derived MCs, we have identified potential predictor genes for detection of PAH as well as a targetable mechanism to restore MPCs and microvascular function. These studies are the first to explore the utility of expanding the study of ABCG2 MPC regulation of the pulmonary microvasculature to the epidermis, in order to identify potential markers for adult lung vascular disease, such as PAH. PMID- 28090292 TI - A new look at bronchopulmonary dysplasia: postcapillary pathophysiology and cardiac dysfunction. AB - Pulmonary hypertension (PH) and right ventricular function are the focus of cardiovascular effects of bronchopulmonary dysplasia (BPD). We assessed cardiac indexes reflecting systemic afterload and pulmonary venous back pressure as pathophysiologic factors. Cardiac parameters were measured by conventional echocardiography in 20 preterm infants with severe BPD and compared with those of 10 preterm infants with no BPD and 20 healthy term infants. In infants with severe BPD, PH was noted in 5 (25%) by tricuspid regurgitation Doppler jet >=2.8 m/s and in 15 (75%) by time to peak velocity/right ventricular ejection time <0.34. Among systemic cardiac indexes, significant impairment of diastolic measures was noted in the BPD group compared with infants with no BPD and term infants. The significance persisted after adjusting for gestational age and birth weight. These included transmitral E/A ratio (1.07 +/- 0.07 vs. 0.91 +/- 0.04 vs. 0.89 +/- 0.09; P < 0.0001), isovolumic relaxation time (68.8 +/- 3.9 vs. 58.5 +/- 7.8 vs. 54.2 +/- 5.7 ms ; P < 0.0001), mitral valve stroke volume (4.7 +/- 0.7 vs. 5.6 +/- 0.6 vs. 5.9 +/- 0.1; P = 0.002), and myocardial performance index (0.33 +/- 0.05 vs. 0.28 +/- 0.01 vs. 0.27 +/- 0.05; P = 0.03). Left ventricular output was significantly lower in the BPD cohort (183 +/- 45 vs. 189 +/- 9 vs. 191 +/- 32 mL/kg/min; P = 0.03). Altered systemic (left-sided) cardiac function was noted in infants with BPD, which may lead to pulmonary venous congestion contributing to a continued need for respiratory support. PMID- 28090291 TI - Macrophage migration inhibitory factor as a novel biomarker of portopulmonary hypertension. AB - Portopulmonary hypertension (POPH) is a poorly understood complication of liver disease associated with significant morbidity and mortality. We sought to identify novel biomarkers of POPH disease presence and severity. We performed a prospective, multicenter, case-control study involving patients with liver disease undergoing right heart catheterization. POPH cases were defined as a mean pulmonary arterial pressure (mPAP) >=25 mmHg and pulmonary vascular resistance (PVR) >240 dynesscm-5. Plasma samples were collected from the systemic and pulmonary circulation, and antibody microarray was used to identify biomarkers. Characterization and validation of a candidate cytokine, macrophage migration inhibitory factor (MIF), was performed using enzyme-linked immunosorbent assay. Continuous variables were compared using a Mann-Whitney U test and correlated with disease severity using Spearman correlation. MIF levels were elevated in both the systemic and pulmonary circulation in patients with POPH compared with controls (median MIF level [interquartile range] in systemic circulation: 46.68 ng/mL [32.31-76.04] vs. 31.19 ng/mL [26.92-42.17], P = 0.009; in pulmonary circulation: 49.59 ng/mL [35.90-108.80] vs. 37.78 [21.78-45.53], P = 0.002). In patients with POPH, MIF levels were positively correlated with PVR (r = 0.58, P = 0.006) and inversely correlated with cardiac output (r = -0.57, P = 0.007). MIF >60 ng/mL or tricuspid regurgitation gradient >50 mmHg had a 92% sensitivity and specificity for the diagnosis of POPH, with a positive predictive value of 86% and a negative predictive value of 96%. MIF is a promising novel biomarker of POPH disease presence and severity in patients with liver disease and portal hypertension. PMID- 28090293 TI - Relevance of angiopoietin-2 and soluble P-selectin levels in patients with pulmonary arterial hypertension receiving combination therapy with oral treprostinil: a FREEDOM-C2 biomarker substudy. AB - : Studies have suggested roles for angiopoietin-2 (Ang-2) and soluble P-selectin (sP-selectin) as biomarkers of disease severity and treatment response in pulmonary arterial hypertension (PAH), but additional data are required for validation. We evaluated these biomarkers using data from FREEDOM-C2, in which patients with PAH receiving stable monotherapy or combination therapy were randomized to receive additional treatment with oral treprostinil (up-titrated from 0.25 mg twice daily) or placebo for 16 weeks. Biomarker analysis was optional in FREEDOM-C2. We measured plasma Ang-2 and sP-selectin levels at baseline and at week 16, and we assessed their association with predefined outcomes (6-minute walk distance [6MWD] change from baseline >40 m, 6MWD >380 m, functional class I/II, and/or N-terminal pro-brain natriuretic peptide [NT proBNP] <1,800 pg/mL at week 16) using Spearman correlation, receiver operating characteristics, and logistic regression. Biomarker data were available for 83 of 157 and 95 of 153 patients in the oral treprostinil and placebo groups, respectively. In the oral treprostinil group, baseline Ang-2 levels correlated with week 16 NT-proBNP levels (P < 0.0001). Baseline Ang-2 >=12 ng/mL was associated with a reduced likelihood of having NT-proBNP <1,800 pg/mL at week 16 (multivariate odds ratio: 0.08; 95% confidence interval: 0.02-0.32). However, Ang 2 showed no significant association with the other assessed outcomes, and sP selectin was not associated or correlated with any of the outcomes. These data suggest that Ang-2 and sP-selectin are not associated with response to oral treprostinil in patients already receiving stable PAH therapy. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00887978. PMID- 28090295 TI - An advanced protocol-driven transition from parenteral prostanoids to inhaled trepostinil in pulmonary arterial hypertension. AB - Patients with pulmonary arterial hypertension (PAH) often require parenteral prostanoids to improve symptoms and signs of PAH. Complications of parenteral prostanoids-such as catheter-related infections and intolerable adverse effects may develop, prompting transition to inhaled prostanoids. We report a prospective, protocol-driven transition from parenteral prostanoids to inhaled prostanoids with monitoring of exercise gas exchange and acute hemodynamics. Three PAH centers recruited patients transitioning from parenteral prostanoids to inhaled trepostinil. Rigid inclusion criteria were used, including parenteral prostanoid dose < 30 ng/kg/min, New York Heart Association functional class (FC) < 3, and pulmonary vascular resistance (PVR) < 6 Wood units. Of the 9 patients meeting initial inclusion criteria, 3 were excluded. In the remaining patients, the parenteral prostanoid was reduced and the inhaled prostanoid was increased over 24-36 hours with continuous hemodynamic monitoring. Exercise capacity and FC were measured at baseline and weeks 1, 4, and 12. All patients were successfully weaned from parenteral prostanoids. An acute PVR decrease was seen with most inhaled prostanoid doses, but PVR varied throughout the transition. Patients tolerated inhaled prostanoids for 9-12 breaths 4 times a day with no treatment limiting adverse events. At week 12, FC was unchanged, and all patients continued to receive inhaled prostanoids without serious adverse events or additional PAH therapy. In 5 of 6 patients, 6-minute walk distance and peak [Formula: see text] were within 10% of baseline. Using a strict transition protocol and rigid patient selection criteria, the parenteral prostanoid to inhaled prostanoid transition appeared safe and well tolerated and did not result in clinical deterioration over 12 weeks. Hemodynamic variability noted acutely during transition in our study did not adversely affect successful transition. (Trial registration: ClinicalTrials.gov identifier: NCT01268553). PMID- 28090294 TI - The effects of pulmonary vasodilating agents on right ventricular parameters in severe group 3 pulmonary hypertension: a pilot study. AB - Pulmonary arterial hypertension (PAH)-approved vasodilators improve right ventricular (RV) function in patients with PAH. However, whether PAH-approved drugs ameliorate RV morphology and function in lung disease-associated pulmonary hypertension (lung-PH) remains unclear. We aimed to prospectively evaluate the changes in RV volume and ejection fraction (RVEF) in 14 consecutive severe lung PH patients treated with PAH-approved vasodilators. Severe lung-PH was defined as a mean pulmonary arterial pressure (MPAP) of >=35 mmHg or an MPAP of >=25 mmHg with a cardiac index (L/min/m2) of <2. Right heart catheterization and cardiac magnetic resonance (CMR) imaging were performed at baseline and at 3 months after starting sildenafil with or without other PAH-approved drugs. Follow-up was conducted at 3 months in 11 participants; compared with baseline values, MPAP and pulmonary vascular resistance (PVR) decreased by 18% and 37%, respectively. Baseline CMR imaging revealed an elevated RV end-diastolic volume index (RVEDVI; mL/m2) of 117.5 +/- 35.9 and a below-average RVEF of 25.2% +/- 7.2%; after 3 months, RVEDVI decreased by 23.7% (P = 0.0061) and RVEF increased by 32.9% (P = 0.0165). Among the 11 patients, 3 were thought to be a stable and homogenous subset in terms of background lung disease and medical management administered. These 3 patients exhibited similar ameliorations in PVR and RVEF, compared with the other 8 patients. PAH-approved drug treatment may improve RV dilatation and systolic function among patients with severe lung-PH. This study was approved by University Hospital Medical Information Network Clinical Trials Registry (UMIN CTR) on September 1, 2013 (UMIN000011541). PMID- 28090296 TI - Endotoxin- and mechanical stress-induced epigenetic changes in the regulation of the nicotinamide phosphoribosyltransferase promoter. AB - Mechanical ventilation, a lifesaving intervention for patients with acute respiratory distress syndrome (ARDS), also unfortunately contributes to excessive mechanical stress and impaired lung physiological and structural integrity. We have elsewhere established the pivotal role of increased nicotinamide phosphoribosyltransferase (NAMPT) transcription and secretion as well as its direct binding to the toll-like receptor 4 (TLR4) in the progression of this devastating syndrome; however, regulation of this critical gene in ventilator induced lung injury (VILI) is not well characterized. On the basis of an emerging role for epigenetics in enrichment of VILI and CpG sites within the NAMPT promoter and 5'UTR, we hypothesized that NAMPT expression and downstream transcriptional events are influenced by epigenetic mechanisms. Concomitantly, excessive mechanical stress of human pulmonary artery endothelial cells or lipopolysaccharide (LPS) treatment led to both reduced DNA methylation levels in the NAMPT promoter and increased gene transcription. Histone deacetylase inhibition by trichostatin A or Sirt-1-silencing RNA attenuates LPS-induced NAMPT expression. Furthermore, recombinant NAMPT administration induced TLR4-dependent global H3K9 hypoacetylation. These studies suggest a complex epigenetic regulatory network of NAMPT in VILI and ARDS and open novel strategies for combating VILI and ARDS. PMID- 28090297 TI - Exhaled nitric oxide in pulmonary arterial hypertension associated with systemic sclerosis. AB - The fractional exhaled concentration of nitric oxide (FENO) has been shown to be reduced in idiopathic pulmonary arterial hypertension (PAH) but has not been adequately studied in PAH associated with systemic sclerosis (SSc). We measured FENO at an expiratory flow rate of 50 mL/s in 21 treatment-naive patients with SSc-associated PAH (SSc-PAH), 94 subjects with SSc without pulmonary involvement, and 84 healthy volunteers. Measurements of FENO at additional flow rates of 100, 150, and 250 mL/s were obtained to derive the flow-independent nitric oxide exchange parameters of maximal airway flux (J'awNO) and steady-state alveolar concentration (CANO). FENO at 50 mL/s was similar (P = 0.22) in the SSc-PAH group (19 +/- 12 parts per billion [ppb]) compared with the SSc group (17 +/- 12 ppb) and healthy control group (21 +/- 11 ppb). No change was observed after 4 months of targeted PAH therapy in 14 SSc-PAH group patients (P = 0.9). J'awNO was modestly reduced in SSc group subjects without lung disease (1.2 +/- 0.5 nl/s) compared with healthy controls (1.64 +/- 0.9; P < 0.05) but was similar to that in the SSc-PAH group. CANO was elevated in individuals with SSc-PAH (4.8 +/- 2.6 ppb) compared with controls with SSc (3.3 +/- 1.4 ppb) and healthy subjects (2.6 +/- 1.5 ppb; P < 0.001 for both). However, after adjustment for the diffusing capacity of CO, there was no significant difference in CANO between individuals with SSc-PAH and controls with SSc. We conclude that FENO is not useful for the diagnosis of PAH in SSc. Increased alveolar nitric oxide in SSc-PAH likely represents impaired diffusion into pulmonary capillary blood. PMID- 28090298 TI - In situ expression of Bcl-2 in pulmonary artery endothelial cells associates with pulmonary arterial hypertension relative to heart failure with preserved ejection fraction. AB - We have previously reported that pulmonary artery endothelial cells (PAECs) can be harvested from the tips of discarded Swan-Ganz catheters after right heart catheterization (RHC). In this study, we tested the hypothesis that the existence of an antiapoptotic phenotype in PAECs obtained during RHC is a distinctive feature of pulmonary arterial hypertension (PAH; World Health Organization group 1) and might be used to differentiate PAH from other etiologies of pulmonary hypertension. Specifically, we developed a flow cytometry-based measure of Bcl-2 activity, referred to as the normalized endothelial Bcl-2 index (NEBI). We report that higher NEBI values are associated with PAH to the exclusion of heart failure with preserved ejection fraction (HFpEF) and that this simple diagnostic measurement is capable of differentiating PAH from HFpEF without presenting addition risk to the patient. If validated in a larger, multicenter study, the NEBI has the potential to assist physicians in the selection of appropriate therapeutic interventions in the common and dangerous scenario wherein patients present a clinical and hemodynamic phenotype that makes it difficult to confidently differentiate between PAH and HFpEF. PMID- 28090299 TI - Tadalafil therapy for sarcoidosis-associated pulmonary hypertension. AB - Sarcoidosis-associated pulmonary hypertension (SAPH) is estimated to occur in at least 5% or more of sarcoidosis patients, and it contributes to significant morbidity and mortality. Optimal therapy for SAPH is not well established. We performed a 24-week open-label trial of tadalafil for SAPH at 2 academic medical centers. Subjects were required to have confirmed sarcoidosis plus a right heart catheterization within 12 months of enrollment showing a mean pulmonary artery pressure >= 25 mmHg, a pulmonary artery wedge pressure <= 15 mmHg, and a calculated pulmonary vascular resistance >= 3 Wood units. Subjects received 20 mg/day of tadalafil for the first 4 weeks and then 40 mg/day for the subsequent 20 weeks. Sixteen patients were screened, 12 of whom met criteria for enrollment. At 24 weeks, there was no overall improvement in 6-minute walk distance (6MWD). Five of the 12 subjects dropped out of the study early (2 for social reasons, 3 for medical reasons). There was no significant change in short form 36, St. George's respiratory questionnaire, or maximum Borg dyspnea scores over the 24 weeks. There were no significant adverse events or laboratory abnormalities clearly related to tadalafil in the cohort. The study did not meet the primary end point of change in 6MWD because of the small sample size. Tadalafil was generally safely administered in this cohort of SAPH patients. There was a relatively high dropout rate but no major adverse events and no clinical worsening. Larger studies are needed to explore this question further. (Trial registration: ClinicalTrials.gov identifier: NCT01324999). PMID- 28090300 TI - BK channels in rat and human pulmonary smooth muscle cells are BKalpha-beta1 functional complexes lacking the oxygen-sensitive stress axis regulated exon insert. AB - A loss of K+ efflux in pulmonary arterial smooth muscle cells (PASMCs) contributes to abnormal vasoconstriction and PASMC proliferation during pulmonary hypertension (PH). Activation of high-conductance Ca2+-activated (BK) channels represents a therapeutic strategy to restore K+ efflux to the affected PASMCs. However, the properties of BK channels in PASMCs-including sensitivity to BK channel openers (BKCOs)-are poorly defined. The goal of this study was to compare the properties of BK channels between PASMCs of normoxic (N) and chronic hypoxic (CH) rats and then explore key findings in human PASMCs. Polymerase chain reaction results revealed that 94.3% of transcripts encoding BKalpha pore proteins in PASMCs from N rats represent splice variants lacking the stress axis regulated exon insert, which confers oxygen sensitivity. Subsequent patch-clamp recordings from inside-out (I-O) patches confirmed a dense population of BK channels insensitive to hypoxia. The BK channels were highly activated by intracellular Ca2+ and the BKCO lithocholate; these responses require BKalpha beta1 subunit coupling. PASMCs of CH rats with established PH exhibited a profound overabundance of the dominant oxygen-insensitive BKalpha variant. Importantly, human BK (hBK) channels in PASMCs from human donor lungs also represented the oxygen-insensitive BKalpha variant activated by BKCOs. The hBK channels showed significantly enhanced Ca2+ sensitivity compared with rat BK channels. We conclude that rat BK and hBK channels in PASMCs are oxygen insensitive BKalpha-beta1 complexes highly sensitive to Ca2+ and the BKCO lithocholate. BK channels are overexpressed in PASMCs of a rat model of PH and may provide an abundant target for BKCOs designed to restore K+ efflux. PMID- 28090301 TI - Pulmonary pulse wave transit time is associated with right ventricular-pulmonary artery coupling in pulmonary arterial hypertension. AB - Pulmonary pulse wave transit time (pPTT), defined as the time for the systolic pressure pulse wave to travel from the pulmonary valve to the pulmonary veins, has been reported to be reduced in pulmonary arterial hypertension (PAH); however, the underlying mechanism of reduced pPTT is unknown. Here, we investigate the hypothesis that abbreviated pPTT in PAH results from impaired right ventricular-pulmonary artery (RV-PA) coupling. We quantified pPTT using pulsed-wave Doppler ultrasound from 10 healthy age- and sex-matched controls and 36 patients with PAH. pPTT was reduced in patients with PAH compared with controls. Univariate analysis revealed the following significant predictors of reduced pPTT: age, right ventricular fractional area change (RV FAC), tricuspid annular plane excursion (TAPSE), pulmonary arterial pressures (PAP), diastolic pulmonary gradient, transpulmonary gradient, pulmonary vascular resistance, and RV-PA coupling (defined as RV FAC/mean PAP or TAPSE/mean PAP). Although the correlations between pPTT and invasive markers of pulmonary vascular disease were modest, RV FAC (r = 0.64, P < 0.0001), TAPSE (r = 0.67, P < 0.0001), and RV-PA coupling (RV FAC/mean PAP: r = 0.72, P < 0.0001; TAPSE/mean PAP: r = 0.74, P < 0.0001) had the strongest relationships with pPTT. On multivariable analysis, only RV FAC, TAPSE, and RV-PA coupling were independent predictors of pPTT. We conclude that shortening of pPTT in patients with PAH results from altered RV-PA coupling, probably occurring as a result of reduced pulmonary arterial compliance. Thus, pPTT allows noninvasive determination of the status of both the pulmonary vasculature and the response of the RV in patients with PAH, thereby allowing monitoring of disease progression and regression. PMID- 28090302 TI - Three-dimensional micro computed tomography analysis of the lung vasculature and differential adipose proteomics in the Sugen/hypoxia rat model of pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a rare disease characterized by significant vascular remodeling. The obesity epidemic has produced great interest in the relationship between small visceral adipose tissue depots producing localized inflammatory conditions, which may link metabolism, innate immunity, and vascular remodeling. This study used novel micro computed tomography (microCT) three-dimensional modeling to investigate the degree of remodeling of the lung vasculature and differential proteomics to determine small visceral adipose dysfunction in rats with severe PAH. Sprague-Dawley rats were subjected to a subcutaneous injection of vascular endothelial growth factor receptor blocker (Sugen 5416) with subsequent hypoxia exposure for 3 weeks (SU/hyp). At 12 weeks after hypoxia, microCT analysis showed a decrease in the ratio of vascular to total tissue volume within the SU/hyp group (mean +/- standard deviation: 0.27 +/- 0.066; P = 0.02) with increased vascular separation (0.37 +/- 0.062 mm; P = 0.02) when compared with the control (0.34 +/- 0.084 and 0.30 +/- 0.072 mm). Differential proteomics detected an up-regulation of complement protein 3 (C3; SU/hyp?control ratio = 2.86) and the adipose tissue-specific fatty acid binding protein-4 (FABP4, 2.66) in the heart adipose of the SU/hyp. Significant remodeling of the lung vasculature validates the efficacy of the SU/hyp rat for modeling human PAH. The upregulation of C3 and FABP4 within the heart adipose implicates small visceral adipose dysfunction. C3 has been associated with vascular stiffness, and FABP4 suppresses peroxisome proliferator-activated receptor, which is a major regulator of adipose function and known to be downregulated in PAH. These findings reveal that small visceral adipose tissue within the SU/hyp model provides mechanistic links for vascular remodeling and adipose dysfunction in the pathophysiology of PAH. PMID- 28090304 TI - The prognostic significance of pulmonary arterial capacitance in pulmonary arterial hypertension: single-center experience. AB - This study explores the prognostic utility of pulmonary arterial capacitance (PAC) in a diverse cohort of patients with pulmonary arterial hypertension (PAH) from a tertiary referral center and compares it with the prognostic utility of other hemodynamic parameters. PAC is a strong independent predictor of mortality in patients with PAH. PMID- 28090303 TI - Genotype-phenotype effects of Bmpr2 mutations on disease severity in mouse models of pulmonary hypertension. AB - More than 350 mutations in the type-2 BMP (bone morphogenetic protein) receptor, BMPR2, have been identified in patients with heritable pulmonary arterial hypertension (HPAH). However, only 30% of BMPR2 mutation carriers develop PAH, and we cannot predict which of these carriers will develop clinical disease. One possibility is that the nature of the BMPR2 mutation affects disease severity. This hypothesis has been difficult to test clinically, given the rarity of HPAH and the complexity of the confounding genetic and environmental risk factors. To test this hypothesis, therefore, we evaluated the susceptibility to experimental pulmonary hypertension (PH) of mice carrying different HPAH-associated Bmpr2 mutations on otherwise identical genetic backgrounds. Mice with Bmpr2DeltaEx4-5 mutations (Bmpr2+/-), in which the mutant protein is not expressed, develop less severe PH in response to hypoxia or hypoxia with vascular endothelial growth factor receptor inhibition than mice with an extracellular-domain Bmpr2DeltaEx2 mutation (Bmpr2DeltaEx2/+), in which the mutant protein is expressed. This was associated with a marked decrease in stabilizing phosphorylation of threonine 495 endothelial nitric oxide synthase (pThr495 eNOS) in Bmpr2DeltaEx2/+ compared to wild-type and Bmpr2+/- mouse lungs. These findings provide the first experimental evidence that BMPR2 mutation types influence the severity of HPAH and suggest that patients with BMPR2 mutations who express mutant BMPR2 proteins by escaping non-sense-mediated messenger RNA decay (NMD- mutations) will develop more severe disease than HPAH patients with NMD+ mutations who do not express BMPR2 mutant proteins. Since decreased levels of pThr495 eNOS are associated with increased eNOS uncoupling, our data also suggest that this effect may result from defects in eNOS function. PMID- 28090305 TI - Resolution of myelofibrosis-associated pulmonary arterial hypertension following allogeneic hematopoietic stem cell transplantation. AB - We present the case of a 62-year-old man with myelofibrosis-associated pulmonary arterial hypertension (PAH) who underwent allogeneic hematopoietic stem cell transplantation with subsequent resolution of disease and PAH. Right heart catheterization was used to guide PAH therapy before and after transplantation. Drug interactions, adverse effects, and renal insufficiency posed clinical challenges for the management of PAH-specific medications after transplantation. PAH improved soon after transplantation, and vasoactive medications were tapered off. Resolution of PAH was confirmed with repeat measurement of pulmonary hemodynamic characteristics. Although the etiology and pathophysiology for the resolution of PAH was unclear, the myelopulmonary pathophysiologic link was likely to have contributed. This is the first report describing resolution of myelofibrosis-associated PAH after allogeneic hematopoietic stem cell transplantation. PMID- 28090306 TI - A case of pulmonary arterial hypertension associated with adult hemophagocytic lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis (HLH) is an aggressive, life-threatening syndrome of excessive immune activation. Presentation is most common among the pediatric population, and cases in adults are rare. The number of nonhematologic presentations described in relation to HLH has been growing. We present a case involving a woman who developed HLH after autologous stem cell transplantation for mantle cell lymphoma. Months later, she received a diagnosis of pulmonary arterial hypertension (PAH) while undergoing treatment for her HLH. To our knowledge, PAH associated with adult HLH has only been described in the literature once before. PAH may now be a potential differential diagnosis for patients with HLH who present with respiratory symptoms. PMID- 28090307 TI - Hemodynamic response to treatment of iron deficiency anemia in pulmonary arterial hypertension: longitudinal insights from an implantable hemodynamic monitor. AB - Despite new therapeutic options, pulmonary arterial hypertension (PAH) remains a progressive disease associated with substantial morbidity and mortality. As such, additional strategies for monitoring and adjunctive management of this disease are important. A 59-year-old woman with scleroderma-associated PAH received an implantable hemodynamic monitor (IHM) as part of a research protocol at our institution. Pulmonary artery pressures, heart rate, and cardiac output (sensor based algorithm) were measured on a daily basis, and parameters of right ventricular (RV) performance and afterload were calculated. At the time of IHM implant, the patient had functional class III symptoms, was receiving triple-drug therapy, and had normal hemoglobin levels. Four months after implant, and with further optimization of prostacyclin therapy, she had improvement in her symptoms. However, shortly thereafter, while the patient was receiving stable drug therapy, her case regressed with worsening symptoms, and the patient received a new diagnosis of iron deficiency anemia. Oral iron supplementation resulted in normalization of hemoglobin levels and improvement in the patient's iron profile. A gradual and sustained reduction in pulmonary pressures was noted after initiation of oral iron accompanied by increased RV performance and favorable reduction in RV afterload. The patient had significant symptomatic improvement. Iron deficiency is an underappreciated yet easily treatable risk factor in PAH. Use of IHM in this case longitudinally illustrates the optimization of pulmonary hemodynamics and RV afterload in tandem with clinical improvement achieved by a simple therapy. PMID- 28090308 TI - Treatment differences in pulmonary arterial hypertension management. PMID- 28090309 TI - Bridging the science into practice. PMID- 28090310 TI - Erratum. AB - [This corrects the article DOI: 10.1086/688060.]. PMID- 28090311 TI - Erratum. AB - [This corrects the article DOI: 10.1086/688058.]. PMID- 28090312 TI - RANKL signaling to the liver associated with type 2 diabetes risk. PMID- 28090313 TI - Inhibiting cathepsin K in mice: impact on fracture repair. PMID- 28090314 TI - CD8+ TEMRA cells: higher background levels may predict delayed fracture healing. PMID- 28090315 TI - Chronic mucocutaneous candidiasis disease associated with inborn errors of IL-17 immunity. AB - Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections affecting the nails, skin and oral and genital mucosae caused by Candida spp., mainly Candida albicans. CMC is an infectious phenotype in patients with inherited or acquired T-cell deficiency. Patients with autosomal dominant (AD) hyper IgE syndrome (HIES), AD signal transducer and activator of transcription 1 (STAT1) gain-of-function, autosomal-recessive (AR) deficiencies in interleukin (IL)-12 receptor beta1 (IL-12Rbeta1), IL-12p40, caspase recruitment domain-containing protein 9 (CARD9) or retinoic acid-related orphan receptor gammaT (RORgammaT) or AR autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy (APECED) develop CMC as a major infectious phenotype that is categorized as Syndromic CMC. In contrast, CMC disease (CMCD) is typically defined as CMC in patients in the absence of any other prominent clinical signs. This definition is not strict; thus, CMCD is currently used to refer to patients presenting with CMC as the main clinical phenotype. The etiology of CMCD is not related to genes that cause severe combined immunodeficiency or combined immunodeficiency, nor to genes responsible for Syndromic CMC. Four genetic etiologies, AR IL-17 receptor A, IL-17 receptor C and ACT1 deficiencies, and AD IL-17F deficiency, are reported to underlie CMCD. Each of these gene defects directly has an impact on IL-17 signaling, suggesting their nonredundant role in host mucosal immunity to Candida. Here, we review current knowledge focusing on IL-17 signaling and the genetic etiologies responsible for, and associated with, CMC. PMID- 28090316 TI - The role of tumour necrosis factor in hepatitis B infection: Jekyll and Hyde. AB - Chronic hepatitis B (CHB) is a major health problem worldwide and is associated with significant long-term morbidity and mortality. The hepatitis B virus (HBV) is a hepatotropic virus that is capable of integrating in the host nucleus permanently resulting in lifelong infection. To date, there is no definitive cure for HBV, as our current treatments cannot eradicate the viral reservoir that has integrated in the liver. Elucidating the immunopathogenesis is key to finding a therapeutic target for HBV as the virus is not in itself cytopathic but the immune response to the virus causes the majority of the cellular injury. In most cases, the virus reaches a state of equilibrium with low viral replication constrained by host immunity. Multiple cytokines have been implicated in the pathogenesis of CHB. Tumor necrosis factor (TNF) has emerged as a key player; on one hand it can facilitate immune-mediated virological control but on the other hand it can cause collateral hepatocyte damage, cirrhosis and possibly promote hepatocellular carcinoma. In this review, we discuss the current understanding of the immunopathogenesis of HBV, focusing on TNF and whether it can be harnessed in therapeutic strategies to cure HBV infection. PMID- 28090317 TI - All-trans retinoic acid enhances cytotoxic effect of T cells with an anti-CD38 chimeric antigen receptor in acute myeloid leukemia. AB - We reported that T cells with anti-CD38-chimeric antigen receptors (CAR) eliminated B-cell lymphoma cells expressing CD38. To employ anti-CD38-CAR against acute myeloid leukemia (AML) blasts not expressing CD38, it is necessary to induce or increase the intensity of CD38 expression. A lactate dehydrogenase (LDH)-releasing assay and flow cytometry showed that anti-CD38-CAR T cells were cytotoxic against AML lines (THP-1 and CMK) expressing high CD38 levels (>99%), in time- and number of effector-dependent manners. In other AML lines (KG1, U937 and HL60) partially expressing CD38, CD38+ AML cells were killed by CD38-specific T cells, but CD38- AML cells remained survived. Intriguingly, 10 nM all-trans retinoic acid (ATRA) augmented CD38 expression in KG1, U937 and HL60 cells and primary leukemic cells from AML patients. Moreover, the withdrawal of ATRA from the medium decreased CD38 expression in AML cells. Killing effects of anti-CD38 CAR T cells against AML lines and AML cells were limited without ATRA, whereas CD38-specific T cells enhanced cytotoxicity on AML cells by ATRA in association with enhanced CD38 expression. These results indicate that anti-CD38-CAR T cells eliminate AML cells through CD38 expression induced by ATRA. PMID- 28090318 TI - Dengue virus antibodies enhance Zika virus infection. AB - For decades, human infections with Zika virus (ZIKV), a mosquito-transmitted flavivirus, were sporadic, associated with mild disease, and went underreported since symptoms were similar to other acute febrile diseases. Recent reports of severe disease associated with ZIKV have greatly heightened awareness. It is anticipated that ZIKV will continue to spread in the Americas and globally where competent Aedes mosquito vectors are found. Dengue virus (DENV), the most common mosquito-transmitted human flavivirus, is both well-established and the source of outbreaks in areas of recent ZIKV introduction. DENV and ZIKV are closely related, resulting in substantial antigenic overlap. Through antibody-dependent enhancement (ADE), anti-DENV antibodies can enhance the infectivity of DENV for certain classes of immune cells, causing increased viral production that correlates with severe disease outcomes. Similarly, ZIKV has been shown to undergo ADE in response to antibodies generated by other flaviviruses. We tested the neutralizing and enhancing potential of well-characterized broadly neutralizing human anti-DENV monoclonal antibodies (HMAbs) and human DENV immune sera against ZIKV using neutralization and ADE assays. We show that anti-DENV HMAbs, cross-react, do not neutralize, and greatly enhance ZIKV infection in vitro. DENV immune sera had varying degrees of neutralization against ZIKV and similarly enhanced ZIKV infection. Our results suggest that pre-existing DENV immunity may enhance ZIKV infection in vivo and may lead to increased disease severity. Understanding the interplay between ZIKV and DENV will be critical in informing public health responses and will be particularly valuable for ZIKV and DENV vaccine design and implementation strategies. PMID- 28090319 TI - The role of liver sinusoidal cells in local hepatic immune surveillance. AB - Although the liver's function as unique immune organ regulating immunity has received a lot of attention over the last years, the mechanisms determining hepatic immune surveillance against infected hepatocytes remain less well defined. Liver sinusoidal cells, in particular, liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs), serve as physical platform for recruitment and anchoring of blood-borne immune cells in the liver. Liver sinusoidal cells also function as portal of entry for infectious microorganisms targeting the liver such as hepatotropic viruses, bacteria or parasites. At the same time, liver sinusoidal cells actively contribute to achieve immune surveillance against bacterial and viral infections. KCs function as adhesion hubs for CD8 T cells from the circulation, which initiates the interaction of virus-specific CD8 T cells with infected hepatocytes. Through their phagocytic function, KCs contribute to removal of bacteria from the circulation and engage in cross talk with sinusoidal lymphocyte populations to achieve elimination of phagocytosed bacteria. LSECs contribute to local immune surveillance through cross presentation of viral antigens that causes antigen-specific retention of CD8 T cells from the circulation. Such cross-presentation of viral antigens activates CD8 T cells to release TNF that in turn triggers selective killing of virus infected hepatocytes. Beyond major histocompatibility complex (MHC)-restricted T cell immunity, CD1- and MR1-restricted innate-like lymphocytes are found in liver sinusoids whose roles in local immune surveillance against infection need to be defined. Thus, liver sinusoidal cell populations bear key functions for hepatic recruitment and for local activation of immune cells, which are both required for efficient immune surveillance against infection in the liver. PMID- 28090321 TI - GM-CSF signalling blockade and chemotherapeutic agents act in concert to inhibit the function of myeloid-derived suppressor cells in vitro. AB - Immune evasion is a recently defined hallmark of cancer, and immunotherapeutic approaches that stimulate an immune response to tumours are gaining recognition. However tumours may evade the immune response and resist immune-targeted treatment by promoting an immune-suppressive environment and stimulating the differentiation or recruitment of immunosuppressive cells. Myeloid-derived suppressor cells (MDSC) have been identified in a range of cancers and are often associated with tumour progression and poor patient outcomes. Pancreatic cancer in particular supports MDSC differentiation via the secretion of granulocyte macrophage colony-stimulating factor (GM-CSF), and MDSC are believed to contribute to the profoundly immune-suppressive microenvironment present in pancreatic tumours. MDSC-targeted therapies that deplete or inhibit this cell population have been proposed as a way to shift the balance in favour of a tumour clearing immune response. In this study, we have modelled MDSC differentiation and function in vitro and this has provided us with the opportunity to test a range of potential MDSC-targeted therapies to identify candidates for further investigation. Using in vitro modelling we show here that the combination of GM CSF-signalling blockade and gemcitabine suppresses both the MDSC phenotype and the inhibition of T-cell function by MDSC. PMID- 28090320 TI - Immunopathogenesis of granulomas in chronic autoinflammatory diseases. AB - Granulomas are clusters of immune cells. These structures can be formed in reaction to infection and display signs of necrosis, such as in tuberculosis. Alternatively, in several immune disorders, such as sarcoidosis, Crohn's disease and common variable immunodeficiency, non-caseating granulomas are formed without an obvious infectious trigger. Despite advances in our understanding of the human immune system, the pathogenesis underlying these non-caseating granulomas in chronic inflammatory diseases is still poorly understood. Here, we review the current knowledge about the immunopathogenesis of granulomas, and we discuss how the involved immune cells can be targeted with novel therapeutics. PMID- 28090322 TI - Vaccination to gain humoral immune memory. AB - The concept of immune memory forms the biological basis for vaccination programs. Despite advancements in the field of immune memory and vaccination, most current vaccines are evaluated by magnitude of antigen-specific antibody titers in serum or mucosa after vaccination. It has been shown, however, that antibody-mediated humoral immune memory is established regardless of the magnitude and duration of immune reactions, suggesting that assessment of vaccine efficacy should be performed for several years after vaccination. This long-term investigation is disadvantageous for prevalent and pandemic infections. Long-lived memory plasma cells and memory helper T cells which contribute to humoral immune memory are generated in the bone marrow after migration of memory cell precursors through bloodstream. Thus, it may be a novel evaluation strategy to assess the precursors of memory cells in the blood in the early phase of the immune reaction(s). We here review recent advances on the generation and maintenance of immune memory cells involved in humoral immunity and introduce a current concept of direct and short-term assessment of humoral immune memory formation upon vaccination as a correlate of protection. PMID- 28090323 TI - High thioredoxin-1 levels in rheumatoid arthritis patients diminish binding and signalling of the monoclonal antibody Tregalizumab. AB - The humanized non-depleting anti-CD4 monoclonal antibody Tregalizumab (BT-061) is able to selectively activate the suppressive function of regulatory T cells and has been investigated up to phase IIb in clinical trials in patients suffering from rheumatoid arthritis (RA). A pharmacokinetic-pharmacodynamic model based on clinical data from RA and healthy volunteers, which used the cell surface CD4 downmodulation as marker of activity, confirmed a stronger effect in healthy volunteers compared with RA patients. We tried to understand this phenomenon and evaluated the influence of the small oxidoreductase thioredoxin-1 (Trx1). To counteract oxidative stress that is strongly associated with RA pathophysiology, the organism employs Trx1. Therefore, increased expression and secretion of Trx1 is found in the synovial fluid and plasma of RA patients. Moreover, the binding site of Tregalizumab is in close proximity to a disulphide bond in domain 2 (D2) of CD4, which is a known target for a reduction by oxidoreductase Trx1. With the experiments reported herein, we demonstrated that specific reduction of the D2 disulphide bond by Trx1 led to diminished binding of Tregalizumab to recombinant human soluble CD4 and membrane-bound CD4 on T cells. Moreover, we showed that this caused changes in the Tregalizumab-induced CD4 signalling pathway via the lymphocyte-specific protein tyrosine kinase p56 Lck and CD4 downmodulation. In summary, we provide evidence that high Trx1 levels in RA patients compared with healthy subjects are a potential reason for diminished binding of Tregalizumab to CD4-positive T cells and offer an explanation for the observed decreased CD4 downmodulation in RA patients in comparison to healthy subjects. PMID- 28090324 TI - Improving ward environments and developing skills for discharge with the implementation of self-catering on a low secure forensic unit. AB - The opportunities for service users to develop skills for more independent living and take control of their environments are limited in secure mental health units. This paper will outline a quality improvement project that changed how the catering services were delivered in a low secure unit in East London NHS Foundation Trust (ELFT). A Quality Improvement methodology was adopted incorporating the Plan, Do, Study, Act (PDSA) cycle which included the trial of service users preparing their own meals on a daily basis. The participation rates were measured and functional daily living skills were recorded. Following success of the trial, long-term implementation of self-catering was agreed, with service users being supported to prepare a shared evening meal every day on the ward with an average of 60% participation. Functional living skills indicated an improvement in the area of process skills. The project aligned with ELFT's aims of service users working in collaboration with staff to implement changes in service delivery. PMID- 28090325 TI - Improving timeliness for acute asthma care for paediatric ED patients using a nurse driven intervention: an interrupted time series analysis. AB - Asthma is the most common chronic paediatric disease treated in the emergency department (ED). Rapid corticosteroid administration is associated with improved outcomes, but our busy ED setting has made it challenging to achieve this goal. Our primary aim was to decrease the time to corticosteroid administration in a large, academic paediatric ED. We conducted an interrupted time series analysis for moderate to severe asthma exacerbations of one to 18 year old patients. A multidisciplinary team designed the intervention of a bedside nurse initiated administration of oral dexamethasone, to replace the prior system of a physician initiated order for oral prednisone. Our baseline and intervention periods were 12 month intervals. Our primary process measure was the time to corticosteroid administration. Other process measures included ED length of stay, admission rate, and rate of emesis. The balance measures included rate of return visits to the ED or clinic within five days, as well as the proportion of discharged patients who were admitted within five days. No special cause variation occurred in the baseline period. The mean time to corticosteroid administration decreased significantly, from 98 minutes in the baseline period to 59 minutes in the intervention period (p < 0.01), and showed special cause variation improvement within two months after the intervention using statistical process control methodology. We sustained the improvement and demonstrated a stable process. The intervention period had a significantly lower admission rate (p<0.01) and emesis rate (p<0.01), with no unforeseen harm to patients found with any of our balance measures. In summary, the introduction of a nurse initiated, standardized protocol for corticosteroid therapy for asthma exacerbations in a paediatric ED was associated with decreased time to corticosteroid administration, admission rates, and post-corticosteroid emesis. PMID- 28090326 TI - Quality improvement: The delivery of true early mobilisation in an intensive care unit. AB - Early mobilisation initiatives within the critical care environment have been shown to improve outcomes for patients. Early mobilisation has been defined as occurring within the first two to five days of the intensive care stay, but in practice this can be difficult to deliver. We conducted a quality improvement (QI) project to deliver early mobilisation in a large general intensive care unit. Mechanically ventilated medical patients received an integrated package of care involving two additional daily sessions of mobility therapy, in combination with minimal sedation where possible. Prospective baseline data was collected from January to March 2012; the QI project commenced in April 2012. Improvement cycle 1 completed in March 2015 and improvement cycle 2 in March 2016. Results have suggested a reduction in time to first mobilisation for intensive care survivors from 16.3 days in 2012, to 4.3 days at the end of improvement cycle 2. This was associated with a decrease in mean intensive care length of stay from 20.8 days in 2012, to 11.2 days at the end of improvement cycle 2. This QI project enabled patients to mobilise out of bed within the first five days of their intensive care stay and to be discharged earlier from the ICU, on going analysis is required to verify these findings. PMID- 28090327 TI - Improving capacity and consent to treatment recording in psychiatric inpatient wards: A multi-centre quality improvement project. AB - Assessment of mental capacity provides an ethical and legal framework for care which values patients' autonomy whilst recognising the instances where it is appropriate to act in patients' best interests. Existing medical literature indicates that mental capacity is poorly documented in psychiatric inpatient settings. The aim of the project was to examine the frequency of capacity and consent to treatment documentation with a view to creating changes in practice by raising awareness about the importance of assessing and documenting mental capacity. A multi-centre quality improvement project was conducted in September 2014 across all general adult psychiatric inpatient wards in the North Central London Training Scheme. The frequency of documentation of capacity and consent to treatment for all adult psychiatric inpatient wards across North Central London was measured. Electronic patient notes were audited retrospectively to ascertain whether capacity and consent to treatment on admission, and within the preceding seven days of data collection, was recorded. Data was collected across three successive time points during a 12 month period following the implementation of changes. A total of 232 patients were included in the baseline measurements. The results highlighted a deficiency in the recording of capacity and consent to treatment for adult psychiatric inpatients. The results showed that, of the patients audited, 49.8% had their capacity and consent to treatment assessed on admission, 61.9% had a capacity assessment in the previous 7 days and 60.5% had consent recorded in the previous 7 days. These findings were presented at local hospital teaching sessions at each of the audited sites. These sessions also gave teaching on mental capacity. Audit cycle 1 was conducted 6 months later, this included 213 patients and showed a 30% improvement in the frequency of documentation across all measures. The results showed that 77% of patients audited had their capacity and consent assessed on admission to the ward, 87.3% had a capacity assessment in the previous 7 days and 85.5% had consent recorded in the previous 7 days. After feedback from the teaching sessions, a clerking proforma was produced that had a prompt to assess to capacity. Audit cycle 2 was conducted 12 months after the initial baseline measurements, had a sample size of 229 patients and a sustained improvement in documentation of 26% from baseline was demonstrated across all measures. This project demonstrated that capacity and consent to treatment was not routinely recorded but that the frequency of recording improved through the use of teaching sessions on mental capacity and the introduction of admission clerking proformas with capacity prompts. PMID- 28090328 TI - Decreasing Time to Pain Relief for Emergency Department Patients with Extremity Fractures. AB - Significant delays occur in providing adequate pain relief for patients who present to the emergency department (ED) with extremity fractures. The median time to pain medication administration for patients presenting to our ED with extremity fractures was 72.5 minutes. We used a multidisciplinary approach to implement three improvement cycles with the goal of reducing the median time to pain medication by 15% over an eight month time period. First, we redesigned nursing triage and treatment processes. Second, we improved nursing documentation standardization to ensure accurate tracking of patients who declined pain medication. Third, through consensus building within our physician group, we implemented a department-wide standard of care to provide early pain relief for extremity fractures. Median time to pain medication for patients with an extremity fracture reduced significantly between the pre-and post-intervention periods (p=0.009). The average monthly median time to medication was 72.5 minutes (95% CI: 57.1 to 88.0) before the intervention (Jan 2013-Oct 2014) and 49.8 minutes (95% CI: 42.7 to 56.9) after the intervention (November 2014 to June 2016). In other words, monthly median time was 31% faster (22.7 minute difference) in the post intervention period. Implementing three key interventions reduced the time to pain medication for patients with extremity injuries. Since June 2016 the reductions in median time to medication have continued to improve. PMID- 28090329 TI - Using the Safer Clinical Systems approach and Model for Improvement methodology to decrease Venous Thrombo-Embolism in Elective Surgical Patients. AB - A significant incidence of post-procedural deep vein thrombosis (DVT) and pulmonary embolus (PE) was identified in patients undergoing surgery at our hospital. Investigation showed an unreliable peri-operative process leading to patients receiving incorrect or missed venous thromboembolism (VTE) prophylaxis. The Trust had previously participated in a project funded by the Health Foundation using the "Safer Clinical Systems" methodology to assess, diagnose, appraise options, and implement interventions to improve a high risk medication pathway. We applied the methodology from that study to this cohort of patients demonstrating that the same approach could be applied in a different context. Interventions were linked to the greatest hazards and risks identified during the diagnostic phase. This showed that many surgical elective patients had no VTE risk assessment completed pre-operatively, leading to missed or delayed doses of VTE prophylaxis post-operatively. Collaborative work with stakeholders led to the development of a new process to ensure completion of the VTE risk assessment prior to surgery, which was implemented using the Model for Improvement methodology. The process was supported by the inclusion of a VTE check in the Sign Out element of the WHO Surgical Safety Checklist at the end of surgery, which also ensured that appropriate prophylaxis was prescribed. A standardised operation note including the post-operative VTE plan will be implemented in the near future. At the end of the project VTE risk assessments were completed for 100% of elective surgical patients on admission, compared with 40% in the baseline data. Baseline data also revealed that processes for chemical and mechanical prophylaxis were not reliable. Hospital wide interventions included standardisation of mechanical prophylaxis devices and anti-thromboembolic stockings (resulting in a cost saving of L52,000), and a Trust wide awareness and education programme. The education included increased emphasis on use of mechanical prophylaxis when chemical prophylaxis was contraindicated. VTE guidelines were also included in the existing junior Doctor guideline App. and a "CLOTS" anticoagulation webpage was developed and published on the hospital intranet. The improvement in VTE processes resulted in an 80% reduction in hospital associated thrombosis following surgery from 0.2% in January 2014 to 0.04% in December 2015 and a reduction in the number of all hospital associated VTE from a baseline median of 9 per month as of January 2014 to a median of 1 per month by December 2015. PMID- 28090330 TI - Mechanochemical functionalization of disulfide linked hydrogels. AB - Poly(ethylene glycol) hydrogels with disulfide linkages are functionalized through applied force. Compression or tension induces bond rupture at the relatively weak disulfide linkages, which will subsequently react through Michael type addition with an acceptor molecule within the gel. We demonstrate the utility of this approach by patterning cell adhesion proteins through compression of a lithographically structured stamp, where cells predominately adhere to the compressed regions. PMID- 28090331 TI - Prevalence of gastrointestinal dysmotility and complications detected by abdominal plain films after lung transplantation: a single-centre cohort study. AB - INTRODUCTION AND AIMS: Gastrointestinal (GI) complications such as gastric retention (GR) and constipation are common after lung transplantation (LT). Abdominal plain films (APFs) are a low-cost diagnostic tool to detect impaired GI function. The goal of our study was to assess the prevalence of GI pathology seen on APF in lung transplant recipients (LTRs) and to identify associated risk factors. METHODS: Retrospective analysis of consecutive LTRs followed up between 2001 and 2013. Demographic, radiographic and clinical data were assessed. RESULTS: 198 patients were included in the study, 166 thereof had more than 1 APF with a mean number of 5 APFs per patient. 163 patients had a detectable radiographic pathology on APF. The proportion of LTR with GR was highest among cystic fibrosis patients (48.5%). Multivariate regression analysis showed a significant association of diabetes with GR with a trend for age and use of opiates as risk factors. Similarly, female sex, advanced age and diabetes showed a trend to be associated with lower GI tract complications. Almost all patients had suffered from at least 1 episode of lower GI dysmotility during a median follow-up of 5.7 years. No clear correlation between GI events and the development of chronic lung allograft dysfunction could be identified. CONCLUSIONS: We found a statistically significant association of diabetes with GR and a progressive increase in the prevalence of GR over time after LT. Lower GI complications affected >80% of LTR and increased over time. Future studies correlating GI transit with APF findings are needed. PMID- 28090332 TI - Long-term effect of intensive lifestyle intervention on cardiovascular risk factors in patients with diabetes in real-world clinical practice: a 5-year longitudinal study. AB - OBJECTIVE: We evaluated long-term impact of sustained weight loss versus weight regain on cardiovascular risk factors in real-world clinical practice. METHODS: We evaluated 129 obese patients with diabetes enrolled in Weight Achievement and Intensive Treatment (Why WAIT) program, a 12-week clinical model of intensive lifestyle intervention. After 1 year, we divided participants into group A, who maintained <7% weight loss (47.3%) and group B (52.7%), who maintained >=7% weight loss. We continued to follow them for a total of 5 years. RESULTS: The total cohort lost 23.8 lbs (-9.7%) at 12 weeks and maintained -16.2 lbs (-6.4%) at 5 years (p<0.001). Group A maintained -8.4 lbs (-3.5%) and group B maintained 23.1 lbs (-9.0%) at 5 years. In group A, A1C decreased from 7.5+/-1.3% to 6.7+/ 0.9% at 12 weeks but increased to 7.7+/-1.4% at 1 year and 8.0+/-1.9% at 5 years. In group B, A1C decreased from 7.4+/-1.2% to 6.4+/-0.9% at 12 weeks and rose to 6.8+/-1.2% at 1 year and 7.3+/-1.5% at 5 years. Despite weight regain, group A maintained improvement in low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol with worsening of serum triglycerides and no change in blood pressure (BP). Group B maintained improvement in lipid profile for 5 years and had significantly lower BP for 18 months. CONCLUSIONS: Weight reduction in patients with diabetes can be maintained for 5 years and is predicted by patients' ability to maintain >=7% weight loss at 1 year. A1C and triglycerides deteriorate with weight regain, while other lipid improvements are maintained. Sustained weight loss is associated with significantly lower A1C for 5 years and lowers BP for 18 months. TRIAL REGISTRATION NUMBER: NCT01937845. PMID- 28090333 TI - Urinary C peptide creatinine ratio in pregnant women with normal glucose tolerance and type 1 diabetes: evidence for insulin secretion. AB - HYPOTHESIS: In pregnancy, urinary C peptide creatinine ratio (UCPCR) reflects endogenous insulin secretion in women with normal glucose tolerance and type 1 diabetes. RESEARCH DESIGN AND METHODS: UCPCR and serum C peptide were measured in 90 glucose-tolerant women at 0 and 120 min during a 75 g oral glucose tolerance test (OGTT) at 28 weeks of gestation. UCPCR was measured in 2 samples obtained over 10 weeks apart in 7 pregnant women with longstanding type 1 diabetes. RESULTS: UCPCROGTT and serum C peptideOGTT of glucose-tolerant women were significantly correlated at 0 and 120 min (rs0.675, 0.541 respectively, p<0.0001). All 7 pregnant women with type 1 diabetes had detectable first sample UCPCR (median (range) 49 (6-1038) pmol/mmol) that rose in 6 women by 477 (29 1491) pmol/mmol. CONCLUSIONS: Detectable UCPCR in pregnant women with normal glucose tolerance and type 1 diabetes is likely to reflect endogenous insulin secretion and hence beta-cell activity. PMID- 28090334 TI - An experimental validation of genomic selection in octoploid strawberry. AB - The primary goal of genomic selection is to increase genetic gains for complex traits by predicting performance of individuals for which phenotypic data are not available. The objective of this study was to experimentally evaluate the potential of genomic selection in strawberry breeding and to define a strategy for its implementation. Four clonally replicated field trials, two in each of 2 years comprised of a total of 1628 individuals, were established in 2013-2014 and 2014-2015. Five complex yield and fruit quality traits with moderate to low heritability were assessed in each trial. High-density genotyping was performed with the Affymetrix Axiom IStraw90 single-nucleotide polymorphism array, and 17 479 polymorphic markers were chosen for analysis. Several methods were compared, including Genomic BLUP, Bayes B, Bayes C, Bayesian LASSO Regression, Bayesian Ridge Regression and Reproducing Kernel Hilbert Spaces. Cross-validation within training populations resulted in higher values than for true validations across trials. For true validations, Bayes B gave the highest predictive abilities on average and also the highest selection efficiencies, particularly for yield traits that were the lowest heritability traits. Selection efficiencies using Bayes B for parent selection ranged from 74% for average fruit weight to 34% for early marketable yield. A breeding strategy is proposed in which advanced selection trials are utilized as training populations and in which genomic selection can reduce the breeding cycle from 3 to 2 years for a subset of untested parents based on their predicted genomic breeding values. PMID- 28090335 TI - Top-down Infliximab Study in Kids with Crohn's disease (TISKids): an international multicentre randomised controlled trial. AB - INTRODUCTION: Crohn's disease (CD) is a chronic inflammatory disease predominantly affecting the gastrointestinal tract. CD usually requires lifelong medication and is accompanied by severe complications, such as fistulae and strictures, resulting in surgery. Infliximab (IFX) is very effective for treating paediatric patients with CD, but is currently only registered for therapy refractory patients-the so-called step-up strategy. We hypothesise that using IFX first-line, that is, top-down, will give more mucosal healing, fewer relapses, less complications, need for surgery and hospitalisation. METHODS AND ANALYSIS: This international multicentre open-label randomised controlled trial includes children, aged 3-17 years, with new-onset, untreated CD with moderate-to-severe disease activity (weighted Paediatric Crohn's Disease Activity Index (wPCDAI)>40). Eligible patients will be randomised to top-down or step-up treatment. Top-down treatment consists of 5 IFX infusions combined with azathioprine (AZA). After these 5 infusions, patients will continue AZA. Patients randomised to step-up will receive standard induction treatment, either oral prednisolone or exclusive enteral nutrition, combined with AZA as maintenance treatment. The primary outcome is clinical remission (wPCDAI<12.5) at 52 weeks without need for additional CD-related therapy or surgery. Total follow-up is 5 years. Secondary outcomes include clinical disease activity, mucosal healing by endoscopy (at week 10 and optionally week 52), faecal calprotectin, growth, quality of life, medication use and adverse events. ETHICS AND DISSEMINATION: Conducted according to the Declaration of Helsinki and Good Clinical Practice. Medical-ethical approval will be obtained for each site. TRIAL REGISTRATION NUMBER: NCT02517684; Pre-results. PMID- 28090336 TI - Medical feminism, working mothers, and the limits of home: finding a balance between self-care and other-care in cross-cultural debates about health and lifestyle, 1952-1956. AB - Post-war medical debates about the psychiatric consequences of married women's economic behaviour witnessed far more divergence and collision between perspectives than has often been acknowledged. Practitioners who approached women primarily as facilitators of family health-as wives and mothers-were mistrustful of the competing demands presented by paid employment. They were faced by a growing spectrum of opinion, however, which represented women as atrophying in the confines of domestic life, and which positioned work as a therapeutic act. Advocates of work tapped into anxieties about family instability by emphasizing the dangers posed by frustrated housewives, shifting clinical faith away from full-time motherhood, but nevertheless allowing responsibilities towards husbands and children to continue to frame argument about women's behaviour. Doctors, researchers and social critics, in this context, became preoccupied with questions of balance, mapping a path which sought to harmonize public and private fulfilment, identity and responsibility. This article traces this discursive shift through a series of conferences held by the Medical Women's International Association during the early-to-mid 1950s, connecting debates in Britain with systems of broader intellectual exchange. It enriches and complicates historical knowledge of post-war relationships between medicine and feminism, at the same time as offering a conceptual and linguistic context for modern discussion about work-life balance and gender. This article is published as part of a collection entitled "On balance: lifestyle, mental health and wellbeing". PMID- 28090337 TI - Editorial. PMID- 28090338 TI - Executive functions predict weight loss in a medically supervised weight loss programme. AB - BACKGROUND: Deficits in executive functions are related to poorer weight loss after bariatric surgery; however, less is known about the role that these deficits may play during participation in nonsurgical weight loss programmes. This study examined associations between objectively measured executive functions and weight loss during participation in a medically supervised weight loss programme. METHODS: Twenty-three adult patients (age 50.4 +/- 15.1, BMI 44.2 +/- 8.8, 68% female, 92% White) enrolled in a medically supervised weight loss programme, involving prescription of a very low calorie diet and strategies to change eating and activity behaviours, underwent comprehensive computerized testing of executive functions at baseline. Weight was obtained at baseline and 8 weeks. Demographic and clinical information were obtained through medical chart review. RESULTS: Participants lost an average of 9.8 +/- 3.4% of their initial body weight at 8 weeks. Fewer correct responses on a set-shifting task and faster reaction time on a response inhibition task were associated with lower weight loss percentage at 8 weeks after adjusting for age, education and depressive symptoms. There were no associations between performance on tests of working memory or planning and weight loss. CONCLUSIONS: This study shows that worse performance on a set-shifting task (indicative of poorer cognitive flexibility) and faster reaction times on a response inhibition test (indicative of higher impulsivity) are associated with lower weight loss among participants in a medically supervised weight loss programme. Pre-treatment assessment of executive functions may be useful in identifying individuals who may be at risk for suboptimal treatment outcomes. Future research is needed to replicate these findings in larger samples and identify underlying mechanisms. PMID- 28090339 TI - A mixed methods approach to improving recruitment and engagement of emerging adults in behavioural weight loss programs. AB - OBJECTIVE: Emerging adults ages 18-25 are at high risk for obesity, but are markedly underrepresented in behavioural weight loss (BWL) programs and experience lower engagement and retention relative to older adults. PURPOSE: To utilize a mixed methods approach to inform future efforts to effectively recruit and engage this high-risk population in BWL programs. METHODS: We used a convergent parallel design in which quantitative and qualitative data were given equal priority. Study 1 (N = 137, age = 21.8 + 2.2, BMI = 30.1 + 4.7) was a quantitative survey, conducted online to reduce known barriers and minimize bias. Study 2 (N = 7 groups, age = 22.3 + 2.2, BMI = 31.5 + 4.6) was a qualitative study, consisting of in person focus groups to gain greater depth and identify contextual factors unable to be captured in Study 1. RESULTS: Weight loss was of interest, but weight itself was not a central motivation; an emphasis on overall lifestyle, self-improvement and fitness emerged as driving factors. Key barriers were time, motivation and money. Recruitment processes should be primarily online with messages tailored specifically to motivations and preferences of this age group. Preferences for a program were reduced intensity and brief, hybrid format with some in-person contact, individual level coaching, experiential learning and peer support. Key methods of promoting engagement and retention were autonomy and choice, money and creating an optimal default. CONCLUSIONS: An individually tailored lifestyle intervention that addresses a spectrum of health behaviours, promotes autonomy and emphasizes activity and fitness may facilitate recruitment and engagement in this population better than traditional BWL protocols. PMID- 28090341 TI - Small weight gains during obesity treatment: normative or cause for concern? AB - OBJECTIVES: The objectives of the study are to characterize the frequency and size of small weight gains during behavioural weight loss treatment and to evaluate the relationship between small weight gains and weight loss outcomes. METHODS: Participants (n = 281) in a year-long behavioural weight loss programme were weighed at treatment sessions, and between-session weight gains were classified into several categories based on size. The occurrence of different gain magnitudes and their relation to weight loss were examined during both the active weight loss (months 1-6) and weight loss maintenance (months 7-12) phases of treatment. RESULTS: Weight gains were common during both phases of treatment, with smaller gains occurring more frequently than larger gains. Greater frequency of all gain magnitudes was associated with lesser weight loss during both phases. Additionally, participants who had just one or two weight gains of the smallest size examined (1.0-1.9 lb) lost less weight than those who had no gains. CONCLUSIONS: Small gains appear to reflect true weight gain due to poor adherence to behavioural recommendations and are associated with worse weight loss outcomes, even when limited in number. Future research should examine how best to prevent small weight gains from occurring and how clinicians and participants should respond when a weight gain does occur to promote weight control success. PMID- 28090340 TI - Recruitment and Retention for a Weight Loss Maintenance Trial Involving Weight Loss Prior to Randomization. AB - OBJECTIVE: A weight loss maintenance trial involving weight loss prior to randomization is challenging to implement due to the potential for dropout and insufficient weight loss. We examined rates and correlates of non-initiation, dropout, and insufficient weight loss during a weight loss maintenance trial. METHODS: The MAINTAIN trial involved a 16-week weight loss program followed by randomization among participants losing at least 4 kg. Psychosocial measures were administered during a screening visit. Weight was obtained at the first group session and 16 weeks later to determine eligibility for randomization. RESULTS: Of 573 patients who screened as eligible, 69 failed to initiate the weight loss program. In adjusted analyses, failure to initiate was associated with lower age, lack of a support person, and less encouragement for making dietary changes. Among participants who initiated, 200 dropped out, 82 lost insufficient weight, and 222 lost sufficient weight for randomization. Compared to losing sufficient weight, dropping out was associated with younger age and tobacco use, whereas losing insufficient weight was associated with non-White race and controlled motivation for physical activity. CONCLUSIONS: Studies should be conducted to evaluate strategies to maximize recruitment and retention of subgroups that are less likely to initiate and be retained in weight loss maintenance trials. PMID- 28090342 TI - 1H-MRS measured ectopic fat in liver and muscle is associated with the metabolic syndrome in Danish girls but not in boys with overweight and obesity. AB - BACKGROUND: The metabolic syndrome (MetS) is a complication to overweight and obesity, which can be observed already in childhood. Ectopic lipid accumulation in muscle and liver has been shown to associate with the development of insulin resistance and dyslipidemia. Thus, the interaction between MetS and ectopic fat may offer clinical relevance. OBJECTIVES: To investigate the prevalence of MetS, or components hereof, and ectopic fat accumulation in liver and skeletal muscle tissue in children, as well as interactions between these. METHODS: Two-hundred and-sixteen children and adolescents (95 boys) with overweight/obesity were investigated, as well as 47 controls (22 boys) with normal weight. The assessments included anthropometry, fasting blood biochemistry and blood pressure measurements. Liver and muscle lipid contents were assessed by proton magnetic resonance spectroscopy. RESULTS: We observed an odds ratio in girls with overweight/obesity of 12.2 (95% confidence interval: [3.8; 49.0]) for exhibiting MetS when hepatic steatosis was present, whereas no association was observed in boys with overweight/obesity (odds ratio 0.7 [0.2; 2.7]). The odds ratio of exhibiting MetS in the presence of muscular steatosis was 3.5 [1.4; 9.5] in girls with overweight/obesity and 1.0 [0.2; 5.6] in boys with overweight/obesity. Similar results were seen for girls with overweight/obesity exhibiting concurrent hepatic and muscular steatoses. CONCLUSION: Hepatic and muscular steatoses were associated with MetS among girls, but not among boys with overweight/obesity. PMID- 28090343 TI - Amylin/leptin synergy is absent in extreme obesity and not restored by calorie restriction-induced weight loss in rats. AB - OBJECTIVE: Co-administration of amylin and leptin induces synergistic and clinically meaningful (>10%) weight loss that is attenuated as the degree of obesity increases. We explored whether calorie restriction (CR) could restore amylin/leptin synergy in very obese rats. METHODS: Sprague Dawley rats on high fat diet (696 +/- 8 g, n = 72) were randomized to three cohorts (C1-C3). Rats in C1 were administered vehicle, rat amylin (50 ug kg-1 d-1), murine leptin (125 ug kg-1 d-1) or amylin and leptin for 28 days (n = 6 per group) via subcutaneous minipump. Simultaneously, C2 and C3 rats initiated CR. After moderate (12.4 +/- 0.3%, 86.7 +/- 2.8 g; C2) or severe (24.9 +/- 0.3%, 172.7 +/- 4.7 g; C3) weight loss, amylin and/or leptin was administered as described. RESULTS: In C1, leptin did not alter weight, and amylin induced 40.2 +/- 6.1 g weight loss (-6.0 +/- 0.9%), which was not enhanced by leptin (44.4 +/- 4.9 g, -6.1 +/- 0.8%). In C2, vehicle-treated (75.1 +/- 7.8 g weight change from start of treatment, 1.1 +/- 0.8% difference from start of pre-CR phase) and leptin-treated rats (68.6 +/- 9.2 g, -1.3 +/- 1.0%) rebounded to pre-restriction weight that was attenuated by amylin (29.2 +/- 11.4 g, -6.2 +/- 0.7%). Leptin did not enhance the effect of amylin (22.8 +/- 11.7 g, -8.3 +/- 1.5%). In C3, vehicle-treated and leptin treated rats regained most of their weight (161.9 +/- 11.8, -2.3 +/- 0.8% and 144.6 +/- 9.5 g, -2.3 +/- 0.9%, respectively), which was attenuated by amylin (91.1 +/- 16.8 g, -11.2 +/- 0.7%), but not enhanced by leptin (83.0 +/- 7.6 g, 10.7 +/- 0.8%). CONCLUSIONS: Extreme obesity associated with leptin resistance perturbs amylin/leptin weight loss synergy in rats, which cannot be restored by pre-treatment weight loss. PMID- 28090344 TI - Tasting profile affects adoption of caloric beverage reduction in a randomized weight loss intervention. AB - OBJECTIVE: The aim of this study was to examine differences in rates of non caloric beverage adoption by participants classified as sweet likers (SLs) or sweet dislikers (measured using a behavioural tasting task). METHODS: Data are a sub-study from a 6-month, three-group, randomized weight loss trial (CHOICE) (body mass index 36.3 +/- 5.8 kg m-2, 84% female, aged 42.2 +/- 10.9 years, 53% African-American) comparing the replacement of caloric beverages with either non caloric sweetened beverages (diet) or water (water) compared with a control group. This sub-study, which included participants within the water (n = 106) and diet (n = 103) groups only, examined whether SLs (n = 33 water; n = 37 diet) varied in their adherence to caloric beverage recommendations compared with sweet dislikers (n = 73 water; n = 76 diet) over the 6-month study. RESULTS: Diet intake and sweet-liking data collected on 190 (3 months) and 169 participants (6 months) were used for analysis. The interaction between SL status and beverage group (diet vs. water) approached significance (P = 0.06) at 3 months but not 6 months. Caloric beverage intake (% energy) at 3 months was significantly higher in SLs within the water group (9.7 +/- 1.4%) compared with SLs in the diet group (5.4 +/- 1.0%, P = 0.03). CONCLUSIONS: Results suggest that SL status may affect the rate in reduction of caloric beverages when water is the recommended substitution. Future studies should explore tailoring beverage recommendations to tasting profile. PMID- 28090345 TI - Electronically captured, patient-reported physical function: an important vital sign in obesity medicine. AB - OBJECTIVES: Impaired physical function (i.e., inability to walk 200 feet, climb a flight of stairs or perform activities of daily living) predicts poor clinical outcomes and adversely impacts medical and surgical weight management. However, routine assessment physical function is seldom performed clinically. The PROMIS Physical Function Short Form 20a (SF-20a) is a validated questionnaire for assessing patient reported physical function, which includes published T-score percentiles adjusted for gender, age and education. However, the effect that increasing levels of obesity has on these percentiles is unclear. We hypothesized that physical function would decline with increasing level of obesity independent of gender, age, education and comorbidity. MATERIALS AND METHODS: This study included 1,627 consecutive weight management patients [(mean +/- SEM), 44.7 +/- 0.3 years and 45.1 +/- 0.2 kg/m2] that completed the PROMIS SF-20a during their initial consultation. We evaluated the association between obesity level and PROMIS T-score percentiles using multiple linear regression adjusting for gender, age, education and Charlson Comorbidity Index (CCI). RESULTS: Multiple linear regression T-score percentiles were lower in obesity class 2 (-12.4%tile, p < 0.0001), class 3 (-17.0%tile, p < 0.0001) and super obesity (-25.1%tile, p < 0.0001) compared to class 1 obesity. CONCLUSION: In patients referred for weight management, patient reported physical function was progressively lower in a dose dependent fashion with increasing levels of obesity, independent of gender, age, education and CCI. PMID- 28090347 TI - Depressive symptoms in women's midlife in relation to their body weight before, during and after childbearing years. AB - OBJECTIVE: This study aimed to examine how weight and weight changes related to pregnancy were associated with depressive symptoms 11-16 years after childbirth. METHOD: We followed 16,998 first-time mothers from the Danish National Birth Cohort up till 16 years after birth and estimated associations between depressive symptoms and pre-pregnancy body mass index (BMI) (kg m-2), weight changes in different time periods, and BMI-adjusted waist circumference 7 years after birth (WCBMI, cm). Depressive symptoms were estimated by the Center for Epidemiologic Studies Depression 10-item scale. Multiple logistic regression analyses were used to estimate odds ratios (OR) and 95% confidence intervals. RESULTS: Compared with normal-weight, we found that underweight, overweight and obesity were associated with greater odds of depressive symptoms (1.29, 1.24 and 1.73, respectively). Compared with weight change +/-1 BMI unit during the total follow-up period, greater odds for depressive symptoms were observed with weight loss (OR 1.14, 0.96-1.36) or gain of 2-2.99 kg m-2 (OR 1.11, 0.92-1.33) or gain of >=3 kg m-2 (OR 1.68, 1.46-1.94). WCBMI > 2.2 cm was associated with greater odds of depressive symptoms (OR 1.16, 0.99-1.36) than waist circumference as predicted by BMI. CONCLUSION: Low and high pre-pregnancy BMI, weight changes and WCBMI larger than predicted were associated with more depressive symptoms in midlife. PMID- 28090346 TI - A GWAS follow-up of obesity-related SNPs in SYPL2 reveals sex-specific association with hip circumference. AB - OBJECTIVE: A novel single-nucleotide polymorphism (SNP) associated with morbid obesity was recently identified by exome sequencing. The purpose of this study was to follow up this low-frequency coding SNP located within the SYPL2 locus and associated with body mass index in order to reveal novel associations with obesity-related traits. METHODS: The body mass index-associated SNP (rs62623713 A>G [chr1:109476817/hg19]) and two tagging SNPs within the SYPL2 locus, rs9661614 T>C (chr1:109479215) and rs485660 G>A (chr1:109480810), were genotyped in the obesity (n = 3,017) and the infogene (n = 676) cohorts, which were further combined, leading to a larger cohort of 3,693 individuals. Association testing was performed by general linear models in the obesity cohort and validated by joint analysis in the combined cohort. RESULTS: rs9661614 and rs485660 were significantly associated with hip circumference (HC) in the obesity cohort, with heterozygotes exhibiting a significantly lower HC. These results were validated by joint analysis for rs9661614 (false discovery rate [FDR]-corrected P = 7.5 * 10-4) and, to a lesser extent, for rs485660 (FDR corrected P = 3.9 * 10-2). The association with HC remained significant for rs9661614 when tested independently in women (FDR-corrected P = 1.7 * 10-2), but not for rs485660 (FDR-corrected P = 0.2). Both associations were absent in men. CONCLUSIONS: This study reveals strong evidence for a novel association between rs9661614 (T>C) and HC in women, which likely reflects a preferential association of SYPL2 to a gynoid profile of fat distribution. The study findings support a clinical significance of SYPL2 worth considering when assessing risk factors associated with obesity. PMID- 28090348 TI - Changes in HbA1c and circulating and adipose tissue androgen levels in overweight obese women with polycystic ovary syndrome in response to electroacupuncture. AB - AIM: Insulin sensitivity is ~40% lower in women with polycystic ovary syndrome (PCOS) than in controls. We tested the hypothesis that 5 weeks of electroacupuncture treatment improves glucose regulation and androgen levels in overweight/obese women with PCOS. MATERIAL AND METHODS: Seventeen women with PCOS, aged 18 to 38 years, with a body mass index (BMI) >=25 kg/m2 and diagnosed with PCOS were included in this experimental and feasibility study and subjected to five weeks of electroacupuncture treatments three times/week. The primary outcome was changes in whole-body glucose homeostasis measured by euglycemic hyperinsulinemic clamp before and after the intervention. Secondary outcome were changes in HbA1c, circulating catecholamines, adipocyte size and adipose tissue expression of sex steroids and nerve growth factor (NGF). RESULTS: No significant change in glucose homeostasis was observed, but HbA1c decreased by 9.5% (p = 0.004), circulating testosterone decreased by 22% (p = 0.0007) and dihydrotestosterone decreased by 12% (p = 0.007). The two vagal activity markers of plasma serotonin levels and the dopamine metabolite homovanillic acid decreased by 21% (p = 0.027) and 20% (p = 0.011), respectively. Adipose tissue concentrations of testosterone decreased by 18% (p = 0.049), and androstenedione decreased by 13% (p = 0.035), and mature NGF/proNGF ratio, a marker of sympathetic activity, increased (p = 0.04). These changes occurred without changes in anthropometrics. CONCLUSION: Five weeks of electroacupuncture treatment improves HbA1c and circulating and adipose tissue androgens in women with PCOS. This effect is mediated, at least in part, via modulation of vagal activity and adipose tissue sympathetic activity. Based on these findings, we have recently initiated a randomized controlled study (NTC02647827). PMID- 28090349 TI - The association between parental separation during childhood and obesity in adulthood: a Danish twin study. AB - OBJECTIVE: The purpose of this study was to examine if parental separation during childhood is associated with obesity in adulthood. METHODS: A co-twin case control study of 146 adult same-sexed twin pairs with discordant body mass index (BMI) (i.e. one of the twins should have a BMI of 20-25 kg/m2, and the co-twin's BMI >= 30 kg/m2) was selected from Danish Twin Registry (DTR). In total of 236 eligible twin individuals participated in the study. Childhood parental separation (defined as separation from one of the biological parents, regardless of the reason for separation) for at least one year prior to age 17 was self reported. The statistical analysis includes logistic and linear regression models using STATA 13.0. RESULTS: There were no differences in the odds of developing obesity in adulthood between the twin who stayed with a father and the co-twin who was separated from him for at least 1 year prior to age 17 [OR = 1.22, 95%CI (0.46-3.34), p = 0.65]. Separation from a mother also showed no differences in the odds for developing obesity [OR = 0.90, 95%CI (0.32-2.46), p = 0.82]. CONCLUSIONS: Because of the limited number of discordant twin pairs for childhood parental separation, we cannot provide evidence to suggest that separation from parents in childhood was associated with developing obesity in adulthood. Further studies of pooling discordant twins from several countries should be considered. PMID- 28090350 TI - Longitudinal quality of life improvement in underserved rural youth with obesity. AB - OBJECTIVE: ACT! (Actively Changing Together) is a family- and community-based intervention targeting youth with obesity. The objective of this study was to establish the longitudinal impact on Health-Related Quality of Life (HRQoL) as well as the relationship with anthropometric and demographic factors. METHODS: Youth (n = 75) aged 8-14 years meeting criteria for overweight or obesity were referred to the programme. Twelve, 90-min classes in English and Spanish were held at the YMCA. Demographics and anthropometrics were assessed, as well as HRQoL that was measured with the child-reported Pediatric Quality of Life Inventory (PedsQLTM) 4.0 Generic Core Scale. Data was collected at three follow up points after completion of the intervention: initial follow-up (n = 65), 6 (n = 41) and 12 months (n = 25). Analysis included paired dependent t-tests between baseline and follow-up, and Pearson's correlations on HRQoL, anthropometric and demographic data. RESULTS: PedsQL scores significantly improved from baseline to all follow-up timepoints (initial follow-up immediately following the intervention, and 6 and 12 months post intervention). Over time, body mass index Z-Score and per cent body fat displayed various points of significance and strengthening correlations. CONCLUSIONS: Longitudinal improvements in HRQoL were sustained up to 12 months following a family- and community-based intervention in this underserved population. Anthropometric measures continuously correlated with and contributed to HRQoL outcomes. PMID- 28090351 TI - The prevalence and practice impact of weight bias amongst Australian dietitians. AB - OBJECTIVES: This study explored weight bias amongst Australian Accredited Practising Dietitians (APDs) and the effect of client weight status on dietetic practice. METHODS: Participants were 201 APDs, recruited using purposive sampling. A self-administered questionnaire, the fat phobia scale (FPS), was completed to assess explicit weight bias. Participants were then randomized to receive either a female within the healthy weight range or female with obesity, accompanied by an identical case study for a condition unrelated to weight. Participants assessed the client based on data provided, provided recommendations and rated their perception of the client. RESULTS: Mean FPS scores indicated mild fat phobia. However, dietetic practice was significantly affected by the client's weight status. Dietitians presented with the female with obesity assessed the client to have significantly lower health and were more likely to provide unsolicited weight management recommendations. In addition, dietitians rated the client as less receptive, less motivated and as having a lower ability to understand and sustain recommendations. CONCLUSIONS: The contribution of this study is the exploration of how weight status may impact dietetic practice including assessment, recommendations and perceptions of the client. Dietitians may practice in a manner that represents or could be perceived as negative implicit weight bias, despite the explicit FPS assessing only mild fat phobia. Further research to understand the extent of the problem and how it impacts client outcomes and to test possible solutions is required. PMID- 28090352 TI - Prevalence of obesity in Malta. AB - BACKGROUND: Obesity is a global epidemic with the Mediterranean island of Malta being no exception. The World Health Organization (WHO) has identified Malta as one of the European countries with the highest obesity prevalence. METHOD: A cross-sectional study was conducted (2014-2016) under the auspices of the University of Malta. The prevalence of overweight-obesity in Malta was calculated and then age stratified for comparisons with previous studies. RESULTS: The study identified 69.75% (95% CI: 68.32-71.18) of the Maltese population to be either overweight or obese. The men overweight/obese prevalence (76.28% 95% CI: 74.41 78.14) was statistically higher than that for women (63.06% 95% CI: 60.92-65.20) (p = 0.0001). Age stratification revealed that both genders had the highest overweight prevalence rates between 55 and 64 years (Men = 23.25% 95% CI: 20.43 26.33; Women = 24.68% 95% CI: 21.44-28.22). Men obesity prevalence rates were highest in the 35 to 44 years group (22.52% 95% CI: 19.65-25.68) while for women it was highest in the 55 to 64 years group (28.90%, 95% CI: 25.44-30.63). CONCLUSION: Over a 35-year period, an overall decrease in the normal and overweight BMI categories occurred with an increase in the prevalence of obesity. An exception was observed in the women, where the prevalence of normal BMI increased over this time period. Also, it appears that while the total population obesity prevalence increased (for 2016), a percentage of the women have shifted from an obese to an overweight status. PMID- 28090354 TI - What weight loss treatment options do geriatric patients with overweight and obesity want to consider? AB - INTRODUCTION: Since the 1990s, a number of weight loss medications have been removed from the USA and or European market because of adverse events associated with these medications. These medications include fenfluramine (heart valve thickening), sibutramine (cardiovascular risk) and rimonabant (depression). This history may affect a patient's desire to consider weight loss medications as an option for weight management. OBJECTIVE: This descriptive study was designed to observe what treatment options the geriatric patient (age 65 or higher) seeking weight loss would like to consider, as well as the reasons they felt they struggled with overweight or obesity. METHODS: A questionnaire was given to 102 geriatric patients with overweight or obesity before starting a weight loss programme at a weight management centre. The questionnaire asked the patient why they felt they were overweight or obese and what treatment options they wished to consider. The geriatric patients were matched with younger patients in body mass index and sex. RESULTS: The three most common perceptions that geriatric patients felt were causes of their increased weight were 'lack of exercise' (76.2%), 'poor food choices' (59.4%) and 'cravings' (47.5%). When geriatric patients were asked what treatment options they would like to discuss, the four most common options requested were 'diet and healthy eating' (67.3%), weight loss medications (57.4%), a request for a 'metabolic work up' (55.4%) and 'exercise' (53.5%). These responses were no different from their younger cohorts. When geriatric patients with a body mass index of 35 or higher were given bariatric surgery as a treatment option, 21.9% marked it as a treatment option they would like to consider. CONCLUSIONS: Over half of geriatric patients desired to discuss weight loss medications as a treatment option. Diet and exercise were also of strong interest, which is in line with current weight management guidelines. PMID- 28090353 TI - Leptin, acylcarnitine metabolites and development of adiposity in the Rhea mother child cohort in Crete, Greece. AB - OBJECTIVE: This study aims to investigate relations of serum leptin at age 4 with development of adiposity and linear growth during 3 years of follow-up among 75 Greek children and to identify serum metabolites associated with leptin at age 4 and to characterize their associations with adiposity gain and linear growth. METHODS: Linear regression models that accounted for maternal age, education and gestational weight gain and child's age and sex were used to examine associations of leptin and leptin-associated metabolites measured at age 4 with indicators of adiposity and linear growth at age 7. RESULTS: Each 1-unit increment in natural log-(ln)-transformed leptin corresponded with 0.33 (95% CI: 0.10, 0.55) units greater body mass index-for-age z-score gain during follow-up. Likewise, higher levels of the leptin-associated metabolites methylmalonyl-carnitine and glutaconyl-carnitine corresponded with 0.14 (95% CI: 0.01, 0.27) and 0.07 (95% CI: -0.01, 0.16) units higher body mass index-for-age z-score gain, respectively. These relationships did not differ by sex or baseline weight status and were independent of linear growth. CONCLUSIONS: These findings suggest that leptin, methylmalonyl-carnitine and possibly glutaconyl-carnitine are associated with weight gain during early childhood. Future studies are warranted to confirm these findings in other populations. PMID- 28090355 TI - DDX59 promotes DNA replication in lung adenocarcinoma. AB - DEAD box proteins are multifunctional proteins involved in every aspect in RNA metabolism and have essential roles in many cellular activities. Despite their importance, many DEAD box proteins remain uncharacterized. In this report, we found DDX59 overexpressed in lung adenocarcinoma. DDX59 knockdown reduced cell proliferation, anchorage-independent cell growth, and caused reduction of tumor formation in immunocompromised mice. In multiple lung cancer cells, we found that DDX59 knockdown inhibits DNA synthesis; wild-type DDX59 but not helicase defective mutant of DDX59 enhances DNA synthesis. DDX59 knockdown caused reduction of MCM protein levels, decreased the loading of MCM ring protein onto chromatin, and therefore inhibited DNA replication. Our study reveals for the first time that DDX59 has an important role in lung cancer development through promoting DNA replication. PMID- 28090356 TI - Long noncoding RNA: noncoding and not coded. PMID- 28090357 TI - Effects of a Home-Based Family-Centred Early Habilitation Program on Neurobehavioural Outcomes of Very Preterm Born Infants: A Retrospective Cohort Study. AB - Preterm children have an increased risk of neurodevelopmental impairments which include psychomotor and language retardation. The objectives of the present retrospective cohort study were to examine the effects of an individually adapted, home-based, and family-centred early developmental habilitation program on neurodevelopmental and behavioural outcomes of very preterm children compared with a standard follow-up at 2 years' corrected age. Enrolled infants were retrospectively assigned to the intervention group (61 subjects) or to the control group (62 subjects) depending on whether they had or had not carried out a home-based family-centred early developmental habilitation program focused on environmental enrichment, parent-guided environmental interaction, and infant development. Developmental outcome was assessed for both groups at 24 months' corrected age using the Bayley Scales of Infant Development 2nd Edition. Intervention significantly improved both cognitive and behavioural outcomes. In addition, males had significantly lower scores than females either before or after treatment. However, the treatment was effective in both genders to the same extent. In conclusion, a timely updated environment suitable to the infant's developmental needs could provide the best substrate where the parent-infant relationship can be practised with the ultimate goal of achieving further developmental steps. PMID- 28090358 TI - Merging and Fractionation of Muscle Synergy Indicate the Recovery Process in Patients with Hemiplegia: The First Study of Patients after Subacute Stroke. AB - Loss of motor coordination is one of the main problems for patients after stroke. Muscle synergy is widely accepted as an indicator of motor coordination. Recently, the characteristics of muscle synergy were quantitatively evaluated using nonnegative matrix factorization (NNMF) with surface electromyography. Previous studies have identified that the number and structure of synergies were associated with motor function in patients after stroke. However, most of these studies had a cross-sectional design, and the changes in muscle synergy during recovery process are not clear. In present study, two consecutive measurements were conducted for subacute patients after stroke and the change of number and structure of muscle synergies during gait were determined using NNMF. Results showed that functional change did not rely on number of synergies in patients after subacute stroke. However, the extent of merging of the synergies was negatively associated with an increase in muscle strength and the range of angle at ankle joint. Our results suggest that the neural changes represented by NNMF were related to the longitudinal change of function and gait pattern and that the merging of synergy is an important marker in patients after subacute stroke. PMID- 28090359 TI - Inhibition of the cAMP/PKA/CREB Pathway Contributes to the Analgesic Effects of Electroacupuncture in the Anterior Cingulate Cortex in a Rat Pain Memory Model. AB - Pain memory is considered as endopathic factor underlying stubborn chronic pain. Our previous study demonstrated that electroacupuncture (EA) can alleviate retrieval of pain memory. This study was designed to observe the different effects between EA and indomethacin (a kind of nonsteroid anti-inflammatory drugs, NSAIDs) in a rat pain memory model. To explore the critical role of protein kinase A (PKA) in pain memory, a PKA inhibitor was microinjected into anterior cingulate cortex (ACC) in model rats. We further investigated the roles of the cyclic adenosine monophosphate (cAMP), PKA, cAMP response element-binding protein (CREB), and cAMP/PKA/CREB pathway in pain memory to explore the potential molecular mechanism. The results showed that EA alleviates the retrieval of pain memory while indomethacin failed. Intra-ACC microinjection of a PKA inhibitor blocked the occurrence of pain memory. EA reduced the activation of cAMP, PKA, and CREB and the coexpression levels of cAMP/PKA and PKA/CREB in the ACC of pain memory model rats, but indomethacin failed. The present findings identified a critical role of PKA in ACC in retrieval of pain memory. We propose that the proper mechanism of EA on pain memory is possibly due to the partial inhibition of cAMP/PKA/CREB signaling pathway by EA. PMID- 28090360 TI - Neurosteroids Involvement in the Epigenetic Control of Memory Formation and Storage. AB - Memory is our ability to store and remember past experiences; it is the result of changes in neuronal circuits of specific brain areas as the hippocampus. During memory formation, neurons integrate their functions and increase the strength of their connections, so that synaptic plasticity is improved and consolidated. All these processes recruit several proteins at the synapses, whose expression is highly regulated by DNA methylation and histone tails posttranslational modifications. Steroids are known to influence memory process, and, among them, neurosteroids are implicated in neurodegenerative disease related to memory loss and cognitive impairment. The epigenetic control of neurosteroids involvement in memory formation and maintenance could represent the basis for neuroregenerative therapies. PMID- 28090361 TI - Effect of Endolymphatic Hydrops on Sound Transmission in Live Guinea Pigs Measured with a Laser Doppler Vibrometer. AB - Objective. This study aimed at describing the mechanism of hearing loss in low frequency and the different dynamic behavior of the umbo, the stapes head, and the round window membrane (RWM) between normal guinea pigs and those with endolymphatic hydrops (EH), using a laser Doppler vibrometer (LDV). Methods. Cochlear sections were stained with hematoxylin and eosin (HE) to evaluate the hydropic ratio (HR). Auditory brainstem responses (ABR) and whole-mount immunostaining were measured. Displacement of the umbo, stapes head, and RWM in response to ear-canal sound was evaluated using a LDV. Results. Mean HR values in EH model of all the turns are larger than the control group. The ABR threshold of the EH group was significantly higher than that of the control. Strong positive correlation was found between HR at apical turn and ABR threshold elevation at 1000 Hz and at subapical turn and ABR threshold elevation at 2000 Hz. FITC phalloidin immunostaining of the cochlear basilar membrane in the apical, subapical, and suprabasal turns showed missing and derangement stereocilia of third-row outer hair cells. The umbo, stapes head, and RWM displacement in ears with EH was generally lower than that of normal ears. The EH-induced differences in stapes head and RWM motion were significant at 0.5 kHz. Conclusion. The LDV results suggested that the higher inner ear impedance in EH affected the dynamic behavior of the two opening windows of the cochlea and then reduced the vibration of the ossicular chain by increasing the afterload, resulting in acoustic dysfunction. The vibration reduction mainly occurred at low frequencies, which has related with the morphology changes of the apical and subapical turns in EH model. PMID- 28090362 TI - A Large Left Ventricle Myxoma: Presenting with Epigastric Pain and Weight Loss. AB - Cardiac myxomas are the most common benign tumors found in the heart. They usually appear in the left atrium. Those originating from the left ventricle (LV) are rare. Although clinical presentation may vary, dyspnea and embolism are the most commonly reported symptoms. In the present case study, a 27-year-old woman with a large myxoma originating from the left ventricular free wall is studied. She had atypical complaints, mainly epigastric discomfort, nausea, vomiting, and anorexia. She was hospitalized for acute abdomen, but subsequent investigations revealed a large myxoma that fully filled the LV and severely compromised the flow of the aortic and mitral valves. After successful emergency tumor resection, all symptoms disappeared. The uncommon presentation caused by these tumors is discussed in this study. PMID- 28090363 TI - Abdominal Massage for the Relief of Constipation in People with Parkinson's: A Qualitative Study. AB - Objectives. To explore the experiences of people with Parkinson's (PwP) who suffer from constipation, the impact this has on their lives, and the effect of using lifestyle changes and abdominal massage as a form of constipation management. Method. Fourteen semistructured interviews were completed (8 males and 6 females; mean age 72.2 years) at the end of a care programme, which consisted of either lifestyle advice and abdominal massage (intervention group; n = 7) or lifestyle advice only (control group; n = 7). Data were analysed using constant-comparison techniques and Framework methods. Themes and key quotes were identified to depict major findings. Findings. Four key themes were identified: (i) the adverse impact of bowel problems on quality of life; (ii) positive experience of behaviour adjustments: experimentation; (iii) abdominal massage as a dynamic and relaxing tool: experiential learning (intervention group only); (iv) abdominal massage as a contingency plan: hesitation (control group only). Constipation was reported as having a significant impact on quality of life. Participants in both groups perceived lifestyle advice to relieve symptoms. Specific improvements were described in those who also received the abdominal massage. Conclusions. Both lifestyle advice and abdominal massage were perceived to be beneficial in relieving symptoms of constipation for PwP. PMID- 28090364 TI - Participation in Cancer Clinical Trials: Researching the Causes of Low Accrual. PMID- 28090365 TI - Nurse Communication About Goals of Care. AB - Conversations about goals of care with the patient and family are a critical component of advanced practice in oncology. However, there are often inadequate team structures, training, or resources available to assist advanced practitioners in initiating these conversations. We conducted a study to assess nurses' perceived role and communication tasks in such conversations about goals of care. In a cross-sectional survey of 109 nurses attending a comprehensive 2 day end-of-life nursing education course, nurses were asked to describe how they would participate in a "goals of care" meeting in three different scenarios. They were also asked what changes they desired in their clinical settings. Nurses overwhelmingly described that their primary task and communication role was to assess patient/family understanding. Nurses referenced their team members and team support with the least frequency across scenarios. Team roles, structure, and process were reported as areas in greatest need of change in patient/family goals of care meetings. These findings demonstrate that lack of preparation to function as a team is a barrier for nurses in communicating about goals of care, and there is a demand to move such conversations upstream in oncology care. PMID- 28090366 TI - Bosutinib Therapy in Patients With Chronic Myeloid Leukemia: Practical Considerations for Management of Side Effects. AB - The past decade has witnessed great advances in the treatment of chronic myeloid leukemia (CML), brought about in large part by the development of BCR-ABL tyrosine kinase inhibitors (TKIs). Bosutinib joins the armamentarium of approved TKIs for the treatment of chronic phase (CP), accelerated phase (AP), and blast phase (BP) Philadelphia chromosome (Ph)-positive CML resistant to or intolerant of prior therapy. Bosutinib has an adverse-event (AE) profile distinct from that of other TKIs. Diarrhea is the predominant toxicity associated with bosutinib treatment; other commonly reported nonhematologic AEs include rash and liver enzyme elevations. Cardiac events, fluid retention, and electrolyte abnormalities are infrequent. Optimal response to bosutinib requires adherence, which depends, in part, upon optimal management of associated toxicities. The oncology clinician can facilitate this process by providing patient education, timely patient follow up, and close monitoring to promptly identify and manage AEs. Thus, optimal patient management requires a thorough and current understanding of toxicity profiles and AE management paradigms. This review provides an overview of bosutinib safety data derived from ongoing clinical trials and offers practical clinical strategies currently used to manage toxicities associated with bosutinib treatment in patients with Ph-positive CP, AP, and BP CML. PMID- 28090367 TI - Novel Uses for Lipid-Lowering Agents. AB - Statin use leads to a reduction in the downstream products of the mevalonate pathway. Knowledge of this pathway has led scientists to investigate the role of statins in cancer prevention and treatment. Statins appear to possess a variety of pleiotropic effects, including inhibition of cell proliferation; enhanced apoptosis; and modulation of inflammation, endothelial function, and angiogenesis. In cancer specifically, experimental studies have found that statins may induce cancer cell apoptosis and inhibit tumor growth, angiogenesis, and metastasis. These mechanisms have steered researchers into evaluating the possible benefit of statins in the prevention and treatment of malignancies. This review will discuss the literature supporting the use of statins to prevent and treat cancer. PMID- 28090368 TI - Applying Metrics to Outpatient Oncology Advanced Practice Providers. PMID- 28090370 TI - Nivolumab in Metastatic Non-Small Cell Lung Cancer. PMID- 28090369 TI - Belinostat for Relapsed or Refractory Peripheral T-Cell Lymphoma. PMID- 28090371 TI - A Case-Based Look at Healthy Weight Loss for Survivors of Cancer. PMID- 28090372 TI - E-Cigarettes: Are They as Safe as the Public Thinks? PMID- 28090373 TI - hGBP-1 Expression Predicts Shorter Progression-Free Survival in Ovarian Cancers, While Contributing to Paclitaxel Resistance. AB - Ovarian cancer is the gynecological cancer with the poorest prognosis. One significant reason is the development of resistance to the chemotherapeutic drugs used in its treatment. The large GTPase, hGBP-1, has been implicated in paclitaxel resistance in ovarian cell lines. Forced expression of hGBP-1 in SKOV3 ovarian cancer cells protects them from paclitaxel-induced cell death. However, prior to this study, nothing was known about whether hGBP-1 was expressed in ovarian tumors and whether its expression correlated with paclitaxel resistance. hGBP-1 is expressed in 17% of ovarian tumors from patients that have not yet received treatment. However, at least 80% of the ovarian tumors that recurred after therapies that included a tax-ane, either paclitaxel or docetaxel, were positive for hGBP-1. In addition, hGBP-1 expression predicts a significantly shorter progression-free survival in ovarian cancers. Based on these studies, hGBP-1 could prove to be a potential biomarker for paclitaxel resistance in ovarian cancer. PMID- 28090374 TI - Neurophysiological Measures and Alcohol Use Disorder (AUD): Hypothesizing Links between Clinical Severity Index and Molecular Neurobiological Patterns. AB - BACKGROUND: In 1987, Cloninger proposed a clinical description and classification of different personality traits genetically defined and independent from each other. Moreover, he elaborated a specific test the TCI to investigate these traits/states. The study of craving in Alcohol Use Disorder (AUD) assumed a greater significance, since ever more data seems to suggest a direct correlation between high levels of craving and a higher risk of relapse in alcoholics. Thus, our study aim is to explore the possible correlations among TCI linked molecular neurobiological pattern (s), craving and alcohol addiction severity measures in a sample of Italian alcoholics. MATERIALS AND METHODS: 191 alcoholics were recruited in a Day Hospital (DH) setting at the Alcohol Addiction Program Latium Region Referral Center, Sapienza University of Rome. After 7 days detoxification treatment a psychodiagnostic protocol was administered, including TCI, VAS-C, ASI and SADQ. All patients signed an Institutional Review Board (IRB) approved informed consent. RESULTS: Principally, we detected a significant positive correlation between HA-scale scores and the VAS scale: increasing in HA-scale corresponds to an increase in craving perception for both intensity (r=0.310; p <= 0.001) and frequency (r=0.246; p <= 0.001). Moreover, perception of dependence severity, measured with SADQ was also found to be significantly associated positively to both HA-scale (r=0.246; p <= 0.001) and NS-scale (r=0.224; p <= 0.01). While, for character scales, Persistence (r=-0.195; p=.008) and Self directedness (r=-0.294; p <= 0.001) was negatively associated with ASI linked to alcohol problems. Self-directedness was also negatively correlated with ASI linked to family and social problems (r=-0.349; p <= 0.001), employment and support problems (r=-0.220; p=0.003) and psychiatric problems (r=-0.358; p <= 0.001). Cooperativeness was a negative correlate with Legal Problems (r=-0.173; p=0.019). and Self-Transcendence was positive correlated with Medical Problems (r=0.276; p <= 0.001). CONCLUSIONS: In view of recent addiction neurobiological theories, such as the "Reward Deficiency Syndrome (RDS)" and the Koob model, our data could suggest that our cohort of patients could possibly be in a particular stage of the course of their addiction history. Thus, if our hypothesis will be confirmed, the TCI-based assessment of alcoholics would allow an optimization of the treatment. Clinicians understanding these newer concepts will be able to translate this information to their patients and potentially enhance clinical outcome (s), because it could suggest a functional hypothesis of neurotransmitter circuits that helps to frame the patient in his/her history of addiction. PMID- 28090375 TI - Autologous Bone Marrow Transplantation in Multiple Sclerosis: Biomarker Relevance for Patient Recruitment and Follow up. AB - BACKGROUND: Despite the current availability of disease modifying therapies for the treatment of multiple sclerosis, there are still patients who suffer from severe neurological dysfunction in the relapsing-remitting or early progressive forms of the disease. For these patients autologous hematopoietic stem cell transplant offers an important therapeutic solution to prevent progression to irreversible disability. In spite of multiple studies in the last two decades, patient inclusion criteria, protocols for peripheral blood stem cell mobilization and bone marrow cell conditioning and methodology of follow up for autologous hematopoietic stem cell transplant in multiple sclerosis have not been strictly unified. METHODS: We reviewed five recent clinical studies that confirmed the positive outcome of transplant in spite of disclosing significant differences in methodology of enrollment including patient disease subtypes, disease duration range, disability, regimens of peripheral blood stem cell mobilization and bone marrow cell conditioning, scheduling of imaging studies after transplant, and absence of laboratory biomarkers consistently applied to these studies. RESULTS: Therapy with autologous hematopoietic stem cell transplant has shown best results among young individuals with severe relapsing-remitting or early progressive disease through its ability to maintain no evidence of disease activity status in a significantly higher proportion of patients after transplant in comparison to patients treated with disease modifying therapies. Important cross-sectional differences in the reviewed studies were found. CONCLUSION: A specific and careful selection of biomarkers, based on the current physiopathological mechanisms known to result in multiple sclerosis, will contribute to a better and earlier patient selection for autologous hematopoietic stem cell transplant and follow up process. An objective and measurable response could be obtained with the determination of biomarkers at the onset of treatment and after follow-up on reconstitution of the immune response. The application of such parameters could also help further our understanding of pathogenesis of the disease. PMID- 28090376 TI - First-principles investigation on elastic and thermodynamic properties of Pnnm-CN under high pressure. AB - The elastic anisotropy and thermodynamic properties of the recently synthesized Pnnm-CN have been investigated using first-principles calculations under high temperature and high pressure. The calculated equilibrium crystal parameters and normalized volume dependence of the resulting pressure agree with available experimental and theoretical results. Within the considered pressure range of 0 90 GPa, the dependences of the bulk modulus, Young's modulus, and shear modulus on the crystal orientation for Pnnm-CN have been systematically studied. The results show that the Pnnm-CN exhibits a well-pronounced elastic anisotropy. The incompressibility is largest along the c-axis. For tension or compression loading, the Pnnm-CN is stiffest along [001] and the most obedient along [100] direction. On the basis of the quasi-harmonic Debye model, we have explored the Debye temperature, heat capacity, thermal expansion coefficient, and Gruneisen parameters within the pressure range of 0-90 GPa and temperature range of 0 1600K. PMID- 28090377 TI - Ordered orthology as a tool in prokaryotic evolutionary inference. AB - Molecular data is accumulated at exponentially increasing pace. This deluge of information should have brought us closer to resolving one of the most fundamental issues in biology - deciphering the history of life on Earth. So far, however, this abundance of data only seems to blur our understanding of the problem. This is largely due to horizontal gene transfer (HGT), the transfer of genetic material between evolutionarily unrelated organisms that transforms the prokaryotic tree into a network of relationships. Recently, we developed a method to infer evolutionary relationships among closely related species where the conventional evolutionary markers do not provide a strong enough signal. The method relies on the loss of synteny, gene order conservation among species that provides a stronger signal, sufficient to classify even strains of a given species. Here we elaborate on this method and suggest further uses of it in the context of detecting HGT events and genome architecture. PMID- 28090378 TI - Transposon for protein engineering. AB - Protein insertional fusion and circular permutation are 2 promising protein engineering techniques for creating integrated functionalities and sequence diversity of a protein, respectively. Finding insertion locations for protein insertional fusion and new termini for circular permutation through a rational approach is not always straightforward, especially, for proteins without detailed structural knowledge. On the contrary, a combinatorial approach facilitates a comprehensive search to evaluate all potential insertion sites and new termini locations. Conventional methods used to create random insertional fusion libraries generate sub-optimal inter-domain linker length and composition between fused proteins. There are also methods available for construction of random circular permutation libraries. However, these methods too, impose many drawbacks, such as significant sequence modification at the new termini of circular permutants and additionally, require re-design of transposons for tailored expression of circular permutants. Furthermore, these conventional methods employ relatively inefficient blunt-end ligation during library construction. In this commentary, we present a concise overview and key findings of engineered Mu transposons, which have recently been developed in our group as a facile and efficient tool to alleviate limitations realized from conventional methods and to construct high quality libraries for random insertional fusion and random circular permutation. PMID- 28090379 TI - Genome wide occurrence and insertion preferences of INGI/RIME and SLACS CRE transposable elements in Trypanosoma brucei. AB - Retrotransposons play significant role in genome remodelling of T. brucei and about 5% of its genome consists of retrotransposons including INGI/RIME elements. INGI is one of the dispersed repetitive elements in T. brucei genome which is found distributed throughout all the chromosomes. SLACS (Spliced Leader Associated Conserved Sequence) however, is more conserved in its nature and lacks the typical poly-distributional pattern of LINE like transposons. We have found total 589 copies of these TEs with only 17.06 % (104 copies out of 589) copies with both ends intact thus showing a majority of truncated copies. Complete SLACS CRE were found only on chromosome 9, whereas, complete INGI/RIME were more ubiquitously distributed. The 50 - 70 bp upstream flanking sequence of these elements shows suitable nucleotide biophysical properties to favor transposition. PMID- 28090380 TI - Transposable elements and circular DNAs. AB - Circular DNAs are extra-chromosomal fragments that become circularized by genomic recombination events. We have recently shown that yeast LTR elements generate circular DNAs through recombination events between their flanking long terminal repeats (LTRs). Similarly, circular DNAs can be generated by recombination between LTRs residing at different genomic loci, in which case the circular DNA will contain the intervening sequence. In yeast, this can result in gene copy number variations when circles contain genes and origins of replication. Here, I speculate on the potential and implications of circular DNAs generated through recombination between human transposable elements. PMID- 28090381 TI - LTRclassifier: A website for fast structural LTR retrotransposons classification in plants. AB - Automatic classification of LTR retrotransposons is a big challenge in the area of massive genomics. Many tools were developed to detect them but automatic classification is somehow challenging. Here we propose a simple approach, LTRclassifier, based on HMM recognition followed by BLAST analyses (i) to classify plant LTR retrotransposons in their respective superfamily, and (ii) to provide automatically a basic functional annotation of these elements. The method was tested on various TE databases, and shown to be robust and fast. This tool is available as a web service implemented at IRD bioinformatics facility, http://LTRclassifier.ird.fr/. PMID- 28090382 TI - Conjugative transmission of antibiotic-resistance from stream water Escherichia coli as related to number of sulfamethoxazole but not class 1 and 2 integrase genes. AB - A conjugation assay was used to determine the effects of phenotypic resistance to one to up to 5 antibiotics, sampling site of origin, presence or absence of class 1 and/or class 2 integrase (intI) genes (intI1 and intI2), and the number of sulfamethoxazole resistance (sul) and trimethoprim resistance (dfr) genes on the transfer frequencies of plasmids from environmental, antibiotic-resistant Escherichia coli. Of 51 sulfamethoxazole and trimethoprim-resistant E. coli isolates conferring at least one mob gene (mobP51, mobF11, mobF12, mobQ11, mobQ12 , or mobQu ), 38 produced transconjugants with an overall mean frequency of 1.60 * 10-3 transconjugants/ donors (T/D) or 5.89 * 10-3 transconjugants/recipients (T/R). The presence or absence of intI1 and intI2 and the presence or absence of different targeted dfr genes (dfrA1, dfrA8, dfrA12, dfrA14, dfrA17, and/or dfrB3) were not statistically related to plasmid transfer frequencies as determined by ANOVA (P >= 0.05). However, E. coli isolates recovered 2 km downstream of wastewater treatment plant effluent input, and those possessing resistance to 3 antibiotics had significantly greater plasmid transfer frequency than their counterparts when calculated as T/D (ANOVA followed by Fisher's least significant difference means comparison, P < 0.05). Greater plasmid transfer frequency calculated as T/D was also measured for E. coli possessing 3 compared to a single sul gene. The in-vitro frequency suggests that horizontal gene transfer of conjugative mediated-antibiotic (sul) resistance genes may be significant among resistant, stream bacteria. PMID- 28090383 TI - The future of transposable element annotation and their classification in the light of functional genomics - what we can learn from the fables of Jean de la Fontaine? AB - Transposable element (TE) science has been significantly influenced by the pioneering ideas of David Finnegan near the end of the last century, as well as by the classification systems that were subsequently developed. Today, whole genome TE annotation is mostly done using tools that were developed to aid gene annotation rather than to specifically study TEs. We argue that further progress in the TE field is impeded both by current TE classification schemes and by a failure to recognize that TE biology is fundamentally different from that of multicellular organisms. Novel genome wide TE annotation methods are helping to redefine our understanding of TE sequence origins and evolution. We briefly discuss some of these new methods as well as ideas for possible alternative classification schemes. Our hope is to encourage the formation of a society to organize a larger debate on these questions and to promote the adoption of standards for annotation and an improved TE classification. PMID- 28090384 TI - Phagebiotics in treatment and prophylaxis of healthcare-associated infections. AB - We have developed a phagebiotic composition using 8 virulent bacteriophages (2 strains of each species) which are able to lyse Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus. The unique character of the developed composition is ensured by particular properties of each bacteriophage comprising the preparation, including their range of lytic activity toward specific bacterial pathogens, morphology of their plaques, cycle of their development, restriction profile of their DNAs, specificity of their genomes (based on complete genome sequencing), and other properties. The preparation did not produce any signs of acute or chronic intoxication in the experimental animals. Therapeutic and prophylactic efficiency of the phagebiotic composition was demonstrated in the prevention and treatment of the experimental acute K. pneumoniae infection in mice. The investigations have shown that the preparation possesses a high therapeutic efficiency and is highly competitive with ciprofloxacin which is very effective against the infective strain K. pneumoniae. Our small-scale clinical trial was aimed to evaluate therapeutic effectiveness of the phagebiotic composition in an epidemiological emergency situation in an intensive care unit, caused by multi-resistant strains of Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. Seventy nine per cent of the initial samples from 14 patients' endotracheal aspirate, blood and urine were contaminated. Twenty-four hours after the 3-day phage therapy (20 ml of cocktail at a titer for each phage 108 pfu/ml were introduced intragastrically through a tube once a day) contamination level dropped to 21%. Hence the obtained results enabled us to create a new phagebiotic composition that may be used as an alternative to antibiotics to treat these healthcare-associated infections. PMID- 28090385 TI - Fecal microbiota transplantation to fight Clostridium difficile infections and other intestinal diseases. AB - We have analyzed fecal bacterial and viral communities of a patient with recurrent C. difficile infection (rCDI) who was cured by fecal microbiota transplantation (FMT). The "Zurich Patient" experienced immediate cure and has remained free of symptoms for now over 5 y. Donor-similar bacterial compositions after 4.5 y post-FMT demonstrated sustainable engraftment of donor microbiota predominated by Bacteroidetes and Firmicutes bacteria. Appearance of beneficial species Faecalibacterium prausnitzii and Akkermansia municiphila was detected while disease-related Proteobacteria decreased. Stabilization of the microbiota took longer than expected from the rapidly improving clinical symptoms, suggesting the need for longer-lasting patient observation. The virome was mainly composed of Caudovirales bacteriophages but surprisingly also contained sequences related to a Chlorella giant virus that normally infects green algae not known to inhabitate the human intestine. FMT is highly effective against rCDI and is presently broadening its application to other conditions including inflammatory bowel disease (IBD). Here, we discuss the prospects and challenges of FMT against rCDI and other indications including a focus on bacteriophages. PMID- 28090386 TI - Structural proteins of Enterococcus faecalis bacteriophage phiEf11. AB - phiEf11, a temperate Siphoviridae bacteriophage, was isolated by induction from a root canal isolate of Enterococcus faecalis. Sequence analysis suggested that the phiEf11 genome included a contiguous 8 gene module whose function was related to head structure assembly and another module of 10 contiguous genes whose products were responsible for tail structure assembly. SDS-PAGE analysis of virions of a phiEf11 derivative revealed 11 well-resolved protein bands. To unify the deduced functional gene assignments emanating from the DNA sequence data, with the structural protein analysis of the purified virus, 6 of the SDS-PAGE bands were subjected to mass spectrometry analysis. 5 of the 6 protein bands analyzed by mass spectrometry displayed identical amino acid sequences to those predicted to be specified by 4 of the ORFs identified in the phiEf11 genome. These included: ORF8 (predicted scaffold protein), ORF10 (predicted major head protein), ORF15 (predicted major tail protein), and ORF23 (presumptive antireceptor). PMID- 28090387 TI - Testing a proposed paradigm shift in analysis of phage DNA packaging. AB - We argue that a paradigm shift is needed in the analysis of phage DNA packaging. We then test a prediction of the following paradigm shift-engendering hypothesis. The motor of phage DNA packaging has two cycles: (1) the well-known packaging ATPase-driven (type 1) cycle and (2) a proposed back-up, shell expansion/contraction-driven (type 2) cycle that reverses type 1 cycle stalls by expelling accidentally packaged non-DNA molecules. We test the prediction that increasing the cellular concentration of all macromolecules will cause packaging active capsids to divert to states of hyper-expansion and contraction. We use a directed evolution-derived, 3-site phage T3 mutant, adapted to propagation in concentrated bacterial cytoplasm. We find this prediction correct while discovering novel T3 capsids previously obscure. PMID- 28090388 TI - Felix Hubert d'Herelle (1873-1949): History of a scientific mind. AB - The discovery of bacteriophage one century ago by the French-Canadian Felix d'Herelle set off controversies as to the nature of bacteriophage as well as over the priority and credit for this discovery. The background and life of d'Herelle reveals a complex, self-taught outsider in science who was strongly influenced by his admiration of Louis Pasteur, but also his attachment to the philosophical positions of early 17th century philosophers, especially Francis Bacon. D'Herelle left substantial unpublished writings on his philosophical musings toward the end of his life. PMID- 28090389 TI - Erratum. AB - [This corrects the article DOI: 10.1080/21597081.2015.1086500.]. PMID- 28090390 TI - My scientific life. PMID- 28090391 TI - Neurotoxin-Induced Catecholaminergic Loss in the Colonic Myenteric Plexus of Rhesus Monkeys. AB - OBJECTIVE: Constipation is a common non-motor symptom of Parkinson's disease (PD). Although pathology of the enteric nervous system (ENS) has been associated with constipation in PD, the contribution of catecholaminergic neurodegeneration to this symptom is currently debated. The goal of this study was to assess the effects of the neurotoxin 6-hydroxydopamine (6-OHDA) on the colonic myenteric plexus and shed light on the role of catecholaminergic innervation in gastrointestinal (GI) function. METHODS: Proximal colon tissue from 6-OHDA treated (n=5) and age-matched control (n=5) rhesus monkeys was immunostained and quantified using ImageJ software. All animals underwent routine daily feces monitoring to assess for constipation or other GI dysfunction. RESULTS: Quantification of tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC)-immunoreactivity (-ir) revealed significant reduction in myenteric ganglia of 6-OHDA-treated animals compared to controls (TH-ir: 87.8%, P<0.0001; AADC-ir: 61.7% P=0.0034). Analysis of pan-neuronal markers (PGP9.5, HuC/D), other neurochemical phenotypes (VIP, nNOS), PD-associated pathology proteins (alpha-synuclein, phosphorylated alpha-synuclein), glial marker GFAP and neuroinflammation and oxidative stress (HLA-DR, CD45, Nitrotyrosine) did not show significant differences. Monitoring of feces revealed frequent (>30% days) soft stool or diarrhea in 2 of the 5 6-OHDA-treated animals and 0 of the 5 control animals during the 2 months prior to necropsy, with no animals exhibiting signs of constipation. CONCLUSION: Systemic administration of 6-OHDA to rhesus monkeys significantly reduced catecholaminergic expression in the colonic myenteric plexus without inducing constipation. These findings support the concept that ENS catecholaminergic loss is not responsible for constipation in PD. PMID- 28090392 TI - New immunotherapeutic paradigms for castration-resistant prostate cancer. PMID- 28090393 TI - SKN-1-independent transcriptional activation of glutathione S-transferase 4 (GST 4) by EGF signaling. AB - In C. elegans research, transcriptional activation of glutathione S-transferase 4 (gst-4) is often used as a read-out for SKN-1 activity. While many heed an assumed non-exclusivity of the GFP reporter signal driven by the gst-4 promoter to SKN-1, this is also often ignored. We here show that gst-4 can also be transcriptionally activated by EOR-1, a transcription factor mediating effects of the epidermal growth factor (EGF) pathway. Along with enhancing exogenous oxidative stress tolerance, EOR-1 inde-pendently of SKN-1 increases gst-4 transcription in response to augmented EGF signaling. Our findings caution researchers within the C. elegans community to always rely on sufficient experimental controls when assaying SKN-1 transcriptional activity with a gst 4p::gfp reporter, such as SKN-1 loss-of-function mutants and/or additional target genes next to gst-4. PMID- 28090394 TI - GExplore 1.4: An expanded web interface for queries on Caenorhabditis elegans protein and gene function. AB - Genetic high-throughput experiments often result in hundreds or thousands of genes satisfying certain experimental conditions. Grouping and prioritizing a large number of genes for further analysis can be a time-consuming challenge. In 2009 we developed a web-based user interface, GExplore, to assist with large scale data-mining related to gene function in Caenorhabditis elegans. The underlying database contained information about Caenorhabditis elegans genes and proteins including domain organization of the proteins, phenotypic descriptions, expression data and Gene Ontology Consortium annotations. These data enable users to quickly obtain an overview of biological and biochemical functions of a large number of genes at once. Since its inception the underlying database has been updated and expanded significantly. Here we describe the current version of GExplore 1.4, documenting the changes since the original release. GExplore 1.4 now contains information about the domain organization of the proteomes of 9 nematode species, can display the location of Caenorhabditis elegans mutations with respect to the domain organization of the proteins, and includes stage specific RNAseq gene expression data generated by the modENCODE project. The underlying database has been reorganized to facilitate independent updates of the different parts of the database and to allow the addition of novel data sets in the future. The web interface is available under http://genome.sfu.ca/gexplore. PMID- 28090395 TI - sta-1 is repressed by mir-58 family in Caenorhabditis elegans. AB - The miR-58 family comprises 6 microRNAs with largely shared functions, and with an overall high expression, because one of its members, miR-58, is the most abundant microRNA in Caenorhabditis elegans. We recently found that 2 TGF-beta signaling pathways, Sma/Mab and Dauer, responsible for body size and dauer formation respectively, among other phenotypes, are downregulated by the miR-58 family. Here, we further explore this family by showing that it also acts through the sta-1 3'UTR. sta-1 encodes a transcription factor, homologous to mammalian STATs, that inhibits dauer formation in association with the TGF-beta Dauer pathway. We also observe that mutants with a constitutively active TGF-beta Dauer pathway express higher levels of sta-1 mRNA. Our results reinforce the view of the miR-58 family and STA-1 as regulators of dauer formation in coordination with the TGF-beta Dauer pathway. PMID- 28090397 TI - Insights about Fall Prevention of Older Adults in the State of Hawai'i. AB - The senior population in Hawai'i is growing at a dramatic pace. In the older population, falls and fall-related injuries are leading causes of morbidity and mortality. Moreover, the health care costs for falls are very high. The State of Hawai'i has taken measures to prevent falls through the promotion of medication reviews, vision checks, home assessments, and exercise. However, current published examinations of fall preventive measures have been insufficient, and more research is needed to confirm risk factors, effectiveness of preventive measures, and to explore future objectives. This paper examined the validity of fall risk factors and fall preventive measures for Hawai'i's seniors by conducting mail questionnaire surveys to a sample of seniors using medical alert services from one company in Hawai'i. The results of chi-square analysis suggest that having reduced ability to perform Activities of Daily Living (ADL) and reduced Instrumental Activities of Daily Living (IADL) were associated with a greater risk of falls (P < .01). In addition, those who fell were more likely to talk about fall preventions with their family members or friends and health providers compared with those who did not (P = .048 and .003, respectively). Evidence-based exercise programs for strengthening muscles and controlling physical balance may be needed to improve ADL and IADL. Furthermore, the results suggest that seniors do not accept that they are at risk of falling before they actually fall. Public health providers should consider how they approach seniors, and how they inform them of the importance of fall prevention across the life span. PMID- 28090398 TI - Life Expectancies in Hawai'i: A Multi-ethnic Analysis of 2010 Life Tables. AB - The objective of this study is to examine longevity disparities in Hawai'i by race/ethnicity and gender based on age-specific death rates in 2010. Abridged life tables for Chinese, Japanese, Filipino, Hawaiians, and Caucasians in Hawai'i are presented for the age groups: <1, 1-4, every 5-year interval from 5-84, and 85+ years for the year of 2010. Death data were provided by the Hawai'i Department of Health Office of Health Status Monitoring, and population data were based on 2010 Census modified based on ethnicity estimates from the Hawai'i Health Survey. Life expectancy at birth in Hawai'i has increased consistently from 69.5 years in 1950 to 82.4 years in 2010. Longevity disparities seen in past decades continue to persist between the longest-living groups, Japanese and Chinese, and the shortest-living group, Native Hawaiians, with a gap of approximately 10 years. In addition, females lived 6 years longer than males on average. Racial/ethnic disparities in longevity can be partially explained by differences in socioeconomic status, health behaviors, health care access, and racism. Native Hawaiians continue to have the shortest life expectancy of the ethnic groups examined, requiring expanded efforts to address Native Hawaiian health across the life course. Our findings also support more ethnic-specific research to understand the health care needs and utilization patterns of each group. PMID- 28090399 TI - Breastfeeding in Samoa: A Study to Explore Women's Knowledge and the Factors which Influence Infant Feeding Practices. AB - A decline in breastfeeding rates in Samoa has been reported over the last century. To assess the length of time women breastfeed, their knowledge of both the advantages of and recommendations for breastfeeding, and the factors that influence their decisions to continue or discontinue breastfeeding, a questionnaire was distributed at Tupua Tamasese Meaole Hospital. One hundred and twenty-one eligible participants were included aged 18-50 years (mean age 28.2). Ninety percent of participants initiated breastfeeding, and the majority (78%) of babies were exclusively breastfed for at least the recommended 6 months. Many mothers introduced complementary (solid) foods later than World Health Organization (WHO) and United Nation's International Children's Fund (UNICEF) recommendations of 6 months. Awareness of the advantages of breastfeeding was mixed. The most widely known advantage was "the development of an emotional bond between mother and baby" (67%). Other advantages were less widely known. Only a small minority were aware that breastfeeding reduces risk of maternal diabetes and aids weight loss post partum. Doctors and healthcare workers were listed as the top factors encouraging breastfeeding. Participants' comments revealed a generally positive attitude towards breastfeeding, a very encouraging finding. Participants identified that the number of breastfeeding breaks available at work and the length of their maternity leave were factors discouraging breastfeeding. Future studies are necessary to determine if problems identified in this study are applicable on a national level. These could be important to determine measures to improve breastfeeding practices in Samoa. PMID- 28090400 TI - Medical School Hotline: Pacific Center for Emerging Infectious Diseases Research. PMID- 28090396 TI - Peers and Obesity during Childhood and Adolescence: A Review of the Empirical Research on Peers, Eating, and Physical Activity. AB - Obesity during childhood and adolescence is a growing problem in the United States, Canada, and around the world that leads to significant physical, psychological, and social impairment. In recent years, empirical research on factors that contribute to the development and maintenance of obesity has begun to consider peer experiences, such as peer rejection, peer victimization, and friendship. Peer experiences have been theoretically and empirically related to the "Big Two" contributors to the obesity epidemic, eating and physical activity, but there has not been a comprehensive review of the extant empirical literature. In this article, we review and synthesize the emerging theoretical and empirical literatures on peer experiences in relation to: (a) eating (food consumption and food selection); and (b) physical activity, during childhood and adolescence. A number of limitations and issues in the theoretical and empirical literatures are also discussed, along with future research directions. In conclusion, we argue that the involvement of children and adolescents' peer networks in prevention and intervention efforts may be critical for promoting and maintaining positive behavioral health trajectories. PMID- 28090401 TI - Insights in Public Health: Challenges Investigating Health Outcomes in Chinese Americans Using Population-Based Survey Data. AB - Chinese Americans constitute the largest percentage of Asian Americans. In Hawai'i, Chinese Americans make up approximately 4.7% of the total state population. Accurately assessing health disparities across specific Asian American subgroups is critically important to health research and policy, as there is often substantial variability in risk and outcomes. However, even for Chinese Americans, the largest of the Asian American subgroups, such analyses can present challenges in population-based surveys. This article considers these challenges generally and then specifically in terms of the issue of health literacy and heart disease in Chinese Americans using existing population-based survey data sets in the United States, California, and Hawai'i. PMID- 28090403 TI - A Review of the Relationship of Atrial Fibrillation and Acute Coronary Syndrome. AB - Atrial fibrillation (AF) is the most common arrhythmia encountered by clinicians. Clinical decision-making focuses on reducing ischemic stroke risk in AF patients; however, AF is also associated with an increased risk of acute coronary syndromes (ACS). Patients with ACS and concurrent AF are less likely to receive appropriate therapies and more likely to experience adverse outcomes than ACS patients in sinus rhythm (SR). Clinicians may be able to stratify ACS patients at increased risk of AF development based on clinical characteristics. Evidence supporting specific therapeutic options for prevention of ACS in AF patients or for prevention of AF in ACS patients is limited, however there is some evidence of differing effects among oral anticoagulant regimens in these populations. Investigations of the relationship of AF with the full spectrum of ACS are not well described and should be the focus of future research. PMID- 28090404 TI - Adolescents' stigma attitudes toward internalizing and externalizing disorders: Cultural influences and implications for distress manifestations. AB - OBJECTIVE: This study examined predictors of stigma attitudes toward common youth emotional behavioral problems to test the hypothesis that interdependent cultural values would be associated with differential stigma towards externalizing versus internalizing disorders. Furthermore, we examined whether problem-specific stigma attitudes would predict adolescent's own self-reported manifestations of distress. METHOD: 1224 Vietnamese American and European American adolescents completed measures of social distance stigma attitudes in response to vignettes depicting youth with internalizing (depression, social anxiety, somatization) and externalizing (alcohol use, aggressive behaviors, delinquency) disorders. A subset of 676 youth also provided self-reports on their own adjustment prospectively over six months. RESULTS: Measurement models revealed clear separation of negatively correlated factors assessing stigma toward externalizing versus internalizing problems. Values related to family interdependence were significantly associated with greater tolerance of internalizing disorders and lower tolerance of externalizing disorders. Stigma towards internalizing disorders was associated with lower concurrent self-reported internalizing symptoms, whereas stigma towards externalizing symptoms was associated with lower concurrent externalizing symptoms and greater decreases in externalizing symptoms over time. CONCLUSIONS: The results of the study suggest that stigma attitudes are differentiated by problem type and may represent one cultural factor shaping distress manifestations. PMID- 28090405 TI - Transcriptomic analysis of diplomonad parasites reveals a trans-spliced intron in a helicase gene in Giardia. AB - BACKGROUND: The mechanisms by which DNA sequences are expressed is the central preoccupation of molecular genetics. Recently, ourselves and others reported that in the diplomonad protist Giardia lamblia, the coding regions of several mRNAs are produced by ligation of independent RNA species expressed from distinct genomic loci. Such trans-splicing of introns was found to affect nearly as many genes in this organism as does classical cis-splicing of introns. These findings raised questions about the incidence of intron trans-splicing both across the G. lambliatranscriptome and across diplomonad diversity in general, however a dearth of transcriptomic data at the time prohibited systematic study of these questions. METHODS: I leverage newly available transcriptomic data from G. lamblia and the related diplomonad Spironucleus salmonicidato search for trans spliced introns. My computational pipeline recovers all four previously reported trans-spliced introns in G. lamblia, suggesting good sensitivity. RESULTS: Scrutiny of thousands of potential cases revealed only a single additional trans spliced intron in G. lamblia, in the p68 helicase gene, and no cases in S. salmonicida. The p68 intron differs from the previously reported trans-spliced introns in its high degree of streamlining: the core features of G. lamblia trans spliced introns are closely packed together, revealing striking economy in the implementation of a seemingly inherently uneconomical molecular mechanism. DISCUSSION: These results serve to circumscribe the role of trans-splicing in diplomonads both in terms of the number of genes effected and taxonomically. Future work should focus on the molecular mechanisms, evolutionary origins and phenotypic implications of this intriguing phenomenon. PMID- 28090407 TI - Development of 15 polymorphic microsatellite markers for Ficus virens (Moraceae). AB - PREMISE OF THE STUDY: Ficus virens (Moraceae) is distributed widely in South and Southeast Asia, Melanesia, and northern Australia, and it is also cultivated outside its original northern range limit in southwestern China. Therefore, the species is well suited to explore the mechanism of range limits of Ficus species. However, little is known about its genetic background. METHODS AND RESULTS: Fifteen polymorphic microsatellite markers were developed using the biotin streptavidin capture method. Polymorphism was tested in 85 F. virens individuals sampled from three populations. The number of alleles ranged from three to 17. The observed and expected heterozygosity of each population varied from 0.0667 to 0.9286 and 0.0650 to 0.8890, respectively. Cross-species amplification was also carried out in eight other Ficus species. CONCLUSIONS: These 15 markers will be valuable for studying the genetic variation and population structure of F. virens and related Ficus species. PMID- 28090406 TI - Leaf-disc grafting for the transmission of Candidatus Liberibacter asiaticus in citrus (Citrus sinensis; Rutaceae) seedlings. AB - PREMISE OF THE STUDY: The search for resistance/tolerance to the devastating citrus huanglongbing disease (syn. HLB or citrus greening) is generating an increasing number of new plants of diverse genetic makeup. As the increasing number of new plants require more space, resources, and time, the need for faster and more efficient HLB screening tests becomes crucial. METHODS AND RESULTS: The leaf-disc grafting system described here consists in replacing a disc of leaf tissue with a similar disc from an infected plant. This can be performed in young seedlings not yet big enough to endure other types of grafting. Graft success and infection rates average approximately 80%. CONCLUSIONS: We describe the successful adaptation of leaf-disc grafting as a powerful screening tool for HLB. The system requires minimal plant material and can be performed in seedlings at a very young age with increased efficiency in terms of time, space, and resources. PMID- 28090408 TI - Development of microsatellite markers for Viscum coloratum (Santalaceae) and their application to wild populations. AB - PREMISE OF THE STUDY: Microsatellite primers were developed for Viscum coloratum (Santalaceae), a semiparasitic medicinal plant that is known for its anticancer properties. Due to excessive human harvesting and loss of suitable habitat of its populations, it has become a potentially threatened species requiring immediate conservation efforts. METHODS AND RESULTS: Based on transcriptome data for V. coloratum, 124 primer pairs were randomly selected for initial validation, of which 19 yielded polymorphic microsatellite loci, with two to six alleles per locus. The usefulness of these markers was assessed for 60 individuals representing three populations of V. coloratum. Observed and expected heterozygosity values ranged from 0.033 to 0.833 and 0.032 to 0.672, respectively. Cross-species amplification for 19 loci in the related species V. album was conducted. CONCLUSIONS: The 19 newly developed loci are expected to be useful for studying the population genetics and ecological conservation of V. coloratum. PMID- 28090409 TI - Development and characterization of 23 microsatellite loci for Rhododendron ovatum (Ericaceae). AB - PREMISE OF THE STUDY: To estimate the genetic variation of Rhododendron ovatum (Ericaceae), a monoecious evergreen shrub, 23 microsatellite markers were identified from its nuclear genome. METHODS AND RESULTS: We developed 16 polymorphic and seven monomorphic microsatellite primers using the biotin streptavidin capture method. The 16 polymorphic loci were investigated further using 89 individuals sampled from three populations in China. The number of alleles per locus ranged from four to 30, indicating a high level of polymorphism. The observed heterozygosity varied from 0.1034 to 0.9333, while the expected heterozygosity ranged from 0.1016 to 0.9542. Of these polymorphic primers, 12 were found to be functional in R. simsii, a congeneric species of R. ovatum. CONCLUSIONS: Moderate to high levels of genetic variation were found in these microsatellite loci, indicating that they can be applied in future studies of Rhododendron genetic structure, contributing to forest management and conservation. PMID- 28090410 TI - Retrospective analysis of heavy metal contamination in Rhode Island based on old and new herbarium specimens. AB - PREMISE OF THE STUDY: Herbarium specimens may provide a record of past environmental conditions, including heavy metal pollution. To explore this potential, we compared concentrations of copper, lead, and zinc in historical and new collections from four sites in Rhode Island, USA. METHODS: We compared historical specimens (1846 to 1916) to congener specimens collected in 2015 at three former industrial sites in Providence, Rhode Island, and one nonindustrial site on Block Island. Leaf material was prepared by UltraWAVE SRC Microwave Digestion, and heavy metal concentrations were measured by inductively coupled plasma-atomic emission spectroscopy. RESULTS: Heavy metal concentrations in the historical and new specimens were measurable for all elements tested, and levels of copper and zinc were comparable in the historical and 2015 collections. By contrast, the concentration of lead declined at all sites over time. Significant variability in heavy metal concentration was observed between taxa, reflecting their varied potential for elemental accumulation. DISCUSSION: It seems clear that herbarium specimens can be used to evaluate past levels of pollution and assess local environmental changes. With careful sampling effort, these specimens can be a valuable part of environmental science research. Broadening the possible applications for herbarium collections in this way increases their relevance in an era of reduced funding for collections-based research. PMID- 28090411 TI - Development of SSR markers by 454 sequencing in the endemic species Gentianella praecox subsp. bohemica (Gentianaceae). AB - PREMISE OF THE STUDY: Polymorphic microsatellite loci were developed and used to genotype individuals of Gentianella praecox subsp. bohemica (Gentianaceae), a highly protected taxon in Europe, to study the genetic structure of the remaining populations. METHODS AND RESULTS: Thirty-eight primer pairs were successfully amplified; of these, 12 polymorphic microsatellite loci were developed using a 454 sequencing approach and used to genotype 180 individuals of G. praecox subsp. bohemica from six populations. Allelic richness ranged between one and nine alleles per locus. We detected a high frequency of polyploid individuals (77.8%). The highest average percentage of heterozygous genotypes was identified for samples from the Hroby population (75.5%). All loci can also be amplified in the congeneric species G. praecox subsp. praecox, G. amarella subsp. amarella, and G. obtusifolia subsp. sturmiana. CONCLUSIONS: These markers will provide knowledge on patterns of gene flow and population genetic structure, which is necessary for current protection actions and for effective conservation of this species in the future. PMID- 28090412 TI - Development, characterization, and cross-amplification of microsatellite markers in the understudied African genus Anthonotha (Fabaceae). AB - PREMISE OF THE STUDY: Anthonotha macrophylla (Fabaceae) is a common tree species throughout the Guineo-Congolian forest that is sometimes confounded with other congeneric species; it is expected to be an interesting phylogeographical model to infer the history of the African dense forests. We developed 18 microsatellite markers from this species and tested their transferability in 15 congeneric species. METHODS AND RESULTS: A genomic library was obtained using the Illumina platform, and 18 polymorphic microsatellite loci were developed. The polymorphic microsatellites displayed two to 24 alleles (average: 11.9 alleles per locus, expected heterozygosity range: 0.18-0.91, mean: 0.64) in three populations of A. macrophylla from Benin, Liberia, and Cameroon. Cross-amplification in one to nine individuals of 15 congeneric Anthonotha species (A. acuminata, A. brieyi, A. cladantha, A. crassifolia, A. ferruginea, A. fragrans, A. gilletii, A. lamprophylla, A. mouandzae, A. noldeae, A. pellegrinii, A. pynaertii, A. stipulacea, A. wijmacampensis, and A. xanderi) showed successful amplification in six to 17 loci, making most of these markers useful at the generic level. CONCLUSIONS: This set of markers will be useful to study species delimitation and the genetic structure of Anthonotha species, and thus to better understand the history of tropical African rainforests. PMID- 28090413 TI - Development of microsatellite markers in Garcinia paucinervis (Clusiaceae), an endangered species of karst habitats. AB - PREMISE OF THE STUDY: Microsatellite markers were developed for Garcinia paucinervis (Clusiaceae), an endangered and endemic tree species of karst habitats, to analyze its genetic diversity and genetic structure. METHODS AND RESULTS: Using shotgun sequencing on an Illumina MiSeq platform, a total of 22 microsatellite primer sets were characterized, of which 17 were identified as polymorphic. For these polymorphic loci, the total number of alleles per locus ranged from two to 12 across 54 individuals from three populations. The observed and expected heterozygosities ranged from 0.000 to 1.000 and from 0.000 to 0.850, respectively. No pair of loci showed significant linkage disequilibrium. Three loci in one population deviated significantly from Hardy-Weinberg equilibrium (P < 0.05). Seven loci (JSL3, JSL5, JSL22, JSL29, JSL32, JSL39, and JSL43) were successfully amplified in G. bracteata. CONCLUSIONS: These markers will be useful in studies on genetic diversity and population structure of G. paucinervis. PMID- 28090415 TI - Non-Melanoma-Associated Dyschromia of the Proximal Nail Fold. AB - Subungual melanoma with pigmentation beneath the nail that extends to involve the proximal nail fold is referred to as Hutchinson's sign. Black or brown subungual discoloration involving the proximal nail fold secondary to other etiologies has been referred to as pseudo-Hutchinson's sign. Three patients with nail discoloration and concurrent dyschromia of the proximal nail fold are described: a female with a chronic subungual hematoma and pseudo-Hutchinson's sign, a male with culture-confirmed Pseudomonas aeruginosa (P. aeruginosa) of the nail with green discoloration involving the proximal nail fold, and a male with an acute subungual hematoma with red-purple subungual discoloration affecting the proximal nail fold. PubMed was searched for the following: black, brown, chloronychia, discoloration, dyschromia, green, hematoma, Hutchinson's sign, nail, nail fold, proximal, pseudo-Hutchinson's sign, red, subungual melanoma, syndrome. The papers were reviewed and appropriate references evaluated. In conclusion, melanoma associated black proximal nail fold pigmentation is referred to as Hutchinson's sign, and non-melanoma-associated black pigmentation has been designated as pseudo-Hutchinson's sign. Subungual nail plate discoloration extending to involve the proximal nail fold may be black, green, or red-purple in patients with melanocytic and non-melanocytic lesions, bacterial infection (Pseudomonas), and acute subungual hematoma, respectively. Instead of creating a new terminology, we suggest that non-black subungual discoloration (green or red-purple) extending to involve the proximal nail fold be referred to as pseudo pseudo-Hutchinson's sign. PMID- 28090416 TI - Post-traumatic Arthritis of the Tarsometatarsal Joint Complex: A Case Report. AB - Tarsometatarsal (TMT) arthritis is characterized by instability and pain in the foot. The commonest cause is post-traumatic arthritis. A Lisfranc injury involves the articulation between the medial cuneiform and the base of the second metatarsal, which is considered a keystone to midfoot integrity. Neglected or undertreated injury to the Lisfranc joint complex leads to secondary arthritis and significant disability. We present a case of a young male patient with a two year-old neglected Lisfranc joint injury and secondary osteoarthritis of the first, second, and fourth TMT joints, which we treated surgically with arthrodesis using screws, with a good functional outcome on final follow-up. PMID- 28090417 TI - Pattern of Local Recurrence and Distant Metastasis in Breast Cancer By Molecular Subtype. AB - BACKGROUND AND PURPOSE: No longer considered a single disease entity, breast cancer is being classified into several distinct molecular subtypes based on gene expression profiling. These subtypes appear to carry prognostic implications and have the potential to be incorporated into treatment decisions. In this study, we evaluated patterns of local recurrence (LR), distant metastasis (DM), and association of survival with molecular subtype in breast cancer patients in the post-adjuvant radiotherapy setting. MATERIAL AND METHODS: The medical records of 1,088 consecutive, non-metastatic breast cancer patients treated at a single institution between 2004 and 2012 were reviewed. Estrogen/progesterone receptors (ER/PR) and human epidermal growth factor receptor-2 (HER2) enrichment were evaluated by immunohistochemistry. Patients were categorized into one of four subtypes: luminal-A (LA; ER/PR+, HER2-, Grade 1-2), luminal-B (LB; ER/PR+, HER2-, Grade > 2), HER2 over-expression (HER2; ER/PR-, HER2+), and triple negative (TN; ER/PR-, HER2-). Results: The median follow-up time was 6.9 years. During the follow-up, 16% (174/1,088) of patients failed initial treatment and developed either LR (48) or DM (126). The prevalence of LR was the highest in TN (12%) and the lowest in LA (2%). Breast or chest wall relapse was the most frequent site (~80%) of recurrence in LA, LB, and HER2 subtypes, whereas the regional lymph nodes and chest wall were the common sites of relapse in the TN group (50.0%). DM rates were 6.4% in LA, 12.1% in LB, 19.2% in HER2, and 27.4% in TN subgroups. Five-year survival rates were 84%, 83%, 84%, and 77% in the LA, LB, HER2 and TN subgroups, respectively. There was a statistically significant association between survival and molecular subtypes in an univariate analysis. In the adjusted multivariate analysis, the following variables were independent prognostic factors for survival: T stage, N stage, and molecular subtype. CONCLUSIONS: Of the four subtypes, the LA subtype tends to have the best prognosis, fairly high survival, and low recurrent or metastases rates. The TN and HER2 subtypes of breast cancer were associated with significantly poorer overall survival and prone to earlier recurrence and metastases. Our results demonstrate a significant association between molecular subtype and survival. The risk of death and relapse/metastases increases fewfold in TN compared to LA. Future prospective studies are warranted and could ultimately lead to the tailoring of adjuvant radiotherapy treatment fields based on both molecular subtype and the more conventional clinicopathologic characteristics. PMID- 28090418 TI - The Forgotten Lumbocostal Ligament: Anatomical Study with Application to Thoracolumbar Surgery. AB - INTRODUCTION: Most ligaments of the human body have been well studied. However, the lumbocostal ligament has received little attention in the extant medical literature and, to our knowledge, has not undergone anatomical study. Therefore, the present study was performed to better characterize this structure's anatomy and relationships. METHODS: In the prone position, 10 adult cadavers underwent dissection of their lumbocostal ligaments. All specimens were unembalmed and had no history of surgery to the spine. The lumbocostal ligament was dissected and measurements made using calipers and a ruler. This ligament's attachments were determined as well as its relationships to surrounding fasciae, muscle, and nerves. RESULTS: A lumbocostal ligament was identified on all sides. The ligament was posterior to the quadratus lumborum muscle on all sides. The mean length of the ligament was 3 cm. The overall shape of the ligaments ranged from short bands to large rhomboidal sheets. Inferiorly, the lumbocostal ligament blended with the middle layer of the thoracolumbar fascia on all sides. The ligament attached to the transverse processes of L1 on 25% of sides and onto the transverse processes of L1 and L2 on 75% of sides. The ligament became taut with rib elevation and was lax with rib depression. CONCLUSIONS: The lumbocostal ligament is a constant structure of the thoracolumbar junction. Appreciation of this ligament can help localize the transverse processes of L1 and L2 and adjacent nerves, such as the regional dorsal rami as they exit near its attachment onto the lumbar transverse processes. PMID- 28090419 TI - The eukaryotic translation initiation factor eIF4E wears a "cap" for many occasions. AB - The eukaryotic translation initiation factor eIF4E plays important roles in controlling the composition of the proteome. Indeed, dysregulation of eIF4E is associated with poor prognosis cancers. The traditional view has been that eIF4E acts solely in translation. However, over the last ~25 years, eIF4E was found in the nucleus where it acts in mRNA export and in the last ~10 years, eIF4E was found in cytoplasmic processing bodies (P-bodies) where it functions in mRNA sequestration and stability. The common biochemical thread for these activities is the ability of eIF4E to bind the 7-methylguanosine cap on the 5' end of mRNAs. Recently, the possibility that eIF4E directly binds some mRNA elements independently of the cap has also been raised. Importantly, the effects of eIF4E are not genome-wide with a subset of transcripts targeted depending on the presence of specific mRNA elements and context-dependent regulatory factors. Indeed, eIF4E governs RNA regulons through co-regulating the expression of groups of transcripts acting in the same biochemical pathways. In addition, studies over the past ~15 years indicate that there are multiple strategies that regulatory factors employ to modulate eIF4E activities in context-dependent manners. This perspective focuses on these new findings and incorporates them into a broader model for eIF4E function. PMID- 28090420 TI - The "periodic table" of the genetic code: A new way to look at the code and the decoding process. AB - Henri Grosjean and Eric Westhof recently presented an information-rich, alternative view of the genetic code, which takes into account current knowledge of the decoding process, including the complex nature of interactions between mRNA, tRNA and rRNA that take place during protein synthesis on the ribosome, and it also better reflects the evolution of the code. The new asymmetrical circular genetic code has a number of advantages over the traditional codon table and the previous circular diagrams (with a symmetrical/clockwise arrangement of the U, C, A, G bases). Most importantly, all sequence co-variances can be visualized and explained based on the internal logic of the thermodynamics of codon-anticodon interactions. PMID- 28090422 TI - Elevated levels of ribosomal proteins eL36 and eL42 control expression of Hsp90 in rhabdomyosarcoma. AB - Mammalian 90 kDa heat shock protein (Hsp90) is a ubiquitous molecular chaperone whose expression is selectively upregulated during stress, although the precise control mechanism of this increase is yet to be fully elucidated. We used polysome profiling to show that Hsp90alpha mRNA is selectively translated, while global translation is inhibited during heat stress. Furthermore, we have identified 2 ribosomal proteins, eL36 and eL42 that modulate Hsp90alpha expression under both normal and heat shock conditions. Importantly, we noted that expression of eL36 and eL42 is elevated in a panel of human rhabdomyosarcomas where it drives high expression of Hsp90 and modulates sensitivity of these cells to an Hsp90 inhibitor 17-AAG. PMID- 28090423 TI - Fusion proteins of Arabidopsis cap-binding proteins: Cautionary "tails" of woe. AB - The use of fluorescent proteins fused to other proteins has been very useful in revealing the location and function of many proteins. However, it is very important to show that the fusion of these reporter proteins does not impact the function of the protein of interest. Plants have 2 forms of the cap-binding protein that function in initiation of translation, eIF4E and a plant specific form, eIFiso4E. In an attempt to determine the cellular localization of eIFiso4E, fusions to GFP were made, but were found to not be competent to rescue the lethal phenotype of plants lacking eIF4E and eIFiso4E. This suggested that the GFP fusions at either the N- or C-terminus of eIFiso4E were not functional. Biochemical analysis of the fusions revealed that eIFiso4E*GFP fusions were not able to bind to m7GTP Sepharose indicating that they were not functional as cap binding proteins. Analysis of eIF4E*GFP fusions, both in yeast and in vitro, showed that the N-terminal fusion may be functional, whereas the C-terminal fusion bound m7GTP Sepharose very poorly and functioned poorly in yeast. These results highlight the importance of verification both biochemically and in vivo that reporter fusions of proteins maintain activity and are stable in order to prevent observations that may result in artifacts. PMID- 28090421 TI - RNA G-quadruplexes and their potential regulatory roles in translation. AB - DNA guanine (G)-rich 4-stranded helical nucleic acid structures called G quadruplexes (G4), have been extensively studied during the last decades. However, emerging evidence reveals that 5'- and 3'-untranslated regions (5'- and 3'-UTRs) as well as open reading frames (ORFs) contain putative RNA G quadruplexes. These stable secondary structures play key roles in telomere homeostasis and RNA metabolism including pre-mRNA splicing, polyadenylation, mRNA targeting and translation. Interestingly, multiple RNA binding proteins such as nucleolin, FMRP, DHX36, and Aven were identified to bind RNA G-quadruplexes. Moreover, accumulating reports suggest that RNA G-quadruplexes regulate translation in cap-dependent and -independent manner. Herein, we discuss potential roles of RNA G-quadruplexes and associated trans-acting factors in the regulation of mRNA translation. PMID- 28090424 TI - Gastric cancer surveillance or prevention plus targeted surveillance. PMID- 28090425 TI - Spread of volunteer and feral maize plants in Central Europe: recent data from Austria. AB - The occurrence of volunteer maize plants in subsequent crops as well as of feral maize plants in non-agricultural areas is an essential issue in risk assessments of genetically modified (GM) maize, with regard to possible contamination of natural habitats with GM material and as contribution to the total adventitious GM content of the non-GM final product. The appearance of feral maize plants has been confirmed for non-agricultural habitats in European areas with Mediterranean climate such as Spain. However, the existence of maize volunteers and feral maize outside cultivation under Central European continental climatic conditions is considered to be extremely unlikely in those winter-cold areas. Here, field observations during 5 years (2007, 2008, 2010, 2011 and 2015) in Austria are presented that confirm the occurrence of volunteer and feral maize under Central European climatic conditions. Most of these plants produced fertile inflorescences with viable pollen and fully developed cobs. Maize kernels may reach the soil by disintegration of cobs due to disease, using crushed maize cobs for game-feeding, left overs in manure dispersed during fertilisation or from transporting and handling of crushed cobs. The evidence of volunteer and feral maize in four Federal States in Austria (Burgenland, Lower Austria, Upper Austria, Styria) emphasises the necessity to consider these hitherto under emphasised factors in an ecological risk assessment (ERA) of GM maize as a possible source for transgenes in non-agricultural habitats, because these plants could act as bridge for the spread of GM material into semi-natural habitats. In accordance with the European Food Safety Authority (EFSA), which states that in principle maize has the potential to survive as a volunteer or feral plant also in regions with cold winters, the investigation of the frequency of their occurrence under Central European conditions should be part of future monitoring programmes in order to assess their potential for permitting transgene spread. PMID- 28090426 TI - Surface topological differences of phage infected uropathogenic Escherichia coli (UPEC) strains, revealed by atomic force microscopy. AB - BACKGROUND: Atomic force microscopy (AFM) is an advance microscopic technique that provides three dimensional structures of cell surfaces with high resolution. In the present study AFM was used for comparative analysis of surface topology of phage infected and uninfected Uropathogenic Escherichia coli (UPEC) cells. Two UPEC strains NE and HN were isolated from urine samples of Urinary tract infection patients and their specific narrow host range lytic phages 3S and HNPhi were isolated from the sewage of different areas. RESULTS: On the basis of one step growth curve both phages characterized as short latent period phages with latency period of about 30 min. On AFM analysis significant difference in topology of healthy and infected cells were observed. It was hypothesized that progeny of both lytic phages released out from their respective host cells in different manner. The image of 3S infected UPEC host cells (NE) revealed multiple internal projections which showed progeny phages released out from host cells through these multiple sites. Whereas images of HNPhi infected HN host cells showed central depression which illustrated that new phages released out through single exit point from the middle of cell. CONCLUSIONS: These results are significant to extend future studies on isolated phages as an effective tool for phage therapy. PMID- 28090427 TI - Review and results of a survey about biosimilars prescription and challenges in the Middle East and North Africa region. AB - BACKGROUND: Only drafts of regulatory guidelines for the registration of biosimilars are available in Lebanon. We analyzed the results of a regional survey conducted in Lebanon to understand the impact of different parameters on the acceptance and future prescription of biosimilars. We also reviewed the current situation of biosimilars around the world. The study surveyed healthcare professionals from the Arab countries, Iran, Belgium and Italy. Data about the participants' specialty, country of residence, their knowledge about biosimilars, biosimilars' prescription, price influence and the manufacturer's credibility were collected. RESULTS: 117 questionnaires were completed and returned: 46 (39.3%) respondents were oncologists. 72 (61.5%) respondents were Lebanese, and the others from Egypt, Syria, Algeria, Iraq, Sudan, Jordan, Iran, Belgium and Italy. 77 (65.8%) respondents had knowledge about biosimilars, of whom 48 (62.3%) considered biosimilars as biologics that demonstrate bioequivalence with the original biodrug and have all preclinical and clinical trials equal to those already performed with the original biodrug. 74 (63.2%) out of 117 respondents agreed that biosimilars in the Arab and Middle Eastern market are already marketed. Among the 48 participants who prescribe biosimilars, the main prescription driver was the drug's approval by the FDA and EMA (68.8%). 71 (60.7%) respondents considered that the main advantage of biosimilars is their lower price and 41 (35%) out of the 117 respondents declared that they should know in which country the drug has been tested/created before using it in their own country. 35% of the respondents thought that the cost of a treatment should not come before its effectiveness or safety/tolerance, given that the biosimilar will be less expensive than the reference drug. CONCLUSIONS: Biosimilars' acceptance and use is increasing worldwide. Only few physicians are aware of biosimilars presence in the market and do prescribe them in Lebanon and the Arab region. This could be mainly explained by lack of confidence in efficacy, safety, manufacturing process and price of these products, and lack of clear legislation. Thus, WHO is finalizing a new guideline for similar biotherapeutic agents. This could be a starting point for the Lebanese government to support the authorization of biosimilars. PMID- 28090428 TI - Erratum to: Crowd behavior representation: an attribute-based approach. AB - [This corrects the article DOI: 10.1186/s40064-016-2786-0.]. PMID- 28090429 TI - Molecular diagnostic markers of Tachysurus fulvidraco and Leiocassis longirostris and their hybrids. AB - BACKGROUND: Bagridae is an important family of catfishes and has a high market demand. Recently, more cultivable Bagridae fishes are being exploited in China, and hybridization of some species has been carried out to achieve better growth performance, favorable sex ratios and better disease resistance. Yet, these hybrids have further increased the difficulties of taxonomy identification due to morphological indistinguishableness. RESULTS: In this study, the molecular identification technologies for Tachysurus fulvidraco, Leiocassis longirostris sand their hybrids were successfully established by using mitochondrial COI and nuclear ITS sequences to identify the maternal and paternal lineage, respectively. CONCLUSION: These molecular diagnostic methods could also be used to manage breeding plans of hybrids, monitor and minimize the negative impacts of hybridization programs in aquaculture. Furthermore, our study could also provide a reference for establishing detection technique for hybrids in other groups of fishes. PMID- 28090430 TI - Effect of chlorhexidine pretreatment on bacterial contamination at rhinoplasty field. AB - BACKGROUND: This study investigated on bacterial contamination of the rhinoplasty field. The effect of preoperative chlorhexidine treatment on decreasing bacterial contamination in the rhinoplasty field is examined. METHODS: Thirty patients who underwent rhinoplasty were block randomized into a chlorhexidine, regular-soap, or control group comprising ten participants each. The chlorhexidine group was subjected to chlorhexidine showering, shampooing, and facial-cleansing 12 h prior to the operation. The regular-soap group was subjected to cleansing with regular soap, and the control group did not have any skin pretreatment. Bacterial cultures were done 12 h preoperatively from nasal cavity and perinasal skin, immediately preoperatively from perinasal skin and at 1 and 2 h intraoperatively from operation field. Culture results were compared between the three groups, according to operation time, or whether infection-prone procedure was performed. RESULTS: The bacterial species and colony-forming unit numbers at preoperative nasal cavity and perinasal skin were similar. In all three groups, Coagulase negative staphylococcus was the most common bacteria found in the rhinoplasty field. The numbers of Staphylococcus aureus and Corynebacterium decreased rapidly after preoperative chlorhexidine treatment. The infection-prone procedure was associated with increased bacterial numbers over time during the operation. In all three groups, there was no postoperative infection in a follow-up period of 6 months. CONCLUSION: Rhinoplasty is confirmed as a clean contaminated operation with skin flora consistently found in the operation field. Chlorhexidine pretreatment in rhinoplasty patients has a tendency to decrease the numbers of Staphylococcus aureus and Corynebacterium on the perinasal skin. LEVEL OF EVIDENCE: Randomized controlled trial, Level I. PMID- 28090431 TI - A Role for 3D Printing in Kidney-on-a-Chip Platforms. AB - The advancement of "kidney-on-a-chip" platforms - submillimeter-scale fluidic systems designed to recapitulate renal functions in vitro - directly impacts a wide range of biomedical fields, including drug screening, cell and tissue engineering, toxicity testing, and disease modelling. To fabricate kidney-on-a chip technologies, researchers have primarily adapted traditional micromachining techniques that are rooted in the integrated circuit industry; hence the term, "chip." A significant challenge, however, is that such methods are inherently monolithic, which limits one's ability to accurately recreate the geometric and architectural complexity of the kidney in vivo. Better reproduction of the anatomical complexity of the kidney will allow for more instructive modelling of physiological and pathophysiological events. Emerging additive manufacturing or "three-dimensional (3D) printing" techniques could provide a promising alternative to conventional methodologies. In this article, we discuss recent progress in the development of both kidney-on-a-chip platforms and state-of-the art submillimeter-scale 3D printing methods, with a focus on biophysical and architectural capabilities. Lastly, we examine the potential for 3D printing based approaches to extend the efficacy of kidney-on-a-chip systems. PMID- 28090432 TI - Update on Chronic Lung Allograft Dysfunction. AB - Chronic lung allograft dysfunction (CLAD) encompasses a range of pathologies that cause a transplanted lung to not achieve or maintain normal function. CLAD manifests as airflow restriction and/or obstruction and is predominantly a result of chronic rejection. Three distinct phenotypes of chronic rejection are now recognized: bronchiolitis obliterans, neutrophilic reversible allograft dysfunction, and restrictive allograft syndrome. Recent investigations have revealed that each phenotype has a unique pathology and histopathological findings, suggesting that treatment regimens should be tailored to the underlying etiology. CLAD is poorly responsive to treatment once diagnosed, and therefore the prevention of the factors that predispose a patient to develop CLAD is critically important. Small and large animal models have contributed significantly to our understanding of CLAD and more studies are needed to develop treatment regimens that are effective in humans. PMID- 28090433 TI - Degradation study of lindane by novel strains Kocuria sp. DAB-1Y and Staphylococcus sp. DAB-1W. AB - BACKGROUND: This study was carried out to isolate and characterize the bacterial strains from lindane-contaminated soil and they were also assessed for their lindane-degrading potential. METHODS: In this study the enrichment culture method was used for isolation of lindane degrading bacterial isolates, in which the mineral salt medium (MSM) supplemented with different concentrations of lindane was used. Further, the screening for the potential lindane degrading isolates was done using the spray plate method and colorimetric dechlorinase enzyme assay. The selected isolates were also studied for their growth response under varying range of temperature, pH, and NaCl. The finally selected isolates DAB-1Y and DAB-1W showing best lindane degradation activity was further subjected to biochemical characterization, microscopy, degradation/kinetic study, and 16S rDNA sequencing. The strain identification were performed using the biochemical characterization, microscopy and the species identifies by 16S rDNA sequence of the two isolates using the standard 16S primers, the 16 S rRNA partial sequence was analyzed through BLAST analysis and phylogenetic tree was generated based on UGPMA clustering method using MEGA7 software. This shows the phylogenetic relationship with the related strains. The two isolates of this study were finally characterized as Kocuria sp. DAB-1Y and Staphylococcus sp. DAB-1W, and their 16S rRNA sequence was submitted to GenBank database with accession numbers, KJ811539 and KX986577, respectively. RESULTS: Out of the 20 isolates, the isolates DAB-1Y and DAB-1W exhibited best lindane-degrading activity of 94 and 98%, respectively, recorded after 8 days of incubation. The optimum growth was observed at temperature 30 degrees C, pH 7, and 5% NaCl observed for both isolates. Of the four isomers of hexachlorocyclohexane, isomer alpha and gamma were the fastest degrading isomers, which were degraded up to 86 and 94% by isolates DAB-1Y and up to 93 and 98% by DAB-1W, respectively, reported after 8 days incubation. Isomer beta was highly recalcitrant in which maximum 35 and 32% lindane degradation was observed even after 28 days incubation by isolates, DAB-1Y and DAB-1W, respectively. At lower lindane concentrations (1-10 mg/L), specific growth rate increased with increase in lindane concentration, maximum being 0.008 and 0.006/day for DAB-1Y and DAB-1W, respectively. The 16 S rRNA partial sequence of isolate DAB-1Y showed similarity with Kocuria sp. by BLAST analysis and was named as Kocuria sp. DAB-1Y and DAB-IW with Staphylococcus sp. DAB-1W. The 16S rDNA sequence of isolate DAB-1Y and DAB-1W was submitted to online at National Centre of Biotechnology Information (NCBI) with GenBank accession numbers, KJ811539 and KX986577, respectively. CONCLUSIONS: This study has demonstrated that Kocuria sp. DAB-1Y and Staphylococcus sp. DAB-1W were found efficient in bioremediation of gamma-HCH and can be utilized further for biodegradation of environmental contamination of lindane and can be utilized in bioremediation program. PMID- 28090434 TI - Exposure to emotionally arousing, contamination-relevant pictorial stimuli interferes with response inhibition: Implication for obsessive-compulsive disorder. AB - Multiple emotional processes are implicated in the pathogenesis of obsessions and compulsions and individuals diagnosed with obsessive-compulsive disorder (OCD) have reliably shown deficits in response inhibition. Little research has tested how emotional processes might interact with cognitive control in the context of OCD. High contamination obsessive-compulsive (OC) and low contamination-OC participants completed an emotional go/no-go task to measure the interfering effects contamination-threat images relative to neutral images on action restraint (errors of commission). Results revealed that high contamination-OC participants committed marginally more commission errors (11.04%) than low contamination-OC participants (10.30%) on neutral no-go trials, but this effect was not significant (p > .05). All participants committed significantly more errors of commission on contamination-threat trails relative to neutral no-go trials, p < .01, but the interfering effects of contamination-threat images was significantly larger (p = .05) for high-contamination-OC participants. Errors of commission almost doubled for high contamination-OC participants on contamination threat no-go trials (20.78%), compared to a more modest increase for low contamination-OC participants (14.80%). These findings suggest that individuals with elevated symptoms of OCD may have significantly more difficulty inhibiting their actions when processing disorder relevant or emotionally arousing information. This observation has implications for the pathogenesis of obsessions and compulsions. PMID- 28090435 TI - 13C Metabolomics: NMR and IROA for Unknown Identification. AB - ABSTRACT BACKGROUND: Isotopic Ratio Outlier Analysis (IROA) is an untargeted metabolomics method that uses stable isotopic labeling and LC-HRMS for identification and relative quantification of metabolites in a biological sample under varying experimental conditions. OBJECTIVE: We demonstrate a method using high-sensitivity 13C NMR to identify an unknown metabolite isolated from fractionated material from an IROA LC-HRMS experiment. METHODS: IROA samples from the nematode Caenorhabditis elegans were fractionated using LC-HRMS using 5 repeated injections and collecting 30 sec fractions. These were concentrated and analyzed by 13C NMR. RESULTS: We isotopically labeled samples of C. elegans and collected 2 adjacent LC fractions. By HRMS, one contained at least 2 known metabolites, phenylalanine and inosine, and the other contained tryptophan and an unknown feature with a monoisotopic mass of m/z 380.0742 [M+H]+. With NMR, we were able to easily verify the known compounds, and we then identified the spin system networks responsible for the unknown resonances. After searching the BMRB database and comparing the molecular formula from LC-HRMS, we determined that the fragments were a modified anthranilate and a glucose modified by a phosphate. We then performed quantum chemical NMR chemical shift calculations to determine the most likely isomer, which was 3'-O-phospho-beta-D-glucopyranosyl-anthranilate. This compound had previously been found in the same organism, validating our approach. CONCLUSION: We were able to dereplicate previously known metabolites and identify a metabolite that was not in databases by matching resonances to NMR databases and using chemical shift calculations to determine the correct isomer. This approach is efficient and can be used to identify unknown compounds of interest using the same material used for IROA. PMID- 28090436 TI - Hormone therapy in transgender adults is safe with provider supervision; A review of hormone therapy sequelae for transgender individuals. AB - INTRODUCTION: Some providers report concern for the safety of transgender hormone therapy (HT). METHODS: This is a systematic literature review of HT safety for transgender adults. RESULTS: Current literature suggests HT is safe when followed carefully for certain risks. The greatest health concern for HT in transgender women is venous thromboembolism. HT among transgender men appears to cause polycythemia. Both groups experienced elevated fasting glucose. There is no increase in cancer prevalence or mortality due to transgender HT. CONCLUSION: Although current data support the safety of transgender HT with physician supervision, larger, long-term studies are needed in transgender medicine. PMID- 28090438 TI - Exploring Mental Health Providers' Interest in Using Web and Mobile-Based Tools in their Practices. AB - A growing number of Internet sites and mobile applications are being developed intended for use in clinical practice. However, during the development process (e.g., creating features and determining use cases), the needs and interests of providers are often overlooked. We explored providers' interests using a mixed methods approach incorporating both qualitative and quantitative research methods. A first study used an interview approach to identify the challenges providers faced, tools they used, and any use of computers and apps specifically. Fifteen providers from both the United States and Canada completed the interview and recordings were transcribed and analyzed using a constructivist grounded theory approach. Four primary themes were identified including challenges, potential tools, access and usability. A second study used a brief survey completed by 132 providers at a large healthcare system to explore current use of and potential interest in Internet and mobile technologies. Although many providers (80.9%) reported recommending some form of technology to patients, this was mostly Internet websites that were predominantly informational/psychoeducational in nature. Overall, these studies combine to suggest a strong interest in websites and apps for use in clinical settings while highlighting potential areas (ease of use, patient security and privacy) that should be considered in the design and deployment of these tools. PMID- 28090437 TI - Evaluation of time-dependent toxicity and combined effects for a series of mono halogenated acetonitrile-containing binary mixtures. AB - Mixture and time-dependent toxicity (TDT) was assessed for a series of mono halogenated acetonitrile-containing combinations. Inhibition of bioluminescence in Aliivibrio fischeri was measured after 15, 30 and 45-min of exposure. Concentration-response (x/y) curves were determined for each chemical alone at each timepoint, and used to develop predicted x/y curves for the dose-addition and independence models of combined effect. The x/y data for each binary mixture was then evaluated against the predicted mixture curves. Two metrics of mixture toxicity were calculated per combined effect model: (1) an EC50-based dose addition (AQ) or independence (IQ) quotient and (2) the mixture/dose-addition (MX/DA) and mixture/independence (MX/I) metrics. For each single chemical and mixture tested, TDT was also calculated. After 45-min of exposure, 25 of 67 mixtures produced curves that were consistent with dose-addition using the MX/DA metric, with the other 42 being less toxic than predicted by MX/DA. Some mixtures had toxicity that was consistent with both dose-addition and independence. In general, those that were less toxic than predicted for dose-addition were also less toxic than predicted for independence. Of the 25 combinations that were consistent with dose-addition, 22 (88%) mixtures contained chemicals for which the individual TDT values were both >80%. In contrast, of the 42 non-dose additive combinations, only 2 (4.8%) of the mixtures had both chemicals with individual TDT values >80%. The results support previous findings that TDT determinations can be useful for predicting chemical mixture toxicity. PMID- 28090439 TI - Overt and covert contrast in L2 phonology. AB - This paper reports results on the acquisition of the English /p/ - /b/ contrast by native speakers of Arabic. This contrast does not exist in the participants' native language (NL). The central finding of this study is that some of the research participants exhibited a covert contrast between these segments in their interlanguage productions. That is, two of the five Arabic-speaking participants who were transcribed as having no contrast between [p] and [b] did, in fact, produced a statistically reliable distinction in voice onset time lags between the two target segments. The existence of such an intermediate stage of covert contrast in the learning of L2 phonology is eminently plausible, in view of the progressive nature of phonological acquisition. Our results help bring the learning of second-language contrasts into conformity with findings of the same phenomenon in the areas of L1 acquisition and phonologically disordered speech. PMID- 28090440 TI - Quantitative musculoskeletal imaging biomarkers. PMID- 28090441 TI - Principal component analysis-T1rho voxel based relaxometry of the articular cartilage: a comparison of biochemical patterns in osteoarthritis and anterior cruciate ligament subjects. AB - BACKGROUND: Quantitative MR, including T1rho mapping, has been extensively used to probe early biochemical changes in knee articular cartilage of subjects with osteoarthritis (OA) and others at risk for cartilage degeneration, such as those with anterior cruciate ligament (ACL) injury and reconstruction. However, limited studies have been performed aimed to assess the spatial location and patterns of T1rho. In this study we used a novel voxel-based relaxometry (VBR) technique coupled with principal component analysis (PCA) to extract relevant features so as to describe regional patterns and to investigate their similarities and differences in T1rho maps in subjects with OA and subjects six months after ACL reconstruction (ACLR). METHODS: T1rho quantitative MRI images were collected for 180 subjects from two separate cohorts. The OA cohort included 93 osteoarthritic patients and 25 age-matched controls. The ACLR-6M cohort included 52 patients with unilateral ACL tears who were imaged 6 months after ACL reconstruction, and 10 age-matched controls. Non-rigid registration on a single template and local Z score conversion were adopted for T1rho spatial and intensity normalization of all the images in the dataset. PCA was used as a data dimensionality reduction to obtain a description of all subjects in a 10-dimensional feature space. Logistic linear regression was used to identify distinctive features of OA and ACL subjects. RESULTS: Global prolongation of the Z-score was observed in both OA and ACL subjects compared to controls [higher values in 1st principal component (PC1); P=0.01]. In addition, relaxation time differences between superficial and deep cartilage layers of the lateral tibia and trochlea were observed to be significant distinctive features between OA and ACL subjects. OA subjects demonstrated similar values between the two cartilage layers [higher value in 2nd principal component (PC2); P=0.008], while ACL reconstructed subjects showed T1rho prolongation specifically in the cartilage superficial layer (lower values in PC2; P<0.0001). T1rho elevation located outside of the weight-bearing area, located in the posterior and anterior aspects of the lateral femoral compartment, was also observed to be a key feature in distinguishing OA subjects from controls [higher value in 6th principal component (PC6); P=0.007]. CONCLUSIONS: This study is the first example of T1rho local/regional pattern analysis and data-driven feature extraction in knees with cartilage degeneration. Our results revealed similarities and differences between OA and ACL relaxation patterns that could be potentially useful to better understand the pathogenesis of post-traumatic cartilage degeneration and the identification of imaging biomarkers for the early stratification of subjects at risk for developing post-traumatic OA. PMID- 28090442 TI - Can MRI accurately detect pilon articular malreduction? A quantitative comparison between CT and 3T MRI bone models. AB - BACKGROUND: Pilon fracture reduction is a challenging surgery. Radiographs are commonly used to assess the quality of reduction, but are limited in revealing the remaining bone incongruities. The study aimed to develop a method in quantifying articular malreductions using 3D computed tomography (CT) and magnetic resonance imaging (MRI) models. METHODS: CT and MRI data were acquired using three pairs of human cadaveric ankle specimens. Common tibial pilon fractures were simulated by performing osteotomies to the ankle specimens. Five of the created fractures [three AO type-B (43-B1), and two AO type-C (43-C1) fractures] were then reduced and stabilised using titanium implants, then rescanned. All datasets were reconstructed into CT and MRI models, and were analysed in regards to intra-articular steps and gaps, surface deviations, malrotations and maltranslations of the bone fragments. RESULTS: Initial results reveal that type B fracture CT and MRI models differed by ~0.2 (step), ~0.18 (surface deviations), ~0.56 degrees (rotation) and ~0.4 mm (translation). Type C fracture MRI models showed metal artefacts extending to the articular surface, thus unsuitable for analysis. Type C fracture CT models differed from their CT and MRI contralateral models by ~0.15 (surface deviation), ~1.63 degrees (rotation) and ~0.4 mm (translation). CONCLUSIONS: Type B fracture MRI models were comparable to CT and may potentially be used for the postoperative assessment of articular reduction on a case-to-case basis. PMID- 28090443 TI - Topographical and depth-dependent glycosaminoglycan concentration in canine medial tibial cartilage 3 weeks after anterior cruciate ligament transection surgery-a microscopic imaging study. AB - BACKGROUND: Medical imaging has become an invaluable tool to diagnose damage to cartilage. Depletion of glycosaminoglycans (GAG) has been shown to be one of the early signs of cartilage degradation. In order to investigate the topographical changes in GAG concentration caused by the anterior cruciate ligament transection (ACLT) surgery in a canine model, microscopic magnetic resonance imaging (uMRI) and microscopic computed tomography (uCT) were used to measure the GAG concentration with correlation from a biochemical assay, inductively coupled plasma optical emission spectroscopy (ICP-OES), to understand where the topographical and depth-dependent changes in the GAG concentration occur. METHODS: This study used eight knee joints from four canines, which were examined 3 weeks after ACLT surgery. From right (n=3) and left (n=1) medial tibias of the ACLT and the contralateral side, two ex vivo specimens from each of four locations (interior, central, exterior and posterior) were imaged before and after equilibration in contrast agents. The cartilage blocks imaged using uMRI were approximately 3 mm * 5 mm and were imaged before and after eight hours submersion in a gadolinium (Gd) contrast agent with an in-plane pixel resolution of 17.6 um2 and an image slice thickness of 1 mm. The cartilage blocks imaged using uCT were approximately 2 mm * 1 mm and were imaged before and after 24 hours submersed in ioxaglate with an isotropic voxel resolution of 13.4 um3. ICP OES was used to quantify the bulk GAG at each topographical location. RESULTS: The pre-contrast uMRI and uCT results did not demonstrate significant differences in GAG between the ACLT and contralateral cartilage at all topographical locations. The post-contrast uMRI and uCT results demonstrated topographically similar significant differences in GAG concentrations between the ACLT and contralateral tibia. Using uMRI, the GAG concentrations (mg/mL) were measured for the ACLT and contralateral respectively, the exterior (54.0+/-3.6; 70.4+/-4.3; P=0.001) and interior (54.9+/-5.9; 71.0+/-5.9; P=0.029) demonstrated significant differences, but not for the central (61.0+/-12.0; 67.4+/-7.2; P=0.438) or posterior (61.6+/-6.3; 70.3+/-4.4; P=0.097) locations. Using uCT, the GAG concentrations (mg/mL) were measured for the ACLT and contralateral respectively, the exterior (68.8+/-0.4; 87.7+/-4.1; P=0.023) and interior (60.5+/-9.1; 82.6+/ 8.7; P=0.039) demonstrated significant differences, but not for the central (53.5+/-5.5; 59.1+/-25.6; P=0.684) or posterior (52.3+/-6.2; 61.5+/-12.7; P=0.325) locations. The depth-dependent GAG (mg/mL) profiles showed significant differences in uMRI for the transitional zone (TZ) [exterior (28.1+/-4.7; 47.0+/ 8.6; P=0.01) and interior (32.6+/-4.8; 43.8+/-8.7; P=0.025)], radial zone (RZ) 1 [exterior (49.6+/-4.8; 71.5+/-5.8; P=0.001) and interior (49.4+/-7.4; 66.7+/-6.8; P=0.041)], and RZ 2 [exterior (74.9+/-4.7; 91.8+/-2.9; P=0.001) and interior (77.1+/-6.0; 94.8+/-4.5; P=0.015)], and in uCT for the superficial zone (SZ) [interior (20.6+/-1.2; 40.4+/-5.4; P=0.004)], TZ [exterior (45.6+/-12.0; 61.8+/ 0.5; P=0.049) and interior (36.3+/-11.7; 60.8+/-2.0; P=0.019)], and RZ 1 [exterior (61.1+/-4.1; 85.3+/-5.6; P=0.039) and interior (53.9+/-4.9; 78.0+/-5.1; P=0.041)] for the ACLT and contralateral, respectively. ICP-OES measured significant differences in GAG were found for the exterior (42.1+/-19.6; 65.3+/ 16.2; P=0.017), central (43.4+/-4.4; 65.3+/-10.6; P=0.0111), and interior (46.8+/ 5.6; 61.7+/-7.3; P=0.0445) but not for the posterior (52.6+/-12.1; 59.0+/-2.6; P=0.9252) medial tibia locations compared for the ACLT and contralateral, respectively. CONCLUSIONS: The detection and correlation between the three techniques show a topographic depth-dependency on the initial GAG loss in injured cartilage. This topographic and high resolution investigation of ACLT cartilage demonstrated the potential of using uMRI and uCT to study and help diagnose cartilage with very early stages of osteoarthritis. PMID- 28090444 TI - Bone marrow edema-like lesions (BMELs) are associated with higher T1rho and T2 values of cartilage in anterior cruciate ligament (ACL)-reconstructed knees: a longitudinal study. AB - BACKGROUND: To evaluate the longitudinal changes of bone marrow edema-like lesions (BMELs) in patients after anterior cruciate ligament (ACL) reconstruction and to investigate the effect of BMELs on cartilage matrix composition changes measured using MR T1rho and T2 mapping. METHODS: Patients with acute ACL tear were enrolled in a prospective study. MR imaging was performed at baseline (before surgeries) and at 6-month, 1-year and 2-year after ACL reconstruction. MR imaging included sagittal high-resolution, 3D fast spin-echo (CUBE) sequences for BMEL evaluation, and 3D T1rho mapping and T2 mapping for cartilage assessment. BMELs were assessed using whole-organ magnetic resonance imaging score (WORMS), and the volume of BMELs was measured by a semi-automatic method. Generalized estimating equation (GEE) was used to explore association between BMELs at baseline and cartilage changes during follow-up. RESULTS: Fifty four patients were included in the present study and 39 patients had completed 2-year follow up. BMELs were noted in 42 injured knees (77.8%) with 105 lesions and in 7 contralateral knees (13.0%) with 9 lesions (chi2=45.763, P<0.001) at the baseline. The WORMS and volume of BMELs of the injured knees were 2.36+/-0.65 and 386.98+/-382.54 mm3 (r=0.681, P<0.001), respectively. 87 BMELs were found at baseline in 34 patients (87.2%) of the 39 patients who had completed 2 years follow-up. During the follow-up, 18 (20.7%), 12 (13.8%), and 5 (5.7%) baseline lesions were still seen at 6-month, 1-year and 2-year, respectively. The changes of BMELs prevalence regarding bone compartments over time points were statistically significant (chi2=163.660, P<0.001). Except T2 value at 6 months, T1rho and T2 values of cartilage overlying baseline BMELs in the injured knees were higher than that of anatomically matched cartilage in the contralateral knees at baseline and each follow-up time-point. In the injured knees, GEE analysis showed that baseline BMELs were significantly associated with higher T1rho and T2 values of cartilage after adjustment of age, gender, body mass index (BMI), effusion and meniscus tear. The association between BMELs and Knee Injury and Osteoarthritis Outcome Scores (KOOS) scores was not statistically significant. CONCLUSIONS: BMEL is a common finding in patients with acute ACL injury and resolves rapidly over time after ACL reconstruction. It is often associated with increased T1rho and T2 values of cartilage. BMEL at baseline is an independent predictor for faster cartilage degeneration during follow-up. PMID- 28090445 TI - Population reference range for developmental lumbar spinal canal size. AB - BACKGROUND: Considerable variability exists in normal developmental lumbar spinal canal size. This impacts the likelihood of neural compromise. Spinal canal development is complete by 17 years. As diseases incurred thereafter do not knowingly affect the developmental size of the spinal canal, it is reasonable to use a selected population undergoing abdominopelvic computed tomography (CT) examination to determine developmental lumbar spinal canal size. METHODS: Study approval was granted by the Clinical Research Ethics Committee. Between Feb 2014 and Jan 2015, mid-vertebral spinal canal cross-sectional area (CSA), depth, width, and vertebral body CSA at each level from L1-L5 was measured, using a semi automated computerized method in 1,080 ambulatory patients (540 males, 540 females, mean age, 50.5+/-17 years). Patient height and weight was measured. RESULTS: A reference range for developmental lumbar spinal canal dimensions was developed at each lumbar level for each sex. There was a 34% variation in spinal canal CSA between smallest and largest quartiles. Developmental spinal canal CSA and depth were consistently smallest at L3, enlarging cranially and caudally. Taller people had slightly larger lumbar spinal canals (P<0.0001). Males had larger spinal canal CSAs than females though relative to vertebral body CSA, spinal canal CSA was larger in females. There was no change in spinal canal CSA with age, weight or BMI (P<0.05). CONCLUSIONS: A population reference range for developmental lumbar spinal canal size was developed. This allows one to objectively determine the degree of developmental spinal canal stenosis present on an individual patient basis. PMID- 28090446 TI - Quantitative imaging methods in osteoporosis. AB - Osteoporosis is characterized by a decreased bone mass and quality resulting in an increased fracture risk. Quantitative imaging methods are critical in the diagnosis and follow-up of treatment effects in osteoporosis. Prior radiographic vertebral fractures and bone mineral density (BMD) as a quantitative parameter derived from dual-energy X-ray absorptiometry (DXA) are among the strongest known predictors of future osteoporotic fractures. Therefore, current clinical decision making relies heavily on accurate assessment of these imaging features. Further, novel quantitative techniques are being developed to appraise additional characteristics of osteoporosis including three-dimensional bone architecture with quantitative computed tomography (QCT). Dedicated high-resolution (HR) CT equipment is available to enhance image quality. At the other end of the spectrum, by utilizing post-processing techniques such as the trabecular bone score (TBS) information on three-dimensional architecture can be derived from DXA images. Further developments in magnetic resonance imaging (MRI) seem promising to not only capture bone micro-architecture but also characterize processes at the molecular level. This review provides an overview of various quantitative imaging techniques based on different radiological modalities utilized in clinical osteoporosis care and research. PMID- 28090448 TI - Quantitative techniques for musculoskeletal MRI at 7 Tesla. AB - Whole-body 7 Tesla MRI scanners have been approved solely for research since they appeared on the market over 10 years ago, but may soon be approved for selected clinical neurological and musculoskeletal applications in both the EU and the United States. There has been considerable research work on musculoskeletal applications at 7 Tesla over the past decade, including techniques for ultra-high resolution morphological imaging, 3D T2 and T2* mapping, ultra-short TE applications, diffusion tensor imaging of cartilage, and several techniques for assessing proteoglycan content in cartilage. Most of this work has been done in the knee or other extremities, due to technical difficulties associated with scanning areas such as the hip and torso at 7 Tesla. In this manuscript, we first provide some technical context for 7 Tesla imaging, including challenges and potential advantages. We then review the major quantitative MRI techniques being applied to musculoskeletal applications on 7 Tesla whole-body systems. PMID- 28090447 TI - Quantitative sodium magnetic resonance imaging of cartilage, muscle, and tendon. AB - Sodium magnetic resonance imaging (MRI), or imaging of the 23Na nucleus, has been under exploration for several decades, and holds promise for potentially revealing additional biochemical information about the health of tissues that cannot currently be obtained from conventional hydrogen (or proton) MRI. This additional information could serve as an important complement to conventional MRI for many applications. However, despite these exciting possibilities, sodium MRI is not yet used routinely in clinical practice, and will likely remain strictly in the domain of exploratory research for the coming decade. This paper begins with a technical overview of sodium MRI, including the nuclear magnetic resonance (NMR) signal characteristics of the sodium nucleus, the challenges associated with sodium MRI, and the specialized pulse sequences, hardware, and reconstruction techniques required. Various applications of sodium MRI for quantitative analysis of the musculoskeletal system are then reviewed, including the non-invasive assessment of cartilage degeneration in vivo, imaging of tendinopathy, applications in the assessment of various muscular pathologies, and assessment of muscle response to exercise. PMID- 28090449 TI - Ultrashort time to echo magnetic resonance techniques for the musculoskeletal system. AB - Magnetic resonance (MR) imaging has been widely implemented as a non-invasive modality to investigate musculoskeletal (MSK) tissue disease, injury, and pathology. Advancements in MR sequences provide not only enhanced morphologic contrast for soft tissues, but also quantitative biochemical evaluation. Ultrashort time to echo (UTE) sequence, in particular, enables novel morphologic and quantitative evaluation of previously unseen MSK tissues. By using short minimum echo times (TE) below 1 msec, the UTE sequence can unveil short T2 properties of tissues including the deepest layers of the articular cartilage, cartilaginous endplate at the discovertebral junction, the meniscus, and the cortical bone. This article will discuss the application of UTE to evaluate these MSK tissues, starting with tissue structure, MR imaging appearance on standard versus short and ultrashort TE sequences, and provide the range of quantitative MR values found in literature. PMID- 28090451 TI - Potential of PET-MRI for imaging of non-oncologic musculoskeletal disease. AB - Early detection of musculoskeletal disease leads to improved therapies and patient outcomes, and would benefit greatly from imaging at the cellular and molecular level. As it becomes clear that assessment of multiple tissues and functional processes are often necessary to study the complex pathogenesis of musculoskeletal disorders, the role of multi-modality molecular imaging becomes increasingly important. New positron emission tomography-magnetic resonance imaging (PET-MRI) systems offer to combine high-resolution MRI with simultaneous molecular information from PET to study the multifaceted processes involved in numerous musculoskeletal disorders. In this article, we aim to outline the potential clinical utility of hybrid PET-MRI to these non-oncologic musculoskeletal diseases. We summarize current applications of PET molecular imaging in osteoarthritis (OA), rheumatoid arthritis (RA), metabolic bone diseases and neuropathic peripheral pain. Advanced MRI approaches that reveal biochemical and functional information offer complementary assessment in soft tissues. Additionally, we discuss technical considerations for hybrid PET-MR imaging including MR attenuation correction, workflow, radiation dose, and quantification. PMID- 28090450 TI - Quantitative magnetic resonance imaging of the lumbar intervertebral discs. AB - Human lumbar spine is composed of multiple tissue components that serve to provide structural stability and proper nutrition. Conventional magnetic resonance (MR) imaging techniques have been useful for evaluation of IVD, but inadequate at imaging the discovertebral junction and ligamentous tissues due primarily to their short T2 nature. Ultrashort time to echo (UTE) MR techniques acquire sufficient MR signal from these short T2 tissues, thereby allowing direct and quantitative evaluation. This article discusses the anatomy of the lumbar spine, MR techniques available for morphologic and quantitative MR evaluation of long and short T2 tissues of the lumbar spine, considerations for T2 relaxation modeling and fitting, and existing and new techniques for spine image post processing, focusing on segmentation. This article will be of interest to radiologic and orthopaedic researchers performing lumbar spine imaging. PMID- 28090452 TI - Classifying thoracolumbar fractures: role of quantitative imaging. AB - This article describes different types of vertebral fractures that affect the thoracolumbar spine and the most relevant contributions of the different classification systems to vertebral fracture management. The vertebral fractures types are based on the three columns model of Denis that includes compression, burst, flexion-distraction and fracture-dislocation types. The most recent classifications systems of these types of fractures are reviewed, including the Thoracolumbar Injury Classification and Severity score (TLICS) and the Arbeitsgemeinschaft fur Osteosynthesefragen Spine Thoracolumbar Injury Classification and Severity score (AOSpine-TLICS). Correct classification requires a quantitative imaging approach in which several measurements determine TLICS or AOSpine-TLICS grade. If the TLICS score is greater than 4, or the AOSpine-TLICS is greater than 5, surgical management is indicated. In this review, the most important imaging findings and measurements on radiography, multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) are described. These include degree of vertebral wedging and percentage of vertebral height loss in compression fractures, degree of interpedicular distance widening and spinal canal stenosis in burst fractures, and the degree of vertebral translation or interspinous widening in more severe fractures types, such as flexion-distraction and fracture-dislocation. These findings and measurements are illustrated with schemes and cases of our archives in a didactic way. PMID- 28090453 TI - South Korean degenerative spondylolisthesis patients had surgical treatment at earlier age than Japanese, American, and European patients: a published literature observation. PMID- 28090454 TI - Giant subperiosteal hematoma. PMID- 28090455 TI - Erratum to systemic review and meta-analysis of diagnostic imaging technologies. AB - [This corrects the article DOI: 10.21037/qims.2016.10.08.]. PMID- 28090456 TI - Chronic endometritis and infertility. AB - Chronic endometritis (CE) is a condition involving the breakdown of the peaceful co-existence between microorganisms and the host immune system in the endometrium. A majority of CE cases produce no noticeable signs or mild symptoms, and the prevalence rate of CE has been found to be approximately 10%. Gynecologists and pathologists often do not focus much clinical attention on CE due to the time-consuming microscopic examinations necessary to diagnose CE, its mild clinical manifestations, and the benign nature of the disease. However, the relationship between CE and infertility-related conditions such as repeated implantation failure and recurrent miscarriage has recently emerged as an area of inquiry. In this study, we reviewed the literature on the pathophysiology of CE and how it may be associated with infertility, as well as the literature regarding the diagnosis and treatment of CE. In addition, we discuss the value of hysteroscopic procedures in the diagnosis and treatment of CE. PMID- 28090457 TI - Glucose-6-phosphate dehydrogenase deficiency does not increase the susceptibility of sperm to oxidative stress induced by H2O2. AB - OBJECTIVE: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect. G6PD plays a key role in the pentose phosphate pathway, which is a major source of nicotinamide adenine dinucleotide phosphate (NADPH). NADPH provides the reducing equivalents for oxidation-reduction reductions involved in protecting against the toxicity of reactive oxygen species such as H2O2. We hypothesized that G6PD deficiency may reduce the amount of NADPH in sperms, thereby inhibiting the detoxification of H2O2, which could potentially affect their motility and viability, resulting in an increased susceptibility to infertility. METHODS: Semen samples were obtained from four males with G6PD deficiency and eight healthy males as a control. In both groups, motile sperms were isolated from the seminal fluid and incubated with 0, 10, 20, 40, 60, 80, and 120 uM concentrations of H2O2. After 1 hour incubation at 37C, sperms were evaluated for motility and viability. RESULTS: Incubation of sperms with 10 and 20 uM H2O2 led to very little decrease in motility and viability, but motility decreased notably in both groups in 40, 60, and 80 uM H2O2, and viability decreased in both groups in 40, 60, 80, and 120 uM H2O2. However, no statistically significant differences were found between the G6PD-deficient group and controls. CONCLUSION: G6PD deficiency does not increase the susceptibility of sperm to oxidative stress induced by H2O2, and the reducing equivalents necessary for protection against H2O2 are most likely produced by other pathways. Therefore, G6PD deficiency cannot be considered as major risk factor for male infertility. PMID- 28090458 TI - Efficient isolation of sperm with high DNA integrity and stable chromatin packaging by a combination of density-gradient centrifugation and magnetic activated cell sorting. AB - OBJECTIVE: This study was carried out to investigate the correlations of the sperm DNA fragmentation index (DFI) with semen parameters and apoptosis, and to investigate the effects of density-gradient centrifugation (DGC) and magnetic activated cell sorting (MACS) on reducing the proportion of sperm with DNA fragmentation and protamine deficiency. METHODS: Semen analysis and a sperm DNA fragmentation assay were performed to assess the correlations between semen parameters and the DFI in 458 semen samples. Sperm with progressive motility or non-apoptosis were isolated by DGC or MACS, respectively, in 29 normozoospermic semen samples. The effects of DGC or MACS alone and of DGC and MACS combined on reducing the amount of sperm in the sample with DNA fragmentation and protamine deficiency were investigated. RESULTS: The sperm DFI showed a significant correlation (r=-0.347, p<0.001) with sperm motility and morphology (r=-0.114, p<0.05) but not with other semen parameters. The DFI (11.5%+/-2.0%) of semen samples was significantly reduced by DGC (8.1%+/-4.1%) or MACS alone (7.4%+/ 3.9%) (p<0.05). The DFI was significantly further reduced by a combination of DGC and MACS (4.1%+/-1.3%, p<0.05). Moreover, the combination of DGC and MACS (1.6%+/ 1.1%, p<0.05) significantly reduced the protamine deficiency rate of semen samples compared to DGC (4.4%+/-3.2%) or MACS alone (3.4%+/-2.2%). CONCLUSION: The combination of DGC and MACS may be an effective method to isolate high quality sperm with progressive motility, non-apoptosis, high DNA integrity, and low protamine deficiency in clinical use. PMID- 28090459 TI - Anti-Mullerian hormone as a predictor of polycystic ovary syndrome treated with clomiphene citrate. AB - OBJECTIVE: This study aimed to determine the threshold of anti-Mullerian hormone (AMH) as predictor of follicular growth failure in polycystic ovary syndrome (PCOS) patients treated with clomiphene citrate (CC). METHODS: Fifty female subjects with PCOS were recruited and divided into two groups based on successful and unsuccessful follicular growth. Related variables such as age, infertility duration, cigarette smoking, use of Moslem hijab, sunlight exposure, fiber intake, body mass index, waist circumference, AMH level, 25-hydroxy vitamin D level, and growth of dominant follicles were obtained, assessed, and statistically analyzed. RESULTS: The AMH levels of patients with successful follicular growth were significantly lower (p=0.001) than those with unsuccessful follicular growth (6.10+/-3.52 vs. 10.43+/-4.78 ng/mL). A higher volume of fiber intake was also observed in the successful follicular growth group compared to unsuccessful follicular growth group (p=0.001). Our study found the probability of successful follicle growth was a function of AMH level and the amount of fiber intake, expressed as Y=-2.35+(-0.312*AMH level)+(0.464*fiber intake) (area under the curve, 0.88; 95% confidence interval, 0.79-0.98; p<0.001). CONCLUSION: The optimal threshold of AMH level in predicting the failure of follicle growth in patients with PCOS treated with CC was 8.58 ng/mL. PMID- 28090460 TI - Efficacy and safety of dienogest in patients with endometriosis: A single-center observational study over 12 months. AB - OBJECTIVE: To evaluate the efficacy and safety of dienogest treatment in patients who had received dienogest for 12 months or more to treat endometriosis. METHODS: We analyzed the clinical data of 188 women with endometriosis who had been treated with 2 mg of dienogest once a day for 12 months or more at a single institute. We evaluated changes in endometriosis-associated pain and endometrioma size, recurrence rate, and adverse events following dienogest administration. Bone mineral density (BMD) was measured in patients who were prescribed dienogest for more than 18 months. RESULTS: Pain was significantly reduced at 12 months after dienogest medication. In those treated with dienogest due to recurrent endometrioma, the size of the endometrioma was significantly decreased at the 12 month and 18-month follow-ups. We found only one case of sonographic recurrence during dienogest administration among those who were treated postoperatively to prevent recurrence (1 of 114, 0.9%). The most common adverse drug reaction was uterine bleeding (3.2%), and other adverse events were generally tolerable and associated with low discontinuation rates (5.2%). Among the 50 patients in whom BMD was measured, 10 patients (20%) had a Z-score below the expected range for age. CONCLUSION: The administration of dienogest for a year or more seems to be highly effective in preventing recurrence after surgery, reducing endometriosis associated pain, and decreasing the size of recurrent endometrioma, with a favorable safety and tolerability profile. However, BMD should be checked in patients on long-term medication due to possible bone loss in some women. PMID- 28090461 TI - Effects of maternal age on embryo quality and pregnancy outcomes using testicular sperm with intracytoplasmic sperm injection. AB - OBJECTIVE: The aim of this study was to evaluate the influence of maternal age on fertilization, embryo quality, and clinical pregnancy in patients undergoing intracytoplasmic sperm injection (ICSI) using testicular sperm from partners with azoospermia. METHODS: A total of 416 ICSI cycles using testicular spermatozoa from partners with obstructive azoospermia (OA, n=301) and non-obstructive azoospermia (NOA, n=115) were analyzed. Female patients were divided into the following age groups: 27 to 31 years, 32 to 36 years, and 37 to 41 years. The rates of fertilization, high-quality embryos, clinical pregnancy, and delivery were compared across maternal age groups between the OA and NOA groups. RESULTS: The rates of fertilization and high-quality embryos were not significantly different among the maternal age groups. Similarly, the clinical pregnancy and delivery rates were not significantly different. The fertilization rate was significantly higher in the OA group than in the NOA group (p<0.05). Age-group analysis revealed that the fertilization and high-quality embryo rates were significantly different between the OA and NOA groups in patients aged 27 to 31 years old, but not for the other age groups. Although the clinical pregnancy and delivery rates differed between the OA and NOA groups across all age groups, significant differences were not observed. CONCLUSION: In couples using testicular sperm from male partners with azoospermia, pregnancy and delivery outcomes were not affected by maternal age. However, women older than 37 years using testicular sperm from partners with azoospermia should be advised of the increased incidence of pregnancy failure. PMID- 28090462 TI - Pretreatment of normal responders in fresh in vitro fertilization cycles: A comparison of transdermal estradiol and oral contraceptive pills. AB - OBJECTIVE: The aim of this study was to investigate the impact of pretreatment with transdermal estradiol (E2) compared to oral contraceptive pills (OCPs) on controlled ovarian stimulation (COS) response in normal responders undergoing fresh in vitro fertilization (IVF)-embryo transfer (ET) cycles. METHODS: A retrospective cohort study was performed of normal responders undergoing fresh IVF-ET cycles who received pretreatment with transdermal E2 versus OCPs prior to fresh IVF-ET. The total days of ovarian stimulation, total dosage of gonadotropins, total number of oocytes, and mature oocytes retrieved were noted. Pregnancy outcomes after ET were also recorded. RESULTS: A total of 2,092 patients met the inclusion criteria: 1,057 and 1,035 patients in the transdermal E2 and OCP groups, respectively. Patients in the OCP group had a longer duration of COS (10.7+/-1.63 days, p<0.01) than the E2 group (9.92+/-1.94 days). Patients in the OCP group also required higher cumulative doses of gonadotropins (2,657.3+/-1,187.9 IU) than those in the E2 group (2,550.1+/-1,270.2 IU, p=0.002). No statistically significant differences were found in the total and mature oocytes retrieved or in the rates of biochemical pregnancy, clinical pregnancy, spontaneous miscarriage, and live birth between the groups. CONCLUSION: Our findings suggest that compared to OCPs, pretreatment with transdermal E2 is associated with a shorter duration of ovarian stimulation and lower gonadotropin utilization, without compromising the oocyte yield or pregnancy outcomes in normal-responder patients undergoing fresh IVF. PMID- 28090463 TI - Efficacy of oxytocin antagonist infusion in improving in vitro fertilization outcomes on the day of embryo transfer: A meta-analysis. AB - OBJECTIVE: Uterine contraction induced by the embryo transfer (ET) process has an adverse effect on embryo implantation. The aim of this study was to determine the effect of oxytocin antagonist supplementation on the day of ET on in vitro fertilization outcomes via a meta-analysis. METHODS: We performed a meta-analysis of randomized controlled trials (RCTs). Four online databases (Embase, Medline, PubMed, and Cochrane Library) were searched through May 2015 for RCTs that investigated oxytocin antagonist supplementation on the day of ET. Studies were selected according to predefined inclusion criteria and meta-analyzed using RevMan 5.3. Only RCTs were included in this study. The main outcome measures were the clinical pregnancy rate, the implantation rate, and the miscarriage rate. RESULTS: A total of 123 studies were reviewed and assessed for eligibility. Three RCTs, which included 1,020 patients, met the selection criteria. The implantation rate was significantly better in patients who underwent oxytocin antagonist infusion (19.8%) than in the control group (11.3%) (n=681; odds ratio [OR], 1.92; 95% confidence interval [CI], 1.25-2.96). No significant difference was found between the two groups in the clinical pregnancy rate (n=1,020; OR, 1.57; 95% CI, 0.92-2.67) or the miscarriage rate (n=456; OR, 0.76; 95% CI, 0.44-1.33). CONCLUSION: The results of this meta-analysis of the currently available literature suggest that the administration of an oxytocin antagonist on the day of ET improves the implantation rate but not the clinical pregnancy rate or miscarriage rate. Additional, large-scale, prospective, randomized studies are necessary to confirm these findings. PMID- 28090464 TI - The efficacy of intrauterine instillation of granulocyte colony-stimulating factor in infertile women with a thin endometrium: A pilot study. AB - OBJECTIVE: The study aimed to investigate the efficacy of intrauterine instillation of granulocyte colony-stimulating factor (G-CSF) on the day of ovulation triggering or oocyte retrieval in infertile women with a thin endometrium. METHODS: Fifty women whose endometrial thickness (EMT) was <=8 mm at the time of triggering during at least one previous in vitro fertilization (IVF) cycle and an index IVF cycle were selected. On the day of triggering (n=12) or oocyte retrieval (n=38), 300 ug of G-CSF was instilled into the uterine cavity. RESULTS: In the 50 index IVF cycles, the mean EMT was 7.2+/-0.6 mm on the triggering day and increased to 8.5+/-1.5 mm on the embryo transfer day (p<0.001). The overall clinical pregnancy rate was 22.0%, the implantation rate was 15.9%, and the ongoing pregnancy rate was 20%. The clinical pregnancy rate (41.7% vs. 15.8%), the implantation rate (26.7% vs. 11.7%), and the ongoing pregnancy rate (41.7% vs. 13.2%) were higher when G-CSF was instilled on the triggering day than when it was instilled on the retrieval day, although this tendency was likewise not statistically significant. Aspects of the stimulation process and mean changes in EMT were similar in women who became pregnant and women who did not. CONCLUSION: Intrauterine instillation of G-CSF enhanced endometrial development and resulted in an acceptable pregnancy rate. Instillation of G-CSF on the triggering day showed better outcomes. G-CSF instillation should be considered as a strategy for inducing endometrial growth and good pregnancy results in infertile women with a thin endometrium. PMID- 28090465 TI - Does intrauterine injection of low-molecular-weight heparin improve the clinical pregnancy rate in intracytoplasmic sperm injection? AB - OBJECTIVE: Heparin can modulate proteins, and influence processes involved in implantation and trophoblastic development. This study aimed to assess the improvement of clinical pregnancy and implantation rates after local intrauterine injection of low-molecular-weight heparin (LMWH) in patients undergoing intracytoplasmic sperm injection (ICSI). METHODS: A randomised case/control design was followed in women scheduled for ICSI. The study arm was injected with intrauterine LMWH during mock embryo transfer immediately following the ovum pickup procedure, while the control arm was given an intrauterine injection with a similar volume of tissue culture media. Side effects, the clinical pregnancy rate, and the implantation rate were recorded. RESULTS: The pregnancy rate was acceptable (33.9%) in the LMWH arm with no significant reported side effects, confirming the safety of the intervention. No statistically significant differences were found in the clinical pregnancy and implantation rates between both groups (p=0.182 and p=0.096, respectively). The odds ratio of being pregnant after intrauterine injection with LMWH compared to the control group was 0.572 (95% confidence interval [CI], 0.27-1.22), while the risk ratio was 0.717 (95% CI, 0.46-1.13; p=0.146). No statistical significance was found between the two groups in other factors affecting implantation, such as day of transfer (p=0.726), number of embryos transferred (p=0.362), or embryo quality. CONCLUSION: Intrauterine injection of LMWH is a safe intervention, but the dose used in this study failed to improve the outcome of ICSI. Based on its safety, further research involving modification of the dosage and/or the timing of administration could result in improved ICSI success rates. PMID- 28090466 TI - Microbiome-Linked Crosstalk in the Gastrointestinal Exposome towards Host Health and Disease. AB - The gastrointestinal exposome represents the integration of all xenobiotic components and host-derived endogenous components affecting the host health, disease progression and ultimately clinical outcomes during the lifespan. The human gut microbiome as a dynamic exposome of commensalism continuously interacts with other exogenous exposome as well as host sentineling components including the immune and neuroendocrine circuit. The composition and diversity of the microbiome are established on the basis of the luminal environment (physical, chemical and biological exposome) and host surveillance at each part of the gastrointestinal lining. Whereas the chemical exposome derived from nutrients and other xenobiotics can influence the dynamics of microbiome community (the stability, diversity, or resilience), the microbiomes reciprocally alter the bioavailability and activities of the chemical exposome in the mucosa. In particular, xenobiotic metabolites by the gut microbial enzymes can be either beneficial or detrimental to the host health although xenobiotics can alter the composition and diversity of the gut microbiome. The integration of the mucosal crosstalk in the exposome determines the fate of microbiome community and host response to the etiologic factors of disease. Therefore, the network between microbiome and other mucosal exposome would provide new insights into the clinical intervention against the mucosal or systemic disorders via regulation of the gut-associated immunological, metabolic, or neuroendocrine system. PMID- 28090467 TI - Early Infant Feeding Practices May Influence the Onset of Symptomatic Celiac Disease. AB - PURPOSE: To study whether breastfeeding and breastfeeding status during gluten introduction influences the age at diagnosis of celiac disease (CD). In addition to study, whether the timing of gluten introduction influences the age at diagnosis of CD. METHODS: It was a hospital based observational study. Total 198 patients diagnosed with CD as per modified European Society of Pediatric Gastroenterology, Hepatology and Nutrition (2012) criteria, aged between 6 months to 6 years were included. Detail history taken with special emphasis on breastfeeding and age of gluten introduction. Standard statistical methods used to analyze the data. RESULTS: Mean+/-standard deviation age of onset and diagnosis of CD in breastfed cases was 2.81+/-1.42 years and 3.68 +/-1.55 years respectively as compared to 1.84+/-1.36 years and 2.70+/-1.65 years respectively in not breastfed cases (p<0.05). Those who had continued breastfeeding during gluten introduction and of longer duration had significantly delayed onset of disease. The age at onset of CD was under one year in 40.42% of the cases, who had started gluten before 6 months of age compared to only 12.58% of those who had started gluten later (p<0.001). The proposed statistical model showed that two variables, i.e., breast feeding status during gluten introduction and age at gluten introduction positively influencing the age at diagnosis of CD. CONCLUSION: Delayed gluten introduction to infant's diet along with continuing breastfeeding, delays symptomatic CD. However, it is not clear from our study that these infant feeding practices provide permanent protection against the disease or merely delays the symptoms. PMID- 28090468 TI - Clinical Features and Extraintestinal Manifestations of Crohn Disease in Children. AB - PURPOSE: The aim of this study was to investigate the clinical features and extraintestinal manifestations (EIMs) of Crohn disease (CD) in Korean pediatric patients. METHODS: The medical records of 73 children diagnosed with CD were retrospectively reviewed. Data regarding baseline demographic and clinical characteristics, including CD phenotype at diagnosis based on the Montreal classification, and clinical features and course of EIMs were investigated. RESULTS: Fifty-two (71.2%) of the patients were males. The mean age of the patients was 12.5 years. The mean follow-up period was 3.4 years. The disease location was ileal in 3 (4.1%) of the patients, colonic in 13 (17.8%), ileocolonic in 56 (76.7%). The clinical behavior was inflammatory in 62 (84.9%) of the patients, stricturing in 8 (11.0%), and penetrating in 3 (4.1%). Perianal abscesses or fistulas were found in 37 (50.7%) of the patients. EIMs observed during the study period were anal skin tag in 25 patients (34.2%), hypertransaminasemia in 20 (27.4%), peripheral arthritis in 2 (2.7%), erythema nodosum in 2 (2.7%), vulvitis in 1 (1.4%), uveitis in 1 (1.4%), and pulmonary thromboembolism in 1 (1.4%). CONCLUSION: Perianal diseases and manifestations were present in more than half of Korean pediatric CD patients at diagnosis. Inspection of the anus should be mandatory in Korean children with suspicious CD, as perianal fistulas, abscesses, and anal skin tags may be the first clue to the diagnosis of CD. PMID- 28090469 TI - The Relationships between Respiratory Virus Infection and Aminotransferase in Children. AB - PURPOSE: We sought to examine the relationship between the clinical manifestations of nonspecific reactive hepatitis and respiratory virus infection in pediatric patients. METHODS: Patients admitted to the pediatric unit of Konyang University Hospital for lower respiratory tract disease between January 1, 2014 and December 31, 2014 and who underwent reverse transcriptase polymerase chain reaction tests were examined. The patients were divided into those with increased levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) and those with normal ALT or AST levels. Further, patients with increased ALT and AST levels were individually compared with patients in the normal group, and the blood test results were compared according to the type of respiratory virus. RESULTS: Patients with increased ALT or AST levels had one more day of hospital stay, on average, compared with patients in the normal group (5.3+/-3.1 days vs. 4.4+/-3.0 days, p=0.019). Patients in the increased ALT level group were younger and had a longer mean hospital stay, compared with patients in the normal group (p=0.022 and 0.003, respectively). The incidences of increased ALT or AST were the highest in adenovirus infections (6/24, 25.0%), followed by enterovirus (2/11, 18.2%) and respiratory syncytial virus A (21/131, 16.0%) infections. CONCLUSION: Nonspecific reactive hepatitis is more common among patients with adenovirus, enterovirus and respiratory syncytial virus infection, as well as among those infected at a younger age. Compared with AST levels, ALT levels are better indicators of the severity of nonspecific reactive hepatitis. PMID- 28090470 TI - Acanthosis Nigricans as a Clinical Predictor of Insulin Resistance in Obese Children. AB - PURPOSE: This study aimed to evaluate the utility of acanthosis nigricans (AN) severity as an index for predicting insulin resistance in obese children. METHODS: The subjects comprised 74 obese pediatric patients who attended the Department of Pediatrics at Chosun University Hospital between January 2013 and March 2016. Waist circumference; body mass index; blood pressure; fasting glucose and fasting insulin levels; lipid profile; aspartate transaminase, alanine transaminase, glycated hemoglobin, C-peptide, and uric acid levels; and homeostatic model assessment insulin resistance (HOMA-IR) and quantitative insulin check sensitivity index (QUICKI) scores were compared between subjects with AN and those without AN. Receiver operating characteristic curves were used to investigate the utility of the AN score in predicting insulin resistance. HOMA IR and QUICKI were compared according to AN severity. RESULTS: The With AN group had higher fasting insulin levels (24.1+/-21.0 mU/L vs. 9.8+/-3.6 mU/L, p<0.001) and HOMA-IR score (5.74+/-4.71 vs. 2.14+/-0.86, p<0.001) than the Without AN group. The AN score used to predict insulin resistance was 3 points or more (sensitivity 56.8%, specificity 83.9%). HOMA-IR scores increased with AN severity, from the Without AN group (mean, 2.15; 95% confidence interval [CI], 1.72-2.57) to the Mild AN (mean, 4.15; 95% CI, 3.04-5.25) and Severe AN groups (mean, 7.22; 95% CI, 5.08-9.35; p<0.001). CONCLUSION: Insulin resistance worsens with increasing AN severity, and patients with Severe AN (AN score >=3) are at increased risk of insulin resistance. PMID- 28090471 TI - Hair Zinc Level Analysis and Correlative Micronutrients in Children Presenting with Malnutrition and Poor Growth. AB - PURPOSE: Zinc deficiency can induce serious clinical problems in the gastrointestinal (GI) system and immune system and can affect growth and development. It is more severe in younger patients. Chronic zinc deficiency is reflected more precisely in hair than in serum. We studied hair zinc levels and other hair and serum micronutrients in chronic malnourished children to identify which micronutrients are affected or correlated with the other ones. METHODS: Hair mineral analyses were performed in 56 children (age, 1-15 years) presenting with malnutrition, poor growth, poor appetite, anorexia, with/without other GI symptoms (diarrhea, abdominal pain, constipation) from August 2012 to March 2015. Biochemical studies for macronutrients and major micronutrients were also conducted. RESULTS: Hair zinc deficiency was diagnosed in 88%, and serum zinc deficiency was diagnosed in 55% of the children. There was no statistical correlation between serum and tissue zinc level. Hair zinc levels were highly correlated with serum vitamin D (r=-0.479, p=0.001), which also showed correlation with hair levels of magnesium and calcium. (r=0.564, 0.339, p=0.001, 0.011). Hair calcium level was correlated with serum pre-albumin (r=0.423, p=0.001). These correlations may explain the phenomenon that the major clinical manifestation of zinc deficiency is poor body growth. Clinical symptoms were resolved in most children after zinc supplementation. CONCLUSION: Hair zinc and mineral analyses are useful as a therapeutic guide in the clinical investigation of children with malnutrition and poor growth. PMID- 28090473 TI - Three Year Old Male with Multiple Dieulafoy Lesions Treated with Epinephrine Injections via Therapeutic Endoscopy. AB - Dieulafoy lesions, vascular anomalies typically found along the gastrointestinal tract, have been viewed as rare and obscure causes of sudden intestinal bleeding, especially in pediatric patients. Since their discovery in the late 19th century, the reported incidence has increased. This is due to an increased awareness of, and knowledge about, their presentation and to advanced endoscopic diagnosis and therapy. Our patient was a three-year-old male, without a complex medical history. He presented to the emergency department with acute hematemesis with blood clots and acute anemia requiring blood transfusion. Endoscopy revealed four isolated Dieulafoy lesions along the lesser curvature of the stomach, which were treated with an epinephrine injection. The Dieulafoy lesion, although thought to be rare, should be considered when investigating an acute gastrointestinal bleed. These lesions have been successfully treated endoscopically. Appropriate anticipation and preparation for diagnosis and therapy can lead to optimal outcomes for the pediatric patient. PMID- 28090472 TI - Prevalence and Risk Factors for the Weight Loss during Hospitalization in Children: A Single Korean Children's Hospital Experience. AB - PURPOSE: Undernutrition during hospitalization increases the risk of nosocomial infection and lengthens the disease courses. The aim of this study was to evaluate the risk factors of weight loss during hospitalization in children. METHODS: All the patients who were admitted in general wards between April and May 2014 were enrolled. Patients aged >18 years and discharged within 2 days were excluded. Weight loss during hospitalization was defined as a decrease in body weight of >2% in 8 hospital days or on the day of discharge. Patients who lost body weight during hospitalization were compared with patients who maintained their body weights. Significant parameters were evaluated by using the multivariate logistic regression analysis. RESULTS: We enrolled 602 patients, of whom 149 (24.8%) lost >2% of their body weight. Complaint of pain (p=0.004), admission to the surgical department (p=0.001), undergoing surgery (p=0.044), undergoing abdominal surgery (p=0.034), and nil per os (NPO) durations (p=0.003) were related to weight loss during hospitalization. The patients who had high weight-for-age tended to lose more body weight (p=0.001). Admission to the surgical department (odds ratio [OR], 1.668; 95% confidence interval [CI], 1.054 2.637; p=0.029) and long NPO durations (OR, 1.496; 95% CI, 1.102-2.031; p=0.010) were independent risk factors of weight loss during hospitalization. The patients with high weight-for-age tended to lose more weight during hospitalization (OR, 1.188; 95% CI, 1.029-1.371; p=0.019). CONCLUSION: Greater care in terms of nutrition should be taken for patients who are admitted in the surgical department and have prolonged duration of nothing by mouth. PMID- 28090474 TI - Post Laparoscopic Cholecystectomy Biloma in a Child Managed by Endoscopic Retrograde Cholangio-Pancreatography and Stenting: A Case Report. AB - Laparoscopic cholecystectomy, though an uncommon surgical procedure in paediatric age group is still associated with a higher risk of post-operative bile duct injuries when compared with the open procedure. Small leaks from extra hepatic biliary apparatus usually lead to the formation of a localized sub-hepatic bile collection, also known as biloma. Such leaks are rare complication after laparoscopic cholecystectomy, especially in paediatric age group. Minor bile leaks can usually be managed non-surgically by percutaneous drainage combined with endoscopic retrograde cholangio-pancreatography (ERCP). However, surgical exploration is required in cases not responding to non-operative management. If not managed on time, such injuries can lead to severe hepatic damage. We describe a case of an eight-year-old girl who presented with biloma formation after laparoscopic cholecystectomy who was managed by ERCP. PMID- 28090475 TI - Use of Omega-3 Polyunsaturated Fatty Acids to Treat Inspissated Bile Syndrome: A Case Report. AB - Inspissated bile syndrome (IBS) is a rare condition in which thick intraluminal bile, including bile plugs, sludge, or stones, blocks the extrahepatic bile ducts in an infant. A 5-week-old female infant was admitted for evaluation of jaundice and acholic stool. Diagnostic tests, including ultrasound sonography, magnetic resonance cholangiopancreatography, and a hepatobiliary scan, were not conclusive. Although the diagnosis was unclear, the clinical and laboratory findings improved gradually on administration of urodeoxycholic acid and lipid emulsion containing omega-3 polyunsaturated fatty acids (PUFAs) for 3 weeks. However, a liver biopsy was suggestive of biliary atresia. This finding forced us to perform intraoperative cholangiography, which revealed a patent common bile duct with impacted thick bile. We performed normal saline irrigation and the symptom was improved, the final diagnosis was IBS. Thus, we herein report that IBS can be treated with omega-3 PUFAs as an alternative to surgical intervention. PMID- 28090476 TI - Correction: Middle East Consensus Statement on the Diagnosis and Management of Functional Gastrointestinal Disorders in <12 Months Old Infants. AB - [This corrects the article on p. 153 in vol. 19, PMID: 27738596.]. PMID- 28090477 TI - The Economic Cost of Implementing Maternal and Neonatal Death Review in a District of Bangladesh. AB - INTRODUCTION: Maternal and neonatal death review (MNDR) introduced in Bangladesh and initially piloted in a district during 2010. MNDR is able to capture each of the maternal, neonatal deaths and stillbirths from the community and government facilities (hospitals). This study aimed to estimate the cost required to implement MNDR in a district of Bangladesh during 2010-2012. MATERIALS AND METHODS: MNDR was implemented in Thakurgaon district in 2010 and later gradually extended until 2015. MNDR implementation framework, guidelines, tools and manual were developed at the national level with national level stakeholders including government health and family planning staff at different cadre for piloting at Thakurgaon. Programme implementation costs were calculated by year of costing and costing as per component of MNDR in 2013. The purchasing power parity conversion rate was 1 $INT = 24.46 BDT, as of 31st Dec 2012. RESULTS: Overall programme implementation costs required to run MNDR were 109,02,754 BDT (445,738 $INT $INT) in the first year (2010). In the following years cost reduced to 8,208,995 BDT (335,609 $INT, during 2011) and 6,622,166 BDT (270,735 $INT, during 2012). The average cost per activity required was 3070 BDT in 2010, 1887 BDT and 2207 BDT required in 2011 and 2012 respectively. Each death notification cost 4.09 $INT, verbal autopsy cost 8.18 $INT, and social autopsy cost 16.35 $INT. Facility death notification cost 2.04 $INT and facility death review meetings cost 20.44 $INT. One death saved by MNDR costs 53,654 BDT (2193 $INT). CONCLUSIONS: Programmatic implementation cost of conducting MPDR give an idea on how much cost will be required to run a death review system for a low income country settings using government health system. PMID- 28090478 TI - The Human Microbiome: A Public Health Approach. PMID- 28090479 TI - Mixed-phenotype acute leukemia (MPAL) and beyond. PMID- 28090480 TI - Copper deficiency mimicking myelodysplastic syndrome. PMID- 28090481 TI - Salvage treatment of relapsed/refractory LCH. PMID- 28090482 TI - Complex cytogenetics in a patient with mixed-phenotype acute leukemia. PMID- 28090483 TI - Emphysematous osteomyelitis due to Escherichia coli in multiple myeloma. PMID- 28090484 TI - Mesenchymal stromal cells in myeloid malignancies. AB - Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal myeloid disorders characterized by hematopoietic insufficiency. As MDS and AML are considered to originate from genetic and molecular defects of hematopoietic stem and progenitor cells (HSPC), the main focus of research in this field has focused on the characterization of these cells. Recently, the contribution of BM microenvironment to the pathogenesis of myeloid malignancies, in particular MDS and AML has gained more interest. This is based on a better understanding of its physiological role in the regulation of hematopoiesis. Additionally, it was demonstrated as a 'proof of principle' that genetic disruption of cells of the mesenchymal or osteoblastic lineage can induce MDS, MPS or AML in mice. In this review, we summarize the current knowledge about the contribution of the BM microenvironment, in particular mesenchymal stromal cells (MSC) to the pathogenesis of AML and MDS. Furthermore, potential models integrating the BM microenvironment into the pathophysiology of these myeloid disorders are discussed. Finally, strategies to therapeutically exploit this knowledge and to interfere with the crosstalk between clonal hematopoietic cells and altered stem cell niches are introduced. PMID- 28090485 TI - Mixed-phenotype acute leukemia: suboptimal treatment when the 2008/2016 WHO classification is used. AB - BACKGROUND: Different criteria have been used to diagnose mixed-phenotype acute leukemia (MPAL), which has impacted the number of individuals diagnosed with this pathology. Better outcomes have been reported when using acute lymphoblastic leukemia (ALL)-type chemotherapy in the treatment of MPAL. METHODS: We compared the outcome of 4 groups of patients with MPAL. Group 1 included patients diagnosed using the 2008/2016 World Health Organization (WHO) classification; group 2 included patients diagnosed using the European Group for the Immunological Characterization of Leukemias (EGIL) criteria; group 3 included patients diagnosed using either the EGIL or the 2008/2016 WHO criteria; and group 4 was comprised of patients diagnosed with MPAL using the EGIL classification only. RESULTS: We found a significantly worse disease-free survival (groups 1-4) and overall survival (OS) (groups 2 and 3) when comparing MPAL patients to other acute leukemia (AL) patients. A significantly better OS was obtained in patients (groups 2-4) treated with ALL-type chemotherapy compared to acute myeloid leukemia (AML)-type regimens. CONCLUSION: In light of these results, and because a trend (P=0.06) was found with regard to a better OS in group 4 when compared to other AL patients, an argument can be made that the 2008/2016 WHO classification is underpowered to diagnose all MPAL cases, potentially resulting in the suboptimal treatment of some individuals with AL. PMID- 28090486 TI - Therapy-related myeloid neoplasms in children and adolescents. AB - BACKGROUND: This retrospective study aimed to characterize and analyze the outcome of therapy-related myeloid neoplasms (t-MNs) in children and adolescents. METHODS: The medical records of 16 patients under 21 years of age at the time of t-MN diagnosis were reviewed. RESULTS: The median patient age was 11.5 years (range, 1.6-20.4 yr). Twelve patients had therapy-related acute myeloid leukemia, 3 patients had myelodysplastic syndrome, and 1 patient had chronic myelomonocytic leukemia. The median latency period was 29 months (range, 11-68 mo). Fourteen patients had cytogenetic aberrations, 8 of whom had an 11q23 abnormality. Of the 13 patients treated with curative intent, 12 patients received myeloid-type induction therapy that led to complete remission (CR) in 8 patients. Nine patients underwent allogeneic transplantation; 4 patients did not undergo transplantation due to chemotherapy-related toxic death (N=3) or parental refusal (N=1). The 5-year overall survival and event-free survival of the 13 patients treated with a curative intent were 46.2% and 30.8%, respectively. For the 9 patients who underwent allogeneic transplantation, the 5-year event-free survival was 66.7%. CONCLUSION: A significant proportion of young patients with t-MNs can experience long-term survival, and allogeneic transplantation plays a key role for attaining cure in these patients. PMID- 28090487 TI - Clinical characteristics and outcomes of varicella zoster virus infection in children with hematologic malignancies in the acyclovir era. AB - BACKGROUND: Although intravenous acyclovir therapy is recommended for varicella zoster virus (VZV) infection in immunocompromised children, the clinical characteristics and outcomes of VZV infection in the acyclovir era have rarely been reported. METHODS: The medical records of children diagnosed with varicella or herpes zoster virus, who had underlying hematologic malignancies, were retrospectively reviewed, and the clinical characteristics and outcomes of VZV infection were evaluated. RESULTS: Seventy-six episodes of VZV infection (herpes zoster in 57 and varicella in 19) were identified in 73 children. The median age of children with VZV infection was 11 years (range, 1-17), and 35 (46.1%) episodes occurred in boys. Acute lymphoblastic leukemia was the most common underlying malignancy (57.9%), and 90.8% of the episodes occurred during complete remission of the underlying malignancy. Acyclovir was administered for a median of 10 days (range, 4-97). Severe VZV infection occurred in 16 (21.1%) episodes. Although the finding was not statistically significant, a previous history of hematopoietic cell transplantation (HCT) appeared to be associated with the development of more severe episodes of herpes zoster (P=0.075). CONCLUSION: Clinical characteristics of VZV infection in immunocompromised children were not significantly different from those without it, and clinical outcomes improved after the introduction of acyclovir therapy. However, risk factors for severe VZV infection require further investigation in a larger population and a prospective setting. PMID- 28090488 TI - Excellent outcome of medical treatment for Kasabach-Merritt syndrome: a single center experience. AB - BACKGROUND: Kasabach-Merritt syndrome (KMS) is a rare but life-threatening illness. The purpose of this study is to report our single-center experience with KMS. METHODS: We reviewed the medical records of 13 patients who were diagnosed with KMS between 1997 and 2012 at Samsung Medical Center. Treatment response was defined as follows: 1) hematologic complete response (HCR) - platelet count >130*109/L without transfusion; 2) clinical complete response (CCR) - complete tumor disappearance or small residual vascular tumor displaying lack of proliferation for at least 6 months after treatment discontinuation. RESULTS: Participants included 7 male and 6 female patients. The median initial hemoglobin levels and platelet counts were 9.7 g/dL (range, 6.6-11.6 g/dL) and 11*109/L (range, 3-38*109/L), respectively. Twelve patients received corticosteroid and interferon-alpha as initial treatment, and the remaining patient received propranolol instead of corticosteroid. Two patients with unsatisfactory response to the initial treatment received weekly vincristine. Successful discontinuation of medication was possible at a median of 301 days (range, 137-579) in all patients except one who was lost to follow-up. The median times to achieve HCR and CCR were 157 days and 332 days, respectively. The probabilities of achieving HCR and CCR were 77% and 54% at 1 year, and 88% and 86% at 2.5 years, respectively. CONCLUSION: The prognosis of KMS in our cohort was excellent. Our data suggest that individualized treatment adaptation according to response may be very important for the successful treatment of patients with KMS. PMID- 28090489 TI - Effect of short-term, high-dose methylprednisolone on oxidative stress in children with acute immune thrombocytopenia. AB - BACKGROUND: Immune thrombocytopenia (ITP) is the most common cause of acquired childhood thrombocytopenia and is characterized by increased immune-mediated destruction of circulating thrombocytes. Oxidative damage may be involved in ITP pathogenesis; paraoxonase (PON) and arylesterase (ARE) enzymes are closely associated with the cellular antioxidant system. We investigated the effect of short-term high-dose methylprednisolone (HDMP) treatment on the total oxidant status (TOS), total antioxidant capacity (TAC), oxidative stress index (OSI), and PON and ARE enzymatic activity in children with acute ITP. METHODS: Thirty children with acute ITP constituted the study group and 30 healthy children constituted the control group. Children with acute ITP were treated with HDMP: 30 mg/kg for 3 days, then 20 mg/kg for 4 days. The TOS, TAC, OSI, PON, and ARE levels were determined before and after 7 days of HDMP treatment. RESULTS: The TAC level (P<0.001), and PON (P<0.001) and ARE (P=0.001) activities were lower and the TOS (P=0.003) and OSI (P<0.001) levels were higher in children with acute ITP than those in healthy children in the control group. We also observed statistically significant increases in the TAC (P<0.01), PON (P<0.001) and ARE levels (P=0.001) and decreases in the TOS (P<0.05) and OSI levels (P<0.05) with 7 days of HDMP treatment compared to their values before treatment. CONCLUSION: Our study demonstrated increased oxidative stress (OSI and TOC) and decreased antioxidant capacity (TAC), PON, and ARE in ITP patients and that steroid treatment could be effective in reducing the oxidative stress. PMID- 28090490 TI - Iron deficiency anemia in infants and toddlers. AB - BACKGROUND: In Korea, the prevalence of anemia and iron deficiency anemia (IDA) among older infants and young children remains high. To detect IDA early and to reduce its adverse impact, we assessed the characteristics of infants and young children who had IDA or were at risk of developing IDA, or who exhibited characteristics associated with severe anemia. METHODS: Among the 1,782 IDA affected children aged 6 months to 18 years who visited the hospital, we retrospectively analyzed the medical records and laboratory data of 1,330 IDA affected children aged 6-23 months who were diagnosed between 1996 and 2013. We excluded patients with a C-reactive protein level >=5 mg/dL. RESULTS: IDA was predominant in boys (2.14:1) during infancy and early childhood. The peak IDA incidence was noted among infants aged 9-12 months. Only 7% patients exhibited symptoms of IDA, while 23.6% patients with severe IDA demonstrated classic symptoms/signs of IDA. Low birth weight (LBW) infants with IDA demonstrated low adherence to iron supplementation. In a multivariate analysis, prolonged breastfeeding without iron fortification (odds ratio [OR] 5.70), and a LBW (OR 6.49) were identified as risk factors of severe anemia. CONCLUSION: LBW infants need more attention in order to increase their adherence to iron supplementation. For the early detection of IDA, nutritional status of all infants, and iron batteries of high-risk infants (LBW infants, infants with prolonged breastfeeding, picky eaters, and/or infants with the presence of IDA symptoms) should be evaluated at their health screening visits. PMID- 28090491 TI - Allelic variance among ABO blood group genotypes in a population from the western region of Saudi Arabia. AB - BACKGROUND: Characterization of the ABO blood group at the phenotype and genotype levels is clinically essential for transfusion, forensics, and population studies. This study elucidated ABO phenotypes and genotypes, and performed an evaluation of their distribution in individuals from the western region of Saudi Arabia. METHODS: One-hundred and seven samples underwent standard serological techniques for ABO blood group phenotype analysis. ABO alleles and genotypes were identified using multiplex polymerase chain reaction, and electrophoretic analysis was performed to evaluate the highly polymorphic ABO locus. RESULTS: A phenotype distribution of 37.4%, 30.8%, 24.3%, and 7.5% was found for blood groups O, A, B, and AB respectively in our study cohort. Genotype analysis identified 10 genotype combinations with the O01/O02 and A102/O02 genotypes being the most frequent with frequencies of 33.6% and 14.95%, respectively. Common genotypes such as A101/A101, A101/A102, A101/B101, B101/B101, and O01/O01 were not detected. Similarly, the rare genotypes, cis-AB01/O02, cis-AB01/O01, and cis AB01/A102 were not found in our cohort. The most frequently observed allele was O02 (35.98%) followed by the A102 allele (17.76%). Furthermore, our findings are discussed in reference to ABO allele and genotype frequencies found in other ethnic groups. CONCLUSION: The study has a significant implication on the management of blood bank and transfusion services in Saudi Arabian patients. PMID- 28090492 TI - The first case of acute myeloid leukemia with solitary t(6;7)(p21.3;p22) passenger translocation that developed at relapse after allogeneic hematopoietic stem cell transplantation in a patient with a normal karyotype at the initial diagnosis. PMID- 28090493 TI - Toxic megacolon and interstitial pneumonia caused by cytomegalovirus infection in a pediatric patient with acute lymphoblastic leukemia receiving chemotherapy. PMID- 28090494 TI - Salvage chemotherapy with R-BAD (rituximab, bendamustine, cytarabine, and dexamethasone) for the treatment of relapsed primary CNS lymphoma. PMID- 28090495 TI - Disseminated cytomegalovirus-associated hemophagocytic lymphohistiocytosis in an elderly patient. PMID- 28090496 TI - Steps taken to alleviate under-reporting of transfusion reactions at a public sector hospital in Pakistan. PMID- 28090497 TI - Factors associated with vasovagal reactions in apheresis plasma and whole blood donors: a statistical-epidemiological study in a European donor cohort. PMID- 28090498 TI - Successful treatment of steroid-refractory immune thrombocytopenia with alemtuzumab. PMID- 28090499 TI - Risk factors associated with high thyroglobulin level following radioactive iodine ablation, measured 12 months after treatment for papillary thyroid carcinoma. AB - PURPOSE: The measurement of serum thyroglobulin (Tg) of papillary thyroid carcinoma patients, 12 months after total thyroidectomy and radioactive iodine (RAI) ablation following thyroxine hormone withdrawal (T4-off Tg) or recombinant human thyroid-stimulating hormone stimulation (rhTSH-Tg), is standard method for monitoring disease status. The aim of this study was to find predictive factors for detectable T4-off Tg during follow-up. METHODS: A retrospective review was conducted of 329 patients who underwent total thyroidectomy and RAI ablation between October 2008 and August 2012. Subjects were assigned to high (>1 ng/mL, n = 53) and low (<=1 ng/mL, n = 276) groups, based on T4-off Tg measured 12 months postoperatively. Demographic and clinicopathological characteristics at diagnosis and follow-up were compared between the 2 groups. RESULTS: The low and high T4 off Tg groups differed with respect to tumor size, preoperative Tg, ablative Tg, cervical lymph node metastasis, thyroglobulinemia out of proportion to results of diagnostic whole body scan, and American Thyroid Association 3-level stratification and restratification. Multivariate analysis confirmed that ablative Tg > 1.0 ng/mL (odds ratio [OR], 10.801; P = 0.001), more than 5 cervical lymph node metastasis (OR, 6.491; P = 0.003), and thyroglobulinemia out of proportion (OR, 9.221; P = 0.000) were risk factors. CONCLUSION: Ablative Tg >1.0 ng/mL, more than 5 cervical lymph node metastasis, and thyroglobulinemia out of proportion were independent factors for T4-off Tg >1 ng/mL 12 months postoperative. In low-risk patients without these risk factors, the possible omission of Tg measurements could be considered during follow-up. PMID- 28090500 TI - A comparison of postoperative pain after conventional open thyroidectomy and single-incision, gasless, endoscopic transaxillary thyroidectomy: a single institute prospective study. AB - PURPOSE: The aim of this study was to compare postoperative pain between single incision, gasless, endoscopic transaxillary thyroidectomy (SET), and conventional open thyroidectomy. METHODS: From March to December 2015, patients with thyroid disease underwent total thyroidectomy or lobectomy. Patient's clinical and pathological characteristics, postoperative pain score using visual analog scale (VAS) were compared between the 2 groups. The primary endpoint was postoperative pain evaluated by VAS score and postoperative analgesic use. Operation time and length of postoperative hospital stay were secondary outcome measures. RESULTS: Conventional, open cervical surgery was performed on 30 patients (group O) and SET was performed on 27 patients (group E). Pain scores in shoulder area, which is the ipsilateral side of the tumor location at 1 hour and 24 hours after surgery, were higher in group E patients (P < 0.05). Pain scores 7 days after surgery did not differ between the 2 groups according to the locations (P < 0.05). CONCLUSION: In conclusion, endocrine surgeons should be concerned about immediate higher postoperative pain scores in patients who undergo SET. PMID- 28090501 TI - Clinical implications of APEX1 and Jagged1 as chemoresistance factors in biliary tract cancer. AB - PURPOSE: Biliary cancer is a highly malignant neoplasm with poor prognosis and most patients need to undergo palliative chemotherapy, however major clinical problem associated with the use of chemotherapy is chemoresistance. So far, we aimed at investigating clinical implications of apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) and Jagged1 as chemoresistance factors in biliary tract cancer. METHODS: We used 5 human biliary tract cancer cell lines (SNU-245, SNU-308, SNU-478, SNU-1079, and SNU-1196), and investigated the chemosensitivity of APEX1 and Jagged1 through 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide (MTT) assay and Western blot. Alternately, the 10 patients of advanced biliary cancer consist of 2 group according to the chemotherapy response examined by immunohistochemistry using APEX1 and Jagged1 antibody, and protein expression level was scored for staining intensity and percent positive cell. RESULTS: The result of MTT assay after APEX1 knockdown showed that strong coexpression of APEX1 and Jagged1 cell line (SNU-245, SNU 1079, and SNU-1196) showed a greater decrease in IC50 of chemotherapeutic agent (5-fluorouracil, gemcitabine and cisplatin). The Western blot analysis of APEX1 and Jagged1 expression in biliary cancer cell lines after APEX1 knockdown definitively demonstrated decreased Jagged1 expression. The APEX1 and Jagged1expression level of immunohistochemistry represented that chemorefractory patients had higher than chemoresponsive patients. CONCLUSION: These results demonstrate that simultaneous high expression of APEX1 and Jagged1 is associated with chemoresistance in biliary cancer and suggest that is a potential therapeutic target for chemoresistance in advanced biliary cancer. PMID- 28090502 TI - Is noncurative gastrectomy always a beneficial strategy for stage IV gastric cancer? AB - PURPOSE: The purpose of this study is to suggest a treatment strategy for stage IV gastric cancer by investigating the behavioral difference between initially and recurrent metastatic disease. METHODS: We reviewed the medical records of the patients who underwent chemotherapy alone for metastatic gastric cancer between January 2006 and September 2013. Patients were divided into those who underwent chemotherapy for metastatic disease since initial diagnosis (IM group) and for metastatic recurrence after curative surgery (RM group). Survival and causes of death were compared between the 2 groups, and significant prognostic factors were also investigated. RESULTS: A total of 170 patients were enrolled in this study. Of these patients, 104 were included in the IM group and 66 in the RM group. Overall survival of the IM group did not differ from that of RM (P = 0.569). In the comparison of the causes of death, the IM group had a greater tendency to die from bleeding (P = 0.054) and pneumonia (P = 0.055). In multivariate analysis, bone metastasis (P < 0.001; HR = 2.847), carcinoma peritonei (P = 0.047; HR = 1.766), and the frequency of chemotherapy (P < 0.001; HR = 0.777) were significantly associated with overall survival of IM group. CONCLUSION: Disease burden mainly contributes to the prognosis of metastatic gastric cancer, although noncurative gastrectomy may be helpful in reducing the mortality of initially metastatic disease. Therefore, disease-burden should be also prioritized in determining the treatment strategies for stage IV gastric cancer. PMID- 28090503 TI - Intracorporeal esophagojejunostomy using hemi-double-stapling technique after laparoscopic total gastrectomy in gastric cancer patients. AB - PURPOSE: To present the feasibility and safety of Roux-en-Y esophagojejunostomy using hemi-double-stapling technique after laparoscopic total gastrectomy. METHODS: We reviewed the outcomes from 58 consecutive patients with gastric cancer who underwent laparoscopic total gastrectomy. The clinicopathological characteristics including postoperative complications were examined. RESULTS: The mean age and body mass index were 57.3 +/- 9.7 years and 23.7 +/- 2.6 kg/m2, respectively. The mean overall total operation was 199.8 +/- 57.0 minutes. Intraoperative blood loss was 81.6 +/- 56.3 mL and there was no open conversion. The patients' hospital stay was a mean 9.6 +/- 2 days. The mean proximal margin of the specimens was 2.7 +/- 1.8 cm. There were 3 cases (5.1%) of anastomosis leakage, but all were controlled successfully by endoscopic stent. CONCLUSION: The circular HDST technique is simple and reliable without any significant demerits with respect to safety concerns or difficulty of operation. PMID- 28090504 TI - Fortune of temporary ileostomies in patients treated with laparoscopic low anterior resection for rectal cancer. AB - PURPOSE: The current study aims to analyze the risk factors for the failure of ileostomy reversal after laparoscopic low anterior resection for rectal cancer. METHODS: All patients who underwent a laparoscopic low anterior resection for rectal cancer with a diverting ileostomy between 2007 and 2014 were abstracted. The patients who underwent and did not undergo a diverting ileostomy procedure were compared regarding patient, tumor, treatment related parameters, and survival. RESULTS: Among 160 (103 males [64.4%], mean [+/- standard deviation] age was 58.1 +/- 11.9 years) patients, stoma reversal was achieved in 136 cases (85%). Anastomotic stricture (n = 13, 52.4%) was the most common reason for stoma reversal. These were the risk factors for the failure of stoma reversal: Male sex (P = 0.035), having complications (P = 0.01), particularly an anastomotic leak (P < 0.001), or surgical site infection (P = 0.019) especially evisceration (P = 0.011), requirement for reoperation (P = 0.003) and longer hospital stay (P = 0.004). Multivariate analysis revealed that male sex (odds ratio [OR], 7.82; P = 0.022) and additional organ resection (OR, 6.71; P = 0.027) were the risk factors. Five-year survival rates were similar (P = 0.143). CONCLUSION: Fifteen percent of patients cannot receive a stoma reversal after laparoscopic low anterior resection for rectal cancer. Anastomotic stricture is the most common reason for the failure of stoma takedown. Having complications, particularly an anastomotic leak and the necessity of reoperation, limits the stoma closure rate. Male sex and additional organ resection are the risk factors for the failure in multivariate analyses. These patients require a longer hospitalization period, but have similar survival rates as those who receive stoma closure procedure. PMID- 28090505 TI - Usefulness of intraopertive ultrasonography during directional atherectomy using SilverHawk/TurboHawk system. AB - PURPOSE: Directional atherectomy (DA) was introduced for the management of infrainguinal arterial stenosis or occlusive lesions. The procedure success rate in the DEFINITIVE LE study was determined using radiologic imaging. The aim of our study was to determine the usefulness of intraoperative ultrasonography (USG) during DA for evaluating the early results of this procedure. METHODS: Patients who underwent DA from January to December 2014 were reviewed retrospectively. Twenty lesions from 14 patients with femoral artery stenosis (>70% stenosis) with short segment occlusive lesions (<2 cm in length) were treated. Among 20 lesions, 3 were treated with the TurboHawk system with a protective device due to lesion calcification. The percentage of stenosis during and after DA was determined with USG. RESULTS: Median follow-up was 5.1 months, and the procedural success rate (<30% stenosis at the end of the procedure) was 100% on angiography, but only 30% on intraoperative USG. On USG, median residual stenosis was 40% (range, 28%-42%) at the end of DA, 40% (range, 30%-55%) at 1 month, 55% (range, 35%-85%) at 6 months, and 64% (range, 60%-100%) at 1 year. There was one dissection, but no cases of perforation, pseudoaneurysm, or thrombosis. Primary patency, which was defined as a peak systolic velocity ratio <=3.5 with no reintervention at 6 months, was found in 18 lesions (90%), and 11 of 14 patients (78.6%) were free of ischemic symptoms such as claudication at 6 months. CONCLUSION: Our results demonstrated that DA with intraoperative USG is an effective treatment option for short segment occlusive lesions of the femoral artery. PMID- 28090506 TI - Cystic duct variation detected by near-infrared fluorescent cholangiography during laparoscopic cholecystectomy. AB - Near-infrared fluorescent cholangiography (NIRFC) is an emerging technique for easy intraoperative recognition of biliary anatomy. We present a case of cystic duct variation detected by NIRFC which had a potential risk for biliary injury if not detected. A 32-year-old female was admitted to the Seoul St. Mary's Hospital for surgery for an incidental gallbladder polyp. We performed laparoscopic cholecystectomy with NIRFC. In fluorescence mode, a long cystic duct and an accessory short hepatic duct joining to the cystic duct were found and the operation was completed safely. The patient recovered successfully. NIRFC is expected to be a promising procedure that will help minimize biliary injury during laparoscopic cholecystectomy. PMID- 28090507 TI - Gastric cancer in pregnancy: is laparoscopic gastrectomy with lymph node dissection feasible and safe? AB - Gastric cancer with pregnancy is rare and usually presents in late and advanced stage. Standard interventions in diagnosing, staging and treatment of cancer may be harmful for the fetus. The treatment of cancer in pregnancy should not differ significantly from the treatment in nonpregnant women. There have been case reports of open gastrectomy for gastric cancer in pregnancy. We present a case of early gastric cancer in a 37-year-old pregnant woman treated with laparoscopic distal gastrectomy with lymph node dissection with no postoperative complications. Laparoscopic distal gastrectomy with lymph node dissection seems to be feasible and safe in pregnancy for a mother and a fetus. PMID- 28090508 TI - Laser applications in surgery. AB - In modern medicine, lasers are increasingly utilized for treatment of a variety of pathologies as interest in less invasive treatment modalities intensifies. The physics behind lasers allows the same basic principles to be applied to a multitude of tissue types using slight modifications of the system. Multiple laser systems have been studied within each field of medicine. The term "laser" was combined with "surgery," "ablation," "lithotripsy," "cancer treatment," "tumor ablation," "dermatology," "skin rejuvenation," "lipolysis," "cardiology," "atrial fibrillation (AF)," and "epilepsy" during separate searches in the PubMed database. Original articles that studied the application of laser energy for these conditions were reviewed and included. A review of laser therapy is presented. Laser energy can be safely and effectively used for lithotripsy, for the treatment of various types of cancer, for a multitude of cosmetic and reconstructive procedures, and for the ablation of abnormal conductive pathways. For each of these conditions, management with lasers is comparable to, and potentially superior to, management with more traditional methods. PMID- 28090509 TI - Innovations in surgery simulation: a review of past, current and future techniques. AB - As a result of recent work-hours limitations and concerns for patient safety, innovations in extraclinical surgical simulation have become a desired part of residency education. Current simulation models, including cadaveric, animal, bench-top, virtual reality (VR) and robotic simulators are increasingly used in surgical training programs. Advances in telesurgery, three-dimensional (3D) printing, and the incorporation of patient-specific anatomy are paving the way for simulators to become integral components of medical training in the future. Evidence from the literature highlights the benefits of including simulations in surgical training; skills acquired through simulations translate into improvements in operating room performance. Moreover, simulations are rapidly incorporating new medical technologies and offer increasingly high-fidelity recreations of procedures. As a result, both novice and expert surgeons are able to benefit from their use. As dedicated, structured curricula are developed that incorporate simulations into daily resident training, simulated surgeries will strengthen the surgeon's skill set, decrease hospital costs, and improve patient outcomes. PMID- 28090510 TI - Augmented and virtual reality in surgery-the digital surgical environment: applications, limitations and legal pitfalls. AB - The continuing enhancement of the surgical environment in the digital age has led to a number of innovations being highlighted as potential disruptive technologies in the surgical workplace. Augmented reality (AR) and virtual reality (VR) are rapidly becoming increasingly available, accessible and importantly affordable, hence their application into healthcare to enhance the medical use of data is certain. Whether it relates to anatomy, intraoperative surgery, or post-operative rehabilitation, applications are already being investigated for their role in the surgeons armamentarium. Here we provide an introduction to the technology and the potential areas of development in the surgical arena. PMID- 28090511 TI - Emerging trends in social media and plastic surgery. AB - Social media has increasingly changed the landscape of medicine and surgery and is rapidly expanding its influence in most peoples' lives. The average person spends nearly 2 hours per day using social media, consuming information about everything from family updates to entertainment news to presidential elections. The concentration of consumers on social media platforms has resulted in direct medicine and medical products marketing to consumers. Similarly, social media is increasingly becoming a platform for interaction between physicians and potential patients. Some physicians have taken this opportunity to better educate patients, while allowing patients to learn more about their surgeons online. These tools can increase internet traffic online to bonafide internet sites, as well as bolster marketing for many hospitals, hospital systems, and individual doctors. It can also serve to increase knowledge about procedures and conditions through direct outreach to patients. Social media is a powerful tool which needs to be utilized wisely to avoid pitfalls. PMID- 28090514 TI - Pancreatic cancer: from bench to bedside. AB - Pancreatic cancer is recognized as the king of carcinoma, and the gap between basic research and clinical practice is difficult to improve the treatment effect. Translational medicine builds an important bridge between pancreatic cancer basic research and clinical practice from the pathogenesis, early diagnosis of pancreatic carcinoma, drug screening, treatment strategies and metastasis prediction. This article will carry on the concrete elaboration to the above several aspects. PMID- 28090513 TI - An update and review of cell-based wound dressings and their integration into clinical practice. AB - Chronic wounds affect over 4 million individuals and pose a significant burden to the US healthcare system. Diabetes, venous stasis, radiation or paralysis are common risk factors for chronic wounds. Unfortunately, the current standard of care (SOC) has a high relapse rate and these wounds continue to adversely affect patients' quality of life. Fortunately, advances in tissue engineering have allowed for the development of cell-based wound dressings that promote wound healing by improving cell migration and differentiation. As the available options continue to increase in quantity and quality, physicians should have a user friendly guide to reference when deciding which dressing to use. The objective of this review is to identify the currently available biologic dressings, describe their indications, and provide a framework for integration into clinical practice. This review included 53 studies consisting of prospective and retrospective cohorts as well as several randomized control trials. Three general categories of cell-based biologic dressings were identified and nine brands were included. Cell-based biologic dressings have shown efficacy in a broad range of scenarios, and studies examining their efficacy have improved our understanding of the pathophysiology of chronic wounds. Amniotic and placental membranes have the widest scope and can be used to treat all subtypes of chronic wounds. Human skin allografts and bioengineered skin substitutes can be used for chronic ulcers but generally require a vascularized wound bed. Autologous platelet rich plasma (PRP) has shown promise in venous stasis ulcers and decubitus ulcers that have failed conventional treatment. Overall, more research is necessary to determine if these novel therapeutic options will change the current SOC, but current studies demonstrate encouraging results in the treatment of chronic wounds. PMID- 28090512 TI - Surgical applications of three-dimensional printing: a review of the current literature & how to get started. AB - Three dimensional (3D) printing involves a number of additive manufacturing techniques that are used to build structures from the ground up. This technology has been adapted to a wide range of surgical applications at an impressive rate. It has been used to print patient-specific anatomic models, implants, prosthetics, external fixators, splints, surgical instrumentation, and surgical cutting guides. The profound utility of this technology in surgery explains the exponential growth. It is important to learn how 3D printing has been used in surgery and how to potentially apply this technology. PubMed was searched for studies that addressed the clinical application of 3D printing in all surgical fields, yielding 442 results. Data was manually extracted from the 168 included studies. We found an exponential increase in studies addressing surgical applications for 3D printing since 2011, with the largest growth in craniofacial, oromaxillofacial, and cardiothoracic specialties. The pertinent considerations for getting started with 3D printing were identified and are discussed, including, software, printing techniques, printing materials, sterilization of printing materials, and cost and time requirements. Also, the diverse and increasing applications of 3D printing were recorded and are discussed. There is large array of potential applications for 3D printing. Decreasing cost and increasing ease of use are making this technology more available. Incorporating 3D printing into a surgical practice can be a rewarding process that yields impressive results. PMID- 28090515 TI - A systematic review of combinatorial treatment with warming and invigorating drugs and levothyroxine for hypothyroidism caused by Hashimoto disease. AB - BACKGROUND: We used the systematic review method to evaluate the clinical efficacy and safety of combinatorial treatment with warming and invigorating drugs and levothyroxine on hypothyroidism caused by Hashimoto thyroiditis (HT). METHODS: We set inclusion and exclusion criteria, searched for studies using electronic databases and manual retrieval, selected studies according to the inclusion and exclusion criteria, and assessed the qualities of the included studies according to the Jadad scale. We performed a meta-analysis and analyzed the biases and sensitivities of the results using Revman 5.3 software. RESULTS: We retrieved 94 and 7 of the studies met the inclusion criteria. Warming and invigorating drugs and levothyroxine increased free triiodothyronine (FT3) and free thyroxine (FT4) levels and reduced thyroid stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TGAb) levels more than levothyroxine alone. However, the FT4 data were not stable. There were no statistically significant differences between the experimental and the control groups with regards to the effects on traditional Chinese medicine (TCM) syndromes and total therapeutic effects. There was insufficient evidence to make conclusions regarding TCM syndromes scores, goiter reduction, recurrence rate, and adverse reactions. CONCLUSIONS: Warming and invigorating drugs combined with levothyroxine may improve treatment of hypothyroidism caused by HT more than levothyroxine alone based on the FT3, FT4, TSH, TPOAb, and TGAb results. Based on the low qualities of the included studies, further evidence is needed to confirm these conclusions. PMID- 28090516 TI - The interplay between genetics, epigenetics and environment in modulating the risk of coronary heart disease. PMID- 28090517 TI - Semi-parametric regression model for survival data: graphical visualization with R. AB - Cox proportional hazards model is a semi-parametric model that leaves its baseline hazard function unspecified. The rationale to use Cox proportional hazards model is that (I) the underlying form of hazard function is stringent and unrealistic, and (II) researchers are only interested in estimation of how the hazard changes with covariate (relative hazard). Cox regression model can be easily fit with coxph() function in survival package. Stratified Cox model may be used for covariate that violates the proportional hazards assumption. The relative importance of covariates in population can be examined with the rankhazard package in R. Hazard ratio curves for continuous covariates can be visualized using smoothHR package. This curve helps to better understand the effects that each continuous covariate has on the outcome. Population attributable fraction is a classic quantity in epidemiology to evaluate the impact of risk factor on the occurrence of event in the population. In survival analysis, the adjusted/unadjusted attributable fraction can be plotted against survival time to obtain attributable fraction function. PMID- 28090519 TI - A rare case of a blood clot masquerading as a retained surgical drain. AB - Surgical drains are commonly used in surgery to reduce post-operative fluid collections. Whilst rare, a retained surgical drain may result in clinical complications and distress to the patient. A retained surgical drain is a potentially avoidable event and surgeons should be aware on how to confirm the presence of a retained surgical drain. We report a rare case of a blood clot masquerading as a retained surgical drain in a patient. The patient is a 55-year old Malay male who presented with left gluteal necrotizing fasciitis. The patient underwent a further 5 debridements with subsequent closure of the wound. Two drains were inserted on closure. Whilst there was no difficulty in removal of the drain, post removal magnetic resonance imaging revealed a tubular structure in the left gluteal region, thought to be a retained drain segment. Intra operatively, the drain segment seen on magnetic resonance imaging (MRI) was not found and instead, a tubular blood clot of similar caliber and length as measured on the MRI was found residing in the gluteal region. This case highlights the need for confirmation of a retained drain segment before surgical removal. Surgeons should be certain of the presence of a retained surgical drain before advocating for surgical removal. Plain radiography remains a useful modality for visualization of radio-opaque surgical drains. PMID- 28090518 TI - Clinical characteristics and molecular pathology of skull ectopic thyroid cancer. AB - Thyroid cancer is very common, but skull ectopic thyroid cancer has not been reported in 50 years of literatures in foreign countries. There are only four cases of the skull ectopic thyroid cancer reported in more than 30 years of domestic literature including the cases in this report. This paper aims to investigate the clinical characteristics and possible molecular mechanisms of this rare disease. Five keywords of "thyroid gland", "ectopic thyroid", "thyroid cancer", "ectopic thyroid cancer" and "metastatic thyroid cancer" were included and 50 years of literatures in the PubMed-MEDLINE and Wanfang database were reviewed. By combining the test data of 2 cases of surgical patient tissue microarray specimens-molecular immunology pathology, the possible molecular mechanisms were analyzed and molecular regulation network diagram was drawn. The skull ectopic thyroid cancer has not been reported in 50 years of literatures in foreign countries and there are only four cases of the skull ectopic thyroid cancer reported in more than 30 years of domestic literature including the cases in this report. The molecular expressions of skull ectopic thyroid cancer, orthotopic thyroid cancer, and metastatic thyroid cancer were not the same: (I) AKT (P=0.012, 0.002) and mTOR (P=0.002, 0.004) were highly expressed in the skull ectopic thyroid cancer; (II) BRAF (P=0.029, 0.014) and ERK (P=0.002, 0.001) were highly expressed in orthotopic thyroid cancer; (III) MMP-9 (P=0.023, 0.016) was highly expressed in metastatic thyroid cancer. According to the molecular information base, the PI3K is predicted to be a key crossing gene of the above three signaling pathways, which showed no significant differences in these three thyroid cancers (P=0.692, 0.388, 0.227), but PI3K has regulation roles in the three signaling pathways of Akt/mTOR, MAPK, and NF-kappaB. PI3K gene is an important starting gene of thyroid cancers. After the canceration starts, due to the fact that the local microenvironments of thyroid cancers in different parts are different, the thyroid cancers are regulated by different signaling pathways. The ectopic thyroid cancer was correlated with Akt/mTOR pathway high expression; orthotopic thyroid was related with MAPK/BRAF/ERK signaling pathway high expression; and the metastatic thyroid cancer was related with NFkB/MMP9 high expression. PMID- 28090520 TI - What should the blood pressure treatment goal be in adults with hypertension in 2016? PMID- 28090521 TI - Big data to the rescue of systemic inflammatory response syndrome: is electronic data mining the way of the future? PMID- 28090522 TI - Lessons learned from BATTLE-2 in the war on cancer: the use of Bayesian method in clinical trial design. PMID- 28090523 TI - Understanding the roles of randomized trials for robotic prostatectomy. PMID- 28090524 TI - The SAMUKeppra study in prehospital status epilepticus: lessons for future study. AB - In the Lancet Neurology article "Prehospital treatment with levetiracetam plus clonazepam or placebo plus clonazepam in status epilepticus (SAMUKeppra): a randomised, double-blind, phase 3 trial" the authors conducted a prehospital, randomized controlled study to determine which treatment is more effective for status epilepticus (SE): benzodiazepine alone, or in combination with levetiracetam (LEV). Although the study had negative results, several aspects of the trial design likely masked any added effect that LEV may have had in controlling SE, including: higher doses of benzodiazepines, lower thresholds for determining cessation of SE, and a smaller sample size. Regardless, the study reaffirms the effectiveness and importance of early and adequate benzodiazepine dosing and helps guide us in designing future studies for treatment of SE. PMID- 28090525 TI - RNAs that make a heart beat. AB - An increase in stress-associated microRNAs has been observed in the heart after an induced myocardial infarction. Liu and colleagues now demonstrate that one of these stress-associated microRNAs, miR-223-3p, can regulate a component of the voltage-gated channel that mediates rapid outward efflux of potassium during an action potential. Aberrations in the potassium current have been associated with ventricular arrhythmia and heart disease. Strikingly, introducing a small RNA antagonist directed against miR-223-3p into rat hearts, while also inducing a myocardial infarction, resulted in a reduction in arrhythmias. We place these studies in the larger context of the field and discuss the potential of anti-miR 223-3p molecules as new therapeutics for myocardial infarction. PMID- 28090526 TI - The necessity to restore the anatomic hip centre in congenital hip disease. AB - Total hip replacement (THR) is the treatment of choice for the patient suffering from end-stage hip osteoarthritis. In the presence of deformities due to congenital hip disease (CHD), THR is, in most of the cases, a difficult task, since the technique of performing such an operation is demanding and the results could vary. We present our experience and preferred strategies focusing on challenges and surgical techniques associated with reconstructing the dysplastic hip. PMID- 28090527 TI - The Ross procedure: an excellent option in the right hands. PMID- 28090528 TI - Uncovering first molecular mechanisms of secondary resistance against PD-1 blockade. PMID- 28090529 TI - Is there a role for microRNAs as novel predictors of prognosis in myocardial infarction? PMID- 28090530 TI - CK1delta: an exploitable vulnerability in breast cancer. PMID- 28090531 TI - At the crossroads from bench to bedside: luteolin is a promising pharmacological agent against myocardial ischemia reperfusion injury. PMID- 28090532 TI - Afatinib for patients with epidermal growth factor receptor mutation-positive non small cell lung cancer: clinical implications of the LUX-Lung 7 study. PMID- 28090533 TI - Professor Julie McMullen: love what you do, do what you love. PMID- 28090534 TI - Erratum to be care the risk of under fit in dose-response meta-analysis when using cubic spline. AB - [This corrects the article DOI: 10.21037/atm.2016.09.27.]. PMID- 28090535 TI - Control of Vector-Borne Human Parasitic Diseases. PMID- 28090536 TI - Prognostic Relevance of Nonsustained Ventricular Tachycardia in Patients with Pulmonary Hypertension. AB - Background. Increased pulmonary vascular resistance in patients with pulmonary hypertension (PH) leads to an increased afterload of right heart and cardiac remodeling which could provide the substrate or trigger for arrhythmias. Supraventricular arrhythmias were associated with clinical deterioration but were not associated with sudden cardiac death (SCD). SCD has been reported to account for approximately 30% of deaths in patients with pulmonary arterial hypertension (PAH). Objective. The role of nonsustained ventricular tachycardia (nsVT) and its prognostic relevance in patients with PH remains unclear. This study evaluated the prognostic relevance of nsVT in patients with PAH and chronic thromboembolic pulmonary hypertension (CTEPH). Methods. Retrospectively, patients with PAH and CTEPH who underwent Holter ECG monitoring and available data of survival were investigated. Results. Seventy-eight (PAH: 55, CTEPH: 23) patients were evaluated. Holter ECG revealed nsVT in 12 patients. Twenty-one patients died during follow-up. In patients with nsVT, tricuspid annular plane systolic excursion was lower (p = 0.001), and systolic pulmonary arterial pressure was higher (p = 0.163). Mean survival of patients without/with nsVT was 155.2 +/- 8.5/146.4 +/- 21.4 months (p = 0.690). The association between arrhythmias and survival was not confounded by age (p = 0.681), gender (p = 0.752), 6-MW distance (p = 0.196), or arterial hypertension (p = 0.238). Conclusions. In patients with PH, nsVT occurs more often than previously reported, and patients with PH group 1 seem to be more at risk. PMID- 28090537 TI - Significant Associations of SOX9 Gene Polymorphism and Gene Expression with the Risk of Osteonecrosis of the Femoral Head in a Han Population in Northern China. AB - Sex determining region Y-box 9 (SOX9) is a key transcription factor involved in cartilage formation during the embryonic development stage and cartilage growth and repair after birth. To explore the roles of polymorphism and expression of the SOX9 gene in the development of osteonecrosis of the femoral head (ONFH), we analyzed the polymorphism of rs12601701 [A/G] and rs1042667 [A/C] and the serum protein expression of the SOX9 gene in 182 patients with ONFH and 179 healthy control subjects. Results revealed that the A-A haplotype of SOX9 gene as well as the GG and AA genotypes of rs12601701 was significantly associated with increased ONFH risk (P = 0.038) and the risk of bilateral hip lesions of ONFH (P = 0.009), respectively. The C-A, A-A, and A-G haplotypes were also statistically associated with the decreased and increased risk of bilateral hip lesions of ONFH (P = 0.03, P = 0.048, and P = 0.013), respectively, while the A-A haplotype closely related to the clinical stages of ONFH (P = 0.041). More importantly, the serum SOX9 protein expression of the ONFH group was greatly decreased compared to control group (P = 0.0001). Our results first showed that the gene polymorphism and gene expression of SOX9 were significantly associated with the risk and clinical phenotypes of ONFH and also indicate that the SOX9 gene may play a key role in the development of ONFH. PMID- 28090538 TI - Factors Associated with Long-Term Control of Type 2 Diabetes Mellitus. AB - Aims. This study assessed factors associated with glycemic control among Saudi patients with Type 2 diabetes mellitus (T2DM). Methods. We conducted an analytical cross-sectional study, which included a random sample of 288 patients with T2DM proportional to the diabetes population of each primary health care center in Jazan city, Kingdom of Saudi Arabia. Results. More than two-thirds (74%) of patients had poor glycemic control. Lack of education, polypharmacy, and duration of diabetes >= 7 years were significantly associated with higher glycated hemoglobin (HbA1c). Moreover, patients who were smoker or divorced were significantly more likely to have higher HbA1c. The patients who did not comply with diet or take their medications as prescribed had poor glycemic control. The study found lower HbA1c levels among patients who received family support or had close relationship with their physicians. Similarly, knowledgeable patients towards diabetes or those with greater confidence in ability to manage self-care behaviors had a lower HbA1c. In contrast, risk factors such as depression or stress were significantly correlated with poorer glycemic control. Conclusion. The majority of T2DM patients had poor glycemic control. The study identified several factors associated with glycemic control. Effective and tailored interventions are needed to mitigate exposure to these risk factors. This would improve glycemic control and reduce the risks inherent to diabetes complications. PMID- 28090539 TI - Elevated Levels of Plasma IgA Autoantibodies against Oxidized LDL Found in Proliferative Diabetic Retinopathy but Not in Nonproliferative Retinopathy. AB - Aims. This study investigated the association of autoantibodies binding to oxidized low-density lipoproteins (oxLDL) in diabetic retinopathy (DR). Methods. Plasma from 229 types 1 and 2 patients with DR including diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) was analysed with ELISA-based assay to determine IgA, IgG, and IgM autoantibody levels binding to oxLDL. The controls were 106 diabetic patients without retinopathy (NoDR) and 139 nondiabetic controls (C). Results. PDR group had significantly higher IgA autoantibody levels than DME or NoDR: mean 94.9 (SD 54.7) for PDR, 75.5 (41.8) for DME (p = 0.001), and 76.1 (48.2) for NoDR (p = 0.008). There were no differences in IgG, IgM, or IgA that would be specific for DR or for DME. Type 2 diabetic patients had higher levels of IgA autoantibodies than type 1 diabetic patients (86.0 and 65.5, resp., p = 0.004) and the highest levels in IgA were found in type 2 diabetic patients with PDR (119.1, p > 0.001). Conclusions. IgA autoantibodies were increased in PDR, especially in type 2 diabetes. The high levels of IgA in PDR, and especially in type 2 PDR patients, reflect the inflammatory process and enlighten the role of oxLDL and its autoantibodies in PDR. PMID- 28090540 TI - Carotid Intima-Media Thickness and Visit-to-Visit HbA1c Variability Predict Progression of Chronic Kidney Disease in Type 2 Diabetic Patients with Preserved Kidney Function. AB - Background/Aims. Subclinical atherosclerosis and long-term glycemic variability have been reported to predict incident chronic kidney disease (CKD) in the general population. However, these associations have not been investigated in patients with type 2 diabetes with preserved kidney function. Methods. We prospectively followed up 162 patients with type 2 diabetes (mean age, 62.3 years; 53.6% men) and assessed whether carotid intima-media thickness (IMT) measured by B-mode ultrasound and visit-to-visit HbA1c variability are associated with deterioration of CKD (incident CKD defined as estimated GFR [eGFR] < 60 mL/min/1.73 m2 and progression of CKD stages) over a median follow-up of 6.0 years. At baseline, 25 patients (15.4%) had CKD. Cox proportional hazards regression models were used for identifying associated factors of CKD deterioration. Results. Estimated GFR decreased from 75.8 +/- 16.3 to 67.4 +/- 18.2 mL/min/1.73 m2 (p < 0.01). Of 162 patients, 32 developed CKD and 8 made a progression of CKD stages. Multivariate Cox regression analysis revealed that carotid IMT (HR: 4.0, 95% CI: 1.1-14.226.7, and p = 0.03) and coefficient of variation of HbA1c (HR: 1.12, 95%: 1.04-1.21, and p = 0.003) were predictors of deterioration of CKD independently of age, mean HbA1c, urinary albumin/creatinine ratio, baseline eGFR, uric acid, and leucocyte count. Conclusions. Subclinical atherosclerosis and long-term glycemic variability predict deterioration of chronic kidney disease (as defined by incident or worsening CKD) in type 2 diabetic patients with preserved kidney function. PMID- 28090541 TI - Empowerment in the Treatment of Diabetes and Obesity. AB - As the available therapies for diabetes and obesity are not effective enough, diabetologists and educators search for new methods to collaborate with patients in order to support their health behaviors. The aim of this review is to discuss perspectives for the development of new empowerment-type therapies in the treatment of diabetes/obesity. Empowerment is a process whereby patients gain the necessary knowledge to influence their own behavior to improve the quality of their lives. It is carried out in five stages: (1) identify the problem, (2) explain the feelings and meanings, (3) build a plan, (4) act, and (5) experience and assess the execution. Although many years have passed since the advent and popularization of the concept of empowerment, the area remains controversial, mainly with regard to the methodology of therapy. Some previous studies have confirmed the positive effect of empowerment on body weight, metabolic control, and quality of life of patients with type 2 diabetes; however, few studies have been conducted in patients with type 1 diabetes. There is still a need to confirm the effectiveness of empowerment in accordance with Evidence Based Medicine by performing long-term observational studies in a large group of patients. In future, empowerment may become part of the standard of care for patients with diabetes and/or obesity. PMID- 28090542 TI - Uninephrectomized High-Fat-Fed Nicotinamide-Streptozotocin-Induced Diabetic Rats: A Model for the Investigation of Diabetic Nephropathy in Type 2 Diabetes. AB - Type 2 diabetes (DM2) could be reproduced in rats with alimentary obesity by using low doses of streptozotocin (LD-STZ) as well as STZ in high doses with preliminary nicotinamide (NA) administration. However, STZ could induce tubulotoxicity. Aim. To develop rat model of DN in NA-STZ-induced DM2 and compare it with LD-STZ-model in order to choose the most relevant approach for reproducing renal glomerular and tubular morphofunctional diabetic changes. Starting at 3 weeks after uninephrectomy, adult male Wistar rats were fed five week high-fat diet and then received intraperitoneally either LD-STZ (40 mg/kg) or NA (230 mg/kg) followed by STZ (65 mg/kg). Control uninephrectomized vehicle injected rats received normal chow. At weeks 10, 20, and 30 (the end of the study), metabolic parameters, creatinine clearance, albuminuria, and urinary tubular injury markers (NGAL, KIM-1) were evaluated as well as renal ultrastructural and light microscopic changes at weeks 20 and 30. NA-STZ-group showed higher reproducibility and stability of metabolic parameters. By week 10, in NA-STZ-group NGAL level was significantly lower compared to LD-STZ-group. By week 30, diabetic groups showed early features of DN. However, morphofunctional changes in NA-STZ-group appeared to be more pronounced than those in STZ-group despite lower levels of KIM-1 and NGAL. We proposed a new rat model of DM2 with DN characterized by stable metabolic disorders, typical renal lesions, and lower levels of tubular injury markers as compared to LD-STZ-induced diabetes. PMID- 28090543 TI - Definition of a critical spatiotemporal window within which primary cilia control midbrain dopaminergic neurogenesis. AB - Midbrain dopaminergic (mDA) neurons are generated in the ventral midbrain floor plate depending on Sonic Hedgehog (SHH) signaling for induction. Primary cilia transduce canonical SHH signals. Loss of intraflagellar transport protein IFT88, essential for ciliary function, disrupts SHH signaling in the ventral midbrain and results in the reduction in mDA progenitors and neurons. We investigate whether conditional inactivation of the kinesin motor protein KIF3A recapitulates phenotypes observed in conditional Ift88 mutants. Conditional Kif3a inactivation reduced the mDA progenitor domain size, but did not result in mDA neuron reduction, most likely because of a delayed loss of cilia and delayed inactivation of SHH signaling. We thereby define a precise spatiotemporal window within which primary cilia-dependent SHH signaling determines mDA fate. PMID- 28090544 TI - EZH2 orchestrates apicobasal polarity and neuroepithelial cell renewal. AB - During early stages of neural development, neuroepithelial cells translocate their nuclei along the apicobasal axis in a harmonized manner with the cell cycle. How cell cycle progression and neuroepithelium polarity are coordinated remains unclear. It has been proposed that developmental cues, epigenetic mechanisms and cell cycle regulators must be linked in order to orchestrate these processes. We have recently discovered that a master epigenetic factor, EZH2 is essential to coordinate these events. EZH2 directly represses the cell cycle regulator p21WAF1/CIP in the chicken spinal cord. By doing so, EZH2 controls neural progenitor cell renewal and fine-tunes Rho signaling pathway, which is essential to maintain neuroepithelial structure. Our findings point to a new role of EZH2 during development that could have potential implication in other areas as cancer. PMID- 28090546 TI - BREATH IS NOT THE CARRIER OF SPEECH. PMID- 28090545 TI - Neuron's little helper: The role of primary cilia in neurogenesis. AB - The generation of new neurons involves a great variety of cell-extrinsic and cell intrinsic signals. The primary cilium, long regarded as an "evolutionary vestige," has emerged as an essential signaling hub in many cells, including neural progenitors and differentiating neurons. Most progenitors harbor an apically-localized primary cilium, which is assembled and disassembled following the cell cycle, while the presence, position and length of this organelle appears to be even more variable in differentiating neurons. One of the main extracellular cues acting through the cilium is Sonic Hedgehog, which modulates spatial patterning, the progression of the cell cycle and the timing of neurogenesis. Other extracellular signals appear to bind to cilia-localized receptors and affect processes such as dendritogenesis. All the observed dynamics, as well as the many signaling pathways depending on cilia, indicate this organelle as an important structure involved in neurogenesis. PMID- 28090547 TI - Using effective connectivity analyses to understand processing architecture: Response to commentaries by Samuel, Spivey and McQueen, Eisner and Norris. PMID- 28090549 TI - Education and peace go together; plus the best 2015 papers of the journal Temperature. PMID- 28090548 TI - Managerial Decision-making for Daily Case Allocation Scheduling and the Impact on Perioperative Quality Assurance. AB - Allocation scheduling for daily surgical cases is a decision-making process tasked to anesthesiologists and nurse managers in the operating room (OR). This manuscript focuses on three major areas: the classification and principles of allocation scheduling on workdays in China, flexible strategies of operational decision-making given differences in planned versus actual OR allocations, and perioperative quality implications of anesthesia scheduling. Improved quality and optimal decision-making in daily surgical case scheduling is seen with shift supervisor-based scheduling of staff and cases when compared with staff and case scheduling managed by the departmental director or chief resident. PMID- 28090550 TI - Laboratory primates: Their lives in and after research. PMID- 28090551 TI - Why is it easier to run in the cold? PMID- 28090552 TI - Hyperthermia during exercise - a double-edged sword. PMID- 28090553 TI - Interactions in human performance: An individual and combined stressors approach. PMID- 28090554 TI - A cellular pathway controlling functional plasma membrane incorporation of the cold sensor TRPM8. PMID- 28090555 TI - Applying systems-level approaches to elucidate regulatory function during mammalian hibernation. PMID- 28090556 TI - Heat acclimation: Gold mines and genes. AB - The underground gold mines of South Africa offer a unique historical setting to study heat acclimation. The early heat stress research was conducted and described by a young medical officer, Dr. Aldo Dreosti. He developed practical and specific protocols to first assess the heat tolerance of thousands of new mining recruits, and then used the screening results as the basis for assigning a heat acclimation protocol. The mines provide an interesting paradigm where the prevention of heat stroke evolved from genetic selection, where only Black natives were recruited due to a false assumption of their intrinsic tolerance to heat, to our current appreciation of the epigenetic and other molecular adaptations that occur with exposure to heat. PMID- 28090557 TI - Prolonged self-paced exercise in the heat - environmental factors affecting performance. AB - In this review we examine how self-paced performance is affected by environmental heat stress factors during cycling time trial performance as well as considering the effects of exercise mode and heat acclimatization. Mean power output during prolonged cycling time trials in the heat (>=30 degrees C) was on average reduced by 15% in the 14 studies that fulfilled the inclusion criteria. Ambient temperature per se was a poor predictor of the integrated environmental heat stress and 2 of the prevailing heat stress indices (WBGT and UTCI) failed to predict the environmental influence on performance. The weighing of wind speed appears to be too low for predicting the effect for cycling in trained acclimatized subjects, where performance may be maintained in outdoor time trials at ambient temperatures as high as 36 degrees C (36 degrees C UTCI; 28 degrees C WBGT). Power output during indoor trials may also be maintained with temperatures up to at least 27 degrees C when humidity is modest and wind speed matches the movement speed generated during outdoor cycling, whereas marked reductions are observed when air movement is minimal. For running, representing an exercise mode with lower movement speed and higher heat production for a given metabolic rate, it appears that endurance is affected even at much lower ambient temperatures. On this basis we conclude that environmental heat stress impacts self-paced endurance performance. However, the effect is markedly modified by acclimatization status and exercise mode, as the wind generated by the exercise (movement speed) or the environment (natural or fan air movement) exerts a strong influence. PMID- 28090558 TI - Leukocyte Hsp72 mRNA transcription does not differ between males and females during heat acclimation. AB - Purpose: Thermotolerance is an acquired state of increased cytoprotection achieved following single or repeated exposures to heat stress, in part characterized by changes in the intracellular 72 kda heat shock protein (HSP72; HSPA1A). Females have demonstrated reduced exercise induced HSP72 in comparison to males. This study examined sex differences in heat shock protein 72 messenger ribonucleic acid (Hsp72 mRNA) transcription during heat acclimation (HA) to identify whether sex differences were a result of differential gene transcription. Methods: Ten participants (5M, 5F) performed 10, 90 min controlled hyperthermia [rectal temperature (Tre) >= 38.5 degrees C] HA sessions over 12 d. Leukocyte Hsp72 mRNA was measured pre and post D1, D5, and D10, via Reverse transcription polymerase chain reaction (RT-QPCR). Results: HA was evidenced by a reduction in resting Tre (-0.4 +/- 0.5 degrees C) and resting heart rate [(HR); 13 +/- 7 beats.min-1] following HA (p <= 0.05). During HA no difference (p > 0.05) was observed in DeltaTre between males (D1 = 1.5 +/- 0.2 degrees C; D5 = 1.6 +/- 0.4 degrees C; D10 = 1.8 +/- 0.3 degrees C) and females (D1 = 1.5 +/- 0.5 degrees C; D5 = 1.4 +/- 0.2 degrees C; D10 = 1.8 +/- 0.3 degrees C). This was also true of mean Tre demonstrating equality of thermal stimuli for mRNA transcription and HA. There were no differences (p > 0.05) in Hsp72 mRNA expression between HA sessions or between males (D1 = +1.8 +/- 1.5-fold; D5 = +2.0 +/- 1.0 fold; D10 = +1.1 +/- 0.4-fold) and females (D1 = +2.6 +/- 1.8-fold; D5 = +1.8 +/- 1.4-fold; D10 = +0.9 +/- 1.9-fold). Conclusions: This experiment demonstrates that there is no difference in Hsp72 mRNA increases during HA between sexes when controlled hyperthermia HA is utilised. Gender specific differences in exercise-induced HSP72 reported elsewhere likely result from post transcriptional events. PMID- 28090559 TI - Potentiation of Ecstasy-induced hyperthermia and FAT/CD36 expression in chronically exercised animals. AB - Fatal hyperthermia as a result of 3,4-methylenedioxymethamphetamine (MDMA) use involves non-esterified free fatty acids (NEFA) and the activation of mitochondrial uncoupling proteins (UCP). NEFA gain access into skeletal muscle via specific transport proteins, including fatty acid translocase (FAT/CD36). FAT/CD36 expression is known to increase following chronic exercise. Previous studies have demonstrated the essential role of NEFA and UCP3 in MDMA-induced hyperthermia. The aims of the present study were to use a chronic exercise model (swimming for two consecutive hours per day, five days per wk for six wk) to increase FAT/CD36 expression in order to: 1) determine the contribution of FAT/CD36 in MDMA (20 mg/kg, s.c.)-mediated hyperthermia; and 2) examine the effects of the FAT/CD36 inhibitor, SSO (sulfo-N-succinimidyl oleate), on MDMA induced hyperthermia in chronic exercise and sedentary control rats. MDMA administration resulted in hyperthermia in both sedentary and chronic exercise animals. However, MDMA-induced hyperthermia was significantly potentiated in the chronic exercise animals compared to sedentary animals. Additionally, chronic exercise significantly reduced body weight, increased FAT/CD36 protein expression levels and reduced plasma NEFA levels. The FAT/CD36 inhibitor, SSO (40 mg/kg, ip), significantly attenuated the hyperthermia mediated by MDMA in chronic exercised but not sedentary animals. Plasma NEFA levels were elevated in sedentary and exercised animals treated with SSO prior to MDMA suggesting attenuation of NEFA uptake into skeletal muscle. Chronic exercise did not alter skeletal muscle UCP3 protein expression levels. In conclusion, chronic exercise potentiates MDMA-mediated hyperthermia in a FAT/CD36 dependent fashion. PMID- 28090560 TI - Perceptions of Secondhand E-Cigarette Aerosol Among Twitter Users. AB - OBJECTIVES: There is considerable debate among the public health community about the health risks of secondhand exposure to the aerosol from electronic cigarettes (e-cigarettes). Despite mounting scientific evidence on the chemical content of e cigarette aerosol, public perceptions of the relative safety of secondhand e cigarette aerosol have not been well characterized. METHOD: This study collected tweets, or messages sent using Twitter, about exposure to secondhand e-cigarette aerosol over a 6-week period in 2015. Tweets were coded on sentiment about e cigarettes (pro-, anti-, or neutral/unknown) and topic (health, social, advertisement, or unknown). RESULTS: The 1519 tweets included 531 pro-e-cigarette tweets, 392 anti-e-cigarette tweets, and 596 neutral tweets. Social tweets far outnumbered health tweets (747 vs. 182, respectively). Social-focused tweets were predominantly pro-e-cigarette, whereas health-focused tweets were predominantly anti-e-cigarette. DISCUSSION: Twitter discussions about secondhand vaping are dominated by pro-e-cigarette social tweets, although there is a presence of anti e-cigarette social tweets and tweets about negative and positive health effects. Public health and regulatory agencies could use social media and traditional media to disseminate the message that e-cigarette aerosol contains potentially harmful chemicals and could be perceived as offensive. This study identifies the prevalent topics and opinions that could be incorporated into health education messages. PMID- 28090561 TI - Diversity in Rotavirus-Host Glycan Interactions: A "Sweet" Spectrum. AB - Interaction with cellular glycans is a critical initial step in the pathogenesis of many infectious agents. Technological advances in glycobiology have expanded the repertoire of studies delineating host glycan-pathogen interactions. For rotavirus, the VP8* domain of the outer capsid spike protein VP4 is known to interact with cellular glycans. Sialic acid was considered the key cellular attachment factor for rotaviruses for decades. Although this is true for many rotavirus strains causing infections in animals, glycan array screens show that many human rotavirus strains bind nonsialylated glycoconjugates, called histo blood group antigens, in a strain-specific manner. The expression of histo-blood group antigens is determined genetically and is regulated developmentally. Variations in glycan binding between different rotavirus strains are biologically relevant and provide new insights into multiple aspects of virus pathogenesis such as interspecies transmission, host range restriction, and tissue tropism. The genetics of glycan expression may affect susceptibility to different rotavirus strains and vaccine viruses, and impact the efficacy of rotavirus vaccination in different populations. A multidisciplinary approach to understanding rotavirus-host glycan interactions provides molecular insights into the interaction between microbial pathogens and glycans, and opens up new avenues to translate findings from the bench to the human population. PMID- 28090563 TI - Targeting alphav Integrins in Pancreatic Fibrosis: Progress in Resolving the Scar. PMID- 28090562 TI - Hepatitis C Virus-Induced Monocyte Differentiation Into Polarized M2 Macrophages Promotes Stellate Cell Activation via TGF-beta. AB - BACKGROUND & AIMS: Monocyte and macrophage (MPhi) activation contributes to the pathogenesis of chronic hepatitis C virus (HCV) infection. Disease pathogenesis is regulated by both liver-resident MPhis and monocytes recruited as precursors of MPhis into the damaged liver. Monocytes differentiate into M1 (classic/proinflammatory) or M2 (alternative/anti-inflammatory) polarized MPhis in response to tissue microenvironment. We hypothesized that HCV-infected hepatoma cells (infected with Japanese fulminant hepatitis-1 [Huh7.5/JFH-1]) induce monocyte differentiation into polarized MPhis. METHODS: Healthy human monocytes were co-cultured with Huh7.5/JFH-1 cells or cell-free virus for 7 days and analyzed for MPhi markers and cytokine levels. A similar analysis was performed on circulating monocytes and liver MPhis from HCV-infected patients and controls. RESULTS: Huh7.5/JFH-1 cells induced monocytes to differentiate into MPhis with increased expression of CD14 and CD68. HCV-MPhis showed M2 surface markers (CD206, CD163, and Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN)) and produced both proinflammatory and anti-inflammatory cytokines. HCV-induced early interleukin 1beta production promoted transforming growth factor (TGF)beta production and MPhi polarization to an M2 phenotype. TGF-beta secreted by M2-MPhi led to hepatic stellate cell activation indicated by increased expression of collagen, tissue inhibitor of metalloproteinase 1, and alpha-smooth muscle actin. In vivo, we observed a significant increase in M2 marker (CD206) expression on circulating monocytes and in the liver of chronic HCV-infected patients. Furthermore, we observed the presence of a unique collagen-expressing CD14+CD206+ monocyte population in HCV patients that correlated with liver fibrosis. CONCLUSIONS: We show an important role for HCV in induction of monocyte differentiation into MPhis with a mixed M1/M2 cytokine profile and M2 surface phenotype that promote stellate cell activation via TGF-beta. We also identified circulating monocytes expressing M2 marker and collagen in chronic HCV infection that can be explored as a biomarker. PMID- 28090564 TI - Hepatocyte Toll-Like Receptor 5 Promotes Bacterial Clearance and Protects Mice Against High-Fat Diet-Induced Liver Disease. AB - BACKGROUND & AIMS: Innate immune dysfunction can promote chronic inflammatory diseases of the liver. For example, mice lacking the flagellin receptor Toll-like receptor 5 (TLR5) show microbial dysbiosis and predisposition to high-fat diet (HFD)-induced hepatic steatosis. The extent to which hepatocytes play a direct role in detecting bacterial products in general, or flagellin in particular, is poorly understood. In the present study, we investigated the role of hepatocyte TLR5 in recognizing flagellin, policing bacteria, and protecting against liver disease. METHODS: Mice were engineered to lack TLR5 specifically in hepatocytes (TLR5DeltaHep) and analyzed relative to sibling controls (TLR5fl/fl). TLR5 messenger RNA levels, responses to exogenous flagellin, elimination of circulating motile bacteria, and susceptibility of liver injury (concanavalin A, carbon tetrachloride, methionine- and choline-deficient diet, and HFD) were measured. RESULTS: TLR5DeltaHep expressed similar levels of TLR5 as TLR5fl/fl in all organs examined, except in the liver, which showed a 90% reduction in TLR5 levels, indicating that hepatocytes accounted for the major portion of TLR5 expression in this organ. TLR5DeltaHep showed impairment in responding to purified flagellin and clearing flagellated bacteria from the liver. Although TLR5DeltaHep mice did not differ markedly from sibling controls in concanavalin A or carbon tetrachloride-induced liver injury models, they showed exacerbated disease in response to a methionine- and choline-deficient diet and HFD. Such predisposition of TLR5DeltaHep to diet-induced liver pathology was associated with increased expression of proinflammatory cytokines, which was dependent on the Nod-like-receptor C4 inflammasome and rescued by microbiota ablation. CONCLUSIONS: Hepatocyte TLR5 plays a critical role in protecting liver against circulating gut bacteria and against diet-induced liver disease. PMID- 28090565 TI - THBS2 Is a Candidate Modifier of Liver Disease Severity in Alagille Syndrome. AB - BACKGROUND & AIMS: Alagille syndrome is an autosomal-dominant, multisystem disorder caused primarily by mutations in JAG1, resulting in bile duct paucity, cholestasis, cardiac disease, and other features. Liver disease severity in Alagille syndrome is highly variable, however, factors influencing the hepatic phenotype are unknown. We hypothesized that genetic modifiers may contribute to the variable expressivity of this disorder. METHODS: We performed a genome-wide association study in a cohort of Caucasian subjects with known pathogenic JAG1 mutations, comparing patients with mild vs severe liver disease, followed by functional characterization of a candidate locus. RESULTS: We identified a locus that reached suggestive genome-level significance upstream of the thrombospondin 2 (THBS2) gene. THBS2 codes for a secreted matricellular protein that regulates cell proliferation, apoptosis, and angiogenesis, and has been shown to affect Notch signaling. By using a reporter mouse line, we detected thrombospondin 2 expression in bile ducts and periportal regions of the mouse liver. Examination of Thbs2-null mouse livers showed increased microvessels in the portal regions of adult mice. We also showed that thrombospondin 2 interacts with NOTCH1 and NOTCH2 and can inhibit JAG1-NOTCH2 interactions. CONCLUSIONS: Based on the genome-wide association study results, thrombospondin 2 localization within bile ducts, and demonstration of interactions of thrombospondin 2 with JAG1 and NOTCH2, we propose that changes in thrombospondin 2 expression may further perturb JAG1 NOTCH2 signaling in patients harboring a JAG1 mutation and lead to a more severe liver phenotype. These results implicate THBS2 as a plausible candidate genetic modifier of liver disease severity in Alagille syndrome. PMID- 28090566 TI - Large Animal Models: The Key to Translational Discovery in Digestive Disease Research. AB - Gastrointestinal disease is a prevalent cause of morbidity and mortality and the use of animal models have been instrumental in studying mechanisms of digestive pathophysiology. As investigators attempt to translate the wealth of basic science information developed from rodent, models, large animal models provide a number of translational advantages. The pig, in particular, is arguably one of the most powerful models of human organ systems, including the gastrointestinal tract. The pig has provided important tools and insight into intestinal ischemia/reperfusion injury, intestinal mucosal repair, as well as new insights into esophageal injury and repair. Porcine model development has taken advantage of the size of the animal, allowing increased surgical and endoscopic access. In addition, cellular tools such as the intestinal porcine epithelial cell line and porcine enteroids are providing the methodology to translate basic science findings using in-depth mechanistic analyses. Further opportunities in porcine digestive disease modeling include developing additional transgenic pig strains. Collectively, porcine models hold great promise for the future of clinically relevant digestive disease research. PMID- 28090567 TI - The RNA polymerase III subunit Polr3b is required for the maintenance of small intestinal crypts in mice. AB - BACKGROUND & AIMS: The continuously self-renewing mammalian intestinal epithelium, with high cellular turnover, depends on adequate protein synthesis for its proliferative capacity. RNA polymerase III activity is closely related to cellular growth and proliferation. Here, we studied the role of Polr3b, a large RNA polymerase III subunit, in the mammalian intestinal epithelium. METHODS: We derived mice with an intestinal epithelium-specific hypomorphic mutation of the Polr3b gene, using VillinCre-mediated gene ablation. Phenotypic consequences of the Polr3b mutation on the intestinal epithelium in mice were assessed using histological and molecular methodologies, including genetic lineage tracing. RESULTS: The Polr3b mutation severely reduced survival and growth in mice during the first postnatal week, the period when the expansion of the intestinal epithelium, and thus the requirement for protein synthesis, are highest. The neonatal intestinal epithelium of Polr3bloxP/loxP;VillinCre mice was characterized by areas with reduced proliferation, abnormal epithelial architecture, loss of Wnt signaling and a dramatic increase in apoptotic cells in crypts. Genetic lineage tracing using Polr3bLoxP/LoxP;Rosa26-lox-stop-lox YFP;VillinCre mice demonstrated that in surviving mutant mice, Polr3b-deficient dying crypts were progressively replaced by 'Cre-escaper' cells that had retained wild type Polr3b function. In addition, enteroids cultured from Polr3bloxP/loxP;VillinCre mice show reduced proliferative activity and increased apoptosis. CONCLUSIONS: We provide evidence for an essential role of the Pol III subunit Polr3b in orchestrating the maintenance of the intestinal crypt during early postnatal development in mice. PMID- 28090569 TI - Mitogen-activated Protein Kinase Kinase Activity Maintains Acinar-to-Ductal Metaplasia and Is Required for Organ Regeneration in Pancreatitis. AB - BACKGROUND & AIMS: Mitogen-activated protein kinase (MAPK) signaling in the exocrine pancreas has been extensively studied in the context of pancreatic cancer, where its potential as a therapeutic target is limited by acquired drug resistance. However, its role in pancreatitis is less understood. We investigated the role of mitogen-activated protein kinase kinase (MEK)-initiated MAPK signaling in pancreatitis to determine the potential for MEK inhibition in treating pancreatitis patients. METHODS: To examine the role of MEK signaling in pancreatitis, we used both genetic and pharmacologic approaches to inhibit the MAPK signaling pathway in a murine model of cerulein-induced pancreatitis. We generated mice harboring inducible short hairpins targeting the MEK isoforms Map2k1 and/or Map2k2 specifically in the pancreatic epithelium. We also used the MEK inhibitor trametinib to determine the efficacy of systemic inhibition in mice with pancreatitis. RESULTS: We demonstrated an essential role for MEK signaling in the initiation of pancreatitis. We showed that both systemic and parenchyma specific MEK inhibition in established pancreatitis induces epithelial differentiation and stromal remodeling. However, systemic MEK inhibition also leads to a loss of the proliferative capacity of the pancreas, preventing the restoration of organ mass. CONCLUSIONS: MEK activity is required for the initiation and maintenance of pancreatitis. MEK inhibition may be useful in the treatment of chronic pancreatitis to interrupt the vicious cycle of destruction and repair but at the expense of organ regeneration. PMID- 28090568 TI - Pathophysiology of Intestinal Na+/H+ exchange. AB - Several members of the SLC9A family of Na+/H+ exchangers are expressed in the gut, with varying expression patterns and cellular localization. Not only do they participate in the regulation of basic epithelial cell functions, including control of transepithelial Na+ absorption, intracellular pH (pH i ), cell volume, and nutrient absorption, but also in cellular proliferation, migration, and apoptosis. Additionally, they modulate the extracellular milieu in order to facilitate other nutrient absorption and to regulate the intestinal microbial microenvironment. Na+/H+ exchangers are frequent targets of inhibition in gastrointestinal pathologies, either by intrinsic factors (e.g. bile acids, inflammatory mediators) or infectious agents and associated microbial toxins. Based on emerging evidence, disruption of NHE activity via impaired expression or function of respective isoforms may contribute not only to local and systemic electrolyte imbalance, but also to the disease severity via multiple mechanisms. Here, we review the current state of knowledge about the roles Na+/H+ exchangers play in the pathogenesis of disorders of diverse origin and affecting a range of GI tissues. PMID- 28090570 TI - Targeted inhibition of pancreatic acinar cell calcineurin is a novel strategy to prevent post-ERCP pancreatitis. AB - BACKGROUND AND AIMS: There is a pressing need to develop effective preventative therapies for post-ERCP pancreatitis (PEP). We demonstrated that early PEP events are induced through the calcium-activated phosphatase calcineurin and that global calcineurin deletion abolishes PEP in mice. A crucial question is whether acinar cell calcineurin controls the initiation of PEP in vivo. METHODS: We used a mouse model of PEP and examined the effects of in vivo acinar cell-specific calcineurin deletion by either generating a conditional knockout line or infusing a novel AAV Ela-iCre into the pancreatic duct of a calcineurin floxed line. RESULTS: We found that PEP is dependent on acinar cell calcineurin in vivo, and this led us to determine that calcineurin inhibitors, infused within the radiocontrast, can largely prevent PEP. CONCLUSIONS: These results provide impetus for launching clinical trials to test the efficacy of intraductal calcineurin inhibitors to prevent PEP. PMID- 28090571 TI - Management Practices of Cats Owned by Faculty, Staff, and Students at Two Midwest Veterinary Schools. AB - Understanding cat owners' housing, care, and management practices is important for promoting cat welfare. A survey study was conducted on the housing and management practices used for cats by students, faculty, and staff of The Ohio State University and Purdue University veterinary colleges. Subjects were 138 cat owner dyads. Most cats (74%) were housed strictly indoors in keeping with common US veterinary recommendations. However, many did not implement best practices outlined for behavior and other welfare needs of indoor cats. The percentage of respondents placing resources where cats could be disrupted while using them was 31%, 53%, and 30% for resting areas, food/water dishes, and litter boxes, respectively. Many cats were not provided a litter box in a private area (35%), in multiple areas of the house (51%), or that was regularly washed (73%). Horizontal scratching opportunities were not provided to 38% of cats; 32% were not provided toys that mimic prey and 91% of cats were fed a diet consisting of >75% dry food. These findings suggest a need for more concerted efforts to educate owners about meeting their cats' welfare needs so as to attenuate risks and improve cat physical and behavioral welfare outcomes. PMID- 28090572 TI - Pleiotrophin is a driver of vascular abnormalization in glioblastoma. AB - In a recent report by Zhang et al., pleiotrophin (PTN) was demonstrated to enhance glioma growth by promoting vascular abnormalization. PTN stimulates glioma vessels through anaplastic lymphoma kinase (Alk)-mediated perivascular deposition of vascular endothelial growth factor (VEGF). Targeting of Alk or VEGF signaling normalizes tumor vessels in PTN-expressing tumors. PMID- 28090573 TI - Nuclear reprogramming of cancer stem cells: Corrupting the epigenetic code of cell identity with oncometabolites. AB - Generation of cancer stem cell (CSC)-like cells might occur through metabolic corruption of the epigenetic codes that govern cell identity. We recently identified how archetypal oncometabolites, without altering the baseline expression of endogenous stem cell maintenance genes but endowing cells with epigenetic states refractory to differentiation, considerably enhance the global kinetic efficiency of nuclear reprogramming processes that generate CSC-like states de novo. This study highlights that metabolo-epigenetic axes of communication can direct the development and maintenance of CSCs during the natural history of cancer diseases. PMID- 28090574 TI - Association between LAPTM4B gene polymorphism and prostate cancer susceptibility in an Iranian population. AB - Lysosome associated protein transmembrane 4 beta (LAPTM4B) is an oncogene associated with many human cancers. In the present study we aimed to examine the possible association between LAPTM4B polymorphism and risk of prostate cancer (PCa) in an Iranian population. This case control study was performed on 168 patients with PCa and 176 controls with benign prostatic hyperplasia (BPH). Genomic DNA was extracted from whole blood and LAPTM4B genotypes were identified by polymerase chain reaction. The distributions of LAPTM4B genotypes were significantly different between PCa patients (60.7% for *1/1, 32.8% for *1/2, and 6.5% for *2/2) and controls (44.9% for *1/1, 49.4% for *1/2, and 5.7% for *2/2). Both the *1/2 and *1/2+*2/2 genotypes significantly decreased the risk of PCa compared with the *1/1 genotype (OR = 49, 95% CI = 0.31-0.77, p = 0.002 and OR = 0.53, 95% CI = 0.34-0.81, p = 0.004, respectively). The minor allele (LAPTM4B*2) was associated with a decreased risk of PCa compared with the LAPTM4B*1 allele (OR = 0.68, 95% CI = 0.48-0.96, p = 0.031). Moreover, LAPTM4B polymorphism was not associated with clinicopathological characteristics of PCa patients. The results of this study showed that LAPTM4B*2 was associated with a decreased risk of PCa but the clinicopathological characteristics of PCa were not linked to LAPTM4B polymorphism. Further studies with larger sample sizes and different ethnicities are needed to confirm our findings. PMID- 28090576 TI - Cancer cells activate damage-tolerant and error-prone DNA synthesis. AB - Trans-lesion synthesis (TLS) is a DNA damage-tolerant and error-prone mode of DNA replication. Recent work shows that many cancer cells coopt an aberrantly expressed germ cell protein, melanoma antigen-A4 (MAGE-A4), to activate TLS. MAGE A4-induced "pathological TLS" provides a potential mechanism through which neoplastic cells can tolerate intrinsic and therapeutic genotoxicity while acquiring mutability. PMID- 28090575 TI - Suv39h1 links the SUMO pathway to constitutive heterochromatin. AB - The Suv39h lysine methyltransferases, known as key enzymes responsible for histone H3 lysine 9 methylation, are critical for heterochromatin protein 1 enrichment at constitutive heterochromatin. Our recent findings reveal a new role for the Suv39h1 paralog that links it to SUMO pathway function at constitutive heterochromatin. PMID- 28090577 TI - Modeling intratumor heterogeneity through CRISPR-barcodes. AB - We have devised a barcoding strategy to recapitulate cancer evolution through the emergence of subclonal mutations of interest, whose effects can be monitored in a dynamic manner. This approach can be easily adapted for a variety of applications, including combined modeling of multiple mechanisms of drug resistance or repair of oncogenic driver mutations in addicted cancer cells. PMID- 28090578 TI - A phenotypic and mechanistic perspective on heterogeneity of HER2-positive breast cancers. AB - Analysis of gene expression and whole-genome features of 64 human epidermal growth factor 2 (HER2)-positive breast tumors supports the idea that their intrinsic heterogeneity actually reflects their cell of origin, suggesting that HER2 amplification is an embedded event in the natural history of these tumors. Possible mechanisms for this event involve breakage-fusion-bridge and chromothripsis. PMID- 28090579 TI - Open chromatin profiling as a novel strategy for identifying cancer cell of origin. AB - Tumor cell of origin is an important prognostic measure but is challenging to assess. We recently demonstrated in acute myeloid leukemia (AML) that the chromatin landscape serves as a biomarker of transformed cell of origin. Thus, open chromatin loci offer important prognostic information as well as targets for development of novel therapies in cancer treatment. PMID- 28090580 TI - Tumors smother their epigenome. AB - DNA hypermethylation is pervasive in tumors, but the factors triggering this modification are largely unknown. We recently demonstrated that the activity of 10-11-translocation methylcytosine dioxygenases, initiators of DNA demethylation, is compromised in hypoxic tumors. The resultant accumulation of methylation inactivates associated genes, linking the tumor microenvironment to epigenetic changes in cancer cells. PMID- 28090581 TI - Two-faced activity of RNF8: What "twists" it from a genome guardian to a cancer facilitator? AB - The RING finger protein 8 (RNF8)-induced ubiquitination signaling cascade promotes DNA repair and maintains genomic stability. Our study reveals an unexpected action of RNF8 in promoting cancer metastasis, cancer stem cell formation, and chemoresistance through the regulation of TWIST lysine 63 (K63) linked ubiquitination, suggesting that RNF8 may serve as a new cancer prognosis marker and therapeutic target. PMID- 28090582 TI - Putting the brakes on transcription at damaged chromatin: Do Polycomb silencers do more than modify histones? AB - One of the cellular responses to DNA damage is to monitor and execute temporary arrest of RNA synthesis at chromatin lesions. The Polycomb silencer BMI1 is a well-known contributor to this process. We recently described a new mode of BMI1 mediated transcription arrest at lesions that involves UBR5 E3 ligase and FACT histone chaperon. PMID- 28090583 TI - Complementing genomics and transcriptomics: Phosphoproteomics illuminates systems biology in prostate cancer. AB - Integration of phosphoproteomics with traditional genomics and transcriptomics provides a more comprehensive overview of the signaling networks in advanced prostate cancer for immediate preclinical and future clinical use. Our recent publication introduces computational approaches for integrating the phosphoproteome, specifically with the intent of identifying important kinase signaling networks in advanced-stage prostate cancer. PMID- 28090584 TI - Retrospective electron microscopy: Preservation of fine structure by freezing and aldehyde fixation. AB - For many years it has been believed that ultrastructural analysis by transmission electron microscopy (TEM) is not possible using frozen tissues. We have developed a TEM method that allows the evaluation of organelles using pancreatic tissue that was previously liquid nitrogen snap-frozen and stored long-term at -80 degrees C. This method is suitable for the quantitative assessment of mitochondria, rough endoplasmic reticulum (RER), and Golgi structures, as well as organelles originating from autophagy signaling. Frozen pancreatic tissue exhibited no signs of freezing- or storage-related damage and was undistinguishable from fresh material subjected to standard glutaraldehyde fixation. Since pancreatic tissue is the most delicate tissue to work with due to the high expression of digestive enzymes, our method is also suitable for other tissue types such as liver. Thus, by applying proper tissue freezing and fixation techniques, retrospective TEM analysis can be performed on mammalian tissues in a time- and cost-saving manner. PMID- 28090585 TI - Circadian Forced Desynchrony of the Master Clock Leads to Phenotypic Manifestation of Depression in Rats. AB - In mammals, a master circadian clock within the suprachiasmatic nucleus (SCN) of the hypothalamus maintains the phase coherence among a wide array of behavioral and physiological circadian rhythms. Affective disorders are typically associated with disruption of this fine-tuned "internal synchronization," but whether this internal misalignment is part of the physiopathology of mood disorders is not clear. To date, depressive-like behavior in animal models has been induced by methods that fail to specifically target the SCN regulation of internal synchronization as the mode to generate depression. In the rat, exposure to a 22 h light-dark cycle (LD22) leads to the uncoupling of two distinct populations of neuronal oscillators within the SCN. This genetically, neurally, and pharmacologically intact animal model represents a unique opportunity to assess the effect of a systematic challenge to the central circadian pacemaker on phenotypic manifestations of mood disorders. We show that LD22 circadian forced desynchrony in rats induces depressive-like phenotypes including anhedonia, sexual dysfunction, and increased immobility in the forced swim test (FST), as well as changes in the levels and turnover rates of monoamines within the prefrontal cortex. Desynchronized rats show increased FST immobility during the dark (active) phase but decreased immobility during the light (rest) phase, suggesting a decrease in the amplitude of the normal daily oscillation in this behavioral manifestation of depression. Our results support the notion that the prolonged internal misalignment of circadian rhythms induced by environmental challenge to the central circadian pacemaker may constitute part of the etiology of depression. PMID- 28090587 TI - Emotional Clarity as a Buffer in the Association Between Perceived Mental Illness Stigma and Suicide Risk. AB - Among people living with psychiatric disorders, mental illness stigma has been identified as a major barrier to recovery by contributing to low self-esteem and interfering with treatment-seeking. The present research examined the association between perceived mental illness stigma and suicide risk severity and considered the role of emotional clarity (i.e., the ability to identify and understand one's emotional experiences), a critical component of emotion regulation, as a moderator of this association. A sample of individuals who had experienced recent psychiatric hospitalizations (N = 184) completed self-report measures of perceived stigma associated with their psychiatric diagnoses, deficits in emotional clarity, and behaviors that have been found to confer risk for suicide. A moderation analysis revealed that perceived mental illness stigma was positively associated with suicide risk severity, but only for individuals who have greater deficits in emotional clarity. These findings highlight the role of emotional clarity as a resource for individuals coping with mental illness stigma and underscore the potential utility of targeting deficits in emotional clarity in prevention and intervention efforts for reducing suicide risk. PMID- 28090588 TI - Quantitative Magnetization Transfer Imaging of the Breast at 3.0 T: Reproducibility in Healthy Volunteers. AB - Quantitative magnetization transfer magnetic resonance imaging provides a means for indirectly detecting changes in the macromolecular content of tissue noninvasively. A potential application is the diagnosis and assessment of treatment response in breast cancer; however, before quantitative magnetization transfer imaging can be reliably used in such settings, the technique's reproducibility in healthy breast tissue must be established. Thus, this study aims to establish the reproducibility of the measurement of the macromolecular-to free water proton pool size ratio (PSR) in healthy fibroglandular (FG) breast tissue. Thirteen women with no history of breast disease were scanned twice within a single scanning session, with repositioning between scans. Eleven women had appreciable FG tissue for test-retest measurements. Mean PSR values for the FG tissue ranged from 9.5% to 16.7%. The absolute value of the difference between 2 mean PSR measurements for each volunteer ranged from 0.1% to 2.1%. The 95% confidence interval for the mean difference was +/-0.75%, and the repeatability value was 2.39%. These results indicate that the expected measurement variability would be +/-0.75% for a cohort of a similar size and would be +/-2.39% for an individual, suggesting that future studies of change in PSR in patients with breast cancer are feasible. PMID- 28090589 TI - Spiral Perfusion Imaging With Consecutive Echoes (SPICETM) for the Simultaneous Mapping of DSC- and DCE-MRI Parameters in Brain Tumor Patients: Theory and Initial Feasibility. AB - Dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) are the perfusion imaging techniques most frequently used to probe the angiogenic character of brain neoplasms. With these methods, T1- and T2/T2*-weighted imaging sequences are used to image the distribution of gadolinium (Gd)-based contrast agents. However, it is well known that Gd exhibits combined T1, T2, and T2* shortening effects in tissue, and therefore, the results of both DCE- and DSC-MRI can be confounded by these opposing effects. In particular, residual susceptibility effects compete with T1 shortening, which can confound DCE-MRI parameters, whereas dipolar T1 and T2 leakage and residual susceptibility effects can confound DSC-MRI parameters. We introduce here a novel perfusion imaging acquisition and postprocessing method termed Spiral Perfusion Imaging with Consecutive Echoes (SPICE) that can be used to simultaneously acquire DCE- and DSC-MRI data, which requires only a single dose of the Gd contrast agent, does not require the collection of a precontrast T1 map for DCE-MRI processing, and eliminates the confounding contrast agent effects due to contrast extravasation. A detailed mathematical description of SPICE is provided here along with a demonstration of its utility in patients with high-grade glioma. PMID- 28090586 TI - Holliday junction trap shows how cells use recombination and a junction-guardian role of RecQ helicase. AB - DNA repair by homologous recombination (HR) underpins cell survival and fuels genome instability, cancer, and evolution. However, the main kinds and sources of DNA damage repaired by HR in somatic cells and the roles of important HR proteins remain elusive. We present engineered proteins that trap, map, and quantify Holliday junctions (HJs), a central DNA intermediate in HR, based on catalytically deficient mutant RuvC protein of Escherichia coli. We use RuvCDefGFP (RDG) to map genomic footprints of HR at defined DNA breaks in E. coli and demonstrate genome-scale directionality of double-strand break (DSB) repair along the chromosome. Unexpectedly, most spontaneous HR-HJ foci are instigated, not by DSBs, but rather by single-stranded DNA damage generated by replication. We show that RecQ, the E. coli ortholog of five human cancer proteins, nonredundantly promotes HR-HJ formation in single cells and, in a novel junction guardian role, also prevents apparent non-HR-HJs promoted by RecA overproduction. We propose that one or more human RecQ orthologs may act similarly in human cancers overexpressing the RecA ortholog RAD51 and find that cancer genome expression data implicate the orthologs BLM and RECQL4 in conjunction with EME1 and GEN1 as probable HJ reducers in such cancers. Our results support RecA overproducing E. coli as a model of the many human tumors with up-regulated RAD51 and provide the first glimpses of important, previously elusive reaction intermediates in DNA replication and repair in single living cells. PMID- 28090591 TI - An advertisement analysis of alcohol products in popular women's magazines. PMID- 28090590 TI - Withania somnifera extract reduces the invasiveness of MDA-MB-231 breast cancer and inhibits cytokines associated with metastasis. AB - AIM: The aim was to examine the anti-proliferative effect of a Withania somnifera (WS) root extract in cell cultures and nude mouse xenografts of breast cancer cell line MDA-MB-231. METHODS: WS root extract was used to treat tumor cells at concentrations up to 100 ug and for nude mouse experiments, the mice received daily WS at 300 mg/kg by oral gavage for 8 weeks. RESULTS: The WS extract reduced viability of MDA-MB-231 cells by 75% and 88% after exposure of the cells to 50 and 100 ug/mL, respectively, compared to vehicle-treated controls. WS extract caused a dose-dependent increase in the percentage of cells in the sub-G1 phase compared to untreated controls by 6% and 10% after exposure to 25 and 50 ug/mL WS extract, respectively. WS extract also inhibited proliferation of xenografted MDA MB-231 cells. The WS extract caused reductions in xenograft size by 60% compared to the untreated control after 8 weeks of treatment. Six of ten mice in the control group showed tumor metastasis to the lung, whereas there was none in the mice treated with the WS extract. At the gene level, WS caused a 75% reduction in chemokine CCL2 expression (P < 0.05) in the xenografted tumors of the treated mice. CONCLUSION: WS root extract inhibited proliferation of breast cancer cells in vitro and in vivo and significantly reduced expression of the cytokine, CCL2. These results warrant further studies to assess the underlying molecular mechanism of the anti-tumor activity of the WS extract in breast cancer. PMID- 28090592 TI - The first genome sequences of human bocaviruses from Vietnam. AB - As part of an ongoing effort to generate complete genome sequences of hand, foot and mouth disease-causing enteroviruses directly from clinical specimens, two complete coding sequences and two partial genomic sequences of human bocavirus 1 (n=3) and 2 (n=1) were co-amplified and sequenced, representing the first genome sequences of human bocaviruses from Vietnam. The sequences may aid future study aiming at understanding the evolution of the pathogen. PMID- 28090593 TI - ultraLM and miniLM: Locator tools for smart tracking of fluorescent cells in correlative light and electron microscopy. AB - In-resin fluorescence (IRF) protocols preserve fluorescent proteins in resin embedded cells and tissues for correlative light and electron microscopy, aiding interpretation of macromolecular function within the complex cellular landscape. Dual-contrast IRF samples can be imaged in separate fluorescence and electron microscopes, or in dual-modality integrated microscopes for high resolution correlation of fluorophore to organelle. IRF samples also offer a unique opportunity to automate correlative imaging workflows. Here we present two new locator tools for finding and following fluorescent cells in IRF blocks, enabling future automation of correlative imaging. The ultraLM is a fluorescence microscope that integrates with an ultramicrotome, which enables 'smart collection' of ultrathin sections containing fluorescent cells or tissues for subsequent transmission electron microscopy or array tomography. The miniLM is a fluorescence microscope that integrates with serial block face scanning electron microscopes, which enables 'smart tracking' of fluorescent structures during automated serial electron image acquisition from large cell and tissue volumes. PMID- 28090594 TI - Effects of tranexamic acid on platelet function and thrombin generation (ETAPlaT): WOMAN trial sub-study. AB - Background. Postpartum haemorrhage (PPH) is a leading cause of maternal death. Tranexamic acid (TXA) has the potential to reduce bleeding and a large randomized placebo controlled trial of its effect in women with PPH (The WOMAN trial) is underway. TXA might also affect coagulation factors and platelets. Objectives. To examine the effect of TXA on thrombin generation, platelet function, fibrinogen, D-dimer and coagulation factors in women with PPH. Methods. We will conduct a sub-study within the WOMAN trial. Women with clinically diagnosed primary PPH after vaginal or caesarean delivery are eligible for inclusion. Blood samples will be collected at baseline and 30 minutes after the first dose of study treatment. Using platelet poor plasma we will measure thrombin generation, fibrinogen, D-dimer, factor V and VIII, and Von Willebrand factor. Platelet function will be evaluated in whole blood using Multiplate(r) tests. Outcomes. The primary outcome is the effect of TXA on thrombin generation. Secondary outcomes include the effect of TXA on platelet function, fibrinogen, D-dimer and coagulation factors. PMID- 28090595 TI - A Case of Coats Disease and Concurrent Anisometropic Amblyopia. AB - PURPOSE: The aim of this report was to demonstrate a case of Coats disease in a patient with concurrent anisometropic amblyopia. OBSERVATIONS: A 10-year-old boy was diagnosed with Coats disease during routine ophthalmic examination. Visual acuity was 20/20 OD and 20/50 OS with cycloplegic refraction of +1.25 (OD) and +3.25 (OS). Examination under anesthesia showed macular exudates in the left eye that encroached near the fovea superotemporally. Despite the poor visual acuity and macular exudates, the foveal architecture of both eyes appeared normal on spectral domain optical coherence tomography. Because of the differing refractive error between the two eyes in the presence of foveal-sparing exudates, anisometropic amblyopia was suspected. After initial laser therapy, the patient was started on a daily patching regimen of the right eye. The patient's vision steadily improved to 20/25 OS with a final cycloplegic refraction of +1.00 (OD), +3.00 (OS) at 2 years. This report demonstrates the importance of assessing for other common and treatable causes of vision loss in the setting of Coats disease. CONCLUSIONS AND IMPORTANCE: This case demonstrates the importance of detecting and correcting for concurrent amblyopia in pediatric retina conditions that may, on fundus examination alone, appear to have a retinal cause for reduced visual acuity. PMID- 28090597 TI - Automatic Segmentation and Quantification of Filamentous Structures in Electron Tomography. AB - Electron tomography is a promising technology for imaging ultrastructures at nanoscale resolutions. However, image and quantitative analyses are often hindered by high levels of noise, staining heterogeneity, and material damage either as a result of the electron beam or sample preparation. We have developed and built a framework that allows for automatic segmentation and quantification of filamentous objects in 3D electron tomography. Our approach consists of three steps: (i) local enhancement of filaments by Hessian filtering; (ii) detection and completion (e.g., gap filling) of filamentous structures through tensor voting; and (iii) delineation of the filamentous networks. Our approach allows for quantification of filamentous networks in terms of their compositional and morphological features. We first validate our approach using a set of specifically designed synthetic data. We then apply our segmentation framework to tomograms of plant cell walls that have undergone different chemical treatments for polysaccharide extraction. The subsequent compositional and morphological analyses of the plant cell walls reveal their organizational characteristics and the effects of the different chemical protocols on specific polysaccharides. PMID- 28090596 TI - Extracellular vesicle associated long non-coding RNAs functionally enhance cell viability. AB - Cells communicate with one another to create microenvironments and share resources. One avenue by which cells communicate is through the action of exosomes. Exosomes are extracellular vesicles that are released by one cell and taken up by neighbouring cells. But how exosomes instigate communication between cells has remained largely unknown. We present evidence here that particular long non-coding RNA molecules are preferentially packaged into exosomes. We also find that a specific class of these exosome associated non-coding RNAs functionally modulate cell viability by direct interactions with L-lactate dehydrogenase B (LDHB), high-mobility group protein 17 (HMG-17), and CSF2RB, proteins involved in metabolism, nucleosomal architecture and cell signalling respectively. Knowledge of this endogenous cell to cell pathway, those proteins interacting with exosome associated non-coding transcripts and their interacting domains, could lead to a better understanding of not only cell to cell interactions but also the development of exosome targeted approaches in patient specific cell-based therapies. PMID- 28090598 TI - Diverse Brains. PMID- 28090600 TI - Learning-Based 3T Brain MRI Segmentation with Guidance from 7T MRI Labeling. AB - Brain magnetic resonance image segmentation is one of the most important tasks in medical image analysis and has considerable importance to the effective use of medical imagery in clinical and surgical setting. In particular, the tissue segmentation of white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF) is crucial for brain measurement and disease diagnosis. A variety of studies have shown that the learning-based techniques are efficient and effective in brain tissue segmentation. However, the learning-based segmentation methods depend largely on the availability of good training labels. The commonly used 3T magnetic resonance (MR) images have insufficient image quality and often exhibit poor intensity contrast between WM, GM, and CSF, therefore not able to provide good training labels for learning-based methods. The advances in ultra-high field 7T imaging make it possible to acquire images with an increasingly high level of quality. In this study, we propose an algorithm based on random forest for segmenting 3T MR images by introducing the segmentation information from their corresponding 7T MR images (through semi-automatic labeling). Furthermore, our algorithm iteratively refines the probability maps of WM, GM, and CSF via a cascade of random forest classifiers to improve the tissue segmentation. Experimental results on 10 subjects with both 3T and 7T MR images in a leave-one out validation, show that the proposed algorithm performs much better than the state-of-the-art segmentation methods. PMID- 28090599 TI - Mas-related G protein coupled receptor-X2: A potential new target for modulating mast cell-mediated allergic and inflammatory diseases. AB - Mast cells (MCs) are tissue resident immune cells that are best known for their roles in allergic and inflammatory diseases. In addition to the high affinity IgE receptor (FcepsilonRI), MCs express numerous G protein coupled receptors (GPCRs), which are the most common targets of drug therapy. Neurokinin 1 receptor (NK-1R) is expressed on MCs and contributes to IgE and non-IgE-mediated responses in mice. Although NK-1R antagonists are highly effective in modulating experimental allergic and inflammatory responses in mice they lack efficacy in humans. This article reviews recent findings that demonstrate that while neuropeptides (NPs) activate murine MCs via NK-1R and Mas related G protein coupled receptor B2 (MrgprB2), they activate human MCs via Mas-related G protein coupled receptor X2 (MRGPRX2). Interestingly, conventional NK-1R antagonists have off-target activity against mouse MrgprB2 but not human MRGPRX2. These findings suggest that the failure to translate studies with NK-1R antagonists from in vivo mouse studies to the clinic likely reflects their lack of effect on human MRGPRX2. A unique feature of MRGPRX2 that distinguishes it from other GPCRs is that it is activated by a diverse group of ligands that include; neuropeptides, cysteine proteases, antimicrobial peptides and cationic proteins released from activated eosinophils. Thus, the development of small molecule MRGPRX2-specific antagonists or neutralizing antibodies may provide new targets for the treatment of MC-mediated allergic and inflammatory diseases. PMID- 28090601 TI - Beyond Classification: Structured Regression for Robust Cell Detection Using Convolutional Neural Network. AB - Robust cell detection serves as a critical prerequisite for many biomedical image analysis applications. In this paper, we present a novel convolutional neural network (CNN) based structured regression model, which is shown to be able to handle touching cells, inhomogeneous background noises, and large variations in sizes and shapes. The proposed method only requires a few training images with weak annotations (just one click near the center of the object). Given an input image patch, instead of providing a single class label like many traditional methods, our algorithm will generate the structured outputs (referred to as proximity patches). These proximity patches, which exhibit higher values for pixels near cell centers, will then be gathered from all testing image patches and fused to obtain the final proximity map, where the maximum positions indicate the cell centroids. The algorithm is tested using three data sets representing different image stains and modalities. The comparative experiments demonstrate the superior performance of this novel method over existing state-of-the-art. PMID- 28090602 TI - Probabilistic Tractography for Topographically Organized Connectomes. AB - While tractography is widely used in brain imaging research, its quantitative validation is highly difficult. Many fiber systems, however, have well-known topographic organization which can even be quantitatively mapped such as the retinotopy of visual pathway. Motivated by this previously untapped anatomical knowledge, we develop a novel tractography method that preserves both topographic and geometric regularity of fiber systems. For topographic preservation, we propose a novel likelihood function that tests the match between parallel curves and fiber orientation distributions. For geometric regularity, we use Gaussian distributions of Frenet-Serret frames. Taken together, we develop a Bayesian framework for generating highly organized tracks that accurately follow neuroanatomy. Using multi-shell diffusion images of 56 subjects from Human Connectome Project, we compare our method with algorithms from MRtrix. By applying regression analysis between retinotopic eccentricity and tracks, we quantitatively demonstrate that our method achieves superior performance in preserving the retinotopic organization of optic radiation. PMID- 28090604 TI - XQ-NLM: Denoising Diffusion MRI Data via x-q Space Non-Local Patch Matching. AB - Noise is a major issue influencing quantitative analysis in diffusion MRI. The effects of noise can be reduced by repeated acquisitions, but this leads to long acquisition times that can be unrealistic in clinical settings. For this reason, post-acquisition denoising methods have been widely used to improve SNR. Among existing methods, non-local means (NLM) has been shown to produce good image quality with edge preservation. However, currently the application of NLM to diffusion MRI has been mostly focused on the spatial space (i.e., the x-space), despite the fact that diffusion data live in a combined space consisting of the x space and the q-space (i.e., the space of wavevectors). In this paper, we propose to extend NLM to both x-space and q-space. We show how patch-matching, as required in NLM, can be performed concurrently in x-q space with the help of azimuthal equidistant projection and rotation invariant features. Extensive experiments on both synthetic and real data confirm that the proposed x-q space NLM (XQ-NLM) outperforms the classic NLM. PMID- 28090603 TI - Spatial Clockwork Recurrent Neural Network for Muscle Perimysium Segmentation. AB - Accurate segmentation of perimysium plays an important role in early diagnosis of many muscle diseases because many diseases contain different perimysium inflammation. However, it remains as a challenging task due to the complex appearance of the perymisum morphology and its ambiguity to the background area. The muscle perimysium also exhibits strong structure spanned in the entire tissue, which makes it difficult for current local patch-based methods to capture this long-range context information. In this paper, we propose a novel spatial clockwork recurrent neural network (spatial CW-RNN) to address those issues. Specifically, we split the entire image into a set of non-overlapping image patches, and the semantic dependencies among them are modeled by the proposed spatial CW-RNN. Our method directly takes the 2D structure of the image into consideration and is capable of encoding the context information of the entire image into the local representation of each patch. Meanwhile, we leverage on the structured regression to assign one prediction mask rather than a single class label to each local patch, which enables both efficient training and testing. We extensively test our method for perimysium segmentation using digitized muscle microscopy images. Experimental results demonstrate the superiority of the novel spatial CW-RNN over other existing state of the arts. PMID- 28090605 TI - Domain Adaptation Methods for Improving Lab-to-field Generalization of Cocaine Detection using Wearable ECG. AB - Mobile health research on illicit drug use detection typically involves a two stage study design where data to learn detectors is first collected in lab-based trials, followed by a deployment to subjects in a free-living environment to assess detector performance. While recent work has demonstrated the feasibility of wearable sensors for illicit drug use detection in the lab setting, several key problems can limit lab-to-field generalization performance. For example, lab based data collection often has low ecological validity, the ground-truth event labels collected in the lab may not be available at the same level of temporal granularity in the field, and there can be significant variability between subjects. In this paper, we present domain adaptation methods for assessing and mitigating potential sources of performance loss in lab-to-field generalization and apply them to the problem of cocaine use detection from wearable electrocardiogram sensor data. PMID- 28090606 TI - Hierarchical Span-Based Conditional Random Fields for Labeling and Segmenting Events in Wearable Sensor Data Streams. AB - The field of mobile health (mHealth) has the potential to yield new insights into health and behavior through the analysis of continuously recorded data from wearable health and activity sensors. In this paper, we present a hierarchical span-based conditional random field model for the key problem of jointly detecting discrete events in such sensor data streams and segmenting these events into high-level activity sessions. Our model includes higher-order cardinality factors and inter-event duration factors to capture domain-specific structure in the label space. We show that our model supports exact MAP inference in quadratic time via dynamic programming, which we leverage to perform learning in the structured support vector machine framework. We apply the model to the problems of smoking and eating detection using four real data sets. Our results show statistically significant improvements in segmentation performance relative to a hierarchical pairwise CRF. PMID- 28090607 TI - Karma Police: Prosecutorial Strategies in Obscenity Cases and the Broader Culture War. PMID- 28090609 TI - A composite generator film impregnated with cellulose nanocrystals for enhanced triboelectric performance. AB - A novel polydimethylsiloxane (PDMS)/cellulose nanocrystal flake (CNCF) composite triboelectric nanogenerator (CTG) using CNCFs as effective dielectrics exhibited a 10-times-enhanced triboelectric performance compared with its pure PDMS counterpart. Positive charges generated on the surface of the CNCFs during cyclic compression boosted electron transfer and induced extra charges. The CTG exhibited an instantaneous output power (density) of 1.65 mW (0.76 mW cm-2) under continuous operation. PMID- 28090608 TI - Elevated expression of serine/threonine phosphatase type 5 correlates with malignant proliferation in human osteosarcoma. AB - Osteosarcoma is the most common primary malignant bone tumor in adolescents and young adults. However, the involvement of serine/threonine phosphatase type 5 (PP5) in osteosarcoma remains unclear. The aim of this study was to evaluate the functional role of PP5 in osteosarcoma cells. Firstly, we found that PP5 is widely expressed in several human osteosarcoma cell lines. Then we used lentivirus-delivered siRNA to silence PP5 expression in Saos-2 and U2OS cell lines. Knockdown of endogenous PP5 expression by shRNA-expressing lentivirus significantly decreased the viability and proliferation of the osteosarcoma cells. Moreover, FACS analysis showed that knockdown of PP5 expression induced a significant arrest in the G0/G1 phase of the cell cycle, which was associated with the inhibition of cell proliferation. Therefore, knockdown of PP5 is likely to provide a novel alternative to targeted therapy of osteosarcoma and deserves further investigation. PMID- 28090610 TI - Highly dispersible edge-selectively oxidized graphene with improved electrical performance. AB - We prepared liquid phase exfoliated edge-selectively oxidized graphene (LPEOG) with a high concentration in water (~14.7 mg ml-1) and a high ratio of a single layer (70%). The edge of graphite was selectively oxidized by step II oxidation of the modified Hummers method, and we subsequently exfoliated the edge selectively oxidized graphite (EOG) into LPEOG. The edge selective oxidation of the LPEOG was confirmed by X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), zeta-potentiometry, Raman spectroscopy, Fourier-transform infrared spectroscopy (FT-IR), atomic force microscopy (AFM), and transmission electron microscopy (TEM). The highly concentrated LPEOG ink can be used in solution processing such as simple drawing or spin casting. Reduced LPEOG showed a higher conductivity (120 000 S m-1) than that of reduced graphene oxide (68 800 S m-1) despite the small lateral size. A transparent conducting film prepared from the LPEOG ink showed a lower surface resistance (~2.97 kOmega sq-1) at a higher transmittance (>83.0 %T) compared to those of the graphene oxide based film. These results indicate that preservation of pi-conjugation of the basal plane of graphene is critical for electrical performance of graphene. Our method facilitates solution processing of graphene for a wide range of applications. PMID- 28090611 TI - Performance of nano-assembly logic gates with a DNA multi-hairpin motif. AB - DNA nano-assemblies have far-reaching implications for molecular computers. Boolean logic gates made from DNA respond to specific combinations of chemical or molecular inputs. In complex samples an assortment of other chemicals and molecules may interfere with the gate's recognition and response mechanisms. For logic gates to accept an increasing number of inputs, while maintaining selectivity, their design must only respond when specific input combinations are available simultaneously. Here we present proof-of-principle for a fluorescent based nano-assembly logic gate for three inputs. Central to the gate's design is a multi-hairpin motif that distinguishes it from other works in this area. The multi-hairpin motif facilitates a larger and increasing number of inputs and a place to generate FRET-based signal enhancement. We will show the nano-assembly logic gate worked in aqueous buffer and in crude MCF-7 cell lysate. We will demonstrate the gate's selectivity against off-analyte cocktails. Finally, multi hairpin motifs with different chemical and physical properties were evaluated to test their logic capabilities. Future work will demonstrate the gate's ability to visually identify specific combinations of oligonucleotides called small non coding RNAs (ncRNAs) in cells. This nano-assembly logic gate for small ncRNA has far reaching cellular computation and single-cell analysis applicability. The gate can be used for basic cellular analysis, computing and observing the unique molecular expression patterns in tumor microenvironments, and advancing the field of therapeutics. PMID- 28090612 TI - Quantum chemical study and isothermal titration calorimetry of beta-cyclodextrin complexes with mianserin in aqueous solution. AB - beta-Cyclodextrin (beta-CD) is studied as a carrier of the drug mianserin (MIA). beta-CD with MIA adducts with 1 : 1 and 2 : 1 stoichiometry are investigated in vacuo and in water using quantum chemical methods: PM6 and B3LYP/6-31G(d,p). An effect of the dispersion correction GD2 and the basis set superposition error on the complexation energies is also evaluated. Additionally, the interaction between MIA hydrochloride and beta-CD in aqueous solution at 298.15 K is examined experimentally by isothermal titration calorimetry. Interaction parameters, such as the binding constant, enthalpy, entropy and Gibbs free energy, are presented. Analysis of the obtained data led to the following conclusions: the interaction of MIA with beta-CD is rather strong; there is no significant energetic difference between the 1 : 1 complexes of beta-CD with S-MIA and R-MIA enantiomers; the 2 : 1 (beta-CD : MIA) adduct is energetically more favorable than 1 : 1; the complex formation of MIA + beta-CD is enthalpy and entropy driven. PMID- 28090613 TI - Expedient and modular access to 2-azabicyclic architectures by iron-catalyzed dehydrative coupling of alcohol-bearing allylic lactams. AB - A high-yielding, cost-effective, modular and environmentally benign approach to [5,5]- or [6,5]-2-azabicyclic architectures bearing vicinal stereocenters, by Fe catalyzed intramolecular dehydrative coupling of readily affordable alcohol bearing allylic lactams is presented. PMID- 28090614 TI - Synthesis and anticancer activity of benzoselenophene and heteroaromatic derivatives of 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI). AB - The current study reports the synthesis of different derivatives of benzoselenophene analogs as well as a diverse series of compounds (14a-p, 15 and 16) from 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI) and benzoselenophene or heteroaromatic acids. The overall yield of scaffold 12 was improved by an one-pot reaction, which helps in large-scale synthesis of CBI, a duocarmycin alkylation subunit analog. The series of compounds were evaluated for their cytotoxicity against SK-OV3 ovarian cancer cell lines, which revealed that benzoselenophene can enhance or maintain the anticancer activity of the duocarmycin analog upon replacing the indole moiety. CBI-benzoselenophenes with N amido substituents at the C-5 position, 14g, 14f and 16 (IC50 = 0.5, 1.2 and 1.6 nM, respectively), were found to be more potent than the CBI-TMI and other benzoselenophene analogs. The CBI-benzoselenophene analogs, 14f and 14g (containing N-acetamido and N-butyramido substituents, respectively), were found to be 8 and 120 times more potent than the corresponding indole analogs of CBI, 14q and 14r, respectively. PMID- 28090615 TI - Correction: Self-assembly of peptides: influence of substrate, pH and medium on the formation of supramolecular assemblies. AB - Correction for 'Self-assembly of peptides: influence of substrate, pH and medium on the formation of supramolecular assemblies' by Priyadharshini Kumaraswamy et al., Soft Matter, 2011, 7, 2744-2754. PMID- 28090617 TI - Updated Instructions to Authors. PMID- 28090616 TI - A copper-catalyzed reaction of oximes with diisopropyl azodicarboxylate: an alternative method for the synthesis of oxime carbonates. AB - A new Cu-catalyzed efficient protocol is described for the transformation of oximes to the corresponding carbonate derivatives. Diisopropyl azodicarboxylate acted as a selective new precursor for the synthesis of oxime carbonates in high yields. The O-H bond cleavage and O-C bond formation occur in the presence of a copper catalyst providing a synthetically useful process, which tolerates a wide range of functional groups. PMID- 28090618 TI - Alan Blum on Why Physicians Need to Be More Active and Creative in the Clinic, Classroom, and Community in Smoking Prevention and Cessation. PMID- 28090619 TI - The Evolving Approach to Management of Cancer Cachexia. AB - Weight loss is distressing to cancer patients and caregivers. Anorexia/cachexia syndrome is characterized by lipolysis and the loss of lean body mass, and is not reversible by increasing caloric intake. The pathophysiology of cancer cachexia is complex and includes symptoms that impact caloric intake, as well as chronic inflammation, hypermetabolism, and hormonal alterations. Cancer patients require routine screening for cachexia and, ideally, interventions should be initiated in the early stages of weight loss. No guidelines exist for the treatment of cancer cachexia. Appetite stimulants, such as megestrol acetate and glucocorticoids, have been shown to increase appetite and weight; however, single pharmaceutical interventions alone for cachexia do not result in meaningful functional outcomes. In the future, clinicians should consider multimodality treatment that is personalized for each patient. These interventions would include nutritional counseling, assessing and treating symptoms that have an impact on caloric intake, and a rational combination of pharmacologic approaches directed at underlying pathophysiology. Use of an appetite stimulant could be considered for patients who exhibit decreased appetite. Treatment with an anti-inflammatory agent should be considered for patients with elevated C-reactive protein, and hormonal alterations resulting from anti-cachexia therapy should be thoughtfully addressed. PMID- 28090620 TI - Early Engagement in Physical Activity and Exercise Is Key in Managing Cancer Cachexia. PMID- 28090621 TI - The Challenges of Treating Cancer Patients on Hemodialysis, or With Chronic Kidney Disease. PMID- 28090622 TI - FDG-PET for Early Response Assessment in Lymphomas: Part 1-Hodgkin Lymphoma. AB - Interim positron emission tomography (PET)/CT has shown encouraging results when used as a prognostic tool early in the course of treatment of advanced Hodgkin lymphoma, allowing for a reduction in treatment for patients with favorable characteristics, while suggesting a benefit from changing therapy for those with a positive scan. For patients with limited disease, a negative scan allows for a decrease in treatment; however, the benefits for those patients whose scans are positive are less certain. Here we critically analyze the role of PET/CT in the early assessment of Hodgkin lymphoma. In Part 2, we will review the role of interim PET/CT in diffuse large B-cell lymphoma (DLBCL), and also explore the question of whether new approaches to quantitative assessment improve the prognostic value of interim PET scans in both Hodgkin lymphoma and DLBCL. PMID- 28090623 TI - PALB2-Positive Breast Cancer in a 40-Year-Old Man. PMID- 28090624 TI - Current Strategies for the Immunotherapy of Multiple Myeloma. AB - The introduction of cellular immunotherapies using genetically modified T cells has revolutionized the treatment of patients with B-cell lymphomas. However, despite the progress made in this field, similarly effective immunotherapeutic approaches have not yet been identified for patients with solid tumors or other hematologic malignancies such as multiple myeloma. Here we outline the most promising novel cellular immune strategies for patients with multiple myeloma. In addition, we highlight combinatorial approaches that, it is hoped, will further optimize cellular immunotherapies for myeloma and lead to deep and durable responses and, possibly, even cures. PMID- 28090625 TI - Insights Into the Appropriate Use of New Antimyeloma Therapies. PMID- 28090626 TI - Active Surveillance of Prostate Cancer. PMID- 28090627 TI - FDG-PET for Early Response Assessment in Lymphomas: Part 2-Diffuse Large B-Cell Lymphoma, Use of Quantitative PET Evaluation. AB - In Part 1, we reviewed the role of interim positron emission tomography (PET)/CT scans in Hodgkin lymphoma. In advanced Hodgkin lymphoma, interim PET is a useful prognostic tool that can be used to implement risk-adapted therapy with potential benefits for both patients who have negative interim scans and those whose scans are positive. Interim PET/CT has not shown as encouraging results in diffuse large B-cell lymphoma (DLBCL), with the exception of germinal center B-cell DLBCL. Thus, quantitative methods of interpreting interim PET scans have been pursued in an effort to improve their predictive value. Early results using the change in maximal standardized uptake value between baseline and interim PET (DeltaSUVmax) to quantitatively interpret interim PET scans in DLBCL patients showed promise, but later results were contradictory. Thus, there is not firm evidence of a prognostic value for interim PET interpreted using either visual or DeltaSUVmax-based analysis in patients with DLBCL. Nor are there data to support altering treatment in DLBCL on the basis of an interim PET scan. More sophisticated methods of quantitative interpretation of interim PET, using metabolic tumor volume and tumor lesion glycolysis measurements, have been investigated in both Hodgkin lymphoma and DLBCL. Although to date studies of these approaches have been small and heterogeneous, they do provide some support for the potential of a PET-derived volumetric approach to discriminate between risk groups better than DeltaSUVmax; this remains to be proven in well-designed large-scale studies. PMID- 28090628 TI - ERK1/2, JNK and STAT3 activation and correlation with tumor differentiation in oral SCC. AB - Signal transducer and activator of transcription 3 (STAT3) and mitogen activated protein kinases (MAPKs), including ERK and JNK, have been implicated in oral squamous cell carcinoma (OSCC) development and progression. Our purpose was to evaluate the levels of activated STAT3, ERK1/2 and JNK by immunohistochemistry in OSCC and to investigate possible correlations of these molecules with each other as well as with the degree of tumor differentiation. Immunohistochemical assessment of the phosphorylated levels of STAT3(tyrosine/ serine), ERK1/2 and JNK was performed in 60 OSCC, including well, moderately and poorly differentiated tumors. Semiquantitative scoring system was used, by calculating intensity of immunostaining, percentage of positive cells and combined scores. Statistics included Fisher's test, Student's T-Test and Kruskal-Wallis analysis, Spearman's correlation coefficient and multivariate logistic regression analyses. Immunohistochemical levels of both pSTAT3(tyr) and pERK1/2 showed statistically significant differences between well and poorly differentiated tumors with the latter receiving higher mean percentage, intensity and total scores. On the other hand, pJNK showed statistically significantly higher intensity levels in moderately compared to poorly differentiated tumors. pSTAT3(ser) immunoexpression did not appear to correlate with tumor differentiation. Between different molecules, more pronounced, pERK1/2 levels exhibited statistically significant positive correlation with pSTAT3(ser), pSTAT3(tyr) and pJNK expression. ERK1/2 and STAT3 activation (as assessed by tyrosine but not serine phosphorylation) could contribute to a less differentiated phenotype in OSCC, while JNK activation may have an opposite, although possibly less pronounced, effect. Positive correlations between MAPK and STAT3 levels may indicate a direct crosstalk and/or regulation by common upstream pathways. PMID- 28090629 TI - What is the "L" in LPDs? Localized as well as lateralized. AB - BACKGROUND: Periodic discharges (PDs) are well established as either periodic lateralized epileptiform discharges (LPDs) or generalized discharges. However, PDs in the midline can currently not be adequately classified as they are not generalized and not lateralized. AIMS OF THE STUDY: To propose a modification of the current LPD classification. METHODS: We here present a paradigmatic case series of three adult patients with midline LPDs. RESULTS: In our patients, ictal electroencephalography (EEG) recordings revealed periodic epileptiform discharges in the midline region. All three patients were non-lesional. CONCLUSION: We, thus, suggest to include periodic localized non-lateralized epileptiform discharges into the term LPDs (in addition to periodic lateralized epileptiform discharges), as they can also be recorded as localized EEG phenomenon in the midline region. PMID- 28090630 TI - A novel homozygous truncating mutation of the SFRP4 gene in Pyle's disease. PMID- 28090631 TI - Operating unit time use is associated with anaesthesia type in below-knee surgery in adults. AB - BACKGROUND: Peripheral nerve blocks could reduce the operating unit and theatre time spent on high-risk patients who are particularly vulnerable to complications of general anaesthesia or have medications that prevent application of central neuraxial blocks. METHODS: Medical record data of 617 and 254 elderly adults undergoing below-knee surgery in Jorvi and Meilahti hospitals (Helsinki University Hospital) between January 2010 and December 2012 were used to investigate the influence of anaesthetic technique on operating theatre times and on operating unit times using flexible parametric survival models. We report operating theatre and unit exit ratios (i.e. hazard ratios but using ratios of exit rates) for different types of anaesthesia. RESULTS: Adjusted analyses: In Jorvi Hospital, anaesthesia type was associated with large initial differentials in operating theatre times. The theatre exit ratios remained lower for general anaesthesia and central neuraxial blocks compared to peripheral nerve blocks until 30 min. In Meilahti Hospital, anaesthesia type did not influence theatre time, but was the best predictor of operating unit times. Compared to peripheral nerve blocks, the exit ratio remained lower for general anaesthesia until five operating unit hours in both hospitals and for central neuraxial blocks until 1 h in Meilahti Hospital and until 3 h in Jorvi Hospital. Holding area was used more in Jorvi Hospital compared to Meilahti Hospital. CONCLUSION: Peripheral nerve block anaesthesia reduces time spent in the operating unit and can reduce time spent in the operating theatre if induced in holding area outside of theatre. PMID- 28090632 TI - Identification of highly selective MMP-14 inhibitory Fabs by deep sequencing. AB - Matrix metalloproteinase (MMP)-14 is an important target for cancer treatment due to its critical roles in tumor invasion and metastasis. Previous failures of all compound-based broad-spectrum MMP inhibitors in clinical trials suggest that selectivity is the key for a successful therapy. With inherent high specificity, monoclonal antibodies (mAbs) therefore arise as attractive inhibitors able to target the particular MMP of interest. As a routine screening method, enzyme linked immunosorbent assays (ELISA) have been applied to panned phage libraries for the isolation of mAbs inhibiting MMP-14. However, because of suboptimal growth conditions and insufficient antibody expression associated with monoclonal ELISA, a considerable number of potentially inhibitory clones might not be identified. Taking advantage of next-generation sequencing (NGS), we monitored enrichment profiles of millions of antibody clones along three rounds of phage panning, and identified 20 Fab inhibitors of MMP-14 with inhibition IC50 values of 10-4,000 nM. Among these inhibitory Fabs, 15 were not found by monoclonal phage ELISA. Particularly, Fab R2C7 exhibited an inhibition potency of 100 nM with an excellent selectivity to MMP-14 over MMP-9. Inhibition kinetics and epitope mapping suggested that as a competitive inhibitor, R2C7 directly bound to the vicinity of the MMP-14 catalytic site. This study demonstrates that deep sequencing is a powerful tool to facilitate the systematic discovery of mAbs with protease inhibition functions. Biotechnol. Bioeng. 2017;114: 1140-1150. (c) 2017 Wiley Periodicals, Inc. PMID- 28090633 TI - Magnetic field effects on particle beams and their implications for dose calculation in MR-guided particle therapy. AB - PURPOSE: To investigate and model effects of magnetic fields on proton and carbon ion beams for dose calculation. METHODS: In a first step, Monte Carlo simulations using Gate 7.1/Geant4.10.0.p03 were performed for proton and carbon ion beams in magnetic fields ranging from 0 to 3 T. Initial particle energies ranged from 60 to 250 MeV (protons) and 120 to 400 MeV/u (carbon ions), respectively. The resulting dose distributions were analyzed focusing on beam deflection, dose deformation, as well as the impact of material heterogeneities. In a second step, a numerical algorithm was developed to calculate the lateral beam position. Using the Runge-Kutta method, an iterative solution of the relativistic Lorentz equation, corrected for the changing particle energy during penetration, was performed. For comparison, a gamma-index analysis was utilized, using a criteria of 2%/2 mm of the local maximum. RESULTS: A tilt in the dose distribution within the Bragg peak area was observed, leading to non-negligible dose distribution changes. The magnitude was found to depend on the magnetic field strength as well as on the initial beam energy. Comparison of the 3 T dose distribution with non-B field (nominal) dose distributions, resulted in a gammamean (mean value of the gamma distribution) of 0.6, with 14.4% of the values above 1 and gamma1 % (1% of all points have an equal or higher gamma value) of 1.8. The presented numerical algorithm calculated the lateral beam offset with maximum errors of less than 2% with calculation times of less than 5 MUs. The impact of tissue interfaces on the proton dose distributions was found to be less than 2% for a dose voxel size of 1 * 1 * 1 mm3 . CONCLUSION: Non-negligible dose deformations at the Bragg peak area were identified for high initial energies and strong magnetic fields. A fast numerical algorithm based on the solution of the energy-corrected relativistic Lorentz equation was able to describe the beam path, taking into account the particle energy, magnetic field, and material. PMID- 28090635 TI - Sonographic Features and Diagnosis of Peripheral Schwannomas. AB - BACKGROUND: To determine the sonographic features of peripheral schwannomas. METHODS: This retrospective study included 54 cases of schwannoma in 51 patients. Ultrasonography (US) and MRI were performed in all patients. The US features of each tumor were analyzed and compared with pathologic findings. The US target sign was compared with the MRI findings. RESULTS: On US, 53 of the 54 schwannomas had a regular shape and clear margins, and one had an irregular shape. Thirty seven of the 54 schwannomas were categorized as solid, 16 as cystic and solid, and one as entirely cystic; distal sound enhancement was associated with 47 schwannomas. The target sign was seen in 24, the rat tail sign in 28, the vessel accompanying sign in 22, and the split fat sign in 5. The entering and exiting nerves were situated centrally in 9 and eccentrically in 19 schwannomas. Vascularity on color Doppler imaging using a 0 to III scale was graded 0 in 4 schwannomas, I in 10, II in 26, and III in 14. Twenty-four target signs were detected in 54 schwannomas by US, and 28 were detected by MRI. There was good agreement between the target signs noted on US and those seen on MRI (kappa = 0.631, p < 0.001). CONCLUSIONS: The sonographic diagnosis of peripheral schwannomas is feasible and reliable. The target sign is a prominent US feature in peripheral schwannomas, comparable to that observed with MRI. (c) 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:127-133, 2017. PMID- 28090636 TI - My Dad Can Beat Your Dad: Agonists, Antagonists, Partial Agonists, and Inverse Agonists. PMID- 28090634 TI - Dietary interventions for fetal growth restriction - therapeutic potential of dietary nitrate supplementation in pregnancy. AB - Fetal growth restriction (FGR) affects around 5% of pregnancies and is associated with significant short- and long-term adverse outcomes. A number of factors can increase the risk of FGR, one of which is poor maternal diet. In terms of pathology, both clinically and in many experimental models of FGR, impaired uteroplacental vascular function is implicated, leading to a reduction in the delivery of oxygen and nutrients to the developing fetus. Whilst mechanisms underpinning impaired uteroplacental vascular function are not fully understood, interventions aimed at enhancing nitric oxide (NO) bioavailability remain a key area of interest in obstetric research. In addition to endogenous NO production from the amino acid l-arginine, via nitric oxide synthase (NOS) enzymes, research in recent years has established that significant NO can be derived from dietary nitrate, via the 'alternative NO pathway'. Dietary nitrate, abundant in green leafy vegetables and beetroot, can increase NO bioactivity, conferring beneficial effects on cardiovascular function and blood flow. Given the beneficial effects of dietary nitrate supplementation to date in non-pregnant humans and animals, current investigations aim to assess the therapeutic potential of this approach in pregnancy to enhance NO bioactivity, improve uteroplacental vascular function and increase fetal growth. PMID- 28090637 TI - Diltiazem prevents stress-induced contractile deficits in cardiomyocytes, but does not reverse the cardiomyopathy phenotype in Mybpc3-knock-in mice. AB - KEY POINTS: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac illness and can lead to diastolic dysfunction, sudden cardiac death and heart failure. Treatment of HCM patients is empirical and current pharmacological treatments are unable to stop disease progression or reverse hypertrophy. In this study, we tested if the non-dihydropyridine Ca2+ channel blocker diltiazem, which previously showed potential to stop disease progression, can improve the phenotype of a HCM mouse model (Mybpc3-targeted knock-in), which is based on a mutation commonly found in patients. Diltiazem improved contractile function of isolated ventricular cardiomyocytes acutely, but chronic application did not improve the phenotype of adult mice with a fully developed HCM. Our study shows that diltiazem has beneficial effects in HCM, but long-term treatment success is likely to depend on characteristics and cause of HCM and onset of treatment. ABSTRACT: Left ventricular hypertrophy, diastolic dysfunction and fibrosis are the main features of hypertrophic cardiomyopathy (HCM). Guidelines recommend beta adrenoceptor or Ca2+ channel antagonists as pharmacological treatment. The Ca2+ channel blocker diltiazem recently showed promising beneficial effects in pre clinical HCM, particularly in patients carrying MYBPC3 mutations. In the present study we evaluated whether diltiazem could ameliorate or reverse the disease phenotype in cells and in vivo in an Mybpc3-targeted knock-in (KI) mouse model of HCM. Sarcomere shortening and Ca2+ transients were measured in KI and wild-type (WT) cardiomyocytes in basal conditions (1-Hz pacing) and under stress conditions (30 nm isoprenaline, 5-Hz pacing) with or without pre-treatment with 1 MUm diltiazem. KI cardiomyocytes exhibited lower diastolic sarcomere length (dSL) at baseline, a tendency to a stronger positive inotropic response to isoprenaline than WT, a marked reduction of dSL and a tendency towards arrhythmias under stress conditions. Pre-treatment of cardiomyocytes with 1 MUm diltiazem reduced the drop in dSL and arrhythmia frequency in KI, and attenuated the positive inotropic effect of isoprenaline. Furthermore, diltiazem reduced the contraction amplitude at 5 Hz but did not affect diastolic Ca2+ load and Ca2+ transient amplitude. Six months of diltiazem treatment of KI mice did not reverse cardiac hypertrophy and dysfunction, activation of the fetal gene program or fibrosis. In conclusion, diltiazem blunted the response to isoprenaline in WT and KI cardiomyocytes and improved diastolic relaxation under stress conditions in KI cardiomyocytes. This beneficial effect of diltiazem in cells did not translate in therapeutic efficacy when applied chronically in KI mice. PMID- 28090639 TI - The Psychometric Validation of the EPDS-K Among Korean Women: Does It Only Measure Depressive Symptoms? AB - PURPOSE: The purpose of this study was to test the validity of the Edinburgh Postnatal Depression Scale-Korean (EPDS-K) and compare the specified models (one , two-, three-factor model, and a model in the current study) in pregnant, first trimester Korean women. DESIGN AND METHODS: The study consisted of two groups of 100 first-trimester Korean women recruited from maternity clinics in Korea. FINDINGS: The results show that the EPDS-K has depression, anxiety, and anhedonia factors, and that the validity of the EPDS-K with Korean women is questionable. PRACTICE IMPLICATIONS: Healthcare providers should test the psychometric properties of tools for screening accuracy, clinical decision-making, and understanding of a phenomenon within different cultural settings. PMID- 28090638 TI - Late gestational intermittent hypoxia induces metabolic and epigenetic changes in male adult offspring mice. AB - KEY POINTS: Late gestation during pregnancy has been associated with a relatively high prevalence of obstructive sleep apnoea (OSA). Intermittent hypoxia, a hallmark of OSA, could impose significant long-term effects on somatic growth, energy homeostasis and metabolic function in offspring. Here we show that late gestation intermittent hypoxia induces metabolic dysfunction as reflected by increased body weight and adiposity index in adult male offspring that is paralleled by epigenomic alterations and inflammation in visceral white adipose tissue. Fetal perturbations by OSA during pregnancy impose long-term detrimental effects manifesting as metabolic dysfunction in adult male offspring. ABSTRACT: Pregnancy, particularly late gestation (LG), has been associated with a relatively high prevalence of obstructive sleep apnoea (OSA). Intermittent hypoxia (IH), a hallmark of OSA, could impose significant long-term effects on somatic growth, energy homeostasis, and metabolic function in offspring. We hypothesized that IH during late pregnancy (LG-IH) may increase the propensity for metabolic dysregulation and obesity in adult offspring via epigenetic modifications. Time-pregnant female C57BL/6 mice were exposed to LG-IH or room air (LG-RA) during days 13-18 of gestation. At 24 weeks, blood samples were collected from offspring mice for lipid profiles and insulin resistance, indirect calorimetry was performed and visceral white adipose tissues (VWAT) were assessed for inflammatory cells as well as for differentially methylated gene regions (DMRs) using a methylated DNA immunoprecipitation on chip (MeDIP-chip). Body weight, food intake, adiposity index, fasting insulin, triglycerides and cholesterol levels were all significantly higher in LG-IH male but not female offspring. LG-IH also altered metabolic expenditure and locomotor activities in male offspring, and increased number of pro-inflammatory macrophages emerged in VWAT along with 1520 DMRs (P < 0.0001), associated with 693 genes. Pathway analyses showed that genes affected by LG-IH were mainly associated with molecular processes related to metabolic regulation and inflammation. LG-IH induces metabolic dysfunction as reflected by increased body weight and adiposity index in adult male offspring that is paralleled by epigenomic alterations and inflammation in VWAT. Thus, perturbations to fetal environment by OSA during pregnancy can have long-term detrimental effects on the fetus, and lead to persistent metabolic dysfunction in adulthood. PMID- 28090640 TI - In the era of IGRT and small- and focal-field external beam radiotherapy, brachytherapy is a dying modality. PMID- 28090642 TI - Depression or Diabetes Distress? AB - PURPOSE: The purpose of this paper is to summarize the need for improved recognition of depression versus diabetes distress and discuss recommendations for appropriate screening tools. PRACTICE IMPLICATIONS: In order to assess for both depression and diabetes distress, a combined approach of using both the WHO 5 and the PAID-20 is a simple and reliable method for detecting depression and assisting in determining the focus of specific aspects of diabetes management based on the patient's reported depressive symptoms. CONCLUSIONS: Routine screening for depression and diabetes distress is essential for improving quality of life and reducing healthcare cost in patients with diabetes. PMID- 28090641 TI - In-vivo quantitative assessment of the therapeutic response in a mouse model of collagen-induced arthritis using 18 F-fluorodeoxyglucose positron emission tomography. AB - Mouse collagen-induced arthritis (CIA) is the most commonly used animal model to investigate underlying pathogenesis of autoimmune arthritis and to demonstrate the therapeutic efficacy of novel drugs in autoimmune arthritis. The conventional read-outs of CIA are clinical score and histopathology, which have several limitations, including (i) subjected to observer bias; and (ii) longitudinal therapeutic efficacy of a new drug cannot be determined. Thus, a robust, non invasive, in-vivo drug screening tool is currently an unmet need. Here we have assessed the utility of 18 F-fluorodeoxyglucose positron emission tomography (18 F-FDG) as an in-vivo screening tool for anti-inflammatory drugs using the mouse CIA model. The radiotracer 18 F-FDG and a PET scanner were employed to monitor CIA disease activity before and after murine anti-tumour necrosis factor (TNF) alpha antibody (CNTO5048) therapy in the mouse CIA model. Radiotracer concentration was derived from PET images for individual limb joints and on a per limb basis, and Spearman's correlation coefficient (rho) was determined with clinical score and histology of the affected limbs. CNTO5048 improved arthritis efficiently, as evidenced by clinical score and histopathology. PET showed an increased uptake of 18 F-FDG with the progression of the disease and a significant decrease in the post-treatment group. 18 F-FDG uptake patterns showed a strong correlation with clinical score (rho = 0.71, P < 0.05) and histopathology (rho = 0.76, P < 0.05). This study demonstrates the potential of 18 F-FDG PET as a tool for in-vivo drug screening for inflammatory arthritis and to monitor the therapeutic effects in a longitudinal setting. PMID- 28090643 TI - The use of instructional design guidelines to increase effectiveness of postpartum hemorrhage simulation training. AB - OBJECTIVE: To compare learning outcomes of postpartum hemorrhage simulation training based on either instructional design guidelines or best practice. METHODS: A pretest-post-test non-equivalent groups study was conducted among obstetrics and gynecology residents in Recife, Brazil, from June 8 to August 30, 2013. The instructional design group included 13 teams, whereas the best practice group included seven teams. A standardized task checklist was used for scenario analysis and the proportion of correctly executed tasks compared (post-test minus pretest). RESULTS: The instructional design group scored higher than the best practice group for total number of tasks completed (median difference 0.46 vs 0.17; P<0.001; effect size [r]=0.72). Similar results were observed for communication (median difference 0.56 vs 0.22; P=0.004; r=0.58), laboratory evaluation (median difference 0.83 vs 0.00; P<0.001; r=0.76), and mechanical management (median difference 0.25 vs -0.15; P=0.048; r=0.39). Speed of learning was also increased. The median differences were 0.20 for the instructional design group compared with 0.05 for the best practice group at 60 seconds (P=0.015; r=0.49), and 0.49 versus 0.26 (P=0.001; r=0.65) at 360 seconds. CONCLUSION: The use of simulation training for postpartum hemorrhage that was based on instructional design guidelines yielded better learning outcomes than did training based on best practice. PMID- 28090644 TI - Evaluation of a telehealth training package to remotely train staff to conduct a preference assessment. AB - Recent advancements in telecommunication technologies make it possible to conduct a variety of healthcare services remotely (e.g., behavioral-analytic intervention services), thereby bridging the gap between qualified providers and consumers in isolated locations. In this study, web-based telehealth technologies were used to remotely train direct-care staff to conduct a multiple-stimulus-without replacement preference assessment. The training package included three components: (a) a multimedia presentation; (b) descriptive feedback from previously recorded baseline sessions; and (c) scripted role-play with immediate feedback. A nonconcurrent, multiple-baseline-across-participants design was used to demonstrate experimental control. Training resulted in robust and immediate improvements, and these effects maintained during 1- to 2-month follow-up observations. In addition, participants expressed high satisfaction with the web based materials and the overall remote-training experience. PMID- 28090645 TI - Neonatal Limb Amputation-An Unusual Form of Postmortem Canine Predation. AB - Cases of postmortem canine predation often involve elderly recluses and their dogs. The face, head, and genitalia are targeted. Two unusual cases of postmortem canine predation of abandoned newborns are described to demonstrate an unusual alternative pattern of mutilation related to the small size of the decedents, marked decomposition, and canine scavenging behavior. Both bodies were abandoned/concealed soon after birth and were subsequently disturbed by dogs. Both were markedly decomposed with absent arms. Other injuries included skin and soft tissue defects of the torsos, with loss of distal portions of the right foot and the left lower leg in one case. No interstitial hemorrhage was observed in any of the exposed soft tissue wounds. There were no significant head or neck injuries. These cases show that patterns of postmortem canine predation will vary depending on the age, physical characteristics, degree of decomposition, and location of decedents. PMID- 28090646 TI - Influence of P-glycoprotein on the disposition of fexofenadine and its enantiomers. AB - OBJECTIVES: P-glycoprotein (P-gp) is responsible for the efflux of a broad variety of human and veterinary drugs. Canine P-gp polymorphisms alter drug disposition and toxicity, but their impact on the disposition of enantiomeric drugs is unknown. Using fexofenadine as a model compound, we developed and validated HPLC-fluorescence methods to determine the effect of P-gp on the disposition of fexofenadine and its enantiomers. METHODS: A chiral CD-Ph column was used for the separation of (R) and (S)-fexofenadine. Determination of racemic fexofenadine was achieved on an XDB-CN column. Fexofenadine and its enantiomers were detected by fluorescence at the excitation wavelength of 220 nm and emission wavelength of 300 nm. These methods were used to measure concentrations of fexofenadine and its enantiomers in Collie plasma after oral administration. KEY FINDINGS: This study demonstrates that P-gp prefers to transport (S) fexofenadine, and P-gp deficiency causes the increase in both (R)-fexofenadine and (S)-fexofenadine in plasma. Racemic fexofenadine, (R)-fexofenadine and (S) fexofenadine were increased in ABCB1-1Delta Collies (118.7, 72.0 and 48.3 ng/ml) compared to wild-type Collies (25.0, 16.5 and 7.7 ng/ml) at 1 h postadministration. The results demonstrate that the stereoselectivity of P-gp plays a key role in the disposition of fexofenadine enantiomers. CONCLUSIONS: The information derived from this drug model will be used to determine whether additional safety or efficacy requirements are necessary for enantiomeric drugs that would be used in dogs or humans. PMID- 28090647 TI - The multifaceted role of extracellular vesicles in metastasis: Priming the soil for seeding. AB - Extracellular vesicles (EVs), including exosomes, play a key role in inter and intracellular communication, promoting the proliferation and invasion of recipient cells to support tumor growth and metastasis. Metastasis comprises multiple steps that first include the detachment of tumor cells through epithelial to mesenchymal transition (EMT), allowing the physical dissemination to distant organs. Thereafter, cancer-derived exosomes are still critical components for preparing the tumor microenvironment by (i) enabling tumor cells to escape from the immunological surveillance and (ii) arranging the pre metastatic site for the engraftment of detached cancer cells. In this review, we discuss the multifaceted role of EVs in the multiple steps of metastasis. Future research directions draw attention to EVs as biological targets for cancer diagnosis, prognosis and therapy. However, due to their significant role in cell communication, they may become a valuable drug delivery system. PMID- 28090648 TI - DisorderING promotes epigenetic order. PMID- 28090650 TI - First words: speech and language interventions in cerebral palsy. PMID- 28090649 TI - The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Outcomes and Metrics of Pharmacogenetic Implementations Across Diverse Healthcare Systems. AB - Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics Program (TPP) of the National Institutes of Health (NIH) Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real-world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene-drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams. TPP participant institutions developed diverse solutions to overcome many barriers, but the use of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provided some consistency among the institutions. The TPP also collected some pharmacogenetic implementation outcomes (scientific, educational, financial, and informatics), which may inform healthcare systems seeking to implement their own pharmacogenetic testing programs. PMID- 28090651 TI - Incidence of skin and respiratory diseases among Danish hairdressing apprentices. AB - BACKGROUND: Hairdressing is one of the professions with the highest risk of occupational skin and respiratory diseases. The incidence of these diseases in hairdressing apprentices has been studied only sparsely. OBJECTIVE: To determine the incidence of skin and respiratory diseases in hairdressing apprentices, and to explore whether hairdressing apprentices leave the trade during training because of these diseases. METHODS: A 3-year follow-up questionnaire study was conducted among 248 hairdressing apprentices and a control group comprising 816 young adults from the general population. RESULTS: The incidence rate ratios (IRRs) for contact urticaria (IRR 4.7, 95%CI: 2.6-8.6), hand eczema (IRR 1.7, 95%CI: 1.1-2.6) and rhinitis symptoms (IRR 1.6, 95%CI: 1.2-2.2) were significantly increased in the hairdressing apprentices, whereas wheezing was similar between groups. During the follow-up period, 21.8% of the hairdressing apprentices had left the trade, and 70.3% of these had left because of health complaints. The most frequently reported reasons for leaving were musculoskeletal pain (47.4%) and skin diseases (47.4%), followed by respiratory symptoms (23.7%). CONCLUSIONS: Hairdressing apprentices are at increased risk for contact urticaria, hand eczema and rhinitis symptoms compared with the general population, and a substantial proportion leave the trade because of these diseases, causing a 'healthy worker survivor effect.' PMID- 28090652 TI - A systematic review of the analgesic efficacy of cannabinoid medications in the management of acute pain. AB - BACKGROUND: Cannabinergic medications have been postulated to demonstrate efficacy in the management of pain. The aim of this systematic review was to assess the analgesic efficacy and adverse effects of cannabinoids when used for the management of acute pain. METHODS: A systematic review was performed by searching the MEDLINE, EMBASE and CENTRAL databases, and the World Health Organization International Clinical Trials Registry Platform for human randomized controlled trials that assessed the analgesic efficacy of cannabinoids compared to placebo or active comparators. The reported outcomes for analgesic efficacy and adverse effects in included studies were qualitatively analysed. RESULTS: Seven studies, including 611 patients were included in the systematic review. In five studies, cannabinoids were found to provide equivalent analgesia to placebo, in one study the analgesia provided by cannabinoids was superior to placebo, and in one study cannabinoids provided analgesia that was inferior to that provided by placebo. No synergistic or additive analgesic effect was observed when cannabinoids were used in combination with opioids. In five of the seven studies, certain adverse effects were more frequent with cannabinoid treatment than with placebo or active comparator. CONCLUSION: On the basis of the available randomized controlled trial evidence, cannabinoids have no role in the management of acute pain. PMID- 28090654 TI - The development of semantic blocking in children. AB - Pictures are named more slowly in the context of semantically related pictures than in the context of unrelated pictures. This semantic blocking effect has been studied extensively in adult participants, and one study has revealed its presence in 6-year-old children. However, little is known about the development of the effect with age. In this study, a blocked cyclic naming procedure was arranged for 5- to 7-year-old and 10- to 12-year-old children. The semantic blocking effect obtained did not differ in size between the two age groups. This finding is tentatively interpreted as evidence that the semantic blocking effect does not have the same underlying cause as interference effects typically observed in naming tasks involving a distractor stimulus, like the Stroop task. Statement of contribution What is already known on this subject? The semantic blocking effect has been demonstrated in adults, but little is known about its development in childhood. Age-related changes in performance in children have been used to distinguish various types of inhibitory control. What does this study add? A semantic blocking effect was obtained in 5- to 7-year-old children and - for the first time - in 10- to 12-year-old children. In the two age groups, the effect was equal in size and did not show up in the first cycles of the experiment. The findings are argued to be in line with the distinction unintentional vs. intentional inhibitory control. PMID- 28090653 TI - Genome-Wide Study Links PNPLA3 Variant With Elevated Hepatic Transaminase After Acute Lymphoblastic Leukemia Therapy. AB - Remission induction therapy for acute lymphoblastic leukemia (ALL) includes medications that may cause hepatotoxicity, including asparaginase. We used a genome-wide association study to identify loci associated with elevated alanine transaminase (ALT) levels after induction therapy in children with ALL enrolled on St. Jude Children's Research Hospital (SJCRH) protocols. Germline DNA was genotyped using arrays and exome sequencing. Adjusting for age, body mass index, ancestry, asparaginase preparation, and dosage, the PNPLA3 rs738409 (C>G) I148M variant, previously associated with fatty liver disease risk, had the strongest genetic association with ALT (P = 2.5 * 10-8 ). The PNPLA3 rs738409 variant explained 3.8% of the variability in ALT, and partly explained race-related differences in ALT. The PNPLA3 rs738409 association was replicated in an independent cohort of 2,285 patients treated on Children's Oncology Group protocol AALL0232 (P = 0.024). This is an example of a pharmacogenetic variant overlapping with a disease risk variant. PMID- 28090655 TI - 30-Second bound and pore water concentration mapping of cortical bone using 2D UTE with optimized half-pulses. AB - PURPOSE: MRI of cortical bone has the potential to offer new information about fracture risk. Current methods are typically performed with 3D acquisitions, which suffer from long scan times and are generally limited to extremities. This work proposes using 2D UTE with half pulses for quantitatively mapping bound and pore water in cortical bone. METHODS: Half-pulse 2D UTE methods were implemented on a 3T Philips Achieva scanner using an optimized slice-select gradient waveform, with preparation pulses to selectively image bound or pore water. The 2D methods were quantitatively compared with previously implemented 3D methods in the tibia in five volunteers. RESULTS: The mean difference between bound and pore water concentration acquired from 3D and 2D sequences was 0.6 and 0.9 mol 1 H/Lbone (3 and 12%, respectively). While 2D pore water methods tended to slightly overestimate concentrations relative to 3D methods, differences were less than scan-rescan uncertainty and expected differences between healthy and fracture prone bones. CONCLUSION: Quantitative bound and pore water concentration mapping in cortical bone can be accelerated by 2 orders of magnitude using 2D protocols with optimized half-pulse excitation. Magn Reson Med 77:945-950, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28090656 TI - Real-time monitoring of tissue displacement and temperature changes during MR guided high intensity focused ultrasound. AB - PURPOSE: The therapy endpoint most commonly used in MR-guided high intensity focused ultrasound is the thermal dose. Although namely correlated with nonviable tissue, it does not account for changes in mechanical properties of tissue during ablation. This study presents a new acquisition sequence for multislice, subsecond and simultaneous imaging of tissue temperature and displacement during ablation. METHODS: A single-shot echo planar imaging sequence was implemented using a pair of motion-encoding gradients, with alternated polarities. A first ultrasound pulse was synchronized on the second lobe of the motion-encoding gradients and followed by continuous sonication to induce a local temperature increase in ex vivo muscle and in vivo on pig liver. Lastly, the method was evaluated in the brain of two volunteers to assess method's precision. RESULTS: For thermal doses higher than the lethal threshold, displacement amplitude was reduced by 21% and 28% at the focal point in muscle and liver, respectively. Displacement value remained nearly constant for nonlethal thermal doses values. The mean standard deviation of temperature and displacement in the brain of volunteers remained below 0.8 degrees C and 2.5 um. CONCLUSION: This new fast imaging sequence provides real-time measurement of temperature distribution and displacement at the focus during HIFU ablation. Magn Reson Med 78:1911-1921, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28090657 TI - Toward greater insights on pharmacokinetics and exposure-response relationships for therapeutic biologics in oncology drug development. AB - There has been increased interest in optimizing dosing regimens for oncology products over the past decade. Investigations to refine dosing regimens often occur after new drug approval. There is growing focus on the use of exposure response (ER) approaches to identify optimal dosing regimens for therapeutic biologics. Herein, we describe several recent observations that have informed our thinking on the use of ER analyses in the dose regimen optimization of therapeutic biologics developed to treat cancer. PMID- 28090658 TI - Analysis of the effects of noise, DWI sampling, and value of assumed parameters in diffusion MRI models. AB - PURPOSE: This study was a systematic evaluation across different and prominent diffusion MRI models to better understand the ways in which scalar metrics are influenced by experimental factors, including experimental design (diffusion weighted imaging [DWI] sampling) and noise. METHODS: Four diffusion MRI models diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), mean apparent propagator MRI (MAP-MRI), and neurite orientation dispersion and density imaging (NODDI)-were evaluated by comparing maps and histogram values of the scalar metrics generated using DWI datasets obtained in fixed mouse brain with different noise levels and DWI sampling complexity. Additionally, models were fit with different input parameters or constraints to examine the consequences of model fitting procedures. RESULTS: Experimental factors affected all models and metrics to varying degrees. Model complexity influenced sensitivity to DWI sampling and noise, especially for metrics reporting non-Gaussian information. DKI metrics were highly susceptible to noise and experimental design. The influence of fixed parameter selection for the NODDI model was found to be considerable, as was the impact of initial tensor fitting in the MAP-MRI model. CONCLUSION: Across DTI, DKI, MAP-MRI, and NODDI, a wide range of dependence on experimental factors was observed that elucidate principles and practical implications for advanced diffusion MRI. Magn Reson Med 78:1767-1780, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28090659 TI - The effect of intradetrusor botulinum neurotoxin type A on urinary NGF, TGF BETA 1, TIMP-2 levels in children with neurogenic detrusor overactivity due to myelodysplasia. AB - AIMS: The aim of this study was to determine the value of urine nerve growth factor (NGF), transforming growth factor beta 1 (TGF-Beta-1), tissue inhibitor of matrix metalloproteinase 2 (TIMP-2) levels to predict the urodynamic profile before and after botulinum neurotoxin type A (BoNT-A) treatment in children with myelodysplasia. METHODS: This prospective study included 15 children with myelodysplasia who underwent intradetrusor BoNT-A injections due to neurogenic detrusor overactivity (NDOA). Urine samples of each child were collected before and after BoNT-A injections, specifically at the first and third postoperative months. Urine samples were analyzed with ELISA method and NGF, TGF-Beta-1, and TIMP-2 levels were measured. Urine marker levels and clinical findings were assessed for statistical significance with Wilcoxon Signed Ranks Test and Friedman Test. RESULTS: A total of 15 children (5 boys and 10 girls) were assigned as the study group. Mean age of the patients was 7.1 +/- 2.5 years (range 2.5-11). A statistically significantly decline was observed in urinary TGF Beta-1 and NGF levels following BoNT-A injections, compared to the preoperative levels (P < 0.05). TIMP-2 levels also tend to decrease following BoNT-A injections but this was not statistically significant compared to the preoperative levels. CONCLUSION: This preliminary study, suggests urinary TGF Beta-1 and NGF as a potent marker in children with NDOA, as they decline following BoNT-A injection. Further studies are needed in identifying their special role in assessing treatment success after invasive interventions. PMID- 28090660 TI - Intermittent catheterization acceptance test (I-CAT): A tool to evaluate the global acceptance to practice clean intermittent self-catheterization. AB - AIM: In certain cases, a patient's anxiety, fear, or misconceptions can represent significant obstacles to the learning of Clean Intermittent Self Catheterization (CISC), and little is known about these psychological barriers. The aim of the present study is thus to construct and validate an "Intermittent Catheterization Acceptance Test (I-CAT)" to evaluate the psychological acceptance of CISC. METHODS: A study was carried out in nine neuro-rehabilitation and urology departments in French university hospitals. Fifty-five items were identified, following a comprehensive review of the literature and cognitive debriefing interviews with patients. Following an initial expert panel meeting (EPM) with a French-speaking neuro-urology study group (GENULF), this list was refined and reduced to a draft I-CAT comprising 34 items. The face validity of the draft I CAT was determined, and the results were then analyzed in a second EPM, leading to the elaboration of a second version of the I-CAT (23 items, 5 dimensions). Psychometric validation of this second version was established from a longitudinal, non-randomized study involving 201 neurological and non neurological patients. Linguistic validation was carried out in English. RESULTS: Following the construct validity analyses, several items were deleted due to item overlap, ceiling effects, or poor content validity and 14 items were retained. Confirmatory factor analysis shows that this version has 2 dimensions. Cronbach's alpha was 0.93. The ICC demonstrated good test-retest reliability and satisfactory responsiveness. CONCLUSION: The upstream identification and solving of potential psychological barriers prior to the learning of CISC could improve patients' acceptance of this procedure. PMID- 28090661 TI - Effect of sagittal plane mechanics on ACL strain during jump landing. PMID- 28090662 TI - Adolescent depression linked to socioeconomic status? Molecular approaches for revealing premorbid risk factors. AB - The means by which social environmental exposures influence risk of mental disorders is a persistent and still open question. A key candidate mechanism for the biologic mediation of environmental effects involves epigenetic factors, which regulate gene function without altering underlying DNA sequence. Recent work has shown that environmental exposures such as childhood abuse, family history of mental disorder, and low socioeconomic status (SES) associate with differential DNA methylation (5mC) - a relatively stable, but modifiable, epigenetic factor. However, the longitudinal relation among SES, 5mC, brain function, and risk of depression remains to be elucidated. Here, we briefly review literature relevant to these associations and discuss recent findings that, for the first time, prospectively demonstrate sequential links between low SES, changes in 5mC, changes in brain function, and risk of depression in a cohort of adolescents. PMID- 28090663 TI - Response from the authors [Re: "Nathan D. Schilaty, Nathaniel A. Bates, Timothy E. Hewett, Letter to the Editor: Effect of sagittal plane mechanics on ACL strain during jump landing"]. PMID- 28090664 TI - Development of a novel dual CD-MEKC system for the systematic flavonoid fingerprinting of Ligaria cuneifolia (R. et P.) Tiegh.-Loranthaceae-extracts. AB - The present work deals with the development and validation of a novel dual CD MEKC system for the systematic flavonoid fingerprinting of Ligaria cuneifolia (R. et P.) Tiegh.-Loranthaceae-extracts. The BGE consisted of 20 mM pH 8.3 borate buffer, 50 mM SDS, a dual CD system based on the combination of 5 mM beta-CD and 2% w/v S-beta-CD, and 10% v/v methanol. The proposed method has been successfully applied to the comparative analysis of extracts from aerial parts and different hosts, geographical areas, and extraction procedures in order to establish the flavonoid fingerprint of L. cuneifolia. The method was validated according to international guidelines. LOD and LOQ, intra and interday precision, and linearity were determined for catechin, epicatechin, procyanidin B2, rutin, quercetin-3-O-glucoside, quercetin-3-O-xyloside, quercetin-3-O-rhamnoside, quercetin-3-O-arabinofuranoside, quercetin-3-O-arabinopyranoside, and quercetin. The CD-MEKC methodology emerges as a suitable alternative to the traditional HPLC for quality control, fingerprinting, and standardization of L. cuneifolia extracts from different sources. PMID- 28090665 TI - Can Patel's tau accurately estimate directionality of connections in brain networks from fMRI? AB - PURPOSE: Investigating directional interactions between brain regions plays a critical role in fully understanding brain function. Consequently, multiple methods have been developed for noninvasively inferring directional connectivity in human brain networks using functional MRI (fMRI). Recent simulations by Smith et al. showed that Patel's tau, a method based on higher-order statistics, was the best approach for inferring directional interactions from fMRI. Because simulations make restrictive assumptions about reality, we set out to verify this finding using experimental fMRI data obtained from a three-region network in a rat model with electrophysiological validation. METHODS: Previous studies have shown that dynamic causal modeling can correctly estimate the directionality of this three-region network; Granger causality can also work after the deconvolution of the hemodynamic response. Therefore, we set out to test the hypothesis that Patel's tau obtained from either raw or deconvolved fMRI data should correctly estimate the directionality of neuronal influences obtained from intracerebral electroencephalogram in this network. RESULTS: Our results indicate that the accuracy of network directionality estimated using Patel's tau was not better than chance. CONCLUSION: First, our results highlight the necessity of experimental validation of simulation results. Second, it is unclear which brain mechanism is modeled by a directionality inferred from Patel's tau. Third, this study shows that a directional connection ascertained by different methods may mean different things and more experimental studies are needed for investigating the neuronal mechanisms underlying the direction of a connection in the brain ascertained by fMRI using different methods. M Magn Reson Med 78:2003-2010, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28090667 TI - Children and young people's conceptualizations of depression: a systematic review and narrative meta-synthesis. AB - BACKGROUND: There is an increasing research interest in conceptualizations of mental illness, examined in association with help-seeking, stigma and treatment preferences. A recent focus on young people's concepts has been identified, with depression being one of the most examined conditions. METHODS: The purpose of this systematic review is to synthesize evidence on children and adolescents' conceptualizations of depression, adopting the model of illness representations. The review further aims to examine developmental trends, gender differences and the role of experience. A systematic review and narrative meta-synthesis were conducted, reviewing 36 studies identified through a systematic search of six databases in March 2016. RESULTS: Thirty-six quantitative and qualitative studies were included. Half of the young people are able to recognize depression, and recognition increases when symptoms are more severe (e.g. suicidality). Young people are able to name a variety of causes for depression. Mental health professionals are considered the appropriate source of help by half of the young people, followed by family and peers. However, stigma constitutes a major barrier to help-seeking. There are developmental trends and gender differences in young people's conceptualization of depression, while experience with depression is associated with a broader conceptualization. CONCLUSIONS: Young people's concepts of depression resemble aspects of adult conceptualizations, however are sometimes incomplete. Further research on younger children and clinical populations is needed. Research on young people's conceptualizations informs both clinical practice and mental health literacy interventions. PMID- 28090666 TI - Quantitative ultrashort echo time imaging for assessment of massive iron overload at 1.5 and 3 Tesla. AB - PURPOSE: Hepatic iron content (HIC) quantification via transverse relaxation rate (R2*)-MRI using multi-gradient echo (mGRE) imaging is compromised toward high HIC or at higher fields due to the rapid signal decay. Our study aims at presenting an optimized 2D ultrashort echo time (UTE) sequence for R2* quantification to overcome these limitations. METHODS: Two-dimensional UTE imaging was realized via half-pulse excitation and radial center-out sampling. The sequence includes chemically selective saturation pulses to reduce streaking artifacts from subcutaneous fat, and spatial saturation (sSAT) bands to suppress out-of-slice signals. The sequence employs interleaved multi-echo readout trains to achieve dense temporal sampling of rapid signal decays. Evaluation was done at 1.5 Tesla (T) and 3T in phantoms, and clinical applicability was demonstrated in five patients with biopsy-confirmed massively high HIC levels (>25 mg Fe/g dry weight liver tissue). RESULTS: In phantoms, the sSAT pulses were found to remove out-of slice contamination, and R2* results were in excellent agreement to reference mGRE R2* results (slope of linear regression: 1.02/1.00 for 1.5/3T). UTE-based R2* quantification in patients with massive iron overload proved successful at both field strengths and was consistent with biopsy HIC values. CONCLUSION: The UTE sequence provides a means to measure R2* in patients with massive iron overload, both at 1.5T and 3T. Magn Reson Med 78:1839-1851, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28090668 TI - Studies of anticancer drug cytotoxicity based on long-term HepG2 spheroid culture in a microfluidic system. AB - Cell-on-a-chip systems have become promising devices to study the effectiveness of new anticancer drugs recently. Several microdevices for liver cancer culture and evaluation of the drug cytotoxicity have been reported. However, there are still no proven reports about high-throughput and simple methods for the evaluation of drug cytotoxicity on liver cancer cells. The paper presents the results of the effects of the anticancer drug (5-fluorouracil, 5-FU) on the HepG2 spheroids as a model of liver cancer. The experiments were based on the long-term 3D spheroid culture in the microfluidic system and monitoring of the effect of 5 FU at two selected concentrations (0.5 mM and 1.0 mM). Our investigations have shown that the initial size of the spheroids has influence on the drug effect. With the increase of the spheroids diameter, the drug resistance (for the two tested 5-FU concentrations) decreases. This phenomenon was observed both through cells metabolism analysis, as well as changes in spheroids sizes. In our research, we have shown that the lower 5-FU (0.5 mM) concentration causes higher decrease in HepG2 spheroids viability. Moreover, due to the microsystem construction, we observe the drug resistance effect (10th day of culture) regardless of the initial size of the created spheroids and the drug concentration. PMID- 28090669 TI - The association between sclerostin and incident type 2 diabetes risk: a cohort study. AB - OBJECTIVE: To determine whether sclerostin is associated with fasting glucose, insulin levels, insulin resistance or increased risk of incident type 2 diabetes. BACKGROUND: Type 2 diabetic patients have a higher risk of fractures. Recent studies suggest sclerostin, a regulator of osteoblast activity, is associated with diabetes. MATERIALS AND METHODS: Sclerostin levels were obtained from 1778 individuals with no history of type 2 diabetes participating in the population based Canadian Multicentre Osteoporosis Study (CaMos) cohort. Participants were followed until diagnosis of type 2 diabetes, death or end of the study period (31 December 2013). The relationship of sclerostin with fasting glucose, insulin levels and homoeostatic model assessment-insulin resistance (HOMA-IR) was studied in linear regression models. Cox proportional hazards models were used to determine the association of sclerostin levels and the risk of incident type 2 diabetes during a mean 7.5 years of follow-up. RESULTS: Fasting glucose, fasting insulin levels and HOMA-IR were weakly correlated with sclerostin levels (Spearman's correlation coefficient: 0.11, P < 0.05; -0.09, P < 0.05; and -0.07, P = 0.02, respectively). Multiple linear regression analyses confirmed a significant association between sclerostin and fasting insulin and HOMA-IR but no significant association with fasting glucose levels. Sclerostin levels were not found to be significantly associated with the risk of incident type 2 diabetes (HR: 1.30; 95% CI: 0.37-4.57). CONCLUSIONS: We observed an association between sclerostin levels with fasting insulin levels and HOMA-IR, but there was no clear association with type 2 diabetes risk. Further studies are needed to understand the role of sclerostin in type 2 diabetes. PMID- 28090671 TI - Laboratory of genetics and physiology 2 (LGP2) plays an essential role in hepatitis C virus infection-induced interferon responses. AB - : Retinoic acid-inducible gene I (RIG-I)-like receptors are cytosolic pattern recognition receptors (PRRs) that detect non-self-RNA and activate downstream interferon (IFN) signaling. One of the RIG-I-like receptors, laboratory of genetics and physiology 2 (LGP2), was originally thought to be a negative feedback regulator in the RIG-I signaling pathway, but growing evidence indicates that LGP2 is one cofactor of melanoma differentiation-associated protein 5 (MDA5) in MDA5-mediated IFN signaling activation. Our previous work showed that MDA5 was the major PRR to sense hepatitis C virus (HCV) infection in hepatocytes, but the role of LGP2 in HCV infection-induced IFN signaling has not been elucidated. In this study, we reported that LGP2 was a positive regulator of HCV infection induced IFN signaling. Knockout of LGP2 in hepatocytes significantly diminished IFN production in response to HCV infection, but not to HCV 3'untranslated region RNA transfection. Mechanistic studies showed that LGP2 exerted its function at a step upstream of MDA5 in the IFN signaling. HCV infection promoted the molecular interaction between LGP2 and MDA5, which, in turn, enhanced MDA5/HCV RNA association. Finally, we demonstrated that the ATPase activity of LGP2 was critical for assisting MDA5/HCV RNA interaction and activating IFN signaling during HCV infection. CONCLUSION: Our work demonstrated that LGP2 plays an essential role in activating IFN signaling against HCV infection by promoting MDA5 recognition of HCV pathogen-associated molecular patterns. (Hepatology 2017;65:1478-1491). PMID- 28090670 TI - An endoplasmic reticulum protein, Nogo-B, facilitates alcoholic liver disease through regulation of kupffer cell polarization. AB - : Nogo-B (Reticulon 4B) is an endoplasmic reticulum (ER) resident protein that regulates ER structure and function. Because ER stress is known to induce M2 macrophage polarization, we examined whether Nogo-B regulates M1/M2 polarization of Kupffer cells and alters the pathogenesis of alcoholic liver disease (ALD). M1 and M2 phenotypes were assessed in relation to Nogo-B expression and disease severity in liver specimens from ALD patients (NCT01875211). Liver specimens from wild-type (WT) and Nogo-B knockout (KO) mice fed a control or Lieber-DeCarli ethanol liquid diet (5% ethanol) for 6 weeks were analyzed for liver injury and steatosis. Kupffer cells isolated from WT and Nogo-B KO mice were assessed for M1 and M2 activation. A significant positive correlation was observed between Nogo-B positive Kupffer cells and disease severity in ALD patients (n = 30, r = 0.66, P = 0.048). Furthermore, Nogo-B-positive Kupffer cells were correlated with M1 activation (inducible nitric oxide synthase) (r = 0.50, P = 0.05) and negatively with markers of M2 status (CD163) (r = -0.48, P = 0.07) in these patients. WT mice exhibited significantly increased liver injury (P < 0.05) and higher hepatic triglyceride levels (P < 0.01) compared with Nogo-B KO mice in response to chronic ethanol feeding. Nogo-B in Kupffer cells promoted M1 polarization, whereas absence of Nogo-B increased ER stress and M2 polarization in Kupffer cells. CONCLUSION: Nogo-B is permissive of M1 polarization of Kupffer cells, thereby accentuating liver injury in ALD in humans and mice. Nogo-B in Kupffer cells may represent a new therapeutic target for ALD. (Hepatology 2017;65:1720 1734). PMID- 28090672 TI - A powerful statistical framework for generalization testing in GWAS, with application to the HCHS/SOL. AB - In genome-wide association studies (GWAS), "generalization" is the replication of genotype-phenotype association in a population with different ancestry than the population in which it was first identified. Current practices for declaring generalizations rely on testing associations while controlling the family-wise error rate (FWER) in the discovery study, then separately controlling error measures in the follow-up study. This approach does not guarantee control over the FWER or false discovery rate (FDR) of the generalization null hypotheses. It also fails to leverage the two-stage design to increase power for detecting generalized associations. We provide a formal statistical framework for quantifying the evidence of generalization that accounts for the (in)consistency between the directions of associations in the discovery and follow-up studies. We develop the directional generalization FWER (FWERg ) and FDR (FDRg ) controlling r-values, which are used to declare associations as generalized. This framework extends to generalization testing when applied to a published list of Single Nucleotide Polymorphism-(SNP)-trait associations. Our methods control FWERg or FDRg under various SNP selection rules based on P-values in the discovery study. We find that it is often beneficial to use a more lenient P-value threshold than the genome-wide significance threshold. In a GWAS of total cholesterol in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), when testing all SNPs with P-values <5*10-8 (15 genomic regions) for generalization in a large GWAS of whites, we generalized SNPs from 15 regions. But when testing all SNPs with P-values <6.6*10-5 (89 regions), we generalized SNPs from 27 regions. PMID- 28090673 TI - Pharmacokinetic/pharmacodynamic integration and modelling of oxytetracycline for the porcine pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida. AB - Pharmacokinetic-pharmacodynamic (PK/PD) integration and modelling were used to predict dosage schedules of oxytetracycline for two pig pneumonia pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida. Minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined in broth and porcine serum. PK/PD integration established ratios of average concentration over 48 h (Cav0-48 h )/MIC of 5.87 and 0.27 MUg/mL (P. multocida) and 0.70 and 0.85 MUg/mL (A. pleuropneumoniae) for broth and serum MICs, respectively. PK/PD modelling of in vitro time-kill curves established broth and serum breakpoint values for area under curve (AUC0-24 h )/MIC for three levels of inhibition of growth, bacteriostasis and 3 and 4 log10 reductions in bacterial count. Doses were then predicted for each pathogen, based on Monte Carlo simulations, for: (i) bacteriostatic and bactericidal levels of kill; (ii) 50% and 90% target attainment rates (TAR); and (iii) single dosing and daily dosing at steady-state. For 90% TAR, predicted daily doses at steady-state for bactericidal actions were 1123 mg/kg (P. multocida) and 43 mg/kg (A. pleuropneumoniae) based on serum MICs. Lower TARs were predicted from broth MIC data; corresponding dose estimates were 95 mg/kg (P. multocida) and 34 mg/kg (A. pleuropneumoniae). PMID- 28090675 TI - Cross-sectional study shows that impaired bone mineral status and metabolism are found in nonmosaic triple X syndrome. AB - AIM: The effect of a supernumerary X chromosome on bones has not been reported, and this study evaluated bone mineral status and metabolism in nonmosaic triple X syndrome. METHODS: This cross-sectional study comprised 19 girls, with a median age of 10.9 years, with nonmosaic triple X syndrome and a control group matched for age and body size. We studied ionised and total calcium, phosphate, parathyroid hormone (PTH), 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D, osteocalcin, bone alkaline phosphatase levels and urinary deoxypyridinoline concentrations. We also measured the phalangeal amplitude-dependent speed of sound (AD-SoS) and the bone transmission time (BTT) Z-scores. RESULTS: Patients with nonmosaic triple X syndrome showed significantly reduced AD-SoS (p < 0.005) and BTT Z-scores (p < 0.0001) compared to the control group, and these results persisted when we divided the sample into prepubertal and pubertal patients (p < 0.05). These patients also had significantly reduced ionised calcium (p < 0.005) and 25(OH)D levels (p < 0.005) and higher phosphate (p < 0.0001) and PTH (p < 0.0001) levels. CONCLUSION: Subjects with nonmosaic triple X syndrome exhibited a significant impairment in bone mineral status and metabolism similar to other X polisomy, such as Klinefelter's syndrome. This suggests the presence of a primary bone deficit and the need for regular and close monitoring of these subjects. PMID- 28090674 TI - Nonstructural protein 5B promotes degradation of the NORE1A tumor suppressor to facilitate hepatitis C virus replication. AB - : Hepatitis C virus (HCV) infection is a common risk factor for the development of liver cancer. The molecular mechanisms underlying this effect are only partially understood. Here, we show that the HCV protein, nonstructural protein (NS) 5B, directly binds to the tumor suppressor, NORE1A (RASSF5), and promotes its proteosomal degradation. In addition, we show that NORE1A colocalizes to sites of HCV viral replication and suppresses the replication process. Thus, NORE1A has antiviral activity, which is specifically antagonized by NS5B. Moreover, the suppression of NORE1A protein levels correlated almost perfectly with elevation of Ras activity in primary human samples. Therefore, NORE1A inactivation by NS5B may be essential for maximal HCV replication and may make a major contribution to HCV-induced liver cancer by shifting Ras signaling away from prosenescent/proapoptotic signaling pathways. CONCLUSION: HCV uses NS5B to specifically suppress NORE1A, facilitating viral replication and elevated Ras signaling. (Hepatology 2017;65:1462-1477). PMID- 28090676 TI - Mutations in TMEM230 are not a common cause of Parkinson's disease. PMID- 28090677 TI - Elucidation of stress-induced degradation products of mangiferin: Method development and validation. AB - The degradation behavior of mangiferin, under various ICH Q1A(R2) recommended stress conditions, was studied using an isocratic elution with mobile phase (pH 2.4), composed of acetonitrile and 1% orthophosphoric acid (12:88 v/v) at a flow rate of 1.0 mL/min, with lambdamax 262 nm. It was suitably adapted for LC-MS studies by replacing with 1% acetic acid (ACN-1% acetic acid; 18:82) and the pH was adjusted to 3.0. Extensive degradation was found to occur during alkaline medium stress studies at 2.31 min of retention time at lambdamax of 235 nm. The mass spectrum of mangiferin, 3 h after treatment with 0.1 M NaOH, clearly shows the rupture of the tricyclic ring, indicating that a fragment at m/z - 269 was formed. Furthermore, the results were supported by nuclear magnetic resonance as well. However, no degradation was observed in other stress conditions. PMID- 28090679 TI - Effect of prucalopride on intestinal gas tolerance in patients with functional bowel disorders and constipation. AB - BACKGROUND AND AIM: Patients with functional bowel disorders develop gas retention and symptoms in response to intestinal gas loads that are well tolerated by healthy subjects. Stimulation of 5HT-4 receptors in the gut has both prokinetic and antinociceptive effects. The aim of this study is to determine the effect of prucalopride, a highly selective 5HT-4 agonist, on gas transit and tolerance in women with functional bowel disorders complaining of constipation. METHODS: Twenty-four women with functional bowel disorders complaining of constipation were included in the study. Patients were studied twice on separate days in a cross-over design. On each study day, an intestinal gas challenge test was performed. During the five previous days, prucalopride (2 mg/day) or placebo was administered. Abdominal symptoms, stool frequency, and stool consistency were recorded during the treatment period on daily questionnaires. RESULTS: During the gas challenge test, prucalopride did not decrease the volume of gas retained in the subset of patients who had significant gas retention (>= 200 mL) while on placebo. However, in those patients who had increased symptoms during the gas test (>= 3 on a 0 to 6 scale) when on placebo, prucalopride did significantly reduce the perception of symptoms (2.3 +/- 0.5 mean score vs 3.5 +/- 0.3 on placebo; P = 0.045). During the treatment period with prucalopride, patients exhibited an increase in the total number of bowel movements and decreased stool consistency compared with placebo. CONCLUSION: Prucalopride reduces abdominal symptoms without modifying gas retention when patients with functional bowel disorders are challenged with the gas transit and tolerance test. European Clinical Trials Database (EudraCT2011-006354-86). PMID- 28090678 TI - The epileptic and nonepileptic spectrum of paroxysmal dyskinesias: Channelopathies, synaptopathies, and transportopathies. AB - Historically, the syndrome of primary paroxysmal dyskinesias was considered a group of disorders as a result of ion channel dysfunction. This proposition was primarily based on the discovery of mutations in ion channels, which caused other episodic neurological disorders such as epilepsy and migraine and also supported by the frequent association between paroxysmal dyskinesias and epilepsy. However, the discovery of the genes responsible for the 3 classic forms of paroxysmal dyskinesias disproved this ion channel theory. On the other hand, novel gene mutations implicating ion channels have been recently reported to produce episodic movement disorders clinically similar to the classic paroxysmal dyskinesias. Here, we review the clinical and pathophysiological aspects of the paroxysmal dyskinesias, further proposing a pathophysiological framework according to which they can be classified as synaptopathies (proline-rich transmembrane protein 2 and myofibrillogenesis regulator gene), channelopathies (calcium-activated potassium channel subunit alpha-1 and voltage-gated sodium channel type 8), or transportopathies (solute carrier family 2 member 1). This proposal might serve to explain similarities and differences among the various paroxysmal dyskinesias in terms of clinical features, treatment response, and natural history. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28090680 TI - Validity of noninvasive composite scores to assess cardiovascular risk in 10-year old children. AB - Agreement between and classification accuracy of six different noninvasive composite scores and a cardiovascular disease (CVD) risk factor score were investigated in 911 (466 boys and 445 girls) 10-year-old Norwegian children. A CVD risk factor score (triglyceride, total cholesterol/HDL ratio, homeostasis model assessment of insulin resistance, systolic blood pressure (SBP), waist-to height ratio (WHtR), and cardiorespiratory fitness) and six noninvasive risk scores (fitness+three different measurements of fatness (body mass index (BMI), WHtR, and skinfolds), with and without inclusion of SBP) were calculated (mean z score by gender). Agreement was assessed using Bland-Altman plots. The ability of noninvasive scores to correctly classify children with clustered CVD risk was examined by receiver operating characteristic (ROC) analysis and Cohen's kappa coefficient (kappa). For both sexes, the noninvasive scores without SBP showed excellent AUC values (AUC=0.93-0.94, 95% CI=0.88-0.98) and moderate kappa values (kappa=0.49-0.64) and had limits of agreement of 0.0+/-0.78-0.89 (arbitrary unit). Inclusion of SBP increased AUC values (AUC=0.96-0.97, 95% CI=0.94-0.99), kappa values (kappa=0.58-0.69), and reduced limits of agreement (0.0+/-0.68 0.76). Noninvasive scores that include fitness and fatness provide acceptable agreement and classification accuracy, allowing for widespread early identification of children that might be at risk for developing CVD later in life. SBP should be included in the noninvasive score to improve classification accuracy if possible. PMID- 28090681 TI - Excess of exercise increases the risk of atrial fibrillation. AB - An interesting and still not well-understood example for old medical wisdom "Sola dosis facit venenum" is the increased prevalence of atrial fibrillation (AF) in athletes. Numerous studies have shown a fourfold to eightfold increased risk of AF in athletes compared to the normal population. Analysis of the existing data suggests a dose-dependent effect of exercise. Moderate exercise seems to have a protective effect and decreases the risk of AF, whereas excessive exercise seems to increase the risk of AF. The described cases illustrate clinical manifestations within the spectrum of AF in elderly athletes, that is, exercise induced AF, vagal AF, chronic AF, and atrial flutter. As the arrhythmia worsened quality of life and exercise capacity in all patients, recovery of sinus rhythm was desired in all described cases. As the atrial disease was advanced on different levels, different treatment regimes were applied. Lifestyle modification and temporary anti-arrhythmic drug therapy could stabilize sinus rhythm in one patient, whereas others needed radiofrequency ablation to achieve a stable sinus rhythm. The patient with the most advanced atrial disease necessitated anti-arrhythmic drug therapy and another left atrial ablation. All described patients remained in sinus rhythm during the long-term follow-up. PMID- 28090682 TI - Pituitary Macrotumor Causing Narcolepsy-Cataplexy in a Dachshund. AB - Familial narcolepsy secondary to breed-specific mutations in the hypocretin receptor 2 gene and sporadic narcolepsy associated with hypocretin ligand deficiencies occur in dogs. In this report, a pituitary mass is described as a unique cause of narcolepsy-cataplexy in a dog. A 6-year-old male neutered Dachshund had presented for acute onset of feeding-induced cataplexy and was found to have a pituitary macrotumor on magnetic resonance imaging (MRI). Cerebral spinal fluid hypocretin-1 levels were normal, indicating that tumor effect on the ventral lateral nucleus of the hypothalamus was not the cause of the dog's narcolepsy-cataplexy. The dog was also negative for the hypocretin receptor 2 gene mutation associated with narcolepsy in Dachshunds, ruling out familial narcolepsy. The Dachshund underwent stereotactic radiotherapy (SRT), which resulted in reduction in the mass and coincident resolution of the cataplectic attacks. Nine months after SRT, the dog developed clinical hyperadrenocorticism, which was successfully managed with trilostane. These findings suggest that disruptions in downstream signaling of hypocretin secondary to an intracranial mass effect might result in narcolepsy-cataplexy in dogs and that brain MRI should be strongly considered in sporadic cases of narcolepsy cataplexy. PMID- 28090683 TI - Similar but not consistent: Revisiting the pitfalls of measuring IgG subclasses with different assays. AB - BACKGROUND: Laboratory quantification of IgG subclasses (IgGSc) is a well established second-line tool for differential diagnosis of immune deficiencies. However, so far there is still no internationally approved standard available for IgGSc, and different assays are prone to produce divergent results. In this study, we evaluated the comparability and equivalence of two commercially available IgGSc assays, one being the Siemens IgGSc assay on a BN ProSpec analyzer and the other being The Binding Site (TBS) IgGSc assay on a Roche cobas c502 analyzer. METHODS: We analyzed a total of 50 patient plasma samples obtained over a 3-month period with both IgGSc assays and compared the resulting data based and the CLSI EP09-A3 method comparison guideline. RESULTS: Depending on the analyzed IgGSc type, the average relative differences in IgGSc concentration (g/L) between the two assays were considerable, starting with -13.5% for IgG1 and 11.3% for IgG2, over -47.3% for IgG4, and up to 52.9% for IgG3. Applying the assay-specific reference intervals, the classification agreement (below, within, or above the reference range) ranged from 88% to 90% for the individual subclasses. However, only 68% of samples showed an overall classification agreement. CONCLUSION: The comparability of the two IgGSc assays proved to be limited and might be considered similar at best on the diagnostic level. Laboratory specialists as well as clinicians therefore should be cautious when using and interpreting IgGSc measurements obtained with different assays or analyzers. PMID- 28090684 TI - PREDICT-PD: An online approach to prospectively identify risk indicators of Parkinson's disease. AB - BACKGROUND: A number of early features can precede the diagnosis of Parkinson's disease (PD). OBJECTIVE: To test an online, evidence-based algorithm to identify risk indicators of PD in the UK population. METHODS: Participants aged 60 to 80 years without PD completed an online survey and keyboard-tapping task annually over 3 years, and underwent smell tests and genotyping for glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 (LRRK2) mutations. Risk scores were calculated based on the results of a systematic review of risk factors and early features of PD, and individuals were grouped into higher (above 15th centile), medium, and lower risk groups (below 85th centile). Previously defined indicators of increased risk of PD ("intermediate markers"), including smell loss, rapid eye movement-sleep behavior disorder, and finger-tapping speed, and incident PD were used as outcomes. The correlation of risk scores with intermediate markers and movement of individuals between risk groups was assessed each year and prospectively. Exploratory Cox regression analyses with incident PD as the dependent variable were performed. RESULTS: A total of 1323 participants were recruited at baseline and >79% completed assessments each year. Annual risk scores were correlated with intermediate markers of PD each year and baseline scores were correlated with intermediate markers during follow-up (all P values < 0.001). Incident PD diagnoses during follow-up were significantly associated with baseline risk score (hazard ratio = 4.39, P = .045). GBA variants or G2019S LRRK2 mutations were found in 47 participants, and the predictive power for incident PD was improved by the addition of genetic variants to risk scores. CONCLUSIONS: The online PREDICT-PD algorithm is a unique and simple method to identify indicators of PD risk. (c) 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 28090685 TI - Zeolite-Based Organic Synthesis (ZeoBOS) of Acortatarin A: First Total Synthesis Based on Native and Metal-Doped Zeolite-Catalyzed Steps. AB - Similarly to polymer-supported assisted synthesis (PSAS), organic synthesis could be envisaged being performed by using zeolites, native or metal-doped, as heterogeneous catalysts. To illustrate this unprecedented Zeolite-Based Organic Synthesis (ZeoBOS), the total synthesis of acortatarin A was achieved through a novel strategy and using five out of eleven synthetic steps catalyzed by H- or metal-doped zeolites as catalysts. Notably, the formation of an yne-pyrrole intermediate with a copper-doped zeolite and the spiroketalization of an alkyne diol with a silver-doped zeolite have been developed as key steps of the synthesis. PMID- 28090686 TI - Effectively enhancing cytotoxic and apoptotic effects of alpha-momorcharin by integrating a heparin-binding peptide. AB - Alpha-momorcharin (alpha-MMC), a type I ribosome-inactivating protein, has attracted a great deal of attention because of its antitumor activity. However, the cytotoxicity of alpha-MMC is limited due to insufficient cellular internalization in cancer cells. To enhance the cytotoxicity of alpha-MMC, a heparin-binding domain derived from heparin-binding epidermal growth factor (named heparin-binding peptide [HBP]) was used as a cell-penetrating peptide and fused to the C-terminus of alpha-MMC. This novel alpha-MMC-HBP fusion protein was expressed and purified with a Ni2+ -resin. The N-glycosidase activity and DNase activity assay indicated that the introduction of HBP did not interfere with the intrinsic bioactivities of alpha-MMC. HBP was able to efficiently carry alpha-MMC into the tested cancer cells and significantly enhance the cytotoxic effects of alpha-MMC in a dose-dependent manner. This enhanced cytotoxic ability occurred due to the higher level of cell apoptosis induced by alpha-MMC-HBP, which was demonstrated in western blot analysis in which alpha-MMC-HBP triggered caspase 8, caspase 9, casapase 3, and PARP more intensely than alpha-MMC alone. alpha-MMC HBP led to an upregulation of cleaved PARP and an increase in the Bax/Bcl-2 ratio. Our study provided a new practical way to greatly improve the antitumor activity of alpha-MMC, which could significantly expand the pharmaceutical applications of alpha-MMC. PMID- 28090687 TI - Prevalence of psychotropic medication use and association with challenging behaviour in adults with an intellectual disability. A total population study. AB - BACKGROUND: There is a high prevalence of psychotropic medication use in adults with Intellectual Disabilities (ID), often in the absence of psychiatric disorder, also associated with challenging behaviour. Previous research has focused on specific sample frames or data from primary care providers. There is also a lack of consistency in the definition of challenging behaviour used. METHODS: We adopted a total population sampling method. Medication data on 265 adults with ID were classified according to the Anatomical Therapeutic Chemical classification system. The Behaviour Problems Inventory - short form classified challenging behaviours. We examined the association between challenging behaviour and the use of psychotropic medication, and whether any association would still be present after accounting for socio-demographic and clinical characteristics. RESULTS: 70.57% of adults with ID were prescribed at least one class of any medication (mean per person =2.62; range 0-14). Psychotropic medications were used by 37.73% of participants with antipsychotics the commonest type used by 21.89% of individuals. Polypharmacy and high dosages were common. Generalised Linear Models indicated significant associations between psychotropic medication and the presence of a psychiatric diagnosis, challenging behaviour, older age and type of residence. Male gender was additionally associated with antipsychotic medication. CONCLUSIONS: The use of a total population sample identified via multiple routes is less likely to overestimate prevalence rates of medication use. Current challenging behaviour was a predictor of medication use after controlling for other variables. Data indicate that there may be differences in prescribing patterns associated with different topographies of challenging behaviours. PMID- 28090689 TI - alpha-Aminoxy Peptoids: A Unique Peptoid Backbone with a Preference for cis-Amide Bonds. AB - alpha-Peptoids, or N-substituted glycine oligomers, are an important class of peptidomimetic foldamers with proteolytic stability. Nevertheless, the presence of cis/trans-amide bond conformers, which contribute to the high flexibility of alpha-peptoids, is considered as a major drawback. A modified peptoid backbone with an improved control of the amide bond geometry could therefore help to overcome this limitation. Herein, we have performed the first thorough analysis of the folding propensities of alpha-aminoxy peptoids (or N-substituted 2 aminoxyacetic acid oligomers). To this end, the amide bond geometry and the conformational properties of a series of model alpha-aminoxy peptoids were investigated by using 1D and 2D NMR experiments, X-ray crystallography, natural bond orbital (NBO) analysis, circular dichroism (CD) spectroscopy, and molecular dynamics (MD) simulations revealing a unique preference for cis-amide bonds even in the absence of cis-directing side chains. The conformational analysis based on the MD simulations revealed that alpha-aminoxy peptoids can adopt helical conformations that can mimic the spatial arrangement of peptide side chains in a canonical alpha-helix. Given their ease of synthesis and conformational properties, alpha-aminoxy peptoids represent a new member of the peptoid family capable of controlling the amide isomerism while maintaining the potential for side-chain diversity. PMID- 28090688 TI - Exosomal miR-146a Contributes to the Enhanced Therapeutic Efficacy of Interleukin 1beta-Primed Mesenchymal Stem Cells Against Sepsis. AB - Improving the immunomodulatory efficacy of mesenchymal stem cells (MSCs) through pretreatment with pro-inflammatory cytokines is an evolving field of investigation. However, the underlying mechanisms have not been fully clarified. Here, we pretreated human umbilical cord-derived MSCs with interleukin-1beta (IL 1beta) and evaluated their therapeutic effects in a cecal ligation and puncture induced sepsis model. We found that systemic administration of IL-1beta pretreated MSCs (betaMSCs) ameliorated the symptoms of murine sepsis more effectively and increased the survival rate compared with naive MSCs. Furthermore, betaMSCs could more effectively induce macrophage polarization toward an anti-inflammatory M2 phenotype through the paracrine activity. Mechanistically, we demonstrated that betaMSC-derived exosomes contributed to the enhanced immunomodulatory properties of betaMSCs both in vitro and in vivo. Importantly, we found that miR-146a, a well-known anti-inflammatory microRNA, was strongly upregulated by IL-1beta stimulation and selectively packaged into exosomes. This exosomal miR-146a was transferred to macrophages, resulted in M2 polarization, and finally led to increased survival in septic mice. In contrast, inhibition of miR-146a through transfection with miR-146a inhibitors partially negated the immunomodulatory properties of betaMSC-derived exosomes. Taken together, IL-1beta pretreatment effectively enhanced the immunomodulatory properties of MSCs partially through exosome-mediated transfer of miR-146a. Therefore, we believe that IL-1beta pretreatment may provide a new modality for better therapeutic application of MSCs in inflammatory disorders. Stem Cells 2017;35:1208-1221. PMID- 28090690 TI - The many faces of autonomic failure in multiple system atrophy. PMID- 28090691 TI - Peg3/PW1 Is a Marker of a Subset of Vessel Associated Endothelial Progenitors. AB - Vascular associated endothelial cell (ECs) progenitors are still poorly studied and their role in the newly forming vasculature at embryonic or postnatal stage remains elusive. In the present work, we first defined a set of genes highly expressed during embryo development and strongly downregulated in the adult mouse. In this group, we then concentrated on the progenitor cell marker Peg3/PW1. By in vivo staining of the vasculature we found that only a subset of cells coexpressed endothelial markers and PW1. These cells were quite abundant in the embryo vasculature but declined in number at postnatal and adult stages. Using a reporter mouse for PW1 expression, we have been able to isolate PW1 positive (PW1posECs) and negative endothelial cells (PW1negECs). PW1-positive cells were highly proliferative in comparison to PW1negECs and were able to form colonies when seeded at clonal dilution. Furthermore, by RNAseq analysis, PW1posECs expressed endothelial cell markers together with mesenchymal and stem cell markers. When challenged by endothelial growth factors in vitro, PW1posECs were able to proliferate more than PW1negECs and to efficiently form new vessels in vivo. Taken together these data identify a subset of vessel associated endothelial cells with characteristics of progenitor cells. Considering their high proliferative potential these cells may be of particular importance to design therapies to improve the perfusion of ischemic tissues or to promote vascular repair. Stem Cells 2017;35:1328-1340. PMID- 28090692 TI - A high-resolution reference genetic map positioning 8.8 K genes for the conifer white spruce: structural genomics implications and correspondence with physical distance. AB - Over the last decade, extensive genetic and genomic resources have been developed for the conifer white spruce (Picea glauca, Pinaceae), which has one of the largest plant genomes (20 Gbp). Draft genome sequences of white spruce and other conifers have recently been produced, but dense genetic maps are needed to comprehend genome macrostructure, delineate regions involved in quantitative traits, complement functional genomic investigations, and assist the assembly of fragmented genomic sequences. A greatly expanded P. glauca composite linkage map was generated from a set of 1976 full-sib progeny, with the positioning of 8793 expressed genes. Regions with significant low or high gene density were identified. Gene family members tended to be mapped on the same chromosomes, with tandemly arrayed genes significantly biased towards specific functional classes. The map was integrated with transcriptome data surveyed across eight tissues. In total, 69 clusters of co-expressed and co-localising genes were identified. A high level of synteny was found with pine genetic maps, which should facilitate the transfer of structural information in the Pinaceae. Although the current white spruce genome sequence remains highly fragmented, dozens of scaffolds encompassing more than one mapped gene were identified. From these, the relationship between genetic and physical distances was examined and the genome wide recombination rate was found to be much smaller than most estimates reported for angiosperm genomes. This gene linkage map shall assist the large-scale assembly of the next-generation white spruce genome sequence and provide a reference resource for the conifer genomics community. PMID- 28090693 TI - Will the Needs-Based Planning of Health Human Resources Currently Undertaken in Several Countries Lead to Excess Supply and Inefficiency? Rejoinder. PMID- 28090694 TI - Graphene Oxide Wrapped SiO2 /TiO2 Hollow Nanoparticles Loaded with Photosensitizer for Photothermal and Photodynamic Combination Therapy. AB - Graphene oxide (GO) enwrapped SiO2 /TiO2 hollow nanoparticles (GO-HNP) are synthesized by the Stober method and used as a nanocarrier for loading protoporphyrin IX (PpIX). The synthesized nanoparticle has high dispersibility and high uniformity in diameter (ca. 50 nm). Furthermore, this nanoparticle shows lambda=808 nm laser induced PpIX release properties (photoinduced "on-off" drug release system). GO-HNP-PpIX is employed for inducing both photothermal therapy (PTT) and photodynamic therapy (PDT). The synergic effect of PTT and PDT exhibits powerful anticancer properties. When cancer cells are treated with GO-HNP-PpIX and irradiated with both visible light and a NIR laser, the cell viability drops dramatically to 2.5 %, which is an anticancer effect approximately 13 times higher than that obtained in a previous study. Moreover, no significant cell damage has been observed under lambda=808 nm laser irradiation. The GO-HNP-PpIX system suggests an external stimuli-responsive efficient anticancer treatment effect toward human breast cancer cells. PMID- 28090695 TI - Erratum. PMID- 28090696 TI - Discrepancies in paper by Chiam et al.: The haemodynamic effects of intravenous paracetamol. PMID- 28090698 TI - Presentation and validation of the DuckEES child and adolescent dynamic facial expressions stimulus set. AB - The stimulus sets presently used to study emotion processing are primarily static pictures of individuals (primarily adults) making emotional facial expressions. However, the dynamic, stereotyped movements associated with emotional expressions contain rich information missing from static pictures, such as the difference between happiness and pride. We created a set of 1.1 s dynamic emotional facial stimuli representing boys and girls aged 8-18. A separate group of 36 individuals (mean [M] age = 19.5 years, standard deviation [SD] = 1.95, 13 male) chose the most appropriate emotion label for each video from a superset of 250 videos. Validity and reliability statistics were performed across all stimuli, which were then used to determine which stimuli should be included in the final stimulus set. We set a criterion for inclusion of 70% agreement with the modal response made for each video. The final stimulus set contains 142 videos of 36 actors (M age = 13.24 years, SD = 2.09, 14 male) making negative (disgust, embarrassment, fear, sadness), positive (happiness, pride), and neutral facial expressions. The percent correct among the final stimuli was high (median = 88.89%; M = 88.38%, SD = 7.74%), as was reliability (kappa = 0.753). PMID- 28090699 TI - Modelling IRF8 Deficient Human Hematopoiesis and Dendritic Cell Development with Engineered iPS Cells. AB - Human induced pluripotent stem (iPS) cells can differentiate into cells of all three germ layers, including hematopoietic stem cells and their progeny. Interferon regulatory factor 8 (IRF8) is a transcription factor, which acts in hematopoiesis as lineage determining factor for myeloid cells, including dendritic cells (DC). Autosomal recessive or dominant IRF8 mutations occurring in patients cause severe monocytic and DC immunodeficiency. To study IRF8 in human hematopoiesis we generated human IRF8-/- iPS cells and IRF8-/- embryonic stem (ES) cells using RNA guided CRISPR/Cas9n genome editing. Upon induction of hematopoietic differentiation, we demonstrate that IRF8 is dispensable for iPS cell and ES cell differentiation into hemogenic endothelium and for endothelial to-hematopoietic transition, and thus development of hematopoietic progenitors. We differentiated iPS cell and ES cell derived progenitors into CD141+ cross presenting cDC1 and CD1c+ classical cDC2 and CD303+ plasmacytoid DC (pDC). We found that IRF8 deficiency compromised cDC1 and pDC development, while cDC2 development was largely unaffected. Additionally, in an unrestricted differentiation regimen, IRF8-/- iPS cells and ES cells exhibited a clear bias toward granulocytes at the expense of monocytes. IRF8-/- DC showed reduced MHC class II expression and were impaired in cytokine responses, migration, and antigen presentation. Taken together, we engineered a human IRF8 knockout model that allows studying molecular mechanisms of human immunodeficiencies in vitro, including the pathophysiology of IRF8 deficient DC. Stem Cells 2017;35:898-908. PMID- 28090700 TI - The Mandarin Chinese version of the Beach Centre Family Quality of Life Scale: development and psychometric properties in Taiwanese families of children with developmental delay. AB - BACKGROUND: Early intervention (EI) practitioners provide individualised family centred services to enhance the quality of life (QOL) of families of children with developmental delay (DD). Family QOL (FQOL) could be an important outcome indictor for EI, but there is no measurement tool for FQOL in Mandarin Chinese. The purpose of this study was to translate the Beach Centre FQOL Scale (BCFQOL) into Mandarin Chinese and to examine the psychometric properties of the scale in families of children with DD. METHODS: Two independent translations were performed by two bilingual professors whose mother tongue was Mandarin, and two back-translations were performed by two bilingual professionals whose mother tongue was English. The translated and back-translated questionnaires were reviewed to revise the questionnaire. Five experts assessed the accuracy, equivalence and cultural appropriateness of the scale, and 10 parents of children with DD were interviewed to examine its readability, clarity and cultural appropriateness. From July to November 2014, we recruited 360 primary caregivers of children with DD who were receiving EI in northern Taiwan to validate the scale. The participants completed the BCFQOL as well as a one item overall ratings of their FQOL. RESULTS: Item analysis was performed to assess each item. Confirmatory factor analysis supported the following five-factor structure as in the original scale: family interaction, parenting, emotional well-being, physical/material well-being and disability-related support. The scale exhibited excellent internal consistency reliability (Cronbach's alpha = 0.96) and test retest reliability at a 2-week interval (intra-class correlation coefficient = 0.92). Contrasted group validity was supported by significantly higher BCFQOL scores in the top quartile of the overall FQOL rating than the lowest quartile. The convergent validity was supported by the significant correlation between the FQOL item and the BCFQOL (r = 0.608, p < 0.01). CONCLUSIONS: This study showed that the Mandarin Chinese version of the BCFQOL is reliable and valid for Taiwanese families of children with DD. The instrument could be applied to assess FQOL in families of children with DD who are receiving EI in order to evaluate family services and supports. PMID- 28090701 TI - The nationwide register-based prevalence of intellectual disability during childhood and adolescence. AB - BACKGROUND: Many studies have evaluated the prevalence of intellectual disability (ID) by focusing on different ages during childhood and adolescence. Although the prevalence of ID is higher in older age groups, how cumulative prevalence increases, and what level it reaches before adulthood, remains unclear. METHOD: We used Care Register for Health Care to retrieve information on individuals born in 1996-2007 with any of the inclusion diagnoses of ID (F7 group and/or aetiological diagnoses) for the period 1996 to 2013. The cumulative prevalence was calculated as percentages for every age based on Finnish population data. RESULTS: The registration of new diagnoses of ID continued steadily throughout the developmental years. The cumulative prevalence reached 1.19% by age 17.5 among those born in 1996. Later-born age groups appeared to receive their first ID diagnoses earlier in childhood. Those born in 1999 reached a cumulative prevalence of 1.21% already by age 14.5. Of all those with ID, 67% had an F7 diagnosis only, 42% had an aetiological diagnosis only and 9% had both diagnoses. CONCLUSIONS: Cumulative prevalence of ID by year, until the age of 18, will provide a better estimate and understanding of the prevalence of ID than a point prevalence at any one point during the developmental years. PMID- 28090702 TI - Intellectual disability and patient activation after release from prison: a prospective cohort study. AB - BACKGROUND: Intellectual disability and patient activation may be important drivers of inequities in health service access and health outcomes for people with intellectual disability transitioning from prison to the community. We assessed the association between intellectual disability and patient activation after prison release and examined whether this association varied, depending on whether intellectual disability was identified prior to prison release. METHODS: Overall, 936 prisoners were screened for intellectual disability by using the Hayes Ability Screening Index and completed the Patient Activation Measure (PAM) within 6 weeks of prison release and again at 1, 3 and 6 months post-release. We estimated the association between intellectual disability status and PAM scores by using a multilevel linear model, adjusting for sociodemographic, behavioural, health and criminogenic factors. We used propensity score matching to estimate the impact of being identified with intellectual disability prior to release from prison on the change in mean PAM score after prison release. RESULTS: Compared with those who screened negative for intellectual disability, ex-prisoners who screened positive, both with and without prior identification of intellectual disability, had significantly decreased mean PAM scores [(B = -4.3; 95% CI: -6.3, -2.4) and (B = -4.5; 95% CI: -6.8, -2.3), respectively] over 6 months of follow up. Among those who reported being identified with intellectual disability prior to release from prison, a significant increase in PAM score at the 6-month follow up interview (B = 5.89; 95% CI: 2.35, 9.42; P = 0.001) was attributable to being identified with intellectual disability prior to release. CONCLUSIONS: Ex prisoners screening positive for possible intellectual disability have decreased patient activation for at least 6 months after release from prison. However, individuals whose possible intellectual disability is unidentified appear to be particularly vulnerable. Incarceration is a pivotal opportunity for the identification of intellectual disability and for initiating transitional linkages to health and intellectual disability-specific community services for this marginalised population. PMID- 28090703 TI - Differentiation of Islet Progenitors Regulated by Nicotinamide into Transcriptome Verified beta Cells That Ameliorate Diabetes. AB - Developmental stage-specific differentiation of stem or progenitor cells into safe and functional cells is of fundamental importance in regenerative medicine, including beta-cell replacement. However, the differentiation of islet progenitor cells (IPCs) into insulin-secreting beta cells remains elusive. Here, we report that the multifunctional molecule nicotinamide (NIC) is a specific differentiation regulator of mouse IPCs. The differentiated cells regulated by NIC exhibited many characteristics of adult beta cells, including ameliorating preclinical diabetes and a highly comparable transcriptome profile. Gene set enrichment analysis showed that during differentiation, numerous IPC transcription factor genes, including Ngn3, Pax4, Fev, and Mycl1, were all down regulated. Pharmacological, biochemical, and gene knockdown analyses collectively demonstrated that NIC regulated the differentiation via inhibiting Sirt1 (silent information regulator transcript 1). Finally, NIC also regulates human IPC differentiation. Thus, our study advances islet developmental biology and impacts on translational research and regenerative therapies to diabetes and other diseases. Stem Cells 2017;35:1341-1354. PMID- 28090704 TI - Effectiveness of telephone-based interventions on health-related quality of life and prognostic outcomes in breast cancer patients and survivors-A meta-analysis. AB - The aim of this meta-analysis was to evaluate the effect of telephone-based interventions on prognostic outcomes and health-related quality of life (HRQoL) in breast cancer patients and survivors. A systematic search of the Cochrane Library, Web of science, Medline, EMBASE, CNKI and CBM database was carried out. Randomised, controlled trials (RCTs) examining the effects of telephone-based intervention versus a control group receiving no telephone intervention, on prognostic outcomes and HRQoL with breast cancer were included. A meta-analysis was conducted to quantify the effects of telephone-based interventions on anxiety, depression, fatigue, self-efficiency, physiological function, social domestic function and quality of life. In total, 14 studies involving 2002 participants were included. Due to the effect of telephone-based interventions, statistically significant results were found on anxiety (standard mean difference [SMD] = -0.16, 95% confidence intervals [CI] [0.01, 0.30], p = .04), self efficiency (SMD = 0.22, 95% CI [-0.34, -0.10], p = .0004), social-domestic function (SMD = 0.19, 95% CI [-0.35, -0.03], p = .02) and quality of life (SMD = 0.54, 95% CI [-1.00, -0.08], p = .02). Although the effects on depression, fatigue and physiological function were in the expected direction, these effects were not statistically significant (p > .05) based on the insufficient evidence. PMID- 28090705 TI - Osteogenic differentiation potential of adipose-derived stem cells from ovariectomized mice. AB - OBJECTIVES: Osteoporosis (OP) is a systemic disease caused by imbalance between bone resorption and bone formation, commonly resulting from post-menopausal oestrogen deficiency. Although osteogenic differentiation potential of adipose derived stem cells (ASCs) has been demonstrated, the effect of OP on osteogenic differentiation of ASCs remains unclear. Here, our work has been designed to compare proliferative capacity and osteogenic differentiation ability of ASCs obtained from osteoporotic mice and normal control mice. MATERIALS AND METHODS: Twenty 14-week-old female C57BL/6 mice were randomly divided into two groups: one, the ovariectomy (OVX) group (n=10), the other being the sham operated (Sham) group (n=10). ASCs and OP-ASCs were obtained from subcutaneous fat of female inguinal sites. Cells were passaged three times prior to subsequent experimentation. The xCELLigence system was used to monitor cell adhesion and proliferation. Mineralized nodules of differentiated ASCs and OP-ASCs were analysed using Alizarin red staining after osteogenic induction. Expressions of osteogenic-specific genes including osteopontin (Opn) and runt-related transcription factor 2 (Runx2) were assessed by real-time PCR and expression of bone-related proteins was detected by Western blotting. RESULTS: Numbers of cells in all groups increased steadily for 6 days; rate of cell proliferation in the Sham group was found to be higher than in the OVX group after 48 hours. Mineralized bone nodular structures were significantly more concentrated in the Sham group than in the OVX group by day 21, and mRNA levels of Runx2 in the OVX group were significantly lower than in the Sham group. Transcript levels of genes coding for Opn showed a similar pattern to those of Runx2. Western blot results indicated that protein expression levels of OPN and RUNX2 in the OVX group were lower than those in the Sham group, at each time point. CONCLUSIONS: These results indicated that the proliferative capacity and osteogenic potential of ASCs were significantly impaired in osteoporotic mice compared to normal controls. However, use of autologous transplantation of modified OP-ASCs for treatment of OP, or combination of composite scaffolds and modified OP-ASCs for repair of osteoporotic bone defects, can overcome shortcomings of other methods. PMID- 28090706 TI - Western blot analysis of sera from dogs with suspected food allergy. AB - BACKGROUND: Food allergy is often suspected in dogs with clinical signs of atopic dermatitis. This diagnosis is confirmed with an elimination diet and a subsequent challenge with regular food. Laboratory tests for the diagnosis of food allergy in dogs are unreliable and/or technically difficult. Cyno-DIAL(r) is a Western blot method that might assist with the selection of an appropriate elimination diet. HYPOTHESIS/OBJECTIVES: To evaluate the performance of Cyno-DIAL(r) for the selection of an elimination diet and diagnosis of food allergy. ANIMALS/METHODS: Thirty eight dogs with atopic dermatitis completed an elimination diet. Combining the results of the diet trials and the challenges, 14 dogs were classified as food allergic (FA), 22 as nonfood-allergic and two as ambiguous cases. RESULTS: Amongst all dogs and amongst dogs with a clinical diagnosis of FA, 3% and 7% (respectively) were positive to Royal Canin Anallergenic(r) , Vet-Concept Kanguru(r) or Vet-Concept Dog Sana(r) ; 8% and 7% to Hill's d/d Duck and Rice(r) ; 8% and 21% to Hill's z/d Ultra Allergen Free(r) ; 53% and 64% to Eukanuba Dermatosis FP(r) ; and 32% and 43% to a home-cooked diet of horse meat, potatoes and zucchini. The specificity and sensitivity of Cyno-DIAL(r) for diagnosing food allergy were 73% and 71%, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Although Cyno-DIAL(r) was considered potentially useful for identifying appropriate foods for elimination diet trials, it cannot be recommended for the diagnosis of food allergy. The Cyno-DIAL(r) test performed better than some previously evaluated ELISA-based tests. PMID- 28090707 TI - Organoselenium-Catalyzed Regioselective C-H Pyridination of 1,3-Dienes and Alkenes. AB - An efficient approach for organoselenium-catalyzed regioselective C-H pyridination of 1,3-dienes to form pyridinium salts has been developed. This method was also successfully applied to direct C-H pyridination of alkenes. Fluoropyridinium reagents, or initially loaded pyridine derivatives, acted as pyridine sources in the pyridination reactions. The obtained pyridinium salts could be further converted under different conditions. This work is the first example of catalytic C-2 direct C-H functionalization of 1,3-dienes and the first case of organoselenium-catalyzed C-H pyridination. PMID- 28090709 TI - Copper-Catalyzed Three-Component Annulations of Alkenes, Nitrosoarenes, and N Hydroxyallylamines To Form Fused Oxazinane/Isoxazolidine Heterocycles. AB - One-pot cascade annulations among nitrosoarenes, alkenes, and N hydroxyallylamines have been achieved with CuCl/O2 catalysts, forming fused oxazinane/isoxazolidine heterocycles with excellent diastereoselectivity (d.r. >20:1). To enhance the synthetic utility, we developed a successive cleavage of the two N-O bonds of the resulting heterocycles. A mechanism involving dipolar [3+2] cycloadditions of nitrone intermediates with their tethered alkenes is postulated for formation of these heterocycles. PMID- 28090708 TI - Effect of semiquantitative culture results from complex host surgical wounds on dehiscence rates. AB - The primary aim of this study was to determine the effect of positive bacterial cultures at the time of closure on dehiscence rates. Pre- and post-debridement wound cultures from patients undergoing serial surgical debridement of infected wounds were compared with outcomes 30 days postoperatively. One-hundred patients were enrolled; 35 were excluded for incomplete culture data. Sixty-five patients were evaluated for species counts, including Coagulase negative Staphylococcus (CoNS), and semiquantitative culture data for each debridement. The post debridement cultures on the date of closure had no growth in 42 patients (64.6%) of which 6 dehisced (14.3%), and 36 remained closed; with no statistically significant difference in dehiscence rates (p = 0.0664). Pre-debridement cultures from the 1st debridement of the 65 patients showed 8 patients had no growth, 29 grew 1 species, 19 grew 2 species, and 9 had 3-5 species. There was a reduction in the number of species and improvement of semiquantitative cultures with each subsequent debridement. The dehiscence rate for those who had 2 debridements (n = 42) was 21.4% at 30 day follow-up and 21.7% in those who had 3 debridements (n = 23). The number of debridements had no statistical significance on dehiscence rates. The presence of CoNS on the day of closure was a statistically significant risk for dehiscence within 30 days (p = 0.0091) postoperatively. This data demonstrates: (1) positive post-debridement cultures (scant/rare, growth in enrichment broth) at the time of closure did not affect overall dehiscence rates (p = 0.0664), (2) the number of species and semiquantitative culture results both improved with each subsequent debridement, (3) the number of surgical debridement did not influence postclosure dehiscence rates. (4) Positive cultures containing CoNS at the time of closure is a risk factor for dehiscence (p = 0.0091). PMID- 28090710 TI - Fibrillatory wave amplitude on transesophageal ECG as a marker of left atrial low voltage areas in patients with persistent atrial fibrillation. AB - BACKGROUND: Low-voltage areas (LVAs) are frequently observed in patients with persistent atrial fibrillation (PeAF) and may represent adverse atrial remodeling. However, noninvasive method of evaluating LAVs is not well established. METHODS: In a cohort of 68 patients with PeAF, endocardial voltage maps of left atrium (LA) were created during sinus rhythm after pulmonary vein isolation (PVI). LVAs were defined as areas with electrogram amplitudes <0.5 mV. LA-LVAs were correlated with clinical, echocardiographic, surface, and transesophageal electrocardiography (TE-ECG) variables. RESULTS: LA voltage mapping revealed any degree of LA-LVAs in 50 (73.5%) patients. Patients with LA LVAs were older, had a longer history of AF, and lower fibrillatory wave (F wave) amplitude on TE-ECG (0.27 +/- 0.06 vs 0.39 +/- 0.08 mv, p < .01) as compared to patients without LA-LVAs. The extent of LA-LVAs was weakly correlated with age (R = 0.36, p = .03) and AF duration (R = 0.26, p = .02), but significantly correlated with F-wave amplitude on TE-ECG (R = -0.57, p < .01). Only F-wave amplitude on TE-ECG was found as independent predictor for the presence of LA LVAs (OR = 1.53, 95% CI = 1.09-2.96, p = .03). A receiver operating characteristic (ROC) curve identified an F-wave amplitude of 0.29 mV (AUC = 0.788; sensitivity = 68.4%; specificity = 73.2%) on TE-ECG as the optimal cutoff value for predicting LA-LVAs. CONCLUSIONS: As a noninvasive investigation, F-wave amplitude on TE-ECG may be used as an indicator for the presence of LA-LVAs. PMID- 28090712 TI - Academie des Sciences Prizes Novartis Chemistry Lectureship 2016-2017 Welch Award in Chemistry. PMID- 28090711 TI - Topical application of nitrosonifedipine, a novel radical scavenger, ameliorates ischemic skin flap necrosis in a mouse model. AB - Ischemic skin flap necrosis can occur in random pattern flaps. An excess amount of reactive oxygen species is generated and causes necrosis in the ischemic tissue. Nitrosonifedipine (NO-NIF) has been demonstrated to possess potent radical scavenging ability. However, there has been no study on the effects of NO NIF on ischemic skin flap necrosis. Therefore, they evaluated the potential of NO NIF in ameliorating ischemic skin flap necrosis in a mouse model. A random pattern skin flap (1.0 * 3.0 cm) was elevated on the dorsum of C57BL/6 mice. NO NIF was administered by topical injection immediately after surgery and every 24 hours thereafter. Flap survival was evaluated on postoperative day 7. Tissue samples from the skin flaps were harvested on postoperative days 1 and 3 to analyze oxidative stress, apoptosis and endothelial dysfunction. The viable area of the flap in the NO-NIF group was significantly increased (78.30 +/- 7.041%) compared with that of the control group (47.77 +/- 6.549%, p < 0.01). NO-NIF reduced oxidative stress, apoptosis and endothelial dysfunction, which were evidenced by the decrease of malondialdehyde, p22phox protein expression, number of apoptotic cells, phosphorylated p38 MAPK protein expression, and vascular cell adhesion molecule-1 protein expression while endothelial nitric oxide synthase protein expression was increased. In conclusion, they demonstrated that NO-NIF ameliorated ischemic skin flap necrosis by reducing oxidative stress, apoptosis, and endothelial dysfunction. NO-NIF is considered to be a candidate for the treatment of ischemic flap necrosis. PMID- 28090713 TI - Nucleotide-Independent Copper(II)-Based Distance Measurements in DNA by Pulsed ESR Spectroscopy. AB - A site-specific Cu2+ binding motif within a DNA duplex for distance measurements by ESR spectroscopy is reported. This motif utilizes a commercially available 2,2'-dipicolylamine (DPA) phosphormadite easily incorporated into any DNA oligonucleotide during initial DNA synthesis. The method only requires the simple post-synthetic addition of Cu2+ without the need for further chemical modification. Notably, the label is positioned within the DNA duplex, as opposed to outside the helical perimeter, for an accurate measurement of duplex distance. A distance of 2.7 nm was measured on a doubly Cu2+ -labeled DNA sequence, which is in exact agreement with the expected distance from both DNA modeling and molecular dynamic simulations. This result suggests that with this labeling strategy the ESR measured distance directly reports on backbone DNA distance, without the need for further modeling. Furthermore, the labeling strategy is structure- and nucleotide-independent. PMID- 28090714 TI - Transplantation of CD51+ Stem Leydig Cells: A New Strategy for the Treatment of Testosterone Deficiency. AB - Stem Leydig cell (SLC) transplantation could provide a new strategy for treating the testosterone deficiency. Our previous study demonstrated that CD51 (also called integrin alphav) might be a putative cell surface marker for SLCs, but the physiological function and efficacy of CD51+ SLCs treatment remain unclear. Here, we explore the potential therapeutic benefits of CD51+ SLCs transplantation and whether these transplanted cells can be regulated by the hypothalamic-pituitary gonadal (HPG) axis. CD51+ cells were isolated from the testes of 12-weeks-old C57BL/6 mice, and we showed that such cells expressed SLC markers and that they were capable of self-renewal, extensive proliferation, and differentiation into multiple mesenchymal cell lineages and LCs in vitro. As a specific cytotoxin that eliminates Leydig cells (LCs) in adult rats, ethane dimethanesulfonate (EDS) was used to ablate LCs before the SLC transplantation. After being transplanted into the testes of EDS-treated rats, the CD51+ cells differentiated into mature LCs, and the recipient rats showed a partial recovery of testosterone production and spermatogenesis. Notably, a testosterone analysis revealed a circadian rhythm of testosterone secretion in cell-transplanted rats, and these testosterone secretions could be suppressed by decapeptyl (a luteinizing hormone-releasing hormone agonist), suggesting that the transplanted cells might be regulated by the HPG axis. This study is the first to demonstrate that CD51+ SLCs can restore the neuroendocrine regulation of testicular function by physiologically recovering the expected episodic changes in diurnal testosterone serum levels and that SLC transplantation may provide a new tool for the studies of testosterone deficiency treatment. Stem Cells 2017;35:1222-1232. PMID- 28090715 TI - Health care professionals knowledge and perception of pharmacovigilance in a tertiary care teaching hospital in Amman, Jordan. AB - RATIONALE, AIMS, AND OBJECTIVES: Underreporting of adverse drug reactions (ADRs) by health care professionals is a common inherent health problem encountered in many countries. This could be explained by the lack of awareness and knowledge about the guidelines to follow to identify and report ADRs. Thus, this study aimed to evaluate the awareness, knowledge, and perceptions among medical doctors and nurses regarding their role as ADRs reporters in Jordan. METHODS: A cross sectional study was conducted between September 2015 to January 2016 at the Jordan University Hospital in Amman. During the study period, a total of 670 validated questionnaires were distributed to medical doctors and nurses in different departments. RESULTS: Most of health care professionals were not aware of the concept of pharmacovigilance. Medical doctors showed a better overall knowledge compared with nurses (P < .05). Interestingly, despite the low level of awareness, the majority of respondents believed in the necessity of reporting ADRs. CONCLUSION: Although there is a low level of awareness among health care professionals regarding pharmacovigilance, there is strong agreement among them about the necessity of reporting ADRs and attending educational sessions about pharmacovigilance which will help them to improve the quality of services they provide. PMID- 28090717 TI - Enantioselective NiH/Pmrox-Catalyzed 1,2-Reduction of alpha,beta-Unsaturated Ketones. AB - The enantioselective 1,2-reduction of alpha,beta-unsaturated ketones was achieved using a NiH catalyst in the presence of pinacolborane. This mild process represents a general method to access a wide variety of structurally diverse alpha-chiral allylic alcohols in excellent yields and enantioselectivity, as well as very high levels of ambidoselectivity for 1,2- over 1,4-reduction. Furthermore, for reactions on a 10 mmol scale, catalyst loadings as low as 0.5 mol % could be employed to deliver product without any detrimental effect on the yield, enantio-, or ambidoselectivity. PMID- 28090716 TI - Does item overlap render measured relationships between pain and challenging behaviour trivial? Results from a multicentre cross-sectional study in 13 German nursing homes. AB - Several studies suggest that pain is a trigger for challenging behaviour in older adults with cognitive impairment. However, such measured relationships might be confounded due to item overlap as instruments share similar or identical items. The purpose of this study was to examine whether the frequently observed association between pain and challenging behaviour might be traced back to item overlap. This multicentre cross-sectional study was conducted in 13 nursing homes and examined pain (measure: Pain Assessment in Advanced Dementia Scale) and challenging behaviour (measure: Cohen-Mansfield Agitation Inventory) in 150 residents with severe cognitive impairment. The extent of item overlap was determined by juxtaposition of both measures' original items. As expected, comparison between these instruments revealed an extensive item overlap. The statistical relationship between the two phenomena can be traced back mainly to the contribution of the overlapping items, which renders the frequently stated relationship between pain and challenging behaviour trivial. The status quo of measuring such associations must be contested: constructs' discrimination and instruments' discrimination have to be discussed critically as item overlap may lead to biased conclusions and assumptions in research as well as to inadequate care measures in nursing practice. PMID- 28090718 TI - An analysis of policies for cotrimoxazole, amoxicillin and azithromycin use in Namibia's public sector: Findings and therapeutic implications. AB - BACKGROUND: Despite Namibia's robust medicine use systems and policies, antibiotic use indicators remain suboptimal. Recent medicine use surveys rank cotrimoxazole, amoxicillin and azithromycin (CAA) among the most used medicines. However, there is rising resistance to CAA (55.9%-96.7%). Unfortunately, to date, there have been limited studies evaluating policies to improve antibiotic use in Namibia. AIM: To evaluate public sector pharmaceutical policies and guidelines influencing the therapeutic use of CAA antibiotics in Namibia. METHODS: Evaluate Namibia's pharmaceutical policies and guidelines for CAA use through quantitative text analysis. The main outcome variables were the existence of antibiotic policies, therapeutic indications per antibiotic and the type/level of healthcare facility allowed to use the antibiotic. RESULTS: Policies for antibiotic use were limited, with only the draft Namibia Medicines Policy having a statement on antibiotic use. Several essential antibiotics had no therapeutic indications mentioned in the guidelines. Twenty-nine antibiotics were listed for 69 therapeutic indications; CAA (49.3%) antibiotics and ATC J01C/J01D (48%) having the highest indications per antibiotic. For CAA antibiotics, this suggested use was mainly for acute respiratory infections (n=22, 37.2%). Published policies (58.6%-17/29) recommended antibiotics for use at the primary healthcare (PHC) level, with CAA antibiotics recommended mostly for respiratory tract infections and genitourinary infections. CONCLUSIONS: Policy and guidelines for antibiotic use in Namibia are not comprehensive and are skewed towards PHCs. Existing policies promote the wide use of CAA antibiotics, which may inadvertently result in their inappropriate use enhancing resistance rates. This calls for the development of more comprehensive antibiotic guidelines and essential medicine lists in tandem with local antimicrobial resistance patterns. In addition, educational initiatives among all key stakeholder groups. PMID- 28090719 TI - Diversity-Oriented Synthesis of Cyclic Azapeptides by A3 -Macrocyclization Provides High-Affinity CD36-Modulating Peptidomimetics. AB - Macrocyclization has enabled the use of peptides in drug discovery creating a need for methods to synthesize diverse peptide macrocycles. Azapeptides have advanced to clinically used drugs, however, few cyclic azapeptides have been studied. A multiple component "A3 -macrocyclization" strategy is described for the preparation of diverse cyclic azapeptides and is demonstrated by the synthesis of 15 growth hormone releasing hormone-6 (GHRP-6) analogs. Certain cyclic aza-GHRP-6 analogs exhibited unprecedented affinity for the CD36 receptor, and capacity to modulate Toll-like receptor agonist-induced overproduction of nitric oxide, and reduce pro-inflammatory cytokine and chemokine production in macrophages. PMID- 28090720 TI - Stereodivergent-at-Metal Synthesis of [60]Fullerene Hybrids. AB - Chiral fullerene-metal hybrids with complete control over the four stereogenic centers, including the absolute configuration of the metal atom, have been synthesized for the first time. The stereochemistry of the four chiral centers formed during [60]fullerene functionalization is the result of both the chiral catalysts employed and the diastereoselective addition of the metal complexes used (iridium, rhodium, or ruthenium). DFT calculations underpin the observed configurational stability at the metal center, which does not undergo an epimerization process. PMID- 28090723 TI - Light-Activated Sensitive Probes for Amine Detection. AB - Our new, simple, and accurate colorimetric method is based on diarylethenes (DAEs) for the rapid detection of a wide range of primary and secondary amines. The probes consist of aldehyde- or ketone-substituted diarylethenes, which undergo an amine-induced decoloration reaction, selectively to give the ring closed isomer. Thus, these probes can be activated at the desired moment by light irradiation, with a sensitivity that allows the detection of amines at concentrations as low as 10-6 m in solution. In addition, the practical immobilization of DAEs on paper makes it possible to detect biogenic amines, such as cadaverine, in the gas phase above a threshold of 12 ppbv within 30 seconds. PMID- 28090721 TI - An Ultrastable and Easily Regenerated Hydrogen-Bonded Organic Molecular Framework with Permanent Porosity. AB - A robust hydrogen-bonded organic framework HOF-TCBP (H4 TCBP=3,3',5,5'-tetrakis (4-carboxyphenyl)-1,1'-biphenyl) has been successfully constructed and structurally characterized. It possesses a permanent 3D porous structure with a 5 fold interpenetrated dia topological network. This activated HOF-TCBP has a high BET surface area of 2066 m2 g-1 and is capable of highly selective adsorption and separation of light hydrocarbons under ambient conditions. It shows excellent thermal stability, as demonstrated by PXRD experiments and N2 adsorption tests. Practical use of HOF-TCBP is facilitated by the ease of its preparation and renewal through rotary evaporation. PMID- 28090722 TI - Bi(IO3 )F2 : The First Metal Iodate Fluoride with a Very Strong Second Harmonic Generation Effect. AB - The first metal iodate fluoride, Bi(IO3 )F2 , with a strong second harmonic generation (SHG) effect has been prepared. Bi(IO3 )F2 crystallizes in the polar space group C2 and features a three-dimensional [BiF2 ]+ cationic framework with IO3 groups capping the inner walls of the one-dimensional tunnels. This [BiF2 ]+ cationic framework acts as a template for the assembly of the polar IO3 units in a favorable superposed fashion, which leads to the polar structure of the material. Bi(IO3 )F2 displays a rather wide transmittance window (0.3-11 MUm) and exhibits a very strong SHG response that is about 11.5 times larger than that of KH2 PO4 (KDP) under 1064 nm laser radiation and the same as that of KTiOPO4 (KTP) under 2.05 MUm laser radiation. Preliminary investigations indicate that Bi(IO3 )F2 is a promising nonlinear optical material in the visible and mid-IR region. PMID- 28090724 TI - Efficacy of topical insulin in wound healing: A preliminary systematic review and meta-analysis of randomized controlled trials. AB - Topical insulin has been shown to promote wound healing in various studies. Considering the absence of a systematic review and quantitative synthesis on the same, the present study was carried out. Using an appropriate search strategy, electronic databases were searched for randomized controlled trials that have compared topical application of insulin in wounds with normal saline. Standardize mean differences were calculated for the following outcome measures: healing rate of ulcers/wound, percent granulation tissue growth, microvessel density, time to heal, wound area and ulcer severity score. Cochrane's risk of bias tool was used for each of the studies and RevMan 5.3 software was used to generate the pooled estimates and Forest plots. The quality of evidence was assessed by the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) working group approach. A total of 8 studies were found eligible to be included in this review and 7 for the meta-analysis. The pooled estimates were as follows: healing rate 0.04 [-1.38, 1.46]; percent granulation tissue-10.99 [-10.07, 32.06], microvessel density-3.01 [-1.67, 7.69] and wound area--6.59 [-9.7, -3.48]. There was only one study for each of the following outcome measures: time to heal and ulcer severity score. Hence, pooling of the results was not attempted for these outcome measures. The studies conducted in this field were preliminary and it was difficult to draw any conclusion regarding the use of insulin topically for wound healing. PMID- 28090725 TI - Non-Aqueous Microwave-Assisted Syntheses of Deca- and Hexa-Molybdovanadates. AB - We report a new approach for the synthesis of heterohexa- and heterodecametalates via the use of non-aqueous, microwave-assisted reaction conditions. The two novel molybdovanadates have been isolated and characterized in the solid and solution states using single-crystal X-ray diffraction, FT-IR, UV/Vis, multinuclear NMR spectroscopy, and ESI-MS. The relative stabilities of the possible structural isomers were probed using dispersion-corrected DFT calculations for both polyoxometalate systems. PMID- 28090726 TI - Trials of new anti-diabetes agents. PMID- 28090728 TI - Exploring Text and Icon Graph Interpretation in Students with Dyslexia: An Eye tracking Study. AB - A growing body of research suggests that individuals with dyslexia struggle to use graphs efficiently. Given the persistence of orthographic processing deficits in dyslexia, this study tested whether graph interpretation deficits in dyslexia are directly related to difficulties processing the orthographic components of graphs (i.e. axes and legend labels). Participants were 80 college students with and without dyslexia. Response times and eye movements were recorded as students answered comprehension questions about simple data displayed in bar graphs. Axes and legends were labelled either with words (mixed-modality graphs) or icons (orthography-free graphs). Students also answered informationally equivalent questions presented in sentences (orthography-only condition). Response times were slower in the dyslexic group only for processing sentences. However, eye tracking data revealed group differences for processing mixed-modality graphs, whereas no group differences were found for the orthography-free graphs. When processing bar graphs, students with dyslexia differ from their able reading peers only when graphs contain orthographic features. Implications for processing informational text are discussed. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28090727 TI - Italian patients with more recent onset of Major Depressive Disorder have a shorter duration of untreated illness. AB - BACKGROUND: Previous investigation on the duration of untreated illness (DUI) in patients with Major Depressive Disorder (MDD) revealed a different latency to first antidepressant treatment, with adverse consequences in terms of outcome for individuals with a longer DUI. Recent reports, moreover, documented a reduced DUI, as observed with the passage of time, in patients with different psychiatric disorders. Hence, the present study was aimed to assess DUI and related variables in a sample of Italian patients with MDD as well as to investigate potential differences in subjects with onset before and after 2000. METHODS: An overall sample of 188 patients with MDD was assessed through a specific questionnaire investigating DUI and other variables related to the psychopathological onset and latency to first antidepressant treatment, after dividing them in two different subgroups on the basis of their epoch of onset. RESULTS: The whole sample showed a mean DUI of approximately 4.5 years, with patients with more recent onset showing a significantly shorter latency to treatment compared with the other group (27.1+/-42.6 vs 75.8+/-105.2 months, P<.05). Other significant differences emerged between the two subgroups, in terms of rates of onset-related stressful events and benzodiazepine prescription, respectively, higher and lower in patients with more recent onset. CONCLUSIONS: Our findings indicate a significant DUI reduction in MDD patients whose onset occurred after vs before 2000, along with other relevant differences in terms of onset-related correlates and first pharmacotherapy. Further studies with larger samples are warranted to confirm the present findings in Italy and other countries. PMID- 28090729 TI - Notes on the use of randomised controlled trials to evaluate complex interventions: Community treatment orders as an illustrative case. AB - Over the past seven decades, randomised controlled trials (RCTs) have revolutionised clinical research and achieved a gold standard status. However, extending their use to evaluate complex interventions is problematic. In this paper we will demonstrate that complex intervention RCTs violate the necessary premises that govern the RCTs logic and underpin their rigour. The lack of blinding, heterogeneity of participants, as well as poor treatment standardisation and difficulty of controlling for confounders, which characterise complex intervention RCTs, can potentially be profoundly detrimental to their integrity. Proponents of this approach argue that matching "real world" circumstances, while maintaining the randomised design, enhances external validity. We counter this argument by pointing out that an inverted U relation exists between internal and external validity, and thus relaxing the experimental conditions beyond a certain threshold can potentially paradoxically render the RCT externally invalid, i.e. its results cannot be used anywhere. We shall illustrate the inappropriate use of RCTs to evaluate community treatment orders and propose an alternative epistemic model that is based on mechanistic reasoning and Cartwright's capacity concept. PMID- 28090730 TI - Opinions and potential solutions regarding dissemination bias from funding agencies of biomedical research in Europe. AB - RATIONALE, AIMS, AND OBJECTIVES: Several studies have found that about half of research results from clinical trials are never published. Until now, there has been little information on the views that funding agencies of biomedical research in Europe have regarding this issue and its possible solutions. METHODS: An electronic survey was conducted among funding agencies from 34 European countries. Participants were asked about their opinions, policies, and potential solutions regarding dissemination bias. On the basis of the results of this survey and the input of the OPEN Consortium and of representatives of stakeholder groups in the knowledge generation process, we formulated recommendations for funding agencies to reduce dissemination bias. RESULTS: We received responses from 64 funding agencies of biomedical medicine from most European countries, out of 245 that were contacted (26%). Of these, 56 funded research at the national and/or international level and were therefore eligible to participate. Policies encouraging publication increased over time: 33 (58.9%) of agencies enforced them in 2005 compared to 38 (67.6%) in 2012. However, only 13 (23.2%) had knowledge of the publications related to research funded in 2005, 23 (41.1%) were able to provide only an estimate, and 20 (35.7%) did not know at all. Regarding recommendations to control dissemination bias, we propose that funding agencies request the dissemination of research results irrespective of the direction of findings. We also call for measures that allow evaluating funded projects past the contractual period and until dissemination of results. Funding agencies should create publicly accessible databases with information on funded projects and dissemination efforts. CONCLUSION: Despite having policies to encourage publication of results, most funding agencies fail to implement such measures or to ensure compliance. We propose recommendations that could be incorporated in the blueprint of calls for proposals and contracts agreed upon by funding agencies and grant recipients. PMID- 28090732 TI - High engagement, high quality: A guiding framework for developing empirically informed asynchronous e-learning programs for health professional educators. AB - E-learning involves the transfer of skills and knowledge via technology so that learners can access meaningful and authentic educational materials. While learner engagement is important, in the context of healthcare education, pedagogy must not be sacrificed for edu-tainment style instructional design. Consequently, health professional educators need to be competent in the use of current web based educational technologies so that learners are able to access relevant and engaging e-learning materials without restriction. The increasing popularity of asynchronous e-learning programs developed for use outside of formal education institutions has made this need more relevant. In these contexts, educators must balance design and functionality to deliver relevant, cost-effective, sustainable, and accessible programs that overcome scheduling and geographic barriers for learners. This paper presents 10 guiding design principles and their application in the development of an e-learning program for general practice nurses focused on behavior change. Consideration of these principles will assist educators to develop high quality, pedagogically sound, engaging, and interactive e-learning resources. PMID- 28090733 TI - Update from the Editors: Plans for 2017. PMID- 28090731 TI - Addition of Ezetimibe to statins for patients at high cardiovascular risk: Systematic review of patient-important outcomes. AB - Ezetimibe is widely used in combination with statins to reduce low-density lipoprotein. We sought to examine the impact of ezetimibe when added to statins on patient-important outcomes. Medline, EMBASE, CINAHL, and CENTRAL were searched through July, 2016. Randomized controlled trials (RCTs) of ezetimibe combined with statins versus statins alone that followed patients for at least 6 months and reported on at least one of all-cause mortality, cardiovascular deaths, non fatal myocardial infarctions (MI), and non-fatal strokes were included. Pairs of reviewers extracted study data and assessed risk of bias independently and in duplicate. Quality of evidence was assessed using the GRADE approach. We conducted a narrative review with complementary subgroup and sensitivity analyses. IMPROVE-IT study enrolled 93% of all patients enrolled in the 8 included trials. Our analysis of the IMPROVE-IT study results showed that in patients at high risk of cardiovascular events, ezetimibe added to statins was associated with i) a likely reduction in non-fatal MI (17 fewer/1000 treated over 6 years, moderate certainty in evidence); ii) a possible reduction in non-fatal stroke (6 fewer/1000 treated over 6 years, low certainty); iii) no impact on myopathy (moderate certainty); iv) potentially no impact on all-cause mortality and cardiovascular death (both moderate certainty); and v) possibly no impact on cancer (low certainty). Addition of ezetimibe to moderate-dose statins is likely to result in 17 fewer MIs and possibly 6 fewer strokes/1000 treated over 6 years but is unlikely to reduce all-cause mortality or cardiovascular death. Patients who place a high value on a small absolute reduction in MI and are not adverse to use of an additional medication over a long duration may opt for ezetimibe in addition to statin therapy. Our analysis revealed no increased specific harms associated with addition of ezetimibe to statins. PMID- 28090735 TI - High-Throughput, Protein-Targeted Biomolecular Detection Using Frequency-Domain Faraday Rotation Spectroscopy. AB - A clinically relevant magneto-optical technique (fd-FRS, frequency-domain Faraday rotation spectroscopy) for characterizing proteins using antibody-functionalized magnetic nanoparticles (MNPs) is demonstrated. This technique distinguishes between the Faraday rotation of the solvent, iron oxide core, and functionalization layers of polyethylene glycol polymers (spacer) and model antibody-antigen complexes (anti-BSA/BSA, bovine serum albumin). A detection sensitivity of ~10 pg mL-1 and broad detection range of 10 pg mL-1 ? cBSA ? 100 ug mL-1 are observed. Combining this technique with predictive analyte binding models quantifies (within an order of magnitude) the number of active binding sites on functionalized MNPs. Comparative enzyme-linked immunosorbent assay (ELISA) studies are conducted, reproducing the manufacturer advertised BSA ELISA detection limits from 1 ng mL-1 ? cBSA ? 500 ng mL-1 . In addition to the increased sensitivity, broader detection range, and similar specificity, fd-FRS can be conducted in less than ~30 min, compared to ~4 h with ELISA. Thus, fd-FRS is shown to be a sensitive optical technique with potential to become an efficient diagnostic in the chemical and biomolecular sciences. PMID- 28090736 TI - RNA Protection is Effectively Achieved by Pullulan Film Formation. AB - RNA is a functionally versatile polymer but suffers from susceptibility to spontaneous and RNase-catalyzed degradation. This vulnerability makes it difficult to preserve RNA for extended periods of time, thus limiting its use in various contexts, including practical applications as functional nucleic acids. Here we present a simple method to preserve RNA by pullulan (a complex sugar produced by Aureobasidium pullulans fungus) film formation. This strategy can markedly suppress both spontaneous and RNase degradation. Importantly, the pullulan film readily dissolves in aqueous solution, thus allowing retrieval of fully functional RNA species. In order to illustrate the advantage of this protective method in a practical application, we engineered a simple paper sensor containing a bacteria-detecting RNA-cleaving DNAzyme. This detection capability of the device was unchanged after storage at room temperature for six months. PMID- 28090737 TI - A framework for how environment contributes to cancer risk. AB - Evolutionary theory explains why metazoan species are largely protected against the negative fitness effects of cancers. Nevertheless, cancer is often observed at high incidence across a range of species. Although there are many challenges to quantifying cancer epidemiology and assessing its causes, we claim that most modern-day cancer in animals - and humans in particular - are due to environments deviating from central tendencies of distributions that have prevailed during cancer resistance evolution. Such novel environmental conditions may be natural and/or of anthropogenic origin, and may interface with cancer risk in numerous ways, broadly classifiable as those: increasing organism body size and/or life span, disrupting processes within the organism, and affecting germline. We argue that anthropogenic influences, in particular, explain much of the present-day cancer risk across life, including in humans. Based on a literature survey of animal species and a parameterised mathematical model for humans, we suggest that combined risks of all cancers in a population beyond c. 5% can be explained to some extent by the influence of novel environments. Our framework provides a basis for understanding how natural environmental variation and human activity impact cancer risk, with potential implications for species ecology. PMID- 28090738 TI - Changes in objectively measured physical activity in adolescents with Down syndrome: the UP&DOWN longitudinal study. AB - BACKGROUND: It is a priority to understand that physical activity behaviour over time is a priority in Down syndrome population in order to design and promote succesfull interventions to maintain or increase levels of physical activity. We aimed to study 1 and 2-year changes in objectively measured physical activity among a relatively large sample of adolescents with Down syndrome. METHODS: This study comprised a total of 99 adolescents with Down syndrome (38 girls) aged from 11 to 20 years old at baseline. Participants with valid accelerometer data at baseline and at least one of the follow-up visits were included in the analysis. RESULTS: Overall, levels of physical activity observed in adolescents with Down syndrome declined from baseline to follow-ups, but these changes were not significant (all P > 0.05). Moderate-to-moderately high tracking of physical activity was observed in adolescents with Down syndrome (all P < 0.001). Youths who met physical activity guidelines at baseline demonstrated a greater decline in physical activity in 1 and 2-year changes (P < 0.05), although they were also more likely to meet physical activity guidelines at 1 and 2-year follow-ups (P < 0.05). CONCLUSIONS: Adolescents with Down syndrome do not change their levels of physical activity at 2-year follow-ups, but those who met physical activity guidelines presented stronger declines in physical activity over time. PMID- 28090739 TI - Obesity-related genetic polymorphisms and adiposity indices in a young Italian population. AB - Pediatric obesity develops when a complex biological predisposition collides with an obesogenic environment. To further elucidate the role of genetics in obesity onset, we performed a candidate-gene association study in a young and sportive Italian population by testing the association of functional polymorphisms in ACE (rs4646994), FTO (rs9939609), MC4R (rs17782313) and PPARG (rs1801282) genes with body mass index (BMI) and waist-to-height ratio (WHtR). We also tested the combinations of identified risk genotypes and epistatic interactions among them to determine the existence of cumulative effects in predicting the predisposition to gain weight. Our results confirm a significant direct influence of MC4R rs17782313 and PPARG rs1801282 on body composition, that is, minor allele homozygotes showed significantly higher BMI (rs17782313, beta = 1.258, P = 0.031; rs1801282, beta = 6.689, P = 1.2 * 10-4 ) and WHtR (rs17782313, beta = 0.021, P = 0.005; rs1801282, beta = 0.069, P = 0.003) values. Moreover, by leveraging multifactor dimensionality reduction and general linear model (GLM) approaches we identified an epistatic interaction between ACE and MC4R, where heterozygosity at ACE rs4646994 seems to protect from the unfavorable predisposition to gain weight given by C/C genotype at MC4R rs17782313 (GLM, P = 0.004). In conclusion, to clarify the role of genetics in multifactorial diseases remains a difficult goal, even for the most investigated polymorphisms and in controlled populations. Further studies on epistasis and gene-gene interaction will help to elucidate this complex scenario. (c) 2017 IUBMB Life, 69(2):98-105, 2017. PMID- 28090740 TI - The impact of a creative play intervention on satisfaction with nursing care: A mixed-methods study. AB - PURPOSE: Hospitalisation can lead to distress for children. Creative play may reduce the adverse effects of hospitalisation on children, as it could lead to children associating satisfaction and fun with their hospital experience. The aim of the current study is to investigate the impact of a creative play intervention on service-care satisfaction measurements of children and their parents. DESIGN AND METHODS: A mixed-methods design consisting of quantitative pre/post assessments and qualitative interviews was used within this study. The research was conducted with 30 children (nexperimental group = 15; ncontrol group = 15). Their parents (n = 30) and their nurse practitioners (n = 20) were also contacted in order to capture their reflections of this intervention which included creative activities with unused clean medical materials. Child participants completed the Patient's Nursing Care Perception Tool and their parents completed the PedsQL Health Care Satisfaction Tool. RESULTS: The two groups did not differ in relation to the Patients' Nursing Care Satisfaction Tool (PNCST) (t(28): 0.348, p = .730) and the PedsQL (t(28): -0.189, p = .852) scores at Time 1 before the intervention; however, significant differences were observed at the end at Time 2 (PNCST: t(28): -11.63, p < .001; PedsQL: t(28): -12.416, p < .001). In qualitative interviews, nurses indicated that their play skills with children had been enhanced by this intervention. Family attendants reported that the intervention improved the nurse-child relationship and their satisfaction with care. PRACTICE IMPLICATIONS: The results have shown that creative play intervention are a feasible nursing intervention which has a strong potential to be effective on child patients' and their attendants' satisfaction with care services. PMID- 28090741 TI - Conformational quiescence of ADAMTS-13 prevents proteolytic promiscuity: reply. PMID- 28090742 TI - A Novel Scale Linking Potency and Dosage to Estimate Anticholinergic Exposure in Older Adults: the Muscarinic Acetylcholinergic Receptor ANTagonist Exposure Scale. AB - Quantification of the anticholinergic exposure insufficiently or imprecisely incorporates dosage information, leading to inaccurate estimations. The aim was to construct a novel scale, including potency and dosage for the quantification of the anticholinergic exposure in older adults. Potency information was retrieved from a previous systematic review. The dosage range for each drug was delineated in minimal, maintenance and maximal dosage for adults and older adults. Dosage information was collected from authoritative sources and reviewed in an expert panel. The Muscarinic Acetylcholinergic Receptor ANTagonist Exposure (MARANTE) scale was tested for clinimetric properties using cohorts of community dwelling older adults and nursing home residents. After three data collection rounds, data for the dosage ranges remained incomplete for 32 active substances. Remaining gaps were filled in, and 11 dosage adjustments were proposed during the expert panel meeting. We chose the values {0; 1; 2) for the categories of potency and {0; 0.5; 1; 1.5; 2) for the levels of dosage ranges, showing good clinimetric properties. Forty-one anticholinergic drugs were prescribed in the two cohorts. Most (61%) were low potency anticholinergics and used for depression (19%, e.g. citalopram). There were 31.8% (median MARANTE 1.5, IQR 1.5-2.5) and 37.6% (median 2, IQR 1.5-2.5) anticholinergic users in the community-dwelling cohort and nursing home cohort, respectively. The MARANTE scale combines potency with the dosage spectrum, to quantify the anticholinergic exposure in older adults. An open feedback system on the list of anticholinergic and proposed anticholinergic potency and dosage values is advised. PMID- 28090743 TI - Cement-associated peri-implant mucositis. A 1-year follow-up after excess cement removal on the peri-implant tissue of dental implants. AB - BACKGROUND: Methacrylate-based cements seem to promote peri-implant tissue inflammation even in the absence of excess cement. PURPOSE: The present study deals with the question of whether the removal of methacrylate cement from the peri-implant sulcus will lead to peri-implant tissues free of inflammation on a 1 year follow-up basis. MATERIAL AND METHODS: Implant supported suprastructures that had been in the mouth for at least 3.5 years either cemented with methacrylate (premier implant cement [PIC]) or zinc eugenol (temp bond [TB]) cement were compared. All superstructures in 33 patients with a total of 61 implants (35 with PIC and 26 with TB) were removed and excess cement, bleeding on probing (BOP), suppurationen and probing depth were documented. Excess cement found was removed, and in all cases the suprastructure was recemented with TB. Patients were followed up after 4 weeks (F1) and 1 year (F2). RESULTS: Excess cement was found around 60% of the implants with PIC. No excess cement was found around implants with TB. At the time of revision therapy, BOP was found around 100% of the implants with PIC and excess cement (PIC+), 93% around implants with PIC but no excess cement (PIC-), and around 42% of the TB-cemented implants (Chi squared P < .01). Suppuration was observed in 86% of the PIC+ implants, in 14% of the PIC- implants and in 0% of the TB implants (Chi-squared P < .01). At the time of both F1 and F2, the inflammation parameters, that is BOP and suppuration, on implant level were significantly reduced in the PIC+ cases (McNemar's test P < .01). For PIC-, BOP was significantly reduced at both points in time (P < .05). For TB no differences were found. Probing depth at F2 had significantly decreased in all groups (t test P < .05). CONCLUSION: The removal of excess cement and recementation with TB had an anti-inflammatory effect on the peri-implant tissues after 1 year. PMID- 28090744 TI - Effects of different hierarchical hybrid micro/nanostructure surfaces on implant osseointegration. AB - BACKGROUND: Hierarchical hybrid micro/nanostructure implant surfaces are considered to better mimic the hierarchical structure of bone and the nanostructures substantively influence osseointegration through managing cell behaviors. PURPOSE: To enhance implant osseointegration for further clinical application, we evaluated the material properties and osseointegration effects of hierarchical surfaces with different nano-morphologies, using a rat model. MATERIALS AND METHODS: Two representative surface fabrication methods, hydrofluoric (HF) acid etching combined with anodization (HF + AN) or magnetron sputtering (HF + MS), were selected. Sample material properties were evaluated by scanning electron microscopy, atomic force microscopy, X-ray diffraction, X-ray photoemission spectroscopy, and epoxy resin docking tensile test. Implants with different surfaces were inserted into the distal femurs of rats. After 12 weeks, osseointegration was examined by microcomputed tomography (micro-CT), histological, and biomechanical tests. RESULTS: Tensile testing demonstrated high bonding strength at coating/implant in the HF + MS group. Micro-CT revealed increased bone volume/total volume and significantly reduced trabecular separation in HF + MS versus other groups. Histological analysis showed significantly higher HF + MS bone-to-implant contact (74.78 +/- 4.40%) versus HF + AN (65.11 +/- 5.10%) and machined samples (56.03 +/- 3.23%). The maximal HF + MS pull-out force increased by 33.7% versus HF + AN. CONCLUSIONS: These results indicated that HF + MS surfaces exhibited superior material property in terms of bonding strength and favorable implant osseointegration compared to other groups. PMID- 28090745 TI - Side-Group-Induced Polymorphism in Self-Assembled Monolayers: 3,5 Bis(trifluoromethyl)benzenethiolate Films on Au(111). AB - The structure and molecular organization of self-assembled monolayers (SAMs) depend on a complex interplay of intermolecular and molecule-substrate interactions, so that even a small change in molecular composition can result in noticeable changes in the SAM structure. Herein we show that decoration of the most basic aromatic SAM constituent, benzenethiol, with two trifluoromethyl groups leads to distinct polymorphism in the respective SAMs, in which the appearance of a specific structural phase or a combination of several different phases is dependent on the parameters of the preparation procedure. High-quality films with a single crystallographic phase and significantly large domains could only be prepared after a short immersion time (5 min) and an additional re immersion of the sample in pure ethanol at an elevated temperature. A standard 24 h immersion at room temperature led to poorly defined films with a large defect density and only a small portion of the surface covered by well-ordered molecular domains. PMID- 28090746 TI - Development of an in vivo visual robot system with a magnetic anchoring mechanism and a lens cleaning mechanism for laparoendoscopic single-site surgery (LESS). AB - BACKGROUND: Surgical robot systems which can significantly improve surgical procedures have been widely used in laparoendoscopic single-site surgery (LESS). For a relative complex surgical procedure, the development of an in vivo visual robot system for LESS can effectively improve the visualization for surgical robot systems. METHODS: In this work, an in vivo visual robot system with a new mechanism for LESS was investigated. A finite element method (FEM) analysis was carried out to ensure the safety of the in vivo visual robot during the movement, which was the most important concern for surgical purposes. A master-slave control strategy was adopted, in which the control model was established by off line experiments. RESULTS: The in vivo visual robot system was verified by using a phantom box. The experiment results show that the robot system can successfully realize the expected functionalities and meet the demands of LESS. CONCLUSION: The experiment results indicate that the in vivo visual robot with high manipulability has great potential in clinical application. PMID- 28090747 TI - Gold(I) Carbenoids: On-Demand Access to Gold(I) Carbenes in Solution. AB - Chloromethylgold(I) complexes of phosphine, phosphite, and N-heterocyclic carbene ligands are easily synthesized by reaction of trimethylsilyldiazomethane with the corresponding gold chloride precursors. Activation of these gold(I) carbenoids with a variety of chloride scavengers promotes reactivity typical of metallocarbenes in solution, namely homocoupling to ethylene, olefin cyclopropanation, and Buchner ring expansion of benzene. PMID- 28090748 TI - Electrochemically Driven Transformation of Amorphous Carbons to Crystalline Graphite Nanoflakes: A Facile and Mild Graphitization Method. AB - Although, in the carbon family, graphite is the most thermodynamically stable allotrope, conversion of other carbon allotropes, even amorphous carbons, into graphite is extremely hard. We report a simple electrochemical route for the graphitization of amorphous carbons through cathodic polarization in molten CaCl2 at temperatures of about 1100 K, which generates porous graphite comprising petaloid nanoflakes. This nanostructured graphite allows fast and reversible intercalation/deintercalation of anions, promising a superior cathode material for batteries. In a Pyr14 TFSI ionic liquid, it exhibits a specific discharge capacity of 65 and 116 mAh g-1 at a rate of 1800 mA g-1 when charged to 5.0 and 5.25 V vs. Li/Li+ , respectively. The capacity remains fairly stable during cycling and decreases by only about 8 % when the charge/discharge rate is increased to 10000 mA g-1 during cycling between 2.25 and 5.0 V. PMID- 28090749 TI - Unconventional Coupling between Ligand Recognition and Allosteric Control in the Multidrug Resistance Gene Regulator, BmrR. AB - BmrR is a multidrug resistance (MDR) regulator that responds to diverse ligands. To obtain insight into signal recognition, allosteric control, and cooperativity, we used a quantitative in vitro transcription assay to determine the ligand dependent activation profiles for a diverse set of cations, zwitterions, and uncharged ligands. As for many other biological switch systems, the data are well described by a modified Hill equation. Parameters extracted from curve fits to the data include L50 , RMAX and N. We found that L50 values correlate directly with DeltaGBIND values, suggesting that the parameter reflects binding, whereas RMAX and N reflect allosteric control and cooperativity, respectively. Our results suggest unconventional coupling between ligand binding and allosteric control, with weakly interacting ligands exhibiting the highest levels of activation. Such properties are in stark contrast to those often exhibited by biological switch proteins, whereby ligand binding and allostery are tightly coupled, yielding both high selectivity and ultrasensitivity. We propose that weakened coupling, as observed for BmrR, may be important for providing robust activation responses to unrelated ligands. We also propose that other MDR proteins and other polyspecific switch systems will show similar features. PMID- 28090750 TI - Professionals' views on mental health service users' education: challenges and support. AB - : WHAT IS KNOWN ON THE SUBJECT?: Mental health service users (MHSUs) may experience disruptions in their education. However, education has been shown to have a positive influence on their recovery, potentially offering them broader employment opportunities. The literature suggests that providing support for MHSUs in their educational efforts may be beneficial and is wished for by the service users themselves. However, there is a lack of mental health professionals' views on the topic in the setting of a community mental health centre. WHAT DOES THIS PAPER ADD TO THE EXISTING KNOWLEDGE?: In the perception of mental health professionals, the predominance of disease in the life of MHSUs and their marginalization may form barriers to their success in education. Professionals can support MHSUs in their educational efforts by strengthening the MHSUs' internal resources and creating a supportive environment with professional expertise available. A service user-centred education might further help MHSUs to achieve their educational goals. Our findings confirm previous knowledge of a recovery-oriented approach to supporting MHSUs' education. This study explored the topic from the professionals' perspective in the context of community mental health centres, which is a fresh view in the research literature. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: The findings suggest which types of support professionals perceive to be required for MHSUs to advance their studies. Knowledge of adequate forms of support can be applied in the mental health nursing practice to develop support measures for service users to advance in their studies. All levels of the community mental health centres should be aware of and adopt a recovery-oriented approach. MHSUs and professionals need to have a shared opinion on the definition of recovery orientation. This requires mutual discussion and the more active involvement of MHSUs in the design of their own rehabilitation process. ABSTRACT: Introduction Studies show the importance of providing support for mental health service users' (MHSUs') education. However, none of these studies explored this support in the community mental health centre setting. The range of MHSUs' educational activities identified in this study varied from participation in courses at the mental health centres to independent studies at different levels of education outside the centres. Aim (1) How do mental health professionals perceive the challenges that may limit service users' potential when they apply for, and complete, their education? (2) How do the professionals describe the methods of rehabilitation aimed at supporting the service users in achieving their educational goals? Method The data were collected from 14 mental health professionals using focus group interviews. Inductive content analysis was then performed. Results Professionals perceive that the predominance of disease and marginalization may be barriers to MHSUs' success in education. Strengthening the MHSUs' internal resources, creating a supportive environment with professional expertise available and service user centred education appeared to support the MHSUs' educational achievements. Our findings confirm previous knowledge of a recovery-oriented approach to support MHSUs' education. However, professionals' views on this topic in the context of community mental health centres have not been investigated previously. Discussion Professionals perceive that a recovery-oriented approach to rehabilitation may support MHSUs in their educational efforts. Implications for practice A recovery oriented approach should be adopted by all levels of the community mental health centres. MHSUs and professionals need to have a shared opinion on the definition of recovery orientation. This requires mutual discussion and a more active involvement of MHSUs in the design of their own rehabilitation process. PMID- 28090751 TI - A Safety Checkpoint to Eliminate Cancer Risk of the Immune Evasive Cells Derived from Human Embryonic Stem Cells. AB - Human embryonic stem cells (hESCs) hold great promise in the regenerative therapy of many currently untreatable human diseases. One of the key bottlenecks is the immune rejection of hESC-derived allografts by the recipient. To overcome this challenge, we have established new approaches to induce immune protection of hESC derived allografts through the coexpression of immune suppressive molecules CTLA4 Ig and PD-L1. However, this in turn raises a safety concern of cancer risk because these hESC-derived cells can evade immune surveillance. To address this safety concern, we developed a safety checkpoint so that the immune evasive hESC derived cells in the graft can be effectively eliminated if any cellular transformation is detected. In this context, we knock-in the suicidal gene herpes simplex virus thymidine kinase (HSVTK) into the constitutive HPRT locus of CP hESCs (knock-in hESCs expressing CTLA4-Ig and PD-L1), denoted CPTK hESCs. Employing humanized mice (Hu-mice) reconstituted with human immune system, we demonstrated that the CPTK hESC-derived cells are protected from immune rejection. In addition, CPTK hESC-derived cells can be efficiently eliminated in vitro and in vivo with FDA approved TK-targeting drug ganciclovir. Therefore, this new safety checkpoint improves the feasibility to use the immune evasive hESC-derived cells for regenerative medicine. Stem Cells 2017;35:1154-1161. PMID- 28090752 TI - Urban-rural disparity and determinants of delivery care utilization in Oromia region, Ethiopia: Community-based cross-sectional study. AB - Low delivery care utilization continues to be a public health problem that significantly contributes to maternal morbidity and mortality, especially in developing countries like Ethiopia. The aim of the study is to determine the extent of urban-rural disparity of delivery care utilization and its determinants. A community-based cross-sectional quantitative study supplemented with qualitative data was conducted from February 15 to March 10, 2014. Data were collected from eligible woman using interviewer-guided semistructured questionnaires and focus group discussions. Logistic regression analysis with 95% confidence interval and p-value less than 5% was used to identify potential determinant variables. From 567 women, institutional delivery care was attended by 45.9% (260) respondents of whom 69.3% were urban and 21.3% were rural. Mass media and antenatal care attendance were the major determinants in urban respondents, whereas children ever born, partners' occupation, women's autonomy, and pregnancy-related health problems were statistically significant associations in rural women. The need for maternal health care is not met to the required level. There is a significant disparity in delivery care attendance among urban and rural women of the study area. Women's empowerment and awareness creation should be extensively worked on through mass media and posters or health information. PMID- 28090753 TI - Inferring infection hazard in wildlife populations by linking data across individual and population scales. AB - Our ability to infer unobservable disease-dynamic processes such as force of infection (infection hazard for susceptible hosts) has transformed our understanding of disease transmission mechanisms and capacity to predict disease dynamics. Conventional methods for inferring FOI estimate a time-averaged value and are based on population-level processes. Because many pathogens exhibit epidemic cycling and FOI is the result of processes acting across the scales of individuals and populations, a flexible framework that extends to epidemic dynamics and links within-host processes to FOI is needed. Specifically, within host antibody kinetics in wildlife hosts can be short-lived and produce patterns that are repeatable across individuals, suggesting individual-level antibody concentrations could be used to infer time since infection and hence FOI. Using simulations and case studies (influenza A in lesser snow geese and Yersinia pestis in coyotes), we argue that with careful experimental and surveillance design, the population-level FOI signal can be recovered from individual-level antibody kinetics, despite substantial individual-level variation. In addition to improving inference, the cross-scale quantitative antibody approach we describe can reveal insights into drivers of individual-based variation in disease response, and the role of poorly understood processes such as secondary infections, in population-level dynamics of disease. PMID- 28090754 TI - Emergence patterns of novelty in European vegetation assemblages over the past 15 000 years. AB - Plant communities are not stable over time and biological novelty is predicted to emerge due to climate change, the introduction of exotic species and land-use change. However, the rate at which this novelty may arise over longer time periods has so far received little attention. We reconstruct the emergence of novelty in Europe for a set of baseline conditions over the past 15 000 years to assess past rates of emergence and investigate underlying causes. The emergence of novelty is baseline specific and, during the early-Holocene, was mitigated by the rapid spread of plant taxa. Although novelty generally increases as a function of time, climate and human-induced landscape changes contributed to a non-linear post-glacial trajectory of novelty with jumps corresponding to periods of rapid changes. Emergence of novelty accelerated during the past 1000 years. Historical cultural landscapes experienced a faster novelty development due to the contribution from anthropogenic land-cover changes. PMID- 28090755 TI - Mythology and reality should never be confused (but often are). PMID- 28090756 TI - Correlating spinal cord injuries with neurogenic bladder pathophysiology. PMID- 28090757 TI - Synergistic effects in combinational drug delivery and thermal ablation using nanotechnology. PMID- 28090758 TI - Bringing clarity or confusion? The role of prostate-specific membrane antigen positron-emission/computed tomography for primary staging in prostate cancer. PMID- 28090759 TI - Raising the bar for systematic reviews with Assessment of Multiple Systematic Reviews (AMSTAR). PMID- 28090760 TI - Expression patterns of cardiac aging in Drosophila. AB - Aging causes cardiac dysfunction, often leading to heart failure and death. The molecular basis of age-associated changes in cardiac structure and function is largely unknown. The fruit fly, Drosophila melanogaster, is well-suited to investigate the genetics of cardiac aging. Flies age rapidly over the course of weeks, benefit from many tools to easily manipulate their genome, and their heart has significant genetic and phenotypic similarities to the human heart. Here, we performed a cardiac-specific gene expression study on aging Drosophila and carried out a comparative meta-analysis with published rodent data. Pathway level transcriptome comparisons suggest that age-related, extra-cellular matrix remodeling and alterations in mitochondrial metabolism, protein handling, and contractile functions are conserved between Drosophila and rodent hearts. However, expression of only a few individual genes similarly changed over time between and even within species. We also examined gene expression in single fly hearts and found significant variability as has been reported in rodents. We propose that individuals may arrive at similar cardiac aging phenotypes via dissimilar transcriptional changes, including those in transcription factors and micro-RNAs. Finally, our data suggest the transcription factor Odd-skipped, which is essential for normal heart development, is also a crucial regulator of cardiac aging. PMID- 28090761 TI - Modest overexpression of FOXO maintains cardiac proteostasis and ameliorates age associated functional decline. AB - Heart performance declines with age. Impaired protein quality control (PQC), due to reduced ubiquitin-proteasome system (UPS) activity, autophagic function, and/or chaperone-mediated protein refolding, contributes to cardiac deterioration. The transcription factor FOXO participates in regulating genes involved in PQC, senescence, and numerous other processes. Here, a comprehensive approach, involving molecular genetics, novel assays to probe insect cardiac physiology, and bioinformatics, was utilized to investigate the influence of heart-restricted manipulation of dFOXO expression in the rapidly aging Drosophila melanogaster model. Modest dFOXO overexpression was cardioprotective, ameliorating nonpathological functional decline with age. This was accompanied by increased expression of genes associated predominantly with the UPS, relative to other PQC components, which was validated by a significant decrease in ubiquitinated proteins. RNAi knockdown of UPS candidates accordingly compromised myocardial physiology in young flies. Conversely, excessive dFOXO overexpression or suppression proved detrimental to heart function and/or organismal development. This study highlights D. melanogaster as a model of cardiac aging and FOXO as a tightly regulated mediator of proteostasis and heart performance over time. PMID- 28090762 TI - Use of ACE inhibition and blood pressure management in deferring dialysis initiation. AB - Elevated blood pressure is one of the most significant risk factor for the development of chronic kidney disease (CKD); its treatment is a milestone in CKD management. While it is accepted that a stricter blood pressure control is indicated in patients with proteinuria or microalbuminuria, the exact degree of blood pressure reduction to be obtained in CKD patients is still under debate. Following more recent interpretation of old trials, a BP target for <140/90 mmHg is suggested for non-proteinuric CKD patients. In those with microalbuminuria/proteinuria, the ideal blood pressure target should be <=130/80 mmHg. Recently, the SPRINT trial put new emphasis on a stricter blood pressure control, mainly from the cardiovascular point of view. The blockers of the renin angiotensin system (RAS) are recommended as first line treatment in all CKD hypertensive patients with micro or macroalbuminuria either diabetics or not. However, their nephroprotective efficacy is less relevant in non-proteinuric patients. The dual RAS blockade was proposed as an additional option. Despite a greater antiproteinuric effect, some large trials in patients at high cardiovascular risk did not demonstrate significant advantage on hard endpoint. Its use is now contraindicated in diabetic CKD patients. Given that RAS blockers can cause acute derangements in kidney function and hyperkalemia, caution is needed with their use, especially in frail and old patients with cardiovascular disease or in the presence of advanced CKD. PMID- 28090763 TI - Sodium and fluid management in the conservative management of chronic kidney disease. AB - Chronic kidney disease (CKD) imposes a significant global health burden. In the United States, one in three adults are at risk for CKD currently affecting over 28 million Americans. While several studies have demonstrated the benefit of treating traditional risk factors in CKD, including hypertension with pharmacologic agents such as blockade of the renin-angiotensin system (RAAS), there is scarce data on the advantages of sodium and fluid management in this population. Both experimental and observational studies have shown improvement in hypertension and cardiovascular outcomes with sodium restriction to <=2.3 grams per day, however, to date there are very few randomized controlled trials demonstrating a benefit in sodium reduction for the prevention or progression of CKD. Similarly, studies on increasing fluid consumption have shown to be advantageous in polycystic kidney disease as well as chronic nephrolithiasis, yet no randomized controlled trials exist on the fluid management in patients with kidney disease. This review aims to explore the evidence of sodium restriction and fluid management in the CKD population as well as underlying mechanisms and clinical barriers of sodium and water management as conservative therapy. PMID- 28090765 TI - Aggregation Kinetics of Diesel Soot Nanoparticles in Wet Environments. AB - Soot produced during incomplete combustion consists mainly of carbonaceous nanoparticles (NPs) with severe adverse environmental and health effects, and its environmental fate and transport are largely controlled by aggregation. In this study, we examined the aggregation behavior for diesel soot NPs under aqueous condition in an effort to elucidate the fundamental processes that govern soot particle-particle interactions in wet environments such as rain droplets or surface aquatic systems. The influence of electrolytes and aqueous pH on colloidal stability of these NPs was investigated by measuring their aggregation kinetics in different aqueous solution chemistries. The results showed that the NPs had negatively charged surfaces and exhibited both reaction- and diffusion limited aggregation regimes with rates depended upon solution chemistry. The aggregation kinetics data were in good agreement with the classic Derjaguin Landau-Verwey-Overbeek (DLVO) theory. The critical coagulation concentrations (CCC) were quantified and the Hamaker constant was derived for the soot (1.4 * 10 20 J) using the colloidal chemistry approach. The study indicated that, depending upon local aqueous chemistry, single soot NPs could remain stable against self aggregation in typical freshwater environments and in neutral cloud droplets but are likely to aggregate under salty (e.g., estuaries) or acidic (e.g., acid rain droplets) aquatic conditions or both. PMID- 28090764 TI - Incremental and infrequent hemodialysis: a new paradigm for both dialysis initiation and conservative management. AB - Registry or national dialysis data show that a sizeable proportion of contemporary dialysis patients have substantial levels of residual kidney function especially upon transitioning to dialysis therapy. However, among incident hemodialysis patients, the prevailing paradigm has been to initiate "full-dose" triweekly treatment schedules irrespective of native kidney function in most developed countries. Recognizing the benefits of residual kidney function upon the health and survival of dialysis patients, there has been growing interest in incremental hemodialysis, in which dialysis frequency and dose are tailored according to the degree of patients' residual kidney function. Infrequent hemodialysis can also be used for those who prefer a more conservative approach in managing uremia. Clinical practice guidelines support the use of twice-weekly hemodialysis among patients with adequate residual kidney function (renal urea clearance >3 mL/min/1.73 m2), and a growing body of evidence indicates that incremental hemodialysis is associated with better preservation of residual kidney function without adversely impacting survival. Nonetheless, incremental hemodialysis remains an underutilized approach in this population. In this review, we will discuss the history of the twice- versus triweekly hemodialysis schedules; current clinical practice guidelines regarding infrequent hemodialysis; emerging data on incremental treatment regimens and outcomes; and guidelines for the practical implementation of incremental and infrequent hemodialysis in the clinical setting. PMID- 28090766 TI - Gas Diffusion Barriers Prepared by Spatial Atmospheric Pressure Plasma Enhanced ALD. AB - In this work, we report on aluminum oxide (Al2O3) gas permeation barriers prepared by spatial ALD (SALD) at atmospheric pressure. We compare the growth characteristics and layer properties using trimethylaluminum (TMA) in combination with an Ar/O2 remote atmospheric pressure plasma for different substrate velocities and different temperatures. The resulting Al2O3 films show ultralow water vapor transmission rates (WVTR) on the order of 10-6 gm-2d-1. In notable contrast, plasma based layers already show good barrier properties at low deposition temperatures (75 degrees C), while water based processes require a growth temperature above 100 degrees C to achieve equally low WVTRs. The activation energy for the water permeation mechanism was determined to be 62 kJ/mol. PMID- 28090768 TI - Tunneling Control: Competition between 6pi-Electrocyclization and [1,5]H Sigmatropic Shift Reactions in Tetrahydro-1H-cyclobuta[e]indene Derivatives. AB - Direct dynamics calculation using canonical variational transtition state theory (CVT) inclusive of small curvature tunneling (SCT) reveals the influential role of quantum mechanical tunneling (QMT) for 2,2a,5,7b-tetrahydro-1H cyclobuta[e]indene derivatives (2a-2j) in governing their product selectivity. 2a 2j follow two distinct reaction channels, namely, 6pi-electrocyclization (2 -> 3) and [1,5]H-sigmatropic shift (2 -> 4), among which the activation barrier is higher for [1,5]H-shift (2 -> 4), thereby favoring the kinetically controlled product (3a-3j) as anticipated. However, SCT calculations show that a narrower barrier and smaller mass of participating atoms make QMT more pronounced for [1,5]H-shift reaction despite its higher activation energy, which results in a competition between kinetic controlled (2 -> 3) and tunneling controlled (2 -> 4) products. At low temperature (T <= 170 K), when QMT is the dominant pathway, the tunneling controlled product (4a-4j) is formed exclusively. As the reaction temperature increases, the role of QMT becomes less prominent and eventually gets kinetically controlled at room temperature. Nevertheless, QMT strongly tunes the product ratio at ambient temperatures by favoring the [1,5]H-shift reaction over 6pi-electrocyclization. For 2a, k[1,5]H-shift:k6pi-electrocyclization increases from 1:13 at CVT level to 1:2 at CVT+SCT level for room temperature. PMID- 28090767 TI - Design of a Hole Trapping Ligand. AB - A new ligand that covalently attaches to the surface of colloidal CdSe/CdS nanorods and can simultaneously chelate a molecular metal center is described. The dithiocarbamate-bipyridine ligand system facilitates hole transfer through energetic overlap at the inorganic-organic interface and conjugation through the organic ligand to a chelated metal center. Density functional theory calculations show that the coordination of the free ligand to a CdS surface causes the formation of two hybridized molecular states that lie in the band gap of CdS. The further chelation of Fe(II) to the bipyridine moiety causes the presence of seven midgap states. Hole transfer from the CdS valence band to the midgap states is dipole allowed and occurs at a faster rate than what is experimentally known for the CdSe/CdS band-edge radiative recombination. In the case of the ligand bound with iron, a two-step process emerges that places the hole on the iron, again at rates much faster than band gap recombination. The system was experimentally assembled and characterized via UV-vis absorbance spectroscopy, fluorescence spectroscopy, time-resolved photoluminescence spectroscopy, and energy dispersive X-ray spectroscopy. Theoretically predicted red shifts in absorbance were observed experimentally, as well as the expected quench in photoluminescence and lifetimes in time-resolved photoluminescence. PMID- 28090769 TI - Synthesis of 1-Thio-Substituted Isoquinoline Derivatives by Tandem Cyclization of Isothiocyanates. AB - A copper-catalyzed tandem arylation-cyclization process to access 1 (arylthio)isoquinolines from isothiocyanates and diaryliodonium salts is described. It is the first general method to construct the potentially useful 1 (arylthio)isoquinoline derivatives. Moreover, 1-(methylthio)isoquinoline derivatives were also achieved successfully with MeOTf instead of diaryliodonium salts under metal-free conditions. Mechanistic studies reveal that these two processes proceed in different routes. This method has been successfully applied to the synthesis of quinazolinone alkaloid rutaecarpine. PMID- 28090770 TI - Highly Oriented SrTiO3 Thin Film on Graphene Substrate. AB - Growth of perovskite oxide thin films on Si in crystalline form has long been a critical obstacle for the integration of multifunctional oxides into Si-based technologies. In this study, we propose pulsed laser deposition of a crystalline SrTiO3 thin film on a Si using graphene substrate. The SrTiO3 thin film on graphene has a highly (00l)-oriented crystalline structure which results from the partial epitaxy. Moreover, graphene promotes a sharp interface by highly suppressing the chemical intermixing. The important role of graphene as a 2D substrate and diffusion barrier allows the expansion of device applications based on functional complex oxides. PMID- 28090771 TI - Differential Adhesive and Bioactive Properties of the Polymeric Surface Coated with Graphene Oxide Thin Film. AB - Surface engineering of implantable devices involving polymeric biomaterials has become an essential aspect for medical implants. A surface enhancement technique can provide an array of unique surface properties that improve its biocompatibility and functionality as an implant. Polyurethane-based implants that have found extensively acclaimed usage as an implant in biomedical applications, especially in the area of cardiovascular devices, still lack any mechanism to ward off bacterial or platelet adhesion. To bring out such a defense mechanism we are proposing a surface modification technique. Graphene oxide (GO) in very thin film form was wrapped onto the electrospun fibroporous polycarbonate urethane (PCU) membrane (GOPCU) by a simple method of electrospraying. In the present study, we have developed a simple single-step method for coating a polymeric substrate with a thin GO film and evaluated the novel antiadhesive activity of these films. SEM micrographs after coating showed the presence of very thin GO films over the PCU membrane. On the GOPCU surface, the contact angle was shifted by ~30 degrees , making the hydrophobic PCU surface slightly hydrophilic, while Raman spectral characterization and mapping showed the presence and distribution of GO over 75% of the membrane. A reduced platelet adhesion on the GOPCU surface was observed; meanwhile, bacterial adhesion also got reduced by 85% for Staphylococcus aureus (Gram positive, cocci) and 64% for Pseudomonas aeruginosa (Gram negative, bacilli). A cell adhesion study conducted using mammalian fibroblast cells projected its proliferation percentage in a MTT assay, with 82% cell survival on PCU and 86% on GOPCU after 24 h culture, while a study for an extended period of 72 h showed 87% of survival on PCU and 88% on GOPCU. This plethora of functionalities by a simple modification technique makes thin GO films a self-sufficient surface engineering material for future biomedical applications. PMID- 28090772 TI - Controlled Growth of 1D MoSe2 Nanoribbons with Spatially Modulated Edge States. AB - Two-dimensional (2D) transition metal dichalcogenides (TMDCs) possess interesting one-dimensional (1D) properties at its edges and inversion domain boundaries, where properties markedly different from the 2D basal plane, such as 1D metallicity and charge density waves, can be observed. Although 2D TMDCs crystals are widely grown by chemical vapor deposition (CVD), the fabrication of 1D TMDCs ribbons is challenging due to the difficulty to confine growth in only one dimension. Here we report the controlled growth of MoSe2 nanoribbons with an aspect ratio >100 by using prepatterned Se reconstructions on Au(100). Using scanning tunneling microscope and spectroscopy (STM/STS), the atomic and electronic structure of MoSe2 nanoribbons are studied. The ultranarrow ribbons show metallic behavior, while wider ribbons show a crossover from metallic to semiconducting behavior going from the edge to the center of the ribbon. The observed conductance modulations of the ultranarrow ribbons are attributed to 1D Moire pattern. Remarkably, it shows a different periodicity compared with the 2D Moire pattern in wider ribbons indicating that the 1D system is softened due to the high ratio of edge to basal plane bonds. Further, we demonstrated that the nanoribbons are stable against ambient conditions, which suggests that 1D TMDCs can be exploited for further applications. PMID- 28090773 TI - Protein Nanoparticle Formation Using a Circularly Permuted alpha-Helix-Rich Trimeric Protein. AB - We here report the production of highly spherical protein nanoparticles based on the domain-swapping oligomerization of a circularly permuted trimeric protein, major histocompatibility complex (MHC) class II associated chaperonin. The size distribution of the nanoparticles can be adjusted to between 40 and 100 nm in diameter, and thus, these particles are suitable as drug carriers following purification under basic conditions. Our approach involves no harsh treatments and could provide an alternative approach for protein nanoparticle formation. PMID- 28090775 TI - Reaction of Push-Pull Enaminoketones and in Situ Generated ortho-Quinone Methides: Synthesis of 3-Acyl-4H-chromenes and 2-Acyl-1H-benzo[f]chromenes as Precursors for Hydroxybenzylated Heterocycles. AB - A simple and efficient method for the synthesis of 4H-chromenes and 1H benzo[f]chromenes containing a trifluoroacetyl or aroyl group in the pyran ring from o-quinone methide precursors and push-pull enaminoketones has been developed. The chromenes are presumably formed through an initial oxa-Diels-Alder reaction, followed by an elimination of amine. The possibility of further transformations of given chromenes to o-hydroxybenzylated pyrazoles, isoxazoles, and pyridines has been demonstrated. PMID- 28090774 TI - Biakamides A-D, Unique Polyketides from a Marine Sponge, Act as Selective Growth Inhibitors of Tumor Cells Adapted to Nutrient Starvation. AB - Biakamides A-D, novel unusually unique polyketides, were isolated from an Indonesian marine sponge (Petrosaspongia sp.) with a constructed bioassay using PANC-1 human pancreatic cancer cells. Through detailed analyses of the one- and two-dimensional NMR spectra of biakamides, planar chemical structures possessing a terminal thiazole, two N-methyl amides, a chloromethylene, and a substituted butyryl moiety were obtained. After elucidation of the configuration of the secondary alcohol moiety in biakamides A and B, the absolute stereostructures of the two secondary methyl groups in biakamides A-D were determined by the asymmetric total syntheses of all possible stereoisomers from the optically pure monoprotected 2,4-dimethyl-1,5-diol. Biakamides A-D showed selective antiproliferative activities against PANC-1 cells cultured under glucose deficient conditions in a concentration-dependent manner. The primary mode of action of biakamides was found to be inhibition of complex I in the mitochondrial electron transport chain. PMID- 28090776 TI - Plasmonic Perovskite Light-Emitting Diodes Based on the Ag-CsPbBr3 System. AB - The enhanced luminescence through semiconductor-metal interactions suggests the great potential of device performance improvement via properly tailored plasmonic nanostructures. Surface plasmon enhanced electroluminescence in an all-inorganic CsPbBr3 perovskite light-emitting diode (LED) is fabricated by decorating the hole transport layer with the synthesized Ag nanorods. An increase of 42% and 43.3% in the luminance and efficiency is demonstrated for devices incorporated with Ag nanorods. The device with Ag introduction indicates identical optoelectronic properties to the controlled device without Ag nanostructures. The increased spontaneous emission rate caused by the Ag-induced plasmonic near-field effect is responsible for the performance enhancement. Therefore, the plasmonic Ag-CsPbBr3 nanostructure studied here provides a novel strategy on the road to the future development of perovskite LEDs. PMID- 28090777 TI - Biodegradable Neuro-Compatible Peptide Hydrogel Promotes Neurite Outgrowth, Shows Significant Neuroprotection, and Delivers Anti-Alzheimer Drug. AB - A novel neuro-compatible peptide-based hydrogel has been designed and developed, which contains microtubule stabilizing and neuroprotective short peptide. This hydrogel shows strong three-dimensional cross-linked fibrillary networks, which can capture water molecules. Interestingly, this hydrogel serves as excellent biocompatible soft material for 2D and 3D (neurosphere) neuron cell culture and provides stability of key cytoskeleton filaments such as microtubule and actin. Remarkably, it was observed that this hydrogel slowly enzymatically degrades and releases neuroprotective peptide, which promotes neurite outgrowth of neuron cell as well as exhibits excellent neuroprotection against anti-NGF-induced toxicity in neuron cells. Further, it can encapsulate anti-Alzheimer and anticancer hydrophobic drug curcumin, releases slowly, and inhibits significantly the growth of a 3D spheroid of neuron cancer cells. Thus, this novel neuroprotective hydrogel can be used for both neuronal cell transplantation for repairing brain damage as well as a delivery vehicle for neuroprotective agents, anti-Alzheimer, and anticancer molecules. PMID- 28090778 TI - Three Novel Spectrin Variants in Jaundiced Neonates. AB - Various mutations in the genes encoding alpha spectrin (SPTA1) or beta spectrin (SPTB) are known to cause erythrocyte membrane disorders, sometimes associated with severe neonatal jaundice and anemia. We used a next-generation sequencing panel to evaluate 3 unrelated neonates who had puzzling cases of nonimmune hemolytic jaundice. In each case, we identified novel mutations in either SPTA1 or SPTB. Correlating erythrocyte morphology, clinical course, and computational analysis, we submit that each of the 3 variants is a probable pathogenic cause of the hereditary hemolytic conditions in these patients. We hope other pediatric practitioners caring for neonates with what appears to be idiopathic severe neonatal hyperbilirubinemia will look for spectrin variants as a possible cause, because additional cases with these specific variants along with this clinical phenotype are needed to confirm our postulate that these 3 cases are indeed pathogenic mutations. PMID- 28090779 TI - Preparation and in vitro/in vivo evaluation of metformin hydrochloride rectal dosage forms for treatment of patients with type II diabetes. AB - BACKGROUND: Metformin hydrochloride (MtHCL) is an oral antidiabetic drug and has many other therapeutic benefits. It has poor bioavailability, narrow absorption window and extensive liver metabolism. Moreover, children and elders face difficulty to swallow the commercial oral tablets. OBJECTIVES: Preparation, in vitro/in vivo evaluation of MtHCL suppositories for rectal administration to solve some of these problems. METHODS: Suppository fatty bases (Witepsol(r), Suppocire(r) and Massa(r); different grades) and PEG bases 1000, 4000 and 6000 (different ratios), were used to prepare rectal suppository formulations each containing 500 mg drug. These were characterized for manufacturing defects, and pharmacotechnical performance and formulations showing superior results were subjected to bioavailability testing in human volunteers compared with the commercial oral tablet (Ref) applying LC-MS/MS developed analytical technique. RESULTS: The preparation method produced suppositories with satisfactory characteristics and free of manufacturing defects. The fatty bases were superior compared with PEG bases regarding the physical characteristics. Three formulations were chosen for bioavailability testing and the results showed comparable bioavailability compared to the Ref. CONCLUSIONS: The fatty bases showed superior characteristics compared with the PEG bases. MtHCL formulated in selected fatty bases could be a potential alternative to the commercial oral tablets particularly for pediatric and geriatric patients. PMID- 28090780 TI - A multi-body dynamics study on a weight-drop test of rat brain injury. AB - Traumatic brain injury (TBI), induced by impact of an object with the head, is a major health problem worldwide. Rats are a well-established animal analogue for study of TBI and the weight-drop impact-acceleration (WDIA) method is a well established model in rats for creating diffuse TBI, the most common form of TBI seen in humans. However, little is known of the biomechanics of the WDIA method and, to address this, we have developed a four-degrees-of-freedom multi-body mass spring-damper model for the WDIA test in rats. An analytical expression of the maximum skull acceleration, one of the important head injury predictor, was derived and it shows that the maximum skull acceleration is proportional to the impact velocity but independent of the impactor mass. Furthermore, a dimensional analysis disclosed that the maximum force on the brain and maximum relative displacement between brain and skull are also linearly proportional to impact velocity. Additionally, the effects of the impactor mass were examined through a parametric study from the developed multi-body dynamics model. It was found that increasing impactor mass increased these two brain injury predictors. PMID- 28090781 TI - Possible role of central interleukins on the anorexigenic effect of lipopolysaccharide in chicks. AB - 1. The purpose of the present study was to determine if central interleukin-1beta (IL1beta), interleukin-6 (IL6) and interleukin-8 (IL8) affect feeding behaviour in chicks (Gallus gallus) and examine if central interleukins are related to the lipopolysaccharide (LPS)-induced anorexia. 2. Intra-abdominal (IA) injection of LPS significantly suppressed feeding behaviour and significantly increased mRNA expression of IL1beta and IL8 in the diencephalon when compared to the control group, while IL6 tended to be increased. 3. Intracerebroventricular (ICV) injection of 200 ng IL1beta significantly decreased food intake at 60 min after the injection while IL6 and IL8 had no effect. 4. IA injection of these ILs (200 ng) had no effect on food intake in chicks. 5. ICV injection of 200 ng IL1beta did not affect water intake and plasma corticosterone concentration, suggesting that central IL1beta might not be related to the regulation of drinking behaviour and the hypothalamus-pituitary-adrenal axis. 6. The present study demonstrated that central IL1beta but not IL6 and IL8 might be related to the inhibition of feeding in chicks. PMID- 28090782 TI - Emil Fischer and the "art of chemical experimentation". AB - What did nineteenth-century chemists know? This essay uses Emil Fischer's classic study of the sugars in 1880s and 90s Germany to argue that chemists' knowledge was not primarily vested in the theories of valence, structure, and stereochemistry that have been the subject of so much historical and philosophical analysis of chemistry in this period. Nor can chemistry be reduced to a merely manipulative exercise requiring little or no intellectual input. Examining what chemists themselves termed the "art of chemical experimentation" reveals chemical practice as inseparable from its cognitive component, and it explains how chemists integrated theory with experiment through reason. PMID- 28090783 TI - Probing the druggability of membrane-bound Rab5 by molecular dynamics simulations. AB - Rab5 is a small GTPase and a key regulator in early endosomal trafficking. Rab5 and its effectors are involved in a large number of infectious diseases and certain types of cancer. We performed us atomistic molecular dynamics simulations of inactive and active full-length Rab5 anchored to a complex model bilayer with composition of the early endosome membrane. Direct interactions between the Rab5 G domain and the bilayer were observed. We found two dominant nucleotide dependent orientations characterised by a different accessibility of the switch regions. The "buried switch" orientation was mainly associated with inactive Rab5 accompanied with a rather extended structure of the hypervariable C-terminal region. Active Rab5 preferred an orientation in which the switch regions are accessible to effector proteins. These structural differences may provide an opportunity to selectively target one Rab5 state and lead to new approaches in the development of Rab5-specific therapies. PMID- 28090784 TI - Effect of resveratrol and tetracycline on the subacute paraquat toxicity in mice. AB - Paraquat (PQ) is a nonselective bipyridyl herbicide widely used in agriculture to control weeds, but its accidental, occupational, or intentional exposure in humans is known to cause pneumo- and neurotoxicity which may proves fatal. Oxidative stress is reported as an underlined mechanism of PQ-induced toxicity in alveolar cells, neurons, and astroglia. PQ generates superoxides both through electron transport reaction (ETC) with nicotinamide adenine dinucleotide dependent oxidoreductase and by the redox cycling via reaction with molecular oxygen. In lungs, it causes edema and inflammation resulting in neutrophils infiltration and subsequent activation of pro-inflammatory cytokines. In the present study, toxicity of subacute oral PQ exposure and effect of resveratrol (Res) and/or tetracycline (TC) on oxidative stress and inflammatory markers in lungs, brain, and liver was studied. Levels of glutathione and malondialdehyde and activities of myeloperoxidase, glutathione peroxidase, and catalase were measured in lungs, brain, and liver. PQ interferes in the function of mitochondrial ETC complexes causing decreased adenosine triphosphate levels, and hence the activities of complexes I and IV were studied in brain tissues. Res, a natural antioxidant, and TC, an antibiotic with its antimicrobial and anti inflammatory properties, offered significant protection from severe oxidative stress and inflammation and ameliorated the general well-being of mice against the toxic outcome of PQ. PMID- 28090785 TI - Thymic cytoarchitecture changes in mice exposed to vanadium. AB - The thymus is a vital immune system organ wherein selection of T-lymphocytes occurs in a process regulated by dendritic and epithelial thymic cells. Previously, we have reported that in a mouse model of vanadium inhalation, a decrease in CD11c dendritic cells was observed. In the present study, we report on a thymic cortex-medulla distribution distortion in these hosts due to apparent effects of the inhaled vanadium on cytokeratin-5 (K5+) epithelial cells in the same mouse model - after 1, 2, and 4 weeks of exposure - by immunohistochemistry. These cells - together with dendritic cells - eliminate autoreactive T-cell clones and regulate the production of regulatory T-cells in situ. Because both cell types are involved in the negative selection of autoreactive clones, a potential for an increase in development of autoimmune conditions could be a possible consequence among individuals who might be exposed often to vanadium in air pollution, including dwellers of highly polluted cities with elevated levels of particulate matter onto which vanadium is often adsorbed. PMID- 28090786 TI - Inorganic nitrite modulates miRNA signatures in acute myocardial in vivo ischemia/reperfusion. AB - Acute myocardial infarction is the leading cause of mortality in the industrialized world. While it is essential to attempt an early reperfusion of ischemic myocardial territories, reperfusion itself adds damage to the heart, the ischemia-reperfusion (I/R) injury. Particularly the injury resulting from the very first minutes of reperfusion remains incompletely understood. MicroRNAs (miRNAs) are dynamic regulators in I/R injury. Nitric oxide (*NO) signaling, in turn, interacts with miRNA signaling. Our previous investigations showed that *NO signaling in I/R could be modulated by nitrite. We therefore sought to investigate the role of miRNAs in nitrite cardioprotection with focus on the first few minutes of reperfusion. The study was conducted in mice in vivo with 30 min of ischemia and 5 min of reperfusion. Mice received a single-dose of nitrite or saline intracardially 5 min prior to reperfusion. We identified nine miRNAs to be up-regulated after 5 min of reperfusion. The up-regulation of almost half of those miRNAs (miR-125a-5p, miR-146b, miR-339-3p, miR-433) was inhibited by nitrite treatment, perpetuating baseline values. In silico analysis revealed the Irak-M gene to be a target of miR-146b and miR-339-3p. Correspondingly, a rise in Irak-M transcript and protein levels occurred by nitrite treatment within the early phase of reperfusion. The results demonstrate that already a very short phase of reperfusion is sufficient for significant dysregulation in cardiac miRNAs expression and that nitrite preserves baseline values of miRNAs in the scale of only a few minutes. These findings hint at a potential novel cardioprotective mechanism of nitrite signaling. PMID- 28090787 TI - Carbonic anhydrase from Apis mellifera: purification and inhibition by pesticides. AB - Carbonic anhydrase (CA) enzymes have been shown to play an important role in ion transport and in pH regulation in several organisms. Despite this information and the wealth of knowledge regarding the significance of CA enzymes, few studies have been reported about bee CA enzymes and the hazardous effects of chemicals. Using Apis mellifera as a model, this study aimed to determine the risk of pesticides on Apis mellifera Carbonic anhydrase enzyme (Am CA). CA was initially purified from Apis mellifera spermatheca for the first time in the literature. The enzyme was purified with an overall purification of ~35-fold with a molecular weight of ~32 kDa. The enzyme was then exposed to pesticides, including tebuconazole, propoxur, carbaryl, carbofuran, simazine and atrazine. The six pesticides dose-dependently inhibited in vitro AmCA activity at low micromolar concentrations. IC50 values for the pesticides were 0.0030, 0.0321, 0.0031, 0.0087, 0.0273 and 0.0165 MUM, respectively. The AmCA inhibition mechanism of these compounds is unknown at this moment. PMID- 28090788 TI - Selection of suitable reference genes for quantitative real-time PCR in trabecular meshwork cells under oxidative stress. AB - Oxidative stress-induced dysfunction in trabecular meshwork (TM) cells is considered a major alteration that can lead to glaucoma. Hydrogen peroxide (H2O2) is the most widely used agent for inducing oxidation in TM cells in vitro. Quantitative real-time PCR (qPCR) is an important method for studying alterations in gene expression, and suitable (i.e. invariant) reference genes must be defined to normalize expression levels. In this study, eight common reference genes, i.e. PRS18, ACTB, B2M, GAPDH, PPIA, HPRT1, YWHAZ, and TBP, were evaluated for use in studies of H2O2-induced dysfunction in TM cells. Three established algorithms, geNorm, NormFinder, and BestKeeper, were used to analyze the reference genes. ACTB expression was least affected by H2O2 treatment in TM cells, and the combination of PPIA and HPRT1 was the most suitable gene pair for normalization. GAPDH and TBP were the most unstable genes and accordingly should be avoided in experiments with TM cells. These results provide a foundation for analyses of the mechanisms underlying glaucoma, and emphasize the importance of selecting suitable reference genes for qPCR studies. PMID- 28090789 TI - Escalating Mental Health Care in Pediatric Emergency Departments. PMID- 28090791 TI - Additive value of "otosclerosis-weighted" images for the CT diagnosis of fenestral otosclerosis. AB - Background Otosclerotic foci are usually seen as minute low-density lesions and this may be attributed to relatively low sensitivity on visual assessment using computed tomography (CT). Otosclerotic foci can be detected by using the accurate region of interest (ROI) setting, while small ROI settings by less-experienced radiologists may result in false negative findings. Purpose To evaluate the diagnostic ability of our proposed method ("otosclerosis-weighted" imaging [OWI]), which is based on reversing the density, compared with conventional CT (CCT) imaging alone. Material and Methods Temporal bone CTs of consecutive patients with otosclerosis were analyzed. Gender- and age-matched control participants were also included. All CT images were obtained using a 64-detector row scanner. OWI was obtained by extracting the temporal bone region using the threshold technique and reversing the density (black to white). Four independent radiologists took part in two reading sessions. In the first session, the observers read only CCT imaging. In the second session, they read OWI along with the CCT imaging. Sensitivity was assessed for the four readers. Results Thirty temporal bones of 25 patients with otosclerosis (3 men, 22 women; mean age, 53.9 +/- 9.0 years) and 30 temporal bones of 30 control participants (4 men, 26 women; mean age, 44.0 +/- 16.2 years) were included. For all observers, reading with a combination of the two methods was associated with a higher sensitivity (63.3 80.0%) than with conventional CT images alone (30.0-60.0%; P < 0.05, each). Conclusion Application of our proposed method based on threshold value may help detect foci of fenestral otosclerosis. PMID- 28090792 TI - Cerebral schistosomiasis: diffusion-weighted imaging helps to differentiate from brain glioma and metastasis. AB - Background Diffusion-weighted imaging (DWI) was introduced into clinical use some years ago. However, its use in the diagnosis of cerebral schistosomiasis has not been reported. Purpose To investigate the ability of the apparent diffusion coefficient (ADC) value of DWI in the diagnosis of cerebral schistosomiasis, and to differentiate it from brain high-grade gliomas and metastasis. Material and Methods Conventional brain MRI with pre-contrast, post-contrast, and DWI was performed on 50 cases of cerebral schistosomiasis, high-grade glioma, and brain metastasis. The ADC values of the three lesions, the proximal and the distal perifocal edema were measured. In order to remove the individual difference effect of ADC values, relative ADC (rADC) values were calculated through dividing the ADC value of the lesion area by that of the contralateral normal white matter. rADC values were used to evaluate the differences among cerebral schistosomiasis, brain high-grade gliomas, and metastasis. Results rADC of cerebral schistosomiasis was significantly lower than rADC of brain metastasis ( P < 0.05), without any significant differences when compared with high-grade gliomas. rADC of proximal perifocal edema in cerebral schistosomiasis was significantly higher than in high-grade gliomas ( P < 0.010), but not different compared with brain metastasis. Conclusion DWI examination with ADC values of lesions and proximal perifocal edema might be helpful in the exact diagnosis of cerebral schistosomiasis. PMID- 28090790 TI - Loss of Interneuron-Derived Collagen XIX Leads to a Reduction in Perineuronal Nets in the Mammalian Telencephalon. AB - Perineuronal nets (PNNs) are lattice-like supramolecular assemblies of extracellular glycoproteins that surround subsets of neuronal cell bodies in the mammalian telencephalon. PNNs emerge at the end of the critical period of brain development, limit neuronal plasticity in the adult brain, and are lost in a variety of complex brain disorders diseases, including schizophrenia. The link between PNNs and schizophrenia led us to question whether neuronally expressed extracellular matrix (ECM) molecules associated with schizophrenia contribute to the assembly of these specialized supramolecular ECM assemblies. We focused on collagen XIX-a minor, nonfibrillar collagen expressed by subsets of telencephalic interneurons. Genetic alterations in the region encoding collagen XIX have been associated with familial schizophrenia, and loss of this collagen in mice results in altered inhibitory synapses, seizures, and the acquisition of schizophrenia related behaviors. Here, we demonstrate that loss of collagen XIX also results in a reduction of telencephalic PNNs. Loss of PNNs was accompanied with reduced levels of aggrecan (Acan), a major component of PNNs. Despite reduced levels of PNN constituents in collagen XIX-deficient mice ( col19a1-/-), we failed to detect reduced expression of genes encoding these ECM molecules. Instead, we discovered a widespread upregulation of extracellular proteases capable of cleaving Acan and other PNN constituents in col19a1-/- brains. Taken together, these results suggest a mechanism by which the loss of collagen XIX speeds PNN degradation and they identify a novel mechanism by which the loss of collagen XIX may contribute to complex brain disorders. PMID- 28090793 TI - Development and validation of a predictor of insufficient enhancement during the hepatobiliary phase of Gd-EOB-DTPA-enhanced magnetic resonance imaging. AB - Background Insufficient enhancement of liver parenchyma negatively affects diagnostic accuracy of Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI). Currently, there is no reliable method for predicting insufficient enhancement during the hepatobiliary phase (HBP) in Gd-EOB-DTPA-enhanced MRI. Purpose To develop a predictor for insufficient enhancement of liver parenchyma during HBP in Gd-EOB-DTPA-enhanced MRI. Material and Methods In order to formulate a HBP enhancement test (HBP-ET), clinical factors associated with relative enhancement ratio (RER) of liver parenchyma were retrospectively determined from the datasets of 156 patients (Development group) who underwent Gd-EOB-DTPA-enhanced MRI between November 2012 and May 2015. The independent clinical factors were identified by Pearson's correlation and multiple stepwise regression analysis; the performance of HBP-ET was compared to Child-Pugh score (CPS), Model for End stage Liver Disease score (MELD), and total bilirubin (TBIL) using receiver operating characteristic (ROC) curve analysis. The datasets of 52 patients (Validation group), which were examined between June 2015 and Oct 2015, were applied to validate the HBP-ET. Results Six biochemical parameters independently influenced RER and were used to develop HBP-ET. The mean HBP-ET score of patients with insufficient enhancement was significantly higher than that of patients with sufficient enhancement ( P < 0.001) in both the Development and Validation groups. HBP-ET (area under the curve [AUC] = 0.895) had better performance in predicting insufficient enhancement than CPS (AUC = 0.707), MELD (AUC = 0.798), and TBIL (AUC = 0.729). Conclusion The HBP-ET is more accurate than routine indicators in predicting insufficient enhancement during HBP, which is valuable to aid clinical decisions. PMID- 28090794 TI - Novel sluggish speed signs on ultrasound is indicative of hemangiomas. AB - Background Hemangiomas are sometimes difficult to diagnose with current techniques. Sluggish speed signs (SSS) are a phenomenon that: (i) cannot be depicted as Doppler flow on Doppler ultrasound; (ii) can be observed as fluid movements on Doppler ultrasound; and (iii) cannot be depicted as waveforms on pulse Doppler mode. We hypothesized that SSS could be diagnostic indicators for hemangiomas. Purpose To evaluate whether ultrasound findings, in particular those relating to SSS, are a reliable tool for detecting hemangiomas compared to magnetic resonance imaging (MRI) and the gold standard for hemangioma diagnosis: pathological examination by biopsy or after surgical resection. Material and Methods Totally, 105 patients (mean age, 44.9 years) with soft-tissue tumors underwent MRI and ultrasound examination before biopsy or tumor resection. Ultrasound findings were compared with MRI as well as pathological findings, which were used as reference. Results Hemangiomas were identified in 16 (6.25%) of the 105 patients. On MRI, flow voids showed sensitivity and specificity values of 81.3% and 96.6%, respectively. On ultrasound examination, SSS was the only finding to show equally high sensitivity (93.8%) and specificity (96.6%) for diagnosing hemangiomas. There was no significant difference in the diagnostic capabilities between these two parameters ( P = 0.479). Conclusion SSS showed a high sensitivity and specificity for diagnosing hemangiomas and therefore are useful diagnostic tools to supplement MRI. PMID- 28090795 TI - Isolation and characterization of anti c-met single chain fragment variable (scFv) antibodies. AB - The receptor tyrosine kinase (RTK) Met is the cell surface receptor for hepatocyte growth factor (HGF) involved in invasive growth programs during embryogenesis and tumorgenesis. There is compelling evidence suggesting important roles for c-Met in colorectal cancer proliferation, migration, invasion, angiogenesis, and survival. Hence, a molecular inhibitor of an extracellular domain of c-Met receptor that blocks c-Met-cell surface interactions could be of great thera-peutic importance. In an attempt to develop molecular inhibitors of c Met, single chain variable fragment (scFv) phage display libraries Tomlinson I + J against a specific synthetic oligopeptide from the extracellular domain of c Met receptor were screened; selected scFv were then characterized using various immune techniques. Three c-Met specific scFv (ES1, ES2, and ES3) were selected following five rounds of panning procedures. The scFv showed specific binding to c-Met receptor, and significantly inhibited proliferation responses of a human colorectal carcinoma cell line (HCT-116). Moreover, anti- apoptotic effects of selected scFv antibodies on the HCT-116 cell line were also evaluated using Annexin V/PI assays. The results demonstrated rates of apoptotic cell death of 46.0, 25.5, and 37.8% among these cells were induced by use of ES1, ES2, and ES3, respectively. The results demonstrated ability to successfully isolate/char acterize specific c-Met scFv that could ultimately have a great therapeutic potential in immuno-therapies against (colorectal) cancers. PMID- 28090796 TI - Impact of C-rel inhibition of cord blood-derived B-, T-, and NK cells. AB - The c-Rel transcription factor is a unique member of the nuclear factor (NF) kappaB family that has a role in curtailing the proliferation, differentiation, cytokine production, and overall activity of B- and T-cells. In addition, c-Rel is a key regulator of apoptosis in that it influences the expression of anti apoptotic genes such as Bcl-2 and Bcl-xL; conversely, inhibition of c-Rel increases cell apoptosis. To better understand the relationship between c-Rel expression and effects on B- and T-cell expansion, the current study evaluated c Rel expression in cord blood mononuclear cells. This particular source was selected as cord blood is an important source of cells used for transplantation and immunotherapy, primarily in treating leukemias. As stem cell factor (SCF) and FLT3 are important agents for hematopoietic stem cell expansion, and cytokines like interleukin (IL)-2, -7, and -15 are essential for T- and B- (and also NK) cell development and proliferation, the current study evaluated c-Rel expression in cord blood mononuclear cells and CD34+ cells, as well as effects on B-, T-, and NK cells associated with alterations in c-Rel expression, using flow cytometry and PCR. The results showed c-Rel expression increased among cells cultured in the presence of SCF and FLT3 but was reduced when IL-2, IL-7, and IL 15 were used all together. Further, inhibition of c-Rel expression by siRNA reduced cord blood-derived B-, T-, and NK cell differentiation and expansion. These results indicated that with cells isolated from cord blood, c-Rel has an important role in B-, T-, and NK cell differentiation and, further, that agents (select cytokines/growth factors) that could impact on its expression might not only affect immune cell profiles in a host but could potentially also limit apoptotic activities in (non-)immune cells in that host. In the context of cancer (immuno)therapy, in particular, when cord blood is used an important source in stem cell transplantation in leukemia patients, such down-regulating changes in c Rel levels could be counter-productive. PMID- 28090797 TI - Dimensions of Attention Associated With the Microstructure of Corona Radiata White Matter. AB - Mirsky proposed a model of attention that included these dimensions: focus/execute, sustain, stabilize, encode, and shift. The neural correlates of these dimensions were investigated within corona radiata subregions in healthy youth. Diffusion tensor imaging and neuropsychological assessments were conducted in 79 healthy, right-handed youth aged 4-17 years. Diffusion tensor imaging maps were analyzed using standardized parcellation methods. Partial Pearson correlations between neuropsychological standardized scores, representing these attention dimensions, and diffusion tensor imaging measures of corona radiata subregions were calculated after adjusting for gender and IQ. Significant correlations were found between the focus/execute, sustain, stabilize, and shift dimensions and imaging metrics in hypothesized corona radiata subregions. Results suggest that greater microstructural white matter integrity of the corona radiata is partly associated with attention across 4 attention dimensions. Findings suggest that white matter microstructure of the corona radiata is a neural correlate of several, but not all, attention dimensions. PMID- 28090798 TI - Switching from branded to generic glatiramer acetate: 15-month GATE trial extension results. AB - BACKGROUND: Open-label 15-month follow-up of the double-blind, placebo-controlled Glatiramer Acetate clinical Trial to assess Equivalence with Copaxone(r) (GATE) trial. OBJECTIVE: To evaluate efficacy, safety, and tolerability of prolonged generic glatiramer acetate (GTR) treatment and to evaluate efficacy, safety, and tolerability of switching from brand glatiramer acetate (GA) to GTR treatment. METHODS: A total of 729 patients received GTR 20 mg/mL daily. Safety was assessed at months 12, 15, 18, 21, and 24 and Expanded Disability Status Scale and magnetic resonance imaging (MRI) scans at months 12, 18, and 24. The presence of glatiramer anti-drug antibodies (ADAs) was tested at baseline and months 1, 3, 6, 9, 12, 18, and 24. RESULTS: The mean number of gadolinium-enhancing lesions in the GTR/GTR and GA/GTR groups was similar at months 12, 18, and 24. The change in other MRI parameters was also similar in the GTR/GTR and GA/GTR groups. The annualized relapse rate (ARR) did not differ between the GTR/GTR and GA/GTR groups, 0.21 and 0.24, respectively. The incidence, spectrum, and severity of reported adverse events did not differ between the GTR/GTR and GA/GTR groups. Glatiramer ADA titers were similar in the GTR/GTR and GA/GTR groups. CONCLUSION: Efficacy and safety of GTR is maintained over 2 years. Additionally, switching from GA to GTR is safe and well tolerated. PMID- 28090799 TI - National HIV Care Continua for Key Populations. AB - We reviewed published national HIV care continua for men who have sex with men (MSM), people who inject drugs (PWID), and female sex workers (FSWs) to track progress toward the 90-90-90 target. We searched the Internet, PubMed, surveillance reports, United Nations Programme on HIV/AIDS country reports, US President's Emergency Plan for AIDS Relief country/regional operational plans, and conference abstracts for the continua and graded them on quality. We found 12 continua for MSM, 7 for PWID, and 5 for FSW from 12 countries. HIV diagnosis, antiretroviral therapy coverage, and viral suppression varied between (1) 5% and 85%, 2% and 73%, and 1% and 72%, respectively for MSM; (2) 54% and 96%, 14% and 80%, and 8% and 68%, respectively for PWID; and (3) 27% and 63%, 8% and 16%, and 2% and 14%, respectively for FSW. Two countries, using data from national cohorts, were high quality. There are limited key population continua in the public domain. Of the few available, none have achieved 90-90-90. Improved monitoring and evaluation of key population continua is necessary to achieve the 90-90-90 target. PMID- 28090800 TI - Similar familial risk in multiple sclerosis subgroups. AB - BACKGROUND: A subgroup of patients diagnosed with multiple sclerosis (MS) present with no oligoclonal bands (OCB) in the cerebrospinal fluid (CSF). Several studies report different clinical characteristics and genetic associations between the two groups. OBJECTIVE: To investigate whether the OCB negative subgroup has a distinct etiology from band positive MS. METHODS: Using nationwide registers to estimate familial risks, which reflect the genetic contribution of a disease. RESULTS: Odds ratios of MS were similar for relatives to band positive and negative patients. CONCLUSION: From the perspective of familial liability, MS without OCB is etiologically closely related to the dominant subgroup of OCB positive MS. PMID- 28090801 TI - Angiotensin-converting enzyme inhibitors attenuate propofol-induced pro-oxidative and antifibrinolytic effect in human endothelial cells. AB - INTRODUCTION: The aim of this study was to investigate the effects of plasma and tissue angiotensin-converting enzyme inhibitors (ACE-Is) against propofol-induced endothelial dysfunction and to elucidate the involved mechanisms in vitro. MATERIALS AND METHODS: We examined the effects of propofol (50 MUM), quinaprilat and enalaprilat (10-5 M) on fibrinolysis (t-PA, PAI-1, TAFI antigen levels), oxidative stress parameters (H2O2 and MDA antigen levels and SOD and NADPH oxidase mRNA levels) and nitric oxide bioavailability (NO2/NO3 concentration and NOS expression at the level of mRNA) in human umbilical vein endothelial cells (HUVECs). RESULTS: We found that both ACE-Is promoted similar endothelial fibrinolytic properties and decreased oxidative stress in vitro. Propofol alone increased the release of antifibrinolytic and pro-oxidative factors from the endothelium and increased mRNA iNOS expression. We also found that the incubation of HUVECs in the presence of propofol following ACE-Is pre-incubation caused weakness of the antifibrinolytic and pro-oxidative potential of propofol and this effect was similar after both ACE-Is. CONCLUSIONS: This observation suggests that the studied ACE-Is exerted protective effects against endothelial cell dysfunction caused by propofol, independently of hemodynamics. PMID- 28090803 TI - Insulin-like growth factor binding protein 2 in bipolar disorder: An expression study in peripheral tissues. AB - OBJECTIVES: Insulin-like growth factor binding protein 2 (IGFBP2) is a member of the family of high-affinity binding proteins (IGFBP1-6) and appears to play a governing role in insulin-like growth factor (IGF) regulation in the central nervous system. This study aimed to investigate the putative involvement of IGFBP2 in mood disorder pathogenesis by measuring its expression levels in patient peripheral tissues. METHODS: IGFBP2 protein and mRNA levels were measured in the serum of 93 controls, 41 bipolar disorder (BD) and 43 major depressive disorder (MDD) patients and in the skin fibroblasts from 15 controls, 12 BD and 23 MDD patients. RESULTS: The results indicated reduced expression of IGFBP2 in both tissues of BD patients, whereas no difference was found in MDD patients compared with controls. CONCLUSIONS: Our findings in peripheral tissues are consistent with previous results in the brain and support a downregulation of IGFBP2 expression that is specific for BD, suggesting a role for this protein in the alterations in neurodevelopment and neuroprotection observed in the disorder. Further studies in independent and larger cohorts are warranted to confirm the involvement of IGFBP2 in BD. PMID- 28090802 TI - Functional deficits induced by cortical microinfarcts. AB - Clinical studies have revealed a strong link between increased burden of cerebral microinfarcts and risk for cognitive impairment. Since the sum of tissue damage incurred by microinfarcts is a miniscule percentage of total brain volume, we hypothesized that microinfarcts disrupt brain function beyond the injury site visible to histological or radiological examination. We tested this idea using a mouse model of microinfarcts, where single penetrating vessels that supply mouse cortex were occluded by targeted photothrombosis. We found that in vivo structural and diffusion MRI reliably reported the acute microinfarct core, based on spatial co-registrations with post-mortem stains of neuronal viability. Consistent with our hypothesis, c-Fos assays for neuronal activity and in vivo imaging of single vessel hemodynamics both reported functional deficits in viable peri-lesional tissues beyond the microinfarct core. We estimated that the volume of tissue with functional deficit in cortex was at least 12-fold greater than the volume of the microinfarct core. Impaired hemodynamic responses in peri-lesional tissues persisted at least 14 days, and were attributed to lasting deficits in neuronal circuitry or neurovascular coupling. These data show how individually miniscule microinfarcts could contribute to broader brain dysfunction during vascular cognitive impairment and dementia. PMID- 28090804 TI - Choline acetyltransferase may contribute to the risk of Tourette syndrome: Combination of family-based analysis and case-control study. AB - OBJECTIVES: Twin and family analyses have revealed a genetic contribution to Tourette syndrome (TS) and post-mortem studies have raised the intriguing possibility of a reduction in cholinergic interneuronsin TS patients. METHODS: We selected five tag SNPs (rs100824791, rs12264845, rs1880676, rs3793790 and rs3793798) of choline acetyltransferase (CHAT) from the Han Chinese population Hapmap database. Genotyping was conducted on 401 TS nuclear family trios and 405 control subjects. Transmission disequilibrium test (TDT) and haplotype relative risk (HRR) analyses were used to analyse the family-based study and a case control study was also used to assess the genetic susceptibility to TS. RESULTS: The results revealed a significant over-transmission of rs3793790 (TDT, chi2 = 9.121, P = 0.003; HRR, chi2 = 6.579, P = 0.01), while case-control analysis found no differences between the two groups (genotype, chi2 = 0.436, P = 0.804; allele, chi2 = 0.149, P = 0.700). Also, rs3793798 also indicated a positive association associated with TS (TDT, chi2 = 5.025, P = 0.028; HRR, chi2 = 0.250, P = 0.617). However, the other three SNPs investigated were found not to be associated with TS in both in the family-based and case-control studies. CONCLUSIONS: Our association analysis demonstrates that CHAT may contribute to TS susceptibility in the Han Chinese population. This gives strong support to the involvement of cholinergic interneurons in the aetiology of TS and reveals a potential therapeutic target. PMID- 28090805 TI - Visually evoked startle response in a patient with epilepsy: a case report and review of the literature. AB - Both symptomatic and genetic, cases with hyperekplexia or startle seizures induced by acoustic stimuli, are previously reported. By contrast, startle response induced by visual stimuli is rare. While visual stimuli are more commonly associated with startle seizures, here we present an 11-year-old girl with epilepsy, motor-mental retardation, and spastic tetraparesis, who had repetitive startle responses by photic stimulation during the electroencephalogram recording, without any spike-and-wave discharges associated with the startles. We report this unique case with startle responses induced both by acoustic and photic stimuli and review the literature related to this exceptionally rare combination of symptoms. PMID- 28090806 TI - Randomised sham-controlled study of high-frequency bilateral deep transcranial magnetic stimulation (dTMS) to treat adult attention hyperactive disorder (ADHD): Negative results. AB - OBJECTIVES: Recent studies support the possible effectiveness of repetitive transcranial magnetic stimulation (rTMS) as a treatment for attention deficit hyperactivity disorder (ADHD). The objective of this study was to evaluate the safety and possible efficacy of bilateral prefrontal deep rTMS for the treatment of adult ADHD. METHODS: Twenty-six adult ADHD patients were randomised blindly to sham or actual deep TMS (dTMS). Twenty daily sessions were conducted using the bilateral H5 dTMS coil (Brainsway, IL) in order to stimulate the prefrontal cortex at 120% of the motor threshold at high frequency. For assessment, Conners' Adult ADHD Rating Scale questionnaire and a computerised continuous performance test, Test of Variables of Attention, were used. RESULTS: No differences in clinical outcomes were detected between the actual dTMS and sham groups. CONCLUSIONS: The presented evidence does not support the utility of bilateral prefrontal stimulation to treat adult ADHD. Due to the small sample size, caution must be exercised in interpreting our preliminary findings. PMID- 28090807 TI - Neurocognitive function in paediatric obsessive-compulsive disorder. AB - OBJECTIVES: The small body of neuropsychological research in paediatric obsessive compulsive disorder (OCD) yields inconsistent results. A recent meta-analysis found small effect sizes, concluding that paediatric OCD may not be associated with cognitive impairments, stressing the need for more research. We investigated neuropsychological performance in a large sample of youths with OCD, while assessing potential moderators. METHODS: Participants with OCD (n = 102) and matched controls (n = 161) were thoroughly screened and blindly evaluated for comorbidities, and completed a neuropsychological battery assessing processing speed, visuospatial abilities (VSA), working memory (WM), non-verbal memory (NVM), and executive functions (EF). RESULTS: Compared to controls, youths with OCD exhibited underperformance on tasks assessing processing speed. On tests of VSA and WM, underperformance was found only on timed tasks. There were no differences on NVM and EF tasks. Notably, the OCD group's standardised scores were in the normative range. Test performance was not associated with demographic or clinical variables. CONCLUSIONS: Youths with OCD exhibited intact performance on memory and EF tests, but slower processing speed, and underperformance only on timed VSA and WM tasks. While the OCD group performed in the normative range, these findings reveal relative weaknesses that may be overlooked. Such an oversight may be of particular importance in clinical and school settings. PMID- 28090808 TI - Biomaterial Encapsulation Is Enhanced in the Early Stages of the Foreign Body Reaction During Conditional Macrophage Depletion in Transgenic Macrophage Fas Induced Apoptosis Mice. AB - Macrophages are pivotal cells during the foreign body reaction (FBR), as they orchestrate the proinflammatory microenvironment inside and around biomaterials by secretion of inflammatory mediators. Furthermore, they are responsible for the degradation of biomaterials and are thought to instruct the fibroblasts that generate a fibrous capsule around implanted biomaterials. In this study, we investigated the events during the FBR when macrophages are not present. Hexamethylenediisocyanate crosslinked collagen scaffolds were implanted in "Macrophage Fas-Induced Apoptosis" mice, which allow "on demand" macrophage depletion. We observed that macrophage depletion completely inhibited inflammatory ingrowth into the scaffolds and resulted in an increased capsule size. Quantitative polymerase chain reaction analysis revealed decreased expression levels of proinflammatory mediators such as TNFalpha and IL1beta, and increased expression levels of collagens and fibroblast-stimulating growth factors such as EGF, FGF1, FGF2, and TGFalpha. Our results indicate that macrophages are indeed crucial for the generation of a proinflammatory microenvironment inside implanted biomaterials, leading to inflammatory ingrowth. In contrast, macrophages do not appear to be important for the generation of a fibrous capsule around implanted biomaterials. In fact, our data suggest that the macrophages present in the capsule might instruct the surrounding fibroblasts to produce less fibroblast-stimulating factors and less collagens. PMID- 28090809 TI - Degradation kinetics of passion fruit pectin in subcritical water. AB - The degradation of passion fruit pectin by subcritical water treatment in a continuous flow-type reactor was investigated in the temperature range of 80-160 degrees C at a constant pressure of 5 MPa. Changes in the degree of polymerization and reducing end formation were monitored and modeled by applying the Emsley equation and zeroth-order kinetics, respectively. The results showed that both the pectin degradation rate constant and the change in the amount of reducing end were enhanced by temperature, and that the temperature dependence of these parameters obeyed the Arrhenius relationship. The activation energies for pectin degradation and reducing end formation were 62.8 and 86.9 kJ/mol, respectively. The non-linear relationship between the ratio of broken galacturonic acid units to the total galacturonic acid units and the change in the amount of reducing end indicated that pectin cleavage became easier as hydrolysis progressed. PMID- 28090810 TI - Enamel remineralization effect of a dentifrice containing calcium sodium phosphosilicate: an optical coherence tomography observation. AB - OBJECTIVE: The purpose of this study was to examine the effects of a dentifrice containing 5% calcium sodium phosphosilicate (CSP) on the remineralization of the enamel using optical coherence tomography (OCT). MATERIALS AND METHODS: Bovine incisors were sliced and shaped in a rectangular form. One group of five specimens was treated with undersaturated 0.1 M lactic acid buffer solution (pH 4.75) for 10 min and then placed in artificial saliva (pH 7.0) (De group). Other specimens were stored in solutions of toothpaste containing CSP for 10 min, followed by 10-min immersion in the lactic acid buffer solution twice a day before storage in artificial saliva (CSP group). An additional group was stored in only artificial saliva (control group). OCT imaging on the selected location of the enamel surface was performed. The peak intensity and width at 1/e2 were recorded in each of the six areas on the sample and averaged, and the sample size of each group was six. The integrated value in units (dB * MUm) was calculated in the area of peak intensity. The data for each group was subjected to one-way repeated-measures ANOVA and Tukey HSD tests (alpha = 0.05). RESULTS: The changes in integrated values of each group were different. A slight but significant increase in the integrated value was observed in the control group, whereas a slight but significant decrease in the value was observed the De group. Integrated values increased in the CSP group. CONCLUSIONS: Remineralization occurred upon immersion in the toothpaste containing CSP. PMID- 28090811 TI - Antibacterial combination therapy using Co3+, Cu2+, Zn2+ and Pd2+ complexes: Their calf thymus DNA binding studies. AB - Four Co(III)-, Cu(II)-, Zn(II)-, and Pd(II)-based potent antibacterial complexes of formula K3[Co(ox)3].3H2O (I), [Cu(bpy)2Cl]Cl.5H2O (II), [Zn(bpy)3]Cl2 (III), and [Pd(bpy)2](NO3)2 (IV) (where ox is oxalate and bpy is 2,2'-bipyridine) were synthesized. They were characterized by elemental analyses, molar conductance measurements, UV-Vis, FTIR, 1H NMR, and 13C NMR spectra. These metal complexes were ordered in three combination series of I + II, I + II + III, and I + II + III + IV. Antibacterial activity was tested for each of these four metal complexes and their combinations against Gram-positive and Gram-negative bacteria. All compounds were more potent antibacterial agents against the Gram negative than those of the Gram-positive bacteria. The four metal complexes showed antibacterial activity in the order I > II > III > IV and the activity of their combinations followed the order of I + II + III + IV > I + II + III > I + II. CT-DNA binding studies of complex I and its three combinations were carried out using UV-vis spectral titration, displacement of ethidium bromide (EB), and electrophoretic mobility assay. The results obtained from UV-vis studies indicated that all series interact effectively with CT-DNA. Fluorescence titration revealed that the complexes quench DNA-EB strongly through the static quenching procedures. The binding constant (Kb), the Stern-Volmer constant (Ksv), and the number of binding sites (n) were determined at different temperatures of 293, 300, and 310 K, respectively. The calculated thermodynamic parameters supported that hydrogen binding and Van der Waals forces play a major role in association of each series of metal complexes with CT-DNA and follow the above binding affinity order for the series. PMID- 28090813 TI - Effects of fostriecin on beta2-adrenoceptor-driven responses in human mast cells. AB - As part of the intracellular processes leading to mast cell and basophil activation, phosphorylation of key substrates is likely to be important. These processes, mediated by phosphatases, are responsible for regulating phosphorylation. The aim of the present study was to determine effects fostriecin - a selective inhibitor of PP2A (protein phosphatase-2) - on beta2-adrenoceptor driven responses in human mast cells. Here, the effects of fostriecin (PP inhibitors) on the inhibition of histamine release from HLMC, on beta adrenoceptor-driven responses in mast cells and on desensitization were investigated. Long-term incubation (24 h) of mast cells with fostriecin (10-6 M) resulted in a significant (p < 0.001) reduction in the maximal response (from 41.2 [+/- 3.0] to 29.9 [+/- 4.2] %) to salbutamol following fostriecin treatment. The results showed that fostriecin pretreatment significantly attenuated the inhibitory effects of salbutamol. Overall, the present study suggested that PP2A has an important role in regulating mast cell beta2-adrenoceptors. PMID- 28090814 TI - Personalized dynamic prediction of death according to tumour progression and high dimensional genetic factors: Meta-analysis with a joint model. AB - Developing a personalized risk prediction model of death is fundamental for improving patient care and touches on the realm of personalized medicine. The increasing availability of genomic information and large-scale meta-analytic data sets for clinicians has motivated the extension of traditional survival prediction based on the Cox proportional hazards model. The aim of our paper is to develop a personalized risk prediction formula for death according to genetic factors and dynamic tumour progression status based on meta-analytic data. To this end, we extend the existing joint frailty-copula model to a model allowing for high-dimensional genetic factors. In addition, we propose a dynamic prediction formula to predict death given tumour progression events possibly occurring after treatment or surgery. For clinical use, we implement the computation software of the prediction formula in the joint.Cox R package. We also develop a tool to validate the performance of the prediction formula by assessing the prediction error. We illustrate the method with the meta-analysis of individual patient data on ovarian cancer patients. PMID- 28090815 TI - Comparison of Genome-Wide and Gene-Specific DNA Methylation Profiling in First Trimester Chorionic Villi From Pregnancies Conceived With Infertility Treatments. AB - BACKGROUND: Assisted reproductive technologies are associated with altered methylation in term placenta. However, it is unclear whether methylation patterns are the result of fertility treatments or intrauterine environment. Thus, we set out to determine whether there are differences in the first-trimester placenta that may be altered by the underlying fertility treatments. Genome-wide DNA methylation analyses from chorionic villus sampling (CVS) from matched singleton pregnancies conceived using in vitro fertilization (IVF), non-IVF fertility treatment (NIFT), or those conceived spontaneously were performed using Illumina Infinium HumanMethylation450 BeadChip from 15 matched CVS samples. Nanofluidic quantitative polymerase chain reaction (qPCR) of differently methylated genes was performed in a confirmatory cohort of 23 IVF conceptions and 24 NIFT conceptions. RESULTS: Global methylation was similar among the IVF, NIFT, and spontaneous conceptions. However, differential methylation from IVF and NIFT pregnancies was present at 34 CpG sites, which was significantly different. Of those, 14 corresponded to known genes, with methylation changes detected at multiple loci in 3 genes, anaphase-promoting complex subunit 2 ( ANAPC2), C-X-C motif chemokine ligand 14 ( CXCL14), and regulating synaptic membrane exocytosis 1 ( RIMS1). Nanofluidic qPCR of differentially methylated genes identified pre T-cell antigen receptor alpha ( PTCRA) to be significantly downregulated in IVF versus NIFT conceptions. CONCLUSION: Although global methylation patterns are similar, there are differences in methylation of specific genes in IVF compared to NIFT conceptions, leading to altered gene expression. PTCRA was differentially methylated and downregulated in IVF conceptions, warranting further investigation. It remains to be determined whether these changes affect placentation and whether it is due to the more profound underlying infertility requiring IVF, yet these data provide unique insight into the first-trimester placental epigenome. PMID- 28090816 TI - Tacit knowledge and risk perceptions: Tullow Oil and lay publics in Ghana's offshore oil region. AB - This study examines how local residents make sense of offshore oil production risks in Ghana's nascent petroleum industry. From a naturalistic-interpretive perspective, it is primarily based on in-depth interviews with community residents: 8 opinion leaders, 15 residents, and 1 journalist. Residents associate Tullow's oil activities with health concerns (e.g. conjunctivitis), environmental challenges (e.g. the emergence of decomposed seaweeds along the shore), and socio economic concerns (e.g. loss of livelihoods, decline in fish harvest, and increased rent and cost of living). Focusing on how the local, practical knowledge of interviewees manifest in their sense of offshore oil risks, the study identifies two strategies-scapegoating and tacit knowing-underlying how residents construe offshore oil risks and benefits. Beyond its theoretical contribution to the social construction of risk process, the study illustrates the challenge the expert-lay publics dichotomy poses (and the potential bridging this dichotomy has) for corporate and societal risk management. PMID- 28090817 TI - Coronary or ventricular rupture after blunt chest trauma? A clinical dilemma. AB - Cardiac rupture (CR) is one of the most serious and life-threatening complications of blunt chest trauma (BCT) usually associated with high mortality. Moreover, its diagnosis and treatment strategies may be extremely challenging for clinicians due to various anatomical localisations of the tear. Whereas most injuries fall under the category of right atrial ruptures, left ventricular lesions represent a rare type of this injury, with greater mortality, particularly in cases of multi-chamber injuries. However, not only cardiac chamber or great vessel ruptures may occur as a result of BCT; a growing number of reports also describe BCT-induced isolated coronary artery injuries, including ruptures. Whereas CR requires immediate surgical treatment, less invasive interventional techniques, such as stent placement and closure with fibrin glue or coils, can be the treatment of choice in selected cases of hemodynamically less relevant coronary artery ruptures. In this report, we present a rare case of a ventricular rupture following BCT, with the tear localized in the right ventricular wall and an occult connection to the left ventricle without ventricular septum injury. Also, another contemporaneous emergency in our department that had to be managed at the same time resulted in challenging the decision-making process. As such an emergency constellation is difficult to manage, this report may help clinicians in difficult situations in terms of diagnosis and choosing the right treatment strategy. PMID- 28090818 TI - Individual differences in proactive interference in verbal and visuospatial working memory. AB - Proactive interference (PI) has been shown to affect working memory (WM) span as well as the predictive utility of WM span measures. However, most of the research on PI has been conducted using verbal memory items, and much less is known about the role of PI in the visuospatial domain. In order to further explore this issue, the present study used a within-subjects manipulation of PI that alternated clusters of trials with verbal and visuospatial to-be-remembered items. Although PI was shown to build and release across trials similarly in the two domains, important differences also were observed. The ability of verbal WM to predict performance on a measure of fluid intelligence was significantly affected by the amount of PI present, consistent with past research, but this proved not to be the case for visuospatial WM. Further, individuals' susceptibility to PI in one domain was relatively independent of their susceptibility in the other domain, suggesting that, contrary to some theories of executive function, individual differences in PI susceptibility may not be domain general. PMID- 28090821 TI - Nurse-led service slashes wait for GP appointment. AB - NURSES ATTENDING the RCN Practice Nurse Association annual conference have showcased wide- ranging service developments made possible through the advent of primary care trusts (PCTs). PMID- 28090819 TI - Toxoplasmic encephalitis relapse rates with pyrimethamine-based therapy: systematic review and meta-analysis. AB - Toxoplasmic encephalitis (TE) is caused by Toxoplasma gondii infection and can be a life-threatening disease in immunocompromised patients. This study evaluated the rate of relapse associated with pyrimethamine-based maintenance therapy (i.e. secondary prophylaxis) in patients with human immunodeficiency virus (HIV) or AIDs treated prior to and after the common use (i.e. 1996) of highly active antiretroviral therapy (HAART) (pre-HAART and post-HAART, respectively). PubMed, Google Scholar, and Cochrane databases were searched to 6 June 2016 using search terms: pyrimethamine, Daraprim, Fansidar, Metakelfin, Fansimef, 5-(4 chlorophenyl)-6-ethyl-2,4-pyrimidinediamine, encephalitis, cerebral, toxoplasmosis, toxoplasmic, and gondii. Single-arm cohort, retrospective, and randomized studies were included. Twenty-six studies with 1,596 patients were included in the analysis; twenty pre-HAART (n = 1,228) studies and six post-HAART (n = 368) were performed. Pooled proportions test for pyrimethamine-based therapy from pre-HAART studies indicated a relapse rate of 19.2% and 18.9% from the fixed effects and random-effects models, respectively. The relapse rate in the post HAART studies was 11.1% (fixed and random effects). Continuous therapy was suggestive of lower incidence of relapse compared with intermittent therapy in the pre-HAART era (range, 18.7 to 17.3% vs. 20.9 to 25.6%, respectively). These findings indicate that the likelihood of relapse associated with pyrimethamine based therepy in patients with HIV and TE decreased after the introduction of HAART to approximately 11%. The findings have important implications as relapse may affect a patient's disease severity and prognosis, increase utilization of health care resources, and result in additional health care expenditure. PMID- 28090820 TI - PALS could disempower nurses. AB - A NEW SYSTEM to deal with patients' complaints is flawed because it will disempower nurses and be difficult to access in primary care settings, the conference heard. PMID- 28090822 TI - Labour initiatives sapping power, not giving it to staff. AB - HEALTH SECRETARY Alan Milburn has clashed with NHS Confederation chief executive Stephen Thornton over nursing initiatives and the devolution of power to frontline staff. PMID- 28090824 TI - Antioxidant vitamins might prevent pre-eclampsia. AB - Pre-eclampsia which causes the deaths of about 75,000 women worldwide every year might be caused by decreased availability of nitric oxide, US researchers say. PMID- 28090823 TI - Once in a lifetime. AB - Adele McEvilly received an NHS Lifetime Achievement award at the first health and social care awards. The award was in recognition of her work at Birmingham Children's Hospital. Ms McEvilly, a former Nursing Standard paediatric nurse of the year, received her award from health secretary Alan Milburn (left) and Olympic oarsman Sir Steve Redgrave. PMID- 28090825 TI - Clinicians should pay more attention to drug side effects. AB - PATIENTS' VIEWS on the adverse effects of antipsychotics should be given greater regard when prescribing choices are made, a study has shown. PMID- 28090826 TI - Police training boosts zero tolerance results. AB - COLLABORATIVE WORKING between nurses and police to promote zero tolerance of illegal drugs on acute mental health wards benefits staff and patients, according to a study. PMID- 28090827 TI - Meditation unlocks prison health. AB - VIPPASANA, an ancient Indian form of meditation, can improve discipline and co operation in prisoners and help treat mental illness, according to a study. PMID- 28090828 TI - RCN election. AB - THE 29-STRONG RCN council is to have 11 new members after election results were revealed last week. PMID- 28090830 TI - Wales to consider PFI concerns. AB - HEALTH MINISTER Jane Hutt has pledged to review and evaluate all five private finance initiative (PFI) projects in Wales following RCN lobbying. PMID- 28090829 TI - On the Move. AB - Promotions / new appointments. PMID- 28090831 TI - Behind the news. AB - IF YOU only had access to the mass media, you could be forgiven for thinking that Creutzfeldt Jakob disease (CJD) equals mad cow disease in humans. PMID- 28090833 TI - From the heart. AB - A chance meeting at Harefield Hospital with transplant surgeon Sir Magdi Yacoub changed my life - but I never dreamed he would also be the one to save it. PMID- 28090832 TI - Rewrite proposals for new nursing council, says RCN. AB - THE RCN is calling on the government to rewrite its proposals for the new Nursing and Midwifery Council (NMC), the body that will replace the UKCC and the four national boards next year. PMID- 28090834 TI - Family. AB - IT HAS long been recognised that much cancer care and advice is given outside specialist units, which has led to continuing concern among some academics over how little nurses seem to know about the hereditary nature of cancer. PMID- 28090835 TI - outside in. AB - Hush a minute. Do you hear that banging sound? It's my arteries, throbbing fit to burst. What do you mean 'don't joke about it'? I'm not joking. My blood pressure is way too high, and that's no joking matter. PMID- 28090836 TI - Call for guidelines on resuscitation of dementia patients. AB - NEARLY ALL nurses think trusts should provide more training on the legal and ethical issues around resuscitating patients who have dementia, according to a study. PMID- 28090837 TI - Age-old practices. AB - The National Service Framework for Older People is a comprehensive strategy that seeks to ensure fair, high quality, integrated health and social care services for older people. It is a ten-year programme of action linking services to support independence and promote good health, specialised services for key conditions, and culture changes so that all older people and their carers are always treated with respect, dignity and fairness. PMID- 28090838 TI - Is nursing bad for you? PMID- 28090839 TI - Age discrimination lurks in student bursary awards. AB - I am a 25-year-old student nurse and have just started my second year of training. Although I know that in September the bursary will be going up, there is one point I would like to make. PMID- 28090842 TI - Mixed response to cancer plans. AB - A NEW cancer strategy for Scotland has received a muted welcome from the RCN. PMID- 28090841 TI - New roles demand more training. AB - MORE TRAINING is needed if practice nurses are to take on the expanded role outlined in the NHS Plan, the conference heard. PMID- 28090843 TI - Inspiring change. AB - Any nurse who has ever felt the strain of pushing against a rigid or 'unfriendly' hospital system will find Dr Elisabeth Kubler-Ross's autobiography heartwarming and encouraging. PMID- 28090844 TI - Nurse Amanda Pinkney claims that after three failed attempts at whistleblowing, she sacrificed her career. She tells her story to Charlotte Alderman. AB - WHEN CONSULTANT gynaecologist Richard Neale was struck off by the General Medical Council (GMC) last year many of the women who suffered at his hands felt vindicated that their complaints had been listened to and acted on. But nurse Amanda Pinkney says she tried to complain about him eight years earlier. PMID- 28090845 TI - Shifting boundaries. AB - FUNNY HOW three different groups of health professionals managed to see the same issue from such widely differing perspectives last week. PMID- 28090846 TI - It doesn't cost anything to ask staff their views. AB - YOU MAY do a double take when you see the story on page 4 . News that a hospital in West Yorkshire has stopped subsidising meals to save money - and hasn't even consulted its staff - will seem out of place and out of time. PMID- 28090847 TI - Find even more information on Nursing Standard. PMID- 28090849 TI - Model setting for students. AB - Clinical placement co-ordinator Kate Wadley, of Birmingham Specialist Community Health NHS Trust, eyes up one of the life-size models at the trust's new clinical skills centre. The L58,000 centre also has a range of 'true-to-life' acute and community settings to help train nursing students. PMID- 28090850 TI - Success story. AB - THE PROBLEMS of staff recruitment and retention are just as acute in the private healthcare sector as they are in the NHS. But one group, Westminster Health Care, has adopted a multipronged approach to the problem including staff education and training, career pathways and home and overseas recruitment drives. PMID- 28090851 TI - ...but doctors in south call for help. AB - THE ROLE of practice nurses in relieving the pressure on GP services was due to be highlighted in the House of Commons this week. PMID- 28090852 TI - Put your heads together. PMID- 28090853 TI - The only nurse on the team. AB - Changing jobs is always hard, but moving from the acute sector to the community as well as taking up a completely new role in a social services team is particularly challenging. PMID- 28090854 TI - What's on: the best of the week's health-related TV and radio. AB - A roundup of the latest nursing news. PMID- 28090855 TI - Practitioner-client Relationships and The Prevention of Abuse A UKCC teaching pack. AB - This teaching pack is aimed at preventing the nurse, midwife or health visitor unwittingly abusing patients or clients. It contains a facilitators' teaching pack, video, CD-ROM and booklet. PMID- 28090856 TI - Going dutch. AB - PRACTITIONER NURSES from the Scottish prison service have the unique experience of providing j primary care for both prisoners and ?d on Dutch soil. Camp Zeist houses complex, purpose built to accommodate the Libyan prisoners who were on trial for alleged arts of terrorism involving the bombing of PanAm Flight 103 over Lockerbie in 1988. PMID- 28090857 TI - Anger over subsidy cut. AB - HOSPITAL STAFF in West Yorkshire are threatening joint industrial action after trust managers decided to stop subsidising meals this month. PMID- 28090859 TI - A&E staff can combat crime. AB - A&E NURSES could do more to help their local communities combat crime, a King's Fund study to be published this week has found. PMID- 28090858 TI - Practice nurses can't take our place, complain GPs... AB - DISAGREEMENT OVER practice nurse roles resurfaced last week at the annual British Medical Association (BMA) conference. PMID- 28090860 TI - We need guidelines on abuse in nursing homes. AB - I read your articles with interest each week and one burning issue that keeps coming up is abuse in the workplace experienced by some nurses. PMID- 28090861 TI - Why doesn't experience count? AB - I am a student nurse doing a diploma course and would like to know how having a degree in economics, languages or any other subject not related to nursing or science enables people to enter the shorter, two-year nursing course. PMID- 28090862 TI - CHI ideally placed to tackle racism. AB - REVELATIONS THAT racism is as rife in nursing as in medicine have prompted calls for discrimination to fall within the Commission for Health Improvement (CHI) remit. PMID- 28090863 TI - Injected stem cells could solve continence problems. AB - Stem cells might come to the rescue of people with urinary incontinence, according to early results from US research. PMID- 28090864 TI - Not all bad attitudes to mental health problems. AB - I read with interest the article 'Changing minds' (features June 20), which outlined many negative attitudes experienced by nurses with mental health problems. PMID- 28090865 TI - Computer-generated letters increase smoking cessation. AB - A brief, general letter might increase smoking cessation rates in a general practice population, Aberdeen researchers say. PMID- 28090866 TI - Defibrillator paddles often placed in wrong position. AB - Teaching of advanced life support skills must place greater emphasis on the position of defibrillator paddles if the success of the procedure is to be optimised. PMID- 28090867 TI - Standard life. AB - One of the joys of summer is the opportunity it affords to wake in the small hours to engage in a trombone sneezing fit courtesy of near-terminal hay fever. It's a mystery why 40 billion pollen particles choose to party in my bedroom but. having woken the neighbours with my nose music and stumbled around red-eyed and trumpeting in search of a wagonload of nostril-plugging tissues. I stagger back to bed. exhausted but woefully awake. PMID- 28090868 TI - Nurses and midwives to bid for 21 per cent rise. AB - NURSES AND midwives are likely to demand a huge pay rise this year in a bid to boost recruitment and bring pay back into line with comparable workers. PMID- 28090869 TI - Conference on cancer brought nurses together. AB - I have just returned from York where I attended the three-day conference 'A journey through cancer: Nurses collaborate', which brought together 13 forums, societies and special interest groups of the RCN. PMID- 28090871 TI - Trust cancels one-midwife scheme. AB - A SCHEME allowing women to be cared for by the same midwife throughout pregnancy, during birth and postnatally has been suspended because of staff shortages. PMID- 28090870 TI - Managers are willing to be flexible if you are too. AB - Having read Ella Wainwright's points (letters July 4) about asking for flexible hours, I would urge nurses not to be put off. PMID- 28090872 TI - Caines admits skill mix mistake. AB - A FORMER NHS personnel director and advocate of diluting skill mix has admitted that the practice may have led to a rise in hospital-acquired infections (HAIs). PMID- 28090874 TI - Time to bolster this vital role. AB - Today Nursing Standard launches a campaign to boost the status of ward sisters and charge nurses. PMID- 28090873 TI - Giving ward leaders power. AB - Ward sisters and charge nurses are pivotal in ensuring that patients receive the highest possible standards of care. But their role has been eroded over the years and many feel they lack the clout to bring about changes and deliver the service that their patients deserve. PMID- 28090875 TI - Survey finds ward managers'pay is inconsistent and inadequate. AB - Most ward sisters and charge nurses are being paid less than unions' recommended salary for their level, a Nursing Standard survey shows. PMID- 28090876 TI - Deaths in older people from heat depend on mild winter. AB - Winters where mortality is low might inflate the pool of older people susceptible to dying from high temperatures the following summer. PMID- 28090877 TI - Criminal record checks to remain in place regardless of pandemic. AB - The requirement to carry out Criminal Records Bureau (CRB) checks on nurses during a pandemic flu outbreak will not be waived by NHS Employers. PMID- 28090878 TI - Higher mortality rate in women infected after heart surgery. AB - Women who develop nosocomial infections while in intensive care have higher mortality rates than men. PMID- 28090879 TI - Webwise. AB - The Health Technology Assessment programme is part of the National Institute for Health Research (NIHR). It produces independent research information about the effectiveness, costs and broader impact of healthcare treatments and tests for those who plan, provide or receive care in the NHS. PMID- 28090882 TI - College's neutral position is the right decision. AB - There have been many letters recently about the RCN changing its stance on assisted dying. There are, however, many that make totally unsubstantiated, emotive comments and include false logic. PMID- 28090884 TI - Giving back one day's pay is an antiquated suggestion. AB - Janet Smith (reflections August 19) suggests we can help the NHS by giving back a day's pay. PMID- 28090886 TI - Assisted suicide stance makes me proud to be an RCN member. AB - I am interested in the range of views expressed by nurses on the neutral stance adopted by the RCN on assisted dying. I now feel proud to be a member of the college. PMID- 28090888 TI - Let nurses undertake drug rounds without distraction. AB - I was interested to read about nursing student Lindsay Martin's experience of a busy medicines round (reflections August 26). PMID- 28090887 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28090889 TI - Treatment of dying prisoners reflects our civilised nature. AB - Dignity in death is widely accepted as important in today's society. However, for prisoners this has been and still remains a controversial issue (analysis August 26). The recent release of convicted terrorist Abdelbaset Alial-Megrahi and train robber Ronnie Biggs has brought this debate back into public discussion. PMID- 28090890 TI - Curricula should cover mental health needs of offenders, report urges. AB - Nurses should receive training in caring for offenders with mental health problems, according to a report into a patient who killed three people. PMID- 28090892 TI - College announces council election results. AB - The RCN has announced the results of its 2009 council elections. The following candidates were elected. PMID- 28090891 TI - Some new nurses are missing out on accelerated pay. AB - I qualified three years ago and have since missed out on accelerated pay. Some of the staff nurses I qualified with were awarded the pay increase after six months and some were not. PMID- 28090893 TI - Praise for nurses after hospital fire. AB - Hospital nurses were praised for their swift actions when a fire broke out. PMID- 28090894 TI - Osteoarthritis:pathogenesis, clinical features and management. AB - Osteoarthritis is a degenerative disorder of the synovial joints that is characterised by joint pain, stiffness and limited range of movement. The majority of nurses will encounter patients with this condition even though this might not be the reason they are seeking health care. This article discusses the associated signs and symptoms, investigations, diagnosis and treatment of this condition. PMID- 28090895 TI - Reader's practice profile literature review. AB - As a junior staff nurse, and as part of my degree, I have to conduct a literature search in the area of palliative care to identify best practice and improve care delivery. PMID- 28090896 TI - Voices - Restore trust in nursing by casting an honest light on us, says Rosemary Cook. AB - The poor reputation of nursing with the public continues to make the news. Schoolchildren say they would not consider it as a career. Patients give examples of thoughtless, inadequate or sometimes shocking nursing care. And healthcare quality regulators probe organisations where low nurse numbers or poor morale are undermining standards. PMID- 28090897 TI - Preparation, training and support:the cornerstones of ward leadership. AB - If patient experience is to be transformed as the government has promised, ward sisters and charge nurses must have greater support. PMID- 28090898 TI - Report blames heavy workload for drug dose errors. AB - Short-staffing in hospitals is leading to medication administration errors by overworked nurses, according to the National Patient Safety Agency (NPSA). PMID- 28090901 TI - PG Cert, PGDip or MSc in health improvement and health promotion. AB - of content The complexities of promoting health and issues affecting health improvement; emphasis on preventable causes of disease, covering obesity, sexually transmitted infections, mental health, alcohol and substance misuse and smoking. PMID- 28090899 TI - Staking a claim. AB - Some nurses in the UK are entitled to tax relief on their employment expenses, but many are failing to claim because of a lack of knowledge and the high cost of advice. PMID- 28090902 TI - Monitoring body praises regulator. AB - Confidence in the Nursing and Midwifery Council (NMC) appears to be improving although there is still room for more progress, a report from the Council for Healthcare Regulatory Excellence (CHRE) says. PMID- 28090903 TI - Hospitals begin programme of pre-operative MRSA screening. AB - Scotland's largest health board has started screening all patients for MRSA when they are admitted to hospital for a planned operation. PMID- 28090904 TI - OutsideIn - Online counselling leaves David Newnham feeling totally inadequate. AB - Imagine being able to get treatment without actually meeting anyone. No more small talk or worrying whether your socks match. Turn up nude if you wish. No one is looking. PMID- 28090905 TI - Ward leaders need Authority if they are to meet their responsibilities. AB - Having the authority 'to make decisions and get things done' is top of the wish list for today's ward sisters and charge nurses. PMID- 28090907 TI - A conflict of principles? PMID- 28090906 TI - Sick stories. AB - Okay, it was the silly season, when the variety of newsworthy items is at an all year low and the media needs to make something out of not very much. PMID- 28090908 TI - 'Give pupils with diabetes equal access to activities'. AB - School pupils with diabetes are missing important parts of the curriculum because they are being withdrawn from physical education and other classes, the RCN claims. PMID- 28090909 TI - Engaging the public takes time and money. AB - Nurses in England say that a lack of resources, capacity and time are the main barriers to better patient and public involvement (PPI), according to RCN-funded research. PMID- 28090910 TI - Hospital refurbishment leads to dramatic fall in patient violence. AB - A L million hospital redevelopment has been credited for a dramatic reduction in the number of violent incidents involving mental health inpatients. PMID- 28090911 TI - Student life - Mutually supportive. AB - Mentoring pre-registration nursing students is an important role for almost all registered nurses, midwives and specialist community public health nurses. PMID- 28090912 TI - Readers panel - A shot in the dark. AB - Our experts consider a hot topic of the day. PMID- 28090913 TI - At risk of becoming one of the worried well. AB - When I developed pains around my rib area recently following a bout of flu, I was convinced I had cracked a rib as this had happened before. I went to a GP who agreed I had either done it again or strained some muscles. So instead of investigating my symptoms I was sent off with painkillers. PMID- 28090914 TI - DH rules out NHS job cuts but staff will have to work 'smarter'. AB - Nurses will have to work 'smarter' to increase productivity, NHS managers said last week after a report commissioned by the Department of Health proposed thousands of job cuts. PMID- 28090915 TI - New chair will ease stress on knees. AB - A former midwife turned entrepreneur has designed a chair to help reduce injuries among healthcare professionals who kneel or squat at work. PMID- 28090916 TI - Men will be put off nursing by drive to bring back old-fashioned uniforms. AB - The new uniforms being issued to staff at the Heart of England NHS Foundation Trust look smart, but they portray an outdated image of nursing (news August 19, letters August 26). PMID- 28090917 TI - Deployed military personnel face respiratory problems. AB - Historically respiratory infections have had a significant effect on United States military missions as a result of close living conditions, stressful work environments and increased exposure to pathogens. Common cold-type respiratory symptoms were widespread and a frequent cause of minor morbidity during operations Desert Shield and Desert Storm. This was especially true during the initial deployment phase. To assess the existing situation, a total of 2,872 deployed troops completed questionnaires between January 2005 and January 2006. PMID- 28090919 TI - Nurses need less paperwork to give more hands-on care. AB - I work on a busy ward in an acute setting and we are short of staff. During a short break recently, I discussed with a colleague the latest report on poor standards of care in the NHS (news September 2). PMID- 28090918 TI - I have experienced a lot of negativity about my gender. AB - I read with interest your news story 'Negative stereotypes prevent men from entering the profession' (August 26). PMID- 28090920 TI - Starting out - I saw a nurse hit a patient - but failed to report the incident. AB - I was helping a staff nurse wash an older patient who had Alzheimer's disease. The patient was confused and disorientated. He needed complete care so we helped him with washing, dressing, eating and toileting. As we tried to turn him on to his. PMID- 28090921 TI - End of life care skills are essential for all students. AB - Further to the art&science article, 'An educational programme for end of life care in an acute setting' (August 12), I agree that modules on communication and bereavement are needed at all stages of nurse training. PMID- 28090923 TI - Robots designed to grin and bear it. AB - Japanese inventors believe they have found a way to take some of the strain off nurses - a bear-shaped robot. PMID- 28090922 TI - Trusts trial discussion sessions to help staff manage emotions. AB - Nurses are helping to pilot an innovative programme that helps staff to cope better with emotional issues on the ward. PMID- 28090924 TI - Survival from lung cancer not improved with thalidomide. AB - Thalidomide in combination with chemotherapy does not improve survival of patients with small cell lung cancer, but is associated with an increase in the risk of thrombotic events. PMID- 28090925 TI - Webwise. AB - Do not be put off by the Medical Protection Society website. Although it is run by a company that is in the main organised for the benefit of doctors, it does provide the same service for nurses, albeit in smaller numbers. PMID- 28090928 TI - Pauline Freeman's death was tragic but the nurses are not to blame. AB - As the 'single qualified nurse' on duty the night Pauline Freeman died at Eastbourne District General Hospital, I would like to respond to some inaccuracies in your article on the subject (features September 6). PMID- 28090929 TI - Outpatient staff carry out many minor procedures. AB - [Figure: see text] The future of outpatient departments has been questioned by the Department of Health (news September 27). Although I work on wards, I know that the staff in the outpatient department at the hospital where I work carry out a great many minor procedures. People who are referred to outpatients are unlikely to have staff simply repeat a history taking and say 'see you in six months' - they are far too busy for such niceties. PMID- 28090930 TI - Misconduct cases are caused by an overstretched service. AB - I am incensed by the misguided and patronising comments made by Sandra Arthur, the new president of the Nursing and Midwifery Council (NMC) (news September 20). PMID- 28090931 TI - I want bullies to write in and justify their behaviour. AB - I feel upset every time I read articles and letters that are sent in about bullying (student focus September 27). I left my job before I was totally crushed by this behaviour. PMID- 28090933 TI - Special meeting will decide NMC response to regulation review. AB - Major changes to misconduct hearings will be considered by nursing's regulatory body at a specially convened meeting next week. PMID- 28090932 TI - Mental health staff 'treat BME patients unfairly'. AB - Health minister Rosie Winterton has accused mental health workers of breaking the law over the poor quality of care for black and minority ethnic (BME) patients. PMID- 28090934 TI - Staff hold shares in social enterprise. AB - Staff nurse Lorna Blackwood, centre, is one of the 600 staff to be issued with share certificates by Central Surrey Health, a new social enterprise which opened for business last week. PMID- 28090935 TI - Careless words. AB - An older relative phoned me for advice. She had received a hospital appointment letter for the diabetic clinic. As far as she knew she was not diabetic. She spent a sleepless night worrying on two accounts - that she had this condition but had not been informed, and that she was losing her marbles. PMID- 28090936 TI - How I gained. PMID- 28090937 TI - Former breast cancer patient sets up charity. AB - A woman who had cancer and was inspired to train as a nurse following her treatment has launched a charity to help other patients. PMID- 28090938 TI - Employers seek ways to keep door open for nurse returners. AB - NHS Employers is trying to persuade trusts to fund return-to-practice courses amid fears that nurses who take career breaks will not be able to get back on the register. PMID- 28090939 TI - Employers toe the line. AB - It is no wonder that staff unions are unhappy about NHS Employers' evidence to the nurses' pay review body this year. There are many reasons why a rise of 2 per cent from next April would be inadequate. For a start, 2 per cent is still only a government inflation target; the latest Consumer Price Index of annual inflation rose to 2.5 per cent in August, up from 2.4 per cent in July, so ministers cannot even claim that prices are moving in the right direction. PMID- 28090940 TI - Unions scathing over managers' call for2 per cent limit on pay rise. AB - Nurses should receive a pay rise of just 2 per cent next April, NHS Employers has told the profession's pay review body (RB). PMID- 28090941 TI - Low morale hits patient outcomes. AB - Evidence that nursing morale directly affects patient outcomes has been revealed by the Healthcare Commission. PMID- 28090943 TI - More respect for HCAs. AB - The HCA had written: 'Bad day and in a lot of pain. Meds are not working. Needs more help.' Who was really paying attention to me that day? PMID- 28090945 TI - Mealtimes are a chance for parents to help with care. AB - As a paediatric matron, I support the idea of mealtime protection. However, I was slightly concerned that readers panel member Scott Justice did not include the most important people in a child's life: parents and carers (reflections October 4). PMID- 28090944 TI - How does genetics play a part in your work? AB - The NHS National Genetics Education and Development Centre wants to find out what nurses think about genetics. Are you confident in applying genetics knowledge at work? Would you like to learn more about how genetics is relevant to your patients? Or do you think that genetics is not important in your current role? PMID- 28090946 TI - My hearing disability is no barrier to work. AB - I applaud the recent correspondence urging deaf students not to give up their studies (letters September 13). There are many hard of hearing and deaf nurses, doctors, physiotherapists, radiologists and audiologists in the NHS. I am profoundly deaf and work on an acute medical/respiratory ward. Disability is not a barrier to nursing. PMID- 28090947 TI - Eight nursing directors named for new regions. AB - Eight of the ten directors of nursing in the new strategic health authorities (SHAs) have now been appointed, the Department of Health said last week. PMID- 28090949 TI - Health staff 'should drive policy'on PCTs. AB - The influence of nurses and other health professionals on decision making in primary care trusts (PCTs) is to be bolstered, health minister Lord Warner said last week. PMID- 28090950 TI - Bullying drove me from my job but i found support. AB - I left the NHS in May of this year because I was being bullied by a senior nurse (student focus, letters September 27). The experience is one I never wish to repeat. My health suffered as a result and I was prescribed antidepressants by my GP, who voiced his disgust at the way I had been treated. I sought help from occupational health in the form of counselling, which played a huge part in my recovery. PMID- 28090948 TI - With obesity on the rise, space is now crucial issue. AB - It was good to see research on spatial requirements in hospital bathrooms (art&science September 27). This backs up what many staff already know from experience - that the amount of space in many healthcare environments is rarely sufficient for safe and appropriate care, even in some newer areas of provision. PMID- 28090951 TI - Hidden distress. AB - 'It is not like the depression we mental health nurses usually see,' my colleague said to me. 'It is more a grim resignation, an apathy or indifference - it is somehow not the same as depression.' His father-in-law has Parkinson's disease and so does my father - suddenly many people in my life are affected by the disease. PMID- 28090953 TI - Paracetamol tablets sold in excess of legislation limits. AB - Legislation limiting the availability of paracetamol is not being adhered to in south London, researchers found. In an attempt to cut the. PMID- 28090952 TI - Bad nursing experience deterred a good student. AB - 'Love me tender' was a touching article (features September 20). Recently, a close nursing student friend of mine became a patient and his experience was of heartless, unloving nursing. PMID- 28090954 TI - Dapoxetine in the treatment of premature ejaculation. AB - Ten per cent of British males report that they 'sometimes' or 'often' experience premature ejaculation. American researchers ( Pryor et al 2006 ) report on two large double-blind randomised studies assessing the efficacy and safety of dapoxetine, a short-acting, selective serotonin-reuptake inhibitor (SSRI) to be used on-demand for treatment of the condition. Accompanying commentary. PMID- 28090955 TI - Starting out - Be the nurse y0u want to be by refusing to kowtow to bullies. AB - It was my first week on placement in A&E and everything was unfamiliar. That weekend my mentors were away on study days. PMID- 28090957 TI - Full breastfeeding reduces infants' hospital admissions. AB - Full breastfeeding would lower the risk of hospital admission as a result of infection among infants under one year of age in industrialised countries. PMID- 28090958 TI - Heart disease risk increased by social isolation of child. AB - Researchers tested the hypothesis that children with peripheral or isolated roles in their peer group are at risk of poor adult health. PMID- 28090959 TI - RCN gets Carter. AB - The RCN has appointed a forthright chief executive and mental health nurse as its next general secretary to replace Beverly Malone. Peter Carter has a reputation as an effective manager with strong opinions on health service reorganisation and government interference in the running of the NHS. PMID- 28090960 TI - Readers panel - Health care on tap. AB - Our experts consider a hot topic of the day. PMID- 28090961 TI - Standard life. AB - I caught the tail end of a conference presentation recently on rituals in health care. I would have liked to have heard the beginning but I had made myself late by avoiding cracks in the pavement. PMID- 28090962 TI - 'Patient-sensitive indicators' key to making real improvements in care. AB - The NHS needs to develop better healthcare indicators if patient care is to improve, RCN general secretary Beverly Malone has told politicians. PMID- 28090963 TI - Student life - Plotting your pathway. AB - It is never too early to start planning your career. Being aware of your interests, which specialties appeal and what is important to you will help you take control of your future. PMID- 28090965 TI - Tories promise a nurse for every school. AB - The Conservatives have promised that every school will have its own nurse if the party wins power at the next general election. PMID- 28090964 TI - Voices -TV drama captured the shock of a cancer diagnosis, says Linda Thomas. AB - Did you see the one-off drama Losing Iton ITV1 recently? The author Paul Mendelson based it on his experiences after being diagnosed with testicular cancer in the late 1980s. PMID- 28090966 TI - Nmc code can protect nurses under pressure. AB - Nurses are being urged to stand up to managers who ask them to carry out tasks for which they are not trained. PMID- 28090967 TI - OutsideIn. AB - As far back as I can remember, I have had a lot of time for space. Pulsars, quasars and distant swirling nebulae were a source of infinite fascination when I was a child. PMID- 28090969 TI - HCA training cuts could impede shift of care into community. AB - Funding for healthcare assistants' (HCAs) training has been slashed as strategic health authorities (SHAs) struggle with their budgets. PMID- 28090970 TI - Health visitors slam Down's storyline. AB - An East Enders episode that showed a health visitor reprimanding a young mother for refusing Down's syndrome screening has been branded 'insensitive and patronising'. PMID- 28090971 TI - Trust offers career breaks for staff to save L4.7 million. AB - A cash-strapped NHS trust is offering staff temporary redundancies until April next year, when it hopes to have enough funds to pay them again. PMID- 28090972 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28090973 TI - Dignity and respect on the agenda for care of older people. AB - A summit for nurse leaders involved in the care of older people is due to be hosted by the Department of Health in London this week. PMID- 28090974 TI - NHS Direct job cuts reduced but services still suffer. AB - Twelve NHS Direct call centres and 196 staff will be axed from the nurse-led telephone advice service, managers confirmed last week. PMID- 28090976 TI - Outside In. AB - There are two ways to descale an electric kettle - the expensive way and the cheap way. PMID- 28090977 TI - Ineligible for maternity benefits. AB - In my final year of a three-year diploma course in nursing studies I became pregnant. I completed the course and am now a fully qualified nurse. PMID- 28090975 TI - Pesticide residues in leafy vegetables and human health risk assessment in North Central agricultural areas of Chile. AB - To investigate pesticide residue concentrations and potential human health risk, a study was conducted in 118 leafy vegetable samples collected in 2014-2015 from the North Central agricultural areas of Chile. The pesticide residues were determined using the multiresidue QuEChERS method by gas chromatography as well as high-performance liquid chromatography. The results indicated that 27% of the total samples contained pesticide residues above the maximum residue limits of each active ingredient. The maximum estimated daily intake obtained for carbon disulphide (CS2), methamidophos, azoxystrobin and cypermethrin were 0.57, 0.07, 0.06 and 0.05 mg kg-1, respectively, which was higher than their acceptable daily intake. It is concluded that inhabitants of the North Central agricultural area of Chile are not exposed to health risks through the consumption of leafy vegetables with the exception of methamidophos. Nevertheless, the high levels of methamidophos detected in leafy vegetables could be considered a potential chronic health risk. PMID- 28090978 TI - Make my day, Arnie, and keep quiet. AB - Arnold Schwarzenegger thinks he can ignore nurses because they are 'a special interest group who don't like me because I'm always kicking their butt' (news February 9). PMID- 28090979 TI - Half-yearly appraisals would help. AB - I am a third-year adult nursing student due to qualify in September this year. PMID- 28090980 TI - Fair pay is all we seek. AB - I trained as a mature student, qualifying in 1986. I also trained as a health visitor and have worked in the same area for more than 16 years. I believed that Agenda for Change would recognise and reward nurses for hard work and their qualifications. I was wrong. PMID- 28090981 TI - Have a heart... save a heart. AB - An appeal to fund 30 heart nurses was launched on Valentine's Day by the British Heart Foundation, which wants to raise L1 million to help pay for 30 nurses. The charity already funds 180 posts, including Katy Stimson (pictured) and wants to continue to provide the funding for at least three years. To donate go to www.bhf.org.uk/realvalentine or call 0800 389 7087. PMID- 28090982 TI - Union concern over primary care billions. AB - NURSING UNIONS have welcomed the Department of Health's L135 billion allocation to primary care trusts (PCTs) in England. PMID- 28090984 TI - Rallies to protect pensions. AB - AN RCN POLL is expected to reveal that most nurses are opposed to the pension reforms revealed by the government last month. PMID- 28090983 TI - Seacole blue plaque plan delayed by building row. AB - PLANS TO honour Mary Seacole are being thwarted by an ongoing dispute between Westminster Council and the manufacturers of Red Bull energy drink. PMID- 28090985 TI - Documentary undermined good work. AB - The two nurses who filmed the footage for the Dispatches programme for three months undermined the good work that most nurses are doing, giving their utmost care to those in need. PMID- 28090986 TI - Negative media affects recruitment. AB - I was saddened and distressed at the care that the patients did not receive from nurses in the Dispatches programme. PMID- 28090987 TI - Too posh or too pushed? AB - I am a third-year student studying for a BSc in adult nursing. I was truly saddened by the Channel 4 documentary Undercover Angels. This was an inaccurate and deceitful portrayal of the nursing profession. PMID- 28090988 TI - Thesciencebit-David Newnham explains just why plastic is so fantastic. AB - Unimaginable though a world without plastics would be, it is only in the past 50 years that these materials have become a ubiquitous aspect of our lives. So what has made them such as success? PMID- 28090989 TI - Superb nursing care is still happening. AB - Reading about the Dispatches: Undercover Angels documentary (news, analysis February 9) brought to mind the care my mother received as a 96 year old in Selly Oak Hospital, Birmingham, about 18 months ago. PMID- 28090990 TI - Mental health nursing set for major overhaul. AB - A MAJOR REVIEW of mental health nursing was announced by England's chief nursing officer Christine Beasley last week. PMID- 28090993 TI - On the move. AB - Promotions / new appointments. PMID- 28090991 TI - Be clear and firm. AB - I had a letter from Kate, who was worried about her escalating stress levels. She had been away from work for six months following a car accident. She felt shaken by the experience and had lost some of her confidence. Kate had recovered physically but knew she was not ready to take on full-time hours. She had therefore decided to return part-time to her old post. PMID- 28090994 TI - Exploited foreign nurses end up washing dishes. AB - An international investigation has discovered evidence that foreign nurses are being intimidated and exploited in the UK. PMID- 28090995 TI - Free us from smoke. AB - Many things in life are debatable, but the fact that smoking is the single biggest avoidable cause of death and disability in developed countries is not one of them. PMID- 28090997 TI - Northern Ireland smoking ban call. AB - Medics have joined forces with nurses in Northern Ireland to campaign for a ban on smoking in public places. PMID- 28090996 TI - Startingout - Student Kathryn Haworth runs her first client session. AB - I had observed a number of smoking cessation appointments when the practice nurse asked if I would like to run the next one. It seemed a huge responsibility and I wondered if I could give appropriate care. PMID- 28090998 TI - High proportion of nurses willing to donate organs. AB - COMPARED WITH members of the public, nurses are almost twice as likely to carry an organ donor card, a survey reveals. PMID- 28091000 TI - Here's to immortality. AB - The news that a 20-year-old woman needed a liver transplant after years of heavy drinking reminded me of Wilfred Owen's poem Anthem for Doomed Youth - a moving reflection on the waste of young lives in the first world war. PMID- 28090999 TI - Standardlife. AB - What does 'a bad nurse' mean? A strange, somewhat philosophical question, and I realise this is your coffee break - but bear with me. This feels important. PMID- 28091001 TI - Welsh academy on recruitment drive. AB - NURSES ARE being invited to join an organisation due to be launched next month to promote nursing in Wales. PMID- 28091002 TI - Half of trusts lack obesity clinics. AB - Obese patients are being denied the help they need from primary care trusts (PCTs). PMID- 28091003 TI - Unison predicts victory in landmark equal pay case. AB - Hundreds of nurses are confident they will each receive tens of thousands of pounds in compensation after claiming they have been denied equal pay. PMID- 28091004 TI - Trust is refused access to tapes. AB - ONE OF the NHS trusts criticised in the Channel 4 Dispatches documentary Undercover Angels says the programme makers have refused its request for help in identifying the nurses accused of poor practice. PMID- 28091005 TI - Documentary gave 'misleading' picture. AB - STEPHEN NICHOLSON, RCN steward at the Royal United Hospital (RUH) in Bath, has his say on the recent Dispatches programme Undercover Angels, which was highly critical of nurses at his hospital. PMID- 28091006 TI - Researchnotes. AB - Advances in research governance and the blending of processes for seeking ethical approval have created a climate dominated by risk aversion. Ethics committees focus their efforts on ensuring risks to participants are proportional to the potential benefits. Unfortunately, the same degree of proportionality is not afforded to the review of low-risk research, much of it coming from the nursing profession. PMID- 28091008 TI - A barrier to health. AB - The 140 mile security fence that divides the West Bank from Israel has caused major access problems for Palestinian healthcare workers and patients, claims a new report. PMID- 28091007 TI - Tsunami aftermath. AB - The effects of the Asian tsunami that struck on December 26 were all too obvious. More than 250,000 people lost their lives, many towns and villages were destroyed and survivors face health problems and the loss of their communities and livelihoods. PMID- 28091009 TI - Vitamin intake in pregnancy link to wheeze and eczema. AB - Maternal antioxidant intakes during pregnancy may modify the risks of developing wheeze and eczema during early childhood. PMID- 28091011 TI - Nurses' decision-making in clinical practice. AB - Aim To identify what decisions nurses make in medical, surgical and critical care areas and compare the results. Method A clinical decision-making questionnaire (CDMQ) consisting of 15 statements was developed. A total of 60 nurses completed the questionnaire: 20 from each of three clinical areas. Results Most nurses, in all specialties, regularly made clinical decisions on direct patient care, which included providing basic nursing care and psychological support, and teaching patients and/or family members. Although nurses in all specialties regularly managed the work environment, they did not make decisions on the ward or unit budget, supervise junior staff or mentor student nurses. Critical care nurses regularly made decisions on their extended roles, such as acting in emergency situations and deciding to change patient medication, while medical and surgical nurses only did this occasionally. Length of clinical experience is significantly related to the frequency of decision-making. Conclusion The decisions nurses make are directly related to the clinical areas in which they work. However, it would be interesting to know if nurses showed particular aptitudes for different types and levels of decision- making and if this is related to other factors such as personality, education and experience in nursing. PMID- 28091013 TI - The Practitioner as Teacher The Practitioner as Teacher Sue Hinchliff Churchill Livingstone 172pp ; L17.99 0 443 07286 8 0443072868. AB - The focus of this book is supporting learning in clinical practice. Five clearly defined sections concentrate on a wide range of issues that indicate the what, why and how in the process of sustaining learning. PMID- 28091012 TI - What's on: The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28091014 TI - Olympics will be good for health. AB - The NHS in London has thrown its weight behind the city's bid to host the 2012 Olympic and Paralympic Games, claiming that there would be many public health benefits if the bid succeeds. The North East London Strategic Health Authority, which covers the area in which most events would be held, is paying for posters (above) promoting the bid to be placed on buses. Chief executive Carolyn Regan said: 'Our campaign aims to harness the inspiration of Olympic achievement to promote the proven benefits of regular exercise.' For further information visit www.fitforlondon2012.nhs.uk. PMID- 28091015 TI - D-day for mental health. AB - THERE COULD be no better time for a review of mental health nursing. It is 11 years since the last one, which in itself suggests change must be overdue if professional practice is to keep pace with health service reforms. As the largest professional group in mental health care, nurses will be relied on to deliver the reforms outlined in the Mental Health Bill, as well as the measures to improve race equality in the service. Nurses will also be promoting good mental health as outlined in last autumn's public health white paper. All these initiatives can only benefit from the chance to take stock. PMID- 28091016 TI - Risk of psychosis in young cannabis users clarified. AB - Cannabis use moderately increases the risk of psychotic symptoms in young people but has a much stronger effect in those with evidence of predisposition to psychosis. PMID- 28091017 TI - Open and shut. AB - The British disease I do not think so. It is the British attitude to drinking that causes difficulties. We all know sections of the population regularly drink themselves into oblivion then often indulge in violent and other antisocial behaviour. Researchers should be asking why this seems to be a uniquely be asking why this seems to be a uniquely British trait. Other European countries have had long opening hours for decades without these sort of problems - unless, of course, the British are on holiday there. Relaxing the licensing laws could actually help - people may see the benefits of drinking alcohol in a more relaxed environment and take things slowly. PMID- 28091019 TI - Weight is a risk factor for treatment mortality in AML. AB - Underweight or overweight children with acute myeloid leukaemia (AML) are more likely to succumb to treatment-related complications than their normal weight counterparts. PMID- 28091018 TI - Injuries less likely in t'ai chithan in other martial arts. AB - Different martial arts have significantly different types and distribution of injuries, a team of researchers from Canada has found. PMID- 28091020 TI - Direct action. AB - Throughout the UK new structures are evolving to commission and supply nursing care in primary care settings. While these tend to concentrate on services historically provided by community trusts and health boards, such as district nursing, health visiting and school nursing, attention is now being directed to practice nursing. PMID- 28091021 TI - Take the reins. AB - THIRTY YEARS after the last major overhaul of services for people with learning disabilities, the government has launched a new White Paper to bring them into the 21st century. PMID- 28091023 TI - Back to the classroom. AB - Jane Lovell (centre left) and Liz Schofield (centre right), both first-year students on an advanced nursing diploma course at Bradford University, are sitting in on classes at Eastburn Junior and Infant School near Keighley, West Yorkshire, for a fortnight to gain knowledge about the development of healthy children. PMID- 28091022 TI - 12-hour shift trial proves effective and popular. AB - A HUGELY successful system involving two 12-hour shifts a week has challenged traditional views that longer hours inevitably mean exhausted staff and worse patient care. PMID- 28091024 TI - Nurses to head up retirement health checks. AB - PILOT PROJECTS aiming to give health checks to everyone retiring from work will be spearheaded by practice and occupational health nurses. PMID- 28091025 TI - Overseas staff get lessons in dialect. AB - OVERSEAS NURSES in Walsall are learning Black Country dialect so they can understand what patients and colleagues are saying. PMID- 28091026 TI - Standard life. AB - I am not one to bear a grudge, but if Nobby Hall ever crosses my path again, he'll wish he'd never belted me 28 years, three months and two days ago near Deirdre Jordan's peg in the F to M section of the school cloakroom. PMID- 28091027 TI - We all make mistakes. PMID- 28091028 TI - Outside in. AB - Children, say the sugar-pop peddlers, the sellers of sticky sweets and the makers of salted fat nibbles, are far too smart to be taken in by television. PMID- 28091030 TI - National service framework standards. AB - 1. Rooting out discrimination: NHS services will be provided, regardless of age, on the basis of clinical need alone. PMID- 28091029 TI - Boost for new intermediate services. AB - NEW INTERMEDIATE care services outlined in the long-awaited English National Service Framework (NSF) for Older People are expected to prevent 70,000 unnecessary admissions to hospital by 2004. PMID- 28091031 TI - Best placed. AB - THERE CAN'T be many nurses who I would wish themselves back to their I student days. But such has been the I pace of change at University Hospital I Lewisham, south London, that Helen I Osiruemu, who qualified last October, hankers to go back. 'I wish I was a student again in the sense that they are getting so much that is beneficial - which I didn't get the chance to do. Now I'm just beginning to learn what they learn as students,' she says. PMID- 28091032 TI - In the hot seat. AB - The dangers of long-haul journeys, whether by car, coach, train or plane are to be spelt out by deep vein thrombosis nurse Tracy Kerr this week. Ms Kerr, who is to hold a sharing good practice forum at Colchester General Hospital where she works, said: 'Anyone who travels for long periods of time by any mode of transport is potentially at risk. You should not remain immobile for more than three hours.' PMID- 28091035 TI - Shock at lack of trust recognition. AB - HEALTH MANAGERS and nurses across the world have expressed astonishment that the NHS does not have a system of accrediting high- performing hospitals. PMID- 28091033 TI - Overhaul for 'out of date' NHS pensions scheme. AB - AN OVERHAUL of the NHS pensions scheme is due next year, bringing a better deal for non-married couples, both straight and gay, and those working past 60. PMID- 28091036 TI - Too much nursing care is delegated to support staff. AB - A HARD-HITTING report from a committee of government advisers has added weight to the RCN's call for the broadest possible definition of nursing care. PMID- 28091038 TI - On the move. AB - Promotions / new appointments. PMID- 28091037 TI - Critical care staffing below standard. AB - NURSE-TO-BED ratios in critical care vary too much in Wales and fall well below recommended standards, research shows. PMID- 28091039 TI - Express yourself. AB - Robin Norwood, well known for her bestseller Women Who Love Too Much, offers a revolutionary perspective on adversity that addresses people's deepest and most disturbing questions. Why is this happening to me? Why now? What does my life mean? PMID- 28091040 TI - Bill goes ahead. AB - THE HEALTH and Social Care Bill will receive Royal Assent this month, if a general election is held in June rather than the previously expected May 3. PMID- 28091041 TI - Ask the experts. AB - am a G grade district nurse and will shortly have to interview for a G grade vacancy in our team. It is at least five years since I last interviewed anyone and I feel my skills need refreshing. I will be leading a panel of three including a GP and a representative from human resources. Can you give me any advice? PMID- 28091042 TI - Cardiac liaison nurses will improve hospital's care. AB - A TEAM of five cardiac liaison nurses is to 'improve care immeasurably' at two specialist heart hospitals investigated over the deaths of dozens of children. PMID- 28091043 TI - MPs urge greater powers for community nurses. AB - HEALTH VISITORS should be given the chance to broaden their horizons and take the lead in improving public health, an influential group of MPs told the government last week. PMID- 28091045 TI - Demonstration over rent hike. AB - STUDENTS FURIOUS over massive rent hikes at their accommodation blocks will demonstrate before a trust board meeting this week. PMID- 28091046 TI - What's on: the best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28091047 TI - The Practitioner as Teacher The Practitioner as Teacher Hinchliff Sue Balliere Tindall/RCN L16.95 0 7020 2447 3 07020 24473. AB - This book focuses on teaching and learning methods with an overview of assessment processes in the move to competency-based professional education and vocational training. PMID- 28091048 TI - Home front. AB - Ninety-year-old Ivy Tabberer protested against the closure of her care home at the Houses of Parliament last week. She was joined by fellow residents in the Havering Action Against Home Closures group and three generations of her family. Ms Tabberer is pictured with daughter Doreen Walpole (left), granddaughter Annette (far right) and great granddaughter Shereen (middle). 'If all the homes close,' said Ms Tabberer, 'where are we going to stay?' PMID- 28091049 TI - L80,000 pay-out. AB - CLINICAL NURSE manager Jane Addo has been awarded almost L80,000 after an industrial tribunal found her employer, Surrey Hampshire Borders NHS Trust, discriminated against her on grounds of race and dismissed her unfairly when they made her redundant three years ago. The tribunal found Ms Addo suffered severe distress. The trust has apologised to Ms Addo and has reviewed its equal opportunities practices. PMID- 28091050 TI - Journey of discovery. AB - Caroline King did not know what to expect when she swapped her health promotion job in Aberdeen for a similar role on the tiny island of Pemba, off the Tanzanian coast. PMID- 28091051 TI - Water fluoridation has improved our lives. AB - As a public health dentist I have seen the reduction in decay and dental pain experienced by children living in areas with fluoridated water. The RCN is to be congratulated for supporting water fluoridation in its manifesto (letters March 14). PMID- 28091052 TI - Pressure on A&E will not disappear overnight. AB - In response to 'Report adds to furore over A&E chaos' (news March 28) we, as RCN stewards at East Kent Hospitals NHS Trust, would like to state the following. PMID- 28091053 TI - 'Real' job evaluation will test new grading structure. AB - FIVE HUNDRED NHS staff including nurses are to have their jobs evaluated over the coming weeks in the next stage of the proposed shake- up of pay and grading. PMID- 28091054 TI - Bursary increases unfair to students outside England. AB - I am disappointed that the recent increase in student bursaries applies to England only. PMID- 28091055 TI - It's what you know, not what you do that counts. AB - The problem with separating nursing care from personal care (perspectives March 14) is that it overlooks that this is an artificial and unnecessary construct. There is no distinction between nursing and personal care in a care setting - be it publicly or privately run. PMID- 28091057 TI - Enjoyable placements will reduce student drop outs. AB - I am a first year nursing student at Birmingham University and have just completed a thoroughly enjoyable and worthwhile placement on ward East 5 at the Queen Elizabeth Hospital in Birmingham. PMID- 28091056 TI - Residents should be able to get up when they want. AB - I read Steven Griffin's response to a question on getting elderly residents in nursing homes up (perspectives February 21) and would like to point out there is no incentive to carry out night assessments. PMID- 28091058 TI - Raising the standard. AB - NURSES WITH a particular interest in the care of older people can be forgiven if they are cheering to the rafters at the moment. The publication - at long last - of the National Service Framework for Older People is good cause for celebration. PMID- 28091059 TI - Success stories. AB - Lorraine Bates and Jack have been coming to the exercise class since it started 18 months ago. PMID- 28091061 TI - Privatisation is 'senseless". AB - THE GOVERNMENT'S private finance initiative (PFI) to fund new hospital buildings was dismissed as 'senseless' by unison general secretary Dave Prentis. PMID- 28091060 TI - Hormone treatments for cattle are not legal in UK. AB - With reference to Fo Ettinger's article 'Eastern promise' (perspectives March 14), as a qualified nurse and dairy farmer I feel I must write to correct some very misleading statements. PMID- 28091062 TI - Who wants to work 12-hour shifts? AB - THE IDEA of working 12-hour shifts never seems too appealing. Indeed, one school of thought believes that such long shifts must surely lead to staff exhaustion and exhausted staff are bound to make more errors. As sure as fate, sickness levels will rise and, therefore, so will spending on agency staff to provide cover. All of which sounds extremely plausible, especially for those of us who have never worked the dreaded dozen-hour shifts. But is it all true, or has a myth grown up around 12-hour shifts that has no basis in fact? PMID- 28091064 TI - Lie-ins stop burn out. AB - NURSES AND other staff should be allowed to sleep in on occasions and so avoid the dangers of 'burn out', Unison's national healthcare conference heard. PMID- 28091063 TI - Fresh call for student salaries. AB - GIVING NURSING students salaries and full employment rights would improve their pay and conditions, and enhance the value and respect they receive from other staff, the Unison conference heard. PMID- 28091065 TI - Trust-wide approach to A&E could cut waiting. AB - MANAGERS OF trusts with high A&E waiting times have been urged to integrate casualty services with other hospital departments. PMID- 28091067 TI - Commons told of MRSA cover-up. AB - THE RCN has defended hospitals from an MP's claims of a cover-up of thousands of deaths from methicillin-resistant Staphylococus aureus (MRSA). PMID- 28091066 TI - You've got the power. AB - IMPROVING PEOPLE'S health often means changing their lifestyles and behaviour, which is never easy But the nurses engaged in community development in the poorer areas of the south coast resort of Bournemouth have found one way to make it happen. PMID- 28091069 TI - Just the ticket. AB - Nurses from Blackpool, Wyre and Fylde Community Health Services NHS Trust last week helped launch a new recruitment campaign to woo nurses back to the profession. The 'return to nursing' slogan will be seen on local bus posters over the next 12 months. PMID- 28091070 TI - Alcohol puts cyclists at high risk of serious injury. AB - People who cycle after drinking alcohol are up to 20 times more likely to sustain fatal or serious injury than those who haven't consumed alcohol. PMID- 28091071 TI - Assault cases fluctuate in seasonal peaks and troughs. AB - The number of people who attend A&E departments after being assaulted is highest between July and September and lowest during February to April. PMID- 28091072 TI - Fewer patients request antibiotics for minor illness. AB - Patients with minor illnesses are less likely to ask GPs for antibiotics, according to Liverpool researchers. PMID- 28091073 TI - A weekly round-up of the latest research and scientific reports from the nursing and medical journals. AB - Packing pathology specimens in dry ice in airtight containers poses a risk of explosion, according to UK researchers. PMID- 28091074 TI - 'Methods and Systems for Tracking, Tracing and Verifying Foods' Greenbelt, MD, USA, 13 15 May 2009. PMID- 28091075 TI - My induction course was a fantastic start to a new job. AB - Following the letter from Pam Regan about her disappointing induction to her trust (letters May 16), I must say how wonderful mine was. The training officers were fantastic and very approachable. They are always on the wards and make you feel part of the team from day one. PMID- 28091076 TI - Chocolates and flowers make acceptable gifts. AB - I am pleased to see common sense has prevailed in the debate about gifts from patients. Some patients are very grateful and it is their way of saying thank you. This is so important (news May 16). PMID- 28091077 TI - Improving health care through Payment by Results. PMID- 28091078 TI - Choose and book system does not accept nurse referrals. AB - I am heartened that the NHS email system is ahead of schedule (letters April 11, May 9). However, there are still areas of the IT programme that do not seem to allow for, or accept, the expanding role of nurses. PMID- 28091079 TI - Experienced practitioners can be trusted to avoid overzealous policing. AB - I found Jane Bates' article about parents being afraid of taking their children to A&E worrying (reflections May 16). I am a first-year nursing student (child branch) near the end of an enlightening community placement, where I have spent many months with dedicated health visitors. PMID- 28091080 TI - Jane Bates' comments are based on hearsay not facts. AB - Jane Bates suggests that families are reluctant to take children to A&E because of 'overzealous policing' by health visitors after an A&E visit (reflections May 16). PMID- 28091082 TI - The best of the week's health-related tv and radio. AB - Our roundup of what's on. PMID- 28091083 TI - Outsidein. AB - I have a splinter. 'Big deal,' you say. 'If you only knew what some people suffer...' And I take your point entirely. What do you think I am? Silly? PMID- 28091084 TI - Groundhog day. AB - I think I have cliche phobia. The symptoms are a feeling of acute despair, pursed lips and grinding teeth. It happens every time I hear nurses complain in the media about the pay rise. PMID- 28091086 TI - Theatre staff are right to take a stand on downgrading. AB - I fully support the theatre nurses from Barnsley who are considering striking (news May 9). Many nursing roles rely on goodwill, which nurses generally give willingly. The proposed downgrading of their roles is anotherexample of the government andNHS taking advantage of nurses' good natures. PMID- 28091087 TI - Reorganisations and targets have left us all demoralised. AB - Many will say nurses have done well from the Blair years, with Agenda for Change and relatively stable pay awards. However, in the 20 years I have worked for the NHS I have never seen such a demoralised workforce. PMID- 28091088 TI - Student life-no barriers to nursing. AB - Having a disability is no longer a barrier to becoming a nurse. Today's universities are accustomed to supporting students with a wide range of disabilities, including dyslexia, diabetes, mental health difficulties, hearing or visual impairments and mobility difficulties. PMID- 28091089 TI - Words of wisdom. PMID- 28091091 TI - 'Judge me on my work'. AB - Many months in hospital when I was a teenager cemented my decision to become a nurse. Although I did not appreciate the obstacles I would face in fulfilling my dream, the pleasure I got then from helping the nurses and parents look after sick children in the ward made me realise this was what I wanted. PMID- 28091092 TI - Unions join forces to maximise the impact of industrial action. AB - Leaders of the RCN and Unison have agreed to synchronise their ballots on industrial action over the staged pay award to maximise the impact of their campaigns. PMID- 28091093 TI - Essential skills study shows mentorship may be failing. AB - As a second-year nursing student, I am taught to check the validity of research material. I was, therefore, surprised by your item Top ten 'essential' skills performed inadequately (news May 16), reporting on a study that asked mentors to list the essential skills they believed newly qualified nurses should have, and then estimate the proportion of staff who were able to carry out the skills appropriately. PMID- 28091094 TI - Pressure for full pay rise in wales. AB - Nurses in Wales are keeping up pressure on the Liberal Democrats and Plaid Cymru to keep their promise to give nurses the full 2.5 per cent pay increase if they win power. PMID- 28091096 TI - Over-75squalify as gym trainers. AB - Older people in Liverpool have qualified as gym trainers in a bid to encourage fitness in the city. PMID- 28091095 TI - Our cancer courses benefit people in all income groups. AB - In response to Gill Oliver's comments about our website (reviews May 2), what we offer at Penny Brohn Cancer Care benefits people with cancer and their supporters at many levels, irrespective of background or financial status. PMID- 28091097 TI - Do 'really cool' badges sum up the essence of nursing? AB - To commemorate international nurses' day on May 12 (news May 9) the RCN West Midlands quality improvement network steering committee attended a conference for clinical support workers and newly qualified nurses. PMID- 28091098 TI - Optimism as brown insists the NHS is safe in his hands. AB - As Gordon Brown prepares to pocket the keys to 10 Downing Street, not everything is hunky-dory in the NHS. PMID- 28091099 TI - Scottish leaders seek urgent meeting with new health secretary. AB - Nursing leaders in Scotland are seeking an urgent meeting with the new cabinet secretary for health and wellbeing - and workforce planning is near the top of their agenda. PMID- 28091100 TI - Watchdog calls for robust action on nutrition. AB - Patients at some NHS trusts in England are not getting the help they need at mealtimes, according to the results of a Healthcare Commission survey. PMID- 28091101 TI - Celebrating in style. AB - Jamaican nurses marked the bicentenary of the Abolition of the Slave Trade Act with music and dance. PMID- 28091102 TI - Working excess hours increases risk of miscarriage. AB - Nurses who work more than 40 hours a week or do nights on a regular basis once they become pregnant run a significant risk of miscarriage within the first 20 weeks of pregnancy. PMID- 28091103 TI - Ban drivers from smoking. AB - Banning smoking while driving would help reduce pressure on nurses in A&E and mental health, according to experts. PMID- 28091104 TI - Animal abuse linked to domestic violence. AB - The link between violence against pets, child abuse and domestic violence is to be investigated by the Royal Society for the Prevention of Cruelty to Animals (RSPCA). PMID- 28091105 TI - Trusts had earmarked sufficient funds to pay the full 2.5 per cent. AB - The 2.5 per cent pay award for NHS staff was affordable and trusts had set aside more than enough cash to pay it in full, according to RCN general secretary Peter Carter. PMID- 28091106 TI - Starting out - I lackedconfidencetospeakup formypatient'sbestinterests. AB - On the first day in my new hospital placement I received a handover and was instructed to work with a healthcare assistant. I was shown to a patient's room by the care assistant and asked to undress and wash an older female patient. PMID- 28091107 TI - RCN leaders head to global conference. AB - Around 3,000 nurses from 96 countries are expected to attend the International Council of Nurses biennial conference in Yokohama, Japan, next week. PMID- 28091109 TI - Regulators accused of breaching own code on product promotion. AB - The Nursing and Midwifery Council (NMC) has been accused of breaching its own Code of Professional Conduct. PMID- 28091108 TI - Performance ratings to include patient respect and dignity. AB - The Healthcare Commission is to start measuring the degree to which staff treat patients with respect, care and dignity. PMID- 28091110 TI - Read all about it - operation cancelled. AB - When the date of my daughter's operation finally arrived, we all hoped it would end Abigail's headaches, which she first reported to our GP almost a year ago. PMID- 28091112 TI - Readers panel-Discrimination or common sense? AB - Our experts consider a hot topic of the day. PMID- 28091111 TI - Webwise. AB - Founded in 1985, Action on Disability and Development (ADD) is a UK-registered charity that works with disabled people in Africa, Cambodia, India and Bangladesh. It is unique in supporting disabled people in Africa and Asia with a rights-based approach. PMID- 28091113 TI - Post-match spectator aggression linked to winning not losing. AB - Watching their rugby team win will not increase fans' happiness and it may make them more aggressive. PMID- 28091115 TI - Standard life. AB - I tell anyone who asks that I gave up nursing because it made me do things to people that I did not like doing. By the end, I had become more custodian than mental health nurse. PMID- 28091116 TI - Voices - There are plenty of ways to commemorate our great historical nurses. AB - Edith Cavell never wanted to be remembered as a martyr or heroine but simply as a nurse who tried to do her duty. RCN general secretary Peter Carter said recently she was 'one of three historical figures in nursing who deserve respect'. May is a good month in which to remember them. PMID- 28091117 TI - Female naval recruits who smoke have poor work performance. AB - Women who are regular smokers when they join the navy are more likely than their non-smoking counterparts to perform poorly. PMID- 28091119 TI - Staff and patients excluded from NHS foundation trust meetings. AB - At least two NHS foundation trusts have banned staff and patients from attending board meetings, Nursing Standard has learned. PMID- 28091120 TI - Irish nurses' victory. AB - Industrial action by nurses in the Republic of Ireland seems to have paid off after they received an improved pay and conditions offer. PMID- 28091121 TI - Advice on avoiding peanuts in pregnancy poorly understood. AB - Government advice for women who are atopic to avoid peanuts during pregnancy and breastfeeding is either being misunderstood by mothers or not explained fully by health professionals. PMID- 28091122 TI - Be positive about diversity. AB - I am delighted to be invited by Nursing Standard to act as guest editor for its first special issue on disabilities. In light of the amended Disability Discrimination Act (2005) and the act's disability equality duty, all public authorities are required to look actively at ways of ensuring that people with disabilities are treated fairly. PMID- 28091123 TI - More people with disabilities gain access to nursing diploma courses. AB - The number of people with a disability who have been accepted on to nurse diploma courses has more than doubled over the past five years, data from the Nursing and Midwifery Admissions Service reveals. PMID- 28091124 TI - South Africa is failing its children with disabilities. AB - Researchers in Switzerland and South Africa claim that South Africa's one million children with disabilities do not receive adequate attention from health, education and social welfare departments ( Saloojee et al 2007 ). PMID- 28091125 TI - Working as a clinical studies officer. AB - I work in the East Midlands hub of the UK Mental Health Research Network. The team hosts eight national and international studies including research in attention deficit disorder and comparisons between drug treatments for bipolar disorder and schizophrenia. PMID- 28091126 TI - Association between perfluoroalkyl substance exposure and asthma and allergic disease in children as modified by MMR vaccination. AB - Perfluoroalkyl substances (PFASs) are highly persistent chemicals that might be associated with asthma and allergy, but the associations remain unclear. Therefore, this study examined whether pre- and postnatal PFAS exposure was associated with childhood asthma and allergy. Measles, mumps, and rubella (MMR) vaccination in early life may have a protective effect against asthma and allergy, and MMR vaccination is therefore taken into account when evaluating these associations. In a cohort of Faroese children whose mothers were recruited during pregnancy, serum concentrations of five PFASs - Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) - were measured at three timepoints (maternal serum in pregnancy week 34-36 and child serum at ages 5 and 13 years) and their association with immunoglobulin E (IgE) (cord blood and at age 7 years) and asthma/allergic diseases (questionnaires at ages 5 and 13 years and skin prick test at age 13 years) was determined. A total of 559 children were included in the analyses. Interactions with MMR vaccination were evaluated. Among 22 MMR-unvaccinated children, higher levels of the five PFASs at age 5 years were associated with increased odds of asthma at ages 5 and 13. The associations were reversed among MMR-vaccinated children. Prenatal PFAS exposure was not associated with childhood asthma or allergic diseases regardless of MMR vaccination status. In conclusion, PFAS exposure at age 5 was associated with increased risk of asthma among a small subgroup of MMR-unvaccinated children but not among MMR-vaccinated children. While PFAS exposure may impact immune system functions, this study suggests that MMR vaccination might be a potential effect-modifier. PMID- 28091128 TI - I always treat patients as if they are lords and ladies. AB - Nursing student Karin Schirmaier is right to point out that patients want to conform, so they will not necessarily tell us how they would like to be addressed, even if we ask them (reflections August 18). PMID- 28091129 TI - Guidance should end mystery of learning difficulties. AB - The recently launched RCN guidance on dyslexia, dyspraxia and dyscalculia (news August 18) provides managers with concise explanations and information on making practical accommodation in the workplace for staff with specific learning difficulties (SpLDs). PMID- 28091127 TI - Amino-modified polystyrene nanoparticles affect signalling pathways of the sea urchin (Paracentrotus lividus) embryos. AB - Polystyrene nanoparticles have been shown to pose serious risk to marine organisms including sea urchin embryos based on their surface properties and consequently behaviour in natural sea water. The aim of this study is to investigate the toxicity pathways of amino polystyrene nanoparticles (PS-NH2, 50 nm) in Paracentrotus lividus embryos in terms of development and signalling at both protein and gene levels. Two sub-lethal concentrations of 3 and 4 MUg/mL of PS-NH2 were used to expose sea urchin embryos in natural sea water (PS-NH2 as aggregates of 143 +/- 5 nm). At 24 and 48 h post-fertilisation (hpf) embryonic development was monitored and variations in the levels of key proteins involved in stress response and development (Hsp70, Hsp60, MnSOD, Phospho-p38 Mapk) as well as the modulation of target genes (Pl-Hsp70, Pl-Hsp60, Pl-Cytochrome b, Pl p38 Mapk, Pl-Caspase 8, Pl-Univin) were measured. At 48 hpf various striking teratogenic effects were observed such as the occurrence of cells/masses randomly distributed, severe skeletal defects and delayed development. At 24 hpf a significant up-regulation of Pl-Hsp70, Pl-p38 Mapk, Pl-Univin and Pl-Cas8 genes was found, while at 48 hpf only for Pl-Univin was observed. Protein profile showed different patterns as a significant increase of Hsp70 and Hsp60 only after 48 hpf compared to controls. Conversely, P-p38 Mapk protein significantly increased at 24 hpf and decreased at 48 hpf. Our findings highlight that PS-NH2 are able to disrupt sea urchin embryos development by modulating protein and gene profile providing new understandings into the signalling pathways involved. PMID- 28091130 TI - Webwise. AB - The Center for Reproductive Rights envisages a world where every woman participates as an equal member of society. Based in the United States, it uses the law to advance reproductive freedom as a fundamental human right that all governments are obliged to protect and fulfil. PMID- 28091132 TI - Ideas needed to promote university health society. AB - I am a first-year adult nursing student at Sheffield Hallam University, student representative for the adult nursing 2010 branch and president of the university's Health Society. PMID- 28091131 TI - Benchmarking is key to prevention of cardiac arrest. AB - The automatic triggering of a critical incident review for all unexpected cardiac arrests, as proposed by the National Patient Safety Agency (news August 25), should enable organisations to identify readily the remedial factors that may contribute towards a 'failure to rescue'. PMID- 28091133 TI - Make a big noise to cause an avalanche of change. AB - The government wants to use the budget deficit as an excuse to make huge changes to the NHS. We need to show that the NHS is enormously popular and has the overwhelming support of the people of the UK. PMID- 28091134 TI - Community engagement in dementia care. AB - Creating a homely area in a dementia care ward is the goal of Bodmin Hospital, part of Cornwall Partnership NHS trust, which is taking part in the Enhancing the Healing Environment (EHE) dementia care scheme. PMID- 28091135 TI - Nurse who lost leg in accident awarded damages. AB - A former psychiatric nursing student who lost her leg in a motorbike accident has been awarded nearly L1 million in compensation. PMID- 28091137 TI - New '111' service set to replace NHS direct after pilots completed. AB - NHS Direct will be replaced by the new non-emergency 111 telephone service if it is rolled out nationwide, the Department of Health (DH) has confirmed. PMID- 28091139 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28091140 TI - Sometimes nurses need a shoulder to cry on too. AB - Louise Stayt's article on the way nurses experience bereavement after the death of critically ill patients to whom they have grown close vividly illustrates their distress (career development August 18). It reminded me of my own experience and those of the teams with whom I worked. PMID- 28091142 TI - 'Fall' in vacancies may be result of deliberate policy to cut costs. AB - Official figures suggest that nurse vacancy rates have fallen, prompting concerns that newly qualified nurses will struggle to find jobs. PMID- 28091141 TI - England's white paper means double whammy for nurses. AB - I enjoyed Howard Catton's analysis of the health white paper (August 18), although enjoyed is perhaps the wrong word. PMID- 28091143 TI - Handheld devices will keep lines of communication open. AB - Further to the news story on the iNurse application for Blackberry mobile phones (August 25), I welcome any initiative that frees up nurses and community teams to spend more time on patient care. PMID- 28091144 TI - Flood aid targets infection risk. AB - Nurses in Pakistan are battling to prevent malnutrition and help people who have contracted waterborne diseases. PMID- 28091145 TI - Unhealthy competition between trusts could damage patient care. AB - Increased competition among NHS trusts is discouraging healthcare workers from sharing information on best practice (news and editorial August 25), with some nurses forbidden from sharing ideas outside their organisation. PMID- 28091146 TI - School nurses need training for complex mental health work. AB - Nearly half of school nurses have not received any post-registration training in mental health despite it being an essential part of their work, according to research. PMID- 28091147 TI - Pre-washed solution for new uniforms. AB - National nurses' uniforms in Wales are being reintroduced after allergic reactions among staff halted the roll-out earlier this year. PMID- 28091148 TI - Extra staff would help combat STIs. AB - More school nurses need to be recruited to tackle the increase in rates of sexually transmitted infections (STIs), the RCN says. PMID- 28091149 TI - Jealously guarding initiatives can only halt progress. AB - I was saddened, but not surprised, to read that an Institute for Employment Studies survey found healthcare workers are being forbidden to share ideas outside their organisation (news and editorial, August 25). PMID- 28091150 TI - Cycling is better for weight control than slow walking. AB - Cycling, similar to brisk walking, is associated with less weight gain than non cycling. An inverse relationship exists, especially among overweight and obese women. PMID- 28091151 TI - Call for action to protect pupils from widespread 'grooming'. AB - School nurses should be looking for signals that pupils are being groomed for sexual exploitation, their annual conference was told. PMID- 28091152 TI - Readers panel - A matter of life and death. PMID- 28091153 TI - Three-year plan could provide lead diabetes roles. AB - Nurses could soon have greater opportunities to influence the provision of diabetes care. PMID- 28091154 TI - Study reveals effects of glucosamine on chronic low back pain. AB - Six months' treatment with glucosamine does not reduce pain for patients with lower back pain and degenerative lumbar osteoarthritis, a study has revealed. PMID- 28091157 TI - RCN urges UK governments to bolster community workforce. AB - The community nursing workforce needs to be well resourced and appropriately deployed to provide quality services through the economic downturn, says the RCN. PMID- 28091156 TI - Age limits. AB - A friend had a memorable visit to casualty, when she turned up with a minor injury. Not only was she seen within 45 minutes of her arrival - surely a national record - but she witnessed the most astonishing behaviour from some of her fellow attendees. PMID- 28091158 TI - Charities and college call for 24/7 care. AB - Round-the-clock district nursing care is needed to improve palliative care, according to a leading cancer charity. PMID- 28091159 TI - Complaints figures on the increase. AB - The RCN has defended the profession after official figures showed the number of complaints about nurses has increased. PMID- 28091160 TI - Colon cancer screening test less accurate in hot temperatures. AB - A study has revealed that the proportion of positive faecal occult blood tests (FOBTs) is significantly smaller in the summer than in the winter. PMID- 28091161 TI - Intensive mobile phone use linked with onset of tinnitus. AB - New research has revealed that people who use mobile phones intensively have an increased risk of developing tinnitus. PMID- 28091162 TI - Workforce. AB - The recent suggestion that assistant practitioners (APs) could be regulated as 'second level nurses' brings us full circle. The nursing profession presided over the demise of the enrolled nurse role, but is now seeing it return as an employer led 'solution' to costs. PMID- 28091163 TI - Small local savings can have huge implications, writes rosemary cook. AB - Multiplication was no one's favourite part of mathematics at school, but there is no doubt it has its uses. PMID- 28091164 TI - 'I see how treatment helps people stay independent'. AB - Home oxygen therapy is a highly technical service tailored to patients' particular needs. My job is to advise professional colleagues and patients about the range of respiratory therapies that Air Products offers in partnership with the NHS to help patients live independently at home. PMID- 28091165 TI - Push for change. PMID- 28091166 TI - A change of scenery. PMID- 28091167 TI - Starting out - Learning disability placement helped me observe boundaries. AB - My first placement was with a young adult who had Down's syndrome and associated learning difficulties. During the placement, I spent one day a week at his specialist secondary school. PMID- 28091169 TI - Back to the community. AB - Community nurses have been placed at the centre of plans to reform the NHS in all four UK countries. There is an assumption that more care will be delivered in, or closer to, patients' homes as the NHS strives to minimise hospital admissions. This is partly driven by the need to save money - as keeping a patient on a hospital ward overnight is so expensive - and also in response to patients' preference to be nearer their families and friends. PMID- 28091170 TI - A nurse with more than one string to his bow. AB - Community nurse Roberto Cassani swapped his day job for the stage at this year's Edinburgh Fringe. PMID- 28091171 TI - Malnutrition screening essential for older patients, says age charity. AB - Nurses are being urged to screen all older patients at risk of malnutrition when they arrive in hospital and throughout their stay. PMID- 28091172 TI - Pressure on universities to find more community placements. AB - Nursing students at the University of Bradford can experience community care by joining teams that specialise in smoking cessation, care of the homeless and cardiac rehabilitation. PMID- 28091174 TI - Great nurses will provide great healthcare services. AB - NHS Ayrshire and Arran nurse director Fiona McQueen is professionally accountable to the board for every aspect of nursing practice, writes Derek Barron. She is politically accountable for healthcare-associated infections, patient safety, public involvement, releasing time to care and all complaints. PMID- 28091175 TI - Union demands consultation on NHS changes. AB - Unison has launched a legal challenge over proposals for 'fundamental changes' contained in the coalition government's health white paper. PMID- 28091176 TI - Cardiovascular plan aims to curb disease. AB - Proposals to improve the prevention of cardiovascular disease in Wales have been published by the Welsh assembly government. PMID- 28091179 TI - Webwise. AB - An emergency air ambulance takes off every ten minutes on average in the UK. Forty per cent of the calls are for road traffic accidents, 24 per cent are for other medical emergencies and 2 per cent are for hospital transfers. PMID- 28091177 TI - Waste-to-biofuel: production of biobutanol from sago waste residues. AB - The main concern of extensive production of biobutanol has been associated with the high cost of the substrate and the relatively low tolerance of Clostridia to biobutanol production. In this study, the use of fermentable cassava waste residue (CWR) as substrate for biobutanol production was investigated using solvent-tolerant Clostridium sp. Four of obligatory, solvent-producing bacteria were isolated from sago industry waste sites. The NSW, PNAS1, SB5 and SBI4 strains showed identical profiles of 16S rRNA gene sequence similarity of Bacillus coagulans, Clostridium bifermentans and Clostridium sp. (97% similarity) and a wide range of carbohydrate substrate; however, the CWR was found to be suitable for the production of biobutanol considerably. Batch culture study was carried out using parameters such as time and temperature and carbon sources have been studied and optimized. Using pre-optimized CWR medium, significant amount of solvent production was observed in NSW, PNAS1, SB5 and SBI4 with 1.53, 3.36, 1.56 and 2.5 g L-1of butanol yield and 6.84, 9.012, 8.32 and 8.22 g L-1of total solvents, respectively. On the basis of these studies, NSW is proposed to represent the B. coagulans for butanol production directly from sago waste residues. PMID- 28091178 TI - Behavioral Assessment of Listening Effort Using a Dual-Task Paradigm. AB - Published investigations ( n = 29) in which a dual-task experimental paradigm was employed to measure listening effort during speech understanding in younger and older adults were reviewed. A summary of the main findings reported in the articles is provided with respect to the participants' age-group and hearing status. Effects of different signal characteristics, such as the test modality, on dual-task outcomes are evaluated, and associations with cognitive abilities and self-report measures of listening effort are described. Then, several procedural issues associated with the use of dual-task experiment paradigms are discussed. Finally, some issues that warrant future research are addressed. The review revealed large variability in the dual-task experimental paradigms that have been used to measure the listening effort expended during speech understanding. The differences in experimental procedures used across studies make it difficult to draw firm conclusions concerning the optimal choice of dual task paradigm or the sensitivity of specific paradigms to different types of experimental manipulations. In general, the analysis confirmed that dual-task paradigms have been used successfully to measure differences in effort under different experimental conditions, in both younger and older adults. Several research questions that warrant further investigation in order to better understand and characterize the intricacies of dual-task paradigms were identified. PMID- 28091181 TI - Nightingale wards offer visible reassurance for everyone. AB - I wish to thank consultant physician Alan Roberts for endorsing my belief that the widespread loss of Nightingale wards has had a detrimental effect on nursing care (reflections January 25). PMID- 28091180 TI - Testing for emotional intelligence raises a number of key questions. AB - Applicants for a nursing degree course at the University of Dundee are undergoing emotional intelligence tests as part of the selection process (news February 15). PMID- 28091182 TI - Bringing back enrolled grade could help bridge the skills gap. AB - There is a skills gap between registered nurses and healthcare assistants (HCAs) at level 3. Is it time to bring back an enrolled nurse equivalent grade to help bridge the gap? PMID- 28091184 TI - Nutritional benefits. PMID- 28091183 TI - Powerful case for learning disability liaison nurses. AB - Linda Phillips' literature review, 'Improving care for people with learning disabilities in hospital' (art & science February 8), was excellent. PMID- 28091185 TI - Patient care is affected by too many audits and paperwork. AB - I have followed your Care campaign with interest and feel that poor standards are due to there being too many managers and not enough nurses. At present we have multiple layers of managers trying to justify their jobs by passing more audits and paperwork down to clinicians, with no effort being made to protect the time to care for patients. PMID- 28091186 TI - Hospital staff all proved to be. AB - Nursing has been getting such a bad press of late that I was anxious when my son was admitted to Hairmyres Hospital in East Kilbride with appendicitis. PMID- 28091189 TI - Nurse numbers will decline, warns expert. AB - The number of nurses is likely to fall over the next few years unless policymakers intervene to halt the decline, a leading workforce expert predicts. PMID- 28091188 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28091190 TI - Volunteers support staff in creating the right mealtime environment. AB - Meal Mates, a voluntary venture to help older patients with eating and drinking, was introduced at Blackpool Teaching Hospitals NHS Foundation Trust in February 2011. PMID- 28091192 TI - Compassionate actions brought couple great joy. AB - 'I can honestly say that we would not have our daughter were it not for Sharon going above and beyond the call of duty,' says Patricia Doohan. PMID- 28091191 TI - Starting out - Discovering the psychology behind good infection control practice. AB - Before starting my nurse training, I had several years' experience as a healthcare assistant (HCA). I was aware of infection control issues and considered myself efficient in infection control practice. PMID- 28091193 TI - 'Nurse helped my daughter cope during difficult times'. AB - Maureen Clarke first met staff nurse Olivia Lines when her five-year-old daughter Laura was diagnosed with cancer last July. PMID- 28091194 TI - Readers panel-Ready for risks. AB - Our experts consider a hot topic of the day. PMID- 28091195 TI - A chance for people to become enthused about activity. AB - For several months, a small group of RCN staff have been quietly engaged in supporting preparations for the Olympic and Paralympic Games. PMID- 28091196 TI - Government misjudged scale of health regulation. AB - Care Quality Commission inspectors should be given greater access to front line nurses when planning how to carrying out inspections, according to a government review. PMID- 28091199 TI - NHS managers endorse calls for healthcare assistant regulation. AB - A commission set up to review care of older people is calling for healthcare assistants to be regulated and greater powers to be given to ward sisters. PMID- 28091197 TI - RCN angry at being barred from health bill summit. AB - The exclusion of nurses from a Downing Street summit on the Health and Social Care Bill has been described as a 'tragic state of affairs' by the RCN. PMID- 28091200 TI - Nursing that exemplifies care campaign's values. AB - 'If there were more nurses like Surinda, the world would be a better place, especially for older people in hospital,' says Ruth Chauhan, who nominated staff nurse Surinda Daliwal for the Patient's Choice award. PMID- 28091203 TI - Unprintable. AB - It was a simple half-term thing. The boys wanted to play badminton at the leisure centre and I needed to let Janet know. 'Gone to badminton,' I texted. But my phone is smart. Despite having known me for two years, it decided that I meant: 'Gone to Bhutan.' PMID- 28091202 TI - NHS Organisations slow to support public health pledges. AB - Only nine NHS organisations have signed up to the Department of Health's public health 'responsibility deal' - a year after it was launched. PMID- 28091204 TI - National pay system must stay, MPs told. AB - Union leaders told MPs that they want nurses' national pay system to remain in place during a health committee session last week. PMID- 28091205 TI - Tribunal orders trust to end increment penalty for sickness. AB - An NHS trust that withheld incremental pay rises from staff for being off sick has been ordered to repay the money in full in a landmark employment tribunal ruling. PMID- 28091206 TI - Passport to more understanding. AB - A 'hospital passport' for people with learning disabilities has been introduced at Guy's and St Thomas' NHS Foundation Trust in London. PMID- 28091207 TI - RCN backs moves to improve care for older people. AB - Nurses are being asked to agree to a code of conduct that aims to guarantee older people receive dignified treatment. PMID- 28091209 TI - Voices - Duty of care to patients should always come first, writes Yvonne Coghill. AB - When the Costa Concordia cruise ship ran aground last month, no one watching the scenes of the stricken vessel could fail to be shocked and horrified by the tragedy. The behaviour of the captain, who allegedly reneged on his duty of care to the people on his ship, caused particular alarm. PMID- 28091210 TI - Never had it so good. AB - One grey November day in 1966, 44 teenagers nervously donned striped uniforms, white starchy hats and aprons and started their nurse training at a I. ondon Hospital. PMID- 28091211 TI - Outpatients. AB - Did you see Call the Midwife, the recent BBC television drama? The newcomer to the East End slums exclaimed, rather plummily, that she never realised 'people lived like this'. PMID- 28091212 TI - Throwing an active lifeline to older people living in isolation. AB - A community nurse who set up an innovative scheme to help improve the health and independence of older people in Liverpool has been nominated by three service users. PMID- 28091213 TI - Scepticism about the efficacy of drug treatment for mental health problems may be unfair. AB - Psychiatric drugs are as effective as many drugs used to treat physical health problems, according to a German review, which suggests that scepticism about the efficacy of drug treatment for mental health problems may be unjustified. PMID- 28091214 TI - Dedication that makes us proud. AB - Four exceptional nurses have been selected as finalists in the 2012 Claire Rayner Patient's Choice Award, organised by Nursing Standard as part of our annual nursing awards. PMID- 28091215 TI - Proton pump inhibitors could inhibit calcium absorption and weaken women's bones. AB - Post-menopausal women are 35 per cent more likely to experience a hip fracture if they take indigestion drugs, suggests a major study. PMID- 28091216 TI - NHS workers in Jersey struggle with the high cost of living. AB - Union representatives are to meet government officials in Jersey to discuss the findings of a survey that show many nurses on the island are struggling to make ends meet. PMID- 28091217 TI - Measuring blood pressure in both arms might identify those in need of vascular treatment. AB - A significant difference in blood pressure between the right and left arm could indicate that a person has an increased risk of heart and circulatory disease, and death. National vascular disease guidelines for the over-forties advise that blood pressure measurements be taken in both arms, but surveys suggest that this is often ignored, with measurements routinely taken in one arm. PMID- 28091218 TI - World in brief. AB - What's happening in nursing across the globe. PMID- 28091220 TI - Constant reform and privatisation distract nurses from core work. AB - The restructuring of healthcare services in an attempt to save money is proving hugely disruptive for nursing staff in south east England. PMID- 28091219 TI - Study profiles smokers who refuse to quit even after cancer diagnosis. AB - A substantial number of people with lung and colorectal cancer continue to smoke after being diagnosed, a study reveals. PMID- 28091221 TI - Student life - Straight from the source. AB - Calls for the involvement of service users in nurse education are not new. In 1996 the English National Board for Nursing, then responsible for education standards, said service users and carers should have a role, particularly in student assessment. PMID- 28091222 TI - Who is your favourite for Patient's Choice award? AB - The finalists in this year's Claire Rayner Patient's Choice award are truly inspiring nurses. They have transformed the lives of people to such an extent that choosing between them will be a challenge for members of the public, who have until March 15 to cast their votes. PMID- 28091224 TI - Listening and learning to make care better. PMID- 28091223 TI - NMC says Asian nurses may need support with delegating work. AB - The Nursing and Midwifery Council has pointed to evidence that suggests nurses from an Asian background may require additional time to develop delegation skills. PMID- 28091225 TI - Hettie Hopkins 1919-2012 Secretary of the RCN Welsh board 1963-78. AB - Hettie Hopkins was a nurse leader and campaigner who was active in the RCN until her death. PMID- 28091226 TI - Sign my e-petition to make changes to misuse of drugs act. AB - My medicines management article (reflections February 8) highlighted legal muddles over the prescription of controlled drugs. The Medicines Act was amended four years ago to allow independent nurse prescribers to prescribe almost all controlled drugs. But the Misuse of Drugs Act needs to amended to make this legally possible. PMID- 28091228 TI - Early signs of autism may be detectable in six-month-old babies. AB - There are no reliable predictors of autism in infancy, but characteristic behaviours begin to be noticeable from the age of two, the earliest age at which a firm diagnosis is made. PMID- 28091229 TI - Opportunity awaits abroad. AB - When politicians admonish UK workers for not being prepared to look for jobs outside of their home towns, they obviously have not heard about nurses heading to Canada, Australia, and New Zealand. PMID- 28091230 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28091231 TI - Pin site care: guidance and key recommendations. AB - Pin site infection is the most common complication of external fixation, a complex orthopaedic procedure used to stabilise fractures and correct limb deformity. The care of pin sites has long been debated among healthcare professionals. It is widely acknowledged that there is a lack of high quality research in this area. In 2010 a meeting with the aim of achieving consensus about pin site care took place, funded by the Royal College of Nursing Society of Orthopaedic and Trauma Nursing. The aim was for practitioners who care for pin sites on a regular basis in adult, paediatric, hospital and community environments around the UK to explore and debate current practice. This article reports the findings of this meeting and discusses the difficulties in creating guidance on this area of practice. PMID- 28091233 TI - Former nurse becomes bishop in yorkshire. AB - Glyn Webster has been made the Bishop of Beverley in Yorkshire, a role that supports Archbishop of York John Sentamu. PMID- 28091234 TI - NHS Commissioning Board begins L3m senior level recruitment drive. AB - The nursing workforce in England has been bolstered with the creation of more than L3 million worth of senior level posts. PMID- 28091235 TI - Webwise. AB - The Centre for Alternative Technology in Machynlleth, mid Wales, is concerned with the search for globally sustainable, whole and ecologically beneficial technologies and ways of life. PMID- 28091237 TI - Behind the worthy words lies a financial black hole. AB - The government's motives are to be commended. Since taking office, health secretary Andrew Lansley and public health minister Anne Milton, a former nurse, have stressed the importance of improving public health. And where better to start than with the nation's young people? PMID- 28091239 TI - Update. AB - UPDATE A table in the learning zone article titled Genetics, mitosis and meiosis (August 1) stated that there are approximately 8,000 people with cystic fibrosis in the UK. Since the article was accepted for publication, new figures have been published by the NHS showing that more than 9,000 people have the condition. PMID- 28091240 TI - Make your opinion heard about plans to alter pay and conditions. AB - The pay 'cartel' in the south west of England has an agenda that threatens the pay, terms and conditions of healthcare staff at 20 NHS trusts (editorial and news August 29). PMID- 28091241 TI - Time to be a united force? PMID- 28091242 TI - Trials of antipsychotic drugs need to be impartial my late mother, who experienced. AB - My late mother, who experienced confusion and memory loss as a result of vascular dementia, was prescribed antipsychotics. Within 24 hours, she experienced agitation, restlessness and terrifying nightmares. The treatment was stopped after three days. PMID- 28091245 TI - Workforce. AB - In 1776 Scottish economist Adam Smith wrote: 'Masters are always and everywhere in a sort of tacit, but constant and uniform combination, not to raise the wages of labour above their actual rate.' PMID- 28091243 TI - Capability assessments record shames paralympics sponsor. AB - It was shocking to read how work capability assessments by private company Atos Healthcare are leading to many nurses with disabilities being denied Employment and Support Allowance (news August 22). PMID- 28091246 TI - Parents in need of asthma education. AB - School nurses should not assume parents understand how to help their children manage asthma, a conference heard. PMID- 28091247 TI - Nurses affected by post-traumatic stress after katrina's devastation. AB - STRESS AFTER KATRINA'S DEVASTATION Nurses working in the United States city of New Orleans following Hurricane Katrina cared for those affected in a football ground and in tents pitched in hospital car parks. PMID- 28091248 TI - Feedback challenge winners share L1m pot to help spread their ideas. AB - Nurses who have developed projects to gather patient feedback have been awarded a share of a L1 million innovation fund to help others replicate their ideas. PMID- 28091249 TI - World in brief. AB - What's happening in nursing across the globe. PMID- 28091250 TI - Care home worker hid his crimes from employer. AB - A nurse worked at two care homes without declaring a conviction for assault, a Nursing and Midwifery Council hearing has been told. PMID- 28091251 TI - High volume of NMC referrals for nurses employed by work capability assessor. AB - At least 27 nurses working for Atos Healthcare, the company contracted to carry out work capability assessments for the government, have been referred to the Nursing and Midwifery Council. PMID- 28091252 TI - Trust jettisons jargon for the more meaningful. AB - A trust has rebranded intentional rounding as 'meaningful and individualised moments', claiming the government's title for the initiative is jargon. PMID- 28091253 TI - Medicines management. AB - I am not a prescriber, but am an advanced life support certifi ed nurse. Am I allowed to administer relevant medicines in a cardiac arrest situation? PMID- 28091254 TI - We must make sure community nursing is properly supported. AB - Rosemary Cook's article on community nursing is timely (careers August 22). The demise of the district nursing role is to be lamented, despite the good service being provided by community nurses. PMID- 28091255 TI - Activities to boost patient morale should be extended to care homes. AB - 'Wards in good cheer' (features August 29) made for great reading. The staff at Walsall Manor Hospital are to be congratulated for trying out simple initiatives that could make a world of difference to the patient experience. PMID- 28091256 TI - Fun game helps break the ice on discussing STIs. AB - School nurses are to be given a bingo-style game called What's My STI? to use with schoolchildren. PMID- 28091257 TI - Planning ahead can help ensure patient's wishes are expressed. AB - The article on cardiopulmonary resuscitation in end of life care (art&science August 22) was thought-provoking, most notably for its focus on the ethical, legal and professional issues associated with any decisions taken in these circumstances. PMID- 28091258 TI - Staff speed up cancer monitoring. AB - Two clinical nurse specialists have cut waiting times for patients with cancer by setting up a fast-track service. PMID- 28091259 TI - Changes to the NHS make it vital to plan for success. AB - Whatever your view of the need for change in the NHS, the unavoidable fact is that it has already changed. Some trusts have chosen the social enterprise route, while others have become foundation trusts or face amalgamation or being taken over by private companies. PMID- 28091260 TI - Radiation in CT scans can increase the risk of cancer among young children. AB - Exposing children to the ionising radiation in CT scans may triple their risk of developing cancer, according to a systematic review of the evidence. PMID- 28091261 TI - Deaths in acute hospitals have fallen, but more needs to be done to aid their prevention. AB - Around 12,000 deaths in acute hospitals in England each year could be prevented, suggests an analysis of the country's hospital mortality figures. PMID- 28091262 TI - Voices. AB - Soon after taking up the post of chief nursing officer for England, I began talking about my ambition to develop a new vision for nursing and midwifery. PMID- 28091263 TI - I feel confident about speaking up care has to protect the dignity of patients. AB - While on placement on a cardiac and endocrine ward, the nurse in charge asked me to manage a bay of four patients due to staff shortages. PMID- 28091264 TI - Setting the ideal mix. AB - Some years ago I had the misfortune and simultaneous good luck to find myself in a cardiac rapid assessment unit, writes Harry Cayton. PMID- 28091267 TI - A fair way to plan your career. AB - The largest jobs fair in the UK for nurses will hit London next week. The annual RCN Bulletin Jobs Fair brings together career-conscious nurses and the organisations that want to employ them. PMID- 28091265 TI - Readers panel - care has become clouded. AB - Our experts consider a hot topic of the day. PMID- 28091268 TI - Keep it simple. AB - 'Your learning style is the way I teach you - that's my attitude,' said an experienced teacher I know. Draconian? Arrogant, even? I don't think so. PMID- 28091270 TI - Nurse shortage prompts interim care home closure. AB - A shortage of nurses in the Isle of Man has led to the temporary closure of a care home for older, mentally ill patients. PMID- 28091269 TI - Staff take action against mileage rate offer. AB - Staff take action against mileage rate offer Nurses were among staff who took a day of industrial action last week in protest at cuts to their mileage rates. PMID- 28091272 TI - Generational differences can cause work clashes. AB - Conflicts are arising between nurses as a result of age differences, according to research. PMID- 28091274 TI - Cataract surgery cuts fracture risk for people aged 65 and over in the year post operation. AB - Older people who have had surgery for cataracts have a significantly lower risk of fractures than people of the same age with cataracts who have not had surgery, a major American study has found. PMID- 28091273 TI - Atrial fibrillation. AB - I encountered atrial fibrillation for the first time on a recent clinical placement. PMID- 28091275 TI - Depression and melancholy following stroke needs more attention by nursing staff. AB - A small, nurse-led study describing the experience of stroke survivors with depressive symptoms in the first weeks following stroke has found that they are living life in 'shades of grey', with no joy or happiness and a profound sense of loss. PMID- 28091276 TI - Little benefit to speech therapy immediately following stroke. AB - Speech and language therapy in the first few months after stroke may be no more effective in restoring functional communication than social contact, according to a randomised controlled trial conducted in the UK. PMID- 28091277 TI - Acne carriage. AB - I could have been a star of stage and screen, a household name, an A-list celeb. After that school play where I kissed the leading lady, I knew the theatre was for me. PMID- 28091278 TI - Brief activity performance measure for upper limb amputees: BAM-ULA. AB - BACKGROUND: Measures of activity performance for adults with upper limb amputation are needed. The purposes of this study were to evaluate the measurement properties of a new measure of activity performance for adults with upper limb amputation, which we call the Brief Activity Measure for Upper Limb Amputees (BAM-ULA) and to compare BAM-ULA scores for users of different types of prostheses. METHODS: In all, 35 persons with upper limb amputation were administered the BAM-ULA, twice within 1 week. Internal consistency and test retest reliability were evaluated. Construct validity was examined by comparing scores by amputation level. Concurrent validity was evaluated by examining correlations with other measures. Exploratory analyses using linear regression compared sub-group scores for users of myoelectric and body-powered devices, and for users of single-degree-of-freedom and multi-articulating devices, controlling for amputation level. RESULTS: The scale alpha was 0.83; intraclass correlation coefficient was 0.91. Item scores differed by amputation level and device type. Persons with transradial amputation completed more items than those with amputations at the transhumeral or shoulder level ( p < 0.05). Users of myoelectric devices completed more items than users of body-powered devices ( p < 0.05). The BAM-ULA strongly correlated with the Activities Measure for Upper Limb Amputees; R = 0.86) and three modified Jebsen-Taylor Hand Function Tests ( R = 0.62-0.68) and moderately correlated with one Jebsen-Taylor Hand Function Test ( R = 0.46) as well as with the Wong-Baker FACES Pain Rating Scale. No differences in scores were found by degree of freedom of the terminal device after controlling for amputation level. CONCLUSION: Analyses support reliability, construct validity, and concurrent validity of the Brief Activity Measure for Upper Limb Amputees. This new briefer measure is easier to score than the Activities Measure for Upper Limb Amputees. Clinical relevance This article reported on the development and evaluation of a brief 10-item measure of activity performance for persons with upper limb impairment, the BAM-ULA. The BAM-ULA takes 10 min to administer and has a simple scoring method, which may facilitate its adoption by clinicians in the field. PMID- 28091279 TI - Aflatoxin M1 in human breast milk in Shahrekord, Iran and association with dietary factors. AB - This survey was conducted to determine the occurrence and levels of aflatoxin M1 (AFM1) in 250 breast milk samples of lactating mothers, obtained from urban and rural regions of Shahrekord, Iran. Moreover, the association between AFM1 occurrence levels and dietary factors was assessed. AFM1 analysis was carried out using the competitive enzyme-linked immunosorbent assay technique for screening and high-performance liquid chromatography with fluorescence detection (HPLC-FLD) for confirmatory purposes. The toxin was detected in 39 samples (15.6%), ranging from 11.1 to 39.3 ng/l, of which 8 samples (3.2%) had levels above the Iranian national standard limit (25 ng/l). AFM1 occurrence and levels in breast milk samples obtained from rural regions were significantly higher (P <= 0.05) than those obtained from urban ones. It might be due to the different dietary patterns in these regions. It was found that dietary habits with more tendencies to consume bread, rice and non-alcoholic beer beverage significantly increased (P <= 0.05) the risk of AFM1 occurrence in breast milk. In addition, higher consumption of bread, olive and traditional cream significantly increased (P <= 0.05) the levels of AFM1 in breast milk samples. Further investigations should be performed to determine more precisely the association between AFM1 occurrence and dietary factors and also the risk of infant exposure to this mycotoxin. PMID- 28091280 TI - Rotation Elastogram Estimation Using Synthetic Transmit-aperture Technique: A Feasibility Study. AB - It is well-documented in literature that benign breast lesions, such as fibroadenomas, are loosely bonded to their surrounding tissue and tend to slip under a small quasi-static compression, whereas malignant lesions being firmly bonded to their surrounding tissue do not slip. Recent developments in quasi static ultrasound elastography have shown that an image of the axial-shear strain distribution can provide information about the bonding condition at the lesion surrounding tissue boundary. Further studies analyzing the axial-shear strain elastograms revealed that nonzero axial-shear strain values appear inside the lesion, referred to as fill-in, only when a lesion is loosely bonded and asymmetrically oriented to the axis of compression. It was argued that the fill in observed in axial-shear strain elastogram is a surrogate of the actual rigid body rotation undergone by such a benign lesion due to slip boundary condition. However, it may be useful and perhaps easy to interpret, if the actual rigid-body rotation of the lesion can itself be visualized directly. To estimate this rotation tensor and its spatial distribution map (called a Rotation Elastogram [RE]), it would be necessary to improve the quality of lateral displacement estimates. Recently, it has been shown in the context of Non-Invasive Vascular Elastography (NIVE) that the Synthetic Transmit Aperture (STA) technique can be adapted for elastography to improve the lateral displacement estimates. Therefore, the focus of this work was to investigate the feasibility of employing the STA technique to improve the lateral displacement estimation and assess the resulting improvement in the RE quality. This investigation was done using both simulation and experimental studies. The image quality metric of contrast-to noise ratio (CNR) was used to evaluate the quality of rotation elastograms. The results demonstrate that the contrast appeared in RE only in the case of loosely bonded inclusion, and the quality of RE improved considerably by employing the STA technique. PMID- 28091281 TI - Satiety and memory enhancing effects of a high-protein meal depend on the source of protein. AB - OBJECTIVE: High- protein diets have become increasingly popular with various touted benefits. However, the extent to which protein quantity and source affects cognitive functioning through altering postprandial amino acid profiles has not been investigated. Further, whether all protein sources are similarly anorexigenic is uncertain. The objective of this study was to determine the influence of protein level and source on Barnes maze performance, satiety and plasma amino acid levels in male Sprague-Dawley rats. METHODS: Rats were entrained to a meal-feeding schedule consisting of a 30 minutes meal, equivalent to 20% of average daily intake, one hour into the dark phase then ad libitum access to food for 5 h. On test days, rats received one of three isocaloric diets as their first meal, hereafter referred to as Egg White (EW), Wheat Gluten (WG), or Basal, and then were measured for cognitive performance, feeding behavior, or plasma amino acid levels via jugular catheter. Percentage energy from protein was 35% for both EW and WG and 20% for Basal with equal amounts provided by EW and WG proteins. RESULTS: Rats provided EW performed similarly to Basal on the Barnes maze, whereas WG performed worse. EW increased satiety, whereas WG reduced satiety relative to Basal. Both EW and WG increased postprandial concentrations of large neutral and branched chain amino acids relative to Basal, but in EW, concentrations were slower to peak, and peaked to a higher level than WG. DISCUSSION: Results demonstrate the importance of protein source for cognition and satiety enhancing effects of a high-protein meal. PMID- 28091283 TI - Trend for men to be back in hospital within a month of being discharged. AB - Men are significantly more likely than women to need urgent hospital care, including readmission, within a month of being discharged. PMID- 28091284 TI - Living alone makes workers much more prone to depression. AB - People who live alone are 80 per cent more likely to be depressed, according to the first major study to examine the risk of depression and solitary living arrangements in people of working age. PMID- 28091282 TI - Hispanic patients are more likely to survive lung cancer than caucasians. AB - Hispanic lung cancer patients appear to live longer than white or black patients, according to research in the United States. The research, along with other studies, suggests that genetic or environmental factors put Hispanic patients at a survival advantage. PMID- 28091285 TI - Pension proposals spark industrial action. AB - Community nurses joined industrial action organised by the Unite union last week, a day after the government announced plans to press ahead with pension reforms. A bill that would bring major changes to public sector pensions is to be published shortly. PMID- 28091286 TI - Scotland clarifies effect of integration on employment. AB - Nurses will not be compelled to transfer to local authority employment under plans to integrate adult health and social care in Scotland. PMID- 28091287 TI - The power to lead. AB - Florence Nightingale, who died more than 100 years ago, set a shining example of what good leadership can achieve. PMID- 28091288 TI - Voices - Investment in community nursing services is vital, according to Peter Carter. AB - In the past few years, RCN members up and down the country have shared concerns about cuts to jobs and services through our Frontline First campaign. The information has been shocking, and shows that the NHS and many of its nursing staff are being stretched to breaking point. PMID- 28091290 TI - 'The NHS he talks about is not the NHS nurses recognise'. PMID- 28091289 TI - Cliche rage. AB - Someone senior and non-clinical once said to me: 'It's all about the patient experience, isn't it?' PMID- 28091291 TI - The hazards of caring. PMID- 28091292 TI - Increase in nurse peers depends on lords reform. AB - The prospect of more nurses joining the House of Lords depends on the outcome of controversial new government proposals. PMID- 28091293 TI - 'Halving the number of MRSA cases has been a fantastic achievement'. AB - When England's chief nursing officer Dame Chris Beasley was appointed to the post in October 2004, MRSA-linked deaths were rarely out of the headlines. PMID- 28091294 TI - Lansley wins respect but few friends at congress. AB - Politicians' credibility is often judged by their readiness to give straight answers to straight questions. By this measure, health secretary Andrew Lansley did little to enhance his reputation when he took the stage at RCN congress in Harrogate this week. PMID- 28091295 TI - Sickle cell and thalassaemia posts are good value and need protecting. AB - Genetic blood disorders sickle cell and thalassaemia affect 12,500 and 800 people respectively in England. PMID- 28091296 TI - Wanted: two high-flyers keen for a 'large, complex' challenge. AB - The Nursing and Midwifery Council is seeking two new leaders with proven business management skills to pull the regulator out of its difficulties. PMID- 28091297 TI - 'We have been able to raise the profile of what nurses do'. AB - Torbay and Southern Devon Health and Care NHS Trust is often held up as an example of how co-operation between health and social care can work. PMID- 28091298 TI - Trust backs down on band 4 role offer. AB - An NHS trust has made a U-turn on its plans to ask registered nurses to consider jobs as assistant practitioners if they want to avoid redundancy. PMID- 28091299 TI - World in brief. AB - What's happening in nursing across the globe. PMID- 28091300 TI - Nurse achievements celebrated. AB - Two iconic nurses were celebrated last week when nursing's contribution to society was recognised across the world. PMID- 28091301 TI - Relaxation exercises to soft music shown to cut number of pre-term births. AB - Some pregnant women admitted to hospital with pre-term labour may be able to prolong their pregnancy by listening to a relaxation training programme, suggests a study from Taiwan. PMID- 28091302 TI - Sleeping too little increases likelihood of obesity, but too much sleep is also bad for you. AB - Lack of sleep should be added to poor diet and sedentary lifestyle as risk factors for obesity, suggests a review of the evidence from sleep restriction studies. PMID- 28091304 TI - Readers panel - A matter of academic record. AB - Our experts consider a hot topic of the day. PMID- 28091303 TI - Starting out - Time spent with a community nurse a matter helped clarify my career goals. AB - Before spending time with a specialist rehabilitation community nurse recently, I was looking forward to the opportunity for two reasons. PMID- 28091306 TI - RCN Head lambasts 'destructive' cuts. AB - The cuts afflicting the NHS across the UK are causing widespread concern among nurses, RCN president Andrea Spyropoulos said in her opening address to this year's congress. PMID- 28091307 TI - Student life - vital support that pays off. AB - Newly qualifi ed nurses moving into community roles face particular challenges because they often work in isolation and may lack the support that those working in a hospital receive from colleagues. PMID- 28091308 TI - Needle stick and sharps injuries: practice update. AB - Member states of the European Union have until May 11 2013 to implement the Council Directive 2010/32/EU Implementing the Framework Agreement on Prevention from Sharps Injuries in the Hospital and Healthcare Sector. The aim of this legislation is to achieve a safe working environment and prevent injuries to healthcare professionals caused by all medical sharps, including needlesticks. This article examines the issues surrounding needlestick and sharps injuries, including risk assessment and prevention, information provision, raising awareness, use of safety devices, training and reporting procedures. PMID- 28091309 TI - Bedazzled. AB - Talk about grumpy old men - you should hear me on the subject of car headlamps. 'I swear they have been getting brighter. The nasty new ones with the blue tinge are dazzling. Who needs lights so bright? People use them as offensive weapons. I blame the government...' And so on. PMID- 28091310 TI - Concentrate on basic nursing care before extended skills. AB - I read with interest Nichola McCarthy's letter (May 2). She says that all nursing students should be taught electrocardiogram (ECG) recording, cannulation, venepuncture and IV administration skills. PMID- 28091312 TI - Are we medicalising normal conditions such as anxiety? AB - The learning zone article (May 2) on the assessment and treatment of patients experiencing anxiety was informative and wide-ranging. It is an excellent, well referenced resource. PMID- 28091313 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 28091315 TI - St Thomas' hospital is the wrong site for mary seacole statue. AB - Your news story, 'Council gives go-ahead for Seacole statue' (May 2), is orrect in declaring that planning permission for a memorial statue for Mary Seacole has been granted. But the plans have been approved by Lambeth Council's planning committee, rather than the council as a whole. PMID- 28091314 TI - Nightingale's emphasis on patient observation provides valuable lessons. AB - Sue Norman, chair of the Florence Nightingale Museum's board of trustees, says Miss Nightingale's nursing philosophy is 'as relevant today as when she devised it more than 150 years ago' (careers May 9). PMID- 28091316 TI - Staff caring for my mother came across as cold and uncaring. AB - My mother was admitted to hospital at the beginning of the year and it was evident from the outset that some staff on the wards would have benefited from reminders about the core values of your Care campaign (features May 2). PMID- 28091317 TI - It seems impractical to pay people to become healthier. AB - Four readers panellists were asked if financial incentives would motivate people to adopt healthy behaviours (reflections May 2). PMID- 28091320 TI - College will fight on over change to pension age. AB - The RCN will continue to fight any increase in NHS nurses' retirement age, RCN general secretary Peter Carter announced in his keynote address to congress. PMID- 28091318 TI - Webwise. AB - The Cavell Nurses' Trust website is part of a rebranding of the charity Nurse Aid, which is a source of financial support for students, registered and retired nurses, and healthcare assistants. PMID- 28091321 TI - Lung cancer campaign targets late diagnosis. AB - As many nurses know, UK survival rates from lung cancer in the first year after diagnosis are very low. Less well known is the impact of late diagnosis. PMID- 28091322 TI - Community nurse numbers 'stretched to breaking point'. AB - The government's target to recruit an extra 4,200 health visitors by 2015 could damage services as community nurses are 'poached' to meet the pledge, the RCN has warned. PMID- 28091324 TI - Overflowing: hospitals struggle to cope with patient numbers. AB - Nurses voted overwhelmingly for an end to the use of inappropriate areas to accommodate A&E patients after hearing how they are being 'shovelled around' to meet targets. PMID- 28091325 TI - A taste of life in the upper house. AB - Entering the Palace of Westminster through the peers' entrance takes us to the centre of political life in the UK. PMID- 28091323 TI - Greek nurses reach. AB - Nurses in Greece have been hit hard by job freezes and 40 per cent wage cuts, as the government attempts to stave off bankruptcy with austerity measures. Hospital wards are understaffed and short of medical supplies following a 50 per cent reduction in the country's health budget. A union representative reveals his fears for the future, and a nurse in Athens explains that her family's income has shrunk so much that buying food is her priority. PMID- 28091327 TI - 'I used to take so much for granted'. AB - Elaine Edwards (pictured) is a gynaecology nurse specialist, nurse hsyteroscopist and staff governor at Frimley Park Hospital NHS Foundation Trust in Surrey: 'I became a governor nine months ago. It has put a lot of things into perspective for me. I took so much for granted before. For example, I did not realise how important the patient pathway codings are for ensuring the trust is paid accurately for GP-commissioned work. I am updated on all the changes that are going on. Meanwhile, the council of governors can learn from me about what is happening on the shop-floor.' PMID- 28091328 TI - High cost of fitness to practise hearings should be scrutinised. AB - As someone who pays fees to the Nursing and Midwifery Council (NMC), I read with interest about the backlog of fitness to practise hearings and the time it takes to deal with cases (analysis April 18). PMID- 28091329 TI - Student who supported grieving parents is a credit to nursing. AB - My attention was drawn to the Starting Out article, 'Sitting in silence with grieving parents gave them support' (reflections May 9). Nursing student Jordan Renouf writes about supporting a baby's parents after a failed attempt at resuscitation in an emergency department. PMID- 28091330 TI - The end of life care my mother received was outstanding. AB - The care of older people in the UK has long been under-resourced and underfunded. The NHS provides excellent acute care and good paediatric services, for example, but falls down in its care of older people. PMID- 28091332 TI - Head and neck imaging. PMID- 28091333 TI - An Ecological Approach to Reducing Potentially Inappropriate Medication Use: Canadian Deprescribing Network. AB - Polypharmacy is growing in Canada, along with adverse drug events and drug related costs. Part of the solution may be deprescribing, the planned and supervised process of dose reduction or stopping of medications that may be causing harm or are no longer providing benefit. Deprescribing can be a complex process, involving the intersection of patients, health care providers, and organizational and policy factors serving as enablers or barriers. This article describes the justification, theoretical foundation, and process for developing a Canadian Deprescribing Network (CaDeN), a network of individuals, organizations, and decision-makers committed to promoting the appropriate use of medications and non-pharmacological approaches to care, especially among older people in Canada. CaDeN will deploy multiple levels of action across multiple stakeholder groups simultaneously in an ecological approach to health system change. CaDeN proposes a unique model that might be applied both in national settings and for different transformational challenges in health care. PMID- 28091334 TI - Concurrent Dawson's Fingers and Area Postrema Lesion in a Mixed Neuroimmune Disorder. PMID- 28091335 TI - High prevalence of HPV infection in the remote villages of French Guiana: an epidemiological study. AB - Cervical cancer is the second most frequent cancer in women in French Guiana. Studies have shown that populations living in the remote areas of the interior have early sexual debut and that multiple sexual partnerships are common. The objective of the present study was thus to determine the prevalence of human papillomavirus (HPV) infection in these areas. A study was conducted in women aged 20-65 years with previous sexual activity. Women were included on a voluntary basis after using local media and leaders to inform them of the visit of the team. HPV infection was defined by the detection of HPV DNA using the Greiner Bio-One kit. In addition to HPV testing cytology was performed. The overall age-standardized prevalence rate was 35%. There was a U-shaped evolution of HPV prevalence by age with women aged >50 years at highest risk for HPV, followed by the 20-29 years group. Twenty-seven percent of women with a positive HPV test had normal cytology. Given the high incidence of cervical cancer in French Guiana and the high prevalence of HPV infections the present results re emphasize the need for screening for cervical cancer in these remote areas. Vaccination against HPV, preferably with a nonavalent vaccine, also seems an important prevention measure. However, in this region where a large portion of the population has no health insurance, this still represents a challenge. PMID- 28091336 TI - Who are the patients that default tuberculosis treatment? - space matters! AB - The goals of this article are: (i) to understand how individual characteristics affect the likelihood of patients defaulting their pulmonary tuberculosis (PTB) treatment regimens; (ii) to quantify the predictive capacity of these risk factors; and (iii) to quantify and map spatial variation in the risk of defaulting. We used logistic regression models and generalized additive models with a spatial component to determine the odds of default across continental Portugal. We focused on new PTB cases, diagnosed between 2000 and 2013, and included some individual information (sex, age, residence area, alcohol abuse, intravenous drug use, homelessness, HIV, imprisonment status). We found that the global default rate was 4.88%, higher in individuals with well-known risk profiles (males, immigrants, HIV positive, homeless, prisoners, alcohol and drug users). Of specific epidemiological interest was that our geographical analysis found that Portugal's main urban areas (the two biggest cities) and one tourist region have higher default rates compared to the rest of the country, after adjusting for the previously mentioneded risk factors. The challenge of treatment defaulting, either due to other individual non-measured characteristics, healthcare system failure or patient recalcitrance requires further analysis in the spatio-temporal domain. Our findings suggest the presence of significant within-country variation in the risk of defaulting that cannot be explained by these classical individual risk factors alone. The methods we advocate are simple to implement and could easily be applied to other diseases. PMID- 28091337 TI - Assessing the social and environmental determinants of pertussis epidemics in Queensland, Australia: a Bayesian spatio-temporal analysis. AB - Pertussis epidemics have displayed substantial spatial heterogeneity in countries with high socioeconomic conditions and high vaccine coverage. This study aims to investigate the relationship between pertussis risk and socio-environmental factors on the spatio-temporal variation underlying pertussis infection. We obtained daily case numbers of pertussis notifications from Queensland Health, Australia by postal area, for the period January 2006 to December 2012. A Bayesian spatio-temporal model was used to quantify the relationship between monthly pertussis incidence and socio-environmental factors. The socio environmental factors included monthly mean minimum temperature (MIT), monthly mean vapour pressure (VAP), Queensland school calendar pattern (SCP), and socioeconomic index for area (SEIFA). An increase in pertussis incidence was observed from 2006 to 2010 and a slight decrease from 2011 to 2012. Spatial analyses showed pertussis incidence across Queensland postal area to be low and more spatially homogeneous during 2006-2008; incidence was higher and more spatially heterogeneous after 2009. The results also showed that the average decrease in monthly pertussis incidence was 3.1% [95% credible interval (CrI) 1.3 4.8] for each 1 degrees C increase in monthly MIT, while average increase in monthly pertussis incidences were 6.2% (95% CrI 0.4-12.4) and 2% (95% CrI 1-3) for SCP periods and for each 10-unit increase in SEIFA, respectively. This study demonstrated that pertussis transmission is significantly associated with MIT, SEIFA, and SCP. Mapping derived from this work highlights the potential for future investigation and areas for focusing future control strategies. PMID- 28091338 TI - Molecular epidemiological analysis to assess the influence of pet-ownership in the biodiversity of Staphylococcus aureus and MRSA in dog- and non-dog-owning healthy households. AB - It has been suggested that zoonotic transmission of Staphylococcus aureus (SA) and methicillin-resistant S. aureus (MRSA) can occur between owners and their pets within the same household. However, the influence that pet-ownership could have in the biodiversity of SA/MRSA strains circulating among owners is not fully understood. The objective of this study was to perform a molecular epidemiological analysis to evaluate and compare the biodiversity of SA/MRSA strains in dog-owning and non-dog-owning healthy households within the same community. Antimicrobial resistance, SCCmec type, USA type and clonality were assessed. Overall, 33.1% (165/499) of human subjects carried SA and 2.8% (14/499) carried MRSA. Among dogs, 7.1% (8/113) carried SA but none were MRSA positive. No difference was detected in the diversity index of SA/MRSA pulsotypes between dog owning and non-dog-owning households; but, a marked variation was still observed in the pulsotypes circulating in each type of household. Additionally, simultaneous carriage of the same SA pulsotype in owner(s) and dog was observed in 57% of households with positive humans and pets. These results demonstrate that dogs can indeed participate in the circulation of SA/MRSA pulsotypes within a home and that the presence of a pet does not seem to favour certain strains within their household. PMID- 28091339 TI - Association of cigarette smoking with a past history and incidence of herpes zoster in the general Japanese population: the SHEZ Study. AB - Few studies have examined the impact of cigarette smoking on the risk for herpes zoster. The Shozu Herpes Zoster (SHEZ) Study is a community-based prospective cohort study over 3 years in Japan aiming to clarify the incidence and predictive and immunological factors for herpes zoster. We investigated the associations of smoking status with past history and incidence of herpes zoster. A total of 12 351 participants provided valid information on smoking status and past history of herpes zoster at baseline survey. Smoking status was classified into three categories (current, former, never smoker), and if currently smoking, the number of cigarettes consumed per day was recorded. The participants were under the active surveillance for first-ever incident herpes zoster for 3 years. We used a logistic regression model for the cross-sectional study on the association between smoking status and past history of herpes zoster, and a Cox proportional hazards regression model for the cohort study on the association with risk of incidence. The multivariable adjusted odd ratios (95% CI) of past history of herpes zoster for current vs. never smokers were 0.67 (0.54-0.80) for total subjects, 0.72 (0.56-0.93) for men and 0.65 (0.44-0.96) for women. The multivariable adjusted hazard ratios (95% CI) of incident herpes zoster for current vs. never smokers were 0.52 (0.33-0.81) for total subjects, 0.49 (0.29 0.83) for men and 0.52 (0.19-1.39) for women. Smoking status was inversely associated with the prevalence and incidence of herpes zoster in the general population of men and women aged ?50 years. PMID- 28091340 TI - Fahr's Disease Presenting as Late-Onset Levodopa-Responsive Parkinsonism. PMID- 28091342 TI - Childhood interleukin-6, C-reactive protein and atopic disorders as risk factors for hypomanic symptoms in young adulthood: a longitudinal birth cohort study. PMID- 28091341 TI - Correlation between infectious disease and soil radiation in Japan: an exploratory study using national sentinel surveillance data. AB - We investigated the relationship between epidemics and soil radiation through an exploratory study using sentinel surveillance data (individuals aged <20 years) during the last three epidemic seasons of influenza and norovirus in Japan. We used a spatial analysis method of a geographical information system (GIS). We mapped the epidemic spreading patterns from sentinel incidence rates. We calculated the average soil radiation [dm (MUGy/h)] for each sentinel site using data on uranium, thorium, and potassium oxide in the soil and examined the incidence rate in units of 0.01 MUGy/h. The correlations between the incidence rate and the average soil radiation were assessed. Epidemic clusters of influenza and norovirus infections were observed in areas with relatively high radiation exposure. A positive correlation was detected between the average incidence rate and radiation dose, at r = 0.61-0.84 (P < 0.01) for influenza infections and r = 0.61-0.72 (P < 0.01) for norovirus infections. An increase in the incidence rate was found between areas with radiation exposure of 0 < dm < 0.01 and 0.15 ? dm < 0.16, at 1.80 [95% confidence interval (CI) 1.47-2.12] times higher for influenza infection and 2.07 (95% CI 1.53-2.61) times higher for norovirus infection. Our results suggest a potential association between decreased immunity and irradiation because of soil radiation. Further studies on immunity in these epidemic-prone areas are desirable. PMID- 28091343 TI - Prediction of transition to psychosis in patients with a clinical high risk for psychosis: a systematic review of methodology and reporting. AB - BACKGROUND: To enhance indicated prevention in patients with a clinical high risk (CHR) for psychosis, recent research efforts have been increasingly directed towards estimating the risk of developing psychosis on an individual level using multivariable clinical prediction models. The aim of this study was to systematically review the methodological quality and reporting of studies developing or validating such models. METHOD: A systematic literature search was carried out (up to 14 March 2016) to find all studies that developed or validated a clinical prediction model predicting the transition to psychosis in CHR patients. Data were extracted using a comprehensive item list which was based on current methodological recommendations. RESULTS: A total of 91 studies met the inclusion criteria. None of the retrieved studies performed a true external validation of an existing model. Only three studies (3.5%) had an event per variable ratio of at least 10, which is the recommended minimum to avoid overfitting. Internal validation was performed in only 14 studies (15%) and seven of these used biased internal validation strategies. Other frequently observed modeling approaches not recommended by methodologists included univariable screening of candidate predictors, stepwise variable selection, categorization of continuous variables, and poor handling and reporting of missing data. CONCLUSIONS: Our systematic review revealed that poor methods and reporting are widespread in prediction of psychosis research. Since most studies relied on small sample sizes, did not perform internal or external cross-validation, and used poor model development strategies, most published models are probably overfitted and their reported predictive accuracy is likely to be overoptimistic. PMID- 28091344 TI - A comprehensive systematic review and meta-analysis of pharmacological and dietary supplement interventions in paediatric autism: moderators of treatment response and recommendations for future research. AB - BACKGROUND: Autism spectrum disorders (ASDs) are pervasive and multifactorial neurodevelopmental conditions, characterized by impairments in social communication and interaction, and restricted, repetitive patterns of behaviour, interests or activities. Treatment options to ameliorate symptoms of ASDs are limited. Heterogeneity complicates the quest for personalized medicine in this population. Our aim was to investigate if there are baseline characteristics of patients that moderate response or trial design features that impede the identification of efficacious interventions for ASDs. METHOD: Literature searches of EMBASE, MEDLINE and PsycINFO identified 43 studies for qualitative assessment of baseline characterization of participants and 37 studies for quantitative analysis of moderators of treatment response. Criteria included blinded randomized controlled trials (RCTs) in paediatric ASD, with at least 10 participants per arm or 20 overall, of oral treatments, including pharmacological interventions and dietary supplements. RESULTS: Random-effects meta-analysis of 1997 participants (81% male) identified three moderators associated with an increase in treatment response: trials located in Europe and the Middle-East; outcome measures designated primary status; and the type of outcome measure. Inconsistent reporting of baseline symptom severity and intellectual functioning prevented analysis of these variables. Qualitative synthesis of baseline characteristics identified at least 31 variables, with only age and gender reported in all trials. Biological markers were included in six RCTs. CONCLUSIONS: Few trials reported adequate baseline characteristics to permit detailed analysis of response to treatment. Consideration of geographical location, baseline severity and intellectual function is required to ensure generalizability of results. The use of biological markers and correlates in ASD trials remains in its infancy. There is great need to improve the application of baseline characterization and incorporation of biological markers and correlates to permit selection of participants into homogeneous subgroups and to inform response to treatment in ASD. PMID- 28091345 TI - Propofol as a Risk Factor for ICU-Acquired Weakness in Septic Patients with Acute Respiratory Failure. AB - BACKGROUND: Critical illness polyneuropathy (CIN) and critical illness myopathy (CIM), together "ICU-Acquired weakness (ICUAW)," occur frequently in septic patients. One of the proposed mechanisms for ICUAW includes prolonged inactivation of sodium channels. Propofol, used commonly in patients with acute respiratory failure (ARF), primarily acts via enhancement of GABAergic transmission but may also increase sodium channel inactivation, suggesting a potential interaction. METHODS: Electronic medical records and EMG reports of patients with ICUAW and a diagnosis of either sepsis, septicaemia, severe sepsis, or septic shock, concurrent with a diagnosis of acute respiratory failure (ARF), were retrospectively analyzed in a single center university hospital. RESULTS: 74 cases were identified (50.0% men, age 58+/-14 years), and compared to age- and sex-matched controls. Of these, 51 (69%) had CIN, 19 (26%) had CIM, and 4 (5%) had both. Propofol exposure was significantly higher in patients with ICUAW compared to controls (63.5% vs. 33.8%, p<0.001). The odds ratio of developing ICUAW with propofol exposure was 3.4 (95% CI:1.7-6.7, p<0.001). Patients with ICUAW had significantly more days in hospital (59+/-44 vs. 30+/-23) and ICU (38+/ 26 vs. 17+/-13), days dependent on mechanical ventilation (27+/-21 vs. 13+/-16), and rates of tracheostomy (79.7% vs. 36.5%) and gastrostomy (75.7% vs. 25.7%) (all p<0.001). They also received a significantly higher number of distinct intravenous antibiotics, cumulative days of antibiotic therapy, and exposure to vasopressors and paralytics. CONCLUSIONS: Propofol exposure may increase the risk of ICUAW in septic patients. An interaction through sodium channel inactivation is hypothesized. PMID- 28091346 TI - The role of metabolomics in determination of new dietary biomarkers. AB - Traditional methods for the assessment of dietary intake are prone to error; in order to improve and enhance these methods increasing interest in the identification of dietary biomarkers has materialised. Metabolomics has emerged as a key tool in the area of dietary biomarker discovery and to date the use of metabolomics has identified a number of putative biomarkers. Applications to identify novel biomarkers of intake have in general taken three approaches: (1) specific acute intervention studies to identify specific biomarkers of intake; (2) searching for biomarkers in cohort studies by correlating to self-reported intake of a specific food/food group(s); (3) analysing dietary patterns in conjunction with metabolomic profiles to identify biomarkers and nutritypes. A number of analytical technologies are employed in metabolomics as currently there is no single technique capable of measuring the entire metabolome. These approaches each have their own advantages and disadvantages. The present review will provide an overview of current technologies and applications of metabolomics in the determination of new dietary biomarkers. In addition, it will address some of the current challenges in the field and future outlooks. PMID- 28091347 TI - Changes in the seroprevalence of cysticercosis in suspected patients in Chandigarh, India between 1998 and 2014: analysis of 17 years of data. AB - Changes in seroprevalence of cysticercosis diagnosed in Chandigarh, India between 1998 and 2014 were investigated by extraction and analysis of data from records held at the Postgraduate Institute of Medical Education and Research in Chandigarh. Among the total number of samples for which cysticercosis had been suspected during this period (N = 9650), 1716 (17.8%) were seropositive. Adults were more likely to be seropositive than children, and women were more likely to be seropositive than men. In addition to there being fewer patients with suspicion of cysticercosis over the data analysis period, the proportion of patients seropositive also reduced significantly. Despite these reductions, which are probably associated with improved infrastructure and sanitation within Chandigarh, and despite meat consumption being relatively rare in this area, the extent of cysticercosis in this population remains problematic. Further efforts should be made to reduce transmission of this infection, with particular emphasis on women. Such efforts should follow the One Health concept, and involve medical efforts (including diagnosis and treatment of T. solium tapeworm carriers), veterinary efforts directed towards meat inspection and prevention of infection of pigs, and environmental health and sanitation engineers (to minimize environmental contamination with human waste). PMID- 28091348 TI - Effects of intermittent fasting on glucose and lipid metabolism. AB - Two intermittent fasting variants, intermittent energy restriction (IER) and time restricted feeding (TRF), have received considerable interest as strategies for weight-management and/or improving metabolic health. With these strategies, the pattern of energy restriction and/or timing of food intake are altered so that individuals undergo frequently repeated periods of fasting. This review provides a commentary on the rodent and human literature, specifically focusing on the effects of IER and TRF on glucose and lipid metabolism. For IER, there is a growing evidence demonstrating its benefits on glucose and lipid homeostasis in the short-to-medium term; however, more long-term safety studies are required. Whilst the metabolic benefits of TRF appear quite profound in rodents, findings from the few human studies have been mixed. There is some suggestion that the metabolic changes elicited by these approaches can occur in the absence of energy restriction, and in the context of IER, may be distinct from those observed following similar weight-loss achieved via modest continuous energy restriction. Mechanistically, the frequently repeated prolonged fasting intervals may favour preferential reduction of ectopic fat, beneficially modulate aspects of adipose tissue physiology/morphology, and may also impinge on circadian clock regulation. However, mechanistic evidence is largely limited to findings from rodent studies, thus necessitating focused human studies, which also incorporate more dynamic assessments of glucose and lipid metabolism. Ultimately, much remains to be learned about intermittent fasting (in its various forms); however, the findings to date serve to highlight promising avenues for future research. PMID- 28091349 TI - Intranasal oxytocin increases facial expressivity, but not ratings of trustworthiness, in patients with schizophrenia and healthy controls. AB - BACKGROUND: Blunted facial affect is a common negative symptom of schizophrenia. Additionally, assessing the trustworthiness of faces is a social cognitive ability that is impaired in schizophrenia. Currently available pharmacological agents are ineffective at improving either of these symptoms, despite their clinical significance. The hypothalamic neuropeptide oxytocin has multiple prosocial effects when administered intranasally to healthy individuals and shows promise in decreasing negative symptoms and enhancing social cognition in schizophrenia. Although two small studies have investigated oxytocin's effects on ratings of facial trustworthiness in schizophrenia, its effects on facial expressivity have not been investigated in any population. METHOD: We investigated the effects of oxytocin on facial emotional expressivity while participants performed a facial trustworthiness rating task in 33 individuals with schizophrenia and 35 age-matched healthy controls using a double-blind, placebo-controlled, cross-over design. Participants rated the trustworthiness of presented faces interspersed with emotionally evocative photographs while being video-recorded. Participants' facial expressivity in these videos was quantified by blind raters using a well-validated manualized approach (i.e. the Facial Expression Coding System; FACES). RESULTS: While oxytocin administration did not affect ratings of facial trustworthiness, it significantly increased facial expressivity in individuals with schizophrenia (Z = -2.33, p = 0.02) and at trend level in healthy controls (Z = -1.87, p = 0.06). CONCLUSIONS: These results demonstrate that oxytocin administration can increase facial expressivity in response to emotional stimuli and suggest that oxytocin may have the potential to serve as a treatment for blunted facial affect in schizophrenia. PMID- 28091351 TI - Supplementing the maternal diet of rats with butyrate enhances mitochondrial biogenesis in the skeletal muscles of weaned offspring. AB - The present study aimed to investigate the effects of maternal dietary butyrate supplementation on energy metabolism and mitochondrial biogenesis in offspring skeletal muscle and the possible mediating mechanisms. Virgin female rats were randomly assigned to either control or butyrate diets (1 % butyrate sodium) throughout gestation and lactation. At the end of lactation (21 d), the offspring were killed by exsanguination from the abdominal aorta under anaesthesia. The results showed that maternal butyrate supplementation throughout gestation and lactation did not affect offspring body weight. However, the protein expressions of G-protein-coupled receptors (GPR) 43 and 41 were significantly enhanced in offspring skeletal muscle of the maternal butyrate-supplemented group. The ATP content, most of mitochondrial DNA-encoded gene expressions, the cytochrome c oxidase subunit 1 and 4 protein contents and the mitochondrial DNA copy number were significantly higher in the butyrate group than in the control group. Meanwhile, the protein expressions of type 1 myosin heavy chain, mitochondrial transcription factor A, PPAR-coactivator-1alpha (PGC-1alpha) and uncoupling protein 3 were significantly increased in the gastrocnemius muscle of the treatment group compared with the control group. These results indicate for the first time that maternal butyrate supplementation during the gestation and lactation periods influenced energy metabolism and mitochondrial biogenesis through the GPR and PGC-1alpha pathways in offspring skeletal muscle at weaning. PMID- 28091350 TI - The effects of flavanone-rich citrus juice on cognitive function and cerebral blood flow: an acute, randomised, placebo-controlled cross-over trial in healthy, young adults. AB - A plausible mechanism underlying flavonoid-associated cognitive effects is increased cerebral blood flow (CBF). However, behavioural and CBF effects following flavanone-rich juice consumption have not been explored. The aim of this study was to investigate whether consumption of flavanone-rich juice is associated with acute cognitive benefits and increased regional CBF in healthy, young adults. An acute, single-blind, randomised, cross-over design was applied with two 500-ml drink conditions - high-flavanone (HF; 70.5 mg) drink and an energy-, and vitamin C- matched, zero-flavanone control. A total of twenty-four healthy young adults aged 18-30 years underwent cognitive testing at baseline and 2-h after drink consumption. A further sixteen, healthy, young adults were recruited for functional MRI assessment, whereby CBF was measured with arterial spin labelling during conscious resting state at baseline as well as 2 and 5 h after drink consumption. The HF drink was associated with significantly increased regional perfusion in the inferior and middle right frontal gyrus at 2 h relative to baseline and the control drink. In addition, the HF drink was associated with significantly improved performance on the Digit Symbol Substitution Test at 2 h relative to baseline and the control drink, but no effects were observed on any other behavioural cognitive tests. These results demonstrate that consumption of flavanone-rich citrus juice in quantities commonly consumed can acutely enhance blood flow to the brain in healthy, young adults. However, further studies are required to establish a direct causal link between increased CBF and enhanced behavioural outcomes following citrus juice ingestion. PMID- 28091352 TI - Elder abuse by abandonment in India: a novel community awareness and intervention strategy. AB - India, along with the rest of the world, is aging rapidly, but more so. Of a total population of over 1.2 billion, the aging population over 60 years is 109 million, projected to rise above 300 million by the year 2050, exceeding the younger population. One important ramification of this highly populous and under resourced setting is that it provides a ripe environment for elder abuse (Chokkanathan and Lee, 2005), a problem besetting vulnerable aging populations globally (Patterson and Ploeg, 2007). PMID- 28091353 TI - The development of a national nutrition and mental health research agenda with comparison of priorities among diverse stakeholders. AB - OBJECTIVE: To develop a national nutrition and mental health research agenda based on the engagement of diverse stakeholders and to assess research priorities by stakeholder groups. DESIGN: A staged, integrated and participatory initiative was implemented to structure a national nutrition and mental health research agenda that included: (i) national stakeholder consultations to prioritize research questions; (ii) a workshop involving national representatives from research, policy and practice to further define priorities; (iii) triangulation of data to formulate the agenda; and (iv) test hypotheses about stakeholder influences on decision making. SETTING: Canada. SUBJECTS: Diverse stakeholders including researchers, academics, administrators, service providers, policy makers, practitioners, non-profit, industry and funding agency representatives, front-line workers, individuals with lived experience of a mental health condition and those who provide care for them. RESULTS: This first-of-its-kind research priority-setting initiative showed points of agreement among diverse stakeholders (n 899) on research priorities aimed at service provision; however, respondents with lived experience of a mental health condition (themselves or a family member) placed emphasis on prevention and mental health promotion-based research. The final integrated agenda identified four research priorities, including programmes and services, service provider roles, the determinants of health and knowledge translation and exchange. These research priorities aim to identify effective models of care, enhance collaboration, inform policy makers and foster knowledge dissemination. CONCLUSIONS: Since a predictor of research uptake is the involvement of relevant stakeholders, a sustained and deliberate effort must continue to engage collaboration that will lead to the optimization of nutrition and mental health-related outcomes. PMID- 28091354 TI - Giant congenital left atrial appendage aneurysm. AB - We present a rare case of an asymptomatic giant congenital left atrial appendage aneurysm in a 19-year-old girl. We believe this is the largest congenital left atrial appendage aneurysm reported without any symptom. PMID- 28091355 TI - A systematic review evaluating the impact of paid home carer training, supervision, and other interventions on the health and well-being of older home care clients. AB - BACKGROUND: Interventions to support and skill paid home carers and managers could potentially improve health and well-being of older home care clients. This is the first systematic review of interventions to improve how home carers and home care agencies deliver care to older people, with regard to clients' health and well-being and paid carers' well-being, job satisfaction, and retention. METHODS: We reviewed 10/731 papers found in the electronic search (to January 2016) fitting predetermined criteria, assessed quality using a checklist, and synthesized data using quantitative and qualitative techniques. RESULTS: Ten papers described eight interventions. The six quantitative evaluations used diverse outcomes that precluded meta-analysis. In the only quantitative study (a cluster Randomized Controlled Trial), rated higher quality, setting meaningful goals, carer training, and supervision improved client health-related quality of life. The interventions that improved client outcomes comprised training with additional implementation, such as regular supervision and promoted care focused around clients' needs and goals. In our qualitative synthesis of four studies, intervention elements carers valued were greater flexibility to work to a needs based rather than a task-based model, learning more about clients, and improved communication with management and other workers. CONCLUSIONS: There is a dearth of evidence regarding effective strategies to improve how home care is delivered to older clients, particularly those with dementia. More research in this sector including feasibility testing of the first home care intervention trials to include health and life quality outcomes for clients with more severe dementia is now needed. PMID- 28091356 TI - Resistance to gastrointestinal parasite infection in Djallonke sheep. AB - Gastrointestinal parasitism places serious constraints on small ruminant production. The situation has been exacerbated by development of drug resistance in many parasite populations, leading to interest in identification of animals with genetically mediated resistance or tolerance to nematode infections. This study assessed the response to natural infection with gastrointestinal nematodes (GIN) in Djallonke sheep during the rainy season in the Sudan-Guinea Savannah region of Burkina Faso. Haemonchus contortus is the most prevalent GIN at this site and time. Djallonke lambs (n=434) were sampled from 40 households and evaluated at a common location in southern Burkina Faso. Lambs were dewormed with levamisole at 2 to 6 months of age and returned to infected pastures. Fecal egg counts (FEC), packed cell volumes (PCV), and FAffa Malan CHArt (FAMACHA(c)) scores were determined 28 and 35 days after deworming. Lamb mortality was monitored throughout the experiment. Least-squares means for BW increased from 13.8+/-0.2 kg at 28 days to 14.0+/-0.2 kg at 35 days (P<0.01). Simple means and medians for FEC were 615 and 100, respectively, at 28 days and 850 and 175, respectively, at 35 days. The FEC exhibited strong right skewness. Following logarithmic transformation and back-transformation of resulting least-squares means to the original scale, FEC were higher (P<0.01) for males (208+/-27) than females (122+/-10). Least-squares means for PCV decreased (P<0.001) from 28 (36.3+/-0.5%) to 35 days (33.7+/-0.5%), and were higher (P<0.01) for females (36.0+/-0.4%) than males (33.9+/-0.7%). Correlations (r) between repeated measurements of BW, FEC, PCV and FAMACHA scores at 28 and 35 days were all positive (P<0.001). The correlation between FAMACHA scores and PCV was negative at 28 (r=-0.14) and 35 days (r=-0.18) (P<0.001). This study revealed that BW was an easily measured predictor of the ability of the lamb to resist infection with GIN and maintain PCV, and confirmed that FAMACHA scores are useful indicators of differences in FEC. Approximately 40% of female and 30% of male lambs did not show detectable levels of infection (i.e. FEC=0) under field conditions. The great variability that was observed in FEC and PCV suggests potential to use Djallonke sheep in breeding programs to enhance resistance to GIN. PMID- 28091357 TI - Assessment of the need for a cardiac morphology curriculum for paediatric cardiology fellows. AB - BACKGROUND: Expert knowledge of cardiac malformations is essential for paediatric cardiologists. Current cardiac morphology fellowship teaching format, content, and nomenclature are left up to the discretion of the individual fellowship programmes. We aimed to assess practices and barriers in morphology education, perceived effectiveness of current curricula, and preferences for a standardised fellow morphology curriculum. METHODS: A web-based survey was developed de novo and administered anonymously via e-mail to all paediatric cardiology fellowship programme directors and associate directors in the United States of America; leaders were asked to forward the survey to fellows. RESULTS: A total of 35 directors from 32 programmes (51%) and 66 fellows responded. Curriculum formats varied: 28 (88%) programmes utilised pathological specimens, 25 (78%) invited outside faculty, and 16 (50%) utilised external conferences. Director nomenclature preferences were split - 6 (19%) Andersonian, 8 (25%) Van Praaghian, and 18 (56%) mixed. Barriers to morphology education included time and inconsistent nomenclature. One-third of directors reported that <90% of recent fellow graduates had adequate abilities to apply segmental anatomy, identify associated cardiac lesions, or communicate complex CHD. More structured teaching, protected time, and specimens were suggestions to improve curricula. Almost 75% would likely adopt/utilise an online morphology curriculum. CONCLUSIONS: Cardiac morphology training varies in content and format among fellowships. Inconsistent nomenclature exists, and inadequate morphology knowledge is perceived to contribute to communication failures, both have potential patient safety implications. There is an educational need for a common, online cardiac morphology curriculum that could allow for fellow assessment of competency and contribute to more standardised communication in the field of paediatric cardiology. PMID- 28091358 TI - A survey of exercise advice and recommendations in United Kingdom paediatric cardiac clinics. AB - BACKGROUND: Physical activity and exercise have important health benefits for children and adolescents with CHD. The objective of this study was to survey the provision of advice and recommendations in United Kingdom paediatric CHD clinics. METHODS: A three-page questionnaire was sent out to paediatric cardiac consultants in the United Kingdom, paediatric consultants with expertise in cardiology, and nursing staff (Paediatricians with Expertise in Cardiology Special Interest Group), as well as all members of the British Congenital Cardiovascular Association. The aim of this questionnaire was to determine the extent and scope of current information provision and to assess the importance that clinicians place on this advice. RESULTS: There were 68 responses in total, and the data showed that, of these, 24 (36%) clinicians had never provided paediatric CHD patients with written advice about exercise. Only 27 (39%) clinicians provided physical activity advice at every appointment. Lack of time during consultation (n=39, 56.9%), lack of training (n=38, 55.2%), and uncertainty about appropriate recommendations (n=38, 55.2%) were identified as the main factors preventing clinicians from providing patients with advice about physical activity. CONCLUSION: Although healthcare providers consider physical activity to be very important, the provision of clear, specific advice and recommendations is underutilised; therefore, more education and provision of resources to support the promotion of exercise need to be provided to clinicians and their support teams. PMID- 28091359 TI - Phyto-oestrogens and colorectal cancer risk: a systematic review and dose response meta-analysis of observational studies. AB - Epidemiological studies suggest that soya consumption as a source of phyto oestrogens and isoflavones may be associated with a reduced risk of colorectal cancer. However, findings have not yet been synthesised for all groups of phyto oestrogens. A meta-analysis was conducted to quantify the association between phyto-oestrogens and colorectal cancer risk. Relevant observational studies published up to June 2016 were identified by searching MEDLINE, EMBASE and Cochrane Library databases. Study-specific relative risks (RR) were pooled in both categorical and dose-response meta-analyses. Out of seventeen identified studies, sixteen were included in the meta-analysis. Comparing the highest with the lowest intake category, inverse associations for phyto-oestrogens overall and by subgroup were observed but were statistically significant in case-controls studies and not in cohort studies. The pooled RR in case-control studies were 0.76 (95 % CI 0.69, 0.84), 0.77 (95 % CI 0.69, 0.85) and 0.70 (95 % CI 0.56, 0.89) for phyto-oestrogens, isoflavones and lignans, respectively, whereas the corresponding pooled RR were 0.95 (95 % CI 0.85, 1.06), 0.94 (95 % CI 0.84, 1.05) and 1.00 (95 % CI 0.64, 1.57) in cohort studies. Dose-response analysis yielded an 8 % reduced risk of colorectal neoplasms for every 20 mg/d increase in isoflavones intake in Asians (pooled RR 0.92; 95 % CI 0.86, 0.97). A non-linear inverse association with colorectal cancer risk was found for lignans intake, but no association for circulating enterolactone concentrations was observed. Thus, study heterogeneity precludes a rigorous conclusion regarding an effect of high exposure to isoflavones on risk of colorectal cancer. Current evidence for an association with lignans exposure is limited. Further prospective studies, particularly evaluating lignans, are warranted to clarify the association between different phyto-oestrogens and colorectal cancer risk. PMID- 28091360 TI - Collagen peptide ingestion alters lipid metabolism-related gene expression and the unfolded protein response in mouse liver. AB - Ingestion of collagen peptide (CP) elicits beneficial effects on the body, including improvement in blood lipid profiles, but the underlying mechanisms remain unclear. The purpose of this study was to investigate the effects of CP ingestion on the liver, which controls lipid metabolism in the body. Male BALB/cCrSlc mice were bred with the AIN-93M diet containing 14 % casein or the AIN-93M-based low-protein diet containing 10 % casein or a diet containing 6 % casein+4 % CP for 10 weeks (n 12/group). Total, free and esterified cholesterol levels in the blood decreased in the CP group. DNA microarray analysis of the liver revealed that expressions of genes related to lipid metabolic processes such as the PPAR signalling pathway and fatty acid metabolism increased in the CP group compared with the 10 % casein group. The expressions of several genes involved in steroid metabolic process, including Cyp7a1 and Cyp8b1, were decreased, despite being targets of transcriptional regulation by PPAR. These data suggest that lipid metabolism in the liver is altered by CP ingestion, and the decrease in blood cholesterol levels in the CP group is not due to enhancement of the steroid metabolic process. On the other hand, expressions of genes related to the unfolded protein response (UPR) significantly decreased at the mRNA level, suggesting that CP ingestion lowers endoplasmic reticulum stress. Indeed, protein levels of phosphorylated inositol-requiring enzyme 1 decreased after CP ingestion. Taken together, CP affects the broader pathways in the liver not only lipid metabolism but also UPR. PMID- 28091361 TI - Responses of plasma glucose metabolism to exogenous insulin infusion in sheep-fed forage herb plantain and exposed to heat. AB - The use of herbal plants as traditional medicines has a century long history. Plantain (Plantago lanceolata L.) is a perennial herb containing bioactive components with free radical scavenging activities. An isotope dilution technique using [U-13C]glucose was conducted to determine the effect of plantain on the responses of plasma glucose metabolism to exogenous insulin infusion in sheep. Six crossbred sheep (three wethers and three ewes; mean initial BW=40+/-2 kg) were fed either a mixed hay of orchardgrass (Dactylis glomerata) and reed canarygrass (Phalaris arundinacea) (MH-diet) or mixed hay and fresh plantain (1 : 1 ratio, dry matter basis, PL-diet) and exposed to a thermoneutral (TN, 20 degrees C; 70% relative humidity (RH)) environment or a heat exposure (HE, 30 degrees C; 70% RH) for 5 days using a crossover design for two 23-day periods. The isotope dilution was conducted on days 18 and 23 of the experimental period during TN and HE, respectively. Plasma concentration of alpha-tocopherol was greater (P<0.0001) for the PL-diet than the MH-diet and remained comparable between environmental treatments. Plasma glucose concentration before isotope dilution technique was reduced for sheep (P=0.05) during HE compared with TN and remained comparable between diets. Plasma glucose turnover rate during the preinfusion period of insulin did not differ (P=0.10) between dietary treatments and between environments (P=0.65). The response of plasma glucose utilization to exogenous insulin administration was lower (P=0.04) for the PL-diet than the MH diet. Under present experimental conditions, the plantain group was found to be resistant to the effects of insulin infusion. PMID- 28091363 TI - Obesity and diabetes in 2017: a new year. PMID- 28091362 TI - Epicutaneous immunotherapy for the treatment of peanut allergy in children and young adults. AB - BACKGROUND: Peanut allergy is common, life-threatening, and without therapeutic options. We evaluated peanut epicutaneous immunotherapy (EPIT) by using Viaskin Peanut for peanut allergy treatment. OBJECTIVE: We sought to evaluate the clinical, safety, and immunologic effects of EPIT for the treatment of peanut allergy. METHODS: In this multicenter, double-blind, randomized, placebo controlled study, 74 participants with peanut allergy (ages 4-25 years) were treated with placebo (n = 25), Viaskin Peanut 100 MUg (VP100; n = 24) or Viaskin Peanut 250 MUg (VP250; n = 25; DBV Technologies, Montrouge, France). The primary outcome was treatment success after 52 weeks, which was defined as passing a 5044 mg protein oral food challenge or achieving a 10-fold or greater increase in successfully consumed dose from baseline to week 52. Adverse reactions and mechanistic changes were assessed. RESULTS: At week 52, treatment success was achieved in 3 (12%) placebo-treated participants, 11 (46%) VP100 participants, and 12 (48%) VP250 participants (P = .005 and P = .003, respectively, compared with placebo; VP100 vs VP250, P = .48). Median change in successfully consumed doses were 0, 43, and 130 mg of protein in the placebo, VP100, and VP250 groups, respectively (placebo vs VP100, P = .014; placebo vs VP250, P = .003). Treatment success was higher among younger children (P = .03; age, 4-11 vs >11 years). Overall, 14.4% of placebo doses and 79.8% of VP100 and VP250 doses resulted in reactions, predominantly local patch-site and mild reactions (P = .003). Increases in peanut-specific IgG4 levels and IgG4/IgE ratios were observed in peanut EPIT-treated participants, along with trends toward reduced basophil activation and peanut-specific TH2 cytokines. CONCLUSIONS: Peanut EPIT administration was safe and associated with a modest treatment response after 52 weeks, with the highest responses among younger children. This, when coupled with a high adherence and retention rate and significant changes in immune pathways, supports further investigation of this novel therapy. PMID- 28091364 TI - Making medicine bespoke. PMID- 28091365 TI - Suicide among health-care workers: time to act. PMID- 28091366 TI - Trastuzumab emtansine and cost-based decision making. PMID- 28091367 TI - Offline: What should be the UK's "bold new role"? PMID- 28091368 TI - Philippines president continues his brutal war on drugs. PMID- 28091369 TI - Colombia fails to tackle malnutrition in Indigenous children. PMID- 28091370 TI - Hellen Gelband: botanist turned policy guru in global health. PMID- 28091371 TI - WHOse agenda for WHOm? Analysing the manifestos of the candidates for Director General of WHO. PMID- 28091372 TI - WHO Director-General candidates: where does mental health feature? PMID- 28091373 TI - The INTERSTROKE study on risk factors for stroke. PMID- 28091374 TI - The INTERSTROKE study on risk factors for stroke. PMID- 28091376 TI - Department of Error. PMID- 28091375 TI - The INTERSTROKE study on risk factors for stroke - Authors' reply. PMID- 28091377 TI - Department of Error. PMID- 28091378 TI - Department of Error. PMID- 28091379 TI - Department of Error. PMID- 28091380 TI - Department of Error. PMID- 28091381 TI - Department of Error. PMID- 28091382 TI - Department of Error. PMID- 28091383 TI - Department of Error. PMID- 28091384 TI - Determination the Role of Rhipicephalus sanguineus for Transmission of Leishmania major to Reservoir Animals. AB - OBJECTIVE: This study aimed to explore the role of Rhipicephalus sanguineus in the transmission of Leishmania major, the etiological agent of zoonotic cutaneous leishmaniasis. METHODS: Ten gerbils (Meriones unguiculatus) were infected with promastigotes of L. major, and 10 gerbils were maintained as controls. In a controlled environment, 2000 R. sanguineus larvae were fed to two gerbils. Following feeding to gerbils, 65 tick pools were prepared from the engorged larvae and molted unfed nymphs. These pools were tested for the presence of L. major using polymerase chain reaction and real time (RT) PCR. RESULTS: One of the infected gerbil was anesthetized and necropsied following the dropping of all fed larvae. Following the examination, amastigotes were detected in all organs and tissues. PCR and RT-PCR were performed to test whether the engorged R. sanguineus larvae successfully took the parasite while feeding and was able to transmit it to the next nymphal stage; however, none of the tick pools were found to be positive for L. major. CONCLUSION: Although L.major was not detected in ticks that fed on gerbils, using dogs in experimental studies related to leishmaniasis will give clearer results in terms of detecting the potential role of insects and acars. PMID- 28091385 TI - Research on Laying Trichostrongylid Nematode Eggs in Cows in the Periparturient Period. AB - OBJECTIVE: This study aimed to comparatively determine the prevalence of trichostrongylid nematodes and egg excretions in cows that are in the periparturient period (PPP) and pregnant cows in the non-periparturient period (NPPP). METHODS: Animal materials are constituted by cows in PPP and NPPP in 10 ranches in Kars and surrounding areas. Stool samples were collected from the rectum of 125 pregnant cows, which were in NPPP during November 2010 - January 2011 and from the same cows in PPP during April-May 2011. Stool samples were analyzed for the presence of nematode eggs by the flotation method. EPG was determined by the McMaster method. RESULTS: Trichostrongylid nematode eggs were detected in seven of 10 dairy cattle ranches (70%). The prevalence rates of trichostrongylid nematodes were 16.8% (21/125) during NPPP and 27.2% (34/125) during PPP. Nineteen of 21 (90.5%) positive samples during NPPP were positive during PPP. Fifteen negative samples during NPPP were positive during PPP with respect to trichostrongylid nematode eggs. The egg count of trichostrongylid during PPP (total, 4350; mean, 34.8; n, 125) was greater than that during NPPP (total, 1250; mean, 10; n, 125). CONCLUSION: Cows had nematode eggs during PPP and played an important role in transmission. PMID- 28091386 TI - Prevalence of Infection with the Larval Form of the Cestode Parasite Taenia saginata in Cattle in Northwest Iran and its Zoonotic Importance. AB - OBJECTIVE: Bovine cysticercosis is a cattle infection caused by a tapeworm, Taenia saginata. While the condition is relatively innocuous, the parasite infects the small intestine of humans in its mature stage and causes a few specific symptoms such as abdominal pain and nausea. METHODS: Between February 2013 and February 2014, a total of 640 cattle were randomly selected from all the cattle sent to the abattoir, and some internal organs and skeletal muscles of these cattle were inspected. RESULTS: Overall, 11 (1.71%) cattle were infected with the larval form of the cestode parasite T. saginata. In addition, the infection was more prevalent in cattle aged above 12 months than in those aged below 12 months [10 (2.06%) vs. 1 (0.64%)]. The prevalence of infection was significantly higher in female animals [8 (3.72%)] than in male animals [3 (0.70%)] (p<0.05). However, no significant difference was found between the rates in the 2 age groups or in different seasons. While the infections were detected in several visceral organs, no significant difference was found between their infection rates. CONCLUSION: The comparatively high prevalence of Cysticercus bovis infection in the cattle in Tabriz, Iran, may contribute to economic and health problems in the country's meat industry. On the other hand, the role of public health education in C. bovis infection control cannot be neglected. PMID- 28091387 TI - Prevalence of Intestinal Parasites in Cats and Their Importance in Terms of Public Health. AB - OBJECTIVE: This study aimed to detect the prevalence of intestinal parasites in cats by fecal examination. METHODS: A total of 100 fecal samples were collected from owned and stray cats in the Kirikkale province. Epidemiological data on the sampled cats (e.g., age, race, and sex) were recorded. The samples were macroscopically investigated for the presence of cestode proglottids. The fecal smears were stained with Giemsa and Carbol fuchsin stains. The samples were prepared by centrifugal flotation with a saturated sugar solution. The slides were examined using light microscopy. RESULTS: Parasites were detected in 47% of feces of cats examined. Protozoa (Isospora spp. and Cryptosporidium spp.) oocysts, gravid proglottid of cestode (Joyeuxiella spp.), and nematode (Toxocara spp. and hookworm) eggs were present in the fecal samples. In this study, 48.9% of cats were infected with one species, and 44.6% and 6.3% of cats were infected with two and three species, respectively. The more prevalent parasite species were Isospora spp. (65.9%) and Toxocara spp. (48.9%). The parasites were found to be more common in stray cats. CONCLUSION: Intestinal parasites were highly prevalent in the cats examined in this study. House cats can have significant parasitic infections, particularly because they are allowed outdoors. House cats should be regularly examined by a veterinarian. PMID- 28091388 TI - Blood Meal Identification of the Mosquito (Diptera: Culicidae) Specimens Belong to Culex pipiens Complex that were Collected from Kayseri Province. AB - OBJECTIVE: This study aimed to determine the host preferences in blood meal of specimens belonging to Culex pipiens complex. METHODS: A total of 1284 female mosquitos were morphologically examined, and genomic DNA isolations were individually performed on 376 (28.4%) specimens that were determined to be Cx. pipiens complex. PCR was performed with primers to specifically amplify the avian and mammalian mitochondrial cytochrome b (mt-cytb) gene region. Amplicons were cloned, and the obtained plasmids were sequenced to determine host species. RESULTS: Of 376 specimens, 148 (39.4%) were positive for the avian and/or mammalian blood meal. Among the positive specimens, 43, 98, and seven were determined to be positive for only mammalian, avian, and both avian and mammalian blood, respectively. Avian host preference in blood meal of the specimens belonging to Cx. pipiens was found to be significant. Of 15 avian blood positive isolates, nine, three, two, and one were designated as blood meal from avian species in Passeriformes, Accipitriformes, Columbiformes, and Strigiformes orders, respectively. While six, four, three, and two out of 15 mammalian blood positive specimens were found to be positive for human, cattle, sheep, and dog blood, respectively. CONCLUSION: Molecular data regarding the host preferences of the Cx. pipiens species complex in blood meal were revealed for the first time in Turkey with this study. PMID- 28091389 TI - TRALI Syndrome During the Treatment of a Plasmodium falciparum Malaria Case. AB - Malaria, which is one of the three most important infectious diseases globally, is endemic in many areas of the world. Plasmodium falciparum is not endemic to Turkey but can be seen after travel to epidemic countries. Transfusion-related acute lung injury (TRALI) syndrome is a rare disease, which may develop following the transfusion of all types of blood products, including plasma. Here we describe a case of TRALI syndrome in a 29-year-old male, who presented with fever after 15 days of returning from a business trip to Burkina Faso. It developed immediately after the infusion of fresh frozen plasma during the treatment of P. falciparum malaria. The patient's condition improved on respiratory support treatment in the intensive care unit for 48 hours without the need of mechanical ventilation. This case indicated that TRALI syndrome has to be considered in the differential diagnosis as an emerging acute lung disease during the treatment of malaria. PMID- 28091390 TI - Demodex spp. Infestation Associated with Treatment-Resistant Chalazia and Folliculitis. AB - Demodecidosis is an ectoparasitosis of pilosebaceous unit caused by demodex mites. The disease may be a primary skin disease or a secondary disease to inflammatory dermatoses such as folliculitis and rosacea. Demodex spp. blepharitis is an infectious ocular disease that is common but always neglected. These mites contain lipase enzymes that help carry bacteria on the surface. The infestation of Demodex spp. has increasingly become a public health concern. A 29 year-old male patient was admitted to our dermatology clinic with a complaint of papules and pustules on his face, which started 4 years ago. A standardized skin biopsy specimen was evaluated in our microbiology laboratory, and we detected Demodex folliculorum mites on his face (3+). There was pruritus of his eyes. A total of four eyelashes were epilated and were then examined under a light microscope for the presence of Demodex infestation. In this study, we discussed the association between acne rocacea, blepharitis, and demodex mites. PMID- 28091391 TI - Slender-horned gazelle (Gazella leptoceros), a new host for Tricholipeurus balanicus (Phthiraptera: Ischnocera: Trichodectidae). AB - This study was performed to provide information on Tricholipeurus balanicus (Werneck 1938) detected on slender-horned gazelles (Gazella leptoceros) (Cuvier 1842). Four slender-horned gazelles kept in the El Hamma Zoological Garden in Algeria were examined for lice in April 2015. Three of the four gazelles were infested with lice; of 37 lice collected from the infested animals, 14 were females, 16 were males, and 7 were nymphs. Lice were mainly found on the back and hind legs of the gazelles. The lice were collected by a forceps, preserved in 70% alcohol, and cleared in 10% KOH for 24 h. Thereafter, they were rinsed in distilled water, transferred to 70% and 99% alcohol, mounted on slides in Canada balsam, examined under a binocular microscope, and identified as Tricholipeurus balanicus (Werneck, 1938). To the best of our knowledge, T. balanicus on G. leptoceros has been reported for the first time. PMID- 28091392 TI - The impact of viral load and time to onset of cytomegalovirus replication on long term graft survival after kidney transplantation. AB - BACKGROUND: Asymptomatic cytomegalovirus (CMV) infection is associated with graft dysfunction and failure. However, no study assessed CMV viral load in terms of the risk for graft failure. METHODS: In a prospective cohort of kidney transplant recipients, we assessed the impact of CMV DNAemia on the overall graft survival and the incidence of moderate-to-severe interstitial fibrosis and tubular atrophy (IF/TA) in protocol biopsy at 36 months. CMV DNAemia was stratified by viral load in whole blood. RESULTS: A total of 180 patients transplanted from October 2003 through January 2011 were included and followed for 4 years; 87 (48%) patients received 3-month prophylaxis with valacyclovir and 45 (25%) with valganciclovir; 48 (27%) were managed by pre-emptive therapy. Within 12 months of transplantation, CMV DNAemia developed in 102 (57%) patients with 36 (20%) having a viral load of >=2,000 copies/ml. Multivariate Cox analysis identified CMV DNAemia as an independent risk factor for graft loss (hazard ratio 3.42; P=0.020); however, after stratification by viral load, only CMV DNAemia >=2,000 copies/ml (hazard ratio 7.62; P<0.001) remained significant. Both early-onset (<3 months; P=0.048) and late-onset (>3 months; P<0.001) CMV DNAemia >=2,000 copies/ml were risk factors for graft loss. The incidence of moderate-to-severe IF/TA was not significantly influenced by CMV DNAemia. CONCLUSIONS: Kidney transplant recipients having CMV DNAemia with a higher viral load irrespective of the time to onset are at increased risk for graft loss. PMID- 28091393 TI - Viral blips were infrequent in treatment-naive adults treated with rilpivirine/emtricitabine/tenofovir DF or efavirenz/emtricitabine/tenofovir DF through 96 weeks. AB - BACKGROUND: The clinical impact of transient episodes of HIV viraemia (viral blips) on virological failure and resistance development is not fully understood. Here we investigated the blip frequency and virological outcomes of HIV-1 infected subjects experiencing viral blips among treatment-naive subjects initiating therapy on rilpivirine (RPV)/emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) or efavirenz (EFV)/FTC/TDF through 96 weeks of treatment. METHODS: Subjects treated with at least one dose of study drug and with at least one post baseline HIV-1 RNA value were included in this analysis. All on-drug HIV-1 RNA data points and FDA snapshot outcome data through week 96 were utilized. A viral blip was defined as after achieving confirmed suppression (two consecutive HIV-1 RNA values <50 copies/ml), any HIV-1 RNA value >=50 copies/ml preceded and followed by HIV-1 RNA <50 copies/ml. RESULTS: Of the 717 subjects with confirmed suppression, 67 (9.3%) experienced >=1 blip through week 96 with similar blip frequencies occurring in both treatment arms (10.7% RPV/FTC/TDF versus 8.0% EFV/FTC/TDF; P=0.25). A significantly higher proportion of subjects with baseline HIV-1 RNA >100,000 copies/ml experienced blips compared to subjects with baseline HIV-1 RNA <=100,000 copies/ml and this was observed in both arms. Of 72 total blip events, 61 (85%) were low-level (50-199 copies/ml). Overall, among subjects with blips, 79% were virological successes at week 96, similar to those subjects without blips (83%; P=0.50). More subjects with blips >=200 copies/ml experienced virological failure compared to subjects with blips <200 copies/ml (36.4% versus 7.1%; P=0.02). CONCLUSIONS: Viral blips were infrequent and similar among subjects treated with RPV/FTC/TDF or EFV/FTC/TDF. Most blips were low-level and most subjects with blips remained virologically suppressed through week 96 without experiencing virological failure. PMID- 28091394 TI - Simplified bionic solutions: a simple bio-inspired vehicle collision detection system. AB - Modern cars are equipped with both active and passive sensor systems that can detect potential collisions. In contrast, locusts avoid collisions solely by responding to certain visual cues that are associated with object looming. In neurophysiological experiments, I investigated the possibility that the 'collision-detector neurons' of locusts respond to impending collisions in films recorded with dashboard cameras of fast driving cars. In a complementary modelling approach, I developed a simple algorithm to reproduce the neuronal response that was recorded during object approach. Instead of applying elaborate algorithms that factored in object recognition and optic flow discrimination, I tested the hypothesis that motion detection restricted to a 'danger zone', in which frontal collisions on the motorways are most likely, is sufficient to estimate the risk of a collision. Furthermore, I investigated whether local motion vectors, obtained from the differential excitation of simulated direction selective networks, could be used to predict evasive steering maneuvers and prevent undesired responses to motion artifacts. The results of the study demonstrate that the risk of impending collisions in real traffic scenes is mirrored in the excitation of the collision-detecting neuron (DCMD) of locusts. The modelling approach was able to reproduce this neuronal response even when the vehicle was driving at high speeds and image resolution was low (about 200 * 100 pixels). Furthermore, evasive maneuvers that involved changing the steering direction and steering force could be planned by comparing the differences in the overall excitation levels of the simulated right and left direction-selective networks. Additionally, it was possible to suppress undesired responses of the algorithm to translatory movements, camera shake and ground shadows by evaluating local motion vectors. These estimated collision risk values and evasive steering vectors could be used as input for a driving assistant, converting the first into braking force and the latter into steering responses to avoid collisions. Since many processing steps were computed on the level of pixels and involved elements of direction-selective networks, this algorithm can be implemented in hardware so that parallel computations enhance the processing speed significantly. PMID- 28091395 TI - A novel onset detection technique for brain-computer interfaces using sound production related cognitive tasks in simulated-online system. AB - OBJECTIVE: Self-paced EEG-based BCIs (SP-BCIs) have traditionally been avoided due to two sources of uncertainty: (1) precisely when an intentional command is sent by the brain, i.e., the command onset detection problem, and (2) how different the intentional command is when compared to non-specific (or idle) states. Performance evaluation is also a problem and there are no suitable standard metrics available. In this paper we attempted to tackle these issues. APPROACH: Self-paced covert sound-production cognitive tasks (i.e., high pitch and siren-like sounds) were used to distinguish between intentional commands (IC) and idle states. The IC states were chosen for their ease of execution and negligible overlap with common cognitive states. Band power and a digital wavelet transform were used for feature extraction, and the Davies-Bouldin index was used for feature selection. Classification was performed using linear discriminant analysis. MAIN RESULTS: Performance was evaluated under offline and simulated online conditions. For the latter, a performance score called true-false-positive (TFP) rate, ranging from 0 (poor) to 100 (perfect), was created to take into account both classification performance and onset timing errors. Averaging the results from the best performing IC task for all seven participants, an 77.7% true-positive (TP) rate was achieved in offline testing. For simulated-online analysis the best IC average TFP score was 76.67% (87.61% TP rate, 4.05% false positive rate). SIGNIFICANCE: Results were promising when compared to previous IC onset detection studies using motor imagery, in which best TP rates were reported as 72.0% and 79.7%, and which, crucially, did not take timing errors into account. Moreover, based on our literature review, there is no previous covert sound-production onset detection system for spBCIs. Results showed that the proposed onset detection technique and TFP performance metric have good potential for use in SP-BCIs. PMID- 28091397 TI - A novel stimulation method for multi-class SSVEP-BCI using intermodulation frequencies. AB - OBJECTIVE: Steady-state visual evoked potential (SSVEP)-based brain-computer interface (BCI) has been widely investigated because of its easy system configuration, high information transfer rate (ITR) and little user training. However, due to the limitations of brain responses and the refresh rate of a monitor, the available stimulation frequencies for practical BCI application are generally restricted. APPROACH: This study introduced a novel stimulation method using intermodulation frequencies for SSVEP-BCIs that had targets flickering at the same frequency but with different additional modulation frequencies. The additional modulation frequencies were generated on the basis of choosing desired flickering frequencies. The conventional frame-based 'on/off' stimulation method was used to realize the desired flickering frequencies. All visual stimulation was present on a conventional LCD screen. A 9-target SSVEP-BCI based on intermodulation frequencies was implemented for performance evaluation. To optimize the stimulation design, three approaches (C: chromatic; L: luminance; CL: chromatic and luminance) were evaluated by online testing and offline analysis. MAIN RESULTS: SSVEP-BCIs with different paradigms (C, L, and CL) enabled us not only to encode more targets, but also to reliably evoke intermodulation frequencies. The online accuracies for the three paradigms were 91.67% (C), 93.98% (L), and 96.41% (CL). The CL condition achieved the highest classification performance. SIGNIFICANCE: These results demonstrated the efficacy of three approaches (C, L, and CL) for eliciting intermodulation frequencies for multi-class SSVEP-BCIs. The combination of chromatic and luminance characteristics of the visual stimuli is the most efficient way for the intermodulation frequency coding method. PMID- 28091398 TI - Diagnosis of a Chinese man with 45,X/46,X,i(Y)(q10)/47,X,i(Y) (q10) *2 mosaic Turner syndrome. PMID- 28091396 TI - Anti-angiogenic activity and antitumor efficacy of amphiphilic twin drug from ursolic acid and low molecular weight heparin. AB - Heparin, a potential blood anti-coagulant, is also known for its binding ability to several angiogenic factors through electrostatic interactions due to its polyanionic character. However, the clinical application of heparin for cancer treatment is limited by several drawbacks, such as unsatisfactory therapeutic effects and severe anticoagulant activity that could induce hemorrhaging. Herein, low molecular weight heparin (LMWH) was conjugated to ursolic acid (UA), which is also an angiogenesis inhibitor, by binding the amine group of aminoethyl-UA (UA NH2) with the carboxylic groups of LMWH. The resulting LMWH-UA conjugate as an amphiphilic twin drug showed reduced anticoagulant activity and could also self assemble into nanomicelles with a mean particle size ranging from 200-250 nm. An in vitro endothelial tubular formation assay and an in vivo Matrigel plug assay were performed to verify the anti-angiogenic potential of LMWH-UA. Meanwhile, the in vivo antitumor effect of LMWH-UA was also evaluated using a B16F10 mouse melanoma model. LMWH-UA nanomicelles were shown to inhibit angiogenesis both in vitro and in vivo. In addition, the i.v. administration of LMWH-UA to the B16F10 tumor-bearing mice resulted in a significant inhibition of tumor growth as compared to the free drug solutions. These findings demonstrate the therapeutic potential of LMWH-UA as a new therapeutic remedy for cancer therapy. PMID- 28091399 TI - Sex determination and maintenance: the role of DMRT1 and FOXL2. AB - In many species, including mammals, sex determination is genetically based. The sex chromosomes that individuals carry determine sex identity. Although the genetic base of phenotypic sex is determined at the moment of fertilization, the development of testes or ovaries in the bipotential early gonads takes place during embryogenesis. During development, sex determination depends upon very few critical genes. When one of these key genes functions inappropriately, sex reversal may happen. Consequently, an individual's sex phenotype may not necessarily be consistent with the sex chromosomes that are present. For some time, it has been assumed that once the fetal choice is made between male and female in mammals, the gonadal sex identity of an individual remains stable. However, recent studies in mice have provided evidence that it is possible for the gonadal sex phenotype to be switched even in adulthood. These studies have shown that two key genes, doublesex and mad-3 related transcription factor 1 (Dmrt1) and forkhead box L2 (Foxl2), function in a Yin and Yang relationship to maintain the fates of testes or ovaries in adult mammals, and that mutations in either gene might have a dramatic effect on gonadal phenotype. Thus, adult gonad maintenance in addition to fetal sex determination may both be important for the fertility. PMID- 28091400 TI - Serum lipid profiles are associated with semen quality. AB - We aimed to explore the associations between different lipid profiles and semen quality in a large-scale general male population. Sperm concentration, total sperm motility, progressive motility, and normal sperm morphology of total 7601 participants were recorded. The association of these semen parameters with the triglyceride, total cholesterol, high-density lipoprotein, low-density lipoprotein, and very low-density lipoprotein of serum lipid profiles was analyzed. Sperm concentration was statistically positively correlated with triglyceride and very low-density lipoprotein (adjusted P = 0.001 and P = 0.005, respectively). Total sperm motility and progressive motility were statistically increased with increasing low-density lipoprotein and cholesterol levels (both adjusted P = 0.008 and P < 0.001, respectively). The similar J-shaped associations (high-low-low-high) were noted between individual lipid profile and normal sperm morphology, especially low-density lipoprotein and cholesterol with statistical significance (adjusted P = 0.017 and P = 0.021, respectively). The prevalence of abnormal total sperm motility and progressive motility was decreased in participants with high levels of cholesterol (P = 0.008 and P = 0.019, respectively), and the reverse J-shaped associations (low-high-high-low) were noted between high-density lipoprotein, triglyceride, very low-density lipoprotein, and the prevalence of abnormal normal sperm morphology (P = 0.010, P = 0.037, and P = 0.025, respectively). A high cholesterol level was associated with better sperm motility. Similar J-shaped associations were noted between all lipid profiles and normal sperm morphology; meanwhile, the reverse J-shaped trends were identified between them and abnormal normal sperm morphology prevalence. PMID- 28091401 TI - Tyrosine Kinase Inhibitor for Treatment of Adult Allogeneic Hematopoietic Stem Cell Transplantation Candidate with Philadelphia-Positive Acute Lymphoblastic Leukemia. PMID- 28091402 TI - Geriatric Assessment to Predict Survival and Risk of Serious Adverse Events in Elderly Newly Diagnosed Multiple Myeloma Patients: A Multicenter Study in China. AB - BACKGROUND: Elderly multiple myeloma (MM) patients often tend to suffer a variety of diseases, so the treatment of choice is very difficult for the elderly myeloma patients. The overall survival (OS) time and side effects with elderly patients are unclear in China. The study tried to find out the role of geriatric assessment in the Chinese elderly MM. METHODS: We retrospectively analyzed the data of 628 newly diagnosed patients from six hospitals from June 2011 to June 2013. A geriatric assessment had been performed to assess comorbidities, cognitive, and physical status for these patients. The primary endpoint was to evaluate different physical states of elderly patients with OS time and treatment related side effects. RESULTS: An additive scoring system (range: 0-5), based on age, Katz's Activity of Daily Living (ADL) and Lawton's Instrumental Activity of Daily Living (IADL) <=5 and Charlson Comorbidity Index (CCI) was developed to identify three groups: fit (score = 0); intermediate-fitness (score = 1); and frail (score >=2). The 3-year OS was 63% in fit patients, 63% in intermediate fitness patients, and 49% in frail patients >=3 hematologic adverse events (AEs) were documented in 45 (35.4%) fit, 34 (34%) intermediate-fitness, and 121 (30.2%) frail patients. The risk of a grade >=3 hematologic AEs was not significantly increase in intermediate-fitness (hazard ratios [HR]: 0.99, 95% confidence interval [CI]: 0.54-1.47, P = 1.000) and in frail patients (HR: 1.16, 95% CI: 0.70-1.93, P = 0.558) compared with fit ones. CONCLUSIONS: MM occurs earlier in life and being advanced when the diagnosis is made in the mainland of China. The overall survival in frailty with International Staging System (ISS) II/III was the worst in all patients. PMID- 28091404 TI - Left Atrial Mechanical Function and Aortic Stiffness in Middle-aged Patients with the First Episode of Atrial Fibrillation. AB - BACKGROUND: In the early stages of atrial remodeling, aortic stiffness might be an indication of an atrial myopathy, in particular, atrial fibrosis. This study aimed to investigate the association between left atrial (LA) mechanical function, assessed by two-dimensional speckle tracking echocardiography, and aortic stiffness in middle-aged patients with the first episode of nonvalvular atrial fibrillation (AF). METHODS: This prospective study included 34 consecutive patients with the first episode of AF, who were admitted to Kartal Kosuyolu Research and Training Hospital between May 2013 and October 2015, and 31 age- and gender-matched healthy controls. During the 1 st month (mostly in the first 2 weeks) following their first admission, 34 patients underwent the first pulse wave measurements. Then, 21 patients were recalled for their second pulse wave measurement at 11.8 +/- 6.0 months following their initial admission. Echocardiographic and pulse wave findings were compared between these 34 patients and 31 healthy controls. We also compared the pulse wave and echocardiographic findings between the first and second measurements in 21 patients. RESULTS: Pulse wave analysis showed no significant differences between the AF patients and healthy controls with respect to PWV (10.2 +/- 2.5 m/s vs. 9.7 +/- 2.1 m/s; P = 0.370), augmentation pressure (9.6 +/- 7.4 mmHg vs. 9.1 +/- 5.7 mmHg; P = 0.740), and aortic pulse pressure (AoPP; 40.4 +/- 14.0 mmHg vs. 42.1 +/- 7.6 mmHg, P = 0.550). The first LA positive peak of strain was inversely related to the augmentation pressure (r = -0.30; P = 0.02) and aortic systolic pressure (r = 0.26, P = 0.04). Comparison between the two consecutive pulse wave measurements in 21 patients showed similar results, except for AoPP. In 21 patients, the AoPP at the second measurement (45.1 +/- 14.1 mmHg) showed a significant increase compared with AoPP at the first measurement (39.0 +/- 10.6 mmHg, P = 0.028), which was also higher than that of healthy controls (42.1 +/- 7.6 mmHg, P = 0.000). CONCLUSION: The association between aortic stiffness with reduced atrial strain and the key role of AoPP in the development of AF should be considered when treating nonvalvular AF patients with normal LA sizes. PMID- 28091403 TI - Chronic Lymphocytic Leukemia Prognostic Index: A New Integrated Scoring System to Predict the Time to First Treatment in Chinese Patients with Chronic Lymphocytic Leukemia. AB - BACKGROUND: The established clinical staging systems (Rai/Binet) of chronic lymphocytic leukemia (CLL) cannot accurately predict the appropriate treatment of patients in the earlier stages. In the past two decades, several prognostic factors have been identified to predict the outcome of patients with CLL, but only a few studies investigated more markers together. To predict the time to first treatment (TTFT) in patients of early stages, we evaluated the prognostic role of conventional markers as well as cytogenetic abnormalities and combined them together in a new prognostic scoring system, the CLL prognostic index (CLL PI). METHODS: Taking advantage of a population of 406 untreated Chinese patients with CLL at early and advanced stage of disease, we identified the strongest prognostic markers of TTFT and, subsequently, in a cohort of 173 patients who had complete data for all 3 variables, we integrated the data of traditional staging system, cytogenetic aberrations, and mutational status of immunoglobulin heavy chain variable region (IGHV) in CLL-PI. The median follow-up time was 45 months and the end point was TTFT. RESULTS: The median TTFT was 38 months and the 5-year overall survival was 80%. According to univariate analysis, patients of advanced Rai stages (P < 0.001) or with 11q- (P = 0.002), 17p- (P < 0.001), unmutated IGHV (P < 0.001), negative 13q- (P = 0.007) and elevated lactate dehydrogenase levels (P = 0.001) tended to have a significantly shorter TTFT. And subsequently, based on multivariate Cox regression analysis, three independent factors for TTFT were identified: advanced clinical stage (P = 0.002), 17p- (P = 0.050) and unmutated IGHV (P = 0.049). Applying weighted grading of these independent factors, a CLL PI was constructed based on regression parameters, which could categorize four different risk groups (low risk [score 0], intermediate low [score 1], intermediate high [score 2] and high risk [score 3-6]) with significantly different TTFT (median TTFT of not reached (NR), 65.0 months, 36.0 months and 19.0 months, respectively, P < 0.001). CONCLUSIONS: This study developed a weighted, integrated CLL-PI prognostic system of CLL patients which combines the critical genetic prognostic markers with traditional clinical stage. This novel modified PI system could be used to discriminate among groups and may help predict the TTFT and prognosis of patients with CLL. PMID- 28091405 TI - Evaluation of Helicobacter pylori Infection in Patients with Chronic Hepatic Disease. AB - BACKGROUND: The 13C urea breath test (13C-UBT) is the gold standard for detecting Helicobacter pylori infection. H. pylori pathogenesis in patients with hepatitis B virus (HBV) and related diseases remains obscure. We used 13C-UBT to detect H. pylori infection in patients with chronic HBV infection, HBV-related cirrhosis, HBV-related hepatic carcinoma, and other chronic hepatic diseases. METHODS: A total of 131 patients with chronic hepatitis B (HB), 179 with HBV-related cirrhosis, 103 with HBV-related hepatic carcinoma, 45 with HBV-negative hepatic carcinoma, and 150 controls were tested for H. pylori infection using 13C-UBT. We compared H. pylori infection rate, liver function, complications of chronic hepatic disease, serum HBV-DNA, serum alpha-fetoprotein (AFP), and portal hypertensive gastropathy (PHG) incidence among groups. RESULTS: HBV-related cirrhosis was associated with the highest H. pylori infection rate (79.3%). H. pylori infection rate in chronic HB was significantly higher than in the HBV negative hepatic carcinoma and control groups (P < 0.001). H. pylori infection rate in patients with HBV-DNA >=10 3 copies/ml was significantly higher than in those with HBV-DNA <103 copies/ml (76.8% vs. 52.4%, P < 0.001). Prothrombin time (21.3 +/- 3.5 s vs. 18.8 +/- 4.3 s), total bilirubin (47.3+/-12.3 MUmol/L vs. 26.6 +/-7.9 MUmol/L), aspartate aminotransferase (184.5 +/- 37.6 U/L vs. 98.4 +/- 23.5 U/L), blood ammonia (93.4 +/- 43.6 MUmol/L vs. 35.5 +/- 11.7 MUmol/L), and AFP (203.4 +/- 62.6 MUg/L vs. 113.2 +/- 45.8 MUg/L) in the 13C-UBT-positive group were significantly higher than in the 13C-UBT-negative group (P < 0.01). The incidence rates of esophageal fundus variceal bleeding (25.4% vs. 16.0%), ascites (28.9% vs. 17.8%), and hepatic encephalopathy (24.8% vs. 13.4%) in the 13C-UBT positive group were significantly higher than in the 13C-UBT-negative group (P < 0.01). The percentages of patients with liver function in Child-Pugh Grade C (29.6% vs. 8.1%) and PHG (43.0% vs. 24.3%) in the 13C-UBT-positive group were significantly higher than in the 13C-UBT-negative group (P < 0.05). CONCLUSIONS: It is possible that H. pylori infection could increase liver damage caused by HBV. H. pylori eradication should be performed in patients with complicating H. pylori infection to delay hepatic disease progression. PMID- 28091406 TI - Awareness of Age-related Macular Degeneration and Its Risk Factors among Beijing Residents in China. AB - BACKGROUND: Age-related macular degeneration (AMD) is a major cause of irreversible blindness, and awareness of this disease is important in the prevention of blindness. However, lack of public awareness of AMD was shown in previous studies, and there was no report of AMD awareness in the Mainland of China. Therefore, the aim of our study was to assess the awareness of AMD and its risk factors among Beijing residents in China. METHODS: A cross-sectional, computer-assisted, telephone investigation was conducted to measure the awareness of AMD among Beijing residents. All the contacts of potential respondents were randomly generated by computer. Only those above 18 years of age and willing to participate in the study were included. The questionnaire for the study was modified from the AMD Alliance International Global Report. Pearson's Chi-square test and binary logistic regression analysis were used to identify the factors that affected the knowledge of AMD. RESULTS: Among 385 Beijing residents who agreed to participate, the awareness of AMD was 6.8%, far below than that of cataract and glaucoma. Participants who were above 30 years of age (odds ratio [OR] 6.17, confidence interval [CI] 1.44-26.57), with experience of health related work (OR 8.11, CI 3.25-20.27), and whose relatives/friends or themselves suffering from AMD (OR 32.18, CI 11.29-91.68) had better AMD awareness. Among those familiar with AMD, only 35% of them identified smoking as a risk factor, and only 23.1% of the residents believed that smoking could lead to blindness. CONCLUSIONS: The sample of Chinese population had limited knowledge of AMD. Educational programs need to be carried out to raise public awareness of AMD. PMID- 28091407 TI - Clinical Characteristics of Patients with Drug-induced Liver Injury. AB - BACKGROUND: Drug is an important cause of liver injury and accounts for up to 40% of instances of fulminant hepatic failure. Drug-induced liver injury (DILI) is increasing while the diagnosis becomes more difficult. Though many drugs may cause DILI, Chinese herbal medicines have recently emerged as a major cause due to their extensive use in China. We aimed to provide drug safety information to patients and health carers by analyzing the clinical and pathological characteristics of the DILI and the associated drug types. METHODS: A retrospective analysis was conducted in 287 patients diagnosed with DILI enrolled in our hospital from January 2011 to December 2015. The categories of causative drugs, clinical and pathological characteristics were reviewed. RESULTS: Western medicines ranked as the top cause of DILI, accounting for 163 out of the 287 DILI patients (56.79%) in our study. Among the Western medicine, antituberculosis drugs were the highest cause (18.47%, 53 patients) of DILI. Antibiotics (18 patients, 6.27%) and antithyroid (18 patients, 6.27%) drugs also ranked among the major causes of DILI. Chinese herbal medicines are another major cause of DILI, accounting for 36.59% of cases (105 patients). Most of the causative Chinese herbal medicines were those used to treat osteopathy, arthropathy, dermatosis, gastropathy, leukotrichia, alopecia, and gynecologic diseases. Hepatocellular hepatitis was prevalent in DILI, regardless of Chinese herbal medicine or Western medicine-induced DILI. CONCLUSIONS: Risks and the rational use of medicines should be made clear to reduce the occurrence of DILI. For patients with liver injury of unknown origin, liver tissue pathological examination is recommended for further diagnosis. PMID- 28091408 TI - Novel Mutation of Cleidocranial Dysplasia-related Frameshift Runt-related Transcription Factor 2 in a Sporadic Chinese Case. AB - BACKGROUND: Cleidocranial dysplasia (CCD) is an autosomal dominant disease that affects the skeletal system. Common symptoms of CCD include hypoplasia or aplasia of the clavicles, delayed or even absent closure of the fontanels, midface hypoplasia, short stature, and delayed eruption of permanent and supernumerary teeth. Previous studies reported a connection between CCD and the haploinsufficiency of runt-related transcription factor 2 (RUNX2). Here, we report a sporadic Chinese case presenting typical symptoms of CCD. METHODS: We made genetic testing on this sporadic Chinese case and identified a novel RUNX2 frameshift mutation: c.1111dupT. In situ immunofluorescence microscopy and osteocalcin promoter luciferase assay were performed to compare the functions of the RUNX2 mutation with those of wild-type RUNX2. RESULTS: RUNX2 mutation was observed in the perinuclear region, cytoplasm, and nuclei. In contrast, wild-type RUNX2 was confined in the nuclei, which indicated that the subcellular compartmentalization of RUNX2 mutation was partially perturbed. The transactivation function on osteocalcin promoter of the RUNX2 mutation was obviously abrogated. CONCLUSIONS: We identified a sporadic CCD patient carrying a novel insertion/frameshift mutation of RUNX2. This finding expanded our understanding of CCD-related phenotypes. PMID- 28091409 TI - Effect of Shensong Yangxin on the Progression of Paroxysmal Atrial Fibrillation is Correlated with Regulation of Autonomic Nerve Activity. AB - BACKGROUND: Shensong Yangxin (SSYX), a traditional Chinese herbal medicine, has long been used clinically to treat arrhythmias in China. However, the mechanism of SSYX on atrial fibrillation (AF) is unknown. In this study, we tested the hypothesis that the effect of SSYX on the progression of paroxysmal AF is correlated with the regulation of autonomic nerve activity. METHODS: Eighteen mongrel dogs were randomly divided into control group (n = 6), pacing group (n = 6), and pacing + SSYX group (n = 6). The control group was implanted with pacemakers without pacing; the pacing group was implanted with pacemakers with long-term intermittent atrial pacing; the pacing + SSYX group underwent long-term intermittent atrial pacing and SSYX oral administration. RESULTS: Compared to the pacing group, the parameters of heart rate variability were lower after 8 weeks in the pacing + SSYX group (low-frequency [LF] component: 20.85 +/- 3.14 vs. 15.3 +/- 1.89 ms 2 , P = 0.004; LF component/high-frequency component: 1.34 +/- 0.33 vs. 0.77 +/- 0.15, P < 0.001). The atrial effective refractory period (AERP) was shorter and the dispersion of the AERP was higher after 8 weeks in the pacing group, while the changes were suppressed by SSYX intake. The dogs in the pacing group had more episodes and longer durations of AF than that in the pacing + SSYX group. SSYX markedly inhibited the increase in sympathetic nerves and upregulation of tumor necrosis factor-alpha and interleukin-6 expression in the pacing + SSYX group. Furthermore, SSYX suppressed the decrease of acetylcholine and alpha7 nicotinic acetylcholine receptor protein induced by long-term intermittent atrial pacing. CONCLUSIONS: SSYX substantially prevents atrial electrical remodeling and the progression of AF. These effects of SSYX may have association with regulating the imbalance of autonomic nerve activity and the cholinergic anti-inflammatory pathway. PMID- 28091410 TI - Molecular Mechanisms of Increased Heart Rate in Shenxianshengmai-treated Bradycardia Rabbits. AB - BACKGROUND: The molecular mechanisms of Shenxianshengmai (SXSM), a traditional Chinese medicine, on bradycardia have been incompletely understood. The study tried to investigate the gene expression profile and proteomics of bradycardia rabbits' hearts after SXSM treatment. METHODS: Twenty-four adult rabbits were randomly assigned in four groups: sham, model, model plus SXSM treatment, and sham plus SXSM treatment groups. Heart rate was recorded in all rabbits. Then, total RNA of atria and proteins of ventricle were isolated and quantified, respectively. Gene expression profiling was conducted by gene expression chip, and quantitative real-time reverse transcription-polymerase chain reaction (RT PCR) was performed to confirm the results of gene expression chip. We used isobaric tags for elative and absolute quantitation and Western blotting to identify altered proteins after SXSM treatment. RESULTS: There was a constant decrease in the mean heart rate (32%, from 238 +/- 6 beats/min to 149 +/- 12 beats/min) after six weeks in model compared with that in sham group. This effect was partially reversed by 4-week SXSM treatment. Complementary DNA microarray demonstrated that the increased acetylcholinesterase and reduced nicotinic receptor were take responsibility for the increased heart rate. In addition, proteins involved in calcium handling and signaling were affected by SXSM treatment. Real-time RT-PCR verified the results from gene chip. Results from proteomics demonstrated that SXSM enhanced oxidative phosphorylation and tricarboxylic acid (TCA) cycle in ventricular myocardium to improve ATP generation. CONCLUSIONS: Long-term SXSM stimulates sympathetic transmission by increasing the expression of acetylcholinesterase and reduces the expression of nicotinic receptor to increase heart rate. SXSM also restored the calcium handling genes and altered genes involved in signaling. In addition, SXSM improves the ATP supply of ventricular myocardium by increasing proteins involved in TCA cycle and oxidation-respiratory chain. PMID- 28091412 TI - Incidence, Development, and Prognosis of Diabetic Kidney Disease in China: Design and Methods. AB - BACKGROUND: Although that glomerulonephritis is the major cause of end-stage renal disease in developing countries such as China, the increasing prevalence of diabetes has contributed to the changing spectrum of predialysis chronic kidney disease. Recent studies have revealed an increased proportion of patients with diabetic kidney disease (DKD) in hemodialysis populations in large cities in China. However, studies regarding the clinical phenotype of DKD in China are extremely limited. The incidence, development, and prognosis of diabetic kidney disease (INDEED) study aims to investigate the incidence, progression, and prognosis of DKD, as well as the associated genetic, behavioral, and environmental factors and biomarkers in patients with DKD in China. METHODS: INDEED study is a prospective cohort study based on all participants with diabetes in the Kailuan study, which is a general population-based cohort study in northern China. Altogether, over 10,000 participants with diabetes will be followed biennially. Questionnaires documenting general characteristics, behavioral and environmental factors, and medical history will be administrated. Anthropometric measurements and a series of laboratory tests will be performed in one central laboratory. The DNA, plasma, and urine samples of every participant will be stored in a biobank for future research. CONCLUSIONS: INDEED study will provide essential information regarding the clinical phenotype and prognosis of patients with DKD in China and will be valuable to identify factors and biomarkers associated with patients with DKD in China. PMID- 28091411 TI - Protective Effects of Calpain Inhibition on Neurovascular Unit Injury through Downregulating Nuclear Factor-kappaB-related Inflammation during Traumatic Brain Injury in Mice. AB - BACKGROUND: In addition to neurons, all components of the neurovascular unit (NVU), such as glial, endothelial, and basal membranes, are destroyed during traumatic brain injury (TBI). Previous studies have shown that excessive stimulation of calpain is crucial for cerebral injury after traumatic insult. The objective of this study was to investigate whether calpain activation participated in NVU disruption and edema formation in a mouse model of controlled cortical impact (CCI). METHODS: One hundred and eight mice were divided into three groups: the sham group, the control group, and the MDL28170 group. MDL28170 (20 mg/kg), an efficient calpain inhibitor, was administered intraperitoneally at 5 min, 3 h, and 6 h after experimental CCI. We then measured neurobehavioral deficits, calpain activity, inflammatory mediator levels, blood-brain barrier (BBB) disruption, and NVU deficits using electron microscopy and histopathological analysis at 6 h and 24 h after CCI. RESULTS: The MDL28170 treatment significantly reduced the extent of both cerebral contusion (MDL28170 vs. vehicle group, 16.90 +/- 1.01 mm? and 17.20 +/- 1.17 mm? vs. 9.30 +/- 1.05 mm? and 9.90 +/- 1.17 mm?, both P < 0.001) and edema (MDL28170 vs. vehicle group, 80.76 +/- 1.25% and 82.00 +/- 1.84% vs. 82.55 +/- 1.32% and 83.64 +/- 1.25%, both P < 0.05), improved neurological scores (MDL28170 vs. vehicle group, 7.50 +/- 0.45 and 6.33 +/- 0.38 vs. 12.33 +/- 0.48 and 11.67 +/- 0.48, both P < 0.001), and attenuated NVU damage resulting (including tight junction (TJ), basement membrane, BBB, and neuron) from CCI at 6 h and 24 h. Moreover, MDL28170 markedly downregulated nuclear factor-kappaB-related inflammation (tumor necrosis factor alpha [TNF-alpha]: MDL28170 vs. vehicle group, 1.15 +/- 0.07 and 1.62 +/- 0.08 vs. 1.59 +/- 0.10 and 2.18 +/- 0.10, both P < 0.001; inducible nitric oxide synthase: MDL28170 vs. vehicle group, 4.51 +/- 0.23 vs. 6.23 +/- 0.12, P < 0.001 at 24 h; intracellular adhesion molecule-1: MDL28170 vs. vehicle group, 1.45 +/- 0.13 vs. 1.70 +/- 0.12, P < 0.01 at 24 h) and lessened both myeloperoxidase activity (MDL28170 vs. vehicle group, 0.016 +/- 0.001 and 0.016 +/- 0.001 vs. 0.024 +/- 0.001 and 0.023 +/- 0.001, P < 0.001 and 0.01, respectively) and matrix metalloproteinase-9 (MMP-9) levels (MDL28170 vs. vehicle group, 0.87 +/- 0.13 and 1.10 +/- 0.10 vs. 1.17 +/- 0.13 and 1.25 +/- 0.12, P < 0.001 and 0.05, respectively) at 6 h and 24 h after CCI. CONCLUSIONS: These findings demonstrate that MDL28170 can protect the structure of the NVU by inhibiting the inflammatory cascade, reducing the expression of MMP-9, and supporting the integrity of TJ during acute TBI. PMID- 28091413 TI - Expert Consensus on Wenxin Granule for Treatment of Cardiac Arrhythmias. PMID- 28091414 TI - Acute Myeloid Leukemia: Advancements in Diagnosis and Treatment. AB - OBJECTIVE: Leukemia is the most common pediatric malignancy and a major cause of morbidity and mortality in children. Among all subtypes, a lack of consensus exists regarding the diagnosis and treatment of acute myeloid leukemia (AML). Patient survival rates have remained modest for the past three decades in AML. Recently, targeted therapy has emerged as a promising treatment. DATA SOURCES: We searched the PubMed database for recently published research papers on diagnostic development, target therapy, and other novel therapies of AML. Clinical trial information was obtained from ClinicalTrials.gov. For the major purpose of this review that is to outline the latest therapeutic development of AML, we only listed the ongoing clinical trials for reference. However, the published results of complete clinical trials were also mentioned. STUDY SELECTION: This article reviewed the latest developments related to the diagnosis and treatment of AML. In the first portion, we provided some novel insights on the molecular basis of AML, as well as provided an update on the classification of AML. In the second portion, we summarized the results of research on potential molecular therapeutic agents including monoclonal antibodies, tyrosine kinase/Fms-like tyrosine kinase 3 (FLT3) inhibitors, epigenetic/demethylating agents, and cellular therapeutic agents. We will also highlight ongoing research and clinical trials in pediatric AML. RESULTS: We described clonal evolution and how it changes our view on leukemogenesis, treatment responses, and disease relapse. Pediatric-specific genomic mapping was discussed with a novel diagnostic method highlighted. In the later portion of this review, we summarized the researches on potential molecular therapeutic agents including monoclonal antibodies, tyrosine kinase/FLT3 inhibitors, epigenetic/demethylating agents, and cellular therapeutic agents. CONCLUSION: Gene sequencing techniques should set the basis for next-generation diagnostic methods of AML, and target therapy should be the focus of future clinical research in the exploration of therapeutic possibilities. PMID- 28091415 TI - Advances of Coagulation Factor XIII. AB - OBJECTIVE: To provide a comprehensive literature review on roles of coagulation factor XIII (FXIII) in coagulation, wound healing, neoplasm, bone metabolism, and pregnancy. DATA SOURCES: All articles in PubMed with key words "Coagulation factor XIII", "wound", "leukemia", "tumor", "bone," and "pregnancy" with published date from 2001 to 2016 were included in the study. Frequently cited publications before 2000 were also included. STUDY SELECTION: We reviewed the role of FXIII in biologic processes as documented in clinical, animal, and in vitro studies. RESULTS: FXIII, a member of the transglutaminase (TG) family, plays key roles in various biological processes. Besides its well-known function in coagulation, the cross-linking of small molecules catalyzed by FXIII has been found in studies to help promote wound healing, improve bone metabolism, and prevent miscarriages. The study has also shown that FXIII concentration level differs in the blood of patients with leukemia and solid tumors and offers promises as a diagnostic indicator. CONCLUSIONS: FXIII has many more biologic functions besides being known as coagulation factor. The TG activity of FXIII contributes to several processes, including wound healing, bone extracellular matrix stabilization, and the interaction between embryo and decidua of uterus. Further research is needed to elucidate the link between FXIII and leukemia and solid tumors. PMID- 28091416 TI - Factors Associated with the Size of HIV DNA Reservoir. AB - OBJECTIVE: To review the recent literatures related to the factors associated with the size of the HIV reservoir and their clinical significance. DATA SOURCES: Literatures related to the size of HIV DNA was collected from PubMed published from 1999 to June 2016. STUDY SELECTION: All relevant articles on the HIV DNA and reservoir were collected and reviewed, with no limitation of study design. RESULTS: The composition and development of the HIV-1 DNA reservoir in either treated or untreated patients is determined by integrated mechanism comprising viral characteristics, immune system, and treatment strategies. The HIV DNA reservoir is a combination of latency and activity. The residual viremia from the stochastic activation of the reservoir acts as the fuse, continuing to stimulate the immune system to maintain the activated microenvironment for the rebound of competent virus once treatment with antiretroviral therapy is discontinued. CONCLUSION: The size of the HIV-1 DNA pool and its composition has great significance in clinical treatment and disease progression. PMID- 28091417 TI - Diagnosis and Treatment of Urinary Incontinence after Orthotopic Ileal Neobladder in China. PMID- 28091418 TI - Radial Probe Endobronchial Ultrasound-guided Lung Biopsy for Histopathological Diagnosis of Cryptogenic Organizing Pneumonia. PMID- 28091419 TI - Two Secondary Primary Malignancies after Bortezomib Therapy for Multiple Myeloma: A Single-center Experience. PMID- 28091420 TI - Compound Heterozygote Mutation of C12orf65 Causes Distal Motor Neuropathy and Optic Atrophy. PMID- 28091421 TI - Massive Pulmonary Embolism in Recovery Period of General Anesthesia: Rapid Diagnosis and Successful Rescue by the Guidance of Transthoracic Echocardiography. PMID- 28091422 TI - Emphysematous Pyelonephritis Treated with Vacuum Sealing Drainage. PMID- 28091423 TI - Xanthogranuloma of the Sellar Region. PMID- 28091424 TI - A Case of Giant Intradural Extramedullary Capillary Hemangioma. PMID- 28091425 TI - A 10 years autopsy-based study of maternal mortality in Lagos State University Teaching Hospital, Lagos, Nigeria. AB - BACKGROUND: Maternal mortality is the death of a woman while pregnant or within 42 days of termination of pregnancy, irrespective of the duration and the site of the pregnancy. Nigeria is among the six countries that record over 50% of all maternal deaths in the world. There are few papers on autopsy based causes of maternal mortality. This paper is to present the causes of maternal mortality that had postmortem done in our center. MATERIALS AND METHODS: This is a 10-year retrospective study of all maternal deaths seen in our center from January 01, 2005 to December 31, 2014. Lagos State University Teaching Hospital is the only state-owned tertiary center and the main referral center in Lagos State. Autopsy records are taken from the death register and other information were extracted from the postmortem reports. RESULTS: Most maternal deaths 98/328 (29.9%) were seen in the age group 26-30 years which was followed by 31-35 years (24.7%). Postpartum hemorrhage was the most common cause of death followed by eclampsia. Direct causes accounted for 60% of maternal deaths with hemorrhage as the most common while cardiovascular related diseases are the most common indirect cause of death. CONCLUSION: The leading causes of death in this study, hemorrhage, cardiovascular disease and eclampsia are highly avoidable and treatable. We recommend that thorough cardiovascular management should be instituted during antenatal care, and the government should focus more on an emergency response such as availability of adequate blood and blood products in the hospitals. PMID- 28091426 TI - MRI-based detailed evaluation of the anatomy of the human coccyx among Turkish adults. AB - AIM: The human coccyx varies considerably in shape and size. The objective of this study was to investigate the morphology and morphometry of the coccyx on pelvic magnetic resonance imaging in asymptomatic individuals among Turkish adults. MATERIALS AND METHODS: This study was conducted retrospectively on the pelvic magnetic resonance images of 456 adult patients without a history of trauma in the coccyx region. The coccygeal vertebrae count, number of bone segments, and intercoccygeal and sacrococcygeal joint fusions were determined from the sagittal plane images. In addition, the length and angles (the sacrococcygeal angle, intercoccygeal joint angle, and sacrococcygeal joint angle) were measured. STATISTICAL ANALYSIS USED: Data were analyzed using the T-test or Mann-Whitney U-test, the ANOVA, or Kruskal-Wallis tests, and the chi-square test was used for the categorical variables. RESULTS: The coccyx is formed by four, five, or three vertebrae in a decreasing ratio. The coccyx is composed of one to five bone segments; one bone segment was found in 2.8% of the cases. Intercoccygeal joint fusions been observed predominantly in the last intercoccygeal joint, with or without sacrococcygeal joint fusion. The coccyx was found to be longer in adult males than in adult females. The sacrococcygeal angle might be anteverted or retroverted. CONCLUSION: The findings are contrary to the conventional knowledge in that the vertebrae shaping the coccyx were completely fused and consisting of a single bone in very few cases. Better understanding of the anatomical variation of the coccyx may be useful for clinicians evaluating patients presenting with conditions in the coccygeal region. PMID- 28091427 TI - Evaluation of surface characteristics of rotary nickel-titanium instruments produced by different manufacturing methods. AB - BACKGROUND: Instrument fracture is a serious concern in endodontic practice. OBJECTIVE: The aim of this study was to investigate the surface quality of new and used rotary nickel-titanium (NiTi) instruments manufactured by the traditional grinding process and twisting methods. MATERIALS AND METHODS: Total 16 instruments of two rotary NiTi systems were used in this study. Eight Twisted Files (TF) (SybronEndo, Orange, CA, USA) and 8 Mtwo (VDW, Munich, Germany) instruments were evaluated. New and used of 4 experimental groups were evaluated using an atomic force microscopy (AFM). New and used instruments were analyzed on 3 points along a 3 mm. section at the tip of the instrument. Quantitative measurements according to the topographical deviations were recorded. The data were statistically analyzed with paired samples t-test and independent samples t test. RESULTS: Mean root mean square (RMS) values for new and used TF 25.06 files were 10.70 +/- 2.80 nm and 21.58 +/- 6.42 nm, respectively, and the difference between them was statistically significant (P < 0.05). Mean RMS values for new and used Mtwo 25.06 files were 24.16 +/- 9.30 nm and 39.15 +/- 16.20 nm respectively, the difference between them also was statistically significant (P < 0.05). CONCLUSION: According to the AFM analysis, instruments produced by twisting method (TF 25.06) had better surface quality than the instruments produced by traditional grinding process (Mtwo 25.06 files). PMID- 28091428 TI - Refractive aim and visual outcome after phacoemulsification: A 2-year review from a Tertiary Private Eye Hospital in Sub-Saharan Africa. AB - AIM: To review the short-term visual outcome of phacoemulsification in adults with uncomplicated cataracts in Eye Foundation Hospital, Lagos, Nigeria. MATERIALS AND METHODS: A retrospective review of records of patients that had phacoemulsification between January 2012 and December 2013 in Eye Foundation Hospital, Lagos, Nigeria, was done. Preoperative visual acuity, refractive aim, intraoperative complications, postoperative unaided, and best-corrected visual acuity at 1 and 3 months were analyzed. Only eyes of adults that had phacoemulsification for uncomplicated cataracts were included in the study, all pediatric cataracts and eyes with ocular comorbidities were excluded. Common ocular comorbidities excluded were corneal opacity/corneal scar, glaucoma, uveitis, pseudo exfoliation syndrome, moderate and severe nonproliferative diabetic retinopathy, macula edema, proliferative diabetic retinopathy, eye trauma, age-related macular degeneration, previous corneal surgery, glaucoma surgery, and previous or simultaneous vitreoretinal surgery. RESULTS: A total of 157 eyes of 119 patients who met the inclusion criteria were analyzed. There were 60 (50.4%) females and 59 (49.6%) males, with age range from 31 to 91 years and a mean of 65.3 +/- 11.10 years. Only eyes with available data were analyzed at 1 and 3 months postoperatively. In 112 eyes (85.7%), the refractive aim was met, 21 eyes (14.3%) did not meet their refractive aim, 20 eyes (12.7%) were excluded, the refractive aim could not be determined from the records as surgeons did not specify, and in 4 eyes, the required information was missing from the case files. An unaided visual acuity of 6/18 and better was achieved in 134 eyes (85.4%) at 1 month and 126 eyes (85.9%) at 3 months whereas best-corrected vision of 6/18 and better was achieved by 145 eyes (92.4%) at 1 month and 146 eyes (98.0%) at 3 months. CONCLUSION: Surgical outcomes after phacoemulsification are comparable with international benchmarks for good outcomes, with 85.4% of eyes achieving within 1 D of spherical equivalent of the refractive aim, 92.4% and 98.0% of eyes also achieving best-corrected visual acuities of 6/18 and better at 1 and 3 postoperative months, respectively. Unaided vision of 6/18 and better was also achieved in 85.4% and 85.9% at 1 and 3 postoperative months, respectively. PMID- 28091429 TI - Chronic kidney disease in Chinese postmenopausal women: A cross-sectional survey. AB - INTRODUCTION: Despite advances in the management of chronic kidney disease (CKD), there is ongoing uncertainty regarding the prevalence of CKD in postmenopausal women. This study was designed to investigate both CKD prevalence and related risk factors in a cohort of postmenopausal Chinese women. MATERIALS AND METHODS: A cross-sectional survey was administered to a nationally representative sample of female Chinese participants, including a total of 47,204 subjects, among whom were 8573 self-reported postmenopausal women. CKD was defined as either an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 body surface area or else the presence of albuminuria. All subjects completed a questionnaire that included items related to their lifestyles and medical histories. Data were collected on blood pressure, serum creatinine, urinary albumin, and urinary creatinine. Risk factors correlated with the presence of CKD were analyzed using logistic regression analysis. RESULTS: Results showed that the adjusted prevalence of an eGFR of < 60 mL/min/1.73 m2 among this postmenopausal survey cohort was 5.3% (95% confidence interval: 4.7-6.1) and of albuminuria, 12.4% (11.7-13.1). The overall prevalence of CKD in this postmenopausal cohort was 16.6% (15.8-17.4). Factors associated with kidney pathology included nephrotoxic drug use, history of cardiovascular disease, hyperuricemia, hypertension, and diabetes (the lower limit of multivariable adjusted odds ratios > 1). CONCLUSION: The current study revealed a high prevalence of CKD in Chinese postmenopausal women. These results provide baseline data for disease prevention and treatment. PMID- 28091430 TI - Impact of informed consent on patient decisions regarding third molar removal. AB - PURPOSE: We investigated whether the order in which patients learned about complication risks affected their anxiety about and willingness to undergo the removal of their third molar. MATERIALS AND METHODS: In total, 171 patients (65 males, 106 females) were included in the study. The distributions of gender and the position of mandibular third molars were recorded. The Amsterdam Preoperative Anxiety and Information Scale and Spielberger's State-Trait Anxiety Inventory were used to evaluate anxiety. Associations of anxiety with timing (pre/post), gender, and the order in which the information was presented in the consent form were analyzed. RESULTS: The most common angulations were horizontal (26.3%) and mesioangular (60.2%), and these were more common in women. All patients obtained significantly higher anxiety scores after reading the consent form. There was no significant difference in anxiety scores, according to the order of information. In total, 88 patients underwent surgery, whereas 83 postponed the extraction after reading the consent form. Women were significantly more anxious than men before the procedure. Patients showed lower anxiety levels after the procedure (P < 0.05). CONCLUSION: Increased anxiety was not associated with the order in which information was presented in the informed consent form. However, the informed consent form itself was a major contributor to increased patient anxiety. Further studies regarding the contents of consent forms and their effects on patient anxiety and decisions regarding third molar removal are needed. PMID- 28091431 TI - Determinants of quality of life among community-dwelling persons with spinal cord injury: A path analysis. AB - CONTEXT: Recent advancement in technology and medical care has resulted in an increase not only in disability arising from spinal cord injury (SCI) but also its attendant challenges such as poor quality of life (QoL). AIM: To test a theoretical model of predictors of QoL among persons with SCI. SETTINGS AND DESIGN: Study was conducted in the South Eastern Nigeria. A longitudinal study design was employed. MATERIALS AND METHODS: A total of 64 persons with SCI discharged from in-hospital admission participated in this study. QoL, state self esteem (SSE), social support satisfaction (SSS), and functional potentials (FPs) were assessed using short form health survey-12, SSE scale, social support questionnaire 6, and spinal cord independent measure III, respectively. Their motor function (MF) and sensory function (SF) were assessed using the motor and sensory subscales of American Spinal Cord Association impairment scale. STATISTICAL ANALYSIS USED: Data obtained were analyzed using path analysis. The level of significance was set at alpha = 0.05. RESULTS: Most of the participants were male (92.3%) with incomplete type of SCI (65.4%). The selected variables (SSE, SSS, FP, MF, and SF) significantly predicted a large percentage (R2 = 0.861) of QoL. All the predictor variables except age had a direct significant effect on QoL (P < 0.05). The trimmed model revealed that SSS (beta =3.04, P = 0.002) had the highest direct effect on QoL. CONCLUSIONS: This study revealed that the combined assessment of SSE, SSS, FP, MF, and SF can be used to predict QoL significantly. Moreover, psychosocial factors are as important as clinical (biological) factors in predicting the outcomes of SCI, especially their QoL. Thus, the study buttresses the need to emphasize on the biopsychosocial model in the rehabilitation of persons with SCI. PMID- 28091432 TI - Depression and posttraumatic stress disorder among road traffic accident victims managed in a Tertiary hospital in Southern Nigeria. AB - BACKGROUND: Psychological responses to traumatic events vary widely across different cultures but studies in the developing countries are scant. The objective of this study is to determine prevalence of depression and posttraumatic stress disorder (PTSD) among patients involved in road traffic accident (RTA) compared with that of the general population using a matched control group. MATERIALS AND METHODS: The study design was case control and employed the convenient sampling technique. All consecutive attendees of the trauma clinic of a Tertiary Hospital who had been involved in RTA in the previous year and met inclusion criteria were recruited to participate in the study. Controls were drawn from patient relatives attending other clinics in the same hospital. The final sample comprised of 46 cases and controls, totaling 92 participants. A Sociodemographic questionnaire, the PTSD, and depression modules of the Mini International neuropsychiatric interview were administered to both groups by trained research assistants. The data were analyzed using IBM SPSS version 22. Statistical significance was set at 0.05. RESULTS: The prevalence of PTSD among cases was 41.3% compared with 13% among controls, whereas the prevalence of depression among cases was 63% compared with 30.4% among the controls. Both of these findings were statistically significant (P < 0.002). Sociodemographic variables such as age, sex, marital status, religion, level of education, and occupation did not have statistically significant relationship with neither PTSD nor depression. CONCLUSION: Mental disorders such as PTSD and depression are common in victims of RTA. They would benefit from comanagement with mental health specialists. PMID- 28091433 TI - Clinical evaluation of microhybrid composites in noncarious cervical lesions: 24 month results. AB - OBJECTIVE: To evaluate the clinical performance of two different microhybrid resin composites in noncarious cervical lesions (NCCLs) after 24 months. SUBJECTS AND METHODS: Ninety-seven NCCLs were restored with either TPH Spectrum (n = 48) or Filtek Z250 (n = 49) using an etch-and-rinse adhesive in 20 patients. The restorations were clinically evaluated using modified United States Public Health Service criteria for retention, color match, marginal discoloration, marginal adaptation, surface texture, anatomic form, postoperative sensitivity, and secondary caries. The restorations were assessed 1 week after placement (baseline) and after 6, 12, and 24 months. Restoration survival rates were calculated using the Kaplan-Meier procedure estimator, and a log-rank test was used to compare the survival distributions (P < 0.05). Statistical analysis was undertaken using Pearson's Chi-square test and Fisher's exact test to assess differences among the restorative materials (P < 0.05). Cochran's Q-test was employed for evaluating differences in the same restorative material between recall periods. RESULTS: The retention rates were 100% at 6 months, 89.6% and 91.8% at 12 months, and 85.4% and 89.8% at 24 months for TPH and Z250, respectively. TPH showed a statistically significant difference in marginal discoloration between the baseline and 24 months results (P < 0.05). Both TPH and Z250 showed statistically significant differences in marginal adaptation between the baseline and 24 months results (P < 0.05). CONCLUSION: Over the 24-month period, both microhybrid resin composites demonstrated acceptable clinical results in NCCLs. PMID- 28091434 TI - Serum obestatin and omentin levels in patients with diabetic nephropathy. AB - INTRODUCTION: Diabetic nephropathy is the leading cause of chronic kidney disease and accounts for almost 45% of all new patients requiring renal replacement therapy. Omentin and obestatin, two novel proteins were suggested to be associated with insulin resistance, type 2 diabetes and cardiovascular risk factors. Thus, we postulated that they may also have an association with diabetic nephropathy which is known to be an independent cardiovascular risk factor. In order to investigate such an association we compared serum omentin and obestatin levels in type 2 diabetic patients with normoalbuminuria (NA) and macroalbuminuria (MA). MATERIALS AND METHODS: A total of 81 type 2 diabetic patients were separated into two groups according to their proteinuria status; patients with NA (n = 39) and patients with MA (n = 42). Two groups were compared in terms of serum omentin and obestatin levels. RESULTS: While s erum omentin levels did not differ among two groups (P = 0.407), serum obestatin levels were significantly higher in MA group (P = 0.001). CONCLUSION: The results of this study showed that higher serum levels of obestatin were associated with macro albuminuria suggesting that obestatin may have a role in underlying pathogenic mechanisms that leads to diabetic nephropathy. PMID- 28091435 TI - Influence of Helicobacter pylori infection on the prevalence and patterns of upper gastrointestinal symptoms in Nigerians with diabetes mellitus. AB - BACKGROUND: Infection with Helicobacter pylori infection is widespread in our environment. However, whether this fact has any bearing on the prevalence and pattern of symptoms referable to the upper gastrointestinal (GI) system in our population of diabetes mellitus (DM) patients has not been much studied. AIM: We embarked on this study to evaluate if H. pylori infection played any significant role in the prevalence and patterns of upper GI symptoms in type 2 DM patients in Lagos, Nigeria. MATERIALS AND METHODS: A case-control design was employed. One hundred consecutive, consenting, and ambulant type 2 DM patients were recruited from the Lagos University Teaching Hospital and 100 age- and sex-matched nondiabetic controls were drawn from medical outpatient clinics of the same hospital. All subjects were investigated for a marker of active infection with H. pylori via stool antigen testing, had anthropometric measurements taken, and completed a structured questionnaire administered to elicit for the presence of various upper GI symptoms over the preceding 3 months prior to the time of the study. The controls were further tested for DM. For analysis, the symptoms were divided into dyspepsia, gastroesophageal reflux (GER), and others. RESULTS: H. pylori infection status was neither significantly associated with dyspepsia in either cases or controls (chi2 [1] = 2.198, P = 0.138) nor significantly associated with the symptomatic suggestion of GER in either cases or controls (chi2 [1] = 3.742, P = 0.053). Moreover, the same held for the other upper GI symptoms in cases or controls (chi2 [1] = 0.157, P = 0.203). H. pylori infection was detected in 18% of DM patients and 13% of controls, but there was no statistical significance in this difference (chi2 [1] = 0.954, P = 0.329). CONCLUSION: Infection with H. pylori does not appear, from the results of this study, to influence the prevalence and patterns of upper GI symptoms in patients with DM in Nigeria. PMID- 28091436 TI - Acute kidney injury in Lagos: Pattern, outcomes, and predictors of in-hospital mortality. AB - CONTEXT: The pattern of acute kidney injury (AKI) differs significantly between developed and developing countries. AIMS: The aim of th study was to determine the pattern and clinical outcomes of AKI in Lagos, Southwest Nigeria. SETTINGS AND DESIGN: A retrospective review of hospital records of all patients with a diagnosis of AKI over a 20-month period. SUBJECTS AND METHODS: Records of 54 patients were reviewed. Information retrieved included, bio-data, etiology of AKI, results of laboratory investigations, and patient outcomes. STATISTICAL ANALYSIS USED: Continuous data are presented as means while categorical data are presented as proportions. The Student's t-test was used to compare means while Chi-square test was used to compare percentages. Logistic regression analysis was used to determine the factors that predicted in-hospital mortality. RESULTS: Twenty-seven (50%) of the patients were male. The mean age of the study population was 39.7 years +/- 16.3 years. Sepsis was the etiology of AKI in 52.1% of cases. Overall, in-hospital mortality was 29.6%. Patients who died had a shorter mean duration of hospital stay (9.2 days vs. 33.9 days [P < 0.01]), lower mean serum bicarbonate (19.5 mmol/L vs. 22.9 mmmol/L [P = 0.02]), were more likely to be admitted unconscious (82.4% vs. 17.6% [P = 0.01]) and to have been admitted to the Intensive Care Unit (37.5% vs. 7.9% [P = 0.01]). In addition, when dialysis was indicated, patients who did not have dialysis were more likely to die (58.3% vs. 41.7% [P = 0.02]). CONCLUSIONS: The pattern of AKI in this study is similar to that from other developing countries. In-hospital mortality remains high although most of the causes are preventable. PMID- 28091437 TI - Radiopacity of bulk fill flowable resin composite materials. AB - OBJECTIVES: The purpose of this study was to evaluate the radiopacity of currently marketed bulk fill flowable dental composite materials (Beautifil Bulk Flowable, SDR Flow, Filtek Bulk Fill Flow, and x-tra Base Bulk Fill). MATERIALS AND METHODS: Six specimens of each material with a thickness of 1 mm were prepared, and digital radiographs were taken, using a CCD sensor along with an aluminum stepwedge and 1 mm-thick tooth slice. The mean gray level of each aluminum stepwedge and selected materials was measured, using the equal-density area tool of Kodak Dental Imaging software. The equivalent thickness of aluminum for each material was then calculated by using the stepwedge values in the CurveExpert version 1.4 program. RESULTS: The radiopacity of bulk fill flowable composites sorted in descending order as follows: Beautifil Bulk Flowable (2.96 mm Al) = x-tra base bulk fill (2.92 mm Al) = SureFil SDR Flow (2.89 mm Al) > Filtek Bulk Fill Flow (2.51 mm Al) (P < 0.05). CONCLUSIONS: As all materials had a radiopacity greater than dentin and enamel; their adequate radiopacity will help the clinicians during radiographic examination of restorations. CLINICAL SIGNIFICANCE: Bulk fill composite materials have greater radiopacity, enabling clinicians to distinguish the bulk fill composites from dentin and enamel. PMID- 28091438 TI - Caudal analgesia for herniotomy: Comparative evaluation of two dose schemes of bupivacaine. AB - OBJECTIVE: There is currently a wide range of volume schemes for bupivacaine caudal anesthesia. This study evaluated the quality of caudal analgesia achieved with a dosing scheme of 0.75 ml/kg compared with 0.5 ml/kg of 0.25% plain bupivacaine for herniotomy. METHODS: After the institutional approval, American Society of Anesthesiologists I-II patients aged between 1 and 6 years scheduled for unilateral inguinal herniotomy with consenting parents/guardian were recruited. The subjects were randomized to receive 0.5 ml/kg (Group 1) or 0.75 ml/kg of 0.25% bupivacaine. Anesthesia was maintained solely with halothane 0.5 1% in 100% oxygen. Postoperatively, pain was assessed using the objective pain scale (OPS). A favorable pain score was defined as <4 (8 point scale) or <5 (10 point scale). The primary outcome was the proportion of subjects with favorable pain scores. RESULTS: Fifty-six patients were enrolled and there was no difference in sociodemographic parameters, preoperative hemodynamic variables, or duration of surgery. Proportions of subjects with favorable OPS scores showed marked differences from 45 min and peaking at 180 min (11 [39%] favorable scores in Group 1 compared to all [100%] favorable scores in Group 2, P< 0.0001). Mean time to first analgesic requirement was 126 +/- 34.2 min in Group 1 compared to 249 +/- 23.7 min in Group 2 (P < 0.0001). There was no difference in the incidence of adverse events between groups. CONCLUSION: This study shows that 0.75 ml/kg of 0.25% plain bupivacaine is superior to the use of 0.5 ml/kg of the same concentration for postherniotomy caudal analgesia with low side effect profile. PMID- 28091439 TI - Is epineurectomy necessary in the surgical management of carpal tunnel syndrome? AB - BACKGROUND: In this study, it was aimed to determine whether median nerve epineurectomy is beneficial in the surgical management of carpal tunnel syndrome (CTS). MATERIALS AND METHODS: The study enrolled 72 patients including 34 patients without epineurectomy (Group A) and 38 patients with epineurectomy (Group B). Surgery was performed in patients with severe electrodiagnostic CTS findings, CTS duration >1 year and flattening along with hypervascularization in median nerve. All patients were assessed by visual analog scale, two-point discrimination test as well as subjective and objective findings at baseline and on the months 1, 3, and 6 after surgery. RESULTS: The mean age was 58.3 years (42 75 years) in 38 patients who underwent an epineurectomy, whereas it was 61.5 years (41-82 years) in 34 patients who did not have an epineurectomy. The groups were similar with regard to age, gender, duration of symptoms, and preoperative physical findings. Mean visual analog scale (VAS) scores were 1.7 in Group A and 1.8 in Group B. Again, these differences were not significant, on physical examination, the average two-point discrimination in the distribution of the median nerve was 4.9 mm (range: 3-11 mm) in Group A and 5.3 mm (range: 3-10 mm) in Group B. In postoperative evaluations, there was a better improvement in visual analog scale scores, two-point discrimination test and subjective symptoms including dysesthesia, pain and nocturnal pain within first 3 months; however, there was no marked difference in objective and subjective findings on the 6th month. No complication or recurrence was observed. CONCLUSION: We believe that median nerve epineurectomy is unnecessary in the surgical management of primary CTS since it has no influence on the midterm outcomes. PMID- 28091440 TI - Nocturnal enuresis in school-aged children with sickle-cell anemia: Any relationship with hyposthenuria? AB - BACKGROUND: Reports show that children with sickle-cell anemia (SCA) have a tendency for nocturnal enuresis when compared with their counterparts with normal hemoglobin. Although nocturnal enuresis in SCA has been attributed to several factors including tubular and even bladder dysfunction, its relationship with hyposthenuria has been questioned in some studies. AIM: The study aims to determine the relationship of hyposthenuria with nocturnal enuresis seen in school-aged children with SCA. SUBJECTS AND METHODS: A cross-sectional study of seventy school-aged children with SCA, who met the study criteria and seventy age and gender-matched controls was conducted at the Sickle-cell Clinic, University of Nigeria Teaching Hospital in Enugu, Southeast Nigeria. The diagnosis of enuresis among the subjects and controls was based on the Diagnostic and Statistical Manual of Mental Disorders-IV criteria while urine specific gravity (USG) was determined on dipstick urinalysis. The frequencies of categorical variables were compared using Chi-square test or Fisher exact test as appropriate and the means of continuous variables with Student's t-test. The level of statistical significance was taken as P< 0.05. RESULTS: The prevalence of hyposthenuria was 4.5% and 8.3% among enuretic and nonenuretic subjects respectively, 6.7% and 10.9% among enuretic and nonenuretic controls and 4.5% and 6.7% among enuretic subjects and controls, respectively. The differences were not statistically significant. The mean +/- standard deviation USG was significantly higher in the subjects than in the controls (1.02 +/- 0.01 vs. 1.01 +/- 0.01, P = 0.013) and enuretic subjects than enuretic controls (1.02 +/- 0.01 vs. 1.01 +/- 0.01, P = 0.007). The prevalence of nocturnal enuresis was significantly higher in male subjects compared to female subjects (odds ratio [OR] [95% confidence interval (95% CI)] =8.14 (2.12, 31.24), chi2 = 12.21, P< 0.001) and male controls (chi2 = 5.57, P = 0.018). Enuretic subjects had a significantly higher prevalence of parental history of childhood enuresis (OR [95% CI] =10.39 [2.45, 44.05], P< 0.002) than the enuretic controls. The relationship between the enuretic subjects and controls with respect to age of attainment of urinary control, family size, socioeconomic class, and sibling history of enuresis were not statistically significant. CONCLUSIONS: Nocturnal enuresis in children with SCA may not be related to hyposthenuria. However, male gender and parental history of childhood enuresis are significant risk factors. PMID- 28091442 TI - Fluoride release/recharging ability and bond strength of glass ionomer cements to sound and caries-affected dentin. AB - OBJECTIVES: The aim of this in vitro study was to evaluate the microtensile bond strength (MUTBS) of different glass ionomer cements (GICs) on sound/caries affected dentin and to assess the fluoride release/recharging ability. METHODS: After creating artificial caries lesions, teeth with sound and caries-affected dentin were assigned to be restored with one of the GICs: Ketac N100; GC Equia; GCP Glass Fill, and tested using a microtensile test. Ten of each material were prepared, and fluoride ion-release was measured at 10 different intervals. After 1.23% acidulated phosphate fluoride-gel immersion, fluoride re-release was then measured at the same intervals. RESULTS: In sound dentin, GC Equia exhibited significantly higher MUTBS value (P < 0.05). The mean MUTBS of Ketac N100 to caries-affected dentin was significantly lower than the other materials (P < 0.05). All materials showed maximal fluoride release at 24 h, GC Equia released the most fluoride. CONCLUSION: The bond strength of GICs is affected by tooth substrate. High-viscosity GICs show higher initial fluoride release as well as greater fluoride recharge capacity. PMID- 28091441 TI - Process and outcome measures of quality of care at the diabetes outpatient clinic, University College Hospital, Ibadan. AB - OBJECTIVE: The study aims to assess the quality of care provided at a diabetes outpatient clinic of a tertiary hospital in Nigeria using quality indicators approved by the National Diabetes Quality Improvement Alliance (NDQIA). MATERIALS AND METHODS: The medical records of patients who had visited the clinic at least two times within a 12 months period preceding the index visit were reviewed during a 5 month period. Process measure indicators, approved by the NDQIA (evaluating the functioning of the clinic) and outcome measures, published by the American Diabetes Association, (evaluating the health status of the attending patients) were retrieved from the medical records. RESULTS: The 332 records reviewed showed that the most consistently performed process measures were blood pressure and weight measurement (>90%). Foot examination was done infrequently (10.5%). Less than 50% had at least an annual low-density lipoprotein cholesterol (LDL-C) and hemoglobin A1c testing done. The mean (standard deviation) HbA1C (%), LDL-C (mg/dL) systolic blood pressure (SBP) (mmHg), and diastolic blood pressure (DBP) (mmHg) were 7.6 (2.0), 107.3 (31.5), 134.3 (20.8), 79.5 (11.0), respectively. HbA1C >8.0%, LDL-C >130 mg/dL, SBP >130 mmHg, and DBP >90 mmHg) were observed in 34.8%, 21.1%, 40.4%, and 23.8%, respectively. CONCLUSION: Although the organization of the outpatient services allowed for good performance with regards to "free" services such as blood pressure and weight measurement, it performed suboptimally for foot examinations. Performance indicators that required payment were consistently underperformed. Regular assessment of the quality of care may help in the identification of opportunities for improvement in the organization and delivery of care. PMID- 28091443 TI - Molecular characterization of exon 28 of von Willebrand's factor gene in Nigerian population. AB - BACKGROUND: Polymorphisms in von Willebrand factor (VWF) gene are an important contributor to the expression of VWF gene and differences in ethnic distribution of these single nucleotide polymorphisms (SNPs) exists. AIMS: Our objective was to molecularly characterize the exon 28 of the VWF gene in the three major ethnic groups of Nigeria. SUBJECTS AND METHODS: We recruited 90 subjects, 45 had a history of bleeding. Questions included those used in the Zimmerman Program for the Molecular and Clinical Biology of von Willebrand disease (VWD), and the bleeding scores were calculated using the Molecular and Clinical Markers for the Diagnosis and Management of type 1 VWD scoring system. Full blood count, coagulation profile, VWF:antigen level and VWF:collagen-binding activities were carried out. Data were analyzed using GraphPad Prism (5.03). GraphPad Software, Inc USA. The BigDye terminator chemistry was used to determine the nucleotide sequences of VWF gene (exon 28). RESULTS: Eight SNPs were identified, rs 216310 (T1547), rs 1800385 (V1565L), rs1800384 (A1515), rs1800383 (D1472H), rs 1800386 (Y1584C), rs 216311 (T1381A), rs 216312 (intronic) and rs 1800381 (P1337). CONCLUSION: The SNPs rs 216311, rs 1800383 and rs 1800386 associated significantly with bleeding in study subjects. rs1800386 occurred in all with bleeding history, no ethnic variations were noted. PMID- 28091444 TI - Impact of visual inspection with acetic acid plus cryotherapy "see and treat" approach on the reduction of the population burden of cervical preinvasive lesions in Southeast Nigeria. AB - OBJECTIVE: The aim of this study is to determine the impact of visual inspection with acetic acid (VIA) plus immediate cryotherapy on the prevalence of VIA detected cervical squamous intraepithelial lesion (SIL). METHODS: Women in four rural communities in Southeast Nigeria were screened with VIA. Women who tested positive to VIA were offered either immediate cryotherapy or large loop excision of the transformation zone based on predetermined eligibility criteria. Cervical biopsies were taken before cryotherapy and examined by consultant histopathologists. All participants were rescreened 1 year later. The main outcome measures were population prevalence of cervical precancers before and after intervention, cure rates, and over-treatment rates. RESULTS: A total of 653 women participated in the study. The prevalence of cervical SIL before the intervention was 8.9% (58/653). The prevalence 1 year later was 1.4% (9/649). This gave an 84.3% reduction in the population prevalence of SIL. The reduction in cervical SIL prevalence was statistically significant (P = 0.0001). The prevalence of high-grade SIL reduced significantly from 4.1% (27/653) preintervention to 0.5% (3/649) 1 year postintervention (P = 0.0001). This gave an 87.8% reduction in the population prevalence of high-grade SIL. Cryotherapy provided a cure rate of 87.9% (95% confidence interval: 76.82-94.33). CONCLUSION: Population cervical cancer prevention using VIA plus immediate cryotherapy leads to significant reduction in the population prevalence of cervical SIL. This has the potential of being an acceptable supplement to cervical cytology for cervical cancer prevention in low-income populations. PMID- 28091446 TI - Correlation between athlete training intensity and cardiac performance. AB - OBJECTIVE: An effective analysis of correlation between training intensity of athletes and cardiac performance is done to develop scientific and reasonable exercise program and to promote health of athletes. METHODS: During December 2013 December 2015, 3600 students from different sports schools were selected for the test. All the athletes were randomly grouped, that is half-hour running group, one-hour running group and 90 -minute running group, which are named A, B, C groups respectively. The three groups of athletes received 5 days of testing per week, and took rest in the remaining two days, maintaining a total of 10 days. Exercise intensity of personnel accepting test was detected by RPE, and effective analysis was made on cardiac function change before and after test of three groups of the college students. RESULTS: Resting heart rates of B, C group students were considerably decreased after exercise. In comparison of falling range of group C and group A, there is a statistically significant difference, P <0.05. CONCLUSION: By strengthening athletes' training intensity, we can effectively enhance athletes' cardiac performance. t As a result, athletes' body becomes healthier, which is conducive to athletes' physical and mental development. PMID- 28091445 TI - Preoperative and intraoperative continuous use of dexmedetomidine on hyperalgesia after patients' remifentanil anesthesia. AB - OBJECTIVE: Analyze clinical use of dexmedetomidine to relieve prognosis of remifentanil anesthesia recovery and analyze intervention effect. MATERIALS AND METHODS: Choose 3600 cases of cerebral functional area operation patients treated in different hospitals during June 2011 and December 2015 for general analysis, group the patients by considering relevant parting of anesthesia recovery by American Society of Anesthesiologists, and divide the patients into dexmedetomidine group and control group according to different use of drugs. The two groups of patients are anesthetized, patients' anesthesia wake-up time and wake-up success rate are recorded, and effect of two types of anesthesia wake-up way are compared. RESULTS: There exists no significant statistical difference in wake-up success rate of the two groups of patients, wake-up time has small difference, but anesthesia recovery quality of dexmedetomidine group is higher, which is conducive to physical rehabilitation of patients and minimize the effects of anesthetics on patients. CONCLUSION: In clinical surgery, after use of remifentanil anesthesia on patients, use of dexmedetomidine for anesthesia recovery can minimize adverse effects of drugs on patients and thus is worthy to be effectively promoted in clinics. PMID- 28091447 TI - Prosthetic rehabilitation of a patient with a resected right temporomandibular joint. AB - This case report presents the prosthodontic rehabilitation of a patient with a resected right mandible, caused by an accident. Right condyle, ramus, and the posterior part of ramus were affected by the accident. These structures were resected, and the mandible was positioned toward the surgical area and a facial asymmetry was occurred. The patient was treated with a bar-retained maxillar denture with a guide ramp and an implant-supported fixed mandibular prosthesis. PMID- 28091448 TI - Oro-dental characteristics of three siblings with Papillon-Lefevre syndrome. AB - Papillon-Lefevre syndrome (PLS) is a rare autosomal recessive disorder, showing oral and dermatological manifestations in the form of aggressive periodontitis, leading to the premature loss of both primary and permanent teeth at a very young age and palmar-plantar hyperkeratosis. It was first described by two French physicians, Papillon and Lefevre in 1924. Immunologic, genetic, or possible bacterial etiologies have been thought to account for etiopathogenesis of PLS. Severe gingival inflammation and periodontal destruction occurred after the eruption of primary teeth. This condition should warn the physicians and dentists as a one of the important sign for the diagnosis of PLS. There have been over 250 cases reported in literature about PLS, but a few of these were in the same family. This study presents oro-dental characteristics, dental treatments, and follow-up of three siblings (age of sisters are 13, 6, and 4 years) with PLS, which is rarely seen in the same family. PMID- 28091449 TI - Crouzon syndrome with multiple supernumerary teeth. AB - Crouzon syndrome (CS) is an autosomal dominant disorder characterized by craniofacial deformities caused by the early closure of cranial sutures. It is diagnosed by the presence of a flat sphenoid bone, protrusion of eyeballs (exophthalmos), and midfacial hypoplasia. Although hypodontia is usually present in cases with CS, supernumerary teeth are rarely seen. A 16-year-old male patient with CS was referred to our clinic. He had a high forehead, beaked nose, hypertelorism, palpebral ptosis, and asymmetrical orbits. Bilateral multiple supernumerary teeth were observed in his upper and lower jaws. Early diagnosis of CS is helpful in dental and craniofacial treatment. Because of multiple facial and oral problems, this patient required a multidisciplinary treatment approach. PMID- 28091450 TI - Smartphone photomicrography: A quick, easy, useful technique for the clinician. PMID- 28091451 TI - [Radiofrequency ablation in combined treatment of metastatic colorectal liver cancer]. AB - AIM: To study surgical and oncological outcomes in patients with metastatic colorectal liver cancer who underwent radiofrequency ablation in the structure of combined approach. MATERIAL AND METHODS: It is a prospective analysis of treatment of 76 patients with metastatic colorectal liver cancer who underwent RFA for the period 2004-2013. Overall survival was analyzed using univariate and multivariate analysis. RESULTS: According to univariate analysis overall 5-year survival is negatively determined by following factors: primary localization of the tumor in rectum (36.2% and 7.2%; p=0.021); bilobed metastatic liver disease (35.9% and 15.4%; p=0.068); metastases dimensions over 5 cm (27.4% and 0%, p=0.091); augmentation of CAE levels over 4 norms (26.7% and 11.4%, p=0.09); RFA as a component of two-stage liver surgery (23.3% and 26.0%, p=0.09). CONCLUSION: RFA is an effective method of local antineoplastic effect for metastatic colorectal cancer. Dimensions of coagulated metastases, volume of metastatic lesion, carcinoembryonic antigen level, ablation as a component of two-stage surgery affect long-term survival after RFA. PMID- 28091452 TI - [Early reconstruction of supra-aortic vessels as a prevention of recurrent ischemic stroke]. AB - AIM: To evaluate the efficacy and safety of supra-aortic vessels reconstruction within acute period of stroke. MATERIAL AND METHODS: Early surgery was performed in 7 patients aged 67+/-9 years. Revascularization was made after 4.6 days after ischemic stroke on the average (range from 2 to 7 days). Neurological status before and after surgery was assessed using NIHSS scale, mean preoperative score was 3.9+/-2.7 (0-7). All patients had ischemic brain lesions (4-32 mm, mean 10 mm) unilateral with carotid stenosis or occlusion. Carotid artery stenting was performed in 2 patients, carotid endarterectomy - in 4 patients and stenting of segment I of the left subclavian artery was made in 1 case. RESULTS: There were no mortality and recurrent postoperative ischemic stroke. Complications occurred in two patients: postoperative hematoma and intraoperative transient ischemic attack that developed during CAS after 5 days of a stroke. There was positive neurological dynamics after revascularization: there was almost 2-fold decrease of mean score of neurological deficit (from 3.9+/-2.7+/-1.7 to 2). CONCLUSION: Early surgical prevention of recurrent stroke (up to 7 days) can be performed effectively and safely in carefully selected patients with ischemic stroke (neurological deficit less than 3 Rankin scores and less than 7 NIHSS scores, ischemic lesion dimensions lass than 4 cm). Reconstruction of supra-aortic vessels in acute stage of stroke improves the neurological status and reduces the degree of motor and sensory disorders. However, currently there are no clear criteria for inclusion and exclusion of patients for early revascularization using both degree of neurological deficit and size of ischemic lesion. So our results need to be confirmed by large trials. PMID- 28091453 TI - [Peculiarities of the course, diagnosis and surgical treatment of non-lactating mastitis]. AB - AIM: To improve treatment of patients with non-lactating mastitis through the study of the course, diagnosis and surgical treatment. MATERIAL AND METHODS: The study included 336 women aged 18-72 years with non-lactating mastitis who were hospitalized into the clinic for the period 1999-2016. RESULTS: Main clinical variants of the disease, spectrum of pathogens and its relationship with clinical forms of mastitis were determined. Also early and long-term outcomes were evaluated followed by formulation of therapeutic and diagnostic concept of surgical care for non-lactating mastitis. Thus, good results were obtained in most cases (95.8% in early period and 92.6% in long-term period). CONCLUSION: Only differentiated approach to diagnostic and curative tactics will allow to achieve good cosmetic and functional results in these patients. PMID- 28091455 TI - [Enhanced recovery protocol in gerontological colon cancer patients]. AB - To develop enhanced recovery protocol for elderly and old patients in elective colon cancer surgery. In Russia as in the most world countries the biggest frequency of colon cancer are among elderly and old people. At the same time surgery treatment of elderly patients compared with young patients accompanied with increased frequency of complications, length of stay in hospital and mortality. Based on own and literature trials authors proposed enhanced recovery protocol for gerontological colon cancer patients. Protocol established on multidisciplinary approach to elderly and old patients treatment and include all stages of perioperative period. PMID- 28091454 TI - [Surgical and combined correction of tracheal and laryngotracheal cicatricial stenosis and restenosis]. AB - AIM: To improve treatment of patients with cicatricial tracheal stenosis using different methods of recanalization and circular resection. MATERIAL AND METHODS: Analysis involved 57 patients with cicatricial tracheal stenosis including 2 post traumatic cases, 27 post-intubation cases, 25 cases after tracheostomy and 3 restenoses after previous circular resection. There were 5 cases of tracheal stenosis combined with tracheoesophageal fistula, 1 patient with chest nodular goiter, 8 cases of unclosed tracheostomy and 3 patients with long-existing laryngotracheal fissure. There were 25 women and 32 men aged 15-65 years. Stenosis length ranged from 3.0 to 4.5 cm in 66.6% of patients. There were 13 (22.8%) patients with subcompensated stenosis (d=0.5-0.7 cm) and 44 (77.2%) cases of decompensated stenosis (d<0.5 cm) combined with suppurative tracheobronchitis that required endosurgical recanalization with stenting or balloon dilatation. 45 patients underwent upper tracheal third resection, 9 - middle third resection, 3 upper third and cricoid cartilage resection. Length of excised segment was 2.5 9.5 cm. Simultaneous suturing of esophageal anterior wall defect was performed in 5 cases. RESULTS: Complete recovery of tracheal lumen was achieved in 54 patients (93%). Restenosis occurred in 4 (7%) cases (3 of them underwent repeated resection with good results and 1 - stenting). CONCLUSION: Circular resection is optimal treatment of cicatricial tracheal stenosis. Endosurgical recanalization is preparatory method prior to radical surgery. PMID- 28091456 TI - [Antegrade endobiliary interventions in undilated bile ducts]. AB - AIM: To show advisability of antegrade transhepatic approach to bile ducts for benign and malignant biliary diseases if endoscopic technique is impossible or ineffective. MATERIAL AND METHODS: 38 patients underwent external biliary drainage followed by endobiliary interventions for the period 2009-2016. RESULTS: In all patients treatment was effective and included following manipulations: antegrade balloon dilatation of stricture of biliodigestive anastomosis, papillodilatation, antegrade dislocation of calculuses from common bile duct to duodenum. There were 2 cases of complications after antegrade interventions. 1 woman died from severe pancreatic necrosis. CONCLUSION: Percutaneous transhepatic cholangiostomy on undilated bile ducts is effective for temporary biliary drainage in closure of external duodenal or biliary fistula, treatment of intra abdominal bilema. The method is indicated in elective endobiliary interventions for choledocholithiasis management, elimination of stricture of biliodigestive anastomosis of major duodenal papilla if endoscopic or conventional approaches are impossible or ineffective. PMID- 28091457 TI - [Laparoscopic cholecystectomy in short-stay hospital]. AB - AIM: To develop the protocol of surgical management of cholelithiasis in short stay hospital. MATERIAL AND METHODS: Surgical treatment of 161 patients with cholelithiasis was analyzed. All of them underwent elective cholecystectomy. Short-stay hospital group included 41 patients. 120 patients were operated in surgical department (group 2). RESULTS: Incidence of intraoperative complications was 2.4% and 3.4% in both groups respectively (p>0.05). Postoperative complications were more frequent in group 2 (8.3% vs. 2.4%, p<0.05). Mean hospital-stay was 1 and 4.4 days in both groups respectively. CONCLUSION: Treatment of chronic calculous cholecystitis is advisable in short-stay hospital. Indications for this approach and its safety in certain patients were determined. The protocol of surgical management of chronic cholecystitis in short-stay hospital was develped. PMID- 28091458 TI - [Morphological and functional aspects of recurrent postoperative ventral hernias]. AB - AIM: To define the optimal treatment of postoperative ventral hernias. MATERIAL AND METHODS: It was performed microscopic examination of intraoperative specimens which were obtained from 40 patients with medium, large and giant hernia. The aim was to reveal ultrastructural changes and morphological features which are associated with abdominal wall weakness in case of postoperative ventral hernia. There were 28 (70%) cases of primary postoperative hernia and 12 (30%) cases of recurrent and multiple-recurrent hernia. In 4 patients polypropylene mesh implants were implanted prior to recurrence. Tissue specimens were obtained from the top of herniation, hernial ring and in 6 cm from the hernial ring. RESULTS AND DISCUSSION: Electron microscopy showed that postoperative ventral hernias are accompanied by ultrastructural destructive changes in cells of the skin, aponeurosis and muscles that indicates on morphofunctional failure of abdominal wall tissues. Swelling and degradation of collagen, fibroblasts vacuolization, capillary sludge of erythrocytes, development of vacuum zones with the fragments of altered collagen fibrils, red blood cells and mast cells are morphological signs of micronecrosis followed by abdominal wall weakness and postoperative ventral hernias. CONCLUSION: Postoperative ventral hernias are associated with morphological and functional failure of abdominal wall due to tissue destructive changes. Therefore, this obviously defective tissue can not be used per se and especially with tension. Mesh implants should be applied. PMID- 28091459 TI - [Evaluation of reparative osteogenesis of distraction regenerate of the fourth metatarsal bone in patients with brachymetatarsia]. AB - AIM: To evaluate reparative osteogenesis of the fourth metatarsal bone using X ray and ultrasonic methods. MATERIAL AND METHODS: Six patients with fourth metatarsal bone dysplasia underwent ultrasound and X-ray examination during distraction and fixation. Data were analyzed. RESULTS: During distraction sonography assessed adequately the length of elongation, activity of bone trabecula formation, features of vascularization and organotypic reconstruction of regenerate. X-ray examination is advisable to determine the terms of device relief during fixation. CONCLUSION: Sonography is preferable during distraction for dynamic monitoring of reparative osteogenesis. X-ray examination is advisable to determine the terms of device relief during fixation. PMID- 28091460 TI - [Diabetes mellitus in surgical clinic]. AB - AIM: To demonstrate that the diagnosis and treatment of diabetes mellitus (DM) are actual today for surgical clinic because morbidity reached pandemic levels. MATERIAL AND METHODS: We defined causality and comorbid relations of DM with some common pancreatic diseases that is especially important for abdominal surgical clinic. Pathogenesis, clinical and laboratory signs of diabetes were determined in patients with surgical pancreatic pathology. RESULTS AND CONCLUSION: Meta analysis of literature data and our own experience are presented in diagrams of surgical patients with hyperglycemia, ketoacidosis, hyperosmolar and lactacidemic syndromes. The main conclusion is need for pathogenetic approach and continuous clinical and laboratory monitoring. PMID- 28091461 TI - [Use of somatostatin analogues in the pancreonecrosis therapy (kliniko experimental research)]. AB - : The article is devoted to the study and optimization of therapeutic strategy in pancreatic necrosis. We studied the effectiveness of clinical application of human somatostatin analog - octreotide in different dosages. Submitted investigationconsists of experimental and clinical parts. MATERIAL AND METHODS: Experimentalmodel of acute destructive pancreatitis onrats of Wistar line with weight of 300+/-30 gwas reproduced.There were 5 animal groups (one control group and four experimental groups). Experimental animals received oktreotidin different doses. In 2 days there were estimated the blood biochemistryand histopathologic features of liver and pancreas of operated animals. In clinical part there were formed two groups of patients out of selected case histories by a principle of similarity of complex therapy differing in oktreotid doses, namely: 1) pancreatonecrosis patients estimated of 3 to 8 points by Ranson scale in whose treatment regimen oktreotid 300 mkg/day (n=70) dose was included; 2) pancreatonecrosispatients estimated of 3 to 8 points by Ransonin whose treatment regimenoktreoid1200 mkg/day (n=38) was included. There were compared indices of lethal outcomes, average bed-days, and dynamics of laboratory findings, number and volume of surgical procedures. RESULTS AND CONCLUSION: Dose-related effect of a synthetic analogue of somatostatin, acetateoktreotid, was proved. Introduction in complex therapy of pancreatonecrosisthe highest possible authorized doses of oktreotid (1200 mkg/day) is conducive to more favorable course of illness, dynamic reduction of amilazemia, decrease of lethal outcomes and total bed-day, and also, reduction of initial and repeated operative procedures. PMID- 28091462 TI - [The modern principles of management of intermittent claudication]. AB - Number of patients with peripheral arterial disease, despite various national public health programs, remains high and has no steady downward trend over the past few decades. Despite recent advances in drug therapy, sonservative approach in the management of peripheral arterial disease is often neglected by vascular surgeons. However, vast majority of patients with intermittent claudication, who receive comprehensive conservative treatment, including risk factor modification, exercise and drug therapy, may get significant improvement in quality of life by partial or complete relief of symptoms related to the disease. Patients strictly adhering to medical recommendations has favorable prognosis and progression of disease to the stage of critical limb ischemia is very unlikely. Noncompliant patients and those who continue smoking in particular, often experience progression of symptoms related to the disease. That may result in the need for surgical intervention aiming to prevent or delay the onset of critical limb ischemia. PMID- 28091463 TI - [Influence of the antihypoxantic therapy on children with generalized peritonitis]. AB - AIM: To improve the results of treatment of a widespread purulent peritonitis in children by optimizing fluid therapy includes the use of combined treatment: reamberin and remaxol. MATERIAL AND METHODS: We studied 269 patients aged 1 to 15 years with a widespread purulent peritonitis treated at the children's surgical departments in Samara from 2001 to 2015. The study group included 179 children who used the optimized infusion therapy. In the study group was allocated to 2 groups: 69 children in infusion therapy which used reamberin and 110 patients in which treatment was applied reamberin and remaxol. The surgical treatment used laparoscopic sanation of the abdomen. Comprehensive survey included a study of dynamics of the white blood cell count, leukocyte index Kalf-Caliph, erythrocyte sedimentation rate, temperature, total albumin concentration, transaminase levels. Catamnesis studied 48 patients with the definition of complex intima media thickness in the projection of basilar, brachial and femoral arteries. RESULTS: A study compared indicators of both groups, revealed a more rapid reduction of intoxication symptomps (leukocytosis, LII, body temperature), the disappearance of enteric disease, recovery of protein-synthetic function of the liver, decrease of cytolytic and mesenchymal-inflammatory syndromes in the main group, especially in the subgroup in which treatment was included remaxol. CONCLUSION: The use of reamberin and remaxol in infusion therapy led to improvement of the results of the treatment of common purulent peritonitis in children. Study catamnesis with the study of the intima-media revealed that children undergoing widespread purulent peritonitis further develop signs of endothelial dysfunction. The developed clinical recommendations to significantly reduce the risk of developing signs of endothelial dysfunction, thereby reducing the possible appearance of vascular pathology in patients who underwent childhood widespread purulent peritonitis. PMID- 28091464 TI - [A true giant aneurysm of gastro-duodenal artery]. PMID- 28091466 TI - [Colonic intussusception in a child]. PMID- 28091465 TI - [Complex endovascular treatment of Budd-Chiari syndrome]. PMID- 28091467 TI - [The history of cochlear implantation]. AB - The creation of cochlear implants has become possible owing to the collaboration in the field of neurophysiology, otorhinolaryngology, audiology, engineering, and psychoacoustics. The experiments carried out in the 1930s were not directly associated with the electrical stimulation of the auditory nerve but had a significant influence on the development of cochlear implants. The first attempt at direct electrical stimulation of the auditory nerve was performed in 1957 using a device that consisted of an active electrode and an implantable induction coil. A good discrimination of intensity but poor frequency discrimination of the acoustic stimuli in a deaf patient was achieved. In 1985, the cochlear implants were approved for the treatment of the adult patients and in 1990 for the children at the age under 2 years. Multi-channel cochlear implantation has been carried out in Russia since 1991 although the efforts to introduce singe-channel implantation were made in the 1980s. Nowadays, there are more than 8000 cochlear implant users in the Russian Federation. Cochlear implantation is performed in a number of clinical centres in several regions of the country funded from the federal budget. PMID- 28091468 TI - [Reoperations after cochlear implantation]. AB - : The objective of the present study: the improvement of the quality and effectiveness of the surgical stage of cochlear implantation on the basis of the comprehensive analysis of performed reoperations. PATIENTS: 84 patients of the 2413 ones who had undergone cochlear implantation were re-examined by revision surgery within various periods after the first intervention. MAIN RESULTS: In certain patients, the correction of the intracochlear electrode array position was performed and in 72 cases the replacement of the implant was done. The most frequent cause of the replacement of the implant was the failure of the device. In the case of the extrusion and inflammation, the two-stage surgical treatment was applied. The exposure of the different parts of the cochlear implant with the duration up to 2 weeks was considered as a complication which could be adequately corrected. The surgical treatment of such patients was carried out in a single stage. The reparation processes at the place of the first intervention were strongly expressed, especially in children. Standardization of the cochlear implantation surgical stage based on the determination of its optimum volume in our Center led to a decrease in the number of reoperations and made the learning process easier to master for young otosurgeons. CONCLUSION: It is can be concluded that the reoperation after primary cochlear implantation is a highly effective technique and, taking into account the listed features, doesn't present difficulties for the qualified otosurgeon. PMID- 28091469 TI - [The role of computer and magnetic resonance imaging in patients with deafness]. AB - : The objective of the present study was to evaluate the potential of CT and MRI for diagnostics of congenital and acquired pathology of the inner ear in the deaf patients. Two groups of the patients were examined. The first group consisted of 75 patients with congenital or acquired deafness etiology. The second group was comprised of 75 patients with deafness associated with acute bacterial meningitis suffered in the preceding period. All the patients were examined by CT and MRI of temporal bones. The results of the study provided a basis for the development of indications for the application of CT and MRI to examine the patients presenting with hearing loss and deafness. CONCLUSION: CT and MRI make it possible to identify individual features of the temporal bone structure significant for the surgical treatment. MRI appears to have an advantage over CT for diagnostics of early obliteration of the cochlea. Both CT and MRI are the optional methods for the examination of the patients with deafness developing after meningitis. PMID- 28091470 TI - [The results of cochlear implantation in the patient with hereditary and non hereditary hearing loss]. AB - The objective of the present study was to evaluate the effectiveness of rehabilitation of the patients after cochlear implantation in the early and late periods after operation taking into consideration the etiology of congenital deafness. The comprehensive clinico-audiological examination performed during the period from 2010 to 2015 involved 246 children who had undergone cochlear implantation (CI). All children were operated at the National Research Center for Audiology and Hearing Rehabilitation in the period from 2003 to 2013. 83 (56%) patients were aged 1 to 3 years at the time of surgery. Their age varied from 3 to 18 years when they underwent the clinico-audiological examination. Thus, the study is based on the experience with cochlear implantation varying from 3 to 12 years. The genetic analysis revealed mutations in the GJB2 gene in 49% of the children, in agreement with the data of earlier studies. 85% of all the children with GJB2 deafness surgically treated at the age under 4 years attend ordinary institutions of learning. Within 24 months after the onset of the observations the majority of the children with hereditary deafness (63%) were referred to the groups with good and excellent results of the rehabilitation and only 6 (12%) patients presented with unsatisfactory results. It was shown that the acquired causes of the loss of hearing including severe prenatal pathology have a negative influence on the long-term outcomes of rehabilitation. The results of the genetic analysis for the elucidation of the cause of impaired hearing can be employed as a prognostic criteria not only for the prediction but also for the guarantee of the success of cochlear implantation provided the rehabilitative process was initiated in a proper time. PMID- 28091471 TI - [The impact of implantable technologies on the quality of life in the patients with hearing loss]. AB - The improvement of the effectiveness of the rehabilitation of the patients with hearing disorders is a priority task for an audiologist. One part of the present work was to assess satisfaction of the patients treated with the use of the hearing aids, drug therapy, and the surgical operations. The aim of the study was to evaluate the influence of the implantation of the Baha bone conduction system on the quality of life of the treated patients. The Russian-language versions of the Glasgow Benefit Inventory and Glasgow Children Benefit inventory questionnaires were used. The survey was conducted among the patients with bilateral moderate and moderate-to-severe conductive hearing loss due to congenital malformation of the external and middle ears or chronic suppurative otitis media followed by canal-down operation. A total of 47 patients took part in the present multicenter study. The results demonstrate the high effectiveness of rehabilitation with the use of the implantable bone conduction system. The beneficial effect of the treatment was especially well apparent in the children. The results are comparable with the data of the similarly designed investigations reported in the literature. Peculiarities of the data obtained in the present study and statistical characteristics made it possible to validate the Russian language versions of the Glasgow Benefit Inventory and Glasgow Children Benefit inventory questionnaires. PMID- 28091472 TI - [The clinical definition and etiology of Pendred syndrome (a review of the literature and clinical observations)]. AB - : The aim of this work was a clinical study of the patients with mutations in the SLC26A4 gene and clinical diagnosis of the Pendred syndrome. The Pendred syndrome is a hereditary autosomal recessive disorder characterized by combined pathology of the inner ear and the thyroid gland. CT of the temporal bones demonstrates the Mondini-type structural anomaly in the inner ear and enlarged vestibular aqueduct. Examination of the thyroid gland reveals hypothyroidism and euthyroid goiter. A total of 20 unrelated children at the age from 2 to 16 years presenting with the hearing loss of different severity were available for the examination. High-resolution CT of the temporal bones demonstrated abnormal development of the inner ear including the Mondini-type structural anomaly and enlarged vestibular aqueduct. Five children with congenital hypothyroidism suffered from bilateral sensorineural impairment of hearing. The routine methods of audiological and molecular genetic examination were used throughout the study. RESULTS: As a result of molecular genetic studies, four out of the 20 patients were found to carry six recessive mutations of the SLC26A4 gene in the compound heterozygous and one such gene in the homozygous state which confirmed the hereditary nature of the disease. The children suffered the hearing loss of varying severity diagnosed at different age. The thyroid hypofunction in one child was identified when it was 2 years of age, and in two children at the age of 8 and 9 years. CONCLUSION: The first step in the diagnosis of the Pendred syndrome among children with congenital hearing loss was a CT scan of the temporal bones that showed incomplete separation of the curls of the cochlea and enlarged vestibular aqueduct. It is necessary to continue to study epidemiology, clinical and molecular genetics of the Pendred syndrome in the Russian population. PMID- 28091473 TI - [Cardiac rhythm disturbances in the children with hearing pathology]. AB - : The aim of the study was to identify cardiac arrhythmias in children presenting with hearing impairments. Hearing loss in the children can occur concurrently with the disturbances of the cardiac rhythms. The detection of this pathology at the diagnostic stage is as important as it is at the stage of rehabilitation including surgical one. PATIENTS AND METHODS: A retrospective analysis of 100 patients (55 boys and 45 girls of the mean age of 4.8 years) operated in 2013 was made. RESULTS: Cardiac arrhythmias and conduction were recorded on the electrocardiograms obtained from 10 patients (4 boys and 6 girls) of the 100 examined ones, which amounted to 10%. The hereditary long QT syndrome (including Jervell-Lange-Nielsen syndrome) has not been identified. CONCLUSION: The timely diagnostics of congenital arrhythmias in the children with hearing impairment makes it possible to significantly reduce the risk of the sudden cardiac death (for example, in the patients presenting with the Jervell-Lange-Nielsen syndrome) and facilitates the choice of the anesthesiological support for the surgical treatment (including cochlear implantation) taking into consideration possible cardiac rhythm disturbances. PMID- 28091474 TI - [The analysis of acoustic activity unsynchronized with the stimulus with the use of TEOAE]. AB - : The presence of ambient noise or the troubled child's behavior during the registration of transiently induced optoacoustic emission (TEOAE) can lead to false positive results at the first stage of hearing screening. The aim of this study is to evaluate the effectiveness of the noise reduction method based on weighted averaging of the data in the frequency and time slot, to check TEOAE, and to improve the effectiveness of universal hearing screening. Particular attention is paid to the analysis of the origin of noise recorded during the UAE. PATIENTS AND METHODS: We have developed a method of noise reduction, based on weighted averaging of the data in the frequency and time cells. In this study, 20 people were examined (9 adults and 11 children). TEOAE was performed using the probe of the ILO 288 instrument manufactured by Otodinamics Ltd. that was connected to the E-MU 0204 sound card. The probe microphone was connected through the preamplifier to one input channel of the sound card, and the second channel was used to receive a signal from the ECG and the respiration recorder. Thereafter, the data thus obtained were processed by several methods, including the method of averaging in the frequency and time slot designed to average a set of implementations that contain a noisy signal. The comparison of the results of the use of noise suppression method based on weighted averaging of the data in the frequency and time cells showed that it increases the accuracy of TEOAE. MAIN RESULTS: Our work suggests that the use of the noise suppression method based on weighted averaging of the data in the frequency and time cells, increases the accuracy of TEOAE. Similar results were obtained by the weighted averaging method. PMID- 28091475 TI - [The Russian-language version of the matrix test (RUMatrix) in free field in patients after cochlear implantation in the long term]. AB - : The deterioration of speech intelligibility in the patients using cochlear implantation (CI) systems is especially well apparent in the noisy environment. It explains why phrasal speech tests, such as a Matrix sentence test, have become increasingly more popular in the speech audiometry during rehabilitation after CI. The Matrix test allows to estimate speech perception by the patients in a real life situation. The objective of this study was to assess the effectiveness of audiological rehabilitation of CI patients using the Russian-language version of the matrix test (RUMatrix) in free field in the noisy environment. 33 patients aged from 5 to 40 years with a more than 3 year experience of using cochlear implants inserted at the National Research Center for Audiology and Hearing Rehabilitation were included in our study. Five of these patients were implanted bilaterally. The results of our study showed a statistically significant improvement of speech intelligibility in the noisy environment after the speech processor adjustment; dynamics of the signal-to-noise ratio changes was -1.7 dB (p<0.001). CONCLUSION: The RUMatrix test is a highly efficient method for the estimation of speech intelligibility in the patients undergoing clinical investigations in the noisy environment. The high degree of comparability of the RUMatrix test with the Matrix tests in other languages makes possible its application in international multicenter studies. PMID- 28091476 TI - [Application of the mathematical model for prognosis in the rehabilitation of children after cochlear implantation]. AB - : Despite the variety of etiological factors, cochlear implantation (CI) remains the only effective method for the rehabilitation of the patients presenting with total deafness. The aim of this study was the enhancement of the efficiency of selection of the candidates for CI, the improvement of the quality of rehabilitation of the patients with cochlear implants, and the determination of the prognostic criteria for clinical trials. PATIENTS AND METHODS: (CI). The decision-making support system (DMSS) based on the artificial neural networks (ANNs) has been created to enhance the efficiency of rehabilitation of the patients with cochlear implants and increase the effectiveness of the selection of candidates for cochlear implantation. The results of the children's rehabilitation after CI have been analyzed by using a mathematical model of artificial neural networks (Kohonen layer). The basis for the assessment of ANNs was formed by the results of the observations of audioverbal perception in 110 patients aged from 6 months to 17 years. The initial data were the average values obtained with the use of the Russian-language version of the Nottingham children's implant profile's test T1 - T3. The testing was performed before CI and 3, 6, 12, 18, and 24 months after it. MAIN RESULTS: The work yielded the four cluster data structure. It made it possible to estimate the effectiveness of the clinical trials in selected classes depending on the etiology of the disease, the age of the patients, and their experience with the application of hearing aids. The reliable estimation of the dynamics of auditory perception at the stage of rehabilitation and prognosis of the outcomes of CI made it possible to take additional preventive and therapeutic measures in the combination with complementary psychological and educational procedures. PMID- 28091477 TI - [The pedagogical evaluation of the pre-school children with cochlear implants]. AB - The objective of the present work was to elaborate the content of comprehensive psycho-pedagogical examination for the assessment of the overall intelligence level in the children presenting with hearing impairments. The complex of studies to be carried out to achieve this purpose encompasses evaluation of the social, physical, and cognitive development of the children as well as peculiarities of their play activities, their speech and hearing abilities. This approach is believed to enable a teacher of deaf and hard of hearing to identify the individual characteristics of each child and determine those of special importance for the elaboration of educational programs on an individual basis taking into consideration variants of children's development (harmonic, uneven, retarded, etc.). To facilitate the implementation of the proposed method, a special electronic tool (a virtual practice for a teacher of deaf) has been created. The virtual practice is believed to be instrumental in the training of the teachers of deaf for the comprehensive evaluation of the children with cochlear implants. In this way, the effectiveness of the development of personalized rehabilitation programs can be substantially increased. PMID- 28091478 TI - [Four sessions of the work of a teacher of deaf at the initial stage of rehabilitation of a child with a cochlear implant]. AB - PURPOSE: To present the system of the teacher of the deaf work with a child with CI and their family at the initial rehabilitation stage aimed at reorganization of interaction between the child with CI and his family and transition of the child to the way of natural development. RESULTS: The paper presents a brief description of the teacher of the deaf systematic work at the initial rehabilitation stage, which includes four work sessions of the teacher, during which the logic of normal development of a hearing child during the first year of their life is reproduced. The main difficulties in interaction with a child with CI, faced by their parents are described. Indicators of completion of each session with a child with CI and their parents are specified. There is noted that 90 children passed to the way of natural development of communication and speech with their relatives and parents sought to improve their interaction with the children. CONCLUSION: The system of the teacher of the deaf work with children after CI surgery, developed in the Institute of Special Education of the Russian Academy of Education, allows to reconstruct interaction between the child and their parents on a normal sensory basis and for a child with CI to pass to the way of natural development of their communication and speech as early age hearing children do. PMID- 28091479 TI - [Rehabilitation of a child with a cochlear implant: the "initial point" of new auditory abilities]. AB - The objective of the present study was to consider the key issue of the method of successful pedagogical rehabilitation of the children after cochlear implantation (CI) developed at the Institute of Special Education, i.e. what should be considered the "initial point" of new auditory abilities for a child carrying a cochlear implant. It was shown that the definition of the "initial point" depends on the understanding of early auditory ontogenesis, success of implantation surgery, accurate connection of the speech-processor and its correct initial adjustment. However, the analysis of the practical experience demonstrated that the majority of the children are unable to benefit from the new opportunities on their own. They need a special support by the teacher of the deaf and the family members for "launching" the new auditory abilities. Both the content and the effectiveness of this work depend on the understanding of early auditory ontogenesis and the skills of the teacher of the deaf. A new approach to the rehabilitation of the children with cochlear implants is proposed based on the interpretation of early auditory ontogenesis in the context of the formation and complication of the emotional communication of a child with the adult relatives. In the frame of the proposed approach to the rehabilitation of the children with cochlear implants, the "initial point" of new auditory abilities is the initiation of an emotional dialogue with the adult relatives on a new sensory basis. This "initial point" is common for different groups of children with an exclusion of deaf children with cochlear implants retaining the ability for the emotional communication with the relatives. In such children, the "initial point" is the point of ontogenesis at which the communication with the environment on the comprehensive sensory foundation was interrupted. PMID- 28091480 TI - [The application of lasers in otorhinolaryngology]. AB - The objective of this review is to summarize and systematize the data concerning the modern laser and laser-based systems, their characteristics, and possible applications in various spheres of medicine including otorhinolaryngology. The application of laser technologies in medical practice gains ever increasing popularity. Lasers have been successfully used during a long period for the diagnostic and therapeutic purposes. At present, they are just as actively applied in different fields of the surgical practice. Otorhinolaryngology makes the most extensive use of neodymium, CO2, and holmium lasers. The latter has the most universal characteristics and is operated in a relatively short wavelength range (lambda=2.01 mcm); moreover, its radiation penetrates as deep as 0.4 mm into the biological tissues. In other words, the holmium laser not only combines the advantages of the CO2 and neodymium lasers but is also devoid of their shortcomings. The holmium laser is considered to be the most promising source of laser radiation for the application in otorhinolaryngological surgery with a potential encompassing the most wide spectrum of surgical manipulations needed to treat pathological changes in the ears, nose, and throat. The application of this instrument in medical practice opens up new prospects for the development of otorhinolaryngology. PMID- 28091481 TI - [The methods of surgical sanation of the difficult to access parts of the middle ear in the patients presenting with chronic suppurative otitis media and concomitant cholesteatoma]. AB - The recurrent cholesteatomic process is one of the main causes of the poor outcome of the surgical treatment in the patients with acquired cholesteatoma of the middle ear. The relapse can be due to the incomplete removal of the cholesteatomic matrix especially from the difficult to access for visual control during the surgical intervention parts of the anterior epitympanic space, medial sinuses of retrotympanum, deep-lying portions of hypotympanum, and retrofacial part of the mastoid cavity. One more cause behind the recurrent process is the retention of the conditions for the secondary retraction of the neotympanic membrane, The objective of the present study was the improvement of the surgical modalities for better visualization and sanation of the difficult to access anatomically complex parts of the middle ear under the eye control, the creation of the conditions for the additional ventilation of the tympanic cavity and the reduction of the risk of development of residual and/or recurrent cholesteatomas. To this effect, we undertook the analysis of the results of 438 primary and 226 secondary (revisional) surgical interventions on the patients presenting with chronic suppurative otitis media and concomitant cholesteatomas. The study has demonstrated that the cause of 14.6% of the cases of residual cholesteatoma was the incomplete removal of its matrix from the anterior epitympanic space, medial sinuses of retrotympanum, deep-lying portions of hypotympanum, and retrofacial part of the mastoid cavity. The proposed surgical strategies reduced the risk of development of residual cholesteatoma from 8.2% to 3.9%. The newly developed method for the additional ventilation of the tympanic cavity allowed the frequency of recurrent cholesteatoma to be decreased from 2.5% to 1.6%. PMID- 28091482 TI - [A study of the efficacy and safety of new cephalosporin in the treatment of acute bacterial rhinosinusitis]. AB - Acute rhinosinusitis is leading in frequency of antibiotic prescribing all over the world. At the same time the problem of antibiotic resistance and safety of antimicrobial drugs becomes more relevant and international. The article describes the basic mechanisms of bacterial resistance and growth of side effects when using macrolides, respiratory fluoroquinilones and beta-lactam antibiotics of different types. Formation of IgE-mediated cephalosporin allergy is associated with the side R1 chain. The R1 structure of cephalosporins I and II generations is similar to penicillins, thus creating conditions for cross-allergy progression. R1 of cephalosporins III and IV generations is represented by a qualitatively different chemical compound (aminothiazol-oxime group) that increases the level of tolerance to these antibiotic types. The data of surveillance study are given to evaluate the efficacy and safety of the new drug Spectracef (active substance is cephalosporin of III generation Cefditoren) when treating acute bacterial rhinosinusitis on an outpatient basis. PMID- 28091483 TI - [The enhanced efficiency of nystagmus detection using the modified Frenzel goggles with congenerous illumination]. AB - The objective of the present study was to evaluate the efficiency and convenience of using the new modified Frenzel goggles in diagnostics of spontaneous nystagmus. It was shown that the modified Frenzel goggles provide more homogeneous lightening of the eyes and better diagnosis of peripheral latent spontaneous nystagmus in comparison with the traditional Frenzel goggles, available at the market. The questionnaire survey held among the doctors using both types of the goggles showed that the modified Frenzel goggles are more convenient for detecting spontaneous nystagmus in everyday practice. PMID- 28091484 TI - [Aesthetic and functional rehabilitation of a patient presenting with the consequences of congenital cleft lip and palate performed taking into consideration the specific ethnic features of the external nose (a case report)]. AB - The article demonstrates the method for reconstructive rhinoplasty used to treat a patient who underwent multiple cheiloplastic surgical interventions taking into consideration ethnic characteristics of the external nose. The operative technique involved the formation of lower lateral cartilage on the side of deformation and medial crura support, dorsum augmentation, and tip projection with the use autological cartilage and an implant. As a result, a significant improvement of the nose function was achieved in the combination with the good aesthetics outcome of the surgery. PMID- 28091485 TI - [Tuberculous lesion of retropharyngeal lymph nodes responsible for labored nasal breathing]. AB - A 62 year-old patient applied for the medical aid with complaints of labored nasal breathing. She was treated for tuberculosis in the childhood, underwent radical mastectomy in connection with left breast cancer in 2007 and adenotomy at the age of 60 years with the good functional outcome. One year after adenotomy, the enlargement of lymph nodes at the left-hand antero-lateral surface of the neck was detected. The histological changes in the lymph nodes corresponded to the picture of tuberculosis. Pharyngoscopy demonstrated an asymmetric protrusion at the posterior wall of the pharynx more prominent on the left side. Examination by spiral computed tomography revealed the presence of two enlarged lymph nodes with the signs of suppurative melting in the retropharyngeal space. These lymph nodes were opened through the posterior pharyngeal wall which resulted in the restoration of the normal pharynx configuration and the normalization of nasal breathing. PMID- 28091486 TI - [Combined physical therapy: general information, interaction between physical factors]. AB - The present article is devoted to problems pertaining to the combined (simultaneous) medical application of the therapeutic physical factors. The classification of the methods used in combined physical therapy is proposed, their advantages over the traditional therapeutic modalities are discussed, the general principles of simultaneous application of the medical physical factors are considered. The possible variants of interaction between such physical factors in the case of their combined application are theoretically determined, the criteria for their quantitative assessment (coefficients of synergism and effectiveness of combination) are offered, examples of their application for the evaluation of the efficiency of the selected combinations are provided. PMID- 28091487 TI - [The application of the International Classification of functioning, disability and health for the evaluation of the effectiveness of rehabilitation: methodology, practical experience, results]. AB - The article highlights the methodology, tools, conditions and limitations of the application of the International Classification of functioning, disability and health (ICF) for the evaluation of the effectiveness of medical rehabilitation. The results of the assessment of the initial level of the patients' functional abilities and their rehabilitation potential are presented with special reference to the selection of interventions and instruments for their realization as envisaged by ICF and allocation of the responsibilities among the professionals taking into consideration the AIM: of the rehabilitative treatment for specific patients. The advantages of the proposed approach are demonstrated on the example of the management of the patients presenting with osteoarthritis. Special attention is given to the information coding techniques and standards for the description of the patients' health conditions at various stages of rehabilitation. PMID- 28091489 TI - [The algorithm for the determination of the sufficient number of dynamic electroneurostimulation procedures based on the magnitude of individual testing voltage at the reference point]. AB - : This article was designed to present evidence of the advantages of the personified approach to the treatment of the patients presenting with arterial hypertension (AH), lumbar spinal dorsopathy (LSD), chronic obstructive pulmonary disease (COPD), and duodenal ulcer (DU) at the stage of exacerbation obtained by the measurements of testing voltage at the reference point (Utest). AIM: The objective of the present study was to develop the algorithm for the determination of the sufficient number (optimal duration) of therapeutic procedures of the protracted treatment with the use of the Utest at the reference point. THE PATIENTS AND METHODS: The study included 647 patients (439 women and 208 men at the age varying from 25 to 72 years) with grade I-II AH, DU at the stage of exacerbation, grades II and III lumbar spinal dorsopathy, grade II-III COPD. The informed written content to participate in the study was obtained from all the patients. They were divided into three groups. Those comprising group 1 were treated by standard therapy, patients of group 2 received the same treatment supplemented by dynamic electroneurostimulation (DENS) while the patients of the third group were given personified DENS in accordance with the determined sufficient number of DENS procedures. RESULTS: The blood pressure in the patients with AH comprising group 3 was found to decrease more significantly in comparison with those in groups 1 an 2 (by 9% and 3% respectively). The intensity of pain syndrome in the patients with lumbar spinal dorsopathy evaluated based on the visual analog scale decreased two-fold in group 3 in comparison with the 1.2 and 1.8 times decrease in groups 1 and 2 respectively. The level of pH in the stomach of patients with DU increased by 33.3% in group 3 in comparison with 12,5%, in group 1 and 21,8% in group 2. Vital capacity of the lungs in the patients of group 3 presenting with COPD and treated with the use of the personified approach was found to increase almost up to 612 ml in comparison with 477 ml in the patients given DENS in combination with standard therapy and only 219 ml in the control group. CONCLUSION: The results of the present study give evidence of the advantage of the personified treatment based on the determination of the sufficient number of the therapeutic procedures needed for the protracted treatment with the use of the Utest at the reference point. This approach can be used as a tool for the evaluation of the functional state of the patients and a method for the management of a chosen therapeutic strategy. PMID- 28091488 TI - [The new directions in the physiotherapeutic applications of the natural potassium salts of the Western Ural]. AB - : Salt therapy (halotherapy) as a non-traditional method for the treatment of various pathological conditions has become an increasingly popular therapeutic modality in Russia and abroad. The Perm region houses one of the largest sylvinite-bearing potash deposits in the world. These salts are possessed of special physical and chemical properties of great value for the treatment of different diseases. The objective of the present work was to develop novel approaches to the application of sylvinite for the treatment and prevention of various diseases. MATERIAL AND METHODS: The subjects of investigations were the modern sylvinite constructions of different types. The study included a total of 195 patients who were randomly divided into two groups. The main group consisted of 50 patients presenting with allergic respiratory diseases, 20 ones with atopic dermatitis, and 21 with vulgar psoriasis. 31 patients had undergone aortocoronary bypass surgery in the preceding period. 49 pregnant women presented with a complicated course of pregnancy. 24 patients suffered from chronic generalized catarrhal gingivitis. The control group was comprised of 188 persons presenting with the same diseases (46, 30, 18, 20, 49, 25 patients in each of the above groups respectively) who received only the traditional pharmacotherapeutic treatment. All the patients underwent evaluation of the respiratory and cardiovascular functions. The clinical manifestations and the skin damage areas were estimated in the patients with atopic dermatitis and vulgar psoriasis. Blood circulation in placenta, the state of the periodontal tissues, and local immunity in the oral cavity mucosa, as well as the subjective psychological status were evaluated. The physical and chemical characteristics of the internal environment of the salt constructions (microclimatic factors, radiation, air ionization, salt aerosol content) were estimated. RESULTS AND DISCUSSION: The data obtained provided a basis for the development and patenting of the methods for the treatment of atopic dermatitis, vulgar psoriasis, placental insufficiency, and chronic generalized catarrhal gingivitis based on the halotherapeutic modalities. CONCLUSION: The results of the long-term hygienic, physical and clinical investigations made it possible to identify the complex of curative factors inherent in the natural mineral sylvinite constructions. These factors are believed to create the optimal conditions for the efficient management of the patients presenting with dermatological, cardiological, obstetrical, and stomatological problems. PMID- 28091490 TI - [The influence of the training of the muscular component of the musculo-venous pump in the lower extremities on the clinical course of varicose vein disease]. AB - : Investigations of the influence of the training of the muscular component of the musculo-venous pump in the lower extremities on the clinical course of varicose vein disease and correction of the step cycle are currently underway. AIM: The objective of the present study was to evaluate the impact of the training of the muscular component of the musculo-venous pump in the lower extremities and of the correction of the step cycle on the quality of life of the patients presenting with varicose vein disease. MATERIAL AND METHODS: The study included 22 patients with varicose veins in the lower extremities (CEAP clinical class C3 or C4). All the patients performed, twice daily during a total of 60 days, a specially designed complex of 7 exercise intended to strengthen the posterior muscle group of the lower legs and correct the step cycle. RESULTS: After 60 days, all the patients reported the appearance of the subjective signs suggesting positive dynamics of their condition. The following statistically significant changes were documented: reduction of the malleolar circumference, improvement of integral characteristics of the quality of life as evaluated with the use of the international questionnaire for the patients with chronic lower limb venous insufficiency (CIVIQ), normalization of the frequency and amplitude of modal oscillations in the soleus muscle revealed by electromyography. The correction of foot rolling muscles and the sequence of activation of the muscles involved in the first five phases of the cycle step increases the strength of contraction of the soleus muscle, promotes venous blood flow in the proximal direction, and thereby enhances the efficiency of the venous outflow. CONCLUSION: The development of adequate gain skills, the correction of the step cycle, and the strengthening of the muscular component of the musculo-venous pump lead to the improvement of the clinical course of varicose vein disease. The proposed complex of physical exercises provides an effective and pathogenetically sound additional tool for the treatment of the patients presenting with this pathology. PMID- 28091492 TI - [The experience with the early rehabilitation of the children presenting with the vertebral cerebrospinal injury]. AB - This article was designed to report the experience with the provision of early rehabilitation care to the children suffering from a spinal-cord injury (SCI) that was gained at the Clinical and Research Institute of Urgent Pediatric Surgery and Traumatology. The authors have developed and describe the combined multidisciplinary approach making it possible to promote the recovery of the children presenting with SCI at the first stage of the rehabilitative treatment. They distinguish three basic periods in the early rehabilitation of the children with this condition, defined the main goals of rehabilitation and the role of each specialist in their achievement. The results of the work provided the basis for the development of a stepwise approach for the extension of the rehabilitation measures and the solution of the tasks facing rehabilitation of the patients with vertebral cerebrospinal injuries. The correction of nutritive losses was found to be a most important component of the early stage of the rehabilitation process preceding the full-scale rehabilitative treatment. The role of various technical devices designed for the patients' re-education in functional motor activities, development and acquisition of the sustained self service skills, enhancement of the patient's mobility, and improvement of his/her quality of life is discussed. The importance of the early beginning of the rehabilitation measures for the children suffering from a vertebral cerebrospinal injury has been confirmed. PMID- 28091491 TI - [The multifunctional therapy of various forms of irritable bowel syndrome]. AB - : Irritable bowel syndrome (IBS) is a pathological condition characterized by heterogeneous etiology, pathogenesis, and clinical symptoms. These characteristics dictate the necessity of prescribing multiple medications for the treatment of IBS. Such compulsory polypharmacy inadvertently enhances the risk of adverse reactions to the treatment, increases its cost, and impairs compliance on the part of the patients. The objective of the present study was to evaluate the effectiveness of the administration of the clorine-bromine brine with the use of sinusoidal modulated current electrophoresis (SMC-phoresis) for the treatment of different forms of IBS. THE PATIENTS AND METHODS: We examined and treated 80 patients with different forms of IBS. The patients were divided into two equal groups comprised of 40 patients each. The patients of the study group were treated with the use of SMS-phoresis of the bromine-chlorine brine based at the "Varzi-yatchi" spa and health resort (the Udmurt Republic) making use of the sparing or stimulating techniques depending on the type of IBS. Each therapeutic course consisted of 10-12 sessions. The patients in the group of comparison received the standard pharmaceutical treatment for IBS (myotropic anti-spasmodics and lactulose). The emphasis was laid on the evaluation of dynamics of the intestinal motor function in different variants of IBS with the use of the EGS-4M apparatus based on the GSRS questionnaire (Gastrointestinal Symptom Rating Scale). Special attention was given to the interpretation of the main gastrointestinal syndromes and the evaluation of the quality of life of the patients in the course of the treatment and after its completion. RESULTS: The main symptoms of IBS after a course of SMC-phoresis with the natural brine were significantly less pronounced compared to those in the patients managed by means of standard pharmacotherapy. Positive dynamics in the clinical picture of the disease had beneficial influence on the quality of life of the patients which approached that of the healthy subjects in the group of comparison. The results of colonography suggested the presence of various types of disturbances of motor function of the intestines. SMC-phoresis of the natural chlorine-bromine brine had a positive influence on dyskinesia associated with diarrhea and constipation associated with IBS, while the effect of the standard pharmaceutical treatment was unidirectional and significantly inferior to it in terms of efficiency. CONCLUSION: The use of complementary therapy can provide a better clinical outcome of IBS and to a greater extent improve the quality of life of the patients presenting with various forms of this pathology. PMID- 28091493 TI - [The health promotion programs for the children based at health promotion institutions]. AB - The research carried out in the framework of the health promotion programs for the children made it possible to obtain characteristics of the patients admitted to health promotion facilities, identify the risk factors for the development of acute respiratory diseases, and substantiate the principles of the differentiated approach to the rehabilitation of such patients based at the institutions of this type taking into consideration the health group to which a concrete patient is referred and the risk factors of acute respiratory diseases. The feasibility and effectiveness of the addition of aromatherapy and treatment with the use of polarized light into the health promotion programs for the children presenting with acute respiratory diseases that they develop during the period of adaptation based at health promotion institutions are discussed. PMID- 28091494 TI - [The significance of the rehabilitative potential for the combined medical rehabilitation of the patients presenting with acute cerebral circulation problems]. AB - This article outlines the current WHO concepts of the process of rehabilitation with special reference to the consideration and the analysis of the concept of rehabilitation potential, its structure, levels, and functions of each level. The main stages and the aim of the comprehensive medical and psychological rehabilitation of the patients presenting with acute cerebrovascular accidents (ACVA) are discussed. The importance of the recoverable and reusable resources at the biological and psychological levels that may play the role of compensatory functions in the patients suffering from acute cerebral circulation disorders is emphasized. The three main stages of the rehabilitation process for the ACVA patients ("diagnostic", "therapeutic", and "verifying") are described. The necessity of the development of the systemic strategy for medical and psychological rehabilitation of the post-stroke patients is substantiated taking into account the criteria for allocating them to the groups of either early or late rehabilitation and the group of patients suffering from the consequences of acute cerebral circulation disorders. It may allow to achieve the optimal level of the patients' well-being, in accordance with the rehabilitation potential currently attainable for the patients undergoing acute cerebrovascular accidents. PMID- 28091495 TI - [Psychopathological characteristics and social functioning of the schizophrenic patients with the T allele of the MTHFR677C>T polymorphism]. AB - AIM: To compare the severity of psychopathological symptoms and characteristics of personal and social functioning in patients with schizophrenia, carriers of different alleles of the MTHFR677C>T polymorphism. MATERIAL AND METHODS: One hundred and fifty patients diagnosed with schizophrenia were genotyped for the MTHFR677C>T polymorphism, some of them were examined using psychometric scales and tests (PANSS, SANS, PSP, CDSS, a battery of cognitive tests etc). RESULTS AND CONCLUSION: Patients with the MTHFR677T variant had greater severity of negative symptoms regardless of psychometric instruments used in the study, greater severity of schizophrenia disorder in whole measured with the PANSS General psychopathological symptoms subscale, higher scores on the PANSS cognitive cluster and lower levels of personal and social functioning measured with the PSP compared to the patients with the MTHFR677CS genotype. The results of psychometric testing are in line with significant differences of MTHFR677T allele carriers from those with the MTHFR677CS genotype in the number of disable patients and the use of different types of psychiatric services. The differences were not related to sex, age, illness duration and depressive symptoms measured with CDSS and PANSS "depression/anxiety" factor. PMID- 28091496 TI - [Clinical presentations of neurological forms of hepatolenticular degeneration in Primorsky Krai]. AB - Clinical characteristics of neurological forms of hepatolenticular degeneration (HLD) were studied in one of the regions of Russia (Primorsky Krai) in the sample of 111 patients at the wide age range (average 35.6 years); mean time since the diagnosis was 13.7 years. According to N.V. Konovalov's classification, 4 groups of patients were identified: I arrhythmic-hyperkinetic form (n=61), II extra pyramidal cortical form (n=30), III tremulous form (n=15), IV tremulous-rigid form (n=6). A main body of clinical manifestations of the pathology at the stage of cerebral signal of HLD manifestation was determined; three degrees of the severity of its course were established. Correlation between clinical HLD manifestation severityand the time since the diagnosis of neurological stage of the disease and its form was noted. Age parameters of the development of different extra-pyramidal disturbances and predictors of the severity of the course were specified. PMID- 28091497 TI - [Hyperprolactinemia associated with neuroleptic treatment: clinical characteristics and an impact on sexual function]. AB - AIM: To study clinical characteristics of antipsychotic-induced hyperprolactinemia (AIH) and an impact of AIH on sexual function in patients with mental disorders treated with neuroleptics for a long time. MATERIAL AND METHODS: A cross-sectional study of 244 consecutive psychiatric in-patients (F/M=140/104) with mental disorders currently taking antipsychotics was carried out. The patients were screened for serum prolactin, sex hormones and gonadotropin levels. The UKU Side effects rating scale (UKU) was used to assess side-effects. For assessment of sexual dysfunction, the Psychotropic-Related Sexual Dysfunction Questionnaire (PRSexDQ) was administered. RESULTS AND CONCLUSION: Asymptomatic AIH was found in 16% of females and in 37% of males. AIH caused menstrual disorders (oligomenorrhea and amenorrhea), galactorrhea in females. AIH was associated with libido decrease and life quality impairment due to sexual dysfunctions in patients of both genders. AIH was associated with orgasm delay and vaginal dryness during sexual intercourse in females. In men, AIH was associated with erectile dysfunction. In contrast to pituitary tumor and idiopathic hyperprolactinemia, there was no association between AIH and weight gain and/or obesity, and hypogonadism in patients of both genders. PMID- 28091498 TI - [The differences in the estimation of depression severity by psychiatrists and patients during the combined treatment with agomelatine (a multicenter study "EMOTSIA")]. AB - AIM: To compare the prognosis of depression severity estimated by the physician and by the patient based on the treatment outcome. MATERIAL AND METHODS: One hundred and seven patients with depression were examined. Mental status was assessed with HAM-D, SHAPS, CGI-S, CGI-I, PGI-S, PGI-I and VAS. A data analysis was performed. RESULTS: There were differences in the estimation of depression severity by psychiatrists and patients. Moreover, the scores on HAM-D and CGI-S were not consistent when assessed by psychiatrists. As the severity of depression decreased and patient's state improved during the treatment with agomelatine (valdoxan), the assessments of the changes by the psychiatrist and the patient became similar. CONCLUSION: Agomelatine (valdoxan) is effective and tolerable in the treatment of depression of any severity. The differences between the psychiatrist's and patient's estimation of the depression severity at baseline using different psychometric scales can level the prognostic value of treatment outcome. PMID- 28091499 TI - [Migraine and depression: efficacy and safety of antidepressant therapy]. AB - AIM: To study an influence of depression on the course of migraine and the efficacy of antidepressants in treatment of depression associated with migraine. MATERIAL AND METHODS: The study consisted of 544 patients with migraine including 240 patients with depression. Patients were examined at the first visit, after 6 months (visit 2) and one year (visit 3). Then patients were interviewed by phone once a year (visits 5, 6, 7, 8), they were asked about a number of days with migraine. Patients with depression were treated with antidepressants. Results and sonclusion. Six types of migraine course were determined: persistent episodic migraine, migraine remission, episodic migraine chronification, chronic migraine regress to episodic migraine, persistent chronic migraine, remitted or wavelike chronic migraine. The presence of depression and skin allodynia predicted the development of persistent and remitted chronic migraine. The effect of antidepressants of different groups was noted in treatment of patients with the combination of chronic migraine and depression. The most pronounced effect was observed with tricyclic antidepressants, the smallest one when selective serotonin reuptake inhibitors were used. PMID- 28091500 TI - [Pathogenetic aspects of the use of cytoflavine in the treatment of shronic post traumatic headache]. AB - AIM: To evaluate the results of using cytoflavin in the treatment of chronic post traumatic headache and analyze possible mechanisms for implementation of therapeutic effects of the drug. MATERIAL AND METHODS: The study included 76 patients (23 men and 53 women) aged 29 - 57 years (mean age - 38.2 +/- 8.3). All patients received standard basic therapy with simple or combination analgesics. In addition to standard treatment, 36 patients received cytoflavin in the dosage of two tablets twice a day for 30 days. Results and sonclusion. At the beginning, at the end and 25 days after the completion of treatment, the intensity and frequency of headache as well as the severity of asthenic and depressive symptoms were analyzed. As a result of treatment in the cytoflavin group, there was a significant regression of asthenic and depressive symptoms, which was consistent with the previous studies. Positive changes in the indicators analyzed were correlated with the decrease in the frequency of cephalalgia. Since cytoflavin has no analgesic properties, the results are indirect evidence for the significance of psychopathological factors in the pathogenesis of chronic post traumatic headache. PMID- 28091501 TI - [Possible applications of rac-hopantenic acid in the treatment of anxiety and depressive disorders in patients with chronic cerebral ischemia]. AB - AIM: To evaluate the efficacy and tolerability of rac-hopantenic acid (pantogam activ) in patients with mixed anxiety-depressive disorder and anxiety-depressive disorder with chronic cerebral ischemia. MATERIAL AND METHODS: A total of 50 patients were examined (30 patients in the main group, 20 patients in the control one). All patients received standard therapy with SSRI antidepressants. Rac hopantenic acid at a daily dose of 1200 mg was included in the complex therapy of patients of the main group. Duration of the therapy with rac-hopantenic acid was 21 days. Psychopathological, psychometric and detailed somatic examinations were performed. RESULTS: In the main group, the combination of pantogam activ and antidepressants promoted distinct balanced nootropic, antidepressant and anxiolytic effects, as well as the improvement of health outcomes. The reduced total number of adverse events (less frequent drowsiness and headaches) was noted as well. CONCLUSION: The rapid and reliable reduction of anxiety, depression and cognitive impairment during concomitant therapy with antidepressants and pantogam activ was identified. PMID- 28091502 TI - [Combined therapy of cerebrovascular disorders with neuroprotectors]. AB - Safety of drugs is one of the priorities of modern medicine. The goal of pharmacological treatment is a search for effective and safety drugs as well as a study of possibilities of combined using of the drugs with opposite effects. Basing on the possible therapeutic interactions, 2-ethyl-6-methyl-3 hydroxypyridine succinate can be recommended as a basic medication for patients with cerebrovascular diseases to normalize the energy metabolism of brain cells. The complex use of cholinergic drugs with different neuroprotective effects is effective from the first hours after admission. Cholinergic drugs (citicoline or choline alfoscerate) as the drugs of the first choice should be justified taking into consideration dysfunction of the brain system activation. Patient's age, the level of consciousness, somatic pathology, previous strokes, cognitive impairment are predictors of treatment efficacy. PMID- 28091503 TI - [Cocarnit in the treatment of diabetic polyneuropathy]. AB - AIM: Study the effect of cocarnit on the peripheral nerve functions in patients with diabetic distal sensorimotor polyneuropathy (DDSP). MATERIAL AND METHODS: Thirty patients with DDSP, aged from 27 to 65 years, mean 55.3+/-10.8 years, with diabetes mellitus duration from 2 to 20 years (mean 8.0+/-5.8 years) received cocarnit as monotherapy in dose of 2 ml daily during 9 days. The intensity and character of pain were assessed with PainDetect, TSS and NSS inquirers, quality of-life was measured with the Russian version of EuroQol-5D questionnarie. The state of the neuromotor apparatus was studied using stimulation electromyography with the analysis of conduction along motor fibers of peripheral nerves and evoked sympathetic skin responses (ESSR). RESULTS: After treatment, there was the improvement of scores on PainDetect by 44.3% (p<0.05), NSS by 41.9% (p<0.05) and TSS by 103.9% (p<0.05). An increase in the impulse conduction velocity, M- and S response amplitudes and normalization of ESSR parameters were observed. In the first turn, the improvement was related to damaged nerves. CONCLUSION: Cocarnit is an effective drug in the treatment of patients with DDSP. PMID- 28091504 TI - [Evaluation of the antitumor potential of cerebrolysin]. AB - AIM: To investigate the effect of cerebrolysin on the growth and metastasis of malignant tumors in mice (a model of lung carcinoma Lewis). MATERIAL AND METHODS: The study was performed on 60 male mice, hybrids F1 (the age of 2-2.5 months, body weight 19-22g.). Transplantable epidermoid Lewis lung carcinoma (LLC) was used as a standard experimental model to evaluate the properties of the potential antitumor agents. Experimental animals were administered a single intraperitoneal injection of cerebrolysin in doses of 524 mg/kg (n=20) and 1800 mg/kg (n=20) daily from 2 to 16 days after tumor transplantation. RESULTS AND CONCLUSION: Compared with the control group (n=20), cerebrolysin induced growth inhibition of LLC during the treatment (7 to 16 days). An impact of the drug was accompanied by the inhibition of the tumor growth rate by 10-15% (p<0.05). Cerebrolysin demonstrated a dose-dependent effect of reducing the large number of metastases: a number of large metastases significantly decreased by 30-50% with the increase of cerebrolysin dose (p=0.01). Cerebrolysin can significantly suppress the growth rate of Lewis lung carcinoma. PMID- 28091505 TI - [The individual and combined antioxidant effects of citicoline and ethylmethylhydroxypyridini succinas]. AB - AIM: To study the antioxidant status of patients with chronic cerebral ischemia (CCI) during the individual treatment with 2-ethyl-6-methyl-3-hydroxypyridine succinate (neurox) and in the combination with citicoline (neipilept). MATERIAL AND METHODS: A study included 40 patients, 18 men and 22 women, aged from 54 to 72 years, with CCI, stage 2, at the decompensation stage complicated with the hypertensive crisis and/or arrhythmia. RESULTS AND CONCLUSION: A significant increase in the serum superoxide dismutase activity after the complex therapy with neurox and neipilept was demonstrated compared to patients treated with neurox. A study of reduced sulfur-hydroxy groups in patients treated with 2-ethyl 6-methyl-3-hydroxypyridine-succinate and patients treated with the combination of 2-ethyl-6-methyl-3-hydroxypyridine-succinate and citicoline, revealed a significant increase in the number of reduced SH- groups after the treatment with neurox compared to the combined use of neurox and neipilept. PMID- 28091506 TI - [Genomic instability in the brain: chromosomal mosaicism in schizophrenia]. AB - AIM: Experimental verification of the hypothesis about the possible involvement of the mosaic genome variations (mosaic aneuploidy) in the pathogenesis of a number of mental illnesses, including schizophrenia and autism: a genetic study of the level of mosaic genome variations in cells of the brain autopsy tissues in healthy controls and schizophrenia. MATERIAL AND METHODS: Autopsy brain tissues of 15 unaffected controls and 15 patients with schizophrenia were analyzed by molecular cytogenetic methods to determine the frequency of chromosomal mutations (the mosaic aneuploidy) in neural human cells. The original collection of chromosome-enumeration DNA probes to autosomes 1, 9, 15, 16, 18 and the sex chromosomes X and Y was used for the interphase cytogenetic analysis of chromosomes in the cells of the brain. RESULTS AND CONCLUSION: The frequency of low-level aneuploidy per individual chromosome was 0.54% (median - 0.53%; 95% confidence interval (CI) CI - 0.41-1.13%) in controls and 1.66% (median - 1.55%; 95% CI -1.32-2.12%) in schizophrenia (p=0.000013). Thus, the three-fold increase in aneuploidy frequency in the brain in schizophrenia was detected. It is suggested that mosaic aneuploidy, as a significant biological marker of genomic instability, may lead to genetic imbalance and abnormal functional activity of neural cells and neural networks in schizophrenia. PMID- 28091507 TI - [Alterations of serum neurospecific proteins concentrations in patients with metabolic syndrome]. AB - AIM: Metabolic syndrome (MS) - is a complex of metabolic, hormonal and clinical disorders which are risk factors for cardiovascular disease. The study aimed to determine the markers NSE, GFAP, MMP-9 in patients with MS and to assess their prognostic value in the development of acute stroke. MATERIAL AND METHODS: A cross-sectional analytical studyincluded 157 patients stratified into 4groups (control group, patients with MS, patients with ischemic stroke and patients with ischemic stroke and MS). Laboratory examinations included measurements of MS parameters(total cholesterol, blood glucose, cholesterol, HDL and LDL, triglycerides) and concentrations of neurospecific markers NSE, GFAP and MMP-9 by ELISA. RESULTS AND CONCLUSION: A relationship between MS and increased concentration of NSE is found. This indicates the presence of neuronal brain injury in patients with metabolic syndrome. There were no changesin the concentrations of GFAP and MMP-9 in patients with MS. PMID- 28091508 TI - [The epidemiology of epilepsy in children in the Republic of Belarus]. AB - AIM: To study the incidence of epilepsy in children in the Republic of Belarus based on the data of the Republican Centre for disease control. MATERIAL AND METHODS: Statistical analysis of the incidence and morbidity of epilepsy in children and adolescents was performed. Based on this analysis, the contribution of epilepsy in the neurologic morbidity in childhood was analyzed. RESULTS AND CONCLUSION: The morbidity and incidence of epilepsy in children averaged 0.35 and 2.4 per 1000 of the child population, respectively, over the last 6 years (2009 2014). The peak incidence of primary epilepsy is between the ages 1-4 years (0.43 per 1000 population for 12 years (2003-2014), of incidence of epilepsy among children, aged 0-17 years, are stable with no significant fluctuations for the last 6 years (2009-2014). The proportion of epilepsy in the structure of neurological disorders (9.51%) remained unchanged. In the period 2003-2014, general incidence of epilepsy among children, aged 5-9 years, has increased from 2.2 to 2.6 per 1000 child population (p<0.05) and from 2.5 to 3.8 (p<0.05) in children, aged 15-18 years, with no changes in the morbidity. PMID- 28091509 TI - [Outcomes and treatment of myasthenic crisis]. AB - AIM: The analysis of fatal outcomes of myasthenic crisis in patients with myasthenia. MATERIAL AND METHODS: The data on 19 patients with myastheniccrisis admitted at the Moscow Regional Research and Clinical Institute ("MONIKI") over 12 years (1997-2009) have been summarized. RESULTS AND CONCLUSION: There are more than 600 patients with myasthenia in the Moscow region, including 13% patients with onset after 60 years. Seventeen patients of 19 were in the intensive care unit. Total death occurred in 7 cases (36.6%). Myocardial infarction, bilateral confluent pneumonia and hemorrhagic pulmonary edema caused death. All patients had concomitant diseases: hypertension, myocardial changes, hyperglycemia and others. Steroids and plasmapheresis were used for treatment of myasthenic crisis. The authors believe that methods of treatment of myasthenic crisis that does not lead to complications in elderly age and are suitable for patients with concomitant diseases, who can't be treated with glucocorticoids and plasmapheresis, should be used in clinical neurology. Normal human intravenous immunoglobulin is recommended in these cases. PMID- 28091510 TI - [The climatotherapy of depressive states in patients with chronic obstructive pulmonary disease]. AB - AIM: To study an effect of sanatorium-climate therapy in patients with chronic obstructive pulmonary disease (COPD) with comorbid depressive disorders. MATERIAL AND METHODS: The scale of depression CES-D and the Spielberger-Khanin scale of anxiety were administered to 146 patients with COPD, treated in the sanatorium in the south coast of Crimea. RESULTS AND CONCLUSION: Depressive disorders were identified in 72.6% of patients, including moderate and severe disorders (41.8%). Anxiety disorders were found in 67.1% of patients. The severity of anxiety depressive disorders was correlated with the COPD degree. It was shown that the sanatorium-resort treatment has a beneficial effect on mental status of the patients. The best results were demonstrated for mild degree of COPD. PMID- 28091511 TI - [The differential diagnosis of amyotrophic lateral sclerosis and subacute herpes virus myelitis]. AB - Differential diagnosis of incurable and potentially curable neurological diseases is an urgent problem of modern neurology. The authors present a case report of subacute herpes virus myelitis, a rare complication of herpes infection by Varicella-Zoster virus. The differential diagnosis with amyotrophic lateral sclerosis is described. PMID- 28091512 TI - [Impressive (sensory) alalia]. AB - Receptive language disorder [F80.2 ICD=10] is the most severe children's language disorder: the child with normal intellect and hearing does not start to comprehend the speech of others and as a consequence - to speak. The etiology is unknown, the prognosis unfavorable. The profound study of the syndrome is necessary for the clarification of diagnostic criteria and creation of the system of adequate medical and pedagogical help, and also in the theoretical aspect. We performed an analysis of the symptomatology and progress of the syndrome (17 children of 2-10 years of age) based on data of onto-, neuro- and psycholinguistics. The analysis reveals two variants of the course of the syndrome; it clarifies behavioral diagnostic criteria and substantiates principal directions of the pedagogical work aimed at habilitation. Also, we discuss possible nature of the brain damage, which in our opinion can help planning medical research. PMID- 28091513 TI - [The First Russian Consensus on the Multilevel Abobotulinumtoxin A Injections in Spastic Forms of Cerebral Palsy]. AB - Spasticity treatment is one of the key aspects of the contemporary cerebral palsy (CP) rehabilitation that influences on the effectiveness of other methods. The paper presents the first Russian document that unites the recommendations for the BTA treatment of CP and could be used as the guideline for the multilevel injections. The Russian consensus on the multilevel botulinum toxin A (BTA) treatment of spastic CP is based on the international data and the results of national studies. The authors describe typical CP spasticity patterns in the upper and lower extremities, give recommended intervals for the BTA (Abobotulinum toxin A) dosages for the whole injection procedure and for the separate muscles. The method of dosage calculation for functional segments is also described. Attention is paid to the frequency, optimal intervals between the repeated injections and the whole duration of BTA treatment. The authors discuss effectiveness and safety of BTA, factors that potentially influence the results of the injections, including ultrasound and electromyography control, and indications for the continuation and termination of treatment. PMID- 28091514 TI - Novel strain properties distinguishing sporadic prion diseases sharing prion protein genotype and prion type. AB - In most human sporadic prion diseases the phenotype is consistently associated with specific pairings of the genotype at codon 129 of the prion protein gene and conformational properties of the scrapie PrP (PrPSc) grossly identified types 1 and 2. This association suggests that the 129 genotype favours the selection of a distinct strain that in turn determines the phenotype. However, this mechanism cannot play a role in the phenotype determination of sporadic fatal insomnia (sFI) and a subtype of sporadic Creutzfeldt-Jakob disease (sCJD) identified as sCJDMM2, which share 129 MM genotype and PrPSc type 2 but are associated with quite distinct phenotypes. Our detailed comparative study of the PrPSc conformers has revealed major differences between the two diseases, which preferentially involve the PrPSc component that is sensitive to digestion with proteases (senPrPSc) and to a lesser extent the resistant component (resPrPSc). We conclude that these variations are consistent with two distinct strains in sFI and sCJDMM2, and that the rarer sFI is the result of a variant strain selection pathway that might be favoured by a different brain site of initial PrPSc formation in the two diseases. PMID- 28091515 TI - Protein crystal nucleation in pores. AB - The most powerful method for protein structure determination is X-ray crystallography which relies on the availability of high quality crystals. Obtaining protein crystals is a major bottleneck, and inducing their nucleation is of crucial importance in this field. An effective method to form crystals is to introduce nucleation-inducing heterologous materials into the crystallization solution. Porous materials are exceptionally effective at inducing nucleation. It is shown here that a combined diffusion-adsorption effect can increase protein concentration inside pores, which enables crystal nucleation even under conditions where heterogeneous nucleation on flat surfaces is absent. Provided the pore is sufficiently narrow, protein molecules approach its walls and adsorb more frequently than they can escape. The decrease in the nucleation energy barrier is calculated, exhibiting its quantitative dependence on the confinement space and the energy of interaction with the pore walls. These results provide a detailed explanation of the effectiveness of porous materials for nucleation of protein crystals, and will be useful for optimal design of such materials. PMID- 28091516 TI - Osteopontin regulates macrophage activation and osteoclast formation in hypertensive patients with vascular calcification. AB - Vascular calcification (VC) is a highly regulated ectopic mineral deposition process involving immune cell infiltration in the vasculatures, which has been recognized to be promoted by hypertension. The matricellular glycoprotein osteopontin (OPN) is strongly induced in myeloid cells as a potential inflammatory mediator of vascular injury. This study aims to examine whether OPN is involved in the regulation of macrophage activation and osteoclast formation in hypertensive subjects with VC. We firstly found an increased proportion of CD11c+CD163- pro-inflammatory peripheral monocytes in hypertensive subjects with VC compared to those without VC by flow cytometric analysis. Primary cultured macrophages from hypertensive subjects with VC also showed altered expression profile of inflammatory factors and higher serum OPN level. Exogenous OPN promoted the differentiation of peripheral monocytes into an alternative, anti inflammatory phenotype, and inhibited macrophage-to-osteoclast differentiation from these VC patients. In addition, calcified vessels showed increased osteoclasts accumulation accompanied with decreased macrophages infiltration in the of hypertensive subjects. Taken together, these demonstrated that OPN exerts an important role in the monocytes/macrophage phenotypic differentiation from hypertensive patients with VC, which includes reducing inflammatory factor expression and attenuating osteoclast formation. PMID- 28091517 TI - Unraveling the enhanced Oxygen Vacancy Formation in Complex Oxides during Annealing and Growth. AB - The reduction of oxides during annealing and growth in low pressure processes is a widely known problem. We hence investigate the influence of mere annealing and of growth in vacuum systems to shed light on the reasons behind the reduction of perovskites. When comparing the existing literature regarding the reduction of the perovskite model material SrTiO3 it is conspicuous that one finds different oxygen pressures required to achieve reduction for vacuum annealing and for chemically controlled reducing atmospheres. The unraveling of this discrepancy is of high interest for low pressure physical vapor depositions of thin films heterostructures to gain further understanding of the reduction of the SrTiO3. For thermal annealing, our results prove the attached measurement devices (mass spectrometer/ cold cathode gauge) to be primarily responsible for the reduction of SrTiO3 in the deposition chamber by shifting the thermodynamic equilibrium to a more reducing atmosphere. We investigated the impact of our findings on the pulsed laser deposition growth at low pressure for LaAlO3/SrTiO3. During deposition the reduction triggered by the presence of the laser plume dominates and the impact of the measurement devices plays a minor role. During post annealing a complete reoxidization of samples is inhibited by an insufficient supply of oxygen. PMID- 28091518 TI - Insights into the molecular basis of long-term storage and survival of sperm in the honeybee (Apis mellifera). AB - Honeybee males produce ejaculates consisting of large numbers of high quality sperm. Because queens never re-mate after a single mating episode early in life, sperm are stored in a specialised organ for years but the proximate mechanisms underlying this key physiological adaptation are unknown. We quantified energy metabolism in honeybee sperm and show that the glycolytic metabolite glyceraldehyde-3-phosphate (GA3P) is a key substrate for honeybee sperm survival and energy production. This reliance on non-aerobic energy metabolism in stored sperm was further supported by our findings of very low levels of oxygen inside the spermatheca. Expression of GA3P dehydrogenase (GAPDH), the enzyme involved in catabolism of GA3P, was significantly higher in stored compared to ejaculated sperm. Therefore, long-term sperm storage seems facilitated by the maintenance of non-aerobic energy production, the need for only the ATP-producing steps of glycolysis and by avoiding sperm damage resulting from ROS production. We also confirm that honeybee sperm is capable of aerobic metabolism, which predominates in ejaculated sperm while they compete for access to the spermatheca, but is suppressed during storage. Consequently, the remarkable reproductive traits of honeybees are proximately achieved by differential usage of energy production pathways to maximise competitiveness and minimise damage of sperm. PMID- 28091519 TI - Universal and uniquely human factors in spontaneous number perception. AB - A capacity for nonverbal numerical estimation is widespread among humans and animals. However, it is currently unclear whether numerical percepts are spontaneously extracted from the environment and whether nonverbal perception is influenced by human exposure to formal mathematics. We tested US adults and children, non-human primates, and numerate and innumerate Tsimane' adults on a quantity task in which they could choose to categorize sets of dots on the basis of number alone, surface area alone or a combination of the two. Despite differences in age, species and education, subjects are universally biased to base their judgments on number as opposed to the alternatives. Numerical biases are uniquely enhanced in humans compared to non-human primates, and correlated with degree of mathematics experience in both the US and Tsimane' groups. We conclude that humans universally and spontaneously extract numerical information, and that human nonverbal numerical perception is enhanced by symbolic numeracy. PMID- 28091520 TI - Phantom vortices: hidden angular momentum in ultracold dilute Bose-Einstein condensates. AB - Vortices are essential to angular momentum in quantum systems such as ultracold atomic gases. The existence of quantized vorticity in bosonic systems stimulated the development of the Gross-Pitaevskii mean-field approximation. However, the true dynamics of angular momentum in finite, interacting many-body systems like trapped Bose-Einstein condensates is enriched by the emergence of quantum correlations whose description demands more elaborate methods. Herein we theoretically investigate the full many-body dynamics of the acquisition of angular momentum by a gas of ultracold bosons in two dimensions using a standard rotation procedure. We demonstrate the existence of a novel mode of quantized vorticity, which we term the phantom vortex. Contrary to the conventional mean field vortex, can be detected as a topological defect of spatial coherence, but not of the density. We describe previously unknown many-body mechanisms of vortex nucleation and show that angular momentum is hidden in phantom vortices modes which so far seem to have evaded experimental detection. This phenomenon is likely important in the formation of the Abrikosov lattice and the onset of turbulence in superfluids. PMID- 28091522 TI - Cr incorporated phase transformation in Y2O3 under ion irradiation. AB - Under irradiation, chemical species can redistribute in ways not expected from equilibrium behavior. In oxide-dispersed ferritic alloys, the phenomenon of irradiation-induced Cr redistribution at the metal/oxide interfaces has drawn recent attention. Here, the thermal and irradiation stability of the FeCr/Y2O3 interface has been systematically studied. Trilayer thin films of 90 nm Fe - 20 at.% Cr (1st layer)/100 nm Y2O3 (2nd layer)/135 nm Fe - 20 at.% Cr (3rd layer) were deposited on MgO substrates at 500 degrees C. After irradiation, Cr diffuses towards and enriches the FeCr/Y2O3 interface. Further, correlated with Cr redistributed into the oxide, an amorphous layer is generated at the interface. In the Y2O3 layer, the original cubic phase is observed to transform to the monoclinic phase after irradiation. Meanwhile, nanosized voids, with relatively larger size at interfaces, are also observed in the oxide layer. First principles calculations reveal that Cr substitution of Y interstitials in Y2O3 containing excess Y interstitials is favored and the irradiation-induced monoclinic phase enhances this process. Our findings provide new insights that may aid in the development of irradiation resistant oxide-dispersed ferritic alloys. PMID- 28091521 TI - Mechanisms of intrinsic resistance and acquired susceptibility of Pseudomonas aeruginosa isolated from cystic fibrosis patients to temocillin, a revived antibiotic. AB - The beta-lactam antibiotic temocillin (6-alpha-methoxy-ticarcillin) shows stability to most extended spectrum beta-lactamases, but is considered inactive against Pseudomonas aeruginosa. Mutations in the MexAB-OprM efflux system, naturally occurring in cystic fibrosis (CF) isolates, have been previously shown to reverse this intrinsic resistance. In the present study, we measured temocillin activity in a large collection (n = 333) of P. aeruginosa CF isolates. 29% of the isolates had MICs <= 16 mg/L (proposed clinical breakpoint for temocillin). Mutations were observed in mexA or mexB in isolates for which temocillin MIC was <=512 mg/L (nucleotide insertions or deletions, premature termination, tandem repeat, nonstop, and missense mutations). A correlation was observed between temocillin MICs and efflux rate of N-phenyl-1-naphthylamine (MexAB-OprM fluorescent substrate) and extracellular exopolysaccharide abundance (contributing to a mucoid phenotype). OpdK or OpdF anion-specific porins expression decreased temocillin MIC by ~1 two-fold dilution only. Contrarily to the common assumption that temocillin is inactive on P. aeruginosa, we show here clinically-exploitable MICs on a non-negligible proportion of CF isolates, explained by a wide diversity of mutations in mexA and/or mexB. In a broader context, this work contributes to increase our understanding of MexAB-OprM functionality and help delineating how antibiotics interact with MexA and MexB. PMID- 28091523 TI - Origin of anti-tumor activity of the cysteine-containing GO peptides and further optimization of their cytotoxic properties. AB - Antitumor GO peptides have been designed as dimerization inhibitors of prominent oncoprotein mucin 1. In this study we demonstrate that activity of GO peptides is independent of the level of cellular expression of mucin 1. Furthermore, these peptides prove to be broadly cytotoxic, causing cell death also in normal cells such as dermal fibroblasts and endometrial mesenchymal stem cells. To explore molecular mechanism of their cytotoxicity, we have designed and tested a number of new peptide sequences containing the key CxC or CxxC motifs. Of note, these sequences bear no similarity to mucin 1 except that they also contain a pair of proximal cysteines. Several of the new peptides turned out to be significantly more potent than their GO prototypes. The results suggest that cytotoxicity of these peptides stems from their (moderate) activity as disulfide oxidoreductases. It is expected that such peptides, which we have termed DO peptides, are involved in disulfide-dithiol exchange reaction, resulting in formation of adventitious disulfide bridges in cell proteins. In turn, this leads to a partial loss of protein function and rapid onset of apoptosis. We anticipate that coupling DO sequences with tumor-homing transduction domains can create a potentially valuable new class of tumoricidal peptides. PMID- 28091524 TI - Formate simultaneously reduces oxidase activity and enhances respiration in Campylobacter jejuni. AB - The foodborne microaerophilic pathogen, Campylobacter jejuni, possesses a periplasmic formate dehydrogenase and two terminal oxidases, which serve to metabolize formate and facilitate the use of oxygen as a terminal electron acceptor, respectively. Formate, a primary energy source for C. jejuni, inhibits oxidase activity in other bacteria. Here, we hypothesized that formate might affect both energy metabolism and microaerobic survival in C. jejuni. Subsequently, we showed that C. jejuni 81-176 (wildtype) exhibited enhanced chemoattraction to and respiration of formate in comparison to other organic acids. Formate also significantly increased C. jejuni's growth, motility, and biofilm formation under microaerobic (5% O2) conditions. However, formate reduced oxidase activity under microaerobic conditions as well as aerotolerance and biofilm formation under ambient oxygen conditions. The expression of genes encoding the ribonucleotide reductase (RNR) and proteins that facilitate the use of alternative electron acceptors generally increased in the presence of formate. Taken together, formate might play a role in optimizing C. jejuni's adaptation to the oxygen-limited gastrointestinal tract of the host. By affecting oxidase activity, formate possibly facilitates shuttling electrons to alternative acceptors, while likely conserving limited oxygen concentrations for other essential functions such as DNA synthesis via RNR which is required for C. jejuni's growth. PMID- 28091525 TI - A fibrolytic potential in the human ileum mucosal microbiota revealed by functional metagenomic. AB - The digestion of dietary fibers is a major function of the human intestinal microbiota. So far this function has been attributed to the microorganisms inhabiting the colon, and many studies have focused on this distal part of the gastrointestinal tract using easily accessible fecal material. However, microbial fermentations, supported by the presence of short-chain fatty acids, are suspected to occur in the upper small intestine, particularly in the ileum. Using a fosmid library from the human ileal mucosa, we screened 20,000 clones for their activities against carboxymethylcellulose and xylans chosen as models of the major plant cell wall (PCW) polysaccharides from dietary fibres. Eleven positive clones revealed a broad range of CAZyme encoding genes from Bacteroides and Clostridiales species, as well as Polysaccharide Utilization Loci (PULs). The functional glycoside hydrolase genes were identified, and oligosaccharide break down products examined from different polysaccharides including mixed-linkage beta-glucans. CAZymes and PULs were also examined for their prevalence in human gut microbiome. Several clusters of genes of low prevalence in fecal microbiome suggested they belong to unidentified strains rather specifically established upstream the colon, in the ileum. Thus, the ileal mucosa-associated microbiota encompasses the enzymatic potential for PCW polysaccharide degradation in the small intestine. PMID- 28091526 TI - A disrupted transsulphuration pathway results in accumulation of redox metabolites and induction of gametocytogenesis in malaria. AB - Intra-erythrocytic growth of malaria parasite is known to induce redox stress. In addition to haem degradation which generates reactive oxygen species (ROS), the parasite is also thought to efflux redox active homocysteine. To understand the basis underlying accumulation of homocysteine, we have examined the transsulphuration (TS) pathway in the parasite, which is known to convert homocysteine to cysteine in higher eukaryotes. Our bioinformatic analysis revealed absence of key enzymes in the biosynthesis of cysteine namely cystathionine-beta-synthase and cystathionine-gamma-lyase in the parasite. Using mass spectrometry, we confirmed the absence of cystathionine, which is formed by enzymatic conversion of homocysteine thereby confirming truncation of TS pathway. We also quantitated levels of glutathione and homocysteine in infected erythrocytes and its spent medium. Our results showed increase in levels of these metabolites intracellularly and in culture supernatants. Our results provide a mechanistic basis for the long-known occurrence of hyperhomocysteinemia in malaria. Most importantly we find that homocysteine induces the transcription factor implicated in gametocytogenesis namely AP2-G and consequently triggers sexual stage conversion. We confirmed this observation both in vitro using Plasmodium falciparum cultures, and in vivo in the mouse model of malaria. Our study implicates homocysteine as a potential physiological trigger of gametocytogenesis. PMID- 28091528 TI - Super-emitters in natural gas infrastructure are caused by abnormal process conditions. AB - Effectively mitigating methane emissions from the natural gas supply chain requires addressing the disproportionate influence of high-emitting sources. Here we use a Monte Carlo simulation to aggregate methane emissions from all components on natural gas production sites in the Barnett Shale production region (Texas). Our total emission estimates are two-thirds of those derived from independent site-based measurements. Although some high-emitting operations occur by design (condensate flashing and liquid unloadings), they occur more than an order of magnitude less frequently than required to explain the reported frequency at which high site-based emissions are observed. We conclude that the occurrence of abnormal process conditions (for example, malfunctions upstream of the point of emissions; equipment issues) cause additional emissions that explain the gap between component-based and site-based emissions. Such abnormal conditions can cause a substantial proportion of a site's gas production to be emitted to the atmosphere and are the defining attribute of super-emitting sites. PMID- 28091527 TI - Sox17 drives functional engraftment of endothelium converted from non-vascular cells. AB - Transplanting vascular endothelial cells (ECs) to support metabolism and express regenerative paracrine factors is a strategy to treat vasculopathies and to promote tissue regeneration. However, transplantation strategies have been challenging to develop, because ECs are difficult to culture and little is known about how to direct them to stably integrate into vasculature. Here we show that only amniotic cells could convert to cells that maintain EC gene expression. Even so, these converted cells perform sub-optimally in transplantation studies. Constitutive Akt signalling increases expression of EC morphogenesis genes, including Sox17, shifts the genomic targeting of Fli1 to favour nearby Sox consensus sites and enhances the vascular function of converted cells. Enforced expression of Sox17 increases expression of morphogenesis genes and promotes integration of transplanted converted cells into injured vessels. Thus, Ets transcription factors specify non-vascular, amniotic cells to EC-like cells, whereas Sox17 expression is required to confer EC function. PMID- 28091530 TI - The autofluorescence characteristics of bacterial intracellular and extracellular substances during the operation of anammox reactor. AB - Anammox is a cost-effective process to treat nitrogenous wastewater. In this work, excitation-emission matrix (EEM) fluorescence spectroscopy was used to characterize the intracellular and extracellular substances of anammox sludge during reactor operation of 276 days. Four main fluorophores were identified from the intracellular substances. Two main protein-like fluorophores were identified from the extracellular substances. Correlation analysis revealed that intracellular 420 peak and humic-like peak had strong correlation with nitrogen removal rate. The two intracellular protein-like peaks had high correlation with MLVSS and MLVSS growth rate. Correlation analysis between different fluorophores discovered that the two peaks in each of these three groups-two intracellular protein-like peaks, two humic acid-like peaks and the two extracellular protein like peaks had strong intercorrelation, which gave evidence of their homology. A specific method for fluorescence monitoring of anammox reactor were put forward, which included typical fluorescence indexes and their possible values for different operation phases. PMID- 28091529 TI - Long non-coding RNA Linc-RAM enhances myogenic differentiation by interacting with MyoD. AB - Long non-coding RNAs (lncRNAs) are important regulators of diverse biological processes. Here we report on functional identification and characterization of a novel long intergenic non-coding RNA with MyoD-regulated and skeletal muscle restricted expression that promotes the activation of the myogenic program, and is therefore termed Linc-RAM (Linc-RNA Activator of Myogenesis). Linc-RAM is transcribed from an intergenic region of myogenic cells and its expression is upregulated during myogenesis. Notably, in vivo functional studies show that Linc RAM knockout mice display impaired muscle regeneration due to the differentiation defect of satellite cells. Mechanistically, Linc-RAM regulates expression of myogenic genes by directly binding MyoD, which in turn promotes the assembly of the MyoD-Baf60c-Brg1 complex on the regulatory elements of target genes. Collectively, our findings reveal the functional role and molecular mechanism of a lineage-specific Linc-RAM as a regulatory lncRNA required for tissues-specific chromatin remodelling and gene expression. PMID- 28091531 TI - TNF-alpha regulates the proteolytic degradation of ST6Gal-1 and endothelial cell cell junctions through upregulating expression of BACE1. AB - Endothelial dysfunction and monocyte adhesion to vascular endothelial cells are two critical steps in atherosclerosis development, and emerging evidence suggests that protein sialylation is involved in these processes. However, the mechanism underlying this phenomenon remains incompletely elucidated. In this study, we demonstrated that treatment with the proinflammatory cytokine TNF-alpha disrupted vascular endothelial cell-cell tight junctions and promoted monocyte endothelial cell adhesion. Western blotting and Sambucus nigra lectin (SNA) blotting analyses revealed that TNF-alpha treatment decreased alpha-2, 6-sialic acid transferase 1 (ST6Gal-I) levels and downregulated VE-Cadherin alpha-2, 6 sialylation. Further analysis demonstrated that TNF-alpha treatment upregulated beta-site amyloid precursor protein enzyme 1 (BACE1) expression, thus resulting in sequential ST6Gal-I proteolytic degradation. Furthermore, our results revealed that PKC signaling cascades were involved in TNF-alpha-induced BACE1 upregulation. Together, these results indicated that the proinflammatory cytokine TNF-alpha impairs endothelial tight junctions and promotes monocyte-endothelial cell adhesion by upregulating BACE1 expression through activating PKC signaling and sequentially cleaving ST6Gal-I. Thus, inhibition of BACE1 expression may be a new approach for treating atherosclerosis. PMID- 28091533 TI - ATP Binding Cassette Transporter ABCA7 Regulates NKT Cell Development and Function by Controlling CD1d Expression and Lipid Raft Content. AB - ABCA7 is an ABC transporter expressed on the plasma membrane, and actively exports phospholipid complexes from the cytoplasmic to the exocytoplasmic leaflet of membranes. Invariant NKT (iNKT) cells are a subpopulation of T lymphocytes that recognize glycolipid antigens in the context of CD1d-mediated antigen presentation. In this study, we demonstrate that ABCA7 regulates the development of NKT cells in a cell-extrinsic manner. We found that in Abca7-/- mice there is reduced expression of CD1d accompanied by an alteration in lipid raft content on the plasma membrane of thymocytes and antigen presenting cells. Together, these alterations caused by absence of ABCA7 negatively affect NKT cell development and function. PMID- 28091534 TI - Fisheries portfolio diversification and turnover buffer Alaskan fishing communities from abrupt resource and market changes. AB - Abrupt shifts in natural resources and their markets are a ubiquitous challenge to human communities. Building resilient social-ecological systems requires approaches that are robust to uncertainty and to regime shifts. Harvesting diverse portfolios of natural resources and adapting portfolios in response to change could stabilize economies reliant on natural resources and their markets, both of which are prone to unpredictable shifts. Here we use fisheries catch and revenue data from Alaskan fishing communities over 34 years to test whether diversification and turnover in the composition of fishing opportunities increased economic stability during major ocean and market regime shifts in 1989. More than 85% of communities show reduced fishing revenues following these regime shifts. However, communities with the highest portfolio diversity and those that could opportunistically shift the composition of resources they harvest, experienced negligible or even positive changes in revenue. Maintaining diversity in economic opportunities and enabling turnover facilitates sustainability of communities reliant on renewable resources facing uncertain futures. PMID- 28091532 TI - Development of the Neuroimmune Modulator Ibudilast for the Treatment of Alcoholism: A Randomized, Placebo-Controlled, Human Laboratory Trial. AB - Current directions in medication development for alcohol use disorder (AUD) emphasize the need to identify novel molecular targets and efficiently screen new compounds aimed at those targets. Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor and was recently found to reduce alcohol intake in rats by ~50%. To advance medication development for AUD, the present study consists of a randomized, crossover, double-blind, placebo-controlled laboratory study of IBUD in nontreatment-seeking individuals with current (ie, past month) mild-to-severe AUD. This study tested the safety, tolerability, and initial human laboratory efficacy of IBUD (50 mg b.i.d.) on primary measures of subjective response to alcohol as well as secondary measures of cue- and stress-induced changes in craving and mood. Participants (N=24) completed two separate 7-day intensive outpatient protocols that included daily visits for medication administration and testing. Upon reaching a stable target dose of IBUD (or matched placebo), participants completed a stress-exposure session (day 5; PM), an alcohol cue exposure session (day 6; AM), and an i.v. alcohol administration session (day 6; PM). Participants stayed overnight after the alcohol administration, and discharge occurred on day 7 of the protocol. Medication conditions were separated by a washout period that was ?7 days. IBUD was well tolerated; however, there were no medication effects on primary measures of subjective response to alcohol. IBUD was associated with mood improvements on the secondary measures of stress exposure and alcohol cue exposure, as well as reductions in tonic levels of craving. Exploratory analyses revealed that among individuals with higher depressive symptomatology, IBUD attenuated the stimulant and mood-altering effects of alcohol as compared with placebo. Together, these findings extend preclinical demonstrations of the potential utility of IBUD for the treatment of AUD and suggest that depressive symptomatology should be considered as a potential moderator of efficacy for pharmacotherapies with neuroimmune effects, such as IBUD. PMID- 28091535 TI - Visualization of the role of host heme on the virulence of the heme auxotroph Streptococcus agalactiae. AB - Heme is essential for several cellular key functions but is also toxic. Whereas most bacterial pathogens utilize heme as a metabolic cofactor and iron source, the impact of host heme during bacterial infection remains elusive. The opportunist pathogen Streptococcus agalactiae does not synthesize heme but still uses it to activate a respiration metabolism. Concomitantly, heme toxicity is mainly controlled by the HrtBA efflux transporter. Here we investigate how S. agalactiae manages heme toxicity versus benefits in the living host. Using bioluminescent bacteria and heme-responsive reporters for in vivo imaging, we show that the capacity of S. agalactiae to overcome heme toxicity is required for successful infection, particularly in blood-rich organs. Host heme is simultaneously required, as visualized by a generalized infection defect of a respiration-negative mutant. In S. agalactiae, HrtBA expression responds to an intracellular heme signal via activation of the two-component system HssRS. A hssRS promoter-driven intracellular luminescent heme sensor was designed to identify host compartments that supply S. agalactiae with heme. S. agalactiae acquires heme in heart, kidneys, and liver, but not in the brain. We conclude that S. agalactiae response to heme is organ-dependent, and its efflux may be particularly relevant in late stages of infection. PMID- 28091536 TI - Simple, Efficient and Controllable Synthesis of Iodo/Di-iodoarenes via Ipsoiododecarboxylation/Consecutive Iodination Strategy. AB - A practical, efficient, and operationally simple strategy for the ipsoiododecarboxylation and di-iodination of aromatic carboxylic acids using the low-cost commercial reagent succinimide (NIS) as iodine source is reported. This iodination or di-iodination process can be easily controlled through reaction conditions, thereby providing corresponding iodination or di-iodination products with high yields. Furthermore, these two reactions can be easily scaled up to gram-scale by using palladium catalyst (0.66 mol%), which provides high isolated yield. PMID- 28091537 TI - Spatio-temporal coordination among functional residues in protein. AB - The microscopic basis of communication among the functional sites in bio macromolecules is a fundamental challenge in uncovering their functions. We study the communication through temporal cross-correlation among the binding sites. We illustrate via Molecular Dynamics simulations the properties of the temporal cross-correlation between the dihedrals of a small protein, ubiquitin which participates in protein degradation in eukaryotes. We show that the dihedral angles of the residues possess non-trivial temporal cross-correlations with asymmetry with respect to exchange of the dihedrals, having peaks at low frequencies with time scales in nano-seconds and an algebraic tail with a universal exponent for large frequencies. We show the existence of path for temporally correlated degrees of freedom among the functional residues. We explain the qualitative features of the cross-correlations through a general mathematical model. The generality of our analysis suggests that temporal cross correlation functions may provide convenient theoretical framework to understand bio-molecular functions on microscopic basis. PMID- 28091538 TI - MircoRNA-145 promotes activation of hepatic stellate cells via targeting kruppel like factor 4. AB - Kruppel-like Factor 4 (KLF4), a target gene of miR-145, can negatively regulate lung fibrosis. However, the potential role of KLF4 and miR-145 in hepatic stellate cells (HSCs) activation or in hepatic fibrosis keeps unclear. This study aims to characterize miR-145 and KLF4 in activated HSCs and liver cirrhotic, and the underlying molecular basis. miR-145 was significantly up-regulated, while KLF4 was dramatically down-regulated during the activation of rat primary HSCs and TGF-betatreated HSCs. Furthermore, miR-145 mimics induced and inhibition of miR-145 reduced alpha-SMA and COL-I expression in primary HSCs. Additionally, the mRNA and protein levels of KLF4 in the liver of cirrhotic patients and rats were significantly down-regulated. alpha-SMA and COL-I were increased after inhibition of KLF4 by specific shRNA in primary HSCs. Forced KLF4 expression led to a reduction of alpha-SMA and COL-I expression in HSCs. miR-145 promotes HSC activation and liver fibrosis by targeting KLF4. PMID- 28091540 TI - Retraction: Heavy metal removal from MSS fly ash by thermal and chlorination treatments. PMID- 28091539 TI - An electromagnetic modulator based on electrically controllable metamaterial analogue to electromagnetically induced transparency. AB - Electromagnetically induced transparency (EIT) is a promising technology for the enhancement of light-matter interactions, and recent demonstrations of the EIT analogue realized in artificial micro-structured medium have remarkably reduced the extreme requirement for experimental observation of EIT spectrum. In this paper, we propose to electrically control the EIT-like spectrum in a metamaterial as an electromagnetic modulator. A diode acting as a tunable resistor is loaded in the gap of paired wires to inductively tune the magnetic resonance, which induces remarkable modulation on the EIT-like spectrum through the metamaterial sample. The experimental measurements confirmed that the prediction of electromagnetic modulation in three narrow bands on the EIT-like spectrum, and a modulation contrast of up to 31 dB was achieved on the transmission through the metamaterial. Our results may facilitate the study on active/dynamical technology in translational metamaterials, which connect extraordinary manipulations on the flow of light in metamaterials, e.g., the exotic EIT, and practical applications in industry. PMID- 28091542 TI - On-line Ammonia Sensor and Invisible Security Ink by Fluorescent Zwitterionic Spirocyclic Meisenheimer Complex. AB - Ammonia is not only a highly important gas for civilization but also contribute significantly for climate change and human health hazard. Highly sensitive ammonia sensor has been developed from a fluorescent zwitterionic spirocyclic Meisenheimer complex. Moreover, formation of this Meisenheimer complex can also be utilized for selective as well as naked eye instant detection of nitro aromatic explosive picric acid. The presence of a quaternary nitrogen atom directly attached to the spiro carbon is the unique feature of this Meisenheimer complex. This excellent photoluminescent (PL) Meisenheimer complex has two distinct stimuli responsive sites. One is sensitive towards acid while the other one is towards the base. These two positions can be modulated by adding one equivalent acid and one equivalent base to result two new products which are non fluorescent. One of these two non fluorescent species was found very exciting because of its UV/Vis transparency. Utilizing this concept we have fabricated an on-line sensor for measuring ammonia in dry or humid and condensing sewer air. The sensor was robust against ambient temperature and humidity variation. We have also developed an invisible ink from this Meisenheimer complex, with potential application for security purpose. PMID- 28091541 TI - Apelin receptor homodimer-oligomers revealed by single-molecule imaging and novel G protein-dependent signaling. AB - The apelin receptor (APJ) belongs to family A of the G protein-coupled receptors (GPCRs) and is a potential pharmacotherapeutic target for heart failure, hypertension, and other cardiovascular diseases. There is evidence APJ heterodimerizes with other GPCRs; however, the existence of APJ homodimers and oligomers remains to be investigated. Here, we measured APJ monomer-homodimer oligomer interconversion by monitoring APJ dynamically on cells and compared their proportions, spatial arrangement, and mobility using total internal reflection fluorescence microscopy, resonance energy transfer, and proximity biotinylation. In cells with <0.3 receptor particles/MUm2, approximately 60% of APJ molecules were present as dimers or oligomers. APJ dimers were present on the cell surface in a dynamic equilibrium with constant formation and dissociation of receptor complexes. Furthermore, we applied interference peptides and MALDI-TOF mass spectrometry to confirm APJ homo-dimer and explore the dimer-interfaces. Peptides corresponding to transmembrane domain (TMD)1, 2, 3, and 4, but not TMD5, 6, and 7, disrupted APJ dimerization. APJ mutants in TMD1 and TMD2 also decreased bioluminescence resonance energy transfer of APJ dimer. APJ dimerization resulted in novel functional characteristics, such as a distinct G-protein binding profile and cell responses after agonist stimulation. Thus, dimerization may serve as a unique mechanism for fine-tuning APJ-mediated functions. PMID- 28091543 TI - Fluctuations in Evolutionary Integration Allow for Big Brains and Disparate Faces. AB - In theory, evolutionary modularity allows anatomical structures to respond differently to selective regimes, thus promoting morphological diversification. These differences can then influence the rate and direction of phenotypic evolution among structures. Here we use geometric morphometrics and phenotypic matrix statistics to compare rates of craniofacial evolution and estimate evolvability in the face and braincase modules of a clade of teleost fishes (Gymnotiformes) and a clade of mammals (Carnivora), both of which exhibit substantial craniofacial diversity. We find that the face and braincase regions of both clades display different degrees of integration. We find that the face and braincase evolve at similar rates in Gymnotiformes and the reverse in Carnivora with the braincase evolving twice as fast as the face. Estimates of evolvability and constraints in these modules suggest differential responses to selection arising from fluctuations in phylogenetic integration, thus influencing differential rates of skull-shape evolution in these two clades. PMID- 28091544 TI - Ultrasound prediction of abnormal infant development in hypertensive pregnant women in the second and third trimester. AB - The objective was to assess the sensitivities and accuracies of Doppler ultrasound parameters in the second and third trimester of hypertensive pregnancies in determining perinatal outcomes. 1,054 pregnancies were retrospectively categorized into three groups (healthy pregnancies (HP, n = 988), pregnancies of hypertensive women (HypP, n = 30) and high-risk hypertension pregnancies (HRHypP, n = 36), depending on gestational hypertension as well as fetal birth weights and pregnancy outcomes. Systolic/diastolic ratio (S/D), resistance index (RI), pulsatility index (PI) of the bilateral uterine artery, umbilical artery and vein as well as venous flow velocity data were monitored by Doppler ultrasound. At 20-27 and 28-32 gestational weeks, uterine artery PIs and RIs were significantly higher in the HRHypP group than in the HP and HypP patients. At gestational weeks 20-27 and 28-32 left plus right PI data with cut off values of 2.35 and 1.73 indicated a risk of stillbirth, premature pregnancy termination and a birth weight of less than 2,500 g with sensitivities of 94.4% and 93.1% as well as specificities of 95.2% and 90.1%, respectively. PMID- 28091545 TI - Improvement of thermoelectric properties and their correlations with electron effective mass in Cu1.98SxSe1-x. AB - Sulphur doping effects on the crystal structures, thermoelectric properties, density-of-states, and effective mass in Cu1.98SxSe1-x were studied based on the electrical and thermal transport property measurements, and first-principles calculations. The X-ray diffraction patterns and Rietveld refinements indicate that room temperature Cu1.98SxSe1-x (x = 0, 0.02, 0.08, 0.16) and Cu1.98SxSe1-x (x = 0.8, 0.9, 1.0) have the same crystal structure as monoclinic-Cu2Se and orthorhombic-Cu2S, respectively. Sulphur doping can greatly enhance zT values when x is in the range of 0.8<= * <=1.0. Furthermore, all doped samples show stable thermoelectric compatibility factors over a broad temperature range from 700 to 1000 K, which could greatly benefit their practical applications. First principles calculations indicate that both the electron density-of-sates and the effective mass for all the compounds exhibit non-monotonic sulphur doping dependence. It is concluded that the overall thermoelectric performance of the Cu1.98SxSe1-x system is mainly correlated with the electron effective mass and the density-of-states. PMID- 28091546 TI - Prebiotic galactooligosaccharides activate mucin and pectic galactan utilization pathways in the human gut symbiont Bacteroides thetaiotaomicron. AB - Galactooligosaccharides (GOS) are prebiotic carbohydrates that impart changes in the gut bacterial composition of formula-fed infants to more closely resemble that of breast-fed infants. Consuming human milk oligosaccharides (HMOs) provides specific bacterial strains with an advantage for colonizing the infant intestine. These same effects are seen in infants after GOS consumption, however GOS are very complex mixtures and the underlying molecular mechanisms of how GOS mimic HMOs are relatively unknown. Here we studied the effects of GOS utilization on a prominent gut symbiont, Bacteroides thetaiotaomicron, which has been previously shown to consume HMOs via mucin O-glycan degradation pathways. We show that several pathways for targeting O-mucin glycans are activated in B. thetaiotaomicron by GOS, as well as the galactan utilization sytem. Characterization of the endo-galactanase from this system identified activity on various longer GOS substrates while a subset of GOS compounds were identified as potential activators of mucin glycan metabolism in B. thetaiotaomicron. Our results show that GOS functions as an inducer of mucin-glycan pathways while providing a nutrient source in the form of beta-(1 -> 4)-galactan. These metabolic features of GOS mixtures may serve to explain the beneficial effects that are seen for GOS supplemented infant formula. PMID- 28091547 TI - Corydalis edulis Maxim. Promotes Insulin Secretion via the Activation of Protein Kinase Cs (PKCs) in Mice and Pancreatic beta Cells. AB - Corydalis edulis Maxim., a widely grown plant in China, had been proposed for the treatment for type 2 diabetes mellitus. In this study, we found that C. edulis extract (CE) is protective against diabetes in mice. The treatment of hyperglycemic and hyperlipidemic apolipoprotein E (ApoE)-/- mice with a high dose of CE reduced serum glucose by 28.84% and serum total cholesterol by 17.34% and increased insulin release. We also found that CE significantly enhanced insulin secretion in a glucose-independent manner in hamster pancreatic beta cell (HIT T15). Further investigation revealed that CE stimulated insulin exocytosis by a protein kinase C (PKC)-dependent signaling pathway and that CE selectively activated novel protein kinase Cs (nPKCs) and atypical PKCs (aPKCs) but not conventional PKCs (cPKCs) in HIT-T15 cells. To the best of our knowledge, our study is the first to identify the PKC pathway as a direct target and one of the major mechanisms underlying the antidiabetic effect of CE. Given the good insulinotropic effect of this herbal medicine, CE is a promising agent for the development of new drugs for treating diabetes. PMID- 28091548 TI - Genome Analysis of a Zygomycete Fungus Choanephora cucurbitarum Elucidates Necrotrophic Features Including Bacterial Genes Related to Plant Colonization. AB - A zygomycete fungus, Choanephora cucurbitarum is a plant pathogen that causes blossom rot in cucurbits and other plants. Here we report the genome sequence of Choanephora cucurbitarum KUS-F28377 isolated from squash. The assembled genome has a size of 29.1 Mbp and 11,977 protein-coding genes. The genome analysis indicated that C. cucurbitarum may employ a plant pathogenic mechanism similar to that of bacterial plant pathogens. The genome contained 11 genes with a Streptomyces subtilisin inhibitor-like domain, which plays an important role in the defense against plant immunity. This domain has been found only in bacterial genomes. Carbohydrate active enzyme analysis detected 312 CAZymes in this genome where carbohydrate esterase family 6, rarely found in dikaryotic fungal genomes, was comparatively enriched. The comparative genome analysis showed that the genes related to sexual communication such as the biosynthesis of beta-carotene and trisporic acid were conserved and diverged during the evolution of zygomycete genomes. Overall, these findings will help us to understand how zygomycetes are associated with plants. PMID- 28091549 TI - Urinary proteomics can define distinct diagnostic inflammatory arthritis subgroups. AB - Current diagnostic tests applied to inflammatory arthritis lack the necessary specificity to appropriately categorise patients. There is a need for novel approaches to classify patients with these conditions. Herein we explored whether urinary proteomic biomarkers specific for different forms of arthritis (rheumatoid arthritis (RA), psoriatic arthritis (PsA), osteoarthritis (OA)) or chronic inflammatory conditions (inflammatory bowel disease (IBD)) can be identified. Fifty subjects per group with RA, PsA, OA or IBD and 50 healthy controls were included in the study. Two-thirds of these populations were randomly selected to serve as a training set, while the remaining one-third was reserved for validation. Sequential comparison of one group to the other four enabled identification of multiple urinary peptides significantly associated with discrete pathological conditions. Classifiers for the five groups were developed and subsequently tested blind in the validation test set. Upon unblinding, the classifiers demonstrated excellent performance, with an area under the curve between 0.90 and 0.97 per group. Identification of the peptide markers pointed to dysregulation of collagen synthesis and inflammation, but also novel inflammatory markers. We conclude that urinary peptide signatures can reliably differentiate between chronic arthropathies and inflammatory conditions with discrete pathogenesis. PMID- 28091551 TI - Reversible Martensitic Transformation under Low Magnetic Fields in Magnetic Shape Memory Alloys. AB - Magnetic field-induced, reversible martensitic transformations in NiCoMnIn meta magnetic shape memory alloys were studied under constant and varying mechanical loads to understand the role of coupled magneto-mechanical loading on the transformation characteristics and the magnetic field levels required for reversible phase transformations. The samples with two distinct microstructures were tested along the [001] austenite crystallographic direction using a custom designed magneto-thermo-mechanical characterization device while carefully controlling their thermodynamic states through isothermal constant stress and stress-varying magnetic field ramping. Measurements revealed that these meta magnetic shape memory alloys were capable of generating entropy changes of 14 J kg-1 K-1 or 22 J kg -1 K-1, and corresponding magnetocaloric cooling with reversible shape changes as high as 5.6% under only 1.3 T, or 3 T applied magnetic fields, respectively. Thus, we demonstrate that this alloy is suitable as an active component in near room temperature devices, such as magnetocaloric regenerators, and that the field levels generated by permanent magnets can be sufficient to completely transform the alloy between its martensitic and austenitic states if the loading sequence developed, herein, is employed. PMID- 28091550 TI - Imbalance of Th17/Treg cells in pathogenesis of patients with human leukocyte antigen B27 associated acute anterior uveitis. AB - Th17 and regulatory T cells, involved in the pathogenesis of several autoimmune diseases, are new lineages of CD4+ T helper cells. However, the role of their imbalance in human leukocyte antigen B27-associated acute anterior uveitis has not been elucidated. In our study, the percentages of Th17 and Treg cells, their molecular markers and related factors in peripheral blood of patients and healthy controls were measured by flow cytometry, real-time RT-PCR and ELISA. We observed a remarkable increase of CD4+ and CD4+IL-17+ T cells in peripheral blood of patients compared to controls. The molecular markers and related factors of Th17 cell were also showed a distinct elevation. Interestingly, we observed an obvious decrease of CD4+CD25+Foxp3+ T cells and Foxp3 mRNA level in patients. The ratio of Th17/Treg in patients was dramatically higher than controls. Moreover, the ratio of Th17/Treg cells had a more significantly positive correlation with the disease activity score than Th17 cells whereas Treg cells had a negative correlation. Our findings demonstrated a distinct increase of Th17 cells and a significant decrease of Treg cells in patients compared to controls. The imbalance of Th17 and Treg cells may play a vital role in the pathogenesis of the disease. PMID- 28091552 TI - Dual sources of water overprinting on the low zircon delta18O metamorphic country rocks: Disequilibrium constrained through inverse modelling of partial reequilibration. AB - Since water is only composed of oxygen and hydrogen, delta18O and delta2H values are thus utilized to trace the origin of water(s) and quantify the water-rock interactions. While Triassic high pressure (HP) and ultrahigh pressure (UHP) metamorphic rocks across the Dabie-Sulu orogen in central-eastern China have been well documented, postcollisional magmatism driven hydrothermal systems are little known. Here we show that two sources of externally derived water interactions were revealed by oxygen isotopes for the gneissic country rocks intruded by the early Cretaceous postcollisional granitoids. Inverse modellings indicate that the degree of disequilibrium (doD) of meteoric water interactions was more evident than that of magmatic one (-65 +/- 1o vs. -20 +/- 2 degrees ); the partial reequilibration between quartz and alkali feldspar oxygen isotopes with magmatic water was achieved at 340 degrees C with a water/rock (W/R) ratio of about 1.2 for an open-hydrothermal system; two-stage meteoric water interactions were unraveled with reequilibration temperatures less than 300 degrees C and W/R ratios around 0.4. The lifetime of fossil magmatic hydrothermal system overprinted on the low zircon delta18O orthogneissic country rocks was estimated to maintain up to 50 thousand years (Kyr) through oxygen exchange modellings. Four-stage isotopic evolutions were proposed for the magmatic water interacted gneiss. PMID- 28091553 TI - Shifts in the fluorescence lifetime of EGFP during bacterial phagocytosis measured by phase-sensitive flow cytometry. AB - Phase-sensitive flow cytometry (PSFC) is a technique in which fluorescence excited state decay times are measured as fluorescently labeled cells rapidly transit a finely focused, frequency-modulated laser beam. With PSFC the fluorescence lifetime is taken as a cytometric parameter to differentiate intracellular events that are challenging to distinguish with standard flow cytometry. For example PSFC can report changes in protein conformation, expression, interactions, and movement, as well as differences in intracellular microenvironments. This contribution focuses on the latter case by taking PSFC measurements of macrophage cells when inoculated with enhanced green fluorescent protein (EGFP)-expressing E. coli. During progressive internalization of EGFP-E. coli, fluorescence lifetimes were acquired and compared to control groups. It was hypothesized that fluorescence lifetimes would correlate well with phagocytosis because phagosomes become acidified and the average fluorescence lifetime of EGFP is known to be affected by pH. We confirmed that average EGFP lifetimes consistently decreased (3 to 2 ns) with inoculation time. The broad significance of this work is the demonstration of how high-throughput fluorescence lifetime measurements correlate well to changes that are not easily tracked by intensity only cytometry, which is affected by heterogeneous protein expression, cell-to cell differences in phagosome formation, and number of bacterium engulfed. PMID- 28091554 TI - Advances and Environmental Conditions of Spring Migration Phenology of American White Pelicans. AB - Spring migration phenology of birds has advanced under warming climate. Migration timing of short-distance migrants is believed to be responsive to environmental changes primarily under exogenous control. However, understanding the ecological causes of the advancement in avian spring migration phenology is still a challenge due to the lack of long-term precise location data. We used 11 years of Global Positioning System relocation data to determine four different migration dates of the annual migration cycle of the American white pelican (Pelecanus erythrorhynchos), a short-distance migrant. We also tested the hypothesis that increases in winter temperature and precipitation on the wintering grounds would advance pelican spring migration. Pelican spring departures and arrivals advanced steadily from 2002 to 2011. Spring departure timing exhibited high repeatability at the upper end of migration timing repeatability reported in literature. However, individual spring departure and arrival dates were not related to winter daily temperature, total winter precipitation, and detrended vegetation green-up dates indexed by the normalized difference vegetation index. Despite high repeatability, the observed between-year variation of spring departure dates was still sufficient for the advancement of spring departure timing. PMID- 28091555 TI - Coulomb excitations of monolayer germanene. AB - The feature-rich electronic excitations of monolayer germanene lie in the significant spin-orbit coupling and the buckled structure. The collective and single-particle excitations are diversified by the magnitude and direction of transferred momentum, the Fermi energy and the gate voltage. There are four kinds of plasmon modes, according to the unique frequency- and momentum-dependent phase diagrams. They behave as two-dimensional acoustic modes at long wavelength. However, for the larger momenta, they might change into another kind of undamped plasmons, become the seriously suppressed modes in the heavy intraband e-h excitations, keep the same undamped plasmons, or decline and then vanish in the strong interband e-h excitations. Germanene, silicene and graphene are quite different from one another in the main features of the diverse plasmon modes. PMID- 28091557 TI - The same oculomotor vermal Purkinje cells encode the different kinematics of saccades and of smooth pursuit eye movements. AB - Saccades and smooth pursuit eye movements (SPEM) are two types of goal-directed eye movements whose kinematics differ profoundly, a fact that may have contributed to the notion that the underlying cerebellar substrates are separated. However, it is suggested that some Purkinje cells (PCs) in the oculomotor vermis (OMV) of monkey cerebellum may be involved in both saccades and SPEM, a puzzling finding in view of the different kinematic demands of the two types of eye movements. Such 'dual' OMV PCs might be oddities with little if any functional relevance. On the other hand, they might be representatives of a generic mechanism serving as common ground for saccades and SPEM. In our present study, we found that both saccade- and SPEM-related responses of individual PCs could be predicted well by linear combinations of eye acceleration, velocity and position. The relative weights of the contributions that these three kinematic parameters made depended on the type of eye movement. Whereas in the case of saccades eye position was the most important independent variable, it was velocity in the case of SPEM. This dissociation is in accordance with standard models of saccades and SPEM control which emphasize eye position and velocity respectively as the relevant controlled state variables. PMID- 28091556 TI - VEGF-B promotes recovery of corneal innervations and trophic functions in diabetic mice. AB - Vascular endothelial growth factor (VEGF)-B possesses the capacity of promoting injured peripheral nerve regeneration and restore their sensory and trophic functions. However, the contribution and mechanism of VEGF-B in diabetic peripheral neuropathy remains unclear. In the present study, we investigated the expression and role of VEGF-B in diabetic corneal neuropathy by using type 1 diabetic mice and cultured trigeminal ganglion (TG) neurons. Hyperglycemia attenuated the endogenous expression of VEGF-B in regenerated diabetic corneal epithelium, but not that of VEGF receptors in diabetic TG neurons and axons. Exogenous VEGF-B promoted diabetic corneal nerve fiber regeneration through the reactivation of PI-3K/Akt-GSK3beta-mTOR signaling and the attenuation of neuronal mitochondria dysfunction via the VEGF receptor-1 and neuropilin-1. Moreover, VEGF B improved corneal sensation and epithelial regeneration in both normal and diabetic mice, accompanied with the elevated corneal content of pigment epithelial-derived factor (PEDF). PEDF blockade partially abolished trophic function of VEGF-B in diabetic corneal re-innervation. In conclusion, hyperglycemia suppressed endogenous VEGF-B expression in regenerated corneal epithelium of diabetic mice, while exogenous VEGF-B promoted recovery of corneal innervations and trophic functions through reactivating PI-3K/Akt-GSK-3beta-mTOR signaling, attenuating neuronal oxidative stress and elevating PEDF expression. PMID- 28091558 TI - Soluble urokinase receptor (suPAR) predicts microalbuminuria in patients at risk for type 2 diabetes mellitus. AB - Early identification of patients at risk of developing diabetic nephropathy is essential. Elevated serum concentrations of soluble urokinase receptor (suPAR) associate with diabetes mellitus and predict onset and loss of renal function in chronic kidney disease. We hypothesize, that suPAR may be an early risk indicator for diabetic nephropathy, preceding microalbuminuria. The relationship of baseline suPAR and incident microalbuminuria was assessed in a prospective long term cohort of subjects at increased risk for type 2 diabetes (TULIP, n = 258). Association with albuminuria at later stages of disease was studied in a cross sectional cohort with manifest type 2 diabetes (ICEPHA, n = 266). A higher baseline suPAR was associated with an increased risk of new-onset microalbuminuria in subjects at risk for type 2 diabetes (hazard ratio 5.3 (95% CI 1.1-25.2, p = 0.03) for the highest vs. lowest suPAR quartile). The proportion of subjects with prediabetes at the end of observation was higher in subjects with new-onset microalbuminuria. suPAR consistently correlated with albuminuria in a separate cohort with manifest type 2 diabetes. Elevated baseline suPAR concentrations independently associate with new-onset microalbuminuria in subjects at increased risk of developing type 2 diabetes. suPAR may hence allow for earlier risk stratification than microalbuminuria. PMID- 28091559 TI - Brain Structural Differences between Normal and Obese Adults and their Links with Lack of Perseverance, Negative Urgency, and Sensation Seeking. AB - In order to examine the difference in brain structure between obese and normal weight individuals, and to explore the relationship between the neuroanatomical changes and impulsivity traits, this study used a voxel-based morphometry method to examine gray matter (GM) volume alterations related to impulsive personality traits in obese individuals relative to normal weight. Eighty adults that completed the UPPS-P Impulsive Behavior Scale were analyzed. Possible GM volume alterations were first analyzed at the whole brain level, and then the relationship between regional GM volume differences and UPPS-P scores were examined in selected regions of interest. Reduced GM volumes were found in the frontal and limbic regions in the obese group compared to normal weight individuals. In the normal weight group, lack of perseverance was negatively correlated with GM volume in the anterior cingulate cortex, and negative urgency was negatively correlated with GM volume in the insula. In the obese group, sensation seeking was negatively correlated with GM volume in the left amygdala and right pallidum. These findings might improve our understanding of the relationship between lack of perseverance, negative urgency, and sensation seeking and body weight fluctuations. PMID- 28091560 TI - Spatio-temporal analysis of malaria incidence in the Peruvian Amazon Region between 2002 and 2013. AB - Malaria remains a major public health problem in the Peruvian Amazon where the persistence of high-risk transmission areas (hotspots) challenges the current malaria control strategies. This study aimed at identifying significant space time clusters of malaria incidence in Loreto region 2002-2013 and to determine significant changes across years in relation to the control measures applied. Poisson regression and purely temporal, spatial, and space-time analyses were conducted. Three significantly different periods in terms of annual incidence rates (AIR) were identified, overlapping respectively with the pre-, during, and post- implementation control activities supported by PAMAFRO project. The most likely space-time clusters of malaria incidence for P. vivax and P. falciparum corresponded to the pre- and first two years of the PAMAFRO project and were situated in the northern districts of Loreto, while secondary clusters were identified in eastern and southern districts with the latest onset and the shortest duration of PAMAFRO interventions. Malaria in Loreto was highly heterogeneous at geographical level and over time. Importantly, the excellent achievements obtained during 5 years of intensified control efforts totally vanished in only 2 to 3 years after the end of the program, calling for sustained political and financial commitment for the success of malaria elimination as ultimate goal. PMID- 28091561 TI - Low Temperature CO oxidation over Iron Oxide Nanoparticles Decorating Internal Structures of a Mesoporous Alumina. AB - Using a chemical vapor deposition method with regulated sample temperatures under ambient pressure conditions, we were able to fully decorate the internal structure of a mesoporous Al2O3 bead (~1 mm in particle diameter) with iron oxide nanoparticles (with a mean lateral size of less than 1 nm). The iron oxide decorated Al2O3 showed a high CO oxidation reactivity, even at room temperature. Very little deactivation of the CO oxidation activity was observed with increasing reaction time at ~100 degrees C. Additionally, this catalyst showed high CO oxidation activity, even after annealing at ~900 degrees C under atmospheric conditions (i.e., the structure of the catalysts could be maintained under very harsh treatment conditions). We show that our catalysts have potential for application as oxidation catalysts in industrial processes due to the simplicity of their fabrication process as well as the high and stable catalytic performance. PMID- 28091562 TI - Unravelling a simple method for the low temperature synthesis of silicon nanocrystals and monolithic nanocrystalline thin films. AB - In this work, we present new results on the plasma processing and structure of hydrogenated polymorphous silicon (pm-Si:H) thin films. pm-Si:H thin films consist of a low volume fraction of silicon nanocrystals embedded in a silicon matrix with medium range order, and they possess this morphology as a significant contribution to their growth comes from the impact on the substrate of silicon clusters and nanocrystals synthesized in the plasma. Quadrupole mass spectrometry, ion flux measurements, and material characterization by transmission electron microscopy (TEM) and atomic force microscopy all provide insight on the contribution to the growth by silicon nanocrystals during PECVD deposition. In particular, cross-section TEM measurements show for the first time that the silicon nanocrystals are uniformly distributed across the thickness of the pm-Si:H film. Moreover, parametric studies indicate that the best pm-Si:H material is obtained at the conditions after the transition between a pristine plasma and one containing nanocrystals, namely a total gas pressure around 2 Torr and a silane to hydrogen ratio between 0.05 to 0.1. From a practical point of view these conditions also correspond to the highest deposition rate achievable for a given RF power and silane flow rate. PMID- 28091563 TI - Androgen receptor gene polymorphisms and risk of prostate cancer: a meta analysis. AB - Although the association between CAG and GGN repeats in the androgen receptor gene and prostate cancer risk has been widely studied, it remains controversial from previous meta-analyses and narrative reviews. Therefore, we performed this meta-analysis to provide more precise estimates with sufficient power. A total of 51 publications with 61 studies for CAG repeats and 14 publications with 16 studies for GGN repeats were identified in the meta-analysis. The results showed that short CAG repeats (<22 repeats) carriers presented an elevated risk of prostate cancer than long CAG repeats (>=22) carriers (OR = 1.31, 95% CI 1.16 to 1.47). Prostate cancer cases presented an average fewer CAG repeats (MD = -0.85, 95% CI -1.28 to -0.42) than controls. Short GGN repeats (<=16) carriers presented an increased risk of prostate cancer than long GGN repeats (>16) carriers (OR = 1.38, 95% CI 1.05 to 1.82). In subgroup analyses, the abovementioned significant association was predominantly observed in Caucasian populations. The meta analysis showed that short CAG and GGN repeats in androgen receptor gene were associated with increased risk of prostate cancer, especially in Caucasians. PMID- 28091564 TI - Mitotic catastrophe is a putative mechanism underlying the weak correlation between sensitivity to carbon ions and cisplatin. AB - In cancer therapy today, carbon ion radiotherapy is used mainly as monotherapy, whereas cisplatin is used concomitantly with X-ray radiotherapy. The effectiveness of concomitant carbon ions and cisplatin is unclear. To obtain the information on the mechanisms potentially shared between carbon ions or X-rays and cisplatin, we assessed the correlation of sensitivity to the single treatments. In 20 human cancer cell lines, sensitivity to X-rays strongly correlated with sensitivity to cisplatin, indicating the presence of potentially shared target mechanisms. Interestingly, the correlation of sensitivity to carbon ions and cisplatin was much weaker than that of sensitivity to X-rays and cisplatin, indicating the presence of potentially different target mechanisms between carbon ions and cisplatin. Assessment of clonogenic cell death by 4',6 diamidino-2-phenylindole dihydrochloride staining showed that mitotic catastrophe was more efficiently induced by carbon ions than by the same physical dose of X rays, while apoptosis and senescence were not. These data indicate that the correlation of sensitivity to carbon ions and cisplatin is weaker than that of sensitivity to X-rays and cisplatin, which are helpful as biological basis to understand the potentially shared mechanism among these treatments. Further investigation is mandatory to elucidate the clinical efficacy of carbon ions and cisplatin combination. PMID- 28091565 TI - 18F-FLT and 18F-FDG PET/CT in Predicting Response to Chemoradiotherapy in Nasopharyngeal Carcinoma: Preliminary Results. AB - The purpose of this study was to explore the feasibility of 18F-Fluorothymidine (18F-FLT) and 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in predicting treatment response of nasopharyngeal carcinoma (NPC). Patients with NPC of Stage II-IVB were prospectively enrolled, receiving 2 cycles of neoadjuvant chemotherapy (NACT), followed by concurrent chemoradiotherapy. Each patient underwent pretreatment and post-NACT FLT PET/CT and FDG PET/CT. Standard uptake values (SUV) and tumor volume were measured. Tumor response to NACT was evaluated before radiotherapy by MRI (magnetic resonance imaging), and tumor regression at the end of radiotherapy was evaluated at 55 Gy, according to RECIST 1.1 Criteria. Finally, 20 patients were consecutively enrolled. At the end of radiotherapy, 7 patients reached complete regression while others were partial regression. After 2 cycles of NACT both FLT and FDG parameters declined remarkably. Parameters of FDG PET were more strongly correlated to tumor regression than those of FLT PET.70% SUVmax was the best threshold to define contouring margin around the target. Some residual lesions after NACT showed by MRI were negative in PET/CT. Preliminary results showed both 18F-FDG and 18F-FLT PET have the potential to monitor and predict tumor regression. PMID- 28091566 TI - Efficient generation of hPSC-derived midbrain dopaminergic neurons in a fully defined, scalable, 3D biomaterial platform. AB - Pluripotent stem cells (PSCs) have major potential as an unlimited source of functional cells for many biomedical applications; however, the development of cell manufacturing systems to enable this promise faces many challenges. For example, there have been major recent advances in the generation of midbrain dopaminergic (mDA) neurons from stem cells for Parkinson's Disease (PD) therapy; however, production of these cells typically involves undefined components and difficult to scale 2D culture formats. Here, we used a fully defined, 3D, thermoresponsive biomaterial platform to rapidly generate large numbers of action potential firing mDA neurons after 25 days of differentiation (~40% tyrosine hydroxylase (TH) positive, maturing into 25% cells exhibiting mDA neuron-like spiking behavior). Importantly, mDA neurons generated in 3D exhibited a 30-fold increase in viability upon implantation into rat striatum compared to neurons generated on 2D, consistent with the elevated expression of survival markers FOXA2 and EN1 in 3D. A defined, scalable, and resource-efficient cell culture platform can thus rapidly generate high quality differentiated cells, both neurons and potentially other cell types, with strong potential to accelerate both basic and translational research. PMID- 28091567 TI - Quantifying the relative contributions of different solute carriers to aggregate substrate transport. AB - Determining the contributions of different transporter species to overall cellular transport is fundamental for understanding the physiological regulation of solutes. We calculated the relative activities of Solute Carrier (SLC) transporters using the Michaelis-Menten equation and global fitting to estimate the normalized maximum transport rate for each transporter (Vmax). Data input were the normalized measured uptake of the essential neutral amino acid (AA) L leucine (Leu) from concentration-dependence assays performed using Xenopus laevis oocytes. Our methodology was verified by calculating Leu and L-phenylalanine (Phe) data in the presence of competitive substrates and/or inhibitors. Among 9 potentially expressed endogenous X. laevis oocyte Leu transporter species, activities of only the uniporters SLC43A2/LAT4 (and/or SLC43A1/LAT3) and the sodium symporter SLC6A19/B0AT1 were required to account for total uptake. Furthermore, Leu and Phe uptake by heterologously expressed human SLC6A14/ATB0,+ and SLC43A2/LAT4 was accurately calculated. This versatile systems biology approach is useful for analyses where the kinetics of each active protein species can be represented by the Hill equation. Furthermore, its applicable even in the absence of protein expression data. It could potentially be applied, for example, to quantify drug transporter activities in target cells to improve specificity. PMID- 28091568 TI - Identification of misexpressed genetic elements in hybrids between Drosophila related species. AB - Crosses between close species can lead to genomic disorders, often considered to be the cause of hybrid incompatibility, one of the initial steps in the speciation process. How these incompatibilities are established and what are their causes remain unclear. To understand the initiation of hybrid incompatibility, we performed reciprocal crosses between two species of Drosophila (D. mojavensis and D. arizonae) that diverged less than 1 Mya. We performed a genome-wide transcriptomic analysis on ovaries from parental lines and on hybrids from reciprocal crosses. Using an innovative procedure of co assembling transcriptomes, we show that parental lines differ in the expression of their genes and transposable elements. Reciprocal hybrids presented specific gene categories and few transposable element families misexpressed relative to the parental lines. Because TEs are mainly silenced by piwi-interacting RNAs (piRNAs), we hypothesize that in hybrids the deregulation of specific TE families is due to the absence of such small RNAs. Small RNA sequencing confirmed our hypothesis and we therefore propose that TEs can indeed be major players of genome differentiation and be implicated in the first steps of genomic incompatibilities through small RNA regulation. PMID- 28091569 TI - Epigenetic regulation of Plasmodium falciparum clonally variant gene expression during development in Anopheles gambiae. AB - P. falciparum phenotypic plasticity is linked to the variant expression of clonal multigene families such as the var genes. We have examined changes in transcription and histone modifications that occur during sporogonic development of P. falciparum in the mosquito host. All var genes are silenced or transcribed at low levels in blood stages (gametocyte/ring) of the parasite in the human host. After infection of mosquitoes, a single var gene is selected for expression in the oocyst, and transcription of this gene increases dramatically in the sporozoite. The same PF3D7_1255200 var gene was activated in 4 different experimental infections. Transcription of this var gene during parasite development in the mosquito correlates with the presence of low levels of H3K9me3 at the binding site for the PF3D7_1466400 AP2 transcription factor. This chromatin state in the sporozoite also correlates with the expression of an antisense long non-coding RNA (lncRNA) that has previously been shown to promote var gene transcription during the intraerythrocytic cycle in vitro. Expression of both the sense protein-coding transcript and the antisense lncRNA increase dramatically in sporozoites. The findings suggest a complex process for the activation of a single particular var gene that involves AP2 transcription factors and lncRNAs. PMID- 28091570 TI - Increasing the potential for malaria elimination by targeting zoophilic vectors. AB - Countries in the Asia Pacific region aim to eliminate malaria by 2030. A cornerstone of malaria elimination is the effective management of Anopheles mosquito vectors. Current control tools such as insecticide treated nets or indoor residual sprays target mosquitoes in human dwellings. We find in a high transmission region in India, malaria vector populations show a high propensity to feed on livestock (cattle) and rest in outdoor structures such as cattle shelters. We also find evidence for a shift in vector species complex towards increased zoophilic behavior in recent years. Using a malaria transmission model we demonstrate that in such regions dominated by zoophilic vectors, existing vector control tactics will be insufficient to achieve elimination, even if maximized. However, by increasing mortality in the zoophilic cycle, the elimination threshold can be reached. Current national vector control policy in India restricts use of residual insecticide sprays to domestic dwellings. Our study suggests substantial benefits of extending the approach to treatment of cattle sheds, or deploying other tactics that target zoophilic behavior. Optimizing use of existing tools will be essential to achieving the ambitious 2030 elimination target. PMID- 28091571 TI - Photoacoustic pump-probe tomography of fluorophores in vivo using interleaved image acquisition for motion suppression. AB - In fluorophores, the excited state lifetime can be modulated using pump-probe excitation. By generating photoacoustic (PA) signals using simultaneous and time delayed pump and probe excitation pulses at fluences below the maximum permissible exposure, a modulation of the signal amplitude is observed in fluorophores but not in endogenous chromophores. This provides a highly specific contrast mechanism that can be used to recover the location of the fluorophore using difference imaging. The practical challenges in applying this method to in vivo PA tomography include the typically low concentrations of fluorescent contrast agents, and tissue motion. The former results in smaller PA signal amplitudes compared to those measured in blood, while the latter gives rise to difference image artefacts that compromise the unambiguous and potentially noise limited detection of fluorescent contrast agents. To address this limitation, a method based on interleaved pump-probe image acquisition was developed. It relies on fast switching between simultaneous and time-delayed pump-probe excitation to acquire PA difference signals in quick succession, and to minimise the effects of tissue motion. The feasibility of this method is demonstrated in tissue phantoms and in initial experiments in vivo. PMID- 28091573 TI - Iron Oxide Films Prepared by Rapid Thermal Processing for Solar Energy Conversion. AB - Hematite is a promising and extensively investigated material for various photoelectrochemical (PEC) processes for energy conversion and storage, in particular for oxidation reactions. Thermal treatments during synthesis of hematite are found to affect the performance of hematite electrodes considerably. Herein, we present hematite thin films fabricated via one-step oxidation of Fe by rapid thermal processing (RTP). In particular, we investigate the effect of oxidation temperature on the PEC properties of hematite. Films prepared at 750 degrees C show the highest activity towards water oxidation. These films show the largest average grain size and the highest charge carrier density, as determined from electron microscopy and impedance spectroscopy analysis. We believe that the fast processing enabled by RTP makes this technique a preferred method for investigation of novel materials and architectures, potentially also on nanostructured electrodes, where retaining high surface area is crucial to maximize performance. PMID- 28091572 TI - A computational psychiatry approach identifies how alpha-2A noradrenergic agonist Guanfacine affects feature-based reinforcement learning in the macaque. AB - Noradrenaline is believed to support cognitive flexibility through the alpha 2A noradrenergic receptor (a2A-NAR) acting in prefrontal cortex. Enhanced flexibility has been inferred from improved working memory with the a2A-NA agonist Guanfacine. But it has been unclear whether Guanfacine improves specific attention and learning mechanisms beyond working memory, and whether the drug effects can be formalized computationally to allow single subject predictions. We tested and confirmed these suggestions in a case study with a healthy nonhuman primate performing a feature-based reversal learning task evaluating performance using Bayesian and Reinforcement learning models. In an initial dose-testing phase we found a Guanfacine dose that increased performance accuracy, decreased distractibility and improved learning. In a second experimental phase using only that dose we examined the faster feature-based reversal learning with Guanfacine with single-subject computational modeling. Parameter estimation suggested that improved learning is not accounted for by varying a single reinforcement learning mechanism, but by changing the set of parameter values to higher learning rates and stronger suppression of non-chosen over chosen feature information. These findings provide an important starting point for developing nonhuman primate models to discern the synaptic mechanisms of attention and learning functions within the context of a computational neuropsychiatry framework. PMID- 28091574 TI - An Inert Pesticide Adjuvant Synergizes Viral Pathogenicity and Mortality in Honey Bee Larvae. AB - Honey bees are highly valued for their pollination services in agricultural settings, and recent declines in managed populations have caused concern. Colony losses following a major pollination event in the United States, almond pollination, have been characterized by brood mortality with specific symptoms, followed by eventual colony loss weeks later. In this study, we demonstrate that these symptoms can be produced by chronically exposing brood to both an organosilicone surfactant adjuvant (OSS) commonly used on many agricultural crops including wine grapes, tree nuts and tree fruits and exogenous viral pathogens by simulating a horizontal transmission event. Observed synergistic mortality occurred during the larval-pupal molt. Using q-PCR techniques to measure gene expression and viral levels in larvae taken prior to observed mortality at metamorphosis, we found that exposure to OSS and exogenous virus resulted in significantly heightened Black Queen Cell Virus (BQCV) titers and lower expression of a Toll 7-like-receptor associated with autophagic viral defense (Am18w). These results demonstrate that organosilicone spray adjuvants that are considered biologically inert potentiate viral pathogenicity in honey bee larvae, and guidelines for OSS use may be warranted. PMID- 28091575 TI - Development and Evaluation of a High Density Genotyping 'Axiom_Arachis' Array with 58 K SNPs for Accelerating Genetics and Breeding in Groundnut. AB - Single nucleotide polymorphisms (SNPs) are the most abundant DNA sequence variation in the genomes which can be used to associate genotypic variation to the phenotype. Therefore, availability of a high-density SNP array with uniform genome coverage can advance genetic studies and breeding applications. Here we report the development of a high-density SNP array 'Axiom_Arachis' with 58 K SNPs and its utility in groundnut genetic diversity study. In this context, from a total of 163,782 SNPs derived from DNA resequencing and RNA-sequencing of 41 groundnut accessions and wild diploid ancestors, a total of 58,233 unique and informative SNPs were selected for developing the array. In addition to cultivated groundnuts (Arachis hypogaea), fair representation was kept for other diploids (A. duranensis, A. stenosperma, A. cardenasii, A. magna and A. batizocoi). Genotyping of the groundnut 'Reference Set' containing 300 genotypes identified 44,424 polymorphic SNPs and genetic diversity analysis provided in depth insights into the genetic architecture of this material. The availability of the high-density SNP array 'Axiom_Arachis' with 58 K SNPs will accelerate the process of high resolution trait genetics and molecular breeding in cultivated groundnut. PMID- 28091576 TI - Adjuvant and carrier protein-dependent T-cell priming promotes a robust antibody response against the Plasmodium falciparum Pfs25 vaccine candidate. AB - Humoral immune responses have the potential to maintain protective antibody levels for years due to the immunoglobulin-secreting activity of long-lived plasma cells (LLPCs). However, many subunit vaccines under development fail to generate robust LLPC responses, and therefore a variety of strategies are being employed to overcome this limitation, including conjugation to carrier proteins and/or formulation with potent adjuvants. Pfs25, an antigen expressed on malaria zygotes and ookinetes, is a leading transmission blocking vaccine (TBV) candidate for Plasmodium falciparum. Currently, the conjugate vaccine Pfs25-EPA/Alhydrogel is in Phase 1 clinical trials in the USA and Africa. Thus far, it has proven to be safe and immunogenic, but it is expected that a more potent formulation will be required to establish antibody titers that persist for several malaria transmission seasons. We sought to determine the contribution of carrier determinants and adjuvants in promoting high-titer, long-lived antibody responses against Pfs25. We found that both adjuvants and carrier proteins influence the magnitude and capacity of Pfs25-specific humoral responses to remain above a protective level. Furthermore, a liposomal adjuvant with QS21 and a TLR4 agonist (GLA-LSQ) was especially effective at inducing T follicular helper (Tfh) and LLPC responses to Pfs25 when coupled to immunogenic carrier proteins. PMID- 28091577 TI - Identification of wood-boring beetles (Cerambycidae and Buprestidae) intercepted in trade-associated solid wood packaging material using DNA barcoding and morphology. AB - Global trade facilitates the inadvertent movement of insect pests and subsequent establishment of populations outside their native ranges. Despite phytosanitary measures, nonnative insects arrive at United States (U.S.) ports of entry as larvae in solid wood packaging material (SWPM). Identification of wood-boring larval insects is important for pest risk analysis and management, but is difficult beyond family level due to highly conserved morphology. Therefore, we integrated DNA barcoding and rearing of larvae to identify wood-boring insects in SWPM. From 2012 to 2015, we obtained larvae of 338 longhorned beetles (Cerambycidae) and 38 metallic wood boring beetles (Buprestidae) intercepted in SWPM associated with imported products at six U.S. ports. We identified 265 specimens to species or genus using DNA barcodes. Ninety-three larvae were reared to adults and identified morphologically. No conflict was found between the two approaches, which together identified 275 cerambycids (23 genera) and 16 buprestids (4 genera). Our integrated approach confirmed novel DNA barcodes for seven species (10 specimens) of woodborers not in public databases. This study demonstrates the utility of DNA barcoding as a tool for regulatory agencies. We provide important documentation of potential beetle pests that may cross country borders through the SWPM pathway. PMID- 28091578 TI - Temporal dynamics of cerebellar and motor cortex physiological processes during motor skill learning. AB - Learning motor tasks involves distinct physiological processes in the cerebellum (CB) and primary motor cortex (M1). Previous studies have shown that motor learning results in at least two important neurophysiological changes: modulation of cerebellar output mediated in-part by long-term depression of parallel fiber Purkinje cell synapse and induction of long-term plasticity (LTP) in M1, leading to transient occlusion of additional LTP-like plasticity. However, little is known about the temporal dynamics of these two physiological mechanisms during motor skill learning. Here we use non-invasive brain stimulation to explore CB and M1 mechanisms during early and late motor skill learning in humans. We predicted that early skill acquisition would be proportional to cerebellar excitability (CBI) changes, whereas later stages of learning will result in M1 LTP-like plasticity modifications. We found that early, and not late into skill training, CBI changed. Whereas, occlusion of LTP-like plasticity over M1 occurred only during late, but not early training. These findings indicate a distinct temporal dissociation in the physiological role of the CB and M1 when learning a novel skill. Understanding the role and temporal dynamics of different brain regions during motor learning is critical to device optimal interventions to augment learning. PMID- 28091579 TI - Impact of age and vaccination history on long-term serological responses after symptomatic B. pertussis infection, a high dimensional data analysis. AB - Capturing the complexity and waning patterns of co-occurring immunoglobulin (Ig) responses after clinical B. pertussis infection may help understand how the human host gradually loses protection against whooping cough. We applied bi-exponential modelling to characterise and compare B. pertussis specific serological dynamics in a comprehensive database of IgG, IgG subclass and IgA responses to Ptx, FHA, Prn, Fim2/3 and OMV antigens of (ex-) symptomatic pertussis cases across all age groups. The decay model revealed that antigen type and age group were major factors determining differences in levels and kinetics of Ig (sub) classes. IgG Ptx waned fastest in all age groups, while IgA to Ptx, FHA, Prn and Fim2/3 decreased fast in the younger but remained high in older (ex-) cases, indicating an age-effect. While IgG1 was the main IgG subclass in response to most antigens, IgG2 and IgG3 dominated the anti-OMV response. Moreover, vaccination history plays an important role in post-infection Ig responses, demonstrated by low responsiveness to Fim2/3 in unvaccinated elderly and by elevated IgG4 responses to multiple antigens only in children primed with acellular pertussis vaccine (aP). This work highlights the complexity of the immune response to this re emerging pathogen and factors determining its Ig quantity and quality. PMID- 28091580 TI - Population expansions dominate demographic histories of endemic and widespread Pacific reef fishes. AB - Despite the unique nature of endemic species, their origin and population history remain poorly studied. We investigated the population history of 28 coral reef fish species, close related, from the Gambier and Marquesas Islands, from five families, with range size varying from widespread to small-range endemic. We analyzed both mitochondrial and nuclear sequence data using neutrality test and Bayesian analysis (EBSP and ABC). We found evidence for demographic expansions for most species (24 of 28), irrespective of range size, reproduction strategy or archipelago. The timing of the expansions varied greatly among species, from 8,000 to 2,000,000 years ago. The typical hypothesis for reef fish that links population expansions to the Last Glacial Maximum fit for 14 of the 24 demographic expansions. We propose two evolutionary processes that could lead to expansions older than the LGM: (a) we are retrieving the signature of an old colonization process for widespread, large-range endemic and paleoendemic species or (b) speciation; the expansion reflects the birth of the species for neoendemic species. We show for the first time that the demographic histories of endemic and widespread reef fish are not distinctly different and suggest that a number of processes drive endemism. PMID- 28091581 TI - Icaritin enhances mESC self-renewal through upregulating core pluripotency transcription factors mediated by ERalpha. AB - Utilization of small molecules in modulation of stem cell self-renewal is a promising approach to expand stem cells for regenerative therapy. Here, we identify Icaritin, a phytoestrogen molecule enhances self-renewal of mouse embryonic stem cells (mESCs). Icaritin increases mESCs proliferation while maintains their self-renewal capacity in vitro and pluripotency in vivo. This coincides with upregulation of key pluripotency transcription factors OCT4, NANOG, KLF4 and SOX2. The enhancement of mESCs self-renewal is characterized by increased population in S-phase of cell cycle, elevation of Cylin E and Cyclin dependent kinase 2 (CDK2) and downregulation of p21, p27 and p57. PCR array screening reveals that caudal-related homeobox 2 (Cdx2) and Rbl2/p130 are remarkably suppressed in mESCs treated with Icaritin. siRNA knockdown of Cdx2 or Rbl2/p130 upregulates the expression of Cyclin E, OCT4 and SOX2, and subsequently increases cell proliferation and colony forming efficiency of mESCs. We then demonstrate that Icaritin co-localizes with estrogen receptor alpha (ERalpha) and activates its nuclear translocation in mESCs. The promotive effect of Icaritin on cell cycle and pluripotency regulators are eliminated by siRNA knockdown of ERalpha in mESCs. The results suggest that Icaritin enhances mESCs self-renewal by regulating cell cycle machinery and core pluripotency transcription factors mediated by ERalpha. PMID- 28091582 TI - Androgen Mediated Regulation of Endoplasmic Reticulum-Associated Degradation and its Effects on Prostate Cancer. AB - The endoplasmic reticulum (ER) comprises thirty percent of the newly translated proteins in eukaryotic cells. The quality control mechanism within the ER distinguishes between properly and improperly folded proteins and ensures that unwanted proteins are retained in the ER and subsequently degraded through ER associated degradation (ERAD). Besides cleaning of misfolded proteins ERAD is also important for physiological processes by regulating the abundance of normal proteins of the ER. Thus it is important to unreveal the regulation patterns of ERAD. Here, we describe that ERAD pathway is regulated by androgen, where its inhibitor SVIP was downregulated, all other ERAD genes were upregulated. Consistently, androgen treatment increased the degradation rate of ERAD substrates. Using several independent techniques, we showed that this regulation is through androgen receptor transactivation. ERAD genes found to be upregulated in prostate cancer tissues and silencing expression of Hrd1, SVIP, and gp78 reduced the in vitro migration and malignant transformation of LNCaP cells. Our data suggests that expression levels of ERAD components are regulated by androgens, that promotes ERAD proteolytic activity, which is positively related with prostate tumorigenesis. PMID- 28091583 TI - Hybrid Dielectric-loaded Nanoridge Plasmonic Waveguide for Low-Loss Light Transmission at the Subwavelength Scale. AB - The emerging development of the hybrid plasmonic waveguide has recently received significant attention owing to its remarkable capability of enabling subwavelength field confinement and great transmission distance. Here we report a guiding approach that integrates hybrid plasmon polariton with dielectric-loaded plasmonic waveguiding. By introducing a deep-subwavelength dielectric ridge between a dielectric slab and a metallic substrate, a hybrid dielectric-loaded nanoridge plasmonic waveguide is formed. The waveguide features lower propagation loss than its conventional hybrid waveguiding counterpart, while maintaining strong optical confinement at telecommunication wavelengths. Through systematic structural parameter tuning, we realize an efficient balance between confinement and attenuation of the fundamental hybrid mode, and we demonstrate the tolerance of its properties despite fabrication imperfections. Furthermore, we show that the waveguide concept can be extended to other metal/dielectric composites as well, including metal-insulator-metal and insulator-metal-insulator configurations. Our hybrid dielectric-loaded nanoridge plasmonic platform may serve as a fundamental building block for various functional photonic components and be used in applications such as sensing, nanofocusing, and nanolasing. PMID- 28091584 TI - Enhancement of Outflow Facility in the Murine Eye by Targeting Selected Tight Junctions of Schlemm's Canal Endothelia. AB - The juxtacanalicular connective tissue of the trabecular meshwork together with inner wall endothelium of Schlemm's canal (SC) provide the bulk of resistance to aqueous outflow from the anterior chamber. Endothelial cells lining SC elaborate tight junctions (TJs), down-regulation of which may widen paracellular spaces between cells, allowing greater fluid outflow. We observed significant increase in paracellular permeability following siRNA-mediated suppression of TJ transcripts, claudin-11, zonula-occludens-1 (ZO-1) and tricellulin in human SC endothelial monolayers. In mice claudin-11 was not detected, but intracameral injection of siRNAs targeting ZO-1 and tricellulin increased outflow facility significantly. Structural qualitative and quantitative analysis of SC inner wall by transmission electron microscopy revealed significantly more open clefts between endothelial cells treated with targeting, as opposed to non-targeting siRNA. These data substantiate the concept that the continuity of SC endothelium is an important determinant of outflow resistance, and suggest that SC endothelial TJs represent a specific target for enhancement of aqueous movement through the conventional outflow system. PMID- 28091586 TI - Corrigendum: Modelling mutational landscapes of human cancers in vitro. PMID- 28091585 TI - MicroRNA-19b is a potential biomarker of increased myocardial collagen cross linking in patients with aortic stenosis and heart failure. AB - This study analyzed the potential associations of 7 myocardial fibrosis-related microRNAs with the quality of the collagen network (e.g., the degree of collagen fibril cross-linking or CCL) and the enzyme lysyl oxidase (LOX) responsible for CCL in 28 patients with severe aortic stenosis (AS) of whom 46% had a diagnosis of chronic heart failure (HF). MicroRNA expression was analyzed in myocardial and blood samples. From the studied microRNAs only miR-19b presented a direct correlation (p < 0.05) between serum and myocardium. Compared to controls both myocardial and serum miR-19b were reduced (p < 0.01) in AS patients. In addition, miR-19b was reduced in the myocardium (p < 0.01) and serum (p < 0.05) of patients with HF compared to patients without HF. Myocardial and serum miR-19b were inversely correlated (p < 0.05) with LOX, CCL and LV stiffness in AS patients. In in vitro studies miR-19b inhibition increased (p < 0.05) connective tissue growth factor protein and LOX protein expression in human fibroblasts. In conclusion, decreased miR-19b may be involved in myocardial LOX up-regulation and excessive CCL, and consequently increased LV stiffness in AS patients, namely in those with HF. Serum miR-19b can be a biomarker of these alterations of the myocardial collagen network in AS patients, particularly in patients with HF. PMID- 28091587 TI - Bacillus volatiles adversely affect the physiology and ultra-structure of Ralstonia solanacearum and induce systemic resistance in tobacco against bacterial wilt. AB - Volatile organic compounds (VOCs) produced by various bacteria have significant potential to enhance plant growth and to control phytopathogens. Six of the most effective antagonistic Bacillus spp. were used in this study against Ralstonia solanacearum (Rsc) TBBS1, the causal agent of bacterial wilt disease in tobacco. Bacillus amyloliquefaciens FZB42 and Bacillus artrophaeus LSSC22 had the strongest inhibitory effect against Rsc. Thirteen VOCs produced by FZB42 and 10 by LSSC22 were identified using gas chromatography-mass spectrometry analysis. Benzaldehyde, 1,2-benzisothiazol-3(2 H)-one and 1,3-butadiene significantly inhibited the colony size, cell viability, and motility of pathogens and negatively influenced chemotaxis. Transmission and scanning electron microscopy revealed severe morphological and ultra-structural changes in cells of Rsc. Furthermore, VOCs altered the transcriptional expression level of PhcA (a global virulence regulator), type III secretion system (T3SS), type IV secretion system (T4SS), extracellular polysaccharides and chemotaxis-related genes, which are major contributors to pathogenicity, resulting in decreased wilt disease. The VOCs significantly up-regulated the expression of genes related to wilt resistance and pathogen defense. Over-expression of EDS1 and NPR1 suggest the involvement of SA pathway in induction of systemic resistance. Our findings provide new insights regarding the potential of antibacterial VOCs as a biocontrol tool against bacterial wilt diseases. PMID- 28091588 TI - High-molecular-weight hyaluronic acid attenuated matrix metalloproteinase-1 and 3 expression via CD44 in tendinopathy. AB - Evidence indicates that hyaluronic acid (HA) mitigates tendinopathy, but the effect of molecular weight is unclear. We investigated the effects of different concentrations and different molecular weights of HA (350 kDa, 1500 kDa, and 3000 kDa) on matrix metalloproteinase (MMP)-1 and -3 expression in IL-1beta-stimulated rat tenocytes, and on their dynamic expression in peritendinous effusion from patients with long head of biceps (LHB) tendinopathy after high-molecular-weight (HMW)-HA treatments. Reverse transcription PCR, real-time PCR, and ELISA were used to determine MMP-1 and -3expression. Because CD44 was clearly expressed in the plasma membranes of cultured tenocytes, OX-50, a CD44 antagonist, was used to inhibit CD44 to evaluate the HA mechanism. HA (3000 kDa) significantly (p < 0.001) downregulated the mRNA and protein expression of MMP-1 and -3 in IL-1beta stimulated tenocytes. Its attenuating effects were dose-dependent (p < 0.01). In OX-50-pretreated cells, the mRNA expression of CD44 was not significantly altered, but the mRNA expression of MMP-1 and -3 was significantly upregulated. Visual analogue scale scores were significantly lower, and MMP-1 and -3 expression was significantly (p < 0.05) lower one month posttreatment. HMW-HA attenuated tendinopathy by downregulating MMP-1 and -3 expression. Inhibiting CD44 blocked the effects of HMW-HA. PMID- 28091589 TI - Platelet, monocyte and neutrophil activation and glucose tolerance in South African Mixed Ancestry individuals. AB - Platelet activation has been described in patients with chronic inflammation, however in type 2 diabetes mellitus it remains controversial. We compared levels of platelet leucocyte aggregates, monocyte and granulocyte activation across glucose tolerance statuses in mixed ancestry South Africans. Individuals (206) were recruited from Bellville-South, Cape Town, and included 66% with normal glucose tolerance, 18.7% pre-diabetes, 8.7% screen-detected diabetes and 6.3% known diabetes. Monocyte and neutrophil activation were measured by calculating the percentage of cells expressing CD142 and CD69 while platelet monocyte aggregates were defined as CD14++ CD42b+ events and platelet neutrophil aggregates as CD16++ CD42b+ events. The percentage of monocytes and neutrophils expressing CD69 and CD142 was significantly higher in known diabetes and prediabetes, but, lowest in screen-detected diabetes (both p <= 0.016). The pattern was similar for platelet monocyte and neutrophil aggregates (both p <= 0.003). In robust linear regressions adjusted for age and gender, known diabetes was significantly and positively associated with the percentage of monocytes expressing CD69 [beta 11.06 (p = 0.016)] and CD42b (PMAs) [19.51 (0.003)] as well as the percentage of neutrophils expressing CD69 [14.19 (<0.0001)] and CD42b [17.7 (0.001)]. We conclude that monitoring platelet activation in diagnosed diabetic patients may have a role in the management and risk stratification. PMID- 28091590 TI - High performance magneto-fluorescent nanoparticles assembled from terbium and gadolinium 1,3-diketones. AB - Polyelectrolyte-coated nanoparticles consisting of terbium and gadolinium complexes with calix[4]arene tetra-diketone ligand were first synthesized. The antenna effect of the ligand on Tb(III) green luminescence and the presence of water molecules in the coordination sphere of Gd(III) bring strong luminescent and magnetic performance to the core-shell nanoparticles. The size and the core shell morphology of the colloids were studied using transmission electron microscopy and dynamic light scattering. The correlation between photophysical and magnetic properties of the nanoparticles and their core composition was highlighted. The core composition was optimized for the longitudinal relaxivity to be greater than that of the commercial magnetic resonance imaging (MRI) contrast agents together with high level of Tb(III)-centered luminescence. The tuning of both magnetic and luminescent output of nanoparticles is obtained via the simple variation of lanthanide chelates concentrations in the initial synthetic solution. The exposure of the pheochromocytoma 12 (PC 12) tumor cells and periphery human blood lymphocytes to nanoparticles results in negligible effect on cell viability, decreased platelet aggregation and bright coloring, indicating the nanoparticles as promising candidates for dual magneto-fluorescent bioimaging. PMID- 28091592 TI - Effective extraction of Arabidopsis adherent seed mucilage by ultrasonic treatment. AB - The Arabidopsis seed coat is composed of two layers of mucilage, a water-soluble non-adherent outer layer and an adherent inner layer. The non-adherent mucilage can easily be extracted by gentle shaking. However, adherent mucilage is extremely difficult to dissociate from the seed coat. Despite various treatments to extract the adherent mucilage, including EDTA, ammonium oxalate, dilute alkali or acid washes, most of it remains on the seed coat. Here, we show for the first time the extraction of almost all of the adherent mucilage from the Arabidopsis seed coat. Our results demonstrate that ultrasonic treatment was able to extract the adherent mucilage effectively within 20 seconds. Adherent mucilage, like non adherent mucilage, is mainly composed of rhamnogalacturonan I (RG I). The crystalline cellulose content in adherent mucilage was measured as 3.7 mg g-1 of dry seed. Compared with non-adherent mucilage, the adherent mucilage exhibits relatively stable levels of sugar under various environmental conditions. In all cases, adherent mucilage showed higher levels of sugar than non-adherent mucilage. The cell wall remnant could associate with the adherent mucilage, which could prevent the extraction of the adherent mucilage. Our results show that ultrasonic treatment is an effective method for the quick extraction of Arabidopsis adherent mucilage with little effort. PMID- 28091591 TI - Intraarterial route increases the risk of cerebral lesions after mesenchymal cell administration in animal model of ischemia. AB - Mesenchymal stem cells (MSCs) are a promising clinical therapy for ischemic stroke. However, critical parameters, such as the most effective administration route, remain unclear. Intravenous (i.v.) and intraarterial (i.a.) delivery routes have yielded varied outcomes across studies, potentially due to the unknown MSCs distribution. We investigated whether MSCs reached the brain following i.a. or i.v. administration after transient cerebral ischemia in rats, and evaluated the therapeutic effects of both routes. MSCs were labeled with dextran-coated superparamagnetic nanoparticles for magnetic resonance imaging (MRI) cell tracking, transmission electron microscopy and immunohistological analysis. MSCs were found in the brain following i.a. but not i.v. administration. However, the i.a. route increased the risk of cerebral lesions and did not improve functional recovery. The i.v. delivery is safe but MCS do not reach the brain tissue, implying that treatment benefits observed for this route are not attributable to brain MCS engrafting after stroke. PMID- 28091593 TI - Economic Development and Forest Cover: Evidence from Satellite Data. AB - Ongoing deforestation is a pressing, global environmental issue with direct impacts on climate change, carbon emissions, and biodiversity. There is an intuitive link between economic development and overexploitation of natural resources including forests, but this relationship has proven difficult to establish empirically due to both inadequate data and convoluting geo-climactic factors. In this analysis, we use satellite data on forest cover along national borders in order to study the determinants of deforestation differences across countries. Controlling for trans-border geo-climactic differences, we find that income per capita is the most robust determinant of differences in cross-border forest cover. We show that the marginal effect of per capita income growth on forest cover is strongest at the earliest stages of economic development, and weakens in more advanced economies, presenting some of the strongest evidence to date for the existence of at least half of an environmental Kuznets curve for deforestation. PMID- 28091595 TI - Geological support for the Umbrella Effect as a link between geomagnetic field and climate. AB - The weakening of the geomagnetic field causes an increase in galactic cosmic ray (GCR) flux. Some researchers argue that enhanced GCR flux might lead to a climatic cooling by increasing low cloud formation, which enhances albedo (umbrella effect). Recent studies have reported geological evidence for a link between weakened geomagnetic field and climatic cooling. However, more work is needed on the mechanism of this link, including whether the umbrella effect is playing a central role. In this research, we present new geological evidence that GCR flux change had a greater impact on continental climate than on oceanic climate. According to pollen data from Osaka Bay, Japan, the decrease in temperature of the Siberian air mass was greater than that of the Pacific air mass during geomagnetic reversals in marine isotope stages (MIS) 19 and 31. Consequently, the summer land-ocean temperature gradient was smaller, and the summer monsoon was weaker. Greater terrestrial cooling indicates that a reduction of insolation is playing a key role in the link between the weakening of the geomagnetic field and climatic cooling. The most likely candidate for the mechanism seems to be the increased albedo of the umbrella effect. PMID- 28091594 TI - Functional analysis reveals that RBM10 mutations contribute to lung adenocarcinoma pathogenesis by deregulating splicing. AB - RBM10 is an RNA splicing regulator that is frequently mutated in lung adenocarcinoma (LUAD) and has recently been proposed to be a cancer gene. How RBM10 mutations observed in LUAD affect its normal functions, however, remains largely unknown. Here integrative analysis of RBM10 mutation and RNA expression data revealed that LUAD-associated RBM10 mutations exhibit a mutational spectrum similar to that of tumor suppressor genes. In addition, this analysis showed that RBM10 mutations identified in LUAD patients lacking canonical oncogenes are associated with significantly reduced RBM10 expression. To systematically investigate RBM10 mutations, we developed an experimental pipeline for elucidating their functional effects. Among six representative LUAD-associated RBM10 mutations, one nonsense and one frameshift mutation caused loss-of-function as expected, whereas four missense mutations differentially affected RBM10 mediated splicing. Importantly, changes in proliferation rates of LUAD-derived cells caused by these RBM10 missense mutants correlated with alterations in RNA splicing of RBM10 target genes. Together, our data implies that RBM10 mutations contribute to LUAD pathogenesis, at least in large part, by deregulating splicing. The methods described in this study should be useful for analyzing mutations in additional cancer-associated RNA splicing regulators. PMID- 28091596 TI - Non-invasive optical estimate of tissue composition to differentiate malignant from benign breast lesions: A pilot study. AB - Several techniques are being investigated as a complement to screening mammography, to reduce its false-positive rate, but results are still insufficient to draw conclusions. This initial study explores time domain diffuse optical imaging as an adjunct method to classify non-invasively malignant vs benign breast lesions. We estimated differences in tissue composition (oxy- and deoxyhemoglobin, lipid, water, collagen) and absorption properties between lesion and average healthy tissue in the same breast applying a perturbative approach to optical images collected at 7 red-near infrared wavelengths (635-1060 nm) from subjects bearing breast lesions. The Discrete AdaBoost procedure, a machine learning algorithm, was then exploited to classify lesions based on optically derived information (either tissue composition or absorption) and risk factors obtained from patient's anamnesis (age, body mass index, familiarity, parity, use of oral contraceptives, and use of Tamoxifen). Collagen content, in particular, turned out to be the most important parameter for discrimination. Based on the initial results of this study the proposed method deserves further investigation. PMID- 28091597 TI - Direct visualization of hydrogen absorption dynamics in individual palladium nanoparticles. AB - Many energy storage materials undergo large volume changes during charging and discharging. The resulting stresses often lead to defect formation in the bulk, but less so in nanosized systems. Here, we capture in real time the mechanism of one such transformation-the hydrogenation of single-crystalline palladium nanocubes from 15 to 80 nm-to better understand the reason for this durability. First, using environmental scanning transmission electron microscopy, we monitor the hydrogen absorption process in real time with 3 nm resolution. Then, using dark-field imaging, we structurally examine the reaction intermediates with 1 nm resolution. The reaction proceeds through nucleation and growth of the new phase in corners of the nanocubes. As the hydrogenated phase propagates across the particles, portions of the lattice misorient by 1.5%, diminishing crystal quality. Once transformed, all the particles explored return to a pristine state. The nanoparticles' ability to remove crystallographic imperfections renders them more durable than their bulk counterparts. PMID- 28091599 TI - A Comprehensive Numerical Model for Simulating Fluid Transport in Nanopores. AB - Since a large amount of nanopores exist in tight oil reservoirs, fluid transport in nanopores is complex due to large capillary pressure. Recent studies only focus on the effect of nanopore confinement on single-well performance with simple planar fractures in tight oil reservoirs. Its impacts on multi-well performance with complex fracture geometries have not been reported. In this study, a numerical model was developed to investigate the effect of confined phase behavior on cumulative oil and gas production of four horizontal wells with different fracture geometries. Its pore sizes were divided into five regions based on nanopore size distribution. Then, fluid properties were evaluated under different levels of capillary pressure using Peng-Robinson equation of state. Afterwards, an efficient approach of Embedded Discrete Fracture Model (EDFM) was applied to explicitly model hydraulic and natural fractures in the reservoirs. Finally, three fracture geometries, i.e. non-planar hydraulic fractures, non planar hydraulic fractures with one set natural fractures, and non-planar hydraulic fractures with two sets natural fractures, are evaluated. The multi well performance with confined phase behavior is analyzed with permeabilities of 0.01 md and 0.1 md. This work improves the analysis of capillarity effect on multi-well performance with complex fracture geometries in tight oil reservoirs. PMID- 28091598 TI - Characterization of two polyvalent phages infecting Enterobacteriaceae. AB - Bacteriophages display remarkable genetic diversity and host specificity. In this study, we explore phages infecting bacterial strains of the Enterobacteriaceae family because of their ability to infect related but distinct hosts. We isolated and characterized two novel virulent phages, SH6 and SH7, using a strain of Shigella flexneri as host bacterium. Morphological and genomic analyses revealed that phage SH6 belongs to the T1virus genus of the Siphoviridae family. Conversely, phage SH7 was classified in the T4virus genus of the Myoviridae family. Phage SH6 had a short latent period of 16 min and a burst size of 103 +/- 16 PFU/infected cell while the phage SH7 latent period was 23 min with a much lower burst size of 26 +/- 5 PFU/infected cell. Moreover, phage SH6 was sensitive to acidic conditions (pH < 5) while phage SH7 was stable from pH 3 to 11 for 1 hour. Of the 35 bacterial strains tested, SH6 infected its S. flexneri host strain and 8 strains of E. coli. Phage SH7 lysed additionally strains of E. coli O157:H7, Salmonella Paratyphi, and Shigella dysenteriae. The broader host ranges of these two phages as well as their microbiological properties suggest that they may be useful for controlling bacterial populations. PMID- 28091600 TI - Urinary profiles of luteinizing hormone, estrogen and progestagen during the estrous and gestational periods in giant pandas (Ailuropda melanoleuca). AB - Luteinizing hormone (LH) is one of the main pituitary hormones that regulate ovulation, however its role has not been studied in giant panda. In this study, we developed an ELISA method for the detection of panda urinary LH. We analyzed urinary hormones of 24 female pandas during 36 breeding periods, we found females could easily be impregnated if the first mating occurred within 10 hours after LH peak. We also found the patterns of the ratios of urinary LH and progestagen in pandas that bred and successfully gave birth were significantly different from those that bred but failed to give birth. These data was the first to provide the urinary LH profiles during the estrous and gestational periods in pandas, and demonstrated that the appearance of the urinary LH peak indicated the timing of ovulation. The LH detection together with estrogen analysis makes the window for successful mating narrower than previously reported. Moreover, detection of urinary LH and progestagen can be used to discriminate between pregnancies and pseudopregnancies/miscarriages in the species. Thus, our findings suggest that LH not only plays a critical role in regulating ovulation but also plays an important role in maintaining pregnancy in the giant panda. PMID- 28091601 TI - Massively parallel digital transcriptional profiling of single cells. AB - Characterizing the transcriptome of individual cells is fundamental to understanding complex biological systems. We describe a droplet-based system that enables 3' mRNA counting of tens of thousands of single cells per sample. Cell encapsulation, of up to 8 samples at a time, takes place in ~6 min, with ~50% cell capture efficiency. To demonstrate the system's technical performance, we collected transcriptome data from ~250k single cells across 29 samples. We validated the sensitivity of the system and its ability to detect rare populations using cell lines and synthetic RNAs. We profiled 68k peripheral blood mononuclear cells to demonstrate the system's ability to characterize large immune populations. Finally, we used sequence variation in the transcriptome data to determine host and donor chimerism at single-cell resolution from bone marrow mononuclear cells isolated from transplant patients. PMID- 28091602 TI - Intragranular cracking as a critical barrier for high-voltage usage of layer structured cathode for lithium-ion batteries. AB - LiNi1/3Mn1/3Co1/3O2-layered cathode is often fabricated in the form of secondary particles, consisting of densely packed primary particles. This offers advantages for high energy density and alleviation of cathode side reactions/corrosions, but introduces drawbacks such as intergranular cracking. Here, we report unexpected observations on the nucleation and growth of intragranular cracks in a commercial LiNi1/3Mn1/3Co1/3O2 cathode by using advanced scanning transmission electron microscopy. We find the formation of the intragranular cracks is directly associated with high-voltage cycling, an electrochemically driven and diffusion controlled process. The intragranular cracks are noticed to be characteristically initiated from the grain interior, a consequence of a dislocation-based crack incubation mechanism. This observation is in sharp contrast with general theoretical models, predicting the initiation of intragranular cracks from grain boundaries or particle surfaces. Our study emphasizes that maintaining structural stability is the key step towards high-voltage operation of layered-cathode materials. PMID- 28091603 TI - Repo-Man/PP1 regulates heterochromatin formation in interphase. AB - Repo-Man is a protein phosphatase 1 (PP1) targeting subunit that regulates mitotic progression and chromatin remodelling. After mitosis, Repo-Man/PP1 remains associated with chromatin but its function in interphase is not known. Here we show that Repo-Man, via Nup153, is enriched on condensed chromatin at the nuclear periphery and at the edge of the nucleopore basket. Repo-Man/PP1 regulates the formation of heterochromatin, dephosphorylates H3S28 and it is necessary and sufficient for heterochromatin protein 1 binding and H3K27me3 recruitment. Using a novel proteogenomic approach, we show that Repo-Man is enriched at subtelomeric regions together with H2AZ and H3.3 and that depletion of Repo-Man alters the peripheral localization of a subset of these regions and alleviates repression of some polycomb telomeric genes. This study shows a role for a mitotic phosphatase in the regulation of the epigenetic landscape and gene expression in interphase. PMID- 28091604 TI - Polyglucose nanoparticles with renal elimination and macrophage avidity facilitate PET imaging in ischaemic heart disease. AB - Tissue macrophage numbers vary during health versus disease. Abundant inflammatory macrophages destruct tissues, leading to atherosclerosis, myocardial infarction and heart failure. Emerging therapeutic options create interest in monitoring macrophages in patients. Here we describe positron emission tomography (PET) imaging with 18F-Macroflor, a modified polyglucose nanoparticle with high avidity for macrophages. Due to its small size, Macroflor is excreted renally, a prerequisite for imaging with the isotope flourine-18. The particle's short blood half-life, measured in three species, including a primate, enables macrophage imaging in inflamed cardiovascular tissues. Macroflor enriches in cardiac and plaque macrophages, thereby increasing PET signal in murine infarcts and both mouse and rabbit atherosclerotic plaques. In PET/magnetic resonance imaging (MRI) experiments, Macroflor PET imaging detects changes in macrophage population size while molecular MRI reports on increasing or resolving inflammation. These data suggest that Macroflor PET/MRI could be a clinical tool to non-invasively monitor macrophage biology. PMID- 28091605 TI - Cubosomes from hierarchical self-assembly of poly(ionic liquid) block copolymers. AB - Cubosomes are micro- and nanoparticles with a bicontinuous cubic two-phase structure, reported for the self-assembly of low molecular weight surfactants, for example, lipids, but rarely formed by polymers. These objects are characterized by a maximum continuous interface and high interface to volume ratio, which makes them promising candidates for efficient adsorbents and host guest applications. Here we demonstrate self-assembly to nanoscale cuboidal particles with a bicontinuous cubic structure by amphiphilic poly(ionic liquid) diblock copolymers, poly(acrylic acid)-block-poly(4-vinylbenzyl)-3-butyl imidazolium bis(trifluoromethylsulfonyl)imide, in a mixture of tetrahydrofuran and water under optimized conditions. Structure determining parameters include polymer composition and concentration, temperature, and the variation of the solvent mixture. The formation of the cubosomes can be explained by the hierarchical interactions of the constituent components. The lattice structure of the block copolymers can be transferred to the shape of the particle as it is common for atomic and molecular faceted crystals. PMID- 28091606 TI - Long-term efficient organic photovoltaics based on quaternary bulk heterojunctions. AB - A major impediment to the commercialization of organic photovoltaics (OPVs) is attaining long-term morphological stability of the bulk heterojunction (BHJ) layer. To secure the stability while pursuing optimized performance, multi component BHJ-based OPVs have been strategically explored. Here we demonstrate the use of quaternary BHJs (q-BHJs) composed of two conjugated polymer donors and two fullerene acceptors as a novel platform to produce high-efficiency and long term durable OPVs. A q-BHJ OPV (q-OPV) with an experimentally optimized composition exhibits an enhanced efficiency and extended operational lifetime than does the binary reference OPV. The q-OPV would retain more than 72% of its initial efficiency (for example, 8.42-6.06%) after a 1-year operation at an elevated temperature of 65 degrees C. This is superior to those of the state-of the-art BHJ-based OPVs. We attribute the enhanced stability to the significant suppression of domain growth and phase separation between the components via kinetic trapping effect. PMID- 28091607 TI - Perceived Stress and Colorectal Cancer Incidence: The Japan Collaborative Cohort Study. AB - Colorectal cancer is the third most common cancer worldwide, and many risk factors for colorectal cancer have been established. However, it remains uncertain whether psychological stress contributes to the onset of colorectal cancer. Therefore, we conducted a large-scale prospective cohort study to confirm the association between perceived stress and colorectal cancer incidence. We identified 680 cases of colon cancer and 330 cases of rectal cancer during a maximum of 21-year follow-up of 61,563 Japanese men and women. Cox regression analysis adjusted for potential confounders revealed a significant association of perceived stress with rectal cancer incidence but not with colon cancer incidence. This finding is partly consistent with that from only one previous study that addressed an association between perceived stress and the risk of colorectal cancer. However, studies on this topic are sparse and warrant further exploration. PMID- 28091608 TI - Binding of N-methylscopolamine to the extracellular domain of muscarinic acetylcholine receptors. AB - Interaction of orthosteric ligands with extracellular domain was described at several aminergic G protein-coupled receptors, including muscarinic acetylcholine receptors. The orthosteric antagonists quinuclidinyl benzilate (QNB) and N methylscopolamine (NMS) bind to the binding pocket of the muscarinic acetylcholine receptor formed by transmembrane alpha-helices. We show that high concentrations of either QNB or NMS slow down dissociation of their radiolabeled species from all five subtypes of muscarinic acetylcholine receptors, suggesting allosteric binding. The affinity of NMS at the allosteric site is in the micromolar range for all receptor subtypes. Using molecular modelling of the M2 receptor we found that E172 and E175 in the second extracellular loop and N419 in the third extracellular loop are involved in allosteric binding of NMS. Mutation of these amino acids to alanine decreased affinity of NMS for the allosteric binding site confirming results of molecular modelling. The allosteric binding site of NMS overlaps with the binding site of some allosteric, ectopic and bitopic ligands. Understanding of interactions of NMS at the allosteric binding site is essential for correct analysis of binding and action of these ligands. PMID- 28091609 TI - Leptin sustains spontaneous remyelination in the adult central nervous system. AB - Demyelination is a common feature of many central nervous system (CNS) diseases and is associated with neurological impairment. Demyelinated axons are spontaneously remyelinated depending on oligodendrocyte development, which mainly involves molecules expressed in the CNS environment. In this study, we found that leptin, a peripheral hormone secreted from adipocytes, promoted the proliferation of oligodendrocyte precursor cells (OPCs). Leptin increased the OPC proliferation via in vitro phosphorylation of extracellular signal regulated kinase (ERK); whereas leptin neutralization inhibited OPC proliferation and remyelination in a mouse model of toxin-induced demyelination. The OPC-specific leptin receptor long isoform (LepRb) deletion in mice inhibited both OPC proliferation and remyelination in the response to demyelination. Intrathecal leptin administration increased OPC proliferation. These results demonstrated a novel molecular mechanism by which leptin sustained OPC proliferation and remyelination in a pathological CNS. PMID- 28091610 TI - Evaluation of hyperspectral LiDAR for monitoring rice leaf nitrogen by comparison with multispectral LiDAR and passive spectrometer. AB - Fast and nondestructive assessment of leaf nitrogen concentration (LNC) is critical for crop growth diagnosis and nitrogen management guidance. In the last decade, multispectral LiDAR (MSL) systems have promoted developments in the earth and ecological sciences with the additional spectral information. With more wavelengths than MSL, the hyperspectral LiDAR (HSL) system provides greater possibilities for remote sensing crop physiological conditions. This study compared the performance of ASD FieldSpec Pro FR, MSL, and HSL for estimating rice (Oryza sativa) LNC. Spectral reflectance and biochemical composition were determined in rice leaves of different cultivars (Yongyou 4949 and Yangliangyou 6) throughout two growing seasons (2014-2015). Results demonstrated that HSL provided the best indicator for predicting rice LNC, yielding a coefficient of determination (R2) of 0.74 and a root mean square error of 2.80 mg/g with a support vector machine, similar to the performance of ASD (R2 = 0.73). Estimation of rice LNC could be significantly improved with the finer spectral resolution of HSL compared with MSL (R2 = 0.56). PMID- 28091611 TI - Multi-response optimization of Artemia hatching process using split-split-plot design based response surface methodology. AB - A novel method, BBD-SSPD is proposed by the combination of Box-Behnken Design (BBD) and Split-Split Plot Design (SSPD) which would ensure minimum number of experimental runs, leading to economical utilization in multi- factorial experiments. The brine shrimp Artemia was tested to study the combined effects of photoperiod, temperature and salinity, each with three levels, on the hatching percentage and hatching time of their cysts. The BBD was employed to select 13 treatment combinations out of the 27 possible combinations that were grouped in an SSPD arrangement. Multiple responses were optimized simultaneously using Derringer's desirability function. Photoperiod and temperature as well as temperature-salinity interaction were found to significantly affect the hatching percentage of Artemia, while the hatching time was significantly influenced by photoperiod and temperature, and their interaction. The optimum conditions were 23 h photoperiod, 29 degrees C temperature and 28 ppt salinity resulting in 96.8% hatching in 18.94 h. In order to verify the results obtained from BBD-SSPD experiment, the experiment was repeated preserving the same set up. Results of verification experiment were found to be similar to experiment originally conducted. It is expected that this method would be suitable to optimize the hatching process of animal eggs. PMID- 28091612 TI - Ribosome profiling-guided depletion of an mRNA increases cell growth rate and protein secretion. AB - Recombinant protein production coopts the host cell machinery to provide high protein yields of industrial enzymes or biotherapeutics. However, since protein translation is energetically expensive and tightly controlled, it is unclear if highly expressed recombinant genes are translated as efficiently as host genes. Furthermore, it is unclear how the high expression impacts global translation. Here, we present the first genome-wide view of protein translation in an IgG producing CHO cell line, measured with ribosome profiling. Through this we found that our recombinant mRNAs were translated as efficiently as the host cell transcriptome, and sequestered up to 15% of the total ribosome occupancy. During cell culture, changes in recombinant mRNA translation were consistent with changes in transcription, demonstrating that transcript levels influence specific productivity. Using this information, we identified the unnecessary resistance marker NeoR to be a highly transcribed and translated gene. Through siRNA knock down of NeoR, we improved the production- and growth capacity of the host cell. Thus, ribosomal profiling provides valuable insights into translation in CHO cells and can guide efforts to enhance protein production. PMID- 28091613 TI - Adrenomedullin promotes angiogenesis in epithelial ovarian cancer through upregulating hypoxia-inducible factor-1alpha and vascular endothelial growth factor. AB - Adrenomedullin (ADM) is a multi-functional peptide related to many kinds of tumors. This study was aimed to investigate the role of ADM on angiogenesis in epithelial ovarian cancer (EOC) and its possible mechanism. The expressions of ADM, vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1alpha (HIF-1alpha) and CD34 were examined by immunohistochemistry staining. The relationship among ADM, HIF-1alpha, VEGF and micro-vessel density (MVD) was assessed in 56 EOC tissues. CAOV3 cells were stably transfected with pcDNA-ADM (plasmid overexpressing ADM gene) or pRNA-shADM (small interfering RNA for ADM gene). Real-time PCR and western blot analysis were performed to detect the expressions of HIF-1alpha and VEGF. The MTT, transwell migration assay and in vitro tube formation analysis were used to evaluate the proliferation, migration, and tube formation ability of human umbilical vein endothelial cells (HUVECs) which were pretreated with ADM or ADM receptor antagonist ADM22-52. Our findings showed that ADM expression was positively correlated with the expressions of HIF 1alpha, VEGF or MVD in EOC. ADM upregulated expression of HIF-1alpha and VEGF in CAOV3 cells. ADM promoted HUVECs proliferation, migration and tube formation. In conclusion, ADM was an upstream molecule of HIF-1alpha/VEGF and it promoted angiogenesis through upregulating HIF-1alpha/VEGF in EOC. PMID- 28091614 TI - Transcriptomic basis for drought-resistance in Brassica napus L. AB - Based on transcriptomic data from four experimental settings with drought resistant and drought-sensitive cultivars under drought and well-watered conditions, statistical analysis revealed three categories encompassing 169 highly differentially expressed genes (DEGs) in response to drought in Brassica napus L., including 37 drought-resistant cultivar-related genes, 35 drought sensitive cultivar-related genes and 97 cultivar non-specific ones. We provide evidence that the identified DEGs were fairly uniformly distributed on different chromosomes and their expression patterns are variety specific. Except commonly enriched in response to various stimuli or stresses, different categories of DEGs show specific enrichment in certain biological processes or pathways, which indicated the possibility of functional differences among the three categories. Network analysis revealed relationships among the 169 DEGs, annotated biological processes and pathways. The 169 DEGs can be classified into different functional categories via preferred pathways or biological processes. Some pathways might simultaneously involve a large number of shared DEGs, and these pathways are likely to cross-talk and have overlapping biological functions. Several members of the identified DEGs fit to drought stress signal transduction pathway in Arabidopsis thaliana. Finally, quantitative real-time PCR validations confirmed the reproducibility of the RNA-seq data. These investigations are profitable for the improvement of crop varieties through transgenic engineering. PMID- 28091615 TI - Pirfenidone controls the feedback loop of the AT1R/p38 MAPK/renin-angiotensin system axis by regulating liver X receptor-alpha in myocardial infarction-induced cardiac fibrosis. AB - Pirfenidone (PFD), an anti-fibrotic small molecule drug, is used to treat fibrotic diseases, but its effects on myocardial infarction (MI)-induced cardiac fibrosis are unknown. The aim of this study was to determine the effects of PFD on MI-induced cardiac fibrosis and the possible underlying mechanisms in rats. After establishment of the model, animals were administered PFD by gavage for 4 weeks. During the development of MI-induced cardiac fibrosis, we found activation of a positive feedback loop between the angiotensin II type 1 receptor (AT1R)/phospho-p38 mitogen-activated protein kinase (p38 MAPK) pathway and renin angiotensin system (RAS), which was accompanied by down-regulation of liver X receptor-alpha (LXR-alpha) expression. PFD attenuated body weight, heart weight, left ventricular weight, left ventricular systolic pressure, and +/-dp/dtmax changes induced by MI, which were associated with a reduction in cardiac fibrosis, infarct size, and hydroxyproline concentration. Moreover, PFD inhibited the AT1R/p38 MAPK pathway, corrected the RAS imbalance [decreased angiotensin converting enzyme (ACE), angiotensin II, and angiotensin II type 1 receptor expression, but increased ACE2 and angiotensin (1-7) activity and Mas expression] and strongly enhanced heart LXR-alpha expression. These results indicate that the cardioprotective effects of PFD may be due, in large part, to controlling the feedback loop of the AT1R/p38 MAPK/RAS axis by activation of LXR-alpha. PMID- 28091616 TI - Wave Function Parity Loss Used to Mitigate Thermal Broadening in Spin-orbit Coupled Zigzag Graphene Analogues. AB - Carrier transport through a graphene zigzag nanoribbon (ZNR) is possible to be blocked by a p-n profile implemented along its transport direction. However, we found that in cases of analogous materials with significant intrinsic spin-orbit coupling (SOC), i.e. silicene and germanene, such a profile on ZNR of these materials allows transmission mostly through spin-orbit coupled energy window due to the loss of the parity of wave functions at different energies caused by SOC. Next, a p-i-n scheme on germanene ZNR is proposed to simultaneously permit edge transmission and decimate bulk transmission. The transmission spectrum is shown to mitigate the effect of thermal broadening on germanene and silicene ZNR based spin-separators by improving spin polarization yield by 400% and 785%, respectively, at 300 K. The importance of proper gate voltage and position for such performance is further elucidated. Finally, the modulation the current output of the proposed U-shape p-i-n device while maintaining its spin polarization is discussed. PMID- 28091617 TI - Switch from sexual to parthenogenetic reproduction in a zebra shark. AB - Parthenogenesis is a natural form of asexual reproduction in which embryos develop in the absence of fertilisation. Most commonly found in plants and invertebrate organisms, an increasing number of vertebrate species have recently been reported employing this reproductive strategy. Here we use DNA genotyping to report the first demonstration of an intra-individual switch from sexual to parthenogenetic reproduction in a shark species, the zebra shark Stegostoma fasciatum. A co-housed, sexually produced daughter zebra shark also commenced parthenogenetic reproduction at the onset of maturity without any prior mating. The demonstration of parthenogenesis in these two conspecific individuals with different sexual histories provides further support that elasmobranch fishes may flexibly adapt their reproductive strategy to environmental circumstances. PMID- 28091619 TI - Erratum: Vectorized magnetometer for space applications using electrical readout of atomic scale defects in silicon carbide. PMID- 28091618 TI - Chemical Isotope Labeling LC-MS for Monitoring Disease Progression and Treatment in Animal Models: Plasma Metabolomics Study of Osteoarthritis Rat Model. AB - We report a chemical isotope labeling (CIL) liquid chromatography mass spectrometry (LC-MS) method generally applicable for tracking metabolomic changes from samples collected in an animal model for studying disease development and treatment. A rat model of surgically induced osteoarthritis (OA) was used as an example to illustrate the workflow and technical performance. Experimental duplicate analyses of 234 plasma samples were carried out using dansylation labeling LC-MS targeting the amine/phenol submetabolome. These samples composed of 39 groups (6 rats per group) were collected at multiple time points with sham operation, OA control group, and OA rats with treatment, separately, using glucosamine/Celecoxib and three traditional Chinese medicines (Epimedii folium, Chuanxiong Rhizoma and Bushen-Huoxue). In total, 3893 metabolites could be detected and 2923 of them were consistently detected in more than 50% of the runs. This high-coverage submetabolome dataset could be used to track OA progression and treatment. Many differentiating metabolites were found and 11 metabolites including 2-aminoadipic acid, saccharopine and GABA were selected as potential biomarkers of OA progression and OA treatment. This study illustrates that CIL LC-MS is a very useful technique for monitoring incremental metabolomic changes with high coverage and accuracy for studying disease progression and treatment in animal models. PMID- 28091620 TI - Role of molecular conformations in rubrene polycrystalline films growth from vacuum deposition at various substrate temperatures. AB - We report on the optical and structural characterization of rubrene polycrystalline films fabricated from vacuum deposition with various substrate temperatures (Tsub). Depending on Tsub, the role of twisted and planar rubrene conformational isomers on the properties of rubrene films is focused. The temperature (T)-dependent inverse optical transmission (IOT) and photoluminescence (PL) spectra were performed on these rubrene films. The origins of these IOT and PL peaks are explained in terms of the features from twisted and planar rubrene molecules and of the band characteristics from rubrene molecular solid films. Here, two rarely reported weak-peaks at 2.431 and 2.605 eV were observed from IOT spectra, which are associated with planar rubrene. Besides, the T-dependence of optical bandgap deduced from IOT spectra is discussed with respect to Tsub. Together with IOT and PL spectra, for Tsub > 170 degrees C, the changes in surface morphology and unit cell volume were observed for the first time, and are attributed to the isomeric transformation from twisted to planar rubrenes during the deposition processes. Furthermore, a unified schematic diagram in terms of Frenkel exciton recombination is suggested to explain the origins of the dominant PL peaks performed on these rubrene films at 15 K. PMID- 28091621 TI - Differential susceptibility and maturation of thymocyte subsets during Salmonella Typhimurium infection: insights on the roles of glucocorticoids and Interferon gamma. AB - The thymus is known to atrophy during infections; however, a systematic study of changes in thymocyte subpopulations has not been performed. This aspect was investigated, using multi-color flow cytometry, during oral infection of mice with Salmonella Typhimurium (S. Typhimurium). The major highlights are: First, a block in the developmental pathway of CD4-CD8- double negative (DN) thymocytes is observed. Second, CD4+CD8+ double positive (DP) thymocytes, mainly in the DP1 (CD5loCD3lo) and DP2 (CD5hiCD3int), but not DP3 (CD5intCD3hi), subsets are reduced. Third, single positive (SP) thymocytes are more resistant to depletion but their maturation is delayed, leading to accumulation of CD24hiCD3hi SP. Kinetic studies during infection demonstrated differences in sensitivity of thymic subpopulations: Immature single positive (ISP) > DP1, DP2 > DN3, DN4 > DN2 > CD4+ > CD8+. Upon infection, glucocorticoids (GC), inflammatory cytokines, e.g. Ifngamma, etc are induced, which enhance thymocyte death. Treatment with RU486, the GC receptor antagonist, increases the survival of most thymic subsets during infection. Studies with Ifngamma-/- mice demonstrated that endogenous Ifngamma produced during infection enhances the depletion of DN2-DN4 subsets, promotes the accumulation of DP3 and delays the maturation of SP thymocytes. The implications of these observations on host cellular responses during infections are discussed. PMID- 28091622 TI - Clinical variations in Parkinson's disease patients with or without REM sleep behaviour disorder: a meta-analysis. AB - This study aimed to evaluate the clinical variations in patients with Parkinson's disease (PD) with (PDRBD) or without REM sleep behaviour disorder (RBD) (Non RBD), and PDRBD patients were classified into Confirmed-RBD (definite diagnosis with polysomnography, PSG) and Probable-RBD (without PSG re-confirmation). The clinical difference between the groups of patients was measured as an odds ratio (OR) or standardized mean difference (SMD, Cohen d). A total of 31 articles with data from 5,785 participants were obtained for our analysis. Overall, the occurrence of Confirmed-RBD was more frequent in male patients (OR = 1.25; p = 0.038), elderly patients (SMD = 0.25; p = 0.000), and patients with longer disease duration (SMD = 0.30; p = 0.000), increased Hoehn-Yahr scale (SMD = 0.30; p = 0.000), and higher UPDRS-III score (SMD = 0.38; p = 0.002). On the other hand, the frequency of Probable-RBD was increased with disease duration (SMD = 0.29; p = 0.000), Hoehn-Yahr scale (SMD = 0.30; p = 0.000), and UPDRS-III score (SMD = 0.26; p = 0.001). Our study indicate that PDRBD patients may have different clinical features compared to patients with Non-RBD. PMID- 28091623 TI - Comparative genomics of canine-isolated Leishmania (Leishmania) amazonensis from an endemic focus of visceral leishmaniasis in Governador Valadares, southeastern Brazil. AB - Leishmaniasis is a highly diverse group of diseases caused by kinetoplastid of the genus Leishmania. These parasites are taxonomically diverse, with human pathogenic species separated into two subgenera according to their development site inside the alimentary tract of the sand fly insect vector. The disease encompasses a variable spectrum of clinical manifestations with tegumentary or visceral symptoms. Among the causative species in Brazil, Leishmania (Leishmania) amazonensis is an important etiological agent of human cutaneous leishmaniasis that accounts for more than 8% of all cases in endemic regions. L. (L.) amazonensis is generally found in the north and northeast regions of Brazil. Here, we report the first isolation of L. (L.) amazonensis from dogs with clinical manifestations of visceral leishmaniasis in Governador Valadares, an endemic focus in the southeastern Brazilian State of Minas Gerais where L. (L.) infantum is also endemic. These isolates were characterized in terms of SNPs, chromosome and gene copy number variations, confirming that they are closely related to a previously sequenced isolate obtained in 1973 from the typical Northern range of this species. The results presented in this article will increase our knowledge of L. (L.) amazonensis-specific adaptations to infection, parasite survival and the transmission of this Amazonian species in a new endemic area of Brazil. PMID- 28091624 TI - Paracrine cross-talk between skeletal muscle and macrophages in exercise by PGC 1alpha-controlled BNP. AB - Activation of resident and infiltrating immune cells is a central event in training adaptation and other contexts of skeletal muscle repair and regeneration. A precise orchestration of inflammatory events in muscle fibers and immune cells is required after recurrent contraction-relaxation cycles. However, the mechanistic aspects of this important regulation remain largely unknown. We now demonstrate that besides a dominant role in controlling cellular metabolism, the peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC 1alpha) also has a profound effect on cytokine expression in muscle tissue. Muscle PGC-1alpha expression results in activation of tissue-resident macrophages, at least in part mediated by PGC-1alpha-dependent B-type natriuretic peptide (BNP) production and secretion. Positive effects of exercise in metabolic diseases and other pathologies associated with chronic inflammation could accordingly involve the PGC-1alpha-BNP axis and thereby provide novel targets for therapeutic approaches. PMID- 28091626 TI - Dynamic contact angles in oil-aqueous polymer solutions. AB - Polymer flooding is an important process in enhanced oil recovery. The displacement front is unstable when low viscosity brine displaces the heavy crude oil in the reservoir. Water-soluble polymers are added to the brine to increase its viscosity which stabilizes the displacement process. To analyze the displacement process at the micro-level, we have investigated the dynamic contact angles in silicone oil-polymer (polyethylene oxide) solution and for the first time. The dynamic contact angle is the apparent contact angle at the three-phase contact line which governs the capillary pressure, and thus is important for the displacement process. The data show no obvious signs of either shear thinning or elastic behavior, although for some systems with highest elastic effects some unexplained effects on dynamic contact angles are observed that correlate with elastic effects. Overall, dynamic contact angles are explained well using existing models for two Newtonian fluids, when the zero shear viscosity is used for the polymer solution. PMID- 28091627 TI - Development of a single-step immunoassay microdevice based on a graphene oxide containing hydrogel possessing fluorescence quenching and size separation functions. AB - An immunoassay, which is an indispensable analytical method both in biological research and in medical fields was successfully integrated into a "single-step" by developing a microdevice composed of a graphene oxide (GO)-containing hydrogel and a poly (dimethylsiloxane) (PDMS) microchannel array with a polyethylene glycol (PEG) coating containing a fluorescently-labelled antibody. Here we used 2 hydroxyethylmethacrylate (HEMA) as a monomer that is easily, and homogeneously, mixed with GO to synthesize the hydrogel. The fluorescence quenching and size separation functions were then optimized by controlling the ratios of HEMA and GO. Free fluorescently-labelled antibody was successfully separated from the immunoreaction mixture by the hydrogel network structure, and the fluorescence was subsequently quenched by GO. In comparison to the previously reported immunoassay system using GO, the present system achieved a very high fluorescence resonance energy transfer (FRET) efficiency (~90%), due to the use of direct adsorption of the fluorescently-labelled antibody to the GO surface; in contrast, the former reported method relied on indirect adsorption of the fluorescently labelled antibody via immunocomplex formation at the GO surface. Finally, the single-step immunoassay microdevice was made by combining the developed hydrogel and the PDMS microchannel with a coating containing the fluorescently-labelled antibody, and successfully applied for the single-step analysis of IgM levels in diluted human serum by simple introduction of the sample via capillary action. PMID- 28091628 TI - In situ X-ray absorption near edge structure studies and charge transfer kinetics of Na6[V10O28] electrodes. AB - Polyoxometalates (POMs) have been reported as promising electrode materials for energy storage applications due to their ability to undergo fast redox reactions with multiple transferred electrons per polyanion. Here we employ a polyoxovanadate salt, Na6[V10O28], as an electrode material in a lithium-ion containing electrolyte and investigate the electron transfer properties of Na6[V10O28] on long and short timescales. Looking at equilibrated systems, in situ V K-edge X-ray absorption near edge structure (XANES) studies show that all 10 V5+ ions in Na6[V10O28] can be reversibly reduced to V4+ in a potential range of 4-1.75 V vs. Li/Li+. Focusing on the dynamic response of the electrode to potential pulses, the kinetics of Na6[V10O28] electrodes and the dependence of the fundamental electron transfer rate k0 on temperature are investigated. From these measurements we calculate the reorganization energy and compare it with theoretical predictions. The experimentally determined reorganization energy of lambda = 184 meV is in line with the theoretical estimate and confirms the hypothesis of small values of lambda for POMs due to electrostatic shielding of the redox center from the solvent. PMID- 28091625 TI - MPLEx: a method for simultaneous pathogen inactivation and extraction of samples for multi-omics profiling. AB - The continued emergence and spread of infectious agents is of great concern, and systems biology approaches to infectious disease research can advance our understanding of host-pathogen relationships and facilitate the development of new therapies and vaccines. Molecular characterization of infectious samples outside of appropriate biosafety containment can take place only subsequent to pathogen inactivation. Herein, we describe a modified Folch extraction using chloroform/methanol that facilitates the molecular characterization of infectious samples by enabling simultaneous pathogen inactivation and extraction of proteins, metabolites, and lipids for subsequent mass spectrometry-based multi omics measurements. This single-sample metabolite, protein and lipid extraction (MPLEx) method resulted in complete inactivation of clinically important bacterial and viral pathogens with exposed lipid membranes, including Yersinia pestis, Salmonella Typhimurium, and Campylobacter jejuni in pure culture, and Yersinia pestis, Campylobacter jejuni, and West Nile, MERS-CoV, Ebola, and influenza H7N9 viruses in infection studies. In addition, >99% inactivation, which increased with solvent exposure time, was also observed for pathogens without exposed lipid membranes including community-associated methicillin resistant Staphylococcus aureus, Clostridium difficile spores and vegetative cells, and adenovirus type 5. The overall pipeline of inactivation and subsequent proteomic, metabolomic, and lipidomic analyses was evaluated using a human epithelial lung cell line infected with wild-type and mutant influenza H7N9 viruses, thereby demonstrating that MPLEx yields biomaterial of sufficient quality for subsequent multi-omics analyses. Based on these experimental results, we believe that MPLEx will facilitate systems biology studies of infectious samples by enabling simultaneous pathogen inactivation and multi-omics measurements from a single specimen with high success for pathogens with exposed lipid membranes. PMID- 28091629 TI - Mapping the sequence-structure relationships of simple cyclic hexapeptides. AB - Cyclic peptides are promising protein-protein interaction modulators with high binding affinities and specificities, as well as enhanced stabilities and oral availabilities over linear analogs. Despite their relatively small size and cyclic architecture, it is currently difficult to predict the favored conformation(s) of most classes of cyclic peptides. An improved understanding of the sequence-structure relationships for cyclic peptides will offer an avenue for the rational design of cyclic peptides as possible therapeutics. In this work, we systematically explored the sequence-structure relationships for two cyclic hexapeptide systems using molecular dynamics simulation techniques. Starting with an all-glycine cyclic hexapeptide, cyclo-G6, we systematically replaced glycine residues with alanines and characterized the structural ensembles of different variants. The same process was repeated with valines to investigate the effects of larger side chains. An analysis of the origin of structure preferences was performed using thermodynamics decomposition and several general observations are reported. PMID- 28091630 TI - Accurate measurement of long range proton-carbon scalar coupling constants. AB - The accuracy and practicality of measuring heteronuclear scalar coupling constants, nJCH, from modern NMR experimental methods is examined, based on F1 or F2 evolution of nJCH in HSQMBC (including EXSIDE) and HMBC experiments. The results from these methods are compared to both robust experimental data (derived from coupled 13C spectra), computed (Density Functional Theory) and literature values where available. We report on the accuracy, ease of use and time efficiency of these multi-dimensional methods and highlight their extent and limitations. PMID- 28091634 TI - Recent advancements and future directions of superficially porous chiral stationary phases for ultrafast high-performance enantioseparations. AB - This review focuses on the use of superficially porous particles (SPPs) as chiral stationary phases for ultra-high performance liquid enantioseparations. In contrast to what happened in achiral separations where core-shell particles invaded the market, the introduction of SPPs in chiral liquid chromatography (LC) has been relatively recent. This is due in part to the technical difficulties in the preparation of these phases, and in part to scarce understanding of mass transfer phenomena in chiral chromatography. As a matter of fact, nowadays, the development of superficially porous CSPs is still in its infancy. This paper covers the most recent advancements in the field of core-shell technology applied to chiral separations. We review the kinds of chiral selectors that have been used for the preparation of these phases, by discussing the advantages of chiral SPPs over their fully-porous counterparts for high efficient high throughput enantioseparations. Notwithstanding the apparently obvious advantages in terms of the mass transfer of chiral SPPs, some critical aspects that could impact their development are presented. PMID- 28091635 TI - Focused electron beam based direct-write fabrication of graphene and amorphous carbon from oxo-functionalized graphene on silicon dioxide. AB - Controlled patterning of graphene is an important task towards device fabrication and thus is the focus of current research activities. Graphene oxide (GO) is a solution-processible precursor of graphene. It can be patterned by thermal processing. However, thermal processing of GO leads to decomposition and CO2 formation. Alternatively, focused electron beam induced processing (FEBIP) techniques can be used to pattern graphene with high spatial resolution. Based on this approach, we explore FEBIP of GO deposited on SiO2. Using oxo-functionalized graphene (oxo-G) with an in-plane lattice defect density of 1% we are able to image the electron beam-induced effects by scanning Raman microscopy for the first time. Depending on electron energy (2-30 keV) and doses (50-800 mC m-2) either reduction of GO or formation of permanent lattice defects occurs. This result reflects a step towards controlled FEBIP processing of oxo-G. PMID- 28091636 TI - Assessing the electrochemical properties of polypyridine and polythiophene for prospective applications in sustainable organic batteries. AB - Conducting polymers are being considered promising candidates for sustainable organic batteries mainly due to their fast electron transport properties and high recyclability. In this work, the key properties of polythiophene and polypyridine have been assessed through a combined theoretical and experimental study focusing on such applications. A theoretical protocol has been developed to calculate redox potentials in solution within the framework of the density functional theory and using continuous solvation models. Here, the evolution of the electrochemical properties of solvated oligomers as a function of the length of the chain is analyzed and then the polymer properties are estimated via linear regressions using ordinary least square. The predicted values were verified against our electrochemical experiments. This protocol can now be employed to screen a large database of compounds in order to identify organic electrodes with superior properties. PMID- 28091637 TI - Investigation of a new bis(carboxylate)triazole-based anchoring ligand for dye solar cell chromophore complexes. AB - A novel anchoring ligand for dye-sensitised solar cell chromophoric complexes, 1 (2,2'-bipyrid-4-yl)-1,2,3-triazole-4,5-dicarboxylic acid (dctzbpy), is described. The new dye complexes [Ru(bpy)2(dctzbpy)][PF6]2 (AS16), [Ir(ppy)2(dctzbpy)][PF6] (AS17) and [Re(dctzbpy)(CO)3Cl] (AS18) were prepared in a two stage procedure with intermediate isolation of their diester analogues, AS16-Et2, AS17-Et2 and AS18-Et2 respectively. Electrochemical analysis of AS16-Et2, AS17-Et2 and AS18 Et2 reveal reduction potentials in the range -1.50 to -1.59 V (vs. Fc+/Fc) which are cathodically shifted with respect to that of the model complex [Ru(bpy)2(dcbH2)]2+ (1) (Ered = -1.34 V, dcbH2 = 2,2'-bipyridyl-4,4'-dicarboxylic acid). This therefore demonstrates that the LUMO of the complex is correctly positioned for favourable electron transfer into the TiO2 conduction band upon photoexcitation. The higher energy LUMOs for AS16 to AS18 and a larger HOMO-LUMO gap result in blue-shifted absorption spectra and hence reduced light harvesting efficiency relative to their dcbH2 analogues. Preliminary tests on TiO2 n-type and NiO p-type DSSCs have been carried out. In the cases of the Ir(iii) and Re(i) based dyes AS17 and AS18 these show inferior performance to their dcbH2 analogues. However, the Ru(ii) dye AS16 (eta = 0.61%) exhibits significantly greater efficiency than 1 (eta = 0.1%). In a p-type cell AS16 shows the highest photovoltaic efficiency (eta = 0.028%), almost three times that of cells incorporating the benchmark dye coumarin C343. PMID- 28091638 TI - Highly ordered sandwich-type (phthalocyaninato)(porphyrinato) europium double decker nanotubes and room temperature NO2 sensitive properties. AB - A sandwich-type (phthalocyaninato)(porphyrinato) europium double-decker complex Eu(TPyP){Pc-(OC8H17)8} [TPyP = meso-tetra(4-pyridyl)porphyrin; Pc-(OC8H17)8 = 2,3,9,10,16,17,23,24-octakis(octyloxy)phthalocyanine] (2) was designed and prepared. For comparative studies, Eu(TPyP)(Pc) (1) was also prepared. Highly ordered nanotubes of complexes 1 and 2 were successfully fabricated by using an anodized alumina oxide (AAO) template method. The nanotubes were comparatively investigated by electronic absorption spectra, scanning electron microscopy (SEM), low-angle X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and energy dispersive spectroscopy (EDS) techniques. Both nanotubes of complexes 1 and 2 showed good conductivities and presented an efficient gas sensing platform for the ultrasensitive detection of NO2 at room temperature. In particular, the detection limit and response/recovery times for the proposed sensors based on complex 2 were lower and faster than those of complex 1, indicating the significant effect of a molecular packing mode on tuning the gas sensing performance of organic semiconductors. PMID- 28091639 TI - Gold nanoparticles stabilized by cationic carbosilane dendrons: synthesis and biological properties. AB - Gold nanoparticles (AuNPs) and polycationic macromolecules are used as gene carriers. Their behaviour is dependent on several factors, such as the size and type of the framework, charge, etc. We have combined both types of systems and prepared AuNPs covered with cationic carbosilane dendrons with the aim to evaluate their biocompatibility. Water soluble dendronized cationic AuNPs were prepared following a straightforward procedure from dendrons, a gold precursor and a reducing agent in water and were characterized by 1H NMR, transmission electron microscopy (TEM), dynamic light scattering (DLS), thermogravimetric analysis (TGA), ultraviolet spectroscopy (UV), and zeta potential (ZP). The biological properties of dendrons and AuNPs were determined by hemolysis, platelet aggregation and lymphocyte proliferation. These assays reflect modification of dendron properties when covering nanoparticles. For dendrons, hemolysis and platelet aggregation are generation dependent whilst, for AuNPs these properties are related to the bigger size of NPs. On the other hand, none of the systems induced lymphocyte proliferation. Selected cationic dendrons and AuNPs were chosen for gene delivery experiments employing a small interference RNA (siRNA Nef) against human immunodeficiency virus (HIV). PMID- 28091640 TI - The binuclear dual emitter [Br(CO)3Re(PN)(NP)Re(CO)3Br] (PN): 3-chloro-6-(4 diphenylphosphinyl)butoxypyridazine, a new bridging P,N-bidentate ligand resulting from the ring opening of tetrahydrofuran. AB - Lithium diphenylphosphide unexpectedly provokes the ring-opening of tetrahydrofuran (THF) and by reaction with 3,6-dichloropyridazine leads to the formation of the ligand 3-chloro-6-(4-diphenylphosphinyl)butoxypyridazine (P?N), which was isolated. The reaction of this ligand with the (Re(CO)3(THF)Br)2 dimer yields the novel complex [Br(CO)3Re(MU-3-chloro-6-(4 diphenylphosphinyl)butoxypyridazine)2Re(CO)3Br] (BrRe(P?N)(N?P)ReBr), which was crystallized in the form of a chloroform solvate, (C46H40Br2Cl2N4O8P2Re2).(CHCl3). The monoclinic crystal (P21/n) displays a bimetallic cage structure with a symmetry inversion centre in the middle of the rhenium to rhenium line. The molecule shows two oxidation signals occurring at +1.50 V and +1.76 V which were assigned to the ReI/ReII and ReII/ReIII metal centered couples, respectively, while signals observed at -1.38 V and -1.68 V were assigned to ligand centered reductions. Experimental and DFT/TDDFT results indicate that the UV-Vis absorption maximum of BrRe(P?N)(N?P)ReBr occurring near 380 nm displays a metal to ligand charge transfer (MLCT) character, which is consistent with CV results. Upon excitation at this wavelength, a weak emission (Phiem < 1 * 10-3) is observed around 580 nm (in dichloromethane) which decays with two distinct lifetimes tau1 and tau2 of 24 and 4.7 ns, respectively. The prevalence of non-radiative deactivation pathways is consistent with efficient internal conversion induced by the high conformational flexibility of the P?N ligand's long carbon chain. Measurements in a frozen solvent at 77 K, where vibrational deactivation is hindered, show intense emission associated with the 3MLCT state. These results demonstrate that BrRe(P?N)(N?P)ReBr preserves the dual emitting nature previously reported for the mononuclear complex RePNBr, with emission associated with and states. PMID- 28091642 TI - Robust, double-shelled ZnGa2O4 hollow spheres for photocatalytic reduction of CO2 to methane. AB - Robust, double-shelled ZnGa2O4 hollow spheres were successfully fabricated by hydrothermally treating an aqueous solution containing Zn(ii), Ga(iii), and citric acid, followed by annealing at 600 degrees C, 700 degrees C, or 800 degrees C in air to remove the carbon species. The hollow structure is expected to trap incident photons to enhance the light absorbance. The sample annealed at 700 degrees C exhibited the optimized photocatalytic performance in the reduction of CO2 in the presence of water vapor to methane. This property is ascribed to the improved crystallinity of the sample, which has fewer defect centers for the recombination of electron-hole pairs compared with that annealed at 600 degrees C. The reduced performance of the sample done at 800 degrees C relative to the one annealed at 700 degrees C is attributed to the formation of additional impurities besides ZnGa2O4, possibly due to partial Zn(ii) evaporation at higher temperature leading to segregation of potential Ga-based oxides. RuO2 and Pt were loaded onto the sample surface to greatly enhance the photocatalytic performance. The best photocatalytic performance was observed in the sample co loaded with Pt and RuO2. PMID- 28091641 TI - Effects of pomegranate extract in supplementing gonadotropin-releasing hormone therapy on idiopathic central precocious puberty in Chinese girls: a randomized, placebo-controlled, double-blind clinical trial. AB - Central precocious puberty (CPP) without organic abnormality is called idiopathic CPP (ICPP). The objective of this trial was to evaluate the effects of pomegranate extract in supplementing gonadotropin-releasing hormone (GnRH) analog therapy on ICPP-affected girls in the Chinese population. 286 girls, diagnosed with ICPP were initially enrolled into this trial, and among them 225 eligible patients were randomized to receive a combinational GnRH analog treatment supplemented with either a placebo or pomegranate extract on a daily basis for a period of 3 months. Their demographics, secondary sexual characteristics and hormone profiles were analyzed at baseline and end of trial. After 3 months of treatment, demographic profiles including bone age, growth velocity and height standard deviation score for bone age, and secondary sexual characteristics including uterus and ovary volume, as well as serum hormone profiles including estradiol, peak luteinizing hormone and insulin-like growth factor 1 were all significantly improved in girls receiving a combinational treatment of both GnRH analog and pomegranate extract. Daily consumption of pomegranate extract was able to supplement and improve the treatment outcomes of the GnRH analog therapy for ICPP in Chinese girls. PMID- 28091643 TI - Improving the zT value of thermoelectrics by nanostructuring: tuning the nanoparticle morphology of Sb2Te3 by using ionic liquids. AB - A systematic study on the microwave-assisted thermolysis of the single source precursor (Et2Sb)2Te (1) in different asymmetric 1-alkyl-3-methylimidazolium- and symmetric 1,3-dialkylimidazolium-based ionic liquids (ILs) reveals the distinctive role of both the anion and the cation in tuning the morphology and microstructure of the resulting Sb2Te3 nanoparticles as evidenced by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX), and X-ray photoelectron spectroscopy (XPS). A comparison of the electrical and thermal conductivities as well as the Seebeck coefficient of the Sb2Te3 nanoparticles obtained from different ILs reveals the strong influence of the specific IL, from which C4mimI was identified as the best solvent, on the thermoelectric properties of as-prepared nanosized Sb2Te3. This work provides design guidelines for ILs, which allow the synthesis of nanostructured thermoelectrics with improved performances. PMID- 28091644 TI - Chiral bidentate [N,S]-ferrocene ligands based on a thiazoline framework. Synthesis and use in palladium-catalyzed asymmetric allylic alkylation. AB - An efficient method to obtain chiral 1,2-disubstituted ferrocenyl ligands has been developed. The introduction of planar chirality was accomplished by using 2 thiazoline as an ortho-directing lithiation group, and moreover, these kinds of ligands possess a central chirality from the amino alcohol used in their synthesis. The X-ray analysis and DFT calculations confirmed the diastereoselectivity of ortho-lithiation and the configuration of the planar chirality. The ability of these new bidentate [N,S]-ferrocene ligands to act in Pd-catalyzed asymmetric allylic alkylation has also been demonstrated and compared with their oxazoline counterparts. PMID- 28091645 TI - Yogurt inhibits intestinal barrier dysfunction in Caco-2 cells by increasing tight junctions. AB - Chronic inflammation disrupts intestinal barrier function and may contribute to the pathology of obesity and other diseases. The goal of this study was to determine the mechanism by which yogurt improves intestinal barrier function. Caco-2 cells were differentiated on Transwell inserts and used as a model of intestinal barrier permeability. Transepithelial electrical resistance (TEER) and flux of 4 kDa fluorescein isothiocyanate-dextran (FD) and lucifer yellow (LY) were used as indicators of monolayer integrity and paracellular permeability. Immunofluorescence microscopy and real time quantitative polymerase chain were used to assess the localization and expression of tight junction proteins known to regulate intestinal permeability. Differentiated cells were treated with a vehicle control (C), inflammatory stimulus (I) (interleukin-1beta, tumor necrosis factor-alpha, interferon-gamma, and lipopolysaccharide), or I and 0.03 g mL-1 yogurt (IY). After 48 h, I reduced Caco-2 TEER by 46%, while IY reduced TEER by only 27% (P < 0.0001). FD and LY flux reflected TEER measurements, with IY having significantly lower permeability than I (P < 0.05). Yogurt also improved localization of occludin and zona occludens protein 1 (ZO-1) at tight junctions of differentiated Caco-2 cells. IY increased Caco-2 claudin-1, ZO-1, and occludin mRNA relative to I (P < 0.05). In a simulated digestion, the barrier-improving bioactivity of yogurt was maintained through the gastric phase, but was reduced to the level of I after intestinal digestion (P < 0.05). Therefore, yogurt improved inflammation-disrupted intestinal barrier function in a Caco-2 model by increasing tight junctions, but the beneficial effect on barrier function was reduced at latter stages of digestion. PMID- 28091646 TI - Molecular hydrogen production from amorphous solid water during low energy electron irradiation. AB - This work investigates the production of molecular hydrogen isotopologues (H2, HD, and D2) during low energy electron irradiation of layered and isotopically labelled thin films of amorphous solid water (ASW) in ultrahigh vacuum. Experimentally, the production of these molecules with both irradiation time and incident electron energy in the range 400 to 500 eV is reported as a function of the depth of a buried D2O layer in an H2O film. H2 is produced consistently in all measurements, reflecting the H2O component of the film, though it does exhibit a modest reduction in intensity at the time corresponding to product escape from the buried D2O layer. In contrast, HD and D2 production exhibit peaks at times corresponding to product escape from the buried D2O layer in the composite film. These features broaden the deeper the HD or D2 is formed due to diffusion. A simple random-walk model is presented that can qualitatively explain the appearance profile of these peaks as a function of the incident electron penetration. PMID- 28091647 TI - Phytosterol nutritional supplement improves pregnancy and neonatal complications of gestational diabetes mellitus in a double-blind and placebo-controlled clinical study. AB - Gestational diabetes mellitus (GDM) is an increasingly serious health problem among pregnant women. Phytosterol-enriched spreads are known to reduce total cholesterol (TC) and low-density lipoprotein (LDL), but little is known about their effects on GDM. We aimed to examine the effect of the daily consumption of phytosterol-enriched spreads on both the maternal and neonatal outcomes of GDM patients. GDM patients during the third trimester of pregnancy were enrolled and assigned randomly to consume a regular spread or phytosterol-enriched spread daily until the end of their pregnancy. Maternal diabetic symptoms such as serum lipid profile, glucose and insulin metabolisms, as well as neonatal complications, were analyzed at the beginning and full-term. The daily consumption of the phytosterol-enriched spread exhibited significant beneficial effects on maternal diabetic symptoms, in terms of improved lipid compositions and glucose metabolism. Moreover, the incidence of neonatal complications was also significantly reduced by the phytosterol-enriched spread, in terms of birth weight, macrosomia, hypoglycemia, respiratory distress and Apgar scores. The daily consumption of a phytosterol-enriched spread is able to improve both the maternal and neonatal outcomes in GDM patients. PMID- 28091648 TI - Efficient synthesis of carborane azo derivatives and their reactivity. AB - An iridium(iii)-catalyzed C-N-bond-forming direct synthesis of carborane azo derivatives was developed. The reaction of o-carborane monocarboxylate with aryldiazonium salt in the presence of a catalytic amount of [Cp*IrCl2]2 and NaOAc in CH3CN at 80 degrees C gave the corresponding carborane azo derivative in good yield. A series of cyclometalated iridium/rhodium complexes that contain Cp*M-B (M = Ir, Rh) bonds, and are stabilised by the intramolecular coordination of nitrogen donors, were successfully isolated and structurally characterised. PMID- 28091649 TI - Optical properties of trinuclear metal chalcogenolate complexes - room temperature NIR fluorescence in [Cu2Ti(SPh)6(PPh3)2]. AB - The optical properties of four isostructural trinuclear chalcogenolato bridged metal complexes [Cu2Sn(SPh)6(PPh3)2], [Cu2Sn(SePh)6(PPh3)2], [Ag2Sn(SPh)6(PPh3)2] and [Cu2Ti(SPh)6(PPh3)2] have been investigated by absorption and photoluminescence spectroscopy and time-dependent density functional theory (TDDFT) calculations. All copper-tin compounds demonstrate near-infrared (NIR) phosphorescence at ~900-1100 nm in the solid state at low temperature, which is nearly absent at ambient temperature. Stokes shifts of these emissions are found to be unusually large with values of about 1.5 eV. The copper-titanium complex [Cu2Ti(SPh)6(PPh3)2] also shows luminescence in the NIR at 1090 nm but with a much faster decay (tau ~ 10 ns at 150 K) and a much smaller Stokes shift (ca. 0.3 eV). Even at 295 K this fluorescence is found to comprise a quantum yield as high as 9.5%. The experimental electronic absorption spectra well correspond to the spectra simulated from the calculated singlet transitions. In line with the large Stokes shifts of the emission spectra the calculations reveal for the copper-tin complexes strong structural relaxation of the excited triplet states whereas those effects are found to be much smaller in the case of the copper-titanium complex. PMID- 28091650 TI - The W@WO3 ohmic contact induces a high-efficiency photooxidation performance. AB - The Schottky-type metal-semiconductor (M-S) junction works well in promoting the separation of photogenerated carriers. In this paper, another type of M-S junction, Ohmic contact of W@WO3, has been developed via an acid partial oxidation strategy. By simply tuning the experimental parameters including the acid concentration and the reaction time, WO3 nanosheets are epitaxially grown on a W core; moreover, the thickness and density of the WO3 shell can be finely controlled. The photocatalytic activities of samples are tested via degradation of gaseous acetaldehyde under UV light irradiation. The results show that the W@WO3 core-shell composite with a thinner and looser WO3 shell exhibits a higher mineralization ability of acetaldehyde to carbon dioxide. An Ohmic contact between the W core and the WO3 shell is fairly confirmed by means of photo electronic measurements. It is believed that the built-in electric field at the interface of the Ohmic contact leads to the migration of photogenerated electrons from WO3 to W, which is beneficial for separation of the electron-hole pairs and hence an enhanced photooxidation ability. PMID- 28091651 TI - Composition-dependent charge transfer and phase separation in the V1-xRexO2 solid solution. AB - The substitution of vanadium in vanadium dioxide VO2 influences the critical temperatures of structural and metal-to-insulator transitions in different ways depending on the valence of the dopant. Rhenium adopts valence states between +4 and +7 in an octahedral oxygen surrounding and is particularly interesting in this context. Structural investigation of V1-xRexO2 solid solutions (0.01 <= x <= 0.30) between 80 and 1200 K using synchrotron X-ray powder diffraction revealed only two polymorphs that resemble VO2: the low-temperature monoclinic MoO2-type form (space group P21/c), and the tetragonal rutile-like form (space group P42/mnm). However, for compositions with 0.03 < x <= 0.15 a phase separation in the solid solution was observed below 1000 K upon cooling down from 1200 K, giving rise to two isostructural phases with slightly different lattice parameters. This is reflected in the appearance of two metal-to-insulator transition temperatures detected by magnetization and specific heat measurements. Comprehensive X-ray photoelectron spectroscopy studies showed that an increased amount of Re leads to a change in the Re valence state from solely Re6+ at a low doping level (<=3 at% Re) via mixed-valence states Re4+/Re6+ for at least 0.03 < x <= 0.10, up to nearly pure Re4+ in V0.70Re0.30O2. Thus, compositions V1-xRexO2 with only one valence state of Re in the material (Re6+ or Re4+) can be obtained as a single phase, while intermediate compositions are subjected to a phase separation, presumably due to different valence states of Re. PMID- 28091653 TI - Trivalent f-elements in human saliva: a comprehensive speciation study by time resolved laser-induced fluorescence spectroscopy and thermodynamic calculations. AB - In the case of oral ingestion of radioactive contaminants, the first contact medium is saliva in the mouth. To gain a first insight into the interaction of radioactive contaminants in human saliva, the speciation of curium (Cm(iii)) and europium (Eu(iii)), i.e., trivalent f-elements, was investigated in different salivary media with time-resolved laser-induced fluorescence spectroscopy (TRLFS). The results indicate that these metal cations are primarily complexed with carbonates and phosphates, forming ternary complexes with a possible stoichiometry of 1 : 1 : 2 (M(iii) : carbonate : phosphate). For charge compensation, calcium is also involved in these ternary complexes. In addition to these inorganic components, organic substances, namely alpha-amylase, show a significant contribution to the speciation of the trivalent f-elements in saliva. This protein is the major enzyme in saliva and catalyzes the hydrolysis of polysaccharides. In this context, the effect of Eu(iii) on the activity of alpha amylase was investigated to reveal the potential implication of these metal cations for the in vivo functions of saliva. The results indicate that the enzyme activity is strongly inhibited by the presence of Eu(iii), which is suppressed by an excess of calcium. PMID- 28091655 TI - Probing the magnetic relaxation and magnetic moment arrangement in a series of Dy4 squares. AB - Three MU4-O bridged Dy4 squares, {[Dy4(MU4 O)(HL1)4(H2O)4]2(NO3)3(OH)}.2H2O.2CH3OH (1), [Dy4(MU4-O)(HL2)4(SCN)2].2H2O.4CH3OH (2) and [Dy4(MU4-O)(H2L3)2(SCN)2].6H2O (3) were assembled by using a Schiff base ligand and its dimerized and reduced congener, respectively. These complexes share a similar MU4-O bridged Dy4 core, while, both the coordination geometry and metal-ligand interactions are slightly changed upon the modulation of the ligands, resulting in distinct single-molecular magnetic (SMM) and single molecular toroic (SMT) properties. In complex 1, the Schiff base ligands are in an antiparallel fashion and all DyIII ions are in a similar coordination geometry, realizing the toroidal arrangement of magnetic moments. For complex 2, the reduced ligand H3L2 in a parallel fashion results in double relaxation processes and a 9-fold increase of the Ueff. Interestingly, with the use of the dimerized ligand H6L3, we obtained complex 3, which is similar to complex 2, while due to the slight changes of the coordination environment both the single molecular magnetic property and toroidal magnetic moments almost disappeared. PMID- 28091654 TI - Cisplatin and valproate released from the bifunctional [Pt(IV)Cl2(NH3)2(valproato)2] antitumor prodrug or from liposome formulations: who does what? AB - The cisplatin-sensitive human ovarian cancer cells A2780 have been challenged with cationic liposomes containing the single drug cisplatin or valproate or their combination with an approximate 1 : 2 molar ratio, i.e. the same ratio present in preformed (OC-6-33)-diamminedichloridobis(valproato)platinum(iv), that releases such metabolites by intracellular Pt(iv) -> Pt(ii) reduction. The results of this comparison confirm that valproate barely penetrates cells unless it is transported by liposomes or it is coordinated to a lipophilic Pt(iv) assembly. The two drugs have a synergistic action, cisplatin being the more potent antiproliferative agent. Even if the preformed (OC-6-33) diamminedichloridobis(valproato)platinum(iv) releases cisplatin and valproate in the same amount as the liposome formulation, the Pt(iv) derivative is more active. This important feature, common to all Pt(iv) complexes having very lipophilic carboxylates, is attributable to their propensity to remain in cells and to continuously bind DNA, unlike cisplatin that is partially removed from cells by efficient efflux pathways. PMID- 28091656 TI - Synthesis and characterisation of p-block complexes of biquinoline at different ligand charge states. AB - The first examples of p-block coordination complexes of biquinoline, namely [(biq)BCl2]Cl and [(biq)BCl2], were synthesized and structurally characterized. The acquired data allowed the estimation of the ligand charge state based on its metrical parameters. The subsequent use of this protocol, augmented with theoretical calculations, revealed ambiguities in the published data for transition metal complexes of biquinoline. PMID- 28091658 TI - Insights into the formation of inorganic heterocycles via cyclocondensation of primary amines with group 15 and 16 halides. AB - Cyclocondensation is a major preparative route for the generation of inorganic heterocycles especially in the case of ring systems involving a Group 15 or 16 element linked to nitrogen. This Perspective will consider recent experimental and computational studies involving the reactions of primary amines (or their synthetic equivalents) with pnictogen and chalcogen halides. The major focus will be a discussion of the identity and role of acyclic intermediates in the reaction pathways to ring formation, as well as the nature of the heterocycles so formed. The similarities and differences between the chemistry of group 15 and 16 systems are emphasised with a view to providing signposts for further investigations. PMID- 28091659 TI - Borane-catalyzed indole synthesis through intramolecular hydroamination. AB - The reaction of 2-alkynyl anilines with catalytic amounts of B(C6F5)3 (5 mol%) resulted in the formation of 2-substituted indoles according to an intramolecular hydroamination in good to excellent yields. Reaction intermediates as well as products were characterized by NMR spectroscopy and by X-ray crystallography. The domino hydroamination/hydrogenation sequence allowed the efficient synthesis of tetrahydroquinoline 8 in good yield. PMID- 28091660 TI - Universal wetting transition of an evaporating water droplet on hydrophobic micro and nano-structures. AB - Water-repellent, rough surfaces have a remarkable and beneficial wetting property: when a water droplet comes in contact with a small fraction of the solid, both liquid-solid adhesion and hydrodynamic drag are reduced. As a prominent example from nature, the lotus leaf-comprised of a wax-like material with micro- and nano-scaled roughness-has recently inspired numerous syntheses of superhydrophobic substrates. Due to the diverse applications of superhydrophobicity, much research has been devoted to the fabrication and investigations of hydrophobic micro-structures using established micro fabrication techniques. However, wetting transitions remain relatively little explored. During evaporation, a water droplet undergoes a wetting transition from a (low-frictional) partial to (adhesive) complete contact with the solid, destroying the superhydrophobicity and the self-cleaning properties of the slippery surface. Here, we experimentally examine the wetting transition of a drying droplet on hydrophobic nano-structures, a previously unexplored regime. In addition, using a theoretical analysis we found a universal criterion of this wetting transition that is characterized by a critical contact angle. Different from previous results showing different critical droplet sizes, our results show a universal, geometrically-dependent, critical contact angle, which agrees well with various data for both hydrophobic micro- and nano-structures. PMID- 28091657 TI - Zinc transport and the inhibition of the L-type calcium channel are two separable functions of ZnT-1. AB - Traditionally, proteins are considered to perform a single role, be it as an enzyme, a channel, a transporter or as a structural scaffold. However, recent studies have described moonlighting proteins that perform distinct and independent functions; for example, TRPM7 is both an ion channel and a kinase. ZnT-1 is a member of the Carrier Diffusion Facilitator family that is expressed throughout the phylogenetic tree from bacteria to humans. Since its cloning in 1995, ZnT-1 is considered a major extruder of Zn2+ based on its capability to protect cells against zinc toxicity. Recently, we reported that ZnT-1 inhibits the L-type calcium channel (LTCC), a major Zn2+ and Ca2+ entry pathway. Here we show that ZnT-1 is a dual-function protein by demonstrating that its abilities to exchange Zn2+/H+ and to inhibit the LTCC are independent of each other and are mediated by different parts of the protein. Specifically, mutations in the membrane-spanning helices that render ZnT-1 unable to transport zinc do not prevent it from inhibiting the LTCC. Moreover, a fragment consisting of the intracellular ZnT-1 C-terminal, which lacks all ion-transfer segments, inhibits the LTCC as efficiently as wild-type ZnT-1. Our data therefore indicates that ZnT 1 performs two structurally independent functions related to zinc homeostasis. PMID- 28091661 TI - Biochemical characterization of the selenoproteome in Gallus gallus via bioinformatics analysis: structure-function relationships and interactions of binding molecules. AB - Knowledge about mammalian selenoproteins is increasing. However, the selenoproteome of birds remains considerably less understood, especially concerning its biochemical characterization, structure-function relationships and the interactions of binding molecules. In this work, the SECIS elements, subcellular localization, protein domains and interactions of binding molecules of the selenoproteome in Gallus gallus were analyzed using bioinformatics tools. We carried out comprehensive analyses of the structure-function relationships and interactions of the binding molecules of selenoproteins, to provide biochemical characterization of the selenoproteome in Gallus gallus. Our data provided a wealth of information on the biochemical functions of bird selenoproteins. Members of the selenoproteome were found to be involved in various biological processes in chickens, such as in antioxidants, maintenance of the redox balance, Se transport, and interactions with metals. Six membrane-bound selenoproteins (SelI, SelK, SelS, SelT, DIO1 and DIO3) played important roles in maintaining the membrane integrity. Chicken selenoproteins were classified according to their ligand binding sites as zinc-containing matrix metalloselenoproteins (Sep15, MsrB1, SelW and SelM), POP-containing selenoproteins (GPx1-4), FAD-interacting selenoproteins (TrxR1-3), secretory transport selenoproteins (GPx3 and SelPa) and other selenoproteins. The results of our study provided new evidence for the unknown biological functions of the selenoproteome in birds. Future research is required to confirm the novel biochemical functions of bird selenoproteins. PMID- 28091652 TI - A novel 3-D photoluminescent cuprous chloride polymer based on bifunctional imidazolate/tetrazolate bridges. AB - A novel 3-D cuprous chloride polymer [CuCl(MU5-L)]n (1, HL = 1-tetrazole-4 imidazole-benzene) has been hydrothermally synthesized and structurally characterized. 1 displays a 3-D network with a bimodal fsc-3,5-Cmce-2 topological type constructed by the linkages of rare [CuCl]+ cations and L- ligands. The photoluminescence properties and density functional theory calculations of 1 have also been studied. PMID- 28091662 TI - Self-assembly, optical, thermal and electrochemical properties of bis-N-benzyl perylene diimide dye. AB - Flexible methylene containing N,N'-bis-(benzyl)-3,4,9,10 perylenebis(dicarboximide) (1) was synthesized. Self-assembled microstructures (hollow tubes, average length and width: 7.7 and 0.8 MUm) of 1 were also prepared (T-1). Comparative studies of the optical, thermal and electrochemical properties of 1 and T-1 have been extensively carried out. The T-1 hallow tubes have shown extremely broad absorption in the near-infrared (300-800 nm) region (NIR) even in solution and intensified conductivity in the solid-state compared to 1. Under daylight and a UV lamp (365 nm), the emission colors of 1 are uniform pink and fluorescent yellow, respectively. Under the same conditions the colors of T-1 change to deep brown and glowing red, respectively. Two different isopotential points obtained through CV scans for 1 indicate the presence of two interconvertible chromophores within the system. The results clearly indicate that the anodic and cathodic processes are extremely intensified in the self assembled T-1 structure. PMID- 28091664 TI - Broadband terahertz modulation in electrostatically-doped artificial trilayer graphene. AB - We report a terahertz optical modulator consisting of randomly stacked trilayer graphene (TLG) deposited on an oxidized silicon substrate by means of THz-Time Domain Spectroscopy (THz-TDS). Here, the gate tuning of the Fermi level of the TLG provides the fundamental basis for the modulation of THz transmission. We measured a 15% change in the THz transmission of this device over a broad frequency range (0.6-1.6 THz). We also observed a strong absorption >80% in the time-domain signals and a frequency independence of the conductivity. Furthermore, unlike previous studies, we find that the underlying silicon substrate, which serves as a gate electrode for the graphene, also exhibits substantial modulation of the transmitted THz radiation under applied voltage biases. PMID- 28091663 TI - Markedly enhanced up-conversion luminescence by combining IR-808 dye sensitization and core-shell-shell structures. AB - Rare-earth-doped up-conversion nanoparticles (UCNPs), which are capable of converting infrared light to shorter-wavelength photons, have attracted worldwide attention due to their unique characteristics. However, the emission brightness of UCNPs is greatly limited by the unsatisfactory absorptivity of lanthanide ions. Herein, we adopted a novel strategy to enhance the up-conversion intensity using NIR dye IR-808 as an antenna to sensitize the core-shell-shell structured NaGdF4:Yb,Er@NaGdF4:Yb@NaNdF4:Yb UCNPs. When excited with 808 nm light, the IR 808 emitted a broadband peak, which perfectly overlapped with the absorption of Nd3+ and Yb3+ ions. Thus, the active shell of NaNdF4:Yb can efficiently capture the emitted NIR photons and transfer them to the transition layer of NaGdF4:Yb. The transition layer acted as an energy bridge to connect the active shell and up converting zone, avoiding the energy back-transfer from the activators to Nd3+ ions. The optimized dye sensitization combined with the well-designed core-shell shell structure tremendously enhances the NIR photon absorptivity of UCNPs and eliminates the deleterious cross-relaxation between the activators and sensitizers, eventually leading to dramatic enhancement of the up-conversion intensity. This study provides a new insight into the dye-sensitized up conversion luminescence of rare earth-based nanoparticles and facilitates their practical applications. PMID- 28091665 TI - Trace element-protein interactions in endolymph from the inner ear of fish: implications for environmental reconstructions using fish otolith chemistry. AB - Otoliths, the biomineralised hearing "ear stones" from the inner ear of fish, grow throughout the lifespan of an individual, with deposition of alternating calciferous and proteinaceous bands occurring daily. Trace element : calcium ratios within daily increments measured by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) are often used in fisheries science to reconstruct environmental histories. There is, however, considerable uncertainty as to which elements are interacting with either the proteinaceous or calciferous zones of the otolith, and thus their utility as indicators of environmental change. To answer this, we used size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) of endolymph, the otolith growth medium, to determine the binding interactions for a range of elements. In addition, we used solution ICP-MS to quantify element concentrations in paired otolith and endolymph samples and determined relative enrichment factors for each. We found 12 elements that are present only in the proteinaceous fraction, 6 that are present only in the salt fraction, and 4 that are present in both. These findings have important implications for the reconstruction of environmental histories based on changes in otolith elemental composition: (1) elements occurring only in the salt fraction are most likely to reflect changes in the physico-chemical environment experienced during life; (2) elements occurring only in the proteinaceous fraction are more likely to reflect physiological rather than environmental events; and (3) elements occurring in both the salt and proteinaceous fractions are likely to be informative about both endogenous and exogenous processes, potentially reducing their utility in environmental reconstructions. PMID- 28091667 TI - Selective recognition of the di/trimethylammonium motif by an artificial carboxycalixarene receptor. AB - Chemical tools that recognise post-translational modifications have promising applications in biochemistry and in therapy. We report a simple carboxycalixarene that selectively binds molecules containing di/trimethylammonium moieties in isolation, in cell lysates and when incorporated in histone peptides. Our findings reveal the potential of using carboxycalixarene-based receptors to study epigenetic regulation. PMID- 28091666 TI - Chemoenzymatic synthesis of unmodified heparin oligosaccharides: cleavage of p nitrophenyl glucuronide by alkaline and Smith degradation. AB - A heparin oligosaccharide having a completely natural structure was successfully synthesized through a chemoenzymatic approach using an unnatural glycosyl acceptor, p-nitrophenyl glucuronide (GlcA-pNP). The use of an inexpensive and commercially available GlcA-pNP acceptor facilitates oligosaccharide recovery and purification on C-18 resin during chemoenzymatic synthesis. Oligosaccharide chain extension and modification afforded a heptasaccharide with gluconic acid residues at its reducing and non-reducing ends. Treatment with periodate oxidation followed by Smith degradation or alkaline elimination resulted in the selective cleavage of vicinal diol-containing glucuronic acid residues affording highly sulfated heparin pentasaccharides having a completely natural structure. This methodology should facilitate the chemoenzymatic synthesis of a family of highly sulfated heparin oligosaccharides with unmodified structures for biological evaluation. PMID- 28091668 TI - Effect of ammonia on chemical vapour deposition and carbon nanotube nucleation mechanisms. AB - Chemical vapour deposition (CVD) growth of carbon nanotubes is currently the most viable method for commercial-scale nanotube production. However, controlling the 'chirality', or helicity, of carbon nanotubes during CVD growth remains a challenge. Recent studies have shown that adding chemical 'etchants', such as ammonia and water, to the feedstock gas can alter the diameter and chirality of nanotubes produced with CVD. To date, this strategy for chirality control remains sub-optimal, since we have a poor understanding of how these etchants change the CVD and nucleation mechanisms. Here, we show how ammonia alters the mechanism of methane CVD and single-walled carbon nanotube nucleation on iron catalysts, using quantum chemical molecular dynamics simulations. Our simulations reveal that ammonia is selectively activated by the catalyst, and this enables ammonia to play a dual role during methane CVD. Following activation, ammonia nitrogen removes carbon from the catalyst surface exclusively via the production of hydrogen (iso)cyanide, thus impeding the growth of extended carbon chains. Simultaneously, ammonia hydrogen passivates carbon dangling bonds, which impedes nanotube nucleation and promotes defect healing. Combined, these effects lead to slower, more controllable nucleation and growth kinetics. PMID- 28091669 TI - Oxidative decarbonylative coupling of aliphatic aldehydes with methacryloyl benzamides to generate isoquinoline-1,3(2H,4H)-diones. AB - Alkyl-substituted isoquinoline-1,3(2H,4H)-diones were prepared by decarbonylative coupling of N-alkyl-N-methacryloylbenzamides and aliphatic aldehydes under metal free conditions. The reaction undergoes subsequent decarbonylation, radical addition and cyclization processes with aliphatic aldehydes as the cheap and abundant alkyl radical source. This procedure offers a complementary approach to the convenient generation of alkyl-substituted isoquinoline-1,3(2H,4H)-diones. PMID- 28091670 TI - Enhanced temperature effect of electrorheological fluid based on cross-linked poly(ionic liquid) particles: rheological and dielectric relaxation studies. AB - Recent research of using poly(ionic liquid) (PIL) particles as the dispersal phase has provided a new strategy to develop a high-performance anhydrous polyelectrolyte-based electrorheological (ER) fluid. However, the working temperature range of the ER fluid of PIL particles is still narrow due to an inherently low glass transfer temperature caused by the plasticization of polyatomic organic counter ions in PILs. In this paper, we develop a new ER system based on cross-linked PIL (C-PIL) particles and demonstrate that crosslinking with a suitable degree only slightly degrades the ER properties but significantly improves the working temperature range of the ER fluid of PIL particles. By using differential scanning calorimetry, rheology, and dielectric spectroscopy, we systematically study the ER properties of C-PILs and their temperature dependence at different crosslinking levels and understand the mechanism behind the improved temperature effect. The results indicate that crosslinking can effectively increase the glass transition temperature of PIL particles and enhance local ion-motion induced interfacial polarization by suppressing the thermally promoted long-range drift of mobile counter ions in the PIL matrix, and this results in the improved temperature effect of the ER fluid of C-PIL particles. PMID- 28091671 TI - Developing the family of picolinate ligands for Mn2+ complexation. AB - We have reported here a series of ligands containing pentadentate 6,6' (azanediylbis(methylene))dipicolinic acid units that differ in the substituent present at the amine nitrogen atom (acetate: H3DPAAA; phenyl: H2DPAPhA; dodecyl: H2DPAC12A; 4-hexylphenyl: H2DPAC6PhA). The protonation constants of the hexadentate DPAAA3- and pentadentate DPAPhA2- ligands and the stability constants of their Mn2+ complexes were determined using pH-potentiometry (25 degrees C, 0.15 M NaCl). The mono-hydrated [Mn(DPAAA)]- complex (log KMnL = 13.19(5)) was found to be considerably more stable than the bis-hydrated [Mn(DPAPhA)] analogue (log KMnL = 9.55(1)). A detailed 1H and 17O NMR relaxometric study was carried out to determine the parameters that govern the proton relaxivities of these complexes. The [Mn(DPAC12A)] complex, which contains a dodecyl lipophilic chain, forms micelles in solution characterized by a critical micellar concentration (cmc) of 96(9) MUM. The lipophilic [Mn(DPAC6PhA)] and [Mn(DPAC12A)] derivatives form rather strong adducts with Human Serum Albumin (HSA) with association constants of 7.1 +/- 0.1 * 103 and 1.3 +/- 0.4 * 105 M-1, respectively. The X-ray structure of the complex {K(H2O)4}{[Mn(DPAAA)(H2O)]}2 shows that the Mn2+ ion in [Mn(DPAAA)]- is coordinated to the six donor atoms of the ligand, a coordinated water molecule completing the pentagonal bipyramidal coordination environment. PMID- 28091672 TI - A RaPID way to discover nonstandard macrocyclic peptide modulators of drug targets. AB - Studies of the fundamental nature of RNA catalysis and the potential mechanism of a shift from the "RNA world" to proteinaceous life lead us to identify a set of ribozymes (flexizymes) capable of promiscuous tRNA acylation. Whilst theoretically and mechanistically interesting in their own right, flexizymes have turned out to have immense practical value for the simple synthesis of tRNAs acylated with unusual amino acids, which in turn can be used for the ribosomal synthesis of peptides containing non-canonical residues. Using this technique, it is possible to synthesise peptides containing a range of structural features (macrocyclic backbones, backbone N-methylation, d-stereochemistry, etc.) commonly observed in natural product secondary metabolites, a chemical class that has historically been a rich source of drug-like molecules. Moreover, when combined with biochemical display screening technologies, this synthetic approach can be used to generate (and screen for target affinity) extremely diverse (in excess of 1012 compound) chemical libraries, making it an extraordinary tool for drug discovery. The current review charts the history of flexizyme technology and its use for non-canonical peptide synthesis and screening. PMID- 28091673 TI - Conformational and electronic effects on the formation of anti cyclobutane pyrimidine dimers in G-quadruplex structures. AB - Cyclobutane pyrimidine dimers (CPDs) are the most commonly formed photochemical products when nucleic acids interact with UV radiation. In duplex DNA, the relative inflexible structure allows for only the cis, syn CPD isomer to be formed. G-quadruplex structures, however, have loops that are more flexible and allow for different orientations of the bases to interact. As a result, the highly unusual formation of an anti CPD has been observed in these structures. Due to the close proximity between two opposing loops containing the TTA sequence in two G-quadruplex structures (called "form-3" and "basket"), a high yield of anti CPD formation was expected in these structures. However, while significant yields of anti CPDs are observed in form-3, the anti CPD is hardly observed in the basket structure. To account for this inconsistency, we examine the process of anti CPD formation in form-3 and basket structures using simulations at the atomistic level. Here, we consider the conformational effect using MD simulations, which show whether the formation of the anti CPD is structurally feasible. Quantum mechanical/molecular mechanical (QM/MM) calculations of excited states are also used to consider the electronic effect by an adjacent guanine base which can quench the formation of the anti CPD through charge transfer (CT). Our results are in qualitative agreement with the experimental results, predicting a significant yield of the anti CPD in the form-3 structure and a negligible yield in the basket structure, while they also predict the formation of the cis, syn CPD between two opposing loops in form-3. Most importantly, our simulation results show that the yields of the anti CPD in the G-quadruplex are affected significantly by both conformational and electronic effects. PMID- 28091674 TI - A site-holding effect of TiO2 surface hydroxyl in the photocatalytic direct synthesis of 1,1-diethoxyethane from ethanol. AB - To understand the mechanism of the photocatalytic direct synthesis of 1,1 diethoxyethane (DEE) from ethanol is vital for enhancing the reaction efficiency. Based on photocatalytic data of different phase TiO2 and F-TiO2 catalysts, radical trapping data, and GC-MS data, we proposed a photocatalytic mechanism for the preparation of both DEE in neat ethanol and 2,3-butanediol (2,3-BD) in ethanol-H2O using photocatalytic methods. In neat ethanol, hydroxyl isn't involved in the catalytic cyclic process but hydroxyl has an indirect site holding effect, thus leading to more hydroxyl groups with higher activity. In ethanol-H2O, although the strong oxidant OH radical is involved, fewer OH groups lead to higher selectivity of 2,3-BD. The interaction of the reactant/solvent with the surface group of the catalyst is important in the activity and selectivity of photocatalytic reactions. This finding gives fundamental insight into the role of TiO2 surface hydroxyl in the photocatalytic dehydrogenation process of alcohols and opens a promising path to obtaining both high selectivity and high conversion in TiO2-based photocatalytic activity. PMID- 28091675 TI - A highly sensitive SERS-based platform for Zn(ii) detection in cellular media. AB - We report a highly sensitive and selective surface-enhanced Raman scattering (SERS)-based detection of aqueous Zn(ii) ions (limit of detection 10-14 M). Spectral changes for a silver nanoparticle-bound Raman reporter upon Zn(ii) chelation constitutes the assay, which is applied to drinking water and to measurements of cellular uptake of Zn(ii). PMID- 28091676 TI - Hemispherical platinum : silver core : shell nanoparticles for miRNA detection. AB - Defects within a self-assembled monolayer (SAM) of dodecanethiol on gold have been used as nucleation sites for the electrodeposition of mushroom shaped platinum nanoparticles (PtNPs). The top surfaces of these PtNPs were then decorated with a layer of silver creating a hemispherical - platinum : silver core : shell nanoparticle (Pt-AgNP). Thiolated probe strand miRNA was then immobilised onto the upper silver surface. These regioselectively modified particles were desorbed by applying a current jump to yield nanoparticles capable of hybridising to a complementary miRNA target with electrocatalysis occurring on the non-functionalized lower surface. A second electrode was functionalized with single stranded capture miRNA that has a sequence that is complementary to an miRNA, miR-132, associated with the childhood cancer, Neuroblastoma but leaves a section of the target available to bind the nucleic acid sequence on the core : shell Pt-AgNPs. Following hybridization of the target and capture strands the surface was exposed to the miRNA labelled electrocatalytic Pt-AgNPs. The concentration of the target was then determined by monitoring the current associated with the reduction of hydrogen peroxide in a solution of H2SO4. Calibration plots of the log[miRNA] vs. faradaic current were linear from 1 aM to 1 MUM and aM concentrations could be detected without the need for chemical amplification of the target, e.g., using PCR or NASBA. The regioselectively modified particles were also immobilised within the interior of gold microcavity arrays via miRNA hybridisation and their Raman properties investigated. PMID- 28091677 TI - Model cheese aroma perception is explained not only by in vivo aroma release but also by salivary composition and oral processing parameters. AB - The aim of the present paper was to determine, from four model cheeses differing in fat content and firmness and consumed by fourteen well characterised subjects, the respective impacts of in vivo aroma release, bolus rheology, chewing activity, mouth coating and salivary composition on dynamic aroma perception. The originality of the approach is that it considers all the parameters together and is able to evaluate their relative contribution using multi-block partial least square (MB-PLS) regression. The fruity aroma perception of the more hydrophilic compound (ethyl propanoate) was related to its dynamic release parameters before swallowing whereas the blue cheese aroma perception of the more hydrophobic compound (nonan-2-one) was related to its dynamic release parameters after swallowing and was highly impacted by mouth coating. Moreover the MB-PLS approach made it possible to evidence the combined effects of saliva composition and cross modal interactions to understand why in some cases dynamic aroma perception could not be explained by dynamic in vivo aroma release data. Subjects with a low sodium content in saliva perceived fruity aroma which is not congruent with saltiness as less intense and salt- congruent (blue cheese) aroma as more intense, which was explained by their higher sensitivity to salt. Subjects with high lipolysis activity perceived fruity aroma which is not congruent to fat as less intense and fat-congruent (blue cheese) aroma as more intense, which should be explained by the link between lipolysis activity and fat sensitivity. These results could be considered for the reformulation of foods towards specific populations taking into account nutritional recommendations. PMID- 28091678 TI - Pepsin egg white hydrolysate modulates gut microbiota in Zucker obese rats. AB - There is limited information that relates the intake of food-derived bioactive peptides and the gut microbiota. We have previously described a pepsin hydrolysate of egg white (EWH) that ameliorates fat accumulation and dyslipidemia, while reducing oxidative stress and inflammation markers in obese Zucker rats. The aim of this study was to associate the beneficial effects of EWH with gut microbiota changes in these animals. Obese Zucker rats received daily 750 mg kg-1 EWH in drinking water for 12 weeks and faeces were analysed for microbial composition and metabolic compounds in comparison with Zucker lean rats and obese controls. EWH supplementation modulated the microbiological characteristics of the obese rats to values similar to those of the lean rats. Specifically, counts of total bacteria, Lactobacillus/Enterococcus and Clostridium leptum in EWH fed obese Zucker rats were more similar to the lean rats than to the obese controls. Besides, feeding the obese Zucker rats with EWH reduced (P < 0.05) the faecal concentration of lactic acid. The physiological benefits of EWH in the improvement of obesity associated complications of Zucker rats could be associated with a more lean-like gut microbiota and a tendency to diminish total short-chain fatty acids (SCFA) production and associated obesity complications. The results warrant the use of pepsin egg white hydrolysate as a bioactive food ingredient. PMID- 28091680 TI - Protective effects of dietary glycine and glutamic acid toward the toxic effects of oxidized mustard oil in rabbits. AB - The protective role of glycine and glutamic acid against the toxic effects of oxidized oil was studied for the first time. Mustard seed oil was thermally oxidized and characterized for quality characteristics and polyphenolic composition using reversed phase HPLC-DAD. Significant changes in the quality characteristics occurred with thermal oxidation. Fourteen polyphenolic compounds were identified and quantified in oils. Quercetin-3-glucoside, quercetin-3 feruloylsophoroside, catechin, quercetin-3-rutinoside, quercetin-3,7-diglucoside, sinapic acid and vanillic acid hexoside were the major compounds in the fresh and oxidized oil. Oxidized, un-oxidized mustard oils, glycine and glutamic acid were given to rabbits alone or in combination. The biochemical responses were studied in terms of haematological and biochemical parameters and histopathology. It has been observed that biochemical and haematological parameters were adversely affected by the oxidized oil, while supplementation of both amino acids was beneficial in normalizing these parameters. Both amino acids alone have no significant effects, however, oxidized oil affected the liver by enhancing fat accumulation, causing hepatitis, reactive Kupffer cells and necrosis. The co administration of oxidized oils with glycine or glutamic acid revealed significant recovery of the liver structure and function. In conclusion, glycine or glutamic acid is beneficial and protective against food toxicity and can be considered as an ameliorative food supplement. PMID- 28091679 TI - Sustainability of renewable fuel infrastructure: a screening LCA case study of anticorrosive graphene oxide epoxy liners in steel tanks for the storage of biodiesel and its blends. AB - Biodiesel is a widely used fuel that meets the renewable fuel standards developed under the Energy Policy Act of 2005. However, biodiesel is known to pose a series of abiotic and biotic corrosion risks to storage tanks. A typical practice (incumbent system) used to protect the tanks from these risks include (i) coating the interior surface of the tank with a solvent-free epoxy (SFE) liner, and (ii) adding a biocide to the tank. Herein, we present a screening-level life-cycle assessment study to compare the environmental performance of a graphene oxide (GO)-epoxy (GOE) liner with the incumbent system. TRACI was used as an impact assessment tool to model the midpoint environmental impacts in ten categories: global warming potential (GWP, kg CO2 eq.); acidification potential (AP, kg SO2 eq.); potential human health damage impacts due to carcinogens (HH-CP, CTUh) and non-carcinogens (HH-NCP, CTUh); potential respiratory effects (REP, kg PM2.5 eq.); eutrophication potential (EP, kg N eq.); ozone depletion potential (ODP kg CFC-11 eq.); ecotoxicity potential (ETXP, CTUe); smog formation potential (SFP kg O3 eq.) and fossil fuel depletion potential (FFDP MJ surplus). The equivalent functional unit of the LCA study was designed to protect 30 m2 of the interior surface (unalloyed steel sheet) of a 10 000 liter biodiesel tank against abiotic and biotic corrosion during its service life of 20 years. Overall, this LCA study highlights the improved environmental performance for the GOE liner compared to the incumbent system, whereby the GOE liner showed 91% lower impacts in ODP impact category, 59% smaller in REP, 62% smaller in AP, 67-69% smaller in GWP and HH-CP, 72-76% smaller in EP, SFP, and FFDP, and 81-83% smaller ETXP and HH-NCP category results. The scenario analysis study revealed that these potential impacts change by less than 15% when the GOE liners are functionalized with silanized-GO nanosheets or GO-reinforced polyvinyl carbazole to improve the antimicrobial properties. The results from an uncertainty analysis indicated that the impacts for the incumbent system were more sensitive to changes in the key modeling parameters compared to that for the GOE liner system. PMID- 28091681 TI - Microbial rRNA sequencing analysis of evaporative cooler indoor environments located in the Great Basin Desert region of the United States. AB - Recent studies conducted in the Great Basin Desert region of the United States have shown that skin test reactivity to fungal and dust mite allergens are increased in children with asthma or allergy living in homes with evaporative coolers (EC). The objective of this study was to determine if the increased humidity previously reported in EC homes leads to varying microbial populations compared to homes with air conditioners (AC). Children with physician-diagnosed allergic rhinitis living in EC or AC environments were recruited into the study. Air samples were collected from the child's bedroom for genomic DNA extraction and metagenomic analysis of bacteria and fungi using the Illumina MiSeq sequencing platform. The analysis of bacterial populations revealed no major differences between EC and AC sampling environments. The fungal populations observed in EC homes differed from AC homes. The most prevalent species discovered in AC environments belonged to the genera Cryptococcus (20%) and Aspergillus (20%). In contrast, the most common fungi identified in EC homes belonged to the order Pleosporales and included Alternaria alternata (32%) and Phoma spp. (22%). The variations in fungal populations provide preliminary evidence of the microbial burden children may be exposed to within EC environments in this region. PMID- 28091683 TI - Geropsychiatric Nursing: What's in Your Toolkit? PMID- 28091682 TI - All-inorganic perovskite quantum dot/mesoporous TiO2 composite-based photodetectors with enhanced performance. AB - High-performance all-inorganic perovskite-based metal/semiconductor/metal (MSM) photodetectors with a bilayer composite film of mesoporous TiO2 and CsPbBr3 quantum dots as a photosensitizer were prepared. The photodetectors demonstrated significantly improved on/off ratios of nearly three orders of magnitude compared to those of pure bromine-based perovskite nanocrystal photodetectors with an MSM structure. PMID- 28091687 TI - Analyzing Change in Nursing Home Information Technology Sophistication: A 2-Year Survey. AB - Nursing home (NH) health information technology (IT) is becoming more prevalent across the country. Currently, a national sample of NHs is being surveyed for 3 consecutive years to determine trends in NH IT sophistication (e.g., measures of IT capabilities, extent of IT use, IT integration with internal and external stakeholders). IT sophistication is measured in resident care, clinical support, and administrative activities. The current article provides details of the differences in NH IT sophistication reported by administrators completing Year 1 and Year 2 surveys. IT in clinical support (i.e., laboratory, pharmacy, and radiology) had the greatest differences. This difference is expected because these areas typically require external contracts, making it dificult to fit IT with existing workflows, which is important for sustained adoption. [Journal of Gerontological Nursing, 43(1), 17-21.]. PMID- 28091686 TI - A Retrospective Chart Review of Two Different Insulin Administration Systems on Glycemic Control in Older Adults in Long-Term Care. AB - The current retrospective chart review compared glycemic control and cost impact of two insulin administration systems, V-Go(r) versus usual care with standard of care (SOC) insulin injections, in eight patients residing in a nursing home (NH). A total of 1,937 blood glucose (BG) values were collected over 61 days. Significant improvements were observed for the V-Go versus SOC group in time in range 100 mg/dL to 200 mg/dL (V-Go 59.09% vs. SOC 34.02%; p < 0.001), reduced BG fluctuations as measured by standard deviation (V-Go 61.2 vs. SOC 92.1; p < 0.001), and improved mean daily BG (V-Go 159.38 mg/dL vs. SOC 223.86 mg/dL; p < 0.001). The estimated A1c change, calculated from BG values, decreased from 8.9% to 7.2% in the V-Go group and increased from 9.0% to 9.4% in the SOC group. Compared to SOC, use of V-Go decreased the mean time for insulin administration by nursing staff by 26.3 minutes per patient per day and associated labor costs by $328.75 per patient per month. Insulin administration with V-Go may improve glycemic control and reduce administration costs compared to existing care in the NH setting. [Journal of Gerontological Nursing, 43(1), 10-16.]. PMID- 28091689 TI - What Research Has Shaped Geriatrics Since the Start of the New Millennium? PMID- 28091690 TI - ? PMID- 28091691 TI - ? PMID- 28091692 TI - ? PMID- 28091693 TI - ? PMID- 28091694 TI - [Evidence-based TEP technique]. AB - The guidelines of all international hernia societies recommend as procedures of choice the laparoendoscopic techniques total extraperitoneal patch plasty (TEP) and transabdominal preperitoneal patch plasty (TAPP) as well as the open Lichtenstein operation for elective inguinal hernia repair. The learning curve associated with the laparoendoscopic techniques, in particular TEP, is longer than that for the open Lichtenstein technique due to the complexity of the procedures. Accordingly, for laparoendoscopic techniques it is particularly important that the operations are conducted in a standardized manner in compliance with the evidence-based recommendations given for the technical details. When procedures are carried out in strict compliance with the guidelines of the international hernia societies, low rates of perioperative complications, complication-related reoperations, recurrences and chronic pain can be expected for TEP. Compliance with the guidelines can also positively impact mastery of the learning curve for TEP. The technical guidelines on TEP are based on study results and on the experiences of numerous experts; therefore, it is imperative that they are implemented in routine surgical practice. PMID- 28091695 TI - [Telemedicine]. PMID- 28091696 TI - Radiation dose reduction in parasinus CT by spectral shaping. AB - INTRODUCTION: Spectral shaping aims to narrow the X-ray spectrum of clinical CT. The aim of this study was to determine the image quality and the extent of radiation dose reduction that can be achieved by tin prefiltration for parasinus CT. METHODS: All scans were performed with a third generation dual-source CT scanner. A study protocol was designed using 100 kV tube voltage with tin prefiltration (200 mAs) that provides image noise levels comparable to a low-dose reference protocol using 100 kV without spectral shaping (25 mAs). One hundred consecutive patients were prospectively enrolled and randomly assigned to the study or control group. All patients signed written informed consent. The study protocol was approved by the local Institutional Review Board and applies to the HIPAA. Subjective and objective image quality (attenuation values, image noise, and contrast-to-noise ratio (CNR)) were assessed. Radiation exposure was assessed as volumetric CT dose index, and effective dose was estimated. Mann-Whitney U test was performed for radiation exposure and for image noise comparison. RESULTS: All scans were of diagnostic image quality. Image noise in air, in the retrobulbar fat, and in the eye globe was comparable between both groups (all p > 0.05). CNReye globe/air did not differ significantly between both groups (p = 0.7). Radiation exposure (1.7 vs. 2.1 mGy, p < 0.01) and effective dose (0.055 vs. 0.066 mSv, p < 0.01) were significantly reduced in the study group. CONCLUSION: Radiation dose can be further reduced by 17% for low-dose parasinus CT by tin prefiltration maintaining diagnostic image quality. PMID- 28091697 TI - Heat shock transcription factor 1 protects against pressure overload-induced cardiac fibrosis via Smad3. AB - : Fibrotic cardiac muscle exhibits high stiffness and low compliance which are major risk factors of heart failure. Although heat shock transcription factor 1 (HSF1) was identified as an intrinsic cardioprotective factor, the role that HSF1 plays in cardiac fibrosis remains unclear. Our study aims to investigate the role of HSF1 in pressure overload-induced cardiac fibrosis and the underlying mechanism. HSF1 phosphorylation was significantly downregulated in transverse aortic constriction (TAC)-treated mouse hearts and mechanically stretched cardiac fibroblasts (cFBs). HSF1 transgenic (TG) mice, HSF1 deficient heterozygote (KO) mice, and their wild-type littermates were subjected to sham or TAC surgery for 4 weeks. HSF1 overexpression significantly attenuated pressure overload-induced cardiac fibrosis and dysfunction. Conversely, HSF1 KO mice showed deteriorated fibrotic response and cardiac dysfunction upon TAC. Moreover, we uncovered that overexpression of HSF1 protected against fibrotic response of cFBs to pressure overload. Mechanistically, we observed that the phosphorylation and the nuclear distribution of the Smad family member 3 (Smad3) were significantly decreased in HSF1-overexpressing mouse hearts, while being greatly increased in HSF1 KO mouse hearts upon TAC, compared to the control hearts, respectively. Similar alteration of Smad3 phosphorylation and nuclear distribution were found in isolated mouse cardiac fibroblasts and mechanically stretched cFBs. Constitutively active Smad3 blocked the anti-fibrotic effect of HSF1 in cFBs. Furthermore, we found a direct binding of phosphorylated HSF1 and Smad3, which can be suppressed by mechanical stress. In conclusion, the present study demonstrated for the first time that HSF1 acts as a novel negative regulator of cardiac fibrosis by blocking Smad3 activation. KEY MESSAGES: HSF1 activity is decreased in fibrotic hearts. HSF1 overexpression attenuates pressure overload-induced cardiac fibrosis and dysfunction. Deficiency of HSF1 deteriorates fibrotic response and cardiac dysfunction upon TAC. HSF1 inhibits phosphorylation and nuclear distribution of Smad3 via direct binding to Smad3. Active Smad3 blocks the anti-fibrotic effect of HSF1. PMID- 28091699 TI - Musculoskeletal MRI findings of juvenile localized scleroderma. AB - BACKGROUND: Juvenile localized scleroderma comprises a group of autoimmune conditions often characterized clinically by an area of skin hardening. In addition to superficial changes in the skin and subcutaneous tissues, juvenile localized scleroderma may involve the deep soft tissues, bones and joints, possibly resulting in functional impairment and pain in addition to cosmetic changes. OBJECTIVE: There is literature documenting the spectrum of findings for deep involvement of localized scleroderma (fascia, muscles, tendons, bones and joints) in adults, but there is limited literature for the condition in children. We aimed to document the spectrum of musculoskeletal magnetic resonance imaging (MRI) findings of both superficial and deep juvenile localized scleroderma involvement in children and to evaluate the utility of various MRI sequences for detecting those findings. MATERIALS AND METHODS: Two radiologists retrospectively evaluated 20 MRI studies of the extremities in 14 children with juvenile localized scleroderma. Each imaging sequence was also given a subjective score of 0 (not useful), 1 (somewhat useful) or 2 (most useful for detecting the findings). RESULTS: Deep tissue involvement was detected in 65% of the imaged extremities. Fascial thickening and enhancement were seen in 50% of imaged extremities. Axial T1, axial T1 fat-suppressed (FS) contrast-enhanced and axial fluid-sensitive sequences were rated most useful. CONCLUSION: Fascial thickening and enhancement were the most commonly encountered deep tissue findings in extremity MRIs of children with juvenile localized scleroderma. Because abnormalities of the skin, subcutaneous tissues and fascia tend to run longitudinally in an affected limb, axial T1, axial fluid-sensitive and axial T1 FS contrast-enhanced sequences should be included in the imaging protocol. PMID- 28091698 TI - [Clotrimazole and ciclopirox olamine respectively in combination with methylprednisolone aceponate as extemporaneous formulations]. AB - The combination of topical fungicide and glucocorticoids has been proven as a successful therapy of cutaneous mycoses with accompanying inflammatory reactions, particularly when used at an early stage. Various national and international therapeutic guidelines recommend this practice. In this context, two individually manufactured formulations have been developed and tested for stability: the combination of methylprednisolone aceponate-a topical glucocorticoid with the therapeutic index of 2.0-with clotrimazole and with ciclopirox olamine, respectively. This has been conducted in compliance with the requirements for quality controlled extemporaneous formulations and the legal framework of the German Pharmacy Working Regulations (Apothekenbetriebsordnung). There are now two formulations for clinical use that are microbiologically, physically, and chemically stable, which combine methylprednisolone aceponate-a glucocorticoid with a good risk-benefit ratio-with the broad-spectrum fungicides clotrimazole and, for the first time, ciclopirox olamine. PMID- 28091701 TI - ? PMID- 28091702 TI - Platelet receptor Gene (P2Y12, P2Y1) and platelet glycoprotein Gene (GPIIIa) polymorphisms are associated with antiplatelet drug responsiveness and clinical outcomes after acute minor ischemic stroke. AB - PURPOSE: Patients with minor ischemic stroke (MIS) are at high risk of recurrent ischemic stroke (RIS). The aim of this study was to evaluate the effects of platelet receptor gene (P2Y12, P2Y1) and glycoprotein gene (GPIIIa) polymorphisms, as well as their interactions, on antiplatelet drug responsiveness and clinical outcomes in patients with acute MIS. METHODS: We prospectively enrolled 426 patients with acute MIS who had been receiving combined aspirin and clopidogrel treatment for at least 3 months. Prevalence of seven variants in P2Y12, P2Y1, and GPIIIa genes were examined using mass spectrometry. Gene-gene interactions were evaluated using generalized multifactor dimensionality reduction (GMDR) analysis. Antiplatelet drug responsiveness was assessed by platelet aggregation assay. All patients were followed for 90 days. Primary outcomes were defined as a composite of RIS, myocardial infarction (MI), and death. RESULTS: The incidence of primary outcomes was 10.8% (46/426; 40 had RIS, 2 died, and 4 had MI) during the first 90 days after stroke. No significant differences were found regarding genotype frequencies of the seven variants between those with and without incidence of primary outcomes. However, we observed significant gene-gene interaction between rs16863323 and rs2317676 polymorphisms. The high-risk interactive genotypes were independently associated with poor antiplatelet drug responsiveness and increased risk of primary outcomes. CONCLUSION: Responsiveness to antiplatelet drugs and the risks for adverse clinical events in this MIS cohort appear to be multifactorial since the outcomes were not mediated by single gene polymorphisms. PMID- 28091700 TI - Computed tomography localization of the appendix in the pediatric population relative to the lumbar spine. AB - BACKGROUND: Computed tomography (CT) is commonly used to evaluate suspected acute appendicitis. Although very effective, CT uses ionizing radiation, exposing patients to an increased risk of cancer. OBJECTIVE: This study assessed the potential for decreasing the field of view of the CT (and therefore the dose to the patient) in the evaluation of suspected acute appendicitis in children. MATERIALS AND METHODS: This study was a retrospective review of prospectively collected data from 212 consecutive patients who underwent CT for suspected acute appendicitis. The most superior aspect of the appendix with respect to vertebral bodies was recorded. Age, gender and diagnosis (negative, acute appendicitis or alternative diagnosis) were noted. RESULTS: The appendix was visualized in 190 of 212 subjects (89.6%). Overall, all visualized appendixes were located at or below the level of L1. Sixty-three of the subjects (29.7%) were diagnosed with acute appendicitis via CT imaging. All appendixes in patients with acute appendicitis were located at or below the level of the L3 vertebral body, predominating at the level of L5. Six subjects (3.1%) received alternative diagnoses, including pneumonia, pyelonephritis, small bowel obstruction and infected urachal cyst. There were no differences in appendix location with regard to diagnosis, gender, or age (P=0.664, 0.748 and 0.705, respectively). CONCLUSION: CT field of view may be decreased to the level of L1 or L3 superiorly, decreasing radiation dose without affecting the rate of appendix visualization. PMID- 28091703 TI - Bolus application of landiolol and esmolol: comparison of the pharmacokinetic and pharmacodynamic profiles in a healthy Caucasian group. AB - PURPOSE: The aim of this prospective study was to compare in non-Asian subjects the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of two short-acting cardioselective beta1-adrenergic antagonists, landiolol and esmolol, after administration of three different bolus dosages. MATERIALS AND METHODS: We conducted a single-center, prospective, double-blinded, randomized study in three cross-over periods with 12 healthy subjects (7 women and 5 men, mean age of 24.5 +/- 6.9 years) each receiving three doses of landiolol (0.1, 0.2, and 0.3 mg/kg BW) either in a newly developed concentrate i.v. formulation (Rapibloc(r) 20 mg/2 mL concentrate) or a lyophilized formulation, or three doses of esmolol (0.5, 1, and 1.5 mg/kg BW) in an i.v. formulation (Brevibloc(r) 100 mg/10 mL). PK and PD parameters, safety, and tolerability were assessed. FINDINGS: Results of the two landiolol formulations were reported previously and were similar. For the landiolol concentrate formulation and esmolol, maximum blood concentrations were rapidly reached (mean t max ranged between 1.8 and 3.0 min for landiolol and 1.8 to 2.4 min for esmolol). The parent drugs disappeared very fast from the blood stream, with a t 1/2 of 3.2 +/- 1.2 (SD) minutes and 3.7 +/- 2.1 (SD) minutes for the low doses of landiolol and esmolol, respectively. Despite comparable injection rates (0.1 or 0.5 mg/kg/15 s for landiolol and esmolol, respectively), the onset of significant heart rate reduction occurred earlier in response to landiolol (1 min) than in response to esmolol (2 min). In addition, significantly lower heart rate values were obtained at every dose level of landiolol, in comparison to esmolol (p < 0.05). Both compounds reduced the systolic blood pressure to a comparable degree. Especially at the highest dose, the duration of blood pressure reduction was longer under esmolol compared to landiolol. Seven mild to moderate adverse events occurred after administration of landiolol, and five occurred after administration of esmolol. No serious adverse events were reported in this study. IMPLICATIONS: Heart rate reduction induced by a new liquid formulation of landiolol occurred faster, was more pronounced, and lasted longer than the effects of corresponding standard esmolol doses. Both agents reduced systolic blood pressure to a comparable degree, but the blood pressure decrease lasted longer after esmolol infusion. The local tolerance and safety profiles of the two formulations were similar. In summary, compared to esmolol, landiolol shows a more prominent and pronounced bradycardic effect in relation to its blood pressure-lowering effect, an action profile that might be of specific advantage in the perioperative setting. TRIAL REGISTRATION: NCT01652898 and 2012 002127-14. https://clinicaltrials.gov/ct2/show/NCT01652898?term=landiolol&rank=7. PMID- 28091704 TI - Medical students' medication communication skills regarding drug prescription-a qualitative analysis of simulated physician-patient consultations. AB - PURPOSE: Poor medication communication of physicians to patients is detrimental, e.g. for medication adherence. Reasons for physicians' deficits in medication communication may be unfavourable conditions in daily practice or already insufficient training during their (undergraduate) medical studies. We explored medical students' communication on new medications in simulated physician-patient conversations to identify actual deficits indicating apparent educational needs. METHODS: Fifth year medical students attending a mandatory course at the University of Cologne had simulated physician-patient consultations aiming at drug prescription. In 2015, 21 consultations were recorded, transcribed and subjected to qualitative content analysis based on the method of inductive coding. RESULTS: Even essential information on drug therapy was often lacking (e.g. adverse effects, drug administration). Some aspects were addressed more frequently than others. This seemed to differ depending on the diagnosis underlying the particular treatment (acute event vs. chronic disease). The extent of information on drug treatments given in simulated physician-patient consultations varied significantly between students. CONCLUSIONS: Fifth year medical students showed appreciable deficits in communicating drug prescriptions to patients though there were remarkable inter-individual differences. Our findings suggest that communication on drug therapy to patients is no self evolving skill. Thus, there is obviously a need for emphasizing medication communication in the training of medical students. Communication aids specifically aiming at medication communication might facilitate learning of adequate medication communication skills. PMID- 28091705 TI - Bacteria of the Family 'Candidatus Midichloriaceae' in Sympatric Zones of Ixodes Ticks: Genetic Evidence for Vertical Transmission. AB - Ixodes ticks transmit infectious agents and also harbor their own parasites and symbionts. The presumptive endosymbiont of Ixodes ricinus, 'Candidatus Midichloria mitochondrii', has a unique ability to invade mitochondria within tick ovarian cells and is transovarially transmitted with 100% efficiency. A closely related bacterium, provisionally named Montezuma (now 'Candidatus Lariskella arthropodarum'), was isolated from the Ixodes persulcatus ticks and human blood in 2004 as well as from Ixodes pavlovskyi in 2015. These microorganisms belong to the family 'Candidatus Midichloriaceae fam. nov.' and were detected not only in tick salivary glands, but also in animal blood. Nevertheless, the relative importance of vertical and horizontal routes for their transmission or maintenance in natural tick populations remains unclear. We analyzed the prevalence of L. arthropodarum and M. mitochondrii in two sympatric zones, where I. persulcatus/I. ricinus and I. persulcatus/I. pavlovskyi cohabit and produce interspecific hybrids. A specificity of the associations of L. arthropodarum with I. persulcatus (100%) and M. mitochondrii with I. ricinus (96.2%) was observed in the sympatric zone in Estonia, possibly showing poor contribution of the horizontal route to the overall prevalence of endosymbionts. L. arthropodarum was observed probably multiplying in I. pavlovskyi and also subjected to transovarial transmission, but much less efficiently compared to I. persulcatus. We revealed two new genetic variants of the rrl-rrf intergenic spacer of L. arthropodarum isolated from I. pavlovskyi ticks that possibly could indicate an ongoing process of adaptation of the microorganism to a new host species. PMID- 28091706 TI - Microclimates Might Limit Indirect Spillover of the Bat Borne Zoonotic Hendra Virus. AB - Infectious diseases are transmitted when susceptible hosts are exposed to pathogen particles that can replicate within them. Among factors that limit transmission, the environment is particularly important for indirectly transmitted parasites. To try and assess a pathogens' ability to be transmitted through the environment and mitigate risk, we need to quantify its decay where transmission occurs in space such as the microclimate harbouring the pathogen. Hendra virus, a Henipavirus from Australian Pteropid bats, spills-over to horses and humans, causing high mortality. While a vaccine is available, its limited uptake has reduced opportunities for adequate risk management to humans, hence the need to develop synergistic preventive measures, like disrupting its transmission pathways. Transmission likely occurs shortly after virus excretion in paddocks; however, no survival estimates to date have used real environmental conditions. Here, we recorded microclimate conditions and fitted models that predict temperatures and potential evaporation, which we used to simulate virus survival with a temperature-survival model and modification based on evaporation. Predicted survival was lower than previously estimated and likely to be even lower according to potential evaporation. Our results indicate that transmission should occur shortly after the virus is excreted, in a relatively direct way. When potential evaporation is low, and survival is more similar to temperature dependent estimates, transmission might be indirect because the virus can wait several hours until contact is made. We recommend restricting horses' access to trees during night time and reducing grass under trees to reduce virus survival. PMID- 28091707 TI - Gastric distension causes changes in heart rate and arterial blood pressure by affecting the crosstalk between vagal and splanchnic systems in anesthetised rats. AB - Various hindbrain nuclei have been demonstrated to be involved in the control of the cardiovascular reflexes elicited by both non-noxious and noxious gastric distension, through parasympathetic and sympathetic activation. The different role played by the branches of autonomic nervous system in exerting these effects and their crosstalk in relation to low-/high-pressure distension rate has not been examined yet. Therefore, in the present work, monolateral and bilateral vagotomy and splanchnicotomy were performed in anesthetised rats to analyse the involvement of hindbrain nuclei in haemodynamic changes caused by gastric distension at high (80 mmHg) and low (15 mmHg) pressure. The analysis of c-Fos expression in neuronal areas involved in cardiovascular control allowed us to examine their recruitment in response to various patterns of gastric distension and the crosstalk between vagal and splanchnic systems. The results obtained show that the low-pressure (non-noxious) gastric distension increases both heart rate and arterial blood pressure. In addition, the vagus nerve and hindbrain nuclei, such as nucleus ambiguous, ventrolateral medulla and lateral reticular nucleus, appear to be primarily involved in observed responses. In particular, we have found that although vagus nerve plays a central role in exerting those cardiovascular reflex changes at low gastric distension, for its functional expression an intact splanchnic system is mandatory. Hence, the absence of splanchnic input attenuates pressor responses or turns them into depressor responses. Instead at high-pressure (noxious) gastric distension, the splanchnic nerve represents the primary component in regulating the reflex cardiovascular effects. PMID- 28091713 TI - ? PMID- 28091710 TI - Role of concurrent vaginal hysterectomy in the outcomes of mesh-based vaginal pelvic organ prolapse surgery. AB - INTRODUCTION AND HYPOTHESIS: Hysterectomy is often performed at the time of pelvic organ prolapse (POP) surgery; yet, there is insufficient evidence regarding the specific effect of hysterectomy on outcomes. We sought to determine the outcomes and associated short-term complications of mesh-based POP surgery with and without concurrent hysterectomy. METHODS: We utilized the New York Statewide Planning and Research Cooperation System (SPARCS) database to identify patients under 55 years of age undergoing surgeries for POP with mesh between 2009 and 2014. Patients who had a hysterectomy at the time of mesh-based POP surgery were compared with those who underwent mesh-based POP surgery without hysterectomy. Outcome measures of the patient groups before and after propensity score matching were compared. We assessed the difference Chi-squared tests and log-rank tests in the entire cohort and Mantel-Haenszel stratified Chi-squared tests and Prentice-Wilcoxon tests in the matched cohort. RESULTS: A total of 1,601 women underwent mesh-based POP surgery. 921 patients underwent concurrent hysterectomy, whereas 680 had mesh-based uterine-preserving POP surgery. After propensity score matching, there was no difference in reintervention rates between groups for up to 3 years. Concurrent hysterectomy with mesh-based POP repair was consistently associated with longer hospitalization (20.0% vs 12.8% stayed longer than 2 days) and higher charges (median charges were $22,689 vs $19,273). CONCLUSIONS: Concurrent hysterectomy during mesh-based POP surgery in patients under 55 years led to more expensive charges and a longer stay compared with uterine-preserving mesh surgery. There was no difference in reintervention rates between groups for up to 3 years. PMID- 28091711 TI - Anticholinergic prescription: are healthcare professionals the real burden? AB - INTRODUCTION AND HYPOTHESIS: Anticholinergic medication is the medical treatment for overactive bladder (OAB). These drugs can act on the central nervous system and can lead to cognitive decline, dementia, and potentially death. Patients taking drugs with anticholinergic effects increase their anticholinergic burden defined as the cumulative effect of taking one or more drugs that can have adverse effects. When prescribing anticholinergic medication for the elderly, we must choose the right drug. We aimed to discover the level of understanding on this subject and its application to real clinical practice amongst our healthcare professionals (HCPs). METHODS: An 18-point questionnaire was distributed to urogynaecologists, general gynaecologists, urologists, geriatricians, general practitioners (GPs), and nurse specialists to assess knowledge on the subject. RESULTS: A total of 96 HCPs completed the questionnaire. The nurse specialists had the highest score in identifying that oxybutynin was the drug most likely to cross the blood-brain barrier (BBB). The urogynaecologists had the highest score in identifying that trospium chloride was least likely to cross the BBB, whereas the GPs had the lowest score. Solifenacin was the most popular anticholinergic drug prescribed in the elderly without dementia. Trospium chloride was the most popular drug prescribed in the elderly with dementia. CONCLUSIONS: We have found that knowledge is lacking amongst all our HCPs, but especially amongst our first line doctors, our GPs. Education is key in developing knowledge and safe prescribing, to improve the care we give to our patients. PMID- 28091712 TI - Two cases of female urethral reconstruction with acellular porcine urinary bladder matrix. AB - INTRODUCTION AND HYPOTHESIS: Female urethral reconstruction via the traditional routes can be limiting for various reasons. Current literature on the use of acellular biologic grafts derived from viscera for female urethral reconstruction is limited. We present two cases of women with complete loss of their posterior urethra presenting for urethral reconstruction. METHODS: Two cases of urethral reconstruction using acellular porcine urinary bladder matrix (UBM), along with labial fat pad transposition and biologic pubovaginal sling are presented. RESULTS: In both cases the UBM graft showed successful conversion to what appeared to be normal urethral mucosa. One woman showed significant improvement in continence and the other showed complete continence. CONCLUSIONS: Female urethral reconstruction using acellular porcine UBM is a viable option for patients who have lost a significant portion of their urethra. Both cases demonstrated transition of the graft into the posterior wall of the urethra with significant improvement in continence. Further studies are needed to confirm that acellular porcine UBM can transform to urethral mucosa in women requiring urethral reconstruction. PMID- 28091709 TI - Use of in silico models for prioritization of heat-induced food contaminants in mutagenicity and carcinogenicity testing. AB - Numerous Maillard reaction and lipid oxidation products are present in processed foods such as heated cereals, roasted meat, refined oils, coffee, and juices. Due to the lack of experimental toxicological data, risk assessment is hardly possible for most of these compounds. In the present study, an in silico approach was employed for the prediction of the toxicological endpoints mutagenicity and carcinogenicity on the basis of the structure of the respective compound, to examine (quantitative) structure-activity relationships for more than 800 compounds. Five software tools for mutagenicity prediction (T.E.S.T., SARpy, CAESAR, Benigni-Bossa, and LAZAR) and three carcinogenicity prediction tools (CAESAR, Benigni-Bossa, and LAZAR) were combined to yield so-called mutagenic or carcinogenic scores for every single substance. Alcohols, ketones, acids, lactones, and esters were predicted to be mutagenic and carcinogenic with low probability, whereas the software tools tended to predict a considerable mutagenic and carcinogenic potential for thiazoles. To verify the in silico predictions for the endpoint mutagenicity experimentally, twelve selected compounds were examined for their mutagenic potential using two different validated in vitro test systems, the bacterial reverse mutation assay (Ames test) and the in vitro micronucleus assay. There was a good correlation between the results of the Ames test and the in silico predictions. However, in the case of the micronucleus assay, at least three substances, 2-amino-6-methylpyridine, 6 heptenoic acid, and 2-methylphenol, were clearly positive although they were predicted to be non-mutagenic. Thus, software tools for mutagenicity prediction are suitable for prioritization among large numbers of substances, but these predictions still need experimental verification. PMID- 28091714 TI - Comparison of potential higher order reference methods for total haemoglobin quantification-an interlaboratory study. AB - The total haemoglobin (Hb) concentration in blood is one of the most frequently measured analytes in clinical medicine because of its significance for evaluating the health state of a human. The spectrophotometric cyanmethaemoglobin (HiCN) method is the internationally accepted conventional reference method to determine this biomarker. It is frequently used in clinical routine diagnostics but is not traceable to the International System of Units and thus does not meet highest metrological demands. A further critical issue is the toxicity of the necessary potassium cyanide. Different methods to solve these problems are reported here. They all were validated against the HiCN method in an interlaboratory comparison by measuring the total Hb concentration present in the certified reference material JCCRM 912-2M. Methods considered were the spectrophotometric alkaline haematin detergent (AHD) method as well as several isotope dilution (ID)-based approaches. The latter include inductively coupled plasma mass spectrometry (ICP MS), species-specific (SS) ICP-MS, organic MS and Raman spectrometry. Graphical abstract ?. PMID- 28091718 TI - ESNR Presidential Address, 2017. PMID- 28091708 TI - The effect of motor overflow on bimanual asymmetric force coordination. AB - Motor overflow, typically described in the context of unimanual movements, refers to the natural tendency for a 'resting' limb to move during movement of the opposite limb and is thought to be influenced by inter-hemispheric interactions and intra-cortical networks within the 'resting' hemisphere. It is currently unknown, however, how motor overflow contributes to asymmetric force coordination task accuracy, referred to as bimanual interference, as there is need to generate unequal forces and corticospinal output for each limb. Here, we assessed motor overflow via motor evoked potentials (MEPs) and the regulation of motor overflow via inter-hemispheric inhibition (IHI) and short-intra-cortical inhibition (SICI) using transcranial magnetic stimulation in the presence of unimanual and bimanual isometric force production. All outcomes were measured in the left first dorsal interosseous (test hand) muscle, which maintained 30% maximal voluntary contraction (MVC), while the right hand (conditioning hand) was maintained at rest, 10, 30, or 70% of its MVC. We have found that as higher forces are generated with the conditioning hand, MEP amplitudes at the active test hand decreased and inter-hemispheric inhibition increased, suggesting reduced motor overflow in the presence of bimanual asymmetric forces. Furthermore, we found that subjects with less motor overflow (i.e., reduced MEP amplitudes in the test hemisphere) demonstrated poorer accuracy in maintaining 30% MVC across all conditions. These findings suggest that motor overflow may serve as an adaptive substrate to support bimanual asymmetric force coordination. PMID- 28091716 TI - Rapid concentration detection and differentiation of bacteria in skimmed milk using surface enhanced Raman scattering mapping on 4-mercaptophenylboronic acid functionalized silver dendrites. AB - A novel method was developed to rapidly concentrate, detect, and differentiate bacteria in skimmed milk using surface enhanced Raman scattering (SERS) mapping on 4-mercaptophenylboronic acid (4-MPBA) functionalized silver (Ag) dendrites. The 4-MPBA functionalized Ag dendritic SERS substrate was used to capture the bacterial cells and enhance the bacterial signal. Salmonella, a significantly important food pathogen, was used as the representative strain to optimize and evaluate the developed method. The capture efficiency for Salmonella enterica subsp enterica BAA1045 (SE1045) was 84.92 +/- 3.25% at 106 CFU/mL and as high as 99.65 +/- 3.58% at 103 CFU/mL. Four different strains, two gram-negative and two gram-positive, can be clearly distinguished by their SERS spectra using principle component analysis. A mapping technique was utilized to automatically collect 400 spectra over an area of 60 MUm * 60 MUm to construct a visual image for a sensitive and statistically reliable detection within 30 min. Using this method, we were able to detect as low as 103 CFU/mL bacterial cells in 50 mM NH4HCO3 solution and 102 CFU/mL cells in both 1% casein and skimmed milk. Our results demonstrate the feasibility of using SERS mapping method coupled with 4-MPBA functionalized Ag dendrites for rapid and sensitive bacteria detection in complex liquid samples. Graphical Abstract A novel SERS mapping method based on 4 mercaptophenylboronic acid functionalized silver (Ag) dendrites was developed to rapidly concentrate, detect, and differentiate bacteria. PMID- 28091719 TI - Thank you, Guy. PMID- 28091717 TI - Bar adsorptive microextraction technique - application for the determination of pharmaceuticals in real matrices. AB - In the present work, bar adsorptive microextraction using miniaturized devices (7.5 * 3.0 mm) coated with suitable sorbent phases, combined with microliquid desorption (100 MUL) followed by high-performance liquid chromatography with diode array detection (BAMUE-MULD/HPLC-DAD), is proposed for the determination of trace level of six pharmaceuticals (furosemide, mebeverine, ketoprofen, naproxen, diclofenac and mefenamic acid) in environmental water and urine matrices. By comparing ten distinct sorbent materials (five polymeric and five activated carbons), the polymer P5 proved to be the most suitable to achieve the best selectivity and efficiency. The solvent volume minimization in the liquid desorption stage demonstrated remarkable effectiveness, being more environmentally friendly, and simultaneously increased the microextraction enrichment factor two-fold. Assays performed through BAMUE(P5, 0.9 mg)-MULD(100 MUL)/HPLC-DAD on 25 mL of ultrapure water samples spiked at the 4.0 MUg/L level yielded average recoveries ranging from 91.4% (furosemide) to 101.0% (ketoprofen) with good precision (RSD < 10.6%), under optimized experimental conditions. The analytical performance showed convenient detection limits (25.0 - 120.0 ng/L), good linear dynamic ranges (0.1 to 24.0 MUg/L), appropriate determination coefficients (r 2 > 0.9983), and excellent repeatability through intraday (RSD < 10.4%)) and interday (RSD < 10.0%) assays. By using the standard addition methodology, the application of the present analytical approach on environmental waters and urine samples revealed the occurrence of trace levels of some pharmaceuticals. The solvent minimization during the back-extraction step associated with the miniaturization of BAMUE devices proved to be a very promising analytical technology for static microextraction analysis. Graphical abstract BAMUE operating under the floating sampling technology for the determination of pharmaceuticals in aqueous media. PMID- 28091715 TI - Highly sensitive glycosylamine labelling of O-glycans using non-reductive beta elimination. AB - When developing biopharmaceuticals, glycans are the most important posttranslational protein modifications that must be addressed because they affect the between-protein interactions that maintain homeostasis. The glycan profile may be defined as a critical quality attribute of a biopharmaceutical. Comprehensive analysis of protein glycosylation must overcome challenges such as the release, labelling, separation and detection of O-glycans. In contrast, N glycans can be readily released non-reductively from peptide backbones using an enzyme such as peptide N-glycosidase F. We developed a highly sensitive protocol using RapiFluor-MS to label glycosylamines for O-glycan analysis combined with a non-enzyme treatment for efficient release of the reduced O-glycans from the glycoproteins. Here we used the cytotoxic T lymphocyte associated protein 4 immunoglobulin G (Ig) fusion protein and fetuin as models for O-glycan analysis and compared the analytical methods glycopeptide mapping, 2-AB labelling and RapiFluor-MS labelling. The structures of major O-glycans and low-abundance O glycans were successfully identified using the third technique, which detected the O-glycans with high sensitivity. PMID- 28091726 TI - Predation cues rather than resource availability promote cryptic behaviour in a habitat-forming sea urchin. AB - It is well known that predators often influence the foraging behaviour of prey through the so-called "fear effect". However, it is also possible that predators could change prey behaviour indirectly by altering the prey's food supply through a trophic cascade. The predator-sea urchin-kelp trophic cascade is widely assumed to be driven by the removal of sea urchins by predators, but changes in sea urchin behaviour in response to predators or increased food availability could also play an important role. We tested whether increased crevice occupancy by herbivorous sea urchins in the presence of abundant predatory fishes and lobsters is a response to the increased risk of predation, or an indirect response to higher kelp abundances. Inside two New Zealand marine reserves with abundant predators and kelp, individuals of the sea urchin Evechinus chloroticus were rarer and remained cryptic (i.e. found in crevices) to larger sizes than on adjacent fished coasts where predators and kelp are rare. In a mesocosm experiment, cryptic behaviour was induced by simulated predation (the addition of crushed conspecifics), but the addition of food in the form of drift kelp did not induce cryptic behaviour. These findings demonstrate that the 'fear' of predators is more important than food availability in promoting sea urchin cryptic behaviour and suggest that both density- and behaviourally mediated interactions are important in the predator-sea urchin-kelp trophic cascade. PMID- 28091724 TI - Automatic CT-based finite element model generation for temperature-based death time estimation: feasibility study and sensitivity analysis. AB - Temperature-based death time estimation is based either on simple phenomenological models of corpse cooling or on detailed physical heat transfer models. The latter are much more complex but allow a higher accuracy of death time estimation, as in principle, all relevant cooling mechanisms can be taken into account.Here, a complete workflow for finite element-based cooling simulation is presented. The following steps are demonstrated on a CT phantom: Computer tomography (CT) scan Segmentation of the CT images for thermodynamically relevant features of individual geometries and compilation in a geometric computer-aided design (CAD) model Conversion of the segmentation result into a finite element (FE) simulation model Computation of the model cooling curve (MOD) Calculation of the cooling time (CTE) For the first time in FE-based cooling time estimation, the steps from the CT image over segmentation to FE model generation are performed semi-automatically. The cooling time calculation results are compared to cooling measurements performed on the phantoms under controlled conditions. In this context, the method is validated using a CT phantom. Some of the phantoms' thermodynamic material parameters had to be determined via independent experiments.Moreover, the impact of geometry and material parameter uncertainties on the estimated cooling time is investigated by a sensitivity analysis. PMID- 28091733 TI - Post-treatment PET/CT and p16 status for predicting treatment outcomes in locally advanced head and neck cancer after definitive radiation. AB - PURPOSE: To retrospectively review post-treatment (post-tx) FDG-PET/CT scans in patients with advanced head and neck squamous cell carcinoma (HNSCC) and known p16 status, treated with definitive (chemo)radiation (RT). METHODS: A total of 108 eligible patients had N2A or greater HNSCC treated with chemoRT from August 1, 2008, to February 28, 2015, with post-tx PET/CT within 6 months after RT. Kaplan-Meier curves, log-rank statistics, and Cox proportional hazards regression were used for statistical analysis. RESULTS: Median follow-up was 2.38 years. Sixty-eight (63.0%) patients had p16+ and 40 (37.0%) had p16- status. Two-year overall survival and recurrence-free survival were 93.4% and 77.8%, respectively. The negative predictive value (NPV) of PET/CT for local recurrence (LR) was 100%. The NPV for regional recurrence (RR) was 96.5% for all patients, 100% for p16+ patients, and 88.5% for p16- patients. The positive predictive value (PPV) of PET/CT for recurrence was 77.3% for all patients, 50.0% for p16+, and 78.6% for p16-. The PPV for LR was 72.7% for all patients, 50.0% for p16+ patients, and 72.7% for p16- patients. The PPV for RR was 50.0% for all patients, 33% for p16+, and 66.6% for p16-. Post-tx PET/CT and p16 status were independent predictors of recurrence-free survival (p < 0.01). CONCLUSIONS: Post-tx PET/CT predicts treatment outcomes in both p16 + and p16- patients, and does so independently of p16 status. P16- patients with negative PET have a 10% risk of nodal recurrence, and closer follow-up in these patients is warranted. PMID- 28091723 TI - Changes in the severity and subtype of Guillain-Barre syndrome admitted to a specialist Neuromedical ICU over a 25 year period. AB - We report a retrospective review of 110 patients with acute Guillain-Barre syndrome (GBS) admitted to a specialised intensive care unit (ICU) in a tertiary referral centre over a 25 year period, the start of which coincided with the widespread introduction of plasma exchange (PE) and intravenous immunoglobulin (IVIG). The results were analysed by comparing 52 patients admitted in the first decade (1991-2000; Group 1) with 58 patients admitted between 2001-2014 (Group 2). Patients in both groups were comparable with respect to age and sex, and had a similar incidence and range of ICU complications. They received a comparable range of immunomodulatory treatments including IVIG and PE. However, the delay from presentation to referral to the tertiary ICU was longer in patients in Group 2. They also required mechanical ventilation for a longer duration, and had longer ICU and hospital stays. In Group 2, there was a higher incidence of axonal neuropathy (51%, compared to 24% in Group 1). Despite the longer delay to referral, the prevalence of axonal neuropathy and the duration of ventilation, overall mortality showed a downward trend (Group 1: 13.5%; Group 2: 5.2%). There was no late mortality in either group after step-down to neuro-rehabilitation or following discharge home or to the referring hospital. The rehabilitation outcomes were similar. This data show a shift in the pattern of referral to a tertiary referral ICU between the first and second decades following the wider availability of IVIG and PE for the treatment of GBS. The possible causes and implications of these findings are discussed. PMID- 28091728 TI - Value of Nonrigid Registration of Pre-Procedure MR with Post-Procedure CT After Radiofrequency Ablation for Hepatocellular Carcinoma. AB - PURPOSE: To evaluate the value of pre-radiofrequency ablation (RFA) MR and post RFA CT registration for the assessment of the therapeutic response of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: A total of 178 patients with single HCC who received RFA as an initial treatment and had available pre RFA MR and post-RFA CT images were included in this retrospective study. Two independent readers (one experienced radiologist, one inexperienced radiologist) scored the ablative margin (AM) of treated tumors on a four-point scale (1, residual tumor; 2, incomplete AM; 3, borderline AM; 4, sufficient AM), in two separate sessions: (1) visual comparison between pre-and post-RFA images; (2) with addition of nonrigid registration for pre- and post-RFA images. Local tumor progression (LTP) rates between low-risk (response score, 3-4) and high-risk groups (1-2) were analyzed using the Kaplan-Meier method at each interpretation session. RESULTS: The patients' reassignments after using the registered images were statistically significant for inexperienced reader (p < 0.001). In the inexperienced reader, LTP rates of low- and high-risk groups were significantly different with addition of registered images (session 2) (p < 0.001), but not significantly different in session 1 (p = 0.101). However, in the experienced reader, LTP rates of low- and high-risk groups were significantly different in both interpretation sessions (p < 0.001). Using the registered images, the cumulative incidence of LTP at 2 years was 3.0-6.6%, for the low-risk group, and 18.6-27.8% for the high-risk group. CONCLUSION: Registration between pre-RFA MR and post-RFA CT images may allow better assessment of the therapeutic response of HCC after RFA, especially for inexperienced radiologists, helping in the risk stratification for LTP. PMID- 28091721 TI - Influence of tooth dimension on the initial mobility based on plaster casts and X ray images : A numerical study. AB - AIMS: The goal was to determine the influence of different geometric parameters of the tooth on the initial tooth mobility and the position of the center of resistance employing numerical models based on scaled X-ray images and plaster casts. METHODS: The dimensions of tooth 21 were measured in 21 patients, using radiographs and dental casts. Length and mesiodistal width of the tooth were obtained from the X-ray image and the orovestibular diameter from the plaster cast. Finite element models were generated. Cortical and cancellous bone and the periodontal ligament were simulated to create realistic models. Root length (11 17 mm), mesiodistal width (6-10 mm) and orovestibular thickness (7-9 mm) were varied in 1-mm steps to generate 105 models. In the simulation, each model was loaded with a force of 10 N in vestibulopalatinal direction and with a torque of 10 Nmm to determine tooth displacements and center of resistance. RESULTS: Initial tooth displacement and thus mobility increased with decreasing total root surface. The shortest, slimmest and thinnest tooth showed a total deflection of 0.14 mm at the incisal edge, while the longest, widest and thickest tooth showed a total deflection of 0.10 mm. Changes in mesiodistal width had the greatest influence on initial tooth mobility and changes in orovestibular thickness the least. The teeth's center of resistance was positioned between 37 and 43% of the root length measured from the cervical margin of the alveolar bone. The center of resistance of the longest dental root investigated was located around 6% more cervically compared to the one of the shortest dental root. The influence of root width and thickness on the position of the center of resistance was significantly lower than root length. CONCLUSION: Geometric parameters significantly impact initial tooth mobility and position of the center of resistance. Thus, tooth dimensions should be considered in orthodontic treatment planning. Dental radiographs represent a sufficient validation tool to estimate the quality of a pure dental tipping during orthodontic treatment, as the orovestibular thickness has little influence. However, for three-dimensional tooth displacements all geometric parameters should be determined accurately using plaster casts or DVT. PMID- 28091725 TI - Genetic polymorphism investigation of the Chinese Yi minority using PowerPlex(r) Y23 STR amplification system. AB - Twenty-three Y-STR loci (DYS576, DYS389I, DYS389 II, DYS448, DYS19, DYS391, DYS481, DYS549, DYS533, DYS438, DYS437, DYS570, DYS635, DYS390, DYS439, DYS392, DYS393, DYS458 DYS456, DYS643, Y-GATA-H4, and DYS385a/b) included in the next generation PowerPlex(r) Y23 System were first investigated in 311 unrelated, healthy male individuals from the Yi minority population residing in the Liangshan Yi Autonomous Prefecture, Sichuan, China. A total of 179 alleles and 297 haplotypes were discovered in the Yi group. In total, 285 haplotypes among them were unique, and the remaining 12 haplotypes were observed in two or three individuals. Haplotype discrimination capacity and haplotype diversity were 0.9550 and 0.9989, respectively. Genetic diversity ranged from 0.4550 (DYS437) to 0.9556 (DYS385a/b). Population comparisons between the Yi minority group and 10 Asian meta-populations comprising 58 individual populations were performed. Both multidimensional scaling plots and phylogenetic analyses demonstrated that the genetic structure of the Chinese Yi ethnicity was extremely different compared to Taiwan indigenous inhabitants among 10 Asian meta-populations. Additionally, the genetic structure resemblance of the Yi group was obtained from a geographically close population (Xuanwei Han) or similar language family groups (Thai populations). Besides, our study has demonstrated that the PowerPlex(r) Y23 System has high polymorphism in a Chinese Yi ethnic population and high discriminatory power for forensic purposes. Population data of the 23 Y-STR obtained from a Yi ethnic population has enriched the Chinese ethnic genetic information. PMID- 28091722 TI - Hyperphosphorylated tau causes reduced hippocampal CA1 excitability by relocating the axon initial segment. AB - Hyperphosphorylated tau has a critical role in tauopathies such as Alzheimer's disease and frontotemporal dementia, impairing neuronal function and eventually leading to neurodegeneration. A critical role for tau is supported by studies in transgenic mouse models that express the P301L tau mutation found in cases of familial frontotemporal dementia, with the accumulation of hyperphosphorylated tau in the hippocampus causing reductions in hippocampal long-term potentiation and impairments in spatial learning and memory. However, what has remained unexplored is the role of hyperphosphorylated tau in reducing neuronal excitability. Here, we show in two complementary P301L tau transgenic mouse models that hyperphosphorylated tau induces a more depolarized threshold for action potential initiation and reduces firing in hippocampal CA1 neurons, which was rescued by the suppression of transgenic tau. Furthermore, using mutagenesis and primary hippocampal neuronal cultures, we reveal that this reduction in neuronal excitability results from the relocation of the axon initial segment (AIS) down the axon in a tau phosphorylation-dependent manner. We also demonstrate that this effect is microtubule-dependent. In addition, pharmacological stabilization was found to prevent both the structural and functional deficits caused by tau hyperphosphorylation. Finally, we demonstrate that the AIS of neurons from tau transgenic mice is further down the axon, which correlates with a reduction in excitability. We therefore propose that a reduction in hippocampal excitability due to a tau-mediated distal relocalization of the AIS contributes to the hippocampal dysfunction observed in tauopathies. PMID- 28091730 TI - Actin isoform expression patterns in adult extracardiac and cardiac rhabdomyomas indicate a different cell of origin. AB - Rhabdomyomas are rare striated muscle-type tumors arising in the heart or in soft tissues. Using a monoclonal antibody specific for the cardiac isoform of alpha actin (alpha-cardiac actin, alpha-CAA), differential expression patterns in striated muscle tissues were reported previously. The purpose of the present study was to determine whether the alpha-actin isoform specificity is maintained in rhabdomyomas according to their origin, comparing extracardiac to cardiac rhabdomyomas. We immunohistochemically investigated adult extracardiac (pharyngeal) rhabdomyomas (n = 4) and cardiac rhabdomyomas (n = 7) employing isoform-specific monoclonal antibodies. The extracardiac rhabdomyomas revealed only a few scattered alpha-CAA-positive tumor cells (antibody cAc1-20.42) while the cardiac rhabdomyomas exhibited abundant expression of alpha-CAA, indicating a close relatedness to cardiac muscle fibers. The alpha-skeletal actin (alpha-SKA) specific monoclonal antibody (3B3) produced the reverse results. General sarcomeric antibodies (HHF35 and Alpha Sr-1) displayed strong positivity in all rhabdomyomas studied. Alpha-smooth muscle actin (alpha-SMA) was negative or heterogeneously positive in extracardiac and cardiac rhabdomyomas. Our results suggest that despite similar morphology, the intrinsic differential alpha-actin isoform specificity of mature skeletal vs. cardiac muscle is maintained in extracardiac and cardiac rhabdomyomas. Thus, adult extracardiac rhabdomyomas differentiate towards mature skeletal muscle although they may exhibit centrally placed nuclei like cardiac muscle cells, while cardiac rhabdomyomas reflect true cardiac muscle differentiation. Our findings appear to indicate a different biological nature of cardiac and extracardiac rhabdomyomas, probably related to a different cell of origin. To our knowledge, this is the first report suggesting a derivation of extracardiac and cardiac rhabdomyomas from skeletal and cardiac muscle cells, respectively. PMID- 28091735 TI - Comprehensive assessment of peripheral blood TCRbeta repertoire in infectious mononucleosis and chronic active EBV infection patients. AB - Epstein-Barr virus (EBV) primary infection is usually asymptomatic, but it sometimes progresses to infectious mononucleosis (IM). Occasionally, some people develop chronic active EBV infection (CAEBV) with underlying immunodeficiency, which belongs to a continuous spectrum of EBV-associated lymphoproliferative disorders (EBV+ LPD) with heterogeneous clinical presentations and high mortality. It has been well established that T cell-mediated immune response plays a critical role in the disease evolution of EBV infection. Recently, high throughput sequencing of the hypervariable complementarity-determining region 3 (CDR3) segments of the T cell receptor (T cell receptor beta (TCRbeta)) has emerged as a sensitive approach to assess the T cell repertoire. In this study, we fully characterized the diversity of peripheral blood TCRbeta repertoire in IM (n = 6) and CAEBV patients (n = 5) and EBV-seropositive controls (n = 5). Compared with the healthy EBV-seropositive controls, both IM and CAEBV patients demonstrate a significant decrease in peripheral blood TCRbeta repertoire diversity, basically, including narrowed repertoire breadth, highly expanded clones, and skewed CDR3 length distribution. However, there is no significant difference between IM and CAEBV patients. Furthermore, we observed some disease related preferences in TRBV/TRBJ usage and combinations, as well as lots of T cell clones shared by different groups (unique or overlapped) involved in public T cell responses, which provide more detailed insights into the divergent disease evolution. PMID- 28091736 TI - Salvage therapy for acute chemorefractory leukemia by allogeneic stem cell transplantation: the Korean experience. AB - Little is known about the characteristics that make patients with acute leukemia suitable for undergoing salvage therapy by allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we analyzed the clinical outcomes of 223 patients with acute leukemia who underwent allo-HSCT while not in complete remission (CR). The primary end points were overall survival (OS) and CR rate. CR was achieved in 79.8% of patients after allo-HSCT. Acute graft-versus-host disease (GVHD) was significantly associated with CR (P = 0.045). During a median follow-up of 30.1 months, the median OS was 6.1 months. OS was significantly longer in patients with good or standard risk cytogenetic characteristics than in those with poor risk cytogenetic characteristics (P = 0.029, P = 0.030, respectively). Patients who received allo-HSCT from a matched sibling donor had better survival than those with unrelated donors (P = 0.015). Primary chemorefractoriness was not associated with poor survival (P = 0.071). The number of chemotherapies before allo-HSCT was significantly correlated with outcome (P = 0.006). Chronic GVHD was a strong predictor of a longer OS (P = 0.025). In conclusion, survival of patients with primary chemorefractory acute leukemia is not lower when treated upfront with allo-HSCT. Hence, allo-HSCT should be actively considered in such patients. Acute and chronic GVHD is associated with better outcomes patients with acute leukemia who have undergone allo-HSCT and not achieved CR. PMID- 28091734 TI - Level of conus medullaris termination in adult population analyzed by kinetic magnetic resonance imaging. AB - PURPOSE: To investigate the change of conus medullaris termination (CMT) level in neutral, flexion and extension positions and to analyze the effects of age and gender on the CMT level. METHODS: The midline sagittal T2-weighted kinetic magnetic resonance imaging (kMRI) study of 585 patients was retrospectively reviewed to identify the level of CMT. All patients were in an upright position. A straight line perpendicular to the long axis of the cord was drawn from the tip of the cord and then subtended to the adjacent vertebra or disk space. The CMT level was labeled in relation to the upper, middle and lower segments of adjacent vertebra or disk space and assigned values from 0 to 12 [0 = upper third of T12 (T12U), and 12 = upper third of L3 (L3U)]. All parameters were collected for neutral, flexion and extension positions. RESULTS: The level of CMT had the highest incidence (17.61%) at L1 lower (L1L) in neutral position, 17.44% at L1 upper (L1U) in flexion, and 16.92% at L1 middle (L1M) in extension with no significant differences among three positions (p > 0.05) in weight-bearing status. Moreover, the level of CMT was not correlated with age (p > 0.05). In terms of gender, the level of CMT was lower in women than in men in neutral position, flexion, and extension (p < 0.05). Furthermore, when divided by age in decades, there was a significant difference between females and males in the age group 60-69 years in neutral, flexion and extension position, respectively (p < 0.05). CONCLUSIONS: The level of CMT in the neutral position was in accordance with previous cadaveric and supine-position MRI studies, and it did not change with flexion and extension. Women had lower CMT level than men, especially in the older population. This information can be very valuable when performing spinal anesthesia and spinal punctures. PMID- 28091727 TI - Intrinsic cardiac ganglia and acetylcholine are important in the mechanism of ischaemic preconditioning. AB - This study aimed to investigate the role of the intrinsic cardiac nervous system in the mechanism of classical myocardial ischaemic preconditioning (IPC). Isolated perfused rat hearts were subjected to 35-min regional ischaemia and 60 min reperfusion. IPC was induced as three cycles of 5-min global ischaemia reperfusion, and provided significant reduction in infarct size (IS/AAR = 14 +/- 2% vs control IS/AAR = 48 +/- 3%, p < 0.05). Treatment with the ganglionic antagonist, hexamethonium (50 MUM), blocked IPC protection (IS/AAR = 37 +/- 7%, p < 0.05 vs IPC). Moreover, the muscarinic antagonist, atropine (100 nM), also abrogated IPC-mediated protection (IS/AAR = 40 +/- 3%, p < 0.05 vs IPC). This indicates that intrinsic cardiac ganglia remain intact in the Langendorff preparation and are important in the mechanism of IPC. In a second group of experiments, coronary effluent collected following IPC, from ex vivo perfused rat hearts, provided significant cardioprotection when perfused through a naive isolated rat heart prior to induction of regional ischaemia-reperfusion injury (IRI) (IS/ARR = 19 +/- 2, p < 0.05 vs control effluent). This protection was also abrogated by treating the naive heart with hexamethonium, indicating the humoral trigger of IPC induces protection via an intrinsic neuronal mechanism (IS/AAR = 46 +/- 5%, p < 0.05 vs IPC effluent). In addition, a large release in ACh was observed in coronary effluent was observed following IPC (IPCeff = 0.36 +/- 0.03 MUM vs C eff = 0.04 +/- 0.04 MUM, n = 4, p < 0.001). Interestingly, however, IPC effluent was not able to significantly protect isolated cardiomyocytes from simulated ischaemia-reperfusion injury (cell death = 45 +/- 6%, p = 0.09 vs control effluent). In conclusion, IPC involves activation of the intrinsic cardiac nervous system, leading to release of ACh in the ventricles and induction of protection via activation of muscarinic receptors. PMID- 28091737 TI - Impact of pelvic fractures on the early clinical outcomes of severely injured trauma patients. AB - BACKGROUND: Pelvic fractures contribute to morbidity and mortality following injury. We sought to study the impact of pelvic fractures on the clinical course and outcomes of trauma patients with a pelvic fracture in comparison to patients with similar injury severity without pelvic fracture to identify potential parameters to track patients' clinical course post-injury. METHODS: A cohort of 206 consecutive blunt trauma survivors, studied over a 5-year period in a level I trauma center of which 75 patients (36.4%) had a pelvic fracture, was included in the study. To perform a retrospective cohort study with matched controls, 60 patients of the pelvic fracture group [(PF), 41 males and 19 females; age: 40 +/- 17; injury severity score (ISS): 26.6 +/- 9.3] were compared to 60 patients without pelvic fracture (non-PF) trauma as controls (41 males and 19 females; age: 40 +/- 13; ISS: 26.9 +/- 7.7), both with matching age (+/-5 years), sex, and ISS (+/-5 points). RESULTS: Statistically significant differences were observed in Intensive Care Unit (ICU) length of stay (LOS), total LOS, and Marshall MOD score between PF and non-PF groups, respectively. Acid-base markers such as pH, lactate, LDH, and base deficit were all significantly altered in PF compared to non-PF cohort upon admission. Moreover, our analysis showed significant differences in inflammatory biomarkers (Prolactin, CRP, and IL-6), and clinical parameters (CPK, Hgb, Platelets count, and WBC) over the 7-day clinical course in patients with PF when compared to non-PF cohort. CONCLUSION: In this matched cohort, patients with pelvic fractures exhibited biochemical and physiological alterations upon admission. Furthermore, our results suggest that pelvic fracture affects the clinical outcomes in severely injured patients, independently of injury severity, mechanism of injury, age or gender. PMID- 28091739 TI - Survival of uncemented cups from a single manufacturer implanted from 1985 to 2013: Finnish Arthroplasty Register data. AB - INTRODUCTION: Total hip arthroplasty (THA) with uncemented implants has been a relatively common procedure in Finland during the recent decades. The most common brand of uncemented implants was chosen for further analysis to study the survivorship of this uncemented cup design in comparison to cemented references. PATIENTS, MATERIALS AND METHODS: Since 1980, The Finnish Arthroplasty Register has collected information on THAs on a national level. This study was based on information of THAs recorded in the Finnish Arthroplasty Register from 1985 to 2013. If patient had undergone bilateral THA, only the first one was included. Altogether, 49,289 THAs were included. RESULTS: The overall 10-year implant survivorship of uncemented implants was 84.3% (95% CI 83.5-85.0%) and of cemented implants 90.6% (90.2-90.0%). The 10-year survival of the contemporary uncemented implants was 90.8% (94.0-95.5%) and 88.5% (84.2-91.7%). The most recently introduced uncemented cup designs had good survivorship rates at 5 years; 10-year survival data are not yet available. CONCLUSIONS: We found that modern uncemented cup designs may provide good long-term survivorship rates comparable with the gold standard of cemented cups. However, polyethylene wear, liner problems and periosthetic osteolysis may still occur, also with modern uncemented acetabular components. PMID- 28091729 TI - Portal Vein Embolization with Contralateral Application of Stem Cells Facilitates Increase of Future Liver Remnant Volume in Patients with Liver Metastases. AB - OBJECTIVES: This study aimed to evaluate the progress of future liver remnant volume (FLRV) in patients with liver metastases after portal vein embolization (PVE) with the application of hematopoietic stem cells (HSCs) and compare it with a patients control group after PVE only. METHODS: Twenty patients (group 1) underwent PVE with contralateral HSC application. Subsequently, CT volumetry with the determination of FLRV was performed at weekly intervals, in total three weeks. A sample of twenty patients (group 2) who underwent PVE without HSC application was used as a control group. RESULTS: The mean of FLRV increased by 173.2 mL during three weeks after the PVE/HSC procedure, whereas by 98.9 mL after PVE only (p = 0.015). Furthermore, the mean daily growth of FLRV by 7.6 mL in group 1 was significantly higher in comparison with 4.1 mL in group 2 (p = 0.007). CONCLUSIONS: PVE with the application of HSC significantly facilitates growth of FLRV in comparison with PVE only. This method could be one of the new suitable approaches to increase the resectability of liver tumours. PMID- 28091738 TI - [Historical pain concepts : Cultural influences on pain perception and interpretation]. AB - In the age of globalization and cultural diversification differing concepts of pain in patient care are of increasing importance. Historical models of the origin and interpretation of pain, which in this article are presented in a cursory and exemplary way, help to understand the panoply of modern concepts outside of medicine. Basically, pain was viewed not only in religion and philosophy but also by premodern physicians as a psychophysical phenomenon crucially depending on the determination by a "soul" therefore creating therapeutic options even before the discovery of an effective analgesia. Furthermore, the historical interpretations of pain in and outside of medicine can still be of profound importance to patients even today. PMID- 28091740 TI - Controlling Eutrophication in A Mediterranean Shallow Reservoir by Phosphorus Loading Reduction: The Need for an Integrated Management Approach. AB - Increased nutrient enrichment in Mediterranean standing waters has enhanced the risk of being affected by cyanobacterial blooms. Because phosphorus abatement is shaped as a crucial strategy for controlling eutrophication, this study introduces a structural thinking, experiential learning laboratory with animation dynamic model elaborated for Cazalegas Reservoir (Spain) to assess the feasibility of implementing a set of internal and external control measures and hydromorphological adjustments to meet the goal of oligotrophication. This shallow reservoir is another case where recurrent eutrophication has led to reach annual mean total phosphorus concentrations (0.16 +/- 0.08 mg total phosphorus/L) over the threshold of current water policies, triggering cyanobacterial growth up to undesirable levels in summer time (approximately 50,000 cells/mL). Modeling results showed that (i) after upgrading water treatment in the main tributary, (ii) applying a lanthanum-modified bentonite into the water column and sediment, and (iii) increasing reservoir water level, in-lake P concentrations and cyanobacterial abundance decreased in an 88% (below 0.01 mg total phosphorus/L) and 84% (below 6000 cells/mL), respectively in the most critical periods. However, the constraints of the proposed management strategies are associated with their costs of implementation and the time span for a stable trophic recovery of the reservoir. In that end, integrated management approaches are aimed to be adopted by water managers to reach adequate ecological status of freshwater bodies. PMID- 28091741 TI - Chemical, Physical, and Biological Factors Shape Littoral Invertebrate Community Structure in Coal-Mining End-Pit Lakes. AB - Aquatic invertebrates form the base of the consumer food web in lakes. In coal mining end-pit lakes, invertebrates are exposed to an environment with potentially challenging physical and chemical features. We hypothesized that the physical and chemical features of end-pit lakes reduce critical littoral habitat and thus reduce invertebrate diversity, thereby limiting the potential for these lakes to be naturalized. We used a multivariate approach using principle component analysis and redundancy analysis to study relationships between invertebrate community structure, habitat features, and water quality in five end pit lakes and five natural lakes in the Rocky Mountain foothills of west-central Alberta, Canada. Results show a significantly different invertebrate community structure was present in end-pit lakes as compared with reference lakes in the same region, which could be accounted for by water hardness, conductivity, slope of the littoral zone, and phosphorus concentrations. Habitat diversity in end-pit lakes was also limited, cover provided by macrophytes was scarce, and basin slopes were significantly steeper in pit lakes. Although water chemistry is currently the strongest influencing factor on the invertebrate community, physical challenges of habitat homogeneity and steep slopes in the littoral zones were identified as major drivers of invertebrate community structure. The addition of floating wetlands to the littoral zone of existing pit lakes can add habitat complexity without the need for large-scale alterations to basing morphology, while impermeable capping of waste-rock and the inclusion of littoral habitat in the planning process of new pit lakes can improve the success of integrating new pit lakes into the landscape. PMID- 28091742 TI - c-jun is differentially expressed in embryonic and adult neural precursor cells. AB - c-jun, a major component of AP-1 transcription factor, has a wide variety of functions. In the embryonic brain, c-jun mRNA is abundantly expressed in germinal layers around the ventricles. Although the subventricular zone (SVZ) of the adult brain is a derivative of embryonic germinal layers and contains neural precursor cells (NPCs), the c-jun expression pattern is not clear. To study the function of c-jun in adult neurogenesis, we analyzed c-jun expression in the adult SVZ by immunohistochemistry and compared it with that of the embryonic brain. We found that almost all proliferating embryonic NPCs expressed c-jun, but the number of c jun immunopositive cells among proliferating adult NPCs was about half. In addition, c-jun was hardly expressed in post-mitotic migrating neurons in the embryonic brain, but the majority of c-jun immunopositive cells were tangentially migrating neuroblasts heading toward the olfactory bulb in the adult brain. In addition, status epilepticus is known to enhance the transient proliferation of adult NPCs, but the c-jun expression pattern was not significantly affected. These expression patterns suggest that c-jun has a pivotal role in the proliferation of embryonic NPCs, but it has also other roles in adult neurogenesis. PMID- 28091743 TI - Increased expression of miR-15b is associated with clinicopathological features and poor prognosis in cervical carcinoma. AB - OBJECTIVE: The aims of this study were to explore the expression of microRNA-15b (miR-15b) in cervical carcinoma and to correlate its expression with clinicopathological characteristics and prognosis. METHODS: Quantitative reverse transcriptase polymerase chain reaction analysis was conducted to quantify the expression level of miR-15b in 607 cervical tissues, including 185 cervical carcinoma tissues, 124 CIN I lesions, 148 CIN II-III lesions, and 150 normal cervical tissues. The 5-year overall cumulative survival rates for all patients with cervical carcinoma were calculated using Kaplan-Meier survival analysis, and multivariate survival analysis of these patients was completed using the stepwise Cox proportional hazards regression model. RESULTS: The expression of miR-15b gradually increased from normal cervical tissues to CIN lesions and then to cervical carcinoma tissues (all P < 0.05), and it was strongly correlated with degree of differentiation, clinical stage, tumor diameter, and lymph-node metastases (all P < 0.05). When the median value of miR-15b expression was used as the cut-off point, patients with high miR-15b expression (above the median) had worse 5-year overall cumulative survival rates than those who exhibited low miR-15b expression (below the median; P < 0.05). Multivariate analysis using the Cox regression model identified miR-15b expression, clinical stage, tumor diameter, and lymph-node metastasis as independent risk factors for cervical carcinoma prognosis (all P < 0.05). CONCLUSION: Our results indicate that elevated miRNA-15b expression is a typical feature in cervical carcinoma, which could be a useful clinical predictor for the early diagnosis and evaluation of cervical carcinoma prognosis. PMID- 28091744 TI - Prediction of Pancreatic Fistula After Distal Pancreatectomy Based on Cross Sectional Images. AB - BACKGROUND: Postoperative pancreatic fistula (POPF) is one of the most common and clinically relevant complications after distal pancreatectomy (DP), occurring in 5-40% of patients. Determining risk factors for this complication may aid in its prevention. This study sought to predict the development of POPF after DP preoperatively and objectively based on radiologic findings. METHODS: This study included 60 patients who underwent DP using a stapler for pancreatic division between June 2011 and January 2013. Fatty infiltration, apparent diffusion coefficients (ADC) on preoperative MRI, pathologic fat, and fibrosis were measured. Pancreatic thickness and cross-sectional area of the pancreas stump on CT scan were also measured. RESULTS: Mean patient age was 60.5 years, 26 patients (46.3%) had pancreatic cancer and 20 (33.3%) underwent laparoscopic surgery. Clinically relevant POPF was observed in 12 patients (20.0%). Linear regression analysis showed a significant correlation between fat quantification on MRI and pathologic fat (pathologic fat = 1.978 * MR fat -6.393, p < 0.001, R 2 = 0.777). Univariate analysis showed that <=8% fat on MRI (p = 0.040), <=5% pathologic fat (p = 0.002), ADC <= 1.3 * 10-3 mm2/s (p = 0.020), thicker pancreas (p = 0.007), and wider cross-sectional area of the pancreas (p = 0.013) were significantly associated with clinically relevant POPF after DP. Multivariate analysis revealed that pancreas thickness >17.6 mm [odds ratio (OR) 6.532, p = 0.064] and cross sectional area >377 mm2 (OR 12.676, p = 0.052) were marginally related to clinically relevant POPF. CONCLUSIONS: Pancreatic thickness and cross-sectional area of the transected surface of the pancreas are marginally significant risk factors for POPF development after DP. Measuring pancreatic thickness and cross sectional area can be a promising tool for the preoperative prediction of POPF. PMID- 28091746 TI - [Improvement of vision through perceptual learning in the case of refractive errors and presbyopia : A critical valuation]. AB - The idea of compensating or even rectifying refractive errors and presbyopia with the help of vision training is not new. For most approaches, however, scientific evidence is insufficient. A currently promoted method is "perceptual learning", which is assumed to improve stimulus processing in the brain. The basic phenomena of perceptual learning have been demonstrated by a multitude of studies. Some of these specifically address the case of refractive errors and presbyopia. However, many open questions remain, in particular with respect to the transfer of practice effects to every-day vision. At present, the method should therefore be judged with caution. PMID- 28091745 TI - Sealing with Cyanoacrylate and a Falciform Patch Cannot Prevent Postoperative Pancreatic Fistula. AB - BACKGROUND: This study aimed to evaluate the effect of a new combined method of covering the pancreatic anastomosis or stump with a cyanoacrylate and a falciform patch (CAFP) on the occurrence of postoperative pancreatic fistula (POPF). METHODS: Patients undergoing a pancreaticoduodenectomy (PD) or a distal pancreatectomy (DP) were recruited over a period of 12 months. The pancreaticojejunostomy in PD and the stump in DP were sealed with cyanoacrylate glue and wrapped in a falciform patch. Incidence and severity of POPF and associated postoperative complications were retrospectively compared with historical controls of 750 PD and 336 DP at the same institution and with current data from the literature. RESULTS: The new method was applied in 27 PD and 25 DP. The rate of clinically relevant POPF after PD with CAFP was 22.2% compared to 14.4% in historical patients, p = 0.26. The rate of clinically relevant POPF after DP with CAFP was 36% compared to 30% in historical patients, p = 0.65. CONCLUSION: Sealing the pancreatic anastomosis or stump with a combination of a cyanoacrylate glue and a falciform patch didn't reduce the rate of POPF after major pancreatic resections. PMID- 28091748 TI - SAGES VTE prophylaxis for laparoscopic surgery guidelines: an update. PMID- 28091749 TI - Irrigation, lavage, colonic hydrotherapy: from beauty center to clinic? PMID- 28091750 TI - Ectomycorrhizal fungal diversity associated with endemic Tristaniopsis spp. (Myrtaceae) in ultramafic and volcano-sedimentary soils in New Caledonia. AB - New Caledonian serpentine (ultramafic) soils contain high levels of toxic heavy metals, in particular nickel, (up to 20 g kg-1) and are deficient in essential elements like carbon, nitrogen and phosphorus while having a high magnesium/calcium ratio. Although previous studies showed that ectomycorrhizal symbioses could play an important role in the adaptation of the endemic plants to ultramafic soils (FEMS Microbiol Ecol 72:238-49, 2010), none of them have compared the diversity of microbial communities from ultramafic vs non-ultramafic soils in New Caledonia. We explored the impact of edaphic characteristics on the diversity of ectomycorrhizal (ECM) fungi associated with different endemic species of Tristaniopsis (Myrtaceae) growing under contrasting soil conditions in the natural ecosystems of New Caledonia. ECM root tips were thus sampled from two different ultramafic sites (Koniambo massif and Desmazures forest) vs two volcano sedimentary ones (Arama and Mont Ninndo). The molecular characterization of the ECM fungi through partial sequencing of the ITS rRNA gene revealed the presence of different dominant fungal genera including, both soil types combined, Cortinarius (36.1%), Pisolithus (18.5%), Russula (13.4%), Heliotales (8.2%) and Boletellus (7.2%). A high diversity of ECM taxa associated with Tristaniopsis species was found in both ultramafic and volcano-sedimentary soils but no significant differences in ECM genera distribution were observed between both soil types. No link could be established between the phylogenetic clustering of ECM taxa and their soil type origin, thus suggesting a possible functional-rather than taxonomical-adaptation of ECM fungal communities to ultramafic soils. PMID- 28091751 TI - Long-term treatment of Parkinson's disease with levodopa and other adjunctive drugs. AB - We report a long-term treatment of Parkinson's disease in out-patient clinics. The patients with Parkinson's disease were evaluated at the time of clinic visit from September 1st, 2015 to February 29th, 2016. Total number of the patients was 498. The age at the evaluation was 69.9 +/- 9.3 years and the age of onset was 60.2 +/- 11.3. Hoehn and Yahr severity was 3.28 +/- 0.94 in patients who were from 16 to 20 years (n = 53) and 3.00 +/- 0.86 in patients from 21 years or more (n = 38) from the onset of the disease to the evaluation. The dose of levodopa was 741 +/- 295 mg per day and the number of levodopa dosing was 5.85 +/- 2.59 times in 16-20 years from the onset to the evaluation and 703 +/- 251 mg/day and 6.03 +/- 3.20 times a day in 21 years or more from the onset to the evaluation. Levodopa was given in most cases into an empty stomach. The incidence of wearing off was 73.6% and dyskinesia was 37.7% in the 16-20 years group and 76.3% and 55.3% in 21 years or more group, respectively. The patients who had 15 years or less from the onset to the evaluation had much milder severity of the disease. Hoehn and Yahr severity, the dose of levodopa, and the incidence of wearing off were about the same as in the literature. But the incidence of dyskinesia was much lower than those appeared in the literature. We discussed reasons why the incidence of dyskinesia was lower in our study. PMID- 28091752 TI - Management of secondary hyperparathyroidism: practice patterns and outcomes of cinacalcet treatment with or without active vitamin D in Austria and Switzerland the observational TRANSIT Study. AB - Secondary hyperparathyroidism is a complex disorder requiring an individualized multicomponent treatment approach. This study was conducted to identify treatment combinations used in clinical practice in Austria and Switzerland and the potential to control this disorder. A total of 333 adult hemodialysis and peritoneal dialysis patients were analyzed. All patients received conventional care prior to initiation of a cinacalcet-based regimen. During the study, treatment components, e.g. cinacalcet, active vitamin D analogues and phosphate binders, were adapted to individual patient requirements and treatment dynamics were documented. Overall, the mean intact parathyroid hormone (iPTH) increased from 64.2 pmol/l to 79.6 pmol/l under conventional therapy and decreased after cinacalcet initiation to 44.0 pmol/l after 12 months (mean decrease between baseline and 12 months -45%). Calcium remained within the normal range throughout the study and phosphorus ranged around the upper limit of normal. The Kidney Disease: Improving Global Outcomes (KDIGO) target achievement for iPTH increased from 44.5% of patients at baseline to 65.7% at 12 months, corrected calcium from 58.9% to 51.9% and phosphorus from 18.4% to 24.4%. On average, approximately 30% of patients adapted their regimen from one observation period to the next. The reasons for changing a given regimen were to attain or maintain any of the bone mineral markers within recommended targets and to avoid developments to extreme values. Some regional differences in practice patterns were identified. No new safety signals emerged. In conclusion, cinacalcet appears to be a necessary treatment component to achieve recommended targets. The detailed composition of the treatment mix should be adapted to patient requirements and reassessed on a regular basis. PMID- 28091753 TI - VTST/MT studies of the catalytic mechanism of C-H activation by transition metal complexes with [Cu2(MU-O2)], [Fe2(MU-O2)] and Fe(IV)-O cores based on DFT potential energy surfaces. AB - High-valent Cu and Fe species, which are generated from dioxygen activation in metalloenzymes, carry out the functionalization of strong C-H bonds. Understanding the atomic details of the catalytic mechanism has long been one of the main objectives of bioinorganic chemistry. Large H/D kinetic isotope effects (KIEs) were observed in the C-H activation by high-valent non-heme Cu or Fe complexes in enzymes and their synthetic models. The H/D KIE depends significantly on the transition state properties, such as structure, energies, frequencies, and shape of the potential energy surface, when the tunneling effect is large. Therefore, theoretical predictions of kinetic parameters such as rate constants and KIEs can provide a reliable link between atomic-level quantum mechanical mechanisms and experiments. The accurate prediction of the tunneling effect is essential to reproduce the kinetic parameters. The rate constants and HD/KIE have been calculated using the variational transition-state theory including multidimensional tunneling based on DFT potential energy surfaces along the reaction coordinate. Excellent agreement was observed between the predicted and experimental results, which assures the validity of the DFT potential energy surfaces and, therefore, the proposed atomic-level mechanisms. The [Cu2(MU-O)2], [Fe2(MU-O)2], and Fe(IV)-oxo species were employed for C-H activation, and their role as catalysts was discussed at an atomic level. PMID- 28091755 TI - Reply to the letter to the editor "chronic disseminated candidiasis" by Kenneth Rolston. PMID- 28091754 TI - A new look at the role of thiolate ligation in cytochrome P450. AB - Protonated ferryl (or iron(IV)hydroxide) intermediates have been characterized in several thiolate-ligated heme proteins that are known to catalyze C-H bond activation. The basicity of the ferryl intermediates in these species has been proposed to play a critical role in facilitating this chemistry, allowing hydrogen abstraction at reduction potentials below those that would otherwise lead to oxidative degradation of the enzyme. In this contribution, we discuss the events that led to the assignment and characterization of the unusual iron(IV)hydroxide species, highlighting experiments that provided a quantitative measure of the ferryl basicity, the iron(IV)hydroxide pKa. We then turn to the importance of the iron(IV)hydroxide state, presenting a new way of looking at the role of thiolate ligation in these systems. PMID- 28091756 TI - [Recommendation on temperature management after cardiopulmonary arrest and severe traumatic brain injury in childhood beyond the neonatal period : Statement of the German Society for Neonatology and Pediatric Intensive Care Medicine (GNPI) and the scientific Working Group for Paediatric Anaesthesia (WAKKA) of the German Society of Anaesthesiology and Intensive Care (DGAI)]. AB - The available data on the effectiveness of therapeutic hypothermia in different patient groups are heterogeneous. Although the benefits have been proven for some collectives, recommendations for the use of hypothermia treatment in other groups are based on less robust data and conclusions by analogy. This article gives a review of the current evidence of temperature management in all age groups and based on this state of knowledge, recommends active temperature management with the primary aim of strict normothermia (36-36.5 degrees C) for 72 hours after cardiopulmonary arrest or severe traumatic brain injury for children beyond the neonatal period. PMID- 28091757 TI - [Renal protection in intensive care : Myths and facts]. AB - BACKGROUND: Acute kidney injury (AKI) is a common and severe complication in patients on the intensive care unit with a significant impact on patient mortality, morbidity and costs of care; therefore, renal protective therapy is most important in these severely ill patients. AIM OF THE REVIEW: Many renal protective strategies have been postulated during the last decades, which are sometimes still in place as a kind of "myth" but which are not always proven by evidence-based "facts". The aim of this review is therefore to question and compare some of these "myths" with the available "facts". RECENT FINDINGS: Most important for renal protection is the early identification of patients at risk for AKI or with acute kidney damage before renal function deteriorates further. A stage-based management of AKI comprises more general measures, such as discontinuation of nephrotoxic agents and adjustment of diuretic doses but most importantly early hemodynamic stabilization with crystalloid volume replacement solutions and vasopressors, such as noradrenaline. The aim is to ensure optimal renal perfusion and perfusion pressure. Patients with known arterial hypertension potentially need higher perfusion pressures. Large amounts of hyperchloremic solutions should be avoided. Volume overload and renal vasodilatory substances can also lead to further deterioration of kidney function. There is still no specific pharmacological therapy for renal protection. PMID- 28091758 TI - [Deaths from propofol abuse : Survey of institutes of forensic medicine in Germany, Austria and Switzerland]. AB - Previous references suggesting a high mortality of propofol addiction in medical personnel were mostly based on surveys of the heads of medical departments or case reports; therefore, a questionnaire was sent to 48 forensic medicine departments in Germany, Austria and Switzerland concerning the number of autopsies carried out between 2002-2112 on medical personnel with the suspicion of abuse of propofol or other analgesics. The response rate was 67%. In 16 out of the 32 responding departments 39 deaths (27 males) were observed with previous connections to anesthesiology, intensive care or emergency departments of which 22 were physicians, 13 nurses, 2 other personnel and 2 were unknown. Propofol was the major cause of death in 33 cases (85%), in 8 cases including 7 with propofol, an unintentional accident was recorded and 29 were determined to be suicide. In 14 cases chronic abuse was denied but actually excluded by toxicological analysis in only 2 cases. In 11 cases involving suicide the question of abuse was not investigated. This survey confirmed previous data about the central role of propofol for the fatal outcome of addiction and suicide of anesthetists and other medical personnel. A dual prevention strategy with low-threshold offers for persons at risk and strategies for early detection is urgently needed including a stricter control of dispensing, improvement in forensic medical documentation and the use of toxicological investigations in every case of suspected abuse. PMID- 28091759 TI - To freeze or not to freeze: heating the debate but cooling the practice? PMID- 28091760 TI - Characteristics of green-blue fluorescence generated from the adaxial sides of leaves of tree species. AB - We discovered that some tree species have leaves whose adaxial sides show bright green-blue fluorescence upon exposure to ultraviolet irradiation. In total, 141 native Japanese species belonging to 47 families were analyzed, and the brightness of the leaf fluorescence, represented by the L* values (Lab color space) of the pictures, was evaluated. The species possessing the brightest fluorescent leaves, with L* > 50, were Camellia japonica, Camellia sasanqua, and Cleyera japonica of Theaceae, Osmanthus heterophyllus and Ligustrum japonicum of Oleaceae, Aucuba japonica of Garryaceae, and Trochodendron aralioides of Trochodendraceae. These species are propagated by pollination or seed dispersion by birds, except T. aralioides. The fluorescence was specifically observed in the cuticle tissues of the epidermal cells, indicating that the fluorescence is a signal to other organisms that can perceive the fluorescence under natural light. Species possessing the bright leaves represented 5% of the total species tested, while species possessing dark leaves, with L* <= 40, represented 88.6%. We deduce that the fluorescence enables the organisms to easily distinguish the minority species possessing bright leaves from the surrounding plants, which were mostly trees species with dark leaves. The structure of A. japonica var. borealis, in which dark leaves only surround its fruits while the rest of the tree is covered by bright leaves, may be useful to signal the presence of fruits to the organisms. We hypothesize that the fluorescence contributes to the propagation of the tree species by helping birds to distinguish these particular trees and/or locate the fruits. PMID- 28091761 TI - On the origins of endogenous thoughts. AB - Endogenous thoughts are thoughts that we activate in a top-down manner or in the absence of the appropriate stimuli. We use endogenous thoughts to plan or recall past events. In this sense, endogenous thinking is one of the hallmarks of our cognitive lives. In this paper, I investigate how it is that we come to possess endogenous control over our thoughts. Starting from the close relation between language and thinking, I look into speech production-a process motorically controlled by the inferior frontal gyrus (IFG). Interestingly, IFG is also closely related to silent talking, as well as volition. The connection between IFG and volition is important given that endogenous thoughts are or at least greatly resemble voluntary actions. Against this background, I argue that IFG is key to understanding the origins of conscious endogenous thoughts. Furthermore, I look into goal-directed thinking and show that IFG plays a key role also in unconscious endogenous thinking. PMID- 28091762 TI - Good jobs, good pay, better health? The effects of job quality on health among older European workers. AB - Using data from the Survey of Health, Ageing and Retirement in Europe, this study presents new evidence on the effects of job quality on the occurrence of severe acute conditions, the level of cardiovascular risk factors, musculoskeletal disorders, mental health, functional disabilities and self-assessed health among workers aged 50+. By combining intrinsic job quality with job insecurity and pay the study maps out multiple potential pathways through which work may affect health and well-being. Levering longitudinal data and external information on early retirement ages allows for accounting of unobserved heterogeneity, selection bias and reverse causality. The empirical findings suggest that inequities in health correlate with inequities in job quality, though a substantial fraction of these associations reflect time-constant unobserved heterogeneity. Still, there is evidence for genuine protective effects of better jobs on musculoskeletal disorders, mental health and general health. The effect could contribute to a substantial number of avoidable disorders among older workers, despite relatively modest effect sizes at the level of individuals. Mental health, in particular, responds to changes in job quality. Selection bias such as the healthy worker effect does not alter the results. But the influence of job quality on health may be transitional among older workers. An in-depth analysis of health dynamics reveals no evidence for persistence. PMID- 28091763 TI - The Prevalence of Trypanosoma cruzi, the Causal Agent of Chagas Disease, in Texas Rodent Populations. AB - Rodent species were assessed as potential hosts of Trypanosoma cruzi, the etiologic agent of Chagas disease, from five sites throughout Texas in sylvan and disturbed habitats. A total of 592 rodents were captured, resulting in a wide taxonomic representation of 11 genera and 15 species. Heart samples of 543 individuals were successfully analyzed by SybrGreen-based quantitative PCR (qPCR) targeting a 166 bp fragment of satellite DNA of T. cruzi. Eight rodents representing six species from six genera and two families were infected with T. cruzi. This is the first report of T. cruzi in the pygmy mouse (Baiomys taylori) and the white-footed mouse (Peromyscus leucopus) for the USA. All infected rodents were from the southernmost site (Las Palomas Wildlife Management Area). No differences in pathogen prevalence existed between disturbed habitats (5 of 131 tested; 3.8%) and sylvan habitats (3 of 40 tested; 7.5%). Most positives (n = 6, 16% prevalence) were detected in late winter with single positives in both spring (3% prevalence) and fall (1% prevalence). Additionally, 30 Triatoma insects were collected opportunistically from sites in central Texas. Fifty percent of these insects, i.e., 13 T. gerstaeckeri (68%), and two T. lecticularia (100%) were positive for T. cruzi. Comparative sequence analyses of 18S rRNA of samples provided identical results with respect to detection of the presence or absence of T. cruzi and assigned T. cruzi from rodents collected in late winter to lineage TcI. T. cruzi from Triatoma sp. and rodents from subsequent collections in spring and fall were different, however, and could not be assigned to other lineages with certainty. PMID- 28091765 TI - ? PMID- 28091764 TI - Isolation of Campylobacter spp. from Three Species of Antarctic Penguins in Different Geographic Locations. AB - The presence of Campylobacter species was studied in three Antarctic penguin species, Adelie (Pygoscelis adeliae), chinstrap (Pygoscelis antarctica) and gentoo (Pygoscelis papua). A total of 390 penguins were captured in 12 different rookeries along the Antarctic Peninsula with differences in the amount of human visitation: six colonies were highly visited [Stranger Point, King George Island (P. papua and P. adeliae); Hannah Point, Livingston Island (P. papua and P. antarctica); Deception Island (P. antarctica); and Paradise Bay, Antarctic Peninsula (P. papua)], and six colonies were rarely visited [Devil's Point, Byers Peninsula, Livingston Island (P. papua); Cierva Cove, Antarctic Peninsula (P. papua); Ronge Island (P. papua and P. antarctica); Yalour Island (P. adeliae); and Avian Island (P. adeliae)]. A total of 23 strains were isolated from penguins from nine different rookeries. Campylobacter lari subsp. lari was isolated from eight samples (seven from P. papua and one from P. adeliae); C. lari subsp. concheus from 13 (ten from P. adeliae and three from P. antarctica) and C. volucris from two samples (both from P. papua). We did not find any significant differences in the prevalence of Campylobacter spp. between the populations in highly and rarely visited areas. This is the first report of C. lari subsp. concheus and C. volucris isolation from penguins in the Antarctic region. PMID- 28091766 TI - Pre-operative intra-articular deep tissue sampling with novel retrograde forceps improves the diagnostics in periprosthetic joint infection. AB - BACKGROUND: Histopathological tissue analysis is a key parameter within the diagnostic algorithm for suspected periprosthetic joint infections (PJIs), conventionally acquired in open surgery. In 2014, Hugle and co-workers introduced novel retrograde forceps for retrograde synovial biopsy with simultaneous fluid aspiration of the knee joint. We hypothesised that tissue samples acquired by retrograde synovial biopsy are equal to intra-operatively acquired deep representative tissue samples regarding bacterial detection and differentiation of periprosthetic infectious membranes. METHOD: Thirty patients (male n = 15, 50%; female n = 15, 50%) with 30 suspected PJIs in painful total hip arthroplasties (THAs) were included in this prospective, controlled, non-blinded trial. The results were compared with intra-operatively obtained representative deep tissue samples. RESULTS: In summary, 27 out of 30 patients were diagnosed correctly as infected (17/17) or non-infected (10/13). The sensitivity to predict a PJI using the Retroforce(r) sampling forceps in addition to standard diagnostics was 85%, the specificity 100%. CONCLUSIONS: Retrograde synovial biopsy is a new and rapid diagnostic procedure under local anaesthesia in patients with painful THAs with similar histological results compared to deep tissue sampling. PMID- 28091767 TI - Intramuscular myxoma: clinical and surgical observation notes on eleven cases. AB - PURPOSE: Intramuscular myxoma (IM) is a benign, soft tissue neoplasm of mesenchymal origin. We report our experience with this tumour. METHOD: This clinical study comprised 11 cases of IM that were operated on between March 2008 and June 2016. Tumour location and size, results of pre-operative radiological studies, preop-erative biopsies, pathology examinations, applied surgical method and post-operative complications were reported for all patients. RESULTS: In total, nine patients with 11 IMs with a mean age of 60.0 years were assessed. Mean follow-up was 39.2 months. Tumours were located in the right thigh (5 patients, 7 IM), left gluteal area (2 patients, 2 IM), right gluteal area (1 IM) and left thigh (1 IM) ranging from 2 * 1 cm to 10 * 17 cm Pre-operative radiological diagnoses were cystic lesion, abscess, bursitis, fibrosarcoma, fibroma, lipoma, malign mesenchymal tumour and IM. Pre-operative biopsy was performed for five cases. All tumours were removed via simple excision and were pathologically consistent with IM. No complication or recurrence was observed during the follow-up period. CONCLUSION: IM is a relatively rare benign tumour, the pre-operative diagnosis of which using radiological and clinical methods is quite difficult, creating pre-operative diagnostic confusion. It is generally diagnosed by microscopic examination. Simple excision with a small margin of surrounding tissue is considered to be sufficient for its treatment. PMID- 28091768 TI - Total hip arthroplasty instability treatment without dual mobility cups: brief overview and experience of other options. AB - Dual mobility cups are getting increasing interest for the prevention, but also in the treatment of THA instability. Nevertheless when a dislocation occurs the main issue remains the knowledge and the correction of the causes of dislocation, including reorientation of the components and soft tissues treatment. There are several options of alternative implants to DMCs including upsizing of the head, and constrained liners. The Authors present how to evaluate patients with THA instability, the advantages and the disadvantages of each procedure and their experience in the treatment of cases without DMCs during a five years' time period. PMID- 28091769 TI - Bousquet dual mobility socket for patient under fifty years old. More than twenty year follow-up of one hundred and thirty one hips. AB - PURPOSE: The aim of this study was to analyze dual mobility cup survival rate on young patients under 50 years old at more than 20 years of follow up. METHODS: One hundred thirty seven hips with a first generation of dual mobility Bousquet cup (Serf) were included. The mean age at the time of the surgery was 41 years and the mean follow-up was 21.9 years. RESULTS: Twenty year follow-up cup survival rate was 77%. No dislocation occurred, 44 hips were revised (including 21 cup aseptic loosenings isolated, 15 Intra Prosthetic Dislocations), seven hips were lost to follow-up, 11 patients died, and 75 hips were still in situ. CONCLUSION: First generation dual mobility cup survival on young patient was comparable with literature results. The main complications, cup aseptic loosening and intra prosthetic dislocation, were wear-related. With improvements of the defects of first generation dual mobility, we might expect an even better survival rate with contemporary DM cups. PMID- 28091770 TI - Relevance of surgery in patients with non-variceal upper gastrointestinal bleeding. AB - INTRODUCTION: Upper GI bleeding remains one of the most common emergencies with a substantial overall mortality rate of up to 30%. In severe ill patients, death does not occur due to failure of hemostasis, either medical or surgical, but mainly from comorbidities, treatment complications, and decreased tolerated blood loss. Management strategies have changed dramatically over the last two decades and include primarily endoscopic intervention in combination with acid suppressive therapy and decrease in surgical intervention. Herein, we present one of the largest patient-based analysis assessing clinical parameters and outcome in patients undergoing endoscopy with an upper GI bleeding. Data were further analyzed to identify potential new risk factors and to investigate the role of surgery. PATIENTS AND METHODS: In this retrospective study, we aimed to analyze outcome of patients with an UGIB and data were analyzed to identify potential new risk factors and the role of surgery. Data collection included demographic data, laboratory results, endoscopy reports, and details of management including blood administration, and surgery was carried out. Patient events were grouped and defined as "overall" events and "operated," "non-operated," and "operated and death" as well as "non-operated and death" where appropriate. Blatchford, clinical as well as complete Rockall-score analysis, risk stratification, and disease-related mortality rate were calculated for each group for comparison. RESULTS: Overall, 253 patients were eligible for analysis: endoscopy was carried out in 96% of all patients, 17% needed surgical intervention after endoscopic failure of bleeding control due to persistent bleeding, and the remaining 4% of patients were subjected directly to surgery. The median length of stay to discharge was 26 days. Overall mortality was 22%; out of them, almost 5% were operated and died. Anticoagulation was associated with a high in-hospital mortality risk (23%) and was increased once patients were taken to surgery (43%). Patients taking steroids presented with a risk of death of 26%, once taken to surgery the risk increased to 80%. Patients with liver cirrhosis had a risk of death of 42%; we observed a better outcome for these patients once taken to theater. Clinically, once scored with Blatchford score, statistical correlation was found for initial need for blood transfusion and surgical intervention. Clinical as well as complete Rockall score revealed a correlation between need for blood transfusion as well as surgical intervention in addition with a decreased outcome with increasing Rockall scores. Risk factor analysis including comorbidity, drug administration, and anticoagulation therapy introduced the combination of tumor and non-steroidal antirheumatic medication as independent risk factors for increased disease-related mortality. CONCLUSION: UGIB remains challenging and endoscopy is the first choice of intervention. Care must be taken once a patient is taking antirheumatic non-steroidal pain medication and suffers from cancer. In patients with presence of liver cirrhosis, an earlier surgical intervention may be considered, in particular for patients with recurrent bleeding. Embolization is not widely available and carries the risk of necrosis of the affected organ and should be restricted to a subgroup of patients not primarily eligible for surgery once endoscopy has failed. Taken together, an interdisciplinary approach including gastroenterologists as well as surgeons should be used once the patient is admitted to the hospital to define the best treatment option. PMID- 28091772 TI - Transient expression of recombinant tissue plasminogen activator (rt-PA) gene in cucurbit plants using viral vector. AB - OBJECTIVE: To use a transient expression system to express a truncated human tissue plasminogen activator (K2S) gene in cucurbit plants. RESULTS: The recombinant tissue plasminogen activator protein (K2S form) was expressed in active form in cucurbit plants. Its molecular weight was 43 kDa. The plant derived rt-PA was determined using goat anti-rabbit antibody by western blotting. Among the infected lines, the highest expression of rt-PA was 62 ng/100 mg per leaf tissue as measured by ELISA. The enzymatic activity of the plant-derived rt PA was 0.8 IU/ml. CONCLUSIONS: The K25 form of rt-PA was expressed for the first time using the viral expression system. Plant-derived rt-PA showed similar potency to commercially-available PA. PMID- 28091771 TI - Localization of parathyroid adenomas using 11C-methionine pet after prior inconclusive imaging. AB - PURPOSE: Minimally invasive parathyroidectomy (MIP) is the recommended treatment in primary hyperparathyroidism (pHPT) for which accurate preoperative localization is essential. The current imaging standard consists of cervical ultrasonography (cUS) and MIBI-SPECT/CT. 11C-MET PET/CT has a higher resolution than MIBI-SPECT/CT. The aim of this study was to determine the diagnostic performance of 11C-MET PET/CT after initial inconclusive or negative localization. METHODS: We performed a retrospective single center cohort study of patients with pHPT undergoing parathyroid surgery after prior negative imaging and later localization by means of 11C-MET PET/CT between 2006 and 2014. Preoperative localization by 11C-MET PET/CT was compared with later surgical localization, intraoperative quick PTH (IOPTH), duration of surgery, histopathology, and follow-up data. Also, differences in duration of surgery between the groups with and without correct preoperative localization were analyzed. RESULTS: In 18/28 included patients a positive 11C-MET-PET/CT result corresponded to the surgical localized adenoma (64%). In 3/28 patients imaging was false positive and no adenoma was found. In 7/28 patients imaging was false negative at the side of the surgically identified adenoma. Sensitivity of 11C-MET PET/CT was 72% (18/25). Duration of surgery of correctly localized patients was significantly shorter compared to falsely negative localized patients (p = 0.045). CONCLUSION: In an intention to treat 11C-MET-PET/CT correctly localized the parathyroid adenoma in 18/28 (64%) patients, after previous negative imaging. A preoperatively correct localized adenoma leads to a more focused surgical approach (MIP) potentially reducing duration of surgery and potentially healthcare costs. PMID- 28091773 TI - The nervous system of airways and its remodeling in inflammatory lung diseases. AB - Inflammatory lung diseases are associated with bronchospasm, cough, dyspnea and airway hyperreactivity. The majority of these symptoms cannot be primarily explained by immune cell infiltration. Evidence has been provided that vagal efferent and afferent neurons play a pivotal role in this regard. Their functions can be altered by inflammatory mediators that induce long-lasting changes in vagal nerve activity and gene expression in both peripheral and central neurons, providing new targets for treatment of pulmonary inflammatory diseases. PMID- 28091774 TI - Development, remodeling and regeneration of the lung: coping with the structural and functional challenges of breathing. PMID- 28091775 TI - Developmental and sex-specific differences in expression of neuropeptides derived from allatotropin gene in the silkmoth Bombyx mori. AB - Allatotropin (AT) and related neuropeptides are widespread bioactive molecules that regulate development, food intake and muscle contractions in insects and other invertebrates. In moths, alternative splicing of the at gene generates three mRNA precursors encoding AT with different combinations of three structurally similar AT-like peptides (ATLI-III). We used in situ hybridization and immunohistochemistry to map the differential expression of these transcripts during the postembryonic development of Bombyx mori. Transcript encoding AT alone was expressed in numerous neurons of the central nervous system and frontal ganglion, whereas transcripts encoding AT with ATLs were produced by smaller specific subgroups of neurons in larval stages. Metamorphosis was associated with considerable developmental changes and sex-specific differences in the expression of all transcripts. The most notable was the appearance of AT/ATL transcripts (1) in the brain lateral neurosecretory cells producing prothoracicotropic hormone; (2) in the male-specific cluster of about 20 neurons in the posterior region of the terminal abdominal ganglion; (3) in the female-specific medial neurons in the abdominal ganglia AG2-7. Immunohistochemical staining showed that these neurons produced a mixture of various neuropeptides and innervated diverse peripheral organs. Our data suggest that AT/ATL neuropeptides are involved in multiple stage and sex-specific functions during the development of B. mori. PMID- 28091776 TI - Nasal masks or binasal prongs for delivering continuous positive airway pressure in preterm neonates-a randomised trial. AB - : The objective of this study was to compare the efficacy and safety of continuous positive airway pressure (CPAP) delivered using nasal masks with binasal prongs. We randomly allocated 72 neonates between 26 and 32 weeks gestation to receive bubble CPAP by either nasal mask (n = 37) or short binasal prongs (n = 35). Primary outcome was mean FiO2 requirement at 6, 12 and 24 h of CPAP initiation and the area under curve (AUC) of FiO2 against time during the first 24 h (FiO2 AUC0-24). Secondary outcomes were the incidence of CPAP failure and nasal trauma. FiO2 requirement at 6, 12 and 24 h (mean (SD); 25 (5.8) vs. 27.9 (8); 23.8 (4.5) vs. 25.4 (6.8) and 22.6 (6.8) vs. 22.7 (3.3)) as well as FiO2 AUC0-24 (584.0 (117.8) vs. 610.6 (123.6)) were similar between the groups. There was no difference in the incidence of CPAP failure (14 vs. 20%; relative risk 0.67; 95% confidence interval 0.24-1.93). Incidence of severe nasal trauma was lower with the use of nasal masks (0 vs. 31%; p < .001). CONCLUSIONS: Nasal masks appear to be as efficacious as binasal prongs in providing CPAP. Masks are associated with lower risk of severe nasal trauma. TRIAL REGISTRATION: CTRI2012/08/002868 What is Known? * Binasal prongs are better than single nasal and nasopharyngeal prongs for delivering continuous positive airway pressure (CPAP) in preventing need for re-intubation. * It is unclear if they are superior to newer generation nasal masks in preterm neonates requiring CPAP. What is New? * Oxygen requirement during the first 24 h of CPAP delivery is comparable with use of nasal masks and binasal prongs. * Use of nasal masks is, however, associated with significantly lower risk of severe grades of nasal injury. PMID- 28091777 TI - Ultrasonography for endotracheal tube position in infants and children. AB - : Ultrasonography (US) has been shown to be effective for verifying endotracheal tube (ETT) position in adults but has been less studied in infants and children. We review the literature regarding US for ETT positioning in the pediatric population. A literature search was conducted using the Ovid and MEDLINE databases with search terms regarding US relating to ETT intubation and positioning in infants and children. Most studies in neonates and infants used the midsagittal suprasternal view. Studies reported >80% visualization of the ETT tip by US, and US interpretation of the ETT position correlated with the XR position in 73-100% of cases. Studies of older children used the suprasternal views, substernal views, and mid-axillary intercostal views. US appears comparable to XR and capnography in determining ETT position in this population. CONCLUSION: US for ETT verification appears to be well tolerated in infants and children and may augment determination of proper ETT position in combination with other ETT verification modalities. Further studies are needed regarding technique and training. What is Known: * Point-of-care ultrasonography is realizing increased availability and use in several pediatric specialties. * Ultrasonography has been shown to be effective for verifying ETT position in adults but have been less studied in infants and children. What is New: * Ultrasonography for endotracheal tube verification appears to be well tolerated in infants and children. * Ultrasonography may augment determination of proper endotracheal tube position in combination with other verification modalities such as radiography and capnography in the pediatric population. PMID- 28091778 TI - Hospital-based surveillance of congenital rubella syndrome in Indonesia. AB - : Congenital rubella syndrome (CRS) has serious consequences, such as miscarriage, stillbirth, and severe birth defects in infants, resulting from rubella virus infection during pregnancy. However, rubella vaccine has not yet been implemented in Indonesia. This study aimed (1) to estimate the incidence of CRS in Indonesia, (2) describe the clinical features of CRS at our referral hospital, and (3) pilot a CRS surveillance system to be extended to other hospitals. We conducted a 4-month prospective surveillance study of infants aged <1 year with suspected CRS in 2013 at an Indonesian hospital. Infants with suspected CRS were examined for rubella-specific IgM antibody or rubella IgG antibody levels. Of 47 suspected cases of CRS, 11/47 (23.4%), 9/47 (19.1%), and 27/47 (57.5%) were diagnosed as laboratory-confirmed, clinically compatible, and discarded CRS, respectively. The most common defects among laboratory-confirmed CRS cases were hearing impairment (100%), congenital cataracts (72.7%), microcephaly (72.7%), and congenital heart defects (45.5%). CONCLUSION: The number of laboratory-confirmed CRS cases among Indonesian infants is high. Furthermore, hearing impairment is the most common clinical feature of CRS in infants. Our findings indicate the importance of implementation of rubella vaccine in Indonesia. Conducting hospital-based surveillance of CRS in other hospitals in Indonesia may be appropriate. What is Known: *Congenital rubella syndrome (CRS) has serious consequences in infants resulting from rubella virus infection during pregnancy. *The incidence of CRS in most developed countries has greatly decreased since implementation of rubella vaccination. *Rubella vaccine has not yet been implemented in many developing countries. What is New: *The number of laboratory-confirmed CRS cases among Indonesian infants was high. *Implementation of rubella vaccine into immunization programs in Indonesia is important because of the high number of CRS cases. *Our study highlights the need for ongoing prospective surveillance of CRS in Indonesia. PMID- 28091779 TI - Early and late outcomes after surgical management of congenital vascular rings. AB - : Persistent respiratory or feeding problems in children may be associated with a congenital vascular ring. Surgical management is fairly standardized, but long term outcomes are not well described. This study aims to investigate clinical presentation, surgical treatment, and risk factors for early mortality and late outcome. Our database revealed 62 surgically treated vascular ring patients between 1993 and 2014. Double aortic arch was the most common diagnosis (53%). Median age at operation was 1 year. Symptoms were mainly respiratory (89%) and feeding problems (32%). Median extubation time and hospital stay were 4 h and 5 days. Mean follow-up was 7.8 +/- 5.8 years. Early mortality was 8% and was related to anatomical diagnosis, concomitant anomalies, and a need for preoperative intubation. Freedom from residual symptoms at 1 and 6 months was 63 and 82%, respectively. Freedom from inhalation therapy at the last follow-up was 82% and was influenced by a type of vascular ring and preoperative ventilation. Dysphagia symptoms always disappeared. CONCLUSION: Surgical relief of tracheoesophageal compression is commonly effective in vascular ring anomalies. Respiratory symptoms necessitating chronic inhalation therapy only persist in a minority of children. Patients with double aortic arch are at increased risk to remain symptomatic, particularly with infectious exacerbations. PMID- 28091780 TI - Letter in response to letter: intraocular use of acid violet 17 at a concentration of 1.5 mg/ml is not safe : By Professor Heinrich Gerding, Department of Ophthalmology, Pallas Kliniken. PMID- 28091781 TI - A semifluorinated alkane (F4H5) as novel carrier for cyclosporine A: a promising therapeutic and prophylactic option for topical treatment of dry eye. AB - PURPOSE: Cyclosporine A (Cs) has been used as effective topical therapy for inflammatory dry eye disease since more than a decade. However, due to its lipophilic character, Cs is formulated as emulsions or oily solutions for topical application. This experimental study aimed to test if the use of semifluorinated alkanes (SFAs) as a preservative-free, well-tolerated non-stinging or burning vehicle maintains or even improves the benefits of Cs in the topical therapy of dry-eye disease. METHODS: Desiccating stress was applied to C57BL/6 mice for 14 consecutive days to induce experimental dry-eye. Cs dissolved in SFA (perfluorobutylpentane = F4H5with 0.5% Ethanol), F4H5 with 0.5% ethanol only, 0.05% Cs (Restasis(r)), and dexamethasone (Monodex(r)) were applied three times daily beginning either at day 4 or day 11 of desiccating stress for up to 3 weeks after end of dry-eye induction. RESULTS: In comparison to other groups, Cs/F4H5 demonstrated high efficacy and earlier reduction of corneal staining. In this study, Cs/F4H5 had the ability to maintain conjunctival goblet cell density once applied on day 4. Flow cytometry analysis from cervical lymphnodes demonstrated a significantly lower CD4+ and CD8+ T-cells in the Cs/F4H5 group following 3 weeks of therapy than at baseline, but no difference in regulatory T cells from regional lymphnodes were seen. CONCLUSIONS: Overall, compared to a commercially available Cs formulation (Restasis(r)) and dexamethasone, Cs/F4H5 was shown to be equally effective but with a significantly faster therapeutic response in reducing signs of dry-eye disease in an experimental mouse model. PMID- 28091782 TI - Adaptation, perceptual learning, and plasticity of brain functions. AB - The capacity for functional restitution after brain damage is quite different in the sensory and motor systems. This series of presentations highlights the potential for adaptation, plasticity, and perceptual learning from an interdisciplinary perspective. The chances for restitution in the primary visual cortex are limited. Some patterns of visual field loss and recovery after stroke are common, whereas others are impossible, which can be explained by the arrangement and plasticity of the cortical map. On the other hand, compensatory mechanisms are effective, can occur spontaneously, and can be enhanced by training. In contrast to the human visual system, the motor system is highly flexible. This is based on special relationships between perception and action and between cognition and action. In addition, the healthy adult brain can learn new functions, e.g. increasing resolution above the retinal one. The significance of these studies for rehabilitation after brain damage will be discussed. PMID- 28091783 TI - Lifetime-Based Oxygen Sensing Properties of palladium(II) and platinum(II) meso tetrakis(4-phenylethynyl)phenylporphyrin. AB - High oxygen permeable [poly(TMSP)] nanofibers incorporating porphyrin macrocycle as luminescence indicators were prepared by electrospinning technique. The porphyrins involves were modified by i) introducing phenylacetylide substituents on the para position of the phenyl moieties and ii) varying the metal centers [Pt(II) or Pd(II)] of the meso-tetrakisphenylporphyrins. A set of nanofibers; (Pt TPP)NF, (Pd-TPP)NF, (Pt-TPA)NF and (Pd-TPA)NF were obtained to study their structure-activity relationship toward oxygen. The lifetime-based technique was privileged to take advantage of their long-lived phosphorescent properties. A two fold enhancement was observed for (Pt-TPA)NF and (Pd-TPA)NF compared to (Pt TPP)NF and (Pd-TPP)NF demonstrating the positive effect of the phenylacetylide moieties on the lifetime. Also, Silver nanoparticles were included in nanofibers to investigate their influence on lifetime-based oxygen sensitivity, showing that the presence of AgNPs only affects (Pd-TPA)NF. PMID- 28091785 TI - Editorial. PMID- 28091784 TI - Recognition of D-Penicillamine Using Schiff Base Centered Fluorescent Organic Nanoparticles and Application to Medicine Analysis. AB - Schiff base centered fluorescent organic compound 1,1'-[(1E,2E)-hydrazine-1,2 diylidenedi(E)methylylidene]- dinaphthalen-2-ol (HN) was synthesized followed by spectral characterization viz., NMR, IR and Mass spectroscopy. The fluorescent nanoparticles of HN prepared using reprecipitation method shows red shifted aggregation induced enhanced emission (AIEE) with respect to HN solution in acetone. The average particle size of nanoparticles (HNNPs) is of 67.2 nm shows sphere shape morphology. The surfactant cetyltrimethyl ammonium bromide (CTAB) used to stabilize HNNPs induces positive charge surface with zeta potential of 11.6 mV. The positive charge of HNNPs responsible to adsorb oppositely charged analyte on its surface with binding interactions. The fluorescence experiments performed with and without addition of different analytes to the aqueous suspension of HNNPs shows selective fluorescence quenching of HNNPs by D Penicillamine (D-PA). The effect of other coexisting analytes does not affect the selective sensing behavior of D-PA. The mechanism of binding between HNNPs and D PA was discussed on the basis of electrostatic interaction and adsorption phenomenon. The results interpreted by using DLS-Zeta sizer, Fluorescence lifetime measurements, conductometric titration supports the electrostatic adsorption between HNNPs and D-PA. The method has extremely low limit of detection (LOD) value 0.021 ppm is of significant as compared to reported methods. The proposed fluorescence quenching method was effectively used for quantitative estimation of D-PA from pharmaceutical medicine. Graphical Abstract The fluorescence quenching based selective recognition of D-Penicillamine (D-PA) by using Schiff base centered fluorescent organic nanoparticles was developed and successfully applied to quantitative determination of D-PA from pharmaceutical samples viz. capsule and tablet. PMID- 28091787 TI - Production of water-soluble yellow pigments via high glucose stress fermentation of Monascus ruber CGMCC 10910. AB - Monascus pigments are secondary metabolites of Monascus species and are mainly composed of yellow pigments, orange pigments and red pigments. In this study, a larger proportion of Monascus yellow pigments could be obtained through the selection of the carbon source. Hydrophilic yellow pigments can be largely produced extracellularly by Monascus ruber CGMCC 10910 under conditions of high glucose fermentation with low oxidoreduction potential (ORP). However, keeping high glucose levels later in the culture causes translation or a reduction of yellow pigment. We presume that the mechanism behind this phenomenon may be attributed to the redox level of the culture broth and the high glucose stress reaction of M. ruber CGMCC 10910 during high glucose fermentation. These yellow pigments were produced via high glucose bio-fermentation without citrinin. Therefore, these pigments can act as natural pigments for applications as food additives. PMID- 28091786 TI - A new look at the drug-resistance investigation of uropathogenic E. coli strains. AB - Bacterial drug resistance and uropathogenic tract infections are among the most important issues of current medicine. Uropathogenic Escherichia coli strains are the primary factor of this issue. This article is the continuation of the previous study, where we used Kohonen relations to predict the direction of drug resistance. The characterized collection of uropathogenic E. coli strains was used for microbiological (the disc diffusion method for antimicrobial susceptibility testing), chemical (ATR/FT-IR) and mathematical (artificial neural networks, Ward's hierarchical clustering method, the analysis of distributions of inhibition zone diameters for antibiotics, Cohen's kappa measure of agreement) analysis. This study presents other potential tools for the epidemiological differentiation of E. coli strains. It is noteworthy that ATR/FT-IR technique has turned out to be useful for the quick and simple identification of MDR strains. Also, diameter zones of resistance of this E. coli population were compared to the population of E. coli strains published by EUCAST. We observed the bacterial behaviors toward particular antibiotics in comparison to EUCAST bacterial collections. Additionally, we used Cohen's kappa to show which antibiotics from the same class are closely related to each other and which are not. The presented associations between antibiotics may be helpful in selecting the proper therapy directions. Here we present an adaptation of interdisciplinary studies of drug resistance of E. coli strains for epidemiological and clinical investigations. The obtained results may be some indication in deciding on antibiotic therapy. PMID- 28091788 TI - New insights into the role of pH and aeration in the bacterial production of calcium carbonate (CaCO3). AB - Over recent years, the implementation of microbially produced calcium carbonate (CaCO3) in different industrial and environmental applications has become an alternative for conventional approaches to induce CaCO3 precipitation. However, there are many factors affecting the biomineralization of CaCO3, which may restrict its application. In this study, we investigated the effects of pH and aeration as the main two influential parameters on bacterial precipitation of CaCO3. The results showed that the aeration had a significant effect on bacterial growth and its rise from 0.5 to 4.5 SLPM could produce 4.2 times higher CaCO3 precipitation. The increase of pH to 12 resulted in 6.3-fold increase in CaCO3 precipitation as compared to uncontrolled-pH fermentation. Morphological characterization showed that the pH is an effective parameter on CaCO3 morphology. Calcite was found to be the predominant precipitate during aeration controlled fermentations, while vaterite was mainly produced at lower pH (up to 10) over controlled-pH fermentations. Further increase in pH resulted in a morphological transition, and vaterite transformed to calcite at the pH ranges between 10 and 12. PMID- 28091789 TI - Comparative investigation on a hexane-degrading strain with different cell surface hydrophobicities mediated by starch and chitosan. AB - Bioremediation usually exhibits low removal efficiency toward hexane because of poor water solubility, which limits the mass transfer rate between the substrate and microorganism. This work aimed to enhance the hexane degradation rate by increasing cell surface hydrophobicity (CSH) of the degrader, Pseudomonas mendocina NX-1. The CSH of P. mendocina NX-1 was manipulated by treatment with starch and chitosan solution of varied concentrations, reaching a maximum hydrophobicity of 52%. The biodegradation of hexane conformed to the Haldane inhibition model, and the maximum degradation rate (nu max) of the cells with 52% CSH was 0.72 mg (mg cell)-1.h-1 in comparison with 0.47 mg (mg cell)-1.h-1 for cells with 15% CSH. The production of CO2 by high CSH cells was threefold higher than that by cells at 15% CSH within 30 h, and the cumulative rates of O2 consumption were 0.16 and 0.05 mL/h, respectively. High CSH was related to low negative charge carried by the cell surface and probably reduced the repulsive electrostatic interactions between hexane and microorganisms. The FT-IR spectra of cell envelopes demonstrated that the methyl chain was inversely proportional to increasing CSH values, but proteins exhibited a positive effect to CSH enhancement. The ratio of extracellular proteins and polysaccharides increased from 0.87 to 3.78 when the cells were treated with starch and chitosan, indicating their possible roles in increased CSH. PMID- 28091790 TI - Chemically modified surface functional groups of Alcaligenes sp. S-XJ-1 to enhance its demulsifying capability. AB - Cell-surface functional groups (amino, carboxyl, hydroxyl, as well as phosphate) were chemically modified in various ways to enhance the demulsification capability of the demulsifying bacteria Alcaligenes sp. S-XJ-1. Results demonstrated that the demulsifying activity was significantly inhibited by amino enrichment with cetyl trimethyl ammonium bromide, amino methylation, hydroxyl acetylation, and phosphate esterification, but was gradually promoted by carboxyl blocking with increasing the extents of esterification. Compared with the raw biomass, an optimal esterification of carboxyl moieties enhanced the demulsification ratio by 26.5% and shortened the emulsion half-life from 24 to 8.8 h. The demulsification boost was found to be dominated by strengthened hydrophobicity (from 53 degrees to 74 degrees ) and weakened electronegativity (from -34.6 to -4.3 mV at pH 7.0) of the cell surface, allowing the rapid dispersion and adsorption of cells onto the oil-water interface. The chemical modification of the functional groups on the biomass surface is a promising tool for the creation of a high-performance bacterial demulsifier. PMID- 28091791 TI - A novel scalable, robust downstream process for oncolytic rat parvovirus: isoelectric point-based elimination of empty particles. AB - The rodent protoparvovirus H-1PV, with its oncolytic and oncosuppressive properties, is a promising anticancer agent currently under testing in clinical trials. This explains the current demand for a scalable, good manufacturing practice-compatible virus purification process yielding high-grade pure infectious particles and overcoming the limitations of the current system based on density gradient centrifugation. We describe here a scalable process offering high purity and recovery. Taking advantage of the isoelectric point difference between full and empty particles, it eliminates most empty particles. Full particles have a significantly higher cationic charge than empty ones, with an isoelectric point of 5.8-6.2 versus 6.3 (as determined by isoelectric focusing and chromatofocusing). Thanks to this difference, infectious full particles can be separated from empty particles and most protein impurities by Convective interaction media(r) diethylaminoethyl (DEAE) anion exchange chromatography: applying unpurified H-1PV to the column in 0.15 M NaCl leaves, the former on the column and the latter in the flow through. The full particles are then recovered by elution with 0.25 M NaCl. The whole large-scale purification process involves filtration, single-step DEAE anion exchange chromatography, buffer exchange by cross-flow filtration, and final formulation in Visipaque/Ringer solution. It results in 98% contaminating protein removal and 96% empty particle elimination. The final infectious particle concentration reaches 3.5E10 plaque forming units (PFU)/ml, with a specific activity of 6.8E11 PFU/mg protein. Overall recovery is over 40%. The newly established method is suitable for use in commercial production. PMID- 28091792 TI - Restoration using Azolla imbricata increases nitrogen functional bacterial groups and genes in soil. AB - Microbial groups are major factors that influence soil function. Currently, there is a lack of studies on microbial functional groups. Although soil microorganisms play an important role in the nitrogen cycle, systematic studies of the effects of environmental factors on microbial populations in relation to key metabolic processes in the nitrogen cycle are seldom reported. In this study, we conducted a systematic analysis of the changes in nitrogen functional groups in mandarin orange garden soil treated with Azolla imbricata. The structures of the major functional bacterial groups and the functional gene abundances involved in key processes of the soil nitrogen cycle were analyzed using high-throughput sequencing (HTS) and quantitative real-time PCR, respectively. The results indicated that returning A. imbricata had an important influence on the composition of soil nitrogen functional bacterial communities. Treatment with A. imbricata increased the diversity of the nitrogen functional bacteria. The abundances of nitrogen functional genes were significantly higher in the treated soil compared with the control soil. Both the diversity of the major nitrogen functional bacteria (nifH bacteria, nirK bacteria, and narG bacteria) and the abundances of nitrogen functional genes in the soil showed significant positive correlations with the soil pH, the organic carbon content, available nitrogen, available phosphorus, and NH4+-N and NO3--N contents. Treatment with 12.5 kg fresh A. imbricata per mandarin orange tree was effective to improve the quality of the mandarin orange garden soil. This study analyzed the mechanism of the changes in functional bacterial groups and genes involved in key metabolic processes of the nitrogen cycle in soil treated by A. imbricata. PMID- 28091793 TI - Attenuation-based kV pair selection in dual source dual energy computed tomography angiography of the chest: impact on radiation dose and image quality. AB - OBJECTIVES: The purpose of this study was to evaluate the impact of attenuation based kilovoltage (kV) pair selection in dual source dual energy (DSDE)-pulmonary embolism (PE) protocol examinations on radiation dose savings and image quality. METHODS: A prospective study was carried out on 118 patients with suspected PE. In patients in whom attenuation-based kV pair selection selected the 80/140Sn kV pair, the pre-scan 100/140Sn CTDIvol (computed tomography dose index volume) values were compared with the pre-scan 80/140Sn CTDIvol values. Subjective and objective image quality parameters were assessed. RESULTS: Attenuation-based kV pair selection switched to the 80/140Sn kV pair ("switched" cohort) in 63 out of 118 patients (53%). The mean 100/140Sn pre-scan CTDIvol was 8.8 mGy, while the mean 80/140Sn pre-scan CTDIvol was 7.5 mGy. The average estimated dose reduction for the "switched" cohort was 1.3 mGy (95% CI 1.2, 1.4; p < 0.001), representing a 15% reduction in dose. After adjusting for patient weight, mean attenuation was significantly higher in the "switched" vs. "non-switched" cohorts in all five pulmonary arteries and in all lobes on iodine maps. CONCLUSIONS: This study demonstrates that attenuation-based kV pair selection in DSDE examination is feasible and can offer radiation dose reduction without compromising image quality. KEY POINTS: * Attenuation-based kV pair selection in dual energy examination is feasible. * It can offer radiation dose reduction to approximately 50% of patients. * Approximate 15% reduction in radiation dose was achieved using this technique. * The image quality is not compromised by use of attenuation based kV pair selection. PMID- 28091794 TI - The impact of liver disorders on perioperative management of reoperative cardiac surgery: a retrospective study in adult congenital heart disease patients. AB - PURPOSE: We evaluated the preoperative prevalence of risk factors for liver disorders and the relationship between the liver disorders and perioperative outcomes in adult congenital heart disease (ACHD) patients. METHODS: This retrospective study included 32 ACHD patients who underwent reoperative cardiac surgery. RESULTS: Preoperatively, 38% of the study patients had risk factors, including congestive liver (CL) due to right heart failure (31%), chronic hepatitis C (HC) (22%), and both CL and HC (16%). The numbers of patients with Child-Pugh scores 5, 6, 7 and 8 were 22, 7, 2 and 1. Median (range) preoperative platelet count and fibrinogen values were 155 (61-330) * 103/MUl and 250 (145 367) mg/dl, respectively. The patients with higher Child-Pugh scores tended to have longer duration of anesthesia and surgery (p = 0.078, 0.078, respectively), and had significantly higher platelet transfusion (p = 0.031). Lower platelet count was associated with longer duration of anesthesia, surgery and cardio pulmonary bypass (CPB), and larger amount of blood loss and platelet transfusion (p = 0.01, 0.011, 0.024, 0.033, 0.021). Lower fibrinogen value was associated with longer duration of anesthesia, surgery and CPB, and larger amount of platelet transfusion (p = 0.015, 0.009, 0.009, 0.023). CONCLUSION: ACHD patients who underwent reoperative cardiac surgery had a high prevalence of risk factors for liver disorders preoperatively, and liver disorders aggravated some intraoperative outcomes. These findings suggest that the prevention of liver disorders is important for reducing the occurrence of poor outcomes, and that ACHD patients with liver disorders need attentive perioperative management. PMID- 28091795 TI - Mood Spectrum Disorders and Perception of Pain. AB - : Evaluation of pain perception in chronic pain patients with a concomitant mood spectrum disorder. DESIGN: The observational retrospective study is based on patient data collected in psychosomatic consultations held at the Gift Institute for Integrative Medicine in Pisa, Italy, from 2002 to 2014. Evoked pain stimulus threshold and tolerance were evaluated using the cold pressor test. Clinical pain intensity and Sensorial, Affective, and Evaluative dimensions were assessed using the Italian Pain Questionnaire, and Anxiety and Depressive symptoms using the Hospital Anxiety Depression Scale. Mood-spectrum disorders were diagnosed via the Mini-International Neuropsychiatric Interview, and affective temperament in accordance with Akiskal and Pinto's criteria (1999). Of a total of 627 chronic pain clinic patients, 381 were diagnosed with a concomitant mood-spectrum (MS) disorder, unipolar (US) in 61.41%. Pain threshold (t = 2.28; p < 0.05) was lower, and all clinical pain dimensions (t = 2.28; p < 0.05) increased, in MS patients compared to those without psychiatric disorders. Pain intensity (F = 3.5, p < 0.05) and cognitive pain component scores (F = 7.84; p < 0.0001) were higher in US and, to a lesser extent Bipolar Spectrum, than in subjects with other (n.112) or no psychiatric disorders (n. 134). Suicide ideation was highest in US (F = 37.20; p < 0.0001), although in BS major depressive episodes had more melancholic features (F = 46.73; P < 0.0001), and a longer history of psychiatric disorders before the pain onset than US (F = 20.31; p < 0.0001). Pain management should take into account pre-existing psychiatric disorders. PMID- 28091797 TI - Mass spectrometric identification of phenol-soluble modulins in the ATCC(r) 43300 standard strain of methicillin-resistant Staphylococcus aureus harboring two distinct phenotypes. AB - Staphylococcus aureus subsp. aureus Rosenbach (ATCC(r) 43300TM) is a representative methicillin-resistant S. aureus (MRSA) strain that is used as a quality control strain for testing the methicillin susceptibility of clinical isolates. It has been consistently observed that colonies with two different colors (golden yellow and white) grow from the ATCC stock on blood agar plates. In this study, staphylococcal peptide and protein profiling was performed using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. From the extract of the potentially hemolytic 43300 strain, we identified a single significant peak at an observed mass-to-charge (m/z) value of 2306.9, which correlates well with the predicted mass of formylated phenol soluble modulin alpha2, a major staphylococcal virulence factor. Subsequent liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed that the hemolytic 43300 cells predominantly produced various phenol-soluble modulins (PSMs) and their export proteins, including four alpha type PSM peptides, PSMbeta1, PSM-mec, PmtC and PmtD. However, none of the PSM peptides was detected in the presumably non-hemolytic 43300 strain, but the export proteins PmtC and PmtD. We found that this MRSA standard strain expresses two distinct phenotypes and that their phenotypic features are more likely associated with PSM toxin production. Therefore, careful attention is needed when MRSA reference strains are utilized for the diagnosis and susceptibility testing of MRSA in clinical settings. PMID- 28091796 TI - Preferences for Smoking Cessation Support from Family and Friends Among Adults with Serious Mental Illness. AB - Engaging natural supports may be a promising strategy to promote the use of evidence-based smoking cessation treatment for individuals with serious mental illness (SMI) who smoke. This qualitative study explored preferences for support for quitting from family and friends among individuals with SMI who participated in cessation treatment. Participants were 41 individuals with SMI enrolled in a Medicaid Demonstration Project of smoking cessation at community mental health centers. Open-ended questions asked during a social network interview explored participants' preferences for more support for quitting smoking from family and friends. The qualitative data was coded and common themes were identified across the dataset. Three primary preferences emerged for smoking cessation support from family members and friends: 1) more practical support for quitting (e.g., financial help with purchasing cessation medications); 2) more emotional support for quitting (e.g., encouraging progress toward quitting); and 3) changing their own smoking behaviors in the presence of participants (e.g., don't smoke around them or offer them cigarettes). Individuals with SMI who participated in smoking cessation treatment at community mental health centers indicated several ways that family members and friends could support their efforts to quit smoking. Understanding how people with SMI want support from family and friends to quit smoking will inform strategies to leverage these natural resources to promote the use of evidence-based smoking cessation treatment and support smoking abstinence for this population. PMID- 28091798 TI - Intake of up to 3 Eggs/Day Increases HDL Cholesterol and Plasma Choline While Plasma Trimethylamine-N-oxide is Unchanged in a Healthy Population. AB - Eggs are a source of cholesterol and choline and may impact plasma lipids and trimethylamine-N-oxide (TMAO) concentrations, which are biomarkers for cardiovascular disease (CVD) risk. Therefore, the effects of increasing egg intake (0, 1, 2, and 3 eggs/day) on these and other CVD risk biomarkers were evaluated in a young, healthy population. Thirty-eight subjects [19 men/19 women, 24.1 +/- 2.2 years, body mass index (BMI) 24.3 +/- 2.5 kg/m2] participated in this 14-week crossover intervention. Participants underwent a 2-week washout with no egg consumption, followed by intake of 1, 2, and 3 eggs/day for 4 weeks each. Anthropometric data, blood pressure (BP), dietary records, and plasma biomarkers (lipids, glucose, choline, and TMAO) were measured during each intervention phase. BMI, waist circumference, systolic BP, plasma glucose, and plasma triacylglycerol did not change throughout the intervention. Diastolic BP decreased with egg intake (P < 0.05). Compared to 0 eggs/day, intake of 1 egg/day increased HDL cholesterol (HDL-c) (P < 0.05), and decreased LDL cholesterol (LDL c) (P < 0.05) and the LDL-c/HDL-c ratio (P < 0.01). With intake of 2-3 eggs/day, these changes were maintained. Plasma choline increased dose-dependently with egg intake (P < 0.0001) while fasting plasma TMAO was unchanged. These results indicate that in a healthy population, consuming up to 3 eggs/day results in an overall beneficial effect on biomarkers associated with CVD risk, as documented by increased HDL-c, a reduced LDL-c/HDL-c ratio, and increased plasma choline in combination with no change in plasma LDL-c or TMAO concentrations. PMID- 28091800 TI - ? PMID- 28091799 TI - Prenatal Risk Factors and the Etiology of ADHD-Review of Existing Evidence. AB - While it is well accepted that attention-deficit/hyperactivity disorder (ADHD) is a highly heritable disorder, not all of the risk is genetic. It is estimated that between 10 and 40% of the variance associated with ADHD is likely to be accounted for by environmental factors. There is considerable interest in the role that the prenatal environment might play in the development of ADHD with previous reviews concluding that despite demonstration of associations between prenatal risk factors (e.g. prematurity, maternal smoking during pregnancy) and ADHD, there remains insufficient evidence to support a definite causal relationship. This article provides an update of research investigating the relationship between prenatal risk factors and ADHD published over the past 3 years. Recently, several epidemiological and data linkage studies have made substantial contributions to our understanding of this relationship. In particular, these studies have started to account for some of the genetic and familial confounds that, when taken into account, throw several established findings into doubt. None of the proposed prenatal risk factors can be confirmed as causal for ADHD, and the stronger the study design, the less likely it is to support an association. We need a new benchmark for studies investigating the etiology of ADHD whereby there is an expectation not only that data will be collected prospectively but also that the design allows the broad range of genetic and familial factors to be accounted for. PMID- 28091801 TI - Residency Diary: My Second Year: September and October 2016. PMID- 28091802 TI - Increased Risk of Revision, Reoperation, and Implant Constraint in TKA After Multiligament Knee Surgery. AB - BACKGROUND: The risk of major complications and revision arthroplasty after TKA in patients who previously underwent multiligament knee surgery have been poorly characterized. QUESTIONS/PURPOSES: Is multiligament knee surgery before TKA associated with (1) worse implant survival, (2) increased use of TKA design constraint, (3) a greater risk for major complications, and (4) poorer scores for pain and function compared with similar patients receiving TKA for primary osteoarthritis? METHODS: Fifty-nine TKAs were performed at our institution between 1985 and 2014 in 59 patients (36 men, 23 women; mean age, 53 years) with a history of previous multiligament knee surgery (>= two ligaments). Of those, we had followup for 39 (66%), 18 (31%), and six (10%) patients at 5, 10, and 15 years, respectively; mean followup was 5.4 years (range, 1-25 years). A two-to one matched control group consisting of patients undergoing primary TKA for the diagnosis of osteoarthritis was selected for comparison. Patients were matched based on gender, age at primary TKA (within 5 years), and date of the TKA (within 5 years). Medical records were reviewed for survivorship, TKA design, complications (reoperation, revision, infection, manipulation under anesthesia, and periprosthetic joint infection), TKA design, and clinical outcomes (Knee Society Scores [KSS], Knee Society Function Score [KSS-F]). RESULTS: The overall 15-year revision-free survival in patients with prior multiligament knee surgery was decreased in comparison to the matched controls (42% [95% CI, 16%-73%] vs 94% [95% CI, 81%-99%]; p < 0.001). Varus-valgus constraint implant design was used for more patients in the multiligament cohort at index TKA than in the matched control group (9/59 [15%] vs 0/110 [0%], respectively; odds ratio [OR], 45; 95% CI, 3-781; p = 0.009). Patients with a history of multiligament knee surgery also were at increased risk of reoperation for any cause (14/59 [24%] vs 7/118 [6%]; OR, 5; 95% CI, 2-14; p = 0.001). With the numbers available, there was no difference in the frequency of manipulation under anesthesia after TKA (10% [6/59] versus 3% [4/118]; p = 0.08) A higher proportion of patients in the multiligament cohort had infections develop compared with the matched controls (4/59 [7%] vs 1/118 [< 1%)], respectively; p = 0.04). There was no difference in the KSS improvement after TKA between the multiligament group and the control group (34 +/- 18 vs 28 +/- 15; p = 0.088). The final KSS and KSS-F scores likewise showed no difference between those groups (88 +/- 13 vs 85 +/- 10; p = 0.232) (85 +/- 17 vs 84 +/- 14; p = 0.75). CONCLUSIONS: A history of multiligament surgery is associated with lower long-term survivorship, higher use of constrained TKA designs, and higher risk of major complications, including reoperation and infection. Further research is necessary to determine if a particular multiligamentous surgical technique can prevent posttraumatic arthritis and TKA complications. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 28091803 TI - A study of hyperelastic models for predicting the mechanical behavior of extensor apparatus. AB - In this research, the nonlinear elastic behavior of human extensor apparatus was investigated. To this goal, firstly the best material parameters of hyperelastic strain energy density functions consisting of the Mooney-Rivlin, Ogden, invariants, and general exponential models were derived for the simple tension experimental data. Due to the significance of stress response in other deformation modes of nonlinear models, the calculated parameters were used to study the pure shear and balance biaxial tension behavior of the extensor apparatus. The results indicated that the Mooney-Rivlin model predicts an unstable behavior in the balance biaxial deformation of the extensor apparatus, while the Ogden order 1 represents a stable behavior, although the fitting of experimental data and theoretical model was not satisfactory. However, the Ogden order 6 model was unstable in the simple tension mode and the Ogden order 5 and general exponential models presented accurate and stable results. In order to reduce the material parameters, the invariants model with four material parameters was investigated and this model presented the minimum error and stable behavior in all deformation modes. The ABAQUS Explicit solver was coupled with the VUMAT subroutine code of the invariants model to simulate the mechanical behavior of the central and terminal slips of the extensor apparatus during the passive finger flexion, which is important in the prediction of boutonniere deformity and chronic mallet finger injuries, respectively. Also, to evaluate the adequacy of constitutive models in simulations, the results of the Ogden order 5 were presented. The difference between the predictions was attributed to the better fittings of the invariants model compared with the Ogden model. PMID- 28091804 TI - Baseline results from the UK SIGNIFY study: a whole-body MRI screening study in TP53 mutation carriers and matched controls. AB - In the United Kingdom, current screening guidelines for TP53 germline mutation carriers solely recommends annual breast MRI, despite the wide spectrum of malignancies typically seen in this group. This study sought to investigate the role of one-off non-contrast whole-body MRI (WB MRI) in the screening of asymptomatic TP53 mutation carriers. 44 TP53 mutation carriers and 44 population controls were recruited. Scans were read by radiologists blinded to participant carrier status. The incidence of malignancies diagnosed in TP53 mutation carriers against general population controls was calculated. The incidences of non malignant relevant disease and irrelevant disease were measured, as well as the number of investigations required to determine relevance of findings. In TP53 mutation carriers, 6 of 44 (13.6, 95% CI 5.2-27.4%) participants were diagnosed with cancer during the study, all of which would be considered life threatening if untreated. Two were found to have two primary cancers. Two participants with cancer had abnormalities on the MRI which were initially thought to be benign (a pericardial cyst and a uterine fibroid) but transpired to be sarcomas. No controls were diagnosed with cancer. Fifteen carriers (34.1, 95% CI 20.5-49.9%) and seven controls (15.9, 95% CI 6.7-30.1%) underwent further investigations following the WB MRI for abnormalities that transpired to be benign (p = 0.049). The cancer detection rate in this group justifies a minimum baseline non-contrast WB MRI in germline TP53 mutation carriers. This should be adopted into national guidelines for management of adult TP53 mutation carriers in addition to the current practice of contrast enhanced breast MRI imaging. PMID- 28091805 TI - Correlation between systemic lupus erythematosus and malignancies: a cross sectional population-based study. AB - Autoimmune conditions reflect dysregulation of the immune system; this may be of clinical significance in the development of several malignancies. Previous studies show an association between systemic lupus erythematosus (SLE) and the development of malignancies; however, their investigations into the development of specific malignancies are inconsistent, and their external validity may be questionable. The main objective of this study is to investigate the association between the presence of SLE and various malignancies, in a large-scale population based study. Data for this study was collected from Clalit Health Services, the largest state-mandated health service organization in Israel. All adult members diagnosed with SLE were included (n = 5018) and their age and sex-matched controls (n = 25,090), creating a cross-sectional population-based study. Medical records of all subjects were analyzed for documentation of malignancies. Logistic regression models were built separately for each malignant condition, controlling for age, gender, BMI, smoking, and socioeconomic status. Diagnosis of malignancy (of any type) was more prevalent in the SLE population (odds ratio [OR] 3.35, 95% confidence interval [CI] 3.02-3.72). SLE diagnosis was also found to be independently associated with higher proportions of non-Hodgkin lymphoma (OR 3.02, 95% CI 2.72-3.33), Hodgkin lymphoma (OR 2.43, 95% CI 1.88-2.99), multiple myeloma (OR 2.57, 95% CI 1.85-3.28), cervix uteri malignancies (OR 1.65, 95% CI 1.10-2.20), and genital organ malignancies (OR 2.32, 95% CI 1.42-3.22), after adjustment for confounding variables. The presence of an SLE diagnosis was found to be independently associated with higher proportions of malignancies, particularly hematologic malignancies. These findings should be considered while treating SLE patients, and possibly supplement their screening routine. PMID- 28091806 TI - Gout in immigrant groups: a cohort study in Sweden. AB - Our aim was to study the association between country of birth and incidence of gout in different immigrant groups in Sweden. The study population included the whole population of Sweden. Gout was defined as having at least one registered diagnosis in the National Patient Register. The association between incidence of gout and country of birth was assessed by Cox regression, with hazard ratios (HRs) and 95% confidence intervals (95% CI), using Swedish-born individuals as referents. All models were conducted in both men and women, and the full model was adjusted for age, place of residence in Sweden, educational level, marital status, neighbourhood socio-economic status and co-morbidities. The risk of gout varied by country of origin, with highest estimates, compared to Swedish born, in fully adjusted models among men from Iraq (HR 1.82, 95% CI 1.54-2.16), and Russia (HR 1.69, 95% CI 1.26-2.27), and also high among men from Austria, Poland, Africa and Asian countries outside the Middle East; and among women from Africa (HR 2.23, 95% CI 1.50-3.31), Hungary (HR 1.98, 95% CI 1.45-2.71), Iraq (HR 1.76, 95% CI 1.13-2.74) and Austria (HR 1.70, 95% CI 1.07-2.70), and also high among women from Poland. The risk of gout was lower among men from Greece, Spain, Nordic countries (except Finland) and Latin America and among women from Southern Europe, compared to their Swedish counterparts. The increased risk of gout among several immigrant groups is likely explained by a high cardio-metabolic risk factor pattern needing attention. PMID- 28091807 TI - Erratum to: Musculoskeletal manifestations of primary hyperparathyroidism. PMID- 28091808 TI - Occupational and environmental scleroderma. Systematic review and meta-analysis. AB - The etiology of systemic sclerosis (SSc) remains unknown; however, several occupational and environmental factors have been implicated. Our objective was to perform a meta-analysis of all studies published on SSc associated with occupational and environmental exposure. The review was undertaken by means of MEDLINE and SCOPUS from 1960 to 2014 and using the terms: "systemic," "scleroderma," or "systemic sclerosis/chemically induced" [MesH]. The Newcastle Ottawa Scale was used for the qualifying assessment. The inverse variance weighted method was performed. The meta-analysis of silica exposure included 15 case-control studies [overall OR 2.81 (95%CI 1.86-4.23; p < 0.001)] and 4 cohort studies [overall RR 17.52 (95%CI 5.98-51.37; p < 0.001)]; the meta-analysis of solvents exposure included 13 case-control studies (overall OR 2.00 [95%CI 1.32 3.02; p = 0.001); the meta-analysis of breast implants exposure included 4 case control studies (overall OR 1.68 (95%CI 1.65-1.71; p < 0.001)) and 6 cohort studies (overall RR 2.13 (95%CI 0.86-5.27; p = 0.10)); the meta-analysis of epoxy resins exposure included 4 case-control studies (overall OR 2.97 (95%CI 2.31 3.83; p < 0.001)), the meta-analysis of pesticides exposure included 3 case control studies (overall OR 1.02 (95%CI 0.78-1.32; p = 0.90)) and, finally, the meta-analysis of welding fumes exposure included 4 studies (overall OR 1.29 (95%CI 0.44-3.74; p = 0.64)). Not enough studies citing risks related to hair dyes have been published to perform an accurate meta-analysis. Silica and solvents were the two most likely substances related to the pathogenesis of SSc. While silica is involved in particular jobs, solvents are widespread and more people are at risk of having incidental contact with them. PMID- 28091809 TI - A review of penetrating brain trauma: epidemiology, pathophysiology, imaging assessment, complications, and treatment. AB - Gunshot injuries are the most common cause of penetrating brain injury (PBI) and carry a high morbidity and mortality. The incidence of PBI has increased over the last decade with an estimated 35,000 civilian deaths annually. Patients that survive to reach the hospital require rapid triage and imaging evaluation. CT findings in conjunction with the Glasgow Coma Scale are typically used to determine which patients are surgical candidates. Radiologists should be familiar with the various injury patterns and imaging findings which are poor prognostic indicators, notably brainstem, bilateral hemispheric, multilobar, or transventricular injuries. Post-traumatic complications, including intracranial infections, cerebrospinal fluid leaks, traumatic intracranial aneurysms, intraventricular hemorrhage, dural venous sinus thrombus, and bullet fragment migration, also have specific imaging features and serious treatment implications. In this article, we review the initial imaging evaluation of penetrating brain injury using computed tomography with and without angiography. We also describe the imaging features of various post-traumatic complications and their treatment implications. Finally, we discuss the clinical and imaging parameters that serve as important prognostic indicators and the surgical management. PMID- 28091810 TI - Severe Lead Toxicosis in a Lionhead Rabbit. AB - INTRODUCTION: Lead toxicosis occurs in veterinary patients, with few reports involving rabbits, and no previous reports using oral calcium disodium EDTA. CASE REPORT: A 7-year-old male castrated Lionhead rabbit presented to the Cornell University Hospital for Animals (CUHA) for evaluation after a 2-day history of lethargy and a 2-week history of hyporexia. The patient had been observed pulling paint from the walls of the home, a house built circa 1900, in the months prior to presentation. The patient was moderately anemic with a hematocrit of 21% with red blood cell morphological changes consistent with lead toxicosis, including basophilic stippling, nucleated red blood cells, and polychromasia. Radiographic images of the abdomen revealed excessive accumulation of gas in the gastrointestinal tract in a pattern consistent with gastric stasis and numerous small mineral to metallic opacities in the cecum. The blood lead concentration was 792 MUg/dL, confirming the diagnosis of lead toxicosis with secondary gastrointestinal stasis. The rabbit was hospitalized for treatment with oral and subcutaneous calcium disodium EDTA for 4 days and then discharged home to the care of the owners. DISCUSSION: Severe lead toxicosis in a rabbit can be treated successfully with oral and subcutaneous calcium disodium EDTA and aggressive supportive treatment. PMID- 28091811 TI - Charge Transfer Dissociation (CTD) Mass Spectrometry of Peptide Cations: Study of Charge State Effects and Side-Chain Losses. AB - 1+, 2+, and 3+ precursors of substance P and bradykinin were subjected to helium cation irradiation in a 3D ion trap mass spectrometer. Charge exchange with the helium cations produces a variety of fragment ions, the number and type of which are dependent on the charge state of the precursor ions. For 1+ peptide precursors, fragmentation is generally restricted to C-CO backbone bonds (a and x ions), whereas for 2+ and 3+ peptide precursors, all three backbone bonds (C-CO, C-N, and N-Calpha) are cleaved. The type of backbone bond cleavage is indicative of possible dissociation channels involved in CTD process, including high-energy, kinetic-based, and ETD-like pathways. In addition to backbone cleavages, amino acid side-chain cleavages are observed in CTD, which are consistent with other high-energy and radical-mediated techniques. The unique dissociation pattern and supplementary information available from side-chain cleavages make CTD a potentially useful activation method for the structural study of gas-phase biomolecules. Graphical Abstract ?. PMID- 28091812 TI - Erratum to: Rib resection using a pneumatic high-speed power drill system for lung cancer with chest wall invasion: our clinical experience. PMID- 28091813 TI - Prolonged air leak following lobectomy can be predicted in lung cancer patients. AB - PURPOSE: The purpose of this study was to identify the factors associated with prolonged air leak (PAL) following pulmonary lobectomy for lung cancer. METHODS: The data of 146 patients who underwent pulmonary lobectomy for lung cancer between August 2010 and July 2015 were retrospectively reviewed. Air leaks were assessed daily by a visual evaluation and were categorized as follows: forced expiratory only (Grade 1), expiratory only (Grade 2), or continuous (Grade 3). Logistic regression analyses were performed to identify the predictors of PAL (>5 days). RESULTS: PAL occurred in 23 patients (16%). An air leak at rest (Grade >= 2) was detected on postoperative day (POD) 1 in 48% of the patients with PAL and 7% of the patients without PAL. A univariate analysis demonstrated that PAL was significantly associated with male sex, a smoking history of >= 40 pack years, a serum albumin level of <=4.0 mg/dL, and an air leak on POD1 (Grade >= 2). A multivariate analysis demonstrated that a serum albumin level of <=4.0 mg/dL (p = 0.027) and an air leak on POD1 (p = 0.006) were independent predictors of PAL. PAL occurred in 75% of the patients with these two risk factors. CONCLUSIONS: The preoperative serum albumin level and the presence of a visually evaluated air leak on POD1 may be useful indicators for the perioperative management of air leaks. PMID- 28091814 TI - Effects of forced movements on learning: Findings from a choice reaction time task in rats. AB - To investigate how motor sensation facilitates learning, we used a sensory-motor association task to determine whether the sensation induced by forced movements contributes to performance improvements in rats. The rats were trained to respond to a tactile stimulus (an air puff) by releasing a lever pressed by the stimulated (compatible condition) or nonstimulated (incompatible condition) forepaw. When error rates fell below 15%, the compatibility condition was changed (reversal learning). An error trial was followed by a lever activation trial in which a lever on the correct or the incorrect response side was automatically elevated at a preset time of 120, 220, 320, or 420 ms after tactile stimulation. This lever activation induced forepaw movement similar to that in a voluntary lever release response, and also induced body movement that occasionally caused elevation of the other forepaw. The effects of lever activation may have produced a sensation similar to that of voluntary lever release by the forepaw on the nonactivated lever. We found that the performance improvement rate was increased by the lever activation procedure on the incorrect response side (i.e., with the nonactivated lever on the correct response side). Furthermore, the performance improvement rate changed depending on the timing of lever activation: Facilitative effects were largest with lever activation on the incorrect response side at 320 ms after tactile stimulation, whereas hindering effects were largest for lever activation on the correct response side at 220 ms after tactile stimulation. These findings suggest that forced movements, which provide tactile and proprioceptive stimulation, affect sensory-motor associative learning in a time-dependent manner. PMID- 28091815 TI - Quantitative validation of sensory mapping in persistent postherniorrhaphy inguinal pain patients undergoing triple neurectomy. AB - PURPOSE: Neurectomy of the inguinal nerves may be considered for selected refractory cases of chronic postherniorrhaphy inguinal pain (CPIP). There is to date a paucity of easily applicable clinical tools to identify neuropathic pain and examine the neurosensory effects of remedial surgery. The present quantitative sensory testing (QST) pilot study evaluates a sensory mapping technique. METHODS: Longitudinal (preoperative, immediate postoperative, and late postoperative) dermatomal sensory mapping and a comprehensive QST protocol were conducted in CPIP patients with unilateral, predominantly neuropathic inguinodynia presenting for triple neurectomy (n = 13). QST was conducted in four areas on the affected, painful side and in one contralateral comparison site. QST variables were compared according to sensory mapping outcomes: (o)/normal sensation, (+)/pain, and (-)/numbness. Diagnostic ability of the sensory mapping outcomes to detect QST-assessed allodynia or hypoesthesia was estimated through calculation of specificity and sensitivity values. RESULTS: Preoperatively, patients exhibited mechanical hypoesthesia and allodynia and pressure allodynia and hyperalgesia in painful areas mapped (+) (p < .05); sensory mapping outcome (+) demonstrated high ability to detect mechanical allodynia [sensitivity 0.74 (95% CI 0.61-0.86), specificity 0.94 (0.84-1.00)] and pressure allodynia [sensitivity 0.96 (0.89-1.00), specificity 1.00 (1.00-1.00)], but not thermal allodynia. Postoperatively, mapped areas of numbness (-) were associated with mechanical and thermal hypoesthesia (p < .05); (-) showed high sensitivity and specificity to detect mechanical and cold hypoesthesia. CONCLUSIONS: Sensory mapping provides an accurate clinical neuropathic assessment with strong correlation to QST findings of preoperative mechanical and pressure allodynia, and postoperative mechanical and thermal hypoesthesia in CPIP patients undergoing neurectomy. PMID- 28091816 TI - Pediatric cerebral sinovenous thrombosis following cranial surgery. AB - PURPOSE: Pediatric cerebral sinovenous thrombosis (CSVT) is an important, though less common subtype of pediatric stroke. It has been linked to several risk factors, including cranial procedures, with few studies highlighting this relationship. The aim of this study was to characterize the diagnosis and treatment of CSVT after cranial surgery. METHODS: An institutional pediatric stroke research database was used to identify all CSVT cases diagnosed within 30 days of cranial surgery from November 2004 to December 2014. Thirteen subjects were retrospectively analyzed for clinical presentation, surgical details, radiographic characteristics, laboratory study results, treatment, and outcome. Diagnostic testing and treatment adhered to a consensus-based institutional stroke protocol. RESULTS: Cranial vault reconstruction, subdural empyema evacuation, and tumor resection were each observed in three subjects. Eleven (85%) subjects had sinus exposure during surgery, and eight (73%) developed thrombus in a sinus within or adjacent to the operative field. Two (15%) had documented iatrogenic sinus injury. On post-operative testing, ten (77%) subjects had prothrombotic abnormalities. Seven (54%) were treated with anti-coagulation therapy (ACT) starting on a median of post-operative day (POD) 3 (IQR 1-3) for a median of 2.9 months (IQR 2.4-5.4). Median time to imaging evidence of partial or complete recanalization was 2.4 months (IQR 0.7-5.1). No symptomatic hemorrhagic complications were encountered. CONCLUSIONS: Pediatric CSVT may be encountered after cranial surgery, and decisions related to anti-coagulation are challenging. The risk of CSVT should be considered in pre-surgical planning and post-operative evaluation of cases with known risk factors. In our study, judicious use of ACT was safe in the post-operative period. PMID- 28091817 TI - Teratomas of the cranial vault: a systematic analysis of clinical outcomes stratified by histopathological subtypes. AB - BACKGROUND: Teratomas of the cranial vault are divided into histopathological subtypes and grouped by prognoses: mature (good prognosis), mixed/malignant and immature teratomas (intermediate prognosis). This schema also includes non teratomatous tumors. The authors of this study sought to elucidate histologically dependent predictors of survival and further clarify the classification system of intracranial teratomas. METHODS: We performed a systematic analysis of the published literature to identify studies describing patients with intracranial teratomas diagnosed with magnetic resonance imaging (MRI) and presenting definite information on histologies, therapies, and outcomes at a minimum follow-up of 2 years. Disease-free (DFS) and overall survival (OS) were evaluated. RESULTS: A total of 18 articles comprised of 134 patients were included. On univariate analysis, male sex and gross-total resection (GTR) were associated with high mean DFS (p = 0.0362 and p < 0.0001, respectively). On multivariate analysis, mature teratomas located in the pineal, and those having undergone subtotal resection (STR) demonstrated high mean OS (p = 0.0023 and p = 0.0044, respectively). Mature and mixed/malignant suprasellar teratomas had equally higher mean OS versus immature suprasellar teratomas (p < 0.0001). Mature and immature teratomas treated with adjuvant therapy had significantly higher mean OS compared to those managed with surgery alone (p = 0.0421 and p = 0.0423, respectively). Males with immature teratomas had the highest mean OS (p < 0.0001). Immature teratomas managed with surgery alone had higher mean DFS, but lower mean OS, compared to those treated with adjuvant therapy (p = 0.0176 and p = 0.0423, respectively). CONCLUSIONS: Our data highlight the divergent nature of the different histopathological subtypes of teratomas, and suggest that survival outcomes are multifactorial. Specifically, male sex, pineal, suprasellar, GTR, and STR were dependent predictors of OS, while histopathology was an independent predictor of OS. PMID- 28091818 TI - Lumbar microdiscectomy for sciatica in adolescents: a multicentre observational registry-based study. AB - BACKGROUND: Lumbar disc herniation (LDH) is rare in the adolescent population. Factors predisposing to LDH in adolescents differ from adults with more cases being related to trauma or structural malformations. Further, there are limited data on patient-reported outcomes after lumbar microdiscectomy in adolescents. Our aim was to compare clinical outcomes at 1 year following single-level lumbar microdiscectomy in adolescents (13-19 years old) compared to younger adults (20 50 years old) with LDH. METHODS: Data were collected through the Norwegian Registry for Spine Surgery. Patients were eligible if they had radiculopathy due to LDH, underwent single-level lumbar microdiscectomy between January 2007 and May 2014, and were between 13 and 50 years old at time of surgery. The primary endpoint was change in Oswestry Disability Index (ODI) 1 year after surgery. Secondary endpoints were generic quality of life (EuroQol five dimensions [EQ 5D]), back pain numerical rating scale (NRS), leg pain NRS and complications. RESULTS: A total of 3,245 patients were included (97 patients 13-19 years old and 3,148 patients 20-50 years old). A significant improvement in ODI was observed for the whole population, but there was no difference between groups (0.6; 95% CI, -4.5 to 5.8; p = 0.811). There were no differences between groups concerning EQ-5D (-0.04; 95% CI, -0.15 to 0.07; p = 0.442), back pain NRS (-0.4; 95% CI, 1.2 to 0.4; p = 0.279), leg pain NRS (-0.4; 95% CI, -1.2 to 0.5; p = 0.374) or perioperative complications (1.0% for adolescents, 5.1% for adults, p = 0.072). CONCLUSIONS: The effectiveness and safety of single-level microdiscectomy are similar in adolescents and the adult population at 1-year follow-up. PMID- 28091821 TI - Headache and anxiety/mood disorders: are we trapped in a cul-de-sac? PMID- 28091819 TI - The status of diagnosis and treatment to intracranial hypotension, including SIH. AB - Intracranial hypotension, especially spontaneous intracranial hypotension (SIH), is a well-recognized entity associated with cerebrospinal fluid (CSF) leaks, and has being recognized better in resent years, while still woefully inadequate. An increasing number of factors including iatrogenic factors are realized to involve in development and progression of intracranial hypotension. The diagnosis remains difficult due to the various clinical manifestations, some of which are nonspecific and easily to be neglected. Multiple imaging tests are optional in CSF leakage identification while clinicians are still confronted with difficulties when making selection resulting from superiorities and disadvantages of different imaging tests. Treatments for intracranial hypotension are multifarious but evidence is anecdotal. Values of autologous epidural blood patching (EBP), the mainstay of first-line interventional treatment currently, is getting more and more regards while there are no systematic review of its efficacy and risks. Hereby, the purpose of this review was to reveal the present strategy of intracranial hypotension diagnosis and treatment by reviewing literatures, coupled with our experience in clinical work. PMID- 28091820 TI - Depression of home cage wheel running: a reliable and clinically relevant method to assess migraine pain in rats. AB - BACKGROUND: The development of new anti-migraine treatments is limited by the difficulty inassessing migraine pain in laboratory animals. Depression of activity is one of the few diagnostic criteria formigraine that can be mimicked in rats. The goal of the present study was to test the hypothesis thatdepression of home cage wheel running is a reliable and clinically relevant method to assess migraine painin rats. METHODS: Adult female rats were implanted with a cannula to inject allyl isothiocyanate (AITC) onto the dura to induce migraine pain, as has been shown before. Rats recovered from implantation surgery for 8 days in cages containing a running wheel. Home cage wheel running was recorded 23 h a day. AITC and the migraine medication sumatriptan were administered in the hour prior to onset of the dark phase. RESULTS: Administration of AITC caused a concentration dependent decrease in wheel running that lasted 3 h. The duration and magnitude of AITC-induced depression of wheel running was consistent following three repeated injections spaced 48 h apart. Administration of sumatriptan attenuated AITC-induced depressionof wheel running when a large dose (1 mg/kg) was administered immediately following AITC administration. Wheel running patterns did not change when sumatriptan was given to naive rats. CONCLUSIONS: These data indicate that home cage wheel running is a sensitive, reliable, and clinically relevant method to assess migraine pain in the rat. PMID- 28091822 TI - Does the Growth Differentiation Balance Hypothesis Explain Allocation to Secondary Metabolites in Combretum apiculatum , an African Savanna Woody Species? AB - The growth differentiation balance hypothesis (GDBH) provides a framework that predicts a trade-off between costs of secondary metabolites (SMs) relative to the demand for photosynthate by growth. However, this hypothesis was developed using empirical evidence from plant species in northern boreal and temperate systems, leaving its applicability to species under different abiotic and biotic conditions questionable and generalizations problematic. The objective of this study was to investigate whether the GDBH explains allocation to SMs in the deciduous African savanna woody species C. apiculatum along a 6-point N gradient. The cornerstone prediction of the GDBH, i.e., the parabolic response in SMs along the N gradient, was not observed, with secondary metabolism showing compound specific responses. Quercetin, myricetin, and kaempferol glycoside concentrations, all produced via the same pathway, responded differently across the N gradient. Flavonol glycoside, cinnamic acid, and quercetin glycoside concentrations decreased as N increased, which provides partial support for the carbon nutrient balance hypothesis. Simulated herbivory had no effect on photosynthesis, decreased foliar N and consequently increased C:N ratio, but did not induce an increase in SMs, with condensed tannins and flavonol glycosides being unaffected. Defoliated plants at low N concentration compensated for lost biomass, which suggests a tolerance response, but as predicted by the limiting resource model, plants at higher N concentration were evidently C limited and thus unable to compensate. Our results show that the GDBH does not explain allocation to SMs in C. apiculatum, and suggest that mechanistic explanations of plant allocation should consider the integrative defensive effect of changed SMs. PMID- 28091823 TI - Skeletal muscle inflammation and atrophy in heart failure. AB - Heart failure represents a systemic disease with profound effects on multiple peripheral tissues including skeletal muscle. Within the context of heart failure, perturbations in skeletal muscle physiology, structure, and function strongly contribute to exercise intolerance and the morbidity of this devastating disease. There is growing evidence that chronic heart failure imparts specific pathological changes within skeletal muscle beds resulting in muscle dysfunction and tissue atrophy. Mechanistically, systemic and local inflammatory responses drive critical aspects of this pathology. In this review, we will discuss pathological mechanisms that drive skeletal muscle inflammation and highlight emerging roles for distinct innate immune subsets that reside within damage muscle tissue focusing on the recently described embryonic and monocyte-derived macrophage lineages. Within this context, we will discuss how immune mechanisms can be differentially targeted to stimulate skeletal muscle inflammation, catabolism, fiber atrophy, and regeneration. PMID- 28091824 TI - Exercise capacity, physical activity, and morbidity. AB - Muscle weakness and atrophy are key characteristics of the aging adult but can also be found in chronically ill patients with heart failure, cancer, renal failure, and chronic infectious diseases all associated with an accelerated level of muscle dysfunction. Reduced physical activity levels and exercise intolerance increase muscle loss and decrease quality of life in both the aging and heart failure populations. The purpose of this review is to provide an overview of the effects of aging and heart failure on skeletal muscle function and how exercise training can improve long-term outcomes associated with skeletal muscle dysfunction. PMID- 28091825 TI - Preoperative sport improves the outcome of lumbar disc surgery: a prospective monocentric cohort study. AB - A lumbar disc herniation resulting in surgery may be an incisive event in a patient's everyday life. The patient's recovery after sequestrectomy may be influenced by several factors. There is evidence that regular physical activity can lower pain perception and improve the outcome after surgery. For this purpose, we hypothesized that patients performing regular sports prior to lumbar disc surgery might have less pain perception and disability thereafter. Fifty-two participants with a single lumbar disc herniation confirmed on MRI treated by a lumbar sequestrectomy were included in the trial. They were categorized into two groups based on their self-reported level of physical activity prior to surgery: group NS, no regular physical activity and group S, with regular physical activity. Further evaluation included a detailed medical history, a physical examination, and various questionnaires: Visual Analog Scale (VAS), Beck Depression-Inventory (BDI), Oswestry Disability Index (ODI), Core Outcome Measure Index (COMI), and the EuroQoL-5Dimension (EQ- 5D). Surgery had an excellent overall improvement of pain and disability (p < 0.005). The ODI, COMI, and EQ-5D differed 6 months after intervention (p < 0.05) favoring the sports group. Leg and back pain on VAS was also significantly less in group B than in group A, 12 months after surgery (p < 0.05). Preoperative regular physical activity is an important influencing factor for the overall satisfaction and disability after lumbar disc surgery. The importance of sports may have been underestimated for surgical outcomes. PMID- 28091826 TI - Paradigms for single-patient multimodality treatment for cerebral aneurysms: single-center eleven-year experience. AB - Endovascular and surgical techniques are conventional options for treating intracranial aneurysms, but criteria for selecting an optimal approach for individual patients remain variable across practitioners and institutions. While endovascular and surgical approaches are generally used alone, both modalities combined in single patients can produce efficacious outcomes. The aim of this study was to evaluate outcomes of combined, concomitant endovascular and surgical modalities in the treatment of multiple and/or complex aneurysms in single patients. Indications, sequencing rationale, and categorization for multimodality treatments are reviewed. All intracranial aneurysms treated at our institution from 2004 to 2014 were reviewed. Single patients who had undergone concomitant endovascular and surgical treatments were eligible for participation in our study. Demographic data and clinical presentation parameters, including location, size, and morphological features of lesions, treatment sequencing, and outcomes were recorded. Our cohort consisted of 27 patients with 57 aneurysms who received concomitant endovascular and surgical treatment of their aneurysm(s). One patient arrived to us after he had an aneurysm clipped at an outside institution and then required treatment for a contralateral ruptured aneurysm. 66.7% of patients were diagnosed with subarachnoid hemorrhage. These were subdivided according to therapeutic approach: clipping and coiling (CL+CO), clipping and stenting (CL+ST), bypass and endovascular parent vessel occlusion (PVO) (BY+PVO), attempted clipping then stenting, and bypass followed by stenting. Glasgow Outcome Scale was as follows: CL-CO-Multiple, 4.17 (five in unruptured patients, 3.75 in ruptured); CO-CL-Multiple, five (all patients had a ruptured aneurysm); CL-CO-Single, three (all patients had a ruptured aneurysm); CO-CL-Single, five (all patients had a ruptured aneurysm). No patients suffered a new neurological deficit as a result of treatment. A total of two mortalities were documented. Concomitant, mutimodality endovascular and surgical therapy may offer a safe and potentially more effective paradigm than single modality approaches for the management of multiple, complex, or "failed" aneurysm treatments in selected patients. PMID- 28091827 TI - Microvascular decompression is an effective therapy for trigeminal neuralgia due to dolichoectatic basilar artery compression: case reports and literature review. PMID- 28091828 TI - Liver X receptor alpha (LXRalpha) promoted invasion and EMT of gastric cancer cells by regulation of NF-kappaB activity. AB - Aberrant expression of Liver X receptor alpha (LXRalpha) has been frequently reported in various types of cancers excluding gastric cancer (GC). Moreover, the role of LXRalpha in human GC has not been previously reported. In this study, we investigated the effect of LXRalpha down-regulation on invasion and EMT of GC. The expression of LXRalpha in GC cell lines was detected by real-time PCR. The LXRalpha siRNA was transiently transfected into GC cells using LipofectamineTM 2000 reagent. Subsequently, cell invasive ability was evaluated by Transwell assays. Western blot and real-time PCR were used to determined the expressions of matrix metalloproteinase-2 and -9 (MMP-2 and -9), E-cadherin, N-cadherin, Vimentin, Snail, Slug, and Twist in GC cells. In addition, the effect of LXRalpha down-regulation on the phosphoinositide 3-kinase (PI3K)/Akt/nuclear factor (NF) kappaB signaling pathway was explored by Western blot. From our results, we found that the expression of LXRalpha was significantly increased in GC tissues and cell lines. Knockdown of LXRalpha suppressed the invasive ability of GC cells. The levels of MMP-2 and -9 were dramatically decreased by down-regulating LXRalpha. In addition, we found a decrease of N-cadherin, Twist, and Slug expressions and an increase of E-cadherin expression, but no influence on the expression levels of Vimentin and Snail. We also found that LXRalpha down regulation might suppress the phosphorylation of Akt, NF-kappaB, and IkappaB. Collectively, our results indicated that down-regulation of LXRalpha was shown to suppress invasion and EMT of GC cells by decreasing the expressions of related proteins through inhibiting the PI3K/Akt/NF-kappaB signaling pathway. PMID- 28091829 TI - Inhibition of DPP-4 Activity and Neuronal Atrophy with Genistein Attenuates Neurological Deficits Induced by Transient Global Cerebral Ischemia and Reperfusion in Streptozotocin-Induced Diabetic Mice. AB - Genistein, an isoflavonoid phytoestrogen, has been known for its potential pharmacological properties especially for neuroprotection and treating diabetes. The present study aims to determine the neuroprotective efficacy of genistein against global cerebral ischemia-reperfusion-induced neuronal injury in streptozotocin-induced diabetic mice and explore the underlying mechanisms. Streptozotocin-induced diabetic mice were subjected to transient cerebral ischemia by occluding both common carotid arteries for 30 min followed by 24 h reperfusion to induce neuronal injury. Effect of genistein (2.5, 5.0, and 10.0 mg/kg, i.p., o.d.) treatment on ischemia-reperfusion-induced neuronal injury in diabetic mice was evaluated in terms of cerebral infarct size, oxidative damage, mitochondrial activity in terms of neuronal apoptosis and cellular viability, dipeptidyl peptidase-4 activity and active glucagon-like peptide-1 concentration, and neurological functions measured as short-term memory and motor performance. Genistein administration following transient cerebral ischemia significantly (p ? 0.0001) counteracted cognitive impairment and re-established (p ? 0.001) motor performance in diabetic mice. Ischemia-reperfusion increased the infarct size, genistein administration prevented the increase in cerebral infarct size (p ? 0.0001) and significantly suppressed (p ? 0.001) the increase in cerebral oxidative stress in transient cerebral ischemia-reperfusion subjected diabetic mice. Genistein treatment significantly (p ? 0.001) reduced neuronal apoptosis and increased cellular viability (p ? 0.0001), almost completely suppressed (p ? 0.0001) the circulating dipeptidyl peptidase-4 activity, and enhanced (p ? 0.0001) glucagon-like peptide-1 concentration in diabetic mice with cerebral ischemia-reperfusion. This study suggests that genistein has potent neuroprotective activity against global cerebral ischemia-reperfusion-induced neuronal injury and consequent neurological deficits in streptozotocin-induced diabetic mice. PMID- 28091830 TI - Physio-pharmacological Investigations About the Anti-inflammatory and Antinociceptive Efficacy of (+)-Limonene Epoxide. AB - D-limonene epoxidation generates (+)-limonene epoxide, an understudied compound in the pharmacologically point of view. Herein, we investigated the anti inflammatory and antinociceptive potentialities of (+)-limonene epoxide and suggested a mechanism of action. The anti-inflammatory potential was analyzed using agents to induce paw edema, permeability, and myeloperoxidase (MPO) activity. Pro-inflammatory cytokines and cell migration of peritoneal cells were also assessed. Antinociceptive effects were evaluated by writhing test induced by acetic acid, formalin, and hot plate assays and contribution of opioid pathways. Pretreated animals with (+)-limonene epoxide showed reduced carrageenan-induced paw edema in all doses (25, 50, and 75 mg/kg) (P < 0.05). At 75 mg/kg, it suppressed edema provoked by compound 48/80, histamine, prostaglandin E2, and serotonin and reduced permeability determined by Evans blue and MPO activity. It also reduced leukocytes, neutrophils, and IL-1beta levels in the peritoneal cavity in comparison with carrageenan group (P < 0.05). (+)-Limonene epoxide diminished abdominal contortions induced by acetic acid (78.9%) and paw licking times in both 1 (41.8%) and 2 (51.5%) phases and a pretreatment with naloxone (3 mg/kg) reverted the antinociceptive action in morphine- and (+)-limonene epoxide treated groups (P < 0.05). Additionally, it enlarged response times to the thermal stimulus after 60 and 90 min. In conclusion, (+)-limonene epoxide inhibited release/activity of inflammatory mediators, vascular permeability, migration of neutrophils and displayed systemic and peripheral analgesic dependent effects of the opioid system. PMID- 28091832 TI - Utility and safety of the SafeSeptTM transseptal guidewire for electrophysiology studies with catheter ablation in pediatric and congenital heart disease. AB - PURPOSE: The atrial transseptal procedure is used in catheter ablation of left sided arrhythmias. Studies in adult patients have shown the SafeSeptTM transseptal guidewire (SSTG) to be effective in atrial transseptal procedures. We analyzed our 5-year experience with SSTG use in pediatric and congenital heart disease patients undergoing catheter ablation. METHODS: This is a single-center retrospective analysis of patients undergoing catheter ablation from 2009 to 2014. We identified all procedures where SSTG was used for atrial transseptal or trans-baffle access. Success of transseptal access and complications were recorded and compared to the standard transseptal approach without the SSTG. RESULTS: One hundred twenty-seven patients underwent 132 attempted atrial transseptal or trans-baffle procedures using SSTG. Median age was 14 (1.2-38) years. Arrhythmia substrates included AV reentrant tachycardia (90.2%), atrial tachycardia (4.5%), ventricular tachycardia (2.3%), and AV nodal reentrant tachycardia (2.3%). Transseptal or trans-baffle access was successful in 96.2% of the SSTG cases compared to 98.9% in the standard transseptal group without SSTG (p = NS). The youngest patient with successful atrial transseptal procedure using SSTG was 4 years old. SSTG was used to successfully cross a surgically created atrial baffle in a patient who had undergone the Mustard procedure. There was one major complication in both groups, 0.8% in the SSTG group compared to the standard transseptal group without SSTG, 1.1% (p = NS). The major complication in the SSTG group occurred when the SSTG crossed the aorta into the coronary artery system and mimicked placement in the left atrial appendage, with subsequent placement of a transseptal sheath into the aorta, requiring sternotomy and surgical intervention. CONCLUSIONS: SSTG is effective for use in atrial transseptal and surgical trans-baffle access in pediatric and congenital heart disease patients. Placement of the SSTG into the pulmonary vein is necessary to avoid major complications, and if not achieved requires additional methods to determine appropriate left atrial placement. PMID- 28091834 TI - Using Twitter to Assess the Public Response to the United States Preventive Services Task Force Guidelines on Lung Cancer Screening with Low Dose Chest CT. AB - To use Twitter to assess the immediate public response to the United States Preventive Services Task Force (USPSTF) 2013 draft guidelines on lung cancer screening with low-dose chest CT (LDCT). The number of tweets including the phrases "lung cancer screening," "lung CT," "chest CT," "low dose computed tomography," "low dose CT," or "LDCT" was recorded for 6 days before and after guidelines release. A systematic sample of 172 tweets from the week following release was coded for user type, tweet opinion, linked article source, and article opinion. Following guidelines' release, the number of daily tweets increased from 13 +/- 8 to 311 +/- 395. The 172 tweets in the week following release were tweeted by 166 unique users including: news organizations/online news gathering accounts (34.9%), general public (21.7%), physicians (12.0%, 6 radiologists), and businesses (11.4%). 23.3% of tweets provided opinion on the guidelines (50.0% favorable, 27.5% concerned toward screening). Most (91.3%) tweets contained links to a total of 46 unique articles, which were authored by lay press (41.3%), non-peer-reviewed medical press (32.6%), and hospital/medical practice websites (10.9%). Among these, 50.0% were favorable, citing mortality reduction (87.0%), published data supporting screening (50.0%), and early detection (43.5%), while 28.3% expressed concern, including false positives (58.9%) and radiation risk (39.1%). Twitter activity rose rapidly after the USPSTF draft guidelines on LDCT. Most users were non-physicians and frequently cited non-peer-reviewed articles. Users maintained an overall favorable view of screening, while expressing various concerns. Considerable opportunity exists for greater radiologist engagement in this online public dialog. PMID- 28091833 TI - The gap between indicated and prescribed stroke prevention therapies in a high risk geriatric population. AB - PURPOSE: The use of oral anticoagulation (OAC) in the elderly population with atrial fibrillation (AF) treated in long-term care (LTC) facilities is inconsistent. We examined the magnitude and sources of the gap between indicated and prescribed OAC in the elderly population with AF. METHODS: We retrospectively scanned the electronic medical record (EMR) and pharmacy data of 25 LTC facilities in Ontario, Canada. The diagnosis of AF was drawn from EMR. Different attributable risk factors for possible failure to prescribe OAC were examined. RESULTS: In total, 3378 active resident data were examined in the 25 LTC facilities. All the residents were >=65 years old with mean age of 85 +/- 8 years and 2449 (72%) were female. We identified 433 (13%) residents with AF with mean age 87 +/- 7 years and mean CHADS2 score of 3 +/- 1. Out of all residents with AF, 273 (63%) were on OAC therapy. Residents were mostly treated with warfarin (N = 114 (42%)), rivaroxaban (N = 71 (26%)) or apixaban (N = 62 (23%)) followed by dabigatran (N = 26 (10%)). Antiplatelet drugs as the only stroke prevention therapy were used in 88 (20%) residents, and 28 (6%) residents were on anticoagulation and antiplatelet drugs. Seventy-two (17%) residents were not on any antiplatelet or antithrombotic therapy. None of the potential attributable risks identified consistently correlated with the failure to prescribe indicated therapy. CONCLUSIONS: This data set suggests that 37% of eligible elderly LTC residents failed to receive recommended stroke prevention therapies. PMID- 28091836 TI - Assessment of edema using STIR+ via 3D cardiovascular magnetic resonance imaging in patients with suspected myocarditis. AB - OBJECTIVE: To evaluate three-dimensional T2-weighted fast spin echo triple inversion recovery sequences (STIR+) for the diagnosis of myocardial edema in patients with suspected early myocarditis after respiratory or gastrointestinal tract viral infection and at follow-up. MATERIALS AND METHODS: We prospectively examined 28 patients with suspected myocarditis and 37 controls matched for gender and age. An ECG-triggered STIR+ was used to cover the entire left ventricle in short-axis images with 10-mm slice thickness and no interslice gap. The global signal intensity ratio (heart muscle in relation to skeletal muscle) was calculated (global STIR+ ratio) to evaluate edema. All patients had repeat examinations at follow-up (mean interval 4.9 months, 1-12 months). RESULTS: The mean global STIR+ ratio was 2.15 +/- 0.4 in the initial examination of patients as compared to 1.78 +/- 0.3 in controls (p < 0.0001) and 1.89 +/- 0.3 in patients at follow-up (p = 0.0001 vs. first visit). Left ventricular ejection fraction did not differ between patients and controls at baseline and at follow-up. CONCLUSION: We could identify a significantly higher global STIR+ ratio in patients with suspected myocarditis compared to controls, and a dynamic change during follow-up. The global STIR+ ratio may, therefore, be useful for the diagnosis of myocarditis and should be further explored. PMID- 28091837 TI - Peritoneal fluid of low CT Hounsfield units as a screening criterion for traumatic bowel perforation. AB - PURPOSE: To investigate whether peritoneal fluid of low CT Hounsfield units is an important screening criterion for traumatic bowel perforation. MATERIALS AND METHODS: We performed a retrospective study on two cohorts of blunt trauma patients who had peritoneal fluid. Intravenous and oral contrast was used for the first cohort (61 patients) as opposed to intravenous contrast only for the second cohort (60 patients). We compared the CT Hounsfield units of peritoneal fluid with bowel perforation. The optimal cutoff value of CT Hounsfield units was determined, and its diagnostic values for bowel perforation were calculated. RESULTS: The mean CT Hounsfield units (HU) of peritoneal fluid with bowel perforation were significantly lower (30.3 +/- 9.0 versus 44.1 +/- 13.6 HU, p = 0.008) in the second cohort. The optimal cutoff value was 43 HU, and its sensitivity, specificity, accuracy and positive likelihood ratio were 100.0, 69.2, 73.3% and 3.3, respectively, for bowel perforation. Comparisons of CT HUs of peritoneal fluid with bowel perforation in the first cohort that used additional oral contrast for CT did not show statistically significant differences. CONCLUSION: Peritoneal fluid of low CT HU is a sensitive and important CT screening criterion for traumatic bowel perforation. PMID- 28091838 TI - Fluid levels in the bleeding brain: a marker for coagulopathy and hematoma expansion. PMID- 28091839 TI - Impact of the 2014-2015 influenza season on the activity of an academic emergency department. AB - The morbidity and mortality of the 2014-2015 influenza season were more important than those in previous years. We assessed the impact of the 2014-2015 influenza season on the length of stay (LOS) and workload in an academic emergency department (ED). This is a monocentric retrospective study. The database of the microbiology laboratory was used to identify influenza nasal swabs performed during the influenza seasons from 2010 to 2015. Patients admitted to the ED during these periods were identified through the administrative database and cross-checked with patients who underwent an influenza nasal swab in the ED. Median LOS was used to estimate the impact of the isolation procedures on ED LOS. Bed occupancy rate and mean LOS in the ED were calculated as proxy of the ED workload. During the 2014-2015 influenza season, 55.9% of ED patients (n = 123) with confirmed influenza were hospitalised. In terms of workload, despite that influenza patients represented only 2.2% of all ED patients during the season, they occupied 28% of ED beds with respiratory isolation during the delay to realise and obtain the test results, as well as during the delay before being discharged home or transferred to a hospital ward. The median ED LOS for influenza-confirmed patients was significantly longer in comparison with all ED patients (21.6 h vs 4.0 for ambulatory patients and 24.7 h vs 12.3 for hospitalised patients). The 2014-2015 influenza season had significant consequences in terms of ED LOS and bed use. It dramatically increased the workload in the ED. PMID- 28091840 TI - Test of Gross Motor Development-3 (TGMD-3) with the Use of Visual Supports for Children with Autism Spectrum Disorder: Validity and Reliability. AB - The validity and reliability of the Test of Gross Motor Development-3 (TGMD-3) were measured, taking into consideration the preference for visual learning of children with autism spectrum disorder (ASD). The TGMD-3 was administered to 14 children with ASD (4-10 years) and 21 age-matched typically developing children under two conditions: TGMD-3 traditional protocol, and TGMD-3 visual support protocol. Excellent levels of internal consistency, test-retest, interrater and intrarater reliability were achieved for the TGMD-3 visual support protocol. TGMD 3 raw scores of children with ASD were significantly lower than typically developing peers, however, significantly improved using the TGMD-3 visual support protocol. This demonstrates that the TGMD-3 visual support protocol is a valid and reliable assessment of gross motor performance for children with ASD. PMID- 28091841 TI - Transumbilical abdominal incision for laparoscopic colorectal surgery does not increase the risk of postoperative surgical site infection. AB - PURPOSE: Besides antibiotic prophylaxis, antiseptic skin preparation is an important measure to prevent surgical site infection (SSI). No reports have detailed the relationship between SSI and umbilical microflora following laparoscopic colorectal cancer with a transumbilical longitudinal incision. METHODS: Risk factors and the rate of SSI were investigated in 453 patients who underwent laparoscopic colorectal resection over a 3-year period. Microbiological samples were collected from the umbilicus and SSI areas. RESULTS: After laparoscopic procedure, we observed SSIs in approximately 5% of cases, with superficial SSI in 15 (3.3%) patients and organ/space SSIs 7 (1.5%). In univariate analysis, preoperative albumin (Alb) value and anastomosis of enterocolostomy were significantly associated with superficial SSI development. Also, age, blood loss, stoma, tumor site (rectum), and Hartmann/abdominal perineal resection (APR) were significant risk factors for organ/space SSI. In multivariate analysis, the preoperative Alb value was the most significant factor associated with a predisposition to superficial SSI. The bacteria detected in SSI were mostly different from those at wound closure. Antibiotic-resistant bacteria were included in organ/space SSI all cases. CONCLUSIONS: SSI development with laparoscopic surgery reportedly occurs in about 3-15% cases. The SSI rate in this study and other reports was comparable. Using small transumbilical longitudinal incision in laparoscopic colorectal surgery is less likely to cause SSI when sufficient control measures are enacted, even though the umbilicus contains resident bacteria in abundance. PMID- 28091842 TI - Squamous cell dysplasia in the proximal rectum of three patients treated for ulcerative colitis on immunomodulators. AB - BACKGROUND: Anal canal high-grade squamous intraepithelial lesion (HSIL) is the precursor to anal cancer. Immunocompromised patients are at increased risk and disease is usually within 3 cm from the anal verge. High-resolution anoscopy (HRA) with an 8-cm anoscope is used to identify and guide cautery treatment of HSIL. PURPOSE: We report three patients with a long-term history of ulcerative colitis (UC) treated with systemic immunomodulators who developed proximally located rectal HSIL. RESULTS/OUTCOMES: Two patients were HIV-negative women, 63 and 48 years old, and the third was a 51-year-old HIV-positive man with underlying UC for 10, 16, and 3 years, respectively. They each presented with a HPV-positive HSIL visibly extending above the limits of the anoscope used for HRA. None developed cancer. All had episodes of active UC. It is unclear what causative role systemic immunomodulators play in predisposing UC patients to proximal HSIL. HSIL probably developed on a tongue of HPV-infected squamous epithelium growing proximally over the inflamed rectum. Islands developed when areas of squamous epithelium degenerated, creating skip areas. DISCUSSION: This study highlights the potential for HSIL to extend into the rectum either as a contiguous patch or isolated islands and the need for heightened surveillance in patients with extensive anal canal HSIL treated with immunodulator therapy. HSIL identified at the limit of the anoscope should be investigated further with colonoscopy, and argon plasma coagulation (APC) ablation can serve as an effective treatment option. Patients are at risk for stricture, but it is unclear what role the UC or the ablation played in stricture formation. PMID- 28091843 TI - The incidence of post-colonoscopy colorectal cancer: a retrospective long-term cohort study using a colonoscopy database. AB - PURPOSE: The cumulative incidence of post-colonoscopy colorectal cancer remains unclear. Our aims were to estimate the incidence of and identify risk factors associated with post-colonoscopy colorectal cancer. METHODS: We conducted a retrospective cohort study using the colonoscopy database of the Department of Gastroenterology, the University of Tokyo Hospital Records from1995-2012. A cohort of 2544 patients, who received multiple colonoscopies without colorectal cancer findings at first colonoscopy, was selected. The primary outcome was post colonoscopy colorectal cancer; data were censored at the date of final colonoscopy. We assessed patients' background characteristics, colonoscopy findings, and cancer characteristics, including location and size. The cumulative incidence of colorectal cancer was evaluated, and a Cox proportional hazards model was used to estimate hazard ratios (HRs). RESULTS: Colorectal cancer was identified in seven (0.77/1000 person-years) patients during the mean follow-up period of 3.6 years (maximum, 17 years). The cumulative incidence of colorectal cancer was 0, 0.47, 0.62, and 0.62% at 1, 5, 10, and 15 years, respectively. Cancer was identified in the rectum in five of seven patients. Polyp size >10 mm (HR 5.7, p = 0.023) and intubation time >30 min (HR 11.6, p = 0.003) at first colonoscopy were associated significantly with an increased incidence of post colonoscopy colorectal cancer. CONCLUSIONS: Although several factors were associated with an increased risk of post-colonoscopy colorectal cancer, the incidence of this disease might be low in patients who received at least twice colonoscopy. High proportion of rectal cancer in post-colonoscopy colorectal cancer should be noted. PMID- 28091844 TI - The obesity paradox in heart failure: a miR-26b affair? PMID- 28091845 TI - Comparison of the clinical results of abdominoperanal intersphincteric resection and abdominoperineal resection for lower rectal cancer. AB - BACKGROUND: The aim of this study was to compare the oncologic results of abdominoperanal intersphincteric resection (ISR) and abdominoperineal resection (APR). METHODS: Between 2003 and 2014, 277 consecutive patients with stage I-III low rectal cancer located within 5 cm from the anal verge underwent curative ISR and APR. A retrospective comparison of these two procedures was performed. RESULTS: Overall, 128 patients underwent ISR and 149 underwent APR. The ISR group had earlier clinical stages and shorter distal margins (p < 0.01). The 5-year relapse-free survival rates in patients who underwent ISR/APR were 84.7/74.7% with T1-2 tumors and 51.3/67.6% with T3-4 tumors. In T3-4 tumors, the rate of local recurrence was higher in the ISR group (13.2%) than in the APR group (3.8%). The 5-year relapse-free survival rates in patients who underwent ISR/APR were 89.7/92.3% for stage I cases, 84.4/87.5% for stage II cases, and 39.8/51.8% for stage III cases. Patients with stage III tumors had high rates of distant recurrence in both groups (24.3 vs. 26.3%). CONCLUSION: ISR is a feasible surgical procedure for T1-2 tumors. Patients with stage III tumors should be considered for adjuvant therapy to control distant recurrence regardless of the surgical procedure. PMID- 28091846 TI - Risk factors of surgical site infections in patients with Crohn's disease complicated with gastrointestinal fistula. AB - PURPOSE: Surgical site infection (SSI) is the most common complication following surgical procedures. This study aimed to determine risk factors associated with SSI in patients with Crohn's disease (CD) complicated with gastrointestinal fistula. METHODS: This was a retrospective review of patients who underwent surgical resection in gastrointestinal fistula patients with CD between January 2013 and January 2015, identified from a prospectively maintained gastrointestinal fistula database. Demographic information, preoperative medication, intraoperative findings, and postoperative outcome data were collected. Univariate and multivariate analysis was carried out to assess possible risk factors for SSI. RESULTS: A total of 118 patients were identified, of whom 75.4% were men, the average age of the patients was 34.1 years, and the average body mass index (BMI) was 18.8 kg/m2. The rate of SSI was 31.4%. On multivariate analysis, preoperative anemia (P = 0.001, OR 7.698, 95% CI 2.273 26.075), preoperative bacteria present in fistula tract (P = 0.029, OR 3.399, 95% CI 1.131-10.220), and preoperative enteral nutrition (EN) <3 months (P < 0.001, OR 11.531, 95% CI 3.086-43.079) were predictors of SSI. Notably, preoperative percutaneous abscess drainage was shown to exert protection against SSI in fistulizing CD (P = 0.037, OR 0.258, 95% CI 0.073-0.920). CONCLUSION: Preoperative anemia, bacteria present in fistula tract, and preoperative EN <3 months significantly increased the risk of postoperative SSI in gastrointestinal fistula complicated with CD. Preoperative identification of these risk factors may assist in risk assessment and then to optimize preoperative preparation and perioperative care. PMID- 28091847 TI - Using the Newly Developed Floor-Sitting Movement Analysis Proforma to Study the Effect of Age and Activity on Floor-Sitting in Indian Adults. AB - Floor-sitting is culturally relevant to the Indian context. The present study aimed to examine the effect of age and activity on the movement patterns used and time taken to perform floor-sitting in Indian adults. Video-recordings of 30 young (23.30 +/- 2.53 years) and 30 older (69.67 +/- 6.45 years) adults performing floor-sitting without and with an activity (simulated feeding) were analyzed using the Floor-sitting Movement Analysis Proforma (FMAP) developed for the study. For inter-rater reliability of the FMAP, two raters analyzed the performance of a random sample of 20 participants. An almost perfect inter-rater agreeability (kappa >= .8) was obtained for the FMAP. Cross-legged sitting was the most preferred (95%) floor-sitting position. Older adults used more number of movement components, asymmetrical patterns, more support, and more time (p < .001) as compared to the young adults. The activity facilitated the use of optimal movement strategies in young and older adults. The activity significantly increased time taken to rise from floor-sitting (p = .004). The study establishes the influence of age and activity on performance of floor-sitting. Older adults use lower developmental movement patterns that may be a "normal" adaptation to age-related sensorimotor changes. Retraining of floor-sitting is a "culturally" desired goal among Indian adults and should involve the practice of age appropriate movement patterns in the context of meaningful activities. PMID- 28091848 TI - A novel combination treatment to stimulate bone healing and regeneration under hypoxic conditions: photobiomodulation and melatonin. AB - Melatonin has anabolic effects on the bone, even under hypoxia, and laser irradiation has been shown to improve osteoblastic differentiation. The aim of this study was to investigate whether laser irradiation and melatonin would have synergistic effects on osteoblastic differentiation and mineralization under hypoxic conditions. MC3T3-E1 cells were exposed to 1% oxygen tension for the hypoxia condition. The cells were divided into four groups: G1-osteoblast differentiation medium only (as the hypoxic condition), G2-treatment with 50 MUM melatonin only, G3-laser irradiation (808 nm, 80 mW, GaAlAs diode) only, and G4 treatment with 50 MUM melatonin and laser irradiation (808 nm, 80 mW, GaAlAs diode). Immunoblotting showed that osterix expression was markedly increased in the melatonin-treated and laser-irradiated cells at 48 and 72 h. In addition, alkaline phosphatase activity significantly increased and continued to rise throughout the experiment. Alizarin Red staining showed markedly increased mineralized nodules as compared with only melatonin-treated or laser-irradiated cells at day 7, which significantly increased by day 14. Moreover, when melatonin treated cells were laser-irradiated, the differentiation and mineralization of cells were found to involve p38 MAPK and PRKD1 signaling mechanisms. However, the enhanced effects of laser irradiation with melatonin were markedly inhibited when the cells were treated with luzindole, a selective melatonin receptor antagonist. Therefore, we concluded that laser irradiation could promote the effect of melatonin on the differentiation and mineralization of MC3T3-E1 cells under hypoxic conditions, and that this process is mediated through melatonin 1/2 receptors and PKRD/p38 signaling pathways. PMID- 28091849 TI - Dynamic optical absorption characteristics of blood after slow and fast heating. AB - Laser treatment is the most effective therapy in dermatology for vascular skin disorders, such as port-wine stains (PWS). Changes in heat-induced absorbance in blood must be determined for accurate numerical simulation and implementation of multi-pulse laser therapy for treatment of PWS. Thermally induced absorbance changes in hemoglobin in blood were compared in vitro between slow water bath heating and fast heating irradiated by using sub-millisecond Nd:YAG laser. Blood composition at different temperatures was calculated by comparing blood absorption spectra with those of pure HbO2, Hb, and metHb at room temperature. Blood absorbance to heat energy were categorized into three stages distinguished by metHb and coagulation points, which are the validity and security thresholds of the optimized therapy, respectively. Rapid laser heating can distinctively enhance blood absorbance by photochemically induced strong instability compared with slow heating at a constant temperature. Slow heating facilitates metHb point at 70 degrees C and coagulation point at 75 degrees C as the temperature of the water bath increases. However, the temperature at which metHb or coagulation point shifts to higher than 10 degrees C when pulses and fluence in laser irradiation change. Laser fluence less than 20 J/cm2 and more than 50 J/cm2 is unsuitable for laser treatment because of its low probability to coagulate vascular hyperplasia and high probability to damage normal tissues adjacent to target lesions, respectively. Few bubbles formed after mediate fluence is beneficial to minimize adverse side-effects. Considering blood absorbance, temperature evolution, and bubble formation, we recommend 30-40 J/cm2 and 2-4 Hz frequency as the optimal laser parameters in sub-millisecond Nd:YAG laser. PMID- 28091850 TI - Repeated applications of photodynamic therapy on Candida glabrata biofilms formed in acrylic resin polymerized. AB - Previous studies have been suggested that photodynamic therapy (PDT) can be used as an adjuvant treatment for denture stomatitis. In this study, we evaluated the effects of multiple sessions of PDT on Candida glabrata biofilms in specimens of polymerized acrylic resin formed after 5 days. Subsequently, four applications of PDT were performed on biofilms in 24-h intervals (days 6-9). Also, we evaluated two types of PDT, including application of laser and methylene blue or light emitting diode (LED) and erythrosine. The control groups were treated with physiological solution. The effects of PDT on biofilm were evaluated after the first and fourth application of PDT. The biofilm analysis was performed by counting the colony-forming units. The results showed that between the days 6 and 9, the biofilms not treated by PDT had an increase of 5.53 to 6.05 log (p = 0.0271). Regarding the treatments, after one application of PDT, the biofilms decreased from 5.53 to 0.89 log. When it was done four applications, the microbial reduction ranged from 6.05 log to 0.11 log. We observed that one application of PDT with laser or LED caused a reduction of 3.36 and 4.64 compared to the control groups, respectively (p = 0.1708). When it was done four applications of PDT, the reductions achieved were 1.57 for laser and 5.94 for LED (p = 0.0001). It was concluded that repeated applications of PDT on C. glabrata biofilms showed higher antimicrobial activity compared to single application. PDT mediated by LED and erythrosine was more efficient than the PDT mediated by laser and methylene blue. PMID- 28091851 TI - Operative Treatments for Reflux After Bariatric Surgery: Current and Emerging Management Options. AB - Gastroesophageal reflux disease (GERD) is a common disorder that has a well established connection with obesity. To ameliorate the morbidity associated with obesity, bariatric procedures have become an established pathway to accomplish sustained weight loss. In some procedures, such as with the Roux-en-Y gastric bypass surgery, weight loss is also accompanied by the resolution of GERD symptoms. However, other popular bariatric surgeries, such as the sleeve gastrectomy, have a controversial impact on their effect on reflux. Consequently, increased attention has been given to the development of strategies for the management of de novo or recurrent reflux after bariatric surgery. This article aims to discuss medical and surgical strategies for reflux after bariatric surgery, and their outcomes. PMID- 28091852 TI - The Influence of Orthography on the Production of Alphabetic, Second-Language Allophones by Speakers of a Non-alphabetic Language. AB - This study investigated the influence of orthographic information on the production of allophones in a second language (L2). Two proficiency levels of native Mandarin speakers learned novel Korean words with potential variants of /h/ based on auditory stimuli, and then they were provided various types of spellings for the variants, including the letters for [[Formula: see text]] and o. Subsequently, picture-naming and spelling recall tasks were given to the Mandarin-speaking learners. The results showed that Mandarin-speaking learners, after exposure to the spellings, began to produce and lexically store the /h/ variants following the given forms of the spellings of words, which provides support for the impact of spellings in the production and lexical storage of L2 allophones. However, the effect of L2-learning experience was not shown to be strong, which suggests difficulty in the native-like attainment of the production of L2 allophones. PMID- 28091853 TI - Does Emotional Arousal Influence Swearing Fluency? AB - This study assessed the effect of experimentally manipulated emotional arousal on swearing fluency. We hypothesised that swear word generation would be increased with raised emotional arousal. The emotional arousal of 60 participants was manipulated by having them play a first-person shooter video game or, as a control, a golf video game, in a randomised order. A behavioural measure of swearing fluency based on the Controlled Oral Word Association Test was employed. Successful experimental manipulation was indicated by raised State Hostility Questionnaire scores after playing the shooter game. Swearing fluency was significantly greater after playing the shooter game compared with the golf game. Validity of the swearing fluency task was demonstrated via positive correlations with self-reported swearing fluency and daily swearing frequency. In certain instances swearing may represent a form of emotional expression. This finding will inform debates around the acceptability of using taboo language. PMID- 28091854 TI - Effect of high ambient temperature on behavior of sheep under semi-arid tropical environment. AB - High environmental temperature is a major constraint in sheep production under semi-arid tropical environment. Behavior is the earliest indicator of animal's adaptation and responses to the environmental alteration. Therefore, the objective of this study was to assess the effects of high ambient temperature on the behavior of sheep under a semi-arid tropical environment. The experiment was conducted for 6 weeks on 16 Malpura cross (Garole * Malpura * Malpura (GMM)) rams. The rams were divided equally into two groups, designated as C and T. The rams of C were kept in comfortable environmental conditions served as control. The rams of T were exposed to a different temperature at different hours of the day in a climatic chamber, to simulate a high environmental temperature of summer in semi-arid tropic. The behavioral observations were taken by direct instantaneous observation at 15-min intervals for each animal individually. The feeding, ruminating, standing, and lying behaviors were recorded twice a week from morning (0800 hours) to afternoon (1700 hours) for 6 weeks. Exposure of rams to high temperature (T) significantly (P < 0.05) decreased the proportion of time spent in feeding during the observation period in most of the hours of the day as compared to the C. The proportion of time spent in rumination and lying was significantly (P < 0.05) lower in the T group compared to the C. The animals of T spent significantly (P < 0.05) more time in rumination in standing position as compared to the C. The overall proportion of time spent in standing, panting in each hour, and total panting time was significantly (P < 0.05) higher in the T as compared to the C. The result of the study indicates that the exposure of sheep to high ambient temperature severely modulates the behavior of sheep which is directed to circumvent the effect of the stressor. PMID- 28091855 TI - Combining dispersion modelling with synoptic patterns to understand the wind borne transport into the UK of the bluetongue disease vector. AB - Bluetongue, an economically important animal disease, can be spread over long distances by carriage of insect vectors (Culicoides biting midges) on the wind. The weather conditions which influence the midge's flight are controlled by synoptic scale atmospheric circulations. A method is proposed that links wind borne dispersion of the insects to synoptic circulation through the use of a dispersion model in combination with principal component analysis (PCA) and cluster analysis. We illustrate how to identify the main synoptic situations present during times of midge incursions into the UK from the European continent. A PCA was conducted on high-pass-filtered mean sea-level pressure data for a domain centred over north-west Europe from 2005 to 2007. A clustering algorithm applied to the PCA scores indicated the data should be divided into five classes for which averages were calculated, providing a classification of the main synoptic types present. Midge incursion events were found to mainly occur in two synoptic categories; 64.8% were associated with a pattern displaying a pressure gradient over the North Atlantic leading to moderate south-westerly flow over the UK and 17.9% of the events occurred when high pressure dominated the region leading to south-easterly or easterly winds. The winds indicated by the pressure maps generally compared well against observations from a surface station and analysis charts. This technique could be used to assess frequency and timings of incursions of virus into new areas on seasonal and decadal timescales, currently not possible with other dispersion or biological modelling methods. PMID- 28091856 TI - Daily rhythmicity of the thermoregulatory responses of locally adapted Brazilian sheep in a semiarid environment. AB - The goal of this study was to evaluate the daily rhythmicity of the thermoregulatory responses of Morada Nova ewes that were raised in a semiarid environment. The experiment was conducted during the dry season. Data were collected from 5:00 a.m. to 4:00 a.m.. Samples were taken over the course of 8 days, with a 1-week interval between sampling periods. During each day that the data were collected, animals were measured once an hour for 24 h in an area directly exposed to solar radiation. The environment was characterized by measuring the following variables: air temperature (TA), relative humidity (RH), Black Globe Humidity Index (BGHI), radiant heat load (RHL), and wind speed (WS). Physiological variables that were measured included rectal temperature (RT, degrees C), respiratory rate (RR, breaths/min), surface temperature (ST, degrees C), and sweating rate (SR, g m2 h-1). We observed that RT, RR, and ST increased as environmental conditions became more stressful. Specifically, environmental conditions became more stressful as RHL, air temperature, and BGHI increased, while RH decreased. All physiological variables of the animals were strongly affected by the time of the day: environmental variables changed drastically between nighttime and noon. Physiological parameters increased sharply from the morning (7:00 a.m.-10:00 a.m.) until noon (11:00 a.m.-2:00 p.m.), except for sweating rate. After noon, these variables began to drop until nighttime (11:00 p.m.-6:00 am), and values of the main physiological indexes were stable during this period. The Morada Nova breed exhibited daily cyclic variations in thermoregulatory responses. Evaporative heat loss mechanisms were triggered during the most stressful times of the day. The first mechanism that animals used was panting, which was an immediate response to environmental heat stress. Cutaneous evaporation had a slower response mechanism to environmental heat stress. Homeothermy conditions were restored to the animals at approximately 5:00 p.m.; however, these findings confirm the importance of providing environmental protection during critical periods of the day, even for locally adapted breeds. These responses suggest that the use of thermal storage allowed the animals to achieve equilibrium with the environment and maintain a stable body temperature. PMID- 28091857 TI - Lack of heart rate variability during sleep-related apnea in patients with temporal lobe epilepsy (TLE)-an indirect marker of SUDEP? AB - PURPOSE: Apneas occurring during sleep may precipitate autonomic instability in epilepsy patients making them susceptible to sudden death (SUDEP). Literature on heart rate variability (HRV) during apnea among patients with temporal lobe epilepsy (TLE) is sparse. The aim of this study was to characterize the HRV during the peri-apneic period in patients with TLE and compare with HRV of matched healthy individuals during the overnight polysomnographic (PSG) recording. Further, the role of carbamazepine (CBZ) in modulating peri-apneic HRV in the above cohort was also assessed. METHODS: Twenty patients diagnosed to have TLE (drug naive (n = 10) or on CBZ monotherapy (n = 10)) were compared with ten healthy controls. In both patients and controls, the time domain, frequency domain, and non-linear HRV indices were analyzed for 2 min before and after apnea/hypopnea termination and compared using paired t test (p <= 0.05). Additionally, the changes in HRV parameters in the peri-apnea/hypopnea period were compared between the three groups using one-way ANOVA followed by post hoc comparison (p <= 0.05). RESULTS: The three study groups were age (p = 0.21) and gender (p = 0.27) matched. In controls (M/F = 5:5; mean age 24.3 +/- 5.0 years), there were significant changes in standard deviation of RR interval (SDNN), low frequency (LF) component and long-term HRV (SD2) parameters in the peri apnea/hypopneic period. Conversely, in drug-naive TLE (M/F = 6:4; mean age: 22.8 +/- 4.1 years), all the HRV parameters, including non-linear measures were comparable in the pre- and post-apneic period. On the other hand, patients on CBZ (M/F = 6:4; mean age 20.5 +/- 4.8 years) showed significant changes in low frequency nu (LFnu) and high-frequency nu (HFnu) components in the peri apnea/hypopneic period. Comparison of the changes in HRV parameters in the peri apnea/hypopnea period in patients with TLE and controls showed significantly lower changes in drug-naive TLE patients in SDNN, LF, and SD2 as compared to controls. CONCLUSIONS: This study showed that there was a lack of apnea-mediated HRV changes in patients with drug-naive TLE. This might suggest a possible alteration in reflex baroreceptor activation in patients with TLE, predisposing them to SUDEP, and this may be worsened with CBZ. PMID- 28091858 TI - Will wearing dentures affect edentulous patients' breathing during sleep? AB - PURPOSES: The purpose of this study is to investigate the effect of wearing dentures on obstructive sleep apnea and hypopnea among completely edentulous patients. METHODS AND MATERIALS: A self-controlled study was conducted among 30 edentulous patients. Polysomnograms were recorded in the sleep laboratory on two consecutive nights. Participants slept with their dentures in one night and without dentures in the other. The apnea and hypopnea index (AHI), lowest oxygen saturation (L-SpO2), and morning blood pressure (MBP) were collected for statistical analysis. RESULTS: Among the edentulous participants, 24 showed a higher AHI when sleeping with dentures. The average AHI for all 30 participants was significantly higher when they slept with dentures than without dentures (16.3 +/- 14.7 vs 13.4 +/- 14.0/h, P < 0.05). Participants in the non-obstructive sleep apnea-hypopnea syndrome (non-OSAHS) subgroup (AHI <5 when sleeping without dentures) had a significant increase in AHI when sleeping with dentures, and nearly half of them (5 out of 11) reached the diagnostic standard for OSAHS (AHI >5). A higher morning diastolic blood pressure was recorded when participants slept with dentures (P < 0.05), while no significant difference was found in the L-SpO2 score and morning systolic blood pressure. CONCLUSIONS: Wearing dentures can lead to significant increase of AHI and diastolic MBP among edentulous people. Hence, we suggest that Chinese edentulous people should remove their dentures before sleep. TRIAL REGISTRATION: ChiCTR-IOR-16008404. PMID- 28091859 TI - Cancer Genetic Counselors' Current Practices and Attitudes Related to the Use of Tumor Profiling. AB - Tumor profiling (TP) is primarily used to identify driver mutations within a tumor for treatment purposes, but it may also identify germline mutations. Current involvement of cancer genetic counselors (GCs) in the TP process is not clear. Members of the National Society of Genetic Counselors Cancer Special Interest Group were invited to participate in a confidential, web-based survey to characterize current practices and attitudes related to the use of TP. Of 105 useable responses, 86.7% of GCs reported their institutions were using TP, although only 6.7% did this routinely. Although 63.7% reported personal involvement in the process, largely with result interpretation and follow-up germline testing, 69.7% reported seeing fewer than 5 patients for this reason and 97.9% desired further education on this topic. Work and regional setting were not predictors of involvement with TP; however, GCs in the academic setting were less aware of who obtains consent (p = 0.001). GCs reported they were not often utilized as a resource regarding TP. Overall, GCs believed TP is beneficial in identifying hereditary cancer syndromes, although most reported finding a germline mutation in <10% of cases. This study provides a snapshot of current GC involvement with TP, and documents the desire by GCs for additional education on tumor profiling. PMID- 28091860 TI - Retesting BRCA1/BRCA2 mutation negative male breast cancer patients using next generation sequencing technologies. PMID- 28091861 TI - Do metastasis-free interval less or more than 24 months for recurrent metastatic breast cancer and primary surgery for de novo metastatic breast cancer matter for survival? PMID- 28091862 TI - The Role of Adolescent Friendship Group Integration and Cohesion in Weapon Related Violent Crime as a Young Adult. AB - Weapon-related violent crime is a serious, complex, and multifaceted public health problem. The present study uses data from Waves I and III of Add Health (n = 10,482, 54% female) to examine how friendship group integration and cohesion in adolescence (ages 12-19) is associated with weapon-related criminal activity as a young adult (ages 18-26). Results indicate that greater cohesion in friendship groups is associated with significantly lower weapon-related criminal activity in young adulthood. In addition, for adolescent girls, a greater number of close friendship ties-an indicator of friendship group integration-is associated with less weapon-related criminal activity in young adulthood. These findings suggest that school-based initiatives to facilitate inclusive and cohesive adolescent peer communities may be an effective strategy to curb weapon-related criminal activity in young adulthood. PMID- 28091863 TI - Fast Progression of Cerebellar Atrophy in PLA2G6-Associated Infantile Neuronal Axonal Dystrophy. AB - Infantile neuronal axonal dystrophy (INAD) is characterized by progressive cerebellar atrophy. MRI has been recommended as a marker of disease progression in cerebellar diseases. We performed a longitudinal brain volumetry study in a couple of bicorial twins with PLA2G6-positive INAD. Brain volumetry was calculated with FreeSurfer software on 3T T1-weighted images acquired at age 28 (t 0) and 36 months (t 1) in patient 1 and at age 22 (t 0) and 31 months (t 1) in patient 2. Data at t 0 were compared to those obtained in 18 control children aged 14-44 months with normal MRI. At t 0, both patients showed markedly lower cerebellar volume compared to controls. At t 1, both patients exhibited a remarkable decrease of cerebellar volume (-25.8% in patient 1; -16.5% in patient 2) and of frontal (-6.8% in patient 1 and -3.3% in patient 2) and occipital ( 9.8% in patient 1 and -9.1% in patient 2) cortical GM volume. Our MRI morphometry study indicates that INAD is characterized by a remarkably fast progression of cerebellar atrophy and mild atrophy of the frontal and occipital cortex presumably secondary to deafferentation in the cortical-pons-cerebellum-rubro thalamus-cortical circuit and visual pathways. PMID- 28091864 TI - Letter to the Editor: Intranasal Glucagon for Hypoglycemia. PMID- 28091865 TI - Improving the diagnostic workup of hyponatremia in the setting of kidney disease: a continuing medical education (CME) initiative. AB - PURPOSE: Hyponatremia is a common electrolyte disorder and is associated with mortality. We examined the frequency of appropriate testing in response to an episode of inpatient hyponatremia in a large urban hospital to better inform our educational intervention. We then evaluated the impact of a live CME activity with a focus on CKD- and ESRD-associated hyponatremia physiology, on diagnostic practices of audience hospitalist attendings. METHODS: We performed a retrospective database analysis of all patients admitted to Montefiore Medical Center in 2014 to examine the performance of hospital staff in response to hyponatremia across all CKD stages. We then did a comparative analysis of diagnostic workup orders for hyponatremic patients admitted to audience members of a live CME activity in the 4 months prior as compared to the 4 months after the activity. RESULTS: The prevalence of hyponatremia was 27% in a cohort of hospitalized patients: 41% of these hyponatremia inpatients had CKD, and 11.4% had ESRD. Overall less than 10% of patients had orders written for serum and urine osmolality without a differential pattern based on CKD or ESRD diagnosis. Among the patients admitted to the CME audience hospitalists, urine/serum osmolality and urine sodium orders occurred infrequently overall and did not differ after vs. before the lecture. DISCUSSION: The frequency of appropriate diagnostic orders written in response to an episode of hyponatremia was very low and did not vary based on degree of CKD. A CME activity with an emphasis on the role of CKD/ESRD in diagnostic accuracy did not improve the order quality in a group of audience hospitalists. Efforts to improve the diagnostic workup of hyponatremia with concomitant kidney disease are crucial to proper management of these patients. PMID- 28091866 TI - Review of Diagnostic Challenges in Occupational Asthma. AB - PURPOSE OF REVIEW: Occupational asthma (OA) is one of the most frequent occupational diseases and its diagnosis is often difficult. This review summarizes its current diagnostic challenges. RECENT FINDINGS: OA is associated with significant health and socio-economic burden. It is underdiagnosed and physicians need to adopt a stepwise approach to confirm the diagnosis. Although early removal from exposure to the offending agent is associated with a better prognosis, physicians should try to confirm the diagnosis of work-related asthma before taking a worker off work. A proper occupational and medical history is very important but is not enough to make the diagnosis of OA. Objective evidence of work-related asthma is required and this represents a serious challenge to most physicians. Measurement of non-specific bronchial responsiveness (NSBR) and spirometry may confirm the diagnosis of asthma but do not confirm the diagnosis of OA. Serial monitoring of peak expiratory flows (PEF), NSBR, and airway inflammation at and off work may confirm the diagnosis of OA but are often difficult to perform. Confirming sensitization by skin prick tests or specific IgE may help to support the diagnosis of OA. Specific inhalation challenges (SIC) in the lab or at work are considered the reference standard but are of limited access. Medical surveillance programs along with primary prevention (reducing exposure) may help to reduce the burden of OA, but the ideal program has yet to be defined. The diagnostic workup of OA remains a challenge and needs a rigorous stepwise evaluation. PMID- 28091867 TI - Arterial (Aortic) Stiffness in Patients with Resistant Hypertension: from Assessment to Treatment. AB - PURPOSE OF REVIEW: The purpose of the review is to examine whether measurement of aortic stiffness could be especially value-adding for risk stratification and treatment among patients with resistant hypertension (RH). RECENT FINDINGS: Adverse arterial remodeling and increased aortic stiffness is associated with RH, and it may be of additional clinical benefit to measure aortic stiffness in these patients. However, there is insufficient evidence to determine whether aortic stiffness is excessively high relative to the level of blood pressure (BP) among people with RH. This issue needs resolution as it could help refine management decisions guided by aortic stiffness. If conventional antihypertensive therapy fails to lower BP in patients with RH, there is good rationale for effectiveness of spironolactone as add on therapy, and this should also improve aortic stiffness. Lifestyle intervention with exercise and diet should be additionally efficacious towards improving BP and aortic stiffness in patients with RH, but there is limited data in this patient population. For better characterization on the effects of BP treatment on aortic stiffness, measures of central aortic BP may help refine management decisions above and beyond conventional arm cuff BP. There is strong evidence to support the use of aortic stiffness as a tool to aid risk stratification in hypertension management. Although there is a theoretical basis for special additional benefit of measuring aortic stiffness in patients with RH (as distinct from uncomplicated hypertension), at this time, there is inadequate data available to make definitive conclusions and is an area for future investigation. PMID- 28091868 TI - The Un-Observed Automated Office Blood Pressure Measurement Technique Used in the SPRINT Study Points to a Standard Target Office Systolic Blood Pressure <140 mmHg. AB - The SPRINT study investigators used the un-observed automated office blood pressure measurement technique. When their achieved systolic blood pressure is corrected, target systolic blood pressure for most people remains unchanged: <140mmHg for prevention of cardiovascular diseases and death. PMID- 28091869 TI - A Positive Approach Toward Asexuality: Some First Steps, But Still a Long Way to Go. PMID- 28091871 TI - ? PMID- 28091870 TI - Perspectives: using polymer modeling to understand the formation and function of nuclear compartments. AB - Compartmentalization is a ubiquitous feature of cellular function. In the nucleus, early observations revealed a non-random spatial organization of the genome with a large-scale segregation between transcriptionally active euchromatin-and silenced-heterochromatin-parts of the genome. Recent advances in genome-wide mapping and imaging techniques have strikingly improved the resolution at which nuclear genome folding can be analyzed and have revealed a multiscale spatial compartmentalization with increasing evidences that such compartment may indeed result from and participate to genome function. Understanding the underlying mechanisms of genome folding and in particular the link to gene regulation requires a cross-disciplinary approach that combines the new high-resolution techniques with computational modeling of chromatin and chromosomes. In this perspective article, we first present how the copolymer theoretical framework can account for the genome compartmentalization. We then suggest, in a second part, that compartments may act as a "nanoreactor," increasing the robustness of either activation or repression by enhancing the local concentration of regulators. We conclude with the need to develop a new framework, namely the "living chromatin" model that will allow to explicitly investigate the coupling between spatial compartmentalization and gene regulation. PMID- 28091872 TI - Impact of revascularization of coronary chronic total occlusion on left ventricular function and electrical stability: analysis by speckle tracking echocardiography and signal-averaged electrocardiogram. AB - The present study aimed to assess the mechanisms of effects of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) from two different aspects: left ventricular (LV) systolic function assessed by two-dimensional speckle tracking echocardiography (2D-STE) and electrical stability evaluated by late potential on signal-averaged electrocardiogram (SAECG). We conducted a prospective observational study with consecutive CTO-PCI patients. 2D-STE and SAECG were performed before PCI, and after 1-day and 3-months of procedure. 2D STE computed global longitudinal strain (GLS) and regional longitudinal strain (RLS) in CTO area, collateral blood-supplying donor artery area, and non-CTO/non donor area. A total of 37 patients (66 +/- 11 years, 78% male) were analyzed. RLS in CTO and donor areas and GLS were significantly improved 1-day after the procedure, but these improvements diminished during 3 months. The improvement of RLS in donor area remained significant after 3-months the index procedure (pre PCI -13.4 +/- 4.8% vs. post-3M -15.1 +/- 4.5%, P = 0.034). RLS in non-CTO/non donor area and LV ejection fraction were not influenced. Mitral annulus velocity was improved at 3-month follow-up (5.0 +/- 1.4 vs. 5.6 +/- 1.7 cm/s, P = 0.049). Before the procedure, 12 patients (35%) had a late potential. All components of the late potential (filtered QRS duration, root-mean-square voltage in the terminal 40 ms, and duration of the low amplitude signal <40 MUV) were not improved. CTO-PCI improved RLS in the donor area at 3-month follow-up without changes of LV ejection fraction. Although higher prevalence of late potential in the current population compared to healthy population was observed, late potential as a surrogate of arrhythmogenic substrate was not influenced by CTO PCI. PMID- 28091873 TI - Prediction of left ventricular contractile recovery using tissue Doppler strain and strain rate measurements at rest in patients undergoing percutaneous coronary intervention. AB - The aim of the study was to assess the ability of tissue Doppler (TD) deformation analysis at rest to predict left ventricular contractile recovery in patients undergoing percutaneous coronary intervention (PCI). This prospective cohort enrolled 67 patients with segmental wall motion abnormality. Assessment of each segment was performed at rest and during low dose Dobutamine stress echocardiography (DSE) using a 4 point scoring system, TD peak systolic strain (PSS) and peak systolic strain rate (PSSR). The study followed up the patients for contractile improvement after 6 months of successful PCI by echocardiography. Of a 319 dysfunctional segments, 155 (49%) showed contractile recovery and 164 (51%) did not. PSS and PSSR at rest were significantly higher in recovered segments compared to segments without recovery (PSS: -7.27 +/- 0.8 Vs. -6.14 +/- 0.7%, PSSR: -0.34 +/- 0.13 Vs. -0.24 +/- 0.1/s. p < 0.0001 both). Similarly, both parameters were significantly higher in the contractile recovery group at follow up (p 0.001). Resting PSSR as well as PSS and PSSR during DSE were significant independent predictors of contractile recovery (p < 0.001 each). For predicting segmental contractile recovery, resting PSSR with a -0.31/s cut-off point had 76% sensitivity and 59% specificity (AUC 0.74), DSE qualitative viability assessment had a sensitivity of 75% and specificity of 77%, DSE PSS with a cut-off point of 9.1% had 74% sensitivity and 63% specificity (AUC 0.77) and DSE PSSR with a cut off point of -0.72/s had 78% sensitivity and 77% specificity (AUC 0.81). Resting PSSR is a modest predictor of segmental contractile recovery after PCI while PSSR during DSE has a comparable diagnostic performance to subjective wall motion scoring. Recovered segments show improvement of deformation parameters after PCI. PMID- 28091874 TI - The influence of dental treatment on the development of osteoradionecrosis after radiotherapy by modern irradiation techniques. AB - OBJECTIVES: The aim of this study was to analyze the influence of dental treatment on the development of osteoradionecrosis (ORN) of the jaw. METHODS: This study included the data of 776 patients who underwent 3D-CRT or IMRT because of head and neck cancer. Sex, dental status before and after radiotherapy (RT), tumor site, bone surgery during tumor operation, concomitant chemotherapy, and the development of an advanced ORN were documented for each patient. The patients' dentitions before and after RT were classified into four groups with regard to the number and localization of the remaining teeth. Differences between the patients with ORN and patients without ORN with regard to the teeth's condition before and after RT, and with regard to the extent of dental treatment were determined descriptively. Cox proportional hazards regression to study the association between dentition and the development of ORN. RESULTS: The extent of dental treatment in patients with and without ORN did not differ in a clinically relevant way. The highest risk of developing ORN was observed in patients who had undergone primary bone surgery during the tumor operation (HR = 5.58, 95%CI 2.91 10.7) and patients who had a tumor in the oral cavity (HR = 4.84, 95%CI 1.37 17.11). CONCLUSIONS: Based on the results of this study, tumor localization and its required treatment are prognostic factors for the development of ORN. CLINICAL SIGNIFICANCE: After implementing a consequent dental treatment scheme, no influence of dentition on the risk of developing ORN could be demonstrated. Patients with a lower risk could prospectively benefit from a more moderate dental treatment scheme. PMID- 28091875 TI - The effect of veneering on the marginal fit of CAD/CAM-generated, copy-milled, and cast metal copings. AB - OBJECTIVE: This in vitro study investigated the marginal fit of metal and zirconia copings before and after veneering on dies with shoulder/chamfer (s/c) finish lines. MATERIALS AND METHODS: Using CAD/CAM, ten (n = 10) each s/c zirconia (NZ) copings and ten (n = 10) each s/c metal (MM) copings were generated. As controls, ten (n = 10) each s/c zirconia copings were copy-milled (ZZ) and ten (n = 10) each s/c metal copings were cast (CC). The vertical marginal discrepancy of the copings was measured at 20 predefined spots of the circular shoulder and chamfer finish lines in microns (MUm) before and after a first and a second veneering firing using a stereomicroscope at *40 magnification. Data were statistically analyzed, and the comparisons of CAD/CAM milled (NZ, MM), copy-milled (ZZ), and cast (CC) copings before and after veneering were made at a significance level of p < 0.05. RESULTS: Gap width at s/c finish lines of ZZ was (91 +/- 11/100 +/- 28) and increased significantly (109 +/- 21/141 +/- 18) after the first firing (ZZ1). NZ showed significantly smaller gaps than ZZ (36 +/- 6/46 +/- 12) and (NZ1) after the first firing (61 +/ 16/71 +/- 29). Gap widths of CC groups (36 +/- 8/25 +/- 4) were not significantly different from NZ but were significantly lower after the (CC1) first veneering firing (40 +/- 8/42 +/- 7). MM copings showed gap values similar to NZ. Second firings did not significantly increase gaps in all groups except ZZ2 of chamfer finish line. CONCLUSION: Veneering increased the marginal gap width of copings. CLINICAL RELEVANCE: Within the limits of this in vitro study, aesthetic ceramic veneering of CAD/CAM-generated copings caused a statistically significant but tolerable loss of marginal fit precision. PMID- 28091876 TI - Hypermethylation of IFN-gamma in oral cancer tissues. AB - OBJECTIVES: The study aimed to evaluate the methylation pattern of the interferon gamma (IFN-gamma) gene in oral cancer tissues compared with normal and benign oral disease tissues. MATERIALS AND METHODS: The oral tissues were gained from the patients of 85 cases of oral squamous cell carcinoma (OSCC), 47 cases of oral dysplastic lesions, and 53 normal biopsies. IFN -gamma methylation in oral tissues was verified through methylation-specific polymerase chain reaction (PCR) and DNA sequencing analyses, and the expression levels of IFN-gamma messenger RNA (mRNA) and protein were detected using real-time reverse transcription (RT)-PCR and enzyme-linked immunosorbent assays, respectively. IFN-gamma was localized in macrophages from oral tissues and detected via immunostaining. RESULTS: IFN-gamma mRNA and protein expression levels were evidently decreased in oral cancer tissues, whereas the IFN-gamma methylation rate was significantly higher in malignant tumors than in benign and normal tissues (normal, 22.6%; benign, 38.3%; and cancer, 55.3%; P < 0.05). Furthermore, the expression of IFN-gamma mRNA was significantly downregulated in oral tumors with methylation compared with tumors without methylation, as determined by real-time RT-PCR (4.76-fold difference; P < 0.05). Likewise, mRNA expression was downregulated by 6.79-fold in oral epithelial dysplasia tissues with methylation compared with those without methylation (P < 0.01). Co-immunostaining to detect MAC2 and IFN-gamma demonstrated that macrophages comprised the main source of IFN-gamma in oral tissues. IFN-gamma methylation demonstrated a significant association with the clinical stage, histopathology grade, and primary tumor. CONCLUSIONS: Aberrant IFN-gamma promoter methylation may be involved in the process of tumorigenesis of oral cancer. CLINICAL RELEVANCE: IFN-gamma hypermethylation during the process of oral carcinogenesis could be useful for the clinical diagnosis and treatment for OSCC. PMID- 28091877 TI - Influence of enamel/dentin thickness on the toxic and esthetic effects of experimental in-office bleaching protocols. AB - OBJECTIVES: This paper aims to assess the whitening effectiveness and toxicity of tooth-bleaching protocols applied to enamel/dentin disks simulating mandibular incisors (ICs) and premolars (PMs). MATERIALS AND METHODS: A 10% hydrogen peroxide (H2O2) gel was applied for 3 * 15, 1 * 15, or 1 * 5 min to enamel/dentin disks simulating mandibular ICs and PMs, and the trans-enamel and trans-dentinal diffusion products were applied to human dental pulp cells (1 h). Professional therapy (35% H2O2-3 * 15 min) was used as positive control, and non-bleached samples were used as negative control. Cell viability and morphology, oxidative stress generation, and odontoblastic marker expression were assessed. The H2O2 diffusion and enamel color change (DeltaE) were also analyzed. RESULTS: The 10% H2O2 gel induced significant cell viability reduction only when applied 3 * 15 min, with the intensity of oxidative stress and down-regulation of odontoblastic markers being higher in the IC group. The other experimental bleaching protocols caused slight alterations regarding the cell parameters evaluated, with intensity being related to enamel/dentin thickness. These effects were also correlated with higher H2O2 diffusion in the IC group. DeltaE values similar as positive control were found for the 10% 3 * 15 and 1 * 15 protocols on IC group, after 4 and 6 sessions. CONCLUSION: Application of a 10% H2O2 bleaching gel for 15 or 45 min to thin dental substrate significantly minimizes cell toxicity in comparison with highly concentrated gels associated with similar esthetic outcomes by increasing the number of bleaching sessions. CLINICAL RELEVANCE: Bleaching gels with 10% H2O2 applied in small teeth for short periods may be an interesting alternative to obtain whitening effectiveness without causing toxicity to pulp cells, which may be able to reduce the tooth hypersensitivity claimed by patients. PMID- 28091878 TI - Insulin Degludec in Clinical Practice: A Review of Japanese Real-World Data. AB - INTRODUCTION: In this literature review we evaluated the real-world clinical effectiveness of switching Japanese diabetic patients from their current insulin regimen to insulin degludec (IDeg). METHODS: Studies were identified from Japanese Diabetes Society (JDS) abstracts (2014-2015) and PubMed (2012 onwards). Inclusion criteria were: Japanese population, >15 participants, and studies switching patients from basal or basal-bolus insulin regimens to IDeg. Randomized controlled trials and case reports were excluded. Weighted mean changes in safety and effectiveness endpoints were calculated using the number of patients in each study. RESULTS: In total, 81 JDS abstracts and seven manuscripts met the search criteria, representing 4238 patients [1028 with type 1 diabetes (T1D), 602 with type 2 diabetes (T2D), 2608 with unspecified or mixed diabetes]. Glycated hemoglobin (HbA1c) was reported in 93% of studies, with an improvement in 84% of these (51% significant, 33% numerical), no change in 12%, and worsening in 4% (3% numerical, 1% significant). Across all studies, the weighted mean absolute change in HbA1c was -0.3% (-2.7 mmol/mol). Basal insulin dose was reported in 58% of studies and was lower in 60% of these (30% significant, 30% numerical), numerically unchanged in 26%, and higher in 14% (2% significant, 12% numerical). The weighted mean change in basal insulin dose was -4.8% and -3.0% for all studies and for studies with only significant results, respectively. The weighted mean change in basal dose based on all studies was -8.9, -5.5, and -2.9% for the T1D, T2D, and unspecified patient populations, respectively. Hypoglycemia was recorded in 31% of the studies. After switching treatment to IDeg, 55% of studies reported decreased hypoglycemia, 29% no change, and 16% an increase. Quality of life (QoL) was measured in 11% of studies, of which 82% reported improved QoL after switching, and 18% reported no change in QoL. CONCLUSION: Switching from a conventional basal insulin to IDeg has the potential to improve HbA1c with a lower insulin dose. Switching to IDeg may also provide a reduced risk of hypoglycemia and improvement in QoL. FUNDING: Novo Nordisk. PMID- 28091879 TI - New medical therapies on the horizon: oral octreotide. AB - Somatostatin analog treatment is first line medical treatment in patients with acromegaly. This drug is currently mainly administered by monthly depot preparations of octreotide and lanreotide. With the innovative transient permeability enhancer, a technology enabling the absorption of drug molecules via transient opening of the tight junctions of the gut epithelium, it is possible to achieve therapeutic octreotide levels after oral ingestion. The present review summarized the preclinical work and the recently reported phase I and III study on oral octreotide capsules in patients with acromegaly. Maintenance of control in 155 participating patients was achieved in 65% at the end of core period. Once controlled on oral octreotide, the response was maintained to the end of the extension phase in 85%. Side effects were comparable to currently available preparations. There was a profound suppression of growth hormone levels, and significant symptom reduction. Currently available parental somatostatin analogs are generally well tolerated and are able to achieve longstanding biochemical control in patients with somatostatin sensitive tumors. Potential advantages of an oral alternative is the lack injection-related side effects, but there will be an ongoing need for a very strict compliance with the 2 daily dose regimen and fasting around drug administrations. A second phase III study is currently being conducted. The potential place in the treatment of acromegaly is discussed. PMID- 28091880 TI - Inhibition of neuronal nitric oxide synthase activity does not alter vasopressin secretion in septic rats. AB - BACKGROUND/PURPOSE: During the early phase of sepsis, hypotension is accompanied by increase of plasma vasopressin hormone (AVP) levels, which decline during the late phase. This hypotension is due in part to increase of nitric oxide (NO) synthesis by nitric oxide synthase (NOS) enzyme. Neuronal isoform of this enzyme (nNOS) is present in vasopressinergics neurons of hypothalamus, but its role in vasopressin secretion during sepsis is unknown. METHODS: We evaluated the role of nNOS in NO production and vasopressin secretion during sepsis. Wistar rats received 7-nitroindazole (50 mg/kg, i.p.), an inhibitor of nNOS activity, or vehicle and were submitted to septic stimulus by cecal ligation and puncture (CLP). At the time points 0, 4, 6, 18 and 24 h after sepsis induction the animals were decapitated and neurohypophysis and hypothalamus were removed for analysis of vasopressin content and NOS activity, respectively. Hematocrit, serum sodium, osmolality, proteins and plasmatic AVP were quantified. RESULTS: Mortality was not affected by 7-nitroindazole (7-NI). Sodium and plasma proteins levels decreased after CLP and the treatment anticipated the protein loss, and delayed serum sodium decrease. Septic animals treated with 7-NI showed decrease of osmolality 4 h after CLP. Nitric oxide synthase activity in hypothalamus increased at 4 and 24 h after CLP and was reduced with 7-NI. Neurohypophysis content of AVP diminished after CLP and 7-NI did not alter this parameter. Plasma AVP levels increased at 6 h and decreased 18 and 24 h after CLP. Treatment with 7 NI did not alter plasma vasopressin levels. CONCLUSION: We concluded that nNOS does not have a substantial role in vasopressin secretion during experimental sepsis. PMID- 28091881 TI - Identifying Metabolites of Meclonazepam by High-Resolution Mass Spectrometry Using Human Liver Microsomes, Hepatocytes, a Mouse Model, and Authentic Urine Samples. AB - Meclonazepam is a benzodiazepine patented in 1977 to treat parasitic worms, which recently appeared as a designer benzodiazepine and drug of abuse. The aim of this study was to identify metabolites suitable as biomarkers of drug intake in urine using high-resolution mass spectrometry, authentic urine samples, and different model systems including human liver microsomes, cryopreserved hepatocytes, and a mice model. The main metabolites of meclonazepam found in human urine were amino meclonazepam and acetamido-meclonazepam; also, minor peaks for meclonazepam were observed in three of four urine samples. These observations are consistent with meclonazepam having a metabolism similar to that of other nitro containing benzodiazepines such as clonazepam, flunitrazepam, and nitrazepam. Both metabolites were produced by the hepatocytes and in the mice model, but the human liver microsomes were only capable of producing minor amounts of the amino metabolite. However, under nitrogen, the amount of amino-meclonazepam produced increased 140 times. This study comprehensively elucidated meclonazepam metabolism and also illustrates that careful selection of in vitro model systems for drug metabolism is needed, always taking into account the expected metabolism of the tested drug. PMID- 28091883 TI - Ground-penetrating radar (GPR) responses for sub-surface salt contamination and solid waste: modeling and controlled lysimeter studies. AB - The assessment of polluted areas and municipal solid waste (MSW) sites using non destructive geophysical methods is timely and much needed in the field of environmental monitoring and management. The objectives of this study are (i) to evaluate the ground-penetrating radar (GPR) wave responses as a result of different electrical conductivity (EC) in groundwater and (ii) to conduct MSW stratification using a controlled lysimeter and modeling approach. A GPR wave simulation was carried out using GprMax2D software, and the field test was done on two lysimeters that were filled with sand (Lysimeter-1) and MSW (Lysimeter-2). A Pulse EKKO-Pro GPR system with 200- and 500-MHz center frequency antennae was used to collect GPR field data. Amplitudes of GPR-reflected waves (sub-surface reflectors and water table) were studied under different EC levels injected to the water table. Modeling results revealed that the signal strength of the reflected wave decreases with increasing EC levels and the disappearance of the subsurface reflection and wave amplitude reaching zero at higher EC levels (when EC >0.28 S/m). Further, when the EC level was high, the plume thickness did not have a significant effect on the amplitude of the reflected wave. However, it was also found that reflected signal strength decreases with increasing plume thickness at a given EC level. 2D GPR profile images under wet conditions showed stratification of the waste layers and relative thickness, but it was difficult to resolve the waste layers under dry conditions. These results show that the GPR as a non-destructive method with a relatively larger sample volume can be used to identify highly polluted areas with inorganic contaminants in groundwater and waste stratification. The current methods of MSW dumpsite investigation are tedious, destructive, time consuming, costly, and provide only point-scale measurements. However, further research is needed to verify the results under heterogeneous aquifer conditions and complex dumpsite conditions. PMID- 28091882 TI - Identification of some main Streptococcus iniae associated proteins: relationship. AB - The surface-associated proteins play a key role in bacterial physiology and pathogenesis, and are the major targets in the development of new vaccines. These proteins contribute to the adaptation of bacteria to different hosts and environments. To study differences at the genomic level, we first sequenced the whole genome of Streptococcus iniae from fish (IUSA-1 strain) and compared it to Streptococcus iniae from human (9117 strain), revealing a high similitude between both strains. To gain further insights into host- and environment-specific differences, we then studied proteins in silico and by High Performance Liquid Chromatography. This approach successfully identified 54 secreted and surface proteins, including several proteins involved in cell wall synthesis and transport of solutes, as well as proteins with yet unknown function. These proteins highlight as interesting targets for further investigation in the interaction between Streptococcus iniae and its environment. Results reported in this study have shown a first analysis about the predicted and experimental associated proteins of Streptococcus iniae isolated from two different hosts: human and fish. PMID- 28091884 TI - Pre-mining trace element and radiation exposure to biota from a breccia pipe uranium mine in the Grand Canyon (Arizona, USA) watershed. AB - The risks to wildlife and humans from uranium (U) mining in the Grand Canyon watershed are largely unknown. In addition to U, other co-occurring ore constituents contribute to risks to biological receptors depending on their toxicological profiles. This study characterizes the pre-mining concentrations of total arsenic (As), cadmium (Cd), copper (Cu), lead (Pb), mercury (Hg), nickel (Ni), selenium (Se), thallium (Tl), U, and zinc (Zn); radiation levels; and histopathology in biota (vegetation, invertebrates, amphibians, birds, and mammals) at the Canyon Mine. Gross alpha levels were below the reporting limit (4 pCi/g) in all samples, and gross beta levels were indicative of background in vegetation (<10-17 pCi/g) and rodents (<10-43.5 pCi/g). Concentrations of U, Tl, Pb, Ni, Cu, and As in vegetation downwind from the mine were likely the result of aeolian transport. Chemical concentrations in rodents and terrestrial invertebrates indicate that surface disturbance during mine construction has not resulted in statistically significant spatial differences in fauna concentrations adjacent to the mine. Chemical concentrations in egg contents and nestlings of non-aquatic birds were less than method quantification limits or did not exceed toxicity thresholds. Bioaccumulation of As, Pb, Se, Tl, and U was evident in Western spadefoot (Spea multiplicata) tadpoles from the mine containment pond; concentrations of As (28.9-31.4 MUg/g) and Se (5.81-7.20 MUg/g) exceeded toxicity values and were significantly greater than in tadpoles from a nearby water source. Continued evaluation of As and Se in biota inhabiting and forging in the mine containment pond is warranted as mining progresses. PMID- 28091885 TI - Assessing the impact of preload on pyrite-rich sediment and groundwater quality. AB - Pyrite-rich sediments would, invariably, undergo redox reactions which would lead to acidic aqueous environment containing solubilized toxic metal species. When such sediments are subjected to preload, a technique employed by geotechnical engineers to improve the load-bearing capacity of highly compressible formation, transient flow of pore water, accompanied by acidity transfer, would occur as a response. Despite the concomitant environmental and socio-economic significance, to date, there has been limited interdisciplinary research on the underpinning geotechnical engineering and geo-environmental science issues for pyrite-rich sediments under preload. In this study, we investigate the effect of pyrite-rich sediment pore water transfer under preload surcharge on the receiving environment and the impact on the groundwater speciation and quality. Sediment samples were obtained at close depth intervals from boreholes established within pristine areas and those subjected to the preload application. Soil and pore water samples were subjected to solid/solution speciation, moisture contents, soil pH and the Atterberg Limits' analyses using standard analytical techniques and methods. Standpipes were also installed in the boreholes for groundwater sampling and in situ monitoring of water quality parameters. It is shown that the imposition of preload surcharge over pyritic sediment created a reducing environment rich in SO42-, iron oxide minerals and organic matter. This reducing environment fostered organic carbon catabolism to generate excess pyrite and bicarbonate alkalinity, which would invariably impact adversely on soil quality and plant growth. These were accompanied by increase in pH, dissolved Al, Ca, Mg and K species beneath the surcharge. PMID- 28091886 TI - Levels of persistent organic pollutants in breast milk of Maya women in Yucatan, Mexico. AB - In this study, 24 breast milk samples, obtained from rural Maya women, from municipalities of Yucatan, Mexico, were analyzed for organochlorine pesticide (OCP) residues by gas chromatography. Recent studies have shown that Maya communities have a poor perception about the proper usage and handling of OCP. The karstic soil in this area has a high vulnerability to groundwater pollution by the use of OCP in agriculture and livestock activities. The impact of the ecosystem on human health is much more critical due to the prevailing poverty and a very low educational level of these communities. About 30% of the Maya population consumes water directly from contaminated wells and sinkholes, resulting in a chronic exposure to OCP. The samples served to identify and quantify high levels of OCP residues (18.43 mg/kg of heptachlor epoxide and 1.92 mg/kg of endrin in the metropolitan zone; 2.10 mg/kg of dieldrin, 0.117 mg/kg of endosulfan II, 0.103 mg/kg of heptachlor, 0.178 mg/kg of endrin, and 0.127 mg/kg of endrin aldehyde in the main agricultural zone and on the west coast). The detected levels of OCP residues are a major concern and represent a potential risk to women and children in the region. This could be associated with the high rates of cervical uterine and breast cancer mortality in Yucatan. Thus, regulations on the usage of OCP and their enforcement are necessary, and it is important to establish a yearly monitoring program for OCP residues in breast milk and groundwater, as well as to implement health promotion programs for women in particular and the general population in general. PMID- 28091888 TI - Testing the CP-correction procedure with different DFT methods on H-bonding complexes of kappa-carrabiose with water molecules. AB - Interaction of water molecules with kappa-carrabiose disaccharide, within three H bonding complexes, was investigated. Particular interest was focused on the way with which the BSSE correction has to be performed. Two strategies were used, either performing BSSE correction during or after optimization. For this aim, several DFT-functionals (hybrid GGA and hybrid meta-GGA) and 6-31 + G* basis set were considered. The results demonstrated the uselessness of including of BSSE-CP correction during optimization for all complexes. From a structural point of view, a proper H-bonding description was obtained using the PBE0 functional for all complexes. The basis set effect on the BSSE using B3LYP functional was also investigated. The reliability of B3LYP/6-31 + G** and B3LYP/6-31++G** models for the complexes involving one or two water molecules was reported while the use of B3LYP/6-311 + G** or B3LYP/6-311++G** levels was shown to be more appropriate for larger complexes equivalent to that involving three water molecules. CP-corrected interaction energies were demonstrated to be closer to CBS-4 M interaction energies than the uncorrected ones. Graphical abstract Functional and basis set effects on BSSE. PMID- 28091887 TI - The morphology of human rod ERGs obtained by silent substitution stimulation. AB - PURPOSE: To record transient ERGs from the light-adapted human retina using silent substitution stimuli which selectively reflect the activity of rod photoreceptors. We aim to describe the morphology of these waveforms and examine how they are affected by the use of less selective stimuli and by retinal pathology. METHODS: Rod-isolating stimuli with square-wave temporal profiles (250/250 ms onset/offset) were presented using a 4 primary LED ganzfeld stimulator. Experiment 1: ERGs were recorded using a rod-isolating stimulus (63 ph Td, rod contrast, C rod = 0.25) from a group (n = 20) of normal trichromatic observers. Experiment 2: Rod ERGs were recorded from a group (n = 5) using a rod isolating stimulus (C rod = 0.25) which varied in retinal illuminance from 40 to 10,000 ph Td. Experiment 3: ERGs were elicited using 2 kinds of non-isolating stimuli; (1) broadband and (2) rod-isolating stimuli which contained varying degrees of L- and M-cone excitation. Experiment 4: Rod ERGs were recorded from two patient groups with rod monochromacy (n = 3) and CSNB (type 1; n = 2). RESULTS: The rod-isolated ERGs elicited from normal subjects had a waveform with a positive onset component followed by a negative offset. Response amplitude was maximal at retinal illuminances <100 ph Td and was virtually abolished at 400 ph Td. The use of non-selective stimuli altered the ERG waveform eliciting more photopic-like ERG responses. Rod ERGs recorded from rod monochromats had similar features to those recorded from normal trichromats, in contrast to those recorded from participants with CSNB which had an electronegative appearance. CONCLUSIONS: Our results demonstrate that ERGs elicited by silent substitution stimuli can selectively reflect the operation of rod photoreceptors in the normal, light adapted human retina. PMID- 28091889 TI - Theoretical insights into the effects of molar ratios on stabilities, mechanical properties, and detonation performance of CL-20/HMX cocrystal explosives by molecular dynamics simulation. AB - To research and estimate the effects of molar ratios on structures, stabilities, mechanical properties, and detonation properties of CL-20/HMX cocrystal explosive, the CL-20/HMX cocrystal explosive models with different molar ratios were established in Materials Studio (MS). The crystal parameters, structures, stabilities, mechanical properties, and some detonation parameters of different cocrystal explosives were obtained and compared. The molecular dynamics (MD) simulation results illustrate that the molar ratios of CL-20/HMX have a direct influence on the comprehensive performance of cocrystal explosive. The hardness and rigidity of the 1:1 cocrystal explosive was the poorest, while the plastic property and ductibility were the best, thus implying that the explosive has the best mechanical properties. Besides, it has the highest binding energy, so the stability and compatibility is the best. The cocrystal explosive has better detonation performance than HMX. In a word, the 1:1 cocrystal explosive is worth more attention and further research. This paper could offer some theoretical instructions and technological support, which could help in the design of the CL 20 cocrystal explosive. PMID- 28091890 TI - A theoretical study of the inhibition effect of PAMAM molecule on silica scale. AB - In this work, the molecular modeling method was performed to study adsorption interaction between PAMAM molecules of different generations and silicic acid molecules, and the inhibition effect on silica scale were discussed. The results show that adsorption energies of PAMAM molecule of generation 1.0 with amine terminated groups are stronger than those of generation 1.5 with terminated carboxyl group. The composition of adsorption interactions are the dominating electrostatic interactions and van de Waals interactions as well as H-bond interactions. It is qualitatively discussed that the inhibition effect of generation 1.0 on silica scale is stronger than that of generation 1.5 in the neutral solution. PMID- 28091891 TI - Adrenal Teratoma: a Case Series and Review of the Literature. AB - Adrenal teratomas are rare neoplasms and there is limited data on their surgical outcomes and long-term prognosis. We aimed to review our institutional experience and compare this to the existing literature on adrenal teratomas in adults and children. An institutional pathology database was searched for cases of adrenal teratoma (June 1956-July 2016). Clinical and imaging data were abstracted from the medical records and pathology slides were obtained for review. In addition, a PubMed search for "adrenal teratoma" from June 1952 to July 2016 was performed to identify reports of primary adrenal teratoma in patients of all ages. Of 7706 patients who underwent adrenalectomy during the study period at our institution, three patients were identified with adrenal teratoma. Patients were 24, 26, and 29 years of age, respectively. Two patients presented with abdominal pain and two of the three underwent a laparoscopic adrenalectomy. A pathologic examination revealed mature cystic teratomas that frequently displayed well-differentiated respiratory, digestive, and squamous epithelia. Eighteen case reports in the literature were identified in patients 17-61 years of age. Patients presented most frequently with abdominal or flank pain (63.6%). Median tumor diameter was 9.0 cm and tumors were frequently left-sided (81.8%), cystic (63.6%), and calcified (72.7%) on either radiologic or pathologic examination. Primary adrenal teratomas are rare neoplasms that typically present as large, left-sided nodules with cystic and calcified components seen radiographically. Although the data are limited, they are generally amenable to laparoscopic resection and have a very favorable prognosis. PMID- 28091892 TI - Bariatric Roux-En-Y Gastric Bypass Surgery: Adipocyte Proteins Involved in Increased Bone Remodeling in Humans. AB - PURPOSE: Bariatric surgery has been associated with bone remodeling changes. The action of adipokines on the expression of receptor activator of nuclear factor kappa beta ligand (RANKL) and osteoprotegerin (OPG) and on an increase in sclerostin could be related to these changes. MATERIALS AND METHODS: This study aimed to assess the repercussions of weight loss, fat mass (FM), and fat-free mass (FFM) loss and biochemical and hormonal changes on bone remodeling markers after Roux-en-Y gastric bypass (RYGB). Anthropometric data, parathyroid hormone (PTH), bone-specific alkaline phosphatase (BSAP), collagen type 1 C-telopeptide (CTX), 25-hydroxy vitamin D (25-OH-VitD), leptin, adiponectin, RANKL, OPG, and sclerostin of 30 menstruating women were measured preoperatively (Pre), and 3, 12, and 24 months (m) after RYGB. RESULTS: Leptin (34.4 (14.7; 51.9) vs. 22.5 (1.9; 52.7) ng/mL) and OPG (3.6 (1.1; 11.5) vs. 3.4 (1.5; 6) pmol/L) decreased, and adiponectin (7.4 (1.7; 18.4) vs. 13.8 (3.0; 34.6) MUg/mL), CTX (0.2 (0.1; 2.2) vs. 0.6 (0.4; 6.0) ng/mL), RANKL (0.1 (0.0; 0.5) vs. 0.3 (0.0; 2.0) pmol/L), and sclerostin (21.7 (3.2; 75.1) vs. 34.8 (6.4; 80.5) pmol/L) increased after 3 m. BSAP increased after 12 m (10.1 (5.4; 18.9) vs. 13.9 (6.9; 30.2) MUg/mL) (p < 0.005). CTX correlated positively with adiponectin at 24 m and inversely with leptin Pre; OPG at 3 m; weight, FM, FFM, and leptin at 24 m. RANKL correlated directly with weight at 3 m. Sclerostin correlated inversely with weight Pre and FM at 3 m. BSAP correlated negatively with 25-OH-VitD at 12 m, and positively with PTH at 24 m. CONCLUSIONS: RYGB induced weight loss, and biochemical, hormonal, and body composition changes are associated with higher bone remodeling. PMID- 28091893 TI - Endoscopic Management of Eroded Bands Following Banded-Gastric Bypass (with Video). AB - BACKGROUND: Banded-gastric bypass is a highly effective bariatric procedure, yet the possibility of band erosion remains a significant drawback. Surgical removal of eroded bands may be associated with significant morbidity. In this study, we assess the efficacy and safety of a solely peroral endoscopic approach for the management of eroded bands in patients with a banded-gastric bypass. MATERIALS AND METHODS: Starting January 2012, all patients with banded-gastric bypass and an eroded band were subjected to an attempt at peroral endoscopic removal using endoscopic scissors and/or argon plasma coagulation (APC), regardless of the circumference of band eroding inside the lumen. RESULTS: Sixteen patients presented with eroded bands, 2 were deemed not amenable to endoscopic removal as only part of the thickness was eroded. Of the 14 patients where endoscopic attempts were performed, 12 (86%) were completely removed successfully, while 2 (14%) were cut but could not be extracted and only the intraluminal portion was trimmed. Complete resolution of symptoms occurred in 13 (93%) while in 1 patient (7%) there was partial improvement. Only one endoscopic session was performed per patient with a median time of 37.5 min per session (22-55 min). No complications were encountered. CONCLUSION: Endoscopic removal of eroded gastric bands in patients with banded-gastric bypass is effective and safe in the majority of patients. When bands are adherent to the gastric wall, removal of the intraluminal portion of the band may lead to full or partial improvement of symptoms. Endoscopic band removal can be attempted even when a small part of band circumference has eroded. PMID- 28091894 TI - Mechanisms of Action of Surgical Interventions on Weight-Related Diseases: the Potential Role of Bile Acids. AB - Surgical interventions for weight-related diseases (SWRD) may have substantial and sustainable effect on weight reduction, also leading to a higher remission rate of type 2 diabetes (T2D) mellitus than any other medical treatment or lifestyle intervention. The resolution of T2D after Roux-en-Y gastric bypass (RYGB) typically occurs too quickly to be accounted for by weight loss alone, suggesting that these operations have a direct impact on glucose homeostasis. The mechanisms underlying these beneficial effects however remain unclear. Recent research suggests that changes in the concentrations of plasma bile acids might contribute to these metabolic changes after surgery. In this review, we aimed to outline the potential role of bile acids in SWRD. We systematically reviewed MEDLINE, SCOPUS, and Web of Science for articles reporting the effect of SWRD on outcomes published between 1969 and 2016. We found that changes in circulating bile acids after surgery may play a major role through activation of the farnesoid X receptor A (FXRA), the fibroblast growth factor 19 (FGF19), and the G protein-coupled bile acid receptor (TGR5). Bile acid concentration increased significantly after RYGB. Some studies suggest that a transitory decrease occurs at 1 week post-surgery, followed by a gradual increase. Most studies have shown the increase to be proportionate by all bile acid subtypes. Bile acids can regulate glucose metabolism through the expression of TGR5 receptor in L cells, resulting in a release of glucagon-like peptide 1 (GLP-1). It may also induce the synthesis and secretion of FGF19 in ileal cells, thereby improving insulin sensitivity and regulating glucose metabolism. All the present SWRD are involved with changes in food stimulation to the stomach. This implies that discovering and developing the antagonists to TGR5 and FXRA may effectively control metabolic syndrome and the elucidation of the mechanisms underlying the physiological effects related to weight loss and T2D remission after surgery may help to identify new drug targets. PMID- 28091895 TI - Author Reply-Bariatric Surgery and Liver Function Tests in Nonalcoholic Fatty Liver Disease. PMID- 28091896 TI - Bariatric Surgery and Liver Function Tests in Nonalcoholic Fatty Liver Disease. PMID- 28091897 TI - Comparative analysis of the visual and refractive outcomes of a refractive segmented multifocal intraocular lens with and without toricity: 1-year results. AB - PURPOSE: To compare the visual and refractive outcomes up to 1 year postoperatively following implantation of a refractive segmented or a refractive segmented toric multifocal intraocular lens (IOL). METHODS: This retrospective study included 108 eyes of 64 patients who underwent cataract surgery with implantation of a refractive segmented multifocal IOL (Lentis Mplus LS-313 MF30 IOL) (LM group) and 81 eyes of 49 patients with implantation of a refractive segmented toric multifocal IOL (Lentis Mplus LU-313 MF30T IOL) (LMT group). The visual and refractive postoperative outcomes and the rate of additional refractive procedures were evaluated up to 1 year postoperatively. RESULTS: The uncorrected distance visual acuity (VA) and uncorrected near VA exceeded 1.0 and 0.60 in decimal VA, respectively, and both were stable postoperative groups. The postoperative subjective refractive astigmatism was also stable and the postoperative refraction was near emmetropia in both groups. No significant differences were found in the need for additional surgical refractive procedures. CONCLUSION: The outcomes with a refractive segmented toric multifocal IOL were comparable to those with a non-toric model despite higher preoperative corneal astigmatism. PMID- 28091898 TI - The outcomes of radiotherapy and factors that predict overall survival in elderly patients with esophageal squamous cell carcinoma. AB - PURPOSE: The aim of this study was to evaluate radiotherapy in terms of both feasibility and efficacy for the treatment of 206 elderly patients (>=70 years) with unresectable ESCC and to investigate the factors that predict overall survival in those patients. METHODS: Totally, 206 elderly patients with esophageal cancer (>=70 years) treated with RT for ESCC in the Harbin Medical University Affiliated Tumor Hospital were retrospectively enrolled. Radiation treatment results and side effects were evaluated. Survival data were estimated using the Kaplan-Meier method, including OS, RFS and DDFS. A multivariate Cox regression analysis was performed to determine the relevant prognostic factors. RESULTS: The median OS and RFS were 20.68 and 24.19 months. Metastases before radiotherapy, having cervical or supraclavicular neoplasm, with lesion length >5 cm were the independent risk factors for OS. The total effective rate was 86.9% (179/206). CONCLUSION: Radiation therapy in elderly patients (>=70 years) can not only obtain good treatment result, but also make patients have better tolerance and reduce the risk of complications. Radiotherapy should be as a primary treatment option for elderly patients with inoperable ESCC. PMID- 28091899 TI - Proteomic Study of Blood Serum in Coronary Atherosclerosis. AB - Changes in the blood serum proteins were assessed in men with coronary atherosclerosis and without coronary heart disease. Proteins were separated by 2D electrophoresis, protein fractions were identified by their peptide fingerprint by MALDI method; fractions with more than twofold increase in protein level were determined. In blood serum of patients with coronary atherosclerosis, the content of C4 complement protein increased and ceruloplasmin level decreased, which is typical of heart failure and coronary heart disease. PMID- 28091900 TI - Antithrombotic Protective Effects of Arg-Pro-Gly-Pro Peptide during Emotional Stress Provoked by Forced Swimming Test in Rats. AB - Blood coagulation was enhanced and all factors (total, enzyme, and non-enzyme) of the fibrinolytic system were suppressed in rats in 60 min after forced swimming test. Argininecontaining tetrapeptide glyproline Arg-Pro-Gly-Pro administered prior to this test activated fibrinolysis and prevented hypercoagulation. Administration of this peptide in 5 min after swimming test also enhanced anticoagulant, fibrinolytic, and antithrombotic activity of the blood. Therefore, glyproline Arg-Pro-Gly-Pro exerted both preventive and curative effects on the hemostasis system and prevented enhancement of blood coagulation provoked by emotional stress modeled by forced swimming test. PMID- 28091901 TI - Contractility of Right Ventricular Myocardium in Male and Female Rats during Physiological and Pathological Hypertrophy. AB - Sex differences in the morphogenesis and adaptation of the mechanisms controlling myocardium contractility during physiological and pathological hypertrophy of the right ventricle were demonstrated in mature rats. The study revealed sex dependent effects of physiological and pathological cardiac hypertrophy on the coefficient of variation of the cardiomyocyte diameter, length-dependent control of the contractile force, and the maximum velocity of isotonic shortening. PMID- 28091902 TI - Nitrogen Oxide, Endothelin-1, and Serotonin in the Blood of Immature Spontaneously Hypertensive Rats. AB - Endothelial function is an early and sensitive marker of subclinical increase of BP in children and adolescents. It is associated with an imbalance of the key vasoactive factors (NO, endothelin-1, and serotonin). Immature spontaneously hypertensive rats (SHR line) are characterized by increased plasma concentrations of NO and endothelin-1 (by 14.7% and 2.9 times, respectively) and increased serotonin content in the plasma and platelets (by 2.7 and 2.3 times, respectively) in comparison with Wistar-Kyoto rats. Platelet count in the blood of SHR rats is by 50% higher than in Wistar-Kyoto rats. PMID- 28091903 TI - Effects of Opioid Peptides on Changes in Lipid Metabolism in Rats Subjected to Swimming Stress. AB - Blood levels of nonesterified fatty acids, total cholesterol, triglycerides, and LDL increased in rats subjected to forced swimming stress. Administration of opioid peptides dynorphin A(1-13), DSLET, or DAGO reduced stress-induced disturbances in lipid metabolism. Dynorphin A(1-13) and DAGO produced the most pronounced effects and prevented an increase in concentrations of nonesterified fatty acids, triglycerides, total cholesterol, and LDL as soon as 39 h after treatment. Only DSLET increased HDL content in the plasma of stressed rats. The observed effects can be explained by the stress-limiting effects of opioids, e.g. attenuation of the effect of catecholamines on the adipose tissue and inhibition of the generation LPO products suppressing activity of the cholesterol metabolizing enzyme. PMID- 28091904 TI - Effects of Release-Active Antibodies to CD4 Receptor on the Level of lck-Kinase in Cultured Mononuclear Cells from Human Peripheral Blood. AB - For evaluation of effects of release-active antibodies to CD4 on cultured lymphocytes from human peripheral blood, we measured intracellular content of lck kinase cell-based ELISA. In cells treated with release-active antibodies to CD4, the content of intracellular lck-kinase significantly (p<0.01) decreased in comparison with the control (purified water processed in a similar way). Phytohemagglutinin had no effect on the concentration of lck-kinase in cells. The decrease in the content of CD4-associated lck protein suggests that the preparation enhanced intracellular coupling of lck-kinase with T-cell receptor and potentiated T-cell immune response. PMID- 28091906 TI - Effect of Mifepristone on Corticosteroid Production in Vitro by Adrenal Glands of Rats with Streptozotocin Diabetes. AB - Changes in pregnenolone and corticosterone production by the adrenal glands of normoglycemic rats receiving the course of intraperitoneal mifepristone or NaCl administration were co-directed, but differed in magnitude. In rats with hyperglycemia, corticosteroid production increased after NaCl administration over 5 days and returned to the initial values after 15-day administration. On the contrary, pregnenolone and corticosterone production was suppressed after 5-day course of mifepristone, but significantly increased after mifepristone administration for 15 days. Intraperitoneal mifepristone administration almost completely abolished the response of rat adrenal glands with normo- and hyperglycemia to ACTH in vitro; this effect did not depend on the duration of administration. PMID- 28091905 TI - Activity of LPO Processes in Women with Polycystic Ovarian Syndrome and Infertility. AB - Specific features of LPO processes and antioxidant defense were studied in patients with polycystic ovarian syndrome (PCOS) and infertility. Changes in LPO processes in patients with PCOS were compensatory, which manifested in increased alpha-tocopherol and retinol concentrations and moderate decrease in superoxide dismutase activity. Intensification of prooxidant processes was found in the group of patients with infertility without PCOS. The observed changes necessitate differentiated approach to the treatment of these patients. PMID- 28091907 TI - Evaluation of the Hepatoprotective Effect of L-Ascorbate 1-(2-Hydroxyethyl)-4,6 Dimethyl-1,2-Dihydropyrimidine-2-One Upon Exposure to Carbon Tetrachloride. AB - Hepatoprotective properties of a new pyrimidine derivative - L-ascorbate 1-(2 hydroxyethyl)-4,6-dimethyl-1,2-dihydropyrimidine-2-one, synthesized on the basis Xymedon, were assessed in white rats exposed to CCl4. The compound under study administered prior to exposure to CCl4 reduced the deviation of biochemical parameters from reference values and severity of structural and morphological changes in liver, when compared to the control. Hepatoprotective properties of the studied compound were more pronounced than those of Xymedon. PMID- 28091908 TI - Effect of Tramadol on Rabbit Uterine Contractile Activity Induced in Late Pregnancy. AB - Effect of Tramadol infusion (5 mg/ml) on oxytocin-induced uterine contractile activity was studied in chronic experiment on female rabbits with different degrees of biological readiness for parturition. In case of sufficient biological readiness for parturition, Tramadol did not change the number of uterine contractions, but increased the amplitude and duration of each contraction against the background of increased creatine phosphate consumption by the myometrium. At the same time, Tramadol infusion to females without biological readiness for partirition suppressed induced uterine contractile activity by reducing the amplitude of each uterine contraction. PMID- 28091909 TI - Modes of Hypotensive Action of Dihydroquercetin in Arterial Hypertension. AB - We studied the effect of dihydroquercetin (20 mg/kg/day intragastrically for 6 weeks) on mean BP and macro- and microrheological blood parameters in hypertensive SHR rats; in vitro effect of dihydroquercetin on the tone in thoracic aorta rings isolated from hypertensive SHR rats were also examined. At the end of the treatment course, the mean BP in the experimental rats decreased by 11%; the left ventricular mass index by 2%, and whole blood viscosity by 7-10% in comparison with control SHR rats; erythrocyte aggregation half-time increased by 15%; plasma viscosity, hematocrit, and erythrocyte deformability did not change. In in vitro experiments, dihydroquercetin (10-8-10-6M) induced relaxation of the isolated thoracic aorta rings in a dose-dependent manner. Hence, the antihypertensive effect of dihydroquercetin results from the decrease in blood viscosity and vasodilation. PMID- 28091910 TI - Inhibition of Apoptosis Stages of Human Blood Lymphocytes after Exposure to Carbon Monoxide in the Presence of Recombinant Interleukin-2. AB - We studied the effect of carbon monoxide (60-, 75-, and 90-min exposure) on the expression of antiapoptotic proteins (survivin and Bcl-2) in human blood lymphocytes in the presence of recombinant IL-2 in an apoptosis-inducing dose (0.1 ng/ml). Incubation of cells in atmosphere with carbon monoxide in the presence of recombinant IL-2 was accompanied by accumulation of Bcl-2 protein with simultaneous decrease of survivin content. It was concluded that carbon monoxide plays a role in the dysregulation of apoptosis of human blood lymphocytes Bcl-2 (i.e. CO inhibits the proapoptotic effect of recombinant IL-2). PMID- 28091911 TI - Biocompatibility of Modified Osteoinductive Calcium-Phosphate Coatings of Metal Implants. AB - The cellular and molecular aspects of immunological compatibility of modified osteoinductive calcium-phosphate coatings formed on technically pure titanium VT1 0 by the plasma electrolytic oxidation technology are studied. The technique of coating modified the process of human peripheral blood leukocyte activation in vitro. The most pronounced functional changes were observed in neutrophil population during whole blood contact with titanium sample without coating and with coating formed by plasma electrolytic oxidation on titanium alloy. Sealing of the oxidation layer pores by ultradispersed polytetrafluoroethylene leads to reduction of cell activation. Composite coatings with ultradispersed polytetrafluoroethylene applied by the electrophoretic method are characterized by the best biocompatibility. The data demonstrate the possibility of modifying biomaterial surfaces for inflammatory response control. PMID- 28091912 TI - Caspase 3, 6, 8, and 9 Gene Expression in Peripheral Blood Leukocytes and Plasma Concentrations of IL-6 and TNF-alpha in Carriers of Different Polymorphic Marker 174G>C Genotypes of IL6 Gene Associated with the Risk of Nonalcoholic Steatohepatitis. AB - We revealed an association of IL6 gene -174G>C polymorphism with the development of nonalcoholic steatohepatitis in the Russian population. The risk is significantly higher in carriers of C allele: OR=1.77 (1.04; 3.02). The effects of -174G>C substitution in IL6 gene involving caspase 9 gene transcripts in peripheral blood leukocytes and on blood content of TNF-alpha in healthy individuals without clinical manifestations of nonalcoholic steatohepatitis were detected. The content of caspase 9 gene transcripts in peripheral blood leukocytes and plasma level of TNF-alpha were significantly higher in healthy subjects carrying C allele than in carriers of GG genotype. The levels of caspases 3, 6, 8, and 9 gene transcripts in peripheral blood leukocytes and plasma concentrations of TNF-alpha in patients with nonalcoholic steatohepatitis did not depend on IL6 genotype by -174GG (L597R), 1798_1799delinsAA (V600K), 1798_1799delinsAG (V600R), and 1799_1800delinsAA (V600E) and NRAS mutation 38G->T (G13V) was possible only by Sanger sequencing. The combination of real-time PCR and sequencing can improve analysis sensitivity and ensure concordance of the tested loci with the international recommendations. PMID- 28091918 TI - Changes in the Level of Circulating hsa-miR-297 and hsa-miR-19b-3p miRNA Are Associated with Generalization of Prostate Cancer. AB - We performed diagnostic classification of plasma specimens from patients with non metastatic and metastatic prostate cancer based on pairs of miRNA that have no individual diagnostic significance. Of 230 miRNA detected in plasma specimens, 3 pairs were diagnostically significant. The miRNA pair hsa-miR-19b-3p and hsa-miR 297 demonstrated highest sensitivity and specificity. Among common target genes of these miRNA, CFL2 gene associated with cell mobility was detected. PMID- 28091919 TI - Effects of Deltorphin II and Its Retroenantio Analog on Cardiac Tolerance to Ischemia and Reperfusion. AB - Selective agonist of delta2-opioid receptors deltorphin II and its retroenantio analog (0.12 mg/kg intravenously) were preventively injected to male Wistar rats 15 min prior to 45-min coronary occlusion or 5 min before 120-min reperfusion. Administration of deltorphin II before artery occlusion and before reperfusion decreased the infarct size/area at risk ratio. Deltorphin II prevented the appearance of ischemia-provoked ventricular arrhythmias and exerted no effect on HR and BP (systolic and diastolic). The retroenantio analog of deltorphin II produced no antiarrhythmic or infarct-limiting effects, but reduced HR without affecting BP. Deltorphin II can be viewed as a promising prototype for a medicinal remedy to treat acute myocardial infarction. PMID- 28091920 TI - Comparative Study of Antitumor Efficiency of Intraperitoneal and Intravenous Cytostatics in Experimental Rats with Disseminated Ovarian Cancer. AB - Antitumor efficiencies of cytostatics dioxadet, cisplatin, mitomycin C, melphalan, and paclitaxel after a single intraperitoneal or intravenous injection in doses of 1.5, 4, 1.5, 2, and 5 mg/kg, respectively, were studied on the model of transplanted ovarian tumor in 124 rats. The antitumor effects were evaluated by the increase in median survival. Dioxadet, cisplatin, and melphalan injected intraperitoneally significantly prolonged the lifespan median - by 79, 88, and 114%, respectively, and were in fact ineffective, when injected intravenously. Intraperitoneal mitomycin C prolonged lifespan median by just 35%, intravenous - by 152%. Paclitaxel injected intraperitoneally and intravenously prolonged the lifespan median by 45 and 81%, respectively. PMID- 28091922 TI - Relationship between Serum Biochemistry in Macaca Mulatta Males and the Duration of Stay in Individual Cage. AB - A relationship between transfer of monkeys from yard to individual cage and duration of stay in individual cage and the serum biochemical parameters is detected in Macaca mulatta males. PMID- 28091921 TI - Levels of miRNA and Hormones in Thoracic Duct Lymph in Rats with Experimental Breast Cancer Induced by N-Methyl-N-Nitrosourea. AB - We studied hormone levels in the thoracic duct lymph and expression of miRNA involved in the pathogenesis of breast cancer induced in rats by intramammary injection of N-methyl-Nnitrosourea. The correlations between miRNA expression and hormone levels depended on the type of treatment. PMID- 28091924 TI - Effects of Acyzol on Zinc Content in Rat Brain and Blood Plasma. AB - Zinc level in the blood plasma and brain of rats was studied by inductively coupled plasma mass spectrometry. Maximum amount of zinc was observed in the cerebellum (15.0+/-5.5 MUg/mg wet tissue). Single intraperitoneal administration of a zinc donor acyzol (24 mg/kg) did not change the content of this element in the tissues. Repeated injections of acyzol (7 injections over 14 days) significantly increased zinc level in rat plasma and brain. This elevation was most pronounced in the forebrain (cortex and subcortical structures). The rise in zinc concentration in blood plasma correlated with its level in the brain. PMID- 28091923 TI - Experimental Study of the Effects of Nanodispersed Ceria on Wound Repair. AB - We studied the effects of nanodispersed ceria on wound healing in vitro and in vivo. It was found that cerium dioxide stimulated wound healing, which manifested in shrinkage of burn wound area (by 1.5 times) and intensification (by 2.4 times) marginal epithelialization. PMID- 28091925 TI - Changes in the Neurochemical Composition of Motor Neurons of the Spinal Cord in Mice under Conditions of Space Flight. AB - Expression of choline acetyltransferase, 200-kDa neurofilament protein, 28-kDa calbindin, neuronal NO synthase, caspase 3, and Ki-67 in the motor neurons of spinal cord segments T3-T5 in male C57Bl/6 mice after 30-day space flight in the Bion-M1 biosatellite was studied by immunohistochemical methods. Under conditions space flight, the size of motoneurons increased, the number of neurons containing choline acetyltransferase and neurofilaments, decreased, and the number of calbindin-positive neurons increased; motoneurons, expressing neuronal NO synthase and caspase 3 appeared, while Ki-67 was not detected. Fragmentation of neurons with the formation structures similar to apoptotic (residual) bodies was observed in individual caspase 3-positive motoneurons. PMID- 28091926 TI - Effect of Hypotensive Drugs on Dynamics of Nitroxide-Producing Renal Function in Rats with Nephrogenic Hypertension. AB - An original model of nephrogenic hypertension in rats was used for histochemical mapping of NADPH diaphorase (NO synthase) in various renal segments to examine the effect of hypotensive drugs furosemide, bendazol, and clonidine on the time course of nitroxide production in the kidneys. In various nephron segments, these drugs modulated NO synthesis in different ways. Clonidine induced a stable up regulation of NO synthesis, which can maintain active vasodilation and gradually diminish the rennin production. Bendazol also enhanced NO synthase activity in renal glomeruli and collecting tubules, but this effect was less pronounced and short lasting. During the first week after injection of bendazol, insignificant elevation of NO synthase activity was observed in the proximal nephron segments. Furosemide exerted the least effect on NO production in kidneys. PMID- 28091927 TI - Effect of New Antiviral Agent Camphecin on Behavior of Mice. AB - We studied the effect of camphecin (1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene aminoethanol) on mouse behavior in the open-field test. Camphecin possesses antiviral activity and inhibits viral replication, but its influence on the nervous system is poorly studied. Single camphecin injection produced no significant changes in behavioral patterns. Chronic camphecin administration (5 times over 2 weeks) to mice of different strains had no significant influence on open field behavior (motor, exploratory activity, anxiety, emotional state and vegetative functions). The findings are discussed in the context of neutral influence of camphecin on animal behavior. PMID- 28091928 TI - Effects of NO Synthase Blocker L-NAME on Functional State of the Neuromotor System during Traumatic Disease of the Spinal Cord. AB - Functional state of the neuromotor system after administration of a nonspecific NO synthase blocker L-NAME was studied on the model of experimental contusion of the spinal cord. Electron paramagnetic resonance measurements of NO production in the damaged segment of the spinal cord were performed for estimation of the dynamics of intensity of NO production during traumatic disease of the spinal cord and selection of optimal period for L-NAME administration. The status of the neuromotor system was evaluated by stimulation electromyography. Treatment with L NAME during the acute period of traumatic injury to the spinal cord sharply reduced the intensity of evoked motor responses and more pronounced increase in excitability of peripheral motor structures. The results suggest that NO system is a factor of regulation of the stress-induced and adaptive responses of the body at the early stage of spinal cord injury. PMID- 28091929 TI - Perception of injury risk among amateur Muay Thai fighters. AB - BACKGROUND: Muay Thai is a style of kickboxing that allows full-contact blows to an unprotected head, torso and legs, and, as in any combat sport, there is an inherent risk of injury. Previous observational studies have shown there is a substantial risk of injury in competitive kickboxing. None of these studies, however, have investigated the potential role of psychological risk factors and, consequently, little is known about the perception of injury risk among these athletes. Notwithstanding the important role risk perception may play in the occurrence and prevention of sports injuries, there is very limited empirical data pertaining to athletes in full-contact combat sports such as Muay Thai. Because the development and successful implementation of effective injury prevention policies for combat sports are likely to benefit from an increased understanding of the perception of injury risk and sport safety attitudes and behavior of its participants, further study is warranted. METHODS: Muay Thai fighters were invited to complete an online survey in which they rated the perceived risk of injury in a range of different sports, including Muay Thai kickboxing. Perceived comparative risk was obtained indirectly by subtracting perceived risk of injury to oneself from perceived risk of injury to a peer. Data were analyzed using descriptive statistics, comparison of means, and ordinal logistic regression. RESULTS: Contrary to the best available epidemiological evidence, Muay Thai fighters perceived the risk of injury in their own sport to be average and significantly lower than that in other collision and contact sports, including popular combat sports such as boxing and mixed martial arts. On average, Muay Thai fighters perceived their own risk injury to be significantly lower compared to their peers (p < 0.001). CONCLUSIONS: There appears to be a mismatch between injury risk perception and actual risk among Muay Thai fighters. Moreover, these athletes also exhibit a slight degree comparative optimism or unrealistic optimism. Because behavior is determined by perceived rather than actual risk, underestimation of injury risk and concomitant overestimation of ability to negotiate risk may lead to an increased frequency of injury. Future injury prevention strategies in combat sports such as Muay Thai kickboxing should consider educational- and psychosocial-based interventions that include efforts to correct erroneous beliefs and attitudes about actual risk of injury in the sport. PMID- 28091930 TI - Non-equilibrium molecular dynamics simulations of the transient Ludwig-Soret effect in a binary Lennard-Jones/spline mixture. AB - A binary isotope mixture of Lennard-Jones/spline particles at equilibrium was perturbed by a sudden change in the system's boundary temperatures. The system's response was determined by non-equilibrium molecular dynamics (NEMD). Three transient processes were studied: 1) The propagation of a pressure (shock) wave, 2) heat diffusivity and conduction, and 3) thermal diffusion (the Ludwig-Soret effect). These three processes occur at different time scales, which makes it possible to separate them in one single NEMD run. The system was studied in liquid, supercritical, and dense gas states with various forms and strengths of the thermal perturbation. The results show that heat was initially transported by two separate mechanisms: 1) heat diffusion as described by the transient heat equation and 2) as a consequence of a pressure wave. The pressure wave travelled faster than the speed of sound, generating a shock wave in the system. Local equilibrium was found in the transient phase, even with very strong perturbations and in the shock front. Although the mass separation due to the Ludwig-Soret effect developed much slower than the pressure and temperature fields in the system at large, it was found that the Soret coefficient could be accurately determined from the initial phase of the transient and close to the heat source. This opens the possibility of a new way to analyse results from transient experiments and thereby minimize effects of gravity and convection due to buoyancy. PMID- 28091931 TI - Identifying Anti-host Effectors in Photorhabdus. AB - The death of the insect host is an essential part of the life cycle of Photorhabdus, and as a result, this bacterium comes equipped with a dazzlingly large array of toxins and virulence factors that ensure rapid insect death. Elucidation of the key players in insect infection and mortality has therefore proved difficult using traditional microbiological techniques such as individual gene knockouts due to the high level of functional redundancy displayed by Photorhabdus virulence factors. Thus, knockout of any individual toxin gene may serve to delay time to death but not to render the bacteria avirulent due to the continued presence of an array of other toxins and virulence factors in the single-gene mutant. This functional redundancy had led to the necessary development of an array of techniques and new model systems for identifying and dissecting apart the action of anti-insect effectors produced by Photorhabdus. These have been pivotal in both the identification of new toxins and virulence factors and in ascribing functions to them. These techniques have gone on to prove valuable in pathogenic bacteria other than Photorhabdus and are likely to be useful in many others. PMID- 28091932 TI - Current Concept of IgG4-Related Disease. AB - IgG4-related disease (IgG4-RD) is a fibroinflammatory disease of unknown etiology, which is characterized by a tendency to form tumefactive lesions, increased serum levels of IgG4, and massive infiltration of IgG4-positive plasma cells with storiform fibrosis and/or obliterative phlebitis. Patients with IgG4 RD have frequently multiorgan involvements such as the pancreas, biliary tree, salivary glands, periorbital tissues, kidneys, lungs, lymph nodes, and retroperitoneum. IgG4-RD mainly affects middle-aged to elderly men except for involvement in lachrymal and salivary glands, so-called Mikulicz's disease. The clinical manifestations of IgG4-RD depend on individually involved organs and respond well to steroid, but the prognosis still remains unclear. Some patients develop serious complications such as obstructive jaundice due to hepatic, gallbladder, or pancreatic lesions; hydronephrosis due to retroperitoneal fibrosis; or respiratory symptoms due to pulmonary lesions. Nomenclatures of individual organ manifestation of IgG4-RD have been internationally consented. PMID- 28091933 TI - Flagellar Regulation and Virulence in the Entomopathogenic Bacteria-Xenorhabdus nematophila and Photorhabdus luminescens. AB - There is a complex interplay between the regulation of flagellar motility and the expression of virulence factors in many bacterial pathogens. Here, we review the literature on the direct and indirect roles of flagellar motility in mediating the tripartite interaction between entomopathogenic bacteria (Photorhabdus and Xenorhabdus), their nematode hosts, and their insect targets. First, we describe the swimming and swarming motility of insect pathogenic bacteria and its impact on insect colonization. Then, we describe the coupling between the expression of flagellar and virulence genes and the dynamic of expression of the flagellar regulon during invertebrate infection. We show that the flagellar type 3 secretion system (T3SS) is also an export apparatus for virulence proteins in X. nematophila. Finally, we demonstrate that phenotypic variation, a common property of the bacterial symbionts of nematodes, also alters flagellar motility in Photorhabdus and Xenorhabdus. Finally, the so-called phenotypic heterogeneity phenomenon in the flagellar gene expression network will be also discussed. As the main molecular studies were performed in X. nematophila, future perspectives for the study of the interplay between flagellum and invertebrate interactions in Photorhabdus will be discussed. PMID- 28091934 TI - Roles of Plasmablasts and B Cells in IgG4-Related Disease: Implications for Therapy and Early Treatment Outcomes. AB - High serum IgG4 concentrations are a striking feature of many patients with IgG4 related disease (IgG4-RD). Blood levels of IgG4 often reach ten, twenty, and even thirty or more times higher than the upper limit of normal. Under the proper clinical circumstances, the finding of an elevated serum IgG4 concentration serves as a useful biomarker for the diagnosis of this condition. This serum IgG4 elevation quickly called attention to the possibility of therapies targeting cells of the B lymphocyte lineage. In addition, a greater understanding of the cellular mechanisms that underpin IgG4-RD has identified peripheral blood plasmablasts as a promising biomarker for this disease. The roles of plasmablasts and B cells in IgG4-RD are discussed in this chapter. PMID- 28091935 TI - Natural Products from Photorhabdus and Other Entomopathogenic Bacteria. AB - Although the first natural products (NP) from Photorhabdus and Xenorhabdus bacteria have been known now for almost 30 years, a huge variety of new compounds have been identified in the last 5-10 years, mainly due to the application of modern mass spectrometry. Additionally, application of molecular methods that allow the activation of NP production in several different strains as well as efficient heterologous expression methods have led to the production and validation of many new compounds. In this chapter we discuss the benefit of using Photorhabdus as a model system for microbial chemical ecology. We also examine non-ribosomal peptide synthetases as the most important pathway for NP production. Finally, we discuss the origin and function of all currently known NPs and the development of the molecular and chemical tools used to identify these NPs faster. PMID- 28091936 TI - Task-Specific Motor Rehabilitation Therapy After Stroke Improves Performance in a Different Motor Task: Translational Evidence. AB - While the stroke survivor with a motor deficit strives for recovery of all aspects of daily life movements, neurorehabilitation training is often task specific and does not generalize to movements other than the ones trained. In rodent models of post-stroke recovery, this problem is poorly investigated as the training task is often the same as the one that measures motor function. The present study investigated whether motor training by pellet reaching translates into enhancement of different motor functions in rats after stroke. Adult rats were subjected to 60-min middle cerebral artery occlusion (MCAO). Five days after stroke, animals received either training consisting of 7 days of pellet reaching with the affected forelimb (n = 18) or no training (n = 18). Sensorimotor deficits were assessed using the sticky tape test and a composite neuroscore. Infarct volumes were measured by T2-weighted MRI on day 28. Both groups of rats showed similar lesion volume and forelimb impairment after stroke. Trained animals improved in the sticky tape test after day 7 post-stroke reaching peak performance on day 14. More reaching attempts during rehabilitation were associated with a better performance in the sticky tape removal time. Task oriented motor training generalizes to other motor functions after experimental stroke. Training intensity correlates with recovery. PMID- 28091937 TI - Ocular mycobacteriosis-dual infection of M. tuberculosis complex with M. fortuitum and M. bovis. AB - BACKGROUND: We report unfavorable outcome in a patient with subretinal granuloma caused by dual infection of Mycobacterium tuberculosis complex with Mycobacterium fortuitum and Mycobacterium bovis in an immunosuppressed, non-HIV patient. We did a systematic review of literature on dual infection due to M. tuberculosis and M. fortuitum via MEDLINE and PUBMED and could not find any case reported of causing this kind of dual infection in the eye. RESULTS: A 38-year-old Indian male patient presented with decreased vision in the left eye for 3 months, diagnosed as tubercular choroidal granuloma with associated retinal angiomatosis proliferans (RAP) lesion. He also had multiple enlarged lymph nodes in the chest, and sternal pus sample was positive for acid-fast bacilli (AFB). M. tuberculosis complex was detected by gene expert. The patient was started on antitubercular treatment (ATT) whereby the lung lesions improved but the ocular lesion showed initial clinical improvement followed by worsening. Twenty-five-gauge diagnostic pars plana core vitreous surgery was done whereby sample demonstrated a large number of AFB on Ziehl-Neelsen stain and auramine-rhodamine stain. The vitreous sample showed growth on routinely inoculated mycobacteria growth indicator tube (MGIT) 960 tubes, and multiplex polymerase chain reaction (PCR), Gene Xpert MTB/ RIF assay (Cepheid, Sunnyvale, CA), and line probe assay (LPA) were positive for ocular tuberculosis. In view of nonresponse to conventional ATT, a suspicion of dual infection of M. tuberculosis complex with a nontubercular mycobacteria was kept and a subculture was made onto the solid Lowenstein-Jensen (LJ) medium from the positive MGIT 960 tubes. Two morphologically distinct types of colonies were obtained on LJ slopes. Subsequently, the two etiological agents were identified as M. fortuitum and M. bovis by PCR from the vitreous sample. CONCLUSIONS: Co infection of M. tuberculosis complex with nontubercular mycobacterium (NTM) has never been reported from ocular tuberculosis before. In immunosuppressed individuals, who test positive for MTB, not responding to the standard ATT, one needs to have a high index of clinical suspicion to rule out associated NTM infection and initiate appropriate multidrug systemic antibiotic therapy early. PMID- 28091938 TI - Distinguishing features of acute Vogt-Koyanagi-Harada disease and acute central serous chorioretinopathy on optical coherence tomography angiography and en face optical coherence tomography imaging. AB - BACKGROUND: The aim of this study is to determine the differences in optical coherence tomography angiography (OCTA) features of acute Vogt-Koyanagi-Harada disease (VKH) and acute central serous chorioretinopathy (CSC). Clinical and imaging data of patients with acute CSC and VKH in a tertiary-care institute were analyzed. Multimodal imaging including fluorescein angiography, indocyanine green angiography (ICGA), and enhanced-depth imaging OCT were performed. OCTA images were analyzed for alterations in retinochoroidal microvasculature. RESULTS: Thirty-four eyes (24 patients; 10 with VKH and 14 with CSC) were included. OCTA en face images showed apparent areas of choriocapillaris flow void due to shadowing effect from overlying subretinal fluid and pigment epithelial detachment in CSC. However, eyes with VKH showed presence of true choriocapillaris flow void on OCTA that corresponded to choriocapillaris ischemia on ICGA. CONCLUSIONS: OCTA is a useful tool to assess choriocapillaris ischemia in VKH and is helpful to differentiate it from CSC in the acute stage. PMID- 28091939 TI - Immuno-PCR technology for detection of natural human antibodies against Lec disaccharide. AB - The development of an immuno-PCR assay for quantitation of low amounts of anti glycan human antibodies is described. The sensitivity of the assay for determination of low-affinity anti-LeC IgM has been found to be 4 ng/ml (~100 pg per sample), thus being two orders of magnitude higher compared to the conventional ELISA with the same antigen. PMID- 28091940 TI - Purification and sequence characterization of chondroitin sulfate and dermatan sulfate from fishes. AB - Chondroitin sulfate (CS) and dermatan sulfate (DS) were extracted and purified from skins or bones of salmon (Salmo salar), snakehead (Channa argus), monkfish (Lophius litulon) and skipjack tuna (Katsuwonus pelamis). Size, structural sequences and sulfate groups of oligosaccharides in the purified CS and DS could be characterized and identified using high performance liquid chromatography (HPLC) combined with Orbitrap mass spectrometry. CS and DS chain structure varies depending on origin, but motif structure appears consistent. Structures of CS and DS oligosaccharides with different size and sulfate groups were compared between fishes and other animals, and results showed that some minor differences of special structures could be identified by hydrophilic interaction chromatography liquid chromatography-fourier transform-mass/mass spectrometry (HILIC-LC-FT MS/MS). For example, data showed that salmon and skipjack CS had a higher percentage content of high-level sulfated oligosaccharides than that porcine CS. In addition, structural information of different origins of CS and DS was analyzed by principal component analysis (PCA) and results showed that CS and DS samples could be differentiated according to their molecular conformation and oligosaccharide fragments information. Understanding CS and DS structure derived from different origins may lead to the production of CS or DS with unique disaccharides or oligosaccharides sequence composition and biological functions. PMID- 28091941 TI - Occurrence of complex type free N-glycans with a single GlcNAc residue at the reducing termini in the fresh-water plant, Egeria densa. AB - In our previous study, we found unique free N-glycans (FNGs), which carry a single GlcNAc residue (GN1) at the reducing-end side and the Lewis-a epitope at the non-reducing-end side, in the culture broth of rice cells. Based on the FNG structural features and the substrate specificity of plant ENGase, we hypothesized that there might be a novel biosynthetic mechanism responsible for the production of these unique GN1-FNGs, in which high-mannose type (HMT)-GN1 FNGs produced in the cytosol from misfolded glycoproteins by ENGase are transported back into the endoplasmic reticulum and processed to plant complex type (PCT)-GN1-FNGs in the Golgi apparatus. Until now, however, PCT-GN1-FNGs had only been found in the culture broth of rice cultured cells and never in plants, suggesting that the formation of PCT-GN1-FNGs might be generated under special or artificial conditions. In this study, we confirm the presence of PCT-GN1-FNGs, HMT-GN1-FNGs and PCT-GN2-FNGs in the fresh-water plant Egeria densa. These results suggest that a mechanism responsible for the production of PCT-GN1-FNG is present in native plant tissues. PMID- 28091942 TI - All-Trans Retinoic Acid supplementation prevents cardiac fibrosis and cytokines induced by Methylglyoxal. AB - Methylglyoxal (MG), a metabolic intermediate of glycolysis is a precursor for endogeneous production of advanced glycation end-products. The increased production of MG have negative influence over the structure and function of different biomolecules and thus plays an important role in the pathogenesis of diabetic cardiac complications. Retinoic acid (RA), an active metabolite of vitamin A, has a major role in preventing cardiac remodeling and ventricular fibrosis. Hence, the objective of the present study was to determine whether rats administered with all-trans retinoic acid (RA) could attenuate MG induced pathological effects. Wistar rats were divided into 4 groups. Group 1 rats were kept as control; Group 2 rats were administrated with MG (75 mg/kg/day) for 8 weeks. Group 3 rats were given RA (Orally, 1.0 mg/kg/day) along with MG; Group 4 rats received RA alone. Cardiac antioxidant status, induction of fibrosis, AGE receptor (RAGE) and cytokines expression was evaluated in the heart tissues. Administration of MG led to depletion of antioxidant enzymes, induction of fibrosis (p < 0.001), up-regulated expression of RAGE (3.5 fold), TGF-beta (4.4 fold), SMAD2 (3.7 fold), SMAD3 (6.0 fold), IL-6 (4.3 fold) and TNF-alpha (5.5 fold) in the heart tissues compared to control rats. Moreover, the exogenous administration of MG caused significant (p < 0.001) increase in the circulating CML levels. Whereas, RA treatment prevented the induction of fibrosis and restored the levels of cytokines and RAGE expression. Methylglyoxal-induced fibrosis can lead to pathological effects in the heart tissues. RA attenuates the effects of MG in the heart, suggesting that it can be of added value to usual diabetic therapy. PMID- 28091943 TI - High-Sensitive Ultraviolet Photodetectors Based on ZnO Nanorods/CdS Heterostructures. AB - The ultraviolet (UV) photodetectors with ZnO nanorods (NRs)/CdS thin film heterostructures on glass substrates have been fabricated and characterized. It can be seen that the UV photoresponsivity of such a device became higher as the ZnO NR length was increased in the investigation. With an incident wavelength of 350 nm and 5 V applied bias, the responsivity of photodetectors based on ZnO NR/CdS heterostructures with the ZnO NR length at 500, 350, and 200 nm and traditional CdS film were at 12.86, 3.83, 0.91, and 0.75 A/W, respectively. The measurement results of the fabricated photodetectors based on ZnO nanorods (NRs)/CdS heterostructures have shown a significant high sensitivity in the range of UV light, which can be useful for the application of UV detection. PMID- 28091944 TI - Controlled Phase Changes of Titania Using Nitrogen Plasma. AB - In this work, the development of a new crystallization technique is reported, using nitrogen plasma (AC) to obtain nanostructured anatase and rutile from amorphous titanium oxide (TiO2). This methodology increases throughput and minimizes thermal effects. Nanostructured amorphous TiO2 was obtained by the sol gel method and subsequently subjected to AC treatment, at a controlled pressure, applying different powers and treatment times in order to obtain phase changes. The obtained samples were characterized using X-ray diffraction (XRD), thermogravimetric analysis (TGA), and X-ray photoelectron spectroscopy (XPS). The results show the crystallization in parallel with anatase and rutile phases with a proportion that is directly related to the applied power in the plasma and the treatment time. This technique allows us to obtain smaller crystals in comparison with those of classic thermal methodologies. It is also demonstrated that the application of plasma represents a novel and innovative method to obtain phase polymorphic changes in titanium oxide without needing to apply prolonged heat treatments at high temperatures and can therefore be taken into consideration as a technique with low energy costs, in comparison with conventional heat treatments. PMID- 28091945 TI - Optimization of InGaAs/InAlAs Avalanche Photodiodes. AB - In this paper, we report a two-dimensional (2D) simulation for InGaAs/InAlAs separate absorption, grading, charge, and multiplication avalanche photodiodes (SAGCM APDs) and study the effect of the charge layer and multiplication layer on the operating voltage ranges of APD. We find that with the increase of the thicknesses as well as the doping concentrations of the charge layer and the multiplication layer, the punchthrough voltage increases; with the increase of the doping concentrations of two layers and the thickness of the charge layer, the breakdown voltage decreases; with the increase of the thickness of the multiplication layer, the breakdown voltage first rapidly declines and then slightly rises. PMID- 28091946 TI - Self-catalyzed Growth of InAs Nanowires on InP Substrate. AB - We report on the self-catalyzed growth of InAs nanowires on InP substrate by metal-organic chemical vapor deposition. At a moderate V/III ratio, tapered nanowires are obtained, suggesting a strong surface diffusion effect. Dense twin faults are observed perpendicular to the nanowire growth direction due to the fluctuation of In atoms in the droplet originating from the surface diffusion effect. At a lower V/III ratio, the nanowires exhibit kinking, which is associated with a high adhesion due to a large sticking coefficient of TMIn. The twin faults are dramatically suppressed and even completely eliminated in the NW branch after kinking, which is attributed to a stable In supply with a negligible diffusion effect. This work provides a method for the fabrication of defect-free InAs nanowires. PMID- 28091947 TI - Characteristics of the Energetic Micro-initiator Through Integrating Al/Ni Nano multilayers with Cu Film Bridge. AB - An energetic micro-initiator through integrating Al/Ni nano-multilayers with Cu film bridge was investigated in this study. The Cu film bridge was initially fabricated with wet etching, and Al/Ni nano-multilayers were alternately deposited on the surface of Cu film bridge by magnetron sputtering. The periodic layer structure of Al/Ni nano-multilayers was verified by scanning electron microscopy. The exothermic reaction in Al/Ni nano-multilayers can be initiated with onset reaction temperature as low as 503 K, and the total reaction heat is about 774.6 J/g. This energetic micro-initiator exhibited improved performances with lower threshold voltage, smaller initiation energy, and higher explosion temperature compared with Cu film bridge. An extra violent explosion phenomenon with longer duration time and larger quantities of ejected product particles was detected on this energetic micro-initiator by high-speed camera. Overall, the electric explosion performances of Cu film bridge can be improved evidently with the integration of Al/Ni nano-multilayers. PMID- 28091948 TI - Demonstration of Logic Operations in High-Performance RRAM Crossbar Array Fabricated by Atomic Layer Deposition Technique. AB - In this paper, resistive random access memory (RRAM)-based crossbar arrays with the cell structure of Pt/[AlO y /HfO x ] m /TiN were fabricated by using atomic layer deposition (ALD) technique. The RRAM devices in the arrays show excellent performances such as good uniformity and high reliability. Based on the fabricated RRAM array, a complete set of basic logic operations including NOR and XNOR were successfully demonstrated. PMID- 28091949 TI - Nonmechanical Infrared Beam Steering Using Blue Addressed Quantum Dot Doped Liquid Crystal Grating. AB - We present a scheme of nonmechanical laser beam steering using ZnS/InP quantum dots doping nematic liquid crystal as the optical recording film. Because of its internal electric field generated by blue laser-induced charge carrier distribution, liquid crystal molecules are reoriented to form a phase grating which make the incident angle steer to the angle as we desire. Being a nonmechanical programmable laser beam steering, the anisotropy of the relative permittivity tensor and blue laser-induced electric carriers play a significant effect in determining the reorientable liquid crystal molecule and reconfigurable phase modulation of the gratings, that determines the steering angle and steering efficiency. PMID- 28091950 TI - Nanorods on surface of GaN-based thin-film LEDs deposited by post-annealing after photo-assisted chemical etching. AB - This study investigates the optoelectronic characteristics of gallium nitride (GaN)-based thin-film light-emitting diodes (TF-LEDs) that are formed by a two step transfer process that involves wet etching and post-annealing. In the two step transfer process, GaN LEDs were stripped from sapphire substrates by the laser lift-off (LLO) method using a KrF laser and then transferred onto ceramic substrates. Ga-K nanorods were formed on the surface of the GaN-based TF-LEDs following photo-assisted chemical etching and photo-enhanced post-annealing at 100 degrees C for 1 min. As a result, the light output power of GaN-based TF LEDs with wet etching and post-annealing was over 72% more than that of LEDs that did not undergo these treatments. PMID- 28091951 TI - Femtosecond Circular Photon Drag Effect in the Ag/Pd Nanocomposite. AB - We report on the observation of the helicity-dependent photoresponse of the 20 MUm-thick silver-palladium (Ag/Pd) nanocomposite films. In the experiment, 120 fs pulses of Ti:S laser induced in the film an electric current perpendicular to the incidence plane. The photoinduced current is a linear function of the incident beam power, and its sign depends on the beam polarization and angle of incidence. In particular, the current is zero for the p- and s-polarized beams, while its sign is opposite for the right- and left-circularly polarized beams. By comparing experimental results with theoretical analysis, we show that the photoresponse of the Ag/Pd nanocomposite originates from the photon drag effect. PMID- 28091952 TI - Nanometric Cutting of Silicon with an Amorphous-Crystalline Layered Structure: A Molecular Dynamics Study. AB - Materials with specific nanometric layers are of great value in both theoretical and applied research. The nanometric layer could have a significant influence on the response to the mechanical loading. In this paper, the nanometric cutting on the layered systems of silicon has been studied by molecular dynamics. This kind of composite structure with amorphous layer and crystalline substrate is important for nanomachining. Material deformation, stress status, and chip formation, which are the key issues in nano-cutting, are analyzed. A new chip formation mechanism, i.e., the mixture of extrusion and shear, has been observed. In addition, from the perspective of engineering, some specific composite models show the desired properties due to the low subsurface damage or large material removal rate. The results enrich the cutting theory and provide guidance on nanometric machining. PMID- 28091953 TI - Fullerene C60 Penetration into Leukemic Cells and Its Photoinduced Cytotoxic Effects. AB - Fullerene C60 as a representative of carbon nanocompounds is suggested to be promising agent for application in photodynamic therapy due to its unique physicochemical properties. The goal of this study was to estimate the accumulation of fullerene C60 in leukemic cells and to investigate its phototoxic effect on parental and resistant to cisplatin leukemic cells. Stable homogeneous water colloid solution of pristine C60 with average 50-nm diameter of nanoparticles was used in experiments. Fluorescent labeled C60 was synthesized by covalent conjugation of C60 with rhodamine B isothiocyanate. The results of confocal microscopy showed that leukemic Jurkat cells could effectively uptake fullerene C60 from the medium. Light-emitting diode lamp (100 mW cm-2, lambda = 420-700 nm) was used for excitation of accumulated C60. A time-dependent decrease of viability was detected when leukemic Jurkat cells were exposed to combined treatment with C60 and visible light. The cytotoxic effect of photoexcited C60 was comparable with that induced by H2O2, as both agents caused 50% decrease of cell viability at 24 h at concentrations about 50 MUM. Using immunoblot analysis, protein phosphotyrosine levels in cells were estimated. Combined action of C60 and visible light was followed by decrease of cellular proteins phosphorylation on tyrosine residues though less intensive as compared with that induced by H2O2 or protein tyrosine kinase inhibitor staurosporine. All tested agents reduced phosphorylation of 55, 70, and 90 kDa proteins while total suppression of 26 kDa protein phosphorylation was specific only for photoexcited C60.The cytotoxic effect of C60 in combination with visible light irradiation was demonstrated also on leukemic L1210 cells both sensitive and resistant to cisplatin. It was shown that relative value of mitochondrial membrane potential measured with tetramethylrhodamine ethyl ester perchlorate (TMRE) probe was lower in resistant cells in comparison with sensitive cells and the drop of mitochondrial potential corresponded to further decrease of resistant cell viability after C60 photoexcitation. The data obtained allow to suggest that C60-mediated photodynamic treatment is a candidate for restoration of drug-resistant leukemic cell sensitivity to induction of mitochondrial way of apoptosis. PMID- 28091954 TI - Methane alleviates copper-induced seed germination inhibition and oxidative stress in Medicago sativa. AB - Recent results discovered the protective roles of methane (CH4) against oxidative stress in animals. However, the possible physiological roles of CH4 in plants are still unknown. By using physiological, histochemical and molecular approaches, the beneficial role of CH4 in germinating alfalfa seeds upon copper (Cu) stress was evaluated. Endogenous production of CH4 was significantly increased in Cu stressed alfalfa seeds, which was mimicked by 0.39 mM CH4. The pretreatment with CH4 significantly alleviated the inhibition of seed germination and seedling growth induced by Cu stress. Cu accumulation was obviously blocked as well. Meanwhile, alpha/beta amylase activities and sugar contents were increased, all of which were consistent with the alleviation of seed germination inhibition triggered by CH4. The Cu-triggered oxidative stress was also mitigated, which was confirmed by the decrease of lipid peroxidation and reduction of Cu-induced loss of plasma membrane integrity in CH4-pretreated alfalfa seedlings. The results of antioxidant enzymes, including ascorbate peroxidase (APX), superoxide dismutase (SOD), catalase (CAT), and guaiacol peroxidase (POD) total or isozymatic activities, and corresponding transcripts (APX1/2, Cu/Zn SOD and Mn-SOD), indicated that CH4 reestablished cellular redox homeostasis. Further, Cu-induced proline accumulation was partly impaired by CH4, which was supported by the alternation of proline metabolism. Together, these results indicated that CH4 performs an advantageous effect on the alleviation of seed germination inhibition caused by Cu stress, and reestablishment of redox homeostasis mainly via increasing antioxidant defence. PMID- 28091955 TI - Genome-wide exploration of silicon (Si) transporter genes, Lsi1 and Lsi2 in plants; insights into Si-accumulation status/capacity of plants. AB - Silicon (Si) is a nonessential, beneficial micronutrient for plants. It increases the plant stress tolerance in relation to its accumulation capacity. In this work, root Si transporter genes were characterized in 17 different plants and inferred for their Si-accumulation status. A total of 62 Si transporter genes (31 Lsi1 and 31 Lsi2) were identified in studied plants. Lsi1s were 261-324 residues protein with a MIP family domain whereas Lsi2s were 472-547 residues with a citrate transporter family domain. Lsi1s possessed characteristic sequence features that can be employed as benchmark in prediction of Si-accumulation status/capacity of the plants. Silicic acid selectivity in Lsi1s was associated with two highly conserved NPA (Asn-Pro-Ala) motifs and a Gly-Ser-Gly-Arg (GSGR) ar/R filter. Two NPA regions were present in all Lsi1 members but some Ala substituted with Ser or Val. GSGR filter was only available in the proposed high and moderate Si accumulators. In phylogeny, Lsi1s formed three clusters as low, moderate and high Si accumulators based on tree topology and availability of GSGR filter. Low-accumulators contained filters WIGR, AIGR, FAAR, WVAR and AVAR, high accumulators only with GSGR filter, and moderate-accumulators mostly with GSGR but some with A/CSGR filters. A positive correlation was also available between sequence homology and Si-accumulation status of the tested plants. Thus, availability of GSGR selectivity filter and sequence homology degree could be used as signatures in prediction of Si-accumulation status in experimentally uncharacterized plants. Moreover, interaction partner and expression profile analyses implicated the involvement of Si transporters in plant stress tolerance. PMID- 28091956 TI - Does caffeine influence the anticholinesterase and antioxidant properties of donepezil? Evidence from in vitro and in vivo studies. AB - Caffeine is adjudged world's most consumed pharmacologically active food component. With reports of the potential cognitive enhancing properties of caffeine, we sought to investigate if caffeine can influence the anticholinesterase and antioxidant properties of donepezil-a selective acetylcholinesterase (AChE) inhibitor used in the management of Alzheimer's disease (AD). In vitro, we investigated the effect of donepezil (DON), caffeine (CAF) and their various combinations on the activity of AChE in rat brain homogenate, as well as determined their antioxidant properties. In vivo, two rat groups were administered single oral dose of DON (5 mg/kg) and CAF (5 mg/kg) separately, while three groups, each received 5 mg/kg DON plus either 5, 50 or 100 mg/kg CAF for three hours, after which the rats were sacrificed and brain isolated. Results show that CAF concentration dependently and synergistically increased the anticholinesterase properties of DON in vitro. Also, CAF produced a significant influence on investigated in vitro antioxidant properties of DON. Furthermore, rats administered 5 mg/kg CAF and DON produced no significant difference in AChE activity compared to rats administered DON alone. However, co administration of either 50 or 100 mg/kg CAF with DON lead to higher AChE activity compared to both control and DON groups. In addition, DON, CAF and their various combinations augmented brain antioxidant status in treated rats. We conclude that while low caffeine consumption may improve the antioxidant properties of donepezil without having a significant influence on its anticholinesterase effect, moderate-high caffeine consumption could also improve the antioxidant properties of donepezil but reduce its anticholinesterase effect; nevertheless, a comprehensive clinical trial is essential to fully explore these possibilities in human AD condition. PMID- 28091957 TI - Point-spread function reconstructed PET images of sub-centimeter lesions are not quantitative. AB - BACKGROUND: PET image reconstruction methods include modeling of resolution degrading phenomena, often referred to as point-spread function (PSF) reconstruction. The aim of this study was to develop a clinically relevant phantom and characterize the reproducibility and accuracy of high-resolution PSF reconstructed images of small lesions, which is a prerequisite for using PET in the prediction and evaluation of responses to treatment. Sets of small homogeneous 18F-spheres (range 3-12 mm diameter, relevant for small lesions and lymph nodes) were suspended and covered by a 11C-silicone, which provided a scattering medium and a varying sphere-to-background ratio. Repeated measurements were made on PET/CT scanners from two vendors using a wide range of reconstruction parameters. Recovery coefficients (RCs) were measured for clinically used volume-of-interest definitions. RESULTS: For non-PSF images, RCs were reproducible and fell monotonically as the sphere diameter decreased, which is the expected behavior. PSF images converged slower and had artifacts: RCs did not fall monotonically as sphere diameters decreased but had a maximum RC for sphere sizes around 8 mm, RCs could be greater than 1, and RCs were less reproducible. To some degree, post-reconstruction filters could suppress PSF artifacts. CONCLUSIONS: High-resolution PSF images of small lesions showed artifacts that could lead to serious misinterpretations when used for monitoring treatment response. Thus, it could be safer to use non-PSF reconstruction for quantitative purposes unless PSF reconstruction parameters are optimized for the specific task. PMID- 28091958 TI - Identification and anticoagulant activity of a novel Kunitz-type protein HA11 from the salivary gland of the tick Hyalomma asiaticum. AB - Kunitz/bovine pancreatic trypsin inhibitor proteins are abundant in the salivary glands of ticks and perform multiple functions in blood feeding, including inhibiting blood coagulation, regulating host blood supply and disrupting host angiogenesis. In this study, we identified a novel gene designated HA11 (Hyalomma asiaticum 11 kDa protein) from the salivary gland of the tick H. asiaticum. HA11 is encoded by a gene with an open reading frame of 306 bp that is translated into a deduced 101 amino acid 11 kDa protein that shares 27% sequence identity with a Kunitz-like protease inhibitor precursor in Amblyomma variegatum. Bioinformatic analysis confirmed HA11 as a member of the Kunitz-type family of inhibitors. Real time-PCR detected HA11 mRNA transcripts in tick larvae and nymphae stages, with levels highest in salivary gland tissue, and transcription was induced by blood feeding. HA11 anticoagulant activity was demonstrated by its ability to delay normal clotting of rabbit plasma in an activated partial thromboplastin time assay. Furthermore, RNA interference confirmed that HA11 influences H. asiaticum development and blood feeding, and the recombinant protein exerted low hemolytic activity. These results suggest HA11 is a novel Kunitz-type anticoagulant protein involved in tick blood feeding that may have potential as an anticoagulant drug or vaccine. PMID- 28091959 TI - Genetic variation in mitochondrial genes of the tick Haemaphysalis flava collected from wild hedgehogs in China. AB - The tick Haemaphysalis flava (Acari: Ixodidae) is an important ectoparasite, which causes direct damage to their hosts and also acts as a vector of various infectious disease agents in China. Despite its significance, the epidemiology, genetics and biology of H. flava has not been studied in detail. In the present study, the genetic variation in three mitochondrial (mt) DNA regions, namely cytochrome c oxidase subunit 1 (cox1) and NADH dehydrogenase subunit 1 and 4 (nad1 and nad4), was examined in H. flava ticks collected from wild hedgehogs in China. A portion of cox1 (pcox1), nad1 (pnad1) and nad4 (pnad4) genes were PCR amplified from individual H. flava ticks and the amplicons were sequenced. The length of the sequences of pcox1, pnad1 and pnad4 were 849, 285 and 626 bp, respectively. The intra-specific sequence variation within H. flava was 0-0.4% for pcox1, 0-0.4% for pnad1 and 0-0.3% for pnad4. However, the inter-specific variation was significantly higher, 12.5-14.3%, 13.6-24.8% and 14.8-19% for pcox1, pnad1 and pnad4, respectively. Phylogenetic analysis based on Maximum likelihood (ML) method using the combined target mt gene sequences confirmed that all isolates of Haemaphysalis were H. flava. The molecular approach employed in this study provides a tool for further elucidating the molecular diversity of H. flava in China and elsewhere in Asia. PMID- 28091960 TI - Alveolar distraction in elderly patients by implant: borne devices for functional aesthetic dental rehabilitation of the jaws. PMID- 28091961 TI - 1H, 13C and 15N backbone and side-chain resonance assignments of the ZnF-UBP domain of USP20/VDU2. AB - Deubiquitinase USP20/VDU2 has been identified as a regulator of multiple proteins including hypoxia-inducible factor (HIF)-1alpha, beta2-adrenergic receptor, and tumor necrosis factor receptor associated factor 6 etc. It contains four structural domains, including an N-terminal zinc-finger ubiquitin binding domain (ZnF-UBP) that potentially helps USP20 to recruit its ubiquitin substrates. Here we report the 1H, 13C and 15N backbone and side-chain resonance assignments of the ZnF-UBP domain of USP20/VDU2. The BMRB accession number is 26901. The secondary structural elements predicted from the NMR data reveal a global fold consisting of three alpha-helices and four beta-strands. The complete assignments can be used to explore the protein dynamics of the USP20 ZnF-UBP and its interactions with monoubiquitin and ubiquitin chains. PMID- 28091962 TI - Knowledge, Attitude, and Practice on Breast Cancer among Health Professionals in Douala References Hospitals, Cameroon. AB - In Cameroon, patients with breast cancer are more often diagnosed at stage III and IV, hence the need of preventives actions. Knowledge and attitude of medical personnel may influence their practice with regards to screening and early detection of breast cancer. Very few is known about this subject in Cameroon. The objective was to describe the knowledge, attitude, and practice of health care professionals on breast cancer risk factors, diagnostic methods, and screening. This was a cross-sectional study conducted during a 6-month period, among health professionals of Douala General Hospital and Laquintinie Hospital, Cameroon.Data were collected using a self-administered questionnaire which included demographic characteristics, questions on breast cancer risk factors, screening, and diagnostic methods. Marks were attributed to each question and calculated for each section. Participants fell in four categories of knowledge, attitude, and practice: very weak, weak, good, and excellent. The software XLStat7.5.2 was used for data analysis. Overall, 445 health professionals were interviewed. The average age was 39 +/- 9 years. The level of knowledge, attitude, and practice was accessed respectively as weak (50.1%), very good (64.5%), and poor (36.4%). The personal practice of female workers was poor (43.0%). Compared to participants with very weak to weak knowledge, those with good to excellent knowledge had 1.55-fold odds of excellent attitude p < 0.0001. After multivariate analysis, the factor associated with good to excellent knowledge was the participant qualification (academic degree). These results suggest the need for training of health professionals in Douala references hospitals on breast cancer risks factors, diagnostic, and screening methods. PMID- 28091963 TI - Pilot Test of Survey to Assess Dental and Dental Hygiene Student Human Papillomavirus-Related Oropharyngeal Cancer Knowledge, Perceptions, and Clinical Practices. AB - This was the first study to develop and pilot test an assessment tool for the examination of human papillomavirus (HPV)-related oropharyngeal cancer (OPC) knowledge, perceptions, and clinical practices of oral health students. An interdisciplinary team developed the tool using surveys that examined this topic in other populations. The tool was then pilot tested at two different dental programs. Results from the pilot informed revisions to the final version of the tool. Of the 46 student participants, 18 were first-year dental hygiene and 28 were first-year dental students. The majority of participants were female (N = 29, 63%) and ages 18 to 29 years old (N = 41, 89%). Four scales used in the questionnaire were analyzed for reliability. Of these, the HPV and HPV-OPC knowledge and the HPV vaccination knowledge scales had Cronbach alphas of 0.71 and 0.79, respectively. Questions assessing HPV and the role of dental professionals had a correlation coefficient of 0.71. Questions assessing willingness to administer vaccines in the dental office had a correlation coefficient of 0.85. Assessing oral health students' HPV-OPC knowledge, perceptions, and clinical practices are important for future assessment of possible HPV-OPC cases. Dental professionals may be optimally positioned to provide HPV patient education. The tool developed and pilot tested in this study can help schools assess their students' knowledge and guide their dental curriculum to address deficiencies. Since this topic has not been effectively examined with dental health students, the results could help improve dental education and dental care. PMID- 28091964 TI - Facing a Fundamental Problem in Prevention Science: the Measurement of a Key Construct. AB - While many attempts have been made to measure various aspects of parenting within a variety of theoretical frameworks, there remains much work to do on the development of reliable and valid measures. Common themes across the papers included in a special issue on the measurement of parenting are discussed. Parenting constructs are a vital part of the work of prevention scientists, and more support is needed for researchers to engage in measurement development. Fortunately, there are some bright spots in this regard today, such as the Common Fund Science of Behavior Change Program sponsored by the National Institutes of Health. PMID- 28091965 TI - Deformability of Human Mesenchymal Stem Cells Is Dependent on Vimentin Intermediate Filaments. AB - Mesenchymal stem cells (MSCs) are being studied extensively due to their potential as a therapeutic cell source for many load-bearing tissues. Compression of tissues and the subsequent deformation of cells are just one type physical strain MSCs will need to withstand in vivo. Mechanotransduction by MSCs and their mechanical properties are partially controlled by the cytoskeleton, including vimentin intermediate filaments (IFs). Vimentin IF deficiency has been tied to changes in mechanosensing and mechanical properties of cells in some cell types. However, how vimentin IFs contribute to MSC deformability has not been comprehensively studied. Investigating the role of vimentin IFs in MSC mechanosensing and mechanical properties will assist in functional understanding and development of MSC therapies. In this study, we examined vimentin IFs' contribution to MSCs' ability to deform under external deformation using RNA interference. Our results indicate that a deficient vimentin IF network decreases the deformability of MSCs, and that this may be caused by the remaining cytoskeletal network compensating for the vimentin IF network alteration. Our observations introduce another piece of information regarding how vimentin IFs are involved in the complex role the cytoskeleton plays in the mechanical properties of cells. PMID- 28091966 TI - Aortic Regurgitation Generates a Kinematic Obstruction Which Hinders Left Ventricular Filling. AB - An incompetent aortic valve (AV) results in aortic regurgitation (AR), where retrograde flow of blood into the left ventricle (LV) is observed. In this work, we parametrically characterized the detailed changes in intra-ventricular flow during diastole as a result of AR in a physiological in vitro left-heart simulator (LHS). The loss of energy within the LV as the level of AR increased was also assessed. The validated LHS consisted of an optically-clear, flexible wall LV and a modular AV holder. Two-component, planar, digital particle image velocimetry was used to visualize and quantify intra-ventricular flow. A large coherent vortical structure which engulfed the whole LV was observed under control conditions. In the cases with AR, the regurgitant jet was observed to generate a "kinematic obstruction" between the mitral valve and the LV apex, preventing the trans-mitral jet from generating a coherent vortical structure. The regurgitant jet was also observed to impinge on the inferolateral wall of the LV. Energy dissipation rate (EDR) for no, trace, mild, and moderate AR were found to be 1.15, 2.26, 3.56, and 5.99 W/m3, respectively. This study has, for the first time, performed an in vitro characterization of intra-ventricular flow in the presence of AR. Mechanistically, the formation of a "kinematic obstruction" appears to be the cause of the increased EDR (a metric quantifiable in vivo) during AR. EDR increases non-linearly with AR fraction and could potentially be used as a metric to grade severity of AR and develop clinical interventional timing strategies for patients. PMID- 28091967 TI - Balancing Ethical Pros and Cons of Stem Cell Derived Gametes. AB - In this review we aim to provide an overview of the most important ethical pros and cons of stem cell derived gametes (SCD-gametes), as a contribution to the debate about reproductive tissue engineering. Derivation of gametes from stem cells holds promising applications both for research and for clinical use in assisted reproduction. We explore the ethical issues connected to gametes derived from embryonic stem cells (both patient specific and non-patient specific) as well as those related to gametes derived from induced pluripotent stem cells. The technology of SCD-gametes raises moral concerns of how reproductive autonomy relates to issues of embryo destruction, safety, access, and applications beyond clinical infertility. PMID- 28091968 TI - Load-Based Lower Neck Injury Criteria for Females from Rear Impact from Cadaver Experiments. AB - The objectives of this study were to derive lower neck injury metrics/criteria and injury risk curves for the force, moment, and interaction criterion in rear impacts for females. Biomechanical data were obtained from previous intact and isolated post mortem human subjects and head-neck complexes subjected to posteroanterior accelerative loading. Censored data were used in the survival analysis model. The primary shear force, sagittal bending moment, and interaction (lower neck injury criterion, LNic) metrics were significant predictors of injury. The most optimal distribution was selected (Weibulll, log normal, or log logistic) using the Akaike information criterion according to the latest ISO recommendations for deriving risk curves. The Kolmogorov-Smirnov test was used to quantify robustness of the assumed parametric model. The intercepts for the interaction index were extracted from the primary risk curves. Normalized confidence interval sizes (NCIS) were reported at discrete probability levels, along with the risk curves and 95% confidence intervals. The mean force of 214 N, moment of 54 Nm, and 0.89 LNic were associated with a five percent probability of injury. The NCIS for these metrics were 0.90, 0.95, and 0.85. These preliminary results can be used as a first step in the definition of lower neck injury criteria for women under posteroanterior accelerative loading in crashworthiness evaluations. PMID- 28091969 TI - Quality of life as predictor for the development of cardiac ischemia in high-risk asymptomatic diabetic patients. AB - BACKGROUND: Ischemia induced by psychological stress and depression is a common phenomenon in stable coronary artery disease (CAD). We evaluated the quality of life (QoL) of diabetic patients screened for CAD and assessed the prognostic value of mental and physical QoL scores to predict the development of new cardiac ischemia. METHODS: Prospective multicentre outcome study. The study comprised 400 asymptomatic diabetic patients without history or symptoms of CAD. They underwent myocardial perfusion single-photon emission computed tomography (MPS) and assessment of QoL by two questionnaires: Hospital Depression and Anxiety Scale (HADS-D and HADS-A) and Medical Outcomes Study Short Form 36 (SF-36) at baseline and after 2 years. Patients with normal MPS received usual care; those with abnormal MPS received medical or combined invasive and medical management. RESULTS: Only mental QoL scores but not physical QoL scores or traditional cardiovascular risk factors were predictive of new ischemia (n = 11/306) during follow-up. The prognostic value for new ischemia as quantified by the area under the receiver operating characteristics curve (AUC) amounted to 0.784 (95% confidence interval (CI) 0.654-0.914, P = 0.002) for HADS-D and to 0.737 (95% CI 0.580-0.893, P = 0.011) for HADS-A. This finding was confirmed by SF-36 mental sum score (AUC 0.688, 95% CI 0.539-0.836, P = 0.036), but not SF-36 physical sum score. QoL scores did not change after 2 years in patients with ischemia at baseline. CONCLUSIONS: QoL scores assessing mental health, particularly depression and anxiety, predicted the development of new cardiac ischemia in asymptomatic diabetic patients. The study is limited by a small number of events (new ischemia) and so the results should be considered hypothesis generating rather than conclusive. PMID- 28091970 TI - Comparison of Two Adsorbent Based de-Bittering Procedures for Neem (Azadirachta indica A. Juss) Tea- Effect on Polyphenols, Anti-Oxidant Capacity, Color and Volatile Profile. AB - Bitterness reduction, especially of foods and beverages containing phytonutrients, is one of the biggest challenges in the food industry because bitterness has a deleterious effect on the taste profile of foods and beverages. Neem (Azadirachta indica A. Juss) is a medicinal tree, indigenous to the Indian subcontinent, whose medicinal properties have led to it being heralded as the tree which is the "panacea for all diseases". However, neem leaf is extremely bitter, in large part due to its limonoid content, making it unpalatable. The objective of this study was to apply two adsorbent based strategies, namely solid phase extraction (SPE) and Amberlite XAD-16 (AMB) resin, to achieve de-bittering of neem tea and to determine the effects of the de-bittering on the bio-active, color and volatile properties. The solid SPE treatment completely removed the flavonol, quercetin, from neem tea while in Amberlite XAD-16 treated tea (AMB) it was only insignificantly (p > 0.05) reduced. We also observed decreases in total phenolic content and consequently anti-oxidant activities after de-bittering. A 62% mean reduction of limonoid aglycones indicated diminished levels of bitterness. The loss of phenolics lead to a visually appreciable color changes in the treated teas. The de-bittering also leads to a loss of sesquiterpenes, ketones and acids from neem tea. In conclusion, we found that while SPE cartridges were more efficient in removing bitterness, they caused a greater reduction in bio-active compounds than AMB XAD-16 resins, which may ultimately affect the health properties of neem tea. PMID- 28091971 TI - Mate Limitation in Fungal Plant Parasites Can Lead to Cyclic Epidemics in Perennial Host Populations. AB - Fungal plant parasites represent a growing concern for biodiversity and food security. Most ascomycete species are capable of producing different types of infectious spores both asexually and sexually. Yet the contributions of both types of spores to epidemiological dynamics have still to been fully researched. Here we studied the effect of mate limitation in parasites which perform both sexual and asexual reproduction in the same host. Since mate limitation implies positive density dependence at low population density, we modeled the dynamics of such species with both density-dependent (sexual) and density-independent (asexual) transmission rates. A first simple SIR model incorporating these two types of transmission from the infected compartment, suggested that combining sexual and asexual spore production can generate persistently cyclic epidemics in a significant part of the parameter space. It was then confirmed that cyclic persistence could occur in realistic situations by parameterizing a more detailed model fitting the biology of the Black Sigatoka disease of banana, for which literature data are available. We discuss the implications of these results for research on and management of Sigatoka diseases of banana. PMID- 28091972 TI - [Secondary prevention with antiplatelet therapy in cardiac rehabilitation]. AB - The long-term increased cardiovascular risk of patients with an acute coronary syndrome (ACS) is a challenging and common clinical problem. Recent evidence demonstrated an ischemic benefit for a prolonged dual antiplatelet therapy beyond the initial 12 months at the cost of an increased bleeding risk. Individual, careful and repeated risk-benefit analyses are essential for an optimized patient management in which cardiovascular rehabilitation providers may play a central role. PMID- 28091975 TI - Update on advanced melanoma treatments: small molecule targeted therapy, immunotherapy, and future combination therapies. AB - Early stage melanomas can achieve remarkable outcomes with surgery alone, but stage IV metastatic melanoma requires significant intervention and has poor outcomes. Here we present evidence on the latest advances in melanoma treatment, discuss the scientific concepts behind new therapies, and analyze the potential of future treatment combinations. PMID- 28091973 TI - Mechanisms on spasmolytic and anti-inflammatory effects of a herbal medicinal product consisting of myrrh, chamomile flower, and coffee charcoal. AB - Inflammatory bowel disease or irritable bowel syndrome are chronic gastrointestinal disorders which are associated with a lifelong therapeutic need. The disease results in physical, psychological, and social problems with an impact on partnership, sexuality, education, and career. Thus, the number of patients and health care professionals relying on traditional and complementary medicines and especially phytotherapy for the treatment of these chronic conditions is increasing over recent years. One traditional herbal medicinal product consisting of chamomile flower, myrrh, and coffee charcoal has been widely used in clinical practice within this indication area. Long-term experience and an increasing understanding of the pharmacological mechanisms substantiate its application and clinical effectiveness. Mainly the spasmolytic and anti-inflammatory effects provide a rationale for its therapeutic application. In addition, synergistic effects between the herbal components contribute to the overall effect of this medication. PMID- 28091974 TI - Clinical trial shows lasting function of a new moisturizing cream against vaginal dryness. AB - Vaginal dryness and associated symptoms may occur in women of any age and are a frequent burden after menopause. The North American Menopause Society recommends long-acting non-hormonal vaginal creams as first-line therapy. A new type of such creams was developed (Remifemin(r) FeuchtCreme in Austria and Germany). This hormone-free cream contains hamamelis virginiana distillate and well-established vaginal cream ingredients. We explored its physical function and tolerability in an open interventional clinical trial. 20 postmenopausal women (54 to 76 years, median 60) treated their vaginal dryness using this cream once daily for 7 days and reported about their symptoms before, 4 to 8 h after first and 14 to 22 h after last application. A physician assessed tolerability and local physical function. All patients completed the study. Local physical function significantly improved from dryness at baseline (mean 4.0 +/- SD 1.8) to a normal moisture level, on average (6.3 +/- 2.1 after first, 6.7 +/- 2.1 after last application, p = 0.0001). Subjective assessment of a feeling vaginal dryness showed a significant improvement at both times (p = 0.0001). Onset and duration of feeling moisturized were reported to be 0 to 2 min and 11.3 +/- 6.9 h after application. All women reported vaginal dryness at baseline. 55 and 80% of patients reported no dryness after first application and at the end of the investigation. The cream was seen at the application site for up to 21 h. Tolerability assessments did not reveal any relevant change over time. There were four adverse events in 4 patients, all not serious and of mild intensity: urinary urgency (2), diarrhoea (1) and mild spotting after first application (1). The latter was caused by the dry surface of the applicator and was avoided by moisturizing the surface of the applicator at subsequent applications. In conclusion, these study results indicate a well-tolerated and long-acting function of this new vaginal moisturizing cream. Further clinical research in more patients will follow. PMID- 28091976 TI - Effectiveness of various innovative learning methods in health science classrooms: a meta-analysis. AB - This study reports the results of a meta-analysis of the available literature on the effectiveness of various forms of innovative small-group learning methods on student achievement in undergraduate college health science classrooms. The results of the analysis revealed that most of the primary studies supported the effectiveness of the small-group learning methods in improving students' academic achievement with an overall weighted average effect-size of 0.59 in standard deviation units favoring small-group learning methods. The subgroup analysis showed that the various forms of innovative and reform-based small-group learning interventions appeared to be significantly more effective for students in higher levels of college classes (sophomore, junior, and senior levels), students in other countries (non-U.S.) worldwide, students in groups of four or less, and students who choose their own group. The random-effects meta-regression results revealed that the effect sizes were influenced significantly by the instructional duration of the primary studies. This means that studies with longer hours of instruction yielded higher effect sizes and on average every 1 h increase in instruction, the predicted increase in effect size was 0.009 standard deviation units, which is considered as a small effect. These results may help health science and nursing educators by providing guidance in identifying the conditions under which various forms of innovative small-group learning pedagogies are collectively more effective than the traditional lecture-based teaching instruction. PMID- 28091977 TI - A Cross-Sectional Snapshot of Sleep Quality and Quantity Among US Medical Students. AB - OBJECTIVE: Fatigue is a well-known risk factor for mood disturbances, decreased cognitive acuity, and impaired judgment. Sleep research in medical students typically focuses on sleep quantity, but less is known about the quality of a student's sleep. The purpose of this investigation was to examine the subjective sleep quality and quantity of US medical students and to identify differences in sleep characteristics across demographic groups. METHODS: Medical students (N = 860) representing 49 medical colleges completed the Medical Outcomes Study Sleep Scale and a demographic questionnaire between December 2015 and March 2016. RESULTS: Although participants reported obtaining nearly 7 h of sleep per night, the majority of students reported indicators of poor sleep quality. First and third year students reported higher rates of sleep-related problems compared to second and fourth year students. First and second year students reported the highest levels of sleep somnolence. Ethnic minority students reported significantly lower levels of sleep adequacy and sleep quantity and significantly higher levels of sleep somnolence than Caucasian students. CONCLUSIONS: Impaired sleep quality may contribute to fatigue in medical students even when sleep quantity seems adequate. Students appear to begin medical school with disrupted sleep patterns that may not improve until their final year of study. Education regarding proper sleep habits and the significant role of sleep quality in sustaining healthy sleep is especially important in the early stages of medical education. Minority, first year, and third year students may benefit the most from learning new behaviors that promote sufficient sleep quality during periods of sustained stress. PMID- 28091978 TI - Patient-specific optimisation of administered activity and acquisition times for 18F-FDG PET imaging. AB - BACKGROUND: The purpose of this study is to identify a method for optimising the administered activity and acquisition time for 18F-FDG PET imaging, yielding images of consistent quality for patients with varying body sizes and compositions, while limiting radiation doses to patients and staff. Patients referred for FDG scans had bioimpedance measurements. They were injected with 3 MBq/kg of 18F up to 370 MBq and scanned on a Siemens Biograph mCT at 3 or 4 min per bed position. Data were rebinned to simulate 2- and 1-min acquisitions. Subjective assessments of image quality made by an experienced physician were compared with objective measurements based on signal-to-noise ratio and noise equivalent counts (NEC). A target objective measure of image quality was identified. The activity and acquisition time required to achieve this were calculated for each subject. Multiple regression analysis was used to identify expressions for the activity and acquisition time required in terms of easily measurable patient characteristics. RESULTS: One hundred and eleven patients were recruited, and subjective and objective assessments of image quality were compared for 321 full and reduced time scans. NEC-per-metre was identified as the objective measure which best correlated with the subjective assessment (Spearman rank correlation coefficient 0.77) and the best discriminator for images with a subjective assessment of "definitely adequate" (area under the ROC curve 0.94). A target of 37 Mcount/m was identified. Expressions were identified in terms of patient sex, height and weight for the activity and acquisition time required to achieve this target. Including measurements of body composition in these expressions was not useful. Using these expressions would reduce the mean activity administered to this patient group by 66 MBq compared to the current protocol. CONCLUSIONS: Expressions have been identified for the activity and acquisition times required to achieve consistent image quality in FDG imaging with reduced patient and staff doses. These expressions might need to be adapted for other systems and reconstruction protocols. PMID- 28091979 TI - Blood perfusion in osteomyelitis studied with [15O]water PET in a juvenile porcine model. AB - BACKGROUND: Osteomyelitis is a serious disease which can be difficult to treat despite properly instituted antibiotic therapy. This appears to be related at least partly to degraded vascularisation in the osteomyelitic (OM) lesions. Studies of perfusion in OM bones are, however, few and not quantitative. Quantitative assessment of perfusion could aid in the selection of therapy. A non invasive, quantitative way to study perfusion is dynamic [15O]water positron emission tomography (PET). We aim to demonstrate that the method can be used for measuring perfusion in OM lesions and hypothesize that perfusion will be less elevated in OM lesions than in soft tissue (ST) infection. The study comprised 11 juvenile pigs with haematogenous osteomyelitis induced by injection of Staphylococcus aureus into the right femoral artery 1 week before scanning (in one pig, 2 weeks). The pigs were dynamically PET scanned with [15O]water to quantify blood perfusion. OM lesions (N = 17) in long bones were studied, using the left limb as reference. ST lesions (N = 8) were studied similarly. RESULTS: Perfusion was quantitatively determined. Perfusion was elevated by a factor 1.5 in OM lesions and by a factor 6 in ST lesions. CONCLUSIONS: Blood perfusion was successfully determined in pathological subacute OM lesions; average perfusion was increased compared to that in a healthy bone, but as hypothesized, the increase was less than in ST lesions, indicating that the infected bone has less perfusion reserve than the infected soft tissue. PMID- 28091980 TI - Comparison of Tc-99m maraciclatide and Tc-99m sestamibi molecular breast imaging in patients with suspected breast cancer. AB - BACKGROUND: Molecular breast imaging (MBI) performed with 99mTc sestamibi has been shown to be a valuable technique for the detection of breast cancer. Alternative radiotracers such as 99mTc maraciclatide may offer improved uptake in breast lesions. The purpose of this study was to compare relative performance of 99mTc sestamibi and 99mTc maraciclatide in patients with suspected breast cancer, using a high-resolution dedicated gamma camera for MBI. Women with breast lesions suspicious for malignancy were recruited to undergo two MBI examinations-one with 99mTc sestamibi and one with 99mTc maraciclatide. A radiologist interpreted MBI studies in a randomized, blinded fashion to assign an assessment score (1-5) and measured lesion size. Lesion-to-background (L/B) ratio was measured with region of-interest analysis. RESULTS: Among 39 analyzable patients, 21 malignant tumors were identified in 21 patients. Eighteen of 21 tumors (86%) were seen on 99mTc sestamibi MBI and 19 of 21 (90%) were seen on 99mTc maraciclatide MBI (p = 1). Tumor extent measured with both radiopharmaceuticals correlated strongly with pathologic size (99mTc sestamibi, r = 0.84; 99mTc maraciclatide, r = 0.81). The L/B ratio in detected breast cancers was similar for the two radiopharmaceuticals: 1.55 +/- 0.36 (mean +/- S.D.) for 99mTc sestamibi and 1.62 +/- 0.37 (mean +/- S.D.) for 99mTc maraciclatide (p = 0.53). No correlation was found between the L/B ratio and molecular subtype for 99mTc sestamibi (r s = 0.12, p = 0.63) or 99mTc maraciclatide (r s = -0.12, p = 0.64). Of 20 benign lesions, 10 (50%) were seen on 99mTc sestamibi and 9 of 20 (45%) were seen on 99mTc maraciclatide images (p = 0.1). The average L/B ratio for benign lesions was 1.34 +/-0.40 (mean +/-S.D.) for 99mTc sestamibi and 1.41 +/-0.52 (mean +/ S.D.) for 99mTc maraciclatide (p = 0.75). Overall diagnostic performance was similar for both radiopharmaceuticals. AUC from ROC analysis was 0.83 for 99mTc sestamibi and 0.87 for 99mTc maraciclatide (p = 0.64). CONCLUSIONS: 99mTc maraciclatide offered comparable lesion uptake to 99mTc sestamibi, in both malignant and benign lesions. There was good correlation between lesion extent and uptake measured from both radiopharmaceuticals. 99mTc maraciclatide offered a marginal (but not significant) improvement in sensitivity over 99mTc sestamibi. Our findings did not support an association between the uptake of either radiopharmaceutical and tumor molecular subtype. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00888589. PMID- 28091981 TI - Environmental Pollutants, Limitations in Physical Functioning, and Frailty in Older Adults. AB - PURPOSE OF REVIEW: Frailty is an age-related syndrome characterized by reductions in strength, endurance, and physiologic function that increase an individual's vulnerability for developing dependence or death. Extensive research is currently being conducted to determine preventable risk factors and mechanistic pathways of frailty. This review summarizes the existing evidence on the potential associations between environmental pollutants, limitations in physical functioning, and frailty among older adults. RECENT FINDINGS: We found only a few studies evaluating the association between specific environmental pollutants and frailty. Cross-sectional studies suggest an association between second-hand smoke and lead exposure with the prevalence of functional limitations and frailty in older adults; they also suggest a link between cobaltum exposure and walking problems. One longitudinal study found an increased risk of frailty after PM2.5 exposure among individuals hospitalized with a myocardial infarction, while another found an inverse association between cadmium and phthalate exposure and hand-grip strength. There is a clear need for more studies to assess the effects of environmental pollution on physical functioning decline, frailty development, and its progression. Environmental and geriatric epidemiologists should work together to address important research challenges. PMID- 28091982 TI - Death from pulmonary embolism of cyanoacrylate glue following gastric varix endoscopic injection. AB - We present the case of a 25 year old woman with a complex past medical history including Crigler-Najjar syndrome (Type 1) with a liver transplant in 1993 and subsequent development of cirrhosis with portal hypertension in the transplanted liver. The deceased presented to hospital with hematemesis and investigations showed a large gastric varix. The varix was injected with cyanoacrylate glue. Within 30 min of injection the patient became acutely hypoxic. Urgent chest X-ray demonstrated radio opaque glue within the pulmonary arteries. It was evident that future treatment was futile and supportive treatment was withdrawn. The deceased was referred for medico legal post mortem examination. The post mortem CT scan performed prior to autopsy showed widespread radio-opaque material within the pulmonary arteries. At autopsy, rubbery grey/tan "clot" occluded the major proximal and segmental pulmonary arteries. Microscopic examination of the "clot" showed clumps of erythrocytes surrounded by foreign material. We discuss this relatively uncommon but well recognized complication of variceal injection with cyanoacrylate glue. PMID- 28091983 TI - Farming deaths - an ongoing problem. PMID- 28091984 TI - Fluid content protected lungs against heat, but not against carbon monoxide inhalation. PMID- 28091985 TI - Frequency of forensic toxicological analysis in external cause deaths among nursing home residents: an analysis of trends. AB - There is a paucity of research examining the utility of forensic toxicology in the investigation of premature external cause deaths of residents in nursing homes. The aim of this study is to describe the frequency and characteristics of toxicological analysis conducted in external cause (injury-related) deaths amongst nursing home residents in Victoria, Australia. This study was a retrospective cohort study examining external cause deaths among nursing home residents during the period July 1, 2000 to December 31, 2012 in Victoria, Australia, using the National Coronial Information System (NCIS). The variables examined comprised: sex, age group, year-of-death, cause and manner of death. One third of deaths among nursing home residents in Victoria resulted from external causes (n = 1296, 33.3%) of which just over one-quarter (361, 27.9%) underwent toxicological analysis as part of the medical death investigation. The use of toxicological analysis varied by cause of death with a relatively low proportion conducted in deaths from unintentional falls (n = 286, 24.9%) and choking (n = 36, 40.4%). The use of toxicological analysis decreased as the decedents age increased. Forensic toxicology has the potential to contribute to improving our understanding of premature deaths in nursing home residents however it remains under used and is possibly undervalued. PMID- 28091986 TI - Shift of microRNA profile upon glioma cell migration using patient-derived spheroids and serum-free conditions. AB - Glioblastoma multiforme (GBM) is the most frequent malignant primary brain tumor. A major reason for the overall median survival being only 14.6 months is migrating tumor cells left behind after surgery. Another major reason is tumor cells having a so-called cancer stem cell phenotype being therefore resistant towards traditional chemo- and radiotherapy. A group of novel molecular targets are microRNAs (miRNAs). MiRNAs are small non-coding RNAs exerting post transcriptional regulation of gene expression. The aim of this study was to identify differentially expressed miRNAs in migrating GBM cells using serum-free stem cell conditions. We used patient-derived GBM spheroid cultures for a novel serum-free migration assay. MiRNA expression of migrating tumor cells isolated at maximum migration speed was compared with corresponding spheroids using an OpenArray Real-Time PCR System. The miRNA profiling revealed 30 miRNAs to be differentially expressed. In total 13 miRNAs were upregulated and 17 downregulated in migrating cells compared to corresponding spheroids. The three most deregulated miRNAs, miR-1227 (up-regulated), miR-32 (down-regulated) and miR 222 (down-regulated), were experimentally overexpressed. A non-significantly increased migration rate was observed after miR-1227 overexpression. A significantly reduced migration rate was observed after miR-32 and miR-222 overexpression. In conclusion a shift in microRNA profile upon glioma cell migration was identified using an assay avoiding serum-induced migration. Both the miRNA profiling and the functional validation suggested that miR-1227 may be associated with increased migration and miR-32 and miR-222 with decreased migration. These miRNAs may represent potential novel targets in migrating glioma cells. PMID- 28091987 TI - Expression and prognostic value of microRNAs in lower-grade glioma depends on IDH1/2 status. AB - Histological and genomic characteristics are widely used in glioma management and research. This study investigated their relationship to the expression and prognostic value of microRNAs (miRNAs) in lower-grade glioma (LGG). A total of 447 LGG samples with available clinical and genomic information from The Cancer Genome Atlas database were reviewed. Samples with isocitrate dehydrogenase (IDH) 1/2 mutations (n = 366) were randomly divided into training and validation sets to establish and confirm a four-miRNA-based risk classifier. We found that IDH1/2 mutation status had greater impact than histological and other genomic features on miRNA expression patterns; 361/487 (74%) of miRNAs were differentially expressed according to IDH1/2 mutation status. Importantly, there were no miRNAs with the same prognostic significance among groups with different IDH1/2 mutation status. For IDH1/2-mut LGG, a four-miRNA risk classifier (miR-10b, miR-130b, miR 1304, and miR-302b) was established that could independently distinguish cases as high or low risk of poor prognosis in both training and validation sets. The risk classifier outperformed individual miRNAs and traditional prognostic factors in terms of sensitivity and specificity. Bioinformatic analyses indicated that high risk samples were more mitotically active than low-risk samples. Taken together, IDH1/2 mutation status had a significant influence on miRNA expression and prognostication in LGG. The four-miRNA-based risk classifier can be used for risk stratification of IDH1/2-mut LGG. PMID- 28091988 TI - Genotoxicity and cytotoxicity reduction of the polluted urban river after ecological restoration: a field-scale study of Jialu River in northern China. AB - To further treat the reclaimed municipal wastewater and rehabilitate the aquatic ecosystem of polluted urban rivers, an 18.5-km field-scale ecological restoration project was constructed along Jialu River, a polluted urban river which receives only reclaimed municipal wastewater from Zhengzhou City without natural upland water dilution. This study investigated the potential efficiency of water quality improvement, as well as genotoxicity and cytotoxicity reduction along the ecological restoration project of this polluted urban river. Results showed that the chemical oxygen demand (COD) and ammonia nitrogen (NH3-N) of the reclaimed municipal effluent were reduced by more than 45 and 70%, respectively, meeting the Chinese surface water environmental quality standard level IV, while the total phosphorus and metal concentrations had no significant reduction along the restoration project, and Pb concentrations in all river water samples exceeded permissible limit in drinking water set by WHO (2006) and China (GB5749-2006). The in vitro SOS/umu assay showed 4-nitroquinoline-1-oxide equivalent (4-NQO-EQ) values of reclaimed municipal wastewater of 0.69 +/- 0.05 MUg/L in April and 0.68 +/- 0.06 MUg/L in December, respectively, indicating the presence of genotoxic compounds. The results of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and hepatic cell apoptosis in zebrafish after a chorionic long-term (21 days) in vivo exposure also demonstrated that the reclaimed municipal wastewater caused significant DNA oxidative damage and cytotoxicity. After the ecological purification of 18.5-km field-scale restoration project, the genotoxicity assessed by in vitro assay was negligible, while the DNA oxidative damage and cytotoxicity in exposed fish were still significantly elevated. The mechanisms of DNA oxidative damage and cytotoxicity caused by the reclaimed municipal wastewater need further study. PMID- 28091989 TI - Hazardous metal pollution in a protected coastal area from Northern Patagonia (Argentina). AB - The San Antonio Bay is a protected natural coastal area of Argentina that has been exposed to mining wastes over the last three decades. Iron and trace metals of potential concern to biota and human health (Cd, Pb, Cu, and Zn) were investigated in the sediments from the bay and in the soils of the Pile (mining wastes). Concentrations of Cd (45 mg kg-1), Pb (42,853 mg kg-1), Cu (24,505 mg kg 1), and Zn (28,686 mg kg-1) in the soils Pile exceeded guidelines for agricultural, residential, and industrial land uses. Risk assessment due to exposure to contaminated soils (Pile) was performed. Hazard quotients were superior to non-risk (HQ >1) for all trace metals, while accumulative hazard quotient index indicated a high risk for children (HI = 93) and moderate for adults (HI = 9). In the bay, sediments closest to the Pile (mudflat and salt marsh) exceeded sediment quality guidelines for protection of biota. Results of different acid extraction methods suggest that most of the pseudototal content was potentially mobile. Principal component analysis indicated that the sites near the Pile (Encerrado channel) were more polluted than the distal ones. Tissues of Spartina spp. located within Encerrado channel showed the highest metal levels among all studied sites. These results show that the problem still persists and the mining wastes are the sources of the pollution. Furthermore, the Encerrado channel is a highly impacted area, as it is shown by their metal enriched sediments. PMID- 28091990 TI - Revaluation of stockpile amount of PFOS-containing aqueous film-forming foam in Japan: gaps and pitfalls in the stockpile survey. AB - Stockpiles of perfluoro-octane sulfonic acid (PFOS) containing aqueous film forming foam (AFFF) have the potential to be emitted by leaching, spills, and during use in fire response and other processes. Several studies have discussed the high levels of stockpiled PFOS-containing AFFF and the risk they pose to the environment; however, there are large gaps in the amounts in Japan compared with other countries. For example, 300 tons are stockpiled in Canada, 2200-2600 tons in Switzerland, 1400 tons in Norway, and 19,000 tons in Japan from their reports for publication. The gap is considered to be a result of lack of surveys of several important sources. In this study, we revaluated the stockpile of AFFF in Japan to verify the reported value and identify the source of this gap based on information available in peer-reviewed papers, governmental reports, and business reports. The major reason for the gap between Japan and other countries was considered to be the survey of stockpiles in car-parking facilities, which accounted for 46.7% of the total amounts in Japan, but were not considered in other countries. These stockpiles indicate a high potential for accidental leaching or spilling of the AFFF by careless storage. Therefore, it is recommended that continual surveys of the AFFF stockpile in car-parking facilities be conducted in the rest of the world. PMID- 28091991 TI - Trophic transfer and effects of gold nanoparticles (AuNPs) in Gammarus fossarum from contaminated periphytic biofilm. AB - This work addressed the trophic transfer and effects of functionalized gold nanoparticles (AuNPs) from periphytic biofilms to the crustacean Gammarus fossarum. Biofilms were exposed for 48 h to 10 nm positively charged functionalized AuNPs at two concentrations, 4.6 and 46 mg/L, and crustaceans G. fossarum grazed on these for 7 days, with daily biofilm renewal. Gold bioaccumulation in biofilm and crustacean were measured to estimate the trophic transfer ratio of these AuNP, and, for the first time, a transcriptomic approach and transmission electron microscopy observations in the crustacean were made. These two approaches showed cellular damage caused by oxidative stress and, in particular, an impact of these AuNPs on mitochondrial respiration. Modulation of digestive enzyme activity was also observed, suggesting modifications of digestive functions. The damage due to these nanoparticles could then have vital consequences for the organisms during chronic exposure. PMID- 28091992 TI - Analysing the correlations of long-term seasonal water quality parameters, suspended solids and total dissolved solids in a shallow reservoir with meteorological factors. AB - To explore the correlations among water quality parameters, suspended solids (SS) and total dissolved solids (TDS) with meteorological factors in a shallow reservoir in China, the long-term variations of water quality were considered. A non-parametric regression method, generalized additive models (GAM), was used to analyse the correlations among eleven physicochemical and biological parameters as well as three meteorological factors (wind speed, rainfall and solar radiation) which we collected from 2000 to 2011. The results indicate that the three meteorological factors may have positive effects on SS. Moreover, statistically significant correlations between many water quality parameters and SS or TDS were exhibited seasonally. The correlations between electrical conductivity (EC) and SS were opposite to correlations between EC and TDS. This finding reveals that TDS have a positive impact on EC, while EC negatively affects SS. The results indicated that many parameters, such as total nitrogen, total phosphorus, biological oxygen demand (BOD) and chemical oxygen demand (COD), were related to SS due to the adsorption of SS. Moreover, both positive and negative correlations between COD and TDS were observed in this freshwater reservoir. The positive correlation between chlorophyll a and SS suggested that the change of SS concentration in autumn was caused by the growth of algae. Meanwhile, significant correlations between SS and meteorological factors were also observed, indicating that meteorological factors had effects on SS dynamics. This study provides useful information regarding the correlations among water quality parameters, SS and TDS with meteorological factors in a freshwater reservoir. PMID- 28091994 TI - Source analysis of organic matter in swine wastewater after anaerobic digestion with EEM-PARAFAC. AB - Swine wastewater is one of the most serious pollution sources, and it has attracted a great public concern in China. Anaerobic digestion technology is extensively used in swine wastewater treatment. However, the anaerobic digestion effluents are difficult to meet the discharge standard. The results from batch experiments showed that plenty of refractory organic matter remained in the effluents after mesophilic anaerobic digestion for 30 days. The effluent total COD (tCOD) and soluble COD (sCOD) were 483 and 324 mg/L, respectively, with the sCOD/tCOD ratio of 0.671. Fluorescence excitation-emission matrix (EEM) coupled with parallel factor analysis (PARAFAC) revealed that the dissolved organic matter in the effluents was tryptophan-like substance, humic acid substance, and fulvic acid substance. Based on the appearance time during anaerobic digestion, tryptophan-like substance and humic acid substance were inferred to originate from the raw swine wastewater, and the fulvic acid substance was inferred to be formed in the anaerobic digestion. This work has revealed the source of residual organic matter in anaerobic digestion of swine wastewater and has provided some valuable information for the post-treatment. PMID- 28091993 TI - Bacterial community structure and prevalence of Pusillimonas-like bacteria in aged landfill leachate. AB - Although several works have been performed from an engineering point of view, a limited number of studies have focused on microbial communities involved in the humification of aged landfill leachates. In this work, cultivation techniques, next-generation sequencing, and phospholipid fatty acid analysis were adopted to decrypt the diversity and the ecophysiological properties of the dominant microbiota in aged landfill leachate. Based on Illumina sequencing, Betaproteobacteria, Bacteroidetes, Actinobacteria, and Alphaproteobacteria dominated the aged landfill leachate. The main taxa identified at genus level were Pusillimonas-like bacteria and Leucobacter (41.46% of total reads), with all of them being also isolated through cultivation. The presence of Pusillimonas like bacteria was also verified by the detection of cyclo17:0 and iso-19:0 fatty acids in aged landfill leachate microbiota. Despite that almost all bacterial isolates exhibited extracellular lipolytic ability, no particular specificity was observed in the type of substrate utilized. The prevalence of effective degraders, such as Pusillimonas-like bacteria, makes the aged landfill leachate an ideal source for isolation of novel microorganisms with potential in situ bioremediation uses. PMID- 28091995 TI - Biodegradability of fluoxetine, mefenamic acid, and metoprolol using different microbial consortiums. AB - The biodegradation of fluoxetine, mefenamic acid, and metoprolol using ammonium nitrite-oxidizing consortium, nitrite-oxidizing consortium, and heterotrophic biomass was evaluated in batch tests applying different retention times. The ammonium-nitrite-oxidizing consortium presented the highest biodegradation percentages for mefenamic acid and metoprolol, of 85 and 64% respectively. This consortium was also capable to biodegrade 79% of fluoxetine. The heterotrophic consortium showed the highest ability to biodegrade fluoxetine reaching 85%, and it also had a high potential for biodegrading mefenamic acid and metoprolol, of 66 and 58% respectively. The nitrite-oxidizing consortium presented the lowest biodegradation of the three pharmaceuticals, of less than 48%. The determination of the selected pharmaceuticals in the dissolved phase and in the biomass indicated that biodegradation was the major removal mechanism of the three compounds. Based on the obtained results, the biodegradation kinetics was adjusted to pseudo-first-order for the three pharmaceuticals. The values of k biol for fluoxetine, mefenamic acid, and metoprolol determined with the three consortiums indicated that ammonium-nitrite-oxidizing and heterotrophic biomass allow a partial biodegradation of the compounds, while no substantial biodegradation can be expected using nitrite-oxidizing consortium. Metoprolol was the less biodegradable compound. The sorption of fluoxetine and mefenamic acid onto biomass had a significant contribution for their removal (6-14%). The lowest sorption coefficients were obtained for metoprolol indicating that the sorption onto biomass is poor (3-4%), and the contribution of this process to the global removal can be neglected. PMID- 28091996 TI - Zeolitic tuffs for acid mine drainage (AMD) treatment in Ecuador: breakthrough curves for Mn2+, Cd2+, Cr3+, Zn2+, and Al3. AB - Zeolitic tuff constitutes a technical and economical feasible alternative to manage acidic waters in initial phases of generation. A study of cation exchange with two zeolitic tuffs from Ecuador and one from Cuba has been conducted using breakthrough curve methodology. Cations Mn2+, Cd2+, Cr3+, Zn2+, and Al3+ have been chosen owing to their presence in underground water in exploration activities (decline development) in Fruta del Norte (Ecuador). Zeolites characterized by X-ray diffraction and thermal stability after heating overnight as heulandites show a similar exchange behavior for the five cations studied. The clinoptilolite sample Tasajeras shows a relevant cation exchange performance expressed in the important increment of spatial time to reach the breakthrough point in comparison with heulandite samples. The maximum length of unused beds was found for Cr3+ and Zn2+ cations showing, therefore, a lower adsorption performance in relation with Mn2+ and Cd2+. A final disposal method of metal loaded zeolites with cement is proposed. PMID- 28091997 TI - Comparative assessment of metallurgical recovery of metals from electronic waste with special emphasis on bioleaching. AB - Waste electrical and electronic equipment (WEEE) or electronic waste (e-waste) is one of the fastest growing waste streams in the urban environment worldwide. The core component of printed circuit board (PCB) in e-waste contains a complex array of metals in rich quantity, some of which are toxic to the environment and all of which are valuable resources. Therefore, the recycling of e-waste is an important aspect not only from the point of waste treatment but also from the recovery of metals for economic growth. Conventional approaches for recovery of metals from e waste, viz. pyrometallurgical and hydrometallurgical techniques, are rapid and efficient, but cause secondary pollution and economically unviable. Limitations of the conventional techniques have led to a shift towards biometallurgical technique involving microbiological leaching of metals from e-waste in eco friendly manner. However, optimization of certain biotic and abiotic factors such as microbial species, pH, temperature, nutrients, and aeration rate affect the bioleaching process and can lead to profitable recovery of metals from e-waste. The present review provides a comprehensive assessment on the metallurgical techniques for recovery of metals from e-waste with special emphasis on bioleaching process and the associated factors. PMID- 28091998 TI - Palliative effects of extra virgin olive oil, gallic acid, and lemongrass oil dietary supplementation on growth performance, digestibility, carcass traits, and antioxidant status of heat-stressed growing New Zealand White rabbits. AB - This study explored the effects of supplemental dietary extra virgin olive oil (EVOO), gallic acid (GA), or lemongrass essential oil (LGEO) on growth performance, nutrient digestibility, carcass traits, lipid peroxidation, hematological, and antioxidative status in growing rabbits under heat stress conditions. A total of 48 male growing New Zealand White rabbits were randomly divided into four equal groups, which received a basal diet without any supplementation or supplemented with 15 g EVOO, 500 mg GA, or 400 mg LGEO/kg of diet, for eight consecutive weeks. Results revealed that the overall mean of temperature humidity index was 84.67 +/- 0.35, reflecting a state of severe heat stress. Moreover, dietary supplementation with EVOO, GA, or LGEO significantly increased live body weight and daily body weight gain but decreased both feed conversion ratio and daily water consumption. Additionally, a significant increase in both organic matter and crude protein digestibility besides a remarkable elevation in the nutritive values of digestible crude protein, total digestible nutrients, and digestible energy, as well as an increase in the numbers of WBCs, lymphocytes, and heterophils was significant in EVOO supplemented rabbits. Supplementation with EVOO, GA, or LGEO in the heat-stressed growing rabbit's diet enhanced catalase activity and reduced glutathione content, whereas EVOO-treated rabbits had the highest values. Also, malondialdehyde activity was reduced in response to all tested additives. In conclusion, these findings suggested that addition of EVOO, GA, or LGEO in growing rabbit's diet could be used effectively to alleviate negative impacts of heat stress load on performance, nutrient digestibility, oxidative status, and hemato-biochemical features. Furthermore, among these additives, EVOO achieved the best effects. PMID- 28091999 TI - Porous nano-cerium oxide wood chip biochar composites for aqueous levofloxacin removal and sorption mechanism insights. AB - The adsorption removal of levofloxacin (LEV), a widely used fluoroquinolone antibiotic, by using the biochars derived from the pyrolysis of pine wood chip pretreated with cerium trichloride was investigated through batch sorption experiments and multiple characterization techniques. The differences in the basic physicochemical properties between Ce-impregnated biochars and the pristine biochars were confirmed by the analysis of elemental compositions, specific surface areas, energy dispersive spectrometry, X-ray diffraction, and thermo gravimetry. FT-IR spectra of the pre- and post-sorption biochars confirmed the chemical adsorption for LEV sorption onto the biochars. Large shifts in the binding energy of Ce3d, O1s, C1s, and N1s regions on the pre- and post-sorption biochars indicated the surface complexation of LEV molecule onto the biochars. The binding species of Ce4+ and Ce3+ identified by X-ray photoelectron spectroscopy reflect the role of Ce oxides during sorption. Batch adsorption showed the significant enhancement of adsorption capacity for LEV after the Ce modification. Batch adsorption kinetic data fitted well with the pseudo-second order model. Both the Langmuir and the Freundlich models reproduced the isotherm data well. Findings from this work indicated that Ce-impregnated biochars can be effective for the removal of aqueous LEV. PMID- 28092000 TI - Direct and indirect effects of wastewater use and herd environment on the occurrence of animal diseases and animal health in Pakistan. AB - The use of wastewater for rearing domestic animals is a common phenomenon in most of the developing countries like Pakistan that face a serious shortage of freshwater resources. However, most of the literature has only focused on the indirect effects of wastewater use on animal health or productivity, and literature on the direct effects of wastewater use is rare. Therefore, this study aims to investigate the direct and indirect effects of wastewater usage on the prevalence of animal diseases and animal health in Pakistan. The study is based on a household-level survey of 360 domestic water buffalo herds collected from 12 districts of Punjab Province, Pakistan. We tested the prevalence of the animal's diseases, animal's health, and wastewater-use preference with various econometric tools, such as the Poisson, negative binomial, and logistic regressions. The findings of the study show that the majority of the farmers use wastewater for buffalo bathing due to the shortage of freshwater resources. Results explore the prevalence of diseases such as clinical mastitis, tick infestation, and foot and mouth disease at the farm level significantly associated with buffalo bathing in the wastewater. Moreover, bathing in wastewater pre- and post-milking also plays a role in the occurrence of diseases. Particularly, if the buffalo's access to wastewater for bathing is within 60 min after milking, the probability of the animals being exposed to mastitis is higher. Furthermore, on investigation, a number of factors are found, such as the distance to the water source, power shortage, groundwater availability, and the education of farmers that influence farmers' behavior of letting their animals take a bath in wastewater. Moreover, the use of different preventive measures improves the animal's health. PMID- 28092001 TI - Genotypic differences in cadmium transport in developing barley grains. AB - Genotypic differences in cadmium (Cd) transport in developing grains of barley (Hordeum vulgare L.) were investigated using detached ears cultured in a nutrient solution containing 0.5 and 5 MUM Cd. Cd concentration in each part of the ear in W6nk2 (a low-grain-Cd-accumulation genotype) was much less than in Zhenong8 (a high accumulator) with 0.5 MUM Cd treatment. However, Cd concentration in W6nk2 grains increased with an increase in external Cd level and was similar to Zhenong8 with 5 MUM Cd treatment. Awn removal, a high relative humidity (RH, 90%) and addition of sucrose markedly decreased grain Cd concentration in Zhenong8 but less affected Cd transport to grain in W6nk2. Stem girdling reduced Cd transport to developing grains with 5 MUM Cd treatment, especially for W6nk2, whereas no effect was found in either genotype with low Cd treatment. Our results suggested that higher grain Cd in Zhenong8 is closely related to a larger capacity for xylem transport and is connected with Cd translocation in xylem and phloem sap. PMID- 28092002 TI - Adaptation of primocane fruiting raspberry plants to environmental factors under the influence of Bacillus strains in Western Siberia. AB - In geographical locations with a short vegetative season and continental climate that include Western Siberia, growing primocane fruiting raspberry varieties becomes very important. However, it is necessary to help the plants to overcome the environmental stress factors. This study aimed to evaluate the impact of the pre-planting treatment of primocane fruiting raspberry root system with Bacillus strains on the following plant development under variable environmental conditions. In 2012, Bacillus subtilis RCAM V-10641, Bacillus amyloliquefaciens RCAM V-10642, and Bacillus licheniformis RCAM V-10562 were used for inoculating the root system of primocane fruiting raspberry cultivar Nedosyagaemaya before planting. The test suspensions were 105 CFU/ml for each bacterial strains. The effects of this treatment on plant growth and crop productivity were estimated in 2012-2015 growing seasons differed by environmental conditions. The pre-planting treatment by the bacterial strains increased the number of new raspberry canes and the number of plant generative organs as well as crop productivity compared to control. In addition, these bacilli acted as the standard humic fertilizer. Variable environmental factors such as air temperature, relative humidity, and winter and spring frosts seriously influenced the plant biological parameters and crop productivity of control plants. At the same time, the pre-planting primocane fruiting root treatment by Bacillus strains decreased the negative effects of abiotic stresses on plants in all years of the research. Of the three strains studied, B. subtilis was shown to reveal the best results in adaptation of primocane fruiting raspberry plants to environmental factors in Western Siberia. For the first time, the role of Bacillus strains in enhancing frost resistance in primocane fruiting raspberry plants was shown. These bacilli are capable of being the basis of multifunctional biological formulations for effective plant and environmental health management in growing primocane fruiting raspberry. PMID- 28092003 TI - Validated electrochemical and chromatographic quantifications of some antibiotic residues in pharmaceutical industrial waste water. AB - Realistic implementation of ion selective electrodes (ISEs) into environmental monitoring programs has always been a challenging task. This could be largely attributed to difficulties in validation of ISE assay results. In this study, the electrochemical response of amoxicillin trihydrate (AMX), ciprofloxacin hydrochloride (CPLX), trimethoprim (TMP), and norfloxacin (NFLX) was studied by the fabrication of sensitive membrane electrodes belonging to two types of ISEs, which are polyvinyl chloride (PVC) membrane electrodes and glassy carbon (GC) electrodes. Linear response for the membrane electrodes was in the concentration range of 10-5-10-2 mol/L. For the PVC membrane electrodes, Nernstian slopes of 55.1, 56.5, 56.5, and 54.0 mV/decade were achieved over a pH 4-8 for AMX, CPLX, and NFLX, respectively, and pH 3-6 for TMP. On the other hand, for GC electrodes, Nernstian slopes of 59.1, 58.2, 57.0, and 58.2 mV/decade were achieved over pH 4 8 for AMX, CPLX, and NFLX, respectively, and pH 3-6 for TMP. In addition to assay validation to international industry standards, the fabricated electrodes were also cross-validated relative to conventional separation techniques; high performance liquid chromatography (HPLC), and thin layer chromatography (TLC) densitometry. The HPLC assay was applied in concentration range of 0.5-10.0 MUg/mL, for all target analytes. The TLC-densitometry was adopted over a concentration range of 0.3-1.0 MUg/band, for AMX, and 0.1-0.9 MUg/band, for CPLX, NFLX, and TMP. The proposed techniques were successfully applied for quantification of the selected drugs either in pure form or waste water samples obtained from pharmaceutical plants. The actual waste water samples were subjected to solid phase extraction (SPE) for pretreatment prior to the application of chromatographic techniques (HPLC and TLC-densitometry). On the other hand, the fabricated electrodes were successfully applied for quantification of the antibiotic residues in actual waste water samples without any pretreatment. This finding assures the suitability of the fabricated ISEs for environmental analysis. PMID- 28092004 TI - Bio-based degradation of emerging endocrine-disrupting and dye-based pollutants using cross-linked enzyme aggregates. AB - In this study, manganese peroxidase (MnP) from an indigenous white-rot fungus Ganoderma lucidum IBL-05 was insolubilized in the form of cross-linked enzyme aggregates (CLEAs) using various aggregating agents, i.e., acetone, ammonium sulfate, ethanol, 2-propanol, and tert-butanol, followed by glutaraldehyde (GA) cross-linking. The precipitant type, MnP, and GA concentrations affected the CLEAs activity recovery and aggregation yield. Among precipitants used, acetone appeared to be the most efficient aggregation agent, providing the highest activity recovery and aggregation yield of 31.26 and 73.46%, respectively. Optimal cross-linking was noticed using 2.0% (v/v) GA and 8:1 (v/v) MnP to GA ratio at 3.0 h cross-linking time under continuous agitation at 4 degrees C. The highest recovered activity and aggregation yield were determined to be 47.57 and 81.26%, respectively. The MnP-CLEAs, thus synthesized, were tested to investigate their bio-catalytic capacity for removing two known endocrine-disrupting chemicals (EDCs), e.g., nonylphenol and triclosan in a packed bed reactor system. The insolubilized MnP efficiently catalyzed the biodegradation of both EDCs, transforming over 80% in the presence of MnP-based system. A maximal of 100% decolorization was recorded for Sitara textile (SIT-based) effluent, followed by 95.5% for Crescent textile (CRT-based) effluent, 88.0% for K&N textile (KIT based) effluent, and 84.2% for Nishat textile (NIT-based) effluent. PMID- 28092005 TI - Investigation of diethylstilbestrol residue level in human urine samples by a specific monoclonal antibody. AB - Diethylstilbestrol (DES) is used as a kind of animal feed additive and affects people's health through the food chain. The purpose of this study is to detect the residue level of DES in 576 human urine samples directly. DES-BSA was used to immunize Balb/c mice. The monoclonal antibody was produced by hybridoma that was screened through cell fusion techniques. Finally, we developed the indirect competitive ELISA method to analyze 576 human urine samples from Zhejiang Province, China. The IC50 of this method was 3.33 ng/mL. The LOD and LOQ were 0.16 and 0.54 ng/mL. Linear range of the standard curve was from LOD to 12.50 ng/mL. There was no cross-reactivity with two kinds of estrogens and two structural analogs with DES. Five hundred seventy-six urine samples were analyzed by the indirect competitive ELISA method, and the detection rate was 98.78%. The mean concentration and geometric mean were 4.70 and 3.50 ng/mL. The indirect competitive ELISA method based on monoclonal antibody was sensitive and reliable for the detection of DES in human urine samples. The results warned us to pay more attention to human health and food safety. PMID- 28092006 TI - The efficiency of Eichhornia crassipes in the removal of organic and inorganic pollutants from wastewater: a review. AB - Water is a basic necessity of life, but due to overextraction and heavy input of nutrients from domestic and industrial sources, the contamination level of water bodies increase. In the last few decades, a potential interest has been aroused to treat wastewater by biological methodologies before discharge into the natural water bodies. Phytoremediation using water hyacinth is found to be an effective biological wastewater treatment method. Water hyacinth (Eichhornia crassipes), a notorious weed, being the most promising plant for removal of contaminants from wastewater is studied extensively in this regard. It has been successfully used to accumulate heavy metals, dyes, radionuclides, and other organic and inorganic contaminants from water at laboratory, pilot, and large scale. The plant materials are also being used as sorbent to separate the contaminant from water. Other than phytoremediation, the plant has been explored for various other purposes like ethanol production and generation of biogases and green manures. Such applications of this have been good support for the technocrats in controlling the growth of the plant. The present paper reviews the phytoremedial application of water hyacinth and its capability to remove contaminants in produced water and wastewater from domestic and isndustrial sources either used as a whole live plant grown in water or use of plant body parts as sorbent has been discussed. PMID- 28092007 TI - Study of the genotoxicity of organic extracts from wastewater-irrigated vegetables using in vitro and in vivo biological tests. AB - The purpose of this study was to explore genotoxicity due to organic pollutants in wastewater-irrigated vegetables using biological and chemical analyses. Chinese cabbages from wastewater-irrigated farmland were taken as the research object. For the in vitro test, DNA damage was characterized in rat hepatocytes exposed to organic extracts from the cabbages using the comet assay. For the in vivo tests, mice were exposed to organic extracts from the cabbages. DNA damage was assessed in mouse peripheral blood lymphocytes (PBLs), and chromosome damage was assessed in bone marrow cells using the comet assay and micronucleus test, respectively. For the chemical analysis, gas chromatography-mass spectrometry (GC/MS) was used to analyze the organic compounds in the organic vegetable extracts. The in vitro test results showed that the comet tail lengths of the DNA in rat hepatocytes were significantly increased in the group dosed with 0.36 g/ml (P < 0.05), and the comet tailing rates of the hepatocytes were significantly increased in the groups dosed with 0.24 and 0.36 g/ml (P < 0.05). The in vivo test results indicated that the comet tail lengths of the DNA in mouse PBLs were increased in the low- and high-dose groups and that the comet tailing rate of the PBLs was increased in the high-dose group (P < 0.05). The chemical analysis results showed that the total organic content in the organic vegetable extracts from the wastewater-irrigated area (1.355 mg/kg) was significantly higher than the content in the cabbage samples from the clean-water-irrigated area (0.089 mg/kg). This finding indicated that wastewater irrigation can cause organic pollution with genetic toxicity in vegetables. This study also showed that in vivo and in vitro biological tests can reflect the joint toxicity of organic pollutants, and the test results were in accordance with the chemical analysis of the organic pollutant compositions. PMID- 28092008 TI - Spatio-temporal variation of septage characteristics of a semi-arid metropolitan city in a developing country. AB - Septage is the solid sludge that accumulates in septic tanks over a period of time. Many of the developing countries in the world face the challenging task of septage management. Due to the high variability in the nature of septage, there is a need to study its physical and chemical characteristics in order to suggest a sustainable treatment methodology. The present study deals with the characterization of septage collected from different locations of Chennai city in India, in two different seasons (summer and winter). The characterization includes parameters such as solids, organics, inorganics, nutrients and heavy metals. Septage showed significant difference in concentrations of pollutants from one season to the other (p > 0.05). The average total solids concentration is found to be 1.6 times higher during winter season than compared to summer season. Average concentrations of solids were 2185 +/- 1070 and 3555 +/- 2935 mg/L during summer and winter, respectively. Liquid characterization of septage showed total chemical oxygen demands (COD) of 905 +/- 603 mg/L (summer) and 1460 +/- 1295 mg/L (winter). Similarly, average soluble biochemical oxygen demand (sBOD) was found to be 117 +/- 54 mg/L during summer and 211 +/- 220 mg/L during winter season. Studies also showed that septage was rich in nutrients such as total nitrogen (4-500 mg/L), ammoniacal nitrogen (2-129 mg/L), total phosphate (5 236 mg/L) and heavy metals such as copper, zinc, lead and manganese. Overall characterization indicates that the collected septage samples are highly variable in nature with respect to sources, season and locations of collection. As the septage is rich in organic matter and nutrients, it can be used as a resource like soil conditioner or as a substitute for chemical fertilizer in agriculture, after proper treatment, leading to a new evolution in sanitation. PMID- 28092009 TI - Polycyclic aromatic hydrocarbons (PAHs) determined by pine needles and semipermeable membrane devices along an altitude profile in Taurus Mountains, Turkey. AB - Polycyclic aromatic hydrocarbons (PAHs) were analyzed at different altitudes of Taurus Mountains in semipermeable membrane devices (SPMD) and in half-, one-and-a half-, and two-and-a-half-year-old pine needles. SPMDs were deployed for three different exposure periods: March to September (Summer), September to March (Winter), and March to March (whole year) at eight sites where needle samples were collected. The values of PAHs in needles were between 4.4 to 6066 pg g/fw in half-year-old, 7.2 to 111,115 pg g/fw in 1.5-year-old, and 9.7 to 85,335 pg g/fw in 2.5-year-old needles. Mass of PAHs collected by SPMDs varied from scenario 1 > scenario 3, with Hubei and Guangdong the provinces with the largest increase and decrease ratios, respectively. (3) In the same scenario, the quota allocation varies in different reduction criteria emphases; if the government emphasizes reduction efficiency, scheme 1 will show obvious adjustment, that is, Hunan, Hubei, Guizhou, and Yunnan will have the largest decrease. The amounts are 4.28, 8.31, 4.04, and 5.97 million tons, respectively. PMID- 28092011 TI - Microbubble moving in blood flow in microchannels: effect on the cell-free layer and cell local concentration. AB - Gas embolisms can hinder blood flow and lead to occlusion of the vessels and ischemia. Bubbles in microvessels circulate as tubular bubbles (Taylor bubbles) and can be trapped, blocking the normal flow of blood. To understand how Taylor bubbles flow in microcirculation, in particular, how bubbles disturb the blood flow at the scale of blood cells, experiments were performed in microchannels at a low Capillary number. Bubbles moving with a stream of in vitro blood were filmed with the help of a high-speed camera. Cell-free layers (CFLs) were observed downstream of the bubble, near the microchannel walls and along the centerline, and their thicknesses were quantified. Upstream to the bubble, the cell concentration is higher and CFLs are less clear. While just upstream of the bubble the maximum RBC concentration happens at positions closest to the wall, downstream the maximum is in an intermediate region between the centerline and the wall. Bubbles within microchannels promote complex spatio-temporal variations of the CFL thickness along the microchannel with significant relevance for local rheology and transport processes. The phenomenon is explained by the flow pattern characteristic of low Capillary number flows. Spatio-temporal variations of blood rheology may have an important role in bubble trapping and dislodging. PMID- 28092012 TI - Results of a randomized controlled trial analyzing telemedically supported case management in the first year after living donor kidney transplantation - a budget impact analysis from the healthcare perspective. AB - : ?: We analyze one-year costs and savings of a telemedically supported case management program after kidney transplantation from the perspective of the German Healthcare System. Recipients of living donor kidney transplantation (N = 46) were randomly allocated to either (1) standard aftercare or (2) standard aftercare plus additional telemedically supported case management. A range of cost figures of each patient's medical service utilization were calculated at month 3, 6 and 12 and analyzed using two-part regression models. In comparison to standard aftercare, patients receiving telemedically supported case management are associated with substantial lower costs related to unscheduled hospitalizations (mean difference: ?3,417.46 per patient for the entire one-year period, p = 0.003). Taking all cost figures into account, patients receiving standard aftercare are associated, on average, with one-year medical service utilization costs of ?10,449.28, while patients receiving telemedically supported case management are associated with ?5,504.21 of costs (mean difference: ? 4,945.07 per patient, p < 0.001). With estimated expenditures of ?3,001.5 for telemedically supported case management of a single patient, we determined a mean difference of ?1,943.57, but this result is not statistically significant (p = 0.128). Sensitivity analyses show that the program becomes cost-neutral at around ten participating patients, and was beneficial starting at 15 patients. Routine implementation of telemedically supported case management in German medium and high-volume transplant centers would result in annual cost savings of ?791,033 for the German healthcare system. Patients with telemedically supported case management showed a lower utilization of medical services as well as better medical outcomes. Therefore, such programs should be implemented in medium and high-volume transplant centers. TRIAL REGISTRATION: DRKS00007634 ( http://www.drks.de/DRKS00007634 ). PMID- 28092013 TI - Sharpening the cutting edge: additional considerations for the UK debates on embryonic interventions for mitochondrial diseases. AB - In October 2015 the UK enacted legislation to permit the clinical use of two cutting edge germline-altering, IVF-based embryonic techniques: pronuclear transfer and maternal spindle transfer (PNT and MST). The aim is to use these techniques to prevent the maternal transmission of serious mitochondrial diseases. Major claims have been made about the quality of the debates that preceded this legislation and the significance of those debates for UK decision making on other biotechnologies, as well as for other countries considering similar legislation. In this article we conduct a systematic analysis of those UK debates and suggest that claims about their quality are over-stated. We identify, and analyse in detail, ten areas where greater clarity, depth and nuance would have produced sharper understandings of the contributions, limitations and wider social impacts of these mitochondrial interventions. We explore the implications of these additional considerations for (i) the protection of all parties involved, should the techniques transfer to clinical applications; (ii) the legitimacy of focussing on short-term gains for individuals over public health considerations, and (iii) the maintenance and improvement of public trust in medical biotechnologies. We conclude that a more measured evaluation of the content and quality of the UK debates is important and timely: such a critique provides a clearer understanding of the possible, but specific, contributions of these interventions, both in the UK and elsewhere; also, these additional insights can now inform the emerging processes of implementation, regulation and practice of mitochondrial interventions. PMID- 28092014 TI - A Rare Entity of Gastrointestinal Stromal Tumour Arising from a Meckel's Diverticulum: a Case Report. PMID- 28092016 TI - Testing Event-Based Forms of Causality. AB - Three fundamental types of causal relations are those of necessity, sufficiency, and necessity and sufficiency. These types are defined in contexts of categorical variables or events. Using statement calculus or Boolean algebra, one can determine which patterns of events are in support of a particular form of causal relation. In this article, we approach the analysis of these forms of causality taking the perspective of the analyst of empirical data. It is proposed using Configural Frequency Analysis (CFA) to test hypotheses about type of causal relation. Models are proposed for two-variable and multi-variable cases. Two CFA approaches are proposed. In the first, individual patterns (configurations) are examined under the question whether they are in support of a particular type of causal relation. In the second, patterns that are in support are compared with corresponding patterns that are not in support. In an empirical example, hypotheses are tested on the prediction of sustainability of change in dietary fat intake habits. PMID- 28092015 TI - Enhancing Cognitive Functioning in Healthly Older Adults: a Systematic Review of the Clinical Significance of Commercially Available Computerized Cognitive Training in Preventing Cognitive Decline. AB - Successfully assisting older adults to maintain or improve cognitive function, particularly when they are dealing with neurodegenerative disorders such as Alzheimer's disease (AD), remains a major challenge. Cognitive training may stimulate neuroplasticity thereby increasing cognitive and brain reserve. Commercial brain training programs are computerized, readily-available, easy-to administer and adaptive but often lack supportive data and their clinical validation literature has not been previously reviewed. Therefore, in this review, we report the characteristics of commercially available brain training programs, critically assess the number and quality of studies evaluating the empirical evidence of these programs for promoting brain health in healthy older adults, and discuss underlying causal mechanisms. We searched PubMed, Google Scholar and each program's website for relevant studies reporting the effects of computerized cognitive training on cognitively healthy older adults. The evidence for each program was assessed via the number and quality (PEDro score) of studies, including Randomized Control Trials (RCTs). Programs with clinical studies were subsequently classified as possessing Level I, II or III evidence. Out of 18 identified programs, 7 programs were investigated in 26 studies including follow-ups. Two programs were identified as possessing Level I evidence, three programs demonstrated Level II evidence and an additional two programs demonstrated Level III evidence. Overall, studies showed generally high methodological quality (average PEDro score = 7.05). Although caution must be taken regarding any potential bias due to selective reporting, current evidence supports that at least some commercially available computerized brain training products can assist in promoting healthy brain aging. PMID- 28092017 TI - Transanal total mesorectal excision for a large leiomyosarcoma at the lower rectum: a case report and literature review. AB - BACKGROUND: Rectal leiomyosarcoma (LMS) is an extremely rare disease. Previously, LMS was not properly distinguishable from gastrointestinal stromal tumor (GIST) until c-kit, a characteristic marker of GIST, was discovered in 1998. No standard therapeutic strategy for gastrointestinal LMS has been established except for surgical resection because of its rarity. Rectal LMS is often accompanied by symptoms, which can enable detection at a small size. However, when a large LMS is detected at the lower rectum, it is difficult to excise due to the narrow pelvic space. CASE PRESENTATION: We present the case of an 86-year-old man with a large LMS. The LMS was asymptomatic and incidentally found at the lower rectum when he visited another hospital for management of benign prostatic hypertrophy. An abdominoperineal resection of the rectum was performed with combined resection of both seminal vesicles and a part of the prostate because tumor invasion was suspected. We used the hybrid method of laparoscopic and transanal total mesorectal excision (TaTME) approaches to achieve negative surgical margins. Late onset urethral injury occurred in the postoperative course, which was successfully treated with a urethral catheter. The patient was discharged and received no adjuvant therapy. Local recurrence did not occur, but multiple lung metastases were detected 4 months later and the patient died 12 months after the surgery. CONCLUSIONS: This is the first report of the hybrid method of laparoscopic and TaTME approaches to remove a large LMS at the lower rectum. PMID- 28092018 TI - Bladder dysfunction in multiple sclerosis: a 6-year follow-up study. AB - Bladder dysfunction (BD) is the most common autonomic disturbance in multiple sclerosis, but often overlooked and undertreated. The purpose of this longitudinal study was to explore the changes in the frequency of BD symptoms in MS cohort after a period of 3 and 6 years of follow-up, as well as to investigate the correlations between the presence of BD symptoms and both clinical characteristics and the health-related quality of life (HRQoL) at each subsequent point of estimation. The study population comprises a cohort of 93 patients with MS (McDonald's criteria, 2001). At each time point (baseline, and at the 3- and 6 year follow-up) of estimation, Expanded Disability Status Scale, Hamilton Rating Scale for Depression, Fatigue Severity Scale, Szasz Sexual Functioning Scale and HRQoL (measured by MSQoL-54) were assessed. The proportion of patients with at least one symptom of BD significantly increased over time, for both men and women (from 48.1% at baseline to 51.9% after 3 years and to 71.4% after 6 years of follow-up for males and from 45.5% at baseline to 50.0% after 3 years and to 66.7% after 6 years of follow-up for females). The most common BD problem was urgency of urination. The presence of BD was statistically significantly associated with higher level of physical disability, sexual dysfunction and HRQoL at each point of follow-up, for both men and women. Our results suggested outstanding frequency of BD in patients with MS, with increasing tendency over time. PMID- 28092019 TI - URB597 and the Cannabinoid WIN55,212-2 Reduce Behavioral and Neurochemical Deficits Induced by MPTP in Mice: Possible Role of Redox Modulation and NMDA Receptors. AB - Several physiological events in the brain are regulated by the endocannabinoid system (ECS). While synthetic cannabinoid receptor (CBr) agonists such as WIN55,212-2 act directly on CBr, agents like URB597, a fatty acid amide hydrolase (FAAH) inhibitor, induce a more "physiological" activation of CBr by increasing the endogenous levels of the endocannabinoid anandamide (AEA). Herein, we compared the pre- and post-treatment efficacy of URB597 and WIN55,212-2 on different endpoints evaluated in the toxic model produced by the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. MPTP (40 mg/kg, s.c., single injection) decreased locomotor activity, depleted the striatal and nigral levels of dopamine (DA), augmented the levels of lipid peroxidation and protein carbonylation in both regions, decreased the striatal protein levels of tyrosine hydroxylase, and increased the striatal protein content of the subunit 1 (NR1) of the N-methyl-D-aspartate receptor (NMDAr). Both URB597 (0.3 mg/kg, i.p., once a day) and WIN55,212-2 (10 MUg/kg, i.p., twice a day), administered for five consecutive days, either before or after the MPTP injection, prevented the alterations elicited by MPTP and downregulated NMDAr. Our results support a modulatory role of the ECS on the toxic profile exerted by MPTP in mice via the stimulation of antioxidant activity and the induction of NMDAr downregulation and hypofunction, and favor the stimulation of CBr as an effective experimental therapeutic strategy. PMID- 28092020 TI - Early-Life Social Isolation-Induced Depressive-Like Behavior in Rats Results in Microglial Activation and Neuronal Histone Methylation that Are Mitigated by Minocycline. AB - Early-life stress is a potent risk factor for development of psychiatric conditions such as depression. The underlying mechanisms remain poorly understood. Here, we used the early-life social isolation (ESI) model of early life stress in rats to characterize development of depressive-like behavior, the role of microglia, levels of histone methylation, as well as expression of glutamate receptor subunits in the hippocampus. We found that depressive-like behavior was induced after ESI as determined by sucrose preference and forced swimming tests. Increased expression of microglial activation marker, Iba1, was observed in the hippocampus of the ESI group, while expression of the microglial CD200 receptor, which promotes microglial quiescence, significantly decreased. In addition, increased levels of proinflammatory cytokines, interleukin 1beta (IL 1beta), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) were observed in the hippocampus of the ESI group. Moreover, ESI increased levels of neuronal H3K9me2 (a repressive marker of transcription) and its associated "writer" enzymes, G9a and G9a-like protein, in the hippocampus. ESI also decreased expression of hippocampal NMDA receptor subunits, NR1, and AMPA receptor subunits, GluR1 and GluR2, which are involved in synaptic plasticity, but it did not affect expression of PSD95 and NR2B. Interestingly, treatment with minocycline to block microglial activation induced by ESI inhibited increases in hippocampal microglia and prevented ESI-induced depressive-like behavior as well as increases in IL-1beta, IL-6, and TNF-alpha. Notably, minocycline also triggered downregulation of H3K9me2 expression and restored expression of NR1, GluR1, and GluR2. These results suggest that ESI induces depressive-like behavior, which may be mediated by microglial signaling. PMID- 28092021 TI - Sunshine vitamin and thyroid. AB - Vitamin D exerts its canonical roles on the musculoskeletal system and in the calcium/phosphorus homeostasis. In the last years, increasing evidences suggested several extra-skeletal actions of this hormone, indicating that vitamin D may produce effects in almost all the body tissues. These are mediated by the presence of vitamin D receptor (VDR) and thanks to the presence of the 1-alpha hydroxylase, the protein that converts the 25-hydroxyvitamin (calcidiol) to the active form 1,25-dihydroxyvitamin (calcitriol). Several studies evaluated the possible role of vitamin D in the pathogenesis of thyroid diseases, and this review will focus on the available data of the literature evaluating the association between vitamin D and thyroid function, vitamin D and autoimmune thyroid diseases, including Hashimoto's thyroiditis, Graves' disease and post partum thyroiditis, and vitamin D and thyroid cancer. PMID- 28092023 TI - White matter alterations in college football players: a longitudinal diffusion tensor imaging study. AB - The aim of this study was to evaluate longitudinal changes in the diffusion characteristics of brain white matter (WM) in collegiate athletes at three time points: prior to the start of the football season (T1), after one season of football (T2), followed by six months of no-contact rest (T3). Fifteen male collegiate football players and 5 male non-athlete student controls underwent diffusion MR imaging and computerized cognitive testing at all three timepoints. Whole-brain tract-based spatial statistics (TBSS) were used to compare fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD), and trace between all timepoints. Average diffusion values were obtained from statistically significant clusters for each individual. No athlete suffered a concussion during the study period. After one season of play (T1 to T2), we observed a significant increase in trace in a cluster located in the brainstem and left temporal lobe, and a significant increase in FA in the left parietal lobe. After six months of no-contact rest (T2 to T3), there was a significant decrease in trace and FA in clusters that were partially overlapping or in close proximity with the initial clusters (T1 to T2), with no significant changes from T1 to T3. Repetitive head impacts (RHI) sustained during a single football season may result in alterations of the brain's WM in collegiate football players. These changes appear to return to baseline after 6 months of no-contact rest, suggesting remission of WM alterations. Our preliminary results suggest that collegiate football players might benefit from periods without exposure to RHI. PMID- 28092022 TI - Relevance of neuroimaging for neurocognitive and behavioral outcome after pediatric traumatic brain injury. AB - This study aims to (1) investigate the neuropathology of mild to severe pediatric TBI and (2) elucidate the predictive value of conventional and innovative neuroimaging for functional outcome. Children aged 8-14 years with trauma control (TC) injury (n = 27) were compared to children with mild TBI and risk factors for complicated TBI (mildRF+, n = 20) or moderate/severe TBI (n = 17) at 2.8 years post-injury. Neuroimaging measures included: acute computed tomography (CT), volumetric analysis on post-acute conventional T1-weighted magnetic resonance imaging (MRI) and post-acute diffusion tensor imaging (DTI, analyzed using tract based spatial statistics and voxel-wise regression). Functional outcome was measured using Common Data Elements for neurocognitive and behavioral functioning. The results show that intracranial pathology on acute CT-scans was more prevalent after moderate/severe TBI (65%) than after mildRF+ TBI (35%; p = .035), while both groups had decreased white matter volume on conventional MRI (ps <= .029, ds >= -0.74). The moderate/severe TBI group further showed decreased fractional anisotropy (FA) in a widespread cluster affecting all white matter tracts, in which regional associations with neurocognitive functioning were observed (FSIQ, Digit Span and RAVLT Encoding) that consistently involved the corpus callosum. FA had superior predictive value for functional outcome (i.e. intelligence, attention and working memory, encoding in verbal memory and internalizing problems) relative to acute CT-scanning (i.e. internalizing problems) and conventional MRI (no predictive value). We conclude that children with mildRF+ TBI and moderate/severe TBI are at risk of persistent white matter abnormality. Furthermore, DTI has superior predictive value for neurocognitive out-come relative to conventional neuroimaging. PMID- 28092024 TI - Introduction: History of SH2 Domains and Their Applications. AB - The Src Homology 2 (SH2) domain is the prototypical protein interaction module that lies at the heart of phosphotyrosine signaling. Since its serendipitous discovery, there has been a tremendous advancement in technologies and an array of techniques available for studying SH2 domains and phosphotyrosine signaling. In this chapter, we provide a glimpse of the history of SH2 domains and describe many of the tools and techniques that have been developed along the way and discuss future directions for SH2 domain studies. We highlight the gist of each chapter in this volume in the context of: the structural biology and phosphotyrosine binding; characterizing SH2 specificity and generating prediction models; systems biology and proteomics; SH2 domains in signal transduction; and SH2 domains in disease, diagnostics, and therapeutics. Many of the individual chapters provide an in-depth approach that will allow scientists to interrogate the function and role of SH2 domains. PMID- 28092025 TI - What Have We Learned from SH2 Domains? AB - SH2 domains first shed light on the key role of modular binding domains in cell signaling. Much of what we now know about the logic and design principles underlying cell signaling mechanisms, and how such mechanisms might have evolved, can be traced back to early work on SH2 domains. Here we briefly outline several key concepts that emerged from such studies. PMID- 28092026 TI - Hidden Markov Models for Protein Domain Homology Identification and Analysis. AB - Protein domain identification and analysis are cornerstones of modern proteomics. The tools available to protein domain researchers avail a variety of approaches to understanding large protein domain families. Hidden Markov Models (HMM) form the basis for identifying and categorizing evolutionarily linked protein domains. Here I describe the use of HMM models for predicting and identifying Src Homology 2 (SH2) domains within the proteome. PMID- 28092028 TI - SH2 Ligand Prediction-Guidance for In-Silico Screening. AB - Systematic identification of binding partners for SH2 domains is important for understanding the biological function of the corresponding SH2 domain-containing proteins. Here, we describe two different web-accessible computer programs, SMALI and DomPep, for predicting binding ligands for SH2 domains. The former was developed using a Scoring Matrix method and the latter based on the Support Vector Machine model. PMID- 28092027 TI - Classification and Lineage Tracing of SH2 Domains Throughout Eukaryotes. AB - Today there exists a rapidly expanding number of sequenced genomes. Cataloging protein interaction domains such as the Src Homology 2 (SH2) domain across these various genomes can be accomplished with ease due to existing algorithms and predictions models. An evolutionary analysis of SH2 domains provides a step towards understanding how SH2 proteins integrated with existing signaling networks to position phosphotyrosine signaling as a crucial driver of robust cellular communication networks in metazoans. However organizing and tracing SH2 domain across organisms and understanding their evolutionary trajectory remains a challenge. This chapter describes several methodologies towards analyzing the evolutionary trajectory of SH2 domains including a global SH2 domain classification system, which facilitates annotation of new SH2 sequences essential for tracing the lineage of SH2 domains throughout eukaryote evolution. This classification utilizes a combination of sequence homology, protein domain architecture and the boundary positions between introns and exons within the SH2 domain or genes encoding these domains. Discrete SH2 families can then be traced across various genomes to provide insight into its origins. Furthermore, additional methods for examining potential mechanisms for divergence of SH2 domains from structural changes to alterations in the protein domain content and genome duplication will be discussed. Therefore a better understanding of SH2 domain evolution may enhance our insight into the emergence of phosphotyrosine signaling and the expansion of protein interaction domains. PMID- 28092029 TI - An Efficient Semi-supervised Learning Approach to Predict SH2 Domain Mediated Interactions. AB - Src homology 2 (SH2) domain is an important subclass of modular protein domains that plays an indispensable role in several biological processes in eukaryotes. SH2 domains specifically bind to the phosphotyrosine residue of their binding peptides to facilitate various molecular functions. For determining the subtle binding specificities of SH2 domains, it is very important to understand the intriguing mechanisms by which these domains recognize their target peptides in a complex cellular environment. There are several attempts have been made to predict SH2-peptide interactions using high-throughput data. However, these high throughput data are often affected by a low signal to noise ratio. Furthermore, the prediction methods have several additional shortcomings, such as linearity problem, high computational complexity, etc. Thus, computational identification of SH2-peptide interactions using high-throughput data remains challenging. Here, we propose a machine learning approach based on an efficient semi-supervised learning technique for the prediction of 51 SH2 domain mediated interactions in the human proteome. In our study, we have successfully employed several strategies to tackle the major problems in computational identification of SH2 peptide interactions. PMID- 28092030 TI - Proteomic Clustering Analysis of SH2 Domain Datasets. AB - Proteomic clustering analysis provides a means of identifying relationships and visualizing those relationships in an extremely complex field of study with many interacting parts. With recent high-throughput studies of Src Homology 2 (SH2) domains, many and varied datasets are being amassed. A strategy for analyzing patterns between these large datasets is required to transform the information into knowledge. The methods for creating neighbor-joining phylogenetic trees, pairs scatter plots, and two-dimensional hierarchical clustering heatmaps are just a few of the diverse methods available to a proteomic researcher. This chapter examines selecting objects to be analyzed, selecting comparison functions to apply to those objects, and pseudo-code for processing data and preparing it for various types of analyses. Here I apply clustering analysis to previous collections of SH2 domains datasets to bring insight into new binding or specificity patterns between the different SH2 domains. PMID- 28092031 TI - Expression and Production of SH2 Domain Proteins. AB - The Src Homology 2 (SH2) domain lies at the heart of phosphotyrosine signaling, coordinating signaling events downstream of receptor tyrosine kinases (RTKs), adaptors, and scaffolds. Over a hundred SH2 domains are present in mammals, each having a unique specificity which determines its interactions with multiple binding partners. One of the essential tools necessary for studying and determining the role of SH2 domains in phosphotyrosine signaling is a set of soluble recombinant SH2 proteins. Here we describe methods, based on a broad experience with purification of all SH2 domains, for the production of SH2 domain proteins needed for proteomic and biochemical-based studies such as peptide arrays, mass-spectrometry, protein microarrays, reverse-phase microarrays, and high-throughput fluorescence polarization (HTP-FP). We describe stepwise protocols for expression and purification of SH2 domains using GST or poly His tags, two widely adopted affinity tags. In addition, we address alternative approaches, challenges, and validation studies for assessing protein quality and provide general characteristics of purified human SH2 domains. PMID- 28092032 TI - Expression and Purification of Soluble STAT5b/STAT3 Proteins for SH2 Domain Binding Assay. AB - When a large hydrophobic full-length protein is expressed in bacteria, it is often challenging to obtain recombinant proteins in the soluble fraction. One way to overcome this challenge is expression of deletion mutants that have improved solubility while maintaining biological activity. In this chapter, we describe a protocol for expression of truncated forms of STAT5b and STAT3 proteins that are soluble and retain SH2-mediated activity for phospho-Tyr peptide recognition. PMID- 28092033 TI - Purification of SOCS (Suppressor of Cytokine Signaling) SH2 Domains for Structural and Functional Studies. AB - Src Homology 2 (SH2) domains are protein domains which have a high binding affinity for specific amino acid sequences containing a phosphorylated tyrosine residue. The Suppressors of Cytokine Signaling (SOCS) proteins use an SH2 domain to bind to components of certain cytokine signaling pathways to downregulate the signaling cascade. The recombinantly produced SH2 domains of various SOCS proteins have been used to undertake structural and functional studies elucidating the method of how such targeting occurs. Here, we describe the protocol for the recombinant production and purification of SOCS SH2 domains, with an emphasis on SOCS3. PMID- 28092034 TI - Expression and Purification of SH2 Domains Using Baculovirus Expression System. AB - Recombinant proteins expressed in bacteria are sometimes insoluble, aggregated, and incorrectly folded. For those Src homology 2 (SH2) domains that are insoluble in bacteria, baculovirus-insect cell expression systems can be an alternative to produce soluble and functionally active proteins. We describe a protocol for cloning and purification of GST-tagged SH2 domains using the Bac-to-Bac baculovirus expression system. PMID- 28092035 TI - Functionally Altered SH2 Domains for Biochemical Studies: Loss-of-Function Mutant and Domain Concatenation. AB - Recombinant modular protein domains have been a convenient proteomics tool for deciphering protein-protein interactions and elucidating the role of protein modifications in cell signaling. To obtain reliable experimental data, these protein domain probes require sufficient specificity and sensitivity. Since naturally evolved protein domains do not always have optimal biochemical characteristics for in vitro assays, functional alterations such as improved affinity are sometimes needed. In this chapter, we describe preparation of loss of-function and concatenated (tandem) SH2 domains that should be widely applicable to both high- and low-throughput phosphoproteomics studies. PMID- 28092036 TI - Creation of Phosphotyrosine Superbinders by Directed Evolution of an SH2 Domain. AB - Commercial antibodies raised against phosphotyrosine have been widely used as reagents to detect or isolate tyrosine-phosphorylated proteins from cellular samples. However, these antibodies are costly and are not amenable to in-house production in an academic lab setting. In this chapter, we describe a method to generate super-high affinity SH2 domains, dubbed the phosphotyrosine superbinders, by evolving a natural SH2 domain using the phage display technology. The superbinders are stable and can be easily produced in Escherichia coli in large quantities. The strategy presented here may also be applied to other protein domains to generate domain variants with markedly enhanced affinities for a specific post-translational modification. PMID- 28092037 TI - Structural Characterization of Monomeric/Dimeric State of p59fyn SH2 Domain. AB - Src homology 2 (SH2) domains are key modulators in various signaling pathways allowing the recognition of phosphotyrosine sites of different proteins. Despite the fact that SH2 domains acquire their biological functions in a monomeric state, a multitude of reports have shown their tendency to dimerize. Here, we provide a technical description on how to isolate and characterize by gel filtration, circular dichroism (CD), and nuclear magnetic resonance (NMR) each conformational state of p59fyn SH2 domain. PMID- 28092038 TI - NMR Chemical Shift Mapping of SH2 Peptide Interactions. AB - Heteronuclear single quantum coherence (HSQC) nuclear magnetic resonance (NMR) experiments offer a rapid and high resolution approach to gaining binding and conformational insights into a protein-peptide interaction. By tracking 1H and 15N chemical shift changes over the course of a peptide titration into isotopically labeled protein, amide NH pairs of amino acids whose chemical environment changes upon peptide binding can be identified. When mapped onto a structure of the protein, this approach can identify the peptide-binding interface or regions undergoing conformation changes within a protein upon ligand binding. Monitoring NMR chemical shift changes can also serve as a screening technique to identify novel interaction partners for a protein or to determine the binding affinity of a weak protein-peptide interaction. Here, we describe the application of NMR chemical shift mapping to the study of peptide binding to the C-terminal SH2 domain of PLCgamma1. PMID- 28092039 TI - Calorimetric Measurement of SH2 Domain Ligand Affinities. AB - Isothermal titration calorimetry (ITC) has emerged as a leading approach in the characterization of protein/ligand interactions. This technique measures the heat change of a system upon binding of a ligand to a biomolecule, and thereby requires no immobilization, intrinsic fluorescence, or labeling of any kind of either species. If properly designed, a single experiment can not only measure the binding affinity, but also determine additional binding and thermodynamic parameters, including the enthalpy, entropy, and the stoichiometry of the interaction. Here, we describe the protocol for the collection of calorimetric data for the binding of peptides to SH2 protein domains. PMID- 28092040 TI - Binding Assays Using Recombinant SH2 Domains: Far-Western, Pull-Down, and Fluorescence Polarization. AB - Recognition of phosphotyrosine-containing sequences by SH2 domains confers specificity in tyrosine kinase pathways. By assessing interactions between isolated SH2 domains and their binding proteins, it is possible to gain insight into otherwise inaccessible complex cellular systems. Far-Western, pull-down, and fluorescence polarization (FP) have been frequently used for characterization of phosphotyrosine signaling. Here, we outline standard protocols for these established assays using recombinant SH2 domain, emphasizing the importance of appropriate sample preparation and assay controls. PMID- 28092041 TI - In-Solution SH2 Domain Binding Assay Based on Proximity Ligation. AB - Protein-protein interactions mediated by SH2 domains confer specificity in tyrosine kinase pathways. Traditional assays for assessing interactions between an SH2 domain and its interacting protein such as far-Western and pull-down are inherently low throughput. We developed SH2-PLA, an in-solution SH2 domain binding assay, that takes advantage of the speed and sensitivity of proximity ligation and real-time PCR. SH2-PLA allows for rapid assessment of SH2 domain binding to a target protein using only a few microliters of cell lysate, thereby making it an attractive new tool to study tyrosine kinase signaling. PMID- 28092042 TI - Alpha-Based Multiplexed Assay for Identifying SH2 Domain Antagonists. AB - Constitutive activation of STAT3/5b frequently occurs in various human malignancies. STAT3/5b activation involves dimerization via intermolecular pTyr SH2 binding; therefore, antagonizing this interaction is a feasible approach to inhibit STAT3/5b activation for cancer therapy. We have developed a multiplexed assay to assess STAT3- and STAT5b-SH2 binding in a single well by combining AlphaLISA and AlphaScreen beads. In this chapter, we describe application of the method for the purpose of identifying new STAT3 and STAT5b antagonists. PMID- 28092043 TI - Characterizing SH2 Domain Specificity and Network Interactions Using SPOT Peptide Arrays. AB - Src Homology 2 (SH2) domains are protein interaction modules that recognize and bind tyrosine phosphorylated ligands. Their ability to distinguish binding to over thousands of potential phosphotyrosine (pTyr) ligands within the cell is critical for the fidelity of receptor tyrosine kinase (RTK) signaling. Within humans there are over a hundred SH2 domains with more than several thousand potential ligands across many cell types and cell states. Therefore, defining the specificity of individual SH2 domains is critical for predicting and identifying their physiological ligands. Here, in this chapter, I describe the broad use of SPOT peptide arrays for examining SH2 domain specificity. An orientated peptide array library (OPAL) approach can uncover both favorable and non-favorable residues, thus providing an in-depth analysis to SH2 specificity. Moreover, I discuss the application of SPOT arrays for paneling SH2 ligand binding with physiological peptides. PMID- 28092044 TI - High-Throughput Quantification of SH2 Domain-Phosphopeptide Interactions with Cellulose-Peptide Conjugate Microarrays. AB - The Src Homology 2 (SH2) domain family primarily recognizes phosphorylated tyrosine (pY) containing peptide motifs. The relative affinity preferences among competing SH2 domains for phosphopeptide ligands define "specificity space," and underpins many functional pY mediated interactions within signaling networks. The degree of promiscuity exhibited and the dynamic range of affinities supported by individual domains or phosphopeptides is best resolved by a carefully executed and controlled quantitative high-throughput experiment. Here, I describe the fabrication and application of a cellulose-peptide conjugate microarray (CPCMA) platform to the quantitative analysis of SH2 domain specificity space. Included herein are instructions for optimal experimental design with special attention paid to common sources of systematic error, phosphopeptide SPOT synthesis, microarray fabrication, analyte titrations, data capture, and analysis. PMID- 28092045 TI - SH2 Domains as Affinity Reagents for Phosphotyrosine Protein Enrichment and Proteomic Analysis. AB - Dynamic tyrosine phosphorylation is a key molecular modulation for many signal transduction events. Because of their low abundance and dynamic nature in cells, the detection and enrichment of phosphotyrosine proteins has long relied on specific antibodies, such as 4G10 and P-Tyr-100. Another well-established approach for phosphotyrosine proteins recognition and enrichment is by their specific binding domains, such as Src homology 2 (SH2) domains. In this chapter, we describe a typical analytical approach for purifying specific SH2 domains, enriching specific phosphotyrosine proteins from activated cells, mass spectrometry analysis, and related data analysis. PMID- 28092046 TI - Identification of Tyrosine Phosphorylated Proteins by SH2 Domain Affinity Purification and Mass Spectrometry. AB - Phosphotyrosine signaling plays a major role in the control of many important biological functions such as cell proliferation and apoptosis. Deciphering of phosphotyrosine-dependent signaling is therefore of great interest paving the way for the understanding of physiological and pathological processes of signal transduction. On the basis of the specific binding of SH2 domains to phosphotyrosine residues, we here present an experimental workflow for affinity purification and subsequent identification of tyrosine phosphorylated proteins by mass spectrometry. In combination with SH2 profiling, a broadly applicable platform for the characterization of phosphotyrosine profiles in cell extracts, our pull down strategy enables researchers by now to identify proteins in signaling cascades which are differentially phosphorylated and selectively recognized by distinct SH2 domains. PMID- 28092047 TI - Analysis of the Global Changes in SH2 Binding Properties Using Mass Spectrometry Supported by Quantitative Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) Technique. AB - Quantitative mass spectrometry (MS)-based proteomics enables fast and reliable analysis of protein complexes. Its robustness and sensitivity effectively substitute traditional antibody-based approaches. Here, we describe the combination of mass spectrometry and Stable Isotope Labeling by Amino acids in Cell culture (SILAC) in characterization of the SH2 domain binding capacity. PMID- 28092048 TI - Using Reciprocal Protein-Peptide Array Screening to Unravel Protein Interaction Networks. AB - Protein-protein interactions (PPIs) play a central role in almost all cellular processes. Recent technological advances have enabled the elucidation of an incredibly complex PPI network within the cell. However, protein interactions driven by posttranslational modifications (PTMs) such as phosphorylation, which comprises a significant part of the PPI network, have proven difficult to decipher systematically. Herein, we describe a reciprocal protein-peptide array strategy to uncover PPIs mediated by tyrosine phosphorylation and the Src homology 2 (SH2) domain. This strategy, namely combining peptide and protein domain arrays for PPI mapping, may be applicable for other peptide-binding modules. PMID- 28092049 TI - Rosette Assay: Highly Customizable Dot-Blot for SH2 Domain Screening. AB - With a growing number of high-throughput studies, structural analyses, and availability of protein-protein interaction databases, it is now possible to apply web-based prediction tools to SH2 domain-interactions. However, in silico prediction is not always reliable and requires experimental validation. Rosette assay is a dot blot-based reverse-phase assay developed for the assessment of binding between SH2 domains and their ligands. It is conveniently customizable, allowing for low- to high-throughput analysis of interactions between various numbers of SH2 domains and their ligands, e.g., short peptides, purified proteins, and cell lysates. The binding assay is performed in a 96-well plate (MBA or MWA apparatus) in which a sample spotted membrane is incubated with up to 96 labeled SH2 domains. Bound domains are detected and quantified using a chemiluminescence or near-infrared fluorescence (IR) imaging system. In this chapter, we describe a practical protocol for rosette assay to assess interactions between synthesized tyrosine phosphorylated peptides and a library of GST-tagged SH2 domains. Since the methodology is not confined to assessment of SH2-pTyr interactions, rosette assay can be broadly utilized for ligand and drug screening using different protein interaction domains or antibodies. PMID- 28092050 TI - Microwestern Arrays for Systems-Level Analysis of SH2 Domain-Containing Proteins. AB - The Microwestern Array (MWA) method combines the scalability and miniaturization afforded by the Reverse Phase Lysate Array (RPLA) approach with the electrophoretic separation characteristic of the Western blot. This technology emulates the creation of an array of small Western blots on a single sheet of nitrocellulose allowing for the sensitive and quantitative measurement of hundreds of proteins from hundreds of cell lysates with minimal cost and maximal accuracy, precision, and reproducibility. The MWA is a versatile technology that can be easily configured for purposes such as antibody screening, cell signaling network inference, protein modification/phenotype regression analysis, and genomic/proteomic relationships. Accordingly, configurations for the MWA can be optimized for maximal numbers of proteins analyzed from small numbers of cell lysates, for small numbers of antibodies against large numbers of cell lysates, or for maximal resolution of protein size achieved by increased electrophoretic separation distance. For example, on a single gel, 6 samples can be printed 96 times if a few samples need to be assayed with a large number of antibodies. Alternatively, up to 100 samples can be assayed with four antibodies on a single gel. Intermediate configurations are also discussed.The efficiency of the MWA is orders of magnitude greater in reagents, labor, and time required per data point relative to the standard Western blotting method and orders of magnitude more sensitive than standard mass spectrometry methods. The MWA is therefore a very attractive approach for capturing global changes in protein abundances and modifications including tyrosine phosphorylation and SH2 domain binding sites. PMID- 28092051 TI - SH2 Binding Site Protection Assay: A Method for Identification of SH2 Domain Interaction Partners by Exploiting SH2 Mediated Phosphosite Protection. AB - Over the last two decades there has been a significant effort in the field to characterize the phosphosite binding specificities of SH2 domains with the goal of deciphering the pY signaling code. Although high throughput studies in various formats using most SH2 domains have collectively provided a rich resource of in vitro SH2-pTyr site specificity maps, this data can only be used approximate what is happening in the cell where protein concentrations and localization are not homogenous, as they are for in vitro experiments. Here we describe an in vivo approach, SH2 site protection assay, which can capture the pTyr binding specificity of SH2 domains in the cell. The basis of this approach is SH2-pY site protection, the ability of SH2 domains to prevent the PTP-dependent dephosphorylation of their pY site binding partners. We overexpress a tracer SH2 domain in cells and quantify the change in abundance of tyrosine phosphorylated sites using MS. Since the method is performed in vivo, it has the advantage of identifying SH2-pY interactions as they occur within in the cell. PMID- 28092052 TI - Real-Time Single Molecule Visualization of SH2 Domain Membrane Recruitment in Growth Factor Stimulated Cells. AB - In the last decade, single molecule tracking (SMT) techniques have emerged as a versatile tool for molecular cell biology research. This approach allows researchers to monitor the real-time behavior of individual molecules in living cells with nanometer and millisecond resolution. As a result, it is possible to visualize biological processes as they occur at a molecular level in real time. Here we describe a method for the real-time visualization of SH2 domain membrane recruitment from the cytoplasm to epidermal growth factor (EGF) induced phosphotyrosine sites on the EGF receptor. Further, we describe methods that utilize SMT data to define SH2 domain membrane dynamics parameters such as binding (tau), dissociation (k d), and diffusion (D) rates. Together these methods may allow us to gain greater understanding of signal transduction dynamics and the molecular basis of disease-related aberrant pathways. PMID- 28092053 TI - SH2 Domain-Based FRET Biosensor for Measuring BCR-ABL Activity in Living CML Cells. AB - Fluorescent proteins (FPs) displaying distinct spectra have shed their light on a wide range of biological functions. Moreover, sophisticated biosensors engineered to contain single or multiple FPs, including Forster resonance energy transfer (FRET)-based biosensors, spatiotemporally reveal the molecular mechanisms underlying a variety of pathophysiological processes. However, their usefulness for applied life sciences has yet to be fully explored. Recently, our research group has begun to expand the potential of FPs from basic biological research to the clinic. Here, we describe a method to evaluate the responsiveness of leukemia cells from patients to tyrosine kinase inhibitors using a biosensor based on FP technology and the principle of FRET. Upon phosphorylation of the tyrosine residue of the biosensor, binding of the SH2 domain to phosphotyrosine induces conformational change of the biosensor and brings the donor and acceptor FPs into close proximity. Therefore, kinase activity and response to kinase inhibitors can be monitored by an increase and a decrease in FRET efficiency, respectively. As in basic research, this biosensor resolves hitherto arduous tasks and may provide innovative technological advances in clinical laboratory examinations. State-of the-art detection devices that enable such innovation are also introduced. PMID- 28092054 TI - SH2 Domain Histochemistry. AB - Among posttranslational modifications, the phosphorylation of tyrosine residues is a key modification in cell signaling. Because of its biological importance, characterization of the cellular state of tyrosine phosphorylation is of great interest. Based on the unique properties of endogenously expressed SH2 domains recognizing tyrosine phosphorylated signaling proteins with high specificity we have developed an alternative approach, coined SH2 profiling, enabling us to decipher complex patterns of tyrosine phosphorylation in various normal and cancerous tissues. So far, SH2 profiling has largely been applied for the analysis of protein extracts with the limitation that information on spatial distribution and intensity of tyrosine phosphorylation within a tissue is lost. Here, we describe a novel SH2 domain based strategy for differential characterization of the state of tyrosine phosphorylation in formaldehyde-fixed and paraffin-embedded tissues. This approach demonstrates that SH2 domains may serve as very valuable tools for the analysis of the differential state of tyrosine phosphorylation in primary tissues fixed and processed under conditions frequently applied by routine pathology laboratories. PMID- 28092056 TI - A Randomised, Placebo-Controlled, Crossover Study Investigating the Effects of Nicotine Gum on Strength, Power and Anaerobic Performance in Nicotine-Naive, Active Males. AB - BACKGROUND: Nicotine use amongst athletes is high and increasing, especially team sports, yet the limited previous studies investigating the performance consequences of this behaviour have not examined the effects of the principal active ingredient, nicotine, per se. Therefore, we determined whether nicotine gum affected muscular and anaerobic performance. METHODS: Nine active males (24 +/- 3 years) completed three trials in a random order in which 20 min prior to testing they chewed 2 mg (NIC-2), 4 mg (NIC-4) nicotine or flavour-matched placebo (PLA) gum. Peak and average peak isometric, concentric and eccentric leg extensor torque was measured followed by vertical counter-movement jump height and a 30-s Wingate test. Heart rate was measured whilst capillary blood samples determined pH, HCO3- and venous blood confirmed the presence of nicotine. RESULTS: Nicotine was confirmed by the presence of its major metabolite, cotinine and participants reported no side effects with nicotine. Peak and average peak isometric and eccentric torque was significantly affected (NIC-2 > PLA; p < 0.05) whilst peak (NIC-2 > PLA; p < 0.05) but not average peak (p > 0.05) concentric torque was different between trials. Counter-movement jump height was similar across trials (p > 0.05). Anaerobic capacity during the Wingate remained similar across trials (p > 0.05); however, pacing strategy (peak power and rate of fatigue) was different during NIC-2 than PLA. pH was affected by nicotine (NIC-2 > PLA; p < 0.05) and was reduced following the Wingate in all trials. HCO3- showed similar responses across trials (p > 0.05) although it was also reduced following the Wingate (p < 0.05), whilst heart rate was significantly affected (NIC-2/NIC-4 > PLA; p < 0.05). CONCLUSIONS: Chewing low-dose (2 mg) nicotine gum 20 min prior to exercise significantly improved leg extensor torque but did not affect counter-movement jump height or Wingate performance compared to a placebo, whilst there were minimal effects of the 4 mg nicotine gum on the performance parameters measured. PMID- 28092055 TI - Differentiating emotional processing and attention in psychopathy with functional neuroimaging. AB - Individuals with psychopathy are often characterized by emotional processing deficits, and recent research has examined the specific contexts and cognitive mechanisms that underlie these abnormalities. Some evidence suggests that abnormal features of attention are fundamental to emotional deficits in persons with psychopathy, but few studies have demonstrated the neural underpinnings responsible for such effects. Here, we use functional neuroimaging to examine attention-emotion interactions among incarcerated individuals (n = 120) evaluated for psychopathic traits using the Hare Psychopathy Checklist-Revised (PCL-R). Using a task designed to manipulate attention to emotional features of visual stimuli, we demonstrate effects representing implicit emotional processing, explicit emotional processing, attention-facilitated emotional processing, and vigilance for emotional content. Results confirm the importance of considering mechanisms of attention when evaluating emotional processing differences related to psychopathic traits. The affective-interpersonal features of psychopathy (PCL R Factor 1) were associated with relatively lower emotion-dependent augmentation of activity in visual processing areas during implicit emotional processing, while antisocial-lifestyle features (PCL-R Factor 2) were associated with elevated activity in the amygdala and related salience network regions. During explicit emotional processing, psychopathic traits were associated with upregulation in the medial prefrontal cortex, insula, and superior frontal regions. Isolating the impact of explicit attention to emotional content, only Factor 1 was related to upregulation of activity in the visual processing stream, which was accompanied by increased activity in the angular gyrus. These effects highlight some important mechanisms underlying abnormal features of attention and emotional processing that accompany psychopathic traits. PMID- 28092057 TI - Maternal Nonstandard Work Schedules and Breastfeeding Behaviors. AB - Objectives Although maternal employment rates have increased in the last decade in the UK, there is very little research investigating the linkages between maternal nonstandard work schedules (i.e., work schedules outside of the Monday through Friday, 9-5 schedule) and breastfeeding initiation and duration, especially given the wide literature citing the health advantages of breastfeeding for mothers and children. Methods This paper uses a population based, UK cohort study, the Millennium Cohort Study (n = 17,397), to investigate the association between types of maternal nonstandard work (evening, night, away from home overnight, and weekends) and breastfeeding behaviors. Results In unadjusted models, exposure to evening shifts was associated with greater odds of breastfeeding initiation (OR 1.71, CI 1.50-1.94) and greater odds of short (OR 1.55, CI 1.32-1.81), intermediate (OR 2.01, CI 1.64-2.47), prolonged partial duration (OR 2.20, CI 1.78-2.72), and prolonged exclusive duration (OR 1.53, CI 1.29-1.82), compared with mothers who were unemployed and those who work other types of nonstandard shifts. Socioeconomic advantage of mothers working evening schedules largely explained the higher odds of breastfeeding initiation and duration. Conclusions Socioeconomic characteristics explain more breastfeeding behaviors among mothers working evening shifts. Policy interventions to increase breastfeeding initiation and duration should consider the timing of maternal work schedules. PMID- 28092058 TI - Sub-Regional Assessment of HPV Vaccination Among Female Adolescents in the Intermountain West and Implications for Intervention Opportunities. AB - Objectives We investigated the similarities and differences in the factors related to human papillomavirus (HPV) vaccination of female adolescents in three sub-regions of the Intermountain West (IW). Methods We analyzed 2011-2012 National Immunization Survey-Teen data. Respondents (parents) who were living in the IW and who had daughters aged 13-17 years old with provider-verified immunization records were included in our analyses. East, Central, and West sub regions were defined based on geographic contiguity and similarity in HPV vaccination rates and sociodemographic characteristics. Survey-weighted Chi square tests and multivariable Poisson regressions were performed. Results In all three sub-regions, older teen age and receipt of other recommended adolescent vaccinations were significantly associated with HPV vaccination. In the East sub region, providers' facility type and source of vaccines were significantly related to HPV vaccination. In the Central sub-region, teens with married parents were significantly less likely to be vaccinated than were those with unmarried parents. In the West sub-region, non-Hispanic teens were significantly less likely to be vaccinated than were Hispanic teens. Conclusions for Practice In order to improve HPV vaccine coverage in the IW, region-wide efforts to target younger teens and to promote the HPV vaccine with other recommended adolescent vaccinations should be supplemented with sub-regional attention to the health care system (East sub-region), to married parents (Central sub-region), and to non-Hispanic teens (West sub-region). PMID- 28092059 TI - The Effects of Race and Ethnicity on the Risk of Large-for-Gestational-Age Newborns in Women Without Gestational Diabetes by Prepregnancy Body Mass Index Categories. AB - Objectives Children born large for gestational age (LGA) are at risk of numerous adverse outcomes. While the racial/ethnic disparity in LGA risk has been studied among women with Gestational Diabetes Mellitus (GDM), the independent effect of race on LGA risk by maternal prepregnancy BMI is still unclear among women without GDM. Therefore, the objective of this study was to assess the association between maternal race/ethnicity and LGA among women without GDM. Methods This was a population-based cohort study of 2,842,278 singleton births using 2012 U.S. Natality data. We conducted bivariate and multivariate logistic regression analyses to assess the association between race and LGA. Due to effect modification by maternal prepregnancy BMI, we stratified our analysis by four BMI subgroups. Results The prevalence of LGA was similar across the different racial/ethnic groups at about 9%, but non-Hispanic Asian Americans had slightly higher prevalence of 11%. After controlling for potential confounders, minority women had higher odds of birthing LGA babies compared to non-Hispanic white women. Non-Hispanic Asian Americans had the highest odds of LGA babies across all BMI categories: underweight (aOR = 2.67; 95% CI: 2.24, 3.05); normal weight (aOR = 2.53; 2.43, 2.62); overweight (aOR = 2.45; 2.32, 2.60) and obese (aOR = 2.05; 1.91, 2.20). Conclusions for practice Racial/ethnic disparities exist in LGA odds, particularly among women with underweight or normal prepregnancy BMI. Most minorities had higher LGA odds than non-Hispanic white women regardless of prepregnancy BMI category. These racial/ethnic disparities should inform public health policies and interventions to address this problem. PMID- 28092061 TI - Status of Breastfeeding and Child Immunization Outcomes in Clients of the Nurse Family Partnership. AB - Background The Nurse-Family Partnership (NFP) is a home visiting program serving first-time, low-income mothers, with an area of focus on healthy early childhood development. Previous foundational trials of program effect on breastfeeding and immunizations have shown a mix of neutral and positive results. The present evaluation investigates these effects following program scale-up, using a large contemporary cohort of clients. Methods Nurse-Family Partnership client breastfeeding and immunization status were compared to National Survey of Children's Health data and National Immunization Survey data, respectively. Sample differences in demographic covariates were adjusted using logistic regression. Results Nurse-Family Partnership clients were significantly more likely to have ever breastfed (adjusted prevalence ratio [aPR: 1.20 (1.17, 1.23)] and maintain breastfeeding at 6 [aPR: 1.17 (1.10, 1.24)] and 12 [aPR: 1.39 (1.25, 1.53)] months, but less likely to exclusively breastfeed at 6 months [aPR: 0.84 (0.70, 0.95)] NFP clients were significantly more likely to be up-to-date on immunizations at 6 [aPR: 1.23 (1.22, 1.25)], 18 [aPR: 1.33 (1.30,1.35)], and 24 [aPR: 1.15 (1.14, 1.16)] months of age than the reference cohort, with no significant difference at 12 months. Discussion Nurse-Family Partnership clients had more beneficial breastfeeding and immunization outcomes than children of mothers with demographically similar profiles. However, exclusive breastfeeding at 6 months lags behind the reference sample and represents a potential area for further improvement. PMID- 28092060 TI - Parenting Self-Efficacy, Parent Depression, and Healthy Childhood Behaviors in a Low-Income Minority Population: A Cross-Sectional Analysis. AB - Objectives Childhood obesity prevention and treatment depends, in part, on parents acting as agents of change for their children. Our objective was to measure the associations between parenting self-efficacy, parent depressive symptoms, and preschool child behaviors that support healthy growth. Methods We performed a cross-sectional analysis of baseline data from a randomized controlled trial. Parenting self-efficacy was measured using a 5-item version of the Parenting Sense of Competence (PSOC-5) scale (alpha= 0.8). Parent depressive symptoms were measured using the Center for Epidemiological Studies-Depression (CESD) scale. Child outcomes included diet (24 h diet recall), physical activity (accelerometry), sleep (parent-report), and media use during meals (parent report). We performed separate multiple linear regressions for each outcome controlling for other covariates. Results The sample consisted of 601 parent child pairs. Median child age was 4.3 (IQR 3.6-5.1) years; median child body mass index (BMI) percentile was 79.1% (IQR 66.8-88.5%); 90% of children were Hispanic/Latino, and 6% of children were non-Hispanic Black. Median parent age was 31.5 (IQR 27.6-36.0) years; 22% of parents met criteria for depression. Parenting self-efficacy (median PSOC-5 25; IQR 24-28) was negatively correlated with depressive symptoms (rho = -0.16; p < 0.001). In adjusted models, higher parenting self-efficacy was associated with duration of child's sleep and fewer meals eaten in front of a TV (p < 0.001). There was a significant interaction of parenting self-efficacy and parental depressive symptoms on child sleep duration (p < 0.001). Parenting self-efficacy and depressive symptoms were not significantly associated with child physical activity or child diet. Conclusions In this minority population, higher parenting self-efficacy was associated with longer child sleep and fewer meals in front the TV, but parent depressive symptoms mitigated that protective effect for child sleep duration. PMID- 28092062 TI - "It's a Very Big Burden on Me": Women's Experiences Using Insulin for Gestational Diabetes. AB - Objectives Gestational Diabetes Mellitus (GDM) affects hundreds of thousands of women each year. Many require medications to manage their blood glucose levels. Only insulin is approved by the U.S. Food and Drug Administration for use in pregnancy. While other medications can be used, their safety remains controversial. Few studies have examined women's lived experience of using insulin for GDM. Our objective in this study was to foreground the voices of women speaking about their treatment experience. Methods We conducted two focus groups including 16 women treated for GDM with medications, primarily insulin. Topics included women's experiences with GDM diagnosis and treatment including concerns about risks and benefits of treatments. Transcripts were analyzed using an inductive coding approach. Results Many women had negative experiences with insulin use, such as feeling that they had no voice in treatment decisions, and received inadequate information about insulin, including about the impact it would have on their daily lives. Many continued to have difficulty managing their blood sugar once on insulin, and they worried about the short term and long term health effects of insulin on themselves and their babies. They wanted more information about non-insulin treatment options as well as more social support. Conclusion In our sample of women with GDM, insulin treatment resulted in negative experiences with emotional and experiential impacts lasting beyond pregnancy. There is a need for more research on other medications for GDM, so that women can have access to more treatment options and better information to guide their choices. PMID- 28092063 TI - Appropriate Use of Progesterone to Prevent Preterm Birth: Approaches to Measurement for Driving Improvement. AB - Introduction Despite strong evidence supporting the benefit of 17-alpha hydroxyprogesterone caproate (17P) in preventing recurrent preterm birth, this treatment still does not reach most eligible patients. This study sought to identify approaches to measuring the appropriate use of 17P, with the goal of helping health systems better monitor and improve the implementation of this intervention. Methods Semi-structured telephone interviews were used to gather data on measures for 17P use being developed and implemented by state team members participating in the Infant Mortality Collaborative Improvement and Innovation Network (IM CoIIN)-a national quality improvement initiative. Strengths and limitations of these measurement approaches were described. Results Six approaches to measuring 17P use to prevent preterm birth were identified: practice-level data, population-based surveys, three measures employing insurance claims with or without linked birth certificate data, and revised birth certificates. Each measure had particular strengths and limitations. Practice level measures were useful in rapid-cycle improvement, but were not generalizable across sites. In contrast, population-based measures (i.e., surveys, claims) were useful for broad comparisons, but were limited in their timeliness, and in how accurately they identified candidates who were truly eligible for 17P. Additionally, such measures required complex data linkage and analytic capabilities. Discussion A variety of imperfect measures for the appropriate use of 17P are available. No "best" measure was identified-the optimal measurement option must fit the specific needs of a health agency. Better data infrastructure and harnessing information from integrated electronic health records could improve the quality of 17P use measurement for improvement efforts. PMID- 28092064 TI - Critical Congenital Heart Disease Newborn Screening Implementation: Lessons Learned. AB - Introduction The purpose of this article is to present the collective experiences of six federally-funded critical congenital heart disease (CCHD) newborn screening implementation projects to assist federal and state policy makers and public health to implement CCHD screening. Methods A qualitative assessment and summary from six demonstration project grantees and other state representatives involved in the implementation of CCHD screening programs are presented in the following areas: legislation, provider and family education, screening algorithms and interpretation, data collection and quality improvement, telemedicine, home and rural births, and neonatal intensive care unit populations. Results The most common challenges to implementation include: lack of uniform legislative and statutory mandates for screening programs, lack of funding/resources, difficulty in screening algorithm interpretation, limited availability of pediatric echocardiography, and integrating data collection and reporting with existing newborn screening systems. Identified solutions include: programs should consider integrating third party insurers and other partners early in the legislative/statutory process; development of visual tools and language modification to assist in the interpretation of algorithms, training programs for adult sonographers to perform neonatal echocardiography, building upon existing newborn screening systems, and using automated data transfer mechanisms. Discussion Continued and expanded surveillance, research, prevention and education efforts are needed to inform screening programs, with an aim to reduce morbidity, mortality and other adverse consequences for individuals and families affected by CCHD. PMID- 28092065 TI - Impact of celecoxib on inflammation during cancer surgery: a randomized clinical trial. AB - PURPOSE: During cancer surgery, prostaglandin-mediated inflammation may promote and activate micrometastatic disease with a consequent increase in long-term cancer recurrence. Cyclooxygenase-2 inhibitors, known to have anti-proliferative properties, may offset such perioperative perturbation. We investigated the effectiveness of these agents to minimize inflammatory changes during cancer surgery. METHODS: Following ethics approval, 32 patients who were to undergo major intracavity cancer surgery were enrolled in this prospective, randomized, clinical trial. The treatment group received 400 mg celecoxib preoperatively followed by five 200 mg 12-hourly doses. The control group received no anti inflammatory agents. Inflammatory and immunomodulatory end points were measured serially. The primary end points were the measured plasma and urinary prostaglandin E metabolite (PGEM) levels 48 hours following surgery. Secondary endpoints included interleukin levels, leucocyte profile, and clinical end points. RESULTS: No differences in the 48-hr plasma or urinary PGEM levels were observed between the celecoxib and control groups. Linear mixed modeling, used to accommodate differences in baseline PGEM levels, showed that celecoxib (cf. control) administration lowered plasma PGEM over the entire 48-hr period following surgery (beta-coefficient = -0.38 pg.ml-1; 95% confidence interval: 0.69 to -0.06; P = 0.021). Celecoxib administration also lowered postoperative pain scores. DISCUSSION: Standard dosing of the cyclooxygenase-2 inhibitor celecoxib slightly reduced perioperative cyclooxygenase activity during cancer surgery. Given cyclooxygenase's role in cancer pathways, we recommend dose finding studies be undertaken before prospective clinical trials are conducted testing the currently unsubstantiated hypothesis that perioperative anti inflammatory administration improves long-term cancer outcomes. This trial was registered at: Australian New Zealand Clinical Trial Registry: ACTRN12615000041550; www.anzctr.org.au. PMID- 28092066 TI - Mentorship in anesthesia: a survey of perspectives among Canadian anesthesia residents. AB - PURPOSE: Mentorship is important for professional and academic growth; however, the role of mentorship in anesthesia is still being defined. We surveyed Canadian anesthesia residents to explore their perceptions of mentorship relationships. METHODS: We administered a 20-item cross-sectional survey to program directors and anesthesia residents in all Canadian departments of anesthesia. Program directors were asked about their mentorship programs, and residents were asked about their perceptions of benefits and barriers to effective mentoring. RESULTS: Sixteen of 17 (94%) program directors and 189 of 585 (32%) anesthesia residents responded to our survey. While 143 of 180 (79%) residents agreed that mentorship was beneficial to overall success as an anesthesiologist, only 11 of 16 (69%) program directors reported formal mentorship as part of their residency program, and only 119 of 189 (63%) residents reported access to a mentor. Barriers reported by residents included insufficient time with mentors, lack of formalized meeting times and objectives, mentor-mentee incompatibility (personal or professional), and lack of resident choice in mentor selection. CONCLUSION: Our study confirms that, despite positive perceptions among residents, mentorship remains underutilized in anesthesia programs. We identify barriers to effective mentorship, including the need to consider resident choice as a means to improve formal anesthesia mentorship programs. PMID- 28092067 TI - Interrelations among the adipocytokines leptin and adiponectin, oxidative stress and aseptic inflammation markers in pre- and early-pubertal normal-weight and obese boys. AB - PURPOSE: Presumed interrelationships among deleterious aspects of adipose tissue metabolism, inflammation, and cellular oxidative stress could be influenced by pubertal hormonal changes. They were investigated in pre- and early pubertal normal-weight and obese boys before and after an exercise bout employed as an energy demanding stimulator. METHODS: Cross-sectional study. Seventy-six healthy pre- (mean +/- SD, 10.6 +/- 0.2 years old, 28 normal-weight, and 11 obese) and early-(11.4 +/- 0.2 years old, 25 normal-weight, and 12 obese) pubertal boys, were blood-sampled before and after a bout of exercise at 70% VO2 max. Leptin, adiponectin, markers of inflammation (high-sensitivity C-reactive protein, high sensitivity IL-6), pro- (thiobarbitouric acid reactive substances, protein carbonyls) and anti- (glutathione, oxidized glutathione, glutathione peroxidase, catalase, total antioxidant capacity) oxidation were measured. RESULTS: Baseline and post-exercise adiponectin was greater and leptin and high-sensitivity C reactive protein were lower in normal-weight than in obese pre- and early pubertal boys, while high sensitivity IL-6 was greater in obese than in normal weight pre-pubertal boys. In pre-pubertal obese boys: at baseline, high sensitivity C-reactive protein correlated negatively with catalase; high sensitivity IL-6 correlated positively with protein carbonyls; Delta (difference during exercise) adiponectin correlated positively with Deltacatalase. In all boys: at baseline, high sensitivity IL-6 correlated positively with leptin and was the best negative and the second best positive predictor for post-exercise glutathione/oxidized glutathione and protein carbonyls, respectively; leptin was the best negative predictor for post-exercise glutathione; waist to height ratio was the best positive predictor for post-exercise thiobarbitouric acid reactive substances; body mass index z-score and adiponectin were, respectively, the best positive predictor for post-exercise protein carbonyls and catalase. CONCLUSIONS: In all subjects, leptin and adiponectin predict negatively and positively anti oxidation, respectively, while high sensitivity IL-6 predicts positively and negatively pro- and anti-oxidation, respectively. High-sensitivity C-reactive protein is increased and negatively associated with anti-oxidation in pre pubertal obese boys, suggesting that childhood obesity is associated with aseptic inflammation and oxidative stress. PMID- 28092068 TI - Differential diagnosis of pituitary masses at magnetic resonance imaging. PMID- 28092069 TI - Treatment of Concomitant OAB and BPH. AB - The etiology of men's lower urinary tract storage and voiding symptoms involves a contribution from both detrusor and outlet. As such, treatment of benign prostatic enlargement (BPE) +/- benign prostatic obstruction (BPO) with standard alpha-adrenergic blockade and 5-alpha reductase inhibitor therapy may leave a population of men with persistent and bothersome urinary storage symptoms. An abundance of adequately powered, randomized, placebo-controlled trials indicate that the use of antimuscarinics and beta-3 adrenergic agonists, either alone or in combination with standard BPE/BPO therapy, leads to improvement in storage symptoms. At the same time, metrics associated with urinary emptying, such as maximum flow rate, post-void residual urinary volume, and incidence of treatment associated urinary retention, appear to be stable and not significantly impacted by the addition of antimuscarinics. PMID- 28092070 TI - Current Bioengineering and Regenerative Strategies for the Generation of Kidney Grafts on Demand. AB - Currently in the USA, one name is added to the organ transplant waiting list every 15 min. As this list grows rapidly, fewer than one-third of waiting patients can receive matched organs from donors. Unfortunately, many patients who require a transplant have to wait for long periods of time, and many of them die before receiving the desired organ. In the USA alone, over 100,000 patients are waiting for a kidney transplant. However, it is a problem that affects around 6% of the word population. Therefore, seeking alternative solutions to this problem is an urgent work. Here, we review the current promising regenerative technologies for kidney function replacement. Despite many approaches being applied in the different ways outlined in this work, obtaining an organ capable of performing complex functions such as osmoregulation, excretion or hormone synthesis is still a long-term goal. However, in the future, the efforts in these areas may eliminate the long waiting list for kidney transplants, providing a definitive solution for patients with end-stage renal disease. PMID- 28092072 TI - Public Sector Employment Inequality in the United States and the Great Recession. AB - Historically in the United States, the public sector has served as an equalizing institution through the expansion of job opportunities for minority workers. This study examines whether the public sector continues to serve as an equalizing institution in the aftermath of the Great Recession. Using data from the Current Population Survey, I investigate changes in public sector employment between 2003 and 2013. My results point to a post-recession double disadvantage for black public sector workers: they are concentrated in a shrinking sector of the economy, and they are more likely than white and Hispanic public sector workers to experience job loss. These two trends are a historical break for the public sector labor market. I find that race and ethnicity gaps in public sector employment cannot be explained by differences in education, occupation, or any of the other measurable factors that are typically associated with employment. Among unemployed workers who most recently worked for the public sector, black women are the least likely to transition into private sector employment. PMID- 28092071 TI - Explaining the Immigrant Health Advantage: Self-selection and Protection in Health-Related Factors Among Five Major National-Origin Immigrant Groups in the United States. AB - Despite being newcomers, immigrants often exhibit better health relative to native-born populations in industrialized societies. We extend prior efforts to identify whether self-selection and/or protection explain this advantage. We examine migrant height and smoking levels just prior to immigration to test for self-selection; and we analyze smoking behavior since immigration, controlling for self-selection, to assess protection. We study individuals aged 20-49 from five major national origins: India, China, the Philippines, Mexico, and the Dominican Republic. To assess self-selection, we compare migrants, interviewed in the National Health and Interview Surveys (NHIS), with nonmigrant peers in sending nations, interviewed in the World Health Surveys. To test for protection, we contrast migrants' changes in smoking since immigration with two counterfactuals: (1) rates that immigrants would have exhibited had they adopted the behavior of U.S.-born non-Hispanic whites in the NHIS (full "assimilation"); and (2) rates that migrants would have had if they had adopted the rates of nonmigrants in sending countries (no-migration scenario). We find statistically significant and substantial self-selection, particularly among men from both higher-skilled (Indians and Filipinos in height, Chinese in smoking) and lower skilled (Mexican) undocumented pools. We also find significant and substantial protection in smoking among immigrant groups with stronger relative social capital (Mexicans and Dominicans). PMID- 28092073 TI - Erratum to: Quantifying Intrinsic and Extrinsic Contributions to Human Longevity: Application of a Two-Process Vitality Model to the Human Mortality Database. PMID- 28092074 TI - Biomimetic Coprecipitation of Silk Fibrin and Calcium Phosphate: Influence of Selenite Ions. AB - Large bone defect creates an urgent need for osteogenic biomaterials. However, bone nonunion and infection are choke points in the therapy of this disease. How to recruit the mesenchymal stem cells to defect sites and increase the cell viability are the critical processes. One effective method was the fabrication of biomimetic silk fibrin/selenium-doped hydroxyapatite (SF/HASe) material, which could create a niche for cell proliferation. So, the aim of the present study was to seek a facile route to prepare this biocomposites and investigate the osteogenic capability. Results showed that the biomimetic coprecipitation was a successful route to prepare SF/HASe biocomposites, which presented higher cell proliferation activity and better modulation of the selenite release during incubation in biological medium. Besides, the biocomposites exhibited weird and porous pot morphology. Such features could provide large surface area for the cells and proteins to attach. Silk fibrin, adhered onto the surface of hydroxyapatite (HA) crystals, plays a crucial impact on the release profile of selenite ions. The release behavior of the selenite ions exhibited stably slow release fashion. Therefore, it is feasible to employ SF/HASe biocomposites to repair bone defects and apply into the therapy of osteosarcoma postoperatively. PMID- 28092075 TI - Boron Affects Immune Function Through Modulation of Splenic T Lymphocyte Subsets, Cytokine Secretion, and Lymphocyte Proliferation and Apoptosis in Rats. AB - This study demonstrated the mechanisms of boron effects in a rat model and provided a scientific basis for the rational of boron use. These findings were achieved by investigating the effects of boron (10, 20, 40, 80, 160, 320, and 640 mg/L in drinking water or 1.5, 3, 6, 12, 24, 48, and 96 mg/kg BW) on rat serum immunoglobulins (IgGs), splenic cytokines, lymphocyte subsets, as well as on lymphocyte proliferation and apoptosis. Addition of 20 (3) and 40 (6) mg/L (mg/kg BW) of boron to drinking water significantly increased rat serum IgG concentrations, splenic IFN-gamma and IL-4 expression as well as the number of splenic CD3+, CD4+ and proliferating cell nuclear antigen (PCNA)+ cells. Supplementation of drinking water with 40 mg/L (6 mg/kg BW) boron also markedly increased splenic IL-2 expression and the CD4+/CD8+ cell ratio and reduced splenic CD8+ cell number. Supplementation with 80 mg/L (12 mg/kg BW) boron significantly increased CD3+ and PCNA+ cell numbers (P < 0.05) and decreased the IL-10 expression in the spleen. Addition of 320 (48) and 640 (96) mg/L (mg/kg BW) boron markedly reduced the serum IgG concentrations; splenic IL-2 and IL-10 expression; the number of CD3+, CD4+ and PCNA+ cells; and increased the number of splenic CD8+ and caspase-3+ cells and promoted caspase-3 expression in CD3+ cells. In conclusion, these findings suggest that the supplementation of rat drinking water with 20(3) and 40(6) mg/L (mg/kg BW) boron can markedly enhance humoral and cellular immune functions, while boron concentrations above 320 mg/L (48 mg/kg BW) can have an inhibitory effect or even toxicity on immune functions. These results exhibit a U-shaped response characteristic of low and high doses of boron supplementation on immune function and imply that proper boron supplementation in food for humans and animals could be used as an immunity regulator. PMID- 28092076 TI - Determination of Trace Elements in Cow Placenta by Tungsten Coil Atomic Emission Spectrometry. AB - Tungsten coil atomic emission spectrometry (WCAES) is used to determine trace levels of Mn (403.1 nm) and Cr (425.5 nm) in cow placenta. All samples were collected in Ilha Solteira, SP, Brazil. The instrumental setup is based on a tungsten filament extracted from 150 W, 15 V microscope light bulbs, a solid state power supply, fused silica lens, crossed Czerny-Turner spectrograph, and a thermoelectrically cooled charge-coupled device detector. The limits of detection (LOD) and quantification (LOQ) for Cr are 2 and 8 MUg L-1, and 20 and 60 MUg L-1 for Mn, respectively. Recoveries for 0.30 mg L-1 spikes of each analyte were in the range 93.0-103.0%, and relative standard deviation (RSD) was between 6.50 and 7.20% for both elements. Placenta samples were microwave-assisted digested with diluted HNO3 and H2O2 and analyzed by WCAES. The results for Cr and Mn were compared with values obtained by tandem inductively coupled plasma mass spectrometry (ICP-MS/MS). No statistically significant difference was observed between the different methods by applying a paired t test at a 95% confidence level. The average concentrations of Cr and Mn in the placentas evaluated were 0.95 +/- 0.22 and 2.64 +/- 0.39 MUg g-1, respectively. By using a short integration time, LODs for Cr and Mn were lower than values reported by recent works using a similar WCAES system. PMID- 28092077 TI - The reference frame for encoding and retention of motion depends on stimulus set size. AB - The goal of this study was to investigate the reference frames used in perceptual encoding and storage of visual motion information. In our experiments, observers viewed multiple moving objects and reported the direction of motion of a randomly selected item. Using a vector-decomposition technique, we computed performance during smooth pursuit with respect to a spatiotopic (nonretinotopic) and to a retinotopic component and compared them with performance during fixation, which served as the baseline. For the stimulus encoding stage, which precedes memory, we found that the reference frame depends on the stimulus set size. For a single moving target, the spatiotopic reference frame had the most significant contribution with some additional contribution from the retinotopic reference frame. When the number of items increased (Set Sizes 3 to 7), the spatiotopic reference frame was able to account for the performance. Finally, when the number of items became larger than 7, the distinction between reference frames vanished. We interpret this finding as a switch to a more abstract nonmetric encoding of motion direction. We found that the retinotopic reference frame was not used in memory. Taken together with other studies, our results suggest that, whereas a retinotopic reference frame may be employed for controlling eye movements, perception and memory use primarily nonretinotopic reference frames. Furthermore, the use of nonretinotopic reference frames appears to be capacity limited. In the case of complex stimuli, the visual system may use perceptual grouping in order to simplify the complexity of stimuli or resort to a nonmetric abstract coding of motion information. PMID- 28092079 TI - The goal of locomotion: Separating the fundamental task from the mechanisms that accomplish it. AB - Human locomotion has been well described but is still not well understood. This is largely true because the observable aspects of locomotion-neuromuscular activity that generates forces and motions-relate to both the task solution and the problem being solved. Identifying the fundamental task achieved in locomotion makes it possible to critically evaluate the motor control strategy used to accomplish the task goal. We contend that the readily observed movements and activities of locomotion should be considered mechanism(s). Our proposal is that the fundamental task of walking and running is analogous to flight, and should be defined in terms of the interaction of the individual's mass with the medium in which it moves: a low-density fluid for flight, or the supporting substrate for legged locomotion. A rigorous definition of the fundamental task can help identify the constraints and opportunities that influence its solution and guide the selection of appropriate mechanisms to accomplish the task effectively. The results from robotics-based modeling studies have demonstrated how the interaction of the mass and substrate can be optimized, making the goal of movement a defined trajectory of the individual's mass. We assessed these concepts by evaluating the ground reaction forces generated by an optimization model that satisfies the task but uses none of the mechanisms that are available to the human leg. Then we compared this model to normal human walking. Although it is obvious that the specific task of locomotion changes with a variety of movement challenges, clearly identifying the fundamental task of locomotion puts all other features in an interpretable context. PMID- 28092080 TI - Soluble Toll-like receptor 2 is a biomarker for sepsis in critically ill patients with multi-organ failure within 12 h of ICU admission. AB - Soluble TLR2 levels are elevated in infective and inflammatory conditions, but its diagnostic value with sepsis-induced multi-organ failure has not been evaluated. 37 patients with a diagnosis of severe sepsis/septic shock (sepsis) and 27 patients with organ failure without infection (SIRS) were studied. Median (IQR) plasma sTLR2 levels were 2.7 ng/ml (1.4-6.1) in sepsis and 0.6 ng/ml (0.4 0.9) in SIRS p < 0.001. sTLR2 showed good diagnostic value for sepsis at cut-off of 1.0 ng/ml, AUC:0.959. We report the ability of sTLR2 levels to discriminate between sepsis and SIRS within 12 h of ICU admission in patients with multi-organ failure. PMID- 28092078 TI - The dot-probe task to measure emotional attention: A suitable measure in comparative studies? AB - For social animals, attending to and recognizing the emotional expressions of other individuals is of crucial importance for their survival and likely has a deep evolutionary origin. Gaining insight into how emotional expressions evolved as adaptations over the course of evolution can be achieved by making direct cross-species comparisons. To that extent, experimental paradigms that are suitable for investigating emotional processing across species need to be developed and evaluated. The emotional dot-probe task, which measures attention allocation toward emotional stimuli, has this potential. The task is implicit, and subjects need minimal training to perform the task successfully. Findings in nonhuman primates, although scarce, show that they, like humans, have an attentional bias toward emotional stimuli. However, the wide literature on human studies has shown that different factors can have important moderating effects on the results. Due to the large heterogeneity of this literature, these moderating effects often remain unnoticed. We here review this literature and show that subject characteristics and differences in experimental designs affect the results of the dot-probe task. We conclude with specific recommendations regarding these issues that are particularly relevant to take into consideration when applying this paradigm to study animals. PMID- 28092082 TI - Brain Barrier Breakdown as a Cause and Consequence of Neuroinflammation in Sepsis. AB - The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) are important for the maintenance of brain homeostasis. During sepsis, peripheral production of proinflammatory cytokines and reactive oxygen species are responsible for structural alterations in those brain barriers. Thus, an increasing permeability of these barriers can lead to the activation of glial cells such as microglia and the production of cytotoxic mediators which in turn act on the brain barriers, damaging them further. Thereby, in this review, we try to highlight how the brain barrier's permeability is not only a cause but a consequence of brain injury in sepsis. PMID- 28092083 TI - Role of Dopamine D2/D3 Receptors in Development, Plasticity, and Neuroprotection in Human iPSC-Derived Midbrain Dopaminergic Neurons. AB - The role of dopamine D2 and D3 receptors (D2R/D3R), located on midbrain dopaminergic (DA) neurons, in the regulation of DA synthesis and release and in DA neuron homeostasis has been extensively investigated in rodent animal models. By contrast, the properties of D2R/D3R in human DA neurons have not been elucidated yet. On this line, the use of human-induced pluripotent stem cells (hiPSCs) for producing any types of cells has offered the innovative opportunity for investigating the human neuronal phenotypes at the molecular levels. In the present study, hiPSCs generated from human dermal fibroblasts were used to produce midbrain DA (mDA) neurons, expressing the proper set of genes and proteins typical of authentic, terminally differentiated DA neurons. In this model, the expression and the functional properties of the human D2R/D3R were investigated with a combination of biochemical and functional techniques. We observed that in hiPSC-derived mDA neurons, the activation of D2R/D3R promotes the proliferation of neuronal progenitor cells. In addition, we found that D2R/D3R activation inhibits nicotine-stimulated DA release and exerts neurotrophic effects on mDA neurons that likely occur via the activation of PI3K dependent mechanisms. Furthermore, D2R/D3R stimulation counteracts both the aggregation of alpha-synuclein induced by glucose deprivation and the associated neuronal damage affecting both the soma and the dendrites of mDA neurons. Taken together, these data point to the D2R/D3R-related signaling events as a biochemical pathway crucial for supporting both neuronal development and survival and protection of human DA neurons. PMID- 28092081 TI - Epigenetics in Alzheimer's Disease: Perspective of DNA Methylation. AB - Research over the years has shown that causes of Alzheimer's disease are not well understood, but over the past years, the involvement of epigenetic mechanisms in the developing memory formation either under pathological or physiological conditions has become clear. The term epigenetics represents the heredity of changes in phenotype that are independent of altered DNA sequences. Different studies validated that cytosine methylation of genomic DNA decreases with age in different tissues of mammals, and therefore, the role of epigenetic factors in developing neurological disorders in aging has been under focus. In this review, we summarized and reviewed the involvement of different epigenetic mechanisms especially the DNA methylation in Alzheimer's disease (AD), late-onset Alzheimer's disease (LOAD), familial Alzheimer's disease (FAD), and autosomal dominant Alzheimer's disease (ADAD). Down to the minutest of details, we tried to discuss the methylation patterns like mitochondrial DNA methylation and ribosomal DNA (rDNA) methylation. Additionally, we mentioned some therapeutic approaches related to epigenetics, which could provide a potential cure for AD. Moreover, we reviewed some recent studies that validate DNA methylation as a potential biomarker and its role in AD. We hope that this review will provide new insights into the understanding of AD pathogenesis from the epigenetic perspective especially from the perspective of DNA methylation. PMID- 28092084 TI - Iron Availability Compromises Not Only Oligodendrocytes But Also Astrocytes and Microglial Cells. AB - When disrupted, iron homeostasis negatively impacts oligodendrocyte (OLG) differentiation and impairs myelination. To better understand myelin formation and OLG maturation, in vivo and in vitro studies were conducted to evaluate the effect of iron deficiency (ID) not only on OLG maturation but also on astrocytes (AST) and microglial cells (MG). In vivo experiments in an ID model were carried out to describe maturational events during OLG and AST development and the reactive profile of MG during myelination when iron availability is lower than normal. In turn, in vitro assays were conducted to explore proliferating and maturational states of each glial cell type derived from control or ID conditions. Studies targeted NG2, PDGFRalpha, CNPAse, CC1, and MBP expression in OLG, GFAP and S100 expression in AST, and CD11b, ED1, and cytokine expression in MG, as well as BrDU incorporation in the three cell types. Our results show that ID affected OLG development at early stages, not only reducing their maturation capacity but also increasing their proliferation and affecting their morphological complexity. AST ID proliferated more than control ones and were more immature, much like OLG. Cytokine expression in ID animals reflected an anti inflammatory state which probably influenced OLG maturation. These results show that ID conditions alter all glial cells and may impact myelin formation, which could be regulated by a mechanism involving a cross talk between AST, MG, and oligodendrocyte progenitors (OPC). PMID- 28092085 TI - Evidence that NF-kappaB and MAPK Signaling Promotes NLRP Inflammasome Activation in Neurons Following Ischemic Stroke. AB - Multi-protein complexes, termed "inflammasomes," are known to contribute to neuronal cell death and brain injury following ischemic stroke. Ischemic stroke increases the expression and activation of nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) Pyrin domain containing 1 and 3 (NLRP1 and NLRP3) inflammasome proteins and both interleukin (IL)-1beta and IL-18 in neurons. In this study, we provide evidence that activation of either the NF kappaB and MAPK signaling pathways was partly responsible for inducing the expression and activation of NLRP1 and NLRP3 inflammasome proteins and that these effects can be attenuated using pharmacological inhibitors of these two pathways in neurons and brain tissue under in vitro and in vivo ischemic conditions, respectively. Moreover, these findings provided supporting evidence that treatment with intravenous immunoglobulin (IVIg) preparation can reduce activation of the NF-kappaB and MAPK signaling pathways resulting in decreased expression and activation of NLRP1 and NLRP3 inflammasomes, as well as increasing expression of anti-apoptotic proteins, Bcl-2 and Bcl-xL, in primary cortical neurons and/or cerebral tissue under in vitro and in vivo ischemic conditions. In summary, these results provide compelling evidence that both the NF-kappaB and MAPK signaling pathways play a pivotal role in regulating the expression and activation of NLRP1 and NLRP3 inflammasomes in primary cortical neurons and brain tissue under ischemic conditions. In addition, treatment with IVIg preparation decreased the activation of the NF-kappaB and MAPK signaling pathways, and thus attenuated the expression and activation of NLRP1 and NLRP3 inflammasomes in primary cortical neurons under ischemic conditions. Hence, these findings suggest that therapeutic interventions that target inflammasome activation in neurons may provide new opportunities in the future treatment of ischemic stroke. PMID- 28092087 TI - Retraction Note to: The Impact of Survivin on Prognosis and Clinicopathology of Glioma Patients: A Systematic Meta-Analysis. PMID- 28092086 TI - Anxiety-Related Behaviours Associated with microRNA-206-3p and BDNF Expression in Pregnant Female Mice Following Psychological Social Stress. AB - Stress during pregnancy can induce various psychological disorders in women. However, the association linking psychological stress during pregnancy with abnormal behaviours in females remains largely unknown. We employed a novel psychological stress model by introducing pregnant mice to witness the defeat process of their mated partner (WDPMP) and examined the effects of WDPMP on depression-/anxiety-like behaviours and on the expression of brain-derived neurotrophic factor (BDNF) and miR-206-3p in the hippocampus, medial prefrontal cortex (mPFC) and amygdala. Compared to pregnant control (PC) mice, pregnant stressed (PS) mice showed decreased sucrose preference during the late period of gestation, and after lactation, they spent less time in the open arms of the elevated plus maze and in the light chamber of the light/dark box. After lactation, decreased BDNF expression in both the hippocampus and mPFC of PS mice was found to be associated with enhanced miR-206-3p levels; meanwhile, elevated BDNF associated with decreased miR-206-3p expression was evident in the amygdala of the same PS mice. DNA methylation level in the Bdnf promoter did not show difference between PC and PS mice in the hippocampus. Transfection of miR-206-3p resulted in decreased BDNF levels in vitro. These results suggest that WDPMP stress during gestation can induce long-term mood alterations in pregnant mice, which may correlate with changes in miR-206-3p and BDNF expression in the hippocampus, mPFC and amygdala. PMID- 28092088 TI - Erratum to: Dihydromyricetin Improves Hypobaric Hypoxia-Induced Memory Impairment via Modulation of SIRT3 Signaling. PMID- 28092089 TI - Time-Dependent Lactate Production and Amino Acid Utilization in Cultured Astrocytes Under High Glucose Exposure. AB - Accumulating investigations have focused on the severity of central nervous system (CNS) complications in diabetic patients. The effects of the high glucose (HG) probably attribute to the metabolic disturbances in CNS. Astrocytes, with powerful ability of metabolic regulation, play crucial roles in physiological and pathological processes in CNS. Hence, an in-depth analysis as to metabolic alterations of astrocytes exposure to HG would facilitate to explore the underlying pathogenesis. In this study, the 1H NMR-based metabonomic approach was performed to characterize the metabolic variations of intracellular metabolites and corresponding culture media in a time-dependent manner. Our results revealed a significant elevation in lactate production and release. Four amino acids, leucine, isoleucine, methionine and tyrosine, were the most important metabolites for utilization. Also, profound disturbances of several metabolic pathways, including osmoregulation, energy metabolism, and cellular biosynthesis were observed. In that sense, the detailed information of astrocyte metabolism under HG exposure provides us a comprehensive understanding of the intrinsic metabolic disorders in CNS during hyperglycemia or diabetes. PMID- 28092090 TI - Prevalence of Mucopolysaccharidosis Types I, II, and VI in the Pediatric and Adult Population with Carpal Tunnel Syndrome (CTS). Retrospective and Prospective Analysis of Patients Treated for CTS. AB - BACKGROUND: We wanted to investigate whether the prevalence of mucopolysaccharidoses (MPS) I, II, and VI was higher than expected in a selected cohort of patients with carpal tunnel syndrome (CTS). CTS is a common finding in patients with MPS, and therefore we screened patients who had undergone surgery for CTS for undiagnosed MPS. PATIENTS AND METHODS: Patients who had been operated for CTS were found in databases from two hospitals. Furthermore, patients who had undergone surgery for CTS when under the age of 18 were retrieved from the National Patient Registry. All included patients had a filter paper blood spot sample taken that was subsequently analyzed enzymatically for MPS I, II, and VI. RESULTS: 425 patients were included. 402 patients tested negative in the first test. 23 had inconclusive result whereof 18 was negative in a second test. The remaining five patients had two inconclusive tests each and were referred for further examination at the Center for Inherited Metabolic Diseases where the diagnosis was excluded. Thus, all included patients were negative for both MPS I, II and VI. DISCUSSION/CONCLUSION: Though our sample size is relatively small, results indicate that MPS is not prevalent in a cohort of adult patients with monosymptomatic CTS, and that screening is not indicated in this setting. PMID- 28092091 TI - Preliminary Results on Long-Term Potentiation-Like Cortical Plasticity and Cholinergic Dysfunction After Miglustat Treatment in Niemann-Pick Disease Type C. AB - Niemann-Pick disease type C (NPC) is a rare autosomal recessive lysosomal storage disorder, which manifests clinically with a wide range of neurological signs and symptoms. We assessed multiple neurological, neuropsychological and neurophysiological biomarkers using a transcranial magnetic stimulation (TMS) multi-paradigm approach in two patients with NPC carrying a homozygous mutation in the NPC1 gene, and in two heterozygous family members.We assessed short interval intracortical inhibition (SICI), intracortical facilitation (ICF), long interval intracortical inhibition (LICI), short-latency afferent inhibition (SAI) and long-term potentiation (LTP)-like cortical plasticity with a paired associative stimulation (PAS) protocol.Baseline SAI and LTP-like plasticity were impaired in both patients with NPC and in the symptomatic heterozygous NPC1 gene mutation carrier. Only a limited decrease in SICI and ICF was observed, while LICI was within normal range in all subjects at baseline. After 12 months of treatment with miglustat, a considerable improvement in SAI and LTP-like plasticity was observed in both patients with NPC. In conclusion, these biomarkers could help to confirm the diagnosis of NPC, and may give an indication of prognostic outcomes in pharmacological trials. PMID- 28092092 TI - Domains of Daily Physical Activity in Children with Mitochondrial Disease: A 3D Accelerometry Approach. AB - Feasible, sensitive and clinically relevant outcome measures are of extreme importance when designing clinical trials. For paediatric mitochondrial disease, no robust end point has been described to date. The aim of this study was to select the domains of daily physical activity, which can be measured by 3D accelerometry, that could serve as sensitive end points in future clinical trials in children with mitochondrial disorders.In this exploratory observational study, 17 patients with mitochondrial disease and 16 age- and sex-matched controls wore 3D accelerometers at the upper leg, upper arm, lower arm and chest during one weekend. Using the raw data obtained by the accelerometers, we calculated the following outcome measures: (1) average amount of counts per hour the sensors were worn; (2) the maximal intensity; (3) the largest area under the curve during 30 min and (4) categorized activities lying, standing or being dynamically active. Measuring physical activity during the whole weekend was practically feasible in all participants. We found good face validity by visually correlating the validation videos and activity diaries to the accelerometer data-graphs. Patients with mitochondrial disorders had significantly lower peak intensity and were resting more, compared to their age- and sex-matched peers.Finally, we suggest domains of physical activity that could be included when measuring daily physical activity in children with mitochondrial disorders, preferably using more user-friendly devices. These include peak activity parameters for the arms (all patients) and legs (ambulatory patients). We recommend using or developing devices that measure these domains of physical activity in future clinical studies. PMID- 28092093 TI - Regenerative endodontics: a true paradigm shift or a bandwagon about to be derailed? AB - AIMS: Regenerative endodontic techniques (RETs) have been hailed as a paradigm shift for the management of traumatised non-vital immature permanent anterior teeth. In this article the aim was to critically appraise the literature with regards to the outcome of regenerative endodontics on root development. METHODS: Critical review of the literature where regenerative endodontic techniques have been used in the management of immature non-vital teeth with continuation of root development as the main outcome reported. RESULTS: Most studies published were in the form of case reports and series with very few randomised controlled trials with a high risk of bias. Continuation of root development following the use of RET has been shown to be unpredictable at best with lower success in those teeth losing vitality as a result of dental trauma. CONCLUSIONS: Despite the high success of regenerative endodontics in terms of periodontal healing including resolution of clinical and radiographic signs and symptoms of infection, continuation of root development remains an unpredictable outcome. The use of a blood clot as a scaffold in regenerative endodontics should be reviewed carefully as that might offer an environment for repair rather than regeneration. In addition, preservation of structures, such as Hertwig's epithelial root sheath, may have an important bearing on the success of this approach and should be further investigated. PMID- 28092094 TI - Comparison and evaluation of stresses generated by rapid maxillary expansion and the implant-supported rapid maxillary expansion on the craniofacial structures using finite element method of stress analysis. AB - BACKGROUND: The study aimed to evaluate and compare the stress distribution and 3 dimensional displacements along the craniofacial sutures in between the Rapid maxillary Expansion (RME) and Implant supported RME (I-RME). METHOD S: Finite element model of the skull and the implants were created using ANSYS software. The finite element model thus built composed of 537692 elements and 115694 nodes in RME model & 543078 elements and 117948 nodes with implants model. The forces were applied on the palatal surface of the posterior teeth to cause 5mm of transverse displacement on either side of the palatal halves, making it a total of 10mm. The stresses and the displacement values were obtained and interpreted. RESULTS: Varying pattern of stress and the displacements with both positive and negative values were seen. The maximum displacement was seen in the case of plain RME model and that too at Pterygomaxillary suture and Mid-palatal suture in descending order. In the case of I-RME maximum displacement was seen at Zygomaticomaxillary suture followed by Pterygomaxillary suture. The displacements produced in all the three planes of space for the plain RME model were greater in comparison to the Implant Supported RME model. And the stresses remained high for all the sutures in case of an I-RME. CONCLUSIONS: There is a definite difference in the stress and the displacement pattern produced by RME and I-RME model and each can be used according to the need of the patient. The stresses generated in case of conventional RME were considerably less than that of the I-RME for all the sutures. PMID- 28092095 TI - Noradrenergic transmission in the central medial thalamic nucleus modulates the electroencephalographic activity and emergence from propofol anesthesia in rats. AB - At present, the mechanisms by which general anesthetics causing loss of consciousness remain unclear. The central medial thalamic nucleus (CMT) is a rarely studied component of the midline thalamic complex, which is deemed to be a part of the nonspecific arousal system. Although the CMT participates in modulating arousal and receives excitatory noradrenergic projections from locus coeruleus, it remains unknown whether the noradrenergic pathway in the CMT takes part in modulating the arousal system. Therefore, we hypothesized that noradrenergic transmission in the CMT is involved in modulating induction and emergence of propofol anesthesia. First, we infused norepinephrine (NE) into the CMT to observe the role of CMT noradrenergic pathway in modulating the anesthetic state induced by propofol. The results showed that microinjection of NE into the CMT accelerated emergence from propofol anesthesia, but had no impact on the induction of or sensitivity to propofol anesthesia in rats. In addition, infusion of NE into the CMT caused electroencephalography changes in the prefrontal cortex and the anterior cingulate cortex. Finally, we used a whole-cell patch clamp to examine the effects of NE on neuronal excitability and GABAergic transmission in the CMT. In the CMT slices, propofol suppressed neuronal excitability and enhanced GABAergic transmission, while application of NE partly reversed these effects. These findings support the hypothesis that the CMT noradrenergic pathway plays an important role in modulating the emergence from general anesthesia. PMID- 28092096 TI - Associations between pre-eclampsia and protein C and protein S levels among pregnant Nigerian women. AB - OBJECTIVE: To evaluate levels of protein C and free protein S among women with pre-eclampsia, and determine whether there is a relationship between deficiencies and pre-eclampsia. METHODS: A cross-sectional study was conducted at a hospital in Nigeria from July 2013 to March 2014 among 90 pregnant women with pre eclampsia (blood pressure >=140/90 mm Hg, proteinuria >=300 mg in 24 hours) and 90 normotensive pregnant women (control group). Plasma levels of protein C and free protein S were analyzed by enzyme-linked immunosorbent assay, and protein C activity by a chromogenic method. RESULTS: Mean protein C antigen and activity levels did not differ between groups (P=0.639 and P=0.444, respectively). The incidence of protein C antigen and activity deficiency also did not differ (P=0.288 and P>0.99, respectively). The mean free protein S antigen level was higher among women with pre-eclampsia (54.48%+/-19.58%) than in the control group (47.23%+/-10.27%; P=0.004). No woman in the control group had protein S deficiency, as compared with 2 (2%) of the women with pre-eclampsia (P=0.497). No association was found between deficiencies of these proteins and pre-eclampsia. CONCLUSION: Deficiencies of protein C and free protein S are unlikely to be etiopathogenetic for pre-eclampsia; therefore, therapeutic intervention should focus on other potential pathogenetic pathways. PMID- 28092097 TI - Complications and parent satisfaction in pediatric osseointegrated bone conduction hearing implants. AB - OBJECTIVE: To assess long-term complication rate and parental satisfaction of osseointegrated bone conduction hearing implants (OBCHIs). STUDY DESIGN: Retrospective chart review of children undergoing OBCHIs. METHODS: A retrospective chart review of children undergoing OBCHIs for the treatment of conductive, mixed, and single-sided sensorineural hearing loss in children. RESULTS: Forty-five subjects were identified with 0.3 to 10.4 years of follow-up. The mean/median age and age range at implant were 9.0/7.8 and 1.7 to 19.1 years. The underlying hearing loss for the cohort included conductive (N = 30), sensorineural (N = 7), and mixed (N = 8) hearing loss. Conductive hearing loss, caused by aural atresia (62.9), was the most common indication for implantation. Fifty-eight complications occurred in 29 subjects, most related to skin infection or overgrowth. Seventeen events required revision surgery, and 18 required oral antibiotics and/or office-based cauterization. Children under the age of 5 years were more likely to have failure of osseointegration or require revision surgery. Parents of 33 subjects underwent a phone interview; 76% rated the overall satisfaction as satisfied or very satisfied. CONCLUSION: A large percentage of children undergoing OBCHI develop postoperative complications, and up to 44% require revision surgery-a figure higher than generally reported and higher than in adults. No factors were found to adequately explain the higher complication rates in children compared to adults. Despite the occurrence of complications, parents viewed this device as satisfactory from many perspectives. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2165-2170, 2017. PMID- 28092098 TI - Evaluation the ethno-pharmacological studies in Iran during 2004-2016: A systematic review. AB - Although Iran has a deep history in herbal medicine and great heritage of ancient medical scholars, few efforts have been made to evaluate ethnopharmacological aspects of medicinal plants in this country. In the present study, the authors have reviewed all important literature about the ethnopharmacological investigations on medicinal plants used in the last decade in Iran. All provinces of Iran were categorized according to a phytogeographical division. Information was collected through bibliographic investigations from scientific journals and books. Afterward, the data were analyzed through the construction of specific ecological regions of the country. Fifty-five references reporting medicinal plants in five ecological zones were retrieved. The Irano-Turanian subregion has produced the greatest number of publications in this field among others (47%). Results illustrate that the most reported botanical families were Lamiaceae and Asteraceae (28.57% and 27.73%, respectively). Among various illnesses reported for these plants, gastrointestinal (30.15%), respiratory problems (14.28%), diabetes (11.11%), and cold/flu (11.11%) were the most cited. The most frequently cited medicinal uses were attributed to decoction and infusion preparations. Iran has a rich history of knowledge about phytotherapy and has also a diverse geographical regions, and a plant flora that is a good candidate for drug discovery. Documentation of indigenous knowledge about herbal medicine used by Iranian tribes is vital for the future development of herbal drugs. Ethnopharmacological studies of Iranian folk medicine with quantitative analytical techniques are warranted to find drug candidates, and also to preserve the precious knowledge of the Iranian folk medicine. PMID- 28092100 TI - Comparing human resource planning models in dentistry: A case study using Canadian Armed Forces dental clinics. AB - OBJECTIVES: To compare two methods of allocating general dentists to Canadian Armed Forces (CAF) dental detachments: a dentist-to-population ratio model and a needs-based model. METHODS: Data obtained from CAF sources were analysed to compare models. Times assigned to treatment plan procedures were used as a proxy for treatment needs. Full-time equivalents (FTEs) were used as an indicator for the number of dentists allocated to each detachment. FTE values were adjusted for military dentists to account for time spent on compulsory nonclinical duties. The paired-samples t test was used to assess differences between the models for all clinics (dental detachments) and by clinic size. RESULTS: The dentist-to population ratio model for the CAF population (n=68 183) estimated an allocation of 83.25 FTE general dentists to CAF dental detachments. Based on a systematic sample of the CAF population (n=2226), the needs-based model estimated the requirement for 64.71 FTE general dentists. The average difference between models was 0.71 FTE (SE=0.273), which was statistically significant (P=0.015). In terms of differences by clinic size, differences were more pronounced in clinics serving more than 4000 CAF personnel (2.63 FTEs, SE=0.613, P=0.008). CONCLUSIONS: The findings reveal differences between estimation models of <1 FTE, with higher estimates produced from the dentist-to-population ratio model. A larger difference was found in clinics with larger populations. The perceived overestimation of dental human resource requirements suggests that changing to a needs-based model may result in cost savings. PMID- 28092099 TI - Calmodulin Binding to Death Receptor 5-mediated Death-Inducing Signaling Complex in Breast Cancer Cells. AB - Activation of death receptor-5 (DR5) leads to the formation of death-inducing signaling complex (DISC) for apoptotic signaling. TRA-8, a DR5 specific agonistic antibody, has demonstrated significant cytotoxic activity in vitro and in vivo without inducing hepatotoxicity. Calmodulin (CaM) that is overexpressed in breast cancer plays a critical role in regulating DR5-mediated apoptosis. However, the mechanism of CaM in regulating DR5-mediated apoptotic signaling remains unknown. In this study, we characterized CaM binding to DR5-mediated DISC for apoptosis in TRA-8 sensitive breast cancer cell lines using co-immunoprecipitation, fluorescence microscopic imaging, caspase signaling analysis, and cell viability assay. Results show that upon DR5 activation, CaM was recruited into DR5-mediated DISC in a calcium dependent manner. CaM antagonist, trifluoperazine (TFP), inhibited CaM recruitment into the DISC and attenuated DISC formation. DR5 oligomerization is critical for DISC formation for apoptosis. TFP decreased TRA-8 activated DR5 oligomerization, which was consistent with TFP's effect on DR5 mediated DISC formation. TFP and Ca2+ chelator, EGTA, impeded TRA-8-activated caspase-dependent apoptotic signaling, and TFP decreased TRA-8-induced cell cytotoxicity. These results demonstrated CaM binding to DR5-mediated DISC in a calcium dependent manner and may identify CaM as a key regulator of DR5-mediated DISC formation for apoptosis in breast cancer. J. Cell. Biochem. 118: 2285-2294, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28092101 TI - The cross-regulation between SOX15 and Wnt signaling pathway. AB - WNT/B-CATENIN signaling pathway is one of the key dysregulated pathways in different tumor types, which regulate the expression of several genes involved in cell proliferation, differentiation, and survival. This pathway is being modulated by sex-determining region Y-box (SOX) family genes. The functions of these genes are suggested as tumor suppressor or oncogene. SOX genes transcribe a group of transcription factors that play important roles in embryonic development and carcinogenesis. Among them, SOX15 is recently been identified as a novel tumor suppressor in pancreatic and esophagus cancers with a potential role in modulating Wnt/b-catenin signaling. This report summarizes the current knowledge about Wnt/b-catenin signaling pathway and its cross talk with SOX15 with particular emphasis on the value of SOX gene expression as prognostic or predictive biomarker in cancer. PMID- 28092103 TI - Species differences in hepatic biotransformation of the anthelmintic drug flubendazole. AB - Flubendazole (FLBZ) is a broad-spectrum benzimidazole anthelmintic used in pigs, poultry, and humans. It has been proposed as a candidate for development for use in elimination programmes for lymphatic filariasis and onchocerciasis in humans. Moreover, FLBZ has shown promise in cancer chemotherapy, particularly for neuroblastoma. This work investigated the hepatic carbonyl-reducing pathway of FLBZ in different species, including humans. Microsomal and cytosolic fractions were obtained from sheep, cattle, pig, hen, rat, and human liver. Both subcellular fractions of each species converted FLBZ into a reduced metabolite (red-FLBZ). The rate of microsomal red-FLBZ production was highest in sheep (1.92 +/- 0.13 nmol/min.mg) and lowest in pigs (0.04 +/- 0.02 nmol/min.mg); cytosolic red-FLBZ production ranged from 0.02 +/- 0.01 (pig) to 1.86 +/- 0.61 nmol/min.mg (sheep). Only subcellular fractions from sheep liver oxidized red-FLBZ to FLBZ in a NADP+ -dependent oxidative reaction. Liver microsomes from both pigs and humans transformed FLBZ to red-FLBZ and a hydrolyzed metabolite. Very significant differences in the pattern of FLBZ metabolism were observed among the tested species and humans. These results reinforce the need for caution in extrapolating data on metabolism, efficacy, and safety of drugs derived from studies performed in different species. PMID- 28092102 TI - MicroRNAs: Potential candidates for diagnosis and treatment of colorectal cancer. AB - Colorectal cancer (CRC) is known as the third common cancer worldwide and an important public health problem in different populations. Several genetics and environmental risk factors are involved in the development and progression of CRC including chromosomal abnormalities, epigenetic alterations, and unhealthy lifestyle. Identification of risk factors and biomarkers could lead to a better understanding of molecular pathways involved in CRC pathogenesis. MicroRNAs (miRNAs) are important regulatory molecules which could affect a variety of cellular and molecular targets in CRC. A large number of studies have indicated deregulations of some known tissue-specific miRNAs, for example, miR-21, miR-9, miR-155, miR-17, miR-19, let-7, and miR-24 as well as circulating miRNAs, for example, miR-181b, miR-21, miR-183, let-7g, miR-17, and miR-126, in patients with CRC. In the current review, we focus on the findings of preclinical and clinical studies performed on tissue-specific and circulating miRNAs as diagnostic biomarkers and therapeutic targets for the detection of patients at various stages of CRC. PMID- 28092104 TI - Quantitative proteomic analysis of gingival crevicular fluids from deciduous and permanent teeth. AB - AIM: Gingivitis commonly progresses to periodontitis in permanent dentition but rarely in deciduous teeth. Little is known about the biochemical differences between gingiva of deciduous and permanent teeth. Here, we compared the protein profiles of gingival crevicular fluids (GCF) from the gingiva of deciduous and permanent teeth. MATERIALS AND METHODS: Forty children with mixed dentition (Hellman's dental age IIIA) were selected and GCF samples were collected from deciduous cuspids and central incisors in the maxilla. Pairs of GCF samples were labelled using isobaric tags to permit quantitative comparison of protein abundance in the samples using liquid chromatography-electron spray ionization tandem mass spectrometry. RESULTS: Sixty-two proteins were upregulated in deciduous teeth GCF and 54 in permanent teeth GCF. In particular, neutrophil derived proteins, including myeloperoxidase and lactoferrin, were repeatedly higher in deciduous teeth GCF than in permanent teeth GCF. These differences were verified using ELISA (p < 0.01). In contrast, immunoglobulin components were upregulated in permanent teeth GCF. CONCLUSIONS: Neutrophil-related proteins were enriched in deciduous teeth GCF and immunoglobulins in permanent teeth GCF. This suggests that neutrophil accumulation plays a protective role in innate immunity against bacterial infection in gingival tissue of deciduous teeth. PMID- 28092105 TI - Effectiveness of water fluoridation in the prevention of dental caries across adult age groups. AB - BACKGROUND: Lifetime access to fluoridated water (FW) is associated with lower caries experience. However, assessing this association in adults is likely affected by age. Cohort stratification and categorization of per cent lifetime access to fluoridated water (% LAFW) within cohorts are current approaches to this assessment. These approaches require an examination of the % LAFW and caries experience variation within and across age groups and their association to inform future analyses. OBJECTIVE: This secondary analysis aimed to examine the age group variation in % LAFW and caries experience; and the association of % LAFW with caries within and across age groups of adults. METHODS: A secondary analysis was undertaken using the Australian National Survey of Adult Oral Health 2004 2006 data on 4090 persons aged 15-91 years randomly sampled by a stratified, multistage probability method. Study participants underwent an interview, an oral examination by trained and standardized dentists to determine decayed, missing or filled tooth surfaces (DMFS) and a mailed self-complete questionnaire which collected residential history to calculate % LAFW. Variations in % LAFW and DMFS across age groups (15-34; 35-44; 45-54; 55+) were examined. Multivariable regression log-link models were generated for DMFS score within each age group. RESULTS: The age groups varied in values and distribution of % LAFW. Caries experience was strongly associated with age. % LAFW was significantly associated with DMFS score in the two younger age groups, but not in the others. Multivariable regression models showed that the highest % LAFW quartile had significantly lower DMFS count than the lowest quartile in the two younger age groups (mean ratios: 0.67 and 0.78, respectively), controlling for other covariates. CONCLUSION: Access to FW was associated with caries experience in Australian adults. The magnitude of associations varied between age groups, dependent on the natural history of caries and its measurement by DMFS. PMID- 28092106 TI - A randomised controlled trial examining the effect of acupuncture at the EX-HN3 (Yintang) point on pre-operative anxiety levels in neurosurgical patients. AB - Pre-operative anxiety is an unpleasant state of psychological distress that occurs in up to 87% of patients awaiting neurosurgical procedures. Sedative medication is undesirable in this population due to the need for early postoperative neurological assessment. Acupuncture has previously been shown to reduce pre-operative anxiety, but studies involving neurosurgical patients are lacking. This single-centre, prospective, randomised controlled trial was designed to determine the effect of acupuncture at the EX-HN3 (Yintang point) on pre-operative anxiety levels in neurosurgical patients. The study was prospectively registered before participant recruitment. After measuring baseline anxiety levels, 128 patients were randomly allocated in a 1:1 ratio by a web based computer program to receive either acupuncture at the EX-HN3 (Yintang) point (acupuncture group) or no intervention (control group). Participants were not blinded, but all analyses were performed by a member of the research team who was unaware of the group allocation. The primary outcome measure was anxiety level after 30 min, as measured by the six-item short form of the State-Trait Anxiety Inventory (possible score range 20-80). Sixty-two patients in each group were subsequently analysed. Median (IQR [range]) anxiety State-Trait Anxiety Inventory score reduced significantly in the acupuncture group (46.7 (36.7-53.3 [23.3-70.0]) to 40.0 (30.0-46.7) [20.0-53.3]), p < 0.001), with no change seen in the control group (41.7 (33.3-53.3 [20.0-76.7]) to 43.3 (36.7-50.0 [20.0-76.7]), p = 0.829). There were no adverse events in either group. Acupuncture at the EX HN3 point reduces pre-operative anxiety levels in patients awaiting neurosurgery. PMID- 28092107 TI - RSV associated hospitalizations in children in Karachi, Pakistan: Implications for vaccine prevention strategies. AB - Major progress is being made in vaccines against Respiratory Syncytial Virus (RSV), with multiple vaccine candidates currently in the clinical phase of development. Making an investment case for public sector financing of RSV vaccine will require estimation of burden, cost-effectiveness, and impact. The aim of this study is to determine the proportion, age distribution and clinical spectrum of RSV associated hospitalizations in children in Karachi, Pakistan. A three years prospective study was conducted at the Aga Khan University Hospital in Karachi, a city of 20 million in south Pakistan, from August 2009 to June 2012. Children less than five years old admitted with acute respiratory infections (ARI) were enrolled. Throat swabs were collected and tested for RSV using real time PCR. Multivariable log binomial regression analysis was performed to identify the associated factors of RSV infection. Out of 1150 children enrolled, RSV was detected among 223 (19%). Highest rate of RSV detection was in young infants less than 3 months of age (48/168, 29%), which accounted for 22% of all RSV detected. Most common diagnosis in RSV positive infants (<12 months of age) was bronchiolitis followed by pneumonia, while in older children between the ages of one and 5 years of age, pneumonia and asthma were the most common diagnosis. Although identified year-round, RSV was most prevalent from August to October with peak in September, coinciding with the rainy season. This study identified RSV to be independently associated with younger age (P = 0.036), rainy season (P < 0.001), post-tussive emesis (P = 0.008), intubation (P = 0.003), and discharge diagnosis of bronchiolitis (P = 0.004). Vaccines against RSV that target this age group are likely to yield remarkable benefit. PMID- 28092108 TI - Pharmacokinetics and pharmacodynamics of the injectable formulation of methadone hydrochloride and methadone in lipid nanocarriers administered orally to horses. AB - We investigated the thermal, electrical and mechanical antinociceptive and physiological effects (heart rate, respiratory rate, arterial blood pressure, head height and abdominal auscultation score), and pharmacokinetics, of 0.5 mg/kg of the injectable formulation (ORAL) or nanoparticulated methadone (NANO) given orally, in six adult mares, using a crossover, blind and prospective design. Repeated-measure models were used to compare parametric data between and within treatments, followed by Tukey's test. Nonparametric data were analysed with Wilcoxon signed-rank, adjusted by Bonferroni tests. Blood samples were also collected up to 6 h after dosing for plasma drug quantification by LC-MS/MS. Methadone pharmacokinetic parameters were determined by noncompartmental and compartmental approaches. There were no differences in pharmacodynamic parameters. No statistical differences were observed in the pharmacokinetic parameters from noncompartmental analysis for both groups, except a significant decrease in peak plasma concentration, increase in apparent volume of distribution per fraction absorbed (Vdss /F) and increased mean residence time (MRT) for NANO. One-compartment open model with first order elimination best described the pharmacokinetic profiles for both groups. Neither ORAL nor NANO administered orally to horses produced antinociception. The nanoencapsulated formulation of methadone given orally to horses did not improve methadone pharmacokinetic parameters or increased systemic body exposure to methadone. PMID- 28092109 TI - Guidelines on red cell transfusion in sickle cell disease. Part I: principles and laboratory aspects. PMID- 28092110 TI - Simultaneous detection of three sex steroid hormone classes using a novel yeast based biosensor. AB - A biosensor detecting estrogens, progestogens, and androgens in complex samples and in a single step is described. Three Arxula adeninivorans yeast strains were created, each strain producing a different recombinant human hormone receptor and a different fluorescent reporter protein. These strains were then mixed to create G1212/YRC102-hHR-fluo, the biological component of the biosensor. During incubation with G1212/YRC102-hHR-fluo, hormones present in a sample bind to their target receptor, which leads to the production of a specific fluorescent protein. Three fluorescence scans of the yeast suspension determine which fluorescence protein has been produced, thus revealing which hormone receptor (estrogen, progesterone, and androgen) has been activated by the hormones or hormone mimics present in the sample. The biosensor has similar sensitivities to the existing A. adeninivorans cell-based assays. The detection of the three hormone classes in one single experiment reduces the labor and time required to assay for the three hormone classes. The biosensor was also trialed with animal serum samples for the detection of progestogens, androgens, and estrogens and gave results that correlated well with ELISA analysis in case of progestogens. These results highlight the potential usefulness of the biosensor for comprehensive determination of hormone status in samples from veterinary origin. Biotechnol. Bioeng. 2017;114: 1539-1549. (c) 2017 Wiley Periodicals, Inc. PMID- 28092111 TI - Design and Synthesis of 5-Substituted Benzo[d][1,3]dioxole Derivatives as Potent Anticonvulsant Agents. AB - A series of 5-substituted benzo[d][1,3]dioxole derivatives was designed, synthesized, and tested for anticonvulsant activity using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens. Neurotoxicity was determined by rotarod test. In the preliminary screening, six compounds, 3a, 3c, 3d, and 4d-f, showed promising anticonvulsant activities in the MES model, and compounds 4c and 4d exhibited full protection against seizures at doses of 300 mg/kg in the scPTZ model. Among the synthesized compounds, 3c as the most active compound showed high protection against the MES-induced seizures with an ED50 value of 9.8 mg/kg and a TD50 value of 229.4 mg/kg after intraperitoneal injection into mice, thus providing compound 3c with a high protective index (TD50 /ED50 ) of 23.4 comparable to those of reference antiepileptic drugs. PMID- 28092112 TI - Aquaporin-2 excretion in hospitalized patients with cirrhosis: Relation to development of renal insufficiency and mortality. AB - BACKGROUND AND AIM: Urinary aquaporin-2 (AQP2) is a parameter of water transport in the principal cells in the distal part of the nephron and involved in water retention in cirrhosis and may be a marker of renal function. The aim of the study was to evaluate AQP2 as a predictor of renal insufficiency and death in patients with cirrhosis. METHODS: Urine samples from 199 patients (90 patients without organ failure [Group 1], 58 patients with organ failure excluding renal failure [Group 2], and 51 patients with organ failure including renal failure [Group 3]) from the CANONIC study were analyzed for urine AQP2 and urine osmolality. RESULTS: There was no difference in AQP2 between the three groups. Urine osmolality was significantly lower in patients in Group 3 versus Group 1 and Group 2 (P = 0.0004). No relation was found between AQP2 and glomerular filtration rate or creatinine; however, AQP2 was a significant predictor of the development of renal insufficiency (P = 0.0485). In a univariate analysis, AQP2 was a significant predictor of 14 and 28-day survival, but this was not confirmed in multivariate analysis. CONCLUSIONS: Aquaporin-2 was not associated with disease severity or markers of renal function but was a predictor for the development of renal insufficiency and death. Therefore, its future use as marker of renal insufficiency could be promising, but further research is needed before it can be considered a clinical useful tool. PMID- 28092113 TI - Hemodialysis Treatment Time: As Important as it Seems? AB - Hemodialysis treatment time and Kt/V can both be considered to be primary measures of hemodialysis adequacy, because when either goes to zero, mortality is certain in patients without residual kidney function. Treatment time is important, but it needs to be adjusted based on surface-area-normalized Kt/V, residual kidney function, and expected ultrafiltration rate. Rescaling dose of dialysis measured as Kt/V to body surface area prevents ultrashort dialysis in small patients, women, and children with minimal residual kidney function. Most if not all of the observational studies of associations between outcome and dialysis session length are probably confounded by dose targeting bias. Once adequate Kt/V (taking into account body surface area) has been provided, adequate dialysis time probably is most relevant in terms of limiting the need for a high fluid removal rate. The latter may adversely impact survival by causing recurrent ischemia to cardiovascular and other tissues. There is little high-quality evidence at this time to support a minimum 4-hour treatment time for all patients, regardless of body size, solute removal, or residual kidney function. On the other hand, there is little evidence that prolonging weekly treatment time up to 24 hours per week is harmful. The final decision regarding treatment time is best individualized, based on patient acceptability and experience, residual kidney function, body surface-area-normalized Kt/V, and expected ultrafiltration rate. PMID- 28092114 TI - Sleep-disordered breathing in pediatric head and neck vascular malformations. AB - OBJECTIVES: To determine the prevalence of sleep-disordered breathing (SDB) symptoms among children with head and neck vascular malformations and to compare obstructive sleep apnea (OSA)-18 scores between children with head and neck vascular malformations and children with non-head and neck vascular malformations. STUDY DESIGN: Retrospective cohort and prospective cross-sectional studies METHODS: Forty-three pediatric subjects with head and neck vascular malformations evaluated at a tertiary-care multidisciplinary vascular anomalies center were included in a retrospective cohort study. Eighty-three consecutive pediatric subjects with vascular malformations evaluated at the same center were included in the prospective cross-sectional study. RESULTS: In the retrospective cohort study, 20 (47%) subjects with head and neck malformations had documented SDB symptoms. Of those with SDB symptoms, five (25%) required long-term tracheotomy. The children with SDB symptoms had greater vascular malformation size, more extensive pharyngeal involvement, greater vascular malformation mass effect on airway, and closer proximity of malformation to airway when compared to children without SDB symptoms. For the prospective cross-sectional study, 23% of pediatric subjects had malformations of the head and neck. Those with head and neck malformations had a higher OSA-18 score and a lower overall quality of life (QOL) score when compared to subjects with non-head and neck malformations. CONCLUSION: Nearly half of children with head and neck vascular malformations have SDB symptoms. Children with head and neck vascular malformations have a higher OSA-18 score and lower overall QOL score when compared to children with non-head and neck vascular malformations. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2159-2164, 2017. PMID- 28092115 TI - Fecal calprotectin level in healthy children aged less than 4 years in South Korea. AB - BACKGROUND: Fecal calprotectin (FC) is non-invasive inflammatory marker indicating various bowel diseases. However, the median-specific cut-off values and the standard deviations (SD) of the FC levels in each age group <4 years were not elucidated. METHODS: Healthy volunteers were enrolled from four kindergartens. A questionnaire was used to confirm that the children met the inclusion criteria, and several demographics and history of bowel symptoms were collected. The FC level was measured. RESULTS: A total of 234 healthy children aged between 6 months and 4 years were recruited. The median FC concentration of all participants was 245 MUg/g (range 12-1033 MUg/g, mean 68.5 MUg/g, SD 123.12 MUg/g). The children were divided into six age groups. The upper limit of 95% CI of median FC values was 135 MUg/g in 7-12 months group, 65 MUg/g in 13-18 months group, 55 MUg/g in 19-24 months group, 40 MUg/g in 25-30 months group, 21 MUg/g in 31-36 months group, and 12 MUg/g in 37-48 months group. A negative correlation trend was found between the age and the FC concentration. CONCLUSION: This is the first study to present the FC median levels in the specific age groups <4 years in Korea. We found a FC level reduction with age, indicating a bowel maturation process and decreased intestinal permeability of the intestinal mucosa. In our study, FC levels reached the values of 50 MUg/g around the age of 2 years. PMID- 28092116 TI - Changes in thyroid cancer incidence, post-2009 American Thyroid Association guidelines. AB - BACKGROUND: The thyroid cancer incidence rate has tripled in the United States since the 1980s, especially among women and small-sized tumors. This trend has been attributed to increased detection due to the availability of ultrasound and fine-needle aspiration technology. In 2009, the American Thyroid Association (ATA) released revisions to their guidelines for well-differentiated thyroid cancers. OBJECTIVE: To examine trends in thyroid cancer incidence rates by tumor size and gender following the 2009 ATA guideline revisions. METHODS: Cases of differentiated thyroid cancer diagnosed from 2000 to 2012 were analyzed from the National Cancer Institute Surveillance Epidemiology and End Results program, 18 registries. Trends in incidence rates based on gender (males, females) and tumor size (< 1.0 cm, 1.0-2.9 cm, 3.0-3.9 cm, >= 4.0 cm) were analyzed using Joinpoint Regression and reported as the annual percentage change (APC). RESULTS: From 2000 to 2009, overall thyroid cancer incidence rates increased rapidly by about 8% per year in both sexes. Incidence rates increased across all tumor sizes, but especially in tumors 1.0 to 2.9 cm (men, APC = 7.7; women, APC = 7.8) and < 1.0 cm (men, APC = 7.8; women = 10.9) for both genders. Since 2009, the trend slowed in men (APC = 3.0) and women (APC = 2.8). The deceleration among females was confined to tumors less than 2.9 cm. Trends for all size groups in males remained constant from 2000 to 2012. CONCLUSION: The rapid increase in thyroid cancer incidence rates over the past three decades has recently slowed, especially among small-sized cancers and women, which coincides with the 2009 ATA guideline revisions. LEVEL OF EVIDENCE: 2c. Laryngoscope, 127:2437-2441, 2017. PMID- 28092117 TI - Directed balloon cytology of the esophagus: A novel device for obtaining circumferential cytologic sampling. AB - OBJECTIVE: Current methods of obtaining esophageal cytology include brush biopsy and blind balloon sampling, among others. These methods can be time-consuming if performed in accordance with acknowledged standards. Further, exact site localization can prove to be difficult. We describe a novel device for esophageal sampling using an esophageal balloon with debriding strips contained within the pleats of the balloon. Inflation brings the latter in contact with the surface to be sampled. Cell capture was compared with the commonly used brush technique in a pig model. METHODS: Separate balloon and standard brush cytology samples were collected from a pig model. Smear and cell pellet preparations were compared regarding cell density and total volume. RESULTS: Adequate samples were obtained with both the brush and balloon. On the cell smear preparations, the cell density was greater when obtained with balloon sampling. Further, the cell pellet volume was significantly greater with the latter as well. The intact morphology of individual rafts of squamous epithelial cells also was comparable between the two methods. In addition, the balloon provided precise mapping of the cytology sites in contrast to the standard brush technique. CONCLUSION: We present an innovative new balloon technology for esophageal sampling, which demonstrated a decreased sampling time interval, precise mapping, and increased cellular volume when compared to a commonly used brush technique. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:1032-1035, 2017. PMID- 28092118 TI - Incorporation of CT-based measurements of trunk anatomy into subject-specific musculoskeletal models of the spine influences vertebral loading predictions. AB - We created subject-specific musculoskeletal models of the thoracolumbar spine by incorporating spine curvature and muscle morphology measurements from computed tomography (CT) scans to determine the degree to which vertebral compressive and shear loading estimates are sensitive to variations in trunk anatomy. We measured spine curvature and trunk muscle morphology using spine CT scans of 125 men, and then created four different thoracolumbar spine models for each person: (i) height and weight adjusted (Ht/Wt models); (ii) height, weight, and spine curvature adjusted (+C models); (iii) height, weight, and muscle morphology adjusted (+M models); and (iv) height, weight, spine curvature, and muscle morphology adjusted (+CM models). We determined vertebral compressive and shear loading at three regions of the spine (T8, T12, and L3) for four different activities. Vertebral compressive loads predicted by the subject-specific CT based musculoskeletal models were between 54% lower to 45% higher from those estimated using musculoskeletal models adjusted only for subject height and weight. The impact of subject-specific information on vertebral loading estimates varied with the activity and spinal region. Vertebral loading estimates were more sensitive to incorporation of subject-specific spinal curvature than subject specific muscle morphology. Our results indicate that individual variations in spine curvature and trunk muscle morphology can have a major impact on estimated vertebral compressive and shear loads, and thus should be accounted for when estimating subject-specific vertebral loading. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2164-2173, 2017. PMID- 28092119 TI - Preserved Affective Sharing But Impaired Decoding of Contextual Complex Emotions in Alcohol Dependence. AB - BACKGROUND: Prior research has repeatedly shown that alcohol dependence is associated with a large range of impairments in psychological processes, which could lead to interpersonal deficits. Specifically, it has been suggested that these interpersonal difficulties are underpinned by reduced recognition and sharing of others' emotional states. However, this pattern of deficits remains to be clarified. This study thus aimed to investigate whether alcohol dependence is associated with impaired abilities in decoding contextual complex emotions and with altered sharing of others' emotions. METHODS: Forty-one alcohol-dependent individuals (ADI) and 37 matched healthy individuals completed the Multifaceted Empathy Test, in which they were instructed to identify complex emotional states expressed by individuals in contextual scenes and to state to what extent they shared them. RESULTS: Compared to healthy individuals, ADI were impaired in identifying negative (Cohen's d = 0.75) and positive (Cohen's d = 0.46) emotional states but, conversely, presented preserved abilities in sharing others' emotional states. CONCLUSIONS: This study shows that alcohol dependence is characterized by an impaired ability to decode complex emotional states (both positive and negative), despite the presence of complementary contextual cues, but by preserved emotion-sharing. Therefore, these results extend earlier data describing an impaired ability to decode noncontextualized emotions toward contextualized and ecologically valid emotional states. They also indicate that some essential emotional competences such as emotion-sharing are preserved in alcohol dependence, thereby offering potential therapeutic levers. PMID- 28092120 TI - Pediatric peritonsillar abscess: Outcomes and cost savings from using transcervical ultrasound. AB - OBJECTIVES: 1) To analyze clinical outcomes of children stratified by ultrasound into three diagnoses: acute tonsillitis, peritonsillar phlegmon, and abscess; and 2) To compare clinical outcomes and financial impact between children who underwent ultrasound protocol to those who did not. STUDY DESIGN: Retrospective analysis between two cohorts: ultrasound protocol group and control group. METHODS: Children with peritonsillar abscess (PTA) diagnosed in the emergency department (ED) were enrolled during a 2-year period for transcervical ultrasound evaluation of bilateral tonsillar fossae. Data from a cohort of patients with PTA prior to ultrasound screening were also collected from retrospective chart review. Outcome variables were analyzed using multivariate logistic regression. RESULTS: Seventy-eight children (mean 12.3 years) were enrolled in the ultrasound protocol, compared to 101 children (mean 13.6 years) evaluated using traditional methods of examination and/or computed tomography (CT) imaging. Demographics between the two groups were not significantly different. Only one-third of patients presumed to have PTA by ED staff had ultrasound findings consistent with abscess. Overall treatment failure rate was 8%, requiring readmission or surgical intervention for abscess. Length of stay, surgical drainage, and radiation exposure from CT scans were reduced significantly in the ultrasound group (P < 0.006). Differences in readmission rates and mean charges between the two groups did not reach significance. CONCLUSION: Peritonsillar abscess is a common infection in the pediatric population, but diagnosis can be challenging. Transcervical ultrasound is a safe, cost-effective, and accurate modality to help stratify patients into medical and surgical treatment arms. LEVEL OF EVIDENCE: 3b. Laryngoscope, 127:1924-1929, 2017. PMID- 28092121 TI - Hox functional diversity: Novel insights from flexible motif folding and plastic protein interaction. AB - How the formidable diversity of forms emerges from developmental and evolutionary processes is one of the most fascinating questions in biology. The homeodomain containing Hox proteins were recognized early on as major actors in diversifying animal body plans. The molecular mechanisms underlying how this transcription factor family controls a large array of context- and cell-specific biological functions is, however, still poorly understood. Clues to functional diversity have emerged from studies exploring how Hox protein activity is controlled through interactions with PBC class proteins, also evolutionary conserved HD containing proteins. Recent structural data and molecular dynamic simulations add further mechanistic insights into Hox protein mode of action, suggesting that flexible folding of protein motifs allows for plastic protein interaction. As we discuss in this review, these findings define a novel type of Hox-PBC interaction, weak and dynamic instead of strong and static, hence providing novel clues to understanding Hox transcriptional specificity and diversity. PMID- 28092122 TI - How Size Determines the Value of Gold: Economic Aspects of Wet Chemical and Laser Based Metal Colloid Synthesis. AB - Gold is one of the most valuable materials, and its monetary value is enhanced by size reduction from bullions to colloidal nanoparticles by a factor of 450. Wet chemical reduction with subsequent centrifugation and pulsed laser ablation in liquids are frequently used for pure colloidal gold synthesis. Both methods provide similar physicochemical nanoparticle properties, but are very different synthesis techniques. However, the costs inherent to these methods are surprisingly seldom discussed. Both methods have in common that the labor effort poses the majority of synthesis costs. Besides an increase in batch size and mass concentration, especially an increase of the nanoparticle productivity via higher laser power and centrifugation capacity reduces synthesis costs if pilot- or industrial-scale applications are intended. In this case, laser-based synthesis is more economical if its productivity exceeds a break-even value of 550 mg h-1 , where the costs arising are limited by the metal costs. In contrast to industrial scale production, wet-chemical synthesis is more feasible for laboratory-scale applications, especially if the advantageous nanoparticle properties provided by laser ablation in liquids are not needed. PMID- 28092123 TI - Complex Hollow Nanostructures: Synthesis and Energy-Related Applications. AB - Hollow nanostructures offer promising potential for advanced energy storage and conversion applications. In the past decade, considerable research efforts have been devoted to the design and synthesis of hollow nanostructures with high complexity by manipulating their geometric morphology, chemical composition, and building block and interior architecture to boost their electrochemical performance, fulfilling the increasing global demand for renewable and sustainable energy sources. In this Review, we present a comprehensive overview of the synthesis and energy-related applications of complex hollow nanostructures. After a brief classification, the design and synthesis of complex hollow nanostructures are described in detail, which include hierarchical hollow spheres, hierarchical tubular structures, hollow polyhedra, and multi-shelled hollow structures, as well as their hybrids with nanocarbon materials. Thereafter, we discuss their niche applications as electrode materials for lithium-ion batteries and hybrid supercapacitors, sulfur hosts for lithium-sulfur batteries, and electrocatalysts for oxygen- and hydrogen-involving energy conversion reactions. The potential superiorities of complex hollow nanostructures for these applications are particularly highlighted. Finally, we conclude this Review with urgent challenges and further research directions of complex hollow nanostructures for energy-related applications. PMID- 28092124 TI - Active Site Mapping of Xylan-Deconstructing Enzymes with Arabinoxylan Oligosaccharides Produced by Automated Glycan Assembly. AB - Xylan-degrading enzymes are crucial for the deconstruction of hemicellulosic biomass, making the hydrolysis products available for various industrial applications such as the production of biofuel. To determine the substrate specificities of these enzymes, we prepared a collection of complex xylan oligosaccharides by automated glycan assembly. Seven differentially protected building blocks provided the basis for the modular assembly of 2-substituted, 3 substituted, and 2-/3-substituted arabino- and glucuronoxylan oligosaccharides. Elongation of the xylan backbone relied on iterative additions of C4 fluorenylmethoxylcarbonyl (Fmoc) protected xylose building blocks to a linker functionalized resin. Arabinofuranose and glucuronic acid residues have been selectively attached to the backbone using fully orthogonal 2-(methyl)naphthyl (Nap) and 2-(azidomethyl)benzoyl (Azmb) protecting groups at the C2 and C3 hydroxyls of the xylose building blocks. The arabinoxylan oligosaccharides are excellent tools to map the active site of glycosyl hydrolases involved in xylan deconstruction. The substrate specificities of several xylanases and arabinofuranosidases were determined by analyzing the digestion products after incubation of the oligosaccharides with glycosyl hydrolases. PMID- 28092125 TI - Rattle-Structured Upconversion Nanoparticles for Near-IR-Induced Suppression of Alzheimer's beta-Amyloid Aggregation. AB - Rose bengal (RB)-loaded upconverting nanocomposites are synthesized as a near infrared (NIR)-responsive inhibitor of Abeta aggregation. Rattle-structured, organosilica shell (ROS) is deposited on NaYF4 :Yb,Er nanocrystals (UCNPs) for high loading efficiency and disaggregation of RB. RB/UCNP@ROS successfully inhibits Abeta self-assembly under NIR irradiation by generating 1 O2 . Furthermore, photoexcited RB/UCNP@ROS is effective in suppressing Abeta-induced cytotoxicity. PMID- 28092126 TI - Stability of a novel corticosteroid nasal irrigation solution: betamethasone 17 valerate added to extemporaneously prepared nasal irrigation solutions. AB - BACKGROUND: There are no commercially available nasal irrigation solutions containing corticosteroids. Instead, such preparations are extemporaneously prepared by adding existing corticosteroid formulations to nasal irrigation solutions. The stability of the corticosteroid betamethasone 17-valerate (B17V), in nasal irrigation solutions of different compositions and pH and stored under different temperatures, was studied to determine the optimal choice of solution and storage conditions. METHODS: Triplicate extemporaneous preparations made with B17V were prepared by adding a predetermined volume of B17V lotion to each nasal irrigation solution: normal saline (NS), sodium bicarbonate (NaHCO3 ) powder dissolved in tap water, and a commercially available powder mixture (FLO Sinus Care Powder), dissolved in tap water or pre-boiled tap water. Preparations were stored at 30 degrees C and 4 degrees C. Sampling was carried out at 0, 1, 2, 6, and 24 hours. The concentrations of B17V and its degradation compound, betamethasone 21-valerate (B21V), were determined by high-performance liquid chromatography. RESULTS: Preparations stored at 30 degrees C contained a lower amount of B17V and higher amount of B21V than those stored at 4 degrees C. B17V stability in nasal irrigation solutions decreased in the following order: NS, FLO in fresh tap water, FLO in pre-boiled tap water, and NaHCO3 . The degradation rate of B17V increased with higher storage temperature and higher pH. CONCLUSION: B17V is most stable when added to NS and least stable in NaHCO3 solution. FLO solution prepared with either cooled boiled water or tap water is an alternative if administered immediately. Storage at 4 degrees C can better preserve stability of B17V, over a period of 24 hours. PMID- 28092127 TI - Induction of P450 genes in Nilaparvata lugens and Sogatella furcifera by two neonicotinoid insecticides. AB - Nilaparvata lugens and Sogatella furcifera are two primary planthoppers on rice throughout Asian countries and areas. Neonicotinoid insecticides, such as imidacloprid (IMI), have been extensively used to control rice planthoppers and IMI resistance consequently occurred with an important mechanism from the over expression of P450 genes. The induction of P450 genes by IMI may increase the ability to metabolize this insecticide in planthoppers and increase the resistance risk. In this study, the induction of P450 genes was compared in S. furcifera treated with IMI and nitromethyleneimidazole (NMI), in two planthopper species by IMI lethal dose that kills 85% of the population (LD85 ), and in N. lugens among three IMI doses (LD15 , LD50 and LD85 ). When IMI and NMI at the LD85 dose were applied to S. furcifera, the expression changes in most P450 genes were similar, including the up-regulation of nine genes and down-regulation of three genes. In terms of the expression changes in 12 homologous P450 genes between N. lugens and S. furcifera treated with IMI at the LD85 dose, 10 genes had very similar patterns, such as up-regulation in seven genes, down-regulation in one gene and no significant changes in two genes. When three different IMI doses were applied to N. lugens, the changes in P450 gene expression were much different, such as up-regulation in four genes at all doses and dose-dependent regulation of the other nine genes. For example, CYP6AY1 could be induced by all IMI doses, while CYP6ER1 was only up-regulated by the LD50 dose, although both genes were reported important in IMI resistance. In conclusion, P450 genes in two planthopper species showed similar regulation patterns in responding to IMI, and the two neonicotinoid insecticides had similar effects on P450 gene expression, although the regulation was often dose-dependent. PMID- 28092128 TI - Biomimetic Supramolecular Polymer Networks Exhibiting both Toughness and Self Recovery. AB - Biomimetic supramolecular dual networks: By mimicking the structure/function model of titin, integration of dynamic cucurbit[8]uril mediated host-guest interactions with a trace amount of covalent cross-linking leads to hierarchical dual networks with intriguing toughness, strength, elasticity, and energy dissipation properties. Dynamic host-guest interactions can be dissociated as sacrificial bonds and their facile reformation results in self-recovery of the dual network structure as well as its mechanical properties. PMID- 28092130 TI - Topological, Valleytronic, and Optical Properties of Monolayer PbS. AB - A PbS monolayer is demonstrated to be a novel platform for topological, valleytronic, and optical phenomena. Compressive strain can turn the trivial monolayer into a topological insulator. Optical pumping can facilitate charge, spin, and valley Hall effects tunable by external strain and light ellipticity. Similar results apply to other IV-VI semiconductors. PMID- 28092129 TI - Bortezomib in the treatment of antibody-mediated rejection in pediatric kidney transplant recipients: A multicenter Midwest Pediatric Nephrology Consortium study. AB - Antibody-mediated rejection leads to allograft loss after kidney transplantation. Bortezomib has been used in adults for the reversal of antibody-mediated rejection; however, pediatric data are limited. This retrospective study was conducted in collaboration with the Midwest Pediatric Nephrology Consortium. Pediatric kidney transplant recipients who received bortezomib for biopsy-proven antibody-mediated rejection between 2008 and 2015 were included. The objective was to characterize the use of bortezomib in pediatric kidney transplant recipients. Thirty-three patients received bortezomib for antibody-mediated rejection at nine pediatric kidney transplant centers. Ninety percent of patients received intravenous immunoglobulin, 78% received plasmapheresis, and 78% received rituximab. After a median follow-up of 15 months, 65% of patients had a functioning graft. The estimated glomerular filtration rate improved or stabilized in 61% and 36% of patients at 3 and 12 months post-bortezomib, respectively. The estimated glomerular filtration rate at diagnosis significantly predicted estimated glomerular filtration rate at 12 months after adjusting for chronic histologic changes (P .001). Fifty-six percent of patients showed an at least 25% reduction in the mean fluorescence intensity of the immune-dominant donor-specific antibody, 1-3 months after the first dose of bortezomib. Non-life threatening side effects were documented in 21 of 33 patients. Pediatric kidney transplant recipients tolerated bortezomib without life-threatening side effects. Bortezomib may stabilize estimated glomerular filtration rate for 3-6 months in pediatric kidney transplant recipients with antibody-mediated rejection. PMID- 28092131 TI - Finish line plant-insect interactions mediated by insect feeding mode and plant interference: a case study of Brassica interactions with diamondback moth and turnip aphid. AB - There are gaps in our understanding of plant responses under different insect phytophagy modes and their subsequent effects on the insect herbivores' performance at late season. Here we compared different types of insect feeding by an aphid, Lipaphis erysimi, and a lepidopteran, Plutella xylostella, and how this affected defensive metabolites in leaves of 2 Brassica species when plants gain maturity. Thiocyanate concentrations after P. xylostella and L. erysimi feeding activities were the same. Total phenolics was higher after the phloem feeder feeding than the folivore activity. The plants compensatory responses (i.e., tolerance) to L. erysimi feeding was significantly higher than the responses to P. xylostella. This study showed that L. erysimi had higher carbon than P. xylostella whereas nitrogen in P. xylostella was 1.42 times that in L. erysimi. Population size of the phloem feeder was not affected by plant species or insect coexistence. However, there was no correlation between plant defensive metabolites and both insects' population size and biomass. This suggests that plant root biomass and tolerance index after different insect herbivory modes are not necessarily unidirectional. Importantly, the interaction between the folivore and the phloem feeder insects is asymmetric and the phloem feeder might be a trickier problem for plants than the folivore. Moreover, as both plants' common and special defenses decreased under interspecific interference, we suggest that specialist insect herbivores can be more challenged in ecosystems in which plants are not involved in interspecific interference. PMID- 28092132 TI - A Columnar Liquid-Crystal Phase Formed by Hydrogen-Bonded Perylene Bisimide J Aggregates. AB - A new perylene bisimide (PBI) dye self-assembles through hydrogen bonds and pi-pi interactions into J-aggregates that in turn self-organize into liquid-crystalline (LC) columnar hexagonal domains. The PBI cores are organized with the transition dipole moments parallel to the columnar axis, which is an unprecedented structural organization in pi-conjugated columnar liquid crystals. Middle and wide-angle X-ray analyses reveal a helical structure consisting of three self assembled hydrogen-bonded PBI strands that constitute a single column of the columnar hexagonal phase. This remarkable assembly mode for columnar liquid crystals may afford new anisotropic LC materials for applications in photonics. PMID- 28092133 TI - Why Are Dithienylethene-Linked Biscobaltocenes so Hard to Photoswitch? AB - Attaching an organometallic unit to a dithienylethene (DTE) molecular switch can allow one to vary its switching and spectroscopic properties, and to create switchable magnetic properties. In this work, two different dithienylethene molecular switches are used as a bridge between two cobalt sandwich units. The only difference between the switching cores is in the size of the cycloalkene ring connecting both thiophene rings. The complexes present different oxidation states for the cobalt atoms, which are demonstrated to determine the switching reaction. The UV/Vis measurements show that while the Co(I) complexes undergo the switching reaction, the Co(II,III) complexes switch poorly. Kohn-Sham density functional theory calculations indicate diabatic ring-closure mechanisms and a large number of excited states hindering the cyclization reaction and favoring the relaxation to the open form of the molecular switch. PMID- 28092134 TI - Reversible Formation of 2D Electron Gas at the LaFeO3 /SrTiO3 Interface via Control of Oxygen Vacancies. AB - A conducting 2D electron gas (2DEG) is formed at the interface between epitaxial LaFeO3 layers >3 unit cells thick and the surface of SrTiO3 single crystals. The 2DEG is exquisitely sensitive to cation intermixing and oxygen nonstoichiometry. It is shown that the latter thus allows the controllable formation of the 2DEG via ionic liquid gating, thereby forming a nonvolatile switch. PMID- 28092135 TI - Self-Supported 3D PdCu Alloy Nanosheets as a Bifunctional Catalyst for Electrochemical Reforming of Ethanol. AB - 3D PdCu alloy nanosheets exhibit enhanced electrocatalytic activity toward hydrogen evolution reaction and ethanol oxidation reaction in alkaline media. Simultaneous hydrogen and acetate production via a solar-powered cell for ethanol reforming has been fabricated using the nanosheets as bifunctional electrocatalysts. The device is promising for the production of both hydrogen and value-added chemicals using renewable energy. PMID- 28092136 TI - Computational fluid dynamic modeling of nose-to-ceiling head positioning for sphenoid sinus irrigation. AB - BACKGROUND: After sinus surgery, patients are commonly instructed to irrigate with saline irrigations with their heads over a sink and noses directed inferiorly (nose-to-floor). Although irrigations can penetrate the sinuses in this head position, no study has assessed whether sphenoid sinus penetration can be improved by irrigating with the nose directed superiorly (nose-to-ceiling). The purpose of this study was to use a validated computational fluid dynamics (CFD) model of sinus irrigations to assess the difference in sphenoid sinus delivery of irrigations after irrigating in a nose-to-floor vs nose-to-ceiling head position. METHODS: Bilateral maxillary antrostomies, total ethmoidectomies, wide sphenoidotomies, and a Draf III frontal sinusotomy were performed on a single fresh cadaver head. CFD models were created from postoperative computed tomography maxillofacial scans. CFD modeling software was used to simulate a 120 mL irrigation to the left nasal cavity with the following parameters: flow rate 30 mL/second, angle of irrigation 20 degrees to the nasal floor, and either nose to-floor or nose-to-ceiling head positioning. RESULTS: In the postoperative CFD models, the sphenoid sinuses were completely penetrated by the irrigation while in a nose-to-ceiling head position. However, no sphenoid sinus penetration occurred in the nose-to-floor position. Other sinuses were similarly penetrated in both head positions, although the ipsilateral maxillary sinus was less penetrated in the nose-to-ceiling position. CONCLUSION: CFD modeling demonstrated that the nose-to-ceiling head position was superior to the nose-to-floor position in delivering a 120-mL irrigation to the sphenoid sinuses. PMID- 28092137 TI - Isolation and characterization of Rhizobium sp. strain YS-1r that degrades lignin in plant biomass. AB - AIMS: The aim of this work was to isolate novel lignin-degrading organisms. METHODS AND RESULTS: Several pure cultures of bacteria that degrade lignin were isolated from bacterial consortia developed from decaying biomass. Among the isolates, Rhizobium sp. strain YS-1r (closest relative of Rhizobium petrolearium strain SL-1) was explored for its lignin-degrading ability. Microcosm studies showed that strain YS-1r was able to degrade a variety of lignin monomers, dimers and also native lignin in switchgrass and alfalfa. The isolate demonstrated lignin peroxidase (LiP) activity when grown on alkali lignin, p-anisoin, switchgrass or alfalfa, and only negligible activity was measured in glucose grown cells suggesting inducible nature of the LiP activity. Analysis of the strain YS-1r genome revealed the presence of a variety of genes that code for various lignin-oxidizing, H2 O2 -producing as well as polysaccharide-hydrolysing enzymes. CONCLUSIONS: This study shows both the genomic and physiological capability of bacteria in the genus Rhizobium to metabolize lignin and lignin like compounds. This is the first detailed report on the lignocellulose-degrading ability of a Rhizobium species and thus this study expands the role of alpha proteobacteria in the degradation of lignin. SIGNIFICANCE AND IMPACT OF THE STUDY: The organism's ability to degrade lignin is significant since Rhizobia are widespread in soil, water and plant rhizospheres and some fix atmospheric nitrogen and also have the ability to degrade aromatic hydrocarbons. PMID- 28092138 TI - Nursing students' attitudes toward research and development within nursing: Does writing a bachelor thesis make a difference? AB - The aim of this study was to investigate the effect of writing a bachelor's thesis on nursing students' attitudes towards research and development in nursing. The study sample consisted of 91 nursing students who were required to complete a bachelor's thesis and 89 nursing students who were not required to complete a bachelor's thesis. Data were collected via self-report questionnaire that was distributed in May and June 2012. The questionnaire comprised 3 parts: (1) demographic items; (2) questions about "scientific activities," and (3) the nursing students' attitudes towards and awareness of research and development within nursing scale (version 2). The mean age of the students was 23 (1.3) years. The students who wrote a bachelor's thesis achieved a median score of 110.0, whereas the students in the other group had a median score of 105.0 on the scale. All the items were assigned a 3 or higher. A statistically significant difference was found between the 2 groups in their attitudes towards and awareness of research (U = 3265.5; P = .025). The results of this study suggest that writing a thesis in nursing education has a positive influence on nursing students' attitudes towards and awareness of research and development in nursing. PMID- 28092139 TI - Content of conventional therapy for the severely affected arm during subacute rehabilitation after stroke: An analysis of physiotherapy and occupational therapy practice. AB - BACKGROUND AND PURPOSE: Physiotherapy (PT) and occupational therapy (OT) are key professions providing treatment for the arm after stroke; however, knowledge about the content of these treatments is scant. Detailed data are needed to replicate interventions, evaluate their effective components, and evaluate PT and OT practice. This paper describes PT and OT treatment for the severely affected arm in terms of duration, content according to components and categories of the International Classification of Human Functioning, Disability and Health, and to analyze differences between professions. METHODS: Design: This is a retrospective analysis of randomized trial data. PARTICIPANTS: 46 patients after stroke with poor arm motor control recruited from inpatient neurological units from three rehabilitation centers in the Netherlands. PROCEDURE: PTs and OTs recorded duration and content of arm treatment interventions for 8 weeks using a bespoke treatment schedule with 15 International Classification of Human Functioning, Disability and Health categories. RESULTS: PTs and OTs spent on average 4-7 min per treatment session (30 min) on arm treatment. OTs spent significantly more time providing arm treatment and treatment at the activities level than PTs. PTs spent 79% of their arm treatment time on body functions, OTs 41%. OTs spent significantly more time on "moving around using transportation," "self care," and "household tasks" categories. CONCLUSIONS: Patients after stroke with a severely affected arm and an unfavorable prognosis for arm motor recovery receive little arm-oriented PT and OT. Therapists spent most arm treatment time on body functions. There was a considerable overlap in the content of PT and OT in 12 of the 15 categories. Results can be generalized only to patients with poor arm motor control and may not represent practice in other countries. PMID- 28092141 TI - Laundry hygiene-how to get more than clean. AB - Although laundering should mainly remove stains and dirt from used and worn textiles, the elimination of microbial contamination is an important aim of the laundry process as well. While industrial and institutional laundering employs standardized processes using high temperatures (i.e. 60 degrees C and above) and bleaching agents to ensure a sufficient hygienic reconditioning of textiles, domestic laundering processes are less defined and not always led by purposeful aims. The strive for energy efficiency of household appliances has resulted in a decrease in washing temperatures in Europe during the last decades and convenience aspects led to an increased use of liquid detergents that do not contain bleach which in turn impacts the antimicrobial efficacy of domestic laundering. This review compiles the different factors that influence the input and removal of micro-organisms in the laundering process and discusses the possible adverse effects of microbial contaminants in the washing machine and on the textiles as well as suitable counteractions. PMID- 28092140 TI - A systematic review of sinonasal oncocytomas and oncocytic carcinomas: Diagnosis, management, and technical considerations. AB - BACKGROUND: Oncocytomas and oncocytic carcinomas are rare tumors of the sinonasal cavity with the propensity for local invasion. This report and systematic review details a case of a nasal oncocytoma involving the lacrimal sac and provides an update of the current literature. METHODS: A systematic literature review was performed using PubMed and Ovid databases. The data obtained from published articles with sinonasal oncocytoma/oncocytic carcinoma as the primary diagnosis included patient demographics, presentation, radiographic and histologic findings, management, and recurrence rates. RESULTS: Twenty cases were identified. The most common symptoms were epistaxis (n = 11) and nasal obstruction (n = 11). Involvement of the nasal cavity was most common (n = 17), followed by the paranasal sinuses (n = 13) and nasolacrimal apparatus (n = 4). Recurrence occurred in 55% of cases. Recurrence was associated with invasion or infiltration found on histology or the presence of both invasion/infiltration and mitotic figures/pleomorphism (p < 0.05), with no significant relationship between recurrence and age at diagnosis (p = 0.42), sex (p = 0.65), and location of tumor (p = 0.14). The authors present the case of a 73-year-old woman with a 5-month history of worsening epistaxis and biopsy-proven oncocytoma. Complete surgical resection of the tumor using combined endonasal endoscopic and anterior orbitotomy approach is described. CONCLUSION: Oncocytomas and oncocytic carcinomas are rare tumors of the sinonasal cavity with a high rate of local recurrence and orbital involvement. Surgical resection is the treatment of choice and complete resection can be achieved with an endoscopic endonasal approach. PMID- 28092142 TI - Identifying the Collective Length in VO2 Metal-Insulator Transitions. AB - The "collective length" in VO2 metal-insulator transitions is identified by controlling nanoscale dopant distribution in thin films. The crossover from the local transition to the collective transition is observed, which originates from the increased instability of the metal-insulator domain boundary. This instability renders the transition collective within the "collective length", which will enable the design of collective electronic devices. PMID- 28092143 TI - Human leucocyte antigen-adverse drug reaction associations: from a perspective of ethnicity. AB - Whilst immune-mediated adverse drug reactions (ADRs) are rare, they are potentially life-threatening and present a major problem for clinicians. The underlying mechanisms that cause ADRs are not fully understood although genomewide association studies (GWAS) and case-control investigations have associated human leucocyte antigen (HLA) alleles as risk factors. There is evidence that a patient's ethnic background can have an impact on their risk of developing an ADR. This review summarizes the evidence related to HLA alleles and ADRs with particular focus on patient ethnicity. Our analysis indicated that many of the alleles which have been associated with ADRs are found at higher frequencies in Asian populations. The data also showed that many of the alleles that are reported to be statistically significantly associated with ADRs are in linkage disequilibrium with each other and that they form haplotypes specific to certain ethnicities indicating at least some of the allele associations may not be causal. PMID- 28092144 TI - Exergaming boxing versus heavy-bag boxing: are these equipotent for individuals with spinal cord injury? AB - BACKGROUND: Current strategies for increased physical activity and exercise in individuals with spinal cord injury (SCI) face many challenges with regards to maintaining their continuity of participation. Barriers cited often include problems with accessing facilities, mundane, monotonous or boring exercises and expensive equipment that is often not adapted for wheelchair users. AIM: To compare the physiological responses and user preferences between conventional heavy-bag boxing against a novel form of video game boxing, known as exergaming boxing. DESIGN: Cross-sectional study. SETTING: Exercise laboratory setting in a university medical center. POPULATION: Seventeen participants with SCI were recruited, of which sixteen were male and only one female. Their mean age was 35.6+/-10.2 years. METHODS: All of them performed a 15-minute physical exercise session of exergaming and heavy-bag boxing in a sitting position. The study assessed physiological responses in terms of oxygen consumption, metabolic equivalent (MET) and energy expenditure between exergaming and heavy-bag boxing derived from open-circuit spirometry. Participants also rated their perceived exertion using Borg's category-ratio ratings of perceived exertion. RESULTS: Both exergaming (MET: 4.3+/-1.0) and heavy-bag boxing (MET: 4.4+/-1.0) achieved moderate exercise intensities in these participants with SCI. Paired t-test revealed no significant differences (P>0.05, Cohen's d: 0.02-0.49) in the physiological or perceived exertional responses between the two modalities of boxing. Post session user survey reported all the participants found exergaming boxing more enjoyable. CONCLUSIONS: Exergaming boxing, was able to produce equipotent physiological responses as conventional heavy-bag boxing. The intensity of both exercise modalities achieved recommended intensities for health and fitness benefits. CLINICAL REHABILITATION IMPACT: Exergaming boxing have the potential to provide an enjoyable, self-competitive environment for moderate vigorous exercise even at the comfort of their homes. PMID- 28092145 TI - The role of diuretic response in prognosis prediction in discharged heart failure patients: the inclusion of diuresis. PMID- 28092146 TI - Bovine pericardium graft augmentation versus native tissue repair in anterior prolapse surgery: a retrospective study. PMID- 28092147 TI - Should serum calcitonin be routinely measured in patients presenting with thyroid nodule? AB - BACKGROUND: The European Thyroid Association recommends serum calcitonin measurement in thyroid nodule cases. In contrast, the American Thyroid Association is ambivalent. In this institution, thyroid nodules cases are subject to a multidisciplinary evaluation of the clinical history and examination, ultrasound and scintigraphy, CT scan and sometimes MRI scan, biochemistry and histopathology of biopsies. We report on the current use of plasma calcitonin measurements in the context of changing practice which has not included screening of all thyroid nodules. METHODS: Laboratory records were searched from the beginning of January 2010 to the end of April 2016 for all serum calcitonin measurements. RESULTS: There were 44 patients (30 females, age range 31 to 87 years with median 57.5) and 14 males, age range 20 to 85 years with median 53.4 years) who had a serum calcitonin measured. Of these 33 patients did not have a detectable serum calcitonin. There were 3 patients who had an initial elevated serum calcitonin which became undetectable over time. Over the same time period, a total of 2070 patients presented with thyroid nodules. Medullary thyroid cancer (MTC) was found in 7 cases. Thus assuming all MTC cases had calcitonin measured, MTC is 7 of 341 (2.05%) of the total thyroid cancer burden at the hospital and 7 of 2070 (0.338%) of all thyroid nodules. Our practice is not to routine screen all nodules for MTC. CONCLUSIONS: Because patients with a nodule are subjected to ultrasound scanning and biopsy, when the nodule size is greater than 5 cm or when there is a modifying ultrasound or clinical characteristic, the consensus at the multidisciplinary conference on thyroids rather than universal calcitonin screening of all nodules is the better option in our judgement. PMID- 28092148 TI - Issues in Nutrition: Foreword. PMID- 28092149 TI - Issues in Nutrition: Nutritional Assessment of Adults. AB - The assessment of nutritional status in adults should begin with a complete history, including intake of fruits and vegetables, sources of fat, and added sugar (eg, sugar-sweetened beverages). The history should include social factors that may impede a patient's ability to obtain food, as well as any factors that might interfere with preparing, chewing, and digesting food and absorbing nutrients. The physical examination should include measurement of height and weight and calculation of body mass index. It also may include measurements of waist circumference and waist to hip ratio, and an evaluation of strength. Laboratory evaluation should include measurement of albumin, prealbumin, and other markers of total body protein stores. No biomarker is completely sensitive or specific. With a range of dietary patterns, it is possible for nutritional gaps specific to those patterns to develop. Identification of a single nutrient deficiency typically reflects an overall weakness in the diet. The Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diets have the most evidence to support them as healthy diets. PMID- 28092150 TI - Issues in Nutrition: Dietary Supplements. AB - The majority of American adults report use of one or more dietary supplements every day or occasionally. The Dietary Supplement Health and Education Act of 1994 defines dietary supplements and regulates their manufacture and distribution. One of the most commonly used supplements is vitamin D. Measurement of serum levels of vitamin D must be undertaken with the caveats that different laboratories define normal levels differently, and that there is rarely a clinical correlation with the actual level. Patients should understand that supplements should not be used to excess, as there are toxicities and other adverse effects associated with most of them. There currently is considerable research being performed on probiotics and how the gut microbiome affects health and disease states. Protein supplements may be useful in reducing mortality rates in elderly patients but they do not appear to increase quality of life. If used, protein supplements should contain essential amino acids. Casein and whey supplements, derived from dairy sources, help transport essential amino acids to tissues. Although there have been many studies investigating the role of vitamin supplements in disease prevention, there have been few conclusive positive results. PMID- 28092151 TI - Issues in Nutrition: Carbohydrates. AB - Carbohydrates include sugars, starches, and dietary fibers. Resistant starches resemble fiber in their behavior in the intestinal tract, and may have positive effects on blood glucose levels and the gut microbiome. Fibers are classified as soluble and insoluble, but most fiber-containing foods contain a mixture of soluble and insoluble fiber. Soluble fiber has been shown to lower low-density lipoprotein cholesterol levels. Many artificial sweeteners and other sugar substitutes are available. Most natural sources of sweeteners also are energy sources. Many artificial sweeteners contain no kilocalories in the amounts typically used. Sugar alcohols may have a laxative effect when consumed in large amounts. Glycemic index and glycemic load are measurements that help quantify serum glucose response after ingestion of particular foods. These measurements may be affected by the combination of foods consumed in a given meal, and the glycemic index may vary among individuals eating the same meal. Eating foods with a low glycemic index may help prevent development of type 2 diabetes. There is no definitive evidence to recommend low-carbohydrate diets over low-fat diets for long-term weight loss; they are equally effective. PMID- 28092152 TI - Issues in Nutrition: Dietary Considerations in Select Chronic Conditions. AB - Chronic diseases that affect the gastrointestinal tract also tend to affect nutrition. The incidence of chronic liver disease is increasing. As the prevalence of obesity rises, so do the incidences of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Patients with chronic liver disease usually have some degree of malnutrition. In the absence of encephalopathy, patients with chronic liver disease should consume more protein than that in the average diet. There is some controversy about whether diet plays a role in the development of inflammatory bowel disease. Patients with ulcerative colitis and Crohn disease frequently present with weight loss as a symptom, and require careful nutritional assessment. Exclusive enteral nutrition plays an important role in inducing remission in children with Crohn disease but the same is not true in adults. Celiac disease is a relatively common enteropathy characterized by an autoimmune response in the intestinal lining. Patients with celiac disease should avoid eating gluten, which is found in wheat, soy, and barley. There is no evidence that gluten avoidance results in improved health outcomes in patients who are not gluten intolerant. PMID- 28092153 TI - Removable Large-Area Ultrasmooth Silver Nanowire Transparent Composite Electrode. AB - In this work, a composite silver nanowire (AgNW) transparent electrode that is large-area ultrasmooth without conductivity or transmittance scarifice, removable but with good resistance to both water and organic solvent, is reported. Via a simple low-temperature solution process without complicated transfer steps or additional pressure pressing, a new kind of AgNWs composite with biocompatible and patternable chitosan polymer complex demonstrates a quite low root-mean square roughness ~7 nm at a largest reported scan size of 50 MUm * 50 MUm, which is among the best flat surface. After long-term exposure to both water and organic solvent, it still shows strong adhesion, unchanged transparency, and no obvious conductivity reduction, suggesting a good stability staying on the substrate. Meanwhile, the polymer and silver nanowire in the composite electrode can be damaged via the same process through concentrated acid or base etching to leave off the substrate, allowing a simple patterning technology. Besides, the imported insulating polymer does not lower down the opto-electrical performance, and a high figure of merit close to 300 is obtained for the composite electrode, significantly outperforming the optoelectronic performance of indium-tin oxide (ITO) coated plastics (~100) and comparable to ITO-coated glass. It shows great advantage to replace ITO as a promising transparent electrode. PMID- 28092154 TI - Correlating the Network Topology of Oxide Glasses with their Chemical Durability. AB - Glasses gradually dissolve and corrode when they are exposed to aqueous solutions, and for many applications it is necessary to understand and predict the kinetics of the glass dissolution. Despite the recent progress in understanding the impact of chemical composition on the dissolution rate, a detailed understanding of the structural and topological origin of chemical durability in solutions of different pH is still largely lacking. Such knowledge would enable the tailoring of glass dissolution kinetics as a function of chemical composition. In a recent study focusing on silicate minerals and glasses, a direct relation was demonstrated between the dissolution rate at high pH and the number of chemical topological constraints per atom (nc) acting within the molecular network [Pignatelli, I.; Kumar, A.; Bauchy, M.; Sant, G. Langmuir 2016, 32, 4434-4439]. Here, we extend this work by studying the bulk dissolution rate (Dr) of a wider range of oxide glasses in various acidic, neutral, and basic solutions. The glass compositions have been selected to obtain a wide range of chemistries and values of nc, from flexible phosphate glasses to stressed-rigid aluminosilicate glasses. We show that, in flexible glasses, the internal modes of deformation facilitate the hydration of the network, whereas, in stressed-rigid glasses, the high number of constraints largely inhibits hydration in basic, neutral, and acidic solutions. Our study of chemical dissolution also allows establishing the kinetic mechanisms, which is controlled through an effective activation energy and depends on pH and glass topology. The energy barrier that needs to be overcome to break a unit atomic constraint is approximately constant for pH > 2, but then decreases at lower pH, indicating a change in dissolution mechanism from hydrolysis to ion exchange at low pH. Thus, with this research and existing topological models, the atomistic design of new oxide glasses with a specific chemical durability for a determined pH could become possible. PMID- 28092156 TI - Inhibition of Cronobacter sakazakii Adhesion to Caco-2 Cells by Commercial Dairy Powders and Raw Buttermilk. AB - Cronobacter sakazakii is a foodborne pathogen that has been associated with severe infections, mainly in neonates. The binding of this bacterium to host cell surfaces represents the first step in the pathogenesis of disease. An ELISA-based assay has been developed using a polyclonal antiserum against C. sakazakii to determine its adhesion to Caco-2 cells. The antiserum used recognized many of the outer membrane proteins of C. sakazakii. A positive correlation was found between the absorbance values obtained by ELISA and the number of bacteria adhered to cells determined by plate counting. The inhibitory effect on bacterial adhesion to cells observed with some dairy products was concentration-dependent. Commercial buttermilk caused the maximal reduction of the adhesion percentage (33.0 +/- 5.07) at the highest concentration assayed (20 mg/mL), followed by butter serum (31.9 +/- 5.36), skim milk (30.4 +/- 5.07), and raw buttermilk (25.6 +/- 3.80). In some cases, significant differences (p < 0.05) were found in the inhibition exerted by the different products evaluated. The results obtained in this study demonstrate that dairy products contain some components with the ability to inhibit the adhesion of C. sakazakii to Caco-2 cells. PMID- 28092157 TI - Formal Total Synthesis of Manzacidin C Based on Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Imines. AB - An enantioselective formal total synthesis of (+)-manzacidin C is described. A key feature of the synthesis is the construction of two chiral centers via the asymmetric 1,3-dipolar cycloaddition of an azomethine imine to methallyl alcohol by the use of (S,S)-DIPT as a chiral auxiliary. PMID- 28092158 TI - Polyolefin Thermoplastics for Multiple Shape and Reversible Shape Memory. AB - This work reports the first pure hydrocarbon thermoplastic polyolefin material with reversible shape memory effect under stress-free or very small external loading condition. A thermoplastic ethylene/1-octene diblock copolymer with designed chain microstructure was synthesized. The polyolefin material performed not only the conventional one-way multishape memory effects, but also a two-way reversible shape memory effect (RSME). The elongation and contraction induced by oriented crystallization with heating was confirmed as the mechanism of RSME without chemical cross-linking. This work demonstrated that the thermoplastic reversible shape memory could be achieved through careful design of chain microstructure, based on sole hydrocarbon materials such as ethylene-1-octene copolymer. PMID- 28092155 TI - Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with Robust Anticancer Efficacy. AB - Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3). Herein we disclose the discovery of a first-in-class potent, selective, and orally bioavailable EED inhibitor compound 43 (EED226). Guided by X-ray crystallography, compound 43 was discovered by fragmentation and regrowth of compound 7, a PRC2 HTS hit that directly binds EED. The ensuing scaffold hopping followed by multiparameter optimization led to the discovery of 43. Compound 43 induces robust and sustained tumor regression in EZH2MUT preclinical DLBCL model. For the first time we demonstrate that specific and direct inhibition of EED can be effective as an anticancer strategy. PMID- 28092159 TI - Probe Decomposition of Methylammonium Lead Iodide Perovskite in N2 and O2 by in Situ Infrared Spectroscopy. AB - Packaging methylammonium lead iodide perovskite (MAPbI3)-based solar cells with N2 or dry air is a promising solution for its application in outdoor photovoltaics. However, the effect of N2 and O2 on the decomposition chemistry and kinetics of MAPbI3 is not yet well-understood. With in situ Fourier transform infrared spectroscopy measurements, we show that the effective activation energy for the degradation of MAPbI3 in N2 is ~120 kJ/mol. The decomposition of MAPbI3 is greatly accelerated by exposure to O2 in the dark. As a result of the synergistic effect between O2 and a HeNe laser (633 nm), the degradation rate is further increased with photon flux. This synergistic effect reduces the effective activation energy of degradation of MAPbI3 to ~50 kJ/mol. The solid decomposition products after annealing in N2 and O2 at 150 degrees C or below do not have absorbance between 650 and 4000 cm-1. PMID- 28092160 TI - Discovery of Metabolite Biomarkers for Acute Ischemic Stroke Progression. AB - Stroke remains a major public health problem worldwide; it causes severe disability and is associated with high mortality rates. However, early diagnosis of stroke is difficult, and no reliable biomarkers are currently established. In this study, mass-spectrometry-based metabolomics was utilized to characterize the metabolic features of the serum of patients with acute ischemic stroke (AIS) to identify novel sensitive biomarkers for diagnosis and progression. First, global metabolic profiling was performed on a training set of 80 human serum samples (40 cases and 40 controls). The metabolic profiling identified significant alterations in a series of 26 metabolites with related metabolic pathways involving amino acid, fatty acid, phospholipid, and choline metabolism. Subsequently, multiple algorithms were run on a test set consisting of 49 serum samples (26 cases and 23 controls) to develop different classifiers for verifying and evaluating potential biomarkers. Finally, a panel of five differential metabolites, including serine, isoleucine, betaine, PC(5:0/5:0), and LysoPE(18:2), exhibited potential to differentiate AIS samples from healthy control samples, with area under the receiver operating characteristic curve values of 0.988 and 0.971 in the training and test sets, respectively. These findings provided insights for the development of new diagnostic tests and therapeutic approaches for AIS. PMID- 28092163 TI - Corrigendum to Simultaneous Orthogonal Drug Detection using Fully Integrated Gas Chromatography with Fourier Transform Infrared Detection and Mass Spectrometric Detection. PMID- 28092161 TI - Estimation of ellagic acid and/or repaglinide effects on insulin signaling, oxidative stress, and inflammatory mediators of liver, pancreas, adipose tissue, and brain in insulin resistant/type 2 diabetic rats. AB - Even though ellagic acid has previously been valued in many models of cancer, so far its full mechanistic effect as a natural antiapoptotic agent in the prevention of type 2 diabetes complications has not been completely elucidated, which was the goal of this study. We fed albino rats a high-fat fructose diet (HFFD) for 2 months to induce insulin resistance/type 2 diabetes and then treated the rats with ellagic acid (10 mg/kg body weight, orally) and/or repaglinide (0.5 mg/kg body weight, orally) for 2 weeks. At the serum level, ellagic acid challenged the consequences of HFFD, significantly improving the glucose/insulin balance, liver enzymes, lipid profile, inflammatory cytokines, redox level, adipokines, ammonia, and manganese. At the tissue level (liver, pancreas, adipose tissue, and brain), ellagic acid significantly enhanced insulin signaling, autophosphorylation, adiponectin receptors, glucose transporters, inflammatory mediators, and apoptotic markers. Remarkably, combined treatment with both ellagic acid and repaglinide had a more pronounced effect than treatment with either alone. These outcomes give new insight into the promising molecular mechanisms by which ellagic acid modulates numerous factors induced in the progression of diabetes. PMID- 28092162 TI - Clinical use of high mobility group box 1 and the receptor for advanced glycation end products in the prognosis and risk stratification of heart failure: a literature review. AB - Heart failure (HF) is a clinical syndrome that represents the end stage of heart disease and remains the leading cause of morbidity and mortality worldwide. As heart failure mortality rates remain elevated, additional biomarkers that facilitate early detection or risk stratification in HF is of particularly great interest. High mobility group box 1 (HMGB1) and receptor for advanced glycation end products (RAGE) cause the activation of intracellular signaling, gene expression, and production of inflammatory cytokines and have been linked to many inflammatory disease states such as diabetes mellitus and atherosclerosis. Few studies have investigated their role in the pathophysiology of HF and any significant correlation remains uncertain. Review of the available literature discussing HMGB1 and RAGE clinical values as independent prognostic variables in HF resulted in the inclusion of 11 studies, which enrolled a total of 2025 heart failure patients. Overall, the data suggests a statistically significant positive correlation between RAGE and HF, with increasing RAGE levels associated with increasing New York Heart Association (NYHA) functional class of heart failure. HMGB1 correlations were not as extensively studied, but there is evidence that both HMGB1 and RAGE have a definite potential as biomarkers for the prognosis and risk stratification of HF patients. PMID- 28092164 TI - Comparing Modified Huddart-Bodenham Scoring System and GOSLON Yardstick to Assess Dental Arch Relationships in Unilateral Cleft Lip and Palate Patients. AB - OBJECTIVE: To test the reliability of the modified Huddart-Bodenham (MHB) numerical scoring system and its agreement with the GOSLON Yardstick categorization for assessing the dental arch relationships in unilateral cleft lip and palate (UCLP) cases. DESIGN: A retrospective study. SETTING: Faculty of Dentistry, The University of Hong Kong. PATIENTS: Forty-one nonsyndromic UCLP consecutive patients attending the Joint Cleft Lip/Palate Clinic at Faculty of Dentistry in the University of Hong Kong were selected. INTERVENTIONS: Study models at 8 to 10 years old (T1) and 10 to 12 years old (T2) were obtained from each patient. MAIN OUTCOME MEASURES: Models were rated with the MHB scoring system and GOSLON Yardstick index. The intra- and interexaminer reliabilities as well as correlation of both scoring systems were evaluated. Furthermore, to investigate the outcome measurements consistency, the MHB scoring system and GOSLON Yardstick were independently used to compare the dental arch relationships from T1 to T2, with the samples split into intervention and nonintervention groups. RESULTS: The MHB scoring system presented good intra- and interexaminer agreement, which were comparable to those of the GOSLON Yardstick. The correlation between the MHB scoring system and GOSLON Yardstick scores was good. Both scoring systems showed similar results when assessing the change in the dental arch relationships from T1 to T2. CONCLUSIONS: The MHB scoring system can be used as an alternative method to the commonly used GOSLON Yardstick for assessing dental deformities in UCLP patients. Both scoring systems showed similar results in assessing the improvement in dental arch relationships. PMID- 28092165 TI - Recommendations for Best Disinfectant Practices to Reduce the Spread of Infection via Wrestling Mats. AB - CONTEXT: At the request of the National Wrestling Coaches Association and the head wrestling coach at our university, we conducted a study of infection transmission in collegiate wrestlers. OBJECTIVE: To examine disinfectant effectiveness and develop best-practice guidelines for minimizing the spread of skin infections via wrestling mats. DESIGN: Controlled laboratory study and crossover study. SETTING: Laboratory and two 15-college wrestling invitational meets. PATIENTS OR OTHER PARTICIPANTS: A total of 231 collegiate wrestlers and 8 officials. INTERVENTION(S): In the laboratory-based part of the study, we measured the bacterial load of mats disinfected with 10% bleach, OxiTitan, Benefect, eWater, and KenClean and inoculated with Staphylococcus epidermidis (strain ATCC 12228) at a concentration of 6.5 * 104 bacteria/cm2. In the empirical part of the study, we used these disinfectants during 2 invitational meets and measured mat and participant bacterial load during competition. Participants were swabbed at weigh-in and after their last bout. Mat bacterial load was monitored hourly. MAIN OUTCOME MEASURE(S): We determined total colony counts and species. RESULTS: With controlled testing, we observed that products claiming to have residual activity reduced bacterial load by 63% over the course of competition compared with nonresidual agents. Only 4 of 182 participating wrestlers tested positive for methicillin-resistant Staphylococcus aureus , which is the normal population occurrence. The predominant species on mats were skin bacteria ( Staphylococcus epidermidis ) and substantial levels of respiratory bacteria ( Streptococcus pneumoniae ), as well as several soil species and a surprisingly low incidence of fecal bacteria ( Escherichia coli ). Disinfectant effectiveness during the meets was consistent with controlled study findings. Cleaning mats with residual disinfectants reduced the average bacterial load by 76% compared with nonresidual cleaners. Using a footbath did not reduce the bacterial load compared with a bleach-cleaned mat, but using alcohol-based hand gel reduced it by 78%. CONCLUSIONS: Best practices based on these data include backward mopping of the mats with a residual disinfectant pulled behind the cleaner, allowing mats to dry before walking on them, having wrestlers use hand gel before each bout, and strongly recommending that all wrestlers receive annual influenza vaccinations. PMID- 28092166 TI - Subchronic metformin pretreatment enhances novel object recognition memory task in forebrain ischemia: behavioural, molecular, and electrophysiological studies. AB - Metformin exerts its effect via AMP-activated protein kinase (AMPK), which is a key sensor for energy homeostasis that regulates different intracellular pathways. Metformin attenuates oxidative stress and cognitive impairment. In our experiment, rats were divided into 8 groups; some were pretreated with metformin (Met, 200 mg/kg) and (or) the AMPK inhibitor Compound C (CC) for 14 days. On day 14, rats underwent transient forebrain global ischemia. Data indicated that pretreatment of ischemic rats with metformin reduced working memory deficits in a novel object recognition test compared to group with ischemia-reperfusion (I-R) (P < 0.01). Pretreatment of the I-R animals with metformin increased phosphorylated cyclic-AMP response element-binding protein (pCREB) and c-fos levels compared to the I-R group (P < 0.001 for both). The level of CREB and c fos was significantly lower in ischemic rats pretreated with Met + CC compared to the Met + I-R group. Field excitatory postsynaptic potential (fEPSP) amplitude and slope was significantly lower in the I-R group compared to the sham operation group (P < 0.001). Data showed that fEPSP amplitude and slope was significantly higher in the Met + I-R group compared to the I-R group (P < 0.001). Treatment of ischemic animals with Met + CC increased fEPSP amplitude and slope compared to the Met + I-R group (P < 0.01). We unravelled new aspects of the protective role of AMPK activation by metformin, further emphasizing the potency of metformin pretreatment against cerebral ischemia. PMID- 28092167 TI - A semi-nested real-time PCR method to detect low chimerism percentage in small quantity of hematopoietic stem cell transplant DNA samples. AB - Chimerism status evaluation of post-allogeneic hematopoietic stem cell transplantation samples is essential to predict post-transplant relapse. The most commonly used technique capable of detecting small increments of chimerism is quantitative real-time PCR. Although this method is already used in several laboratories, previously described protocols often lack sensitivity and the amount of the DNA required for each chimerism analysis is too high. In the present study, we compared a novel semi-nested allele-specific real-time PCR (sNAS-qPCR) protocol with our in-house standard allele-specific real-time PCR (gAS-qPCR) protocol. We selected two genetic markers and analyzed technical parameters (slope, y-intercept, R2, and standard deviation) useful to determine the performances of the two protocols. The sNAS-qPCR protocol showed better sensitivity and precision. Moreover, the sNAS-qPCR protocol requires, as input, only 10 ng of DNA, which is at least 10-fold less than the gAS-qPCR protocols described in the literature. Finally, the proposed sNAS-qPCR protocol could prove very useful for performing chimerism analysis with a small amount of DNA, as in the case of blood cell subsets. PMID- 28092168 TI - Associations Between At-Risk Alcohol Use, Substance Use, and Smoking with Lipohypertrophy and Lipoatrophy Among Patients Living with HIV. AB - OBJECTIVE: To examine associations between lipohypertrophy and lipoatrophy and illicit drug use, smoking, and at-risk alcohol use among a large diverse cohort of persons living with HIV (PLWH) in clinical care. METHODS: 7,931 PLWH at six sites across the United States completed 21,279 clinical assessments, including lipohypertrophy and lipoatrophy, drug/alcohol use, physical activity level, and smoking. Lipohypertrophy and lipoatrophy were measured using the FRAM body morphology instrument and associations were assessed with generalized estimating equations. RESULTS: Lipohypertrophy (33% mild, 4% moderate-to-severe) and lipoatrophy (20% mild, 3% moderate-to-severe) were common. Older age, male sex, and higher current CD4 count were associated with more severe lipohypertrophy (p values <.001-.03). Prior methamphetamine or marijuana use, and prior and current cocaine use, were associated with more severe lipohypertrophy (p values <.001 .009). Older age, detectable viral load, and low current CD4 cell counts were associated with more severe lipoatrophy (p values <.001-.003). In addition, current smoking and marijuana and opiate use were associated with more severe lipoatrophy (p values <.001-.03). Patients with very low physical activity levels had more severe lipohypertrophy and also more severe lipoatrophy than those with all other activity levels (p values <.001). For example, the lipohypertrophy score of those reporting high levels of physical activity was on average 1.6 points lower than those reporting very low levels of physical activity (-1.6, 95% CI: -1.8 to -1.4, p < .001). CONCLUSIONS: We found a high prevalence of lipohypertrophy and lipoatrophy among a nationally distributed cohort of PLWH. While low levels of physical activity were associated with both lipohypertrophy and lipoatrophy, associations with substance use and other clinical characteristics differed between lipohypertrophy and lipoatrophy. These results support the conclusion that lipohypertrophy and lipoatrophy are distinct, and highlight differential associations with specific illicit drug use. PMID- 28092170 TI - A single molecular marker to distinguish between species of Dioscorea. AB - Yams are species of the genus Dioscorea (family Dioscoreaceae), which consists of approximately 630 species. The majority of the world production of yams occurs in Africa with 58.8 million t annually, but they are also produced in the Americas and Asia. The saponins in yams have been reported to possess various properties to improve health. The tuber and aerial parts of various species often share morphological similarities, which can cause problems in the proper identification of sample material. For example, the rootstocks and aerial parts of Dioscorea villosa L. share similarities with Dioscorea polystachia Turcz. Dioscorea bulbifera L. may be mistaken for Dioscorea alata L. owing to similar morphologies. Various molecular analyses have been published to help with the identification of species and varieties within the genus Dioscorea. The multi loci or single-locus analysis has resulted in varying success, some with only a limited discrimination rate. In the present study, a single nuclear genomic region, biparentally inherited, was analyzed for its usefulness as a molecular marker for species identification and discrimination between D. bulbifera, D. villosa, D. nipponica, D. alata, D. caucasica, and D. deltoidea samples. The results of this study show that the LFY genomic region can be useful as a molecular marker to distinguish between samples. PMID- 28092169 TI - National Athletic Trainers' Association Position Statement: Management of Acute Skin Trauma. AB - OBJECTIVE: To present recommendations for the cleansing, debridement, dressing, and monitoring of acute skin trauma in patients. BACKGROUND: Acute skin trauma is common during participation in athletic and recreational activities. Clinical decisions and intervention protocols after injury vary among athletic trainers and are often based on ritualistic practices. An understanding of cleansing, debridement, and dressing techniques; clinical features of infection and adverse reactions; and monitoring of acute skin trauma is critical for certified athletic trainers and other allied health and medical professionals to create a local wound environment that promotes healing and lessens the risk of complications. RECOMMENDATIONS: These guidelines are intended to provide the certified athletic trainer and others participating in athletic health care with specific knowledge about and recommendations for the management of acute skin trauma. PMID- 28092171 TI - A pangenotypic, single tablet regimen of sofosbuvir/velpatasvir for the treatment of chronic hepatitis C infection. AB - INTRODUCTION: Hepatitis C virus (HCV) infects nearly 170 million people worldwide and is a leading cause of progressive liver damage, cirrhosis, and hepatocellular carcinoma. Curative therapies have historically relied on interferon-based treatments and were limited by significant toxicity and poor response rates, particularly among patients with prior treatment failure and advanced hepatic fibrosis. The recent advent of direct acting antiviral (DAA) agents which target key steps in the HCV viral life cycle has transformed the landscape of HCV treatment by offering highly effective and well tolerated interferon-free treatments. However, current therapies are genotype-specific and have variable efficacy amongst less prevalent HCV variants. Areas covered: This review covers the preclinical and clinical development of sofosbuvir/velpatasvir (SOF/VEL), an interferon-free, once daily, pangenotypic treatment for the treatment of chronic hepatitis C virus (HCV) infection. All relevant literature from 2014 through September of 2016 is included. Expert opinion: SOF/VEL offers the promise of a single tablet, interferon- and ribavirin-free treatment that has extremely high efficacy in persons with chronic HCV infection regardless of genotype, subtype, treatment history or fibrosis status. It is expected to play a major role on a global scale in the therapeutic armamentarium against this ubiquitous threat to human health. PMID- 28092172 TI - Analysis of Indium Tin Oxide Film Using Argon Fluroide (ArF) Laser-Excited Atomic Fluorescence of Ablated Plumes. AB - A two-pulse laser-excited atomic fluorescence (LEAF) technique at 193 nm wavelength was applied to the analysis of indium tin oxide (ITO) layer on polyethylene terephthalate (PET) film. Fluorescence emissions from analytes were induced from plumes generated by first laser pulse. Using this approach, non selective LEAF can be accomplished for simultaneous multi-element analysis and it overcomes the handicap of strict requirement for laser excitation wavelength. In this study, experimental conditions including laser fluences, times for gating and time delay between pulses were optimized to reveal high sensitivity with minimal sample destruction and penetration. With weak laser fluences of 100 and 125 mJ/cm2 for 355 and 193 nm pulses, detection limits were estimated to be 0.10% and 0.43% for Sn and In, respectively. In addition, the relation between fluorescence emissions and number of laser shots was investigated; reproducible results were obtained for Sn and In. It shows the feasibility of depth profiling by this technique. Morphologies of samples were characterized at various laser fluences and number of shots to examine the accurate penetration. Images of craters were also investigated using scanning electron microscopy (SEM). The results demonstrate the imperceptible destructiveness of film after laser shot. With such weak laser fluences and minimal destructiveness, this LEAF technique is suitable for thin-film analysis. PMID- 28092180 TI - N-acetylcysteine a possible protector against indomethacin-induced peptic ulcer: crosstalk between antioxidant, anti-inflammatory, and antiapoptotic mechanisms. AB - This study investigated the gastroprotective effects of N-acetylcysteine (NAC) against indomethacin-induced gastric ulcer in rats. Ulceration was induced by a single oral administration of indomethacin (30 mg/kg). 50 male albino rats were allocated into 5 equal groups: control group received normal saline orally, indomethacin group rats received normal saline orally for 5 days and indomethacin (50 mg/kg) on the last day, ranitidine group received ranitidine (reference drug) orally for 5 days (50 mg/kg) before receiving indomethacin (50 mg/kg) on the last day, and NAC groups received NAC orally at 300 and 500 mg/kg, respectively, for 5 days before receiving indomethacin (50 mg/kg) on the last day. Gastric tissue interleukin-1beta (IL-1beta), interferon-gamma (IFN-gamma), and caspase-3 levels were immunoassayed. Total thiol (T-SH), myeloperoxidase (MPO), and glucose-6 phosphate dehydrogenase (G6PD) were determined by spectrophotometry. Cytokine induced neutrophil chemoattractant 2alpha (CINC-2alpha) gene expression was evaluated in addition to Bcl-2 immunohistochemistry. Pretreatment with NAC improved the inflammatory, apoptotic, and redox status in a dose-dependent manner particularly in NAC 500 mg/kg pretreated group. These results show a role for NAC in improving indomethacin-induced gastric ulceration via antioxidative, antiapoptotic, and anti-inflammatory interactive mechanisms. PMID- 28092181 TI - Impaired redox environment modulates cardiogenic and ion-channel gene expression in cardiac-resident and non-resident mesenchymal stem cells. AB - Redox homeostasis plays a crucial role in the regulation of self-renewal and differentiation of stem cells. However, the behavioral actions of mesenchymal stem cells in redox imbalance state remain elusive. In the present study, the effect of redox imbalance that was induced by either hydrogen peroxide (H2O2) or ascorbic acid on human cardiac-resident (hC-MSCs) and non-resident (umbilical cord) mesenchymal stem cells (hUC-MSCs) was evaluated. Both cells were sensitive and responsive when exposed to either H2O2 or ascorbic acid at a concentration of 400 umol/L. Ascorbic acid pre-treated cells remarkably ameliorated the reactive oxygen species level when treated with H2O2. The endogenous antioxidative enzyme gene (Sod1, Sod2, TRXR1 and Gpx1) expressions were escalated in both MSCs in response to reactive oxygen species elevation. In contrast, ascorbic acid pre treated hUC-MSCs attenuated considerable anti-oxidative gene (TRXR1 and Gpx1) expressions, but not the hC-MSCs. Similarly, the cardiogenic gene (Nkx 2.5, Gata4, Mlc2a and beta-MHC) and ion-channel gene ( IKDR, IKCa, Ito and INa.TTX) expressions were significantly increased in both MSCs on the oxidative state. On the contrary, reduced environment could not alter the ion-channel gene expression and negatively regulated the cardiogenic gene expressions except for troponin-1 in both cells. In conclusion, redox imbalance potently alters the cardiac resident and non-resident MSCs stemness, cardiogenic, and ion-channel gene expressions. In comparison with cardiac-resident MSC, non-resident umbilical cord MSC has great potential to tolerate the redox imbalance and positively respond to cardiac regeneration. Impact statement Human mesenchymal stem cells (h-MSCs) are highly promising candidates for tissue repair in cardiovascular diseases. However, the retention of cells in the infarcted area has been a major challenge due to its poor viability and/or low survival rate after transplantation. The regenerative potential of mesenchymal stem cells (MSCs) repudiate and enter into premature senescence via oxidative stress. Thus, various strategies have been attempted to improve the MSC survival in 'toxic' conditions. Similarly, we investigated the response of cardiac resident MSC (hC-MSCs) and non-resident MSCs against the oxidative stress induced by H2O2. Supplementation of ascorbic acid (AA) into MSCs culture profoundly rescued the stem cells from oxidative stress induced by H2O2. Our data showed that the pre-treatment of AA is able to inhibit the cell death and thus preserving the viability and differentiation potential of MSCs. PMID- 28092182 TI - An estrogen receptor beta-selective agonist inhibits non-alcoholic steatohepatitis in preclinical models by regulating bile acid and xenobiotic receptors. AB - Non-alcoholic steatohepatitis (NASH) affects 8-10 million people in the US and up to 75% of obese individuals. Despite this, there are no approved oral therapeutics to treat NASH and therefore the need for novel approaches exists. The estrogen receptor beta (ER-beta)-selective agonist, beta-LGND2, inhibits body weight and white adipose tissue, and increases metabolism, resulting in higher energy expenditure and thermogenesis. Due to favorable effects of beta-LGND2 on obesity, we hypothesized that beta-LGND2 will prevent NASH directly by reducing lipid accumulation in the liver or indirectly by favorably changing body composition. Male C57BL/6 mice fed with high fat diet (HFD) for 10 weeks or methionine choline-deficient diet for four weeks and treated with vehicle exhibited altered liver weights by twofold and increased serum transaminases by 2 6-folds. These changes were not observed in beta-LGND2-treated animals. Infiltration of inflammatory cells and collagen deposits, an indication of fibrosis, were observed in the liver of mice fed with HFD for 10 weeks, which were effectively blocked by beta-LGND2. Gene expression studies in the liver indicate that pregnane X receptor target genes were significantly increased by HFD, and the increase was inhibited by beta-LGND2. On the other hand, metabolomics indicate that bile acid metabolites were significantly increased by beta-LGND2. These studies demonstrate that an ER-beta agonist might provide therapeutic benefits in NASH by directly modulating the function of xenobiotic and bile acid receptors in the liver, which have important functions in the liver, and indirectly, as demonstrated before, by inhibiting adiposity. Impact statement Over 75-90% of those classified as clinically obese suffer from co morbidities, the most common of which is non-alcoholic steatohepatitis (NASH). While there are currently no effective treatment approaches for NASH, data presented here provide preliminary evidence that an estrogen receptor beta selective ligand could have the potential to reduce lipid accumulation and inflammation, and protect liver from NASH. PMID- 28092183 TI - Therapeutic effects of hyaluronidase on acquired lymphedema using a newly developed mouse limb model. AB - Acquired lymphedema is one of the most dreaded side effects of cancer treatment, such as surgical treatment or irradiation. However, due to the lack of appropriate animal models, there is no effective therapeutic method to cure acquired lymphedema. To develop a reproducible acquired lymphedema animal model, we devised a mouse hind limb model by removing a superficial inguinal lymph node, a popliteal lymph node, a deep inguinal lymph node, and the femoral lymphatic vessel. We measured the volume of lymphedematous leg and observed the change in level of hyaluronic acid (HA) and lymphangiogenic factors after injecting hyaluronidase. Our model showed the distinguishable swelling and the reliable symptoms compared to previously reported models. In the lymphedematous regions of our model, we confirmed that HA, a major component of extracellular matrix, accumulated to higher levels than in a normal mouse. This lymphedema volume was rapidly reduced by treating hyaluronidase. Following hyaluronidase injection, the lymphedematous region of our model resembled a normal hind limb. Our findings indicated that hyaluronidase promoted lymphangiogenesis on the lymphedematous limb. Based on hyaluronidase treatment in the lymphedematous region, this could potentially be a new therapeutic approach for acquired lymphedema mediated through the modification of the size of HA fragments. Impact statement In this manuscript, the essence of the work described in this manuscript involves the development of (1) a mouse limb model showing acquired lymphedema and (2) a potent therapeutic treatment using hyaluronidase to remedy acquired lymphedema in our model. In order to develop a reproducible acquired lymphedema animal model that reflects the most common symptoms experienced by lymphedema patients, we devised a mouse hind limb model by removing lymph nodes and lymphatics. Our model showed the distinguishable swelling and the reliable symptoms compared to previously reported models. In the lymphedematous regions of our model, we confirmed that hyaluronic acid (HA) accumulated to higher levels than in a normal mouse. This lymphedema volume was rapidly reduced by treating the lymphedematous leg with hyaluronidase, which also degraded high molecular weight HA to low molecular weight HA. Immunohistochemical analysis, quantitative real-time PCR analysis and lymphangioscintigraphy showed that hyaluronidase enhanced lymphangiogenesis in the lymphedematous limb. PMID- 28092184 TI - Mood, motives, and money: An examination of factors that differentiate online and non-online young adult gamblers. AB - Background and aims To date, there is a lack of research on psychological factors associated with young adult online gambling. The current study examined differences between young adult online and non-online gamblers, using information gathered at baseline and over 30 days during which participants reported on their moods, gambling behaviors, and reasons for initiating and discontinuing gambling. Methods Participants were 108 young adult regular gamblers (i.e., gambling four or more times in the past month) who participated in a 30-day daily diary study. Results Male gender, baseline coping motives for gambling and negative affect averaged across the 30 days emerged as significant correlates of online gambling, over and above other background variables. Online gamblers also scored higher on a baseline measure of pathological gambling. Over the 30 days of self-monitoring, online gamblers spent more time gambling, and won more money gambling, whereas non-online gamblers consumed more alcohol while gambling. Online gambling was more often initiated to make money, because of boredom and to demonstrate skills, whereas non-online gambling was more often initiated for social reasons and for excitement. Online gambling was more often discontinued because of boredom, fatigue or distress, whereas non-online gambling was discontinued because friends stopped gambling or mood was improved. Discussion and conclusions This study provides preliminary evidence that coping strategies may be particularly important to reduce risks for online gamblers, whereas strategies for non-online gamblers should focus on the social aspects of gambling. PMID- 28092185 TI - The development of the Problematic Series WatchingScale (PSWS). AB - Background and aims The goal of the present study was to create a short ProblematicSeries Watching Scale (PSWS). Methods On the basis of the six components model of Griffiths ( 2005 ), six items were identifiedcovering all components of problematic series watching. Confirmatoryfactor analyses were carried out on two independent samples (N1 = 366, N2 = 752). Results The PSWS has appropriate factor structure and reliability. Theamount of free time was not, but the series watching time was associatedwith PSWS scores. Women had higher scores than men. Discussion Before PSWS, no prior scale has been created to measure problematicseries watching. Further research is needed to properly assess itsvalidity and reliability; and for examining whether extensive serieswatching can lead to health-related and psychosocial problems. Conclusions In the increasingly digitalized world there are many motivationalforces which encourage people watching online series. In the lightof these changes, research on problematic series watching will beprogressively relevant. PMID- 28092186 TI - Under the influence of Facebook? Excess use of social networking sites and drinking motives, consequences, and attitudes in college students. AB - Background and aims Excessive use of social networking sites (SNS) has recently been conceptualized as a behavioral addiction (i.e., "disordered SNS use") using key criteria for the diagnosis of substance dependence and shown to be associated with a variety of impairments in psychosocial functioning, including an increased risk of problem drinking. This study sought to characterize associations between "disordered SNS use" and attitudes towards alcohol, drinking motives, and adverse consequences resulting from alcohol use in young adults. Methods Undergraduate students (n = 537, 64.0% female, mean age = 19.63 years, SD = 4.24) reported on their use of SNSs and completed the Alcohol Use Disorders Identification Test, Temptation and Restraint Inventory, Approach and Avoidance of Alcohol and Drinking Motives Questionnaires, and Drinker Inventory of Consequences. Results Respondents meeting previously established criteria for "disordered SNS use" were significantly more likely to use alcohol to cope with negative affect and to conform to perceived social norms, reported significantly more conflicting (i.e., simultaneous positive and negative) attitudes towards alcohol, and had experienced significantly more, and more frequent adverse consequences from drinking in their inter- and intrapersonal, physical, and social functioning, compared to individuals without problems related to SNS use. Discussion and conclusions Findings add to an emerging body of literature suggesting a link between excess or maladaptive SNS use and problems related to alcohol in young adults and point to emotion dysregulation and coping motives as potential shared risk factors for substance and behavioral addictions in this demographic. PMID- 28092187 TI - Online and live regular poker players: Do they differ in impulsive sensation seeking and gambling practice? AB - Background and aims Online gambling appears to have special features, such as anonymity, speed of play and permanent availability, which may contribute to the facilitation and increase in gambling practice, potentially leading to problem gambling. The aims of this study were to assess sociodemographic characteristics, gambling practice and impulsive sensation seeking among a population of regular poker players with different levels of gambling intensity and to compare online and live players. Methods 245 regular poker players (180 online players and 65 live players) completed online self-report scales assessing sociodemographic data, pathological gambling (SOGS), gambling practice (poker questionnaire) and impulsive sensation seeking (ImpSS). We used SOGS scores to rank players according to the intensity of their gambling practice (non-pathological gamblers, problem gamblers and pathological gamblers). Results All poker players displayed a particular sociodemographic profile: they were more likely to be young men, executives or students, mostly single and working full-time. Online players played significantly more often whereas live players reported significantly longer gambling sessions. Sensation seeking was high across all groups, whereas impulsivity significantly distinguished players according to the intensity of gambling. Discussion Our results show the specific profile of poker players. Both impulsivity and sensation seeking seem to be involved in pathological gambling, but playing different roles. Sensation seeking may determine interest in poker whereas impulsivity may be involved in pathological gambling development and maintenance. Conclusions This study opens up new research perspectives and insights into preventive and treatment actions for pathological poker players. PMID- 28092188 TI - A longitudinal study of factors explaining attitude change towards gambling among adolescents. AB - Background and aims No previous study has investigated changes in attitudes toward gambling from under legal gambling age to legal gambling age. The aim of the present study was therefore to investigate attitudinal changes during this transition and to identify predictors of corresponding attitude change. Methods In all 1239 adolescents from a national representative sample participated in two survey waves (Wave 1; 17.5 years; Wave 2; 18.5 years). Results From Wave 1 to Wave 2 the sample became more acceptant toward gambling. A regression analysis showed that when controlling for attitudes toward gambling at Wave 1 males developed more acceptant attitudes than females. Neuroticism was inversely related to development of acceptant attitudes toward gambling from Wave 1 to Wave 2, whereas approval of gambling by close others at Wave 1 was positively associated with development of more acceptant attitudes. Continuous or increased participation in gambling was related to development of more acceptant attitudes from Wave 1 to Wave 2. Conclusions Attitudes toward gambling became more acceptant when reaching legal gambling age. Male gender, approval of gambling by close others and gambling participation predicted development of positive attitudes toward gambling whereas neuroticism was inversely related to development of positive attitudes toward gambling over time. PMID- 28092190 TI - Examining personalized feedback interventions for gambling disorders: A systematic review. AB - Background and aims Personalized feedback interventions (PFI) have shown success as a low-cost, scalable intervention for reducing problematic and excessive consumption of alcohol. Recently, researchers have begun to apply PFI as an intervention method for problematic gambling behaviors. A systematic review of the literature on PFI as an intervention/prevention method for gambling behaviors was performed. Methods Studies were included if they met the following criteria: the design included both a PFI group and a comparison group, and the interventions focused on gambling prevention and/or reduction. Six relevant studies were found meeting all criteria. Results Results revealed that PFI treatment groups showed decreases in a variety of gambling behaviors as compared to control groups, and perceived norms on gambling behaviors significantly decreased after interventions as compared to control groups. Conclusions Overall, the research suggests that while PFI applied to gambling is still in its infancy, problematic gamblers appear to benefit from programs incorporating PFIs. Further, PFI may also be used as a promising source of preventative measures for individuals displaying at-risk gambling behaviors. While, evidence is still limited, and additional research needs to be conducted with PFI for gambling problems, the preliminary positive results along with the structure of PFI as a scalable and relatively inexpensive intervention method provides promising support for future studies. PMID- 28092189 TI - Life adverse experiences in relation with obesity and binge eating disorder: A systematic review. AB - Background and aims Several studies report a positive association between adverse life experiences and adult obesity. Despite the high comorbidity between binge eating disorder (BED) and obesity, few authors have studied the link between trauma and BED. In this review the association between exposure to adverse life experiences and a risk for the development of obesity and BED in adulthood is explored. Methods Based on a scientific literature review in Medline, PubMed and PsycInfo databases, the results of 70 studies (N = 306,583 participants) were evaluated including 53 studies on relationship between adverse life experiences and obesity, 7 studies on post-traumatic stress disorder (PTSD) symptoms in relation to obesity, and 10 studies on the association between adverse life experiences and BED. In addition, mediating factors between the association of adverse life experiences, obesity and BED were examined. Results The majority of studies (87%) report that adverse life experiences are a risk factor for developing obesity and BED. More precisely a positive association between traumatic experiences and obesity and PTSD and obesity were found, respectively, in 85% and 86% of studies. Finally, the great majority of studies (90%) between trauma and the development of BED in adulthood strongly support this association. Meanwhile, different factors mediating between the trauma and obesity link were identified. Discussion and conclusions Although research data show a strong association between life adverse experiences and the development of obesity and BED, more research is needed to explain this association. PMID- 28092191 TI - Psychometric properties of the Internet Addiction Test in Turkish. AB - Background and aims In this study, the Internet Addiction Test (IAT) was adapted to Turkish language, which was originally developed by Young (1998) in English to measure the presence and severity of the Internet dependency. The main purpose was to ensure that the psychometric features and the factor structure of the test were suitable for Turkish university students. Method The study was conducted in two sequent phases. Participants were 990 undergraduate students from several public universities in Turkey. Results In the first phase, an exploratory factor analysis (EFA) was applied to figure out the factor structure of the Turkish version of the IAT. The EFA revealed four factors, which explained 46.02% of the total variance. In the following phase, a confirmatory factor analysis (CFA) was conducted with a different sample, to verify the factor structure that was found in the initial EFA. The CFA resulted four-factor model was satisfactory for the Turkish version of the IAT. These four factors were named as Mood, Relationship, Responsibilities, and Duration. Conclusions Based on the findings, the administration of Turkish version of the IAT provided acceptable results on undergraduate students. PMID- 28092192 TI - Do I feel ill because I crave for work or do I crave for work because I feel ill? A longitudinal analysis of work craving, self-regulation, and health. AB - Background The theory of work craving defines workaholism as a pathological work addiction which comprises: (a) obsessive-compulsive desire to work, (b) anticipation of self-worth compensatory incentives from working, (c) anticipation of reduction of negative emotions or withdrawal symptoms from working, and (d) neurotic perfectionism. Research has shown that workaholism is associated with adverse health outcomes. However, the antecedents of workaholism and the causal direction of the relationship with health have been largely neglected. Aims In the present longitudinal study, we expect that work craving is predicted by deficits in emotional self-regulation (i.e., low action orientation) and mediates the relationship between self-regulation deficits and symptoms of psychological distress. We expected work craving to have an effect on later psychological distress symptoms, but not psychological distress symptoms to have an effect on later work craving. Methods In a sample of 170 German employees, a half longitudinal design using two times of measurement was implemented to specify the paths of two different structural equation models of mediation: (a) action orientation to later work craving and work craving to later psychological distress, and alternatively, (b) the temporal order of action orientation to later distress and distress to later work craving. Results Our data indicated that work craving partially mediated the relationship between self-regulation deficits and psychological distress, but psychological distress symptoms were not found to increase later work craving. Conclusions The presented longitudinal study indicates important mechanisms of work craving, especially by highlighting the influence of self-regulation deficits on work craving and, in turn, psychological distress. PMID- 28092193 TI - The impact of precommitment on risk-taking while gambling: A preliminary study. AB - Background and aims Precommitment refers to the ability to prospectively restrict the access to temptations. This study examined whether risk-taking during gambling is decreased when an individual has the opportunity to precommit to his forthcoming bet. Methods Sixty individuals participated in a gambling task that consisted of direct choice (simply chose one monetary option among four available ones, ranging from low-risk to high-risk options) or precommitment trials (before choosing an amount, participants had the opportunity to make a binding choice that made high-risk options unavailable). Results We found that participants utilized the precommitment option, such that risk-taking was decreased on precommitment trials compared to direct choices. Within the precommitment trials, there was no significant difference in risk-taking following decisions to restrict versus non-restrict. Discussion These findings suggest that the opportunity to precommit may be sufficient to reduce the attractiveness of risk. Conclusions Present results might be exploited to create interventions aiming at enhancing one's ability to anticipate self-control failures while gambling. PMID- 28092194 TI - Maladaptive perfectionism as mediator among psychological control, eating disorders, and exercise dependence symptoms in habitual exerciser. AB - Background and aims The current study examined the mediating role of maladaptive perfectionism among parental psychological control, eating disorder symptoms, and exercise dependence symptoms by gender in habitual exercisers. Methods Participants were 348 Italian exercisers (n = 178 men and n = 170 women; M age = 20.57, SD = 1.13) who completed self-report questionnaires assessing their parental psychological control, maladaptive perfectionism, eating disorder symptoms, and exercise dependence symptoms. Results Results of the present study confirmed the mediating role of maladaptive perfectionism for eating disorder and exercise dependence symptoms for the male and female exercisers in the maternal data. In the paternal data, maladaptive perfectionism mediated the relationships between paternal psychological control and eating disorder and exercise dependence symptoms as full mediator for female participants and as partial mediator for male participants. Discussion Findings of the present study suggest that it may be beneficial to consider dimensions of maladaptive perfectionism and parental psychological control when studying eating disorder and exercise dependence symptoms in habitual exerciser. PMID- 28092195 TI - Serum BDNF levels in patients with gambling disorder are associated with the severity of gambling disorder and Iowa Gambling Task indices. AB - Background and aims Gambling disorder (GD) shares many similarities with substance use disorders (SUDs) in clinical, neurobiological, and neurocognitive features, including decision-making. We evaluated the relationships among, GD, decision-making, and brain-derived neurotrophic factor (BDNF), as measured by serum BDNF levels. Methods Twenty-one male patients with GD and 21 healthy sex- and age-matched control subjects were evaluated for associations between serum BDNF levels and the Problem Gambling Severity Index (PGSI), as well as between serum BDNF levels and Iowa Gambling Task (IGT) indices. Results The mean serum BDNF levels were significantly increased in patients with GD compared to healthy controls. A significant correlation between serum BDNF levels and PGSI scores was found when controlling for age, depression, and duration of GD. A significant negative correlation was obtained between serum BDNF levels and IGT improvement scores. Discussion These findings support the hypothesis that serum BDNF levels constitute a dual biomarker for the neuroendocrine changes and the severity of GD in patients. Serum BDNF level may serve as an indicator of poor decision-making performance and learning processes in GD and help to identify the common physiological underpinnings between GD and SUDs. PMID- 28092196 TI - Risky online behaviors among adolescents: Longitudinal relations among problematic Internet use, cyberbullying perpetration, and meeting strangers online. AB - Background and aims This study aims to analyze the cross-sectional and longitudinal relationship between three major risky online behaviors during adolescence: problematic Internet use, cyberbullying perpetration, and meeting strangers online. An additional objective was to study the role of impulsivity irresponsibility as a possible explanatory variable of the relationships between these risky online behaviors. Methods The study sample was 888 adolescents that completed self-report measures at time 1 and time 2 with an interval of 6 months. Results The findings showed a significant cross-sectional relationship between the risky online behaviors analyzed. At the longitudinal level, problematic Internet use at time 1 predicted an increase in the perpetration of cyberbullying and meeting strangers online at time 2. Furthermore, meeting strangers online increased the likelihood of cyberbullying perpetration at time 2. Finally, when impulsivity-irresponsibility was included in the model as an explanatory variable, the relationships previously found remained significant. Discussion These results extend traditional problem behavior theory during adolescence, also supporting a relationship between different risky behaviors in cyberspace. In addition, findings highlighted the role of problematic Internet use, which increased the chances of developing cyberbullying perpetration and meeting strangers online over time. However, the results suggest a limited role of impulsivity-irresponsibility as an explicative mechanism. Conclusions The findings suggest that various online risk activities ought to be addressed together when planning assessment, prevention and intervention efforts. PMID- 28092197 TI - From the mouths of social media users: A focus group study exploring the social casino gaming-online gambling link. AB - Background and aims The potential link between social casino gaming and online gambling has raised considerable concerns among clinicians, researchers and policy makers. Unfortunately, however, there is a paucity of research examining this potential link, especially among young adults. This represents a significant gap given young adults are frequently exposed to and are players of social casino games. Methods To better understand the potential link between social casino games and online gambling, we conducted three focus groups (N = 30) at two large Canadian Universities with college students who were avid social media users (who are regularly exposed to social casino games). Results Many participants spontaneously mentioned that social casino games were a great opportunity to build gambling skills before playing for real money. Importantly, some participants expressed a belief that there is a direct progression from social casino gaming to online gambling. Conversely, others believed the transition to online gambling depended on a person's personality, rather than mere exposure to social casino games. While many young adults in our focus groups felt immune to the effects of social casino games, there was a general consensus that social casino games may facilitate the transition to online gambling among younger teenagers (i.e., 12-14 yr olds), due to the ease of accessibility and early exposure. Discussion The results of the present research point to the need for more study on the effects of social casino gambling as well as a discussion concerning regulation of social casino games in order to minimize their potential risks. PMID- 28092198 TI - Attentional bias in excessive Internet gamers: Experimental investigations using an addiction Stroop and a visual probe. AB - Background and aims Internet Gaming Disorder is included in the Diagnostic and statistical manual of mental disorders (5th edition) as a disorder that merits further research. The diagnostic criteria are based on those for Substance Use Disorder and Gambling Disorder. Excessive gamblers and persons with Substance Use Disorder show attentional biases towards stimuli related to their addictions. We investigated whether excessive Internet gamers show a similar attentional bias, by using two established experimental paradigms. Methods We measured reaction times of excessive Internet gamers and non-gamers (N = 51, 23.7 +/- 2.7 years) by using an addiction Stroop with computer-related and neutral words, as well as a visual probe with computer-related and neutral pictures. Mixed design analyses of variance with the between-subjects factor group (gamer/non-gamer) and the within subjects factor stimulus type (computer-related/neutral) were calculated for the reaction times as well as for valence and familiarity ratings of the stimulus material. Results In the addiction Stroop, an interaction for group * word type was found: Only gamers showed longer reaction times to computer-related words compared to neutral words, thus exhibiting an attentional bias. In the visual probe, no differences in reaction time between computer-related and neutral pictures were found in either group, but the gamers were faster overall. Conclusions An attentional bias towards computer-related stimuli was found in excessive Internet gamers, by using an addiction Stroop but not by using a visual probe. A possible explanation for the discrepancy could lie in the fact that the visual probe may have been too easy for the gamers. PMID- 28092200 TI - The challenges surrounding preclinical testing in transcatheter device development and the implications on the clinic. AB - INTRODUCTION: Transcatheter devices have contributed significantly to the advances achieved in treating many cardiovascular conditions over the last few decades. Sophisticated and detailed preclinical testing is not only a regulatory requirement to support an investigational device exemption (IDE) application, but more crucially its success and accuracy is needed to safeguard patients during the subsequent clinical testing stages. Areas covered: This article covers the regulatory background as well as specific considerations related to pre-clinical testing of transcatheter devices. Expert commentary: The lifecycle of a device is complex, but the period of commercialization may be short with little time for manufacturers to recuperate the costs associated with device development and (pre) clinical testing. Regulatory bodies such as the FDA require comprehensive data on pre-clinical testing prior to considering approval of an investigational device exemption to start trials in humans, which should include some data on safety and efficacy of a device. Preclinical testing needs to evaluate a variety of factors, such biocompatibility, material performance, durability, toxicology, particulation, protection against user error and device malfunction, potential hazards, and many more. PMID- 28092201 TI - Evaluation of a steroid releasing sinus implant for the treatment of patients undergoing frontal sinus surgery for chronic rhinosinusitis. AB - INTRODUCTION: Management of the frontal sinus places great demands on the otolaryngologist. Given that the fronto-ethmoidal region is susceptible to recurrent inflammation, scarring, and stenosis, maintaining long-term patency of the frontal sinus is a difficult challenge. Oral and topical anti-inflammatory therapy, post-operative stenting, and 'home-brew' drug elution have been used for the treatment of the frontal sinus with mixed success. Recently an implant has been approved for post-operative placement into the frontal recess. This implant provides reliable and consistent steroid drug elution to address inflammation of the frontal recess secondary to chronic sinusitis. Areas covered: This review discusses the development and application of steroid eluting implants in the postoperative care of patients with chronic frontal sinusitis. All randomized controlled trials evaluating steroid eluting implants are discussed. Relevant supporting material discussing background, economics, safety are included. Expert commentary: Steroid eluting implants fulfill a unique niche in the treatment following frontal sinus surgery. They are shown to decrease the need for post operative interventions and improve outcomes in patients with chronic sinusitis. There is significant potential for growth in the use of steroid eluting implants. PMID- 28092202 TI - Is DNA testing for hemochromatosis diagnosis reliable? PMID- 28092204 TI - Impact of combination therapy and early de-escalation on outcome of ventilator associated pneumonia caused by Pseudomonas aeruginosa. AB - BACKGROUND: Pseudomonas aeruginosa is a common cause of ventilator-associated pneumonia (VAP). Guidelines recommend dual coverage of P. aeruginosa, but the beneficial effect of combination therapy is controversial. We described antibiotic prescriptions and evaluated the clinical impact of initial combination antibiotic therapy and de-escalation strategy in patients with VAP caused by P. aeruginosa. METHODS: Between 1994 and 2014, all 100 patients with VAP caused by P. aeruginosa in our intensive care unit (ICU) were included in a retrospective cohort study to evaluate the prognostic impact of initial combination antibiotic therapy. RESULTS: Eighty-five patients received initial combination antibiotic therapy and 15 monotherapy. Nine patients received inadequate initial antibiotic therapy. De-escalation was performed in 42 patients. Thirty-nine patients died in the ICU. Factors independently associated with death were SAPS II score [SAPS II >=40 versus <40: hazard ratio (HR) 2.49, 95% confidence interval (CI) 1.08-5.70, p = 0.03] and septic shock (HR = 4.80, 95% CI = 1.90-12.16, p < 0.01) at onset of VAP. Initial combination antibiotic therapy (HR = 1.97, 95% CI = 0.56-6.93, p = 0.29) and early de-escalation (HR = 0.59, 95% CI = 0.27-1.31, p = 0.19) had no impact on mortality. In multivariate analysis, the risk for inappropriate initial antibiotic therapy was higher in cases with multi-drug resistant P. aeruginosa [odd ratio (OR) = 7.11, 95% CI = 1.42-35.51, p = 0.02], but lower in cases with initial combination antibiotic therapy (OR = 0.12, 95% CI = 0.02-0.63, p = 0.01). CONCLUSION: In our cohort, combination therapy increased the likelihood of appropriate therapy but did not seem to impact on mortality. PMID- 28092203 TI - Machine Learning of Three-dimensional Right Ventricular Motion Enables Outcome Prediction in Pulmonary Hypertension: A Cardiac MR Imaging Study. AB - Purpose To determine if patient survival and mechanisms of right ventricular failure in pulmonary hypertension could be predicted by using supervised machine learning of three-dimensional patterns of systolic cardiac motion. Materials and Methods The study was approved by a research ethics committee, and participants gave written informed consent. Two hundred fifty-six patients (143 women; mean age +/- standard deviation, 63 years +/- 17) with newly diagnosed pulmonary hypertension underwent cardiac magnetic resonance (MR) imaging, right-sided heart catheterization, and 6-minute walk testing with a median follow-up of 4.0 years. Semiautomated segmentation of short-axis cine images was used to create a three dimensional model of right ventricular motion. Supervised principal components analysis was used to identify patterns of systolic motion that were most strongly predictive of survival. Survival prediction was assessed by using difference in median survival time and area under the curve with time-dependent receiver operating characteristic analysis for 1-year survival. Results At the end of follow-up, 36% of patients (93 of 256) died, and one underwent lung transplantation. Poor outcome was predicted by a loss of effective contraction in the septum and free wall, coupled with reduced basal longitudinal motion. When added to conventional imaging and hemodynamic, functional, and clinical markers, three-dimensional cardiac motion improved survival prediction (area under the receiver operating characteristic curve, 0.73 vs 0.60, respectively; P < .001) and provided greater differentiation according to difference in median survival time between high- and low-risk groups (13.8 vs 10.7 years, respectively; P < .001). Conclusion A machine-learning survival model that uses three-dimensional cardiac motion predicts outcome independent of conventional risk factors in patients with newly diagnosed pulmonary hypertension. Online supplemental material is available for this article. PMID- 28092205 TI - Effect of polidocanol foam administration into rat peripheral veins on pulmonary parenchyma. AB - Background Sclerotherapy has been gaining increased acceptance and popularity as an effective therapy for the treatment of varicose veins. This attention has fed growing interest into the safety and potential complications of this procedure. There is no evidence of pulmonary complications from foam sclerotherapy in humans; however, animal studies have shown possible damage. The aim of this study is to show the changes in rat pulmonary parenchyma after the injection of 1% polidocanol Tessari foam into the peripheral vein using histological analysis of the inflammatory and fibrosis processes. Methods Twenty-four Wistar rats were divided into the following four groups: 24 h polidocanol, seven-day polidocanol, 28-day polidocanol, and control group. After the foam was injected into the lateral saphenous vein, the lungs of the rats were removed for histological analysis. Results Alveolar edema was observed in only the 24 h group (P < 0.005). Vessel thickening was observed in the seven-and 28-day groups (P < 0.001). Interstitial fibrosis was found in only the 28-day group (P = 0.006). There was no evidence of venous or arterial thrombosis in either group. Conclusion Polidocanol Tessari foam injection into rat peripheral veins causes alveolar edema, vessel thickening, and interstitial fibrosis. PMID- 28092206 TI - Impact of UK NICE clinical guidelines 168 on referrals to a specialist academic leg ulcer service. AB - Background Leg ulcers are a common cause of morbidity and disability and result in significant health and social care expenditure. The UK National Institute for Health and Care Excellence (NICE) Clinical Guideline (CG)168, published in July 2013, sought to improve care of patients with leg ulcers, recommending that patients with a break in the skin below the knee that had not healed within two weeks be referred to a specialist vascular service for diagnosis and management. Aim Determine the impact of CG168 on referrals to a leg ulcer service. Methods Patients referred with leg ulceration during an 18-month period prior to CG168 (January 2012-June 2013) and an 18-month period commencing six months after (January 2014-June 2015) publication of CG168 were compared. Results There was a two-fold increase in referrals (181 patients, 220 legs vs. 385 patients, 453 legs) but no change in mean age, gender or median-duration of ulcer at referral (16.6 vs. 16.2 weeks). Mean-time from referral to specialist appointment increased (4.8 vs. 6 weeks, p = 0.0001), as did legs with superficial venous insufficiency (SVI) (36% vs. 44%, p = 0.05). There was a trend towards more SVI endovenous interventions (32% vs. 39%, p = 0.271) with an increase in endothermal (2 vs. 32 legs, p = 0.001) but no change in sclerotherapy (24 vs. 51 legs) treatments. In both groups, 62% legs had compression. There was a reduction in legs treated conservatively with simple dressings (26% vs. 15%, p = 0.0006). Conclusions Since CG168, there has been a considerable increase in leg ulcer referrals. However, patients are still not referred until ulceration has been present for many months. Although many ulcers are multi-factorial and the mainstay of treatment remains compression, there has been an increase in SVI endovenous intervention. Further efforts are required to persuade community practitioners to refer patients earlier, to educate patients and encourage further investment in chronically underfunded leg ulcer services. PMID- 28092208 TI - The effects of mental fatigue on cricket-relevant performance among elite players. AB - This study investigated the effects of a mentally fatiguing test on physical tasks among elite cricketers. In a cross-over design, 10 elite male cricket players from a professional club performed a cricket run-two test, a Batak Lite reaction time test and a Yo-Yo-Intermittent Recovery Level 1 (Yo-Yo-IR1) test, providing a rating of perceived exertion (RPE) after completing a 30-min Stroop test (mental fatigue condition) or 30-min control condition. Perceived fatigue was assessed before and after the two conditions and motivation was measured before testing. There were post-treatment differences in the perception of mental fatigue (P < 0.001; d = -7.82, 95% CIs = -9.05-6.66; most likely). Cricket run two (P = 0.002; d = -0.51, 95% CIs = -0.72-0.30; very likely), Yo-Yo-IR1 distance (P = 0.023; d = 0.39, 95% CIs = 0.14-0.64; likely) and RPE (P = 0.001; d = -1.82, 95% CIs = -2.49-1.14; most likely) were negatively affected by mental fatigue. The Batak Lite test was not affected (P = 0.137), yet a moderate (d = 0.41, 95% CIs = -0.05-0.87) change was likely. Mental fatigue, induced by an app-based Stroop test, negatively affected cricket-relevant performance. PMID- 28092209 TI - Executive function is an important consideration for coping strategy use in people with multiple sclerosis. AB - INTRODUCTION: Executive function deficits are prevalent in people with multiple sclerosis (PwMS), and PwMS use less adaptive coping than healthy controls. This cross-sectional study assessed whether there is a relationship between executive function and coping in PwMS. METHOD: One hundred and seven participants with relapsing remitting or secondary progressive MS (n = 83 and 24, respectively; age M = 48.8 +/- 11.1 years) completed measures of coping and executive function. RESULTS: A positive relationship was found between verbal fluency and use of active, emotional, and instrumental social support coping, and total executive function and substance abuse coping. There was a negative relationship between coping strategies and core (social support, acceptance, religion, restraint, and total coping), higher order (denial and humor), and total executive function indices (acceptance, religion, behavioral disengagement, denial, and total coping). CONCLUSION: These directional differences provide support for the importance of specific executive functions in coping strategy utilization. Understanding these relationships will assist psychologists and neuropsychologists with patient psychoeducation, adaptive coping strategy intervention and management for PwMS with reduced executive function ability. PMID- 28092207 TI - Healthcare burden of depression in adults with arthritis. AB - INTRODUCTION: Arthritis and depression are two of the top disabling conditions. When arthritis and depression exist in the same individual, they can interact with each other negatively and pose a significant healthcare burden on the patients, their families, payers, healthcare systems, and society as a whole. Areas covered: The primary objective of this review is to summarize, identify knowledge gaps and discuss the challenges in estimating the healthcare burden of depression among individuals with arthritis. Electronic literature searches were performed on PubMed, Embase, EBSCOhost, Scopus, the Cochrane Library, and Google Scholar to identify relevant studies. Expert Commentary: Our review revealed that the prevalence of depression varied depending on the definition of depression, type of arthritis, tools and threshold points used to identify depression, and the country of residence. Depression exacerbated arthritis-related complications as well as pain and was associated with poor health-related quality of life, disability, mortality, and high financial burden. There were significant knowledge gaps in estimates of incident depression rates, depression attributable disability, and healthcare utilization, direct and indirect healthcare costs among individuals with arthritis. PMID- 28092210 TI - The insights of health and welfare professionals on hurdles that impede economic evaluations of welfare interventions. AB - BACKGROUND: Four hurdles associated with economic evaluations in welfare interventions were identified and discussed in a previous published literature review. These hurdles include (i) 'Ignoring the impact of condition-specific outcomes', (ii) 'Ignoring the impact of QoL externalities', (iii) 'Calculation of costs from a too narrow perspective' and (iv) 'The lack of well-described & standardized interventions'. This study aims to determine how healthcare providers and social workers experience and deal with these hurdles in practice and what solutions or new insights they would suggest. METHODS: Twenty-two professionals of welfare interventions carried out in Flanders, were interviewed about the four described hurdles using a semi-structured interview. A thematic framework was developed to enable the qualitative analysis. The analysis of the semi-structured interviews was facilitated through the use of the software program QRS NVivo 10. RESULTS: The interviews revealed a clear need to tackle these hurdles. The interviewees confirmed that further study of condition specific outcomes in economic evaluations are needed, especially in the field of mental health and stress. The proposed dimensions for the condition-specific questionnaires varied however between the groups of interviewees (i.e. general practitioners vs social workers). With respect to QoL externalities, the interviewees confirmed that welfare interventions have an impact on the social environment of the patient (friends and family). There was however no consensus on how this impact of QoL externalities should be taken into account in welfare interventions. Professionals also suggested that besides health care costs, the impact of welfare interventions on work productivity, the patients' social life and other items should be incorporated. Standardization appears to be of limited added value for most of the interviewees because they need a certain degree of freedom to interpret the intervention. Furthermore, the target population of the interventions is diverse which requires a tailor-made approach. CONCLUSION: This qualitative research demonstrated that these hurdles occur in practice. The proposed solutions for these hurdles can contribute to the improvement of the methodological quality of economic evaluations of welfare interventions. PMID- 28092211 TI - Spanish Adaptation of the Frommelt Attitude Toward Care of the Dying Scale (FATCOD-S) in Nursing Undergraduates. AB - The Frommelt Attitude Toward Care of the Dying Scale (FATCOD) is designed to assess the attitudes of professionals and trainees toward caring for the dying patient and their family members. In this study the main aim is to adapt the FATCOD to a Spanish context (FATCOD-S). In addition, the relations between FATCOD S, sociodemographic variables, emotional intelligence, and death attitudes have been analyzed. A sample of 669 Spanish nursing students from four Universities responded to a questionnaire. The exploratory factor analysis (EFA) concludes a structure composed of two significant factors. A confirmatory factor analysis (CFA) was carried out. The CFA supported a two-factor model. Students with past experience of death and those who had received training in palliative care scored significantly higher on both factors of the FATCOD-S ( p < 0.01). The FATCOD-S is an effective and valid tool for measuring the attitudes of Spanish nursing students toward caring for patients at the end of life. PMID- 28092212 TI - Systemic medications used in treatment of common dermatological conditions: safety profile with respect to pregnancy, breast feeding and content in seminal fluid. AB - Prescribing for pregnant or lactating patients and male patients wishing to father children can be a difficult area for dermatologists. There is a lack of review articles of commonly used systemic medications in dermatology with respect to their effects on developing embryogenesis and their potential transfer across the placenta, in breast milk and in seminal fluid. This paper aims to provide an up to date summary of evidence to better equip dermatologists to inform patients about the effects of systemic medications commonly used in dermatology to treat conditions such as atopic dermatitis, psoriasis and acne, on current and future embryogenesis and fertility. PMID- 28092213 TI - Cellular and Molecular Factors Influencing Tendon Repair. AB - Tendons are complex connective tissues that transmit tensile forces between muscles and tendons. Tendon injuries are among the most common orthopedic problems with long-term disability as a frequent consequence due to prolonged healing time. Furthermore, the repair tissue is of inferior quality, predisposing patients to high rates of recurrence following initial injury. Coordinated cellular processes and biological factors under the influence of mechanical loading are involved in tendon healing and our understanding of these events lags behind other musculoskeletal tissues. Tendons are relatively hypocellular and hypovascular, with little or no intrinsic regenerative capacity. Studies have documented fatty degeneration, chondrogenic dysplasia, and ectopic ossification within tendon repair tissue. The underlying pathogenesis for these metaplastic changes that compromise the quality of tendon repair tissue is poorly understood. The purpose of this review is to compile literature reporting molecular processes that regulate/control the phenotype of cells responsible for abnormal matrix deposition at repair site. In addition, recent studies reporting the interplay of mechanotransduction and cellular responses during tendon repair are summarized. Identifying the links between cellular, biological, and mechanical parameters involved in tendon repair is paramount to develop successful therapies for tendon healing. PMID- 28092214 TI - Treatment of Delta Hepatitis: Today and in the Future - A review. AB - Hepatitis delta virus (HDV) is a defective satellite virus and propagates in the presence of Hepatitis B virus (HBV) surface antigen (HBsAg). Approximately 5% of the people who infected with HBV are also infected with HDV. Chronic hepatitis caused by delta is the most severe form of chronic viral hepatitis including accelerated fibrosis, liver decompensation and development of hepatocellular carcinoma. Interferon-based therapies still remain the only treatment option of the hepatitis delta. The beneficiary effects of the interferon-based therapies, however, stop frequently with termination of the given therapy and relapse rate is very high. Accordingly, the efficiency rate of this treatment does not exceed 30%. On the other hand, serious side effects of interferons are another troublesome leading to withdrawal of the therapy. The main goal of the current treatments is clearance of HBsAg. There is no available drug acting directly against the HDV. New therapies interacting with HDV life cycle are under investigation. While prenylation inhibitors act on merely HDV, viral entry inhibitors and HBsAg release inhibitors would be used in the treatment of both HBV and HDV. We hope that in the future, the use of novel therapies and HBV vaccination provide to clinicians to cope with this troublesome agent. PMID- 28092215 TI - Therapeutic implications from the pathogenesis of Raynaud's phenomenon. AB - INTRODUCTION: Raynaud's phenomenon (RP) can be either primary (idiopathic) or secondary to a number of different diseases/conditions, when vasopasm can be superimposed upon structural vascular abnormality or a hyperviscosity state and may then lead to severe ischaemia with tissue damage. Treatment must be tailored to the individual. Areas covered: This review discusses how increased understanding of the pathogenesis of RP has driven and is driving new approaches to therapy, and how we are now better able to predict which patients presenting with RP are likely to have an underlying disease requiring specific intervention. Medline searches (1946 to August 2016) were conducted for 'Raynaud's' in combination with relevant terms including different drugs. All papers identified were English language, with abstracts. Expert commentary: Randomised controlled trials of RP present particular challenges. The major aim must continue to be development of safe, effective treatments for patients across the spectrum of RP. PMID- 28092216 TI - Metabolism of metofluthrin in rats: I. Identification of metabolites. AB - 1. Metofluthrin (2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (Z/E)-(1R)-trans-2,2 dimethyl-3-(1-propenyl)-cyclopropanecarboxylate) is a novel pyrethroid insecticide, which has E/Z isomers at prop-1-enyl group. 2. Rats were orally dosed with each [14C]-labelled E/Z isomer, and the excreta were collected for isolation and identification of metabolites. Analysis of the excreta by LC/MS and NMR revealed formation of 33 and 23 (total 42) metabolites from rats dosed with Z isomer and E-isomer, respectively. 3. Major metabolic reactions were cleavage of ester linkage, O-demethylation, hydroxylation, epoxidation or reduction of double bond, glutathione conjugation and its further metabolism, hydroxylation of epoxide and formation of lactone ring. Notably, the acid side, 2,2-dimethyl-3-(1 propenyl)-cyclopropanecarboxylic acid, was much more variously metabolised compared to chrysanthemic acid, the acid side of the known pyrethroids. 4. Major metabolites for Z-isomer mostly retained ester linkage with 1,2-dihydroxypropyl group and/or 2-methylalcohol of cyclopropane ring, while most of those for E isomer received hydrolysis of the ester linkage without oxidation at the 1 propenyl group or the gem-methyl groups, suggesting epoxidation and hydroxylation could occur more easily on Z-isomer. 5. As the novel metabolic pathways for pyrethroids, isomerisation of omega-carboxylic acid moiety, reduction or hydration of double bond and cleavage of cyclopropane ring via epoxidation were suggested. PMID- 28092217 TI - Development, construct validity and test-retest reliability of a field-based wheelchair mobility performance test for wheelchair basketball. AB - The aim of this study was to develop and describe a wheelchair mobility performance test in wheelchair basketball and to assess its construct validity and reliability. To mimic mobility performance of wheelchair basketball matches in a standardised manner, a test was designed based on observation of wheelchair basketball matches and expert judgement. Forty-six players performed the test to determine its validity and 23 players performed the test twice for reliability. Independent-samples t-tests were used to assess whether the times needed to complete the test were different for classifications, playing standards and sex. Intraclass correlation coefficients (ICC) were calculated to quantify reliability of performance times. Males performed better than females (P < 0.001, effect size [ES] = -1.26) and international men performed better than national men (P < 0.001, ES = -1.62). Performance time of low (<=2.5) and high (>=3.0) classification players was borderline not significant with a moderate ES (P = 0.06, ES = 0.58). The reliability was excellent for overall performance time (ICC = 0.95). These results show that the test can be used as a standardised mobility performance test to validly and reliably assess the capacity in mobility performance of elite wheelchair basketball athletes. Furthermore, the described methodology of development is recommended for use in other sports to develop sport-specific tests. PMID- 28092218 TI - Analysis of the Effect of Chronic and Low-Dose Radiation Exposure on Spermatogenic Cells of Male Large Japanese Field Mice ( Apodemus speciosus ) after the Fukushima Daiichi Nuclear Power Plant Accident. AB - In this study we analyzed the effect of chronic and low-dose-rate (LDR) radiation on spermatogenic cells of large Japanese field mice ( Apodemus speciosus ) after the Fukushima Daiichi Nuclear Power Plant (FNPP) accident. In March 2014, large Japanese field mice were collected from two sites located in, and one site adjacent to, the FNPP ex-evacuation zone: Tanashio, Murohara and Akogi, respectively. Testes from these animals were analyzed histologically. External dose rate from radiocesium (combined 134Cs and 137Cs) in these animals at the sampling sites exhibited 21 MUGy/day in Tanashio, 304-365 MUGy/day in Murohara and 407-447 MUGy/day in Akogi. In the Akogi group, the numbers of spermatogenic cells and proliferating cell nuclear antigen (PCNA)-positive cells per seminiferous tubule were significantly higher compared to the Tanashio and Murohara groups, respectively. TUNEL-positive apoptotic cells tended to be detected at a lower level in the Murohara and Akogi groups compared to the Tanashio group. These results suggest that enhanced spermatogenesis occurred in large Japanese field mice living in and around the FNPP ex-evacuation zone. It remains to be elucidated whether this phenomenon, attributed to chronic exposure to LDR radiation, will benefit or adversely affect large Japanese field mice. PMID- 28092219 TI - The 21st Century Cures Act: pharmacoeconomic boon or bane? AB - Barriers to entry in healthcare markets constitute one of the overriding concerns of health economists. The recent enactment of the 21st Century Cures Act in the United States reduces statutory entry barriers to the discovery, development, testing, and licensing of drugs and medical devices. Drug and device makers also see the burdensome and time-consuming requirements of the Food and Drug Administration?s approval process as key barriers to lowering the costs of their products, considering it takes a decade of research amounting to $1 billion just to bring a single drug to the market. Along with novel opportunities for medical product innovation and faster treatment of diseases, the expedited approval process carries with it contentious challenges involving the safety, efficacy and value of drugs and devices. The ensuing trade-offs and unintended consequences of such a regulatory game-changer bring to the fore one of the most enduring debates between medicine and economics: Whether - or to what extent - cost and efficiency factors affect clinical inquiry into possible solutions to human illnesses. The practical and theoretical contributions of pharmacoeconomics should enlighten contemporary and future issues and discussions surrounding the implementation of this landmark legislation. After all, despite its undeniably good intent and far reaching significance, no law can ever be perfect. PMID- 28092220 TI - Using teledentistry in clinical practice as an enabler to improve access to clinical care: A qualitative systematic review. AB - Background Access to dental care is important for overall health, but can remain problematic for those in rural or isolated locations. It can be difficult to encourage clinicians to choose or continue a rural health career. Teledentistry is showing some promise as a strategy to support rural, isolated and new health care workers. This study aims to explore the quantitative and qualitative framework associated with teledentistry in an effort to uncover the interaction of multiple influences on its delivery and sustainability. Methods A systematic search of the literature was undertaken and studies were included if they evaluated consultative teledentistry, reports on implementation of teledentistry in practice or attitudes to teledentistry. Studies were evaluated qualitatively. Results Thirty-nine studies were included focusing on the accuracy, effectiveness or description a teledentistry project in practice. Five main themes were identified in the qualitative analysis: (1) using information and communication technology (ICT), (2) regulatory and system improvements, (3) accuracy of teledentistry, (4) effectiveness, including increasing access to clinical services, efficiencies and acceptability, and (5) building and increasing clinical capacity of the dental workforce. Conclusion Teledentistry provides a viable option for remote screening, diagnosis, consultation, treatment planning and mentoring in the field of dentistry. Rapidly developing information and communication technologies have increasingly shown improving cost effectiveness, accuracy and efficient remote assistance for clinicians. There is high acceptability for teledentistry amongst clinicians and patients alike. Remuneration of advising clinicians is critical to sustainability. PMID- 28092221 TI - Tuberculosis mimicking primary systemic vasculitis: not to be missed! AB - Infections are an important differential diagnosis in patients presenting with features of systemic vasculitis. We report a young lady with constitutional features, leg ulcers, digital gangrene and absent peripheral pulses with cervical adenopathy. Chest imaging revealed multiple necrotic lung lesions and involvement of left subclavian artery at its origin from the aorta, Histopathology from cervical lymph nodes showed multiple caseated lymph nodes, which in the context of a positive Mantoux test led us to diagnose tuberculosis and institute appropriate therapy. This is only the second report of tuberculosis presenting as peripheral gangrene, cutaneous ulcers and absent pulses, and serves to educate rheumatologists regarding the need to consider infections as mimics of vasculitis, especially in the developing countries. PMID- 28092222 TI - Varied presentations of leptospirosis: experience from a tertiary care hospital in north India. AB - Leptospirosis has been recognised as an emerging global public health problem. The aim of our study was to explore the epidemiological and clinical pattern of disease occurrence in suspected cases and to search for any existing co infections. Ours was a retrospective study in patients with acute febrile illness in north India over a period of three years (April 2011 to June 2014). Serological diagnosis of leptospirosis was made using the PanBio IgM ELISA kit. Using modified Faine's criteria, presumptive and possible diagnosis was made in 57% and 34% cases, respectively. Most of the affected population was resident in north and central India. Nineteen patients showed co-infection with other common pathogens prevailing locally. There is a need to increase awareness and understand the local sero-epidemiological pattern of leptospirosis so that timely preventive and curative action may be taken by healthcare authorities. PMID- 28092223 TI - Vesico-umbilical fistula in a child with severe vesico-ureteral reflux and bladder diverticulum. PMID- 28092224 TI - Visual map and instruction-based bicycle navigation: a comparison of effects on behaviour. AB - Cycling with a classic paper map was compared with navigating with a moving map displayed on a smartphone, and with auditory, and visual turn-by-turn route guidance. Spatial skills were found to be related to navigation performance, however only when navigating from a paper or electronic map, not with turn-by turn (instruction based) navigation. While navigating, 25% of the time cyclists fixated at the devices that present visual information. Navigating from a paper map required most mental effort and both young and older cyclists preferred electronic over paper map navigation. In particular a turn-by-turn dedicated guidance device was favoured. Visual maps are in particular useful for cyclists with higher spatial skills. Turn-by-turn information is used by all cyclists, and it is useful to make these directions available in all devices. Practitioner Summary: Electronic navigation devices are preferred over a paper map. People with lower spatial skills benefit most from turn-by-turn guidance information, presented either auditory or on a dedicated device. People with higher spatial skills perform well with all devices. It is advised to keep in mind that all users benefit from turn-by-turn information when developing a navigation device for cyclists. PMID- 28092225 TI - Comparison of dysphagia outcomes between rostral and caudal lateral medullary infarct patients. AB - OBJECTIVE: A detailed knowledge of dysphagia outcomes in lateral medullary infarct (LMI) patients would enable proper establishment of swallowing therapy goals and strategies. However, little is known about the impact of infarct location on dysphagia outcomes in patients with LMI. METHODS: Twenty patients with rostral LMI (rostral group) and 20 patients with caudal LMI (caudal group) participated in the study. All patients underwent swallowing therapy, which included compensatory treatments and strengthening exercises, for >3 months. Dysphagia evaluation was performed twice (during the subacute stage and six months after stroke onset) using videofluoroscopic swallowing studies. Dysphagia degree was assessed using the functional dysphagia scale (FDS), the penetration aspiration scale (PAS) and the American Speech-Language-Hearing Association (ASHA) National Outcome Measurement System (NOMS) swallowing scale. RESULTS: In the subacute stage, the rostral group had significantly higher FDS and PAS scores and a significantly lower ASHA NOMS score than the caudal group. Patients from both groups showed significant improvement from the initial evaluation to the six month evaluation. There were no significant differences in these scale scores between the two groups at the six-month evaluation. CONCLUSION: In the subacute stage, patients in the rostral group had more severe dysphagia than those in the caudal group. Dysphagia improved in both groups after 3-6 months of swallowing therapy. At six months after onset, there were no significant differences in dysphagia severity between the two groups. Recovery from dysphagia after LMI was observed regardless of the infarct location. PMID- 28092226 TI - Drug supply in in-patient nursing care facilities: reasons for irregularities in quality reviews AB - Background: Quality checks of the independent German Health Insurance Medical Service in in-patient nursing care facilities pursuant to Articles 114 et seqq. SGB XI [11th Book of the Social Code] also comprise the Pflegerische Medikamentenversorgung (PMV) [drug supply by nursing personnel]. Irregularities are described in quality reports in the reviewer's own words. This investigation was intended to categorise the reasons for the above irregularities. Methods: The bases for the examination are the reports of quality checks of all of in-patient nursing care facilities conducted in 2014 (regular quality checks) in Hamburg and Schleswig-Holstein (N = 671), in which the PMV was examined for 5 742 randomly selected residents. Results: With regard to the documentation, inexplicable drug intakes (5.8 %) were found most frequently, followed by missing information on dosages and application provisions (0.8 % each), which were registered as irregularities at the residents. In the documentation of on-demand medication, insufficient indication data (3.2 %), missing daily maximum dosages (0.8 %) and missing single doses (0.6 %) were most commonly ascertained. The most frequent reasons for medication handling irregularities for the residents were false positioning (6.0 %), missing and respectively false data on consumption and on when the medical packaging was opened (3.5 %), as well as medication not directly administered using the blister (0.7 %). As for subordinate classifications of false positioning, incorrect dosages were revealed most often, followed by drugs with an exceeded expiry date and by out-of-stock drugs. Systematic patient related factors with influence on PMV could not be determined. Conclusions: The extent of the irregularities and their type prompt a further increase in the efforts to improve the quality of nursing care facilities. The results can be used as a basis for designing specific initiatives to improve the PMV. PMID- 28092227 TI - The reliability of the Extra Load Index as a measure of relative load carriage economy. AB - The aim of this study was to measure the reliability of the extra load index (ELI) as a method for assessing relative load carriage economy. Seventeen volunteers (12 males, 5 females) performed walking trials at 3 km.h-1, 6 km.h-1 and a self-selected speed. Trial conditions were repeated 7 days later to assess test-retest reliability. Trials involved four 4-minute periods of walking, each separated by 5 min of rest. The initial stage was performed unloaded followed in a randomised order by a second unloaded period and walking with backpacks of 7 and 20 kg. Results show ELI values did not differ significantly between trials for any of the speeds (p = 0.46) with either of the additional loads (p = 0.297). The systematic bias, limits of agreement and coefficients of variation were small in all trial conditions. We conclude the ELI appears to be a reliable measure of relative load carriage economy. Practitioner Summary: This paper demonstrates that the ELI is a reliable measure of load carriage economy at a range of walking speeds with both a light and heavy load. The ELI, therefore, represents a useful tool for comparing the relative economy associated with different load carriage systems. PMID- 28092228 TI - A comparative study of vocational education and occupational safety and health training in China and the UK. AB - In order to enhance Chinese workers' occupational safety awareness, it is essential to learn from developed countries' experiences. This article investigates thoroughly occupational safety and health (OSH) in China and the UK; moreover, the article performs a comparison of Chinese and British OSH training related laws, regulations and education system. The following conclusions are drawn: China's work safety continues to improve, but there is still a large gap compared with the UK. In China a relatively complete vocational education and training (VET) system has been established. However, there exist some defects in OSH. In the UK, the employer will not only pay attention to employees' physiological health, but also to their mental health. The UK's VET is characterized by classification and grading management, which helps integrate OSH into the whole education system. China can learn from the UK in the development of policies, VET and OSH training. PMID- 28092229 TI - Decamethylcyclopentasiloxane (D5). AB - Decamethylcyclopentasiloxane (D5; CAS No. 541-02-6) is a precursor in the production of siloxane polymers for industry and medicine and is a carrier ingredient in many toiletries and cosmetics. D5 has a relatively low order of toxicity following acute administration via the oral, dermal, and inhalation routes of exposure. It is not considered to be a dermal or eye irritant or a dermal sensitizer. There is no appreciable dermal absorption of D5 based on results from in vivo and in vitro studies. It has not been shown to be genotoxic/mutagenic when tested in a number of short-term in vitro and in vivo assays and did not cause reproductive or developmental toxicity in rats. Inhalation exposure of rats to 160 ppm D5 for up to 24 months produced adverse effects in the liver (weight changes and hepatocellular hypertrophy) and uterus (increased incidence of endometrial adenocarcinoma, endometrial adenoma, and adenomatous polyps in several animals); however, the results of recent mode-of action studies are consistent with a uterine tumorigenesis mechanism that is not relevant for humans. Based on the results of the chronic inhalation study, 160 ppm was determined to be the no-observed-adverse-effect level (NOAEL) and was selected as the point of departure for the derivation of the workplace environmental exposure level (WEEL(r)) value. This NOAEL was adjusted to account for interindividual variability and residual uncertainty regarding upper respiratory tract changes still occurring at 160 ppm. The resulting 8-h time weighted average WEEL value of 10 ppm is expected to provide a significant margin of safety against any potential adverse health effects in workers exposed to airborne D5. PMID- 28092230 TI - Octamethylcyclotetrasiloxane (D4). AB - Octamethylcyclotetrasiloxane (D4; CAS No. 556-67-2) is used as a monomer in the manufacture of polymeric materials, which are widely used in various industrial and/or medical applications, such as breast implants. D4 has a relatively low order of toxicity following acute administration via the oral, dermal, and inhalation routes of exposure and is not considered to be a dermal or eye irritant or to be a dermal sensitizer. There is no appreciable dermal absorption of D4 based on results from in vivo and in vitro studies. D4 has not been shown to be genotoxic/mutagenic when tested in a number of short-term in vitro and in vivo assays. Overall, studies have demonstrated adverse effects on specific female reproductive endpoints at higher exposure concentrations; however, no D4 exposure-specific effects were noted with respect to developmental endpoints. Inhalation exposure of rats to 700 ppm D4 for up to 24 months produced effects in the liver, kidney, and uterus (weight changes, hepatocellular hypertrophy, endometrial hyperplasia, and nephropathy). Changes in the nasal epithelium (eosinophilic globules) were also noted at 150 and 700 ppm. Despite 24 months of exposure, only mild to minimal inflammatory responses were found at 150 ppm, and overall, the basic integrity of the respiratory tract was unchanged at this dose. At 700 ppm, there was an increased incidence of endometrial adenomas in female rats. Based on the adverse changes in the respiratory tract, kidney, and female reproductive tract in the chronic inhalation study, 150 ppm was determined to be the no-observed-adverse-effect level (NOAEL) and was selected as the point of departure for the derivation of the workplace environmental exposure level (WEEL(r)) value. The inhalation NOAEL was adjusted to account for interindividual variability and residual uncertainty regarding upper respiratory tract changes still occurring at 150 ppm. An 8-h time-weighted average WEEL value of 10 ppm is expected to provide a significant margin of safety against any potential adverse health effects in workers exposed to airborne D4. PMID- 28092231 TI - Retraction notice. PMID- 28092232 TI - Retraction notice. PMID- 28092233 TI - Editorial. PMID- 28092234 TI - Retraction notice. PMID- 28092235 TI - Hospital cost and length of stay in idiopathic pulmonary fibrosis. AB - OBJECTIVE: To provide a detailed picture of the economic impact of hospitalization in idiopathic pulmonary fibrosis (IPF) and to identify factors associated with cost and length of stay (LOS). METHODS: In this retrospective cross-sectional study using the Nationwide Inpatient Sample (NIS), this study included hospitalizations for IPF (ICD-9-CM 516.3) with a principal diagnosis of respiratory disease (ICD-9-CM 460-519) from 2009-2011; lung transplant admissions were excluded. Total inpatient cost, LOS, in-hospital death, and discharge disposition were reported. Linear regression models were used to determine variables predictive of LOS and cost. RESULTS: From 2009-2011, 22,350 non transplant IPF patients with a principal diagnosis of respiratory disease were admitted: mean (+/-SE) age was 70.0 (0.32), and 49.1% were female. While in hospital, 11.4% of patients received mechanical ventilation and 8.9% received non invasive ventilation. Mean (+/-SE) LOS was 7.4 (0.15) days overall (p < .001). The mean (+/-SD) admission cost was $16,042 (+/-631). Of hospitalized patients, 14.1% died, 20.6% transferred facilities, and 46.4% were routinely discharged. The adjusted LOS (95% CI) for patients with and without mechanical ventilation was 16.1 days (15-17.5) vs. 6.3 (6-6.5); adjusted costs were $48,772 (43,979 53,565) vs. $11,861 (11,292-12,431). LIMITATIONS: The positive predictive value of the algorithm used to identify IPF is not optimal. The NIS database does not follow patients longitudinally, and claims after admission are not available. Claims do not indicate whether listed diagnoses were present on admission or developed during hospitalization. The exclusion of transplant-related expenditures lead to under-estimation of cost. CONCLUSION: Using a nationally representative database, we found IPF respiratory-related hospitalizations represent a significant economic burden with ~7,000 non-transplant IPF admissions per year, at a mean cost of $16,000 per admission. Mechanical ventilation is associated with statistically significant increases in LOS and cost. Therapeutic advances that reduce rates and costs of IPF hospitalizations are needed. PMID- 28092236 TI - [The Journals role in continuing medical education]. AB - In the 19th century, the first journals in medicine appeared in order to disseminate knowledge among creators and discoverers, but especially among users of knowledge, some of these journals continue to be published nowadays. Subsequently, an organization that initially aspired to collect, sort, archive and distribute the publications: the Index Medicus. Over time, it was imperative to create indexes that measure the performance of journals and with that of researchers. PMID- 28092237 TI - [Diagnostic assessment of neumonitis due to cement dust exposition]. PMID- 28092238 TI - [Diphallia or perineal lipoma?] PMID- 28092239 TI - [Emergency Room: where are the specialists?] PMID- 28092240 TI - [Letter to the editor about the article "Bibliographic review: diabetic macular edema, repercussions and treatment"]. PMID- 28092241 TI - [Response to comment on article: "Reflections concerning the care process in the emergency medical services"]. PMID- 28092242 TI - [Prehospital emergency care injuries from external causes in a region of Venezuela]. AB - BACKGROUND: Worldwide, approximately 3 500 000 people die every year as a result of injuries from external causes, in Venezuela these arte the third leading cause of overall morbidity. Nevertheless, in the country there are no records of the defining aspects of prehospital emergency care as a tool to address this socio health problem, the aim of this investigation. METHODS: A descriptive, transversal, field study based on the information recorded daily for a year paramedics was performed. RESULTS: A total 1493 injured by external causes were reported, with a mean age of 29.5 +/- 12 years, 84.5% male. Injuries mostly less moderate (69.4%) were due to severe land transport accidents (70.9%) occurred during the day (75.9%), between monday and friday (72.9%), attended in 20 minutes or less, and transferred in 97.3% of cases. CONCLUSIONS: The economically productive young men in areas with higher population density and urbanism are mostly affected by injuries from external causes. In both genres land transport accidents are the most common causes of injury with lower-moderate severity. The care that paramedics provide can be considered adequate. PMID- 28092243 TI - [Botulinum toxin A and physical therapy in gait in cerebral palsy]. AB - BACKGROUND: Cerebral palsy (PCI) is the leading cause of disability in children. Botulinum toxin type A (TBA) is a treatment to improve the function and pattern in the gait, although with a few studies that quantify the improvement. METHODS: Quasi-experimental study was conducted from May 2010 to September 2011, in Integrated Rehabilitation Center, in 36 patients with spastic PCI. Was evaluated: functionality of travel by the scale of Koman, speed of the gait with tone scale of Ashworth and arches of passive mobility, were applied TBA and was sent to 10 sessions of physical therapy, with measurements taken before, the 1st and 4th month. RESULTS: 30 Patients completed the study, between the ages of 2 and 12 years, the majority had improvement in the functionality of the gear, tone, dorsiflexion and abduction of ankles to the motion, which was maintained at 4 months. CONCLUSIONS: Botulinum toxin is an effective treatment to increase the arches of mobility and functionality of the gait of patients with hemiparesis and spastic paraparesis. PMID- 28092244 TI - [Depression and burden on primary caregivers of elderly persons with physical dependence of the UMF 171]. AB - BACKGROUND: According to the National Health and Nutrition Survey of 2012, more than a quarter of older adults (26.9%) have some degree of disability, requiring a primary caregiver to perform basic activities of daily living. The aim is to determine the prevalence of depression and burden on primary caregivers of elderly persons with physical dependence. METHODS: A descriptive cross-sectional study with non-probability sampling that included the primary caregivers of elderly patients with physical dependence. Barthel scale was applied as a tool to measure the level of physical dependence in elderly patients; while the primary caregivers were applied to the Beck Depression and Zarit scale for assessing the level of caregiver burden. A sample of 76 primary caregivers was calculated and descriptive statistical analysis was performed. RESULTS: Of the 76 primary caregivers, 55.3% were without depression, 32.9% had mild depression, and 11.8% with moderate depression. According to the Zarit scale, 40.8% had no burden, 44.7% had burden light, and 14.5% intense burden. CONCLUSIONS: The role of primary caregiver is a stressful task which can interfere with their family health; so our role is to provide care not only to the geriatric dependent patients, but also to their caregiver. PMID- 28092245 TI - [Effect of the DiabetIMSS program on cardiovascular risk, blood pressure and HDL cholesterol in patients with metabolic syndrome]. AB - OBJECTIVE: The aim of this paper is to evaluate the effect of the DiabetIMSS program on cardiovascular risk, blood pressure and HDL cholesterol in patients with metabolic syndrome. METHODS: Quasi-experimental intervention study. Non probabilistic convenience sampling. 35 subjects in the educational strategy one year were included. The following variables were collected: age, gender, smoking, total cholesterol, HDL cholesterol, systolic and diastolic blood pressure; cardiovascular risk calculator based on Framingham is calculated. Descriptive and inferential statistical percentages with Student t test was used. RESULTS: There was an increase in the proportion of subjects increased their subsequent figures HDL cholesterol intervention, there by generating an increase of protective factor (p < 0.05). Because of the blood pressure a marked improvement in all ranges of blood pressure (p < 0.05) was presented. CONCLUSIONS: The educational strategy for the control of diabetic patients presented a favorable performance in HDL-cholesterol and blood pressure, reducing the risk of cardiovascular patients. PMID- 28092246 TI - [Neonatal Hearing Screening and Early Intervention, a screening program to evaluate all infants to identify the hearing impaired]. AB - BACKGROUND: Neonatal Hearing Screening and Early Intervention (NHSEI) is a screening program to evaluate all infants and identify those with hearing impairment. The objective of this work was to determine the factors associated with hearing loss in NHSEI program. METHODS: Analytical cross-sectional study was performed. 234 infants were included in the NHSEI program, hearing was evaluated with transitory evoked otoacoustic emissions (TEOE) at frequencies of 1.5 to 4.5 kHz, and intensity of stimuli of 40-60 dB. The variables were: age from one to 28 days, sex, gestational age and perinatal history. Data was analyzed with descriptive statistics and binary logistic regression. RESULTS: The presence of risk factors in newborns resulted in significant omnibus test (p < 0.05) predicted value by Nagelkerke R square model of 77%. The background inherited family acquired infection, craniofacial abnormalities, low birth weight, respiratory distress at birth and genetic syndromes were factors significantly associated (p < 0.05) to hearing loss in infants. CONCLUSIONS: The incidence of hearing impairment in infants diagnosed by newborn hearing program was higher (5/234 newborns) than the reported in the literature. PMID- 28092247 TI - [Emergency obstetric causes and Immediate Response Team in a secondary hospital]. AB - BACKGROUND: The aim of this work is to describe the causes of the obstetric emergency, which motivates the activation of the Immediate Response Team at a second level hospital of the Instituto Mexicano del Seguro Social, which has not an Intensive Care Unit for Adult Patients. METHODS: Retrospective observational study of the causes of obstetric emergency that occurred in the domains of Admission, Hospitalization, Labor, Delivery Room, Operating Room and Recovery of the Hospital General de Zona 53 of the IMSS, during the years 2014 and 2015. RESULTS: In 2014, were attended 3915 women due to obstetric cause; of them, 75 cases were of obstetric emergency and 3276 live births. In 2015, were 4390 women with 3842 live births and 80 cases of obstetric emergency. The main domains where performed the Immediate Response Team were: Labor, Admission and Recovery. In 2014, preeclampsia-eclampsia-Hellp ranked first as a cause of obstetric emergency: 42 cases, also in 2015: 36 cases; followed by obstetric hemorrhage with 28 and 34 cases, respectively. In 2014, there was a maternal death from severe preeclampsia and extensive liver rupture. CONCLUSIONS: Consolidation of Immediate Response Team at a hospital, according to the healthcare environment, it is essential, above all, within the meaning given by staff members. PMID- 28092248 TI - [Pulmonary thromboembolism: Recent experience of 4 years at a cardiology hospital]. AB - It comprised a series of cases over a period of 4 years, held at the Hospital of Cardiology of the Centro Medico Nacional Siglo XXI, IMSS. From 2008 to 2011, admitted to Emergency 184 patients with suspected pulmonary embolism, of which 41 were removed; of the 143 remaining cases, only 127 patients was diagnosed with PE. The other 16 patients had other diagnoses. In 86% of patients showed electrocardiographic pattern S1Q3T3 and 39% had RBBB, in 17 (13.3%) patients there was hemodynamic instability, and in 94.4% showed enlargement of the right chambers by echocardiography, 55.9% showed paradoxical septal motion, PASP was 66.2+22.8 mm Hg and in 43.3% the Mc Connell sign was positive. A total of 48 patients (37.7%) received thrombolysis, the remaining patients received conventional medical treatment with anticoagulation. Overall mortality was 14%. PMID- 28092249 TI - [Zika virus and their means of delivery, rather than Aedes]. AB - In the present work an exposition of the most frequent vectors of the arboviruses is made highlighting the ones of the genus Aedes, of these in each geographic distribution there are specific subgeneros, in Africa emphasizes A. africanus, A. opok and A. vitatus like those in charge of The propagation of arboviruses. In Asia and Oceania, A. hensilii and A. polynesiensis stand out, and A. albopictus, in addition to A. koreicus and A. japonicus, the latter also responsible for dissemination in North America. It is mentioned in the wave that struck to South America the greater importance of other genera like Culex, emphasizing C. pipiens, C. perfuscus, C. quinquefasciatus and C. nigripalpus; Also genera like Anopheles emphasizing A. coustani, A. albimanus and A. pseudopunctipennis (Central America and Mexico). Therefore the importance of other vectors other than Aedes as the participants in the American wave is pointed out. PMID- 28092250 TI - [Osteoarthrosis: implementation of current diagnostic and therapeutic algorithms]. AB - In the modern world, among the different clinical presentations of osteoarthritis, gonarthrosis and coxarthrosis exhibit the highest prevalence. In this paper, the characteristics of osteoarthritis and the different scales of assessment and classification of this pathology are exposed, to provide an exhibition of current evidence generated around diagnostic algorithms and treatment of osteoarthritis, with emphasis set out in the knee and hip, as these are the most frequent; a rational procedure for monitoring patients with osteoarthritis based on characteristic symptoms and the severity of the condition is also set. Finally, reference is made to the therapeutic benefits of the recent introduction of viscosupplementation with Hylan GF-20. PMID- 28092251 TI - [Acute appendicitis. Surgical and non-surgical treatment]. AB - Appendicitis represents a common disease for the surgeon with a relative risk between 7-8%. It was thought that if more time passed between diagnosis and treatment, the risk for complications, such as perforation or abscess formation, was higher; nevertheless; the evolution is variable, making necessary the development of different strategies such as antibiotic use only, interval surgery or endoscopic treatment. The purpose of this study is to make a revision in the management of appendicitis comparing conservative and surgical treatment. It is known that traditional management of appendicitis is appendectomy with a complication rate of 2.5% to 48%. Nowadays, laparoscopy is the approach of choice by many surgeons and there have proposed new invasive techniques such as endoscopic treatment with the use of prosthesis and ambulatory surgery. Antibiotic use is essential in the management of appendicitis. Its use as the only strategy to treat this disease has the purpose of lowering costs and diminishing complications related to surgery or the resection of the organ. We conclude that the ideal management of appendicitis remains controversial and it will depend of the clinical characteristics of each patient and the resources available. PMID- 28092252 TI - [Accessibility to health services: theoretical debate on determinants and implications in the public health policy]. AB - This paper presents the theorical development of accesibility as process and product. The process consists of the elements that converge to meet the objectives of providing medical care in a timely manner. As product is a component of effective care. Accesibility itself is subject to a combination of economic, cultural, social, geographic and contextual aspects. Beyond the right of persons to receive health care, availability of institutions and the means to achieve. PMID- 28092253 TI - [Mexican treatment goals for plaque psoriasis]. AB - Psoriasis is a chronic inflammatory disease with a worldwide prevalence between 6 and 39% in moderate to severe forms. In European countries like Germany and England was identified that only one third of patients with moderate to severe forms will receive systemic management, this fact motivated to integrate into Europe an international consensus on treatment goals with the aim of providing support to the dermatologist by algorithms that serve as a therapeutic guide that allows you to gain control short and long term effects of this disease. The European group met to develop the definitions of severity of psoriasis, treatment goals for moderate to severe disease, and optimization options and / or therapeutic transition than a paper published in 2011 was obtained. In Mexico a working group of experts on biological therapy (GTEB), made up of 10 members and an extended group of 150 dermatologists' voters in the country for the purpose of issuing Mexico's position on the proposals of the European group was formed. In this document the findings of the Working Group of Experts on Biological Therapy in Mexico are listed. PMID- 28092254 TI - [What do adults die in Mexico? Impact on the economic and social development of the nation. The global burden of cardiovascular disease]. AB - Noncommunicable diseases have been established as a clear threat, not only to human health but also to the development and economic growth. Claiming 63% of all deaths, these diseases are currently the main murderer worldwide. The increase in the prevalence and importance of noncommunicable diseases specifically of cardiovascular risk factors such as hypertension, diabetes, dyslipidemia and obesity is the result of a complex interplay between health, economic growth and development, which is strongly associated with universal trends such as the aging of the world population, rapid unplanned urbanization, and the globalization of unhealthy lifestyles.Cardiovascular disease refers to a group of diseases involving the heart, blood vessels, or the consequences of poor blood supply due to a vascular source ill. About 82% of the burden of mortality is caused by ischemic heart disease or coronary heart disease (IHD), Stroke (both hemorrhagic and ischemic), hypertensive heart disease or congestive heart failure (CHF). The Hospital de Cardiologia of the Centro Medico Nacional Siglo XXI, serves the call to improve through innovation and technological development this area of health the "tele cardiology" (regulatory center of myocardial code), with clear objectives in the short, medium and long term. PMID- 28092255 TI - [The importance of promoting the bioethical seeds in the University]. AB - One of the main scopes for institutions dedicated to preparing professionals in health is to increase their bioethics profile. To achieve this scope, these institutions have included lessons in bioethics into their study plans. Another way to increase the profile of the students, as the authors of this article propose, is creating bioethics seeds through a bioethics interest diagnostic on the students' preferences in their first year of the Justo Sierra University using a particular clinical case. The results found indicated that students show more interest in learning the physiopathology, diagnostics, and therapy of the pathologies than bioethics. The authors concluded that in order to increase this profile, the students are encouraged to discuss and reflect on bioethical situations that help them to construct their own opinion and decisions. PMID- 28092256 TI - [Resection of intracardiac myxoma. Case report]. AB - Myxomas are the most common benign cardiac tumors, which are considered emergency surgery. The resection should not be delayed because 8-9% of affected patients may die due to intracardiac blood flow obstruction. We presente a clinical case of a 47 year old female, history of dyslipidemia. Disease starts with retrosternal oppression feeling, dyspnea on moderate exercise, dizziness, pain in joints hands. Arrhytmic heart sounds, diastolic mitral murmur II/IV, breth sounds present, no lymph. Laboratory: hemoglobin 11.0, leucocyte 9000, glucose 96 mg/dL, chest RX medium arch prominence cardiac silhouette. ECO transthoracic LVEF 60 %, with left atrial intracardiac tumor 13x11 cm, pedicle fixed the interatrial septum, the mitral valve bulges, with mild mitral valve. Half sternotomy is performed intracardiac tumor resection, pericardial placement interatrial with extracorporeal circulation support 65', aortic clamping time of 40'. Intracardiac tumor surgical findings interatrial septum fixed to left side, pedicle, rounded, yellow, multiloculated, soft, 13x10 cm in diameter. Histopathological diagnosis cardiac myxoma. We conclude that the tumor resection was carried in a timely manner with satisfactory evolution. PMID- 28092257 TI - [Chilaiditi's sign and syndrome. Case report]. AB - The interposition of a portion of the colon between the liver and the diaphragm is called Chilaiditi sign and discovered incidentally during radiological study for other reasons and usually asymptomatic presentation. When the discovery is accompanied by clinical symptoms such as abdominal pain, nausea, vomiting, bloating, constipation called Chilaiditi Syndrome. The Chilaiditi sign is a very rare condition, and the Chilaiditi syndrome is even more, especially if associated with other acute diseases. We report the case of a man of 41 years was admitted with right upper quadrant abdominal pain, nausea, vomiting, difficulty was diagnosed with radiographic and tomographic images making the differential diagnosis with lung abscess and diaphragmatic hernia. The final diagnosis was Chilaiditi Syndrome associated with acute pancreatitis and penumonia. PMID- 28092258 TI - [Frontal fibrosing alopecia: case series and literature review]. AB - Frontal fibrosing alopecia is a disease characterized by a symmetric and progressive loss of hair in the fronto-temporal and fronto-parietal lines that generally affects postmenopausal women. It is considered a variant of lichen planus pilaris for its clinical and histopathological features; although, its etiopathology is still unknown. In this report, we analyzed 4 cases of this disease and we discussed its clinical and histopathological characteristics, as well as their course after initiating treatment. PMID- 28092259 TI - [First case of chikungunya fever in Hermosillo, Sonora, Mexico]. AB - The Chikungunya is an arbovirus first described during a 1952 outbreak of febrile exantematic disease in southern Tanganyika (now Tanzania). It is a virus within the alphavirus genus of the Togaviridae family, it is usually transmitted to humans by Aedes mosquitoes. Typically, the disease manifests as acute onset of fever and joint pains. This study describes the clinical characteristics the first imported case infected with chikungunya fever (CHIK) in Hermosillo, Sonora, Mexico. We report the case of a 30 years old man seen in our emergency department due to fever, polyarthralgia, rash and headache. This patient has been in Tapachula, Chiapas, a jungle area in southern Mexico, and he returned from a 45 days trip before the onset his symptoms. The chikungunya viral infection (CHIK) was diagnosed by RT-PCR procedure. Paracetamol therapy was administered and his clinical course was self-limited. We concluded that with the increase of mosquito's habitat by global warming and frequent traveling, CHIK reemerged and showed global distribution recently. This disease must be suspected in patients with compatible clinical symptoms returning from epidemic/endemic areas. CHIK must be diagnosed on the basis of clinical, epidemiological and laboratory criteria. PMID- 28092260 TI - [Down syndrome and heart block secondary to neonatal lupus]. AB - In Down syndrome, so far, has not been reported it's association with congenital heart block, this entity is rare and occurred in only 1% of mothers who have systemic lupus erythematosus, the presence of anti-Ro antibodies cross the placenta presenting neonatal lupus with skin lesions and congenital heart block, bradycardia, which is why we describe the following case. This is a new male end product of asymptomatic young mother, but serological birth with stigmata of Down syndrome, birth presents congenital bradycardia rare manifestation abnormalities, but common in children of mothers with lupus are initiated study protocol, realizing you including laboratory tests and immunological studies cabinet as electrocardiogram and echocardiogram, which gave tone to take the mother immunological studies, being positive antiRo. We concluded that the risk of heart block in a patient with Down syndrome is the same as for the general population. PMID- 28092261 TI - Structural insights into the mechanism of the DEAH-box RNA helicase Prp43. AB - The DEAH-box helicase Prp43 is a key player in pre-mRNA splicing as well as the maturation of rRNAs. The exact modus operandi of Prp43 and of all other spliceosomal DEAH-box RNA helicases is still elusive. Here, we report crystal structures of Prp43 complexes in different functional states and the analysis of structure-based mutants providing insights into the unwinding and loading mechanism of RNAs. The Prp43*ATP-analog*RNA complex shows the localization of the RNA inside a tunnel formed by the two RecA-like and C-terminal domains. In the ATP-bound state this tunnel can be transformed into a groove prone for RNA binding by large rearrangements of the C-terminal domains. Several conformational changes between the ATP- and ADP-bound states explain the coupling of ATP hydrolysis to RNA translocation, mainly mediated by a beta-turn of the RecA1 domain containing the newly identified RF motif. This mechanism is clearly different to those of other RNA helicases. PMID- 28092262 TI - Vocal development in a Waddington landscape. AB - Vocal development is the adaptive coordination of the vocal apparatus, muscles, the nervous system, and social interaction. Here, we use a quantitative framework based on optimal control theory and Waddington's landscape metaphor to provide an integrated view of this process. With a biomechanical model of the marmoset monkey vocal apparatus and behavioral developmental data, we show that only the combination of the developing vocal tract, vocal apparatus muscles and nervous system can fully account for the patterns of vocal development. Together, these elements influence the shape of the monkeys' vocal developmental landscape, tilting, rotating or shifting it in different ways. We can thus use this framework to make quantitative predictions regarding how interfering factors or experimental perturbations can change the landscape within a species, or to explain comparative differences in vocal development across species. PMID- 28092263 TI - Transcription leads to pervasive replisome instability in bacteria. AB - The canonical model of DNA replication describes a highly-processive and largely continuous process by which the genome is duplicated. This continuous model is based upon in vitro reconstitution and in vivo ensemble experiments. Here, we characterize the replisome-complex stoichiometry and dynamics with single molecule resolution in bacterial cells. Strikingly, the stoichiometries of the replicative helicase, DNA polymerase, and clamp loader complexes are consistent with the presence of only one active replisome in a significant fraction of cells (>40%). Furthermore, many of the observed complexes have short lifetimes (<8 min), suggesting that replisome disassembly is quite prevalent, possibly occurring several times per cell cycle. The instability of the replisome complex is conflict-induced: transcription inhibition stabilizes these complexes, restoring the second replisome in many of the cells. Our results suggest that, in contrast to the canonical model, DNA replication is a largely discontinuous process in vivo due to pervasive replication-transcription conflicts. PMID- 28092264 TI - Centriolar SAS-7 acts upstream of SPD-2 to regulate centriole assembly and pericentriolar material formation. AB - The centriole/basal body is a eukaryotic organelle that plays essential roles in cell division and signaling. Among five known core centriole proteins, SPD 2/Cep192 is the first recruited to the site of daughter centriole formation and regulates the centriolar localization of the other components in C. elegans and in humans. However, the molecular basis for SPD-2 centriolar localization remains unknown. Here, we describe a new centriole component, the coiled-coil protein SAS 7, as a regulator of centriole duplication, assembly and elongation. Intriguingly, our genetic data suggest that SAS-7 is required for daughter centrioles to become competent for duplication, and for mother centrioles to maintain this competence. We also show that SAS-7 binds SPD-2 and regulates SPD-2 centriolar recruitment, while SAS-7 centriolar localization is SPD-2-independent. Furthermore, pericentriolar material (PCM) formation is abnormal in sas-7 mutants, and the PCM-dependent induction of cell polarity that defines the anterior-posterior body axis frequently fails. We conclude that SAS-7 functions at the earliest step in centriole duplication yet identified and plays important roles in the orchestration of centriole and PCM assembly. PMID- 28092265 TI - The fibronectin synergy site re-enforces cell adhesion and mediates a crosstalk between integrin classes. AB - Fibronectin (FN), a major extracellular matrix component, enables integrin mediated cell adhesion via binding of alpha5beta1, alphaIIbbeta3 and alphav-class integrins to an RGD-motif. An additional linkage for alpha5 and alphaIIb is the synergy site located in close proximity to the RGD motif. We report that mice with a dysfunctional FN-synergy motif (Fn1syn/syn) suffer from surprisingly mild platelet adhesion and bleeding defects due to delayed thrombus formation after vessel injury. Additional loss of beta3 integrins dramatically aggravates the bleedings and severely compromises smooth muscle cell coverage of the vasculature leading to embryonic lethality. Cell-based studies revealed that the synergy site is dispensable for the initial contact of alpha5beta1 with the RGD, but essential to re-enforce the binding of alpha5beta1/alphaIIbbeta3 to FN. Our findings demonstrate a critical role for the FN synergy site when external forces exceed a certain threshold or when alphavbeta3 integrin levels decrease below a critical level. PMID- 28092266 TI - TGF-beta reduces DNA ds-break repair mechanisms to heighten genetic diversity and adaptability of CD44+/CD24- cancer cells. AB - Many lines of evidence have indicated that both genetic and non-genetic determinants can contribute to intra-tumor heterogeneity and influence cancer outcomes. Among the best described sub-population of cancer cells generated by non-genetic mechanisms are cells characterized by a CD44+/CD24- cell surface marker profile. Here, we report that human CD44+/CD24- cancer cells are genetically highly unstable because of intrinsic defects in their DNA-repair capabilities. In fact, in CD44+/CD24- cells, constitutive activation of the TGF beta axis was both necessary and sufficient to reduce the expression of genes that are crucial in coordinating DNA damage repair mechanisms. Consequently, we observed that cancer cells that reside in a CD44+/CD24- state are characterized by increased accumulation of DNA copy number alterations, greater genetic diversity and improved adaptability to drug treatment. Together, these data suggest that the transition into a CD44+/CD24- cell state can promote intra-tumor genetic heterogeneity, spur tumor evolution and increase tumor fitness. PMID- 28092268 TI - Phenotypic outcomes in Mouse and Human Foxc1 dependent Dandy-Walker cerebellar malformation suggest shared mechanisms. AB - FOXC1 loss contributes to Dandy-Walker malformation (DWM), a common human cerebellar malformation. Previously, we found that complete Foxc1 loss leads to aberrations in proliferation, neuronal differentiation and migration in the embryonic mouse cerebellum (Haldipur et al., 2014). We now demonstrate that hypomorphic Foxc1 mutant mice have granule and Purkinje cell abnormalities causing subsequent disruptions in postnatal cerebellar foliation and lamination. Particularly striking is the presence of a partially formed posterior lobule which echoes the posterior vermis DW 'tail sign' observed in human imaging studies. Lineage tracing experiments in Foxc1 mutant mouse cerebella indicate that aberrant migration of granule cell progenitors destined to form the posterior-most lobule causes this unique phenotype. Analyses of rare human del chr 6p25 fetal cerebella demonstrate extensive phenotypic overlap with our Foxc1 mutant mouse models, validating our DWM models and demonstrating that many key mechanisms controlling cerebellar development are likely conserved between mouse and human. PMID- 28092267 TI - Cryo-EM structure of the ATP-sensitive potassium channel illuminates mechanisms of assembly and gating. AB - KATP channels are metabolic sensors that couple cell energetics to membrane excitability. In pancreatic beta-cells, channels formed by SUR1 and Kir6.2 regulate insulin secretion and are the targets of antidiabetic sulfonylureas. Here, we used cryo-EM to elucidate structural basis of channel assembly and gating. The structure, determined in the presence of ATP and the sulfonylurea glibenclamide, at ~6 A resolution reveals a closed Kir6.2 tetrameric core with four peripheral SUR1s each anchored to a Kir6.2 by its N-terminal transmembrane domain (TMD0). Intricate interactions between TMD0, the loop following TMD0, and Kir6.2 near the proposed PIP2 binding site, and where ATP density is observed, suggest SUR1 may contribute to ATP and PIP2 binding to enhance Kir6.2 sensitivity to both. The SUR1-ABC core is found in an unusual inward-facing conformation whereby the two nucleotide binding domains are misaligned along a two-fold symmetry axis, revealing a possible mechanism by which glibenclamide inhibits channel activity. PMID- 28092270 TI - Multimodal individualized concept of hemodynamic monitoring. AB - PURPOSE OF REVIEW: To discuss the pathophysiological rationale of advanced hemodynamic monitoring in the critically ill and also to highlight the importance of a multimodal, individualized approach. RECENT FINDINGS: There are several clinical studies and animal experiments evaluating, which hemodynamic endpoint should be the best target during fluid management. Recent systematic reviews and meta-analyses also investigated the effects of advanced hemodynamic endpoints targeted hemodynamic management on outcome mainly in high-risk surgical patients. Although most of these studies report positive results, this knowledge does not seem to affect our everyday practice. According to large international surveys, most physicians still rely on inappropriate indices. One of the reasons could be that target values applied in these studies can be misleading in the individual patient. Therefore, we describe the concept of an individualized approach, in which normalizing the components of oxygen delivery are put in the context of the patients' individual response by evaluating components of oxygen consumption, and organ perfusion. SUMMARY: Advanced hemodynamic monitoring-based management provides a number of benefits, which could be better tailored for the patients' actual needs by putting this into a multimodal, individualized approach. PMID- 28092269 TI - Analysis of microtubule growth dynamics arising from altered actin network structure and contractility in breast tumor cells. AB - The periphery of epithelial cells is shaped by opposing cytoskeletal physical forces generated predominately by two dynamic force generating systems-growing microtubule ends push against the boundary from the cell center, and the actin cortex contracts the attached plasma membrane. Here we investigate how changes to the structure and dynamics of the actin cortex alter the dynamics of microtubules. Current drugs target actin polymerization and contraction to reduce cell division and invasiveness; however, the impacts on microtubule dynamics remain incompletely understood. Using human MCF-7 breast tumor cells expressing GFP-tagged microtubule end-binding-protein-1 (EB1) and coexpression of cytoplasmic fluorescent protein mCherry, we map the trajectories of growing microtubule ends and cytoplasmic boundary respectively. Based on EB1 tracks and cytoplasmic boundary outlines, we calculate the speed, distance from cytoplasmic boundary, and straightness of microtubule growth. Actin depolymerization with Latrunculin-A reduces EB1 growth speed as well as allows the trajectories to extend beyond the cytoplasmic boundary. Blebbistatin, a direct myosin-II inhibitor, reduced EB1 speed and yielded less straight EB1 trajectories. Inhibiting signaling upstream of myosin-II contractility via the Rho-kinase inhibitor, Y-27632, altered EB1 dynamics differently from Blebbistatin. These results indicate that reduced actin cortex integrity can induce distinct alterations in microtubule dynamics. Given recent findings that tumor stem cell characteristics are increased by drugs which reduce actin contractility or stabilize microtubules, it remains important to clearly define how cytoskeletal drugs alter the interactions between these two filament systems in tumor cells. PMID- 28092271 TI - Trauma and transfusion. PMID- 28092272 TI - Material-Dependent Implant Artifact Reduction Using SEMAC-VAT and MAVRIC: A Prospective MRI Phantom Study. AB - OBJECTIVE: The aim of this study was to compare the degree of artifact reduction in magnetic resonance imaging achieved with slice encoding for metal artifact correction (SEMAC) in combination with view angle tilting (VAT) and multiacquisition variable resonance image combination (MAVRIC) for standard contrast weightings and different metallic materials. METHODS: Four identically shaped rods made of the most commonly used prosthetic materials (stainless steel, SS; titanium, Ti; cobalt-chromium-molybdenum, CoCr; and oxidized zirconium, oxZi) were scanned at 3 T. In addition to conventional fast spin-echo sequences, metal artifact reduction sequences (SEMAC-VAT and MAVRIC) with varying degrees of artifact suppression were applied at different contrast weightings (T1w, T2w, PDw). Two independent readers measured in-plane and through-plane artifacts in a standardized manner. In addition, theoretical frequency-offset and frequency offset-gradient maps were calculated. Interobserver agreement was assessed using intraclass correlation coefficient. RESULTS: Interobserver agreement was almost perfect (intraclass correlation coefficient, 0.86-0.99). Stainless steel caused the greatest artifacts, followed by CoCr, Ti, and oxZi regardless of the imaging sequence. While for Ti and oxZi rods scanning with weak SEMAC-VAT showed some advantage, for SS and CoCr, higher modes of SEMAC-VAT or MAVRIC were necessary to achieve artifact reduction. MAVRIC achieved better artifact reduction than SEMAC VAT at the cost of longer acquisition times. Simulations matched well with the apparent geometry of the frequency-offset maps. CONCLUSIONS: For Ti and oxZi implants, weak SEMAC-VAT may be preferred as it is faster and produces less artifact than conventional fast spin-echo. Medium or strong SEMAC-VAT or MAVRIC modes are necessary for significant artifact reduction for SS and CoCr implants. KEY POINTS: PMID- 28092273 TI - In Vivo Testing of Extracorporeal Membrane Ventilators: iLA-Activve Versus Prototype I-Lung. AB - A side-by-side comparison of the decarboxylation efficacy of two pump-driven venovenous extracorporeal lung assist devices, i.e., a first prototype of the new miniaturized ambulatory extracorporeal membrane ventilator, I-lung versus the commercial system iLA-activve for more than a period of 72 hours in a large animal model. Fifteen German Landrace pigs were anesthetized and underwent mechanical hypoventilation to induce severe hypercapnia. Decarboxylation was accomplished by either the I-lung or the iLA-activve via a double lumen catheter in the jugular vein. Sham-operated pigs were not connected to extracorporeal devices. Cardiovascular, respiratory, and metabolic parameters were continuously monitored, combined with periodic arterial blood sampling for subsequent clinical blood diagnostics, such as gas exchange, hemolysis, coagulation parameters, and cytokine profiles. At the termination of the studies, lung tissue was harvested and examined histologically for pulmonary morphology and leukocyte tissue infiltration. Both extracorporeal devices showed high and comparable efficacy with respect to carbon dioxide elimination for more than 72 hours and were not associated with either bleeding events or clotting disorders. Pigs of both groups showed cardiovascular and hemodynamic stability without marked differences to sham-operated animals. Groups also did not differ in terms of inflammatory and metabolic parameters. We established a preclinical in vivo porcine model for comparative long-term testing of I-lung and iLA-activve. The I-lung prototype proved to be safe and feasible, providing adequate decarboxylation without any adverse events. Once translated into the clinical treatment, the new miniaturized and transportable I-lung device might represent a promising tool for treating awake and mobilized patients with decompensated pulmonary disorders. PMID- 28092274 TI - Power Profiles and In Vitro Optical Quality of Scleral Contact Lenses: Effect of the Aperture and Power. AB - OBJECTIVE: To assess the power profile and in vitro optical quality of scleral contact lenses with different powers as a function of the optical aperture. METHODS: The mini and semiscleral contact lenses (Procornea) were measured for five powers per design. The NIMO TR-1504 (Lambda-X) was used to assess the power profile and Zernike coefficients of each contact lens. Ten measurements per lens were taken at 3- and 6-mm apertures. Furthermore, the optical quality of each lens was described in Zernike coefficients, modulation transfer function, and point spread function (PSF). A convolution of each lens PSF with an eye-chart image was also computed. RESULTS: The optical power fluctuated less than 0.5 diopters (D) along the optical zone of each lens. However, the optical power obtained for some lenses did not match with its corresponding nominal one, the maximum difference being 0.5 D. In optical quality, small differences were obtained among all lenses within the same design. Although significant differences were obtained among lenses (P<0.05), these showed small impact in the image quality of each convolution. CONCLUSIONS: Insignificant power fluctuations were obtained along the optical zone measured for each scleral lens. Additionally, the optical quality of both lenses has showed to be independent of the lens power within the same aperture. PMID- 28092275 TI - Mechanistic insights from combining genomics with metabolomics. AB - PURPOSE OF REVIEW: Metabolomics directly measure substrates and products of biological processes and pathways. Based on instrumentation and throughput advances, the use of metabolomics has only recently become feasible at the population level. This has led to an intense interest in using the new information in combination with genomics, and other omics technologies, to give biological context to the rapidly accumulating associations between genes and diseases or their risk factors. RECENT FINDINGS: The use of metabolomics-genomic associations for the metabolic characterization of genes of interest has confirmed known pathways and permitted the identification of new ones. These include the unknown metabolite X12063 linking statins to myopathies, the role of glycerophospholipids in cholesterol metabolism, the structure of lipoprotein (a), the lipoprotein lipase-independent effect of Apolipoprotein C-III coding and the role of branched chain amino acids in the antagonistic coregulation of levels of HDLs and triglyceride. SUMMARY: The findings reviewed illustrate the importance of integrating metabolomics and genomics for the greater understanding of biological mechanisms. The limitations of the current approaches are also discussed together with approaches that will be required to make the most of the current multiomics data available. PMID- 28092276 TI - Asialoglycoprotein receptors as important mediators of plasma lipids and atherosclerosis. AB - PURPOSE OF REVIEW: This review seeks to describe the role of the asialoglycoprotein receptor (ASGR) in modulating non-HDL lipoprotein levels, platelet numbers and atherosclerosis. RECENT FINDINGS: Genetics studies have revealed that ASGR haplodeficiency provides protection from atherosclerosis. The potential interactions of ASGR with LDL receptor may regulate the rate of LDL uptake and as a result may lower plasma non-HDL cholesterol. ASGR clears senescent platelets and induces the expression of hepatic thrombopoietin. Platelet activity promotes plaque formation and atherosclerosis. SUMMARY: ASGR is a multifunctional receptor specializing in clearance of desialylated glycoproteins and platelets. The impact of ASGR on the levels of plasma non-HDL cholesterol makes it a potential therapeutic target for the treatment of hypercholesterolemia and atherosclerosis. PMID- 28092277 TI - Hierarchical Linear Modeling for Analysis of Ecological Momentary Assessment Data in Physical Medicine and Rehabilitation Research. AB - Ecological momentary assessment (EMA) methods collect real-time data in real world environments, which allow physical medicine and rehabilitation researchers to examine objective outcome data and reduces bias from retrospective recall. The statistical analysis of EMA data is directly related to the research question and the temporal design of the study. Hierarchical linear modeling, which accounts for multiple observations from the same participant, is a particularly useful approach to analyzing EMA data. The objective of this paper was to introduce the process of conducting hierarchical linear modeling analyses with EMA data. This is accomplished using exemplars from recent physical medicine and rehabilitation literature. PMID- 28092278 TI - Delayed-Onset Central Pain due to Degeneration of Ischemic Transcallosal Fibers After Corpus Callosum Hemorrhage. AB - AIMS: A patient developed delayed-onset central pain due to degeneration of the spinothalamic tract resulting from degeneration of the ischemic transcallosal fibers, in the aftermath of a corpus callosum (CC) hemorrhage. The detection and diagnosis of these lesions using diffusion tensor tractography are described. METHODS: A 59-yr-old man underwent conservative management for hemorrhages in the CC and lateral ventricle that resulted from hitting his head against a wall while falling. He began to feel pain in his right upper and lower extremities approximately 11/2 yrs after the initial injury. The pain was characterized as constant tingling, numb, and cool sensation without allodynia or hyperalgesia (visual analogue scale score, 5). RESULTS: Disruption of transcallosal fibers in the genu and isthmus of the CC was observed on diffusion tensor tractography 1 mo after the initial injury. By 3 yrs, the diffusion tensor tractography showed that transcallosal fibers in the isthmus (67.8%-77.9%) of the CC had disappeared, and the left spinothalamic tract had become thinner. CONCLUSION: The results suggest that central pain can occur without direct injury of the spinothalamic tract and point up the need for evaluation of the spinothalamic tract and transcallosal fibers in patients with a CC lesion who complain of central pain. PMID- 28092279 TI - Association between long-term blood pressure control and ten-year progression in carotid arterial stiffness among hypertensive individuals: the multiethnic study of atherosclerosis. AB - BACKGROUND: Arterial stiffness was shown to be higher among hypertensive patients with diabetes than those without diabetes and among older than younger hypertensive patients. We examined whether the association between long-term blood pressure (BP) control and 10-year progression in carotid arterial stiffness varies by diabetes status and age. METHODS: Participants were 906 individuals with hypertension at baseline and three follow-up visits in the Multi-Ethnic Study of Atherosclerosis (mean age 63.7 years, 44% males). Participants with SBP of less than 140 mmHg and DBP of less than 90 mmHg were considered to have a controlled BP. Arterial stiffness was measured using distensibility coefficient * 10/mmHg and Young's elastic modulus (YEM * 10 mmHg) at baseline and after a mean of 9.5 years (visit 5). Multiple linear regression model was used for the analysis. RESULTS: Having controlled BP at three visits (distensibility coefficient: beta = 3.6, P = 0.004; YEM: beta = -6.8, P = 0.07) or four visits (distensibility coefficient: beta = 2.4, P = 0.04; YEM: beta = -6.8, P = 0.05), when compared with having uncontrolled BP at all four visit, was associated with lesser progression in arterial stiffness. In a stratified analysis, arterial stiffness progression was slower only among nondiabetics with controlled BP at three visits (distensibility coefficient: beta = 4.3, P = 0.002; YEM: beta = 8.8, P = 0.04) or four visits (beta = 3.7, P = 0.01; YEM: beta = -10.4, P = 0.01) and among those less than 70 years with controlled BP at three visits (distensibility coefficient: beta = 4.9, P = 0.004; YEM: beta = -10.6, P = 0.01) or four visits (distensibility coefficient: beta = 2.9, P = 0.07; YEM: beta = 7.6, P = 0.03). CONCLUSION: These findings suggest that controlling BP alone may not be sufficient to slow progression of arterial stiffness among hypertensive patients with concurrent diabetes and elderly hypertensive patients. PMID- 28092280 TI - Challenges and opportunities to enhance global drug development in neonates. AB - PURPOSE OF REVIEW: This study reviews the history of neonatal drug development, recent legislative efforts designed to facilitate the study of therapeutic agents in neonates, and future steps necessary to advance drug development. RECENT FINDINGS: Although many federal regulations have been introduced over the past 15 years to encourage pediatric and neonatal drug development, the majority of medications that are used in the Neonatal Intensive Care Unit are not approved by the Food and Drug Administration (FDA) for use in neonates. There are many challenges that investigators encounter in conducting neonatal clinical trials. The Critical Path Institute working in conjunction with the FDA has developed several consortia, including the International Neonatal Consortium and Pediatric Trials Consortium, to address these concerns and facilitate interactions of researchers, regulators, funding agencies, industry, and others across the globe to produce regulatory ready and high quality data for neonatal therapeutics. SUMMARY: Neonatal drug development is an area which deserves significant attention if we hope to continue to improve outcomes. With the help of international collaborations, it is possible to accelerate efficient and high quality neonatal research through multidisciplinary teams that share data, knowledge, and expertise to advance medical innovation and regulatory science. PMID- 28092281 TI - Renal tubular acidosis. AB - PURPOSE OF REVIEW: To facilitate the understanding and knowledge of renal tubular acidosis by providing a summarized information on the known clinical and biochemical characteristics of this group of diseases, by updating the genetic and molecular bases of the primary forms renal tubular acidosis and by examining some issues regarding the diagnosis of distal renal tubular acidosis (RTA) in the daily clinical practice. RECENT FINDINGS: The manuscript presents recent findings on the potential of next-generation sequencing to disclose new pathogenic variants in patients with a clinical diagnosis of primary RTA and negative Sanger sequencing of known genes. The current review emphasizes the importance of measuring urinary ammonium for a correct clinical approach to the patients with metabolic acidosis and discusses the diagnosis of incomplete distal RTA. SUMMARY: We briefly update the current information on RTA, put forward the need of additional studies in children to validate urinary indexes used in the diagnosis of RTA and offer a perspective on diagnostic genetic tests. PMID- 28092283 TI - Inherited disorders of tubular transport. PMID- 28092282 TI - Neonatal palliative care. AB - PURPOSE OF REVIEW: A significant number of newborns are affected by life-limiting or life-threatening conditions. When prolongation of survival is no longer a goal, or prognosis is uncertain, a plan of care focused on the infant's comfort is essential. The aim of this article is to review the most recent and relevant literature regarding neonatal palliative care (NPC). RECENT FINDINGS: A variety of perinatal and NPC programs are described, but most programs focus exclusively on end-of-life care. Moreover, there is a great need to standardize practices and obtain follow-up quality measures.Guidelines to address infants' basic needs, to achieve a state of comfort, are proposed. A multidisciplinary team addressing the infants' medical and nonmedical needs, parental grieving process, and providers' distress is recommended. SUMMARY: NPC is a unique multidisciplinary approach for the care of newborns affected by life-limiting or complex medical conditions with uncertain prognosis. Standardized guidelines should be implemented with the goal of achieving a state of comfort for newborns throughout the course of illness. Further studies are warranted to assess whether NPC effectively promotes newborns' comfort and parents and providers' satisfaction. PMID- 28092284 TI - Persistent Fever in Medical Intensive Care Unit: Evans Syndrome Versus Actinomycotic Osteomyelitis? PMID- 28092285 TI - Perioperative beta-Blockers in Patients Undergoing Noncardiac Surgery-Scientific Misconduct and Clinical Guidelines. AB - BACKGROUND: beta-blocker use in perioperative period of noncardiac surgeries has been a topic of debate since many years. Earlier studies conducted in the 90s showed decreased cardiac adverse events and improved postoperative outcomes with beta-blocker use. Based on this, the ACCF and ESC published guidelines strongly supporting beta-blocker use. But contemporaneous studies conducted revealed conflicting evidence and have also proven some of the earlier studies to be fraudulent. Although ACCF guidelines have been updated to partially reflect the changes, ESC guidelines continue to support beta-blocker use. AREAS OF UNCERTAINTY: In light of the ACCF and ESC guidelines supporting beta-blocker use in perioperative period of noncardiac surgeries, our aim was to review the available literature and consolidate evidence in this regard. DATA SOURCES: PubMed search was conducted to include relevant studies between 1950 and 2015. RESULTS: We reviewed 24 eligible studies and few debates conducted in this regard. Based on our review, our findings were as follows: beta-blockers should be continued throughout perioperative period in patients who were on beta blockers before surgery for other indications such as angina, hypertension, and symptomatic arrhythmias. Preoperative beta-blockers are indicated in patients undergoing high risk vascular surgery or those having high preoperative Cardiac Risk Index Score. In patients with intermediate-to-low cardiac risk, the proven benefit is not sufficient enough to suggest universal use. CONCLUSIONS: Based on our review, we conclude that the use of beta-blockers in perioperative period of noncardiac surgeries should be determined on an individual basis based on risk benefit analysis. Guideline organizations should update their recommendations based on new evidence. PMID- 28092286 TI - Childhood Traumatic Brain Injury and the Associations With Risk Behavior in Adolescence and Young Adulthood: A Systematic Review. AB - OBJECTIVE: To systematically review the evidence that childhood traumatic brain injury (TBI) is associated with risk behavior in adolescence and young adulthood. Risk behavior included one or more of the following: use of substances, including alcohol, tobacco, and illicit substances; involvement in criminal behavior; and behavioral issues with conduct. METHODS: A literature search was conducted using these terms: child, pediatric, traumatic brain injury, head injury, adolescent, psychosocial, antisocial, conduct, substance use. Studies describing original research were included if they reported outcomes over the age of 13 years in participants who sustained a TBI between birth and age 13 years. RESULTS: Six journal articles were reviewed based on 4 separate studies. Three articles indicated a relationship between childhood TBI and increased problematic substance use in adolescence and young adulthood. Three articles supported an association between childhood TBI and later externalizing behavior; however, 2 articles did not support this link. CONCLUSION: More research is warranted to explore the association between childhood TBI and later risk behavior as the relationship is not currently understood. Future research should build on existing longitudinal research with continued use of medical records for identifying TBI and inclusion of a non-brain-related trauma group to control for general injury effects. PMID- 28092288 TI - Sutureless aortic valves: who is the right patient? AB - PURPOSE OF REVIEW: Sutureless aortic valve replacement (AVR) has emerged as an alternative to traditional AVR for patients with aortic stenosis who present a higher surgical risk, such as the elderly, or those with small or highly calcified aortic roots. With transcatheter aortic valve implantation - the other major AVR alternative - being used in increasingly lower-risk patients, the place of sutureless valves in the AVR landscape needs to be defined. In this review, we discuss recent data and expert opinion as it pertains to the subject of sutureless AVR. RECENT FINDINGS: Several recent studies have evaluated the performance of sutureless valves in a variety of clinical contexts, including minimally invasive operations and high-risk surgical procedures. The optimal surgical technique for sutureless AVR has been refined through the publication of several reports addressing technical considerations. Reduction in operative times represents the main advantage of sutureless valves over conventional surgical prostheses, and the possibility of complete annular decalcification - and hence a reduced incidence of paravalvular leak - is the primary advantage over TAVI. SUMMARY: Sutureless valves have emerged as an attractive option for high-risk patients or for complex surgeries where a minimization of bypass time is critical. However, there is limited data regarding long-term outcomes, durability or reoperation. PMID- 28092287 TI - Current and future management of the young child with early onset wheezing. AB - PURPOSE OF REVIEW: In this review, we discuss current thinking in relation to available guidelines for the care of preschool-aged children with recurrent wheezing, while highlighting the gaps in our knowledge and discussing changes that could occur over the next 5 years. RECENT FINDINGS: The Asthma Predictive Index as well as allergen-specific IgE, peripheral eosinophil count and exhaled nitric oxide are perhaps underutilized sources of information that can assist in predicting progression to asthma and response to therapies. Inhaled corticosteroids and leukotriene receptor antagonists decrease impairment and exacerbation frequency in wheezing children but are not disease modifying. Macrolides may be useful during acute wheezing episodes for preventing progression to more severe symptoms. Monoclonal antibodies targeting IgE and TH2 cytokines have been successful in trials of adults and older children with asthma, but trials in younger children are needed. SUMMARY: Establishing the phenotype and endotype of young wheezing children can be useful for prognostication of future asthma risk as well as for selection of the most appropriate treatment. Primary asthma prevention strategies are needed during the critical developmental window in early life prior to the onset of irrecoverable loss of lung function. PMID- 28092289 TI - The impact of obesity on heart failure. AB - PURPOSE OF REVIEW: Obesity, a growing global health problem, contributes to the development of heart failure. However, increased BMI seems protective for those with established disease, a phenomenon known as the 'obesity paradox'. In this review, we outline the mechanism through which obesity can contribute to the development of heart failure, explore the concept of obesity paradox, and highlight the challenges that obesity presents for advanced heart failure therapy. RECENT FINDINGS: Although the mechanism underlying the obesity paradox is complex, meta-analysis shows that intentional weight loss through bariatric surgery can indeed improve cardiac structure and function. With regard to ventricular assist device therapy in obese patients, recent studies demonstrate that while obesity was indeed associated with higher likelihood of complications, there were no statistically significant differences in terms of mortality or delisting from cardiac transplant waiting list. SUMMARY: Obesity is strongly associated with the development of heart failure, through direct and indirect mechanisms. Although clear consensus regarding weight reduction in this patient population is lacking, there is mounting clinical evidence that intentional weight loss may be beneficial, in spite of the well-recognized obesity paradox, particularly as the presence of obesity presents unique challenges in the advanced therapy of heart failure patients. PMID- 28092290 TI - Clinical recommendations of cardiac magnetic resonance, Part II: inflammatory and congenital heart disease, cardiomyopathies and cardiac tumors: a position paper of the working group 'Applicazioni della Risonanza Magnetica' of the Italian Society of Cardiology. AB - The current document was developed by the working group on the 'application of cardiac magnetic resonance' of the Italian Society of Cardiology to provide a perspective on the current state of technical advances and clinical cardiac magnetic resonance applications and to inform cardiologists how to implement their clinical and diagnostic pathway with the introduction of this technique in the clinical practice. Appropriateness criteria were defined using a score system: score 1-3 = inappropriate (test is not generally acceptable and is not a reasonable approach for the indication), score 4-6 = uncertain (test may be generally acceptable and may be a reasonable approach for the indication but more research and/or patient information is needed to classify the indication definitively) and score 7-9 = appropriate (test is generally acceptable and is a reasonable approach for the indication). PMID- 28092291 TI - Diagnosing myocarditis with magnetic resonance. PMID- 28092292 TI - Epicardial collaterals spasm as a cause of ST elevation myocardial infarction. PMID- 28092293 TI - The Association Between Symptomatic and Diagnostic Depression and Pain Among the Elderly Population in South Korea. AB - The exact nature of pain (amount or severity) associated with in depression in the elderly population has not been studied extensively yet. We investigated the association between the characteristics of pain and both symptomatic and diagnostic depression using data from the 2012 Korean Longitudinal Study of Aging (2164 men, 2066 women). Symptomatic depression was identified a score of 12 or higher on the 10-item Center for Epidemiologic Studies-Depression Scale. Odds ratios with a 95% confidence interval was calculated for depression using multiple logistic regression models after adjusting for age, sex, socioeconomic status, health behavioral factors, and chronic diseases. The fully adjusted odds ratio (95% confidence interval) for symptomatic/diagnostic depression were "1" = 2.09 (1.62-2.49)/1.71 (1.03-2.86), "2" = 1.88 (1.42-2.49)/1.82 (1.05-3.13), and ">3" = 2.27 (1.71-3.01)/3.21 (1.94-5.32), and 1.86 (1.48-2.33)/1.57 (1.00-2.49) for mild, 1.74 (1.22-2.48)/2.10 (1.11-3.98) for moderate, and 5.41 (3.77 7.77)/7.34 (4.15-12.99) for severe of pain. The results indicated a significant association between the number of sites and severity of pain and the prevalence of depression in the Korean elderly. PMID- 28092294 TI - Outcomes of a Combined Approach of Percutaneous Coronary Revascularization and Cardiac Valve Surgery. AB - A subset of patients requiring coronary revascularization and valve surgery may benefit from a combined approach of percutaneous coronary intervention (PCI) and valve surgery, as opposed to the standard median sternotomy approach of combined coronary artery bypass and valve surgery. To evaluate its potential benefits and limitations, a literature search was performed using PubMed, EMBASE, Ovid, and the Cochrane library, through March 2016 to identify all studies involving a combined approach of PCI and valve surgery in patients with coronary artery and valvular disease. There were five studies included in the study with a total of 324 patients, of which 75 (23.1%) had a history of previous cardiac surgery. The interval between PCI and surgery ranged from simultaneous intervention to a median of 38 days (interquartile range, 18-65 days). The surgical approach performed consisted of a minimally invasive one or median sternotomy. There were 275 single valve surgery (84.9%) and 49 double-valve surgery (15.1%) with a 30 day mortality ranging from 0% to 5.5%. The 1-year survival ranged from 78% to 96%, and the follow-up period ranged from 1.3 to 5 years. Herein, we present a review of the literature using this technique. PMID- 28092295 TI - Income, Family Context, and Self-Regulation in 5-Year-Old Children. AB - OBJECTIVE: Self-regulation (SR) is a core aspect of child development with enduring effects on health and wellbeing across the lifespan. Early childhood poverty may shape SR development. This study examined the cross-sectional relationship among family income, family context, and SR in 5-year-old children. METHODS: A total of 140 five-year-old children and their mothers participated in the study. Children completed a battery of SR tasks; mothers completed questionnaires. Cognitive and emotional SR composite scores were generated based on a principal component analysis of the SR tasks. The SR scores were first regressed on family income (in 10 levels ranging from <5000 to 150,000+) adjusting for age, sex, and race of the child; family context variables were subsequently added to the models. RESULTS: Controlling for age, sex, and race, each level increase in family income was associated with 0.04 SD increase in emotional SR (p = .32) and 0.08 SD increase in cognitive SR (p = .01). In fully adjusted models, exposure to household instability and experiencing 10 or more negative life events was associated with worse emotional SR; exposure to mother's depressive symptoms was associated with worse cognitive SR. Higher income buffered children's SR from some contextual risk factors. Family contextual variables explained 62% of the correlation between higher income and better cognitive SR scores. CONCLUSION: Income-based cognitive SR disparities were associated with family contextual factors. Screening for family adversity in pediatric care and linking families to needed resources may protect children's developing SR capacities, with benefits to health and well-being. PMID- 28092296 TI - Qualitative Analysis of Parental Observations on Quality of Life in Australian Children with Down Syndrome. AB - OBJECTIVE: There are many challenges to health, functioning, and participation for children with Down syndrome; yet, the quality-of-life (QOL) domains important for this group have never been clearly articulated. This study investigated parental observations to identify QOL domains in children with Down syndrome and determined whether domains differed between children and adolescents. METHODS: The sample comprised 17 families whose child with Down syndrome was aged 6 to 18 years. Primary caregivers took part in semistructured telephone interviews to explore aspects of their child's life that were satisfying or challenging. Qualitative thematic analysis was implemented using a grounded theory framework to identify domains. The coded data set was divided into 2 groups (childhood and adolescence) at 3 age cut points to observe whether differences existed between the coded domains and domain elements: (1) 6 to 11 years with 12 to 18 years; (2) 6 to 13 years with 14 to 18 years; and (3) 6 to 15 years with 16 to 18 years. RESULTS: Eleven domains were identified: physical health, behavior and emotion, personal value, communication, movement and physical activity, routines and predictability, independence and autonomy, social connectedness and relationships, variety of activities, nature and outdoors, and access to services. No differences in domains and domain elements were identified across childhood and adolescence. CONCLUSION: Our data form a preliminary framework from which to design investigations of the child's perspectives on life quality and suggest a range of necessary supports and services. PMID- 28092297 TI - Vascular Adaptations to Habitual Exercise in Older Adults: Time for the Sex Talk. AB - Regular exercise is promoted as a therapeutic strategy for age-associated endothelial dysfunction. Improvements in endothelial function are observed with endurance exercise in older men, but are diminished or absent in older women. This article examines the hypothesis that sex hormones modulate vascular adaptations to exercise training by influencing antioxidant defense systems, mitochondrial function, oxidative stress, and intracellular signaling. PMID- 28092300 TI - Self-Administered Lidocaine Gel for Pain Control With First-Trimester Surgical Abortion: A Randomized Controlled Trial: Correction. PMID- 28092298 TI - Individualized Exercise Interventions for Spinal Pain. AB - Exercise is the most effective treatment for the management and prevention of spinal pain; yet on average, it delivers small to moderate treatment effects, which are rarely long lasting. This review examines the hypothesis that outcome of exercise interventions can be optimized when targeted toward the right patients and when tailored to address the neuromuscular impairments of each individual. PMID- 28092301 TI - Practice Bulletin No. 156: Obesity in Pregnancy: Correction. PMID- 28092302 TI - Committee Opinion No. 675: Management of Vulvar Intraepithelial Neoplasia: Correction. PMID- 28092303 TI - Pregnancy Outcomes in Women With a History of Previable, Preterm Prelabor Rupture of Membranes: Correction. PMID- 28092304 TI - Structural Failure Sites in Anterior Vaginal Wall Prolapse: Identification of a Collinear Triad: Correction. PMID- 28092305 TI - Prevalence and Impact of Inflammatory Bowel Disease-Irritable Bowel Syndrome on Patient-reported Outcomes in CCFA Partners. AB - BACKGROUND: Inflammatory bowel disease (IBD) patients with persistent symptoms despite no or minimal inflammation are frequently described as having an overlap of IBD and irritable bowel syndrome (IBD-IBS). Limited data are available on how IBS impacts the individual patient with IBD. In this study, we aimed to evaluate the prevalence of IBD-IBS and investigate its impact on patient-reported outcomes. METHOD: We performed a cross-sectional analysis within the CCFA Partners Study. Bivariate analyses and logistic regression models were used to investigate associations between IBD-IBS and various demographic, disease factors, and patient-reported outcomes including anxiety, depression, sleep disturbances, pain interference, and social satisfaction. RESULTS: Of the 6309 participants included, a total of 1279 (20%) reported a coexisting IBS diagnosis. The prevalence of IBD-IBS in this cohort was similar within disease subtypes. A diagnosis of IBD-IBS was associated with higher narcotic use compared with those with no IBS diagnosis for both Crohn's disease, 17% versus 11% (P < 0.001) and ulcerative colitis/indeterminate colitis, 9% versus 5% (P < 0.001). Quality of life, as measured by Short Inflammatory Bowel Disease Questionnaire (SIBDQ) was lower in patients with IBD-IBS compared with those without. IBD-IBS diagnosis was associated with anxiety, depression, fatigue, sleep disturbances, pain interference, and decreased social satisfaction. CONCLUSIONS: In this sample of patients with IBD, high prevalence of concomitant IBS diagnosis was observed. IBD IBS diagnosis was associated with increased narcotic use and adverse patient reported outcome. Appropriate diagnosis, treatment, and counseling may help improve the functional status of IBD-IBS patients and decrease narcotic use. PMID- 28092306 TI - Tripeptide K(D)PT Is Well Tolerated in Mild-to-moderate Ulcerative Colitis: Results from a Randomized Multicenter Study. AB - BACKGROUND: K(D)PT showed marked anti-inflammatory properties in preclinical studies and exhibited very low toxicity in phase I and preclinical trials. In this study, efficacy and safety of oral K(D)PT were evaluated in patients with mild-to-moderate active ulcerative colitis. METHODS: A multicenter, randomized, double-blind, phase IIa trial was performed comparing add-on oral K(D)PT twice a day (20, 50, or 100 mg) with placebo in patients with mild-to-moderate active ulcerative colitis on baseline medication. The primary objective was to determine the difference in time to sustained improvement in colitis activity index (CAI) of >=50% at week 8 between pooled K(D)PT group and placebo. Secondary endpoints included remission rates and CAI response at different time points. RESULTS: Compared with placebo, K(D)PT (pooled group) resulted in significantly higher proportions of patients in remission at 2 and 4 weeks, (2 wk: P = 0.0349; 4 wk: P = 0.0278) and a significantly higher proportion of patients with CAI response at week 8 (P = 0.0434). K(D)PT (pooled group) met the primary endpoint after additional analyses. Because of high placebo response rates, subgroup analyses tried to identify patients with unquestionably active and more severe, but still moderate, disease (CAI score >=9 or taking more than one concomitant medication). These subgroups showed earlier and statistically significant CAI responses to K(D)PT versus placebo. All doses of K(D)PT were well tolerated. CONCLUSIONS: Despite a very high placebo rate after week 4, study data in this preliminary trial strongly suggest that add-on K(D)PT is efficacious in patients with mild-to moderate ulcerative colitis. Moreover, K(D)PT showed an excellent safety profile. PMID- 28092307 TI - The PROSIT-BIO Cohort: A Prospective Observational Study of Patients with Inflammatory Bowel Disease Treated with Infliximab Biosimilar. AB - BACKGROUND: Few data are available on the safety and efficacy of infliximab biosimilar CT-P13 in patients with ulcerative colitis and Crohn's disease. METHODS: A prospective, multicenter, cohort study using a structured database. RESULTS: Consecutive patients (313 Crohn's disease and 234 ulcerative colitis) were enrolled from 31 referral centers; 311 patients were naive to anti-tumor necrosis factor alpha, 139 had a previous exposure to biologics, and the remaining 97 were switched to CT-P13 after a mean of 18 +/- 14 infusions of infliximab. The mean follow-up was 4.3 +/- 2.8 months, and the total follow-up time was 195 patient-years. After 2061 infusions, 66 serious adverse events were reported (12.1%), 38 (6.9%) of them were infusion-related reactions. The biosimilar had to be stopped in 29 (5.3%) cases for severe infusion reactions (8 naive, 19 previous exposed, and 2 switch), and in further 16 patients (2.9%) for other serious adverse events. Infusion reactions were significantly more frequent in patients pre-exposed to infliximab than to other anti-tumor necrosis factor alpha (incidence rate ratio = 2.82, 95% CI: 1.05-7.9). The efficacy of the biosimilar was evaluated in 434 patients who received treatment for at least 8 weeks, using time-to-event methods for censored observations: 35 patients were primary failures (8.1%). After further 8, 16, and 24 weeks, the efficacy estimations were 95.7%, 86.4%, and 73.7% for naive, 97.2%, 85.2%, and 62.2% for pre-exposed, and 94.5%, 90.8%, and 78.9% for switch, respectively (log-rank P = 0.64). CONCLUSIONS: Although no direct comparison was performed, preliminary data on efficacy and safety of CT-P13 were in line with those of infliximab. PMID- 28092308 TI - Increasing Incidence of Crohn's Disease with Familial Clustering in the Kingdom of Bahrain: A 25-Year Population-based Study. AB - BACKGROUND: The incidence of Crohn's disease has been increasing in developed countries; whether this trend has extended to countries in Middle East, especially in the Arab world, remains unclear. Our aim was to study the epidemiology, incidence, time trends and clustering of Crohn's disease within the population of the Kingdom of Bahrain. METHODS: A retrospective case-cohort study was conducted on patients diagnosed with Crohn's disease at Bahrain Specialist Hospital between 1990 and 2015. The diagnosis was based on clinical, radiological, endoscopic, and histological examinations. RESULTS: Five hundred twenty-two cases were eligible for analysis; 14.5% were below the age of 19 with a male-to-female ratio of 1.1:1. The overall incidence was 4.8/100,000 person years and significantly increased from 5.5/100,000 person-years during the 1990's to 8.0/100,000 person-years during the last study period [incidence rate ratio (IRR) 0.32, 95% CI = 0.26-0.42]. This trend was persistent for adults, children, men and women. There were 129 patients with at least one family member diagnosed with Crohn's disease consisting of 40 families. Three clusters were identified based on first or second degree relationship of the family member. The mean interval for diagnosis between family members was significantly shorter between siblings than second degree relatives; (2.0 +/- 1.2 years) versus (5.0 +/- 2.8 years), respectively; (P = 0.04). CONCLUSIONS: The incidence rate of Crohn's disease in Bahrain is comparable to the U.S.A and has increased for men and women in all age groups. Crohn's disease clusters were common among families and included up to 3 generations consistent with presence of a common source or common genetic factors. PMID- 28092309 TI - Microbiota-targeted therapies on the intensive care unit. AB - PURPOSE OF REVIEW: The composition and diversity of the microbiota of the human gut, skin, and several other sites is severely deranged in critically ill patients on the ICU, and it is likely that these disruptions can negatively affect outcome. We here review new and ongoing studies that investigate the use of microbiota-targeted therapeutics in the ICU, and provide recommendations for future research. RECENT FINDINGS: Practically every intervention in the ICU as well as the physiological effects of critical illness itself can have a profound impact on the gut microbiota. Therapeutic modulation of the microbiota, aimed at restoring the balance between 'pathogenic' and 'health-promoting' microbes is therefore of significant interest. Probiotics have shown to be effective in the treatment of ventilator-associated pneumonia, and the first fecal microbiota transplantations have recently been safely and successfully performed in the ICU. However, all-encompassing data in this vulnerable patient group remain sparse, and only a handful of novel studies that study microbiota-targeted therapies in the ICU are currently ongoing. SUMMARY: Enormous strides have been made in characterizing the gut microbiome of critically ill patients in the ICU, and an increasing amount of preclinical data reveals the huge potential of microbiota targeted therapies. Further understanding of the causes and consequences of dysbiosis on ICU-related outcomes are warranted to push the field forward. PMID- 28092310 TI - New insights into the gut as the driver of critical illness and organ failure. AB - PURPOSE OF REVIEW: The gut has long been hypothesized to be the 'motor' of multiple organ dysfunction syndrome. This review serves as an update on new data elucidating the role of the gut as the propagator of organ failure in critical illness. RECENT FINDINGS: Under basal conditions, the gut absorbs nutrients and serves as a barrier that prevents approximately 40 trillion intraluminal microbes and their products from causing host injury. However, in critical illness, gut integrity is disrupted with hyperpermeability and increased epithelial apoptosis, allowing contamination of extraluminal sites that are ordinarily sterile. These alterations in gut integrity are further exacerbated in the setting of preexisting comorbidities. The normally commensal microflora is also altered in critical illness, with increases in microbial virulence and decreases in diversity, which leads to further pathologic responses within the host. SUMMARY: All components of the gut are adversely impacted by critical illness. Gut injury can not only propagate local damage, but can also cause distant injury and organ failure. Understanding how the multifaceted components of the gut interact and how these are perturbed in critical illness may play an important role in turning off the 'motor' of multiple organ dysfunction syndrome in the future. PMID- 28092312 TI - Synchronous Presentation of Renal Cell Carcinoma and Hodgkin Lymphoma in an Adolescent. AB - BACKGROUND: Coincidence of renal cell carcinoma (RCC) and hematologic malignancies has been reported in adults but not in children. OBSERVATION: We report a case of a 16-year-old girl in whom RCC was incidentally discovered on the computed tomography scan that was performed to stage her underlying Hodgkin lymphoma. Analysis of constitutional cytogenetics for common genetic aberrations that predispose to RCC did not reveal any mutations or genetic variations. However, cytogenetics on the RCC tumor demonstrated a rare reciprocal translocation between chromosomes 6 and 11, t(6;11)(p21;q12). After undergoing partial nephrectomy with regional lymphadenectomy and treatment with multiagent chemotherapy, patient is cancer-free, now 33 months from end of therapy. CONCLUSIONS: This case highlights the importance for histologic confirmation of a renal mass when concurrently discovered during the diagnostic evaluation of other malignancies. PMID- 28092313 TI - SURGICAL MANAGEMENT OF TRACTIONAL RETINOSCHISIS ASSOCIATED WITH VITREOUS HEMORRHAGE IN RETINOPATHY OF PREMATURITY. AB - PURPOSE: The tractional retinoschisis is a poorly understood, rare, and likely underappreciated entity in retinopathy of prematurity. The purpose of this article is to describe clinical findings and surgical management of tractional retinoschisis in retinopathy of prematurity, masquerading as Stage 4 retinopathy of prematurity retinal detachment. METHODS: A retrospective review of a single case with literature review and case discussion. RESULTS: In this report, we describe a child with retinopathy of prematurity and tractional schisis, who initially presented with vitreous hemorrhage and was effectively managed by vitrectomy and inner wall retinectomy. At 5 months after vitrectomy, the child demonstrated complete collapse of the retinoschisis with intact posterior pole and brisk light perception. CONCLUSION: Vitrectomy with or without inner wall retinectomy is effective in the management of tractional retinoschisis. PMID- 28092314 TI - NOVEL TECHNIQUE FOR SUBRETINAL FLUID DRAINAGE WITH CHANDELIER-ASSISTED SCLERAL BUCKLE SURGERY: CANNULA-CONTROLLED DRAINAGE. AB - PURPOSE: To report a novel technique for subretinal fluid drainage in scleral buckle surgery. METHODS: A 26-gauge intravenous cannula with its needle was used to puncture the sclera; then, the needle (metallic part) was withdrawn to further introduce the cannula into the subretinal space. In addition, we describe using the 25-gauge microcannula of the chandelier light to inject the balanced salt solution to help restore the intraocular pressure and push the subretinal fluid through the intravenous cannula under direct visualization. RESULTS: An 82-year old gentleman with chronic rhegmatogenous retinal detachment with subretinal bands who was at a high risk for intraoperative bleeding since he was on dual antiplatelet therapy. He underwent chandelier light-assisted scleral buckle with subretinal fluid drainage using cannula controlled drainage, which resulted in complete intraoperative subretinal fluid drainage with no complications and successful flattening of the retina in the postoperative follow-up. CONCLUSION: Subretinal fluid drainage using this technique with chandelier-assisted scleral buckle surgery is a new method which might improve the safety profile of subretinal fluid drainage during scleral buckle surgery. PMID- 28092315 TI - CHOROIDAL BLOOD VESSELS IN RETINAL PIGMENT EPITHELIAL ATROPHY USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. AB - PURPOSE: To observe choroidal blood vessels in cases sharply demarcated with retinal pigment epithelium (RPE) atrophy at the macular area using en-face optical coherence tomography angiography (OCTA) and standard en-face optical coherence tomography (OCT). METHODS: The retrospective study included 12 eyes (8 patients; 5 men, 3 women; average age, 64.3 years) with RPE atrophy seen by ophthalmoscopy. The macular areas with normal and atrophic RPE sections were examined using en-face OCTA with an 840-nm light source (RTVue XR Avanti; Optovue Inc), which system can obtain standard en-face OCT images at identical areas. Images on en-face OCTA and standard en-face OCT were compared with each other when the segmentation range was being set as the full thickness of the choroid by the attached software. RESULTS: Choroidal blood vessels were seen as black on standard en-face OCT images in all cases. However, the choroidal vessels on OCTA were depicted as white in the RPE atrophic area and black in the normal areas. CONCLUSION: Choroidal blood vessels in the normal sections of RPE were visualized in black on standard en-face OCT and OCTA with an 840-nm light source; however, those in the atrophic parts were observed as white, or with bloodstream, on OCTA images. Choroidal blood vessels cannot be evaluated accurately in commercially available OCTA systems because of blockage of light by the RPE. PMID- 28092316 TI - Expanded Newborn Screening: Challenges to NICU Nurses. AB - BACKGROUND: Newborn screening programs provide testing for all newborns born in this country for conditions that can potentially cause death or disability. Currently each state is responsible for its programs and the number of disorders screened varies from state to state. The current universal recommended metabolic screening panel may include 32 to 58 disorders. Expansion of the programs has impacted the role of nurses in the neonatal intensive care units (NICUs). Nurses are responsible for facilitating the screening process, educating the family, and assisting with follow-up. In addition, they are the first-line defense for emotional, spiritual, and social support. PURPOSE: To review of the expansion of this program over time and discuss challenges the NICU nurse encounters. METHODS/SEARCH STRATEGY: Research literatures along with the national recommendation by governmental and professional agencies were reviewed to obtain evidence on current practice recommendations. FINDINGS/RESULTS/IMPLICATIONS FOR PRACTICE AND RESEARCH: NICU nurses face several challenges with the expansion of newborn screening programs. This includes gaining knowledge to answer questions posed by empowered parents and educate them appropriately; ensuring quality of the process that minimizes errors and optimal communication; and, addressing ethical concerns about the storage and subsequent use of specimens. New and ongoing research can measure and ensure provision of quality services provided through the NICUs globally. PMID- 28092317 TI - Ideal Site for Skin Temperature Probe Placement on Infants in the NICU: A Review of Literature. AB - BACKGROUND: Maintaining normothermia and prevention of hypothermia are critical determinants of morbidity and mortality in infants. Noninvasive monitoring of skin temperature using skin temperature probes (STPs) has been a practice in neonatal intensive care units (NICUs) for decades. Incubators and radiant warmers use feedback mechanisms from the STP readings to determine the heat output to maintain normothermia. Placing the STP on an ideal site on the infant's body is essential for optimum servo control of the temperature. More importantly, where is the ideal site for the STP placement? Clinical practice guidelines (CPGs) vary on information regarding the site and proper placement of the STPs. The literature is analyzed to identify evidence for the ideal STP placement on infants in NICUs. PURPOSE: To review the literature for evidence for ideal placement for skin temperature probe placement on an infant. SEARCH STRATEGY: OVID/MEDLINE, CINAHL, Cochrane databases, and CPGs were searched to identify research, literature reviews, and guidelines for ideal sites for STP placement. Twenty documents were reviewed. RESULTS: Guidelines vary in suggested sites for STP placement. The majority of the studies compared temperature measurement between abdomen and axilla. Although a Cochrane review found abdominal skin as an ideal site, other studies did not find any difference between axially and abdominal skin temperature measurements. IMPLICATIONS FOR PRACTICE AND RESEARCH: Placing the STP on an ideal site is essential for accurate and safe monitoring of skin temperature in infants. NICU nurses are uniquely positioned to undertake research to identify the ideal site for STP placement to guide safe practice and impact optimal neonatal outcome. PMID- 28092318 TI - Opening Injection Pressure Is Higher in Intraneural Compared With Perineural Injections During Simulated Nerve Blocks of the Lower Limb in Fresh Human Cadavers. AB - BACKGROUND AND OBJECTIVES: Needle-induced nerve trauma and intraneural injection can lead to neurologic injury during peripheral nerve blocks. In this study, we assessed the utility of opening injection pressure (OIP), time to OIP, and rate of rise to OIP in detecting needle-nerve contact and intraneural injection. METHODS: Five common ultrasound-guided blocks of the femoral, saphenous, subgluteal sciatic, tibial, and common peroneal nerves were simulated in 10 fresh cadavers. Opening injection pressure was defined as peak psi in the 60-second interval during which the injection is initiated. Pressure-time curves were constructed separately for intraneural and perineural injections for each of the 5 nerves studied. RESULTS: Opening injection pressure was higher for intraneural than for perineural injections (P < 0.001), ranging from 21.5 psi (1111.9 mm Hg) to 25.8 psi (1334.2 mm Hg) for intraneural injections and from 3.8 psi (196.5 mm Hg) to 6.1 psi (315.5 mm Hg) for perineural injections. Time to OIP tended to be shorter for intraneural than for perineural injections, particularly for the subgluteal sciatic, tibial, and common peroneal nerves. Curves of intraneural injections had steep slopes with high peaks; curves of perineural injections had low slopes followed by plateaus. Rise to OIP was greater for intraneural than for perineural injections. CONCLUSIONS: In our fresh human cadaver model, OIP detected intraneural needle placement. Monitoring of OIP could be useful in detecting and/or preventing intraneural injection during nerve blocks in the clinical setting. PMID- 28092319 TI - Network Inefficiency: A Rosetta Stone for the Mechanism of Anesthetic-induced Unconsciousness. PMID- 28092320 TI - Does a Platelet Transfusion Independently Affect Bleeding and Adverse Outcomes in Cardiac Surgery? AB - BACKGROUND: Conflicting results have been reported concerning the effect of platelet transfusion on several outcomes. The aim of this study was to assess the independent effect of a single early intraoperative platelet transfusion on bleeding and adverse outcomes in cardiac surgery patients. METHODS: For this observational study, 23,860 cardiac surgery patients were analyzed. Patients who received one early (shortly after cardiopulmonary bypass while still in the operating room) platelet transfusion, and no other transfusions, were defined as the intervention group. By matching the intervention group 1:3 to patients who received no early transfusion with most comparable propensity scores, the reference group was identified. RESULTS: The intervention group comprised 169 patients and the reference group 507. No difference between the groups was observed concerning reinterventions, thromboembolic complications, infections, organ failure, and mortality. However, patients in the intervention group experienced less blood loss and required vasoactive medication 139 of 169 (82%) versus 370 of 507 (74%; odds ratio, 1.65; 95% CI, 1.05 to 2.58), prolonged mechanical ventilation 92 of 169 (54%) versus 226 of 507 (45%; odds ratio, 1.47; 94% CI, 1.03 to 2.11), prolonged intensive care 95 of 169 (56%) versus 240 of 507 (46%; odds ratio, 1.49; 95% CI, 1.04 to 2.12), erythrocytes 75 of 169 (44%) versus 145 of 507 (34%; odds ratio, 1.55; 95% CI, 1.08 to 2.23), plasma 29 of 169 (17%) versus 23 of 507 (7.3%; odds ratio, 2.63; 95% CI, 1.50-4.63), and platelets 72 of 169 (43%) versus 25 of 507 (4.3%; odds ratio, 16.4; 95% CI, 9.3-28.9) more often compared to the reference group. CONCLUSIONS: In this retrospective analysis, cardiac surgery patients receiving platelet transfusion in the operating room experienced less blood loss and more often required vasoactive medication, prolonged ventilation, prolonged intensive care, and blood products postoperatively. However, early platelet transfusion was not associated with reinterventions, thromboembolic complications, infections, organ failure, or mortality. PMID- 28092321 TI - Dexmedetomidine Disrupts the Local and Global Efficiencies of Large-scale Brain Networks. AB - BACKGROUND: A clear understanding of the neural basis of consciousness is fundamental to research in clinical and basic neuroscience disciplines and anesthesia. Recently, decreased efficiency of information integration was suggested as a core network feature of propofol-induced unconsciousness. However, it is unclear whether this finding can be generalized to dexmedetomidine, which has a different molecular target. METHODS: Dexmedetomidine was administered as a 1-MUg/kg bolus over 10 min, followed by a 0.7-MUg . kg . h infusion to healthy human volunteers (age range, 18 to 36 yr; n = 15). Resting-state functional magnetic resonance imaging data were acquired during baseline, dexmedetomidine induced altered arousal, and recovery states. Zero-lag correlations between resting-state functional magnetic resonance imaging signals extracted from 131 brain parcellations were used to construct weighted brain networks. Network efficiency, degree distribution, and node strength were computed using graph analysis. Parcellated brain regions were also mapped to known resting-state networks to study functional connectivity changes. RESULTS: Dexmedetomidine significantly reduced the local and global efficiencies of graph theory-derived networks. Dexmedetomidine also reduced the average brain connectivity strength without impairing the degree distribution. Functional connectivity within and between all resting-state networks was modulated by dexmedetomidine. CONCLUSIONS: Dexmedetomidine is associated with a significant drop in the capacity for efficient information transmission at both the local and global levels. These changes result from reductions in the strength of connectivity and also manifest as reduced within and between resting-state network connectivity. These findings strengthen the hypothesis that conscious processing relies on an efficient system of information transfer in the brain. PMID- 28092322 TI - Opioidergic tone and pain susceptibility: interactions between reward systems and opioid receptors. PMID- 28092323 TI - Brain substrates of reward processing and the MU-opioid receptor: a pathway into pain? AB - The processing of reward and reinforcement learning seems to be important determinants of pain chronicity. However, reward processing is already altered early in life and if this is related to the development of pain symptoms later on is not known. The aim of this study was first to examine whether behavioural and brain-related indicators of reward processing at the age of 14 to 15 years are significant predictors of pain complaints 2 years later, at 16 to 17 years. Second, we investigated the contribution of genetic variations in the opioidergic system, which is linked to the processing of both, reward and pain, to this prediction. We used the monetary incentive delay task to assess reward processing, the Children's Somatization Inventory as measure of pain complaints and tested the effects of 2 single nucleotide polymorphisms (rs1799971/rs563649) of the human MU-opioid receptor gene. We found a significant prediction of pain complaints by responses in the dorsal striatum during reward feedback, independent of genetic predisposition. The relationship of pain complaints and activation in the periaqueductal gray and ventral striatum depended on the T allele of rs563649. Carriers of this allele also showed more pain complaints than CC-allele carriers. Therefore, brain responses to reward outcomes and higher sensitivity to pain might be related already early in life and may thus set the course for pain complaints later in life, partly depending on a specific opioidergic genetic predisposition. PMID- 28092324 TI - Long-term use of opioids for nonmalignant pain among community-dwelling persons with and without Alzheimer disease in Finland: a nationwide register-based study. AB - Persons with Alzheimer disease (AD) commonly present with chronic nonmalignant pain, but long-term use of opioids among this population has not been studied previously. Our aim was to investigate the prevalence of long-term (>=180 days) use of opioids for nonmalignant pain and associated factors among community dwelling persons with AD and to compare the prevalence with a matched cohort without AD. The Medication use and Alzheimer's disease (MEDALZ) cohort was used for this study, comprising all community-dwelling persons diagnosed with AD in Finland during 2005 to 2011 and their matched comparison persons without AD. After exclusion of persons with active cancer treatment, 62,074 persons with and 62,074 persons without AD were included in this study. Data were collected from nationwide registers. Opioids were used by 13,111 persons with and by 16,659 without AD. Overall long-term opioid use was more common among persons without AD (8.7%) than among persons with AD (7.2%, P < 0.0001). However, among opioid users, prevalence of long-term opioid use was slightly higher among persons with AD than among those without AD (34.2% vs 32.3%, respectively, P = 0.0004). Long term use of transdermal opioids was more than 2-fold among opioid users with AD (13.2%) compared with users without AD (5.5%). Factors associated with long-term opioid use included AD, age >=80 years, female sex, rheumatoid arthritis, osteoporosis, low socioeconomic position, history of substance abuse, and long term benzodiazepine use. Prevalence of long-term opioid use was somewhat similar among both groups. Among persons with AD, long-term opioid use was strongly associated with transdermal opioids. PMID- 28092325 TI - Persistent pain after motor vehicle collision: comparative effectiveness of opioids vs nonsteroidal antiinflammatory drugs prescribed from the emergency department-a propensity matched analysis. AB - Each year millions of Americans present to the emergency department (ED) for care after a motor vehicle collision (MVC); the majority (>90%) are discharged to home after evaluation. Acute musculoskeletal pain is the norm in this population, and such patients are typically discharged to home with prescriptions for oral opioid analgesics or nonsteroidal antiinflammatory drugs (NSAIDs). The influence of acute pain management on subsequent pain outcomes in this common ED population is unknown. We evaluated the effect of opioid analgesics vs NSAIDs initiated from the ED on the presence of moderate to severe musculoskeletal pain and ongoing opioid use at 6 weeks in a large cohort of adult ED patients presenting to the ED after MVC (n = 948). The effect of opioids vs NSAIDs was evaluated using an innovative quasi-experimental design method using propensity scores to account for covariate imbalances between the 2 treatment groups. No difference in risk for moderate to severe musculoskeletal pain at 6 weeks was observed between those discharged with opioid analgesics vs NSAIDs (risk difference = 7.2% [95% confidence interval: -5.2% to 19.5%]). However, at follow-up participants prescribed opioids were more likely than those prescribed NSAIDs to report use of prescription opioids medications at week 6 (risk difference = 17.5% [95% confidence interval: 5.8%-29.3%]). These results suggest that analgesic choice at ED discharge does not influence the development of persistent moderate to severe musculoskeletal pain 6 weeks after an MVC, but may result in continued use of prescription opioids. Supported by NIAMS R01AR056328 and AHRQ 5K12HS022998. PMID- 28092326 TI - Using placebos as an opioid-sparing method of pain management. PMID- 28092327 TI - Reply. PMID- 28092328 TI - Critical comments on Williams and Craig's recent proposal for revising the definition of pain. PMID- 28092329 TI - Reply. PMID- 28092330 TI - Prediction of Anastomotic Leakage After Laparoscopic Low Anterior Resection in Male Rectal Cancer by Pelvic Measurement in Magnetic Resonance Imaging. AB - OBJECTIVE: Anastomotic leakage after laparoscopic low anterior resection in male rectal cancer patients with a narrow pelvis cannot be easily resolved. The objective of this study is to assess numerical information of narrow pelvis and to determine whether prediction of morbidity can be possible. METHODS: Retrospective medical record review was performed. From July 2007 to January 2013, 43 consecutive male patients with low rectal cancer who underwent laparoscopic low anterior resection were divided into the anastomotic leakage negative group and anastomotic leakage-positive group. Eleven anatomic parameters were measured from preoperative magnetic resonance imaging of pelvis and a new index called "pelvic index" was calculated. RESULTS: The pelvic index (difference between the interspinous distance and the diameter of the mesorectum divided by the depth of the cavity of the lesser pelvis) in the leakage-positive group was significantly smaller than that in the negative group (P=0.038). Comparison between those 2 groups at the border of the cut-off value of the pelvic index (13.0) showed a significant difference. CONCLUSIONS: Preoperative assessment by the pelvic index can predict the narrow pelvis and risk of anastomotic leakage. PMID- 28092331 TI - Reply: Effectiveness of Autologous Fat Grafting in Adherent Scars: Results Obtained by a Comprehensive Scar Evaluation Protocol. PMID- 28092332 TI - Freestyle Pedicled Perforator Flaps: Applying the Reconstructive Ladder to Optimize Outcomes. PMID- 28092334 TI - Is Enhanced Recovery the New Standard of Care in Microsurgical Breast Reconstruction? AB - BACKGROUND: At present, there are limited data available regarding the use and feasibility of enhanced recovery pathways for patients undergoing microsurgical breast reconstruction. The authors sought to assess patient outcomes before and after the introduction of an enhanced recovery pathway that was adopted at a single cancer center. METHODS: A multidisciplinary enhanced recovery pathway was developed for patients undergoing deep inferior epigastric perforator or free transverse rectus abdominis myocutaneous flap breast reconstruction. Core elements of the enhanced recovery pathway included substituting intravenous patient-controlled analgesia with ketorolac and transversus abdominis plane blocks using liposomal bupivacaine, as well as intraoperative goal-directed fluid management. Patients who underwent surgery between April and August of 2015 using the enhanced recovery pathway were compared with a historical control cohort. The primary endpoints were hospital length of stay and total postoperative opioid consumption. RESULTS: In total, 91 consecutive patients were analyzed (enhanced recovery pathway, n = 42; pre-enhanced recovery pathway, n = 49). Mean hospital length of stay was significantly shorter in the enhanced recovery pathway group than in the pre-enhanced recovery pathway group (4.0 days versus 5.0 days; p < 0.0001). Total postoperative morphine equivalent consumption was also lower in the enhanced recovery pathway group (46.0 mg versus 70.5 mg; p = 0.003). There was no difference in the incidence of 30-day complications between the groups (p = 0.6). CONCLUSION: The adoption of an enhanced recovery pathway for deep inferior epigastric perforator and transverse rectus abdominis myocutaneous flap reconstruction by multiple surgeons significantly decreased opioid consumption and reduced length of stay by 1 day. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28092335 TI - Distribution Pattern of the Superior and Inferior Labial Arteries: Impact for Safe Upper and Lower Lip Augmentation Procedures. AB - BACKGROUND: Understanding the precise position and course of the superior and inferior labial arteries within the upper lip and the lower lip is crucial for safe and complication-free applications of volumizing materials. METHODS: One hundred ninety-three anatomical head specimens (56.5 percent female cadavers) of Caucasian ethnicity were investigated in this large multicenter anatomical study. In total, six 3-cm-long vertical incisions were performed on each lip (midline and 1 cm medial to the angles of the mouth) to identify the position of the superior and inferior labial arteries in relation to the orbicularis oris muscle. RESULTS: Three different positions of the superior and inferior labial arteries were identified: submucosal (i.e., between the oral mucosa and the orbicularis oris muscle in 78.1 percent of the cases), intramuscular (i.e., between the superficial and deep layers of the orbicularis oris muscle in 17.5 percent of the cases), and subcutaneous (i.e., between the skin and the orbicularis oris muscle in 2.1 percent of the cases). The variability in changing the respective position along the labial course was 29 percent for the total upper and 32 percent for the total lower lip. The midline location was identified in both the upper and lower lips to be the most variable. CONCLUSIONS: Based on the results of this investigation, a safer location for the application of volumizing material is the subcutaneous plane in the paramedian location of both the upper lip and the lower lip. Care has to be taken when aiming to inject in the midline, as the artery can be identified more frequently in superficial positions. PMID- 28092336 TI - Construction of Expanded Prefabricated Adipose Tissue Using an External Volume Expansion Device. AB - BACKGROUND: Multiple studies have demonstrated that mechanical forces promote the growth of adipose tissue. However, the mechanism of adipose tissue regeneration induced by mechanical forces remains unclear. METHODS: In an experiment using rats, prefabricated adipose tissue with a vessel pedicle was expanded using an external volume expansion device. The volume of fat flaps was tested at different time points. Cell proliferation and angiogenesis were analyzed using immunofluorescence. The expression of adipogenic genes and inflammatory cytokines was evaluated using real-time polymerase chain reaction analysis and enzyme linked immunosorbent assay, respectively. RESULTS: There were more CD31 cells and Ki67/CD34 cells in the experimental group than in the control group. The number of Ki67/CD34 cells peaked at 1 to 4 weeks. However, the expression levels of peroxisome proliferator-activated receptor-gamma and CCAAT/enhancer-binding protein-beta were highest from 4 to 12 weeks in the experimental group. Compared with the control group, the experimental group showed more proinflammatory cytokines: interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, and macrophage migration inhibitory factor. CONCLUSIONS: The construction of expanded prefabricated adipose tissue by mechanical forces is a dynamic and complex process. Mechanical forces promoted cell proliferation and angiogenesis in the early stage of adipose tissue regeneration (before 4 weeks) and induced adipogenic differentiation at a later stage (after 4 weeks) through up-regulation of macrophage migration inhibitory factor, which provided an adipogenic inductive microenvironment. PMID- 28092337 TI - Anatomical Basis and Clinical Application of Synovial Flaps in the Wrist and Distal Forearm. AB - BACKGROUND: Neuropathic symptoms after median nerve repair at the wrist or secondary to refractory carpal tunnel syndrome may become debilitating. These symptoms develop because of perineural adhesions, intraneural fibrosis, and fixation of the nerve to the transverse carpal ligament after surgery, and often require neurolysis. Interposition of vascularized soft tissue over the median nerve at the time of neurolysis prevents recurrence of such adhesions. The synovial flap, fashioned from the synovial lining of the flexor tendon sheath, is an ideal tissue for this purpose. Previous authors have described the surgical technique of the synovial flap, but the anatomical basis and design of the flap have not been previously discussed. METHODS: Twenty fresh cadaver upper extremities were injected with Microfil to analyze the arterial anatomy, flap dimensions, and arc of rotation of the flexor tendon synovium mobilized as a flap suitable for coverage of the median nerve at the wrist. The authors determined that both radial and ulnar-based flaps are clinically useful for providing coverage in the wrist and distal forearm. This flap was used in 18 patients with complicated median nerve lesions in this region. RESULTS: All patients had an uncomplicated postoperative course. Of 13 patients treated for posttraumatic median nerve neuromas, all but two had significant resolution of symptoms. CONCLUSIONS: When used as a vascularized flap, the flexor tendon synovium provides adequate protection of the median nerve. Flap dimensions and vascularity of this tissue make it an ideal local flap option when performing reoperative surgery on the median nerve. PMID- 28092338 TI - Quantifying Long-Term Retention of Excised Fat Grafts: A Longitudinal, Retrospective Cohort Study of 108 Patients Followed for Up to 8.4 Years. AB - BACKGROUND: Predicting the degree of fat graft retention is essential when planning reconstruction or augmentation with free fat grafting. Most surgeons observe volume loss over time after fat grafting; however, the portion lost to resorption after surgery is still poorly defined, and the time to reach steady state is unknown. METHODS: The authors compiled a retrospective, longitudinal cohort of patients with vestibular schwannoma who had undergone ablative surgery and reconstruction with excised fat between the years 2006 and 2015. Fat volume retention was quantified by computed tomography and magnetic resonance imaging and used to model a graft retention trajectory and determine the volumetric steady state. In addition, the authors evaluated the association between graft retention and secondary characteristics, such as sex and transplant volume. RESULTS: A total of 108 patients were included. The average baseline graft volume was 18.1 +/- 4.8 ml. The average time to reach steady state was 806 days after transplantation. By this time, the average fat graft retention was 50.6 percent (95 percent CI, 46.4 to 54.7 percent). No statistically significant association was found between baseline graft volume and retention. Fat graft retention over time was significantly higher in men than in women (57.7 percent versus 44.5 percent; p < 0.001). CONCLUSIONS: The authors' data provide evidence that the time to reach fat graft volumetric steady state is considerably longer than previously expected. Fat grafts continue to shrink long after the initial hypoxia induced tissue necrosis has been cleared, thus indicating that factors other than blood supply may be more influential for fat graft retention. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28092339 TI - beta-Adrenergic Receptor Blockers Reduce the Occurrence of Keloids and Hypertrophic Scars after Cardiac Device Implantation: A Single-Institution Case Control Study. AB - BACKGROUND: Keloids and hypertrophic scars are characterized by excessive proliferation of fibroblasts; abnormal accumulation of extracellular matrix; and clinical findings of raised, red, itchy, and painful lesions. There are few sufficient interventions for keloids, and the development of new therapeutic agents is urgently needed. Several studies suggest that a therapeutic possibility is beta-adrenergic receptor blocker treatment. METHODS: In this single-center case-control study, patients who had undergone cardiac device implantation 7 to 23 months earlier were identified. The implantation incision scars of the patients were deemed to be normal or abnormal depending on their redness. The cases (abnormal scars) and controls (normal scars) were compared in terms of their beta-blocker use rates. RESULTS: Of the 45 eligible patients, 12 and 33 patients were cases and controls, respectively. The cases tended to be less likely to have taken blockers than the controls (25 percent versus 45.5 percent). This difference became significant when the patients whose scars were diagnosed 7 or 8 months after implantation were excluded from the analysis: the age-adjusted odds ratios of the patients who were diagnosed 8 to 23 and 9 to 23 months after implantation were 0.10 (95 percent CI, 0.00 to 0.83; p = 0.0309) and 0.11 (95 percent CI, 0.00 to 0.98; p = 0.047), respectively. CONCLUSIONS: beta-Blockers may be an effective alternative modality for preventing and treating keloids and hypertrophic scars. Large-scale multicenter prospective studies that use histology to diagnose scars and diagnose the postoperative scars at the most suitable period are needed to confirm the effectiveness of blockers for abnormal scars. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28092340 TI - Decompression Surgery Alone Versus Decompression Plus Fusion in Symptomatic Lumbar Spinal Stenosis: A Swiss Prospective Multicenter Cohort Study With 3 Years of Follow-up. AB - STUDY DESIGN: Retrospective analysis of a prospective, multicenter cohort study. OBJECTIVE: To estimate the added effect of surgical fusion as compared to decompression surgery alone in symptomatic lumbar spinal stenosis patients with spondylolisthesis. SUMMARY OF BACKGROUND DATA: The optimal surgical management of lumbar spinal stenosis patients with spondylolisthesis remains controversial. METHODS: Patients of the Lumbar Stenosis Outcome Study with confirmed DLSS and spondylolisthesis were enrolled in this study. The outcomes of this study were Spinal Stenosis Measure (SSM) symptoms (score range 1-5, best-worst) and function (1-4) over time, measured at baseline, 6, 12, 24, and 36 months follow-up. In order to quantify the effect of fusion surgery as compared to decompression alone and number of decompressed levels, we used mixed effects models and accounted for the repeated observations in main outcomes (SSM symptoms and SSM function) over time. In addition to individual patients' random effects, we also fitted random slopes for follow-up time points and compared these two approaches with Akaike's Information Criterion and the chi-square test. Confounders were adjusted with fixed effects for age, sex, body mass index, diabetes, Cumulative Illness Rating Scale musculoskeletal disorders, and duration of symptoms. RESULTS: One hundred thirty-one patients undergoing decompression surgery alone (n = 85) or decompression with fusion surgery (n = 46) were included in this study. In the multiple mixed effects model the adjusted effect of fusion compared with decompression alone surgery on SSM symptoms was 0.06 (95% confidence interval: 0.16-0.27) and -0.07 (95% confidence interval: -0.25-0.10) on SSM function, respectively. CONCLUSION: Among the patients with degenerative lumbar spinal stenosis and spondylolisthesis our study confirms that in the two groups, decompression alone and decompression with fusion, patients distinctively benefited from surgical treatment. When adjusted for confounders, fusion surgery was not associated with a more favorable outcome in both SSM scores as compared to decompression alone surgery. LEVEL OF EVIDENCE: 3. PMID- 28092341 TI - Unilateral Spinous Process Noncovering Hook Type Patient-specific Drill Template for Thoracic Pedicle Screw Fixation: A Pilot Clinical Trial and Template Classification. AB - STUDY DESIGN: Prospective clinical pilot study. OBJECTIVE: To confirm the accuracy of thoracic pedicle screw placement by using the unilateral spinous noncovering hook type patient-specific drill template (PSDT) made through rapid prototyping (RP) and to analyze previously reported PSDT designs and their characteristics. SUMMARY OF BACKGROUND DATA: Pedicle screw fixation is the most common form of the posterior instrumentation of the thoracic and lumbar spine. Various techniques have been introduced to improve pedicle screw placement. Among them PSDT with a preplanned trajectory has been considered a promising solution; however, we don't have consensus on proper character of the template. METHODS: Preoperative spiral three-dimensional (3D) computed tomography (CT) was performed on the thoracic spine. The images were stored in DICOM format and transferred to a workstation running MIMICS 17.0 software to generate a 3D reconstruction template for the desired thoracic vertebra. The accurate trajectory and screw diameter and length were calculated with UG Imageware 12.1. The guide template was sterilized and used intraoperatively to assist with the placement of thoracic pedicle screws. After all pedicle trajectory screws had been inserted. We reviewed 12 previous reports and classified them according to the shape and system of PSDT that met the inclusion criteria of the review. RESULTS: Ten screws were placed by using the PSDT without violating the single laminar cortex. There was no violation of the spinal canal or the cortex of pedicle on postoperative CT scans. The results of 13 PSDT types included in the current study suggested that there is no significant difference in accuracy between the PSDTs. CONCLUSION: The unilateral spinous process noncovering hook type PSDT made through RP provided an accurate trajectory for the thoracic vertebra, and the classification of PSDT in this study could be helpful for further studies. LEVEL OF EVIDENCE: 5. PMID- 28092342 TI - INTEGRITY OF OUTER RETINAL LAYERS AFTER RESOLUTION OF CENTRAL INVOLVED DIABETIC MACULAR EDEMA. AB - PURPOSE: To evaluate the integrity of outer retina layers after resolution of central involved diabetic macular edema (DME) and to demonstrate the effect of various baseline factors for the final vision and final external limiting membrane (ELM) integrity. METHODS: Fifty-nine eyes of 48 patients with resolved DME were included. Several optical coherence tomography parameters including central subfield thickness, maximum foveal thickness, foveal center point thickness, and the extent of the ellipsoidal (ISe) layer and ELM damage were assessed at the time of DME and after resolution of DME. Eyes having laser scars near the fovea were excluded. Final visual acuity was classified as good (Snellen>=20/40, logarithm of the minimum angle of resolution <=0.3) or impaired (Snellen <20/40, logarithm of the minimum angle of resolution >0.3) for the logistic regression analysis. Zero Inflated Poison Regression model was used to find the best predictors for post-treatment ELM damage. RESULTS: External limiting membrane and inner segment ellipsoidal band layers were disrupted in 16 eyes (27.2%) and 21 eyes (35.5%) at the final visit, respectively. Baseline ELM damage (p=0.001), baseline impaired vision (p= 0.013), and the most recent glycosylated hemoglobin level (p=0.018) were the best set of parameters for having impaired final visual acuity. Baseline vision, severity of diabetic retinopathy, absence of intravitreal injection, central subfield thickness, and history of extrafoveal macular laser (not within 1 mm of fovea) (p<0.001, for all parameters) were independent predictors for the final ELM damage. CONCLUSION: Outer retinal layers may be damaged even after complete resolution of DME, where inner segment ellipsoidal band layer damage appeared to be more common than ELM damage. Poorly controlled diabetic patients with damaged ELM and worse vision at the time of DME were more likely to have ELM damage and subsequent impaired vision after complete resolution of DME. PMID- 28092343 TI - NATURAL COURSE OF PATIENTS DISCONTINUING TREATMENT FOR AGE-RELATED MACULAR DEGENERATION AND FACTORS ASSOCIATED WITH VISUAL PROGNOSIS. AB - PURPOSE: To evaluate the 24-month natural course of visual changes in patients discontinuing treatment despite persistent or recurrent fluid and factors predictive of visual prognosis. METHODS: This retrospective, observational study included 35 patients (35 eyes) who initially received anti-vascular endothelial growth factor treatment for neovascular age-related macular degeneration (AMD), but discontinued treatment despite persistent or recurrent fluid. The best corrected visual acuity (BCVA) at treatment discontinuation was determined and compared with the 24-month BCVA, which was then compared between polypoidal choroidal vasculopathy and other neovascular age-related macular degeneration subtypes. Baseline characteristics predictive of visual outcome and the degree of visual change were also analyzed. RESULTS: The mean number of anti-vascular endothelial growth factor injections before treatment discontinuation was 4.0 +/- 1.6. The mean logarithm of minimal angle of resolution of BCVA at treatment discontinuation and that at 24 months were 1.02 +/- 0.20 (Snellen equivalents = 20/209) and 1.60 +/- 0.56 (20/796), respectively (P < 0.001). The 24-month BCVA was not different between polypoidal choroidal vasculopathy and other neovascular age-related macular degeneration subtypes (P = 0.803). The type of fluid (intraretinal fluid vs. no intraretinal fluid) was predictive of 24-month BCVA (P = 0.004) and the degree of changes in BCVA (P = 0.043). CONCLUSION: Marked deterioration in visual acuity was noted in patients discontinuing treatment, regardless of neovascular age-related macular degeneration subtypes. The presence of intraretinal fluid was associated with worse visual prognosis, suggesting that patients with intraretinal fluid should be strongly warned about their poor prognosis before they decide to discontinue treatment. PMID- 28092344 TI - CHORIOCAPILLARIS SIGNAL VOIDS IN MATERNALLY INHERITED DIABETES AND DEAFNESS AND IN PSEUDOXANTHOMA ELASTICUM. AB - PURPOSE: To evaluate the pattern of choriocapillaris signal voids in maternally inherited diabetes and deafness and in pseudoxanthoma elasticum in eyes before the development of any geographic atrophy. METHODS: The choriocapillaris under the central macula was imaged with the Optovue RTVue XR Avanti using a 10 MUm slab thickness. Automatic local thresholding of the resultant raw data extracted areas of absent flow signal, called signal voids, and these were counted and logarithmically binned. The signal void patterns were analyzed in four eyes of two patients with maternally inherited diabetes and deafness and four eyes of three patients with pseudoxanthoma elasticum. None of the patients had geographic atrophy. These data were compared with 55 eyes of 38 healthy control subjects and analyzed with generalized estimating equations. RESULTS: The choriocapillaris images in maternally inherited diabetes and deafness and pseudoxanthoma elasticum show that the model of signal voids followed a power law distribution, but with a slope and offset much lower than the normal control group, adjusted for age (P < 0.001). The eyes in the disease group were much more likely to have signal voids greater than 40,000 MUm. CONCLUSION: Before the development of any overt geographic atrophy, patients with maternally inherited diabetes and deafness and pseudoxanthoma elasticum show pronounced abnormalities of choriocapillaris flow. Current clinical measures of retinal pigment epithelial health only look for areas of cell death, as in geographic atrophy. It is not possible to determine from current imaging if the choriocapillaris loss precedes potential loss of function of the retinal pigment epithelium, such as secretion of vascular endothelial growth factor. PMID- 28092345 TI - Acute effects of a beverage containing bitter melon extract (CARELA) on postprandial glycemia among prediabetic adults. AB - BACKGROUND: Acute ingestion of bitter melon (BM) has been shown to suppress the postprandial glycemic response in diabetics, but its impact on glucose regulation among individuals with impaired glucose tolerance is unclear. Moreover, one's glucose tolerance level may influence the effectiveness of BM. This study aimed to examine the acute effects of a beverage containing BM extract on blood glucose regulation during an oral glucose tolerance test (OGTT) among prediabetics. METHODS: Ten prediabetic adults completed two OGTTs-glucose only (D2) and glucose+BM (D3). Responders were identified as subjects whose area under the glucose curve (AUCglu) during D3 was lower than D2. To compare the acute effects of the beverage among individuals with varying glucose tolerance levels, subjects were grouped by their glucose response pattern-Fastpeak (peak glucose (Glupeak) at 30 min postglucose (30P)) and Slowpeak (Glupeak after 30P). RESULTS: During D3, responders (n=5) experienced a 13.2% reduction in AUCglu (95% confidence interval (CI): -18.1% to -8.3%), 12.2% reduction in mean glucose (95% CI: -17.3% to -7.0%) and 10.6% reduction in Glupeak (95% CI: -17.5% to -3.7%); plasma glucose was reduced by 9.1% at 30P (95% CI: -15.6% to -2.6%), -24.0% at 60P (95% CI: -36.8% to -11.2%) and -20.0% at 90P (95% CI: -35.8% to -4.2%) during D3. No between-trial differences were noted for Fastpeak or Slowpeak. CONCLUSIONS: Acute ingestion of BM prior to the second OGTT (D3) led to a reduced postprandial glucose response in 50% of the subjects but did not affect the insulin response. Furthermore, the effectiveness of the beverage was seemingly uninfluenced by the subjects' glucose tolerance level. Although BM has shown to aid blood glucose management in diabetics, it remains uncertain why only a portion of subjects responded positively to the BM extract in the current study. PMID- 28092346 TI - Differential hypothalamic leptin sensitivity in obese rat offspring exposed to maternal and postnatal intake of chocolate and soft drink. AB - BACKGROUND/OBJECTIVE: Intake of high-energy foods and maternal nutrient overload increases the risk of metabolic diseases in the progeny such as obesity and diabetes. We hypothesized that maternal and postnatal intake of chocolate and soft drink will affect leptin sensitivity and hypothalamic astrocyte morphology in adult rat offspring. METHODS: Pregnant Sprague-Dawley rats were fed ad libitum chow diet only (C) or with chocolate and high sucrose soft drink supplement (S). At birth, litter size was adjusted into 10 male offspring per mother. After weaning, offspring from both dietary groups were assigned to either S or C diet, giving four groups until the end of the experiment at 26 weeks of age. RESULTS: As expected, adult offspring fed the S diet post weaning became obese (body weight: P<0.01, %body fat per kg: P<0.001) and this was due to the reduced energy expenditure (P<0.05) and hypothalamic astrogliosis (P<0.001) irrespective of maternal diet. Interesting, offspring born to S-diet-fed mothers and fed the S diet throughout postnatal life became obese despite lower energy intake than controls (P<0.05). These SS offspring showed increased feed efficiency (P<0.001) and reduced fasting pSTAT3 activity (P<0.05) in arcuate nucleus (ARC) compared with other groups. The findings indicated that the combination of the maternal and postnatal S-diet exposure induced persistent changes in leptin signalling, hence affecting energy balance. Thus, appetite regulation was more sensitive to the effect of leptin than energy expenditure, suggesting differential programming of leptin sensitivity in ARC in SS offspring. Effects of the maternal S diet were normalized when offspring were fed a chow diet after weaning. CONCLUSIONS: Maternal intake of chocolate and soft drink had long-term consequences for the metabolic phenotype in the offspring if they continued on the S diet in postnatal life. These offspring displayed obesity despite lowered energy intake associated with alterations in hypothalamic leptin signalling. PMID- 28092347 TI - Haploidentical transplantation with post-infusion cyclophosphamide in advanced Hodgkin lymphoma. AB - We investigated the use of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in the treatment of advanced Hodgkin lymphoma (HL). Sixty-two consecutive HL patients underwent haplo-HSCT. Unmanipulated stem cells and post transplant cyclophosphamide were given to all patients as GVHD prophylaxis. At 100 days, the cumulative incidence of grades 2-3 and grades 3-4 acute GVHD was 23% and 4%, respectively. The chronic GVHD (cGVHD) cumulative incidence was 16%, with one patient experiencing severe cGVHD. The 3-year OS, PFS, relapse rates and 1-year non-relapse mortality (NRM) were 63%, 59%, 21% and 20%, respectively. Uncontrolled disease status and high hematopoietic cell transplantation comorbidity index (HCT-CI) were associated with lower OS, whereas PBSC was an independent protective factor. Uncontrolled disease and HCT-CI >2 was predictive for NRM. Finally, disease status other than CR was predictive of relapse. In conclusion, haplo-HSCT is a valid treatment in advanced HL, offering excellent rates of survival and acceptable toxicities. PMID- 28092348 TI - Major molecular response prior to allogeneic hematopoietic stem cell transplantation predicts better outcome in adult Philadelphia-positive acute lymphoblastic leukemia in first remission. PMID- 28092349 TI - Recipient/donor HLA and CMV matching in recipients of T-cell-depleted unrelated donor haematopoietic cell transplants. AB - Improving haematopoietic cell transplantation outcomes by selection of an HLA matched unrelated donor is best practice; however, donor selection by secondary characteristics is controversial. We studied 1271 recipients with haematological malignancies who underwent T-cell-depleted allografts and had complete data on HLA-matching status for six loci (HLA-A, -B, -C, -DRB1, -DQB1, -DPB1) and clinical outcome data. Five-year overall survival was 40.6%. HLA mismatching (at HLA-A, -B, -C, -DRB1, -DQB1) relative risk (RR) 1.22, 95% confidence interval (CI) 1.2-1.5, P=0.033 for 1 mismatch and RR 1.46, 95% CI 1.1-1.9, P=0.009 for >1 mismatch) and CMV mismatching (RR 1.37, 95% CI 1.2-1.6, P<0.001) were significantly associated with inferior survival. Donors aged <30 years showed a trend towards better survival. The multivariate model for mortality, combining CMV and HLA-match status, found an RR of 1.36 (95% CI 1.1-1.7, P=0.003) for HLA matched/CMV mismatched, an RR of 1.22 (95% CI 0.99-1.5, P=0.062) for HLA mismatched/CMV matched and an RR of 1.81 (95% CI 1.4-2.3, P=<0.001) for HLA/ CMV mismatched, compared with the HLA/CMV-matched recipients. These data suggest that HLA and CMV matching status should be considered when selecting unrelated donors and that CMV matching may abrogate the effect of an HLA mismatch. PMID- 28092350 TI - Long term renal survival in patients undergoing T-Cell depleted versus conventional hematopoietic stem cell transplants. AB - Calcineurin inhibitor (CNI)-sparing T-cell depleted (TCD) hematopoietic stem cell transplants (HSCTs) are presumed to be less nephrotoxic than conventional HSCTs. We evaluated incidence and risk factors for kidney failure and chronic kidney disease (CKD) in 231 TCD and 212 conventional HSCT recipients. Kidney failure required a median glomerular filtration rate (GFR) <60 ml/min/1.73 m2 for ?100 days anytime after 180-days post-HSCT. Two-year cumulative incidence (CI) of kidney failure was 42% in the conventional versus 31% in the TCD group (P=0.005). TCD, age, acute kidney injury and number of toxic CNI levels all impacted on kidney failure, which was associated with increased all-cause mortality (hazard ratio 2.86 (95% CI: 1.88-4.36), P<0.001). Renal recovery occurred in 28% of kidney failure patients whereas the remaining patients were defined to have CKD. In those with baseline GFR>60 ml/min/1.73 m2, only exposure to nephrotoxic medications was associated with CKD (P=0.033). In the myeloablative-conditioning subgroup only total body irradiation was associated with CKD (P=0.013). Of all patients, five (1.13%) required dialysis. These results confirm an impact of TCD on kidney failure but not CKD for which other risk factors such as radiation or nephrotoxic drug exposure may have a role. PMID- 28092351 TI - Pulmonary complications post hematopoietic stem cell transplant in dyskeratosis congenita: analysis of oxidative stress in lung fibroblasts. PMID- 28092352 TI - Professor David Grimwade (1962-2016). PMID- 28092353 TI - Non-myeloablative conditioning for second hematopoietic cell transplantation for graft failure in patients with non-malignant disorders: a prospective study and review of the literature. AB - Allogeneic hematopoietic cell transplantation (HCT) effectively treats several non-malignant disorders such as selected lysosomal disorders, cerebral adrenoleukodystrophy and hemoglobinopathies. However, rates of graft failure (GF) in non-malignant populations exceed those of patients with malignant indications for HCT. Salvage conditioning regimens and outcomes for second HCT for GF vary immensely in the literature. We report 17 consecutive pediatric patients with non malignant disorders who underwent a second allogenic HCT for GF using a non myeloablative, low-dose busulfan-based regimen. Graft sources for the second transplant included umbilical cord blood, unrelated bone marrow and unrelated PBSCs. Median age at time of second HCT was 6.6 years (1.1-14.6 years). Fourteen of seventeen patients (82%) achieved engraftment, with a 3-year overall survival of 82% (95% CI, 54-94%). Day 100 transplant-related mortality was 12% (95% CI, 0 27%). CMV and adenovirus reactivation occurred in 30% and fungal infections in 18%. The incidence of grade II-IV acute GvHD disease was 35% (95% CI, 13-58%) with only 6% grade III-IV (95% CI, 0-17%). In summary, we illustrate excellent overall survival and acceptable toxicity using a non-myeloablative conditioning regimen for second HCT as salvage therapy for first GF in patients with non malignant conditions. PMID- 28092354 TI - Use of defibrotide to treat transplant-associated thrombotic microangiopathy: a retrospective study of the Paediatric Diseases and Inborn Errors Working Parties of the European Society of Blood and Marrow Transplantation. PMID- 28092355 TI - Highly favorable outcome in BRCA-mutated metastatic breast cancer patients receiving high-dose chemotherapy and autologous hematopoietic stem cell transplantation. PMID- 28092356 TI - Treatment pathways and resource use associated with recurrent Hodgkin lymphoma after autologous stem cell transplantation. PMID- 28092357 TI - Risk of sinusoidal obstruction syndrome in allogeneic stem cell transplantation after prior gemtuzumab ozogamicin treatment: a retrospective study from the Acute Leukemia Working Party of the EBMT. AB - Gemtuzumab ozogamicin (GO) may increase the risk of sinusoidal obstruction syndrome (SOS) when used prior to allogeneic stem cell transplantation (HSCT). We assessed SOS incidence and outcomes after HSCT of 146 adults, with a median age of 50 years, previously receiving GO. SOS prophylaxis was used in 69 patients (heparin n=57, ursodeoxycholic acid n=8, defibrotide n=4). Cumulative incidence (CI) of SOS was 8% (n=11), with death in 3 patients. Median interval between last GO dose and HSCT was 130 days. Overall survival (OS) and SOS incidence did not differ for patients receiving GO ?3.5 months before HSCT and the others. CI of acute and chronic GVHD was 31% and 25%, respectively. Probability of OS and leukemia-free survival (LFS) at 5 years was 40% and 37%, respectively. Relapse incidence and non-relapse mortality were 42% and 21%, respectively. In multivariate analysis, active disease at HSCT was associated with relapse and worse LFS and OS (P<0.03). Liver abnormalities before HSCT correlated with worse OS (P<0.03). Use of low-dose GO prior to HSCT is associated with an acceptable SOS incidence. Prospective studies investigating the role and the utility of SOS prophylaxis are warranted. PMID- 28092358 TI - Recurrent RNA motifs as scaffolds for genetically encodable small-molecule biosensors. AB - Allosteric RNA devices are increasingly being viewed as important tools capable of monitoring enzyme evolution, optimizing engineered metabolic pathways, facilitating gene discovery and regulators of nucleic acid-based therapeutics. A key bottleneck in the development of these platforms is the availability of small molecule-binding RNA aptamers that robustly function in the cellular environment. Although aptamers can be raised against nearly any desired target through in vitro selection, many cannot easily be integrated into devices or do not reliably function in a cellular context. Here, we describe a new approach using secondary- and tertiary-structural scaffolds derived from biologically active riboswitches and small ribozymes. When applied to the neurotransmitter precursors 5 hydroxytryptophan and 3,4-dihydroxyphenylalanine, this approach yielded easily identifiable and characterizable aptamers predisposed for coupling to readout domains to allow engineering of nucleic acid-sensory devices that function in vitro and in the cellular context. PMID- 28092359 TI - Lysine relay mechanism coordinates intermediate transfer in vitamin B6 biosynthesis. AB - Substrate channeling has emerged as a common mechanism for enzymatic intermediate transfer. A conspicuous gap in knowledge concerns the use of covalent lysine imines in the transfer of carbonyl-group-containing intermediates, despite their wideuse in enzymatic catalysis. Here we show how imine chemistry operates in the transfer of covalent intermediates in pyridoxal 5'-phosphate biosynthesis by the Arabidopsis thaliana enzyme Pdx1. An initial ribose 5-phosphate lysine imine is converted to the chromophoric I320 intermediate, simultaneously bound to two lysine residues and partially vacating the active site, which creates space for glyceraldehyde 3-phosphate to bind. Crystal structures show how substrate binding, catalysis and shuttling are coupled to conformational changes around strand beta6 of the Pdx1 (betaalpha)8-barrel. The dual-specificity active site and imine relay mechanism for migration of carbonyl intermediates provide elegant solutions to the challenge of coordinating a complex sequence of reactions that follow a path of over 20 A between substrate- and product-binding sites. PMID- 28092360 TI - Chemical proteomics reveals ADP-ribosylation of small GTPases during oxidative stress. AB - ADP-ribosylation is a post-translational modification that is known to be involved in cellular homeostasis and stress but has been challenging to analyze biochemically. To facilitate the detection of ADP-ribosylated proteins, we show that an alkyne-adenosine analog, N6-propargyl adenosine (N6pA), is metabolically incorporated in mammalian cells and enables fluorescence detection and proteomic analysis of ADP-ribosylated proteins. Notably, our analysis of N6pA-labeled proteins that are upregulated by oxidative stress revealed differential ADP ribosylation of small GTPases. We discovered that oxidative stress induced ADP ribosylation of Hras on Cys181 and Cys184 in the C-terminal hypervariable region, which are normally S-fatty-acylated. Downstream Hras signaling is impaired by ADP ribosylation during oxidative stress, but is rescued by ADP-ribosyltransferase inhibitors. Our study demonstrates that ADP-ribosylation of small GTPases not only is mediated by bacterial toxins but is endogenously regulated in mammalian cells. N6pA provides a useful tool to characterize ADP-ribosylated proteins and their regulatory mechanisms in cells. PMID- 28092361 TI - Designed cell consortia as fragrance-programmable analog-to-digital converters. AB - Synthetic biology advances the rational engineering of mammalian cells to achieve cell-based therapy goals. Synthetic gene networks have nearly reached the complexity of digital electronic circuits and enable single cells to perform programmable arithmetic calculations or to provide dynamic remote control of transgenes through electromagnetic waves. We designed a synthetic multilayered gaseous-fragrance-programmable analog-to-digital converter (ADC) allowing for remote control of digital gene expression with 2-bit AND-, OR- and NOR-gate logic in synchronized cell consortia. The ADC consists of multiple sampling-and quantization modules sensing analog gaseous fragrance inputs; a gas-to-liquid transducer converting fragrance intensity into diffusible cell-to-cell signaling compounds; a digitization unit with a genetic amplifier circuit to improve the signal-to-noise ratio; and recombinase-based digital expression switches enabling 2-bit processing of logic gates. Synthetic ADCs that can remotely control cellular activities with digital precision may enable the development of novel biosensors and may provide bioelectronic interfaces synchronizing analog metabolic pathways with digital electronics. PMID- 28092362 TI - The role of endothelial HIF-1 alphain the response to sublethal hypoxia in C57BL/6 mouse pups. AB - Chronic sublethal hypoxia, a complication of premature birth, is associated with cognitive and motor handicaps. Responsiveness to and recovery from this hypoxic environment is dependent on induction of HIF-1 alpha in the cells affected. Microvascular endothelial-glial and microvascular endothelial-neuronal precursor interactions have been found to be dynamic and reciprocal, involving autocrine and paracrine signaling, with response and recovery correlated with baseline levels and levels of induction of HIF-1 alpha.To ascertain the roles of endothelial HIF-1 alpha in the responses of brain microvascular endothelial cells (EC) and neuronal precursors to hypoxia, we examined the effects of the presence and absence of endothelial HIF-1 alpha expression in culture and in cells comprising the subventricular zone (SVZ) and dentate gyrus under normoxic and hypoxic conditions. We used C57BL/6 WT and EC HIF-1 alpha -deficient mice and brain microvascular ECs isolated from these mice in western blots, immunofluorescence, and behavioral studies to examine the roles of EC HIF-1 alpha behaviors of endothelial and neuronal precursor cells (NPCs) in SVZ and hippocampal tissues under normoxic and hypoxic conditions and behaviors of these mice in open field activity tests. Analyses of ECs and SVZ and dentate gyrus tissues revealed effects of the absence of endothelial HIF-1 alpha on proliferation and apoptosis as well as open field activity, with both ECs and neuronal cells exhibiting decreased proliferation, increased apoptosis, and pups exhibiting gender-specific differences in open field activities. Our studies demonstrate the autocrine and paracrine effects of EC HIF-1 alpha-modulating proliferative and apoptotic behaviors of EC and NPC in neurogenic regions of the brain and gender-specific behaviors in normoxic and hypoxic settings. PMID- 28092363 TI - Mouse models of UV-induced melanoma: genetics, pathology, and clinical relevance. AB - Melanocytes, a neural crest cell derivative, produce pigment to protect keratinocytes from ultraviolet radiation (UVR). Although melanocytic lesions such as nevi and cutaneous malignant melanomas are known to be associated with sun exposure, the role of UVR in oncogenesis is complex and has yet to be clearly elucidated. UVR appears to have a direct mutational role in inducing or promoting melanoma formation as well as an indirect role through microenvironmental changes. Recent advances in the modeling of human melanoma in animals have built platforms upon which prospective studies can begin to investigate these questions. This review will focus exclusively on genetically engineered mouse models of UVR-induced melanoma. The role that UVR has in mouse models depends on multiple factors, including the waveband, timing, and dose of UVR, as well as the nature of the oncogenic agent(s) driving melanomagenesis in the model. Work in the field has examined the role of neonatal and adult UVR, interactions between UVR and common melanoma oncogenes, the role of sunscreen in preventing melanoma, and the effect of UVR on immune function within the skin. Here we describe relevant mouse models and discuss how these models can best be translated to the study of human skin and cutaneous melanoma. PMID- 28092364 TI - Proof of the quantitative potential of immunofluorescence by mass spectrometry. AB - Protein expression in formalin-fixed, paraffin-embedded patient tissue is routinely measured by Immunohistochemistry (IHC). However, IHC has been shown to be subject to variability in sensitivity, specificity and reproducibility, and is generally, at best, considered semi-quantitative. Mass spectrometry (MS) is considered by many to be the criterion standard for protein measurement, offering high sensitivity, specificity, and objective molecular quantification. Here, we seek to show that quantitative immunofluorescence (QIF) with standardization can achieve quantitative results comparable to MS. Epidermal growth factor receptor (EGFR) was measured by quantitative immunofluorescence in 15 cell lines with a wide range of EGFR expression, using different primary antibody concentrations, including the optimal signal-to-noise concentration after quantitative titration. QIF target measurement was then compared to the absolute EGFR concentration measured by Liquid Tissue-selected reaction monitoring mass spectrometry. The best agreement between the two assays was found when the EGFR primary antibody was used at the optimal signal-to-noise concentration, revealing a strong linear regression (R2=0.88). This demonstrates that quantitative optimization of titration by calculation of signal-to-noise ratio allows QIF to be standardized to MS and can therefore be used to assess absolute protein concentration in a linear and reproducible manner. PMID- 28092365 TI - Cancer cell chemokines direct chemotaxis of activated stellate cells in pancreatic ductal adenocarcinoma. AB - The mechanisms by which the extreme desmoplasia observed in pancreatic tumors develops remain unknown and its role in pancreatic cancer progression is unsettled. Chemokines have a key role in the recruitment of a wide variety of cell types in health and disease. Transcript and protein profile analyses of human and murine cell lines and human tissue specimens revealed a consistent elevation in the receptors CCR10 and CXCR6, as well as their respective ligands CCL28 and CXCL16. Elevated ligand expression was restricted to tumor cells, whereas receptors were in both epithelial and stromal cells. Consistent with its regulation by inflammatory cytokines, CCL28 and CCR10, but not CXCL16 or CXCR6, were upregulated in human pancreatitis tissues. Cytokine stimulation of pancreatic cancer cells increased CCL28 secretion in epithelial tumor cells but not an immortalized activated human pancreatic stellate cell line (HPSC). Stellate cells exhibited dose- and receptor-dependent chemotaxis in response to CCL28. This functional response was not linked to changes in activation status as CCL28 had little impact on alpha smooth muscle actin levels or extracellular matrix deposition or alignment. Co-culture assays revealed CCL28-dependent chemotaxis of HPSC toward cancer but not normal pancreatic epithelial cells, consistent with stromal cells being a functional target for the epithelial derived chemokine. These data together implicate the chemokine CCL28 in the inflammation-mediated recruitment of cancer-associated stellate cells into the pancreatic cancer parenchyma. PMID- 28092366 TI - Malignant melanoma of sun-protected sites: a review of clinical, histological, and molecular features. AB - In most cases of cutaneous melanoma, ultraviolet (UV) radiation is recognized as a prominent risk factor. Less is known regarding the mechanisms of mutagenesis for melanoma arising in sun-protected sites, such as acral and mucosal melanoma. Acral and mucosal melanoma share many common features, including a late age of onset, a broad radial growth phase with prominent lentiginous growth, the presence of field cancerization cells, and, in most cases, lack of a precursor nevus. In addition to early chromosomal instability, many of the same genes are also involved in these two distinct melanoma subtypes. To better understand non UV-mediated pathogenesis in melanoma, we conducted a joint literature review of clinical, histological, and molecular features in acral and mucosal melanoma. We also reviewed the current literature regarding aberrations in KIT, PDGFRA, TERT, and other commonly involved genes. By comparing common features of these two subtypes, we suggest potential mechanisms underlying acral and/or mucosal melanoma and offer direction for future investigations. PMID- 28092367 TI - Molecular architecture and dynamics of ASH1 mRNA recognition by its mRNA transport complex. AB - mRNA localization is an essential mechanism of gene regulation and is required for processes such as stem-cell division, embryogenesis and neuronal plasticity. It is not known which features in the cis-acting mRNA localization elements (LEs) are specifically recognized by motor-containing transport complexes. To the best of our knowledge, no high-resolution structure is available for any LE in complex with its cognate protein complex. Using X-ray crystallography and complementary techniques, we carried out a detailed assessment of an LE of the ASH1 mRNA from yeast, its complex with its shuttling RNA-binding protein She2p, and its highly specific, cytoplasmic complex with She3p. Although the RNA alone formed a flexible stem loop, She2p binding induced marked conformational changes. However, only joining by the unstructured She3p resulted in specific RNA recognition. The notable RNA rearrangements and joint action of a globular and an unfolded RNA binding protein offer unprecedented insights into the step-wise maturation of an mRNA-transport complex. PMID- 28092368 TI - Molecular insights into lipid-assisted Ca2+ regulation of the TRP channel Polycystin-2. AB - Polycystin-2 (PC2), a calcium-activated cation TRP channel, is involved in diverse Ca2+ signaling pathways. Malfunctioning Ca2+ regulation in PC2 causes autosomal-dominant polycystic kidney disease. Here we report two cryo-EM structures of distinct channel states of full-length human PC2 in complex with lipids and cations. The structures reveal conformational differences in the selectivity filter and in the large exoplasmic domain (TOP domain), which displays differing N-glycosylation. The more open structure has one cation bound below the selectivity filter (single-ion mode, PC2SI), whereas multiple cations are bound along the translocation pathway in the second structure (multi-ion mode, PC2MI). Ca2+ binding at the entrance of the selectivity filter suggests Ca2+ blockage in PC2MI, and we observed density for the Ca2+-sensing C-terminal EF hand in the unblocked PC2SI state. The states show altered interactions of lipids with the pore loop and TOP domain, thus reflecting the functional diversity of PC2 at different locations, owing to different membrane compositions. PMID- 28092369 TI - Context-dependent role for chromatin remodeling component PBRM1/BAF180 in clear cell renal cell carcinoma. AB - A subset of clear cell renal cell carcinoma (ccRCC) tumors exhibit a HIF1A gene mutation, yielding two ccRCC tumor types, H1H2 type expressing both HIF1alpha and HIF2alpha, and H2 type expressing HIF2alpha, but not functional HIF1alpha protein. However, it is unclear how the H1H2 type ccRCC tumors escape HIF1's tumor-suppressive activity. The polybromo-1 (PBRM1) gene coding for the BAF180 protein, a component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, is inactivated in 40% ccRCCs, the function and mechanism of BAF180 mutation is unknown. Our previous study indicates that BAF180-containing SWI/SNF chromatin remodeling complex is a co-activator for transcription factor HIF to induce HIF target genes. Thus, our questions are if BAF180 is involved in HIF-mediated hypoxia response and if PBRM1/BAF180 mutation has any association with the HIF1A retention in H1H2 type ccRCC. We report here that BAF180 is mutated in H1H2 ccRCC cell lines and tumors, and BAF180 re-expression in H1H2 ccRCC cell lines reduced cell proliferation/survival, indicating that BAF180 has tumor-suppressive role in these cells. However, BAF180 is expressed in HIF1 deficient H2 ccRCC cell lines and tumors, and BAF180 knockdown in H2 type ccRCC cell lines reduced cell proliferation/survival, indicating that BAF180 has tumor promoting activity in these cells. In addition, our data show that BAF180 functions as co-activator for HIF1- and HIF2-mediated transcriptional response, and BAF180's tumor-suppressive and -promoting activity in ccRCC cell lines depends on co-expression of HIF1 and HIF2, respectively. Thus, our studies reveal that BAF180 function in ccRCC is context dependent, and that mutation of PBRM1/BAF180 serves as an alternative strategy for ccRCC tumors to reduce HIF1 tumor-suppressive activity in H1H2 ccRCC tumors. Our studies define distinct functional subgroups of ccRCCs based on expression of BAF180, and suggest that BAF180 inhibition may be a novel therapeutic target for patients with H2, but not H1H2, ccRCC tumors. PMID- 28092370 TI - API5 confers cancer stem cell-like properties through the FGF2-NANOG axis. AB - Immune selection drives the evolution of tumor cells toward an immune-resistant and cancer stem cell (CSC)-like phenotype. We reported that apoptosis inhibitor-5 (API5) acts as an immune escape factor, which has a significant role in controlling immune resistance to antigen-specific T cells, but its functional association with CSC-like properties remains largely unknown. In this study, we demonstrated for the first time that API5 confers CSC-like properties, including NANOG expression, the frequency of CD44-positive cells and sphere-forming capacity. Critically, these CSC-like properties mediated by API5 are dependent on FGFR1 signaling, which is triggered by E2F1-dependent FGF2 expression. Furthermore, we uncovered the FGF2-NANOG molecular axis as a downstream component of API5 signaling that is conserved in cervical cancer patients. Finally, we found that the blockade of FGFR signaling is an effective strategy to control API5high human cancer. Thus, our findings reveal a crucial role of API5 in linking immune resistance and CSC-like properties, and provide the rationale for its therapeutic application for the treatment of API5+ refractory tumors. PMID- 28092371 TI - Neuroimmune regulation during intestinal development and homeostasis. AB - Interactions between the nervous system and immune system are required for organ function and homeostasis. Evidence suggests that enteric neurons and intestinal immune cells share common regulatory mechanisms and can coordinate their responses to developmental challenges and environmental aggressions. These discoveries shed light on the physiology of system interactions and open novel perspectives for therapy designs that target underappreciated neurological immunological commonalities. Here we highlight findings that address the importance of neuroimmune cell units (NICUs) in intestinal development, homeostasis and disease. PMID- 28092372 TI - Direct control of regulatory T cells by keratinocytes. AB - Environmental challenges to epithelial cells trigger gene expression changes that elicit context-appropriate immune responses. We found that the chromatin remodeler Mi-2beta controls epidermal homeostasis by regulating the genes involved in keratinocyte and immune-cell activation to maintain an inactive state. Mi-2beta depletion resulted in rapid deployment of both a pro-inflammatory and an immunosuppressive response in the skin. A key target of Mi-2beta in keratinocytes is the pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP). Loss of TSLP receptor (TSLPR) signaling specifically in regulatory T (Treg) cells prevented their activation and permitted rapid progression from a skin pro-inflammatory response to a lethal systemic condition. Thus, in addition to their well-characterized role in pro-inflammatory responses, keratinocytes also directly support immune-suppressive responses that are critical for re establishing organismal homeostasis. PMID- 28092373 TI - Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression. AB - The aggregation of hypertrophic macrophages constitutes the basis of all granulomatous diseases, such as tuberculosis or sarcoidosis, and is decisive for disease pathogenesis. However, macrophage-intrinsic pathways driving granuloma initiation and maintenance remain elusive. We found that activation of the metabolic checkpoint kinase mTORC1 in macrophages by deletion of the gene encoding tuberous sclerosis 2 (Tsc2) was sufficient to induce hypertrophy and proliferation, resulting in excessive granuloma formation in vivo. TSC2-deficient macrophages formed mTORC1-dependent granulomatous structures in vitro and showed constitutive proliferation that was mediated by the neo-expression of cyclin dependent kinase 4 (CDK4). Moreover, mTORC1 promoted metabolic reprogramming via CDK4 toward increased glycolysis while simultaneously inhibiting NF-kappaB signaling and apoptosis. Inhibition of mTORC1 induced apoptosis and completely resolved granulomas in myeloid TSC2-deficient mice. In human sarcoidosis patients, mTORC1 activation, macrophage proliferation and glycolysis were identified as hallmarks that correlated with clinical disease progression. Collectively, TSC2 maintains macrophage quiescence and prevents mTORC1-dependent granulomatous disease with clinical implications for sarcoidosis. PMID- 28092374 TI - The movers and shapers in immune privilege of the CNS. AB - Discoveries leading to an improved understanding of immune surveillance of the central nervous system (CNS) have repeatedly provoked dismissal of the existence of immune privilege of the CNS. Recent rediscoveries of lymphatic vessels within the dura mater surrounding the brain, made possible by modern live-cell imaging technologies, have revived this discussion. This review emphasizes the fact that understanding immune privilege of the CNS requires intimate knowledge of its unique anatomy. Endothelial, epithelial and glial brain barriers establish compartments in the CNS that differ strikingly with regard to their accessibility to immune-cell subsets. There is a unique system of lymphatic drainage from the CNS to the peripheral lymph nodes. We summarize current knowledge on the cellular and molecular mechanisms involved in immune-cell trafficking and lymphatic drainage from the CNS, and we take into account differences in rodent and human CNS anatomy. PMID- 28092375 TI - Postprandial macrophage-derived IL-1beta stimulates insulin, and both synergistically promote glucose disposal and inflammation. AB - The deleterious effect of chronic activation of the IL-1beta system on type 2 diabetes and other metabolic diseases is well documented. However, a possible physiological role for IL-1beta in glucose metabolism has remained unexplored. Here we found that feeding induced a physiological increase in the number of peritoneal macrophages that secreted IL-1beta, in a glucose-dependent manner. Subsequently, IL-1beta contributed to the postprandial stimulation of insulin secretion. Accordingly, lack of endogenous IL-1beta signaling in mice during refeeding and obesity diminished the concentration of insulin in plasma. IL-1beta and insulin increased the uptake of glucose into macrophages, and insulin reinforced a pro-inflammatory pattern via the insulin receptor, glucose metabolism, production of reactive oxygen species, and secretion of IL-1beta mediated by the NLRP3 inflammasome. Postprandial inflammation might be limited by normalization of glycemia, since it was prevented by inhibition of the sodium glucose cotransporter SGLT2. Our findings identify a physiological role for IL 1beta and insulin in the regulation of both metabolism and immunity. PMID- 28092377 TI - Neuroimmune communication. PMID- 28092378 TI - Opto-valleytronic imaging of atomically thin semiconductors. AB - Transition metal dichalcogenide semiconductors represent elementary components of layered heterostructures for emergent technologies beyond conventional optoelectronics. In their monolayer form they host electrons with quantized circular motion and associated valley polarization and valley coherence as key elements of opto-valleytronic functionality. Here, we introduce two-dimensional polarimetry as means of direct imaging of the valley pseudospin degree of freedom in monolayer transition metal dichalcogenides. Using MoS2 as a representative material with valley-selective optical transitions, we establish quantitative image analysis for polarimetric maps of extended crystals, and identify valley polarization and valley coherence as sensitive probes of crystalline disorder. Moreover, we find site-dependent thermal and non-thermal regimes of valley polarized excitons in perpendicular magnetic fields. Finally, we demonstrate the potential of wide-field polarimetry for rapid inspection of opto-valleytronic devices based on atomically thin semiconductors and heterostructures. PMID- 28092376 TI - Infectious immunity in the central nervous system and brain function. AB - Inflammation is emerging as a critical mechanism underlying neurological disorders of various etiologies, yet its role in altering brain function as a consequence of neuroinfectious disease remains unclear. Although acute alterations in mental status due to inflammation are a hallmark of central nervous system (CNS) infections with neurotropic pathogens, post-infectious neurologic dysfunction has traditionally been attributed to irreversible damage caused by the pathogens themselves. More recently, studies indicate that pathogen eradication within the CNS may require immune responses that interfere with neural cell function and communication without affecting their survival. In this Review we explore inflammatory processes underlying neurological impairments caused by CNS infection and discuss their potential links to established mechanisms of psychiatric and neurodegenerative diseases. PMID- 28092379 TI - Structure, fragmentation patterns, and magnetic properties of small nickel oxide clusters. AB - We report a comprehensive theoretical study of the structural and electronic properties of neutral and charged nickel oxide clusters, NinOm0/+/- (n = 3-8 and m = 1-10), in the context of recent experiments of photodissociation and Ion Mobility Mass Spectrometry. By means of density functional theory calculations in the generalized gradient approximation for exchange and correlation, we determined the putative ground states as well as the low-energy structural- and spin-isomers which were then used to explore the favorable fragmentation channels of the nickel oxide cationic clusters, and the resulting most abundant products, in good qualitative agreement with photodissociation measurements. Apart from stoichiometries different from those of their nickel oxide macroscopic counterparts, we found a tendency to form compact Ni subclusters, with reentrance of low-coordinated structures close to the equiatomic Ni-O concentration, taking the form of alternating Ni-O rings in the smaller sizes, in good qualitative agreement with Ion Mobility Mass Spectrometry measurements. This structural pattern is manifested in a drop of the total spin magnetic moment close to the equiatomic concentration due to the formation of antiparallel magnetic couplings. Although antiparallel couplings are found to a more or less extent in most clusters, especially in the oxygen rich phase, we identified certain clusters of special interest in the context of magnetic grains because of their large total magnetic moment and abundance. There are even some nickel oxide clusters with a higher total moment than their pure Ni counterparts, due to parallel magnetic couplings and the contribution of the oxygen atoms to the total moment. PMID- 28092380 TI - Chromatin immunoprecipitation in microfluidic droplets: towards fast and cheap analyses. AB - Genetic organization is governed by the interaction of DNA with histone proteins, and differential modifications of these proteins is a fundamental mechanism of gene regulation. Histone modifications are primarily studied through chromatin immunoprecipitation (ChIP) assays, however conventional ChIP procedures are time consuming, laborious and require a large number of cells. Here we report for the first time the development of ChIP in droplets based on a microfluidic platform combining nanoliter droplets, magnetic beads (MB) and magnetic tweezers (MT). The droplet approach enabled compartmentalization and improved mixing, while reducing the consumption of samples and reagents in an integrated workflow. Anti-histone antibodies grafted to MB were used as a solid support to capture and transfer the target chromatin from droplets to droplets in order to perform chromatin immunoprecipitation, washing, elution and purification of DNA. We designed a new ChIP protocol to investigate four different types of modified histones with known roles in gene activation or repression. We evaluated the performances of this new ChIP in droplet assay in comparison with conventional methods. The proposed technology dramatically reduces analytical time from a few days to 7 hours, simplifies the ChIP protocol and decreases the number of cells required by 100 fold while maintaining a high degree of sensitivity and specificity. Therefore this droplet-based ChIP assay represents a new, highly advantageous and convenient approach to epigenetic analyses. PMID- 28092382 TI - A vascularized and perfused organ-on-a-chip platform for large-scale drug screening applications. AB - There is a growing awareness that complex 3-dimensional (3D) organs are not well represented by monolayers of a single cell type - the standard format for many drug screens. To address this deficiency, and with the goal of improving screens so that drugs with good efficacy and low toxicity can be identified, microphysiological systems (MPS) are being developed that better capture the complexity of in vivo physiology. We have previously described an organ-on-a-chip platform that incorporates perfused microvessels, such that survival of the surrounding tissue is entirely dependent on delivery of nutrients through the vessels. Here we describe an arrayed version of the platform that incorporates multiple vascularized micro-organs (VMOs) on a 96-well plate. Each VMO is independently-addressable and flow through the micro-organ is driven by hydrostatic pressure. The platform is easy to use, requires no external pumps or valves, and is highly reproducible. As a proof-of-concept we have created arrayed vascularized micro tumors (VMTs) and used these in a blinded screen to assay a small library of compounds, including FDA-approved anti-cancer drugs, and successfully identified both anti-angiogenic and anti-tumor drugs. This 3D platform is suitable for efficacy/toxicity screening against multiple tissues in a more physiological environment than previously possible. PMID- 28092383 TI - Computational study of the interplay between intermolecular interactions and CO2 orientations in type I hydrates. AB - Carbon dioxide (CO2) molecules show a rich orientation landscape when they are enclathrated in type I hydrates. Previous studies have described experimentally their preferential orientations, and some theoretical works have explained, but only partially, these experimental results. In the present paper, we use classical molecular dynamics and electronic density functional theory to advance in the theoretical description of CO2 orientations within type I hydrates. Our results are fully compatible with those previously reported, both theoretical and experimental, the geometric shape of the cavities in hydrate being, and therefore, the steric constraints, responsible for some (but not all) preferential angles. In addition, our calculations also show that guest-guest interactions in neighbouring cages are a key factor to explain the remaining experimental angles. Besides the implication concerning equation of state hydrate modeling approximations, the conclusion is that these guest-guest interactions should not be neglected, contrary to the usual practice. PMID- 28092381 TI - Miniaturized devices for point of care molecular detection of HIV. AB - The HIV pandemic affects 36.7 million people worldwide, predominantly in resource poor settings. Nucleic acid-based molecular detection of HIV plays a significant role in antiretroviral treatment monitoring for HIV patients, as well as diagnosis of HIV infection in infants. Currently available molecular diagnostic methods are complex, time-consuming and relatively expensive, thus limiting their use in resource-poor settings. Recent advances in microfluidics technology have made possible low-cost integrated miniaturized devices for molecular detection and quantification of HIV at the point of care. We review recent technical advances in molecular testing of HIV using microfluidic technology, with a focus on assays based on isothermal nucleic acid amplification. Microfluidic components for sample preparation, isothermal amplification and result detection are discussed and compared. We also discuss the challenges and future directions for developing an integrated "sample-to-result" microfluidic platform for HIV molecular detection. PMID- 28092384 TI - Emerging investigator series: a 14-year depositional ice record of perfluoroalkyl substances in the High Arctic. AB - To improve understanding of long-range transport of perfluoroalkyl substances to the High Arctic, samples were collected from a snow pit on the Devon Ice Cap in spring 2008. Snow was analyzed for perfluoroalkyl acids (PFAAs), including perfluoroalkyl carboxylic acids (PFCAs) and perfluoroalkyl sulfonic acids (PFSAs), as well as perfluorooctane sulfonamide (FOSA). PFAAs were detected in all samples dated from 1993 to 2007. PFAA fluxes ranged from <1 to hundreds of ng per m2 per year. Flux ratios of even-odd PFCA homologues were mostly between 0.5 and 2, corresponding to molar ratios expected from atmospheric oxidation of fluorotelomer compounds. Concentrations of perfluorobutanoic acid (PFBA) were much higher than other PFCAs, suggesting PFBA loading on the Devon Ice Cap is influenced by additional sources, such as the oxidation of heat transfer fluids. All PFCA fluxes increased with time, while PFSA fluxes generally decreased with time. No correlations were observed between PFAAs and the marine aerosol tracer, sodium. Perfluoro-4-ethylcyclohexanesulfonate (PFECHS) was detected for the first time in an atmospherically - derived sample, and its presence may be attributed to aircraft hydraulic system leakage. Observations of PFAAs from these samples provide further evidence that atmospheric oxidation of volatile precursors is an important source of PFAAs to the Arctic environment. PMID- 28092385 TI - Visual detection of multiple genetically modified organisms in a capillary array. AB - There is an urgent need for rapid, low-cost multiplex methodologies for the monitoring of genetically modified organisms (GMOs). Here, we report a C[combining low line]apillary A[combining low line]rray-based L[combining low line]oop-mediated isothermal amplification for M[combining low line]ultiplex visual detection of nucleic acids (CALM) platform for the simple and rapid monitoring of GMOs. In CALM, loop-mediated isothermal amplification (LAMP) primer sets are pre-fixed to the inner surface of capillaries. The surface of the capillary array is hydrophobic while the capillaries are hydrophilic, enabling the simultaneous loading and separation of the LAMP reaction mixtures into each capillary by capillary forces. LAMP reactions in the capillaries are then performed in parallel, and the results are visually detected by illumination with a hand-held UV device. Using CALM, we successfully detected seven frequently used transgenic genes/elements and five plant endogenous reference genes with high specificity and sensitivity. Moreover, we found that measurements of real-world blind samples by CALM are consistent with results obtained by independent real time PCRs. Thus, with an ability to detect multiple nucleic acids in a single easy-to-operate test, we believe that CALM will become a widely applied technology in GMO monitoring. PMID- 28092387 TI - Two-dimensional C12Mn2/C12Cr2 as a room-temperature half metal/antiferromagnetic semiconductor: a systematic study. AB - Ferromagnetism in half-metallic two-dimensional (2D) materials can lead to unique spintronics applications. In this paper, we report first-principle calculations that predict 2D single-layer C12Mn2 as a ferromagnetic half metal, and 2D single layer C12Cr2 as an antiferromagnetic semiconductor. A systematic study is carried out to demonstrate the reliability of our research. We employ a bottom-up method to investigate the structural and magnetic stability of single, two and more Cr or Mn atoms on graphyne at room temperature. The very high Curie/Neel temperatures of 2D C12Mn2/C12Cr2, respectively, indicate the stability of room temperature ferromagnetism/antiferromagnetism. With perfect spin filtering, 2D C12Mn2 would be a promising material for future spintronics design. PMID- 28092386 TI - Closer insight into the structure of moderate to densely branched comb polymers by combining modelling and linear rheological measurements. AB - Synthesis of combs with well-entangled backbones and long branches with high densities has always been a challenge. Steric hindrance frequently leads to coupling of chains and structural imperfections that cannot be easily distinguished by traditional characterization methods. Research studies have therefore tried to use a combination of different methods to obtain more information on the actual microstructures. In this work, a grafting-from approach is used to synthesize poly(n-butyl acrylate) combs using atom transfer radical polymerization (ATRP) in three steps including the synthesis of a backbone, cleavage of protecting groups and growth of side branches. We have compared the linear viscoelastic properties theoretically predicted by a time marching algorithm (TMA) tube based model with the measured rheological behaviour to provide a better insight into the actual microstructure formed during synthesis. For combs with branches smaller than an entanglement, no discernible hierarchical relaxation can be distinguished, while for those with longer branches, a high frequency plateau made by entangled branches can be separated from backbone's relaxation. Dilution of the backbone, after relaxation of side branches, may accelerate the final relaxation, while extra friction can delay it especially for longer branches. Such a comparison provides a better assessment of the microstructure formed in combs. PMID- 28092388 TI - Exploration and analysis of drug modes of action through feature integration. AB - Identifying drug modes of action (MoA) is of paramount importance for having a good grasp of drug indications in clinical tests. Anticipating MoA can help to discover new uses for approved drugs. Here we first used a drug-set enrichment analysis method to discover significant biological activities in every mode of action category. Then, we proposed a new computational model, a probability ensemble approach based on Bayesian network theory, which integrated chemical, therapeutic, genomic and phenotypic properties of over a thousand of FDA approved drugs to assist with the prediction of MoA. 10-fold cross validation tests demonstrate that this method can achieve better performances than four other methods with the area under the receiver operating characteristic (ROC) curves. Finally, we further conducted a large-scale prediction for drug-MoA pairs. Using the Cardiovascular Agents category as an example, several predicted drug-MoA pairs were supported by literature resources. PMID- 28092389 TI - A new method for developing defect-rich graphene nanoribbons/onion-like carbon@Co nanoparticles hybrid materials as an excellent catalyst for oxygen reactions. AB - Herein, a novel material with an excellent electrocatalytic activity for the oxygen reduction reaction (ORR), composed of onion-like carbon@Co nanoparticles (NPs) incorporated on defect-rich N-doped graphene nanoribbons (C@Co-NGR), is prepared via a combination of nitric acid etching and subsequent high-temperature treatment of the as-synthesized C@Co-N doped carbon nanotubes. The as-prepared C@Co-NGR exhibits excellent electrocatalytic activity for the ORR in 0.10 M KOH with a half-wave potential of 0.830 V (vs. a reversible hydrogen electrode, RHE), which is 21 mV more positive than that of a commercial 20 wt% Pt/C catalyst. Moreover, it shows a higher stability and better methanol tolerance than the commercial Pt/C catalyst in alkaline solution, with almost no shift in the ORR polarization curve after 3000 cycles and no change of the ORR peak in the cyclic voltammogram in the presence of 1.0 M methanol. Most importantly, the C@Co-NGR also exhibits a comparable activity for the oxygen evolution reaction (OER) in 0.10 M KOH solution, in which the overpotential needed to achieve a current density of 10 mA cm-2 is 410 mV, comparable to that of the state-of-the-art commercial RuO2 catalyst (370 mV, vs. RHE). This makes the C@Co-NGR one of the best non-precious-metal catalyst for OER and ORR in alkaline solution ever reported. PMID- 28092390 TI - ASTHMA - comparing the impact of vitamin D versus UVR on clinical and immune parameters. AB - The incidence of asthma has increased markedly since the 1960s and is currently estimated to affect more than 300 million individuals worldwide. A number of environmental factors are implicated in asthma pathogenesis, one of which is vitamin D. Vitamin D deficiency is a global health concern and has increased in parallel with asthma incidence. Epidemiological studies report associations between low vitamin D status, assessed as circulating levels of 25-hydroxyvitamin D, with asthma incidence, severity, exacerbations and responses to treatment. This has led to clinical studies to test whether increasing the levels of vitamin D improves asthma management. Despite being highly variable in dosing regimens, design and outcomes, meta-analyses suggest overall positive outcomes with respect to reduced asthma exacerbations and steroid requirements. The primary mechanism for increasing vitamin D levels in the body is through exposure of the skin to the ultraviolet B (UVB) component of ultraviolet radiation (UVR), most commonly from sun exposure. However, only a limited number of studies investigating the impact of UVR on the asthmatic response have been performed; these generally report on the impact of latitude as a surrogate of sun exposure, or address this in animal models. To the best of our knowledge no comprehensive trials to assess the impact of UVB radiation on asthma outcomes have been performed. Within this review we discuss observational and clinical studies in this field, and innate and adaptive immune mechanisms through which UVR and vitamin D may impact respiratory health, and asthma. We highlight the heterogeneity of asthmatic disease, which is likely to impact upon the efficacy of interventional studies, and briefly overview more recent findings relating to the impact of vitamin D/UVR on the development of asthma. PMID- 28092391 TI - Correlation of focal adhesion assembly and disassembly with cell migration on nanotopography. AB - Selective cell adhesion is desirable to control cell growth and migration on biomedical implants. Mesenchymal cell migration is regulated through focal adhesions (FAs) and can be modulated by their microenvironment, including changes in surface topography. We use the Number and Molecular Brightness (N&B) imaging analysis to provide a unique perspective on FA assembly and disassembly. This imaging analysis generates a map of real-time fluctuations of protein monomers, dimers, and higher order aggregates of FA proteins, such as paxillin during assembly and disassembly. We show a dynamic view of how nanostructured surfaces (nanoline gratings or nanopillars) regulate single molecular dynamics. In particular, we report that the smallest nanopillars (100 nm spacing) gave rise to a low population of disassembling adhesion clusters of ~2 paxillin proteins whereas the larger nanopillars (380 nm spacing) gave rise to a much larger population of larger disassembling clusters of ~3-5 paxillin proteins. Cells were more motile on the smaller nanopillars (spaced 100-130 nm apart) compared to all other surfaces studied. Thus, physical nanotopography influences cell motility, adhesion size, and adhesion assembly and disassembly. We report for the first time, with single molecular detection, how nanotopography influences cell motility and protein reorganization in adhesions. PMID- 28092392 TI - The in silico identification of human bile salt export pump (ABCB11) inhibitors associated with cholestatic drug-induced liver injury. AB - Drug-induced liver injury (DILI) is one of the major causes of drug attrition and failure. Currently, there is increasing evidence that direct inhibition of the human bile salt export pump (BSEP/ABCB11) by drugs and/or metabolites is one of the most important mechanisms of cholestatic DILI. In the present study, we employ two in silico methods, random forest (RF) and the pharmacophore method, to recognize potential BSEP inhibitors that could cause cholestatic DILI, with the aim of mitigating the risk of cholestatic DILI to some extent. The RF model achieved the best prediction performance, producing AUC (area under receiver operating characteristic curve) values of 0.901, 0.929 and 0.996 for leave-one out cross-validation, the test set and the external test set, respectively, indicating that the built RF model has a satisfactory identification ability. As a complement to the RF model, the pharmacophore model was also built and was proved to be reliable with good predictive performance based on the internal and external validation results. Further analysis indicates that hydrophobicity, molecular size and polarity are important factors that influence the inhibitory activity of BSEP. Furthermore, the two models are applied to screen FDA-approved small molecule drugs, among which the drugs with the potential risk of cholestatic DILI are reported. In conclusion, the RF and pharmacophore models that we present can be considered as integrated screening tools to indicate the potential risk of cholestatic DILI by inhibition of BSEP. PMID- 28092393 TI - Surgical Treatment of Adult-Onset Esotropia: Characteristics and Outcomes. AB - PURPOSE: To describe the characteristics of the strabismus, surgical management, and outcomes of patients who underwent surgery for adult-onset esotropia. METHODS: This was a retrospective case study of patients at an academic tertiary referral center who underwent surgical treatment of esotropia acquired at or after age 18 years. Primary outcome measures were resolution of diplopia in primary position and a deviation of 10 prism diopters or less in primary gaze. Additional clinical parameters were assessed. RESULTS: Of 248 patients with adult onset esotropia who underwent strabismus surgery, all experienced diplopia preoperatively except those with sensory esotropia. The four most common diagnoses were cranial nerve VI palsy in 36% (90 of 248), thyroid eye disease in 18% (45 of 248), age-related distance esotropia in 15% (38 of 248), and decompensated latent esodeviations in 13% (31 of 248) of patients. A variety of surgical procedures were employed, and adjustable sutures were used in 79% (196 of 248). Approximately 80% (158 of 197) of patients present at the 2-month postoperative follow-up visit were aligned within 10 prism diopters, and 72% (140 of 195) experienced resolution of diplopia. Success rates were significantly higher in patients with adjustable sutures. Reoperation rates were low overall at 15% (37 of 248) and were highest in cranial nerve VI palsies and lowest in age related distance esotropia. Dose-response calculations showed a non-significantly smaller effect per millimeter of recession and resection in cranial nerve VI palsy and age-related distance esotropia. CONCLUSIONS: The causes of adult-onset esotropia are diverse. A variety of surgical approaches are employed and, in conjunction with adjustable sutures, provide a good rate of diplopia resolution and acceptable ocular alignment. [J Pediatr Ophthalmol Strabismus. 2017;54(2):104 111.]. PMID- 28092394 TI - Morphological Evaluation of Meibomian Glands in Children and Adolescents Using Noncontact Infrared Meibography. AB - PURPOSE: To compare, in vivo, differences in meibomian gland morphology between children and adolescents. METHODS: Sixty-nine patients were included in this study and divided into two groups: children (n = 31; age range: 3 to 11 years) and adolescents (n = 39; age range: 12 to 18 years). Images of meibomian glands were obtained by infrared meibography and analyzed using ImageJ software (developed by the National Institutes of Health; available at http://rsb.info.nih.gov/ij/download.html). Meibomian gland loss, the number of meibomian gland ducts, the relative width of the meibomian gland ducts, and the percent area of the meibomian gland acini were compared between the two groups. RESULTS: Meibomian gland loss was found in both groups, but the meiboscore was not significantly different between the two groups (0.35 +/- 0.6 vs 0.41 +/- 0.8, t = -0.314, P > .05). The number of meibomian gland ducts (25.85 +/- 3.25 vs 23.23 +/- 3.06, t = -3.437, P < .05), relative width of the meibomian gland ducts (69.62% +/- 5% vs 66.1% +/- 7%, t = -2.454, P < .05), and percent area of the meibomian gland acini (57.7% +/- 4% vs 55.5% +/- 4%, t = 2.571, P < .05) in the upper eyelid were significantly greater in adolescents than in children. However, no significant differences were found in the lower eyelid between the two groups. CONCLUSIONS: Meibography is useful for the assessment of ocular surface conditions in children and adolescents. Meibomian gland loss occurs in both children and adolescents. The meibomian glands of the upper eyelid exhibit more morphological changes in adolescents than in children. [J Pediatr Ophthalmol Strabismus. 2017;54(2):78-83.]. PMID- 28092395 TI - Intraocular Pressure Changes Following Intravitreal Melphalan and Topotecan for the Treatment of Retinoblastoma With Vitreous Seeding. AB - PURPOSE: To investigate the impact of intravitreal chemotherapy on intraocular pressure (IOP) in children with retinoblastoma. METHODS: This was a retrospective study of 10 eyes of 10 patients with retinoblastoma (7 males, 3 females, mean age: 33.6 +/- 9.4 months) with vitreous seeding injected with intravitreal melphalan and topotecan. IOP was measured with Tonopen (Reichert, Inc., Buffalo, NY) at baseline prior to injecting and then repeatedly following each intravitreal injection. RESULTS: Mean pre-injection IOP was 8.2 +/- 2.3 mm Hg (range: 4 to 12 mm Hg). Mean IOP 1 to 30 seconds after intravitreal melphalan (first injection) was 45.4 +/- 14.3 mm Hg. The IOP of 89.5% of patients declined to 29 mm Hg or less in a mean 153.3 +/- 97.5 seconds. Mean IOP 1 to 30 seconds after intravitreal topotecan (second injection) was 44.5 +/- 11.0 mm Hg, which decreased to 31.0 +/- 5.0 mm Hg by 150 seconds after injection. No significant relationship was found between age and post-injection IOP elevation. IOP exceeded the calculated mean arterial perfusion pressure in four encounters. CONCLUSIONS: Intravitreal chemotherapy caused a transient rise in IOP. Post-injection IOP elevations can reach levels that may exceed mean arterial pressure. [J Pediatr Ophthalmol Strabismus. 2017;54(3):185-190.]. PMID- 28092396 TI - Agreement Between Three Optical Coherence Tomography Devices to Assess the Insertion Distance and Thickness of Horizontal Rectus Muscles. AB - PURPOSE: To assess the agreement between two different spectral domain (SD-OCT) and one swept source (SS-OCT) optical coherence tomography device to measure the insertion distance and the thickness of the horizontal rectus muscles. METHODS: Seventy eyes from 35 healthy patients were studied. Three OCT instruments Spectralis (Heidelberg Engineering Inc., Heidelberg, Germany), Cirrus 5000 (Carl Zeiss Meditec, Dublin, CA), and Triton (Topcon, Inc., Tokyo, Japan)-were used to measure the limbus insertion distance and the thickness of the lateral rectus and medial rectus muscles. The intraclass correlation coefficient (ICC) was calculated to determine the reproducibility and the agreement between the three methods. RESULTS: Measurement of the limbus insertion distance was possible in 100% of cases with the three OCT devices. The thickness could be measured in 75% or more patients with Spectralis, 74% or more with Cirrus, and 78% or more with Triton. The agreement of the insertion distance measurements between the three devices ranged from an ICC of 0.629 or greater to 0.887; for the muscle thickness, the ICC ranged from 0.495 or greater to 0.854. The best agreement existed between the Spectralis and Topcon devices for insertion distance (ICC = 0.715 to 0.887) and for muscle thickness (ICC = 0.641 to 0.854). The reproducibility of each device was good and was higher for insertion distance (ICC = 0.880) than for muscle thickness (ICC = 0.736). The highest reproducibility values were obtained with Triton. CONCLUSIONS: The three OCT devices permitted accurate and reproducible measurements of the limbus insertion distance and the thickness of the horizontal rectus muscles, showing moderate to good agreement between the SS-OCT and the two SD-OCT instruments. [J Pediatr Ophthalmol Strabismus. 2017;54(3):168-176.]. PMID- 28092397 TI - Update on Orthokeratology in Managing Progressive Myopia in Children: Efficacy, Mechanisms, and Concerns. AB - Myopia is an important public health issue, and high myopia may lead to severe complications if left untreated. Orthokeratology lenses, worn overnight to reshape the cornea, are one of many recent modalities used to slow down the progression of myopia in children. This treatment has been proven successful, as evidenced by decreased spherical refractive error and axial length relative to the control at interval follow-up ranging from 6 months to 5 years. In this systematic review, the authors collected published controlled studies that analyzed the efficacy of orthokeratology lens wear and calculated longitudinal relative changes in axial length, revealing a weighted average of -45.1% change in axial length at the 2-year follow-up. The exact mechanism by which orthokeratology lenses reduce myopia progression is unknown, but research shows that the corneal reshaping decreases peripheral hyperopic defocus and therefore increases peripheral myopic defocus to likely reduce stimuli for axial elongation and subsequent development of myopia. Use of orthokeratology lenses is generally safe, but cases of associated infectious keratitis may have a higher incidence of virulent organisms such as Pseudomonas, Acanthamoeba, and antibacterial-resistant strains of Staphylococcus, partially due to the required overnight use of these lenses. Orthokeratology is regarded as one of the most effective non pharmacologic measures to slow progression of myopia in children and, with regular follow-up to ensure safety, continues to be one of the most effective treatments for myopia management around the world. [J Pediatr Ophthalmol Strabismus. 2017;54(3):142-148.]. PMID- 28092398 TI - Rate of Strabismus Detection on Digital Photographs Increases by Using Off-center Near Target. AB - PURPOSE: To increase the detection rate of strabismus on digital photographs, with the ultimate aim of developing a new automated strabismus detection algorithm. METHODS: In this prospective case series, the authors acquired digital face photographs of 409 children with manifest or latent strabismus, using a 14 million-pixel camera with CCD image sensor. Of the last 52 enrolled, 34 image sets were selected for this study: 29 with manifest and 5 with latent strabismus. Images were taken at a distance of 40 to 70 cm in primary position, with the camera lens as the fixation target and in slight off-center fixation, and using a novel target of small light-emitting diodes mounted onto the camera case. The location of the corneal light reflection was manually calculated in relation to the center of the pupil in both eyes and ocular deviation as the difference in corneal light reflection location between the two eyes. In orthotropia, the expected deviation is zero. RESULTS: In children with phorias, the mean corneal light reflection location difference between the eyes was -0.10 +/- 0.14 mm in primary position and -2.02 +/- 0.39 mm in off-center fixation. Using a threshold of +/-0.5 mm on either side of zero for central and of 2 mm for off-center fixation, sensitivity to detect strabismus increased from 65.6% in central to 79.3% in off-center fixation, respectively. The calculation of specificity will require inclusion of a population of individuals without strabismus. CONCLUSIONS: Off-center fixation onto a near target ensures that participants are actively looking at the target and may increase accommodative effort, thereby increasing the detection rate of strabismus. [J Pediatr Ophthalmol Strabismus. 2017;54(2):90 96.]. PMID- 28092399 TI - Association of Dietary Patterns With Global and Domain-Specific Cognitive Decline in Chinese Elderly. AB - BACKGROUND: Significant differences exist between eastern and western diets, and the way in which Chinese dietary intake relates to specific cognitive domains remains unclear. We aimed to assess the association between dietary patterns (DPs) and cognitive decline in Chinese elderly. SETTING: Participants were recruited from the elderly health checkup program of a teaching hospital in Taipei, Taiwan. PARTICIPANTS: A total of 475 elders (age >=65) were included in this prospective cohort study. MEASUREMENTS: The outcome comprised the decline of global and domain-specific cognition between baseline (2011-2013) and follow-up (2013-2015). Dietary data from the previous year were collected via a food frequency questionnaire at baseline, and a factor analysis was performed to identify DPs. Multivariable linear regression and logistic regression models were used to assess associations between Chinese DPs and cognitive decline over 2 years adjusting for selected covariates. RESULTS: Three DPs (vegetable, meat, and traditional) were identified. Moderate- or high-score "vegetable" DP significantly protected against decline of logical memory (recall I: beta = 0.16 0.18, odds ratio (OR) = 0.42-0.48; recall II: beta = 0.17-0.21); while high-score DP increased executive function decline (beta = -0.22). A high-score "meat" DP was related to decline of verbal fluency-total score (beta = -0.19); while moderate- or high-score "meat" DP protected against attention decline (beta = 0.20-0.22). High-score "traditional" DP protected against decline of logical memory-recall I (beta = 0.18). No significant association was observed for global cognition. CONCLUSION: These findings suggest that three DPs identified in Chinese elderly were associated with different cognitive domains. Further research is needed to explore the efficacy of dietary interventions in reducing cognitive decline in older adults. PMID- 28092400 TI - Aging, the Medical Subspecialties, and Career Development: Where We Were, Where We Are Going. AB - Historically, the medical subspecialties have not focused on the needs of older adults. This has changed with the implementation of initiatives to integrate geriatrics and aging research into the medical and surgical subspecialties and with the establishment of a home for internal medicine specialists within the annual American Geriatrics Society (AGS) meeting. With the support of AGS, other professional societies, philanthropies, and federal agencies, efforts to integrate geriatrics into the medical and surgical subspecialties have focused largely on training the next generation of physicians and researchers. They have engaged several subspecialties, which have followed parallel paths in integrating geriatrics and aging research. As a result of these combined efforts, there has been enormous progress in the integration of geriatrics and aging research into the medical and surgical subspecialties, and topics once considered to be geriatric concerns are becoming mainstream in medicine, but this integration remains a work in progress and will need to adapt to changes associated with healthcare reform. PMID- 28092401 TI - Randomized clinical trial of preoperative oral versus intravenous iron in anaemic patients with colorectal cancer. AB - BACKGROUND: Treatment of preoperative anaemia is recommended as part of patient blood management, aiming to minimize perioperative allogeneic red blood cell transfusion. No clear evidence exists outlining which treatment modality should be used in patients with colorectal cancer. The study aimed to compare the efficacy of preoperative intravenous and oral iron in reducing blood transfusion use in anaemic patients undergoing elective colorectal cancer surgery. METHODS: Anaemic patients with non-metastatic colorectal adenocarcinoma were recruited at least 2 weeks before surgery and randomized to receive oral (ferrous sulphate) or intravenous (ferric carboxymaltose) iron. Perioperative changes in haemoglobin, ferritin, transferrin saturation and blood transfusion use were recorded until postoperative outpatient review. RESULTS: Some 116 patients were included in the study. There was no difference in blood transfusion use from recruitment to trial completion in terms of either volume of blood administered (P = 0.841) or number of patients transfused (P = 0.470). Despite this, increases in haemoglobin after treatment were higher with intravenous iron (median 1.55 (i.q.r. 0.93-2.58) versus 0.50 (-0.13 to 1.33) g/dl; P < 0.001), which was associated with fewer anaemic patients at the time of surgery (75 versus 90 per cent; P = 0.048). Haemoglobin levels were thus higher at surgery after treatment with intravenous than with oral iron (mean 11.9 (95 per cent c.i. 11.5 to 12.3) versus 11.0 (10.6 to 11.4) g/dl respectively; P = 0.002), as were ferritin (P < 0.001) and transferrin saturation (P < 0.001) levels. CONCLUSION: Intravenous iron did not reduce the blood transfusion requirement but was more effective than oral iron at treating preoperative anaemia and iron deficiency in patients undergoing colorectal cancer surgery. PMID- 28092403 TI - A novel mutation conferring the nonbrittle phenotype of cultivated barley. AB - The nonbrittle rachis, resulting in a seed head which does not shatter at maturity, is one of the key phenotypes that distinguishes domesticated barley from its wild relatives. The phenotype is associated with two loci, Btr1 and Btr2, with all domesticated barleys thought to have either a 1 bp deletion in Btr1 or an 11 bp deletion in Btr2. We used a PCR genotyping method with 380 domesticated barley landraces to identify those with the Btr1 deletion and those with the Btr2 deletion. We discovered two landraces, from Serbia and Greece, that had neither deletion. Instead these landraces possess a novel point mutation in Btr1, changing a leucine to a proline in the protein product. We confirmed that plants carrying this mutation have the nonbrittle phenotype and identified wild haplotypes from the Gaziantep region of southeast Turkey as the closest wild relatives of these two landraces. The presence of a third mutation conferring the nonbrittle phenotype of domesticated barley shows that the origin of this trait is more complex than previously thought, and is consistent with recent models that view the transition to agriculture in southwest Asia as a protracted and multiregional process. PMID- 28092402 TI - gammadelta T cells are indispensable for interleukin-23-mediated protection against Concanavalin A-induced hepatitis in hepatitis B virus transgenic mice. AB - Hepatitis B virus surface antigen (HBsAg) carriers are highly susceptible to liver injury triggered by environmental biochemical stimulation. Previously, we have reported an inverse correlation between gammadelta T cells and liver damage in patients with hepatitis B virus (HBV). However, whether gammadelta T cells play a role in regulating the hypersensitivity of HBsAg carriers to biochemical stimulation-induced hepatitis is unknown. In this study, using HBV transgenic (HBs-Tg) and HBs-Tg T-cell receptor-delta-deficient (TCR-delta-/- ) mice, we found that mice genetically deficient in gammadelta T cells exhibited more severe liver damage upon Concanavalin A (Con A) treatment, as indicated by substantially higher serum alanine aminotransferase levels, further elevated interferon-gamma (IFN-gamma) levels and more extensive necrosis. gammadelta T-cell deficiency resulted in elevated IFN-gamma in CD4+ T cells but not in natural killer or natural killer T cells. The depletion of CD4+ T cells and neutralization of IFN gamma reduced liver damage in HBs-Tg and HBs-Tg-TCR-delta-/- mice to a similar extent. Further investigation revealed that HBs-Tg mice showed an enhanced interleukin-17 (IL-17) signature. The administration of exogenous IL-23 enhanced IL-17A production from Vgamma4 gammadelta T cells and ameliorated liver damage in HBs-Tg mice, but not in HBs-Tg-TCR-delta-/- mice. In summary, our results demonstrated that gammadelta T cells played a protective role in restraining Con A-induced hepatitis by inhibiting IFN-gamma production from CD4+ T cells and are indispensable for IL-23-mediated protection against Con A-induced hepatitis in HBs-Tg mice. These results provided a potential therapeutic approach for treating the hypersensitivity of HBV carriers to biochemical stimulation-induced liver damage. PMID- 28092404 TI - Metformin vs myoinositol: which is better in obese polycystic ovary syndrome patients? A randomized controlled crossover study. AB - CONTEXT: Due to the central role of metabolic abnormalities in the pathophysiology of polycystic ovary syndrome (PCOS), insulin sensitizing agents have been proposed as a feasible treatment option. OBJECTIVE: To investigate which is the more effective between metformin and myoinositol (MYO) on hormonal, clinical and metabolic parameters in obese patients with PCOS. STUDY DESIGN: Crossover randomized controlled study. PATIENTS: Thirty-four PCOS obese women (age: 25.62 +/- 4.7 years; BMI: 32.55 +/- 5.67 kg/m2 ) were randomized to receive metformin (850 mg twice a day) or MYO (1000 mg twice a day) for 6 months. After a 3 month washout, the same subjects received the other compound for the following 6 months. MEASUREMENTS: Ultrasonographic pelvic examinations, hirsutism score, anthropometric and menstrual pattern evaluation, hormonal profile assays, oral glucose tolerance test (OGTT) and lipid profile at baseline and after 6 months of treatment were performed. RESULTS: Both metformin and MYO significantly reduced the insulin response to OGTT and improved insulin sensitivity. Metformin significantly decreased body weight and improved menstrual pattern and Ferriman Gallwey score. Metformin treatment was also associated with a significant decrease in LH and oestradiol levels, androgens and anti-mullerian hormone levels. None of these clinical and hormonal changes were observed during MYO administration. CONCLUSIONS: Both treatments improved the glyco-insulinaemic features of obese PCOS patients, but only metformin seems to exert a beneficial effect on the endocrine and clinical features of the syndrome. PMID- 28092405 TI - Thrombin contributes to protective immunity in pneumonia-derived sepsis via fibrin polymerization and platelet-neutrophil interactions. AB - : Essentials Immunity and coagulation are linked during sepsis but the role of thrombin is not fully elucidated. We investigated the effect of thrombin inhibition on murine Klebsiella pneumosepsis outcome. Thrombin is crucial for survival and limiting bacterial growth in pneumonia derived sepsis. Thrombin improves host defense via fibrin and enhancement of platelet-neutrophil interactions. SUMMARY: Background Innate immunity and coagulation are closely linked during sepsis. Their interaction can be detrimental to the outcome because of microvascular failure but can also enhance host defense. The role of thrombin therein has not been fully elucidated. Objective We aimed to investigate the contribution of thrombin to the host response during pneumonia-derived sepsis. Methods Mice treated with the specific thrombin inhibitor dabigatran or control chow were infected with the common human sepsis pathogen Klebsiella (K.) pneumoniae via the airways. In subsequent infection experiments, mice were additionally treated with ancrod to deplete fibrinogen. Ex vivo Klebsiella growth was assessed by incubating human whole blood or specific blood components in various conditions with Klebsiella. Results Thrombin inhibition by dabigatran enhanced bacterial outgrowth and spreading, and accelerated mortality. Thrombin inhibition did not influence neutrophil recruitment to the lung or activation or neutrophil extracellular trap formation. Dabigatran reduced D-dimer formation and fibrin deposition in the lung. Fibrin depletion also enhanced bacterial outgrowth and spreading, and thrombin inhibition had no additional effect. Both thrombin and fibrin polymerization inhibited ex vivo Klebsiella outgrowth in human whole blood, which was neutrophil dependent, and the effect of thrombin required the presence of platelets and platelet protease activated receptor-1. In vivo thrombin inhibition reduced platelet-neutrophil complex formation and endothelial cell activation, but did not prevent sepsis-induced thrombocytopenia or organ damage. Conclusions These results suggest that thrombin plays an important role in protective immunity during pneumonia-derived sepsis by fibrin polymerization and enhancement of platelet-neutrophil interactions. PMID- 28092406 TI - LlFH1-mediated interaction between actin fringe and exocytic vesicles is involved in pollen tube tip growth. AB - Pollen tube tip growth is an extreme form of polarized cell growth, which requires polarized exocytosis based on a dynamic actin cytoskeleton. However, the molecular basis for the connection between actin filaments and exocytic vesicles is unclear. Here, we identified a Lilium longiflorum pollen-specific formin (LlFH1) and found that it localized at the apical vesicles and plasma membrane (PM). Overexpression of LlFH1 induced excessive actin cables in the tube tip region, and downregulation of LlFH1 eliminated the actin fringe. Fluorescence recovery after photobleaching (FRAP) analysis revealed that LlFH1-labeled exocytic vesicles exhibited an initial accumulation at the shoulder of the apex and coincided with the leading edge of the actin fringe. Time-lapse analysis suggested that nascent actin filaments followed the emergence of the apical vesicles, implying that LlFH1 at apical vesicles could initiate actin polymerization. Biochemical assays showed that LlFH1 FH1FH2 could nucleate actin polymerization, but then capped the actin filament at the barbed end and inhibited its elongation. However, in the presence of lily profilins, LlFH1 FH1FH2 could accelerate barbed-end actin elongation. In addition, LlFH1 FH1FH2 was able to bundle actin filaments. Thus, we propose that LlFH1 and profilin coordinate the interaction between the actin fringe and exocytic vesicle trafficking during pollen tube growth of lily. PMID- 28092407 TI - Study of potential health effects of electromagnetic fields of telephony and Wi Fi, using chicken embryo development as animal model. AB - The objective of this study is to investigate possible biological effects of radiofrequency electromagnetic fields (RF-EMF) as used in modern wireless telecommunication in a well-controlled experimental environment using chicken embryo development as animal model. Chicken eggs were incubated under continuous experimental exposure to GSM (1.8 GHz), DECT (1.88 GHz), UMTS (2.1 GHz), and WLAN (5.6 GHz) radiation, with the appropriate modulation protocol, using a homogeneous field distribution at a field strength of approximately 3 V/m, representing the maximum field level in a normal living environment. Radiation shielded exposure units/egg incubators were operating in parallel for exposed and control eggs in a climatized homogeneous environment, using 450 eggs per treatment in three successive rounds per treatment. Dosimetry of the exposure (field characteristics and specific absorption rate) were studied. Biological parameters studied included embryo death during incubation, hatching percentage, and various morphological and histological parameters of embryos and chicks and their organs, and gene expression profiles of embryos on day 7 and day 18 of incubation by microarray and qPCR. No conclusive evidence was found for induced embryonic mortality or malformations by exposure to the used EMFs, or for effects on the other measured parameters. Estimated differences between treatment groups were always small and the effect of treatment was not significant. In a statistical model that ignored possible interaction between rounds and exposure units, some of the many pairwise comparisons of exposed versus control had P values lower than 0.05, but were not significant after correction for multiple testing. Bioelectromagnetics. 38:186-203, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28092408 TI - Network structure and local adaptation in co-evolving bacteria-phage interactions. AB - Numerous theoretical and experimental studies have investigated antagonistic co evolution between parasites and their hosts. Although experimental tests of theory from a range of biological systems are largely concordant regarding the influence of several driving processes, we know little as to how mechanisms acting at the smallest scales (individual molecular and phenotypic changes) may result in the emergence of structures at larger scales, such as co-evolutionary dynamics and local adaptation. We capitalized on methods commonly employed in community ecology to quantify how the structure of community interaction matrices, so-called bipartite networks, reflected observed co-evolutionary dynamics, and how phages from these communities may or may not have adapted locally to their bacterial hosts. We found a consistent nested network structure for two phage types, one previously demonstrated to exhibit arms race co evolutionary dynamics and the other fluctuating co-evolutionary dynamics. Both phages increased their host ranges through evolutionary time, but we found no evidence for a trade-off with impact on bacteria. Finally, only bacteria from the arms race phage showed local adaptation, and we provide preliminary evidence that these bacteria underwent (sometimes different) molecular changes in the wzy gene associated with the LPS receptor, while bacteria co-evolving with the fluctuating selection phage did not show local adaptation and had partial deletions of the pilF gene associated with type IV pili. We conclude that the structure of phage bacteria interaction networks is not necessarily specific to co-evolutionary dynamics, and discuss hypotheses for why only one of the two phages was, nevertheless, locally adapted. PMID- 28092409 TI - Quantification of brown and white adipose tissue based on Gaussian mixture model using water-fat and T2* MRI in adolescents. AB - PURPOSE: To develop a technique for the separation and quantification of brown adipose tissue (BAT) and white adipose tissue (WAT) using fat fraction and T2* intensity based on the Gaussian mixture model (GMM). MATERIALS AND METHODS: Chemical-shift water-fat and T2* images were acquired at the neck, supraclavicular, interscapular, and paravertebral regions in 24 volunteers (Obese: n = 12, female/male = 6/6, body mass index [BMI] = 31.3 +/- 2.3 kg/m2 , age = 16.1 +/- 0.6; Normal weight: n = 12, female/male = 6/6, BMI = 21.2 +/- 2.4 kg/m2 , age = 12.9 +/- 2.4) using a 3T scanner with the chemical-shift water-fat mDixon sequence. BAT and WAT were clustered based on the Gaussian mixture model using the expectation-maximization algorithm. Results and reproducibility were compared and assessed using independent t-tests and intraclass correlation coefficient. RESULTS: BAT in obese participants was predominately found at the supraclavicular region and in normal-weight participants it was more scattered and distributed in interscapular-supraclavicular, axillary, and spine regions. Absolute volume of BAT was higher in the obese group (Obese: 315.2 mL [+/-89.1], Normal weight: 248.5 mL [+/-86.4]), but BAT/WAT ratios were significantly higher (P = 0.029) in the normal group. T2* of BAT (P = 0.04) and volume of WAT (P < 0.001) were significantly lower in the normals. Within-group comparison between male and female indicated no significant differences were found in volume (P = 0.776 (normal), 0.501 [obese]), T2* (P = 0.908 [normal], 0.249 [obese]) and fat fraction of BAT (P = 0.985 [normal], 0.108 [obese]). The intraclass correlation coefficient showed a good reproducibility in volume (BAT: 0.997, WAT: 0.948), T2* (BAT: 0.969, WAT: 0.983), and fat-fraction (BAT: 0.952, WAT: 0.517). CONCLUSION: BAT identified by this method was in agreement with other studies in terms of location, fat-fraction value, and T2* intensity. The proposed GMM-based segmentation could be a useful nonradiation imaging method for assessment of adipose tissue, in particular for serial follow-up of volume changes after drug or lifestyle interventions for obesity. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:758-768. PMID- 28092410 TI - Big Five personality characteristics are associated with depression subtypes and symptom dimensions of depression in older adults. AB - OBJECTIVE: This study examined the associations of personality characteristics with both subtypes and symptom dimensions of depression in older adults. METHODS: Three hundred and seventy-eight depressed older adults participated in the Netherlands Study of Depression in Older Persons. Personality characteristics were assessed by the NEO-Five Factor Inventory. Subtypes and symptom dimensions of depression were determined using the Composite International Diagnostic Interview and the Inventory of Depressive Symptomatology (IDS). Multinomial logistic regression analyses were performed to examine the associations between personality and atypical, melancholic, and unspecified subtypes of major depression. Linear regression analyses examined the associations between personality and the IDS mood, somatic, and motivation symptom dimensions. The analyses were adjusted for confounders and additionally adjusted for depression severity. RESULTS: Neuroticism, Extraversion, Conscientiousness, and Agreeableness were associated with specified (atypical or melancholic) major depression compared with unspecified major depression in the bivariate analyses but lost their significance after adjustments for functional limitations and severity of depression. Neuroticism was positively associated with the IDS mood and motivation symptom dimensions, also in the adjusted models. Further, Extraversion and Agreeableness were negatively associated with the IDS mood symptom dimension, and Extraversion and Conscientiousness were negatively associated with the IDS motivation symptom dimension. None was associated with the IDS somatic symptom dimension. CONCLUSIONS: This study demonstrated the association of personality characteristics with mood and motivational symptoms of late-life depression. The lacking ability of personality to differentiate between melancholic and atypical depression seems to be largely explained by severity of depressive symptoms. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28092411 TI - Measurement of arterial transit time and renal blood flow using pseudocontinuous ASL MRI with multiple post-labeling delays: Feasibility, reproducibility, and variation. AB - PURPOSE: To evaluate the feasibility, reproducibility, and variation of renal perfusion and arterial transit time (ATT) using pseudocontinuous arterial spin labeling magnetic resonance imaging (PCASL MRI) in healthy volunteers. MATERIALS AND METHODS: PCASL MRI at 3T was performed in 25 healthy volunteers on two different occasions. The ATT and ATT-corrected renal blood flow (ATT-cRBF) were calculated at four different post-labeling delay points (0.5, 1.0, 1.5, and 2.0 s) and evaluated for each kidney and subject. The intraclass correlation (ICC) and Bland-Altman plot were used to assess the reproducibility of the PCASL MRI technique. The within-subject coefficient of variance was determined. RESULTS: Results were obtained for 46 kidneys of 23 subjects with a mean age of 38.6 +/- 9.8 years and estimated glomerular filtration rate (eGFR) of 89.1 +/- 21.2 ml/min/1.73 m2 . Two subjects failed in the ASL MRI examination. The mean cortical and medullary ATT-cRBF for the subjects were 215 +/- 65 and 81 +/- 21 ml/min/100 g, respectively, and the mean cortical and medullary ATT were 1141 +/- 262 and 1123 +/- 245 msec, correspondingly. The ICC for the cortical ATT-cRBF was 0.927 and the within-subject coefficient of variance was 14.4%. The ICCs for the medullary ATT-cRBF and the cortical and medullary ATT were poor. The Bland-Altman plot for cortical RBF showed good agreement between the two measurements. CONCLUSION: PCASL MRI is a feasible and reproducible method for measuring renal cortical perfusion. In contrast, ATT for the renal cortex and medulla has poor reproducibility and high variation. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:813-819. PMID- 28092412 TI - Population dynamics of hepatitis C virus subtypes in injecting drug users on methadone maintenance treatment in China associated with economic and health reform. AB - The extensive genetic heterogeneity of hepatitis C virus (HCV) requires in-depth understanding of the population dynamics of different viral subtypes for more effective control of epidemic outbreaks. We analysed HCV sequences data from 125 participants in Wuhan, China. These participants were newly infected by subtype 1b (n=13), 3a (n=15), 3b (n=50) and 6a (n=39) while on methadone maintenance treatment (MMT). Bayesian phylogenies and demographic histories were inferred for these subtypes. Participants infected with HCV-1b and 3a were clustered in well supported monophyletic clades, indicating local subepidemics. Subtypes 3b and 6a strains were intermixed with other Chinese isolates, as well as isolates from other Asian countries, reflecting ongoing across geographic boundary transmissions. Subtypes 1b and 3a declined continuously during the past ten years, consistent with the health and economic reform in China, while subtype 3b showed ongoing exponential growth and 6a was characterized by several epidemic waves, possibly related to the recently growing number of travellers between China and other Asian countries. In conclusion, results of this study suggest that HCV subtype 3b and 6a subepidemics in China are currently not under control, and new epidemic waves may emerge given the rapid increase in international travelling following substantial economic growth. PMID- 28092413 TI - Disruption of right posterior parietal cortex by continuous Theta Burst Stimulation alters the control of body balance in quiet stance. AB - Control of body balance relies on the integration of multiple sensory modalities. Lightly touching an earth-fixed reference augments the control of body sway. We aimed to advance the understanding of cortical integration of an afferent signal from light fingertip contact (LT) for the stabilisation of standing body balance. Assuming that right-hemisphere Posterior Parietal Cortex (rPPC) is involved in the integration and processing of touch for postural control, we expected that disrupting rPPC would attenuate any effects of light touch. Eleven healthy right handed young adults received continuous Theta Burst Stimulation over the left- and right-hemisphere PPC with sham stimulation as an additional control. Before and after stimulation, sway of the blindfolded participants was assessed in Tandem-Romberg stance with and without haptic contact. We analysed sway in terms of the variability of Centre-of-Pressure (CoP) rate of change as well as Detrended Fluctuation Analysis of CoP position. Light touch decreased sway variability in both directions but showed direction-specific changes in its dynamic complexity: a positive increase in complexity in the mediolateral direction coincided with a reduction in the anteroposterior direction. rPPC disruption affected the control of body sway in two ways: first, it led to an overall decrease in sway variability irrespective of the presence of LT; second, it reduced the complexity of sway with LT at the contralateral, non-dominant hand. We speculate that rPPC is involved in the active exploration of the postural stability state, with utilisation of LT for this purpose if available, by normally inhibiting mechanisms of postural stiffness regulation. PMID- 28092414 TI - DCE-MRI of the prostate using shutter-speed vs. Tofts model for tumor characterization and assessment of aggressiveness. AB - PURPOSE: To quantify Tofts model (TM) and shutter-speed model (SSM) perfusion parameters in prostate cancer (PCa) and noncancerous peripheral zone (PZ) and to compare the diagnostic performance of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to Prostate Imaging and Reporting and Data System (PI RADS) classification for the assessment of PCa aggressiveness. MATERIALS AND METHODS: Fifty PCa patients (mean age 60 years old) who underwent MRI at 3.0T followed by prostatectomy were included in this Institutional Review Board approved retrospective study. DCE-MRI parameters (Ktrans , ve , kep [TM&SSM] and intracellular water molecule lifetime taui [SSM]) were determined in PCa and PZ. Differences in DCE-MRI parameters between PCa and PZ, and between models were assessed using Wilcoxon signed-rank tests. Receiver operating characteristic (ROC) analysis for differentiation between PCa and PZ was performed for individual and combined DCE-MRI parameters. Diagnostic performance of DCE-MRI parameters for identification of aggressive PCa (Gleason >=8, grade group [GG] >=3 or pathology stage pT3) was assessed using ROC analysis and compared with PI RADSv2 scores. RESULTS: DCE-MRI parameters were significantly different between TM and SSM and between PZ and PCa (P < 0.037). Diagnostic performances of TM and SSM for differentiation of PCa from PZ were similar (highest AUC TM: Ktrans +kep 0.76, SSM: taui +kep 0.80). PI-RADS outperformed TM and SSM DCE-MRI for identification of Gleason >=8 lesions (AUC PI-RADS: 0.91, highest AUC DCE-MRI: Ktrans +taui SSM 0.61, P = 0.002). The diagnostic performance of PI-RADS and DCE MRI for identification of GG >=3 and pT3 PCa was not significantly different (P > 0.213). CONCLUSION: SSM DCE-MRI did not increase the diagnostic performance of DCE-MRI for PCa characterization. PI-RADS outperformed both TM and SSM DCE-MRI for identification of aggressive cancer. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:837-849. PMID- 28092416 TI - Persistence of antibody to Hepatitis A virus 20 years after receipt of Hepatitis A vaccine in Alaska. AB - Hepatitis A vaccine is recommended for children >=1 year old to prevent hepatitis A virus (HAV) infection. However, the duration of vaccine-induced immunity is unknown. We evaluated a cohort of Alaska Native persons 20 years after HAV vaccination. Children aged 3-6 years had been previously randomized to receive three doses of HAV vaccine (360 ELISA units/dose) at: (i) 0,1,2 months; (ii) 0,1,6 months; and (iii) 0,1,12 months. We measured anti-HAV antibody concentrations every 2-3 years; described geometric mean concentrations (GMC) and the proportion with protective antibody (>=20 mIU mL-1 ) over time; and modelled the change in GMC using fractional polynomial regression. Of the 144 participants, after 20 years 52 (36.1%) were available for the follow-up (17, 18, 17 children in Groups A, B and C, respectively). Overall, 46 (88.5%) of 52 available participants had anti-HAV antibody concentrations >=20 mIU mL-1 , and overall GMC was 107 mIU mL-1 . Although GMC levels were lower in Group A (60; CI 34-104) than in Group B (110; CI 68-177) or Group C (184; CI 98-345) (B vs C: P=.168; A vs B/C: P=.011), there was no difference between groups after adjusting for peak antibody levels post-vaccination (P=.579). Models predicted geometric mean concentrations of 124 mIU mL-1 after 25 years, and 106 mIU mL-1 after 30 years. HAV vaccine provides protective antibody levels 20 years after childhood vaccination. Lower antibody levels in Group A may be explained by a lower initial peak response. Our results suggest a booster vaccine dose is unnecessary for at least 25-30 years. PMID- 28092415 TI - Cluster microRNAs miR-194 and miR-215 suppress the tumorigenicity of intestinal tumor organoids. AB - Tumor stem cells with self-renewal and multipotent capacity play critical roles in the initiation and progression of cancer. Recently, a new 3-D culture system known as organoid culture has been developed, allowing Lgr5-positive stem cells to form organoids that resemble the properties of original tissues. Here we established organoids derived from intestinal tumors of Apcmin/+ mice and normal intestinal epithelia of C57BL/6J mice and investigated the roles of microRNA (miRNA) in intestinal tumor organoids. The results of microarray analyses revealed that expression of the cluster miRNAs, miR-194 and miR-215 was markedly suppressed in intestinal tumor organoids in comparison with organoids derived from normal intestinal epithelia. Enforced expression of miR-194 resulted in inhibition of E2f3, a positive regulator of the cell cycle and growth suppression of intestinal tumor organoids. In addition, enforced expression of miR-215 suppressed the cancer stem cell signature through downregulation of intestinal stem cell markers including Lgr5. These findings indicate that the miRNA cluster including miR-194 and miR-215 plays important roles in suppressing the growth and attenuating the stemness of intestinal tumor organoids. PMID- 28092417 TI - Dense Semi-Clathrates at High Pressure: A Study of the Water-tert-Butylamine System. AB - In situ high-pressure crystallization and diffraction techniques have been applied to obtain two very structurally distinct semi-clathrates of the tert butylamine-water system with hydration numbers 5.65 and 5.8, respectively, thereby considerably reducing a notable hydration gap between the monohydrate and the 71/4 -hydrate that results when crystallization space is explored by temperature alone. Both structures can be considered as an intriguing solid-state example of hydrophobic hydration, in which the water network creates wide tert butylamine-filled channels stabilized by cross-linking hydrogen bonds. The existence of interconnected channels might also add low hydration structures to a list of potential targets for hydrogen storage. A detailed analysis of the topology of host water and host-guest interactions is reported and extended to those of other hydrates of the compound. This analysis offers new insight into properties of the tert-butylamine-water system and provides some clues as to the occurrence of the sizable number of hydrates of this compound. PMID- 28092418 TI - An examination of the etiologic overlap between the genetic and environmental influences on insomnia and common psychopathology. AB - BACKGROUND: Insomnia is comorbid with internalizing and externalizing psychiatric disorders. However, the extent to which the etiologic influences on insomnia and common psychopathology overlap is unclear. There are limited genetically informed studies of insomnia and internalizing disorders and few studies of overlap exist with externalizing disorders. METHODS: We utilized twin data from the Virginia Adult Twin Studies of Psychiatric and Substance Use Disorders (total n = 7,500). Insomnia, internalizing disorders (major depressive disorder [MDD], generalized anxiety disorder [GAD]), and alcohol abuse or dependence (AAD) were assessed at two time points, while antisocial personality disorder (ASPD) was assessed once. Cholesky decompositions were performed in OpenMx and longitudinal measurement models were run on available phenotypes to reduce measurement error. RESULTS: The latent additive genetic influences on insomnia overlapped significantly (56% for females, 74% for males) with MDD and were shared completely (100%) with GAD. There was significant overlap of latent unique environmental influences, with overlap ranging from 38 to 100% across disorders. In contrast, there was less genetic overlap between insomnia and externalizing disorders, with 18% of insomnia's heritability shared with AAD and 23% with ASPD. Latent unique environmental overlap between insomnia and both externalizing disorders was negligible. CONCLUSIONS: The evidence for substantial genetic overlap between insomnia and stable aspects of both internalizing disorders suggests that there may be few insomnia-specific genes and investigation into unique environmental factors is important for understanding insomnia development. The modest overlap between insomnia and externalizing disorders indicates that these disorders are genetically related, but largely etiologically distinct. PMID- 28092420 TI - Immune modulation by the hepatitis C virus core protein. AB - Hepatitis C virus (HCV) infection is currently the most important cause of chronic viral hepatitis in the world and one of the most frequent indications for liver transplantation. HCV uses different strategies to evade the innate and adaptive immune response, and this evasion plays a key role in determining viral persistence. Several HCV viral proteins have been described as immune modulators. In this review, we will focus on the effect of HCV nucleocapsid core protein in the function of immune cells and its correlation with the findings observed in HCV chronically infected patients. Effects on immune cell function related to both extracellular and intracellular HCV core localization will be considered. This review provides an updated perspective on the mechanisms involved in HCV evasion related to one single HCV protein, which could become a key tool in the development of new antiviral strategies able to control and/or eradicate HCV infection. PMID- 28092419 TI - Improving access to health care for chronic hepatitis B among migrant Chinese populations: A systematic mixed methods review of barriers and enablers. AB - Migrant Chinese populations in Western countries have a high prevalence of chronic hepatitis B but often experience poor access to health care and late diagnosis. This systematic review aimed to identify obstacles and supports to timely and appropriate health service use among these populations. Systematic searches resulted in 48 relevant studies published between 1996 and 2015. Data extraction and synthesis were informed by models of healthcare access that highlight the interplay of patient, provider and health system factors. There was strong consistent evidence of low levels of knowledge among patients and community members; but interventions that were primarily focused on increasing knowledge had only modest positive effects on testing and/or vaccination. There was strong consistent evidence that Chinese migrants tend to misunderstand the need for health care for hepatitis B and have low satisfaction with services. Stigma was consistently associated with hepatitis B, and there was weak but consistent evidence of stigma acting as a barrier to care. However, available evidence on the effects of providing culturally appropriate services for hepatitis B on increasing uptake is limited. There was strong consistent evidence that health professionals miss opportunities for testing and vaccination. Practitioner education interventions may be important, but evidence of effectiveness is limited. A simple prompt in patient records for primary care physicians improved the uptake of testing, and a dedicated service increased targeted vaccination coverage for newborns. Further development and more rigorous evaluation of more holistic approaches that address patient, provider and system obstacles are needed. PMID- 28092421 TI - Carfilzomib, lenalidomide and dexamethasone in patients with heavily pretreated multiple myeloma: A phase 1 study in Japan. AB - This is the first study in which the carfilzomib, lenalidomide and dexamethasone (KRd) regimen was evaluated in heavily pretreated multiple myeloma. This study is a multicenter, open-label phase 1 study of KRd in Japanese patients with relapsed or refractory multiple myeloma (RRMM) patients. The objectives were to evaluate the safety, tolerability, efficacy and pharmacokinetics of the regimen. Carfilzomib was administrated intravenously over 10 min on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. In cycle 1, the dosage for days 1 and 2 was 20 mg/m2 , followed by 27 mg/m2 . Lenalidomide and dexamethasone were administered at 25 mg (days 1-21) and 40 mg (days 1, 8, 15 and 22), respectively. Twenty-six patients were enrolled. Patients had received a median of four prior regimens and 88.5% and 61.5% received previous bortezomib and lenalidomide, respectively. High-risk cytogenetics were seen in 53.8% of patients. The overall response rate was 88.5%. A higher rate of hyperglycemia was observed than in a previous carfilzomib monotherapy study, but this was attributed to dexamethasone. Carfilzomib pharmacokinetics were not affected by lenalidomide and dexamethasone. The KRd regimen was well tolerated and showed efficacy in Japanese RRMM patients. PMID- 28092422 TI - International consensus principles for ethical wildlife control. AB - Human-wildlife conflicts are commonly addressed by excluding, relocating, or lethally controlling animals with the goal of preserving public health and safety, protecting property, or conserving other valued wildlife. However, declining wildlife populations, a lack of efficacy of control methods in achieving desired outcomes, and changes in how people value animals have triggered widespread acknowledgment of the need for ethical and evidence-based approaches to managing such conflicts. We explored international perspectives on and experiences with human-wildlife conflicts to develop principles for ethical wildlife control. A diverse panel of 20 experts convened at a 2-day workshop and developed the principles through a facilitated engagement process and discussion. They determined that efforts to control wildlife should begin wherever possible by altering the human practices that cause human-wildlife conflict and by developing a culture of coexistence; be justified by evidence that significant harms are being caused to people, property, livelihoods, ecosystems, and/or other animals; have measurable outcome-based objectives that are clear, achievable, monitored, and adaptive; predictably minimize animal welfare harms to the fewest number of animals; be informed by community values as well as scientific, technical, and practical information; be integrated into plans for systematic long-term management; and be based on the specifics of the situation rather than negative labels (pest, overabundant) applied to the target species. We recommend that these principles guide development of international, national, and local standards and control decisions and implementation. PMID- 28092423 TI - 1 H qNMR Quantification of Annonaceous Acetogenins in Crude Extracts of Annona muricata L. Fruit Pulp. AB - INTRODUCTION: Annonaceous acetogenins (AAGs) constitute a group of environmental neurotoxins, possibly implicated in sporadic atypical Parkinsonism/dementia complexes. The recent evidencing of complex mixtures of AAGs in edible fruits and derived food products requires efficient and practical analytical tools for an estimation of human exposure. OBJECTIVE: To develop a simple method for the direct quantitation of the majority of AAGs (sub-types 1a and 1b) within crude extracts, using commonly available 1 H-NMR spectrometers, for food control. METHODOLOGY: Method development was carried out on 400 MHz and 300 MHz spectrometers, for routine application on fruits crude extracts of Annona muricata L. The method was validated with annonacin and squamocin as reference compounds. Two internal standards (ISs), fumaric acid and dimethyl fumarate, were successfully used, in deuterated methanol (CD3 OD) and deuterated chloroform (CDCl3 ), respectively. RESULTS: Quantitation was carried out using signals corresponding to the deshielded ethylenic protons characterising most AAGs, at delta 7.18 or delta 6.98 ppm in CDCl3 . The limit of quantification (LOQ) was 2.5 mM, with acceptable accuracy, and the limit of detection (LOD) was 0.5 mM. The AAGs contents measured in seven distinct fruit samples of Annona muricata ranged from 14 MUmol to 226 MUmol of AAGs per 100 g fresh pulp (i.e. 0.14 mmol to 1.3 mmol of AAGs per fruit). CONCLUSION: A simple, accurate and specific method for quantification of AAGs content was developed and validated for routine application to fruit pulp crude extracts. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28092424 TI - Continuous Films of Self-Assembled Graphene Quantum Dots for n-Type Doping of Graphene by UV-Triggered Charge Transfer. AB - The demands to examine components serving as one of the active layers in heterostructures of 2D materials have been recently increasing. Nanomaterials synthesized from a solution process and their self-assembly can provide a promising route to build a new type of mixed dimensional heterostructures, and several methodologies have been reported previously to construct 2D assemblies from colloidal nanostructures in solution. Graphene quantum dots (GQDs), receiving much interest due to the tunable optical band gap and the capability of chemical functionalization, are considered as emerging nanomaterials for various optoelectronic and biological applications. This study fabricates a closely packed GQDs film (GQDF) from colloidal solutions using a solvent-assisted Langmuir Blodgett method, and investigates the optical and electrical characteristics of the heterostacked graphene/GQD film (G/GQDF) structures. It is observed that the GQDF plays a role not only as a buffer layer that isolates Chemical Vapor Deposited graphene (CVD graphene) from undesired p-doping but also as a photoactive layer that triggers n-doping of the heterostacked CVD graphene film. The n-doping density of the G/GQDF device is proportional to UV irradiation time, but its carrier mobility remains constant regardless of doping densities, which are unique characteristics that have not been observed in other doping methods. PMID- 28092425 TI - Chemical Composition of the Essential Oil of Nigeria Grown Hoslundia opposita Vahl (Lamiaceae) Dried Leaves and Its Bioactivity against Cowpea Seed Bruchid. AB - Due to several ecological and human hazards of synthetic pesticides in postharvest crop protection, there is the need to search for eco-friendly alternatives. In this study, chemical composition and insecticidal activities of essential oil (EO) obtained from Hoslundia opposita dried leaves were evaluated against cowpea seed bruchid. Eight constituents, predominated by oxygenated monoterpenes (78.86%), were identified using Gas Chromatography (GC)/MS. The constituents were 1,8-cineole (1; 61.15%), followed by alpha-terpineol (2; 16.81%), beta-phellandrene (3; 13.24%), beta-farnesene (4; 3.55%), alpha-pinene (5; 1.89%), Germacrene D (6; 1.83%), cis-sabinene hydrate (7; 0.90%) and caryophyllene (8; 0.63%). In fumigation bioassay, at 6 h after exposure (HAE), 0.78 ml EO/l air caused 35.33% mortality which was significantly lower than 60.90% and 63.6% observed at 3.15 and 6.25 ml/l air, respectively. Mortality reached 90.0% at 24 HAE regardless of the applied concentration. Lethal time for 50% of the bruchids (LT50 ) at concentration of 0.78 ml/l air (6.89 h) was higher than the LT50 at 3.15 and 6.25 ml/l air (4.72 and 4.44 h, respectively). H. opposita EO reduced Callosobruchus maculatus oviposition, while progeny emergence observed in EO-treated seeds (2.42 - 25.73) was significantly (P < 0.05) lower than 51.56 observed in control. The results confirm H. opposita EO's potentials for control of cowpea bruchids. PMID- 28092427 TI - Layer Dependence and Light Tuning Surface Potential of 2D MoS2 on Various Substrates. AB - Here surface potential of chemical vapor deposition (CVD) grown 2D MoS2 with various layers is reported, and the effect of adherent substrate and light illumination on surface potential of monolayer MoS2 are investigated. The surface potential of MoS2 on Si/SiO2 substrate decreases from 4.93 to 4.84 eV with the increase in the number of layer from 1 to 4 or more. Especially, the surface potentials of monolayer MoS2 are strongly dependent on its adherent substrate, which are determined to be 4.55, 4.88, 4.93, 5.10, and 5.50 eV on Ag, graphene, Si/SiO2 , Au, and Pt substrates, respectively. Light irradiation is introduced to tuning the surface potential of monolayer MoS2 , with the increase in light intensity, the surface potential of MoS2 on Si/SiO2 substrate decreases from 4.93 to 4.74 eV, while increases from 5.50 to 5.56 eV on Pt substrate. The I-V curves on vertical of monolayer MoS2 /Pt heterojunction show the decrease in current with the increase of light intensity, and Schottky barrier height at MoS2 /Pt junctions increases from 0.302 to 0.342 eV. The changed surface potential can be explained by trapped charges on surface, photoinduced carriers, charge transfer, and local electric field. PMID- 28092426 TI - Incomplete reversibility of platelet inhibition following prolonged exposure to ticagrelor. AB - : Essentials Irreversible platelet inhibition persists after reversibly-binding ticagrelor is discontinued. Reversibility of platelet inhibition by ticagrelor and its active metabolite was assessed. Incomplete recovery was observed after prolonged exposure to ticagrelor. Activated GPIIb-IIIa and P-selectin, not platelet reactivity index, showed irreversibility. SUMMARY: Introduction Ticagrelor is described as a reversible P2Y12 antagonist. However, residual platelet inhibition persists after discontinuation of ticagrelor when plasma levels are undetectable. We assessed the reversibility of platelet inhibition by ticagrelor and its active metabolite (T-AM) in comparison with cangrelor and prasugrel's active metabolite (P-AM). Methods Whole blood was treated in vitro with ~ 50% inhibitory concentrations of ticagrelor, T-AM, cangrelor, P-AM and assessed for ADP-stimulated activated GPIIb-IIIa and P-selectin and vasodilator stimulated phosphoprotein (VASP) platelet reactivity index (PRI) before and after 100-fold dilution. Results Platelets exposed for 30 min to ticagrelor, T-AM or cangrelor showed full recovery of activated GPIIb-IIIa but only partial recovery of P-selectin. Longer exposure (24 h) to the drug decreased reversibility of activated GPIIb-IIIa by ticagrelor (65.1% [49.5-80.6], % of vehicle with 95% confidence interval [CI]) and T-AM (88.8% [79.2-98.3]), but not by cangrelor (101.4% [96.4-106.4]). Compared with 30 min exposure, the reversibility of P selectin further decreased after 24 h exposure to ticagrelor (from 91.8% [82.1 101.5] to 51.8% [45.5-85.0]), but not T-AM (from 79.0% [67.8-90.3] to 77.4% [61.8 93.1]) or cangrelor (from 76.0% [67.6-84.4] to 76.2% [70.6-81.8]). In contrast, 24 h exposure to ticagrelor, T-AM and cangrelor resulted in full recovery of platelet reactivity as measured by PRI. Platelets exposed to P-AM showed no recovery of ADP reactivity. Conclusions Incomplete recovery after prolonged exposure to ticagrelor, observed by activated GPIIb-IIIa and P-selectin but not upstream VASP signaling, suggests that P2Y12 regains functionality and irreversible changes occur independent of VASP signaling. PMID- 28092428 TI - Reproducibility of clinical events adjudications in a trial of venous thromboembolism prevention. AB - : Essentials The reproducibility of Clinical Events Committee (CEC) adjudications is almost unexplored. A random selection of events from a venous thromboembolism trial was blindly re-adjudicated. 'Unexplained sudden deaths' (possible fatal embolism) explained most discordant adjudications. A precise definition for CEC adjudication of this type of events is needed and proposed. SUMMARY: Background When clinical trials use clinical endpoints, establishing independent Clinical Events Committees (CECs) is recommended to homogenize the interpretation of investigators' data. However, the reproducibility of CEC adjudications is almost unexplored. Objectives To assess the reproducibility of CEC adjudications in a trial of venous thromboembolism (VTE) prevention. Methods The PREVENU trial, a multicenter trial of VTE prevention, included 15 351 hospitalized medical patients. The primary endpoint was the composite of symptomatic VTE, major bleeding or unexplained sudden death (interpreted as possible fatal pulmonary embolism [PE]) at 3 months. The CEC comprised a chairman and four pairs of adjudicators. Of 2970 adjudicated clinical events, a random selection of 179 events (121 deaths, 40 bleeding events, and 18 VTE events) was blindly resubmitted to the CEC. Kappa values and their 95% confidence intervals (CIs) were calculated to measure adjudication agreement. Results Overall, 18 of 179 (10.1%, 95% CI 6.5-15.3%) adjudications proved discordant. Agreement for the PREVENU composite primary endpoint was good (kappa = 0.73, 95% CI 0.61-0.85). When analyzed separately, agreements were very good for non-fatal VTE events (1, 95% CI not applicable), moderate for all (fatal and non-fatal) VTE events (0.58, 95% CI 0.34-0.82), good for fatal and non-fatal major bleeding events (0.71, 95% CI 0.55-0.88), and moderate for all fatal events (0.60, 95% CI 0.40-0.81). Unexplained sudden death interpreted as possible fatal PE was responsible for nine of 18 (50%) discordant adjudications. Conclusion The reproducibility of CEC adjudications was good or very good for non-fatal VTE and bleeding events, but insufficient for VTE-related deaths, for which more precise and widely accepted definitions are needed. PMID- 28092429 TI - Residents' understanding of adult congenital heart disease. AB - OBJECTIVE: Medical residents are exposed to increasing numbers of adults with congenital heart disease (ACHD). While inadequate ACHD knowledge may lead to inappropriate practice, this educational deficit has not been investigated. Our aim was to analyze residents' attitudes, perceived ability, and knowledge of ACHD medicine. DESIGN, METHODS, OUTCOME MEASURES: A single center, multiprogram cross sectional study was conducted in 2015 using an electronic survey to assess 472 medical residents' perceived knowledge and self-assessed skills related to ACHD medicine. Demographic data obtained included age, gender, level of training and program type. RESULTS: The survey was completed by 25% of surveyed residents (N = 116, median age 29.5 years, 39% male). Responses were received from Family Physician (FP; 8.5%), Internal Medicine (43%), Pediatrics (34%), Internal Medicine-Pediatrics (IM-P; 7%), and Transitional residents (4%). There was no difference between ACHD knowledge and year of residency (P = NS). IM-P residents were more confident in their knowledge and assessment of ACHD patients (P < .05). Those with prior cardiology elective during residency (59%) demonstrated a significant correlation with ACHD knowledge (P < .05) and confidence in ability to assess ACHD patients (P < .05). Overall, knowledge and confidence in ACHD assessment trended towards a positive correlation (P = .061, gamma statistic = 0.8). Residents' learning preferences included ACHD lectures (81.6%) and web sites (60.2%). CONCLUSION: Most residents in this study lacked ACHD knowledge or comfort level required to care for adults with complex defects. Still, residents remain interested in teaching venues to improve examination skills. Residency programs should include routine cardiology electives to prepare residents to care for this complex group of patients. PMID- 28092430 TI - Optimal Reactivity and Improved Self-Healing Capability of Structurally Dynamic Polymers Grafted on Janus Nanoparticles Governed by Chain Stiffness and Spatial Organization. AB - Structurally dynamic polymers are recognized as a key potential to revolutionize technologies ranging from design of self-healing materials to numerous biomedical applications. Despite intense research in this area, optimizing reactivity and thereby improving self-healing ability at the most fundamental level pose urgent issue for wider applications of such emerging materials. Here, the authors report the first mechanistic investigation of the fundamental principle for the dependence of reactivity and self-healing capabilities on the properties inherent to dynamic polymers by combining large-scale computer simulation, theoretical analysis, and experimental discussion. The results allow to reveal how chain stiffness and spatial organization regulate reactivity of dynamic polymers grafted on Janus nanoparticles and mechanically mediated reaction in their reverse chemistry, and, particularly, identify that semiflexible dynamic polymers possess the optimal reactivity and self-healing ability. The authors also develop an analytical model of blob theory of polymer chains to complement the simulation results and reveal essential scaling laws for optimal reactivity. The findings offer new insights into the physical mechanism in various systems involving reverse/dynamic chemistry. These studies highlight molecular engineering of polymer architecture and intrinsic property as a versatile strategy in control over the structural responses and functionalities of emerging materials with optimized self-healing capabilities. PMID- 28092431 TI - Test-Paper-Like Photonic Crystal Viscometer. AB - A test-paper-like photonic crystal (PC) viscometer is fabricated based on the positive correlation between viscosity and the infiltration time for viscous liquid to entirely soak the PC film. It can be broadly used in different occasions to quickly determine the viscosity for many liquids, considering its portable and disposable characteristics and the requirement of little samples. PMID- 28092432 TI - Highly Ordered Nanoring Arrays Formed by Templated Si-Containing Triblock Terpolymer Thin Films. AB - Laterally ordered nanorings with a periodicity of 38 nm are produced from the directed self-assembly of poly(1,1-dimethylsilacyclobutane)-block-polystyrene block-poly(methyl methacrylate) thin films on topographically patterned substrates. Such nanoscale arrays with vertically oriented rings are highly desired in technological applications including memory using magnetic recording, metamaterial, waveguide, etc. PMID- 28092433 TI - Design and Analysis of Localized DNA Hybridization Chain Reactions. AB - Theoretical models of localized DNA hybridization reactions on nanoscale substrates indicate potential benefits over conventional DNA hybridization reactions. Recently, a few approaches have been proposed to speed-up DNA hybridization reactions; however, experimental confirmation and quantification of the acceleration factor have been lacking. Here, a system to investigate localized DNA hybridization reactions on a nanoscale substrate is presented. The system consists of six metastable DNA hairpins that are tethered to a long DNA track. The localized DNA hybridization reaction of the proposed system is triggered by a DNA strand which initiates the subsequent self-assembly. Fluorescence kinetics indicates that the half-time completion of a localized DNA hybridization chain reaction is six times faster than the same reaction in the absence of the substrate. The proposed system provides one of the first known quantification of the speed-up of DNA hybridization reactions due to the locality effect. PMID- 28092434 TI - 3D Probed Lipid Dynamics in Small Unilamellar Vesicles. AB - Single-molecule fluorescence correlation spectroscopy overcomes the resolution barrier of optical microscopy (10~-20 nm) and is utilized to look into lipid dynamics in small unilamellar vesicles (SUVs; diameter < 100 nm). The fluorescence trajectories of lipid-like tracer 1,1'-dioctadecyl-3,3,3',3' tetramethylindodicarbocyanine (DiD) in the membrane bilayers are acquired at a single-molecule level. The autocorrelation analysis yields the kinetic information on lipid organization, oxygen transport, and lateral diffusion in SUVs' membrane. First, the isomerization feasibility may be restricted by the addition of cholesterols, which form structure conjugation with DiD chromophore. Second, the oxygen transport is prevented from the ultrasmall cluster and cholesterol-rich regions, whereas it can pass through the membrane region with liquid-disordered phase (Ld ) and defects. Third, by analyzing 2D spectra correlating the lipid diffusion coefficient and triplet-state lifetime, the heterogeneity in lipid bilayer can be precisely visualized such as lipid domain with different phases, the defects of lipid packing, and DiD-induced "bouquet" ultrasmall clusters. PMID- 28092435 TI - Microbial biotransformation of five pyrrolidinophenone-type psychoactive substances in wastewater and a wastewater isolated Pseudomonas putida strain. AB - Wastewater-based epidemiology (WBE) employs the analysis of wastewater to detect and quantify drug use and discharge within a community. In this work, transformation products (TP) by microbes in the environment were identified after incubations in wastewater and an isolated microbial strain. The microbial strain was isolated from an enrichment culture of wastewater supplemented with 3,4 methylenedioxy-pyrovalerone, and identified by matrix assisted laser desorption - time of flight mass spectrometry as Pseudomonas putida (P. putida). Five pyrrolidinophenone-type psychoactive substances (PPPS) were then incubated in wastewater and in P. putida tryptic soy broth (TSB) growth cultures. TPs were identified using liquid chromatography coupled to mass spectrometry techniques. All TPs observed in P. putida TSB growth cultures were also identified in wastewater incubations. The main TP for all PPPSs in P. putida TSB growth cultures, and two PPPSs incubated in wastewater, were the N-desalkyl-carboxy-TPs. The study showed P. putida TSB growth cultures used for identification of TPs in wastewater, represent parts of the microbial community. With data provided in this type of experiments more information will be available to select targets for monitoring drug use by WBE. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28092436 TI - Single Upconversion Nanoparticle-Bacterium Cotrapping for Single-Bacterium Labeling and Analysis. AB - Detecting and analyzing pathogenic bacteria in an effective and reliable manner is crucial for the diagnosis of acute bacterial infection and initial antibiotic therapy. However, the precise labeling and analysis of bacteria at the single bacterium level are a technical challenge but very important to reveal important details about the heterogeneity of cells and responds to environment. This study demonstrates an optical strategy for single-bacterium labeling and analysis by the cotrapping of single upconversion nanoparticles (UCNPs) and bacteria together. A single UCNP with an average size of ~120 nm is first optically trapped. Both ends of a single bacterium are then trapped and labeled with single UCNPs emitting green light. The labeled bacterium can be flexibly moved to designated locations for further analysis. Signals from bacteria of different sizes are detected in real time for single-bacterium analysis. This cotrapping method provides a new approach for single-pathogenic-bacterium labeling, detection, and real-time analysis at the single-particle and single-bacterium level. PMID- 28092437 TI - 3D Porous Nanoarchitectures Derived from SnS/S-Doped Graphene Hybrid Nanosheets for Flexible All-Solid-State Supercapacitors. AB - 3D porous nanoarchitectures derived from SnS/S-doped graphene hybrid nanosheets are successfully prepared by controllable thermal conversion of oleylamine-capped mixed-phase SnS2 -SnS nanodisks precursors, and employed as electroactive material to fabricate flexible, symmetric, all-solid-state supercapacitors. The fabricated solid devices exhibit very high areal specific capacitance (2.98 mF cm 2 ), good cycling stability (99% for 10 000 cycles), excellent flexibility, and desirable mechanical stability. PMID- 28092438 TI - Biofunctionalization of Nerve Interface via Biocompatible Polymer-Roughened Pt Black on Cuff Electrode for Chronic Recording. AB - Peripheral nerve cuff electrodes with roughened Pt black (BPt) are coated with polyethylene glycol (PEG) and Nafion (NF). Although the influence of coated PEG and Nafion on roughened BPt on the electrical properties is weak, the cuff electrode with BPt/PEG and BPt/Nafion exhibits some very important properties. For example, it markedly decreases interfacial impedance, increases charge storage capacity (CSC) due to retaining the BPt surface structure, good stability without exfoliation in repetitive cyclic voltammetry scanning because it is protected by PEG or Nafion coating. In cell viability test, Nafion-coated BPt does not show cytotoxicity to rat Schwann cell line (S16) at 24 and 72 h with the Nafion coating ranging from 0.1 to 10 mg cm-2 . In addition, real-time polymerase chain reaction (PCR) analysis indicates that Schwann cell differentiation (S100 calcium-binding protein B, myelin basic protein, peripheral myelin protein 22), proliferation (proliferating cell nuclear antigen, cyclin-dependent kinase 1 (CDK1)), and adhesion molecules (neural cell adhesion molecule, laminin, fibronectin) are upregulated up to 5 mg cm-2 of Nafion. In animal study, the BPt/Nafion reduces infiltration of fibrotic tissue with high axonal maintenance with upregulation of proliferation (CDK1), adhesion (laminin, neuronal cell adhesion molecule), and neurotrophic factor receptor-related (gdnf family receptor alpha 1) mRNA expressions. PMID- 28092439 TI - Molecular Details of the PH Domain of ACAP1BAR-PH Protein Binding to PIP Containing Membrane. AB - ACAP1 proteins were previously reported to specifically bind PIP2-containing cell membranes and form well-structured protein lattices in order to conduct membrane tubulation. We carried out molecular dynamics simulations to characterize orientation of the PH domains with respect to the BAR domains inside the protein dimer. Followed by molecular dynamics simulations, we present a comprehensive orientation analysis of PH domain under different states including unbound and bound with lipids. We have examined two binding pockets on the PH domain and present PMF profiles of the two pockets to account for their preference to PIP2 lipids. Combining orientation analysis and studies of binding pockets, our simulations results reveal valuable molecular basis for protein-lipid interactions of ACAP1 proteins during membrane remodeling process. PMID- 28092440 TI - Molecular Interactions between Graphene and Biological Molecules. AB - Applications of graphene have extended into areas of nanobio-technology such as nanobio-medicine, nanobio-sensing, as well as nanoelectronics with biomolecules. These applications involve interactions between proteins, peptides, DNA, RNA etc. and graphene, therefore understanding such molecular interactions is essential. For example, many applications based on using graphene and peptides require peptides to interact with (e.g., noncovalently bind to) graphene at one end, while simultaneously exposing the other end to the surrounding medium (e.g., to detect analytes in solution). To control and characterize peptide behavior on a graphene surface in solution is difficult. Here we successfully probed the molecular interactions between two peptides (cecropin P1 and MSI-78(C1)) and graphene in situ and in real-time using sum frequency generation (SFG) vibrational spectroscopy and molecular dynamics (MD) simulation. We demonstrated that the distribution of various planar (including aromatic (Phe, Trp, Tyr, and His)/amide (Asn and Gln)/Guanidine (Arg)) side-chains and charged hydrophilic (such as Lys) side-chains in a peptide sequence determines the orientation of the peptide adsorbed on a graphene surface. It was found that peptide interactions with graphene depend on the competition between both planar and hydrophilic residues in the peptide. Our results indicated that part of cecropin P1 stands up on graphene due to an unbalanced distribution of planar and hydrophilic residues, whereas MSI-78(C1) lies down on graphene due to an even distribution of Phe residues and hydrophilic residues. With such knowledge, we could rationally design peptides with desired residues to manipulate peptide-graphene interactions, which allows peptides to adopt optimized structure and exhibit excellent activity for nanobio-technological applications. This research again demonstrates the power to combine SFG vibrational spectroscopy and MD simulation in studying interfacial biological molecules. PMID- 28092441 TI - Local Mode Analysis: Decoding IR Spectra by Visualizing Molecular Details. AB - Integration of experimental and computational approaches to investigate chemical reactions in proteins has proven to be very successful. Experimentally, time resolved FTIR difference-spectroscopy monitors chemical reactions at atomic detail. To decode detailed structural information encoded in IR spectra, QM/MM calculations are performed. Here, we present a novel method which we call local mode analysis (LMA) for calculating IR spectra and assigning spectral IR-bands on the basis of movements of nuclei and partial charges from just a single QM/MM trajectory. Through LMA the decoding of IR spectra no longer requires several simulations or optimizations. The novel approach correlates the motions of atoms of a single simulation with the corresponding IR bands and provides direct access to the structural information encoded in IR spectra. Either the contributions of a particular atom or atom group to the complete IR spectrum of the molecule are visualized, or an IR-band is selected to visualize the corresponding structural motions. Thus, LMA decodes the detailed information contained in IR spectra and provides an intuitive approach for structural biologists and biochemists. The unique feature of LMA is the bidirectional analysis connecting structural details to spectral features and vice versa spectral features to molecular motions. PMID- 28092442 TI - Upconverted Photosensitization of Tb Visible Emission by NIR Yb Excitation in Discrete Supramolecular Heteropolynuclear Complexes. AB - Addition of Tb3+ salts to a solution of a (YbLD) complex in D2O resulted in the formation of [(YbLD)2Tbx] (x = 1 to 3) complexes that, upon NIR excitation at 980 nm, showed an unprecedented Yb to Tb upconversion sensitization phenomenon resulting in the observation of the typical green emission of Tb. PMID- 28092443 TI - Kinetics and Structure of a Cold-Adapted Hetero-Octameric ATP Phosphoribosyltransferase. AB - Adenosine 5'-triphosphate phosphoribosyltransferase (ATPPRT) catalyzes the first step in histidine biosynthesis, the condensation of ATP and 5-phospho-alpha-d ribosyl-1-pyrophosphate to generate N1-(5-phospho-beta-d-ribosyl)-ATP and inorganic pyrophosphate. The enzyme is allosterically inhibited by histidine. Two forms of ATPPRT, encoded by the hisG gene, exist in nature, depending on the species. The long form, HisGL, is a single polypeptide chain with catalytic and regulatory domains. The short form, HisGS, lacks a regulatory domain and cannot bind histidine. HisGS instead is found in complex with a regulatory protein, HisZ, constituting the ATPPRT holoenzyme. HisZ triggers HisGS catalytic activity while rendering it sensitive to allosteric inhibition by histidine. Until recently, HisGS was thought to be catalytically inactive without HisZ. Here, recombinant HisGS and HisZ from the psychrophilic bacterium Psychrobacter arcticus were independently overexpressed and purified. The crystal structure of P. arcticus ATPPRT was determined at 2.34 A resolution, revealing an equimolar HisGS-HisZ hetero-octamer. Steady-state kinetics indicate that both the ATPPRT holoenzyme and HisGS are catalytically active. Surprisingly, HisZ confers only a modest 2-4-fold increase in kcat. Reaction profiles for both enzymes cannot be distinguished by 31P nuclear magnetic resonance, indicating that the same reaction is catalyzed. The temperature dependence of kcat shows deviation from Arrhenius behavior at 308 K with the holoenzyme. Interestingly, such deviation is detected only at 313 K with HisGS. Thermal denaturation by CD spectroscopy resulted in Tm's of 312 and 316 K for HisZ and HisGS, respectively, suggesting that HisZ renders the ATPPRT complex more thermolabile. This is the first characterization of a psychrophilic ATPPRT. PMID- 28092444 TI - Engineering of the Bacillus circulans beta-Galactosidase Product Specificity. AB - Microbial beta-galactosidase enzymes are widely used as biocatalysts in industry to produce prebiotic galactooligosaccharides (GOS) from lactose. GOS mixtures are used as beneficial additives in infant formula to mimic the prebiotic effects of human milk oligosaccharides (hMOS). The structural variety in GOS mixtures is significantly lower than in hMOS. Since this structural complexity is considered as the basis for the multiple biological functions of hMOS, it is important to broaden the variety of GOS structures. In this study, residue R484 near +1 subsite of the C-terminally truncated beta-galactosidase from Bacillus circulans (BgaD-D) was subjected to site saturation mutagenesis. Especially the R484S and R484H mutant enzymes displayed significantly altered enzyme specificity, leading to a new type of GOS mixture with altered structures and linkage types. The GOS mixtures produced by these mutant enzymes contained 14 structures that were not present in the wild-type enzyme GOS mixture; 10 of these are completely new structures. The GOS produced by these mutant enzymes contained a combination of (beta1 -> 3) and (beta1 -> 4) linkages, while the wild-type enzyme has a clear preference toward (beta1 -> 4) linkages. The yield of the trisaccharide beta-d Galp-(1 -> 3)-beta-d-Galp-(1 -> 4)-d-Glcp produced by mutants R484S and R484H increased 50 times compared to that of the wild-type enzyme. These results indicate that residue R484 is crucial for the linkage specificity of BgaD-D. This is the first study showing that beta-galactosidase enzyme engineering results in an altered GOS linkage specificity and product mixture. The more diverse GOS mixtures produced by these engineered enzymes may find industrial applications. PMID- 28092445 TI - miR-29b promotes skin wound healing and reduces excessive scar formation by inhibition of the TGF-beta1/Smad/CTGF signaling pathway. AB - The hypertrophic scar is a medical difficulty of humans, which has caused great pain to patients. Here, we investigated the inhibitory effect of miR-29b on scar formation. The scalded model was established in mice and miR-29b mimics or a negative control was subcutaneously injected into the injury skin. Then various molecular biological experiments were performed to assess the effect of miR-29b on scar formation. According to our present study, first, the results demonstrated that miR-29b was down-regulated in thermal injury tissue and miR-29b treatment could promote wound healing, inhibit scar formation, and alleviate histopathological morphologic alteration in scald tissues. Additionally, miR-29b treatment suppressed collagen deposition and fibrotic gene expression in scar tissues. Finally, we found that miR-29b treatment inhibited the TGF beta1/Smad/CTGF signaling pathway. Taken together, our data suggest that miR-29b treatment has an inhibitory effect against scar formation via inhibition of the TGF-beta1/Smad/CTGF signaling pathway and may provide a potential molecular basis for future treatments for hypertrophic scars. PMID- 28092446 TI - When the Next Disease Strikes: How To Communicate (and How Not To). PMID- 28092447 TI - Healthcare Preparedness: Saving Lives. PMID- 28092448 TI - Prevention of the Development or Use of Biological Weapons. PMID- 28092449 TI - Long noncoding RNA as an indicator differentiating schizophrenia from major depressive disorder and generalized anxiety disorder in nonpsychiatric hospital. AB - AIM: Depression and anxiety are common symptoms for schizophrenia (SZ) in the early onset. This study aimed to determine whether long noncoding RNAs (lncRNAs) can be indicators for diagnosing SZ in nonpsychiatric hospitals. MATERIALS & METHODS: Three upregulated SZ lncRNAs, six downregulated major depressive disorder (MDD) lncRNAs and three upregulated generalized anxiety disorder (GAD) lncRNAs were cross-validated in 45 SZ patients, 48 MDD patients, 52 GAD patients and 40 controls by reverse transcription-PCR. RESULTS: Three SZ lncRNAs were significantly downregulated in GAD patients. The expression of the six MDD lncRNAs showed an opposite trend in SZ patients, and the three GAD lncRNAs also showed significant differences between SZ and GAD patients. CONCLUSION: The three upregulated SZ lncRNAs are not entirely replicated in MDD and GAD patients and could be potential indicators for distinguishing SZ from MDD and GAD in nonpsychiatric hospital. PMID- 28092451 TI - Assessing and Addressing US Health Security Risks. PMID- 28092450 TI - Preintervention Profiles of Information, Motivational, and Behavioral Self Efficacy for Methamphetamine Use and HIV Medication Adherence Among Gay and Bisexual Men. AB - Although rates of crystal methamphetamine use in the United States have fallen from their peak in the mid-2000s, use remains a major public health concern, which disproportionately affects gay and bisexual men (GBM). It poses a particular challenge for HIV-positive men, for whom it has been linked to medication adherence problems as well as compromised immune function. Although the information, motivation, and behavioral skills (IMB) model has been widely used to conceptualize health behavior, little is known about GBM's initial levels of information, motivation, and behavioral self-efficacy to improve HIV medication adherence and to reduce crystal methamphetamine use at the outset of treatment. The present study identified profiles of IMB factors related to HIV medication adherence and crystal methamphetamine use in a sample of 210 HIV positive GBM who consented to participate in an intervention study. Results indicated three distinct patterns of IMB factors. The largest group was ready to change both adherence and methamphetamine use (n = 104). This group also had depression scores that were significantly lower than other groups. A second group appeared ready to change medication adherence, but was ambivalent about changing methamphetamine use (n = 60). This group reported significantly more symptoms of methamphetamine dependence than the other groups. A third group was characterized by global IMB barriers to change (n = 46). Results are discussed in the context of tailoring psychoeducation, motivational interviewing, and cognitive behavioral interventions to match these preintervention patterns of IMB factors. PMID- 28092452 TI - Partnering with Communities to Foster Trust, Save More Lives, and Prompt Recovery in Epidemics and Disasters. PMID- 28092453 TI - International Engagement Is Critical to Fighting Epidemics. PMID- 28092454 TI - Maintaining US Leadership in Emerging Biotechnologies to Grow the Economy of the Future. PMID- 28092455 TI - Funding and Organization of US Federal Health Security Programs. PMID- 28092456 TI - Improving Biosurveillance Systems to Enable Situational Awareness During Public Health Emergencies. PMID- 28092458 TI - A Biosafety Agenda to Spur Biotechnology Development and Prevent Accidents. PMID- 28092457 TI - Insulin Sensitivity and Inflammation Mediate the Impact of Fitness on Cerebrovascular Health in Adolescents. AB - BACKGROUND/OBJECTIVES: To investigate in adolescents the relationships between retinal vessel diameter, physical fitness, insulin sensitivity, and systemic inflammation. METHODS: We evaluated 157 adolescents, 112 with excessive weight and 45 lean, all without type 2 diabetes mellitus. All received detailed evaluations, including measurements of retinal vessel diameter, insulin sensitivity, levels of inflammation, and physical fitness. RESULTS: Overweight/obese adolescents had significantly narrower retinal arteriolar and wider venular diameters, significantly lower insulin sensitivity, and physical fitness. They also had decreased levels of anti-inflammatory and increased levels of proinflammatory markers as well as an overall higher inflammation balance score. Fitness was associated with larger retinal arteriolar and narrower venular diameters and these relationships were mediated by insulin sensitivity. We demonstrate that inflammation also mediates the relationship between fitness and retinal venular, but not arterial diameter; insulin sensitivity and inflammation balance score jointly mediate this relationship with little overlap in their effects. CONCLUSIONS: Increasing fitness and insulin sensitivity and reducing inflammation among adolescents carrying excess weight may improve microvascular integrity. Interventions to improve physical fitness and insulin function and reduce inflammation in adolescents, a group likely to benefit from such interventions, may reduce not only cardiovascular disease in middle age, but also improve cerebrovascular function later in life. PMID- 28092459 TI - Toward High-Throughput and Multiplexed Imaging of Genome Organization. AB - Dr. Eric Joyce from the Department of Genetics at the University of Pennsylvania was awarded The President's Innovation award at the annual Society of Biomolecular Imaging and Informatics meeting held in Boston, September 2016. Chromosome interactions are a fundamental aspect of nuclear organization that can activate and silence genes or even direct chromosome rearrangements. However, the molecular mechanisms underlying how chromosomal segments find each other and form stable interactions within cells remain unknown. To address this gap, we have recently developed two technologies that use fluorescent in situ hybridization (FISH) to interrogate chromosome positioning at single-cell resolution. The first is a technology for high-throughput FISH, and the other, called Oligopaints, is a new type of probe that reduces the cost and increases the resolution of FISH. Here, I review our use of these two technologies to uncover and characterize the molecular mechanisms that govern chromosome pairing in Drosophila. I further describe how these methods should benefit a broad spectrum of research fields, including those focusing on chromatin looping, compaction, replication, homologous recombination, and DNA repair. PMID- 28092460 TI - A Three-Dimensional Lymphatic Endothelial Cell Tube Formation Assay to Identify Novel Kinases Involved in Lymphatic Vessel Remodeling. AB - The lymphatic system is a series of vessels that transport cells and excess fluid from tissues to the blood vascular system. Normally quiescent, the lymphatics can grow or remodel in response to developmental, immunological, or cells pathological stimuli. Lymphatic vessels comprise lymphatic endothelial cells (LECs) that can respond to external growth factors by undergoing proliferation, migration, adhesion, and tube and lumen formation into new vessel structures, a process known as lymphangiogenesis. To understand the key gene and signaling pathways necessary for lymphangiogenesis and lymphatic vessel remodeling, we have developed a three-dimensional LEC tube formation assay to explore the role of kinase signaling in these processes. The collagen-overlay-based assay was used with primary human adult dermal LECs to investigate a library of 60 tyrosine kinase (TK) and TK-like genes by siRNA knockdown. Nine candidate genes were identified and characterized for their ability to modify key parameters of lymphatic tube formation, including tube length, area, thickness, branching, and number of blind-ended sacs. Four genes-ZAP70, IRAK4, RIPK1, and RIPK2-were identified as high-confidence hits after tertiary deconvolution screens and demonstrate the utility of the assay to define LEC genes critical for the formation of tube structures. This assay facilitates the identification of potential molecular targets for novel drugs designed to modulate the remodeling of lymphatics that is important for the metastatic spread of cancer and other pathologies. PMID- 28092461 TI - SBI2 HCS/HCA 3D Imaging: Best Practices and Unmet Needs Colloquium. PMID- 28092462 TI - Adolescent Cardiovascular Functional and Structural Outcomes of Growth Trajectories from Infancy: Prospective Community-Based Study. AB - BACKGROUND: Adult BMI trajectories outperform single BMI measurements as predictors of cardiovascular mortality; however, it is unknown whether this also holds in childhood. We aimed to identify BMI trajectory categories from birth to adolescence, and examine their associations with adolescent cardiovascular function and structure. METHODS: Adolescents from a community-based prospective birth cohort completed 11-16 BMI measurements between birth and adolescence. BMI trajectory categories were identified using latent class analysis. Associations between trajectories and cardiovascular outcomes (14 years) were assessed using adjusted linear regression models (n = 187). Cardiovascular outcomes included systolic/diastolic blood pressure, augmentation index, pulse wave velocity, carotid intima-media thickness, and retinal arteriole-to-venule ratio. Regression models were adjusted for child age, gender, height, socioeconomic status, and puberty status at outcome. RESULTS: Three BMI trajectories emerged that diverged sharply by the age of 1 year. BMI increments were thereafter roughly parallel for those in the low normal (39%) and high normal (51%) groups, but steeper in the consistently overweight (10%) group, which was notable for lack of an obvious adiposity rebound. Cardiovascular function and structure were similar across the three trajectory groups. The only exception was augmentation index, which was 7.8% (95% CI: 2.6 to 13.0) higher in the consistently overweight individuals than the low normal individuals. CONCLUSIONS: We found little evidence that those with consistently higher BMI from infancy experienced poorer cardiovascular function or structure by the age of 14 years. Nonetheless, childhood BMI trajectories track strongly, meaning resolution of risky BMI, while essential to decrease later cardiovascular risk, is unlikely without intervention. PMID- 28092463 TI - CCAAT/Enhancer-Binding Protein beta Mediates the Killing of Toxoplasma gondii by Inducing Autophagy in Nonhematopoietic Cells. AB - Autophagy is a main defense strategy by which infected host cells can virtually induce the killing of parasite, including Toxoplasma gondii. However, the regulatory mechanisms of autophagy in T. gondii-infected nonhematopoietic cells are still unknown. Emerging evidence indicates that CCAAT/enhancer-binding protein beta (C/EBP beta) is associated with the regulation of autophagy. Herein, we hypothesized that C/EBP beta plays roles in inducing autophagy in nonhematopoietic cells. Expression of C/EBP beta was aberrantly regulated in endothelial cells and retinal pigment epithelial cells challenged by T. gondii. Inhibition of C/EBP beta reduced the killing of T. gondii in nonhematopoietic cells, whereas C/EBP beta overexpression resulted in the enhancement of killing of T. gondii as well as the increase in autophagy in infected cells. Furthermore, the mammalian target of rapamycin (mTOR) activation was found to be reduced by C/EBP beta overexpression, but increased by C/EBP beta inhibition. The increase in T. gondii killing induced by C/EBP beta overexpression was blocked by the mTOR activator phosphatidic acid and was increased by the inhibitor AZD8055. In conclusion, we demonstrate that C/EBP beta expression is increased in nonhematopoietic cells infected by T. gondii, resulting in the activation of autophagy in host cells by inhibiting mTOR pathway. PMID- 28092465 TI - A medieval physician: Amirdovlat Amasiatsi (1420-1495). AB - We aimed to acquaint the reader with a medieval physician, Amirdovlat Amasiatsi, who lived and practiced in the 15th century Anatolia. Amirdovlat wrote several books on medicine mainly focusing on phytotherapy and pharmacology using medicinal plants, animal-derived products and minerals. All his works were written in Middle Armenian, spoken Armenian language of the time. In his writings, Amirdovlat described unique recipes that represent a portrayal of medical knowledge and practice at the time in Anatolia where he lived and worked. He discussed the physical and therapeutic properties as well as geographic distributions of various plants and minerals, using different languages, mainly Turkish, Greek, Arabic, French and Persian. Amirdovlat's works not only enhanced our understanding of Armenian medical practices but also provided great deal of information on those of Ancient Greco-Roman as well as Islamic world, demonstrating close relationship of Armenian medicine with Greco-Roman and Islamic medicine. Amirdovlat accomplished this by amalgamating the past and contemporary practices of his time. In this regard, Amirdovlat's works, in particular "Useless for the Ignorant", are very unique playing a significant role in preserving traditions and heritage of different cultures. PMID- 28092464 TI - Expectations for Treatment in Pediatric Weight Management and Relationship to Attrition. AB - BACKGROUND: Attrition in pediatric weight management negatively impacts treatment outcomes. A potentially modifiable contributor to attrition is unmet family expectations. This study aimed to evaluate the association between adolescent and parent/guardian treatment expectations and attrition. PATIENTS AND METHODS: A prospective, nonrandomized, uncontrolled, single-arm pilot trial was conducted among 12 pediatric weight management programs in the Children's Hospital Association's FOCUS on a Fitter Future collaborative. Parents/guardians and adolescents completed an expectations/goals survey at their initial visit, with categories including healthier food/drinks, physical activity/exercise, family support/behavior, and weight management goals. Attrition was assessed at 3 months. RESULTS: From January to August 2013, 405 parents/guardians were recruited and reported about their children (203 adolescents, 202 children <12 years). Of the 203 adolescents, 160 also self-reported. Attrition rate was 42.2% at 3 months. For adolescents, greater interest in family support/behavior skills was associated with decreased odds of attrition at 3 months [odds ratio (OR) 0.75, 95% confidence interval (CI) 0.57-0.98, p = 0.04]. The more discordant the parent/adolescent dyad responses in this category, the higher the odds of attrition at 3 months (OR 1.36, 95% CI 1.04-1.78, p = 0.02). Weight loss was an important weight management goal for both adolescents and parents. For adolescents with this goal, the median weight-loss goal was 50 pounds. Attrition was associated with adolescent weight-loss goals above the desired median (50% above the median vs. 28% below the median, p = 0.02). CONCLUSIONS: Assessing initial expectations may help tailor treatment to meet families' needs, especially through focus on family-based change and realistic goal setting. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT01753063. PMID- 28092466 TI - Clinical performance of the Solana(r) Point-of-Care Trichomonas Assay from clinician-collected vaginal swabs and urine specimens from symptomatic and asymptomatic women. AB - BACKGROUND: Solana(r) (Quidel) is a new rapid (<40 min.) point-of-care (POC) test for qualitative detection of Trichomonas vaginalis (TV) DNA. The assay has two steps: 1) specimen preparation, and 2) amplification and detection using isothermal Helicase-Dependent Amplification (HDA). The objective was to demonstrate the performance of Solana for vaginal swabs and female urines based on comparison to wet mount and TV culture. Performance was also compared to the Aptima-TV assay. METHODS: Urine and four clinician-collected vaginal swabs were collected. The first two were used for FDA composite reference (wet mount; InPouch TV Culture). The third swab was used for Solana. Sensitivity/specificity were based on the reference method. A specimen was considered positive if either test was positive. The fourth swab was for Aptima-TV. RESULTS: Vaginal swabs and urines were obtained from 501 asymptomatic and 543 symptomatic women. Prevalence of TV by was 11.5%. For swabs, Solana(r) demonstrated high sensitivity and specificity from asymptomatic (100%/98.9%) and symptomatic (98.6%/98.5%) women, as well as for urines from asymptomatic (98.0%/98.4%) and symptomatic (92.9%/97.9%) women, compared to the reference method. Compared to Aptima-TV, the sensitivity/specificity was 89.7%/99.0% for swabs and 100%/98.9% for urines. CONCLUSION: The Solana(r) assay performed well compared to the reference assays. PMID- 28092467 TI - Early investigational antibiotics for the treatment of acute exacerbations of chronic bronchitis. AB - INTRODUCTION: Acute exacerbations in patients with chronic bronchitis are a leading cause of hospitalizations and death. Bacteria contribute significantly to such exacerbations. The aim of this review was to explore the potential role of investigational antibiotics in the treatment of these episodes. Areas covered: The available literature in PubMed database, in websites related to investigational drugs and in websites of the producing companies has been searched. The in vitro activity against pathogens involved in acute exacerbations of chronic bronchitis and the pharmacokinetic profile of antibiotics currently under development were taken into consideration for inclusion in the review. Expert opinion: Several novel antimicrobial agents have completed preclinical and Phase I studies and were well-tolerated. Further investigation is mandatory in order to evaluate their future in treatment of chronic bronchitis exacerbations and discover potential advantages compared to already approved antimicrobials. PMID- 28092468 TI - Protecting the Nation from Health Security Threats. PMID- 28092470 TI - Strengthening the US Medical Countermeasure Enterprise for Biological Threats. PMID- 28092469 TI - Investigational drugs in recent clinical trials for treatment-resistant depression. AB - INTRODUCTION: The authors describe the medications for treatment-resistant depression (TRD) in phase II/III of clinical development in the EU and USA and provide an opinion on how current treatment can be improved in the near future. Areas covered: Sixty-two trials were identified in US and EU clinical trial registries that included six investigational compounds in recent phase III development and 12 others in recent phase II clinical trials. Glutamatergic agents have been the focus of many studies. A single intravenous dose of the glutamatergic modulator ketamine produces a robust and rapid antidepressant effect in persons with TRD; this effect continues to remain significant for 1 week. This observation was a turning point that opened the way for other, more selective glutamatergic modulators (intranasal esketamine, AVP-786, AVP-923, AV 101, and rapastinel). Of the remaining compounds, monoclonal antibodies open highly innovative therapeutic options, based on new pathophysiological approaches to depression. Expert commentary: Promising new agents are emerging for TRD treatment. Glutamatergic modulators likely represent a very promising alternative to monoaminergic antidepressant monotherapy. We could see the arrival of the first robust and rapid acting antidepressant drug in the near future, which would strongly facilitate the ultimate goal of recovery in persons with TRD. PMID- 28092472 TI - Using biomarkers to predict and to prevent cardiotoxicity of cancer therapy. AB - INTRODUCTION: Cardiotoxicity is a common complication that may compromise the clinical effectiveness of anticancer therapy. The current standard for monitoring cardiac function detects cardiotoxicity only when a functional impairment has already occurred, not allowing for any early preventive strategy. Areas covered: A novel approach, based on the use of biomarkers has recently emerged, resulting in a very effective tool for early, real-time identification, and monitoring of cardiotoxicity. In particular, cardiac troponin elevation during chemotherapy allows to identify patients more prone to develop myocardial dysfunction and cardiac events. In these patients, use of angiotensin-converting enzyme inhibitors, such as enalapril, has shown to be effective in improving clinical outcomes, giving the chance for cardioprotective strategies in a selected population. The authors reviewed the currently available data about the role of biomarkers in this setting. Expert commentary: Early identification of patients at high risk of cardiotoxicity by cardiac biomarkers - in particular troponin - provides a rationale for targeted preventive strategies against cancer therapy induced left ventricular dysfunction and its associated clinical complications, with the advantage of limiting prophylactic therapy only to a restricted number of patients. Although the major international oncologic societies encourage this approach, some limitations to a routinely use of biomarkers still exist. PMID- 28092471 TI - Genomics pipelines and data integration: challenges and opportunities in the research setting. AB - INTRODUCTION: The emergence and mass utilization of high-throughput (HT) technologies, including sequencing technologies (genomics) and mass spectrometry (proteomics, metabolomics, lipids), has allowed geneticists, biologists, and biostatisticians to bridge the gap between genotype and phenotype on a massive scale. These new technologies have brought rapid advances in our understanding of cell biology, evolutionary history, microbial environments, and are increasingly providing new insights and applications towards clinical care and personalized medicine. Areas covered: The very success of this industry also translates into daunting big data challenges for researchers and institutions that extend beyond the traditional academic focus of algorithms and tools. The main obstacles revolve around analysis provenance, data management of massive datasets, ease of use of software, interpretability and reproducibility of results. Expert commentary: The authors review the challenges associated with implementing bioinformatics best practices in a large-scale setting, and highlight the opportunity for establishing bioinformatics pipelines that incorporate data tracking and auditing, enabling greater consistency and reproducibility for basic research, translational or clinical settings. PMID- 28092473 TI - Changing the Culture of Academic Medicine: Critical Mass or Critical Actors? AB - PURPOSE: By 2006, women constituted 34% of academic medical faculty, reaching a critical mass. Theoretically, with critical mass, culture and policy supportive of gender equity should be evident. We explore whether having a critical mass of women transforms institutional culture and organizational change. METHODS: Career development program participants were interviewed to elucidate their experiences in academic health centers (AHCs). Focus group discussions were held with institutional leaders to explore their perceptions about contemporary challenges related to gender and leadership. Content analysis of both data sources revealed points of convergence. Findings were interpreted using the theory of critical mass. RESULTS: Two nested domains emerged: the individual domain included the rewards and personal satisfaction of meaningful work, personal agency, tensions between cultural expectations of family and academic roles, and women's efforts to work for gender equity. The institutional domain depicted the sociocultural environment of AHCs that shaped women's experience, both personally and professionally, lack of institutional strategies to engage women in organizational initiatives, and the influence of one leader on women's ascent to leadership. CONCLUSIONS: The predominant evidence from this research demonstrates that the institutional barriers and sociocultural environment continue to be formidable obstacles confronting women, stalling the transformational effects expected from achieving a critical mass of women faculty. We conclude that the promise of critical mass as a turning point for women should be abandoned in favor of "critical actor" leaders, both women and men, who individually and collectively have the commitment and power to create gender-equitable cultures in AHCs. PMID- 28092474 TI - Novel histone deacetylase 6 (HDAC6) selective inhibitors: a patent evaluation (WO2014181137). AB - INTRODUCTION: Histone deacetylases (HDACs) are known to deacetylate histones and other proteins, which makes HDAC inhibitors able to affect cell survival, cell signaling, transport, and gene expression. Those effects have been associated to the therapeutic success of HDAC inhibitors. Class I-selective or pan-HDAC inhibitors have been approved for cancer therapy by the US Food and Drug Administration (FDA). Moreover, HDAC6 selective inhibitors entered phase I and II clinical trials for treating multiple myeloma. The development of potent and selective HDAC inhibitors is a hot topic in current drug discovery. Areas covered: The invention described in this patent (WO2014181137) is related to hydroxamic acid derivatives with inhibitory activity towards HDACs, their synthetic process and pharmaceutical formulations, as well as a method for treating patients suffering from a list of selected tumoral, inflammatory, cardiac and chronic disorders. Expert opinion: The compounds disclosed within this patent are selective against HDAC6 and their structure is related to tubastatin A, a known HDAC6 selective inhibitor. They are newly synthesized diarylamines showing an improved selectivity profile compared to other diarylamines under clinical investigation. PMID- 28092476 TI - A Reviewer's Guide to an Evaluation of the Scientific Literature. PMID- 28092475 TI - Temperature Development on the External Root Surface During Laser-Assisted Endodontic Treatment Applying a Microchopped Mode of a 980 nm Diode Laser. AB - OBJECTIVE: The aim of this article was to investigate the temperature increase of the external root surface during laser-assisted endodontic treatment using a diode laser (980 nm) in a microchopped mode. METHODS: Ten freshly extracted, human maxillary incisors with mature apices were collected, prepared to size F4 at working length (ProTaper; Dentsply Maillefer, Ballaigues, Switzerland), mounted to a holder, and irradiated (using spiral movements in coronal direction) with a diode laser (GENTLEray 980 Classic Plus; KaVo, Biberach, Germany) with a 200 MUm fiber in four different treatment groups: Group 1 (control group) was irradiated in six cycles of 5-sec irradiation/20-sec pause with 2.5 W in the pulse mode. Groups 2 to 4 were irradiated at six cycles of 5-sec irradiation/20 sec pause in the microchopped mode (Group 2-1.6 W; Group 3-2.0 W; Group 4-2.5 W). The applied mode was 25 ms on/25 ms off. Within the on period, the laser delivered an intermittent sequence of energy complexes and the maximum output was equal to the nominated output of the device (12 W). Canals were kept moist by sterile saline irrigation in between irradiations, and temperature changes were continuously measured using a thermal imaging camera. Recordings were analyzed by a mixed model (analysis of variance [ANOVA] for repeated measurements). RESULTS: The highest mean of temperature rise, 1.94 degrees C +/- 1.07 degrees C, was measured in Group 4, followed by Group 3 (1.74 degrees C +/- 1.22 degrees C) and Group 2 (1.58 degrees C +/- 1.18 degrees C). The lowest increase occurred in Group 1 (1.06 degrees C +/- 1.20 degrees C). There was a significant difference (p = 0.041) between the groups. Significant differences were found between Groups 1 and 4 (p = 0.007) and 1 and 2 (p = 0.035). In addition, a marginally significant difference between Groups 1 and 2 (p = 0.052) was noted. There was no significant difference between Groups 2, 3, and 4. Despite the low mean values reported, the highest temperature increase (+5.7 degrees C) was measured in one of the specimens of treatment Group 2 at the middle third. CONCLUSIONS: Under the conditions used and within the limitations of the study, the microchopped diode laser irradiation is a safe possible treatment option in laser-assisted endodontic treatment, concerning the temperature elevation on the external root surface. PMID- 28092477 TI - Long-Term Oncological Outcomes of Endoscopic Stenting as a Bridge to Surgery Versus Emergency Surgery for Malignant Colorectal Obstruction: A Comparative Study. AB - AIM: With consideration of the theoretical link between the stent insertion and the increased risk of tumor cells spillaged, which may lead to distant metastases, there is a concern about long-term clinical outcomes after the usage of self-expanding metallic stents (SEMS) as a "bridge to surgery" in the malignant colorectal obstruction (MCO) treatment. This cohort study aimed to compare the long-term oncological outcomes of SEMS as a bridge to surgery (SEMS group) with those of emergency surgery (ES group) for MCO. METHODS: Twenty-seven patients who underwent semielective curative resection after endoscopic SEMS insertion were included from October 2007 to December 2012 in the SEMS group were compared with 33 patients who underwent emergency curative surgery for MCO during the same period in the ES group. The clinical pathologic characteristics and the overall survival (OS) rate were compared between the two groups. RESULTS: There were no significant differences in demographics, tumor stage, location, and histology between the SEMS and ES groups. The median OS times were 37 months for the SEMS group and 23 months for the ES group. The proportions of patients who received postoperative adjuvant chemotherapy were comparable (SEMS group versus ES group, 70.4% versus 45.5%; P = .138). There were no significant differences in terms of the long-term oncological outcome between two groups in the 3-year OS rate (55.6% versus 39.4%; P = .2119) and the 5-year OS rate (48.1% versus 36.4%; P = .3570). CONCLUSIONS: Long-term oncological outcomes of the SEMS group were comparable to those of the ES group. PMID- 28092478 TI - Editorial. PMID- 28092479 TI - Prospects for proteomics in kidney stone disease. PMID- 28092480 TI - A nurse working for the Third Reich: Eva Justin, RN, PhD. AB - Eugenics underpinned the Nazi race theories which saw the murder of over 10 million people from "undesirable" groups, including Sinti (referred to in Nazi times as "Gypsies"), during the Holocaust. Eva Justin, from Dresden, completed a doctoral dissertation which examined a group of Sinti children of St Josef's Home in Mulfingen, Germany. She aimed to prove the racial inferiority of these children; her work was done with no informed consent, and the children were sent to Auschwitz after her experiments. The study was supported by senior Nazis, supervised by Nazi "scientists" and examined by committed Nazis. We argue that her work was biased, poorly designed, and ultimately unethical, but was in keeping with methods of the emerging disciplines of anthropology and racial hygiene, in Germany and other countries, at the time. It is not possible to say that her work caused the children to meet their deaths (of the 39 children she included, only four survived); however, she did reinforce the Nazi racial theories. It is unfortunate that one of the first nurses in the world to receive a PhD did so through research attempting to prove that a group of children were "racially inferior" in support of National Socialism. PMID- 28092482 TI - Alfred Caleb Taylor (1860-1927): X-ray pioneer and martyr. AB - Alfred Caleb Taylor was the first radiographer at the Peterborough Infirmary and Dispensary from 1896 to 1923. He constructed the first X-ray apparatus and oversaw the development of the X-ray service in Peterborough. He contracted a chronic radiation dermatitis from exposure to X-rays which was a source of considerable suffering for him. When he died in 1927, X-ray dermatitis was considered to have contributed to his death, and he was recognised as an X-ray martyr and a victim of science. In spite of his achievements and his ill-health from working with X-rays, his name is not included on the Martyrs Memorial in Hamburg. PMID- 28092481 TI - The effect of main urine inhibitors on the activity of different DNA polymerases in loop-mediated isothermal amplification. AB - BACKGROUND: The use of rapid amplification methods to detect pathogens in biological samples is mainly limited by the amount of pathogens present in the sample and the presence of inhibiting substances. Inhibitors can affect the amplification efficiency by either binding to the polymerase, interacting with the DNA, or interacting with the polymerase during primer extension. Amplification is performed using DNA polymerase enzymes and even small changes in their activity can influence the sensitivity and robustness of molecular assays Methods: The main purpose of this research was to examine which compounds present in urine inhibit polymerases with strand displacement activity. To quantify the inhibition, we employed quantitative loop-mediated isothermal amplification Results: The authors found that the presence of BSA, Mg 2+, and urea at physiologically relevant concentrations, as well as acidic or alkaline conditions did not affect the activity of any of the tested polymerases. However, addition of salt significantly affected the activity of the tested polymerases. CONCLUSION: These findings may aid in the development of more sensitive, robust, cost effective isothermal amplification based molecular assays suitable for both point-of-care testing and on-site screening of pathogens directly from unprocessed urine which avoid the need for long and tedious DNA purification steps prior to amplification. PMID- 28092483 TI - Photodynamic Inactivation of Cariogenic Pathogens Using Curcumin as Photosensitizer. AB - OBJECTIVE: This investigation assessed the susceptibility of Streptococcus mutans and Lactobacillus acidophilus to Photodynamic Therapy (PDT) when grown simultaneously in dentine carious lesions. BACKGROUND DATA: PDT is a technique that utilizes light to activate photosensitizers in the presence of oxygen to produce reactive radicals. MATERIALS AND METHODS: A culture medium of 1% glucose, 2% sucrose, 1% young primary culture of L. acidophilus 108 CFU/mL, and S. mutans 108 CFU/mL was utilized to inoculate the bacterial induced caries on human dentine slabs. Different concentrations of the photosensitizer (0.75, 1.5, 3.0, 4.0, and 5.0 g/L) were activated through exposure to the light-emitting diode source with a central wavelength of 450 nm and a fluency of 5.7 J/cm2. Two light intensities (19 and 47.5 mW/cm2) were tested. Four different groups were analyzed: L-D- (control group), L-D+ (drug group), L+D+1 (PDT group 1, light intensity of 19 mW/cm2), and L+D+2 (PDT group 2, light intensity of 47.5 mW/cm2). ANOVA/Tukey tests were utilized to compare groups (alpha = 5%). RESULTS: Both light intensities required 5.0 g/L of curcumin for significant bacterial reduction (p < 0.05). No significant effect was found for L-D+, thus proving the absence of a potential inherent toxicity. CONCLUSIONS: Curcumin has a toxic effect on microorganisms at appreciable concentrations upon photoactivation. However, it was required to use the maximum concentration of the drug for a successful procedure. PMID- 28092484 TI - An amended history of tissue culture: Concerning Harrison, Burrows, Mall, and Carrel. AB - The origin of tissue culture is commonly dated to 1907 and credited to Ross Harrison at Hopkins Medical School. But an unpublished letter from the 1942 offers a different interpretation and gives priority to Montrose Burrows with important contributions for the development of cell culture by Franklin Mall at Hopkins and Alexis Carrel at the Rockefeller Institute in New York City. The early development of tissue culture is reviewed and its applications in modern biology and medicine are briefly outlined. PMID- 28092485 TI - Enduring biographic heritage - Medical numismatics. AB - The most enduring archive of medical biography is that composed of coins and medals. More than 20,000 commemorative and tribute medals comprise the domain of medical numismatics. Several thousand of these portray individual doctors whose lives and work are thus recorded in gold, silver, bronze and the alloys of medallic art. Such enduring records range from the names and images of the most famous and significant of doctors in international perspective, to those held in local or parochial esteem by their peers. The medical numismatic archive includes medals and coins which portray the gods of medicine; founders of the profession such as Hippocrates and Galen; and those who have been held in local esteem, all such that the record of their service to medicine might not be forgotten. PMID- 28092486 TI - Use of polyclonal/monoclonal antibody therapies in transplantation. AB - INTRODUCTION: For over thirty years, antibody (mAb)-based therapies have been a standard component of transplant immunosuppression, and yet much remains to be learned in order for us to truly harness their therapeutic capabilities. Current mAbs used in transplant directly target and destroy graft-destructive immune cells, interrupt cytokine and costimulation-dependent T and B cell activation, and prevent down-stream complement activation. Areas covered: This review summarizes our current approaches to using antibody-based therapies to prevent and treat allograft rejection. It also provides examples of promising novel mAb therapies, and discusses the potential for future mAb development in transplantation. Expert opinion: The broad capability of antibodies, in parallel with our growing ability to synthetically modulate them, offers exciting opportunities to develop better biologic therapeutics. In order to do so, we must further our understanding about the basic biology underlying allograft rejection, and gain better appreciation of how characteristics of therapeutic antibodies affect their efficacy. PMID- 28092487 TI - Strengthening US Public Health Preparedness and Response Operations. PMID- 28092488 TI - Low-Level Laser Therapy in Enhancing Wound Healing and Preserving Tissue Thickness at Free Gingival Graft Donor Sites: A Randomized, Controlled Clinical Study. AB - OBJECTIVE: The aim of this study was to determine the effects of low-level laser therapy (LLLT) on wound healing at free gingival graft (FGG) donor sites. MATERIALS AND METHODS: Forty patients requiring FGG were selected for this randomized, controlled, and double-blinded prospective clinical trial. The FGG donor sites were treated with LLLT and compared with an untreated control group. The Wound-Healing Index (WHI), tissue consistency, color match, and H2O2 bubbling test for the evaluation of complete wound epithelialization were recorded on the 3rd, 7th, 14th and 21st days. The pain-burning level, number of analgesics, and bleeding were recorded for 7 days. Donor area soft tissue thickness (TT) was measured at baseline and at the first month. RESULTS: The prevalence of Complete Wound Epithelization was higher in the LLLT group than in the control group on the 14th day (p < 0.001). The bleeding was lower in the test group than in the control group during the first 2 days (p <= 0.001). Higher WHI Scores were observed in the test group relative to the control group at all visits (p <= 0.001). Color match scores were higher in the test group than in the control group at the first 3 visits (p < 0.05). The TT changed from 4.62 +/- 0.79 to 4.71 +/- 0.82 mm in the LLLT group and from 4.23 +/- 0.62 to 4.01 +/- 0.68 mm in the control group. CONCLUSIONS: It can be concluded that LLLT enhances FGG donor site wound healing and preserves TT at palatinal donor sites. PMID- 28092489 TI - Akhawayni or Al-Akhawayni: Which term is correct? PMID- 28092490 TI - Dr. Fraser Macintosh Rose, OBE, MB ChB (Edin), FCGP (1897-1972) co-founder of the Royal College of General Practitioners. AB - Fraser Rose was a general practitioner in Preston, Lancashire, England and a medical politician. He was one of two doctors who in 1951 took the initial steps and subsequently played a major role in the founding of the College of General Practitioners, later to become the Royal College of General Practitioners. This paper examines his life, his career in general practice and medical politics, and his unique contribution to the 'Steering Committee' that set up the College. PMID- 28092491 TI - An analysis of the hospitals of Sultan Suleyman and Hurrem: Two different approaches to healthcare in sixteenth-century Ottoman Empire. AB - This study concentrates on two monumental Ottoman pious endowments, each with a major component devoted to healing. The first is the hospital of the Haseki Mosque Complex built by the wife of Sultan Suleyman the Magnificent. An examination of the deed and the modus operandi of this endowment will impart a sense of the role that women of the ruling class played in Ottoman society as builders and healers in the sixteenth century. The analysis of the Haseki Hospital will be followed by an examination of the hospital that is part of the Suleymaniye Mosque Complex built by Sultan Suleyman. The differences between the two perspectives in the promotion of public health will be emphasized, arguing that the Sultan's approach to healthcare was academic and research-oriented, whereas his wife's was holistic and devoted to rehabilitation. The endowment deeds and the physical layouts of the two hospitals shed light upon a dual approach to healthcare with gender-specific roles affirmed and shaped by Hurrem and Suleyman the Magnificent, who each built hospitals of their own in Istanbul, the Ottoman capital city. PMID- 28092492 TI - Self-Care in Palliative Care Nursing and Medical Professionals: A Cross-Sectional Survey. AB - BACKGROUND: Self-care is an important consideration for palliative care professionals. To date, few details have been recorded about the nature or uptake of self-care practices in the palliative care workforce. As part of a broader mixed methods study, this article reports findings from a national survey of nurses and doctors. OBJECTIVE: The objective of this study was to examine perceptions, education, and practices relating to self-care among palliative care nursing and medical professionals. DESIGN: A cross-sectional survey using REDCap software was conducted between April and May 2015. Perceived importance of self care, self-care education and planning, and self-care strategies most utilized were explored. Descriptive statistics were calculated and content analysis used to identify domains of self-care. SETTING/SUBJECTS: Three hundred seventy-two palliative care nursing and medical professionals practicing in Australia. RESULTS: Most respondents regarded self-care as very important (86%). Some rarely practised self-care and less than half (39%) had received training in self-care. Physical self-care strategies were most commonly reported, followed closely by social self-care and inner self-care. Self-care plans had been used by a small proportion of respondents (6%) and over two-thirds (70%) would consider using self-care plans if training could be provided. CONCLUSIONS: Self-care is practised across multiple health related domains, with physical self-care strategies used most frequently. Australian palliative care nurses and doctors recognize the importance of self-care practice, but further education and training are needed to increase their understanding of, and consistency in, using effective self-care strategies. These findings carry implications for professional practice and future research. PMID- 28092493 TI - Enhancing Collaborative Case Diagnoses Through Unified Medical Language System Based Disambiguation: A Case Study of the Zika Virus. AB - BACKGROUND: During clinical case diagnoses, especially in low-resourced areas, the use of vocabularies within Unified Medical Language System (UMLS) can strengthen discussions between health professionals and, in certain cases, eliminate the need, enabling faster treatment. INTRODUCTION: This article presents the benefits of using UMLS as a collaborative discussion tool and verifies its impact. MATERIALS AND METHODS: The Sanar system has been improved by UMLS when using text retrieval to extract relevant medical concepts from cases investigated by the user and to provide contextualized searches of related articles. An experiment was conducted, focused on team engagement and discussion of a Zika virus case using Sanar, both with and without UMLS contextualization. RESULTS: The use of the tool was measured, and it was determined that the discussion in the group with UMLS support was more complete based on better information and inclusion of more variables. Clinicians involved responded to a questionnaire evaluating the relevance of functions. DISCUSSION: From the questionnaire showed that most of the group supported UMLS as important in complex diagnostics; the use of knowledge extraction before discussion is relevant to align knowledge of participants with more variables, such as the Zika virus, and to minimize the need for interaction in widely discussed cases. CONCLUSIONS: Based on the results obtained with the questionnaire, the use of UMLS provides acceleration in the diagnostic process that precedes interaction with other health professionals through clinical discussion tools. For future work, a mobile version will support offline navigation for locations with limited Internet access. PMID- 28092494 TI - Zebrafish Are Able to Detect Ethanol in Their Environment. AB - Zebrafish have become a popular animal model for studying the development of alcohol addiction. Several behavioral paradigms for studying alcohol addiction have been developed for zebrafish, including conditioned place preference, alcohol-induced tolerance, and withdrawal. However, alcohol choice preference tasks have not been established in zebrafish as of yet. The ability of zebrafish to detect alcohol in their environment is required in alcohol choice or preference tasks. To our knowledge, it is currently unknown whether zebrafish are able to detect alcohol in their environment immediately following bath immersion. In the current study, we analyzed the time course of alcohol-induced behavioral changes of zebrafish while being immersed in alcohol solution in a 1.5 L tank. We recorded each trial in high-definition and quantified behavioral responses using automated video tracking-based and manual observation-based methods to quantify temporal changes in alcohol-induced behaviors. As alcohol is known to require several minutes of bath immersion to reach the brain in zebrafish, we argued that behavioral responses before this time point would prove zebrafish's ability to detect this substance in the water. Our results show that a 60-min exposure to 1% alcohol alters behavioral responses in a time-dependent manner. Notably, alcohol exposure significantly increased absolute turn angle, decreased distance to bottom, and variance of distance to bottom within the first 3 min immediately following exposure, a response that occurred before alcohol could reach the brain of the subjects in measurable amounts. These results imply that zebrafish are able to detect alcohol in their environment immediately following immersion into the drug solution. PMID- 28092495 TI - Nonhypervascular Pancreatic Neuroendocrine Tumors: Differential Diagnosis from Pancreatic Ductal Adenocarcinomas at MR Imaging-Retrospective Cross-sectional Study. AB - Purpose To determine useful magnetic resonance (MR) imaging features to differentiate nonhypervascular pancreatic neuroendocrine tumors (PNETs) from pancreatic ductal adenocarcinomas (PDACs). Materials and Methods The institutional review board approved this retrospective study and waived the informed consent requirement. Seventy-four patients with surgically confirmed PNETs and 82 patients with PDACs who underwent gadobutrol-enhanced MR imaging were included. Two radiologists independently evaluated the morphologic characteristics and temporal enhancement patterns of each tumor. Quantitative analysis, including measurement of tumor size, maximal upstream parenchymal thickness (MUPT), contrast-to-noise ratio, and apparent diffusion coefficient values, was performed. Uni- and multivariate logistic regression analyses were performed to identify relevant features to differentiate between PNETs and PDACs. Results On the basis of arterial enhancement, 38 PNETs (51%, 38 of 74) were hypervascular and 36 PNETs (49%, 36 of 74) were nonhypervascular. At MR imaging, nonhypervascular PNETs showed significantly higher frequencies of a well-defined margin, portal hyper- or isoenhancement, and MUPT of 10 mm or greater but lower frequencies of ductal dilatation, vascular invasion, and peripancreatic infiltration when compared with PDACs (P < .05 for all). At multivariate analysis, a well-defined margin and portal hyper- or isoenhancement were independent significant differentiators of PNETs from PDACs (odds ratio, 20.3 and 16.1, respectively). When applying the criteria of a well-defined margin and portal hyper- or isoenhancement, 64% of sensitivity and 99% of specificity were observed for the differential diagnosis of PNETs from PDACs. Conclusion A well defined margin and hyper- or isoenhancement in the portal venous phase are useful MR imaging features that are more common in nonhypervascular PNETs and may help discriminate nonhypervascular PNETs from PDACs. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28092496 TI - The Effect of Contrast Material on Radiation Dose at CT: Part I. Incorporation of Contrast Material Dynamics in Anthropomorphic Phantoms. AB - Purpose To develop a method to incorporate the propagation of contrast material into computational anthropomorphic phantoms for estimation of organ dose at computed tomography (CT). Materials and Methods A patient-specific physiologically based pharmacokinetic (PBPK) model of the human cardiovascular system was incorporated into 58 extended cardiac-torso (XCAT) patient phantoms. The PBPK model comprised compartmental models of vessels and organs unique to each XCAT model. For typical injection protocols, the dynamics of the contrast material in the body were described according to a series of patient-specific iodine mass-balance differential equations, the solutions to which provided the contrast material concentration time curves for each compartment. Each organ was assigned to a corresponding time-varying iodinated contrast agent to create the contrast material-enhanced five-dimensional XCAT models, in which the fifth dimension represents the dynamics of contrast material. To validate the accuracy of the models, simulated aortic and hepatic contrast-enhancement results throughout the models were compared with previously published clinical data by using the percentage of discrepancy in the mean, time to 90% peak, peak value, and slope of enhancement in a paired t test at the 95% significance level. Results The PBPK model allowed effective prediction of the time-varying concentration curves of various contrast material administrations in each organ for different patient models. The contrast-enhancement results were in agreement with results of previously published clinical data, with mean percentage, time to 90% peak, peak value, and slope of less than 10% (P > .74), 4%, 7%, and 14% for uniphasic and 12% (P > .56), 4%, 12%, and 14% for biphasic injection protocols, respectively. The exception was hepatic enhancement results calculated for a uniphasic injection protocol for which the discrepancy was less than 25%. Conclusion A technique to model the propagation of contrast material in XCAT human models was developed. The models with added contrast material propagation can be applied to simulate contrast-enhanced CT examinations. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28092497 TI - Polymyxin B Hemoperfusion for Sepsis and Septic Shock: A Systematic Review and Meta-Analysis. AB - BACKGROUND: To evaluate the efficacy and safety of direct hemoperfusion with polymyxin B-immobilized fiber (PMX-DHP) therapy in patients with sepsis. DESIGN: A systematic review and meta-analysis of four major databases: Cochrane Central Register of Controlled Trials, MEDLINE, Scopus, and Science Citation Index Expanded. STUDY SELECTION: Randomized controlled trials comparing PMX-DHP with conventional therapy on the outcome of mortality in patients with severe sepsis/septic shock. DATA EXTRACTION: Two reviewers independently applied eligibility criteria, assessed quality, and extracted data. Primary outcomes were mortality and adverse events. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate quality of evidence and grade the strength of recommendation. RESULTS: In seven trials enrolling 841 patients, assessment for risk of bias indicated variations in study quality from high (n = 4) to unclear (n = 3) resulting from a lack of adequate randomization, blinding, and incomplete outcomes. Polymyxin B-immobilized fiber therapy was associated with lower mortality (risk ratio, 0.65; 95% confidence interval [CI], 0.47-0.89; p = 0.007; I2 = 72%). Significant heterogeneity among trials was explained partly by study venue and baseline mortality rate. Meta-regression analysis revealed a significant negative slope between effect size of PMX-DHP therapy and baseline mortality rate in individual studies (p = 0.003), suggesting the probability of a beneficial effect with PMX-DHP increased with increasing baseline risk. Polymyxin B-immobilized fiber therapy did not increase the risk of hemoperfusion-related adverse events. The quality of the body of evidence was considered low for both mortality and adverse events. CONCLUSIONS: Polymyxin B-immobilized fiber therapy was associated with reduced mortality in sepsis/septic shock. Based on the low quality of evidence, therapeutic use of PMX-DHP for survival benefit may be recommended conditionally for patients with high risk of death. Additional large randomized controlled trials are needed to confirm or refute this evidence. PMID- 28092498 TI - Adaptive Fuzzy Output Feedback Control for Switched Nonlinear Systems With Unmodeled Dynamics. AB - This paper investigates a robust adaptive fuzzy control stabilization problem for a class of uncertain nonlinear systems with arbitrary switching signals that use an observer-based output feedback scheme. The considered switched nonlinear systems possess the unstructured uncertainties, unmodeled dynamics, and without requiring the states being available for measurement. A state observer which is independent of switching signals is designed to solve the problem of unmeasured states. Fuzzy logic systems are used to identify unknown lumped nonlinear functions so that the problem of unstructured uncertainties can be solved. By combining adaptive backstepping design principle and small-gain approach, a novel robust adaptive fuzzy output feedback stabilization control approach is developed. The stability of the closed-loop system is proved via the common Lyapunov function theory and small-gain theorem. Finally, the simulation results are given to demonstrate the validity and performance of the proposed control strategy. PMID- 28092500 TI - A Model of a Synthetic Biological Communication Interface between Mammalian Cells and Mechatronic Systems. AB - The creation of communication interfaces between abiotic and biotic systems represents a significant research challenge. In this work, we design and model a system linking the biochemical signaling pathways of mammalian cells to the actions of a mobile robotic prosthesis. We envision this system as a robotic platform carrying an optically monitored bioreactor that harbors mammalian cells. The cellular, optical signal is captured by an onboard fluorescent microscope and converted into an electronic signal. We first present a design for the overall cell-robot system, with a specific focus on the design of the synthetic gene networks needed for the system. We use these synthetic networks to encode motion commands within the cell's endogenous, oscillatory calcium signaling pathways. We then describe a potential system whereby this oscillatory signal could be outputted and monitored as a change in cellular fluorescence. Next, we use the changes resulting from the synthetic biological modifications as new parameters in a simulation of a well-established mathematical model for intracellular calcium signaling. The resulting signal is processed in the frequency domain, with specific frequencies activating cognate robot motion subroutines. PMID- 28092501 TI - Parallel Molecular Distributed Detection With Brownian Motion. AB - This paper explores the in vivo distributed detection of an undesired biological agent's (BAs) biomarkers by a group of biological sized nanomachines in an aqueous medium under drift. The term distributed, indicates that the system information relative to the BAs presence is dispersed across the collection of nanomachines, where each nanomachine possesses limited communication, computation, and movement capabilities. Using Brownian motion with drift, a probabilistic detection and optimal data fusion framework, coined molecular distributed detection, will be introduced that combines theory from both molecular communication and distributed detection. Using the optimal data fusion framework as a guide, simulation indicates that a sub-optimal fusion method exists, allowing for a significant reduction in implementation complexity while retaining BA detection accuracy. PMID- 28092502 TI - Capacity Evaluation of a Quantum-Based Channel in a Biological Context. AB - Nanotechnology, as enabler of the miniaturization of devices in a scale ranging from 1 to few hundreds of nm , represents a viable solution for " alternative" communication paradigms that could be effective in complex networked systems, as body area networks. Traditional communication paradigms are not effective in the context of joint body and nano-networked systems, for several reasons, and then novel approaches have been investigated such as nanomechanical, electromagnetic, acoustic, molecular, etc. On the other hand, quantum phenomena represent a natural direction for developing nanotechnology, since it has to be considered as a new scale where new phenomena can occur and can be exploited for information purpose. Specific quantum particles are phonons, the quanta of mechanical vibrations (i.e., acoustic excitations), that can be analyzed as potential information carriers in a body networked context. In this paper we will focus on the generation of phonons from photon-phonon interaction, by irradiating a sample of human tissue with an electro-magnetic field, and then we will theoretically derive the information capacity and the bit rate in the frequency range [103 - 1012] Hz. PMID- 28092503 TI - Propagation Modeling and Analysis of Molecular Motors in Molecular Communication. AB - Molecular motor networks (MMNs) are networks constructed from molecular motors to enable nanomachines to perform coordinated tasks of sensing, computing, and actuation at the nano- and micro- scales. Living cells are naturally enabled with this same mechanism to establish point-to-point communication between different locations inside the cell. Similar to a railway system, the cytoplasm contains an intricate infrastructure of tracks, named microtubules, interconnecting different internal components of the cell. Motor proteins, such as kinesin and dynein, are able to travel along these tracks directionally, carrying with them large molecules that would otherwise be unreliably transported across the cytoplasm using free diffusion. Molecular communication has been previously proposed for the design and study of MMNs. However, the topological aspects of MMNs, including the effects of branches, have been ignored in the existing studies. In this paper, a physical end-to-end model for MMNs is developed, considering the location of the transmitter node, the network topology, and the receiver nodes. The end-to-end gain and group delay are considered as the performance measures, and analytical expressions for them are derived. The analytical model is validated by Monte-Carlo simulations and the performance of MMNs is analyzed numerically. It is shown that, depending on their nature and position, MMN nodes create impedance effects that are critical for the overall performance. This model could be applied to assist the design of artificial MMNs and to study cargo transport in neurofilaments to elucidate brain diseases related to microtubule jamming. PMID- 28092499 TI - Nanoparticles for siRNA-Based Gene Silencing in Tumor Therapy. AB - Gene silencing through RNA interference (RNAi) has emerged as a potential strategy in manipulating cancer causing genes by complementary base-pairing mechanism. Small interfering RNA (siRNA) is an important RNAi tool that has found significant application in cancer therapy. However due to lack of stability, poor cellular uptake and high probability of loss-of-function due to degradation, siRNA therapeutic strategies seek safe and efficient delivery vehicles for in vivo applications. The current review discusses various nanoparticle systems currently used for siRNA delivery for cancer therapy, with emphasis on liposome based gene delivery systems. The discussion also includes various methods availed to improve nanoparticle based-siRNA delivery with target specificity and superior efficiency. Further this review describes challenges and perspectives on the development of safe and efficient nanoparticle based-siRNA-delivery systems for cancer therapy. PMID- 28092504 TI - Wall Shear Rate Measurement: Validation of a New Method Through Multiphysics Simulations. AB - Wall shear stress is known to affect the vessel endothelial function and to be related to important pathologies like the development of atherosclerosis. It is defined as the product of the blood viscosity by the blood velocity gradient at the wall position, i.e., the wall shear rate (WSR). The WSR measurement is particularly challenging in important cardiovascular sites, like the carotid bifurcation, because of the related complex flow configurations characterized by high spatial and temporal gradients, wall movement, and clutter noise. Moreover, accuracy of any method for WSR measurement can be effectively tested only if reliable gold standard WSR values, considering all the aforementioned disturbing effects, are available. Unfortunately, these requirements are difficult to achieve in a physical phantom, so that the accuracy test of the novel WSR measurement methods was so far limited to straight pipes and/or similar idealistic configurations. In this paper, we propose a new method for WSR measurement and its validation based on a mathematical model of the carotid bifurcation, which, exploiting fluid-structure simulations, is capable of reproducing realistic flow configuration, wall movement, and clutter noise. In particular, the profile near the wall, not directly measurable because affected by clutter, is estimated through a power-law fitting and compared with the gold standard provided by the model. In this condition, the WSR measurements featured an accuracy of +/-20 %. A preliminary test on a volunteer confirmed the feasibility of the WSR method for in vivo application. PMID- 28092505 TI - Fabrication of Linear Array and Top-Orthogonal-to-Bottom Electrode CMUT Arrays With a Sacrificial Release Process. AB - The microfabrication processes for sacrificial-release-based capacitive micromachined ultrasound transducer arrays are provided with an emphasis on top orthogonal-to-bottom electrode 2-D arrays. These arrays have significant promise for high-quality 3-D imaging with reduced wiring complexity compared with fully wired arrays. The protocols and best practices are outlined in significant detail along with design considerations and notes of caution for pitfalls and factors impacting yield. PMID- 28092506 TI - Wideband 2-D Array Design Optimization With Fabrication Constraints for 3-D US Imaging. AB - Ultrasound (US) 2-D arrays are of increasing interest due to their electronic steering capability to investigate 3-D regions without requiring any probe movement. These arrays are typically populated by thousands of elements that, ideally, should be individually driven by the companion scanner. Since this is not convenient, the so-called microbeamforming methods, yielding a prebeamforming stage performed in the probe handle by suitable custom integrated circuits, have so far been implemented in a few commercial high-end scanners. A possible approach to implement relatively cheap and efficient 3-D US imaging systems is using 2-D sparse arrays in which a limited number of elements can be coupled to an equal number of independent transmit/receive channels. In order to obtain US beams with adequate characteristics all over the investigated volume, the layout of such arrays must be carefully designed. This paper provides guidelines to design, by using simulated annealing optimization, 2-D sparse arrays capable of fitting specific applications or fabrication/implementation constraints. In particular, an original energy function based on multidepth 3-D analysis of the beam pattern is also exploited. A tutorial example is given, addressed to find the N e elements that should be activated in a 2-D fully populated array to yield efficient acoustic radiating performance over the entire volume. The proposed method is applied to a 32 *32 array centered at 3 MHz to select the 128, 192, and 256 elements that provide the best acoustic performance. It is shown that the 256 element optimized array yields sidelobe levels even lower (by 5.7 dB) than that of the reference 716-element circular and (by 10.3 dB) than that of the reference 1024-element array. PMID- 28092507 TI - Real-Time Intravascular Ultrasound and Photoacoustic Imaging. AB - Combined intravascular ultrasound and intravascular photoacoustic (IVUS/IVPA) imaging is an emerging hybrid modality being explored as a means of improving the characterization of atherosclerotic plaque anatomical and compositional features. While initial demonstrations of the technique have been encouraging, they have been limited by catheter rotation and data acquisition, displaying, and processing rates on the order of several seconds per frame as well as the use of off-line image processing. Herein, we present a complete IVUS/IVPA imaging system and method capable of real-time IVUS/IVPA imaging, with online data acquisition, image processing, and display of both IVUS and IVPA images. The integrated IVUS/IVPA catheter is fully contained within a 1-mm outer diameter torque cable coupled on the proximal end to a custom-designed spindle enabling optical and electrical coupling to system hardware, including a nanosecond-pulsed laser with a controllable pulse repetition frequency capable of greater than 10 kHz, motor and servo drive, a US pulser/receiver, and a 200-MHz digitizer. The system performance is characterized and demonstrated on a vessel-mimicking phantom with an embedded coronary stent intended to provide IVPA contrast within content of an IVUS image. PMID- 28092508 TI - Ultrasonic Shear Wave Elasticity Imaging Sequencing and Data Processing Using a Verasonics Research Scanner. AB - Ultrasound elasticity imaging has been developed over the last decade to estimate tissue stiffness. Shear wave elasticity imaging (SWEI) quantifies tissue stiffness by measuring the speed of propagating shear waves following acoustic radiation force excitation. This paper presents the sequencing and data processing protocols of SWEI using a Verasonics system. The selection of the sequence parameters in a Verasonics programming script is discussed in detail. The data processing pipeline to calculate group shear wave speed (SWS), including tissue motion estimation, data filtering, and SWS estimation, is demonstrated. In addition, the procedures for calibration of beam position, scanner timing, and transducer face heating are provided to avoid SWS measurement bias and transducer damage. PMID- 28092509 TI - A BCI-based Environmental Control System for Patients with Severe Spinal Cord Injuries. AB - : This study proposes an event-related potential (ERP) BCI-based environmental control system that integrates household electrical appliances, a nursing bed, and an intelligent wheelchair to provide daily assistance to paralyzed patients with severe spinal cord injuries (SCIs). METHODS: An asynchronous mode is used to switch the environmental control system on or off or to select a device (e.g., a TV) for achieving selfpaced control. In the asynchronous mode, we introduce several pseudo-keys and a verification mechanism to effectively reduce the false operation rate. By contrast, when the user selects a function of the device (e.g., a TV channel), a synchronous mode is used to improve the accuracy and speed of BCI detection. Two experiments involving six SCI patients were conducted separately in a nursing bed and a wheelchair, and the patients were instructed to control the nursing bed, the wheelchair, and household electrical appliances (an electric light, an air conditioner, and a TV). RESULTS: The average false rate of BCI commands in the control state was 10.4%, whereas the average false operation ratio was 4.9% (a false BCI command might not necessarily result in a false operation according to our system design). During the idle state, there was an average of 0.97 false positives per minute, which did not result in any false operations. CONCLUSION: All SCI patients could use the proposed ERP BCIbased environmental control system satisfactorily. SIGNIFICANCE: The proposed ERP-based environmental control system could be used to assist patients with severe SCIs in their daily lives. PMID- 28092510 TI - Unobtrusive and Wearable Systems for Automatic Dietary Monitoring. AB - The threat of obesity, diabetes, anorexia, and bulimia in our society today has motivated extensive research on dietary monitoring. Standard self-report methods such as 24-h recall and food frequency questionnaires are expensive, burdensome, and unreliable to handle the growing health crisis. Long-term activity monitoring in daily living is a promising approach to provide individuals with quantitative feedback that can encourage healthier habits. Although several studies have attempted automating dietary monitoring using wearable, handheld, smart-object, and environmental systems, it remains an open research problem. This paper aims to provide a comprehensive review of wearable and hand-held approaches from 2004 to 2016. Emphasis is placed on sensor types used, signal analysis and machine learning methods, as well as a benchmark of state-of-the art work in this field. Key issues, challenges, and gaps are highlighted to motivate future work toward development of effective, reliable, and robust dietary monitoring systems. PMID- 28092511 TI - The Concept of Effective Inflow: Application to Interictal Localization of the Epileptogenic Focus From iEEG. AB - GOAL: Accurate determination of the epileptogenic focus is of paramount diagnostic and therapeutic importance in epilepsy. The current gold standard for focus localization is from ictal (seizure) onset and thus requires the occurrence and recording of multiple typical seizures of a patient. Localization of the focus from seizure-free (interictal) periods remains a challenging problem, especially in the absence of interictal epileptiform activity. METHODS: By exploring the concept of effective inflow, we developed a focus localization algorithm (FLA) based on directed connectivity between brain sites. Subsequently, using the measure of generalized partial directed coherence over a broad frequency band in FLA for the analysis of interictal periods from long-term (days) intracranial electroencephalographic signals, we identified the brain region that is the most frequent receiver of maximal effective inflow from other brain regions. RESULTS: In six out of nine patients with temporal lobe epilepsy, the thus identified brain region was a statistically significant outlier (p < 0.01) and coincided with the clinically assessed epileptogenic focus. In the remaining three patients, the clinically assessed focus still exhibited the highest inflow, but it was not deemed an outlier (p > 0.01). CONCLUSIONS: These findings suggest that the epileptogenic focus is a region of intense influence from other regions interictally, possibly as a mechanism to keep it under control in seizure-free periods. SIGNIFICANCE: The developed framework is expected to assist with the accurate epileptogenic focus localization, reduce hospital stay and healthcare cost, and provide guidance to treatment of epilepsy via resective surgery or neuromodulation. PMID- 28092512 TI - A Hidden Markov Model for Seismocardiography. AB - We propose a hidden Markov model approach for processing seismocardiograms. The seismocardiogram morphology is learned using the expectation-maximization algorithm, and the state of the heart at a given time instant is estimated by the Viterbi algorithm. From the obtained Viterbi sequence, it is then straightforward to estimate instantaneous heart rate, heart rate variability measures, and cardiac time intervals (the latter requiring a small number of manual annotations). As is shown in the conducted experimental study, the presented algorithm outperforms the state-of-the-art in seismocardiogram-based heart rate and heart rate variability estimation. Moreover, the isovolumic contraction time and the left ventricular ejection time are estimated with mean absolute errors of about 5 [ms] and [Formula: see text], respectively. The proposed algorithm can be applied to any set of inertial sensors; does not require access to any additional sensor modalities; does not make any assumptions on the seismocardiogram morphology; and explicitly models sensor noise and beat-to-beat variations (both in amplitude and temporal scaling) in the seismocardiogram morphology. As such, it is well suited for low-cost implementations using off-the-shelf inertial sensors and targeting, e.g., at-home medical services. PMID- 28092513 TI - Automatic Nuclear Segmentation Using Multiscale Radial Line Scanning With Dynamic Programming. AB - In the diagnosis of various cancers by analyzing histological images, automatic nuclear segmentation is an important step. However, nuclear segmentation is a difficult problem because of overlapping nuclei, inhomogeneous staining, and presence of noisy pixels and other tissue components. In this paper, we present an automatic technique for nuclear segmentation in skin histological images. The proposed technique first applies a bank of generalized Laplacian of Gaussian kernels to detect nuclear seeds. Based on the detected nuclear seeds, a multiscale radial line scanning method combined with dynamic programming is applied to extract a set of candidate nuclear boundaries. The gradient, intensity, and shape information are then integrated to determine the optimal boundary for each nucleus in the image. Nuclear overlap limitation is finally imposed based on a Dice coefficient measure such that the obtained nuclear contours do not severely intersect with each other. Experiments have been thoroughly performed on two datasets with H&E and Ki-67 stained images, which show that the proposed technique is superior to conventional schemes of nuclear segmentation. PMID- 28092514 TI - A Multivariate Approach for Patient-Specific EEG Seizure Detection Using Empirical Wavelet Transform. AB - OBJECTIVE: This paper investigates the multivariate oscillatory nature of electroencephalogram (EEG) signals in adaptive frequency scales for epileptic seizure detection. METHODS: The empirical wavelet transform (EWT) has been explored for the multivariate signals in order to determine the joint instantaneous amplitudes and frequencies in signal adaptive frequency scales. The proposed multivariate extension of EWT has been studied on multivariate multicomponent synthetic signal, as well as on multivariate EEG signals of Children's Hospital Boston-Massachusetts Institute of Technology (CHB-MIT) scalp EEG database. In a moving-window-based analysis, 2-s-duration multivariate EEG signal epochs containing five automatically selected channels have been decomposed and three features have been extracted from each 1-s part of the 2-s duration joint instantaneous amplitudes of multivariate EEG signals. The extracted features from each oscillatory level have been processed using a proposed feature processing step and joint features have been computed in order to achieve better discrimination of seizure and seizure-free EEG signal epochs. RESULTS: The proposed detection method has been evaluated over 177 h of EEG records using six classifiers. We have achieved average sensitivity, specificity, and accuracy values as 97.91%, 99.57%, and 99.41%, respectively, using tenfold cross-validation method, which are higher than the compared state of art methods studied on this database. CONCLUSION: Efficient detection of epileptic seizure is achieved when seizure events appear for long duration in hours long EEG recordings. SIGNIFICANCE: The proposed method develops time-frequency plane for multivariate signals and builds patient-specific models for EEG seizure detection. PMID- 28092515 TI - Toward a Run-to-Run Adaptive Artificial Pancreas: In Silico Results. AB - OBJECTIVE: Contemporary and future outpatient long-term artificial pancreas (AP) studies need to cope with the well-known large intra- and interday glucose variability occurring in type 1 diabetic (T1D) subjects. Here, we propose an adaptive model predictive control (MPC) strategy to account for it and test it in silico. METHODS: A run-to-run (R2R) approach adapts the subcutaneous basal insulin delivery during the night and the carbohydrate-to-insulin ratio (CR) during the day, based on some performance indices calculated from subcutaneous continuous glucose sensor data. In particular, R2R aims, first, to reduce the percentage of time in hypoglycemia and, secondarily, to improve the percentage of time in euglycemia and average glucose. In silico simulations are performed by using the University of Virginia/Padova T1D simulator enriched by incorporating three novel features: intra- and interday variability of insulin sensitivity, different distributions of CR at breakfast, lunch, and dinner, and dawn phenomenon. RESULTS: After about two months, using the R2R approach with a scenario characterized by a random 30% variation of the nominal insulin sensitivity the time in range and the time in tight range are increased by 11.39% and 44.87%, respectively, and the time spent above 180 mg/dl is reduced by 48.74%. CONCLUSIONS: An adaptive MPC algorithm based on R2R shows in silico great potential to capture intra- and interday glucose variability by improving both overnight and postprandial glucose control without increasing hypoglycemia. SIGNIFICANCE: Making an AP adaptive is key for long-term real-life outpatient studies. These good in silico results are very encouraging and worth testing in vivo. PMID- 28092516 TI - Single-Camera-Based Method for Step Length Symmetry Measurement in Unconstrained Elderly Home Monitoring. AB - OBJECTIVE: single-camera-based gait monitoring is unobtrusive, inexpensive, and easy-to-use to monitor daily gait of seniors in their homes. However, most studies require subjects to walk perpendicularly to camera's optical axis or along some specified routes, which limits its application in elderly home monitoring. To build unconstrained monitoring environments, we propose a method to measure step length symmetry ratio (a useful gait parameter representing gait symmetry without significant relationship with age) from unconstrained straight walking using a single camera, without strict restrictions on walking directions or routes. METHODS: according to projective geometry theory, we first develop a calculation formula of step length ratio for the case of unconstrained straight line walking. Then, to adapt to general cases, we propose to modify noncollinear footprints, and accordingly provide general procedure for step length ratio extraction from unconstrained straight walking. RESULTS: Our method achieves a mean absolute percentage error (MAPE) of 1.9547% for 15 subjects' normal and abnormal side-view gaits, and also obtains satisfactory MAPEs for non-side-view gaits (2.4026% for 45 degrees -view gaits and 3.9721% for 30 degrees -view gaits). The performance is much better than a well-established monocular gait measurement system suitable only for side-view gaits with a MAPE of 3.5538%. CONCLUSION: Independently of walking directions, our method can accurately estimate step length ratios from unconstrained straight walking. SIGNIFICANCE: This demonstrates our method is applicable for elders' daily gait monitoring to provide valuable information for elderly health care, such as abnormal gait recognition, fall risk assessment, etc. OBJECTIVE: single-camera-based gait monitoring is unobtrusive, inexpensive, and easy-to-use to monitor daily gait of seniors in their homes. However, most studies require subjects to walk perpendicularly to camera's optical axis or along some specified routes, which limits its application in elderly home monitoring. To build unconstrained monitoring environments, we propose a method to measure step length symmetry ratio (a useful gait parameter representing gait symmetry without significant relationship with age) from unconstrained straight walking using a single camera, without strict restrictions on walking directions or routes. METHODS: according to projective geometry theory, we first develop a calculation formula of step length ratio for the case of unconstrained straight-line walking. Then, to adapt to general cases, we propose to modify noncollinear footprints, and accordingly provide general procedure for step length ratio extraction from unconstrained straight walking. RESULTS: Our method achieves a mean absolute percentage error (MAPE) of 1.9547% for 15 subjects' normal and abnormal side-view gaits, and also obtains satisfactory MAPEs for non-side-view gaits (2.4026% for 45 degrees -view gaits and 3.9721% for 30 degrees -view gaits). The performance is much better than a well-established monocular gait measurement system suitable only for side view gaits with a MAPE of 3.5538%. CONCLUSION: Independently of walking directions, our method can accurately estimate step length ratios from unconstrained straight walking. SIGNIFICANCE: This demonstrates our method is applicable for elders' daily gait monitoring to provide valuable information for elderly health care, such as abnormal gait recognition, fall risk assessment, etc. PMID- 28092517 TI - Transformations Based on Continuous Piecewise-Affine Velocity Fields. AB - We propose novel finite-dimensional spaces of well-behaved transformations. The latter are obtained by (fast and highly-accurate) integration of continuous piecewise-affine velocity fields. The proposed method is simple yet highly expressive, effortlessly handles optional constraints (e.g., volume preservation and/or boundary conditions), and supports convenient modeling choices such as smoothing priors and coarse-to-fine analysis. Importantly, the proposed approach, partly due to its rapid likelihood evaluations and partly due to its other properties, facilitates tractable inference over rich transformation spaces, including using Markov-Chain Monte-Carlo methods. Its applications include, but are not limited to: monotonic regression (more generally, optimization over monotonic functions); modeling cumulative distribution functions or histograms; time-warping; image warping; image registration; real-time diffeomorphic image editing; data augmentation for image classifiers. Our GPU-based code is publicly available. PMID- 28092518 TI - Compositional Model Based Fisher Vector Coding for Image Classification. AB - Deriving from the gradient vector of a generative model of local features, Fisher vector coding (FVC) has been identified as an effective coding method for image classification. Most, if not all, FVC implementations employ the Gaussian mixture model (GMM) as the generative model for local features. However, the representative power of a GMM can be limited because it essentially assumes that local features can be characterized by a fixed number of feature prototypes, and the number of prototypes is usually small in FVC. To alleviate this limitation, in this work, we break the convention which assumes that a local feature is drawn from one of a few Gaussian distributions. Instead, we adopt a compositional mechanism which assumes that a local feature is drawn from a Gaussian distribution whose mean vector is composed as a linear combination of multiple key components, and the combination weight is a latent random variable. In doing so we greatly enhance the representative power of the generative model underlying FVC. To implement our idea, we design two particular generative models following this compositional approach. In our first model, the mean vector is sampled from the subspace spanned by a set of bases and the combination weight is drawn from a Laplace distribution. In our second model, we further assume that a local feature is composed of a discriminative part and a residual part. As a result, a local feature is generated by the linear combination of discriminative part bases and residual part bases. The decomposition of the discriminative and residual parts is achieved via the guidance of a pre-trained supervised coding method. By calculating the gradient vector of the proposed models, we derive two new Fisher vector coding strategies. The first is termed Sparse Coding-based Fisher Vector Coding (SCFVC) and can be used as the substitute of traditional GMM based FVC. The second is termed Hybrid Sparse Coding-based Fisher vector coding (HSCFVC) since it combines the merits of both pre-trained supervised coding methods and FVC. Using pre-trained Convolutional Neural Network (CNN) activations as local features, we experimentally demonstrate that the proposed methods are superior to traditional GMM based FVC and achieve state-of-the-art performance in various image classification tasks. PMID- 28092519 TI - Newton-Type Greedy Selection Methods for $?ell _0$ -Constrained Minimization. AB - We introduce a family of Newton-type greedy selection methods for -constrained minimization problems. The basic idea is to construct a quadratic function to approximate the original objective function around the current iterate and solve the constructed quadratic program over the cardinality constraint. The next iterate is then estimated via a line search operation between the current iterate and the solution of the sparse quadratic program. This iterative procedure can be interpreted as an extension of the constrained Newton methods from convex minimization to non-convex -constrained minimization. We show that the proposed algorithms converge asymptotically and the rate of local convergence is superlinear up to certain estimation error. Our methods compare favorably against several state-of-the-art greedy selection methods when applied to sparse logistic regression and sparse support vector machines. PMID- 28092520 TI - Robust Matrix Factorization by Majorization Minimization. AB - -norm based low rank matrix factorization in the presence of missing data and outliers remains a hot topic in computer vision. Due to non-convexity and non smoothness, all the existing methods either lack scalability or robustness, or have no theoretical guarantee on convergence. In this paper, we apply the Majorization Minimization technique to solve this problem. At each iteration, we upper bound the original function with a strongly convex surrogate. By minimizing the surrogate and updating the iterates accordingly, the objective function has sufficient decrease, which is stronger than just being non-increasing that other methods could offer. As a consequence, without extra assumptions, we prove that any limit point of the iterates is a stationary point of the objective function. In comparison, other methods either do not have such a convergence guarantee or require extra critical assumptions. Extensive experiments on both synthetic and real data sets testify to the effectiveness of our algorithm. The speed of our method is also highly competitive. PMID- 28092521 TI - Measuring and Predicting Tag Importance for Image Retrieval. AB - Textual data such as tags, sentence descriptions are combined with visual cues to reduce the semantic gap for image retrieval applications in today's Multimodal Image Retrieval (MIR) systems. However, all tags are treated as equally important in these systems, which may result in misalignment between visual and textual modalities during MIR training. This will further lead to degenerated retrieval performance at query time. To address this issue, we investigate the problem of tag importance prediction, where the goal is to automatically predict the tag importance and use it in image retrieval. To achieve this, we first propose a method to measure the relative importance of object and scene tags from image sentence descriptions. Using this as the ground truth, we present a tag importance prediction model to jointly exploit visual, semantic and context cues. The Structural Support Vector Machine (SSVM) formulation is adopted to ensure efficient training of the prediction model. Then, the Canonical Correlation Analysis (CCA) is employed to learn the relation between the image visual feature and tag importance to obtain robust retrieval performance. Experimental results on three real-world datasets show a significant performance improvement of the proposed MIR with Tag Importance Prediction (MIR/TIP) system over other MIR systems. PMID- 28092522 TI - Active Self-Paced Learning for Cost-Effective and Progressive Face Identification. AB - This paper aims to develop a novel cost-effective framework for face identification, which progressively maintains a batch of classifiers with the increasing face images of different individuals. By naturally combining two recently rising techniques: active learning (AL) and self-paced learning (SPL), our framework is capable of automatically annotating new instances and incorporating them into training under weak expert recertification. We first initialize the classifier using a few annotated samples for each individual, and extract image features using the convolutional neural nets. Then, a number of candidates are selected from the unannotated samples for classifier updating, in which we apply the current classifiers ranking the samples by the prediction confidence. In particular, our approach utilizes the high-confidence and low confidence samples in the self-paced and the active user-query way, respectively. The neural nets are later fine-tuned based on the updated classifiers. Such heuristic implementation is formulated as solving a concise active SPL optimization problem, which also advances the SPL development by supplementing a rational dynamic curriculum constraint. The new model finely accords with the "instructor-student-collaborative" learning mode in human education. The advantages of this proposed framework are two-folds: i) The required number of annotated samples is significantly decreased while the comparable performance is guaranteed. A dramatic reduction of user effort is also achieved over other state of-the-art active learning techniques. ii) The mixture of SPL and AL effectively improves not only the classifier accuracy compared to existing AL/SPL methods but also the robustness against noisy data. We evaluate our framework on two challenging datasets, which include hundreds of persons under diverse conditions, and demonstrate very promising results. Please find the code of this project at: http://hcp.sysu.edu.cn/projects/aspl/. PMID- 28092523 TI - Longitudinal Study of Automatic Face Recognition. AB - The two underlying premises of automatic face recognition are uniqueness and permanence. This paper investigates the permanence property by addressing the following: Does face recognition ability of state-of-the-art systems degrade with elapsed time between enrolled and query face images? If so, what is the rate of decline w.r.t. the elapsed time? While previous studies have reported degradations in accuracy, no formal statistical analysis of large-scale longitudinal data has been conducted. We conduct such an analysis on two mugshot databases, which are the largest facial aging databases studied to date in terms of number of subjects, images per subject, and elapsed times. Mixed-effects regression models are applied to genuine similarity scores from state-of-the-art COTS face matchers to quantify the population-mean rate of change in genuine scores over time, subject-specific variability, and the influence of age, sex, race, and face image quality. Longitudinal analysis shows that despite decreasing genuine scores, 99% of subjects can still be recognized at 0.01% FAR up to approximately 6 years elapsed time, and that age, sex, and race only marginally influence these trends. The methodology presented here should be periodically repeated to determine age-invariant properties of face recognition as state-of the-art evolves to better address facial aging. PMID- 28092524 TI - CODE: Coherence Based Decision Boundaries for Feature Correspondence. AB - A key challenge in feature correspondence is the difficulty in differentiating true and false matches at a local descriptor level. This forces adoption of strict similarity thresholds that discard many true matches. However, if analyzed at a global level, false matches are usually randomly scattered while true matches tend to be coherent (clustered around a few dominant motions), thus creating a coherence based separability constraint. This paper proposes a non linear regression technique that can discover such a coherence based separability constraint from highly noisy matches and embed it into a correspondence likelihood model. Once computed, the model can filter the entire set of nearest neighbor matches (which typically contains over 90 percent false matches) for true matches. We integrate our technique into a full feature correspondence system which reliably generates large numbers of good quality correspondences over wide baselines where previous techniques provide few or no matches. PMID- 28092525 TI - Light Field Reconstruction Using Shearlet Transform. AB - In this article we develop an image based rendering technique based on light field reconstruction from a limited set of perspective views acquired by cameras. Our approach utilizes sparse representation of epipolar-plane images (EPI) in shearlet transform domain. The shearlet transform has been specifically modified to handle the straight lines characteristic for EPI. The devised iterative regularization algorithm based on adaptive thresholding provides high-quality reconstruction results for relatively big disparities between neighboring views. The generated densely sampled light field of a given 3D scene is thus suitable for all applications which require light field reconstruction. The proposed algorithm compares favorably against state of the art depth image based rendering techniques and shows superior performance specifically in reconstructing scenes containing semi-transparent objects. PMID- 28092527 TI - Block-Matching Distortion Correction of Echo-Planar Images With Opposite Phase Encoding Directions. AB - By shortening the acquisition time of MRI, Echo Planar Imaging (EPI) enables the acquisition of a large number of images in a short time, compatible with clinical constraints as required for diffusion or functional MRI. However such images are subject to large, local distortions disrupting their correspondence with the underlying anatomy. The correction of those distortions is an open problem, especially in regions where large deformations occur. We propose a new block matching registration method to perform EPI distortion correction based on the acquisition of two EPI with opposite phase encoding directions (PED). It relies on new transformations between blocks adapted to the EPI distortion model, and on an adapted optimization scheme to ensure an opposite symmetric transformation. We present qualitative and quantitative results of the block-matching correction using different metrics on a phantom dataset and on in-vivo data. We show the ability of the block-matching to robustly correct EPI distortion even in strongly affected areas. PMID- 28092528 TI - Low-Rank and Adaptive Sparse Signal (LASSI) Models for Highly Accelerated Dynamic Imaging. AB - Sparsity-based approaches have been popular in many applications in image processing and imaging. Compressed sensing exploits the sparsity of images in a transform domain or dictionary to improve image recovery fromundersampledmeasurements. In the context of inverse problems in dynamic imaging, recent research has demonstrated the promise of sparsity and low-rank techniques. For example, the patches of the underlying data are modeled as sparse in an adaptive dictionary domain, and the resulting image and dictionary estimation from undersampled measurements is called dictionary-blind compressed sensing, or the dynamic image sequence is modeled as a sum of low-rank and sparse (in some transform domain) components (L+S model) that are estimated from limited measurements. In this work, we investigate a data-adaptive extension of the L+S model, dubbed LASSI, where the temporal image sequence is decomposed into a low rank component and a component whose spatiotemporal (3D) patches are sparse in some adaptive dictionary domain. We investigate various formulations and efficient methods for jointly estimating the underlying dynamic signal components and the spatiotemporal dictionary from limited measurements. We also obtain efficient sparsity penalized dictionary-blind compressed sensing methods as special cases of our LASSI approaches. Our numerical experiments demonstrate the promising performance of LASSI schemes for dynamicmagnetic resonance image reconstruction from limited k-t space data compared to recent methods such as k-t SLR and L+S, and compared to the proposed dictionary-blind compressed sensing method. PMID- 28092529 TI - Sub-Category Classifiers for Multiple-Instance Learning and its Application to Retinal Nerve Fiber Layer Visibility Classification. AB - We propose a novel multiple instance learning method to assess the visibility (visible/not visible) of the retinal nerve fiber layer (RNFL) in fundus camera images. Using only image-level labels, our approach learns to classify the images as well as to localize the RNFL visible regions. We transform the original feature space to a discriminative subspace, and learn a region-level classifier in that subspace. We propose a margin-based loss function to jointly learn this subspace and the region-level classifier. Experiments with a RNFL dataset containing 884 images annotated by two ophthalmologists give a system-annotator agreement (kappa values) of 0:73 and 0:72 respectively, with an inter-annotator agreement of 0:73. Our system agrees better with the more experienced annotator. Comparative tests with three public datasets (MESSIDOR and DR for diabetic retinopathy, UCSB for breast cancer) show that our novel MIL approach improves performance over the state-of-the-art. Our Matlab code is publicly available at https://github.com/ManiShiyam/Sub-category-classifiersfor- Multiple-Instance Learning/wiki. PMID- 28092530 TI - Feasibility of Multiplane-Transmit Beamforming for Real-Time Volumetric Cardiac Imaging: A Simulation Study. AB - Today's 3-D cardiac ultrasound imaging systems suffer from relatively low spatial and temporal resolution, limiting their applicability in daily clinical practice. To address this problem, 3-D diverging wave imaging with spatial coherent compounding (DWC) as well as 3-D multiline-transmit (MLT) imaging have recently been proposed. Currently, the former improves the temporal resolution significantly at the expense of image quality and the risk of introducing motion artifacts, whereas the latter only provides a moderate gain in volume rate but mostly preserves quality. In this paper, a new technique for real-time volumetric cardiac imaging is proposed by combining the strengths of both approaches. Hereto, multiple planar (i.e., 2-D) diverging waves are simultaneously transmitted in order to scan the 3-D volume, i.e., multiplane transmit (MPT) beamforming. The performance of a 3MPT imaging system was contrasted to that of a 3-D DWC system and that of a 3-D MLT system by computer simulations during both static and moving conditions of the target structures while operating at similar volume rate. It was demonstrated that for stationary targets, the 3MPT imaging system was competitive with both the 3-D DWC and 3-D MLT systems in terms of spatial resolution and sidelobe levels (i.e., image quality). However, for moving targets, the image quality quickly deteriorated for the 3-D DWC systems while it remained stable for the 3MPT system while operating at twice the volume rate of the 3-D-MLT system. The proposed MPT beamforming approach was thus demonstrated to be feasible and competitive to state-of-the-art methodologies. PMID- 28092531 TI - A 200-1380-kHz Quadrifrequency Focused Ultrasound Transducer for Neurostimulation in Rodents and Primates: Transcranial In Vitro Calibration and Numerical Study of the Influence of Skull Cavity. AB - Low intensity transcranial focused ultrasound has been demonstrated to produce neuromodulation in both animals and humans. Primarily for technical reasons, frequency is one of the most poorly investigated critical wave parameters. We propose the use of a quadri-band transducer capable of operating at 200, 320, 850, and 1380 kHz for further investigation of the frequency dependence of neuromodulation efficacy while keeping the position of the transducer fixed with respect to the subject's head. This paper presents the results of the transducer calibration in water, in vitro transmission measurements through a monkey skull flap, 3-D simulations based on both a MU -computed tomography ( MU CT)-scan of a rat and on CT-scans of two macaques. A maximum peak pressure greater than 0.52 MPa is expected at each frequency in rat and macaque heads. According to the literature, our transducer can achieve neuromodulation in rodents and primates at each four frequencies. The impact of standing waves is shown to be most prominent at the lowest frequencies. PMID- 28092532 TI - Improved Shear Wave Group Velocity Estimation Method Based on Spatiotemporal Peak and Thresholding Motion Search. AB - Quantitative ultrasound elastography is increasingly being used in the assessment of chronic liver disease. Many studies have reported ranges of liver shear wave velocity values for healthy individuals and patients with different stages of liver fibrosis. Nonetheless, ongoing efforts exist to stabilize quantitative ultrasound elastography measurements by assessing factors that influence tissue shear wave velocity values, such as food intake, body mass index, ultrasound scanners, scanning protocols, and ultrasound image quality. Time-to-peak (TTP) methods have been routinely used to measure the shear wave velocity. However, there is still a need for methods that can provide robust shear wave velocity estimation in the presence of noisy motion data. The conventional TTP algorithm is limited to searching for the maximum motion in time profiles at different spatial locations. In this paper, two modified shear wave speed estimation algorithms are proposed. The first method searches for the maximum motion in both space and time [spatiotemporal peak (STP)]; the second method applies an amplitude filter [spatiotemporal thresholding (STTH)] to select points with motion amplitude higher than a threshold for shear wave group velocity estimation. The two proposed methods (STP and STTH) showed higher precision in shear wave velocity estimates compared with TTP in phantom. Moreover, in a cohort of 14 healthy subjects, STP and STTH methods improved both the shear wave velocity measurement precision and the success rate of the measurement compared with conventional TTP. PMID- 28092533 TI - Linear System Models for Ultrasonic Imaging: Intensity Signal Statistics. AB - Despite a great deal of work characterizing the statistical properties of radio frequency backscattered ultrasound signals, less is known about the statistical properties of demodulated intensity signals. Analysis of intensity is made more difficult by a strong nonlinearity that arises in the process of demodulation. This limits our ability to characterize the spatial resolution and noise properties of B-mode ultrasound images. In this paper, we generalize earlier results on two-point intensity covariance using a multivariate systems approach. We derive the mean and autocovariance function of the intensity signal under Gaussian assumptions on both the object scattering function and acquisition noise, and with the assumption of a locally shift-invariant pulse-echo system function. We investigate the limiting cases of point statistics and a uniform scattering field with a stationary distribution. Results from validation studies using simulation and data from a real system applied to a uniform scattering phantom are presented. In the simulation studies, we find errors less than 10% between the theoretical mean and variance, and sample estimates of these quantities. Prediction of the intensity power spectrum (PS) in the real system exhibits good qualitative agreement (errors less than 3.5 dB for frequencies between 0.1 and 10 cyc/mm, but with somewhat higher error outside this range that may be due to the use of a window in the PS estimation procedure). We also replicate the common finding that the intensity mean is equal to its standard deviation (i.e., signal-to-noise ratio = 1) for fully developed speckle. We show how the derived statistical properties can be used to characterize the quality of an ultrasound linear array for low-contrast patterns using generalized noise equivalent quanta directly on the intensity signal. PMID- 28092534 TI - A $k$ -Space Pseudospectral Method for Elastic Wave Propagation in Heterogeneous Anisotropic Media. AB - This paper presents the theory of the k -space method generalized to model elastic wave propagation in heterogeneous anisotropic media. The k -space methods are promising time integration techniques giving, in conjunction with collocation spectral methods, accurate and efficient numerical schemes for problems in heterogeneous media. In this paper, the k -space operator is derived in a spatially continuous form using the Fourier analysis of the displacement formalism of elastodynamics. An efficient numerical algorithm is then constructed by applying a Fourier collocation spectral method, leading to define the discrete k -space scheme. The proposed method is temporally exact for homogeneous media, unconditionally stable for heterogeneous media, and also allows larger time steps without loss of accuracy. Implementation of the method is discussed in detail. The method is validated through a set of numerical tests. The numerical results show the efficacy of the method compared with the conventional schemes. PMID- 28092535 TI - Super-Resolution Person Re-Identification With Semi-Coupled Low-Rank Discriminant Dictionary Learning. AB - Person re-identification has been widely studied due to its importance in surveillance and forensics applications. In practice, gallery images are high resolution (HR), while probe images are usually low resolution (LR) in the identification scenarios with large variation of illumination, weather, or quality of cameras. Person re-identification in this kind of scenarios, which we call super-resolution (SR) person re-identification, has not been well studied. In this paper, we propose a semi-coupled low-rank discriminant dictionary learning (SLD2L) approach for SR person re-identification task. With the HR and LR dictionary pair and mapping matrices learned from the features of HR and LR training images, SLD2L can convert the features of the LR probe images into HR features. To ensure that the converted features have favorable discriminative capability and the learned dictionaries can well characterize intrinsic feature spaces of the HR and LR images, we design a discriminant term and a low-rank regularization term for SLD2L. Moreover, considering that low resolution results in different degrees of loss for different types of visual appearance features, we propose a multi-view SLD2L (MVSLD2L) approach, which can learn the type specific dictionary pair and mappings for each type of feature. Experimental results on multiple publicly available data sets demonstrate the effectiveness of our proposed approaches for the SR person re-identification task. PMID- 28092536 TI - Improved Denoising via Poisson Mixture Modeling of Image Sensor Noise. AB - This paper describes a study aimed at comparing the real image sensor noise distribution to the models of noise often assumed in image denoising designs. A quantile analysis in pixel, wavelet transform, and variance stabilization domains reveal that the tails of Poisson, signal-dependent Gaussian, and Poisson-Gaussian models are too short to capture real sensor noise behavior. A new Poisson mixture noise model is proposed to correct the mismatch of tail behavior. Based on the fact that noise model mismatch results in image denoising that undersmoothes real sensor data, we propose a mixture of Poisson denoising method to remove the denoising artifacts without affecting image details, such as edge and textures. Experiments with real sensor data verify that denoising for real image sensor data is indeed improved by this new technique. PMID- 28092537 TI - Detail-Enhanced Multi-Scale Exposure Fusion. AB - Multi-scale exposure fusion is an effective image enhancement technique for a high dynamic range (HDR) scene. In this paper, a new multi-scale exposure fusion algorithm is proposed to merge differently exposed low dynamic range (LDR) images by using the weighted guided image filter to smooth the Gaussian pyramids of weight maps for all the LDR images. Details in the brightest and darkest regions of the HDR scene are preserved better by the proposed algorithm without relative brightness change in the fused image. In addition, a new weighted structure tensor is introduced to the differently exposed images and it is adopted to design a detail extraction component for the proposed fusion algorithm, such that users are allowed to manipulate fine details in the enhanced image according to their preference. The proposed multi-scale exposure fusion algorithm is also applied to design a simple single image brightening algorithm for both low-light imaging and back-light imaging. PMID- 28092538 TI - Spatio-Temporal Closed-Loop Object Detection. AB - Object detection is one of the most important tasks of computer vision. It is usually performed by evaluating a subset of the possible locations of an image, that are more likely to contain the object of interest. Exhaustive approaches have now been superseded by object proposal methods. The interplay of detectors and proposal algorithms has not been fully analyzed and exploited up to now, although this is a very relevant problem for object detection in video sequences. We propose to connect, in a closed-loop, detectors and object proposal generator functions exploiting the ordered and continuous nature of video sequences. Different from tracking we only require a previous frame to improve both proposal and detection: no prediction based on local motion is performed, thus avoiding tracking errors. We obtain three to four points of improvement in mAP and a detection time that is lower than Faster Regions with CNN features (R-CNN), which is the fastest Convolutional Neural Network (CNN) based generic object detector known at the moment. PMID- 28092539 TI - Object-Based Multiple Foreground Segmentation in RGBD Video. AB - We present an RGB and Depth (RGBD) video segmentation method that takes advantage of depth data and can extract multiple foregrounds in the scene. This video segmentation is addressed as an object proposal selection problem formulated in a fully-connected graph, where a flexible number of foregrounds may be chosen. In our graph, each node represents a proposal, and the edges model intra-frame and inter-frame constraints on the solution. The proposals are selected based on an RGBD video saliency map in which depth-based features are utilized to enhance the identification of foregrounds. Experiments show that the proposed multiple foreground segmentation method outperforms related techniques, and the depth cue serves as a helpful complement to RGB features. Moreover, our method provides performance comparable to the state-of-the-art RGB video segmentation techniques on regular RGB videos with estimated depth maps. PMID- 28092540 TI - Robust and Discriminative Labeling for Multi-Label Active Learning Based on Maximum Correntropy Criterion. AB - Multi-label learning draws great interests in many real world applications. It is a highly costly task to assign many labels by the oracle for one instance. Meanwhile, it is also hard to build a good model without diagnosing discriminative labels. Can we reduce the label costs and improve the ability to train a good model for multi-label learning simultaneously? Active learning addresses the less training samples problem by querying the most valuable samples to achieve a better performance with little costs. In multi-label active learning, some researches have been done for querying the relevant labels with less training samples or querying all labels without diagnosing the discriminative information. They all cannot effectively handle the outlier labels for the measurement of uncertainty. Since maximum correntropy criterion (MCC) provides a robust analysis for outliers in many machine learning and data mining algorithms, in this paper, we derive a robust multi-label active learning algorithm based on an MCC by merging uncertainty and representativeness, and propose an efficient alternating optimization method to solve it. With MCC, our method can eliminate the influence of outlier labels that are not discriminative to measure the uncertainty. To make further improvement on the ability of information measurement, we merge uncertainty and representativeness with the prediction labels of unknown data. It cannot only enhance the uncertainty but also improve the similarity measurement of multi-label data with labels information. Experiments on benchmark multi-label data sets have shown a superior performance than the state-of-the-art methods. PMID- 28092541 TI - Quality Assessment of Sharpened Images: Challenges, Methodology, and Objective Metrics. AB - Most of the effort in image quality assessment (QA) has been so far dedicated to the degradation of the image. However, there are also many algorithms in the image processing chain that can enhance the quality of an input image. These include procedures for contrast enhancement, deblurring, sharpening, up-sampling, denoising, transfer function compensation, etc. In this work, possible strategies for the quality assessment of sharpened images are investigated. This task is not trivial because the sharpening techniques can increase the perceived quality, as well as introduce artifacts leading to the quality drop (over-sharpening). Here, the framework specifically adapted for the quality assessment of sharpened images and objective metrics comparison in this context is introduced. However, the framework can be adopted in other quality assessment areas as well. The problem of selecting the correct procedure for subjective evaluation was addressed and a subjective test on blurred, sharpened, and over-sharpened images was performed in order to demonstrate the use of the framework. The obtained ground-truth data were used for testing the suitability of state-ofthe- art objective quality metrics for the assessment of sharpened images. The comparison was performed by novel procedure using ROC analyses which is found more appropriate for the task than standard methods. Furthermore, seven possible augmentations of the no reference S3 metric adapted for sharpened images are proposed. The performance of the metric is significantly improved and also superior over the rest of the tested quality criteria with respect to the subjective data. PMID- 28092542 TI - Bayesian Face Sketch Synthesis. AB - Exemplar-based face sketch synthesis has been widely applied to both digital entertainment and law enforcement. In this paper, we propose a Bayesian framework for face sketch synthesis, which provides a systematic interpretation for understanding the common properties and intrinsic difference in different methods from the perspective of probabilistic graphical models. The proposed Bayesian framework consists of two parts: the neighbor selection model and the weight computation model. Within the proposed framework, we further propose a Bayesian face sketch synthesis method. The essential rationale behind the proposed Bayesian method is that we take the spatial neighboring constraint between adjacent image patches into consideration for both aforementioned models, while the state-of-the-art methods neglect the constraint either in the neighbor selection model or in the weight computation model. Extensive experiments on the Chinese University of Hong Kong face sketch database demonstrate that the proposed Bayesian method could achieve superior performance compared with the state-of-the-art methods in terms of both subjective perceptions and objective evaluations. PMID- 28092543 TI - A Robust Wrap Reduction Algorithm for Fringe Projection Profilometry and Applications in Magnetic Resonance Imaging. AB - In this paper, we present an effective algorithm to reduce the number of wraps in a 2D phase signal provided as input. The technique is based on an accurate estimate of the fundamental frequency of a 2D complex signal with the phase given by the input, and the removal of a dependent additive term from the phase map. Unlike existing methods based on the discrete Fourier transform (DFT), the frequency is computed by using noise-robust estimates that are not restricted to integer values. Then, to deal with the problem of a non-integer shift in the frequency domain, an equivalent operation is carried out on the original phase signal. This consists of the subtraction of a tilted plane whose slope is computed from the frequency, followed by a re-wrapping operation. The technique has been exhaustively tested on fringe projection profilometry (FPP) and magnetic resonance imaging (MRI) signals. In addition, the performance of several frequency estimation methods has been compared. The proposed methodology is particularly effective on FPP signals, showing a higher performance than the state-of-the-art wrap reduction approaches. In this context, it contributes to canceling the carrier effect at the same time as it eliminates any potential slope that affects the entire signal. Its effectiveness on other carrier-free phase signals, e.g., MRI, is limited to the case that inherent slopes are present in the phase data. PMID- 28092544 TI - Discriminative Multi-View Interactive Image Re-Ranking. AB - Given an unreliable visual patterns and insufficient query information, content based image retrieval is often suboptimal and requires image re-ranking using auxiliary information. In this paper, we propose a discriminative multi-view interactive image re-ranking (DMINTIR), which integrates user relevance feedback capturing users' intentions and multiple features that sufficiently describe the images. In DMINTIR, heterogeneous property features are incorporated in the multi view learning scheme to exploit their complementarities. In addition, a discriminatively learned weight vector is obtained to reassign updated scores and target images for re-ranking. Compared with other multi-view learning techniques, our scheme not only generates a compact representation in the latent space from the redundant multi-view features but also maximally preserves the discriminative information in feature encoding by the large-margin principle. Furthermore, the generalization error bound of the proposed algorithm is theoretically analyzed and shown to be improved by the interactions between the latent space and discriminant function learning. Experimental results on two benchmark data sets demonstrate that our approach boosts baseline retrieval quality and is competitive with the other state-of-the-art re-ranking strategies. PMID- 28092545 TI - Heterogeneous Face Recognition: A Common Encoding Feature Discriminant Approach. AB - Heterogeneous face recognition is an important, yet challenging problem in face recognition community. It refers to matching a probe face image to a gallery of face images taken from alternate imaging modality. The major challenge of heterogeneous face recognition lies in the great discrepancies between different image modalities. Conventional face feature descriptors, e.g., local binary patterns, histogram of oriented gradients, and scale-invariant feature transform, are mostly designed in a handcrafted way and thus generally fail to extract the common discriminant information from the heterogeneous face images. In this paper, we propose a new feature descriptor called common encoding model for heterogeneous face recognition, which is able to capture common discriminant information, such that the large modality gap can be significantly reduced at the feature extraction stage. Specifically, we turn a face image into an encoded one with the encoding model learned from the training data, where the difference of the encoded heterogeneous face images of the same person can be minimized. Based on the encoded face images, we further develop a discriminant matching method to infer the hidden identity information of the cross-modality face images for enhanced recognition performance. The effectiveness of the proposed approach is demonstrated (on several public-domain face datasets) in two typical heterogeneous face recognition scenarios: matching NIR faces to VIS faces and matching sketches to photographs. PMID- 28092546 TI - Geometry Guided Multi-Scale Depth Map Fusion via Graph Optimization. AB - In depth discontinuous and untextured regions, depth maps created by multiple view stereopsis are with heavy noises, but existing depth map fusion methods cannot handle it explicitly. To tackle the problem, two novel strategies are proposed: 1) a more discriminative fusion method, which is based on geometry consistency, measuring the consistency, and stability of surface geometry computed on both partial and global surfaces, different from traditional methods only using visibility consistency; 2) a graph optimization method which fuses pyramids of depth maps as mutual complementary information is available in different scales, and differs from existing multi-scale fusion methods. The method considers both sampling scale of a point and relations among points, and is proven to be solvable by graph cuts. Experimental results verify the superior performance of the proposed method to the traditional visibility consistency based methods, and the proposed method is also compared favorably with a number of state-of-the-art methods. Moreover, the proposed method achieves the highest completeness among all the methods compared. PMID- 28092547 TI - Asymmetrically Compressed Stereoscopic 3D Videos: Quality Assessment and Rate Distortion Performance Evaluation. AB - Objective quality assessment of stereoscopic 3D video is challenging but highly desirable, especially in the application of stereoscopic video compression and transmission, where useful quality models are missing, that can guide the critical decision making steps in the selection of mixed-resolution coding, asymmetric quantization, and pre- and post-processing schemes. Here we first carry out subjective quality assessment experiments on two databases that contain various asymmetrically compressed stereoscopic 3D videos obtained from mixed resolution coding, asymmetric transform-domain quantization coding, their combinations, and the multiple choices of postprocessing techniques. We compare these asymmetric stereoscopic video coding schemes with symmetric coding methods and verify their potential coding gains. We observe a strong systematic bias when using direct averaging of 2D video quality of both views to predict 3D video quality. We then apply a binocular rivalry inspired model to account for the prediction bias, leading to a significantly improved full reference quality prediction model of stereoscopic videos. The model allows us to quantitatively predict the coding gain of different variations of asymmetric video compression, and provides new insight on the development of high efficiency 3D video coding schemes. PMID- 28092548 TI - Linear Spectral Clustering Superpixel. AB - In this paper, we present a superpixel segmentation algorithm called linear spectral clustering (LSC), which is capable of producing superpixels with both high boundary adherence and visual compactness for natural images with low computational costs. In LSC, a normalized cuts-based formulation of image segmentation is adopted using a distance metric that measures both the color similarity and the space proximity between image pixels. However, rather than directly using the traditional eigen-based algorithm, we approximate the similarity metric through a deliberately designed kernel function such that pixel values can be explicitly mapped to a high-dimensional feature space. We then apply the conclusion that by appropriately weighting each point in this feature space, the objective functions of the weighted K-means and the normalized cuts share the same optimum points. Consequently, it is possible to optimize the cost function of the normalized cuts by iteratively applying simple K-means clustering in the proposed feature space. LSC possesses linear computational complexity and high memory efficiency, since it avoids both the decomposition of the affinity matrix and the generation of the large kernel matrix. By utilizing the underlying mathematical equivalence between the two types of seemingly different methods, LSC successfully preserves global image structures through efficient local operations. Experimental results show that LSC performs as well as or even better than the state-of-the-art superpixel segmentation algorithms in terms of several commonly used evaluation metrics in image segmentation. The applicability of LSC is further demonstrated in two related computer vision tasks. PMID- 28092549 TI - Learning Short Binary Codes for Large-scale Image Retrieval. AB - Large-scale visual information retrieval has become an active research area in this big data era. Recently, hashing/binary coding algorithms prove to be effective for scalable retrieval applications. Most existing hashing methods require relatively long binary codes (i.e., over hundreds of bits, sometimes even thousands of bits) to achieve reasonable retrieval accuracies. However, for some realistic and unique applications, such as on wearable or mobile devices, only short binary codes can be used for efficient image retrieval due to the limitation of computational resources or bandwidth on these devices. In this paper, we propose a novel unsupervised hashing approach called min-cost ranking (MCR) specifically for learning powerful short binary codes (i.e., usually the code length shorter than 100 b) for scalable image retrieval tasks. By exploring the discriminative ability of each dimension of data, MCR can generate one bit binary code for each dimension and simultaneously rank the discriminative separability of each bit according to the proposed cost function. Only top-ranked bits with minimum cost-values are then selected and grouped together to compose the final salient binary codes. Extensive experimental results on large-scale retrieval demonstrate that MCR can achieve comparative performance as the state of-the-art hashing algorithms but with significantly shorter codes, leading to much faster large-scale retrieval. PMID- 28092550 TI - $L_{0}$ Gradient Projection. AB - Minimizing L0 gradient, the number of the non-zero gradients of an image, together with a quadratic data-fidelity to an input image has been recognized as a powerful edge-preserving filtering method. However, the L0 gradient minimization has an inherent difficulty: a user-given parameter controlling the degree of flatness does not have a physical meaning since the parameter just balances the relative importance of the L0 gradient term to the quadratic data fidelity term. As a result, the setting of the parameter is a troublesome work in the L0 gradient minimization. To circumvent the difficulty, we propose a new edge preserving filtering method with a novel use of the L0 gradient. Our method is formulated as the minimization of the quadratic data-fidelity subject to the hard constraint that the L0 gradient is less than a user-given parameter alpha . This strategy is much more intuitive than the L0 gradient minimization because the parameter alpha has a clear meaning: the L0 gradient value of the output image itself, so that one can directly impose a desired degree of flatness by alpha . We also provide an efficient algorithm based on the so-called alternating direction method of multipliers for computing an approximate solution of the nonconvex problem, where we decompose it into two subproblems and derive closed form solutions to them. The advantages of our method are demonstrated through extensive experiments. PMID- 28092551 TI - Hierarchical Image Segmentation Based on Iterative Contraction and Merging. AB - In this paper, we propose a new framework for hierarchical image segmentation based on iterative contraction and merging. In the proposed framework, we treat the hierarchical image segmentation problem as a sequel of optimization problems, with each optimization process being realized by a contraction-and-merging process to identify and merge the most similar data pairs at the current resolution. At the beginning, we perform pixel-based contraction and merging to quickly combine image pixels into initial region-elements with visually indistinguishable intra-region color difference. After that, we iteratively perform region-based contraction and merging to group adjacent regions into larger ones to progressively form a segmentation dendrogram for hierarchical segmentation. Comparing with the state-of-the-art techniques, the proposed algorithm can not only produce high-quality segmentation results in a more efficient way, but also keep a lot of boundary details in the segmentation results. PMID- 28092552 TI - Discriminative Elastic-Net Regularized Linear Regression. AB - In this paper, we aim at learning compact and discriminative linear regression models. Linear regression has been widely used in different problems. However, most of the existing linear regression methods exploit the conventional zero-one matrix as the regression targets, which greatly narrows the flexibility of the regression model. Another major limitation of these methods is that the learned projection matrix fails to precisely project the image features to the target space due to their weak discriminative capability. To this end, we present an elastic-net regularized linear regression (ENLR) framework, and develop two robust linear regression models which possess the following special characteristics. First, our methods exploit two particular strategies to enlarge the margins of different classes by relaxing the strict binary targets into a more feasible variable matrix. Second, a robust elastic-net regularization of singular values is introduced to enhance the compactness and effectiveness of the learned projection matrix. Third, the resulting optimization problem of ENLR has a closed-form solution in each iteration, which can be solved efficiently. Finally, rather than directly exploiting the projection matrix for recognition, our methods employ the transformed features as the new discriminate representations to make final image classification. Compared with the traditional linear regression model and some of its variants, our method is much more accurate in image classification. Extensive experiments conducted on publicly available data sets well demonstrate that the proposed framework can outperform the state-of-the-art methods. The MATLAB codes of our methods can be available at http://www.yongxu.org/lunwen.html. PMID- 28092553 TI - Deep Aesthetic Quality Assessment With Semantic Information. AB - Human beings often assess the aesthetic quality of an image coupled with the identification of the image's semantic content. This paper addresses the correlation issue between automatic aesthetic quality assessment and semantic recognition. We cast the assessment problem as the main task among a multi-task deep model, and argue that semantic recognition task offers the key to address this problem. Based on convolutional neural networks, we employ a single and simple multi-task framework to efficiently utilize the supervision of aesthetic and semantic labels. A correlation item between these two tasks is further introduced to the framework by incorporating the inter-task relationship learning. This item not only provides some useful insight about the correlation but also improves assessment accuracy of the aesthetic task. In particular, an effective strategy is developed to keep a balance between the two tasks, which facilitates to optimize the parameters of the framework. Extensive experiments on the challenging Aesthetic Visual Analysis dataset and Photo.net dataset validate the importance of semantic recognition in aesthetic quality assessment, and demonstrate that multitask deep models can discover an effective aesthetic representation to achieve the state-of-the-art results. PMID- 28092554 TI - Graph Laplacian Regularization for Image Denoising: Analysis in the Continuous Domain. AB - Inverse imaging problems are inherently underdetermined, and hence, it is important to employ appropriate image priors for regularization. One recent popular prior-the graph Laplacian regularizer-assumes that the target pixel patch is smooth with respect to an appropriately chosen graph. However, the mechanisms and implications of imposing the graph Laplacian regularizer on the original inverse problem are not well understood. To address this problem, in this paper, we interpret neighborhood graphs of pixel patches as discrete counterparts of Riemannian manifolds and perform analysis in the continuous domain, providing insights into several fundamental aspects of graph Laplacian regularization for image denoising. Specifically, we first show the convergence of the graph Laplacian regularizer to a continuous-domain functional, integrating a norm measured in a locally adaptive metric space. Focusing on image denoising, we derive an optimal metric space assuming non-local self-similarity of pixel patches, leading to an optimal graph Laplacian regularizer for denoising in the discrete domain. We then interpret graph Laplacian regularization as an anisotropic diffusion scheme to explain its behavior during iterations, e.g., its tendency to promote piecewise smooth signals under certain settings. To verify our analysis, an iterative image denoising algorithm is developed. Experimental results show that our algorithm performs competitively with state-of-the-art denoising methods, such as BM3D for natural images, and outperforms them significantly for piecewise smooth images. PMID- 28092555 TI - Progressive Shape-Distribution-Encoder for Learning 3D Shape Representation. AB - Since there are complex geometric variations with 3D shapes, extracting efficient 3D shape features is one of the most challenging tasks in shape matching and retrieval. In this paper, we propose a deep shape descriptor by learning shape distributions at different diffusion time via a progressive shape-distribution encoder (PSDE). First, we develop a shape distribution representation with the kernel density estimator to characterize the intrinsic geometry structures of 3D shapes. Then, we propose to learn a deep shape feature through an unsupervised PSDE. Specially, the unsupervised PSDE aims at modeling the complex non-linear transform of the estimated shape distributions between consecutive diffusion time. In order to characterize the intrinsic structures of 3D shapes more efficiently, we stack multiple PSDEs to form a network structure. Finally, we concatenate all neurons in the middle hidden layers of the unsupervised PSDE network to form an unsupervised shape descriptor for retrieval. Furthermore, by imposing an additional constraint on the outputs of all hidden layers, we propose a supervised PSDE to form a supervised shape descriptor. For each hidden layer, the similarity between a pair of outputs from the same class is as large as possible and the similarity between a pair of outputs from different classes is as small as possible. The proposed method is evaluated on three benchmark 3D shape data sets with large geometric variations, i.e., McGill, SHREC'10 ShapeGoogle, and SHREC'14 Human data sets, and the experimental results demonstrate the superiority of the proposed method to the existing approaches. PMID- 28092556 TI - Study of Saliency in Objective Video Quality Assessment. AB - Reliably predicting video quality as perceived by humans remains challenging and is of high practical relevance. A significant research trend is to investigate visual saliency and its implications for video quality assessment. Fundamental problems regarding how to acquire reliable eye-tracking data for the purpose of video quality research and how saliency should be incorporated in objective video quality metrics (VQMs) are largely unsolved. In this paper, we propose a refined methodology for reliably collecting eye-tracking data, which essentially eliminates bias induced by each subject having to view multiple variations of the same scene in a conventional experiment. We performed a large-scale eye-tracking experiment that involved 160 human observers and 160 video stimuli distorted with different distortion types at various degradation levels. The measured saliency was integrated into several best known VQMs in the literature. With the assurance of the reliability of the saliency data, we thoroughly assessed the capabilities of saliency in improving the performance of VQMs, and devised a novel approach for optimal use of saliency in VQMs. We also evaluated to what extent the state of-the-art computational saliency models can improve VQMs in comparison to the improvement achieved by using "ground truth" eye-tracking data. The eye-tracking database is made publicly available to the research community. PMID- 28092557 TI - Single Image Super-Resolution Using Global Regression Based on Multiple Local Linear Mappings. AB - Super-resolution (SR) has become more vital, because of its capability to generate high-quality ultra-high definition (UHD) high-resolution (HR) images from low-resolution (LR) input images. Conventional SR methods entail high computational complexity, which makes them difficult to be implemented for up scaling of full-high-definition input images into UHD-resolution images. Nevertheless, our previous super-interpolation (SI) method showed a good compromise between Peak-Signal-to-Noise Ratio (PSNR) performances and computational complexity. However, since SI only utilizes simple linear mappings, it may fail to precisely reconstruct HR patches with complex texture. In this paper, we present a novel SR method, which inherits the large-to-small patch conversion scheme from SI but uses global regression based on local linear mappings (GLM). Thus, our new SR method is called GLM-SI. In GLM-SI, each LR input patch is divided into 25 overlapped subpatches. Next, based on the local properties of these subpatches, 25 different local linear mappings are applied to the current LR input patch to generate 25 HR patch candidates, which are then regressed into one final HR patch using a global regressor. The local linear mappings are learned cluster-wise in our off-line training phase. The main contribution of this paper is as follows: Previously, linear-mapping-based conventional SR methods, including SI only used one simple yet coarse linear mapping to each patch to reconstruct its HR version. On the contrary, for each LR input patch, our GLM-SI is the first to apply a combination of multiple local linear mappings, where each local linear mapping is found according to local properties of the current LR patch. Therefore, it can better approximate nonlinear LR-to-HR mappings for HR patches with complex texture. Experiment results show that the proposed GLM-SI method outperforms most of the state-of-the art methods, and shows comparable PSNR performance with much lower computational complexity when compared with a super-resolution method based on convolutional neural nets (SRCNN15). Compared with the previous SI method that is limited with a scale factor of 2, GLM-SI shows superior performance with average 0.79 dB higher in PSNR, and can be used for scale factors of 3 or higher. PMID- 28092558 TI - Discriminant Context Information Analysis for Post-Ranking Person Re Identification. AB - Existing approaches for person re-identification are mainly based on creating distinctive representations or on learning optimal metrics. The achieved results are then provided in the form of a list of ranked matching persons. It often happens that the true match is not ranked first but it is in the first positions. This is mostly due to the visual ambiguities shared between the true match and other "similar" persons. At the current state, there is a lack of a study of such visual ambiguities which limit the re-identification performance within the first ranks. We believe that an analysis of the similar appearances of the first ranks can be helpful in detecting, hence removing, such visual ambiguities. We propose to achieve such a goal by introducing an unsupervised post-ranking framework. Once the initial ranking is available, content and context sets are extracted. Then, these are exploited to remove the visual ambiguities and to obtain the discriminant feature space which is finally exploited to compute the new ranking. An in-depth analysis of the performance achieved on three public benchmark data sets support our believes. For every data set, the proposed method remarkably improves the first ranks results and outperforms the state-of-the-art approaches. PMID- 28092559 TI - Learning to Hash With Optimized Anchor Embedding for Scalable Retrieval. AB - Sparse representation and image hashing are powerful tools for data representation and image retrieval respectively. The combinations of these two tools for scalable image retrieval, i.e., sparse hashing (SH) methods, have been proposed in recent years and the preliminary results are promising. The core of those methods is a scheme that can efficiently embed the (high-dimensional) image features into a low-dimensional Hamming space, while preserving the similarity between features. Existing SH methods mostly focus on finding better sparse representations of images in the hash space. We argue that the anchor set utilized in sparse representation is also crucial, which was unfortunately underestimated by the prior art. To this end, we propose a novel SH method that optimizes the integration of the anchors, such that the features can be better embedded and binarized, termed as Sparse Hashing with Optimized Anchor Embedding. The central idea is to push the anchors far from the axis while preserving their relative positions so as to generate similar hashcodes for neighboring features. We formulate this idea as an orthogonality constrained maximization problem and an efficient and novel optimization framework is systematically exploited. Extensive experiments on five benchmark image data sets demonstrate that our method outperforms several state-of-the-art related methods. PMID- 28092560 TI - Diffeomorphic Multi-Frame Non-Rigid Registration of Cell Nuclei in 2D and 3D Live Cell Images. AB - To gain a better understanding of cellular and molecular processes, it is important to quantitatively analyze the motion of subcellular particles in live cell microscopy image sequences. Since, generally, the subcellular particles move and cell nuclei move as well as deform, it is important to decouple the movement of particles from that of the cell nuclei using non-rigid registration methods. We have developed a diffeomorphic multi-frame approach for non-rigid registration of cell nuclei in 2D and 3D live cell fluorescence microscopy images. Our non rigid registration approach is based on local optic flow estimation, exploits information from multiple consecutive image frames, and determines diffeomorphic transformations in the log-domain, which allows efficient computation of the inverse transformations. To register single images of an image sequence to a reference image, we use a temporally weighted mean image, which is constructed based on inverse transformations and multiple consecutive frames. Using multiple consecutive frames improves the registration accuracy compared to pairwise registration, and using a temporally weighted mean image significantly reduces the computation time compared with previous work. In addition, we use a flow boundary preserving method for regularization of computed deformation vector fields, which prevents from over-smoothing compared to standard Gaussian filtering. Our approach has been successfully applied to 2D and 3D synthetic as well as real live cell microscopy image sequences, and an experimental comparison with non-rigid pairwise, multi-frame, and temporal groupwise registration has been carried out. PMID- 28092561 TI - Realistic Data-Driven Traffic Flow Animation Using Texture Synthesis. AB - We present a novel data-driven approach to populate virtual road networks with realistic traffic flows. Specifically, given a limited set of vehicle trajectories as the input samples, our approach first synthesizes a large set of vehicle trajectories. By taking the spatio-temporal information of traffic flows as a 2D texture, the generation of new traffic flows can be formulated as a texture synthesis process, which is solved by minimizing a newly developed traffic texture energy. The synthesized output captures the spatio-temporal dynamics of the input traffic flows, and the vehicle interactions in it strictly follow traffic rules. After that, we position the synthesized vehicle trajectory data to virtual road networks using a cage-based registration scheme, where a few traffic-specific constraints are enforced to maintain each vehicle's original spatial location and synchronize its motion in concert with its neighboring vehicles. Our approach is intuitive to control and scalable to the complexity of virtual road networks. We validated our approach through many experiments and paired comparison user studies. PMID- 28092562 TI - Line Graph or Scatter Plot? Automatic Selection of Methods for Visualizing Trends in Time Series. AB - Line graphs are usually considered to be the best choice for visualizing time series data, whereas sometimes also scatter plots are used for showing main trends. So far there are no guidelines that indicate which of these visualization methods better display trends in time series for a given canvas. Assuming that the main information in a time series is its overall trend, we propose an algorithm that automatically picks the visualization method that reveals this trend best. This is achieved by measuring the visual consistency between the trend curve represented by a LOESS fit and the trend described by a scatter plot or a line graph. To measure the consistency between our algorithm and user choices, we performed an empirical study with a series of controlled experiments that show a large correspondence. In a factor analysis we furthermore demonstrate that various visual and data factors have effects on the preference for a certain type of visualization. PMID- 28092563 TI - Effects of Different Types of Virtual Reality Display on Presence and Learning in a Safety Training Scenario. AB - The increasing availability of head-mounted displays (HMDs) for home use motivates the study of the possible effects that adopting this new hardware might have on users. Moreover, while the impact of display type has been studied for different kinds of tasks, it has been scarcely explored in procedural training. Our study considered three different types of displays used by participants for training in aviation safety procedures with a serious game. The three displays were respectively representative of: (i) desktop VR (a standard desktop monitor), (ii) many setups for immersive VR used in the literature (an HMD with narrow field of view and a 3-DOF tracker), and (iii) new setups for immersive home VR (an HMD with wide field of view and 6-DOF tracker). We assessed effects on knowledge gain, and different self-reported measures (self-efficacy, engagement, presence). Unlike previous studies of display type that measured effects only immediately after the VR experience, we considered also a longer time span (2 weeks). Results indicated that the display type played a significant role in engagement and presence. The training benefits (increased knowledge and self efficacy) were instead obtained, and maintained at two weeks, regardless of the display used. The paper discusses the implications of these results. PMID- 28092564 TI - Static Versus Dynamic Decoding Algorithms in a Non-Invasive Body-Machine Interface. AB - In this study, we consider a non-invasive body-machine interface that captures body motions still available to people with spinal cord injury (SCI) and maps them into a set of signals for controlling a computer user interface while engaging in a sustained level of mobility and exercise. We compare the effectiveness of two decoding algorithms that transform a high-dimensional body signal vector into a lower dimensional control vector on six subjects with high level SCI and eight controls. One algorithm is based on a static map from current body signals to the current value of the control vector set through principal component analysis (PCA), the other on dynamic mapping a segment of body signals to the value and the temporal derivatives of the control vector set through a Kalman filter. SCI and control participants performed straighter and smoother cursor movements with the Kalman algorithm during center-out reaching, but their movements were faster and more precise when using PCA. All participants were able to use the BMI's continuous, two-dimensional control to type on a virtual keyboard and play pong, and performance with both algorithms was comparable. However, seven of eight control participants preferred PCA as their method of virtual wheelchair control. The unsupervised PCA algorithm was easier to train and seemed sufficient to achieve a higher degree of learnability and perceived ease of use. PMID- 28092565 TI - A Passive EEG-BCI for Single-Trial Detection of Changes in Mental State. AB - Traditional brain-computer interfaces often exhibit unstable performance over time. It has recently been proposed that passive brain-computer interfaces may provide a way to complement and stabilize these traditional systems. In this study, we investigated the feasibility of a passive brain-computer interface that uses electroencephalography to monitor changes in mental state on a single-trial basis. We recorded cortical activity from 15 locations while 11 able-bodied adults completed a series of challenging mental tasks. Using a feature clustering algorithm to account for redundancy in EEG signal features, we classified self reported changes in fatigue, frustration, and attention levels with 74.8 +/- 9.1%, 71.6 +/- 5.6%, and 84.8 +/- 7.4% accuracy, respectively. Based on the most frequently-selected features across all participants, we note the importance of the frontal and central electrodes for fatigue detection, posterior alpha band and frontal beta band activity for frustration detection, and posterior alpha band activity for attention detection. Future work will focus on integrating these results with an active brain-computer interface. PMID- 28092566 TI - WAKE-Up Exoskeleton to Assist Children With Cerebral Palsy: Design and Preliminary Evaluation in Level Walking. AB - This paper presents the modular design and control of a novel compliant lower limbmulti-joint exoskeleton for the rehabilitation of ankle kneemobility and locomotion of pediatric patients with neurological diseases, such as Cerebral Palsy (CP). The device consists of an untethered powered knee-ankle-foot orthosis (KAFO), addressed as WAKE-up (Wearable Ankle Knee Exoskeleton), characterized by a position control and capable of operating synchronously and synergistically with the human musculoskeletal system. The WAKE-up mechanical system, control architecture and feature extraction are described. Two test benches were used to mechanically characterize the device. The full system showed a maximum value of hysteresis equal to 8.8% and a maximum torque of 5.6 N m/rad. A pre-clinical use was performed, without body weight support, by four typically developing children and three children with CP. The aims were twofold: 1) to test the structure under weight-bearing conditions and 2) to ascertain its ability to provide appropriate assistance to the ankle and the knee during overground walking in a real environment. Results confirm the effectiveness of the WAKE-up design in providing torque assistance in accordance to the volitionalmovements especially in the recovery of correct foot landing at the start of the gait cycle. PMID- 28092567 TI - Inter-Joint Coordination Deficits Revealed in the Decomposition of Endpoint Jerk During Goal-Directed Arm Movement After Stroke. AB - It is well documented that neurological deficits after stroke can disrupt motor control processes that affect the smoothness of reaching movements. The smoothness of hand trajectories during multi-joint reaching depends on shoulder and elbow joint angular velocities and their successive derivatives as well as on the instantaneous arm configuration and its rate of change. Right-handed survivors of unilateral hemiparetic stroke and neurologically-intact control participants held the handle of a two-joint robot and made horizontal planar reaching movements. We decomposed endpoint jerk into components related to shoulder and elbow joint angular velocity, acceleration, and jerk. We observed an abnormal decomposition pattern in the most severely impaired stroke survivors consistent with deficits of inter-joint coordination. We then used numerical simulations of reaching movements to test whether the specific pattern of inter joint coordination deficits observed experimentally could be explained by either a general increase in motor noise related to weakness or by an impaired ability to compensate for multi-joint interaction torque. Simulation results suggest that observed deficits in movement smoothness after stroke more likely reflect an impaired ability to compensate for multi-joint interaction torques rather than the mere presence of elevated motor noise. PMID- 28092568 TI - Equivalent Discrete-Time Channel Modeling for Molecular Communication With Emphasize on an Absorbing Receiver. AB - This paper introduces the equivalent discrete-time channel model (EDTCM) to the area of diffusion-based molecular communication (DBMC). Emphasis is on an absorbing receiver, which is based on the so-called first passage time concept. In the wireless communications community the EDTCM is well known. Therefore, it is anticipated that the EDTCM improves the accessibility of DBMC and supports the adaptation of classical wireless communication algorithms to the area of DBMC. Furthermore, the EDTCM has the capability to provide a remarkable reduction of computational complexity compared to random walk based DBMC simulators. Besides the exact EDTCM, three approximations thereof based on binomial, Gaussian, and Poisson approximation are proposed and analyzed in order to further reduce computational complexity. In addition, the Bahl-Cocke-Jelinek-Raviv (BCJR) algorithm is adapted to all four channel models. Numerical results show the performance of the exact EDTCM, illustrate the performance of the adapted BCJR algorithm, and demonstrate the accuracy of the approximations. PMID- 28092569 TI - Discovery of microRNAs and Transcription Factors Co-Regulatory Modules by Integrating Multiple Types of Genomic Data. AB - It is well known that regulators known as microRNA (miRNA) and transcription factor (TF) have been found to play an important role in gene regulation. However, there are few researches of collaborative regulatory (co-regulatory) mechanism between miRNA and TF on system level (function level). Meanwhile, recent advances in high-throughput genomic technologies have enabled researchers to collect diverse large-scale genomic data, which can be used to study the co regulatory mechanism between miRNA and TF. In this paper, we propose a novel method called Sparse Network regularized non-negative matrix factorization for co regulatory modules identification which adopts multiple non-negative matrix factorization framework to identify co-regulatory modules including miRNAs, TFs and genes. This method jointly integrates miRNA, TF and gene expression profiles, and additional priori networks were added in a regularized manner. In addition, to avoid the sparsity of these networks, we employ the sparsity penalties to the variables to achieve modular solutions. The mathematical formulation can be effectively solved by an iterative multiplicative updating algorithm. We apply this method to multiple genomic data including the expression profiles of miRNAs, TFs and genes on breast cancer obtained from TCGA, priori miRNA-gene regulations, TF-gene regulations and gene-gene interactions. The results show that the miRNAs, TFs and genes of the co-regulatory modules are significantly associated and modules have a reasonable size distribution. Furthermore, the co-regulatory modules are significantly enriched in Gene Ontology biological processes and Kyoto Encyclopedia of Genes and Genomes pathways, respectively. PMID- 28092570 TI - Identifying Epigenetic Biomarkers using Maximal Relevance and Minimal Redundancy Based Feature Selection for Multi-Omics Data. AB - Epigenetic Biomarker discovery is an important task in bioinformatics. In this article, we develop a new framework of identifying statistically significant epigenetic biomarkers using maximal-relevance and minimal-redundancy criterion based feature (gene) selection for multi-omics dataset. Firstly, we determine the genes that have both expression as well as methylation values, and follow normal distribution. Similarly, we identify the genes which consist of both expression and methylation values, but do not follow normal distribution. For each case, we utilize a gene-selection method that provides maximal-relevant, but variable weighted minimum-redundant genes as top ranked genes. For statistical validation, we apply t-test on both the expression and methylation data consisting of only the normally distributed top ranked genes to determine how many of them are both differentially expressed andmethylated. Similarly, we utilize Limma package for performing non-parametric Empirical Bayes test on both expression and methylation data comprising only the non-normally distributed top ranked genes to identify how many of them are both differentially expressed and methylated. We finally report the top-ranking significant gene-markerswith biological validation. Moreover, our framework improves positive predictive rate and reduces false positive rate in marker identification. In addition, we provide a comparative analysis of our gene-selection method as well as othermethods based on classificationperformances obtained using several well-known classifiers. PMID- 28092571 TI - Machine Learned Replacement of N-Labels for Basecalled Sequences in DNA Barcoding. AB - This study presents a machine learning method that increases the number of identified bases in Sanger Sequencing. The system post-processes a KB basecalled chromatogram. It selects a recoverable subset of N-labels in the KB-called chromatogram to replace with basecalls (A,C,G,T). An N-label correction is defined given an additional read of the same sequence, and a human finished sequence. Corrections are added to the dataset when an alignment determines the additional read and human agree on the identity of the N-label. KB must also rate the replacement with quality value of in the additional read. Corrections are only available during system training. Developing the system, nearly 850,000 N labels are obtained from Barcode of Life Datasystems, the premier database of genetic markers called DNA Barcodes. Increasing the number of correct bases improves reference sequence reliability, increases sequence identification accuracy, and assures analysis correctness. Keeping with barcoding standards, our system maintains an error rate of percent. Our system only applies corrections when it estimates low rate of error. Tested on this data, our automation selects and recovers: 79 percent of N-labels from COI (animal barcode); 80 percent from matK and rbcL (plant barcodes); and 58 percent from non-protein-coding sequences (across eukaryotes). PMID- 28092572 TI - PSPEL: In Silico Prediction of Self-Interacting Proteins from Amino Acids Sequences Using Ensemble Learning. AB - Self interacting proteins (SIPs) play an important role in various aspects of the structural and functional organization of the cell. Detecting SIPs is one of the most important issues in current molecular biology. Although a large number of SIPs data has been generated by experimental methods, wet laboratory approaches are both time-consuming and costly. In addition, they yield high false negative and positive rates. Thus, there is a great need for in silico methods to predict SIPs accurately and efficiently. In this study, a new sequence-based method is proposed to predict SIPs. The evolutionary information contained in Position Specific Scoring Matrix (PSSM) is extracted from of protein with known sequence. Then, features are fed to an ensemble classifier to distinguish the self interacting and non-self-interacting proteins. When performed on Saccharomyces cerevisiae and Human SIPs data sets, the proposed method can achieve high accuracies of 86.86 and 91.30 percent, respectively. Our method also shows a good performance when compared with the SVM classifier and previous methods. Consequently, the proposed method can be considered to be a novel promising tool to predict SIPs. PMID- 28092573 TI - Environment Sensitivity-based Cooperative Co-evolutionary Algorithms for Dynamic Multi-objective Optimization. AB - Dynamic multi-objective optimization problems (DMOPs) not only involve multiple conflicting objectives, but these objectives may also vary with time, raising a challenge for researchers to solve them. This paper presents a cooperative co evolutionary strategy based on environment sensitivities for solving DMOPs. In this strategy, a new method that groups decision variables is first proposed, in which all the decision variables are partitioned into two subcomponents according to their interrelation with environment. Adopting two populations to cooperatively optimize the two subcomponents, two prediction methods, i.e., differential prediction and Cauchy mutation, are then employed respectively to speed up their responses on the change of the environment. Furthermore, two improved dynamic multi-objective optimization algorithms, i.e., DNSGAII-CO and DMOPSO-CO, are proposed by incorporating the above strategy into NSGA-II and multi-objective particle swarm optimization, respectively. The proposed algorithms are compared with three state-of-the-art algorithms by applying to seven benchmark DMOPs. Experimental results reveal that the proposed algorithms significantly outperform the compared algorithms in terms of convergence and distribution on most DMOPs. PMID- 28092574 TI - Dynamics in Epistasis Analysis. AB - Finding regulatory relationships between genes, including the direction and nature of influence between them, is a fundamental challenge in the field of molecular genetics. One classical approach to this problem is epistasis analysis. Broadly speaking, epistasis analysis infers the regulatory relationships between a pair of genes in a genetic pathway by considering the patterns of change in an observable trait resulting from single and double deletion of genes. While classical epistasis analysis has yielded deep insights on numerous genetic pathways, it is not without limitations. Here, we explore the possibility of dynamic epistasis analysis, in which, in addition to performing genetic perturbations of a pathway, we drive the pathway by a time-varying upstream signal. We explore the theoretical power of dynamical epistasis analysis by conducting an identifiability analysis of Boolean models of genetic pathways, comparing static and dynamic approaches. We find that even relatively simple input dynamics greatly increases the power of epistasis analysis to discriminate alternative network structures. Further, we explore the question of experiment design, and show that a subset of short time-varying signals, which we call dynamic primitives, allow maximum discriminative power with a reduced number of experiments. PMID- 28092575 TI - A CMOS Current Steering Neurostimulation Array With Integrated DAC Calibration and Charge Balancing. AB - An 8-channel current steerable, multi-phasic neural stimulator with on-chip current DAC calibration and residue nulling for precise charge balancing is presented. Each channel consists of two sub-binary radix DACs followed by wide swing, high output impedance current buffers providing time-multiplexed source and sink outputs for anodic and cathodic stimulation. A single integrator is shared among channels and serves to calibrate DAC coefficients and to closely match the anodic and cathodic stimulation phases. Following calibration, the differential non-linearity is within +/-0.3 LSB at 8-bit resolution, and the two stimulation phases are matched within 0.3%. Individual control in digital programming of stimulation coefficients across the array allows altering the spatial profile of current stimulation for selection of stimulation targets by current steering. Combined with the self-calibration and current matching functions, the current steering capabilities integrated on-chip support use in fully implanted neural interfaces with autonomous operation for and adaptive stimulation under variations in electrode and tissue conditions. As a proof-of concept we applied current steering stimulation through a multi-channel cuff electrode on the sciatic nerve of a rat. PMID- 28092576 TI - Multiple-Instance Learning for Medical Image and Video Analysis. AB - Multiple-instance learning (MIL) is a recent machine-learning paradigm that is particularly well suited to medical image and video analysis (MIVA) tasks. Based solely on class labels assigned globally to images or videos, MIL algorithms learn to detect relevant patterns locally in images or videos. These patterns are then used for classification at a global level. Because supervision relies on global labels, manual segmentations are not needed to train MIL algorithms, unlike traditional single-instance learning (SIL) algorithms. Consequently, these solutions are attracting increasing interest from the MIVA community: since the term was coined by Dietterich et al. in 1997, 73 research papers about MIL have been published in the MIVA literature. This paper reviews the existing strategies for modeling MIVA tasks as MIL problems, recommends general-purpose MIL algorithms for each type of MIVA tasks, and discusses MIVA-specific MIL algorithms. Various experiments performed in medical image and video datasets are compiled in order to back up these discussions. This meta-analysis shows that, besides being more convenient than SIL solutions, MIL algorithms are also more accurate in many cases. In other words, MIL is the ideal solution for many MIVA tasks. Recent trends are discussed, and future directions are proposed for this emerging paradigm. PMID- 28092578 TI - Experienced Gray Wolf Optimization Through Reinforcement Learning and Neural Networks. AB - In this paper, a variant of gray wolf optimization (GWO) that uses reinforcement learning principles combined with neural networks to enhance the performance is proposed. The aim is to overcome, by reinforced learning, the common challenge of setting the right parameters for the algorithm. In GWO, a single parameter is used to control the exploration/exploitation rate, which influences the performance of the algorithm. Rather than using a global way to change this parameter for all the agents, we use reinforcement learning to set it on an individual basis. The adaptation of the exploration rate for each agent depends on the agent's own experience and the current terrain of the search space. In order to achieve this, experience repository is built based on the neural network to map a set of agents' states to a set of corresponding actions that specifically influence the exploration rate. The experience repository is updated by all the search agents to reflect experience and to enhance the future actions continuously. The resulted algorithm is called experienced GWO (EGWO) and its performance is assessed on solving feature selection problems and on finding optimal weights for neural networks algorithm. We use a set of performance indicators to evaluate the efficiency of the method. Results over various data sets demonstrate an advance of the EGWO over the original GWO and over other metaheuristics, such as genetic algorithms and particle swarm optimization. PMID- 28092577 TI - Social Touch Technology: A Survey of Haptic Technology for Social Touch. AB - This survey provides an overview of work on haptic technology for social touch. Social touch has been studied extensively in psychology and neuroscience. With the development of new technologies, it is now possible to engage in social touch at a distance or engage in social touch with artificial social agents. Social touch research has inspired research into technology mediated social touch, and this line of research has found effects similar to actual social touch. The importance of haptic stimulus qualities, multimodal cues, and contextual factors in technology mediated social touch is discussed. This survey is concluded by reflecting on the current state of research into social touch technology, and providing suggestions for future research and applications. PMID- 28092579 TI - Cooperative Adaptive Output Regulation for Second-Order Nonlinear Multiagent Systems With Jointly Connected Switching Networks. AB - This paper studies the cooperative global robust output regulation problem for a class of heterogeneous second-order nonlinear uncertain multiagent systems with jointly connected switching networks. The main contributions consist of the following three aspects. First, we generalize the result of the adaptive distributed observer from undirected jointly connected switching networks to directed jointly connected switching networks. Second, by performing a new coordinate and input transformation, we convert our problem into the cooperative global robust stabilization problem of a more complex augmented system via the distributed internal model principle. Third, we solve the stabilization problem by a distributed state feedback control law. Our result is illustrated by the leader-following consensus problem for a group of Van der Pol oscillators. PMID- 28092580 TI - Determination of the Edge of Criticality in Echo State Networks Through Fisher Information Maximization. AB - It is a widely accepted fact that the computational capability of recurrent neural networks (RNNs) is maximized on the so-called "edge of criticality." Once the network operates in this configuration, it performs efficiently on a specific application both in terms of: 1) low prediction error and 2) high short-term memory capacity. Since the behavior of recurrent networks is strongly influenced by the particular input signal driving the dynamics, a universal, application independent method for determining the edge of criticality is still missing. In this paper, we aim at addressing this issue by proposing a theoretically motivated, unsupervised method based on Fisher information for determining the edge of criticality in RNNs. It is proved that Fisher information is maximized for (finite-size) systems operating in such critical regions. However, Fisher information is notoriously difficult to compute and requires the analytic form of the probability density function ruling the system behavior. This paper takes advantage of a recently developed nonparametric estimator of the Fisher information matrix and provides a method to determine the critical region of echo state networks (ESNs), a particular class of recurrent networks. The considered control parameters, which indirectly affect the ESN performance, are explored to identify those configurations lying on the edge of criticality and, as such, maximizing Fisher information and computational performance. Experimental results on benchmarks and real-world data demonstrate the effectiveness of the proposed method. PMID- 28092581 TI - An Integrated Maximum Current Density Approach for Noninvasive Detection of Myocardial Infarction. AB - We present a new approach of integrated maximum current density (IMCD) for the noninvasive detection of myocardial infarction (MI) using magnetocardiography (MCG) data acquired from a superconducting quantum interference device (SQUID) system. In this paper, we investigated the relationship of the maximum current density (MCD) in the current density map and the underlying equivalent current dipole (ECD) based on a novel method of reconstructing the ECD in the extremum circle of the magnetic field map. The performance of IMCD and the integrated ECD (IECD) approaches were also evaluated by using 61-channel MCG data from 39 healthy subjects and 102 patients with ST elevation myocardial infarction (STEMI). Statistical analysis of the healthy and STEMI groups demonstrate that the IMCD approach obtains sensitivity and specificity up to 91.2% and 84.6%, somewhat higher than that of IECD, respectively. The results indicate that IMCD provides spatiotemporal information regarding cardiac electrical activity during ventricular repolarization. This approach may be helpful to diagnose MI in clinic application. The physical concept of the approach is also explained in this paper. PMID- 28092582 TI - Automatic Prediction of Health Status Using Smartphone-Derived Behavior Profiles. AB - OBJECTIVE: Current methods of assessing the affect patients' health has on their daily lives are extremely limited. The aim of this paper is to develop a sensor based approach to health status measurement in order to objectively measure health status. METHODS: Techniques to generate human behavior profiles, derived from the smartphone accelerometer and gyroscope sensors, are proposed. Experiments, using SVM regression models, are then conducted in order to evaluate the use of the proposed behavior profiles as a predictor of health status. RESULTS: Experiments were conducted on data from 171 participants, with an average of 114 h of data per participant. Regression models were trained and tested on the 10 SF-36 self-ratings. Results showed that the eight individual SF 36 scales and two component scores could be predicted with an average correlation of 0.683 and 0.698, respectively. General health was predicted with an average correlation of 0.752. CONCLUSION: Research shows that the clinically important difference for SF-36 self-ratings are approximately 10 points. Health status prediction errors in this study were 11.7 points on average. While the problem has not been fully solved, this paper presents a hugely promising direction for health status prediction. SIGNIFICANCE: Using the proposed techniques, health status could be measured using unobtrusive, inexpensive, and already available hardware. It could provide a means for clinicians to accurately and objectively assess the daily life benefits of treatments on an individual patient basis. PMID- 28092583 TI - Deep Learning and Insomnia: Assisting Clinicians With Their Diagnosis. AB - Effective sleep analysis is hampered by the lack of automated tools catering to disordered sleep patterns and cumbersome monitoring hardware. In this paper, we apply deep learning on a set of 57 EEG features extracted from a maximum of two EEG channels to accurately differentiate between patients with insomnia or controls with no sleep complaints. We investigated two different approaches to achieve this. The first approach used EEG data from the whole sleep recording irrespective of the sleep stage (stage-independent classification), while the second used only EEG data from insomnia-impacted specific sleep stages (stage dependent classification). We trained and tested our system using both healthy and disordered sleep collected from 41 controls and 42 primary insomnia patients. When compared with manual assessments, an NREM + REM based classifier had an overall discrimination accuracy of 92% and 86% between two groups using both two and one EEG channels, respectively. These results demonstrate that deep learning can be used to assist in the diagnosis of sleep disorders such as insomnia. PMID- 28092584 TI - Temporally Coherent Illumination Normalization for Indocyanine Green Video Angiography. AB - Indocyanine green (ICG) angiography is an imaging method for doctors to observe choroidal abnormalities in human eyes. The ICG angiograms typically exhibit inhomogeneous illumination, which poses serious difficulties for the development of computer-aided diagnostic tools. In this paper, we propose a novel illumination normalization method to alleviate the inhomogeneous illumination in ICG video angiograms. In particular, we first align the viewpoint of the input ICG video angiogram using an image registration method. Then, we acquire temporal information using time-dependent intrinsic image and compute the corresponding illumination image. Finally, we correct inhomogeneous illumination from the illumination image by estimating contrast and luminosity distortion. We have conducted extensive evaluation using ICG video angiograms of 60 patients. Two video quality assessment methods are utilized to evaluate the performance of our proposed illumination normalization method. The results show that our proposed method can help improve the visual quality of ICG video angiogram. Visual evaluation by a human expert also confirms that our method yields better illumination normalization results. PMID- 28092586 TI - Consensus Problem Over High-Order Multiagent Systems With Uncertain Nonlinearities Under Deterministic and Stochastic Topologies. AB - The leaderless consensus problem over a class of high-order nonlinear multiagent systems (MASs) is studied. A robust protocol is proposed which guarantees achieving consensus in the network in the presences of uncertainties in agents models. Achieving consensus in the case of stochastic links failure is studied as well. Based on the concept super-martingales, it is shown that if the probability of the network connectivity is not zero, under some conditions, achieving almost sure consensus in the network can be guaranteed. Despite existing consensus protocols for high-order stochastic networks, the proposed consensus protocol in this paper is robust to uncertain nonlinearities in the agents models, and it can be designed independent of knowledge on the set of feasible topologies (topologies with nonzero probabilities). Numerical examples for a team of single link flexible joint manipulators with fourth-order models verify the accuracy of the proposed strategy for consensus control of high-order MASs with uncertain nonlinearities. PMID- 28092585 TI - Saliency-Based Lesion Segmentation Via Background Detection in Dermoscopic Images. AB - The segmentation of skin lesions in dermoscopic images is a fundamental step in automated computer-aided diagnosis of melanoma. Conventional segmentation methods, however, have difficulties when the lesion borders are indistinct and when contrast between the lesion and the surrounding skin is low. They also perform poorly when there is a heterogeneous background or a lesion that touches the image boundaries; this then results in under- and oversegmentation of the skin lesion. We suggest that saliency detection using the reconstruction errors derived from a sparse representation model coupled with a novel background detection can more accurately discriminate the lesion from surrounding regions. We further propose a Bayesian framework that better delineates the shape and boundaries of the lesion. We also evaluated our approach on two public datasets comprising 1100 dermoscopic images and compared it to other conventional and state-of-the-art unsupervised (i.e., no training required) lesion segmentation methods, as well as the state-of-the-art unsupervised saliency detection methods. Our results show that our approach is more accurate and robust in segmenting lesions compared to other methods. We also discuss the general extension of our framework as a saliency optimization algorithm for lesion segmentation. PMID- 28092587 TI - Learning Domain-Invariant Subspace Using Domain Features and Independence Maximization. AB - Domain adaptation algorithms are useful when the distributions of the training and the test data are different. In this paper, we focus on the problem of instrumental variation and time-varying drift in the field of sensors and measurement, which can be viewed as discrete and continuous distributional change in the feature space. We propose maximum independence domain adaptation (MIDA) and semi-supervised MIDA to address this problem. Domain features are first defined to describe the background information of a sample, such as the device label and acquisition time. Then, MIDA learns a subspace which has maximum independence with the domain features, so as to reduce the interdomain discrepancy in distributions. A feature augmentation strategy is also designed to project samples according to their backgrounds so as to improve the adaptation. The proposed algorithms are flexible and fast. Their effectiveness is verified by experiments on synthetic datasets and four real-world ones on sensors, measurement, and computer vision. They can greatly enhance the practicability of sensor systems, as well as extend the application scope of existing domain adaptation algorithms by uniformly handling different kinds of distributional change. PMID- 28092588 TI - A Many-Objective Evolutionary Algorithm Using A One-by-One Selection Strategy. AB - Most existing multiobjective evolutionary algorithms experience difficulties in solving many-objective optimization problems due to their incapability to balance convergence and diversity in the high-dimensional objective space. In this paper, we propose a novel many-objective evolutionary algorithm using a one-by-one selection strategy. The main idea is that in the environmental selection, offspring individuals are selected one by one based on a computationally efficient convergence indicator to increase the selection pressure toward the Pareto optimal front. In the one-by-one selection, once an individual is selected, its neighbors are de-emphasized using a niche technique to guarantee the diversity of the population, in which the similarity between individuals is evaluated by means of a distribution indicator. In addition, different methods for calculating the convergence indicator are examined and an angle-based similarity measure is adopted for effective evaluations of the distribution of solutions in the high-dimensional objective space. Moreover, corner solutions are utilized to enhance the spread of the solutions and to deal with scaled optimization problems. The proposed algorithm is empirically compared with eight state-of-the-art many-objective evolutionary algorithms on 80 instances of 16 benchmark problems. The comparative results demonstrate that the overall performance of the proposed algorithm is superior to the compared algorithms on the optimization problems studied in this paper. PMID- 28092589 TI - Policy Iteration for $H_?infty $ Optimal Control of Polynomial Nonlinear Systems via Sum of Squares Programming. AB - Sum of squares (SOS) polynomials have provided a computationally tractable way to deal with inequality constraints appearing in many control problems. It can also act as an approximator in the framework of adaptive dynamic programming. In this paper, an approximate solution to the optimal control of polynomial nonlinear systems is proposed. Under a given attenuation coefficient, the Hamilton-Jacobi Isaacs equation is relaxed to an optimization problem with a set of inequalities. After applying the policy iteration technique and constraining inequalities to SOS, the optimization problem is divided into a sequence of feasible semidefinite programming problems. With the converged solution, the attenuation coefficient is further minimized to a lower value. After iterations, approximate solutions to the smallest -gain and the associated optimal controller are obtained. Four examples are employed to verify the effectiveness of the proposed algorithm. PMID- 28092590 TI - Adaptive Neural Synchronization Control for Bilateral Teleoperation Systems With Time Delay and Backlash-Like Hysteresis. AB - This paper considers the master and slave synchronization control for bilateral teleoperation systems with time delay and backlash-like hysteresis. Based on radial basis functions neural networks' approximation capabilities, two improved adaptive neural control approaches are developed. By Lyapunov stability analysis, the position and velocity tracking errors are guaranteed to converge to a small neighborhood of the origin. The contributions of this paper can be summarized as follows: 1) by using the matrix norm established using the weight vector of neural networks as the estimated parameters, two novel control schemes are developed and 2) the hysteresis inverse is not required in the proposed controllers. The simulations are performed, and the results show the effectiveness of the proposed method. PMID- 28092591 TI - Relational-Regularized Discriminative Sparse Learning for Alzheimer's Disease Diagnosis. AB - Accurate identification and understanding informative feature is important for early Alzheimer's disease (AD) prognosis and diagnosis. In this paper, we propose a novel discriminative sparse learning method with relational regularization to jointly predict the clinical score and classify AD disease stages using multimodal features. Specifically, we apply a discriminative learning technique to expand the class-specific difference and include geometric information for effective feature selection. In addition, two kind of relational information are incorporated to explore the intrinsic relationships among features and training subjects in terms of similarity learning. We map the original feature into the target space to identify the informative and predictive features by sparse learning technique. A unique loss function is designed to include both discriminative learning and relational regularization methods. Experimental results based on a total of 805 subjects [including 226 AD patients, 393 mild cognitive impairment (MCI) subjects, and 186 normal controls (NCs)] from AD neuroimaging initiative database show that the proposed method can obtain a classification accuracy of 94.68% for AD versus NC, 80.32% for MCI versus NC, and 74.58% for progressive MCI versus stable MCI, respectively. In addition, we achieve remarkable performance for the clinical scores prediction and classification label identification, which has efficacy for AD disease diagnosis and prognosis. The algorithm comparison demonstrates the effectiveness of the introduced learning techniques and superiority over the state-of-the-arts methods. PMID- 28092592 TI - Adaptive Fuzzy Bounded Control for Consensus of Multiple Strict-Feedback Nonlinear Systems. AB - This paper studies the adaptive fuzzy bounded control problem for leader-follower multiagent systems, where each follower is modeled by the uncertain nonlinear strict-feedback system. Combining the fuzzy approximation with the dynamic surface control, an adaptive fuzzy control scheme is developed to guarantee the output consensus of all agents under directed communication topologies. Different from the existing results, the bounds of the control inputs are known as a priori, and they can be determined by the feedback control gains. To realize smooth and fast learning, a predictor is introduced to estimate each error surface, and the corresponding predictor error is employed to learn the optimal fuzzy parameter vector. It is proved that the developed adaptive fuzzy control scheme guarantees the uniformly ultimate boundedness of the closed-loop systems, and the tracking error converges to a small neighborhood of the origin. The simulation results and comparisons are provided to show the validity of the control strategy presented in this paper. PMID- 28092593 TI - Robust Estimation of ARX Models With Time Varying Time Delays Using Variational Bayesian Approach. AB - This paper is concerned with robust identification of processes with time-varying time delays. In reality, the delay values do not simply change randomly, but there is a correlation between consecutive delays. In this paper, the correlation of time delay is modeled by the transition probability of a Markov chain. Furthermore, the measured data are often contaminated by outliers, and therefore, -distribution is adopted to model the measurement noise. The variational Bayesian (VB) approach is applied to estimate the model parameters along with time delays. Compared with the classical expectation-maximization algorithm, VB approach has the advantage of capturing the uncertainty of the estimated parameter and time delays by providing their full probabilities. The effectiveness of the proposed method is demonstrated by both a numerical example and a pilot-scale hybrid-tank experiment. PMID- 28092594 TI - Adaptive Trajectory Tracking of Nonholonomic Mobile Robots Using Vision-Based Position and Velocity Estimation. AB - Despite tremendous efforts made for years, trajectory tracking control (TC) of a nonholonomic mobile robot (NMR) without global positioning system remains an open problem. The major reason is the difficulty to localize the robot by using its onboard sensors only. In this paper, a newly designed adaptive trajectory TC method is proposed for the NMR without its position, orientation, and velocity measurements. The controller is designed on the basis of a novel algorithm to estimate position and velocity of the robot online from visual feedback of an omnidirectional camera. It is theoretically proved that the proposed algorithm yields the TC errors to asymptotically converge to zero. Real-world experiments are conducted on a wheeled NMR to validate the feasibility of the control system. PMID- 28092595 TI - Command Filter-Based Adaptive Neural Tracking Controller Design for Uncertain Switched Nonlinear Output-Constrained Systems. AB - In this paper, a new adaptive approximation-based tracking controller design approach is developed for a class of uncertain nonlinear switched lower triangular systems with an output constraint using neural networks (NNs). By introducing a novel barrier Lyapunov function (BLF), the constrained switched system is first transformed into a new system without any constraint, which means the control objectives of the both systems are equivalent. Then command filter technique is applied to solve the so-called "explosion of complexity" problem in traditional backstepping procedure, and radial basis function NNs are directly employed to model the unknown nonlinear functions. The designed controller ensures that all the closed-loop variables are ultimately boundedness, while the output limit is not transgressed and the output tracking error can be reduced arbitrarily small. Furthermore, the use of an asymmetric BLF is also explored to handle the case of asymmetric output constraint as a generalization result. Finally, the control performance of the presented control schemes is illustrated via two examples. PMID- 28092596 TI - A General Framework of Dynamic Constrained Multiobjective Evolutionary Algorithms for Constrained Optimization. AB - A novel multiobjective technique is proposed for solving constrained optimization problems (COPs) in this paper. The method highlights three different perspectives: 1) a COP is converted into an equivalent dynamic constrained multiobjective optimization problem (DCMOP) with three objectives: a) the original objective; b) a constraint-violation objective; and c) a niche-count objective; 2) a method of gradually reducing the constraint boundary aims to handle the constraint difficulty; and 3) a method of gradually reducing the niche size aims to handle the multimodal difficulty. A general framework of the design of dynamic constrained multiobjective evolutionary algorithms is proposed for solving DCMOPs. Three popular types of multiobjective evolutionary algorithms, i.e., Pareto ranking-based, decomposition-based, and hype-volume indicator-based, are employed to instantiate the framework. The three instantiations are tested on two benchmark suites. Experimental results show that they perform better than or competitive to a set of state-of-the-art constraint optimizers, especially on problems with a large number of dimensions. PMID- 28092597 TI - Role of probiotics in nutrition and health of small ruminants. AB - Small ruminants represent an important economic source in small farm systems and agriculture. Feed is the main component of livestock farming, which has gained special attention to improve animal performance. Many studies have been done to improve feed utilisation through addition of feed additives. For a long period, antibiotics have been widely used as growth promoters in livestock diets. Due to their ban in many countries, search for alternative feed additives has been intensified. Probiotics are one of these alternatives recognised to be safe to the animals. Use of probiotics in small ruminant nutrition has been confirmed to improve animal health, productivity and immunity. Probiotics improved growth performance through enhancing of rumen microbial ecosystem, nutrient digestibility and feed conversion rate. Moreover, probiotics have been reported to stabilise rumen pH, increase volatile fatty acids production and to stimulate lactic acid utilising protozoa, resulting in a highly efficient rumen function. Furthermore, use of probiotics has been found to increase milk production and can reduce incidence of neonatal diarrhea and mortality. However, actual mechanisms through which probiotics exert these functions are not known. Since research on application of probiotics in small ruminants is scarce, the present review attempts to discuss the potential roles of this class of feed additives on productive performance and health status of these animals. PMID- 28092598 TI - Evaluation of venous blood gas levels, blood chemistry and haemocytometric parameters in milk fed veal calves at different periods of livestock cycle. AB - An evaluation of blood chemistry profile in relation to specific stages of livestock cycle can help better understand variations in physiological conditions in order to adjust management systems to animal needs. In addition to basal hematological investigation, the acid-base balance and blood gases are essential tools in evaluating metabolism in calves. The relationship between blood gas parameters, diet and growth should be further investigated. The aim of this study was to evaluate changes in acid-base status, blood gases, serum chemistry and hematological parameters in veal calves at different periods of livestock cycle. One hundred twenty-eight healthy cross breeding calves were enrolled in a farm in North-East Italy. Blood samplings were carried out from the jugular vein on day 1 (t1), 60 (t2) and 150 (t3) after arrival. Blood gas analysis was performed and hematological parameters were evaluated. One-way ANOVA and Tukey-Kramer post-hoc test were performed to assess differences between blood parameter values at the different periods. The main differences in blood gas parameter levels during the livestock cycle concerned pH, Base Excess and HCO3 with higher values recorded in t3. Urea, creatinine, gamma-glutamyl transpeptidase and bilirubin mean values were significantly higher in t1 than in t2 and t3. Aspartate aminotransferase increased from t1 to t2 and t3. Alkaline Phosphatase was higher in t2. Fe levels severely dropped in t2 and in t3, and the decrease led to a restrained but significant reduction in haemoglobin values. A correspondent decrease in the other haemocytometric parameters was found. PMID- 28092599 TI - Wild boars (Sus scrofa) as bioindicators of environmental levels of selenium in Poland. AB - The objective of the study was to determine selenium content in selected organs (liver, kidney) of wild boars from different regions of Poland. Materials for the study were obtained from 28 sites located in 16 provinces of Poland. Selenium concentrations in organs were determined using spectrofluorometric methods after wet mineralization in HNO3 and HClO4 mixture. Mean selenium concentrations in the investigated wild boars from Poland were 0.230 MUg/g wet weight in the liver and 1.327 MUg/g w.w. in the kidneys. Hepatic and nephric Se concentrations ranged from 0.036-0.626 MUg/g w.w. and 0.322-4.286 MUg/g w.w., respectively. Selenium concentrations in the wild boars differed considerably according to geographical location. Concentrations of selenium were highest in wild boars from south eastern provinces and lowest in animals from northern provinces. Most of Poland's area is environmentally deficient in this trace element, as evidenced by marginal selenium levels in the organs of the wild boars. PMID- 28092600 TI - Influence of horse breed on transepidermal water loss. AB - Non-invasive methods of skin condition assessment include, among others, the evaluation of transepidermal water loss (TEWL). The aim of the study was to examine whether TEWL values depend on horse breed. The study was conducted on four breeds: "Felin" ponies (FP) (n=16), Polish koniks (PK) (n=15), Polish cold blooded horses (PcbH) (n=11) and Wielkopolska horses (WH) (n=12). It was found that horse breed influences TEWL values. In the neck region, statistically significant differences were found between PK and FP (p=0.006), and PK and WH (p=0.0005). In the lumbar region, there were statistically significant differences between FP and PK (p=0.0009), FP and PcbH (p=0.0016) as well as between PK and WH (p=0.000037), and PcbH and WH (p=0.0006). In the inguinal region statistically significant differences were found between FP and PK (p=0.0003), FP and PcbH (p=0.0005), PK and WH (p=0.009) and PcbH and WH (p=0.006). In the lip region statistically significant differences were observed between FP and PK (p=0.013) as well as between PK and PcbH (p=0.029) and PK and WH (p=0.009). In the examination of TEWL animal breed should be taken into consideration. The non-significant differences found in three of the examined body regions may suggest that these regions are the most adequate for TEWL assessment. PMID- 28092601 TI - Prevalence of inclusion body hepatitis (IBH) in Poland from 2010-2014. AB - This study investigated the prevalence of inclusion body hepatitis (IBH) infections during the past five years (2010-2014) in broiler chicken flocks in Poland. The diagnosis of IBH was based on anatomopathological investigations and histopathological analyzes. IBH was the most prevalent disease in broiler flocks in Poland (10.4%) during this time period, and occurred as a primary infection. The fewest cases of IBH occurred in the summer, suggesting that the temperature may have been a possible stressor that increased susceptibility to IBH. However, over the last 5 years the occurrence of clinical IBH cases in Poland has systematically decreased. PMID- 28092602 TI - The investigation of correlation among selected biochemical parameters and vital signs in dairy herd to design the bio-cybernetic dairy cow model. AB - The paper presents investigations of the relationship between the biochemical parameters and vital signs in dairy cows. We analyzed the welfare and functioning of a dairy herd using biochemical parameters and vital signs. Life and biochemical parameters were examined. In the model indicators useful for monitoring the herd are: the age of the cows, the number of cows' lactating, daily amount of received milk, length of lactation period for cows in the herd, the length of inter-calving period for cows, the number of days to effective insemination, the amount of protein in the feed, the level of beta-oxidation in leucocytes, glucose transport through red blood cells and plasma insulin. Based on the results the mathematical model was designed allowing the presentation of a cybernetic model of cow's organism. There was constructed a multi-equation model which determined the relationships between the selected variables describing the state of dairy cows in the herd and variables that characterize their welfare with its statistical verification. PMID- 28092603 TI - Gut microbiota isolated from the European pond turtle (Emys orbicularis) and its antimicrobial resistance. AB - The aim of the study was to isolate cultivable gut microbiota from European pond turtles kept at the Lithuanian Zoo and to determine antimicrobial resistance of the isolates. The study subjects included 8 elderly turtles living at the Lithuanian Zoo for about 50 years as well as their offspring - 24 young individuals (1-2 years old) that were hatched at the same zoo. Animals were not exposed by treatment with antimicrobials during the last 3 years. Gut samples were taken from the cloaca and inoculated onto universal media. Isolates then were identified using sequence analysis of 16S rRNA. The antimicrobial susceptibility testing was performed using the agar diffusion method according to Kirby-Bauer. Clinical breakpoints according to CLSI whenever possible, were used for interpretation of susceptibility. Bacterial isolates resistant to at least three antimicrobials of different classes were treated as multi-resistant. Fifty two bacterial isolates were obtained and identified from turtle gut samples. The most prevalent genera included Aeromonas, Chryseobacterium and Citrobacter. Fifty percent of the isolates obtained from elderly turtles (CI 95% - 19.01-80.99) and 54.8% (CI 95% - 39.75-69.85) of the isolates from young animals were identified as multi-resistant. The most common resistance rates of the isolates from both groups of the turtles were observed toward ampicillin (86.6%), ciprofloxacin (61.5%) and gentamicin (40.4%). The lowest number of resistant isolates were detected toward combination of sulfamethoxazole-trimethoprim (26.9%). The study revealed that European pond turtles kept in captivity are carriers of multi resistant bacteria however, further studies need to be performed to investigate whether the resistant microorganisms are natural microbiota for this species or they were acquired in the zoo. PMID- 28092604 TI - Replication kinetics of neuropathogenic and non-neuropathogenic equine herpesvirus type 1 (EHV-1) strains in primary murine neurons and ED cell line. AB - Equine herpesvirus type 1 (EHV-1) causes respiratory infections, abortion and neurological disorders in horses. Molecular epidemiology studies have demonstrated that a single-point mutation in DNA polymerase gene, resulting in an amino acid variation (N752/D752), is significantly associated with the neuropathogenic potential of EHV-1 strains. The aim of the study was to elucidate if there are any differences between neuropathogenic (EHV-1 26) and non neuropathogenic (Jan-E and Rac-H) EHV-1 strains in their ability to infect neuronal cells. For the tested EHV-1 strains, cytopathic effect (CPE) was manifested by changed morphology of cells, destruction of actin cytoskeleton and nuclei degeneration, which led to focal degeneration. Moreover, EHV-1 26 strain caused fusion of the infected cells to form syncytia in culture. Real-time PCR analysis demonstrated that both neuropathogenic and non-neuropathogenic EHV-1 strains replicated in neurons and ED cells (equine dermal cell line) at a similar level. We can assume that a point mutation in the EHV-1 polymerase does not affect viral replication in this cell type. PMID- 28092605 TI - Molecular diversity of Clostridium botulinum and phenotypically similar strains. AB - This study was undertaken to examine phenotypic and genetic features of strains preliminary classified as Clostridium botulinum species. The phenotypic characteristics were assessed with different culture media and biochemical tests. The genetic characterization included detection of botulinum toxin genes by PCR and macrorestriction analysis with SmaI, XhoI and SacII by PFGE (Pulsed-field Gel Electrophoresis). Despite similar biochemical properties of all analysed strains, only 47% of them contained genes determining toxicity specific to C. botulinum species. The most valuable differentiation of C. botulinum and C. botulinum-like strains was obtained after SmaI digestion. The highest affinity was observed among C. botulinum type B profiles which was even up to 100%. It was found 100% of affinity between C. botulinum and C. botulinum-like strains, however, the similarity among C. botulinum and C. botulinum-like was generally lower than 80%. PMID- 28092606 TI - Molecular characterization and expression analysis of the NLR family CARD containing five transcripts in the pig. AB - The NOD-like receptor (NLR) family caspase recruitment domain-containing 5 (NLRC5) is one of the newly discovered and largest NLR family members. The NLRC5 has recently received extensive attention because of its important role in regulating innate and adaptive immune responses. The NLRC5 in many vertebrates, such as humans, mice, cattle, and horses, has already been proven and studied. However, the NLRC5 gene characteristics of pigs remain unclear. Thus, we completely cloned the NLRC5 cDNA sequence of the pig using the rapid amplification of cDNA ends(RACE) technology. A characteristic and tissue expression analysis was also conducted on the pig sequence. The sequence analysis showed that the complete cDNA sequence of the NLRC5 of the pig is 6638 bp, and the open reading frame is 5538 bp which encoded 1846 amino acids. The protein prediction analysis indicates that the overall performance of the NLRC5 protein of the pig is hydrophilic and possesses a typical nucleotide binding and oligomerization domain(NBD) and 20 leucine-rich repeats(LRRs). The homology analysis result indicates that the NLRC5 transcript in pigs is highly homologous to cattle, sheep, macaques, and humans, and accounts for around 80%. The genetic evolutionary tree analysis shows that the NLRC5 transcript in pigs has the closest evolutionary relationship with cattle and sheep. Further tissue expression analysis shows that immune organ systems (e.g., lymph node and spleen) and mucosa organs (e.g., intestinal lymph node, stomach, and lungs) possess high expressions with NLRC5 mRNA. The result of this study indicates that the NLRC5 transcript in pigs is relatively conservative among mammals and may play a vital role in immune reaction, which provides a basis for further studies on the NLRC5 function in the pig immune system and the role in comparative immunity. PMID- 28092607 TI - ProANP as a screening biomarker for hypertrophic cardiomyopathy in Maine coon cats. AB - : The aim of this study was to determine if atrial natriuretic peptide can be used as an early screening tool for hypertrophic cardiomyopathy in Maine coon cats. ANIMALS: The study was performed in 43 Maine coon cats of both sexes, aged 11 to 92 months. Clinical and echocardiographic examinations were done and proANP serum concentrations were measured every three months over a period of one year (each cat had a total of five examinations). Cats were divided into 3 groups based on echocardiographic results: group 1 - healthy cats, group 2 - cats with unequivocal hypertrophic cardiomyopathy results, group 3 - cats with HCM. The study showed that the concentration of atrial natriuretic peptide correlates with the severity of HCM. A significant increase in serum concentration of this peptide was observed in cats from group 3, but it did not differ significantly between cats from group 2 and the healthy animals (p>0.05). A correlation was also found between proANP and age of the cats (p<0.01, r=0.5578) as well as between the ejection fraction (p=0.0285, r=0.5305) and end-systolic left ventricular diameter (p=0.05, r=0.48) in the affected animals. Atrial natriuretic peptide may be used to help in the diagnosis of advanced stages of HCM in Maine coon cats. Cats with high levels of proANP should be assigned to echocardiographic studies to confirm the disease. PMID- 28092608 TI - White and red blood cell picture in rabbits experimentally infected with strains of the rabbit haemorrhagic disease (RHD) virus without or with variable haemagglutination capacity. AB - The aim of the study was to establish if haemagglutination of rabbit haemorrhagic disease virus (RHDV) affects haematological picture of peripheral blood in rabbits and the pathogenicity of the virus. The study analyzed white and red blood cell picture in rabbits experimentally infected with two non haemagglutinating (HA-) RHDV strains (Frankfurt and Asturias) and one strain with variable haemagglutination capacity (HA+/-) (Hagenow). Studies with HA- and HA +/ are rare and relate only to 4 HA- strains (2 RHDV: BLA and Rainham; 2 RHDVa: Pv97 and 9905) and 1 HA+/- RHDV strain: ZD, where less changes in haematological indices and less pathogenicity were observed. We found that changes caused by HA- Frankfurt strain were related to the number of neutrophils and thrombocytes, while in HA- strain Asturias, in thrombocytes and leukocytes. Changes evoked by HA+/- Hagenow strain pertained to the number of eosinophils, thrombocytes, leukocytes, monocytes, and concentration of hemoglobin. Mortality caused by the Frankfurt strain was 100% between 36 and 48 h post infection (p.i.), while that caused by Asturias strain was 100% between 24 and 36 h p.i., and that observed in case of Hagenow strain was 90% between 36 and 48 h p.i. The changes in haematological picture caused by the HA- and HA+/- RHDV strains were less intensive than those found in case of the HA+ RHDV strains, which cannot be confirmed for pathogenicity, and is not in line with the existing hypothesis suggesting higher pathogenicity in HA+ viruses. PMID- 28092609 TI - Horse-Expert: An aided expert system for diagnosing horse diseases. AB - In contrast to the rapid development of the horse husbandry in China, the ability of horse veterinarians to diagnose diseases has not been improved and only a few domain experts have considerable expertise. At present, many expert systems have been developed for diseases diagnosis, but few for horse diseases diagnosis have been studied in depth. This paper presents the design and development of a computer-aided expert system for diagnosing horse diseases. We suggest an approach for diagnosis of horse diseases based on the analysis of diagnostic characteristics and the experiential knowledge of domain experts. It is based on using evidence-weighted uncertainty reasoning theory, which is a combination of evidence theory and an uncertainty pass algorithm of confidence factors. It enables drawing of inferences with atypical clinical signs and the uncertainty of the user's subjective understanding. It reduces the influence of subjective factors on diagnostic accuracy. The system utilizes a user friendly interface for users and requests a confidence factor from users when feedback is given to the system. Horse-Expert combines the confidence factors with weight factors assigned to clinical signs by experts during the knowledge acquisition process to make diagnostic conclusions. The system can diagnose 91 common horse diseases, and provides suggestions for appropriate treatment options. In addition, users can check the medical record through statistical charts. The system has been tested in seven demonstration areas of Xinjiang province in northwestern China. By constantly maintaining and updating the knowledge base, the system has potential application in veterinary practice. PMID- 28092610 TI - Effects of antioxidant vitamins (A, D, E) and trace elements (Cu, Mn, Se, Zn) on some metabolic and reproductive profiles in dairy cows during transition period. AB - The objective of this study was to determine the effects of some antioxidant vitamins and trace elements on some metabolic and postpartum reproductive profiles in dairy cows during transition period. In the study, altogether 20 clinically healthy Brown Swiss dairy cows (aged 4-5 years-old) under the same management and feeding conditions in periparturient period were used. The animals were divided into two equal groups: control (C) and treatment (T) group (n=10 for each group). Vitamins (A, D, E) and trace elements (Cu, Mn, Se, Zn) were administered intramuscularly into the cows of the T group, while isotonic saline, as placebo, was injected subcutaneously into those in the C group. Blood samples were collected by venipuncture of the jugular vein at the beginning of transition period, parturition and 3-weeks after the parturition. The metabolic and reproductive parameters were determined. In the C group, statistically significant changes were observed in the levels of non-esterified fatty acids (NEFA), high density lipoprotein (HDL), low density lipoprotein (LDL), total protein (TP) (p<0.05), glucose (GLU), progesterone (P4) (p<0.01), total cholesterol (T.CHOL), triglycerides (TG), UREA, creatinine (CRSC) and total bilirubin (TBIL) (p<0.001). In the T group, significant changes in the levels of NEFA, TBIL (p<0.05), T.CHOL, HDL, LDL (p<0.01), TG, GLU, P4, TAC and TOC (p<0.001) were observed. It was concluded that the administration of various vitamins and trace elements could be effective to improve some metabolic and reproductive profiles in dairy cows during the transition period. PMID- 28092611 TI - Prevalence of Bovine herpesvirus type 4 in aborting dairy cows. AB - Bovine herpesvirus type 4 (BHV-4) is related to many different conditions: infertility, postpartal metritis, vulvovaginitis, mastitis, encephalitis, calf pneumonia, keratoconjunctivitis, cutaneous lesions, digital dermatitis and abortion. In this study a retrospective PCR examination of 100 extracted DNA samples from aborting cows was performed in order to determine: prevalence of BHV 4 in abortive cattle, whether coinfections BHV-4 with other abortifacient pathogens are present in the same sample and to determine the month of gestation when BHV-4 associated abortions were detected. Out of 100 examined samples, the BHV-4 genome was detected in 21 samples (21%). In two samples we detected coinfection of BHV-4 with bovine viral diarrhea virus (BVDV) and in one with Neospora caninum. Most of the BHV-4-associated abortions were detected during the seventh month of gestation. It was concluded that an active BHV-4 infection was present among cows that aborted on the farms examined. The high prevalence of the BHV-4 genome in abortion material suggests that this virus may have cause the abortions. Further studies and examinations are needed to establish causative connection between presence of BHV-4 and abortion. PMID- 28092612 TI - Evaluation of serum cytokine levels in recurrent airway obstruction. AB - Recurrent airway obstruction (RAO) represents a serious health problem and is traditionally classified as an allergic disease, where contact with an antigen can induce clinical airway inflammation, bronchial hyper-responsiveness and reversible airway obstruction. Previous studies have demonstrated the presence of the Th2 response in the lungs of human patients with asthma and horses with heaves. These cells are involved in the production of cytokines which regulate the synthesis of immunoglobulins. 40 horses were evaluated: 30 horses with RAO and 10 healthy animals. The expression levels of interferon-alpha 1 (IFN-alpha1), interferon-gamma (IFN-gamma), interleukin-1beta, (IL-1beta), IL-2, IL-4, IL-13 and tumor necrosis factor alpha (TNF-alpha) were measured in the serum obtained from control and RAO-susceptible horses during crisis. In all the patients, serum cytokine levels were detected. Serum median IL-13 and IFN-gamma levels were significantly higher in RAO-affected horses than in the healthy group (p < 0.001). The serum median IFN-alpha1, IL-1beta, IL-2, IL-4, and TNF-alpha levels were similar in both groups. These results indicate a low variability of the levels of cytokines and a high frequency of their detection in serum samples from horses with RAO. Immune mechanisms involved in equine RAO are more complex than those defined by a simple Th1/Th2 dichotomy. PMID- 28092613 TI - Effects of udder infections with Staphylococcus xylosus and Staphylococcus warneri on the composition and physicochemical changes in cows milk. AB - The aim of this study was an evaluation of the effects of two species of coagulase negative staphylococci (CNS), Staphylococcus xylosus and Staphylococcus warneri, on the changes in technological parameters of cows' milk. The study was conducted in a herd of Slovak Pied cattle breed (with share of HF blood). Based on the performance results from three subsequent months, cows in the 2nd and 3rd lactation with SCC up to 200 thousand/ml (8 heads, 32 quarters), and above 800 thousand/ml (8 heads, 32 quarters), after the 4th month of lactation, were selected. The samples were subjected to microbiological analysis, total bacteria count, somatic cell count; basic milk composition and physicochemical properties were also examined. The research has found the impact of bacterial infection on the increasing (p<0.05) of the number of somatic cells and a decrease (p<0.01) in protein levels in milk due to both types of staphylococci. There was a significant (p<0.05) reduction in C8: 0, C10: 0 and the total amount of saturated fatty acids in the milk of the infected cows in comparison to the healthy ones. The research also revealed higher (p<0.01) levels of C14: 0 and C20: 1 in milk from the healthy cows. PMID- 28092614 TI - The distribution of different virulence grass carp reovirus strains in some neglected tissues. AB - Grass carp reovirus (GCRV) is the causative agent of hemorrhagic disease in infected grass carp. During an outbreak, a mortality rate of up to 85% can be experienced, thus leading to substantial economic losses. The current understanding of disease pathogenesis is limited, with the distribution and dynamics of replication amongst different GCRV strains in vivo largely unknown. We determined distribution of different GCRV strains in infected grass carp, especially in some neglected tissues, such as the gill, brain, blood and so on. The results showed elevated viral RNA copy numbers in the blood, with some tissues such as the kidney, heart, brain, and bladder exhibiting even higher viral loads following infection with the virulent GCRV-CL strain. Even more interesting is that the brain exhibited the highest viral load, with a copy number of 800,000 following GCRV-CL infection. Overall, this study provides further insight into GCRV viral load distributions following infection and potentially identified some new viral tropism sites to provide a foundation for further studies aimed at characterizing GCRV viral pathogenesis. PMID- 28092615 TI - Immunoreactivity of arcuate nucleus astrocytes in rats after intragastric administration of habanero peppers (Capsicum Chinese Jacq.). AB - Habanero pepper fruits contain capsaicin (CAP) characterised by a spicy taste. Astrocytes express vanilloid receptor (TRPV1), which interacts with cannabinoids including CAP. Only a few studies revealed that CAP leads to alterations of the arcuate nucleus (ARC) structures. The aim of this study was to analyse the GFAP (GFAP-IR) and S100beta (S100beta-IR) immunoreactive astrocytes of ARC in adult rats after intragastric administration of habanero pepper fruits. Adult, Wistar rats received a peanut oil - control group (C) - and oil suspension of habanero pepper fruits at a dose of 0.08 g dm/kg b.w. for 7 days - E1 group - and 28 days E2 group. After euthanasia, the brains were embedded in paraffin blocks using a routine histological technique. Frontal slices of ARC were immunohistochemically stained for GFAP and S100beta using specific antibodies in the peroxidase antiperoxidase method. Astrocytes of ARC were morphologically and morphometrically analysed under a light microscope. The results of the study did not reveal statistically significant changes in the density of GFAP-IR cells in E1 and E2 groups of rats in comparison with group C. A statistically significant increase in the density of S100beta-IR astrocytes was observed in the E1 group and a decrease in the E2 group. Astrocytes with expression of both studied proteins were characterised by morphological alterations in ARC in the E2 group. The obtained results suggest an influence of CAP contained in habanero pepper fruits on the reactivity of astroglia, which may have an impact on the astrocyte neuron interactions in order to maintain a proper activity of nervous cells in ARC. PMID- 28092616 TI - Generation and characterization of a monoclonal antibody against duck Tembusu virus envelope protein. AB - Duck Tembusu virus (DTMUV) is a newly emerging pathogenic flavivirus that has caused massive economic losses to the duck industry in China. Envelope (E) protein of DTMUV is an important structural protein, which is able to induce protective immune response in target animals and can be used as specific serological diagnosis tool. In this study, a novel monoclonal antibody, designated mAb 3E9, was generated against DTMUV E protein. It is positive in indirect ELISA against both His-E protein and the purified whole viral antigen. Also, this mAb showed positive reaction with DTMUV in Western blot and indirect immunofluorescence assay, and the isotype was IgG1. End-point neutralizing assay performed in BHK-21 cells revealed that the neutralization titer of 3E9 against DTMUV JS804 strain reached 1:50. Furthermore, functional studies revealed that 3E9 blocks infection of DTMUV at a step on viral attachment. The anti-E mAbs produced in the present work may be valuable in developing an antigen-capture ELISA test for antigen detection or a competitive ELISA test for antibody detection or therapeutic medicine for DTMUV in poultry. PMID- 28092617 TI - Supplementation of pigs diet with zinc and copper as alternative to conventional antimicrobials. AB - Modern commercial pig farming systems inflict increased stress in animals, which often leads to various negative changes in the gastro-intestinal tract, especially in the case of piglets. Ban of antibiotics, used as growth promoters, has caused a need for alternatives to conventional antimicrobials in swine diets. Use of pre-/or probiotics, organic acids and plant extracts is often recommended, but it seems that zinc oxide and cooper salts, which were traditionally included in high doses to piglets diet, possess the highest efficacy. In commercial conditions feeding piglets with high doses of Zn and/or Cu stimulates piglets daily gain and decreases feed conversion factor. However, as heavy metals Zn and Cu tend to accumulate in soil and cause serious environmental pollution of soil and tap-water. Furthermore, high zinc concentrations (2500/3000 mg/kg feed) in feed may have an impact on development of antimicrobial resistance, and may regulate the expression of genes that modify piglets' immune response. Therefore, the use of high doses of ZnO and/or Cu salts, as growth promoter, has always been a subject of discussion, and caused different legal status of such treatment in various EU countries. This short review describes current European Food Safety Authority (EFSA) point of view on the use of ZnO in medicated feed. The higher bioavailability of recently introduced new sources or forms of these metals allows for substantial reduction of dietary inclusion rate, which should have a positive outcome for pigs health and the environment. PMID- 28092618 TI - Evaluation of portable blood glucose meters using canine and feline pooled blood samples. AB - This study evaluated the accuracy and reproducibility of a human portable blood glucose meter (PBGM) for canine and feline whole blood. Reference plasma glucose values (RPGV) were concurrently measured using glucose oxidation methods. Fifteen healthy dogs and 6 healthy cats were used for blood sampling. Blood glucose concentrations and hematocrits were adjusted using pooled blood samples for our targeted values. A positive correlation between the PBGM and RPGV was found for both dogs (y = 0.877, x = -24.38, r = 0.9982, n = 73) and cats (y = 1.048, x = 27.06, r = 0.9984, n = 69). Acceptable results were obtained in error grid analysis between PBGM and RPGV in both dogs and cats; 100% of these results were within zones A and B. Following ISO recommendations, a PBGM is considered accurate if 95% of the measurements are within +/- 15 mg/dl of the RPGV when the glucose concentration is <100 mg/dl and within +/-15% when it is >=100 mg/dl; however, small numbers of samples were observed inside the acceptable limits for both dogs (11%, 8 of 73 dogs) and cats (39%, 27 of 69 cats). Blood samples with high hematocrits induced lower whole blood glucose values measured by the PBGM than RPGV under hypoglycemic, normoglycemic, and hyperglycemic conditions in both dogs and cats. Therefore, this device is not clinically useful in dogs and cats. New PBGMs which automatically compensate for the hematocrit should be developed in veterinary practice. PMID- 28092619 TI - Concentration of lactoferrin and immunoglobulin G in cows' milk in relation to health status of the udder, lactation and season. AB - The aim of this study was to analyze an effect of udder health status, somatic cell count (SCC), stage and number of lactations, and different seasons on the concentration of lactoferrin (LF) and immunoglobulin G (IgG) in quarter milk samples (n=120) from crossbreed (Lithuanian Black-and-White & Holstein) dairy cows. Quarter health status was based on SCC and microbiological analysis. The highest mean value of LF and IgG were observed in quarters with subclinical mastitis 0.1 +/- 0.02 mg/ml and 0.41 +/- 0.06 mg/ml, respectively. Grouping the data according to SCC revealed increased LF (0.07 +/- 0.01 mg/ml as against 0.06 +/- 0.01 mg/ml) and IgG values (0.27 +/- 0.05 mg/ml as against 0.23 +/- 0.02 mg/ml) in DQ (SCC from 201,000 >= 401,000 cells/ml) compared to HQ (SCC up to 200,000 cells/ml). The milk LF and IgG levels were effected by stage of lactation (p<0.01 and p<0.05, respectively) and season of the year (p<0.001 and p<0.001, respectively). Nevertheless, SCC and subsequent lactation (p>0.05) had no effect on these immunity components. PMID- 28092620 TI - Correlation between peripheral blood cell transcriptomic profile and clinical parameters of chronic mitral valve disease in Dachshunds. AB - Studies identifying specific pathologically expressed genes have been performed on diseased myocardial tissue samples, however less invasive studies on gene expression of peripheral blood mononucleated cells give promising results. This study assessed transcriptomic data that may be used to evaluate Dachshunds with chronic mitral valve disease. Dachshunds with different stages of heart disease were compared to a control, healthy group. Microarray data analysis revealed clusters of patients with similar expression profiles. The clusters were compared to the clinical classification scheme. Unsupervised classification of the studied groups showed three clusters. Clinical and laboratory parameters of patients from the cluster 1 were in accordance with those found in patients without heart disease. Data obtained from patients from the cluster 3 were typical of advanced heart failure patients. Comparison of the cluster 1 and 3 groups revealed 1133 differentially expressed probes, 7 significantly regulated process pathways and 2 significantly regulated Ariadne Metabolic Pathways. This study may serve as a guideline for directing future research on gene expression in chronic mitral valve disease. PMID- 28092621 TI - Cholesterol Deficiency - new genetic defect transmitted to Polish Holstein Friesian cattle. AB - The aim of the study was to find out whether carriers of new genetic defect Cholesterol Deficiency (CD) occur in the population of Polish Holstein-Friesian bulls. Twenty seven bulls were included in the analysis. Bulls were selected as having in the pedigree known carrier of CD (Maughlin Storm CANM000005457798). All bulls were diagnosed by the test described by Menzi et al. (2016) by using allele specific PCR. Among 27 bulls, 9 new CD carriers were found. Our results show that causal mutation for CD is already transmitted to Polish Holstein-Friesian cattle. The results are sufficient ground to take practical action in order to avoid further spreading of mutation causing CD. PMID- 28092622 TI - Electroencephalographic changes associated with non-invasive nociceptive stimulus in minimally anaesthetised dogs. AB - Electroencephalography (EEG) has been reported as an objective, non-invasive and stress free technique for nociceptive studies. Electrical stimuli can be used to evaluate the efficacy of centrally acting agents. Peripheral nerve stimulator can be a good and cheap source of electric stimulus for studies of nociception, and studies evaluating analgesic effect of drugs under EEG. In this study suitability of peripheral nerve stimulator, and milliamperage for nociceptive studies under electroencephalography were evaluated. Six dogs were subjected to electric stimulus of 20, 40, 60 and 80 milliamperes (mAs) before and after tramadol administration at 4 mg/kg IV. Electroencephalograph was recorded during electric stimulus prior tramadol (pre-tramadol) and during electric stimulus after tramadol (post-tramadol) under minimal anaesthesia. Anaesthesia was induced with propofol and maintained with halothane at a stable concentration between 0.85 and 0.95%. Pre-tramadol median frequency (MF) increased significantly (p<0.05) at 40, 60 and 80 mAs post-electric stimulus compared to baseline MF. No difference in pre-tramadol MF was observed between 60 and 80 mAs. Tramadol produced significant effect by depression of MF at all intensities. The effect was less evident at 80 mAs. The results revealed that tramadol produced evident effect between 20 and 60 mAs. Thus, it is concluded that nerve stimulator can be used with the current between 20 and 60 mAs for nociceptive studies. PMID- 28092623 TI - Ultrasonography: a method used for pregnancy imaging of the fire salamander (Salamandra salamandra). AB - Ultrasound imaging has more frequently been used in veterinary medicine of amphibians and reptiles. In this study, we have verified the usefulness of ultrasound imaging in pregnancy determination of the fire salamander Salamandra salamandra. We have also undertaken to estimate the number of larvae and their developmental stage directly in the oviducts. Three gravid females from Lower Silesia (southern Poland) were examined. Due to the small size of the scanned animals, and the particular arrangement of embryos in the oviducts and ultrasound beams dispersal, the method proved to be inaccurate. Therefore, the minimum number of well-visualized larvae was determined. The maximum number of larvae was established on the basis of the visible fragments of embryos. After birth, we found that the number of larvae born was included in the "min-max" range in only one case. In the remaining two salamanders the number of larvae was higher than estimated in 3 to 7 individuals. The results showed that ultrasound imaging allows the minimum number of larvae in salamander; oviducts to be specified. However, total length measurements were possible only for single and clearly visible embryos. PMID- 28092625 TI - Adrenergic control of pinealocyte chondriome - an in vitro study. AB - Norepinephrine released from sympathetic innervation plays the main role in the regulation of melatonin secretion in mammalian pinealocytes. The present study was conducted for the following reasons: 1) to establish whether the pinealocyte chondriome is controlled by norepinephrine, 2) to determine the effect of adrenergic stimulation on mitochondria, and 3) to characterize adrenoceptors involved in the regulation of the chondriome. The static organ culture of the pineal gland was used. The explants were incubated for 5 consecutive days in control medium and between 20:00 and 08:00 in medium with the presence of 10 MUM norepinephrine - adrenergic agonist; isoproterenol - beta-adrenoceptor agonist; cirazoline, methoxamine, M-6364 - alfa1 - adrenoceptors agonists or PMA - activator of PKC. The explants were then subjected to ultrastructural examination and morphometric analysis. The incubation of explants in the presence of norepinephrine or isoproterenol caused a decrease in the relative volume and the numerical density of mitochondria and induced an increase in the percentage of free mitochondria in pinealocytes. Significant changes in these parameters were not observed after treatment with methoxamine, cirazoline, M-6463 and PMA. The results obtained show that the chondriome of pig pinealocytes is controlled by norepinephrine acting via beta-adrenoceptors. Adrenergic stimulation, repeated for five consecutive days of organ culture, causes a decrease in the number of mitochondria and a shift in the distribution of mitochondria from the form of networks and filaments into the form of single particles. This indicates the intensive remodeling of the mitochondria network, which is closely linked to the metabolic status of the cell. PMID- 28092624 TI - Changes in reticulorumen content temperature and pH according to time of day and yearly seasons. AB - The monitoring of rumen content temperature can be useful for the evaluation of cow health condition and heat. The aim of this research was to evaluate the influence of the circadian rhythm (time of day) and season on reticulorumen acidity (pH) and temperatures (RT) in lactating dairy cows. The research was performed on ten 2nd - lactation, clinically healthy Lithuanian Black and White fresh dairy cows (up to 1 day after calving). The cows were milked twice daily at 05:00 and 17:00. The cows were kept in a loose housing system, and were fed a feed ration throughout the year at the same time, balanced according to their physiological needs. Cow feeding took place every day at 06:00 and 18:00. The pH and temperature of the contents of cow reticulorumens were measured using specific smaXtec boluses manufactured for animal care. The temperature starts rising 6 hours after the evening feeding and milking, whereas 1 hour after the morning milking, it starts decreasing. The lowest temperature observed in the springtime was 38.81+/-0.001, and the highest was in autumn 39.17+/-0.001. The pH starts decreasing 3 hours after the morning feed, whereas 4 hours after the evening feed, it starts increasing. The lowest pH was observed in the summertime 5.99+/-0.001, and the highest was in autumn and springtime - 6.18+/-0.001. In conclusion the reticulorumen temperature in lactating cows was found to be influenced by the circadian rhythm and season. The acidity of the reticulorumen content changes similar to the temperature. The pH of the reticulorumen contents was also found to be influenced by the circadian rhythm and season. PMID- 28092626 TI - The impact of surface geometry, cavitation, and condensation on wetting transitions: posts and reentrant structures. AB - The fundamental impacts of surface geometry on the stability of wetting states, and the transitions between them are elucidated for square posts and reentrant structures in three dimensions. We identify three principal outcomes of particular importance for future surface design of liquid-repellent surfaces. Firstly, we demonstrate and quantify how capillary condensation and vapour cavitation affect wetting state stabilities. At high contact angles, cavitation is enhanced about wide, closely-spaced square posts, leading to the existence of suspended states without an associated collapsed state. At low contact angles, narrow reentrant pillars suppress condensation and enable the suspension of even highly wetting liquids. Secondly, two distinct collapse mechanisms are observed for 3D reentrant geometries, base contact and pillar contact, which are operative at different pillar heights. As well as morphological differences in the interface of the penetrating liquid, each mechanism is affected differently by changes in the contact angle with the solid. Finally, for highly-wetting liquids, condensates are shown to critically modify the transition pathways in both the base contact and pillar contact modes. PMID- 28092627 TI - The effect of surface transport on water desalination by porous electrodes undergoing capacitive charging. AB - Capacitive deionization (CDI) is a technology in which water is desalinated by ion electrosorption into the electric double layers (EDLs) of charging porous electrodes. In recent years significant advances have been made in modeling the charge and salt dynamics in a CDI cell, but the possible effect of surface transport within diffuse EDLs on these dynamics has not been investigated. We here present theory which includes surface transport in describing the dynamics of a charging CDI cell. Through our numerical solution to the presented models, the possible effect of surface transport on the CDI process is elucidated. While at some model conditions surface transport enhances the rate of CDI cell charging, counter-intuitively this additional transport pathway is found to slow down cell charging at other model conditions. PMID- 28092628 TI - Ultrafast adiabatic second harmonic generation. AB - We introduce a generalization of the adiabatic frequency conversion method for an efficient conversion of ultrashort pulses in the full nonlinear regime. Our analysis takes into account dispersion as well as two-photon processes and Kerr effect, allowing complete analysis of any three waves with arbitrary phase mismatched design and any nonlinear optical process. We use this analysis to design an efficient and robust second harmonic generation, the most widely used nonlinear process for both fundamental and applied research. We experimentally show that such design not only allows for very efficient conversion of various of ultrashort pulses, but is also very robust to variations in the parameters of both the nonlinear crystal and the incoming light. These include variation of more than 100 degrees C in the crystal temperature, a wide bandwidth of up to 75 nm and a chirp variation of 300 fs to 3.5 ps of the incoming pulse. Also, we show the dependency of the adiabatic second harmonic generation design on the pump intensity and the crystal length. Our study shows that two photon absorption plays a critical role in such high influence nonlinear dynamics, and that it must be considered in order to achieve agreement with experimental results. PMID- 28092629 TI - Transition metal substitution for H in graphane: a high-throughput study. AB - This systematic study of transition metal (TM) substitution for H on graphane TM x H1-x C, (TM = Sc, Ti, V, Cr, Mn) combines ab initio calculations and cluster expansion to explore a huge variety of structures in more than 20 supercells over the full concentration range from x = 0 to 1. We find energetically favorable structures at each concentration in supercells not studied before. At low x the lowest-energy structures contain lines and bands of TM atoms. For the larger atoms (Sc, Ti, V) the ordering becomes complex at higher concentrations, and their increased interaction in graphene causes H atoms to detach from the graphene to positions above the TMs. The smaller atoms (Cr, Mn) have much simpler ordering that favors TM atoms all on one side before filling the other side. At full coverage (x = 1), the TM atoms remain well bound to the graphene, the structure being more stable than a free monolayer by 0.5 to 0.8 eV. The binding energies of TM atoms are strongly enhanced by the binding of H to graphene, with strengths similar to the bulk cohesive energy of Ti. PMID- 28092630 TI - Comparative Monte Carlo study on the performance of integration- and list-mode detector configurations for carbon ion computed tomography. AB - Ion beam therapy offers the possibility of a highly conformal tumor-dose distribution; however, this technique is extremely sensitive to inaccuracies in the treatment procedures. Ambiguities in the conversion of Hounsfield units of the treatment planning x-ray CT to relative stopping power (RSP) can cause uncertainties in the estimated ion range of up to several millimeters. Ion CT (iCT) represents a favorable solution allowing to directly assess the RSP. In this simulation study we investigate the performance of the integration-mode configuration for carbon iCT, in comparison with a single-particle approach under the same set-up. The experimental detector consists of a stack of 61 air-filled parallel-plate ionization chambers, interleaved with 3 mm thick PMMA absorbers. By means of Monte Carlo simulations, this design was applied to acquire iCTs of phantoms of tissue-equivalent materials. An optimization of the acquisition parameters was performed to reduce the dose exposure, and the implications of a reduced absorber thickness were assessed. In order to overcome limitations of integration-mode detection in the presence of lateral tissue heterogeneities a dedicated post-processing method using a linear decomposition of the detector signal was developed and its performance was compared to the list-mode acquisition. For the current set-up, the phantom dose could be reduced to below 30 mGy with only minor image quality degradation. By using the decomposition method a correct identification of the components and a RSP accuracy improvement of around 2.0% was obtained. The comparison of integration- and list-mode indicated a slightly better image quality of the latter, with an average median RSP error below 1.8% and 1.0%, respectively. With a decreased absorber thickness a reduced RSP error was observed. Overall, these findings support the potential of iCT for low dose RSP estimation, showing that integration-mode detectors with dedicated post-processing strategies can provide a RSP accuracy comparable to list-mode configurations. PMID- 28092631 TI - Optoelectrofluidic printing system for fabricating hydrogel sheets with on-demand patterned cells and microparticles. AB - This paper presents a novel optoelectrofluidic printing system that facilitates not only the optoelectrofluidic patterning of microparticles and mammalian cells but also the harvesting of the patterned microparticles encapsulated within poly(ethylene glycol) dicarylate (PEGDA) hydrogel sheets. Although optoelectrofluidic technology has numerous advantages for programmable and on demand patterning and the feasibility of manipulating single microparticles, practical applications using existing laboratory infrastructure in biological and clinical research fields have been strictly restricted due to the impossibility of recovering the final patterned product. In order to address these harvesting limitations, PEGDA was employed to utilize optoelectrofluidic printing. The Clausius-Mossotti factor was calculated to investigate the dielectrophoretic mobility of the microparticle and the cell in the PEGDA precursor solution. As a proof of concept, three basic controllabilities of the optoelectrofluidic printing system were characterized: the number of microparticles, the distance between the microparticle columns, and the ratio of two different microparticles. Furthermore, the optoelectrofluidic patterning and printing of human liver carcinoma cells (HepG2) were demonstrated in 5 min with a single-cell level of resolution. The appropriate ranges of frequency were experimentally defined based on the calculated result of the dielectrophoretic mobility of HepG2 cells. Finally, optoelectrofluidically cell-patterned hydrogel sheets were successfully recovered under a highly viable physiological condition. PMID- 28092632 TI - The tilt-dependent potential of mean force of a pair of DNA oligomers from all atom molecular dynamics simulations. AB - Electrostatic interactions between DNA molecules have been extensively studied experimentally and theoretically, but several aspects (e.g. its role in determining the pitch of the cholesteric DNA phase) still remain unclear. Here, we performed large-scale all-atom molecular dynamics simulations in explicit water and 150 mM sodium chloride, to reconstruct the potential of mean force (PMF) of two DNA oligomers 24 base pairs long as a function of their interaxial angle and intermolecular distance. We find that the potential of mean force is dominated by total DNA charge, and not by the helical geometry of its charged groups. The theory of homogeneously charged cylinders fits well all our simulation data, and the fit yields the optimal value of the total compensated charge on DNA to ~65% of its total fixed charge (arising from the phosphorous atoms), close to the value expected from Manning's theory of ion condensation. The PMF calculated from our simulations does not show a significant dependence on the handedness of the angle between the two DNA molecules, or its size is on the order of [Formula: see text]. Thermal noise for molecules of the studied length seems to mask the effect of detailed helical charge patterns of DNA. The fact that in monovalent salt the effective interaction between two DNA molecules is independent on the handedness of the tilt may suggest that alternative mechanisms are required to understand the cholesteric phase of DNA. PMID- 28092633 TI - Unconventional superconductivity in generalized Hubbard model: role of electron hole symmetry breaking terms. AB - We investigate the effect of the electron-hole (e-h) symmetry breaking on d-wave superconductivity induced by non-local effects of correlations in the generalized Hubbard model. The symmetry breaking is introduced in a two-fold manner: by the next-to-nearest neighbor hopping of electrons and by the charge-bond interaction the off-diagonal term of the Coulomb potential. Both terms lead to a pronounced asymmetry of the superconducting order parameter. The next-to-nearest neighbor hopping enhances superconductivity for h-doping, while diminishes it for e doping. The charge-bond interaction alone leads to the opposite effect and, additionally, to the kinetic-energy gain upon condensation in the underdoped regime. With both terms included, with similar amplitudes, the height of the superconducting dome and the critical doping remain in favor of h-doping. The influence of the charge-bond interaction on deviations from [Formula: see text] symmetry of the shape of the gap at the Fermi surface in the momentum space is briefly discussed. PMID- 28092634 TI - Correlation of cation distribution with the hyperfine and magnetic behaviour of Ni0.3Zn0.4Co0.2Cu0.1Fe2O4 nanoparticles and their microwave absorption properties when encapsulated in multi-walled carbon nanotubes. AB - Nanocrystalline samples of Ni0.3Zn0.4Co0.2Cu0.1Fe2O4 (NZCCF) are prepared by a simple co-precipitation method. To obtain nanoparticles of different sizes, the as prepared sample is annealed at 400, 600, 800 and 1000 degrees C. Nanoparticles of the sample annealed at 600 degrees C are encapsulated in multi walled carbon nanotubes (MWCNT). To confirm the crystallographic phase, x-ray diffraction (XRD) patterns are analyzed by the Rietveld method and cation distribution in A- and B-sites is estimated from the analysis. Occupancy of Zn2+ ions in A-site and that of Fe3+ ions in B-site increase with the increase of annealing temperature (T A) and lattice parameters lie within 8.365-8.398 A. Morphology of the encapsulated sample is examined by taking micrographs in high resolution transmission electron microscope (HRTEM). Hyperfine behaviour of the prepared samples is studied by analyzing Mossbauer spectra recorded at room temperature (RT) and 77 K. Average values of isomer shift (IS) are found to decrease with the increase of crystallite size. Static and dynamic magnetic hysteresis loops are recorded to analyze the magnetic properties of the sample. Maximum saturation magnetization of ~75 emu g-1 is obtained for the sample of NZCCF annealed at 800 degrees C with crystallite size of ~48 nm. Microwave absorption capability of the encapsulated sample is measured by recording the reflection loss in X and K u bands of microwave region of frequency. Maximum value of reflection loss is -25.71 dB observed at 15.24 GHz for a sample layer thickness of 1 mm. Moreover, the reflection loss is less than -10 dB for the entire range of observation (8-18 GHz) which shows that MWCNT encapsulated NZCCF could be considered as a potential candidate for applications in microwave devices. PMID- 28092635 TI - Evaluating the accuracy of a three-term pencil beam algorithm in heterogeneous media. AB - The goal of this work was to evaluate the accuracy of our in-house analytical dose calculation code against MCNPX data in heterogeneous phantoms. The analytical model utilizes a pencil beam model based on Fermi-Eyges theory to account for multiple Coulomb scattering and a least-squares fit to Monte Carlo data to account for nonelastic nuclear interactions as well as any remaining, uncharacterized scatter (the 'nuclear halo'). The model characterized dose accurately (up to 1% of maximum dose in broad fields (4 * 4 cm2 and 10 * 10 cm2) and up to 0.01% in a narrow field (0.1 * 0.1 cm2) fit to MCNPX data). The accuracy of the model was benchmarked in three types of stylized phantoms: (1) homogeneous, (2) laterally infinite slab heterogeneities, and (3) laterally finite slab heterogeneities. Results from homogeneous phantoms and laterally infinite slab heterogeneities showed high levels of accuracy (>98% of points within 2% or 0.1 cm distance-to-agreement (DTA)). However, because range straggling and secondary particle production were not included in our model, central-axis dose differences of 2-4% were observed in laterally infinite slab heterogeneities when compared to Monte Carlo dose. In the presence of laterally finite slab heterogeneities, the analytical model resulted in lower pass rates (>96% of points within 2% or 0.1 cm DTA), which was attributed to the use of the central-axis approximation. PMID- 28092636 TI - An analysis of intrinsic variations of low-frequency shear wave speed in a stochastic tissue model: the first application for staging liver fibrosis. AB - Shear wave elastography is increasingly being used to non-invasively stage liver fibrosis by measuring shear wave speed (SWS). This study quantitatively investigates intrinsic variations among SWS measurements obtained from heterogeneous media such as fibrotic livers. More specifically, it aims to demonstrate that intrinsic variations in SWS measurements, in general, follow a non-Gaussian distribution and are related to the heterogeneous nature of the medium being measured. Using the principle of maximum entropy (ME), our primary objective is to derive a probability density function (PDF) of the SWS distribution in conjunction with a lossless stochastic tissue model. Our secondary objective is to evaluate the performance of the proposed PDF using Monte Carlo (MC)-simulated shear wave (SW) data against three other commonly used PDFs. Based on statistical evaluation criteria, initial results showed that the derived PDF fits better to MC-simulated SWS data than the other three PDFs. It was also found that SW fronts stabilized after a short (compared with the SW wavelength) travel distance in lossless media. Furthermore, in lossless media, the distance required to stabilize the SW propagation was not correlated to the SW wavelength at the low frequencies investigated (i.e. 50, 100 and 150 Hz). Examination of the MC simulation data suggests that elastic (shear) wave scattering became more pronounced when the volume fraction of hard inclusions increased from 10 to 30%. In conclusion, using the principle of ME, we theoretically demonstrated for the first time that SWS measurements in this model follow a non-Gaussian distribution. Preliminary data indicated that the proposed PDF can quantitatively represent intrinsic variations in SWS measurements simulated using a two-phase random medium model. The advantages of the proposed PDF are its physically meaningful parameters and solid theoretical basis. PMID- 28092637 TI - Non-invasive classification of breast microcalcifications using x-ray coherent scatter computed tomography. AB - We investigate the use of energy dispersive x-ray coherent scatter computed tomography (ED-CSCT) as a non-invasive diagnostic method to differentiate between type I and type II breast calcifications. This approach is sensitive to the differences of composition and internal crystal structure of different types of microcalcifications. The study is carried out by simulating a CSCT system with a scanning pencil beam, considering a polychromatic x-ray source and an energy resolving photon counting detector. In a first step, the multidimensional angle and energy distributed CSCT data is reduced to the projection-space distributions of only a few components, corresponding to the expected target composition: adipose, glandular tissue, weddellite (calcium oxalate) for type I calcifications, and hydroxyapatite for type II calcifications. The maximum likelihood estimation of scatter components algorithm used, operating in the projection space, takes into account the polychromatic source, the detector response function and the energy dependent attenuation. In the second step, component images are reconstructed from the corresponding estimated component projections using filtered backprojection. In a preliminary step the coherent scatter differential cross sections for hydroxyapatite and weddellite minerals were determined experimentally. The classification of type I or II calcifications is done using the relative contrasts of their components as the criterion. Simulation tests were carried out for different doses and energy resolutions for multiple realizations. The results were analyzed using relative/receiver operating characteristic methodology and show good discrimination ability at medium and higher doses. The noninvasive CSCT technique shows potential to further improve the breast diagnostic accuracy and reduce the number of breast biopsies. PMID- 28092638 TI - MR elastography to measure the effects of cancer and pathology fixation on prostate biomechanics, and comparison with T 1, T 2 and ADC. AB - MRI is under evaluation for image-guided intervention for prostate cancer. The sensitivity and specificity of MRI parameters is determined via correlation with the gold-standard of histopathology. Whole-mount histopathology of prostatectomy specimens can be digitally registered to in vivo imaging for correlation. When biomechanical-based deformable registration is employed to account for deformation during histopathology processing, the ex vivo biomechanical properties are required. However, these properties are altered by pathology fixation, and vary with disease. Hence, this study employs magnetic resonance elastography (MRE) to measure ex vivo prostate biomechanical properties before and after fixation. A quasi-static MRE method was employed to measure high resolution maps of Young's modulus (E) before and after fixation of canine prostate and prostatectomy specimens (n = 4) from prostate cancer patients who had previously received radiation therapy. For comparison, T 1, T 2 and apparent diffusion coefficient (ADC) were measured in parallel. E (kPa) varied across clinical anatomy and for histopathology-identified tumor: peripheral zone: 99(+/ 22), central gland: 48(+/-37), tumor: 85(+/-53), and increased consistently with fixation (factor of 11 +/- 5; p < 0.02). T 2 decreased consistently with fixation, while changes in T 1 and ADC were more complex and inconsistent. The biomechanics of the clinical prostate specimens varied greatly with fixation, and to a lesser extent with disease and anatomy. The data obtained will improve the precision of prostate pathology correlation, leading to more accurate disease detection and targeting. PMID- 28092639 TI - Lithographic patterning of antibodies by direct lift-off and improved surface adhesion. AB - The inherent property of antibodies binding to their antigen with high specificity makes them a strong candidate for sensing and detection applications. Microscale patterning of antibodies is desired for the miniaturization of sensors and fundamental cell biology studies. However, existing methodologies to pattern antibodies at the microscale are multi-step. In this work, we demonstrate microscale patterning of antibodies on a glass coverslip in a single step photolithography process. The microscale features of the photoresist were generated on the coverslip using photolithography, and the antibody solution was incubated. Acetone lift-off of the antibody incubated photoresist, and subsequent washing by isopropanol (IPA), produced a micro-array of antibodies. The functionality of patterned primary antibody was confirmed using the corresponding antigen and strict controls. One of the striking features of this method of patterning is that the process steps and chemicals inherently improve the adhesion between the antibodies and glass without the need to functionalize the glass surface. We performed an ultrasonication test, detergent washing test, and Scotch tape test to show improved adhesion. Using appropriate controls, we show that the interaction taking place between the antibodies and the glass surface, after our process, is stronger than the simple physisorption taking place between the antibodies and the glass surface, without any treatment. PMID- 28092640 TI - A Tale of Two Heat Strokes: A Comparative Case Study: Erratum. PMID- 28092641 TI - Performance characterization of a novel electronic number connection test to detect minimal hepatic encephalopathy in cirrhotic patients. AB - BACKGROUND AND AIM: Hepatic encephalopathy (HE) is a frequent complication of cirrhosis, characterized by cognitive deficits that negatively impact patients' quality of life. The mild, minimal hepatic encephalopathy (mHE) can only be detected by psychometric tests and early mHE detection can prevent more severe complications or even survival times. Here, we aimed to investigate the feasibility and validity of the novel-developed electronic number connection test (eNCT), which is designed as a fast and easy-to-perform mHE patient self-test. METHODS: The eNCT design was inspired by the paper-pencil number connection test version A, showing 25 numbers on the screen (1-25), in a random order. The time required to tap on all digits in the correct order was measured. A total of 238 individuals (112 patients with liver cirrhosis) were enrolled in this study and eNCT times were compared with well-established paper-pencil tests. The Psychometric Hepatic Encephalopathy Score test battery was used to detect mHE and cut-off values for mHE detection by the eNCT were defined. RESULTS: Overall, cirrhotic patients showed significantly slower test completion times compared with control participants. The eNCT performance was inversely correlated with Psychometric Hepatic Encephalopathy Score test performance in cirrhotic patients, independent of the HE status. Thirty cirrhotic patients fulfilled the mHE criteria and receiver operating characteristic curve analysis showed high sensitivity (>82%) and specificity (>85%) for mHE detection. Finally, the eNCT showed excellent test-retest reliability (intraclass correlation coefficient=0.94). CONCLUSION: The novel eNCT is a reliable HE self-test to monitor cognitive function and detect cognitive impairment in cirrhotic patients. PMID- 28092642 TI - The number of patients with chronic hepatitis C in times of new therapy options: a retrospective observational study on German health insurance funds data. AB - AIM/OBJECTIVES/BACKGROUND: Chronic hepatitis C (CHC) virus infection is a leading cause of liver-related morbidity and mortality. In Germany, as in many other countries, there is a lack of comprehensive epidemiological data. Routine data from sickness funds can support the estimation of the true prevalence and incidence of CHC. METHODS: In this article, the results of annual and quarterly analyses of prevalence and incidence for the years 2007-2013 are presented using data of several German sickness funds. RESULTS: Overall, the prevalence rate remained relatively stable at 0.2%, which is lower than the general assumption for Germany of 0.3%. CONCLUSION: We found that despite the introduction of the breakthrough designated triple therapies with telaprevir or boceprevir in 2011, there was no increase of prevalence or incidence between 2010 and 2011. PMID- 28092643 TI - Physical Activity and Sedentary Time among Children with Disabilities at School. AB - PURPOSES: Physical activity (PA) is important for the development of children with disabilities, but rarely does this population meet the recommended standards. Schools are salient locations for PA, but little is known about how specific school settings affect the PA of children with diverse disabilities. We assessed PA and sedentary time (ST) of children with disabilities in three school settings (physical education, recess, lunchtime). METHODS: Participants included 259 children from 13 Hong Kong special schools for five primary disabilities: visual impairments, hearing impairments, physical disabilities, intellectual disabilities, and social development problems. Children wore accelerometers at school for 3 d, and the time (min and %) they engaged in moderate-to-vigorous PA (MVPA) and ST was extracted for each school setting by sex. Analyses included multiple linear mixed models to determine differences in MVPA and ST by sex across disability types, adjusting for body mass index, grade level, and duration in each setting. RESULTS: Overall, children spent 70% of their day at school being sedentary and accrued little MVPA (mean, 17 +/- 4.2 min daily). Children with intellectual disabilities (severe) had especially low levels of MVPA. All three settings contributed significantly to both MVPA and ST, with recess contributing more to MVPA than physical education or lunchtime. CONCLUSIONS: This is the first study to examine MVPA and ST among different disability types at school using accelerometry. Given the low levels of PA, this population should receive priority in the development of cost-effective interventions to improve their PA opportunities. PMID- 28092644 TI - Modified Slow Mohs Technique for Treatment of Cellular Neurothekeoma of the Lip in a Pediatric Patient. PMID- 28092645 TI - Phenotypes and treatment response: it's difficult to make predictions, especially about the future. PMID- 28092647 TI - Dietary intake mediates the relationship of body fat to pain. AB - Prior studies have documented an association of obesity with chronic pain, but the mechanism explaining the association remains unknown. This study evaluated the degree to which dietary intake of foods with anti-inflammatory effects mediates the relationship of body fat to body pain. Ninety-eight community residing healthy adults (60% women; mean age = 43.2 +/- 15.3 years; range: 20-78 years) participated in a home-based study of home environment, food-related behaviors, health, and adiposity. During a 3-hour home visit evaluation, 3 measures of body fat were collected, including height and weight for calculation of body mass index (BMI). Participants also completed a 24-hour food recall interview and self-report measures of bodily pain (BP; BP subscale from the Medical Outcomes Study Short Form-36) and psychological distress (Hospital Anxiety and Depression Scale). Quality of dietary intake was rated using the Healthy Eating Index-2010. Mediation models were conducted with the PROCESS macro in SAS 9.3. Mean BMI was consistent with obesity (30.4 +/- 7.8; range: 18.2 53.3), and BP values (73.2 +/- 22.1; range: 0-100) and dietary intake quality (59.4 +/- 15.5; range: 26.8-88.1) were consistent with population norms. Modeling in PROCESS revealed that Healthy Eating Index-2010 scores mediated the relationship between BMI and BP (bindirect = -0.34, 95% confidence interval = 0.68 to -0.13). The mediation model remained significant when controlling for biomechanical factors (arthritis/joint pain), medication use, psychological distress, age, and education, and models remained significant using the other 2 body fat measures. Thus, the data indicate that dietary intake of foods with anti inflammatory effects mediates the relationship of body fat to body pain in healthy men and women. PMID- 28092648 TI - Does brief chronic pain management education change opioid prescribing rates? A pragmatic trial in Australian early-career general practitioners. AB - We aimed to evaluate the effect of pain education on opioid prescribing by early career general practitioners. A brief training workshop was delivered to general practice registrars of a single regional training provider. The workshop significantly reduced "hypothetical" opioid prescribing (in response to paper based vignettes) in an earlier evaluation. The effect of the training on "actual" prescribing was evaluated using a nonequivalent control group design nested within the Registrar Clinical Encounters in Training (ReCEnT) cohort study: 4 other regional training providers were controls. In ReCEnT, registrars record detailed data (including prescribing) during 60 consecutive consultations, on 3 occasions. Analysis was at the level of individual problem managed, with the primary outcome factor being prescription of an opioid analgesic and the secondary outcome being opioid initiation. Between 2010 and 2015, 168,528 problems were recorded by 849 registrars. Of these, 71% were recorded by registrars in the nontraining group. Eighty-two percentages were before training. Opioid analgesics were prescribed in 4382 (2.5%, 95% confidence interval [CI]: 2.40-2.63) problems, with 1665 of these (0.97%, 95% CI: 0.91-1.04) representing a new prescription. There was no relationship between the training and total prescribing after training (interaction odds ratio: 1.01; 95% CI: 0.75-1.35; P value 0.96). There was some evidence of a reduction in initial opioid prescriptions in the training group (interaction odds ratio: 0.74; 95% CI: 0.48 1.16; P value 0.19). This brief training package failed to increase overall opioid cessation. The inconsistency of these actual prescribing results with "hypothetical" prescribing behavior suggests that reducing opioid prescribing in chronic noncancer pain requires more than changing knowledge and attitudes. PMID- 28092646 TI - Ex vivo nonviral gene delivery of MU-opioid receptor to attenuate cancer-induced pain. AB - Virus-mediated gene delivery shows promise for the treatment of chronic pain. However, viral vectors have cytotoxicity. To avoid toxicities and limitations of virus-mediated gene delivery, we developed a novel nonviral hybrid vector: HIV-1 Tat peptide sequence modified with histidine and cysteine residues combined with a cationic lipid. The vector has high transfection efficiency with little cytotoxicity in cancer cell lines including HSC-3 (human tongue squamous cell carcinoma) and exhibits differential expression in HSC-3 (~45-fold) relative to HGF-1 (human gingival fibroblasts) cells. We used the nonviral vector to transfect cancer with OPRM1, the MU-opioid receptor gene, as a novel method for treating cancer-induced pain. After HSC-3 cells were transfected with OPRM1, a cancer mouse model was created by inoculating the transfected HSC-3 cells into the hind paw or tongue of athymic mice to determine the analgesic potential of OPRM1 transfection. Mice with HSC-3 tumors expressing OPRM1 demonstrated significant antinociception compared with control mice. The effect was reversible with local naloxone administration. We quantified beta-endorphin secretion from HSC-3 cells and showed that HSC-3 cells transfected with OPRM1 secreted significantly more beta-endorphin than control HSC-3 cells. These findings indicate that nonviral delivery of the OPRM1 gene targeted to the cancer microenvironment has an analgesic effect in a preclinical cancer model, and nonviral gene delivery is a potential treatment for cancer pain. PMID- 28092649 TI - New-onset depression following stable, slow, and rapid rate of prescription opioid dose escalation. AB - Recent studies suggest that longer durations of opioid use, independent of maximum morphine equivalent dose (MED) achieved, is associated with increased risk of new-onset depression (NOD). Conversely, other studies, not accounting for duration, found that higher MED increased probability of depressive symptoms. To determine whether rate of MED increase is associated with NOD, a retrospective cohort analysis of Veterans Health Administration data (2000-2012) was conducted. Eligible patients were new, chronic (>90 days) opioid users, aged 18 to 80, and without depression diagnoses for 2 years before start of follow-up (n = 7051). Mixed regression models of MED across follow-up defined 4 rate of dose change categories: stable, decrease, slow increase, and rapid increase. Cox proportional hazard models assessed the relationship of rate of dose change and NOD, controlling for pain, duration of use, maximum MED, and other confounders using inverse probability of treatment-weighted propensity scores. Incidence rate for NOD was 14.1/1000PY (person-years) in stable rate, 13.0/1000PY in decreasing, 19.3/1000PY in slow increasing, and 27.5/1000PY in rapid increasing dose. Compared with stable rate, risk of NOD increased incrementally for slow (hazard ratio = 1.22; 95% confidence interval: 1.05-1.42) and rapid (hazard ratio = 1.58; 95% confidence interval: 1.30-1.93) rate of dose increase. Faster rates of MED escalation contribute to NOD, independent of maximum dose, pain, and total opioid duration. Dose escalation may be a proxy for loss of control or undetected abuse known to be associated with depression. Clinicians should avoid rapid dose increase when possible and discuss risk of depression with patients if dose increase is warranted for pain. PMID- 28092650 TI - Sociodemographic disparities in chronic pain, based on 12-year longitudinal data. AB - Existing estimates of sociodemographic disparities in chronic pain in the United States are based on cross-sectional data, often treat pain as a binary construct, and rarely test for nonresponse or other types of bias. This study uses 7 biennial waves of national data from the Health and Retirement Study (1998-2010; n = 19,776) to describe long-term pain disparities among older (age 51+) American adults. It also investigates whether pain severity, reporting heterogeneity, survey nonresponse, and/or mortality selection might bias estimates of social disparities in pain. In the process, the article clarifies whether 2 unexpected patterns observed cross-sectionally-plateauing of pain above age 60, and lower pain among racial/ethnic minorities-are genuine or artefactual. Findings show high prevalence of chronic pain: 27.3% at baseline, increasing to 36.6% thereafter. Multivariate latent growth curve models reveal extremely large disparities in pain by sex, education, and wealth, which manifest primarily as differences in intercept. Net of these variables, there is no racial/ethnic minority disadvantage in pain scores, and indeed a black advantage vis-a-vis whites. Pain levels are predictive of subsequent death, even a decade in the future. No evidence of pain-related survey attrition is found, but surveys not accounting for pain severity and reporting heterogeneity are likely to underestimate socioeconomic disparities in pain. The lack of minority disadvantage (net of socioeconomic status) appears genuine. However, the age related plateauing of pain observed cross-sectionally is not replicated longitudinally, and seems partially attributable to mortality selection, as well as to rising pain levels by birth cohort. PMID- 28092652 TI - Erratum. PMID- 28092653 TI - Erratum. PMID- 28092651 TI - Long-lasting antinociceptive effects of green light in acute and chronic pain in rats. AB - Treatments for chronic pain are inadequate, and new options are needed. Nonpharmaceutical approaches are especially attractive with many potential advantages including safety. Light therapy has been suggested to be beneficial in certain medical conditions such as depression, but this approach remains to be explored for modulation of pain. We investigated the effects of light-emitting diodes (LEDs), in the visible spectrum, on acute sensory thresholds in naive rats as well as in experimental neuropathic pain. Rats receiving green LED light (wavelength 525 nm, 8 h/d) showed significantly increased paw withdrawal latency to a noxious thermal stimulus; this antinociceptive effect persisted for 4 days after termination of last exposure without development of tolerance. No apparent side effects were noted and motor performance was not impaired. Despite LED exposure, opaque contact lenses prevented antinociception. Rats fitted with green contact lenses exposed to room light exhibited antinociception arguing for a role of the visual system. Antinociception was not due to stress/anxiety but likely due to increased enkephalins expression in the spinal cord. Naloxone reversed the antinociception, suggesting involvement of central opioid circuits. Rostral ventromedial medulla inactivation prevented expression of light-induced antinociception suggesting engagement of descending inhibition. Green LED exposure also reversed thermal and mechanical hyperalgesia in rats with spinal nerve ligation. Pharmacological and proteomic profiling of dorsal root ganglion neurons from green LED-exposed rats identified changes in calcium channel activity, including a decrease in the N-type (CaV2.2) channel, a primary analgesic target. Thus, green LED therapy may represent a novel, nonpharmacological approach for managing pain. PMID- 28092654 TI - Promoter Polymorphism of Toll-Like Receptor 4 is Associated with a Decreased Risk of Coronary Artery Disease: A Case-Control Study in the Chinese Han Population. AB - BACKGROUND Coronary artery disease (CAD) is considered a chronic inflammatory disease of the blood vessels. Toll-like receptor 4 (TLR4) is a transmembrane receptor involved in inflammatory reactions. The aim of this study was to determine the association between polymorphisms in the promoter region and 3' untranslated region (3'-UTR) of TLR4, and the associated CAD risk. MATERIAL AND METHODS This study enrolled 424 participants with CAD and 424 controls without CAD. The polymorphisms in the promoter region and 3'-UTR of TLR4 were identified from the HapMap database, including rs10116253, rs10983755, and rs11536889. Genomic DNA was extracted from peripheral blood. Polymerase chain reaction restriction fragment length polymorphism was performed to identify genotype polymorphisms. Relative luciferase activity was measured using the dual luciferase reporter assay system. RESULTS TLR4 rs10116253 in the promoter region was associated with CAD risk. The variant (CC+TC) genotypes of rs10116253 were associated with a decreased CAD risk (OR 95% CI 0.73 (0.54-0.98), p=0.034). In the stratification analyses, the variant (CC+TC) genotypes of rs10116253 were observed to have a relationship with decreased CAD risk in the male subgroup (OR: 95% CI 0.68 (0.48-0.98), p=0.041). Moreover, the variant CC and (CC+TC) genotypes of rs10116253 were correlated with a decreased CAD risk in participants younger than 60-year-old (TC: OR (95% CI 0.62 (0.39-0.98), p=0.042; TC+CC: OR 95% CI 0.63 (0.41-0.98), p=0.039). Regarding rs10116253, the luciferase activity of the mutant C allele construct was lower than that of the wild T allele construct (5.215+/-0.009 vs. 5.304+/-0.041; p=0.087). CONCLUSIONS The results provided evidence of an association between the TLR4 rs10116253 in the promoter region and a reduced risk of CAD. PMID- 28092655 TI - Circadian- and UPR-dependent control of CPEB4 mediates a translational response to counteract hepatic steatosis under ER stress. AB - The cytoplasmic polyadenylation element-binding (CPEB) proteins regulate pre-mRNA processing and translation of CPE-containing mRNAs in early embryonic development and synaptic activity. However, specific functions in adult organisms are poorly understood. Here we show that CPEB4 is required for adaptation to high-fat-diet- and ageing-induced endoplasmic reticulum (ER) stress, and subsequent hepatosteatosis. Stress-activated liver CPEB4 expression is dual-mode regulated. First, Cpeb4 mRNA transcription is controlled by the circadian clock, and then its translation is regulated by the unfolded protein response (UPR) through upstream open reading frames within the 5'UTR. Thus, the CPEB4 protein is synthesized only following ER stress but the induction amplitude is circadian. In turn, CPEB4 activates a second wave of UPR translation required to maintain ER and mitochondrial homeostasis. Our results suggest that combined transcriptional and translational Cpeb4 regulation generates a 'circadian mediator', which coordinates hepatic UPR activity with periods of high ER-protein-folding demand. Accordingly, CPEB4 deficiency results in non-alcoholic fatty liver disease. PMID- 28092656 TI - Influence of node abundance on signaling network state and dynamics analyzed by mass cytometry. AB - Signaling networks are key regulators of cellular function. Although the concentrations of signaling proteins are perturbed in disease states, such as cancer, and are modulated by drug therapies, our understanding of how such changes shape the properties of signaling networks is limited. Here we couple mass-cytometry-based single-cell analysis with overexpression of tagged signaling proteins to study the dependence of signaling relationships and dynamics on protein node abundance. Focusing on the epidermal growth factor receptor (EGFR) signaling network in HEK293T cells, we analyze 20 signaling proteins during a 1-h EGF stimulation time course using a panel of 35 antibodies. Data analysis with BP R2, a measure that quantifies complex signaling relationships, reveals abundance dependent network states and identifies novel signaling relationships. Further, we show that upstream signaling proteins have abundance-dependent effects on downstream signaling dynamics. Our approach elucidates the influence of node abundance on signal transduction networks and will further our understanding of signaling in health and disease. PMID- 28092657 TI - Lipid production in Yarrowia lipolytica is maximized by engineering cytosolic redox metabolism. AB - Microbial factories have been engineered to produce lipids from carbohydrate feedstocks for production of biofuels and oleochemicals. However, even the best yields obtained to date are insufficient for commercial lipid production. To maximize the capture of electrons generated from substrate catabolism and thus increase substrate-to-product yields, we engineered 13 strains of Yarrowia lipolytica with synthetic pathways converting glycolytic NADH into the lipid biosynthetic precursors NADPH or acetyl-CoA. A quantitative model was established and identified the yield of the lipid pathway as a crucial determinant of overall process yield. The best engineered strain achieved a productivity of 1.2 g/L/h and a process yield of 0.27 g-fatty acid methyl esters/g-glucose, which constitutes a 25% improvement over previously engineered yeast strains. Oxygen requirements of our highest producer were reduced owing to decreased NADH oxidization by aerobic respiration. We show that redox engineering could enable commercialization of microbial carbohydrate-based lipid production. PMID- 28092658 TI - Mutation effects predicted from sequence co-variation. AB - Many high-throughput experimental technologies have been developed to assess the effects of large numbers of mutations (variation) on phenotypes. However, designing functional assays for these methods is challenging, and systematic testing of all combinations is impossible, so robust methods to predict the effects of genetic variation are needed. Most prediction methods exploit evolutionary sequence conservation but do not consider the interdependencies of residues or bases. We present EVmutation, an unsupervised statistical method for predicting the effects of mutations that explicitly captures residue dependencies between positions. We validate EVmutation by comparing its predictions with outcomes of high-throughput mutagenesis experiments and measurements of human disease mutations and show that it outperforms methods that do not account for epistasis. EVmutation can be used to assess the quantitative effects of mutations in genes of any organism. We provide pre-computed predictions for ~7,000 human proteins at http://evmutation.org/. PMID- 28092659 TI - REM sleep selectively prunes and maintains new synapses in development and learning. AB - The functions and underlying mechanisms of rapid eye movement (REM) sleep remain unclear. Here we show that REM sleep prunes newly formed postsynaptic dendritic spines of layer 5 pyramidal neurons in the mouse motor cortex during development and motor learning. This REM sleep-dependent elimination of new spines facilitates subsequent spine formation during development and when a new motor task is learned, indicating a role for REM sleep in pruning to balance the number of new spines formed over time. Moreover, REM sleep also strengthens and maintains newly formed spines, which are critical for neuronal circuit development and behavioral improvement after learning. We further show that dendritic calcium spikes arising during REM sleep are important for pruning and strengthening new spines. Together, these findings indicate that REM sleep has multifaceted functions in brain development, learning and memory consolidation by selectively eliminating and maintaining newly formed synapses via dendritic calcium spike-dependent mechanisms. PMID- 28092662 TI - Neuroimmune communication. PMID- 28092660 TI - The role of peripheral immune cells in the CNS in steady state and disease. AB - The CNS is protected by the immune system, including cells that reside directly within the CNS and help to ensure proper neural function, as well as cells that traffic into the CNS with disease. The CNS-resident immune system is comprised mainly of innate immune cells and operates under homeostatic conditions. These myeloid cells in the CNS parenchyma and at CNS-periphery interfaces are highly specialized but also extremely plastic cells that immediately react to any changes in CNS homeostasis and become reactive in the context of neurodegenerative disorders such as Alzheimer's disease or Parkinson's disease. However, when the blood-brain barrier is impaired during CNS diseases such as multiple sclerosis or altered with cerebral ischemia, peripheral adaptive and innate immune cells, including monocytes, neutrophils, T cells and B cells, can enter the CNS, where they execute distinct cell-mediated effects. On the basis of these observations, we assess strategies for targeting peripheral immune cells to reduce CNS disease burden. PMID- 28092661 TI - Interactions between the microbiota, immune and nervous systems in health and disease. AB - The diverse collection of microorganisms that inhabit the gastrointestinal tract, collectively called the gut microbiota, profoundly influences many aspects of host physiology, including nutrient metabolism, resistance to infection and immune system development. Studies investigating the gut-brain axis demonstrate a critical role for the gut microbiota in orchestrating brain development and behavior, and the immune system is emerging as an important regulator of these interactions. Intestinal microbes modulate the maturation and function of tissue resident immune cells in the CNS. Microbes also influence the activation of peripheral immune cells, which regulate responses to neuroinflammation, brain injury, autoimmunity and neurogenesis. Accordingly, both the gut microbiota and immune system are implicated in the etiopathogenesis or manifestation of neurodevelopmental, psychiatric and neurodegenerative diseases, such as autism spectrum disorder, depression and Alzheimer's disease. In this review, we discuss the role of CNS-resident and peripheral immune pathways in microbiota-gut-brain communication during health and neurological disease. PMID- 28092663 TI - Neural regulation of immunity: molecular mechanisms and clinical translation. AB - Studies bridging neuroscience and immunology have identified neural pathways that regulate immunity and inflammation. Recent research using methodological advances in molecular genetics has improved our understanding of the neural control of immunity. Here we outline mechanistic insights, focusing on translational relevance and conceptual developments. We also summarize findings from recent clinical studies of bioelectronic neuromodulation in inflammatory and autoimmune diseases. PMID- 28092664 TI - Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. AB - Low-grade, chronic inflammation has been associated with many diseases of aging, but the mechanisms responsible for producing this inflammation remain unclear. Inflammasomes can drive chronic inflammation in the context of an infectious disease or cellular stress, and they trigger the maturation of interleukin-1beta (IL-1beta). Here we find that the expression of specific inflammasome gene modules stratifies older individuals into two extremes: those with constitutive expression of IL-1beta, nucleotide metabolism dysfunction, elevated oxidative stress, high rates of hypertension and arterial stiffness; and those without constitutive expression of IL-1beta, who lack these characteristics. Adenine and N4-acetylcytidine, nucleotide-derived metabolites that are detectable in the blood of the former group, prime and activate the NLRC4 inflammasome, induce the production of IL-1beta, activate platelets and neutrophils and elevate blood pressure in mice. In individuals over 85 years of age, the elevated expression of inflammasome gene modules was associated with all-cause mortality. Thus, targeting inflammasome components may ameliorate chronic inflammation and various other age-associated conditions. PMID- 28092665 TI - Antibody 10-1074 suppresses viremia in HIV-1-infected individuals. AB - Monoclonal antibody 10-1074 targets the V3 glycan supersite on the HIV-1 envelope (Env) protein. It is among the most potent anti-HIV-1 neutralizing antibodies isolated so far. Here we report on its safety and activity in 33 individuals who received a single intravenous infusion of the antibody. 10-1074 was well tolerated and had a half-life of 24.0 d in participants without HIV-1 infection and 12.8 d in individuals with HIV-1 infection. Thirteen individuals with viremia received the highest dose of 30 mg/kg 10-1074. Eleven of these participants were 10-1074-sensitive and showed a rapid decline in viremia by a mean of 1.52 log10 copies/ml. Virologic analysis revealed the emergence of multiple independent 10 1074-resistant viruses in the first weeks after infusion. Emerging escape variants were generally resistant to the related V3-specific antibody PGT121, but remained sensitive to antibodies targeting nonoverlapping epitopes, such as the anti-CD4-binding-site antibodies 3BNC117 and VRC01. The results demonstrate the safety and activity of 10-1074 in humans and support the idea that antibodies targeting the V3 glycan supersite might be useful for the treatment and prevention of HIV-1 infection. PMID- 28092666 TI - Loss of MU opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia. AB - Opioid pain medications have detrimental side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). Tolerance and OIH counteract opioid analgesia and drive dose escalation. The cell types and receptors on which opioids act to initiate these maladaptive processes remain disputed, which has prevented the development of therapies to maximize and sustain opioid analgesic efficacy. We found that MU opioid receptors (MORs) expressed by primary afferent nociceptors initiate tolerance and OIH development. RNA sequencing and histological analysis revealed that MORs are expressed by nociceptors, but not by spinal microglia. Deletion of MORs specifically in nociceptors eliminated morphine tolerance, OIH and pronociceptive synaptic long-term potentiation without altering antinociception. Furthermore, we found that co-administration of methylnaltrexone bromide, a peripherally restricted MOR antagonist, was sufficient to abrogate morphine tolerance and OIH without diminishing antinociception in perioperative and chronic pain models. Collectively, our data support the idea that opioid agonists can be combined with peripheral MOR antagonists to limit analgesic tolerance and OIH. PMID- 28092667 TI - Oncogenic BRAF fusions in mucosal melanomas activate the MAPK pathway and are sensitive to MEK/PI3K inhibition or MEK/CDK4/6 inhibition. AB - Despite remarkable progress in cutaneous melanoma genomic profiling, the mutational landscape of primary mucosal melanomas (PMM) remains unclear. Forty six PMMs underwent targeted exome sequencing of 111 cancer-associated genes. Seventy-six somatic nonsynonymous mutations in 42 genes were observed, and recurrent mutations were noted on eight genes, including TP53 (13%), NRAS (13%), SNX31 (9%), NF1 (9%), KIT (7%) and APC (7%). Mitogen-activated protein kinase (MAPK; 37%), cell cycle (20%) and phosphatidylinositol 3-kinase (PI3K)-mTOR (15%) pathways were frequently mutated. We biologically characterized a novel ZNF767 BRAF fusion found in a vemurafenib-refractory respiratory tract PMM, from which cell line harboring ZNF767-BRAF fusion were established for further molecular analyses. In an independent data set, NFIC-BRAF fusion was identified in an oral PMM case and TMEM178B-BRAF fusion and DGKI-BRAF fusion were identified in two malignant melanomas with a low mutational burden (number of mutation per megabase, 0.8 and 4, respectively). Subsequent analyses revealed that the ZNF767 BRAF fusion protein promotes RAF dimerization and activation of the MAPK pathway. We next tested the in vitro and in vivo efficacy of vemurafenib, trametinib, BKM120 or LEE011 alone and in combination. Trametinib effectively inhibited tumor cell growth in vitro, but the combination of trametinib and BKM120 or LEE011 yielded more than additive anti-tumor effects both in vitro and in vivo in a melanoma cells harboring the BRAF fusion. In conclusion, BRAF fusions define a new molecular subset of PMM that can be targeted therapeutically by the combination of a MEK inhibitor with PI3K or cyclin-dependent kinase 4/6 inhibitors. PMID- 28092668 TI - Upregulation of RET induces perineurial invasion of pancreatic adenocarcinoma. AB - Tumor spread along nerves, a phenomenon known as perineurial invasion, is common in various cancers including pancreatic ductal adenocarcinoma (PDAC). Neural invasion is associated with poor outcome, yet its mechanism remains unclear. Using the transgenic Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, we investigated the mechanism of neural invasion in PDAC. To detect tissue-specific factors that influence neural invasion by cancer cells, we characterized the perineurial microenvironment using a series of bone marrow transplantation (BMT) experiments in transgenic mice expressing single mutations in the Cx3cr1, GDNF and CCR2 genes. Immunolabeling of tumors in KPC mice of different ages and analysis of human cancer specimens revealed that RET expression is upregulated during PDAC tumorigenesis. BMT experiments revealed that BM-derived macrophages expressing the RET ligand GDNF are highly abundant around nerves invaded by cancer. Inhibition of perineurial macrophage recruitment, using the CSF-1R antagonist GW2580 or BMT from CCR2-deficient donors, reduced perineurial invasion. Deletion of GDNF expression by perineurial macrophages, or inhibition of RET with shRNA or a small-molecule inhibitor, reduced perineurial invasion in KPC mice with PDAC. Taken together, our findings show that RET is upregulated during pancreas tumorigenesis and its activation induces cancer perineurial invasion. Trafficking of BM-derived macrophages to the perineurial microenvironment and secretion of GDNF are essential for pancreatic cancer neural spread. PMID- 28092670 TI - Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality. AB - Recent evidence has implicated the transmembrane co-receptor neuropilin-1 (NRP1) in cancer progression. Primarily known as a regulator of neuronal guidance and angiogenesis, NRP1 is also expressed in multiple human malignancies, where it promotes tumor angiogenesis. However, non-angiogenic roles of NRP1 in tumor progression remain poorly characterized. In this study, we define NRP1 as an androgen-repressed gene whose expression is elevated during the adaptation of prostate tumors to androgen-targeted therapies (ATTs), and subsequent progression to metastatic castration-resistant prostate cancer (mCRPC). Using short hairpin RNA (shRNA)-mediated suppression of NRP1, we demonstrate that NRP1 regulates the mesenchymal phenotype of mCRPC cell models and the invasive and metastatic dissemination of tumor cells in vivo. In patients, immunohistochemical staining of tissue microarrays and mRNA expression analyses revealed a positive association between NRP1 expression and increasing Gleason grade, pathological T score, positive lymph node status and primary therapy failure. Furthermore, multivariate analysis of several large clinical prostate cancer (PCa) cohorts identified NRP1 expression at radical prostatectomy as an independent prognostic biomarker of biochemical recurrence after radiation therapy, metastasis and cancer-specific mortality. This study identifies NRP1 for the first time as a novel androgen-suppressed gene upregulated during the adaptive response of prostate tumors to ATTs and a prognostic biomarker of clinical metastasis and lethal PCa. PMID- 28092669 TI - Interplay between epigenetics and metabolism in oncogenesis: mechanisms and therapeutic approaches. AB - Epigenetic and metabolic alterations in cancer cells are highly intertwined. Oncogene-driven metabolic rewiring modifies the epigenetic landscape via modulating the activities of DNA and histone modification enzymes at the metabolite level. Conversely, epigenetic mechanisms regulate the expression of metabolic genes, thereby altering the metabolome. Epigenetic-metabolomic interplay has a critical role in tumourigenesis by coordinately sustaining cell proliferation, metastasis and pluripotency. Understanding the link between epigenetics and metabolism could unravel novel molecular targets, whose intervention may lead to improvements in cancer treatment. In this review, we summarized the recent discoveries linking epigenetics and metabolism and their underlying roles in tumorigenesis; and highlighted the promising molecular targets, with an update on the development of small molecule or biologic inhibitors against these abnormalities in cancer. PMID- 28092671 TI - PDE4D promotes FAK-mediated cell invasion in BRAF-mutated melanoma. AB - The cyclic AMP (cAMP) signaling pathway is critical in melanocyte biology for regulating differentiation. It is downregulated by phosphodiesterase (PDE) enzymes, which degrade cAMP itself. In melanoma evidence suggests that inhibition of the cAMP pathway by PDE type 4 (PDE4) favors tumor progression. For example, in melanomas harboring RAS mutations, the overexpression of PDE4 is crucial for MAPK pathway activation and proliferation induced by oncogenic RAS. Here we showed that PDE4D is overexpressed in BRAF-mutated melanoma cell lines, constitutively disrupting the cAMP pathway activation. PDE4D promoted melanoma invasion by interacting with focal adhesion kinase (FAK) through the scaffolding protein RACK1. Inhibition of PDE4 activity or inhibition of PDE4D interaction with FAK reduced invasion. PDE4D expression is increased in patients with advanced melanoma and PDE4D-FAK interaction is detectable in situ in metastatic melanoma. Our study establishes the role of PDE4D in BRAF-mutated melanoma as regulator of cell invasion, and suggests its potential as a target for preventing metastatic dissemination. PMID- 28092672 TI - BPGAP1 spatially integrates JNK/ERK signaling crosstalk in oncogenesis. AB - Simultaneous hyperactivation of stress-activated protein kinase/c-Jun N-terminal protein kinase (SAPK/JNK) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling cascades has been reported in carcinogenesis. However, how they are integrated to promote oncogenesis remains unknown. By analyzing breast invasive carcinoma database (The Cancer Genome Altas), we found that the mRNA expression levels of both JNK1 and ERK2 are positively correlated with the mRNA level of EEA1, an endosome associated protein, indicating the potential JNK/ERK crosstalk at endosome. Unbiased screen of different endosome-associated Rab GTPases reveals that late endosome serves as a unique platform to integrate JNK/ERK signaling. Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation. Consequently, phosphorylated BPGAP1 facilitates endosomal ERK signaling transduction to the nucleus, driving cell proliferation and transformation via the ERK-Myc-CyclinA axis. BPGAP1 therefore provides a crucial spatiotemporal checkpoint where JNK and MP1/MEK1 work in concert to regulate endosomal and nuclear ERK signaling in cell proliferation control. PMID- 28092673 TI - IRF7 regulates the development of granulocytic myeloid-derived suppressor cells through S100A9 transrepression in cancer. AB - Accumulation of myeloid-derived suppressor cells (MDSCs) is one of the major obstacles against achieving appropriate anti-tumor immune responses and successful tumor immunotherapy. Granulocytic MDSCs (G-MDSCs) are common in tumor bearing hosts. However, the mechanisms regulating the development of MDSCs, especially G-MDSCs, remain poorly understood. In this report, we showed that interferon regulatory factor 7 (IRF7) plays an important role in the development of G-MDSCs, but not monocytic MDSCs. IRF7 deficiency caused significant elevation of G-MDSCs, and therefore enhanced tumor growth and metastasis in mice. IRF7 deletion did not affect the suppressive activity of G-MDSCs. Mechanistic studies showed that S100A9, a negative regulator of myeloid cell differentiation, was transrepressed by the IRF7 protein. S100A9 knockdown almost completely abrogated the effects of IRF7 deletion on G-MDSC development and tumor metastasis. Importantly, IRF7 expression levels negatively correlated with the G-MDSC frequency and tumor metastasis, as well as S100A9 expression, in cancer patients. In summary, our study demonstrated that IRF7 represents a novel regulator of G MDSC development in cancer, which may have predictive value for tumor progression. PMID- 28092674 TI - A targetable HB-EGF-CITED4 axis controls oncogenesis in lung cancer. AB - Aberrant epidermal growth factor (EGF) receptor (EGFR) signaling contributes to neoplastic initiation and progression in lung. Mutated EGFR has become as an important therapeutic target in lung cancer, whereas targeted treatment is not available for wild-type EGFR or its ligands. In this study, we found that heparin binding (HB)-EGF, a member of the EGF family, was highly expressed in a subset of lung cancer, proliferation of which was dependent on HB-EGF signaling. Silencing of HB-EGF with RNA interference inhibited cell cycle progression in lung cancer cells. We observed that, upon HB-EGF induction, CITED4 was induced through a signal transducer and activator of transcription 3 (STAT3)-dependent pathway, regulating cell proliferation. CITED4 interacted with MYC and potentiated MYC mediated transactivation of the CCND1 promoter, leading to cell cycle progression. Correlation analysis revealed that HB-EGF and CITED4 were significantly positively associated in primary lung tumors, and expression of HB EGF predicted a poor survival outcome in patients. In vitro and in vivo experiments revealed that pharmacological inhibition of HB-EGF with CRM197 significantly attenuated tumor cell growth. Thus, CITED4 functions as a molecular switch in HB-EGF-induced growth control, and HB-EGF provides a novel therapeutic target for lung cancer intervention. PMID- 28092675 TI - Unbalancing p53/Mdm2/IGF-1R axis by Mdm2 activation restrains the IGF-1-dependent invasive phenotype of skin melanoma. AB - Melanoma tumors usually retain wild-type p53; however, its tumor-suppressor activity is functionally disabled, most commonly through an inactivating interaction with mouse double-minute 2 homolog (Mdm2), indicating p53 release from this complex as a potential therapeutic approach. P53 and the tumor-promoter insulin-like growth factor type 1 receptor (IGF-1R) compete as substrates for the E3 ubiquitin ligase Mdm2, making their relative abundance intricately linked. Hence we investigated the effects of pharmacological Mdm2 release from the Mdm2/p53 complex on the expression and function of the IGF-1R. Nutlin-3 treatment increased IGF-1R/Mdm2 association with enhanced IGF-1R ubiquitination and a dual functional outcome: receptor downregulation and selective downstream signaling activation confined to the mitogen-activated protein kinase/extracellular signal regulated kinase pathway. This Nutlin-3 functional selectivity translated into IGF-1-mediated bioactivities with biphasic effects on the proliferative and metastatic phenotype: an early increase and late decrease in the number of proliferative and migratory cells, while the invasiveness was completely inhibited following Nutlin-3 treatment through an impaired IGF-1-mediated matrix metalloproteinases type 2 activation mechanism. Taken together, these experiments reveal the biased agonistic properties of Nutlin-3 for the mitogen-activated protein kinase pathway, mediated by Mdm2 through IGF-1R ubiquitination and provide fundamental insights into destabilizing p53/Mdm2/IGF-1R circuitry that could be developed for therapeutic gain. PMID- 28092676 TI - Intracellular IL-37b interacts with Smad3 to suppress multiple signaling pathways and the metastatic phenotype of tumor cells. AB - Multiple signaling pathways that promote tumor cell metastasis are differentially activated in low/non-metastatic and metastatic tumor cells, resulting in the differential expression of metastasis-related genes. The underlying mechanism may involve the alterations of the intrinsic negative regulation in tumor cells. Here we report that the differential expression of interleukin-37b (IL-37b) in tumor cells alters the intrinsic negative regulation of signaling pathways, resulting in the difference of metastatic capacity. IL-37b could bind Smad3 and suppress Smad pathway by interfering with the formation and nuclear translocation of Smad2/3/4 complex. In turn, Smad3 could function as a co-regulator, enabling IL 37b to suppress multiple non-Smad pathways. IL-37b-Smad3 translocated into nucleus to upregulate the expression of non-receptor protein tyrosine phosphatases (PTPNs), thus promoting dephosphorylation to suppress the activation of tyrosine phosphorylation-dependent signaling pathways such as ERK, p38 MAPK, JNK, PI3K, NF-kappaB, and STAT3 pathways. Intriguingly, 13 of 17 PTPNs, most of which are metastasis suppressors, were downregulated in metastatic tumor cells because of the low expression of IL-37b. The marked decrease of intracellular IL 37b attenuated the intrinsic negative regulation in tumor cells, resulting in the enhanced activation of multiple signaling pathways and the increased capacity of invasiveness and metastatic colonization. Consistently, low expression of IL-37b in tumors was significantly associated with poor prognosis of cancer patients. Taken together, these findings reveal that intracellular IL-37b is a critical factor in the negative regulation of multiple signaling pathways that modulate the expression of metastasis-related genes, and suggest that IL-37b expression in tumor cells can potentially be a histopathological prognostic parameter for cancer patients and a therapeutic target for preventing tumor metastasis. PMID- 28092677 TI - WNT/beta-catenin signaling regulates mitochondrial activity to alter the oncogenic potential of melanoma in a PTEN-dependent manner. AB - Aberrant regulation of WNT/beta-catenin signaling has a crucial role in the onset and progression of cancers, where the effects are not always predictable depending on tumor context. In melanoma, for example, models of the disease predict differing effects of the WNT/beta-catenin pathway on metastatic progression. Understanding the processes that underpin the highly context dependent nature of WNT/beta-catenin signaling in tumors is essential to achieve maximal therapeutic benefit from WNT inhibitory compounds. In this study, we have found that expression of the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), alters the invasive potential of melanoma cells in response to WNT/beta-catenin signaling, correlating with differing metabolic profiles. This alters the bioenergetic potential and mitochondrial activity of melanoma cells, triggered through regulation of pro-survival autophagy. Thus, WNT/beta-catenin signaling is a regulator of catabolic processes in cancer cells, which varies depending on the metabolic requirements of tumors. PMID- 28092679 TI - Genome-wide analysis of p53-regulated transcription in Myc-driven lymphomas. AB - The tumour suppressor p53 is a transcription factor that controls cellular stress responses. Here, we dissected the transcriptional programmes triggered upon restoration of p53 in Myc-driven lymphomas, based on the integrated analysis of p53 genomic occupancy and gene regulation. p53 binding sites were identified at promoters and enhancers, both characterized by the pre-existence of active chromatin marks. Only a small fraction of these sites showed the 20 base-pair p53 consensus motif, suggesting that p53 recruitment to genomic DNA was primarily mediated through protein-protein interactions in a chromatin context. p53 also targeted distal sites devoid of activation marks, at which binding was prevalently driven by sequence recognition. In all instances, the relevant motif was the canonical unsplit consensus element, with no clear evidence for p53 recruitment by split motifs. At promoters, p53 binding to the consensus motif was associated with gene induction, but not repression, indicating that the latter was most likely indirect. Altogether, our data highlight key features of genome recognition by p53 and provide unprecedented insight into the pathways associated with p53 reactivation and tumour regression, paving the way for their therapeutic application. PMID- 28092678 TI - 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 is essential for p53-null cancer cells. AB - The bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 (PFKFB4) controls metabolic flux through allosteric regulation of glycolysis. Here we show that p53 regulates the expression of PFKFB4 and that p53-deficient cancer cells are highly dependent on the function of this enzyme. We found that p53 downregulates PFKFB4 expression by binding to its promoter and mediating transcriptional repression via histone deacetylases. Depletion of PFKFB4 from p53 deficient cancer cells increased levels of the allosteric regulator fructose-2,6 bisphosphate, leading to increased glycolytic activity but decreased routing of metabolites through the oxidative arm of the pentose-phosphate pathway. PFKFB4 was also required to support the synthesis and regeneration of nicotinamide adenine dinucleotide phosphate (NADPH) in p53-deficient cancer cells. Moreover, depletion of PFKFB4-attenuated cellular biosynthetic activity and resulted in the accumulation of reactive oxygen species and cell death in the absence of p53. Finally, silencing of PFKFB4-induced apoptosis in p53-deficient cancer cells in vivo and interfered with tumour growth. These results demonstrate that PFKFB4 is essential to support anabolic metabolism in p53-deficient cancer cells and suggest that inhibition of PFKFB4 could be an effective strategy for cancer treatment. PMID- 28092680 TI - Utilizing somatic mutation data from numerous studies for cancer research: proof of concept and applications. AB - Large cancer projects measure somatic mutations in thousands of samples, gradually assembling a catalog of recurring mutations in cancer. Many methods analyze these data jointly with auxiliary information with the aim of identifying subtype-specific results. Here, we show that somatic gene mutations alone can reliably and specifically predict cancer subtypes. Interpretation of the classifiers provides useful insights for several biomedical applications. We analyze the COSMIC database, which collects somatic mutations from The Cancer Genome Atlas (TCGA) as well as from many smaller scale studies. We use multi label classification techniques and the Disease Ontology hierarchy in order to identify cancer subtype-specific biomarkers. Cancer subtype classifiers based on TCGA and the smaller studies have comparable performance, and the smaller studies add a substantial value in terms of validation, coverage of additional subtypes, and improved classification. The gene sets of the classifiers are used for threefold contribution. First, we refine the associations of genes to cancer subtypes and identify novel compelling candidate driver genes. Second, using our classifiers we successfully predict the primary site of metastatic samples. Third, we provide novel hypotheses regarding detection of subtype-specific synthetic lethality interactions. From the cancer research community perspective, our results suggest that curation efforts, such as COSMIC, have great added and complementary value even in the era of large international cancer projects. PMID- 28092682 TI - Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. AB - The extent of heterogeneity among driver gene mutations present in naturally occurring metastases-that is, treatment-naive metastatic disease-is largely unknown. To address this issue, we carried out 60* whole-genome sequencing of 26 metastases from four patients with pancreatic cancer. We found that identical mutations in known driver genes were present in every metastatic lesion for each patient studied. Passenger gene mutations, which do not have known or predicted functional consequences, accounted for all intratumoral heterogeneity. Even with respect to these passenger mutations, our analysis suggests that the genetic similarity among the founding cells of metastases was higher than that expected for any two cells randomly taken from a normal tissue. The uniformity of known driver gene mutations among metastases in the same patient has critical and encouraging implications for the success of future targeted therapies in advanced stage disease. PMID- 28092681 TI - Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance. AB - Multidrug-resistant tuberculosis (MDR-TB), caused by drug-resistant strains of Mycobacterium tuberculosis, is an increasingly serious problem worldwide. Here we examined a data set of whole-genome sequences from 5,310 M. tuberculosis isolates from five continents. Despite the great diversity of these isolates with respect to geographical point of isolation, genetic background and drug resistance, the patterns for the emergence of drug resistance were conserved globally. We have identified harbinger mutations that often precede multidrug resistance. In particular, the katG mutation encoding p.Ser315Thr, which confers resistance to isoniazid, overwhelmingly arose before mutations that conferred rifampicin resistance across all of the lineages, geographical regions and time periods. Therefore, molecular diagnostics that include markers for rifampicin resistance alone will be insufficient to identify pre-MDR strains. Incorporating knowledge of polymorphisms that occur before the emergence of multidrug resistance, particularly katG p.Ser315Thr, into molecular diagnostics should enable targeted treatment of patients with pre-MDR-TB to prevent further development of MDR-TB. PMID- 28092683 TI - Case-control association mapping by proxy using family history of disease. AB - Collecting cases for case-control genetic association studies can be time consuming and expensive. In some situations (such as studies of late-onset or rapidly lethal diseases), it may be more practical to identify family members of cases. In randomly ascertained cohorts, replacing cases with their first-degree relatives enables studies of diseases that are absent (or nearly absent) in the cohort. We refer to this approach as genome-wide association study by proxy (GWAX) and apply it to 12 common diseases in 116,196 individuals from the UK Biobank. Meta-analysis with published genome-wide association study summary statistics replicated established risk loci and yielded four newly associated loci for Alzheimer's disease, eight for coronary artery disease and five for type 2 diabetes. In addition to informing disease biology, our results demonstrate the utility of association mapping without directly observing cases. We anticipate that GWAX will prove useful in future genetic studies of complex traits in large population cohorts. PMID- 28092684 TI - Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing. AB - Deadenylases are best known for degrading the poly(A) tail during mRNA decay. The deadenylase family has expanded throughout evolution and, in mammals, consists of 12 Mg2+-dependent 3'-end RNases with substrate specificity that is mostly unknown. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia. We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase. toe1-morphant zebrafish displayed midbrain and hindbrain degeneration, modeling PCH-like structural defects in vivo. Surprisingly, we found that TOE1 associated with small nuclear RNAs (snRNAs) incompletely processed spliceosomal. These pre-snRNAs contained 3' genome-encoded tails often followed by post-transcriptionally added adenosines. Human cells with reduced levels of TOE1 accumulated 3'-end-extended pre-snRNAs, and the immunoisolated TOE1 complex was sufficient for 3'-end maturation of snRNAs. Our findings identify the cause of a neurodegenerative syndrome linked to snRNA maturation and uncover a key factor involved in the processing of snRNA 3' ends. PMID- 28092685 TI - Precision oncology for acute myeloid leukemia using a knowledge bank approach. AB - Underpinning the vision of precision medicine is the concept that causative mutations in a patient's cancer drive its biology and, by extension, its clinical features and treatment response. However, considerable between-patient heterogeneity in driver mutations complicates evidence-based personalization of cancer care. Here, by reanalyzing data from 1,540 patients with acute myeloid leukemia (AML), we explore how large knowledge banks of matched genomic-clinical data can support clinical decision-making. Inclusive, multistage statistical models accurately predicted likelihoods of remission, relapse and mortality, which were validated using data from independent patients in The Cancer Genome Atlas. Comparison of long-term survival probabilities under different treatments enables therapeutic decision support, which is available in exploratory form online. Personally tailored management decisions could reduce the number of hematopoietic cell transplants in patients with AML by 20-25% while maintaining overall survival rates. Power calculations show that databases require information from thousands of patients for accurate decision support. Knowledge banks facilitate personally tailored therapeutic decisions but require sustainable updating, inclusive cohorts and large sample sizes. PMID- 28092687 TI - A charge density wave-like instability in a doped spin-orbit-assisted weak Mott insulator. AB - Layered perovskite iridates realize a rare class of Mott insulators that are predicted to be strongly spin-orbit coupled analogues of the parent state of cuprate high-temperature superconductors. Recent discoveries of pseudogap, magnetic multipolar ordered and possible d-wave superconducting phases in doped Sr2IrO4 have reinforced this analogy among the single layer variants. However, unlike the bilayer cuprates, no electronic instabilities have been reported in the doped bilayer iridate Sr3Ir2O7. Here we show that Sr3Ir2O7 realizes a weak Mott state with no cuprate analogue by using ultrafast time-resolved optical reflectivity to uncover an intimate connection between its insulating gap and antiferromagnetism. However, we detect a subtle charge density wave-like Fermi surface instability in metallic electron doped Sr3Ir2O7 at temperatures (TDW) close to 200 K via the coherent oscillations of its collective modes, which is reminiscent of that observed in cuprates. The absence of any signatures of a new spatial periodicity below TDW from diffraction, scanning tunnelling and photoemission based probes suggests an unconventional and possibly short-ranged nature of this density wave order. PMID- 28092686 TI - Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. AB - During the progression of pancreatic ductal adenocarcinoma (PDAC), heterogeneous subclonal populations emerge that drive primary tumor growth, regional spread, distant metastasis, and patient death. However, the genetics of metastases largely reflects that of the primary tumor in untreated patients, and PDAC driver mutations are shared by all subclones. This raises the possibility that an epigenetic process might operate during metastasis. Here we report large-scale reprogramming of chromatin modifications during the natural evolution of distant metastasis. Changes were targeted to thousands of large chromatin domains across the genome that collectively specified malignant traits, including euchromatin and large organized chromatin histone H3 lysine 9 (H3K9)-modified (LOCK) heterochromatin. Remarkably, distant metastases co-evolved a dependence on the oxidative branch of the pentose phosphate pathway (oxPPP), and oxPPP inhibition selectively reversed reprogrammed chromatin, malignant gene expression programs, and tumorigenesis. These findings suggest a model whereby linked metabolic epigenetic programs are selected for enhanced tumorigenic fitness during the evolution of distant metastasis. PMID- 28092688 TI - Buckled two-dimensional Xene sheets. AB - Silicene, germanene and stanene are part of a monoelemental class of two dimensional (2D) crystals termed 2D-Xenes (X = Si, Ge, Sn and so on) which, together with their ligand-functionalized derivatives referred to as Xanes, are comprised of group IVA atoms arranged in a honeycomb lattice - similar to graphene but with varying degrees of buckling. Their electronic structure ranges from trivial insulators, to semiconductors with tunable gaps, to semi-metallic, depending on the substrate, chemical functionalization and strain. More than a dozen different topological insulator states are predicted to emerge, including the quantum spin Hall state at room temperature, which, if realized, would enable new classes of nanoelectronic and spintronic devices, such as the topological field-effect transistor. The electronic structure can be tuned, for example, by changing the group IVA element, the degree of spin-orbit coupling, the functionalization chemistry or the substrate, making the 2D-Xene systems promising multifunctional 2D materials for nanotechnology. This Perspective highlights the current state of the art and future opportunities in the manipulation and stability of these materials, their functions and applications, and novel device concepts. PMID- 28092689 TI - Three-dimensional imaging of dislocation dynamics during the hydriding phase transformation. AB - Crystallographic imperfections significantly alter material properties and their response to external stimuli, including solute-induced phase transformations. Despite recent progress in imaging defects using electron and X-ray techniques, in situ three-dimensional imaging of defect dynamics remains challenging. Here, we use Bragg coherent diffractive imaging to image defects during the hydriding phase transformation of palladium nanocrystals. During constant-pressure experiments we observe that the phase transformation begins after dislocation nucleation close to the phase boundary in particles larger than 300 nm. The three dimensional phase morphology suggests that the hydrogen-rich phase is more similar to a spherical cap on the hydrogen-poor phase than to the core-shell model commonly assumed. We substantiate this using three-dimensional phase field modelling, demonstrating how phase morphology affects the critical size for dislocation nucleation. Our results reveal how particle size and phase morphology affects transformations in the PdH system. PMID- 28092690 TI - Post-translational selective intracellular silencing of acetylated proteins with de novo selected intrabodies. AB - The ability to selectively interfere with post-translationally modified proteins would have many biological and therapeutic applications. However, post translational modifications cannot be selectively targeted by nucleic-acid-based interference approaches. Here we describe post-translational intracellular silencing antibody technology (PISA), a method for selecting intrabodies against post-translationally modified proteins. We demonstrate our method by generating intrabodies against native acetylated proteins and showing functional interference in living cells. PMID- 28092691 TI - Effective detection of variation in single-cell transcriptomes using MATQ-seq. AB - The quantification of transcriptional variation in single cells, particularly within the same cell population, is currently limited by the low sensitivity and high technical noise of single-cell RNA-seq assays. We report multiple annealing and dC-tailing-based quantitative single-cell RNA-seq (MATQ-seq), a highly sensitive and quantitative method for single-cell sequencing of total RNA. By systematically determining technical noise, we show that MATQ-seq captures genuine biological variation between whole transcriptomes of single cells. PMID- 28092692 TI - SMiLE-seq identifies binding motifs of single and dimeric transcription factors. AB - Resolving the DNA-binding specificities of transcription factors (TFs) is of critical value for understanding gene regulation. Here, we present a novel, semiautomated protein-DNA interaction characterization technology, selective microfluidics-based ligand enrichment followed by sequencing (SMiLE-seq). SMiLE seq is neither limited by DNA bait length nor biased toward strong affinity binders; it probes the DNA-binding properties of TFs over a wide affinity range in a fast and cost-effective fashion. We validated SMiLE-seq by analyzing 58 full length human, mouse, and Drosophila TFs from distinct structural classes. All tested TFs yielded DNA-binding models with predictive power comparable to or greater than that of other in vitro assays. De novo motif discovery on all JUN FOS heterodimers and several nuclear receptor-TF complexes provided novel insights into partner-specific heterodimer DNA-binding preferences. We also successfully analyzed the DNA-binding properties of uncharacterized human C2H2 zinc-finger proteins and validated several using ChIP-exo. PMID- 28092693 TI - Pathogenic Streptococcus strains employ novel escape strategy to inhibit bacteriostatic effect mediated by mammalian peptidoglycan recognition protein. AB - Pathogenic streptococcal species are responsible for some of the most lethal and prevalent animal and human infections. Previous reports have identified a candidate pathogenicity island (PAI) in two highly virulent clinical isolates of Streptococcus suis type 2, a causative agent of high-mortality streptococcal toxic shock syndrome. This PAI contains a type-IVC secretion system C subgroup (type-IVC secretion system) that is involved in the secretion of unknown pathogenic effectors that are responsible for streptococcal toxic shock syndrome caused by highly virulent strains of S. suis. Both virulence protein B4 and virulence protein D4 were demonstrated to be key components of this type-IVC secretion system. In this study, we identify a new PAI family across 3 streptococcal species; Streptococcus genomic island contains type-IV secretion system, which contains a genomic island type-IVC secretion system and a novel PPIase molecule, SP1. SP1 is shown to interact with a component of innate immunity, peptidoglycan recognition protein (PGLYRP-1) and to perturb the PGLYRP 1-mediated bacteriostatic effect by interacting with protein PGLYRP-1. Our study elucidates a novel mechanism by which bacteria escape by components of the innate immune system by secretion of the SP1 protein in pathogenic Streptococci, which then interacts with PGLYRP-1 from the host. Our results provide potential targets for the development of new antimicrobial drugs against bacteria with resistance to innate host immunity. PMID- 28092694 TI - Proton pump inhibitors: Risks of long-term use. AB - Proton pump inhibitors are among the most commonly prescribed classes of drugs, and their use is increasing, in particular for long-term treatment, often being over-prescribed and used for inappropriate conditions. In recent years, considerable attention has been directed towards a wide range of adverse effects, and even when a potential underlying biological mechanism is plausible, the clinical evidence of the adverse effect is often weak. Several long-term side effects have been investigated ranging from interaction with other drugs, increased risk of infection, reduced intestinal absorption of vitamins and minerals, and more recently kidney damage and dementia. The most recent literature regarding these adverse effects and their association with long-term proton pump inhibitor treatment is reviewed, and the mechanisms through which these possible complications might develop are discussed. PMID- 28092698 TI - Microfluidics and Miniaturization 2017. PMID- 28092695 TI - Absorption, distribution and excretion of the anti-tuberculosis drug delamanid in rats: Extensive tissue distribution suggests potential therapeutic value for extrapulmonary tuberculosis. AB - Delamanid (OPC-67683, DeltybaTM, nitro-dihydro-imidazooxazoles derivative) is approved for the treatment of adult pulmonary multidrug-resistant tuberculosis. The absorption, distribution and excretion of delamanid-derived radioactivity were investigated after a single oral administration of 14 C-delamanid at 3 mg/kg to rats. In both male and female rats, radioactivity in blood and all tissues reached peak levels by 8 or 24 h post-dose, and thereafter decreased slowly. Radioactivity levels were 3- to 5-fold higher in lung tissue at time to maximum concentration compared with plasma. In addition, radioactivity was broadly distributed in various tissues, including the central nervous system, eyeball, placenta and fetus, indicating that 14 C-delamanid permeated the brain, retinal and placental blood barriers. By 168 h post-dose, radioactivity in almost all the tissues was higher than that in the plasma. Radioactivity was also transferred into the milk of lactating rats. Approximately 6% and 92% of radioactivity was excreted in the urine and feces, respectively, indicating that the absorbed radioactivity was primarily excreted via the biliary route. No significant differences in the absorption, distribution and excretion of 14 C-delamanid were observed between male and female rats. The pharmacokinetic results suggested that delamanid was broadly distributed to the lungs and various tissues for a prolonged duration of time at concentrations expected to effectively target tuberculosis bacteria. These data indicate that delamanid, in addition to its previously demonstrated efficacy in pulmonary tuberculosis, might be an effective therapeutic approach to treating extrapulmonary tuberculosis. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28092699 TI - Infection of human intestinal epithelial cells by invasive bacteria activates NF kappaB and increases ICAM-1 expression through NOD1. AB - BACKGROUND/AIMS: Nucleotide-binding oligomerization domain 1 (NOD1) is required for primary intestinal epithelial cells (IECs) to respond to natural mucopeptides secreted by gram-negative bacteria. Infection of human IECs with invasive bacteria up-regulates intercellular adhesion molecule-1 (ICAM-1) expression. However, the role of NOD family members in host defense has been largely unknown. The aim of this study was to determine whether there is a functional role for NOD1 in the up-regulation of ICAM-1 expression in invasive bacteria-infected IECs. METHODS: ICAM-1 mRNA expression was compared between controls, Caco-2 or HT29 cells transfected with an empty vector, and IECs stably transfected with a dominant-negative (DN) NOD1. Expression was compared using qualitative reverse transcription polymerase chain reaction (RT-PCR), real-time RT-PCR, and flow cytometry after infection with enteroinvasive Escherichia coli O29:NM or Shigella flexneri. Nuclear factor kB (NF-kappaB) activation was determined by electrophoretic mobility shift assays. RESULTS: DN NOD1 significantly inhibited the up-regulation of ICAM-1 expression in response to an enteroinvasive bacterial infection. The Caco-2 cells transfected with DN NOD1 manifested marked inhibition of NF-kB activation in response to E. coli O29:NM infection. CONCLUSIONS: Signaling through NOD1 may play an essential role in neutrophil trafficking following infection with enteroinvasive bacteria. PMID- 28092700 TI - Association between thyroid autoimmunity and Helicobacter pylori infection. AB - BACKGROUND/AIMS: There have been controversial reports linking Helicobacter pylori infection to autoimmune thyroid disease (AITD). However, data regarding the relationship are limited for Asian populations, which have an extremely high prevalence of H. pylori infection. We performed this study to investigate the association between H. pylori infection and AITD in Koreans. METHODS: This study involved adults aged 30 to 70 years who had visited a health promotion center. A total of 5,502 subjects were analysed. Thyroid status was assessed by free thyroxine, thyroid stimulating hormone, and anti-thyroid peroxidase antibody (TPO Ab). Immunoglobulin G (IgG) antibodies to H. pylori were measured as an indication of H. pylori infection. We compared the prevalence of TPO-Ab in subjects with and without H. pylori infection. RESULTS: H. pylori IgG antibodies were found in 2,875 subjects (52.3%), and TPO-Ab were found in 430 (7.8%). Individuals positive for H. pylori Ab were older than those negative for H. pylori Ab (p < 0.01). The proportion of females was significantly higher in the TPO-Ab positive group (41.0% vs. 64.2%, p < 0.01). Prevalence of TPO-Ab positivity was higher in subjects with H. pylori infection (8.6% vs. 7.00%, p = 0.03), and this association was significant after adjusting for age, sex, and body mass index (odds ratio, 1.02; 95% confidence interval, 1.00 to 1.03; p = 0.04). CONCLUSIONS: In our study, prevalence of TPO-Ab positivity is more frequent in subjects with H. pylori infection. Our findings suggest H. pylori infection may play a role in the development of autoimmune thyroiditis. PMID- 28092701 TI - Hypogonadotrophic hypogonadism due to a mutation in the luteinizing hormone beta subunit gene. PMID- 28092702 TI - Multiple metastasis of follicular variant of papillary thyroid carcinoma coexistent with malignant melanoma. PMID- 28092703 TI - Enantioselective Three-Component Amination of Enecarbamates Enables the Synthesis of Structurally Complex Small Molecules. AB - The control of asymmetric synthesis tools represents a major challenge, especially when it comes to the synthesis of bioactive molecules. In this context, the asymmetric synthesis of 1,2-diamines through amination of enecarbamates has been proposed as a highly efficient and tunable approach. Indeed, reactivity of the latter species could be exploited to realize a double functionalization via an electrophilic amination followed by nucleophilic trapping. Herein, we describe a chiral phosphoric acid catalyzed electrophilic amination of enecarbamates with dibenzyl azodicarboxylate and oxygenated or thiol containing nucleophiles affording stable precursors of alpha-hydrazinoimines in high yields and with almost complete enantioselectivities (up to >99%). These precursors were successfully functionalized with various silylated nucleophiles without epimerization of the stereogenic center, giving access to a wide range of 1,2-disubstituted 1,2-diamines. We also show that the thiolated precursors were successfully engaged in a Friedel-Crafts reaction against a variety of aromatic and heteroaromatic nucleophiles, leading to various 1-(hetero)aryl-1,2-diamines without loss of enantioselectivity and with complete diastereoselectivity. Reductive N-N bond cleavage provided the N,N-diprotected 1,2-diamines with no loss in diastereo- or enantioselectivity. The protocol was successfully scaled up to a multigram scale and the catalyst was successfully recovered, demonstrating the potential applications of this new methodology. PMID- 28092704 TI - X-ray Reflectivity Study of the Interaction of an Imidazolium-Based Ionic Liquid with a Soft Supported Lipid Membrane. AB - Ionic liquids (ILs) are important for their antimicrobial activity and are found to be toxic to some microorganisms. To shed light on the mechanism of their activities, the interaction of an imidazolium-based IL 1-butyl-3 methylimidazolium tetrfluoroborate ([BMIM][BF4]) with E. coli bacteria and cell membrane-mimicking lipid mono- and bilayers has been studied. The survival of the bacteria and corresponding growth inhibition are observed to be functions of the concentration of the IL. The IL alters the pressure-area isotherm of the monolayer formed at an air-water interface by the 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC) lipid. The in-plane elasticity of the lipid layer is reduced as a consequence of the insertion of this IL. The X-ray reflectivity study from a polymer-supported lipid bilayer shows strong perturbation in the self-assembled structure of the bilayer due to the interaction. As a consequence, there is a considerable decrease in bilayer thickness and a corresponding increase in electron density. These results, however, depend on the chain configurations of the lipid molecules. PMID- 28092706 TI - [Editor's Note: The Man as Integrating Center of Bioethics]. PMID- 28092705 TI - O-H Activation by an Unexpected Ferryl Intermediate during Catalysis by 2 Hydroxyethylphosphonate Dioxygenase. AB - Activation of O-H bonds by inorganic metal-oxo complexes has been documented, but no cognate enzymatic process is known. Our mechanistic analysis of 2 hydroxyethylphosphonate dioxygenase (HEPD), which cleaves the C1-C2 bond of its substrate to afford hydroxymethylphosphonate on the biosynthetic pathway to the commercial herbicide phosphinothricin, uncovered an example of such an O-H-bond cleavage event. Stopped-flow UV-visible absorption and freeze-quench Mossbauer experiments identified a transient iron(IV)-oxo (ferryl) complex. Maximal accumulation of the intermediate required both the presence of deuterium in the substrate and, importantly, the use of 2H2O as solvent. The ferryl complex forms and decays rapidly enough to be on the catalytic pathway. To account for these unanticipated results, a new mechanism that involves activation of an O-H bond by the ferryl complex is proposed. This mechanism accommodates all available data on the HEPD reaction. PMID- 28092707 TI - [Introduction. What is Environmental Ethics? From its Roots to the Future]. PMID- 28092708 TI - [Applying Ethics, Placating Ethics, or Applying ourselves to Ethics? A Critical View of Environmental Ethics as Applied Ethics]. AB - There is actually a pervasive tendency to consider environmental ethics and bioethics as specific cases pertaining to a supposed kind of "applied ethics". Application can be understood in two different meanings: a concrete sense, as in technical applications, and a psychological meaning, as when we mentally apply ourselves to a task. Ethics has been always thought as a practical knowledge, in a "praxical" sense and not in a "poietic" one. Ethics has to do with "ends" not with "means"; in this sense ethics is "useless". Since ethics has to do with the ultimate meaning of things, ethical choices give meaning to all practical activities. In that sense ethics instead of being useless must be considered as "over-useful" (Maritain). Nowadays politics tend to instrumentalize ethics in order to political objectives. The consequence has been the reconceptualization of specific ethics as applied ethics. Environmental ethics and bioethics are then submitted to politics following the logic of technical applications. Environmental ethics and bioethics considered as applied ethics are at risk to becoming not only useless, but also meaningless. PMID- 28092709 TI - The Centrality of Philosophical Anthropology to (a Future) Environmental Ethics. AB - While environmental ethics has successfully established itself in philosophy, as presently conceived it is still largely irrelevant to grappling the global ecological crisis because, as Alasdair MacIntyre has argued, ethical philosophy itself is in grave disorder. MacIntyre's historically oriented recovery of virtue ethics is defended, but it is argued that even MacIntyre was too constrained by received assumptions to overcome this disorder. As he himself realized, his ideas need to be integrated and defended through philosophical anthropology. However, it is suggested that current defenders of philosophical anthropology have not done it justice. To appreciate its importance it is necessary accept that we are cultural beings in which the core of culture is the conception of what are humans. This is presupposed not only in thought but in social practices and forms of life. This was understood by Aristotle, but modernity has been straightjacketed by the Seventeenth Century scientific revolution and Hobbes' philosophical anthropology, identifying knowledge and with techno-science and eliminating any place for questioning this conception of humans. The only conception of humanity that could successfully challenge and replace Hobbes' philosophical anthropology, it is argued, is Hegel's philosophical anthropology reformulated and developed on naturalistic foundations. This involves subordinating science to a reconceived humanities with a fundamentally different role accorded to ethics, placing it at the center of social life, politics and economics and at the centre of the struggle to transform culture and society to create an ecologically sustainable civilization. PMID- 28092710 TI - [Sobre la (No) Responsabilidad de la Tecnociencia en los Problemas Ambientales y la Busqueda de Politica]. AB - In this paper I propose to reflect upon modern configuration of technique, i.e., technoscience, and our responsibility towards environmental management. I show that the technological products of our world imply a certain attitude of aggression towards nature, contrasting with the attitude of protection from her, which was peculiar of the pre-technological world. Finally I suggest recovering the classical notion of politics as a possible alternative for controlling techno scientific imperatives. PMID- 28092711 TI - [The Future of Ecology: Wisdom as The Speculative Centre of Environmental Ethics]. AB - This article argues that it is necessary to go back to Potter's proposal to rediscover a concept of bioethics wider than medical ethics, and strongly connected to environmental ethics. The two disciplines share, among others, the following dimensions: the consciousness of the sin as a consequence of recent technological developments; the need for a salvation; the need for a science of survival; wisdom as a possible solution. Referring to the latter, the work of Van Rennselaer Potter (father of bioethics) and Arne Naess (father of deep ecology, and in a broader sense, of environmental ethics) are particularly linked: it seems that wisdom should be the virtue providing answers about our way of dwelling the world. Finally, we will argue about the need for a practical wisdom (phronesis) for the future of environmental ethics. PMID- 28092712 TI - [Global Bioethics and Biocultural Ethics]. AB - The biocultural ethic recovers an understanding of the vital links between the life habits of the coinhabitants (humans and other-than-human) that share a habitat. The "3Hs" formal framework of the biocultural ethics provides a conceptual and methodological tool to understand and to better manage complex eco social or biocultural systems in heterogeneous regions of the planet. From the global bioethics originally proposed by V.R. Potter, the integration of theory and praxis promoted by Alfredo Pradenas in the Bioethics Society of Chile, and the conceptual framework of biocultural ethics (including traditions of philosophical thought, scientific and Amerindians), I develop a comparative analysis of: 1. an ecosystemic and intercultural concept of the human body, 2. an intercultural understanding of health with complementary Western and Native American medicinal practices, and 3. an appreciation and respect for the fundamental links among the life habits, the habitats where they take place, and the well-being and identity of the communities of cohabitants. Implicit links in the "3Hs" biocultural ethics are present in the archaic meanings of the term ethos. This understanding retrieves a primordial root in the genesis of Western ethics, which did not start bounded to how to inhabit or dwell, but also considered where to inhabit and with whom to co-inhabit. I propose to restore the complexity and breadth of the concept of ethics originated in Ancient Greece, to reaffirm the common roots of bioethics and environmental ethics contained in Potter's global bioethics, and to incorporate the systemic and contextual perspective of the biocultural ethic that values biological and cultural diversity (and their interrelationships), to sustain a conception of human health interconnected with the sustainability of the biosphere. PMID- 28092713 TI - "The Anthropocene", Ecosystem Management, and Environmental Virtue. AB - *Portions of this article are drawn from: Sandler, R. Environmental Ethics: Theory in Practice, Oxford University Press, New York, in press. In this article I consider contrasting views on the implications of rapid, macroscale anthropogenic change for environmental ethics, particularly ecosystem management, species conservation, and environmental virtue. I begin by reviewing the Anthropocene debate, which has become a primary point of discourse on whether we ought to embrace a more interventionist stance regarding ecosystem management and species conservation. I then discuss the challenges posed by rapid ecological change to predominant ecosystem management and species conservation practices. I argue that these challenges not withstanding, we ought not go all in on interventionist management, even as novel conservation and management techniques can be justified in particular cases. It is possible to adopt a more forward looking normative stance, without licensing robust interventionism. Finally, I discuss the implications of this for some environmental virtues. PMID- 28092714 TI - The Food in our Future: Where Will We Find Ethics? AB - Food and agricultural systems are in large part driven by technology. Together with public policy, the kinds of technologies that are induced into, or chosen by actors in, food systems, dictates their structure and activities. The "Big Story" or ideology which underlies research, development and adoption of technologies provides the justification for choices we make about the future of the food system. A combination of productionism -more is better, and "feed the world"- is what governs, and seems to be what will govern Western food systems. Important ethical questions include whether more is better and whether we will feed the world with our technology and policy. But a parallel question is how will we include critical consideration of the continued legitimacy of our Big Story? This system, after all, has worked well for the past century. PMID- 28092715 TI - [Family: a Challenge for the Future of our Earth]. AB - The Universal Declaration of Human Rights recognizes the family as the basic cell of society, highlighting its importance, the need to protect it, to promote it as a natural and fundamental group unit of society. To reflect on the effects that the actual culture is in the family is important from the situation as it is now presented, then move to raise the changes seen necessary to ensure their own future and that of their habitat that is Earth. To accomplish this first task some study results World Family Map 2015 is glossed. Later reflections on the binomial environmental ecology and human ecology, where the importance of adequate from anthropological concepts to succeed in each of these fields. The current decline of culture directly affects the family by undermining one of its main bases, human love, which is a real threat. They are proposed some challenges for the family and mentioned strategies to address them. As outlined that conclusion not to follow the activity of endangering the human species and destroy the planet, it is necessary to change the current social structure and culture, beginning with the family; must be helped to become aware of their problems and limitations, so that later you can give truly human solutions to these problems, almost always produced by the same man. PMID- 28092716 TI - View Points of an Ecologist on Practical Environmental Ethic: Socioecology, Common-Pool Resources and Conservation. AB - The paper centers on environmental practical ethic point of views according to a professional ecologist. Ecology and the science of Socio-ecology are defined. The framework of the Millennium Ecosystem Assessment initiative (MA 2003), including the use of ecosystems as the environmental unit of analysis, ecosystem services and human well-being as the center for assessment are discussed. Common-pool resources (CPR) and the allegory of the tragedy of the commons are used to illustrate main scientific and ethical environmental approaches, and above all to highlight the case of climate change, considering "air-atmosphere" as a CPR. The need to adopt practical personal environmental ethical positions is highlighted. Furthermore, on climate change, a discussion on the need to develop environmental and socio-ecological polycentric approaches: top-down and bottom-up, is included. An updated discussion on the concept of conservation, including main scientific and ethic points of view, is presented. Pope Francis's Encyclical, Laudato Si', is used to highlight environmental, socio-ecological and ethical aspects behind the comprehensive concept of Integral Ecology. The paper ends with a short synthesis on Earth modern unseen and astonishing environmental and socio ecological rates of changes, and identifying the main barriers for personal environmental engagement. A call is done regarding the urgent need for socio environmental ethic personal engagement and collective actions. PMID- 28092717 TI - The Culture War, Modern Economics, and Environmental Education in The United States. AB - Teaching ethics in public schools in the United States has been made almost impossible because of the Culture War and Modern Economics. When Catholics began to migrate to the United States in the early nineteenth century, they found that Protestant religion and ethics were taught in public schools and they created their own parochial schools. This controversy has continued for two hundred years. To encourage the Catholics to send their children to the public schools, by 1860 religion and ethics had been removed from the public schools. Concern about the teaching of ethics spread to other religious and non-religious groups. These groups attack the teaching of ethics as the indoctrination of the personal values of teachers, and when teachers include alternative ethical views to avoid indoctrination they are accused of relativism. According to Modern Economics, value terms are meaningless unless they have been translated into economic terms based on willingness to pay. This approach overlooks the social values that make up the cultural heritage of a society. Although children acquire these social values tacitly, since they are not taught these values as a common heritage, they come to believe that they invented them ahistorically and that they are just how they feel (ethical emotivism). By teaching children social values as a common heritage, the charges of indoctrination and relativism and the replacement of these values with economic terms can be avoided, later permitting a more objective role for ethics in public affairs among adults. PMID- 28092719 TI - [Commentary on The Case: Request for Vasectomy Reversion in HIV Male with Serodiscordant Couple]. PMID- 28092718 TI - [Case: Request for Vasectomy Reversion in HIV Male with Serodiscordant Couple]. PMID- 28092720 TI - [Rethinking Intellectual Disability: A Professor, a Family and an Exceptional Child]. PMID- 28092721 TI - Use of MALDI-TOF mass spectrometry in the battle against bacterial infectious diseases: recent achievements and future perspectives. AB - INTRODUCTION: Advancements in microbial identification occur increasingly faster as more laboratories explore, refine and extend the use of mass spectrometry in the field of microbiology. Areas covered: This review covers the latest knowledge found in the literature for quick identification of various classes of bacterial pathogens known to cause human infection by the use of MALDI-TOF MS technology. Except for identification of bacterial strains, more researchers try to 'battle time' in favor of the patient. These novel approaches to identify bacteria directly from clinical samples and even determine antibiotic resistance are extensively revised and discussed. Expert commentary: Mass spectrometry is the future of bacterial identification and creates a new era in modern microbiology. Its incorporation in routine practice seems to be not too far, providing a valuable alternative, especially in terms of time, to conventional techniques. If the technology further advances, quick bacterial identification and probable identification of common antibiotic resistance might guide patient decision making regarding bacterial infectious diseases in the near future. PMID- 28092722 TI - Synthetic and natural Peroxisome Proliferator-Activated Receptor (PPAR) agonists as candidates for the therapy of the metabolic syndrome. AB - INTRODUCTION: Peroxisome proliferator-activated receptors (PPARs) are the molecular targets of hypolipidemic and insulin-sensitizing drugs and implicated in a multitude of processes that fine-tune the functions of all organs in vertebrates. As transcription factors they sense endogenous and exogenous lipid signaling molecules and convert these signals into intricate gene responses that impact health and disease. The PPARs act as modulators of cellular, organ, and systemic processes, such as lipid and carbohydrate metabolism, making them valuable for understanding body homeostasis influenced by nutrition and exercise. Areas covered: This review concentrates on synthetic and natural PPAR ligands and how they have helped reveal many aspects of the transcriptional control of complex processes important in health. Expert opinion: The three PPARs have complementary roles in the fine-tuning of most fundamental body functions, especially energy metabolism. Understanding their inter-relatedness using ligands that simultaneously modulate the activity of more than one of these receptors is a major goal. This approach may provide essential knowledge for the development of dual or pan-PPAR agonists or antagonists as potential new health-promoting agents and for nutritional approaches to prevent metabolic diseases. PMID- 28092723 TI - Pertuzumab and breast cancer: another piece in the anti-HER2 puzzle. AB - INTRODUCTION: The mechanism of action of pertuzumab, a recombinant anti-HER2 humanized monoclonal antibody, is complementary to trastuzumab's. On 8 June 2012, the Food and Drug Administration approved the combination of pertuzumab with trastuzumab and docetaxel as first-line treatment of HER2-positive metastatic breast cancer. Furthermore, pertuzumab is the first drug to be approved in the neoadjuvant setting using a pathological complete response as an endpoint. Areas covered: The review provides insights into the main mechanisms of action of pertuzumab. In addition, it gives complete coverage of the landmark clinical and translational trials for this agent. Expert opinion: The new therapeutic algorithm in the treatment of HER2-positive advanced disease and the awaited results of the Aphinity trial are expected to impact the sequence of anti-HER2 treatment. Accordingly, the value of pertuzumab beyond progression needs to be properly studied. Furthermore, to improve the toxicity profile and efficacy of future treatment, new pertuzumab-based regimens are being investigated. PMID- 28092724 TI - The pediatric Rome IV criteria: what's new? AB - INTRODUCTION: Functional gastrointestinal disorders (FGIDs) are common in children of all ages and comprise of a wide range of conditions related to the gastrointestinal tract that cannot be attributed to structural or biochemical abnormalities. FGIDs are diagnosed according to the symptom-based Rome criteria. Areas covered: In 2016, the revised pediatric Rome IV criteria were published, these revised criteria are discussed in this review article. For the youngest age group (neonates/toddlers), the criteria for infant colic have undergone the most notable revisions. The most prominent changes in Rome IV were made in the criteria for children/adolescents, with the definition of two new FGIDs (functional nausea and functional vomiting) and the restructuring of the criteria for functional abdominal pain disorders, including the definition of FGID subtypes for functional dyspepsia and irritable bowel syndrome. Expert commentary: Overall, the Rome IV have been refined and are expected to improve the process of diagnosing FGIDs in the pediatric population and to better facilitate the healthcare professional in distinguishing different clinical entities. These changes will likely benefit future research and clinical care. PMID- 28092725 TI - Strontium ranelate, a promising disease modifying osteoarthritis drug. AB - INTRODUCTION: The articular cartilage and subchondral bone may have potential crosstalk in the development and progression of osteoarthritis (OA). Strontium ranelate (SrR) has the ability to dissociate the bone remodeling process and to change the balance between bone resorption and bone formation. Its effect on subchondral bone makes it a potential disease- modifying osteoarthritis drug (DMOAD) in the treatment of OA. The aim of the current review is to summarize up to-date pharmacological and clinical data of SrR for OA treatment. Areas covered: A literature search was performed on PubMed and European Medicines Agency (EMA) website for all publications and documents related to SrR and OA. References of related studies were searched by hand. Treatment with SrR, especially at the dosage of 2 g/day, was associated with reduced radiographic knee OA progression, and with meaningful clinical improvement. It was also significantly associated with decreased MRI-assessed cartilage volume loss (CVL) and bone marrow lesions (BMLs). Expert opinion: SrR could be a promising DMOAD particularly for OA patients with bone phenotypes. The clinical efficacy and side effects of SrR for OA treatment need to be further investigated in future clinical trials before clinical application. PMID- 28092726 TI - Pathophysiology, incidence and predictors of conduction disturbances during Transcatheter Aortic Valve Implantation. AB - INTRODUCTION: Over the past decade, transcatheter aortic valve implantation (TAVI) has evolved rapidly toward an extremely reproducible, safe and effective procedure, with a marked reduction of its related complications. However, the occurrence of conduction disturbances and the need for permanent pacemaker implantation (PPI) after TAVI remains a concern. Areas covered: In this article review, we will go through the mechanisms involved in conduction disturbances after TAVI, and we will discuss the key aspects of pathophysiology, incidence and predictors of conduction disturbances following Transcatheter Aortic Valve Implantation. The evaluation of patient's valve anatomy and the selection of the most appropriate prosthesis have been proposed as a valuable options to reduce the incidence of conductions disturbances. Moreover, in recent times, a great number of new TAVI devices, so-called 'second-generation devices', have been introduced to address the limitations of the first-generation devices, including conduction disturbance, with scarce results. Expert commentary: Conduction disturbances after TAVI are increasingly recognized as an important issue in TAVI complications. Further characterization of the procedural- and patient-related factors that contribute to the development of conduction abnormalities will help to improve prosthesis designs and patient selection, making TAVI even more safer. PMID- 28092727 TI - Sitting ducks face chronic disease: an analysis of newspaper coverage of sedentary behaviour as a health issue in Australia 2000-2012. AB - Issue addressed This study examines how sedentary behaviour (too much sitting) was covered as a health issue by Australian newspapers and how physical activity was framed within this newspaper coverage. Methods Articles featuring sedentary behaviour published in Australian newspapers between 2000 and 2012 were analysed for content and framing. Main outcome measures were volume, number and content of newspaper articles; framing and types of sedentary behaviour; responsibility for the problem of and solutions to high levels of sedentary behaviour; and physical activity mentions and how it was framed within sedentary behaviour coverage. Results Out of 48 articles, prolonged sitting was framed as bad for health (52%) and specifically as health compromising for office workers (25%). Adults who sat a lot were framed as 'easy targets' for ill health (21% of headlines led with 'sitting ducks' or 'sitting targets'). Prolonged sitting was framed as an issue of individual responsibility (>90%) with less mention of environmental and sociocultural contributors. Thirty-six of 48 articles mentioned physical activity; 39% stated that being physically active does not matter if a person sits for prolonged periods of time or that the benefits of physical activity are undone by too much sitting. Conclusions News coverage should reflect the full socio-ecological model of sedentary behaviour and continually reinforce the independent and well-established benefits of health-enhancing physical activity alongside the need to limit prolonged sitting. So what? It is important that the entire 'move more, sit less, every day!' message is communicated by news media. PMID- 28092728 TI - Effect of time interval between the second Improvest(r) dose and slaughter and corn dried distillers grains with solubles feeding strategies on carcass composition, primal cutout, and pork quality of immunologically castrated pigs. AB - Effects of dried distillers grains with solubles (DDGS) feeding strategies on carcass composition, primal cutout, and lean quality of immunologically castrated (IC; n=863) pigs were evaluated, and consisted of: 1) corn-soybean meal (CS) diet (PCon); 2) CS+40% DDGS (NCon); 3) CS+40, 30, 20, or 10% DDGS fed in phases 1 to 4, respectively (SD); or 4) CS+40% DDGS fed in phase 1 to 3 and CS in phase 4 (WD). All pigs received the first dose of Improvest(r) at 11weeks. of age, and the second dose was administered at either 9, 7, or 5weeks. before slaughter at 24weeks. of age. The SD and WD improved carcass dressing percentage and resulted in intermediate primal cut yields and pork loin quality compared with pigs fed PCon and NCon. Increasing the time interval between second dose of Improvest(r) and slaughter increased adipose tissue accretion but did not affect lean quality of pork. PMID- 28092729 TI - Diverse functions for different forms of nuclear actin. AB - In addition to its essential roles as part of the cytoskeleton, actin has also been linked to many processes in the nucleus. Recent data has demonstrated the presence of both monomeric and polymeric actin in the nucleus, and implied distinct functional roles for these actin pools. Monomeric actin seems to be involved in regulation of gene expression through transcription factors, chromatin regulating complexes and RNA polymerases. In addition to cytoplasmic actin regulators, nuclear proteins, such as emerin, can regulate actin polymerization properties specifically in this compartment. Besides of structural roles, nuclear actin filaments may be required for organizing the nuclear contents and for the maintenance of genomic integrity. PMID- 28092730 TI - Serum AGR2 as a useful biomarker for pituitary adenomas. AB - OBJECTIVE: This study aims to evaluate whether the serum Anterior Gradient-2 (AGR2) can be used as a potential biomarker screening in the diagnosis of Pituitary adenomas(PAs). PATIENTS AND METHODS: The serum AGR2 protein levels were preoperatively measured in 163 PA patients, 43 patients with other sellar lesions excluding PAs, 7 patients with prostate cancer as a positive control and 20 normal people(10 female and 10 male) using Enzyme-Linked ImmunoSorbent Assay (ELISA). Differences in the serum AGR2 level between different groups were analyzed for statistical significance with a Mann-Whitney U test. RESULTS: The data showed that serum AGR2 level was significantly higher in the serum of PA patients (250.10+/-79.14ng/ml) than the patients with other sellar lesions (220.84+/-79.62ng/ml, P=0.017) and normal people (163.67+/-50.38ng/ml, P <0.001). Receiver operating characteristic (ROC) curve analysis was used. The detected area under the curve (AUC) was 0.835. The calculated optimal cut-off point for AGR2 level in serum samples was 158.63ng/ml (Youden index=0.564). The sensitivity was 91.4% and the specificity was 65.0%. Despite the variety of PA clinical features, the serum level of AGR2 are definite in PAs, although there may be a difference between male or female patients. CONCLUSION: Our data suggests AGR2 as a potential biomarker for the diagnosis of PAs. PMID- 28092731 TI - Biological removal of selenate and ammonium by activated sludge in a sequencing batch reactor. AB - Wastewaters contaminated by both selenium and ammonium need to be treated prior to discharge into natural water bodies, but there are no studies on the simultaneous removal of selenium and ammonium. A sequencing batch reactor (SBR) was inoculated with activated sludge and operated for 90days. The highest ammonium removal efficiency achieved was 98%, while the total nitrogen removal was 75%. Nearly a complete chemical oxygen demand removal efficiency was attained after 16days of operation, whereas complete selenate removal was achieved only after 66days. The highest total Se removal efficiency was 97%. Batch experiments showed that the total Se in the aqueous phase decreased by 21% with increasing initial ammonium concentration from 50 to 100mgL-1. This study showed that SBR can remove both selenate and ammonium via, respectively, bioreduction and partial nitrification-denitrification and thus offer possibilities for treating selenium and ammonium contaminated effluents. PMID- 28092732 TI - Enhancement of lipid productivity by adopting multi-stage continuous cultivation strategy in Nannochloropsis gaditana. AB - In the present study, a novel process-based cultivation system was designed to improve lipid productivity of Nannochloropsis gaditana, an oleaginous microalga that has high potential for biofuel production. Specifically, four flat-panel photobioreactors were connected in series, and this system was subjected to continuous chemostat cultivation by feeding fresh medium to the first reactor at dilution rates of 0.028 and 0.056day-1, which were determined based on Monod kinetics. The results show that the serially connected photobioreactor system achieved 20.0% higher biomass productivity and 46.1% higher fatty acid methyl ester (FAME) productivity than a conventional single photobioreactor with equivalent dilution rate. These results suggest that a process-based approach using serially connected photobioreactors for microalgal cultivation can improve the productivity of lipids that can be used for biofuel production. PMID- 28092733 TI - Enzymatic synthesis of an ezetimibe intermediate using carbonyl reductase coupled with glucose dehydrogenase in an aqueous-organic solvent system. AB - (4S)-3-[(5S)-5-(4-Fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one ((S)-ET-5) is an important chiral intermediate in the synthesis of chiral side chain of ezetimibe. Recombinant Escherichia coli expressing carbonyl reductase (CBR) was successfully constructed in this study. The total E. coli biomass and the specific activity of recombinant CBR in 5L fermenter culture were 10.9gDCWL-1 and 14900.3Ug-1DCW, respectively. The dual-enzyme coupled biocatalytic process in an aqueous-organic biphasic solvent system was first constructed using p-xylene as the optimal organic phase under optimized reaction conditions, and 150gL-1 (4S)-3-[5-(4-fluorophenyl)-1,5-dioxophentyl]-4-phenyl-1,3-oxazolidin-2-one (ET-4) was successfully converted to (S)-ET-5 with a conversion of 99.1% and diastereomeric excess of 99% after 24-h, which are the highest values reported to date for the production of (S)-ET-5. PMID- 28092734 TI - Combined utilization of nutrients and sugar derived from wheat bran for d-Lactate fermentation by Sporolactobacillus inulinus YBS1-5. AB - To decrease d-Lactate production cost, wheat bran, a low-cost waste of milling industry, was selected as the sole feedstock. First, the nutrients were recovered from wheat bran by acid protease hydrolysis. Then, cellulosic hydrolysates were prepared from protease-treated samples after acid pretreatment and enzymatic saccharification. The combined use of nutrients and hydrolysates as nitrogen and carbon sources for fermentation by S. inulinus YB1-5 resulted in d-Lactate levels of 99.5g/L, with an average production efficiency of 1.94g/L/h and a yield of 0.89g/g glucose. Moreover, fed-batch simultaneous saccharification and fermentation process at 40 degrees C, 20% (w/v) solid loading and 20FPU/g solid cellulase concentration was obtained. d-Lactate concentrations, yield, productivity, and optical purity were 87.3g/L, 0.65g/g glucose, 0.81g/L/h and 99.1%, respectively. This study provided a feasible procedure that can help produce cellulosic d-Lactate using agricultural waste without external nutrient supplementation. PMID- 28092735 TI - Toxicity assessment of arsenic and cobalt in the presence of aquatic humic substances of different molecular sizes. AB - The release of contaminants in aquatic ecosystems can be influenced by humic acids. In this study, toxicity tests using environmentally relevant concentrations of arsenic and cobalt were conducted both in the presence and absence of aquatic humic substances (AHS) and the fractions of different molecular sizes in the range of (<5, 5-10;10-30; 30-100 and >100kDa) using the microcrustacean Ceriodaphnia dubia. AHS together with arsenic reduced the toxicity, and the toxicity decreased in fractions of larger molecular size AHS. Despite the presence of cobalt, the reduction in toxicity was not observed and that depended on the molecular size of AHS. There was a trend of enhanced toxicity for Co in fractions of larger molecular sizes, opposed to that found for arsenic. Thus, the humic substances alter toxicity of trace elements, and this effect varies depending on the size of the humic substances. PMID- 28092736 TI - Negative effect of chronic cadmium exposure on growth, histology, ultrastructure, antioxidant and innate immune responses in the liver of zebrafish: Preventive role of blue light emitting diodes. AB - The present study explored the possible preventive effects of blue light emitting diodes (LEDs) on cadmium (Cd)-induced oxidative stress and immunotoxicity in zebrafish. To this end, zebrafish were exposed to a white fluorescent bulb or blue LEDs (LDB, peak at 450nm, at an irradiance of 0.9W/m2), and 0 or 30ugL-1 waterborne Cd for 5 weeks. Growth performance, survival rate, and hepatic histology, ultrastructure, antioxidant and innate immune responses were determined in zebrafish. Cd exposure alone reduced growth and survival rate, and induced oxidative damage and changes in histology and ultrastructure. However, Cd exposure in combination with LDB apparently relieved these negative effects. The alleviation of adverse effects might result from the up-regulation of antioxidant and innate immune genes at transcriptional, translational, or post-translational levels. Cd exposure alone dramatically enhanced mRNA levels of nuclear transcription factor kappaB (NF-kappaB) and E2-related factor (Nrf2). However, compared to Cd exposure alone, Cd exposure in combination with LDB apparently down-regulated both genes. Taken together, our results suggest that chronic Cd exposure induced a negative effect on zebrafish, possibly involved in NF-kappaB induced immunotoxicity and Nrf2-induced oxidative stress. Finally, for the first time, our data demonstrated that LDB could protect fish against Cd toxicity. PMID- 28092737 TI - Complex molecular changes induced by chronic progestogens exposure in roach, Rutilus rutilus. AB - In our previous study, we measured 0.23-13.67ng/L progestogens (progesterone, drospirenone, levonorgestrel) in natural waters in the catchment area of the largest shallow lake of Central Europe, Lake Balaton. Progestogen contaminations act as potent steroids with mixed progestagenic, androgenic and mild estrogenic effects that is why our aim was to investigate the morphological and molecular effects of mixture of progesterone, drospirenone, and levonorgestrel in environmentally relevant (10ng/L) and higher (50 and 500ng/L) exposure concentrations in common roach, Rutilus rutilus. Steroids (e.g. progestogens) and the protein deglycase DJ-1 chaperon molecule aim the same target molecules in cells, therefore, we hypothesized that a relationship may exist between progestogens and DJ-1. Furthermore, our other aim was to follow the changes of signal molecules of different biological function due to progestogen treatment in serum and brain. Adult roaches were exposed to 10, 50 and 500ng/L of mixture of progestogen for 42 days and their somatic indices (brain-somatic, liver-somatic, gonadosomatic and kidney-somatic) were measured. Vitellogenin (VTG) expression (estrogen effect) or inhibition (androgen effect) in fish is a widely used biomarker so we measured its changes in liver by ELISA. To determine the quantity and to map the spatial distribution of DJ-1 chaperon protein the brain and liver tissues were analyzed by ELISA and immunohistochemistry. Furthermore, we also studied molecular alterations: a) in the serum by measuring cholesterol, low density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride concentrations and b) in brain homogenate using a cell stress array kit (26 protein). The somatic index of liver and kidney significantly in all the treated groups, whereas the gonadosomatic index of 500ng/L treated group showed significant decrease compared to control animals. VTG level increased significantly in 500ng/L progestogen treated group. Since the concentration of DJ 1 significantly increased in brain and liver in all progestogen treatment groups, the DJ-1 protein could be able to a more sensitive marker than VTG. Serum LDL and cholesterol levels of exposed fish were significantly decreased. DJ-1 was mediated through the stimulation of the expression of LDL-receptor which facilitates reuptake subsequently. In summary, our observations unfolded new data about molecular alterations induced by the combined action of environmental progestogens. In addition, the DJ-1 chaperon protein as a possible biomarker helped to trace the abiotic chemical environmental contaminations, like progestogens in the freshwater ecosystems. PMID- 28092738 TI - Hearing children's voices? Including children's perspectives on their experiences of domestic violence in welfare reports prepared for the English courts in private family law proceedings. AB - This research examined Children and Family Court Advisory and Support Service (Cafcass) reports prepared for private family court proceedings in domestic violence cases in England. The research found that in cases where children's accounts identified them as victims of violence, these disclosures regularly disappeared from report recommendations. Particular discourses regarding 'child welfare' and 'contact' were identified, which routinely impacted on the ways in which children's voices were taken into account. Whilst culturally there has undoubtedly been an influential move towards including children's perspectives in decision-making that affects them, how these views are interpreted and represented is subject to adult 'gate-keeping' and powerful cultural and professional ideologies regarding 'child welfare' and 'post-separation family relationships'. This research found that the unrelenting influence of deeply embedded beliefs regarding the preservation or promotion of relationships with fathers continues to have the effect of marginalising issues of safeguarding, including children's voiced experiences of violence, in all but the most exceptional of cases. Rather, safeguarding concerns in respect of domestic violence and child abuse were persistently overshadowed by a dominant presumption of the overall benefits of contact with fathers. PMID- 28092739 TI - An EMG-driven biomechanical model of the canine cervical spine. AB - Due to the frequency of cervical spine injuries in canines, the purpose of this effort was to develop an EMG-driven dynamic model of the canine cervical spine to assess a biomechanical understanding that enables one to investigate the risk of neck disorders. A canine subject was recruited in this investigation in order to collect subject specific data. Reflective markers and a motion capture system were used for kinematic measurement; surface electrodes were used to record electromyography signals, and with the aid of force plate kinetics were recorded. A 3D model of the canine subject was reconstructed from an MRI dataset. Muscles lines of action were defined through a new technique with the aid of 3D white light scanner. The model performed well with a 0.73 weighted R2 value in all three planes. The weighted average absolute error of the predicted moment was less than 10% of the external moment. The proposed model is a canine specific forward-dynamics model that precisely tracks the canine subject head and neck motion, calculates the muscle force generated from the twelve major moment producing muscles, and estimates resulting loads on specific spinal tissues. PMID- 28092740 TI - Temporal variations in early developmental decisions: an engine of forebrain evolution. AB - Tight control of developmental timing is pivotal to many major processes in developmental biology, such as patterning, fate specification, cell cycle dynamics, cell migration and connectivity. Temporal change in these ontogenetic sequences is known as heterochrony, a major force in the evolution of body plans and organogenesis. In the last 5 years, studies in fish and rodents indicate that heterochrony in signaling during early development generates diversity in forebrain size and complexity. Here, we summarize these findings and propose that, additionally to spatio-temporal tuning of neurogenesis, temporal and quantitative modulation of signaling events drive pivotal changes in shape, size and complexity of the forebrain across evolution, participating to the generation of diversity in animal behavior and emergence of cognition. PMID- 28092741 TI - Waste to energy ash monofill mining: An environmental characterization of recovered material. AB - Samples of combined bottom and fly ash produced at a U.S. waste-to-energy facility were collected from an ash monofill. These samples represented ash monofilled between 1991 and 2008. The ash samples were characterized for total element content and leachability; trends in these parameters were evaluated as a function of sample depth and ash age. Comparison to risk thresholds was used to assess the relative magnitude of the total and leachable mass of elements in the monofilled ash. Natural carbonation was found to have occurred in the monofilled ash, reducing the pH and leachability of Al and Pb. Sb was the element with the highest leachable concentration when compared to risk thresholds, driven primarily by the pH of the ash (9.8). The release of Mo, Sr, Ba, Na and K (all readily soluble elements in ash) was higher (48-122%) when comparing the samples taken from the 0 to 1.5m bore to the 6.1-7.62m bore; total concentration analysis also demonstrated that more of these elements were present in the deeper samples (25-53%). These data support the hypothesis that as infiltrating rainwater moves through an ash monofill leached concentrations are depleted from the upper layers of the ash first. PMID- 28092742 TI - Short-term in vivo exposure to graphene oxide can cause damage to the gut and testis. AB - Graphene oxide (GO) has unique physicochemical properties and also has a potentially widespread use in every field of daily life (industry, science, medicine). Demand for nanotechnology is growing every year, and therefore many aspects of its toxicity and biocompatibility still require further clarification. This research assesses the in vivo toxicity of pure and manganese ion contaminated GO that were administrated to Acheta domesticus with food (at 200mgkg-1 of food) throughout their ten-day adult life. Our results showed that short-term exposure to graphene oxide in food causes an increase in the parameters of oxidative stress of the tested insects (catalase - CAT, total antioxidant capacity - TAC), induces damage to the DNA at a level of approximately 35% and contributes to a disturbance in the stages of the cell cycle and causes an increase of apoptosis. Moreover, upon analyzing histological specimens, we found numerous degenerative changes in the cells of the gut and testis of Acheta domesticus as early as ten days after applying GO. A more complete picture of the GO risk can help to define its future applications and methods for working with the material, which may help us to avoid any adverse effects and damage to the animal. PMID- 28092743 TI - Stable isotope composition of mercury forms in flue gases from a typical coal fired power plant, Inner Mongolia, northern China. AB - Mercury forms emitted from coal combustion via air pollution control devices are speculated to carry different Hg isotope signatures. Yet, their Hg isotope composition is still not reported. Here, we present the first onsite Hg isotope data for gaseous elemental Hg (GEM) and gaseous oxidized Hg (GOM) of flue gases from a typical lignite-fired power plant (CFPP). Significant mass dependent fractionation (MDF) and insignificant mass independent fractionation (MIF) are observed between feed coal and coal combustion products. As compared to feed coal (delta202Hg=-2.04+/-0.250/00), bottom ash, GEM and GOM in flue gases before and after wet flue gas desulfurization system significantly enrich heavy Hg isotopes by 0.7-2.60/00 in delta202Hg, while fly ash, desulfurization gypsum and waste water show slight but insignificant enrichment of light Hg isotopes. GEM is significantly enriched heavy Hg isotopes compared to GOM and Hg in fly ash. Our observations verify the previous speculation on Hg isotope fractionation mechanism in CFPPs, and suggest a kinetically-controlled mass dependent Hg isotope fractionation during transformation of Hg forms in flue gases. Finally, our data are compared to Hg isotope compositions of atmospheric Hg pools, suggesting that coal combustion Hg emission is likely an important atmospheric Hg contributor. PMID- 28092744 TI - Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways. AB - Quercetin, a bioflavonoid contained in several vegetables daily consumed, has been studied for long time for its antiinflammatory and anticancer properties. Quercetin interacts with multiple cancer-related pathways such as PI3K/AKT, Wnt/beta-catenin and STAT3. These pathways are hyperactivated in primary effusion lymphoma (PEL), an aggressive B cell lymphoma whose pathogenesis is strictly linked to the oncogenic virus Kaposis' Sarcoma-associated Herpesvirus (KSHV). In this study, we found that quercetin inhibited PI3K/AKT/mTOR and STAT3 pathways in PEL cells, and as a consequence, it down-regulated the expression of the prosurvival cellular proteins such as c-FLIP, cyclin D1 and cMyc. It also reduced the release of IL-6 and IL-10 cytokines, leading to PEL cell death. Moreover, quercetin induced a prosurvival autophagy in these cells and increased the cytotoxic effect of bortezomib, a proteasomal inhibitor, against them. Interestingly, quercetin decreased also the expression of latent and lytic KSHV proteins involved in PEL tumorigenesis and up-regulated the surface expression of HLA-DR and calreticulin, rendering the dying cells more likely detectable by the immune system. The results obtained in this study indicate that quercetin, which does not exert any cytotoxicity against normal B cells, may represent a good candidate for the treatment of this aggressive B cell lymphoma, especially in combination with autophagy inhibitors or with bortezomib. PMID- 28092745 TI - Omija fruit ethanol extract improves adiposity and related metabolic disturbances in mice fed a high-fat diet. AB - This study investigated the biological and molecular mechanisms underlying the antiobesity effect of omija fruit ethanol extract (OFE) in mice fed a high-fat diet (HFD). C57BL/6J mice were fed an HFD (20% fat, w/w) with or without OFE (500 mg/kg body weight) for 16 weeks. Dietary OFE significantly increased brown adipose tissue weight and energy expenditure while concomitantly decreasing white adipose tissue (WAT) weight and adipocyte size by up-regulating the expression of brown fat-selective genes in WAT. OFE also improved hepatic steatosis and dyslipidemia by enhancing hepatic fatty acid oxidation-related enzymes activity and fecal lipid excretion. In addition to steatosis, OFE decreased the expression of pro-inflammatory genes in the liver. Moreover, OFE improved glucose tolerance and lowered plasma glucose, insulin and homeostasis model assessment of insulin resistance, which may be linked to decreases in the activity of hepatic gluconeogenic enzymes and the circulating level of gastric inhibitory polypeptide. These findings suggest that OFE may protect against diet-induced adiposity and related metabolic disturbances by controlling brown-like transformation of WAT, fatty acid oxidation, inflammation in the liver and fecal lipid excretion. Improved insulin resistance may be also associated with its antiobesity effects. PMID- 28092746 TI - Supranutritional selenium intake from enriched milk casein impairs hepatic insulin sensitivity via attenuated IRS/PI3K/AKT signaling and decreased PGC 1alpha expression in male Sprague-Dawley rats. AB - Selenium (Se)-enriched milk provides antioxidant benefits and has therapeutic potential against cancer. However, both antidiabetic and prodiabetic effects have been attributed to Se. Our objective was to evaluate the effect of Se-enriched milk casein on insulin sensitivity in rats when given at the requirement of 0.25 ppm Se and supranutritionally on both low- and high-fat diets. Two hundred sixteen male Sprague-Dawley rats were fed low- or high-fat diets containing one, two or eight times the Se requirement in a randomized block design. After 7 weeks, 72 rats were subjected to the hyperinsulinemic-euglycemic clamp with [3 3H]glucose infusion to estimate glucose fluxes. Tissues were collected from the remaining 144 rats 8 min after ip saline or insulin injection. During hyperinsulinemic-euglycemic clamps, glucose infusion rate was 22% lower (P=.058), and endogenous glucose production was 76% higher (P=.054) when Se content increased from one to eight times the requirement on low-fat diets, indicating impaired hepatic insulin sensitivity. Se also decreased the ability for insulin to stimulate Akt phosphorylation at Thr308. Hepatic oxidation state and expression of selenoprotein P and glutathione peroxidase-1 were unaffected while expression of insulin receptor substrate (IRS)-1 and-2 and PPARgamma coactivator 1alpha (PGC-1alpha) decreased with supranutritional Se and high-fat intake. In addition, hepatic expression of regulatory and catalytic subunits of phosphatidylinositol 3-kinase (PI3K) decreased with supranutritional intake of Se. Se intake from enriched casein up to eight times the requirement impairs hepatic insulin sensitivity in a mechanism similar to fat feeding, via attenuated IRS/PI3K/Akt signaling and decreased PGC-1alpha expression. PMID- 28092747 TI - Ecological control line: A decade of exploration and an innovative path of ecological land management for megacities in China. AB - Ecological control line is a system innovation in the field of ecological environment protection in China and it has become as an important strategy of national ecological protection. Ten years have passed since the first ecological control line in Shenzhen was delimited in 2005. This study examines the connotations of ecological control line and the current study status in China and abroad, and then takes a brief description about the delimitation background and existing problems of the ecological control line in Shenzhen. The problem-solving strategy is gradually transforming from extensive management to refined management. This study proposes a differential ecological space management model that merges the space system, management system, and support system. The implementation paths include the following five aspects: delimiting ecological bottom lines to protect core ecological resources; formulating access systems for new construction projects to strictly control new construction; implementing construction land inventory reclamation assisted by market means; regulating boundary adjusting procedures and processes; and constructing ecological equity products by using multiple means to implement rights relief. Finally, this study illustrates the progress of the implementation and discusses the rigorousness and flexibility problems of ecological control line and calls for the promotion of the legislation. The management model and implementation paths proposed in this study have referential significance for developing countries and megacities to achieve ecological protection and sustainable development. PMID- 28092748 TI - Optimizing selective cutting strategies for maximum carbon stocks and yield of Moso bamboo forest using BIOME-BGC model. AB - The selective cutting method currently used in Moso bamboo forests has resulted in a reduction of stand productivity and carbon sequestration capacity. Given the time and labor expense involved in addressing this problem manually, simulation using an ecosystem model is the most suitable approach. The BIOME-BGC model was improved to suit managed Moso bamboo forests, which was adapted to include age structure, specific ecological processes and management measures of Moso bamboo forest. A field selective cutting experiment was done in nine plots with three cutting intensities (high-intensity, moderate-intensity and low-intensity) during 2010-2013, and biomass of these plots was measured for model validation. Then four selective cutting scenarios were simulated by the improved BIOME-BGC model to optimize the selective cutting timings, intervals, retained ages and intensities. The improved model matched the observed aboveground carbon density and yield of different plots, with a range of relative error from 9.83% to 15.74%. The results of different selective cutting scenarios suggested that the optimal selective cutting measure should be cutting 30% culms of age 6, 80% culms of age 7, and all culms thereafter (above age 8) in winter every other year. The vegetation carbon density and harvested carbon density of this selective cutting method can increase by 74.63% and 21.5%, respectively, compared with the current selective cutting measure. The optimized selective cutting measure developed in this study can significantly promote carbon density, yield, and carbon sink capacity in Moso bamboo forests. PMID- 28092749 TI - Public value at risk from Phytophthora ramorum and Phytophthora kernoviae spread in England and Wales. AB - Heritage gardens, heathland and woodland are increasingly under threat from the non-native tree and plant diseases Phytophthora ramorum and Phytophthora kernoviae. However, there exist only limited literature that estimates the public non-market value that may be lost from a continued spread of Phytophthora ramorum and Phytophthora kernoviae into these habitats. This paper therefore uses a contingent valuation survey to assess the non-extractive public use and non-use values at risk from an uncontrolled spread of these diseases in England and Wales. Results estimate that L1.446bn of public value is at risk in England and Wales per year from an uncontrolled spread of Phytophthora ramorum and Phytophthora kernoviae. The greatest public value at risk, of L578 m/year, is from an uncontrolled spread of these diseases to heritage gardens, while the lowest public value at risk, of L386 m/year, is from disease spread to heathland. The findings of this paper should help policymakers make informed decisions as to the public resources to dedicate towards Phytophthora ramorum and Phytophthora kernoviae control in England and Wales. In this regard, the current control programme to contain these diseases appears cost-effective in light of the public value at risk estimates produced by this paper. PMID- 28092750 TI - Assessing common birds' ecological requirements to address nature conservation in permanent crops: Lessons from Italian vineyards. AB - Viticulture has contributed to shaping cultural landscapes in several regions across all continents. Recent farming intensification is causing landscape homogenization and biodiversity loss in several of those areas, but knowledge about the impacts on biodiversity in vineyards is still scarce. Simplified agro ecosystems resulting from intensification host mainly generalist and common species, which still play a key role in the regulation of ecosystems and in the provision of ecosystem services. We assessed the abundance of 11 common bird species at 47 linear transects in a vineyard-dominated landscape in Trentino (NE Italy), in both spring and winter, and analysed abundance variation in relation to three independent groups of predictors: landscape, management, and topographic climatic variables. In the majority of species (7), abundance was primarily or considerably affected by landscape attributes. However, an additional 5 species were largely affected by management practices, often with conspicuous seasonal differences. Overall, landscape and management heterogeneity positively affected the abundance of 6 species. Vineyard cover (and in particular the new spalliera trellising system) was negatively related with the abundance of 6 species, with the strongest impacts occurring in winter. On the contrary, the cover of marginal habitats had major positive effects over 8 species. Hedgerows, tree rows, and dry stone walls, as well as traditional pergola vineyards and landscape and management heterogeneity should be conserved or restored in viticultural landscapes to promote the abundance of common bird species. This strategy would ensure the maintenance of the ecosystem services they provide, while promoting the general sustainability of the agroecosystem. PMID- 28092751 TI - The effect of listing the lesser prairie chicken as a threatened species on rural property values. AB - This paper estimates the effect of Endangered Species Act protections for the lesser prairie chicken (Tympanuchus pallidicinctus) on rural property values in Oklahoma. The political and legal controversy surrounding the listing of imperiled species raises questions about the development restrictions and opportunity costs the Endangered Species Act imposes on private landowners. Examining parcel-level sales data before and after the listing of the endemic lesser prairie chicken, we employ difference-in-differences (DD) regression to measure the welfare costs of these restrictions. While our basic DD regression provides evidence the listing was associated with a drop in property values, this finding does not hold up in models that control for latent county and year effects. The lack of a significant price effect is confirmed by several robustness checks. Thus, the local economic costs of listing the lesser prairie chicken under the Endangered Species Act appear to have been small. PMID- 28092752 TI - Optimising UK urban road verge contributions to biodiversity and ecosystem services with cost-effective management. AB - Urban road verges can contain significant biodiversity, contribute to structural connectivity between other urban greenspaces, and due to their proximity to road traffic are well placed to provide ecosystem services. Using the UK as a case study we review and critically evaluate a broad range of evidence to assess how this considerable potential can be enhanced despite financial, contractual and public opinion constraints. Reduced mowing frequency and other alterations would enhance biodiversity, aesthetics and pollination services, whilst delivering costs savings and potentially being publically acceptable. Retaining mature trees and planting additional ones is favourable to residents and would enhance biodiversity, pollution and climate regulation, carbon storage, and stormwater management. Optimising these services requires improved selection of tree species, and creating a more diverse tree stock. Due to establishment costs additional tree planting and maintenance could benefit from payment for ecosystem service schemes. Verges could also provide areas for cultivation of biofuels and possibly food production. Maximising the contribution of verges to urban biodiversity and ecosystem services is economical and becoming an increasingly urgent priority as the road network expands and other urban greenspace is lost, requiring enhancement of existing greenspace to facilitate sustainable urban development. PMID- 28092753 TI - Immobilization and reduction of bioavailability of lead in shooting range soil through hydrothermal treatment. AB - Immobilization of Pb in contaminated soil by hydrothermal treatment (HT) under subcritical conditions was investigated using a lab-scale apparatus. The Pb immobilization was evaluated thorough investigating the transformation of Pb fractions and by single chemical extraction. The results showed that HT and treatment temperature significantly affected the immobilization through redistribution of Pb fractions. The results of bioavailability and eco-toxicity assessment demonstrated a drastic decrease in the bioavailable fraction from 41.33 to 14.66%, and an increase in the non-bioavailable fraction from 2.90 to 15.76%. Moreover, the leaching potential of Pb was significantly reduced after treatment. Based on the risk assessment code (RAC), the treated soil residues exhibited medium risk (21.7-14.6 of RAC value for treated soil), which represented a decrease from high risk (41.3 for untreated soil). Immobilization was associated with Pb fractionation from weakly bound to stable fractions. A variety of mechanisms including adsorption and precipitation were suspected to be responsible for Pb immobilization. The findings of this study suggest that the HT may facilitate quantitative reduction of the bioavailability and eco-toxicity of Pb-contaminated soil. Considering the effectiveness of HT in remediating contaminated soil with organic pollutants, this approach might enable remediation of soil co-contaminated with organics and heavy metals. PMID- 28092754 TI - Public participation GIS for improving wood burning emissions from residential heating and urban environmental management. AB - A crowdsourcing study supported by a public participation GIS tool was designed and carried out in two Norwegian regions. The aim was to improve the knowledge about emissions from wood burning for residential heating in urban areas based on the collection of citizens' localized insights. We focus on three main issues: 1) type of dwelling and residential heating source; 2) wood consumption and type of wood appliances; and 3) citizens' perception of the urban environment. Our study shows the importance of wood burning for residential heating, and of the resulted particle emissions, in Norwegian urban areas. Citizens' localized insights on environmental perception highlight the areas in the city that require particular attention as part of clean air strategies. Information about environmental perception is combined with existing environmental data showing certain correlation. The results support the urban environmental management based on co benefit approaches, achieving several outcomes from a single policy measure. Measures to reduce urban air pollution will have a positive impact on the citizens' environmental perception, and therefore on their quality of life, in addition to reducing the negative consequences of air pollution on human health. The characterization of residential heating by fuelwood is still a challenging activity. Our study shows the potential of a crowdsourcing method as means for bottom-up approaches designed to increase our knowledge on human activities at urban scale that result on emissions. PMID- 28092755 TI - Coagulation-flocculation sequential with Fenton or Photo-Fenton processes as an alternative for the industrial textile wastewater treatment. AB - In this study, the industrial textile wastewater was treated using a chemical based technique (coagulation-flocculation, C-F) sequential with an advanced oxidation process (AOP: Fenton or Photo-Fenton). During the C-F, Al2(SO4)3 was used as coagulant and its optimal dose was determined using the jar test. The following operational conditions of C-F, maximizing the organic matter removal, were determined: 700 mg/L of Al2(SO4)3 at pH = 9.96. Thus, the C-F allowed to remove 98% of turbidity, 48% of Chemical Oxygen Demand (COD), and let to increase in the BOD5/COD ratio from 0.137 to 0.212. Subsequently, the C-F effluent was treated using each of AOPs. Their performances were optimized by the Response Surface Methodology (RSM) coupled with a Box-Behnken experimental design (BBD). The following optimal conditions of both Fenton (Fe2+/H2O2) and Photo-Fenton (Fe2+/H2O2/UV) processes were found: Fe2+ concentration = 1 mM, H2O2 dose = 2 mL/L (19.6 mM), and pH = 3. The combination of C-F pre-treatment with the Fenton reagent, at optimized conditions, let to remove 74% of COD during 90 min of the process. The C-F sequential with Photo-Fenton process let to reach 87% of COD removal, in the same time. Moreover, the BOD5/COD ratio increased from 0.212 to 0.68 and from 0.212 to 0.74 using Fenton and Photo-Fenton processes, respectively. Thus, the enhancement of biodegradability with the physico-chemical treatment was proved. The depletion of H2O2 was monitored during kinetic study. Strategies for improving the reaction efficiency, based on the H2O2 evolution, were also tested. PMID- 28092756 TI - Effects of assisted outpatient treatment and health care services on psychotic symptoms. AB - RATIONALE: An ongoing debate concerns acceptability, benefits, and shortcomings of coercive treatment such as assisted outpatient treatment (AOT). The hypothesis that involuntary commitment to outpatient treatment may lead to a better clinical outcome for a subgroup of persons with severe mental illness (SMI) is controversial. Nonetheless, positive effects of AOT may be mediated by an increased availability of healthcare resources or increased service use. OBJECTIVE: The purpose of the present study is to evaluate the course of delusions, hallucinations, and negative symptoms among patients with SMI receiving AOT compared to patients receiving non-compulsory treatment (NCT). Moreover, we assessed if the effects of AOT on psychotic symptoms were mediated by increased healthcare service use. METHODS: This study used a quasi experimental design to examine the effect of AOT and the use of healthcare services on psychotic symptoms. In total, 76 (41.3%) participants with SMI received AOT, and 108 (58.7%) received NCT. The participants were interviewed at baseline every 3 months up to 1 year. Propensity score matching was used to control for group differences. RESULTS: In the basic model, AOT was associated with lower severity of psychotic symptoms over all follow-up points. In the model including healthcare service use, the frequency of case manager visits predicted a reduction in severity of all psychotic symptoms. The frequency of visits to the outpatient clinics, frequency of emergency room, and psychiatrist visits were independently associated with lower levels of delusional symptoms. Psychiatrist visits were related to a decrease in negative symptoms. CONCLUSION: Results indicate that the treatment benefits of AOT are enhanced with the increased use of mental healthcare services, suggesting that the positive effect of AOT on psychotic symptoms is related to the availability of mental healthcare service use. Coercive outpatient treatment might be more effective through greater use of intensive services. PMID- 28092757 TI - Climate change threats to family farmers' sense of place and mental wellbeing: A case study from the Western Australian Wheatbelt. AB - 'Sense of place' has become a central concept in the analysis of the cultural, personal and mental health risks posed by a changing climate. However, such place related understandings of mental health and wellbeing remain largely limited to Indigenous health contexts. In this article we argue the relevance of sense of place in understanding the mental health impacts of climate change on family farmers who retain close living and working relationships to the land. We conducted a community-based qualitative case study located in the Western Australian Wheatbelt - a region that has experienced some of the most significant climate change in Australia. A three-part interview series was conducted with 22 family farmers between February 2013 and April 2014, and 15 interviews with various agricultural and mental health key informants. The research findings reveal that recently observed patterns of climate change have exacerbated farmers' worries about the weather, undermined notions of self-identity, and contributed to cumulative and chronic forms of place-based distress, culminating in heightened perceived risk of depression and suicide. The research findings highlight the tightly coupled ecosystem health-human health relationships that exist for family farmers living in regions affected by climate change, as well as the significance of farmers' place-based attachments and identities for their mental health and wellbeing. PMID- 28092758 TI - Between a rock and a hard place: Economic expansion and social responsibility in UK media discourses on the global alcohol industry. AB - CONTEXT: Transnational alcohol corporations (TACs) employ a range of strategies to achieve their business objectives, including attempts to frame perceptions of their activities in media debates. TACs aim to achieve a favourable regulatory environment by presenting themselves as socially responsible actors. However, the need to secure financial investment means they must also emphasise their potential for growth. This article investigates tensions between these objectives in coverage of the global alcohol industry in the UK print media. METHODS: This article examines coverage of the world's four largest TACs in five British daily newspapers and one industry publication between March 2012 and February 2013. 477 articles were identified for analysis through keyword searches of the LexisNexis database. Thematic coding of articles was conducted using Nvivo software. FINDINGS: Two conflicting framings of the alcohol industry emerge from our analysis. The first presents TACs as socially responsible actors; key partners to government in reducing alcohol-related harms. This is targeted at policy-makers and the public in an attempt to shape policy debates. The second framing highlights TACs' potential for economic growth by establishing new markets and identifying new customer bases. This is targeted at an audience of potential investors. CONCLUSIONS: A fundamental contradiction lies at the heart of these framings, reflecting the tensions that exist between TACs' political and financial strategies. Alcohol industry involvement in policy-making thus involves a fundamental conflict of interests. Consequently, the UK government should reassess the prominence it currently affords to the industry in the development and delivery of alcohol policy. PMID- 28092759 TI - Effects of donor proliferation in development aid for health on health program performance: A conceptual framework. AB - Development aid for health increased dramatically during the past two decades, raising concerns about inefficiency and lack of coherence among the growing number of global health donors. However, we lack a framework for how donor proliferation affects health program performance to inform theory-based evaluation of aid effectiveness policies. A review of academic and gray literature was conducted. Data were extracted from the literature sample on study design and evidence for hypothesized effects of donor proliferation on health program performance, which were iteratively grouped into categories and mapped into a new conceptual framework. In the framework, increases in the number of donors are hypothesized to increase inter-donor competition, transaction costs, donor poaching of recipient staff, recipient control over aid, and donor fragmentation, and to decrease donors' sense of accountability for overall development outcomes. There is mixed evidence on whether donor proliferation increases or decreases aid volume. These primary effects in turn affect donor innovation, information hoarding, and aid disbursement volatility, as well as recipient country health budget levels, human resource capacity, and corruption, and the determinants of health program performance. The net effect of donor proliferation on health will vary depending on the magnitude of the framework's competing effects in specific country settings. The conceptual framework provides a foundation for improving design of aid effectiveness practices to mitigate negative effects from donor proliferation while preserving its potential benefits. PMID- 28092761 TI - Chlorinated and ultraviolet radiation -treated reclaimed irrigation water is the source of Aeromonas found in vegetables used for human consumption. AB - Wastewater is increasingly being recognized as a key water resource, and reclaimed water (or treated wastewater) is used for irrigating vegetables destined for human consumption. The aim of the present study was to determine the diversity and prevalence of Aeromonas spp. both in reclaimed water used for irrigation and in the three types of vegetables irrigated with that water. Seven of the 11 (63.6%) samples of reclaimed water and all samples of vegetables were positive for the presence of Aeromonas. A total of 216 Aeromonas isolates were genotyped and corresponded to 132 different strains that after identification by sequencing the rpoD gene belonged to 10 different species. The prevalence of the species varied depending on the type of sample. In the secondary treated reclaimed water A. caviae and A. media dominated (91.4%) while A. salmonicida, A. media, A. allosaccharophila and A. popoffii represented 74.0% of the strains in the irrigation water. In vegetables, A. caviae (75.0%) was the most common species, among which a strain isolated from lettuce had the same genotype (ERIC pattern) as a strain recovered from the irrigation water. Furthermore, the same genotype of the species A. sanarellii was recovered from parsley and tomatoes demonstrating that irrigation water was the source of contamination and confirming the risk for public health. PMID- 28092760 TI - Serum brain-derived neurotrophic factor and stability of depressive symptoms in coronary heart disease patients: A prospective study. AB - OBJECTIVE: Brain-derived neurotrophic factor (BDNF) supports neurogenesis, angiogenesis, and promotes the survival of various cell types in the brain and the coronary system. Moreover, BDNF is associated with both coronary heart disease (CHD) and depression. The current study aims to investigate whether serum BDNF levels are associated with the course of depressive symptoms in CHD patients. METHODS: At baseline, N=225 CHD patients were enrolled while hospitalized. Of these, N=190 (84%) could be followed up 6 months later. Depressive symptoms were assessed both at baseline and at the 6-months follow-up using the Patient Health Questionnaire (PHQ-9). Serum BDNF concentrations were measured using fluorometric Enzyme-linked immunosorbent assays (ELISA). RESULTS: Logistic regression models showed that lower BDNF levels were associated with persistent depressive symptoms, even after adjustment for age, sex, smoking and potential medical confounders. The incidence of depressive symptoms was not related to lower BDNF levels. However, somatic comorbidity (as measured by the Charlson Comorbidity Index) was significantly associated with the incidence of depressive symptoms. CONCLUSIONS: Our findings suggest a role of BDNF in the link between CHD and depressive symptoms. Particularly, low serum BDNF levels could be considered as a valuable biomarker for the persistence of depressive symptoms among depressed CHD patients. PMID- 28092762 TI - A novel approach for exposure assessment in air pollution epidemiological studies using neuro-fuzzy inference systems: Comparison of exposure estimates and exposure-health associations. AB - Many epidemiological studies have used proximity to sources as air pollution exposure assessment method. However, proximity measures are not generally good surrogates because of their complex non-linear relationship with exposures. Neuro fuzzy inference systems (NFIS) can be used to map complex non-linear systems, but its usefulness in exposure assessment has not been extensively explored. We present a novel approach for exposure assessment using NFIS, where the inputs of the model were easily-obtainable proximity measures, and the output was residential exposure to an air pollutant. We applied it to a case-study on NH3 pollution, and compared health effects and exposures estimated from NFIS, with those obtained from emission-dispersion models, and linear and non-linear regression proximity models, using 10-fold cross validation. The agreement between emission-dispersion and NFIS exposures was high (Root-mean-square error (RMSE) =0.275, correlation coefficient (r)=0.91) and resulted in similar health effect estimates. Linear models showed poor performance (RMSE=0.527, r=0.59), while non-linear regression models resulted in heterocedasticity, non-normality and clustered data. NFIS could be a useful tool for estimating individual air pollution exposures in epidemiological studies on large populations, when emission-dispersion data are not available. The tradeoff between simplicity and accuracy needs to be considered. PMID- 28092763 TI - Growth and antioxidant defense responses of wheat seedlings to di-n-butyl phthalate and di (2-ethylhexyl) phthalate stress. AB - Phthalate acid esters (PAEs) are vital environmental hormone-like chemicals that are noxious to plants, animals, and human beings. In this study, the influences of di-n-butyl phthalate (DBP) and di (2-ethylhexyl) phthalate (DEHP) on the seed germination, root morphology, and various physiological changes of wheat seedlings were investigated by analyzing superoxide anion (O2-) accumulation, antioxidant enzyme activity, and lipid peroxidation. DBP and DEHP were found to obviously inhibit germination only at high concentrations, but significantly affected root morphology even at lower concentrations. Their toxic effects were the most severe on root elongation, followed by shoot elongation, and were the least severe on germination rate, indicating that root elongation was the best index for evaluating DBP and DEHP eco-toxicity. DBP and DEHP also enhanced O2- and malondialdehyde levels and membrane permeability, as well as produced changes in the antioxidant status and PAE content in the stem and leaf (combined tissues, hereafter shoot) and root tissues. The activities of superoxide dismutase, catalase, and peroxidase increased at low and medium DBP and DEHP concentrations, but declined at high PAE concentrations. These results indicated that PAEs could exert oxidative damage in the early development stage of wheat, particularly at higher concentrations. DBP and DEHP accumulation was higher in the roots than in the shoot tissues, and their levels in these tissues increased with increasing PAE concentrations, supporting their more-serious toxic effects on roots than those on shoots. Further, the physicochemical properties of DBP rendered it more harmful than DEHP. PMID- 28092764 TI - Common deregulated gene expression profiles and morphological changes in developing zebrafish larvae exposed to environmental-relevant high to low concentrations of glucocorticoids. AB - Synthetic glucocorticoids have been detected in environmental waters and their biological potency have raised concerns of their impact on aquatic vertebrates especially fish. In this study, developing zebrafish larvae exposed to representative glucocorticoids (dexamethasone, prednisolone and triamcinolone) at 50 pM to 50 nM from 3 h post-fertilisation to 5 days post-fertilisation were investigated. Microarray analysis identified 1255, 1531, and 2380 gene probes, which correspondingly mapped to 660, 882 and 1238 human/rodent homologs, as deregulated by dexamethasone, prednisolone and triamcinolone, respectively. A total of 248 gene probes which mapped to 159 human/rodent homologs were commonly deregulated by the three glucocorticoids. These homologs were associated with over 20 molecular functions from cell cycle to cellular metabolisms, and were involved in the development and function of connective tissue, nervous, haematological, and digestive systems. Glucocorticoid receptor signalling, NRF2 mediated oxidative stress response and RAR signalling were among the top perturbed canonical pathways. Morphological analyses using four transgenic zebrafish lines revealed that the hepatic and endothelial-vascular systems were affected by all three glucocorticoids while nervous, pancreatic and myeloid cell systems were affected by one of them. Quantitative real-time PCR detected significant change in the expression of seven genes at 50 pM of all three glucocorticoids, a concentration comparable to total glucocorticoids reported in environmental waters. Three genes (cry2b, fbxo32, and klhl38b) responded robustly to all glucocorticoid concentrations tested. The common deregulated genes with the associated biological processes and morphological changes can be used for biological inference of glucocorticoid exposure in fish for future studies. PMID- 28092765 TI - Cytotoxic, genotoxic and mutagenic evaluation of surface waters from a coal exploration region. AB - Coal mining generates a considerable amount of waste, which is disposed of in piles or dams near mining sites. As a result, leachates may reach rivers and streams, promoting the wide dispersion of contaminants in solution and as particulate matter. The present study evaluated the cytotoxic, genotoxic, and mutagenic action of surface waters collected around a thermoelectric power plant and the largest mining area in Brazil (Candiota). Four sites in Candiota stream were selected, and samples were collected in winter and summer. Water samples were analyzed using the comet and CBMN assays in V79 and HepG2 cells. Furthermore, genotoxicity of water samples was evaluated in vivo using the SMART in Drosophila melanogaster. In addition, polycyclic aromatic hydrocarbons and inorganic elements were quantified. The results indicate that water samples exhibited no genotoxic and mutagenic activities, whether in vitro or in vivo. On the other hand, surface water samples collected in sites near the power plant in both summer and winter inhibited cell proliferation and induced increased frequencies of V79 cell death, apoptosis, and necrosis. The cytotoxicity observed may be associated with the presence of higher concentration of inorganic elements, especially aluminum, silicon, sulfur, titanium and zinc at sites 1 and 2 in the stream, as well as with the complex mixture present in the coal, in both seasons. Therefore, the results obtained point to the toxicity potential of water samples with the influence of coal mining and combustion processes and the possible adverse effects on the health of exposed organisms. PMID- 28092766 TI - Effect of multi-walled carbon nanotubes on phytotoxicity of sediments contaminated by phenanthrene and cadmium. AB - To implement effective control and abatement programs for contaminants accumulating in sediments, strategies are needed for evaluating the quality of amended sediments. In this study, phytotoxicity of the sediments contaminated by cadmium and phenanthrene was evaluated after in situ remediation with multi walled carbon nanotubes (MWCNTs) as adsorbents. Adsorption experiments and measurement of aqueous concentrations of the contaminants in overlying water were used to investigate the remediation effectiveness from physical and chemical aspects. The results indicated that MWCNTs showed a much better adsorption performance towards phenanthrene and Cd(II) compared with the sediments. The in situ remediation with MWCNTs could distinctly decrease the aqueous concentrations of phenanthrene and Cd(II) released from the sediments, reducing environmental risk towards overlying water. Influences of MWCNTs dose, MWCNTs diameter, and contact time on phtotoxicity of the contaminated sediments were studied. No significant inhibition of the amended sediments on germination of the test species was observed in the experiments, while the root growth was more sensitive than biomass production to the changes of contaminant concentrations. The analysis of Pearson correlation coefficients between evaluation indicators and associated remediation parameters suggested that phytotoxicity of sediments might inaccurately indicate the changes of pollutant content, but it was significant in reflecting the ecotoxicity of sediments after remediation. PMID- 28092767 TI - Effects of oil dispersant on ozone oxidation of phenanthrene and pyrene in marine water. AB - This work investigated effects of a popular oil dispersant (Corexit EC9500A) on oxidation of phenanthrene and pyrene (two model polycyclic aromatic hydrocarbons) in Gulf coast seawater under simulated atmospheric ozone. The degradation data followed a two-stage pseudo-first order kinetics, a slower initial reaction rate followed by a much faster rate in longer time. The ozonation rate for pyrene was faster than that for phenanthrene. The presence of 18 and 180 mg/L of the dispersant inhibited the first-order degradation rate by 32-80% for phenanthrene, and 51-85% for pyrene. In the presence of 18 mg/L of the dispersant, the pyrene degradation rate increased with increasing ozone concentration, but decreased with increasing solution pH and temperature, while remained independent of ionic strength. For the first time, the results indicate that atmospheric ozone may play a significant role in the weathering of dispersed persistent oil components in natural and engineered systems. PMID- 28092768 TI - Mercury levels in herring gulls and fish: 42 years of spatio-temporal trends in the Great Lakes. AB - Total mercury levels in aquatic birds and fish communities have been monitored across the Canadian Great Lakes by Environment and Climate Change Canada (ECCC) for the past 42 years (1974-2015). These data (22 sites) were used to examine spatio-temporal variability of mercury levels in herring gull (Larus argentatus) eggs, lake trout (Salvelinus namaycush), walleye (Sander vitreus), and rainbow smelt (Osmerus mordax). Trends were quantified with dynamic linear models, which provided time-variant rates of change of mercury concentrations. Lipid content (in both fish and eggs) and length in fish were used as covariates in all models. For the first three decades, mercury levels in gull eggs and fish declined at all stations. In the 2000s, trends for herring gull eggs reversed at two sites in Lake Erie and two sites in Lake Ontario. Similar trend reversals in the 2000s were observed for lake trout in Lake Superior and at a single station in Lake Ontario. Mercury levels in lake trout continued to slowly decline at all of the remaining stations, except for Lake Huron, where the levels remained stable. A post-hoc Bayesian regression analysis suggests strong trophic interactions between herring gulls and rainbow smelt in Lake Superior and Lake Ontario, but also pinpoints the likelihood of a trophic decoupling in Lake Huron and Lake Erie. Continued monitoring of mercury levels in herring gulls and fish is required to consolidate these trophic shifts and further evaluate their broader implications. PMID- 28092769 TI - Spatiotemporal change of phosphorous speciation and concentration in stormwater in the St. Lucie Estuary watershed, South Florida. AB - Phosphorous (P) concentration in stormwater runoff varies at different spatial and temporal scales. Excessive P loading from agriculture system into the St. Lucie Estuary (SLE) contributed to water quality deterioration in southern Indian River Lagoon. This study examines the spatial and temporal shifts of different P forms in runoff and storm water under different land use, water management, and rainfall conditions. Storm water samplings were conducted monthly between April 2013 and December 2014 in typical farmland and along the waterway (Canal C-24) that connects lands to the SLE. Concentrations of different P forms and related water quality variables were measured. Approximately 89% of the collected water samples contained total P (TP) concentrations exceeding the total maximum daily load (TMDL) level (0.081 mg L-1). Concentrations of different P forms declined from agricultural field furrows to the canal and then increased from the upstream to the downstream in the canal where urban activities dominated land use. Total dissolved P (TDP) was the predominant form of TP, followed by PO4-P. Speciation and concentrations of P varied with sites and sampling times, but were significantly higher in the summer months (from June to September) than in the winter. Water pH explained ~20% of TP variation. Spatiotemporal variations of P concentrations and compositions provide a data-based guide for development of best management practices (BMPs) to minimize P export from the SLE watershed. PMID- 28092770 TI - Magnolin inhibits prostate cancer cell growth in vitro and in vivo. AB - BACKGROUND: Magnolin is the most active ingredient in the herb Magnolia fargesii, which has been traditionally used in oriental medicine to treat headaches and nasal congestion. Recent researches demonstrate that Magnolin inhibits cancer cell migration and invasion. MATERIALS AND METHODS: This study used cell culture and the BALB/c nu/nu mouse xenograft model to investigate whether or not magnolin can inhibit the growth of PC3 and Du145 prostate cancer cells. MTT assay and flow cytometry were performed to estimate the proliferation, cycle, and apoptosis of the cells in vitro. Clone formation assay was also conducted. In the animal study, Ki-67 immunostaining and TUNEL assay were carried out to evaluate cell proliferation and apoptosis, respectively. To elucidate the possible mechanism by which magnolin attenuates prostate cancer cell growth, we estimated the expression levels of Akt/p-Akt, P53, P21, BCL-2, and cleaved Caspase3 by using Western blot 48h after magnolin-treatment of the cells. RESULTS: Magnolin inhibited the proliferation and viability of the tumor cells by triggering cell cycle arrest via P53/P21 activation and inducing apoptosis in vitro and in vivo. Magnolin downregulated the phosphorylation of Akt protein kinase and upregulated cleaved Caspase3 during anti-proliferation and pro-apoptosis. CONCLUSION: Magnolin may be a novel medicine for prostate cancer therapy. PMID- 28092772 TI - The expression of endothelin-1 in chronic lymphocytic leukemia is controlled by epigenetic mechanisms and extracellular stimuli. AB - Endothelin-1 (ET-1) is a hormone peptide widely expressed and is involved in several biological processes, important not only for normal cell function but also for tumor development, including cell proliferation, invasion, metastasis, angiogenesis and osteogenesis. In accordance, ET-1 was already shown to contribute to the growth and progression of many different solid cancers. We recently demonstrated that ET-1 has a role in the pathogenesis of chronic lymphocytic leukemia (CLL) where it is abnormally expressed. In the context of this malignancy, ET-1 is able to mediate survival, drug-resistance and growth signals in leukemic cells. Previous studies, not conducted in CLL, have shown that ET-1 regulatory mechanisms are numerous and cell specific. Here, we valued the expression of ET-1 in CLL, in relation to DNA methylation but also in response to stimulation of some important pathways for the dialogue between CLL and microenvironment. We found that a high methylation of ET-1 first intron affects the basal expression of ET-1 in CLL. Moreover, we showed that the activation of CD40 or Toll-like receptor (TLR) by extracellular stimuli produces an augment of ET-1 level in CLL cells. Finally, we demonstrated the fundamental role of NF-kB signalling pathway in promoting and maintaining ET-1 expression in CLL cells, both in basal conditions and after CD40 activation. PMID- 28092771 TI - Plant peroxisomes: A nitro-oxidative cocktail. AB - Although peroxisomes are very simple organelles, research on different species has provided us with an understanding of their importance in terms of cell viability. In addition to the significant role played by plant peroxisomes in the metabolism of reactive oxygen species (ROS), data gathered over the last two decades show that these organelles are an endogenous source of nitric oxide (NO) and related molecules called reactive nitrogen species (RNS). Molecules such as NO and H2O2 act as retrograde signals among the different cellular compartments, thus facilitating integral cellular adaptation to physiological and environmental changes. However, under nitro-oxidative conditions, part of this network can be overloaded, possibly leading to cellular damage and even cell death. This review aims to update our knowledge of the ROS/RNS metabolism, whose important role in plant peroxisomes is still underestimated. However, this pioneering approach, in which key elements such as beta-oxidation, superoxide dismutase (SOD) and NO have been mainly described in relation to plant peroxisomes, could also be used to explore peroxisomes from other organisms. PMID- 28092773 TI - How does a newly encountered face become familiar? The effect of within-person variability on adults' and children's perception of identity. AB - Adults and children aged 6years and older easily recognize multiple images of a familiar face, but often perceive two images of an unfamiliar face as belonging to different identities. Here we examined the process by which a newly encountered face becomes familiar, defined as accurate recognition of multiple images that capture natural within-person variability in appearance. In Experiment 1 we examined whether exposure to within-person variability in appearance helps children learn a new face. Children aged 6-13years watched a 10 min video of a woman reading a story; she was filmed on a single day (low variability) or over three days, across which her appearance and filming conditions (e.g., camera, lighting) varied (high variability). After familiarization, participants sorted a set of images comprising novel images of the target identity intermixed with distractors. Compared to participants who received no familiarization, children showed evidence of learning only in the high-variability condition, in contrast to adults who showed evidence of learning in both the low- and high-variability conditions. Experiment 2 highlighted the efficiency with which adults learn a new face; their accuracy was comparable across training conditions despite variability in duration (1 vs. 10min) and type (video vs. static images) of training. Collectively, our findings show that exposure to variability leads to the formation of a robust representation of facial identity, consistent with perceptual learning in other domains (e.g., language), and that the development of face learning is protracted throughout childhood. We discuss possible underlying mechanisms. PMID- 28092774 TI - The lonely road to paranoia. A path-analytic investigation of loneliness and paranoia. AB - Loneliness and paranoia are related, but the mechanisms that link them to each other remain unclear. Systematic reviews on loneliness propose a social-cognitive model in which loneliness leads to negative evaluations of other persons and a lack of interpersonal trust. However, the data discussed in these reviews are based on healthy individuals. Building on this model, the present study investigated 1) whether negative interpersonal schemata mediate the association between loneliness and paranoia and 2) whether a low level of perceived social support and less frequent social contact are related to loneliness. Using a cross sectional design, sixty-five participants with a diagnosis of schizophrenia were recruited online and completed questionnaire-based measures of loneliness, paranoia, negative interpersonal schemata, perceived social support and frequency of social contact. Data were analyzed taking a path-analytic approach. The association between loneliness and paranoia was significantly and fully mediated by negative schemata of others. Moreover, a low level of perceived social support was significantly associated with loneliness, whereas self-reported frequency of social contact was not. The present results highlight the potential role of interpersonal negative schemata in the formation and maintenance of paranoia and elucidate the crucial role of loneliness in the way individuals construe themselves within a social environment. PMID- 28092775 TI - Alcohol use and suicidality in firefighters: Associations with depressive symptoms and posttraumatic stress. AB - Both suicidality and alcohol use disorders are significant public health concerns among firefighters, and alcohol use is associated with increased suicide risk. In addition, firefighters endorse high rates of symptoms of depression and posttraumatic stress disorder (PTSD). Thus, the current investigation examined associations between alcohol dependence and suicide risk among a large sample of firefighters. Specifically, this study examined the indirect effects of alcohol dependence on suicidality outcomes via both depression and posttraumatic stress, using structural equation modeling. A total of 2883 male firefighters completed a self-report survey, containing measures of alcohol use, suicidality, PTSD, and depressive symptoms. Results indicated good model fit. The latent alcohol dependence variable was directly related to the latent suicide risk variable. However, when depression and posttraumatic stress latent variables were added into the model, alcohol dependence was no longer associated with suicide risk. Furthermore, alcohol dependence was indirectly related to suicide risk via latent depression and posttraumatic stress variables. Indirect effects were established after controlling for relevant covariates. Clinical implications are discussed. PMID- 28092776 TI - Periosteum tissue engineering in an orthotopic in vivo platform. AB - The periosteum plays a critical role in bone homeostasis and regeneration. It contains a vascular component that provides vital blood supply to the cortical bone and an osteogenic niche that acts as a source of bone-forming cells. Periosteal grafts have shown promise in the regeneration of critical size defects, however their limited availability restricts their widespread clinical application. Only a small number of tissue-engineered periosteum constructs (TEPCs) have been reported in the literature. A current challenge in the development of appropriate TEPCs is a lack of pre-clinical models in which they can reliably be evaluated. In this study, we present a novel periosteum tissue engineering concept utilizing a multiphasic scaffold design in combination with different human cell types for periosteal regeneration in an orthotopic in vivo platform. Human endothelial and bone marrow mesenchymal stem cells (BM-MSCs) were used to mirror both the vascular and osteogenic niche respectively. Immunohistochemistry showed that the BM-MSCs maintained their undifferentiated phenotype. The human endothelial cells developed into mature vessels and connected to host vasculature. The addition of an in vitro engineered endothelial network increased vascularization in comparison to cell-free constructs. Altogether, the results showed that the human TEPC (hTEPC) successfully recapitulated the osteogenic and vascular niche of native periosteum, and that the presented orthotopic xenograft model provides a suitable in vivo environment for evaluating scaffold-based tissue engineering concepts exploiting human cells. PMID- 28092777 TI - Controlling the 3D architecture of Self-Lifting Auto-generated Tissue Equivalents (SLATEs) for optimized corneal graft composition and stability. AB - Ideally, biomaterials designed to play specific physical and physiological roles in vivo should comprise components and microarchitectures analogous to those of the native tissues they intend to replace. For that, implantable biomaterials need to be carefully designed to have the correct structural and compositional properties, which consequently impart their bio-function. In this study, we showed that the control of such properties can be defined from the bottom-up, using smart surface templates to modulate the structure, composition, and bio mechanics of human transplantable tissues. Using multi-functional peptide amphiphile-coated surfaces with different anisotropies, we were able to control the phenotype of corneal stromal cells and instruct them to fabricate self lifting tissues that closely emulated the native stromal lamellae of the human cornea. The type and arrangement of the extracellular matrix comprising these corneal stromal Self-Lifting Analogous Tissue Equivalents (SLATEs) were then evaluated in detail, and was shown to correlate with tissue function. Specifically, SLATEs comprising aligned collagen fibrils were shown to be significantly thicker, denser, and more resistant to proteolytic degradation compared to SLATEs formed with randomly-oriented constituents. In addition, SLATEs were highly transparent while providing increased absorption to near-UV radiation. Importantly, corneal stromal SLATEs were capable of constituting tissues with a higher-order complexity, either by creating thicker tissues through stacking or by serving as substrate to support a fully-differentiated, stratified corneal epithelium. SLATEs were also deemed safe as implants in a rabbit corneal model, being capable of integrating with the surrounding host tissue without provoking inflammation, neo-vascularization, or any other signs of rejection after a 9-months follow-up. This work thus paves the way for the de novo bio-fabrication of easy-retrievable, scaffold-free human tissues with controlled structural, compositional, and functional properties to replace corneal, as well as other, tissues. PMID- 28092778 TI - Electrocortical consequences of image processing: The influence of working memory load and worry. AB - Research suggests that worry precludes emotional processing as well as biases attentional processes. Although there is burgeoning evidence for the relationship between executive functioning and worry, more research in this area is needed. A recent theory suggests one mechanism for the negative effects of worry on neural indicators of attention may be working memory load, however few studies have examined this directly. The goal of the current study was to document the influence of both visual and verbal working memory load and worry on attention allocation during processing of emotional images in a cued image paradigm. It was hypothesized that working memory load will decrease attention allocation during processing of emotional images. This was tested among 38 participants using a modified S1-S2 paradigm. Results indicated that both the visual and verbal working memory tasks resulted in a reduction of attention allocation to the processing of images across stimulus types compared to the baseline task, although only for individuals low in worry. These data extend the literature by documenting decreased neural responding (i.e., LPP amplitude) to imagery both the visual and verbal working memory load, particularly among individuals low in worry. PMID- 28092779 TI - Aberrant spontaneous neural activity and correlation with evoked-brain potentials in first-episode, treatment-naive patients with deficit and non-deficit schizophrenia. AB - The goals of the study were to analyze spontaneous neural activity between deficit and non-deficit schizophrenia (DS, NDS) using resting-state fMRI, and to investigate the correlation of fMRI with clinical features and evoked brain potentials. The amplitude of low frequency fluctuation (ALFF) was measured in 41 DS participants, 42 NDS participants, and 42 healthy controls. ALFF in the bilateral cerebellum posterior lobe was significantly decreased in patients, while ALFF in the right fusiform gyrus and the bilateral putamen was significantly increased. In schizophrenia patients, ALFF in the right putamen positively correlated with excited/activation on Positive and Negative Syndrome Scale (PANSS-EXC/ACT). In DS patients, ALFF in the right insula was significantly increased than in controls and positively correlated with S2-P50 amplitude of sensory gating P50. ALFF in the left cerebellum posterior lobe negatively correlated with negative symptoms and withdrawn on PANSS (PANSS-NS, PANSS-WIT), ALFF in the right putamen positively correlated with PANSS-WIT. In NDS patients, ALFF in the middle temporal gyrus decreased than in controls and negatively correlated with P3b subcomponent of P300 latency. ALFF in the left cerebellum posterior lobe negatively correlated with PANSS-EXC/ACT. The middle temporal gyrus in NDS or the right insula in DS may show spatiotemporal defects. PMID- 28092780 TI - Standardization of 106Ru/Rh by live-timed anticoincidence counting and gamma emission determination. AB - The absolute activity standardization measurement system of radionuclide by live timed anticoincidence counting was implemented at LNMRI in 2008 to reduce the effects of some correction factors on the determination of activity with coincidence counting technique used for decades in the laboratory, for example, the corrections of dead time and resolution. With the live-timed anticoincidence system, the variety of radionuclides that can be calibrated by LNMRI was increased in relation to the type of decay. The objective of this study was to standardize the 106Ru activity, determine gamma emission probabilities by spectrometric method for some energies, and estimate measurement uncertainties. PMID- 28092781 TI - Social consequences of subclinical negative symptoms: An EMG study of facial expressions within a social interaction. AB - BACKGROUND AND OBJECTIVES: The negative symptoms of schizophrenia are related to lower social functioning even in non-clinical samples, but little is known about the distinct social consequences of motivational and expressive negative symptoms. In this study we focused on expressive negative symptoms and examined how these symptoms and varying degrees of pro-social facial expressiveness (smiling and mimicry of smiling) relate to the social evaluations by face-to-face interaction partners and to social support. METHODS: We examined 30 dyadic interactions within a sample of non-clinical participants (N = 60) who were rated on motivational and expressive negative symptoms with the Clinical Assessment Interview for Negative Symptoms (CAINS). We collected data on both interaction partners' smiling-muscle (zygomaticus major) activation simultaneously with electromyography and assessed the general amount of smiling and the synchrony of smiling muscle activations between interaction partners (mimicry of smiling). Interaction partners rated their willingness for future interactions with each other after the interactions. RESULTS: Interaction partners of participants scoring higher on expressive negative symptoms expressed less willingness for future interactions with these participants (r = -0.37; p = 0.01). Smiling behavior was negatively related to expressive negative symptoms but also explained by motivational negative symptoms. Mimicry of smiling and both negative symptom domains were also associated with participants' satisfaction with their social support network. LIMITATIONS: Non-clinical sample with (relatively) low levels of symptoms. CONCLUSIONS: Expressive negative symptoms have tangible negative interpersonal consequences and directly relate to diminished pro-social behavior and social support, even in non-clinical samples. PMID- 28092782 TI - An intestinal carcinoid causing transient jejunal intussusception in an adult-A case report. AB - INTRODUCTION: Transient jejunal intussusception in an adult is a rare clinical finding as reported in the English literature. The diagnosis is usually a matter of exclusion given the extremely rare nature of this medical condition. PRESENTATION OF THE CASE: A young female presented to our hospital with abdominal pain and distention of six months duration. The episodes were intermittent in nature and resolved with conservative management. The aetiology remained obscure until a computerized tomography(CT) scan diagnosed a small bowel intussusceptionIntraoperatively a small bowel tumour was identified and resected. Pathology confirmed an intestinal carcinoid of the small bowel with no evidence of metastatic disease. DISCUSSION: Transient jejunal intussusception is a rare finding with only eight reported cases in the English literature. All previously reported cases have been ascribed to benign aetiologies and to our knowledge this is the first case of a malignancy causing transient jejunal intussusception. The management is usually conservative unless an actual cause for the intussusception can be ascertained. The diagnosis is usually one of exclusion and CT scan remains the gold standard in eliciting a diagnosis. CONCLUSION: Transient jejunal intussuception in adults is an extremely rare pathological condition and the diagnosis is usually entertained as a matter of exclusion. PMID- 28092783 TI - Pulmonary emboli cardiac arrest with CPR complication: Liver laceration and massive abdominal bleed, a case report. AB - INTRODUCTION: Massive pulmonary emboli may cause right ventricular failure and backward stasis with parenchymal organ swelling thus increasing the risk for laceration, e.g. if CPR is needed. PRESENTATION OF CASE: A 28-year-old Colombian female with no medical history but taking contraceptive pills and having had a recent longer flight was admitted to Danderyds hospital Emergency Department because of respiratory failure. She developed cardiac arrest in the emergence department following the emergent diagnosis of pulmonary emboli. Cardio-pulmonary resuscitation was initiated, initially with manual and subsequent mechanical compressions with a so called LUCAS device. Patients did not respond properly to the CPR and showed signs of hypovolemia. Emergent ultrasound raised suspicion of abdominal bleed. Emergent laparotomy confirmed liver laceration and massive haemorrhage. CONCLUSION: Pulmonary emboli with subsequent right ventricular failure may cause backwards stasis, and parenchymal organ e.g. liver enlargement. The risk for laceration injuries and internal bleed must be acknowledged when applying external forces as in case of cardiac arrest and need for resuscitation. Frequent and vigilant control of positioning of manual as well as mechanical compressions is of importance. PMID- 28092784 TI - Inflammatory myofibroblastic tumor involving liver, gallbladder, pylorus & duodenum: A rare case presentation. AB - Inflammatory myofibroblastic tumors are rare benign tumors that can mimic malignancy of unknown aetiology. It has spectrum of myofibroblastic proliferation along with varying amount of inflammatory infiltrate. Recently, the concept of this lesion being reactive has been challenged based on the clinical demonstration of recurrences and metastasis and cytogenetic evidence of acquired clonal chromosomal abnormalities. We hereby report a case of inflammatory myofibroblastic tumor involving liver, gallbladder pylorus and 1st part of duodenum. PMID- 28092785 TI - Integrated SSFP for functional brain mapping at 7T with reduced susceptibility artifact. AB - Balanced steady-state free precession (bSSFP) offers an alternative and potentially important tool to the standard gradient-echo echo-planar imaging (GE EPI) for functional MRI (fMRI). Both passband and transition band based bSSFP have been proposed for fMRI. The applications of these methods, however, are limited by banding artifacts due to the sensitivity of bSSFP signal to off resonance effects. In this article, a unique case of the SSFP-FID sequence, termed integrated-SSFP or iSSFP, was proposed to overcome the obstacle by compressing the SSFP profile into the width of a single voxel. The magnitude of the iSSFP signal was kept constant irrespective of frequency shift. Visual stimulation studies were performed to demonstrate the feasibility of fMRI using iSSFP at 7T with flip angles of 4 degrees and 25 degrees , compared to standard bSSFP and gradient echo (GRE) imaging. The signal changes for the complex iSSFP signal in activated voxels were 2.48+/-0.53 (%) and 2.96+/-0.87 (%) for flip angles (FA) of 4 degrees and 25 degrees respectively at the TR of 9.88ms. Simultaneous multi-slice acquisition (SMS) with the CAIPIRIHNA technique was carried out with iSSFP scanning to detect the anterior temporal lobe activation using a semantic processing task fMRI, compared with standard 2D GE-EPI. This study demonstrates the feasibility of iSSFP for fMRI with reduced susceptibility artifacts, while maintaining robust functional contrast at 7T. PMID- 28092787 TI - Perfect 1JCH-resolved HSQC: Efficient measurement of one-bond proton-carbon coupling constants along the indirect dimension. AB - A versatile 1JCH-resolved HSQC pulse scheme for the speedy, accurate and automated determination of one-bond proton-carbon coupling constants is reported. The implementation of a perfectBIRD element allows a straightforward measurement from the clean doublets obtained along the highly resolved F1 dimension, even for each individual 1JCHa and 1JCHb in diastereotopic HaCHb methylene groups. Real time homodecoupling during acquisition and other alternatives to minimize accidental signal overlapping in overcrowded spectra are also discussed. PMID- 28092786 TI - Imaging thiol redox status in murine tumors in vivo with rapid-scan electron paramagnetic resonance. AB - Thiol redox status is an important physiologic parameter that affects the success or failure of cancer treatment. Rapid scan electron paramagnetic resonance (RS EPR) is a novel technique that has shown higher signal-to-noise ratio than conventional continuous-wave EPR in in vitro studies. Here we used RS EPR to acquire rapid three-dimensional images of the thiol redox status of tumors in living mice. This work presents, for the first time, in vivo RS EPR images of the kinetics of the reaction of 2H,15N-substituted disulfide-linked dinitroxide (PxSSPx) spin probe with intracellular glutathione. The cleavage rate is proportional to the intracellular glutathione concentration. Feasibility was demonstrated in a FSa fibrosarcoma tumor model in C3H mice. Similar to other in vivo and cell model studies, decreasing intracellular glutathione concentration by treating mice with l-buthionine sulfoximine (BSO) markedly altered the kinetic images. PMID- 28092788 TI - Patient-level meta-analysis of efficacy and hypoglycaemia in people with type 2 diabetes initiating insulin glargine 100U/mL or neutral protamine Hagedorn insulin analysed according to concomitant oral antidiabetes therapy. AB - AIMS: Evaluate efficacy and hypoglycaemia according to concomitant oral antidiabetes drug (OAD) in people with type 2 diabetes initiating insulin glargine 100U/mL (Gla-100) or neutral protamine Hagedorn (NPH) insulin once daily. METHODS: Four studies (target fasting plasma glucose [FPG] ?100mg/dL [?5.6mmol/L]; duration ?24weeks) were included. Standardised data from 2091 subjects (Gla-100, n=1024; NPH insulin, n=1067) were analysed. Endpoints included glycated haemoglobin (HbA1c) and FPG change, glycaemic target achievement, hypoglycaemia, weight change, and insulin dose. RESULTS: Mean HbA1c and FPG reductions were similar with Gla-100 and NPH insulin regardless of concomitant OAD (P=0.184 and P=0.553, respectively) and similar proportions of subjects achieved HbA1c <7.0% (P=0.603). There was a trend for more subjects treated with Gla-100 achieving FPG ?100mg/dL versus NPH insulin (relative risk [RR] 1.09 [95% confidence interval (CI) 0.97-1.23]; P=0.135). Plasma glucose confirmed (<70mg/dL) overall and nocturnal hypoglycaemia incidences and rates were lower with Gla-100 versus NPH insulin (overall RR 0.93 [95% CI 0.87-1.00]; P=0.041; nocturnal RR 0.73 [95% CI 0.65-0.83]; P<0.001). After 24weeks, weight gain and insulin doses were higher with Gla-100 versus NPH insulin (2.7kg vs 2.3kg, P=0.009 and 0.42U/kg vs 0.39U/kg; P=0.003, respectively). Insulin doses were higher when either insulin was added to sulfonylurea alone. CONCLUSIONS: Pooled results from treat-to-target trials in insulin-naive people with type 2 diabetes demonstrate a significantly lower overall and nocturnal hypoglycaemia risk across different plasma glucose definitions with Gla-100 versus NPH insulin at similar glycaemic control. OAD therapy co-administered with Gla-100 or NPH insulin impacts glycaemic control and overall nocturnal hypoglycaemia risk. PMID- 28092789 TI - Facial emotion recognition among typically developing young children: A psychometric validation of a subset of NimStim stimuli. AB - We evaluated the psychometric properties of NimStim taking into account the effects of chronological age on the ability of typically developing young children (aged 2-6 years old) to recognize basic facial expressions (i.e., happy, sad, angry, and fearful). We also examined the psychometric sufficiency of NimStim under race-matched and -mismatched facial emotion stimuli. In the current study, race-matched stimuli referred to when children with African American backgrounds received African American faces to rate their emotions and vice versa for race-mismatched stimuli. Results of the current study represent the first psychometric analysis of reliability and validity for using NimStim pictures depicting happy, sad, angry, and fearful with typically developing children aged 2-6 years old as well as examining race-matched versus -mismatched stimuli. Analyses revealed the psychometric sufficiency of a subset of pictures depicting happy, sad, angry, and fearful from NimStim among young children across race matched and mismatched stimuli. PMID- 28092790 TI - Comparison of quality of life in homeless and non-homeless Chinese patients with psychiatric disorders. AB - To date, there are no data on quality of life (QOL) and its correlates in homeless Chinese patients with psychiatric disorders. This study aimed to compare QOL between homeless and non-homeless patients with psychiatric disorders in China. A total of 278 homeless and 222 non-homeless patients matched in age and gender were consecutively recruited. Socio-demographic and clinical data were collected from medical records. A clinical interview was conducted using standardized instruments. The physical and mental QOL in both groups were lower than the normative data for Chinese general population, but there was no significant difference in any QOL domain between the two groups. Multivariate analyses of homeless patients revealed that male gender was associated with higher physical QOL, while living in cities and lower education level were associated with higher mental QOL. In non-homeless patients, use of second generation antipsychotics was associated with lower physical QOL, while having more severe depressive symptoms was associated with lower mental QOL. Longitudinal studies are warranted to clarify the contributing factors of QOL in both homeless and non-homeless patients. PMID- 28092791 TI - Minor physical anomalies in bipolar I and bipolar II disorders - Results with the Mehes Scale. AB - Minor physical anomalies (MPAs) are external markers of abnormal brain development, so the more common appearence of these signs among bipolar I and bipolar II patients can confirm the possibility of a neurodevelopmental deficit in these illnesses. The aim of the present study was to investigate the rate and topological profile of minor physical anomalies in patients with bipolar I and - first in literature - with bipolar II disorders compared to matched healthy control subjects. Using a list of 57 minor physical anomalies (the Mehes Scale), 30 bipolar I and 30 bipolar II patients, while as a comparison 30 matched healthy control subjects were examined. Significant differences were detected between the three groups comparing the total number of minor physical anomalies, minor malformations and phenogenetic variants and in the cases of the ear and the mouth regions. The individual analyses of the 57 minor physical anomalies by simultaneous comparison of the three groups showed, that in the cases of furrowed tongue and high arched palate were significant differences between the three groups. The results can promote the concept, that a neurodevelopmental deficit may play a role in the etiology of both bipolar I and bipolar II disorders. PMID- 28092792 TI - Curiosity improves coping efficacy and reduces suicidal ideation severity among military veterans at risk for suicide. AB - Curiosity, the tendency to engage in novel and challenging opportunities, may be an important source of resilience for those at risk for suicide. We hypothesized that curiosity would have a buffering effect against risk conferred by multiple sources of distress, whereby curiosity would be associated with reduced suicidal ideation and increased coping efficacy. As part of a larger intervention trial designed to improve coping skills and reduce suicidal ideation, 117 military veterans with suicidal ideation completed measures of curiosity and distress (perceived stress, depression, anxiety, and sleep disturbances) at baseline, and completed measures of suicidal ideation and coping efficacy (to stop negative thoughts, to enlist support from friends and family) at baseline and 3-, 6-, and 12-week follow up. Growth curve models showed that curiosity moderated the association between distress and suicidal ideation at baseline and that curiosity moderated the association between distress and increased coping efficacy to stop negative thoughts over time. Findings suggest that curiosity may buffer against the effect of heightened levels of distress on suicidal ideation and help facilitate stronger gains in coping efficacy over time. Additional work should further examine the role of curiosity as a protective factor for veterans with suicidal ideation. PMID- 28092793 TI - High dilutions of antimony modulate cytokines production and macrophage - Leishmania (L.) amazonensis interaction in vitro. AB - BACKGROUND: In previous results mice treated with high dilutions of antimony presented reduction of monocyte migration to the site of infection with increase in B lymphocytes population in the local lymph node. AIMS: To know the mechanisms involved, a series of in vitro studies was done, using co-cultures of macrophages (RAW 264.7) and Leishmania (L.) amazonensis treated with different dilutions of antimony (Antimonium crudum or AC), in different times. METHODOLOGY: Spreading, phagocytosis, the oxidative activity of macrophages, the viability of free promastigotes and the cytokines/chemokines concentration in the supernatant were evaluated. The assays were performed in quadruplicate. RESULTS: Cells treated with AC 30cH (10-58M) and AC 200cH (10-398M) presented a temporary reduction of the spreading after 02h of incubation, followed by increase after 48h, being the most significant increase observed after the AC 200cH treatment. However, the percentage of internalized parasites at 48, 96 and 120h of incubation was also higher in cells treated with AC 200cH. It is suggested that the AC 200cH improves the ability of phagocytes to internalize the parasites, but not to digest them. The cytokines-chemokines panel corroborated these results. Both dilutions potentiated the parasite-induced reduction of cytokines production, especially IL 6, IL 12 p40 and gamma-IFN, after 48h of incubation. In addition, the production of MIP-1 beta (CCL4), a chemokine involved in chronic inflammation, was also reduced after 120h. A specific effect of AC 30cH was seen by the inhibition of two peaks of CCL2 (MCP-1) observed in infected macrophages, at 24 and 120h. Since this cytokine is an important chemokine for monocytes, it explains the results obtained formerly in vivo. The morphology of macrophages after acridine orange staining revealed that the treatment with AC 30cH reduced substantially the acid vacuoles in the cytoplasm, indicating a certain inability of these cells to digest the parasites. On the other hand, a large peak of VEGF-A, associated with increase of internalized parasites was observed after 120h of treatment with AC 200cH, which could be associated to the regulation of the chronic inflammation events by M1-M2 polarization. There was no statistical difference among groups regarding the production of TNF, NO and H2O2, showing that the drugs do not alter macrophage cytotoxic activity. A clear quantitative and qualitative variation of the modulatory effects of AC 30cH and 200cH was seen, in function of time. CONCLUSIONS: Both dilutions were able to potentiate the decrease of most of cytokines and chemokines induced by the parasite infection in vitro, which explains the clinical improvement seen previously in vivo, however, the mechanisms involved and the epidemiological significance of these findings are still under discussion. PMID- 28092794 TI - beta-defensin 3 modulates macrophage activation and orientation during acute inflammatory response to Porphyromonas gingivalis lipopolysaccharide. AB - beta-defensin 3, a multifunctional antimicrobial peptide, has immuno-regulatory activities. We investigated the modulatory mechanism of human beta-defensin 3 (hBD3) on acute inflammatory response resulted from Porphyromonas gingivalis lipopolysaccharide (P.g-LPS), which plays a pro-inflammatory role in periodontal infection and its derived systemic inflammation. P.g-LPS was administrated to mice and murine macrophages alone or along with hBD3. P.g-LPS could lead to acute inflammation as soon as 2h. And it was observed that hBD3 significantly decreased the production of pro-inflammatory biomarkers of in response to P.g-LPS in vivo and in vitro in the early stage. Interestingly, although hBD3 as well as P.g-LPS stimulated the expression of TLR2 mRNA in macrophages in this study, hBD3 exhibited suppressive effect on the downstream NF-kappaB signaling pathway activated by P.g-LPS. And above all, hBD3 could polarize macrophages into M2 phenotype and this contributed to its anti-inflammatory property. These results indicated that hBD3 could have therapeutic effect on systemic inflammation associated with periodontal infections via modulating macrophage activation and orientation. PMID- 28092795 TI - Moderate aerobic exercise training for improving reproductive function in infertile patients: A randomized controlled trial. AB - This study investigated for the first time the changes in seminal markers of inflammation, oxidative stress status, semen parameters, sperm DNA integrity as well as pregnancy rate following 24weeks of moderate aerobic exercise in infertile patients. A total of 1026 sedentary men (aged 25-40years) attending the infertility clinic with history of more than one year of infertility, were screened and 419 were randomized to either exercise (EX, n=210) or non-exercise (NON-EX, n=209) groups. Exercise training favorably attenuated seminal markers of both inflammation (IL-1beta, IL-6, IL-8, and TNF-alpha) and oxidative stress (ROS, MDA, 8-Isoprostane) as well as enhanced antioxidant defense system (SOD, catalase and TAC) (P<0.05). These changes correlate with favorable improvements in semen parameters, sperm DNA integrity and pregnancy rate (P<0.05). The results provide information about the effectiveness of moderate aerobic exercise training as a treatment option for male factor infertility. The 4-week detraining period was not enough to reverse all benefits promoted by exercise intervention. PMID- 28092796 TI - Global open data management in metabolomics. AB - Chemical Biology employs chemical synthesis, analytical chemistry and other tools to study biological systems. Recent advances in both molecular biology such as next generation sequencing (NGS) have led to unprecedented insights towards the evolution of organisms' biochemical repertoires. Because of the specific data sharing culture in Genomics, genomes from all kingdoms of life become readily available for further analysis by other researchers. While the genome expresses the potential of an organism to adapt to external influences, the Metabolome presents a molecular phenotype that allows us to asses the external influences under which an organism exists and develops in a dynamic way. Steady advancements in instrumentation towards high-throughput and highresolution methods have led to a revival of analytical chemistry methods for the measurement and analysis of the metabolome of organisms. This steady growth of metabolomics as a field is leading to a similar accumulation of big data across laboratories worldwide as can be observed in all of the other omics areas. This calls for the development of methods and technologies for handling and dealing with such large datasets, for efficiently distributing them and for enabling re-analysis. Here we describe the recently emerging ecosystem of global open-access databases and data exchange efforts between them, as well as the foundations and obstacles that enable or prevent the data sharing and reanalysis of this data. PMID- 28092797 TI - Undergraduate nursing student mentors' experiences of peer mentoring in Korea: A qualitative analysis. AB - BACKGROUND: Although mentoring involves the achievement of a mutual relationship between mentors and mentees, most studies have focused on the effects of mentoring on the mentees rather than that on the mentors, which necessitates the need to identify mentors' experiences to provide original resources for mentoring. OBJECTIVES: The purpose of this study was to explore the mentoring experience of nursing students who participated as mentors in a mentoring learning program, to offer evidence-based resources for nursing educators to develop mentoring programs and to use mentorship as an educational method. DESIGN: A qualitative content analysis of transcribed focus groups was conducted to describe and explore the undergraduate nursing students' mentoring experiences. SETTING: This study was conducted in two nursing schools in South Korea. PARTICIPANTS: Fifteen student mentors from the peer mentoring program participated in the present study. They were aged between 21 and 24years, and 87% of the participants were female. METHODS: The experiences of the mentors were explored through focus groups, and the collected data were analyzed by content analysis. RESULTS: The mentors' experiences could be summarized by the core theme, "Self-growth as a leader," consisting of the following themes: taking pride, guiding mentees, coping with conflicts, and building leadership. CONCLUSION: The themes and codes derived from mentors' experiences would provide evidence-based guidelines and resources for nursing educators and professionals in related disciplines regarding successful peer mentoring, which could facilitate self-growth and foster the development of leadership skills in undergraduate students. PMID- 28092798 TI - Acute kidney injury and risk of deep vein thrombosis and pulmonary embolism in Taiwan: A nationwide retrospective cohort study. AB - INTRODUCTION: Chronic kidney disease (CKD) increases risk for deep vein thrombosis (DVT) and pulmonary embolism (PE). However, few studies have investigated the relationship between acute kidney injury (AKI) and risk of DVT and PE. Therefore, we conducted a nationwide longitudinal cohort study to determine whether patients with AKI are associated with increased risk of developing DVT and PE. METHODS: We included >30years-old inpatients (n=4734) receiving the diagnosis of AKI from 2000 to 2006 and their age-and sex-matched non-AKI inpatients using medical service in the same year (n=47.340). Diagnosis of DVT and PE was recorded within 5-year after the AKI event or index use of medical service. The hazard ratios were analyzed using Cox regression model and adjustments were made for demographic factors, selected comorbidities and treatments. A time-dependent covariate survival analysis was performed for variations of some comorbidities, treatments and hospitalization. Competing risk regression (CRR) model was also used to adjust the risk for death. Propensity score matching was used to minimize potential selection bias. We also performed sensitivity analysis to examine the effect of other possible residual confounding factors. RESULTS: After adjusting for demographic characteristics, selected comorbidities and treatment, AKI remained a predisposing factor with a 1.44-fold (95% CI, 1.04-2.01) and 1.49-fold (95% CI, 1.12-1.97) increase in patients who were at a risk for developing DVT within 3 and 5years. AKI also remained a significant predisposing factor with a 2.66-fold (95% CI, 1.49-3.20) increase in patients who were at a risk for developing PE within 3years. However, there were no significant results for PE within 5years. The hazard ratios of time-dependent covariate survival analysis and CRR model showed the similar results. CONCLUSIONS: Risk of DVT and PE is higher in patients with AKI than in the general population. PMID- 28092799 TI - Fibrin improves skin wound perfusion in a diabetic rat model. AB - : The fibrin matrix of the thrombus that is formed directly after wounding, is an important determinant of the success of the early phase of wound healing. This phase is often impaired in patients with diabetes. A promising approach to improve skin wound healing is the application of a pro-angiogenic fibrin matrix onto the wound. We studied this in 59 female WAG/RijCrl diabetic rats, in which we created two dorsal full-thickness wounds of which one was treated with a human physiological fibrin matrix (2mg/ml) and one with PBS as control. Wound healing parameters were determined at different time points. The wound closure was significantly improved in fibrin-treated wounds on day 3 and 7. Also, fibrin treated wounds showed a significantly higher perfusion on day 28 and 35 compared to control wounds (p<0.05). CD68 staining revealed that human fibrin did not induce an immune response. IN CONCLUSION: the application of a fibrin matrix on a diabetic wound showed improved perfusion and an increased early closure rate of the wound area. PMID- 28092800 TI - Effect of venepuncture process design on efficiency and failure rates: A simulation model study for secondary care. AB - BACKGROUND: Healthcare aims to deliver good patient outcomes. For many clinical procedures there are multiple alternative task sequences that can be performed. These deviations can influence procedure reliability, efficiency of usage of hospital resources and risk to staff and patient safety. Venepuncture is one of the most common invasive procedures in healthcare. Literature of clinical practice shows evidence of wide variability in the procedure order and the duration of each step, which can depend on attributes, such as patient health, sampling method and staff skills. OBJECTIVE: To use a computer simulation model based on Petri nets to evaluate the impact on outcomes of commonly practiced deviations from the venepuncture procedure guideline and variations in key dependent variables. The outcomes considered include the probability of successfully obtaining a blood sample and the procedure completion time. DESIGN: A computer simulation model was constructed using the Petri net technique which mimics the different variations of the venepuncture procedure. Qualitative and quantitative data for the model was collected from the literature and through interviews and questionnaire responses from doctors and phlebotomists. Statistics on the reliability and duration for different variations were then calculated from the model output. SETTING: A digital laboratory to model venepuncture in secondary care. RESULTS: The model showed that the common practice of applying the tourniquet prior to vein identification and releasing it after sample tubes are filled may result in a ten-fold increase in sample haemolysis, compared to the recommended guideline procedure. Equipment layout on wards and patient vein prominence were identified as the two most important factors influencing time efficiency of blood sample collection. CONCLUSIONS: Petri net computer models were shown to be an effective method for evaluating the success rate and completion time of the venepuncture procedure under alternative task sequences and variations in key dependent variables. The results obtained from the model showed a significant increase in the rate of sample laboratory rejection due to haemolysis when commonly practiced deviations from the guideline procedure were performed. The rate of failure to collect a sample and the mean time for performing the procedure increased significantly for patients with less prominent veins and when the procedure was performed on unfamiliar wards. These results highlight the need for healthcare providers to ensure guidelines are followed when performing venepuncture, equipment layouts are standardised across locations and that the vein prominence of different patient groups is considered when allocating resources for blood sample collection. PMID- 28092801 TI - The association between personal income and aging: A population-based 13-year longitudinal study. AB - INTRODUCTION: Population aging is set to increase the elder dependency ratio, causing a rapid increase in healthcare expenditures and financial burden on the government. This study aims to construct an aging score from age-related diseases and to perform longitudinal analyses to examine the association between personal income and aging. METHODS: A total of 86,838 subjects drawn from a community with 384,617 residents in northern Taiwan were examined. Personal income and aging related diseases were measured from the National Health Insurance database during 1997-2010. Multiple linear regression and stratified analyses were used. RESULTS: Our results indicate that subjects with low personal income (defined as monthly income <=610 USD) can have high aging scores as calculated by selected aging related diseases. In stratified analyses, moreover, subjects with low personal income tended to have higher aging scores across different anthropometric groups. The association was particularly evident in subjects >60years old, and they were noted across multiple strata, including those of catastrophic illness as well as type of primary care setting. CONCLUSIONS: This study found evidence for association between low income and aging in a population with compulsory health insurance program, where accessibility barriers were low in terms of health care resources and personal socioeconomic status. The economic inequity causes difference in aging process, which deserves for future interventions. PMID- 28092802 TI - Signal and binding. I. Physico-chemical response to macromolecule-ligand interactions. AB - Obtaining a detailed knowledge about energetics of ligand-macromolecule interactions is a prerequisite for elucidation of the nature, behavior, and activities of the formed complexes. The most commonly used methods in characterizing molecular interactions are physico-chemical techniques based mainly on spectroscopic, calorimetric, hydrodynamic, etc., measurements. The major advantage of the physico-chemical methods is that they do not require large quantities of material and, if performed carefully, do not perturb examined reactions. Applications of several different physico-chemical approaches, commonly encountered in analyses of biochemical interactions, are here reviewed and discussed, using examples of simple binding reactions. It is stressed that without determination of the relationship between the measured signal and the total average degree of binding, the performed analysis of a single physico chemical titration curve may provide only fitting parameters, instead of meaningful interaction parameters, already for the binding systems with only two ligand molecules. Some possible pitfalls in the analyses of single titration curves are discussed. PMID- 28092803 TI - OX40: Structure and function - What questions remain? AB - OX40 is a type 1 transmembrane glycoprotein, reported nearly 30 years ago as a cell surface antigen expressed on activated T cells. Since its discovery, it has been validated as a bone fide costimulatory molecule for T cells and member of the TNF receptor family. However, many questions still remain relating to its function on different T cell sub-sets and with recent interest in its utility as a target for antibody-mediated immunotherapy, there is a growing need to gain a better understanding of its biology. Here, we review the expression pattern of OX40 and its ligand, discuss the structure of the receptor:ligand interaction, the downstream signalling it can elicit, its function on different T cell subsets and how antibodies might engage with it to provide effective immunotherapy. PMID- 28092804 TI - Enhancement of NK cell-mediated lysis of non-small lung cancer cells by nPKC activator, ingenol 3,20 dibenzoate. AB - The IFN-gamma production is crucial for NK cell-mediated lysis of cancer cells. Thus increasing the IFN-gamma production by NK cells may be an ideal strategy to improve their tumoricidal effect. Since the focus on new drug development has shifted towards natural products, limited information is out there about natural products that enhance the IFN-gamma production by NK cells. In this study, through a high-throughput screening, we have identified a natural product ingenol 3,20 dibenzoate (IDB), an activator of tumor suppressor protein kinase C (PKC) isozymes, could increase the IFN-gamma production and degranulation by NK cells, especially when NK cells were stimulated by non-small lung cancer (NSCLC) cells. IDB also significantly enhanced the NK cell-mediated lysis of NSCLC cells. Furthermore, PKC inhibitor, sotrastaurin abrogated IDB-induced IFN-gamma production, degranulation and cytotoxicity, but did not affect IFN-gamma production by NK cells without IDB treatment and NSCLC cell stimulation. The IFN gamma neutralization reversed the IDB-induced enhancement of NK cell mediated killing. In conclusion, our study indicated that IDB enhanced NK cell-mediated lysis of NSCLC cells is dependent on specific PKC mediated IFN-gamma production and degranulation. Thus, IDB may have a promising application in clinic for NK cell-based cancer immunotherapy. PMID- 28092805 TI - Circumstantial evidence of life history events in loricate choanoflagellates. AB - Sex is found in all major eukaryotic groups of organisms. It has been known for some time that the choanoflagellates also possess the genes involved in meiosis and a full sexual cycle was also recently accounted for in Salpingoeca rosetta. With reference to the loricate choanoflagellates the current status is that only circumstantial evidence, from wild material of Bicosta spinifera, exists in favour of documenting division patterns that go beyond plain asexual division, and that has the potential to represent stages in a sexual life cycle. Here we present further evidence from wild material documenting possible morphotype changes that might similarly indicate the existence of complex life cycles. In this particular case, it revolves around the existence of so-called 'combination loricas' (i.e. two loricas that occur physically united), representing consistent species combinations from the genera Acanthocorbis and Stephanoeca. PMID- 28092806 TI - Life-cycle, ultrastructure, and phylogeny of Parvilucifera corolla sp. nov. (Alveolata, Perkinsozoa), a parasitoid of dinoflagellates. AB - Recent studies of marine protists have revealed parasites to be key components of marine communities. Here we describe a new species of the parasitoid genus Parvilucifera that was observed infecting the dinoflagellate Durinskia baltica in salt marshes of the Catalan coast (NW Mediterranean). In parallel, the same species was detected after the incubation of seawater from the Canary Islands (Lanzarote, NE Atlantic). The successful isolation of strains from both localities allowed description of the life cycle, ultrastructure, and phylogeny of the species. Its infection mechanism consists of a free-living zoospore that penetrates a dinoflagellate cell. The resulting trophont gradually degrades the dinoflagellate cytoplasm while growing in size. Once the host is consumed, schizogony of the parasitoid yields a sporocyte. After cytokinesis is complete, the newly formed zoospores are released into the environment and are ready to infect new host cells. A distinguishing feature of the species is the radial arrangement of its zoospores around the central area of the sporocyte during their formation. The species shows a close morphological similarity with other species of the genus, including P. infectans, P. sinerae, and P. rostrata. PMID- 28092807 TI - Application of the DREADD technique in biomedical brain research. AB - The DREADD (Designer Receptors Exclusively Activated by Designer Drugs) technique is a new chemogenetic approach allowing for selective and remote control of neural activity with a high degree of spatial resolution. Since its discovery in 2007 the DREADD technique was successfully employed into basic research, and together with the optogenetic method provided so far the best tool to influence the activity of the brain circuits and cell populations. The first aim of this review was to concisely describe the technique with regard to such issues like the history of its development, biochemistry as well as modes of the designer receptors delivery and expression. The other aim was to summarize approaches employed for probing of the brain circuits using the DREADD technique and to characterize the current knowledge of the method's application in medical research focusing on two diseases - Parkinson's disease and drug addiction - in which designer receptors were found notably valuable. PMID- 28092808 TI - Antinociceptive effect of co-administered NMDA and histamine H4 receptor antagonists in a rat model of acute pain. AB - BACKGROUND: The histamine H4 receptor (H4R) has attracted a lot of attention in terms of its role in antinociception. The N-Methyl-d-aspartic acid (NMDA) receptor is a well-characterized participant in pain pathways. However, it's influence on H4R signaling is poorly understood. Thus, in the present study we investigated the effect of a selective H4R antagonist JNJ7777120 (25mg/kg) and a NMDA receptor antagonist MK-801 (0.1-10MUg) on nociceptive thresholds in a rat acute pain model. METHODS: The influence of intrathecally (it), intracerebroventricularly (icv) and intraplantarly (ipl) administered MK-801 co injected with JNJ7777120 administered intraperitoneally (ip) was determined in the modified Randall-Selitto paw pressure, the tail flick and plantar tests. RESULTS: Both ip JNJ7777120 as well as MK-801 delivered it and ipl increased nociceptive pain thresholds. It and ipl pretreatment with MK-801 additively augmented JNJ7777120 mechanical antinociception. A weaker effect was also observed after it co-administration with MK-801 and JNJ7777120 in the tail flick test. Intracerebroventricular MK-801 failed to produce any effect nor did ipl MK 801 in the plantar test. CONCLUSIONS: The results show for the first time that the H4R and NMDA receptors play a significant role in antinociception in an acute non-inflammatory pain. Furthermore, the blockage of NMDA receptors at the peripheral and spinal, but not supraspinal sites produces a profound antinociceptive response upon simultaneous H4R antagonism. Thus, this study clearly demonstrates the relevance of NMDA and H4R receptors in the modulation of pain signals and that their role is not exclusively limited to their modulatory activity in inflammatory pain states. PMID- 28092809 TI - Retained surgical sponge. PMID- 28092810 TI - Expectation and futurity: The remarkable success of genetic determinism. AB - Genetic determinism is nowadays largely questioned and widely criticized. However, if we look at the history of biology in the last one hundred years, we realize that genetic determinism has always been controversial. Why, then, did it acquire such relevance in the past despite facing longstanding criticism? Through the analysis of some of the ambitious expectations of future scientific applications, this article explores the possibility that part of the historical success of genetic determinism lies in the powerful rhetorical strategies that have connected the germinal matter with alluring bio-technological visions. Indeed, in drawing on the recent perspectives of "expectation studies" in science and technology, it will be shown that there has been an interesting historical relationship between reductionist notions of the gene as a hereditary unit, coded information or functional DNA segment, and startling prophecies of what controlling such an entity might achieve. It will also be suggested that the well known promissory nature of genomics is far older than the emergence of biotechnology in the 1970s. At least from the time of the bio-utopias predicted by J.B.S. Haldane and J. S. Huxley, the gene has often been surrounded by what I call the "rhetoric of futurity": a promissory rhetoric that, despite momentous changes in the life sciences throughout the 20th century, has remained relatively consistent over time. PMID- 28092811 TI - Towards the structure of the TIR-domain signalosome. AB - TIR (Toll/interleukin-1 receptor/resistance protein) domains feature in animal, plant and bacterial proteins involved in innate immunity pathways and associated processes. They function through protein:protein interactions, in particular self association and homotypic association with other TIR domains. Structures of TIR domains from all phyla have been determined, but common association modes have only emerged for plant and bacterial TIR domains, and not for mammalian TIR domains. Numerous attempts involving hybrid approaches, which have combined structural, computational, mutagenesis and biophysical data, have failed to converge onto common models of how these domains associate and function. We propose that the available data can be reconciled in the context of higher-order assembly formation, and that TIR domains function through signaling by cooperative assembly formation (SCAF). PMID- 28092812 TI - Delta14CO2 from dark respiration in plants and its impact on the estimation of atmospheric fossil fuel CO2. AB - Radiocarbon (14C) has been widely used for quantification of fossil fuel CO2 (CO2ff) in the atmosphere and for ecosystem source partitioning studies. The strength of the technique lies in the intrinsic differences between the 14C signature of fossil fuels and other sources. In past studies, the 14C content of CO2 derived from plants has been equated with the 14C content of the atmosphere. Carbon isotopic fractionation mechanisms vary among plants however, and experimental study on fractionation associated with dark respiration is lacking. Here we present accelerator mass spectrometry (AMS) radiocarbon results of CO2 respired from 21 plants using a lab-incubation method and associated bulk organic matter. From the respired CO2 we determine Delta14Cres values, and from the bulk organic matter we determine Delta14Cbom values. A significant difference between Delta14Cres and Delta14Cbom (P < 0.01) was observed for all investigated plants, ranging from -42.30/00 to 10.10/00. The results show that Delta14Cres values are in agreement with mean atmospheric Delta14CO2 for several days leading up to the sampling date, but are significantly different from corresponding bulk organic Delta14C values. We find that although dark respiration is unlikely to significantly influence the estimation of CO2ff, an additional bias associated with the respiration rate during a plant's growth period should be considered when using Delta14C in plants to quantify atmospheric CO2ff. PMID- 28092813 TI - Walking mechanics for patellofemoral pain subjects with similar self-reported pain levels can differ based upon neuromuscular activation. AB - Patellofemoral pain (PFP) is often studied on subjects who are classified using only self-reported data. Neuromuscular activation influences movement mechanics for PFP subjects, but is not likely to be self-reported. We compared lower extremity mechanics, during a common movement (walking), between two subdivisions of a group of PFP subjects that were similar, based on common self-report tools, but different, based on a common objective measure of quadriceps activation. Our intent was to highlight the importance of objectively considering neuromuscular activation when researching PFP movement mechanics. Thirty similar PFP research subjects (based on four common self-report tools) were divided into two subdivisions, based on different quadriceps central activation ratios (CAR): a quadriceps deficit (QD; CAR <0.95) group and a no quadriceps deficit (NQD; CAR >=0.95) group. All subjects in both groups performed five walking trials, while common mechanical characteristics were measured: 3D ground reaction force, and 3D joint kinematics and kinetics. Functional statistics were used to compare mechanical characteristics between the groups across the entire stance phase of gait (alpha=0.05). Numerous differences were found between the two groups for ground reaction force, and joint kinematics and kinetics. For example, the NQD group exhibited 5% greater vertical ground reaction force at peak impact, and 5% less vertical ground reaction force during the unloading portion of stance, relative to the QD group. The results indicate that when researching movement mechanics associated with PFP, it is important to consider objectively-measured neuromuscular activation characteristics that are not likely to be self-reported by PFP subjects. PMID- 28092814 TI - A participatory action research study exploring women's understandings of the concept of informed choice during pregnancy and childbirth in Ireland. AB - OBJECTIVE: to explore women's understandings and definitions of the concept of informed choice during pregnancy and childbirth. METHODS: a three-phase action research approach. In the first phase of the study (reported in this paper), fifteen women were interviewed to establish their understandings and experiences of informed choice. SETTING: Dublin, Ireland in a large maternity hospital. PARTICIPANTS: fifteen postnatal women who gave birth to a live healthy infant, women attended obstetric or midwifery-led care. FINDINGS: we found that multiple factors influence how women define informed choice including; their expectations of exercising choice, their sense of responsibility towards their infant, their sense of self and the quality of their relationships with maternity care professionals. The interdependence of the mother-baby relationship deems that in the context of pregnancy and childbirth, women's definitions, perceptions and experiences of informed choice should be considered to be relational. Women consider that informed choice means more than just the provision of information; rather it requires an in-depth discussion with a professional who is known to them. Women's understandings reveal that informed choice, is not only defined by but contingent on the quality of women's relationships with their caregiver and their ability to engage in a process of shared decision-making with them. KEY CONCLUSION: Informed choice is defined and experienced as a relational construct, the support provided by maternity care professionals to women in contemporary maternity care must reflect this. PMID- 28092815 TI - Facile fabrication of Fe(3)O(4) octahedra/nanoporous copper network composite for high-performance anode in Li-Ion batteries. AB - Fe3O4 octahedra embedded in conductive nanoporous copper (NPC) network are straightforwardly fabricated by means of alloy refining followed by facile electroless dealloying in mild condition. During selectively dissolving the Al from FeCuAl alloy, the residual Cu atoms assemble to form sponge-like nanostructure, meanwhile the Fe atoms undergo spontaneous oxidation and aggregation to grow into Fe3O4 octahedra travelled through NPC network. Owing to the combination of conductive NPC network, Fe3O4 octahedra exhibit dramatically enhanced lithium storage performances with excellent reversible capacity, enhanced rate performance, as well outstanding cyclability compared with pure Fe3O4 octahedra. Especially, Fe3O4/Cu nanocomposite shows superior cycling stability with the excellent reversible capacity of 664.0 and 512.6mAhg-1 retained over 500 cycles at the current densities of 300 and 1000mAg-1, respectively. Moreover, it shows good rate capability even when cycled at 1000mAg 1. With the advantages of exceptional performances and facile preparation, the as made Fe3O4/Cu nanocomposite shows prospective application potential as an advanced anode material in lithium ion batteries. PMID- 28092816 TI - Encapsulation of cisplatin in a pegylated calcium phosphate nanoparticle (CPNP) for enhanced cytotoxicity to cancerous cells. AB - HYPOTHESIS: Exchange of the chloride ion (Cl-) ligands of cisplatin with carboxylates is widely used in fabricating cisplatin loaded nanoparticles for improved cancer therapy. However, the dynamic exchange may cause premature cisplatin release and even disintegration of the nanoparticles in Cl--containing medium such as in plasma. Molecules bearing carboxylates are capable of mediating the mineralization process of calcium phosphate; therefore, it is possible to overcome the disadvantage by sequestering cisplatin in a calcium phosphate nanoparticle (CPNP). EXPERIMENTS: With the hypothesis, precipitation reaction of calcium nitrate and disodium hydrogen phosphate was performed in a solution of poly(ethylene glycol)-poly(acrylic acid) block copolymers with their carboxylates partly conjugated with cisplatin. Then, structure, physicochemical properties, and bioactivity of the product were carefully investigated with multiple characterization methods. FINDINGS: It was revealed a pegylated, cisplatin encapsulated CPNP was prepared; and with appropriate mole ratio of cisplatin to carboxylates, the nanoparticle encapsulated cisplatin efficiently (>90%), was stable and almost entirely prevented the cisplatin release in Cl--containing medium at pH 7.4 but released them in an acidic condition, and showed moderately and greatly enhanced cytotoxicities to the lung cancer cell line A549 and its cisplatin resistance form A549R respectively in comparison with the free cisplatin. PMID- 28092817 TI - Porous bimetallic PdNi catalyst with high electrocatalytic activity for ethanol electrooxidation. AB - Porous bimetallic PdNi catalysts were fabricated by a novel method, namely, reduction of Pd and Ni oxides prepared via calcining the complex chelate of PdNi dimethylglyoxime (PdNi-dmg). The morphology and composition of the as-prepared PdNi were investigated by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD). Furthermore, the electrochemical properties of PdNi catalysts towards ethanol electrooxidation were also studied by electrochemical impedance spectrometry (EIS), cyclic voltammetry (CV) and chronoamperometry (CA) measurement. In comparison with porous Pd and commercial Pd/C catalysts, porous structural PdNi catalysts showed higher electrocatalytic activity and durability for ethanol electrooxidation, which may be ascribed to Pd and Ni property, large electroactive surface area and high electron transfer property. The Ni exist in the catalyst in the form of the nickel hydroxides (Ni(OH)2 and NiOOH) which have a high electron and proton conductivity enhances the catalytic activity of the catalysts. All results highlight the great potential application of the calcination-reduction method for synthesizing high active porous PdNi catalysts in direct ethanol fuel cells. PMID- 28092818 TI - Heterostructured ZnFe(2)O(4)/TiO(2) nanotube arrays with remarkable visible-light photoelectrocatalytic performance and stability. AB - A series of heterostructured ZnFe2O4/TiO2-nanotube arrays (NTAs) with remarkable visible-light photoelectrocatalytic (PEC) activity were successfully prepared via a two-step process of anodization and impregnation, followed by annealing. The structure and morphology of the as-prepared ZnFe2O4/TiO2-NTAs samples, PEC degradation abilities and photoelectrochemical performances, as well as long-term stabilities toward degradation of methyl orange (MO) solution under visible-light irradiation were deeply investigated. Results showed that forming a heterojunction by combination of TiO2-NTAs with ZnFe2O4 successfully extended the absorption edge of TiO2-NTAs to visible-light region. Among all the ZnFe2O4/TiO2 NTAs samples, the 2-ZnFe2O4/TiO2-NTAs sample, named ZT(2), obtained the best PEC activity and the highest photocurrent density under visible-light irradiation. Moreover, the ZT(2) sample retained a good reproducibility and high stability after 20days of PEC degradation. The outstanding visible-light PEC activity and photocurrent response of the ZT(2) sample were attributed to the proper amount of ZnFe2O4 nanoparticles loaded onto the TiO2-NTAs, which not only dramatically improved the visible-light absorption of TiO2-NTAs, but also assisted the separation of photo-induced electron-hole pairs and reduced their recombination by forming a ZnFe2O4/TiO2-NTAs heterojunction. The reaction mechanism responsible for the enhanced visible-light PEC performance of the ZnFe2O4/TiO2-NTAs heterostructure was also discussed. PMID- 28092819 TI - Silver nanoparticles supported over mesoporous alumina as an efficient nanocatalyst for N-alkylation of hetero (aromatic) amines and aromatic amines using alcohols as alkylating agent. AB - We have successfully embedded rhombohedral crystallites of silver nanoparticles (Ag-NPs) over mesoporous alumina (Ag@Al2O3) material for the first time. The Ag@Al2O3 has been characterized by powder X-ray diffraction (PXRD), ultra high resolution transmission electron microscopy (UHR-TEM), scanning electron microscopy (SEM), N2 adsorption/desorption isotherm, Fourier transform infrared spectroscopy (FT-IR), ultraviolet-visible absorption spectra (UV-Vis), and thermogravimetric analysis (TGA). The PXRD confirms the presence of the rhombohedral phase of Ag nanoparticles. The agglomeration of the silver nanoparticle having a dimension of 80-90nmhas been clearly observed from UHR-TEM images. This novel nanocatalyst showed excellent catalytic activity towards the N alkylation of hetero (aromatic) amines and aromatic amines using alcohols as the alkylating agent. The catalyst is heterogeneous in nature and can be recovered and recycled more than five reaction cycles without any noticeable loss in its catalytic activity. PMID- 28092820 TI - PCR screening of an African fermented pearl-millet porridge metagenome to investigate the nutritional potential of its microbiota. AB - Cereals are staple foods in most African countries, and many African cereal-based foods are spontaneously fermented. The nutritional quality of cereal products can be enhanced through fermentation, and traditional cereal-based fermented foods (CBFFs) are possible sources of lactic acid bacteria (LAB) with useful nutritional properties. The nutritional properties of LAB vary depending on the species and even on the strain, and the microbial composition of traditional CBFFs varies from one traditional production unit (TPU) to another. The nutritional quality of traditional CBFFs may thus vary depending on their microbial composition. As the isolation of potentially useful LAB from traditional CBFFs can be very time consuming, the aim of this study was to use PCR to assess the nutritional potential of LAB directly on the metagenomes of pearl-millet based fermented porridges (ben-saalga) from Burkina Faso. Genes encoding enzymes involved in different nutritional activities were screened in 50 metagenomes extracted from samples collected in 10 TPUs in Ouagadougou. The variability of the genetic potential was recorded. Certain genes were never detected in the metagenomes (genes involved in carotenoid synthesis) while others were frequently detected (genes involved in folate and riboflavin production, starch hydrolysis, polyphenol degradation). Highly variable microbial composition - assessed by real-time PCR - was observed among samples collected in different TPUs, but also among samples from the same TPU. The high frequency of the presence of genes did not necessarily correlate with in situ measurements of the expected products. Indeed, no significant correlation was found between the microbial variability and the variability of the genetic potential. In spite of the high rate of detection (80%) of both genes folP and folK, encoding enzymes involved in folate synthesis, the folate content in ben-saalga was rather low (median: 0.5MUg/100g fresh weight basis). This work highlighted the limit of evaluating the nutritional potential of the microbiota of traditional fermented foods by the only screening of genes in metagenomes, and suggests that such a screening should be completed by a functional analysis. PMID- 28092821 TI - Efficacy of vacuum steam pasteurization for inactivation of Salmonella PT 30, Escherichia coli O157:H7 and Enterococcus faecium on low moisture foods. AB - Low moisture foods such as nuts, spices, and seeds have been implicated in several outbreaks due to Salmonella or E. coli O157:H7 contamination. Such foods may be consumed raw, and can be used as ingredients in other food products. While numerous thermal inactivation studies have been conducted for Salmonella on nuts, studies on other seeds and grains are minimal. Product water activity can influence the thermal resistance of pathogens, where thermal resistance increases as water activity decreases, leading to a requirement for higher temperatures and longer exposure times to achieve significant reduction of pathogen numbers. Vacuum steam pasteurization uses steam under vacuum, which can be operated at temperatures above and below 100 degrees C. The objective of this study was to determine the efficacy of vacuum steam pasteurization for inactivation of pathogens on whole flaxseed, quinoa, sunflower kernels, milled flaxseed and whole black peppercorns. The use of E. faecium as a potential surrogate for Salmonella and E. coli O157:H7 in vacuum steam pasteurization was also evaluated. Pasteurization for 1min at 75 degrees C yielded average log reductions of 5.48+/ 1.22, 5.71+/-0.40 and 5.23+/-0.61 on flaxseed, 4.29+/-0.92, 5.89+/-0.26 and 2.39+/-0.83 on quinoa, and 4.01+/-0.74, 5.40+/-0.83 and 2.99+/-0.92 on sunflower kernels for Salmonella PT 30, E. coli O157:H7 and E. faecium, respectively. Similarly, on milled flaxseed and black peppercorns average log reductions of 3.02+/-0.79 and 6.10+/-0.64CFU/g were observed for Salmonella PT 30 after 1min of treatment at 75 degrees C but, on average, >6.0 log reductions were observed after pasteurization at 85 degrees C. Our data demonstrate that vacuum steam pasteurization can be effectively used to reduce pathogens on these low moisture foods at temperature as low as 75 and 85 degrees C, and that E. faecium may be used as a potential surrogate for Salmonella PT 30 and E. coli O157:H7. PMID- 28092822 TI - Combination of Everolimus with Sorafenib for Solid Renal Tumors in Tsc2+/- Mice Is Superior to Everolimus Alone. AB - Tuberous sclerosis (TSC) is an inherited tumor syndrome caused by mutations in TSC1 or TSC2 that lead to aberrant activation of mTOR and development of tumors in multiple organs including the kidneys. The mTOR inhibitors rapamycin and everolimus (rapalogs) have demonstrated clinical efficacy in treating TSC associated tumors including renal angiomyolipomas. However, tumor responses are usually only partial, and regrowth occurs after drug withdrawal. TSC-associated tumors are highly vascular, and TSC patients with renal angiomyolipomas have elevated levels of circulating vascular endothelial growth factor (VEGF) A and VEGFD. Sorafenib inhibits multiple kinases including VEGF receptors and has been used to treat metastatic epithelioid angiomyolipoma in one case, but formal trials have not been undertaken. In this study, we investigated tumor angiogenesis and the therapeutic efficacy of everolimus in combination with sorafenib for renal tumors in Tsc2+/- mice. We found that these tumors exhibited remarkably variable angiogenesis despite consistent aberrant activation of mTOR and increased expression of HIF1alpha and VEGFA. Treatment of 11-month-old Tsc2+/ mice for 2 months with a combination of everolimus and sorafenib significantly reduced the number and size of solid renal tumors, whereas everolimus or sorafenib alone did not. These results suggest that inhibition of mTOR and multiple kinases including VEGF receptors using combination therapy could hold promise for the treatment of TSC-associated tumors that have responded inadequately to a rapalog alone. PMID- 28092824 TI - Chemically modified amino porphyrin/TiO2 for the degradation of Acid Black 1 under day light illumination. AB - In this paper, for the first time, chemically modified 5,10,15,20-meso-tetra (para-amino)-phenyl-porphyrin/TiO2 (TPAPP/TiO2) was prepared and used for the degradation of an azo dye Acid Black 1 (AB 1) under direct sunlight. Initially, TiO2 was prepared by sol-gel method. Before making a TPAPP/TiO2 composite, the surface modification of TiO2 was carried out with glycidoxypropyltrimethoxy silane (GPTMS) which acts as a coupling agent. This is an epoxy terminated silane and could easily bond to the amino group of TPAPP through epoxy cleavage. The formation of TPAPP/TiO2 was confirmed by different characterization techniques such as FT-IR, XRD, SEM and DRS. The photocatalytic activity of TiO2 was highly influenced by TPAPP. A mechanism was proposed for AB 1 degradation by TPAPP/TiO2 under sun light. PMID- 28092825 TI - Non-invasive techniques for revealing the palette of the Romantic painter Francesco Hayez. AB - This paper describes the first systematic analysis of the palette of Francesco Hayez, one of the most outstanding artists of European Romanticism, whose painting technique has never been extensively investigated despite the plethora of artistic studies. He lived in a particular moment in the history of painting, as in the first half of the 19th century many synthetic pigments were available, also in tin tubes, but traditional materials were still used. Sixteen paintings on canvas and on panels, created between 1823 and 1868, were analyzed in situ through non-invasive techniques (infrared reflectography and infrared reflection spectroscopy). Imaging investigation provided clues on painting technique, revealing some cases of pentimenti and underdrawings. A preliminary survey was carried out on a hundred pure pigments used up to the 19th century and on new synthetic colours, in order to attain reference spectra for the interpretation of painting spectra. The portable infrared instrument provided insight into Hayez's painting materials, identifying barite, ivory black, lead-tin yellow, Naples yellow, ochres, Prussian blue, and white lead. The pigments were often blended, to obtain a unique fabric appearance or to attain cold shades. The results pointed to a siccative oil as a binder, mixed with white lead so that it could act as a catalyzer in polymerization reactions, and in some cases with a proteinaceous binder and resins. The preparation was made with gypsum and white lead mixed with a siccative oil. The results showed that the artist used a typical traditional palette, throughout his career, in order to lead to brilliant colours and with long-term stability. Anyway, the possible presence of cobalt blue in a few paintings suggests that Hayez had probably started testing the new colours, since the second decade of 19th century. PMID- 28092823 TI - pH, Lactate, and Hypoxia: Reciprocity in Regulating High-Affinity Monocarboxylate Transporter Expression in Glioblastoma. AB - Highly malignant brain tumors harbor the aberrant propensity for aerobic glycolysis, the excessive conversion of glucose to lactic acid even in the presence of ample tissue oxygen. Lactic acid is rapidly effluxed to the tumor microenvironment via a group of plasma-membrane transporters denoted monocarboxylate transporters (MCTs) to prevent "self-poisoning." One isoform, MCT2, has the highest affinity for lactate and thus should have the ability to respond to microenvironment conditions such as hypoxia, lactate, and pH to help maintain high glycolytic flux in the tumor. Yet, MCT2 is considered to not respond to hypoxia, which is counterintuitive. Its response to tumor lactate has not been reported. In this report, we experimentally identify the transcription initiation site/s for MCT2 in astrocytes (normal) and glioma (tumor). We then use a BACmid library to isolate a 4.2-kbp MCT2 promoter-exon I region and examine promoter response to glycolysis-mediated stimuli in glioma cells. Reporter analysis of nested-promoter constructs indicated response of MCT2 to hypoxia, pH, lactate, and glucose, the major physiological "players" that facilitate a tumor's growth and proliferation. Immunoblot analysis of native MCT2 expression under altered pH and hypoxia reflected the reporter data. The pH-mediated gene regulation studies we describe are the first to record H+-based reporter studies for any mammalian system and demonstrate the exquisite response of the MCT2 gene to minute changes in tumor pH. Identical promoter usage also provides the first evidence of astrocytes harnessing the same gene regulatory regions to facilitate astrocyte-neuron lactate shuttling, a metabolic feature of normal brain. PMID- 28092826 TI - Synthesis, pH dependent photometric and electrochemical investigation, redox mechanism and biological applications of novel Schiff base and its metallic derivatives. AB - A novel Schiff base, 1-((2, 4-dimethylphenylimino)methyl)naphthalen-2-ol abbreviated as (HL) and its four metallic complexes were synthesized and confirmed by 1H and 13C NMR, FTIR, TGA and UV-Visible spectroscopy. Schiff base was also characterized by X-ray analysis. The photometric and electrochemical responses of all the synthesized compounds were investigated in a wide pH range. Structures of the compounds were optimized computationally for the evaluation of different physico-chemical parameters. On the basis of electrochemical results the redox mechanistic pathways of the compounds were proposed. The cytotoxicity analysis on Hela cells revealed that HL and its complexes inhibit cell growth as revealed from their IC50 values (HL):106.7MUM, (L2VO): 40.66MUM, (L2Sn): 5.92MUM, (L2Zn): 42.82 and (L2Co): 107.68MUM. The compounds were tested for anti-diabetic, triglyceride, cholesterol, anti-microbial, anti-fungal and enzyme inhibition activities. The results revealed that HL and its complexes are promising new therapeutic options as these compounds exhibit strong activity against cancer cells, diabetics, fungal and microbial inhibition. PMID- 28092827 TI - Conjugated polymer with carboxylate groups-Hg2+ system as a turn-on fluorescence probe for label-free detection of cysteine-containing compounds. AB - In this work, a turn on fluorescent sensor, based on Hg2+ coordination conjugated polymer, was developed to detect cysteine-containing compounds. The fluorescence of conjugated polymer (poly(2,5-bis (sodium 4-oxybutyrate) -1,4 - phenylethynylene-alt-1,4-phenyleneethynylene; PPE-OBS) would be quenched by Hg2+ because of the coordination-induced aggregation and electron transfers of PPE-OBS toward Hg2+. When there were some cysteine-containing compounds in PPE-OBS-Hg2+ system, the fluorescence of PPE-OBS would be recovered. It indicated that the PPE OBS-Hg2+ system could be used to detect cysteine-containing compounds. Under the optimized conditions, the experiment results showed that there were particularly linear range, high sensitivity and selectivity over other amino acids. The limit of detection (LOD) of cysteine (Cys), homocysteine (Hcy) and glutathione (GSH) were 0.725MUmolL-1, 0.982MUmolL-1 and 1.21MUmolL-1 by using this sensor. In addition, Cys standard recovery in several green tea drink and honey samples was also demonstrated. The recovery of Cys was range from 96.3 to 105.0% and RSD was less than 3.25%. The satisfactory results demonstrated that the proposed method could be as a potential fluorescent method for determining cysteine-containing compounds in real samples. PMID- 28092828 TI - A flexible microbial co-culture platform for simultaneous utilization of methane and carbon dioxide from gas feedstocks. AB - A new co-cultivation technology is presented that converts greenhouse gasses, CH4 and CO2, into microbial biomass. The methanotrophic bacterium, Methylomicrobium alcaliphilum 20z, was coupled to a cyanobacterium, Synechococcus PCC 7002 via oxygenic photosynthesis. The system exhibited robust growth on diverse gas mixtures ranging from biogas to those representative of a natural gas feedstock. A continuous processes was developed on a synthetic natural gas feed that achieved steady-state by imposing coupled light and O2 limitations on the cyanobacterium and methanotroph, respectively. Continuous co-cultivation resulted in an O2 depleted reactor and does not require CH4/O2 mixtures to be fed into the system, thereby enhancing process safety considerations over traditional methanotroph mono-culture platforms. This co-culture technology is scalable with respect to its ability to utilize different gas streams and its biological components constructed from model bacteria that can be metabolically customized to produce a range of biofuels and bioproducts. PMID- 28092829 TI - Enhancing 4-propylheptane dissociation with nickel nanocluster based on molecular dynamics simulations. AB - In the present work, a 0.4nm nickel cluster has been theoretically studied. Its equilibrium structural parameters have been calculated by the DFT method based on the PBEH1PBE hybrid functional and split-valence basis set Lanl2DZ including effective core potentials. We have systematically considered diverse spin states of this cluster and find out its ground state. The relative stability of these states depends on the HOMO-LUMO gap. The interaction of the Ni6 with 4 propylheptane S10N22 has been studied to simulate the process of catalytic cracking of hydrocarbons. The optimization of this structure has been performed by the omegaPBE/Lanl2DZ_ecp method (the TeraChem V.1.9 program package) with no symmetry restrictions; the electron shells of the metal were described by effective core pseudopotentials. For visualization and quantitative estimation of the bonding bonds between the nickel nanocluster and 4-propylheptane, the analysis of weak interactions based on RGD has been performed. To confirm the proposition about the formation of Ni-H bonds, we have scrutinized critical points of electronic density. Values of laplasian of electronic density and Bader atomic charge distribution in the global minimum of the total energy have been estimated by the AIMAll 15.05.18 program suite. Finally, we have simulated interaction of Ni6 with 4-propylheptane in terms of the Born-Oppenheimer ab initio molecular dynamics. The results of the molecular dynamics simulation provide pair radial distribution function CH at 1500 degrees C and a detailed picture of the processes occurring in the system. PMID- 28092830 TI - TRPV1 antagonism by piperazinyl-aryl compounds: A Topomer-CoMFA study and its use in virtual screening for identification of novel antagonists. AB - Transient Receptor Potential Vanilloid, member 1 (TRPV1), is a non-selective cation channel belonging to the transient receptor potential (TRP) family of ion channels. It occurs in the peripheral and central nervous system, activated by a variety of exogenous and endogenous stimuli, thus playing a key role in transmission of pain. This has been a target for chronic pain since more than a decade and a number of antagonists that progressed into clinical trials have failed due to the unexpected side effect of core body temperature rise, thus halting progress in this field. Of late, there has been an upsurge in research on this target, with the rat TRPV1 structure being determined, many new antagonists discovered that are temperature-neutral and many new therapeutic avenues being discovered for TRPV1, including diseases of respiratory and digestive systems, skin and bladder. Towards identifying diverse compounds to decipher the role of this target in various indications, here we report a 3D-QSAR model built using the new topomer-CoMFA methodology on a series of piperazinyl-aryl TRPV1 antagonists and the use of this model, along with a pharmacophore model and the shape of one of the potent compounds of this series, to virtually screen a subset of the ZINC database to find novel and diverse hits. These can serve as starting points to develop modality-selective antagonists for chronic pain and to elucidate the critical role of TRPV1 in the various new therapeutic areas. PMID- 28092831 TI - DFT study on the chemical sensing properties of B24N24 nanocage toward formaldehyde. AB - It has been previously shown that the toxic formaldehyde gas (H2CO) cannot be detected by pristine BC2N, carbon, and BN nanotubes, BC3 nanosheet and graphene. Herein, density functional theory calculations were employed to investigate the electronic and structural behavior of a pristine B24N24 nanocluster toward H2CO molecules. It was found that [4,6] BN bonds of the nanocluster are the most favorable sites for the H2CO adsorption, compared to the [4,8], and [6,8] ones. When an H2CO molecule is adsorbed on a [4,6] BN bond, an energy of about 16.40kcal/mol is released and the HOMO-LUMO gap of the cluster is decreased from 6.45 to 2.98eV. Thus, the electrical conductivity of the cluster is significantly increased, indicating that it can produce an electronic noise at the presence of H2CO molecules. Increasing the number of adsorbed H2CO molecules, the electrical conductivity more increases. The recovery time for the H2CO from the surface of B24N24 is calculated to be very short (~1.02s). Also, the UV-vis spectrum shows that the lambdamax of the B24N24 shows a large redshift upon the adsorption process and transfers from the UV to the visible region. PMID- 28092832 TI - Sampling conformational space of intrinsically disordered proteins in explicit solvent: Comparison between well-tempered ensemble approach and solute tempering method. AB - Intrinsically disordered proteins (IDPs) are a class of proteins that expected to be largely unstructured under physiological conditions. Due to their heterogeneous nature, experimental characterization of IDP is challenging. Temperature replica exchange molecular dynamics (T-REMD) is a widely used enhanced sampling method to probe structural characteristics of these proteins. However, its application has been hindered due to its tremendous computational cost, especially when simulating large systems in explicit solvent. Two methods, parallel tempering well-tempered ensemble (PT-WTE) and replica exchange with solute tempering (REST), have been proposed to alleviate the computational expense of T-REMD. In this work, we select three different IDP systems to compare the sampling characteristics and efficiencies of the two methods Both the two methods could efficiently sample the conformational space of IDP and yield highly consistent results for all the three IDPs. The efficiencies of the two methods: are compatible, with about 5-6 times better than the plain T-REMD. Besides, the advantages and disadvantages of each method are also discussed. Specially, the PT WTE method could provide temperature dependent data of the system which could not be achieved by REST, while the REST method could readily be used to a part of the system, which is quite efficient to simulate some biological processes. PMID- 28092833 TI - Study of molecular interactions between Chitosan and Vi Antigen. AB - Chitosan has attracted much interest due to its special physical and chemical properties related to drug administration. Nanoparticles delivery systems from Vi Antigen are a promising approach in the struggle against typhoid fever. In this paper, we reported the obtainment and the characterization of Vi Antigen by Infrared spectroscopy as well as Molecular Modeling and Computational Chemistry studies of the Chitosan-Vi Antigen interaction through theoretical models. The results of the theoretical and experimental Infrared spectroscopy showed important bands related to N-Acetyl and O-Acetyl groups present in Vi Antigen. Important interactions related to its adsorption were observed through three dimensional optimized structures. Two models were proposed for the Chitosan-Vi Antigen in adsorption system, one as a monomer and another as an optimized tetrasaccharide antigen. The Molecular Modeling studies presented the best conformation and binding site on the nanoparticle Chitosan-Vi Antigen in models proposed. Interactions were observed between O-Acetyl and N-Acetyl groups the Vi Antigen and hydroxy, amino and methyl groups the Chitosan. PMID- 28092834 TI - Computational exploration of regioselectivity and atmospheric lifetime in NO3 initiated reactions of CH3OCH3 and CH3OCH2CH3. AB - The NO3-initiated reactions of CH3OCH3 and CH3OCH2CH3 have been investigated by the BHandHLYP method in conjunction with the 6-311G(d,p) basis set. Thermodynamic and kinetic data are further refined using the comparatively accurate CCSD(T) method. According to the values of reaction enthalpies (DeltaHr,298theta) and reaction Gibbs free energies (DeltaGr,298theta) from CH3OCH2CH3 with NO3 system, we find that H-abstraction pathway from the alpha-CH2 group is more exothermic. It is further confirmed by the calculated CH bond dissociation energy of CH3OCH2CH3 molecule. All the rate constants, computed through means of canonical variational transition state with small-curvature tunneling correction, are fitted to the three-parameter expressions k1=1.54*10-23T3.34exp(-1035.53/T) and k2=3.55*10-26T4.31exp(-281.24/T)cm3molecule-1s-1 and branching ratios are computed over the temperature range 200-600K. The branching ratios are also discussed. The atmospheric lifetimes of CH3OCH3 and CH3OCH2CH3 determined by the NO3 radical are about 270 and 29days, respectively. PMID- 28092835 TI - Effects of the central potassium ions on the G-quadruplex and stabilizer binding. AB - Human telomeres undertake the structure of intra-molecular parallel G-quadruplex in the presence of K+ in eukaryotic cell. Stabilization of the telomere G quadruplex represents a potential strategy to prevent telomere lengthening by telomerase in cancer therapy. Current work demonstrates that the binding of central K+ with the parallel G-quadruplex is a coordinated water directed step wise process. The K+ above the top G-tetrad is prone to leak into environment and the 5'-adenine quickly flips over the top G-tetrad, leading to the bottom gate of G-tetrads as the only viable pathway of K+ binding. Present molecular dynamics studies on the two most potent stabilizers RHPS4 and BRACO-19 reveal that the central K+ has little influence on the binding conformations of the bound stabilizers. But without the central K+, either RHPS4 or BRACO-19 cannot stabilize the structure of G-quadruplex. The binding strength of stabilizers evaluated by the MM-PBSA method follows the order of BRACO-19> RHPS4, which agrees with the experimental results. The difference in binding affinities between RHPS4 and BRACO-19 is probably related to the ability to form intramolecular hydrogen bonds and favorable van del Waals interactions with G quadruplex. In the models that have one central K+ located at the upper/lower binding site, the corresponding top/bottom stacked stabilizers show more favorable binding affinities, indicating the apparent promoting effect of central K+ on the stabilizer binding. Our findings provide further insights into the regulatory effect of K+ on the G-quadruplex targeted binding, which is meaningful to the development of G-quadruplex stabilizers. PMID- 28092836 TI - Antiviral drug acyclovir exhibits antitumor activity via targeting betaTrCP1: Molecular docking and dynamics simulation study. AB - The critical role of betaTrCP1 in cancer development makes it a discerning target for the development of small drug like molecules. Currently, no inhibitor exists that is able to target its substrate binding site. Through molecular docking and dynamics simulation assays, we explored the comparative binding pattern of betaTrCP1-WD40 domain with ACV and its phospho-derivatives (ACVMP, ACVDP and ACVTP). Consequently, through principal component analysis, betaTrCP1-ACVTP was found to be more stable complex by obscuring a reduced conformational space than other systems. Thus based on the residual contribution and hydrogen bonding pattern, ACVTP was considered as a noteworthy inhibitor which demarcated binding in the cleft formed by betaTrCP1-WD40 specific beta-propeller. The outcomes of this study may provide a platform for rational design of specific and potent inhibitor against betaTrCP1, with special emphasis on anticancer activity. PMID- 28092837 TI - Differential diagnosis of a paroxysmal neurological event: Do neurologists know how to clinically recognize it? AB - PURPOSE: To investigate ability to recognize paroxysmal neurological events (PNE) based on video-recorded events alone in a group of physicians treating prevalent neurological conditions. METHODS: Total of 12 patients' videos (6 epileptic seizures (ES), 4 psychogenic nonepileptic seizures (PNES), 2 other nonepileptic seizures (oNES)) were selected. Videos were displayed once to physicians blind to clinical data and final diagnosis. Physicians determined their clinical choice: ES, PNES, oNES, and I don't know (IDK). When ES was chosen, subjects determined type of ES: focal ES, secondary generalized tonic-clonic seizure (GTCS), primary GTCS, and IDK. RESULTS: In total 145 physicians (62% female, mean age 46.2+/ 9years) (neurologists 58.6%, neuropsychiatrists 25.5%, psychiatrists 5%, and neurology residents 10.3%) were enrolled. Physician's exposure to patients with epilepsy per week was diverse: <=1 patient (43.7%); 1-7 patients (37.2%); >7 patients (14.5%). Reported frequency of observation of PNE was as follows: frequent (21.4%), sometimes (47.6%); rarely (26.9%); never (2.1%). Majority of subjects were not EEG readers (60.7%). Median percentage (Mdn%) of correct answers (CA) was 75% (range 25-100). Predictor of better PNE recognition was higher frequency of clinical exposure to PNE (OR 1.65; CI95% 1.11-2.45; p=0.013). Mdn% of ES CA was 83.3%, (range 33.3-100), and of PNES CA was 50% (range 0-100). Physicians were more accurate in ES than PNES identification (p<0,001). Mdn% of type of ES CA was 50%, (range 0-100). CONCLUSIONS: We demonstrate the need for education about clinical features of PNE across subgroups of physicians who deliver neurological service, with emphasis on PNES and ES type classification. PMID- 28092838 TI - Development and validation of the stigma scale for epilepsy in Turkey. AB - OBJECTIVE: Epilepsy is a chronic disease with an increased risk of stigma. The aim of this study was to investigate the efficacy of a scale developed by the authors to determine the level of stigma in Turkish patients with epilepsy and their relatives. METHODS: In this pilot study, two scales were developed, one consisting of 32 questions for the patients and one of 20 questions for the patients' relatives. Initially, a total of 30 patients with epilepsy and 30 relatives of the patients were included. The Cronbach's alpha coefficient was calculated in a reliability analysis of validity applying the scales to 302 patients and 201 relatives of the patients. The Pearson correlation coefficient was used for the reliability analysis of the test-retest. The t-test was used in paired series, and factor analysis was conducted. The correlation between the clinical and demographical data and the stigma scores was evaluated. RESULTS: The scales were applied to participants twice under the same conditions in one-week interval. In the test-retest analysis, the internal consistency of the scales was high and reliable. In the analysis of the patients, the Cronbach's alpha value of the scale was found to be 0.915. In the factor analysis, the questions were grouped into five factors including social isolation, discrimination, insufficiency, false beliefs, and stigma resistance. The factors with the highest contribution to the stigma level were social isolation and discrimination. In the stigma scores, a significant correlation was found between the age of the patient, frequency of seizures, education status, level of income, and the amount of antiepileptic drugs used. In the analysis of the patients' relatives, the Cronbach's alpha value of the scale was found to be 0.892. In the factor analysis, the questions were classified as discrimination, prejudgments, and false beliefs. The factor which most contributed to the stigma level was discrimination. A significant correlation was found in the stigma scores between sex, education status, marital status, and income distribution. CONCLUSION: According to our study results, it is clearly seen that both patients and their relatives suffer from epilepsy-associated stigma. Patients with epilepsy and their relatives are faced with discrimination in society, resulting in social isolation. We, therefore, believe that both patients and their relatives should be informed in detail about discrimination to overcome this challenge. PMID- 28092839 TI - Effect and mechanism of Sorbus pohuashanensis (Hante) Hedl. flavonoids protect against arsenic trioxide-induced cardiotoxicity. AB - The cardiotoxicity of arsenic trioxide (ATO) limits its clinical application in cancer treatment. Evidences suggest that sorbus has antioxidant activity and its consumption has been linked with improved cardioprotection. In this study, we investigated the cardio-protective effect and mechanisms of Sorbus pohuashanensis (Hante) Hedl. flavonoids (SPF) against ATO in BALB/c mice and H9c2 cells. Eleven major flavonoids were confirmed by ultra-performance liquid chromatography electrospray ionization quadrupole time of flight mass spectrometry (UPLC-ESI-Q TOF-MS). SPF recovered the ATO-induced disordered electrocardiogram (ECG) and abnormal cardiac structure in the heart of mice. At the same time, SPF significantly reduced levels of creatine kinase (CK), creatine kinase-MB (CK-MB) lactate dehydrogenase (LDH), and glutamic oxaloacetic transaminase (GOT) against ATO-induced injury and inhibited ATO-induced apoptosis both in vivo and in vitro. In addition, SPF regulated ATO-induced oxidative stress damage by increasing the levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in vivo and in vitro, and reducing reactive oxygen species (ROS). Analysis of the oxidative stress pathways showed that SPF prevented the ATO induced downregulation of phosphorylated protein kinase B (p-Akt) in vivo and in vitro. Pre-treatment of H9c2 cells with SPF inhibited attenuation of nuclear factor (Nrf2) and heme oxygenase (HO-1). Hence, SPF could be used as a preventive and therapeutic plant ingredient against ATO-induced cardiotoxicity. PMID- 28092840 TI - Suppressive effect of Spirulina fusiformis on diclofenac-induced hepato-renal injury and gastrointestinal ulcer in Wistar albino rats: A biochemical and histological approach. AB - CONTEXT: The non-steroidal anti-inflammatory drug (NSAID), diclofenac causes hepato-renal toxicity and gastric ulcer. The aim of this study was to investigate the protective effect of Spirulina fusiformis on Diclofenac-induced toxicity in Wistar albino rats. METHODS: Rats were treated as follows: normal control (group I); diclofenac (50mg/kgb.w., i.p.) treated rats (group II); diclofenac-induced (50mg/kgb.w., i.p.) rats treated with Spirulina fusiformis (400mg/kgb.w., p.o.) (group III); diclofenac-induced (50mg/kgb.w., i.p.) rats treated with silymarin (25mg/kgb.w., p.o.) (group IV); Spirulina fusiformis (400mg/kgb.w., p.o.) alone treated rats (groupV). Biochemical (liver and kidney functional markers) and antioxidant parameters (enzymic and non-enzymic antioxidants) were measured in the blood and tissue homogenates of the rats. Evaluation of intestinal ulcer score and assessment of liver and kidney histology were also done. DISCUSSION: Alterations in the levels of biochemical and antioxidant assays and histopathological changes in liver and kidney proved the toxic effect of diclofenac. The ulcer score was significantly increased in the diclofenac treated rats. Spirulina fusiformis showed to reduce such changes and was able to restore normal antioxidant status in the rats. CONCLUSION: Our study proves the hepato renal and gastroprotective activity of Spirulina fusiformis in diclofenac-treated rats. PMID- 28092841 TI - Phytochemical study and protective effect of Trigonella foenum graecum (Fenugreek seeds) against carbon tetrachloride-induced toxicity in liver and kidney of male rat. AB - Liver and kidney diseases are a global concern, therefore considerable efforts to obtain fine herbs useful as drugs from medicinal plants are currently in progress. The aim of this work was to study the antioxidant effects of previous supplementation with fenugreek seeds (FS) against carbon tetrachloride (CCl4) toxicity in the liver and kidney. CCl4 toxicity was induced by one dose (i.g. 5ml CCl4/kg of body weight, 50% CCl4 in olive oil) after 7 weeks of normal diet or diet rich in 10% of grinded fenugreek seeds (20g of pellet rat food/rat/day). 24h after the treatment with CCl4, all animals were scarified and biological analyses were performed. A phytochemical study of fenugreek seed extract (FSE) was also carried out. The phytochemical analysis of FS and FSE revealed the presence of polyphenols (5.92+/-0.02mg EGA/g DM), flavonoids (0.44+/-0.19mg ER/g DM), polysaccharides and trace elements. DPPH radical-scavenging activity of FSE showed an EC50 of 285.59+/-2.01MUg/ml. In vivo, CCl4 administration significantly (p<0.05) induced an increase liver and kidney biomarkers. A significant (p<0.05) alteration of the antioxidant enzyme activities was also observed. In animals pretreated with FS, the studied parameters were much less shifted. These results indicate that the supplementation with fenugreek seeds is significantly effective in protecting the liver and kidneys from CCl4 toxicity. PMID- 28092842 TI - Blocking TGF-beta1 by P17 peptides attenuates gastric cancer cell induced peritoneal fibrosis and prevents peritoneal dissemination in vitro and in vivo. AB - Our previous study demonstrated that the peritoneal stroma environment favors proliferation of tumor cells by serving as a rich source of growth factors and chemokines known to be involved in tumor metastasis. In this study, we investigated the interaction between gastric cancer cells and peritoneal mesothelial cells, and determined the effects of TGF-beta1 in this processing. Human peritoneal tissues and peritoneal wash fluid were obtained, which examined by hematoxylin and eosin staining or ELISA for measurements of TGF-beta1 levels. The peritoneal mesothelial cells were co-incubated with the supernatants of gastric cancer, the expression of TGF-beta1, collagen and fibronectin was observed by ELISA and western blot. We then investigated the effects of serum free conditioned media from HSC-39 gastric cancer cells on the peritoneum of nude mice, and the effects of peritoneal fibrosis on the development of peritoneal metastasis in vivo. The peritoneum from gastric patients were thickened and contained extensive fibrosis. After co-culture both gastric tumor cells and mesothelial cells, we found that TGF-beta1 expression was greatly increased in the co-culture system compared to individual culture condition. Serum-free Conditioned Media from HSC-39 was able to induce extracellular matrix expression in vitro and in vivo, and tumorigenicity in mice with peritoneal fibrosis was greater than in mice with normal peritoneum, while blocking TGF-beta1 by peptide P17 can partially inhibit these effects. In conclusion, these results indicated that the interaction of gastric cancer with peritoneal fibrosis and determined that TGF-beta1 plays a key role in induction of peritoneal fibrosis, which in turn affected dissemination of gastric cancer. PMID- 28092843 TI - Therapeutic effects of bach1 siRNA on human breast adenocarcinoma cell line. AB - BACKGROUND: Despite the great improvements in clinical and therapeutic techniques in recent years, many advanced breast cancer patients still died of the postoperative recurrence and metastasis of disease. Bach1 plays a role in the development of the invasive phenotypes of cancer, cell division and apoptosis in tumor cells. The aim of this study was to investigate the effect of specific bach1 siRNAs, on the proliferation, migration, invasive, induction of apoptosis, cell cycle arrest and alter EMT related miRNA of MDA-MB-468 cells (breast cancer). METHODS: siRNA transfection was performed with transfection reagent. The expression levels of Bach1 mRNA and protein were measured by qRT-PCR and western blot analysis, respectively. The survival of cells was determined using MTT assay cells, apoptosis using Tunel assay, Cell migration using scratch assay and Cell cycle analysis by Propidium Iodide (PI) DNA staining method by using flow cytometry on the MDA-MB-468. The expression levels of MMP-9 and CXCR4 were measured by qRT-PCR. RESULTS: Transfection with siRNA significantly suppressed the expression of bach1 gene in dose dependent manner after 48h (p<0.0001). Surprisingly, treatment with bach1 siRNA arrest cell cycle in S phases (p<0.0001). Moreover siRNA transfection had effects on breast adenocarcinoma cells and inhibits the migration (p<0.0001), proliferation (p<0.0001), cell cycle arrest (p=0.03) and induces apoptosis (p<0.0001) and reduces the expression of miR-21 (P=0.0014). CONCLUSION: Our results suggest that the bach1 can be considered as a potent adjuvant in breast cancer therapy. PMID- 28092844 TI - Enhanced effect in combination of curcumin- and ketoconazole-loaded methoxy poly (ethylene glycol)-poly (epsilon-caprolactone) micelles. AB - In order to enhance water-solubility and realize controlled release while keeping synergistic effects of ketoconazole and curcumin, drug-loaded methoxy poly (ethylene glycol)-b-poly (epsilon-caprolactone) micelles were prepared through thin membrane hydration method. Transmission electric microscopy and dynamitic light scattering characterization revealed the formation of ketoconazole- and curcumin-loaded micelles with an average size of 44.70nm and 39.56nm, respectively. The drug-loaded micelles endowed the two drugs' slow controlled release with water-solubility enhanced to 85 and 82000 folds higher than the corresponding raw drugs, respectively. In vitro antifungal activity test, chequerboard test and inhibition zone test indicated that efficacy of ketoconazole-loaded micelles was improved by introduction of curcumin-loaded micelles with a low fractional inhibitory concentration index (0.073). Biofilm formation inhibition assay also demonstrated that participation of curcumin loaded micelles obviously strengthened the inhibition of fungal biofilms formation induced by ketoconazole-loaded micelles. The high synergistic activity of combinations is encouraging and the MPEG-PCL micelle is a potential drug delivery system for the combination of ketoconazole and curcumin. PMID- 28092845 TI - Cinnamaldehyde potentially attenuates gestational hyperglycemia in rats through modulation of PPARgamma, proinflammatory cytokines and oxidative stress. AB - Cinnamon has a history of use for medicinal purposes and its major benefits have been linked to cinnamaldehyde. The present study aimed to investigate the hypoglycemic action of cinnamaldehyde against fatty-sucrosed diet/streptozotocin (FSD/STZ)-rat model of gestational diabetes. Female albino rats were divided into three groups. Group I fed with normal diet (ND) while group II and III were fed with FSD for eight weeks (five weeks pre-gestational and three weeks gestational). Rats of group III were administered with a daily oral dose of 20mg/kg cinnamaldehyde one week before mating onward. At the 7th day of gestation, FSD-fed rats were injected intraperitoneally with STZ (25mg/kg b.wt.) to induce gestational diabetes. Pre-mating treatment of cinnamaldehyde controls hyperphagia and glucose intolerance during the gestational period than in diabetic rats. It also reduced levels of fructosamine, total cholesterols, triglycerides, leptin, tumor necrosis factor-alpha (TNF-alpha), malondialdehyde (MDA) and nitric oxide (NO), while it significantly increased levels of high density lipoprotein (HDL)-cholesterol, adiponectin, liver glycogen, reduced glutathione (GSH) and catalase activity at term pregnancy. In addition, cinnamaldehyde administration up-regulated the mRNA expression of peroxisome proliferated activated receptor-gamma (PPARgamma) and also ameliorated the number of viable fetuses, implantation loss sites, fetal glucose and insulin levels. In conclusion, cinnamaldehyde has safe hypoglycemic action on gestational diabetes by potentiating insulin secretion and sensitivity through activating the antioxidant defense system, suppressing pro-inflammatory cytokines production, upregulating PPARgamma gene expression and alleviating the reproductive performance. PMID- 28092846 TI - Status epilepticus in patients with cirrhosis: How to avoid misdiagnosis in patients with hepatic encephalopathy. AB - PURPOSE: Status epilepticus (SE) in patients with cirrhosis is a rare but serious situation. Diagnosis may be difficult in emergency presentation, especially when patients present with hepatic encephalopathy (HE). Misdiagnosis must be avoided since some anti-epileptic drugs aggravate HE. In this retrospective study, we therefore assessed the frequency of SE in patients with cirrhosis, evaluated the accuracy of diagnosis and determined rates of mortality. METHOD: We reviewed data from all patients hospitalized from 2005 to 2013 in the Hepatology ICU for complications of cirrhosis with an initial diagnosis of SE. We attempted to reach a consensus decision on a possible diagnosis of SE in reviews of EEG traces and medical records by an expert electrophysiologist, a hepatologist and a neurologist. RESULTS: An initial diagnosis of SE was made for 20 patients with cirrhosis. Critical review suggested that 15 of these patients were correctly diagnosed with true SE. However, initial diagnoses may have been mistaken for at least 3 patients, who presented clinical and electrical signs of HE without evidence for SE. Overall, we estimated a prevalence of 0.7% for SE in patients with cirrhosis (15 of 2010 patients admitted to our ICU) in our series. In hospital mortality was of 73%. In the 12 months after the SE episode, mortality was 87%. CONCLUSION: As SE may be misdiagnosed in patients with cirrhosis, a joint review of the patients by neurologists and hepatologists could reduce errors in diagnosis. PMID- 28092847 TI - Repetitive transcranial magnetic stimulation for the treatment of post-stroke depression: A systematic review and meta-analysis of randomized controlled clinical trials. AB - BACKGROUND: Every year, more than fifteen million people worldwide experience a stroke, nearly 30% of stroke survivors are likely to experience post-stroke depression (PSD). Repetitive transcranial magnetic stimulation (rTMS) is one of the emerging techniques which assist in targeting rehabilitation after stroke. Although deterioration of PSD greatly affects the recovery and quality of life of stroke sufferers, the effect of rTMS therapy has not been systematically studied. OBJECTIVE: A systematic review and meta-analysis was conducted to determine the effect of rTMS on PSD. METHODS: We carried out a systematic review and meta analysis of randomized controlled trials (RCTs) of rTMS for the treatment of PSD. Primary outcome was severity of depression measured by the Hamilton Depression Rating Scale (HAMD). Secondary outcomes were response rates, remission rates, stroke severity and ability to perform daily activities. RESULTS: 22 RCTs studies (n=1764 patients) were included. The results demonstrated that rTMS was beneficial on PSD using three scales: HAMD (MD=-6.09, 95% CI: -7.74, -4.45, P<0.001); response rates (OR=3.46, 95% CI: 2.52, 4.76, P<0.00001); remission rates (OR 0.99, 95% CI: 0.56, 1.75, P<0.00001); National Institutes of Health Stroke Scale (NIHSS) (MD=-2.74, 95% CI: -3.33, -2.15, P<0.001); Activities of daily living (ADL) (SMD=-1.20, 95% CI: 0.68, 1.72, P<0.001); Montgomery-Asberg Depression Scale (MARDE) (MD=-6.21; 95% CI: -9.34, -3.08; P=0.0001); CONCLUSION: In present meta-analysis, the positive findings suggest rTMS has beneficial effects on PSD. However, those findings should be treated with caution because of heterogeneity and potential biases. PMID- 28092848 TI - The initial use of arterial spin labeling perfusion and diffusion-weighted magnetic resonance images in the diagnosis of nonconvulsive partial status epileptics. AB - BACKGROUND: In the diagnosis of nonconvulsive status epilepticus (NCSE), capture of ongoing ictal electroencephalographic (EEG) findings is the gold standard; however, this is practically difficult without continuous EEG monitoring facilities. Magnetic resonance imaging (MRI), including diffusion-weighted imaging (DWI) and perfusion MRI with arterial spin labeling (ASL), have been applied mainly in emergency situations. Recent reports have described that ictal MRI findings, including ictal hyperperfusion on ASL and cortical hyperintensity of cytotoxic edema on DWI, can be obtained from epileptically activated cortex. We demonstrate the characteristics and clinical value of ictal MRI findings. METHODS: Fifteen patients diagnosed as having NCSE (eight had complex partial status epilepticus (SE) and seven subtle SE) who underwent an initial MRI and subsequent EEG confrmation, participated in this study. Follow-up MRI and repeated routine EEG were performed. RESULTS: In 11 patients (73%), ictal MRI findings were obtained on both DWI and ASL, while in four (27%) patients, ictal hyperperfusion was found on ASL without any DWI findings being obtained. In all 10 patients with an epileptogenic lesion, there was a tight topographical relationship between the lesion and the localization of ictal MRI findings. In the other five patients, ictal MRI findings were useful to demonstrate the pathophysiological mechanism of NCSE of non-lesional elderly epilepsy, or 'de novo' NCSE of frontal origin as situation-related NCSE. Ictal MRI findings are generally transient; however, in three cases they still persisted, even though ictal EEG findings had completely improved. CONCLUSION: The present study clearly demonstrates that the initial use of ASL and DWI could help to diagnose partial NCSE and also combined use of the MRI and EEG allows documentation of the pathophysiological mechanism in each patient. PMID- 28092849 TI - Magnesium and manganese affect photosynthesis, essential oil composition and phenolic compounds of Tanacetum parthenium. AB - The accumulation of plant defense metabolites is closely associated with the concentration of nutrient elements, yet data related to the interactive effects of two nutrients on the deployment of phenolics and terpenoids are scare. In the present study, the interaction between magnesium (Mg) and manganese (Mn) on nutrient uptake, photosynthesis, oxidative status and the accumulation of phenolics and terpenoids in the leaves of feverfew plants grown at different concentrations of Mg and Mn was investigated. Nutrient uptake and photosynthesis were associated with the amount of applied Mg but could be modified by the concentration of Mn. Phenolic biosynthetic enzymes and individual phenolics were not only induced by Mg, but their levels were also dependent on the Mn supply. Additionally, the proportion of monoterpenes was enhanced by a deficiency of Mg rather than an excess of Mn. Deprivation of Mg also decreased the proportion of sesquiterpenes in the essential oil. Therefore, it appears that a high Mg and a low Mn supply lead to a marked shift from monoterpene to sesquiterpene production. Phenolic compounds also differentially accumulated under varying Mg and Mn concentrations. These results suggest a profound effect of the combined supply of Mg and Mn on the biosynthesis of terpenes and phenolics. PMID- 28092850 TI - Tomato SlGGP-LIKE gene participates in plant responses to chilling stress and pathogenic infection. AB - Plants are always exposed to abiotic and biotic stresses which can adversely affect their growth and development. As an important antioxidant, AsA plays a vital role in plant defence against damage caused by stresses. In this study, we cloned a tomato GDP-L-galactose phosphorylase-like (SlGGP-LIKE) gene and investigated its role in resistance to abiotic and biotic stresses by using antisense transgenic (AS) tomato lines. The AsA content in AS plants was lower than that in WT plants. Under chilling stress, the growth of AS plants was inhibited significantly, and they yielded higher levels of ROS, REC and MDA but demonstrated weaker APX activity than that shown by WT plants. Additionally, the declined values of Pn, Fv/Fm, oxidisable P700, and D1 protein content of PSII in AS lines were significant. Furthermore, the effect on xanthophyll cycle of AS plants was more severe than that on WT plants, and the ratio of zeaxanthin (Z)/(V + A + Z) and (Z + 0.5 A)/(V + A + Z) in AS lines was lower than that in WT plants. In spite of chilling stress, under Pseudomonas syringae pv.tomato (Pst) DC3000 strain infection, AS plants showed lesser bacterial cell growth and dead cells than those shown by WT plants. This finding indicated that AS plants demonstrated stronger resistance against pathogenic infection. Results suggest that SlGGP-LIKE gene played an important role in plant defence against chilling stress and pathogenic infection. PMID- 28092851 TI - Plasmid DNA affinity partitioning using polyethylene glycol - sodium sulfate aqueous two-phase systems. AB - Extraction of plasmid DNA (pDNA) from an alkaline bacterial cell lysate has been investigated using partitioning and affinity partitioning in aqueous two-phase systems (ATPSs) containing 12% (w/w) polyethylene glycol and 12% (w/w) sodium sulfate. In this work, a modified 20bp pyrimidine oligonucleotide acting as a triplex-forming oligonucleotide (TFO) was employed as an affinity ligand to improve the partition behavior. The pUC118 plasmid was chosen to be extracted because of its specific oligonucleotide recognition sequence. In order to find the proper conditions, operational parameters such as PEG molecular weight, pH and lysate load were also studied. The results showed that adding the affinity ligand strongly changed the partitioning behavior of pDNA without any considerable impact on the partitioning of RNA and protein content. The best achieved result was at pH=6 and PEG MW of 600Da and 60% of lysate load. In these conditions, 67% of pDNA was recovered in the top phase while the contaminants mainly accumulated in the bottom phase. PMID- 28092852 TI - Graphene oxide adsorbent based dispersive solid phase extraction coupled with multi-pretreatment clean-up for analysis of trace aflatoxins in traditional proprietary Chinese medicines. AB - Graphene oxide (GO)-based dispersive solid phase extraction (D-SPE) method combined with multi-step preparation has been proposed for the evaluation of trace aflatoxins in proprietary Chinese medicines (PCM). After being extracted by methanol, the sample was purified based on multi-step preparation, including dehydration with MgSO4/NaCl and cleanup with neutral alumina. Then GO was used as an adsorbent in D-SPE method for further preconcentration of aflatoxins prior to high performance liquid chromatography-fluorescence detection. The selected conditions were investigated. The Box-Behnken design (BBD) was used to optimize factors affecting adsorption procedure. Under the optimized conditions, good linear relationships had been achieved with the correlation coefficient (R2) varying from 0.9904 to 0.9990. The LODs and LOQs were ranging from 0.020 to 0.041ng/mL and 0.061 to 0.125ng/mL, respectively. The results of the recoveries were 74.0-102.7% for the four aflatoxins, while the precisions from 1.8% to 7.2% were obtained, which indicated that the method was suitable for the analysis of aflatoxins in PCM. PMID- 28092853 TI - Operative vaginal delivery and invasive procedures in pregnancy among women living with HIV. AB - OBJECTIVES: To describe the use and outcomes of operative delivery and invasive procedures in pregnancy amongst women living with HIV. STUDY DESIGN: The National Study of HIV in Pregnancy and Childhood (NSHPC) is a comprehensive population based surveillance study in the UK and Ireland. The NSHPC has collected data on operative delivery since 2008, and invasive procedures in pregnancy (amniocentesis, cordocentesis, chorionic villus sampling) from 2012. Descriptive analyses were conducted on 278 pregnancies expected to deliver from 1 January 2008 with outcome reported to the NSHPC by 31 March 2016. RESULTS: Among 9372 pregnancies in 2008-2016, there were 9072 livebirths with 251 operative deliveries and 27 invasive procedures in pregnancy reported. Information was available for 3023/3490 vaginal deliveries, and use of forceps or vacuum reported in 251deliveries (8.2%), increasing over calendar time to almost 10% by 2014-16. Forceps were used twice as often as vacuum delivery, and forceps use increased over time. One infant delivered operatively is known to have acquired HIV. From 2012 there were 4063 pregnancies resulting in 3952 livebirths, 83 terminations and 28 stillbirths. 2163/4063 had information on use (or not) of invasive procedures in pregnancy. Amniocentesis was reported in 25/2163 pregnancies, there was one report of chorionic villus sampling and one of cordocentesis. There were no reported transmissions following invasive procedures in pregnancy. CONCLUSIONS: This is the largest study to date to report on operative delivery in women living with HIV on combined antiretroviral therapy (cART), and provides an up-to-date picture of invasive procedures during pregnancy in this group. Findings from this comprehensive national study are reassuring but numbers are currently low; on-going monitoring is crucial as obstetric care of women with HIV becomes normalised. PMID- 28092854 TI - Biopharmaceutical characterization of praziquantel cocrystals and cyclodextrin complexes prepared by grinding. AB - Mechanochemical activation using several different co-grinding additives was applied as a green chemistry approach to improve physiochemical and biopharmaceutical properties of praziquantel (PZQ). Liquid assisted grinding with an equimolar amount of citric acid (CA), malic acid (MA), salicylic acid (SA) and tartaric acid (TA) gained in cocrystal formation, which all showed pH-dependent solubility and dissolution rate. However, the most soluble cocrystal of PZQ with MA was chemically unstable, as seen during the stability testing. Equimolar cyclodextrin complexes prepared by neat grinding with amorphous hydroxypropyl beta-cyclodextrin (HPbetaCD) and randomly methylated beta-cyclodextrin (MEbetaCD) showed the highest improvement in drug solubility and the dissolution rate, but only PZQ/HPbetaCD product presented an acceptable chemical and photostability profile. A combined approach, by co-grinding the drug with both MA and HPbetaCD in equimolar ratio, also gave highly soluble amorphous product which again was chemical instable and therefore not suitable for the pharmaceutical use. Studies on Caco-2 monolayer confirmed the biocompatibility of PZQ/HPbetaCD complex and showed that complexation did not adversely affect the intrinsically high PZQ permeability (Papp(PZQ)=(3.72+/-0.33)*10-5cms-1 and Papp(PZQ/HPbetaCD)=(3.65+/ 0.21)*10-5cms-1; p>0.05). All this confirmed that the co-grinding with the proper additive is as a promising strategy to improve biopharmaceutical properties of the drug. PMID- 28092855 TI - LC-MS/MS determination of d-mannose in human serum as a potential cancer biomarker. AB - Several metabolites in human serum have been identified as potential cancer biomarkers for early detection. This study focuses on the LC-MS/MS method development and validation of d-mannose in human serum. Surrogate blank serum, coupled with stable isotope d-mannose-13C6, as internal standard, was used for generating standard curves ranging from 1 to 50MUg/mL. Separation was achieved by an Agilent 1200 series HPLC equipped with a SUPELCOGELTM Pb, 6% Crosslinked column with HPLC water as a mobile phase at flow rate of 0.5mL/min at 80 degrees C. Mass detection was performed under negative ionization electrospray. Inter- and intra-day accuracy and precision were <2%. The extraction recovery and matrix effect were 104.1%-105.5% and 97.0%-100.0%, respectively. This method was successfully applied for the quantification of d-mannose in the serum samples of 320 esophageal cancer patients and 323 healthy volunteers. We report a simple, specific and reproducible LC-MS/MS method for the quantification of d-mannose in human serum as a potential cancer biomarker. PMID- 28092856 TI - Separation of antibody drug conjugate species by RPLC: A generic method development approach. AB - This study reports the use of modelling software for the successful method development of IgG1 cysteine conjugated antibody drug conjugate (ADC) in RPLC. The goal of such a method is to be able to calculate the average drug to antibody ratio (DAR) of and ADC product. A generic method development strategy was proposed including the optimization of mobile phase temperature, gradient profile and mobile phase ternary composition. For the first time, a 3D retention modelling was presented for large therapeutic protein. Based on a limited number of preliminary experiments, a fast and efficient separation of the DAR species of a commercial ADC sample, namely brentuximab vedotin, was achieved. The prediction offered by the retention model was found to be highly reliable, with an average error of retention time prediction always lower than 0.5% using a 2D or 3D retention models. For routine purpose, four to six initial experiments were required to build the 2D retention models, while 12 experiments were recommended to create the 3D model. At the end, RPLC can therefore be considered as a good method for estimating the average DAR of an ADC, based on the observed peak area ratios of RPLC chromatogram of the reduced ADC sample. PMID- 28092857 TI - Universal efavirenz determination in transport study, rat placenta perfusion and placenta lysate by HPLC-UV. AB - Efavirenz is an antiretroviral drug used in the treatment of HIV-positive patients. A simple, fast and sensitive high-performance liquid chromatography (HPLC) method was developed in order to determine efavirenz in three types of samples provided from pharmacokinetic studies. The analysis took 5min and was performed using a C18 analytical column (Discovery HS C18, 150*4.6mm, particle size of 5MUm) in isocratic mode with a mobile phase containing acetonitrile and water (65:35, v/v), a flow rate of 1.6mLmin-1, a sample volume of 10MUL and UV detection at 245nm. Three different sample matrices (Opti-MEM medium, Krebs perfusion liquid and tissue lysate) and their treatment (dilution, SPE) were considered. The validated method was applied for the analysis of 805 real samples arising from in vitro transcellular transport assays and in vivo organ perfusion experiments in order to evaluate the interaction of efavirenz with ATP-dependent drug efflux transporters. The lack of interaction of efavirenz with ABCB1, ABCG2 and ABCC2 transporters as well as technical aspects of this analysis, including the adhesion of efavirenz to the plastic materials and the stability of the drug during different tissue lysis approaches are discussed. PMID- 28092858 TI - The synthesis and antistaphylococcal activity of 9, 13-disubstituted berberine derivatives. AB - A series of novel 9, 13-disubstituted berberine derivatives have been synthesized and evaluated for the antibacterial activities against Staphylococcus aureus, including Newman strain and multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108, and NRS-271). Compound 20 shows the most potent activity against the growth of Newman strain, with a MIC value of 0.78 MUg/mL, which is comparable with the positive control vancomycin. In addition, compound 20, 21, and 33 are highly antistaphylococcal active against five strains of multidrug-resistant S. aureus, with MIC values of 0.78-1.56 MUg/mL. Of note, theses antibacterial active compounds have no obvious toxicity to the viability of human fibroblast (HAF) cells at the MIC concentration. PMID- 28092859 TI - N-(2-(arylmethylimino)ethyl)-7-chloroquinolin-4-amine derivatives, synthesized by thermal and ultrasonic means, are endowed with anti-Zika virus activity. AB - Zika virus (ZIKV), an emerging Flavivirus, was recently associated with severe neurological complications and congenital diseases. Therefore, development of antiviral agents capable of inhibiting ZIKV replication is urgent. Chloroquine is a molecule with a confirmed safety history for use with pregnant women, and has been found to exhibit anti-ZIKV activity at concentrations around 10 MUM. This suggests that modifications to the chloroquine structure could be promising for obtaining more effective anti-ZIKV agents. Here, we report the ability of a series of N-(2-(arylmethylimino)ethyl)-7-chloroquinolin-4-amine derivatives to inhibit ZIKV replication in vitro. We have found that the quinoline derivative, N (2-((5-nitrofuran-2-yl)methylimino)ethyl)-7-chloroquinolin-4-amine, 40, was the most potent compound within this series, reducing ZIKV replication by 72% at 10 MUM. Compound 40 exhibits an EC50 value of 0.8 +/- 0.07 MUM, compared to that of chloroquine of 12 +/- 3.2 MUM. Good activities were also obtained for other compounds, including those with aryl groups = phenyl, 4-fluorophenyl, 4 nitrophenyl, 2,6-dimethoxyphenyl, 3-pyridinyl and 5-nitrothien-2-yl. Syntheses of these quinoline derivatives have been obtained both by thermal and ultrasonic means. The ultrasonic method produced comparable yields to the thermal (reflux) method in very much shorter times 30-180 s compared to 30-180 min reactions times. These results indicate that this group of compounds is a good follow-up point for the potential discovery of new drugs against the Zika disease. PMID- 28092860 TI - Design, synthesis and biological evaluation of quinazoline-phosphoramidate mustard conjugates as anticancer drugs. AB - A series of novel compounds with phosphoramide mustard functionality incorporated into the quinazoline scaffold of EGFR/HER2 inhibitors were designed and synthesized as multi-target-directed ligands against tumor cells. In vitro assays showed that tumor cell lines with high HER2 level were more sensitive to the compounds than tumor cells with low HER2 level. Compound 10d (EMB-3) was one of the most potent inhibitors with IC50 of 7.4 nM and 82 nM against EGFR and HER2, respectively. The mechanism studies were also supported by the effect of 10d induced DNA damage in MDA-MB-468 cells. In vivo efficacy study showed that 10d could significantly inhibit H522 tumor xenograft model with a TGI of 68% at dose of 100 mg/kg (QDx28, p.o.) and no significant body weight loss was observed. MTD study indicated that compound 10d had no acute toxicity to mice at doses up to 900 mg/kg (single dose). PMID- 28092861 TI - A deafening flash! Visual interference of auditory signal detection. AB - In some people, visual stimulation evokes auditory sensations. How prevalent and how perceptually real is this? 22% of our neurotypical adult participants responded 'Yes' when asked whether they heard faint sounds accompanying flash stimuli, and showed significantly better ability to discriminate visual 'Morse code' sequences. This benefit might arise from an ability to recode visual signals as sounds, thus taking advantage of superior temporal acuity of audition. In support of this, those who showed better visual relative to auditory sequence discrimination also had poorer auditory detection in the presence of uninformative visual flashes, though this was independent of awareness of visually-evoked sounds. Thus a visually-evoked auditory representation may occur subliminally and disrupt detection of real auditory signals. The frequent natural correlation between visual and auditory stimuli might explain the surprising prevalence of this phenomenon. Overall, our results suggest that learned correspondences between strongly correlated modalities may provide a precursor for some synaesthetic abilities. PMID- 28092862 TI - Protective effects of total flavonoids of Astragalus against adjuvant-induced arthritis in rats by regulating OPG/RANKL/NF-kappaB pathway. AB - BACKGROUND: Astragalus membranaceus Bunge is one of the oldest and most frequently used crude herbs in traditional Chinese medicine. The total flavonoids of Astragalus (TFA) are the main active components isolated from Astragalus membranaceus Bunge. Our recent study has shown its potential immunomodulatory and anti-inflammatory effects in vivo and in vitro. However, its anti-arthritic effects and mechanisms of action involved have not been elucidated. The aim of this study was to evaluate the protective effects and possible mechanisms of TFA on Freund's complete adjuvant (FCA)-induced arthritis in rats. METHODS: Wistar rats were intradermally injected FCA into the right hind metatarsal footpads to establish adjuvant-arthritic model. The rats were intragastrically administered daily with TFA at 25, 50 and 100mg/kg for 28days after FCA induction. Body weight, primary paw swelling, arthritis index, thymus and spleen indices were measured. The levels of serum tumor necrosis factor (TNF)-alpha, interleukin (IL) 1beta, prostaglandin (PG)E2, osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL) were determined using ELISA. Histopathological changes and scores in joint tissues were examined using hematoxylin and eosin (H&E). The expression of nuclear factor (NF)-kappaB p65 in synovial tissues was assayed using immunohistochemical method. RESULTS: TFA significantly increased body weight, attenuated primary paw swelling and arthritis index, decreased thymus and spleen indices of rats induced by FCA. Furthermore, TFA significantly inhibited serum TNF-alpha, IL-1beta, PGE2 and RANKL production, and promoted serum OPG production and OPG/RANKL ratio of rats induced by FCA. Histopathological examination indicated that TFA significantly attenuated inflammatory cell infiltration, synovial hyperplasia, pannus formation, and bone and cartilage damage. Immunohistochemical assay indicated that TFA inhibited NF-kappaB p65 expression in synovial tissues of rats induced by FCA. CONCLUSIONS: These results suggest that TFA exerts potential protective effects against FCA-induced arthritis in rats by regulating OPG/RANKL/NF-kappaB pathway. PMID- 28092863 TI - Adipose-derived stem cells ameliorate renal interstitial fibrosis through inhibition of EMT and inflammatory response via TGF-beta1 signaling pathway. AB - Adipose-derived stem cells (ADSCs) have been successfully used to treat acute kidney injury or acute renal failure. However, the effect of ADSCs on treating renal interstitial fibrosis remains unknown. Here, we assessed the therapeutic efficacy of ADSCs on renal interstitial fibrosis induced by unilateral ureter obstruction (UUO) and explored the potential mechanisms. After 7days of UUO, rats were injected with ADSCs (5*106) or vehicle via tail vein. We found that ADSCs administration significantly ameliorated renal interstitial fibrosis, the occurrence of epithelial-mesenchymal transition (EMT) and inflammatory response. Furthermore, ADSCs administration could inhibit the activation of transforming growth factor-beta1 (TGF-beta1) signaling pathway, which might play a crucial role in renal interstitial fibrosis of the UUO model rats. These results suggested that ADSCs treatment attenuates renal interstitial fibrosis possibly through inhibition of EMT and inflammatory response via TGF-beta1 signaling pathway. Therefore, ADSCs may be an effective therapeutic strategy for the treatment of renal interstitial fibrosis. PMID- 28092864 TI - Augmentation of humoral and cellular immunity in response to Tetanus and Diphtheria toxoids by supercritical carbon dioxide extracts of Hippophae rhamnoides L. leaves. AB - Hippophae rhamnoides L. commonly known as Seabuckthorn (SBT), a wild shrub of family Elaegnacea, has extensively used for treating various ailments like skin diseases, jaundice, asthma, lung troubles. SBT leaves have been reported to possess several pharmacological properties including immunomodulatory, antioxidant, anti-inflammatory, antimicrobial and tissue regeneration etc. The present study was undertaken to evaluate the adjuvant property of supercritical carbon dioxide extracts (SCEs 300ET and 350ET) of SBT leaves in balb/c mice immunized with Tetanus and Diphtheria toxoids. The dynamic changes in the immune response were measured in terms of humoral and cell-mediated immune responses. We have seen the effect of SCEs on immunoglobulin subtypes and secondary immune response generation. In addition, the effect of SCEs on antigen specific cellular immunity was evaluated. Our results show that SCEs 300ET and 350ET significantly enhanced antibody titers in response to both TT and DT antigens. The secondary immune response generated was significantly increased in case of TT immunized animals. SCEs also enhanced cytokine levels (IFN-gamma, IL-4, TNF-alpha and IL 1beta) and increased lymphoproliferation. Besides, both SCEs did not show any toxic effects. Therefore, the study suggests that SCEs are safe and have potent immunostimulatory activity and hence, seems to be a promising balanced Th1 and Th2 directing immunological adjuvant for various veterinary as well as human vaccines. PMID- 28092865 TI - Investigations on the immunosuppressive activity of derivatives of mycophenolic acid in immature dendritic cells. AB - The main activity of mycophenolic acid 1 (MPA) and its analogs is the inhibition of proliferation of T cells. Here, we hypothesized that MPA and its conjugates inhibits also the activity of antigen-presenting cells (APC) including dendritic cells (DCs). We tested the effect of novel amino acid derivatives of MPA and conjugates of MPA with acridines/acridones on DCs by flow cytometry, ELISA and MLR assay. Both acridines/acridone derivatives could inhibit the maturation of DC, as shown by the decreased expression of B7 family receptors. It was confirmed in the mixed leucocyte reaction (MLR), in which T cells challenged with DCs pretreated with the analogs showed decreased proliferation and reduced cytokine secretion. The most interesting activity in this series of studies, that is, the suppression of CD86 receptor expression, decreased cytokine production and suppressed mixed leucocyte reaction, exhibited (mycophenoyl-N-3-propyl)-9 acridone-4-carboxamide ester 5a and (mycophenoyl-N-5-pentyl)-9-acridone-4 carboxamide ester 5b. These compounds reduced also the secretion of IL-2 and IL 15. In addition, they increased secretion of suppressive IL-10. Equally promising results were obtained for the N-mycophenoyl-D-glutamic acid 4b, which previously gave the highest value of selectivity. Acridone derivatives of MPA are therefore good immunosuppressive drug candidates for further testing. PMID- 28092866 TI - Transmembrane tumor necrosis factor-alpha promotes the recruitment of MDSCs to tumor tissue by upregulating CXCR4 expression via TNFR2. AB - Myeloid-derived suppressor cells (MDSCs) accumulated in tumor sites promote immune evasion. We found that TNFR deficiency-induced rejection of transplanted tumor was accompanied with markedly decreased accumulation of MDSCs. However, the mechanism(s) behind this phenomenon is not completely understood. Here, we demonstrated that TNFR deficiency did not affect the amount of MDSCs in bone marrow (BM), but decreased accumulation of Gr-1+CD11b+ MDSCs in the spleen and tumor tissues. The chemotaxis of Tnfr-/- MDSCs was prominently decreased in response to both tumor cell culture supernatants and tumor tissue homogenates from Tnfr-/- and wild-type mice, indicating an effect of TNFR signaling on chemokine receptor expression in MDSCs. We used real-time PCR to detect gene expression for several chemokine receptors in MDSCs from BM and found that CXCR4 was the most affected molecule at the transcriptional level in Tnfr-/- MDSCs. Neutralizing CXCR4 in wild-type MDSCs by a specific antibody blocked their chemotactic migration. Interestingly, it was tmTNF-alpha, but not sTNF-alpha, that induced CXCR4 expression in MDSCs. This effect of tmTNF-alpha was totally blocked in TNFR2-/- but not in TNFR1-/- MDSCs, and partially inhibited by PDTC or SB203580, an inhibitor of NF-kappaB or p38 MAPK pathway, respectively. Adoptive transfer of wild-type MDSCs restored MDSCs accumulation in tumors of Tnfr-/- mice, but this could be partially blocked by treatment with a CXCR4 inhibitor AMD3100. Our data suggest that tmTNF-alpha upregulates CXCR4 expression that promotes chemotaxis of MDSCs to tumor, and give a new insight into a novel mechanism by which tmTNF-alpha facilitates tumor immune evasion. PMID- 28092868 TI - A practical evaluation of measurement uncertainty in gamma-ray efficiency curve determination through an analytical approach. AB - An example of uncertainty evaluation of an efficiency curve is reported. In the applied method, the efficiency curve is determined through the weighted least square method based on measured efficiencies employing a mixed-radionuclide standard source. The variance-covariance matrix of the efficiencies is determined by evaluating the uncertainties of the counting, the calibrated radioactivities, the correction factors for true coincidence summing, and the inadequacy of the fitting function. The proposed method can be a basis to develop a more general procedure. PMID- 28092867 TI - Expression of MMP-2 and TIMP-1 during rapid maxillary expansion in rats. AB - OBJECTIVE: The aim of this study was to investigate the expression of MMP-2 and TIMP-1 during midpalatal suture expansion in rats. DESIGN: 72 male Wistar rats were randomly divided into 2 groups: the experimental group and the control group. In the experimental group, opening loops were applied across the midpalatal suture with an initial force of 50g, whereas in the control group, rats were subjected to sham installation of opening loops without activation. On day 1, 4, 7 and 14, nine rats from each group were sacrificed, and the maxillae were dissected and prepared for Immunohistochemistry (IHC) and RT- PCR examination of MMP-2 and TIMP-1 expression. RESULTS: The results of IHC and Real Time PCR revealed that both protein and mRNA expression of MMP-2 and TIMP-1 were significantly increased after midpalatal expansion, and the ratio of MMP-2/TIMP-1 was also significantly enhanced. CONCLUSIONS: The data suggested that MMP-2 and TIMP-1 might play an important role during the mid-palatal suture remodeling process of maxillary expansion. PMID- 28092869 TI - Chronic myelogenous leukemia evolving after treatment of multiple myeloma. PMID- 28092870 TI - Anaplastic variant of plasma cell myeloma with Dutcher bodies. PMID- 28092871 TI - Discrete vacuoles in lymphocytes as a subtle clue to mantle cell lymphoma. PMID- 28092872 TI - Diagnostic pitfall: primary effusion lymphoma with rare cytokeratin immunoreactivity. PMID- 28092873 TI - Reverse variant of follicular lymphoma: uncommon morphology in a common lymphoma. PMID- 28092874 TI - Marked stress dyspoiesis secondary to sepsis and extracorporeal membrane oxygenation. PMID- 28092875 TI - Gelatinous transformation of the bone marrow from anorexia nervosa. PMID- 28092876 TI - Unexpected cause of high fever in the blood film. PMID- 28092878 TI - Amelanotic melanoma in the bone marrow. PMID- 28092877 TI - Peripheral blood findings in GM1 gangliosidosis. PMID- 28092879 TI - Acute myeloid leukemia with erythrophagocytosis indicative of KAT6A rearrangement. PMID- 28092880 TI - Lymphocytosis, villi, and nucleoli: a variant of hairy cell leukemia. PMID- 28092881 TI - Unexpected babesiosis in a patient with worsening anemia after allogeneic hematopoietic stem cell transplantation. PMID- 28092882 TI - Blastic plasmacytoid dendritic cell neoplasm associated with chronic myelomonocytic leukemia. PMID- 28092883 TI - Rhabdomyosarcoma presenting with leukemic phase and massive bone marrow infiltration. PMID- 28092884 TI - Gray-zone lymphoma: a complex reality. PMID- 28092885 TI - Plasma cell leukemia mimicking acute myeloid leukemia. PMID- 28092886 TI - EBV-associated aggressive natural killer cell leukemia. PMID- 28092887 TI - Acute myeloid leukemia with myelodysplasia-related changes demonstrating prominent basophilic differentiation. PMID- 28092889 TI - Acquired elliptocytosis in the setting of a refractory anemia with excess blasts and del(20q). PMID- 28092888 TI - Abnormal chromatin clumping in myeloblasts. PMID- 28092890 TI - Cytokeratin-type intermediate filaments in a gastric myeloid sarcoma: a diagnostic pitfall. PMID- 28092891 TI - Hemophagocytic lymphohistiocytosis secondary to iatrogenic disseminated histoplasmosis. PMID- 28092892 TI - Deformation of erythroblasts in transient erythroblastopenia of childhood caused by HHV-6. PMID- 28092893 TI - Folding two lobes, you don't get a cup? PMID- 28092894 TI - Apoptotic neutrophils in ascitic fluid. PMID- 28092895 TI - Intravascular large B-cell lymphoma in a kidney biopsy. PMID- 28092896 TI - Primary effusion lymphoma and concurrent progressive Kaposi sarcoma associated with elevated interleukin-6. PMID- 28092897 TI - Bone marrow smear examination in the diagnosis of Niemann-Pick B disease. PMID- 28092898 TI - Florid erythrophagocytosis by neutrophils in peripheral blood. PMID- 28092899 TI - B cells mimicking blasts after an allogeneic stem cell transplantation. PMID- 28092900 TI - Mimics of megakaryocytes: giant bizarre myeloma cells. PMID- 28092901 TI - A Waldenstrom amyloidoma. PMID- 28092902 TI - Morphology of Niemann-Pick type C metabolic storage disorder. PMID- 28092903 TI - You GATA look at the marrow! PMID- 28092904 TI - CML with complex chromosome rearrangements and dysplastic megakaryocytes. PMID- 28092905 TI - Endocranial Morphology of the Extinct North American Lion (Panthera atrox). AB - The extinct North American lion (Panthera atrox) is one of the largest felids (Mammalia, Carnivora) to have ever lived, and it is known from a plethora of incredibly well-preserved remains. Despite this abundance of material, there has been little research into its endocranial anatomy. CT scans of a skull of P. atrox from the Pleistocene La Brea Tar pits were used to generate the first virtual endocranium for this species and to elucidate previously unknown details of its brain size and gross structure, cranial nerves, and inner-ear morphology. Results show that its gross brain anatomy is broadly similar to that of other pantherines, although P. atrox displays less cephalic flexure than either extant lions or tigers, instead showing a brain shape that is reminiscent of earlier felids. Despite this unusual reduction in flexure, the estimated absolute brain size for this specimen is one of the largest reported for any felid, living or extinct. Its encephalization quotient (brain size as a fraction of the expected brain mass for a given body mass) is also larger than that of extant lions but similar to that of the other pantherines. The advent of CT scans has allowed nondestructive sampling of anatomy that cannot otherwise be studied in these extinct lions, leading to a more accurate reconstruction of endocranial morphology and its evolution. PMID- 28092907 TI - Sinus Thrombosis after Endovascular Treatment of Vein of Galen Aneurysmal Malformation. PMID- 28092906 TI - Association between Nicotinamide Phosphoribosyltransferase and de novo Lipogenesis in Nonalcoholic Fatty Liver Disease. AB - OBJECTIVE: This study explored the association between serum nicotinamide phosphoribosyltransferase (NAMPT) and hepatic de novo lipogenesis (DNL) in nonalcoholic fatty liver disease (NAFLD) and determined whether or not this association is sex dependent. SUBJECTS AND METHODS: In this cross-sectional study, 62 consecutive patients (32 males, 30 females) with NAFLD were recruited. Serum NAMPT (by ELISA), palmitic acid, and the DNL index of erythrocyte membranes as markers of hepatic DNL (by gas chromatography) were analyzed. The controlled attenuation parameter (CAP) and body impedance analyzer were used to assess hepatic and body fat, respectively. Univariate and multiple linear regressions (to adjust for confounders) were used to analyze the association of serum NAMPT with palmitic acid, DNL index, CAP, and body fat. RESULTS: The respective values of serum NAMPT (2.44 +/- 1.03 vs. 2.45 +/- 1.13 ng/mL, p = 0.98), DNL index (3.11 [2.60-3.71] vs. 3.05 [2.40-3.59], p = 0.90), and palmitic acid (20.55% [15.34 24.04] vs. 22.64% [21.15-25.95], p = 0.07) were not significantly different between men and women, but those of CAP (326 [300-340] vs. 300 [261.25-329], p = 0.002) and body fat (37.71 +/- 3.80 vs. 26.60 +/- 5.70, p < 0.001) were significantly higher in women. In women, serum NAMPT had a significant negative association with the DNL index (beta = -0.56, p = 0.01). The DNL index also had a significant negative association with body fat (beta = -0.46, p = 0.02). In men, the only significant association was the positive association between serum NAMPT and CAP (beta = 0.35, p = 0.035). CONCLUSION: Higher serum NAMPT in women was associated with a lower hepatic DNL index, while in men it was associated with higher hepatic fat and had no association with the DNL index. Therefore, the serum NAMPT level interpretation for NAFLD prognosis is probably sex dependent. PMID- 28092908 TI - 2016 Biennial Meeting of the American Society for Stereotactic and Functional Neurosurgery, Chicago, IL, USA, June 18-21, 2016: Abstracts. PMID- 28092909 TI - Immune-Mediated Neuropathies following Autologous Stem Cell Transplantation for Multiple Myeloma: Case Series and Review of the Literature. AB - Neuropathy is a common finding in patients with multiple myeloma. Several different factors can cause neuropathy in these patients, such as the underlying disease itself, medications used for treatment, or immune-mediated processes. Immune-mediated neuropathies (IMN) consist of a heterogeneous spectrum of peripheral nerve disorders. Although IMN is associated with several hematological disorders, it remains a very rare complication of hematopoietic stem cell transplantation (HCT). We describe our experiences of 3 patients with multiple myeloma who experienced IMN following autologous HCT (auto-HCT). These 3 patients were felt to have IMN clearly attributable to auto-HCT because of a clear temporal association with auto-HCT and absence of any other obvious causative factor. The variety in their clinical presentations, diagnostic approach, and approaches to management are explained. The pathophysiology of how HCT may predispose to IMN remains poorly understood. Our report helps highlight several potential causes of this phenomenon, such as a paraneoplastic syndrome, immune reconstitution syndrome, or drug toxicity. We emphasize that a comprehensive approach is needed to address this rare entity, and that there should be a low threshold to initiate immune-specific therapy, such as plasmapheresis, if symptoms do not resolve spontaneously. PMID- 28092910 TI - Effects of in utero and Postnatal Exposure to Secondhand Smoke on Lung Function by Gender and Asthma Status: The Seven Northeastern Cities (SNEC) Study. AB - BACKGROUND: Little information exists on whether gender or asthma status modifies the effects of secondhand smoke (SHS) exposure on lung function. OBJECTIVE: To evaluate whether gender or asthma status modifies the association of SHS exposure with lung function. METHODS: A total of 6,740 children (average 11.6 years) were recruited from 24 districts of 7 cities in northeast China in 2012. SHS exposure included exposure to environmental and maternal smoking both in utero and during early childhood (postnatal). Lung function was measured using electronic spirometers. Two-step regressions were used to analyze the association between SHS and lung function. RESULTS: In utero and postnatal exposure to SHS was independently associated with decreased lung function in both genders; however, this association was greater among males. For example, when exposed to maternal smoking during pregnancy, the adjusted odds ratio (aOR) for decreased forced vital capacity (FVC) was 6.46 (95% confidence interval [CI]: 2.58-16.17) among males, while only 2.16 (95% CI: 0.96-4.88) among females. More positive associations between SHS exposure and decreased lung function were detected among nonasthmatic compared with asthmatic children. Nonasthmatics had significantly larger deficits from in utero exposure to maternal smoking, which concerned decreased lung FVC function (aOR = 2.58, 95% CI: 1.28-5.21) and decreased lung forced expiratory volume in 1 s (FEV1) function (aOR = 2.32, 95% CI: 1.01-5.33). A similar pattern was also observed for the associations between SHS exposure and continuous pulmonary function test measurements. CONCLUSIONS: SHS exposure was associated with decreased lung function. Males and nonasthmatics seem to be more susceptible than their respective counterparts. PMID- 28092911 TI - Behaviour of CD11b-Positive Cells in an Animal Model of Laser-Induced Choroidal Neovascularisation. AB - BACKGROUND/AIM: Immune cells, e.g. microglial cells of the retina, appear to be involved in pathological processes in neovascular age-related macular degeneration. Therefore, the purpose of this study was to immunohistochemically check the expression of various factors and cytokines by CD11b-positive (CD11b+) immune cells in an animal model of choroidal neovascularisation (CNV). METHODS: We used the animal model of laser-induced CNV in mice. Eyes were isolated at 1, 4, 7, and 14 days after laser treatment. Cryosections were prepared and checked immunohistochemically for the presence of different growth factors and cytokines on microglial cells and other immune cells identified by CD11b immunoreactivity. RESULTS: We found that the number of CD11b+ cells at the laser spots increased dramatically 4 days after laser treatment, the majority of them entering the laser spot most probably by migration. CD11b+ cells in the laser spot were positive for a variety of pro-angiogenic factors, such as PDGF-beta, FGF-1, FGF 2, and TGF-beta1. They were also positive for some inflammatory cytokines, in particular TNF-alpha, IL-6, and CXCL1. In non-treated retinas, CD11b+ cells showed almost no immunoreactivity for these proteins. CONCLUSION: Microglial cells, macrophages, and other CD11b+ cells may promote the neovascularisation in the laser spot and show a moderate inflammatory behaviour. Immunoreactivity for most of these molecules was found to decrease during the time of observation. Modulation of immune cell activity may thus be a tool to reduce the extent of CNV. PMID- 28092912 TI - Production and Rheological Properties of Welan Gum Produced by Sphingomonas sp. ATCC 31555 with Different Nitrogen Sources. AB - This study aimed to investigate the effect of nitrogen sources on the production and rheological properties of welan gum produced by Sphingomonas sp. ATCC 31555. Six different nitrogen sources were used for ATCC 31555 fermentation, and 2 of these were further analyzed due to their more positive influence on welan gum production and bacterial biomass. Bacterial biomass, welan gum yield, welan viscosity, molecular weight, monosaccharide composition, acyl content, and welan structure were analyzed. Welan gum production and the biomass concentration of ATCC 31555 were higher in media containing NaNO3 and beef extract. Welan viscosity decreased at higher temperatures of 30-90 degrees C, and it increased with a higher welan concentration. In the media containing NaNO3 (3 g.L-1), welan viscosity was higher at 30-70 degrees C and a welan solution concentration of 6 10 g.L-1. With a reduced NaNO3 concentration, the molecular weight of welan gum and the molar ratio of mannose decreased, but the molar ratio of glucuronic acid increased. With different nitrogen sources, the acetyl content of welan gum differed but its structure was similar. NaNO3 and beef extract facilitated welan production. A reduced NaNO3 concentration promoted welan viscosity. PMID- 28092914 TI - Paraneoplastic Cerebellar Degeneration Associated with Pelvic Liposarcoma: A Rare Case Report. AB - Paraneoplastic cerebellar degeneration (PCD) is one of the most common paraneoplastic neurological syndromes characterized by the rapid development of severe cerebellar ataxia. In this report, a 23-year-old female with noticeable dizziness and gait instability was described. The enhanced CT scanning suggested the presence of a pelvic tumor. Then, PCD was established. Postoperative pathological result defined it as a liposarcoma (LS) with dedifferentiation. Interestingly, clinical symptoms disappeared after the surgical removal of the pelvic tumor. To our knowledge, this was the first case report with PCD due to LS. PMID- 28092913 TI - Umbilical Venous Catheter Malposition Is Associated with Necrotizing Enterocolitis in Premature Infants. AB - OBJECTIVE: The etiology of necrotizing enterocolitis (NEC) remains elusive despite known associations with several factors, including intestinal ischemia related to the effects of umbilical arterial catheterization on the mesenteric circulation. However, the role of the mesenteric venous circulation has yet to be studied as a potential cause of NEC. We examined the association between umbilical venous catheter (UVC) position and the development of NEC in premature infants. DESIGN: A prospective cohort study was performed to examine the effect of UVC on portosystemic shunting via the ductus venosus (DV) and its potential role in NEC. RESULTS: We recruited 132 premature infants, 62 of which had a birth weight <=1,500 g. NEC was noted in 12 (19%) patients. All infants weighing <=1,500 g underwent an attempt at UVC insertion. The UVC status was classified as appropriate (n = 39), unsuccessful (n = 9), or malpositioned (n = 14). Among the NEC patients, 7 (58%) had a UVC malposition and 3 (25%) had an unsuccessful attempt. These rates were significantly higher than in patients without NEC (14 and 12%, respectively). Multivariable logistic regression analysis confirmed birth weight (OR 2.2, 95% CI 1.2-4.7, p = 0.001) and UVC malpositioning (OR 6.9, 95% CI 1.6-35.4, p = 0.007) as independent risk factors associated with NEC. CONCLUSIONS: Unrecognized withdrawal of a UVC into the portal vein or DV is associated with an increased incidence of NEC in infants weighing <=1,500 g. The data support the need for additional studies to examine this effect. Confirmation of a causal relationship will raise the need to reassess UVC insertion criteria and strategies for more closely monitoring the catheter tip position. PMID- 28092915 TI - Malignant Mixed Mullerian Tumour of the Uterus: Analysis of 44 Cases. AB - OBJECTIVES: The aim of our study was to evaluate the clinicopathological features and prognostic factors of uterine carcinosarcoma. PATIENTS AND METHODS: In this retrospective study, the clinical characteristics of 44 patients with uterine MMMT were evaluated. Survival curves were estimated by the Kaplan-Meier method and compared by the log-rank test. RESULTS: Forty-four patients with uterine carcinosarcoma were referred to our unit between 1995 and 2015. Their median age was 66.5 years. All women underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Twenty-five percent had omental resection. Pelvic lymphadenectomy was performed in 18.2% of the cases. Twenty-six of the patients presented with stage I/II disease, 17 with advanced stages. In 20.5% of the cases there were metastases at diagnosis. Forty women received adjuvant chemotherapy, with complete remission in 67.9% of the cases. Recurrences were observed in 27.3% of the women. Disease-free and overall survival was 27 and 103 months, respectively. The FIGO stage, histological type, tumour size, chemotherapy regimen, pelvic lymphadenectomy, and myometrial invasion did not affect survival. CONCLUSIONS: Uterine MMMT is an aggressive tumour, often diagnosed at an advanced stage and with a high rate of metastases or recurrences. Because of its rarity, its management is controversial and fixed prognostic factors cannot be defined. PMID- 28092916 TI - Differences in Peripheral Blood Lymphocytes between Brand-Name and Generic Tacrolimus Used in Stable Liver Transplant Recipients. AB - OBJECTIVES: In this study, peripheral blood lymphocytes were compared between a brand-name and a generic tacrolimus group in stable liver transplant recipients. SUBJECTS AND METHODS: Sixteen patients who underwent ABO-compatible living donor liver transplants between 2012 and 2013 and had stable graft function were included in this study. Ten patients received brand-name tacrolimus and 6 patients received generic tacrolimus. CD3, CD4, CD8, gammadelta, CD4+FoxP3+, and CD3-CD56+ T cells were analyzed in peripheral blood obtained preoperatively and 4, 8, 12, and 24 weeks after liver transplantation. Categorical variables were compared using a chi2 test or Fisher exact test, and continuous variables were compared using the Mann-Whitney U test. RESULTS: Regarding the baseline and perioperative characteristics, there were no statistically significant differences between the 2 groups. Immunosuppression also was not different. Subtype analysis of T-cell populations carried out in parallel showed similar levels of CD3, CD4, CD8, and gammadeltaT cells with brand-name tacrolimus and generic tacrolimus in stable liver transplant recipients. However, the levels of CD4+Foxp3+ and CD3-CD56+ T cells were higher in the brand-name tacrolimus group than in the generic tacrolimus group 8 weeks after transplantation (p < 0.05). CONCLUSIONS: The level of CD4+Foxp3+ T cells was higher in the brand-name tacrolimus group than in the generic tacrolimus group after transplantation. This finding showed that brand-name tacrolimus could have more potential immunosuppressive activity than generic tacrolimus regarding the contribution of CD4+Foxp3+ T cells to graft tolerance in liver transplant recipients. PMID- 28092917 TI - Is Fat Mass Accretion of Late Preterm Infants Associated with Insulin Resistance? AB - BACKGROUND: Late preterm infants show a major fat mass accretion from birth to term. The contribution of preterm birth to the development of the metabolic syndrome is still under investigation. OBJECTIVES: To evaluate body composition changes in late preterm infants during the first 3 months and to investigate their insulin sensitivity and resistance. METHODS: We conducted an observational, longitudinal study. A total of 216 late preterm infants underwent body composition assessment using an air displacement plethysmograph at term and at 3 months of corrected age. In a subgroup of infants (n = 48) the blood glucose and insulin concentration were determined at term and insulin resistance (homeostasis model assessment for insulin resistance; HOMA-IR) and sensitivity (quantitative insulin sensitivity check index; QUICKI) were then calculated. The reference group comprised 71 healthy term infants. RESULTS: The mean birth weight and gestational age were 2,390 +/- 391 g and 35.2 +/- 0.8 weeks, respectively. At term the fat mass index (kg/m2) of late preterm infants, born adequate for their gestational age and small for their gestational age, was higher than that of term infants (2.08 +/- 0.82 vs. 1.62 +/- 0.64 vs. 1.03 +/- 0.36, p < 0.005, respectively), whereas at 3 months of corrected age no difference was found among the groups. The mean values of glucose, insulin, HOMA-IR, and QUICKI were within the 5th and 95th percentiles. CONCLUSIONS: On the basis of these preliminary findings, fat mass accretion of late preterm infants appears not to be associated with perturbation of the glucose homeostasis. PMID- 28092918 TI - Complete Sequence and Organization of pFR260, the Bacillus thuringiensis INTA Fr7 4 Plasmid Harboring Insecticidal Genes. AB - We report the complete sequence and analysis of pFR260, a novel megaplasmid of 260,595 bp from the Bacillus thuringiensis strain INTA Fr7-4 isolated in Argentina. It carries 7 insecticidal genes: 3 cry8 copies previously reported, 2 vip1, and 2 vip2. Also, it carries a gene encoding a putative atypical Cry protein. These genes are arranged in a region of approximately 105 kbp in size with characteristics of a pathogenicity island with a potential coleopteran specific insecticide profile. DNA strand composition asymmetry, as determined by GC skew analysis, and the presence of a Rep protein involved in the initiation of replication suggest a bidirectional theta mechanism of replication. In addition, many genes involved in conjugation and a CRISPR-Cas system were detected. The pFR260 sequence was deposited in GenBank under accession number KX258624. PMID- 28092919 TI - Compensatory water effects link yearly global land CO2 sink changes to temperature. AB - Large interannual variations in the measured growth rate of atmospheric carbon dioxide (CO2) originate primarily from fluctuations in carbon uptake by land ecosystems. It remains uncertain, however, to what extent temperature and water availability control the carbon balance of land ecosystems across spatial and temporal scales. Here we use empirical models based on eddy covariance data and process-based models to investigate the effect of changes in temperature and water availability on gross primary productivity (GPP), terrestrial ecosystem respiration (TER) and net ecosystem exchange (NEE) at local and global scales. We find that water availability is the dominant driver of the local interannual variability in GPP and TER. To a lesser extent this is true also for NEE at the local scale, but when integrated globally, temporal NEE variability is mostly driven by temperature fluctuations. We suggest that this apparent paradox can be explained by two compensatory water effects. Temporal water-driven GPP and TER variations compensate locally, dampening water-driven NEE variability. Spatial water availability anomalies also compensate, leaving a dominant temperature signal in the year-to-year fluctuations of the land carbon sink. These findings help to reconcile seemingly contradictory reports regarding the importance of temperature and water in controlling the interannual variability of the terrestrial carbon balance. Our study indicates that spatial climate covariation drives the global carbon cycle response. PMID- 28092920 TI - Evolutionary genomics of the cold-adapted diatom Fragilariopsis cylindrus. AB - The Southern Ocean houses a diverse and productive community of organisms. Unicellular eukaryotic diatoms are the main primary producers in this environment, where photosynthesis is limited by low concentrations of dissolved iron and large seasonal fluctuations in light, temperature and the extent of sea ice. How diatoms have adapted to this extreme environment is largely unknown. Here we present insights into the genome evolution of a cold-adapted diatom from the Southern Ocean, Fragilariopsis cylindrus, based on a comparison with temperate diatoms. We find that approximately 24.7 per cent of the diploid F. cylindrus genome consists of genetic loci with alleles that are highly divergent (15.1 megabases of the total genome size of 61.1 megabases). These divergent alleles were differentially expressed across environmental conditions, including darkness, low iron, freezing, elevated temperature and increased CO2. Alleles with the largest ratio of non-synonymous to synonymous nucleotide substitutions also show the most pronounced condition-dependent expression, suggesting a correlation between diversifying selection and allelic differentiation. Divergent alleles may be involved in adaptation to environmental fluctuations in the Southern Ocean. PMID- 28092922 TI - The Effectiveness of Free Vascularized Fibular Flaps in Osteonecrosis of the Femoral Head and Neck: A Systematic Review. AB - Background Free vascularized fibular flaps (FVFFs) are accepted surgical options to treat osteonecrosis of the femoral head and neck (ONFHN) to prevent conversion to total hip replacement (THR), yet many studies are single institution cohorts, with little generalizability. Purpose The purpose of this study was to perform a systematic review examining the comparative effectiveness of FVFF to treat ONFHN, particularly preventing conversion to a THR and improving hip function/symptoms. Methods We searched PubMed and EMBASE databases using femoral head, free fibula, and femoral neck keywords. Articles were excluded if not translated into English, n < 10 hips, article was a compilation/review, outcomes were not relevant, or prior to 1994. If from the same institution, we included the largest cohort and excluded others within the same timeline. Two investigators independently reviewed articles and reported number of patients/hips, average age/follow-up time/graft survival before THR, Harris hip score, THR rate, complications, and radiographic progression rates. Results We identified 128 and 157 articles from PubMed and EMBASE. After screening/duplicate removal, 21 studies were included from 14 institutions in 9 countries. Overall, 71% were level IV evidence. The average patient number was 129, number of hips was 166, age at surgery was 34 years, and follow-up time was 92 months. HHS improved on average 21.7 points, with the number of patients requiring THR being 19.4%. Graft survival before THR was 5.2 years, and 47.7% of hips had radiographic progression. Conclusions There is a significant amount of level IV evidence describing the favorable role of FVFF to treat ONFHN. Although efficacious, there is a need for higher level evidence. The level of evidence is 3. PMID- 28092921 TI - The ligand Sas and its receptor PTP10D drive tumour-suppressive cell competition. AB - Normal epithelial cells often exert anti-tumour effects against nearby oncogenic cells. In the Drosophila imaginal epithelium, clones of oncogenic cells with loss of-function mutations in the apico-basal polarity genes scribble or discs large are actively eliminated by cell competition when surrounded by wild-type cells. Although c-Jun N-terminal kinase (JNK) signalling plays a crucial role in this cell elimination, the initial event, which occurs at the interface between normal cells and polarity-deficient cells, has not previously been identified. Here, through a genetic screen in Drosophila, we identify the ligand Sas and the receptor-type tyrosine phosphatase PTP10D as the cell-surface ligand-receptor system that drives tumour-suppressive cell competition. At the interface between the wild-type 'winner' and the polarity-deficient 'loser' clones, winner cells relocalize Sas to the lateral cell surface, whereas loser cells relocalize PTP10D there. This leads to the trans-activation of Sas-PTP10D signalling in loser cells, which restrains EGFR signalling and thereby enables elevated JNK signalling in loser cells, triggering cell elimination. In the absence of Sas PTP10D, elevated EGFR signalling in loser cells switches the role of JNK from pro apoptotic to pro-proliferative by inactivating the Hippo pathway, thereby driving the overgrowth of polarity-deficient cells. These findings uncover the mechanism by which normal epithelial cells recognize oncogenic polarity-deficient neighbours to drive cell competition. PMID- 28092923 TI - Teasing apart NAD+ metabolism in inflammation: commentary on Zhou et al. (2016). Br J Pharmacol 173: 2352-2368. PMID- 28092924 TI - Evaluation of the use of rotational thromboelastometry in the assessment of FXI deficency. AB - INTRODUCTION: The absence of a reliable clinical test to predict bleeding tendency leaves factor XI (FXI)-deficient individuals at risk of overtreatment or under treatment. AIM: To assess whether rotational thromboelastometry has value in detection of FXI deficiency and identification of bleeding tendency. METHODS: Thromboelastometry was measured in whole blood and platelet-rich plasma (PRP) samples containing corn trypsin inhibitor (CTI) from controls (n = 50) and FXI deficient individuals (n = 93) at tissue factor (TF) 0.12 pm. The effect of tissue plasminogen activator was also assessed. For analysis, FXI-deficient individuals were divided into bleeders (n = 24) and non-bleeders (n = 44) based on experience of tonsillectomy and/or dental extraction prior to diagnosis. RESULTS: In whole blood, thromboelastometry distinguished those with major FXI deficiency (FXI:C <= 15 IU dL-1 ) but not partial deficiency from control populations, but did not identify bleeding phenotype. In PRP, bleeders had significantly longer clot formation time [CFT; 434 +/- 179 s vs. 277 +/- 70 s (mean +/- SD); P < 0.05] and smaller alpha angle [43.8 +/- 9.5 degrees vs. 52.4 +/- 5.8 degrees (mean +/- SD); P < 0.05] compared to non-bleeders. However, these parameters were found to depend on multiple additional variables and on an individual basis, ROC analysis showed test specificity for bleeding phenotype identification to be only 38.5% at 100% sensitivity: CFT (area under first derivative curve: AUC = 0.8091, P = 0.0014), alpha angle (AUC = 0.7804, P = 0.006). CONCLUSION: Thromboelastometry in PRP with CTI samples triggered with TF 0.12 pm was able to distinguish between bleeders and non-bleeders in FXI deficiency, but poor specificity restricts its clinical application as a test to identify bleeding phenotype. Further technical advances to the assay may allow better discrimination. PMID- 28092925 TI - Risk-based management of dental procedures in patients with inherited bleeding disorders: Development of a Dental Bleeding Risk Assessment and Treatment Tool (DeBRATT). AB - INTRODUCTION: Successful outcomes in dental management for patients with inherited bleeding disorders require close collaboration between haematology teams and dentists. AIM: To review outcomes of an interdisciplinary pathway for dental procedures by assessing adequacy and appropriateness of haemostatic management. METHODS: Two hundred dental procedures in 30 patients with inherited bleeding disorders were included. A Dental Bleeding Risk Assessment and Treatment Tool (DeBRATT) was developed to identify four categories of bleeding risk (no risk, low, moderate and high risk of bleeding) in relation to the severity of the bleeding disorder and the invasiveness of dental procedure. The adequacy and appropriateness of haemostatic therapy provided in relation to the bleeding risk was assessed with reference to the published literature. Treatment was classified as appropriate, over or under-treatment. Bleeding complication was the primary outcome. RESULTS: A high level of dental disease was noted, with 83% of patients having at least one decayed tooth and 46.7% having chronic gum disease. A total of 59.1% of the dental procedures in patients with mild bleeding disorders were over-treated (n = 65/110) and 8.9% in patients with severe disorders had an extended duration of treatment (n = 7/79). One bleeding complication was observed in a patient with Von Willebrand's disease and severe thrombocytopenia. All other procedures (99.5%) were uneventful. CONCLUSION: DeBRATT enables a risk-based approach for the management of dental procedures in patients with inherited bleeding disorders. The tool facilitates a comprehensive evaluation of bleeding risk with the potential to minimize unnecessary treatment and aid interdisciplinary communication among different clinical teams. PMID- 28092926 TI - Effect of gravity and microgravity on intracranial pressure. AB - KEY POINTS: Astronauts have recently been discovered to have impaired vision, with a presentation that resembles syndromes of elevated intracranial pressure on Earth. Gravity has a profound effect on fluid distribution and pressure within the human circulation. In contrast to prevailing theory, we observed that microgravity reduces central venous and intracranial pressure. This being said, intracranial pressure is not reduced to the levels observed in the 90 deg seated upright posture on Earth. Thus, over 24 h in zero gravity, pressure in the brain is slightly above that observed on Earth, which may explain remodelling of the eye in astronauts. ABSTRACT: Astronauts have recently been discovered to have impaired vision, with a presentation that resembles syndromes of elevated intracranial pressure (ICP). This syndrome is considered the most mission critical medical problem identified in the past decade of manned spaceflight. We recruited five men and three women who had an Ommaya reservoir inserted for the delivery of prophylactic CNS chemotherapy, but were free of their malignant disease for at least 1 year. ICP was assessed by placing a fluid-filled 25 gauge butterfly needle into the Ommaya reservoir. Subjects were studied in the upright and supine position, during acute zero gravity (parabolic flight) and prolonged simulated microgravity (6 deg head-down tilt bedrest). ICP was lower when seated in the 90 deg upright posture compared to lying supine (seated, 4 +/- 1 vs. supine, 15 +/- 2 mmHg). Whilst lying in the supine posture, central venous pressure (supine, 7 +/- 3 vs. microgravity, 4 +/- 2 mmHg) and ICP (supine, 17 +/- 2 vs. microgravity, 13 +/- 2 mmHg) were reduced in acute zero gravity, although not to the levels observed in the 90 deg seated upright posture on Earth. Prolonged periods of simulated microgravity did not cause progressive elevations in ICP (supine, 15 +/- 2 vs. 24 h head-down tilt, 15 +/- 4 mmHg). Complete removal of gravity does not pathologically elevate ICP but does prevent the normal lowering of ICP when upright. These findings suggest the human brain is protected by the daily circadian cycles in regional ICPs, without which pathology may occur. PMID- 28092927 TI - Preventive behaviors by the level of perceived infection sensitivity during the Korea outbreak of Middle East Respiratory Syndrome in 2015. AB - OBJECTIVES: This study was performed to investigate the relationship between community residents' infection sensitivity and their levels of preventive behaviors during the 2015 Middle East Respiratory Syndrome (MERS) outbreak in Korea. METHODS: Seven thousands two hundreds eighty one participants from nine areas in Gyeonggi-do including Pyeongtaek, the origin of the outbreak in 2015 agreed to participate in the survey and the data from 6,739 participants were included in the final analysis. The data on the perceived infection sensitivity were subjected to cluster analysis. The levels of stress, reliability/practice of preventive behaviors, hand washing practice and policy credibility during the outbreak period were analyzed for each cluster. RESULTS: Cluster analysis of infection sensitivity due to the MERS outbreak resulted in classification of participants into four groups: the non-sensitive group (14.5%), social concern group (17.4%), neutral group (29.1%), and overall sensitive group (39.0%). A logistic regression analysis found that the overall sensitive group with high sensitivity had higher stress levels (17.80; 95% confidence interval [CI], 13.77 to 23.00), higher reliability on preventive behaviors (5.81; 95% CI, 4.84 to 6.98), higher practice of preventive behaviors (4.53; 95% CI, 3.83 to 5.37) and higher practice of hand washing (2.71; 95% CI, 2.13 to 3.43) during the outbreak period, compared to the non-sensitive group. CONCLUSIONS: Infection sensitivity of community residents during the MERS outbreak correlated with gender, age, occupation, and health behaviors. When there is an outbreak in the community, there is need to maintain a certain level of sensitivity while reducing excessive stress, as well as promote the practice of preventive behaviors among local residents. In particular, target groups need to be notified and policies need to be established with a consideration of the socio-demographic characteristics of the community. PMID- 28092928 TI - Meta-analysis for genome-wide association studies using case-control design: application and practice. AB - This review aimed to arrange the process of a systematic review of genome-wide association studies in order to practice and apply a genome-wide meta-analysis (GWMA). The process has a series of five steps: searching and selection, extraction of related information, evaluation of validity, meta-analysis by type of genetic model, and evaluation of heterogeneity. In contrast to intervention meta-analyses, GWMA has to evaluate the Hardy-Weinberg equilibrium (HWE) in the third step and conduct meta-analyses by five potential genetic models, including dominant, recessive, homozygote contrast, heterozygote contrast, and allelic contrast in the fourth step. The 'genhwcci' and 'metan' commands of STATA software evaluate the HWE and calculate a summary effect size, respectively. A meta-regression using the 'metareg' command of STATA should be conducted to evaluate related factors of heterogeneities. PMID- 28092929 TI - The effect of smoking on lung cancer: ethnic differences and the smoking paradox. AB - The objectives of this review were to determine whether the smoking paradox still exists and to summarize possible explanations for the smoking paradox. Based on published data, we compared the risk of cigarette smoking for lung cancer in Western and Asian countries. We extracted data from the relevant studies about annual tobacco consumption, lung cancer mortality rates according to smoking status from each country, and possible explanations for the smoking paradox. A significantly greater risk of lung cancer death was found among current smokers in Asian countries than among nonsmokers, with relative risks (RRs) of 4.0 to 4.6 for Koreans, 3.7 to 5.1 for Japanese, and 2.4 to 6.5 for Chinese. Although a significantly greater risk of lung cancer was present among current smokers in Asian countries, the RRs in Asian countries were much lower than those reported in Western countries (range, 9.4 to 23.2). Possible explanations for the smoking paradox included epidemiologic characteristics, such as the smoking amount, age at smoking initiation, and the use of filtered or mild tobacco. The smoking paradox definitely exists, but may be explained by major epidemiologic characteristics. Therefore, the smoking paradox should not be interpreted as indicating that tobacco is safer or less harmful for Asians. PMID- 28092930 TI - Prevalence of latent tuberculosis infection among tuberculosis laboratory workers in Iran. AB - OBJECTIVES: The risk of transmission of Mycobacterium tuberculosis from patients to health care workers (HCWs) is a neglected problem in many countries, including Iran. The aim of this study was to estimate the prevalence of latent tuberculosis (TB) infection (LTBI) among TB laboratory staff in Iran, and to elucidate the risk factors associated with LTBI. METHODS: All TB laboratory staff (689 individuals) employed in the TB laboratories of 50 Iranian universities of medical sciences and a random sample consisting of 317 low-risk HCWs were included in this cross-sectional study. Participants with tuberculin skin test indurations of 10 mm or more were considered to have an LTBI. RESULTS: The prevalence of LTBI among TB laboratory staff and low-risk HCWs was 24.83% (95% confidence interval [CI], 21.31 to 27.74%) and 14.82% (95% CI, 11.31 to 19.20%), respectively. No active TB cases were found in either group. After adjusting for potential confounders, TB laboratory staff were more likely to have an LTBI than low-risk HCWs (prevalence odds ratio, 2.06; 95% CI, 1.35 to 3.17). CONCLUSIONS: This study showed that LTBI are an occupational health problem among TB laboratory staff in Iran. This study reinforces the need to design and implement simple, effective, and affordable TB infection control programs in TB laboratories in Iran. PMID- 28092931 TI - The criteria for metabolic syndrome and the national health screening and education system in Japan. AB - Two major definitions of metabolic syndrome have been proposed. One focuses on the accumulation of risk factors, a measure used by the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI); the other focuses on abdominal obesity, a measure used by the International Diabetes Federation (IDF) and the Japanese government. The latter definition takes waist circumference (WC) into consideration as an obligatory component, whereas the former does not. In 2009, the IDF, NHLBI, AHA, and other organizations attempted to unify these criteria; as a result, WC is no longer an obligatory component of those systems, while it remains obligatory in the Japanese criteria. In 2008, a new Japanese cardiovascular screening and education system focused on metabolic syndrome was launched. People undergoing screening are classified into three groups according to the presence of abdominal obesity and the number of metabolic risk factors, and receive health educational support from insurers. This system has yielded several beneficial outcomes: the visibility of metabolic syndrome at the population level has drastically improved; preventive measures have been directed toward metabolic syndrome, which is expected to become more prevalent in future generations; and a post-screening education system has been established. However, several problems with the current system have been identified and are under debate. In this review, we discuss topics related to metabolic syndrome, including (1) the Japanese criteria for metabolic syndrome; (2) metabolic syndrome and the universal health screening and education system; and (3) recent debates about Japanese criteria for metabolic syndrome. PMID- 28092932 TI - The burden of infectious and cardiovascular diseases in India from 2004 to 2014. AB - OBJECTIVES: In India, both communicable and non-communicable diseases have been argued to disproportionately affect certain socioeconomic strata of the population. Using the 60th (2004) and 71st (2014) rounds of the National Sample Survey, this study assessed the balance between infectious diseases and cardiovascular diseases (CVD) from 2004 to 2014, as well as changes in the disease burden in various socioeconomic and demographic subpopulations. METHODS: Prevalence rates, hospitalization rates, case fatality rates, and share of in patients deaths were estimated to compare the disease burdens at these time points. Logistic regression and multivariate decomposition were used to evaluate changes in disease burden across various socio-demographic and socioeconomic groups. RESULTS: Evidence of stagnation in the infectious disease burden and rapid increase in the CVD burden was observed. Along with the drastic increase in case fatality rate, share of in-patients deaths became more skewed towards CVD from 2004 to 2014. Logistic regression analysis demonstrated a significant shift of the chance of succumbing to CVD from the privileged class, comprising non Scheduled Castes and Tribes, more highly educated individuals, and households with higher monthly expenditures, towards the underprivileged population. Decomposition indicated that a change in the probability of suffering from CVD among the subcategories of age, social groups, educational status, and monthly household expenditures contributed to the increase in CVD prevalence more than compositional changes of the population from 2004 to 2014. CONCLUSIONS: This study provides evidence of the ongoing tendency of CVD to occur in older population segments, and also confirms the theory of diffusion, according to which an increased probability of suffering from CVD has trickled down the socioeconomic gradient. PMID- 28092933 TI - Estimation of the size of the iatrogenic Creutzfeldt-Jakob disease outbreak associated with cadaveric dura mater grafts in Korea. AB - Purpose: This study estimated the overall magnitude of Creutzfeldt-Jakob disease (iCJD) based on dura graft cases in Korea using a mathematical model. Methods: We estimated the number of annual cases of dura grafts performed between 1980 and 1995 by applying the proportion of dura grafts recorded by the Health Insurance Review Agency claim dataset in Korea to the number of nationwide neurosurgery cases. The distribution of the incubation period was assumed to fall under a Weibull distribution with density function or a log-logistic distribution with density function. Results: The total number of neurosurgeries performed from 1980 to 1995 was estimated to be 263,945, and among these surgeries, 37% used dura graft products. Between the years of 1980 and 2020, our model predicts that the total number of iCJD cases was between 14.9 and 33.2 (95% CI: 13.4-50.9). Notably, we estimated that the cumulative number of iCJD cases caused by dura grafts between 1980 and 2011 was approximately 13.3 to 27.3 (95% CI: 12.2-40.6). Conclusions: Estimations made using this model are consistent with the actual development of cases, indicating that this model is valid for future projection. Based on our model, we postulate that iCJD will undergo a sharp decline from 2012 to 2020. PMID- 28092934 TI - Visceral leishmaniasis treatment outcome and its determinants in northwest Ethiopia. AB - OBJECTIVES: Poor treatment outcomes of visceral leishmaniasis (VL) are responsible for the high mortality rate of this condition in resource-limited settings such as Ethiopia. This study aimed to identify the proportion of poor VL treatment outcomes in northwest Ethiopia and to evaluate the determinants associated with poor outcomes. METHODS: A hospital-based retrospective study was conducted among 595 VL patients who were admitted to Kahsay Abera Hospital in northwest Ethiopia from October 2010 to April 2013. Data were entered into Epi Info version 7.0 and exported to SPSS version 20 for analysis. Bivariate and multivariate logistic regression models were fitted to identify the determinants of VL treatment outcomes. Adjusted odds ratio (aORs) with 95% confidence intervals (CIs) were used, and p-values <0.05 were considered to indicate statistical significance. RESULTS: The proportion of poor treatment outcomes was 23.7%. Late diagnosis (>=29 days) (aOR, 4.34; 95% CI, 2.22 to 8.46), severe illness at admission (inability to walk) (aOR, 1.63; 95% CI, 1.06 to 2.40) and coinfection with VL and human immunodeficiency virus (HIV) (aOR, 2.72; 95% CI, 1.40 to 5.20) were found to be determinants of poor VL treatment outcomes. CONCLUSIONS: Poor treatment outcomes, such as death, treatment failure, and non adherence, were found to be common. Special attention must be paid to severely ill and VL/HIV-coinfected patients. To improve VL treatment outcomes, the early diagnosis and treatment of VL patients is recommended. PMID- 28092935 TI - Alloying Strategy in Cu-In-Ga-Se Quantum Dots for High Efficiency Quantum Dot Sensitized Solar Cells. AB - I-III-VI2 group "green" quantum dots (QDs) are attracting increasing attention in photoelectronic conversion applications. Herein, on the basis of the "simultaneous nucleation and growth" approach, Cu-In-Ga-Se (CIGSe) QDs with light harvesting range of about 1000 nm were synthesized and used as sensitizer to construct quantum dot sensitized solar cells (QDSCs). Inductively coupled plasma atomic emission spectrometry (ICP-AES), wild-angle X-ray diffraction (XRD), and X ray photoelectron spectroscopy (XPS) analyses demonstrate that the Ga element was alloyed in the Cu-In-Se (CISe) host. Ultraviolet photoelectron spectroscopy (UPS) and femtosecond (fs) resolution transient absorption (TA) measurement results indicate that the alloying strategy could optimize the electronic structure in the obtained CIGSe QD material, thus matching well with TiO2 substrate and favoring the photogenerated electron extraction. Open circuit voltage decay (OCVD) and impedance spectroscopy (IS) tests indicate that the intrinsic recombination in CIGSe QDSCs was well suppressed relative to that in CISe QDSCs. As a result, CIGSe based QDSCs with use of titanium mesh supported mesoporous carbon counter electrode exhibited a champion efficiency of 11.49% (Jsc = 25.01 mA/cm2, Voc = 0.740 V, FF = 0.621) under the irradiation of full one sun in comparison with 9.46% for CISe QDSCs. PMID- 28092936 TI - Effect of Ozonation and Biological Activated Carbon Treatment of Wastewater Effluents on Formation of N-nitrosamines and Halogenated Disinfection Byproducts. AB - Ozonation followed by biological activated carbon (O3/BAC) is being considered as a key component of reverse osmosis-free advanced treatment trains for potable wastewater reuse. Using a laboratory-scale O3/BAC system treating two nitrified wastewater effluents, this study characterized the effect of different ozone dosages (0-1.0 mg O3/mg dissolved organic carbon) and BAC empty bed contact times (EBCT; 15-60 min) on the formation after chlorination or chloramination of 35 regulated and unregulated halogenated disinfection byproducts (DBPs), 8 N nitrosamines, and bromate. DBP concentrations were remarkably similar between the two wastewaters across O3/BAC conditions. Ozonation increased bromate, TCNM, and N-nitrosodimethylamine, but ozonation was less significant for other DBPs. DBP formation generally decreased significantly with BAC treatment at 15 min EBCT, but little further reduction was observed at higher EBCT where low dissolved oxygen concentrations may have limited biological activity. The O3/BAC-treated wastewaters met regulatory levels for trihalomethanes (THMs), haloacetic acids (HAAs), and bromate, although N-nitrosodimethylamine exceeded the California Notification Level in one case. Regulated THMs and HAAs dominated by mass. When DBP concentrations were weighted by measures of their toxic potencies, unregulated haloacetonitriles, haloacetaldehydes, and haloacetamides dominated. Assuming toxicity is additive, the calculated DBP-associated toxicity of the O3/BAC-treated chloraminated effluents were comparable or slightly higher than those calculated in a recent evaluation of Full Advanced Treatment trains incorporating reverse osmosis. PMID- 28092937 TI - Updating the U.S. Life Cycle GHG Petroleum Baseline to 2014 with Projections to 2040 Using Open-Source Engineering-Based Models. AB - The National Energy Technology Laboratory produced a well-to-wheels (WTW) life cycle greenhouse gas analysis of petroleum-based fuels consumed in the U.S. in 2005, known as the NETL 2005 Petroleum Baseline. This study uses a set of engineering-based, open-source models combined with publicly available data to calculate baseline results for 2014. An increase between the 2005 baseline and the 2014 results presented here (e.g., 92.4 vs 96.2 g CO2e/MJ gasoline, + 4.1%) are due to changes both in modeling platform and in the U.S. petroleum sector. An updated result for 2005 was calculated to minimize the effect of the change in modeling platform, and emissions for gasoline in 2014 were about 2% lower than in 2005 (98.1 vs 96.2 g CO2e/MJ gasoline). The same methods were utilized to forecast emissions from fuels out to 2040, indicating maximum changes from the 2014 gasoline result between +2.1% and -1.4%. The changing baseline values lead to potential compliance challenges with frameworks such as the Energy Independence and Security Act (EISA) Section 526, which states that Federal agencies should not purchase alternative fuels unless their life cycle GHG emissions are less than those of conventionally produced, petroleum-derived fuels. PMID- 28092938 TI - 50 Years of Accounts. PMID- 28092939 TI - For Better or Worse, Iron Overload by Superparamagnetic Iron Oxide Nanoparticles as a MRI Contrast Agent for Chronic Liver Diseases. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) have recently been used as an effective magnetic resonance imaging (MRI) contrast agent for the noninvasive diagnosis of chronic liver diseases including nonalcohol fatty liver diseases, nonalcohol steatohepatitis, and cirrhosis as well as liver tumors. However, the potential risk of the iron overload by SPIONs has been highly underestimated in chronic liver diseases. While most of SPIONs have been shown safe in the healthy group, significant toxicity potential by the iron overload has been revealed through immunotoxicity, lipid peroxidation, and fatty acid and cholesterol metabolism in cirrhosis as a high risk factor. As a result, the systems toxicology assessments of SPIONs are crucial in both healthy ones and chronic liver disease models to determine the margin of safety. In addition, the challenge of the iron overload by SPIONs requires better designed SPIONs as MRI contrast agents for chronic liver diseases such as the biodegradable nanocluster assembly with urine clearance. PMID- 28092940 TI - A Special Issue of CRT: Celebrating Volume 30. PMID- 28092941 TI - 21st Century Cell Culture for 21st Century Toxicology. AB - There is no good science in bad models. Cell culture is especially prone to artifacts. A number of novel cell culture technologies have become more broadly available in the 21st century, which allow overcoming limitations of traditional culture and are more physiologically relevant. These include the use of stem-cell derived human cells, cocultures of different cell types, scaffolds and extracellular matrices, perfusion platforms (such as microfluidics), 3D culture, organ-on-chip technologies, tissue architecture, and organ functionality. The physiological relevance of such models is further enhanced by the measurement of biomarkers (e.g., key events of pathways), organ specific functionality, and more comprehensive assessment cell responses by high-content methods. These approaches are still rarely combined to create microphysiological systems. The complexity of the combination of these technologies can generate results closer to the in vivo situation but increases the number of parameters to control, bringing some new challenges. In fact, we do not argue that all cell culture needs to be that sophisticated. The efforts taken are determined by the purpose of our experiments and tests. If only a very specific molecular target to cell response is of interest, a very simple model, which reflects this, might be much more suited to allow standardization and high-throughput. However, the less defined the end point of interest and cellular response are, the better we should approximate organ- or tissue-like culture conditions to make physiological responses more probable. Besides these technologic advances, important progress in the quality assurance and reporting on cell cultures as well as the validation of cellular test systems brings the utility of cell cultures to a new level. The advancement and broader implementation of Good Cell Culture Practice (GCCP) is key here. In toxicology, this is a major prerequisite for meaningful and reliable results, ultimately supporting risk assessment and product development decisions. PMID- 28092942 TI - Advances in Structural and Single-Molecule Methods for Investigating DNA Lesion Bypass and Repair Polymerases. AB - Innovative advances in X-ray crystallography and single-molecule biophysics have yielded unprecedented insight into the mechanisms of DNA lesion bypass and damage repair. Time-dependent X-ray crystallography has been successfully applied to view the bypass of 8-oxo-7,8-dihydro-2'-deoxyguanine (8-oxoG), a major oxidative DNA lesion, and the incorporation of the triphosphate form, 8-oxo-dGTP, catalyzed by human DNA polymerase beta. Significant findings of these studies are highlighted here, and their contributions to the current mechanistic understanding of mutagenic translesion DNA synthesis (TLS) and base excision repair are discussed. In addition, single-molecule Forster resonance energy transfer (smFRET) techniques have recently been adapted to investigate nucleotide binding and incorporation opposite undamaged dG and 8-oxoG by Sulfolobus solfataricus DNA polymerase IV (Dpo4), a model Y-family DNA polymerase. The mechanistic response of Dpo4 to a DNA lesion and the complex smFRET technique are described here. In this perspective, we also describe how time-dependent X-ray crystallography and smFRET can be used to achieve the spatial and temporal resolutions necessary to answer some of the mechanistic questions that remain in the fields of TLS and DNA damage repair. PMID- 28092944 TI - Reaction Chemistry to Characterize the Molecular Initiating Event in Skin Sensitization: A Journey to Be Continued. AB - The publication by the OECD of the adverse outcome pathway (AOP) for skin sensitization has accelerated the development and validation of mechanistic tests and testing strategies to assess the potential of new molecules to trigger skin allergies. The molecular initiating event (MIE) in the AOP is reaction with skin peptides/proteins. It is followed by a number of cellular events. Currently, only one in chemico test to characterize the MIE was proposed to and underwent adoption by the OECD, while two cell-based assays have completed the process. A multitude of further cellular assays is currently in the validation pipeline, but no further reactivity test has gone through full standardization. Here, we review data on in chemico methods, identify gaps, and discuss how these methods can be improved to better characterize the MIE and to become even more informative. We focus on the importance of kinetics, the information gained from studying adduct formation, and the difficulties posed by side reactions such as peptide oxidation. We then highlight mechanistic insights from reaction chemistry: the relative contribution of different target nucleophiles, the migration of amino acid modifications, and the potential of peptide-cross-linking. We illustrate in a case study how kinetic in chemico methods might have been used to better predict the risk of three preservatives, which have led to serious epidemics of contact dermatitis. In a case study on Michael acceptors, we show the impact of additional substituents around the electrophilic olefin moiety on reactivity, and we highlight the shortcomings which current in silico methods to predict reaction chemistry still have, illustrating the need for experimental in chemico data to improve such models. Finally, based on the information reviewed and the presented case studies, a strong argument is made to continue the journey of developing nonredundant, informative in chemico methods, and not to solely focus on new cell based methods to further populate the AOP for skin sensitization. PMID- 28092945 TI - Nicotine Metabolism and Smoking: Ethnic Differences in the Role of P450 2A6. AB - Nicotine is the primary addictive agent in tobacco, and P450 2A6 (gene name: CYP2A6) is the primary catalyst of nicotine metabolism. It was proposed more than 20 years ago that individuals who metabolize nicotine poorly would smoke less, either fewer cigarettes per day or less intensely per cigarette, compared to smokers who metabolize nicotine more efficiently. These poor metabolizers would then be less likely to develop lung cancer due to their lower exposure to the many carcinogens delivered with nicotine in each puff of smoke. Numerous studies have reported that smokers who carry reduced activity or null CYP2A6 alleles do smoke less. Yet only in Asian populations, both Japanese and Chinese, which have a high prevalence of genetic variants, has a link between CYP2A6, smoking dose, and lung cancer been established. In other ethnic groups, it has been challenging to confirm a direct link between P450 2A6-mediated nicotine metabolism and the risk of lung cancer. This challenge is due in part to the difficulty in accurately quantifying smoking dose and accurately predicting or measuring P450 2A6-mediated nicotine metabolism. Biomarkers of nicotine metabolism and smoking exposure, including the ratio of trans-3-hydroxycotine to cotinine, a measure of P450 2A6 activity and plasma cotinine, or urinary total nicotine equivalents (the sum of nicotine and six metabolites) as measures of exposure are useful for addressing this challenge. However, to take full advantage of these biomarkers in the study of ethnic/racial differences in the risk of lung cancer requires the complete characterization of nicotine metabolism across ethnic/racial groups. Variation in metabolism pathways, other than those catalyzed by P450 2A6, can impact biomarkers of both nicotine metabolism and dose. This is clearly important for smokers with low levels of UGT2B10-catalyzed nicotine and cotinine glucuronidation because the UGT2B10 genotype influences plasma cotinine levels. Cotinine is not glucuronidated in 15% of African American smokers (compared to 1% of Whites) due to the prevalence of a UGT2B10 splice variant. This variant contributes significantly to the higher plasma cotinine levels per cigarette in this group and may also influence the accuracy of the 3HCOT to cotinine ratio as a measure of P450 2A6 activity. PMID- 28092943 TI - Context Matters: Contribution of Specific DNA Adducts to the Genotoxic Properties of the Tobacco-Specific Nitrosamine NNK. AB - The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent pulmonary carcinogen in laboratory animals. It is classified as a Group 1 human carcinogen by the International Agency for Cancer Research. NNK is bioactivated upon cytochrome P450 catalyzed hydroxylation of the carbon atoms adjacent to the nitrosamino group to both methylating and pyridyloxobutylating agents. Both pathways generate a spectrum of DNA damage that contributes to the overall mutagenic and toxic properties of this compound. NNK is also reduced to form 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which is also carcinogenic. Like NNK, NNAL requires metabolic activation to DNA alkylating agents. Methyl hydroxylation of NNAL generates pyridylhydroxybutyl DNA adducts, and methylene hydroxylation leads to DNA methyl adducts. The consequence of this complex metabolism is that NNK generates a vast spectrum of DNA damage, any form of which can contribute to the overall carcinogenic properties of this potent pulmonary carcinogen. This Perspective reviews the chemistry and genotoxic properties of the collection of DNA adducts formed from NNK. In addition, it provides evidence that multiple adducts contribute to the overall carcinogenic properties of this chemical. The adduct that contributes to the genotoxic effects of NNK depends on the context, such as the relative amounts of each DNA alkylating pathway occurring in the model system, the levels and genetic variants of key repair enzymes, and the gene targeted for mutation. PMID- 28092947 TI - Pyrrolizidine Alkaloids: Metabolic Activation Pathways Leading to Liver Tumor Initiation. AB - Pyrrolizidine alkaloids (PAs) and PA N-oxides are a class of phytochemical carcinogens contained in over 6000 plant species spread around the world. It has been estimated that approximately half of the 660 PAs and PA N-oxides that have been characterized are cytotoxic, genotoxic, and tumorigenic. It was recently determined that a genotoxic mechanism of liver tumor initiation mediated by PA derived DNA adducts is a common metabolic activation pathway of a number of PAs. We proposed this set of PA-derived DNA adducts could be a common biological biomarker of PA exposure and a potential biomarker of PA-induced liver tumor formation. We have also found that several reactive secondary pyrrolic metabolites can dissociate and interconvert to other secondary pyrrolic metabolites, resulting in the formation of the same exogenous DNA adducts. This present perspective reports the current progress on these new findings and proposes future research needed for obtaining a greater understanding of the role of this activation pathway and validating the use of this set of PA-derived DNA adducts as a biological biomarker of PA-induced liver tumor initiation. PMID- 28092946 TI - Carcinogenesis of the Oral Cavity: Environmental Causes and Potential Prevention by Black Raspberry. AB - Worldwide, cancers of the oral cavity and pharynx comprise the sixth most common malignancies. Histologically, more than 90% of oral cancers are squamous cell carcinoma (SCC). Epidemiologic data strongly support the role of exogenous factors such as tobacco, alcohol, and human papilloma virus infection as major causative agents. Avoidance of risk factors has only been partially successful, and survival rates have not improved despite advances in therapeutic approaches. Therefore, new or improved approaches to prevention and/or early detection are critical. Better understanding of the mechanisms of oral carcinogenesis can assist in the development of novel biomarkers for early detection and strategies for disease prevention. Toward this goal, several animal models for carcinogenesis in the oral cavity have been developed. Among these are xenograft, and transgenic animal models, and others employing the synthetic carcinogens such as 7,12-dimethylbenz[a]anthracene in hamster cheek pouch and 4-nitroquinoline-N oxide in rats and mice. Additional animal models employing environmental carcinogens such as benzo[a]pyrene and N'-nitrosonornicotine have been reported. Each model has certain advantages and disadvantages. Models that (1) utilize environmental carcinogens, (2) reflect tumor heterogeneity, and (3) accurately represent the cellular and molecular changes involved in the initiation and progression of oral cancer in humans could provide a realistic platform. To achieve this goal, we introduced a novel nonsurgical mouse model to study oral carcinogenesis induced by dibenzo[a,l]pyrene (DB[a,l]P), an environmental pollutant and tobacco smoke constituent, and its diol epoxide metabolite (+/-) anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene [(+/-) anti-DB[a,l]PDE]. On the basis of a detailed comparison of oral cancer induced by DB[a,l]P with that induced by the other above-mentioned oral carcinogens with respect to dose, duration, species and strain, cellular and molecular targets, and relative carcinogenic potency, our animal model may offer a more realistic platform to study oral carcinogenesis. In this perspective, we also discuss our preclinical studies to demonstrate the potential of black raspberry extracts on the prevention of OSCC. Specifically, we were the first to demonstrate that black raspberry inhibited DB[a,l]P-DNA binding and of particular importance its capacity to enhance the repair of DB[a,l]P-induced bulky lesions in DNA. We believe that the information presented in this perspective will stimulate further research on the impact of environmental carcinogens in the development of oral cancer and may lead to novel strategies toward the control and prevention of this disease. PMID- 28092949 TI - Label-Free Separation of Induced Pluripotent Stem Cells with Anti-SSEA-1 Antibody Immobilized Microfluidic Channel. AB - When induced pluripotent stem cells (iPSCs) are routinely cultured, the obtained cells are a heterogeneous mixture, including feeder cells and partially differentiated cells. Therefore, a purification process is required to use them in a clinical stage. We described a label-free separation of iPSCs using a microfluidic channel. Antibodies against stage-specific embryonic antigen 1 (SSEA 1) was covalently immobilized on the channel coated with a phospholipid polymer. After injection of the heterogeneous cell suspension containing iPSCs, the velocity of cell movement under a liquid flow condition was measured. The mean velocity of the cell movement was 2.1 mm/sec in the unmodified channel, while that in the channel with the immobilized-antibody was 0.4 mm/sec. The eluted cells were fractionated by eluting time. As a result, the SSEA-1 positive iPSCs were mainly contained in later fractions, and the proportion of iPSCs was increased from 43% to 82% as a comparison with the initial cell suspension. These results indicated that iPSCs were selectively separated by the microfluidic channel. This channel is a promising device for label-free separation of iPSCs based on their pluripotent state. PMID- 28092948 TI - Oral Cell DNA Adducts as Potential Biomarkers for Lung Cancer Susceptibility in Cigarette Smokers. AB - This perspective considers the use of oral cell DNA adducts, together with exposure and genetic information, to potentially identify those cigarette smokers at highest risk for lung cancer, so that appropriate preventive measures could be initiated at a relatively young age before too much damage has been done. There are now well established and validated analytical methods for the quantitation of urinary and serum metabolites of tobacco smoke toxicants and carcinogens. These metabolites provide a profile of exposure and in some cases lung cancer risk, but they do not yield information on the critical DNA damage parameter that leads to mutations in cancer growth control genes such as KRAS and TP53. Studies demonstrate a correlation between changes in the oral cavity and lung in cigarette smokers, due to the field effect of tobacco smoke. Oral cell DNA is readily obtained in contrast to DNA samples from the lung. Studies in which oral cell DNA and salivary DNA have been analyzed for specific DNA adducts are reviewed; some of the adducts identified have also been previously reported in lung DNA from smokers. The multiple challenges of developing a panel of oral cell DNA adducts that could be routinely quantified by mass spectrometry are discussed. PMID- 28092950 TI - Two-Phase Contiguous Supported Lipid Bilayer Model for Membrane Rafts via Polymer Blotting and Stenciling. AB - The supported lipid bilayer has been portrayed as a useful model of the cell membrane compatible with many biophysical tools and techniques that demonstrate its appeal in learning about the basic features of the plasma membrane. However, some of its potential has yet to be realized, particularly in the area of bilayer patterning and phase/composition heterogeneity. In this work, we generate contiguous bilayer patterns as a model system that captures the general features of membrane domains and lipid rafts. Micropatterned polymer templates of two types are investigated for generating patterned bilayer formation: polymer blotting and polymer lift-off stenciling. While these approaches have been used previously to create bilayer arrays by corralling bilayers patches with various types of boundaries impenetrable to bilayer diffusion, unique to the methods presented here, there are no physical barriers to diffusion. In this work, interfaces between contiguous lipid phases define the pattern shapes, with continuity between them allowing transfer of membrane-bound biomolecules between the phases. We examine effectors of membrane domain stability including temperature and cholesterol content to investigate domain dynamics. Contiguous patterning of supported bilayers as a model of lipid rafts expands the application of the SLB to an area with current appeal and brings with it a useful toolset for characterization and analysis. These combined tools should be helpful to researchers investigating lipid raft dynamics and function and biomolecule partitioning studies. Additionally, this patterning technique may be useful for applications such as bioseparations that exploit differences in lipid phase partitioning or creation of membranes that bind species like viruses preferentially at lipid phase boundaries, to name a few. PMID- 28092951 TI - CuSO4/H2O2-Triggered Polydopamine/Poly(sulfobetaine methacrylate) Coatings for Antifouling Membrane Surfaces. AB - Mussel-inspired polydopamine (PDA) coatings have been broadly exploited for constructing functional membrane surfaces. One-step codeposition of PDA with antifouling polymers, especially zwitterionic polymers, has been regarded as a promising strategy for fabricating antifouling membrane surfaces. However, one challenge is that the codeposition is usually a slow process over 10 h or even several days. Herein, we report that CuSO4/H2O2 is able to notably accelerate the codeposition process of PDA with poly(sulfobetaine methacrylate) (PSBMA). In our case, PSBMA is facilely anchored to the polypropylene microporous membrane (PPMM) surfaces within 1 h with the assistance of PDA because of its strong interfacial adhesion. The PDA/PSBMA-coated PPMMs show excellent surface hydrophilicity, high water permeation flux (7506 +/- 528 L/m2.h at 0.1 MPa), and an outstanding antifouling property. Moreover, the antifouling property is maintained after the membranes are treated with acid and alkali solutions as well as organic solvents. To recap, it provides a facile, universal, and time-saving strategy for exploiting high-efficiency and durable antifouling membrane surfaces. PMID- 28092952 TI - Total Synthesis of Zaragozic Acid C: Implementation of Photochemical C(sp3)-H Acylation. AB - Zaragozic acid C (1) was isolated as a potent squalene synthase inhibitor. The 2,8-dioxabicyclo[3.2.1]octane core of 1 is decorated with the three hydroxycarbonyl (C3,4,5), two hydroxy (C4,7), one acyloxy (C6), and one alkyl (C1) groups. Installation of the contiguous C4- and C5-fully substituted carbons presents a formidable synthetic challenge. Our approach to address this problem used a two-step photochemical C(sp3)-H acylation. Persilylated d-gluconolactone 4 was derivatized into 3 with the 1,2-diketone moiety at the C5-tetrasubstituted center. Norrish-Yang cyclization of 3 under violet LED irradiation followed by oxidative opening of the resultant alpha-hydroxycyclobutanone regio- and stereoselectively transformed the electron-rich tertiary C(sp3)-H bond at C4 into a C(sp3)-C bond to produce densely functionalized 2. A subsequent series of judicious functional group transformations gave rise to 1. PMID- 28092953 TI - Sub-10 nm Nanopattern Architecture for 2D Material Field-Effect Transistors. AB - Two-dimensional materials (2DMs) are competitive candidates in replacing or supplementing conventional semiconductors owing to their atomically uniform thickness. However, current conventional micro/nanofabrication technologies realize hardly ultrashort channel and integration, especially for sub-10 nm. Meanwhile, experimental device performance associated with the scaling of dimension needs to be investigated, due to the short channel effects. Here, we show a novel and universal technological method to fabricate sub-10 nm gaps with sharp edges and steep sidewalls. The realization of sub-10 nm gaps derives from a corrosion crack along the cleavage plane of Bi2O3. By this method, ultrathin body field-effect transistors (FETs), consisting of 8.2 nm channel length, 6 nm high-k dielectric, and 0.7 nm monolayer MoS2, exhibit no obvious short channel effects. The corresponding current on/off ratio and subthreshold swing reaches to 106 and 140 mV/dec, respectively. Moreover, integrated circuits with sub-10 nm channel are capable of operating as digital inverters with high voltage gain. The results suggest our technological method can be used to fabricate the ultrashort channel nanopatterns, build the experimental groundwork for 2DMs FETs with sub-10 nm channel length and 2DMs integrated circuits, and offer new potential opportunities for large-scale device constructions and applications. PMID- 28092955 TI - Flow optimization in vascular networks. AB - The development of mathematical models for studying phenomena observed in vascular networks is very useful for its potential applications in medicine and physiology. Detailed 3D studies of flow in the arterial system based on the Navier-Stokes equations require high computational power, hence reduced models are often used, both for the constitutive laws and the spatial domain. In order to capture the major features of the phenomena under study, such as variations in arterial pressure and flow velocity, the resulting PDE models on networks require appropriate junction and boundary conditions. Instead of considering an entire network, we simulate portions of the latter and use inflow and outflow conditions which realistically mimic the behavior of the network that has not been included in the spatial domain. The resulting PDEs are solved numerically using a discontinuous Galerkin scheme for the spatial and Adam-Bashforth method for the temporal discretization. The aim is to study the effect of truncation to the flow in the root edge of a fractal network, the effect of adding or subtracting an edge to a given network, and optimal control strategies on a network in the event of a blockage or unblockage of an edge or of an entire subtree. PMID- 28092954 TI - Modeling and simulation for toxicity assessment. AB - The effect of various toxicants on growth/death and morphology of human cells is investigated using the xCELLigence Real-Time Cell Analysis High Troughput in vitro assay. The cell index is measured as a proxy for the number of cells, and for each test substance in each cell line, time-dependent concentration response curves (TCRCs) are generated. In this paper we propose a mathematical model to study the effect of toxicants with various initial concentrations on the cell index. This model is based on the logistic equation and linear kinetics. We consider a three dimensional system of differential equations with variables corresponding to the cell index, the intracellular concentration of toxicant, and the extracellular concentration of toxicant. To efficiently estimate the model's parameters, we design an Expectation Maximization algorithm. The model is validated by showing that it accurately represents the information provided by the TCRCs recorded after the experiments. Using stability analysis and numerical simulations, we determine the lowest concentration of toxin that can kill the cells. This information can be used to better design experimental studies for cytotoxicity profiling assessment. PMID- 28092956 TI - Mathematical analysis of a quorum sensing induced biofilm dispersal model and numerical simulation of hollowing effects. AB - We analyze a mathematical model of quorum sensing induced biofilm dispersal. It is formulated as a system of non-linear, density-dependent, diffusion-reaction equations. The governing equation for the sessile biomass comprises two non linear diffusion effects, a degeneracy as in the porous medium equation and fast diffusion. This equation is coupled with three semi-linear diffusion-reaction equations for the concentrations of growth limiting nutrients, autoinducers, and dispersed cells. We prove the existence and uniqueness of bounded non-negative solutions of this system and study the behavior of the model in numerical simulations, where we focus on hollowing effects in established biofilms. PMID- 28092957 TI - Germinal center dynamics during acute and chronic infection. AB - The ability of the immune system to clear pathogens is limited during chronic virus infections where potent long-lived plasma and memory B-cells are produced only after germinal center B-cells undergo many rounds of somatic hypermutations. In this paper, we investigate the mechanisms of germinal center B-cell formation by developing mathematical models for the dynamics of B-cell somatic hypermutations. We use the models to determine how B-cell selection and competition for T follicular helper cells and antigen influences the size and composition of germinal centers in acute and chronic infections. We predict that the T follicular helper cells are a limiting resource in driving large numbers of somatic hypermutations and present possible mechanisms that can revert this limitation in the presence of non-mutating and mutating antigen. PMID- 28092958 TI - Moments of von Mises and Fisher distributions and applications. AB - The von Mises and Fisher distributions are spherical analogues to the Normal distribution on the unit circle and unit sphere, respectively. The computation of their moments, and in particular the second moment, usually involves solving tedious trigonometric integrals. Here we present a new method to compute the moments of spherical distributions, based on the divergence theorem. This method allows a clear derivation of the second moments and can be easily generalized to higher dimensions. In particular we note that, to our knowledge, the variance covariance matrix of the three dimensional Fisher distribution has not previously been explicitly computed. While the emphasis of this paper lies in calculating the moments of spherical distributions, their usefulness is motivated by their relationship to population statistics in animal/cell movement models and demonstrated in applications to the modelling of sea turtle navigation, wolf movement and brain tumour growth. PMID- 28092959 TI - Mixed vaccination strategy for the control of tuberculosis: A case study in China. AB - This study first presents a mathematical model of TB transmission considering BCG vaccination compartment to investigate the transmission dynamics nowadays. Based on data reported by the National Bureau of Statistics of China, the basic reproduction number is estimated approximately as R0=1.1892. To reach the new End TB goal raised by WHO in 2015, considering the health system in China, we design a mixed vaccination strategy. Theoretical analysis indicates that the infectious population asymptotically tends to zero with the new vaccination strategy which is the combination of constant vaccination and pulse vaccination. We obtain that the control of TB is quicker to achieve with the mixed vaccination. The new strategy can make the best of current constant vaccination, and the periodic routine health examination provides an operable environment for implementing pulse vaccination in China. Numerical simulations are provided to illustrate the theoretical results and help to design the final mixed vaccination strategy once the new vaccine comes out. PMID- 28092960 TI - Mathematical analysis and dynamic active subspaces for a long term model of HIV. AB - a long-term model of HIV infection dynamics [8] was developed to describe the entire time course of the disease. It consists of a large system of ODEs with many parameters, and is expensive to simulate. In the current paper, this model is analyzed by determining all infection-free steady states and studying the local stability properties of the unique biologically-relevant equilibrium. Active subspace methods are then used to perform a global sensitivity analysis and study the dependence of an infected individual's T-cell count on the parameter space. Building on these results, a global-in-time approximation of the T-cell count is created by constructing dynamic active subspaces and reduced order models are generated, thereby allowing for inexpensive computation. PMID- 28092961 TI - Effect of the epidemiological heterogeneity on the outbreak outcomes. AB - Multi-host pathogens infect and are transmitted by different kinds of hosts and, therefore, the host heterogeneity may have a great impact on the outbreak outcome of the system. This paper deals with the following problem: consider the system of interacting and mixed populations of hosts epidemiologically different, what would be the outbreak outcome for each host population composing the system as a result of mixing in comparison to the situation with zero mixing? To address this issue we have characterized the epidemic response function for a single-host population and defined a heterogeneity index measuring how host systems are epidemiologically different in terms of generation time, basic reproduction number R0 and, therefore, epidemic response function. Based on the individual epidemiological characteristics of populations, with heterogeneities and mixing affinities, the response of subpopulations in a multi-host system is compared to that of a single-host system. The case of a two-host system, in which the infection transmission depends solely on the infection susceptibility of the receiver, is analyzed in detail. Three types of responses are observed: dilution, amplification or no effect, corresponding to lower, higher or equal attack rates, respectively, for a host population in an interacting multi-host system compared to the zero-mixing situation. We find that no effect is generally observed for zero heterogeneity. A dilution effect is always observed for all the host populations when their individual R0,i < 1. Whereas, when at least one of the individual R0,i > 1, then the hosts ''i'' with R0,i > R0,j undergo a dilution effect while the hosts ''j'' undergo an amplification effect. PMID- 28092962 TI - Effects of selection and mutation on epidemiology of X-linked genetic diseases. AB - The epidemiology of X-linked recessive diseases, a class of genetic disorders, is modeled with a discrete-time, structured, non linear mathematical system. The model accounts for both de novo mutations (i.e., affected sibling born to unaffected parents) and selection (i.e., distinct fitness rates depending on individual's health conditions). Assuming that the population is constant over generations and relying on Lyapunov theory we found the domain of attraction of model's equilibrium point and studied the convergence properties of the degenerate equilibrium where only affected individuals survive. Examples of applications of the proposed model to two among the most common X-linked recessive diseases (namely the red and green color blindness and the Hemophilia A) are described. PMID- 28092963 TI - Mathematical modeling of continuous and intermittent androgen suppression for the treatment of advanced prostate cancer. AB - Prostate cancer is one of the most prevalent types of cancer among men. It is stimulated by the androgens, or male sexual hormones, which circulate in the blood and diffuse into the tissue where they stimulate the prostate tumor to grow. One of the most important treatments for advanced prostate cancer has become androgen deprivation therapy (ADT). In this paper we present three different models of ADT for prostate cancer: continuous androgen suppression (CAS), intermittent androgen suppression (IAS), and periodic androgen suppression. Currently, many patients in the U.S. receive CAS therapy of ADT, but many undergo a relapse after several years and experience adverse side effects while receiving treatment. Some clinical studies have introduced various IAS regimens in order to delay the time to relapse, and/or to reduce the economic costs and adverse side effects. We will compute and analyze parameter sensitivity analysis for CAS and IAS which may give insight to plan effective data collection in a future clinical trial. Moreover, a periodic model for IAS is used to develop an analytical formulation for relapse times which then provides information about the sensitivity of relapse to the parameters in our models. PMID- 28092964 TI - A note on the global properties of an age-structured viral dynamic model with multiple target cell populations. AB - Some viruses can infect different classes of cells. The age of infection can affect the dynamics of infected cells and viral production. Here we develop a viral dynamic model with the age of infection and multiple target cell populations. Using the methods of semigroup and Lyapunov function, we study the global asymptotic property of the steady states of the model. The results show that when the basic reproductive number falls below 1, the infection is predicted to die out. When the basic reproductive number exceeds 1, there exists a unique infected steady state which is globally asymptotically stable. The model can be extended to study virus dynamics with multiple compartments or coinfection by multiple types of viruses. We also show that under some scenarios the age structured model can be reduced to an ordinary differential equation system with or without time delays. PMID- 28092965 TI - A national analysis of dental waiting lists and point-in-time geographic access to subsidised dental care: can geographic access be improved by offering public dental care through private dental clinics? AB - INTRODUCTION: Australia is one of the least densely populated countries in the world, with a population concentrated on or around coastal areas. Up to 33% of the Australian population are likely to have untreated dental decay, while people with inadequate dentition (fewer than 21 teeth) account for up to 34% of Australian adults. Historically, inadequate access to public dental care has resulted in long waiting lists, received much media coverage and been the subject of a new federal and state initiative. The objective of this research was to gauge the potential for reducing the national dental waiting list through geographical advantage, which could arise from subcontracting the delivery of subsidised dental care to the existing network of private dental clinics across Australia. METHODS: Eligible population data were collected from the Australian Bureau of Statistics website. Waiting list data from across Australia were collected from publicly available sources and confirmed through direct communication with each individual state or territory dental health body. Quantum geographic information system software was used to map distribution of the eligible population across Australia by statistical area, and to plot locations of government and private dental clinics. Catchment areas of 5 km for metropolitan clinics and 5 km and 50 km for rural clinics were defined. The number of people on the waiting list and those eligible for subsidised dental care covered by each of the catchment areas was calculated. Percentage of the eligible population and those on the waiting list that could benefit from the potential improvement in geographic access was ascertained for metropolitan and rural residents. RESULTS: Fifty three percent of people on the waiting list resided within metropolitan areas. Rural and remote residents made up 47% of the population waiting to receive care. The utilisation of both government and private dental clinics for the delivery of subsidised dental care to the eligible population has the potential to improve geographic access for up to 25% of those residing within metropolitan areas and up to 59% for eligible country residents. CONCLUSIONS: This research finds that utilisation of the existing network of private dental practices across Australia for delivery of subsidised dental care could dramatically increase geographic reach, reduce waiting lists, and possibly make good oral health a more realistic goal to achieve for the economically disadvantaged members of the community. In addition, this approach has the potential to improve service availability in rural and remote areas for entire communities where existing socioeconomic dynamics do not foster new practice start-up. PMID- 28092966 TI - Avian influenza prevalence among hunter-harvested birds in a remote Canadian First Nation community. AB - INTRODUCTION: Avian influenza virus (AIV) prevalence has been associated with wild game and other bird species. The contamination of these birds may pose a greater risk to those who regularly hunt and consumed infected species. Due to resident concerns communicated by local Band Council, hunter-harvested birds from a remote First Nation community in subArctic Ontario, Canada were assessed for AIV. Hunters, and especially those who live a subsistence lifestyle, are at higher risk of AIV exposure due to their increased contact with wild birds, which represent an important part of their diet. METHODS: Cloacal swabs from 304 harvested game birds representing several species of wild birds commonly hunted and consumed in this First Nation community were analyzed for AIV using real-time reverse transcription polymerase chain reaction. Subtyping was performed using reverse transcription polymerase chain reaction. Sequences were assembled using Lasergene, and the sequences were compared to Genbank. RESULTS: In total, 16 of the 304 cloacal swab samples were positive for AIV. Of the 16 positive samples, 12 were found in mallard ducks, 3 were found in snow geese (wavies), and 1 positive sample was found in partridge. The AIV samples were subtyped, when possible, and found to be positive for the low pathogenic avian influenza virus subtypes H3 and H4. No samples were positive for subtypes of human concern, namely H5 and H7. CONCLUSIONS: This work represents the first AIV monitoring program results of hunter-harvested birds in a remote subsistence First Nation community. Community-level surveillance of AIV in remote subsistence hunting communities may help to identify future risks, while educating those who may have the highest exposure about proper handling of hunted birds. Ultimately, only low pathogenic strains of AIV were found, but monitoring should be continued and expanded to safeguard those with the highest exposure risk to AIV. PMID- 28092967 TI - Disparities in dental health of rural Australians: hospitalisation rates and utilisation of public dental services in three communities in North Queensland. AB - INTRODUCTION: The oral health of rural Australians continues to lag behind that of those living in metropolitan areas. Research has shown that people living in rural areas are more likely to suffer from dental caries (decay), visit the dentist less often and have poorer access to oral health services. The purpose of the study was to examine hospitalisations for dental conditions and utilisation of public dental services in three rural communities in Queensland compared with the whole of Queensland. METHODS: Aggregated hospitalisation data for dental conditions and counts of public outpatient service data were requested for residents of three rural communities in Queensland and for the whole of Queensland for the calendar year 2013. Hospitalisation rates per 1000 and risk ratios were calculated to examine the risk of hospitalisation for dental procedures for those living in the selected rural communities and the rest of Queensland. Data were grouped by gender, age and Indigenous status and comparisons made between Queensland and the rural communities. Outpatient service data were converted to percentage of all services delivered to allow comparisons between groups of different sizes. Population data were grouped into age cohorts and compared with the proportion of public oral health services delivered to each age cohort. RESULTS: Residents of the rural communities were twice as likely to be hospitalised and children aged 0-14 years living in the communities were three times more likely to be hospitalised for dental conditions compared to residents of the rest of Queensland. Outpatient oral service data showed that the proportion of services delivered to children aged up to 14 years living in the rural communities was less than the whole of Queensland. Interestingly, in one rural community where the public dental service was open to all, the distribution of public oral health services aligned with the age distribution of the population. CONCLUSIONS: The study showed that residents of these rural communities experience poorer oral health and are a greater risk of hospitalisation for dental conditions compared with the whole of Queensland. Whilst public dental services account for a small proportion of all dental care across the state, service utilisation data provide a unique insight into the population groups who may not be accessing public dental services. In the rural context, more effective use of the local workforce and a flexible approach to funding models could have a positive impact on access to dental care. PMID- 28092968 TI - Effect of Suture Caliber and Number of Core Strands on Repair of Acute Achilles Ruptures: A Biomechanical Study. AB - BACKGROUND: Controversy exists regarding the ideal Achilles rupture treatment; however, operative treatment is considered for athletes and active patients. The ideal repair construct is evolving, and the effect of suture caliber or number of core strands has not been studied. METHODS: Simulated mid-substance Achilles ruptures were performed in 24 cadavers. Specimens were randomized to three 6-core strand style repair constructs: (1) 4 No. 2 sutures and two 2-mm tapes (2T); (2) 2 No. 2 sutures and four 2-mm tapes (4T); (3) 12 (double-6-strand) strand repair (12 No. 2-0 sutures [12S]). Repairs were subjected to a cyclic loading protocol representative of postoperative rehabilitation. These data were compared to a previously published standard open repair technique (6-core strands with No. 2 sutures) on 9 specimens tested under the same conditions.6 Results: No significant elongation differences were observed between the repair groups and the previously published standard repair group in the first 2 stages of the simulated rehabilitation protocol. Both the 2T and 12S repairs survived a significantly greater number of cycles to failure ( P = 0.0005, P = 0.0267, respectively) and had a significantly higher failure load ( P = .0005, P = .0118, respectively) compared to the previously published data. These 2 constructs consistently survived the advanced stages of the simulated rehabilitation protocol. The majority of repairs failed at the knots. CONCLUSIONS: In this study, the 2T and 12S constructs survived the later stages of our simulated rehabilitation protocol, suggesting that they may be able to accommodate a more aggressive clinical rehabilitation protocol. Substituting suture-tape for 2 core strands or doubling the core strands with a smaller-caliber suture created a biomechanically stronger construct. CLINICAL RELEVANCE: Achilles repair with an added nonabsorbable, high-tensile strength tape allowed for a stronger construct that may allow for a more aggressive, early rehabilitation protocol and earlier return to function. PMID- 28092969 TI - Problem Internet Use and Internet Gaming Disorder: a survey of health literacy among psychiatrists from Australia and New Zealand. AB - OBJECTIVES: Research is limited on psychiatrists' opinions on the concepts of Internet Gaming Disorder (IGD) and Problematic Internet Use (PIU). We aimed to assess health literacy among psychiatrists on IGD/PIU. METHODS: A self-report survey was administered online to members of the Royal Australia and New Zealand College of Psychiatrists (RANZCP) ( n=289). RESULTS: The majority (93.7%) were familiar with the concepts of IGD/PIU. The majority (78.86%) thought it is possible to be 'addicted' to non-gaming internet content, and 76.12% thought non gaming addictions could possibly be included in classificatory systems. Forty eight (35.6%) felt that IGD maybe common in their practice. Only 22 (16.3%) felt they were confident in managing IGD. Child psychiatrists were more likely to screen routinely for IGD (11/45 vs. 7/95; Fishers Exact test chi2=7.95, df=1, p<0.01) and were more likely to elicit specific symptoms of addiction (16/45 vs. 9/95; Fishers Exact test chi2=14.16, df=1, p<0.001). CONCLUSIONS: We recommend adoption of terms alternate to PIU/IGD which are more in line with the content of material irrespective of medium of access. Screening instruments/ protocols are needed to assist in early diagnosis and service planning. Barriers to screening would need to be addressed both in research and service settings. PMID- 28092970 TI - Surgery of Anterior Skull Base Lesions in Children. AB - INTRODUCTION: Lesions affecting the anterior skull base represent a rare group of craniofacial pathologies. A tumor of the facial midline, meningitis, or rhinoliquorrhea may be indicative of malformations like dermoid cysts, gliomas, encephaloceles, or nasal fistulas. METHODS: We present a case series of 13 children (4 months to 12 years; 8 males, 5 females) with lesions involving the anterior skull base, which were treated surgically in an interdisciplinary setting. This case series includes cases of nasal fistulae (n = 5), nasal cysts (n = 5), aneurysmal bone cyst, nasal glioma, and meningoencephalocele (n = 1). RESULTS: All lesions were resected with a transnasal, transcutaneous, and/or transcranial approach with reconstruction of the anterior skull base if intracranial/intradural extension was detected. In 5 cases, a dura leakage was visible, which was sealed via Onlay-technique in 3 cases, whereas in 2 cases involving a greater dural defect, the GAP-CAS technique was performed. No complications occurred, and no recurrence was visible in a long-term follow-up. An algorithm for a systematic approach to these various pathologies is provided. CONCLUSION: Congenital pathologies of the anterior skull base are rare, challenging to diagnose, and present as clinical emergencies. An interdisciplinary surgical approach is needed for best functional and aesthetic results. PMID- 28092971 TI - Literature Review of Idiopathic Toe Walking: Etiology, Prevalence, Classification, and Treatment. AB - PURPOSE: The main objective of this review is to gather the information available about idiopathic toe walking (ITW), its prevalence and classification, and possible therapeutic approaches. In addition, this review aims to clarify the differences between idiopathic toe walkers and tiptoe walkers with underlying neurological or muscle deficiency as primary conditions. Understanding its causes and learning to make a differential diagnosis will help determine the adequate therapeutic approach. METHODS: This is a review of different articles and case studies from 1967 to 2016. The information was gathered to update and unify all the information about ITW that has been published. CONCLUSION: The literature offers limited research regarding the possible etiology, prevalence, classification, and evaluation of ITW. This review puts together all the information regarding the etiology, prevalence, classifications, evaluation, and treatment of ITW. LEVELS OF EVIDENCE: Level IV. PMID- 28092972 TI - Tracking Dynamic Interactions Between Structural and Functional Connectivity: A TMS/EEG-dMRI Study. AB - Transcranial magnetic stimulation (TMS) in combination with neuroimaging techniques allows to measure the effects of a direct perturbation of the brain. When coupled with high-density electroencephalography (TMS/hd-EEG), TMS pulses revealed electrophysiological signatures of different cortical modules in health and disease. However, the neural underpinnings of these signatures remain unclear. Here, by applying multimodal analyses of cortical response to TMS recordings and diffusion magnetic resonance imaging (dMRI) tractography, we investigated the relationship between functional and structural features of different cortical modules in a cohort of awake healthy volunteers. For each subject, we computed directed functional connectivity interactions between cortical areas from the source-reconstructed TMS/hd-EEG recordings and correlated them with the correspondent structural connectivity matrix extracted from dMRI tractography, in three different frequency bands (alpha, beta, gamma) and two sites of stimulation (left precuneus and left premotor). Each stimulated area appeared to mainly respond to TMS by being functionally elicited in specific frequency bands, that is, beta for precuneus and gamma for premotor. We also observed a temporary decrease in the whole-brain correlation between directed functional connectivity and structural connectivity after TMS in all frequency bands. Notably, when focusing on the stimulated areas only, we found that the structure-function correlation significantly increases over time in the premotor area controlateral to TMS. Our study points out the importance of taking into account the major role played by different cortical oscillations when investigating the mechanisms for integration and segregation of information in the human brain. PMID- 28092973 TI - Elevated ambulatory systolic-diastolic pressure regression index is genetically determined in hypertensive patients with coronary heart disease. AB - OBJECTIVES: Ambulatory systolic-diastolic pressure regression index (ASDPRI) as a composite marker of cardiovascular (CV) properties is related to CV complications. However, genetic determinants of ASDPRI are not known. The aim of this study is to report the relationship between certain single nucleotide polymorphisms (SNP) and ASDPRI in hypertensive patients with CAD confirmed by coronary angiography. METHODS: A total of 1345 hypertensive subjects with CAD were included. SNPs were selected from genome-wide association studies. SNPs were reported to be associated with coronary artery disease risk. There were significant differences in 24 h and daytime and nighttime ASDPRIs for PHCTR1, LPA and ADAMTS7 polymorphisms. Genetic risk score (GRS18) was constructed to evaluate additive effect of 18 SNPs for ASDPRI. RESULTS: Analysis of covariance revealed a significant relationship between the PPAB2B (beta - 0.85; 95 CI -1.85--0.16, p < 0.02), WDR12 (beta - 1.31; 95 CI -2.19--0.43, p < 0.01) polymorphisms and nighttime ASDPRI dipping. Analysis of covariance revealed a significant relationship between GRS 18 and 24-h ASDPRI (beta 0.34; 95 CI 0.16-0.31, p < 0.01). CONCLUSIONS: In conclusion, ADAMTS7 and LPA polymorphisms are related to 24-h ASDPRI but PPAB2B and WDR12 gene polymorphisms are associated with nighttime ASDPRI dipping. A total of 24-h ASDPRI is determined by GRS18. PMID- 28092974 TI - The Development of a Brief Version of the Posttraumatic Cognitions Inventory (PTCI-9). AB - Negative posttraumatic cognitions lead to the development and maintenance of posttraumatic stress disorder symptoms. There is a need for a brief measure to assess these cognitions. Participants were administered the Posttraumatic Cognitions Inventory (PTCI) and measures of mental health symptomatology. These data were used to develop a brief version of the PTCI (PTCI-9) in 223 male and female veterans, which was then examined in a sample of 117 female civilians. Confirmatory factor analyses demonstrated an acceptable fit in both samples. The PTCI-9 total and subscale scores showed strong internal consistencies (Cronbach's alphas = .80-.87) and strong correlations with the PTCI in veterans ( rs = .90 .96) and civilians ( rs = .91-.96). Measurement invariance testing demonstrated partial invariance between the two samples. The PTCI-9 significantly correlated with measures of PTSD, depression, and quality of life. These findings demonstrate that the PTCI-9 is a reliable and valid measure of posttraumatic cognitions that can reduce patient and provider burden. PMID- 28092975 TI - Characterisation of the antiproliferative constituents and activity of Ficus exasperata (Vahl) on ovarian cancer cells -a preliminary investigation. AB - Ovarian cancer is one of the most common gynaecological cancers today. This study therefore investigates the anticancer effects of Ficus exasperata extracts and fractions on ovarian cancer cells. The antiproliferative activity of the crude extracts (1 mg/mL) was assessed using the MTT assay on A2780 (ovarian cancer) cell line. Bio-activity guided fractionation was performed and preliminary identification was further achieved using high resolution mass spectrometry and nuclear magnetic resonance spectroscopy. All crude extracts tested exhibited antiproliferative activity except for the methanol extract which interestingly showed proliferative effects. Five fatty acids were identified from the active fractions (FB1-10 and FB1-12). FB1-12 exhibited an IC50 value of 15.20 MUg/mL. The least potent fraction (FB1-4 + 5) had an IC50 value of 34.51 MUg/mL. H1-HEX and H1-MET exhibited 97.2 and 97.9%, respectively, compared to control. This study therefore provides proof-of-principle that fatty acids of Ficus exasperata exhibit significant antiproliferative effects on ovarian cancer cells. PMID- 28092979 TI - Endovascular treatment of HIV-associated spontaneous common carotid artery pseudoaneurysm in a case of miliary and CNS tuberculosis. AB - HIV and tuberculosis infections are known to be associated with vasculopathy including occlusive disease and aneurysm formation. We report a case of 43-year old male with miliary and central nervous system (CNS) tuberculosis; recently, diagnosed as HIV seropositive, on antiretroviral and antitubercular treatment presenting with painful neck swelling. He was found to have common carotid artery (CCA) pseudoaneurysm that was managed by endovascular stent grafting. HIV vasculopathy-related CCA pseudoaneurysm is a potentially life-threatening rare entity. Treatment of an immunocompromised patient by endovascular approach minimizes hospital stay and avoids wound-related complications. To the best of our knowledge, there has been no case report describing endovascular treatment of CCA pseudoaneurysm in an HIV-positive patient with low CD4 count and coexistent disseminated tuberculosis. PMID- 28092977 TI - Hypertension is associated with increased mortality in patients with ischaemic heart disease after revascularization with percutaneous coronary intervention - a report from SCAAR. AB - BACKGROUND: The prognostic role of hypertension on long-term survival after percutaneous coronary intervention (PCI) is limited and inconsistent. We hypothesize that hypertension increases long-term mortality after PCI. METHODS: We analyzed data from SCAAR (Swedish Coronary Angiography and Angioplasty Registry) for all consecutive patients admitted coronary care units in Sweden between January 1995 and May 2013 and who underwent PCI due to ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI)/unstable angina (UA) or stable angina pectoris. We used Cox proportional hazards regression for statistical modelling on complete-case data as well as on imputed data sets. We used interaction test to evaluate possible effect modulation of hypertension on risk estimates in several pre-specified subgroups: age categories, gender, diabetes, smoking and indication for PCI (STEMI, NSTEMI/UA and stable angina). RESULTS: During the study period, 175,892 consecutive patients underwent coronary angiography due to STEMI, NSTEMI/UA or stable angina. 78,100 (44%) of these had hypertension. Median follow-up was 5.5 years. After adjustment for differences in patient's characteristics, hypertension was associated with increased risk for mortality (HR 1.12, 95% CI 1.09-1.15, p < .001). In subgroup analysis, risk was highest in patients less than 65 years, in smokers and in patients with STEMI. The risk was lowest in patients with stable angina (p < .001 for interaction test). CONCLUSION: Hypertension is associated with higher mortality in patients with STEMI, NSTEMI/UA or stable angina who are treated with PCI. PMID- 28092978 TI - Variability in Foot and Ankle Case Volume in Orthopaedic Residency Training. AB - : Surgical case volume during orthopaedic surgical residency is a concern among trainees and program directors alike. With an ongoing trend toward further subspecialization and the rapid development of new techniques and devices, the breadth of procedures that residents are exposed to continues to increase. Accreditation Council for Graduate Medical Education surgical case logs from 2009 to 2013 for graduating orthopaedic surgery residents were examined to assess the national averages of orthopaedic procedures logged by graduating orthopaedic surgery residents in the leg/ankle and foot/toes categories. This investigation revealed that there was an 8% increase in the total number of leg/ankle cases and 12% increase in foot/toes cases performed by graduating orthopaedic surgery residents, which has not significantly increased from 2009 to 2013. Across years examined in this study, significant variability existed between the 10th and 90th percentiles for total foot and ankle resident case exposure (P < .05), particularly within ankle arthroscopy, where there was a 15-fold difference in the number of arthroscopy cases performed by residents in the 90th percentile compared with the 10th percentile. The overall volume of foot and ankle cases performed by graduating orthopaedic surgery residents has increased despite not being statistically significantly from 2009 to 2013. LEVELS OF EVIDENCE: Level III: Cohort study. PMID- 28092981 TI - Erratum. PMID- 28092980 TI - Hydrogeochemical and isotope study of perched aquifers in the Cuvelai-Etosha Basin, Namibia. AB - A hydrogeochemical and stable isotope study (2H and 18O) was carried out in the Cuvelai-Etosha Basin in order to characterize available groundwater and to identify possible recharge mechanisms for the perched aquifers. Data were collected during seven field campaigns between 2013 and 2015 from a total of 24 shallow and deep groundwater hand-dug wells. In the investigated groundwaters, hydrogencarbonate is the dominating anion in both well types, whereas cations vary between calcium and magnesium in deep wells, and sodium and potassium in shallow wells. Groundwater chemistry is controlled by dissolution of carbonate minerals, silicate weathering and ion exchange. Stable isotopic composition suggests that deep groundwater is recharged by high-intensity/large rainfall events, whereas the shallow wells can even be recharged by less-intense/small rainfall events. Water in deep wells reflect a mixture of water influenced by evaporation during or before infiltration and water that infiltrated through fast preferential pathways, whereas shallow wells are strongly influenced by evaporation. The findings of this research contribute to improve the understanding of hydrogeochemistry, recharge paths and temporal variations of perched aquifers. PMID- 28092982 TI - Second malignancy risk in prostate cancer and radiotherapy. PMID- 28092983 TI - Essential oil constituents and antimicrobial activity of Pycnocycla bashagardiana Mozaff. from Iran. AB - Pycnocycla bashagardiana is a rare endemic and endangered species that has been used in folkloric medicine in Southern Iran. This study aimed to evaluate the essential oil constituents and antimicrobial activity of wild and cultivated p. bashagardiana. The aerial parts of wild and cultivated plants were collected from two provinces of Iran. The essential oil was isolated by hydrodistillation and analyzed by a combination of capillary GC and GC-MS. The main components in wild plants were myristicin (39.12%), (E)-beta-ocimene (21.97%), sabinene (15.0%) and cis-iso-miristicin (2.67%) and in cultivated plants, (E)-beta-ocimene (55.40%), myristicin (18.27%), (Z)-beta-ocimene (12.47%) and cis-iso-miristicin (2.94%) were the main constituents in essential oil. The in vitro antimicrobial activity of the essential oil of P. bashagardiana were studied against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli and Candida albicans for the first time. The results showed that the oil exhibited strong antimicrobial activity against all the tested pathogens. PMID- 28092984 TI - Vipera ammodytes bites treated with antivenom ViperaTAb: a case series with pharmacokinetic evaluation. AB - CONTEXT: In clinical practice it is difficult to differentiate between V. berus and V. ammodytes venomous bites. In the past this was not a concern, but due to the current shortage in ViperfavTM and European viper venom antiserum availability, V. a. ammodytes venomous bites have recently been treated with ViperaTAb(r), which is a pharmaceutical formulation containing a monospecific ovine Fab fragments against the venom of V. berus. OBJECTIVE: To evaluate ViperaTAb(r) in V. a. ammodytes envenomations. MATERIALS AND METHODS: This is a prospective case series of three consecutive patients envenomed by V. a. ammodytes snakebite treated with ViperaTAb(r). V. ammodytes venom, neurotoxic ammodytoxins, and Fab fragment levels were determined in serum samples and a pharmacokinetic analysis of the antivenom Fab fragments was carried out. RESULTS: Three patients bitten by V. a. ammodytes with extensive local swelling, neurological symptoms and recurrent thrombocytopenia were treated with ViperaTAb(r). V. ammodytes venom was detected in serum of all three patients. Ammodytoxins were detected in the serum of only the most severely envenomed patient who developed neurological symptoms. In the presented moderate cases, a dose of 8 mL of ViperaTAb(r) reduced swelling and improved systemic effects, such as thrombocytopenia. However, this dose of ViperaTAb(r) was not effective in the most severely envenomed patient with the highest serum values of V. ammodytes venom. In this case ViperaTAb(r) did not stop local swelling and it had no effect on neurological signs. ViperaTAb(r)'s systemic clearance, distribution and elimination half-lives were 4.3-13.4 mL/h/kg, 1.2-3.2 h and 14.1-55.4 h, respectively. CONCLUSIONS: In patients envenomed by V. a. ammodytes venom, ViperaTAb(r) reduces moderate swelling and temporarily improves systemic effects, except neurological symptoms. ViperaTAb(r) application induces a decrement of V. ammodytes venom level in the blood, but did not affect serum concentration of neurotoxic ammodytoxins in the one patient with measurable concentrations. PMID- 28092985 TI - Plague and war: political breakdown and the spread of HIV. AB - This exploratory data analysis finds a negative relationship between some types of war and HIV prevalence (i.e. as the former increases in intensity, the latter decreases). The study uses a longer time-frame and broader range of countries than similar studies, with explicit differentiation between sub-Saharan African and other developing countries. The study uses a variety of methods for analyzing time-series-cross-section data. These methods serve as both a robustness check for the results as well as a real-world demonstration of common suggestions for TSCS data. PMID- 28092986 TI - The Treatment of Primary Orthostatic Hypotension. AB - OBJECTIVE: To review the efficacy and safety of pharmacological and nonpharmacological strategies used to treat primary orthostatic hypotension (OH). DATA SOURCES: A literature review using PubMed and MEDLINE databases searching hypotension, non-pharmacological therapy, midodrine, droxidopa, pyridostigmine, fludrocortisone, atomoxetine, pseudoephedrine, and octreotide was performed. STUDY SELECTION AND DATA EXTRACTION: Randomized or observational studies, cohorts, case series, or case reports written in English between January 1970 and November 2016 that assessed primary OH treatment in adult patients were evaluated. DATA SYNTHESIS: Based on the chosen criteria, it was found that OH patients make up approximately 15% of all syncope patients, predominantly as a result of cardiovascular or neurological insults, or offending medication. Nonpharmacological strategies are the primary treatment, such as discontinuing offending medications, switching medication administration to bedtime, avoiding large carbohydrate-rich meals, limiting alcohol, maintaining adequate hydration, adding salt to diet, and so on. If these fail, pharmacotherapy can help ameliorate symptoms, including midodrine, droxidopa, fludrocortisone, pyridostigmine, atomoxetine, sympathomimetic agents, and octreotide. CONCLUSIONS: Midodrine and droxidopa possess the most evidence with respect to increasing blood pressure and alleviating symptoms. Pyridostigmine and fludrocortisone can be used in patients who fail to respond to these agents. Emerging evidence with low-dose atomoxetine is promising, especially in those with central autonomic failure, and may prove to be a viable alternative treatment option. Data surrounding other therapies such as sympathomimetic agents or octreotide are minimal. Medication management of primary OH should be guided by patient-specific factors, such as tolerability, adverse effects, and drug-drug and drug-disease interactions. PMID- 28092987 TI - Emerging treatment approaches for myeloma-related bone disease. AB - INTRODUCTION: Multiple myeloma is characterized by the presence of osteolytic lesions that leads to devastating skeletal-related events in the majority of patients. Myeloma bone disease is attributed to increased osteoclastic and suppressed osteoblastic activity. Areas covered: Bisphosphonates remain the main treatment option, however they have limitations on their own. Understanding the pathogenesis of myeloma bone disease may provide a roadmap for new therapeutic approaches. The pathway of RANKRANKLOPG pathway has revealed denosumab, a monoclonal antibody targeting RANKL as a novel emerging therapy for myeloma related bone disease. Furthermore, the Wnt signaling inhibitors dicckopf-1 and sclerostin that are implicated in the pathogenesis of bone destruction of myeloma are now targeted by novel monoclonal antibodies. Activin-A is a TGF-beta superfamily member which increases osteoclast activity and inhibits osteoblast function in myeloma; sotatercept and other molecules targeting activin-A have entered into clinical development. Several other molecules and pathways that play an important role in the pathogenesis of bone destruction in myeloma, such as periostin, adiponectin, Notch and BTK signaling are also targeted in an attempt to develop novel therapies for myeloma-related bone disease. Expert commentary: We summarize the current advances in the biology of myeloma bone disease and the potential therapeutic targets. PMID- 28092988 TI - Measurement Invariance of the Prodromal Questionnaire-Brief Among White, Asian, Hispanic, and Multiracial Populations. AB - The Prodromal Questionnaire-Brief is a scale that is used to screen individuals for risk for the development of psychosis. It has promising psychometric properties in clinical and nonclinical populations, including undergraduates. However, the measurement invariance of the scale has not been examined in Asian, White, Hispanic, and Multiracial samples. A total of 2,767 undergraduates at two large public U.S. universities completed the Prodromal Questionnaire-Brief. The Total scores had configural and scalar invariance, while the Distress scores displayed configural, metric, and partial scalar invariance. Follow-up analyses revealed that three items were responsible for the lack of complete scalar invariance for the Distress scores. This suggests that the Total and Distress scores are measuring the same construct across groups and mean scores represent the same level of latent prodromal traits across groups. Mean comparisons for the Distress Scale across ethnicity should be interpreted with caution because it lacks complete scalar invariance. White and Hispanic participants had lower Total scores that Multiracial and Asian participants, and this pattern emerged for 13 items. For the distress items that were scalar invariant, the Asian group reported more distress than the White and Hispanic groups, while the Multiracial group reported more distress than the White group. PMID- 28092989 TI - Therapeutic complement inhibition: a promising approach for treatment of neuroimmunological diseases. AB - INTRODUCTION: Autoimmunity is an important cause of disease both in the central and peripheral nervous systems. Aetiologies and clinical manifestations are complex and heterogeneous. Inappropriate control of complement activation at inappropriate sites has been recognized as a major determinant in several neurological conditions, including Guillain-Barre syndrome and neuromyelitis optica. In each case pathogenesis is thought to be associated with generation of autoantibodies which upon binding guide activation of the complement system to self-tissue. Areas covered: Modulation of the complement system activation at such sites may represent a novel therapeutic approach for treatment of immune mediated inflammatory conditions. In this review we focus on the therapeutic effects of complement inhibitors in Guillain-Barre syndrome and neuromyelitis optica and highlight recent developments within the field. Expert Commentary: Conventional first line treatment strategies in GBS and NMO have the potential disadvantage of causing widespread immunosuppressive effects. A more targeted approach may therefore be more effective and less disruptive to the immune system, especially in the case of NMO, which requires long term immunosuppression. Modulation of the complement system may hold the key and has already been shown to be of clinical benefit in other non-neurological conditions, including paroxysmal nocturnal hemoglobinuria and hereditary angioedema. PMID- 28092990 TI - In-hospital statin underutilization among high-risk patients: delayed uptake of the 2013 cholesterol guidelines in a U.S. cohort. AB - OBJECTIVES: Clinician utilization of the 2013 cholesterol lowering guidelines remains variable and unknown. We sought to examine statin prescribing patterns and compare rates among specialists who treat high-risk cardiovascular patients admitted to the hospital. METHODS: We retrospectively (via chart review) examined four specialty groups: (i) Cardiology, (ii) Cardiovascular or Vascular (CV) Surgery, (iii) Neurology, and (iv) Internal Medicine. Adult patients were included based on a discharge diagnosis of acute coronary syndrome, coronary artery bypass graft surgery, carotid endarterectomy, acute ischemic stroke, transient ischemic attack, or high-risk chest pain. Prescribing patterns were evaluated 6 months and 18 months after the release of the 2013 guidelines. High intensity statin was defined as atorvastatin 40-80 mg or rosuvastatin 20-40 mg per day. RESULTS: 632 patients were included in our study. The following percentages of patients were discharged on high-intensity statin (6 months; 18 months): (i) Cardiology (80%; 85%), (ii) CV Surgery (52%, 65%), (iii) Neurology (59%; 66%), and (iv) Internal Medicine (45%; 48%). Among the four groups, Cardiology was the most likely to discharge patients on high-intensity statin (p < 0.001) in 2014 and in 2015. Cardiology, CV Surgery, and Neurology significantly increased the percentage of patients on high-intensity statin from pre-admission to time of discharge in both years. CONCLUSION: High-intensity statin therapy is underutilized among high-risk cardiovascular patients admitted to the hospital. Variations exist in prescribing patterns of different specialties who manage high risk populations. This data can be used to test quality improvement interventions to improve rates of high-intensity statin utilization among high-risk patients prior to hospital discharge. PMID- 28092991 TI - Reproducibility and relative validity of food group intake in a food frequency questionnaire developed for Nepalese diet. AB - We developed a food frequency questionnaire (FFQ) designed to measure the dietary practices of adult Nepalese. The present study examined the validity and reproducibility of the FFQ. To evaluate the reproducibility of the FFQ, 116 subjects completed two 115-item FFQ across a four-month interval. Six 24-h dietary recalls were collected (1 each month) to assess the validity of the FFQ. Seven major food groups and 23 subgroups were clustered from the FFQ based on macronutrient composition. Spearman correlation coefficients evaluating reproducibility for all food groups were greater than 0.5, with the exceptions of oil. The correlations varied from 0.41 (oil) to 0.81 (vegetables). All crude spearman coefficients for validity were greater than 0.5 except for dairy products, pizzas/pastas and sausage/burgers. The FFQ was found to be reliable and valid for ranking the intake of food groups for Nepalese dietary intake. PMID- 28092992 TI - +1q: amplifying the bad genes in myeloma. PMID- 28092993 TI - Do all patients with chronic myeloid leukemia need to receive interferon during pregnancy? PMID- 28092994 TI - Current status and future prospects of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) clinical trials in ovarian cancer. AB - The natural history of advanced-stage epithelial ovarian cancer is one of clinical remission after surgery and platinum/taxane-based intravenous (IV) and/or intraperitoneal (IP) chemotherapy followed by early or late recurrence in the majority of patients. Prevention of progression and recurrence remains a major hurdle in the management of ovarian cancer. Recently, many investigators have evaluated the use of normothermic and hyperthermic intraoperative IP drug delivery as a management strategy. This is a narrative review of the current status of clinical trials of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) in ovarian cancer and the future directions for this treatment strategy. The existing studies on HIPEC in patients with epithelial ovarian cancer are mostly retrospective in nature, are heterogeneous with regards to combined inclusion of primary and recurrent disease and lack unbiased data. Until data are available from evidence-based trials, it is reasonable to conclude that surgical cytoreduction and HIPEC is a rational and interesting, though still investigative, approach in the management of epithelial ovarian cancer, whose use should be employed within prospective clinical trials. PMID- 28092995 TI - FDG PET in follicular lymphoma: more than a staging test? PMID- 28092996 TI - Chromosome 1 amplification has similar prognostic value to del(17p13) and t(4;14)(p16;q32) in multiple myeloma patients: analysis of real-life data from the Polish Myeloma Study Group. AB - The study aimed to assess prognostic significance of del(13q14), del(17p13), t(4;14)(p16;q32), and amp(1q21) in newly diagnosed myeloma patients treated mostly with thalidomide-based therapies. All genetic abnormalities except del(13q14) were independent prognostic factors associated with shortened progression-free survival (PFS) and overall survival (OS). Patients with no abnormalities, one abnormality, and >=2 abnormalities had a median PFS of 41.8, 17.0, and 10.0 months, respectively; a median OS was not reached, 48.0 and 23.3 months, respectively. According to the presence of amp(1q21), t(4;14)(p16;q32), and del(17p13) and the International Staging System (ISS), we stratified patients into low-risk, intermediate-risk and high-risk groups. A median PFS was 52.9, 25.6, and 10.0 months, respectively; a median OS was not reached, 64.0 and 25.0 months, respectively. In conclusion, our study confirmed the prognostic value of cytogenetic changes and showed that prognostic models based on ISS and cytogenetic studies should include not only del(17p13) and t(4;14)(p16;q32), but also amp(1q21). PMID- 28092997 TI - The t(8;21) fusion protein RUNX1-ETO downregulates PKM2 in acute myeloid leukemia cells. PMID- 28092998 TI - Treatment patterns and outcomes with subcutaneous bortezomib in patients with relapsed mantle cell lymphoma: a retrospective, observational study of patient medical records from US community oncology practices. PMID- 28092999 TI - Second malignancies in survivors of chronic myelomonocytic leukemia: a U.S. population-based study. PMID- 28093000 TI - Circulating proteasomes: circling myeloma with a new potential biomarker. PMID- 28093001 TI - miR-505-5p and miR-193b-3p: potential biomarkers of imatinib response in patients with chronic myeloid leukemia. PMID- 28093002 TI - Predictive value of some hematological parameters for non-invasive and invasive mole pregnancies. AB - AIM: The aim of this study was to discriminate mole pregnancies and invasive forms among cases with first trimester vaginal bleeding by the utilization of some complete blood count parameters conjunct to sonographic findings and beta human chorionic gonadotropin concentration. MATERIALS AND METHODS: Consecutive 257 cases with histopathologically confirmed mole pregnancies and 199 women without mole pregnancy presented with first trimester vaginal bleeding who admitted to Zeynep Kamil Women and Children's Health Training Hospital between January 2012 and January 2016 were included in this cross-sectional study. The serum beta HCG level at presentation, and beta hCG levels at 1st, 2nd and 3rd weeks of postevacuation with some parameters of complete blood count were utilized to discriminate cases with molar pregnancy and cases with invasive mole among first trimester pregnants presented with vaginal bleeding and abnormal sonographic findings. RESULTS: Levels of beta hCG at baseline (AUC = 0.700, p < 0.05) and 1st (AUC = 0.704, p < 0.05), 2nd (AUC = 0.870, p < 0.001) and 3rd (AUC = 0.916, p < 0.001) weeks of postevacuation period were significant predictors for the cases with persistent disease. While area under curve for mean platelet volume is 0.715, it means that mean platelet volume has 21.5% additional diagnostic value for predicting persistency in molar patients. For 8.55 cut-off point for mean platelet volume, sensitivity is 84.6% and specificity is 51.6%. Area under curve for platelet/lymphocyte ratio is 0.683 means that platelet/lymphocyte ratio has additional 18.3% diagnostic value. For 102.25 cut off point sensitivity is 86.6% and specificity is 46.2. CONCLUSIONS: Simple, widely available complete blood count parameters may be used as an adjunct to other risk factors to diagnose molar pregnancies and predict postevacuation trophoblastic disease. PMID- 28093003 TI - Outcome for patients with relapsed/refractory aggressive lymphoma treated with gemcitabine and oxaliplatin with or without rituximab; a retrospective, multicentre study. AB - The treatment of relapsed aggressive lymphoma remains a challenge. Platinum containing chemotherapy is standard of care. Gemcitabine/oxaliplatin (Gem-Ox) with or without rituximab (R) is an outpatient regimen with a favorable toxicity profile. This retrospective 'real world' study reports outcomes for 44 unselected patients with relapsed/refractory aggressive lymphoma treated with Gem-Ox +/- R. 41% had primary refractory disease. The overall response rate (ORR) was 43% with a complete response (CR) of 30%. Response to the prior treatment regimen significantly affected the ORR with only 8% achieving CR if prior remission was <12 months. Grade 3-4 hematological toxicity was common and 22% had febrile neutropenia. Eight patients proceeded to stem cell transplant. Overall, outcomes remain poor with a median overall survival of 8 months. In this high-risk group of patients, Gem-Ox +/- R results in similar responses to other more toxic, inpatient regimens and should therefore be considered as second line therapy in relapsed lymphoma. PMID- 28093004 TI - Immunotherapy with the trifunctional anti-CD20 * anti-CD3 antibody FBTA05 in a patient with relapsed t(8;14)-positive post-transplant lymphoproliferative disease. PMID- 28093005 TI - Cardiac and respiratory effects of deep regional hyperthermia using an 8-MHz radiofrequency-capacitive device on patients with cancer. AB - PURPOSE: Hyperthermia (HT), an adjuvant therapy for variable cancers, may cause physiological changes in the patients, which may lead to cardiovascular problems. Among various HT treatments, the physiological effects of deep regional HT are still unclear. We examined the physiological alterations throughout deep regional HT to improve the HT safety. MATERIALS AND METHODS: Thirty-one patients (age: 61+/-12 years) with cancer received HT in the thoracic or upper abdominal regions using an 8-MHz radiofrequency-capacitive-device for 50 min. Rectal temperature (Trec), systolic and diastolic blood pressures (SBP and DBP), pulse rate (PR), respiratory rate (RR), percutaneous oxygen saturation (SpO2), and sweating volume were evaluated throughout HT. RESULTS: At 50 min after starting HT, Trec, PR, and RR were significantly increased compared with the baseline values (Trec: 38.2+/ 1.4 vs. 36.3+/-0.8 degrees C, p < 0.001, PR: 104+/-15 vs. 85+/-16 bpm, p < 0.05, RR: 23+/-3 vs. 21+/-3/min, p < 0.05). Although the average SBP and DBP were both stable during HT in a recumbent position, these values dropped significantly in a standing position (SBP: 113+/-16 vs. 127+/-18 mmHg, p < 0.001, DBP: 70+/-12 vs. 75+/-13 mmHg, p < 0.01). The total amount of sweating was 356+/-173 g/m2 on average. CONCLUSIONS: Deep regional HT increased the deep body temperature and resulted in an increase of sweating with peripheral vasodilatation. Consequently, a significant reduction in BP would be induced on standing after HT. Careful attention is needed for patients receiving HT, especially when standing after HT. PMID- 28093006 TI - Blood malignancies presenting with mutations at equivalent residues in RUNX1-2 suggest a common leukemogenic pathway. PMID- 28093007 TI - Thalidomide analog CC-122 induces a refractory state in monocytes from patients with diffuse large B cell lymphoma. PMID- 28093008 TI - Hearing-loss-associated gene detection in neonatal intensive care unit. AB - OBJECTIVE: To investigate the frequency and mutation spectrum of hearing loss associated gene mutation in Neonatal Intensive Care Unit (NICU). METHODS: Neonates (n=2305) admitted to NICU were enrolled in this study. Nine prominent hearing loss-associated genes, GJB2 (35 del G, 176 del 16,235 del C, 299 del AT), GJB3 (538 C > T), SLC26A4 (IVS7-2A > G, 2168 A > G) and mtDNA 12S rRNA(1555 A > G, 1494 C > T), were detected. RESULT: There were 73 cases hearing-loss associated gene mutation among 2305 cases, the mutation frequency was 3.1%, with 40 cases GJB2 (235del C) mutation (54.8%), 6 cases GJB2 (299 del AT) mutation (8.2%), 21 cases SLC26A4 (IVS 7-2 A > G) mutation (28.7%), 4 cases SLC26A4 (2168 A > G) mutation (5.5%), 2 cases of GJB2 (235del C) combined SLC26A4 (IVS 7-2 A > G, 2168 A > G) mutation (2.8%). Among 73 gene mutation cases, preterm neonates presented in 18 cases, accounting for 24.7% (18/73); hyperbilirubinemia in 13 cases, accounting for 17.8% (13/73); Torch Syndrome in 15 cases, with 12 cases CMV, 2 cases rubella, 1 case toxoplasm, respectively, totally accounting for 20.54% (15/73); neonatal pneumonia in 12 cases, accounting for 16.4% (12/73); birth asphyxia in 5 cases, accounting for 6.9% (5/73); sepsis in 5 cases, accounting for 6.9% (5/73); others in 5 cases, accounting for 6.8% (5/73) . CONCLUSIONS: The frequency of hearing loss-associated gene mutation was higher in NICU.There were hearing loss-associated gene mutations in the NICU, suggesting this mutation may complicate with perinatal high-risk factors. PMID- 28093010 TI - Correction to: Factors influencing the fabrication of albumin-bound drug nanoparticles (ABDns): Part I. Albumin-bound betulinic acid nanoparticles (ABBns). PMID- 28093009 TI - Genetic identification of prey species from teeth in faeces from the Endangered leopard cat Prionailurus bengalensis using mitochondrial cytochrome b gene sequence. AB - To understand the dietary ecology of the leopard cat (Prionailurus bengalensis), DNA analysis was performed to identify prey species using DNA isolated from teeth harvested from the faeces of this feline species. From 70 DNA samples, a total of 52 mitochondrial DNA (mtDNA) cytochrome b (cytb) gene sequences of mammals were identified. The results of a sequence identity test indicated that those sequences were derived from four rodent species (Apodemus agrarius, Apodemus peninsulae, Eothenomys regulus and Tamias sibiricus) and two shrew species (Crocidura lasiura and Crocidura shantungensis). The sequences contained nine unique cytb sequences from site 1 and 13 from site 2. These results indicate that the leopard cat hunts rodents and shrews, and at least nine animals at site 1 and 13 animals at site 2 were eaten. These findings suggest that the animal molecular signatures that remain undigested in the faeces may provide useful ecological information about food items and may contribute to a better understanding of the leopard cat's feeding ecology. PMID- 28093011 TI - Individuals with dark eyes and hair exhibit higher pain sensitivity. AB - Emerging evidence suggests that some phenotypic features, such as eye or hair colour, might predict pain. We investigated if light and dark eye and hair colour would influence pain in 60 healthy subjects divided in groups of 15 according to their eye-hair colour and gender. Pressure pain thresholds (PPTs), cold pressor test (CPT), and quality of the perceived pain were assessed. Findings indicated that dark pigmentation phenotype is more sensitive in response to CPT. PMID- 28093012 TI - Male coping through a long-term cancer trajectory. Secondary outcomes from a RTC examining the effect of a multidisciplinary rehabilitation program (RePCa) among radiated men with prostate cancer. AB - BACKGROUND: The objective of this study was to examine if rehabilitation influenced self-reported male coping styles during and up to three years after treatment with radiotherapy for prostate cancer. MATERIALS AND METHODS: In a single-center oncology unit in Odense, Denmark, 161 prostate cancer patients treated with radiotherapy and androgen deprivation therapy were included in a randomized controlled trial from 2010 to 2012. The trial examined the effect of a multidisciplinary rehabilitation program within six months of treatment consisting of two nursing counseling sessions and two instructive sessions with a physical therapist (n = 79), or standard care (n = 82). As secondary outcomes coping was measured before radiotherapy, one month after radiotherapy (baseline), six month post-intervention (assessment) and three years after radiotherapy (follow-up) by the Mini-mental adjustment to cancer scale (Mini-MAC). The male coping styles towards the illness are expressed in five mental adjustment styles: Fighting Spirit, Helplessness-Hopelessness, Anxious Preoccupation, Fatalism and Cognitive Avoidance. Descriptive analysis and multiple linear regression analysis adjusting for the longitudinal design were conducted. RESULTS: Most coping styles remained stable during the patient trajectory but Anxious Preoccupation declined from before radiotherapy to follow-up in both intervention and control groups. After six months the intervention group retained Fighting Spirit significantly (p = 0.025) compared with controls, but after three years this difference evened out. After three years the intervention group had lower Cognitive Avoidance (p = 0.044) than the controls. Factors as educational level, and depression influenced the use of coping styles after three years. CONCLUSION: Multidisciplinary rehabilitation in irradiated prostate cancer patients retained the adjustment style Fighting Spirit stable after six months of radiotherapy, and in the long term reduced Cognitive Avoidance. Thus, the rehabilitation program supported the patient's active coping style and played down the passive coping style. PMID- 28093013 TI - Long term changes in health complaints after removal of amalgam restorations. AB - OBJECTIVE: Concerns over adverse effects of mercury released from dental amalgam sometimes lead patients to request removal of their amalgam restorations. Several studies report improvement of subjective health after removal of amalgam restorations, but the mechanisms are unclear. The aim of this paper is to present data on long term changes in intensity of health complaints after amalgam removal in a group of patients with health complaints self-attributed to dental amalgam. Data from the five years follow-up in a clinical trial are presented and related to potential determinants of change. MATERIALS AND METHODS: Patients previously referred to a specialty unit for health complaints attributed to amalgam restorations were included in the study. The 20 participants who were allocated to the treatment group had all amalgam restorations removed and replaced with other dental restorative materials. Intensity of health complaints was calculated from questionnaire data and personality variables were measured by MMPI-2. RESULTS: At the follow-up five years after the amalgam removal was completed, intensity of general health complaints was significantly reduced (p=.001), but the symptom load was still high. The reduction was significantly correlated with concentration of mercury in urine at pre-treatment. There were no significant correlations with personality variables. CONCLUSIONS: Removal of amalgam restorations was followed by a long term reduction of general health complaints, which was associated with mercury concentration in urine before amalgam removal. Additional studies are needed to confirm the potential mechanisms for the observed reduction. PMID- 28093014 TI - Using InVivoStat to perform the statistical analysis of experiments. AB - The need to improve reproducibility and reliability of animal experiments has led some journals to increase the stringency of the criteria that must be satisfied before manuscripts can be considered suitable for publication. In this article we give advice on experimental design, including minimum group sizes, calculating statistical power and avoiding pseudo-replication, which can improve reproducibility. We also give advice on normalisation, transformations, the gateway analysis of variance strategy and the use of p-values and confidence intervals. Applying all these statistical procedures correctly will strengthen the validity of the conclusions. We discuss how InVivoStat, a free-to-use statistical software package, which was designed for life scientists, especially animal researchers, can be used to help with these principles. PMID- 28093015 TI - Prevalence and incidence of doctor-diagnosed Dupuytren's disease: a population based study. AB - : The prevalence and incidence of doctor-diagnosed Dupuytren's disease in the general population is unknown. From the healthcare register for Skane region (population 1.3 million) in southern Sweden, we identified all residents aged ?20 years (on 31 December 2013), who 1998 to 2013 had consulted a doctor and received the diagnosis Dupuytren's disease (International Classification of Diseases 10th Revision code M720). During the 16 years, 7207 current residents (72% men) had been diagnosed with Dupuytren's disease; the prevalence among men was 1.35% and among women 0.5%. Of all people diagnosed, 56% had received treatment (87% fasciectomy). In 2013, the incidence of first-time doctor-diagnosed Dupuytren's disease among men was 14 and among women five per 10,000. The annual incidence among men aged ?50 years was 27 per 10,000. Clinically important Dupuytren's disease is common in the general population. LEVEL OF EVIDENCE: III. PMID- 28093016 TI - Acute and residual effects in adolescent rats resulting from exposure to the novel synthetic cannabinoids AB-PINACA and AB-FUBINACA. AB - Synthetic cannabinoids (SCs) have rapidly proliferated as recreational drugs, and may present a substantial health risk to vulnerable populations. However, information on possible effects of long-term use is sparse. This study compared acute and residual effects of the popular indazole carboxamide SC compounds AB PINACA and AB-FUBINACA in adolescent rats with ?9-tetrahydrocannabinol (THC) and control treatments. Albino Wistar rats were injected (i.p.) with AB-PINACA or AB FUBINACA every second day (beginning post-natal day (PND) 31), first at a low dose (0.2 mg/kg on 6 days) followed by a higher dose (1 mg/kg on a further 6 days). THC-treated rats received equivalent doses of 6 * 1 mg/kg and 6 * 5 mg/kg. During drug treatment, THC, AB-PINACA, and AB-FUBINACA decreased locomotor activity at high and low doses, increased anxiety-like behaviours and audible vocalisations, and reduced weight gain. Two weeks after dosing was completed, all cannabinoid pre-treated rats exhibited object recognition memory deficits. These were notably more severe in rats pre-treated with AB-FUBINACA. However, social interaction was reduced in the THC pre-treated group only. Six weeks post-dosing, plasma levels of cytokines interleukin (IL)-1alpha and IL-12 were reduced by AB FUBINACA pre-treatment, while cerebellar endocannabinoids were reduced by THC and AB-PINACA pre-treatment. The acute effects of AB-PINACA and AB-FUBINACA were broadly similar to those of THC, suggesting that acute SC toxicity in humans may be modulated by dose factors, including inadvertent overdose and product contamination. However, some lasting residual effects of these different cannabinoid receptor agonists were subtly different, hinting at recruitment of different mechanisms of neuroadaptation. PMID- 28093017 TI - The Bone Health Team: A Team-Based Approach to Improving Osteoporosis Care for Primary Care Patients. AB - BACKGROUND: Significant improvements in secondary prevention of osteoporotic fractures have been noted with fracture liaison services. However, similar models for the primary prevention of such fractures have not been reported. OBJECTIVE: To determine the impact of a Bone Health Team (BHT) on osteoporosis screening and treatment rates in U.S. veterans in primary care practices. DESIGN: Historical cohort study of a primary care-based intervention of a BHT from February 2013 to February 2015. SETTING: Community-based outpatient clinics of the Salt Lake City Veterans Affairs Health Care System. PARTICIPANTS: Men aged 70 years and older and women aged 65 years and older. INTERVENTION: Enrollment in the BHT. MEASUREMENTS: Rates of dual energy x-ray absorptiometry (DXA) completion, chart diagnosis of osteoporosis or osteopenia, completion of vitamin D measurement, and initiation of fracture reducing medication. RESULTS: Our cohort consisted of 7644 individuals, 975 of whom were exposed to the BHT and 6669 of whom were not. Comparison of patients exposed to the BHT versus non-exposed subjects demonstrated a substantial increase in all outcome measures studied. Hazard ratios (HRs) from multivariable cox proportional hazard models were: measurement of vitamin D, HR = 1.619 ( P < .001); chart diagnosis of osteopenia, HR = 37.00 ( P < .001); chart diagnosis of osteoporosis, HR = 16.38 ( P < .001); osteoporosis medication, HR = 17.03 ( P < .001); and completion of DXA, HR = 139.9 ( P < .001). CONCLUSIONS AND RELEVANCE: The implementation of a dedicated BHT produced significantly increased rates of intermediate osteoporosis outcome measures in US veterans in primary care practices. Additional research describing medication adherence rates and cost-effectiveness is forthcoming. PMID- 28093018 TI - Algorithm for bionic hand reconstruction in patients with global brachial plexopathies. AB - OBJECTIVE Global brachial plexus lesions with multiple root avulsions are among the most severe nerve injuries, leading to lifelong disability. Fortunately, in most cases primary and secondary reconstructions provide a stable shoulder and restore sufficient arm function. Restoration of biological hand function, however, remains a reconstructive goal that is difficult to reach. The recently introduced concept of bionic reconstruction overcomes biological limitations of classic reconstructive surgery to restore hand function by combining selective nerve and muscle transfers with elective amputation of the functionless hand and its replacement with a prosthetic device. The authors present their treatment algorithm for bionic hand reconstruction and report on the management and long term functional outcomes of patients with global brachial plexopathies who have undergone this innovative treatment. METHODS Thirty-four patients with posttraumatic global brachial plexopathies leading to loss of hand function consulted the Center for Advanced Restoration of Extremity Function between 2011 and 2015. Of these patients, 16 (47%) qualified for bionic reconstruction due to lack of treatment alternatives. The treatment algorithm included progressive steps with the intent of improving the biotechnological interface to allow optimal prosthetic hand replacement. In 5 patients, final functional outcome measurements were obtained with the Action Arm Research Test (ARAT), the Southampton Hand Assessment Procedure (SHAP), and the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. RESULTS In all 5 patients who completed functional assessments, partial hand function was restored with bionic reconstruction. ARAT scores improved from 3.4 +/- 4.3 to 25.4 +/- 12.7 (p = 0.043; mean +/- SD) and SHAP scores improved from 10.0 +/- 1.6 to 55 +/- 19.7 (p = 0.042). DASH scores decreased from 57.9 +/- 20.6 to 32 +/- 28.6 (p = 0.042), indicating decreased disability. CONCLUSIONS The authors present an algorithm for bionic reconstruction leading to useful hand function in patients who lack biological treatment alternatives for a stiff, functionless, and insensate hand resulting from global brachial plexopathies. PMID- 28093019 TI - Prophylactic and curative effect of rosemary leaves extract in a bleomycin model of pulmonary fibrosis. AB - CONTEXT: Pulmonary fibrosis is a devastating disease without effective treatment. Rosemary is appreciated since ancient times for its medicinal properties, while biomolecules originated from the plant have an antioxidant and antifibrotic effect. OBJECTIVE: The effects of Rosmarinus officinalis L. (Lamiaceae) leaves extract (RO) on bleomycin-induced lung fibrosis were investigated. MATERIALS AND METHODS: Male Wistar rats were given a single dose of bleomycin (BLM, 4 mg/kg, intratracheal), while RO (75 mg/kg, intraperitoneal) was administered 3 days later and continued for 4 weeks (BLM/RO1-curative group). Alternatively, RO was administered 2 weeks before BLM and continued 15 days thereafter (BLM/RO2 prophylactic group). Antioxidant activities of RO and lung tissues were studied by standard methods. Histological staining revealed lung architecture and collagen deposition. RO was characterized for its polyphenol content and by high performance liquid chromatography. RESULTS: RO polyphenol content was 60.52 mg/g of dry weight, carnosic and rosmarinic acids being major components (6.886 and 2.351 mg/g). Antioxidant effect of RO (DPPH and FRAP assay) expressed as IC50 values were 2.23 MUg/mL and 0.074 MUg/mL, respectively. In BLM/RO1 and BLM/RO2 lung architecture was less compromised compared to BLM, which was reflected in lower fibrosis score (2.33 +/- 0.33 and 1.8 +/- 0.32 vs 3.7 +/- 0.3). Malondialdehyde levels were attenuated (141% and 108% vs 258% of normal value). Catalase and glutathione-S-transferase activities were normalized (103% and 117% vs 59%, 85% and 69% vs 23%, respectively). DISCUSSION AND CONCLUSION: RO has a protective effect against BLM-induced oxidative stress and lung fibrosis due to its phenolic compounds. PMID- 28093020 TI - What causes the greater perceived similarity of consonant-transposed nonwords? AB - Nonwords created by transposing two non-adjacent orthographic consonants (CONDISER) have been reported to produce more priming for their baseword (CONSIDER), and to be classified as a nonword less readily than nonwords created by transposing two orthographic vowels (CINSODER). We investigate the origin of this difference and its relevance for theories of letter position coding. In the unprimed versions of the lexical decision and same-different tasks, a consonant vowel difference was found in the transposition condition, not when those letters are substituted (Experiment 1). We found that when transpositions involved the disruption of a consonant cluster (OPMITAL), reaction times were slowed compared to when transpositions involved only letters that are separated (CHOLOCATE; Experiment 2). As transpositions more frequently disrupt in consonant clusters than vowel clusters, this introduces a confound in studies investigating consonant and vowel transposition effects. Consistent with the idea that letter order is harder to resolve in clusters, the difference between consonants and vowels was eliminated when transpositions involve singleton consonants or vowels rather than those in clusters (Experiment 3). These results suggest that the precision of position coding does not differ between consonants and vowels, but that consonant-vowel status plays a role in structuring orthographic representations. PMID- 28093021 TI - Altering ethanol pharmacokinetics to treat alcohol use disorder: Can you teach an old dog new tricks? AB - Disulfiram was the first pharmacotherapy approved to treat alcohol use disorder in the 1950s. Disulfiram alters ethanol pharmacokinetics and causes uncomfortable reactions (e.g. headache, tachycardia, nausea, flushing and hypotension) when alcohol is consumed. Subsequently, a better understanding of the neurobiological pathways involved in alcohol use disorder led to the development of other medications (e.g. naltrexone and acamprosate). These neurobiological-based medications act on alcohol use disorder-related phenotypes including craving, stress, and/or withdrawal. The original approach to treat alcohol use disorder, by altering ethanol pharmacokinetics has been much less investigated. Recent research on ethanol pharmacokinetics has shed light on the mechanisms of action underlying alcohol use disorder and how some medications that alter ethanol pharmacokinetics may be helpful in treating alcohol use disorder. This review summarizes and discusses the complex pharmacokinetics of ethanol, and proposes that altering ethanol pharmacokinetics via novel pharmacological approaches may be a viable approach to treat alcohol use disorder. PMID- 28093022 TI - Blunted neural response to anticipation, effort and consummation of reward and aversion in adolescents with depression symptomatology. AB - Neural reward function has been proposed as a possible biomarker for depression. However, how the neural response to reward and aversion might differ in young adolescents with current symptoms of depression is as yet unclear. Thirty-three adolescents were recruited, 17 scoring low on the Mood and Feelings Questionnaire (low risk group) and 16 scoring high (high risk group). Our functional magnetic resonance imaging task measured; anticipation (pleasant/unpleasant cue), effort (achieve a pleasant taste or avoid an unpleasant taste) and consummation (pleasant/unpleasant tastes) in regions of interest; ventral medial prefrontal cortex, pregenual cingulate cortex, the insula and ventral striatum. We also examined whole brain group differences. In the regions of interest analysis we found reduced activity in the high risk group in the pregenual cingulate cortex during anticipation and reduced pregenual cingulate cortex and ventral medial prefrontal cortex during effort and consummation. In the whole brain analysis we also found reduced activity in the high risk group in the prefrontal cortex and the precuneus during anticipation. We found reduced activity in the hippocampus during the effort phase and in the anterior cingulate/frontal pole during consummation in the high risk group. Increased anhedonia measures correlated with decreased pregenual cingulate cortex activity during consummation in the high risk group only. Our results are the first to show that adolescents with depression symptoms have blunted neural responses during the anticipation, effort and consummation of rewarding and aversive stimuli. This study suggests that interventions in young people at risk of depression, that can reverse blunted responses, might be beneficial as preventative strategies. PMID- 28093023 TI - Sustained employability and health-related quality of life in cancer survivors up to four years after diagnosis. AB - BACKGROUND: Most cancer survivors are able to return to work at some point after diagnosis. However, literature on sustained employability and health-related quality of life (HRQoL) is limited. Therefore, the aims of this study were to explore the influence of change in employment status on HRQoL in cancer survivors long term after diagnosis, and to identify predictors of work continuation in occupationally active survivors. MATERIAL AND METHODS: We used prospective data (T0 = two years after diagnosis, T1 = one-year follow-up, and T2 = two-year follow-up) from a cohort of cancer survivors that had an employment contract and were of working age at T0 (N = 252, 69.8% female). Groups were formed on the basis of change in employment status: 'continuously not working' (19.8%), 'positive change in employment status' (5.6%), 'negative change in employment status' (14.7%), and 'continuously working' (59.9%). ANCOVA was used to explore the relationship between change in employment status and HRQoL at T1. Generalized estimating equations (GEE) were used to identify predictors of work continuation (at T1 and T2) in survivors that were occupationally active at T0 (N = 212). RESULTS: 'Continuously working' survivors scored significantly better on the EORTC QLQ-C30 scales: role functioning, fatigue, pain, constipation, global health/QoL and the Summary score, than 'continuously not working' survivors, and better on physical, role and emotional functioning, fatigue, financial impact, global health/QoL and the Summary score than survivors with a 'negative change in employment status' (effect size range = 0.49-0.74). In occupationally active survivors, a high score on current work ability was associated with work continuation one year later [odds ratio (OR) 1.46; 95% CI 1.11-1.92]. CONCLUSION: Cancer survivors 'continuously working' function better and have a better health and QoL than those who are not able to work. However, in occupationally active cancer survivors, one should monitor those with low self-perceived work ability, because they have an increased risk to discontinue their work. PMID- 28093024 TI - Reliability and validity of the Turkish version of the Rapid Estimate of Adult Literacy in Dentistry (TREALD-30). AB - OBJECTIVE: To culturally adapt the Turkish version of Rapid Estimate of Adult Literacy in Dentistry (TREALD-30) for Turkish-speaking adult dental patients and to evaluate its psychometric properties. MATERIAL AND METHODS: After translation and cross-cultural adaptation, TREALD-30 was tested in a sample of 127 adult patients who attended a dental school clinic in Istanbul. Data were collected through clinical examinations and self-completed questionnaires, including TREALD 30, the Oral Health Impact Profile (OHIP), the Rapid Estimate of Adult Literacy in Medicine (REALM), two health literacy screening questions, and socio behavioral characteristics. Psychometric properties were examined using Classical Test Theory (CTT) and Rasch analysis. RESULTS: Internal consistency (Cronbach's Alpha = 0.91) and test-retest reliability (Intraclass correlation coefficient = 0.99) were satisfactory for TREALD-30. It exhibited good convergent and predictive validity. Monthly family income, years of education, dental flossing, health literacy, and health literacy skills were found as stronger predictors of patients'oral health literacy (OHL). Confirmatory factor analysis (CFA) confirmed a two-factor model. The Rasch model explained 37.9% of the total variance in this dataset. In addition, TREALD-30 had eleven misfitting items, which indicated evidence of multidimensionality. The reliability indeces provided in Rasch analysis (person separation reliability = 0.91 and expected-a posteriori/plausible reliability = 0.94) indicated that TREALD-30 had acceptable reliability. CONCLUSION: TREALD-30 showed satisfactory psychometric properties. It may be used to identify patients with low OHL. Socio-demographic factors, oral health behaviors and health literacy skills should be taken into account when planning future studies to assess the OHL in both clinical and community settings. PMID- 28093025 TI - A fuzzy integral method based on the ensemble of neural networks to analyze fMRI data for cognitive state classification across multiple subjects. AB - The huge number of voxels in fMRI over time poses a major challenge to for effective analysis. Fast, accurate, and reliable classifiers are required for estimating the decoding accuracy of brain activities. Although machine-learning classifiers seem promising, individual classifiers have their own limitations. To address this limitation, the present paper proposes a method based on the ensemble of neural networks to analyze fMRI data for cognitive state classification for application across multiple subjects. Similarly, the fuzzy integral (FI) approach has been employed as an efficient tool for combining different classifiers. The FI approach led to the development of a classifiers ensemble technique that performs better than any of the single classifier by reducing the misclassification, the bias, and the variance. The proposed method successfully classified the different cognitive states for multiple subjects with high accuracy of classification. Comparison of the performance improvement, while applying ensemble neural networks method, vs. that of the individual neural network strongly points toward the usefulness of the proposed method. PMID- 28093026 TI - Out of sight, out of mind: racial retrieval cues increase the accessibility of social justice concepts. AB - Photographs provide critical retrieval cues for personal remembering, but few studies have considered this phenomenon at the collective level. In this research, we examined the psychological consequences of visual attention to the presence (or absence) of racially charged retrieval cues within American racial segregation photographs. We hypothesised that attention to racial retrieval cues embedded in historical photographs would increase social justice concept accessibility. In Study 1, we recorded gaze patterns with an eye-tracker among participants viewing images that contained racial retrieval cues or were digitally manipulated to remove them. In Study 2, we manipulated participants' gaze behaviour by either directing visual attention toward racial retrieval cues, away from racial retrieval cues, or directing attention within photographs where racial retrieval cues were missing. Across Studies 1 and 2, visual attention to racial retrieval cues in photographs documenting historical segregation predicted social justice concept accessibility. PMID- 28093027 TI - Effects of amphetamine and methylphenidate on attentional performance and impulsivity in the mouse 5-Choice Serial Reaction Time Task. AB - BACKGROUND: Few studies have investigated the effects of conventional attention deficit-hyperactivity disorder (ADHD) medication in the mouse 5-choice serial reaction time task (5-CSRTT), and rat studies have yielded inconsistent results. OBJECTIVE: We aimed to examine the effects of acute methylphenidate (MPH) and amphetamine (AMPH) treatment in the mouse 5-CSRTT. METHODS: Trained male C57Bl/6J mice were tested in a variable stimulus duration schedule. Effects of AMPH (0.25, 0.5, and 1 mg/kg) and MPH (0.5, 1.0, and 2.0 mg/kg) on discriminative accuracy, omissions, and premature responses were assessed. Saline treatment data determined high- and low-attentive (LA), and high- and low-impulsive (LI) subgroups according to the upper and lower 30th percentiles, respectively. RESULTS: In the LA subgroup accuracy was improved by 0.5 mg/kg AMPH and 2 mg/kg MPH, while no effect was found in the high-attentive (HA) subgroup. Premature responses were increased by 1 mg/kg AMPH and 0.5 mg/kg MPH for all animals, and by 1 mg/kg AMPH for the LI subgroup. CONCLUSIONS: The use of variable stimulus duration, along with the division into high- and LA, and high-and LI subgroups, may improve the sensitivity of the 5-CSRTT when investigating drug effects on attention and impulsivity. PMID- 28093028 TI - Helicoidal splinting after wrist surgery: a laboratory study. PMID- 28093029 TI - Low doses of mirtazapine or quetiapine for transient insomnia: A randomised, double-blind, cross-over, placebo-controlled trial. AB - Low doses of the antidepressant mirtazapine or the neuroleptic quetiapine are often prescribed off-label for insomnia. However, studies on the effects on sleep and hangover effects the following day are scarce. In this randomised, double blind, cross-over, placebo-controlled trial, the influence of 7.5 mg mirtazapine and 50 mg quetiapine on both normal sleep and sleep disturbed by acoustic stress (traffic noise) as a model for transient insomnia was assessed. Additionally, hangover effects on next-day alertness and cognitive functioning were examined. A total of 19 healthy men without sleep complaints completed three treatment sessions, each session consisting of three consecutive nights in one of the mirtazapine, quetiapine or placebo conditions. Sleep was assessed using polysomnography and the Leeds Sleep Evaluation Questionnaire. Daytime sleepiness and cognitive functioning were assessed using the Leeds Sleep Evaluation Questionnaire, Karolinska Sleepiness Scale, Digit Symbol Substitution Task, Psychomotor Vigilance Task and an addition task. Under acoustic stress, both mirtazapine and quetiapine increased total sleep time by half an hour and reduced the number of awakenings by 35-40% compared to placebo. While quetiapine specifically increased the duration of non-rapid eye movement sleep, stage N2, mirtazapine mainly increased deep sleep stage N3. Subjects reported that both mirtazapine and quetiapine eased getting to sleep and improved sleep quality. Both drugs caused daytime sleepiness and lessened sustained attention. These findings support the use of low doses of mirtazapine and quetiapine for the treatment of insomnia. Further prospective studies on the long-term effects regarding effectiveness and adverse effects are needed. PMID- 28093030 TI - Caregiver Asthma in Urban Families: Implications for School Absenteeism. AB - Asthma is a significant contributor to missed school days, especially for children living in urban settings. This preliminary study examined the impact of caregiver asthma on school absenteeism in a sample of 102 urban children with asthma from African American, Latino, and non-Latino White backgrounds. Caregivers and children participated in a single research session; 32 caregivers had asthma. Children of caregivers with asthma missed more days of school than children whose caregivers did not have asthma (3.97 vs. 2.43 days, p < .05, Cohen's d = .40). Other indicators of child asthma morbidity (e.g., hospitalizations) did not differ across caregiver asthma status. Findings highlight that caregiver asthma may be an added risk factor for school absenteeism among children with asthma. For children with a high frequency of asthma-related school absenteeism, school nurses may find it useful to provide educational resources and referrals for caregivers with asthma. PMID- 28093031 TI - The inhibitory effects of five alkaloids on the substrate transport mediated through human organic anion and cation transporters. AB - 1. Human solute carrier transporters (SLCs) are important membrane proteins mediate the cellular transport of many endogenous and exogenous substances. Organic anion/cation transporters (OATs/OCTs) and organic anion transporting polypeptides (OATPs) are essential SLCs involved in drug influx. Drug-drug/herb interactions through competing for specific SLCs often lead to unsatisfied therapeutic outcomes and/or unwanted side effects. In this study, we comprehensively investigated the inhibitory effects of five clinically relevant alkaloids (dendrobine, matrine, oxymatrine, tryptanthrin and chelerythrine) on the substrate transport through several OATs/OCTs and OATPs. 2. We performed transport functional assay and kinetic analysis on the HEK-293 cells over expressing each SLC gene. 3. Our data showed tryptanthrin significantly inhibited the transport activity of OAT3 (IC50 = 0.93 +/- 0.22 MUM, Ki = 0.43 MUM); chelerythrine acted as a potent inhibitor to the substrate transport mediated through OATP1A2 (IC50 = 0.63 +/- 0.43 MUM, Ki = 0.60 MUM), OCT1 (IC50 = 13.60 +/- 2.81 MUM) and OCT2 (IC50 =10.80 +/- 1.16 MUM). 4. Our study suggested tryptanthrin and chelerythrine could potently impact on the drug transport via specific OATs/OCTs. Therefore, the co-administration of these alkaloids with drugs could have clinical consequences due to drug-drug/herb interactions. Precautions should be warranted in the multi-drug therapies involving these alkaloids. PMID- 28093032 TI - Editorial. Myoelectric functional hand prosthesis for total brachial plexus injury. PMID- 28093033 TI - The Functional Impact of Sleep Disorders in Children With ADHD. AB - OBJECTIVE: Children with ADHD display higher rates of sleep problems, and both sleep disorders and ADHD have been shown to affect functioning in childhood. The current study examines the frequency and relationship between sleep problems and ADHD, and their impact on quality of life (QoL) and functional impairment. METHOD: Parents of 192 children with ADHD ( M = 10.23 years) completed measures regarding their child's ADHD symptoms (Swanson, Nolan and Pelham [SNAP]), sleep disorders (Pediatric Sleep Questionnaire [PSQ]), QoL (Child Health Illness Profile [CHIP-PE]), and functioning (Weiss Functional Impairment Rating Scale Parent Report [WFIRS-P]). RESULTS: Common sleep complaints in participants were insomnia, excessive daytime sleepiness (EDS), and variability in sleep schedule. Regression analysis indicated that sleep problems and ADHD symptoms independently predicted lower levels of QoL (Delta R2 = .12, p < .001) and social functioning (Delta R2 = .12, p < .001). CONCLUSION: The results suggest that ADHD may coexist with somnolence and that both conditions have a significant impact on a child's functioning and QoL. PMID- 28093034 TI - Fear of cancer recurrence and unmet needs among breast cancer survivors in the first five years. A cross-sectional study. AB - BACKGROUND: It is unclear to which degree the services available after end of treatment are sufficient to meet the needs of women treated for breast cancer. The aim of the present study was to identify patient-reported supportive care needs and the prevalence of fear of cancer recurrence (FCR) following end of treatment in women treated for breast cancer. MATERIAL AND METHODS: Using a cross sectional design, women treated for breast cancer (n = 155; mean age 63) completed questionnaires concerning supportive care needs and FCR. Inclusion criteria were: >=18 years of age and treated for primary breast cancer at Aarhus University Hospital, Aarhus, Denmark and between three months and five years after diagnosis. Associations between demographic characteristics, clinical factors, side effects, late effects and the two dependent variables, unmet needs (examined with linear regression model), and FCR (examined with logistic regression model) were analyzed. RESULTS: The response rate was 79.9%. Almost all (82.6%) women reported at least one unmet need (mean number 9.3; range 0-34). More than half (59.3%) of the unmet needs were rated as strong unmet needs. The most frequent unmet needs were concerned with doctors collaborate to coordinate care; the need for having ongoing dialog with healthcare providers to receive available local health care services, understandable and up-to-date information, to manage side effects and feeling reassured that the best medical care are given. Having unmet needs were associated with young age, short time since primary surgery, and having clinical FCR. FCR was reported by 54.8% of the women and was associated with short time since primary surgery, having chemotherapy, having unmet needs, and moderate to severe muscle and joint pain and fatigue. CONCLUSIONS: Breast cancer survivors experience substantial unmet needs years after end of treatment, particularly among younger women and women having clinical FCR. Furthermore, FCR is frequent among women, particularly when closer in time to primary surgery. PMID- 28093035 TI - Cognitive emotion regulation in adulthood and old age: positive gaze preferences across two strategies. AB - While positive emotional functioning may be enhanced across adulthood and old age, research is mixed as to the types of regulatory strategies that are more or less beneficial for facilitating well-being. The goal of the present study was to examine how specific cognitive emotion regulation strategies assumed to rely on varying levels of effortful processing (selective attention vs. reappraisal) would impact regulatory behaviors (via eye gaze deployment) and resultant affective outcomes. Participants viewed a series of positive, negative, and neutral film clips while their eyes were tracked across three conditions: passive viewing, selective attention, and reappraisal. Results revealed that (a) both younger and older adults displayed positive fixation preferences and showed mood improvement across both regulatory conditions and (b) there was a marginal association between positive fixation and post-regulation mood. Implications for linking positivity to emotion regulation and well-being across adulthood are discussed. PMID- 28093036 TI - Combining nanoscale magnetic nimodipine liposomes with magnetic resonance image for Parkinson's disease targeting therapy. AB - AIM: To enhance drug targeting and blood-brain barrier penetration for Parkinson's disease (PD), a novel nanoscale magnetic nimodipine (NMD) delivery system was designed and prepared. MATERIALS & METHODS: The PD rats were established and treated with free NMD or Fe3O4-modified NMD liposomes (Fe3O4-NMD lips). Then, factional anisotropy values were measured by MRI to evaluate therapy efficacy. RESULTS: Fe3O4-NMD-lips showed the best neuroprotective effect, and the NMD concentration of lesions was 2.5-fold higher in Fe3O4-NMD-lips group than that of free NMD group. CONCLUSION: These results demonstrated that the magnetic drug system had a great potential to cross the blood-brain barrier and provided a noninvasive and effective therapeutic strategy for PD. PMID- 28093037 TI - Encapsulation of lemongrass oil with cyclodextrins by spray drying and its controlled release characteristics. AB - Inclusion of the two isomers of citral (E-citral and Z-citral), components of lemongrass oil, was investigated within the confines of various cyclodextrin (alpha-CD, beta-CD and gamma-CD) host molecules. Aqueous complex formation constants for E-citral with alpha-CD, beta-CD and gamma-CD were determined to be 123, 185, and 204 L/mol, respectively, whereas Z-citral exhibited stronger affinities (157, 206, and 253 L/mol, respectively). The binding trend gamma-CD > beta-CD > alpha-CD is a reflection of the more favorable geometrical accommodation of the citral isomers with increasing cavity size. Encapsulation of lemongrass oil within CDs was undertaken through shaking citral:CD (1:1, 1.5:1, and 2:1 molar ratio) mixtures followed by spray drying. Maximum citral retention occurred at a 1:1 molar ratio with beta-CD and alpha-CD demonstrating the highest levels of total E-citral and Z-citral retention, respectively. Furthermore, the beta-CD complex demonstrated the slowest release rate of all inclusion complex powders. PMID- 28093038 TI - Metabonomic Strategy for the Evaluation of Chinese Medicine Salvia miltiorrhiza and Dalbergia odorifera Interfering with Myocardial Ischemia/Reperfusion Injury in Rats. AB - Extract of Salvia miltiorrhiza and Dalbergia Odorifera (SM-DOO) has been traditionally used for the prevention and treatment of cardiovascular diseases. However, information regarding the pharmacodyamic material basis and potential mechanism remain unknown. Male Sprague-Dawley rats were divided into four groups: Sham, Model, Diltiazem, and SM-DOO group, n = 6. Rats were pretreated with homologous drugs for 7 days, and then subjected to 30 minutes of ischemia followed by 180 minutes of reperfusion. Cardioprotection effects of SM-DOO on myocardial ischemia/reperfusion (MI/R) injury rats were examined by hemodynamics, infarct area, histopathology, biochemical indicators, and Western blot analysis. Metabonomics technology was further performed to evaluate the endogenous metabolites profiling systematically. According to the results of pattern recognition analysis, a clear separation of MI/R injury in the Model group and Sham group was achieved and SM-DOO pretreatment group was located much closer to the Sham group than the Model group, which was consistent with results of biochemistry and histopathological assay. Moreover, potential biomarkers were identified to elucidate the drug mechanism of SM-DOO, which may be related with pathways of energy metabolism, especially tricarboxylic acid (TCA) cycle (citric acid) and beta-oxidation of fatty acids (3-hydroxybutyric, palmitoleic acid, heptadecanoic acid, and arachidonic acid). In addition, the protein expressions of p-AMPK and p-ACC in the SM-DOO group were significantly elevated, while the levels of carnitine palmitoyl-CoA transferase-1 (CPT-1), p-PDK, and p-PDC were dramatically reduced by SM-DOO. In conclusion, SM-DOO pretreatment could ameliorate MI/R injury by intervening with energy metabolism, especially TCA cycle and beta-oxidation of fatty acids. This work showed that the metabonomics method combinate with conventional pharmacological methods is a promising tool in the efficacy and mechanism research of traditional Chinese medicines. PMID- 28093039 TI - Clarifying the Construct of Occupational Engagement for Occupational Therapy Practice. AB - Occupational engagement (OE) has been presented as a core construct in occupational therapy; however, its broad conceptualization and confounding definitions are problematic. Clarifying the construct of OE would help occupational therapists to explicate the nature of their practice. The purpose of this study was to explore occupational therapists' perspectives of the construct of OE. Qualitative descriptive methodology was used to collect data using semistructured interviews with nine practicing occupational therapists in the Greater Toronto Area. Qualitative content analysis, using an inductive approach, was employed to uncover emerging categories. Participants spoke about transitioning from therapeutic engagement to OE with a client by following a client's path of choice. The essential elements and influencers of OE were highlighted, and the relationship between OE and occupational performance was discussed. The findings provide an initial understanding of essential elements necessary to enable clients to initiate engagement in therapy and then, subsequently, in occupations of their choice. PMID- 28093040 TI - Cadmium in liver and kidneys of domestic Balkan and Alpine dairy goat breeds from Montenegro and Serbia. AB - Concentrations of cadmium (Cd) were determined in the samples of 144 animals around 1 and of 144 animals around 4 years old. Cd was analysed by inductively coupled plasma-optical emission spectrometry (ICP-OES), after microwave digestion. Cd concentrations were higher (p < 0.05) in kidney than in liver and higher (p < 0.05) in older animals than in young ones. In domestic Balkan goat which was raised in a free-ranged system Cd accumulation was lower (p < 0.05) than in Alpine goat raised in an intensive production system. Geographic region did influence Cd accumulation only in older animals. Higher Cd levels (p < 0.05) were determined in goats from Serbia. The highest obtained Cd concentrations in both tissues were lower than maximum levels set by European and national legislation for ruminants (cattle and sheep). PMID- 28093041 TI - Blastocyst Development in a Single Medium Compared to Sequential Media: A Prospective Study With Sibling Oocytes. AB - The aim of the present study was to compare blastocyst formation rates after embryo culture in a single medium (Global) as compared to sequential media (ISM1/BlastAssist). In this prospective trial with sibling oocytes, 542 metaphase II (MUIotaIota) oocytes from 31 women were randomly and equally divided to be fertilized and cultured to the blastocyst stage in either sequential media (ISM1/BlastAssist; n = 271 MII oocytes) or a single medium (Global; n = 271 MII oocytes). In both groups, embryos were cultured in an interrupted fashion with media changes on day 3. Embryo transfer was performed on day 5. Blastocyst formation rates on day 5 (61.7% +/- 19.9% vs 37.0% +/- 25.5%, P < .001) were significantly higher following culture in Global as compared to ISM1/BlastAssist, respectively. Fertilization rates, cleavage rates, and percentage of good quality embryos on day 3 were similar between Global and ISM1/BlastAssist, respectively. The percentages of good quality blastocysts (63.0% +/- 24.8% vs 32.1% +/- 37.2%, P < .001), blastocysts selected for transfer (27.8% +/- 19.2% vs 11.1% +/- 14.4%, P = .005), and utilization rates (62.5% +/- 24.8% vs 39.0% +/- 25.2%, P < .001) were significantly higher in Global as compared to ISM1/BlastAssist, respectively. In conclusion, culture in Global was associated with higher blastocyst formation rates compared to ISM1/BlastAssist, suggesting that the single medium may provide better support to the developing embryo. PMID- 28093042 TI - Chloramphenicol stereoisomers need to be distinguished: consequences observed from a proficiency test. AB - Although the use of chloramphenicol (CAP) as a veterinary drug is banned in the European Union and many other countries, monitoring for CAP residues in food is routine. Positive detections are few, but taken extremely seriously. European Union laboratories analysing for CAP should validate methods according to European Commission Decision 2002/657/EC, must be accredited to ISO 17025, and will generally participate in proficiency testing (PT) schemes, such as those offered by the Food Analysis Performance Assessment Scheme (FAPAS(r)). The FAPAS PTs aim to cover a wide range of relevant matrices including honey, prawns, fish, milk and kidney. Test materials are prepared either by animal dosing studies or by spiking raw matrix. The most common method reported by FAPAS participants used to screen for CAP residues is LC-MS/MS, but ELISA kits are increasingly being used. A recent PT round highlighted that the result obtained might be correlated with the type of analytical method being employed. Follow-up investigations have demonstrated that some of these variations in data are a function of the different stereoisomeric forms of CAP. This paper discusses the implication of this research on method validation requirements and European Union legislation. PMID- 28093043 TI - Electrospun Yarn Reinforced NanoHA Composite Matrix as a Potential Bone Substitute for Enhanced Regeneration of Segmental Defects. AB - Nanohydroxyapatite (nanoHA) is a well-established synthetic bone substitute with excellent osteoconduction and osteointegration. However, brittleness coupled with slow degradation curtails its load-bearing and bone regeneration potential, respectively. To address these limitations, nanoHA composite matrix reinforced with electrospun fibrous yarns was fabricated and tested in vitro and in vivo. Different weight percentages (5, 10, 15 wt%) and varying lengths (short and continuous) of poly(l-lactic acid) yarns were randomly dispersed in a gelatinous matrix containing nanoHA. This significantly improved the compressive strength as well as work of fracture, especially for continuous yarns at high weight percentages (10 and 15 wt%). Incorporation of yarns did not adversely affect the pore size (50-350 MUm) or porosity of the scaffolds as well as the in vitro cellular response. Finally, when tested in a critical-sized femoral segmental defect in rat, the nanocomposite scaffolds induced osteoblast cell infiltration at 2 months that subsequently underwent increased mature lamellar bone formation at 4 months, in both the mid and peripheral defect regions. Histomorphometric analysis demonstrated that new bone formation and biomaterial degradation were significantly enhanced in the composite scaffold when compared to commercially available HA. Overall, the composite matrix reinforced with electrospun yarns proved to be a potential bone substitute having an appropriate balance between mechanical strength, porosity, biodegradation, and bone regeneration ability. PMID- 28093044 TI - Changes in biosynthesis of exopolysaccharide in Lactococcus lactis subspecies cremoris treated by moderate pulsed electric field treatment. AB - Metabolome analysis and physicochemical analyses were executed with cell extracts of a Lactococcus lactis subspecies cremoris strain treated by moderate pulsed electric field (PEF) to elucidate the mechanism of enhanced production of exopolysaccharide (EPS) by the treatment. Metabolome analysis by capillary electrophoresis time of flight mass spectrometry annotated 224 metabolites from the cytoplasmic extract of the strain, which, however, showed no significant changes in metabolites related to the EPS production. Electron microscopic observation and chemical analysis of undecaprenoids as carrier of EPS biosynthetic intermediates suggested that PEF treatment dissociated immature EPSs from the intermediates due to the focal electro-condensation of hydrogen ions at the cell surface. Thus, liberated undecaprenyl phosphates were recycled efficiently, which resulted in mass increase of EPS with smaller molecular weight. The study suggested the feasibility of moderate PEF treatment as a food processing technique and revealed the mechanism of enhanced production of EPS by the treatment. PMID- 28093046 TI - Sensitivity and specificity of Urdu version of the PHQ-9 to screen depression in patients with coronary artery disease. AB - BACKGROUND: The Patient Health Questionnaire (PHQ-9) possesses many characteristics of a good screening tool and has the capacity to be used for screening depression in patients with coronary artery disease (CAD). AIM: To examine the psychometric properties and criterion validity of the PHQ-9 to screen and detect depression in patients with CAD in Pakistan. DESIGN: In this validation study, 150 patients with CAD completed the Urdu version of the PHQ-9. The major depressive episode module of the Mini International Neuropsychiatric Interview (MINI) was used as the gold standard. RESULTS: The Urdu version of the PHQ-9 revealed a good internal consistency with Cronbach's alpha of 0.83. Optimal sensitivity (76%) and specificity (76%) were achieved using the cut-off score of PHQ-9 >=6, with area under the ROC curve of 0.86. CONCLUSION: The Urdu version of the PHQ-9 has acceptable psychometric properties to screen and detect major depression in patients with CAD. PMID- 28093045 TI - Exploring urban health in Cape Town, South Africa: an interdisciplinary analysis of secondary data. AB - BACKGROUND: With modern information technology, an overwhelming amount of data is available on different aspects of societies. Our research investigated the feasibility of using secondary data sources to get an overview of determinants of health and health outcomes in different population strata of Cape Town, a large city of South Africa. METHODS: The methodological approach of secondary-data analysis was similar in the different disciplines: Biological Anthropology, Public Health, Environmental Health, Mental Health, Palliative Care, Medical Psychology and Sociology at the University of Freiburg and Public Health at the University of Cape Town. The teams collected information on Cape Town through Internet searches and published articles. The information was extracted, analyzed, condensed, and jointly interpreted. RESULTS: Data show the typical picture of a population in epidemiological and demographic transition exposed to often difficult social, mental, and physical environmental conditions. Comparison between low and higher socioeconomic districts demonstrated that the former had higher air pollution, poorer water quality, and deficient sanitary conditions in addition to sub-optimal mental health services and palliative care. CONCLUSION: Although important information gaps were identified, the data draw attention to critical public health interventions required in poor health districts, and to motivate for pro-equity policies. PMID- 28093047 TI - Three-Dimensional Cell Printing of Large-Volume Tissues: Application to Ear Regeneration. AB - The three-dimensional (3D) printing of large-volume cells, printed in a clinically relevant size, is one of the most important challenges in the field of tissue engineering. However, few studies have reported the fabrication of large volume cell-printed constructs (LCCs). To create LCCs, appropriate fabrication conditions should be established: Factors involved include fabrication time, residence time, and temperature control of the cell-laden hydrogel in the syringe to ensure high cell viability and functionality. The prolonged time required for 3D printing of LCCs can reduce cell viability and result in insufficient functionality of the construct, because the cells are exposed to a harsh environment during the printing process. In this regard, we present an advanced 3D cell-printing system composed of a clean air workstation, a humidifier, and a Peltier system, which provides a suitable printing environment for the production of LCCs with high cell viability. We confirmed that the advanced 3D cell-printing system was capable of providing enhanced printability of hydrogels and fabricating an ear-shaped LCC with high cell viability. In vivo results for the ear-shaped LCC also showed that printed chondrocytes proliferated sufficiently and differentiated into cartilage tissue. Thus, we conclude that the advanced 3D cell-printing system is a versatile tool to create cell-printed constructs for the generation of large-volume tissues. PMID- 28093048 TI - Myofibroblasts Are Evidence of Chronic Tissue Microtrauma at the Endometrial Myometrial Junctional Zone in Uteri With Adenomyosis. AB - BACKGROUND: Adenomyosis (AM) uteri exhibit hyperperistalsis. The latter causes a chronic tissue trauma at the endometrial-myometrial junctional zone (EMJZ). Upon tissue trauma, microdehiscences in the myometrium facilitate the translocation of basal endometrial fragments into the myometrium. There, a metaplasia (mediated by transforming growth factor beta1 [TGFbeta1] and connective tissue growth factor [CTGF]) occurs and AM lesions develop. The abundance of myofibroblasts in a tissue hallmarks metaplasia and points to a tissue microtrauma. MATERIALS AND METHODS: To study if myofibroblasts-as an evidence of tissue microtrauma-are more abundant at EMJZ in AM-uteri, a case-control experimental study was carried out at Charite University Hospital-Endometriosis Research Centre. In all, 18 uteri with AM and 14 uteri without AM were obtained during laparoscopy-assisted vaginal hysterectomy. The immunolabeling of myofibroblastic metaplasia (alpha smooth muscle actin [ASMA] and collagen I), differentiated smooth muscle marker (desmin) and metaplasia mediators (TGF-beta receptors 1, 2, 3 and CTGF) was investigated. The ultrastructure of myofibroblasts at EMJZ of AM uterus was characterized by transmission electron microscopy, in addition to an in vitro study to characterize myofibroblasts in the endometrium of non-AM uterus. RESULTS: Immunolabeling of ASMA and collagen I was significantly higher at EMJZ of AM uteri versus non-AM uteri. Furthermore, myofibroblasts were ultrastructurally characterized at EMJZ of AM. Endometrium of non-AM uterus exhibited 5% to 8% of its cells, expressing ASMA and collagen I. No difference was noted regarding metaplasia mediators immunolabeling between both the groups. CONCLUSION: The abundant and persistent myofibroblasts (expressing ASMA/collagen I) at EMJZ in AM uteri are ultra-/microscopic evidence of chronic tissue trauma. They are of nonmyometrial origin, as they lack desmin immunolabeling. PMID- 28093049 TI - Efficient Variational Approach to Multimodal Registration of Anatomical and Functional Intra-Patient Tumorous Brain Data. AB - This paper addresses the functional localization of intra-patient images of the brain. Functional images of the brain (fMRI and PET) provide information about brain function and metabolism whereas anatomical images (MRI and CT) supply the localization of structures with high spatial resolution. The goal is to find the geometric correspondence between functional and anatomical images in order to complement and fuse the information provided by each imaging modality. The proposed approach is based on a variational formulation of the image registration problem in the frequency domain. It has been implemented as a C/C[Formula: see text] library which is invoked from a GUI. This interface is routinely used in the clinical setting by physicians for research purposes (Inscanner, Alicante, Spain), and may be used as well for diagnosis and surgical planning. The registration of anatomic and functional intra-patient images of the brain makes it possible to obtain a geometric correspondence which allows for the localization of the functional processes that occur in the brain. Through 18 clinical experiments, it has been demonstrated how the proposed approach outperforms popular state-of-the-art registration methods in terms of efficiency, information theory-based measures (such as mutual information) and actual registration error (distance in space of corresponding landmarks). PMID- 28093050 TI - Second-toe wrap-around flap for reconstruction of a ring avulsion injury. PMID- 28093051 TI - Prolonged job strain and subsequent risk of cancer in women - a longitudinal study, based on the Danish Nurse Cohort. AB - BACKGROUND: The role of psychological stress in cancer risk is continuously debated. Stress at work is the most common form of stress and previous studies have shown inconsistent results regarding cancer risk. In this longitudinal study, we examined the association between prolonged job strain across six years and subsequent cancer risk. METHODS AND MATERIALS: We used data from 6571 cancer free women from the Danish Nurse Cohort aged 45-70 years at inclusion, and self reported questionnaires on job strain at baseline in 1993 and again in 1999. Prolonged job strain was defined as high job busyness and speed, and low control in both 1993 and 1999. Information on cancer diagnosis was obtained from the Danish Cancer Registry. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for overall cancer as well as subgroups of virus immune-related, hormone-related, digestive and lung cancers according to level of prolonged job strain. The women were followed from 1 January 2000 until cancer diagnosis, emigration, death or 31 December 2013 (mean follow-up 13 years) and models were adjusted for potential confounders. Effect modification was examined according to working nightshifts and full time. RESULTS: No significant differences in the risk of overall cancer or any of the cancer subgroups were identified in relation to prolonged busyness, speed, influence, or overall job strain. Effect modification by working full time was observed when examining job influence in relation to overall cancer risk, and by working nightshifts when examining job influence in relation to hormone related cancer risk. However, none of the associations were significant in stratified analyses. CONCLUSION: We found no evidence of an increased risk of any cancer among women with prolonged job strain. Since a large proportion of cancer patients perceive psychological stress as a possible cause of their cancer disease, it is of importance to communicate these findings to the public. PMID- 28093052 TI - Extracellular Signal-Regulated Kinase/Nuclear Factor-Erythroid2-like2/Heme Oxygenase-1 Pathway-Mediated Mitophagy Alleviates Traumatic Brain Injury-Induced Intestinal Mucosa Damage and Epithelial Barrier Dysfunction. AB - Gastrointestinal dysfunction is one of several physiologic complications in patients with traumatic brain injury (TBI). TBI can result in increased intestinal permeability resulting from apoptosis of intestinal epithelial cells, which contain a large number of mitochondria for persisting barrier function. Autophagy of damaged mitochondria (mitophagy) controls the quality of the mitochondria and regulates cellular homeostasis. However, the exact mechanism of mitophagy that underlies the pathological changes induced by TBI is unknown. Here, we report that mitophagy decreases the intestinal epithelial cell damage and apoptosis that are activated in a rat model of controlled cortical impact (CCI). CCI-induced mitophagy is associated with an increase in 3-nitrotyrosine and 4-hydroxynonenal, indicating that oxidative stress may increase in response to mitochondrial disturbance. CCI also results in the expression of the tight junction proteins zonula occludens-1 (ZO-1) and occludin, which may regulate the in vivo intestinal hyperpermeability induced by CCI. Additionally, CCI-induced mitophagy was shown to be mediated by the oxidative stress-related extracellular signal-regulated kinase (ERK)/nuclear factor-erythroid2-like2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway, which may serve to reduce the apoptosis induced by oxidative stress. These results suggest that CCI-induced mitophagy serves to diminish apoptosis-mediated intestinal epithelial cell damage and to improve intestinal permeability, via ERK/Nrf2/HO-1 signaling. These findings may be useful in the design of rational approaches for the prevention and treatment of symptoms associated with TBI. PMID- 28093053 TI - Examiner's experience and the outcome interpretation of ICDAS and Nyvad's system a prospective in vitro study. AB - OBJECTIVE: To evaluate, prospectively, the influence of examiner's experience in interpreting and applying the caries detection systems ICDAS (IC) and Nyvad (NY). MATERIAL AND METHODS: Twelve second-year undergraduate dental students (UG) and 12 postgraduates (PG) MSc level analysed and codified 77 clinical dental caries photographs at three different moments: initially, without any training; after one week of receiving training through a theoretical class; and after two years. Reproducibility and correlation was evaluated; sensitivity, specificity and area under ROC curve (AUC) were dichotomized according to the presence of cavitation (IC) and in relation to disease activity (NY). RESULTS: IC presented good kappa values for the first two evaluations. Both criteria resulted in good Spearman's correlation after two years (IC = UG: 0.89; PG: 0.93/NY = UG: 0.81; PG: 0.82). Sensitivity, specificity and AUC were statistically higher in the third evaluation by UG for Nyvad. CONCLUSIONS: ICDAS criteria seem to be instinctively understood by students without clinical experience. Nyvad's concepts performed better after two years where the students deepened their theoretical knowledge and experienced clinical practice, collaborating with the identification of activity signs. PMID- 28093054 TI - Impact of Psychological Stress on Pain Perception in an Animal Model of Endometriosis. AB - PURPOSE: Pain in patients with endometriosis is considered a significant source of stress but does not always correlate with severity of the condition. We have demonstrated that stress can worsen endometriosis in an animal model. Here, we tested the impact of a psychological stress protocol on pain thresholds and pain receptors. METHODS: Endometriosis was induced in female rats by suturing uterine horn tissue next to the intestinal mesentery. Sham rats had sutures only. Rats were exposed to water avoidance stress for 7 consecutive days or handled for 5 minutes (no stress). Fecal pellets and serum corticosterone (CORT) levels were measured as an index of anxiety. Pain perception was assessed using hot plate and Von Frey tests. Substance P, enkephalin, endomorphin-2, Mu opioid receptor (MOR), and neurokinin-1 receptor expression in the spinal cord were measured by immunohistochemistry. RESULTS: Fecal pellets and CORT were significantly higher in the endo-stress (ES) group than endo-no stress (ENS; P < .01) and sham-no stress groups (SNS; P < .01). The ES rats had more colonic damage ( P < .001 vs SNS; P < .05 vs ENS), vesicle mast cell infiltration ( P < .01 vs ENS), and more severe vesicles than ENS. The ES developed significant hyperalgesia ( P < .05) but stress reversed the allodynic effect caused by endo ( P < .001). The MOR expression was significantly reduced in ENS versus SNS ( P < .05) and more enkephalin expression was found in endo groups. CONCLUSION: Animals subjected to stress develop more severe symptoms but interestingly stress seems to have beneficial effects on abdominal allodynia, which could be a consequence of the stress-induced analgesia phenomenon. PMID- 28093055 TI - Low Rates of HIV Testing Among Adults With Severe Mental Illness Receiving Care in Community Mental Health Settings. AB - OBJECTIVE: This research aimed to characterize HIV testing rates among Medicaid recipients with severe mental illness who received public specialty mental health services. METHODS: This retrospective cohort study examined California Medicaid records from October 1, 2010, to September 30, 2011 (N=56,895). Study participants were between age 18 and 67, utilized specialty mental health care services, were prescribed antipsychotic medications, and were not dually eligible for Medicare. Adjusted Poisson regression models were used to estimate the overall effects of predictor variables on HIV testing prevalence. RESULTS: During the study period, 6.7% of people with severe mental illness received HIV testing. Men were 32% less likely to be tested for HIV than women (p<.001). Compared with whites, Asians/Pacific Islanders were 53% less likely and blacks were 82% more likely to be tested (p<.001). Those with comorbid drug or alcohol use disorders were more likely to be tested than those without such disorders (p<.001). Utilization of nonpsychiatric medical care was the strongest predictor of HIV testing (p<.001). CONCLUSIONS: Most adults with severe mental illness receiving public specialty mental health services were not tested for HIV during a one-year period. Public health administrators must prioritize HIV testing for early identification of HIV infection and prevention of HIV transmission. PMID- 28093057 TI - If It Works for Pills, Can It Work for Skills? Direct-to-Consumer Social Marketing of Evidence-Based Psychological Treatments. AB - The emergence of evidence-based psychological treatments (EVPTs) is a scientific success story, but unfortunately the application of these empirically supported procedures has been slow to gain ground in treatment-as-usual settings. This Open Forum commentary argues that direct-to-consumer (DTC) marketing, which has worked well in communicating the advantages of various medicines, should perhaps be considered for use in social marketing of EVPTs. DTC marketing of pharmaceuticals is a long-standing advertising strategy in the United States. In fact, DTC marketing of psychotropic medicines is quite a success story. The authors recommend various strategies for using marketing science to devise DTC advertising of EVPTs, discuss previous research on DTC campaigns, and describe initiatives launched in the United Kingdom and Europe to promote EVPTs. Suggestions for evaluating and regulating DTC marketing of EVPTs are included. Finally, the potential for DTC marketing of EVPTs to increase mental health literacy and reduce health disparities is explored. PMID- 28093056 TI - Using Peer Navigators to Address the Integrated Health Care Needs of Homeless African Americans With Serious Mental Illness. AB - OBJECTIVE: The study examined the impact of a peer navigator program (PNP) developed by a community-based participatory research team and used with a group of African Americans with serious mental illness who were homeless. METHODS: Sixty-seven research participants were randomly assigned to receive PNP or treatment as usual (control) for one year. Data on general health and mental health, recovery, and quality of life were collected at baseline and at four, eight, and 12 months. RESULTS: Findings from group * trial analyses of variance of omnibus measures of the four constructs showed significant impact over the year for participants in PNP compared with those in the control group, with analyses showing small to moderate effect sizes: general health status (eta2=.24), psychological experience of physical health (eta2=.42), recovery (eta2=.36), and quality of life (eta2=.14). These differences emerged even though both groups showed significant reductions in homelessness and increases in insurance coverage. CONCLUSIONS: Implications for improving in-the-field health care for this population are discussed. Whether these results occurred because navigators were peers per se needs to be examined in future research. PMID- 28093058 TI - Off-Label Prescribing of Psychotropic Medication, 2005-2013: An Examination of Potential Influences. AB - OBJECTIVE: This study examined rates of psychotropic prescriptions for various on and off-label uses in 2005 and 2013 in the context of changes in labeled indications. METHODS: The National Disease and Therapeutic Index, a survey of nationally representative office-based physicians that identifies the diagnosis attached to each prescription, was used to capture the number of psychiatric medications prescribed for a particular diagnosis in 2005 (N=4,120) and 2013 (N=4,140). Labeled indications for each year were abstracted, and the association of prescribing patterns and changes in labeled indications was evaluated. RESULTS: Expanded labeling was associated with increased use of antidepressants for anxiety (an increase of 3.4 percentage points); antipsychotics for depression (8.3), bipolar disorder (3.4), and tic disorders, autism, and related disorders (1.5); and anxiolytics for anxiety disorders (5.5). Use of antidepressants for depression decreased, by 5.6 percentage points, as did use of antipsychotics (4.6) and anxiolytics (.7) for dementia-related disorders and of antipsychotics for attention-deficit and related disorders (2.7), likely reflecting black box warnings and evidence of side effects. Off-label use of antidepressants for attention deficit and related disorders and anxiolytics for bipolar disorders increased by 1.1 and 1.3 percentage points, respectively. CONCLUSIONS: FDA labeling plays an important but imperfect role in influencing how providers select medications. Prescribing increases for medications with new indications. Conversely, black box warnings of potentially dangerous side effects result in decreased prescribing. However, labeled indications often lag the science, and prescribing patterns should be tracked to inform the need for more education, research, and labeling changes. PMID- 28093059 TI - Insurance Coverage and Treatment Use Under the Affordable Care Act Among Adults With Mental and Substance Use Disorders. AB - OBJECTIVE: Many adults who have mental or substance use disorders or both experience insurance-related barriers to care, contributing to low treatment utilization. Expanded insurance under the Affordable Care Act (ACA) could improve coverage and access. The study identified changes in coverage and treatment use following 2014 ACA insurance expansions. METHODS: Data from the National Survey on Drug Use and Health were used to identify individuals ages 18-64 screening positive for any mental disorder (N=29,962) or substance use disorder (N=19,243) for two periods: 2011-2013 and 2014. Regression-adjusted means were calculated for insurance rates and treatment used in each period overall and among individuals with household incomes <=200% of the federal poverty level (FPL). RESULTS: Compared with 2011-2013, in 2014 significant reductions were seen in the uninsured rate for individuals with mental disorders (-5.4 percentage points, p<.01) and substance use disorders (-5.1 percentage points, p<.01). Increases in insurance coverage occurred mostly through Medicaid. Insurance gains were larger for adults with incomes <=200% of FPL compared with the overall sample. Use of mental health treatment increased by 2.1 percentage points (p=.04), but use of substance use disorder treatment did not change. No significant changes were noted in treatment settings for mental and substance use disorder treatments. Payment by Medicaid for substance use disorder treatment increased by 7.4 percentage points (p=.05). CONCLUSIONS: Sizable increases in coverage for adults with mental disorders and adults with substance use disorders were identified in the year following the 2014 ACA expansions; however, low treatment rates among this population remain a concern. Initiatives to engage the newly insured in treatment are needed. PMID- 28093060 TI - Follow-Up Care After Emergency Department Visits for Mental and Substance Use Disorders Among Medicaid Beneficiaries. AB - OBJECTIVE: This study examined whether characteristics of Medicaid beneficiaries were associated with receipt of follow-up care after discharge from the emergency department (ED) following a visit for mental or substance use disorders. METHODS: Medicaid fee-for-service claims from 15 states and the District of Columbia in 2008 were used to calculate whether adults received follow-up (seven and 30 days) after being discharged from the ED following a visit for mental disorders (N=31,952 discharges) or substance use disorders (N=13,337 discharges). Random effects logistic regression was used to model the odds of receiving follow-up as a function of beneficiary characteristics. RESULTS: Receipt of follow-up varied widely across states and by beneficiary characteristics. The odds of seven- and 30-day follow-up after mental health ED discharges were lower among males; African Americans versus whites; and beneficiaries who qualified for Medicaid on the basis of income rather than disability, beneficiaries with depression and other mood disorders compared with other psychiatric diagnoses, and (at seven-day follow-up) beneficiaries who lived in rural versus metropolitan areas. In contrast, the odds of follow-up after substance use disorder ED discharges were lower among whites (seven-day follow-up) and among beneficiaries who qualified for Medicaid on the basis of disability rather than income, who were diagnosed as having drug use disorders rather than alcohol use disorders, or who lived in metropolitan versus suburban areas (seven- and 30-day follow-ups). CONCLUSIONS: State Medicaid programs have an opportunity to improve follow-up after ED visits for mental and substance use disorders, perhaps by focusing on groups of beneficiaries who are less likely to receive follow-up. PMID- 28093061 TI - Polyphyllin II Restores Sensitization of the Resistance of PC-9/ZD Cells to Gefitinib by a Negative Regulation of the PI3K/Akt/mTOR Signaling Pathway. AB - BACKGROUND: EGFR tyrosine kinase inhibitors (TKIs) are widely used for advanced nonsmall cell lung cancer (NSCLC) patients with a sensitizing EGFR mutation and provide a promising treatment strategy. However, acquired resistance to EGFR-TKIs restricts their application. The mechanisms underlying acquired resistance to TKIs have been explored and Phosphoinositide 3- kinase (PI3K)/Akt/mTOR pathway plays a very important role in NSCLC development as well as EGFR-TKI resistance. Polyphyllin II(PP II) is the main steroidal saponin constituent which derives from the root of Paris polychylia. OBJECTIVE: We examined the sensitizing effect of PP II to gefitinib on proliferation, apoptosis, PI3K/Akt/mTOR signaling pathway and tumor growth on gefitinib-resistant NSCLC in vitro and in vivo. METHODS: Gefitinib-resistant PC-9/ZD cells and gefitinib-sensitive PC-9 cells were used. In the absence of PI3K siRNA, MTT assay, Annexin V/PI analyses, Western blot, and Immunohistochemistry analysis by TUNEL assays for xenograft model were carried out. RESULTS: PP II promoted the anti-proliferative effects of gefitinib and gefitinib-induced apoptosis via activation of caspases and cleavage of PARP. PP II elevated sensitization of gefitinib through targeting the PI3K/Akt/mTOR. PP II with gefitinib treatment was more effective in inhibiting tumor growth and PI3K inactivation on gefitinib-resistant xenograft. CONCLUSION: The results indicated that PP II elevated sensitization of drug-resistant PC-9/ZD cells to gefitinib through the inhibition of PI3K/Akt/mTOR signaling pathway. It provides a potential new strategy to overcome gefitinib resistance for EGFR-TKI resistant NSCLC. PMID- 28093062 TI - Derivation of economic values for production traits in aquaculture species. AB - BACKGROUND: In breeding programs for aquaculture species, breeding goal traits are often weighted based on the desired gains but economic gain would be higher if economic values were used instead. The objectives of this study were: (1) to develop a bio-economic model to derive economic values for aquaculture species, (2) to apply the model to determine the economic importance and economic values of traits in a case-study on gilthead seabream, and (3) to validate the model by comparison with a profit equation for a simplified production system. METHODS: A bio-economic model was developed to simulate a grow-out farm for gilthead seabream, and then used to simulate gross margin at the current levels of the traits and after one genetic standard deviation change in each trait with the other traits remaining unchanged. Economic values were derived for the traits included in the breeding goal: thermal growth coefficient (TGC), thermal feed intake coefficient (TFC), mortality rate (M), and standard deviation of harvest weight ([Formula: see text]). For a simplified production system, improvement in TGC was assumed to affect harvest weight instead of growing period. Using the bio economic model and a profit equation, economic values were derived for harvest weight, cumulative feed intake at harvest, and overall survival. RESULTS: Changes in gross margin showed that the order of economic importance of the traits was: TGC, TFC, M, and [Formula: see text]. Economic values in ? (kg production)-1 (trait unit)-1 were: 0.40 for TGC, -0.45 for TFC, -7.7 for M, and -0.0011 to 0.0010 for [Formula: see text]. For the simplified production system, similar economic values were obtained with the bio-economic model and the profit equation. The advantage of the profit equation is its simplicity, while that of the bio-economic model is that it can be applied to any aquaculture species, because it can include any limiting factor and/or environmental condition that affects production. CONCLUSIONS: We confirmed the validity of the bio-economic model. TGC is the most important trait to improve, followed by TFC and M, and the effect of [Formula: see text] on gross margin is small. PMID- 28093063 TI - Whole-genome sequence-based genomic prediction in laying chickens with different genomic relationship matrices to account for genetic architecture. AB - BACKGROUND: With the availability of next-generation sequencing technologies, genomic prediction based on whole-genome sequencing (WGS) data is now feasible in animal breeding schemes and was expected to lead to higher predictive ability, since such data may contain all genomic variants including causal mutations. Our objective was to compare prediction ability with high-density (HD) array data and WGS data in a commercial brown layer line with genomic best linear unbiased prediction (GBLUP) models using various approaches to weight single nucleotide polymorphisms (SNPs). METHODS: A total of 892 chickens from a commercial brown layer line were genotyped with 336 K segregating SNPs (array data) that included 157 K genic SNPs (i.e. SNPs in or around a gene). For these individuals, genome wide sequence information was imputed based on data from re-sequencing runs of 25 individuals, leading to 5.2 million (M) imputed SNPs (WGS data), including 2.6 M genic SNPs. De-regressed proofs (DRP) for eggshell strength, feed intake and laying rate were used as quasi-phenotypic data in genomic prediction analyses. Four weighting factors for building a trait-specific genomic relationship matrix were investigated: identical weights, -(log10 P) from genome-wide association study results, squares of SNP effects from random regression BLUP, and variable selection based weights (known as BLUP|GA). Predictive ability was measured as the correlation between DRP and direct genomic breeding values in five replications of a fivefold cross-validation. RESULTS: Averaged over the three traits, the highest predictive ability (0.366 +/- 0.075) was obtained when only genic SNPs from WGS data were used. Predictive abilities with genic SNPs and all SNPs from HD array data were 0.361 +/- 0.072 and 0.353 +/- 0.074, respectively. Prediction with -(log10 P) or squares of SNP effects as weighting factors for building a genomic relationship matrix or BLUP|GA did not increase accuracy, compared to that with identical weights, regardless of the SNP set used. CONCLUSIONS: Our results show that little or no benefit was gained when using all imputed WGS data to perform genomic prediction compared to using HD array data regardless of the weighting factors tested. However, using only genic SNPs from WGS data had a positive effect on prediction ability. PMID- 28093064 TI - Erratum to: Integrative analysis of multi-omics data for identifying multi markers for diagnosing pancreatic cancer. PMID- 28093065 TI - Comparison of alternative approaches to single-trait genomic prediction using genotyped and non-genotyped Hanwoo beef cattle. AB - BACKGROUND: Genomic predictions from BayesA and BayesB use training data that include animals with both phenotypes and genotypes. Single-step methodologies allow additional information from non-genotyped relatives to be included in the analysis. The single-step genomic best linear unbiased prediction (SSGBLUP) method uses a relationship matrix computed from marker and pedigree information, in which missing genotypes are imputed implicitly. Single-step Bayesian regression (SSBR) extends SSGBLUP to BayesB-like models using explicitly imputed genotypes for non-genotyped individuals. METHODS: Carcass records included 988 genotyped Hanwoo steers with 35,882 SNPs and 1438 non-genotyped steers that were measured for back-fat thickness (BFT), carcass weight (CWT), eye-muscle area, and marbling score (MAR). Single-trait pedigree-based BLUP, Bayesian methods using only genotyped individuals, SSGBLUP and SSBR methods were compared using cross validation. RESULTS: Methods using genomic information always outperformed pedigree-based BLUP when the same phenotypic data were modeled from either genotyped individuals only or both genotyped and non-genotyped individuals. For BFT and MAR, accuracies were higher with single-step methods than with BayesB, BayesC and BayesCpi. Gains in accuracy with the single-step methods ranged from +0.06 to +0.09 for BFT and from +0.05 to +0.07 for MAR. For CWT, SSBR always outperformed the corresponding Bayesian methods that used only genotyped individuals. However, although SSGBLUP incorporated information from non genotyped individuals, prediction accuracies were lower with SSGBLUP than with BayesC (pi = 0.9999) and BayesB (pi = 0.98) for CWT because, for this particular trait, there was a benefit from the mixture priors of the effects of the single nucleotide polymorphisms. CONCLUSIONS: Single-step methods are the preferred approaches for prediction combining genotyped and non-genotyped animals. Alternative priors allow SSBR to outperform SSGBLUP in some cases. PMID- 28093066 TI - Predictive performance of genomic selection methods for carcass traits in Hanwoo beef cattle: impacts of the genetic architecture. AB - BACKGROUND: Hanwoo beef is known for its marbled fat, tenderness, juiciness and characteristic flavor, as well as for its low cholesterol and high omega 3 fatty acid contents. As yet, there has been no comprehensive investigation to estimate genomic selection accuracy for carcass traits in Hanwoo cattle using dense markers. This study aimed at evaluating the accuracy of alternative statistical methods that differed in assumptions about the underlying genetic model for various carcass traits: backfat thickness (BT), carcass weight (CW), eye muscle area (EMA), and marbling score (MS). METHODS: Accuracies of direct genomic breeding values (DGV) for carcass traits were estimated by applying fivefold cross-validation to a dataset including 1183 animals and approximately 34,000 single nucleotide polymorphisms (SNPs). RESULTS: Accuracies of BayesC, Bayesian LASSO (BayesL) and genomic best linear unbiased prediction (GBLUP) methods were similar for BT, EMA and MS. However, for CW, DGV accuracy was 7% higher with BayesC than with BayesL and GBLUP. The increased accuracy of BayesC, compared to GBLUP and BayesL, was maintained for CW, regardless of the training sample size, but not for BT, EMA, and MS. Genome-wide association studies detected consistent large effects for SNPs on chromosomes 6 and 14 for CW. CONCLUSIONS: The predictive performance of the models depended on the trait analyzed. For CW, the results showed a clear superiority of BayesC compared to GBLUP and BayesL. These findings indicate the importance of using a proper variable selection method for genomic selection of traits and also suggest that the genetic architecture that underlies CW differs from that of the other carcass traits analyzed. Thus, our study provides significant new insights into the carcass traits of Hanwoo cattle. PMID- 28093067 TI - CAPZA1 modulates EMT by regulating actin cytoskeleton remodelling in hepatocellular carcinoma. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) elicits dramatic changes, including cytoskeleton remodelling as well as changes in gene expression and cellular phenotypes. During this process, actin filament assembly plays an important role in maintaining the morphology and movement of tumour cells. Capping protein, a protein complex referred to as CapZ, is an actin-binding complex that can regulate actin cytoskeleton remodelling. CAPZA1 is the alpha1 subunit of this complex, and we hypothesized that CAPZA1 regulates EMT through the regulation of actin filaments assembly, thus reducing the metastatic ability of hepatocellular carcinoma (HCC) cells. METHODS: Immunohistochemistry was used to detect CAPZA1 expression in 129 HCC tissues. Western blotting and qPCR were used to detect CAPZA1, EMT markers and EMT transcription factors in HCC cells. Transwell migration and invasion assays were performed to observe the migration and invasion of HCC cells. Cell Counting Kit-8 (CCK-8) was used to detect the proliferation of HCC cells. Immunoprecipitation was used to detect the interaction between CAPZA1 and actin filaments. Finally, a small animal magnetic resonance imager (MRI) was used to observe metastases in HCC cell xenografts in the liver. RESULTS: CAPZA1 expression levels were negatively correlated with the biological characteristics of primary HCC and patient prognosis. CAPZA1 expression was negatively correlated with the migration and invasion of HCC cells. CAPZA1 down regulation promoted the migration and invasion of HCC cells. Conversely, CAPZA1 overexpression significantly inhibited the migration and invasion of HCC cells. Moreover, CAPZA1 expression levels were correlated with the expression of the EMT markers E-cadherin, N-cadherin and Vimentin. Furthermore, the expression of Snail1 and ZEB1 were negatively correlated with CAPZA1 expression levels. Similarly, CAPZA1 significantly inhibited intrahepatic metastases of HCC cells in an orthotopic transplantation tumour model. CONCLUSIONS: CAPZA1 inhibits EMT in HCC cells by regulating actin cytoskeleton remodelling, thereby reducing the metastatic ability of the cells. Together, our data suggest that CAPZA1 could be a useful biomarker for clinical determination of the prognosis of HCC patients. PMID- 28093068 TI - Potential of gene drives with genome editing to increase genetic gain in livestock breeding programs. AB - BACKGROUND: This paper uses simulation to explore how gene drives can increase genetic gain in livestock breeding programs. Gene drives are naturally occurring phenomena that cause a mutation on one chromosome to copy itself onto its homologous chromosome. METHODS: We simulated nine different breeding and editing scenarios with a common overall structure. Each scenario began with 21 generations of selection, followed by 20 generations of selection based on true breeding values where the breeder used selection alone, selection in combination with genome editing, or selection with genome editing and gene drives. In the scenarios that used gene drives, we varied the probability of successfully incorporating the gene drive. For each scenario, we evaluated genetic gain, genetic variance [Formula: see text], rate of change in inbreeding ([Formula: see text]), number of distinct quantitative trait nucleotides (QTN) edited, rate of increase in favourable allele frequencies of edited QTN and the time to fix favourable alleles. RESULTS: Gene drives enhanced the benefits of genome editing in seven ways: (1) they amplified the increase in genetic gain brought about by genome editing; (2) they amplified the rate of increase in the frequency of favourable alleles and reduced the time it took to fix them; (3) they enabled more rapid targeting of QTN with lesser effect for genome editing; (4) they distributed fixed editing resources across a larger number of distinct QTN across generations; (5) they focussed editing on a smaller number of QTN within a given generation; (6) they reduced the level of inbreeding when editing a subset of the sires; and (7) they increased the efficiency of converting genetic variation into genetic gain. CONCLUSIONS: Genome editing in livestock breeding results in short , medium- and long-term increases in genetic gain. The increase in genetic gain occurs because editing increases the frequency of favourable alleles in the population. Gene drives accelerate the increase in allele frequency caused by editing, which results in even higher genetic gain over a shorter period of time with no impact on inbreeding. PMID- 28093070 TI - Clonidine is effective for the treatment of primary idiopathic hyperhidrosis and hot flushes: a case report. AB - BACKGROUND: While primary hyperhidrosis can be seen in men, accompanying hot flushes is rarely seen in men. Primary hyperhidrosis is thought to be related to overactivity of the sympathetic nervous system while hot flushes are believed to be related to altered peripheral vascular reactivity and a narrowed thermoregulatory zone. CASE PRESENTATION: I report the case of a 29-year-old man of Arab origin who presented to a dermatology clinic with a complaint of generalized sweating, with heavier involvement of his inguinal region, axilla, and lower back. His complaint was associated with a transient hot sensation and erythema over the affected areas. He did not respond to topical antiperspirants containing aluminum chloride, topical aluminum chloride, or to botulinum toxin A injected in both inguinal areas. He was then referred to an endocrinology clinic to rule out secondary causes of hyperhidrosis and hot flushes; a primary diagnosis was confirmed. He did not respond to oral glycopyrrolate and additionally was complaining of its anticholinergic side effects. The glycopyrrolate was then replaced with oral clonidine 0.15 mg twice a day. Clonidine was well tolerated without remarkable side effects and he quickly started to feel marked improvement which was maintained for 2 years. CONCLUSIONS: I report an atypical presentation of primary hyperhidrosis and hot flushes that was effectively controlled by clonidine without remarkable side effects. Further research on a large number of patients may be required before recommending clonidine in similar conditions. PMID- 28093069 TI - Assessing the progression of chronic periodontitis using subgingival pathogen levels: a 24-month prospective multicenter cohort study. AB - BACKGROUND: The diagnosis of the progression of periodontitis presently depends on the use of clinical symptoms (such as attachment loss) and radiographic imaging. The aim of the multicenter study described here was to evaluate the diagnostic use of the bacterial content of subgingival plaque recovered from the deepest pockets in assessing disease progression in chronic periodontitis patients. METHODS: This study consisted of a 24-month investigation of a total of 163 patients with chronic periodontitis who received trimonthly follow-up care. Subgingival plaque from the deepest pockets was recovered and assessed for bacterial content of Porphyromonas gingivalis, Prevotella intermedia, and Aggregatibacter actinomycetemcomitans using the modified Invader PLUS assay. The corresponding serum IgG titers were measured using ELISA. Changes in clinical parameters were evaluated over the course of 24 months. The sensitivity, specificity, and prediction values were calculated and used to determine cutoff points for prediction of the progression of chronic periodontitis. RESULTS: Of the 124 individuals who completed the 24-month monitoring phase, 62 exhibited progression of periodontitis, whereas 62 demonstrated stable disease. The P. gingivalis counts of subgingival plaque from the deepest pockets was significantly associated with the progression of periodontitis (p < 0.001, positive predictive value = 0.708). CONCLUSIONS: The P. gingivalis counts of subgingival plaque from the deepest pockets may be associated with the progression of periodontitis. PMID- 28093071 TI - SPAG6 and L1TD1 are transcriptionally regulated by DNA methylation in non-small cell lung cancers. AB - BACKGROUND: DNA methylation regulates together with other epigenetic mechanisms the transcriptional activity of genes and is involved in the pathogenesis of malignant diseases including lung cancer. In non-small cell lung cancer (NSCLC) various tumor suppressor genes are already known to be tumor-specifically methylated. However, from the vast majority of a large number of genes which were identified to be tumor-specifically methylated, tumor-specific methylation was unknown so far. Thus, the major aim of this study was to investigate in detail the mechanism(s) responsible for transcriptional regulation of the genes SPAG6 and L1TD1 in NSCLCs. METHODS: We analysed publically available RNA-sequencing data and performed gene expression analyses by RT-PCR. DNA methylation analyses were done by methylation-sensitive high-resolution melt analyses and bisulfite genomic sequencing. We additionally investigated protein expression using immunohistochemistry. Cell culture experiments included tumor cell growth, proliferation, viability as well as colony formation assays. Moreover, we performed xenograft experiments using immunodeficient mice. RESULTS: We observed frequent downregulation of SPAG6 and L1TD1 mRNA expression in primary tumor (TU) samples compared to corresponding non-malignant lung tissue (NL) samples of NSCLC patients. We furthermore observed re-expression of both genes after treatment with epigenetically active drugs in most NSCLC cell lines with downregulated SPAG6 and L1TD1 mRNA expression. Frequent tumor-specific DNA methylation of SPAG6 and L1TD1 was detected when we analysed TU and corresponding NL samples of NSCLC patients. ROC curve analyses demonstrated that methylation of both genes is able to distinguish between TU and NL samples of these patients. Immunohistochemistry revealed a close association between SPAG6/L1TD1 methylation and downregulated protein expression of these genes. Moreover, by performing functional assays we observed reduced cell growth, proliferation and viability of pCMV6-L1TD1 transfected NSCLC cells. In addition, reduced volumes of tumors derived from pCMV6-L1TD1 compared to pCMV6-ENTRY transfected NCI-H1975 cells were seen in a xenograft tumor model. CONCLUSIONS: Overall, our results demonstrate that SPAG6 and L1TD1 are tumor-specifically methylated in NSCLCs and that DNA methylation is involved in the transcriptional regulation of these genes. Moreover, in vitro as well as in vivo experiments revealed tumor-cell growth suppressing properties of L1TD1 in NSCLC cells. PMID- 28093072 TI - In vitro effects of hyaluronic acid on human periodontal ligament cells. AB - BACKGROUND: Hyaluronic acid (HA) has been reported to have a positive effect on periodontal wound healing following nonsurgical and surgical therapy. However, to date, a few basic in vitro studies have been reported to investigating the potential of HA on human periodontal ligament (PDL) cell regeneration. Therefore, the aim of this study was to investigate the effect of HA on PDL cell compatibility, proliferation, and differentiation in vitro. METHODS: Either non cross-linked (HA_ncl) or cross-linked (HA_cl) HA was investigated. Human PDL cells were seeded in 7 conditions as follows (1) Control tissue culture plastic (TCP) (2) dilution of HA_ncl (1:100), (3) dilution of HA_ncl (1:10), 4) HA_ncl directly coated onto TCP, (5) dilution of HA_cl (1:100), 6) dilution of HA_cl (1:10) and (7) HA_cl directly coated onto TCP. Samples were then investigated for cell viability using a live/dead assay, an inflammatory reaction using real-time PCR and ELISA for MMP2, IL-1 and cell proliferation via an MTS assay. Furthermore, the osteogenic potential of PDL cells was assessed by alkaline phosphatase(ALP) activity, collagen1(COL1) and osteocalcin(OCN) immunostaining, alizarin red staining, and real-time PCR for genes encoding Runx2, COL1, ALP, and OCN. RESULTS: Both HA_ncl and HA_cl showed high PDL cell viability (greater than 90%) irrespective of the culturing conditions. Furthermore, no significant difference in both mRNA and protein levels of proinflammatory cytokines, including MMP2 and IL-1 expression was observed. Both diluted HA_ncl and HA_cl significantly increased cell numbers compared to the controlled TCP samples at 3 and 5 days. HA_ncl and HA_cl in standard cell growth media significantly decreased ALP staining, COL1 immunostaining and down-regulated early osteogenic differentiation, including Runx2, COL1, and OCN mRNA levels when compared to control samples. When osteogenic differentiation medium (ODM) was added, interestingly, the expression of early osteogenic markers increased by demonstrating higher levels of COL1 and ALP expression; especially in HA 1:10 diluted condition. Late stage osteogenic markers remained inhibited. CONCLUSIONS: Both non-cross-linked and cross-linked HA maintained high PDL cell viability, increased proliferation, and early osteogenic differentiation. However, HA was consistently associated with a significant decrease in late osteogenic differentiation of primary human PDL cells. Future in vitro and animal research is necessary to further characterize the effect of HA on periodontal regeneration. PMID- 28093073 TI - Application of meta-omics techniques to understand greenhouse gas emissions originating from ruminal metabolism. AB - Methane emissions from ruminal fermentation contribute significantly to total anthropological greenhouse gas (GHG) emissions. New meta-omics technologies are beginning to revolutionise our understanding of the rumen microbial community structure, metabolic potential and metabolic activity. Here we explore these developments in relation to GHG emissions. Microbial rumen community analyses based on small subunit ribosomal RNA sequence analysis are not yet predictive of methane emissions from individual animals or treatments. Few metagenomics studies have been directly related to GHG emissions. In these studies, the main genes that differed in abundance between high and low methane emitters included archaeal genes involved in methanogenesis, with others that were not apparently related to methane metabolism. Unlike the taxonomic analysis up to now, the gene sets from metagenomes may have predictive value. Furthermore, metagenomic analysis predicts metabolic function better than only a taxonomic description, because different taxa share genes with the same function. Metatranscriptomics, the study of mRNA transcript abundance, should help to understand the dynamic of microbial activity rather than the gene abundance; to date, only one study has related the expression levels of methanogenic genes to methane emissions, where gene abundance failed to do so. Metaproteomics describes the proteins present in the ecosystem, and is therefore arguably a better indication of microbial metabolism. Both two-dimensional polyacrylamide gel electrophoresis and shotgun peptide sequencing methods have been used for ruminal analysis. In our unpublished studies, both methods showed an abundance of archaeal methanogenic enzymes, but neither was able to discriminate high and low emitters. Metabolomics can take several forms that appear to have predictive value for methane emissions; ruminal metabolites, milk fatty acid profiles, faecal long-chain alcohols and urinary metabolites have all shown promising results. Rumen microbial amino acid metabolism lies at the root of excessive nitrogen emissions from ruminants, yet only indirect inferences for nitrogen emissions can be drawn from meta-omics studies published so far. Annotation of meta-omics data depends on databases that are generally weak in rumen microbial entries. The Hungate 1000 project and Global Rumen Census initiatives are therefore essential to improve the interpretation of sequence/metabolic information. PMID- 28093074 TI - Insights into the design and interpretation of iCLIP experiments. AB - BACKGROUND: Ultraviolet (UV) crosslinking and immunoprecipitation (CLIP) identifies the sites on RNAs that are in direct contact with RNA-binding proteins (RBPs). Several variants of CLIP exist, which require different computational approaches for analysis. This variety of approaches can create challenges for a novice user and can hamper insights from multi-study comparisons. Here, we produce data with multiple variants of CLIP and evaluate the data with various computational methods to better understand their suitability. RESULTS: We perform experiments for PTBP1 and eIF4A3 using individual-nucleotide resolution CLIP (iCLIP), employing either UV-C or photoactivatable 4-thiouridine (4SU) combined with UV-A crosslinking and compare the results with published data. As previously noted, the positions of complementary DNA (cDNA)-starts depend on cDNA length in several iCLIP experiments and we now find that this is caused by constrained cDNA ends, which can result from the sequence and structure constraints of RNA fragmentation. These constraints are overcome when fragmentation by RNase I is efficient and when a broad cDNA size range is obtained. Our study also shows that if RNase does not efficiently cut within the binding sites, the original CLIP method is less capable of identifying the longer binding sites of RBPs. In contrast, we show that a broad size range of cDNAs in iCLIP allows the cDNA starts to efficiently delineate the complete RNA-binding sites. CONCLUSIONS: We demonstrate the advantage of iCLIP and related methods that can amplify cDNAs that truncate at crosslink sites and we show that computational analyses based on cDNAs-starts are appropriate for such methods. PMID- 28093075 TI - GAVIN: Gene-Aware Variant INterpretation for medical sequencing. AB - We present Gene-Aware Variant INterpretation (GAVIN), a new method that accurately classifies variants for clinical diagnostic purposes. Classifications are based on gene-specific calibrations of allele frequencies from the ExAC database, likely variant impact using SnpEff, and estimated deleteriousness based on CADD scores for >3000 genes. In a benchmark on 18 clinical gene sets, we achieve a sensitivity of 91.4% and a specificity of 76.9%. This accuracy is unmatched by 12 other tools. We provide GAVIN as an online MOLGENIS service to annotate VCF files and as an open source executable for use in bioinformatic pipelines. It can be found at http://molgenis.org/gavin . PMID- 28093077 TI - Genome Informatics 2016. AB - A report on the Genome Informatics conference, held at the Wellcome Genome Campus Conference Centre, Hinxton, United Kingdom, 19-22 September 2016. PMID- 28093076 TI - Genetic source tracking of an anthrax outbreak in Shaanxi province, China. AB - BACKGROUND: Anthrax is an acute zoonotic infectious disease caused by the bacterium known as Bacillus anthracis. From 26 July to 8 August 2015, an outbreak with 20 suspected cutaneous anthrax cases was reported in Ganquan County, Shaanxi province in China. The genetic source tracking analysis of the anthrax outbreak was performed by molecular epidemiological methods in this study. METHODS: Three molecular typing methods, namely canonical single nucleotide polymorphisms (canSNP), multiple-locus variable-number tandem repeat analysis (MLVA), and single nucleotide repeat (SNR) analysis, were used to investigate the possible source of transmission and identify the genetic relationship among the strains isolated from human cases and diseased animals during the outbreak. RESULTS: Five strains isolated from diseased mules were clustered together with patients' isolates using canSNP typing and MLVA. The causative B. anthracis lineages in this outbreak belonged to the A.Br.001/002 canSNP subgroup and the MLVA15-31 genotype (the 31 genotype in MLVA15 scheme). Because nine isolates from another four provinces in China were clustered together with outbreak-related strains by the canSNP (A.Br.001/002 subgroup) and MLVA15 method (MLVA15-31 genotype), still another SNR analysis (CL10, CL12, CL33, and CL35) was used to source track the outbreak, and the results suggesting that these patients in the anthrax outbreak were probably infected by the same pathogen clone. CONCLUSIONS: It was deduced that the anthrax outbreak occurred in Shaanxi province, China in 2015 was a local occurrence. PMID- 28093078 TI - Treatment outcomes for multidrug-resistant tuberculosis under DOTS-Plus: a systematic review and meta-analysis of published studies. AB - BACKGROUND: Anti-tuberculosis drug resistance is a major public health problem that threatens the progress made in tuberculosis care and control worldwide. Treatment success rates of multidrug-resistant tuberculosis (MDR-TB) is a key issue that cannot be ignored. There is a paucity of evidence that assessed studies on the treatment of MDR-TB, which focus on the effectiveness of the directly observed treatment, short-course (DOTS)-Plus program. Therefore, it is crucial to assess and summarize the overall treatment outcomes for MDR-TB patients enrolled in the DOTS-Plus program in recent years. The purpose of this study was to thus assess and summarize the available evidence for MDR-TB treatment outcomes under DOTS-Plus. METHODS: A systematic review and meta analysis of published literature was conducted. Original studies were identified using the databases MEDLINE(r)/PubMed(r), Hinari, and Google Scholar. Heterogeneity across studies was assessed using the Cochran's Q test and I2 statistic. Pooled estimates of treatment outcomes were computed using the random effect model. RESULTS: Based on the 14 observational studies included in the meta analysis, it was determined that 5 047 patients reported treatment outcomes. Of these, the pooled prevalence, 63.5% (95% CI: 58.4-68.5%) successfully completed full treatment (cured or treatment completed) with a pooled cure rate of 55.6%, whereas 12.6% (95% CI: 9.0-16.2%) of the patients died, 14.2% (95% CI: 11.6 16.8%) defaulted from therapy, and 7.6% (95% CI: 5.6-9.7%) failed therapy. Overall 35.4% (95% CI: 30-40.8%) of patients had unsuccessful treatment outcomes. An unsatisfactorily high percentage 43% (95% CI: 32-54%) of unsuccessful treatment outcomes was observed among patients who were enrolled in standardized treatment regimens. CONCLUSION: This study revealed that patients with MDR-TB exhibited a very low treatment success rate compared to the World Health Organization 2015 target of at least 75 to 90%. The high default rate observed by conducting this literature review could possibly explain the spread of the MDR-TB strain in various populations. A better treatment success rate was observed among patients in individualized treatment regimens than in standardized ones. Conducting further individual-based meta-analysis is recommended to identify potential factors for defaulting treatment using large-scale and multi-center studies. PMID- 28093079 TI - Albumin and surgical site infection risk in orthopaedics: a meta-analysis. AB - BACKGROUD: Surigical site infection has been a challenge for surgeons for many years, the prevalence of serum albumin <3.5g/dL has been reported to be associated with increased orthopaedic complications. However, the prognostic implications and significance of serum albumin <3.5g/dL after orthopaedic surgeries remain ambiguity. In this study, we performed a meta-analysis to access the predictive value of serum albumin level on SSI. METHODS: A basic data search was performed in PubMed and Web of Science, in addition, references were manually searched. All of the observational studies contained preoperative albumin, outcomes of SSI or valuable data that could be abstracted and analysed for meta analysis in orthopaedics. All of the studies were assessed using the classic Newcastle Ottawa Scale (NOS). They conformed to critical quality evaluation standards, and the final data analysis was performed with RevMan 5.2 software. RESULTS: A total of 112,183 patients included in 13 studies were involved. The pooled MD of albumin between the infection group and the non-infection group was MD = -2.28 (95 % CI -3.97-0.58), which was statistically significant (z = 2.63, P = 0.008). The pooled RR of infection when comparing albumin <3.5 with albumin >3.5 was 2.39 (95 % CI 1.57 3.64), which was statistically significant (z = 4.06, P < 0.0001). Heterogeneity were found in the pooled MD of albumin and in the pooled RR for infection (P = 0.05, I2 = 61 % and P = 0.003, I2 = 68 %). No publication bias occurred based on two basically symmetrical funnel plots. CONCLUSION: Our meta-analysis demonstrated that an albumin level <3.5 g/dL had an almost 2.5 fold increased risk of SSI in orthopaedics, although this conclusion requires well-designed prospective cohort studies to be confirmed further. PMID- 28093080 TI - Efficacy of fluralaner against Otodectes cynotis infestations in dogs and cats. AB - BACKGROUND: The efficacy of fluralaner for the treatment of Otodectes cynotis infestations in dogs and cats was evaluated after oral (dogs) or topical administration (dogs and cats). Twenty-four dogs and sixteen cats were experimentally infested with O. cynotis and randomly allocated to equal sized groups (n = 8/group). Dog groups were treated once, either orally with fluralaner at a minimum dose of 25 mg/kg body weight, topically with fluralaner at a dose of 25 mg/kg body weight or topically with saline solution (control). Cat groups were treated once, either topically with fluralaner at a dose of 40 mg/kg body weight or topically with saline solution. Ears of all animals were examined otoscopically for live visible mites and the amount of debris and cerumen before, and 14 and 28 days after treatment. Twenty-eight days after treatment, animals were sedated and both ears were flushed to obtain the total number of live mites per animal. The efficacy was calculated, based on the results of the ear flushing, by comparing mean live mite counts in the fluralaner treated groups versus the saline solution treated group. RESULTS: A single topical treatment of cats with fluralaner reduced the mean mite counts by 100% (P < 0.001) at 28 days after treatment. Similarly, a single oral or topical treatment of dogs with fluralaner reduced the mean mite counts by 99.8% (P < 0.001) at 28 days after treatment. Cats treated topically with fluralaner had no mites visible during otoscopic examination at either 14 or 28 days after treatment. All dogs treated orally or topically with fluralaner had no mites visible during otoscopic examination at 28 days after treatment. At 14 days after treatment, only 1-2 mites were visible in three dogs (oral treatment: 2 dogs, topical treatment: 1 dog). All fluralaner-treated animals showed improvement in the amount of cerumen exudation compared with observations performed before treatment. No treatment related adverse events were observed in any dogs or cats enrolled in these studies. CONCLUSIONS: In this study, fluralaner administered topically to cats and orally or topically to dogs was highly effective against Otodectes cynotis mite infestations. PMID- 28093081 TI - The most important questions in cancer research and clinical oncology : Question 1. Could the vertical transmission of human papilloma virus (HPV) infection account for the cause, characteristics, and epidemiology of HPV-positive oropharyngeal carcinoma, non-smoking East Asian female lung adenocarcinoma, and/or East Asian triple-negative breast carcinoma? AB - Specific research foci: (1) Mouse models of gamma-herpes virus-68 (gammaHV-68) and polyomavirus (PyV) infections during neonatal versus adult life. (2) For human papilloma virus (HPV)-positive oropharyngeal carcinoma (OPC)-(a) Asking the question: Is oral sex a powerful carcinogen? (b) Examining the evidence for the vertical transmission of HPV infection. (c) Examining the relationship between HPV and Epstein-Barr virus (EBV) infections and nasopharyngeal cancer (NPC) in West European, East European, and East Asian countries. (d) Examining the association between HPV-positive OPC and human leukocyte antigen (HLA). (3) For non-smoking East Asian female lung adenocarcinoma-(a) Examining the incidence trends of HPV-positive OPC and female lung adenocarcinoma according to birth cohorts. (b) Examining the association between female lung adenocarcinoma and HPV. (c) Examining the associations of lung adenocarcinoma with immune modulating factors. (4) For triple-negative breast carcinoma (TNBC) in East Asians-(a) Examining the association between TNBC and HPV. (b) Examining the unique epidemiological characteristics of patients with TNBC. A summary "epidemiological" model tying some of these findings together. PMID- 28093082 TI - Less extrusion debris during the retreatment of curved canals using twisted files with higher rotational speeds: an ex vivo study. AB - BACKGROUND: Debris extrusion from the apical foramen can be problematic in severely curved canals. This study aimed to assess the use of Twisted Files (TF) at different rotational speeds during retreatment, compared with manual technique using Triple-Flex Files (TFF). METHODS: Forty-eight mesiobuccal root canals were randomized to four groups (n = 12 per group). In groups A, B, and C, gutta-percha was removed using TF at 500, 1000, and 1500 rpm, respectively, while it was removed using TFF in group D. Apical debris was collected in a pre-weighed centrifuge tube. The weight of dry debris was assessed by comparing the pre- and post-instrumentation weight for each group. RESULTS: Instrumentation in group D (0.69 +/- 0.04 mg) extruded significantly more debris than any of the TF groups (A: 0.54 +/- 0.05 mg; B: 0.48 +/- 0.04 mg; C: 0.42 +/- 0.03 mg; all P < 0.001). In addition, increasing the rotational speed of TF decreased the amount of extruded debris (A vs. B: P = 0.006; B vs. C: P < 0.001; A vs. C: P < 0.001). CONCLUSIONS: TF at 1500 rpm produced less apical extrusion debris than other TF operating speeds and TFF. PMID- 28093083 TI - Genetic analysis of teat number in pigs reveals some developmental pathways independent of vertebra number and several loci which only affect a specific side. AB - BACKGROUND: Number of functional teats is an important trait in commercial swine production. As litter size increases, the number of teats must also increase to supply nutrition to all piglets. Therefore, a genome-wide association analysis was conducted to identify genomic regions that affect this trait in a commercial swine population. Genotypic data from the Illumina Porcine SNP60v1 BeadChip were available for 2951 animals with total teat number (TTN) records. A subset of these animals (n = 1828) had number of teats on each side recorded. From this information, the following traits were derived: number of teats on the left (LTN) and right side (RTN), maximum number of teats on a side (MAX), difference between LTN and RTN (L - R) and absolute value of L - R (DIF). Bayes C option of GENSEL (version 4.61) and 1-Mb windows were implemented. Identified regions that explained more than 1.5% of the genomic variation were tested in a larger group of animals (n = 5453) to estimate additive genetic effects. RESULTS: Marker heritabilities were highest for TTN (0.233), intermediate for individual side counts (0.088 to 0.115) and virtually nil for difference traits (0.002 for L - R and 0.006 for DIF). Each copy of the VRTN mutant allele increased teat count by 0.35 (TTN), 0.16 (LTN and RTN) and 0.19 (MAX). 15, 18, 13 and 18 one-Mb windows were detected that explained more than 1.0% of the genomic variation for TTN, LTN, RTN, and MAX, respectively. These regions cumulatively accounted for over 50% of the genomic variation of LTN, RTN and MAX, but only 30% of that of TTN. Sus scrofa chromosome SSC10:52 Mb was associated with all four count traits, while SSC10:60 and SSC14:54 Mb were associated with three count traits. Thirty three SNPs accounted for nearly 39% of the additive genetic variation in the validation dataset. No effect of piglet sex or percentage of males in litter was detected, but birth weight was positively correlated with TTN. CONCLUSIONS: Teat number is a heritable trait and use of genetic markers would expedite selection progress. Exploiting genetic variation associated with teat counts on each side would enhance selection focused on total teat counts. These results confirm QTL on SSC4, seven and ten and identify a novel QTL on SSC14. PMID- 28093084 TI - Association between DNA mismatch repair gene polymorphisms and platinum-based chemotherapy toxicity in non-small cell lung cancer patients. AB - BACKGROUND: Chemotherapy toxicity is a serious problem from which non-small cell lung cancer (NSCLC) patients suffer. The mismatch repair (MMR) system is associated with platinum-based chemotherapy toxicity in NSCLC patients. In this study, we aimed to investigate the relationship between genetic polymorphisms in the MMR pathway and platinum-based chemotherapy toxicity in NSCLC patients. METHODS: A total of 220 Chinese lung cancer patients who received at least two cycles of platinum-based chemotherapy were recruited for this study. Toxicity was evaluated in each patient after two cycles of chemotherapy. A total of 44 single nucleotide polymorphisms were selected to investigate their associations with platinum-based chemotherapy toxicity. RESULTS: MutS homolog 2 (MSH2) rs6544991 [odds ratio (OR) 2.98, 95% confidence interval (CI) 1.20-7.40, P = 0.019] was associated with gastrointestinal toxicity in the dominant model; MSH3 rs6151627 (OR 2.38, 95% CI 1.23-4.60, P = 0.010), rs6151670 (OR 2.05, 95% CI 1.07-3.93, P = 0.031), and rs7709909 (OR 2.38, 95% CI 1.23-4.64, P = 0.010) were associated with hematologic toxicity in the dominant model. Additionally, MSH5 rs805304 was significantly associated with overall toxicity (OR 2.21, 95% CI 1.19-4.09, P = 0.012), and MSH5 rs707939 was significantly associated with both overall toxicity (OR 0.42, 95% CI 0.23-0.76, P = 0.004) and gastrointestinal toxicity (OR 0.44, 95% CI 0.20-0.96, P = 0.038) in the dominant model. CONCLUSION: Genetic polymorphisms in the MMR pathway are potential clinical markers for predicting chemotherapy toxicity in NSCLC patients. PMID- 28093085 TI - Gene design, fusion technology and TEV cleavage conditions influence the purification of oxidized disulphide-rich venom peptides in Escherichia coli. AB - BACKGROUND: Animal venoms are large, complex libraries of bioactive, disulphide rich peptides. These peptides, and their novel biological activities, are of increasing pharmacological and therapeutic importance. However, recombinant expression of venom peptides in Escherichia coli remains difficult due to the significant number of cysteine residues requiring effective post-translational processing. There is also an urgent need to develop high-throughput recombinant protocols applicable to the production of reticulated peptides to enable efficient screening of their drug potential. Here, a comprehensive study was developed to investigate how synthetic gene design, choice of fusion tag, compartment of expression, tag removal conditions and protease recognition site affect levels of solubility of oxidized venom peptides produced in E. coli. RESULTS: The data revealed that expression of venom peptides imposes significant pressure on cysteine codon selection. DsbC was the best fusion tag for venom peptide expression, in particular when the fusion was directed to the bacterial periplasm. While the redox activity of DsbC was not essential to maximize expression of recombinant fusion proteins, redox activity did lead to higher levels of correctly folded target peptides. With the exception of proline, the canonical TEV protease recognition site tolerated all other residues at its C terminus, confirming that no non-native residues, which might affect activity, need to be incorporated at the N-terminus of recombinant peptides for tag removal. CONCLUSIONS: This study reveals that E. coli is a convenient heterologous host for the expression of soluble and functional venom peptides. Using the optimal construct design, a large and diverse range of animal venom peptides were produced in the uM scale. These results open up new possibilities for the high-throughput production of recombinant disulphide-rich peptides in E. coli. PMID- 28093086 TI - Do children's previous dental experience and fear affect their perceived oral health-related quality of life (OHRQoL)? AB - BACKGROUND: Oral health-related quality of life (OHRQoL) has been used to describe the consequences of oral health conditions and treatments in children. A better understanding of OHRQoL and its relationship with dental fear and previous dental experience is necessary to improve children's oral health status. The aim of this study was to investigate the association of dental history and experience with dental fear and the OHRQoL of children aged 11 to 14 years. METHODS: A cross sectional study was conducted using a multi-stage stratified sample of 1,312 middle school children. Information regarding OHRQoL was collected from the children using the Child Perceptions Questionnaire (CPQ11-14), and information regarding dental fear was collected using the Children's Fear Survey Schedule Dental Subscale (CFSS-DS). Information on past dental experiences and sociodemographic data were collected from the parents using self-administered questionnaires. Dental examinations were performed to assess caries experience. RESULTS: The multivariable model indicated that dental fear was the strongest predictor of OHRQoL as the fearful children had on average CPQ11-14 scores that were 10 units higher than those of the non-fearful children. Regarding past dental experience, pain as the reason for the most recent dental visit was associated with poor OHRQoL, while receiving a filling during the previous dental visits was significantly associated with better OHRQoL. In addition, a larger number of siblings, a lower family income, a lower paternal education level, health problems and prior hospitalization were significantly associated with poor OHRQoL. CONCLUSION: This study identified that dental fear and some factors related to previous dental experience are associated with OHRQoL. In dental practice, children with dental fear should be identified, guided and treated early to avoid deterioration of their OHRQoL. PMID- 28093087 TI - Incidence of Venous Thromboembolism in cancer patients treated with Cisplatin based chemotherapy - a cohort study. AB - BACKGROUND: Cancer related thrombosis not only increases morbidity and mortality but also poses a significant financial burden on health care system. Risk of venous thromboembolism (VTE) in these patients substantially increases with the addition of chemotherapy. Lately, cisplatin has been implicated as an independent factor. There is little data estimating the risk of venous thromboembolism in patients receiving cisplatin based chemotherapy when compared to other chemotherapeutic agents. METHODS: Patients who had received chemotherapy between November 2010 and October 2012 were retrospectively identified from a single institute cancer registry. 200 patients who had received cisplatin based chemotherapy were identified as the exposed group while 200 patients who had received non-Cisplatin based regimens were identified as the non-exposed group. Patients were followed for development of VTE throughout the entire duration of therapy and one month thereafter. Cox proportional hazard model was used to compute relative risks with 95% confidence intervals. RESULTS: The baseline characteristics were similar in the two groups. Mean age for the entire cohort was 55.4 +/- 10.7 years and male to female ratio was almost 1:1. On univariate analysis, cisplatin based chemotherapy, presence of central venous catheter, female gender, poor performance status, high risk stratification according to the Khorana model and use of granulocyte colony stimulating factor were all significantly associated with the development of VTE. The crude relative risk for the incidence of VTE in cisplatin group was 2.8 (95% CI, 1.4 - 4.2) times compared to the non-Cisplatin group. When the relative risk was adjusted for the above variables in multivariable analysis, it increased to 3.3 (95% CI, 1.6 - 6.8) compared to the control group. CONCLUSION: A high incidence of VTE in patients receiving cisplatin based chemotherapy was demonstrated in this study. Prospective studies are warranted to establish this observation with certainty and to explore the possible use of thromboprophylaxis in patients receiving cisplatin based chemotherapeutic regimens. PMID- 28093088 TI - Diagnostic impact of [18F]flutemetamol PET in early-onset dementia. AB - BACKGROUND: Early-onset dementia patients often present with atypical clinical symptoms, hampering an accurate clinical diagnosis. The purpose of the present study was to assess the diagnostic impact of the amyloid-positron emission tomography (PET) imaging agent [18F]flutemetamol in early-onset dementia patients, in terms of change in (confidence in) diagnosis and patient management plan. METHODS: This prospective bi-center study included 211 patients suspected of early-onset dementia who visited a tertiary memory clinic. Patients were eligible with Mini Mental State Examination >= 18 and age at diagnosis <= 70 years and in whom the diagnostic confidence was <90% after routine diagnostic work-up. All patients underwent [18F]flutemetamol PET, which was interpreted as amyloid-negative or amyloid-positive based on visual rating. Before and after disclosing the PET results, we assessed the diagnostic confidence (using a visual analog scale of 0-100%) and clinical diagnosis. The impact of [18F]flutemetamol PET on the patient management plan was also evaluated. RESULTS: [18F]flutemetamol PET scans were positive in 133 out of 211 (63%) patients, of whom 110 out of 144 (76%) patients had a pre-PET Alzheimer's disease (AD) diagnosis and 23 out of 67 (34%) patients had a non-AD diagnosis. After disclosure of PET results, 41/211 (19%) diagnoses changed. Overall, diagnostic confidence increased from 69 +/- 12% to 88 +/- 15% after disclosing PET results (P < 0.001; in 87% of patients). In 79 (37%) patients, PET results led to a change in patient management and predominantly the initiation of AD medication when PET showed evidence for amyloid pathology. CONCLUSIONS: [18F]flutemetamol PET changed clinical diagnosis, increased overall diagnostic confidence, and altered the patient management plan. Our results suggest that amyloid PET may have added value over the standardized diagnostic work-up in early-onset dementia patients with uncertain clinical diagnosis. This study provides evidence for the recommendations put forward in the appropriate use criteria for amyloid PET in clinical practice. TRIAL REGISTRATION: Nederlands Trial Register NTR3743 . Registered 7 December 2012. PMID- 28093089 TI - Atrial septal defect with right-to-left shunt in the absence of pulmonary hypertension. AB - We describe the case of a 27-year-old gentleman who developed late-onset clubbing and cyanosis. Transoesophageal echocardiography revealed a 27-mm ostium secundum atrial septal defect and a large, floppy Eustachian valve directing right atrial blood to the left side of the heart. PMID- 28093090 TI - Potential involvement of dietary advanced glycation end products in impairment of skeletal muscle growth and muscle contractile function in mice. AB - Diets enriched with advanced glycation end products (AGE) have recently been related to muscle dysfunction processes. However, it remains unclear whether long term exposure to an AGE-enriched diet impacts physiological characteristics of skeletal muscles. Therefore, we explored the differences in skeletal muscle mass, contractile function and molecular responses between mice receiving a diet high in AGE (H-AGE) and low in AGE (L-AGE) for 16 weeks. There were no significant differences between L-AGE and H-AGE mice with regard to body weight, food intake or epididymal fat pad weight. However, extensor digitorum longus (EDL) and plantaris (PLA) muscle weights in H-AGE mice were lower compared with L-AGE mice. Higher levels of N epsilon -(carboxymethyl)-l-lysine, a marker for AGE, in EDL muscles of H-AGE mice were observed compared with L-AGE mice. H-AGE mice showed lower muscle strength and endurance in vivo and lower muscle force production of PLA muscle in vitro. mRNA expression levels of myogenic factors including myogenic factor 5 and myogenic differentiation in EDL muscle were lower in H-AGE mice compared with L-AGE mice. The phosphorylation status of 70-kDa ribosomal protein S6 kinase Thr389, an indicator of protein synthesis signalling, was lower in EDL muscle of H-AGE mice than that of L-AGE mice. These findings suggest that long-term exposure to an AGE-enriched diet impairs skeletal muscle growth and muscle contractile function, and that these muscle dysfunctions may be attributed to the inhibition of myogenic potential and protein synthesis. PMID- 28093091 TI - Is there an association between diet and depression in children and adolescents? A systematic review. AB - This review critically evaluates previous studies investigating the association between dietary intake of children and young people and depression and related mental health problems. A systematic literature search was conducted using electronic databases such as PsycINFO, MEDLINE, PubMed and Cochrane. A total of twenty studies were identified that met inclusion criteria and were subsequently rated for quality. The studies used a range of methods to measure dietary intake and mental health. Important potential confounding variables (e.g. socio-economic status) were often not included or controlled. There were also inconsistencies in the use of key constructs, which made comparisons between studies difficult. Despite some contradictory results, overall there was support for an association between healthy dietary patterns or consumption of a high-quality diet and lower levels of depression or better mental health. Similarly, there was a relationship between unhealthy diet and consumption of low-quality diet and depression or poor mental health. However, where significant relationships were reported, effect sizes were small. Future research on the relationship between diet and mental health in young people should use more clearly defined constructs to define diet and include or control for important confounders. PMID- 28093092 TI - Evaluation of Analysis Conditions for Laser-Pulsed Atom Probe Tomography: Example of Cemented Tungsten Carbide. AB - Cemented tungsten carbide has been analyzed using laser-pulsed atom probe tomography (APT). The influence of experimental parameters, including laser pulse energy, pulse repetition rate, and specimen base temperature, on the acquired data were evaluated from different aspects, such as mass spectrum, chemical composition, noise-to-signal ratio, and multiple events. Within all the applied analysis conditions, only 1 MHz pulse repetition rate led to a strong detector saturation effect, resulting in a largely biased chemical composition. A comparative study of the laser energy settings showed that an ~12 times higher energy was required for the less focused green laser of the LEAPTM 3000X HR system to achieve a similar evaporation field as the finer spot ultraviolet laser of the LEAPTM 5000 XS system. PMID- 28093093 TI - Innovations for Tomorrow: Summary of the 2016 Disaster Health Education Symposium. AB - In an effort to enhance education, training, and learning in the disaster health community, the National Center for Disaster Medicine and Public Health (NCDMPH) gathered experts from around the nation in Bethesda, Maryland, on September 8, 2016, for the 2016 Disaster Health Education Symposium: Innovations for Tomorrow. This article summarizes key themes presented during the disaster health symposium including innovations in the following areas: training and education that saves lives, practice, teaching, sharing knowledge, and our communities. This summary article provides thematic content for those unable to attend. Please visit http://ncdmph.usuhs.edu/ for more information. (Disaster Med Public Health Preparedness. 2017;11:160-162). PMID- 28093094 TI - Impact of Hurricane Exposure on Reproductive Health Outcomes, Florida, 2004. AB - OBJECTIVE: Prenatal hurricane exposure may be an increasingly important contributor to poor reproductive health outcomes. In the current literature, mixed associations have been suggested between hurricane exposure and reproductive health outcomes. This may be due, in part, to residual confounding. We assessed the association between hurricane exposure and reproductive health outcomes by using a difference-in-difference analysis technique to control for confounding in a cohort of Florida pregnancies. METHODS: We implemented a difference-in-difference analysis to evaluate hurricane weather and reproductive health outcomes including low birth weight, fetal death, and birth rate. The study population for analysis included all Florida pregnancies conceived before or during the 2003 and 2004 hurricane season. Reproductive health data were extracted from vital statistics records from the Florida Department of Health. In 2004, 4 hurricanes (Charley, Frances, Ivan, and Jeanne) made landfall in rapid succession; whereas in 2003, no hurricanes made landfall in Florida. RESULTS: Overall models using the difference-in-difference analysis showed no association between exposure to hurricane weather and reproductive health. CONCLUSIONS: The inconsistency of the literature on hurricane exposure and reproductive health may be in part due to biases inherent in pre-post or regression-based county-level comparisons. We found no associations between hurricane exposure and reproductive health. (Disaster Med Public Health Preparedness. 2017;11:407-411). PMID- 28093095 TI - Pregnant Women's Awareness of Social Capital in the Great East Japan Earthquake Affected Areas of Miyagi Prefecture: The Japan Environment and Children's Study. AB - OBJECTIVE: We aimed to clarify the correlation between the 2011 Great East Japan Earthquake and pregnant women's awareness of social capital 3 to 9 months after the tsunami disaster. METHODS: We analyzed data on responses to a questionnaire by 7451 pregnant women in their second to third trimesters. The proportions of social capital-related items were calculated in the north and south coastal areas of Miyagi Prefecture and were compared with national samples. The factors associated with social capital were estimated by use of multivariate logistic regression analyses. RESULTS: The proportion of women feeling that they had helpful neighbors was higher (69.0% vs 56.7%, P=0.0005), the proportion of women regarding their communities as safe and secure was lower (51.7% vs 62.4%, P=0.002), and the proportion of women feeling that most people were trustworthy was lower (23.7% vs 32.9%, P=0.006) in the north coastal area than nationwide. Such differences were not observed in the less severely affected south coastal area. Age of 35 years or older, extended family, college or university graduation, and being multiparous were associated with the feeling of having helpful neighbors. CONCLUSION: The current status of pregnant women's awareness of social capital in disaster-affected areas was revealed. Continuous monitoring and support may be necessary to address this issue.(Disaster Med Public Health Preparedness. 2017;11:355-364). PMID- 28093097 TI - Present-day central African forest is a legacy of the 19th century human history. AB - The populations of light-demanding trees that dominate the canopy of central African forests are now aging. Here, we show that the lack of regeneration of these populations began ca. 165 ya (around 1850) after major anthropogenic disturbances ceased. Since 1885, less itinerancy and disturbance in the forest has occurred because the colonial administrations concentrated people and villages along the primary communication axes. Local populations formerly gardened the forest by creating scattered openings, which were sufficiently large for the establishment of light-demanding trees. Currently, common logging operations do not create suitable openings for the regeneration of these species, whereas deforestation degrades landscapes. Using an interdisciplinary approach, which included paleoecological, archaeological, historical, and dendrological data, we highlight the long-term history of human activities across central African forests and assess the contribution of these activities to present-day forest structure and composition. The conclusions of this sobering analysis present challenges to current silvicultural practices and to those of the future. PMID- 28093098 TI - TLR-induced immunomodulatory cytokine expression by human gingival stem/progenitor cells. AB - During therapeutic application, mesenchymal stem cells (MSCs) may interact with their environment via their expressed toll-like-receptors (TLRs) leading to pro- or anti-inflammatory immune responses. The present study aimed to describe the gingival margin-derived stem/progenitor cells' (G-MSCs) TLR-induced immune regulatory response to specific TLR agonists. Gingival cells were obtained, immunomagnetically sorted via anti-STRO-1 antibodies and seeded out to achieve colony forming units (CFUs). G-MSCs were investigated for stem cell characteristics and TLR expression. Specific TLR agonists were applied and m-RNA expression of pro- and anti-inflammatory factors was analyzed via real-time polymerase chain reaction. G-MSCs showed all characteristics of stem/progenitor cells. All TLR agonists induced pro-inflammatory cytokines, except for the TLR3 agonist, which significantly promoted the anti-inflammatory response. (p?0.05, Wilcoxon-Signed-Ranks-Test). TLR-induced immunomodulation by G-MSCs could impact their therapeutic potential in vivo. Two distinctive pro-inflammatory and an anti inflammatory TLR-induced phenotypes of G-MSCs become noticeable in this study. PMID- 28093100 TI - Increased Risk of Stroke in Patients With Nonarteritic Anterior Ischemic Optic Neuropathy: A Nationwide Retrospective Cohort Study. PMID- 28093099 TI - [Infective endocarditis: Clinical features and prognosis between 2004 and 2014 in a non-teaching hospital]. AB - AIMS: Despite diagnostic and therapeutic advances, infective endocarditis (IE) remains a severe disease. The aim of the study was to describe clinical features and prognosis of patients with IE in a non-teaching hospital and compare them with current data and a similar study conducted 10 years earlier in the same center. METHODS: We performed a single institution retrospective study including all patients with Duke-Li definite IE between 2004 and 2014. RESULTS: Ninety-four patients were included. Results are consistent with current French and international data, including in-hospital death rate of 16%. In accordance with literature, we report on an increase in Staphylococcus and health care-associated IE and endocarditis on pacemaker leads, but without significant difference compared to our previous study. In univariate analyses, renal failure, age over 77 years and Staphylococcus aureus IE were associated with in-hospital mortality. In multivariate analyses, predictors of in-hospital death were renal failure and lack of surgery. There was a non-significant trend of excess mortality in Staphylococcus endocarditis and in patients with heart failure. CONCLUSION: IE remains a severe disease and S. aureus is more often involved. IE seems to be safely managed in a peripheral hospital provided that there is a partnership with a reference hospital. PMID- 28093101 TI - Autoinmune pancreatitis: Differential diagnosis with pancreatic adenocarcinoma. PMID- 28093096 TI - Structural biology of supramolecular assemblies by magic-angle spinning NMR spectroscopy. AB - In recent years, exciting developments in instrument technology and experimental methodology have advanced the field of magic-angle spinning (MAS) nuclear magnetic resonance (NMR) to new heights. Contemporary MAS NMR yields atomic-level insights into structure and dynamics of an astounding range of biological systems, many of which cannot be studied by other methods. With the advent of fast MAS, proton detection, and novel pulse sequences, large supramolecular assemblies, such as cytoskeletal proteins and intact viruses, are now accessible for detailed analysis. In this review, we will discuss the current MAS NMR methodologies that enable characterization of complex biomolecular systems and will present examples of applications to several classes of assemblies comprising bacterial and mammalian cytoskeleton as well as human immunodeficiency virus 1 and bacteriophage viruses. The body of work reviewed herein is representative of the recent advancements in the field, with respect to the complexity of the systems studied, the quality of the data, and the significance to the biology. PMID- 28093102 TI - Proteomic changes in the ileum of sheep infected with Mycobacterium avium subspecies paratuberculosis. AB - Johne's disease (JD) is a chronic enteritis of ruminants caused by Mycobacterium avium subspecies paratuberculosis (MAP). To identify the processes activated in the sheep intestine during natural MAP infection, and to provide a panel of differential host and pathogen proteins with diagnostic and prognostic potential, a differential shotgun proteomics workflow, including mass spectrometry, label free quantisation and pathway analysis, was applied to ileal tissues of ewes with and without JD. Out of 2889 total proteins identified, 384 were differentially expressed and 341 were expressed at a higher level in JD. On the basis of Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) analysis, these proteins were involved in numerous relevant biological networks and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including inhibition of phagosome acidification (such as V-ATPase), bacterial invasion, leucocyte recruitment and activation, and antimicrobial activity (such as haptoglobin, lactoferrin, cathelicidins, calgranulins and interleukins). A total of 28 MAP proteins were identified, including bacterioferritin, beta-lactamase and heparin binding haemagglutinin (HBHA), a mycobacterial adhesin crucial for dissemination of infection. PMID- 28093103 TI - Urinary 3-hydroxypropyl mercapturic acid (3-HPMA) concentrations in dogs with acute spinal cord injury due to intervertebral disc herniation. AB - The aim of this study was to investigate urinary 3-hydroxypropyl mercapturic acid (3-HPMA), a metabolite of acrolein, as a novel biomarker in acute spinal cord injury (ASCI) due to intervertebral disc herniation in dogs. Urine from 10 client owned dogs with ASCI collected at presentation and 10 control dogs was analyzed for 3-HPMA. The median urinary 3-HPMA concentration in ASCI dogs was significantly higher than in control dogs, but was not correlated with the severity of ASCI. The median urinary 3-HPMA concentration in intact dogs was higher than in neutered dogs. Higher urinary 3-HPMA concentrations in dogs after ASCI support a role for acrolein, a cytotoxic by-product of lipid peroxidation, in canine ASCI. Urinary 3-HPMA could be used as a biomarker in future clinical trials to measure the effect of therapeutic intervention of reducing acrolein after ASCI. PMID- 28093104 TI - Faecal shedding of canine parvovirus after modified-live vaccination in healthy adult dogs. AB - Since little is known about the persistence and faecal shedding of canine parvovirus (CPV) in dogs after modified-live vaccination, diagnostic tests for CPV can be difficult to interpret in the post-vaccination period. The primary aim of this study was to determine the incidence, duration and extent of CPV vaccine virus shedding in adult dogs and to investigate related factors, including the presence of protective antibodies, increase in anti-CPV antibody titres and development of any gastrointestinal side-effects. A secondary objective was to assess prevalence of CPV field virus shedding in clinically healthy dogs due to subclinical infections. One hundred adult, healthy privately owned dogs were vaccinated with a commercial CPV-2 modified-live vaccine (MLV). Faeces were tested for the presence of CPV DNA on days 0 (prior to vaccination), 3, 7, 14, 21 and 28 by quantitative real-time PCR. Pre- and post-vaccination serum titres were determined by haemagglutination inhibition on days 0, 7 and 28. Transient excretion of CPV DNA was detected in 2.0% of dogs before vaccination. About one quarter of dogs (23.0%) shed CPV DNA during the post-vaccination period, but field and vaccine virus differentiation by VP2 gene sequencing was only successful in few samples. Faecal CPV excretion occurred despite protective serum antibody titres. Post-vaccination CPV shedding was not related to adequate antibody response after vaccination or to the occurrence of gastrointestinal side effects. Despite individual differences, CPV DNA was detectable for up to 28 days after vaccination, although the faecal CPV DNA load in these clinically healthy dogs was very low. PMID- 28093105 TI - Comparison of submaximal exercise test results and severity of brachycephalic obstructive airway syndrome in English bulldogs. AB - Canine brachycephalic obstructive airway syndrome (BOAS) is a complex respiratory disease related to congenitally flattened facial and skull anatomy. BOAS causes respiratory distress, heat and exercise intolerance, and gastrointestinal signs. English bulldogs (EB) have a high prevalence of BOAS. Currently, the severity of BOAS signs in veterinary practice is assessed subjectively. To reduce BOAS in brachycephalic breeds, an objective and easy-to-use tool could help breeders select healthier animals. Exercise tests, such as the 6 min walk test (distance walked measured) or the 1000 m walk test (duration measured), could be used to assess the severity of BOAS, as exercise intolerance and impaired recovery are key features of BOAS. This study evaluated the severity of signs and anatomic components of BOAS in a group of prospectively recruited young adult EBs (n = 28) and investigated the correlations of the 6 min walk test or the 1000 m walk test with a veterinary assessment of BOAS severity, using an ordinal 4 level scale of respiratory signs. EBs with more severe BOAS walked a shorter distance, more slowly and their recovery from exercise took longer than those with only mild signs of BOAS. Control dogs of different breeds (n = 10) performed the exercise tests significantly better (i.e. longer distance, faster time and recovery) than EBs. Increases in body temperature during exercise were significantly higher in EBs than in controls. The results of this study support the use of exercise tests for objective evaluation of the severity of BOAS in EBs. PMID- 28093106 TI - Genetic and epigenetic aberrations of p16 in feline primary neoplastic diseases and tumor cell lines of lymphoid and non-lymphoid origins. AB - The p16 gene acts as a tumor suppressor by regulating the cell cycle and is frequently inactivated in human and canine cancers. The aim of this study was to characterize genetic and epigenetic alterations of the p16 in feline lymphoid and non-lymphoid malignancies, using 74 primary tumors and 11 tumor cell lines. Cloning of feline p16 and subsequent sequence analysis revealed 11 germline sequence polymorphisms in control cats. Bisulfite sequencing analysis of the p16 promoter region in a feline lymphoma cell line revealed that promoter methylation was associated with decreased mRNA expression. Treatment with a demethylating agent restored mRNA expression of the silenced p16. PCR amplification and sequencing analysis detected homozygous loss (five tumors, 6.7%) and a missense mutation (one tumor, 1.4%) in the 74 primary tumors analyzed. Methylation specific PCR analysis revealed promoter methylation in 10 primary tumors (14%). Promoter methylation was frequent in B cell lymphoid tumors (7/21 tumors, 33%). These genetic and epigenetic alterations were also observed in lymphoma and mammary gland carcinoma cell lines, but not detected in non-neoplastic control specimens. These data indicate that molecular alterations of the p16 locus may be involved in the development of specific types of feline cancer, and warrant further studies to evaluate the clinical value of this evolutionarily-conserved molecular alteration in feline cancers. PMID- 28093107 TI - Characterization and identification of microbial communities in bovine necrotic vulvovaginitis. AB - Bovine necrotic vulvovaginitis (BNVV) is a severe and potentially fatal disease of post-partum cows that emerged in Israel after large dairy herds were merged. While post-partum cows are commonly affected by mild vulvovaginitis (BVV), in BNVV these benign mucosal abrasions develop into progressive deep necrotic lesions leading to sepsis and death if untreated. The etiology of BNVV is still unknown and a single pathogenic agent has not been found. We hypothesized that BNVV is a polymicrobial disease where the normally benign vaginal microbiome is remodeled and affects the local immune response. To this end, we compared the histopathological changes and the microbial communities using 16S rDNA metagenetic technique in biopsies taken from vaginal lesions in post-partum cows affected by BVV and BNVV. The hallmark of BNVV was the formation of complex polymicrobial communities in the submucosal fascia and abrogation of neutrophil recruitment in these lesions. Additionally, there was a marked difference in the composition of bacterial communities in the BNVV lesions in comparison to the benign BVV lesions. This difference was characterized by the abundance of Bacteroidetes and lower total community membership in BNVV. Indicator taxa for BNVV were Parvimonas, Porphyromonas, unclassified Veillonellaceae, Mycoplasma and Bacteroidetes, whereas unclassified Clostridiales was an indicator for BVV. The results support a polymicrobial etiology for BNVV. PMID- 28093108 TI - Antimicrobial stewardship in the treatment of equine bacterial infections. PMID- 28093109 TI - Neonatal Anaplasma platys infection in puppies: Further evidence for possible vertical transmission. AB - Anaplasma platys, the aetiological agent of infectious canine cyclic thrombocytopaenia, infects platelets of dogs, usually causing mild or asymptomatic disease. Although A. platys is transmitted by ticks, as for other Anaplasma species, alternative modes of transmission may be involved. The aim of the present study was to evaluate the occurrence of A. platys infection in litters of puppies, which could suggest possible vertical transmission. Twelve litters, together with the respective bitches, were included in the study for the detection of A. platys DNA by PCR, followed by sequencing. Five puppies, from 2/4 litters <28 days of age, tested positive for A. platys DNA. No puppies from eight litters 1-3 months of age tested positive for A. platys DNA. The identical sequences (16S rRNA and gltA partial gene), the absence of ticks on puppies at the time of collection and the young age of the five infected puppies suggest vertical transmission of A. platys. This mode of transmission might contribute to the maintenance and spread of the pathogen in canine populations. PMID- 28093110 TI - Furthering our understanding of positive urine cultures in dogs. PMID- 28093111 TI - Efficacy of tildipirosin metaphylaxis for the prevention of respiratory disease, otitis and mortality in pre-weaned Holstein calves. AB - The aim of this study was to evaluate the efficacy of two metaphylactic approaches (long acting antibiotic injected once at 10 days of life or twice at 10 and 35 days of life) on the prevention of bovine respiratory disease (BRD), otitis and mortality in high-risk group-housed pre-weaned Holstein heifer calves. The antibiotic of choice for the metaphylactic approach was a long acting macrolide (tildipirosin) administered subcutaneously at the base of the neck at a dose of 1 mL per 45 kg body weight. A clinical trial was carried out on one dairy farm with random allocation of newborn calves to one of three treatments: (1) control (CTR); (2) one injection at 10 days of life (M1); and (3) two injections at 10 and 35 days of life (M2). Study heifers (n = 795) were reared in group pens of 25 calves per pen and fed unrestricted acidified non-saleable milk from day 1 to day 65 of life. Cox proportional hazard and general linear mixed models were used to evaluate the effect of treatment on mortality, BRD and otitis, and average daily weight gain. The birth weights, proportions of calves with inadequate transfer of passive immunity, proportions of calves born from primiparous dams and proportions of calves born from assisted parturitions were not different among CTR, M1 and M2 treatments. A significantly lower hazard of being affected with BRD and/or otitis (but not for BRD or otitis alone) was observed for M1 (hazard ratio, HR = 0.70, P = 0.009) and M2 (HR = 0.72, P = 0.01) when compared to the CTR group. Metaphylactic treatments had no effect on mortality, otitis and average daily weight gain during the pre-weaning period. PMID- 28093112 TI - Clinical indicators of blood gas disturbances, elevated L-lactate concentration and other abnormal blood parameters in newborn beef calves. AB - Blood gas disturbances, commonly resulting from dystocia, are associated with failed transfer of passive immunity, morbidity and mortality in newborn calves. Modified APGAR scores intended to identify compromised calves are not widely adopted due to lack of practicality and inconsistent associations with blood parameters. The objective of this study was to determine clinical indicators of acidemia in newborn beef calves. Blood parameters at 10 min and 24 h after birth were compared to at-birth clinical examination parameters and calving characteristics in 77 commercial beef calves. There were no associations between heart rate or respiratory rate and blood pH or blood L-lactate concentration (LAC; r < 0.25); however, LAC was highly correlated with blood pH (r, -0.86). Abnormal mucous membrane color (red, white or blue) was associated with increased LAC (P = 0.002) but not decreased blood pH (P = 0.07). Abnormal results for tests of muscle tonicity and reflexes, namely inability to completely withdraw the tongue when pinched and a weak suckle reflex, were associated with decreased blood pH and increased LAC (P <0.05). Calves born to primiparous dams or from an assisted calving also had decreased blood pH and increased LAC (P <0.05). Differences in blood pH between at-birth categories resolved for all parameters by 24 h after birth, except for tongue withdrawal (P= 0.04). In conclusion, traditional APGAR parameters, heart rate, respiratory rate and mucous membrane color were not useful for the identification of acidemic calves; however, tongue withdrawal, calving ease, and parity should be included in such an assessment. Utilizing hand-held LAC meters may be a practical method to quickly identify compromised calves with acidemia in a field setting. PMID- 28093113 TI - A new year for The Veterinary Journal. PMID- 28093114 TI - In vitro effects of the toll-like receptor agonists monophosphoryl lipid A and CpG-rich oligonucleotides on cytokine production by equine cells. AB - Insect bite hypersensitivity (IBH) is an equine allergic dermatitis to Culicoides spp. antigens. Attempts at using allergen-specific immunotherapy (AIT) as a treatment for IBH have so far proven unsuccessful. Toll-like receptor (TLR) agonists can promote a shift in the immune response from the allergy-promoting T helper cell 2 (Th2) response towards a Th1 and/or regulatory response. The aim of this study was to evaluate two immunomodulatory TLR agonists in vitro as potential vaccine adjuvants for a more efficacious AIT in IBH. Peripheral blood mononuclear cells (PBMCs) from healthy and IBH-affected horses were stimulated with the TLR-agonists monophosphoryl lipid A (MPLA) or CpG-rich oligodeoxynucleotides (CpG-ODN) in the presence or absence of Culicoides spp. allergens. Cytokine concentrations of interferon (IFN)-alpha, IFN-gamma, interleukin (IL)-4, IL-10 and IL-17 were quantified in the supernatants of stimulated PBMCs. MPLA induced IL-10 secretion in all horses, regardless of presence and nature of antigens, while suppressing antigen-induced production of IFN-gamma, IL-4 and IL-17. CpG-ODN significantly increased IFN-alpha, IFN-gamma and IL-4 production, but had little effect on IL-10 production. In conclusion, MPLA promotes a regulatory immune response and is therefore a promising adjuvant candidate for allergy vaccines in horses. While C-class CpG-ODN is an unsuitable adjuvant for AIT, it induces IFN-gamma and IFN-alpha, and thus may be a useful adjuvant in combination with vaccines for equine infectious or neoplastic diseases. PMID- 28093115 TI - Use of an implantable pump for controlled subcutaneous insulin delivery in healthy cats. AB - The aim of this study was to examine the safety and reliability of a research grade implantable pump for controlled delivery of insulin glargine in cats. For this purpose, a small telemetrically controlled drug delivery pump with a refillable reservoir was implanted into the subcutaneous tissues of the dorsal neck in 10 clinically healthy cats. The reservoir was filled with insulin glargine, and the pump was programmed to deliver four boluses of 0.25 IU/kg, 2-3 weeks apart. As a control, insulin glargine (0.25 IU/kg) was injected SC. Blood glucose and plasma insulin glargine concentrations were measured before each bolus and SC injection and for 8 h afterward. Cats were monitored for signs of discomfort. Pumps were easily implanted and well tolerated by all cats. The experiment was completed in five of 10 cats. In four, the pump failed because of technical reasons; another cat developed severe hypoglycaemia attributable to insulin leakage. Overall, plasma insulin glargine increased after six of eight (75%) initial boluses and after one of 16 (6%) successive boluses. Glucose decreased after seven of eight (88%) initial boluses and after four of 16 (25%) successive boluses. Only the first bolus significantly increased plasma insulin glargine (P = 0.008) and decreased glucose (P = 0.008). Of 20 SC injections, 10 (50%) increased plasma insulin glargine (P <0.001) and 12 (60%) decreased glucose (P <0.001). The pump did not cause discomfort in cats, but life-threatening hypoglycaemia occurred in one. Frequent device problems suggest that the pump needs improvements. Because successive boluses did not increase plasma insulin glargine, this type of insulin may not be appropriate with the pump. PMID- 28093116 TI - Captive and free-living urban pigeons (Columba livia) from Brazil as carriers of multidrug-resistant pathogenic Escherichia coli. AB - Thirty Escherichia coli isolates from captive and free-living pigeons in Brazil were characterised. Virulence-associated genes identified in pigeons included those which occur relatively frequently in avian pathogenic E. coli (APEC) from commercial poultry worldwide. Eleven of 30 E. coli isolates from pigeons, belonging mainly to B1 and B2 phylogenetic groups, had high or intermediate pathogenicity for 1-day-old chicks. The frequency of multi-drug resistant (MDR) E. coli in captive pigeons was relatively high and included one isolate positive for the extended-spectrum beta-lactamase (ESBL) gene blaCTX-M-8. Pulsed field gel electrophoresis (PFGE) showed high heterogeneity among isolates. There is potential for pigeons to transmit antibiotic resistant pathogenic E. coli to other species through environmental contamination or direct contact. PMID- 28093117 TI - The biological prosthesis is a viable option for abdominal wall reconstruction in pediatric high risk defects. AB - BACKGROUND: Our aim was to explore the indications for and outcome of biological prostheses to repair high risk abdominal wall defects in children. METHODS: A retrospective chart review was performed of all cases of abdominal wall reconstruction in a single institution between 2007 and 2015. Demographic and clinical variables, technique and complications were described and compared between prosthesis types. RESULTS: A total of 23 patients underwent abdominal wall reconstruction using a biological prosthesis including 17 neonates. The main indication was gastroschisis (17 patients) followed by ruptured omphalocele and miscellaneous conditions. AllodermTM was most commonly used followed by SurgisisTM, StratticeTM, Flex-HDTM and PermacolTM. In 22 cases wounds were contaminated or infected. Open bowel/stomas were present in 9 cases. Skin was not closed in 11 cases. Post-operative complication rate was 30% and hernia recurrence rate was 17% after a mean follow-up time of 16 months. CONCLUSIONS: The use of a biological prosthesis may offer advantages over a synthetic mesh in pediatric high risk abdominal wall defects. The surgeon should be ready to consider its use in selected cases. PMID- 28093118 TI - Surgical Fires and Operative Burns: Lessons Learned From a 33-Year Review of Medical Litigation. AB - OBJECTIVE: We aimed to understand the setting and litigation outcomes of surgical fires and operative burns. METHODS: Westlaw, an online legal research data-set, was utilized. Data were collected on patient, procedure, and case characteristics. RESULTS: One hundred thirty-nine cases were identified; 114 (82%) operative burns and 25 (18%) surgical fires. Median plaintiff (patient) age was 46 (IQR:28-59). Most common site of operative burn was the face (26% [n = 36]). Most common source of injury was a high energy device (43% [n = 52]). Death was reported in 2 (1.4%) cases. Plaintiff age <18 vs age 18-50 and mention of a non-surgical physician as a defendant both were shown to be independently associated with an award payout (OR = 4.90 [95% CI, 1.23-25.45]; p = .02) and (OR = 4.50 [95% CI, 1.63-13.63]; p = .003) respectively. Plaintiff award payment (settlement or plaintiff verdict) was reported in 83 (60%) cases; median award payout was $215,000 (IQR: $82,000-$518,000). CONCLUSION: High energy devices remain as the most common cause of injury. Understanding and addressing pitfalls in operative care may mitigate errors and potentially lessen future liability. LEVEL OF EVIDENCE: III. PMID- 28093119 TI - Impact of minimally invasive vs. open distal pancreatectomy on use of adjuvant chemoradiation for pancreatic adenocarcinoma. AB - BACKGROUND: Published data examining the impact of minimally invasive distal pancreatectomy (MIDP) on survival are generally limited to experiences from high volume institutions. Our aim was to compare utilization of adjuvant chemoradiation and time from surgery until its initiation following MIDP vs. open surgery (ODP) at a national level. METHODS: Adult patients undergoing distal pancreatectomy for Stage I and II pancreatic adenocarcinoma were identified from the National Cancer Data Base, 2010-2012. RESULTS: A total of 1807 patients underwent distal pancreatectomy for adenocarcinoma at 506 institutions (27.9% MIDP). After adjustment, those who underwent MIDP were more likely to have complete tumor resections and a shorter hospital length of stay. Patients undergoing MIDP vs. ODP were more likely to receive adjuvant chemotherapy; time to initiation of adjuvant chemotherapy or radiation was not different between groups. After adjustment, overall survival for MIDP vs. ODP remained similar (HR 0.85, CI 0.67-1.10, p = 0.21). CONCLUSION: MIDP is associated with increased use of adjuvant chemotherapy; further study is needed to understand the etiology and impact of this association. PMID- 28093120 TI - Elucidating rhizosphere processes by mass spectrometry - A review. AB - The presented review discusses state-of-the-art mass spectrometric methods, which have been developed and applied for investigation of chemical processes in the soil-root interface, the so-called rhizosphere. Rhizosphere soil's physical and chemical characteristics are to a great extent influenced by a complex mixture of compounds released from plant roots, i.e. root exudates, which have a high impact on nutrient and trace element dynamics in the soil-root interface as well as on microbial activities or soil physico-chemical characteristics. Chemical characterization as well as accurate quantification of the compounds present in the rhizosphere is a major prerequisite for a better understanding of rhizosphere processes and requires the development and application of advanced sampling procedures in combination with highly selective and sensitive analytical techniques. During the last years, targeted and non-targeted mass spectrometry based methods have emerged and their combination with specific separation methods for various elements and compounds of a wide polarity range have been successfully applied in several studies. With this review we critically discuss the work that has been conducted within the last decade in the context of rhizosphere research and elemental or molecular mass spectrometry emphasizing different separation techniques as GC, LC and CE. Moreover, selected applications such as metal detoxification or nutrient acquisition will be discussed regarding the mass spectrometric techniques applied in studies of root exudates in plant bacteria interactions. Additionally, a more recent isotope probing technique as novel mass spectrometry based application is highlighted. PMID- 28093121 TI - Phenyltrichlorosilane-functionalized magnesium oxide microspheres: Preparation, characterization and application for the selective extraction of dioxin-like polycyclic aromatic hydrocarbons in soils with matrix solid-phase dispersion. AB - Magnesium oxide microspheres functionalized with phenyltrichlorosilane (PTS-MgO) were synthesized by surface modification through silanization reaction, which was confirmed by Fourier transform infrared (FT-IR), scanning electron microscopy (SEM), X-ray diffraction (XRD), thermogravimetry analysis (TGA) and N2 adsorption desorption. The result indicated that PTS-MgO not only possessed the ability of enhancing the retention with PAHs, but also weakening the interference from chlorinated compounds. As a sorbent for the matrix solid-phase dispersion (MSPD) extraction, PTS-MgO was used to selectively extract seven dioxin-like polycyclic aromatic hydrocarbons (DL-PAHs) from soil samples. Various parameters affecting the recoveries of seven DL-PAHs were investigated and optimized, such as sorbent/sample mass ratio, grinding time, rinsing and eluting conditions. Under the optimized conditions, the developed method combining MSPD with HPLC-FLD exhibited good sensitivity (0.02-0.12 ng g-1 detection of limits) and linearity (linear correlation coefficient greater than 0.9997). Satisfactory recoveries with DL-PAHs spiked at two levels (10 and 80 ng g-1) were obtained in the range of 72.2-113.1% with RSD < 9.6%, indicating that PTS-MgO had a potential in MSPD extraction of DL-PAHs in soils. Additionally, the proposed MSPD-HPLC-FLD method was also verified by detecting seven DL-PAHs in the standard reference soil. Based on the developed method, DL-PAHs in soil samples were detected with the concentration ranging from 70.08 to 555.05 ng g-1 dry weight (dw). The total toxic equivalency quotients (TEQ) of seven DL-PAHs varied from 9.93 to 143.94 ng TEQ/g dw. PMID- 28093122 TI - Sequential enzymatic derivatization coupled with online microdialysis sampling for simultaneous profiling of mouse tumor extracellular hydrogen peroxide, lactate, and glucose. AB - Probing tumor extracellular metabolites is a vitally important issue in current cancer biology. In this study an analytical system was constructed for the in vivo monitoring of mouse tumor extracellular hydrogen peroxide (H2O2), lactate, and glucose by means of microdialysis (MD) sampling and fluorescence determination in conjunction with a smart sequential enzymatic derivatization scheme-involving a loading sequence of fluorogenic reagent/horseradish peroxidase, microdialysate, lactate oxidase, pyruvate, and glucose oxidase-for step-by-step determination of sampled H2O2, lactate, and glucose in mouse tumor microdialysate. After optimization of the overall experimental parameters, the system's detection limit reached as low as 0.002 mM for H2O2, 0.058 mM for lactate, and 0.055 mM for glucose, based on 3 MUL of microdialysate, suggesting great potential for determining tumor extracellular concentrations of lactate and glucose. Spike analyses of offline-collected mouse tumor microdialysate and monitoring of the basal concentrations of mouse tumor extracellular H2O2, lactate, and glucose, as well as those after imparting metabolic disturbance through intra-tumor administration of a glucose solution through a prior implanted cannula, were conducted to demonstrate the system's applicability. Our results evidently indicate that hyphenation of an MD sampling device with an optimized sequential enzymatic derivatization scheme and a fluorescence spectrometer can be used successfully for multi-analyte monitoring of tumor extracellular metabolites in living animals. PMID- 28093123 TI - Synthesis of stable isotopically labeled peptides with filter-assisted enzymatic labeling for the diagnosis of hepatitis B virus infection utilizing mass spectrometry-based proteomics strategy. AB - A facile method for the preparation of stable isotopically labeled peptides was developed by means of filter-assisted tryptic 16O/18O water labeling, which could be directly applied to the determination of hepatitis B virus infection from human serum with tandem mass spectrometry. Tryptic peptides of hepatitis B surface antigen or hepatitis B e antigen from different subtypes of hepatitis B virus were synthesized with traditional solid-phase peptide synthesis as potential biomarkers. Trypsin catalyzed oxygen-18 exchange at their amidated c terminus of arginine or lysine residue. The protease catalyzed oxygen-18 to oxygen-16 back exchange reaction was eliminated due to the complete removal of trypsin by the centrifugal filter containing a thin membrane associated with molecular weight cut-off of 10 KDa. The synthetic isotopic peptides were spiked into trichloroacetic acid/acetone precipitated human serum as internal standards and were selectively detected with multiplexed parallel reaction monitoring on a hybrid quadrupole-orbitrap mass spectrometer. The limit of detection for all synthetic peptides were in the range of 0.09 fmol-1.13 fmol. The results indicated that the peptide YLWEWASVR derived from hepatitis B surface antigen was quantified approximately 200 fmol per MUl serum and may serve as a diagnostic biomarker for the detection of hepatitis B virus infected disease. PMID- 28093124 TI - The co-feature ratio, a novel method for the measurement of chromatographic and signal selectivity in LC-MS-based metabolomics. AB - Evaluation of analytical procedures, especially in regards to measuring chromatographic and signal selectivity, is highly challenging in untargeted metabolomics. The aim of this study was to suggest a new straightforward approach for a systematic examination of chromatographic and signal selectivity in LC-MS based metabolomics. By calculating the ratio between each feature and its co eluting features (the co-features), a measurement of the chromatographic selectivity (i.e. extent of co-elution) as well as the signal selectivity (e.g. amount of adduct formation) of each feature could be acquired, the co-feature ratio. This approach was used to examine possible differences in chromatographic and signal selectivity present in samples exposed to three different sample preparation procedures. The capability of the co-feature ratio was evaluated both in a classical targeted setting using isotope labelled standards as well as without standards in an untargeted setting. For the targeted analysis, several metabolites showed a skewed quantitative signal due to poor chromatographic selectivity and/or poor signal selectivity. Moreover, evaluation of the untargeted approach through multivariate analysis of the co-feature ratios demonstrated the possibility to screen for metabolites displaying poor chromatographic and/or signal selectivity characteristics. We conclude that the co-feature ratio can be a useful tool in the development and evaluation of analytical procedures in LC-MS-based metabolomics investigations. Increased selectivity through proper choice of analytical procedures may decrease the false positive and false negative discovery rate and thereby increase the validity of any metabolomic investigation. PMID- 28093125 TI - Hairpin stabilized fluorescent silver nanoclusters for quantitative detection of NAD+ and monitoring NAD+/NADH based enzymatic reactions. AB - A set of 90 mer long ssDNA candidates, with different degrees of cytosine (C levels) (% and clusters) was analyzed for their function as suitable Ag nanocluster (AgNC) nucleation scaffolds. The sequence (P4) with highest C-level (42.2%) emerged as the only candidate supporting the nucleation process as evident from its intense fluorescence peak at lambda660 nm. Shorter DNA subsets derived from P4 with only stable hairpin structures could support the AgNC formation. The secondary hairpin structures were confirmed by PAGE, and CD studies. The number of base pairs in the stem region also contributes to the stability of the hairpins. A shorter 29 mer sequence (Sub 3) (DeltaG = -1.3 kcal/mol) with 3-bp in the stem of a 7-mer loop conferred highly stable AgNC. NAD+ strongly quenched the fluorescence of Sub 3-AgNC in a concentration dependent manner. Time resolved photoluminescence studies revealed the quenching involves a combined static and dynamic interaction where the binding constant and number of binding sites for NAD+ were 0.201 L mol-1 and 3.6, respectively. A dynamic NAD+ detection range of 50-500 MUM with a limit of detection of 22.3 MUM was discerned. The NAD+ mediated quenching of AgNC was not interfered by NADH, NADP+, monovalent and divalent ions, or serum samples. The method was also used to follow alcohol dehydrogenase and lactate dehydrogenase catalyzed physiological reactions in a turn-on and turn-off assay, respectively. The proposed method with ssDNA-AgNC could therefore be extended to monitor other NAD+/NADH based enzyme catalyzed reactions in a turn-on/turn-off approach. PMID- 28093126 TI - Sensitive detection of DNA methyltransferase using the dendritic rolling circle amplification-induced fluorescence. AB - The analysis of DNA methylation and MTase activities is very important in the early clinical diagnosis of cancer, on purposes of providing insights into the mechanism of gene repression and developing novel drugs of treating methylation related diseases. Combining the dendritic rolling circle amplification and Mg2+ dependent DNAzyme with a function of catalyzing the generation of a fluorophore labeled nucleic acid acting as readout signal for the analyses, a new fluorescent method for DNA methyltransferase detection was reported. In the presence of DNA methyltransferases (MTase), the methylation-responsive sequence of double stranded DNA probe was methylated and then cleaved by the methylation-sensitive restriction endonuclease DpnI. The cleaved hybrid DNA probe then functioned as a signal primer to initiate the dendritic rolling circle amplification reaction, containing a circular DNA and a structurally tailored hairpin structure. Subsequently, the circular nucleic acid template produced a complementary sequence to the Mg2+-dependent DNAzyme and a sequence identical to the loop region of the co-added hairpin structure. At last, a fluorescence readout signal was afforded by the DNAzyme-catalyzed cleavage of a fluorophore/quencher-modified substrate. This method enabled the analysis of the target MTase with a detection limit up to 0.36 U mL-1, and a dynamic range was obtained from 1.0 to 10 U mL-1. Moreover, the proposed strategy was successfully applied in real sample assay. With this assay, the inhibitors of MTase were evaluated and screened which might be helpful for the discovery of anticancer drugs. PMID- 28093127 TI - Magnetic beads-based DNA hybridization chain reaction amplification and DNAzyme recognition for colorimetric detection of uranyl ion in seafood. AB - A novel colorimetric biosensor, which employs DNAzyme-functionalized magnetic beads (MBs) as recognition probe, enzyme-assisted catalytic oxidation of TMB (3,3',5,5'-tetramethylbenzidine sulfate) as signal and DNA hybridization chain reaction as amplification strategy, has been developed for detecting trace uranyl ion (UO22+) in seafood and aqueous environment with high sensitivity and specificity. We demonstrated that UO22+ can specifically cleave DNAzyme immobilized on MBs surface to release a short single-strand DNA (primer), and the released primer trigger DNA hybridization chain reaction to form a long one dimensional DNA concatamer on the MBs surface. The resulting long DNA concatamer could capture a large amount of HRP to generate the one UO22+-to-multiple HRP amplification effect. Upon the addition of TMB-H2O2 solution, the HRP-tagged DNA concatamer-MBs conjugates could catalyze the H2O2-mediated oxidation of TMB, and thus results in a color change from colorless to blue in solution. This provided a sensitive and selective sensing platform for the visual or colorimetric detection of UO22+. The proposed biosensor has high sensitivity and strong anti interference capability, it can be used to detect as low as 2.5 ppb (9.25 nM) of UO22+ by naked-eye observation and 0.09 ppb (0.33 nM) of UO22+ by UV-visible spectrometry with no interference of other ions and a RSD <= 6% (n = 5). With the help of this method, we have successfully determined trace UO22+ in fish muscle and river water with a recovery of 93-106%. High sensitivity and specificity, as well operation convenience, low cost and strong resistibility to the matrix, which makes our method a potential approach for the on-site detection of UO22+ in seafood and aqueous environment. PMID- 28093128 TI - Alcohol use disorders. PMID- 28093129 TI - Transplanted lives. PMID- 28093130 TI - Bespoke practice. PMID- 28093131 TI - Halfdan Mahler. PMID- 28093132 TI - Controlled-release oxycodone improves pain management after uterine artery embolisation for symptomatic fibroids. AB - AIM: To evaluate if pre- and post-procedure administration of controlled-release oxycodone (CRO) in combination with standard analgesia improves pain control and decreases the amount of required post-procedure opioids in uterine fibroid embolisation (UFE). MATERIALS AND METHODS: Between January 2009 and March 2010, 60 consecutive women were prospectively randomised in two groups for UFE: the control group, in which 30 patients underwent the standard anaesthetic procedure and the CRO group, in which 30 patients underwent the standard anaesthetic procedure with the addition of CRO. Age, pain, nausea/vomiting, fibroid volume, length of hospital stay, and use and dose of morphine received via the patient controlled analgesia (PCA) device in both groups were evaluated to compare the two methods of pain control. Fibroid volume as measured at magnetic resonance imaging (MRI) was evaluated for correlation with post-embolisation pelvic pain over a period of 24 hours. RESULTS: A significant difference was seen in the pain scores at 24 hours (p=0.029), with less pain in the CRO group. More patients from the control group required morphine (p=0.017), and at higher levels (p=0.130). Pruritus was lower in patients of the CRO group, probably because they received less morphine (p=0.029). No correlation was seen between leiomyoma volume and pain levels over 24 hours (Spearman's rho=0.02; p=0.881). Length of hospital stay was not different between the two groups. CONCLUSION: The addition of CRO to standard analgesia for UFE provides more effective analgesia, with a reduction in pain scores in 24 hours, less morphine use, and decreased side effects, mainly pruritus. PMID- 28093135 TI - Re: Population-Based Assessment of Cancer-Specific Mortality after Local Tumour Ablation or Observation for Kidney Cancer: A Competing Risks Analysis. PMID- 28093134 TI - Management of Clostridium difficile Infection in Inflammatory Bowel Disease: Expert Review from the Clinical Practice Updates Committee of the AGA Institute. AB - The purpose of this expert review is to synthesize the existing evidence on the management of Clostridium difficile infection in patients with underlying inflammatory bowel disease. The evidence reviewed in this article is a summation of relevant scientific publications, expert opinion statements, and current practice guidelines. This review is a summary of expert opinion in the field without a formal systematic review of evidence. Best Practice Advice 1: Clinicians should test patients who present with a flare of underlying inflammatory bowel disease for Clostridium difficile infection. Best Practice Advice 2: Clinicians should screen for recurrent C difficile infection if diarrhea or other symptoms of colitis persist or return after antibiotic treatment for C difficile infection. Best Practice Advice 3: Clinicians should consider treating C difficile infection in inflammatory bowel disease patients with vancomycin instead of metronidazole. Best Practice Advice 4: Clinicians strongly should consider hospitalization for close monitoring and aggressive management for inflammatory bowel disease patients with C difficile infection who have profuse diarrhea, severe abdominal pain, a markedly increased peripheral blood leukocyte count, or other evidence of sepsis. Best Practice Advice 5: Clinicians may postpone escalation of steroids and other immunosuppression agents during acute C difficile infection until therapy for C difficile infection has been initiated. However, the decision to withhold or continue immunosuppression in inflammatory bowel disease patients with C difficile infection should be individualized because there is insufficient existing robust literature on which to develop firm recommendations. Best Practice Advice 6: Clinicians should offer a referral for fecal microbiota transplantation to inflammatory bowel disease patients with recurrent C difficile infection. PMID- 28093136 TI - Re: Homogeneous T1 Hyperintense Renal Lesions with Smooth Borders: Is Contrast Enhanced MR Imaging Needed? PMID- 28093137 TI - Re: Quantitative Assessment of Solid Renal Masses by Contrast-Enhanced Ultrasound with Time-Intensity Curves: How we do it. PMID- 28093138 TI - Re: Efficacy and Safety of Axitinib in Elderly Patients with Metastatic Renal Cell Carcinoma. PMID- 28093140 TI - Re: Trends in Kidney Cancer among the Elderly in Denmark, 1980-2012. PMID- 28093139 TI - Re: Trends in Cancer of the Urinary Bladder and Urinary Tract in Elderly in Denmark, 2008-2012. PMID- 28093141 TI - Re: Utility and Significance of Ureteric Frozen Section Analysis during Radical Cystectomy. PMID- 28093142 TI - Re: Comprehensive Genomic Profiling of 295 Cases of Clinically Advanced Urothelial Carcinoma of the Urinary Bladder Reveals a High Frequency of Clinically Relevant Genomic Alterations. PMID- 28093143 TI - Re: Predictive Parameters of Symptomatic Hematochezia following 5-Fraction Gantry Based SABR in Prostate Cancer. PMID- 28093144 TI - Re: Study of Testosterone-Guided Androgen Deprivation Therapy in Management of Prostate Cancer. PMID- 28093145 TI - Re: Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. PMID- 28093146 TI - Re: Magnetic Resonance Imaging-Ultrasound Fusion Biopsy during Prostate Cancer Active Surveillance. PMID- 28093147 TI - Re: Urologist-Level Correlation in the Use of Observation for Low- and High-Risk Prostate Cancer. PMID- 28093148 TI - Re: The Metabolic Co-Regulator PGC1alpha Suppresses Prostate Cancer Metastasis. PMID- 28093149 TI - Re: Late Relapses in Stage I Testicular Cancer Patients on Surveillance. PMID- 28093150 TI - Re: Inhibition of the Hexosamine Biosynthetic Pathway Promotes Castration Resistant Prostate Cancer. PMID- 28093151 TI - Re: DaPeCa-1: Diagnostic Accuracy of Sentinel Lymph Node Biopsy in 222 Patients with Penile Cancer at Four Tertiary Referral Centres-A National Study from Denmark. PMID- 28093152 TI - Re: N-Glycosylation Critically Regulates Function of Oxalate Transporter SLC26A6. PMID- 28093153 TI - Re: Molecular Modifiers Reveal a Mechanism of Pathological Crystal Growth Inhibition. PMID- 28093154 TI - Re: Patients Attending Shared Medical Appointments for Metabolic Stone Prevention have Decreased Stone Risk Factors. PMID- 28093155 TI - Re: Response of Germ-Free Mice to Colonization with O. formigenes and Altered Schaedler Flora. PMID- 28093156 TI - Re: Conservative Therapy is an Effective Option in Patients with Localized Infection after Penile Implant Surgery. PMID- 28093157 TI - Re: Evidence-Based Management Guidelines on Peyronie's Disease. PMID- 28093158 TI - Re: Robotic-Assisted Laparoscopic Pyeloplasty: Analysis of Symptomatic Patients with Equivocal Renal Scans. PMID- 28093159 TI - Re: Reoperation Rates for Penile Prosthetic Surgery. PMID- 28093160 TI - Re: Successful Outcomes in Robot-Assisted Laparoscopic Pyeloplasty Using a Unidirectional Barbed Suture. PMID- 28093161 TI - Re: Perioperative Events and Complications in Minimally Invasive Live Donor Nephrectomy: A Systematic Review and Meta-Analysis. PMID- 28093162 TI - Re: Affective Symptoms and the Overactive Bladder-A Systematic Review. PMID- 28093163 TI - Re: Adolescent Urology and Transitional Care. PMID- 28093164 TI - Re: Trends in Mesh Use for Pelvic Organ Prolapse Repair from the Medicare Database. PMID- 28093165 TI - Re: Pelvic Organ Prolapse Surgery in Academic Female Pelvic Medicine and Reconstructive Surgery Urology Practice in the Setting of the Food and Drug Administration Public Health Notifications. PMID- 28093166 TI - Re: Comparison of the Effects of beta3-Adrenoceptor Agonism on Urinary Bladder Function on Conscious, Anesthetized, and Spinal Cord Injured Rats. PMID- 28093167 TI - Re: Retrograde Transport of Radiolabelled Botulinum Neurotoxin Type A to the CNS after Intradetrusor Injection in Rats. PMID- 28093168 TI - Re: Drug Adherence and Clinical Outcomes for Patients under Pharmacological Therapy for Lower Urinary Tract Symptoms Related to Benign Prostatic Hyperplasia: Population-Based Cohort Study. PMID- 28093169 TI - Re: Prospective, Randomized, Multinational Study of Prostatic Urethral Lift versus Transurethral Resection of the Prostate: 12-Month Results from the BPH6 Study. PMID- 28093170 TI - Re: Effects of Mediterranean Diet on Sexual Function in People with Newly Diagnosed Type 2 Diabetes: The MEDITA Trial. PMID- 28093171 TI - Re: Sex and Intimacy after Stroke. PMID- 28093172 TI - Re: Lifestyle Factors and Premature Ejaculation: Are Physical Exercise, Alcohol Consumption, and Body Mass Index Associated with Premature Ejaculation and Comorbid Erectile Problems? PMID- 28093173 TI - Re: Is Risk of Artificial Urethral Sphincter Cuff Erosion Higher in Patients with Penile Prosthesis? PMID- 28093174 TI - Re: Preserved Erectile Function in the Aged Transgenic Rat Harboring Human Tissue Kallikrein 1. PMID- 28093175 TI - Re: Treatment of Diabetes Mellitus-Induced Erectile Dysfunction Using Endothelial Progenitor Cells Genetically Modified with Human Telomerase Reverse Transcriptase. PMID- 28093176 TI - Re: Effects of Testosterone Treatment in Older Men. PMID- 28093178 TI - Re: One Uterus Bridging Three Generations: First Live Birth after Mother-to Daughter Uterus Transplantation. PMID- 28093177 TI - Re: Testosterone Treatment and Sexual Function in Older Men with Low Testosterone Levels. PMID- 28093179 TI - Re: Bioengineered Uterine Tissue Supports Pregnancy in a Rat Model. PMID- 28093180 TI - Re: Emoting Infertility Online: A Qualitative Analysis of Men's Forum Posts. PMID- 28093181 TI - Re: Inequity between Male and Female Coverage in State Infertility Laws. PMID- 28093182 TI - Re: Can IVF Influence Human Evolution? PMID- 28093183 TI - Re: Congenital Infundibulopelvic Stenosis: Indications for Intervention, Surgical Technique, and Review of Literature. PMID- 28093184 TI - Re: Early Mercaptoacetyltriglycine (MAG-3) Diuretic Renography Results after Pyeloplasty. PMID- 28093185 TI - Re: Anuria Since Birth: Does it Impact Outcome of Kidney Transplant in Infants? PMID- 28093186 TI - Re: Reoperative Robotic Pyeloplasty in Children. PMID- 28093187 TI - Re: Do Overweight and Obese Pediatric Stone Formers Have Differences in Metabolic Abnormalities Compared with Normal-Weight Stone Formers? PMID- 28093189 TI - Advancing High-Value Health Care: A New AJM Column Dedicated to Cost-Conscious Care Quality Improvement. PMID- 28093190 TI - Ghrelin fibers from lateral hypothalamus project to nucleus tractus solitaries and are involved in gastric motility regulation in cisplatin-treated rats. AB - Ghrelin can alleviate cancer chemotherapy-induced dyspepsia in rodents, though the neural mechanisms involved are not known. Therefore, ghrelin projections from the lateral hypothalamus (LH) and its involvement in the regulation of gastric motility in cisplatin-treated rats were investigated with a multi-disciplined approach. Retrograde tracing combined with fluoro-immunohistochemical staining were used to investigate ghrelin fiber projections arising from LH and projecting to nucleus tractus solitaries (NTS). Results revealed that ghrelin fibers originating in LH project to NTS. Expression of ghrelin and its receptor growth hormone secretagogue receptor (GHS-R1a) in LH and NTS were detected by Western Blot. 2days after cisplatin dosing, expression of ghrelin in LH decreased while GHS-R1a in both LH and NTS increased. In electrophysiological experiments, the effects of N-methyl-d-aspartate (NMDA) microinjection in LH on neuronal discharge of gastric distension-responsive neurons in NTS and gastric motility were assessed. NMDA in LH excited most of ghrelin-responsive gastric distension (GD) sensitive neurons in NTS and promoted gastric motility. This effect was partially blocked by ghrelin antibody in NTS. Furthermore, the excitatory effects of NMDA in cisplatin-treated rats were weaker than those in saline-treated rats. Behaviorally, cisplatin induced a significant increase of kaolin consumption and decrease of food intake. These studies reveal a decreased expression of ghrelin in LH and up-regulation of GHS-R1a in LH and NTS, which are involved in the regulation of GD neuronal discharge in NTS and gastric motility. PMID- 28093191 TI - RE: Galen Wagner, another perspective. PMID- 28093192 TI - Spectrum of mutations in leiomyosarcomas identified by clinical targeted next generation sequencing. AB - Recurrent genomic mutations in uterine and non-uterine leiomyosarcomas have not been well established. Using a next generation sequencing (NGS) panel of common cancer-associated genes, 25 leiomyosarcomas arising from multiple sites were examined to explore genetic alterations, including single nucleotide variants (SNV), small insertions/deletions (indels), and copy number alterations (CNA). Sequencing showed 86 non-synonymous, coding region somatic variants within 151 gene targets in 21 cases, with a mean of 4.1 variants per case; 4 cases had no putative mutations in the panel of genes assayed. The most frequently altered genes were TP53 (36%), ATM and ATRX (16%), and EGFR and RB1 (12%). CNA were identified in 85% of cases, with the most frequent copy number losses observed in chromosomes 10 and 13 including PTEN and RB1; the most frequent gains were seen in chromosomes 7 and 17. Our data show that deletions in canonical cancer-related genes are common in leiomyosarcomas. Further, the spectrum of gene mutations observed shows that defects in DNA repair and chromosomal maintenance are central to the biology of leiomyosarcomas, and that activating mutations observed in other common cancer types are rare in leiomyosarcomas. PMID- 28093193 TI - HBXIP over expression as an independent biomarker for cervical cancer. AB - BACKGROUND: Emerging evidence demonstrated that hepatitis B virus X-interacting protein (HBXIP) has broad roles in cancers. However, high-level expression of HBXIP has been correlated with human malignancies, suggesting roles in carcinogenesis and tumor progression. The aim of the study is to investigate the role and mechanism of HBXIP oncogene and the correlation to the clinicopathological status in cervical cancers. METHODS: A total of 107 cervical cancer patients with strict follow-up, 105 cervical intraepithelial neoplasia (CIN) and 31 normal cervical epithelia samples were selected for immunohistochemical (IHC) staining of HBXIP protein. Additionally, the cervical cancer cell line of SiHa was included in this study. The relationship between HBXIP expression and clinicopathological characteristics were analyzed to verify the clinical value of HBXIP protein expression in patient prognosis, and survival rates were calculated using the Kaplan-Meier method. RESULTS: HBXIP protein showed a mainly cytoplasmic staining pattern in cervical cancers by using IHC staining in paraffin embedded cervical cancer tissues and IF staining in SiHa cervical cancer cells. The strongly positive rate of HBXIP protein expression was significantly higher in cervical SCCs and CINs than in normal cervical epithelia. HBXIP protein over-expression was significantly correlated with the clinical stage, differentiation, lymph node metastasis, HPV infection, the over-expression of P63 and overall survival rates in cervical cancer. All of these data defined that HBXIP was involved in the progression of the cervical cancer. However, the detailed mechanism need to the further study. CONCLUSIONS: HBXIP over-expression appears to associate with cervical cancer progression, and may potentially be used as a cervical cancer biomarker for the early diagnosis, prognostic evaluation and therapeutic target for cervical cancer. PMID- 28093194 TI - Effects of Neuromuscular Electrical Stimulation During Hemodialysis on Peripheral Muscle Strength and Exercise Capacity: A Randomized Clinical Trial. AB - OBJECTIVE: To evaluate the effects of neuromuscular electrical stimulation of high and low frequency and intensity, performed during hemodialysis, on physical function and inflammation markers in patients with chronic kidney disease (CKD). DESIGN: Randomized clinical trial. SETTING: Hemodialysis clinic. PARTICIPANTS: Patients with CKD (N=51) were randomized into blocks of 4 using opaque sealed envelopes. They were divided into a group of high frequency and intensity neuromuscular electrical stimulation and a group of low frequency and intensity neuromuscular electrical stimulation. INTERVENTIONS: The high frequency and intensity neuromuscular electrical stimulation group was submitted to neuromuscular electrical stimulation at a frequency of 50Hz and a medium intensity of 72.90mA, and the low frequency and intensity neuromuscular electrical stimulation group used a frequency of 5Hz and a medium intensity of 13.85mA, 3 times per week for 1 hour, during 12 sessions. MAIN OUTCOME MEASURES: Peripheral muscle strength, exercise capacity, levels of muscle trophism marker (insulin growth factor 1) and levels of proinflammatory (tumor necrosis factor alpha) and anti-inflammatory (interleukin 10) cytokines. RESULTS: The high frequency and intensity neuromuscular electrical stimulation group showed a significant increase in right peripheral muscle strength (155.35+/-65.32Nm initial vs 161.60+/-68.73Nm final; P=.01) and left peripheral muscle strength (156.60+/-66.51Nm initial vs 164.10+/-69.76Nm final; P=.02) after the training, which did not occur in the low frequency and intensity neuromuscular electrical stimulation group for both right muscle strength (109.40+/-32.08Nm initial vs 112.65+/-38.44Nm final; P=.50) and left muscle strength (113.65+/-37.79Nm initial vs 116.15+/-43.01Nm final; P=.61). The 6-minute walk test distance (6MWTD) increased in both groups: high frequency and intensity neuromuscular electrical stimulation group (435.55+/-95.81m initial vs 457.25+/-90.64m final; P=.02) and low frequency and intensity neuromuscular electrical stimulation group (403.80+/ 90.56m initial vs 428.90+/-87.42m final; P=.007). The groups did not differ in peripheral muscle strength and 6MWTD after the training protocol. In the high frequency and intensity neuromuscular electrical stimulation group, a correlation was observed between the initial and final values of 6MWTD and muscle strength. In the low frequency and intensity neuromuscular electrical stimulation group, correlations occurred only between the 6MWTD and the initial muscle strength. Only the low frequency and intensity neuromuscular electrical stimulation group increased levels of insulin growth factor 1 (252.38+/-156.35pg/mL initial vs 336.97+/-207.34pg/mL final; P=.03), and only the high frequency and intensity neuromuscular electrical stimulation group reduced levels of interleukin 10 (7.26+/-1.81pg/mL vs 6.32+/-1.54pg/mL; P=.03). The groups showed no differences in tumor necrosis factor alpha levels. CONCLUSIONS: Patients with CKD on hemodialysis improve exercise capacity after peripheral neuromuscular electrical stimulation of high and low frequency and intensity. However, the benefits on muscle and inflammatory outcomes seem to be specific for the adopted electrical stimulation strategy. PMID- 28093195 TI - Health and functioning of adolescents conceived by assisted reproductive technology. AB - OBJECTIVE: To evaluate the general health, mental health, and cognitive ability of assisted reproductive technology (ART)-conceived adolescents. DESIGN: A nested case-control study within a historic cohort. SETTING: Not applicable. PATIENT(S): A total of 253 ART-conceived adolescents born between 1982 and 1993 and 253 matched references according to birth year, gender, and the high-school they attended. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Medical and psychiatric diagnoses, and cognitive ability recorded at the military preinduction screening (ages 16-17 years) and doctor's appointments throughout the military service. RESULT(S): No differences were detected in general and mental health of ART adolescents or cognitive ability, compared with the reference group. Similar results were obtained after stratification for gender and singleton births. The ART adolescents had fewer cases of discharge from military service due to health reasons (4% vs. 8.3%). Follow-up during the military service revealed that male ART adolescents had significantly more doctor's appointments compared with the reference group (23.80 +/- 15.59 vs. 19.95 +/- 13.79). CONCLUSION(S): Our preliminary results provide reassurance that in the long-run health and functioning of ART-conceived adolescents is not compromised. Further studies with larger cohorts are needed to confirm these results. PMID- 28093196 TI - A prospective single centre pilot evaluation of a serum calprotectin assay in unselected GI patients. AB - BACKGROUND: Whilst C-reactive protein (CRP) is an established serum marker of inflammation, its use in gastroenterology has been limited by its poor sensitivity and specificity for GI disease. Faecal calprotectin (FC) has been adopted into mainstream GI practice as a sensitive but non-specific marker of intestinal inflammation. However, stool samples collection for FC can be challenging and the possibility of utilising a sensitive and specific serum biomarker of intestinal inflammation in luminal gastroenterology is an attractive prospect. This work investigates the performance of serum calprotectin (SC) compared to current biomarkers, FC and CRP, in an unselected cohort of patients attending our GI unit. METHODS: Patients attending in and outpatients within an adult GI service who submitted a stool sample for FC analysis were identified. A total of 109 who had a serum sample obtained within one day of stool sample collection had the serum analysed for CRP and SC and the correlation between these biomarkers was investigated. RESULTS: The intraclass correlation coefficient (ICC) between SC, FC and CRP was 0.10, 95% CI -0.09-0.28 and 0.18, 95% CI -0.01-0.35, respectively. The ICC between FC and CRP was 0.18, 95% CI 0.01-0.35. CONCLUSIONS: Our data reveals that there is no significant correlation between SC and FC, nor between SC and CRP in a large unselected cohort of GI patients. Therefore, as a serum biomarker for intestinal inflammation, SC is unlikely to be of clinical utility and the search for an appropriate serum GI biomarker continues. PMID- 28093197 TI - Influence of the bacterial growth phase on the magnetic properties of magnetosomes synthesized by Magnetospirillum gryphiswaldense. AB - BACKGROUND: The magnetosome biosynthesis is a genetically controlled process but the physical properties of the magnetosomes can be slightly tuned by modifying the bacterial growth conditions. METHODS: We designed two time-resolved experiments in which iron-starved bacteria at the mid-logarithmic phase are transferred to Fe-supplemented medium to induce the magnetosomes biogenesis along the exponential growth or at the stationary phase. We used flow cytometry to determine the cell concentration, transmission electron microscopy to image the magnetosomes, DC and AC magnetometry methods for the magnetic characterization, and X-ray absorption spectroscopy to analyze the magnetosome structure. RESULTS: When the magnetosomes synthesis occurs during the exponential growth phase, they reach larger sizes and higher monodispersity, displaying a stoichiometric magnetite structure, as fingerprinted by the well defined Verwey temperature. On the contrary, the magnetosomes synthesized at the stationary phase reach smaller sizes and display a smeared Verwey transition, that suggests that these magnetosomes may deviate slightly from the perfect stoichiometry. CONCLUSIONS: Magnetosomes magnetically closer to stoichiometric magnetite are obtained when bacteria start synthesizing them at the exponential growth phase rather than at the stationary phase. GENERAL SIGNIFICANCE: The growth conditions influence the final properties of the biosynthesized magnetosomes. This article is part of a Special Issue entitled "Recent Advances in Bionanomaterials" Guest Editors: Dr. Marie-Louise Saboungi and Dr. Samuel D. Bader. PMID- 28093198 TI - Mild hypothermia pretreatment protects hepatocytes against ischemia reperfusion injury via down-regulating miR-122 and IGF-1R/AKT pathway. AB - BACKGROUND: Mild hypothermia has been well known as an effective way to reduce ischemia reperfusion injury (IRI), while the mechanisms are still unclear. More and more evidences have indicated that miRNAs should been involved in the regulation of IRI and expecially some miRNAs have shown temp-responsiveness for temperature variation. Therefore, the role of miR-122 in mild hypothermia pretreatment after IRI was investigated. METHODS: We established a LO2 cell anoxia-reoxygenation injury model to simulate liver IRI. Five groups of differently pretreated L02 cells were studied. ALT, AST and LDH as well as cell viability were measured. Flow cytometric analysis was used to evaluate the apoptosis. The expression of miR-122 was quantified by qRT-PCR. Insulin-like growth factor 1 receptor (IGF-1R), protein kinase B (p-AKT), AKT, forkhead box O3a (p-FOXO3a) and Caspase3 were examined using western blot analysis. RESULTS: We found that mild hypothermia pretreatment could reduce the hepatocellular injury and induce a significant down-regulation in miR-122 expression after IRI. However, those effects of protection were attenuated by overexpressed miR-122 blockade. We further demonstrated that down-regulation of miR-122 promoted IGF-1R translation and AKT activity, suppressed FOXO3a activity and Caspase3 expression after mild hypothermia pretreatment, which was abrogated by miR-122 mimic. CONCLUSION: Our data clearly demonstrate that mild hypothermia pretreatment can down-regulate miR-122 to protect hepatocytes against IRI through activation IGF 1R/AKT signaling pathway and inhibit cells apoptosis. PMID- 28093199 TI - Effect of different cryo-devices on in vitro maturation and development of vitrified-warmed immature buffalo oocytes. AB - The aim of the study was to identify a cryo-device that would be best suited for the vitrification of buffalo immature cumulus-oocyte complexes (COCs) as judged by viability and meiotic competence of the vitrified-warmed oocytes and their development ability following in vitro fertilization (IVF). The expression of oocyte secreting factors and their receptors (GDF9, BMP15, BMPR2, TGFBR1) and apoptosis related genes (BCL2, BAX, P53, C-MYC) were compared in vitrified-warmed oocytes after in vitro maturation. COCs from the ovaries of slaughtered buffaloes were vitrified in a combination of dimethyl sulfoxide, ethylene glycol, and sucrose using either a conventional straw (CS), open pulled straw (OPS), cryoloop (CL), hemistraw (HS) or cryotop (CT). The fresh COCs were exposed to vitrification and warming solutions as in other vitrification methods without plunging in to liquid nitrogen (EC). The viability of vitrified-warmed COCs, 2 h post warming in HS and CT was similar to fresh and EC groups but significantly higher than CS and OPS methods. The proportions of oocytes with first polar body after 24 h in vitro maturation were significantly higher in HS and CT methods than in CS, OPS and CL methods. The development ability of these vitrified-warmed oocytes to blastocyst stage following IVF in all vitrified groups was significantly lower than control and EC groups. Among the vitrified groups, the blastocyst rate in HS, CT and CL groups was significantly higher than in OPS and CS groups. It was also observed that the expression levels of GDF9, BMP15, BMPR2, TGFBR1, BCL2, BAX, P53 and C-MYC genes in vitrified-warmed COCs in CT, HS and CL groups were similar to control. The results indicated that HS, CT and CL are more suitable cryo-devices for vitrification of buffalo immature oocytes. PMID- 28093200 TI - Postoperative serum thioredoxin concentrations correlate with delirium and cognitive dysfunction after hip fracture surgery in elderly patients. AB - BACKGROUND: Oxidative stress correlates with occurrence and development of postoperative delirium (POD) and cognitive dysfunction (POCD). Thioredoxin (TRX) is a potent anti-oxidant and its circulating concentrations reflect extent of brain injury. We determined the relation of serum TRX concentrations to POD and POCD in elderly patients undergoing hip fracture surgery. METHODS: In this prospective, observatory study, TRX concentrations in preoperative and postoperative serum from 192 patients and serum from 192 controls were measured using an enzyme-linked immunosorbent assay. The relationship between TRX concentrations and risk of POD and POCD was assessed using a multivariate analysis. RESULTS: As compared to the controls, postoperative, but not preoperative serum TRX concentrations were significantly increased in the patients. Furthermore, postoperative TRX concentrations and age were identified as the independent predictors for POD and POCD. Also, area under receiver operating characteristic curve (AUC) of postoperative TRX concentrations was obviously higher than that of age in the prediction of POD and POCD. Additionally, in a combined logistic-regression model, TRX concentrations significantly improved the AUCs of age to predict POD and POCD. CONCLUSIONS: TRX in postoperative serum may be a potential biomarker to predict POD and POCD in elder patients undergoing hip fracture surgery. PMID- 28093201 TI - Molecular targets of the Warburg effect and inflammatory cytokines in the pathogenesis of pulmonary artery hypertension. AB - Pulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by increased pulmonary arterial pressure and vasoconstriction and structural remolding of pulmonary arterioles. Recent clinical and experimental studies have discovered the relationship between metabolic alterations and the pathogenesis of PAH. The primary metabolic alteration, previously demonstrated in various cancers, is a gradual change in energy generated from complete aerobic cellular respiration to from solely "aerobic glycolysis," termed the "Warburg effect." Understanding the Warburg effect of metabolic dysregulation and its interaction with inflammatory mechanisms in the pathogenesis of PAH has provided a valuable explanation of this disease and has guided formulation of new clinical treatments at the molecular level. PMID- 28093202 TI - Sensorless Hinfinity speed-tracking synthesis for surface-mount permanent magnet synchronous motor. AB - In this paper, a sensorless speed tracking control is proposed for a surface mount permanent magnet synchronous motor by using a nonlinear Hinfinity controller via stator currents measurements for feedback. An output feedback nonlinear Hinfinity-controller was designed such that the undisturbed system is uniformly asymptotically stable around the desired speed reference, while also the effects of external vanishing and non-vanishing disturbances, noise, and input backlash were attenuated locally. The rotor position was calculated from the causal dynamic output feedback compensator and from the desired speed reference. The existence of the proper solutions of the perturbed differential Riccati equations ensures stabilizability and detectability of the control system. The efficiency of the proposed sensorless controller was supported by numerical simulations. PMID- 28093203 TI - A compound scheme on parameters identification and adaptive compensation of nonlinear friction disturbance for the aerial inertially stabilized platform. AB - A compound scheme is proposed to compensate the effect of nonlinear friction disturbance on the control precision of a three-axis inertially stabilized platform (ISP) for aerial remote sensing applications. The scheme consists of friction parameters identification and adaptive compensation. A LuGre model-based ISP friction model is first developed. Then, a comprehensive experimental scheme is proposed to obtain the static friction parameters. Further, the dynamic parameters are identified by experiments and dynamic optimization. On the basis of identified parameters and Lyapunov stability theory, a backstepping integral adaptive compensator is designed to compensate the nonlinear friction disturbance. Simulations and experiments are carried out to validate the scheme. The results show that the compound scheme can accurately obtain the friction parameters and improve the control precision and stability of ISP. PMID- 28093204 TI - Chin Symphysis Bone, Allograft, and Platelet-Rich Fibrin: Is the Combination Effective in Repair of Alveolar Cleft? AB - PURPOSE: Secondary grafting of alveolar defects with iliac crest bone is a common treatment method in cleft patients. The aim of this study was to evaluate the effectiveness of the combination of symphysis bone, allograft, and platelet-rich fibrin in regeneration of alveolar defects compared with iliac bone graft. MATERIALS AND METHODS: In this randomized clinical trial, patients with unilateral alveolar defects were divided randomly into two categories. Group A comprised patients in whom the combination of chin symphysis bone plus allogeneic bone material plus leukocyte- and platelet-rich fibrin was considered for treatment. Group B comprised patients in whom iliac bone graft was considered. Cone beam computed tomography before treatment and 1 year postoperatively was used for measurement of bone formation (bone volume in cubic centimeters). The data were analyzed by paired t and chi2 tests via SPSS software (version 23; IBM, Armonk, NY). P < .05 was considered significant. RESULTS: Each group included 10 patients (with 6 male patients in group A and 5 male patients in group B). The mean age of patients in groups A and B was 9.5 +/- 1.5 years and 9.9 +/- 1.9 years, respectively. The mean volume of alveolar defects was 0.89 +/- 0.29 cm3 in group A and 0.95 +/- 0.27 cm3 in group B. The percentage of bone regeneration in groups A and B was 69.5% and 73.8%, respectively. CONCLUSIONS: It seems that chin symphysis bone plus allogeneic bone material plus platelet-rich fibrin is a proper combination for bone regeneration in alveolar defects with a small to moderate volume range. PMID- 28093205 TI - Characterization of peak capacity of microbore liquid chromatography columns using gradient kinetic plots. AB - The performance of micro-liquid chromatography columns with an inner diameter of 0.3mm was investigated on a dedicated micro-LC system for gradient elution. Core shell as well as fully porous particle packed columns were compared on the basis of peak capacity and gradient kinetic plot limits. The results for peak capacity showed the superior performance of columns packed with sub-2MUm fully porous particles compared to 3.0MUm fully porous and 2.7MUm core-shell particles within a range of different gradient time to column void time ratios. For ultra-fast chromatography a maximum peak capacity of 16 can be obtained using a 30s gradient for the sub-2MUm fully porous particle packed column. A maximum peak capacity of 121 can be achieved using a 5min gradient. In addition, the influence of an alternative detector cell on the basis of optical waveguide technology and contributing less to system variance was investigated showing an increased peak capacity for all applied gradient time/column void time ratios. Finally, the influence of pressure was evaluated indicating increased peak capacity for maximum performance whereas a limited benefit for ultra-fast chromatography with gradient times below 30s was observed. PMID- 28093206 TI - Urea-formaldehyde monolithic column for hydrophilic in-tube solid-phase microextraction of aminoglycosides. AB - A novel urea-formaldehyde (UF) monolithic column has been developed and exploited as a sorbent for hydrophilic in-tube solid-phase microextraction (in-tube SPME) of aminoglycosides (AGs). Because of the innate hydrophilicity, UF monolith showed high extraction efficiency towards these hydrophilic analytes. The adsorption capacities for target compounds dissolved in water/ACN (1:1, v/v) were in the range of 5.18-7.36MUg/cm. Due to the lack of a chromophore, evaporative light scattering detector (ELSD) was selected as the detector for AGs, and coupled with the online in-tube SPME-HPLC system. Several factors of the online system, such as trifluoroacetic acid (TFA) and ACN percentage in the sampling solution, ionic strength in the sample solution, elution volume, sampling and elution flow rate, were optimized with respect to the extraction efficiencies. Under the optimized conditions, the limits of detection (LODs) of streptomycin, tobramycin and neomycin were discovered in the range of 3.0-5.2MUg/kg. The recoveries were ranged from 82.1 to 96.7% with relative standard deviations (RSDs) of 2.3-5.1% (n=4) at spiking levels of 50, 200 and 500MUg/kg, respectively. The excellent applicability of the UF monolithic column was examined by the determination of streptomycin in practical tilapia samples, which showed the potential advantages for the analysis of polar analytes in complicated samples. PMID- 28093207 TI - p53 mediates the suppression of cancer cell invasion by inducing LIMA1/EPLIN. AB - The tumor suppressor gene p53 is frequently mutated in human cancer. p53 executes various functions, such as apoptosis induction and cell cycle arrest, by modulating transcriptional regulation. In this study, LIM domain and Actin binding protein 1 (LIMA1) was identified as a target of the p53 family using a cDNA microarray. We also evaluated genome-wide occupancy of the p53 protein by performing chromatin immunoprecipitation-sequencing (ChIP-seq) and identified two p53 response elements in the LIMA1 gene. LIMA1 protein levels were increased by treatment with nutlin-3a, a small molecule that activates endogenous p53. In addition, LIMA1 expression was significantly downregulated in cancers compared with normal tissues. Knockdown of LIMA1 significantly enhanced cancer cell invasion and partially inhibited p53-induced suppression of cell invasion. Furthermore, low expression of LIMA1 in cancer patients correlated with decreased survival and poor prognosis. Thus, p53-induced LIMA1 inhibits cell invasion, and the downregulation of LIMA1 caused by p53 mutation results in decreased survival in cancer patients. Collectively, this study reveals the molecular mechanism of LIMA1 downregulation in various cancers and suggests that LIMA1 may be a novel prognostic predictor and a therapeutic target for cancer. PMID- 28093209 TI - Combinatorial effect of Bacillus amyloliquefaciens AG1 biosurfactant and Bacillus thuringiensis Vip3Aa16 toxin on Spodoptera littoralis larvae. AB - Spodoptera littoralis, one of the most serious and destructive agricultural pests in the world, is very susceptible to Vip3 toxin. In order to develop a new efficient bioinsecticide and to prevent the development of resistance by the target pest, insecticidal activity of biosurfactant produced by Bacillus amyloliquefaciens AG1 was evaluated against S. littoralis. Bioassays revealed the susceptibility of the first instar larvae of this pest to AG1 biosurfactant with an LC50 of 245ng/cm2. Moreover, the histopathology examination of the larval midgut treated by AG1 biosurfactant showed vacuolization, necrosis and disintegration of the basement membrane. Binding experiments revealed that the AG1 biosurfactant recognized three putative receptors located in the brush border membrane vesicles of S. littoralis with sizes of 91, 72 and 64kDa. Competition assays using biotinylated metabolites indicated that AG1 biosurfactant and Vip3Aa16 toxin did not compete for the same S. littoralis receptors. When combined, AG1 biosurfactant and Vip3Aa16 showed an additive effect against S. littoralis larvae. These findings suggested that B. amyloliquefaciens AG1 biosurfactant could be a promising biocontrol agent to eradicate S. littoralis and to prevent resistance development by this pest. PMID- 28093208 TI - Selective reporting of antibiotic susceptibility test results in European countries: an ESCMID cross-sectional survey. AB - Selective reporting of antibiotic susceptibility test (AST) results is one possible laboratory-based antibiotic stewardship intervention. The primary aim of this study was to identify where and how selective reporting of AST results is implemented in Europe both in inpatient and in outpatient settings. An ESCMID cross-sectional, self-administered, internet-based survey was conducted among all EUCIC (European Committee on Infection Control) or EUCAST (European Committee on Antimicrobial Susceptibility Testing) national representatives in Europe and Israel. Of 38 countries, 36 chose to participate in the survey. Selective reporting of AST results was implemented in 11/36 countries (31%), was partially implemented in 4/36 (11%) and was limited to local initiatives or was not adopted in 21/36 (58%). It was endorsed as standard of care by health authorities in only three countries. The organisation of selective reporting was everywhere discretionally managed by each laboratory, with a pronounced intra- and inter country variability. The most frequent application was in uncomplicated community acquired infections, particularly urinary tract and skin and soft-tissue infections. The list of reported antibiotics ranged from a few first-line options, to longer reports where only last-resort antibiotics were hidden. Several barriers to implementation were reported, mainly lack of guidelines, poor system support, insufficient resources, and lack of professionals' capability. In conclusion, selective reporting of AST results is poorly implemented in Europe and is applied with a huge heterogeneity of practices. Development of an international framework, based on existing initiatives and identified barriers, could favour its dissemination as one important element of antibiotic stewardship programmes. PMID- 28093210 TI - Neuroprotection by Paeoniflorin in the MPTP mouse model of Parkinson's disease. AB - Paeoniflorin (PF) is a major bioactive ingredient in Radix Paeonia alba roots that has low toxicity and has been shown to have neuroprotective effects. Our in vitro experiments suggested that PF affords a significant neuroprotective effect against MPP+-induced damage and apoptosis in PC12 cells through Bcl-2/Bax/caspase 3 pathway. The objectives of the present study were to explore the potential neuroprotective effect of PF in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson's disease (PD). Our results demonstrated that PF treatment ameliorated the behavioral deficits of "in spontaneous motor activity and latency to fall of the rotarod test", and reduced dopaminergic cell loss that were induced by MPTP in a dose-dependent manner in an in vivo model of PD. In addition, we found that treatment of PF protected dopaminergic neurons by preventing MPTP-induced decreases in striatal and substantia nigra dopaminergic transporter (DAT) and tyrosine hydroxylase (TH) protein levels, and by changing dopamine catabolism and inhibiting dopamine turnover. Furthermore, it was also associated with up-regulation of the Bcl-2/BAD ratio, and inhibition of the activation of caspase-9 and caspase-3. These results showed that PF promoted dopamine neuron survival in vivo due to the MAO-B inhibition, and the PI3K/Akt signaling pathway may have mediated the protection of PF against MPTP, suggesting that PF treatment might represent a neuroprotective treatment for PD. PMID- 28093211 TI - Pharmacological properties of SAK3, a novel T-type voltage-gated Ca2+ channel enhancer. AB - T-type voltage-gated Ca2+ channels (T-VGCCs) function in the pathophysiology of epilepsy, pain and sleep. However, their role in cognitive function remains unclear. We previously reported that the cognitive enhancer ST101, which stimulates T-VGCCs in rat cortical slices, was a potential Alzheimer's disease therapeutic. Here, we introduce a more potent T-VGCC enhancer, SAK3 (ethyl 8' methyl-2',4-dioxo-2-(piperidin-1-yl)-2'H-spiro[cyclopentane-1,3'-imidazo [1,2 a]pyridin]-2-ene-3-carboxylate), and characterize its pharmacological properties in brain. Based on whole cell patch-clamp analysis, SAK3 (0.01-10 nM) significantly enhanced Cav3.1 currents in neuro2A cells ectopically expressing Cav3.1. SAK3 (0.1-10 nM nM) also enhanced Cav3.3 but not Cav3.2 currents in the transfected cells. Notably, Cav3.1 and Cav3.3 T-VGCCs were localized in cholinergic neurve systems in hippocampus and in the medial septum. Indeed, acute oral administration of SAK3 (0.5 mg/kg, p.o.), but not ST101 (0.5 mg/kg, p.o.) significantly enhanced acetylcholine (ACh) release in the hippocampal CA1 region of naive mice. Moreover, acute SAK3 (0.5 mg/kg, p.o.) administration significantly enhanced hippocampal ACh levels in olfactory-bulbectomized (OBX) mice, rescuing impaired memory-related behaviors. Treatment of OBX mice with the T-VGCC-specific blocker NNC 55-0396 (12.5 mg/kg, i.p.) antagonized both enhanced ACh release and memory improvements elicited by SAK3 administration. We also observed that SAK3-induced ACh releases were significantly blocked in the hippocampus from Cav3.1 knockout (KO) mice. These findings suggest overall that T VGCCs play a key role in cognition by enhancing hippocampal ACh release and that the cognitive enhancer SAK3 could be a candidate therapeutic in Alzheimer's disease. PMID- 28093212 TI - Long-term sera storage does not significantly modify the interpretation of toxoplasmosis serologies. AB - BACKGROUND: Serological investigation of Toxoplasma gondii can answer many questions about toxoplasmosis in human pathology. Along these lines, studies on serum storage in biobanks need to be performed especially in terms of determining the impact of storage on relevance of sera analysis after freezing. This study assessed the impact of long-term sera storage on the stability of anti-Toxoplasma immunoglobulins. MATERIAL AND METHODS: The stability of anti-Toxoplasma IgG and IgM was studied in 244 and 242 sera respectively, stored at -20 degrees C from one month to ten years. ELISA-immunoassay (Vidas(r), bioMerieux) was used for initial and post-storage analyses. Linear models for repeated measures and subgroup analyses were performed to assess the effect of storage duration and sample characteristics on immunoglobulins stability. RESULTS: Until ten years, the variability attributed to storage (maximum 8.07% for IgG, 13.17% for IgM) was below the variations inherent to the serological technique and allowed by quality assurance systems (15%). Subgroup analysis reported no variation attributed to sera storage. Serological interpretation was modified for 3 sera (1.2%) tested for IgM, all stored more than seven years. CONCLUSION: Anti-Toxoplasma immunoglobulins can reliably be measured for at least up to six years of storage with no modification of interpretation of toxoplasmosis serologies. PMID- 28093213 TI - Characterization of the efficiency and uncertainty of skimmed milk flocculation for the simultaneous concentration and quantification of water-borne viruses, bacteria and protozoa. AB - In this study, the use of skimmed milk flocculation (SMF) to simultaneously concentrate viruses, bacteria and protozoa was evaluated. We selected strains of faecal indicator bacteria and pathogens, such as Escherichia coli and Helicobacter pylori. The viruses selected were adenovirus (HAdV 35), rotavirus (RoV SA-11), the bacteriophage MS2 and bovine viral diarrhoea virus (BVDV). The protozoa tested were Acanthamoeba, Giardia and Cryptosporidium. The mean recoveries with q(RT)PCR were 66% (HAdV 35), 24% (MS2), 28% (RoV SA-11), 15% (BVDV), 60% (E. coli), 30% (H. pylori) and 21% (Acanthamoeba castellanii). When testing the infectivity, the mean recoveries were 59% (HAdV 35), 12% (MS2), 26% (RoV SA-11) and 0.7% (BVDV). The protozoa Giardia lamblia and Cryptosporidium parvum were studied by immunofluorescence with recoveries of 18% and 13%, respectively. Although q(RT)PCR consistently showed higher quantification values (as expected), q(RT)PCR and the infectivity assays showed similar recoveries for HAdV 35 and RoV SA-11. Additionally, we investigated modelling the variability and uncertainty of the recovery with this method to extrapolate the quantification obtained by q(RT)PCR and estimate the real concentration. The 95% prediction intervals of the real concentration of the microorganisms inoculated were calculated using a general non-parametric bootstrap procedure adapted in our context to estimate the technical error of the measurements. SMF shows recoveries with a low variability that permits the use of a mathematical approximation to predict the concentration of the pathogen and indicator with acceptable low intervals. The values of uncertainty may be used for a quantitative microbial risk analysis or diagnostic purposes. PMID- 28093214 TI - The UPR reduces glucose metabolism via IRE1 signaling. AB - Neurons are highly dependent on glucose. A disturbance in glucose homeostasis therefore poses a severe risk that is counteracted by activation of stress responses to limit damage and restore the energy balance. A major stress response that is activated under conditions of glucose deprivation is the unfolded protein response (UPR) that is aimed to restore proteostasis in the endoplasmic reticulum. The key signaling of the UPR involves the transient activation of a transcriptional program and an overall reduction of protein synthesis. Since the UPR is strategically positioned to sense and integrate metabolic stress signals, it is likely that - apart from its adaptive response to restore proteostasis - it also directly affects metabolic pathways. Here we investigate the direct role of the UPR in glucose homeostasis. O-GlcNAc is a post-translational modification that is highly responsive to glucose fluctuations. We find that UPR activation results in decreased O-GlcNAc modification, in line with reduced glucose metabolism. Our data indicate that UPR activation has no direct impact on the upstream processes in glucose metabolism; glucose transporter expression, glucose uptake and hexokinase activity. In contrast, prolonged UPR activation decreases glycolysis and mitochondrial metabolism. Decreased mitochondrial respiration is not accompanied by apoptosis or a structural change in mitochondria indicating that the reduction in metabolic rate upon UPR activation is a physiological non apoptotic response. Metabolic decrease is prevented if the IRE1 pathway of the UPR is inhibited. This indicates that activation of IRE1 signaling induces a reduction in glucose metabolism, as part of an adaptive response. PMID- 28093215 TI - Melanocortin 4 receptor constitutive activity inhibits L-type voltage-gated calcium channels in neurons. AB - The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor (GPCR) that is expressed in several brain nuclei playing a crucial role in the regulation of energy balance controlling the homeostasis of the organism. It displays both agonist-evoked and constitutive activity, and moreover, it can couple to different G proteins. Most of the research on MC4R has been focused on agonist induced activity, while the molecular and cellular basis of MC4R constitutive activity remains scarcely studied. We have previously shown that neuronal N-type voltage-gated calcium channels (CaV2.2) are inhibited by MC4R agonist-dependent activation, while the CaV subtypes that carry L- and P/Q-type current are not. Here, we tested the hypothesis that MC4R constitutive activity can affect CaV, with focus on the channel subtypes that can control transcriptional activity coupled to depolarization (L-type, CaV1.2/1.3) and neurotransmitter release (N- and P/Q-type, CaV2.2 and CaV2.1). We found that MC4R constitutive activity inhibits specifically CaV1.2/1.3 and CaV2.1 subtypes of CaV. We also explored the signaling pathways mediating this inhibition, and thus propose that agonist dependent and basal MC4R activation modes signal differentially through Gs and Gi/o pathways to impact on different CaV subtypes. In addition, we found that chronic incubation with MC4R endogenous inverse agonist, agouti and agouti related peptide (AgRP), occludes CaV inhibition in a cell line and in amygdaloid complex cultured neurons as well. Thus, we define new mechanisms of control of the main mediators of depolarization-induced calcium entry into neurons by a GPCR that displays constitutive activity. PMID- 28093216 TI - Longitudinal variation of serum periostin levels in adults with stable asthma. PMID- 28093218 TI - 'The effect of different genres of music on the stress levels of kennelled dogs'. AB - Classical music has been shown to reduce stress in kennelled dogs; however, rapid habituation of dogs to this form of auditory enrichment has also been demonstrated. The current study investigated the physiological and behavioural response of kennelled dogs (n=38) to medium-term (5days) auditory enrichment with five different genres of music including Soft Rock, Motown, Pop, Reggae and Classical, to determine whether increasing the variety of auditory stimulation reduces the level of habituation to auditory enrichment. Dogs were found to spend significantly more time lying and significantly less time standing when music was played, regardless of genre. There was no observable effect of music on barking, however, dogs were significantly (z=2.2, P<0.05) more likely to bark following cessation of auditory enrichment. Heart Rate Variability (HRV) was significantly higher, indicative of decreased stress, when dogs were played Soft Rock and Reggae, with a lesser effect observed when Motown, Pop and Classical genres were played. Relative to the silent period prior to auditory enrichment, urinary cortisol:creatanine (UCCR) values were significantly higher during Soft Rock (t=2.781, P<0.01) and the second silent control period following auditory enrichment (t=2.46, P<0.05). Despite the mixed response to different genres, the physiological and behavioural changes observed remained constant over the 5d of enrichment suggesting that the effect of habituation may be reduced by increasing the variety of auditory enrichment provided. PMID- 28093217 TI - Abnormal CD161+ immune cells and retinoic acid receptor-related orphan receptor gammat-mediate enhanced IL-17F expression in the setting of genetic hypertension. AB - BACKGROUND: Hypertension is considered an immunologic disorder. However, the role of the IL-17 family in genetic hypertension in the spontaneously hypertensive rat (SHR) has not been investigated. OBJECTIVE: We tested the hypothesis that enhanced TH17 programming and IL-17 expression in abundant CD161+ immune cells in SHRs represent an abnormal proinflammatory adaptive immune response. Furthermore, we propose that this response is driven by the master regulator retinoic acid receptor-related orphan receptor gammat (RORgammat) and a nicotinic proinflammatory innate immune response. METHODS: We measured expression of the CD161 surface marker on splenocytes in SHRs and normotensive control Wistar-Kyoto (WKY) rats from birth to adulthood. We compared expression of IL-17A and IL-17F in splenic cells under different conditions. We then determined the functional effect of these cytokines on vascular reactivity. Finally, we tested whether pharmacologic inhibition of RORgammat can attenuate hypertension in SHRs. RESULTS: SHRs exhibited an abnormally large population of CD161+ cells at birth that increased with age, reaching more than 30% of the splenocyte population at 38 weeks. The SHR splenocytes constitutively expressed more RORgammat than those of WKY rats and produced more IL-17F on induction. Exposure of WKY rat aortas to IL-17F impaired endothelium-dependent vascular relaxation, whereas IL-17A did not. Moreover, in vivo inhibition of RORgammat by digoxin decreased systolic blood pressure in SHRs. CONCLUSIONS: SHRs have a markedly enhanced potential for RORgammat-driven expression of proinflammatory and prohypertensive IL-17F in response to innate immune activation. Increased RORgammat and IL-17F levels contribute to SHR hypertension and might be therapeutic targets. PMID- 28093219 TI - A mixed glucocorticoid/mineralocorticoid receptor modulator dampens endocrine and hippocampal stress responsivity in male rats. AB - Aberrant glucocorticoid secretion is implicated in the pathophysiology of stress related disorders (i.e., depression, anxiety). Glucocorticoids exert biological effects via mineralocorticoid (MR) and glucocorticoid (GR) receptors. Previous data from our laboratory indicate that GR antagonism/modulation (i.e., mifepristone, CORT 108297) regulate endocrine, behavioral, and central stress responses. Because of the dynamic interplay between MR and GR on HPA axis regulation and emotionality, compounds targeting both receptors are of interest for stress-related pathology. We investigated the effects of CORT 118335 (a dual selective GR modulator/MR antagonist) on endocrine, behavioral, and central (c Fos) stress responses in male rats. Rats were treated for five days with CORT 118335, imipramine (positive control), or vehicle and exposed to restraint or forced swim stress (FST). CORT 118335 dampened corticosterone responses to both stressors, without a concomitant antidepressant-like effect in the FST. Imipramine decreased corticosterone responses to restraint stress; however, the antidepressant-like effect of imipramine in the FST was independent of circulating glucocorticoids. These findings indicate dissociation between endocrine and behavioral stress responses in the FST. CORT 118335 decreased c-Fos expression only in the CA1 division of the hippocampus. Imipramine decreased c Fos expression in the basolateral amygdala and CA1 and CA3 divisions of the hippocampus. Overall, the data indicate differential effects of CORT 118335 and imipramine on stress-induced neuronal activity in various brain regions. The data also highlight a complex relationship between neuronal activation in stress and mood regulatory brain regions and the ensuing impact on endocrine and behavioral stress responses. PMID- 28093220 TI - Increased oxytocin levels among abstinent heroin addicts: Association with aggressiveness, psychiatric symptoms and perceived childhood neglect. AB - A disruption of the oxytocin system seems to affect a variety of brain functions including emotions, mood and social behavior possibly underlying severe social deficits and susceptibility for substance use and mental health disorders. Early life adversity, such as insecure attachment in childhood, has been suggested to influence oxytocin tone contributing to a condition of neurobiological vulnerability. Aim of the present study was to investigate oxytocin serum levels in abstinent heroin addicted patients, in comparison with healthy controls, and the possible correlation with co-occurring psychiatric symptoms, aggressiveness and perception of parental neglect. Eighteen (18) abstinent patients, affected by heroin use disorders, and 18 control subjects, who never used drugs or abused alcohol, were included in the study and submitted to 1) collection of a blood sample for oxytocin assay, 2) Symptoms Check List 90 for psychiatric symptoms evaluation 3) Buss Durkee Hostility Inventory to measure aggressiveness 4) Child Experience of Care and Abuse-Questionnaire to retrospectively test the perception of parental neglect. Heroin exposure extent and heroin dosages were also recorded. Oxytocin serum levels were unexpectedly significantly higher among abstinent patients affected by heroin use disorders and positively correlated with psychiatric symptoms, aggressiveness and mother neglect scores. No correlation was evidenced between oxytocin and heroin exposure extent or dosages. Our findings appear to contradict the simplistic view of oxytocin as a pro-social hormone and confirm previous evidence concerning the peptide levels direct association with aggressive behavior and mood disorders. Considering a more complex mechanism, oxytocin would increase the sensitivity to social salience cues related to contextual or inter-individual factors, promoting pro-sociality in "safe" conditions and, in contrast, inducing more defensive and "anti-social" emotions and behaviors when the social cues are interpreted as "unsafe". This latter condition is often characterizing the clinical history of addicted patients. PMID- 28093221 TI - Exposure to metal oxide nanoparticles in physiological fluid induced synergistic biological effects in a keratinocyte model. AB - Nanoparticles (NPs) possess distinctive physicochemical properties that in addition to differentiating them from their bulk counterparts can induce negative cellular consequences. Standard in vitro systems have served as the primary model for NP safety evaluations, but suffer from a lack physiological relevance. One way to overcome this limitation and evaluate NP characteristics under more accurate conditions is through the use of artificial physiological fluids, which mimic the composition of in vivo environments. In this study, we identified that copper oxide (CuO) and titanium dioxide (TiO2) NPs displayed modified behavior when dispersed in artificial interstitial fluid (IF) versus traditional media, including extensive agglomeration and increased particle deposition. When keratinocyte cells underwent CuO NP exposure, synergistic stress and toxicity responses occurred within an IF environment, correlating with augmented particle deposition. However, following IF incubation alone or concurrently with TiO2 NPs, which are not innately toxic, no combinatorial responses were identified. These results indicate that synergistic outcomes arise when toxic NPs undergo fluid induced alterations to key physicochemical properties and behaviors. This study highlights the necessity of carrying out NP characterization and safety assessments in physiologically-representative environments; as altered behavior patterns have the potential to induce bioresponses not identified within traditional models. PMID- 28093222 TI - Swainsonine-induced lysosomal storage disease in goats caused by the ingestion of Sida rodrigoi Monteiro in North-western Argentina. AB - There are numerous poisonous plants that can induce intralysosomal accumulation of glycoproteins and neurologic syndromes. Here we describe for the first time, a disease caused by ingesting Sida rodrigoi Monteiro in goats in North-western Argentina. The animals showed weight loss, indifference to the environment, unsteady gait and ataxia. Histopathologic studies showed vacuolization in cells of various organs, mainly in the CNS. The material deposited in the cells was positive for LCA (Lens culinaris agglutinin), WGA (Triticum vulgaris agglutinin), sWGA (succinyl-Triticum vulgaris agglutinin) and Con-A (Concanavalia ensiformis agglutinin) lectins. Finally, toxic levels of swansonine were identified in the plant. The present investigation allowed to recognize S. rodrigoi Monteiro poisoning as a plant induced alpha-mannosidosis. PMID- 28093223 TI - Cytotoxicity and apoptosis induced by mixed mycotoxins (T-2 and HT-2 toxin) on primary hepatocytes of broilers in vitro. AB - T-2 and HT-2 (T-2/HT-2) induced cytotoxicity and apoptosis in hepatocytes from broilers. In this study, hepatocytes treated with T-2/HT-2 were analyzed for cytotoxic effects and apoptosis and for the associated mechanisms. To assay cytotoxicity, we used the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) viability assay, hematoxylin-eosin staining and aspartase transaminase and alanine transaminase (ALT/AST) activities. We evaluated apoptosis by fluorescence microscopy using the Terminal transferase nick-end labeling (TUNEL) assay. The apoptotic ratio and the apoptotic stage of the hepatocytes were next assessed with fluorescently labeled (FITC) Annexin V and propidium iodide (PI) staining. Finally, expression levels of apoptosis-related mRNAs were assessed by real-time PCR and those of apoptosis-related proteins by western blotting. We found that cells treated with T-2/HT-2 showed, in a dose dependent manner, significantly lower cell viabilities (P < 0.05) and markedly increased intercellular spaces, dead cells and ALT/AST activities. T-2/HT-2 treatment also significantly increased the number of apoptotic cells and the apoptotic ratio (P < 0.05). T-2/HT-2 induced early stage apoptosis of the hepatocytes and levels of apoptosis-related mRNAs and proteins changed in a manner implicating them in the apoptotic process. These changes occurred from 0 to 24 h of T-2/HT-2 exposure. Expression of bax and caspase-7 mRNAs was significantly upregulated, in a time-dependent manner, during this period (P < 0.05). Levels of mRNAs for caspase-3 and caspase-9 were increased from 0 to 12 h (P < 0.05) and then decreased after 12 h (P < 0.05). There were no significant effects on expression of bcl-2 mRNA (P > 0.05). Expression of all apoptosis related proteins examined, except for bcl-2, was significantly increased from 0 to 24 h in a time-dependent manner (P < 0.05). Overall, T-2/HT-2 induced cytotoxicity and apoptosis in hepatocytes. The resulting changes in mRNA and protein expression were shown that several apoptosis-related proteins were involved in the liver toxicity of these agents. PMID- 28093224 TI - Beta-2-adrenoreceptor polymorphism at position 16 determines the clinical severity of chronic obstructive pulmonary disease. AB - The Arg/Arg homozygosity at codon 16 of the beta-2-adrenoreceptor (ADRB2) gene has been thought to predispose asthma patients to a poorer therapeutic response to beta-2-mimetics, or to worse control of the disease. In contrast, the results of the studies analysing the effect of ADRB2 polymorphisms on the response to beta-2-adrenoreceptor agonists in chronic obstructive pulmonary disease (COPD) patients are sparse and inconclusive. The aim of this research was to verify if p.Arg16Gly (c.46A > G) and p.Gly27Glu (c.79G > C) single nucleotide polymorphisms (SNPs) exert a negative effect on the selected clinical indicators of COPD. The SNPs of the ADRB2 were identified by multiplex allele-specific PCR on DNA isolated from the venous blood leukocytes of 92 patients with stable grade COPD. In addition, all of the patients were asked about the course of COPD during the 12 months preceding the study, including the frequency of exacerbations requiring hospitalisation, the number of antibiotic therapy courses given due to the lower respiratory tract infection, and the number of courses of systemic corticosteroid therapy administered due to the exacerbation of COPD. Arg/Arg homozygotes at codon 16 required at least two courses of antibiotic therapy administered as a result of a lower respiratory tract infection significantly more frequently than carriers of other polymorphic variants of the ADRB2. Moreover, they were the only ones who required three or more courses of corticosteroid therapy due to COPD exacerbation. No significant relationships were observed between the polymorphism at codon 27 and the analysed clinical indicators of COPD severity. These data suggested that Arg/Arg homozygosity at codon 16 of the ADRB2 gene predisposes patients to a clinically more severe course of COPD. PMID- 28093225 TI - IL-4R suppresses airway inflammation in bronchial asthma by inhibiting the IL 4/STAT6 pathway. AB - OBJECTIVE: This study aims to explore the mechanisms of how IL-4R suppresses airway inflammation in bronchial asthma by inhibiting the IL-4/STAT6 pathway. METHODS: A total of 27 BALB/c male mice were selected and divided into control, asthma and IL-4R groups. Ovalbumin-induced mouse asthma model was established. Maximal pulmonary resistance was recorded. Hematoxylin and eosin (HE) and periodic acid Schiff (PAS) staining were conducted to observe the pathological changes in lung tissue. Optical microscope was used to detect numbers of total cells, mastocytes, eosinophils (EOS), neutrophils, and lymphocytes. Enzyme-linked immunosorbent assay (ELISA) was adopted for the levels of immunoglobulin (IgE), IL-4, IL-5, IL-13 and interferon (IFN)-gamma, flow cytometry for the percentages of IL-4+ CD4+, IFN-gamma+ CD4+ and IFN-gamma+/IL-4+ in total thymus-derived (T) cells, qRT-PCR for the mRNA expressions of IL-4, IL-5, IL-13, STAT6, pSTAT6, suppressor of cytokine signaling (SOCS), inducible nitric oxide synthase (iNOS) and vascular cell adhesion molecule (VCAM)-1, and Western blotting for the protein expressions of STAT6 and pSTAT6. RESULTS: Compared with the control group, the asthma group had irregular tissue structure and severe inflammation, increases in maximal pulmonary resistance, numbers of total cells, EOS, neutrophils, and lymphocytes, levels of IgE, IL-4, IL-5 and IL-13, percentages of IFN-gamma+ CD4+ and IFN-gamma+/IL-4+ in total T cells, mRNA expressions of IL-4, IL-5, IL-13, STAT6, pSTAT6, SOCS, iNOS and VCAM-1, and protein expressions of STAT6 and pSTAT6, but decreases in IFN-gamma level and percentage of IL-4+ CD4+ in total T cells. Compared with the asthma group, the IL-4R group had relatively regular tissue structure and light inflammation, declined maximal RL, numbers of total cells, EOS, neutrophils, and lymphocytes, contents of IgE, IL-4, IL-5 and IL-13, percentages of IFN-gamma+ CD4+ and IFN-gamma+/IL-4+ in total T cells, mRNA expressions of IL-4, IL-5, IL-13, STAT6, pSTAT6, SOCS, iNOS and VCAM-1, and protein expressions of STAT6 and pSTAT6, but elevated IFN-gamma content and percentage of IL-4+ CD4+ in total T cells. CONCLUSION: Our results demonstrate that IL-4R can suppress airway inflammation in bronchial asthma by inhibited the IL-4/STAT6 pathway, which may provide a new therapeutic approach for the treatment of bronchial asthma. PMID- 28093227 TI - Wnt/beta-catenin signaling activates nephronectin expression in osteoblasts. AB - Nephronectin (Npnt), an extracellular matrix protein, is considered to play critical roles as an adhesion molecule in the development and functions of various organs and tissues, such as the kidneys and bone. In the present study, we found that Wnt3a strongly enhanced Npnt mRNA expression in osteoblast-like MC3T3-E1 cells, while it also induced an increase in Npnt gene expression in both time- and dose-dependent manners via the Wnt/beta-catenin signaling pathway. These results suggest novel mechanisms for Wnt3a-induced osteoblast proliferation and cell survival via Npnt gene expression. PMID- 28093226 TI - Conformational Transitions and Alternating-Access Mechanism in the Sarcoplasmic Reticulum Calcium Pump. AB - Ion pumps are integral membrane proteins responsible for transporting ions against concentration gradients across biological membranes. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), a member of the P-type ATPases family, transports two calcium ions per hydrolyzed ATP molecule via an "alternating-access" mechanism. High-resolution crystallographic structures provide invaluable insight on the structural mechanism of the ion pumping process. However, to understand the molecular details of how ATP hydrolysis is coupled to calcium transport, it is necessary to gain knowledge about the conformational transition pathways connecting the crystallographically resolved conformations. Large-scale transitions in SERCA occur at time-scales beyond the current reach of unbiased molecular dynamics simulations. Here, we overcome this challenge by employing the string method, which represents a transition pathway as a chainofstates linking two conformational endpoints. Using a multiscale methodology, we have determined all-atom transition pathways for three main conformational transitions responsible for the alternating-access mechanism. The present pathways provide a clear chronology and ordering of the key events underlying the active transport of calcium ions by SERCA. Important conclusions are that the conformational transition that leads to occlusion with bound ATP and calcium is highly concerted and cooperative, the phosphorylation of Asp351 causes areorganization of the cytoplasmic domains that subsequently drives the opening of the luminal gate, and thereclosing of luminal gate induces a shift in the cytoplasmic domains that subsequently enables the dephosphorylation of Asp351-P. Formation of transient residue-residue contacts along the conformational transitions predicted by the computations provide an experimental route to test the general validity of the computational pathways. PMID- 28093228 TI - NDRG2, suppressed expression associates with poor prognosis in pancreatic cancer, is hypermethylated in the second promoter in human gastrointestinal cancers. AB - Although N-myc downstream regulated gene 2 (NDRG2) is frequently downregulated in various cancers and is considered to be a candidate tumor suppressor gene, molecular mechanisms of the expressional suppression that lead to cancers are largely unknown. Recent studies indicated that epigenetic suppression of NDRG2 involved carcinogenesis and progression in several tumor types, and we demonstrated positive association with NDRG2 suppression and poor prognosis in pancreatic cancer. In this study, we analyzed mRNA and protein expressions of NDRG2 in 26 cancer cell lines (20 colorectal and 6 gastric cancers) and found that many cell lines showed variously reduced NDRG2 expressions. Furthermore, NDRG2 expressions were significantly reduced in primary resected cancer tissues compared to corresponding normal tissues immunohistochemically (19 of 20 colorectal and 14 of 17 gastric cancers). Treatment with 5-Aza-2' deoxycytidine predominantly upregulated NDRG2 expressions in NDRG2 low-expressing cell lines. Bisulfite sequencing analyses and methylation specific PCR revealed that methylation status at one of the two promoters (around exon 2) correlated well with the suppressed expression, and this is the major promoter in colorectal and gastric cancer cell lines. Our present results suggest that hypermethylation in promoter around exon 2 is functioning as essential factors of NDRG2 silencing in gastrointestinal cancers. PMID- 28093229 TI - Antimicrobial activity and mechanism of PDC213, an endogenous peptide from human milk. AB - Human milk has always been considered an ideal source of elemental nutrients to both preterm and full term infants in order to optimally develop the infant's tissues and organs. Recently, hundreds of endogenous milk peptides were identified in human milk. These peptides exhibited angiotensin-converting enzyme inhibition, immunomodulation, or antimicrobial activity. Here, we report the antimicrobial activity and mechanism of a novel type of human antimicrobial peptide (AMP), termed PDC213 (peptide derived from beta-Casein 213-226 aa). PDC213 is an endogenous peptide and is present at higher levels in preterm milk than in full term milk. The inhibitory concentration curve and disk diffusion tests showed that PDC213 had obvious antimicrobial against S. aureus and Y. enterocolitica, the common nosocomial pathogens in neonatal intensive care units (NICUs). Fluorescent dye methods, electron microscopy experiments and DNA-binding activity assays further indicated that PDC213 can permeabilize bacterial membranes and cell walls rather than bind intracellular DNA to kill bacteria. Together, our results suggest that PDC213 is a novel type of AMP that warrants further investigation. PMID- 28093230 TI - Gastrin-releasing peptide induces monocyte adhesion to vascular endothelium by upregulating endothelial adhesion molecules. AB - Gastrin-releasing peptide (GRP) is a neuropeptide that plays roles in various pathophysiological conditions including inflammatory diseases in peripheral tissues; however, little is known about whether GRP can directly regulate endothelial inflammatory processes. In this study, we showed that GRP promotes the adhesion of leukocytes to human umbilical vein endothelial cells (HUVECs) and the aortic endothelium. GRP increased the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) by activating nuclear factor-kappaB (NF-kappaB) in endothelial cells. In addition, GRP activated extracellular signal-regulated kinase 1/2 (ERK1/2), p38MAPK, and AKT, and the inhibition of these signaling pathways significantly reduced GRP-induced monocyte adhesion to the endothelium. Overall, our results suggested that GRP may cause endothelial dysfunction, which could be of particular relevance in the development of vascular inflammatory disorders. PMID- 28093231 TI - The effects of 6-Gingerol on reproductive improvement, liver functioning and Cyclooxygenase-2 gene expression in estradiol valerate - Induced polycystic ovary syndrome in Wistar rats. AB - 6-Gingerol is the major pungent ingredient of ginger with anti-inflammatory and antioxidant properties. In this study, we evaluate the effects of 6-gingerol on the biochemical parameters and ovarian histological improvements in estradiol valerate (EV) induced PCOS rats. Thirty six female Wistar rats were divided into 4 groups: control, received normal diet, PCOS control, received 4 mg/kg EV injection for 28 days and two experimental groups, received an EV injection for 28 days and followed by 6-gingerol (200 MUg/kg and 400 MUg/kg) for 14 days. The administration of EV led to increase body and ovarian weights, abnormality in serum sex steroid profile, decrease in antioxidant activity and increase in COX-2 gene expression. 6-gingerol treatments, particularly the 400 MUg/kg dose, markedly attenuated these alterations. 6-gingerol showed beneficial effects in the EV induced PCOS rats via decreased expression of COX-2, restored biochemical parameters to normal and decreased of cysts in the ovaries. PMID- 28093232 TI - Phospholipase Cepsilon deficiency delays the early stage of cutaneous wound healing and attenuates scar formation in mice. AB - This study aimed to investigate the role of phospholipase Cepsilon (PLCepsilon) in the skin wound healing process. PLCepsilon, an effect factor of Ras/Rap small G protein, plays a crucial role in skin inflammation by regulating inflammatory cytokines. Inflammatory responses are closely associated with wound healing. Full thickness skin wounds were made in the PLCepsilon knockout (KO) and wild-type (WT) mice, and the healing process was analyzed. The macroscopic wound closure rate declined in the PLCepsilon KO mice on days 3, 4, and 5 after wounding, following the decreased expression of interleukin (IL)-6, chemokine (C-X-C motif) ligand (Cxcl)-1, Cxcl-2, and chemokine (C-C motif) ligand (Ccl) 20. The proliferation rate of epidermal keratinocytes was not affected by PLCepsilon, but silencing of PLCepsilon resulted in the delayed migration of keratinocytes. Moreover, the scars were found to be much smaller in the PLCepsilon KO mice than in the WT mice. The mRNA expression of Ccl20, collagen (Col) 6a1, and Col17a1 decreased in the PLCepsilon KO mice. These results were in agreement with a previous hypothesis that PLCepsilon might delay the early stage of cutaneous wound healing by inhibiting the migration of keratinocytes, and decrease the expression of Col6a1, Col17a1, and Ccl20 by inhibiting the inflammatory response to reduce scar formation. This study shed light on a novel role of PLCepsilon in wound healing and provided new therapeutic approaches to target PLCepsilon for diminishing scar formation after injury. PMID- 28093233 TI - Changes in vascular responsiveness during a hyperglycemia challenge measured by near-infrared spectroscopy vascular occlusion test. AB - BACKGROUND: Postprandial hyperglycemia is associated with impaired vascular responsiveness. Recent studies have established the use of a near-infrared spectroscopy (NIRS)-derived approach, combined with a vascular occlusion test (VOT), to examine vascular responsiveness within the microvasculature in normoglycemia. The aim of this study was to examine whether this NIRS-VOT technique could detect differences in vascular responsiveness following a hyperglycemic challenge. METHODS AND RESULTS: Fourteen young healthy individuals participated in the study. Participants underwent five vascular occlusion tests (pre, 30, 60, 90 and 120min after glucose ingestion). Vascular responsiveness was determined by the slope 2 of oxygen saturation (Slope 2 StO2) and the area under the curve of oxygen saturation (StO2AUC) signal. All individuals had a significant increase in blood glucose concentration after 30min (p<0.001), 60min (p<0.001) and 90min (p<0.01) after glucose ingestion. The Slope 2 StO2 increased at 90min (p<0.01) after glucose ingestion. Conversely, The StO2AUC was significantly decreased 90min following the glucose challenge (p<0.01). A negative correlation was observed between average StO2AUC and average Slope 2 StO2 (r=-0.995; p<0.05). CONCLUSION: This study showed that the NIRS-VOT technique is capable of detecting differential changes in vascular responsiveness to a hyperglycemic challenge, as indicated by a steeper Slope 2 StO2 and decreased StO2AUC following 90min of an oral glucose challenge. PMID- 28093234 TI - The 1910HK/RR two-component system is essential for the virulence of Streptococcus suis serotype 2. AB - Streptococcus suis serotype 2 is a major zoonotic pathogen, and the two-component system plays an important role in bacterial pathogenesis. The present study targeted the 1910HK/RR two-component system of S. suis 2. A 1910HK/RR deletion mutant (Delta1910HK/RR) and the corresponding complementation strain (CDelta1910HK/RR) were constructed in S. suis 2 strain 05ZYH33. 1910HK/RR deletion had no effect on S. suis 2 growth, but significantly inhibited the adherence and invasion of S. suis 2 to HEp-2 cells. Analysis of the role of 1910HK/RR in murine and pig infection models demonstrated that 1910HK/RR played a distinct role in the virulence of S. suis 2. In addition, deletion of 1910HK/RR significantly impaired the survival of 05ZYH33 in human blood. These data provided important insights into the pathogenesis of S. suis 2. PMID- 28093235 TI - Expression profile of lncRNA in human bronchial epithelial cells response to Talaromyces marneffei infection: A microarray analysis. AB - Talaromyces marneffei is an important opportunistic pathogenic fungus capable of causing systemic lethal infection through inhalation of its conidia. However, little is known about the pathogenesis and interactions between Talaromyces marneffei and host. The aim of this study was to identify potential long noncoding RNAs (lncRNAs) and coding genes associated with interactions between airway epithelial cell and Talaromyces marneffei conidia. We carried out a microarray analysis to determine the expression profile of lncRNA and mRNA in human bronchial epithelial cell in response to Talaromyces marneffei infection. Compared to control group, we found that 370 and 149 lncRNAs were up and down regulated, respectively. Meanwhile, the expression level of 269 and 60 mRNAs was increased and decreased, respectively. To understand the potential role of the differentially expressed lncRNAs, we performed functional annotations of the corresponding coding genes using gene ontology and pathway analyses. Our results provide insights into the pathogenesis of early infection by Talaromyces marneffei. PMID- 28093236 TI - Extracellular ATP and adenosine: The Yin and Yang in immune responses? AB - Extracellular adenosine 5'-triphosphate (ATP) and adenosine molecules are intimately involved in immune responses. ATP is mostly a pro-inflammatory molecule and is released during hypoxic condition and by necrotic cells, as well as by activated immune cells and endothelial cells. However, under certain conditions, for instance at low concentrations or at prolonged exposure, ATP may also have anti-inflammatory properties. Extracellular ATP can activate both P2X and P2Y purinergic receptors. Extracellular ATP can be hydrolyzed into adenosine in a two-step enzymatic process involving the ectonucleotidases CD39 (ecto apyrase) and CD73. These enzymes are expressed by many cell types, including endothelial cells and immune cells. The counterpart of ATP is adenosine, which is produced by breakdown of intra- or extracellular ATP. Adenosine has mainly anti inflammatory effects by binding to the adenosine, or P1, receptors (A1, A2A, A2B, and A3). These receptors are also expressed in many cells, including immune cells. The final effect of ATP and adenosine in immune responses depends on the fine regulatory balance between the 2 molecules. In the present review, we will discuss the current knowledge on the role of these 2 molecules in the immune responses. PMID- 28093237 TI - Transgenerational epigenetics: Integrating soma to germline communication with gametic inheritance. AB - Evidence supporting germline mediated epigenetic inheritance of environmentally induced traits has increasingly emerged over the past several years. Although the mechanisms underlying this inheritance remain unclear, recent findings suggest that parental gamete-borne epigenetic factors, particularly RNAs, affect post fertilization and developmental gene regulation, ultimately leading to phenotypic appearance in the offspring. Complex processes involving gene expression and epigenetic regulation are considered to perpetuate across generations. In addition to transfer of germline factors, epigenetic inheritance via gametes also requires a mechanism whereby the information pertaining to the induced traits is communicated from soma to germline. Despite violating a century-old view in biology, this communication seems to play a role in transmission of environmental effects across generations. Circulating RNAs, especially those associated with extracellular vesicles like exosomes, are emerging as promising candidates that can transmit gene regulatory information in this direction. Cumulatively, these new observations provide a basis to integrate epigenetic inheritance. With significant implications in health, disease and ageing, the latter appears poised to revolutionize biology. PMID- 28093238 TI - A model of the mitochondrial basis of bipolar disorder. AB - BACKGROUND: Bipolar disorder phenomenologically is a biphasic disorder of energy availability; increased in mania and decreased in depression. In consort, there is accumulating evidence indicating increased mitochondrial respiration and ATP production in bipolar mania which contrasts with decreased mitochondrial function in patients in the euthymic or depressive phase of the illness. Consequently, the central thesis of this paper is that bipolar disorder is due to a phasic dysregulation of mitochondrial biogenergetics. The elements responsible for this dysregulation may thus represent critical treatment targets for mood disorders, and are the subject of this paper. DISCUSSION: There are many potential mediators of mitochondrial function which collectively are implicated in bipolar disorder. Levels of oxidative stress, pro-inflammatory cytokines and intracellular calcium ions are all higher in bipolar mania than in the euthymic and depressive phases of the illness. Increased levels of calcium ions can partly account for increased oxidative phosphorylation via well documented pathways such as the modulation of the F1-FO elements of ATP synthase. Likewise, increased levels of oxidative stress and pro-inflammatory cytokines lead to the upregulation of AMPK, SIRT-1, SIRT-3 and NAD+ which directly stimulate oxidative phosphorylation. Uric acid and melatonin are also differentially elevated in bipolar mania and both molecules stimulate the production of ATP. The pro-apoptotic, neurotoxic and mitotoxic effects of elevated glutamate, dopamine and GSK-3 in bipolar mania may be counterbalanced by higher basal levels and activity of p53, Bcl-2, PI3K and Akt in an environment of elevated uric acid and decreased BDNF. SUMMARY: Details of these pathways are discussed as an explanatory model for the existence of increased ATP generation in mania. We also offer a model explaining the biphasic nature of mitochondrial respiration in bipolar disorder and the transition between mania and depression based on increasing levels of TNFalpha, ROS, NO, AMPK and SIRT-1 together with the antagonistic relationship between p53 and NF kappaB. PMID- 28093239 TI - Application of technology to social communication impairment in childhood and adolescence. AB - Social communication impairment has been implicated in various mental health disorders. The primary aim of this review paper is to summarize the extant research on the development and application of technologies to address social communication deficits, conceptualized according to the four constructs outlined by the NIMH's Research Domain Criteria (RDoC), transdiagnostically in children and adolescents. An exhaustive and systematic search yielded 69 peer-reviewed articles meeting all inclusion criteria (i.e., used technology, applied the technology to target impairment in at least one of four constructs of social communication, included a child or adolescent samples). We found limited use of technology for exploration of impairment in reception of non-facial communication, compared to the other social communication constructs. In addition, there has been an overwhelming focus on social communication impairment in children and adolescents with Autism Spectrum Disorder (ASD), with relatively few studies evaluating technology application in other clinical populations. Implications for future directions for technological interventions to treat social communication impairments transdiagnostically are discussed. PMID- 28093240 TI - The crystal structure of Pseudomonas aeruginosa lipoxygenase Ala420Gly mutant explains the improved oxygen affinity and the altered reaction specificity. AB - Secreted LOX from Pseudomonas aeruginosa (PA-LOX) has previously been identified as arachidonic acid 15S-lipoxygenating enzyme. Here we report that the substitution of Ala420Gly in PA-LOX leads to an enzyme variant with pronounced dual specificity favoring arachidonic acid 11R-oxygenation. When compared with other LOX-isoforms the molecular oxygen affinity of wild-type PA-LOX is 1-2 orders of magnitude lower (Km O2 of 0.4mM) but Ala420Gly exchange improved the molecular oxygen affinity (Km O2 of 0.2mM). Experiments with stereo-specifically deuterated linoleic acid indicated that the formation of both 13S- and 9R-HpODE involves abstraction of the proS-hydrogen from C11 of the fatty acid backbone. To explore the structural basis for the observed functional changes (altered specificity, improved molecular oxygen affinity) we solved the crystal structure of the Ala420Gly mutant of PA-LOX at 1.8A resolution and compared it with the wild-type enzyme. Modeling of fatty acid alignment at the catalytic center suggested that in the wild-type enzyme dioxygen is directed to C15 of arachidonic acid by a protein tunnel, which interconnects the catalytic center with the protein surface. Ala420Gly exchange redirects intra-enzyme O2 diffusion by bifurcating this tunnel so that C11 of arachidonic acid also becomes accessible for O2 insertion. PMID- 28093241 TI - New isatin derivative inhibits neurodegeneration by restoring insulin signaling in brain. AB - Diabetes is associated with neurodegeneration. Glycation ensues in diabetes and glycated proteins cause insulin resistance in brain resulting in amyloid plaques and NFTs. Also glycation enhances gliosis by promoting neuroinflammation. Currently there is no therapy available to target neurodegenration in brain therefore, development of new therapy that offers neuroprotection is critical. The objective of this study was to evaluate mechanistic effect of isatin derivative URM-II-81, an anti-glycation agent for improvement of insulin action in brain and inhibition of neurodegenration. Methylglyoxal induced stress was inhibited by treatment with URM-II-81. Also, Ser473 and Ser9 phosphorylation of Akt and GSK-3beta respectively were restored by URM-II-81. Effect of URM-II-81 on axonal integrity was studied by differentiating Neuro2A using retinoic acid. URM II-81 restored axonal length in MGO treated cells. Its effects were also studied in high fat and low dose streptozotocin induced diabetic mice where it reduced RBG levels and inhibited glycative stress by reducing HbA1c. URM-II-81 treatment also showed inhibition of gliosis in hippocampus. Histological analysis showed reduced NFTs in CA3 hippocampal region and restoration of insulin signaling in hippocampii of diabetic mice. Our findings suggest that URM-II-81 can be developed as a new therapeutic agent for treatment of neurodegenration. PMID- 28093243 TI - Clinical Study on efficacy of allopurinol in patients with acute coronary syndrome and its functional mechanism. AB - OBJECTIVE: To investigate the therapeutic effect of allopurinol treatment on acute coronary syndrome and to elucidate its possible mechanism. METHODS: Patients with acute coronary syndrome (n = 100) were recruited as research subjects in our hospital. The patients were randomly divided into two groups, an allopurinol group (n = 50) and a control group (n = 50). These two groups were treated with conventional antiplatelet, anticoagulation and anti-ischemic therapy; allopurinol therapy was added to the allopurinol group based on conventional treatment indications. Biochemical markers such as serum creatinine, uric acid, BNP, blood glucose and blood lipid were compared between the two groups. Indicators of oxidative stress and inflammatory response (MDA, OX-LDL, NO, hs-CRP and TNF-alpha), as well as cardiovascular events during 2-years follow up, were recorded. RESULTS: On admission, there was no difference in serum creatinine, uric acid, BNP, blood glucose or lipid levels between the two groups (P > 0.05). However, after 1 month of treatment, these levels were improved in patients in the allopurinol group compared to the control group (P < 0.05). MDA, OX-LDL, hs-CRP and TNF-alpha decreased after treatment periods of 14 days and 1 month. They were also decreased at 3 month, 6 month, 1 year, and 2 year follow-up visits. However, data from the allopurinol group demonstrated significantly lower levels than in the control group (P < 0.05). Additionally, compared with the control group, allopurinol treatment significantly elevated the level of NO (P < 0.05). The total effective rates of the allopurinol group are much higher than in the control group for both angina pectoris (93.2% and 76%, respectively) and ECG (96% and 82%, respectively). Most patients in the allopurinol group (n = 40) and the control group (n = 41) received stent implantation with no significant difference shown between them. The incidence of cardiovascular events during 2 years of follow-up in the allopurinol group was 10%; it was 30% in the control group. CONCLUSION: Allopurinol has a remarkable effect in the treatment of ACS and can improve the oxidative stress and inflammatory reaction indicators of patients. The protective mechanism of allopurinol might be achieved by suppressing the secretion and release of inflammatory mediators such as TNF alpha, hs-CRP, OX-LDL and MDA while increasing levels of NO. PMID- 28093244 TI - Novel Mutations on EGFR Leu792 Potentially Correlate to Acquired Resistance to Osimertinib in Advanced NSCLC. PMID- 28093245 TI - Editorial Comment. PMID- 28093242 TI - The Zn2+-sensing receptor, ZnR/GPR39, upregulates colonocytic Cl- absorption, via basolateral KCC1, and reduces fluid loss. AB - Administration of zinc, as a complement to oral rehydration solutions, effectively diminishes duration and severity of diarrhea, but it is not known whether it merely fulfills a nutritional deficiency, or if zinc has a direct role of regulating solute absorption. We show that Zn2+ acts via a specific receptor, ZnR/GPR39, to reduce fluid loss. Intestinal fluid secretion triggered by cholera toxin (CTx) was lower in WT mice compared to ZnR/GPR39 KO. In the absence of dietary Zn2+ we observed similar fluid accumulation in WT and ZnR/GPR39 KO mice, indicating that Zn2+ and ZnR/GPR39 are both required for a beneficial effect of Zn2+ in diarrhea. In primary colonocytes and in Caco-2 colonocytic cells, activation of ZnR/GPR39 enhanced Cl- transport, a critical factor in diarrhea, by upregulating K+/Cl- cotransporter (KCC1) activity. Importantly, we show basolateral expression of KCC1 in mouse and human colonocytes, thus identifying a novel Cl- absorption pathway. Finally, inhibition of KCC-dependent Cl- transport enhanced CTx-induced fluid loss. Altogether, our data indicate that Zn2+ acting via ZnR/GPR39 has a direct role in controlling Cl- absorption via upregulation of basolateral KCC1 in the colon. Moreover, colonocytic ZnR/GPR39 and KCC1 reduce water loss during diarrhea and may therefore serve as effective drug targets. PMID- 28093246 TI - Editorial Comment. PMID- 28093247 TI - Editorial Comment. PMID- 28093249 TI - Reply by Authors. PMID- 28093248 TI - Reply by Authors. PMID- 28093250 TI - Editorial Comment. PMID- 28093251 TI - Malalignment after minimally invasive plate osteosynthesis in distal femoral fractures. AB - INTRODUCTION: Although minimally invasive plate osteosynthesis (MIPO) is a preferred operative treatment for fractures of the distal femur, malalignment is a significant concern because of indirect reduction of the fracture. The purpose of this study, therefore, was to evaluate radiologic alignment after MIPO for distal femoral fractures. PATIENTS AND METHODS: Of the 138 patients with fracture of the distal femur who underwent MIPO, we enrolled 51 patients in whom bilateral rotational alignment could be assessed by postoperative computed tomography (CT). The patients included 32 men and 19 women, with a mean age of 54.3 years. Thirteen patients had femoral shaft fractures (according to the AO/OTA classification: 32-A, n=2; 32-B, n=6; 32-C, n=5), whereas 38 patients had distal femoral fractures (33-A, n=7; 33-C, n=31). Coronal and sagittal alignments were assessed using simple radiography, whereas rotational alignment was assessed using CT. According to the difference between the affected and unaffected sides, we divided the patients into satisfactory and unsatisfactory groups (reference point of 8 degrees , using Handolin's classification). Thereafter, we determined which factors can lead to malalignment, including fracture location (distal femoral shaft fracture or metaphyseal fracture), fracture pattern (simple fracture, n=15; complex fractures, n=36 patients), coronal and sagittal alignments, and combined ipsilateral long bone fractures. RESULTS: Coronal and sagittal alignment were satisfactory in 96.2% (average, 2.8 degrees ) and 98% (average, 2.2 degrees ), respectively, whereas the rotational alignment was satisfactory in 56.9% of patients. Leg length discrepancy was satisfactory in 92.3% of the patients (average, 10.9mm). Concerning rotational malalignment, an unsatisfactory result was obtained in 48.6% of subjects with complex fractures and 26.7% of subjects with simple fractures (p=0.114). No significant correlation was noted between the angular deformity in the coronal and sagittal planes and the degree of rotational alignment (p=0.607 and 0.774, respectively). CONCLUSIONS: Regardless of the fracture pattern, rotational malalignment may occur at an extremely high rate after MIPO for fractures of the distal femur. PMID- 28093252 TI - Low energy open ankle fractures in the elderly: Outcome and treatment algorithm. AB - BACKGROUND: With an aging but still active population, open ankle fractures are increasingly presenting as low energy fragility injuries, sharing many characteristics with that of hip fractures. Yet, there is little in the literature on the management and outcome of these fractures. The primary aim of this study was to describe the outcome following open, ankle fragility fracture. Our secondary aim was to identify potential factors that improved outcome. METHODS: All consecutive, low energy open ankle fractures treated at a Level I Trauma Centre over a five-year period were included. The method of fracture fixation, soft tissue closure, patient demographics, complications and mortality were recorded. Functional outcome was assessed using the Enneking Scoring system. RESULTS: The cohort comprised 61 patients with a mean age of 73 years (range 27 100); 50 (82%) were females and all patients requiring operative intervention. The overall rate of complication was 24.5% (n=15), with reoperation due to loss of reduction, non-union, infection or amputation required in 7 cases (11.5%). The one-year mortality was 23%. The mean Enneking score, measuring functional outcome, was 36 out of 40 (SD: 6, range: 16-40). It was significantly higher for those treated with internal fixation (37, SD: 5 range: 16-40) than those with external fixation (31, SD: 6 range: 21-38) (p=0.01). Similarly, definitive wound closure - primary closure (37, SD: 5) or flap with split thickness skin graft (SSG) (36, SD: 6) - led to better outcomes than non-definitive closure (31, SD: 8). CONCLUSIONS: The high morbidity associated with low energy ankle fractures is likely to reflect the hosts' reserves and is comparable to other fractures seen in the elderly. It is evident that definitive fracture fixation providing absolute, rather than relative stability; and definitive wound cover, with either primary closure or flap and SSG, enable early mobilization and shorter hospital stays with improved overall functional outcomes. PMID- 28093253 TI - Orthopaedic surgical training and collaborative research in North East England: The 'CORNET' experience. PMID- 28093254 TI - Risperidone ameliorated Abeta1-42-induced cognitive and hippocampal synaptic impairments in mice. AB - Alzheimer's disease (AD) is a complex neurodegenerative disorder with cognitive impairment and major neuropathologic hallmark of amyloid-beta (Abeta) peptides. Risperidone, an atypical antipsychotic, can improve concentration and cognitive deficit in schizophrenia patients. In this study, behavior tests including Morris Water Maze test, Step-through passive avoidance test, Open Field test, Step-Down test, Hole-Board test and Novel object recognition test were preformed to examine the effect of Risperidone on Abeta1-42-induced cognitive dysfunction in both long term and short-term memory. Furthermore, ELISA assay was conducted to measure the levels of Abeta1-42, BACE1 and p-Tau in the hippocampus and cortex. Moreover, primary cortical neuron was cultured in vitro, and the cell viability, mitochondrial membrane potential, and the level of p-Akt, GSK3beta and Caspase-3 protein were measured. For behavior tests, the results showed that Risperidone significantly reversed the Abeta1-42-induced dysfunction in learning, memory, locomotor activity and exploratory behavior. As detected by ELISA assay, risperidone decreased the levels of Abeta1-42, BACE1 and p-Tau in the hippocampus and cortex of AD model mice. Biochemical assay showed that Risperidone reversed the Abeta1-42-induced decrease of cell viability and mitochondrial membrane potential in cultured cortical neurons. The expression of p-Akt was increased, whereas the expression of GSK3beta and Caspase-3 were decreased. These results suggested that Risperidone may be used as a promising candidate for AD treatment, for its effects of inhibiting Abeta generation and improving cognitive impairment in mice. PMID- 28093255 TI - NLRP3 gene knockout blocks NF-kappaB and MAPK signaling pathway in CUMS-induced depression mouse model. AB - BACKGROUND: Abundant researches indicate that neuroinflammation has important roles in the pathophysiology of depression. Our previous study found that the NLRP3 inflammasome mediated stress-induced depression-like behavior in mice via regulating neuroinflammation. However, it still remains unclear that how the NLRP3 inflammasome influences related inflammatory signaling pathway to contribute to neuroinflammation in depression. METHODS: We used wild-type mice and NLRP3 gene knockout mice to explore the role of NLRP3 inflammasome and related inflammatory signaling pathways in chronic unpredictable mild stress (CUMS) induced depression mouse model. RESULTS: Both wild-type and NLRP3 knockout stress group mice gained less weight than control group mice after 4 weeks CUMS exposure. The wild-type mice subjected to 4 weeks CUMS displayed depression-like behaviors, including decreased sucrose preference and increased immobility time in the tail suspension test. The NLRP3 knockout stress group mice didn't demonstrate depression-like behaviors. The levels of interleukin-1beta protein in serum and hippocampi of CUMS exposed wild-type mice were significantly higher, while the NLRP3 knockout stress group mice didn't show an elevation of interleukin-1beta levels. Similarly to early researches, we found that CUMS led to promoted NLRP3 expression in hippocampi. In addition, the hippocampi in CUMS exposed wild-type mice had higher p-JNK and p-p38 protein expression, which indicated activation of the mitogen-activated protein kinases (MAPK) pathway. The knockout of NLRP3 gene inhibited CUMS-induced activation of the MAPK pathway. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) protein complex was activated in the hippocampi of wild-type mice after CUMS exposure, while knockout of NLRP3 gene hindered its activation. CONCLUSIONS: These data further proved that the NLRP3 inflammasome mediated CUMS-induced depression-like behavior. The NLRP3 inflammasome regulated CUMS-induced MAPK pathway and NF-kappaB protein complex activation in depression mouse model. Further researches targeting the NLRP3 inflammasome-signaling pathway might be under a promising future in the prevention and treatment of depression. PMID- 28093256 TI - Effects of gut microbiota on the microRNA and mRNA expression in the hippocampus of mice. AB - BACKGROUNDS: Gut microbiota is increasingly recognized as an important environmental factor that could influence the brain function and behaviors through the microbiota-gut-brain axis. METHOD: Here, we used the germ-free (GF) mice to explore the effect of gut microbiota on hippocampal microRNA (miRNA) and messenger RNAs (mRNAs) expression. RESULTS: Behavioral tests showed that, compared to specific pathogen-free (SPF) mice, the GF mice displayed more center time, center distance and less latency to familiar food. Colonization of the GF mice with gut microbiota from SPF mice did not reverse these behaviors. However, 7 differentially expressed miRNAs and 139 mRNAs were significantly restored. Through microRNA Target Filter analysis, 4 of 7 restored miRNAs had 2232 target mRNAs. Among these target mRNAs, 21 target mRNAs levels were decreased. Further analysis showed that the most significant GO terms were metabolic process (GO: 0008152), binding (GO: 0005488) and cell part (GO: 0044464) for biological process, molecular function and cellular component, respectively, and the most significantly altered pathway was axon guidance (mmu04360). CONCLUSIONS: These findings indicated that colonization of gut microbiota to adolescent GF mice was not sufficient to reverse the behavioral alterations. Gut microbiota could significantly influence the expression levels of miRNAs and mRNAs in hippocampus. Our results could provide original and valuable data for researchers to further study the microbiota-gut-brain axis. PMID- 28093257 TI - Selective preservation of cholinergic MeCP2 rescues specific Rett-syndrome-like phenotypes in MeCP2stop mice. AB - RTT is a neurodevelopmental disorder characterized by growth regression, motor dysfunction, stereotypic hand movements, and autism features. Typical Rett syndrome (RTT) is predominantly caused by mutations in X-linked MeCP2 gene which encodes methyl-CpG-binding protein 2 (MeCP2). The brain-abundant MeCP2 protein mainly functions as a transcriptional regulator for neurodevelopment-associated genes. Specific functions of MeCP2 in certain neuron types remain to be known. Although cholinergic system is an important modulating system in brain, how MeCP2 in cholinergic neurons contribute to RTT has not been clearly understood. Here we use a mouse model with selectively activated endogenous MeCP2 in cholinergic neurons in otherwise MeCP2stop mice to determine the cholinergic MeCP2 effects on rescuing the RTT-like phenotypes. We found cholinergic MeCP2 preservation could reverse some aspects of the RTT-like phenotypes in mice including hypolocomotion and increased anxiety level, and delay the onset of underweight, instead of improving the hypersocial abnormality and the poor general conditions such as short lifespan, low brain weight, and increasing severity score. Our findings suggest that selective activation of cholinergic MeCP2 is sufficient to reverse the locomotor impairment and increased anxiety-like behaviors at least in early symptomatic stage, supporting future development of RTT therapies associated with cholinergic system. PMID- 28093258 TI - Stooping, crouching, and standing - Characterizing balance control strategies across postures. AB - BACKGROUND: While stooping and crouching postures are critical for many activities of daily living, little is known about the balance control mechanisms employed during these postures. Accordingly, the purpose of this study was to characterize the mechanisms driving net center of pressure (COPNet) movement across three postures (standing, stooping, and crouching) and to investigate if control in each posture was influenced by time. METHODS: Ten young adults performed the three postures for 60s each. Kinetic signals were collected via a force platform under each foot. To quantify mechanisms of control, correlations (CorrelLR) were calculated between the left and right COP trajectories in the anterior-posterior (AP) and medio-lateral (ML) directions. To examine the potential effects of time on balance control strategies, outcomes during the first 30s were compared to the last 30s. RESULTS: CorrelLR values did not differ across postures (AP: p = 0.395; ML: p = 0.647). Further, there were no main effects of time on CorrelLR (AP: p = 0.976; ML: p = 0.105). A significant posture time interaction was observed in the ML direction (p = 0.045) characterized by 35% decreases in CorrelLR over time for stooping (p = 0.022). CONCLUSION: The dominant controllers of sway (i.e., AP: ankle plantar/dorsi flexors; ML: hip load/unload mechanism) are similar across quiet stance stooping, and crouching. Changes in ML control strategies over time suggests that fatigue could affect prolonged stooping more so than crouching or standing. PMID- 28093259 TI - Suspending loads decreases load stability but may slightly improve body stability. AB - Here, we seek to determine how compliantly suspended loads could affect the dynamic stability of legged locomotion. We theoretically model the dynamic stability of a human carrying a load using a coupled spring-mass-damper model and an actuated spring-loaded inverted pendulum model, as these models have demonstrated the ability to correctly predict other aspects of locomotion with a load in prior work, such as body forces and energetic cost. We report that minimizing the load suspension natural frequency and damping ratio significantly reduces the stability of the load mass but may slightly improve the body stability of locomotion when compared to a rigidly attached load. These results imply that a highly-compliant load suspension could help stabilize body motion during human, animal, or robot load carriage, but at the cost of a more awkward (less stable) load. PMID- 28093260 TI - Shear and pressure under the first ray in neuropathic diabetic patients: Implications for support of the longitudinal arch. AB - OBJECTIVE: To assess dynamic arch support in diabetic patients at risk for Charcot neuroarthopathy whose arch index has not yet shown overt signs of foot collapse. METHODS: Two indirect measures of toe flexor activation (ratios: peak hallux pressure to peak metatarsal pressure - Ph/Pm; peak posterior hallux shear to peak posterior metatarsal shear - Sh/Sm) were obtained with a custom built system for measuring shear and pressure on the plantar surface of the foot during gait. In addition, the tendency of the longitudinal arch to flatten was measured by quantifying the difference in shear between the 1st metatarsal head and the heel (Sflatten) during the first half of the stance phase. Four stance phases from the same foot for 29 participants (16 control and 13 neuropathic diabetic) were assessed. RESULTS: The peak load ratio under the hallux (Ph/Pm) was significantly higher in the control group (2.10+/-1.08 versus 1.13+/-0.74, p=0.033). Similarly, Sh/Sm was significantly higher in the control group (1.87+/ 0.88 versus 0.88+/-0.45, p=0.004). The difference in anterior shear under the first metatarsal head and posterior shear under the lateral heel (Sflatten) was significantly higher in the diabetic group (p<0.01). Together these findings demonstrate reduced plantar flexor activity in the musculature responsible for maintaining the longitudinal arch. CONCLUSIONS: With no significant difference in arch index between the two groups, but significant differences in Ph/Pm, Sh/Sm and Sflatten the collective results suggest there are changes in muscle activity that precede arch collapse. PMID- 28093261 TI - Experimental evaluation of a new morphological approximation of the articular surfaces of the ankle joint. AB - The mechanical characteristics of the ankle such as its kinematics and load transfer properties are influenced by the geometry of the articulating surfaces. A recent, image-based study found that these surfaces can be approximated by a saddle-shaped, skewed, truncated cone with its apex oriented laterally. The goal of this study was to establish a reliable experimental technique to study the relationship between the geometry of the articular surfaces of the ankle and its mobility and stability characteristics and to use this technique to determine if morphological approximations of the ankle surfaces based on recent discoveries, produce close to normal behavior. The study was performed on ten cadavers. For each specimen, a process based on medical imaging, modeling and 3D printing was used to produce two subject specific artificial implantable sets of the ankle surfaces. One set was a replica of the natural surfaces. The second approximated the ankle surfaces as an original saddle-shaped truncated cone with apex oriented laterally. Testing under cyclic loading conditions was then performed on each specimen following a previously established technique to determine its mobility and stability characteristics under three different conditions: natural surfaces; artificial surfaces replicating the natural surface morphology; and artificial approximation based on the saddle-shaped truncated cone concept. A repeated measure analysis of variance was then used to compare between the three conditions. The results show that (1): the artificial surfaces replicating natural morphology produce close to natural mobility and stability behavior thus establishing the reliability of the technique; and (2): the approximated surfaces based on saddle-shaped truncated cone concept produce mobility and stability behavior close to the ankle with natural surfaces. PMID- 28093262 TI - The anchor-based minimal important change, based on receiver operating characteristic analysis or predictive modeling, may need to be adjusted for the proportion of improved patients. AB - OBJECTIVES: Patients have their individual minimal important changes (iMICs) as their personal benchmarks to determine whether a perceived health-related quality of life (HRQOL) change constitutes a (minimally) important change for them. We denote the mean iMIC in a group of patients as the "genuine MIC" (gMIC). The aims of this paper are (1) to examine the relationship between the gMIC and the anchor based minimal important change (MIC), determined by receiver operating characteristic analysis or by predictive modeling; (2) to examine the impact of the proportion of improved patients on these MICs; and (3) to explore the possibility to adjust the MIC for the influence of the proportion of improved patients. STUDY DESIGN AND SETTING: Multiple simulations of patient samples involved in anchor-based MIC studies with different characteristics of HRQOL (change) scores and distributions of iMICs. In addition, a real data set is analyzed for illustration. RESULTS: The receiver operating characteristic-based and predictive modeling MICs equal the gMIC when the proportion of improved patients equals 0.5. The MIC is estimated higher than the gMIC when the proportion improved is greater than 0.5, and the MIC is estimated lower than the gMIC when the proportion improved is less than 0.5. Using an equation including the predictive modeling MIC, the log-odds of improvement, the standard deviation of the HRQOL change score, and the correlation between the HRQOL change score and the anchor results in an adjusted MIC reflecting the gMIC irrespective of the proportion of improved patients. CONCLUSION: Adjusting the predictive modeling MIC for the proportion of improved patients assures that the adjusted MIC reflects the gMIC. LIMITATIONS: We assumed normal distributions and global perceived change scores that were independent on the follow-up score. Additionally, floor and ceiling effects were not taken into account. PMID- 28093263 TI - "Cross-sectional" stepped wedge designs always reduce the required sample size when there is no time effect. PMID- 28093264 TI - The CONSORT guidelines for noninferiority trials should be updated to go beyond the absolute risk difference. PMID- 28093265 TI - Developmental tracing of oocyte development in gonadal soma-derived factor deficiency medaka (Oryzias latipes) using a transgenic approach. AB - Gonadal soma-derived factor (gsdf) is reported to be a male initiator in medaka based on loss- and gain- of function via targeted disruption, or transgenic over expression. However, little is known about how gsdf promotes undifferentiated gonad entry into male pathways or prevents entry into the female pathway. We utilized a visible folliculogenesis system with a reporter cassette of dual-color fluorescence expression to identify difference between oocyte development from wildtype and gsdf deficiency medaka. A red fluorescent protein (RFP) is driven by a major component of the synaptonemal complex (SYCP3) promoter which enables RFP expression solely in oocytes after the onset of meiosis, and a histone 2b-EGFP fused protein (H2BEGFP) under the control of an elongation factor (EF1alpha) promoter, wildly used as a mitotic reporter of cell cycle. This mitosis-meiosis visible switch revealed that early meiotic oocytes present in gsdf deficiency were more than those in wildtype ovaries, corresponding to the decrease of inhibin expression detected by real-time qPCR analysis, suggesting gsdf is tightly involved in the process of medaka oocyte development at early stage. PMID- 28093266 TI - Comparative analysis of NK cell receptor repertoire in adults and very elderly subjects with cytomegalovirus infection. AB - Human cytomegalovirus (HCMV) infection in children and young adults has been associated with changes in the innate immune system. We herein analyzed the possible effect of very long term HCMV infection on the expression of several NK cell receptors. Ninety HCMV-seropositive individuals were included and classified as young adults (n=30), elderly (n=30) and very elderly subjects (n=30). A peripheral blood sample was obtained and the expression of NK cell receptors (NKG2A, NKG2C, ILT2, CD161, KIR2DL1, KIR3DL1, and KIR3DL2) by NK and other lymphocyte subsets was assessed by flow cytometry. In addition, the frequency of the sixteen KIR genes was analyzed by polymerase chain reaction. We found a significant increase in the number of NKG2C+ NK and T cells in elderly individuals compared to young adults accompanied by an opposite trend in the number of NKG2A+ lymphocytes, and ILT2+ cells were also increased in elderly individuals. A significant increase in the levels of CD3-CD56+NKG2C+CD57+ cells was also detected in the elderly groups. Finally, KIR gene analysis revealed that the KIR genotype 2 was significantly less frequent in the elderly individuals. Our results support that long-term infection by HCMV exerts a significant progressive effect on the innate immune system. PMID- 28093267 TI - Interleukin 6 induces cell proliferation of clear cell renal cell carcinoma by suppressing hepaCAM via the STAT3-dependent up-regulation of DNMT1 or DNMT3b. AB - Interleukin 6 (IL-6), a tumor promoting cytokine, has been largely implicated in the development of renal cell carcinoma (RCC). Hepatocyte cell adhesion molecule (hepaCAM) is a novel tumor suppressor, which is lost or down-regulated in many cancer types including RCC. In the present study, we intensively investigated the connection between IL-6 and hepaCAM in RCC. Our analysis of RCC tissues, adjacent tissues and paired serum samples from RCC patients revealed that IL-6 was elevated in patient serum and RCC tissue, whereas hepaCAM was completely lost or significantly down-regulated. Furthermore, we observed an association between IL 6 increase and hepaCAM decrease in RCC tissue samples. In the section of cytological researches, we found in RCC cell lines that IL-6 was a direct upstream regulator of hepaCAM, and that hepaCAM down-regulation was involved in IL-6-driven cell proliferation. We also demonstrated that IL-6-mediated promoter hypermethylation largely accounted for the hepaCAM loss in RCC, and it was STAT3 dependent. Additionally, our data showed that DNMT1 up-regulation induced by IL 6/STAT3 signaling was indispensable for IL-6-mediated hepaCAM loss in RCC cell lines ACHN and 769-P, while DNMT3b up-regulation was crucial for hepaCAM loss in A498. Our findings provide a novel signal pathway regulating cell proliferation, potentially representing a therapeutic target for RCC. PMID- 28093268 TI - Bronchiectasis Rheumatoid Overlap Syndrome Is an Independent Risk Factor for Mortality in Patients With Bronchiectasis: A Multicenter Cohort Study. AB - BACKGROUND: This study assessed if bronchiectasis (BR) and rheumatoid arthritis (RA), when manifesting as an overlap syndrome (BROS), were associated with worse outcomes than other BR etiologies applying the Bronchiectasis Severity Index (BSI). METHODS: Data were collected from the BSI databases of 1,716 adult patients with BR across six centers: Edinburgh, United Kingdom (608 patients); Dundee, United Kingdom (n = 286); Leuven, Belgium (n = 253); Monza, Italy (n = 201); Galway, Ireland (n = 242); and Newcastle, United Kingdom (n = 126). Patients were categorized as having BROS (those with RA and BR without interstitial lung disease), idiopathic BR, bronchiectasis-COPD overlap syndrome (BCOS), and "other" BR etiologies. Mortality rates, hospitalization, and exacerbation frequency were recorded. RESULTS: A total of 147 patients with BROS (8.5% of the cohort) were identified. There was a statistically significant relationship between BROS and mortality, although this relationship was not associated with higher rates of BR exacerbations or BR-related hospitalizations. The mortality rate over a mean of 48 months was 9.3% for idiopathic BR, 8.6% in patients with other causes of BR, 18% for RA, and 28.5% for BCOS. Mortality was statistically higher in patients with BROS and BCOS compared with those with all other etiologies. The BSI scores were statistically but not clinically significantly higher in those with BROS compared with those with idiopathic BR (BSI mean, 7.7 vs 7.1, respectively; P < .05). Patients with BCOS had significantly higher BSI scores (mean, 10.4), Pseudomonas aeruginosa colonization rates (24%), and previous hospitalization rates (58%). CONCLUSIONS: Both the BROS and BCOS groups have an excess of mortality. The mechanisms for this finding may be complex, but these data emphasize that these subgroups require additional study to understand this excess mortality. PMID- 28093269 TI - Invasive Disease vs Urinary Antigen-Confirmed Pneumococcal Community-Acquired Pneumonia. AB - BACKGROUND: The burden of pneumococcal disease is measured only through patients with invasive pneumococcal disease. The urinary antigen test (UAT) for pneumococcus has exhibited high sensitivity and specificity. We aimed to compare the pneumococcal pneumonias diagnosed as invasive disease with pneumococcal pneumonias defined by UAT results. METHODS: A prospective observational study of consecutive nonimmunosuppressed patients with community-acquired pneumonia was performed from January 2000 to December 2014. Patients were stratified into two groups: invasive pneumococcal pneumonia (IPP) defined as a positive blood culture or pleural fluid culture result and noninvasive pneumococcal pneumonia (NIPP) defined as a positive UAT result with negative blood or pleural fluid culture result. RESULTS: We analyzed 779 patients (15%) of 5,132, where 361 (46%) had IPP and 418 (54%) had NIPP. Compared with the patients with IPP, those with NIPP presented more frequent chronic pulmonary disease and received previous antibiotics more frequently. Patients with IPP presented more severe community acquired pneumonia, higher levels of inflammatory markers, and worse oxygenation at admission; more pulmonary complications; greater extrapulmonary complications; longer time to clinical stability; and longer length of hospital stay compared with the NIPP group. Age, chronic liver disease, mechanical ventilation, and acute renal failure were independent risk factors for 30-day crude mortality. Neither IPP nor NIPP was an independent risk factor for 30-day mortality. CONCLUSIONS: A high percentage of confirmed pneumococcal pneumonia is diagnosed by UAT. Despite differences in clinical characteristics and outcomes, IPP is not an independent risk factor for 30-day mortality compared with NIPP, reinforcing the importance of NIPP for pneumococcal pneumonia. PMID- 28093270 TI - Cardiac magnetic resonance tissue tracking in right ventricle: Feasibility and normal values. AB - PURPOSE: To investigate right ventricular (RV) strain in patients without identified cardiac pathology using cardiac magnetic resonance tissue tracking (CMR TT). METHODS: A total of 50 consecutive patients with no identified cardiac pathology were analyzed. RV longitudinal and circumferential strain was assessed by CMR TT. The age range was 4-81years with a median of 32years (interquartile range, 15 to 56years). RESULTS: Analysis time per patient was <5min. The peak longitudinal strain (Ell) was -22.11+/-3.51%. The peak circumferential strains (Ecc) for global, basal, mid-cavity and apical segments were as follows: -11.69+/ 2.25%, -11.00+/-2.45%, -11.17+/-3.36%, -12.90+/-3.34%. There were significant gender differences in peak Ecc at the base (P=0.04) and the mid-cavity (P=0.03) with greater deformation in females than in males. On Bland-Altman analysis, peak Ell (mean bias, 0.22+/-1.67; 95% CI -3.05 to 3.49) and mid-cavity Ecc (mean bias, 0.036+/-1.75; 95% CI, -3.39 to 3.47) had the best intra-observer agreement and inter-observer agreement, respectively. CONCLUSIONS: RV longitudinal and circumferential strains can be quickly assessed with good intra-observer and inter-observer variability using TT. PMID- 28093271 TI - Characterization and clinical validation of MCM2 and TOP2A monoclonal antibodies in the BD ProExTM C assay: An immunoassay which detects aberrant S-phase induction in cervical tissue. AB - BACKGROUND: The Papanicolaou (Pap) screen has been successful in reducing cervical cancer; but exhibits low sensitivity when detecting cervical dysplasia. Use of molecular biomarkers in Pap tests may improve diagnostic accuracy. DESIGN: Monoclonal antibodies to Minichromosome Maintenance Protein 2 (MCM2) and DNA Topoisomerase II alpha (TOP2A) were selected for use in IHC based on their ability to differentiate normal from diseased cervical tissues in tissue microarrays. Enhanced Green Fluorescent Protein Western blot analysis was used to help identify binding epitopes specific to MCM2 and TOP2A antibody clones. Antibody affinity was determined by solution phase affinity measurement and immunohistochemistry was performed using high affinity MCM2 or TOP2A antibodies on serial histological sections. RESULTS: Antibody clones to MCM2 and TOP2A clones were selected based on their ability to detect over expression in abnormal cervical epithelia. In IHC, MCM2-27C5.6 and MCM2-26H6.19 demonstrated superior staining in abnormal cervical tissue over the MCM2-CRCT2.1 antibody. A combination of MCM2 and TOP2A antibodies showed greater staining when compared to staining with any of the antibodies alone on serial histological sections. Distinct linear epitopes were elucidated for each of the MCM2 and TOP2A clones. Affinity values (Kd) for MCM2 or TOP2A antibodies had a similar range. In a research study, the MCM2 and TOP2A (BD ProExTM C) antibody cocktail showed increased epithelia staining with increasing dysplasia. The use of BD ProExTM C in combination with H&E staining enhanced immunohistochemical discrimination of dysplastic and non-dysplastic FFPE cervical tissue specimens. CONCLUSIONS: BD ProExTM C containing MCM2 and TOP2A antibodies showed strong specific nuclear staining that correlated with increased dysplasia and lesion severity. Enhanced performance of the antibodies was linked to their unique topography recognition. BD ProExTM C incorporates antibodies that enhance detection of CIN2+ cervical disease. PMID- 28093272 TI - A method for obtaining simian immunodeficiency virus RNA sequences from laser capture microdissected and immune captured CD68+ and CD163+ macrophages from frozen tissue sections of bone marrow and brain. AB - Laser capture microdissection (LCM) is used to extract cells or tissue regions for analysis of RNA, DNA or protein. Several methods of LCM are established for different applications, but a protocol for consistently obtaining lentiviral RNA from LCM captured immune cell populations is not described. Obtaining optimal viral RNA for analysis of viral genes from immune-captured cells using immunohistochemistry (IHC) and LCM is challenging. IHC protocols have long antibody incubation times that increase risk of RNA degradation. But, immune capture of specific cell populations like macrophages without staining for virus cannot result in obtaining only a fraction of cells which are productively lentivirally infected. In this study we sought to obtain simian immunodeficiency virus (SIV) RNA from SIV gp120+ and CD68+ monocyte/macrophages in bone marrow (BM) and CD163+ perivascular macrophages in brain of SIV-infected rhesus macaques. Here, we report an IHC protocol with RNase inhibitors that consistently results in optimal quantity and yield of lentiviral RNA from LCM-captured immune cells. PMID- 28093274 TI - A direct quantitative PCR-based measurement of herpes simplex virus susceptibility to antiviral drugs and neutralizing antibodies. AB - Herpes simplex viruses (HSV) are common human pathogens that can cause painful but benign manifestations and recurrent complaints, but can also cause significant morbidity and mortality on infection of the eye or brain and with disseminated infection of an immunosuppressed patient or a neonate. HSV growth inhibition measurement by plaque or yield reduction is a key task in the development of novel antiviral compounds but the manual methods are very labour intensive. The sensitive and specific PCR technology could be an effective method for quantitation of HSV DNA related to virus replication; however the currently described PCR approaches have a major limitation, namely the requirement of purification of DNA from the infected cells. This limitation makes this approach unfeasible for high-throughput screenings. The monitoring of HSV specific antibody titre is essential in vaccination trials and in the improvement of HSV based oncolytic virotherapy. Usually, conventional cytopathic effect-based and plaque reduction neutralization tests are applied to measure the neutralization titre, but these methods are also time-consuming. To overcome this, we developed a quantitative PCR (qPCR) method for the detection of HSV-2 DNA directly from the infected cells (direct qPCR) and the method was further adapted to measure the titre of HSV specific neutralizing antibody in human sera. The conditions of direct qPCR assay were optimized to measure the antiviral activity of known and novel antiviral substances. Using HSV-2 seronegative and seropositive patients' sera, the validity of the direct qPCR neutralization test was compared to traditional cytopathic effect-based assay. The direct qPCR method was able to detect the HSV-2 DNA quantitatively between multiplicity of infection 1/64 and 1/4194304, indicating that the dynamic range of the detection was approximately 65,500 fold with high correlation between the biological and technical replicates. As a proof of the adaptability of the method, we applied the direct qPCR for antiviral inhibitory concentration 50 (IC50) measurements of known and novel antiviral compounds. The measured IC50 of acyclovir was ~0.28MUg/ml, similar to the previously published IC50 value. The IC50 of novel antiviral candidates was between 1.6-3.1MUg/ml. The direct qPCR-based neutralization titres of HSV positive sera were 1:32-1:64, identical to the neutralization titres determined using a traditional neutralization assay. The negative sera did not inhibit the HSV-2 replication in either of the tests. Our direct qPCR method for the HSV-2 growth determination of antiviral IC50 and neutralization titre is less time-consuming, less subjective and a more accurate alternative to the traditional plaque titration and growth reduction assays. PMID- 28093275 TI - Reverse-transcription loop-mediated isothermal amplification for rapid detection of respiratory syncytial virus directly from nasopharyngeal swabs. AB - Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infection in young infants and a major cause of nosocomial infection in pediatric care. Currently available RSV point-of-care tests are of limited sensitivity and relatively expensive. We developed and evaluated a novel RSV rapid test for use at point-of-care, based on reverse-transcription loop-mediated isothermal amplification (RT-LAMP) for direct testing of nasopharyngeal swab specimens. RT LAMP can detect RSV within 30min, without the need for RNA extraction. The sensitivity of our RT-LAMP assay was 70-80% in comparison to RT-PCR. The RT-LAMP test sensitivity is at least equivalent to currently available rapid antigen detection tests (RADT), and the cost of RT-LAMP test reagents is only approximately 10% of that of commercially available RADT tests. RT-LAMP appears to be an attractive alternative to RADT, particularly in settings with limited financial resources. Future improvements could include lyophilization of test reagents and automated read-out of RT-LAMP results. PMID- 28093273 TI - Identification of Fhit as a post-transcriptional effector of Thymidine Kinase 1 expression. AB - FHIT is a genome caretaker gene that is silenced in >50% of cancers. Loss of Fhit protein expression promotes accumulation of DNA damage, affects apoptosis and epithelial-mesenchymal transition, though molecular mechanisms underlying these alterations have not been fully elucidated. Initiation of genome instability directly follows Fhit loss and the associated reduced Thymidine Kinase 1 (TK1) protein expression. The effects on TK1 of Fhit knockdown and Fhit induction in the current study confirmed the role of Fhit in regulating TK1 expression. Changes in Fhit expression did not impact TK1 protein turnover or transcription from the TK1 promoter, nor steady-state levels of TK1 mRNA or turnover. Polysome profile analysis showed that up-regulated Fhit expression resulted in decreased TK1 RNA in non-translating messenger ribonucleoproteins and increased ribosome density on TK1 mRNA. Fhit does not bind RNA but its expression increased luciferase expression from a transgene bearing the TK1 5'-UTR. Fhit has been reported to act as a scavenger decapping enzyme, and a similar result with a mutant (H96) that binds but does not cleave nucleoside 5',5'-triphosphates suggests the impact on TK1 translation is due to its ability to modulate the intracellular level of cap-like molecules. Consistent with this, cells expressing Fhit mutants with reduced activity toward cap-like dinucleotides exhibit DNA damage resulting from TK1 deficiency, whereas cells expressing wild-type Fhit or the H96N mutant do not. The results have implications for the mechanism by which Fhit regulates TK1 mRNA, and more broadly, for its modulation of multiple functions as tumor suppressor/genome caretaker. PMID- 28093276 TI - Asymmetry in visual information processing depends on the strength of eye dominance. AB - Unlike handedness, sighting eye dominance, defined as the eye unconsciously chosen when performing monocular tasks, is very rarely considered in studies investigating cerebral asymmetries. We previously showed that sighting eye dominance has an influence on visually triggered manual action with shorter reaction time (RT) when the stimulus appears in the contralateral visual hemifield with respect to the dominant eye (Chaumillon et al. 2014). We also suggested that eye dominance may be more or less pronounced depending on individuals and that this eye dominance strength could be evaluated through saccadic peak velocity analysis in binocular recordings (Vergilino-Perez et al. 2012). Based on these two previous studies, we further examine here whether the strength of the eye dominance can modulate the influence of this lateralization on manual reaction time. Results revealed that participants categorized as having a strong eye dominance, but not those categorized as having a weak eye dominance, exhibited the difference in RT between the two visual hemifields. This present study reinforces that the analysis of saccade peak velocity in binocular recordings provides an effective tool to better categorize the eye dominance. It also shows that the influence of eye dominance in visuo-motor tasks depends on its strength. Our study also highlights the importance of considering the strength of eye dominance in future studies dealing with brain lateralization. PMID- 28093277 TI - Evaluating the relationship between sublexical and lexical processing in speech perception: Evidence from aphasia. AB - Several studies have reported that aphasic patients may perform substantially better on lexical than sublexical perception tasks (e.g., Miceli et al., 1980). These findings challenge claims made by models of speech perception which assume obligatory sublexical processing (e.g., McClelland and Elman, 1986; Norris, 1994). However, prior studies have not closely matched the phonological similarity of targets and distractors or task demands of the sublexical and lexical perception tasks. The current study addressed shortcomings of these prior studies, testing 13 aphasic patients on sublexical and lexical tasks matched in phonological similarity of stimuli and task demands. When the lexical and sublexical tasks were not matched (Experiment 1a), as in prior studies (e.g., Miceli et al., 1980), several patients with impaired sublexical perception were within the control range on tasks tapping lexical perception. In contrast, when the lexical and sublexical tasks (sublexical: syllable discrimination, auditory written syllable matching (AWSM); lexical: word discrimination, lexical decision, and picture-word matching (PWM)) were matched on these factors (Experiments 1b and 2), in most instances, patients were impaired on both sublexical and lexical tasks relative to controls and performance on the lexical tasks was not significantly greater than that on the sublexical tasks. For two patients, performance on one lexical task was statistically better than that on one sublexical task, but the advantage was not replicated across other task comparisons. The current study is consistent with models of speech perception which assume obligatory sublexical processing and fails to support models that do not require successful sublexical perception in order to access lexical levels (e.g., Goldinger, 1998; Hickok and Poeppel, 2000). PMID- 28093278 TI - Similar patterns of brain activation abnormalities during emotional and non emotional judgments of faces in a schizophrenia family study. AB - Schizophrenia patients have impaired performance and abnormal brain activation during facial emotion recognition, which may represent a marker of genetic liability to schizophrenia. However, it remains unclear whether the impairment is specific to recognizing emotion from faces or is instead attributable to more generalized dysfunction. The current study aimed to distinguish between specific and generalized neural dysfunction underlying impaired facial emotion recognition in schizophrenia and examine associations with genetic liability. Twenty-eight schizophrenia patients, 27 nonpsychotic first-degree relatives, and 27 community controls underwent functional magnetic resonance imaging while making judgments about either the emotion or age of emotional faces. Patients had performance deficits during the emotion and age discrimination conditions compared to relatives and controls, while relatives had intact performance. Patients had hypoactivation compared to controls across conditions, mainly in medial prefrontal cortex. Unlike controls, patients demonstrated a failure to recruit the dorsomedial prefrontal cortex, a region involved in social cognition and decision-making, and relatives had a pattern of recruitment intermediate between patients and controls. Compared to controls, relatives had greater deactivation of regions associated with the default mode network, and patients had similar findings during age discrimination. The common patterns of performance deficits and activation abnormalities during emotion and age discrimination in schizophrenia suggest that generalized cognitive impairment, notably in social cognition and decision-making, contributes to impaired facial emotion recognition. Similar functional activation patterns in relatives, despite intact performance, suggest that brain activation may represent a more sensitive marker of genetic liability than behaviour. Hyperdeactivation of default mode network regions in relatives may represent cognitive inefficiency, or compensatory mechanisms that help maintain intact performance. PMID- 28093280 TI - Metronomics in the neoadjuvant and adjuvant treatment of breast cancer. AB - The concept of metronomic chemotherapy (MC) has evolved from a descriptive preclinical phenomenon encompassing inhibition of angiogenesis to a clinically validated treatment concept involving multiple potential mechanisms of action. Clinicians are progressively more incline to consider MC as a component of mainstream medical oncology practice in advanced breast cancer. However, more recently MC has been tested even in the adjuvant/neoadjuvant setting, taking the opportunity to obtain tumor specimens and blood samples, in order to identify tumor-specific or patient-specific biomarkers for personalizing treatments. In addition, the antiangiogenic and pro-immune nature of metronomic chemotherapy made triple negative breast cancer (TNBC) a good candidate for exploring low-dose maintenance treatment in the adjuvant setting or in combination with immunomodulatory drugs. The potential development of MC in breast cancer pass through the research to identify biomarkers and individual tumor characteristics that can better address the use of this treatment strategy in the future. Finally, the subjective attitude of patients represents one of the major factors that influence the choice and acceptance of a therapeutic program. Personal preference and considerations about quality of life should guide the treatment choice eventually prioritizing the use of MC. Nevertheless, more robust data from randomized phase III trials are needed in the future, in order to make clinicians more confident in using metronomic strategies. PMID- 28093281 TI - Kindlin-2 in pancreatic stellate cells promotes the progression of pancreatic cancer. AB - Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis associated with pancreatic ductal adenocarcinoma (PDAC). Kindlin-2 is a focal adhesion protein that regulates the activation of integrins. This study aimed to clarify the role of kindlin-2 in PSCs in pancreatic cancer. Kindlin-2 expression in 79 resected pancreatic cancer tissues was examined by immunohistochemical staining. Kindlin-2-knockdown immortalized human PSCs were established using small interfering RNA. Pancreatic cancer cells were treated with conditioned media of PSCs, and the cell proliferation and migration were examined. SUIT-2 pancreatic cancer cells were subcutaneously injected into nude mice alone or with PSCs and the size of the tumors was monitored. Kindlin-2 expression was observed in PDAC and the peritumoral stroma. Stromal kindlin-2 expression was associated with shorter recurrence-free survival time after R0 resection. Knockdown of kindlin-2 resulted in decreased proliferation, migration, and cytokine expression in PSCs. The PSC-induced proliferation and migration of pancreatic cancer cells were suppressed by kindlin-2 knockdown in PSCs. In vivo, co-injection of PSCs increased the size of the tumors, but this effect was abolished by kindlin-2 knockdown in PSCs. In conclusion, kindlin-2 in PSCs promoted the progression of pancreatic cancer. PMID- 28093282 TI - IL-1beta induces up-regulation of BIRC3, a gene involved in chemoresistance to doxorubicin in breast cancer cells. AB - Epithelial to mesenchymal transition (EMT) of tumor cells facilitates their progress to metastasis. In the tumor microenvironment the inflammatory cytokine 1beta (IL-1beta) has been associated with tumor development and invasiveness. IL 1beta-induced EMT triggers the expression of markers associated with malignancy. We have recently reported that an IL-1beta-highly responsive clone (6D cells) from non-invasive MCF-7 breast cancer cells activates PI3K/Rac and IL-1RI/beta catenin pathways that up-regulate the transcription of genes involved in an EMT like process. However, a correlation between the EMT program induced by a pro inflammatory environment, and the acquisition of chemoresistance has not been yet determined in these cells. In this work, we report the expression of cell survival genes after IL-1beta stimulation of 6D cells. The expression of CDKN1A, TP63, SFN and, particularly, BIRC3 was found to be up-regulated in a RNA-seq analysis and validated by qPCR. Cells stimulated with IL-1beta when challenged with doxorubicin showed resistance to the drug, whereas silencing of BIRC3 decreased viability of the cells treated with the drug. Our present results show that IL-1beta confers doxorubicin resistance to breast cancer cells, underlining the importance of an inflammatory environment in cancer malignancy. PMID- 28093279 TI - Obesity and insulin resistance are associated with reduced activity in core memory regions of the brain. AB - Increasing research in animals and humans suggests that obesity may be associated with learning and memory deficits, and in particular with reductions in episodic memory. Rodent models have implicated the hippocampus in obesity-related memory impairments, but the neural mechanisms underlying episodic memory deficits in obese humans remain undetermined. In the present study, lean and obese human participants were scanned using fMRI while completing a What-Where-When episodic memory test (the "Treasure-Hunt Task") that assessed the ability to remember integrated item, spatial, and temporal details of previously encoded complex events. In lean participants, the Treasure-Hunt task elicited significant activity in regions of the brain known to be important for recollecting episodic memories, such as the hippocampus, angular gyrus, and dorsolateral prefrontal cortex. Both obesity and insulin resistance were associated with significantly reduced functional activity throughout the core recollection network. These findings indicate that obesity is associated with reduced functional activity in core brain areas supporting episodic memory and that insulin resistance may be a key player in this association. PMID- 28093283 TI - Lipophilic triphenylphosphonium derivatives enhance radiation-induced cell killing via inhibition of mitochondrial energy metabolism in tumor cells. AB - It has recently been reported that radiation enhances mitochondrial energy metabolism in various tumor cell lines. To examine how this radiation-induced alteration in mitochondrial function influences tumor cell viability, various lipophilic triphenylphosphonium (TPP+) cation derivatives and related compounds such as 4-hydroxy-2,2,6,6-tetramethyl-1-oxy-piperidin (Tempol) with TPP+ (named "Mito-") were designed to inhibit the mitochondrial electron transport chain. Mito-(CH2)10-Tempol (M10T) and its derivatives, Mito-(CH2)5-Tempol (M5T), Mito (CH2)10-Tempol-Methyl (M10T-Me), Mito-C10H21 (M10), and C10H21-Tempol (10T), were prepared. In HeLa human cervical adenocarcinoma cells and A549 human lung carcinoma cells, the fractional uptake of the compound into mitochondria was highest among the TTP+ analogs conjugated with Tempol (M10T, M5T, and 10T). M10T, M10T-Me, and M10 exhibited strong cytotoxicity and enhanced X-irradiation-induced reproductive cell death, while 10T and M5T did not. Furthermore, M10T, M10T-Me, and M10 decreased basal mitochondrial membrane potential and intracellular ATP. M10T treatment inhibited X-ray-induced increases in ATP production. These results indicate that the TPP cation and a long hydrocarbon linker are essential for radiosensitization of tumor cells. The reduction in intracellular ATP by lipophilic TPP+ is partly responsible for the observed radiosensitization. PMID- 28093284 TI - Pancreatic cancer: Stroma and its current and emerging targeted therapies. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies with a 5-year survival rate of 8%. Dense, fibrotic stroma associated with pancreatic tumors is a major obstacle for drug delivery to the tumor bed and plays a crucial role in pancreatic cancer progression. Targeting stroma is considered as a potential therapeutic strategy to improve anti-cancer drug efficacy and patient survival. Although numerous stromal depletion therapies have reached the clinic, they add little to overall survival and are often associated with toxicity. Furthermore, increasing evidence suggests the anti-tumor properties of stroma. Its complete ablation enhanced tumor progression and reduced survival. Consequently, efforts are now focused on developing stromal targeted therapies that normalize the reactive stroma and avoid the extremes: stromal abundance vs. complete depletion. In this review, we summarized the state of current and emerging anti-stromal targeted therapies, with major emphasis on the role of miRNAs in PDAC stroma and their potential use as novel therapeutic agents to modulate PDAC tumor-stromal interactions. PMID- 28093285 TI - The depletion of ATM inhibits colon cancer proliferation and migration via B56gamma2-mediated Chk1/p53/CD44 cascades. AB - Ataxia-telangiectasia mutated (ATM) protein kinase is a major guardian of genomic stability, and its well-established function in cancer is tumor suppression. Here, we report an oncogenic role of ATM. Using two isogenic sets of human colon cancer cell lines that differed only in their ATM status, we demonstrated that ATM deficiency significantly inhibits cancer cell proliferation, migration, and invasion. The tumor-suppressive function of ATM depletion is not modulated by the compensatory activation of ATR, but it is associated with B56gamma2-mediated Chk1/p53/CD44 signaling pathways. Under normal growth conditions, the depletion of ATM prevents B56gamma2 ubiquitination and degradation, which activates PP2A mediated Chk1/p53/p21 signaling pathways, leading to senescence and cell cycle arrest. CD44 was validated as a novel ATM target based on its ability to rescue cell migration and invasion defects in ATM-depleted cells. The activation of p53 induced by ATM depletion suppresses CD44 transcription, thus resulting in epithelial-mesenchymal transition (EMT) and cell migration suppression. Our study suggests that ATM has tumorigenic potential in post-formed colon neoplasia, and it supports ATM as an appealing target for improving cancer therapy. PMID- 28093286 TI - BMP4 promotes metastasis of hepatocellular carcinoma by an induction of epithelial-mesenchymal transition via upregulating ID2. AB - The role of bone morphogenetic protein 4 (BMP4), a crucial epithelial-mesenchymal transition (EMT) mediator, in the progression of hepatocellular carcinoma (HCC) patients heretofore has not been elucidated. The present study analyzed BMP4 expression in tumors and paired non-tumorous liver tissue and its correlation with clinicopathological characteristics from two independent cohorts consisting of 420 HCC patients. Functional analysis of BMP4 was performed in Bel-7402 and HCCLM3 HCC cells, and in a murine HCC model. The downstream targets of BMP4 in HCC were screened and confirmed. The results indicated that BMP4 expression was significantly increased in HCC tissue and highly metastatic HCC cells. BMP4 expression was correlated with vein invasion, overall survival and recurrence free survival of HCC. BMP4 promoted HCC EMT and metastasis in vitro, and consistently in vivo. BMP4 knockdown blocked EMT and tumor metastasis in nude mice. ID2 was up-regulated by recombinant human BMP4, resulting in HCC EMT. Knockdown of ID2 blocked BMP4-induced EMT. In conclusion, BMP4 promotes invasion and metastasis of HCC by an induction of EMT via up-regulating ID2. BMP4 may be a valuable prognostic factor and potential therapeutic target for HCC therapy. PMID- 28093287 TI - Diagnostic accuracy of imaging devices in glaucoma: A meta-analysis. AB - Imaging devices such as the Heidelberg retinal tomograph-3 (HRT3), scanning laser polarimetry (GDx), and optical coherence tomography (OCT) play an important role in glaucoma diagnosis. A systematic search for evidence-based data was performed for prospective studies evaluating the diagnostic accuracy of HRT3, GDx, and OCT. The diagnostic odds ratio (DOR) was calculated. To compare the accuracy among instruments and parameters, a meta-analysis considering the hierarchical summary receiver-operating characteristic model was performed. The risk of bias was assessed using quality assessment of diagnostic accuracy studies, version 2. Studies in the context of screening programs were used for qualitative analysis. Eighty-six articles were included. The DOR values were 29.5 for OCT, 18.6 for GDx, and 13.9 for HRT. The heterogeneity analysis demonstrated statistically a significant influence of degree of damage and ethnicity. Studies analyzing patients with earlier glaucoma showed poorer results. The risk of bias was high for patient selection. Screening studies showed lower sensitivity values and similar specificity values when compared with those included in the meta analysis. The classification capabilities of GDx, HRT, and OCT were high and similar across the 3 instruments. The highest estimated DOR was obtained with OCT. Diagnostic accuracy could be overestimated in studies including prediagnosed groups of subjects. PMID- 28093288 TI - Assessing the Impact of Lithium Chloride on the Expression of P-Glycoprotein at the Blood-Brain Barrier. AB - In addition to extruding drugs from the brain, P-glycoprotein (P-gp) at the blood brain barrier (BBB) facilitates the brain-to-blood clearance of beta-amyloid (Abeta) and is down-regulated in Alzheimer's disease. Studies suggest that the mood-stabilizing drug lithium exerts a protective effect against Alzheimer's disease. Although the mechanisms underlying this effect are not fully understood, evidence suggests that lithium chloride (LiCl) increases P-gp expression in vitro, albeit at concentrations substantially outside the therapeutic window. Therefore, we investigated the effects of pharmacologically-relevant concentrations of LiCl on P-gp expression using in vitro and in vivo approaches. Swiss outbred mice administered LiCl (300 mg/kg/day, 21 days) showed no change in brain microvascular P-gp protein expression. Furthermore, P-gp transcript and protein levels were unaltered by LiCl (1.25-5 mM, 24 h) in human immortalized brain endothelial cells, while both gene and protein expression were significantly enhanced by the P-gp up-regulator, SR12813 by 1.5-fold and 2.0 fold, respectively. P-gp efflux function was also unaffected by LiCl in vitro, by measuring accumulation of the fluorescent P-gp substrate rhodamine-123. This suggests therefore that LiCl is unlikely to affect the BBB efflux of Abeta or other P-gp substrates at pharmacologically-relevant concentrations, suggesting that the Abeta-lowering effects of LiCl are unrelated to elevated BBB P-gp expression. PMID- 28093289 TI - R- and S-Warfarin Were Transported by Breast Cancer Resistance Protein: From In Vitro to Pharmacokinetic-Pharmacodynamic Studies. AB - Warfarin, a racemate of R- and S-warfarin, is an important oral anticoagulant with narrow therapeutic window. Being an acidic drug, warfarin (pKa = 4.94) exists mainly as anion under physiological pH. We hypothesized that the transport of warfarin anion across cell membrane was mediated by breast cancer resistance protein (BCRP), an efflux transporter having a variety of acidic substrates. This study aimed at verifying that warfarin was a substrate of BCRP. Cell lines and mice were used for transport assay and pharmacokinetic-pharmacodynamic studies, respectively. The concentrations of R- and S-warfarin were simultaneously determined by liquid chromatography-mass spectrometry method. Transport assay showed that the intracellular concentrations of R- and S-warfarin in MDCKII-BCRP were significantly lower than those in MDCKII. In addition, Ko143, a potent BCRP inhibitor, significantly inhibited the efflux transport of R- and S-warfarin in MDCKII-BCRP, but not in MDCKII. Pharmacokinetic study showed that the plasma concentrations of R- and S-warfarin in Bcrp-/- mice were significantly higher than those in wild-type mice at 6 h after dosing. Anticoagulation measurement showed that the international normalized ratio in Bcrp-/- mice was significantly higher than that in wild-type mice at 24 h after dosing. In conclusion, R- and S warfarin were transported by BCRP. PMID- 28093290 TI - Editorial. PMID- 28093291 TI - Editorial. PMID- 28093292 TI - Multiparametric Magnetic Resonance/Ultrasound Fusion Prostate Biopsy: Number and Spatial Distribution of Cores for Better Index Tumor Detection and Characterization. AB - PURPOSE: We evaluated the minimum core number for better index tumor detection to determine the best core site as well as biopsy Gleason score heterogeneity in the same index lesion. The aim was to optimize the highest Gleason score detection. MATERIALS AND METHODS: A total of 327 patients with negative digital rectal examination underwent magnetic resonance imaging/transrectal ultrasound fusion targeted biopsy for elevated/rising prostate specific antigen and/or 1 or more detectable lesions on multiparametric magnetic resonance imaging after a previous negative standard biopsy. Depending on the diameter of each index lesion (8 or less, or greater than 8 mm) 4 or 6 cores, respectively, were taken according to a well determined sequence. RESULTS: Of the patients 166 (50.7%) had prostate cancer, including 79 (47.6%) with an 8 mm or less index lesion and 87 (52.4%) with a greater than 8 mm index lesion. Of patients with an index tumor 8 mm or less 7 (8.9%) had 1, 31 (39.2%) had 2, 27 (34.2%) had 3 and 14 (17.7%) had 4 positive cores. Similarly, of patients with a lesion greater than 8 mm 8 (9.2%) had 1, 30 (34.5%) had 2, 13 (14.9%) had 3, 14 (16.1%) had 4, 12 (13.8%) had 5 and 10 (11.5%) had 6 positive cores. The major prevalence of positive cores was observed in the center of the target. Gleason score heterogeneity was found in 12.6% of those with an 8 mm or less target vs 26.4% with a target greater than 8 mm. In the center of the target there was a slight prevalence of Gleason pattern 4 or greater, or a lesser pattern. CONCLUSIONS: Approaching magnetic resonance imaging/transrectal ultrasound fusion targeted biopsy with a single core might be inadequate. Rather, taking 2 cores in the center of the index lesion may provide more accurate cancer detection and optimize the chances of finding the highest Gleason pattern. PMID- 28093293 TI - Core Needle Biopsy and Fine Needle Aspiration Alone or in Combination: Diagnostic Accuracy and Impact on Management of Renal Masses. AB - PURPOSE: Fine needle aspiration with and without concurrent core needle biopsy is a minimally invasive method to diagnose and assist in management of renal masses. We assessed the pathological accuracy of fine needle aspiration compared to and associated with core needle biopsy and the impact on management. MATERIALS AND METHODS: We performed a single institution, retrospective study of 342 cases from 2001 to 2015 with small and large renal masses (4 or less and greater than 4 cm, respectively). Diagnostic and concordance rates, and the impact on management were analyzed. RESULTS: Adequacy rates for fine needle aspiration only, core needle biopsy only and fine needle aspiration plus core needle biopsy were 21%, 12% and 8% (aspiration vs aspiration plus biopsy p <0.026). In the aspiration plus biopsy group adding aspiration to biopsy and biopsy to aspiration reduced the inadequacy rate from 23% to 8% and from 27% to 8% for a total reduction rate of 15% and 19%, respectively, corresponding to 32 cases (9.3%). Rapid on-site examination contributed to a 22.5% improvement in fine needle aspiration adequacy rates. In this cohort 30% of aspiration only, 5% of biopsy only and 12% of aspiration plus biopsy could not be subtyped (aspiration vs biopsy p <0.0001, aspiration vs aspiration plus biopsy p <0.0127 and biopsy vs aspiration plus biopsy p = 0.06). The diagnostic concordance rate with surgical resection was 99%. Conversion of an inadequate specimen to an adequate one by a concurrent procedure impacted treatment in at least 29 of 32 patients. Limitations include the retrospective design and accuracy measurement based on surgical intervention. CONCLUSIONS: Fine needle aspiration plus core needle biopsy vs at least fine needle aspiration alone may improve diagnostic yield when sampling renal masses but it has subtyping potential similar to that of core needle biopsy only. PMID- 28093294 TI - Strehler-Mildvan correlation is a degenerate manifold of Gompertz fit. AB - Gompertz empirical law of mortality is often used in practical research to parametrize survival fraction as a function of age with the help of just two quantities: the Initial Mortality Rate (IMR) and the Gompertz exponent, inversely proportional to the Mortality Rate Doubling Time (MRDT). The IMR is often found to be inversely related to the Gompertz exponent, which is the dependence commonly referred to as Strehler-Mildvan (SM) correlation. In this paper, we address fundamental uncertainties of the Gompertz parameters inference from experimental Kaplan-Meier plots and show, that a least squares fit often leads to an ill-defined non-linear optimization problem, which is extremely sensitive to sampling errors and the smallest systematic demographic variations. Therefore, an analysis of consequent repeats of the same experiments in the same biological conditions yields the whole degenerate manifold of possible Gompertz parameters. We find that whenever the average lifespan of species greatly exceeds MRDT, small random variations in the survival records produce large deviations in the identified Gompertz parameters along the line, corresponding to the set of all possible IMR and MRDT values, roughly compatible with the properly determined value of average lifespan in experiment. The best fit parameters in this case turn out to be related by a form of SM correlation. Therefore, we have to conclude that the combined property, such as the average lifespan in the group, rather than IMR and MRDT values separately, may often only be reliably determined via experiments, even in a perfectly homogeneous animal cohort due to its finite size and/or low age-sampling frequency, typical for modern high-throughput settings. We support our findings with careful analysis of experimental survival records obtained in cohorts of C. elegans of different sizes, in control groups and under the influence of experimental therapies or environmental conditions. We argue that since, SM correlation may show up as a consequence of the fitting degeneracy, its appearance is not limited to homogeneous cohorts. In fact, the problem persists even beyond the simple Gompertz mortality law. We show that the same degeneracy occurs exactly in the same way, if a more advanced Gompertz Makeham aging model is employed to improve the modeling. We explain how SM type of relation between the demographic parameters may still be observed even in extremely large cohorts with immense statistical power, such as in human census datasets, provided that systematic historical changes are weak in nature and lead to a gradual change in the mean lifespan. PMID- 28093295 TI - In silico enhancement of the stability and activity of keratinocyte growth factor. AB - Keratinocyte growth factor (KGF), a member of the fibroblast growth factor (FGF) family, has been implicated in some biological processes such as cell proliferation, development and differentiation. High mitogenic activity of this protein has made it very suitable for repairing radiation-and chemotherapy induced damages. Palifermin, which has been developed from human KGF, is clinically applied to reduce the incidence and duration of cancer therapeutic agents. However, the activity of Palifermin is limited during treatment due to its poor stability. In this study, we have improved the stability and activity of recombinant human KGF (Palifermin) using a computational mutagenesis approach. According to the KGF multiple sequence alignment among different species as well as literature-based information, we have generated several mutations using PyMOL program and evaluated their effects on the stability and activity of KGF in silico. In order to preserve the KGF activity, we did not change the predicted functional residues. Prior to mutagenesis, the 3D structure of rhKGF was predicted by Modeller v9.15 program and quantitative evaluation of predicted models were carried out using VADAR and PROSESS servers. The stability and activity of rhKGF mutants were analyzed using GROMACS molecular dynamics (MD) simulations and docking tools, respectively. The results showed that N159S (N105S in rhKGF sequence) and I172V (I118V in rhKGF) substitutions caused an increased stability and affinity of the rhKGF to Fibroblast growth factor receptor 2 (FGFR2). We will evaluate the effects of favorable mutations on the rhKGF stability and activity in vitro. PMID- 28093296 TI - Inhibition of CD44v3 and CD44v6 function blocks tumor invasion and metastatic colonization. AB - The prevention of cancer cell dissemination and secondary tumor formation are major goals of cancer therapy. Here, we report on the development of a new CD44 targeted copolymer carrying multiple copies of the A5G27 peptide, known for its ability to bind specifically to CD44v3 and CD44v6 on cancer cells and inhibit tumor cell migration, invasion, and angiogenesis. We hypothesized that conjugation of A5G27 to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer would enhance tumor tissue accumulation, promote selective binding to cancer cells, with concomitant increased inhibition of cancer cell invasiveness and migration. Fluorescein-5-isothiocyanate or the near-infrared fluorophore IR783 were attached to the copolymer backbone through a non-cleavable linkage to assess in vitro binding to cancer cells and biodistribution of the polymer in 4T1 murine mammary adenocarcinoma-bearing mice, respectively. The anti-migratory activity was evaluated both in vitro and in vivo. The binding of the targeted copolymer to cancer cells correlated well with the level of CD44 expression, with the polymer being internalized more efficiently by cancer cells. Pre-treatment of mice with polymer-bound A5G27 significantly inhibited lung colonization of migrating 4T1 cells in vivo, with the targeted copolymer accumulating preferentially in subcutaneous 4T1 tumors, when compared to a non-targeted system. As such, the HPMA copolymer-A5G27 conjugate is a promising candidate for inhibiting cancer cell migration and can also be used as a drug or imaging probe carrier for detection and treatment of cancer. PMID- 28093298 TI - Metronomic chemotherapy using orally active carboplatin/deoxycholate complex to maintain drug concentration within a tolerable range for effective cancer management. AB - Metronomic chemotherapy has translated into favorable toxicity profile and capable of delaying tumor progression. Despite its promise, conventional injectable chemotherapeutics are not meaningful to use as metronomic due to the necessity of frequent administration for personalized therapy in long-term cancer treatments. This study aims to exploit the benefits of the oral application of carboplatin as metronomic therapy for non-small cell lung cancer (NSCLC). We developed an orally active carboplatin by physical complexation with a deoxycholic acid (DOCA). The X-ray diffraction (XRD) patterns showed the disappearance of crystalline peaks from carboplatin by forming the complex with DOCA. In vivo pharmacokinetic (PK) study confirmed the oral absorption of carboplatin/DOCA complex. The oral bioavailability of carboplatin/DOCA complex and native carboplatin were calculated as 24.33% and 1.16%, respectively, when a single 50mg/kg oral dose was administered. Further findings of oral bioavailability during a low-dose daily administration of the complex (10mg/kg) for 3weeks were showed 19.17% at day-0, 30.27% at day-7, 26.77% at day-14, and 22.48% at day-21, demonstrating its potential for metronomic chemotherapy. The dose dependent antitumor effects of oral carboplatin were evaluated in SCC7 and A549 tumor xenograft mice. It was found that the oral carboplatin complex exhibited potent anti-tumor activity at 10mg/kg (74.09% vs. control, P<0.01) and 20mg/kg dose (86.22% vs. control, P<0.01) in A549 tumor. The number of TUNEL positive cells in the tumor sections was also significantly increased during oral therapy (3.95% in control, whereas 21.37% and 32.39% in 10mg/kg and 20mg/kg dose, respectively; P<0.001). The enhanced anti-tumor efficacy of oral metronomic therapy was attributed with its antiangiogenic mechanism where new blood vessel formation was notably decreased. Finally, the safety of oral complex was confirmed by three weeks toxicity studies; there were no significant systemic or local abnormalities found in mice at 10mg/kg daily oral dose. Our study thus describes an effective and safe oral formulation of carboplatin as a metronomic chemotherapy. PMID- 28093297 TI - Bottom-up synthesis of carbon nanoparticles with higher doxorubicin efficacy. AB - Nanomedicine requires intelligent and non-toxic nanomaterials for real clinical applications. Carbon materials possess interesting properties but with some limitations due to toxic effects. Interest in carbon nanoparticles (CNPs) is increasing because they are considered green materials with tunable optical properties, overcoming the problem of toxicity associated with quantum dots or nanocrystals, and can be utilized as smart drug delivery systems. Using black tea as a raw material, we synthesized CNPs with a narrow size distribution, tunable optical properties covering visible to deep red absorption, non-toxicity and easy synthesis for large-scale production. We utilized these CNPs to label subcellular structures such as exosomes. More importantly, these new CNPs can escape lysosomal sequestration and rapidly distribute themselves in the cytoplasm to release doxorubicin (doxo) with better efficacy than the free drug. The release of doxo from CNPs was optimal at low pH, similar to the tumour microenvironment. These CNPs were non-toxic in mice and reduced the tumour burden when loaded with doxo due to an improved pharmacokinetics profile. In summary, we created a new delivery system that is potentially useful for improving cancer treatments and opening a new window for tagging microvesicles utilized in liquid biopsies. PMID- 28093299 TI - Freeze concentration-induced PLGA and polystyrene nanoparticle aggregation: Imaging and rational design of lyoprotection. AB - Long-term storage of stable nanoparticulate systems is critical to the utilization of nanotechnology in biomedical applications. Freeze-drying or lyophilization is the most commonly used approach to preparing stable injectable nano formulations. A detailed understanding of the freezing stress on nanoparticles is essential to the successful preservation of original particle attributes and to the development of reliable lyophilization processes. However, visualization of the freezing process and the underlying mechanisms that result in particle aggregation remains challenging. Here, we show a clear causal relationship between the freeze-concentration event and particle aggregation by employing correlative imaging techniques, encompassing both real-time dynamic visualization and super-resolution imaging for frozen systems. Direct evidence was obtained to corroborate the particle isolation hypothesis. Moreover, ice-ice, ice-air and ice-container interfaces were identified as hotspots for generating freezing stress on susceptible nanoparticles. In light of these observations, sphere close packing models were explored. Based on the relationship between jammed particles and void fraction within a confined interfacial space, we are able to define the boundary condition of the minimal 'cryoprotectant to particle ratio' required for effective design space of particle isolation and cryoprotection. These findings clearly demonstrated the utility of visualization techniques and modeling in elucidating the mechanism of freezing stress and protection, providing guiding tools to the rational design of cryoprotectant containing nano formulations and processes. PMID- 28093300 TI - The Surgeon as the Second Victim? Results of the Boston Intraoperative Adverse Events Surgeons' Attitude (BISA) Study. AB - BACKGROUND: An intraoperative adverse event (iAE) is often directly attributable to the surgeon's technical error and/or suboptimal intraoperative judgment. We aimed to examine the psychological impact of iAEs on surgeons as well as the surgeons' attitude about iAE reporting. STUDY DESIGN: We conducted a web-based cross-sectional survey of all surgeons at 3 major teaching hospitals of the same university. The 29-item questionnaire was developed using a systematic closed and open approach focused on assessing the surgeons' personal account of iAE incidence, emotional response to iAEs, available support systems, and perspective about the barriers to iAE reporting. RESULTS: The response rate was 44.8% (n = 126). Mean age of respondents was 49 years, 77% were male, and 83% performed >150 procedures/year. During the last year, 32% recalled 1 iAE, 39% recalled 2 to 5 iAEs, and 9% recalled >6 iAEs. The emotional toll of iAEs was significant, with 84% of respondents reporting a combination of anxiety (66%), guilt (60%), sadness (52%), shame/embarrassment (42%), and anger (29%). Colleagues constituted the most helpful support system (42%) rather than friends or family; a few surgeons needed psychological therapy/counseling. As for reporting, 26% preferred not to see their individual iAE rates, and 38% wanted it reported in comparison with their aggregate colleagues' rate. The most common barriers to reporting iAEs were fear of litigation (50%), lack of a standardized reporting system (49%), and absence of a clear iAE definition (48%). CONCLUSIONS: Intraoperative AEs occur often, have a significant negative impact on surgeons' well-being, and barriers to transparency are fear of litigation and absence of a well-defined reporting system. Efforts should be made to support surgeons and standardize reporting when iAEs occur. PMID- 28093301 TI - Protocol-Driven Management of Suspected Common Duct Stones. AB - BACKGROUND: Common duct stones can be diagnosed by magnetic resonance cholangiopancreatography (MRCP), endoscopic ultrasound (EUS)/ERCP, and intraoperative cholangiogram (IOC). In 2015, our group adopted a standard approach of preoperative EUS/ERCP followed by laparoscopic cholecystectomy for patients with an admission bilirubin >4.0 mg/dL. For bilirubin <4.0 mg/dL, laparoscopic cholecystectomy with IOC was the initial procedure. Postoperative EUS/ERCP with endoscopic sphincterotomy was pursued for positive IOC. Exclusions included clinical suspicion of malignancy and surgically altered anatomy making endoscopic management impractical. STUDY DESIGN: A retrospective comparison of protocol and pre-protocol (baseline) patients was performed, looking at patient demographics, presence of pancreatitis, common duct stone risk factors, comorbidities, length of hospitalization, and postoperative morbidity. Statistical analysis was performed with t-test, chi-square, and Wilcoxon rank-sum test with significance at p < 0.05. RESULTS: There were 56 patients in each group, with a mean +/- SD age of 50.5 +/- 20.88 years and 49.3 +/- 20.92 years, respectively (p = NS). There were no significant differences between baseline and protocol patients with respect to individual and cumulative preoperative comorbidities, pancreatitis, elevation of liver function tests, bilirubin, common duct size, and postoperative morbidity. There were fewer endoscopies (22 vs 35; p = 0.014), and shorter length of stay in protocol patients (2.8 days vs 3.8 days; p = 0.025). CONCLUSIONS: Protocol-driven management of patients with suspected common duct stones reduced the number of endoscopies and length of hospitalization, with no change in postoperative morbidity. This approach has the potential to decrease endoscopy-related morbidity and overall cost without affecting quality of care. PMID- 28093302 TI - Aging and risky decision-making: New ERP evidence from the Iowa Gambling Task. AB - Several pieces of evidence have highlighted the presence of an age-related decline in risky decision-making (DM), but the reason of this decline is still unclear. The aim of the present study was to investigate the neural correlates of feedback processing in risky DM. Twenty-one younger (age <50 years) and 15 older (age >50 years) adults were tested with the Iowa Gambling Task (IGT) during Event Related Potentials (ERP) recording. The analysis was focused on the feedback related negativity (FRN) and P3, two ERP components that represent different stages of feedback processing. Behavioral results revealed that older adults, despite showing a significant learning trend, completed the IGT with a gain of a smaller amount of money compared to the younger ones. ERP results revealed that while the FRN response was comparable in the two groups, the P3 amplitude was significantly reduced after negative feedback in older adults, compared with the younger ones. Furthermore, the difference in the P3 amplitude evoked by positive and negative feedback was significantly correlated with age. Hence, the present findings suggest that older adults seem to be less willing to shift attention from positive to negative information, and that this relevant change in the later stages of feedback processing could be the cause of a poor performance in risky DM contexts. PMID- 28093303 TI - Chlorogenic acid rescues sensorineural auditory function in a diabetic animal model. AB - Recently, many studies have reported that sensorineural hearing impairment related to neurological disorders may be caused by diabetes mellitus. However, to date, only a small number of studies have investigated the treatment of sensorineural hearing impairment. In the present study, the effects of chlorogenic acid on diabetic auditory pathway impairment were evaluated by neuro electrical physiological measurements and morphological investigations. We have shown that CA efficiently prevents the progression of auditory pathway dysfunction caused by DM using auditory brainstem responses and auditory middle latency responses in mice. Additionally, using transient-evoked otoacoustic emissions measurement and scanning electron microscope observation of hair cells in DM mice, we found that CA may aid in the recovery from outer hair cell and otic hair cell damage. In conclusion, CA has beneficial effects for the management of diabetic sensorineural auditory dysfunction. PMID- 28093304 TI - Chloride conducting light activated channel GtACR2 can produce both cessation of firing and generation of action potentials in cortical neurons in response to light. AB - Optogenetics is a powerful technique in neuroscience that provided a great success in studying the brain functions during the last decade. Progress of optogenetics crucially depends on development of new molecular tools. Light activated cation-conducting channelrhodopsin2 was widely used for excitation of cells since the emergence of optogenetics. In 2015 a family of natural light activated chloride channels GtACR was identified which appeared to be a very promising tool for using in optogenetics experiments as a cell silencer. Here we examined properties of GtACR2 channel expressed in the rat layer 2/3 pyramidal neurons by means of in utero electroporation. We have found that despite strong inhibition the light stimulation of GtACR2-positive neurons can surprisingly lead to generation of action potentials, presumably initiated in the axonal terminals. Thus, when using the GtACR2 in optogenetics experiments, its ability to induce action potentials should be taken into account. Our results also open an interesting possibility of using the GtACR2 both as cell silencer and cell activator in the same experiment varying the pattern of light stimulation. PMID- 28093305 TI - Role of leptin in conditioned place preference to high-fat diet in leptin deficient ob/ob mice. AB - Leptin is an adipocyte-derived anorexic hormone that exerts its effects via the hypothalamus and other brain regions, including the reward system. Leptin deficient ob/ob mice that present morbid obesity, hyperphagia, insulin resistance, and infertility are one of the most investigated mouse models of obesity. Conditioned place preference (CPP) paradigm is a standard behavioral model to evaluate the rewarding value of substrates. While leptin is reported to decrease the CPP of lean mice for high fat diet (HFD), it is unknown how CPP toward HFD is affected by leptin replacement in the pathophysiological condition of ob/ob mice. In the present study, we performed the CPP test in order to clarify the effect of leptin on the preference of ob/ob mice for HFD. Ob/ob mice had a significantly higher HFD preference in CPP test when compared with wild type (WT) mice and this preference was suppressed to the levels comparable to the WT mice by leptin replacement with or without normalization of body weight. These results demonstrate that leptin decreases the reward value of HFD independently of obesity, suggesting that leptin reduces food intake by suppressing the hedonic feeding pathway in ob/ob mice. PMID- 28093306 TI - Establishing between-session reliability of TMS-conditioned soleus H-reflexes. AB - Transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) can be used to evaluate descending corticomotor influences on spinal reflex excitability through modulation of the Hoffman reflex (H-reflex). The purpose of this study was to characterize between-session reliability of cortical, spinal, and cortical conditioned spinal excitability measures collected from the soleus muscle. Thirteen able-bodied young adult participants were tested over four sessions. Intraclass correlation coefficients were calculated to quantify between-session reliability of active motor threshold (AMT), unconditioned H-reflexes (expressed as a percentage of Mmax), and conditioned H-reflexes using short-latency facilitation (SLF) and long-latency facilitation (LLF). Pearson correlation coefficients were calculated to assess associations between H-reflex facilitation and unconditioned H-reflex amplitude. Between-session reliability for SLF (ICC=0.71) was higher than for LLF (ICC=0.45), was excellent for AMT (ICC=0.95), and was moderate for unconditioned H-reflexes (ICC=0.63). Our results suggest moderate-to-good reliability of SLF and LLF to evaluate cortical influences on spinal reflex excitability across multiple testing sessions in able-bodied individuals. PMID- 28093307 TI - The Impact of Baseline Functional Bladder Capacity on Short-term Neuromodulation Outcomes. AB - OBJECTIVE: To evaluate the impact of functional bladder capacity (FBC) on clinical outcomes after a staged neuromodulation procedure. MATERIALS AND METHODS: Adults in our prospective neuromodulation database were evaluated. Data were collected from medical records, voiding diaries (FBC defined as average volume per void), Interstitial Cystitis Symptom Index-Problem Index, Overactive Bladder Questionnaire, and Global Response Assessment over 3 months. Descriptive statistics, Pearson's chi-square tests, Wilcoxon rank sum tests, logistic regression, repeated measures analyses, and Spearman correlation coefficients were performed. RESULTS: Of the 216 patients (mean age 59 years; 84% female), most had urinary urgency and frequency with or without urge incontinence (71%), a sacral lead placement (82%), and implantable pulse generator (IPG) implantation (92%). Baseline FBC was similar between implanted and not implanted patients (P = .17); however implanted patients had a median 19 mL increase in FBC after lead placement compared to a 2.7 mL decrease in explanted patients (P = .0014). There was a strong association between percent change in FBC after lead placement and IPG implantation (P = .021; C-statistic 0.68), but baseline FBC (mL) was not associated. Baseline FBC (mL), or percent change in FBC after lead placement, was not related to symptom improvement. When grouped by baseline FBC < 150 mL and FBC >= 150 mL, FBC only improved significantly in the <150 group but both demonstrated significant improvements in symptoms. CONCLUSION: FBC improvements were associated with IPG implantation but not other symptom measures. Patients with low FBC (baseline FBC < 150) also achieved significant improvements in symptoms. PMID- 28093308 TI - Antibiotic Coating of the Artificial Urinary Sphincter (AMS 800): Is it Worthwhile? AB - OBJECTIVE: To investigate the impact of the antibiotic coating InhibiZone on the infection and explantation rates of the AMS 800 in comparison to the AMS 800 without InhibiZone. MATERIALS AND METHODS: We retrospectively identified 305 patients with an AMS 800 in a multicenter cohort study. Patients were subsequently divided into InhibiZone and without InhibiZone-coated groups. Infection and explantation rates were analyzed by univariate and consecutively by multivariate logistic regression adjusted to variable risk factors. The infection free interval was estimated by Kaplan-Meier plot and compared by the log-rank test. A P value below .05 was considered statistically significant. RESULTS: We identified 47 patients with InhibiZone and 258 without InhibiZone coating. In univariate analysis, we could not identify a significant difference in infection (P = .932) or explantation (P = .715) rates between the groups. In multivariate analysis, impaired wound healing (P = .008) and urethral erosion (P < .001) were independent predictors for infection. The InhibiZone coating neither demonstrated significant influence on the infection rate (P = .534) nor on the explantation rate (P = .214). There was no significant difference in estimated infection-free survival between the groups (P = .265). CONCLUSION: The antibiotic coating of the AMS 800 had no significant impact on infection or explantation rates in our cohort. PMID- 28093310 TI - Effects of glucose and insulin administration on glucose transporter expression in the North Pacific spiny dogfish (Squalus suckleyi). AB - Elasmobranchs (sharks, skates, and rays) are a primarily carnivorous group of fish, consuming few carbohydrates. Further, they tend to exhibit delayed responses to glucose and insulin administration in vivo relative to mammals, leading to a presumption of glucose-intolerance. To investigate the glucoregulatory capabilities of the spiny dogfish (Squalus suckleyi), plasma glucose concentration, muscle and liver glycogen content, and glucose transporter (glut1 and 4) mRNA levels were measured following intra-arterial administration of bovine insulin (10ngkg-1) or an approximate doubling of fasting plasma glucose concentration. Within 6h, following glucose administration, approximately half of the introduced glucose load had been cleared, with control levels being restored by 24h post-injection. It was determined that plasma clearance was due in part to increased uptake by the tissues as muscle and liver glycogen content increased significantly, correlating with an upregulation of glut mRNA levels. Following administration of bovine insulin, plasma glucose steadily decreased through 18h before returning toward control levels. Observed decreases in plasma glucose following insulin injection were, however, relatively minor, and no increases in tissue glycogen content were observed. glut4 and glycogen synthase mRNA levels did significantly increase in the muscle in response to insulin, but no changes occurred in the liver. The responses observed mimic what occurs in mammals and teleosts, thus suggesting a conserved mechanism for glucose homeostasis in vertebrates and a high degree of glucose tolerance in these predominantly carnivorous fish. PMID- 28093309 TI - Paracoccidioides spp. catalases and their role in antioxidant defense against host defense responses. AB - Dimorphic human pathogenic fungi interact with host effector cells resisting their microbicidal mechanisms. Yeast cells are able of surviving within the tough environment of the phagolysosome by expressing an antioxidant defense system that provides protection against host-derived reactive oxygen species (ROS). This includes the production of catalases (CATs). Here we identified and analyzed the role of CAT isoforms in Paracoccidioides, the etiological agent of paracoccidioidomycosis. Firstly, we found that one of these isoforms was absent in the closely related dimorphic pathogen Coccidioides and dermatophytes, but all of them were conserved in Paracoccidioides, Histoplasma and Blastomyces species. We probed the contribution of CATs in Paracoccidioides by determining the gene expression levels of each isoform through quantitative RT-qPCR, in both the yeast and mycelia phases, and during the morphological switch (transition and germination), as well as in response to oxidative agents and during interaction with neutrophils. PbCATP was preferentially expressed in the pathogenic yeast phase, and was associated to the response against exogenous H2O2. Therefore, we created and analyzed the virulence defects of a knockdown strain for this isoform, and found that CATP protects yeast cells from H2O2 generated in vitro and is relevant during lung infection. On the other hand, CATA and CATB seem to contribute to ROS homeostasis in Paracoccidioides cells, during endogenous oxidative stress. CAT isoforms in Paracoccidioides might be coordinately regulated during development and dimorphism, and differentially expressed in response to different stresses to control ROS homeostasis during the infectious process, contributing to the virulence of Paracoccidioides. PMID- 28093311 TI - Long non-coding RNA FTH1P3 facilitates oral squamous cell carcinoma progression by acting as a molecular sponge of miR-224-5p to modulate fizzled 5 expression. AB - A growing body of evidence has indicated that long non-coding RNAs (lncRNAs) function as competing endogenous RNAs (ceRNAs) during tumorigenesis. In this study, the qRT-PCR results revealed that the lncRNA ferritin heavy chain 1 pseudogene 3 (FTH1P3) was over-expressed in oral squamous cell carcinoma (OSCC) and decreased the survival rate of OSCC patients. Ectopic expression of FTH1P3 facilitates cell proliferation and colony formation in OSCC cells. Moreover, FTH1P3 acted as a competitive endogenous RNA (ceRNA), effectively becoming sponge for miR-224-5p and thereby modulating the expression of fizzled 5. Importantly, expression analysis revealed that both FTH1P3 and fizzled 5 were up-regulated in OSCC cell lines and tissues, and over-expression of fizzled 5 also functioned as an oncogene in OSCC cells. Our data demonstrated FTH1P3 facilitated OSCC progression by acting as a molecular sponge of miR-224-5p to modulate fizzled 5 expression. Thus, targeting the ceRNA network referring FTH1P3 may be a therapeutic target for treatment of OSCC. PMID- 28093312 TI - Palliative Medicine and Preparedness Planning for Patients Receiving Left Ventricular Assist Device as Destination Therapy-Challenges to Measuring Impact and Change in Institutional Culture. AB - CONTEXT: Although left ventricular assist devices as destination therapy (DT LVAD) can improve survival, quality of life, and functional capacity in well selected patients with advanced heart failure, there remain unique challenges to providing quality end-of-life care in this population. Palliative care involvement is universally recommended, but how to best operationalize this care and measure success is unknown. OBJECTIVES: To characterize the process of preparedness planning (PP) for patients receiving DT-LVAD at our institution and better understand opportunities for quality improvement or procedural transferability. METHODS: Retrospective review of 107 consecutive patients undergoing DT-LVAD implantation at a single institution between 2009 and 2013. Information regarding demographics, advance care planning, and mortality was abstracted from the medical record and analyzed. Findings were compared with a historical cohort who received DT-LVAD implantation at the same institution before the development of PP (2003-2009). RESULTS: Mean age of patients receiving DT-LVAD was 64.3 years (SD +/- 10.7). At last follow-up, 46 patients (43%) had died. Mean post-DT-LVAD survival in this group was 1.1 years (SD +/- 1.2). Eighty nine percent of patient had palliative care consultation before implantation, and 70% completed PP. Although 66% of patients completed an advance directive (AD) preimplantation, only two ADs (2.8%) specifically mentioned DT-LVAD and none addressed core elements of PP. AD completion rates improved from 47% before our policy on PP (P = 0.012). CONCLUSION: A disconnect was evident between the rigor of PP discussions and the content of ADs in the medical record. We urge that future efforts focus on narrowing this gap. PMID- 28093313 TI - Knockdown of nuclease activity in the gut enhances RNAi efficiency in the Colorado potato beetle, Leptinotarsa decemlineata, but not in the desert locust, Schistocerca gregaria. AB - The responsiveness towards orally delivered dsRNA and the potency of a subsequent environmental RNA interference (RNAi) response strongly differs between different insect species. While some species are very sensitive to dsRNA delivery through the diet, others are not. The underlying reasons for this may vary, but degradation of dsRNA by nucleases in the gut lumen is believed to play a crucial role. The Colorado potato beetle, Leptinotarsa decemlineata, is a voracious defoliator of potato crops worldwide, and is currently under investigation for novel control methods based on dsRNA treatments. Here we describe the identification and characterization of two nuclease genes exclusively expressed in the gut of this pest species. Removal of nuclease activity in adults increased the sensitivity towards dsRNA and resulted in improved protection of potato plants. A similar strategy in the desert locust, Schistocerca gregaria, for which we show a far more potent nuclease activity in the gut juice, did however not lead to an improvement of the RNAi response. Possible reasons for this are discussed. Taken together, the present data confirm a negative effect of nucleases in the gut on the environmental RNAi response, and further suggest that interfering with this activity is a strategy worth pursuing for improving RNAi efficacy in insect pest control applications. PMID- 28093314 TI - Remote sensing of multiple vital signs using a CMOS camera-equipped infrared thermography system and its clinical application in rapidly screening patients with suspected infectious diseases. AB - BACKGROUND: Infrared thermography (IRT) is used to screen febrile passengers at international airports, but it suffers from low sensitivity. This study explored the application of a combined visible and thermal image processing approach that uses a CMOS camera equipped with IRT to remotely sense multiple vital signs and screen patients with suspected infectious diseases. METHODS: An IRT system that produced visible and thermal images was used for image acquisition. The subjects' respiration rates were measured by monitoring temperature changes around the nasal areas on thermal images; facial skin temperatures were measured simultaneously. Facial blood circulation causes tiny color changes in visible facial images that enable the determination of the heart rate. A logistic regression discriminant function predicted the likelihood of infection within 10s, based on the measured vital signs. Sixteen patients with an influenza-like illness and 22 control subjects participated in a clinical test at a clinic in Fukushima, Japan. RESULTS: The vital-sign-based IRT screening system had a sensitivity of 87.5% and a negative predictive value of 91.7%; these values are higher than those of conventional fever-based screening approaches. CONCLUSIONS: Multiple vital-sign-based screening efficiently detected patients with suspected infectious diseases. It offers a promising alternative to conventional fever based screening. PMID- 28093315 TI - Using acoustic reflex threshold, auditory brainstem response and loudness judgments to investigate changes in neural gain following acute unilateral deprivation in normal hearing adults. AB - Unilateral auditory deprivation induces a reduction in the acoustic reflex threshold (ART) and an increase in loudness. These findings have been interpreted as a compensatory change in neural gain, governed by changes in excitatory and inhibitory neural inputs. There is also evidence to suggest that changes in neural gain can be measured using the auditory brainstem response (ABR). The present study extended Munro et al. (2014) [J. Acoust. Soc. Am. 135, 315-322] by investigating changes after 4 days of unilateral earplug use to: (i) ART, (ii) ABR and (iii) loudness. Because changes may occur during the post-deprivation test session (day 4), ART measurements were taken 1 h and 2 h post-earplug removal. There was a significant reduction in ART in the treatment ear immediately after the removal of the earplug, which is consistent with a compensatory increase in neural gain. A novel finding was the significant return of ARTs to baseline within 2 h of earplug removal. A second novel finding was a significant decrease in the mean amplitude of ABR wave V in the treatment ear, but a significant increase in the control ear, both after 4 days of deprivation. These changes in the ABR are in the opposite direction to those predicted. We were unable to replicate the change in loudness reported in previous deprivation studies; however, the short period of earplug use may have contributed to this null finding. PMID- 28093316 TI - Molecular mechanisms of UVB-induced senescence of dermal fibroblasts and its relevance for photoaging of the human skin. AB - Due to its ability to cross the epidermis and reach the upper dermis where it causes cumulative DNA damage and increased oxidative stress, UVB is considered the most harmful component of sunlight to the skin. The consequences of chronic exposition to UVB are related to photoaging and photocarcinogenesis. There are limitations to the study of human skin aging and for this reason the use of models is required. Human dermal fibroblasts submitted to mild and repeated doses of UVB are considered a versatile model to study UVB effects in the process of skin photoaging, which depends on the accumulation of senescent cells, in particular in the dermis. Here we provide updated information about the current model of UVB-induced senescence with special emphasis on the process of protein quality control. PMID- 28093318 TI - Massive Vulvar Linear Verrucous Epidermal Nevus Presenting at Menarche. AB - BACKGROUND: Epidermal nevi are benign hamartomatous growths of the skin that present at birth and develop in early childhood often linearly along the "lines of Blaschko." Verrucous linear epidermal nevi are the most common epidermal nevi and often are located on the trunk or extremities. There is minimal evidence regarding vulvar involvement and subsequent management of the associated cosmetic deformity in this anatomic location. CASE: An 11-year-old menarchal girl who underwent full-thickness dermal excision of a 9.6 * 4.5 * 3.2 cm left benign vulvar epidermal nevus (noninflammatory type) with primary reconstruction and closure using a mons rotational skin flap. SUMMARY AND CONCLUSION: Surgical excision of large vulvar nevi can be achieved with desirable cosmetic outcomes with use of rotational skin flaps and primary closure. PMID- 28093317 TI - Stem cell therapies in preclinical models of stroke. Is the aged brain microenvironment refractory to cell therapy? AB - : Stroke is a devastating disease demanding vigorous search for new therapies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizing impediments that may be related to unfavorable age-associated environments. Recent results using a variety of drug, cell therapy or combination thereof suggest that, (i) treatment with Granulocyte-Colony Stimulating Factor (G CSF) in aged rats has primarily a beneficial effect on functional outcome most likely via supportive cellular processes such as neurogenesis; (ii) the combination therapy, G-CSF with mesenchymal cells (G-CSF+BM-MSC or G-CSF+BM-MNC) did not further improve behavioral indices, neurogenesis or infarct volume as compared to G-CSF alone in aged animals; (iii) better results with regard to integration of transplanted cells in the aged rat environment have been obtained using iPS of human origin; (iv) mesenchymal cells may be used as drug carriers for the aged post-stroke brains. CONCLUSION: While the middle aged brain does not seem to impair drug and cell therapies, in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a much longer time. PMID- 28093319 TI - Anti-inflammatory effect of the Salvia sclarea L. ethanolic extract on lipopolysaccharide-induced periodontitis in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Salvia sclarea L., clary, is an aromatic plant traditionally used in folk medicine for the treatment of various diseases and conditions. Although it has been primarily used as a stomachic, there are data on traditional use of S. sclarea as an agent against gingivitis, stomatitis and aphthae. AIM OF THE STUDY: The aim of the study was to examine the effect of the S. sclarea ethanolic extract on the lipopolysaccharide (LPS)-induced periodontitis in rats from the immunological and histopathological standpoint. MATERIAL AND METHODS: Periodontal inflammation in rats was induced by repeated injections of LPS from Escherichia coli into the interdental papilla between the first and second right maxillary molars. The extract was administered two times a day by oral gavage (200mg/kg body weight). The inflammatory status was assessed by the measurements of proinflammatory cytokines interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) of gingival tissues and descriptive analysis of histological sections of periodontium. Chemical characterization of the extract was determined using high performance liquid chromatography system (HPLC). Antioxidant activity of the extract was estimated with two in vitro complementary methods: 2,2-diphenyl-1-picrylhydrazyl and beta-carotene/linoleic acid models. RESULTS: Treatment with S. sclarea extract, compared to the untreated group of the rats, significantly diminished the process of inflammation decreasing the levels of IL-1beta, IL-6 and TNF alpha, reducing the gingival tissue lesions and preserving bone alveolar resorption. Considerably smaller number of inflammatory cells and larger number of fibroblasts was noticed. The administration of the extract three days earlier did not have significant preventive effects. Rosmarinic acid was the predominant compound in the extract. The extract showed strong antioxidant effects in both test systems. CONCLUSIONS: S. sclarea extract manifested anti-inflammatory effect in LPS-induced periodontitis suggesting that it may have a role as a therapeutic agent in periodontal diseases. Having in mind that overproduction of reactive oxygen species is connected to periodontitis, the strong antioxidant capacity may be contributable to anti-inflammatory properties of the extract. PMID- 28093320 TI - Activation and pathogenic manipulation of the sensors of the innate immune system. AB - The innate immune system detects the presence of microbes through different families of pattern-recognition receptors (PRRs). PRRs detect pathogens of all origins and trigger signaling events that activate innate and adaptive immunity. These events need to be tightly regulated in order to ensure optimal activation when required, and minimal signaling in the absence of microbial encounters. This regulation is achieved, at least in part, through the precise subcellular positioning of receptors and downstream signaling proteins. Consequently, mislocalization of these proteins inhibits innate immune pathways, and pathogens have evolved to alter host protein localization as a strategy to evade immune detection. This review describes the importance of subcellular localization of various PRR families and their adaptors, and highlights pathogenic immune evasion strategies that operate by altering immune protein localization. PMID- 28093321 TI - Sulfur compound oxidation and carbon co-assimilation in the haloalkaliphilic sulfur oxidizers Thioalkalivibrio versutus and Thioalkalimicrobium aerophilum. AB - Alkaliphilic sulfur-oxidizing bacteria are highly abundant in naturally occurring soda lakes, where they are found both in surface waters and sediments. Here we studied oxidation of sulfide and thiosulfate in batch cultures of Thioalkalimicrobium aerophilum and Thioalkalivibrio versutus, two species that represent different metabolic types, as indicated by the absence or presence of sulfur production during growth, respectively. With thiosulfate, both species showed the expected sulfur oxidation patterns; however, during growth on sulfide, both T. aerophilum and T. versutus produced sulfur as an intermediate. While T. aerophilum likely uses a Sox-type sulfur oxidation pathway, T. versutus appeared to use a combination of some Sox proteins with heterodisulfide reductase complexes, which is supported by gene expression data. Interestingly, intermediate sulfur production by T. versutus occurred when the sulfur source in the medium had been nearly exhausted, which is unlike what has been described for the well-studied Dsr/Sox pathway in phototrophic sulfur bacteria. Inclusion of some carbon sources (acetate, propionate, fructose) slightly enhanced growth of T. versutus and T. aerophilum in batch cultures, suggesting that carbon co assimilation may be occurring. Our results indicate that sulfur oxidation processes in alkaliphilic sulfur oxidizers are more complex than previously assumed, and that the enzymes involved warrant further study. PMID- 28093322 TI - Anti-pathogenic and probiotic attributes of Lactobacillus salivarius and Lactobacillus plantarum strains isolated from feces of Algerian infants and adults. AB - Sixty-seven (67) lactic acid bacteria (LAB) isolates belonging to Lactobacillus genus were isolated from human feces and tested for their auto-aggregation and cell surface hydrophobicity in order to establish their adhesion capabilities, a prerequisite for probiotic selection. Strains with the upmost auto-aggregation and cell surface hydrophobicity scores were identified by MALDI-TOF spectrometry and 16S rDNA sequencing as Lactobacillus plantarum (p25lb1 and p98lb1) and Lactobacillus salivarius (p85lb1 and p104lb1). These strains were also able to adhere to human epithelial colorectal adenocarcinoma Caco-2 cells, with percentages ranging from 4.68 to 9.59%. They displayed good survival under conditions mimicking the gastrointestinal environment and remarkably impeded adhesion and invasion of human Caco-2 by Listeria monocytogenes and Enteropathogenic Escherichia coli. It should also be noted that Lb. plantarum p98lb1 was able to reduce in vitro cholesterol concentration by about 32%, offering an additional health attribute. PMID- 28093323 TI - In vitro gastric survival of commercially available probiotic strains and oral dosage forms. AB - Although the intestinal microbial community is still incompletely understood, there is strong evidence of the benefits of using probiotics to address some medical states or conditions. As a result, the probiotics oral supplements market has exploded during the last few years. However, while their sensitivity to gastric juices, acidic pH and bile is well known, most of these oral forms would not guarantee any survival of the strains in such conditions. In this work, we have studied the resistance to simulated gastric juices of several commercially available probiotics products. These included sixteen strains and ten oral forms such as enteric/non-enteric capsules/tablets and microencapsulated strains. Results demonstrated that all tested strains showed high sensitivity to acidic conditions and suggested that most of these microorganisms would not show any viability when immersed in the stomach at fasting. Most probiotics oral forms did not provide any protection to strains, unless these forms presented strong enteric protection. Consequently, the efficacy of non-enteric products to fully provide to the patient the benefits related to the consumption of probiotics supplement would be strongly questionable. This study underlines the chasm between the current opinion about probiotics protection needs and the products proposed by many companies in the dietary supplements area. PMID- 28093324 TI - Synthesis, characterization, and in-vitro antitumor activity of the polyethylene glycol (350 and 1000) succinate derivatives of the tocopherol and tocotrienol isomers of Vitamin E. AB - Vitamin E refers to a group of saturated tocopherol (T) isomers and the biologically more active unsaturated tocotrienol (T3) isomers. PEGylated alpha tocopherol, commercially known as Vitamin E TPGS, has been used as an emulsifier and therapeutic agent for children with vitamin E deficiency. Limited information, however, is available about the PEG conjugates of the tocotrienol isomers of vitamin E. The current work was therefore undertaken to synthesize and characterize the water soluble polyethylene glycol (PEG 350 and 1000) derivatives of T and T3. Yield and the identity of the synthesized products were confirmed by 1H NMR, mass spectroscopy, HPLC, and thermal analysis. The self-assembly of the PEGylated vitamin E isomers in water at critical micelle concentrations (CMC) was further confirmed by size, zeta, and Cryo-TEM image analysis. While stable at pH 7.4, PEG conjugates were found to rapidly hydrolyze at pH 1.2. Our data showed that PEGylated T3 isomers were significantly more active as inhibitors for P glycoprotein than PEGylated T. The in vitro cytotoxicity of the conjugates was also tested against a large panel of normal and tumorigenic cells. Of the conjugates, gamma-T3PGS 1000 and delta-T3PGS 1000 were found to have the least toxicity against non-tumorigenic breast and pancreatic cell lines, which may be advantageous for its use as functional excipients in drug delivery. The results from the current work have demonstrated the feasibility of synthesizing PEGylated conjugates of vitamin E isomers and highlighted the potential use of these conjugates in drug delivery as functional and safer excipients especially for gamma-T3PGS 1000 and delta-T3PGS 1000 conjugate. PMID- 28093325 TI - Gold nanostar-polymer hybrids for siRNA delivery: Polymer design towards colloidal stability and in vitro studies on breast cancer cells. AB - To overcome the low bioavailability of siRNA (small interfering RNA) and to improve their transfection efficiency, the use of non-viral delivery carriers is today a feasible approach to transform the discovery of these incredibly potent and versatile drugs into clinical practice. Polymer-modified gold nanoconstructs (AuNCs) are currently viewed as efficient and safe intracellular delivery carriers for siRNA, as they have the possibility to conjugate the ability to stably entrap and deliver siRNAs inside cells with the advantages of gold nanoparticles, which can act as theranostic agents and radiotherapy enhancers through laser-induced hyperthermia. In this study, AuNCs were prepared by coating Gold Nano Stars (GNS) with suitable functionalised polymers, to give new insight on the choice of the coating in order to obtain colloidal stability, satisfying in vitro transfection behaviour and reliability in terms of homogeneous results upon GNS type changing. For this goal, GNS synthesized with three different sizes and shapes were coated with two different polymers: i) alpha-mercapto-omega-amino polyethylene glycol 3000Da (SH-PEG3000-NH2), a hydrophilic linear polymer; ii) PHEA-PEG2000-EDA-LA (PPE-LA), an amphiphilic hydroxyethylaspartamide copolymer containing a PEG moiety. Both polymers contain SH or SS groups for anchoring on gold surface and NH2 groups, which can be protonated in order to obtain a positive surface for successive siRNA layering. The effect of the features of the coating polymers on siRNA layering, and the extent of intracellular uptake and luciferase gene silencing effect were evaluated for each of the obtained coated GNS. The results highlight that amphiphilic biocompatible polymers with multi grafting function are more suitable for ensuring the colloidal stability and the effectiveness of these colloidal systems, compared to the coating with linear PEG. PMID- 28093326 TI - In vivo pharmacokinetic studies and intracellular delivery of methotrexate by means of glycine-tethered PLGA-based polymeric micelles. AB - Methotrexate (MTX) is a widely used drug for the management of various kinds of cancers. However, numerous challenges are associated with MTX like poor aqueous solubility, dose-dependent side effects and poor-bioavailability. With an aim to explore the potential benefits in drug delivery of MTX, it was intended to fabricate glycine-PLGA-based polymeric micelles. Glycine was chemically linked to PLGA and the linkage was confirmed by FT-IR, and NMR-Spectroscopy. The developed polymeric micelles offered substantial loading to MTX with a pH-dependent drug release profile. The drug was released maximally at the cancer cell pH vis-a-vis blood plasma pH. The cytotoxicity of drug against MDA-MB-231 cell lines was enhanced by approx. 100% and the confocal laser scanning microscopy confirmed the localization of dye-tagged nanocarriers in the interiors of cancer cells. The bioavailable fraction of the drug was increased by approx. 4-folds, whereas elimination half-life was enhanced by around two-folds in Wistar rats. The novel approach offers a biodegradable and promising carrier for the better delivery of anticancer agents with immense promises of efficacy enhancement, improved delivery and better pharmacokinetic profile. PMID- 28093327 TI - Amorphous solid dispersion of cyclosporine A prepared with fine droplet drying process: Physicochemical and pharmacokinetic characterization. AB - The present study aimed to develop an amorphous solid dispersion (ASD) of cyclosporine A (CsA) by a fine droplet drying (FDD) process for improvement in oral absorption of CsA. CsA and hydroxypropyl cellulose-SSL were dissolved in 1,4 dioxane, and the solution was powdered by the FDD process to obtain the ASD formulation of CsA (ASD/CsA). The ASD/CsA was characterized in terms of morphology, particle size distribution, crystallinity, dissolution behavior, physicochemical stability, and pharmacokinetic behavior in rats. The ASD/CsA was obtained in the form of uniform spherical particles, and the span factor was calculated to be ca. 0.4. CsA in the formulation existed in an amorphous state. The ASD/CsA exhibited a higher dissolution behavior of CsA than amorphous CsA, whereas storage of the ASD/CsA under accelerated conditions led to impairment in the dissolution behavior. The constant release of CsA from non-aged ASD/CsA was observed during dissolution testing. After oral administration of CsA samples (10mg-CsA/kg) in rats, the ASD/CsA showed a high and sustained plasma concentration of CsA as evidenced by a 18-fold increase in the oral bioavailability of CsA compared with amorphous CsA. From these findings, the FDD process might be an efficacious option for the ASD formulation of CsA with enhanced biopharmaceutics properties. PMID- 28093328 TI - Cinnamaldehyde induces apoptosis and reverses epithelial-mesenchymal transition through inhibition of Wnt/beta-catenin pathway in non-small cell lung cancer. AB - Cinnamaldehyde, the main chemical component of the essential oil separated from the traditional herb Cinnamomum cassia, has been demonstrated to be an efficient cytotoxic agent against several human cancers. The present experiment showed that cinnamaldehyde dose-dependently depresses the proliferation of three types of NSCLC cells and induces cell apoptosis in vitro and in vivo. Moreover, cinnamaldehyde attenuated CoCl2-induced EMT and decreased matrix metalloprotease (MMP) family while the in vivo study showed the same trend. Mechanistically, cinnamaldehyde imitated the suppressive effect of XAV939 on cell motility and EMT which could be impaired by LiCl. Collectively, our research demonstrated for the first time that cinnamaldehyde is able to inhibit NSCLC cell growth by inducing apoptosis and reverse EMT through terminating Wnt/beta-catenin pathway, which might supply further insight into cinnamaldehyde-mediated anti-tumor effect against NSCLC for better prognosis. PMID- 28093329 TI - Antioxidant, antitumor and immunostimulatory activities of the polypeptide from Pleurotus eryngii mycelium. AB - The objective of this study was to investigate the antioxidant, antitumor and immunological activities of the polypeptide from Pleurotus eryngii mycelium (PEMP). The ability of the polypeptide to stimulate Ana-1 macrophages to englobe neutral red, secrete NO, H2O2, TNF-alpha, and IL-6, increase TLR2 and TLR4 expression levels and Ana-1 cell survival rate were investigated to study its immunocompetence. Its antitumor activities were studied by examining the survival of cervical, breast, and stomach cancer cells. The antioxidant activities of the polypeptide were studied by examining its reducing power and its ability to scavenge DPPH, O2-, and OH radicals. The results showed that the PEMP was a good antioxidant with antitumor and immunostimulatory activities that was concentration dependent. At concentrations from 0.05 to 2mg/mL, it inhibited the proliferation of cancer cells, but promoted the proliferation of macrophages, TNF alpha and IL-6 secretion, TLR2 and TLR4 expression and increased macrophage phagocytic ability through NO and H2O2 release. From 0.2 to 1mg/mL, the polypeptide had strong reducing power to clear free radical of DPPH, O2-, OH-, with a concentration-response relationship. Based on these results, PEMP has potential applications in functional foods as a natural anti-aging and anti-virus agent with antioxidant and immunostimulatory activities. PMID- 28093330 TI - Effect of solution plasma process with bubbling gas on physicochemical properties of chitosan. AB - In the present work, solution plasma process (SPP) with bubbling gas was used to prepare oligochitosan. The effect of SPP irradiation with bubbling gas on the degradation of chitosan was evaluated by the intrinsic viscosity reduction rate and the degradation kinetic. The formation of OH radical was studied. Changes of the physicochemical properties of chitosan were measured by scanning electron microscopy, X-ray diffraction, and thermogravimetric analysis, as well as ultraviolet-visible, Fourier-transform infrared, and 13C nuclear magnetic resonance spectroscopy. The results indicated an obvious decrease in the intrinsic viscosity reduction rate after SPP irradiation with bubbling gas, and that the rate with bubbling was higher than that without. The main chemical structure of chitosan remained intact after irradiation, but changes in the morphology, crystallinity, and thermal stability of oligochitosan were observed. In particular, the crystallinity and thermal stability tended to decrease. The present study indicated that SPP can be effectively used for the degradation of chitosan. PMID- 28093331 TI - Synthesis of 2-alkenyl-3-butoxypropyl guar gum with enhanced rheological properties. AB - A new guar gum derivative was synthesized though the nucleophilic substitution of sodium hydroxide-activated guar gum with n-butyl glycidyl (BGE) ether. The physicochemical properties of 2-alkenyl-3-butoxypropyl guar gum (ABPG) were characterized by attenuated total reflection Fourier transform infrared spectrometry (ATR-FTIR), X-ray diffraction (XRD) and thermal gravimetric analyses (TGA). The results showed that sodium hydroxide can be effectively substituted with BGE to form the ABPG. The steady and dynamic rheological properties of the aqueous solution and ABPG gel were determined using an RS6000 rheometer. Compared with the guar gum, ABPG enhanced the thickening property and improved the solution stability. The ABPG gel exhibited good temperature resistance and shear stability properties. PMID- 28093332 TI - Chitin and chitinase: Role in pathogenicity, allergenicity and health. AB - Chitin, a polysaccharide with particular abundance in fungi, nematodes and arthropods is immunogenic. It acts as a threat to other organisms, to tackle which they have been endowed with chitinase enzyme. Even if this enzyme is not present in all organisms, they possess proteins having chitin-binding domain(s) (ChtBD). Many lethal viruses like Ebola, and HCV (Hepatitis C virus) have these domains to manipulate their carriers and target organisms. In keeping with the basic rule of survival, the self-origin (own body component) chitins and chitinases are protective, but that of non-self origin (from other organisms) are detrimental to health. The exogenous chitins and chitinases provoke human innate immunity to generate a deluge of inflammatory cytokines, which injure organs (leading to asthma, atopic dermatitis etc.), and in persistent situations lead to death (multiple sclerosis, systemic lupus erythromatosus (SLE), cancer, etc.). Unfortunately, chitin-chitinase-stimulated hypersensitivity is a common cause of occupational allergy. On the other hand, chitin, and its deacetylated derivative chitosan are increasingly proving useful in pharmaceutical, agriculture, and biocontrol applications. This critical review discusses the complex nexus of chitin and chitinase and assesses both their pathogenic as well as utilitarian aspects. PMID- 28093333 TI - Characterization of oral disintegrating film of peanut skin extract-Potential route for buccal delivery of phenolic compounds. AB - This paper aimed to develop and characterize oral disintegrating films (ODF) based on gelatin and hydroxypropyl methylcellulose (HPMC) incorporated with peanut skin extract (PSE) as phenolic compounds vehicle. Films were prepared by casting technique varying the polymer ratio (GEL:HPMC 100:0, 25:75, 50:50, 75:25, 0:100) and PSE concentration (20 and 30g/100g film-forming solution). Formulations with high content of gelatin presented insoluble complex possibly due to cross-linking between gelatin and polyphenols. For formulations which gelatin was in a minority or equal concentration of HPMC, the increase in the PSE concentration favored the association of rich phases in gelatin and HPMC. This also increased inter- and intramolecular bonding which led to a more compact matrix and reduction of films elongation and tensile strength around 45%. The HPMC film with PSE (20%) presented tensile strength of 26.63+/-1.89MPa, elongation of 4.97+/-0.41%, contact angle of 67.17+/-0.41 degrees and disintegration time of 17.87+/-1.77s. In the in vitro release profile, 80% of phenolics were released in 5min, and in accelerated stability test the films retained 60% of the total phenolic compounds. HPMC-based film can be a good alternative to vehicle the active compounds present in peanut skin. PMID- 28093334 TI - In vitro antitumor and antiangiogenic effects of Bothropoidin, a metalloproteinase from Bothrops pauloensis snake venom. AB - Breast cancer is a highly malignant carcinoma and remains the second leading cause of mortality among women. The antitumor effects of metalloproteinases and disintegrins from snake venom on various types of cancer cells have been investigated. In this study, we evaluated the antitumor and antiangiogenic effects on MDA-MB-231 human breast cancer cells and endothelial cells induced by Bothropoidin, a disintegrin-like metalloproteinase isolated from Bothrops pauloensis snake venom. At 24h after treatment at 100MUg/mL, Bothropoidin exerted a moderate cytotoxic effect of 30% on MDA-MB-231 versus 10% cytotoxicity against MCF10A (a non-tumorigenic breast cell line), a significant difference that suggests a possible preference by this protein for targets in cancer cells. Early and late apoptosis of MDA-MB-231 was observed after Bothropoidin treatment (10MUg/mL and 40MUg/mL). Furthermore, this toxin inhibited not only the adhesion of MDA-MB-231 cells in a dose-dependent manner but also cell migration by approximately 45%. In addition, Bothropoidin decreased endothelial cells viability and adhesion in Matrigel and inhibited in vitro angiogenesis in Matrigel stimulated by bFGF, showing significantly fewer formed vessels. The results demonstrated that Bothropoidin has potent in vitro antitumor and antiangiogenic effect and represents a biotechnological tool for elucidating the antitumor effect of disintegrins-like metalloproteinases in cancer cells. PMID- 28093335 TI - Intracoerulear microinjection of orexin-A induces morphine withdrawal-like signs in rats. AB - Orexin (hypocretin) neuropeptides play a pivotal role in expression of opioid withdrawal signs. Hypothalamic orexinergic neurons provide dense afferents for the nucleus locus coeruleus (LC). Somatic signs of opioid withdrawal are associated with the enhanced activity of LC neurons. In addition, intra-LC administration of orexin-A leads to the hyperactivity of LC neurons. The present study was an attempt to investigate whether intra-LC microinjection of orexin-A induces morphine withdrawal-like signs in both morphine dependent and control rats. To end this, adult male Wistar rats weighing 250-300g were used. For induction of morphine dependence, animals received morphine sulfate subcutaneously (10mg/kg, s.c.) at an interval of 12h for 9days. On day 10, intra LC orexin injection (100MUM, 200nl) was carried out two hours after last morphine administration. Morphine withdrawal-like signs were assessed in a transparent Plexiglas test chamber (30cm diameter, 50cm height) for 25min. Orexin-A microinjection induced some morphine withdrawal-like signs in both morphine dependent (chewing, scratching, rearing, teeth chattering, wet-dog shake and paw tremor) and control (chewing, scratching, rearing, sniffing, wet-dog shake and head tremor) rats. Furthermore, microinjection of SB-334867, a selective orexin type-1 receptor antagonist before orexin-A significantly suppressed orexin induced morphine withdrawal-like signs. It seems that orexin-A, via increasing the activity of LC neurons, mediates the induction of some morphine withdrawal like signs independent of morphine dependence. PMID- 28093336 TI - Peripheral nerve injury potentiates excitatory synaptic transmission in locus coeruleus neurons. AB - Peripheral nerve injury (PNI) is believed to cause maladaptive changes at synaptic level, leading to neuropathic pain which is difficult to treat with common analgesic drugs. Noradrenergic locus coeruleus (LC) neurons have a crucial role in neuropathic pain modulation. In this study we examined whether chronic constriction injury (CCI) could affect glutamatergic synaptic transmission in LC neurons. CCI was performed on P10 to P12 Sprague Dawley pups. Seven days after CCI, horizontal slices of brainstem (300MUm thick) were prepared and whole-cell patch clamp recording was performed. Evoked and spontaneous excitatory postsynaptic currents (eEPSC and sEPSC) were recorded from LC neurons at a holding potential of -70mV, in the presence of bicuculline (20MUM). The sEPSCs recorded from LC neurons of neuropathic rats showed a significant increase in amplitude, but not in frequency. The eEPSC amplitude in neurons of rats under gone CCI was significantly increased compared to the control group (P<0.05). The paired pulse ratio (PPR) elicited with different inter-stimulus intervals (50 250ms) did not show any difference between neurons of CCI and control pups. This study shows that PNI increases excitatory synaptic transmission in LC neurons 7days after chronic constriction injury. The observed synaptic potentiation is mainly due to postsynaptic mechanisms. PMID- 28093337 TI - NK cell phenotypic and functional shifts coincide with specific clinical phases in the natural history of chronic HBV infection. AB - BACKGROUND: Chronic HBV infection can be divided into 4 distinct clinical phases: immune tolerant, immune active, inactive carrier, and HBeAg-negative hepatitis. Using a systems biology approach, we recently identified innate immune response components, specifically NK cells as a distinctive factor of specific HBV clinical phases. To expand on this study and identify the underlying immunological mechanisms, we performed a comprehensive profiling of NK cells in chronic HBV infection. METHODS: Peripheral blood from untreated chronic HBV patients was used to analyze phenotypic markers, as well as cytokine production and cytoxicity of NK cells. RESULTS: The overall composition, phenotype, and cytolytic activity of the NK cells remained constant across all clinical phases, with the exception of a few specific markers (KIRs, NKp46). CD56bright NK cells of chronic HBV patients differed in their ability to produce IFN-gamma between the clinical phases pre- and post-HBeAg seroconversion. CONCLUSION: This depicts a shift in NK cell characteristics between the immune active, under heavy viral or immune pressure, and inactive carrier phases, that coincides with HBeAg seroconversion. Although these changes in NK cells do not appear to be completely responsible for differences in liver damage characteristic of specific clinical phases, they could provide a step toward understanding immune dysregulation in chronic HBV infection. PMID- 28093338 TI - A virus-like particle vaccination strategy expands its tolerance to H3N2 antigenic drift by enhancing neutralizing antibodies against hemagglutinin stalk. AB - Seasonal influenza viruses impact public health annually due to their continual evolution. However, the current inactivated seasonal vaccines provide poor protection against antigenically drifted viruses and require periodical reformulation through hit-and-miss predictions about which strains will circulate during the next season. To reduce the impact caused by vaccine mismatch, we investigated the drift-tolerance of virus-like particles (VLP) as an improved vaccine candidate. The cross-protective humoral immunity elicited by the H3N2-VLP vaccine constructed for the 2011-2012 season was examined against viruses isolated from 2010 to 2015 in Taiwan evolving chronologically through clades 1, 4, 5, 3B and 3C, as well as viruses that were circulating globally in 2005, 2007 and 2009. Mouse immunization results demonstrated that H3N2-VLP vaccine elicited superior immunological breadth in comparison with the cognate conventional whole inactivated virus (WIV) vaccine. Titers of neutralizing antibodies against heterologous strains representing each epidemic period in the VLP group were significantly higher than in the WIV group, indicating the antibody repertoire induced by the H3N2-VLPs was insensitive to viral antigenic drift over a span of at least 10 years. Noticeably, H3N2-VLP elicited higher levels of anti-stalk antibodies than H3N2-WIV, which offset the ineffectiveness caused by antigenic drift. This advantageous effect was attributed to the uncleaved precursor of their HA proteins. These results suggest a mechanism through which VLP-induced humoral immunity may better tolerate the evolutionary dynamics of influenza viruses and point to the possible use of a VLP vaccine as a method by which the requirement for annual updates of seasonal influenza vaccines may be diminished. PMID- 28093339 TI - Short-term clinical safety profile of brincidofovir: A favorable benefit-risk proposition in the treatment of smallpox. AB - Brincidofovir (BCV, CMX001) is an orally available, long-acting, broad-spectrum antiviral that has been evaluated in healthy subjects in Phase I studies and in hematopoietic cell transplant recipients and other immunocompromised patients in Phase II/III clinical trials for the prevention and treatment of cytomegalovirus and adenovirus infections. BCV has also shown in vitro activity against orthopoxviruses such as variola (smallpox) virus, and is under advanced development as a treatment for smallpox under the US FDA's 'Animal Rule'. The anticipated treatment regimen for smallpox is a total weekly dose of 200 mg administered orally for 3 consecutive weeks. To assess the benefit-to-risk profile of BCV for the treatment of smallpox, we evaluated short-term safety data associated with comparable doses from Phase I studies and from adult and pediatric subjects in the cytomegalovirus and adenovirus clinical programs. When administered at doses and durations similar to that proposed for the treatment of smallpox, BCV was generally well tolerated in both adults and pediatric subjects. The most common adverse events were mild gastrointestinal events and asymptomatic, transient, and reversible elevations in serum transaminases. The data presented herein indicate a favorable safety profile for BCV for the treatment of smallpox, and support its continued development for this indication. PMID- 28093340 TI - Bacteriological profile of ocular surface flora in meibomian gland dysfunction. AB - PURPOSE: To compare the bacteriological profile of meibomian gland secretion and conjunctival cul-de-sac in subjects with and without meibomian gland dysfunction (MGD). METHODS: This hospital-based study enrolled 201 eyes from 201 MGD patients and 84 eyes from 84 age- and gender-matched controls. Samples from the conjunctivae and meibomian gland secretion were obtained. Both aerobic and anaerobic cultures were performed. Differences in the culture-positivity and bacterial strains between two groups were compared. RESULTS: 36.9% and 10.7% of the control meibomian gland secretion recovered aerobes and anaerobes, respectively. A higher rate of aerobic (44.0%) and similar rate of anaerobic (10.7%) bacteria were isolated from the conjunctival cul-de-sac in these controls. Patients with MGD showed significantly higher positive culture rates from both the meibomian gland secretion (75.6% for aerobes and 34.3% for anaerobes) and conjunctival cul-de-sac (64.7% for aerobes and 30.8% for anaerobes). All p values were <= 0.001. In both groups and at either location, the predominant species isolated were Staphylococcus epidermidis (aerobes) and Propionibacterium acnes (anaerobes). Of note, the MGD patients harbor a much more complex bacterial profile than the controls. CONCLUSION: Both aerobic and anaerobic bacteria can be isolated from the ocular surface of healthy subjects. Patients with MGD demonstrate significantly higher culture positivity and more complex bacterial profiles than the controls. Bacterial related cytotoxicity and/or inflammation may contribute to the pathological process of MGD. PMID- 28093342 TI - March 2017 Editor-in-Chief Letter. PMID- 28093341 TI - Physicians, Poverty, and Profits: Can Robin Hood Finance Health Care in Developing Countries? PMID- 28093343 TI - Moyamoya and Inflammation. AB - BACKGROUND: More than 50 years have elapsed since moyamoya disease was initially described; however, the disease etiology remains unknown. Although certain genetic loci and immunologic characteristics are associated with moyamoya disease, this does not fully explain its pathophysiology. An association with inflammatory disease has been postulated but not rigorously explored. We sought to examine the epidemiologic association of moyamoya and inflammatory diseases by analyzing data from a large administrative database. METHODS: The National Inpatient Sample database for 2009-2012 was obtained. The diagnoses of moyamoya disease and inflammatory diseases were made using the International Classification of Disease, 9th revision. Sample prevalence, sex, age, and admission type were recorded. Patients were grouped into inflammatory disease clusters on the basis of the presence of diagnosis codes for atherosclerotic, adult-onset autoimmune, and juvenile-onset autoimmune diseases. RESULTS: There were 2633 total admissions for moyamoya disease. Atherosclerotic (P < 0.05) and juvenile-onset autoimmune disease (P < 0.05) were associated with moyamoya disease in both pediatric and adult patient groups. Adult-onset autoimmune disease was associated with moyamoya disease in pediatric (P < 0.05) but not adult groups. CONCLUSION: Moyamoya is associated with inflammatory disease clusters in both pediatric and adult populations. Further studies are warranted to investigate the pathophysiologic association between moyamoya disease and inflammatory disease processes. PMID- 28093344 TI - Unusual Intracerebral Presentation of a Myxoid Neurofibroma. AB - BACKGROUND: Neurofibromas are benign nerve sheath tumors that usually affect peripheral nerves and are related to neurofibromatosis type 1; however, they have not been described as a cause of intraparenchymal brain tumor. CASE DESCRIPTION: We report a case of intracranial myxoid neurofibroma in a 19-year-old female patient manifested as an intense and progressive cephalea, followed by nausea, vomiting, photophobia, and phonophobia. Computed tomography and magnetic resonance imaging showed an extant, expansive left frontoparietal parafalcine/parasagittal tumor. Histopathologic examination determined S-100 protein and CD34 positivity, as well as sparse expression of Ki67 protein, and indicated Schwann cells with characteristic wavy nuclei and intraneural fibroblasts in a myxoid background. Together, these observations characterized the tumor as myxoid neurofibroma. The tumor was excised, and the patient recovered without deficits and with no signs of recurrence after 6 years of follow-up. CONCLUSIONS: This is a novel presentation of a myxoid neurofibroma. The tumorigenesis mechanisms are likely complex and possibly involve the differentiation of Schwann cells present in adrenergic autonomic nerves in the subarachnoid arterial branches or in trigeminal nerves present in the meningeal convexity. PMID- 28093345 TI - Stereotactic Radiosurgery for Melanoma Brain Metastases: A Comprehensive Clinical Case Series. AB - BACKGROUND: Melanoma has high propensity to metastasize to the brain. With recent gains in improving patient survival, stereotactic radiosurgery (SRS) may offer an effective and less neurotoxic alternative to whole-brain radiation. In the study, we report on the safety and efficacy of SRS in treating melanoma brain metastases in 87 patients. METHODS: This retrospective multicenter study examined 87 patients with 309 metastases who underwent single-dose or multifractionated SRS for treatment of intracranial metastases from malignant melanoma. RESULTS: A total of 87 patients with a median age of 62 years (26-85) were treated from 2007 2014. Eighty patients (92%) also had extracranial metastases at time of treatment, and 69 patients (79%) had uncontrolled systemic disease. Seventy-nine patients (91%) underwent single-dose fractions, 7 (8%) underwent 3 fractions, and 1 (1%) was treated in 5 fractions. The mean tumor volume (GTV) treated was 1.92 cc. Five patients developed symptoms of acute phase toxicity, and 4 developed late phase toxicity. None had radionecrosis. The median survival was 6 months. The Kaplan-Meier 1-year survival rate was 31%, and the 1-year local control rate was 91%. The 1-year survival rate for BRAF-positive patients was 42%, and for BRAF-negative patients it was 27%. Forty-two patients (48%) had distant intracranial recurrences, and 1-year distant control rate was 32%. CONCLUSIONS: SRS is a safe and effective treatment option for intracranial metastases from malignant melanoma. This paper serves as a reference for what is achievable in the absence of highly effective systemic therapy. PMID- 28093346 TI - Impact of Obesity on Complications and 30-Day Readmission Rates After Cranial Surgery: A Single-Institutional Study of 224 Consecutive Craniotomy/Craniectomy Procedures. AB - BACKGROUND: The prevalence of obesity is increasing at a disparaging rate in the United States. Although previous studies have associated obesity with increased surgical complications and readmission rates, the impact of obesity on surgical outcomes after cranial surgery remains understudied. The aim of this study is to assess the effect of obesity on complication and 30-day readmission rates after cranial surgery. METHODS: The medical records of 224 consecutive patients (nonobese, n = 164; obese, n = 60) undergoing either craniotomy or craniectomy at a major academic institution in 2011 were reviewed. Preoperative body mass index equal to or greater than 30 kg/m2 was classified as obese. The primary outcome investigated in this study was the rate of intraoperative and postoperative complications and 30-day readmissions after craniectomy/craniotomy. RESULTS: Baseline patient characteristics and comorbidities were similar between the cohorts. The mean body mass indexes for both cohorts were significantly different (nonobese, 22.8 +/- 4.2 kg/m2 vs. obese, 45.1 +/- 15.9 kg/m2; P < 0.0001). Most patients underwent tumor excision in both cohorts (nonobese, 64.0% vs. obese, 66.7%; P = 0.75). Compared with the nonobese cohort, the obese cohort had significantly higher estimated blood loss (nonobese, 209.9 +/- 201.3 mL vs. obese, 284.9 +/- 250.0 mL; P = 0.04), but similar length of operation (nonobese, 187.3 +/- 89.4 minutes vs. obese, 209.6 +/- 100.5; P = 0.14). Length of hospital stay and rate of postoperative complications were similar between both cohorts. Obese patients had increased rate of 30-day readmission, but this was not statistically significant (nonobese, 3.1% vs. obese, 6.7%; P = 0.25). CONCLUSIONS: Our study suggests that obesity may not have a significant impact on surgical outcomes after cranial surgery. PMID- 28093347 TI - A Novel Invasive-Related Biomarker in Three Subtypes of Nonfunctioning Pituitary Adenomas. AB - OBJECTIVE: To identify biomarkers key to invasiveness of the 3 subtypes of nonfunctioning pituitary adenomas (NFPAs) and provide a guidance for therapeutic decision making and identification of potential adjuvant drugs. METHODS: Fifty NFPA tumor tissues obtained from transsphenoidal surgery were used in the study. Three invasive NFPAs and 4 noninvasive NFPAs were used for gene expression microarray analyses. In addition, there are 5 invasive NFPAs and 4 noninvasive NFPAs used for proteomic analyses. Invasive-related biomarkers were identified by bioinformatics analysis by integrating the transcriptomics and proteomics data sets. All 3 subtypes of NFPAs (null cell adenomas, oncocytomas, and gonadotroph adenomas) were used to validate differentially expressed candidate biomarkers by means of quantitative real-time reverse transcription polymerase chain reaction and Western blot. The level of EZR was downregulated in pituitary adenoma cell line GH3 to investigate the invasive effect of EZR on GH3 cells by using the RNA interference technique. RESULTS: Eight genes involved in the invasion function were found by bioinformatics analysis, and the EZR gene was identified as a novel invasive-related biomarker in the 3 subtypes of NFPAs. The expression level of EZR was found higher in terms of invasiveness than the noninvasive ones of the 3 subtypes of NFPAs. Moreover, the knockdown of EZR inhibited the invasion of GH3 cells in vitro. CONCLUSIONS: EZR is a novel biomarker in terms of invasion among the 3 subtypes of NFPAs, and it is a promising guide for therapeutic decision making as well. PMID- 28093348 TI - Caudally Directed Inferior Facetal and Transfacetal Screws for C1-C2 and C1-2-3 Fixation. AB - An alternative caudally directed C2 inferior facetal screw is described. Such screw insertion can form the axial stabilization point in cases undergoing atlantoaxial lateral mass plate/rod and screw fixation and those undergoing C1-2 and C1-2-3 spinal fixation. The C2 screw courses from the medial point of the pedicle-laminar junction and travels caudally and laterally toward the C2-3 articulation. Deploying a longer screw that traverses in a transarticular fashion into the facetal mass of C3 vertebra, one can perform C1-2-3 stabilization. Sixteen patients underwent C2 inferior facetal or C2-3 transarticular screw in combination with a C1 screw for atlantoaxial fixation. Three of these patients with multilevel spinal instability underwent atlantoaxial and C2-3 fixation using the discussed technique. The technical issues, anatomic subtleties, and indication for use of the C2 inferior facetal screws are discussed. With an average follow-up of 9 months, all screws have successfully provided stability that resulted in arthrodesis of the treated spinal segments. A caudally directed C2 inferior facetal screw can enhance the armamentarium of the surgeon, provide an alternative to conventional techniques or a bailout option, and add to the safety of the procedure of atlantoaxial lateral mass fixation in anatomically challenged situations. PMID- 28093349 TI - Combining Internal Carotid Ligation with Low-Flow Bypass for Treating Large-Giant Cavernous Sinus Segment Aneurysms: A Report of Four Cases. AB - OBJECTIVE: We summarize the treatment effectiveness and experience of 4 patients who underwent internal carotid ligation combined with low-flow bypass as a treatment for large-giant cavernous sinus segment (CS ICA) aneurysms. METHODS: Surgery-suitable patients with large-giant CS ICA aneurysms received internal carotid ligation combined with low-flow superficial temporal artery-middle cerebral artery bypass surgery. All the patients were followed up for aneurysm prognosis, anastomosis patency, and occurrences of low-flow-related ischemic complications. RESULTS: Four suitable cases between 2012 and 2015 were studied. They consisted of 1 man and 3 women, with the mean age of 56.3 +/- 11.9 years. Maximum and minimum aneurysm diameter were 26 mm and 20 mm, respectively, with an average of 22.3 +/- 2.6 mm. During surgery, the mean blockage time of the middle cerebral artery was 19.3 +/- 1.3 minutes. Postoperative computed tomography angiography examination indicated that thrombosis could be found in the aneurysm lumen. No patient was found with low-flow-related ischemic complications after surgery. The mean postoperative follow-up time was 25.0 +/- 10.4 months. During the follow-up period, no patient showed low-flow-related ischemic complications or aneurysm recurrence. CONCLUSIONS: For patients with large-giant CS ICA aneurysms, treatment of internal carotid ligation combined with low-flow superficial temporal artery-middle cerebral artery bypass surgery was an effective and safe surgical strategy. To improve surgery safety and for appropriate selection of surgery cases, the details, risks, and benefits associated with the surgery should be considered by the surgeon. PMID- 28093350 TI - A visual screen for diet-regulated proteins in the Drosophila ovary using GFP protein trap lines. AB - The effect of diet on reproduction is well documented in a large number of organisms; however, much remains to be learned about the molecular mechanisms underlying this connection. The Drosophila ovary has a well described, fast and largely reversible response to diet. Ovarian stem cells and their progeny proliferate and grow faster on a yeast-rich diet than on a yeast-free (poor) diet, and death of early germline cysts, degeneration of early vitellogenic follicles and partial block in ovulation further contribute to the ~60-fold decrease in egg laying observed on a poor diet. Multiple diet-dependent factors, including insulin-like peptides, the steroid ecdysone, the nutrient sensor Target of Rapamycin, AMP-dependent kinase, and adipocyte factors mediate this complex response. Here, we describe the results of a visual screen using a collection of green fluorescent protein (GFP) protein trap lines to identify additional factors potentially involved in this response. In each GFP protein trap line, an artificial GFP exon is fused in frame to an endogenous protein, such that the GFP fusion pattern parallels the levels and subcellular localization of the corresponding native protein. We identified 53 GFP-tagged proteins that exhibit changes in levels and/or subcellular localization in the ovary at 12-16 hours after switching females from rich to poor diets, suggesting them as potential candidates for future functional studies. PMID- 28093351 TI - In vitro uptake and transport studies of PEG-PLGA polymeric micelles in respiratory epithelial cells. AB - Polymeric micelles are considered promising carriers for pulmonary drug delivery. Their interaction with the respiratory epithelium, however, is mostly unknown. In the present study, methoxypoly (ethylene glycol) (mPEG)-poly (lactic-co-glycolic acid) (PLGA) micelles containing curcumin acetate (CA) or a mixture of CA and Nile Red (NR) were prepared using the solvent evaporation method. Calu-3 and NCI H441 human respiratory epithelial cell monolayers were used as in vitro models of upper and lower respiratory tract epithelium barrier, respectively, to study the cellular uptake and transport of the vesicles. The results show that Calu-3 and NCI-H441 cells internalized micellar particles and that micelles were able to translocate across the cell monolayers. Micelles were more readily internalized into and permeated across Calu-3 cell monolayers when compared to NCI-H441 cells. Furthermore, the presence of inhibitors of endocytic processes, such as methyl beta-cyclodextrin, NaN3 and hypertonic sucrose attenuated the cellular uptake and trafficking of micelles. In conclusion, this study demonstrated that mPEG-PLGA micelles translocate human respiratory epithelium in vitro through clathrin-, energy- and cholesterol-mediated endocytosis. PMID- 28093352 TI - CYP24A1 loss of function: Clinical phenotype of monoallelic and biallelic mutations. AB - CYP24A1, encoding the vitamin D-24-hydroxylase, is of major clinical and physiologic importance, serving to regulate the catabolism of 1,25-(OH)2D, the physiologically active vitamin D metabolite. In addition to facilitating catabolism of 1,25-(OH)2D, CYP24A1 also enhances the turnover and elimination of 25-OHD, the abundant precursor metabolite and storage form of the vitamin. CYP24A1 can be stimulated hormonally by 1,25-(OH)2D and by FGF23, whereas CYP27B1, encoding the vitamin D-1alpha-hydroxylase, is stimulated hormonally by parathyroid hormone (PTH) and downregulated by FGF23. Thus CYP24A1 and CYP27B1, together, provide for alternate and regulated fates of 25-OHD, and control the availability of the active metabolite, 1,25-(OH)2D, depending upon physiologic needs. These two enzymes, are therefore central to the homeostatic control of vitamin D metabolism, and as a result affect calcium metabolism in critical ways. Disruption of CYP24A1 in mice results in elevated circulating 1,25-(OH)2D, substantiating the importance of the enzyme in the maintenance of vitamin D metabolism. The consequential skeletal phenotype in these mice further demonstrates the biologic sequelae of the disruption of the vitamin D pathway, and illustrates a specific developmental pathology mediated largely by oversupply of 1,25-(OH)2D. More recent evidence has identified loss of function mutations in CYP24A1 in association with hypercalcemia, hypercalciuria and nephrolithiasis in humans. Initial reports described certain variant mutations in CYP24A1 as an unrecognized cause of "Idiopathic Infantile Hypercalcemia," and more recently older children and adults have been identified with a similar phenotype. Over 25 likely disease-causing variants are described. Homozygous and compound heterozygote mutations account for the overwhelming majority of cases, however the heterozygous loss-of-function mutations of CYP24A1 do not appear to consistently result in symptomatic hypercalcemia. Considerations ripe for exploration include the potential role for such mutations in the tolerance to challenges to the calcium homeostatic system, such as changes in dietary calcium intake, vitamin D supplementation, sunlight exposure or pregnancy. PMID- 28093353 TI - Vitamin D metabolites in captivity? Should we measure free or total 25(OH)D to assess vitamin D status? AB - There is general consensus that serum 25(OH)D is the best biochemical marker for nutritional vitamin D status. Whether free 25(OH)D would be a better marker than total 25(OH)D is so far unclear. Free 25(OH)D can either be calculated based on the measurement of the serum concentrations of total 25(OH)D, vitamin D-binding protein (DBP), albumin, and the affinity between 25(OH)D and its binding proteins in physiological situations. Free 25(OH)D can also be measured directly by equilibrium dialysis, ultrafitration or immunoassays. During the vitamin D workshop held in Boston in March 2016, a debate was organized about the measurements and clinical value of free 25(OH)D, and this debate is summarized in the present manuscript. Overall there is consensus that most cells apart from the renal tubular cells are exposed to free rather than to total 25(OH)D. Therefore free 25(OH)D may be highly relevant for the local production and action of 1,25(OH)2D. During the debate it became clear that there is a need for standardization of measurements of serum DBP and of direct measurements of free 25(OH)D. There seems to be very limited genetic or racial differences in DBP concentrations or (probably) in the affinity of DBP for its major ligands. Therefore, free 25(OH)D is strongly correlated to total 25(OH)D in most normal populations. Appropriate studies are needed to define the clinical implications of free rather than total 25(OH)D in normal subjects and in disease states. Special attention is needed for such studies in cases of abnormal DBP concentrations or when one could expect changes in its affinity for its ligands. PMID- 28093354 TI - Low dose resveratrol ameliorates mitochondrial respiratory dysfunction and enhances cellular reprogramming. AB - Mitochondrial disease is associated with a wide variety of clinical presentations, even among patients carrying heteroplasmic mitochondrial DNA (mtDNA) mutations, probably because of variations in mutant mtDNA proportions at the tissue and organ levels. Although several case reports and clinical trials have assessed the effectiveness of various types of drugs and supplements for the treatment of mitochondrial diseases, there are currently no cures for these conditions. In this study, we demonstrated for the first time that low dose resveratrol (RSV) ameliorated mitochondrial respiratory dysfunction in patient derived fibroblasts carrying homoplasmic mtDNA mutations. Furthermore, low dose RSV also facilitated efficient cellular reprogramming of the patient-derived fibroblasts into induced pluripotent stem cells, partly due to improved cellular viability. Our results highlight the potential of RSV as a new therapeutic drug candidate for the treatment of mitochondrial diseases. PMID- 28093355 TI - Evaluating the therapeutic potential of idebenone and related quinone analogues in Leber hereditary optic neuropathy. AB - Leber hereditary optic neuropathy (LHON) is an important cause of mitochondrial blindness among young adults. In this study, we investigated the potential of four quinone analogues (CoQ1, CoQ10, decylubiquinone and idebenone) in compensating for the deleterious effect of the m.11778G>A mitochondrial DNA mutation. The LHON fibroblast cell lines tested exhibited reduced cell growth, impaired mitochondrial bioenergetics and elevated levels of reactive oxygen species (ROS). Idebenone increased ATP production and reduced ROS levels, but the effect was partial and cell-specific. The remaining quinone analogues had variable effects and a negative impact on certain mitochondrial parameters was observed in some cell lines. PMID- 28093356 TI - Laser and photochemotherapy for the treatment of oral mucositis in young patients: Randomized clinical trial. AB - BACKGROUND: The aim of the present study was to evaluate the effect of low-level laser therapy (LLLT) combined with photochemotherapy (PCT) for the treatment of chemotherapy-induced oral mucositis in young patients. METHODS: A randomized, blind, clinical trial with a split-mouth design was conducted involving a sample of 15 cancer patients aged three to 16 years at the Aldenora Bello Hospital in the city of Sao Luis, Brazil. The treatments (PCT+LLLT and LLLT alone) were randomly determined for each side of the oral cavity. The patients were blinded to the type of therapy performed on each side. The outcome was the area of the lesion measured in cm2 over an eight-day evaluation period. Treatment and follow up of the lesions under evaluation as well as other lesions occurred until complete remission. Friedman and Wilcoxon tests were employed. Significance was set at a 95% confidence level (alpha=0.05) and the effect size was calculated. RESULTS: A statistically significant difference was found between therapies for lesion area on Days 6-8 (p=0.020, 0.011 and 0.005, respectively), which was confirmed by the moderate effect size. Lesions submitted to PCT+LLLT had a smaller area at the end of the evaluation period. CONCLUSION: Based on the present findings, PCT+LLLT had a greater therapeutic effect in comparison to LLLT alone regarding the reduction in the degree of severity of chemotherapy-induced oral mucositis. PMID- 28093357 TI - Are the innate and adaptive immune systems setting hypertension on fire? AB - Hypertension is the most common chronic cardiovascular disease and is associated with several pathological states, being an important cause of morbidity and mortality around the world. Low-grade inflammation plays a key role in hypertension and the innate and adaptive immune systems seem to contribute to hypertension development and maintenance. Hypertension is associated with vascular inflammation, increased vascular cytokines levels and infiltration of immune cells in the vasculature, kidneys and heart. However, the mechanisms that trigger inflammation and immune system activation in hypertension are completely unknown. Cells from the innate immune system express pattern recognition receptors (PRR), which detect conserved pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) that induce innate effector mechanisms to produce endogenous signals, such as inflammatory cytokines and chemokines, to alert the host about danger. Additionally, antigen-presenting cells (APC) act as sentinels that are activated by PAMPs and DAMPs to sense the presence of the antigen/neoantigen, which ensues the adaptive immune system activation. In this context, different lymphocyte types are activated and contribute to inflammation and end-organ damage in hypertension. This review will focus on experimental and clinical evidence demonstrating the contribution of the innate and adaptive immune systems to the development of hypertension. PMID- 28093358 TI - Mapping the functional connectome traits of levels of consciousness. AB - Examining task-free functional connectivity (FC) in the human brain offers insights on how spontaneous integration and segregation of information relate to human cognition, and how this organization may be altered in different conditions, and neurological disorders. This is particularly relevant for patients in disorders of consciousness (DOC) following severe acquired brain damage and coma, one of the most devastating conditions in modern medical care. We present a novel data-driven methodology, connICA, which implements Independent Component Analysis (ICA) for the extraction of robust independent FC patterns (FC traits) from a set of individual functional connectomes, without imposing any a priori data stratification into groups. We here apply connICA to investigate associations between network traits derived from task-free FC and cognitive/clinical features that define levels of consciousness. Three main independent FC-traits were identified and linked to consciousness-related clinical features. The first one represents the functional configuration of a "resting" human brain, and it is associated to a sedative (sevoflurane), the overall effect of the pathology and the level of arousal. The second FC-trait reflects the disconnection of the visual and sensory-motor connectivity patterns. It also relates to the time since the insult and to the ability of communicating with the external environment. The third FC-trait isolates the connectivity pattern encompassing the fronto-parietal and the default-mode network areas as well as the interaction between left and right hemispheres, which are also associated to the awareness of the self and its surroundings. Each FC-trait represents a distinct functional process with a role in the degradation of conscious states of functional brain networks, shedding further light on the functional sub-circuits that get disrupted in severe brain-damage. PMID- 28093359 TI - fMRI characterisation of widespread brain networks relevant for behavioural variability in fine hand motor control with and without visual feedback. AB - A bilateral visuo-parietal-motor network is responsible for fine control of hand movements. However, the sub-regions which are devoted to maintenance of contraction stability and how these processes fluctuate with trial-quality of task execution and in the presence/absence of visual feedback remains unclear. We addressed this by integrating behavioural and fMRI measurements during right-hand isometric compression of a compliant rubber bulb, at 10% and 30% of maximum voluntary contraction, both with and without visual feedback of the applied force. We quantified single-trial behavioural performance during 1) the whole task period and 2) stable contraction maintenance, and regressed these metrics against the fMRI data to identify the brain activity most relevant to trial-by trial fluctuations in performance during specific task phases. fMRI-behaviour correlations in a bilateral network of visual, premotor, primary motor, parietal and inferior frontal cortical regions emerged during performance of the entire feedback task, but only in premotor, parietal cortex and thalamus during the stable contraction period. The trials with the best task performance showed increased bilaterality and amplitude of fMRI responses. With feedback, stronger BOLD-behaviour coupling was found during 10% compared to 30% contractions. Only a small subset of regions in this network were weakly correlated with behaviour without feedback, despite wider network activated during this task than in the presence of feedback. These findings reflect a more focused network strongly coupled to behavioural fluctuations when providing visual feedback, whereas without it the task recruited widespread brain activity almost uncoupled from behavioural performance. PMID- 28093360 TI - Ultra-high field MRI: Advancing systems neuroscience towards mesoscopic human brain function. AB - Human MRI scanners at ultra-high magnetic field strengths of 7 T and higher are increasingly available to the neuroscience community. A key advantage brought by ultra-high field MRI is the possibility to increase the spatial resolution at which data is acquired, with little reduction in image quality. This opens a new set of opportunities for neuroscience, allowing investigators to map the human cortex at an unprecedented level of detail. In this review, we present recent work that capitalizes on the increased signal-to-noise ratio available at ultra high field and discuss the theoretical advances with a focus on sensory and motor systems neuroscience. Further, we review research performed at sub-millimeter spatial resolution and discuss the limits and the potential of ultra-high field imaging for structural and functional imaging in human cortex. The increased spatial resolution achievable at ultra-high field has the potential to unveil the fundamental computations performed within a given cortical area, ultimately allowing the visualization of the mesoscopic organization of human cortex at the functional and structural level. PMID- 28093361 TI - NEIL1 is a candidate gene associated with common variable immunodeficiency in a patient with a chromosome 15q24 deletion. AB - We report the first patient with an interstitial deletion of chromosome 15q24.1 q24.3 associated with common variable immunodeficiency (CVID). The 18-year old female patient's clinical and immunological phenotype was compared with 8 additional previously published patients with chr15q24 deletions. A CGH analysis estimated the deletion to be 3.767Mb in size (chr15: 74,410,916-78,178,418) and the result was confirmed using qRT-PCR. We defined an immune-related commonly deleted region (ICDR) within the chromosomal band 15q24.2, deleted in all four patients with different forms of antibody deficiencies. Mutations in the 14 genes within this ICDR were not identified in the remaining allele in our patient by WES and gene expression analyses showed haploinsufficiency of all the genes. Among these genes, we consider Nei Like DNA Glycosylase 1 (NEIL1) as a likely candidate gene due to its crucial role in B-cell activation and terminal differentiation. PMID- 28093362 TI - Hypoxia-inducible factor-1alpha inhibition modulates airway hyperresponsiveness and nitric oxide levels in a BALB/c mouse model of asthma. AB - : Hypoxia-inducible factor (HIF)-1alpha is a master regulator of inflammation and is upregulated in alveolar macrophages and lung parenchyma in asthma. HIF-1alpha regulates select pathways in allergic inflammation, and thus may drive particular asthma phenotypes. This work examines the role of pharmacologic HIF-1alpha inhibition in allergic inflammatory airway disease (AIAD) pathogenesis in BALB/c mice, which develop an airway hyperresponsiveness (AHR) asthma phenotype. Systemic treatment with HIF-1alpha antagonist YC-1 suppressed the increase in HIF 1alpha expression seen in control AIAD mice. Treatment with YC-1 also decreased AHR, blood eosinophilia, and allergic inflammatory gene expression: IL-5, IL-13, myeloperoxidase and iNOS. AIAD mice had elevated BAL levels of NO, and treatment with YC-1 eliminated this response. However, YC-1 did not decrease BAL, lung or bone marrow eosinophilia. We conclude that HIF-1alpha inhibition in different genetic backgrounds, and thus different AIAD phenotypes, decreases airway resistance and markers of inflammation in a background specific manner. CAPSULE SUMMARY: Asthma is a common disease that can be difficult to control with current therapeutics. We describe how pharmacologic targeting of a specific transcription factor, HIF-1alpha, suppresses asthmatic airway reactivity and inflammation. PMID- 28093363 TI - Alignment of collagen fiber in knitted silk scaffold for functional massive rotator cuff repair. AB - : Rotator cuff tear is one of the most common types of shoulder injuries, often resulting in pain and physical debilitation. Allogeneic tendon-derived decellularized matrices do not have appropriate pore size and porosity to facilitate cell infiltration, while commercially-available synthetic scaffolds are often inadequate at inducing tenogenic differentiation. The aim of this study is to develop an advanced 3D aligned collagen/silk scaffold (ACS) and investigate its efficacy in a rabbit massive rotator cuff tear model. ACS has similar 3D alignment of collagen fibers as natural tendon with superior mechanical characteristics. Based on ectopic transplantation studies, the optimal collagen concentration (10mg/ml), pore diameter (108.43+/-7.25MUm) and porosity (97.94+/ 0.08%) required for sustaining a stable macro-structure conducive for cellular infiltration was determined. Within in vitro culture, tendon stem/progenitor cells (TSPCs) displayed spindle-shaped morphology, and were well-aligned on ACS as early as 24h. TSPCs formed intercellular contacts and deposited extracellular matrix after 7days. With the in vivo rotator cuff repair model, the regenerative tendon of the ACS group displayed more conspicuous native microstructures with larger diameter collagen fibrils (48.72+/-3.75 vs. 44.26+/-5.03nm) that had better alignment and mechanical properties (139.85+/-49.36vs. 99.09+/-33.98N) at 12weeks post-implantation. In conclusion, these findings demonstrate the positive efficacy of the macroporous 3D aligned scaffold in facilitating rotator cuff tendon regeneration, and its practical applications for rotator cuff tendon tissue engineering. STATEMENT OF SIGNIFICANCE: Massive rotator cuff tear is one of the most common shoulder injuries, and poses a formidable clinical challenge to the orthopedic surgeon. Tissue engineering of tendon can potentially overcome the problem. However, more efficacious scaffolds with good biocompatibility, appropriate pore size, favorable inductivity and sufficient mechanical strength for repairing massive rotator cuff tendon injuries need to be developed. In this study, we developed a novel macroporous 3D aligned collagen/silk scaffold, and demonstrated that this novel scaffold enhanced the efficacy of rotator cuff tendon regeneration by inducing aligned supracellular structures similar to natural tendon, which in turn enhanced cellular infiltration and tenogenic differentiation of stem/progenitor cells from both the tendon itself and surrounding tissues. Hence, it can potentially be a clinically useful application for tendon tissue engineering. PMID- 28093364 TI - Fabrication of nanofibrous electrospun scaffolds from a heterogeneous library of co- and self-assembling peptides. AB - : Self-assembling (SAPs) and co-assembling peptides (CAPs) are driving increasing enthusiasm as synthetic but biologically inspired biomaterials amenable of easy functionalization for regenerative medicine. On the other hand, electrospinning (ES) is a versatile technique useful for tailoring the nanostructures of various biomaterials into scaffolds resembling the extracellular matrices found in organs and tissues. The synergistic merging of these two approaches is a long-awaited advance in nanomedicine that has not been deeply documented so far. In the present work, we describe the successful ES of a library of diverse SAPs and CAPs into biomimetic nanofibrous mats. Our results suggest that suitable ES solutions are characterized by high concentrations of peptides, providing backbone physical chain entanglements, and by random coil/alpha-helical conformations while beta sheet aggregation may be detrimental to spinnability. The resulting peptide fibers feature interconnected seamless mats with nanofibers average diameters ranging from ~100nm to ~400nm. Also, peptide chemical nature and ES set up parameters play pivotal roles in determining the conformational transitions and morphological properties of the produced nanofibers. Far from being an exhaustive description of the just-opened novel field of ES-assembled peptides, this seminal work aims at shining a light on a still missing general theory for the production of electrospun peptidic biomaterials bringing together the spatial, biochemical and biomimetic of these two techniques into unique scaffolds for tissue engineering. STATEMENT OF SIGNIFICANCE: Construction of peptide hydrogels has received considerable attention due to their potential as nanostructures amenable of easy functionalization and capable of creating microenvironments suited for culturing cells and triggering tissue regeneration. They display a superior biocompatibility unmatched by other known synthetic biomaterials so far. However, their applications are confined to body fillers because most of them do spontaneously form hydrogels, while effective tissue regeneration often requires well-defined fibrous scaffolds. In this work, we developed electrospun fibers of various peptides (cross-beta self-assembling, hierarchically assembling, functionalized, co-assembling) and we provided a deep understanding of the crucial phenomena to be taken into account when peptides fibers fabrication. These results open new venues for exploring novel regenerative applications of peptide nanofibrous scaffolds. PMID- 28093365 TI - Vitamin B3 metal-organic frameworks as potential delivery vehicles for therapeutic nitric oxide. AB - The synthesis and structural characterization of two isostructural metal (M=Ni, Co) 3D framework structure that integrate vitamin B3 building blocks with NO delivery capabilities and low toxicity is presented. The compounds with a formula [M2(MU2-H2O)(MU-vitamin B3)4].2H2O contain two crystallographic distinct divalent metal centres connected by a bridging water and carboxylate group from vitamin B3. The porous compounds have the capability of storing and releasing nitric oxide (NO) in a slow and reversible manner, with released amounts of 2.6 and 2.0MUmol NOmgsolid-1, on the Ni and Co compound, respectively. The NO release followed a convenient slow release kinetic profile in both gas and liquid phases. Haemoglobin tests demonstrated that NO is released to the medium in a biologically active form, thus suitable to trigger the desired response in biological systems. The toxicity of the samples with and without loaded NO was evaluated from cytotoxicity tests in HeLa and HEKn cells, showing low toxicity of the compounds at concentrations below 180MUgcm-3. The overall results indicate that these bio based MOFs are of interest for therapeutic applications related with NO delivery. STATEMENT OF SIGNIFICANCE. PMID- 28093366 TI - Strategy for constructing vascularized adipose units in poly(l-glutamic acid) hydrogel porous scaffold through inducing in-situ formation of ASCs spheroids. AB - : Vascularization is of great importance to adipose tissue regeneration. Here we introduced a paradigm that using scaffold to induce ASC spheroids, so to promote vascularized adipose tissue regeneration. Poly (l-glutamic acid) (PLGA) was activated by EDC, followed by being cross-linked by Adipic dihydrazide (ADH) to form a homogeneous hydrogel. Lyophilization was then carried out to create porous structure. The PLGA hydrogel scaffold possessed a significant swollen hydrophilic network to weaken cell-scaffold adhesion but drive ASCs to aggregate to form spheroids. Increase of seeding cell density was proved to result in the increase of spheroid size, upregulating angiogenic genes (VEGF and FGF-2) expression by enhancing the hypoxia-induced paracrine secretion. Also, the adipogenic differentiation of ASCs was achieved in spheroids in vitro. Moreover, the in vivo vascularized adipose tissue regeneration was evaluated in the dorsum of nude mice. After 12weeks post-implantation, the significant angiogenesis was found in both adipogenic induced and non-induced engineered tissue. In adipogenic induced group, the clear ring-like morphology, the large vacuole in the middle of the cell and the Oil red O staining demonstrated adipose tissue formation. STATEMENT OF SIGNIFICANCE: Vascularization is of great importance to adipose tissue regeneration. Adipose derived stem cell (ASC) spheroids possessed not only the high efficiency of vascularization, but also the improved differentiation ability. Several research works have illustrated the advantage of ASC spheroids in vascularization. However, in adipose regeneration, ASC spheroid was rarely used. Even so, it is reasonable to believe that ASC spheroids hold a great promise in vascularized adipose tissue engineering. Thus in the present study, we introduced a method to create lots of ASC spheroids that acted as lots of individual adipogenesis and angiogenesis units inside of a porous hydrogel scaffold. Then, the scaffold carrying ASC spheroids was implanted subcutaneously in nude mice to preliminarily evaluate the adipose tissue generation and blood vessel formation. PMID- 28093367 TI - Effect of construction of TiO2 nanotubes on platelet behaviors: Structure property relationships. AB - : Blood compatibility of TiO2 nanotubes (TNTs) has been assessed in rabbit platelet-rich plasma (PRP), which combines activation of both blood plasma coagulation and platelets. We find that (i) amorphous TiO2 nanotubes (TNTs) with relatively larger outer diameters led to reduced platelet adhesion/activation, (ii) TNTs with relatively smaller outer diameters in a predominately rutile phase also inhibited platelet adhesion and activation, and (iii) a pervasive fibrin network formed on larger outer diameter TNTs in a predominately anatase phase. Thus, this study suggests that combined effect of crystalline phase and surface chemistry controls blood-contact behavior of TNTs. A more comprehensive mechanism is proposed for understanding hemocompatibility of TiO2 which might prove helpful as a guide to prospective design of TiO2-based biomaterials. STATEMENT OF SIGNIFICANCE: To realize optimal design and construction of biomaterials with desired properties for blood contact materials, a comprehensive understanding of structure-property relationships is required. In the existing literature, TiO2 nanotube has been reported to be a good candidate for biomedical applications. However, it is noticeable that the blood compatibility of TiO2 nanotubes (TNTs) remains obscure or even inconsistent in the previously published works. The inconsistency could derive from different research protocols, material properties or blood sources. Thus, a thorough investigation of the effect of surface properties on blood compatibility is crucial to the development of titanium based materials. In this paper, we explored the effect of surface properties on the response of platelet-rich plasma, especially surface morphology, chemistry, wettability and crystalline phase. The results indicated that crystalline phase was a dominant factor in platelet behaviors. Reduced adhesion and activation of platelets were observed on amorphous and rutile dominated TNTs, whereas anatase dominated TNTs activated the formation of fibrin network. We further proposed a hypothetical mechanism for better understanding of how surface properties affect the response of platelet-rich plasma. Therefore, this study expands the fundamental understanding of the structure-property relationships of titanium based materials. PMID- 28093369 TI - Rehabilitation of the Pontine Ataxia-Dysmetria Syndrome. AB - : We present a case of a patient with significant ataxia and dysmetria following a lacunar pontine infarction and review the literature on this uncommon syndrome. The patient had an excellent clinical course with near resolution of symptoms and signs in less than 3 weeks. We illustrate the patient's ataxia and dysmetria with videos and also use the videos to demonstrate and characterize the features of the dysmetria. Interestingly, the characteristics of the dysmetria appear to be different from those seen in patients with dysmetria arising from a cerebellar or thalamic lesion. We discuss the likely neurophysiologic mechanisms responsible for the condition and recovery. Simple noninvasive study of patients with ataxia and dysmetria secondary to a pontine lacunar infarct may be most helpful in elucidating the contribution of pontocerebellar fibers to motor control. LEVEL OF EVIDENCE: V. PMID- 28093368 TI - Surface modification of PdlLGA microspheres with gelatine methacrylate: Evaluation of adsorption, entrapment, and oxygen plasma treatment approaches. AB - : Injectable poly (dl-lactic-co-glycolic acid) (PdlLGA) microspheres are promising candidates as biodegradable controlled release carriers for drug and cell delivery applications; however, they have limited functional groups on the surface to enable dense grafting of tissue specific biocompatible molecules. In this study we have evaluated surface adsorption, entrapment and oxygen plasma treatment as three approaches to modify the surfaces of PdlLGA microspheres with gelatine methacrylate (gel-MA) as a biocompatible and photo cross-linkable macromolecule. Time of flight secondary ion mass spectroscopy (TOF SIMS) and X ray photoelectron spectroscopy (XPS) were used to detect and quantify gel-MA on the surfaces. Fluorescent and scanning electron microscopies (SEM) were used to image the topographical changes. Human mesenchymal stem cells (hMSCs) of immortalised cell line were cultured on the surface of gel-MA modified PdlLGA microspheres and Presto-Blue assay was used to study the effect of different surface modifications on cell proliferation. Data analysis showed that the oxygen plasma treatment approach resulted in the highest density of gel-MA deposition. This study supports oxygen plasma treatment as a facile approach to modify the surface of injectable PdlLGA microspheres with macromolecules such as gel-MA to enhance proliferation rate of injected cells and potentially enable further grafting of tissue specific molecules. STATEMENT OF SIGNIFICANCE: Poly (dl lactic co-glycolic) acid (PdlLGA) microspheres offer limited functional groups on their surface to enable proper grafting of tissue specific bioactive molecules. To overcome this limitation, previous approaches have suggested using alkaline solutions to introduce active groups to the surface; however, they may compromise surface topography and lose any potential surface patterns. Plasma polymerisation of bioactive monomers has been suggested to enhance surface biocompatibility; however, it is not applicable on low vapour pressure macromolecules such as most extracellular matrix (ECM) proteins and growth factors. This study aims to evaluate three different approaches to modify the surface of PdlLGA microspheres with gelatine-methacrylate (gel-MA) to enable further grafting of cross-linkable biomolecules without compromising the surface topography or the biocompatibility of the system. PMID- 28093370 TI - A Comparison of Locomotor Therapy Interventions: Partial-Body Weight-Supported Treadmill, Lokomat, and G-EO Training in People With Traumatic Brain Injury. AB - BACKGROUND: Literature in the application of gait training techniques in persons with traumatic brain injury (TBI) is limited. Current techniques require multiple staff and are physically demanding. The use of a robotic locomotor training may provide improved training capacity for this population. OBJECTIVE: To examine the impact of 3 different modes of locomotor therapy on gait velocity and spatiotemporal symmetry using an end effector robot (G-EO); a robotic exoskeleton (Lokomat), and manual assisted partial-body weight-supported treadmill training (PBWSTT) in participants with traumatic brain injury. DESIGN: Randomized, prospective study. SETTING: Tertiary rehabilitation hospital. PARTICIPANTS: A total of 22 individuals with >=12 months chronic TBI with hemiparetic pattern able to walk overground without assistance at velocities between 0.2 and 0.6 m/s. INTERVENTION: Eighteen sessions of 45 minutes of assigned locomotor training. OUTCOME MEASURES: Overground walking self-selected velocity (SSV), maximal velocity (MV), spatiotemporal asymmetry ratio, 6-Minute Walk Test (6MWT), and mobility domain of Stroke Impact Scale (MSIS). RESULTS: Severity in walking dysfunction was similar across groups as determined by walking velocity data. At baseline, participants in the Lokomat group had a baseline velocity that was slightly slower compared with the other groups. Training elicited a statistically significant median increase in SSV for all groups compared with pretraining (Lokomat, P = .04; G-EO, P = .03; and PBWSTT, P = .02) and MV excluding the G-EO group (Lokomat, P = .04; PBWSTT, P = .03 and G-EO, P = .15). There were no pre post significant differences in swing time, stance time, and step length asymmetry ratios at SSV or MV for any of the interventions. Mean rank in the change of SSV and MV was not statistically significantly different between groups. Participants in the G-EO and PBWSTT groups significantly improved their 6MWT posttraining (P = .04 and .03, respectively). The MSIS significantly improved only for the Lokomat group (P = .04 and .03). The data did not elicit between-groups significant differences for 6MWT and MSIS. There was less use of staff for Lokomat than G-EO. CONCLUSIONS: Locomotor therapy using G-EO, Lokomat, or PBWSTT in individuals with chronic TBI increased SSV and MV without significant changes in gait symmetry. Staffing needed for therapy provision was the least for the Lokomat. A larger study may further elucidate changes in gait symmetry and other training parameters. LEVEL OF EVIDENCE: II. PMID- 28093371 TI - Sonographically Guided Knee Meniscus Injections: Feasibility, Techniques, and Validation. AB - BACKGROUND: There is a growing interest in the use of biologic agents such as platelet-rich plasma and mesenchymal stem/stromal cells to treat musculoskeletal injuries, including meniscal tears. Although previous research has documented the role of diagnostic ultrasound to evaluate meniscal tears, sonographically guided (SG) techniques to specifically deliver therapeutic agents into the meniscus have not been described. OBJECTIVE: To describe and validate SG injection techniques for the body and posterior horn of the medial and lateral meniscus. DESIGN: Prospective, cadaveric laboratory investigation. SETTING: Academic institution procedural skills laboratory. SUBJECTS: Five unenbalmed cadaveric knee-ankle-foot specimens from 5 donors (3 female and 2 male) ages 33-92 years (mean age 74 years) with body mass indices of 21.1-32.4 kg/m2 (mean 24.1 kg/m2). METHODS: A single, experienced operator completed SG injections into the bodies and posterior horns of the medial and lateral menisci of 5 unenbalmed cadaveric knees using colored latex and a 22-gauge, 38-mm needle. After injection, coinvestigators dissected each specimen to assess latex distribution within the menisci and identify injury to intra-articular and periarticular structures. MAIN OUTCOME MEASURES: Latex location within the target region of meniscus (accurate/inaccurate), and iatrogenic injury to "at risk" intra- and periarticular structures (present/absent). RESULTS: Seventeen of 20 injections were accurate. Two of 3 inaccurate injections infiltrated the posterior horn of the medial meniscus instead of the targeted meniscal body. One inaccurate lateral meniscus injection did not contain latex despite sonographically accurate needle placement. No specimen exhibited injury to regional neurovascular structures or intra-articular hyaline cartilage. CONCLUSIONS: SG meniscus injections are feasible and can accurately and safely deliver injectates such as regenerative agents into bodies and posterior horns of the medial and lateral menisci. The role of SG intrameniscal injections in the treatment of patients with degenerative and traumatic meniscal disorders warrants further exploration. LEVEL OF EVIDENCE: Not applicable. PMID- 28093372 TI - Does Trainee Involvement in Fluoroscopic Injections Affect Fluoroscopic Time, Immediate Pain Reduction, and Complication Rate? AB - BACKGROUND: Patients have expressed concern about undergoing procedures involving trainees, even with direct attending physician supervision. Little literature has examined the effect of trainee involvement on patient outcomes. OBJECTIVE: We aimed to evaluate the effect of trainee involvement on patient complications, immediate pain reduction, and fluoroscopic time for different fluoroscopic injection types. DESIGN: Retrospective review. SETTING: Four academic outpatient institutions with Accreditation Council for Graduate Medical Education (ACGME) accredited residency (physical medicine and rehabilitation, or anesthesiology) or fellowship (sports medicine or pain medicine) programs from 2000 to 2015. PATIENTS: All patients receiving fluoroscopically guided hip (HI), sacroiliac joint (SIJI), transforaminal epidural (TFEI), and/or interlaminar epidural injections (ILEI, performed at only 1 institution). METHODS: Outcome measures were examined based on the presence or absence of a trainee during the procedure. MAIN OUTCOME MEASUREMENTS: The primary outcome was the number of immediate complications, with secondary outcomes being fluoroscopic time per injection (FTPI) and immediate numeric rating scale percentage improvement. RESULTS: Trainees were involved in 67.0% of all injections (N = 7,833). Complication rates or improvements in numeric rating scale scores showed no significant differences with trainee involvement for any injection type (P > .05). Trainee involvement was associated with increased FTPI for ILEIs (18.2 +/- 10.1 seconds with trainees versus 15.1 +/- 8.5 seconds without trainees, P < .001), but not for HIs (P = .60) or SIJIs (P = .51). Trainee involvement with TFEIs was dependent on institution for outcome with respect to FTPI (P < .001), with 28.1 +/- 17.9 seconds with trainees and 32.1 +/- 22.1 seconds without trainees (P = 0.51). CONCLUSIONS: This large multicenter study of academic institutions demonstrates that trainee involvement in fluoroscopically guided injections does not affect immediate patient complications or pain improvement. Trainee involvement does not increase fluoroscopic time for most injections, although there is an institutional difference seen. This study supports the notion that appropriate trainee supervision likely does not compromise patient safety for fluoroscopically guided injections. LEVEL OF EVIDENCE: II. PMID- 28093373 TI - Improved Arousal and Motor Function Using Zolpidem in a Patient With Space Occupying Intracranial Lesions: A Case Report. AB - : Patients with disorders of consciousness (DOC) have profound functional limitations with few treatment options for improving arousal and quality of life. Zolpidem is a nonbenzodiazepine hypnotic used to treat insomnia that has also been observed to paradoxically improve arousal in those with DOC, such as the vegetative or minimally conscious states. Little information exists on its use in patients with DOC who have intracranial space-occupying lesions. We present a case of a 24-year-old man in a minimally conscious state due to central nervous system lymphoma who was observed to have increased arousal and improved motor function after the administration of zolpidem. LEVEL OF EVIDENCE: V. PMID- 28093374 TI - Predictors of Pharmacological Intervention in Adolescents With Protracted Symptoms After Sports-Related Concussion. AB - BACKGROUND: Although recovery after concussion is spontaneous and typically occurs within 2-3 weeks, a subset of adolescents develop persistent symptoms after a sports-related concussion. Medications are frequently prescribed as part of a comprehensive treatment approach to alleviate these symptoms; however, there are no guidelines for prescription of pharmacologic therapy after concussion. OBJECTIVE: To investigate common factors that are associated with the use of medications (antiepileptic, antidepressant, neurostimulant, or sleeping medication) during recovery from a sports-related concussion. DESIGN: Retrospective observational study. SETTING: Single-center specialty concussion center. PARTICIPANTS: A total of 100 adolescents, between the ages of 12 and 18 years, who sustained concussion due to sports. ASSESSMENT OF RISK FACTORS: Independent variables collected included age at the time of concussion, gender, sports played, personal history of prior concussion or mental health disorder, and personal or family history of headache (eg, migraines) or seizure disorder. MAIN OUTCOME MEASURE: Prescription of medications for treatment of concussion. RESULTS: Twenty-four patients (24%) were prescribed medications in this study, all of whom reported headache at the time of medication prescription. Amantadine was the most commonly prescribed medication, with amitriptyline and melatonin also being prescribed. Among the demographic information collected, only age and gender met criteria for inclusion in the regression model. Logistic regression analysis demonstrated that the odds that female participants were prescribed medications was 3.790 (95% confidence interval = 1.262-11.380) higher than male participants. A higher symptom score on the initial Post Concussion Symptom Scale (PCSS) was associated with increased odds of being prescribed medications (odds ratio = 1.031, 95% CI = 1.009-1.052). CONCLUSIONS: The current study found that initial symptom severity and female gender were associated with use of medication in recovery from sports-related concussion among variables available for study. LEVEL OF EVIDENCE: II. PMID- 28093375 TI - Biomechanical strength and failure mechanism of different tubercula refixation methods within the framework of an arthroplasty for shoulder fracture. AB - BACKGROUND: Tuberosity repair in shoulder fracture prosthesis implantation still remains a challenge often leading to poor functional outcomes, despite a variety of materials and suggested suture patterns. We aimed to evaluate, which forces currently used suture and cerclage materials withstand and to assess whether they are useful with regard to stability of reconstruction of tuberosities and which failure modes they display. MATERIAL AND METHODS: Using sheep infraspinatus tendons with attached tuberosities three different suture materials (suture 1: Ethibond size 2; suture 2: Orthocord size 2; suture 3: Fiberwire size 5) and a 0.8mm titanium cerclage wire were investigated. For each suture material as well as the cerclage wire 6 tests were carried out. A material testing machine was used to perform cyclic loading tests (20mm/min, Fmin=50N, Fmax=100N, respectively after 50 cycles: Fmax+50N until failure). Outcome measures and thus comparison criteria were the maximum holding force, number of cycles reached, total elongation of the system (tendon and suture) and qualitative appraisal and documentation of the mechanism of failure. RESULTS: Overall average maximum forces between the fixation materials differed significantly (P=0.003), especially suture 3 (braided polyethylene coating, non-resorbable polyfile UHMW core) displayed superior results in comparison to the cerclage wire (P=0.016). Although, primary elongation of the cerclage technique was significantly lower compared to the suture materials (P=0.002). All tests showed a high initial lengthening and caused incision-like defects in the bone or tendon and led to failure and huge displacement of the tuberosities. DISCUSSION: Currently used suture and cerclage materials have a limited usefulness for refixation of tuberosities due to an increased risk of obstruction for bony consolidation. LEVEL OF EVIDENCE: Basic science, Biomechanics. PMID- 28093376 TI - A new angle and its relationship with early fixation failure of femoral neck fractures treated with three cannulated compression screws. AB - BACKGROUND: The Pauwels angle has been used widely, however an accurate evaluation of this angle is difficult because of deformity of the affected lower extremity. Therefore we designed a new measurement of the orientation of femoral neck fracture and applied this in a retrospective study to assess: (1) its reproducibility, (2) its advantages compared with the Pauwels angle, (3) its relationship with the short-term prognosis treated with three cannulated compression screws. HYPOTHESIS: This new measurement is reproducible and has some reference meaning for the treatment of femoral neck fractures. METHODS: Two hundred and twenty-eight patients with femoral neck fractures treated with three cannulated compression screws were retrospectively analyzed. The VN angle, which was the angle between the fracture line and the vertical of the neck axis, and the Pauwels angle were measured respectively. The method of ICC was performed to assess the reproducibility of the two angles, and the absolute value of difference in pre-operative and post-operative radiographs was used to evaluate the uniformity of the two angles. These fractures were divided into four groups according to VN angle (VN<0 degrees (n=92), 0 degrees <=VN<10 degrees (n=82), 10 degrees <=VN<15 degrees (n=26), VN>=15 degrees (n=28)), and the short-term (within 6 months) fixation results of radiographs in these fractures were evaluated. RESULTS: The ICC of the VN angle and the Pauwels angle in pre operative radiographs were 0.937 (95% confidence interval (CI): 0.922-0.950) and 0.942 respectively (95% CI: 0.914-0.970), indicating both angles had a good inter rater reproducibility. However, there was a great difference between the Pauwels angle in pre-operative and post-operative radiographs (P=0.037), the absolute difference was 10.66+/-6.47 (range: 1.72-38.48), while no statistical difference for the VN angle (P=0.084) and the absolute difference was 2.20+/-1.63 (range: 0.05-7.56). The overall fixation failure rate which was defined as screw loosening, varus collapse, obvious fracture displacement or femoral neck shortening was 11.84%, and the mean failure rates according to VN angles were respectively 0%, 3.24% (95% CI: 1.64-4.84), 22.69% (95% CI: 16.43-28.96), 65.45% (95% CI: 59.36-71.53). The mean failure rates of fractures according to post operative Pauwels angle (<30 degrees , 30-50 degrees , >50 degrees ) were respectively 0%, 1.46% (95% CI: 1.42-1.50) and 36.24% (95% CI: 34.93-37.54). DISCUSSION: The VN angle has a good inter-rater reproducibility, a higher reliability than the Pauwels angle and is closely related to the short-term prognosis of femoral neck fractures treated with cannulated compression screws. LEVEL OF EVIDENCE: Level IV, retrospective diagnostic study. PMID- 28093377 TI - Ten-year experience of retrievable inferior vena cava filters in a tertiary referral center. AB - PURPOSE: A significant proportion of patients undergoing surgery have an increased incidence of acute pulmonary embolus (PE). We analyzed all patients who had a retrievable inferior vena cava (IVC) filter placed preoperatively for PE prophylaxis and investigated the long-term outcomes of the patients who did not have their filter removed. METHODS: Patients who underwent retrievable IVC filter insertion and attempted removal were identified from the radiology information systems database in a large tertiary referral university teaching hospital. Results of all clinical investigations (including computed tomography, magnetic resonance imaging, ultrasonography, and plain radiography) while the IVC filters were in situ were reviewed. RESULTS: In total, 393 retrievable IVC filters were inserted, 254 with the indication of preoperative thromboembolic prophylaxis. Recurrent PE was reported in five patients (1.9%) despite the IVC filter. Of the 254 retrievable filters inserted prior to surgery, an attempt at retrieval was made in 168 filters (66.1%). Successful retrieval at the first attempt occurred in 143 cases (85.1%), while 25 cases failed or were aborted (14.9%). No attempt at retrieval was made in 86 (33.9%) patients and a significant proportion of these patients had undergone cancer surgery (P < 0.0107). In those patients where there was no attempt at retrieval, there was an association between cancer surgery and a shorter absolute survival time (P < 0.0001). CONCLUSION: The majority of attempted filter retrievals were successful, and a proportion of nonretrieved IVC filters are accounted for in patients who underwent cancer surgery and ultimately died with the filter in situ. A departmental protocol is recommended to ensure the filter is removed where appropriate and possible. PMID- 28093379 TI - The Epital Care Model: A New Person-Centered Model of Technology-Enabled Integrated Care for People With Long Term Conditions. AB - BACKGROUND: There is worldwide recognition that the future provision of health care requires a reorganization of provision of care, with increased empowerment and engagement of patients, along with skilled health professionals delivering services that are coordinated across sectors and organizations that provide health care. Technology may be a way to enable the creation of a coherent, cocreative, person-centered method to provide health care for individuals with one or more long-term conditions (LTCs). It remains to be determined how a new care model can be introduced that supports the intentions of the World Health Organization (WHO) to have integrated people-centered care. OBJECTIVE: To design, pilot, and test feasibility of a model of health care for people with LTCs based on a cocreative, iterative, and stepwise process in a way that recognizes the need for person-centered care, and embraces the use of digital technology. METHODS: The overall research method was inspired by action research and used an agile, iterative approach. In 2012, a living lab was established in a Danish municipality which allowed for the freedom of redesigning health care processes. As the first step, a wide group of stakeholders was gathered to create a layout for the reorganization of services and development of technology, based on established principles for innovative management of people with chronic conditions. The next three steps were (1) a proof of concept in 2012, (2) a pilot study, and (3) a feasibility study from 2013 to 2015, in which a total of 93 chronic obstructive pulmonary disease (COPD) patients were enrolled. Citizens were provided a tablet-based solution for remote follow-up and communication purposes, and access to a 24/7 response and coordination center that coordinated both virtual and face-to-face support for COPD management. In step five the initial model was extended with elements that support continuity of care. Beginning in the autumn of 2013, 1102 frail elderly individuals were included and offered two additional services: an outgoing acute medical team and a local subacute bed function. RESULTS: Based on the findings from the iterative process, and evolving technology and workflow solutions, we propose a robust and feasible model that can provide a framework for developing solutions to support an active life with one or more LTCs. The resulting Epital Care Model (ECM) consists of six stages, and serves as a template for how a digitally-enhanced health service can be provided based on patients' medical needs. The model is designed to be a proactive, preventive, and monitoring health care system that involves individuals in the management of their own health conditions. CONCLUSIONS: The ECM is in accordance with WHO's framework for integrated people-centered health services, and may serve as a framework for the development of new technologies and provide a template for future reorganization. PMID- 28093380 TI - Cleveland Clinic to re-evaluate its Wellness Institute after director questions vaccines. PMID- 28093378 TI - Factors Associated With Weight Change in Online Weight Management Communities: A Case Study in the LoseIt Reddit Community. AB - BACKGROUND: Recent research has shown that of the 72% of American Internet users who have looked for health information online, 22% have searched for help to lose or control weight. This demand for information has given rise to many online weight management communities, where users support one another throughout their weight loss process. Whether and how user engagement in online communities relates to weight change is not totally understood. OBJECTIVE: We investigated the activity behavior and analyze the semantic content of the messages of active users in LoseIt (r/loseit), a weight management community of the online social network Reddit. We then explored whether these features are associated with weight loss in this online social network. METHODS: A data collection tool was used to collect English posts, comments, and other public metadata of active users (ie, users with at least one post or comment) on LoseIt from August 2010 to November 2014. Analyses of frequency and intensity of user interaction in the community were performed together with a semantic analysis of the messages, done by a latent Dirichlet allocation method. The association between weight loss and online user activity patterns, the semantics of the messages, and real-world variables was found by a linear regression model using 30-day weight change as the dependent variable. RESULTS: We collected posts and comments of 107,886 unique users. Among these, 101,003 (93.62%) wrote at least one comment and 38,981 (36.13%) wrote at least one post. Median percentage of days online was 3.81 (IQR 9.51). The 10 most-discussed semantic topics on posts were related to healthy food, clothing, calorie counting, workouts, looks, habits, support, and unhealthy food. In the subset of 754 users who had gender, age, and 30-day weight change data available, women were predominant and 92.9% (701/754) lost weight. Female gender, body mass index (BMI) at baseline, high levels of online activity, the number of upvotes received per post, and topics discussed within the community were independently associated with weight change. CONCLUSIONS: Our findings suggest that among active users of a weight management community, self declaration of higher BMI levels (which may represent greater dissatisfaction with excess weight), high online activity, and engagement in discussions that might provide social support are associated with greater weight loss. These findings have the potential to aid health professionals to assist patients in online interventions by focusing efforts on increasing engagement and/or starting discussions on topics of higher impact on weight change. PMID- 28093381 TI - Media must report celebrity health stories responsibly. PMID- 28093382 TI - Aspirin for frequent episodic tension-type headache has limited evidence. PMID- 28093384 TI - Qualitative evidence synthesis to improve implementation of clinical guidelines. PMID- 28093383 TI - Effect of minimal acupuncture for infantile colic: a multicentre, three-armed, single-blind, randomised controlled trial (ACU-COL). AB - BACKGROUND: Evidence for treating infantile colic with acupuncture is contradictory. AIM: To evaluate and compare the effect of two types of acupuncture versus no acupuncture in infants with colic in public child health centres (CHCs). METHODS: A multicentre, randomised controlled, single-blind, three-armed trial (ACU-COL) comparing two styles of acupuncture with no acupuncture, as an adjunct to standard care, was conducted. Among 426 infants whose parents sought help for colic and registered their child's fussing/crying in a diary, 157 fulfilled the criteria for colic and 147 started the intervention. All infants received usual care plus four extra visits to CHCs with advice/support (twice a week for 2 weeks), comprising gold standard care. The infants were randomly allocated to three groups: (A) standardised minimal acupuncture at LI4; (B) semi-standardised individual acupuncture inspired by Traditional Chinese Medicine; and (C) no acupuncture. The CHC nurses and parents were blinded. Acupuncture was given by nurses with extensive experience of acupuncture. RESULTS: The effect of the two types of acupuncture was similar and both were superior to gold standard care alone. Relative to baseline, there was a greater relative reduction in time spent crying and colicky crying by the second intervention week (p=0.050) and follow-up period (p=0.031), respectively, in infants receiving either type of acupuncture. More infants receiving acupuncture cried <3 hours/day, and thereby no longer fulfilled criteria for colic, in the first (p=0.040) and second (p=0.006) intervention weeks. No serious adverse events were reported. CONCLUSIONS: Acupuncture appears to reduce crying in infants with colic safely. TRIAL REGISTRATION NUMBER: NCT01761331; Results. PMID- 28093385 TI - Switzerland voted against a universal basic income. PMID- 28093386 TI - Association of Facebook Use With Compromised Well-Being: A Longitudinal Study. AB - Face-to-face social interactions enhance well-being. With the ubiquity of social media, important questions have arisen about the impact of online social interactions. In the present study, we assessed the associations of both online and offline social networks with several subjective measures of well-being. We used 3 waves (2013, 2014, and 2015) of data from 5,208 subjects in the nationally representative Gallup Panel Social Network Study survey, including social network measures, in combination with objective measures of Facebook use. We investigated the associations of Facebook activity and real-world social network activity with self-reported physical health, self-reported mental health, self-reported life satisfaction, and body mass index. Our results showed that overall, the use of Facebook was negatively associated with well-being. For example, a 1-standard deviation increase in "likes clicked" (clicking "like" on someone else's content), "links clicked" (clicking a link to another site or article), or "status updates" (updating one's own Facebook status) was associated with a decrease of 5%-8% of a standard deviation in self-reported mental health. These associations were robust to multivariate cross-sectional analyses, as well as to 2-wave prospective analyses. The negative associations of Facebook use were comparable to or greater in magnitude than the positive impact of offline interactions, which suggests a possible tradeoff between offline and online relationships. PMID- 28093387 TI - Dying at home of cancer: whose needs are being met? The experience of family carers and healthcare professionals (a multiperspective qualitative study). AB - OBJECTIVES: Supporting patients to die in the place of their choosing is an important aspect of end of life care. Our study set out to answer the question: 'How does the home environment influence perceptions of quality of death, and the experience of caring for the dying at home, for family carers and healthcare professionals (HCPs)? METHODS: A qualitative approach, using multiperspective interviews with bereaved family carers (n=15) and a nominated HCP (n=13) ensured depth of insight gained into supporting a home death. The semistructured interviews were audio recorded, transcribed verbatim and analysed using Framework. RESULTS: We found that the home environment enabled normality, a sense of control and individualised care which family carers often perceived as contributing towards a good death. However, the home environment created challenges for both family carers and HCPs, due to the differing and at times conflicting needs of the dying person and their family carers. CONCLUSIONS: We have shed light on the complexity of balancing the demands and the satisfaction of caring for someone dying at home. The ability to manage these conflicting needs influenced whether carers perceived the home setting as the best place for the person to have received care in their last days of life. PMID- 28093388 TI - University fresher campaign doubles meningitis vaccination rate, UK study finds. PMID- 28093389 TI - "Unresponsive" complaints system is failing NHS patients. PMID- 28093390 TI - Margaret McCartney: Theresa May and the blame game. PMID- 28093391 TI - Universal basic income may be a Trojan horse. PMID- 28093392 TI - Russia plans to ban tobacco sales to all citizens born after 2014. PMID- 28093393 TI - Prescription data for open toe sandals syndrome. PMID- 28093395 TI - Australian health minister resigns amid scandal over expense claims. PMID- 28093394 TI - Angry GPs hit back at PM over seven day service threats. PMID- 28093397 TI - Are we doing ineffective CPR? PMID- 28093396 TI - Bogus doctor jailed a second time for using fake credentials. PMID- 28093399 TI - New Beginnings. PMID- 28093398 TI - Efficacy and Safety of Smoking Cessation Interventions in Patients With Cardiovascular Disease: A Network Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Although the efficacy and safety of smoking cessation interventions are well established, their efficacy and safety in patients with cardiovascular disease (CVD) remain unclear. The objective of this study was to evaluate the efficacy and safety of pharmacological and behavioral smoking cessation interventions in CVD patients via a meta-analysis of randomized controlled trials. METHODS AND RESULTS: EMBASE, PsycINFO, MEDLINE, PubMed, and the Cochrane Tobacco Addiction Specialized Register were searched for randomized controlled trials evaluating the efficacy of smoking cessation pharmacotherapies and behavioral therapies in CVD patients. Outcomes of interest were smoking abstinence at 6 and 12 months, defined using the most rigorous criteria reported. Data were pooled across studies for direct comparisons using random-effects models. Network meta-analysis using a graph-theoretical approach was used to generate the indirect comparisons. Seven pharmacotherapy randomized controlled trials (n=2809) and 17 behavioral intervention randomized controlled trials (n=4666) met our inclusion criteria. Our network meta-analysis revealed that varenicline (relative risk [RR]: 2.64; 95% confidence interval [CI], 1.34-5.21) and bupropion (RR: 1.42; 95% CI, 1.01-2.01) were associated with greater abstinence than placebo. The evidence about nicotine replacement therapies was inconclusive (RR: 1.22; 95% CI, 0.72-2.06). Telephone therapy (RR: 1.47; 95% CI: 1.15-1.88) and individual counseling (RR: 1.64, 95% CI: 1.17-2.28) were both more efficacious than usual care, whereas in-hospital behavioral interventions were not (RR: 1.05; 95% CI, 0.78-1.43). CONCLUSIONS: Our meta-analysis suggests varenicline and bupropion, as well as individual and telephone counseling, are efficacious for smoking cessation in CVD patients. PMID- 28093400 TI - Evaluating Value Series. PMID- 28093401 TI - Sixty seconds on . . . antidepressants. PMID- 28093402 TI - Local authorities must take responsibility for housing homeless people. PMID- 28093403 TI - Review fails to advise on cannabis use because of poor research. PMID- 28093404 TI - Development and application of an algorithm to compute weighted multiple glycan alignments. AB - Motivation: A glycan consists of monosaccharides linked by glycosidic bonds, has branches and forms complex molecular structures. Databases have been developed to store large amounts of glycan-binding experiments, including glycan arrays with glycan-binding proteins. However, there are few bioinformatics techniques to analyze large amounts of data for glycans because there are few tools that can handle the complexity of glycan structures. Thus, we have developed the MCAW (Multiple Carbohydrate Alignment with Weights) tool that can align multiple glycan structures, to aid in the understanding of their function as binding recognition molecules. Results: We have described in detail the first algorithm to perform multiple glycan alignments by modeling glycans as trees. To test our tool, we prepared several data sets, and as a result, we found that the glycan motif could be successfully aligned without any prior knowledge applied to the tool, and the known recognition binding sites of glycans could be aligned at a high rate amongst all our datasets tested. We thus claim that our tool is able to find meaningful glycan recognition and binding patterns using data obtained by glycan-binding experiments. The development and availability of an effective multiple glycan alignment tool opens possibilities for many other glycoinformatics analysis, making this work a big step towards furthering glycomics analysis. Availability and Implementation: http://www.rings.t.soka.ac.jp. Contact: kkiyoko@soka.ac.jp. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28093407 TI - Protein multiple sequence alignment benchmarking through secondary structure prediction. AB - Motivation: Multiple sequence alignment (MSA) is commonly used to analyze sets of homologous protein or DNA sequences. This has lead to the development of many methods and packages for MSA over the past 30 years. Being able to compare different methods has been problematic and has relied on gold standard benchmark datasets of 'true' alignments or on MSA simulations. A number of protein benchmark datasets have been produced which rely on a combination of manual alignment and/or automated superposition of protein structures. These are either restricted to very small MSAs with few sequences or require manual alignment which can be subjective. In both cases, it remains very difficult to properly test MSAs of more than a few dozen sequences. PREFAB and HomFam both rely on using a small subset of sequences of known structure and do not fairly test the quality of a full MSA. Results: In this paper we describe QuanTest, a fully automated and highly scalable test system for protein MSAs which is based on using secondary structure prediction accuracy (SSPA) to measure alignment quality. This is based on the assumption that better MSAs will give more accurate secondary structure predictions when we include sequences of known structure. SSPA measures the quality of an entire alignment however, not just the accuracy on a handful of selected sequences. It can be scaled to alignments of any size but here we demonstrate its use on alignments of either 200 or 1000 sequences. This allows the testing of slow accurate programs as well as faster, less accurate ones. We show that the scores from QuanTest are highly correlated with existing benchmark scores. We also validate the method by comparing a wide range of MSA alignment options and by including different levels of mis-alignment into MSA, and examining the effects on the scores. Availability and Implementation: QuanTest is available from http://www.bioinf.ucd.ie/download/QuanTest.tgz. Contact: quan.le@ucd.ie. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28093408 TI - VCF-kit: assorted utilities for the variant call format. AB - Summary: The variant call format (VCF) is a popular standard for storing genetic variation data. As a result, a large collection of tools has been developed that perform diverse analyses using VCF files. However, some tasks common to statistical and population geneticists have not been created yet. To streamline these types of analyses, we created novel tools that analyze or annotate VCF files and organized these tools into a command-line based utility named VCF-kit. VCF-kit adds essential utilities to process and analyze VCF files, including primer generation for variant validation, dendrogram production, genotype imputation from sequence data in linkage studies, and additional tools. Availability and Implementation: https://github.com/AndersenLab/VCF-kit. Contact: erik.andersen@northwestern.edu. PMID- 28093409 TI - DeuteRater: a tool for quantifying peptide isotope precision and kinetic proteomics. AB - Motivation: Using mass spectrometry to measure the concentration and turnover of the individual proteins in a proteome, enables the calculation of individual synthesis and degradation rates for each protein. Software to analyze concentration is readily available, but software to analyze turnover is lacking. Data analysis workflows typically don't access the full breadth of information about instrument precision and accuracy that is present in each peptide isotopic envelope measurement. This method utilizes both isotope distribution and changes in neutromer spacing, which benefits the analysis of both concentration and turnover. Results: We have developed a data analysis tool, DeuteRater, to measure protein turnover from metabolic D 2 O labeling. DeuteRater uses theoretical predictions for label-dependent change in isotope abundance and inter-peak (neutromer) spacing within the isotope envelope to calculate protein turnover rate. We have also used these metrics to evaluate the accuracy and precision of peptide measurements and thereby determined the optimal data acquisition parameters of different instruments, as well as the effect of data processing steps. We show that these combined measurements can be used to remove noise and increase confidence in the protein turnover measurement for each protein. Availability and Implementation: Source code and ReadMe for Python 2 and 3 versions of DeuteRater are available at https://github.com/JC-Price/DeuteRater . Data is at https://chorusproject.org/pages/index.html project number 1147. Critical Intermediate calculation files provided as Tables S3 and S4. Software has only been tested on Windows machines. Contact: jcprice@chem.byu.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28093410 TI - FASTdoop: a versatile and efficient library for the input of FASTA and FASTQ files for MapReduce Hadoop bioinformatics applications. AB - Summary: MapReduce Hadoop bioinformatics applications require the availability of special-purpose routines to manage the input of sequence files. Unfortunately, the Hadoop framework does not provide any built-in support for the most popular sequence file formats like FASTA or BAM. Moreover, the development of these routines is not easy, both because of the diversity of these formats and the need for managing efficiently sequence datasets that may count up to billions of characters. We present FASTdoop, a generic Hadoop library for the management of FASTA and FASTQ files. We show that, with respect to analogous input management routines that have appeared in the Literature, it offers versatility and efficiency. That is, it can handle collections of reads, with or without quality scores, as well as long genomic sequences while the existing routines concentrate mainly on NGS sequence data. Moreover, in the domain where a comparison is possible, the routines proposed here are faster than the available ones. In conclusion, FASTdoop is a much needed addition to Hadoop-BAM. Availability and Implementation: The software and the datasets are available at http://www.di.unisa.it/FASTdoop/ . Contact: umberto.ferraro@uniroma1.it. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28093411 TI - Age- and Sex-Related Influences on Left Ventricular Mechanics in Elderly Individuals Free of Prevalent Heart Failure: The ARIC Study (Atherosclerosis Risk in Communities). AB - BACKGROUND: Advanced age is related to left ventricular (LV) remodeling. We sought to investigate the relationships between aging, elevated hemodynamic load, cardiac mechanics, and LV remodeling in an elderly community-based population. METHODS AND RESULTS: We studied 1105 subjects (76+/-5 years, 61% women) without prevalent heart failure, who attended the visit 5 of the ARIC study (Atherosclerosis Risk in Communities). LV global longitudinal strain, global circumferential strain, and torsion indices were analyzed using 3-dimensional echocardiography. Advanced age was associated with greater LV concentricity, lower myocardial diastolic relaxation, reduced global longitudinal strain (adjusted estimate, 0.39+/-0.19% (SE)/decade; P=0.038), borderline greater global circumferential strain (adjusted estimate, -0.59+/-0.36% (SE)/decade; P=0.08), and higher torsion indices (adjusted estimate for torsion, 0.33+/-0.04 degrees (SE)/decade; P<0.001). In addition, greater concentricity was associated with decreased global longitudinal strain and greater torsion in multivariable models (all P<0.001). Women showed smaller LV cavity size, greater concentricity, lower myocardial relaxation velocity E', though demonstrated greater global longitudinal strain, global circumferential strain, and torsion than men (all P<0.05). Overall, subjects with hypertension and increasing age were more likely to have higher torsion, though the association between advanced age and greater torsion was more pronounced in women than in men (both interaction P<0.05). CONCLUSIONS: In an asymptomatic, senescent community-dwelling population, we observed a distinct, sex-specific pattern of cardiac remodeling. Although we observed worse diastolic and longitudinal function with advanced age or elevated load in both sexes, a significant increase of torsion was more pronounced in women. PMID- 28093413 TI - Persistence of Cardiac Remodeling in Preadolescents With Fetal Growth Restriction. AB - BACKGROUND: Fetal growth restriction (FGR) affects 5% to 10% of newborns and is associated with increased cardiovascular mortality in adulthood. We evaluated whether prenatal cardiovascular changes previously demonstrated in FGR persist into preadolescence. METHODS AND RESULTS: A cohort study of 58 FGR (defined as birth weight below 10th centile) and 94 normally grown fetuses identified in utero and followed-up into preadolescence (8-12 years of age) by echocardiography and 3-dimensional shape computational analysis. Compared with controls, FGR preadolescents had a different cardiac shape, with more spherical and smaller hearts. Left ventricular ejection fraction was similar among groups, whereas FGR had decreased longitudinal motion (decreased mitral annular systolic peak velocities: control median, 0.11 m/s [interquartile range, 0.09-0.12] versus FGR median 0.09 m/s [interquartile range, 0.09-0.10]; P<0.01) and impaired relaxation (isovolumic relaxation time: control, 0.21 ms [interquartile range, 0.12-0.35] versus FGR, 0.35 ms [interquartile range, 0.20-0.46]; P=0.04). Global longitudinal strain was decreased (control mean, -22.4% [SD, 1.37] versus FGR mean, -21.5% [SD, 1.16]; P<0.001) compensated by an increased circumferential strain and with a higher prevalence of postsystolic shortening in FGR as compared with controls. These differences persisted after adjustment for parental ethnicity and smoking, prenatal glucocorticoid administration, preeclampsia, gestational age at delivery, days in intensive care unit, sex, age, and body surface area at evaluation. CONCLUSIONS: This study provides evidence that cardiac remodeling induced by FGR persists until preadolescence with findings similar to those reported in their prenatal life and childhood. The findings support the hypothesis of primary cardiac programming in FGR for explaining the association between low birth weight and cardiovascular risk in adulthood. PMID- 28093414 TI - Fetal Growth Restriction and Long-Term Cardiovascular Risk: Is It Time to Get With the Program? PMID- 28093412 TI - Beyond Bernoulli: Improving the Accuracy and Precision of Noninvasive Estimation of Peak Pressure Drops. AB - BACKGROUND: Transvalvular peak pressure drops are routinely assessed noninvasively by echocardiography using the Bernoulli principle. However, the Bernoulli principle relies on several approximations that may not be appropriate, including that the majority of the pressure drop is because of the spatial acceleration of the blood flow, and the ejection jet is a single streamline (single peak velocity value). METHODS AND RESULTS: We assessed the accuracy of the Bernoulli principle to estimate the peak pressure drop at the aortic valve using 3-dimensional cardiovascular magnetic resonance flow data in 32 subjects. Reference pressure drops were computed from the flow field, accounting for the principles of physics (ie, the Navier-Stokes equations). Analysis of the pressure components confirmed that the spatial acceleration of the blood jet through the valve is most significant (accounting for 99% of the total drop in stenotic subjects). However, the Bernoulli formulation demonstrated a consistent overestimation of the transvalvular pressure (average of 54%, range 5%-136%) resulting from the use of a single peak velocity value, which neglects the velocity distribution across the aortic valve plane. This assumption was a source of uncontrolled variability. CONCLUSIONS: The application of the Bernoulli formulation results in a clinically significant overestimation of peak pressure drops because of approximation of blood flow as a single streamline. A corrected formulation that accounts for the cross-sectional profile of the blood flow is proposed and adapted to both cardiovascular magnetic resonance and echocardiographic data. PMID- 28093415 TI - The Aging Human Heart. PMID- 28093416 TI - Noninvasive Estimation of the Severity of Aortic Stenosis: Going Beyond Bernoulli. PMID- 28093417 TI - Cardiovascular risk of patients with gout seen at rheumatology clinics following a structured assessment. AB - OBJECTIVES: Gout-associated cardiovascular (CV) risk relates to comorbidities and crystal-led inflammation. The aim was to estimate the CV risk by prediction tools in new patients with gout and to assess whether ultrasonographic carotid changes are present in patients without high CV risk. METHODS: Cross-sectional study. Consecutive new patients with crystal-proven gout underwent a structured CV consultation, including CV events, risk factors and two risk prediction tools-the Systematic COronary Evaluation (SCORE) and the Framingham Heart Study (FHS). CV risk was stratified according to current European guidelines. Carotid ultrasound (cUS) was performed in patients with less than very high CV risk. The presence of carotid plaques was studied depending on the SCORE and FHS by the area under the curve (AUC) of receiver operating curves. RESULTS: 237 new patients with gout were recruited. CV stratification by scores showed a predominance of very high (95 patients, 40.1%) and moderate (72 patients, 30.5%) risk levels. cUS was performed in 142 patients, finding atheroma plaques in 66 (46.5%, 95% CI 37.8 to 54.2). Following cUS findings, patients classified as very high risk increased from 40.1% up to 67.9% (161/237 patients). SCORE and FHS predicted moderately (AUC 0.711 and 0.683, respectively) the presence of atheroma plaques at cUS. CONCLUSIONS: The majority of patients presenting with gout may be at very high CV risk, indicating the need for initiating optimal prevention strategies at this stage. Risk prediction tools appear to underestimate the presence of carotid plaque in patients with gout. PMID- 28093418 TI - Cell-specific epigenome-wide DNA methylation profile in long-term cultured minor salivary gland epithelial cells from patients with Sjogren's syndrome. AB - OBJECTIVES: The aetiology of primary Sjogren's syndrome (pSS), also referred to as autoimmune epithelitis, is incompletely understood but includes an epigenetic contribution. Accordingly, the aim of this study was to investigate DNA methylation in salivary gland epithelial cells (SGEC), and to compare results with those publicly available from pSS B and T cells. METHODS: Long-term cultured SGEC were selected to conduct an epigenome-wide association study (EWAS) in patients with pSS with comparison to controls using the HumanMethylation 450 K array from Illumina. RESULTS: The analysis of differentially methylated CpG (DMC) uncovered 4662 positions corresponding to 2560 genes, and 575 genes with two or more DMC sites (DMCs), in SGEC as compared with controls. Further analysis highlighted an important proportion of interferon-regulated genes (61%), the calcium pathway (hypomethylated) and the Wnt pathway (hypermethylated). When comparing SGEC with pSS T and/or B cell results, an important overlap was observed with respect to differentially methylated genes (38.8%) and pSS risk factors (71.4%), although such assertion was not true when comparing DMCs. CONCLUSIONS: This study conducted in SGEC emphasises the role of DNA methylation in pSS pathogenesis and supports the necessity to conduct pure cell analysis for future EWAS studies when analysing salivary glands from patients with pSS. PMID- 28093419 TI - The risk of fracture among patients with psoriatic arthritis and psoriasis: a population-based study. AB - OBJECTIVE: To determine the risk of fracture and osteoporosis among patients with psoriatic arthritis (PsA) and psoriasis, compared with the general population and patients with rheumatoid arthritis (RA). METHODS: A population-based cohort study was performed in The Health Improvement Network in the UK using data from 1994 to 2014. Patients aged 18-89 years with PsA or psoriasis and up to five unexposed controls matched by practice and start date within that practice were included. Patients with RA and matched controls were included for comparison. Severe psoriasis was defined by a code for psoriasis and either phototherapy or a systemic medication for psoriasis. Incidence and adjusted HRs (aHR) for fracture (all, hip, vertebral) were calculated. RESULTS: Patients with PsA (n=9788), psoriasis (n=158 323) and controls (n=821 834) were identified. Patients with PsA had an elevated risk of all fracture aHR 1.26 (1.06 to 1.27). Patients with mild psoriasis had elevated risk of all fractures, vertebral and hip fracture: aHR 1.07 (1.05 to 1.10), 1.17 (1.03 to 1.33) and 1.13 (1.04 to 1.22). Patients with severe psoriasis had significantly elevated risk of all fracture and vertebral fracture: aHR 1.26 (1.15 to 1.39) and 2.23 (1.54 to 3.22). CONCLUSIONS: PsA and psoriasis are associated with an elevated risk for fracture. PMID- 28093421 TI - GP views on strategies to cope with increasing workload: a qualitative interview study. AB - BACKGROUND: The existence of a crisis in primary care in the UK is in little doubt. GP morale and job satisfaction are low, and workload is increasing. In this challenging context, finding ways for GPs to manage that workload is imperative. AIM: To explore what existing or potential strategies are described by GPs for dealing with their workload, and their views on the relative merits of each. DESIGN AND SETTING: Semi-structured, qualitative interviews with GPs working within NHS England. METHOD: All GPs working within NHS England were eligible. Of those who responded to advertisements, a maximum-variation sample was selected and interviewed until data saturation was reached. Data were analysed thematically. RESULTS: Responses were received from 171 GPs, and, from these, 34 were included in the study. Four main themes emerged for workload management: patient-level, GP-level, practice-level, and systems-level strategies. A need for patients to take greater responsibility for self management was clear, but many felt that GPs should not be responsible for this education. Increased delegation of tasks was felt to be key to managing workload, with innovative use of allied healthcare professionals and extended roles for non clinical staff suggested. Telephone triage was a commonly used tool for managing workload, although not all participants found this helpful. CONCLUSION: This in depth qualitative study demonstrates an encouraging resilience among GPs. They are proactively trying to manage workload, often using innovative local strategies. GPs do not feel that they can do this alone, however, and called repeatedly for increased recruitment and more investment in primary care. PMID- 28093420 TI - Incidence of venous thromboembolism in care homes: a prospective cohort study. AB - BACKGROUND: Care home residents have venous thromboembolism (VTE) risk profiles similar to medical inpatients; however, the epidemiology of VTE in care homes is unclear. AIM: To determine the incidence of VTE in care homes. DESIGN AND SETTING: Observational cohort study of 45 care homes in Birmingham and Oxford, UK. METHOD: A consecutive sample of care home residents was enrolled and followed up for 12 months. Data were collected via case note reviews of care home and GP records; mortality information was supplemented with Health and Social Care Information Centre (now called NHS Digital) cause of death data. All potential VTE events were adjudicated by an independent committee according to three measures of diagnostic certainty: definite VTE (radiological evidence), probable VTE (high clinical indication but no radiological evidence), or possible VTE (VTE cannot be ruled out). (Study registration number: ISTCTN80889792.) RESULTS: There were 1011 participants enrolled, and the mean follow-up period was 312 days (standard deviation 98 days). The incidence rate was 0.71 per 100 person years of observation (95% confidence interval [CI] = 0.26 to 1.54) for definite VTE, 0.83 per 100 person years (95% CI = 0.33 to 1.70) for definite and probable VTE, and 2.48 per 100 person years (95% CI = 1.53 to 3.79) for definite, probable, and possible VTE. CONCLUSION: The incidence of VTE in care homes in this study (0.71 2.48 per 100 person years) is substantial compared with that in the community (0.117 per 100 person years) and in people aged >=70 years (0.44 per 100 person years). Further research regarding risk stratification and VTE prophylaxis in this population is needed. PMID- 28093422 TI - GPs' perceptions of workload in England: a qualitative interview study. AB - BACKGROUND: GPs report the lowest levels of morale among doctors, job satisfaction is low, and the GP workforce is diminishing. Workload is frequently cited as negatively impacting on commitment to a career in general practice, and many GPs report that their workload is unmanageable. AIM: To gather an in-depth understanding of GPs' perceptions and attitudes towards workload. DESIGN AND SETTING: All GPs working within NHS England were eligible. Advertisements were circulated via regional GP e-mail lists and national social media networks in June 2015. Of those GPs who responded, a maximum-variation sample was selected until data saturation was reached. METHOD: Semi-structured, qualitative interviews were conducted. Data were analysed thematically. RESULTS: In total, 171 GPs responded, and 34 were included in this study. GPs described an increase in workload over recent years, with current working days being long and intense, raising concerns over the wellbeing of GPs and patients. Full-time partnership was generally not considered to be possible, and many participants felt workload was unsustainable, particularly given the diminishing workforce. Four major themes emerged to explain increased workload: increased patient needs and expectations; a changing relationship between primary and secondary care; bureaucracy and resources; and the balance of workload within a practice. Continuity of care was perceived as being eroded by changes in contracts and working patterns to deal with workload. CONCLUSION: This study highlights the urgent need to address perceived lack of investment and clinical capacity in general practice, and suggests that managing patient expectations around what primary care can deliver, and reducing bureaucracy, have become key issues, at least until capacity issues are resolved. PMID- 28093423 TI - Medical and psychosocial factors associated with antibiotic prescribing in primary care: survey questionnaire and factor analysis. AB - BACKGROUND: Acute upper respiratory infections (AURI) are the leading causes of antibiotic prescribing in primary care although antibiotics are often not indicated. AIM: To gain an understanding of the knowledge, attitudes, and practices (KAP) of GPs in Singapore and the associated latent factors to guide the implementation of an effective programme to reduce antibiotic use in primary care. DESIGN AND SETTING: An anonymous survey on the KAP of antibiotic use in AURI of GPs in Singapore. METHOD: KAP survey questionnaires were posted to all GPs from a database. To ascertain the latent factors affecting prescribing patterns, exploratory factor analysis was performed. RESULTS: Among 427 responses, 351 (82.2%) were from GPs working in private practice. It was found that 58.4% of GPs in the private versus 72.4% of those in the public sector recognised that >80% of AURIs were caused by viruses (P = 0.02). The majority of GPs (353/427; 82.7%) felt that antibiotics were overprescribed in primary care. Significant factors associated with low antibiotic prescribing were good medical knowledge and clinical competency (adjusted odds ratio [aOR] 3.2, 95% confidence interval [CI] = 2.4 to 4.3), good clinical practice (aOR 2.7 [95% CI = 2.0 to 3.6]), availability of diagnostic tests (aOR 1.4 [95% CI = 1.1 to 1.8]), and desire to improve clinical practice (aOR 1.5 [95% CI = 1.2 to 1.9]). The conservative practice of giving antibiotics 'to be on the safe side' is significantly less likely to be associated with low antibiotic prescribing (aOR 0.7 [95% CI = 0.5 to 0.9]). CONCLUSION: This is the first KAP survey on antibiotic prescribing for AURI among GPs in Singapore. With the latent factors identified, future interventions should be directed at addressing these factors to reduce inappropriate antibiotic prescribing. PMID- 28093424 TI - Strongyloides hyperinfection syndrome and VRE pneumonia. AB - Immunocompromised patients have high risk of infections from bacteria, viruses, fungi and parasites. One of these infections is those caused by Strongyloides stercoralis Immunocompromised patients are at risk of hyperinfection syndrome which is characterised with more systemic manifestation and a higher risk of morbidity and mortality. This can be complicated by coinfection with enteric organisms, specifically Gram-negative. Enterococci are Gram-positive cocci which are inhabitants of the human gastrointestinal tract. Even though enterococci can cause serious infections in multiple sites, they are a rare cause of pneumonia. We present a case of disseminated strongyloides with vancomycin-resistant enterococcus causing pneumonia. The patient had a complicated course with respiratory failure and septic shock. He died eventually due to his severe infections. After a literature review, we could not find a similar case of coinfection of disseminated strongyloides with vancomycin-resistant enterococcus pneumonia in immune-compromised patients. PMID- 28093425 TI - Unexpected complication of colonoscopy. AB - The authors present a rare case of a 71-year-old man presenting with large bowel obstruction after attempted colonoscopy. The procedure was impossible to complete due to a tight sigmoid stricture and the patient presented with an acute abdomen the following day. He was managed conservatively and discharged before returning for an elective laparoscopic sigmoid colectomy. The potential differentials of an acute abdomen post-colonoscopy are discussed and the literature reviewed on this rare complication. Finally, the authors review whether there is pressure on endoscopists to 'complete' colonoscopies (by achieving caecal intubation) based on regulatory indices in quality, and how this might have to be disregarded in unfavourable circumstances. PMID- 28093426 TI - Oesophageal presentation of Crohn's disease. AB - Crohn's disease (CD) is characterised by a transmural inflammatory process, which can affect any part of the digestive tract; however, CD with oesophageal presentation is rare. We report a case of a previously healthy young woman with symptoms of dysphagia, odynophagia, chest pain and weight loss, who presented oesophageal ulcers at upper endoscopy and whose histology revealed granulomatous oesophagitis. After complementary study, a mild ileocaecal involvement of CD was demonstrated. The patient became asymptomatic with proton pump inhibitor and a course of prednisolone. Mucosal healing was obtained after maintenance therapy with azathioprine. In the absence of extraoesophageal symptoms, oesophageal CD may be overlooked. CD must always be considered as differential diagnosis in the presence of oesophageal ulcers. PMID- 28093427 TI - Bilateral presence of radix entomolaris in first and second permanent mandibular molars identified in a Caucasian woman. PMID- 28093428 TI - Exploring health literacy competencies towards patient education programme for Chinese-speaking healthcare professionals: a Delphi study. AB - OBJECTIVES: To achieve consensus on a set of competencies in health literacy practice based on a literature review and expert consultation. SETTING: Hospitals and community health centres in Taiwan. METHOD: A 2-stage modified Delphi study involving a literature review was conducted, followed by qualitative interviews and 3 rounds of email-based data collection over a 3-month period in 2011. PARTICIPANTS: 15 Chinese healthcare practitioners with more than 6 months' experience in patient education were interviewed to collect data on health literacy practice. 24 experts (12 academic scholars in health literacy and 12 professionals with training related to health literacy practice) were invited to participate in the Delphi process. RESULTS: Qualitative data from the interviews were analysed and summarised to form 99 competency items for health literacy practice, which were categorised into 5 domains of health literacy practice including those pertaining to knowledge and skills. Consensus was reached on 92 of 99 competencies, using a modified Delphi technique. CONCLUSIONS: The 92 competencies in health literacy practice embraced core components of patient education in the Chinese healthcare profession. PMID- 28093429 TI - Paediatric ED BiPAP continuous quality improvement programme with patient analysis: 2005-2013. AB - OBJECTIVE: In paediatric moderate-to-severe asthmatics, there is significant bronchospasm, airway obstruction, air trapping causing severe hyperinflation with more positive intraplural pressure preventing passive air movement. These effects cause an increased respiratory rate (RR), less airflow and shortened inspiratory breath time. In certain asthmatics, aerosols are ineffective due to their inadequate ventilation. Bilevel positive airway pressure (BiPAP) in acute paediatric asthmatics can be an effective treatment. BiPAP works by unloading fatigued inspiratory muscles, a direct bronchodilation effect, offsetting intrinsic PEEP and recruiting collapsed alveoli that reduces the patient's work of breathing and achieves their total lung capacity quicker. Unfortunately, paediatric emergency department (PED) BiPAP is underused and quality analysis is non-existent. A PED BiPAP Continuous Quality Improvement Program (CQIP) from 2005 to 2013 was evaluated using descriptive analytics for the primary outcomes of usage, safety, BiPAP settings, therapeutics and patient disposition. INTERVENTIONS: PED BiPAP CQIP descriptive analytics. SETTING: Academic PED. PARTICIPANTS: 1157 patients. INTERVENTIONS: A PED BiPAP CQIP from 2005 to 2013 for the usage, safety, BiPAP settings, therapeutic response parameters and patient disposition was evaluated using descriptive analytics. PRIMARY AND SECONDARY OUTCOMES: Safety, usage, compliance, therapeutic response parameters, BiPAP settings and patient disposition. RESULTS: 1157 patients had excellent compliance without complications. Only 6 (0.5%) BiPAP patients were intubated. BiPAP median settings: IPAP 18 (16,20) cm H2O range 12-28; EPAP 8 cmH2O (8,8) range 6-10; inspiratory-to-expiratory time (I:E) ratio 1.75 (1.5,1.75). Pediatric Asthma Severity score and RR decreased (p<0.001) while tidal volume increased (p<0.001). Patient disposition: 325 paediatric intensive care units (PICU), 832 wards, with 52 of these PED ward patients were discharged home with only 2 hours of PED BiPAP with no returning to the PED within 72 hours. CONCLUSIONS: BiPAP is a safe and effective therapeutic option for paediatric patients with asthma presenting to a PED or emergency department. This BiPAP CQIP showed significant patient compliance, no complications, improved therapeutics times, very low intubations and decreased PICU admissions. CQIP analysis demonstrated that using a higher IPAP, low EPAP with longer I:E optimises the patient's BiPAP settings and showed a significant improvement in PAS, RR and tidal volume. BiPAP should be considered as an early treatment in the PED severe or non-responsive moderate asthmatics. PMID- 28093430 TI - Development and validation of a prediction model for gestational hypertension in a Ghanaian cohort. AB - OBJECTIVE: To develop and validate a prediction model for identifying women at increased risk of developing gestational hypertension (GH) in Ghana. DESIGN: A prospective study. We used frequencies for descriptive analysis, chi2 test for associations and logistic regression to derive the prediction model. Discrimination was estimated by the c-statistic. Calibration was assessed by calibration plot of actual versus predicted probability. SETTING: Primary care antenatal clinics in Ghana. PARTICIPANTS: 2529 pregnant women in the development cohort and 647 pregnant women in the validation cohort. Inclusion criterion was women without chronic hypertension. PRIMARY OUTCOME: Gestational hypertension. RESULTS: Predictors of GH were diastolic blood pressure, family history of hypertension in parents, history of GH in a previous pregnancy, parity, height and weight. The c-statistic of the original model was 0.70 (95% CI 0.67-0.74) and 0.68 (0.60 to 0.77) in the validation cohort. Calibration was good in both cohorts. The negative predictive value of women in the development cohort at high risk of GH was 92.0% compared to 94.0% in the validation cohort. CONCLUSIONS: The prediction model showed adequate performance after validation in an independent cohort and can be used to classify women into high, moderate or low risk of developing GH. It contributes to efforts to provide clinical decision-making support to improve maternal health and birth outcomes. PMID- 28093431 TI - Which is best for osteoporotic vertebral compression fractures: balloon kyphoplasty, percutaneous vertebroplasty or non-surgical treatment? A study protocol for a Bayesian network meta-analysis. AB - INTRODUCTION: Osteoporotic vertebral compression fractures (OVCFs) commonly cause both acute and chronic back pain, substantial spinal deformity, functional disability and decreased quality of life and increase the risk of future vertebral fractures and mortality. Percutaneous vertebroplasty (PVP), balloon kyphoplasty (BK) and non-surgical treatment (NST) are mostly used for the treatment of OVCFs. However, which treatment is preferred is unknown. The purpose of this study is to comprehensively review the literature and ascertain the relative efficacy and safety of BK, PVP and NST for patients with OVCFs using a Bayesian network meta-analysis. METHODS AND ANALYSIS: We will comprehensively search PubMed, EMBASE and the Cochrane Central Register of Controlled Trials, to include randomided controlled trials that compare BK, PVP or NST for treating OVCFs. The risk of bias for individual studies will be assessed according to the Cochrane Handbook. Bayesian network meta-analysis will be performed to compare the efficacy and safety of BK, PVP and NST. The quality of evidence will be evaluated by GRADE. ETHICS AND DISSEMINATION: Ethical approval and patient consent are not required since this study is a meta-analysis based on published studies. The results of this network meta-analysis will be submitted to a peer reviewed journal for publication. PROSPERO REGISTRATION NUMBER: CRD42016039452; Pre-results. PMID- 28093432 TI - Adiposity, physical activity and risk of diabetes mellitus: prospective data from the population-based HUNT study, Norway. AB - BACKGROUND: Physical activity may counteract the adverse effects of adiposity on cardiovascular mortality; however, the evidence of a similar effect on diabetes is sparse. This study examines whether physical activity may compensate for the adverse effect of adiposity on diabetes risk. METHODS: The study population consisted of 38 231 individuals aged 20 years or more who participated in two consecutive waves of the prospective longitudinal Nord-Trondelag Health Study in Norway: in 1984-1986 and in 1995-1997. A Poisson regression model with SEs derived from robust variance was used to estimate adjusted risk ratios of diabetes between categories of body mass index and physical activity. RESULTS: Risk of diabetes increased both with increasing body mass (Ptrend <0.001) and with decreasing physical activity level (Ptrend <0.001 in men and 0.01 in women). Combined analyses showed that men who were both obese and had low activity levels had a risk ratio of 17 (95% CI 9.52 to 30) compared to men who were normal weight and highly active, whereas obese men who reported high activity had a risk ratio of 13 (95% CI 6.92 to 26). Corresponding analysis in obese women produced risk ratios of 15 (95% CI 9.18 to 25) and 13 (95% CI 7.42 to 21) among women reporting low and high activity levels, respectively. CONCLUSIONS: This study shows that overweight and obesity are associated with a substantially increased risk of diabetes, particularly among those who also reported being physically inactive. High levels of physical activity were associated with a lower risk of diabetes within all categories of body mass index, but there was no clear evidence that being physically active could entirely compensate for the adverse effect of adiposity on diabetes risk. PMID- 28093433 TI - Is questionnaire-based sitting time inaccurate and can it be improved? A cross sectional investigation using accelerometer-based sitting time. AB - OBJECTIVES: To investigate the differences between a questionnaire-based and accelerometer-based sitting time, and develop a model for improving the accuracy of questionnaire-based sitting time for predicting accelerometer-based sitting time. METHODS: 183 workers in a cross-sectional study reported sitting time per day using a single question during the measurement period, and wore 2 Actigraph GT3X+ accelerometers on the thigh and trunk for 1-4 working days to determine their actual sitting time per day using the validated Acti4 software. Least squares regression models were fitted with questionnaire-based siting time and other self-reported predictors to predict accelerometer-based sitting time. RESULTS: Questionnaire-based and accelerometer-based average sitting times were ~272 and ~476 min/day, respectively. A low Pearson correlation (r=0.32), high mean bias (204.1 min) and wide limits of agreement (549.8 to -139.7 min) between questionnaire-based and accelerometer-based sitting time were found. The prediction model based on questionnaire-based sitting explained 10% of the variance in accelerometer-based sitting time. Inclusion of 9 self-reported predictors in the model increased the explained variance to 41%, with 10% optimism using a resampling bootstrap validation. Based on a split validation analysis, the developed prediction model on ~75% of the workers (n=132) reduced the mean and the SD of the difference between questionnaire-based and accelerometer-based sitting time by 64% and 42%, respectively, in the remaining 25% of the workers. CONCLUSIONS: This study indicates that questionnaire-based sitting time has low validity and that a prediction model can be one solution to materially improve the precision of questionnaire-based sitting time. PMID- 28093434 TI - Forty years of shunt surgery at Rigshospitalet, Denmark: a retrospective study comparing past and present rates and causes of revision and infection. AB - OBJECTIVE: The objective of this study is to review our experience of shunt surgery by investigating 40 years of development in terms of rates of revision and infection, shunt survival and risk factors. DESIGN AND PARTICIPANTS: Medical records and operative reports were reviewed retrospectively for all patients who underwent primary shunt surgery at our department in the years 2010 to 2012. All results were compared with a previous study from our department. A mixed population consisting of 434 patients was included. Adults (>=15 years) accounted for 89.9% of all patients and the mean follow-up time was 1.71 years. RESULTS: Overall, 42.6% had a revision of which 65.4% fell within 6 months postoperatively. Low age, high-risk diagnoses and less severe brain injury were associated with a higher risk of revision. One and 5-year shunt survival probabilities were 66.2% (61.5-70.9) and 48.0% (41.1-54.9). Within 4 weeks postoperatively, 3.2% had an infection and overall infection rate was 5.5%. Short duration of surgery and the use of antibiotic prophylaxis were associated with a lower risk of infection. The most frequent causes of revision were valve defects (18.4%) and proximal defects or obstructions (15.7%). Compared to the previous study, no convincing improvement was found with regard to the revision rate (42.6% vs 48.3%, p 0.060) or overall infection rate (5.5% vs 7.4%, p 0.261). CONCLUSIONS: Regardless of changes in patient demographics, techniques and equipment, risk of revision and infection still constitutes a major challenge in shunt surgery. The absence of convincing improvements calls for more studies concerning strategies to reduce complications. PMID- 28093435 TI - Asthma and lung cancer, after accounting for co-occurring respiratory diseases and allergic conditions: a systematic review protocol. AB - INTRODUCTION: Asthma is one of the most frequently diagnosed respiratory diseases in the UK, and commonly co-occurs with other respiratory and allergic diseases, such as chronic obstructive pulmonary disease (COPD) and atopic dermatitis. Previous studies have shown an increased risk of lung cancer related to asthma, but the evidence is mixed when accounting for co-occurring respiratory diseases and allergic conditions. A systematic review of published data that investigate the relationship between asthma and lung cancer, accounting for co-occurring respiratory and allergic diseases, will be conducted to investigate the independent association of asthma with lung cancer. METHODS AND ANALYSIS: A systematic review will be conducted, and include original reports of cohort, cross-sectional and case-control studies of the association of asthma with lung cancer after accounting for co-occurring respiratory diseases. Articles published up to June 2016 will be included, and their selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A standardised data extraction form will be developed and pretested, and descriptive analyses will be used to summarise the available literature. If appropriate, pooled effect estimates of the association between asthma and lung cancer, given adjustment for a specific co-occurring condition will be estimated using random effects models. Potential sources of heterogeneity and between study heterogeneity will also be investigated. ETHICS AND DISSEMINATION: The study will be a review of published data and does not require ethical approval. Results will be disseminated through a peer-reviewed publication. TRIAL REGISTRATION NUMBER: International Prospective Register for Systematic Reviews (PROSPERO) number CRD42016043341. PMID- 28093436 TI - Burden of disease associated with lower levels of income among US adults aged 65 and older. AB - BACKGROUND: Persons aged 65 years and older represent a heterogeneous group whose prevalence in the USA is expected to markedly increase. Few investigations have examined the total burden of disease attributable to lower levels of income in a single number that accounts for morbidity and mortality. METHODS: We ascertained respondents' health-related quality of life (HRQOL) scores and mortality status from the 2003 to 2004, 2005 to 2006, 2007 to 2008 and 2009 to 2010 cohorts of the National Health and Nutrition Examination Survey (NHANES) with mortality follow up through 31 December 2011. A mapping algorithm based on respondents' age and answers to the 4 core Healthy Days questions was used to obtain values of a preference-based measure of HRQOL, the EuroQol five dimensions questionnaire (EQ 5D) index, which enables quality-adjusted life years (QALYs) to be calculated. We included only respondents aged 65 years and older at the baseline, yielding a total sample size of 4952. We estimated mean QALYs according to different categories of income based on the percentage of Federal Poverty Level (FPL). RESULTS: After adjusting for age, gender and education, the remaining QALYs decreased with each successive decrement of category of income, ranging from 18.4 QALY (>=500% FPL) to 8.6 QALY (<100% FPL). Compared with participants with a mean income of >=250% FPL, participants with an income <250% FPL had significant losses in QALY for most of the sociodemographic groups examined. In contrast, persons with a lower educational attainment did not show a corresponding loss in QALY according to income category. CONCLUSIONS: This study confirmed the association between lower income category and greater burden of disease, as measured by QALYs lost, among the US population aged 65 years and older. Our findings provide additional evidence of the role played by other key determinants of health and how factors not traditionally addressed by the healthcare system impact the life cycle of individuals and communities. PMID- 28093437 TI - Risk of sepsis in patients with amyotrophic lateral sclerosis: a population-based retrospective cohort study in Taiwan. AB - OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, and sepsis is a frequent cause of death in hospitalised patients. We investigated the relationship between ALS and the subsequent risk of sepsis. DESIGN: A retrospective cohort analysis. SETTING: Patients with ALSs diagnosed between 2000 and 2010 in Taiwan National Health Insurance Research Database. PARTICIPANTS: We included 701 and 2804 patients as the ALS and the non-ALS groups, respectively. OUTCOME MEASURES: The risk of sepsis was calculated by Cox proportional hazards regression model. RESULTS: During the follow-up period, the incidence density rates were 77.8 and 11.1 per 1000 person-years in the ALS and non-ALS groups, respectively. After adjusting for sex, age, Charlson comorbidity index score, life-support measures, and beta2-adrenoceptor agonists treatment, the ALS group had a higher risk of sepsis (HR=3.42; 95% CI 2.60 to 4.50) than the non-ALS group. An increase of the risk was observed in patients with ALS receiving life support treatment measures, whereas a decrease of the risk was associated with treatment of beta2-adrenoceptor agonists. CONCLUSIONS: The risk of sepsis is associated with a prior ALS diagnosis, and may be increased by the use of life support measures and decreased by beta2-adrenoceptor agonists. PMID- 28093438 TI - Risk for metabolic diseases in normal weight individuals with visceral fat accumulation: a cross-sectional study in Japan. AB - OBJECTIVE: To investigate the association between visceral fat area (VFA) and metabolic syndrome (Mets) among normal weight Japanese. DESIGN: A cross-sectional study. SETTING: The health check-up centre of the Takeda Hospital group in Kyoto, Japan. METHODS: This study involved 1674 men and 1448 women aged 30-74 years who underwent medical check-ups in 2012 in the health check-up centre. They were stratified by Body Mass Index (BMI cut-off for obesity is set at 23.0 kg/m2 for Asians): normal weight 18.5-22.9 kg/m2 or higher weight >=23.0 kg/m2. The age adjusted ORs of the 2nd to 4th groups of sex-specific VFA quartiles compared with the 1st quartile for a Mets component clustering were estimated. The clustering was having two or more of the following factors: high blood pressure, high fasting blood glucose (FBG), low high-density lipoprotein cholesterol (HDL-C) and high triglycerides. Statistical analyses were conducted in 2016. RESULTS: Participants in the 2nd to 4th VFA quartiles had significantly higher clustering risks; ORs were 3.4 (1.5 to 8.0), 6.3 (2.8 to 14.2) and 9.3 (4.2 to 20.7) for normal weight participants, and 1.7 (1.2 to 2.6), 2.6 (1.8 to 3.9) and 6.0 (4.1 to 8.8) for higher weight participants, respectively. The ORs of the 4th VFA quartile for Mets components were significantly higher; ORs for normal weight participants were 2.1 (1.5 to 3.0) (high blood pressure), 2.4 (1.4 to 4.2) (high FBG), 5.2 (2.1 to 12.9) (low HDL-C) and 12.0 (5.7 to 25.3) (high triglycerides), and higher weight participants were 3.9 (2.8 to 5.5), 4.1 (2.8 to 6.2), 3.9 (2.2 to 6.9) and 5.0 (3.4 to 7.4), respectively. CONCLUSIONS: Among participants with normal weight, as well as those of higher weight, dose-dependent responses were observed between VFA and risk for Mets components and the clustering among Japanese adults. VFA may be useful information for interventions to improve metabolic risk factors in people with normal weight. PMID- 28093439 TI - National estimation of children in residential care institutions in Cambodia: a modelling study. AB - OBJECTIVES: The primary objective of this study was to collect baseline data on the number of children living in residential care institutions in Cambodia. The secondary objective was to describe the characteristics of the children (eg, age, sex, duration of stay, education and health). The data were intended to guide recent efforts by the Government of Cambodia to reduce the number of children living in residential care institutions and increase the number of children growing up in supportive family environments. SETTING: Data were collected in Cambodia across 24 sites at the commune level. Communes-administrative divisions roughly equivalent to counties-were selected by the National Institute of Statistics using a two-stage sampling method. DESIGN: Government lists and key informant interviews were used to construct a complete roster of institutions across the 24 communes. All identified institutions were visited to count the number of children and gather data on their basic characteristics. The rate of children in residential care in the selected communes was calculated as a percentage of total population using a Poisson model. This rate was applied to all districts in Cambodia with at least one reported residential care institution. PARTICIPANTS: A total of 3588 children were counted across 122 institutions. A child living in a residential care institution was defined as anyone under the age of 18 years who was sleeping in the institution for at least four nights per week during the data collection period. RESULTS: There are an estimated 48 775 children living in residential care institutions in Cambodia. The vast majority of children have a living parent and are school-aged. More than half are between 13 and 17 years of age. CONCLUSIONS: Nearly 1 of every 100 children in Cambodia is living in residential care. This raises substantial concerns for child health, protection and national development. PMID- 28093440 TI - Cross-sectional, descriptive study of Chagas disease among citizens of Bolivian origin living in Munich, Germany. AB - PURPOSE: Chagas disease (CD) has become a global health issue mainly due to migration. Germany lacks surveillance data and is home to a large Latin American immigrant population. Recognising that Bolivia is the country with the highest CD prevalence in Latin America, this cross-sectional, descriptive pilot study investigated CD and associated factors among citizens of Bolivian origin living in Munich, Germany. METHODS: Participants completed a questionnaire in order to collect socioeconomic and health-related data. In addition, serology was performed. In case of positive serological tests, PCR diagnostic and clinical staging together with disease management was initiated. Qualitative research was conducted to identify personal and community barriers as well as strategies to increase CD awareness among the population at risk. RESULTS: Between June 2013 and June 2014, 43 people from Bolivia (or descendants) were enrolled. A total of 9.3% (4/43), of whom two women were of childbearing age, tested seropositive (ELISA and IFAT), and one also by PCR. For 2/4 positive participants, clinical evaluation was performed and the indeterminate form of CD was diagnosed. Knowledge about CD symptoms and ways of transmission were completely absent among 55.8% (24/43, 2/4 with CD) and 30.2% (13/43, 1/4 with CD) of participants, respectively. A total of 27.9% (12/43, 0/4 with CD) of participants had donated blood prior to the study, whereas 62.8% (27/43, 3/4 with CD) were motivated to donate blood in the future. The qualitative research identified lack of knowledge as well as stigma and fears related to CD. CONCLUSIONS: Despite the small number of participants, the prevalence of CD as well as the potential risk of non vectorial transmission was alarming. Campaigns adapted for Latin American migrants as well as control strategies should be developed and put in place in order to prevent non-vectorial transmission and actively detect cases of CD in Germany. PMID- 28093441 TI - Influence of premium versus value brand names on the smoking experience in a plain packaging environment: an experimental study. AB - OBJECTIVE: To examine the effect of branding, as indicated by brand name, on evaluation of the cigarette smoking experience. DESIGN: Between-subjects and within-subjects experimental study. Participants were randomly allocated to smoke a cigarette from a pack featuring a premium brand name and a cigarette from a pack featuring a value brand name. Within each condition, participants unknowingly smoked two identical cigarettes (either two premium or two value cigarettes). SETTING: Australia, October 2014, 2 years after tobacco plain packaging implementation. PARTICIPANTS: 81 current cigarette smokers aged 19-39 years. From apparently premium and value brand-name packs, 40 smokers were allocated to smoke the same actual premium cigarettes and 41 were allocated to smoke the same actual value cigarettes. PRIMARY OUTCOME MEASURES: Experienced taste (flavour, satisfaction, enjoyment, quality, liking, mouthfeel and aftertaste), harshness, dryness, staleness, harm/strength measures (strength, tar, lightness, volume of smoke), draw effort and purchase intent. RESULTS: Cigarettes given a premium brand name were rated as having a better taste, were less harsh and less dry than identical cigarettes given a value brand name. This pattern was observed irrespective of whether the two packs actually contained premium or value cigarettes. These effects were specific: the brand name did not influence ratings of cigarette variant attributes (strength, tar, volume of smoke, lightness and draw effort). CONCLUSIONS: Despite the belief that brand names represent genuine differences between cigarette products, the results suggest that at least some of this perceived sensory difference is attributable to brand image. PMID- 28093442 TI - Rococo study: a real-world evaluation of an over-the-counter medicine in acute cough (a multicentre, randomised, controlled study). AB - OBJECTIVES: To investigate the efficacy and safety of CS1002, an over-the-counter cough treatment containing diphenhydramine, ammonium chloride and levomenthol in a cocoa-based demulcent. DESIGN: A multicentre, randomised, parallel group, controlled, single-blinded study in participants with acute upper respiratory tract infection-associated cough. SETTING: 4 general practitioner (GP) surgeries and 14 pharmacies in the UK. PARTICIPANTS: Participants aged >=18 years who self referred to a GP or pharmacist with acute cough of <7 days' duration. Participant inclusion criterion was cough severity >=60 mm on a 0-100 mm visual analogue scale (VAS). Exclusion criteria included current smokers or history of smoking within the past 12 months (including e-cigarettes). 163 participants were randomised to the study (mean participant age 38 years, 57% females). INTERVENTIONS: Participants were randomised to CS1002 (Unicough) or simple linctus (SL), a widely used cough treatment, and treatment duration was 7 days or until resolution of cough. MAIN OUTCOME MEASURES: The primary analysis was intention-to-treat (157 participants) and comprised cough severity assessed using a VAS after 3 days' treatment (prespecified primary end point at day 4). Cough frequency, sleep disruption, health status (Leicester Cough Questionnaire (LCQ acute)) and cough resolution were also assessed. RESULTS: At day 4 (primary end point), the adjusted mean difference (95% CI) in cough severity VAS between CS1002 and SL was -5.9 mm (-14.4 to 2.7), p=0.18. At the end of the study (day 7) the mean difference in cough severity VAS was -4.2 mm (-12.2 to 3.9), p=0.31. CS1002 was associated with a greater reduction in cough sleep disruption (mean difference -11.6 mm (-20.6 to 2.7), p=0.01) and cough frequency (mean difference 8.1 mm (-16.2 to 0.1), p=0.05) compared with SL. There was greater improvement in LCQ-acute quality of life scores with CS1002 compared with SL: mean difference (95% CI) 1.2 (0.05 to 2.36), p=0.04 after 5 days' treatment. More participants prematurely stopped treatment due to cough improvement in the CS1002 group (24.4%) compared with SL (10.7%; p=0.02). Adverse events (AEs) were comparable between CS1002 (20.5%) and SL (27.6%) and largely related to the study indication. 6 participants (7%) in the CS1002 group reduced the dose of medication due to drowsiness/tiredness, which subsequently resolved. These events were not reported by participants as AEs. CONCLUSIONS: Although the primary end point was not achieved, CS1002 was associated with greater reductions in cough frequency, sleep disruption and improved health status compared with SL. TRIAL REGISTRATION NUMBER: EudraCT number 2014-004255-31. PMID- 28093443 TI - Impact of advanced autonomous non-medical practitioners in emergency care: protocol for a scoping study. AB - INTRODUCTION: Emergency care services are looking for new models of care delivery to deal with changing patient demographics and increased pressures. It has been suggested that advanced non-medical practitioners might be valuable for delivering such new models of care. However, it is not clear what the impact of the deployment of advanced non-medical practitioners in emergency care is. This scoping study addresses the following research question: What is known from the literature about the different types of impact of the deployment of advanced (autonomous) non-medical practitioners in emergency care? METHODS AND ANALYSIS: A scoping study will be undertaken to examine and map the impact of the deployment of advanced non-medical practitioners in emergency care. The scoping study follows the methodology proposed by Arksey and O'Malley. Searches will be carried out on databases of peer-reviewed literature and other sources to systematically identify and characterise the literature. Papers will be screened using a 2-stage process to identify the most relevant literature. Papers will be screened by title and abstract, followed by full-text review. Data abstraction and synthesis will be performed using a narrative thematic analysis. ETHICS AND DISSEMINATION: We will communicate the findings to Health Education England, NHS Improvement and the Royal College of Emergency Medicine through existing links provided by members of the project team. We anticipate that the findings will also be of interest to other similar organisations internationally. By identifying gaps in the research literature, we anticipate that the study will generate recommendations for informing future high-quality research studies about the impact of advanced non-medical practitioners in emergency care as well as in other settings. The research findings will be submitted for publication to relevant peer-reviewed journals as well as professional magazines. The scoping study uses only previously published material, and does not require ethical review. PMID- 28093445 TI - Correction. PMID- 28093444 TI - Chinese patent medicine Fei-Liu-Ping ointment as an adjunctive treatment for non small cell lung cancer: protocol for a systematic review. AB - INTRODUCTION: Fei-Liu-Ping ointment has been widely applied as adjunctive drug in the treatment of non-small cell lung cancer (NSCLC). However, there has been no systematic review of research findings regarding the efficacy of this treatment. Here, we provide a protocol for assessing the effectiveness and safety of Fei-Liu Ping ointment in the treatment of NSCLC. METHODS AND ANALYSIS: The electronic databases to be searched will include MEDLINE (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Excerpt Medica Database (EMBASE), China National Knowledge Infrastructure (CNKI), China Scientific Journal Database (VIP), Wanfang Database and Chinese Biomedical Literature Database (CBM). Papers in English or Chinese published from inception to 2016 will be included without any restrictions. We will conduct a meta-analysis of randomised controlled trial if possible. The therapeutic effects according to the standard for treatment of solid tumours by the WHO and the quality of life as evaluated by Karnofsky score and weight will be applied as the primary outcomes. We will also evaluate the data synthesis and risk of bias using Review Manager 5.3 software. DISSEMINATION: The results of this review will offer implications for the use of Fei-Liu-Ping ointment as an adjunctive treatment for NSCLC. This knowledge will inform recommendations by surgeons and researchers who are interested in the treatment of NSCLC. The results of this systematic review will be disseminated through presentation at a conference and publication of the data in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: PROSPERO CRD42016036911. PMID- 28093446 TI - Tumor-Infiltrating Merkel Cell Polyomavirus-Specific T Cells Are Diverse and Associated with Improved Patient Survival. AB - Tumor-infiltrating CD8+ T cells are associated with improved survival of patients with Merkel cell carcinoma (MCC), an aggressive skin cancer causally linked to Merkel cell polyomavirus (MCPyV). However, CD8+ T-cell infiltration is robust in only 4% to 18% of MCC tumors. We characterized the T-cell receptor (TCR) repertoire restricted to one prominent epitope of MCPyV (KLLEIAPNC, "KLL") and assessed whether TCR diversity, tumor infiltration, or T-cell avidity correlated with clinical outcome. HLA-A*02:01/KLL tetramer+ CD8+ T cells from MCC patient peripheral blood mononuclear cells (PBMC) and tumor-infiltrating lymphocytes (TIL) were isolated via flow cytometry. TCRbeta (TRB) sequencing was performed on tetramer+ cells from PBMCs or TILs (n = 14) and matched tumors (n = 12). Functional avidity of T-cell clones was determined by IFNgamma production. We identified KLL tetramer+ T cells in 14% of PBMC and 21% of TIL from MCC patients. TRB repertoires were strikingly diverse (397 unique TRBs were identified from 12 patients) and mostly private (only one TCRb clonotype shared between two patients). An increased fraction of KLL-specific TIL (>1.9%) was associated with significantly increased MCC-specific survival P = 0.0009). T-cell cloning from four patients identified 42 distinct KLL-specific TCRa/b pairs. T-cell clones from patients with improved MCC-specific outcomes were more avid (P < 0.05) and recognized an HLA-appropriate MCC cell line. T cells specific for a single MCPyV epitope display marked TCR diversity within and between patients. Intratumoral infiltration by MCPyV-specific T cells was associated with significantly improved MCC-specific survival, suggesting that augmenting the number or avidity of virus specific T cells may have therapeutic benefit. Cancer Immunol Res; 5(2); 137-47. (c)2017 AACR. PMID- 28093447 TI - Inflammasomes and Cancer. AB - Inflammation affects all stages of tumorigenesis. A key signaling pathway leading to acute and chronic inflammation is through activation of the caspase-1 inflammasome. Inflammasome complexes are assembled on activation of certain nucleotide-binding domain, leucine-rich repeat-containing proteins (NLR), AIM2 like receptors, or pyrin. Of these, NLRP1, NLRP3, NLRC4, NLRP6, and AIM2 influence the pathogenesis of cancer by modulating innate and adaptive immune responses, cell death, proliferation, and/or the gut microbiota. Activation of the inflammasome and IL18 signaling pathways is largely protective in colitis associated colorectal cancer, whereas excessive inflammation driven by the inflammasome or the IL1 signaling pathways promotes breast cancer, fibrosarcoma, gastric carcinoma, and lung metastasis in a context-dependent manner. The clinical relevance of inflammasomes in multiple forms of cancer highlights their therapeutic promise as molecular targets. In this review, we explore the crossroads between inflammasomes and the development of various tumors and discuss possible therapeutic values in targeting the inflammasome for the prevention and treatment of cancer. Cancer Immunol Res; 5(2); 94-99. (c)2017 AACR. PMID- 28093448 TI - Eating Alone Yet Living With Others Is Associated With Mortality in Older Men: The JAGES Cohort Survey. AB - Objectives: Eating by oneself may be a risk factor for poor nutritional and mental statuses among older adults. However, their longitudinal association with mortality in relation to coresidential status is unknown. Method: We conducted a 3-year follow-up of participants in the Japan Gerontological Evaluation Study, a population-based cohort of 65 years or older Japanese adults. We analyzed mortality for 33,083 men and 38,698 women from 2010 to 2013 and used. Cox regression models were used to estimate hazard ratios (HR) for mortality. Results: A total of 3,217 deaths occurred during the follow-up. Compared with men who ate and lived with others, the HRs after adjusting for age and health status were 1.48 (95% confidence intervals [CI]: 1.26-1.74) for men who ate alone yet lived with others and 1.19 (95% CI: 1.01-1.41) for men who ate and lived alone. Among women, the adjusted HR was 1.18 (95% CI: 0.97-1.43) for women who ate alone yet lived with others and 1.10 (95% CI: 0.93-1.29) for women who ate and lived alone. Discussion: A setting in which older adults eat together may be protective for them. Promotion of this intervention should focus on men who eat alone yet live with others. PMID- 28093449 TI - Fluoride levels in drinking water and hypothyroidism: Response to Grimes and Newton et al. PMID- 28093450 TI - Editorial note: Peckham versus Newton. PMID- 28093451 TI - Are fluoride levels in drinking water associated with hypothyroidism prevalence in England? Comments on the authors' response to earlier criticism. PMID- 28093452 TI - A Time to Save. AB - Group B Streptococcus (GBS), characterized by Lancefield in 1933, was not recognized as a human pathogen until the early 1970s when it emerged and replaced Escherichia coli as the most common cause of sepsis and meningitis among neonates and young infants. This article briefly gives a personnel account of the discovery of clinical syndromes of GBS distinguished by age at onset, vertical mode of transmission for early-onset disease, meningeal tropism for GBS capsular (CPS) type III strains, and protective CPS epitopes. It also reviews the difficult evolution of the now routine program for antenatal GBS culture screening and intrapartum antibiotic prophylaxis, development of the first GBS candidate vaccines, clinical trials documenting the immunogenicity and safety of CPS tetanus toxoid conjugate vaccines, ongoing need to prevent morbidity and mortality in neonates and young infants, and critical need for commercial vaccines for routine use in pregnant women. PMID- 28093453 TI - Interactions between microsatellite instability and human gut colonization by Escherichia coli in colorectal cancer. AB - Recent studies suggest that colonization of colonic mucosa by pathogenic Escherichia coli could be involved in the development of colorectal cancer (CRC), especially through the production of genotoxins such as colibactin and/or by interfering with the DNA mismatch repair (MMR) pathway that leads to microsatellite instability (MSI). The present study, performed on 88 CRC patients, revealed a significant increase in E. coli colonization in the MSI CRC phenotype. In the same way, E. coli persistence and internalization were increased in vitro in MMR-deficient cells. Moreover, we demonstrated that colibactin-producing E. coli induce inhibition of the mutL homologue 1 (MLH1) MMR proteins, which could lead to genomic instability. However, colibactin-producing E. coli were more frequently identified in microsatellite stable (MSS) CRC. The present study suggests differences in the involvement of colibactin-producing E. coli in colorectal carcinogenesis according to the CRC phenotype. Further host pathogen interactions studies should take into account CRC phenotypes. PMID- 28093454 TI - Mdm proteins: critical regulators of embry ogenesis and homeostasis. AB - Mdm2 and Mdm4 are negative regulators of the tumor suppressor p53; hence, this relationship is the focus of many cancer related studies. A multitude of experiments across various developmental stages have been conducted to explore the tissue-specific roles of these proteins in the mouse. When Mdm2 or Mdm4 are deleted in the germline or specific tissues, they display different phenotypic defects, some of which lead to embryonic lethality. Mdm2 loss is often more deleterious than loss of its homolog Mdm4 All tissues experience activation of p53 target genes upon loss of Mdm2 or Mdm4; however, the degree to which the p53 pathway is perturbed is highly tissue-specific and does not correlate to the severity of the morphological phenotypes. Therefore, a need for further understanding of how these proteins regulate p53 activity is warranted, as therapeutic targeting of the p53 pathway is rapidly evolving and gaining attention in the field of cancer research. In this review, we discuss the tissue specificity of Mdm proteins in regulating p53 and expose the need for investigation at the cell-specific level. PMID- 28093455 TI - Genomewide landscape of gene-metabolome associations in Escherichia coli. AB - Metabolism is one of the best-understood cellular processes whose network topology of enzymatic reactions is determined by an organism's genome. The influence of genes on metabolite levels, however, remains largely unknown, particularly for the many genes encoding non-enzymatic proteins. Serendipitously, genomewide association studies explore the relationship between genetic variants and metabolite levels, but a comprehensive interaction network has remained elusive even for the simplest single-celled organisms. Here, we systematically mapped the association between > 3,800 single-gene deletions in the bacterium Escherichia coli and relative concentrations of > 7,000 intracellular metabolite ions. Beyond expected metabolic changes in the proximity to abolished enzyme activities, the association map reveals a largely unknown landscape of gene metabolite interactions that are not represented in metabolic models. Therefore, the map provides a unique resource for assessing the genetic basis of metabolic changes and conversely hypothesizing metabolic consequences of genetic alterations. We illustrate this by predicting metabolism-related functions of 72 so far not annotated genes and by identifying key genes mediating the cellular response to environmental perturbations. PMID- 28093456 TI - Effect of lipid-bound apolipoprotein A-I cysteine mutant on ATF3 in RAW264.7 cells. AB - Activating transcription factor 3 (ATF3) is a TLR-induced repressor that plays an important role in the inhibition of specific inflammatory signals. We previously constructed recombinant high density lipoproteins (rHDL) (including rHDLWT, rHDLM, rHDL228 and rHDL74) and found that rHDL74 had a strong anti-inflammatory ability. In the present study, we investigate the roles of recombinant apolipoprotein A-I (ApoA-I) (rHDLWT) and its cysteine mutant HDLs (rHDLM, rHDL228 and rHDL74) on ATF3 function in RAW264.7 cells stimulated by lipopolysaccharide. Our results showed that compared with the LPS group, rHDL74 can decrease the level of TNF-alpha and IL-6, whereas rHDL228 increases their expression levels. RT-PCR and Western blotting results showed that compared with the LPS group, rHDL74, rHDLWT and rHDLM can markedly increase the expression level of ATF3, whereas the level of ATF3 decreases in the rHDL228 group. In summary, the different anti-inflammatory mechanisms of the ApoA-I cysteine mutants might be associated with the regulation of ATF3 level. PMID- 28093458 TI - Single-cell gene expression analysis reveals diversity among human spermatogonia. AB - STUDY QUESTION: Is the molecular profile of human spermatogonia homogeneous or heterogeneous when analysed at the single-cell level? SUMMARY ANSWER: Heterogeneous expression profiles may be a key characteristic of human spermatogonia, supporting the existence of a heterogeneous stem cell population. WHAT IS KNOWN ALREADY: Despite the fact that many studies have sought to identify specific markers for human spermatogonia, the molecular fingerprint of these cells remains hitherto unknown. STUDY DESIGN, SIZE, DURATION: Testicular tissues from patients with spermatogonial arrest (arrest, n = 1) and with qualitatively normal spermatogenesis (normal, n = 7) were selected from a pool of 179 consecutively obtained biopsies. Gene expression analyses of cell populations and single-cells (n = 105) were performed. Two OCT4-positive individual cells were selected for global transcriptional capture using shallow RNA-seq. Finally, expression of four candidate markers was assessed by immunohistochemistry. PARTICIPANTS/MATERIALS, SETTING, METHODS: Histological analysis and blood hormone measurements for LH, FSH and testosterone were performed prior to testicular sample selection. Following enzymatic digestion of testicular tissues, differential plating and subsequent micromanipulation of individual cells was employed to enrich and isolate human spermatogonia, respectively. Endpoint analyses were qPCR analysis of cell populations and individual cells, shallow RNA seq and immunohistochemical analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Unexpectedly, single-cell expression data from the arrest patient (20 cells) showed heterogeneous expression profiles. Also, from patients with normal spermatogenesis, heterogeneous expression patterns of undifferentiated (OCT4, UTF1 and MAGE A4) and differentiated marker genes (BOLL and PRM2) were obtained within each spermatogonia cluster (13 clusters with 85 cells). Shallow RNA-seq analysis of individual human spermatogonia was validated, and a spermatogonia specific heterogeneous protein expression of selected candidate markers (DDX5, TSPY1, EEF1A1 and NGN3) was demonstrated. LIMITATIONS, REASONS FOR CAUTION: The heterogeneity of human spermatogonia at the RNA and protein levels is a snapshot. To further assess the functional meaning of this heterogeneity and the dynamics of stem cell populations, approaches need to be developed to facilitate the repeated analysis of individual cells. WIDER IMPLICATIONS OF THE FINDINGS: Our data suggest that heterogeneous expression profiles may be a key characteristic of human spermatogonia, supporting the model of a heterogeneous stem cell population. Future studies will assess the dynamics of spermatogonial populations in fertile and infertile patients. LARGE SCALE DATA: RNA-seq data is published in the GEO database: GSE91063. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Max Planck Society and the Deutsche Forschungsgemeinschaft DFG Research Unit FOR 1041 Germ Cell Potential (grant numbers SCHO 340/7-1, SCHL394/11-2). The authors declare that there is no conflict of interest. PMID- 28093459 TI - Syphilis and HIV: Is HAART at the heart of this epidemic? PMID- 28093457 TI - Functional analysis of the mammalian RNA ligase for IRE1 in the unfolded protein response. AB - The unfolded protein response (UPR) is a conserved signalling pathway activated on the accumulation of unfolded proteins within the endoplasmic reticulum (ER), termed ER stress. Upon ER stress, HAC1/XBP1 undergoes exon/intron-specific excision by inositol requiring enzyme 1 (IRE1) to remove an intron and liberate the 5' and 3' exons. In yeast, the 5' and 3' HAC1 exons are subsequently ligated by tRNA ligase (Rlg1p), whereas XBP1 ligation in mammalian cells is catalysed by a recently identified ligase, RtcB. In the present study, RNA ligase activity of the human RtcB (hRtcB) involved in the unconventional splicing of XBP1/HAC1 mRNA was explored in an rlg1-100 mutant yeast strain. Distinct from Escherichia coli RtcB and Rlg1p, expression of hRtcB alone inefficiently complemented HAC1/XBP1 splicing and the hRtcB cofactor (archease) was required to promote enzymatic activity of hRtcB to catalyse RNA ligation. PMID- 28093460 TI - A double-edged sword: does highly active antiretroviral therapy contribute to syphilis incidence by impairing immunity to Treponema pallidum? AB - BACKGROUND AND HYPOTHESIS: Recently, the world has experienced a rapidly escalating outbreak of infectious syphilis primarily affecting men who have sex with men (MSM); many are taking highly active antiretroviral therapy (HAART) for HIV-1 infection. The prevailing hypothesis is that HAART availability and effectiveness have led to the perception among both individuals who are HIV-1 infected and those who are uninfected that HIV-1 transmission has become much less likely, and the effects of HIV-1 infection less deadly. This is expected to result in increased sexual risk-taking, especially unprotected anal intercourse, leading to more non-HIV-1 STDs, including gonorrhoea, chlamydia and syphilis. However, syphilis incidence has increased more rapidly than other STDs. We hypothesise that HAART downregulates the innate and acquired immune responses to Treponema pallidum and that this biological explanation plays an important role in the syphilis epidemic. METHODS: We performed a literature search and developed a mathematical model of HIV-1 and T. pallidum confection in a population with two risk groups with assortative mixing to explore the consequence on syphilis prevalence of HAART-induced changes in behaviour versus HAART-induced biological effects. CONCLUSIONS AND IMPLICATIONS: Since rising syphilis incidence appears to have outpaced gonorrhoea and chlamydia, predominantly affecting HIV-1 positive MSM, behavioural factors alone may be insufficient to explain the unique, sharp increase in syphilis incidence. HAART agents have the potential to alter the innate and acquired immune responses in ways that may enhance susceptibility to T. pallidum. This raises the possibility that therapeutic and preventative HAART may inadvertently increase the incidence of syphilis, a situation that would have significant and global public health implications. We propose that additional studies investigating the interplay between HAART and enhanced T. pallidum susceptibility are needed. If our hypothesis is correct, HAART should be combined with enhanced patient management including frequent monitoring for pathogens such as T. pallidum. PMID- 28093461 TI - Coil embolization of left ventricular outflow tract pseudoaneurysms: techniques and 5-year results. AB - We present 3 cases of percutaneous coil embolization of left ventricular outflow tract (LVOT) pseudoaneurysms. All patients had a history of repetitive aortic root surgery and/or inflammatory disease. Computed tomography showed pseudoaneurysms connecting the sacs to the LVOT lumen. In each case, a 6-Fr catheter was advanced to the sac by the transfemoral approach. A 0.052-in coil was placed across the tract. There was no significant complications associated with the procedure. No recurrence was evident in any case during the 5-year follow-up. Coil embolization may be an effective treatment for these pseudoaneurysms in patients with complicated histories of aortic root surgery. PMID- 28093462 TI - Predictors and impact of massive bleeding in acute type A aortic dissection. AB - Objectives: Bleeding complications associated with acute type A aortic dissection (aTAAD) are a well-known clinical problem. Here, we evaluated predictors of massive bleeding related to aTAAD and associated surgery and assessed the impact of massive bleeding on complications and survival. Methods: This retrospective study of 256 patients used Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) criteria to define massive bleeding, which was met by 66 individuals (Group I) who were compared to the remaining patients (Group II). Multivariable logistic regression was used to identify independent predictors of massive bleeding and in-hospital mortality, Kaplan-Meier estimates for analysis of late survival, and Cox regression analysis to evaluate independent predictors of late mortality. Results: Independent predictors of massive bleeding included symptom duration (odds ratio [OR], 0.974 per hour increment; 95% confidence interval [CI], 0.950-0.999; P = 0.041) and DeBakey type 1 dissection (OR, 2.652; 95% CI, 1.004-7.008; P = 0.049). In-hospital mortality was higher in Group I (30.3% vs 8.0%, P <0.001). Kaplan-Meier estimates of survival indicated poorer survival for Group I at 1, 3 and 5 years (68.8 +/- 5.9% vs 92.8 +/- 1.9%; 65.2 +/- 6.2% vs 85.3 +/- 2.7%; 53.9 +/- 6.9% vs 82.1 +/- 3.3 %, respectively; log rank P < 0.001). Re-exploration for bleeding was an independent predictor of in-hospital (OR, 3.109; 95% CI, 1.044-9.256; P = 0.042) and late mortalities (hazard ratio, 3.039; 95% CI, 1.605-5.757; P = 0.001). Conclusions: Massive bleeding in patients with aTAAD is prompted by shorter symptom duration and longer extent of dissection and has deleterious effects on outcomes of postoperative complications as well as in-hospital and late mortalities. PMID- 28093463 TI - Bidirectional cavopulmonary anastomosis with additional pulmonary blood flow: good or bad pre-Fontan strategy. AB - Objectives: This study aimed to evaluate the influence of preserved additional pulmonary blood flow (APBF) on survival after bidirectional cavopulmonary shunt (BCPS) and completion of Fontan circulation. Methods: From March 2003 and April 2015, 156 patients with a single ventricle underwent BCPS. After performing propensity score analysis (1:1) for the entire sample, 50 patients with APBF (APBF group) were matched with 50 patients without APBF (no-APBF group). Results: Age ( P = 0.90), sex ( P = 0.57), weight ( P = 0.75), single ventricle morphology ( P = 0.87), type of neonatal palliative procedure ( P = 0.52), saturation ( P = 0.35), ejection fraction ( P = 0.90), Nakata index ( P = 0.70) and mean pulmonary artery pressure ( P = 0.72) were not significantly different between the groups. No significant survival difference was demonstrated ( P = 0.54). One and 4-year survival rates were both 89.1% +/- 4.6% in the APBF group and 87.2% +/- 4.9% and 83.4% +/- 5.9%, respectively, in the no-APBF group. There was no significant difference in rates of Fontan completion ( P = 0.24), which was achieved in 22 patients from the APBF group (55.0%) and 26 patients from the no-APBF group (65.0%). However, Fontan completion occurred significantly earlier in the no-APBF group ( P < 0.01). In this group, Fontan procedure was performed before 36 months of inter-stage period in 45.9% +/- 8.5% of cases (95% CI 31.0-63.7%) compared to only 13.3 +/- 5.6% (95% CI 5.8-29.1%) in the APBF group. Conclusions: Our study demonstrates that APBF does not affect survival after BCPS or Fontan completion rate. APBF allows postponing the Fontan procedure without a negative effect on clinical status. PMID- 28093464 TI - Socioeconomic Status, Smoke Exposure, and Health Outcomes in Young Children With Cystic Fibrosis. AB - BACKGROUND: Lower socioeconomic status (SES) and environmental tobacco smoke (ETS) exposure are both associated with poorer disease outcomes in cystic fibrosis (CF), and children with low SES are disproportionately exposed to ETS. We analyzed a large cohort of young children with CF to distinguish the impact of SES and ETS on clinical outcomes. METHODS: The Early Pseudomonas Infection Control Observational study enrolled Pseudomonas-negative young children with CF <13 years of age. An enrollment survey assessed SES and ETS exposures. Forced expiratory volume in 1 second (FEV1), crackles and wheezes, and weight-for-age percentile were assessed at each clinical encounter over at least 4 years. Repeated measures analyses estimated the association of SES and ETS exposures with longitudinal clinical outcomes, adjusting for confounders. RESULTS: Of 1797 participants, 1375 were eligible for analysis. Maternal education was high school or less in 28.1%, 26.8% had household income <$40 000, and 43.8% had Medicaid or no insurance. Maternal smoking after birth was present in 24.8%, more prevalent in household with low SES. In separate models, lower SES and ETS exposure were significantly associated with lower FEV1% predicted, presence of crackles or wheezes, and lower weight percentile. In combined models, effect estimates for SES changed minimally after adjustment for ETS exposures, whereas estimates for ETS exposures were attenuated after adjusting for SES. CONCLUSIONS: ETS exposure was disproportionately high in low SES families in this cohort of children with CF. Lower SES and ETS exposure had independent adverse effects on pulmonary and nutritional outcomes. Estimated effect of SES on FEV1 decreased minimally after ETS adjustment, suggesting health disparity risks independent of ETS exposure. PMID- 28093465 TI - Neonatal Abstinence Syndrome and High School Performance. AB - BACKGROUND AND OBJECTIVES: Little is known of the long-term, including school, outcomes of children diagnosed with Neonatal abstinence syndrome (NAS) (International Statistical Classification of Disease and Related Problems [10th Edition], Australian Modification, P96.1). METHODS: Linked analysis of health and curriculum-based test data for all children born in the state of New South Wales (NSW), Australia, between 2000 and 2006. Children with NAS (n = 2234) were compared with a control group matched for gestation, socioeconomic status, and gender (n = 4330, control) and with other NSW children (n = 598 265, population) for results on the National Assessment Program: Literacy and Numeracy, in grades 3, 5, and 7. RESULTS: Mean test scores (range 0-1000) for children with NAS were significantly lower in grade 3 (359 vs control: 410 vs population: 421). The deficit was progressive. By grade 7, children with NAS scored lower than other children in grade 5. The risk of not meeting minimum standards was independently associated with NAS (adjusted odds ratio [aOR], 2.5; 95% confidence interval [CI], 2.2-2.7), indigenous status (aOR, 2.2; 95% CI, 2.2-2.3), male gender (aOR, 1.3; 95% CI, 1.3-1.4), and low parental education (aOR, 1.5; 95% CI, 1.1-1.6), with all Ps < .001. CONCLUSIONS: A neonatal diagnostic code of NAS is strongly associated with poor and deteriorating school performance. Parental education may decrease the risk of failure. Children with NAS and their families must be identified early and provided with support to minimize the consequences of poor educational outcomes. PMID- 28093466 TI - Effects of Sacubitril/Valsartan Versus Olmesartan on Central Hemodynamics in the Elderly With Systolic Hypertension: The PARAMETER Study. AB - Effective treatment of systolic hypertension in elderly patients remains a major therapeutic challenge. A multicenter, double-blind, randomized controlled trial with sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, was conducted to determine its effects versus olmesartan (angiotensin receptor blocker) on central aortic pressures, in elderly patients (aged >=60 years) with systolic hypertension and pulse pressure >60 mm Hg, indicative of arterial stiffness. Patients (n=454; mean age, 67.7 years; mean seated systolic blood pressure, 158.6 mm Hg; mean seated pulse pressure, 69.7 mm Hg) were randomized to receive once-daily sacubitril/valsartan 200 mg or olmesartan 20 mg, force titrated to double the initial doses after 4 weeks, before primary assessment at 12 weeks. The study extended double-blind treatment for 12 to 52 weeks, during which amlodipine (2.5-5 mg) and subsequently hydrochlorothiazide (6.25-25 mg) were added-on for patients not achieving blood pressure target (<140/90). At week 12, sacubitril/valsartan reduced central aortic systolic pressure (primary assessment) greater than olmesartan by -3.7 mm Hg (P=0.010), further corroborated by secondary assessments at week 12 (central aortic pulse pressure, -2.4 mm Hg, P<0.012; mean 24-hour ambulatory brachial systolic blood pressure and central aortic systolic pressure, -4.1 mm Hg and -3.6 mm Hg, respectively, both P<0.001). Differences in 24-hour ambulatory pressures were pronounced during sleep. After 52 weeks, blood pressure parameters were similar between treatments (P<0.002); however, more patients required add-on antihypertensive therapy with olmesartan (47%) versus sacubitril/valsartan (32%; P<0.002). Both treatments were equally well tolerated. The PARAMETER study (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Measuring Arterial Stiffness in the Elderly), for the first time, demonstrated superiority of sacubitril/valsartan versus olmesartan in reducing clinic and ambulatory central aortic and brachial pressures in elderly patients with systolic hypertension and stiff arteries. PMID- 28093468 TI - One Step Further Toward a Targeted Screening Program. PMID- 28093467 TI - Blood Pressure Trajectories From Childhood to Young Adulthood Associated With Cardiovascular Risk: Results From the 23-Year Longitudinal Georgia Stress and Heart Study. AB - The purpose of this study is to identify subgroups of individuals with similar trajectories in blood pressure (BP) from childhood to young adulthood and to determine the relationship of BP trajectories with carotid intima-media thickness (IMT) and left ventricular mass index (LVMI). BP was measured <=16 times during a 23-year period in 683 participants from childhood to young adulthood. IMT and LVMI were measured in 551 participants and 546 participants, respectively. Using latent class models, 3 trajectory groups in BP from childhood to young adulthood were identified, including high-increasing, moderate-increasing, and low increasing groups. We found that trajectory of systolic BP was a significant predictor of both IMT and LVMI with increased rate of growth in systolic BP associated with higher levels of IMT and LVMI (Pfor trend <0.001). Similar to the BP trajectory groups from childhood to young adulthood, 3 trajectory groups in BP during childhood (<=18 years) were identified, and participants in the high increasing group had thicker IMT (P<0.001) and increased LVMI (P=0.043) in comparison with those in the low-increasing group. Results were similar for mid BP trajectories but not for diastolic BP trajectories. Our results suggested that different BP trajectories exist from childhood to young adulthood, and the trajectories were independently associated with IMT and LVMI. We, for the first time, reported the association between systolic BP trajectories derived from childhood with subclinical cardiovascular risk in young adulthood, indicating that monitoring trajectories of BP from childhood may help identify a high cardiovascular risk population in early life. PMID- 28093469 TI - Assembly of the elongated collagen prolyl 4-hydroxylase alpha2beta2 heterotetramer around a central alpha2 dimer. AB - Collagen prolyl 4-hydroxylase (C-P4H), an alpha2beta2 heterotetramer, is a crucial enzyme for collagen synthesis. The alpha-subunit consists of an N terminal dimerization domain, a central peptide substrate-binding (PSB) domain, and a C-terminal catalytic (CAT) domain. The beta-subunit [also known as protein disulfide isomerase (PDI)] acts as a chaperone, stabilizing the functional conformation of C-P4H. C-P4H has been studied for decades, but its structure has remained elusive. Here, we present a three-dimensional small-angle X-ray scattering model of the entire human C-P4H-I heterotetramer. C-P4H is an elongated, bilobal, symmetric molecule with a length of 290 A. The dimerization domains from the two alpha-subunits form a protein-protein dimer interface, assembled around the central antiparallel coiled-coil interface of their N terminal alpha-helices. This region forms a thin waist in the bilobal tetramer. The two PSB/CAT units, each complexed with a PDI/beta-subunit, form two bulky lobes pointing outward from this waist region, such that the PDI/beta-subunits locate at the far ends of the betaalphaalphabeta complex. The PDI/beta-subunit interacts extensively with the CAT domain. The asymmetric shape of two truncated C-P4H-I variants, also characterized in the present study, agrees with this assembly. Furthermore, data from these truncated variants show that dimerization between the alpha-subunits has an important role in achieving the correct PSB-CAT assembly competent for catalytic activity. Kinetic assays with various proline rich peptide substrates and inhibitors suggest that, in the competent assembly, the PSB domain binds to the procollagen substrate downstream from the CAT domain. PMID- 28093470 TI - Active-site maturation and activity of the copper-radical oxidase GlxA are governed by a tryptophan residue. AB - GlxA from Streptomyces lividans is a mononuclear copper-radical oxidase and a member of the auxiliary activity family 5 (AA5). Its domain organisation and low sequence homology make it a distinct member of the AA5 family in which the fungal galactose 6-oxidase (Gox) is the best characterised. GlxA is a key cuproenzyme in the copper-dependent morphological development of S. lividans with a function that is linked to the processing of an extracytoplasmic glycan. The catalytic sites in GlxA and Gox contain two distinct one-electron acceptors comprising the copper ion and a 3'-(S-cysteinyl) tyrosine. The latter is formed post translationally through a covalent bond between a cysteine and a copper-co ordinating tyrosine ligand and houses a radical. In GlxA and Gox, a second co ordination sphere tryptophan residue (Trp288 in GlxA) is present, but the orientation of the indole ring differs between the two enzymes, creating a marked difference in the pi-pi stacking interaction of the benzyl ring with the 3'-(S cysteinyl) tyrosine. Differences in the spectroscopic and enzymatic activity have been reported between GlxA and Gox with the indole orientation suggested as a reason. Here, we report a series of in vivo and in vitro studies using the W288F and W288A variants of GlxA to assess the role of Trp288 on the morphology, maturation, spectroscopic and enzymatic properties. Our findings point towards a salient role for Trp288 in the kinetics of copper loading and maturation of GlxA, with its presence essential for stabilising the metalloradical site required for coupling catalytic activity and morphological development. PMID- 28093471 TI - Interaction studies between periplasmic cytochromes provide insights into extracellular electron transfer pathways of Geobacter sulfurreducens. AB - Geobacter bacteria usually prevail among other microorganisms in soils and sediments where Fe(III) reduction has a central role. This reduction is achieved by extracellular electron transfer (EET), where the electrons are exported from the interior of the cell to the surrounding environment. Periplasmic cytochromes play an important role in establishing an interface between inner and outer membrane electron transfer components. In addition, periplasmic cytochromes, in particular nanowire cytochromes that contain at least 12 haem groups, have been proposed to play a role in electron storage in conditions of an environmental lack of electron acceptors. Up to date, no redox partners have been identified in Geobacter sulfurreducens, and concomitantly, the EET and electron storage mechanisms remain unclear. In this work, NMR chemical shift perturbation measurements were used to probe for an interaction between the most abundant periplasmic cytochrome PpcA and the dodecahaem cytochrome GSU1996, one of the proposed nanowire cytochromes in G. sulfurreducens The perturbations on the haem methyl signals of GSU1996 and PpcA showed that the proteins form a transient redox complex in an interface that involves haem groups from two different domains located at the C-terminal of GSU1996. Overall, the present study provides for the first time a clear evidence for an interaction between periplasmic cytochromes that might be relevant for the EET and electron storage pathways in G. sulfurreducens. PMID- 28093472 TI - Social Status-Dependent Shift in Neural Circuit Activation Affects Decision Making. AB - In a social group, animals make behavioral decisions that fit their social ranks. These behavioral choices are dependent on the various social cues experienced during social interactions. In vertebrates, little is known of how social status affects the underlying neural mechanisms regulating decision-making circuits that drive competing behaviors. Here, we demonstrate that social status in zebrafish (Danio rerio) influences behavioral decisions by shifting the balance in neural circuit activation between two competing networks (escape and swim). We show that socially dominant animals enhance activation of the swim circuit. Conversely, social subordinates display a decreased activation of the swim circuit, but an enhanced activation of the escape circuit. In an effort to understand how social status mediates these effects, we constructed a neurocomputational model of the escape and swim circuits. The model replicates our findings and suggests that social status-related shift in circuit dynamics could be mediated by changes in the relative excitability of the escape and swim networks. Together, our results reveal that changes in the excitabilities of the Mauthner command neuron for escape and the inhibitory interneurons that regulate swimming provide a cellular mechanism for the nervous system to adapt to changes in social conditions by permitting the animal to select a socially appropriate behavioral response.SIGNIFICANCE STATEMENT Understanding how social factors influence nervous system function is of great importance. Using zebrafish as a model system, we demonstrate how social experience affects decision making to enable animals to produce socially appropriate behavior. Based on experimental evidence and computational modeling, we show that behavioral decisions reflect the interplay between competing neural circuits whose activation thresholds shift in accordance with social status. We demonstrate this through analysis of the behavior and neural circuit responses that drive escape and swim behaviors in fish. We show that socially subordinate animals favor escape over swimming, while socially dominants favor swimming over escape. We propose that these differences are mediated by shifts in relative circuit excitability. PMID- 28093473 TI - Differential Regulation of NMDA Receptor-Mediated Transmission by SK Channels Underlies Dorsal-Ventral Differences in Dynamics of Schaffer Collateral Synaptic Function. AB - Behavioral, physiological, and anatomical evidence indicates that the dorsal and ventral zones of the hippocampus have distinct roles in cognition. How the unique functions of these zones might depend on differences in synaptic and neuronal function arising from the strikingly different gene expression profiles exhibited by dorsal and ventral CA1 pyramidal cells is unclear. To begin to address this question, we investigated the mechanisms underlying differences in synaptic transmission and plasticity at dorsal and ventral Schaffer collateral (SC) synapses in the mouse hippocampus. We find that, although basal synaptic transmission is similar, SC synapses in the dorsal and ventral hippocampus exhibit markedly different responses to theta frequency patterns of stimulation. In contrast to dorsal hippocampus, theta frequency stimulation fails to elicit postsynaptic complex-spike bursting and does not induce LTP at ventral SC synapses. Moreover, EPSP-spike coupling, a process that strongly influences information transfer at synapses, is weaker in ventral pyramidal cells. Our results indicate that all these differences in postsynaptic function are due to an enhanced activation of SK-type K+ channels that suppresses NMDAR-dependent EPSP amplification at ventral SC synapses. Consistent with this, mRNA levels for the SK3 subunit of SK channels are significantly higher in ventral CA1 pyramidal cells. Together, our findings indicate that a dorsal-ventral difference in SK channel regulation of NMDAR activation has a profound effect on the transmission, processing, and storage of information at SC synapses and thus likely contributes to the distinct roles of the dorsal and ventral hippocampus in different behaviors.SIGNIFICANCE STATEMENT Differences in short- and long-term plasticity at Schaffer collateral (SC) synapses in the dorsal and ventral hippocampus likely contribute importantly to the distinct roles of these regions in cognition and behavior. Although dorsal and ventral CA1 pyramidal cells exhibit markedly different gene expression profiles, how these differences influence plasticity at SC synapses is unclear. Here we report that increased mRNA levels for the SK3 subunit of SK-type K+ channels in ventral pyramidal cells is associated with an enhanced activation of SK channels that strongly suppresses NMDAR activation at ventral SC synapses. This leads to striking differences in multiple aspects of synaptic transmission at dorsal and ventral SC synapses and underlies the reduced ability of ventral SC synapses to undergo LTP. PMID- 28093474 TI - Behavioral Status Influences the Dependence of Odorant-Induced Change in Firing on Prestimulus Firing Rate. AB - The firing rate of the mitral/tufted cells in the olfactory bulb is known to undergo significant trial-to-trial variability and is affected by anesthesia. Here we ask whether odorant-elicited changes in firing rate depend on the rate before application of the stimulus in the awake and anesthetized mouse. We find that prestimulus firing rate varies widely on a trial-to-trial basis and that the stimulus-induced change in firing rate decreases with increasing prestimulus firing rate. Interestingly, this prestimulus firing rate dependence was different when the behavioral task did not involve detecting the valence of the stimulus. Finally, when the animal was learning to associate the odor with reward, the prestimulus firing rate was smaller for false alarms compared with correct rejections, suggesting that intrinsic activity reflects the anticipatory status of the animal. Thus, in this sensory modality, changes in behavioral status alter the intrinsic prestimulus activity, leading to a change in the responsiveness of the second-order neurons. We speculate that this trial-to-trial variability in odorant responses reflects sampling of the massive parallel input by subsets of mitral cells.SIGNIFICANCE STATEMENT The olfactory bulb must deal with processing massive parallel input from ~1200 distinct olfactory receptors. In contrast, the visual system receives input from a small number of photoreceptors and achieves recognition of complex stimuli by allocating processing for distinct spatial locations to different brain areas. Here we find that the change in firing rate elicited by the odorant in second-order mitral cells depends on the intrinsic activity leading to a change of magnitude in the responsiveness of these neurons relative to this prestimulus activity. Further, we find that prestimulus firing rate is influenced by behavioral status. This suggests that there is top-down modulation allowing downstream brain processing areas to perform dynamic readout of olfactory information. PMID- 28093475 TI - Hippocampal Contribution to Context Encoding across Development Is Disrupted following Early-Life Adversity. AB - Context can drastically influence responses to environmental stimuli. For example, a gunshot should provoke a different response at a public park than a shooting range. Little is known about how contextual processing and neural correlates change across human development or about individual differences related to early environmental experiences. Children (N = 60; 8-19 years, 24 exposed to interpersonal violence) completed a context encoding task during fMRI scanning using a delayed match-to-sample design with neutral, happy, and angry facial cues embedded in realistic background scenes. Outside the scanner, participants completed a memory test for context-face pairings. Context memory and neural correlates of context encoding did not vary with age. Larger hippocampal volume was associated with better context memory. Posterior hippocampus was recruited during context encoding, and greater activation in this region predicted better memory for contexts paired with angry faces. Children exposed to violence had poor memory of contexts paired with angry faces, reduced hippocampal volume, and atypical neural recruitment on encoding trials with angry faces, including reduced hippocampal activation and greater functional connectivity between hippocampus and ventrolateral prefrontal cortex (vlPFC). Greater hippocampus-vlPFC connectivity was associated with worse memory for contexts paired with angry faces. Posterior hippocampus appears to support context encoding, a process that does not exhibit age-related variation from middle childhood to late adolescence. Exposure to dangerous environments in childhood is associated with poor context encoding in the presence of threat, likely due to greater vlPFC-dependent attentional narrowing on threat cues at the expense of hippocampus-dependent processing of the broader context.SIGNIFICANCE STATEMENT The ability to use context to guide reactions to environmental stimuli promotes flexible behavior. Remarkably little research has examined how contextual processing changes across development or about influences of the early environment. We provide evidence for posterior hippocampus involvement in context encoding in youth and lack of age-related variation from middle childhood to late adolescence. Children exposed to interpersonal violence exhibited poor memory of contexts paired with angry faces and atypical neural recruitment during context encoding in the presence of threatening facial cues. Heightened attention to threat following violence exposure may come at the expense of encoding contextual information, which may ultimately contribute to pathological fear expressed in safe contexts. PMID- 28093477 TI - Differential Presynaptic ATP Supply for Basal and High-Demand Transmission. AB - The relative contributions of glycolysis and oxidative phosphorylation to neuronal presynaptic energy demands are unclear. In rat hippocampal neurons, ATP production by either glycolysis or oxidative phosphorylation alone sustained basal evoked synaptic transmission for up to 20 min. However, combined inhibition of both ATP sources abolished evoked transmission. Neither action potential propagation failure nor depressed Ca2+ influx explained loss of evoked synaptic transmission. Rather, inhibition of ATP synthesis caused massive spontaneous vesicle exocytosis, followed by arrested endocytosis, accounting for the disappearance of evoked postsynaptic currents. In contrast to its weak effects on basal transmission, inhibition of oxidative phosphorylation alone depressed recovery from vesicle depletion. Local astrocytic lactate shuttling was not required. Instead, either ambient monocarboxylates or neuronal glycolysis was sufficient to supply requisite substrate. In summary, basal transmission can be sustained by glycolysis, but strong presynaptic demands are met preferentially by oxidative phosphorylation, which can be maintained by bulk but not local monocarboxylates or by neuronal glycolysis.SIGNIFICANCE STATEMENT Neuronal energy levels are critical for proper CNS function, but the relative roles for the two main sources of ATP production, glycolysis and oxidative phosphorylation, in fueling presynaptic function in unclear. Either glycolysis or oxidative phosphorylation can fuel low-frequency synaptic function and inhibiting both underlies loss of synaptic transmission via massive vesicle release and subsequent failure to endocytose lost vesicles. Oxidative phosphorylation, fueled by either glycolysis or endogenously released monocarboxylates, can fuel more metabolically demanding tasks such as vesicle recovery after depletion. Our work demonstrates the flexible nature of fueling presynaptic function to maintain synaptic function. PMID- 28093476 TI - Muscarinic Acetylcholine Receptors and M-Currents Underlie Efferent-Mediated Slow Excitation in Calyx-Bearing Vestibular Afferents. AB - Stimulation of vestibular efferent neurons excites calyx and dimorphic (CD) afferents. This excitation consists of fast and slow components that differ >100 fold in activation kinetics and response duration. In the turtle, efferent mediated fast excitation arises in CD afferents when the predominant efferent neurotransmitter acetylcholine (ACh) activates calyceal nicotinic ACh receptors (nAChRs); however, it is unclear whether the accompanying efferent-mediated slow excitation is also attributed to cholinergic mechanisms. To identify synaptic processes underlying efferent-mediated slow excitation, we recorded from CD afferents innervating the turtle posterior crista during electrical stimulation of efferent neurons, in combination with pharmacological probes and mechanical stimulation. Efferent-mediated slow excitation was unaffected by nAChR compounds that block efferent-mediated fast excitation, but were mimicked by muscarine and antagonized by atropine, indicating that it requires ACh and muscarinic ACh receptor (mAChR) activation. Efferent-mediated slow excitation or muscarine application enhanced the sensitivity of CD afferents to mechanical stimulation, suggesting that mAChR activation increases afferent input impedance by closing calyceal potassium channels. These observations were consistent with suppression of a muscarinic-sensitive K+-current, or M-current. Immunohistochemistry for putative M-current candidates suggested that turtle CD afferents express KCNQ3, KCNQ4, and ERG1-3 potassium channel subunits. KCNQ channels were favored as application of the selective antagonist XE991 mimicked and occluded efferent mediated slow excitation in CD afferents. These data highlight an efferent mediated mechanism for enhancing afferent sensitivity. They further suggest that the clinical effectiveness of mAChR antagonists in treating balance disorders may also target synaptic mechanisms in the vestibular periphery, and that KCNQ channel modulators might offer similar therapeutic value.SIGNIFICANCE STATEMENT Targeting the efferent vestibular system (EVS) pharmacologically might prove useful in ameliorating some forms of vestibular dysfunction by modifying ongoing primary vestibular input. EVS activation engages several kinetically distinct synaptic processes that profoundly alter the discharge rate and sensitivity of first-order vestibular neurons. Efferent-mediated slow excitation of vestibular afferents is of considerable interest given its ability to elevate afferent activity over an extended time course. We demonstrate for the first time that efferent-mediated slow excitation of vestibular afferents is mediated by muscarinic acetylcholine receptor (mAChR) activation and the subsequent closure of KCNQ potassium channels. The clinical effectiveness of some anti-mAChR drugs in treating motion sickness suggest that we may, in fact, already be targeting the peripheral EVS. PMID- 28093478 TI - Long Noncoding RNA Malat1 Regulates Cerebrovascular Pathologies in Ischemic Stroke. AB - The study was designed to determine the role of long noncoding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript 1 (Malat1), in ischemic stroke outcome. Primary mouse brain microvascular endothelial cells (BMECs) were cultured and treated with Malat1 GapmeR before 16 h oxygen and glucose depravation (OGD). Cell death was assayed by LDH and MTT methods. Malat1 knock out and wild-type mice were subjected to 1 h of middle cerebral artery occlusion (MCAO) and 24-72 h of reperfusion. To explore the underlying mechanism, apoptotic and inflammatory factors were measured by qPCR, ELISA, and Western blotting. The physical interaction between Malat1 and apoptotic or inflammatory factors was measured by RNA immunoprecipitation. Increased Malat1 levels were found in cultured mouse BMECs after OGD as well as in isolated cerebral microvessels in mice after MCAO. Silencing of Malat1 by Malat1 GapmeR significantly increased OGD induced cell death and Caspase 3 activity in BMECs. Silencing of Malat1 also significantly aggravated OGD-induced expression of the proapoptotic factor Bim and proinflammatory cytokines MCP-1, IL-6, and E-selectin. Moreover, Malat1 KO mice presented larger brain infarct size, worsened neurological scores, and reduced sensorimotor functions. Consistent with in vitro findings, significantly increased expression of proapoptotic and proinflammatory factors was also found in the cerebral cortex of Malat1 KO mice after ischemic stroke compared with WT controls. Finally, we demonstrated that Malat1 binds to Bim and E-selectin both in vitro and in vivo Our study suggests that Malat1 plays critical protective roles in ischemic stroke.SIGNIFICANCE STATEMENT Accumulative studies have demonstrated the important regulatory roles of microRNAs in vascular and neural damage after ischemic stroke. However, the functional significance and mechanisms of other classes of noncoding RNAs in cerebrovascular pathophysiology after stroke are less studied. Here we demonstrate a novel role of Malat1, a long noncoding RNA that has been originally identified as a prognostic marker for non small cell lung cancer, in cerebrovascular pathogenesis of ischemic stroke. Our experiments have provided the first evidence that Malat1 plays anti-apoptotic and anti-inflammatory roles in brain microvasculature to reduce ischemic cerebral vascular and parenchymal damages. Our studies also suggest that lncRNAs can be therapeutically targeted to minimize poststroke brain damage. PMID- 28093479 TI - Paired Stimulation for Spike-Timing-Dependent Plasticity in Primate Sensorimotor Cortex. AB - Classic in vitro studies have described spike-timing-dependent plasticity (STDP) at a synapse: the connection from neuron A to neuron B is strengthened (or weakened) when A fires before (or after) B within an optimal time window. Accordingly, more recent in vivo works have demonstrated behavioral effects consistent with an STDP mechanism; however, many relied on single-unit recordings. The ability to modify cortical connections becomes useful in the context of injury, when connectivity and associated behavior are compromised. To avoid the need for long-term, stable isolation of single units, one could control timed activation of two cortical sites with paired electrical stimulation. We tested the hypothesis that STDP could be induced via prolonged paired stimulation as quantified by cortical evoked potentials (EPs) in the sensorimotor cortex of awake, behaving monkeys. Paired simulation between two interconnected sites produced robust effects in EPs consistent with STDP, but only at 2/15 tested pairs. The stimulation protocol often produced increases in global network excitability or depression of the conditioned pair. Together, these results suggest that paired stimulation in vivo is a viable method to induce STDP between cortical populations, but that factors beyond activation timing must be considered to produce conditioning effects.SIGNIFICANCE STATEMENT Plasticity of neural connections is important for development, learning, memory, and recovery from injury. Cellular mechanisms underlying spike-timing-dependent plasticity have been studied extensively in vitro Recent in vivo work has demonstrated results consistent with the previously defined cellular mechanisms; however, the output measure in these studies was typically an indirect assessment of plasticity at the neural level. Here, we show direct plasticity in recordings of neuronal populations in awake, behaving nonhuman primates induced by paired electrical stimulation. In contrast to in vitro studies, we found that plastic effects were only produced between specific cortical areas. These findings suggest that similar mechanisms drive plasticity in vitro and in vivo, but that cortical architecture may contribute significantly to site-dependent effects. PMID- 28093480 TI - Comprehensive screening for PD-L1 expression in thyroid cancer. AB - PD-L1 expression is being considered a potential biomarker for response of anti PD-1 or anti-PD-L1 agents in various tumors. The reported frequency of PD-L1 positivity varies in thyroid carcinomas, and multiple factors may contribute to the variability in PD-L1 positivity. We evaluated the PD-L1 expression in various thyroid cancers on a large scale. A total of 407 primary thyroid cancers with a median 13.7-year of follow-up were included. We evaluated the frequency of PD-L1 expression using a rabbit monoclonal antibody (clone SP142). In addition, we analyzed the relationships between PD-L1 expression and clinicopathologic factors, including TERT promoter, BRAF status and disease progression. Tumoral PD L1 was expressed in 6.1% of papillary thyroid carcinomas, 7.6% of follicular thyroid carcinomas and 22.2% of anaplastic thyroid carcinomas. The distribution of PD-L1 positivity was different according to cancer histology types (P < 0.001). All PD-L1-positive cases of follicular thyroid carcinoma and anaplastic thyroid carcinoma showed strong intensity. The proportions of positivity in PD-L1 positive anaplastic thyroid carcinomas were more than 80%. PD-L1 in immune cells was positive in 28.5% of papillary thyroid carcinoma, 9.1% of follicular thyroid carcinomas and 11.1% of anaplastic thyroid carcinomas. There was no significant association between clinicopathologic variables, disease progression, oncogenic mutation and PD-L1 expression. PD-L1 was highly expressed in a subset of patients with advanced thyroid cancer, such as follicular and anaplastic thyroid carcinoma. Identification of PD-L1 expression may have direct therapeutic relevance to patients with refractory thyroid cancer. PMID- 28093481 TI - Phylogenetic and pathogenic analysis of Mycoplasma Synoviae isolated from native chicken breeds in China. AB - Mycoplasma synoviae (M. synoviae) infection leads to serious economic losses in the world every year. Between 2013 and 2014, the infectious synovitis, caused by M. synoviae infection, occurred in native chickens in China and resulted in the loss of millions of chickens in Chinese poultry farms. However, there has been no data about phylogenetic and pathogenic analysis of Chinese M. synoviae isolates. In this study, a total of 110 M. synoviae strains were isolated from M. synoviae infected chickens. The isolates identified in the present study were classified into a new distinct subgroup based on analysis of the 5'-end vlhA sequences, tentatively termed the K group. In addition, though the pathogenicity was significantly different among isolates, there was no close relationship between pathogenicity and genotype for Chinese M. synoviae based on a pathogenic analysis of the 5'-end of the vlhA gene. PMID- 28093482 TI - Dissemination of blaOXA-58 in Proteus mirabilis isolates from Germany. AB - Objectives: Characterization of Proteus mirabilis isolates harbouring bla OXA-58 with emphasis on the genetic environment of this resistance determinant. Methods: Strains of P. mirabilis ( n = 37) isolated from different patients were tested for the presence of bla OXA-58 . The genetic context of bla OXA-58 was determined by WGS of two strains and Sanger sequencing. Clonality of the strains was assessed by PFGE. Susceptibility testing was performed by microdilution according to EUCAST. Results: Four strains isolated in different geographical regions of Germany were positive for bla OXA-58 , and WGS showed that this resistance gene was harboured on a plasmid. Sanger sequencing confirmed the presence of two nearly identical plasmids, 6219 and 6208 bp in size, in all four strains. Upstream of bla OXA-58 an IS Aba 3-like transposase gene was located. The P. mirabilis strains were not clonally related according to PFGE. MICs of meropenem for three of the strains were only just above the EUCAST breakpoint and the Carba NP test was positive for only two of the strains. Conclusions: To our knowledge, this is the first description of bla OXA-58 in the species P. mirabilis . The resistance gene is harboured by almost identical plasmids in strains not clonally related and from different geographical regions. Apart from an IS Aba 3-like transposase gene upstream of bla OXA-58 the genetic context is different from bla OXA-58 harboured on plasmids in the genus Acinetobacter . With MICs of meropenem well below the EUCAST breakpoint or only just above it and equivocal or false negative results from the Carba NP test, bla OXA-58 can be easily overlooked in P. mirabilis . PMID- 28093483 TI - Treatment simplification to atazanavir/ritonavir + lamivudine versus maintenance of atazanavir/ritonavir + two NRTIs in virologically suppressed HIV-1-infected patients: 48 week results from a randomized trial (ATLAS-M). AB - Background: Combination ART (cART)-related toxicities and costs have prompted the need for treatment simplification. The ATLAS-M trial explored 48 week non inferior efficacy of simplification to atazanavir/ritonavir + lamivudine versus maintaining three-drug atazanavir/ritonavir-based cART in virologically suppressed patients. Methods: We performed an open-label, multicentre, randomized, non-inferiority study, enrolling HIV-infected adults on atazanavir/ritonavir + two NRTIs, with stable HIV-RNA <50 copies/mL and CD4 + >200 cells/mm 3 . Main exclusion criteria were hepatitis B virus coinfection, past virological failure on or resistance to study drugs, recent AIDS and pregnancy. Patients were randomly assigned 1:1 to either switch to 300 mg of atazanavir/100 mg of ritonavir once daily and 300 mg of lamivudine once daily (atazanavir/ritonavir + lamivudine arm) or to continue the previous regimen (atazanavir/ritonavir + two NRTIs arm). The primary study outcome was the maintenance of HIV-RNA <50 copies/mL at week 48 of the ITT-exposed (ITT-e) analysis with switch = failure. The non-inferiority margin was 12%. This study is registered at ClinicalTrials.gov, number NCT01599364. Results: Between July 2011 and June 2014, 266 patients were randomized (133 to each arm). After 48 weeks, the primary study outcome was met by 119 of 133 patients (89.5%) in the atazanavir/ritonavir + lamivudine arm and 106 of 133 patients (79.7%) in the atazanavir/ritonavir + two NRTIs arm [difference atazanavir/ritonavir + lamivudine versus atazanavir/ritonavir + two NRTIs arm: +9.8% (95% CI + 1.2 to + 18.4)], demonstrating non-inferiority and superior efficacy of the atazanavir/ritonavir + lamivudine arm. Virological failure occurred in two (1.5%) patients in the atazanavir/ritonavir + lamivudine arm and six (4.5%) patients in the atazanavir/ritonavir + two NRTIs arm, without resistance selection. A similar proportion of adverse events occurred in both arms. Conclusions: Treatment simplification to atazanavir/ritonavir + lamivudine showed non-inferior efficacy (superiority on post-hoc analysis) and a comparable safety profile over continuing atazanavir/ritonavir + two NRTIs in virologically suppressed patients. PMID- 28093484 TI - MIC of amoxicillin/clavulanate according to CLSI and EUCAST: discrepancies and clinical impact in patients with bloodstream infections due to Enterobacteriaceae. AB - Objectives: To compare results of amoxicillin/clavulanate susceptibility testing using CLSI and EUCAST methodologies and to evaluate their impact on outcome in patients with bacteraemia caused by Enterobacteriaceae. Patients and methods: A prospective observational cohort study was conducted in 13 Spanish hospitals. Patients with bacteraemia due to Enterobacteriaceae who received empirical intravenous amoxicillin/clavulanate treatment for at least 48 h were included. MICs were determined following CLSI and EUCAST recommendations. Outcome variables were: failure at the end of treatment with amoxicillin/clavulanate (FEAMC); failure at day 21; and 30 day mortality. Classification and regression tree (CART) analysis and logistic regression were performed. Results: Overall, 264 episodes were included; the urinary tract was the most common source (64.7%) and Escherichia coli the most frequent pathogen (76.5%). Fifty-two isolates (19.7%) showed resistance according to CLSI and 141 (53.4%) according to EUCAST. The kappa index for the concordance between the results of both committees was only 0.24. EUCAST-derived, but not CLSI-derived, MICs were associated with failure when considered as continuous variables. CART analysis suggested a 'resistance' breakpoint of > 8/4 mg/L for CLSI-derived MICs; it predicted FEAMC in adjusted analysis (OR = 1.96; 95% CI: 0.98-3.90). Isolates with EUCAST-derived MICs >16/2 mg/L independently predicted FEAMC (OR = 2.10; 95% CI: 1.05-4.21) and failure at day 21 (OR= 3.01; 95% CI: 0.93-9.67). MICs >32/2 mg/L were only predictive of failure among patients with bacteraemia from urinary or biliary tract sources. Conclusions: CLSI and EUCAST methodologies showed low agreement for determining the MIC of amoxicillin/clavulanate. EUCAST-derived MICs seemed more predictive of failure than CLSI-derived ones. EUCAST-derived MICs >16/2 mg/L were independently associated with therapeutic failure. PMID- 28093485 TI - Molecular insights into fosfomycin resistance in Escherichia coli. AB - Objectives: Fosfomycin activity in Escherichia coli depends on several genes of unknown importance for fosfomycin resistance. The objective was to characterize the role of uhpT , glpT , cyaA and ptsI genes in fosfomycin resistance in E. coli. Methods: WT E. coli BW25113 and null mutants, Delta uhpT , Delta glpT , Delta cyaA , Delta ptsI , Delta glpT-uhpT , Delta glpT-cyaA , Delta glpT-ptsI , Delta uhpT-cyaA , Delta uhpT-ptsI and Delta ptsI-cyaA , were studied. Susceptibility to fosfomycin was tested using CLSI guidelines. Fosfomycin mutant frequencies were determined at concentrations of 64 and 256 mg/L. Fosfomycin in vitro activity was tested using time-kill assays at concentrations of 64 and 307 mg/L (human C max ). Results: Fosfomycin MICs were: WT E. coli BW25113 (2 mg/L), Delta glpT (2 mg/L), Delta uhpT (64 mg/L), Delta cyaA (8 mg/L), Delta ptsI (2 mg/L), Delta glpT-uhpT (256 mg/L), Delta glpT-cyaA (8 mg/L), Delta glpT-ptsI (2 mg/L), Delta uhpT-cyaA (512 mg/L), Delta uhpT-ptsI (64 mg/L) and Delta ptsI-cyaA (32 mg/L). In the mutant frequency assays, no mutants were recovered from BW25113. Mutants appeared in Delta glpT , Delta uhpT , Delta cyaA and Delta ptsI at 64 mg/L and in Delta uhpT and Delta cyaA at 256 mg/L. Delta glpT-ptsI , but not Delta glpT-cyaA , Delta uhpT-cyaA or Delta uhpT-ptsI , increased the mutant frequency compared with the highest frequency found in each single mutant. In time-kill assays, all mutants regrew at 64 mg/L. Initial bacterial reductions of 2-4 log 10 cfu/mL were observed for all strains, except for Delta uhpT-ptsI , Delta glpT-uhpT and Delta uhpT-cyaA . Only Delta glpT and Delta ptsI mutants were cleared using 307 mg/L. Conclusions: Fosfomycin MIC may not be a good efficacy predictor, as highly resistant mutants may appear, depending on other pre existing mutations with no impact on MIC. PMID- 28093488 TI - Correction: Genomic EWSR1 Fusion Sequence as Highly Sensitive and Dynamic Plasma Tumor Marker in Ewing Sarcoma. PMID- 28093489 TI - Correction: The Future Is Now: Chimeric Antigen Receptors as New Targeted Therapies for Childhood Cancer. PMID- 28093487 TI - A Pilot Trial of the Combination of Vemurafenib with Adoptive Cell Therapy in Patients with Metastatic Melanoma. AB - PURPOSE: This pilot feasibility clinical trial evaluated the coadministration of vemurafenib, a small-molecule antagonist of BRAFV600 mutations, and tumor infiltrating lymphocytes (TIL) for the treatment of metastatic melanoma. EXPERIMENTAL DESIGN: A metastatic tumor was resected for growth of TILs, and patients were treated with vemurafenib for 2 weeks, followed by resection of a second lesion. Patients then received a nonmyeloablative preconditioning regimen, infusion of autologous TILs, and high-dose interleukin-2 administration. Vemurafenib was restarted at the time of TIL infusion and was continued for 2 years or until disease progression. Clinical responses were evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. Metastases resected prior to and after 2 weeks of vemurafenib were compared using TCRB deep sequencing, immunohistochemistry, proliferation, and recognition of autologous tumor. RESULTS: The treatment was well tolerated and had a safety profile similar to that of TIL or vemurafenib alone. Seven of 11 patients (64%) experienced an objective clinical response, and 2 patients (18%) had a complete response for 3 years (one response is ongoing at 46 months). Proliferation and viability of infusion bag TILs and peripheral blood T cells were inhibited in vitro by research-grade vemurafenib (PLX4032) when approaching the maximum serum concentration of vemurafenib. TCRB repertoire (clonotypes numbers, clonality, and frequency) did not significantly change between pre- and post-vemurafenib lesions. Recognition of autologous tumor by T cells was similar between TILs grown from pre- and post-vemurafenib metastases. CONCLUSIONS: Coadministration of vemurafenib and TILs was safe and feasible and generated objective clinical responses in this small pilot clinical trial. Clin Cancer Res; 23(2); 351-62. (c)2016 AACRSee related commentary by Cogdill et al., p. 327. PMID- 28093490 TI - Retraction: Effective Targeting of Triple-Negative Breast Cancer Cells by PF 4942847, a Novel Oral Inhibitor of Hsp 90. PMID- 28093492 TI - A Surgeon's View on the Pathogenesis of Atherosclerosis. PMID- 28093493 TI - Adding Rigor to Stroke Rate Investigations in Patients With Atrial Fibrillation. PMID- 28093491 TI - Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation. AB - Frontotemporal dementia (FTD)-causing mutations in the CHMP2B gene lead to the generation of mutant C-terminally truncated CHMP2B. We report that transgenic mice expressing endogenous levels of mutant CHMP2B developed late-onset brain volume loss associated with frank neuronal loss and FTD-like changes in social behaviour. These data are the first to show neurodegeneration in mice expressing mutant CHMP2B and indicate that our mouse model is able to recapitulate neurodegenerative changes observed in FTD. Neuroinflammation has been increasingly implicated in neurodegeneration, including FTD. Therefore, we investigated neuroinflammation in our CHMP2B mutant mice. We observed very early microglial proliferation that develops into a clear pro-inflammatory phenotype at late stages. Importantly, we also observed a similar inflammatory profile in CHMP2B patient frontal cortex. Aberrant microglial function has also been implicated in FTD caused by GRN, MAPT and C9orf72 mutations. The presence of early microglial changes in our CHMP2B mutant mice indicates neuroinflammation may be a contributing factor to the neurodegeneration observed in FTD. PMID- 28093494 TI - Exercise Dynamics in Secondary Mitral Regurgitation: Pathophysiology and Therapeutic Implications. AB - Secondary mitral valve regurgitation (MR) remains a challenging problem in the diagnostic workup and treatment of patients with heart failure. Although secondary MR is characteristically dynamic in nature and sensitive to changes in ventricular geometry and loading, current therapy is mainly focused on resting conditions. An exercise-induced increase in secondary MR, however, is associated with impaired exercise capacity and increased mortality. In an era where a multitude of percutaneous solutions are emerging for the treatment of patients with heart failure, it becomes important to address the dynamic component of secondary MR during exercise as well. A critical reappraisal of the underlying disease mechanisms, in particular the dynamic component during exercise, is of timely importance. This review summarizes the pathophysiological mechanisms involved in the dynamic deterioration of secondary MR during exercise, its functional and prognostic impact, and the way current treatment options affect the dynamic lesion and exercise hemodynamics in general. PMID- 28093495 TI - Effect of Clopidogrel by Smoking Status on Secondary Stroke Prevention. PMID- 28093496 TI - Letter by Colli and Gerosa Regarding Article, "Transapical Beating-Heart Mitral Valve Repair With an Expanded Polytetrafluoroethylene Cordal Implantation Device: Initial Clinical Experience". PMID- 28093497 TI - Response by Gammie et al to Letter Regarding Article, "Transapical Beating-Heart Mitral Valve Repair With an Expanded Polytetrafluoroethylene Cordal Implantation Device: Initial Clinical Experience". PMID- 28093498 TI - Letter by Dhruva and Redberg Regarding Article, "Sex and Race/Ethnicity Differences in Implantable Cardioverter-Defibrillator Counseling and Use Among Patients Hospitalized With Heart Failure: Findings From the Get With The Guidelines-Heart Failure Program". PMID- 28093499 TI - Response by Hess et al to Letter Regarding Article, "Sex and Race/Ethnicity Differences in Implantable Cardioverter-Defibrillator Counseling and Use Among Patients Hospitalized With Heart Failure: Findings From the Get With The Guidelines-Heart Failure Program". PMID- 28093500 TI - Cytosolic thioredoxin reductase 1 is required for correct disulfide formation in the ER. AB - Folding of proteins entering the secretory pathway in mammalian cells frequently requires the insertion of disulfide bonds. Disulfide insertion can result in covalent linkages found in the native structure as well as those that are not, so called non-native disulfides. The pathways for disulfide formation are well characterized, but our understanding of how non-native disulfides are reduced so that the correct or native disulfides can form is poor. Here, we use a novel assay to demonstrate that the reduction in non-native disulfides requires NADPH as the ultimate electron donor, and a robust cytosolic thioredoxin system, driven by thioredoxin reductase 1 (TrxR1 or TXNRD1). Inhibition of this reductive pathway prevents the correct folding and secretion of proteins that are known to form non-native disulfides during their folding. Hence, we have shown for the first time that mammalian cells have a pathway for transferring reducing equivalents from the cytosol to the ER, which is required to ensure correct disulfide formation in proteins entering the secretory pathway. PMID- 28093501 TI - Discrete cytosolic macromolecular BRAF complexes exhibit distinct activities and composition. AB - As a central element within the RAS/ERK pathway, the serine/threonine kinase BRAF plays a key role in development and homeostasis and represents the most frequently mutated kinase in tumors. Consequently, it has emerged as an important therapeutic target in various malignancies. Nevertheless, the BRAF activation cycle still raises many mechanistic questions as illustrated by the paradoxical action and side effects of RAF inhibitors. By applying SEC-PCP-SILAC, we analyzed protein-protein interactions of hyperactive BRAFV600E and wild-type BRAF (BRAFWT). We identified two macromolecular, cytosolic BRAF complexes of distinct molecular composition and phosphorylation status. Hyperactive BRAFV600E resides in large complexes of higher molecular mass and activity, while BRAFWT is confined to smaller, slightly less active complexes. However, expression of oncogenic K-RasG12V, either by itself or in combination with RAF dimer promoting inhibitors, induces the incorporation of BRAFWT into large, active complexes, whereas pharmacological inhibition of BRAFV600E has the opposite effect. Thus, the quaternary structure of BRAF complexes is shaped by its activation status, the conformation of its kinase domain, and clinically relevant inhibitors. PMID- 28093502 TI - Heat strain, volume depletion and kidney function in California agricultural workers. AB - BACKGROUND: Agricultural work can expose workers to increased risk of heat strain and volume depletion due to repeated exposures to high ambient temperatures, arduous physical exertion and limited rehydration. These risk factors may result in acute kidney injury (AKI). METHODS: We estimated AKI cumulative incidence in a convenience sample of 283 agricultural workers based on elevations of serum creatinine between preshift and postshift blood samples. Heat strain was assessed based on changes in core body temperature and heart rate. Volume depletion was assessed using changes in body mass over the work shift. Logistic regression models were used to estimate the associations of AKI with traditional risk factors (age, diabetes, hypertension and history of kidney disease) as well as with occupational risk factors (years in farm work, method of payment and farm task). RESULTS: 35 participants were characterised with incident AKI over the course of a work shift (12.3%). Workers who experienced heat strain had increased adjusted odds of AKI (1.34, 95% CI 1.04 to 1.74). Piece rate work was associated with 4.24 odds of AKI (95% CI 1.56 to 11.52). Females paid by the piece had 102.81 adjusted odds of AKI (95% CI 7.32 to 1443.20). DISCUSSION: Heat strain and piece rate work are associated with incident AKI after a single shift of agricultural work, though gender differences exist. Modifications to payment structures may help prevent AKI. PMID- 28093503 TI - Work and health in Latin America: results from the working conditions surveys of Colombia, Argentina, Chile, Central America and Uruguay. AB - OBJECTIVE: To describe working and employment conditions, and health status between non-agricultural employees with a written contract from Colombia, Argentina, Chile, Central America and Uruguay. METHODS: We compared data from the first working condition surveys (WCS) of Colombia, Argentina, Chile, Central America and Uruguay. For comparative purposes, we selected a subsample of 15 241 non-agricultural employees aged 18-64 years and working with a written contract. We calculated prevalences and 95% CIs for the selected variables on working and employment conditions, and health status, separated by sex. RESULTS: Across all countries, at least 40% of women and 58% of men worked >40 hours a week. The most prevalent exposures were repetitive movements, followed by noise and manual handling, especially among men. Psychosocial exposures were very common among both sexes. Workers in Chile (33.4% of women and 16.6% of men) and Central America (24.3% of women and 19.1% of men) were more likely to report poor self perceived health and were least likely to do so in Colombia (5.5% of women and 4.2% of men). The percentage of workers reporting occupational injuries was <10% across all countries. CONCLUSIONS: This study provides, for the first time, a broad picture of work and health in different Latin American countries, based on the national WCSs available. This allows for a better understanding of occupational health and could serve as a baseline for future research and surveillance of work and health in the Region. However, greater efforts are needed to improve WCSs comparability. PMID- 28093504 TI - A model of type 2 diabetes in the guinea pig using sequential diet-induced glucose intolerance and streptozotocin treatment. AB - Type 2 diabetes is a leading cause of morbidity and mortality among noncommunicable diseases, and additional animal models that more closely replicate the pathogenesis of human type 2 diabetes are needed. The goal of this study was to develop a model of type 2 diabetes in guinea pigs, in which diet induced glucose intolerance precedes beta-cell cytotoxicity, two processes that are crucial to the development of human type 2 diabetes. Guinea pigs developed impaired glucose tolerance after 8 weeks of feeding on a high-fat, high carbohydrate diet, as determined by oral glucose challenge. Diet-induced glucose intolerance was accompanied by beta-cell hyperplasia, compensatory hyperinsulinemia, and dyslipidemia with hepatocellular steatosis. Streptozotocin (STZ) treatment alone was ineffective at inducing diabetic hyperglycemia in guinea pigs, which failed to develop sustained glucose intolerance or fasting hyperglycemia and returned to euglycemia within 21 days after treatment. However, when high-fat, high-carbohydrate diet-fed guinea pigs were treated with STZ, glucose intolerance and fasting hyperglycemia persisted beyond 21 days post-STZ treatment. Guinea pigs with diet-induced glucose intolerance subsequently treated with STZ demonstrated an insulin-secretory capacity consistent with insulin independent diabetes. This insulin-independent state was confirmed by response to oral antihyperglycemic drugs, metformin and glipizide, which resolved glucose intolerance and extended survival compared with guinea pigs with uncontrolled diabetes. In this study, we have developed a model of sequential glucose intolerance and beta-cell loss, through high-fat, high-carbohydrate diet and extensive optimization of STZ treatment in the guinea pig, which closely resembles human type 2 diabetes. This model will prove useful in the study of insulin-independent diabetes pathogenesis with or without comorbidities, where the guinea pig serves as a relevant model species. PMID- 28093505 TI - Modeling the ferrochelatase c.315-48C modifier mutation for erythropoietic protoporphyria (EPP) in mice. AB - Erythropoietic protoporphyria (EPP) is caused by deficiency of ferrochelatase (FECH), which incorporates iron into protoporphyrin IX (PPIX) to form heme. Excitation of accumulated PPIX by light generates oxygen radicals that evoke excessive pain and, after longer light exposure, cause ulcerations in exposed skin areas of individuals with EPP. Moreover, ~5% of the patients develop a liver dysfunction as a result of PPIX accumulation. Most patients (~97%) have a severe FECH mutation (Mut) in trans to an intronic polymorphism (c.315-48C), which reduces ferrochelatase synthesis by stimulating the use of an aberrant 3' splice site 63 nt upstream of the normal site for exon 4. In contrast, with the predominant c.315-48T allele, the correct splice site is mostly used, and individuals with a T/Mut genotype do not develop EPP symptoms. Thus, the C allele is a potential target for therapeutic approaches that modify this splicing decision. To provide a model for pre-clinical studies of such approaches, we engineered a mouse containing a partly humanized Fech gene with the c.315-48C polymorphism. F1 hybrids obtained by crossing these mice with another inbred line carrying a severe Fech mutation (named m1Pas) show a very strong EPP phenotype that includes elevated PPIX in the blood, enlargement of liver and spleen, anemia, as well as strong pain reactions and skin lesions after a short period of light exposure. In addition to the expected use of the aberrant splice site, the mice also show a strong skipping of the partly humanized exon 3. This will limit the use of this model for certain applications and illustrates that engineering of a hybrid gene may have unforeseeable consequences on its splicing. PMID- 28093507 TI - Mosaic expression of Atrx in the mouse central nervous system causes memory deficits. AB - The rapid modulation of chromatin organization is thought to play a crucial role in cognitive processes such as memory consolidation. This is supported in part by the dysregulation of many chromatin-remodelling proteins in neurodevelopmental and psychiatric disorders. A key example is ATRX, an X-linked gene commonly mutated in individuals with syndromic and nonsyndromic intellectual disability. The consequences of Atrx inactivation for learning and memory have been difficult to evaluate because of the early lethality of hemizygous-null animals. In this study, we evaluated the outcome of brain-specific Atrx deletion in heterozygous female mice. These mice exhibit a mosaic pattern of ATRX protein expression in the central nervous system attributable to the location of the gene on the X chromosome. Although the hemizygous male mice die soon after birth, heterozygous females survive to adulthood. Body growth is stunted in these animals, and they have low circulating concentrations of insulin growth factor 1. In addition, they are impaired in spatial, contextual fear and novel object recognition memory. Our findings demonstrate that mosaic loss of ATRX expression in the central nervous system leads to endocrine defects and decreased body size and has a negative impact on learning and memory. PMID- 28093506 TI - The tyrosine kinase receptor Tyro3 enhances lifespan and neuropeptide Y (Npy) neuron survival in the mouse anorexia (anx) mutation. AB - Severe appetite and weight loss define the eating disorder anorexia nervosa, and can also accompany the progression of some neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Although acute loss of hypothalamic neurons that produce appetite-stimulating neuropeptide Y (Npy) and agouti-related peptide (Agrp) in adult mice or in mice homozygous for the anorexia (anx) mutation causes aphagia, our understanding of the factors that help maintain appetite regulatory circuitry is limited. Here we identify a mutation (C19T) that converts an arginine to a tryptophan (R7W) in the TYRO3 protein tyrosine kinase 3 (Tyro3) gene, which resides within the anx critical interval, as contributing to the severity of anx phenotypes. Our observation that, like Tyro3-/- mice, anx/anx mice exhibit abnormal secondary platelet aggregation suggested that the C19T Tyro3 variant might have functional consequences. Tyro3 is expressed in the hypothalamus and other brain regions affected by the anx mutation, and its mRNA localization appeared abnormal in anx/anx brains by postnatal day 19 (P19). The presence of wild-type Tyro3 transgenes, but not an R7W-Tyro3 transgene, doubled the weight and lifespans of anx/anx mice and near-normal numbers of hypothalamic Npy-expressing neurons were present in Tyro3-transgenic anx/anx mice at P19. Although no differences in R7W-Tyro3 signal sequence function or protein localization were discernible in vitro, distribution of R7W-Tyro3 protein differed from that of Tyro3 protein in the cerebellum of transgenic wild-type mice. Thus, R7W-Tyro3 protein localization deficits are only detectable in vivo Further analyses revealed that the C19T Tyro3 mutation is present in a few other mouse strains, and hence is not the causative anx mutation, but rather an anx modifier. Our work shows that Tyro3 has prosurvival roles in the appetite regulatory circuitry and could also provide useful insights towards the development of interventions targeting detrimental weight loss. PMID- 28093510 TI - De novo formation of a symptomatic arachnoid cyst in an adult. PMID- 28093508 TI - Vertical sleeve gastrectomy reduces blood pressure and hypothalamic endoplasmic reticulum stress in mice. AB - Bariatric surgery, such as vertical sleeve gastrectomy (VSG), causes remarkable improvements in cardiometabolic health, including hypertension remission. However, the mechanisms responsible remain undefined and poorly studied. Therefore, we developed and validated the first murine model of VSG that recapitulates the blood pressure-lowering effect of VSG using gold-standard radiotelemetry technology. We used this model to investigate several potential mechanisms, including body mass, brain endoplasmic reticulum (ER) stress signaling and brain inflammatory signaling, which are all critical contributors to the pathogenesis of obesity-associated hypertension. Mice fed on a high-fat diet underwent sham or VSG surgery and radiotelemeter implantation. Sham mice were fed ad libitum or were food restricted to match their body mass to VSG operated mice to determine the role of body mass in the ability of VSG to lower blood pressure. Blood pressure was then measured in freely moving unstressed mice by radiotelemetry. VSG decreased energy intake, body mass and fat mass. Mean arterial blood pressure (MAP) was reduced in VSG-operated mice compared with both sham-operated groups. VSG-induced reductions in MAP were accompanied by a body mass-independent decrease in hypothalamic ER stress, hypothalamic inflammation and sympathetic nervous system tone. Assessment of gut microbial populations revealed VSG-induced increases in the relative abundance of Gammaproteobacteria and Enterococcus, and decreases in Adlercreutzia These results suggest that VSG reduces blood pressure, but this is only partly due to the reduction in body weight. VSG-induced reductions in blood pressure may be driven by a decrease in hypothalamic ER stress and inflammatory signaling, and shifts in gut microbial populations. PMID- 28093512 TI - Letter re: The clinical spectrum of Caspr2 antibody-associated disease. PMID- 28093513 TI - Author response: The clinical spectrum of Caspr2 antibody-associated disease. PMID- 28093514 TI - Letter re: Huntington disease reduced penetrance alleles occur at high frequency in the general population. PMID- 28093515 TI - Author response: Huntington disease reduced penetrance alleles occur at high frequency in the general population. PMID- 28093516 TI - Tilt-induced vasovagal syncope and psychogenic pseudosyncope: Overlapping clinical entities. PMID- 28093517 TI - Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL). PMID- 28093518 TI - Clinical Reasoning: Sudden-onset pulsatile headache in a previously healthy young man. PMID- 28093519 TI - Teaching Video NeuroImages: Functional saccadic oculomotor disturbances. PMID- 28093520 TI - Teaching Video NeuroImages: Alternating horizontal single saccadic pulses in progressive supranuclear palsy. PMID- 28093521 TI - Oncostatin M Suppresses Activation of IL-17/Th17 via SOCS3 Regulation in CD4+ T Cells. AB - Oncostatin M (OSM) is a pleiotropic cytokine and a member of the IL-6 family. It has both proinflammatory and anti-inflammatory functions and is involved in the activation of STAT3 and STAT5. Rheumatoid arthritis is an autoimmune disease that causes chronic and excessive inflammation. Rheumatoid arthritis can lead to induction of Th17 cells, which express IL-17. The aim of this study was to measure the effects of OSM on the proliferation of regulatory T cells and Th17 cells from mice. IL-2 immune complex suppressed the development of collagen induced arthritis in mice and altered the regulatory T/Th17 cell balance by increasing OSM expression. OSM mitigated the proliferation of Th17 cells and decreased the expression of IL-17 and IL-21. It promoted the activation of suppressor of cytokine signaling 3 (SOCS3), STAT3, and STAT5. Inhibition of SOCS3, STAT3, and STAT5 lessened the OSM-induced reduction in proliferation of Th17 cells. These observations suggest that OSM can inhibit Th17 differentiation by reciprocally controlling SOCS3, STAT3, and STAT5. PMID- 28093522 TI - Cutting Edge: Human CD49e- NK Cells Are Tissue Resident in the Liver. AB - Most knowledge on NK cells is based on studies of what are now known as conventional NK cells in the mouse spleen or human peripheral blood. However, recent studies in mice indicate the presence of tissue-resident NK cells in certain organs, such as the liver, that display different markers and transcription factor dependencies as compared with conventional NK cells. In this study, we provide evidence from cytometry by time-of-flight analysis and humanized mice indicating that human CD49e- NK cells are tissue resident in the liver. Thus, these studies indicate that tissue-resident NK cells are evolutionarily conserved in humans and mice, providing a foundation to explore their role in human disease. PMID- 28093523 TI - Cutting Edge: NANOG Activates Autophagy under Hypoxic Stress by Binding to BNIP3L Promoter. AB - Hypoxia upregulates the core pluripotency factors NANOG, SOX2, and OCT4, associated with tumor aggressiveness and resistance to conventional anticancer treatments. We have previously reported that hypoxia-induced NANOG contributed in vitro to tumor cell resistance to autologous-specific CTL and in vivo to the in situ recruitment of immune-suppressive cells. In this study, we investigated the mechanisms underlying NANOG-mediated tumor cell resistance to specific lysis under hypoxia. We demonstrated the tumor-promoting effect of hypoxia on tumor initiation into immunodeficient mice using human non-small lung carcinoma cells. We next showed a link between NANOG and autophagy activation under hypoxia because inhibition of NANOG decreased autophagy in tumor cells. Chromatin immunoprecipitation and luciferase reporter assays revealed a direct binding of NANOG to a transcriptionally active site in a BNIP3L enhancer sequence. These data establish a new link between the pluripotency factor NANOG and autophagy involved in resistance to CTL under hypoxia. PMID- 28093524 TI - Age-Associated B Cells Express a Diverse Repertoire of VH and Vkappa Genes with Somatic Hypermutation. AB - The origin and nature of age-associated B cells (ABCs) in mice are poorly understood. In this article, we show that their emergence required MHC class II and CD40/CD40L interactions. Young donor B cells were adoptively transferred into congenic recipients and allowed to remain for 1 mo in the absence of external Ag. B cells expressing the T-bet transcription factor, a marker for ABCs, were generated after multiple cell divisions from C57BL/6 donors but not from MHC class II- or CD40-deficient donors. Furthermore, old CD154 (CD40L)-deficient mice did not accrue ABCs, confirming that they arise primarily through T-dependent interactions. To determine what Igs ABCs express, we sequenced VH and Vkappa rearranged genes from unimmunized 22-mo-old C57BL/6 mice and showed that they had a heterogeneous repertoire, which was comparable to that seen in old follicular and marginal zone B cell subsets. However, in contrast to the follicular and marginal zone cells, ABCs displayed significant somatic hypermutation. The mutation frequency was lower than found in germinal center cells after deliberate immunization, suggesting that ABCs have undergone mild stimulation from endogenous Ags over time. These observations show that quiescent ABCs are Ag experienced cells that accumulate during T cell-dependent responses to diverse Ags during the life of an individual. PMID- 28093525 TI - MAFB Determines Human Macrophage Anti-Inflammatory Polarization: Relevance for the Pathogenic Mechanisms Operating in Multicentric Carpotarsal Osteolysis. AB - Macrophage phenotypic and functional heterogeneity derives from tissue-specific transcriptional signatures shaped by the local microenvironment. Most studies addressing the molecular basis for macrophage heterogeneity have focused on murine cells, whereas the factors controlling the functional specialization of human macrophages are less known. M-CSF drives the generation of human monocyte derived macrophages with a potent anti-inflammatory activity upon stimulation. We now report that knockdown of MAFB impairs the acquisition of the anti inflammatory profile of human macrophages, identify the MAFB-dependent gene signature in human macrophages and illustrate the coexpression of MAFB and MAFB target genes in CD163+ tissue-resident and tumor-associated macrophages. The contribution of MAFB to the homeostatic/anti-inflammatory macrophage profile is further supported by the skewed polarization of monocyte-derived macrophages from multicentric carpotarsal osteolysis (Online Mendelian Inheritance in Man #166300), a pathology caused by mutations in the MAFB gene. Our results demonstrate that MAFB critically determines the acquisition of the anti inflammatory transcriptional and functional profiles of human macrophages. PMID- 28093529 TI - Anaplastic large cell lymphoma of the spinal cord. PMID- 28093527 TI - Human Cystic Fibrosis Macrophages Have Defective Calcium-Dependent Protein Kinase C Activation of the NADPH Oxidase, an Effect Augmented by Burkholderia cenocepacia. AB - Macrophage intracellular pathogen killing is defective in cystic fibrosis (CF), despite abundant production of reactive oxygen species (ROS) in lung tissue. Burkholderia species can cause serious infection in CF and themselves affect key oxidase components in murine non-CF cells. However, it is unknown whether human CF macrophages have an independent defect in the oxidative burst and whether Burkholderia contributes to this defect in terms of assembly of the NADPH oxidase complex and subsequent ROS production. In this article, we analyze CF and non-CF human monocyte-derived macrophages (MDMs) for ROS production, NADPH assembly capacity, protein kinase C expression, and calcium release in response to PMA and CF pathogens. CF MDMs demonstrate a nearly 60% reduction in superoxide production after PMA stimulation compared with non-CF MDMs. Although CF MDMs generally have increased total NADPH component protein expression, they demonstrate decreased expression of the calcium-dependent protein kinase C conventional subclass alpha/beta leading to reduced phosphorylation of NADPH oxidase components p47 phox and p40 phox in comparison with non-CF MDMs. Ingestion of B. cenocepacia independently contributes to and worsens the overall oxidative burst deficits in CF MDMs compared with non-CF MDMs. Together, these results provide evidence for inherent deficits in the CF macrophage oxidative burst caused by decreased phosphorylation of NADPH oxidase cytosolic components that are augmented by Burkholderia These findings implicate a critical role for defective macrophage oxidative responses in persistent bacterial infections in CF and create new opportunities for boosting the macrophage immune response to limit infection. PMID- 28093526 TI - Cathepsin K Deficiency Ameliorates Systemic Lupus Erythematosus-like Manifestations in Faslpr Mice. AB - Cysteinyl cathepsin K (CatK) is expressed in osteoclasts to mediate bone resorption, but is also inducible under inflammatory conditions. Faslpr mice on a C57BL/6 background develop spontaneous systemic lupus erythematosus-like manifestations. Although normal mouse kidneys expressed negligible CatK, those from Faslpr mice showed elevated CatK expression in the glomeruli and tubulointerstitial space. Faslpr mice also showed elevated serum CatK levels. CatK deficiency in Faslpr mice reduced all tested kidney pathologies, including glomerulus and tubulointerstitial scores, glomerulus complement C3 and IgG deposition, chemokine expression and macrophage infiltration, and serum autoantibodies. CatK contributed to Faslpr mouse autoimmunity and pathology in part by its activity in TLR-7 proteolytic processing and consequent regulatory T (Treg) cell biology. Elevated TLR7 expression and proteolytic processing in Faslpr mouse kidneys and Tregs showed significantly reduced levels in CatK deficient mice, leading to increased spleen and kidney Treg content. Purified CD4+CD25highFoxp3+ Tregs from CatK-deficient mice doubled their immunosuppressive activity against T effector cells, compared with those from CatK-sufficient mice. In Faslpr mice, repopulation of purified Tregs from CatK-sufficient mice reduced spleen sizes, autoantibody titers, and glomerulus C3 and IgG deposition, and increased splenic and kidney Treg contents. Tregs from CatK-deficient mice had significantly more potency than CatK-sufficient Tregs in reducing spleen sizes, serum autoantibody titers, and glomerulus C3 deposition, and in increasing splenic and kidney Treg content. This study established a possible role of CatK in TLR7 proteolytic activation, Treg immunosuppressive activity, and lupus autoimmunity and pathology. PMID- 28093530 TI - What causes occupational asthma in cleaners? PMID- 28093528 TI - A B Cell Epitope Peptide Derived from the Major Grass Pollen Allergen Phl p 1 Boosts Allergen-Specific Secondary Antibody Responses without Allergen-Specific T Cell Help. AB - More than 40% of allergic patients suffer from grass pollen allergy. Phl p 1, the major timothy grass pollen allergen, belongs to the cross-reactive group 1 grass pollen allergens that are thought to initiate allergic sensitization to grass pollen. Repeated allergen encounter boosts allergen-specific IgE production and enhances clinical sensitivity in patients. To investigate immunological mechanisms underlying the boosting of allergen-specific secondary IgE Ab responses and the allergen epitopes involved, a murine model for Phl p 1 was established. A B cell epitope-derived peptide of Phl p 1 devoid of allergen specific T cell epitopes, as recognized by BALB/c mice, was fused to an allergen unrelated carrier in the form of a recombinant fusion protein and used for sensitization. This fusion protein allowed the induction of allergen-specific IgE Ab responses without allergen-specific T cell help. Allergen-specific Ab responses were subsequently boosted with molecules containing the B cell epitope derived peptide without carrier or linked to other allergen-unrelated carriers. Oligomeric peptide bound to a carrier different from that which had been used for sensitization boosted allergen-specific secondary IgE responses without a detectable allergen-specific T cell response. Our results indicate that allergen specific secondary IgE Ab responses can be boosted by repetitive B cell epitopes without allergen-specific T cell help by cross-linking of the B cell epitope receptor. This finding has important implications for the design of new allergy vaccines. PMID- 28093531 TI - Lifestyle Factors and Early Clinical Outcome in Patients With Acute Stroke: A Population-Based Study. AB - BACKGROUND AND PURPOSE: We examined the associations of individual and combined lifestyle factors with early adverse stroke outcomes. METHODS: A total of 82 597 patients were identified from nationwide registries. Lifestyle factors at the time of stroke admission included body mass index (kg/m2), smoking habits, and alcohol intake, which were grouped (healthy, moderately healthy, moderately unhealthy, and unhealthy). The associations between lifestyle and outcomes were examined using multivariable regression. RESULTS: A total of 18.3% had a severe stroke, 7.8% pneumonia, 12.5% urinary tract infection, and 9.9% died within 30 days. The association between lifestyle, stroke severity, and mortality, respectively, differed according to sex. Unhealthy lifestyle was associated with lower risk of severe stroke (adjusted odds ratio [OR], 0.73; 95% confidence interval [CI], 0.63-0.84) and 30-day mortality among men (adjusted OR, 0.71; 95% CI, 0.58-0.87), but not among women (severe stroke: adjusted OR, 1.14; 95% CI, 0.85-1.55, and mortality: adjusted OR, 1.34; 95% CI, 0.90-1.99). No sex differences were found for pneumonia and urinary tract infection. Unhealthy lifestyle was not associated with a statistically significant increased risk of developing in-hospital pneumonia (adjusted OR, 1.30; 95% CI, 0.98-1.73) or urinary tract infection (adjusted OR, 0.98; 95% CI, 0.72-1.33). Underweight was associated with a higher 30-day mortality (men: adjusted OR, 1.71; 95% CI, 1.50 1.96, and women: adjusted OR, 1.46; 95% CI, 1.34-1.60). CONCLUSIONS: Healthy lifestyle was not associated with a lower risk of adverse stroke outcomes, in particularly among men. However, underweight may be a particular concern being associated with an increased risk of adverse outcomes among both sexes. PMID- 28093532 TI - Soil Ingestion is Associated with Child Diarrhea in an Urban Slum of Nairobi, Kenya. AB - Diarrhea is a leading cause of mortality in children under 5 years of age. We conducted a cross-sectional study of 54 children aged 3 months to 5 years old in Kibera, an urban slum in Nairobi, Kenya, to assess the relationship between caregiver-reported soil ingestion and child diarrhea. Diarrhea was significantly associated with soil ingestion (adjusted odds ratio = 9.9, 95% confidence interval = 2.1-47.5). Soil samples from locations near each household were also collected and analyzed for Escherichia coli and a human-associated Bacteroides fecal marker (HF183). Escherichia coli was detected in 100% of soil samples (mean 5.5 log colony forming units E. coli per gram of dry soil) and the Bacteroides fecal marker HF183 was detected in 93% of soil samples. These findings suggest that soil ingestion may be an important transmission pathway for diarrheal disease in urban slum settings. PMID- 28093533 TI - Effect of Deworming on Indices of Health, Cognition, and Education Among Schoolchildren in Rural China: A Cluster-Randomized Controlled Trial. AB - AbstractSoil-transmitted helminths (STHs) infect over one billion people worldwide. There is concern that chronic infection with STHs among school-aged children may detrimentally affect their development, including their health, cognition, and education. However, two recent Cochrane reviews examining the impact of deworming drugs for STH on nutrition, hemoglobin, and school performance found that randomized controlled trials (RCTs) in the literature provide an insufficient evidence base to draw reliable conclusions. This study uses a cluster-RCT to add to existing evidence by assessing the impact of a deworming intervention on nutrition, cognition, and school performance among schoolchildren in rural China. The intervention, implemented by local health practitioners in a setting with a baseline infection prevalence of 41.9% (95% confidence interval [CI] = 39.8%, 43.9%) and infection intensity of 599.5 eggs per gram of feces among positive-tested schoolchildren (95% CI = 473.2, 725.8), consisted of distributing a 400-mg dose of albendazole accompanied with educational training about STH infection, treatment, and prevention. The intervention was conducted twice over the course of the study-at baseline in May 2013 and later in November 2013. We found that the deworming intervention reduced both infection prevalence and infection intensity, but these declines in infection were not accompanied by an impact on outcomes of nutrition, cognition, or school performance. Our interpretation is that the impact of deworming was attenuated by the light infection intensity in our sample population. Evidence from future RCTs is needed to assess the effect of deworming on key outcomes in areas with moderate and severe worm infections. PMID- 28093534 TI - The Role of Adherence on the Impact of a School-Based Water, Sanitation, and Hygiene Intervention in Mali. AB - AbstractStudies assessing the impacts of school-based water, sanitation, and hygiene (WASH) interventions have revealed inconsistent improvements in pupils' health and educational outcomes. This may be in part due to suboptimal project fidelity or adherence. As part of a matched-control trial of a comprehensive school-based WASH project in Mali, we measured the degree to which schools met four prespecified WASH targets, comprised of 15 criteria, 0-3 years after program implementation. We compared achievement of the targets and criteria between beneficiary and matched control schools, and compared achievement within beneficiary schools at baseline and at follow-up visits. We assessed the "as treated" associations between WASH target achievement and pupil diarrhea, respiratory symptoms, and absence. Between 44% and 81% of beneficiary schools achieved each target. Although adherence was inconsistent across schools, beneficiary schools, on average, met more WASH targets than matched control schools, and beneficiary schools also met more WASH targets at follow-up than at baseline. Very few of the targets were individually associated with health and absenteeism outcomes. Increasing achievement of multiple WASH targets together was associated with a lower odds of pupils having diarrhea (P trend < 0.01) and having respiratory symptoms (P trend < 0.01), but was not associated with roll call absence (P trend = 0.14) or pupil-reported absence (P trend = 0.41). These results indicate that a comprehensive WASH intervention and a focus on increasing adherence may help maximize the health effects of school WASH programs, but that WASH alone might not be sufficient to decrease pupils' absenteeism. PMID- 28093535 TI - Hepatitis E in Singapore: A Case-Series and Viral Phylodynamics Study. AB - AbstractThe incidence of hepatitis E in Singapore appears to be increasing. A retrospective case-series study of patients diagnosed with hepatitis E in a tertiary hospital from 2009 to 2013 was conducted. Of 16 cases, eight (50%) were solid-organ transplant recipients (SOTRs), and 14 (88%) were found infected by genotype 3 hepatitis E virus (HEV-3). Bayesian inferences based on HEV subgenomic sequences from seven cases suggest that HEV-3 strains were introduced to Singapore as two principal lineages. Within limitations of the study, it can be inferred that one lineage, in the 3efg clade, emerged about 83 years ago, probably originating from Japan, whereas the other, in the 3abchij clade, emerged about 40 years ago, from the United States. Establishment and subsequent transmissions of strains from these two lineages likely contribute to the current endemicity of hepatitis E in Singapore. PMID- 28093536 TI - Noma: Overview of a Neglected Disease and Human Rights Violation. AB - Noma is an orofacial gangrene affecting malnourished children and mainly observed in tropical countries, particularly sub-Saharan Africa. Epidemiological data on noma are scarce, but a current estimate of the global incidence is 30,000-40,000 cases per year, with a mortality rate of approximately 85% and a burden of disease calculated to be a loss of 1-10 million disability-adjusted life years. The etiology of noma is multifactorial with malnutrition as an ever present factor, often in combination with concomitant diseases, such as measles, malaria, and human immunodeficiency virus (HIV), and poor oral hygiene. The pathogenesis is a fast-spreading, noncontagious gangrenous infection occurring in the face, often preceded by acute necrotizing gingivitis, and stomatitis. Rare microbiological studies suggest an opportunistic infection caused by an imbalance in normal intraoral microorganisms. Prevention lies in food security, measles vaccination, prevention of malaria and HIV, including the early detection and treatment of necrotizing gingivitis and stomatitis. Early treatment with antibiotics may prevent gangrene or reduce its extent. Late treatment consists of surgical rehabilitation, which is often complex. However, access to medical care is very limited for noma patients due to the extremely poor conditions in which they live that are frequently located in remote rural areas. The authors support the United Nations Human Rights Council Resolution 19/7 adopted on March 22, 2012 "The right to food," and advocate for the inclusion of noma on the list of neglected tropical diseases to encourage more medical and institutional attention for this often lethal or very mutilating infectious gangrene. PMID- 28093537 TI - Dengue Epidemic in Postconflict Swat District, Khyber Pakhtunkhwa, Pakistan, 2013. AB - AbstractSwat, a lush green valley of 1.3 million persons, remained under militant insurgency from 2007 to 2009, which damaged the health infrastructure. An outbreak of dengue fever (DF) was declared in the valley in 2013. To investigate this outbreak, we established active surveillance of national hospitals and private clinics, reviewed available clinical and laboratory records, and conducted entomological survey. From August to November 2013, 16,000 suspected patients with acute febrile illness were presented to health facilities. Among those, 9,036 were confirmed positive for DF by clinical manifestation and presence of nonstructural protein 1-soluble antigen. Of 9,036 patients, majority were men and aged 21-40. The epidemic peaked in September 2013 (N = 6,487). The attack rate was 7.18/1,000 populations. Among the confirmed case-patients, 36 deaths were reported, and proportion of mortality was 0.4%. Each year, increase in age was significantly associated with risk of complication due to DF leading to death (P < 0.001). PMID- 28093538 TI - Prevalence and Determinants of Cryptosporidium Infection in an Underdeveloped Rural Region of Southwestern China. AB - Few studies have focused on the epidemiology of Cryptosporidium in resource challenged settings in China. We report a community-based cross-sectional study to investigate the prevalence of Cryptosporidium infection and its risk factors and associations with hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) infections. The prevalence of Cryptosporidium infection was 12.6% (95% confidence interval = 11.0-14.3). Individuals living in households with >= 5 family members and raising domestic pigs tended to have a greater risk of Cryptosporidium infection. In addition, Cryptosporidium infection was significantly associated with HBV infection. There were no significant associations of Cryptosporidium infection with HIV viral load and HBV viral load. Further studies are needed to determine the association of Cryptosporidium infection with HBV infection. PMID- 28093539 TI - Leishmaniasis in Thailand: A Review of Causative Agents and Situations. AB - Before 1999, leishmaniasis was considered an imported disease in Thailand. Since then, autochthonous leishmaniasis was reported in both immmunocompetent and immmunocompromised patients especially in human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). A new species was identified and named as Leishmania siamensis consisting of two lineages, that is, lineages TR and PG. Analysis of isoenzymes has clarified the more commonly detected L. siamensis lineage PG as Leishmania martiniquensis (MON-229), a species originally reported from the Martinique Island, whereas the L. siamensis lineage TR has been identified as the true novel species, L. siamensis (MON-324). Both cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL) have been found among Thai patients. Disseminated CL and VL could be presented in some reported patients who had HIV/AIDS coinfection. So far, only sporadic cases have been reported; thus, the true prevalence of leishmaniasis should be determined in Thailand among the high-risk populations such as people with HIV/AIDS. A recent survey among animals identified L. martiniquensis DNA in black rats (Rattus rattus) suggesting a potential animal reservoir. In addition, L. martiniquensis DNA was identified in Sergentomyia gemmea and Sergentomyia barraudi, the predominant sandfly species in the affected areas. However, further studies are needed to prove that these sandflies could serve as the vector of leishmaniasis in Thailand. PMID- 28093540 TI - Human Granulocytic Anaplasmosis as a Cause of Febrile Illness in Korea Since at Least 2006. AB - AbstractHuman granulocytic anaplasmosis (HGA) is a tick-borne rickettsial zoonosis with fever, thrombocytopenia, and leukopenia. HGA has been reported in Korea in 2013 but it is uncertain how long it has existed. A retrospective study was conducted on patients who underwent bone marrow examination due to fever and cytopenia, with no clear hematologic or microbiologic causes, from 2003 through 2012. Laboratory diagnosis was made by detecting 16S rRNA genes of Anaplasma phagocytophilum from the stored blood samples. Among the 70 patients, five (7.1%) HGA cases were found, and the earliest case dated back to 2006. Two cases met the diagnostic criteria of hemophagocytic lymphohistiocytosis (HLH) and were fatal. Although HGA has been prevalent in Korea since at least 2006, it is not always diagnosed and has posed a possible lethal health risk to the people in Korea. HGA should be considered as a cause of fever with cytopenia or HLH. PMID- 28093541 TI - Association of Toll-Like Receptor 3 and Toll-Like Receptor 9 Single Nucleotide Polymorphisms with Hepatitis C Virus Infection and Hepatic Fibrosis in Egyptian Patients. AB - Toll-like receptors (TLRs) are recognized as fundamental contributors to the immune system function against infections. Hepatitis C virus (HCV) infection represents a global health problem especially in Egypt having the highest HCV prevalence worldwide where HCV infection is a continuing epidemic. The aim of the present study was to investigate the possible association between genetic variation in TLR-3 and TLR-9 and HCV infection and hepatic fibrosis in chronic HCV-positive Egyptian patients. The present study included 100 naive chronic HCV positive patients and 100 age- and sex-matched healthy controls. Genotyping of TLR-3 (_7 C/A [rs3775296]), TLR-3 (c.1377C/T [rs3775290]) and TLR-9 (1237T/C [rs5743836]) were done by polymerase chain reaction restriction fragment length polymorphism technique. Frequency of polymorphic genotypes in TLR-3 (_7 C/A), TLR 3 (c.1377C/T) and TLR-9 (1237T/C) were not significantly different between studied HCV-positive patients and controls with P values 0.121, 0.112, and 0.683, respectively. TLR-3 c.1377 T-allele was associated with advanced stage of hepatic fibrosis (P = 0.003). PMID- 28093542 TI - Disease Burden of Dengue in the Philippines: Adjusting for Underreporting by Comparing Active and Passive Dengue Surveillance in Punta Princesa, Cebu City. AB - AbstractDengue virus (DENV) is a serious threat to public health. Having reliable estimates of the burden of dengue is important to inform policy and research, but surveillance systems are not designed to capture all symptomatic DENV infections. We derived the rate of reporting of dengue by comparing active surveillance of symptomatic DENV infections in a prospective community-based seroepidemiological cohort study (N = 1008) of acute febrile illness in Punta Princesa, Cebu City, Philippines, with passive surveillance data from the Cebu City Health Department. Febrile episodes detected in a weekly follow-up of participants were tested for serotype-specific DENV by hemi-nested reverse transcription-polymerase chain reaction (nested RT-PCR) and acute/convalescent blood samples tested by dengue IgM/IgG enzyme immunoassay. We estimated the burden of dengue in the Philippines in disability-adjusted life years (DALYs), and conducted a probabilistic sensitivity analysis using Monte-Carlo simulations to address uncertainty. The results showed a 21% cumulative reporting rate of symptomatic DENV infections, equivalent to an expansion factor of 4.7 (95% certainty level [CL]: 2.2-15.1). Based on surveillance data in the Philippines for 2010-2014, we estimated 794,255 annual dengue episodes (95% CL: 463,000-2,076,000) and a disease burden of 535 (95% CL: 380-994) DALYs per million population using age weights and time discounting and 997 (95% CL: 681-1,871) DALYs per million population without age and time adjustments. Dengue imposes a substantial burden in the Philippines; almost 10 times higher than estimated for rabies, about twice the burden of intestinal fluke infections, and about 10% of the burden of tuberculosis. Our estimates should inform policy makers and raise awareness among the public. PMID- 28093543 TI - Intestinal Parasite Infections and Accuracy of Direct Thin and Thick Smear, Formol-Ether Sedimentation, Centrifugal Flotation, and Mini-FLOTAC Techniques Among Patients with Gastrointestinal Tract Disorders from the Greater Cairo Region, Egypt. AB - The aim of the present study was to assess the frequency of intestinal parasitic infection among patients with gastrointestinal tract disorders from the Greater Cairo region, Egypt. In addition, a comparison was made of the accuracy of direct thin and thick smear, formol-ether sedimentation (FEC), centrifugal flotation (CF), and mini-FLOTAC techniques in the diagnosis of infection. Out of 100 patients, the overall prevalence of parasitic infection was 51%. Only 6% had dual infection. Giardia lamblia was the most common parasite (26%), followed by Hymenolepis nana (20%), Entamoeba coli (8%), and Enterobius vermicularis (3%). Except the statistically significant association between E. vermicularis infection and perianal itching and insomnia (P < 0.001), age, gender, and complaints of the examined individuals had no association with prevalence of parasitic infection. Both FEC and CF were equally the most accurate techniques (accuracy = 98.2%, confidence interval [CI] = 0.95-1.0, and kappa index = 0.962), whereas the Kato-Katz method was the least accurate (accuracy = 67.5%, CI = 0.57 0.78, and kappa index = 0.333). However, mini-FLOTAC-ZnSO4 was the most accurate for diagnosis of helminthic infection, and FEC was more accurate for diagnosis of protozoal infection (accuracy = 100%, CI = 1.0-1.0, and kappa index = 1). PMID- 28093544 TI - Annual Incidence of Lassa Virus Infection in Southern Mali. AB - AbstractPreviously, we reported a high seroprevalence rate of Lassa virus antibodies in inhabitants of three villages in southern Mali where infected rodents have been demonstrated. Herein, we report a 1-year follow-up study in which we were able to collect a second blood samples from 88.7% of participants of the same cohort. We identified 23 seroconversions for IgG antibodies reactive against Lassa virus, representing an incidence of 6.3% (95% confidence interval = 3.8-8.8%). Seroconversion was frequently seen in preteenage children (12/23, 51.7%) and two household/familial clusters were identified. These results confirm active transmission of Lassa virus is occurring in southern Mali and appropriate diagnostic testing should be established for this etiological agent of severe viral hemorrhagic fever. PMID- 28093545 TI - Die Another Day, James Bond's smoking over six decades. AB - We aimed to examine smoking-related content in all 24 James Bond movies in the Eon Productions series from 1962 to 2015. There were favourable downward trends for any smoking by James Bond (p=0.015 for trend), and for tobacco-related spy gadgetry (p=0.009). Around 20% of Bond's 60 sexual partners smoked in each decade, and most recently in 2012. There were regular mentions of smoking risks to health (starting from 1967) and product placement of branded packs was present in two movies. Overall, the persisting smoking content remains problematic from a public health perspective, especially given the popularity of this movie series. PMID- 28093546 TI - Time-course and mechanisms of homeostatic plasticity in layers 2/3 and 5 of the barrel cortex. AB - Recent studies have shown that ocular dominance plasticity in layer 2/3 of the visual cortex exhibits a form of homeostatic plasticity that is related to synaptic scaling and depends on TNFalpha. In this study, we tested whether a similar form of plasticity was present in layer 2/3 of the barrel cortex and, therefore, whether the mechanism was likely to be a general property of cortical neurons. We found that whisker deprivation could induce homeostatic plasticity in layer 2/3 of barrel cortex, but not in a mouse strain lacking synaptic scaling. The time-course of homeostatic plasticity in layer 2/3 was similar to that of L5 regular spiking (RS) neurons (L5RS), but slower than that of L5 intrinsic bursting (IB) neurons (L5IB). In layer 5, the strength of evoked whisker responses and ex vivo miniature excitatory post-synaptic currents (mEPSCs) amplitudes showed an identical time-course for homeostatic plasticity, implying that plasticity at excitatory synapses contacting layer 5 neurons is sufficient to explain the changes in evoked responses. Spontaneous firing rate also showed homeostatic behaviour for L5IB cells, but was absent for L5RS cells over the time course studied. Spontaneous firing rate homeostasis was found to be independent of evoked response homeostasis suggesting that the two depend on different mechanisms.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'. PMID- 28093547 TI - Functional consequences of pre- and postsynaptic expression of synaptic plasticity. AB - Growing experimental evidence shows that both homeostatic and Hebbian synaptic plasticity can be expressed presynaptically as well as postsynaptically. In this review, we start by discussing this evidence and methods used to determine expression loci. Next, we discuss the functional consequences of this diversity in pre- and postsynaptic expression of both homeostatic and Hebbian synaptic plasticity. In particular, we explore the functional consequences of a biologically tuned model of pre- and postsynaptically expressed spike-timing dependent plasticity complemented with postsynaptic homeostatic control. The pre- and postsynaptic expression in this model predicts (i) more reliable receptive fields and sensory perception, (ii) rapid recovery of forgotten information (memory savings), and (iii) reduced response latencies, compared with a model with postsynaptic expression only. Finally, we discuss open questions that will require a considerable research effort to better elucidate how the specific locus of expression of homeostatic and Hebbian plasticity alters synaptic and network computations.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'. PMID- 28093548 TI - Astrocytic control of synaptic function. AB - Astrocytes intimately interact with synapses, both morphologically and, as evidenced in the past 20 years, at the functional level. Ultrathin astrocytic processes contact and sometimes enwrap the synaptic elements, sense synaptic transmission and shape or alter the synaptic signal by releasing signalling molecules. Yet, the consequences of such interactions in terms of information processing in the brain remain very elusive. This is largely due to two major constraints: (i) the exquisitely complex, dynamic and ultrathin nature of distal astrocytic processes that renders their investigation highly challenging and (ii) our lack of understanding of how information is encoded by local and global fluctuations of intracellular calcium concentrations in astrocytes. Here, we will review the existing anatomical and functional evidence of local interactions between astrocytes and synapses, and how it underlies a role for astrocytes in the computation of synaptic information.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'. PMID- 28093549 TI - A metaplasticity view of the interaction between homeostatic and Hebbian plasticity. AB - Hebbian and homeostatic plasticity are two major forms of plasticity in the nervous system: Hebbian plasticity provides a synaptic basis for associative learning, whereas homeostatic plasticity serves to stabilize network activity. While achieving seemingly very different goals, these two types of plasticity interact functionally through overlapping elements in their respective mechanisms. Here, we review studies conducted in the mammalian central nervous system, summarize known circuit and molecular mechanisms of homeostatic plasticity, and compare these mechanisms with those that mediate Hebbian plasticity. We end with a discussion of 'local' homeostatic plasticity and the potential role of local homeostatic plasticity as a form of metaplasticity that modulates a neuron's future capacity for Hebbian plasticity.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'. PMID- 28093550 TI - Experience-dependent homeostasis of 'noise' at inhibitory synapses preserves information coding in adult visual cortex. AB - Synapses are intrinsically 'noisy' in that neurotransmitter is occasionally released in the absence of an action potential. At inhibitory synapses, the frequency of action potential-independent release is orders of magnitude higher than that at excitatory synapses raising speculations that it may serve a function. Here we report that the frequency of action potential-independent inhibitory synaptic 'noise' (i.e. miniature inhibitory postsynaptic currents, mIPSCs) is highly regulated by sensory experience in visual cortex. Importantly, regulation of mIPSC frequency is so far the predominant form of functional plasticity at inhibitory synapses in adults during the refractory period for plasticity and is a locus of rapid non-genomic actions of oestrogen. Models predict that regulating the frequency of mIPSCs, together with the previously characterized synaptic scaling of miniature excitatory PSCs, allows homeostatic maintenance of both the mean and variance of inputs to a neuron, a necessary feature of probabilistic population codes. Furthermore, mIPSC frequency regulation allows preservation of the temporal profile of neural responses while homeostatically regulating the overall firing rate. Our results suggest that the control of inhibitory 'noise' allows adaptive maintenance of adult cortical function in tune with the sensory environment.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'. PMID- 28093551 TI - Multiple shared mechanisms for homeostatic plasticity in rodent somatosensory and visual cortex. AB - We compare the circuit and cellular mechanisms for homeostatic plasticity that have been discovered in rodent somatosensory (S1) and visual (V1) cortex. Both areas use similar mechanisms to restore mean firing rate after sensory deprivation. Two time scales of homeostasis are evident, with distinct mechanisms. Slow homeostasis occurs over several days, and is mediated by homeostatic synaptic scaling in excitatory networks and, in some cases, homeostatic adjustment of pyramidal cell intrinsic excitability. Fast homeostasis occurs within less than 1 day, and is mediated by rapid disinhibition, implemented by activity-dependent plasticity in parvalbumin interneuron circuits. These processes interact with Hebbian synaptic plasticity to maintain cortical firing rates during learned adjustments in sensory representations.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'. PMID- 28093553 TI - Enhancement of visual cortex plasticity by dark exposure. AB - Dark rearing is known to delay the time course of the critical period for ocular dominance plasticity in the visual cortex. Recent evidence suggests that a period of dark exposure (DE) may enhance or reinstate plasticity even after closure of the critical period, mediated through modification of the excitatory-inhibitory balance and/or removal of structural brakes on plasticity. Here, we investigated the effects of a week of DE on the recovery from a month of monocular deprivation (MD) in the primary visual cortex (V1) of juvenile mice. Optical imaging of intrinsic signals revealed that ocular dominance in V1 of mice that had received DE recovered slightly more quickly than of mice that had not, but the level of recovery after three weeks was similar in both groups. Two-photon calcium imaging showed no significant difference in the recovery of orientation selectivity of excitatory neurons between the two groups. Parvalbumin-positive (PV+) interneurons exhibited a smaller ocular dominance shift during MD but again no differences in subsequent recovery. The percentage of PV+ cells surrounded by perineuronal nets, a structural brake on plasticity, was lower in mice with than those without DE. Overall, DE causes a modest enhancement of mouse visual cortex plasticity.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'. PMID- 28093552 TI - Integrating Hebbian and homeostatic plasticity: the current state of the field and future research directions. AB - We summarize here the results presented and subsequent discussion from the meeting on Integrating Hebbian and Homeostatic Plasticity at the Royal Society in April 2016. We first outline the major themes and results presented at the meeting. We next provide a synopsis of the outstanding questions that emerged from the discussion at the end of the meeting and finally suggest potential directions of research that we believe are most promising to develop an understanding of how these two forms of plasticity interact to facilitate functional changes in the brain.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'. PMID- 28093554 TI - Tumour necrosis factor-mediated homeostatic synaptic plasticity in behavioural models: testing a role in maternal immune activation. AB - The proinflammatory cytokine tumour necrosis factor-alpha (TNFalpha) has long been characterized for its role in the innate immune system, but more recently has been found to have a distinct role in the nervous system that does not overlap with other proinflammatory cytokines. Through regulation of neuronal glutamate and GABA receptor trafficking, TNF mediates a homeostatic form of synaptic plasticity, but plays no direct role in Hebbian forms of plasticity. As yet, there is no evidence to suggest that this adaptive plasticity plays a significant role in normal development, but it does maintain neuronal circuit function in the face of several types of disruption. This includes developmental plasticity in primary sensory cortices, as well as modulating the response to antidepressants, chronic antipsychotics and drugs of abuse. TNF is also a prominent component of the neuroinflammation occurring in most neuropathologies, but the role of TNF-mediated synaptic plasticity in this context remains to be determined. We tested this in a maternal immune activation (MIA) model of neurodevelopmental disorders. Using TNF-/- mice, we observed that TNF is not required for the expression of abnormal social or anxious behaviour in this model. This indicates that TNF does not uniquely contribute to the development of neuronal dysfunction in this model, and suggests that during neuroinflammatory events, compensation between the various proinflammatory cytokines is the norm.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'. PMID- 28093555 TI - Variance and invariance of neuronal long-term representations. AB - The brain extracts behaviourally relevant sensory input to produce appropriate motor output. On the one hand, our constantly changing environment requires this transformation to be plastic. On the other hand, plasticity is thought to be balanced by mechanisms ensuring constancy of neuronal representations in order to achieve stable behavioural performance. Yet, prominent changes in synaptic strength and connectivity also occur during normal sensory experience, indicating a certain degree of constitutive plasticity. This raises the question of how stable neuronal representations are on the population level and also on the single neuron level. Here, we review recent data from longitudinal electrophysiological and optical recordings of single-cell activity that assess the long-term stability of neuronal stimulus selectivities under conditions of constant sensory experience, during learning, and after reversible modification of sensory input. The emerging picture is that neuronal representations are stabilized by behavioural relevance and that the degree of long-term tuning stability and perturbation resistance directly relates to the functional role of the respective neurons, cell types and circuits. Using a 'toy' model, we show that stable baseline representations and precise recovery from perturbations in visual cortex could arise from a 'backbone' of strong recurrent connectivity between similarly tuned cells together with a small number of 'anchor' neurons exempt from plastic changes.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'. PMID- 28093556 TI - The dialectic of Hebb and homeostasis. AB - It has become widely accepted that homeostatic and Hebbian plasticity mechanisms work hand in glove to refine neural circuit function. Nonetheless, our understanding of how these fundamentally distinct forms of plasticity compliment (and under some circumstances interfere with) each other remains rudimentary. Here, I describe some of the recent progress of the field, as well as some of the deep puzzles that remain. These include unravelling the spatial and temporal scales of different homeostatic and Hebbian mechanisms, determining which aspects of network function are under homeostatic control, and understanding when and how homeostatic and Hebbian mechanisms must be segregated within neural circuits to prevent interference.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'. PMID- 28093557 TI - Hebbian plasticity requires compensatory processes on multiple timescales. AB - We review a body of theoretical and experimental research on Hebbian and homeostatic plasticity, starting from a puzzling observation: while homeostasis of synapses found in experiments is a slow compensatory process, most mathematical models of synaptic plasticity use rapid compensatory processes (RCPs). Even worse, with the slow homeostatic plasticity reported in experiments, simulations of existing plasticity models cannot maintain network stability unless further control mechanisms are implemented. To solve this paradox, we suggest that in addition to slow forms of homeostatic plasticity there are RCPs which stabilize synaptic plasticity on short timescales. These rapid processes may include heterosynaptic depression triggered by episodes of high postsynaptic firing rate. While slower forms of homeostatic plasticity are not sufficient to stabilize Hebbian plasticity, they are important for fine-tuning neural circuits. Taken together we suggest that learning and memory rely on an intricate interplay of diverse plasticity mechanisms on different timescales which jointly ensure stability and plasticity of neural circuits.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'. PMID- 28093559 TI - Gradation (approx. 10 size states) of synaptic strength by quantal addition of structural modules. AB - Memory storage involves activity-dependent strengthening of synaptic transmission, a process termed long-term potentiation (LTP). The late phase of LTP is thought to encode long-term memory and involves structural processes that enlarge the synapse. Hence, understanding how synapse size is graded provides fundamental information about the information storage capability of synapses. Recent work using electron microscopy (EM) to quantify synapse dimensions has suggested that synapses may structurally encode as many as 26 functionally distinct states, which correspond to a series of proportionally spaced synapse sizes. Other recent evidence using super-resolution microscopy has revealed that synapses are composed of stereotyped nanoclusters of alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA) receptors and scaffolding proteins; furthermore, synapse size varies linearly with the number of nanoclusters. Here we have sought to develop a model of synapse structure and growth that is consistent with both the EM and super-resolution data. We argue that synapses are composed of modules consisting of matrix material and potentially one nanocluster. LTP induction can add a trans-synaptic nanocluster to a module, thereby converting a silent module to an AMPA functional module. LTP can also add modules by a linear process, thereby producing an approximately 10-fold gradation in synapse size and strength.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'. PMID- 28093558 TI - Glutamatergic synapses are structurally and biochemically complex because of multiple plasticity processes: long-term potentiation, long-term depression, short-term potentiation and scaling. AB - Synapses are complex because they perform multiple functions, including at least six mechanistically different forms of plasticity. Here, I comment on recent developments regarding these processes. (i) Short-term potentiation (STP), a Hebbian process that requires small amounts of synaptic input, appears to make strong contributions to some forms of working memory. (ii) The rules for long term potentiation (LTP) induction in CA3 have been clarified: induction does not depend obligatorily on backpropagating sodium spikes but, rather, on dendritic branch-specific N-methyl-d-aspartate (NMDA) spikes. (iii) Late LTP, a process that requires a dopamine signal (and is therefore neoHebbian), is mediated by trans-synaptic growth of the synapse, a growth that occurs about an hour after LTP induction. (iv) LTD processes are complex and include both homosynaptic and heterosynaptic forms. (v) Synaptic scaling produced by changes in activity levels are not primarily cell-autonomous, but rather depend on network activity. (vi) The evidence for distance-dependent scaling along the primary dendrite is firm, and a plausible structural-based mechanism is suggested.Ideas about the mechanisms of synaptic function need to take into consideration newly emerging data about synaptic structure. Recent super-resolution studies indicate that glutamatergic synapses are modular (module size 70-80 nm), as predicted by theoretical work. Modules are trans-synaptic structures and have high concentrations of postsynaptic density-95 (PSD-95) and alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA) receptor. These modules function as quasi independent loci of AMPA-mediated transmission and may be independently modifiable, suggesting a new understanding of quantal transmission.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity.' PMID- 28093560 TI - Integrating Hebbian and homeostatic plasticity: introduction. AB - Hebbian plasticity is widely considered to be the mechanism by which information can be coded and retained in neurons in the brain. Homeostatic plasticity moves the neuron back towards its original state following a perturbation, including perturbations produced by Hebbian plasticity. How then does homeostatic plasticity avoid erasing the Hebbian coded information? To understand how plasticity works in the brain, and therefore to understand learning, memory, sensory adaptation, development and recovery from injury, requires development of a theory of plasticity that integrates both forms of plasticity into a whole. In April 2016, a group of computational and experimental neuroscientists met in London at a discussion meeting hosted by the Royal Society to identify the critical questions in the field and to frame the research agenda for the next steps. Here, we provide a brief introduction to the papers arising from the meeting and highlight some of the themes to have emerged from the discussions.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'. PMID- 28093561 TI - Homeostatic plasticity mechanisms in mouse V1. AB - Mechanisms thought of as homeostatic must exist to maintain neuronal activity in the brain within the dynamic range in which neurons can signal. Several distinct mechanisms have been demonstrated experimentally. Three mechanisms that act to restore levels of activity in the primary visual cortex of mice after occlusion and restoration of vision in one eye, which give rise to the phenomenon of ocular dominance plasticity, are discussed. The existence of different mechanisms raises the issue of how these mechanisms operate together to converge on the same set points of activity.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'. PMID- 28093562 TI - Factors Associated with a Family's Delay of Decision for Organ Donation After Brain Death. AB - BACKGROUND This study aimed to explore the factors associated with a family's delay of decision for organ donation after brain death, and to investigate the effect of such a delay on organ donation. MATERIAL AND METHODS Medical records and data on counseling about organ donation with the families of 107 brain-dead potential donors between September 2012 and March 2016 at a single tertiary medical center were retrospectively reviewed. RESULTS The final consent rate was 58% (62/107), and successful donation was performed in 40% (43/107). Ninety-two families (86%) made a decision within 48 hours, whereas 15 (14%) required more than 48 hours for a final decision. In univariate and multivariate analyses, the independent factors associated with a decision delay were mean arterial pressure <=60 mm Hg and coma therapy. In the early decision group (<48 hours), the consent and successful donation rates were 55% (51/92) and 39% (36/92), respectively, whereas in the delayed decision group (>=48 hours), these rates were 73% (11/15) and 47% (7/15), respectively. The consent and successful donation rates were not inferior in the delayed decision group. CONCLUSIONS These findings justify continuous efforts to maintain organ viability and to extend counseling to encourage donation even if the family cannot decide immediately. PMID- 28093563 TI - Asymptomatic Mild Hyperperfusion for the Prediction of Clinical Outcome in Postoperative Patients After Subarachnoid Hemorrhage. AB - BACKGROUND Delayed cerebral ischemia (DCI) is one of the main causes of poor outcomes after subarachnoid hemorrhage (SAH). The early identification of DCI by noninvasive imaging modalities would provide valuable information of therapeutic intervention for improving the patient outcomes. We aimed to describe the clinical features of cerebral blood flow (CBF) data obtained from the single photon emission computed tomography (SPECT) during the risk period for DCI after SAH. MATERIAL AND METHODS Clinical data from 94 SAH patients who underwent surgical clipping of anterior circulation aneurysms were reviewed retrospectively. 99mTc-HMPAO SPECT images were visually and semiquantitatively analyzed on days 7 and 14 after SAH. RESULTS In all cases, the areas of hypoperfusion were found in the middle cerebral artery territories. By contrast, the areas of mild hyperperfusion were always detected on the surgical side, the prevalence which increased from days 7 (n=28; 30%) to 14 (n=48; 51%) without neurological defects. Univariate analysis revealed that the hyperperfusion on day 14 had a significant relationship with functional outcome at 3 months (P=0.04). Multivariate analysis including age, clinical SAH grade, DCI, and hyperperfusion on day 14 showed that DCI (P=0.004; odds ratio [OR], 0.10; 95% confidence interval [CI], 0.02-0.48) and hyperperfusion on day 14 (P=0.002; OR, 2.44; 95% CI, 1.40-4.29) were independently associated with functional outcome at 3 months. CONCLUSIONS Delayed mild hyperperfusion around the surgical site can predict good prognosis after SAH, although it may hinder the CBF diagnosis of focal ischemia attributable to DCI. PMID- 28093564 TI - Postoperative Conversion Disorder Presenting as Inspiratory Stridor and Hemiparesis in a Pediatric Patient. AB - BACKGROUND Postoperative conversion disorder is rare and has been reported. The diagnosis is usually made after all major organic causes have been ruled out. CASE REPORT We describe a case of a 13-year-old female who presented in the post anesthesia care unit with acute-onset inspiratory stridor and unresponsiveness to verbal or painful stimuli after receiving a general anesthetic for upper endoscopy. Later in the post-anesthesia care unit, she presented with acute-onset right hemiplegia and sensory loss. She was first evaluated for causes of her stridor and unresponsiveness. The evaluation revealed paradoxical vocal cord movement, and all laboratory test values were normal. For her hemiplegia and sensory loss, she was evaluated for stroke with head MRI and CT scans, which were normal. CONCLUSIONS After extensive workup and consideration of multiple etiologies for her presenting signs and symptoms, the most likely diagnosis was conversion disorder. PMID- 28093565 TI - Treatment-free remission in chronic myeloid leukemia: floating between expectation and evidence. PMID- 28093566 TI - Estrogen-dependent association of HDAC4 with fear in female mice and women with PTSD. AB - Women are at increased risk of developing post-traumatic stress disorder (PTSD) following a traumatic event. Recent studies suggest that this may be mediated, in part, by circulating estrogen levels. This study evaluated the hypothesis that individual variation in response to estrogen levels contributes to fear regulation and PTSD risk in women. We evaluated DNA methylation from blood of female participants in the Grady Trauma Project and found that serum estradiol levels associates with DNA methylation across the genome. For genes expressed in blood, we examined the association between each CpG site and PTSD diagnosis using linear models that adjusted for cell proportions and age. After multiple test correction, PTSD associated with methylation of CpG sites in the HDAC4 gene, which encodes histone deacetylase 4, and is involved in long-term memory formation and behavior. DNA methylation of HDAC4 CpG sites were tagged by a nearby single-nucleotide polymorphism (rs7570903), which also associated with HDAC4 expression, fear-potentiated startle and resting-state functional connectivity of the amygdala in traumatized humans. Using auditory Pavlovian fear conditioning in a rodent model, we examined the regulation of Hdac4 in the amygdala of ovariectomized (OVX) female mice. Hdac4 messenger RNA levels were higher in the amygdala 2 h after tone-shock presentations, compared with OVX homecage control females. In naturally cycling females, tone-shock presentations increased Hdac4 expression relative to homecage controls for metestrous (low estrogen) but not the proestrous (high estrogen) group. Together, these results support an estrogenic influence of HDAC4 regulation and expression that may contribute to PTSD in women. PMID- 28093567 TI - Beta-amyloid sequelae in the eye: a critical review on its diagnostic significance and clinical relevance in Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder. There is no test for its definitive diagnosis in routine clinical practice. Although phase III clinical trials have failed, only symptomatic treatment is currently available; a possible reason for these failed trials is that intervention commenced at an advanced stage of the disease. The hallmarks of an AD brain include plaques comprising of extracellular beta-amyloid (Abeta) protein aggregates and intracellular hyperphosphorylated neurofibrillary tangles of tau. Research into the preclinical diagnosis of AD has provided considerable evidence regarding early neuropathological changes using brain Abeta imaging and the cerebrospinal fluid biomarkers, Abeta and tau. Both these approaches have limitations that are expensive, invasive or time consuming and thus preclude them from screening at-risk population. Recent studies have demonstrated the presence of Abeta plaques in the eyes of AD subjects, which is positively associated with their brain Abeta burden. Thus ocular biomarkers point to a potential avenue for an earlier, relatively low-cost diagnosis in order for therapeutic interventions to be effective. Here we review the literature that spans the investigation for the presence of Abeta in aging eyes and the significance of its deposition in relation to AD pathology. We discuss clinical studies investigating in vivo imaging of Abeta in the eye and its association with brain Abeta burden and therapies that target ocular Abeta. Finally, we focus on the need to characterize AD-specific retinal Abeta to differentiate Abeta found in some eye diseases. Based on the current evidence, we conclude that integration of ocular biomarkers that can correctly predict brain Abeta burden would have an important role as a non-invasive, yet economical surrogate marker in the diagnostic process of AD. PMID- 28093569 TI - Translational evaluation of translocator protein as a marker of neuroinflammation in schizophrenia. AB - Positron emission tomography (PET) imaging with radiotracers that target translocator protein 18 kDa (TSPO) has become a popular approach to assess putative neuroinflammatory processes and associated microglia activation in psychotic illnesses. It remains unclear, however, whether TSPO imaging can accurately capture low-grade inflammatory processes such as those present in schizophrenia and related disorders. Therefore, we evaluated the validity of TSPO as a disease-relevant marker of inflammation using a translational approach, which combined neurodevelopmental and neurodegenerative mouse models with PET imaging in patients with recent-onset schizophrenia and matched controls. Using an infection-mediated neurodevelopmental mouse model, we show that schizophrenia relevant behavioral abnormalities and increased inflammatory cytokine expression are associated with reduced prefrontal TSPO levels. On the other hand, TSPO was markedly upregulated in a mouse model of acute neurodegeneration and reactive gliosis, which was induced by intrahippocampal injection of kainic acid. In both models, the changes in TSPO levels were not restricted to microglia but emerged in various cell types, including microglia, astrocytes and vascular endothelial cells. Human PET imaging using the second-generation TSPO radiotracer [11C]DPA 713 revealed a strong trend towards reduced TSPO binding in the middle frontal gyrus of patients with recent-onset schizophrenia, who were previously shown to display increased levels of inflammatory cytokines in peripheral and central tissues. Together, our findings challenge the common assumption that central low grade inflammation in schizophrenia is mirrored by increased TSPO expression or ligand binding. Our study further underscores the need to interpret altered TSPO binding in schizophrenia with caution, especially when measures of TSPO are not complemented with other markers of inflammation. Unless more selective microglial markers are available for PET imaging, quantification of cytokines and other inflammatory biomarkers, along with their molecular signaling pathways, may be more accurate in attempts to characterize inflammatory profiles in schizophrenia and other mental disorders that lack robust reactive gliosis. PMID- 28093570 TI - Vitamin D administration, cognitive function, BBB permeability and neuroinflammatory factors in high-fat diet-induced obese rats. AB - OBJECTIVES: The purpose of this research was to investigate the effects of vitamin D administration on cognitive function, nuclear factor-kappaB (NF kappaB), brain-derived neurotrophic factor (BDNF) concentration in the hippocampus and blood-brain barrier (BBB) permeability in high-fat diet (HFD) induced obese rats. METHODS: Male Wistar rats were fed either a control diet or HFD for 16 weeks (n=20); then, each group was randomized into two subgroups supplemented orally with 500 IU kg-1 vitamin D for 5 weeks. A Morris water maze (MWM) test was performed at the 21st week to examine cognitive function. BBB permeability was characterized by Evans blue dye in the hippocampus. BDNF and NF kappaB concentrations in the hippocampus and serum vitamin D concentrations were also measured. RESULTS: HFD led to a significant delay in escape latency time and reduced time of MWM probe test because of increased NF-kappaB and decreased BDNF concentrations in the hippocampus. Vitamin D supplementation in the HFD group significantly reduced body weight, NF-kappaB concentrations, BBB permeability and increased BDNF concentrations in the hippocampus. CONCLUSIONS: Vitamin D reversed HFD-induced cognitive impairments by reduction of the NF-kappaB and elevation of BDNF concentrations and modulation of the BBB permeability in rats' hippocampus. PMID- 28093568 TI - GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium. AB - The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ?1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome wide significance level (P<5 * 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness. PMID- 28093571 TI - Roux-en-Y gastric bypass increases systemic but not portal bile acid concentrations by decreasing hepatic bile acid uptake in minipigs. AB - Roux-en-Y gastric bypass (RYGB) surgery is widely used in the management of morbid obesity. RYGB improves metabolism independently of weight loss by still unknown mechanisms. Bile acids (BAs) are good candidates to explain this benefit, since they regulate metabolic homeostasis and their systemic concentrations increase upon RYGB. Here we analyzed the mechanisms underlying the increase in systemic BA concentrations after RYGB and the role of the liver therein. To this aim, we used the Gottingen-like minipig, a human-size mammalian model, which allows continuous sampling and simultaneous analysis of pre-hepatic portal and systemic venous blood. BA concentrations and pool composition were measured in portal blood, containing intestinal reabsorbed BAs and compared to systemic blood during a standardized meal test before and after RYGB. Systemic total BA concentrations increased after RYGB, due to an increase in conjugated BAs. Interestingly, the ratio of portal:systemic conjugated BAs decreased after RYGB, indicating a role for the liver in systemic BA concentrations changes. In line, hepatic expression of BA transporter genes decreased after RYGB. Our results show that the increase in systemic BAs after surgery is due to decreased selective hepatic recapture. Thus, alterations in hepatic function contribute to the increase in systemic BAs after RYGB. PMID- 28093572 TI - Longitudinal changes in body mass index of children affected by the Great East Japan Earthquake. AB - BACKGROUND: The evacuation and disruption in housing caused by the 2011 Great East Japan Earthquake and following nuclear radiation may have influenced child health in many respects. However, studies regarding longitudinal childhood growth are limited. Therefore, in this study we aimed to explore the influence of the earthquake on longitudinal changes in body mass index in preschool children. METHODS: Participants were children from nursery schools who cooperated with the study in the Iwate, Miyagi and Fukushima prefectures. The exposed group consisted of children who experienced the earthquake during their preschool-age period (4-5 years old). The historical control group included children who were born 2 years earlier than the exposed children in the same prefectures. Trajectories regarding body mass index and prevalence of overweight/obesity were compared between the two groups using multilevel analysis. Differences in the changes in BMI between before and after the earthquake, and proportion of overweight/obesity was compared between the two groups. We also conducted subgroup analysis by defining children with specific personal disaster experiences within the exposed group. RESULTS: A total of 9722 children were included in the study. Children in the exposed group had higher body mass indices and a higher proportion of overweight after the earthquake than the control group. These differences were more obvious when confined to exposed children with specific personal disaster experiences. CONCLUSIONS: Children's growth and development-related health issues such as increased BMI after natural disasters should evoke great attention. PMID- 28093574 TI - An acoustically-driven vocal tract model for stop consonant production. AB - The purpose of this study was to further develop a multi-tier model of the vocal tract area function in which the modulations of shape to produce speech are generated by the product of a vowel substrate and a consonant superposition function. The new approach consists of specifying input parameters for a target consonant as a set of directional changes in the resonance frequencies of the vowel substrate. Using calculations of acoustic sensitivity functions, these "resonance deflection patterns" are transformed into time-varying deformations of the vocal tract shape without any direct specification of location or extent of the consonant constriction along the vocal tract. The configuration of the constrictions and expansions that are generated by this process were shown to be physiologically-realistic and produce speech sounds that are easily identifiable as the target consonants. This model is a useful enhancement for area function based synthesis and can serve as a tool for understanding how the vocal tract is shaped by a talker during speech production. PMID- 28093575 TI - Development process of an assessment tool for disruptive behavior problems in cross-cultural settings: the Disruptive Behavior International Scale - Nepal version (DBIS-N). AB - Systematic processes are needed to develop valid measurement instruments for disruptive behavior disorders (DBDs) in cross-cultural settings. We employed a four-step process in Nepal to identify and select items for a culturally valid assessment instrument: 1) We extracted items from validated scales and local free list interviews. 2) Parents, teachers, and peers (n=30) rated the perceived relevance and importance of behavior problems. 3) Highly rated items were piloted with children (n=60) in Nepal. 4) We evaluated internal consistency of the final scale. We identified 49 symptoms from 11 scales, and 39 behavior problems from free-list interviews (n=72). After dropping items for low ratings of relevance and severity and for poor item-test correlation, low frequency, and/or poor acceptability in pilot testing, 16 items remained for the Disruptive Behavior International Scale-Nepali version (DBIS-N). The final scale had good internal consistency (alpha=0.86). A 4-step systematic approach to scale development including local participation yielded an internally consistent scale that included culturally relevant behavior problems. PMID- 28093573 TI - Impact of lifestyle intervention for obese women during pregnancy on maternal metabolic and inflammatory markers. AB - BACKGROUND: Offspring of obese mothers have increased risk of developing obesity and related short- and long-term disease. The cause is multifactorial and may partly be explained by the unfavorable intrauterine environment. Intervention during pregnancy leading to a healthier lifestyle among obese may alter this. OBJECTIVE: To assess the effect of lifestyle intervention on markers of maternal metabolism and inflammation in 'the TOP (Treatment of Obese Pregnant Women) study', a randomized controlled trial. METHODS: In the TOP-study 425 participants with body mass index ?30 kg/m2 were randomized to intervention with dietary advices and physical activity assessed by pedometer (PA+D), physical activity assessed by pedometer (PA) or control (C). Of 389 participants completing the study 376 had available blood samples. Serum was analyzed for insulin, c-peptide, lipid profile, leptin, high-sensitivity CRP (hsCRP) and Soluble urokinase Plasminogen Activator Receptor (suPAR), in week 18-20 and 28-30, and simultaneously a 2-h oral glucose-tolerance-test was performed. Diet was assessed in gestational week 11-14 and 36-37 using a validated 360-item Food Frequency Questionnaire. RESULTS: Median levels of hsCRP in gestational week 28-30 were lower in each of the intervention groups (8.3 mg/l in PA+D group, P=0.03; and 8.8 mg/l in PA group, P=0.02) versus the control group (11.5 mg/l). Obtaining 11 000 steps per day as aimed for resulted in a 21% lower hsCRP compared to non compliant women. Women reporting high carbohydrate intake had around 30% higher hsCRP concentrations in late gestation than women reporting the lowest intake. There were no differences in lipid profile or any of the metabolic markers in gestational week 28-30 when comparing the intervention and control groups. CONCLUSIONS: Lifestyle intervention in obese women can reduce hsCRP representing a marker of inflammation during pregnancy. The effect may partly be mediated by more physical activity and partly by changes in intake of carbohydrates and the glycaemic load. PMID- 28093576 TI - Synthetic alpha-Hydroxytropolones as Inhibitors of HIV Reverse Transcriptase Ribonuclease H Activity. AB - HIV Reverse Transcriptase-associated ribonuclease H activity is a promising enzymatic target for drug development that has not been successfully targeted in the clinic. While the alpha-hydroxytropolone-containing natural products beta thujaplicinol and manicol have emerged as some of the most potent leads described to date, structure-function studies have been limited to the natural products and semi-synthetic derivatives of manicol. Thus, a library of alpha-hydroxytropolones synthesized through a convenient oxidopyrylium cycloaddition/ring-opening sequence have been tested in in vitro and cell-based assays, and have been analyzed using computational support. These studies reveal new synthetic alpha hydroxytropolones that, unlike the natural product leads they are derived from, demonstrate protective antiviral activity in cellular assays. PMID- 28093578 TI - Mouse Liver Mitochondria Isolation, Size Fractionation, and Real-time MOMP Measurement. AB - The mitochondrial pathway of apoptosis involves a complex interplay between dozens of proteins and lipids, and is also dependent on the shape and size of mitochondria. The use of cellular models in past studies has not been ideal for investigating how the complex multi-factor interplay regulates the molecular mechanisms of mitochondrial outer membrane permeabilization (MOMP). Isolated systems have proven to be a paradigm to deconstruct MOMP into individual steps and to study the behavior of each subset of MOMP regulators. In particular, isolated mitochondria are key to in vitro studies of the BCL-2 family proteins, a complex family of pro-survival and pro-apoptotic proteins that directly control the mitochondrial pathway of apoptosis (Renault et al., 2013). In this protocol, we describe three complementary procedures for investigating in real-time the effects of MOMP regulators using isolated mitochondria. The first procedure is "Liver mitochondria isolation" in which the liver is dissected from mice to obtain mitochondria. "Mitochondria labeling with JC-1 and size fractionation" is the second procedure that describes a method to label, fractionate by size and standardize subpopulations of mitochondria. Finally, the "Real-time MOMP measurements" protocol allows to follow MOMP in real-time on isolated mitochondria. The aforementioned procedures were used to determine in vitro the role of mitochondrial membrane shape at the level of isolated cells and isolated mitochondria (Renault et al., 2015). PMID- 28093577 TI - Epigenetic Research in Neuropsychiatric Disorders: the "Tissue Issue". AB - PURPOSE OF REVIEW: Evidence has linked neuropsychiatric disorders with epigenetic marks as either a biomarker of disease, biomarker of exposure, or mechanism of disease processes. Neuropsychiatric epidemiologic studies using either target brain tissue or surrogate blood tissue each have methodological challenges and distinct advantages. RECENT FINDINGS: Brain tissue studies are challenged by small sample sizes of cases and controls, incomplete phenotyping, post-mortem timing, and cellular heterogeneity, but the use of a primary disease relevant tissue is critical. Blood-based studies have access to much larger sample sizes and more replication opportunities, as well as the potential for longitudinal measurements, both prior to onset and during the course of treatments. Yet, blood studies also are challenged by cell-type heterogeneity, and many question the validity of using peripheral tissues as a brain biomarker. Emerging evidence suggests that these limitations to blood-based epigenetic studies are surmountable, but confirmation in target tissue remains important. SUMMARY: Epigenetic mechanisms have the potential to help elucidate biology connecting experiential risk factors with neuropsychiatric disease manifestation. Cross tissue studies as well as advanced epidemiologic methods should be employed to more effectively conduct neuropsychiatric epigenetic research. PMID- 28093579 TI - Progression of Transsynaptic Retinal Degeneration With Spectral-Domain Optical Coherence Tomography. AB - PURPOSE: To illustrate the progression of retrograde transsynaptic retinal degeneration using spectral- domain optical coherence tomography (SD-OCT). OBSERVATIONS: A 60 year-old man with a stroke was followed over a 17-month period using SD-OCT of the macula, ganglion cell layer (GCC), and retinal nerve fiber layer. Transsynaptic retinal degeneration progressed over this time. CONCLUSIONS AND IMPORTANCE: Retrograde transsynaptic retinal degeneration may occur in patients with homonymous visual field loss caused by post-geniculate neurologic disease. This is best detected as homonymous thinning of the retina, corresponding to the pattern of visual field loss, using SD-OCT of the GCC and macula. The retinal changes occur at a variable time following the onset of neurologic disease. PMID- 28093580 TI - Observation of a metal-centered B2-Ta@B18- tubular molecular rotor and a perfect Ta@B20- boron drum with the record coordination number of twenty. AB - A tubular molecular rotor B2-Ta@B18- (1) and boron drum Ta@B20- (2) with the highest coordination number of twenty in chemistry are observed via a joint photoelectron spectroscopy and first-principles theory investigation. PMID- 28093581 TI - A ratiometric fluorescent chemosensor for selective and visual detection of phosgene in solutions and in the gas phase. AB - A ratiometric fluorescent chemosensor, Phos-1, was constructed with 4,5 diaminonaphthalimide as a fluorophore for selective and visual detection of phosgene. The sensing mechanism was demonstrated to be the phosgene molecule acylating both amine groups of Phos-1. A test paper with Phos-1 was fabricated for facile, selective and visual detection of phosgene gas. PMID- 28093582 TI - A novel aggregation-induced emission platform from 2,3-diphenylbenzo[b]thiophene S,S-dioxide. AB - New aggregation-induced emission (AIE) luminogens with high solid-state emission efficiencies are developed by adopting a benzo[b]thiophene S,S-dioxide core, and steric and electronic effects on the AIE property are elucidated. PMID- 28093583 TI - Interaction of organic ions with proteins. AB - In this study we have investigated how different proteins interact with big organic ions. Two ions that are similar in size and chemical structure (Ph4B- anion and Ph4As+ cation) were studied. The proteins chosen are the two major allergenic proteins of cow's milk, beta-lactoglobulin and beta-casein, and bovine serum albumin, BSA, as the reference protein. First, a quantitative study to determine the hydrophobic degree of the proteins was performed. Then, electrokinetic and stability measurements on protein-coated polystyrene (PS) microspheres as a function of the tetraphenyl ion concentration were carried out. Our results show that the affinity of the organic ions depends on the hydrophobicity of the interface. Big charge inversions and re-stabilization patterns were observed at very low concentrations of tetraphenyl ions for the most hydrophobic protein studied (with beta-casein). Besides, the ionic concentrations needed to destabilize these colloidal systems were roughly one order of magnitude lower for the anion than for the cation. In addition, we studied conformational changes of the adsorbed proteins with a quartz crystal microbalance. Proteins were adsorbed onto hydrophobic flat substrates and then exposed to the tetraphenyl ions. The protein films swelled or collapsed as a function of the accumulation of tetraphenyl ions. Similarly to the electrokinetic/stability studies, the ionic concentration necessary to trigger structural changes of the protein films was one order of magnitude larger for the cation than for the anion. All the results evidence that the accumulation of these organic ions on an interface depends directly on its degree of hydrophobicity. We attribute the different interactions of the anion and the cation with these interfaces to their dissimilar hydration, which makes the anion show a more hydrophobic behaviour than the cation. PMID- 28093584 TI - Phase diagram and superconductivity of compressed zirconium hydrides. AB - It is known that pressure can be applied to fundamentally alter the bonding patterns between the chemical elements. By employing an unbiased structure search method based on a particle swarm optimization (PSO) methodology, the phase diagram and crystal structures of Zr-H compounds are systematically investigated at a high pressure up to 150 GPa. Interestingly, some unexpectedly stable compounds with unusual chemical and physical properties are predicted to be formed, for example, four stable and metallic species with stoichiometries of ZrH, ZrH2, ZrH3, and ZrH6 are identified for the first time. It is interesting to note that Cmc21-ZrH6 adopts intriguing structures with H2 units. Surprisingly, it is found that Cmcm-ZrH is superconducting with Tc as high as 10.6 K. Our study opens a novel avenue for designing superconducting Zr-H compounds by applying pressure. PMID- 28093585 TI - Surface-mounted MOF templated fabrication of homochiral polymer thin film for enantioselective adsorption of drugs. AB - A self-polymerized chiral monomer 3,4-dihydroxy-l-phenylalanine (l-DOPA) has been introduced into the pores of an achiral surface-mounted metal organic framework (SURMOF), and then the homochiral poly(l-DOPA) thin film has been successfully formed after UV light irradiation and etching of the SURMOF. Remarkably, such a poly(l-DOPA) thin film exhibited enantioselective adsorption of naproxen. This study opened a SURMOF-templated approach for preparing porous polymer thin films. PMID- 28093586 TI - A highly efficient bifunctional heterogeneous catalyst for morphological control of discharged products in Na-air batteries. AB - Heterogeneous catalysts with Co3O4 and liquid redox mediators were utilized for the morphological control of discharged products in SABs. With Co3O4 nanowires/C as air cathodes, the discharge product tended to be like nanoflakes. However, after the addition of ferrocene to the electrolyte, the discharge product tended to be like nanofilms and the cyclic performance can achieve 570 cycles. PMID- 28093587 TI - A copper(ii) metal-organic hydrogel as a multifunctional precatalyst for CuAAC reactions and chemical fixation of CO2 under solvent free conditions. AB - A copper(ii) metal-organic hydrogel has been synthesised and characterised. This hydrogel is an efficient, reusable precatalyst for CuAAC reactions and chemical fixation of CO2 under solvent free conditions. PMID- 28093588 TI - One-pot synthesis of quaternary carbon centered cyclobutanes via Pd(ii)-catalyzed cascade C(sp3)-H activations. AB - A novel approach toward quaternary carbon centered cyclobutanes through Pd(ii) catalyzed sequential intramolecular methylene C-H alkylation and intermolecular methine C-H bond arylation, alkenylation, alkylation, alkynylation, allylation, benzylation or alkoxylation is described. These quaternary carbon centered cyclobutanes could be further diversified through Pd(ii)-catalyzed gamma-C(sp3)-H bond activations. The synthetic utility of this novel approach was exemplified by its application to the synthesis of a bioactive small molecule. PMID- 28093589 TI - Selective bond breaking of CO2 in phase-locked two-color intense laser fields: laser field intensity dependence. AB - Selective bond breaking of CO2 in phase-locked omega-2omega two-color intense laser fields (lambda = 800 nm and 400 nm, total field intensity I ~ 1014 W cm-2) has been investigated by coincidence momentum imaging. The CO+ and O+ fragment ions produced by two-body Coulomb explosion, CO22+ -> CO+ + O+, exhibit asymmetric distributions along the laser polarization direction, showing that one of the two equivalent C-O bonds is selectively broken by the laser fields. At a field intensity higher than 2 * 1014 W cm-2, the largest fragment asymmetry is observed when the relative phase phi between the omega and 2omega laser fields is ~0 and pi. On the other hand, an increase of the asymmetry and a shift of the phase providing the largest asymmetry are observed at lower field intensities. The selective bond breaking and its dependence on the laser field intensity are discussed in terms of a mechanism involving deformation of the potential energy surfaces and electron recollision in intense laser fields. PMID- 28093590 TI - Hydrogen diffusion into the subsurfaces of model metal catalysts from first principles. AB - Diffusion pathways of atomic hydrogen on model catalyst surfaces and into subsurfaces are of great significance in the exploration of novel catalytic hydrogenation in heterogeneous catalysis. We present in detail the diffusion pathways of hydrogen on seven different open and closed model catalyst surfaces from first principles calculations. Seven transition metal catalysts with thirteen different crystal surfaces, i.e., Co(001), Ni(100) and Ni(111), Pd(100) and (111), Pt(100) and (111), Cu(100) and (111), Ag(100) and (111) and Au(100) and (111), are taken into account. Thirteen corresponding potential energy surfaces (PESs) are constructed for modelling hydrogen diffusion on these model catalyst surfaces and into the subsurfaces by interpolating ab initio density functional theory energy points (~2000 for each surface). The minimum energy diffusion pathways for hydrogen on the surfaces and into the subsurfaces are globally searched for based on PESs using a mesh method, and are in excellent agreement with those calculated from the nudged elastic band method. Furthermore, the important substrate relaxation effect can decrease the diffusion barriers for hydrogen into catalyst subsurfaces. The high reactivity of subsurface reactants mainly comes from the residual energy of subsurface hydrogen emerging from the subsurface onto the surface. PMID- 28093591 TI - Hidden negative linear compressibility in lithium l-tartrate. AB - By decoupling the mechanical behaviour of building units for the first time in a wine-rack framework containing two different strut types, we show that lithium l tartrate exhibits NLC with a maximum value, Kmax = -21 TPa-1, and an overall NLC capacity, chiNLC = 5.1%, that are comparable to the most exceptional materials to date. Furthermore, the contributions from molecular strut compression and angle opening interplay to give rise to so-called "hidden" negative linear compressibility, in which NLC is absent at ambient pressure, switched on at 2 GPa and sustained up to the limit of our experiment, 5.5 GPa. Analysis of the changes in crystal structure using variable-pressure synchrotron X-ray diffraction reveals new chemical and geometrical design rules to assist the discovery of other materials with exciting hidden anomalous mechanical properties. PMID- 28093592 TI - Synthesis and optical and electrochemical properties of julolidine-structured pyrido[3,4-b]indole dye. AB - The julolidine-structured pyrido[3,4-b]indole dye ET-1 has been newly designed and developed as a small D-A fluorescent dye. ET-1 showed bathochromic shifts of the fluorescence band upon changing from aprotic solvents to protic solvents, as well as positive fluorescence solvatochromism. Moreover, it was found that ET-1 can form a 1 : 1 Py(N)-B complex with boron trifluoride and a hydrogen-bonded proton transfer (Py(N)-H) complex with trifluoroacetic acid, which exhibit photoabsorption and fluorescence bands at a longer wavelength region than the pristine ET-1. Based on optical (photoabsorption and fluorescence spectroscopy) and electrochemical (cyclic voltammetry) measurements, Lippert-Mataga plots, 1H NMR spectral measurement and density functional theory (DFT) calculation, this work indicated that the Py(N)-B complex or the Py(N)-H complex is effectively formed and stable in solution. This is due to the strong Py(N)-B interaction or Py(N)-hydrogen-bond, which can be attributed to the enhanced basicity or the accumulated electron density on the nitrogen atom of the pyridine ring caused by the introduction of a julolidine (quinolizidine) moiety as a strong electron donating group. We propose that the D-A-type dye ET-1 based on the julolidine structured pyrido[3,4-b]indole possesses the ability to act as a calorimetric and fluorescent sensor for Bronsted and Lewis acids. PMID- 28093593 TI - Self-assembled 4-(1,2-diphenylbut-1-en-1-yl)aniline based nanoparticles: podophyllotoxin and aloin as building blocks. AB - The ability of 4-(1,2-diphenylbut-1-en-1-yl)aniline as a self-assembly inducer is reported. The conjugation of this moiety with aloin or podophyllotoxin resulted in spherical nanoparticles that were characterized by Dynamic Light Scattering (DLS), Transmission Electron Microscopy (TEM) and NanoSight technology. A preliminary biological evaluation on two cancer cell lines is reported. PMID- 28093594 TI - Fast and accurate MAS-DNP simulations of large spin ensembles. AB - A deeper understanding of parameters affecting Magic Angle Spinning Dynamic Nuclear Polarization (MAS-DNP), an emerging nuclear magnetic resonance hyperpolarization method, is crucial for the development of new polarizing agents and the successful implementation of the technique at higher magnetic fields (>10 T). Such progress is currently impeded by computational limitation which prevents the simulation of large spin ensembles (electron as well as nuclear spins) and to accurately describe the interplay between all the multiple key parameters at play. In this work, we present an alternative approach to existing cross-effect and solid-effect MAS-DNP codes that yields fast and accurate simulations. More specifically we describe the model, the associated Liouville-based formalism (Bloch-type derivation and/or Landau-Zener approximations) and the linear time algorithm that allows computing MAS-DNP mechanisms with unprecedented time savings. As a result, one can easily scan through multiple parameters and disentangle their mutual influences. In addition, the simulation code is able to handle multiple electrons and protons, which allows probing the effect of (hyper)polarizing agents concentration, as well as fully revealing the interplay between the polarizing agent structure and the hyperfine couplings, nuclear dipolar couplings, nuclear relaxation times, both in terms of depolarization effect, but also of polarization gain and buildup times. PMID- 28093595 TI - Mortality and Cause of Death in Patients with Pemphigus. AB - All-cause and cause-specific mortality among patients with pemphigus compared with the general population is yet to be established. This study investigated overall mortality and cause-specific mortality in a large immunopathologically validated cohort of patients with pemphigus. Mortality of patients with pemphigus was compared with age- and gender-matched control subjects in the general population. All-cause and cause-specific standardized mortality ratios (SMRs) were estimated. The study cohort included 245 patients newly-diagnosed with pemphigus between January 1990 and June 2016, contributing 2,679.4 person-years of follow-up. Overall, 48 deaths were observed during a mean follow-up period of 10.9 +/- 8.1 years, which was more than twice the number expected (SMR 2.4; 95% confidence interval (95% CI) 1.82-3.20). The SMRs for death due to infections (22.6; 95% CI 13.6-35.3), namely pneumonia (25.7; 95% CI 11.7-48.8) and septicaemia (8.6; 95% CI 1.7-25.0), and due to cardiovascular diseases (2.8; 95% CI 1.0-6.0) were significantly higher than expected. Overall mortality among patients with pemphigus is 2.4-times greater than for the general population, mainly due to infections. PMID- 28093596 TI - Diagnostic Value of Linear Fluorescence Along the Basement Membrane of Sweat Gland Ducts in Bullous Pemphigoid. AB - Linear IgG deposits along the basement membrane of adnexa has been proposed to be useful in the diagnosis of bullous pemphigoid (BP), but no controlled studies have been performed. This study evaluated linear IgG fluorescence of the basement membrane of sweat gland ducts (SGD) and other adnexa in perilesional biopsies from patients with BP (n = 64) and controls (n = 82), using direct immunofluorescence microscopy. Fluorescence intensity was graded semi quantitatively. Positive SGDs were found in 58 (90.6%) patients with BP and 44 (53.7%) controls, a statistically significant difference (p < 0.0001). The sensitivity of positive SGDs for BP was high (90.6%), but the specificity was low (46.3%). Only strong fluorescence intensity was associated with high specificity. In conclusion, positive SGDs in direct immunofluorescence microscopy are highly sensitive for BP; however, only strong fluorescence has acceptable specificity. Weak positivity of SGDs without linear fluorescence of the epidermal basement membrane may not be sufficiently specific for BP. PMID- 28093597 TI - Telangiectatic Mycosis Fungoides: A New Clinicopathological Presentation Mimicking Acquired Naevoid Telangiectasia. PMID- 28093598 TI - Increased Incidence of Cutaneous Vasculitic Ulcers: 30-year Results from a Population-based Retrospective Study. PMID- 28093599 TI - Risk Factors for De Novo Squamous Cell Carcinoma Development in Renal Transplant Recipients with a Previous Squamous Cell Carcinoma. PMID- 28093600 TI - Vascular Patterns in Cutaneous Ulcerated Basal Cell Carcinoma: A Retrospective Blinded Study Including Dermoscopy. AB - The aim of this retrospective study was to determine the type and prevalence of vascular patterns in the ulcerated and non-ulcerated portions of histologically proven basal cell carcinomas (BCCs) and correlate them with other dermoscopic and clinical features, including the clinically supposed diagnosis. Three authors retrospectively collected 156 clinical and 156 dermoscopic digital images of ulcerated BCCs (histologically confirmed); each image was blindly evaluated by 2 other authors, who did not know the histological diagnosis. Seventeen lesions were completely ulcerated, while 139 lesions presented ulcerated and non ulcerated portions. Correct clinical diagnosis was associated with the type of lesion, in particular 90.6% of partially ulcerated lesions were correctly diagnosed with clinical-dermoscopic examination, compared with 11.8% of totally ulcerated lesions (chi2 = 64.00, p = 0.000). Presence of arborizing pattern in the ulcerated portion was associated with a correct diagnosis (Fisher's exact test, p = 0.015). Correct diagnosis was also associated with absence of dotted pattern in the non-ulcerated area (chi2 = 16.18, p = 0.000); the absence of hairpin (chi2 = 6.08, p = 0.000) and glomerular patterns were associated with correct diagnosis in the ulcerated areas (chi2 = 18.64, p = 0.000). In case of completely ulcerated BCC the clinician lacks the means to correctly identify the correct nature of the lesion, and is driven towards an incorrect diagnostic conclusion. PMID- 28093601 TI - Ambulatory Photodynamic Therapy for Superficial Basal Cell Carcinoma: An Effective Light Source? PMID- 28093602 TI - Annular Erythematous Scaly Lesions on the Face: A Quiz. PMID- 28093603 TI - Monitoring Ingenol Mebutate Gel Treatment of Actinic Keratoses by Reflectance Confocal Microscopy. PMID- 28093604 TI - Pretreatment with 5-Fluorouracil Cream Enhances the Efficacy of Daylight-mediated Photodynamic Therapy for Actinic Keratosis. AB - The efficacy of photodynamic therapy (PDT) with methyl aminolevulinate is reduced when treating actinic keratosis (AK) on the extremities in comparison with the face and scalp. Studies indicate that PDT efficacy can be improved by combining PDT with other treatment modalities. This randomized intra-individual study investigated whether pretreatment with topical 5% 5-fluorouracil (5-FU) enhanced the treatment efficacy of daylight-mediated PDT in 24 patients with AKs on the hands. One hand of each patient was given 7 days of pretreatment with 5-FU twice daily before daylight-PDT, whereas the other hand was treated with daylight-PDT alone. At 3-month follow-up the overall lesion response rate was significantly higher for the combination of 5-FU and daylight-PDT (62.7%) than for daylight-PDT alone (51.8%) (p = 0.001). Furthermore, pain and erythema in relation to treatment were similar in the 2 groups (p = 1.0 and p = 0.2, respectively). Combination therapy is a safe and effective method to improve daylight-PDT for acral AKs. PMID- 28093605 TI - Erratum to: Animal cognition in a human-dominated world. PMID- 28093606 TI - Erratum to: Adjusting foraging strategies: a comparison of rural and urban common mynas (Acridotheres tristis). PMID- 28093607 TI - Osmopriming-induced salt tolerance during seed germination of alfalfa most likely mediates through H2O2 signaling and upregulation of heme oxygenase. AB - The present study showed that osmopriming or pretreatment with low H2O2 doses (2 mM) for 6 h alleviated salt-reduced seed germination. The NADPH oxidase activity was the main source, and superoxide dismutase (SOD) activity might be a secondary source of H2O2 generation during osmopriming or H2O2 pretreatment. Hematin pretreatment similar to osmopriming improved salt-reduced seed germination that was coincident with the enhancement of heme oxygenase (HO) activity. The semi quantitative RT-PCR confirmed that osmopriming or H2O2 pretreatment was able to upregulate heme oxygenase HO-1 transcription, while the application of N,N dimethyl thiourea (DMTU as trap of endogenous H2O2) and diphenyleneiodonium (DPI as inhibitor of NADPHox) not only blocked the upregulation of HO but also reversed the osmopriming-induced salt attenuation. The addition of CO-saturated aqueous rescued the inhibitory effect of DMTU and DPI on seed germination and alpha-amylase activity during osmopriming or H2O2 pretreatment, but H2O2 could not reverse the inhibitory effect of ZnPPIX (as HO inhibitor) or Hb (as CO scavenger) that indicates that the CO acts downstream of H2O2 in priming-driven salt acclimation. The antioxidant enzymes and proline synthesis were upregulated in roots of seedlings grown from primed seeds, and these responses were reversed by adding DMTU, ZnPPIX, and Hb during osmopriming. These findings for the first time suggest that H2O2 signaling and upregulation of heme oxygenase play a crucial role in priming-driven salt tolerance. PMID- 28093608 TI - Spatiotemporal drivers of energy expenditure in a coastal marine fish. AB - Animal behavior and energy expenditure often vary significantly across the landscape, and quantifying energy expenditure over space and time provides mechanistic insight into ecological dynamics. Yet, spatiotemporal variability in energy expenditure has rarely been explored in fully aquatic species such as fish. Our objective was to quantify spatially explicit energy expenditure for a tropical marine teleost fish, bonefish (Albula vulpes), to examine how bonefish energetics vary across landscape features and temporal factors. Using a swim tunnel respirometer, we calibrated acoustic accelerometer transmitters implanted in bonefish to estimate their metabolic rates and energy expenditure, and applied this technology in situ using a fine-scale telemetry system on a heterogeneous reef flat in Puerto Rico. Bonefish energy expenditure varied most among habitats, with significant interactions between habitat and temporal factors (i.e., diel period, tide state, season). The energy expenditure was generally highest in shallow water habitats (i.e., seagrass and reef crest). Variation in activity levels was the main driver of these differences in energy expenditure, which in shallow, nearshore habitats is likely related to foraging. Bonefish moderate energy expenditure across seasonal fluctuations in temperature, by selectively using shallow nearshore habitats at moderate water temperatures that correspond with their scope for activity. Quantifying how animals expend energy in association with environmental and ecological factors can provide important insight into behavioral ecology, with implications for bioenergetics models. PMID- 28093609 TI - Periprosthetic fracture around a stable femoral stem treated with locking plate osteosynthesis: distal femoral locking plate alone versus with cerclage cable. AB - To promote rapid bone healing, an adequate stable fixation implant with a percutaneous reduction instrument should be used for Vancouver type B1 or C fractures. The objective of this study was to describe radiographic and clinical outcomes of patients with periprosthetic fracture (PPF) around a stable femoral stem, treated with a distal femoral locking plate alone or with a cerclage cable. A total of 21 patients with PPF amenable to either a reverse distal femoral locking plate (LCP DF(r)) alone or with a cerclage cable, with a mean age of 75.7 years, were included. In these patients, ten fractures were treated with a reverse LCP DF(r) alone and were classified as group I, and 11 additionally received a cerclage cable and were classified as group II. Group II had a significantly longer operation time (P = 0.019) than group I and included one patient with nonunion at the final 24-month follow-up visit after the initial fracture reduction. However, this difference in nonunion rate for the two groups is more likely to inappropriate indications than surgical techniques. When comparing the stability of the fractures in both groups, there was no statistically significant difference, which might be attributed to the stable fixed-angle implant. PMID- 28093610 TI - The new WHO 2016 classification of brain tumors-what neurosurgeons need to know. AB - BACKGROUND: The understanding of molecular alterations of tumors has severely changed the concept of classification in all fields of pathology. The availability of high-throughput technologies such as next-generation sequencing allows for a much more precise definition of tumor entities. Also in the field of brain tumors a dramatic increase of knowledge has occurred over the last years partially calling into question the purely morphologically based concepts that were used as exclusive defining criteria in the WHO 2007 classification. METHODS: Review of the WHO 2016 classification of brain tumors as well as a search and review of publications in the literature relevant for brain tumor classification from 2007 up to now. RESULTS: The idea of incorporating the molecular features in classifying tumors of the central nervous system led the authors of the new WHO 2016 classification to encounter inevitable conceptual problems, particularly with respect to linking morphology to molecular alterations. As a solution they introduced the concept of a "layered diagnosis" to the classification of brain tumors that still allows at a lower level a purely morphologically based diagnosis while partially forcing the incorporation of molecular characteristics for an "integrated diagnosis" at the highest diagnostic level. In this context the broad availability of molecular assays was debated. On the one hand molecular antibodies specifically targeting mutated proteins should be available in nearly all neuropathological laboratories. On the other hand, different high-throughput assays are accessible only in few first-world neuropathological institutions. As examples oligodendrogliomas are now primarily defined by molecular characteristics since the required assays are generally established, whereas molecular grouping of ependymomas, found to clearly outperform morphologically based tumor interpretation, was rejected from inclusion in the WHO 2016 classification because the required assays are currently only established in a small number of institutions. CONCLUSION: In summary, while neuropathologists have now encountered various challenges in the transitional phase from the previous WHO 2007 version to the new WHO 2016 classification of brain tumors, clinical neurooncologists now face many new diagnoses allowing a clearly improved understanding that could offer them more effective therapeutic opportunities in neurooncological treatment. The new WHO 2016 classification presumably presents the highest number of modifications since the initial WHO classification of 1979 and thereby forces all professionals in the field of neurooncology to intensively understand the new concepts. This review article aims to present the basic concepts of the new WHO 2016 brain tumor classification for neurosurgeons with a focus on neurooncology. PMID- 28093611 TI - A highly divergent Puumala virus lineage in southern Poland. AB - Puumala virus (PUUV) represents one of the most important hantaviruses in Central Europe. Phylogenetic analyses of PUUV strains indicate a strong genetic structuring of this hantavirus. Recently, PUUV sequences were identified in the natural reservoir, the bank vole (Myodes glareolus), collected in the northern part of Poland. The objective of this study was to evaluate the presence of PUUV in bank voles from southern Poland. A total of 72 bank voles were trapped in 2009 at six sites in this part of Poland. RT-PCR and IgG-ELISA analyses detected three PUUV positive voles at one trapping site. The PUUV-infected animals were identified by cytochrome b gene analysis to belong to the Carpathian and Eastern evolutionary lineages of bank vole. The novel PUUV S, M and L segment nucleotide sequences showed the closest similarity to sequences of the Russian PUUV lineage from Latvia, but were highly divergent to those previously found in northern Poland, Slovakia and Austria. In conclusion, the detection of a highly divergent PUUV lineage in southern Poland indicates the necessity of further bank vole monitoring in this region allowing rational public health measures to prevent human infections. PMID- 28093612 TI - [GeSRU e. V. - a success story]. PMID- 28093613 TI - Recent trends in the distribution of causative diseases of fever of unknown origin. AB - Fever of unknown origin is a challenging diagnostic problem and the aim of this research was to analyze trends in the distribution of its causative diseases. This retrospective study makes a comparison between two different clinical series of patients from two different periods: 227 from period 1 (1998-2002) and 602 from period 2 (2008-2012). There were fewer infections (31.72% vs.16.45%) and more miscellaneous causes (5.29% vs. 13.12%) in the period 2 series, whereas no significant differences in autoimmune diseases, malignancies and undiagnosed cases were found. Adult onset Still's disease and lymphoma occupied the largest proportion in autoimmune diseases (75.00%) and malignancies (89.81%), respectively. Interestingly, the autoimmune diseases group, instead of infections, was found to be the leading category of the causative diseases in fever of unknown origin, which is contrary to previous reports. Further, adult onset Still's disease and lymphoma were suggested to be valued more highly in view of the large and rising proportions found in this study. These trends could support the diagnosis and treatment of fever of unknown origin better in the future. PMID- 28093614 TI - ? PMID- 28093615 TI - The Open Abdomen Route by EuraHS: introduction of the data set and initial results of procedures and procedure-related complications. AB - INTRODUCTION: Open abdomen management has become a well-established strategy in the treatment of serious intra-abdominal pathologies. Key objectives are fistula prevention and high fascial closure rates. The current level of evidence on laparostoma is insufficient. This is due to the rareness of laparostomas, the heterogeneity of study cohorts, and broad diversity of techniques. Collecting data in a standardised, multicentre registry is necessary to draw up evidence based guidelines. MATERIALS AND METHODS: In order to improve the level of evidence on laparostomy, CAMIN (surgical working group for military and emergency surgery) of DGAV (German Society for General and Visceral Surgery), initiated the implementation of a laparostomy registry. This registry was established as the Open Abdomen Route by EuraHS (European Registry of Abdominal Wall Hernias). Key objectives include collection of data, quality assurance, standardisation of therapeutic concepts and the development of guidelines. Since 1 May 2015, the registry is available as an online database called Open Abdomen Route of EuraHS (European Registry of Abdominal Wall Hernias). It includes 11 categories for data collection, including three scheduled follow-up examinations. RESULTS: As part of this pilot study, all entries of the first 120 days were analysed, resulting in a review of 82 patients. At 44%, secondary peritonitis was the predominant indication. The mortality rate was 22%. A comparison of methods with and without fascial traction reveals fascial closure rates of 67% and 25%, respectively (intention-to-treat analysis, p < 0.03). Inert visceral protection was used in 67% of patients and achieved a small bowel fistula incidence of only 5.5%. DISCUSSION: Optimising laparostomy management techniques in order to achieve low incidence of fistulation and high fascial closure rates is possible. The method that ensures the best possible outcome-based on current evidence-would involve fascial traction, visceral protection and negative pressure. The laparostomy registry is a useful tool for quickly generating sufficient evidence for open abdomen treatment. PMID- 28093616 TI - Rare germline alterations in cancer-related genes associated with the risk of multiple primary tumor development. AB - : Multiple primary tumors (MPT) have been described in carriers of inherited cancer predisposition genes. However, the genetic etiology of a large proportion of MPT cases remains unclear. We reviewed 267 patients with hereditary cancer predisposition syndromes (HCPS) that underwent genetic counseling and selected 22 patients with MPT to perform genomic analysis (CytoScan HD Array, Affymetrix) aiming to identify new alterations related to a high risk of developing MPT. Twenty patients had a positive family history of cancer and 11 met phenotypic criteria for HCPS. Genetic testing for each of the genes associated with these syndromes revealed negative results for pathogenic mutations. Seventeen rare germline copy number variations (CNVs) covering 40 genes were identified in 11 patients, including an EPCAM/MSH2 deletion in one Lynch syndrome patient. An enrichment analysis revealed a significant number of genes (where the CNVs are mapped) associated with carcinogenesis and/or related to functions implicated with tumor development, such as proliferation and cell survival. An interaction network analysis highlighted the importance of TP53 pathway in cancer emergence. A high number of germline copy-neutral loss of heterozygosity (cnLOH) was identified in nine cases, particularly in two patients. Eighteen genes were covered by both rare CNVs and cnLOH, including 14 related to tumorigenesis and seven genes (ABCC1, KDM4C, KIAA0430, MYH11, NDE1, PIWIL2, and ULK2) specifically associated with cellular growth and proliferation. Overall, we identified 14 cases with rare CNVs and/or cnLOH that may contribute to the risk of MPT development. KEY MESSAGE: CNVs may explain the risk of hereditary cancer syndromes in MPT patients. CNVs affecting genes related to cancer are candidates to be involved in MPT risk. EPCAM/MSH2 deletions should be investigated in patients suspected to have LS. Gene enrichment related to the TP53 network is associated with MPT development. cnLOH and CNVs contribute to the risk of MPT development. PMID- 28093617 TI - The developing temporal bone: computed tomography measurements and assessment of suture closure from birth to 18 years of age. AB - PURPOSE: To describe the normal CT appearance of the developing temporal bone in children from birth to 18 years of age. METHODS: Two hundred and six temporal bone CTs of children from 0.14 to 18.95 years were retrospectively selected and reviewed. Temporal bones were measured in a standardized slice orientation using the length of the basal turn of the cochlea, the length and width of the petrous bone, the coronal extent, trailing edge and anterior-posterior dimension of the temporal bone and the angle between petrous bone's length and the midsagittal line in the axial plane showing the basal turn of the cochlea in its greatest extent. Two sutures, two synchondroses and three fissures of the temporal bone were evaluated and graded. RESULTS: Chosen measurements and calculations demonstrate an increase of values from 0 to 18 years with the greatest increase occurring during the first 2 years of life. The angle between the basal turn of the cochlea and the midsagittal line shows a large variability. Logarithmic trend lines illustrate larger measurements of males as compared to females. The ratio of the basal turn of the cochlea and the length of the petrous bone is about 1:4.1 (f/m) during the first year of life and about 1:6.1 (f)/1:6.8 (m) from 17 years onwards. Results of suture closure are described using box-and-whisker plots. CONCLUSIONS: The developing temporal bone grows the most during the first 2 years of life. Knowledge of changing proportions and suture closure is essential for evaluation of temporal bone CT of children. PMID- 28093618 TI - MRI assessment of calf injuries in Australian Football League players: findings that influence return to play. AB - OBJECTIVE: Calf muscle strains have become increasingly prevalent in recent seasons of the Australian Football League (AFL) and represent a significant cause of time lost from competition. The purpose of this study was to examine the association between MRI features of calf muscle strains and games missed and to thereby identify parameters that are of prognostic value. MATERIALS AND METHODS: A retrospective analysis of MRI scans of AFL players with calf strains referred to a musculoskeletal radiology clinic over a 5-year period (2008-2012) was performed. The muscle(s) and muscle component affected, the site and size of strain, and the presence of an intramuscular tendon tear or intermuscular fluid were recorded. These data were cross-referenced with whether a player missed at least one game. Imaging features of prognostic value were thus identified. RESULTS: Sixty-three athletes had MRI scans for calf muscle strains. Soleus strains were more common than strains of other muscles. Players with soleus strains were more likely to miss at least one game if they had multiple muscle involvement (p = 0.017), musculotendinous junction strains (p = 0.046), and deep strains (p = 0.036). In a combined analysis of gastrocnemius and soleus strains, intramuscular tendon tears were observed in a significantly greater proportion of players who missed games (p = 0.010). CONCLUSION: Amongst AFL players with calf injuries, there is an association between missing at least one game and multiple muscle involvement, musculotendinous junction strains, deep strain location, and intramuscular tendon tears. In this setting, MRI may therefore provide prognostic information to help guide return-to-play decisions. PMID- 28093619 TI - Dendritic cells in autoimmunity, infections, and cancer. PMID- 28093620 TI - Inflammatory bowel disease and cancer response due to anti-CTLA-4: is it in the flora? AB - Checkpoint inhibitors blocking CTLA-4 (ipilimumab) and PD-1 (nivolumab, pembrolizumab) have transfigured our cancer treatment paradigm. However, these drugs can induce immune-related adverse events that share clinical and pathological characteristics with immune-mediated diseases. One of the most severe immune-related adverse event observed with anti-CTLA-4 is an enterocolitis that mirrors naturally occurring inflammatory bowel disease. This paper reviews the clinical, immunological, and microbiota data associated with the immune related enterocolitis induced by the cancer immunotherapy blocking CTLA-4, ipilimumab. A parallel analysis of the mechanisms underlying inflammatory bowel diseases on the one hand, and anti-CTLA-4-induced colitis on the other hand, stresses the crucial role of the gut microbiota and of resident Treg in the genesis of both iatrogenic and spontaneous inflammatory bowel diseases. PMID- 28093622 TI - Quantification of Chloroflexi Eikelboom morphotype 1851 for prediction and control of bulking events in municipal activated sludge plants in Japan. AB - The dominant filamentous bacteria associated with bulking incidents in Japanese activated sludge plants with nutrient removal were identified and their quantitative correlations with sludge settleability were assessed, with the aim of controlling bulking incidents by specifically suppressing bacterial growth. Fluorescence in situ hybridization (FISH) analyses using existing oligonucleotide FISH probes indicated that the presence of Eikelboom type 1851 filamentous bacteria belonging to the phylum Chloroflexi is correlated with biomass settleability in the municipal wastewater treatment plants examined. Real-time quantitative PCR (qPCR) assays developed in this study also showed a linear correlation between type 1851 filament members and sludge settleability, with the exception of some winter samples. The real-time qPCR assays and 16S ribosomal RNA gene amplicon sequencing to reveal the microbial community of activated sludge showed that the abundance of type 1851 at 200 mL g-1 of sludge volume index was estimated to be about 1.9% of the total microbial cells. The abundance of type 1851 served as a bulking indicator in plants where type 1851 was dominant. PMID- 28093621 TI - Outcome of elderly undergoing extracorporeal life support in refractory cardiogenic shock. AB - BACKGROUND: The current study presents data from a real-world cohort of patients with refractory cardiogenic shock (CS) undergoing extracorporeal life support (ECLS) focusing on the comparison of elderly versus younger patients. METHODS AND RESULTS: One hundred consecutive patients with refractory CS underwent percutaneous ECLS implantation performed by interventional cardiologists. Follow up was performed at hospital discharge as well as at a median of 18 months [interquartile range 15-36]. Patients were grouped according to median age (<=60 versus >60 years). ECLS could be weaned in more than half of the cohort (n = 56, 56%) with no differences between the age groups (p = 1.00). Despite similar rates of initial haemodynamic stabilisation, in-hospital mortality was higher in patients >60 years (82% versus 58%, p = 0.02). At mid-term follow-up, only three patients were alive in the group of patients >60 years. This resulted in a mortality rate of 94% in the elderly in comparison with 68% in patients aged <=60 years (p = 0.001). CONCLUSIONS: Despite a high rate of initial successful ECLS weaning, mid-term prognosis of patients with CS undergoing ECLS above the age of 60 years is poor with superior results in patients aged <=60 years. PMID- 28093623 TI - What factor within the Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) criteria is most strongly correlated with trauma induced DIC? A retrospective study using thromboelastometry in a single center in Japan. AB - PURPOSE: The diagnostic criteria for disseminated intravascular coagulation (DIC) established by the Japanese Association for Acute Medicine (JAAM) is able to diagnose DIC accurately and promptly. The aim of this retrospective study is to evaluate the degree of association between each parameter of JAAM DIC criteria and the diagnosis of trauma induced DIC (T-DIC) utilizing thromboelastometry (ROTEM). METHODS: Trauma patients transported to our hospital with ROTEM performed in the emergency department between January 2013 and December 2015 were enrolled in this study. We evaluated (1) the characteristics of T-DIC, (2) the relationships between T-DIC and each parameter of the JAAM DIC criteria and (3) the diagnostic accuracies of each parameter for T-DIC by statistical measurement. RESULTS: All 72 patients (21 T-DIC and 51 control) were included in primary analysis. T-DIC was significantly related to younger age, more severe trauma scores, more cases of massive transfusions, and remarkable coagulation abnormality detected by standard coagulation tests. In the cases of T-DIC, ROTEM showed longer clotting time, lower acceleration, lower clot firmness, and inhibited fibrinolysis in EXTEM/INTEM. Within the JAAM DIC score, PT-INR >=1.2 was the most accurate factor for T-DIC diagnosis; sensitivity 60.0%, specificity 100.0%, and accuracy 88.7%. PT-INR >=1.2 was statistically correlated with the JAAM DIC score (p < 0.001, r = 0.709). The univariate analysis based on 1.2 of PT INR indicated statistical differences in most categories of ROTEM, which is similar to analysis performed for the presence and absence of T-DIC. CONCLUSIONS: Among JAAM DIC criteria, the PT-INR >=1.2 was the most accurate factor for both the diagnosis of T-DIC and the evaluation of its severity. PMID- 28093624 TI - Osteoporotic vertebral body fractures of the thoracolumbar spine: indications and techniques of a 360 degrees -stabilization. AB - Unstable vertebral body fragility fractures of the thoracolumbar spine can occur with or without relevant trauma. Initially, a standardized diagnostic algorithm including magnetic resonance tomography is recommended to detect accompanied further vertebral body fractures, to interpret the individual fracture stability, and to screen for relevant traumatic intervertebral disc lesions. Aim of the therapy is to assure fast mobilization and to maintain spinal alignment. Unstable fracture morphology is defined by vertebral body fractures including a relevant defect of the posterior vertebral cortex as well as type B or C fractures. With respect of type A fractures, a combined anterior-posterior approach including a primary cement-augmented posterior stabilization and anterior spondylodesis is indicated in those patients with relevant intervertebral lesions or in those suffering from high-energy accidents resulting in unstable burst-type fractures. The others will benefit from hybrid stabilizations including cement-augmented posterior stabilizations and cement augmentation (kyphoplasty) of the fractured level to gain a ventral transosseous stability. In addition, individually adapted antiosteoporotic therapy is essential. PMID- 28093625 TI - Ultralow dose CT for pulmonary nodule detection with chest x-ray equivalent dose a prospective intra-individual comparative study. AB - PURPOSE: To prospectively evaluate the accuracy of ultralow radiation dose CT of the chest with tin filtration at 100 kV for pulmonary nodule detection. MATERIALS AND METHODS: 202 consecutive patients undergoing clinically indicated chest CT (standard dose, 1.8 +/- 0.7 mSv) were prospectively included and additionally scanned with an ultralow dose protocol (0.13 +/- 0.01 mSv). Standard dose CT was read in consensus by two board-certified radiologists to determine the presence of lung nodules and served as standard of reference (SOR). Two radiologists assessed the presence of lung nodules and their locations on ultralow dose CT. Sensitivity and specificity of the ultralow dose protocol was compared against the SOR, including subgroup analyses of different nodule sizes and types. A mixed effects logistic regression was used to test for independent predictors for sensitivity of pulmonary nodule detection. RESULTS: 425 nodules (mean diameter 3.7 +/- 2.9 mm) were found on SOR. Overall sensitivity for nodule detection by ultralow dose CT was 91%. In multivariate analysis, nodule type, size and patients BMI were independent predictors for sensitivity (p < 0.001). CONCLUSIONS: Ultralow dose chest CT at 100 kV with spectral shaping enables a high sensitivity for the detection of pulmonary nodules at exposure levels comparable to plain film chest X-ray. KEYPOINTS: * 91% of all lung nodules were detected with ultralow dose CT * Sensitivity for subsolid nodule detection is lower in ultralow dose CT (77.5%) * The mean effective radiation dose in 202 patients was 0.13 mSv * Ultralow dose CT seems to be feasible for lung cancer screening. PMID- 28093626 TI - Contrast-enhanced CT in determining resectability in patients with pancreatic carcinoma: a meta-analysis of the positive predictive values of CT. AB - OBJECTIVE: To obtain a summary positive predictive value (sPPV) of contrast enhanced CT in determining resectability. METHODS: The MEDLINE and EMBASE databases from JAN2005 to DEC2015 were searched and checked for inclusion criteria. Data on study design, patient characteristics, imaging techniques, image evaluation, reference standard, time interval between CT and reference standard, and data on resectability/unresectablity were extracted by two reviewers. We used a fixed-effects or random-effects approach to obtain sPPV for resectability. Several subgroups were defined: 1) bolus-triggering versus fixed timing; 2) pancreatic and portal phases versus portal phase alone; 3) all criteria (liver metastases/lymphnode involvement/local advanced/vascular invasion) versus only vascular invasion as criteria for unresectability. RESULTS: Twenty-nine articles were included (2171 patients). Most studies were performed in multicentre settings, initiated by the department of radiology and retrospectively performed. The I2-value was 68%, indicating heterogeneity of data. The sPPV was 81% (95%CI: 75-86%). False positives were mostly liver, peritoneal, or lymphnode metastases. Bolus-triggering had a slightly higher sPPV compared to fixed-timing, 87% (95%CI: 81-91%) versus 78% (95%CI: 66-86%) (p = 0.077). No differences were observed in other subgroups. CONCLUSIONS: This meta analysis showed a sPPV of 81% for predicting resectability by CT, meaning that 19% of patients falsely undergo surgical exploration. KEY POINTS: * Predicting resectability of pancreatic cancer by CT is 81% (95%CI: 75-86%). * The percentage of patients falsely undergoing surgical exploration is 19%. * The false positives are liver metastases, peritoneal metastases, or lymph node metastases. PMID- 28093627 TI - [Validation of the German version of the 6-item screener : Brief cognitive test with broad application possibilities]. AB - BACKGROUND: Especially during admission the detection of cognitive deficits relevant to everyday life should burden patient and examiner as little as possible. The 6-item screener (SIS) takes approximately 1 min, is easy to learn, does not require any material and is independent of the patient's visual and fine motor skills. The test was first published in 2002 by Callahan who approved the present German translation. OBJECTIVE: We checked the convergent and discriminant validity, reliability and sensitivity to change of the German translation among geriatric patients. MATERIAL AND METHODS: A total of 165 patients in an acute geriatric department performed the SIS (4 times), the mini mental state examination (MMSE, 2 times), clock-drawing test according to Shulman (2 times), the Regensburg verbal fluency test (2 times) and the Montgomery-Asberg depression rating scale within a period of 16 days. The overall judgment of a physician blinded to the test results served as the reference standard. RESULTS: The SIS closely correlated with the medical judgment (-0.729). The retest reliability was 0.705 and the internal consistency 0.821 (Cronbach's alpha). The sensitivity to detect cognitive deficits relevant to activities of daily living was 100% if a threshold of 5 points was chosen. The achievement of maximum points largely rules out even mild cognitive impairment. CONCLUSION: The SIS is a valid, reliable short cognitive test. Using a threshold of 5 points the SIS detects cognitive deficits relevant to daily living with a higher sensitivity than the MMSE with a threshold of 25. When the maximum score is achieved there are no medical indications for further cognitive assessment of clinically unremarkable geriatric patients. The brevity and simple application of the SIS also enable its application outside geriatric wards. PMID- 28093628 TI - Perioperative patient education improves long-term satisfaction rates of low-risk prostate cancer patients after radical prostatectomy. AB - PURPOSE: To evaluate patient-reported functional outcomes after radical prostatectomy (RP) and to analyse the effect of perioperative patient education on satisfaction rates among low-risk prostate cancer patients. METHODS: Inclusion criteria encompassed low-risk prostate cancer patients as defined by the D'Amico criteria, undergoing nerve-sparing RP without pelvic lymph node dissection. Patient-centred functional outcomes, subjective evaluation of perioperative counselling, and patient satisfaction rates were documented. Stress urinary incontinence (SUI) was assessed by daily pad usage. Erectile dysfunction (ED) was assessed using IIEF5 score. Patients' histories were attained from the electronic medical records. The effect of pre-defined predictive features for satisfaction rates was analysed in low-risk patients. Statistical analyses included Fisher's exact test, Mann-Whitney-U test, and binary logistic regression models (p < 0.05). RESULTS: 266 patients met the inclusion criteria. Median follow-up was 94 months (68-118). The global satisfaction rate was 75.1%. Regarding SUI, 69.5% of patients required no pads. 67.1% felt very well informed, while 11.7% felt poorly educated about postoperative SUI. Regarding ED, an IIEF score of >=18 was reached by 33.7%. 59.6% felt very well educated, while 13.0% felt poorly informed. Poor patient counselling regarding SUI and ED led to significantly decreased long-term satisfaction rates [40.7, 33.3% (p < 0.001)]. In multivariate analysis, poor ED patient counselling [OR 0.190, 95% CI 0.055-0.652 (p = 0.008)], and postoperative IIEF5 score [OR 3.061, 95% CI 1.013-3.111 (p = 0.013)] could be confirmed as independent predictors for patient satisfaction. CONCLUSIONS: Patient-centred functional outcome analysis has illustrated the importance of perioperative patient education on long-term patient satisfaction rates after RP in low-risk prostate cancer patients. PMID- 28093629 TI - Liquid release as a source of potential drug exposure during the handling of intravenous infusions in nursing. AB - PURPOSE: This study aims at experimentally determining the incidence and extent of liquid releases onto the operator's hands and into the work environment during common nursing operations involving infusions. METHODS: A sequence of operations related to the preparation and administration of infusions was conducted by three subjects for 15 times each using fluorescein marked infusion solutions and two different infusion sets (standard set vs. safety-optimized set). Unintended release of liquid was quantified by glove and surface wipe sampling and HPLC/FD analysis of the samples. Operations concerning the disposal of infusions were also part of the study. RESULTS: In over 90% of the simulations, a release of infusion solution was observed in a standard workflow, comprising priming and decapping the infusion set, connecting it to a peripheral intravenous (IV) cannula, and detaching it again. Based on median values (229 vs. 26 MUl), the release of infusion solution was about ninefold higher when using the non optimized standard infusion set. During decapping, a hand contamination was found in a majority of cases. CONCLUSIONS: The handling of infusions may involve a risk of nurses' exposure to active agents by release of infusion solution into the work environment. According to our results with different infusion sets, exposure risks can be reduced technically and by appropriate handling. Nevertheless, hand contaminations found for both sets emphasize the necessity for additional measures such as more consistent use of protective gloves. PMID- 28093631 TI - [Retinal artery occlusion]. AB - Retinal artery occlusion leads to profound visual impairment in the affected eye. It is rarely caused by local ophthalmic pathologies. Most patients present with a large number of cardio- and cerebrovascular risk factors. Visual loss is the leading symptom in central retinal artery occlusion (CRAO), whereas a circumscribed visual field defect is claimed in branch retinal artery occlusion (BRAO). Although many attempts have been made to improve the course of the disease, no effective therapy is available. There is some hope that intravenous fibrinolysis could influence the natural course but the therapeutic window is small (ca. 4.5 h), and treatment efficacy is still not proven. It is important for ophthalmologists to guide the patients to a comprehensive and prompt neurological and cardiological diagnostic work-up. PMID- 28093630 TI - Brassica napus DS-3, encoding a DELLA protein, negatively regulates stem elongation through gibberellin signaling pathway. AB - KEY MESSAGE: Identification and characterization of a semi-dwarfing gene ds-3 encoding a mutant DELLA protein regulating plant height through gibberellin signaling pathway. Lodging is one of the most important factors causing severe yield loss in oilseed rape. Utilization of semi-dwarf varieties has been proved the most effective way to increase lodging resistance and yield in many crops. To develop semi-dwarf germplasm in oilseed rape, we identified a semi-dwarf mutant ds-3 which showed a reduced response to phytohormones gibberellins (GAs). Genetic analysis indicated the dwarfism was controlled by a single semi-dominant gene, ds 3. The DS-3 gene was mapped to a genomic region on chromosome C07, which is syntenic to the region of a previously identified semi-dwarf gene ds-1 (BnaA06.RGA). In this region, DS-3 (BnaC07.RGA) gene was identified to encode a DELLA protein that functions as a repressor in GA signaling pathway. A substitution of proline to leucine was identified in ds-3 in the conserved VHYNP motif, which is essential for GA-dependent interaction between gibberellin receptor GID1 and DELLA proteins. Segregation analysis in the F2 population derived from the cross between ds-1 and ds-3 demonstrated that BnaA06.RGA displayed a stronger effect on plant height than BnaC07.RGA, indicating that different RGA genes may play different roles in stem elongation. In addition to BnaA06.RGA and BnaC07.RGA, two more RGA genes (BnaA09.RGA and BnaC09.RGA) were identified in the Brassica napus (B. napus) genome. Reverse-transcription polymerase chain reaction (RT-PCR) and yeast two-hybrid (Y2H) assays suggest that both BnaA09.RGA and BnaC09.RGA are transcribed in leaves and stems and can mediate GA signaling in vivo. These genes represent potential targets for screening ideal semi-dwarfing alleles for oilseed rape breeding. PMID- 28093632 TI - Ureterocystoneostomy in complex oncological cases with an "Uebelhoer" modified Boari bladder flap. AB - PURPOSE: The study aims to describe the technique and analyze the outcome of an arcuated bladder incision with building of a triangular flap, first described by Uebelhoer (UBBF), as a modification of the classical rectangular Boari bladder flap (BBF), that is often viable, but can present difficulties, such as reduced flap vascularization and mobility in pretreated patients. METHODS: Twelve consecutive patients with distal or mid ureteral leakage or stenosis, that underwent UBBF, were retrospectively analyzed. We assessed postoperative morbidity using Clavien-Dindo classification. Short- and long-term functional outcomes were assessed using glomerular filtration rate (GFR), ultrasound, and renal scintigraphy. RESULTS: Patients underwent UBBF during initial oncological surgery in five cases and due to ureteral defects following oncological surgery or radiotherapy in seven cases. Median patient age was 57 (interquartile range (IQR) 46-72), defect length was 7.5 cm (IQR 5-8 cm), and median follow-up period was 41 (IQR 36-48) months. In short-term follow-up, 11/13 postoperative morbidities were Clavien-Dindo level I-II complications, mostly infections. Two level IIIa complications occurred. One anastomotic leakage was treated sufficiently with temporarily ureteral stenting and one voiding disorder needed intervention. In the long-term follow-up, 84% of patients had improved or constant GFR. In the one-year renal scintigraphy, no urodynamically relevant voiding disorder occurred. CONCLUSIONS: The UBBF is a reliable procedure to reconstruct ureteral trauma even in complex oncological, pretreated patients suffering from distal or mid ureteral defects. It can be performed easily by a modified arcuate incision and provides good long-term functional outcomes. PMID- 28093633 TI - Dietary potassium intake is beneficial to bone health in a low calcium intake population: the Korean National Health and Nutrition Examination Survey (KNHANES) (2008-2011). AB - : Dietary potassium may neutralize acid load and reduce calcium loss from the bone, leading to beneficial effect on bone mineral density. In this nationwide Korean population study, dietary potassium intake was associated with improved bone mineral density in older men and postmenopausal women. INTRODUCTION: Nutrition is a major modifiable factor that affects bone health. The accompanying anion in dietary potassium may act as an alkaline source by neutralizing the acid load and reducing calcium loss from the bone. We aimed to evaluate the association between dietary potassium intake and bone mineral density (BMD) in the Korean population. METHODS: We analyzed a total of 3135 men aged >50 years and 4052 postmenopausal women from the Korean National Health and Nutrition Examination Survey (KNHANES). Lumbar spine, total hip, and femur neck BMD were measured using dual energy X-ray absorptiometry. The daily food intake was assessed using a food frequency questionnaire. RESULTS: When we divided the participants into tertiles based on the intake of potassium intake, the highest potassium intake tertile group showed a significantly higher total hip and femur neck BMD as compared to lower tertile groups (0.914 +/- 0.004, 0.928 +/- 0.003, 0.925 +/- 0.004 mg/day across the tertiles, P = .014 for total hip; 0.736 +/- 0.003, 0.748 +/- 0.003, 0.750 +/- 0.004 mg/day, P = .012 for femur neck). Postmenopausal women in the highest potassium intake tertile group showed significantly higher lumbar, total hip, and femur neck BMD as compared to those in lower potassium intake tertile groups (0.793 +/- 0.004, 0.793 +/- 0.003, 0.805 +/- 0.004 mg/day across the tertiles, P = .029 for lumbar spine; 0.766 +/- 0.003, 0.770 +/- 0.002, 0.780 +/- 0.003 mg/day, P = .002 for total hip; 0.615 +/- 0.003, 0.619 +/- 0.002, 0.628 +/- 0.003 mg/day, P = .002 for femur neck). CONCLUSIONS: Dietary potassium intake was positively associated with BMD in men aged >50 years and postmenopausal women, indicating the beneficial effects of dietary potassium intake on bone health. PMID- 28093634 TI - International Osteoporosis Foundation and European Calcified Tissue Society Working Group. Recommendations for the screening of adherence to oral bisphosphonates. AB - : Adherence to oral bisphosphonates is low. A screening strategy is proposed based on the response of biochemical markers of bone turnover after 3 months of therapy. If no change is observed, the clinician should reassess the adherence to the treatment and also other potential issues with the drug. INTRODUCTION: Low adherence to oral bisphosphonates is a common problem that jeopardizes the efficacy of treatment of osteoporosis. No clear screening strategy for the assessment of compliance is widely accepted in these patients. METHODS: The International Osteoporosis Foundation and the European Calcified Tissue Society have convened a working group to propose a screening strategy to detect a lack of adherence to these drugs. The question to answer was whether the bone turnover markers (BTMs) PINP and CTX can be used to identify low adherence in patients with postmenopausal osteoporosis initiating oral bisphosphonates for osteoporosis. The findings of the TRIO study specifically address this question and were used as the basis for testing the hypothesis. RESULTS: Based on the findings of the TRIO study, specifically addressing this question, the working group recommends measuring PINP and CTX at baseline and 3 months after starting therapy to check for a decrease above the least significant change (decrease of more than 38% for PINP and 56% for CTX). Detection rate for the measurement of PINP is 84%, for CTX 87% and, if variation in at least one is considered when measuring both, the level of detection is 94.5%. CONCLUSIONS: If a significant decrease is observed, the treatment can continue, but if no decrease occurs, the clinician should reassess to identify problems with the treatment, mainly low adherence. PMID- 28093635 TI - Different intraoperative kinematics, stability, and range of motion between cruciate-substituting ultracongruent and posterior-stabilized total knee arthroplasty. AB - PURPOSE: The aim of this study was the comparison of intraoperative kinematics, stability, and range of motion (ROM) between the native osteoarthritic knee and cruciate-substituting fixed-bearing total knee arthroplasty (TKA) using both an ultracongruent (UC) and a posterior-stabilized (PS) insert design in the same patient. We hypothesized less knee flexion and less antero-posterior stability in the UC TKA. METHODS: Intraoperative measurements of kinematics, stability, and ROM were performed in 40 patients before soft-tissue release and bone cuts, and after implantation of the final femoral and tibial implants with both a UC insert and a PS insert. All measurements were performed using a navigation system. RESULTS: Kinematics changed significantly from a constant posterior femoral rollback before surgery to a paradoxical anterior translation during initial knee flexion with both inserts, but less pronounced with the PS insert (p < 0.001). There was significantly more posterior femoral rollback with the PS insert compared to the UC insert (p < 0.01). Stability measurements demonstrated no differences at full extension and 30 degrees of knee flexion but significantly increased antero-posterior translation in 60 degrees and 90 degrees of knee flexion with the UC insert compared to the PS insert (p < 0.001). ROM measurements demonstrated improvement of knee flexion from 118 degrees at the beginning of the surgery to 123 degrees with the UC insert and 128 degrees with the PS insert (p < 0.001). CONCLUSION: The use of a UC insert intraoperatively resulted in less antero-posterior stability and slightly less knee flexion compared to a PS insert. Surgeons should be aware of these differences when deciding for one of these options to substitute the posterior cruciate ligament (PCL). The impact of these findings on clinical outcome needs further investigation. LEVEL OF EVIDENCE: II. PMID- 28093636 TI - Non-surgical treatment of pubic overload and groin pain in amateur football players: a prospective double-blinded randomised controlled study. AB - PURPOSE: The incidence of groin pain in athletes is steadily increasing. Symptomatic pubic overload with groin pain and aseptic osteitis pubis represent well-known and frequently misdiagnosed overuse injuries in athletes. This study investigated the benefits of standardised non-surgical treatment for swift return to-football. METHODS: In a prospective double-blinded controlled study, 143 amateur football players with groin pain as well as radiological signs and clinical symptoms of pubic overload were analysed for 1 year. Two randomised study groups participated in an intensive physical rehabilitation programme, either with or without shock wave therapy. The control group did not participate in any standardised rehabilitation programme but only stopped participating in sports activity. Follow-up examinations took place 1, 3 months and 1 year after the beginning of therapy. Endpoints were visual analogue scale (VAS), functional tests, the time of return-to-football, recurrent complaints and changes in the MR image. RESULTS: Forty-four football players with groin pain and aseptic osteitis pubis were randomised into two study groups; 26 received shock wave therapy, 18 did not. Clinical examination showed pubic overload as a multi-located disease. Players receiving shock wave therapy showed earlier pain relief in the VAS (p < 0.001) and returned to football significantly earlier (p = 0.048) than players without this therapy. Forty-two of 44 players of both study groups returned to football within 4 months after the beginning of therapy and had no recurrent groin pain within 1 year after trauma. Fifty-one players of the control group returned to football after 240 days (p < 0.001), of whom 26 (51%) experienced recurrent groin pain. Follow-up MRI scans did not show any effect of shock wave therapy. CONCLUSION: Non-surgical therapy is successful in treating pubic overload and osteitis pubis in athletes. Shock wave therapy as a local treatment significantly reduced pain, thus enabling return-to-football within 3 months after trauma. Early and correct diagnosis is essential for successful intensive physiotherapy. LEVEL OF EVIDENCE: I. PMID- 28093637 TI - Exploring differences in adverse symptom event grading thresholds between clinicians and patients in the clinical trial setting. AB - PURPOSE: Symptomatic adverse event (AE) monitoring is essential in cancer clinical trials to assess patient safety, as well as inform decisions related to treatment and continued trial participation. As prior research has demonstrated that conventional concordance metrics (e.g., intraclass correlation) may not capture nuanced aspects of the association between clinician and patient-graded AEs, we aimed to characterize differences in AE grading thresholds between doctors (MDs), registered nurses (RNs), and patients using the Bayesian Graded Item Response Model (GRM). METHODS: From the medical charts of 393 patients aged 26-91 (M = 62.39; 43% male) receiving chemotherapy, we retrospectively extracted MD, RN and patient AE ratings. Patients reported using previously developed Common Terminology Criteria for Adverse Events (CTCAE) patient-language adaptations called STAR (Symptom Tracking and Reporting). A GRM was fitted to calculate the latent grading thresholds between MDs, RNs and patients. RESULTS: Clinicians have overall higher average grading thresholds than patients when assessing diarrhea, dyspnea, nausea and vomiting. However, RNs have lower grading thresholds than patients and MDs when assessing constipation. The GRM shows higher variability in patients' AE grading thresholds than those obtained from clinicians. CONCLUSIONS: The present study provides evidence to support the notion that patients report some AEs that clinicians might not consider noteworthy until they are more severe. The availability of GRM methodology could serve to enhance clinical understanding of the patient symptomatic experience and facilitate discussion where AE grading discrepancies exist. Future work should focus on capturing explicit AE grading decision criteria from MDs, RNs, and patients. PMID- 28093638 TI - Depletion of p42.3 gene inhibits proliferation and invasion in melanoma cells. AB - PURPOSE: The p42.3 gene is identified recently, and the upregulated expression has been characterized in a variety of human cancers and embryonic tissues but not yet in malignant melanoma. In this study, we explored the role of p42.3 gene in the development of melanoma. METHODS: The expression of p42.3 was detected by immunohistochemistry staining of 261 cases of patient lesions, including nevi and melanoma, and its correlation with clinical pathological characteristics and prognosis was analyzed. Furthermore, a series of in vitro assays were used to investigate the biological function of p42.3 in melanoma cells. RESULTS: Immunohistochemistry staining showed an elevated expression level of p42.3 in melanoma compared to nevi (P = 0.001). Statistical analysis indicated that this high level was well correlated with patients' clinical stage (P = 0.045), but not with gender, age, clinical type, mitotic rate, and overall survival (P > 0.05). Moreover, in vitro assays showed knockdown p42.3 gene expression could inhibit the biological profiling, including proliferation, migration, and invasion of melanoma cells, and also affect PI3K/Akt pathway, MAPK pathway, and beta-catenin. CONCLUSIONS: This study suggests that p42.3, acting like an oncogene, is involved in the malignant transformation process of melanoma and may serve as a biomarker for diagnostic and treatment purposes. PMID- 28093639 TI - The effectiveness of radiotherapy for leukemia cutis. AB - BACKGROUND: Leukemia cutis (LC) is a rare clinical presentation of leukemia that is associated with poor prognosisabs. To date, the value of radiotherapy (RT) for the treatment of LC remains controversial. Therefore, the aim of this study was to analyse the effectiveness of various RT doses for LC. METHODS AND MATERIALS: Between January 2000 and January 2016, 13 patients underwent RT at our institution after exhibiting progressive disease following other treatment modalities. RESULTS: A total of 36 radiation courses were administered to 13 patients (8 females, 5 males) with a median age of 41 years (range 2-76). Radiation modalities included 32 focal treatments, while total skin electron beam therapy was applied to four patients. The median RT dose was 27 Gy (range 8-34). A complete response rate (CRR) to RT was achieved for 32/36 (89%) lesions (100% for AML lesions versus 33% for the other leukemias; P < 0.001). The median duration of local control (DOLC) for the entire cohort was 38 months (range 0 98), while the median survival (MS) from the time of LC presentation was 13 months (range 2.5-106). The CRR for the LC lesions treated with high-dose regimens (>26 Gy) versus low-dose regimens (<=26 Gy) was 95 versus 83%, respectively (P = 0.26), and the median DOLC was 44 months versus 10 months, respectively (P = 0.019). AML patients had a better long-term outcome than the other patients according to median DOLC (40 months versus 2 months, respectively; P < 0.001) and MS (24 versus 6 months, P = 0.004). RT was well tolerated without significant adverse events. CONCLUSION: A radiation dose <=26 Gy confer a comparable CRR to high-dose regimens and appears to be an effective treatment for controlling LC progression. However, radiation doses >26 Gy were associated with a longer DOLC. LC patients with underlying AML are associated with better outcome compared with other types of leukemia. PMID- 28093641 TI - Dwell times and risk of non-elective removal of 1-French peripherally inserted central catheters according to catheter tip position in very preterm infants. AB - : We investigated dwell times and risk of non-elective removal of 975 single lumen 1-French peripherally inserted central catheters (1FR-PICC) according to tip position in a cohort of very preterm infants with a mean (SD) gestational age of 27+6 (2+1) weeks and a mean (SD) birth weight of 988 (294) g over an eight year period. Infants with a 1FR-PICC inserted for continuous infusion of intravenous fluids within the first 30 days of life were eligible. Dwell times of PICC with elective versus non-elective removal, risk of non-elective removal of PICC according to tip position, and differences between upper versus lower limb catheter insertion were analysed. 33.8% PICC were removed non-electively. Median (IQR) dwell time was 193 (142-287) versus 154 (102-260) h for elective versus non elective removal (p < 0.001). Non-elective removal was more common for lower limb insertion sites: 41 versus 31% (p = 0.002). PICC were significantly more likely to be removed non-electively when located in the axillary (odds ratio (OR) 2.08), cephalic (OR 8.93), external iliac (OR 4.99), and femoral (OR 10.31) vein. CONCLUSION: In this cohort, dwell times of 1FR-PICC lines removed non-electively were similar to 1.9- or 2.0FR-PICC. PICC tips positioned in the axillary, cephalic, external iliac, and femoral veins had a higher risk of non-elective removal. What is Known: *Peripherally inserted central catheters (PICC) are widely used in neonatal intensive care. *Previous studies focused on 2-French PICC and newborns of all gestational ages. What is New: *Dwell times of 1-French PICC removed non-electively were similar to 2-French PICC. *1-French PICC tips positioned more peripherally had a higher risk of non-elective removal. PMID- 28093640 TI - Polypharmacy and potentially inappropriate medications: a cross-sectional analysis among 451 nursing homes in France. AB - PURPOSE: The quality of drug therapy is an important issue for nursing homes. This study aimed to assess the prevalence of polypharmacy and potentially inappropriate medications (PIMs) in a large sample of nursing home residents by using the data recorded during the preparation of pill dispensers. METHODS: This is a cross-sectional study that included 451 nursing homes across France. Information about the medications received by the 30,702 residents (73.8% women) living in these nursing homes was extracted from the system that assists in the preparation of pill dispensers in pharmacies. The anonymized database included age, sex, and medications prescribed to residents, as well as nursing home characteristics (capacity, legal status). Factors associated with excessive polypharmacy (>=10 different drugs) and PIMs according to the Laroche list were studied using multilevel regression models. RESULTS: The average number of drugs prescribed was 6.9 +/- 3.3, and excessive polypharmacy concerned 21.1% of the residents (n = 6468). According to the Laroche list, 47.4% of residents (n = 14,547) received at least one PIM. Benzodiazepines (excessive doses, long-acting benzodiazepines, and combination of benzodiazepines) and anticholinergic medications (hydroxyzine, cyamemazine, alimemazine) accounted for a large part of PIMs. Individual characteristics (age, gender) influenced the risk of receiving PIMs whereas nursing home characteristics (capacity, legal status) influenced the risk of excessive polypharmacy. CONCLUSIONS: This study shows that polypharmacy and PIMs remain highly prevalent among nursing home residents. Main PIMs concerned psychotropic and anticholinergic medications. PMID- 28093642 TI - The ethical framework for performing research with rare inherited neurometabolic disease patients. AB - : The need for performing clinical trials to develop well-studied and appropriate medicines for inherited neurometabolic disease patients faces ethical concerns mainly raising from four aspects: the diseases are rare; include young and very young patients; the neurological impairment may compromise the capability to provide 'consent'; and the genetic nature of the disease leads to further ethical implications. This work is intended to identify the ethical provisions applicable to clinical research involving these patients and to evaluate if these cover the ethical issues. Three searches have been performed on the European regulatory/legal framework, the literature and European Union-funded projects. The European legal framework offers a number of ethical provisions ruling the clinical research on paediatric, rare, inherited diseases with neurological symptoms. In the literature, relevant publications deal with informed consent, newborn genetic screenings, gene therapy and rights/interests of research participants. Additional information raised from European projects on sharing patients' data from different countries, the need to fill the gap of the regulatory framework and to improve information to stakeholders and patients/families. CONCLUSION: Several recommendations and guidelines on ethical aspects are applicable to the inherited neurometabolic disease research in Europe, even though they suffer from the lack of a common ethical approach. What is Known: * When planning and conducting clinical trials, sponsors and researchers know that clinical trials are to be performed according to well established ethical rules, and patients should be aware about their rights. * In the cases of paediatric patients, vulnerable patients unable to provide consent, genetic diseases' further rules apply. What is New: * This work discusses which ethical rules apply to ensure protection of patient's rights if all the above mentioned features coexist. * This work shows available data and information on how these rules have been applied. PMID- 28093643 TI - High Content of Dicranin in Anisothecium spirale (Mitt.) Broth., a Moss from Eastern Himalayas and Its Chemotaxonomic Significance. AB - Chemical investigation of Anisothecium spirale (Mitt.) Broth. (Family Dicranaceae), an epiphytic moss from the Darjeeling district hill region of the Eastern Himalayas was performed for the first time. Analysis of neutral lipid and phospholipid classes as well as their respective fatty acids revealed the presence of a significantly high content of octadeca-6-yn-9,12,15-trienoic acid, an acetylenic fatty acid commonly known as dicranin. Dicranin and a less abundant acetylenic fatty acid were detected in neutral lipids. The unique nature of the fatty acid signature supports the view of considering dicranin as chemotaxonomic marker for Dicranaceae members. PMID- 28093645 TI - Erratum to: Urinary angiotensin converting enzyme 2 is strongly related to urinary nephrin in type 2 diabetes patients. PMID- 28093644 TI - Guidelines for proton pump inhibitor prescriptions in paediatric intensive care unit. AB - Background Stress ulcer prophylaxis (SUP) is recommended in some situations to prevent upper gastrointestinal bleeding and is a component of standard care for patients admitted to the intensive care unit (ICU). Proton pump inhibitors (PPIs), already among the most widely prescribed drug classes, are being increasingly used. Objective To describe PPI prescribing patterns and their changes after the dissemination of guidelines. Setting Paediatric ICU (PICU), Robert-Debre Teaching Hospital, Paris, France, which admits about 800 patients annually, from full-term neonates to 18-year-olds. Method Prospective observational study with two 6-week observation periods (July-August and September-October, 2013), before and after dissemination in the PICU of PPI prescribing guidelines. Main outcome measure Changes in PPI prescribing patterns (prevalence, dosage, and indication) after the guidelines. Results The number of patients admitted to the PICU was 77 (mean age 4.6 years [range 1 day-18 years]) before and 70 (mean age 3.8 years [range 1 day-17 years]) after the guidelines. During both periods, SUP was the most common reason for PPI prescribing. The proportion of patients prescribed PPIs dropped significantly, from 51% before the guidelines to 30% after the guidelines (p < 0.001). Mean daily dosage also decreased significantly, from 1.5 mg/kg/(range 0.5-4.4) to 1.1 mg/kg (range 0.7 1.8) (p < 0.002). None of the patients experienced upper gastrointestinal bleeding during either period. Conclusion Off-label PPI prescribing for SUP was common in our PICU. The introduction of guidelines was associated with a significant decrease in PPI use and dosage. This study confirms that guidelines can change PPI prescribings patterns in paediatric practice. PMID- 28093647 TI - Evaluation of Particle Size Influence on Proximate Composition, Physicochemical, Techno-Functional and Physio-Functional Properties of Flours Obtained from Persimmon (Diospyros kaki Trumb.) Coproducts. AB - The aim of the work was to study the influence of particle size in the composition, physicochemical, techno-functional and physio-functional properties of two flours obtained from persimmon (Diospyros kaki Trumb. cvs. 'Rojo Brillante' (RBF) and 'Triump' (THF) coproducts. The cultivar (RBF and THF) and particle size significantly affected all parameters under study, although depending on the evaluated property, only one of these effects predominated. Carbohydrates (38.07-46.98 g/100 g) and total dietary fiber (32.07-43.57 g/100 g) were the main components in both flours (RBF and THF). Furthermore, insoluble dietary fiber represented more than 68% of total dietary fiber content. All color properties studied were influenced by cultivar and particle size. For both cultivars, the lower particle size, the higher lightness and hue values. RBF flours showed high values for emulsifying activity (69.33-74.00 mL/mL), while THF presented high values for water holding capacity (WHC: 9.47-12.19 g water/g sample). The bile holding capacity (BHC) and fat/oil binding values were, in general, higher in RBF (19.61-12.19 g bile/g sample and 11.98-9.07, respectively) than THF (16.12-12.40 g bile/g sample and 9.78-7.96, respectively). The effect of particle size was really evident in both WHC and BHC. Due to their dietary fiber content, techno-functional and physio-functional properties, persimmon flours seem to have a good profile to be used as potential functional ingredient. PMID- 28093646 TI - Mechanisms of inhibitory action of TRK-130 (Naltalimide), a MU-opioid receptor partial agonist, on the micturition reflex. AB - PURPOSE: To clarify the mechanism of inhibitory action of TRK-130 (Naltalimide), a unique u-opioid receptor partial agonist, on the micturition reflex. METHODS: The effect of TRK-130 on isovolumetric rhythmic bladder contractions (RBCs) was examined in guinea pigs, the effect of which was clarified by co-treatment with naloxone or in spinal cord transection. The effect of TRK-130 on urodynamic parameters was also observed in guinea pigs. In addition, the effect of TRK-130 on bladder contraction induced by peripheral stimulation of the pelvic nerve was investigated in rats. RESULTS: TRK-130 (0.001-0.01 mg/kg, iv) dose-dependently inhibited RBCs, which was dose-dependently antagonized by naloxone; however, the antagonism susceptibility was different from morphine (1 mg/kg, iv). The minimum effective dose (0.003 mg/kg) of TRK-130 remained similar in spinal cord transected animals. TRK-130 (0.0025 mg/kg, iv) increased bladder capacity without changing the voiding efficiency, maximum flow rate, and intravesical pressure at the maximum flow rate, whereas oxybutynin (1 mg/kg, iv) increased the bladder capacity but affected the other parameters. TRK-130 (0.005 mg/kg, iv) did not produce significant changes on the bladder contractions induced by peripheral stimulation of the pelvic nerve, while oxybutynin (1 mg/kg, iv) significantly suppressed the bladder contractions. CONCLUSIONS: These results suggest that TRK 130 enhances the bladder storage function by modulating the afferent limb of the micturition reflex through u-opioid receptors in the spinal cord. TRK-130 could be a more effective and safer therapeutic agent with a different fashion from antimuscarinics and conventional opioids for overactive bladder. PMID- 28093648 TI - Predicting cell viability within tissue scaffolds under equiaxial strain: multi scale finite element model of collagen-cardiomyocytes constructs. AB - Successful tissue engineering and regenerative therapy necessitate having extensive knowledge about mechanical milieu in engineered tissues and the resident cells. In this study, we have merged two powerful analysis tools, namely finite element analysis and stochastic analysis, to understand the mechanical strain within the tissue scaffold and residing cells and to predict the cell viability upon applying mechanical strains. A continuum-based multi-length scale finite element model (FEM) was created to simulate the physiologically relevant equiaxial strain exposure on cell-embedded tissue scaffold and to calculate strain transferred to the tissue scaffold (macro-scale) and residing cells (micro scale) upon various equiaxial strains. The data from FEM were used to predict cell viability under various equiaxial strain magnitudes using stochastic damage criterion analysis. The model validation was conducted through mechanically straining the cardiomyocyte-encapsulated collagen constructs using a custom-built mechanical loading platform (EQUicycler). FEM quantified the strain gradients over the radial and longitudinal direction of the scaffolds and the cells residing in different areas of interest. With the use of the experimental viability data, stochastic damage criterion, and the average cellular strains obtained from multi-length scale models, cellular viability was predicted and successfully validated. This methodology can provide a great tool to characterize the mechanical stimulation of bioreactors used in tissue engineering applications in providing quantification of mechanical strain and predicting cellular viability variations due to applied mechanical strain. PMID- 28093650 TI - Diabetes mellitus is associated with increased bleeding in pulmonary embolism receiving conventional anticoagulant therapy: findings from a "real-world" study. AB - Bleeding refers to the most important complication during anticoagulation therapy in patients with pulmonary embolism (PE). However, the incidence and risk factors of bleeding in Chinese population with anticoagulant therapy remains unknown. Although diabetes mellitus (DM) has been demonstrated to increase the risk of PE, little information of its influence on anticoagulation-associated bleeding risk can be available. In our study, 563 acute PE patients, who fulfilled the including criteria were enrolled from a single center and received conventional anticoagulant therapy. And there were 539 patients completed the 3 months following-up. The cumulative incidences of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) were 3.0% (95% CI 1.01-3.05) and 14.0% (95% CI 1.47-5.21), respectively. Besides, anemia (OR 3.52, 95% CI 1.12-11.41) and recent history of MB (OR 8.14, 95% CI 1.41-31.95) were independently associated with MB. Age >65 year (OR 1.51, 95% CI 1.12-3.11), cancer (OR 2.01, 95% CI 1.12 4.01) and therapeutic range (TTR) during 3 months (OR 0.93, 95% CI 0.91-0.98) were independently associated with CRNMB. Additionally, DM was an independent risk factor for both MB (OR 2.11, 95% CI 1.10-4.12) and CRNMB (OR 2.11, 95% CI 1.10-4.12). Notably, the incidence of MB or CRNMB was significantly higher in DM patients than non-DM patients. At the end of 3-month follow-up, the HbA1C in CRNMB group was 8.3%, yet it was 7.0% in non-CRNMB group among diabetic patients (p = 0.04). In conclusions, the bleeding rates are high in patients with acute PE who receive anticoagulant therapy. In addition to the already known bleeding risk factors, DM can also increase the bleeding risk significantly. Thus, good glycemic control may be essential after prescription of anticoagulant therapy. PMID- 28093649 TI - Naturalistic Experimental Designs as Tools for Understanding the Role of Genes and the Environment in Prevention Research. AB - Before genetic approaches were applied in experimental studies with human populations, they were used by animal and plant breeders to observe, and experimentally manipulate, the role of genes and environment on specific phenotypic or behavioral outcomes. For obvious ethical reasons, the same level of experimental control is not possible in human populations. Nonetheless, there are natural experimental designs in human populations that can serve as logical extensions of the rigorous quantitative genetic experimental designs used by animal and plant researchers. Applying concepts such as cross-fostering and common garden rearing approaches from the life science discipline, we describe human designs that can serve as naturalistic proxies for the controlled quantitative genetic experiments facilitated in life sciences research. We present the prevention relevance of three such human designs: (1) children adopted at birth by parents to whom they are not genetically related (common garden approach); (2) sibling designs where one sibling is reared from birth with unrelated adoptive parents and the other sibling is reared from birth by the biological mother of the sibling pair (cross-fostering approach); and (3) in vitro fertilization designs, including egg donation, sperm donation, embryo donation, and surrogacy (prenatal cross-fostering approach). Each of these designs allows for differentiation of the effects of the prenatal and/or postnatal rearing environment from effects of genes shared between parent and child in naturalistic ways that can inform prevention efforts. Example findings from each design type are provided and conclusions drawn about the relevance of naturalistic genetic designs to prevention science. PMID- 28093651 TI - Infections in intensive care unit adult patients harboring multidrug-resistant Pseudomonas aeruginosa: implications for prevention and therapy. AB - The purpose of this paper was to report the burden and characteristics of infection by multidrug-resistant Pseudomonas aeruginosa (MDR-PA) in clinical samples from intensive care unit (ICU) adults, and to identify predictors. This was a retrospective observational study at four medical-surgical ICUs. The case cohort comprised adults with documented isolation of an MDR-PA strain from a clinical specimen during ICU stay. Multivariate analysis was performed to identify predictors for MDR-PA infection. During the study period, 5667 patients were admitted to the ICU and P. aeruginosa was isolated in 504 (8.8%). MDR-PA was identified in 142 clinical samples from 104 patients (20.6%); 62 (43.6%) of these samples appeared to be true infections. One hundred and eighteen (83.1%) isolates were susceptible only to amikacin and colistin, and 13 (9.2%) were susceptible only to colistin. Overall, the MIC50 to meropenem was 16 MUg/mL and the MIC90 was >32 MUg/mL, with 60.4% of respiratory samples being MIC >32 MUg/mL to meropenem. Independent predictors for MDR-PA infection were fever/hypothermia [odds ratio (OR) 9.09], recent antipseudomonal cephalosporin therapy (OR 6.31), vasopressors at infection onset (OR 4.40), and PIRO (predisposition, infection, response, and organ dysfunction) score >2 (OR 2.06). This study provides novel information that may be of use for the clinical management of patients harboring MDR-PA and for the control of the spread of this organism. PMID- 28093652 TI - Structural basis for the isotype-specific interactions of ferredoxin and ferredoxin: NADP+ oxidoreductase: an evolutionary switch between photosynthetic and heterotrophic assimilation. AB - In higher plants, ferredoxin (Fd) and ferredoxin-NADP+ reductase (FNR) are each present as distinct isoproteins of photosynthetic type (leaf type) and non photosynthetic type (root type). Root-type Fd and FNR are considered to facilitate the electron transfer from NADPH to Fd in the direction opposite to that occurring in the photosynthetic processes. We previously reported the crystal structure of the electron transfer complex between maize leaf FNR and Fd (leaf FNR:Fd complex), providing insights into the molecular interactions of the two proteins. Here we show the 2.49 A crystal structure of the maize root FNR:Fd complex, which reveals that the orientation of FNR and Fd remarkably varies from that of the leaf FNR:Fd complex, giving a structural basis for reversing the redox path. Root FNR was previously shown to interact preferentially with root Fd over leaf Fd, while leaf FNR retains similar affinity for these two types of Fds. The structural basis for such differential interaction was investigated using site-directed mutagenesis of the isotype-specific amino acid residues on the interface of Fd and FNR, based on the crystal structures of the FNR:Fd complexes from maize leaves and roots. Kinetic and physical binding analyses of the resulting mutants lead to the conclusion that the rearrangement of the charged amino acid residues on the Fd-binding surface of FNR confers isotype-specific interaction with Fd, which brings about the evolutional switch between photosynthetic and heterotrophic redox cascades. PMID- 28093653 TI - The administrative project of Helicobacter pylori infection screening among junior high school students in an area of Japan with a high incidence of gastric cancer. AB - OBJECTIVE: Helicobacter pylori infection is a common chronic infection that is closely associated with gastric cancer, known to be decreasing worldwide. We set up an administrative project of screening examination for H. pylori infection in junior high school students in Akita Prefecture to investigate the current prevalence of H. pylori infection in childhood in an area where the incidence of gastric cancer is particularly high. SUBJECTS AND METHODS: All students in their second or third year of junior high school (13 to 15 years old) in two cities in Akita Prefecture were recruited. First, a urine-based enzyme-linked immunosorbent assay for detection of H. pylori antibody was performed. Then, a 13C-urea breath test (13C-UBT) was carried out in students who tested positive on the urinary test. Written informed consent was obtained from all participants and their parents. RESULTS: A total of 1813 students were recruited in this study; 1765 (97.3%) students agreed to participate in this project and underwent a screening examination. Among 96 students (5.4%) testing positive for H. pylori on the initial screening examination, 90 (93.7%, 90/96) underwent a subsequent 13C-UBT, and 85 (4.8%, 85/1765) were diagnosed as positive for H. pylori. CONCLUSIONS: The current prevalence of H. pylori infection among students was low even in an area of Japan with a high incidence of gastric cancer. PMID- 28093654 TI - Long-term outcomes of laparoscopy-assisted distal gastrectomy with suprapancreatic nodal dissection for clinical stage I gastric cancer: a multicenter phase II trial (JCOG0703). AB - BACKGROUND: Laparoscopic gastrectomy has become a common surgical treatment for gastric cancer in eastern Asian countries. However, a large-scale prospective study to investigate the benefit of laparoscopy-assisted distal gastrectomy (LADG) regarding long-term outcomes has never been reported. We have already reported the short-term outcomes of this study. Here we report long-term outcomes as the secondary endpoints of this study after a 5-year follow-up period. METHODS: This study comprised patients with clinical stage I gastric cancer who were able to undergo a distal gastrectomy. LADG with D1 plus suprapancreatic lymph node dissection was performed by credentialed gastric surgeons who had each conducted at least 30 LADG and 30 open gastrectomy procedures. The primary endpoint was the proportion of patients who developed either anastomotic leakage or pancreatic fistula. The secondary endpoints included overall survival and relapse-free survival. RESULTS: From November 2007 to September 2008, 176 eligible patients were enrolled, comprising 140 patients with pathological stage IA disease, 23 patients with pathological stage IB disease, 9 patients with pathological stage II disease, and 4 patients with pathological stage IIIA disease. No patients had recurrent disease, and three of the patients died within the follow-up period. The 5-year overall survival was 98.2% (95% confidence interval 94.4-99.4%) and the 5-year relapse-free survival was 98.2% (95% confidence interval 94.4-99.4%). CONCLUSIONS: The long-term outcomes of stage I gastric cancer patients undergoing LADG seem comparable to those of patients undergoing an open procedure, although this result should be confirmed by a randomized control trial. We have already completed accrual of 921 patients for a multicenter randomized phase III trial (JCOG0912) to confirm the noninferiority of LADG compared with open gastrectomy in terms of relapse-free survival. PMID- 28093655 TI - Antibacterial efficacy and cytotoxicity of low intensity direct current activated silver-titanium implant system prototype. AB - Silver-based devices activated by electric current are of interest in biomedicine because of their broad-spectrum antimicrobial activity. This study investigates the in vitro antibacterial efficacy and cytotoxicity of a low intensity direct current (LIDC)-activated silver-titanium implant system prototype designed for localized generation and delivery of silver ions at the implantation site. First, the antibacterial efficacy of the system was assessed against methicillin resistant Staphylococcus aureus (MRSA) over 48 h at current levels of 3 and 6 uA in Mueller-Hinton broth. The cytotoxicity of the system was then evaluated over 48 h in two phases using an in vitro model with in which the activated electrodes were suspended in growth medium in a cell-seeded tissue culture plate. In phase 1, the system was tested on human osteosarcoma (MG-63) cell line and compared to titanium controls. In phase-2, the cytotoxicity characteristics were validated with normal human diploid osteoblast cells. The LIDC-activated system demonstrated high antimicrobial efficacy against MRSA, but was also toxic to human cells immediately surrounding the electrodes. The statistical analysis showed that the cytotoxicity was a result of the presence of silver, and the electric activation did not make it worse. PMID- 28093656 TI - Measurement of crude-cell-extract glycerol dehydratase activity in recombinant Escherichia coli using coupled-enzyme reactions. AB - Glycerol dehydratase (GDHt), which converts glycerol to 3-hydroxypropionaldehyde, is essential to the production of 1,3-propanediol (1,3-PDO) or 3-hydroxypropionic acid (3-HP). A reliable GDHt activity assay in crude-cell extract was developed. In the assay, GDHt converted 1,2-propanediol (1,2-PDO) to propionaldehyde, which was further converted to 1-propionic acid by aldehyde dehydrogenase (KGSADH) or to 1-propanol by yeast-alcohol dehydrogenase (yADH), while the NADH concentration change was monitored spectrophotometrically. Cells should be disintegrated by Bead Beater/French Press, not by chemical methods (BugBuster(r)/B-PERTM), because the reagents significantly inactivated GDHt and coupling enzymes. Furthermore, in the assay mixture, a much higher activity of KGSADH (>200-fold) or yADH (>400 fold) than that of GDHt should have been maintained. Under optimal conditions, both KGSADH and yADH showed practically the same activity. The coupled-enzyme assay method established here should prove to be applicable to recombinant strains developed for the production of 3-HP and/or 1,3-PDO from glycerol. PMID- 28093658 TI - Distinguishing Pathways from Negative Emotions to Suicide Ideation and to Suicide Attempt: the Differential Mediating Effects of Nonsuicidal Self-Injury. AB - Negative emotion (NE) is one of the most widely examined risk factors for suicide ideation (SI) and suicide attempt (SA). However, little is known about the possibly different mechanisms underlying the pathways from NE to these two different suicide phenomena. Nonsuicidal self-injury (NSSI) is related to both negative emotions and suicidality. Thus, the present study aimed to test the differential roles of NSSI in the pathways from NE (specified by depression, anxiety, and stress) to SI and from NE to SA. This study hypothesized that NSSI served as a mediator in the relationship from NE to SA, but not in the relationship from NE to SI. We assessed the study variables among 3600 Chinese students (56.6% females, mean age = 14.63 years) for 3times at 6-month intervals. Structural equation modeling was used to test the hypotheses. Results partly supported the hypothesized longitudinal mediation model, such that NSSI fully mediated the relation from NE to SA in females, while partially mediated the relation from NE to SI in both females and males. Findings of this study may help to better understand the distinct mechanisms underlying the relationships from NE to SI and SA. Moreover, our finding regarding gender differences suggests the different emphases in suicide prevention and intervention programs across genders. PMID- 28093659 TI - Clinical and molecular relevance of mutant-allele tumor heterogeneity in breast cancer. AB - PURPOSE: Intra-tumor heterogeneity (ITH) plays a pivotal role in driving breast cancer progression and therapeutic resistance. We used a mutant-allele tumor heterogeneity (MATH) algorithm to measure ITH and explored its correlation with clinical parameters and multi-omics data. METHODS: We assessed 916 female breast cancer patients from The Cancer Genome Atlas. We calculated the MATH values from whole-exome sequencing data and further investigated their correlation with clinical characteristics, somatic mutations, somatic copy number alterations (SCNAs), and gene enrichment. RESULTS: The patients were divided into low, intermediate, and high MATH groups. High T stage, African American race, and triple-negative or basal-like subtype were associated with a higher MATH level (all P < 0.001). In hormone receptor-positive and human epidermal growth factor receptor-negative patients, the high MATH group showed a tendency toward a worse overall survival (P = 0.052); Furthermore, the TP53 mutation rate increased as MATH was elevated (P < 0.001), whereas CDH1 mutations were correlated with a lower level of MATH (P = 0.002). Several focal and arm-level SCNA events were more common in the high MATH group (P < 0.05), including Chr8q24 with only the MYC gene in the "peak" region. Similarly, high MATH was associated with gene set enrichment related to the MYC pathway and proliferation. CONCLUSION: Our integrative analysis reveals the clinical and genetic relevance of ITH in breast cancer. These results also suggest the origin and natural history of clonal evolution and intra-tumor genetic heterogeneity, which warrant further investigation. PMID- 28093660 TI - Privacy-Preserving Integration of Medical Data : A Practical Multiparty Private Set Intersection. AB - Medical data are often maintained by different organizations. However, detailed analyses sometimes require these datasets to be integrated without violating patient or commercial privacy. Multiparty Private Set Intersection (MPSI), which is an important privacy-preserving protocol, computes an intersection of multiple private datasets. This approach ensures that only designated parties can identify the intersection. In this paper, we propose a practical MPSI that satisfies the following requirements: The size of the datasets maintained by the different parties is independent of the others, and the computational complexity of the dataset held by each party is independent of the number of parties. Our MPSI is based on the use of an outsourcing provider, who has no knowledge of the data inputs or outputs. This reduces the computational complexity. The performance of the proposed MPSI is evaluated by implementing a prototype on a virtual private network to enable parallel computation in multiple threads. Our protocol is confirmed to be more efficient than comparable existing approaches. PMID- 28093657 TI - Advances in clinical neurology through the journal "Neurological Sciences" (2015 2016). PMID- 28093661 TI - Evolution of a neglected ureteral stent. PMID- 28093662 TI - A cost-effectiveness analysis of lisdexamfetamine dimesylate in the treatment of adults with attention-deficit/hyperactivity disorder in the UK. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurobehavioral disorder in children that may persist into adulthood. Lisdexamfetamine dimesylate (LDX) is approved in many countries for ADHD treatment in children, adolescents, and adults. OBJECTIVES: Estimate the cost effectiveness of LDX as a first- or second-line treatment for adults with ADHD from the United Kingdom (UK) National Health Service (NHS) perspective compared with methylphenidate extended release (MPH-ER) and atomoxetine (ATX). METHODS: A 1-year decision-analytic model was developed. Health outcomes included response, non-response and inability to tolerate. Efficacy data were obtained from a mixed treatment comparison (MTC). Response was a score of 1 or 2 on the Clinical Global Impression-Improvement scale. Tolerability was assessed by discontinuation rates due to adverse events. Utilities were identified via a systematic literature review. Health care resource use estimates were obtained via a survey of clinicians. Daily drug costs were estimated from mean doses reported in the trials used in the MTC. One-way and probabilistic sensitivity analyses (PSAs) were performed. RESULTS: LDX dominated MPH-ER and ATX; reducing mean per-patient annual cost by L5 and L200, and increasing mean quality-adjusted life years (QALYs) by 0.005 and 0.009, respectively. In the PSA, the probability of cost effectiveness for LDX vs. MPH-ER and ATX at a threshold of L20,000 per QALY was 61% and 80%, respectively. CONCLUSIONS: From the perspective of the UK NHS, LDX is likely to provide a cost-effective treatment for adults with ADHD. This conclusion may be drawn with more certainty in comparison with ATX than with MPH ER. PMID- 28093663 TI - Large, Prospective Analysis of the Reasons Patients Do Not Pursue BRCA Genetic Testing Following Genetic Counseling. AB - Genetic counseling (GC) and genetic testing (GT) identifies high-risk individuals who benefit from enhanced medical management. Not all individuals undergo GT following GC and understanding the reasons why can impact clinical efficiency, reduce GT costs through appropriate identification of high-risk individuals, and demonstrate the value of pre-GT GC. A collaborative project sponsored by the Michigan Department of Health and Human Services prospectively collects anonymous data on BRCA-related GC visits performed by providers in Michigan, including demographics, patient/family cancer history, GT results, and reasons for declining GT. From 2008 to 2012, 10,726 patients underwent GC; 3476 (32.4%) did not pursue GT. Primary reasons included: not the best test candidate (28.1%), not clinically indicated (23.3%), and insurance/out of pocket cost concerns (13.6%). Patient disinterest was the primary reason for declining in 17.1%. Insurance/out of pocket cost concerns were the primary reason for not testing in 13.4% of untested individuals with private insurance. Among untested individuals with breast and/or ovarian cancer, 22.5% reported insurance/out of pocket cost concerns as the primary reason for not testing and 6.6% failed to meet Medicare criteria. In a five-year time period, nearly one-third of patients who underwent BRCA GC did not pursue GT. GT was not indicated in almost half of patients. Insurance/out of pocket cost concerns continue to be barriers. PMID- 28093664 TI - Cell proliferation and differentiation during the three dimensional reconstitution of eccrine sweat glands. AB - The aim of this study is to characterize the cell proliferation and proliferating cell types during three-dimensional reconstitution of eccrine sweat glands. Eccrine sweat gland cells suspended in Matrigel were injected subcutaneously into the inguinal regions of nude mice. At 1, 2, 4, 6, 8, 14, 21, 28, 35 and 42 days post-implantation, Matrigel plugs were immunostained for Ki67, to detect cycling cells, and the Ki67 labeling index at different time points was calculated. Three pairs of antibodies, Ki67/K7, Ki67/K14 and Ki67/alpha-SMA, were used to identify proliferating cell types in the plugs, on days 28, 35 and 42, by immunofluorescence double staining. The Ki67 labeling index on the first day of implantation was 30.53%, rapidly reached a peak value of 81.43% at 2 days post implantation, and then decreased gradually to a low of 2.87% at 42 days. Double immunofluorescence staining showed that K14/Ki67 double-stained cells accounted for 80% of the Ki67-positive cells, whereas K7/Ki67 and alpha-SMA/Ki67 double stained cells each accounted for 10% of the Ki67-positive population on days 28, 35, or 42 post-implantation. We conclude that eccrine sweat gland cells rapidly enter the cell cycle after implantation, but quickly show decreased cell proliferation and increased cell differentiation. PMID- 28093665 TI - Disproportionality and Disparities among Sexual Minority Youth in Custody. AB - Research indicates that sexual minority youth are disproportionately criminalized in the U.S. and subjected to abusive treatment while in correctional facilities. However, the scope and extent of disparities based on sexual orientation remains largely overlooked in the juvenile justice literature. This study, based on a nationally representative federal agency survey conducted in 2012 (N = 8785; 9.9% girls), reveals that 39.4% of girls and 3.2% of boys in juvenile correctional facilities identified as lesbian, gay, or bisexual. These youth, particularly gay and bisexual boys, report higher rates of sexual victimization compared to their heterosexual peers. Sexual minority youth, defined as both lesbian, gay, and bisexual identified youth as well as youth who identified as straight and reported some same-sex attraction, were also 2-3 times more likely than heterosexual youth to report prior episodes of detention lasting a year or more. Implications for future research and public policy are discussed. PMID- 28093667 TI - Low and Increasing Trajectories of Perpetration of Physical Dating Violence: 7 Year Associations with Suicidal Ideation, Weapons, and Substance Use. AB - Understanding the interrelation among problem behaviors and their change over time is fundamental for prevention research. The Healthy Teens Longitudinal Study followed a cohort of adolescents from Grades 6-12. Prior research identified two distinct trajectories of perpetration of physical dating violence: Low and Increasing. The purpose of this study was to examine whether adolescents in these two trajectories differed longitudinally on other problem behaviors: (1) suicidal ideation and attempts, (2) weapon-carrying and threats with a weapon, and (3) substance use, particularly alcohol and marijuana. The sample consisted of 588 randomly-selected students (52% males; 49% White, 36% Black, 12% Latino). Students completed a self-reported, computer-based survey each spring from Grades 6-12. To examine significant differences by perpetration of physical dating violence trajectory, we used Chi-square test and generalized estimating equations modeling. Across most grades, significantly more students in Increasing than in the Low trajectory reported suicidal ideation and attempts, carried a weapon, and threatened someone with a weapon. Adolescents in the Increasing trajectory also had higher trajectories of alcohol use, being drunk, and marijuana use than those in the Low trajectory. All differences were already significant in Grade 6. The difference in the rate of change between groups was not significant. This longitudinal study highlights that problem behaviors-physical dating violence, suicidal ideation and attempts, weapon carrying and threats, marijuana and alcohol use-cluster together as early as sixth grade and the clustering persists over time. The combination of these behaviors poses a great public health concern and highlight the need for early interventions. PMID- 28093668 TI - Molecular characterization of HOXC8 gene and methylation status analysis of its exon 1 associated with the length of cashmere fiber in Liaoning cashmere goat. AB - Homeobox protein Hox-C8 (HOXC8) is a member of Hox family. It is expressed in the dermal papilla of the skin and is thought to be associated with the hair inductive capacity of dermal papilla cells. In the present study, we isolated and characterized a full-length open reading frame of HOXC8 cDNA from the skin tissue of Liaoning cashmere goat, as well as, established a phylogenetic relationship of goat HOXC8 with that of other species. Also, we investigated the effect of methylation status of HOXC8 exon 1 at anagen secondary hair follicle on the cashmere fiber traits in Liaoning cashmere goat. The sequence analysis indicated that the obtained cDNA was 1134-bp in length containing a complete ORF of 729-bp. It encoded a peptide of 242 amino acid residues in length. The structural analysis indicated that goat HOXC8 contained a typical homeobox domain. The phylogenetic analysis revealed that Capra hircus HOXC8 had a closer genetic relationship with that of Ovis aries, followed by Bos Taurus and Bubalus bubalis. The methylation analysis suggested that the methylation degree of HOXC8 exon 1 in anagen secondary hair follicle might be involved in regulating the growth of cashmere fiber in Liaoning cashmere goat. Our results provide new evidence for understanding the molecular structural and evolutionary characteristics of HOXC8 in Liaoning cashmere goat, as well as, for further insight into the role of methylation degree of HOXC8 exon 1 regulates the growth of cashmere fiber in goat. PMID- 28093669 TI - Genetic diversity and population structure of Anastrepha striata (Diptera: Tephritidae) in three natural regions of southwestern Colombia using mitochondrial sequences. AB - Anastrepha striata is widely distributed across the Americas and is a pest of economically important crops, especially crops of the Myrtaceae family. Insect population structures can be influenced by the presence of physical barriers or characteristics associated with habitat differences. This study evaluated the effect of the Western Andes on the population structure of A. striata. Individuals were collected from Psidium guajava fruits from three natural regions of southwestern Colombia (Pacific Coast, mountainous region and the inter-Andean valley of the Cauca River). Based on a 1318 bp concatenated of the genes Cytochrome Oxidase subunit I (COI) and NADH dehydrogenase subunit 6 (ND6), 14 haplotypes with few changes among them (between 1 and 3) were found. There was only one dominant haplotype in all three regions. No genetic structure associated with the three eco-geographical regions of the study was found. Moreover, the Western Andes are not an effective barrier for the genetic isolation of the populations from the Pacific Coast compared with the inter-Andean valley populations. This genetic homogeneity could be partially due to anthropogenic intervention, which acts as a dispersal agent of infested fruits. Another hypothesis to explain the lack of structure would be the relatively recent arrival of A. striata to the region, as indicated by an analysis of the demographic history, which reveals a process of population expansion. This study represents the first attempt to understand the population genetics of A. striata in Colombia and could contribute to the integral management of this pest. PMID- 28093670 TI - Natural Colorants: Historical, Processing and Sustainable Prospects. AB - With the public's mature demand in recent times pressurized the textile industry for use of natural colorants, without any harmful effects on environment and aquatic ecosystem, and with more developed functionalities simultaneously. Advanced developments for the natural bio-resources and their sustainable use for multifunctional clothing are gaining pace now. Present review highlights historical overview of natural colorants, classification and predominantly processing of colorants from sources, application on textiles surfaces with the functionalities provided by them. Chemistry of natural colorants on textiles also discussed with relevance to adsorption isotherms and kinetic models for dyeing of textiles. PMID- 28093671 TI - Evaluation of laboratory-scale in situ capping sediments with purple parent rock to control the eutrophication. AB - In this study, the effectiveness of controlling the eutrophication using purple parent rock to cap the sediments was evaluated in the laboratory scale. Sediments were collected from Sanxikou reservoir (China) in July 2013. Then, three types of purple parent rock (T1f, J3p, and J2s) which are distributed widely in southwest China were used to cap the sediments. Limestone and calcite were used as the contrast group, because they had been reported as effective controls on eutrophication. Then, they were incubated at 20 degrees C for 46 days. The results indicated that the application of purple parent rock as a barrier material can effectively inhibit the release of nutrient elements in sediments, and the inhibition rates of total nitrogen (TN), total phosphorus (TP), ammonium (NH4-N), and nitrate (NO3-N) were much better than that of limestone and calcite. Among the three types of purple parent rock, J3p exhibited the best inhibitory effect on the release of nitrogen in sediments, and the inhibition efficiency of TN, NH4-N, and NO3-N was 59.7, 77.6, and 45.1%, respectively. As for T1f, it exhibited the best inhibitory effect on the release of TP in sediments with the inhibition rate of 94.4%. Whereas all these capping materials showed weak inhibition on release of organic matter in sediments, and the inhibition efficiencies were less than 20%. Moreover, these treatments could also cause distinct changes in the microbial community in sediments and overlying water, and the contents of TN and TP in all capping materials increased. All results demonstrated that purple parent rock could inhibit the release of nutrient in sediments through mechanical interception, physical adsorption, and chemical absorption as well as changing the microbial activity in the covering layer, sediments, or overlying water. PMID- 28093672 TI - Influence of QuEChERS modifications on recovery and matrix effect during the multi-residue pesticide analysis in soil by GC/MS/MS and GC/ECD/NPD. AB - A QuEChERS extraction followed by GC/MS/MS and GC-MUECD/NPD for 216 pesticide and metabolites determination in soil simultaneously were developed and compared. Volume of water, volume and polarity of solvent, and cleanup sorbents (C18, GCB, PSA) were optimized. The QuEChERS with and without purification step were applied to estimate effectiveness of the method. The recovery and matrix effect (ME) were critical parameters within each tested procedure. The optimal method without cleanup was validated. Accuracy (expressed as recovery), precision (expressed as RSD), linearity, LOQ, and uncertainty were determined. The recoveries at the three spiking levels using matrix-matched standards ranged between 65 and 116% with RSD <=17 and 60-112% with RSD <=18% for MS/MS and MUEC/NP, respectively. The LOQ ranged from 0.005-0.01 mg/kg for MS/MS to 0.05 mg/kg for MUEC/NP. The ME for most of pesticides resulted in enhancement of the signal and depended on the analyte and detection system: MS/MS showed ME from -25 to 74%, while MUEC/NP from -45 to 96%. A principal component analysis was performed to explain the relationships between physicochemical parameters and ME of 216 pesticides. The QuEChERS protocol without the cleanup step is a promising option to make the method less expensive and faster. This methodology was applied in routine analysis of 263 soil samples in which p,p' DDT was the most frequently detected (23.5% of samples) and pendimethalin with the highest concentration (1.63 mg/kg). PMID- 28093673 TI - Metagenomic insights into effects of spent engine oil perturbation on the microbial community composition and function in a tropical agricultural soil. AB - Analyzing the microbial community structure and functions become imperative for ecological processes. To understand the impact of spent engine oil (SEO) contamination on microbial community structure of an agricultural soil, soil microcosms designated 1S (agricultural soil) and AB1 (agricultural soil polluted with SEO) were set up. Metagenomic DNA extracted from the soil microcosms and sequenced using Miseq Illumina sequencing were analyzed for their taxonomic and functional properties. Taxonomic profiling of the two microcosms by MG-RAST revealed the dominance of Actinobacteria (23.36%) and Proteobacteria (52.46%) phyla in 1S and AB1 with preponderance of Streptomyces (12.83%) and Gemmatimonas (10.20%) in 1S and Geodermatophilus (26.24%), Burkholderia (15.40%), and Pseudomonas (12.72%) in AB1, respectively. Our results showed that soil microbial diversity significantly decreased in AB1. Further assignment of the metagenomic reads to MG-RAST, Cluster of Orthologous Groups (COG) of proteins, Kyoto Encyclopedia of Genes and Genomes (KEGG), GhostKOALA, and NCBI's CDD hits revealed diverse metabolic potentials of the autochthonous microbial community. It also revealed the adaptation of the community to various environmental stressors such as hydrocarbon hydrophobicity, heavy metal toxicity, oxidative stress, nutrient starvation, and C/N/P imbalance. To the best of our knowledge, this is the first study that investigates the effect of SEO perturbation on soil microbial communities through Illumina sequencing. The results indicated that SEO contamination significantly affects soil microbial community structure and functions leading to massive loss of nonhydrocarbon degrading indigenous microbiota and enrichment of hydrocarbonoclastic organisms such as members of Proteobacteria and Actinobacteria. PMID- 28093674 TI - Prospect of recovering phosphorus in magnesium slag-packed wetland filter. AB - Phosphorus recovery from wastewater not only reduces the unbearable impacts of excessive nutrient discharge on environmental systems but also favor the reuse of phosphorus resource. Based on the mechanism as well as technical analysis for major phosphorus recovery techniques including struvite precipitation and wetland substrate adsorption, a novel magnesium slag-packed wetland filter and corresponding operational procedures are proposed, which aim to reduce the dependence of using magnesium-containing chemical reagent as magnesium sources for struvite precipitation, and improve the accumulation and recovery performance for struvite precipitation within porous wetland substrate. Results from preliminary experiments indicated that magnesium slag particles with approximately 2 mm in diameter can recover 43.20-72.39% phosphorus from 1-25 mol/L PO43- solution, and the presence of 5-50 mol/L NH4+ contributed to 11.71 29.11% enhancement of phosphorus recovery mainly due to struvite precipitation. The detected generation of struvite via XRD spectrum analysis partly demonstrated the potential of phosphorus recovery in magnesium slag-packed wetland filter. The proposed phosphorus recovery technology is free of secondary pollution and solid waste generation; phosphorus-saturated (mainly due to struvite precipitation and adsorption) magnesium slag particles can be potentially used as phosphorus fertilizer and thus partly solved the traditional shortages of disposing phosphorus-saturated substrate due to low phosphorus contents. PMID- 28093675 TI - Solar photocatalytic degradation of textile effluent with TiO2, ZnO, and Nb2O5 catalysts: assessment of photocatalytic activity and mineralization. AB - The photocatalytic degradation of textile effluent was investigated using TiO2, ZnO, and Nb2O5 catalysts under solar irradiation. The procedures were carried out at ambient conditions in April 2014, with pH 3.0 and catalyst concentration of 0.250 g L-1. The photocatalytic activity of the oxides was evaluated by means of kinetic efficiency (rate constant and half-life time), chemical oxygen demand reduction, and absorbance reduction at 228, 254, 284, 310, 350, 500, and 660 nm (lambdamax). Mineralization in terms of the formation of inorganic ions and toxicity reduction using bioassays with Artemia salina were performed. TiO2 reduced the absorbance at 660 nm (lambdamax) after 300 min of solar irradiation around 94 and 93%; and 68 and 60% of COD, respectively. ZnO showed lower photocatalytic activity giving 64 and 42% of absorbance and COD reduction, respectively. The photocatalytic activity of Nb2O5 was very close to TiO2-P25. In this sense, Nb2O5 becomes a promising alternative to replace the commercial TiO2 P25. Bioassays confirmed the efficacy of treatment, increasing the lethal concentration of 27.59 (in natura) to 131.95% in the presence of Nb2O5. PMID- 28093676 TI - Aryl hydrocarbon receptor signaling involved in the invasiveness of LNCaP cells. AB - There is now mounting evidence that the aryl hydrocarbon receptor (AhR) plays an important role in physiologic responses such as development, cell cycle regulation, immune function and also malignant transformation in various tissues. The strong nuclear AhR expression is observed in the invasive phenotype, and an elevated nuclear AhR expression is associated with a poor prognosis of human prostate cancer. On the other hand, there are conflicting results that the AhR deficiency results in increased susceptibility to prostate tumors in mouse model. In the present study, we investigated AhR expression and its role in the growth and invasiveness of human prostate cancer cells. The AhR protein expression was detected in prostate cancer cell lines and human prostate cancer tissues. A small interfering RNA targeting AhR, constitutive active AhR expression vector, and AhR agonist and antagonist were used to moderate its expression and signaling. The induction of AhR signaling attenuated invasiveness of prostate cancer cells without affecting the cellular growth rate. These results suggest that AhR signaling in prostate cancer cells facilitates invasion of these cells, and modulation with this signaling can be a potential therapeutic target of invasive tumors. PMID- 28093677 TI - Communication Intervention for Young Children with Severe Neurodevelopmental Disabilities Via Telehealth. AB - Young children with neurodevelopmental disorders such as autism spectrum disorders (ASD) and Rett syndrome often experience severe communication impairments. This study examined the efficacy of parent-implemented communication assessment and intervention with remote coaching via telehealth on the acquisition of early communication skills of three young children with ASD (2) and Rett syndrome (1). Efficacy of the intervention was evaluated using single case experimental designs. First, functional assessment was used to identify idiosyncratic/potentially communicative responses and contexts for each child. Next, parents implemented functional communication training (FCT). All of the children acquired the targeted communication responses. The findings support the efficacy of telehealth as a service delivery model to coach parents on intervention strategies for their children's early communication skills. PMID- 28093678 TI - Changes in serum vascular endothelial growth factor and endostatin concentrations associated with circulating endothelial progenitor cells after acute ischemic stroke. AB - Angiogenesis is an important pathophysiological response to cerebral ischemia, and can be modulated by vascular endothelial growth factor (VEGF) and endostatin. Circulating endothelial progenitor cells (EPCs) also play an important role as an endogenous repair mechanism for ischemic injury. We sought to investigate early changes in the expression of VEGF and endostatin in serum and the circulating EPCs in patients with acute ischemic stroke (AIS) and analyzed the relations between them. The peripheral blood and serum samples were obtained from 30 patients at 1, 3, 5 and 7 d after AIS. Flow cytometry was used to quantify EPCs, and VEGF and endostatin were measured by enzyme linked immunosorbent assay. Correlation analysis was performed to assess the relations between them. Receiver operating characteristic (ROC) curve was used to appraise the value of EPCs levels in predicting the 90-day prognosis after AIS. Compared with control subjects, circulating EPCs numbers increased from a very lower initial level (P < 0.001) until 7 d after AIS. Serum VEGF and endostatin levels increased and peaked at 3 d and 5 d post-stroke (both P < 0.001), respectively. A significant correlation (P = 0.001) was found between peak serum VEGF concentration and peak endostatin concentration. VEGF/endostatin ratio at day 1 and day 3 after AIS significantly correlated with circulating EPCs numbers at day 5 (P < 0.001) and day 7 post-stroke (P < 0.001). ROC curve analysis suggested that circulating EPCs number at day 7 had a significantly predictive power for good prognosis. VEGF and endostatin may mediate EPCs proliferation in the early phase of ischemic stroke, and the circulating EPCs levels can be a predictor of clinical outcome in AIS. PMID- 28093679 TI - Effect of Single Nucleotide Polymorphisms of Toll-Like Receptor 4 (TLR 4) on Reproductive Performance and Immune Function in Dairy Cows. AB - In dairy cows, inflammatory diseases caused by infection with pathogenic bacteria post calving affect ovarian functions. This study examined the relationship between single-nucleotide polymorphisms (SNPs) of Toll-like receptor 4 (TLR4), reproductive performances [the number of artificial insemination (AI) application and days open], and immune cell functions (apoptosis and migration). Two hundred Holstein cows from the Obihiro University farm were included. The SNPs of TLR4 were genotyped by PCR-restriction fragment length polymorphism (PCR-RFLP) method. Polymorphonuclear leukocytes (PMNs) and peripheral blood mononuclear cells (PBMCs) were isolated from whole blood. The number of AI application in the animals with T/C genotype in the TLR4 exon3 was lower than that in animals with C/C genotype (1.6 +/- 0.2 and 2.2 +/- 0.2, respectively). Among the animals with TLR4 exon3 polymorphisms, the days open was shorter for the T/C cows than that for C/C cows (100.7 +/- 6.9 days and 136.6 +/- 9.0 days, respectively). The SNPs in the TLR4 intron did not affect the number of AI and days open. The apoptosis percentage of PMNs treated with lipopolysaccharide (LPS; 0.001 and 1 MUg/ml) tended to be lower in the T/C genotype compared to that in the C/C genotype. The transmigration rates of PMNs, and IL-1beta production in PBMCs were tended to be higher for the animals with the T/C genotype compared to those for animals with the C/C genotype. Taken together, these results suggest that TLR4 polymorphisms offer a meaningful tool to judge the reproductive potential and immune activity in individual cows. PMID- 28093680 TI - The international diffuse intrinsic pontine glioma registry: an infrastructure to accelerate collaborative research for an orphan disease. AB - Diffuse intrinsic pontine glioma (DIPG), a rare, often fatal childhood brain tumor, remains a major therapeutic challenge. In 2012, investigators, funded by the DIPG Collaborative (a philanthropic partnership among 29 private foundations), launched the International DIPG Registry (IDIPGR) to advance understanding of DIPG. Comprised of comprehensive deidentified but linked clinical, imaging, histopathological, and genomic repositories, the IDIPGR uses standardized case report forms for uniform data collection; serial imaging and histopathology are centrally reviewed by IDIPGR neuro-radiologists and neuro pathologists, respectively. Tissue and genomic data, and cell cultures derived from autopsies coordinated by the IDIPGR are available to investigators for studies approved by the Scientific Advisory Committee. From April 2012 to December 2016, 670 patients diagnosed with DIPG have been enrolled from 55 participating institutions in the US, Canada, Australia and New Zealand. The radiology repository contains 3558 studies from 448 patients. The pathology repository contains tissue on 81 patients with another 98 samples available for submission. Fresh DIPG tissue from seven autopsies has been sent to investigators to develop primary cell cultures. The bioinformatics repository contains next generation sequencing data on 66 tumors. Nine projects using data/tissue from the IDIPGR by 13 principle investigators from around the world are now underway. The IDIPGR, a successful alliance among philanthropic agencies and investigators, has developed and maintained a highly collaborative, hypothesis-driven research infrastructure for interdisciplinary and translational projects in DIPG to improve diagnosis, response assessment, treatment and outcome for patients. PMID- 28093681 TI - Quantifying the Benefits of Dimethyl Fumarate Over beta Interferon and Glatiramer Acetate Therapies on Work Productivity Outcomes in MS Patients. AB - INTRODUCTION: Dimethyl fumarate (DMF) is a novel oral therapy used for the treatment of relapse-remitting multiple sclerosis (RRMS). In two 2-year pivotal Phase 3 trials in patients with RRMS, DMF significantly reduced disease activity based on both clinical and magnetic resonance imaging (MRI) findings and demonstrated an acceptable safety profile. However, there is currently a lack of comparative data which explore the relationship between work productivity and health-related quality of life (HRQoL) outcomes in RRMS and how these differ among RRMS therapies, including DMF. METHODS: We explored this relationship through patient-reported data from the EuroQol Five-Dimensions (EQ-5D) tool, Work Productivity and Activity Impairment Questionnaire (WPAI), and the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS) using the Adelphi MS DSP(r) dataset. RESULTS: Our data demonstrated that patients receiving DMF experienced better outcomes, relative to patients receiving beta (beta)interferons or glatiramer acetate, in all WPAI subscales [overall; average treatment effect (ATE) -13.92, 95% confidence interval (CI) -18.87 to -7.08; p < 0.001], EQ-5D (ATE +0.075, 95% Cl 0.014-0.136; p = 0.016) and HAQUAMS [ATE -0.45, 95% Cl -0.61 to -0.29; p < 0.001]. The EQ-5D and HAQUAMS were used with WPAI to determine the relationship between HRQoL outcomes and work productivity. Multiple linear regression analyses were performed, adjusting for age, sex, body mass index, ethnicity and number of comorbid conditions. CONCLUSIONS: These data demonstrate that therapy with DMF was associated with increased work productivity and HRQoL for patients with RRMS and that these outcomes were consistently improved compared to outcomes with interferon and glatiramer acetate therapies. PMID- 28093682 TI - Association between ischemic heart disease and systemic lupus erythematosus-a large case-control study. AB - Ischemic heart disease (IHD) is a well identified cause of mortality in systemic lupus erythematosus (SLE) patients due to an accelerated premature atherosclerosis. We investigated the proportion of comorbid IHD among SLE patients derived from a large, national real-life database. Using data from the largest HMO in Israel, the Clalit Health Services, we selected for patients with SLE. These patients were compared with age and sex matched controls with regards to the proportion of IHD in a case-control study. Chi-square and t tests were used for univariate analysis, and a logistic regression model was used for multivariate analysis. The study included 5018 patients with SLE and 25090 age and sex-frequency matched controls. The prevalence of IHD in patients with SLE was increased in comparison to controls (11.3 and 3.1%, P < 0.001). In a multivariate analysis, SLE was associated with IHD (OR 3.77, 95% confidence interval 3.34-4.26). We have confirmed that SLE patients suffer a high prevalence of IHD. Our data supports that SLE is an independent risk factor for IHD. When evaluating by gender, the risk seems even more substantial in females. No significant difference was found in the risk of IHD in SLE among the difference socioeconomic strata. PMID- 28093683 TI - Simple Clinical Score to Predict 24-Week Survival Times in Patients with Inoperable Malignant Distal Biliary Obstruction as a Tool for Selecting Palliative Metallic or Plastic Stents. AB - BACKGROUND AND AIM: Endoscopic biliary drainage (EBD) is the mainstay treatment for inoperable malignant distal biliary obstruction (MDBO). Some authorities suggest that metallic stents are more cost-effective than plastic stents in patients with expected survival of at least 6 months. However, studies attempting to define the predictive factors for such survival times are limited. This study aims to develop a scoring system for predicting a survival time of <24 weeks in these patients. METHOD: Patients with MDBO from inoperable periampullary cancers who underwent EBD at Songklanagarind Hospital during 2004-2009 were retrospectively analyzed. Baseline clinical, laboratory, and imaging data were retrieved. The survival time data were retrieved from the medical records and Thailand's civil registration database. Multivariate Cox regression model coefficients were used in the development of a survival time prediction scoring system. RESULTS: Ninety-eight patients were included. The overall median survival was 17.6 weeks. Fifty-seven (58.1%) survived <24 weeks. By multivariate analysis, cancer type and liver metastasis were significant predictive factors. The Simple Clinical Score (SCS) was calculated from (2* liver metastasis) + (1* pancreatic cancer) - (2* ampullary cancer) - (1* cholangiocarcinoma), when 1 and 0 were used for the presence and absence of each factor, respectively. The cutoff value of the score >=0 had a sensitivity and specificity of 0.77 and 0.63, respectively, for predicting a survival time of <24 weeks, with AUC of 0.76. The median survival of patients with SCS <0 and >=0 was 36.6 and 13.1 weeks, respectively. CONCLUSION: The scoring system from this study may be beneficial for clinicians to select the appropriate stents in endoscopic biliary drainage in inoperable MDBO patients. PMID- 28093684 TI - Portocaval Paraganglioma : First Case Report and Review of Literature. PMID- 28093685 TI - Sleep duration, obesity, and asthma, in Florida adolescents: analysis of data from the Florida Youth Risk Behavior Survey (2009-2013). AB - PURPOSE: To examine the association between sleep duration and asthma among Florida high school students and whether body mass index (BMI) modifies this association. METHODS: This cross-sectional analysis included 16,728 participants in the Florida Youth Risk Behavior Survey (2009-2013). Using logistic regression, we examined the association between sleep duration and asthma, and, after controlling for potential confounders, analyzed the interaction between sleep duration and BMI. RESULTS: Sleeping for less than 7 h or more than 8 h on school night was associated with increased odds of current asthma. Compared with 7-8 h of sleep per night, sleeping for <7 h had an OR of 1.22 (95% CI 1.07, 1.40), while sleeping for >=9 h had and OR of 1.31 (1.06, 1.63). When stratified by body mass index (BMI), these associations were significant only in overweight adolescents, with those sleeping for <7 or >=9 h having approximately twice the odds of having current asthma (OR = 1.75 (1.45, 2.11) and OR = 2.00 (1.32, 3.02) respectively), compared with normal weight adolescents who slept for 7-8 h per night. CONCLUSION: The association between sleep duration and asthma in adolescents is modified by BMI. Short and long sleep durations are associated with asthma in overweight adolescents while no significant association is seen in those with normal BMI. PMID- 28093686 TI - Pregnancy Intention and Pregnancy Outcome: Systematic Review and Meta-Analysis. AB - Introduction Previous systematic reviews concluded that rigorous research on the relationships between pregnancy intentions and pregnancy outcomes is limited. They further noted that most studies were conducted in high-income countries and had methodological limitations. We aim to assess the current evidence base for the relationship between pregnancy intention and miscarriage, stillbirth, low birthweight (LBW) and neonatal mortality. In March 2015 Embase, PubMed, Scopus and PsychInfo were searched for studies investigating the relationship between pregnancy intention and the outcomes of interest. Methods Studies published since 1975 and in English, French or Spanish were included. Two reviewers screened titles and abstracts, read the full text of identified articles and extracted data. Meta-analyses were conducted where possible. Results Thirty-seven studies assessing the relationships between pregnancy intention and LBW were identified. A meta-analysis of 17 of these studies found that unintended pregnancies are associated with 1.41 times greater odds of having a LBW baby (95%CI 1.31, 1.51). Eight studies looking at miscarriage, stillbirth or neonatal death were found. The limited data concerning pregnancy loss and neonatal mortality precluded meta analysis but suggest these outcomes may be more common in unintended pregnancies. Discussion While there seems to be an increased risk of adverse pregnancy outcome in unintended pregnancies, there has been little improvement in either the quantity of evidence from low-income countries or in the quality of evidence generally. Longitudinal studies of pregnancy intention and pregnancy outcome, where pregnancy intention is assessed prospectively with a validated measure and where analyses include confounding or mediating factors, are required in both high- and low-income countries. PMID- 28093687 TI - Maternal Birthplace is Associated with Low Birth Weight Within Racial/Ethnic Groups. AB - Introduction While disparities in low birth weight (LBW) incidence by racial/ethnic group are well known, differences in LBW incidence by maternal birthplace within racial/ethnic groups, and particularly, differences after adjustment for pregnancy complications, are less clear. Methods We conducted a population-based study of LBW using 113,760 singleton, live birth records from King County, Washington (2008-2012), a region in the Pacific Northwest with a large immigrant population. Study participants were Asian, non-Hispanic black, Hispanic, Native Hawaiian/Other Pacific Islander (NHOPI), and non-Hispanic white women. Using multivariable logistic regression models, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) to estimate relative risk of LBW (<2500 g) related to maternal race/ethnicity and birthplace (defined by the Millennium Development Goals Regional Groupings). Results Compared with non-Hispanic white women, non-Hispanic black, Asian Indian, Filipino, Japanese, and Vietnamese women had 1.57-2.23-fold higher, statistically significant, risk of having a LBW infant, and NHOPI and Mexican women had 1.30-1.33-fold, statistically significant, higher risk. LBW risk was lower for Asian women from Eastern Asia (OR 0.68, 95% CI 0.55-0.85), non-Hispanic black women from Sub-Saharan Africa (OR 0.58, 95% CI 0.47-0.73), and non-Hispanic white women from other developed countries (OR 0.83, 95% CI 0.69-1.00), as compared with their US-born racial/ethnic counterparts. Results were, in general, similar after adjustment for pregnancy complications. Conclusions Compared with most other racial/ethnic groups, non-Hispanic whites had lower risk of LBW. Foreign-born women had lower risk of LBW compared with their US-born counterparts in the majority of racial/ethnic groups. Pregnancy complications had minimal effect on the associations. PMID- 28093688 TI - Kentucky Health Access Nurturing Development Services Home Visiting Program Improves Maternal and Child Health. AB - BACKGROUND AND OBJECTIVES: Home visitation programs are one of the numerous efforts to help reduce the rates of preterm birth and low birth weight as well as offering other improvements in maternal and child health and development. The Kentucky Health Access Nurturing Development Services (HANDS) is a voluntary, home visiting program serving first-time, high-risk mothers. This study's objective was to evaluate the impact of HANDS on maternal and child health outcomes. METHODS: HANDS administrative data, live birth certificate records and data from the Division of Child Protection and Safety were used in these analyses. We analyzed 2253 mothers who were referred to HANDS between July 2011 and June 2012 and received a minimum of one prenatal home visit (mean number of prenatal visits = 12.9) compared to a demographically similar group of women (n = 2253) who did not receive a visit. Chi square statistics and conditional logistic regression models were used to evaluate the impact of HANDS. RESULTS: HANDS participants had lower rates of preterm delivery (OR 0.74, 95% CI 0.61-0.88) and low birth weight infants (OR 0.54, 95% CI 0.44-0.67). HANDS participants also were significantly less likely to have a substantiated report of child maltreatment compared to controls (OR 0.53, 95% CI 0.43-0.65). HANDS participants also had an increase in adequate prenatal care and a reduction in maternal complications during pregnancy. Of particular important, outcomes improved as the number of prenatal home visits increased: among women receiving 1-3 prenatal home visits was 12.1%, the rate among women receiving 4-6 prenatal home visits was 13.2%, while the rate of PTB among those receiving 7 or more prenatal home visits was 9.4%. CONCLUSIONS: HANDS program participation appears to result in significant improvements in maternal and child health outcomes, most specifically for those receiving seven or more prenatal home visits. As a state-wide, large scale home visiting program, this has significant implications for the continued improvement of maternal and child health outcomes in Kentucky. PMID- 28093690 TI - Knowledge, Attitudes and Perceptions About Routine Childhood Vaccinations Among Jewish Ultra-Orthodox Mothers Residing in Communities with Low Vaccination Coverage in the Jerusalem District. AB - Background and aims Childhood vaccinations are an important component of primary prevention. Maternal and Child Health (MCH) clinics in Israel provide routine vaccinations without charge. Several vaccine-preventable-diseases outbreaks (measles, mumps) emerged in Jerusalem in the past decade. We aimed to study attitudes and knowledge on vaccinations among mothers, in communities with low immunization coverage. Methods A qualitative study including focus groups and semi-structured interviews. Results Low immunization coverage was defined below the district's mean (age 2 years, 2013) for measles-mumps-rubella-varicella 1st dose (MMR1?MMRV1) and diphtheria-tetanus-pertussis 4th dose (DTaP4), 96 and 89%, respectively. Five communities were included, all were Jewish ultra-orthodox. The mothers' (n = 87) median age was 30 years and median number of children 4. Most mothers (94%) rated vaccinations as the main activity in the MCH clinics with overall positive attitudes. Knowledge about vaccines and vaccination schedule was inadequate. Of vaccines scheduled at ages 0-2 years (n = 13), the mean number mentioned was 3.9 +/- 2.8 (median 4, range 0-9). Vaccines mentioned more often were outbreak-related (measles, mumps, polio) and HBV (given to newborns). Concerns about vaccines were obvious, trust issues and religious beliefs were not. Vaccination delay was very common and timeliness was considered insignificant. Practical difficulties in adhering to the recommended schedule prevailed. The vaccinations visits were associated with pain and stress. Overall, there was a sense of self-responsibility accompanied by inability to influence others. Conclusion Investigating maternal knowledge and attitudes on childhood vaccinations provides insights that may assist in planning tailored intervention programs aimed to increase both vaccination coverage and timeliness. PMID- 28093691 TI - Middle age enhances expression of innate immunity genes in a female mouse model of pulmonary fibrosis. AB - The lungs are highly sensitive to tissue fibrosis, with a clear age-related component. Among the possible triggers of pulmonary fibrosis are repeated inhalations of fine organic particles. How age affects this response, is still far from being fully understood. We examined the impact of middle-age on gene expression in pulmonary fibrosis, using the novel "inhalation challenge set" mouse model. Our results demonstrate that the response of female mice to exposure of Pantoea agglomerans extract primarily involves various immune-related pathways and cell-cell/cell-extracellular matrix interactions. We found that middle-age had a strong effect on the response to the P. agglomerans-induced lung fibrosis, featured by a more rapid response and increased magnitude of expression changes. Genes belonging to innate immunity pathways (such as the TLR signaling and the NK cell mediated cytotoxicity) were particularly up-regulated in middle-aged animals, suggesting that they may be potential targets for the treatment of pulmonary fibrosis caused by inhalations of organic particles. Our analysis also highlights the relevance of the "inhalation challenge set" mouse model to lung aging and related pathology. PMID- 28093689 TI - Characterizing a "Big Data" Cohort of Over 200,000 Low-Income U.S. Infants and Children for Obesity Research: The ADVANCE Early Life Cohort. AB - Introduction Low-income populations have elevated exposure to early life risk factors for obesity, but are understudied in longitudinal research. Our objective was to assess the utility of a cohort derived from electronic health record data from safety net clinics for investigation of obesity emerging in early life. Methods We examined data from the PCORNet ADVANCE Clinical Data Research Network, a national network of Federally-Qualified Health Centers serving >1.7 million safety net patients across the US. This cohort includes patients who, in 2012 2014, had >=1 valid body mass index measure when they were 0-5 years of age. We characterized the cohort with respect to factors required for early life obesity research in vulnerable subgroups: sociodemographic diversity, weight status based on World Health Organization (<2 years) or Centers for Disease Control (>=2 years) growth curves, and data longitudinality. Results The cohort includes 216,473 children and is racially/ethnically diverse (e.g., 17.9% Black, 45.4% Hispanic). A majority (56.9%) had family incomes below the Federal Poverty Level (FPL); 32% were <50% of FPL. Among children <2 years, 7.6 and 5.3% had high and low weight-for-length, respectively. Among children 2-5 years, 15.0, 12.7 and 2.4% were overweight, obese, and severely obese, respectively; 5.3% were underweight. In the study period, 79.2% of children had >=2 BMI measures. Among 4 5 year olds, 21.9% had >1 BMI measure when they were <2 years. Discussion The ADVANCE Early Life cohort offers unique opportunities to investigate early life determinants of obesity in the understudied population of low income and minority children. PMID- 28093692 TI - A case of fatal Clostridium perfringens bacteremia and sepsis following CT-guided liver biopsy of a rare neuroendocrine hepatic tumor. PMID- 28093693 TI - A simple post mortem room angiography method for the investigation of traumatic basal subarachnoid hemorrhage. AB - Identifying the site of vascular bleeding in fatal cases of traumatic basal subarachnoid hemorrhage (TBSAH) is important, but can be very difficult to achieve when there is extensive blood clot in the posterior cranial fossa. Post mortem angiography in these circumstances has been reported previously but with mixed results, and is rarely used in current practice within the United Kingdom. We have developed a simple and effective post mortem angiography method, using fluoroscopy and clear modern contrast medium, suitable for use in the autopsy room. Contrast medium was injected through an angiographic catheter positioned (with water filled balloon) in the extracranial vertebral artery (ECVA) just behind the clavicle, whilst the base of the skull and upper cervical spine area was visualized by fluoroscopy following digital subtraction of the bony images. The procedure was developed over a series of 8 TBSAH cases and using unfixed cadaveric specimens. A clear leak point was identified in 3 cases and the likely site indicated in a further fatality (all with tears subsequently confirmed by histology). In 4 cases, the bleeding point was not identified by angiography. In 7 deaths, the anatomy of the upper cervical loops and intracranial course of the vertebral arteries were well delineated by angiography and several small loop segments were documented. In 1 case, with severe degenerative vascular disease, extracranial vessel wall trauma and luminal thrombosis, angiography was unsuccessful above the level of the first cervical (C1) vertebra. Injecting contrast through the internal carotid artery, just above the bifurcation, was also shown to visualize the anterior cerebral circulation well. This method is likely to identify the main site of vascular tearing in about 50% of cases of TBSAH and to delineate the important anatomy of the vessels, prior to dissection of the upper neck and posterior fossa, thus minimizing handling artefacts and guiding the histological sampling of the vessels. PMID- 28093694 TI - Comparative Analysis on the Effect of Plantago Species Aqueous Extracts on Tissue Trace Element Content in Rats. AB - The primary objective of this study is to assess the influence of water extracts of Plantago major L., Plantago lanceolata L., and Plantago maxima Juss. ex Jacq. leaves on tissue trace element content in healthy adult Wistar rats. Twenty-eight female Wistar rats consumed pure drinking water or one of the three aqueous extracts of Plantago for 1 month. The extracts and liver, serum, hair, and adipose tissue of the rats were examined for trace element contents using inductively coupled plasma mass spectrometry. The aqueous extracts of Plantago species contained significant levels of trace elements, which were highest in P. lanceolata and P. major. The administration of every extract led to an increase in V and Si levels in the rats. At the same time, the consumption of P. lanceolata aqueous extract resulted in the accumulation of toxic elements (As, Pb) in the rats' tissues. Despite the rather high concentration of heavy metals in the P. major leaf extract, its administration did not result in the accumulation of these elements. In turn, P. maxima extract induced a significant decrease in the tissue levels of Al, Cr, I, Li, and Mn in the rats. The beneficial effect of the P. major and P. maxima preparations may be at least partially associated with the increased supply of essential trace elements, whereas the use of P. lanceolata may be harmful due to the possibility of heavy metal overexposure. PMID- 28093695 TI - Serum Zinc Deficiency and its Relation to Liver Fibrosis in Chronic HCV: a Real Life Egyptian Study. AB - Zinc is essential for the activation of approximately 300 metallo-enzymes. Serum and hepatic zinc is decreased in chronic liver disease patients, and zinc depletion has been suggested to accelerate liver fibrosis. The study was designed to assess Zinc status in chronic HCV Egyptian patients and its relationship to fibrosis stage diagnosed by FibroScan. This was a cross-sectional study on 297 Egyptian patients with naive chronic HCV. All patients underwent laboratory tests (including assessment of serum Zinc) and liver stiffness measurement (LSM) by Transient Elastography (FibroScan(r)). The study included 170 (57.2%) females and 127 (42.8%) males with a mean age 52.4 +/- 10.2 years. Most of the patients had zinc deficiency as the mean zinc level was 55.5 +/- 30.7 MUg/dl. The FibroScan scores showed that 97 patients had mild to moderate fibrosis (<=F2), while 200 patients had advanced to severe fibrosis (?F2). Zinc level was significantly lower in patients with ?F2 than those with <=F2 (52 +/- 30.7 vs 62.5 +/- 29.7, p value: 0.005), as the zinc values decreased with the progression of liver fibrosis. Serum zinc level had a negative significant correlation with INR and negative significant correlation with FibroScan score but no correlation to bilirubin, ALT, AST, or albumin. Most of Egyptian chronic liver disease patients had zinc deficiency. Zinc level gets significantly lower with progression of fibrosis. Zinc supplementation is essential before and during antiviral therapy for HCV. PMID- 28093697 TI - Sensory deafferentation syndromes: a case of Charles Bonnet and musical ear syndrome. PMID- 28093698 TI - ? PMID- 28093696 TI - Secondary haemophagocytic lymphohistiocytosis triggered by postnatally acquired cytomegalovirus infection in a late preterm infant. AB - Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory condition with impairment of cytotoxic T-cells and natural killer cells. Causes in infants are mostly hereditary immune defects as well as various infectious triggering factors, amongst these cytomegalovirus (CMV). Vertical CMV transmission may occur in utero, during birth, and by breast feeding. Usually, a CMV infection transmitted via breast milk is symptomatic only in very immature preterm infants. We report on a late preterm infant born after 35 + 5 weeks of gestation with a birth weight of 1840 g, being admitted to our intensive care unit at the age of 9 weeks with acute enteritis and severe dehydration. After a prolonged recovery, the infant developed a sepsis-like condition with hyperpyrexia, hepatosplenomegaly, and pancytopenia. Combination with high ferritin levels (2809 MUg/l), hypertriglyceridaemia (481 mg/dl), elevated soluble IL-2 receptor (sCD25, 9120 U/ml), and reduced perforin expression allowed diagnosis of HLH, caused by an acute CMV infection. Since connatal CMV infection had been ruled out earlier, we report the rare case of secondary HLH triggered by a postnatally acquired symptomatic CMV infection in an immunocompetent infant, most likely transmitted via breast milk. The infant was successfully treated with ganciclovir without need for immunosuppressive therapy. PMID- 28093699 TI - Anti-Alzheimer's disease activity of compounds from the root bark of Morus alba L. AB - The inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) plays important roles in prevention and treatment of Alzheimer's disease (AD). Among the individual parts of Morus alba L. including root bark, branches, leaves, and fruits, the root bark showed the most potent enzyme inhibitory activities. Therefore, the aim of this study was to evaluate the anti-AD activity of the M. alba root bark and its isolate compounds, including mulberrofuran G (1), albanol B (2), and kuwanon G (3) via inhibition of AChE, BChE, and BACE1. Compounds 1 and 2 showed strong AChE- and BChE-inhibitory activities; 1-3 showed significant BACE1 inhibitory activity. Based on the kinetic study with AChE and BChE, 2 and 3 showed noncompetitive-type inhibition; 1 showed mixed-type inhibition. Moreover, 1-3 showed mixed-type inhibition against BACE1. The molecular docking simulations of 1-3 demonstrated negative binding energies, indicating a high affinity to AChE and BACE1. The hydroxyl group of 1-3 formed hydrogen bond with the amino acid residues located at AChE and BACE1. Consequently, these results indicate that the root bark of M. alba and its active compounds might be promising candidates for preventive and therapeutic agents for AD. PMID- 28093700 TI - Postdiagnostic use of beta-blockers and other antihypertensive drugs and the risk of recurrence and mortality in head and neck cancer patients: an observational study of 10,414 person-years of follow-up. AB - INTRODUCTION: Growing evidence indicates that norepinephrine promotes cancer growth and metastasis whereas beta-blockers decrease these risks. This study aimed to examine the clinical impact of beta-blockers and other hypertensive drugs on disease recurrence and survival in patients with head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: This study analyzed a cohort of 1274 consecutive patients who received definitive treatments for previously untreated HNSCC at our tertiary referral center between January 2001 and December 2012. Antihypertensive use was considered positive if patients were on medication from HNSCC diagnosis to at least 1 year after treatment initiation. Cox proportional hazard models were utilized to determine associations between antihypertensive drugs and recurrence, survival, and second primary cancer (SPC) occurrence. RESULTS: Hypertension itself was not a significant variable of recurrence and survival and no antihypertensive drug use affected SPC occurrence (all P > 0.1). After controlling for clinical factors, calcium-channel blocker use remained an independent variable for index cancer recurrence, and beta blocker use was significantly associated with poor cancer-specific mortality, competing mortality, and all-cause mortality (all P < 0.05). beta-blocker use significantly affected competing and all-cause mortalities in normotensive patients, and calcium-channel blocker use affected index cancer recurrence in normotensive patients (all P < 0.05). CONCLUSIONS: Our data show that beta blocker use is associated with decreased survival and calcium-channel blockers is associated with increased cancer recurrence in patients of HNSCC. PMID- 28093702 TI - Rabies virus vaccine as an immune adjuvant against cancers and glioblastoma: new studies may resurrect a neglected potential. AB - To review the literature about the use of Rabies Virus-Vaccine (RV-V) as an anticancer immunotherapeutic modality in the light of recent findings. The literature search in relevant databases with the following key words: Rabies virus, cancer, remission. Remissions occured following RV-V injections in patients with cervical cancer and melanoma. Pilot clinical studies showed that RV V injections enhanced survival in glioblastoma patients, which is supported by findings in GL261 mouse glioma model. If public health studies demonstrate protective role of RV-V against certain types of cancers, it can be benefitted as a novel immune adjuvant in clinic. PMID- 28093701 TI - Cancer incidence in Spain, 2015. AB - PURPOSE: Periodic cancer incidence estimates of Spain from all existing population-based cancer registries at any given time are required. The objective of this study was to present the current situation of cancer incidence in Spain. METHODS: The Spanish Network of Cancer Registries (REDECAN) estimated the numbers of new cancer cases occurred in Spain in 2015 by applying the incidence-mortality ratios method. In the calculus, incidence data from population-based cancer registries and mortality data of all Spain were used. RESULTS: In 2015, nearly a quarter of a million new invasive cancer cases were diagnosed in Spain, almost 149,000 in men (60.0%) and 99,000 in women. Globally, the five most common cancers were those of colon-rectum, prostate, lung, breast and urinary bladder. By gender, the four most common cancers in men were those of prostate (22.4%), colon-rectum (16.6%), lung (15.1%) and urinary bladder (11.7%). In women, the most common ones were those of breast (28.0%), colon-rectum (16.9%), corpus uteri (6.2%) and lung (6.0%). In recent years, cancer incidence in men seems to have stabilized due to the fact that the decrease in tobacco-related cancers compensates for the increase in other types of cancer like those of colon and prostate. In women, despite the stabilization of breast cancer incidence, increased incidence is due, above all, to the rise of colorectal and tobacco related cancers. CONCLUSION: To reduce these incident cancer cases, improvement of smoking control policies and extension of colorectal cancer screening should be the two priorities in cancer prevention for the next years. PMID- 28093703 TI - African-American and Caribbean-Born Men's Perceptions of Prostate Cancer Fear and Facilitators for Screening Behavior: a Pilot Study. AB - This study describes how a concurrent exploratory mixed methodology (CEMM) approach was used to investigate perceptions of prostate cancer (CaP) fear and facilitators of screening behavior in African-American (AA) and Caribbean-born (CB) black men for instrument development. A quantitative paper-based questionnaire was modified, adapted, and administered to participants from the Personal Integrative Model of Prostate Cancer Disparity Survey and the Powe Fatalism Inventory. Focus groups and individual interviews were conducted and analyzed using thematic analysis. Of the 31 participants, 17 (55%) were CB black men and 14 (45%) were AA men. CB black men reported significantly higher mean perception of CaP treatment scores compared to AA men (8.23 versus 6.14, p < 0.05). Overall, the focus group and interview data revealed highly interrelated key themes. These themes included perceived barriers to CaP screening (e.g., health-care affordability), misconceptions about CaP (e.g., limited knowledge), and misinformation about CaP (e.g., conflicting CaP screening information from health-care providers). Feeling responsible to make sure family members were taken care of and the role of a significant other were reported as motivation for visiting the doctor. As a result of the CEMM design, a reliable survey instrument was developed to measure CaP fear and facilitators for screening behavior within subpopulations of AA men, which is important because despite their shared genetic ancestry, AA and CB black males may have very different lifestyles. PMID- 28093704 TI - Extracellular Vesicles in Multiple Sclerosis as Possible Biomarkers: Dream or Reality? AB - Extracellular vesicles are recently described as specialized structures for intercellular communication. Their role in the central nervous system was diffusely studied in both physiological and pathological condition. In particular, an increased extracellular vesicle number was detected in several autoimmune diseases, including multiple sclerosis, a chronic autoimmune, inflammatory, demyelinating and neurodegenerative disease. This chapter summarizes the available information on the involvement of the extracellular vesicles in multiple sclerosis pathogenesis and their possible use as biomarker of therapy efficacy. PMID- 28093705 TI - Manipulation of Oxygen and Endoplasmic Reticulum Stress Factors as Possible Interventions for Treatment of Multiple Sclerosis: Evidence for and Against. AB - Multiple sclerosis (MS) is normally considered a chronic inflammatory disease of the central nervous system (CNS), where T-cells breaching the blood brain barrier react against proteins of the axonal myelin sheaths, leading to focal plaques and demyelination in the brain and spinal cord. Many current therapies are immunosuppressive in nature and are designed to target the immune system at an early stage of the disease. But there is no cure and MS may evolve into a neurodegenerative disease, where immunomodulatory treatments appear less effective. Neurodegeneration is influenced by oxidative and endoplasmic reticulum (ER) mediated stress which can be induced independently of immune processes. Since 1970, MS patients have been self-managing their long term symptoms using hyperbaric oxygen and reporting improvement in their symptoms, especially bladder control. In contrast, the majority of clinical trial evidence does not support the views of patients. Therefore does oxygen under pressure affect brain tissue by modulating oxidative or ER stress at the cellular level resulting in CNS tissue repair or deterioration? This chapter reviews our understanding and the role of oxidative and ER stress in the context of employing hyperoxia treatments to treat MS and evaluate its effects on neural cells. PMID- 28093706 TI - Heat Shock Proteins in Multiple Sclerosis. AB - Multiple sclerosis (MS) is an immune-mediated and neurodegenerative central nervous system disease, mostly affect myelin sheaths. The MS pathogenesis is still under debate. It is influenced by genetic, environment factors. Heat shock proteins (HSPs) are highly conserved proteins seen in all organisms. Not only heat stress but also under many stress conditions they are overexpressed. Their roles in MS pathogenesis are highly correlated with their location (intracellular or extracellular). In this chapter, we will discuss the role of HSP in MS pathogenesis. PMID- 28093707 TI - Meaning of Self in Multiple Sclerosis: Implications for Treatment and Rehabilitation. AB - Low participation of multiple sclerosis (MS) patients in the therapeutic process is considered a primary area in research on the management of this condition. One of the key research directions is the role of self and self-involvement in MS patients. Clinical symptoms of MS and unpredictability of this condition may affect patients' attitude to their self and self-involvement. Self-image and self appraisal of one's abilities to cope with the disease exert significant effects not only on patient's emotional status but also on their behavior. This assumption is consistent with the cognitive-behavioral paradigm according to which emotions and behaviors of an individual reflect specific self interpretation, self-assessed situational context and self-perceived ability to cope with a given situation. Enforcement of self-esteem and self-efficacy may promote self-management and thus, increase patients' participation in the therapeutic process. In this paper, we briefly review recent advances in research on the role of self in treatment and rehabilitation of MS patients. PMID- 28093708 TI - Multiple Sclerosis and EIF2B5: A Paradox or a Missing Link. AB - Multiple sclerosis (MS) is an encumbering inflammatory condition of the central nervous system (CNS) caused by axonal demyelination. There is sufficient evidence suggesting role of eukaryotic translation initiation factor 2B (EIF2B) gene family encoding the five subunits of eIF2B complex-alpha, beta, gamma, delta and epsilon respectively, in causing vanishing white matter (VWM) disease of the brain. Incidentally researchers have proposed overlapping between MS and VWM in terms of clinical, biochemical and genetic aspects, which incited us to write this chapter to explore the association between EIF2B5 and MS. eIF2B plays an essential role in translation initiation and its regulation in eukaryotes. Among EIF2B gene family, EIF2B5 gene encodes the catalytic and a crucial epsilon subunit of the eIF2B protein as most of the alterations have been found in this gene. The recent findings on the association between EIF2B5 and MS susceptibility point towards unfathomable and contentious role of EIF2B5 in MS development. This chapter briefly reviews the insights gleaned from recent studies conducted in understanding the association between EIF2B5 and MS risk. The need of hour is to conduct large scale conclusive studies aimed at expounding the mechanisms behind this relationship. PMID- 28093709 TI - Molecular Genetic and Epigenetic Basis of Multiple Sclerosis. AB - Multiple Sclerosis (MS) is a chronic immune-mediated disease of spinal cord and brain. The initial event in MS occurs when activated CD4+ T cells in periphery exacerbates immune responses by stimulating immune cells such as B cells, CD8+ cells, mast cells, granulocytes and monocytes. These proinflammatory cells pass blood brain barrier by secreting proinflammatory cytokines including TNF-alpha and INF-gamma which activate adhesion factors. APCs (antigen-presenting cells) reactivate CD4+ T cells after infiltrating the CNS and CD4+ T cells produce cytokines and chemokines. These proinflammatory cytokines aggravate inflammation by inducing myelin phagocytosis through microglia and astrocytes activation. MS is believed to have a multifactorial origin that includes a combination of multiple genetic, environmental and stochastic factors. Although the exact component of MS risks that can be explained by these factors is difficult to determine, estimates based on genetic and epidemiological studies suggest that up to 60-70 % of the total risk of MS may be contribute to genetic factors. In continue, firstly we provide an overview of the current understanding of epigenetic mechanisms, and so present evidence of how the epigenetic modifications contribute to increased susceptibility of MS. We also explain how specified epigenetic modifications may influence the pathophysiology and key aspects of disease in MS (demyelination, remyelination, inflammation, and neurodegeneration). Finally, we tend to discuss how environmental factors and epigenetic mechanisms may interact to have an effect on MS risk and clinical outcome and recommend new therapeutic interventions that might modulate patients' epigenetic profiles. PMID- 28093710 TI - Role of Oligodendrocyte Dysfunction in Demyelination, Remyelination and Neurodegeneration in Multiple Sclerosis. AB - Oligodendrocytes (OLs) are the myelinating cells of the central nervous system (CNS) during development and throughout adulthood. They result from a complex and well controlled process of activation, proliferation, migration and differentiation of oligodendrocyte progenitor cells (OPCs) from the germinative niches of the CNS. In multiple sclerosis (MS), the complex pathological process produces dysfunction and apoptosis of OLs leading to demyelination and neurodegeneration. This review attempts to describe the patterns of demyelination in MS, the steps involved in oligodendrogenesis and myelination in healthy CNS, the different pathways leading to OLs and myelin loss in MS, as well as principles involved in restoration of myelin sheaths. Environmental factors and their impact on OLs and pathological mechanisms of MS are also discussed. Finally, we will present evidence about the potential therapeutic targets in re myelination processes that can be accessed in order to develop regenerative therapies for MS. PMID- 28093711 TI - Clinical Neurophysiology of Multiple Sclerosis. AB - Different neurophysiological methods such as evoked potentials (EP), testing of the autonomic nervous system (ANS) or polysomnography have the potential to detect clinically silent lesions or to confirm the existence of an association between a clinical symptom and multiple sclerosis (MS); previously undetected by MRI. Therefore, in the most recent MRI criteria for the diagnosis of MS (MAGNIMS consensus guidelines), neurophysiological confirmation of optic nerve dysfunction (slowed conduction on visual EP), support dissemination in space and, in patients without concurrent visual symptoms, dissemination in time. In this chapter we will review the existing evidence regarding the role of different neurophysiological tests (specifically the role of EPs, autonomic nervous system testing and sleep testing in MS) in the diagnosis and management of MS. PMID- 28093712 TI - Multiple Sclerosis Epidemiology in Europe. AB - Multiple sclerosis is characterized by a non-homogeneous distribution around the world. Some authors in past described a latitude gradient, with increasing risk from the equator to North and South Poles, but this theory is still controversial. Regarding Europe, there are many articles in the literature concerning the epidemiology of this disease but, unfortunately, they are not always comparable due to different methodologies, they do not cover all countries in the continent, and most of them reported data of small areas and rarely at a national level. In 2012 there were 20 national registries that could help to describe the epidemiology of the disease and, in addition, there is an European Register for Multiple Sclerosis that collect data from already existing national or regional MS registries and databases. Another valid alternative to obtain epidemiological data, also at national level, in a routinely and cost-saving way is through administrative data that are of increasing interest in the last years. PMID- 28093713 TI - Timing of Future Remyelination Therapies and Their Potential to Stop Multiple Sclerosis Progression. AB - Prior to the onset of demyelination in multiple sclerosis (MS), early oligodendrocyte injury, axonal degeneration and astroglial scarring occur. The irreversible progressive phase of MS begins when the axonal loss threshold is reached. Progressive disease onset has the highest impact on a poor prognosis in MS. Conversion to progressive disease is essentially an age-dependent process independent of disease duration and initial disease course. Although prevention of relapses has been the primary approach in the disease management, incomplete recovery from even the first relapse correlates with the long-term neurodegenerative phenotype of progressive MS onset. Therefore, the provider should review each patient's potential for relapse-related disability and start DMDs with the goal of preventing relapses. Existing immunomodulatory medications used to prevent MS relapses do not prevent long-term disability, which requires agents focused on remyelination and axonal repair. If applied immediately after a relapse rather than during the progressive phase of MS, remyelination-stimulating strategies may result in full recovery and prevention of long-term neurodegeneration and progressive disease course. PMID- 28093714 TI - Neuroplasticity-Based Technologies and Interventions for Restoring Motor Functions in Multiple Sclerosis. AB - Motor impairments are very common in multiple sclerosis (MS), leading to a reduced Quality of Life and active participation. In the past decades, new insights into the functional reorganization processes that occur after a brain injury have been introduced. Specifically, the motor practice seems to be determinant to induce neuroplastic changes and motor recovery. More recently, these findings have been extended to multiple sclerosis, in particular, it has been hypothesized that disease progression, functional reorganization and disability are mutually related. For this reason, neuroplasticity-based technologies and interventions have been rapidly introduced in MS rehabilitation. Constraint-induced movement therapy (CIMT), robotics and virtual reality training are new rehabilitative interventions that deliver an intensive e task-specific practice, which are two critical factors associated with functional improvements and cortical reorganization. Another promising strategy for enhancing neuroplastic changes is non-invasive brain stimulation that can be used with a priming effect on motor training. The aims of this chapter are to review the evidence of neuroplastic changes in multiple sclerosis and to present technologies and interventions that have been tested in clinical trials. PMID- 28093715 TI - Detection of PR-39, a porcine host defence peptide, in different cell sub-linages in pigs infected with Actinobacillus pleuropneumoniae. AB - Innate immunity is critically important for the outcome of infection in many diseases. It was previously shown that cathelicidin PR-39, an important porcine multifunctional host defence peptide, is elevated in bronchoalveolar lavage fluid and respiratory tract tissue after experimental infection with Actinobacillus pleuropneumoniae (A.pp.). To date, neutrophil polymorphonuclear leukocytes (PMNs) are thought to be the only source of PR-39. The aim of this study was to further characterize PR-39+ cells and selected immune cell populations in lung tissue during the peracute (7-10 hours), acute (2 days), reconvalescent (7 days) and chronic (21 days) stages of experimental infection with A.pp. serotype 2. In total, six mock-infected control pigs and 12 infected pigs were examined. Using immunofluorescence double-labeling, antibodies against PR-39 were combined with antibodies against CD3 (T-cells), CD79 (B-cells), Iba1 (activated macrophages), TTF-1 (lung epithelial cells expressing surfactant proteins), macrophage/L1 protein and myeloperoxidase (MPO, cells of the myeloid linage). In the peracute and acute phases of infection, total PR-39+ cells and myeloid linage cells increased, whereas CD3+ cells and TTF-1+ cells decreased. Double labeling revealed that most Macrophage/L1 protein+ cells and to a lesser extent MPO+ cells co-expressed PR-39. In addition, few bronchial epithelial cells and type 2 alveolar epithelial cells (both identified with TTF-1) produced PR-39. Occasionally, CD3+ T cells expressing PR-39 were seen in infected animals. Taken together, this study identifies cell types, other than PMNs, in lungs of A.pp. infected pigs that are capable of producing PR-39. In addition, these findings provide further insights into the dynamics of different immune cell populations during A.pp.-infection. PMID- 28093716 TI - Syphilitic chancre and condylomata lata possibly coexisting with neurosyphilis. PMID- 28093717 TI - Sixteen novel mutations in PNPLA1 in patients with autosomal recessive congenital ichthyosis reveal the importance of an extended patatin domain in PNPLA1 that is essential for proper human skin barrier function. AB - BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous group of rare Mendelian skin disorders characterized by cornification and differentiation defects of keratinocytes. Mutations in nine genes including PNPLA1 are known to cause nonsyndromic forms of ARCI. To date, only 10 distinct pathogenic mutations in PNPLA1 have been reported. OBJECTIVES: To identify new causative PNPLA1 mutations. METHODS: We screened genetically unresolved cases, including our ARCI collection, comprising more than 700 families. Screening for mutations was performed either by direct Sanger sequencing or in combination with a multigene panel, followed by sequence and mutation analysis. RESULTS: Here we report on 16 novel mutations present in patients from 17 families. While all previously reported mutations and most of our novel mutations are located within the core patatin domain, we report five novel PNPLA1 mutations that are downstream of this domain. Thus, as recently described for PNPLA2, we hypothesize that a region larger than the core domain is required for full enzymatic activity of PNPLA1 in human skin barrier formation. CONCLUSIONS: We estimate the frequency of PNPLA1 mutations among patients with ARCI to be around 3%. Most of our patients were born as collodion babies and showed a relatively mild ichthyosis phenotype. In four unrelated patients we observed a cyclic scaling course, which seems to be a potential phenotypic variation in a small percentage of patients with PNPLA1 mutations. The variability of the clinical manifestations and the lack of typical clinical features are specific for patients with PNPLA1 mutations, and emphasize the importance of DNA sequencing for differential diagnosis of ARCIs. PMID- 28093718 TI - Ribosomal protein S3 gene silencing protects against experimental allergic asthma. AB - BACKGROUND AND PURPOSE: Ribosomal protein S3 (RPS3) is a 40S ribosomal protein of the S3P family essential for implementing protein translation. RPS3 has recently been found to interact with the p65 subunit of the NF-kappaB complex and promote p65 DNA-binding activity. Persistent activation of the NF-kappaB pathway is evident in allergic asthma. We hypothesized that gene silencing of lung RPS3 can ameliorate allergic airway inflammation. EXPERIMENTAL APPROACH: The gene silencing efficacy of RPS3 siRNA was screened in three different mouse cell lines by real-time PCR and immunoblotting. Protective effects of intratracheal RPS3 siRNA in a house dust mite (HDM) mouse asthma model were determined by measuring cell counts in lung lavage fluid and lung sections, lung cytokine profiles and airway hyperresponsiveness (AHR). KEY RESULTS: RPS3 siRNA markedly knocked down RPS3 levels in all mouse cell lines tested, and in mouse lung tissues, blocked TNF-alpha- or HDM-induced release of mediators by the cultured cells and reduced eosinophil counts in lung lavage fluid from the HDM mouse asthma model. RPS3 siRNA lessened HDM-induced airway mucus hypersecretion, cytokine production and serum IgE elevation. Moreover, RPS3 knockdown significantly suppressed methacholine-induced AHR in experimental asthma. RPS3 siRNA disrupted TNF-alpha induced NF-kappaB activation in a NF-kappaB reporter gene assay in vitro and prevented the nuclear accumulation of p65 subunit and p65 transcriptional activation in HDM-challenged lungs and cells. CONCLUSIONS AND IMPLICATIONS: RPS3 gene silencing ameliorates experimental asthma, probably by disrupting NF-kappaB activity. RPS3 could be a novel therapeutic target for allergic airway inflammation. PMID- 28093720 TI - Septum resection for women of reproductive age with a septate uterus. AB - BACKGROUND: Women with a septate uterus are at increased risk for subfertility, recurrent miscarriage, and preterm birth. Restoration of the anatomy of the uterus by hysteroscopic septum resection is an established intervention. This treatment has been assessed mainly in retrospective cohort studies, which suggested a positive effect on pregnancy outcomes. The major flaw in these studies is the before/after design, which will always favour the tested intervention. OBJECTIVES: To determine whether hysteroscopic septum resection in women of reproductive age with a septate uterus improves live birth rates and to assess the safety of this procedure. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register (inception to May 2016), the Cochrane Central Register of Controlled Trials (CENTRAL CRSO) (inception to May 2016), MEDLINE (1946 to May 2016), Embase (1974 to May 2016), PsycINFO (1806 to May 2016), and CINAHL database (1982 to May 2016). We also searched trial registers for ongoing and registered trials, reference lists, the Cochrane Library, unpublished dissertations and theses, conference abstracts, OpenGrey, LILACS, PubMed, and Google. SELECTION CRITERIA: We planned to include randomised controlled trials that assessed the effect on reproductive outcomes and the safety of hysteroscopic septum resection in women of reproductive age with a septate uterus. DATA COLLECTION AND ANALYSIS: If there had been studies to include, two review authors would have independently selected studies, assessed trial risk of bias, and extracted data. They would also have contacted study authors for additional information. MAIN RESULTS: As in the 2011 version of this review, we identified no randomised controlled trials for inclusion in this update. AUTHORS' CONCLUSIONS: Hysteroscopic septum resection in women of reproductive age with a septate uterus is performed worldwide to improve reproductive outcomes. At present, there is no evidence to support the surgical procedure in these women. Randomised controlled trials are urgently needed. Two trials are currently underway. PMID- 28093719 TI - Metabolic nodal response as a prognostic marker after neoadjuvant therapy for oesophageal cancer. AB - BACKGROUND: The ability to predict recurrence and survival after neoadjuvant chemotherapy (NAC) and surgery for oesophageal cancer remains elusive. This study evaluated the role of [18 F]fluorodeoxyglucose (FDG) PET-CT in assessing tumour and nodal response as a prognostic marker. METHODS: This was a single-centre UK cohort study. From 2006 to 2014, patients with oesophageal cancer staged with PET CT before NAC, and restaged by CT or PET-CT before resection, were included. Pathological tumour response was evaluated using Mandard regression grades. Metabolic tumour and nodal responses (mTR and mNR respectively) were quantified using absolute and threshold reductions. RESULTS: Among 294 included patients, mTR and mNR independently predicted prognosis before surgery. After surgery, mNR (but not mTR), pathological tumour response, resection margin status and pathological node category predicted prognosis. Patients with FDG-avid nodal disease after NAC were at high risk of recurrence/death at 1 and 2 years (43 and 71 per cent respectively; P = 0.030 and P = 0.025 versus patients without avid nodes), and had a worse prognosis than patients with non-avid nodal metastases: hazard ratio 4.19 (95 per cent c.i. 1.87 to 9.40) and 2.11 (1.12 to 3.97) respectively versus patients without nodal metastases. Considering mTR and mNR response separately improved prognostication. CONCLUSION: mNR is a novel prognostic factor, independent of conventional N status. Primary and nodal tumours may respond discordantly and patients with FDG-avid nodes after NAC have a poor prognosis. PMID- 28093721 TI - Application of autologous hematopoietic stem cell transplantation for pemphigus. AB - BACKGROUND: Pemphigus is a rare and fatal autoimmune disease for which the treatment options are limited. This study aimed to evaluate the efficacy of autologous peripheral hematopoietic stem cell transplantation (APHSCT) for pemphigus. METHODS: We conducted APHSCT for 12 pemphigus patients (seven males and five females, mean age 23.8 years) with life-threatening complications or who responded poorly to conventional therapy. Peripheral blood stem cells were mobilized with cyclophosphamide, granulocyte colony-stimulating factor, and rituximab, and purified autologous CD34+ stem cells were infused. Overall survival rate, progression-free survival, and adverse events were recorded. RESULTS: With a mean follow-up period of 80.3 months, overall survival and complete clinical remission rates were 92% (11/12) and 75% (9/12), respectively. Adverse effects included pyrexia, allergy, infection, and elevation of enzymes. Only one patient died of severe sepsis and multiple organ failure 2 months after APHSCT. CONCLUSION: Overall APHSCT is a promising therapeutic option for pemphigus. PMID- 28093722 TI - Triptan use in Australia 1997-2015: A pharmacoepidemiological study. AB - OBJECTIVE: This study examined the use of triptan derivatives in Australia between 1997 and 2015, based on a national drug reimbursement database, and compared patterns of use with available international data. METHODS: We obtained publically available data on the number of prescriptions for triptans marketed in Australia (sumatriptan, eletriptan, rizatriptan, zolmitriptan, naratriptan). Dispensed use was measured as defined daily dose (DDD per 1000 population per day) for Australia's concessional beneficiaries (low-income earners, people with disabilities, and seniors). RESULTS: Total triptan use increased at an average annual rate of 112% over the 18-year period. Sumatriptan was the preferred triptan throughout (average annual increase 45%). Zolmitriptan and naratriptan use peaked in 2004, then decreased. Rizatriptan and eletriptan became available in 2010. There were 3.2-fold and 5.9-fold annual increases in their use from 2011 to 2105. There was some evidence suggesting that pattern of triptan use in concessional beneficiaries probably reflected pattern of overall triptan use in Australia. CONCLUSIONS: The use of triptan derivatives in Australia per head of population for treating migraine attacks continued to increase over the 18-year period studied, with use of recently introduced derivatives more than substituting for decreased use of older triptans. This suggests that the available treatments of migraine attacks had achieved what were considered less than adequate therapeutic outcomes. PMID- 28093723 TI - Meta-analysis and trial sequential analysis of triclosan-coated sutures for the prevention of surgical-site infection. AB - BACKGROUND: Triclosan-coated sutures (TCS) were developed to reduce the risk of surgical-site infection (SSI). Level 1A evidence of effectiveness has been presented in various recent meta-analyses, yet well designed RCTs have not been able to reproduce these favourable results. The aim of this study was to evaluate all available evidence critically with comprehensive analysis to seek a more reliable answer regarding the effectiveness of TCS in the prevention of SSI. METHODS: PubMed, MEDLINE, Embase and Cochrane Library databases were searched from 1990 to November 2015 for RCTs that compared TCS with sutures that were exactly the same, but uncoated, in the prevention of SSI. Pooled relative risks (RRs) with corresponding 95 per cent confidence intervals were estimated using a random-effects model. Metaregression was used to substantiate subgroup effects, trial sequential analysis was employed to assess the risk of random error, and quality of evidence was determined using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. RESULTS: Twenty-one RCTs including 6462 patients were included. Risk of bias was serious. Pooled effects showed a RR of 0.72 (95 per cent c.i. 0.60 to 0.86; P < 0.001) for all publications. At a risk of 138 SSIs per 1000 procedures, the use of TCS reduced this by 39 (95 per cent c.i. 19, 55). Trial sequential analysis confirmed a RR reduction of 15 per cent for the use of TCS. CONCLUSION: GRADE assessment shows moderate-quality evidence that TCS are effective in reducing SSI. Trial sequential analysis indicates that the effect was robust, and additional data are unlikely to alter the summary effect. PMID- 28093724 TI - The Potential of High-Dimensional Propensity Scores in Health Services Research: An Exemplary Study on the Quality of Care for Elective Percutaneous Coronary Interventions. AB - OBJECTIVE: Evaluating the potential of the high-dimensional propensity score (HDPS) to control for residual confounding in studies analyzing quality of care based on administrative health insurance data. DATA SOURCE: Secondary data from 2004 to 2009 from three German statutory health insurance providers. STUDY DESIGN: We conducted a retrospective cohort study in patients with elective percutaneous coronary interventions (PCIs) and compared the mortality risk between the in- and outpatient setting using Cox regression. Adjustment for predefined confounders was performed using conventional propensity score (PS) techniques. Further, an HDPS was calculated based on predefined and empirically selected confounders from the database. PRINCIPAL FINDINGS: Conventional PS methods showed a decreased mortality risk for outpatient compared to inpatient PCIs, while trimming of patients with nonoverlap in the HDPS distribution and weighting resulted in a comparable risk. Most comorbidities were less prevalent in the HDPS-trimmed population compared to the original one. CONCLUSION: The HDPS methodology may reduce residual confounding by rendering the studied cohort more comparable through restriction. However, results cannot be generalized for the entire study population. To provide unbiased results, full assessment of all unmeasured confounders from proxy information in the database would be necessary. PMID- 28093725 TI - Shape and geometry control of the Drosophila tracheal tubule. AB - For efficient respiration, tubular airways must be constructed with an optimal diameter and length for the dimensions of the body. In Drosophila, the growth of embryonic tracheal tubules proceeds in two dimensions, by axial elongation and diameter expansion. The growth forces in each dimension are controlled by distinct genetic programs and cellular mechanisms. Recent studies reveal that the apical cortex and the apical extracellular matrix filling the luminal space are essential for the generation, balancing, and equilibrium of these growth forces. We here discuss the mechanical properties and architecture of the apical cortex and extracellular matrix, and their crucial roles in the tissue-level coordination of tubule shape and geometry. PMID- 28093726 TI - A preoperative and intraoperative scoring system to predict nodal metastasis in endometrial cancer. AB - OBJECTIVE: To develop a scoring system that guides surgical decision-making regarding the need to perform lymphadenectomy. METHODS: A retrospective study was performed of patients who underwent complete surgical staging of endometrial cancer between 2003 and 2014 at three centers in Brazil. Preoperative and intraoperative risk factors were used to develop a scoring system to predict lymph node metastasis. RESULTS: Among 329 patients included, 71 (21.6%) had positive lymph nodes and 259 (78.4%) had negative lymph nodes. The characteristics associated with nodal metastasis in univariate analysis included the level of cancer antigen 125 (P<0.001), preoperative histological grade (P<0.001), endometrial thickness (P=0.012), and pathologic features including tumor size (P<0.001), tumor extension (P<0.001), and lower uterine segment involvement (P<0.001). On multivariate logistic regression analysis, tumor grade, tumor extension, and lower uterine segment involvement remained significantly associated. The resulting scoring system showed good accuracy as demonstrated by an area under the receiver operating characteristic curve of 0.858 (95% confidence interval 0.804-0.913). CONCLUSION: A highly accurate scoring system for the prediction of lymph node metastasis was developed on the basis of three preoperative and intraoperative risk factors. After validation, this model could greatly aid clinicians in the surgical management of endometrial cancer. PMID- 28093727 TI - Gene expression boundary scaling and organ size regulation in the Drosophila embryo. AB - How the shape and size of tissues and organs is regulated during development is a major question in developmental biology. Such regulation relies upon both intrinsic cues (such as signaling networks) and extrinsic inputs (such as from neighboring tissues). Here, we focus on pattern formation and organ development during Drosophila embryogenesis. In particular, we outline the importance of both biochemical and mechanical tissue-tissue interactions in size regulation. We describe how the Drosophila embryo can potentially provide novel insights into how shape and size are regulated during development. We focus on gene expression boundary scaling in the early embryo and how size is regulated in three organs (hindgut, trachea, and ventral nerve cord) later in development, with particular focus on the role of tissue-tissue interactions. Overall, we demonstrate that Drosophila embryogenesis provides a suitable model system for studying spatial and temporal scaling and size control in vivo. PMID- 28093728 TI - Meta-analysis of the potential economic impact following introduction of absorbable antimicrobial sutures. AB - BACKGROUND: Despite several randomized trials, systematic reviews and meta analyses that have demonstrated the effectiveness of antimicrobial (triclosan coated or -impregnated) sutures (TCS), the clinical and economic impact of using these sutures compared with conventional non-antimicrobial-coated absorbable sutures (NCS) remains poorly documented. METHODS: An independent systematic review and meta-analysis of all published evidence from January 2005 to September 2016 comparing TCS with NCS was conducted. Surgical-site infection (SSI) was the primary outcome. The results of the meta-analysis were used in a decision-tree deterministic and stochastic cost model, using the National Health Service (NHS England)-based cost of inpatient admissions for infections and differential costs of TCS versus NCS. RESULTS: Thirty-four studies were included in the final assessment from an initial 163 identified citations; 20 of 34 studies were randomized, and 17 of 34 reported blinding of physicians and assessors. Using a random-effects model, the odds ratio for SSI in the TCS compared with NCS control groups was statistically significant (odds ratio 0.61, 95 per cent c.i. 0.52 to 0.73; P < 0.001). There was significant heterogeneity (I2 = 49 per cent). Using random-effects event estimates of SSI for TCS and NCS for each individual wound type, the mean savings per surgical procedure from using antimicrobial sutures were significant: L91.25 (90 per cent c.i. 49.62 to 142.76) (?105.09 (57.15 to 164.41); exchange rate 15 November 2016) across all wound types. CONCLUSION: The reviewed literature suggested that antimicrobial sutures may result in significant savings across various surgical wound types. PMID- 28093729 TI - Knowledge about, attitude toward, and practice of skin lightening products use and its social correlates among university students in five Association of Southeast Asian Nations (ASEAN) countries. AB - BACKGROUND: The aim of this study was to investigate the knowledge about, attitude toward, and use of skin lightening products (SLP) and its social and psychological correlates among university students from five Association of Southeast Asian Nations (ASEAN) countries. METHODS: In a cross sectional survey, 3259 undergraduate university students (Mean age = 20.5 years, SD = 1.6) from five ASEAN countries responded to an anonymous questionnaire. Multivariate logistic regression analysis was used to identify associations between sociodemographic characteristics, knowledge, attitude, poor mental health, and SLP use. RESULTS: Overall, 79.1% of the students were aware that the use of SLP can harm the skin, and 30.1% knew the active ingredients of SLP. Most students had a positive perception of having a lighter skin tone and SLP. Overall, the prevalence of SLP use over the past 12 months was 30.7%, 16.7% of male, and 30.0% of female students, ranging from 13.4% in Myanmar to 69.4% in Thailand. In multivariate logistic regression analysis, among women, older age, coming from a poorer family, residing in an upper middle income country, awareness of active skin lightening ingredients, and poor mental health were associated with SLP, while among men, not aware of the negative effects of SLP and awareness of active skin lightening ingredients and poor mental health were associated with SLP use. CONCLUSION: A high prevalence of SLP use was found in a large sample of ASEAN university students, and several social and mental health-related risk factors were found that may help in guiding interventions. PMID- 28093730 TI - Tumor necrosis factor alpha gene promoter -238G/A polymorphism increases the risk of psoriasis vulgaris in Indian patients. AB - BACKGROUND: Tumor necrosis factor alpha (TNFalpha) gene -238G/A polymorphism (rs361525) is associated with psoriasis in several populations worldwide. To the best of our knowledge, there is no information about this polymorphism in Indian psoriatic patients. This study was undertaken to fill the gap in knowledge. METHODS: This case-control study involved 72 patients with psoriasis vulgaris (PsV) and 72 age and gender matched healthy individuals. TNFalpha -238G/A polymorphism was genotyped by PCR-RFLP method. RESULTS: TNFalpha -238A allele was 5 times commoner in PsV patients than in the control group (P = 4.1 * 10-7 ; odds ratio [OR] = 6.5 [0.95 CI: 2.9-14.6]). Distribution of the genotypes in the two groups showed statistically significant difference in dominant genetic model (P = 2.3 * 10-7 ) and not in recessive genetic model (P = 2.5 * 10-1 ). Odds ratio for the occurrence of -238A genotype in PsV patients was 8.8 (0.95 CI: 3.5-20.2). The association showed no major difference when PsV patients were subgrouped into type I and type II categories and tested separately. Subgroup analysis on the basis of disease severity showed higher association with the moderate-severe subgroup (P = 2.4 * 10-9 , OR 15.4 [0.95 CI: 5.8-41.0]) than with mild subgroup (P = 1.3 * 10-2 , OR 3.8 [0.95 CI: 1.3-10.9]). CONCLUSIONS: Our results indicate that TNFalpha gene -238G/A polymorphism increases the risk of developing psoriasis vulgaris among Indians. Also, the data show that severity and not the type affects the strength of association in this population. PMID- 28093731 TI - Sexual activity among Nigerian women following successful obstetric fistula repair. AB - OBJECTIVE: To evaluate post-operative sexual activity among women who have undergone obstetric fistula repair. METHODS: The present descriptive cross sectional study recruited married women who had undergone successful obstetric fistula repair who were attending reunion activities at Bingham University Teaching Hospital, Jos, Nigeria, between March 13 and March 15, 2014. Participants were interviewed regarding penetrative vaginal intercourse after surgery, and any changes in sexual desire, arousal, orgasm, sexual satisfaction, and the presence of coital pain compared with before they experienced obstetric fistula. RESULTS: There were 102 patients who participated in interviews; 23 (22.5%) reported not being able to engage in penetrative vaginal intercourse and 12 (52%) of these patients ascribed this to a "tight" or "narrow" vagina. Compared with the pre-fistula period, 63 (61.7%) patients reported reduced sexual desire, 57 (55.9%) reported lack of or inadequate lubrication during intercourse, 12 (11.8%) reported anorgasmia, and 60 (58.8%) reported reduced attainment of orgasm. Dyspareunia was reported by 48 (47.1%) patients; 43 (90%) experienced superficial or deep dyspareunia, and 5 (10%) experienced both. A lack of and lower sexual satisfaction were reported by 20 (19.6%) and 40 (39.2%) patients, respectively. CONCLUSION: Following obstetric fistula repair, many women experienced difficulty engaging in penetrative vaginal intercourse and reported sexual dysfunction. Management of sexual dysfunction should be part of fistula rehabilitation programs. PMID- 28093733 TI - ABILHAND-Kids questionnaire: responsive to change or room for change? PMID- 28093732 TI - Long-term hormone therapy for perimenopausal and postmenopausal women. AB - BACKGROUND: Hormone therapy (HT) is widely provided for control of menopausal symptoms and has been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women. This is an updated version of a Cochrane review first published in 2005.OBJECTIVES: To assess effects of long term HT (at least 1 year's duration) on mortality, cardiovascular outcomes, cancer, gallbladder disease, fracture and cognition in perimenopausal and postmenopausal women during and after cessation of treatment.SEARCH METHODS: We searched the following databases to September 2016: Cochrane Gynaecology and Fertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and PsycINFO. We searched the registers of ongoing trials and reference lists provided in previous studies and systematic reviews.SELECTION CRITERIA: We included randomised double-blinded studies of HT versus placebo, taken for at least 1 year by perimenopausal or postmenopausal women. HT included oestrogens, with or without progestogens, via the oral, transdermal, subcutaneous or intranasal route.DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias and extracted data. We calculated risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, along with 95% confidence intervals (CIs). We assessed the quality of the evidence by using GRADE methods.MAIN RESULTS: We included 22 studies involving 43,637 women. We derived nearly 70% of the data from two well-conducted studies (HERS 1998; WHI 1998). Most participants were postmenopausal American women with at least some degree of comorbidity, and mean participant age in most studies was over 60 years. None of the studies focused on perimenopausal women.In relatively healthy postmenopausal women (i.e. generally fit, without overt disease), combined continuous HT increased the risk of a coronary event (after 1 year's use: from 2 per 1000 to between 3 and 7 per 1000), venous thromboembolism (after 1 year's use: from 2 per 1000 to between 4 and 11 per 1000), stroke (after 3 years' use: from 6 per 1000 to between 6 and 12 per 1000), breast cancer (after 5.6 years' use: from 19 per 1000 to between 20 and 30 per 1000), gallbladder disease (after 5.6 years' use: from 27 per 1000 to between 38 and 60 per 1000) and death from lung cancer (after 5.6 years' use plus 2.4 years' additional follow-up: from 5 per 1000 to between 6 and 13 per 1000).Oestrogen-only HT increased the risk of venous thromboembolism (after 1 to 2 years' use: from 2 per 1000 to 2 to 10 per 1000; after 7 years' use: from 16 per 1000 to 16 to 28 per 1000), stroke (after 7 years' use: from 24 per 1000 to between 25 and 40 per 1000) and gallbladder disease (after 7 years' use: from 27 per 1000 to between 38 and 60 per 1000) but reduced the risk of breast cancer (after 7 years' use: from 25 per 1000 to between 15 and 25 per 1000) and clinical fracture (after 7 years' use: from 141 per 1000 to between 92 and 113 per 1000) and did not increase the risk of coronary events at any follow-up time.Women over 65 years of age who were relatively healthy and taking continuous combined HT showed an increase in the incidence of dementia (after 4 years' use: from 9 per 1000 to 11 to 30 per 1000). Among women with cardiovascular disease, use of combined continuous HT significantly increased the risk of venous thromboembolism (at 1 year's use: from 3 per 1000 to between 3 and 29 per 1000). Women taking HT had a significantly decreased incidence of fracture with long-term use.Risk of fracture was the only outcome for which strong evidence showed clinical benefit derived from HT (after 5.6 years' use of combined HT: from 111 per 1000 to between 79 and 96 per 1000; after 7.1 years' use of oestrogen-only HT: from 141 per 1000 to between 92 and 113 per 1000). Researchers found no strong evidence that HT has a clinically meaningful impact on the incidence of colorectal cancer.One trial analysed subgroups of 2839 relatively healthy women 50 to 59 years of age who were taking combined continuous HT and 1637 who were taking oestrogen-only HT versus similar-sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT: Their absolute risk remained low, at less than 1/500. However, other differences in risk cannot be excluded, as this study was not designed to have the power to detect differences between groups of women within 10 years of menopause.For most studies, risk of bias was low in most domains. The overall quality of evidence for the main comparisons was moderate. The main limitation in the quality of evidence was that only about 30% of women were 50 to 59 years old at baseline, which is the age at which women are most likely to consider HT for vasomotor symptoms.AUTHORS' CONCLUSIONS: Women with intolerable menopausal symptoms may wish to weigh the benefits of symptom relief against the small absolute risk of harm arising from short-term use of low-dose HT, provided they do not have specific contraindications. HT may be unsuitable for some women, including those at increased risk of cardiovascular disease, increased risk of thromboembolic disease (such as those with obesity or a history of venous thrombosis) or increased risk of some types of cancer (such as breast cancer, in women with a uterus). The risk of endometrial cancer among women with a uterus taking oestrogen-only HT is well documented.HT is not indicated for primary or secondary prevention of cardiovascular disease or dementia, nor for prevention of deterioration of cognitive function in postmenopausal women. Although HT is considered effective for the prevention of postmenopausal osteoporosis, it is generally recommended as an option only for women at significant risk for whom non-oestrogen therapies are unsuitable. Data are insufficient for assessment of the risk of long-term HT use in perimenopausal women and in postmenopausal women younger than 50 years of age. PMID- 28093734 TI - YAP is essential for 3D organogenesis withstanding gravity. AB - Cells of our body are constantly exposed to physical forces such as tissue tension. In recent years, it has been shown that such mechanical signals greatly influence a number of cellular processes, including proliferation, differentiation, and migration. Conversely, cells maintain the mechanical properties of tissues by remodeling their own extracellular environment. To date, however, it is unclear about the molecular mechanisms to maintain the mechanical environment ("mechano-homeostasis") in which extracellular mechanical cues are integrated with cell proliferation and differentiation to ensure tissue, organ and body form. In this review, we outline the molecular basis of mechanotransduction, and overview some useful techniques for measuring cellular tension. In the latter part, we describe our recent finding that a transcriptional cofactor YAP plays a crucial role in three-dimensional organ formation and its maintenance by controlling tissue tension, and functions as a key molecule governing mechano-homeostasis. PMID- 28093736 TI - Inadvertent carotid catheterisation. PMID- 28093737 TI - Forcing functions and their consequences - a reply. PMID- 28093735 TI - Challenges faced by older nurses in Singapore: a mixed methods study. AB - BACKGROUND: In Singapore, employees aged 62-65 can continue to be employed if they meet the re-employment eligibility criteria. This policy, coupled with an ageing workforce, calls for age-friendly initiatives, specific to work-related challenges faced by older nurses. AIM: To determine work-related challenges faced by older nurses. METHODS: A mixed method sequential explanatory study was conducted with nurses, aged 50 and above, working in a healthcare cluster in Singapore. In the quantitative phase, a questionnaire was administered to 534 nurses to elicit work-related challenges, then in-depth interviews with 30 nurses were carried out to help explain why certain tasks and work circumstances became harder. RESULTS: Results of the survey indicated that the top three challenges were coping with changes, working with computers and reading labels. Place of work, salary range, gender and race were significantly associated with different work-related challenges. Five themes emerged from the qualitative data: physical demands of work and workload, new technology, need for further education, working with younger nurses and in intercultural teams, and changing public expectations and professional image. DISCUSSION AND CONCLUSION: The study supports the current literature on the challenges older nurses face with technological advancement. However, older nurses in our study reported less aches and pain as compared to that reported elsewhere. There is a need for specific strategies that will address changes in work processes and environment in order to retain older nurses. IMPLICATIONS FOR NURSING AND NURSING POLICY: When devising age-friendly work improvement initiatives, it is important for nurse leaders to factor in the needs of nurses working in different care environments, who are of different ranks, or are from different ethnic backgrounds. PMID- 28093738 TI - Bootstrapping and resampling. PMID- 28093739 TI - Presumed air entrainment through the gastric port of a paediatric i-gel device. PMID- 28093740 TI - Barriers to challenging senior anaesthetists' decisions. PMID- 28093741 TI - Ultrasound evaluation of cricoid pressure vs. 'paralaryngeal pressure' - a reply. PMID- 28093742 TI - Correction. PMID- 28093743 TI - Epidural securement device failure. PMID- 28093744 TI - A method of recording electronic anaesthetic monitor data for research. PMID- 28093745 TI - Epidural pump malfunction - manufacturer's reply. PMID- 28093746 TI - Presumed air entrainment through the gastric port of a paediatric i-gel(r) device - manufacturer's reply. PMID- 28093747 TI - Ultrasound evaluation of cricoid pressure vs. 'paralaryngeal pressure'. PMID- 28093748 TI - Epidural pump malfunction. PMID- 28093749 TI - Forcing functions and their consequences. PMID- 28093750 TI - What is a Jungian analyst dreaming when myth comes to mind? Thirdness as an aspect of the anima media natura. AB - Listening analytically is not listening just to what is said but listening to what is just below the surface waiting to be said. This paper looks at Jung's insight into a 'third thing' being created intra-psychically and within the analytic encounter. Ogden's concept of an 'analytic third' is used to describe the clinical aspects of this thirdness. This paper explores: how the state of thirdness is created and accessed through use of reverie and associative dreaming; how the material emerging from it is used in a from or about manner; and the eventual fate of the third in a successful analysis by a reexamination of plates four and ten of the Rosarium. The focus is particularly on the awareness and possible meanings of mythological motifs appearing in the mind of the analyst while in session. Thirdness can be viewed as the interpersonal aspect of the anima media natura and functions in a way that informs us of permeability in and between individuals, while the operation of the anima mundi means that there is always an inseparability of the individual with the world. PMID- 28093751 TI - The emergence of the ecological mind in Hua-Yen/Kegon Buddhism and Jungian psychology. AB - The complexity associated with deep interconnectedness in nature is beginning to be articulated and elaborated in the field of ecological studies. While some parallels to the psyche have been made and the field of Eco-psychology has been developing, Jung's explicit contribution by way of the image of rhizomes has not been considered in detail. Philosopher Gilles Deleuze acknowledges borrowing the term from Jung, though he disagreed with Jung's Empedoclean use of the term. The paper presents some fundamental properties of rhizomes along with contemporary scientific research on mycorrhizal (fungal) networks. Comparisons are made, first with classical symbolic forms, demonstrating some overlap but also some differences. Then comparison of rhizomal networks is made to those found both in mammalian brains and in recent images of the 'cosmic web'. While no hard conclusions can be drawn from these images, their remarkable similarities are suggestive of a need to reconsider what is meant by 'intelligence'. The cosmic web is one of the largest structures in the known universe (clusters of galaxies which form into filaments and walls) with empty spaces in between. Exploration of the structure of this web leads to a discussion of dark matter and dark energy, current hot topics in science, probing into the mysteries of our 'Big-Bang' cosmology. An additional comparison of the emerging image of the universe as a whole with the ancient Chinese Buddhist cosmological vision from the Hua-Yen School (Kegon in Japan) again reveals profound parallels. The potential convergence of aspects of subjective, or meditative, explorations with objective scientific constructions is striking and offers links between East and West, as well as potential confirmation of the objective aspects of empathy. PMID- 28093754 TI - Editorial. PMID- 28093753 TI - A lemma science of mind: the potential of the Kegon (Flower Ornament) Sutra. AB - The paper argues for a new perspective on the relationship between Buddhism and European psychology, or sciences of the mind, based in the Kegon Sutra, a text that emerged in the early stages of Mahayana Buddhism (3rd - 5th century CE). The basis of European science is logos intellection, formalized by Aristotle as following three laws: the law of identity, the law of contradiction and the law of the excluded middle. Logic in the Buddhist tradition, by contrast, is based in lemma (meaning to understand as a whole not with language, but with intuition). Lemma-based science born in the Buddhist tradition shows that rational perception is possible even without the three laws of logos. The Kegon Sutra, which explains what Buddha preached only a week after he attained enlightenment, is unified under the logic of lemma and can be seen as an effort to create a 'lemma science of the mind'. The fundamental teaching of the Kegon Sutra is explored, and its principles are compared with primary process thinking and the unconscious as outlined by Freud and Jung. Jung's research of Eastern texts led him to create a science of the mind that went further than Freud: his concept of synchronicity is given by way of example and can be seen anew within the idea of a lemma-based science. PMID- 28093755 TI - XIV International Conference : Dissociation: Trauma and the Self The Roosevelt Hotel, New York, 20th - 23rd April 2017. PMID- 28093756 TI - Mottainai: a Japanese sense of anima mundi. AB - The Japanese expression 'Mottainai!' can be translated as 'What a waste!' or 'Don't be wasteful!' However, mottainai means much more than that. It expresses a sense of concern or regret for whatever is wasted because its intrinsic value is not properly utilized. Buddhism and Japan's indigenous religion, Shinto, are integral to the Japanese psyche, accordingly the other-than-human world is also experienced and lived in daily life. In the Japanese worldview everything in nature is endowed with spirit, every individual existence is dependent on others and all are connected in an ever-changing world. Mottainai offers a glimpse of the anima mundi inherent in this worldview. This contrasts with our anthropocentric Zeitgeist, which manifests outwardly as environmental crisis and inwardly as fixation upon social interactions, especially through communication technologies, to the exclusion of all else. Jung's statement, 'The decisive question for man is: Is he related to something infinite or not? That is the telling question of his life', has never been more pertinent. Encounters beyond the human world could be understood as touching this 'something infinite', and the apparent benefits of such experiences in the analytical process are illustrated with clinical vignettes from the author's practice. PMID- 28093757 TI - The Journal of Analytical Psychology Special issue: call for papers. PMID- 28093758 TI - From Freudian narcissism to the Buddhist notion of anatman, via Jung's idea of identity. AB - Starting from the question the youthful Carl Gustav pondered as he sat on 'his' stone - 'Am I he who sits on the stone, or am I the stone on which he sits?' - the author has attempted to show that, for Jung, the idea of identity is founded on a wilful non-determination. This stance results in ethical and methodological repercussions that differentiate it both from the Freudian project and from Hindu and Buddhist thought, while at the same time having much in common with them. The paper refers to the notions of emergence and (Varela et al. 1992) enaction and argues that the concept of the archetype, especially in relation to the self, merits a re-evaluation in light of the new scientific paradigm. PMID- 28093759 TI - Supervising away from home: clinical, cultural and professional challenges. AB - This paper explores some challenges of supervising clinical work of trainees, known as 'routers', who live in countries with diverse cultural, social and political traditions, and the analysts who travel to supervise them. It is written as an evolving dialogue between the authors, who explore together the effects of their own culture of origin, and in particular the legacy and values of their own training institutes on the styles and models of analytic supervision. Their dialogue is framed around the meaning of home and experiences of homesickness for analysts working away from home in an interactive field of strangeness in countries where analytical psychology is a relatively new discipline. The authors outline the findings from their own qualitative survey, where other supervisors working abroad, and those they have supervised, describe their experiences and their encounters with difference. The dialogue ends with both authors discussing what they have learned about teaching and supervising abroad, the implications for more flexible use of Jungian concepts, and how such visits have changed their clinical practice in their home countries. PMID- 28093761 TI - Soul in the world: symbolic culture as the medium for psyche. AB - Whilst the loss of a sense of living connection with the material world is mainly associated with the scientific revolution in seventeenth century Europe, it can be traced back to Plato's introduction of a hierarchy between soul and body. Jung's attempted solution to this - esse in anima - is ingenious but maintains the Cartesian split by which the aliveness of the world is reduced to a projection of psychic forces (the archetypes). An alternative approach is proposed, rooted in the Aristotelean emphasis on practical activity that sees the soul as a function of our way of being in the world. Human cognition is extended and distributed by our social and material engagement with the world, especially via collective representations whose symbolic character is constitutive of the reality of the world in which we live. Despite the dominance of 'scientific Cartesian' representations in the modern Western world, there remain numerous instances of participation mystique that cannot be captured by the Cartesian notion of projection. These indicate an opening to ways of being in the world that may lead us out of the impasse of the Cartesian matrix. PMID- 28093762 TI - Floating worlds and their phantoms in the aftermath of social catastrophes. AB - In this paper the author describes certain kinds of images (phantoms) that appear in the aftermath of social catastrophes. These phantoms come with an underlying narrative structure, which the author describes as phantom narratives. Phantom narratives show how the unconscious, working at the group and individual levels, provides political and social contexts within which the individual may find a different kind of containment for these catastrophes. In this way their suffering may be potentially processed psychologically and related to symbolically. PMID- 28093763 TI - Where East meets West: in the house of individuation. AB - The psychological process of individuation as experienced in Jungian work may lead to states of consciousness that resemble advanced spiritual developments across religious traditions and cultures. This is where Westerners may reach a common ground with the East. In the essentials and with respect to the final goal there is little difference among the many ways to the self, even if the cultural features in the landscape are disparate. In late stage Jungian analysis and individuation and in what Erich Neumann calls 'centroversion', the personal and the impersonal aspects of the personality accumulate around the ego-self axis to form a composite identity. In this complex structure the ego does not vanish but is joined to the impersonal archetypal levels of the psyche and identity thus becomes at once individual and archetypal. This is the third stage of conjunction as described by Jung in Mysterium Coniunctionis and it is identical to the type of consciousness depicted in the final scenes of Zen Buddhism's Ten Ox-Herding Pictures. PMID- 28093765 TI - Does an aggressor's target choice matter? Assessing change in the social network prestige of aggressive youth. AB - Based on a social dominance approach, aggression is conceptualized as a strategy used to gain position, power, and influence within the peer network. However, aggression may only be beneficial when targeted against particular peers; both victims' social standing and the number of victims targeted may impact aggressors' social standing. The current study examined associations between aggressors' targeting tendencies (victims' social standing and number of victims) and aggressors' own social standing, both concurrently and over time. Analyses were conducted using three analytic samples of seventh and eighth grade aggressors (Ns ranged from 161 to 383, 49% girls; 50% Latina/o). Participants nominated their friends; nominations were used to calculate social network prestige. Peer nominations were used to identify aggressors and their victim(s). For each aggressor, number of victims and victims' social network prestige were assessed. Aggressors with more victims and with highly prestigious victims had higher social network prestige themselves, and they increased more in prestige over time than aggressors with fewer victims and less prestigious victims (though there were some differences across analytic samples). Findings have implications for the need to extend the social dominance approach to better address the links between aggressors and victims. Aggr. Behav. 43:364-374, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28093764 TI - Pre-ischaemic mitochondrial substrate constraint by inhibition of malate aspartate shuttle preserves mitochondrial function after ischaemia-reperfusion. AB - KEY POINTS: Pre-ischaemic administration of aminooxiacetate (AOA), an inhibitor of the malate-aspartate shuttle (MAS), provides cardioprotection against ischaemia-reperfusion injury. The underlying mechanism remains unknown. We examined whether transient inhibition of the MAS during ischaemia and early reperfusion by AOA treatment could prevent mitochondrial damage at later reperfusion. The AOA treatment preserved mitochondrial respiratory capacity with reduced mitochondrial oxidative stress during late reperfusion to the same extent as ischaemic preconditioning (IPC). However, AOA treatment, but not IPC, reduced the myocardial interstitial concentration of tricarboxylic acid cycle intermediates at the onset of reperfusion. The results obtained in the present study demonstrate that metabolic regulation by inhibition of the MAS at the onset of reperfusion may be beneficial for the preservation of mitochondrial function during late reperfusion in an IR-injured heart. ABSTRACT: Mitochondrial dysfunction plays a central role in ischaemia-reperfusion (IR) injury. Pre ischaemic administration of aminooxyacetate (AOA), an inhibitor of the malate aspartate shuttle (MAS), provides cardioprotection against IR injury, although the underlying mechanism remains unknown. We hypothesized that a transient inhibition of the MAS during ischaemia and early reperfusion could preserve mitochondrial function at later phase of reperfusion in the IR-injured heart to the same extent as ischaemic preconditioning (IPC), which is a well-validated cardioprotective strategy against IR injury. In the present study, we show that pre-ischaemic administration of AOA preserved mitochondrial complex I-linked state 3 respiration and fatty acid oxidation during late reperfusion in IR injured isolated rat hearts. AOA treatment also attenuated the excessive emission of mitochondrial reactive oxygen species during state 3 with complex I-linked substrates during late reperfusion, which was consistent with reduced oxidative damage in the IR-injured heart. As a result, AOA treatment reduced infarct size after reperfusion. These protective effects of MAS inhibition on the mitochondria were similar to those of IPC. Intriguingly, the protection of mitochondrial function by AOA treatment appears to be different from that of IPC because AOA treatment, but not IPC, downregulated myocardial tricarboxilic acid (TCA)-cycle intermediates at the onset of reperfusion. MAS inhibition thus preserved mitochondrial respiratory capacity and decreased mitochondrial oxidative stress during late reperfusion in the IR-injured heart, at least in part, via metabolic regulation of TCA cycle intermediates in the mitochondria at the onset of reperfusion. PMID- 28093766 TI - Psychometric Evaluation of the Sex After Myocardial Infarction Knowledge Test in Iranian Context. AB - PURPOSE: To translate, adapt, and assess the psychometric properties of the Sex After MI Knowledge Test in Iranian context (where MI is myocardial infarction). DESIGN AND METHODS: A cross-sectional descriptive survey was performed. The sample comprised 250 patients with MI. Confirmatory factor analysis was applied to extract three indicators. FINDINGS: The Sex After MI Knowledge Test indicated good reproducibility (Cronbach's alpha = .76, Intraclass correlation (ICC) = 0.729, CI = 0.7280-0.781, p < .001 ICC: Intraclass correlation). Nonnormed and normed fit indices (FI) were 0.89, and incremental and comparative FIs were 0.90. Goodness-of-fit index (GFI) and adjusted GFI were below the criteria. After a varimax rotation, the first six items of the instrument explained 58.71% of total variance. PRACTICE IMPLICATIONS: The instrument showed acceptable psychometric properties in terms of construct validity and internal consistency. The instrument might be used to stimulate conversations patients with MI regarding sexual knowledge and concerns. PMID- 28093767 TI - Progress in modification of sunflower oil to expand its industrial value. AB - Increasing the sunflower seed oil content as well as improving its quality makes it compatible for industrial demands. This is an important breeding objective of sunflower which increases its market value and ensures high returns for the producers. The present review focuses on determining the progress of improving sunflower seed oil content and modifying its quality by empirical and advanced molecular breeding methods. It is known that the sunflower oil content and quality have been altered through empirical selection methods and mutation breeding programmes in various parts of the world. Further improvement in seed oil content and its components (such as phytosterols, tocopherols and modified fatty acid profile) has been slowed down due to low genetic variation in elite germplasm and complex of hereditary traits. Introgression from wild species can be carried out to modify the fatty acids profile and tocopherol contents with linkage drags. Different transgenes introduced through biotechnological methods may produce novel long-chain fatty acids within sunflower oil. Bio-engineering of sunflower oil could allow it to be used in diverse industrial products such as bio-diesel or bio-plastics. These results showed that past and current trends of modifying sunflower oil quality are essential for its further expansion as an oilseed crop. (c) 2017 Society of Chemical Industry. PMID- 28093768 TI - Short-term and long-term follow-up of pulmonary function in patients with COPD after total laryngectomy: A prospective study. AB - OBJECTIVE: There exists no standardized method for examining lung function in laryngectomized patients. STUDY DESIGN AND METHODS: We established a base plate adapter (BPA) system for patients after laryngectomy. In 10 patients with chronic obstructive pulmonary disease (COPD), we evaluated pulmonary function before laryngectomy, as well as 2 weeks and 3 months after laryngectomy. RESULTS: The BPA system was well tolerated and delivered reliable results comparable to measurements with a mouthpiece. The parameters forced expiratory volume in one second (FEV1 ), forced vital capacity (FVC), and mean forced expiratory flow between 25% and 75% of forced vital capacity (MFEF25-75 ) changed in the early postoperative examinations (2 weeks postoperative), whereas MFEF25-75 , FEF75 , peak expiratory flow (PEF), and peak inspiratory flow (PIF)) showed differences from baseline in long-term follow-up (3 months postoperative). CONCLUSION: We provide a practicable method of lung function testing in laryngectomized patients with COPD that is essential to tailor inhalation therapy despite tracheotomy. Lung function measurements of laryngectomized patients with COPD should be performed under stable clinical conditions a few weeks after surgery. Guidelines of COPD might be complemented considering the subgroup of laryngectomized patients. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2045-2049, 2017. PMID- 28093769 TI - Low migratory connectivity is common in long-distance migrant birds. AB - Estimating how much long-distance migrant populations spread out and mix during the non-breeding season (migratory connectivity) is essential for understanding and predicting population dynamics in the face of global change. We quantify variation in population spread and inter-population mixing in long-distance, terrestrial migrant land-bird populations (712 individuals from 98 populations of 45 species, from tagging studies in the Neotropic and Afro-Palearctic flyways). We evaluate the Mantel test as a metric of migratory connectivity, and explore the extent to which variance in population spread can be explained simply by geography. The mean distance between two individuals from the same population during the non-breeding season was 743 km, covering 10-20% of the maximum width of Africa/South America. Individuals from different breeding populations tended to mix during the non-breeding season, although spatial segregation was maintained in species with relatively large non-breeding ranges (and, to a lesser extent, those with low population-level spread). A substantial amount of between population variation in population spread was predicted simply by geography, with populations using non-breeding zones with limited land availability (e.g. Central America compared to South America) showing lower population spread. The high levels of population spread suggest that deterministic migration tactics are not generally adaptive; this makes sense in the context of the recent evolution of the systems, and the spatial and temporal unpredictability of non-breeding habitat. The conservation implications of generally low connectivity are that the loss (or protection) of any non-breeding site will have a diffuse but widespread effect on many breeding populations. Although low connectivity should engender population resilience to shifts in habitat (e.g. due to climate change), we suggest it may increase susceptibility to habitat loss. We hypothesize that, because a migrant species cannot adapt to both simultaneously, migrants generally may be more susceptible to population declines in the face of concurrent anthropogenic habitat and climate change. PMID- 28093770 TI - Mortality event involving larvae of the carpet shell clam Ruditapes decussatus in a hatchery: isolation of the pathogen Vibrio tubiashii subsp. europaeus. AB - Diseases caused by bacteria belonging to the genus Vibrio are a common, as yet unresolved, cause of mortality in shellfish hatcheries. In this study, we report the results of routine microbiological monitoring of larval cultures of the carpet shell clam Ruditapes decussatus in a hatchery in Galicia (NW Spain). Previous episodes of mortality with signs similar to those of vibriosis affecting other species in the installation indicated the possibility of bacterial infection and led to division of the culture at the early D-veliger larval stage. One batch was cultured under routine conditions, and the other was experimentally treated with antibiotic (chloramphenicol). Differences in larval survival were assessed, and culturable bacterial population in clams and sea water was evaluated, with particular attention given to vibrios. Severe mortalities were recorded from the first stages of culture onwards. The pathogen Vibrio tubiashii subsp. europaeus was detected in both batches, mainly associated with larvae. Moreover, initial detection of the pathogen in the eggs suggested the vertical transmission from broodstock as a possible source. Experimental use of antibiotic reduced the presence and diversity of vibrios in sea water, but proved inefficient in controlling vibrios associated with larvae from early stages and it did not stop mortalities. PMID- 28093771 TI - Improving prospective memory performance with future event simulation in traumatic brain injury patients. AB - OBJECTIVE: Previous studies have shown that traumatic brain injury (TBI) patients have difficulties with prospective memory (PM). Considering that PM is closely linked to independent living it is of primary interest to develop strategies that can improve PM performance in TBI patients. METHOD: This study employed Virtual Week task as a measure of PM, and we included future event simulation to boost PM performance. Study 1 evaluated the efficacy of the strategy and investigated possible practice effects. Twenty-four healthy participants performed Virtual Week in a no strategy condition, and 24 healthy participants performed it in a mixed condition (no strategy - future event simulation). In Study 2, 18 TBI patients completed the mixed condition of Virtual Week and were compared with the 24 healthy controls who undertook the mixed condition of Virtual Week in Study 1. All participants also completed a neuropsychological evaluation to characterize the groups on level of cognitive functioning. RESULTS: Study 1 showed that participants in the future event simulation condition outperformed participants in the no strategy condition, and these results were not attributable to practice effects. Results of Study 2 showed that TBI patients performed PM tasks less accurately than controls, but that future event simulation can substantially reduce TBI-related deficits in PM performance. The future event simulation strategy also improved the controls' PM performance. CONCLUSIONS: These studies showed the value of future event simulation strategy in improving PM performance in healthy participants as well as in TBI patients. PRACTITIONER POINTS: TBI patients performed PM tasks less accurately than controls, confirming prospective memory impairment in these patients. Participants in the future event simulation condition out-performed participants in the no strategy condition. Future event simulation can substantially reduce TBI-related deficits in PM performance. Future event simulation strategy also improved the controls' PM performance. PMID- 28093772 TI - The Reciprocity of Prosocial Behavior and Positive Affect in Daily Life. AB - OBJECTIVE: To examine whether prosocial behaviors help sustain a positive mood, we tested the dynamic reciprocal associations between prosocial behavior and positive affect (PA) in daily life. A second aim was to examine whether the personality traits Neuroticism and Extraversion moderate these associations. METHOD: The study included a community sample (N = 553). Participants completed an electronic diary assessing prosocial behavior and PA three times a day over 30 days. A subsample of 322 participants filled out the NEO Five-Factor Inventory to assess Neuroticism and Extraversion. Multilevel autoregressive models were performed to examine the within-person bidirectional associations between prosocial behavior and PA and possible moderation by Neuroticism and Extraversion. RESULTS: Within individuals, more PA was followed by more prosocial behavior at the next assessment, and more prosocial behavior was followed by more PA. The effect of prosocial behavior on PA was stronger for individuals high on Neuroticism. Extraversion did not moderate the associations under study. CONCLUSIONS: The findings indicate that prosocial behavior and PA reinforce each other in daily life. Prosocial behavior seems most beneficial for individuals high on Neuroticism. PMID- 28093773 TI - Establishment of a cell line for assessing drugs as canine P-glycoprotein substrates: proof of principle. AB - P-glycoprotein (P-gp), encoded by the ABCB1 (MDR1) gene, dramatically impacts drug disposition. P-gp is expressed in the intestines, biliary canaliculi, renal tubules, and brain capillaries where it functions to efflux substrate drugs. In this capacity, P-gp restricts oral absorption, enhances biliary and renal excretion, and inhibits central nervous system entry of substrate drugs. Many drugs commonly used in veterinary medicine are known substrates for canine P-gp (vincristine, loperamide, ivermectin, others). Because these drugs have a narrow therapeutic index, defective P-gp function can cause serious adverse drug reactions due to enhanced brain penetration and/or decreased clearance. P-gp dysfunction in dogs can be intrinsic (dogs harboring ABCB1-1Delta) or acquired (drug interactions between a P-gp inhibitor and P-gp substrate). New human drug candidates are required to undergo assessment for P-gp interactions according to FDA and EMA regulations to avoid adverse drug reactions and drug-drug interactions. Similar information regarding canine P-gp could prevent adverse drug reactions in dogs. Because differences in P-gp substrates have been documented between species, one should not presume that human or murine P-gp substrates are necessarily canine P-gp substrates. Thus, our goal was to develop a cell line for assessing drugs as canine P-gp substrates. PMID- 28093774 TI - Comparative pharmacokinetics of diaveridine in pigs and chickens following single intravenous and oral administration. AB - Comparative pharmacokinetic profiles of diaveridine following single intravenous and oral dose of 10 mg/kg body weight in healthy pigs and chickens were investigated, respectively. Concentrations of diaveridine in plasma samples were determined using a validated high-performance liquid chromatography-ultraviolet (HPLC-UV) method. The concentration-time data were subjected to noncompartmental kinetic analysis by WinNonlin program. The corresponding pharmacokinetic parameters in pigs or chickens after single intravenous administration were as follows, respectively: t1/2beta (elimination half-life) 0.74 +/- 0.28 and 3.44 +/ 1.07 h; Vd (apparent volume of distribution) 2.70 +/- 0.99 and 3.86 +/- 0.92 L/kg; ClB (body clearance) 2.59 +/- 0.62 and 0.80 +/- 0.14 L/h/kg; and AUC0 infinity (area under the blood concentration vs. time curve) 4.11 +/- 1.13 and 12.87 +/- 2.60 MUg?h/mL. The corresponding pharmacokinetic parameters in pigs or chickens after oral administration were as follows, respectively: t1/2beta 1.78 +/- 0.41 and 2.91 +/- 0.57 h; Cmax (maximum concentration) 0.43 +/- 0.24 and 1.45 +/- 0.57 MUg/mL; Tmax (time to reach Cmax ) 1.04 +/- 0.67 and 3.25 +/- 0.71 h; and AUC0-infinity 1.33 +/- 0.55 and 9.28 +/- 2.69 MUg?h/mL. The oral bioavailability (F) of diaveridine in pigs or chickens was determined to be 34.6% and 72.2%, respectively. There were significant differences between the pharmacokinetics profiles in these two species. PMID- 28093775 TI - How does temperature influences the development of lactococcosis? Transcriptomic and immunoproteomic in vitro approaches. AB - Lactococcus garvieae is the aetiological agent of lactococcosis, a haemorrhagic septicaemia that affects marine and freshwater fish, with special incidence and economic relevance in farmed rainbow trout. Water temperature is one of the most important predisposing factors in the development of lactococcosis outbreaks. Lactococcosis in trout usually occur when water temperatures rise to about 18 degrees C, while fish carriers remain asymptomatic at temperatures below 13 degrees C. The aim of this work was to analyse the differences in the complete transcriptome response of L. garvieae grown at 18 degrees C and at 13 degrees C and to identify the immunogenic proteins expressed by this bacterium at 18 degrees C. Our results show that water temperature influences the expression of L. garvieae genes involved in the lysis of part of the bacterial cell population and in the cold response bacterial adaptation. Moreover, the surface immunogenic protein profile at 18 degrees C suggests an important role of the lysozyme-like enzyme, WxL surface proteins and some putative moonlighting proteins (proteins with more than one function, usually associated with different cellular locations) as virulence factors in L. garvieae. The results of this study could provide insights into the understanding of the virulence mechanisms of L. garvieae in fish. PMID- 28093776 TI - A message from the "True" ground. PMID- 28093777 TI - Description of non-covalent interactions in SCC-DFTB methods. AB - We have analyzed the description of non-covalent interactions in multiple variants of the self-consistent charges density functional tight binding (SCC DFTB) method. While the description of London dispersion can be easily improved by empirical correction, hydrogen bonding poses a much more difficult problem. We have implemented an interaction energy decomposition scheme that allowed us to quantify the error at the level of first-order electrostatic and polarization terms. Both are underestimated because of the monopole approximation used in SCC DFTB, with the latter being affected also by the use of minimal basis set. Among the methods tested, SCC-DFTB with the empirical D3H4 corrections worked best. To make this correction compatible with the latest development in SCC-DFTB, we have reparameterized it for use with third-order SCC-DFTB with the 3OB parameter set. (c) 2017 Wiley Periodicals, Inc. PMID- 28093778 TI - Brainstem reflex excitability changes in patients with amyotrophic lateral sclerosis. AB - INTRODUCTION: In this study we explored brainstem reflex excitability changes, blink reflex recovery cycles (BRRCs), and masseter inhibitory reflexes (MIRs) in patients with amyotrophic lateral sclerosis (ALS). METHODS: Fourteen ALS patients and 14 healthy control subjects were recruited. The BRRC was examined at interstimulus intervals (ISIs) of 100, 200, 300, 400, 500, and 600 ms. The latencies and durations of silent period 1 (SP1) and silent period 2 (SP2) of the MIR were measured. RESULTS: Decreased R2 area suppression was prominent in the ALS group at ISIs of 200, 300, and 400 ms (P < 0.02), whereas no significant differences between groups at 100, 500, and 600 ms ISIs (P > 0.05) were observed. SP2 duration was significantly prolonged in the ALS group compared with controls (P = 0.01). CONCLUSIONS: Brainstem inhibitory and excitatory interneuronal activity is altered in ALS, possibly brought about by physiological and morphological changes at the cortical or bulbar levels. Muscle Nerve 56: 925-929, 2017. PMID- 28093779 TI - Reaching multi-nanosecond timescales in combined QM/MM molecular dynamics simulations through parallel horsetail sampling. AB - We report an enhanced sampling technique that allows to reach the multi nanosecond timescale in quantum mechanics/molecular mechanics molecular dynamics simulations. The proposed technique, called horsetail sampling, is a specific type of multiple molecular dynamics approach exhibiting high parallel efficiency. It couples a main simulation with a large number of shorter trajectories launched on independent processors at periodic time intervals. The technique is applied to study hydrogen peroxide at the water liquid-vapor interface, a system of considerable atmospheric relevance. A total simulation time of a little more than 6 ns has been attained for a total CPU time of 5.1 years representing only about 20 days of wall-clock time. The discussion of the results highlights the strong influence of the solvation effects at the interface on the structure and the electronic properties of the solute. (c) 2017 Wiley Periodicals, Inc. PMID- 28093780 TI - Subacute demyelinating polyradiculoneuropathy complicating Epstein-Barr virus infection in GATA2 haploinsufficiency. AB - INTRODUCTION: Autosomal dominant haploinsufficiency of GATA2 causes monocytopenia and natural killer cell lymphopenia, resulting in predisposition to mycobacterial, fungal, and viral infections. METHODS: Herein we report on the clinical, serologic, electrophysiologic, and pathologic evaluations of a 29-year old woman with GATA2 haploinsufficiency and active Epstein-Barr virus (EBV) infection complicated by subacute painful neuropathy. RESULTS: Nerve conduction and electromyography studies showed predominantly demyelinating sensorimotor polyradiculoneuropathy. Lumbar spine MRI showed thickening and enhancement of the cauda equina nerve roots. Serum and cerebrospinal fluid anti-IgG and IgM EBV capsid and nucleic acid antibodies were positive. Sural nerve biopsy showed microvasculitis and an increased frequency of fibers with segmental demyelination. Intravenous immunoglobulin and steroids improved the patient's neuropathy. CONCLUSION: GATA2 mutation-related immunodeficiency may predispose to EBV-associated subacute demyelinating polyradiculoneuropathy by both viral susceptibility and immune dysregulation. In patients who present in this manner, immunodeficiency syndromes should be considered when lymphomatous infiltration is excluded. Immunotherapy can be helpful. Muscle Nerve 57: 150-156, 2018. PMID- 28093781 TI - The dynamic landscape of liver transplant in the era of effective hepatitis C virus therapy. PMID- 28093782 TI - Relapsing polychondritis as an unusual cause of multiple cranial nerve palsies-A Case report. PMID- 28093783 TI - Maltreatment increases spontaneous false memories but decreases suggestion induced false memories in children. AB - We examined the creation of spontaneous and suggestion-induced false memories in maltreated and non-maltreated children. Maltreated and non-maltreated children were involved in a Deese-Roediger-McDermott false memory paradigm where they studied and remembered negative and neutral word lists. Suggestion-induced false memories were created using a misinformation procedure during which both maltreated and non-maltreated children viewed a negative video (i.e., bank robbery) and later received suggestive misinformation concerning the event. Our results showed that maltreated children had higher levels of spontaneous negative false memories but lower levels of suggestion-induced false memories as compared to non-maltreated children. Collectively, our study demonstrates that maltreatment both increases and decreases susceptibility to memory illusions depending on the type of false memory being induced. Statement of contribution What is already known on this subject? Trauma affects memory. It is unclear how trauma affects false memory. What does this study add? This study focuses on two types of false memories. PMID- 28093784 TI - Electrodiagnosis of reversible conduction failure in Guillain-Barre syndrome. AB - INTRODUCTION: In this study we propose electrodiagnostic criteria for early reversible conduction failure (ERCF) in axonal Guillain-Barre syndrome (GBS) and apply them to a cohort of GBS patients. METHODS: Serial nerve conduction studies (NCS) were retrospectively analyzed in 82 GBS patients from 3 centers. The criteria for the presence of ERCF in a nerve were: (i) a 50% increase in amplitude of distal compound muscle action potentials or sensory nerve action potentials; or (ii) resolution of proximal motor conduction block with an accompanying decrease in distal latencies or compound muscle action potential duration or increase in conduction velocities. RESULTS: Of 82 patients from 3 centers, 37 (45%) had ERCF, 21 (26%) had a contrasting evolution pattern, and 8 (10%) had both. Sixteen patients did not show an amplitude increase of at least 50%. CONCLUSION: Our proposed criteria identified a group of patients with a characteristic evolution of NCS abnormality that is consistent with ERCF. Muscle Nerve 56: 919-924, 2017. PMID- 28093785 TI - Primary biliary cholangitis: Treatment options finally expand. PMID- 28093786 TI - Reply. PMID- 28093787 TI - In situ data analytics and indexing of protein trajectories. AB - The transition toward exascale computing will be accompanied by a performance dichotomy. Computational peak performance will rapidly increase; I/O performance will either grow slowly or be completely stagnant. Essentially, the rate at which data are generated will grow much faster than the rate at which data can be read from and written to the disk. MD simulations will soon face the I/O problem of efficiently writing to and reading from disk on the next generation of supercomputers. This article targets MD simulations at the exascale and proposes a novel technique for in situ data analysis and indexing of MD trajectories. Our technique maps individual trajectories' substructures (i.e., alpha-helices, beta strands) to metadata frame by frame. The metadata captures the conformational properties of the substructures. The ensemble of metadata can be used for automatic, strategic analysis within a trajectory or across trajectories, without manually identify those portions of trajectories in which critical changes take place. We demonstrate our technique's effectiveness by applying it to 26.3k helices and 31.2k strands from 9917 PDB proteins and by providing three empirical case studies. (c) 2017 Wiley Periodicals, Inc. PMID- 28093789 TI - Chronic Infection of the Prostate by Chlamydia muridarum Is Accompanied by Local Inflammation and Pelvic Pain Development. AB - BACKGROUND: Chlamydia trachomatis urogenital infections are the leading cause of sexually transmitted bacterial infections. Although the prevalence of chlamydial infection is similar in men and women, current research is mainly focused on women, neglecting the study of male genital tract infections. We, therefore, investigated Chlamydia infection in the rodent male genital tract. MATERIALS AND METHODS: Male NOD and C57BL/6 mice were inoculated in the meatus urethra with C. muridarum. Bacterial DNA, leukocyte infiltration of male genital tract tissues, pelvic pain, and Chlamydia-specific immune responses were analyzed at different time points. RESULTS AND CONCLUSIONS: The inoculation of C. muridarum in the meatus urethra of male mice resulted in an ascending and widely disseminated infection of the male genital tract. C. muridarum remained longer and with the highest bacterial burdens in the prostate, thus showing a special tropism for this organ. Infection caused leukocyte infiltration, mainly composed by neutrophils, and also induced early pelvic pain development that rapidly dropped and resolved as the infection became chronic. Bacterial load and leukocyte infiltration was observed in all prostate lobes, although dorsolateral prostate was the most affected lobe. Interestingly, immune responses induced by both mice strains were characterized by the production of high levels of IL-10 during early stages of the infection, with highest and sustained levels observed in NOD mice, which showed to be less efficient in clearing the infection. Chronic infection of the prostate accompanied by local inflammation and pelvic pain development described herein have important implications for the improvement of the diagnosis and for the design of new efficient therapies. Prostate 77:517-529, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28093788 TI - North American Population-Based Validation of the National Comprehensive Cancer Network Practice Guideline Recommendation of Pelvic Lymphadenectomy in Contemporary Prostate Cancer. AB - BACKGROUND: National Comprehensive Cancer Network (NCCN) guidelines recommend a pelvic lymph node dissection (PLND) in prostate cancer (PCa) patients treated with radical prostatectomy (RP) if a nomogram predicted risk of lymph node invasion (LNI) is >=2%. We examined this and other thresholds, including nomogram validation. METHODS: We examined records of 26,713 patients treated with RP and PLND between 2010 and 2013, within the Surveillance, Epidemiology, and End Results database. Nomogram thresholds of 2-5% were tested and external validation was performed. RESULTS: LNI was recorded in 4.7% of patients. Nomogram accuracy was 80.4% and maintained minimum accuracy of 75.6% in subgroup analyses, according to age, race, and nodal yield >10. With the NCCN recommended 2% nomogram threshold, PLND could be avoided in 22.3% of patients at the expense of missing 3.0% of individuals with LNI. Alternative thresholds of 3%, 4%, and 5% yielded respective PLND avoidance rates of 60.4%, 71.0%, and 79.8% at the expense of missing 17.8%, 27.2%, and 36.6% of patients with LNI. NCCN cut-off recommendation was best satisfied with a threshold of <2.6%, at which PLND could be avoided in 13,234 patients (49.5%) versus missing 141 patients with LNI (11.2%). CONCLUSION: NCCN LNI nomogram remains accurate in contemporary patients. However, the 2% threshold appears to be too strict, since only 22.3% of PLNDs can be avoided, instead of the stipulated 47.7%. The optimal 2.6% threshold allows a higher rate of PLND avoidance (49.5%), at the cost of 11.2% missed instances of LNI, as recommended by NCCN guidelines. PATIENT SUMMARY. External validation in contemporary SEER prostate cancer patients showed that the NCCN nomogram remains accurate for predicting lymph node invasion and seems to be optimal at an alternative 2.6% threshold, with best ratio of avoided pelvic lymph node dissections (49.5%) and missed LNIs (11.2%), as recommended by NCCN guideline. Prostate 77:542-548, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28093790 TI - A case series of family-based treatment for adolescents with atypical anorexia nervosa. AB - The aim of this case series was to examine engagement in and outcomes of family based treatment (FBT) for adolescents with DSM-5 atypical AN, that is, adolescents who were not underweight at presentation. Consecutive referrals for FBT of adolescents with atypical AN to a specialist child and adolescent eating disorder program were examined. Engagement in treatment (i.e., dose of treatment, completion rate), and changes in psychological symptomatology (i.e., eating disorder symptoms, depressive symptoms, self-esteem, obsessive compulsiveness), weight, and menstrual function were examined. The need for additional interventions (i.e., hospitalization and medication), and estimated remission rates were also examined. The sample comprised 42 adolescents aged 12-18 years (88% female). Engagement in FBT was high, with 83% completing at least half the treatment dose. There were significant decreases in eating disorder and depressive symptoms during FBT (p < .05) but no improvement in self-esteem. There was no significant change in percent of median BMI for age and gender for the sample as a whole (105 vs. 106%, p = .128). However, adolescents who were not admitted to hospital prior to FBT gained some weight (M = 3.4 kg) while those who were admitted did not gain weight during FBT (M = 0.2 kg, p < .01). The overall remission rate ranged from 38 to 52% depending on the criteria applied. FBT appears to be an effective treatment for adolescents with atypical AN. However, more research is needed into systematic adaptations of FBT and other treatments that could improve overall remission rates. PMID- 28093791 TI - Local Therapy Improves Overall Survival in Patients With Newly Diagnosed Metastatic Prostate Cancer. AB - BACKGROUND: The role of local therapy, in the form of radiation therapy (RT) or radical prostatectomy(RP), and its association on outcomes is not well established in patients with metastatic prostate cancer. METHODS: Using the National Cancer Database (NCDB), we evaluated patterns of care and outcomes among patients diagnosed with metastatic prostate cancer from 2004 to 2013 treated with local therapy (RP, intensity-modulated radiation therapy [IMRT], or 2D/3D conformal radiation therapy [CRT]). The association between local therapy, co variates, and outcomes was assessed in a multivariable Cox proportional hazards model and Propensity score (PS) matching was performed to balance confounding factors. Survival was estimated using the Kaplan-Meier method. RESULTS: Among the 1,208,180 patients in the NCDB with prostate cancer, 6,051 patients met the inclusion criteria. No local therapy was used in 5,224 patients, while 622 (10.3%), 52 (0.9%), 153 (2.5%) patients received RP, IMRT, and 2D/3D-CRT, respectively. Use of local therapy was associated with younger age (<=70), lower co-morbidity score, lower T-stage, Gleason score <8, node-negative status, private, and Medicare insurance, higher income quartile, and treatment at comprehensive or academic/research programs (P < 0.05). Five-year overall survival for patients receiving local therapy was 45.7% versus 17.1% for those not receiving local therapy (P < 0.01). In multivariate analysis, RP (HR = 0.51; 95%CI, 0.45-0.59, P < 0.01) and IMRT (HR = 0.47; 95%CI, 0.31-0.72, P < 0.01) were independently associated with superior overall survival. After PS-matching, the use of local therapy (RP or IMRT) remained significantly associated with overall survival (HR = 0.35; 95%CI, 0.30-0.41, P < 0.01). CONCLUSIONS: The use of RP and IMRT, to treat the primary disease, was associated with improvements in overall survival for patients with metastatic prostate cancer. We have identified patient specific variations in the use of local therapy that may be tested in subsequent prospective clinical trials to improve patient outcomes in this setting. Prostate 77: 559-572, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28093792 TI - Prognostic Role of Preoperative Serum Lipid Levels in Patients Undergoing Radical Prostatectomy for Clinically Localized Prostate Cancer. AB - BACKGROUND: The prognostic role of preoperative serum lipid levels in patients undergoing radical prostatectomy (RP) for clinically localized prostate cancer (PCa) is unclear. The aim of the present study was to investigate preoperative serum lipid levels in patients with clinically localized PCa undergoing RP and their association with clinicopathological features and oncological outcome. METHODS: Preoperative lipid levels (total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides) and statin use from consecutive patients with clinically localized PCa undergoing RP in a tertiary referral center between 2008 and 2015 were recorded and patients were followed prospectively. Logistic regression analysis was used to test the association between lipid levels and clinicopathological parameters. Lipid values were analyzed both as continuous and dichotomized variables. Univariable and multivariable Cox regression analyses were performed to identify predictors for recurrence-free survival (RFS). Recurrence was defined as rising and verified PSA levels >0.1 ng/ml. RESULTS: Our cohort consisted of 371 men with a median age of 63 years (range 41-78 years) and a median preoperative PSA value of 6.79 ng/ml (0.43-81.4 ng/ml). Median follow-up was 28 months (1-64). No association was found between lipid levels and adverse pathological characteristics such as >=pT3, Gleason score >=8, positive nodal status and positive surgical margins. Recurrence occurred in 49 patients (15.4%) at a median time of 18 months (2-51 month). Compared to low LDL cholesterol, high LDL cholesterol was associated with longer RFS in univariable analysis (continuous: Hazard Ratio (HR): 0.67, 95%-Confidence Interval (CI): 0.47-0.96, P = 0.03; 3 mM cut-point: HR: 0.44, 95%-CI: 0.24-0.79, P = 0.006). Neither levels of other lipids, nor statin use were associated with RFS. Preoperative LDL cholesterol remained an independent predictor for PCa recurrence in a multivariable model adjusted for age, preoperative PSA, statin use, tumor stage, Gleason score, nodal status and surgical margin status (continuous: HR: 0.66, 95% CI: 0.44-0.99, P = 0.04; 3 mM cut-point: HR: 0.41, 95%-CI: 0.21-0.78, P = 0.007). CONCLUSIONS: This is the first prospective study showing the potential adverse and independent prognostic role of low preoperative LDL cholesterol levels in patients with localized PCa undergoing RP. Prostate 77:549-556, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28093793 TI - Sex-dependent effects of letrozole on anxiety in middle-aged rats. AB - Aromatase catalyzes the conversion of testosterone to estradiol and is involved in the physiological effects of sex hormones on brain function. Animal experiments have shown that the aromatase inhibitor, letrozole, can induce anxiety in young ovariectomized females that are used as a model of aging. Whether or not these effects would be similar in intact middle-aged animals is unknown. The aim of our study was to analyze the effects of letrozole on anxiety in middle-aged rats of both sexes. Fifteen month old male and female rats were treated daily with either letrozole or vehicle for 2 weeks. The elevated plus maze was used to test anxiety-like behaviour. Sex differences were found not only in plasma concentrations of testosterone but also in the effects of letrozole treatment on plasma testosterone (P<.05). The interaction between sex and treatment was also proven in locomotor activity (P<.05) and time spent in the open arms of the elevated plus maze (P<.05). Letrozole-treated male rats spent 95% less time in the open arms of the elevated plus maze than the control rats did (P<.05) suggesting an anxiogenic effect of aromatase inhibition. This difference was not found between letrozole-treated and vehicle-treated females. In contrast to previous experiments on young animals, letrozole seems to induce anxiety in male but not in female middle-aged rats. This sex-specific effect might be related to sex differences of oestrogen and androgen signalling in aging brains. These results should be taken into account in clinical applications of letrozole, especially in men. PMID- 28093794 TI - Design, Synthesis, and Biological Evaluation of Novel Quinazoline Clubbed Thiazoline Derivatives. AB - A novel series of quinazoline clubbed thiazoline derivatives was rationally designed and synthesized. The newly synthesized compounds were evaluated for in vitro dipeptidyl peptidase IV (DPP-4) inhibitory activity. Compounds that showed good to moderate activity were compared using linagliptin as standard. Compound 4x (IC50 = 1.12 nM) exhibited the most promising results. The special chemical feature of compound 4x also imparts good inhibition selectivity for DPP-4 over DPP-8/9. Moreover, docking of compound 4x into the active site of DPP-4 illustrates its possible binding interactions. PMID- 28093796 TI - The Role of Perceived Burden and Social Support in Suicide and Depression. AB - In a sample of 114 military veterans with depression histories, perceived burden was related to depression symptoms and suicide attempt history. After accounting for perceived burden, sense of belonging was negatively related to depression. Among the areas of social support, family support was inversely related to both depression and suicide history. After accounting for family support, personal meaning from relationships and friend support were related to depression. The results of this study suggest that perceived burdensomeness may be a stronger determinant of suicidality than sense of belonging or social support. This study highlights the contribution of perceived burdensomeness to suicide and depression. PMID- 28093795 TI - Natural history of pure autonomic failure: A United States prospective cohort. AB - OBJECTIVE: To define the clinical features and biomarkers that predict which patients with pure autonomic failure will develop Parkinson disease, dementia with Lewy bodies, or multiple system atrophy. METHODS: One hundred patients who presented with pure autonomic failure were recruited at 5 medical centers in the United States. Seventy-four patients agreed to be followed prospectively. Patients underwent clinical evaluations including neurological rating scales, sleep questionnaires, smell test, and sympathetic and parasympathetic cardiovascular autonomic function tests. RESULTS: At enrollment, patients were 68 +/- 12 years old (median +/- interquartile range) and had had autonomic failure for 5 +/- 7 years. Within 4 years of follow-up, 25 of 74 subjects (34%) developed dementia with Lewy bodies (n = 13), Parkinson disease (n = 6), or multiple system atrophy (n = 6). The presence of probable rapid eye movement (REM) sleep behavior disorder was strongly associated with the development of a manifest central nervous system (CNS) synucleinopathy (odds ratio = 7.1). Patients who phenoconverted to multiple system atrophy had younger age at onset of autonomic failure, severe bladder/bowel dysfunction, preserved olfaction, and a cardiac chronotropic response upon tilt > 10 beats per minute. Those who phenoconverted to Parkinson disease or dementia with Lewy bodies had decreased olfaction, a lesser chronotropic response to tilt, and a longer duration of illness. The small group of patients retaining the pure autonomic failure phenotype had very low plasma norepinephrine levels, slow resting heart rate, no REM sleep behavior disorder, and preserved smell. INTERPRETATION: Patients presenting with pure autonomic failure are at high risk of phenoconverting to a manifest CNS synucleinopathy. Specific clinical features predict future diagnosis. Ann Neurol 2017;81:287-297. PMID- 28093798 TI - The Student Volunteer Army: a 'repeat emergent' emergency response organisation. AB - This paper seeks to contribute to understanding of the factors associated with an effective emergent emergency response organisation and to provide new insights into this understudied area. It examines, through an analysis of a range of textual resources, the emergence and re-emergence of the Student Volunteer Army (SVA) during the devastating earthquakes in Canterbury, New Zealand, in 2010-11. This evaluation is conducted in relation to the four key features of an effective emergency response organisation: adaptability; direction; leadership; and communication. In addition, the paper aims to further understanding of 'emergency entrepreneurship' and thus of the values and strategies that underpin social entrepreneur organisations in times of normalcy. The paper concludes that the unique position of the SVA as a 'repeat emergent' emergency response organisation enabled it to innovate continually and to improve repeatedly its systems, relationships, and image, such that it exhibited features common to emergent and established emergency response organisations. PMID- 28093797 TI - Adverse reactions to dietary supplements containing red yeast rice: assessment of cases from the Italian surveillance system. AB - AIMS: Red yeast rice (RYR) is contained in dietary supplements for patients with dyslipidemia. RYR supplements contain monacolin K, which is chemically identical to lovastatin, a licensed drug with a well-known risk profile. We aim to describe the safety profile of RYR by analysing spontaneous reports of suspected adverse reactions (ARs). METHODS: Within the Italian Surveillance System of Natural Health Products, suspected ARs were collected and evaluated by a multidisciplinary group of experts to assess causality using the WHO-UMC system or the CIOMS/RUCAM score, for hepatic reactions. The public version of the WHO Vigibase was also queried. RESULTS: From April 2002 to September 2015, out of 1261 total reports, 52 reports concerning 55 ARs to RYR dietary supplements were collected. ARs consisted in myalgia and/or increase in creatine phosphokinase (19), rhabdomyolysis (1), liver injury (10), gastrointestinal reactions (12), cutaneous reactions (9) and other reactions (4). Women were involved in 70% of cases. In 13 cases, the reaction required hospitalization, and 28 patients were taking other medications. Dechallenge was positive in 40 reactions (73%), rechallenge was positive in 7. Causality resulted as certain (1), probable (31, 56%), possible (18, 34%), unlikely (3) or unassessable (2). Similar distribution emerged from the WHO-Vigibase. CONCLUSIONS: The potential safety signals of myopathies and liver injury raise the hypothesis that the safety profile of RYR is similar to that of statins. Continuous monitoring of dietary supplements should be promoted to finally characterize their risk profile, thus supporting regulatory bodies for appropriate actions. PMID- 28093799 TI - Computing the Z Score and Centiles for Cross-sectional Analysis: A Practical Approach. AB - Although Z scores have been reported in the literature, one of the problems for the nonstatistician is understanding the systematic approach used to compute the predicted mean and standard deviation, components of the Z score equation, which may vary as the independent variable changes over time (eg, gestational age). This review focuses on a step-by-step analysis using linear, quadratic, and fractional polynomials to compute the mean and standard deviation as a function of a continuous independent variable. Once the mean and standard deviation are computed, the Z score and centile can be derived and Z score calculators created that enable investigators to implement the results in the laboratory and/or clinical setting. PMID- 28093800 TI - Evaluation of the Normal Tonsils in Pediatric Patients With Ultrasonography. AB - OBJECTIVES: To evaluate how well the tonsils can be viewed, in addition to echogenicity, using ultrasound, and to compare these results between children younger and older than the age of 3. METHODS: We evaluated the tonsils of 99 patients (72.0 +/- 59.1 months) by ultrasound. Ultrasound scans of both the left and right side, in both the transverse and longitudinal planes, were obtained. Images were scored with one of four grades according to how well the tonsil border could be distinguished, 0 being the worst and 3 being the best. Grades 2 or 3 (>50% of the tonsil border was detectable) in both tonsils, in either the transverse or longitudinal image, were considered "evaluable." Echogenicity was designated as imperceptible, low echoic, or striated in appearance. Statistical analysis was performed using the Mann-Whitney U test. RESULTS: Bilateral tonsils were evaluable in 96.0% (96/99) of cases. The mean grades were 2.44 +/- 0.65/2.03 +/- 0.68 in the right transverse/longitudinal images, and 2.40 +/- 0.59/2.12 +/- 0.73 in the left transverse/longitudinal images. The grades in children older than the age of 3 were significantly higher than those in younger patients (all P < .05). Echogenicity classification on the right and left side revealed a striated appearance in 97.0% (96/99) and 90.0% (89/99) of cases, respectively. CONCLUSIONS: The tonsils of almost all pediatric patients could be evaluated by ultrasound, particularly for patients older than 3 years. Additionally, a striated pattern of the tonsils was observed in most cases. PMID- 28093802 TI - Simple matters in complex times. PMID- 28093801 TI - From questions to answers: Examining the role of pediatric surveillance units in eating disorder research. AB - Pediatric Surveillance Units (PSUs) provide a unique model for the study of pediatric eating disorders (EDs). Australia, Britain, and Canada have surveillance programs that have generated valuable epidemiological and clinical data on early-onset eating disorders (EOED). The PSUs represent an important collaborative tool that has helped shape our understanding of EOEDs and offers potential to contribute to decisions regarding health resource allocation and public health policy. This paper reviews the role of PSUs as a unique model to study pediatric EDs and its success in translating the knowledge generated by these programs into improving the health of children and adolescents with EDs worldwide. PMID- 28093803 TI - Novel ECG-Synchronized Pulsatile ECLS System With Various Heart Rates and Cardiac Arrhythmias: An In Vitro Study. AB - The objective of this study is to evaluate electrocardiography (ECG)-synchronized pulsatile flow under varying heart rates and different atrial and ventricular arrhythmias in a simulated extracorporeal life support (ECLS) system. The ECLS circuit consisted of an i-cor diagonal pump and console, an iLA membrane ventilator, and an 18 Fr arterial cannula. The circuit was primed with lactated Ringer's solution and packed red blood cells (hematocrit 35%). An ECG simulator was used to trigger pulsatile flow and to generate selected cardiac rhythms. All trials were conducted at a flow rate of 2.5 L/min at room temperature for normal sinus rhythm at 45-180 bpm under non-pulsatile and pulsatile modes. Various atrial and ventricular arrhythmias were also tested. Real-time pressure and flow data were recorded using a custom-based data acquisition system. The energy equivalent pressure (EEP) generated by pulsatile flow was always higher than the mean pressure. No surplus hemodynamic energy (SHE) was recorded under non pulsatile mode. Under pulsatile mode, SHE levels increased with increasing heart rates (45-120 bpm). SHE levels under a 1:2 assist ratio were higher than the 1:1 and 1:3 assist ratios with a heart rate of 180 bpm. A similar trend was recorded for total hemodynamic energy levels. There was no statistical difference between the two perfusion modes with regards to pressure drops across the ECLS circuit. The main resistance and energy loss came from the arterial cannula. The i-cor console successfully tracked electrocardiographic signals of 12 atrial and ventricular arrhythmias. Our results demonstrated that the i-cor pulsatile ECLS system can be synchronized with a normal heart rate or with various atrial/ventricular arrhythmias. Further in vivo studies are warranted to confirm our findings. PMID- 28093804 TI - Successful Bridge-to-Transplant of Functionally Univentricular Patients With a Modified Continuous-Flow Ventricular Assist Device. AB - A continuous flow extracorporeal ventricular assist device (VAD) was modified to support functionally univentricular infants and children awaiting heart transplantation. A centrifugal VAD, designed to flow from 1.5 to 8 L/min, was used as a bridge-to-transplant in four patients with functionally univentricular circulation. A variable restrictive recirculation shunt permitted lower flow ranges in small patients. In hypoxic patients, an oxygenator was incorporated into the circuit. From 2012 to 2015, the modified VAD was placed in four patients with Glenn physiology. Age ranged from 0.97 to 6.98 years (median = 2.2 yrs). Body surface area ranged from 0.41 to 0.84 m2 (median = 0.54 m2 ). One patient was on extracorporeal membrane oxygenation prior to VAD. A recirculation shunt was used in three patients. Three patients required temporary use of an oxygenator for 4, 10, and 27 days. Median time on the VAD was 32.3 days (range = 23-43 days). A decrease in the cavopulmonary pressure was noted in all patients, as was a fall in the B-type natriuretic peptide. Three patients survived transplant and were discharged at 28-82 days post-transplantation. One patient died after 35 days of support. Two patients experienced major bleeding events. Two patients experienced cerebrovascular accidents, one major and one minor. The centrifugal VAD successfully supported palliated functionally univentricular patients awaiting heart transplantation. The modified recirculation shunt facilitated the successful support of patients in whom optimal flows were substantially lower than that recommended by the manufacturer. The continuous flow VAD effectively decompressed the cavopulmonary system. The design allowed placement of an in-line oxygenator in hypoxic patients. Further investigation is required to decrease the thromboembolic events, and associated morbidity, in patients supported with this device. PMID- 28093805 TI - HeartWare Ventricular Assist Device Implantation in Patients With Fontan Physiology. AB - We aim to describe the clinical course of a series of patients with hypoplastic left heart syndrome and refractory systolic heart failure supported with a HeartWare ventricular assist device (HVAD) following Fontan palliation. This is a retrospective review of three consecutive patients supported with a HVAD following Fontan palliation through February 2016. Data include patient characteristics, operative variables, postimplantation hemodynamic/device parameters, event outcomes, and duration of HVAD support. Patient ages were 11.7, 13.5, and 17.5 years, respectively, at the time of HVAD implant. The duration of HVAD support was 148, 272, and 271 days, respectively, of which 86, 222, and 211 were outpatient days. Inflow cannula position was the morphologic right ventricle with depth adjustment and manipulation of the tricuspid subvalvar apparatus to ensure good inflow. Echocardiographic, hemodynamic, and noninvasive oximetric monitoring resulted in high RPM settings for all patients. Despite various complications, all patients were successfully transplanted and discharged home alive. We present three patients bridged to transplantation using the HVAD following Fontan palliation. We demonstrate potential for durable support with transition to outpatient care while awaiting heart transplantation in a subset of patients status post Fontan surgery. PMID- 28093806 TI - Outcomes of the Twelfth International Conference on Pediatric Mechanical Circulatory Support Systems and Pediatric Cardiopulmonary Perfusion. PMID- 28093807 TI - Report on the 43rd Congress of the European Society for Artificial Organs and the 3rd Middle East Conference on Biomedical Engineering. PMID- 28093808 TI - Dr. Yves Durandy, February 20, 1947-October 6, 2016. PMID- 28093810 TI - A Hybrid Pediatric Cardiopulmonary Bypass Circuit for Complex Suprahepatic Inferior Vena Cava Reconstruction. PMID- 28093811 TI - Routine Use of Distal Arterial Perfusion in Pediatric Femoral Venoarterial Extracorporeal Membrane Oxygenation. AB - Lower-extremity ischemia is a significant complication in children on femoral venoarterial extracorporeal membrane oxygenation (VA ECMO). Our institution currently routinely uses distal perfusion catheters (DPCs) in all femoral arterial cannulations in attempts to reduce ischemia. We performed a single center, retrospective review of pediatric patients supported with femoral VA ECMO from January 2005 to November 2015. The outcomes of patients with prophylactic DPC placement at cannulation (prophylactic DPC) were compared to a historical group with DPCs placed in response only to clinically evident ischemic changes (reactive DPC). Ischemic complication requiring invasive intervention (fasciotomy or amputation) was the primary outcome. Twenty-nine patients underwent a total of 31 femoral arterial cannulations, 17 with prophylactic DPC and 14 with reactive DPC. Ischemic complications requiring invasive intervention developed in 2 of 17 (12%) prophylactic DPC patients versus 4 of 14 (29%) reactive DPC. In the reactive DPC group, 7 of 14 (50%) had ischemic changes postcannulation, six underwent DPC placement, and three out of six of these patients still required invasive intervention. One of the seven patients had ischemic changes, did not undergo DPC, and required amputation. While a greater percentage of patients in the prophylactic group was cannulated during extracorporeal cardiopulmonary resuscitation (ECPR), statistical significance was not otherwise demonstrated. We demonstrate feasibility of superficial femoral artery (SFA) access in pediatric patients. We note fewer ischemic complications with prophylactic DPC placement, and observe that salvaging a limb with a reactive DPC was only successful 50% of the time. Although there was no statistical difference in the primary outcome between the two groups, limitations and confounding factors include small sample size and a greater percentage of patients in the prophylactic DPC group cannulated with ECPR in progress. PMID- 28093812 TI - Factors predicting incidence of post-operative delirium in older people following hip fracture surgery: a systematic review and meta-analysis. AB - OBJECTIVE: Delirium is one of the most common complications following hip fracture surgery in older people. This study identified pre- and peri-operative factors associated with the development of post-operative delirium following hip fracture surgery. METHODS: Published and unpublished literature were searched to identify all evidence reporting variables on patient characteristics, on admission, intra-operative and post-operative management assessing incident delirium in older people following hip fracture surgery. Pooled odds ratio (OR) and mean difference of those who experienced delirium compared to those who did not were calculated for each variable. Evidence was assessed using the Downs and Black appraisal tool and interpreted using the GRADE approach. RESULTS: A total of 6704 people (2090 people with post-operative delirium) from 32 studies were analysed. There was moderate evidence of nearly a two-times greater probability of post-operative delirium for those aged 80 years and over (OR: 1.77; 95% CI: 1.09, 2.87), whether patients lived in a care institution pre-admission (OR: 2.65; 95% CI: 1.79, 3.92), and a six-times greater probability of developing post operative delirium with a pre-admission diagnosis of dementia (OR: 6.07, 95% CI: 4.84, 7.62). There was no association with intra-operative variables and probability of delirium. CONCLUSION: Clinicians treating people with a hip fracture should be vigilant towards post-operative delirium if their patients are older, have pre-existing cognitive impairment and poorer overall general health. This is also the case for those who experience post-operative complications such as pneumonia or a urinary tract infection. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28093813 TI - Nerolidol Protects Against LPS-induced Acute Kidney Injury via Inhibiting TLR4/NF kappaB Signaling. AB - Acute kidney injury (AKI) is a critical care syndrome, resulting in acute reduction of renal function and up to 22% mortality of hospitalized patients. Nerolidol is a major component in several essential oils that possesses various pharmacological properties. The present study aimed to investigate the potential effect of nerolidol on lipopolysaccharide (LPS)-induced AKI. Nerolidol dose dependently reduced the pathological injuries of kidney induced by LPS in rats. Nerolidol significantly decreased the levels of blood urea nitrogen and creatinine in LPS-treated rats in a dose-dependent manner. In addition, nerolidol inhibited LPS-induced decrease of cell viability in NRK-52E rat proximal tubular cells, which effect was concentration dependent. Nerolidol notably inhibited the increase of TNFalpha and IL-1beta in LPS-treated rats and the mRNA expression of TNFalpha and IL-1beta in LPS-treated NRK-52E cells. Nerolidol suppressed the increase of toll-like receptor 4 (TLR4) expression, phosphorylation and nuclear translocation of p65 NF-kappaB in kidneys of LPS-treated rats and LPS-treated NRK 52E cells. Overexpression of TLR4 and p65 NF-kappaB significantly suppressed nerolidol-induced inhibition of TNFalpha and IL-1beta expression and increase of cell viability in LPS-treated cells. In summary, we found that nerolidol played a critical anti-inflammatory effects through inhibition of TLR4/NF-kappaB signaling and protected against LPS-induced AKI. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28093814 TI - Management of sickle cell disease in patients undergoing cardiac surgery. AB - Sickle cell disease is a life-limiting inherited hemoglobinopathy that poses inherent risk for surgical complications following cardiac operations. In this review, we discuss preoperative considerations, intraoperative decision-making, and postoperative strategies to optimize the care of a patient with sickle cell disease undergoing cardiac surgery. PMID- 28093815 TI - Nigella sativa Supplementation Improves Asthma Control and Biomarkers: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - Poor compliance with conventional asthma medications remains a major problem in achieving asthma control. Nigella sativa oil (NSO) is used traditionally for many inflammatory conditions such as asthma. We aimed to investigate the benefits of NSO supplementation on clinical and inflammatory parameters of asthma. NSO capsules 500 mg twice daily for 4 weeks were used as a supplementary treatment in a randomized, double-blind, placebo-controlled trial in asthmatics (clinicaltrials.gov: NCT02407262). The primary outcome was Asthma Control Test score. The secondary outcomes were pulmonary function test, blood eosinophils and total serum Immunoglobulin E. Between 1 June and 30 December 2015, 80 asthmatics were enrolled, with 40 patients in each treatment and placebo groups. After 4 weeks, ten patients had withdrawn from each group. Compared with placebo, NSO group showed a significant improvement in mean Asthma Control Test score 21.1 (standard deviation = 2.6) versus 19.6 (standard deviation = 3.7) (p = 0.044) and a significant reduction in blood eosinophils by -50 (-155 to -1) versus 15 (-60 to 87) cells/MUL (p = 0.013). NSO improved forced expiratory volume in 1 second as percentage of predicted value by 4 (-1.25 to 8.75) versus 1 (-2 to 5) but non significant (p = 0.170). This randomized, double-blind, placebo-controlled trial demonstrated that NSO supplementation improves asthma control with a trend in pulmonary function improvement. This was associated with a remarkable normalization of blood eosinophlia. Future studies should follow asthmatics for longer periods in a multicentre trial. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28093816 TI - Fetal trisomy 8 mosaicism associated with truncus arteriosus Type I. PMID- 28093817 TI - Cryptic inbreeding depression in a growing population of a long-lived species. AB - Genetic effects are often overlooked in endangered species monitoring, and populations showing positive growth are often assumed to be secure. However, the continued reproductive success of a few individuals may mask issues such as inbreeding depression, especially in long-lived species. Here, we test for inbreeding depression in little spotted kiwi (Apteryx owenii) by comparing a population founded with two birds to one founded with 40 birds, both from the same source population and both showing positive population growth. We used a combination of microsatellite genotypes, nest observations and modelling to examine the consequences of assessing population viability exclusively via population growth. We demonstrate (i) significantly lower hatching success despite significantly higher reproductive effort in the population with two founders; (ii) positive growth in the population with two founders is mainly driven by ongoing chick production of the founding pair; and (iii) a substantial genetic load in the population founded with two birds (10-15 diploid lethal equivalents). Our results illustrate that substantial, cryptic inbreeding depression may still be present when a population is growing, especially in long lived species with overlapping generations. PMID- 28093818 TI - Intraoperative Microstimulation Predicts Outcome of Postoperative Macrostimulation in Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease. AB - BACKGROUND: In deep brain stimulation (DBS) of the subthalamic nucleus for treatment of Parkinson's Disease, a commonly encountered stimulation side effect is involuntary muscle contractions from spread of electrical current to cortico spinal and cortico-bulbar fibers in the internal capsule. During surgery, a variety of techniques, including microelectrode recording (MER), are used to avoid positioning the DBS electrode too close to the internal capsule. At some centers, MER includes stimulating through the microelectrode (microstimulation). OBJECTIVE: To assess if intraoperative microstimulation can help avoid positioning the DBS electrode too close to the internal capsule. MATERIALS AND METHODS: From clinical records, we compiled microelectrode and DBS-electrode locations, microstimulation effect thresholds and DBS side effect thresholds. RESULTS: We found that capsular macrostimulation thresholds were significantly lower in cases where capsular microstimulation effects were observed. In addition, we found that lower-threshold for microstimulation-induced involuntary muscle contractions from a given DBS electrode contact predicts a lower threshold for involuntary muscle contractions as a side effect of stimulation with that contact. Specifically, our results suggest that capsular macrostimulation thresholds below 2V are avoided when the product of microstimulation threshold (in uA) and distance (in mm) is greater than 500. CONCLUSIONS: intraoperative microstimulation can help avoid positioning the DBS electrode too close to the internal capsule. PMID- 28093819 TI - Investigation of the quasi-simultaneous arrival (QSA) effect on a CAMECA IMS 7f GEO. AB - RATIONALE: IMS 7f-GEO isotope ratio applications increasingly involve analyses (e.g., S- or O- isotopes, coupled with primary ion currents <30 pA) for which quasi-simultaneous arrival (QSA) could compromise precision and accuracy of data. QSA and associated correction have been widely investigated for the CAMECA NanoSIMS instruments, but not for the IMS series. METHODS: Sulfur and oxygen isotopic ratio experiments were performed using an electron multiplier (EM) detector, employing Cs+ primary ion currents of 1, 2, 5 and 11.5 pA (nominal) and a variety of secondary ion transmissions to vary QSA probability. An experiment to distinguish between QSA undercounting and purported aperture-related mass fractionation was performed using an EM for 16 O- and 18 O- plus an additional 16 O- measurement using a Faraday cup (FC) detector. An experiment to investigate the accuracy of the QSA correction was performed by comparing S isotopic ratios obtained using an EM with those obtained on the same sample using dual FCs. RESULTS: The QSA effect was observed on the IMS-7f-GEO, and QSA coefficients (beta) of ~0.66 were determined, in agreement with reported NanoSIMS measurements, but different from the value (0.5) predicted using Poisson statistics. Aperture-related fractionation was not sufficient to explain the difference but uncertainties in primary ion flux measurement could play a role. When QSA corrected, the isotope ratio data obtained using the EM agreed with the dual FC data, within statistical error. CONCLUSIONS: QSA undercounting could compromise isotope ratio analyses requiring ~1 * 105 counts per second for the major isotope and primary currents <20 pA. The error could be >80/00 for a 1 pA primary current. However, correction can be accurately applied. For instrumental mass fractionation (IMF)-corrected data, the magnitude of the error resulting from not correcting for QSA is dependent on the difference in secondary ion count rate between the unknown and standard analyses. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28093820 TI - Synthesis of 2,2,2,-Trichloroethyl Aryl- and Vinyldiazoacetates by Palladium Catalyzed Cross-Coupling. AB - An efficient and convenient synthesis of 2,2,2-trichloroethyl (TCE) aryl- and vinyldiazoacetates was achieved by palladium-catalyzed cross-coupling reactions between TCE diazoacetates and aryl or vinyl iodides. The broad substrate scope allows for rapid and facile formation of TCE aryl- and vinyldiazoacetates, which recently have emerged as versatile reagents for rhodium-carbene chemistry. PMID- 28093821 TI - Decreasing Rates of Pediatric Bipolar Within an Outpatient Practice. AB - PROBLEM: Pediatric bipolar disorder (PBD) prevalence is estimated to be 1-3%. Nationally and internationally, rates of PBD have increased by over 400%. However, in Iowa and at one psychiatric clinic in Iowa, from 2008-2013, there was a decrease in PBD diagnosis of 33 and 51.2% respectively. This study examined the diagnosing practices of PBD by local providers in one outpatient mental health center. METHOD: Parents completed a screening packet to differentiate between PBD and attention deficit hyperactivity disorder (ADHD) using three tools: Child Mania Rating Scale (CMRS), Child Behavior Checklist-Mania Scale (CBCL-MS), and the NICHQ Vanderbilt. Symptom agreement analysis between the screeners and the provider's clinical diagnoses was performed using ANOVA and Tukey HSD posthoc analysis. FINDINGS: A 19.6% of the participants were positive for PBD on the CMRS and 55.9% were positive on the CBCL-MS. A total of 36.60% were positive for ADHD on the Vanderbilt. The screening data compared to the provider's clinical diagnosis showed no diagnostic agreement for PBD (p < .05). Providers' rates of diagnosing PBD did not match the rate of PBD symptoms identified by the screeners. CONCLUSION: Further evidence to determine the criteria and use of current screening measures for PBD is needed to guide practice for distinguishing PBD from related disorders. PMID- 28093822 TI - The role of guilt sensitivity in OCD symptom dimensions. AB - : Although some studies have found that guilt may precede, motivate, or be a consequence of obsessive-compulsive disorder (OCD), the relationship between guilt and OCD has been under investigated. The studies that explored the role of trait guilt (guilt propensity) in OCD reported inconsistent findings and failed to support its predictive role. Since it has been suggested that OCD patients perceive guilt in a more threatening manner, it might also be relevant to test to what extent they negatively evaluate the experience of guilt (i.e., guilt sensitivity; GS). Study 1 investigated the psychometric properties of a new 10 item Italian measure developed to assess GS-named Guilt Sensitivity Questionnaire in a nonclinical sample (N = 473). Results from exploratory factor analyses supported the unidimensionality of the scale. It also showed excellent internal consistency and good discriminant validity. Study 2 investigated the role of GS in OCD symptoms, in particular with regard to responsibility for harm obsessions and checking compulsions, using a heterogeneous OCD sample (N = 61) and a control group of patients with anxiety disorders (N = 47). GS was the unique significant predictor of checking related OCD symptoms independent of negative mood states and obsessive beliefs. Guilt Sensitivity Questionnaire scores of patients with responsibility for harm concerns were significantly higher than those of patients with other kinds of obsessive concerns and with anxiety disorders. Findings supported the hypothesis that GS plays a relevant role in OCD symptoms when checking rituals are primarily involved. Implications for current cognitive behavioral models are discussed. KEY PRACTITIONER MESSAGE: Guilt sensitivity may play a role in checking-related OCD symptoms. We developed a psychometrically sound unidimensional 10-item scale to assess guilt sensitivity. Guilt sensitivity was a unique predictor of checking-related OCD symptoms. Targeting beliefs about the intolerability/dangerousness of experiencing guilt may be useful. Acceptance based approaches may be helpful as they promote the acceptance of guilt. PMID- 28093823 TI - Sleep and its associations with perceived and objective cognitive impairment in individuals with multiple sclerosis. AB - Problems with sleep and cognitive impairment are common among people with multiple sclerosis (MS). The present study examined the relationship between self reported sleep and both objective and perceived cognitive impairment in MS. Data were obtained from the baseline assessment of a multi-centre intervention trial (NCT00841321). Participants were 121 individuals with MS. Nearly half (49%) of participants met the criteria for objective cognitive impairment; however, cognitively impaired and unimpaired participants did not differ on any self reported sleep measures. Nearly two-thirds (65%) of participants met the criteria for 'poor' sleep, and poorer sleep was significantly associated with greater levels of perceived cognitive impairment. Moreover, the relationships between self-reported sleep and perceived cognitive impairment were significant beyond the influence of clinical and demographic factors known to influence sleep and cognitive functioning (e.g. age, sex, education level, disability severity, type of MS, disease duration, depression and fatigue). However, self-reported sleep was not associated with any measures of objective cognitive impairment. Among different types of perceived cognitive impairment, poor self-reported sleep was most commonly related to worse perceived executive function (e.g. planning/organization) and prospective memory. Results from the present study emphasize that self-reported sleep is significantly and independently related to perceived cognitive impairment in MS. In terms of clinical implications, interventions focused on improving sleep may help improve perceived cognitive function and quality of life in this population; however, the impact of improved sleep on objective cognitive function requires further investigation. PMID- 28093825 TI - Three decades of continuous wrist-activity recording: analysis of sleep duration. AB - Motor activity recording by a wrist-worn device is a common method to monitor the rest-activity cycle. The first author wore an actimeter continuously for more than three decades, starting in 1982 at the age of 43.5 years. Until November 2006 analysis was performed on a 15-min time base, and subsequently on a 2-min time base. The timing of night-time sleep was determined from the cessation and re-occurrence of daytime-level activity. Sleep duration declined from an initial 6.8 to 6 h in 2004. The declining trend was reversed upon retirement, whereas the variance of sleep duration declined throughout the recording period. Before retirement, a dominant 7-day rhythm of sleep duration as well as an annual periodicity was revealed by spectral analysis. These variations were attenuated or vanished during the years after retirement. We demonstrate the feasibility of continuous long-term motor activity recordings to study age-related variations of the rest-activity cycle. Here we show that the embeddedness in a professional environment imparts a temporal structure to sleep duration. PMID- 28093824 TI - Excess mortality after hip fracture in elderly persons from Europe and the USA: the CHANCES project. AB - BACKGROUND: Hip fractures are associated with diminished quality of life and survival especially amongst the elderly. OBJECTIVE: All-cause mortality after hip fracture was investigated to assess its magnitude. METHODS: A total of 122 808 participants from eight cohorts in Europe and the USA were followed up for a mean of 12.6 years, accumulating 4273 incident hip fractures and 27 999 deaths. Incident hip fractures were assessed through telephone interviews/questionnaires or national inpatient/fracture registries, and causes of death were verified with death certificates. Cox proportional hazards models and the time-dependent variable methodology were used to assess the association between hip fracture and mortality and its magnitude at different time intervals after the injury in each cohort. We obtained the effect estimates through a random-effects meta-analysis. RESULTS: Hip fracture was positively associated with increased all-cause mortality; the hazard ratio (HR) in the fully adjusted model was 2.12, 95% confidence interval (CI) 1.76-2.57, after adjusting for potential confounders. This association was stronger amongst men [HR: 2.39, 95% CI: 1.72-3.31] than amongst women [HR: 1.92, 95% CI: 1.54-2.39], although this difference was not significant. Mortality was higher during the first year after the hip fracture [HR: 2.78, 95% CI: 2.12-3.64], but it remained elevated without major fluctuations after longer time since hip fracture [HR (95% CI): 1.89 (1.50-2.37) after 1-4 years; 2.15 (1.81-2.55) after 4-8 years; 1.79 (1.57-2.05) after 8 or more years]. CONCLUSION: In this large population-based sample of older persons across eight cohorts, hip fracture was associated with excess short- and long term all-cause mortality in both sexes. PMID- 28093826 TI - Highly sensitive detection of E2 activity in ubiquitination using an artificial RING finger. AB - The ubiquitin-conjugating (E2) enzymes of protein ubiquitination are associated with various diseases such as leukemia, lung cancer, and breast cancer. Rapid and accurate detection of E2 enzymatic activities remains poor. Here, we described the detection of E2 activity on a signal accumulation ISFET biosensor (AMIS sensor) using an artificial RING finger (ARF). The use of ARF enables the simplified detection of E2 activity without a substrate. The high-sensitivity quantitative detection of E2 activities was demonstrated via real-time monitoring over a response range of femtomolar to micromolar concentrations. Furthermore, the monitoring of E2 activities was successfully achieved using human acute promyelocytic leukemia cells following treatment with the anticancer drug bortezomib, which allowed the assessment of the pathological conditions. This strategy is extremely simple and convenient, and the present detection could be widely applied to specific E2s for various types of cancers. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd. PMID- 28093827 TI - Trajectories of sleep and cardiac sympathetic activity indexed by pre-ejection period in childhood. AB - Fragmented and insufficient sleep has been implicated in disrupted autonomic nervous system activity during resting state conditions in typically developing children. Towards explication of these relations over development, the current study tested reciprocal relations between the development of sleep parameters (efficiency, duration, latency) and cardiac sympathetic nervous system (SNS) activity indexed by pre-ejection period (PEP) during waking-resting state conditions throughout middle and late childhood. Whether sleep derives changes in PEP or vice versa was examined. A longitudinal design was employed and latent growth modelling was used to examine the research questions. During the first assessment, 282 children aged 9.44 years (65% European American, 35% African American) participated. Two more assessments followed, with a 1-year lag between consecutive study waves. Sleep was examined with 7 nights of actigraphy in the child's home. Controlling for many potential confounds (sex, race/ethnicity, body mass index and family socioeconomic status), higher sleep efficiency and more sleep minutes predicted increases in PEP (less SNS activity) over 3 years. PEP did not predict changes in sleep efficiency or duration over time and there were no significant effects for sleep latency. Findings highlight the probable direction of effects between these two key bioregulatory systems. High levels of cardiac SNS activity are associated with many negative health outcomes, and thus these findings may have important implications. PMID- 28093828 TI - A systematic review on ethnomedicines of anti-cancer plants. AB - Cancer is a serious health problem and the second leading cause of death around the globe. Present review is an attempt to provide utmost information based on ethno-pharmacological and toxicological aspects of anti-cancer plants of the world. A total of 276 articles published in English journals and containing maximum ethnomedicinal information were reviewed using several data sources such as; Google scholar, Web of Science, Scopus, PubMed and floras of different countries. A total of 199 anti-cancer plants were recorded in present review and results indicated that traditional medicines are mostly being use in developing countries for cancer treatment. Traditionally and scientifically skin and breast cancer types gained more focus. Seventy plants were reportedly analyzed for in vitro activities while 32 plants were having in-vivo reports. Twenty nine pure compounds (mostly phenolic) were reportedly isolated from anti-cancer plants and tested against different cancer cell lines. Inspite having better efficiency of ethnomedicines as compared to synthetic drugs, several plants have also shown toxic effects on living system. Therefore, we invite researchers attention to carry out detailed ethno-pharmacological and toxicological studies on un-explored anti-cancer plants in order to provide reliable knowledge to the patients and develop novel anti-cancer drugs. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28093829 TI - Unprecedented Access to beta-Arylated Selenophenes through Palladium-Catalysed Direct Arylation. AB - Several reported methods allow access to alpha-arylated selenophenes, whereas the synthesis of beta-arylated selenophenes remains very challenging. Here, the Pd catalysed coupling of benzenesulfonyl chlorides with selenophenes affording regiospecific beta-arylated selenophenes is reported. The reaction proceeds with easily accessible catalyst, base and substrates, and tolerates a variety of substituents both on the benzene and selenophene moieties. This transformation allows the programmed synthesis of polyarylated selenophenes with potential applications in pharmaceutical and materials chemistry, as the installation of aryl groups at the desired positions can be achieved. PMID- 28093830 TI - Age affects sleep microstructure more than sleep macrostructure. AB - It is well known that the quantity and quality of physiological sleep changes across age. However, so far the effect of age on sleep microstructure has been mostly addressed in small samples. The current study examines the effect of age on several measures of sleep macro- and microstructure in 211 women (22-71 years old) of the 'Sleep and Health in Women' study for whom ambulatory polysomnography was registered. Older age was associated with significantly lower fast spindle (effect size f2 = 0.32) and K-complex density (f2 = 0.19) during N2 sleep, as well as slow-wave activity (log) in N3 sleep (f2 = 0.21). Moreover, total sleep time (f2 = 0.10), N3 sleep (min) (f2 = 0.10), rapid eye movement sleep (min) (f2 = 0.11) and sigma (log) (f2 = 0.05) and slow-wave activity (log) during non rapid eye movement sleep (f2 = 0.09) were reduced, and N1 sleep (f2 = 0.03) was increased in older age. No significant effects of age were observed on slow spindle density, rapid eye movement density and beta power (log) during non-rapid eye movement sleep. In conclusion, effect sizes indicate that traditional sleep stage scoring may underestimate age-related changes in sleep. PMID- 28093831 TI - Light-Controlled Reversible Modulation of Frontier Molecular Orbital Energy Levels in Trifluoromethylated Diarylethenes. AB - Among bistable photochromic molecules, diarylethenes (DAEs) possess the distinct feature that upon photoisomerization they undergo a large modulation of their pi electronic system, accompanied by a marked shift of the HOMO/LUMO energies and hence oxidation/reduction potentials. The electronic modulation can be utilized to remote-control charge- as well as energy-transfer processes and it can be transduced to functional entities adjacent to the DAE core, thereby regulating their properties. In order to exploit such photoswitchable systems it is important to precisely adjust the absolute position of their HOMO and LUMO levels and to maximize the extent of the photoinduced shifts of these energy levels. Here, we present a comprehensive study detailing how variation of the substitution pattern of DAE compounds, in particular using strongly electron accepting and chemically stable trifluoromethyl groups either in the periphery or at the reactive carbon atoms, allows for the precise tuning of frontier molecular orbital levels over a broad energy range and the generation of photoinduced shifts of more than 1 eV. Furthermore, the effect of different DAE architectures on the transduction of these shifts to an adjacent functional group is discussed. Whereas substitution in the periphery of the DAE motif has only minor implications on the photochemistry, trifluoromethylation at the reactive carbon atoms strongly disturbs the isomerization efficiency. However, this can be overcome by using a nonsymmetrical substitution pattern or by combination with donor groups, rendering the resulting photoswitches attractive candidates for the construction of remote-controlled functional systems. PMID- 28093833 TI - Cracking the code: residents' interpretations of written assessment comments. AB - CONTEXT: Interest is growing in the use of qualitative data for assessment. Written comments on residents' in-training evaluation reports (ITERs) can be reliably rank-ordered by faculty attendings, who are adept at interpreting these narratives. However, if residents do not interpret assessment comments in the same way, a valuable educational opportunity may be lost. OBJECTIVES: Our purpose was to explore residents' interpretations of written assessment comments using mixed methods. METHODS: Twelve internal medicine (IM) postgraduate year 2 (PGY2) residents were asked to rank-order a set of anonymised PGY1 residents (n = 48) from a previous year in IM based solely on their ITER comments. Each PGY1 was ranked by four PGY2s; generalisability theory was used to assess inter-rater reliability. The PGY2s were then interviewed separately about their rank-ordering process, how they made sense of the comments and how they viewed ITERs in general. Interviews were analysed using constructivist grounded theory. RESULTS: Across four PGY2 residents, the G coefficient was 0.84; for a single resident it was 0.56. Resident rankings correlated extremely well with faculty member rankings (r = 0.90). Residents were equally adept at reading between the lines to construct meaning from the comments and used language cues in ways similarly reported in faculty attendings. Participants discussed the difficulties of interpreting vague language and provided perspectives on why they thought it occurs (time, discomfort, memorability and the permanency of written records). They emphasised the importance of face-to-face discussions, the relative value of comments over scores, staff-dependent variability of assessment and the perceived purpose and value of ITERs. They saw particular value in opportunities to review an aggregated set of comments. CONCLUSIONS: Residents understood the 'hidden code' in assessment language and their ability to rank-order residents based on comments matched that of faculty. Residents seemed to accept staff-dependent variability as a reality. These findings add to the growing evidence that supports the use of narrative comments and subjectivity in assessment. PMID- 28093832 TI - IL-15-deficient mice develop enhanced allergic responses to airway allergen exposure. AB - BACKGROUND: Interleukin-15 is a pleiotropic cytokine that is critical for the development and survival of multiple haematopoietic lineages. Mice lacking IL-15 have selective defects in populations of several pro-allergic immune cells including natural killer (NK) cells, NKT cells, and memory CD8+ T cells. We therefore hypothesized that IL-15-/- mice will have reduced inflammatory responses during the development of allergic airway disease (AAD). OBJECTIVE: To determine whether IL-15-/- mice have attenuated allergic responses in a mouse model of AAD. METHODS: C57BL/6 wild-type (WT) and IL-15-/- mice were sensitized and challenged with ovalbumin (OVA), and the development of AAD was ascertained by examining changes in airway inflammatory responses, Th2 responses, and lung histopathology. RESULTS: Here, we report that IL-15-/- mice developed enhanced allergic responses in an OVA-induced model of AAD. In the absence of IL-15, OVA challenged mice exhibited enhanced bronchial eosinophilic inflammation, elevated IL-13 production, and severe lung histopathology in comparison with WT mice. In addition, increased numbers of CD4+ T and B cells in the spleens and bronchoalveolar lavage (BAL) were also observed. Examination of OVA-challenged IL 15Ralpha-/- animals revealed a similar phenotype resulting in enhanced airway eosinophilia compared to WT mice. Adoptive transfer of splenic CD8+ T cells from OVA-sensitized WT mice suppressed the enhancement of eosinophilia in IL-15-/- animals to levels observed in WT mice, but had no further effects. CONCLUSION AND CLINICAL RELEVANCE: These data demonstrate that mice with an endogenous IL-15 deficiency are susceptible to the development of severe, enhanced Th2-mediated AAD, which can be regulated by CD8+ T cells. Furthermore, the development of disease as well as allergen-specific Th2 responses occurs despite deficiencies in several IL-15-dependent cell types including NK, NKT, and gammadelta T cells, suggesting that these cells or their subsets are dispensable for the induction of AAD in IL-15-deficient mice. PMID- 28093834 TI - Seasonality of pathogens causing community-acquired pneumonia. AB - BACKGROUND AND OBJECTIVE: Seasonal distribution of microbial aetiology in patients with community-acquired pneumonia (CAP) may add important information both for epidemiologists and clinicians. We investigate the seasonal distribution of microbial aetiology in CAP. METHODS: This prospective observational study was carried out in the Hospital Clinic of Barcelona, Spain (January 2003-December 2014). RESULTS: We studied 4431 patients with CAP, of whom 2689 (61%) were males. Microbial aetiology was identified in 1756 patients (40%). CAP was most frequent in winter (34%) but two-third of patients with CAP presented in other seasons. Seasonal variations included Streptococcus pneumoniae (winter 21% vs spring 17% vs summer 14% vs autumn 13%, overall P < 0.001). Influenza viruses were most prevalent in autumn (6%) and winter (5%) compared with spring (3%) and summer (1%) (overall P < 0.001). Legionella pneumophila was most frequent in autumn (4%) and summer (4%) compared with spring (2%) and winter (1%) (overall P < 0.001). Incidence of polymicrobial pneumonia also differed between seasons (winter 7% vs spring 5% vs summer 3% vs autumn 6%, overall P = 0.001). We observed a significant correlation between the lowest seasonal average temperature and polymicrobial pneumonia, pneumococcal pneumonia, and influenza viruses; conversely, L. pneumophila was more common when temperatures were higher. CONCLUSION: CAP should not be regarded as a seasonal disease but occurs throughout all seasons. However, S. pneumoniae, influenza viruses, polymicrobial pneumonia and L. pneumophila are clearly subject to seasonal variations. PMID- 28093835 TI - The assessment and treatment of unhealthy exercise in adolescents with anorexia nervosa: A Delphi study to synthesize clinical knowledge. AB - This study aimed to explore and synthesize expert clinical knowledge on defining and managing unhealthy exercise in adolescents with AN. The Delphi methodology was used. Clinicians (n = 25) considered experts in the treatment of AN in adolescents were recruited internationally to form the panel. The first round of the questionnaires was comprised of five open-ended questions regarding defining, assessing, and treating unhealthy exercise in adolescents with AN. Statements were derived from this data using content analysis, and included as Likert-based items in two subsequent rounds, in which panellists were required to rate their level of agreement for each item. All 25 respondents completed the three rounds of questionnaires. Consensus was achieved for 59.0% of the items included in the second and third round of questionnaires. Although consensus was not achieved, compulsive exercise was the preferred term for the panel when referring to unhealthy exercise in adolescents with AN. The panel clearly delineated features of unhealthy and healthy exercise, and endorsed a number of items considered important to assess for when evaluating exercise in this clinical population. A variety of treatment approaches and strategies reached consensus. Notably, for those who are medically stable and progressing toward recovery, the panel recommended initial exercise restriction practices and reintroducing healthy exercise behaviors, rather than exercise cessation practices. The current findings can serve as preliminary treatment guidelines. A unified approach to labeling and defining unhealthy exercise in the eating disorder literature and clinical settings is required to achieve further progress. PMID- 28093836 TI - Incremental validity of weight suppression in predicting clinical impairment in bulimic syndromes. AB - Research has shown that weight suppression (WS; the difference between a person's highest and current body weight in pounds) is a robust predictor of weight gain and eating-disorder (ED) symptoms among individuals with bulimic syndromes. Given the important prognostic role that WS plays in ED course and outcome, we hypothesized that WS would represent a clinically useful indicator of impairment for bulimic syndromes. We further posited that WS would demonstrate incremental validity above-and-beyond other proposed indicators in explaining clinical impairment in bulimic syndromes. Participants were community-recruited adults (N = 101; 80.2% female) with full-threshold (n = 51) or subthreshold (n = 50) bulimia nervosa. Other indicators of impairment included body mass index, frequency of inappropriate compensatory behaviors, lifetime history of any internalizing disorder, and multiple purging. Clinical impairment was assessed with the clinical impairment assessment (CIA). Hierarchical linear regression tested whether WS added to the explanation of CIA score variance above-and-beyond other indicators of bulimic-syndrome impairment. WS was significantly associated with clinical impairment (p = .011), but did not demonstrate incremental validity over other independent variables in predicting CIA scores. WS explained an additional 1.7% of the variance in CIA scores above-and-beyond other variables and the independent effect of WS on CIA scores represented a medium-sized effect (Cohen's d = 0.521). Results suggested that WS may be an indicator of ED-related clinical impairment. Inquiring about WS could be an informative component of routine bulimic-syndrome assessment, given that WS explains some of the variance in clinical impairment in bulimic syndromes. PMID- 28093837 TI - Effects of simulation education on oral care practices - a randomized controlled trial. AB - BACKGROUND: Implementation of evidence-based oral care protocols, nurse education programmes and assessment tools may reduce the risk of developing ventilator associated pneumonia by increasing critical care nurses' knowledge and skills in adhering to current oral care recommendations. AIMS: To evaluate the longitudinal effects of single-dose simulation education with structured debriefing and verbal feedback on critical care nurses' knowledge and skills in adhering to current oral care recommendations. DESIGN: A randomized controlled trial with repeated measurements. METHOD: The data for the study were collected in a single academic centre in a 22-bed adult, mixed, medical-surgical intensive care unit in Finland from February 2012 to March 2014. The effectiveness of simulation education was evaluated through the validated Ventilator Bundle Questionnaire and Observation Schedule at baseline (n = 30) and 24 months (n = 17) after simulation education. Data were analysed using a linear mixed model and intention-to-treat analyses. RESULTS: During the study period, the average knowledge score in the intervention group increased significantly (44.0% to 56.0% of the total score) in the final post-intervention measurement (pt = 0.51, pg = 0.002, pt*g = 0.023). However, single-dose simulation education with structured debriefing and verbal feedback had no impact on critical care nurses' skill scores. CONCLUSION: Single-dose simulation education had only a minimal effect on critical care nurses' knowledge and skills in adhering to current oral care recommendations. Despite increased awareness, there was no significant difference in oral care practices between the study groups after simulation education. RELEVANCE FOR CLINICAL PRACTICE: The need for regularly repeated educational sessions with theoretical training and practical exercises and direct feedback is evident. Certain aspects of oral care, such as prevention of microaspiration of oropharyngeal secretions and moistening of oral mucosa and lips, require more reinforcement than others. PMID- 28093838 TI - Fusaric acid contributes to virulence of Fusarium oxysporum on plant and mammalian hosts. AB - Fusaric acid (FA) is amongst the oldest identified secondary metabolites produced by Fusarium species, known for a long time to display strong phytotoxicity and moderate toxicity to animal cells; however, the cellular targets of FA and its function in fungal pathogenicity remain unknown. Here, we investigated the role of FA in Fusarium oxysporum, a soil-borne cross-kingdom pathogen that causes vascular wilt on more than 100 plant species and opportunistic infections in humans. Targeted deletion of fub1, encoding a predicted orthologue of the polyketide synthase involved in FA biosynthesis in F. verticillioides and F. fujikuroi, abolished the production of FA and its derivatives in F. oxysporum. We further showed that the expression of fub1 was positively controlled by the master regulator of secondary metabolism LaeA and the alkaline pH regulator PacC through the modulation of chromatin accessibility at the fub1 locus. FA exhibited strong phytotoxicity on tomato plants, which was rescued by the exogenous supply of copper, iron or zinc, suggesting a possible function of FA as a chelating agent of these metal ions. Importantly, the severity of vascular wilt symptoms on tomato plants and the mortality of immunosuppressed mice were significantly reduced in fub1Delta mutants and fully restored in the complemented strains. Collectively, these results provide new insights into the regulation and mode of action of FA, as well as on the function of this phytotoxin during the infection process of F. oxysporum. PMID- 28093840 TI - A Unique Genetically Encoded FRET Pair in Mammalian Cells. AB - Forster resonance energy transfer (FRET) between two suitable fluorophores is a powerful tool to monitor dynamic changes in protein structure in vitro and in vivo. The ability to genetically encode a FRET pair represents a convenient "labeling-free" strategy to incorporate them into target protein(s). Currently, the only genetically encoded FRET pairs available for use in mammalian cells use fluorescent proteins. However, their large size can lead to unfavorable perturbations, particularly when two are used at the same time. Additionally, fluorescent proteins are largely restricted to a terminal attachment to the target, which might not be optimal. Here, we report the development of an alternative genetically encoded FRET pair in mammalian cells that circumvents these challenges by taking advantage of a small genetically encoded fluorescent unnatural amino acid as the donor and enhanced green fluorescent protein (EGFP) as the acceptor. The small size of Anap relative to fluorescent proteins, and the ability to co-translationally incorporate it into internal sites on the target protein, endows this novel FRET pair with improved versatility over its counterparts that rely upon two fluorescent proteins. PMID- 28093839 TI - Serum undercarboxylated osteocalcin correlates with hemoglobin A1c in children with recently diagnosed pediatric diabetes. AB - BACKGROUND: Osteocalcin (OC), a hormone secreted by osteoblasts, improves beta cell function in vitro and in vivo. We aimed to understand the relationship between OC and hemoglobin A1c (HbA1c) in pediatric diabetes. METHODS: Children (n = 70; mean [SD] age = 11.8 years [3.1]; 34.3% non-Hispanic white, 46.3% Hispanic, 14.9% African-American, 4.5% other) newly diagnosed with diabetes (69.1% type 1 diabetes [T1D], 30.9% type 2 diabetes [T2D]) were studied. We collected clinical data at diagnosis and first clinical visit (V1) 9 weeks later (interquartile range [IQR] = 7.9-12.0). Serum undercarboxylated OC (uOC) and carboxylated OC (cOC) were measured 7.0 weeks (IQR 4.3-8.9) after diagnosis. RESULTS: Mean [SD] uOC was 20.3 (19.6) ng/mL, cOC 29.7 [13.7] ng/mL and u/cOC 0.68 [0.81]. uOC, cOC, or u/cOC were not different by gender, race/ethnicity, age, diabetes type, BMI percentile, or random C-peptide, glucose or HbA1c at diagnosis. However, among 61 children with V1 within 4 months of diagnosis, uOC was higher in those with V1 HbA1c < 7.5% (HbA1c < 58 mmol/mol) (uOC=33.1 [22.0]) compared with children with HbA1c >= 7.5% (uOC=17.4 [2.3], P = .0004). The difference was larger among patients with T2D (34.6 and 4.7 ng/mL, respectively, P = .0001) than T1D (32.2 and 19.3, P = .0169), and in males (36.1 and 17.4, P = .018) than females (27.6 and 17.3, P = .072). Analysis for u/cOC were similar while there were no differences in cOC. uOC was inversely correlated with HbA1c at V1 (Spearman's rho = -0.29, P = .02). CONCLUSION: Our findings suggest that serum uOC is inversely related to HbA1c shortly after diagnosis of pediatric diabetes. This potentially modifiable factor of glucose metabolism warrants further studies. PMID- 28093841 TI - Effect of valsartan on kidney outcomes in people with impaired glucose tolerance. AB - AIMS: To examine the effect of valsartan on kidney outcomes in patients with impaired glucose tolerance (IGT). METHODS: In a double-blind randomized trial, 9306 patients with IGT were assigned to valsartan (160 mg daily) or placebo. The co-primary endpoints were the development of diabetes and two composite cardiovascular outcomes. Prespecified renal endpoints included: the composite of renal death, end-stage renal disease (ESRD) or doubling of serum creatinine; estimated glomerular filtration rate (eGFR) <=30 mL/min/1.73 m2 ; hospitalization for renal failure; and progression from normoalbuminuria to microalbuminuria, microalbuminuria to macroalbuminuria, and normoalbuminuria to macroalbuminuria. The median follow-up was 6.2 years. RESULTS: Valsartan reduced the incidence of diabetes but not cardiovascular events. In the valsartan group, 25/4631 patients (0.5%), vs 26/4675 (0.6%) patients in the placebo group, developed ESRD or experienced doubling of serum creatinine (hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.55-1.66; P = .87). Few patients in either group developed an eGFR of <=30 mL/min/1.73 m2 or had a renal hospitalization. Fewer patients on valsartan (237/4084 [5.8%]) than on placebo (342/4092 [8.4%]) developed microalbuminuria (HR 0.68, 95% CI 0.57-0.80; P < .0001), and fewer valsartan treated patients developed macroalbuminuria. Overall, urinary albumin-to creatinine ratio (UACR) was 11% lower with valsartan (95% CI 8-13; P < .0001) and 9% lower (95% CI 6-11; P < .0001) after adjusting for both glucose and blood pressure. CONCLUSIONS: The effect of valsartan on UACR was not wholly explained by change in blood pressure or glucose. Valsartan reduced the incidence of microalbuminuria in IGT without increasing the incidence of hyperkalaemia or renal dysfunction compared with placebo. PMID- 28093842 TI - Gilbert syndrome in patients with type 1 diabetes-Prevalence, glycemic control, and microalbuminuria. AB - BACKGROUND: Gilbert syndrome (GS) is a common hereditary condition, characterized by intermittent unconjugated hyperbilirubinemia. In adults with type 2 diabetes and GS, a markedly lower prevalence of nephropathy was documented, suggesting a beneficial effect of hyperbilirubinemia. We investigated the prevalence of GS among individuals with type 1 diabetes mellitus (T1DM), and the prevalence of microalbuminuria. METHODS: The prevalence of GS was assessed in 401 (204 female) patients with T1DM, median age 21.0 years, (interquartile range [IQR], 15.7 27.9), median disease duration 10.8 years (IQR, 5.7-15.8); and was compared with GS prevalence in 181 children (control). The prevalence of microalbuminuria was assessed in patients with T1DM and GS (group I) and compared with that of patients with T1DM alone (group II), in a ratio of 1:2 matched by gender, age, and duration of diabetes. RESULTS: The prevalence of GS in TIDM patients was significantly higher than in the control group (10.7% vs 3.3% respectively, p = .004), with no gender difference. Patients with T1DM and GS had significantly lower HbA1c levels than did those with T1DM alone 7.3 +/- 1.2 vs 7.9 +/- 1.3% respectively (56 +/- 13 vs 63 +/- 14 mmol/mol), p = .02. The rate of microalbuminuria was 14.0% vs 11.0% for patients with T1DM and GS, compared with those with T1DM alone (p = .6). CONCLUSIONS: The occurrence of GS was 3-fold higher among individuals with T1DM than in a healthy control group. Despite better glycemic control, the rate of microalbuminuria was similar among young individuals with T1DM and GS, and those with T1DM alone, suggesting no protective value to elevated bilirubin. PMID- 28093843 TI - The discovery of the virulence gene ToxA in the wheat and barley pathogen Bipolaris sorokiniana. AB - Bipolaris sorokiniana is the causal agent of multiple diseases on wheat and barley and is the primary constraint to cereal production throughout South Asia. Despite its significance, the molecular basis of disease is poorly understood. To address this, the genomes of three Australian isolates of B. sorokiniana were sequenced and screened for known pathogenicity genes. Sequence analysis revealed that the isolate BRIP10943 harboured the ToxA gene, which has been associated previously with disease in the wheat pathogens Parastagonospora nodorum and Pyrenophora tritici-repentis. Analysis of the regions flanking ToxA within B. sorokiniana revealed that it was embedded within a 12-kb genomic element nearly identical to the corresponding regions in P. nodorum and P. tritici-repentis. A screen of 35 Australian B. sorokiniana isolates confirmed that ToxA was present in 12 isolates. Sequencing of the ToxA genes within these isolates revealed two haplotypes, which differed by a single non-synonymous nucleotide substitution. Pathogenicity assays showed that a B. sorokiniana isolate harbouring ToxA was more virulent on wheat lines that contained the sensitivity gene when compared with a non-ToxA isolate. This work demonstrates that proteins that confer host specific virulence can be horizontally acquired across multiple species. This acquisition can dramatically increase the virulence of pathogenic strains on susceptible cultivars, which, in an agricultural setting, can have devastating economic and social impacts. PMID- 28093844 TI - Dispersal and neutral sampling mediate contingent effects of disturbance on plant beta-diversity: a meta-analysis. AB - A major challenge in ecology, conservation and global-change biology is to understand why biodiversity responds differently to similar environmental changes. Contingent biodiversity responses may depend on how disturbance and dispersal interact to alter variation in community composition (beta-diversity) and assembly mechanisms. However, quantitative syntheses of these patterns and processes across studies are lacking. Using null-models and meta-analyses of 22 factorial experiments in herbaceous plant communities across Europe and North America, we show that disturbance diversifies communities when dispersal is limited, but homogenises communities when combined with increased immigration from the species pool. In contrast to the hypothesis that disturbance and dispersal mediate the strength of niche assembly, both processes altered beta diversity through neutral-sampling effects on numbers of individuals and species in communities. Our synthesis suggests that stochastic effects of disturbance and dispersal on community assembly play an important, but underappreciated, role in mediating biotic homogenisation and biodiversity responses to environmental change. PMID- 28093845 TI - Response to comment on 'Randomization inference for treatment effects on a binary outcome'. PMID- 28093846 TI - Speaking a tone language enhances musical pitch perception in 3-5-year-olds. AB - Young children learn multiple cognitive skills concurrently (e.g., language and music). Evidence is limited as to whether and how learning in one domain affects that in another during early development. Here we assessed whether exposure to a tone language benefits musical pitch processing among 3-5-year-old children. More specifically, we compared the pitch perception of Chinese children who spoke a tone language (i.e., Mandarin) with English-speaking American children. We found that Mandarin-speaking children were more advanced at pitch processing than English-speaking children but both groups performed similarly on a control music task (timbre discrimination). The findings support the Pitch Generalization Hypothesis that tone languages drive attention to pitch in nonlinguistic contexts, and suggest that language learning benefits aspects of music perception in early development. A video abstract of this article can be viewed at: https://youtu.be/UY0kpGpPNA0. PMID- 28093847 TI - Quality of life and clinical correlates in older adults living in the community and in nursing homes in Macao. AB - AIM: There have been no previous studies of quality of life (QOL) in older adults in Macao. This study aimed to examine QOL in relation to the sociodemographic and clinical characteristics of adults aged >=50 years in Macao. METHODS: A sample of 451 subjects (203 living in the community, 248 living in nursing homes) was interviewed using standardized instruments. Basic sociodemographic and clinical data including QOL were collected. RESULT: There were no significant differences between the community and nursing home groups in any of the QOL domains. Multiple linear regression analyses revealed that poor physical QOL was significantly predicted by severe depressive symptoms, insomnia, major medical conditions, unmarried status, and lower education ( F 11,438 = 26.2, P < 0.001), which accounted for 38.2% of the variance. Poor psychological QOL was significantly predicted by severe depressive symptoms and lower educational level ( F 11,438 = 24.3, P < 0.001), which accounted for 36.4% of the variance. Poor social QOL was significantly predicted by severe depressive symptoms, male gender, and unmarried status ( F 11,438 = 5.6, P < 0.001), which accounted for 12.5% of the variance. Poor environment QOL was significantly predicted by lower educational level, severe depressive symptoms, and younger age ( F 11,438 = 6.6, P < 0.001), which accounted for 12.1% of the variance. CONCLUSION: Older Macanese adults had poorer scores on physical and social QOL domains than the general Hong Kong Chinese population. Their QOL was more strongly related to severe depressive symptoms, major medical conditions, and insomnia. PMID- 28093848 TI - One mutation, two distinct disease variants: unravelling the impact of transthyretin amyloid fibril composition. AB - Although hereditary transthyretin (h-ATTR) amyloidosis is a monogenetic disease, a large variation in its phenotype has been observed. The common hypothesis of amyloid fibril formation involves dissociation of the transthyretin (TTR) tetramer into monomers that after misfolding reassemble into amyloid fibrils. This notion is partly challenged by the finding of two distinct types of amyloid fibrils. One of these, type A, consists of C-terminal ATTR fragments and full length TTR, whereas the other, type B, consists only of full-length TTR. All organs of an individual patient contain ATTR deposits of either type A or type B fibrils, and the composition in each individual remains unchanged over time. The finding of two distinct types of ATTR fibrils suggests that there are at least two different pathways in operation for ATTR fibril formation. For the most common European mutation, TTR Val30Met, ATTR fibril composition is related to the outcome of liver transplantation, which is the first successful treatment for the disease, and the penetrance of the trait. In addition, the presence of C-terminal ATTR fragments has an impact on the affinity for various tracers used for noninvasive imaging of amyloid depositions such as 99 m-technetium-diphosphono propanodicarboxylic acid scintigraphy and positron emission tomography utilizing Pittsburgh component B, and even for the gold standard diagnostic procedure, tissue biopsy stained by Congo red and examined under polarized light. The importance of amyloid fibril composition needs to be taken into consideration when designing clinical trials of treatment modalities, and also in the evaluation of diagnostic methods such as imaging techniques. PMID- 28093851 TI - New year's greetings. PMID- 28093849 TI - Obesity and type 2 diabetes are associated with elevated PCSK9 levels in young women. AB - BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of low-density lipoprotein cholesterol and cardiovascular disease risk, and is an emerging therapeutic target. OBJECTIVE: We compared serum PCSK9 levels in young adults, with and without type 2 diabetes. SUBJECTS AND METHODS: Cross sectional analysis was conducted in a cohort, aged 15 to 26 years, in Cincinnati, OH, from 2005 to 2010. Serum PCSK9 levels were measured in 94 youth with type 2 diabetes, 93 obese control subjects, and 99 lean control subjects. Correlative analyses were conducted to determine significant covariates of PCSK9 by group and sex, and multivariate linear regression models were used to study the independent determinants of PCSK9. RESULTS: In females, PCSK9 levels were significantly increased in the obese and type 2 diabetes subjects relative to the lean controls (P < .01). Moreover, PCSK9 was positively correlated with multiple metabolic parameters in females: body mass index, systolic blood pressure, fasting glucose, fasting insulin, and C-reactive protein levels (P <= .02). In males, PCSK9 levels were decreased overall compared with females (P = .03), and did not differ between the lean, obese, or type 2 diabetes groups. CONCLUSIONS: Obesity and type 2 diabetes were associated with significantly higher levels of PCSK9 in young women, but not in young men. These data suggest that sex could modify the effects of obesity and diabetes on PCSK9 in young adults. PMID- 28093852 TI - Factors influencing fatigue among mothers with hospitalized children: A structural equation model. AB - PURPOSE: The aim of this study was to identify the physiological, psychological, and situational factors affecting fatigue among mothers of hospitalized children. DESIGN AND METHODS: This study used a cross-sectional descriptive design with a self-report questionnaire. Participants were 211 mothers with children younger than 6 years old who were admitted to general hospitals. Based on the theory of unpleasant symptoms, the physiological, psychological, and situational factors were tested using structural equation modeling. RESULTS: Mothers' fatigue was influenced by physiological (beta = .24), situational, and psychological factors (beta = .17), and situational (beta = .37) factors such as the mother's sleeping hours, the child's adaptation to hospitalization, anxiety and having support with their housework. These three factors explained 31.34% of the variance in fatigue. In particular, it was found that the psychological factors exacerbate the negative influence of the situational factors on fatigue. Moreover, the situational factors were most strongly related to mothers' fatigue, and they had an indirect effect via the psychological factors as a mediator. PRACTICE IMPLICATIONS: It is necessary to implement a nursing intervention that targets the controllable factors such as anxiety and children's adaptation to hospitalization that were identified in this study. Pediatric nursing care should not be limited to treating children's illnesses, but should be extended to providing family-centered care. PMID- 28093854 TI - Reduced representation genome sequencing reveals patterns of genetic diversity and selection in apple. AB - Identifying DNA sequence variations is a fundamental step towards deciphering the genetic basis of traits of interest. Here, a total of 20 cultivated and 10 wild apples were genotyped using specific-locus amplified fragment sequencing, and 39,635 single nucleotide polymorphisms with no missing genotypes and evenly distributed along the genome were selected to investigate patterns of genome-wide genetic variations between cultivated and wild apples. Overall, wild apples displayed higher levels of genetic diversity than cultivated apples. Linkage disequilibrium (LD) decays were observed quite rapidly in cultivated and wild apples, with an r2 -value below 0.2 at 440 and 280 bp, respectively. Moreover, bidirectional gene flow and different distribution patterns of LD blocks were detected between domesticated and wild apples. Most LD blocks unique to cultivated apples were located within QTL regions controlling fruit quality, thus suggesting that fruit quality had probably undergone selection during apple domestication. The genome of the earliest cultivated apple in China, Nai, was highly similar to that of Malus sieversii, and contained a small portion of genetic material from other wild apple species. This suggested that introgression could have been an important driving force during initial domestication of apple. These findings will facilitate future breeding and genetic dissection of complex traits in apple. PMID- 28093855 TI - Typical and atypical appearance of early-onset Alzheimer's disease: A clinical, neuroimaging and neuropathological study. AB - The International Working Group (IWG) has classified Alzheimer's disease (AD) as two different types, the typical form and the atypical form, but clinicopathological studies of atypical AD are limited. Because atypical AD cases usually present with early-onset dementia, we investigated 12 patients with early onset AD, including two patients with typical AD and 10 patients with atypical AD. Of these patients, six had the posterior variant, three had the frontal variant and one had the logopenic variant mixed with semantic dementia. We reported MRI, single-photon emission CT and neuropathological findings in six representative cases. We also described a "left temporal variant" of AD presenting with transcortical cortical sensory aphasia, which has not been reported previously and is another subtype of the posterior variant of AD. We found a significant correlation between regional cerebral blood flow and counts of NFTs in the cerebral cortices. An atypical presentation with focal neuropsychological symptoms roughly correlated with the density of NFTs in the cerebral cortex and more directly related to spongiform changes in the superficial layers of these areas. In contrast, the distribution of amyloid depositions was diffuse and did not necessarily correlate with focal neuropsychological symptoms. Braak staging or ABC score is not necessarily appropriate to evaluate atypical AD, and instead, spongiform changes in addition to tau pathology in the association cortices better explain the diversity of atypical AD. Interestingly, another patient with a posterior variant of AD had a novel type of atypical plaque, which we referred to as "lucent plaque". They were recognizable with HE staining in the circumference and dystrophic neurites were abundant with Gallyas-Braak staining. These plaques demonstrated intense immunoreactivity to both tau AT-8 and amyloid beta (Abeta), suggesting a peculiar coexistence pattern of amyloid and tau in these plaques. Clinicopathological studies of atypical AD will provide a new understanding of the pathophysiology of AD. PMID- 28093853 TI - Randomized clinical trial comparing the efficacy and safety of treatment with the once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor omarigliptin or the once daily DPP-4 inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled on metformin monotherapy. AB - AIM: To compare the efficacy and safety of the once-weekly oral dipeptidyl peptidase-4 (DPP-4) inhibitor omarigliptin or once-daily DPP-4 inhibitor sitagliptin in patients with type 2 diabetes (T2DM) and inadequate glycaemic control on metformin. MATERIALS AND METHODS: Patients with T2DM with a glycated haemoglobin (HbA1c) concentration >=6.5% to <=9.0% while on a stable dose of metformin (>=1500 mg/d) were randomized in a double-blind manner to receive omarigliptin 25 mg once weekly (n = 322) or sitagliptin 100 mg once daily (n = 320). The primary analysis assessed whether omarigliptin was non-inferior to sitagliptin in reducing HbA1c at week 24, based on the criterion of having an upper bound of the 95% confidence interval (CI) about the difference less than the non-inferiority bound of 0.3%. RESULTS: The mean baseline HbA1c was 7.5% in both groups. After 24 weeks, the least squares (LS) mean change in HbA1c from baseline was -0.47% in the omarigliptin group and -0.43% in the sitagliptin group, with a between-group difference of -0.03% (95% CI -0.15, 0.08). This result met the prespecified criterion for declaring non-inferiority. The LS mean change from baseline in fasting plasma glucose and the percentage of patients with HbA1c <7.0% or <6.5% at week 24 were similar in the two treatment groups. There were no notable differences in adverse events and the incidence of symptomatic hypoglycaemia was low and similar in the groups. CONCLUSIONS: In patients with T2DM and inadequate glycaemic control on metformin, the addition of omarigliptin 25 mg once weekly or sitagliptin 100 mg once daily led to similar improvements in glycaemic control. Both agents were generally well tolerated with a low incidence of hypoglycaemia. PMID- 28093856 TI - The Nature of Metal-Metal Interactions in Dimeric Hydrides and Halides of Group 11 Elements in the Light of High Level Relativistic Calculations. AB - The titular calculations show that charges at metal atoms M are apparently the main factor governing the nature of M???M interactions in two-nuclear coinage metal complexes, and there are certain critical values of positive charges on M atoms, on exceeding which the pair-wise M???M interactions and/or the binding between M atoms in such complexes become repulsive despite negative formation energies of such complexes, short M-M internuclear distances, and the existence of a bond critical point (BCP) between M atoms. PMID- 28093857 TI - Can blood flow restriction augment muscle activation during high-load training? AB - INTRODUCTION: Blood flow restriction has been shown to augment muscle activation and increase muscle size when combined with low-load training; however, much less is known on whether blood flow restriction can augment muscle activation during high-load exercise. PURPOSE: To determine whether applying blood flow restriction can augment muscle activation with traditional high-load resistance exercise. METHOD: Ten individuals completed two sets of elbow flexion exercise to volitional fatigue. The control arm rested for 3 min between sets while the experimental arm had blood flow restriction applied for 3 min. RESULT: The blood flow restricted arm completed significantly fewer repetitions in set 2 in comparison with set 1 [set 1: 9 (1), set 2: 4 (1); P<0.001], whereas no meaningful differences were observed in the control arm [set 1: 8 (1), set 2: 7 (1); P = 0.057]. There was no interaction for muscle activation (P = 0.851) with both conditions significantly lower at the start of set 2 [87 (26)%] in comparison with the end of set 1 [106 (40)%] or end of set 2 [103 (33)%]. CONCLUSION: The application of blood flow restriction does not augment muscle activation present with high-load exercise and would seem unlikely to induce greater muscle hypertrophy. PMID- 28093858 TI - Parent perceptions of health promotion for school-age children with spina bifida. AB - PURPOSE: To gain insight into how parents develop their beliefs of health promotion for their children with spina bifida (SB) and how they develop and promote health promotion practices for their children. DESIGN: Qualitative, exploratory design with semi-structured interviews of parents of children between 6 and 12 years of age diagnosed with SB was used for this study. RESULTS: Perceptions of health promotion were maintaining healthy bowel function and managing SB care. Good bowel function and SB management is health promotion and adequate bowel function is viewed as a marker of health. Maintaining healthy bowel function was identified by parents as the key marker of health for their children with SB. Further, the term health promotion brought up plans, concerns, and goals more related to their child's physiologic functioning and health care needs rather than promoting health and avoiding preventable disease. PRACTICE IMPLICATIONS: Nurses and healthcare providers are in unique and powerful positions for strategizing with parents on how to integrate health promotion into the lives of children with SB. Team-based, whole-person, holistic assessment and teaching inclusive of promoting healthy lifestyle behaviors in addition to providing excellent care related to their physiologic systems affected by SB can improve how we promote health for these children. PMID- 28093859 TI - Anion-Templated Nanosized Silver Alkynyl Clusters: Cluster Engineering and Solution Behavior. AB - Assembly of nanosized polynuclear metal clusters from simple building blocks usually involves complicated self-organization processes and thus is a long standing challenge. Here, we demonstrate the controllable assembly, single crystal structures and solution behaviors of four molecular assemblies based on nanosized silver alkynyl clusters, formulated as {[(CrO4 )2 Cl@Ag42 (PhC=C)34 (CF3 COO)2 ]?CF3 COO} (1), {(NH4 )[(CrO4 )2 Cl@Ag42 (PhC=C)34 (CrO4 )(H2 O)2 ]?2BF4 ?CH3 OH}n (2), [(CrO4 )@Ag22 (PhC=C)16 (CF3 SO3 )4 ]n (3), and {[(CrO4 )2 @Ag31 (PhC=C)22 (CF3 SO3 )4 ]?CF3 SO3 ?2CH3 OH?H2 O}n (4). In the presence of concomitant CrO42- and Cl- templates, we could isolate a discrete cluster 1 and a polymeric chain-like compound 2 by using different silver salts. Both 1 and 2 have a similar 42-metallic cage, which traps two CrO42- and one Cl- as anion templates. Using sole CrO42- template, 3 and 4 were simultaneously isolated in a one-pot reaction. Both of them are 1D chain structures based on single CrO42- templated Ag18 and double CrO42- templated Ag30 clusters, respectively. HR-ESI-MS was used to study the solution behaviors of 1-4. This work has the following purposes: i) it presents the cluster engineering concept used in the assembly of polynuclear silver alkynyl clusters; ii) it exemplifies template effects from hetero and homo anions; and iii) it provides a controllable way to achieve assembly of silver alkynyl clusters. PMID- 28093860 TI - Monolithic implant-supported lithium disilicate (LS2) crowns in a complete digital workflow: A prospective clinical trial with a 2-year follow-up. AB - BACKGROUND: The technical development of digital processing allows the production of anatomically full-contoured implant-supported restorations. PURPOSE: The aim of this prospective clinical trial was to analyze the treatment concept of monolithic lithium disilicate (LS2) single-unit restorations in a complete digital workflow. MATERIAL AND METHODS: Forty-four patients were restored with 50 screw-retained monolithic implant LS2 crowns bonded to pre-fabricated titanium abutments on soft tissue level implants (Institut Straumann AG, Basel, Switzerland) in premolar and molar sites. All implant restorations were digitally designed after intraoral optical scanning (IOS) and CAD/CAM-processing without physical model situations. Study participants were clinically and radiographically examined based on an annually performed follow-up. The "Functional Implant Prosthodontic Score" (FIPS) was applied for objective outcome assessment after 2 years of loading. Five variables were defined for FIPS evaluation, resulting in a maximum score of 10 per implant restoration. Descriptive statistics were calculated for mean scores standard deviations, medians, and Q25 -Q75 . RESULTS: All patients could be successfully treated within two clinical appointments. No clinical modifications were necessary for the seating of the monolithic crowns, neither for interproximal nor occlusal sites. The implant LS2 restorations demonstrated survival rates of 100% without any technical or biological complications after 2 years. The mean total FIPS score was 7.7 +/- 1.0, ranging from 6 to 10. CONCLUSIONS: CAD/CAM-produced monolithic implant crowns out of LS2 in a complete digital workflow seem to be a feasible treatment concept for the rehabilitation of single-tooth gaps in posterior sites under mid-term observation. PMID- 28093862 TI - The International Journal of Geriatric Psychiatry in Perspective. PMID- 28093861 TI - Laparoscopic-endoscopic cooperative surgery for a duodenal neuroendocrine tumor: A case report. AB - For neuroendocrine tumor G1, local resection is one of the primary treatment options. Endoscopic submucosal dissection has been proven to ensure complete resection with sufficient margins. However, duodenal endoscopic submucosal dissection has a high risk of duodenal perforation because of the thin duodenal wall and poor endoscopic maneuverability. During laparoscopic dissection, suturing can resolve perforation. Therefore, laparoscopic-endoscopic cooperative surgery (LECS) can ensure complete resection with a minimal margin to prevent stenosis, and suturing can resolve perforation. In short, LECS combines the advantages of both techniques. In the present case, a duodenal neuroendocrine tumor G1 in a 75-year-old man was successfully treated using LECS. The patient remained free from recurrence at 21 months postoperatively. LECS is feasible for a neuroendocrine tumor G1 <=20 mm in size that has not invaded the muscularis propria or the lymphatic and venous vessels. PMID- 28093863 TI - Do self-reports provide valid information about driving fitness in seniors? PMID- 28093864 TI - Alzheimer's disease and Toxoplasma gondii infection; seromolecular assess the possible link among patients. PMID- 28093866 TI - Advancing Clinical and Translational Science. PMID- 28093865 TI - Nanoscale physicochemical properties of chain- and step-growth polymerized PEG hydrogels affect cell-material interactions. AB - Poly(ethylene glycol) (PEG) hydrogels provide a versatile platform to develop cell instructive materials through incorporation of a variety of cell adhesive ligands and degradable chemistries. Synthesis of PEG gels can be accomplished via two mechanisms: chain and step growth polymerizations. The mechanism dramatically impacts hydrogel nanostructure, whereby chain polymerized hydrogels are highly heterogeneous and step growth networks exhibit more uniform structures. Underpinning these alterations in nanostructure of chain polymerized hydrogels are densely-packed hydrophobic poly(methyl methacrylate) or poly(acrylate) kinetic chains between hydrophilic PEG crosslinkers. As cell-material interactions, such as those mediated by integrins, occur at the nanoscale and affect cell behavior, it is important to understand how different modes of polymerization translate into nanoscale mechanical and hydrophobic heterogeneities of hydrogels. Therefore, chain- and step-growth polymerized PEG hydrogels with macroscopically similar macromers and compliance (for example, methacrylate-functionalized PEG (PEGDM), MW = 10 kDa and norbornene functionalized 4-arm PEG (PEGnorb), MW = 10 kDa) were used to examine potential nanoscale differences in hydrogel mechanics and hydrophobicity using atomic force microscopy (AFM). It was found that chain-growth polymerized network yielded greater heterogeneities in both stiffness and hydrophobicity as compared to step growth polymerized networks. These nanoscale heterogeneities impact cell-material interactions, particularly human mesenchymal stem cell (hMSC) adhesion and spreading, which has implications in use of these hydrogels for tissue engineering applications. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1112-1122, 2017. PMID- 28093867 TI - Paramedic resuscitation competency: A survey of Australian and New Zealand emergency medical services. AB - OBJECTIVE: We have previously established that paramedic exposure to out-of hospital cardiac arrest (OHCA) is relatively rare, therefore clinical exposure cannot be relied on to maintain resuscitation competency. We aimed to identify the current practices within emergency medical services (EMS) for developing and maintaining paramedic resuscitation competency. METHODS: We developed and conducted an online cross-sectional survey of Australian and New Zealand EMS in 2015. The survey was piloted by one EMS and targeted at education managers. RESULTS: A total of nine of the 10 EMS responded to the survey. All EMS reported that they provide resuscitation training to paramedics at the commencement of their employment (median 16 h, interquartile range [IQR]: 7-80). With the exception of one EMS that did not provide any refresher training, a median of 4 h (IQR: 1-7) resuscitation training was provided to paramedics annually. All EMS used cardiac arrest simulations and skill stations to train paramedics. Paramedic exposure to OHCA was not taken into account to determine their training needs. Resuscitation competency was tested by EMS: annually (3/9), biennially (4/9) or not at all (2/9). Two EMS used CPR-feedback devices in clinical practice and only one EMS regularly performed formal debriefing after OHCA cases. Barriers to resuscitation competency included: difficulty removing paramedics from clinical duties for training and a lack of paramedic exposure to OHCA. CONCLUSION: All of the surveyed EMS provided initial resuscitation training to paramedics, but competency testing and refresher training practices varied between services. A lack of individual exposure to cardiac arrest and training time were identified as barriers to resuscitation competency. PMID- 28093868 TI - Applicability of the Chinese version of the Personal and Social Performance scale in patients with severe mental disorders. AB - INTRODUCTION: This study was designed to determine the reliability and validity of the Chinese version of the Personal and Social Performance scale (PSP-CHN) and assess the applicability of using the PSP-CHN in patients with severe mental disorders. METHODS: A total of 285 outpatients with severe mental disorders, 220 with schizophrenia and 65 with major depressive disorder, were enrolled into the study. Both diagnoses were made using the DSM-IV. All the patients were assessed with the PSP-CHN, the GAF, and the CGI-S. In addition, the PANSS and the MADRS were used to assess the patients with schizophrenia and major depressive disorder, respectively. RESULTS: The PSP-CHN showed good internal consistency (Cronbach alpha = 0.839, n = 285), high interrater reliability for total scores (intraclass correlation coefficient, ICC = 0.865, n = 48), and good test-retest reliability (ICC = 0.892, n = 130). The PSP-CHN total score showed a statistically significant positive correlation with the GAF score (r = 0.927, P < .01, n = 285), as well as a significant negative correlation with the CGI-S total score (r = -0.793, P < .01, n = 285), the PANSS total score (r = -0.694, P < .01, n = 220), and the MADRS total score (r = -0.721, P < .01, n = 65). DISCUSSION: We were able to demonstrate that the PSP-CHN is a reliable and valid measurement tool to assess the personal and social functioning in patients with severe mental disorders. PMID- 28093870 TI - Acute management of autoimmune toxicity in cancer patients on immunotherapy: Common toxicities and the approach for the emergency physician. AB - When a patient receiving anti-cancer treatment presents acutely unwell, an understanding of associated side effects of their therapy is critical. This review will discuss the approach to patients receiving anti-cancer treatment with immunotherapy presenting with autoimmune toxicities in the emergency setting. These toxicities are commonly referred to as immune-related adverse events (irAE). IrAE might consist of, but are not limited to, dermatologic, gastrointestinal (diarrhoea, colitis), hepatic, endocrine (thyroid dysfunction, hypophysitis, adrenal crisis), renal, ocular and pulmonary toxicity. General principles of managing these irAE in the acute setting will be outlined. Steroid therapy is a critical component of the treatment algorithm, being administered at high doses and for prolonged periods to switch off immune over-activation. Prompt intervention might prevent multi-organ failure and fatality, and allow patients to remain on effective anti-cancer therapy. PMID- 28093869 TI - Biosynthesis of micro- and nanocrystals of Pb (II), Hg (II) and Cd (II) sulfides in four Candida species: a comparative study of in vivo and in vitro approaches. AB - Nature produces biominerals (biogenic minerals) that are synthesized as complex structures, in terms of their physicochemical properties. These biominerals are composed of minerals and biological macromolecules. They are produced by living organisms and are usually formed through a combination of chemical, biochemical and biophysical processes. Microorganisms like Candida in the presence of heavy metals can biomineralize those metals to form microcrystals (MCs) and nanocrystals (NCs). In this work, MCs and NCs of PbS, HgS or HgCl2 as well as CdS are synthesized both in vitro (gels) and in vivo by four Candida species. Our in vivo results show that, in the presence of Pb2+ , Candida cells are able to replicate and form extracellular PbS MCs, whereas in the presence of Hg2+ and Cd2+ , they did synthesize intercellular MCs from HgS or HgCl2 and CdS NCs respectively. The MCs and NCs biologically obtained in Candida were compared with those PbS, HgS and CdS crystals synthetically obtained in vitro through the gel method (grown either in agarose or in sodium metasilicate hydrogels). This is, to our knowledge, the first time that the biosynthesis of the various MCs and NCs (presented in several species of Candida) has been reported. This biosynthesis is differentially regulated in each of these pathogens, which allows them to adapt and survive in different physiological and environmental habitats. PMID- 28093871 TI - Reply. PMID- 28093872 TI - Nitrogenated Azaphilone Derivatives through a Silver-Catalysed Reaction of Imines from ortho-Alkynylbenzaldehydes. AB - Nitrogenated azaphilones are interesting natural products with a wide range of applications. The structure of these compounds is characterized by the presence of an isoquinolinone framework. Here, we describe a new multicomponent silver catalysed reaction that allows the transformation of simple imines derived from ortho-alkynylbenzaldehydes into complex nitrogenated azaphilone-type molecules in a straightforward way. This atom-economical process is high yielding, technically very simple and proceeds through a series of cascade processes that imply cycloisomerisation and formal cross-coupling reactions. This conceptually new process formally involves the synchronised catalytic generation and selective coupling of a nucleophile (isoquinolinone) and an electrophile (isoquinolinium). Some interesting colour properties of the synthesized azaphilone-type molecules are discussed. PMID- 28093873 TI - Diagnostic and management challenges from childhood, puberty through to transition in severe insulin resistance due to insulin receptor mutations. AB - Two Caucasian girls, both of normal weight and body mass indices, were diagnosed with type A insulin resistance (IR) in childhood. Case 1 presented with premature adrenarche aged 7 years, then by age 12 years had hirsutism, acne, acanthosis nigricans, and asymptomatic diabetes. Subsequent investigation revealed raised adiponectin (15.3 mg/L) and heterozygous p.Pro1205Leu mutation in the INSR gene encoding the insulin receptor. She experienced postprandial hypoglycaemia on metformin; acarbose was trialled and discontinued aged 16 years, as she became normoglycaemic. Hirsutism was treated with topical eflornithine, oral spironolactone and flutamide, and laser therapy. Unfortunately, diabetes reemerged in young adulthood with obesity. Case 2: during an emergency admission for acute abdominal pain aged 11 years, hyperglycaemia was noted which led to further investigation. An oral glucose tolerance test showed diabetes and ultrasound showed polycystic ovaries. Further investigations revealed raised adiponectin (18 mg/L) and compound heterozygous mutations in the INSR gene: p.Pro1263Ala and p.Ser748Leu (latter probable normal variant). She was treated with metformin and experienced postprandial hypoglycaemia. Symptoms of hyperandrogenism were controlled by flutamide. She maintained a healthy weight and reassessment at young adulthood showed resolution of diabetes. Type A IR may present in childhood with overlapping features of common endocrine entities such as premature adrenarche and polycystic ovarian syndrome. Patients with abnormal glucose tolerance yet normal weight merit screening with adiponectin; raised adiponectin levels prompt insulin receptor mutational analysis. Postprandial hypoglycaemia is characteristic. Management includes optimization of glycaemic control with oral hypoglycaemic agents and maintenance of healthy weight, and controlling the effects of hyperandrogenism. PMID- 28093874 TI - Management of coronary artery disease and acute coronary syndrome in the chronic kidney disease population-A review of the current literature. AB - Coronary Artery Disease (CAD) is a large contributor to morbidity and mortality in the chronic kidney disease (CKD) and end-stage renal disease (ESRD) population. Due to the fact that many large-scale trials evaluating management for acute coronary syndromes (ACS) and CAD have excluded patients with CKD, there is a paucity of data investigating medical management of CAD and revascularization strategies of these patients. Further, while there have been many advances in the treatment for ACS and CAD, both medically and technologically, few studies have focused on the CKD population and many predate these advancements in management. Newer studies that include CKD patients have shown heterogeneity in various outcomes, making management decisions challenging. In this review, we summarize the epidemiologic significance of ACS and CAD in patients with CKD, discuss the diagnosis of ACS in this patient population, and review the therapeutic interventions in patients with CKD. PMID- 28093875 TI - What are the evolutionary origins of stomatal responses to abscisic acid in land plants? AB - The evolution of active stomatal closure in response to leaf water deficit, mediated by the hormone abscisic acid (ABA), has been the subject of recent debate. Two different models for the timing of the evolution of this response recur in the literature. A single-step model for stomatal control suggests that stomata evolved active, ABA-mediated control of stomatal aperture, when these structures first appeared, prior to the divergence of bryophyte and vascular plant lineages. In contrast, a gradualistic model for stomatal control proposes that the most basal vascular plant stomata responded passively to changes in leaf water status. This model suggests that active ABA-driven mechanisms for stomatal responses to water status instead evolved after the divergence of seed plants, culminating in the complex, ABA-mediated responses observed in modern angiosperms. Here we review the findings that form the basis for these two models, including recent work that provides critical molecular insights into resolving this intriguing debate, and find strong evidence to support a gradualistic model for stomatal evolution. PMID- 28093876 TI - Development of poly(lactide-co-glycolide) nanoparticles functionalized with a mitochondria penetrating peptide. AB - The development of mitochondria-targeting cell permeable vectors represents a promising therapeutic approach for several diseases, such as cancer and oxidative pathologies. Nevertheless, access to mitochondria can be difficult. A new hybrid material composed by poly(lactide-co-glycolide) (PLGA) functionalized with a 6 mer mitochondria penetrating peptide (MPP), consisting in alternating arginine and unnatural cyclohexylalanine, was developed. Circular dichroism, FT-IR and DSC studies indicated that the conjugation of the peptide with the polymer led to the obtainment of a more rigid material with respect to both PLGA and MPP as such. In particular, a conformational rearrangement to a helical structure was observed for MPP. MPP-PLGA conjugates were used for the preparation of nanoparticles that showed no cytotoxicity in MTT assay, suggesting their putative use for future studies on mitochondria targeting. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd. PMID- 28093877 TI - A Shovel-Ready Solution to Fill the Nursing Data Gap in the Interdisciplinary Clinical Picture. AB - PURPOSE: To critically evaluate 2014 American Academy of Nursing (AAN) call-to action plan for generating interoperable nursing data. DATA SOURCES: Healthcare literature. DATA SYNTHESIS: AAN's plan will not generate the nursing data needed to participate in big data science initiatives in the short term because Logical Observation Identifiers Names and Codes and Systematized Nomenclature of Medicine - Clinical Terms are not yet ripe for generating interoperable data. Well-tested viable alternatives exist. CONCLUSIONS: Authors present recommendations for revisions to AAN's plan and an evidence-based alternative to generating interoperable nursing data in the near term. These revisions can ultimately lead to the proposed terminology goals of the AAN's plan in the long term. PMID- 28093878 TI - In Pursuit of Greater Reproducibility and Credibility of Early Clinical Biomarker Research. PMID- 28093879 TI - Valproate-induced encephalopathy in a comorbid elderly woman. PMID- 28093880 TI - PEG-Induced Synthesis of Coordination-Polymer Isomers with Tunable Architectures and Iodine Capture. AB - Controllable synthesis of coordination polymer (CP) isomers and revealing their structure-property relationships remain enormous challenges. Three new supramolecular isomers have been synthesized by tuning the poly(ethylene glycol) (PEG) content in the feed. These supramolecular isomers have the same framework formula of [Cu2 I2 (tppe)] and different architectures from the classical 2D stacking framework to a 3D entangled system with the coexistence of interpenetration and polycatenation, and a 3D topological framework. Interestingly, these CPs could be utilized for capturing iodine molecules. According to multiple complementary experiments and crystallographic analyses, iodine capture is mainly based on halogen-bond interactions in the inorganic {Cu2 I2 } building blocks of the framework. The present study describes a structure property relationship in supramolecular isomerism with distinct topological structures. PMID- 28093881 TI - A case of anaplastic lymphoma kinase (ALK)-positive ciliated muconodular papillary tumor (CMPT) of the lung. AB - Ciliated muconodular papillary tumor (CMPT) is a rare papillary tumor that arises in the peripheral lung fields and is associated with the proliferation of ciliate d and goblet cells and increased mucin production. We report a case of CMPT involving the rearrangement of the anaplastic lymphoma kinase (ALK) gene. The patient was an 84-year-old Japanese female who had exhibited a small nodular shadow on chest computed tomography during a regular checkup 10 years ago. She underwent a partial resection of segment S10 of the right lung. The cut surface of the surgical specimen revealed a well-circumscribed, jelly-like mass measuring 8 * 8 * 10 mm. Histologically, the tumor was composed of a mixture of ciliated, goblet, and basal cells arranged in a papillary pattern together with pools of mucin. A diagnosis of CMPT was made. The lung tumor cells were subjected to fluorescent in situ hybridization and highly sensitive immunohistochemical staining for the ALK protein, both of which produced positive results. CMPT usually follows a favorable course, but the exact nature of this tumor; i.e., whether it is benign or malignant, has not been established. This is the first reported case of an ALK-positive CMPT. PMID- 28093883 TI - Consumers in mental health service leadership: A systematic review. AB - Contemporary mental health policies call for greater involvement of mental health service consumers in all aspects and at all levels of service planning, delivery, and evaluation. The extent to which consumers are part of the decision-making function of mental health organizations varies. This systematic review synthesizes empirical and review studies published in peer-reviewed academic journals relating to consumers in leadership roles within mental health organizations. The Cochrane Library, Medline, and PsycINFO were searched for articles specifically analysing and discussing consumers' mental health service leadership. Each article was critically appraised against the inclusion criteria, with 36 articles included in the final review. The findings of the review highlight current understandings of organizational resources and structures in consumer-led organizations, determinants of leadership involvement, and how consumer leadership interacts with traditional mental health service provision. It appears that organizations might still be negotiating the balance between consumer leadership and traditional structures and systems. The majority of included studies represent research about consumer-run organizations, with consumer leadership in mainstream mental health organizations being less represented in the literature. Advocates of consumer leadership should focus more on emphasizing how such leadership itself can be a valuable resource for organizations and how this can be better articulated. This review highlights the current gaps in understandings of consumer leadership in mental health, including a need for more research exploring the benefits of consumer leadership for other consumers of services. PMID- 28093882 TI - The gastrointestinal tract of farmed mink (Neovison vison) maintains a diverse mucosa-associated microbiota following a 3-day fasting period. AB - Although it is well documented that the gut microbiota plays an important role in health and disease in mammalian species, this area has been poorly studied among carnivorous animals, especially within the mustelidae family. The gastrointestinal tract of carnivores is characterized by its short length and fast transit time, as compared to omnivores and herbivores, which is due to the low level of inherent fermentation. Mink represents an example of this, which have a GI tract only four times the length of the body and a transit time of approximately 4-5 hr. In this study, we used high-throughput 16S rRNA gene sequencing to explore the resident gut microbiota of the mink in terms of intra and interindividual diversity. We report, for the first time, that the mucosa associated bacterial community within the colon is diverse and dissimilar from the community found in the feed. We found large interindividual differences in bacterial composition between individual animals being dominated generally by the phylum Firmicutes, but in some cases also Proteobacteria or Fusobacteria. The bacterial load and community structure within the mucus was not severely impacted by 3 days of fasting, which implies that a resident and stable microbiota is hosted by these animals. PMID- 28093884 TI - Considering the culture of blame in mental health care and service delivery. PMID- 28093885 TI - Claims to the benefits of clinical supervision: A critique of the policy development process and outcomes in New South Wales, Australia. AB - The historical development of clinical supervision has been variously interpreted in the international literature. Creditable evidence has accumulated, particularly over the past two decades, to show that clinical supervision has a positive demonstrable effect on supervisees. However, comparatively little research evidence has entered the public domain on any effect that clinical supervision might have on other nominated outcomes. In Australia, developments in clinical supervision were recently prompted by initiatives at national and state levels. Since 2010, lead agencies for these have sought feedback from professional bodies and organizations on a number of inter-related draft policy documents. The present article tracked changes over time between the draft and final versions of these documents in New South Wales, and reviewed the original sources of literature cited within them. The strength of evidence upon which the final published versions were reportedly predicated was scrutinized. Upon examination, claims to the wider benefits of clinical supervision were found to be unconvincingly supported, not least because the examples selected by the agencies from the international literature and cited in their respective documents were either silent, parsimonious, or contradictory. Many claims remain at the level of folklore/hypothetical propositions, therefore, and stay worthy of rigorous empirical testing and faithful public reporting. Such investigations have been acknowledged as notoriously difficult to conduct. The present article identified noteworthy examples in the contemporary literature that signpost robust ways forward for empirical outcomes-orientated research, the findings from which might strengthen the evidence base of future policy documents. PMID- 28093887 TI - Collagen hydrogel scaffold promotes mesenchymal stem cell and endothelial cell coculture for bone tissue engineering. AB - The generation of functional, vascularized tissues is a key challenge for the field of tissue engineering. Before clinical implantations of such tissue engineered bone constructs can succeed, tactics to promote neovascularization need to be strengthened. We have previously demonstrated that the tubular perfusion system (TPS) bioreactor is an effective culturing method to augment osteogenic differentiation and maintain viability of human mesenchymal stem cells (hMSC). Here, we devised a strategy to address the need for a functional microvasculature by designing an in vitro coculture system that simultaneously cultures osteogenic differentiating hMSCs with endothelial cells (ECs). We utilized the TPS bioreactor as a dynamic coculture environment, which we hypothesize will encourage prevascularization of endothelial cells and early formation of bone tissue and could aid in anastomosis of the graft with the host vasculature after patient implantation. To evaluate the effect of different natural scaffolds for this coculture system, the cells were encapsulated in alginate and/or collagen hydrogel scaffolds. We discovered the necessity of cell to-cell proximity between the two cell types as well as preference for the natural cell binding capabilities of hydrogels like collagen. We discovered increased osteogenic and angiogenic potential as seen by amplified gene and protein expression of ALP, BMP-2, VEGF, and PECAM. The TPS bioreactor further augmented these expressions, indicating a synergistic effect between coculture and applied shear stress. The development of this dynamic coculture platform for the prevascularization of engineered bone, emphasizing the importance of the construct microenvironments and will advance the clinical use of tissue engineered constructs. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1123-1131, 2017. PMID- 28093886 TI - Regulatory elements in molecular networks. AB - Regulatory elements determine the connectivity of molecular networks and mediate a variety of regulatory processes ranging from DNA looping to transcriptional, posttranscriptional, and posttranslational regulation. This review highlights our current understanding of the different types of regulatory elements found in molecular networks with a focus on DNA regulatory elements. We highlight technical advances and current challenges for the mapping of regulatory elements at the genome-wide scale, and describe new computational methods to uncover these elements via reconstructing regulatory networks from large genomic datasets. WIREs Syst Biol Med 2017, 9:e1374. doi: 10.1002/wsbm.1374 For further resources related to this article, please visit the WIREs website. PMID- 28093888 TI - Synthesis of Butyl Levulinate Based on alpha-Angelica Lactone in the Presence of Easily Separable Heteropoly Acid Catalysts. AB - A series of choline (Ch)-exchanged heteropoly acids (HOCH2 CH2 N(CH3 )3 )x H(6-x) P2 W18 O62 [abbreviated as Chx H(6-x) P2 W18 O62 , x=1-6] was synthesized and used as catalysts for the reaction of alpha-angelica lactone (alpha-AL) with n butanol to form butyl levulinate (BL). The solubility of Chx H(6-x) P2 W18 O62 in the reaction mixture was temperature dependent: The catalysts were soluble under the reaction conditions and precipitated upon cooling of the reaction mixture. This facilitated recovery of the catalysts from the liquid phase. Importantly, an increase of the Ch content caused a decrease of the catalyst solubility. Catalytic activity of Chx H(6-x) P2 W18 O62 for the reaction with n-butanol appeared to be in good agreement with the concentration of Bronsted-acidic sites. The results suggest that the reaction proceeded through formation of pseudo-butyl levulinate as intermediate. Ch2 H4 P2 W18 O62 exhibited the best balance between catalytic activity and temperature-dependent solubility. The yield of BL reached 79.4 % at full conversion of alpha-AL at a moderate temperature of 75 degrees C in an open system. Chx H(6-x) P2 W18 O62 could be successfully reused five times without significant loss of activity. PMID- 28093889 TI - Power in methods: language to infants in structured and naturalistic contexts. AB - Methods can powerfully affect conclusions about infant experiences and learning. Data from naturalistic observations may paint a very different picture of learning and development from those based on structured tasks, as illustrated in studies of infant walking, object permanence, intention understanding, and so forth. Using language as a model system, we compared the speech of 40 mothers to their 13-month-old infants during structured play and naturalistic home routines. The contrasting methods yielded unique portrayals of infant language experiences, while simultaneously underscoring cross-situational correspondence at an individual level. Infants experienced substantially more total words and different words per minute during structured play than they did during naturalistic routines. Language input during structured play was consistently dense from minute to minute, whereas language during naturalistic routines showed striking fluctuations interspersed with silence. Despite these differences, infants' language experiences during structured play mirrored the peak language interactions infants experienced during naturalistic routines, and correlations between language inputs in the two conditions were strong. The implications of developmental methods for documenting the nature of experiences and individual differences are discussed. PMID- 28093890 TI - Long-term follow-up of treatment of erectile dysfunction after radical prostatectomy using nerve grafts and end-to-side somatic-autonomic neurorraphy: a new technique. AB - OBJECTIVE: To study a novel penile reinnervation technique using four sural nerve grafts and end-to-side neurorraphies connecting bilaterally the femoral nerve and the cavernous corpus and the femoral nerve and the dorsal penile nerves. PATIENTS AND METHODS: Ten patients (mean [+/- sd; range] age 60.3 [+/- 4.8; 54-68] years), who had undergone radical prostatectomy (RP) at least 2 years previously, underwent penile reinnervation in the present study. Four patients had undergone radiotherapy after RP. All patients reported satisfactory sexual activity prior to RP. The surgery involved bridging of the femoral nerve to the dorsal nerve of the penis and the inner part of the corpus cavernosum with sural nerve grafts and end-to-side neurorraphies. Patients were evaluated using the International Index of Erectile Function (IIEF) questionnaire and pharmaco-penile Doppler ultrasonography (PPDU) preoperatively and at 6, 12 and 18 months postoperatively, and using a Clinical Evolution of Erectile Function (CEEF) questionnaire, administered after 36 months. RESULTS: The IIEF scores showed improvements with regard to erectile dysfunction (ED), satisfaction with intercourse and general satisfaction. Evaluation of PPDU velocities did not reveal any difference between the right and left sides or among the different time points. The introduction of nerve grafts neither caused fibrosis of the corpus cavernosum, nor reduced penile vascular flow. CEEF results showed that sexual intercourse began after a mean of 13.7 months with frequency of sexual intercourse varying from once daily to once monthly. Acute complications were minimal. The study was limited by the small number of cases. CONCLUSIONS: A total of 60% of patients were able to achieve full penetration, on average, 13 months after reinnervation surgery. Patients previously submitted to radiotherapy had slower return of erectile function. We conclude that penile reinnervation surgery is a viable technique, with effective results, and could offer a new treatment method for ED after RP. PMID- 28093891 TI - Multifaceted effects of antimetabolite and anticancer drug, 2-deoxyglucose on eukaryotic cancer models budding and fission yeast. AB - Glycolytic inhibitors are of interest therapeutically as they are effective against cancers that display increased glycolytic rate and mitochondrial defects. 2-Deoxyglucose (2-DG) is one such glycolytic inhibitor and was identified to be a competitive inhibitor of glucose. Studies from past few decades have shown that the mechanism of action of 2-DG is complex involving several metabolic and signaling pathways. Budding yeast Saccharomyces cerevisiae and fission yeast Schizosaccharomyces pombe are two important models for studying metabolism, cell cycle and cell signaling. These two unicellular eukaryotes are Crabtree positive yeasts exhibiting a metabolism similar to that of cancer cells. Effects of 2-DG in yeast is of interest owing to these similarities and hence yeasts have emerged as ideal model organisms to study the mode of action and resistance to 2-DG. In this review, we summarize the studies on biological effect and resistance to 2-DG in budding and fission yeasts and give an insight into its possible mechanism of action as models for understanding cancer metabolism and drugs affecting cancer progression. (c) 2017 IUBMB Life, 69(3):137-147, 2017. PMID- 28093892 TI - Multinucleated giant cells in the implant bed of bone substitutes are foreign body giant cells-New insights into the material-mediated healing process. AB - In addition to macrophages, multinucleated giant cells (MNGCs) are involved in the tissue reaction to a variety of biomaterials. Especially in the case of bone substitute materials it has been assumed that the MNGCs are osteoclasts, based on the chemical and physical similarity of many materials to the calcified matrix and the bony environment in which they are used. However, many studies indicate that these cells belong to the cell line of the foreign body giant cells (FBGCs), which are of "inflammatory origin", although they have been shown to possess both a pro- and also anti-inflammatory phenotype. Moreover, no information is available about their role in the tissue reaction to bone substitute materials. The present study was conducted to analyze the origin of MNGCs in the implant beds of a synthetic and a xenogeneic bone substitute and focused on the application of immunohistochemical methods. Two antibodies against integrin molecules specific for osteoclasts (beta-3 integrin) or FBGCs (beta-2 integrin) were used to distinguish both giant cell types. The results of the present study indicate that the MNGCs induced by both kinds of bone substitutes are FBGCs, as they express only beta-2 integrin in contrast to the osteoclasts outside of the immediate implantation areas, which only demonstrate beta-3 integrin expression. These data give new insight into the tissue reaction to both xenogeneic and synthetic bone substitutes. Based on this new knowledge further research concerning the proteomic profile of the FBGCs especially based on the different physicochemical properties of bone substitutes is necessary. This may show that specific characteristics of bone substitutes may exhibit a substantial influence on the regeneration process via the expression of anti-inflammatory molecules by FBGCs. Based on this information it may be possible to formulate and choose bone substitutes that can guide the process of bone tissue regeneration on the molecular level. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1105-1111, 2017. PMID- 28093893 TI - Arabidopsis thaliana GLUTATHIONE-S-TRANSFERASE THETA 2 interacts with RSI1/FLD to activate systemic acquired resistance. AB - A partly infected plant develops systemic acquired resistance (SAR) and shows heightened resistance during subsequent infections. The infected parts generate certain mobile signals that travel to the distal tissues and help to activate SAR. SAR is associated with epigenetic modifications of several defence-related genes. However, the mechanisms by which mobile signals contribute to epigenetic changes are little known. Previously, we have shown that the Arabidopsis REDUCED SYSTEMIC IMMUNITY 1 (RSI1, alias FLOWERING LOCUS D; FLD), which codes for a putative histone demethylase, is required for the activation of SAR. Here, we report the identification of GLUTATHIONE-S-TRANSFERASE THETA 2 (GSTT2) as an interacting factor of FLD. GSTT2 expression increases in pathogen-inoculated as well as pathogen-free distal tissues. The loss-of-function mutant of GSTT2 is compromised for SAR, but activates normal local resistance. Complementation lines of GSTT2 support its role in SAR activation. The distal tissues of gstt2 mutant plants accumulate significantly less salicylic acid (SA) and express a reduced level of the SA biosynthetic gene PAL1. In agreement with the established histone modification activity of FLD, gstt2 mutant plants accumulate an enhanced level of methylated and acetylated histones in the promoters of WRKY6 and WRKY29 genes. Together, these results demonstrate that GSTT2 is an interactor of FLD, which is required for SAR and SAR-associated epigenetic modifications. PMID- 28093894 TI - Importance of Body Water in the Efficacy of Convective Solute Transport in Online Hemodiafiltration. AB - High-volume online hemodiafiltration (OL-HDF) has been associated with improved patient survival compared to conventional hemodialysis in recent trials, where the importance of convective volume (CV) in this benefit is noted. The purpose of this study was to determine the corporal composition parameters influencing the efficacy of CV in the removal of different molecular weight (MW) molecules. Demographic data, corporal composition parameters with bioimpedance spectroscopy, dialysis features and the reduction rates of different MW molecules in a four hour OL-HDF session were collected in 61 patients. We observed a significant negative correlation of beta2-microglobulin, cystatin-C, myoglobin and prolactin reduction rates with body surface area, weight, total body extracellular (ECW) and intracellular water (ICW), lean tissue mass and body cellular mass. The multivariable regression analysis identified ECW and ICW as the only corporal composition factors independently associated to the relative elimination of beta2 microglobulin (Beta: -0.801, P = 0.002 for ECW and Beta: -1.710, P = 0.001 for ICW), cystatin-C (Beta: -0.656, P = 0.010 for ECW and Beta: -1.511, P = 0.004 for ICW) and myoglobin (Beta: -0.745, P = 0.014 for ECW and Beta: -2.103, P = 0.001 for ICW), in addition to CV. Prolactin reduction was only associated with ICW (Beta: -1.540, P = 0.028). When adjusting CV with ECW and ICW, only the ratio CV/ECW was an independent predictor for higher elimination of beta2 microglobulin, cystatin-C and myoglobin. The corporal composition parameters independently associated to the reduction of medium-sized molecules are the extracellular and intracellular water. The ratio "convective volume/extracellular water" predicts higher efficacy of convective transport. Adjusting the convective volume to patient features could be useful to monitor the efficacy of OL-HDF and to prescribe individualized therapies. PMID- 28093895 TI - Identification of a conserved cis-regulatory element controlling mid-diencephalic expression of mouse Six3. AB - The sine oculis homeobox protein Six3 plays pivotal roles in the development of the brain and craniofacial structures. In humans, SIX3 haploinsufficiency results in holoprosencephaly, a defect in anterior midline formation. Although much is known about the evolutionarily conserved functions of Six3, the regulatory mechanism responsible for the expression pattern of Six3 remains relatively unexplored. To understand how the transcription of Six3 is controlled during embryogenesis, we screened ~300 kb of genomic DNA encompassing the Six3 locus for cis-acting regulatory elements capable of directing reporter gene expression to sites of Six3 transcription in transgenic mouse embryos. We identified a novel enhancer element, whose activity recapitulates endogenous Six3 expression in the ventral midbrain, pretectum, and thalamus. Cross-species comparisons revealed that this Six3 brain enhancer is functionally conserved in other vertebrates. We also showed that normal Six3 transcription in the ventral midbrain and pretectum is dependent on Ascl1, a basic helix-loop-helix proneural factor. Moreover, loss of Ascl1 resulted in downregulation of the Six3 brain enhancer activity, emphasizing its unique role in regulating Six3 expression in the developing brain. PMID- 28093896 TI - Intravenous Combined with Topical Administration of Tranexamic Acid in Primary Total Hip Arthroplasty: A Randomized Controlled Trial. AB - OBJECTIVE: Although there are still some controversies, large previous studies have confirmed that intravenous (i.v.) tranexamic acid (TXA) can effectively reduce blood loss and transfusions in total hip arthroplasty (THA) without increasing the risk of deep venous thrombosis. However, few studies have investigated the combination of i.v. and topical application of TXA in primary THA. The purpose of our current study is to examine whether i.v. combined with topical administration of TXA decreases postoperative blood loss and transfusion rates after THA. METHODS: From December 2013 to May 2014, all adult patients undergoing primary THA at our arthroplasty center were considered for inclusion in the present study. Included patients were randomly assigned to two groups by computer-generated list number: a TXA group and a placebo group. Patients in the TXA group received i.v. (15 mg/kg) combined with topical administration (1.0 g) of TXA during the THA procedure, and patients in the other group received the same dosage of normal saline both i.v. and topically. Our primary outcome measures were total blood loss (calculated using Gross's equation), hemoglobin, hematocrit and platelet concentration changes on the third postoperative day, the amount of drainage, the amount of intraoperative blood loss, the frequency of transfusion, and the number of blood units transfused. Secondary outcome measures were the length of postoperative stay, range of hip motion (measured by goniometer), Harris hip scores (HHS), and any perioperative complications or events such as infection, DVT or PE. Range of motion and HHS were measured at 3 week follow-up and compared with preoperative values. RESULTS: This trial included 100 patients (50 in each group). Patients in the TXA group had significantly higher postoperative hemoglobin (103 vs 87.7 g/dL, P < 0.01), lower hemoglobin changes (32.2 vs 44.9 g/dL, P < 0.01), higher postoperative hematocrit (0.32 vs 0.27 L/L, P < 0.01), lower hematocrit changes (0.1 vs 0.14 L/L, P < 0.01), lower total blood loss (822 vs 1100 mL, P = 0.004), lower drainage (117.8 vs 242.4 mL, P < 0.01), lower intraoperative blood loss (193.8 vs 288.2 mL, P < 0.01), and lower transfusion rate (2% vs 34%, P < 0.01) compared with those in the placebo group. No statistical difference was found in postoperative platelets between the two groups. There were no differences in perioperative complications or venous thromboembolism (VTE) events. CONCLUSIONS: The combined administration of i.v. and topical TXA resulted in a clinically relevant reduction in blood loss, compared with placebo group. No thromboembolic complications were observed. This randomized controlled trial supports the combined i.v. and topical administration of TXA in primary THA. PMID- 28093898 TI - Effect of Heat Treatment on the Nitrogen Content and Its Role on the Carbon Dioxide Adsorption Capacity of Highly Ordered Mesoporous Carbon Nitride. AB - Mesoporous carbon nitrides (MCNs) with rod-shaped morphology and tunable nitrogen contents have been synthesized through a calcination-free method by using ethanol washed mesoporous SBA-15 as templates at different carbonization temperatures. Carbon tetrachloride and ethylenediamine were used as the sources of carbon and nitrogen, respectively. The resulting MCN materials were characterized with low- and high-angle powder XRD, nitrogen adsorption, high-resolution (HR) SEM, HR-TEM, elemental analysis, X-ray photoelectron spectroscopy, and X-ray absorption near edge structure techniques. The carbonization temperature plays a critical role in controlling not only the crystallinity, but also the nitrogen content and textural parameters of the samples, including specific surface area and specific pore volume. The nitrogen content of MCN decreases with a concomitant increase in specific surface area and specific pore volume, as well as the crystallinity of the samples, as the carbonization temperature is increased. The results also reveal that the structural order of the materials is retained, even after heat treatment at temperatures up to 900 degrees C with a significant reduction of the nitrogen content, but the structure is partially damaged at 1000 degrees C. The carbon dioxide adsorption capacity of these materials is not only dependent on the textural parameters, but also on the nitrogen content. The MCN prepared at 900 degrees C, which has an optimum BET surface area and nitrogen content, registers a carbon dioxide adsorption capacity of 20.1 mmol g-1 at 273 K and 30 bar, which is much higher than that of mesoporous silica, MCN-1, activated carbon, and multiwalled carbon nanotubes. PMID- 28093897 TI - Presence of early stage cancer does not impair the early protein metabolic response to major surgery. AB - BACKGROUND: Combined bilateral mastectomy and reconstruction is a common major surgical procedure in women with breast cancer and in those with a family history of breast cancer. As this large surgical procedure induces muscle protein loss, a preserved anabolic response to nutrition is warranted for optimal recovery. It is unclear whether the presence of early stage cancer negatively affects the protein metabolic response to major surgery as this would mandate perioperative nutritional support. METHODS: In nine women with early stage (Stage II) breast malignancy and nine healthy women with a genetic predisposition to breast cancer undergoing the same large surgical procedure, we examined whether surgery influences the catabolic response to overnight fasting and the anabolic response to nutrition differently. Prior to and within 24 h after combined bilateral mastectomy and reconstruction surgery, whole body protein synthesis and breakdown rates were assessed after overnight fasting and after meal intake by stable isotope methodology to enable the calculation of net protein catabolism in the post-absorptive state and net protein anabolic response to a meal. RESULTS: Major surgery resulted in an up-regulation of post-absorptive protein synthesis and breakdown rates (P < 0.001) and lower net protein catabolism (P < 0.05) and was associated with insulin resistance and increased systemic inflammation (P < 0.01). Net anabolic response to the meal was reduced after surgery (P < 0.05) but higher in cancer (P < 0.05) indicative of a more preserved meal efficiency. The significant relationship between net protein anabolism and the amount of amino acids available in the circulation (R2 = 0.85, P < 0.001) was independent of the presence of non-cachectic early stage breast cancer or surgery. CONCLUSIONS: The presence of early stage breast cancer does not enhance the normal catabolic response to major surgery or further attenuates the anabolic response to meal intake within 24 h after major surgery in patients with non-cachectic breast cancer. This indicates that the acute anabolic potential to conventional feeding is maintained in non-cachectic early stage breast cancer after major surgery. PMID- 28093899 TI - Crucial Role of Donor Density in the Performance of Oxynitride Perovskite LaTiO2 N for Photocatalytic Water Oxidation. AB - LaTiO2 N photocatalysts were prepared by thermal ammonolysis of flux-synthesized La2 Ti2 O7 and La2 TiO5 , and were investigated for water oxidation. Though LaTiO2 N derived from La2 TiO5 appears defect-free by UV/Vis/near-IR and electron paramagnetic resonance (EPR) spectroscopy, its performance is much lower than that of conventional La2 Ti2 O7 -derived LaTiO2 N with defects. It is shown by Mott-Schottky analysis that La2 TiO5 -derived LaTiO2 N has significantly lower donor density; this can result in insufficient built-in electric field for the separation of photogenerated electrons and holes. The lower donor density is also consistent with the smaller difference between the Fermi level and the valence band maximum, which accounts for a lower oxidative power of the holes. In light of this discovery, the donor density was increased substantially by introducing anion vacancies through annealing in Ar. This resulted in improved performance. The CoOx -assisted La2 TiO5 -derived LaTiO2 N annealed at 713 degrees C has a higher quantum efficiency (25 %) at 450 nm than high-performance conventional CoOx /LaTiO2 N (21 %). PMID- 28093900 TI - Who is responsible for metabolic screening for mental health clients taking antipsychotic medications? AB - Metabolic syndrome is common in mental health consumer populations, and is linked to cardiovascular disease, stroke and diabetes. Metabolic screening is a way of recognising consumers who are at risk of developing metabolic syndrome but internationally screening rates remain low. A retrospective audit was completed at one Australian public mental health service on the case files of 100 randomly selected consumers to determine nurses level of compliance with metabolic screening policies over a 12 month period. Consumers included in the review were prescribed antipsychotic medications for at least 12 months and had their care in the community coordinated by mental health nurses. Data were entered into an Excel spreadsheet for analysis. Low levels of metabolic screening were identified and these levels decreased over the 12 months under review. No consumers had metabolic screening that recorded all parameters at three monthly intervals over the 12 month period. Only one consumer had every metabolic parameter recorded on the physical health screen tool at baseline assessment. The findings demonstrated that while there is increased awareness of co-morbid physical health issues in this consumer population, the translation of guidelines and policy directives to clinical practice to address this disparity remains low. Improving physical health outcomes is the responsibility of all health professionals, particularly doctors who prescribe and nurses who administer antipsychotic medications regularly to mental health consumers. Moreover, nurses are well placed to demonstrate leadership in reducing the rate of metabolic syndrome through the delivery of holistic care that includes effective screening programs. PMID- 28093901 TI - Does hospital readmission following colorectal cancer resection and enhanced recovery after surgery affect long term survival? AB - AIM: Hospital readmission is undesirable for patients and care providers as this can affect short-term recovery and carries financial consequences. It is unknown if readmission has long-term implications. We aimed to investigate the impact of 30-day readmission on long-term overall survival (OS) following colorectal cancer resection within enhanced recovery after surgery (ERAS) care and explore the reasons for and the severity and details of readmission episodes. METHOD: A dedicated, prospectively populated database was reviewed. All patients were managed within an established ERAS programme. Five-year OS was calculated using the Kaplan-Meier method. The number, reason for and severity of 30-day readmissions were classified according to the Clavien-Dindo (CD) system, along with total (initial and readmission) length of stay (LoS). Multivariate analysis was used to identify factors predicting readmission. RESULTS: A total of 1023 consecutive patients underwent colorectal cancer resection between 2002 and 2015. Of these, 166 (16%) were readmitted. Readmission alone did not have a significant impact on 5-year OS (59% vs 70%, P = 0.092), but OS was worse in patients with longer total LoS (20 vs 14 days, P = 0.04). Of the readmissions, 121 (73%) were minor (CD I-II) and 27 (16%) required an intervention of which 16 (10%) were returned to theatre. Gut dysfunction 32 (19%) and wound complications 23 (14%) were the most frequent reasons for readmission. Prolonged initial LoS, rectal cancer and younger age predicted for hospital readmission. CONCLUSION: Readmission does not have a significant impact on 5-year OS. A broad range of conditions led to readmission, with the majority representing minor complications. PMID- 28093902 TI - Making sense of metabolic obesity and hedonic obesity. AB - Body weight is neither stationary nor does it change unidirectionally. Rather, body weight usually oscillates up and down around a set point. Two types of forces determine the direction of weight changes. Forces that push body weight away from the set point are defined as non-homeostatic and are governed by multiple mechanisms, including, but not limited to, hedonic regulation of food intake. Forces that restore the set point weight are defined as homeostatic, and they operate through mechanisms that regulate short-term energy balance driven by hunger and satiation and long-term energy balance driven by changes in adiposity. In the normal physiological state, the deviation of body weight from the set point is usually small and temporary, and is constantly corrected by homeostatic forces. Metabolic obesity develops when body weight set point is shifted to an abnormally high level and the obese body weight becomes metabolically defended. In hedonic obesity, the obese body weight is maintained by consistent overeating due to impairments in the reward system, although the set point is not elevated. Adaptive increases in energy expenditure are elicited in hedonic obesity because body weight is elevated above the set point. Neither subtype of obesity undergoes spontaneous resolution unless the underlying disorders are corrected. In this review, the need for both appropriate patient stratification and tailored treatments is discussed in the context of the new framework of metabolic and hedonic obesity. PMID- 28093903 TI - Selectivity Enhancement in Heterogeneous Photocatalytic Transformations. AB - Photocatalysis has been invariably considered as an unselective process (especially in water) for a fairly long period of time, and the investigation on selective photocatalysis has been largely neglected. In recent years, the field of selective photocatalysis is developing rapidly and now extended to several newer applications. This review focuses on the overall strategies which can improve the selectivity of photocatalysis encompassing a wide variety of photocatalysts, and modifications thereof, as well as the related vital processes of industrial significance such as reduction and oxidation of organics, inorganics, and CO2 transformation. Comprehensive and successful strategies for enhancing the selectivity in photocatalysis are abridged to reinvigorate and stimulate future investigations. In addition, nonsemiconductor type photocatalysts, such as Ti-Si molecular sieves and carbon quantum dots (CQDs), are also briefly appraised in view of their special role in special selective photocatalysis, namely epoxidation reactions, among others. In the end, a summary and outlook on the challenges and future directions in the research field are included in the comprehensive review. PMID- 28093905 TI - Inkjet Printing of Soft, Stretchable Optical Waveguides through the Photopolymerization of High-Profile Linear Patterns. AB - Optical waveguides have been fabricated via photopolymerization of stable, inkjet printed patterns. In order to obtain high-profile lines, the properties of both the ink and the substrate were adjusted. We prove that suitable patterns, with contact angles close to 90 degrees , can be printed by using not fully cured, "sticky" PDMS as a substrate. In addition, we propose a simple sliding-drop experiment to show the crucial difference in how the ink dewets the "sticky" and the fully cured substrate, which is otherwise difficult to demonstrate. The light attenuation vs strain curve of the obtained waveguides was determined experimentally and was found to be almost linear within the measured strain range. PMID- 28093904 TI - Supramolecular Polymer Dot Ensemble for Ratiometric Detection of Lectins and Targeted Delivery of Imaging Agents. AB - A supramolecular, polymer-dot-based ensemble has been developed for the ratiometric detection of lectins and targeted delivery of glycoprobes. Self assembly between a blue-emitting polymer dot and a red-emitting glycoprobe, results in an ensemble that shows red emission upon excitation of the polymer dot because of Forster resonance energy transfer. Resulting in ratiometric detection of lectins in buffer solution as well as targeted delivery of the glycoprobe to cells that highly express a sugar receptor. Unlike conventional systems where both the agent and vector are codelivered intracellularly, our ensemble developed here shows a receptor-controlled dissociation on the cell membrane. PMID- 28093906 TI - Floating and Sinking of a Pair of Spheres at a Liquid-Fluid Interface. AB - Spheres floating at liquid-fluid interfaces cause interfacial deformations such that their weight is balanced by the resultant forces of surface tension and hydrostatic pressure while also satisfying a contact angle condition. Determining the meniscus shape around several floating spheres is a complicated problem because the vertical locations of the spheres and the horizontal projections of the three-phase contact lines are not known a priori. Here, a new computational algorithm is developed to simultaneously satisfy the nonlinear Laplace-Young equation for the meniscus shape, the vertical force balance, and the geometric properties of the spheres. We implement this algorithm to find the shape of the interface around a pair of floating spheres and the horizontal force required to keep them at a fixed center-center separation. Our numerical simulations show that the ability of a pair of spheres to float (rather than sink) depends on their separation. Similar to previous work on horizontal cylinders, sinking may be induced at close range for small spheres that float when isolated. However, we also discover a new and unexpected behavior: at intermediate inter-particle distances, spheres that would sink in isolation can float as a pair. This effect is more pronounced for spheres of radius comparable to the capillary length, suggesting that this effect is a result of hydrostatic pressure, rather than surface tension. An approximate solution confirms these phenomena and shows that the mechanism is indeed the increased supporting force provided by the hydrostatic pressure. Finally, the horizontal force of capillary attraction between the spheres is calculated using the results of the numerical simulations. These results show that the classic linear superposition approximation (due to Nicolson) can lose its validity for relatively heavy particles at close range. PMID- 28093907 TI - Diastereoselective Electrophilic alpha-Hydroxyamination of N-tert-Butanesulfinyl Imidates. AB - Diastereoselective alpha-hydroxyamination of N-tert-butanesulfinyl imidates using nitrosoarenes is reported. A catalytic amount of base effectively promotes the hydroxyamination reaction of alpha-aryl-substituted imidates, and the resulting alpha-hydroxyamino imidates can be transformed into a range of synthetically useful intermediates. PMID- 28093908 TI - Thermal Ring Contraction Reactions of 9-Aryl-5H,7H-[1,2,5]thiadiazolo[3,4 h][2,3,4]benzothiadiazepine 6,6-Dioxides. Experimental and Computational Studies for Understanding the Course of the Transformations. AB - When refluxing with sodium hydrogen carbonate in acetonitrile, 7-chloro-5-(4 fluorophenyl)-1,3-dihydro-2,3,4-benzothiadiazepine 2,2-dioxide afforded, after loss of dinitrogen and subsequent ring contraction, the corresponding sulfone in 83% yield. Similar treatment of the related thiadiazolo-fused tricycles, i.e. 9 aryl-5H,7H-[1,2,5]thiadiazolo[3,4-h][2,3,4]benzothiadiazepine 6,6-dioxides, resulted in a substantially different product mixture: formation of sultines and benzocyclobutenes was observed, while only small amounts of the sulfones were formed, if any. Density functional theory calculations support the mechanism proposed for the transformations involving a zwitterionic intermediate formed by the tautomerization of the thiadiazepine ring followed by dinitrogen extrusion. When starting from 7-chloro-substituted 2,3,4-benzothiadiazepine 2,2-dioxide, the formation of sulfone via o-quinodimethane is the preferred pathway from the zwitterion. However, in the case of thiadiazolobenzothiadiazepine 6,6-dioxides it has been found that the ring closure of the zwitterion leading to the formation of sultines was kinetically preferred over the loss of sulfur dioxide leading to o-quinodimethane, which is the key intermediate to benzocyclobutene-type products. The calculations explain the differences observed between the product distributions of the chloro-substituted and the thiadiazolo-fused derivatives. PMID- 28093909 TI - Transition-Metal-Free Amination of Pyridine-2-sulfonyl Chloride and Related N Heterocycles Using Magnesium Amides. AB - A new transition-metal-free amination of pyridine-2-sulfonyl chloride and related N-heterocycles using magnesium amides of type R2NMgCl.LiCl is reported. Additionally, the directed ortho-magnesiation of pyridine-2-sulfonamides using TMPMgCl.LiCl was investigated. Reaction of the magnesium intermediates with various electrophiles and subsequent amination using magnesium amides led to a range of 2,3-functionalized pyridines. Also, cyclization reactions providing an aza-indole and an aza-carbazole were carried out. PMID- 28093910 TI - Structural and Spectral Properties of Photochromic Diarylethenes: Size Effect of the Ethene Bridge. AB - The effect of the size of the ethene bridge on the structural and spectral properties of photochromic diarylethenes, which remains a poorly understood phenomenon, was studied as applied to diarylethenes containing unsymmetrical (cyclohexenone and cyclopentenone) and symmetrical (cyclohexene and cyclopentene) ethene bridges. Thiophene, oxazole, and imidazole derivatives were used as aryl moieties. An increase in the size of the ethene bridge in the cycloalkenone series was found to be accompanied by a hypsochromic shift of the absorption maximum of the photoinduced form, whereas no difference was found for cycloalkenes. A detailed analysis of the NMR spectra (including 2D experiments) revealed previously unknown effects associated with the existence of an intramolecular hydrogen bond (CH...N) between the six-membered ethene bridge and the azole substituents. The NMR experimental data obtained were confirmed by DFT quantum chemical calculations and X-ray analysis. It was found that an intramolecular hydrogen bond favors an increase of the quantum yield of the photocyclization reaction. PMID- 28093911 TI - Synthesis of Multisubstituted Allenes, Furans, and Pyrroles via Tandem Palladium Catalyzed Substitution and Cycloisomerization. AB - A palladium-catalyzed propargyl substitution reaction of propargyl acetates with indium organothiolates is developed for the synthesis of multisubstituted allenyl sulfides. This procedure can be applied to the synthesis of multisubstituted furans and pyrroles via tandem palladium-catalyzed propargyl substitution and cycloisomerization reaction in one pot. PMID- 28093912 TI - Alternative Route Toward Nitrones: Experimental and Theoretical Findings. AB - Nitrones are important building blocks for natural and biologically active compounds, used as spin-trap reagents and therapeutic agents. All this makes nitrones intriguing and valuable compounds for fundamental studies and as useful chemicals in various synthetic strategies. Therefore, nitrones are still of great interest and in the limelight of researches. With our initial goal to solve synthetic problems toward 5-phenyl-2,2'-bipyridine (Phbpy), we found that this reaction can proceed through the formation of 6-phenyl-3-(pyridin-2-yl)-1,2,4 triazin-4(3H)-ol (4-OH), which rapidly isomerizes to a 3,4-dihydro-1,2,4-triazine based nitrone, namely 6-phenyl-3-pyridin-2-yl-2,3-dihydro-1,2,4-triazin-4-oxide (4'), This encouraged us to study condensation of hydrazonophenylacetaldehyde oxime (2), obtained from 2-isonitrosoacetophenone (1), with other aldehydes. The reaction with both salicylaldehyde and p-tolualdehyde leads to the open-chain isomers, namely (2-hydroxybenzylidene)hydrazono-2-phenylacetaldehyde oxime (5) and (4-methylbenzylidene)hydrazono-2-phenylacetaldehyde oxime (6), respectively. The latter product exists in solution in equilibrium with its cyclic isomer 6 phenyl-3-(4-methylphenyl)-2,3-dihydro-1,2,4-triazin-4-oxide (6'), while the former one exists in solution exclusively in the open-chain form. It was also found that 2 reacts with acetone with the formation of 3,3-dimethyl-6-phenyl-2,3 dihydro-1,2,4-triazin-4-oxide (7'), which also exists in solution in equilibrium with its open-chain isomer 2-phenyl-2-(propan-2-ylidenehydrazono)acetaldehyde oxime (7). The static DFT as well as ab initio molecular dynamics simulations have corroborated the experimental findings. PMID- 28093913 TI - Synergistic Photoredox/Nickel Coupling of Acyl Chlorides with Secondary Alkyltrifluoroborates: Dialkyl Ketone Synthesis. AB - Visible light photoredox/nickel dual catalysis has been employed in the cross coupling of acyl chlorides with potassium alkyltrifluoroborates. This protocol, based on single-electron-mediated alkyl transfer, circumvents the restriction of using reactive alkylmetallic nucleophiles in transition-metal-catalyzed acylation and achieves a mild and efficient method for the synthesis of unsymmetrical alkyl ketones. In this approach, a variety of acyl chlorides have been successfully coupled with structurally diverse potassium alkyltrifluoroborates, generating the corresponding ketones with good yields. PMID- 28093914 TI - Semisynthesis of (-)-Rutamarin Derivatives and Their Inhibitory Activity on Epstein-Barr Virus Lytic Replication. AB - (+)-Rutamarin inhibits EBV lytic DNA replication with an IC50 of 7.0 MUM. (-) Chalepin, a (-)-rutamarin derivative, was isolated from the whole plant of Ruta graveolens and used as a precursor of (-)-rutamarin. Altogether, 28 (-)-rutamarin derivatives were synthesized starting from (-)-chalepin. Of these, 16 compounds (2a-e, 3b-e, 3g, 4f, 4k, 4m-p) were found to be more potent against EBV lytic DNA replication than (-)-chalepin. Compounds 4m, 4n, and 4p exhibited IC50 values of 1.5, 0.32, and 0.83 MUM and showed selectivity index values (SI) of 801, 211, and >120, respectively. Thus, compounds 4m, 4n, and 4p are considered promising leads for further laboratory investigation. PMID- 28093916 TI - Understanding Coulomb Scattering Mechanism in Monolayer MoS2 Channel in the Presence of h-BN Buffer Layer. AB - As the thickness becomes thinner, the importance of Coulomb scattering in two dimensional layered materials increases because of the close proximity between channel and interfacial layer and the reduced screening effects. The Coulomb scattering in the channel is usually obscured mainly by the Schottky barrier at the contact in the noise measurements. Here, we report low-temperature (T) noise measurements to understand the Coulomb scattering mechanism in the MoS2 channel in the presence of h-BN buffer layer on the silicon dioxide (SiO2) insulating layer. One essential measure in the noise analysis is the Coulomb scattering parameter (alphaSC) which is different for channel materials and electron excess doping concentrations. This was extracted exclusively from a 4-probe method by eliminating the Schottky contact effect. We found that the presence of h-BN on SiO2 provides the suppression of alphaSC twice, the reduction of interfacial traps density by 100 times, and the lowered Schottky barrier noise by 50 times compared to those on SiO2 at T = 25 K. These improvements enable us to successfully identify the main noise source in the channel, which is the trapping detrapping process at gate dielectrics rather than the charged impurities localized at the channel, as confirmed by fitting the noise features to the carrier number and correlated mobility fluctuation model. Further, the reduction in contact noise at low temperature in our system is attributed to inhomogeneous distributed Schottky barrier height distribution in the metal-MoS2 contact region. PMID- 28093915 TI - Oscarellin, an Anthranilic Acid Derivative from a Philippine Sponge, Oscarella stillans, as an Inhibitor of Inflammatory Cytokines in Macrophages. AB - A new anthranilic acid derivative (1) was isolated from a Philippine sponge, Oscarella stillans (Bergquist and Kelly). The structure of compound 1, named oscarellin, was determined as 2-amino-3-(3'-aminopropoxy)benzoic acid from spectroscopic data and confirmed by synthesis. We examined the immunomodulating effect of compound 1 and its mechanism in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Our data indicated that the expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 were significantly reduced by the pretreatment of 1 (0.1-10 MUM) for 2 h. In addition, compound 1 suppressed activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH2 termimal kinase (JNK), but not p38 mitogen-activated protein kinase (MAPK) in LPS stimulated RAW 264.7 cells. Compound 1 abrogated LPS-induced nuclear factor kappaB (NF-kappaB) and activator protein-1 (AP-1) activities, whereas the induction of activating transcription factor-3 (ATF-3) was increased. Taken together, our results suggest that compound 1 attenuates pro-inflammatory cytokines via the suppression of JNK, ERK, AP-1, and NF-kappaB and the activation of the ATF-3 signaling pathway. PMID- 28093917 TI - Cobalt(II)-Catalyzed Oxidative C-H Arylation of Indoles and Boronic Acids. AB - Co(II)-catalyzed C-H C2 selective arylation of indoles with boronic acids through monodentate chelation assistance has been achieved for the first time. The unique features of this methodology include mild reaction conditions, highly C2 regioselectivity, and employment of a Grignard reagent-free catalytic system. A wide range of substrates, including unreactive arenes, are well tolerated, which enables the construction of the coupling products efficiently. This new strategy provides an alternative and versatile approach to construct biaryls using inexpensive cobalt catalyst. PMID- 28093918 TI - A General Approach to the Aza-Diketomorpholine Scaffold. AB - A stereoconservative three-step synthesis to access to 1,2,4-oxadiazine-3,6-dione is presented. This underexplored platform could be considered as a constrained oxy-azapeptide or an aza-diketomorpholine, the methodology being then successfully applied to produce enantiopure aza-analogs of diketomorpholine natural products. Importantly, the first crystal structures were obtained and compared to diketomorpholine and diketopiperazine structures. Finally, a straightforward procedure concerning the coupling of this heterocyclic scaffold with various amino acids to afford original pseudodipeptide analogs was described. PMID- 28093919 TI - Iridium-Catalyzed Asymmetric Hydrogenation of Ketones with Accessible and Modular Ferrocene-Based Amino-phosphine Acid (f-Ampha) Ligands. AB - A series of tridentate ferrocene-based amino-phosphine acid (f-Ampha) ligands have been successfully developed. The f-Ampha ligands are extremely air stable and exhibited excellent performance in the Ir-catalyzed asymmetric hydrogenation of ketones (full conversions, up to >99% ee, and 500 000 TON). DFT calculations were performed to elucidate the reaction mechanism and the importance of the COOH group. Control experiments also revealed that the -COOH group played a key role in this reaction. PMID- 28093920 TI - Inspiratory muscle training is effective to reduce postoperative pulmonary complications and length of hospital stay: a systematic review and meta-analysis. AB - PURPOSE: This study systematically review and meta-analyse the effectiveness of inspiratory muscle training (IMT) to reduce postoperative pulmonary complications (PPC) and length of hospital stay (LOS), both in the preoperative and/or postoperative periods of cardiac, pulmonary, and abdominal surgical patients. Sensitive analysis was performed to examine which patients benefit more from IMT according to methodological features (quality of studies and sample size), patient's characteristics (pulmonary risk stratification, age, and body mass index), type of surgery, period of training, and training protocols (training doses and level of supervision). METHODS: The literature search was made in the electronic databases PubMed(r), EBSCO, Web of Science(r), PEDro and Scopus(r). Only randomized controlled trials were included. Data extraction, quality assessment and meta-analysis were performed. RESULTS: We included 17 randomized controlled trials in the systematic review, of which, 12 were included for the PPC meta-analysis and 11 for the LOS meta-analysis. IMT significantly reduced the risk of PPC (Risk Ratio (RR) = 0.50, 95%CI: 0.39, 0.64, I2 = 0.0%), and a decrease in LOS (Mean Difference = -1.41, 95%CI: -2.07, -0.75, I2 = 0.0%). CONCLUSION: IMT is effective to reduce PPC and LOS in patients undergoing surgery. Implications for Rehabilitation Physiotherapy interventions with inspiratory muscle training (IMT) are effective to reduce postoperative pulmonary complications (PPC) and length of hospital stay (LOS) after major surgery, and should start preoperatively. Rehabilitation with IMT is beneficial at all ages and risk levels, but older and high-risk patients benefit more, as well as pulmonary surgery patients. IMT is more effective if it is supervised, and prescription target at least two-week period, sessions with more than 15 minutes, with imposed load increment, and adding other exercise modes. PMID- 28093921 TI - Microbial genomics and antimicrobial susceptibility testing. AB - INTRODUCTION: Antimicrobial susceptibility testing is key in modern clinical microbiology. With pandemic emergence of (multi-)antibiotic resistance, methods to detect and quantify resistance of clinically important bacterial species are imperative. Historically, antimicrobial susceptibility testing (AST) was mostly performed using methods relying on bacterial growth. Such methods may be time consuming and more rapid alternatives have been actively sought for. Areas covered: Among the new AST methods there are many that focus on detection of causal resistance genes and/or gene mutations. The approaches most used are based on nucleic acid amplification and, more recently, high-throughput (next generation) sequencing of amplified targets and complete microbial genomes. The authors provide a review of PCR-mediated and genomic AST methods used for human and veterinary pathogens and show where these approaches work well or may become difficult to interpret. Expert commentary: Microbial genome sequencing will play an important role in the field of AST, but there remain issues to be resolved. These include the development of user friendly data analysis, reducing the duration and cost of sequencing and comprehensiveness of the databases. In addition, clinical evaluation studies need to be performed involving real-life patients. PMID- 28093923 TI - Cultural Differences in Young Adults' Perceptions of the Probability of Future Family Life Events. AB - Most young adults are exposed to family caregiving; however, little is known about their perceptions of their future caregiving activities such as the probability of becoming a caregiver for their parents or providing assistance in relocating to a nursing home. This study examined the perceived probability of these events among 182 young adults and the following predictors of their probability ratings: gender, ethnicity, work or volunteer experience, experiences with caregiving and nursing homes, expectations about these transitions, and filial piety. Results indicated that Asian or South Asian participants rated the probability of being a caregiver as significantly higher than Caucasian participants, and the probability of placing a parent in a nursing home as significantly lower. Filial piety was the strongest predictor of the probability of these life events, and it mediated the relationship between ethnicity and probability ratings. These findings indicate the significant role of filial piety in shaping perceptions of future life events. PMID- 28093922 TI - Toll-like receptors and their soluble forms differ in the knee and thumb basal osteoarthritic joints. AB - Background and purpose - Although the pathogenesis of osteoarthritis (OA) is not well understood, chondrocyte-mediated inflammatory responses (triggered by the activation of innate immune receptors by damage-associated molecules) are thought to be involved. We examined the relationship between Toll-like receptors (TLRs) and OA in cartilage from 2 joints differing in size and mechanical loading: the first carpometacarpal (CMC-I) and the knee. Patients and methods - Samples of human cartilage obtained from OA CMC-I and knee joints were immunostained for TLRs (1-9) and analyzed using histomorphometry and principal component analysis (PCA). mRNA expression levels were analyzed with RT-PCR. Collected synovial fluid (SF) samples were screened for the presence of soluble forms of TLR2 and TLR4 by enzyme-linked immunosorbent assay (ELISA). Results - In contrast to knee OA, TLR expression in CMC-I OA did not show grade-dependent overall profile changes, but PCA revealed that TLR expression profiles clustered according to their cellular compartment organization. Protein levels of TLR4 were substantially higher in knee OA than in CMC-I OA, while the opposite was the case at the mRNA level. ELISA assays confirmed the presence of soluble forms of TLR2 and TLR4 in SF, with sTLR4 being considerably higher in CMC-I OA than in knee OA. Interpretation - We observed that TLRs are differentially expressed in OA cartilage, depending on the joint. Soluble forms of TLR2 and TLR4 were detected for the first time in SF of osteoarthritic joints, with soluble TLR4 being differentially expressed. Together, our results suggest that negative regulatory mechanisms of innate immunity may be involved in the pathomolecular mechanisms of osteoarthritis. PMID- 28093924 TI - Effects of an adapted cardiac rehabilitation programme on arterial stiffness in patients with type 2 diabetes without cardiac disease diagnosis. AB - PURPOSE: To determine the effects of a 12-week cardiac rehabilitation programme of aerobic and resistance exercise training on arterial stiffness, peak calf vasodilatory reserve, and haemostatic markers in patients with type 2 diabetes. METHODS: Observational cohort study examining effects of 12 weeks of exercise training in 23 subjects (13 men, 10 women; mean age of 56.1 +/- 10.1 years) with type 2 diabetes mellitus. Subjects performed exercise training for 12 weeks [aerobic training 5 days/week, 70%-75% peak cardiovascular fitness (VO2peak) and resistance training 2-3 days/week, 60% of one repetition maximum]. Vascular stiffness (pulse-wave velocity), augmentation index, peak calf vasodilatory reserve, and VO2peak were measured pre- and post-exercise training. Secondary outcomes included heart rate variability and haemostatic measures. RESULTS: VO2peak increased by 16% (20.1 +/- 5.5 vs 23.2 +/- 8.8 mL/kg/min, p = 0.002) and abdominal circumference was reduced (101.9 +/- 13.3 vs 97.9 +/- 12.7 cm, p < 0.03). Vascular function was improved including central arterial stiffness (central pulse-wave velocity: 8.44 +/- 1.75 vs 8.02 +/- 1.60 m/s, p = 0.026) and the aortic augmentation index (21.7 +/- 10.6% vs 18.3 +/- 12.6%, p = 0.005); peak calf vasodilatory reserve increased from 30.3 +/- 10.6 mL/100 mL/min to 38.0 +/- 15.3 mL/100 mL/min ( p = 0.04). No changes were seen in heart rate variability, blood lipids, glycated haemoglobin and C-reactive protein. CONCLUSION: A 12-week cardiac rehabilitation programme of aerobic and resistance training significantly reduces arterial stiffness and improves aerobic fitness in individuals with type 2 diabetes mellitus. PMID- 28093925 TI - Hypermethylation of antisense long noncoding RNAs in acute lymphoblastic leukemia. AB - AIM: Long noncoding RNAs serve critical regulatory functions highly specific for a tissue and its developmental stage. Antisense long ncRNA (AS-lncRNA) methylation changes in acute lymphoblastic leukemia (ALL) versus normal pre-B cell lymphoblasts were evaluated to identify potential differential methylation in this group of genes. MATERIALS & METHODS: The methylome of ALL and normal lymphoblasts was examined by the methylated CpG island recovery assay followed by NGS. CONCLUSION: The potential effect of trans regulation by AS-lncRNA through DNA/RNA binding is significant as sequence alignment analysis of the 25 most differentially methylated AS-lncRNAs revealed 368 genes containing highly similar sequences with a median nucleotide identity of 90.8% and binding span of 122 base pairs. Regulation of biological processes and anatomical structure development were over represented. ALL classification schemes based on AS-lncRNA methylation can provide new insights into its pathogenesis and treatment. PMID- 28093926 TI - Oestradiol treatment for mood stabilisation in borderline personality disorder. PMID- 28093927 TI - Impact of social disadvantage and parental offending on rates of criminal offending among offspring of women with severe mental illness. AB - OBJECTIVE: Children of parents with severe mental illness have an increased risk of offending. Studies suggest that risk factors such as parental offending and social disadvantage may be associated with the increased risk. This paper assesses the impact of these risk factors on offending rates in the offspring of women with severe mental illness compared to offspring of unaffected women. METHODS: This is part of a longitudinal record-linked whole-population study of 467,945 children born in Western Australia from 1980 to 2001 to mothers with severe mental illness and mothers with no recorded psychiatric illness. These data were linked to Western Australia corrective services data producing a dataset of 12,999 people with at least one offence (3.7% of birth cohort). Cox proportional hazard was used to calculate incidence rate ratios of offspring offending. RESULTS: The offending rate for offspring of mothers with severe mental illness (cases) was almost three times the rate for offspring of unaffected mothers (comparison) with an unadjusted incidence rate ratio of 2.75 (95% confidence interval: [2.58, 2.93]). Adjusting for sex, indigenous status, socio-economic status and geographical remoteness reduced the rate ratio by 24% to incidence rate ratio 2.10, 95% confidence interval: [1.97, 2.23]. Adjusting for parental offending further reduced the rate ratio by 23% to incidence rate ratio 1.62, 95% confidence interval: [1.52, 1.72]. The mean age at first recorded offence was significantly lower for cases compared to comparison offspring. CONCLUSION: Children of mothers with a severe mental illness have a higher rate of offending than children of unaffected mothers, and social disadvantage and parental offending have a major impact on this rate. Services supporting these vulnerable children need to focus on improving the social environment in which they and their families live in. PMID- 28093928 TI - Functional electrical stimulation therapy for severe hemiplegia: Randomized control trial revisited. AB - BACKGROUND: Stroke is the leading cause of long-term disability. Stroke survivors seldom improve their upper-limb function when their deficit is severe, despite recently developed therapies. PURPOSE: This study aims to assess the efficacy of functional electrical stimulation therapy in improving voluntary reaching and grasping after severe hemiplegia. METHOD: A post hoc analysis of a previously completed randomized control trial ( clinicaltrials.gov , No. NCT00221078) was carried out involving 21 participants with severe upper-limb hemiplegia (i.e., Fugl-Meyer Assessment-Upper Extremity [FMA-UE] <= 15) resulting from stroke. FINDINGS: Functional Independence Measure Self-Care subscores increased 22.8 (+/ 6.7) points in the intervention group and 9 (+/-6.5) in the control group, following 40 hr of equal-intensity therapy. FMA-UE score changes were 27.2 (+/ 13.5) and 5.3 (+/-11.0) for the intervention and control groups, respectively. IMPLICATIONS: The results may represent the largest upper-limb function improvements in any stroke population to date, especially in those with severe upper-limb deficit. PMID- 28093930 TI - An Australian collaborative research network: Building the evidence for inpatient psychiatry. PMID- 28093929 TI - Characterization of mitochondrial DNA polymorphisms in the Han population in Liaoning Province, Northeast China. AB - This study characterized the genetic variations of mitochondrial DNA (mtDNA) to elucidate the maternal genetic structure of Liaoning Han Chinese. A total of 317 blood samples of unrelated individuals were collected for analysis in Liaoning Province. The mtDNA samples were analyzed using two distinct methods: sequencing of the hypervariable sequences I and II (HVSI and HVSII), and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis of the coding region. The results indicated a high gene diversity value (0.9997 +/- 0.0003), a high polymorphism information content (0.99668) and a random match probability (0.00332). These samples were classified into 305 haplotypes, with 9 shared haplotypes. The most common haplogroup was D4 (12.93%). The principal component analysis map, the phylogenetic tree map, and the genetic distance matrix all indicated that the genetic distance of the Liaoning Han population from the Tibetan group was distant, whereas that from the Miao group was relatively close. PMID- 28093931 TI - Usefulness of human papillomavirus detection in oral rinse as a biomarker of oropharyngeal cancer. AB - CONCLUSION: The detection of human papillomavirus (HPV)-DNA in oral rinse with auto-nested GP5+/GP6 + PCR is useful as a biomarker of oropharyngeal cancer. BACKGROUND: This study aimed to determine the usefulness of oral rinse to detect HPV-DNA as a biomarker of HPV-positive oropharyngeal cancer (OPC). PATIENTS AND METHODS: One hundred and ten patients with various head and neck diseases, including 19 patients with OPC, were enrolled. Oral rinse and tonsillar swab were collected, and auto-nested GP5+/GP6 + PCR for HPV-DNA was performed. For oropharyngeal cancer, p16 immunostaining was also conducted. RESULTS: The rate of HPV-DNA detection in both oral rinse and tonsillar swab was significantly higher in OPC compared with non-OPC upper respiratory tract cancer and non-cancer diseases. HPV-DNA was detected in oral rinse in nine out of 12 p16-positive OPC cases, while none of the p16-negative OPC cases demonstrated detectable HPV-DNA. All p16-positive cases were also positive for HPV-DNA in tumor tissue. Based on p16 immunostaining, the sensitivity and specificity of HPV-DNA detection in oral rinse were 75% and 100%, respectively. Among eight of nine evaluable OPC cases positive for HPV-DNA in oral rinse at diagnosis, HPV-DNA was undetectable in oral rinse in seven cases after treatment. PMID- 28093932 TI - Involvement of p53 and Bcl-2 in sensory cell degeneration in aging rat cochleae. AB - CONCLUSION: p53 and Bcl-2 (B-cell lymphoma 2) are involved in the process of sensory cell degeneration in aging cochleae. OBJECTIVE: To determine molecular players in age-related hair cell degeneration, this study examined the changes in p53 and Bcl-2 expression at different stages of apoptotic and necrotic death of hair cells in aging rat cochleae. METHODS: Young (3-4 months) and aging (23-24 months) Fisher 344/NHsd rats were used. The thresholds of the auditory brainstem response (ABR) were measured to determine the auditory function. Immunolabeling was performed to determine the expression of p53 and Bcl-2 proteins in the sensory epithelium. Propidium iodide staining was performed to determine the morphologic changes in hair cell nuclei. RESULTS: Aging rats exhibited a significant elevation in ABR thresholds at all tested frequencies (p < 0.001). The p53 and Bcl-2 immunoreactivity was increased in aging hair cells showing the early signs of apoptotic changes in their nuclei. The Bcl-2 expression increase was also observed in hair cells displaying early signs of necrosis. As the hair cell degenerative process advanced, p53 and Bcl-2 immunoreactivity became reduced or absent. In the areas where no detectable nuclear staining was present, p53 and Bcl-2 immunoreactivity was absent. PMID- 28093933 TI - Acute kidney injury in idiopathic nephrotic syndrome of childhood is a major risk factor for the development of chronic kidney disease. AB - BACKGROUND: Acute kidney injury (AKI) is an important complication of idiopathic nephrotic syndrome (INS) and is associated with adverse outcomes, especially the development of chronic kidney disease (CKD). We aimed to determine the clinical profile of children with INS who developed AKI and its short-term outcome. MATERIAL AND METHODS: This prospective study was conducted from March 2014 to October 2015. A total of 119 children of INS (age: 2-18 years) fulfilling the pediatric RIFLE criteria for the diagnosis of AKI were enrolled and followed up for 3 months to determine the outcome. Factors predisposing to CKD were studied. RESULTS: The mean age at presentation was 8.8 +/- 3.59 years and males were 74 (62.2%). At presentation, 61 (51.3%) children were in Risk category, 43 (36.1%) in Injury category, and 15 (12.6%) in Failure category. Most of them (41.2%) had steroid-resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS) on histopathology (33.6%). Infections were the major predisposing factor for AKI in 67 (56.3%) cases. Drug toxicity was the next common, found in 52 (43.7%) children. A total of 65 (54.6%) children recovered from AKI, while 54 (45.4%) did not. CKD developed in 49 (41.2%) non-recovered cases and 5 (4.2%) children succumbed to acute illness. SRNS, cyclosporine use, FSGS on histology, and drug toxicity were significant factors associated with the development of CKD. CONCLUSION: AKI associated with INS is a reversible condition in most cases but it can progress to CKD, especially among those who have SRNS, FSGS, and drug toxicity. PMID- 28093934 TI - Efficacy and safety of oral sildenafil in treatment of pediatric head and neck lymphatic malformations. AB - CONCLUSIONS: Low dose oral sildenafil citrate tablets are safe and effective to decrease the lesions volume in some LMs children, especially with macrocystic lesion or mixed type. OBJECTIVE: To evaluate the efficacy and safety of oral sildenafil in treatment of pediatric head and neck lymphatic malformations (LMs). SUBJECTS AND METHODS: In this open-label study, 21 children diagnosed with LMs were given oral sildenafil and stopped at week 24. Volume change of lesions compared with baseline was used to evaluate therapeutic outcome. The improvement of various symptoms and the adverse effects of sildenafil were recorded during the follow-up period. RESULTS: Eight patients (38.0%) showed excellent improvement (>75-100%), one patient (4.8%) had good (>50-75%), two patients (9.6%) had fair (>25-50%), three patients (14.3%) had minimal (0-25%), and seven patients (33.3%) had no improvement. The snoring or stridor completely disappeared in two subjects, although there was no apparent decrease in LMs size. Moreover, all three patients with macrocystic lesions displayed a positive response to sildenafil treatment, followed by mixed type (9/12, 75%). Only two out of six patients with microcystic lesions had minimal clearance. Only four patients showed transient mild diarrhea, there was no other adverse effect in this series. PMID- 28093935 TI - New methods for monitoring mitochondrial biogenesis and mitophagy in vitro and in vivo. AB - Removal of damaged mitochondria through mitophagy is critical for maintaining cellular homeostasis and functions. Increasing evidence implicates mitophagy in red blood cell differentiation, neurodegeneration, macrophage-mediated inflammation, ischemia, adipogenesis, drug-induced tissue injury, and cancer. Considerable progress has been made toward understanding the biochemical mechanisms involved in mitophagy regulation. However, few reliable assays to monitor and quantify mitophagy have been developed, particularly in vivo. In this review, we summarize the recent development of three assays, MitoTimer, mt-Keima and mito-QC, for monitoring and quantifying mitophagy in cells and in animal tissues. We also discuss the advantages and limitations of these three assays when using them to monitor and quantify mitophagy. Impact statement Removal of damaged mitochondria through mitophagy is critical for maintaining cellular homeostasis and functions. However, reliable quantitative assays to monitor mitophagy, particularly in vivo, are just emerging. This review will summarize the current novel quantitative assays to monitor mitophagy in vivo. PMID- 28093936 TI - Biological activities of Rosmarinus officinalis L. (rosemary) extract as analyzed in microorganisms and cells. AB - R. officinalis L. is an aromatic plant commonly used as condiment and for medicinal purposes. Biological activities of its extract were evaluated in this study, as antimicrobial effect on mono- and polymicrobial biofilms, cytotoxicity, anti-inflammatory capacity, and genotoxicity. Monomicrobial biofilms of Candida albicans, Staphylococcus aureus, Enterococcus faecalis, Streptococcus mutans and Pseudomonas aeruginosa and polymicrobial biofilms composed of C. albicans with each bacterium were formed in microplates during 48 h and exposed for 5 min to R. officinalis L. extract (200 mg/mL). Its cytotoxic effect was examined on murine macrophages (RAW 264.7), human gingival fibroblasts (FMM-1), human breast carcinoma cells (MCF-7), and cervical carcinoma cells (HeLa) after exposure to different concentrations of the extract, analyzed by MTT, neutral red (NR), and crystal violet (CV) assays. The anti-inflammatory activity was evaluated on RAW 264.7 non-stimulated or stimulated by lipopolysaccharide (LPS) from Escherichia coli and treated with different concentrations of the extract for 24 h. Interleukin-1 beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) were quantified by ELISA. Genotoxicity was verified by the frequency of micronuclei (MN) at 1000 cells after exposure to concentrations of the extract for 24 h. Data were analyzed by T-Test or ANOVA and Tukey Test ( P <= 0.05). Thus, significant reductions in colony forming units per milliliter (CFU/mL) were observed in all biofilms. Regarding the cells, it was observed that concentrations <= 50 mg/mL provided cell viability of above 50%. Production of proinflammatory cytokines in the treated groups was similar or lower compared to the control group. The MN frequency in the groups exposed to extract was similar or less than the untreated group. It was shown that R. officinalis L. extract was effective on mono- and polymicrobial biofilms; it also provided cell viability of above 50% (at <= 50 mg/mL), showed anti-inflammatory effect, and was not genotoxic. Impact statement Rosmarinus officinalis L. extract effectively contributed to in vitro control of important species of microorganisms such as Candida albicans, Staphylococcus aureus, Enterococcus faecalis, Streptococcus mutans, and Pseudomonas aeruginosa in mono- and polymicrobial biofilms that are responsible for several infections in oral cavity as in other regions of the body. Furthermore, this extract promoted also cell viability above 50% at concentrations <= 50 mg/mL, excellent anti-inflammatory effect, showing inhibition or reduction of the synthesis of proinflammatory cytokines, being also non-genotoxic to cell lines studied. Thus, this extract may be a promising therapeutic agent that can be added in some medical and dental formulations such as toothpastes, mouthwashes, irrigating root canals, ointments, soaps, in order to control pathogenic microorganisms and biofilms, with anti-inflammatory effect and absence of cytotoxic and genotoxic. PMID- 28093938 TI - Capacity and consent. AB - INTRODUCTION: Healthcare practitioners have a legal, ethical and professional obligation to obtain patient consent for all healthcare treatments. There is increasing evidence which suggests dissonance and variation in practice in assessment of decision-making capacity and consent processes. AIMS: This study explores healthcare practitioners' knowledge and practices of assessing decision making capacity and obtaining patient consent to treatment in the acute generalist setting. METHODS: An exploratory descriptive cross-sectional survey design, using an online questionnaire, method was employed with all professional groups invited via email to participate. Data were collected over 3 months from July to September 2015. Survey content and format was reviewed by the liaison psychiatry team and subsequently contained five sections (demographics, general knowledge and practice, delirium context, legal aspects and education/training). Descriptive, univariate and bivariate analysis of quantitative data and qualitative content analysis of qualitative data were undertaken. Ethical considerations: The study was approved by the institutional Human Research and Ethics Committee and informed consent was taken to be provided by participants upon completion and submission of the de-identified survey. RESULTS: In total, 86 participants engaged the survey with n = 24, exiting at the first consent question. Almost two-thirds of respondents indicated that all treatments required patient consent. Knowledge of consent and decision-making capacity as legal constructs was deficient. Decision-making capacity was primarily assessed using professional judgement and perceived predominantly as the responsibility of medical and psychology staff. A range of patient psychological and behavioural symptoms were identified as indicators requiring assessment of decision-making capacity. Despite this, many patients with delirium have their decision-making capacity assessed and documented only sometimes. Uncertain knowledge and inconsistent application of legislative frameworks are evident. Many participants were unsure of the legal mechanisms for obtaining substitute consent in patients with impaired decision-making capacity and refusing treatment. CONCLUSION: The legal context of decision-making capacity and consent to treatment appears complex for healthcare practitioners. Professional, ethical and legal standards of care in this context can benefit from structured education programmes and supportive governance processes. An understanding of why 'duty of care' is being used as a framework within the context of impaired decision-making capacity is warranted, alongside a review of the context of Duty of Care within health policy, guidance and faculty teaching. PMID- 28093937 TI - Unmet needs in developing nanoparticles for precision medicine. PMID- 28093939 TI - Do catalytic nanoparticles offer an improved therapeutic strategy to combat dental biofilms? PMID- 28093940 TI - Self-targeted salinomycin-loaded DSPE-PEG-methotrexate nanomicelles for targeting both head and neck squamous cell carcinoma cancer cells and cancer stem cells. AB - AIM: To target both head and neck squamous cell carcinoma (HNSCC) cells and cancer stem cells (CSCs) by salinomycin-loaded DSPE-PEG-MTX (synthesized using DSPE-PEG2000-NH2 and methotrexate) nanomicelles (M-SAL-MTX). MATERIALS & METHODS: The characterization, antitumor activity and mechanism of M-SAL-MTX were evaluated. RESULTS & CONCLUSION: M-SAL-MTX showed enhanced inhibitory effect toward both HNSCC CSCs and non-CSCs compared with a single treatment of methotrexate and salinomycin. In nude mice-bearing HNSCC xenografts, M-SAL-MTX suppressed tumor growth more effectively than other controls including combination of methotrexate and salinomycin. Therefore, M-SAL-MTX may provide a strategy for treating HNSCC by targeting both HNSCC CSCs and HNSCC cells. PMID- 28093941 TI - Novel surface-engineered solid lipid nanoparticles of rosuvastatin calcium for low-density lipoprotein-receptor targeting: a Quality by Design-driven perspective. AB - AIM: The present studies describe Quality by Design-oriented development and characterization of surface-engineered solid lipid nanoparticles (SLNs) of rosuvastatin calcium for low density lipoprotein-receptor targeting. MATERIALS & METHODS: SLNs were systematically prepared employing Compritol 888 and Tween-80. Surface modification of SLNs was accomplished with Phospholipon 90G and DSPE-mPEG 2000 as the ligands for specific targeting to the low density lipoprotein receptors. SLNs were evaluated for size, potential, entrapment, drug release performance and gastric stability. Also, the formulations were evaluated for cellular cytotoxicity, uptake and permeability, pharmacokinetic, pharmacodynamic and biochemical studies. RESULTS & CONCLUSION: Overall, the studies ratified enhanced biopharmaceutical performance of the surface-engineered SLNs of rosuvastatin as a novel approach for the management of hyperlipidemia-like conditions. PMID- 28093942 TI - Self-assembling peptide nanostructures on aligned poly(lactide-co-glycolide) nanofibers for the functional regeneration of sciatic nerve. AB - AIM: Regeneration of functional peripheral nerve tissue at critical-sized defect requires extracellular matrix analogs impregnated with appropriate biosignals to regulate the cell fate process and subsequent tissue progression. The aim of the study was to develop electrospun aligned nanofibers as architectural analogs integrated with RADA16-I-BMHP1 as biofunctional peptides. MATERIALS & METHODS: Aligned poly(lactide-co-glycolide) (PLGA)-RADA16-I-BMHP1 nanofibers were fabricated and characterized for their in vitro potential using rat Schwann cell line and in vivo potential using a 10 mm sciatic nerve transection rat model. RESULTS: PLGA-peptide scaffolds significantly promoted higher expression of genotypic markers and bipolar extension of Schwann cells. Further, PLGA-peptide treated animals promoted the native collagen organization, remyelination and showed significantly higher recovery of sensorimotor and motor function than PLGA treated groups (p < 0.05). CONCLUSION: Our results demonstrate that self assembling peptide nanostructures on aligned PLGA nanofibers provided better cell matrix communication with significant functional restoration of the sciatic nerve. PMID- 28093943 TI - Clinical Evidence Supporting US Food and Drug Administration Premarket Approval of High-Risk Otolaryngologic Devices, 2000-2014. AB - The US Food and Drug Administration (FDA) approves high-risk medical devices based on premarket pivotal clinical studies demonstrating reasonable assurance of safety and effectiveness and may require postapproval studies (PAS) to further inform benefit-risk assessment. We conducted a cross-sectional analysis using publicly available FDA documents to characterize industry-sponsored pivotal studies and PAS of high-risk devices used in the treatment of otolaryngologic diseases. Between 2000 and 2014, the FDA approved 23 high-risk otolaryngologic devices based on 28 pivotal studies. Median enrollment was 118 patients (interquartile range, 67-181), and median duration of longest primary effectiveness end point follow-up was 26 weeks (interquartile range, 16-96). Fewer than half were randomized (n = 13, 46%), blinded (n = 12, 43%), or controlled (n = 10, 36%). The FDA required 23 PASs for 16 devices (70%): almost two-thirds (n = 15, 65%) monitored long-term performance, and roughly one-third (n = 8, 35%) focused on subgroups. Otolaryngologists should be aware of limitations in the strength of premarket evidence when considering the use of newly approved devices. PMID- 28093944 TI - Healing efficacy of fracture-targeted GSK3beta inhibitor-loaded micelles for improved fracture repair. AB - AIM: To evaluate the fracture healing capabilities of a GSK3beta inhibitor, 6 bromoindirubin-3'-oxime, coupled with an aspartic acid octapeptide in a micellar delivery system. MATERIALS & METHODS: The efficacy of the intravenously administered micelles to accelerate healing of femoral fracture in mice was evaluated. Micro-computed tomography analysis was employed to obtain bone density, total volume, relative volume, trabecular thickness and trabecular spacing. RESULTS: Both fracture bone mineral density and volume were significantly higher in the micelle treatment groups when compared with controls. The fracture-targeted micelle demonstrates fracture-specific bone anabolism and biocompatibility in off-target tissues. CONCLUSION: Accelerated fracture healing in mice was achieved by targeting the GSK3beta inhibitor, 6-bromoindirubin-3' oxime, to the fracture site. PMID- 28093945 TI - A feasibility study to improve practice nurses' competence and confidence in providing care for mothers and infants. AB - BACKGROUND: Postnatal care is best provided in primary health care settings, yet Practice Nurses (PNs) lack relevant training and report difficulty in providing postnatal care. AIM: To evaluate the feasibility of a pilot educational intervention in improving PN competence and confidence to care for mothers and infants in the first postnatal year. DESIGN: A feasibility study. METHODS: PNs were recruited from selected general practices Queensland, Australia to undertake the pilot educational intervention that included a pre-intervention survey, two day education program, program evaluation and completion of a practice journal. RESULTS: Thirteen PNs from three general practices participated, with 31% completing all study components. Evaluation of the intervention was positive and all participants reported increased confidence and competence in providing postnatal care. Following detailed consideration of feasibility (process, resource, management and scientific assessment) we propose that changes to intervention delivery and data collection should be incorporated into a larger trial. PMID- 28093946 TI - Commentary: Endovascular Treatment of Popliteal Lesions Requires Advanced Physician Skills. PMID- 28093947 TI - Comparative Effectiveness of Partial versus Total Tonsillectomy in Children. AB - Objective To assess the effectiveness of partial versus total tonsillectomy in children. Data Sources MEDLINE, EMBASE, and Cochrane Library from January 1980 to June 2016. Review Methods Two investigators independently screened studies and extracted data. Investigators independently assessed risk of bias and strength of evidence of the literature. Heterogeneity precluded quantitative analysis. Results In 16 eligible randomized controlled trials (RCTs), definitions of "partial" tonsillectomy varied. In addition to comparing partial with total tonsil removal, 11 studies compared surgical techniques (eg, coblation). In studies comparing the same technique, return to normal diet or activity was faster with partial removal (more favorable outcomes in 4 of 4 RCTs). In studies with differing surgical techniques, return to normal diet and activity was faster with partial versus total tonsillectomy (more favorable outcomes in 5 of 6 studies). In 3 of 4 RCTs, partial tonsillectomy was associated with more throat infections than total tonsillectomy. Differences between groups were generally not statistically significant for obstructive symptom persistence, quality of life, or behavioral outcomes. Across all studies, 10 (6%) of roughly 166 children had tonsillar regrowth after partial tonsillectomy. Conclusions Data do not allow firm conclusions regarding the comparative benefit of partial versus total removal; however, neither surgical technique nor extent of surgery appears to affect outcomes markedly. Partial tonsillectomy conferred moderate advantages in return to normal diet/activity but was also associated with tonsillar regrowth and symptom recurrence. Effects may be due to confounding given differences in populations and surgical approaches/techniques. Heterogeneity and differences in the operationalization of "partial" tonsillectomy limited comparative analyses. PMID- 28093949 TI - Scottish Cardiac Society 24th annual general meeting. PMID- 28093950 TI - GEMS 2015 Abstract Submission for Publication. PMID- 28093948 TI - Design and evaluation of a stearylated multicomponent peptide-siRNA nanocomplex for efficient cellular siRNA delivery. AB - AIM: To develop a new synthetic peptide-based nanoparticulate siRNA delivery system. MATERIALS & METHODS: DEN-K(GALA)-TAT-K(STR) was generated by incorporating stearic acid into a multicomponent peptide (DEN-K(GALA)-TAT), containing a cationic poly-L-lysine dendron, an endosome-disrupting peptide GALA and a cell-penetrating peptide TAT(48-60). Its physicochemical characteristics, size, toxicity, cellular uptake and gene knockdown activity of the peptide/siRNA complexes were studied. RESULTS: DEN-K(GALA)-TAT-K(STR) exhibited a pH-responsive behavior, which assists with endosomal escape. When siRNA was delivered by DEN K(GALA)-TAT-K(STR), it showed a significantly enhanced cellular uptake, compared with the nonlipidic peptide. This system also displayed enhanced knockdown efficiency and reduced cytotoxicity over the widely used delivery system branched 25-kDa polyethyleneimine. CONCLUSION: Our stearylated multicomponent delivery system has great potential as an efficient siRNA delivery vector. PMID- 28093951 TI - Qualitative comparison of polyethylene terephthalate flakes from various collection systems in Germany. AB - In 2003, a deposit system for one-way packaging was introduced in Germany. Since that time, polyethylene terephthalate beverage packaging is collected through various collection systems, a deposit system, a reusable packaging system and the 'Green Dot' (the dual system) with the yellow bag. The manner of collection had a decisive influence on the quality of the generated recycled materials. The research at hand shows for the first time how the quality of polyethylene terephthalate flakes depends on the type of collection system. The results are based on a 14-year time frame, during which the quality of the polyethylene terephthalate flakes was examined using the different collection systems. The criterion used was the amount of contamination of polyethylene terephthalate flakes with various polymers, metals and other substances. Grain size and bulk density were also compared. The outcome shows that material from the deposit systems resulted in a better quality of polyethylene terephthalate (PET) flakes. PMID- 28093952 TI - Nanocarriers protecting toward an intestinal pre-uptake metabolism. AB - Pre-uptake metabolism within the GI tract is responsible for the poor oral bioavailability of numerous drugs. As nanocarriers function as a 'shield', protecting incorporated drugs from enzymatic attack, there is an increasing interest in utilizing them as a tool for overcoming drug degradation. Degradation of carriers resulting in the release of incorporated drugs, mucus permeation, enzyme inhibitory properties and their toxicity are crucial factors that must be taken into account when designing proper nanocarriers. The use of polymer- and lipid-based nanocarriers as protective vehicles are discussed within this review. Lipid-based carriers and novel mucopenetrating particles seem to have a great potential in avoiding metabolizing enzymes. Accordingly, nanocarriers are promising tools for improving the bioavailability of drugs, being sensitive to a pre-uptake metabolism. PMID- 28093953 TI - Case study: Is the 'catch-all-plastics bin' useful in unlocking the hidden resource potential in the residual waste collection system? AB - Austria's performance in the collection of separated waste is adequate. However, the residual waste still contains substantial amounts of recyclable materials - for example, plastics, paper and board, glass and composite packaging. Plastics (lightweight packaging and similar non-packaging materials) are detected at an average mass content of 13% in residual waste. Despite this huge potential, only 3% of the total amount of residual waste (1,687,000 t y-1) is recycled. This implies that most of the recyclable materials contained in the residual waste are destined for thermal recovery and are lost for recycling. This pilot project, commissioned by the Land of Lower Austria, applied a holistic approach, unique in Europe, to the Lower Austrian waste management system. It aims to transfer excess quantities of plastic packaging and non-packaging recyclables from the residual waste system to the separately collected waste system by introducing a so-called 'catch-all-plastics bin'. A quantity flow model was constructed and the results showed a realistic increase in the amount of plastics collected of 33.9 wt%. This equals a calculated excess quantity of 19,638 t y-1. The increased plastics collection resulted in a positive impact on the climate footprint (CO2 equivalent) in line with the targets of EU Directive 94/62/EG (Circular Economy Package) and its Amendments. The new collection system involves only moderate additional costs. PMID- 28093954 TI - Inhibitory effect of high calcium concentration on municipal solid waste leachate treatment by the activated sludge process. AB - This research focused on the inhibitory effects of Ca on the aerobic biological treatment of landfill leachate containing extremely high Ca concentrations. When the Ca concentration in leachate to be treated was more than 4500 mg l-1, the total organic carbon removal rate was significantly reduced and the processing time to achieve the same removal efficiency was 1.4 times that in the control treatment without added Ca. In contrast, the total nitrogen and ammonia nitrogen (NH4+-N) removal efficiencies were positively related to the Ca concentration, increasing from 65.2% to 81.2% and from 69.2% to 83.7%, respectively, when the dosage of added Ca increased from zero to 8000 mg l-1. During aerobic treatment, the reductions of solution Ca concentration were in the range of 1003-2274 mg l-1 and were matched with increases in the Ca content in the residual sludge. The inhibition threshold of Ca in the leachate treated by the activated sludge process appeared to be 4500 mg l-1, which could be realized by controlling the influent Ca concentration and using an appropriate sludge return ratio in the activated sludge process. PMID- 28093956 TI - Praluent (Alirocumab)-Induced Renal Injury. PMID- 28093955 TI - Anatomically Realistic Simulations of Liver Ablation by Irreversible Electroporation. AB - Irreversible electroporation is a novel tissue ablation technique which entails delivering intense electrical pulses to target tissue, hence producing fatal defects in the cell membrane. The present study numerically analyzes the potential impact of liver blood vessels on ablation by irreversible electroporation because of their influence on the electric field distribution. An anatomically realistic computer model of the liver and its vasculature within an abdominal section was employed, and blood vessels down to 0.4 mm in diameter were considered. In this model, the electric field distribution was simulated in a large series of scenarios (N = 576) corresponding to plausible percutaneous irreversible electroporation treatments by needle electrode pairs. These modeled treatments were relatively superficial (maximum penetration depth of the electrode within the liver = 26 mm) and it was ensured that the electrodes did not penetrate the vessels nor were in contact with them. In terms of total ablation volume, the maximum deviation caused by the presence of the vessels was 6%, which could be considered negligible compared to the impact by other sources of uncertainty. Sublethal field magnitudes were noticed around vessels covering volumes of up to 228 mm3. If in this model the blood was substituted by a liquid with a low electrical conductivity (0.1 S/m), the maximum volume covered by sublethal field magnitudes was 3.7 mm3 and almost no sublethal regions were observable. We conclude that undertreatment around blood vessels may occur in current liver ablation procedures by irreversible electroporation. Infusion of isotonic low conductivity liquids into the liver vasculature could prevent this risk. PMID- 28093957 TI - New Faculty Members at Touro College of Pharmacy-New York. PMID- 28093958 TI - President's Address. PMID- 28093960 TI - Journal watch: diagnostic nanoparticles. PMID- 28093961 TI - Submental Ultrasonographic Parameters among Patients with Obstructive Sleep Apnea. AB - Objective This study aimed to determine the value of submental ultrasonography (US) parameters for diagnostic workup among patients with obstructive sleep apnea (OSA) and to determine whether there is a correlation between US findings and the severity of OSA. Study Design Cross-sectional analysis. Setting Tertiary education hospital. Subjects and Methods The study included 147 patients with suspected OSA who underwent submental US to evaluate various parameters following overnight polysomnography. US findings were compared with the apnea-hypopnea index and other parameters. Results All US parameters, except for subcutaneous tissue thickness, were significantly different among patients with OSA. Of note, distance between lingual arteries (DLA), geniohyoid muscle thickness (GMT), and lateral parapharyngeal wall thickness (LPWT) were significantly greater in the patients with severe OSA than those with mild and moderate OSA ( P < .001). GMT had the strongest correlation with OSA ( r = 0.419, P < .001); LPWT and DLA also had high correlation coefficient values ( r = 0.343, P < .001, and r = 0.342, P < .001, respectively). Stepwise regression analysis showed that GMT (beta = 0.243, P = 0.004), LPWT (beta = 0.236, P = 0.004), and DLA (beta = 0.204, P = 0.008) were the most significant factors for predicting the severity of OSA according to the apnea-hypopnea index. Conclusion Submental US can be used to determine whether there is a correlation between US findings and severity of OSA. GMT could be considered a novel parameter for determining the severity of OSA. PMID- 28093962 TI - The LMSR method for providing a multidimensional understanding of growth standard in human fetuses. AB - A new nonlinear multivariate regression method called the LMSR method is proposed, by which a multidimensional understanding for the development process of human fetuses can be provided. Statistically important quantities such as median, skewness, coefficient of variation, and correlation of underlying structure can be described by corresponding smooth curves. Those curves can be obtained by a fine combination of a multivariate power transformation of data and penalized likelihood. It will be shown that the LMSR method and some associated tools are clearly efficient in analyzing development process of human fetuses. PMID- 28093963 TI - An efficient test based on the inferential model for the non-inferiority of odds ratio in matched-pairs design. AB - Non-inferiority of one treatment to another based on odds ratio for the matched pair design is a common issue in the medical research. Liu et al. derived two asymptotic tests, delta method and score test, which can be applicable for large samples but may tend to be liberal for small sample sizes. Jin et al. proposed an IM-based method that can control the type I risk well but may be somewhat conservative. In this paper, we extend the IM-based method to RIM-based test using the randomized plausibility function. We prove that our new proposed method is not only valid but also efficient. Simulation studies confirm that the RIM based test is better than other methods. A numerical example illustrates the proposed method. PMID- 28093964 TI - CUSUM chart to monitor autocorrelated counts using Negative Binomial GARMA model. AB - Cumulative sum control charts have been used for health surveillance due to its efficiency to detect soon small shifts in the monitored series. However, these charts may fail when data are autocorrelated. An alternative procedure is to build a control chart based on the residuals after fitting autoregressive moving average models, but these models usually assume Gaussian distribution for the residuals. In practical health surveillance, count series can be modeled by Poisson or Negative Binomial regression, this last to control overdispersion. To include serial correlations, generalized autoregressive moving average models are proposed. The main contribution of the current article is to measure the impact, in terms of average run length on the performance of cumulative sum charts when the serial correlation is neglected in the regression model. Different statistics based on transformations, the deviance residual, and the likelihood ratio are used to build cumulative sum control charts to monitor counts with time varying means, including trend and seasonal effects. The monitoring of the weekly number of hospital admissions due to respiratory diseases for people aged over 65 years in the city Sao Paulo-Brazil is considered as an illustration of the current method. PMID- 28093965 TI - IRMA study: Prevalence of subdiaphragmatic visceral infarction in ischemic stroke and atrial fibrillation. AB - Background Occult atrial fibrillation (AF) may, in part, explain cryptogenic stroke. A 22% prevalence of subdiaphragmatic visceral infarction (SDVI) among patients with ischemic stroke (IS) due to AF has been reported, using abdominal MRI. We sought to assess the reproducibility of this method and to confirm that SDVI is more prevalent in cases of AF-caused IS than in IS of other etiologies. Methods In consecutive patients admitted to our hospital, we compared SDVI prevalence in three groups: patients with IS due to AF (IS+/AF+ group), patients with stroke of another determined cause (IS+/AF- group) and patients with AF without stroke (IS-/AF+ group). Results A total of 111 patients were included. The median time between inclusion and abdominal MRI was six days. SDVI was more frequent in the IS+/AF+ group ( n = 10; 21.3%), than in IS+/AF- ( n = 1; 3.3%) and IS-/AF+ ( n = 0) groups, p = 0.002. The most frequent localization was the kidney. Conclusions The prevalence of SDVI was higher among patients with AF caused IS. In cases of cryptogenic stroke, a positive abdominal MRI may suggest occult AF as the cause and identify a high risk of AF in this subgroup of patients. PMID- 28093966 TI - Physical inactivity is a strong risk factor for stroke in the oldest old: Findings from a multi-ethnic population (the Northern Manhattan Study). AB - Background The fastest growing segment of the population is those age >=80 who have the highest stroke incidence. Risk factor management is complicated by polypharmacy-related adverse events. Aims To characterize the impact of physical inactivity for stroke by age in a multi-ethnic prospective cohort study (NOMAS, n = 3298). Methods Leisure time physical activity was assessed by a validated questionnaire and our primary exposure was physical inactivity (PI). Participants were followed annually for incident stroke. We fit Cox-proportional hazard models to calculate hazard ratios and 95% confidence intervals (HR 95% CI) for the association of PI and other risk factors with risk of stroke including two-way interaction terms between the primary exposures and age (<80 vs. >=80). Results The mean age was 69 +/- 10.3 years and 562 (17%) were >=80 at enrolment. PI was common in the cohort (40.8%). Over a median of 14 years, we found 391 strokes. We found a significant interaction of age >=80 on the risk of stroke with PI ( p = 0.03). In stratified models, PI versus any activity (adjusted HR 1.60, 95%CI 1.05 2.42) was associated with an increased risk of stroke among those >=80. Conclusion Physical inactivity is a treatable risk factor for stroke among those older than age 80. Improving activity may reduce the risk of stroke in this segment of the population. PMID- 28093967 TI - Anchored Lentiviral Vector Episomes for Stem Cell Gene Therapy in Fanconi Anemia. AB - Fanconi anemia (FA) is an autosomal recessive, multisystem DNA repair disorder with prominent defects in the hematopoietic stem cell maintenance that result in the progressive attrition and failure in the early school age. Allogeneic stem cell transplantation has proved curative for patients with suitable donors. This, along with the characteristic survival advantage of phenotypically normal over non-corrected FA stem cells underscores the compelling rationale for stem cell gene therapy in the FA. While integrating lentiviral vectors (LV) have become the preferred platform for genetic correction in several hematologic and immunodeficiency disorders, the residual oncogenic potential by these vectors raises concerns in the FA stem cells about insertional mutagenic genetic lesions. On this backdrop, investigators are developing a new generation of non integrating viral vectors capable of nuclear persistence through serial mitotic cycles and stable under selection to offset the comparatively lower transduction rates. Here, we review the competing approaches to develop such non-integrating lentiviral (NILV) episome vectors that faithfully replicate in the stem cells. PMID- 28093968 TI - Quantification of Etodolac in Human Plasma for Pharmacokinetics and Bioequivalence Studies in 27 Korean Subjects. AB - OBJECTIVE: We developed a simple and validated liquid chromatography tandem mass spectrometry( LC-MS/MS) for quantification of etodolac using pioglitazone as an internal standard (IS) to assess pharmacokinetics and to appraise bioequivalence of two formulations of etodolac (reference and tested) in 27 healthy Korean subjects. METHODS: Isocratic mobile phase consisted of 10 mM ammonium formate and acetonitrile were used to separate the analytes on a Gemini C18 column. Also, analytes were analyzed by MS/MS in multiple reaction monitoring (MRM) mode using the transitions of (M+H)+ ions, m/z 288.2-> 172.3 and m/z 357.1-> 134.2 for quantification of etodolac and IS each. The standard calibration curves displayed significant linearity within the range of 0.2-30.0 MU g/mL (r2=0.9956, 1/x2 weighting) with LLOQ of 0.1 MUg/mL. RESULTS: The retention times of etodolac and the IS were 0.77 min and 0.57 min each, indicating the high-throughput potential of the proposed method. The pharmacokinetic parameters were calculated from the plasma samples and data form the reference and test drugs were represented as follows; Area under plasma concentration-time curve (AUCt) (78.03 vs. 84.00 MUgxh/mL), AUCinfinity (86.67 vs. 93.92 MUgxh/mL), maximal plasma concentration (Cmax) (19.49 vs. 18.94 MUg/mL), time for maximal concentrations (Tmax) (2.13 vs. 2.26 h), Plasma elimination half-life (T1/2) (8.12 vs. 8.47 h), elimination rate constant (lambdaz) (0.0853 vs. 0.0818 h-1). Pharmacokinetic parameters with 90% confidence interval fall within the bioequivalence range of 80-125%. CONCLUSION: Thus, the new testified method was successfully applied for the pharmacokinetic and bioequivalence studies for two etodolac formulations. PMID- 28093969 TI - Traumatic Brain Injury: Preclinical Imaging Diagnostic(s) and Therapeutic Approaches. AB - BACKGROUND: Traumatic brain injury (TBI) is the result of an external physical force to the head that harms the brain. TBI is a major public health problem worldwide and mainly results from falls, vehicle accidents and violence. Clinical problem: The management of TBI, causing a wide spectrum of possible health outcomes, has barely changed over the years as encouraging outcomes from many pre clinical therapeutic and pharmacological studies have only rarely been translated to the clinical situation. New management options: In the last decades management of TBI is rapidly advancing and new innovative imaging modalities with sophisticated treatment options by using nanomedicine based drug delivery systems are under investigation. Nano formulations such as PLGA, exosomes and liposomes have the advantage of a targeted and controlled delivery of their cargo, such as diagnostic probes and/or therapeutic drugs. SUMMARY: Here we provide an overview of new promising pre-clinical developments in TBI management that may find their way to the clinic in the near future. Nanotechnology and nanomedicine in TBI intervention may establish new platforms for targeted drug delivery to the traumatized brain to improve the quality of life and survival of TBI patients. PMID- 28093970 TI - Evaluation of Salivary Vitamin C and Catalase in HIV Positive and Healthy HIV Negative Control Group. AB - BACKGROUND: Saliva is a complex oral biologic fluid secreted by major and minor salivary glands. Saliva has immunological, enzymatic and antioxidant defense mechanisms. Infection with human immunodeficiency virus (HIV) is a life threatening disease. OBJECTIVE: The aim of this study was to evaluate salivary vitamin C and catalase levels in HIV-positive patients in comparison to a healthy control group. METHOD: Forty-nine HIV-infected individuals and 49 healthy subjects were selected. Five mL of unstimulated saliva was collected in 5 minutes using a sterilized Falcon tube with Navazesh method. Catalase and vitamin C levels were assessed by spectrophotometric assay. Data were analyzed with STATA 12. RESULTS: Salivary catalase levels were 7.99+/-2.40 and 8.37+/-1.81 in the case and control groups, respectively. Catalase level was lower in the case group but the difference was not statistically significant (P=0.380). Salivary vitamin C levels in the case and control groups were 3.76+/-1.92 and 4.87+/-2.20, respectively (P=0.009). CONCLUSION: HIV can alter salivary antioxidant capacity as well as vitamin C and catalase levels. Saliva may reflect serum antioxidative changes in these patients. Therefore, further research is necessary on salivary and serum oxidants and the antioxidant changes. PMID- 28093972 TI - Conformation as the Therapeutic Target for Neurodegenerative Diseases. AB - Therapeutic strategies that target pathways of protein misfolding and the toxicity of intermediates along these pathways are mainly at discovery and early development stages, with the exception of monoclonal antibodies that have mainly failed to produce convincing clinical benefits in late stage trials. The clinical failures represent potentially critical lessons for future neurodegenerative disease drug development. More effective drugs may be achieved by pursuing the following two strategies. First, conformational targeting of aggregates of misfolded proteins, rather than less specific binding that includes monomer subunits, which vastly outnumber the toxic targets. Second, since neurodegenerative diseases frequently include more than one potential protein pathology, generic targeting of aggregates by shape might also be a crucial feature of a drug candidate. Incorporating both of these critical features into a viable drug candidate along with high affinity binding has not been achieved with small molecule approaches or with antibody fragments. Monoclonal antibodies developed so far are not broadly acting through conformational recognition. Using GAIM (General Amyloid Interaction Motif) represents a novel approach that incorporates high affinity conformational recognition for multiple protein assemblies, as well as recognition of an array of assemblies along the misfolding pathway between oligomers and fibers. A GAIM-Ig fusion, NPT088, is nearing clinical testing. PMID- 28093971 TI - Preparation Methods and Antioxidant Activities of Polysaccharides and Their Derivatives. AB - BACKGROUND: In recent years, the antioxidant effects of polysaccharides have become a hot spot in the field of polysaccharide research. METHOD: Herein, the action mechanisms of polysaccharide antioxidation and scavenging free radicals were analyzed. The research progresses on the preparation methods and antioxidant properties of polysaccharides and their derivatives were summarized. CONCLUSION: Investigating the antioxidant activities of polysaccharides and their derivatives can find useful polysaccharides and their derivatives, which have great potential as natural antioxidants used in functional foods or medicines. PMID- 28093973 TI - Adsorptive Removal of Metal Ions from Water using Functionalized Biomaterials. AB - BACKGROUND: Synthesis and modification of cost-effective sorbents for removing heavy metals from water resources is an area of significance. It had been reported that materials with biological origins, such as agricultural and animal waste, are excellent alternatives to conventional adsorbents due to their higher affinity, capacity and selectivity towards metal ions. These properties of biomaterials help to reduce or detoxify metal ions concentration in contaminated water to acceptable regulatory standards. OBJECTIVE: Synthesis of novel, efficient, cost effective, eco-friendly biomaterials for heavy metal adsorption from water is still an area of challenge. METHOD: In this comprehensive review, acompilation of patents as well as published articles is carried out to outline the properties of different biomaterials based on their precursors along withdetailed description of biomaterial morphology and various surface modification approaches. RESULTS: A detailed study of the performance of adsorbents and the role of physical and chemical modification in terms of enhancing their potential for metal adsorption from water is compiled here. The factors affecting adsorption behavior i.e., capacity and affinity of e biomaterials is also compiled. CONCLUSION: This paper presents a concise review of reported studies on the synthesis and modification of biomaterials, their use for heavy metal removal from waters and future prospects of this technology. PMID- 28093974 TI - Anticancer Properties of Traditional Chinese Medicine. AB - BACKGROUND: Cancer is a systemic disease. Cancer occurrence is associated with several factors, including cell proliferation, apoptosis, metastasis, tumor microenvironment and immune system. Traditional Chinese medicine (TCM) has been widely used for thousands of years in China for its anti-cancer therapeutic effect. The advantage of using TCM is related to its action on multiple signaling pathways and molecular targets related to cancer, whilst causing few adverse effects. OBJECTIVE: The review focuses on the most recent studies on TCM through examples that demonstrate the anticancer effects and the mechanisms. CONCLUSION: The review shows a large number of works which demonstrated that TCM is useful in the treatment of various types of cancers through different mechanisms of action. The results indicate that TCM exerts its anticancer effects through apoptosis induction, proliferation inhibition, metastasis suppression, multidrug resistance reversal and immune function regulation. Moreover, TCM can improve patients' quality of life. The advantage of TCM suggests that TCM may represent a promising therapeutic approach for patients with diverse cancers. PMID- 28093975 TI - Molecular Modeling and Dynamics Simulation Analysis of KATNAL1 for Identification of Novel Inhibitor of Sperm Maturation. AB - BACKGROUND: Hormone based birth control often causes various side effects. A recent study revealed that temporary infertility without changing hormone levels can be attained by inhibiting Katanin p60 ATPase-containing subunit A-like 1 protein (KATNAL1) which is critical for sperm maturation in the testes. OBJECTIVE: This study aimed at attaining the most energetically stable three dimensional (3D) structure of KATNAL1 protein using comparative modeling followed by screening of a ligand library of known natural spermicidal compounds for their binding affinity with KATNAL1. This in turn may inhibit the development of mature sperm in the seminiferous epithelium. METHOD: A series of computational techniques were used for building the 3D structure of KATNAL1 which was further optimized by molecular dynamics (MD) simulation. For revealing the ATP binding mode of KATNAL1, docking study was carried out using the optimized model obtained from the MD simulation. The docking study was also employed to test the binding efficiency of the ligand library. RESULTS: Molecular docking study confirmed the ATP binding of KATNAL1 with various hydrophobic and hydrogen bond interactions. Binding efficiency of the ligand library suggested that calotropin, a cardenolide of Calotropis procera showed the highest binding efficiency against the target protein without toxicity. MD simulation of the docked complex validated the results of the docking study. CONCLUSION: This study revealed the ATP binding mode of KATNAL1 and identified calotropin as a potential lead molecule against it showing high binding efficiency with good bioavailability and no mutagenicity. Further in vitro and in vivo bioassay of calotropin could facilitate the development of novel non-hormonal male-specific contraceptive in near future. PMID- 28093976 TI - Chemoinformatics Profiling of the Chromone Nucleus as a MAO-B/A2AAR Dual Binding Scaffold. AB - BACKGROUND: In the context of the current drug discovery efforts to find disease modifying therapies for Parkinson's disease (PD) the current single target strategy has proved inefficient. Consequently, the search for multi-potent agents is attracting more and more attention due to the multiple pathogenetic factors implicated in PD. Multiple evidences points to the dual inhibition of the monoamine oxidase B (MAO-B), as well as adenosine A2A receptor (A2AAR) blockade, as a promising approach to prevent the neurodegeneration involved in PD. Currently, only two chemical scaffolds has been proposed as potential dual MAO-B inhibitors/A2AAR antagonists (caffeine derivatives and benzothiazinones). METHODS: In this study, we conduct a series of chemoinformatics analysis in order to evaluate and advance the potential of the chromone nucleus as a MAO-B/A2AAR dual binding scaffold. RESULTS: The information provided by SAR data mining analysis based on network similarity graphs and molecular docking studies support the suitability of the chromone nucleus as a potential MAOB/ A2AAR dual binding scaffold. Additionally, a virtual screening tool based on a group fusion similarity search approach was developed for the prioritization of potential MAO B/A2AAR dual binder candidates. Among several data fusion schemes evaluated, the MEAN-SIM and MIN-RANK GFSS approaches demonstrated to be efficient virtual screening tools. Then, a combinatorial library potentially enriched with MAO B/A2AAR dual binding chromone derivatives was assembled and sorted by using the MIN-RANK and then the MEAN-SIM GFSS VS approaches. CONCLUSION: The information and tools provided in this work represent valuable decision making elements in the search of novel chromone derivatives with a favorable dual binding profile as MAOB inhibitors and A2AAR antagonists with the potential to act as a disease modifying therapeutic for Parkinson's disease. PMID- 28093978 TI - Perspective in Medicinal Chemistry: Structure-Based Drug Design. PMID- 28093979 TI - Editorial: Small and Supramolecular Chemistry in Drug Design, Drug Discovery and Drug Delivery. PMID- 28093977 TI - The Amyloid Cascade Hypothesis in Alzheimer's Disease: It's Time to Change Our Mind. AB - Since its discovery in 1984, the beta amyloid peptide has treaded the boards of neurosciences as the star molecule in Alzheimer's disease pathogenesis. In the last decade, however, this vision has been challenged by evidence-based medicine showing the almost complete failure of clinical trials that experimented anti amyloid therapies with great hopes. Moreover, data have accumulated which clearly indicate that this small peptide plays a key role in the physiological processes of memory formation. In the present review, we will discuss the different aspects of the amyloid cascade hypothesis, highlighting its pros and cons, and we will analyse the results of the therapeutic approaches attempted to date that should change the direction of Alzheimer's disease research in the future. PMID- 28093980 TI - Emerging Advances in Nanomedicine as a Nanoscale Pharmacotherapy in Rheumatoid Arthritis: State of the Art. AB - There are several significant setbacks including limited bioavailability, high clearance, and further current therapies require higher and frequent dosing to gain desired therapeutic effects. Nanomedicines have been widely investigated for rheumatoid arthritis (RA). Though, higher doses also increase the incidence of dreadful adverse effects. Further, nanocarrier properties are tuned by the use of different approaches like varied methods of loading, hydrophilic polymers and targeting ligands, to change the physicochemical properties including higher encapsulation, better penetrating ability to biological barriers, thus preventing the uptake of various nanocarriers by liver and spleen. Along with these they provide longer circulation which enhances drug localization at the inflamed site and selective targeting to enhance the therapeutic index of anti-rheumatic drugs. However, the optimal properties also depend on the route of administration and nanocarrier size, thus larger size show more retention upon local injection and smaller sized ones are more optimal for passive targeting. The present review discusses the emergence of nano-carriers for anti-rheumatic drugs, which delivers drug molecule to the inflamed site by topical, intra-articular (i.a) and intra venous (i.v) administration to achieve therapeutic efficacy by passive and active drug targeting. Advancements have been made extensively but still better investigations are needed to optimize the risk-benefit ratio for the development of safe and stable targeting nanocarriers for the effective treatment of rheumatoid arthritis (RA). PMID- 28093981 TI - Chemical and Biological Aspects of the Natural 1,4-Benzoquinone Embelin and its (semi-)Synthetic Derivatives. AB - BACKGROUND: Like the impressive biological properties of embelin, its chemical aspects have raised the interest of scientists in the field as well. A detailed understanding of the chemistry of embelin is necessary to fully exploit it medicinally. METHODS: Search for embelin isolation and its chemical modifications was carried out using web-based literature searching tools such as Pubmed and Scifinder. Pertinent literature is covered up to 2016. Structures of bioactive embelin derivatives are provided. RESULTS: Pure embelin, obtained from Embelia ribes berries extraction or by total synthesis, was applied for a number of biological assays. Semi-synthetic and total synthetic approaches led to new high affinity embelin-derived inhibitors of crucial protein targets and to new embelin derivatives with improved pharmacological properties (e.g., with better water solubility or as applications for drug carrier systems). CONCLUSION: This review provides a summary of the rich chemistry of embelin and the latest developments in the field of optimized (semi-)synthetic embelin derivatives including their biological activities. PMID- 28093982 TI - PDE7-Selective and Dual Inhibitors: Advances in Chemical and Biological Research. AB - Phosphodiesterase 7 (PDE7) is an intracellular enzyme that specifically hydrolyzes the second messenger, cyclic-3',5'-adenosine monophosphate (cAMP), into inactive noncyclic nucleotide, 5'-AMP. To date, many structurally diverse compounds with PDE7 inhibitory properties have been described, including selective PDE7 inhibitors, dual PDE4/PDE7, PDE7/PDE8, and PDE7/GSK-3 inhibitors, and non-selective PDE inhibitors with high affinity for PDE7. Inhibitors of PDE7 have provided beneficial effects in animal models of inflammatory and neurological disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and many others. This review is a comprehensive summary of the current state-of-the-art in the field of design and synthesis of PDE7 inhibitors, their physicochemical properties, biological evaluation, and structure-activity relationships as well as it highlights the updated evidence for a potential therapeutic utility of these compounds. Moreover, new approaches to obtain more effective and safer PDE7 inhibitors than those available now are presented. PMID- 28093984 TI - Polymer Conjugated Gold Nanoparticles in Biomedical Applications. AB - BACKGROUND: Research interest on the properties of polymer conjugated gold nanoparticle (GNP) in biomedicine is rapidly rising because of the extensive evidences for their unique properties. In the field of biomedicine, GNPs have been widely used because of their inertness and low levels of cytotoxicity. Therefore, when exposed to cells, they are less prone to exert damaging effects. GNPs are capable of being functionalized as desired and are ideal as they do not encourage undesired side reactions that might counter react with the intention of the functionalization. Biofouling is an occurrence that takes place at cellular and biological molecular level, binds non-specifically on the detection surface and forms a wrong output. This undesired incidence can be avoided by conjugating the surface of biomolecules with polymers. Densely packed repeating chains of polymers such as polyethylene glycol are capable of decreasing non-specific reactions. Applications of polymer conjugated GNPs in the field of biomedicine are as biosensors, delivery and therapeutic agents. CONCLUSION: Therefore, the properties and applications of polymer conjugated GNPs are studied widely as overviewed here. PMID- 28093983 TI - An Approach Towards Structure Based Antimicrobial Peptide Design for Use in Development of Transgenic Plants: A Strategy for Plant Disease Management. AB - Antimicrobial peptides (AMPs), also known as host defense peptides (HDPs), are ubiquitous and vital components of innate defense response that present themselves as potential candidates for drug design, and aim to control plant and animal diseases. Though their application for plant disease management has long been studied with natural AMPs, cytotoxicity and stability related shortcomings for the development of transgenic plants limit their usage. Newer technologies like molecular modelling, NMR spectroscopy and combinatorial chemistry allow screening for potent candidates and provide new avenues for the generation of rationally designed synthetic AMPs with multiple biological functions. Such AMPs can be used for the control of plant diseases that lead to huge yield losses of agriculturally important crop plants, via generation of transgenic plants. Such approaches have gained significant attention in the past decade as a consequence of increasing antibiotic resistance amongst plant pathogens, and the shortcomings of existing strategies that include environmental contamination and human/animal health hazards amongst others. This review summarizes the recent trends and approaches used for employing AMPs, emphasizing on designed/modified ones, and their applications toward agriculture and food technology. PMID- 28093985 TI - Ketogenic Diet and Other Dietary Intervention Strategies in the Treatment of Cancer. AB - Pre-clinical and clinical studies have investigated the role of a dysregulated metabolism in the sustainability of tumor initiation and progression. One of the most familiar metabolic alterations encountered in several types of cancers is the upregulation of glycolysis, which is also maintained in conditions of normal oxygen tension (aerobic glycolysis, Warburg effect) while oxidative phosphorylation is apparently reduced. As a result, cancer cells convert most incoming glucose to lactate. Although more rapid, adenosine triphosphate (ATP) production by glycolysis is less efficient in terms of ATP generated per unit of glucose consumed than oxidative phosphorylation. The consequence is that tumor cells require an abnormally higher rate of glucose compared to the normal counterpart. New evidence shows that other metabolic substrates such as glutamine may also have an important role in cancer metabolism. Ketogenic diet (KD) replaces all but non-starchy vegetable carbohydrates with low to moderate amounts of proteins and high amounts of monounsaturated and polyunsaturated fats. The rationale of KD is valid both because it lowers carbohydrate uptake possibly leading to cancer cell starvation and apoptosis and, at the same time, increases the levels of ketone bodies available for energy production in normal cells but not in cancer cells which have an allegedly downregulated oxidative phosphorylation. For this reason, several authors speculate on the possibility to evaluate KD as a novel approach in the treatment of cancer. In this review we will assess the data supporting the use of such alimentary regimen and its impact on tumor development and progression. PMID- 28093986 TI - Antimicrobial Polymers: Mimicking Amino Acid Functionali ty, Sequence Control and Three-dimensional Structure of Host-defen se Peptides. AB - Peptides and proteins control and direct all aspects of cellular function and communication. Having been honed by nature for millions of years, they also typically display an unsurpassed specificity for their biological targets. This underlies the continued focus on peptides as promising drug candidates. However, the development of peptides into viable drugs is hampered by their lack of chemical and pharmacokinetic stability and the cost of large scale production. One method to overcome such hindrances is to develop polymer systems that are able to retain the important structural features of these biologically active peptides, while being cheaper and easier to produce and manipulate chemically. This review illustrates these principles using examples of polymers designed to mimic antimicrobial host-defence peptides. The host-defence peptides have been identified as some of the most important leads for the next generation of antibiotics as they typically exhibit broad spectrum antimicrobial ability, low toxicity toward human cells and little susceptibility to currently known mechanisms of bacterial resistance. Their movement from the bench to clinic is yet to be realised, however, due to the limitations of these peptides as drugs. The literature provides a number of examples of polymers that have been able to mimic these peptides through all levels of structure, starting from specific amino acid sidechains, through to more global features such as overall charge, molecular weight and threedimensional structure (e.g. alpha-helical). The resulting optimised polymers are able retain the activity profile of the peptides, but within a synthetic macromolecular construct that may be better suited to the development of a new generation of antimicrobial therapeutics. Such work has not only produced important new leads to combat the growing threat of antibiotic resistance, but may also open up new ways for polymers to mimic other important classes of biologically active peptides. PMID- 28093989 TI - Preface. PMID- 28093987 TI - The Prognostic Value of Heart Type Fatty Acid Binding Protein in Patients with Suspected Acute Coronary Syndrome: A Systematic Review. AB - BACKGROUND: Heart type fatty acid protein (HFABP) is a cytosolic protein released early after acute coronary syndrome (ACS) even in the absence of myocardial necrosis. OBJECTIVES: The purpose of this systematic review was to determine whether HFABP levels in patients with suspected, or confirmed ACS, improve risk stratification when added to established means of risk assessment. METHODS: We searched Medline, Pubmed and Embase databases from inception to July 2015 to identify prospective studies with suspected or confirmed ACS, who had HFABP measured during the index admission with at least 1 month follow up data. A prognostic event was defined as allcause mortality or acute myocardial infarction (AMI). RESULTS: 7 trials providing data on 6935 patients fulfilled inclusion criteria. There were considerable differences between studies and this was manifest in variation in prognostic impact of elevated HFABP(Odds ratio range 1.2 15.2 for death). All studies demonstrated that HFABP provide unadjusted prognostic information and in only one study this was negated after adjusting for covariates. A combination of both negative troponin and normal HFABP conferred a very low event rate. No study evaluated the incremental value of HFABP beyond that of standard risk scores. Only one study used a high sensitive troponin assay. CONCLUSION: There was marked heterogeneity in prognostic impact of HFABP in ACS between studies reflecting differences in sampling times and population risk. Prospective studies of suspected ACS with early sampling of HFABP in the era of high sensitivity troponin are necessary to determine the clinical value of HFABP. HFABP should not currently be used clinically as a prognostic marker in patients with suspected ACS. PMID- 28093988 TI - Adherence to Secondary Prophylaxis for Acute Rheumatic Fever and Rheumatic Heart Disease: A Systematic Review. AB - BACKGROUND: Optimal delivery of regular benzathine penicillin G (BPG) injections prescribed as secondary prophylaxis for acute rheumatic fever (ARF) and rheumatic heart disease (RHD) is vital to preventing disease morbidity and cardiac sequelae in affected pediatric and young adult populations. However, poor uptake of secondary prophylaxis remains a significant challenge to ARF/RHD control programs. OBJECTIVE: In order to facilitate better understanding of this challenge and thereby identify means to improve service delivery, this systematic literature review explored rates of adherence and factors associated with adherence to secondary prophylaxis for ARF and RHD worldwide. METHODS: MEDLINE was searched for relevant primary studies published in the English language from 1994-2014, and a search of reference lists of eligible articles was performed. The methodological quality of included studies was evaluated using a modified assessment tool. RESULTS: Twenty studies were included in the review. There was a range of adherence to varying regimens of secondary prophylaxis reported globally, and a number of patient demographic, clinical, socio-cultural and health care service delivery factors associated with adherence to secondary prophylaxis were identified. CONCLUSION: Insights into factors associated with lower and higher adherence to secondary prophylaxis may be utilized to facilitate improved delivery of secondary prophylaxis for ARF and RHD. Strategies may include ensuring an effective active recall system, providing holistic care, involving community health workers and delivering ARF/RHD health education. PMID- 28093990 TI - Insight to Pharmacokinetics of TKIs: Optimizing Practical Guidelines for Individualized Therapy. AB - OBJECTIVE: Tyrosine kinase inhibitors (TKIs) are widely used drugs which have high availability in reducing the activity of BCR-ABL1 tyrosine kinase, therefore they play an indispensable role in the treatment of Chronic myeloid leukemia (CML). Imatinib, dasatinib and nilotinib have been proved to have absolute bioavailability and stable blood concentration in humans. TKIs pharmacokinetics has close relationships with the clinical response and clinical treatment of CML. METHOD: We conducted a systematic PubMed search to look for studies relating to TKIs pharmacokinetics with proper inclusion/exclusion criteria. After looking through a large number of references, we investigated that different generations of TKIs could be influenced by many factors. We chose some typical factors which were closely linked to the common treatment of CML. These factors contain daily dose, diet, individual variability, drug-drug interaction, drugs resistance and drug withdrawal. RESULTS: By summarizing up these influence factors, we hope it can make a contribution to clinical therapy. Above all, the relationship between influence factors and the clinical therapeutic effect is the key point that our research pays attention to. CONCLUSION: This review highlights certain influence factors of TKIs clinical pharmacokinetics. PMID- 28093991 TI - Cancer Nanotechnology: Recent Trends and Developments in Strategies for Targeting Cancer Cells to Improve Cancer Imaging and Treatment. AB - OBJECTIVE: Nanotechnology is a multidisciplinary field, which have the potential to cover applications in many subjects such as biology, chemistry and physics. METHOD: The combined efforts of these subjects can lead to the successful engineering of nanodevices and nanovectors for targeted delivery and sensing/detection of cancer cells/tissues. The modulation of nanomaterials at surface and bulk level further adds value to this technology and develop strategies for early detection of precancerous and malignant cells from biological fluids. Furthermore, the novel nanotechnology-based imaging modalities have the prospects to offer non-invasive cancer imaging and treatment response study in real-time. RESULT: This review covers the advantages of nanotechnology, which have been exploited for effective and targeted delivery of anti-cancer agents. CONCLUSION: Moreover, the initiatives taken by National Cancer Laboratory, USA to improve the clinical success of nanomedicines and nanovectors have also been comprehensively summarized. PMID- 28093992 TI - Effects of Thyroid Hormones and their Metabolites on Learning and Memory in Normal and Pathological Conditions. AB - BACKGROUND: Classical thyroid hormones have an established necessary role in the normal development of the central nervous system, and they have been recently considered as decisive factors influencing cognitive functions in the adult brain and involved in the development of Alzheimer's disease. The picture summarizing thyroid hormone effects on the adult brain, however, does not only include classical thyroid hormones but also the products of their peripheral metabolism. These latter have been considered as inactive breakdown products for long but recently were proved to produce significant biological effects. OBJECTIVE: In this review article we presented recent evidence supporting the hypothesis that thyroid hormones exert a neuroprotective effect in the brain areas involved in learning and memory. Moreover, we summarized the evidence that suggests that non classical thyroid hormones produce significant neurological effects in the adult brain. We also discussed the possible role of thyroid hormones in the cognitive impairment, typical of Alzheimer's disease. METHODS: A comprehensive review of the literature based on the current knowledge of the effects of classical and nonclassical thyroid hormones on the adult brain and their role in Alzheimer's disease was performed. RESULTS: The available literature suggests that both classical and non-classical thyroid hormones act as neuroprotective agents in the brain areas related to learning and memory. Their role in these areas supports the idea that they may be involved in the development of Alzheimer's disease. CONCLUSION: Thyroid hormones produce significant neurological effects, act as neuroprotective agents and might be considered as future diagnostic and therapeutic tools for Alzheimer's disease. PMID- 28093993 TI - Methods of Screening-Purification and Antimicrobial Potentialities of Bacteriocin in Health Care. AB - BACKGROUND: Bacteriocin have been tested as safe and effective alternative molecules over the currently used chemotherapeutic agents. Thus, being an important clinical significance, its screening and recovery methods along with its application are poorly described. Therefore, their screening, purification strategies and utilities must me extended. Thus, in this review, we, summarize potential application, various screening and purification methods used for recovery of bacteriocins. METHODS: To complete this review, many reviews and previously published reports were studied. We, concentrated on review question and exclusion and inclusion criteria. The quality of content was evaluated by the quality the quality contents evaluation method. The standard method is used to describe the useful contents of available resources and appraised. RESULTS: One hundred twenty research and review reports were used to complete this report. Sixty reports were used to make a collective information on screening and production of Bacteriocin Eighty two papers were used to explore the antimicrobial, therapeutic, diagnostic etc potentialities of bacteriocin in diverse field. The summarize form of data also presented in the form of tables and figures. This review describes the various methods and parameters that must be considered during the screening and purification methods. Moreover, the useful information is collected in regard represent it therapeutic potentialities in various fields for the welfare of human being. CONCLUSIONS: The conclusion of this review presented the significance of a fundamental framework for planning to understanding the basic requirement needed for fast, cost effective screening and purification of bacteriocins. The summered area of their utilities also helpful to extend the research field of bacteriocin. Thus, this report would be useful not only to scale up the screening and production strategies faster at economical rate, but also provides a platform to extend the research field of bacteriocin in many ways. PMID- 28093994 TI - Viral Infection and Obesity: Current Status and Future Prospective. AB - BACKGROUND: The association of pathogenic viruses with obesity has now been well known in both human and animals. Globally, human obesity has become a serious problem leading to the emergence of multiple lifethreatening diseases. Adenoviruses contribute a significant role in the induction of obesity by affecting various pathways. Due to impaired immunity, obese individuals are more prone to nosocomial infections leading to complications of obesity. In contrast, several other important factors contributing to human obesity are known. METHODS: Currently, many published reports showed strong evidence of the role and linkage of Ad36 infection in human obesity. The Ad36 pathogenesis effect on the hepatic steatosis reduces leptin gene expression, reduced antibody response in vaccination, reduces immune system, insulin sensitivity, increases glucose uptake, activates the lipogenic and pro-inflammatory pathways in adipose tissue increases the level of Macrophage Chemo attractant Protein-1 leading chronic inflammation and affect lipid metabolism. RESULTS: The E4-ORF1 gene of Ad36 play an important role in the induction of adipogenesis and regulation of adipocyte differentiation and also known to activate the sensitizing effect of insulin. The use of E4-ORF1gene as a ligand to develop new drugs against diabetes and the prevention of Ad36 infection by an effective vaccination will attract researchers and open new area of research in the field of obesity and obesity-related multiple diseases. CONCLUSION: Therefore, the identification and management of important contributory factors by identifying the regulation of adipocyte differentiation leading to a chronic condition like adipogenesis and insulin resistance resulting in obesity is an urgent requirement globally for human health. PMID- 28093995 TI - Glycosides as Possible Lead Antimalarial in New Drug Discovery: Future Perspectives. AB - Malaria remains one of the major public health problems worldwide and it is responsible for a large number of morbidity and mortality. Especially, in the third world countries, it is still alarming. The development of drugresistant to Plasmodium falciparum strains has further degraded the overall situation. However, a limited number of effective drugs available emphasize how essential it is to establish new anti-malarial compounds. New antimalarial agents with distinctive structures and mechanism of action from the natural origin are thus immediately required to treat sensitive and drug-resistant strains of malaria. Over the years, phytopharmaceuticals have provided numerous lead compounds. Similarly, the success rate of botanicals in terms of clinical significance is also very high. Of them, glycoside is one of the most widely distributed and emerging class of plant secondary metabolites. This review provides an outlook to recently isolated glycosides from plants with marked antimalarial effects in an in-vitro and in-vivo protocols and thus ideal candidates for clinical trials to ascertain their clinical utility and or led compounds. PMID- 28093996 TI - Challenges Related to Glycemic Control in Type 2 Diabetes Mellitus Patients. AB - Diabetes mellitus (DM) is a chronic disease with long-term complications. Glycemic control is an important part in management of DM. The first line in treatment of type 2 DM (T2DM) is diet and life style change. Metformin is the first choice of medication in T2DM patients. Sulfonylureas have high risk of hypoglycemia. Glinides are associated with lower risk of hypoglycemia in comparison to sulfonylureas. Also, alpha-glucosidase inhibitors decrease the polysaccharides' digestion in small intestine and are less effective in comparison to metformin and sulfonylureas in lowering hemoglobin A1c (HbA1c). These have no risk for hypoglycemia, but gastrointestinal symptoms are common. Thiazolidinediones are known as insulin sensitizers and are effective for a longer duration in comparison to sulfonylureas, however, have side effects such as fluid retention, edema and heart failure. Incretin mimetics including exenatide and liraglutide act through increase in insulin secretion by pancreatic beta cells, in a glucose-dependent manner. Therefore, these are associated with no risk of hypoglycemia. Pramlintide is an amylin agonist which is also effective in lowering postprandial blood glucose. Sitagliptin and vildagliptin are dipeptidyl peptidase-4 inhibitors and have no risk of hypoglycemia when used as monotherapy. Canagliflozin and dapagliflozin decrease blood glucose level by increasing urinary glucose excretion and are associated with weight loss. PMID- 28093997 TI - Sonication-Assisted Nanoprecipitation in Drug Delivery. AB - Sonication-assisted nanoprecipitation provides an effective tool for nanomedicine engineering in therapeutic improvement. In the scope of this review, original works in interdisciplinary areas of using sonication with precipitation method for nanoparticulate drug delivery systems and its applications in management of different diseases are discussed. The use of sonication-assisted nanoprecipitation has been proved to improve drug bioavailability, which attracts tremendous interests as an effective strategy for drug delivery. However, many challenges still remain. To overcome these barriers, different approaches such as precipitation method, rational design, optimization and modification have been investigated. Accordingly, current knowledge of sonication-assisted nanoprecipitation proposes a broad perspective and optimization for the applications of nanotechnology in drug delivery. PMID- 28093998 TI - Potential of Plant Alkaloids as Antipyretic Drugs of Future. AB - Fever or Pyrexia means abnormal rise in body temperature above the usual range of normal in response to a variety of infectious, immunological and neoplastic stimuli. To normalize these febrile conditions, several synthetic agents are in clinical practice such as acetaminophen, ibuprofen, and aspirin. However, they are having many side effects which sometimes challenge their applications. The various sources are under investigation worldwide to overcome issues of unwanted effects and to better therapeutic response. In this scenario botanicals such as alkaloids, the most widely distributed and studied plant secondary metabolites, could effectively produce the molecules with better antipyretic effect and safety profile. The current review deals with 21 isolated alkaloids from 14 plants species having some antipyretic effect in preliminary screening/preclinical studies with the possible mechanism and structural edges. Therefore, these alkaloids of plant origin are candidates for further detail studies to ascertain their mechanism(s) and clinical utility or as lead compounds for future drugs. PMID- 28093999 TI - Health-related quality of life with hereditary angioedema following prophylaxis with subcutaneous C1-inhibitor with recombinant hyaluronidase. AB - BACKGROUND: To estimate health-related quality-of-life changes in patients with hereditary angioedema due to C1-inhibitor (C1-INH) deficiency who received subcutaneous C1-INH with recombinant hyaluronidase (rHuPH20) for attack prophylaxis in a randomized, double-blind, dose-ranging, cross-over study. METHODS: Patients with type I/II hereditary angioedema received 1000 U of C1-INH with 24,000 U of rHuPH20 or 2000 U of C1-INH with 48,000 U of rHuPH20 every 3-4 days for 8 weeks and then crossed over for another 8-week period. The study was terminated early as a precaution related to non-neutralizing antibodies to rHuPH20. The Angioedema Quality of Life questionnaire (AE-QoL) was administered at weeks 1 and 5 of both periods, and at 1 week after the second treatment period. Changes in AE-QoL scores were calculated over both treatment periods and within each treatment period for patients with >=4 weeks of treatment. RESULTS: Forty-one patients had evaluable AE-QoL data, and 22 patients completed treatment. At screening, 43% of the patients were receiving intravenous C1-INH. A significant average AE-QoL total score decline (improvement) of -8.1 (95% confidence interval, -13.7 to -2.5) was observed from baseline to the end of the study, and significant AE-QoL score declines were observed in the Functioning, Fear/Shame, and Nutrition domains. Patients on 2000 U reported higher mean AE-QoL score declines in Functioning and Nutrition domains relative to the 1000 U dose. Overall, 43.9% of all the patients, 45.5% of the study completers, and 46.7% of the nonprophylaxis users at baseline on high treatment doses achieved a reduction in the AE-QoL total score of six points. CONCLUSION: Despite early termination and prestudy prophylactic intravenous C1-INH use by 43% of the patients, improved AE-QoL scores were observed after <=16 weeks of subcutaneous C1-INH-rHuPH20 prophylaxis. PMID- 28094000 TI - Molecular Tracing of the Origin of Six Different Plant Species in Bee Honey Using Real-Time PCR. AB - The quality of honey is significantly influenced by floral origin. Mislabeling floral species occurs frequently in bee honey products. To protect consumers from economic fraud and maintain a fair market environment, methods to identify floral species in honey are necessary. In our study, real-time PCRs were established, targeting six honey types mainly produced in China (canola, Chinese milkvetch, Chinese chaste tree, locust tree, litchi, and longan). Sensitivity testing on DNA from plant tissues exhibited LODs of about 0.5-5 pg/MUL. For DNA extracts of pollen sediments from different honey species, LODs ranged from 13.6 to 403.2 pg/MUL. In an experiment to determine the practical LODs of honey in which adulterant honey was spiked in the genuine honey, adulterant honey as low as about 0.1-0.5% was detected in 90-100% in 10 parallel tests. Additionally, pollen was spiked in the honey and stored under various conditions to investigate the migration of pollen DNA into the honey supernatant. Finally, the efficiency of our method was investigated by testing honey samples of unknown compositions from different geographic regions. Of the 159 honey samples that were supposed to be monofloral that had been collected in five provinces, a small portion were found to be contaminated with foreign pollen (7%). The methods proved to be specific, sensitive, and reliable in identifying the six plant species in honey, which would be a useful tool during the market supervision and QC of honey products. PMID- 28094001 TI - Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors. AB - Kinase inhibitors are effective cancer therapies, but tumors frequently develop resistance. Current strategies to circumvent resistance target the same or parallel pathways. We report here that targeting a completely different process, autophagy, can overcome multiple BRAF inhibitor resistance mechanisms in brain tumors. BRAFV600Emutations occur in many pediatric brain tumors. We previously reported that these tumors are autophagy-dependent and a patient was successfully treated with the autophagy inhibitor chloroquine after failure of the BRAFV600E inhibitor vemurafenib, suggesting autophagy inhibition overcame the kinase inhibitor resistance. We tested this hypothesis in vemurafenib-resistant brain tumors. Genetic and pharmacological autophagy inhibition overcame molecularly distinct resistance mechanisms, inhibited tumor cell growth, and increased cell death. Patients with resistance had favorable clinical responses when chloroquine was added to vemurafenib. This provides a fundamentally different strategy to circumvent multiple mechanisms of kinase inhibitor resistance that could be rapidly tested in clinical trials in patients with BRAFV600E brain tumors. PMID- 28094003 TI - Recombinant thrombomodulin suppresses tumor growth of pancreatic cancer by blocking thrombin-induced PAR1 and NF-kappaB activation. AB - BACKGROUND: Thrombomodulin, an anticoagulant that inhibits thrombin-induced growth factor promotion, also has an anti-inflammatory effect. Furthermore, thrombomodulin inhibits nuclear factor-kappa B activation, which plays a crucial role in cancer progression. We assessed the antitumor activity of recombinant thrombomodulin for pancreatic cancer. METHODS: A xenograft orthotopic model was established in mice by implantation of human pancreatic cancer cells. The animals were treated with intraperitoneal injection of recombinant thrombomodulin 5 times a week for 4 weeks. Nuclear factor-kappa B activation was evaluated by measuring nuclear localization of the p65. Efficacy of recombinant thrombomodulin on the signal transduction of nuclear factor-kappa B was measured in vitro under preconditioning with thrombin or epidermal growth factor. RESULTS: Tumor growth was suppressed by recombinant thrombomodulin (P < .05). Recombinant thrombomodulin inhibited the expression of IkappaB kinase beta (P < .05) and pIkappaBalpha (P < .01), as well as the activation of nuclear factor-kappa B NF kappaB (P < .001). Furthermore, recombinant thrombomodulin inhibited thrombin induced protease activate receptor 1 and nuclear factor-kappa B activation in vitro (P < .05). The number of Ki67-positive cells was decreased by recombinant thrombomodulin (P < .01). Recombinant thrombomodulin also suppressed body weight loss associated with pancreatic cancer (P < .05). No obvious adverse effects were observed. CONCLUSION: Recombinant thrombomodulin significantly suppressed tumor growth against human pancreatic cancer by blocking thrombin-induced nuclear factor-kappa B activation without adverse effects. PMID- 28094002 TI - The RFamide receptor DMSR-1 regulates stress-induced sleep in C. elegans. AB - In response to environments that cause cellular stress, animals engage in sleep behavior that facilitates recovery from the stress. In Caenorhabditis elegans, stress-induced sleep(SIS) is regulated by cytokine activation of the ALA neuron, which releases FLP-13 neuropeptides characterized by an amidated arginine phenylalanine (RFamide) C-terminus motif. By performing an unbiased genetic screen for mutants that impair the somnogenic effects of FLP-13 neuropeptides, we identified the gene dmsr-1, which encodes a G-protein coupled receptor similar to an insect RFamide receptor. DMSR-1 is activated by FLP-13 peptides in cell culture, is required for SIS in vivo, is expressed non-synaptically in several wake-promoting neurons, and likely couples to a Gi/o heterotrimeric G-protein. Our data expand our understanding of how a single neuroendocrine cell coordinates an organism-wide behavioral response, and suggest that similar signaling principles may function in other organisms to regulate sleep during sickness. PMID- 28094004 TI - The vertebrae and ribs of Homo naledi. AB - Hominin evolution featured shifts from a trunk shape suitable for climbing and housing a large gut to a trunk adapted to bipedalism and higher quality diets. Our knowledge regarding the tempo, mode, and context in which these derived traits evolved has been limited, based largely on a small-bodied Australopithecus partial skeleton (A.L. 288-1; "Lucy") and a juvenile Homo erectus skeleton (KNM WT 15000; "Turkana Boy"). Two recent discoveries, of a large-bodied Australopithecus afarensis (KSD-VP-1/1) and two Australopithecus sediba partial skeletons (MH1 and MH2), have added to our understanding of thorax evolution; however, little is known about thorax morphology in early Homo. Here we describe hominin vertebrae, ribs, and sternal remains from the Dinaledi chamber of the Rising Star cave system attributed to Homo naledi. Although the remains are highly fragmented, the best-preserved specimens-two lower thoracic vertebrae and a lower rib-were found in association and belong to a small-bodied individual. A second lower rib may belong to this individual as well. All four of these individual elements are amongst the smallest known in the hominin fossil record. H. naledi is characterized by robust, relatively uncurved lower ribs and a relatively large spinal canal. We expect that the recovery of additional material from Rising Star Cave will clarify the nature of these traits and shed light on H. naledi functional morphology and phylogeny. PMID- 28094005 TI - Imprinted genes and the regulation of placental endocrine function: Pregnancy and beyond. AB - Genomic imprinting is an epigenetic process responsible for the monoallelic expression of a subset of genes in mammals. Imprinted genes have been demonstrated to play important functions prenatally regulating fetal growth and placental development with some functions persisting beyond pregnancy to influence both metabolism and behaviour in adults. This review focuses on the function of imprinted genes in regulating placental hormones, and the probability that these functions manifest their impact beyond pregnancy. PMID- 28094007 TI - Obtaining the biomechanical behavior of ascending aortic aneurysm via the use of novel speckle tracking echocardiography. AB - INTRODUCTION: Ex vivo measurement of ascending aortic biomechanical properties may help understand the risk for rupture or dissection of dilated ascending aortas. A validated in vivo method that can predict aortic biomechanics does not exist. Speckle tracking transesophageal echocardiography (TEE) has been used to measure ventricular stiffness; we sought to determine whether speckle TEE could be adapted to estimate aortic stiffness in vivo and compare these findings with those obtained by ex vivo tissue measurements. METHODS: A total of 17 patients undergoing ascending aortic resection were recruited to with a mean aortic diameter was 56.16 +/- 15 mm. Intraoperative speckle TEE tracking analysis was used to calculate aortic stiffness index using the following equation: beta2=ln(SBP/DBP)/AoS, where beta2 is the stiffness index; SBP is systolic blood pressure; DBP is diastolic blood pressure; and AoS is the circumferential strain. Ex vivo stiffness was obtained by mechanical tissue testing according to previously described methods. The aortic ring at the pulmonary trunk was divided into 4 equal quadrants. RESULTS: The in vivo stiffness index for the inner curvature, anterior wall, outer curvature, and posterior wall were 0.0544 +/- 0.0490, 0.0295 +/- 0.0199, 0.0411 +/- 0.0328, and 0.0502 +/- 0.0320, respectively. The mean ex vivo 25% apparent stiffness for inner curvature, anterior wall, outer curvature, and posterior wall were 0.0616 +/- 0.0758 MPa, 0.0352 +/- 0.00992 MPa, 0.0405 +/- 0.0199 MPa, and 0.0327 +/- 0.0106 MPa, respectively. The patient-matched ex vivo 25% apparent stiffness and in vivo stiffness index were not significantly different (P = .8617, 2-way analysis of variance with repeated measures). CONCLUSIONS: The use of speckle TEE appears to be a promising technique to estimate ex vivo mechanical properties of the ascending aortic tissue. PMID- 28094006 TI - Salt, aldosterone and extrarenal Na+ - sensitive responses in pregnancy. AB - Outside of pregnancy excessive salt consumption is known to be harmful being linked to increased blood pressure and cardiovascular disease. However, pregnancy represents a major change to a woman's physiology resulting in an intimate adaptation to environmental conditions. It is now becoming apparent that salt is essential for a number of these changes during pregnancy including haematological, cardiac adaptations as well as directly influencing placental development and the uteroplacental immune environment. The present review discusses the important role that salt has during normal pregnancy and evidence will also be presented to show how the placenta may act as a salt sensing organ temporarily, yet substantially regulating maternal blood pressure. PMID- 28094008 TI - Discussion. PMID- 28094009 TI - q-space Myelin Map imaging: A new imaging technique for treatment evaluation in multiple sclerosis. PMID- 28094010 TI - El Greco depicted his own neurological disabilities. PMID- 28094012 TI - Mammalian Mitochondria and Aging: An Update. AB - Mitochondria were first postulated to contribute to aging more than 40 years ago. During the following decades, multiple lines of evidence in model organisms and humans showed that impaired mitochondrial function can contribute to age associated disease phenotypes and aging. However, in contrast to the original theory favoring oxidative damage as a cause for mtDNA mutations, there are now strong data arguing that most mammalian mtDNA mutations originate as replication errors made by the mtDNA polymerase. Currently, a substantial amount of mitochondrial research is focused on finding ways to either remove or counteract the effects of mtDNA mutations with the hope of extending the human health- and lifespan. This review summarizes the current knowledge regarding the formation of mtDNA mutations and their impact on mitochondrial function. We also critically discuss proposed pathways interlinked with mammalian mtDNA mutations and suggest future research strategies to elucidate the role of mtDNA mutations in aging. PMID- 28094011 TI - Metabolomics and Metabolic Diseases: Where Do We Stand? AB - Metabolomics, or the comprehensive profiling of small molecule metabolites in cells, tissues, or whole organisms, has undergone a rapid technological evolution in the past two decades. These advances have led to the application of metabolomics to defining predictive biomarkers for incident cardiometabolic diseases and, increasingly, as a blueprint for understanding those diseases' pathophysiologic mechanisms. Progress in this area and challenges for the future are reviewed here. PMID- 28094013 TI - Pulmonary outcome of esophageal atresia patients and its potential causes in early childhood. AB - INTRODUCTION: The aim of this study was to illustrate the pulmonary long term outcome of patients with repaired esophageal atresia and to further examine causes and correlations that might have led to this outcome. METHODS: Twenty seven of 62 possible patients (43%) aged 5-20years, with repaired esophageal atresia were recruited. Body plethysmography and spirometry were performed to evaluate lung function, and the Bruce protocol treadmill exercise test to assess physical fitness. Results were correlated to conditions such as interpouch distance, gastroesophageal reflux or duration of post-operative mechanical ventilation. RESULTS: Seventeen participants (63%) showed abnormal lung function at rest or after exercise. Restrictive ventilatory defects (solely restrictive or combined) were found in 11 participants (41%), and obstructive ventilatory defects (solely obstructive or combined) in 13 subjects (48%). Twenty-two participants (81%) performed the Bruce protocol treadmill exercise test to standard. The treadmill exercise results were expressed in z-score and revealed to be significantly below the standard population mean (z-score=-1.40). Moreover, significant correlations between restrictive ventilatory defects and the interpouch distance; duration of post-operative ventilation; gastroesophageal reflux disease; plus recurrent aspiration pneumonia during infancy; were described. CONCLUSION: It was shown that esophageal atresia and associated early complications have significant impact on pulmonary long term outcomes such as abnormal lung function and, in particular restrictive ventilatory defects. Long running and regular follow-ups of patients with congenital esophageal atresia are necessary in order to detect and react to the development and progression of associated complications such as ventilation disorders or gastroesophageal reflux disease. LEVEL OF EVIDENCE: Prognosis study, Level II. PMID- 28094014 TI - A new methodology for assessment of pectus excavatum correction after bar removal in Nuss procedure: Preliminary study. AB - PURPOSE: The objective is to present a new methodology to assess quantitatively the impact of bar removal on the anterior chest wall, among patients with pectus excavatum who have undergone the Nuss procedure, and present a preliminary study using this methodology. METHODS: We propose to acquire, for each patient, the surface of the anterior chest wall using a three-dimensional laser scanner at subsequent time points (short term: before and after surgery; long term: follow up visit, 6months, and 12months after surgery). After surfaces postprocessing, the changes are assessed by overlapping and measuring the distances between surfaces. In this preliminary study, three time points were acquired and two assessments were performed: before vs after bar removal (early) and before vs 2 8weeks after bar removal (interim). In 21 patients, the signed distances and volumes between surfaces were computed and the data analysis was performed. RESULTS: This methodology revealed useful for monitoring changes in the anterior chest wall. On average, the mean, maximum, and volume variations, in the early assessment, were -0.1+/-0.1cm, -0.6+/-0.2cm, and 47.8+/-22.2cm3, respectively; and, in the interim assessment, were -0.5+/-0.2cm, -1.3+/-0.4cm, and 122.1+/ 47.3cm3, respectively (p<0.05). Data analysis revealed that the time the bar was in situ was inversely and significantly correlated with postretraction and was a relevant predictor of its decrease following surgery (p<0.05). Additionally, gender and age suggested influencing the outcome. CONCLUSIONS: This methodology is novel, objective and safe, helping on follow-up of pectus excavatum patients. Moreover, the preliminary study suggests that the time the bar was in situ may be the main determinant of the anterior chest wall retraction following bar removal. Further studies should continue to corroborate and reinforce the preliminary findings, by increasing the sample size and performing long-term assessments. LEVELS OF EVIDENCE: III. PMID- 28094015 TI - A Nordic multicenter survey of long-term bowel function after transanal endorectal pull-through in 200 patients with rectosigmoid Hirschsprung disease. AB - OBJECTIVE: Transanal endorectal pull-through (ERPT) is the most popular technique to treat Hirschsprung disease (HD). Still, there is limited knowledge on long term bowel function. This cross-sectional, multicenter study assessed long-term bowel function in a large HD population and examined predictors of poor outcome. METHODS: Patients older than four years or their parents filled out a validated questionnaire on bowel function. Clinical details were recorded retrospectively from medical records. RESULTS: 73/200 (37%) patients reported absolutely no impaired bowel function, meaning no constipation, fecal accidents, stoma, appendicostomy or need for enemas. Seven (4%) had a stoma, and 33 (17%) used antegrade or rectal colonic enemas. Most disarrangements of fecal control and constipation were significantly less common in older age group, but abnormal defecation frequency and social problems remained unchanged. Syndromic patients (n=31) experienced frequent fecal accidents (46%) more often than nonsyndromic (14%, P<0.001). Having a syndrome (adjusted OR 5.6, 95% CI 2.1-15, P=0.001) or a complete transanal ERPT (adjusted OR 2.4, 95% CI 1.1-5.7, P=0.038) was significantly associated with poor outcome defined as having a stoma, an appendicostomy, daily fecal accidents or need of regular rectal wash outs. CONCLUSION: A significant number of HD patients experience bowel problems many years after definite surgery. Fecal control was significantly better in older than younger HD patients, but some continued to have considerable bowel problems also as adults. A total transanal ERPT was associated with poorer outcome. Long term follow-up of HD patients is warranted. Prognosis Study: Level II. PMID- 28094018 TI - Single-Cell Analysis Reveals a Close Relationship between Differentiating Dopamine and Subthalamic Nucleus Neuronal Lineages. AB - Stem cell engineering and grafting of mesencephalic dopamine (mesDA) neurons is a promising strategy for brain repair in Parkinson's disease (PD). Refinement of differentiation protocols to optimize this approach will require deeper understanding of mesDA neuron development. Here, we studied this process using transcriptome-wide single-cell RNA sequencing of mouse neural progenitors expressing the mesDA neuron determinant Lmx1a. This approach resolved the differentiation of mesDA and neighboring neuronal lineages and revealed a remarkably close relationship between developing mesDA and subthalamic nucleus (STN) neurons, while also highlighting a distinct transcription factor set that can distinguish between them. While previous hESC mesDA differentiation protocols have relied on markers that are shared between the two lineages, we found that application of these highlighted markers can help to refine current stem cell engineering protocols, increasing the proportion of appropriately patterned mesDA progenitors. Our results, therefore, have important implications for cell replacement therapy in PD. PMID- 28094016 TI - A Single-Cell Roadmap of Lineage Bifurcation in Human ESC Models of Embryonic Brain Development. AB - During human brain development, multiple signaling pathways generate diverse cell types with varied regional identities. Here, we integrate single-cell RNA sequencing and clonal analyses to reveal lineage trees and molecular signals underlying early forebrain and mid/hindbrain cell differentiation from human embryonic stem cells (hESCs). Clustering single-cell transcriptomic data identified 41 distinct populations of progenitor, neuronal, and non-neural cells across our differentiation time course. Comparisons with primary mouse and human gene expression data demonstrated rostral and caudal progenitor and neuronal identities from early brain development. Bayesian analyses inferred a unified cell-type lineage tree that bifurcates between cortical and mid/hindbrain cell types. Two methods of clonal analyses confirmed these findings and further revealed the importance of Wnt/beta-catenin signaling in controlling this lineage decision. Together, these findings provide a rich transcriptome-based lineage map for studying human brain development and modeling developmental disorders. PMID- 28094017 TI - Predictive Markers Guide Differentiation to Improve Graft Outcome in Clinical Translation of hESC-Based Therapy for Parkinson's Disease. AB - Stem cell treatments for neurodegenerative diseases are expected to reach clinical trials soon. Most of the approaches currently under development involve transplantation of immature progenitors that subsequently undergo phenotypic and functional maturation in vivo, and predicting the long-term graft outcome already at the progenitor stage remains a challenge. Here, we took an unbiased approach to identify predictive markers expressed in dopamine neuron progenitors that correlate with graft outcome in an animal model of Parkinson's disease through gene expression analysis of >30 batches of grafted human embryonic stem cell (hESC)-derived progenitors. We found that many of the commonly used markers did not accurately predict in vivo subtype-specific maturation. Instead, we identified a specific set of markers associated with the caudal midbrain that correlate with high dopaminergic yield after transplantation in vivo. Using these markers, we developed a good manufacturing practice (GMP) differentiation protocol for highly efficient and reproducible production of transplantable dopamine progenitors from hESCs. PMID- 28094019 TI - The first model of keeping energy balance and optimal psycho affective development: Breastfed infants. AB - BACKGROUND: Breastfed infants follow a peculiar growth fashion characterized by a rapid weight gain in the first weeks of life, then followed by a fast decrease in growth rates, a capacity to self-regulate the sense of hungry and satiety, and a minor propensity towards overweight and obesity later on, in parallel with a better neurodevelopmental performance. METHODS: We searched studies investigating the relationship between the feeding mode in infancy and the energy balance, so the possible associations with total energy expenditure and intake regulation. We focused the research on the interaction with the neuropsychological development and the possible role of microbiome in determinating the normal generation and regular functioning of the brain through the so named "gut-brain axis". RESULTS: Total energy expenditure (TEE) is different for breast-fed and formula-fed infants, in particular the feeding mode seems to affect the sleep organisation. Long-term breastfeeding, is one of the most studied factors of neurodevelopment, several studies reporting beneficial effects on child neuropsychological development. Probably this effect is modulated by genetic variations in fatty acid metabolism. Increasing data also showed that the intestinal microbiome exerts several functions which are able to influence neurodevelopment. LIMITATIONS: There is considerable controversy over whether nutrition in early life has a long-term influence on neurodevelopment. Other studies are needed to confirm the association between breastfeeding and brain development. CONCLUSIONS: The key points of energy disposal, the role and effects of the instestinal flora represent promising fields of investigation possibly leading to indications for the wide area of preventive medicine. PMID- 28094020 TI - The Wertheim hysterectomy: Development, modifications, and impact in the present day. AB - Ernst Wertheim was a pioneer in the history of the surgical treatment of cervical cancer. His English-language manuscript "The extended abdominal operation for carcinoma uteri (based on 500 operative cases)," which was published in 1912, detailed his standardization of the radical hysterectomy and formed the basis of the current treatment for early stage cervical cancer. We contextualize the Wertheim hysterectomy, emphasizing medical advances that allowed for its development and subsequent modification. We then discuss modifications to the originally proposed procedure, including a maximally extended parametrical resection pioneered by Takayama, and the addition of the Taussig en bloc lymph node dissection by Meigs, both of which afforded an improved mortality profile due to decreased disease recurrence. Finally, we discuss progress that has been made in the present day, such as the development of nerve-sparing and fertility sparing surgeries, as well as the introduction of the robotic platform. In this way, we hope to provide a historical background for the Wertheim hysterectomy-a cornerstone of gynecologic oncology. PMID- 28094021 TI - Neuropsychological characteristics of encephalopathy in Susac's Syndrome - Case report. AB - Susac's Syndrome (SS) is a rare, autoimmune angiopathy characterized by hearing loss, retinal artery occlusions and encephalopathy, which is usually expressed in multifocal neurological signs and symptoms, confusion state and cognitive impairment. There have been few descriptions of neuropsychological assessment of SS. We present a case study of 29-year-old woman who developed full SS. During the post-acute stage of disease, she was admitted to neurorehabilitation ward to improve her cognitive-behavioral and motor functioning. The initial assessment revealed attention, memory and executive dysfunctions, as well as behavioral changes including impulsivity, affective dysregulation and reduced self-awareness of disease deficits. After five weeks recovery process supported by rehabilitation program, improvement was observed, although some cognitive behavioral deficits were still present in the follow-up assessment. PMID- 28094022 TI - A case report of an adolescent with cluster headaches following neck trauma: Coincidence or trigger? AB - Posttraumatic headaches usually have tension-type or migraine-like characteristics. A correlation between head trauma and cluster headaches (CH) has been previously reported. CH in children are rare and require thorough differential diagnosis. We present an original case of a 15-year-old boy with cluster headaches associated with allodynia probably evoked by a neck trauma. Severe headache attacks started one month after neck trauma. At the beginning clinical presentation of our patient's headaches was very misleading. Headaches were bilateral and associated with infection. Initial diagnosis of sinusitis was made. During further observation headaches have become unilateral with typical for CH associated symptoms and additionally with allodynia. Other causes of secondary CH like cervicogenic headaches, brain tumor and vascular malformation have been excluded. The boy has undergone prophylactic treatment based on flunarizine and gabapentin with good result. Possible pathogenesis of our patient's headaches has been proposed and diagnostic traps discussed. PMID- 28094023 TI - Monodisperse silica-filled composite restoratives mechanical and light transmission properties. AB - OBJECTIVES: The aim of this study was to formulate resin-based composites using spherical silica particulate fillers with graded size (75, 150, 350, 500, and 1000nm), and to evaluate the influence of their size and loading on the mechanical and light transmission properties of the resulting material. METHODS: A series of five spherical silica fillers were synthesized, and then formulated with BisGMA/TEGDMA or UDMA/TEGDMA resins. These were then tested for maximum filler loading, flexural strength and modulus, as well as transparency and depth of cure. RESULTS: Low dispersity spherical silica particles of 75, 150, 350, 500, and 1000nm were synthesized. Maximum loading was 70wt% for the three largest particle, and decreased for the smaller sizes, where UDMA-based resins allowed slightly higher loading. When maximally loaded, the largest particle sizes produced the highest flexural properties. However, when using the same loading, all filler sized produced similar flexural strengths and moduli. The optical properties and depth of cure were increased as the filler size decreased. SIGNIFICANCE: While hybrid filler particles are the norm in commercial materials, by studying and understanding the influence of individual components on the material properties, we can finely tune the properties of the materials as desired. PMID- 28094024 TI - Effect of nanoclay addition on physical, chemical, optical and biological properties of experimental dental resin composites. AB - OBJECTIVE: To prepare organically modified montmorillonite (OM MMT) and assess mechanical, physical, chemical and biological effects of its introduction into resin-composites. METHODS: Natural MMT clay was modified by a methacrylate functionalized quaternary ammonium intercalating agent. Interlayer distance was measured by X-ray diffraction. Dental composites were then prepared with x=0, 1, 2.5, 5 or 7.5wt.% of OM MMT, (75-x) wt.% of silanated barium glass and 25wt.% of methacrylate based matrix). Relative weight loss was measured and the effect of the substitution on mechanical properties was studied by dynamic mechanical analysis and hardness tests. Properties of resin composites were evaluated in terms of water sorption, light transmittance, biological tests and by high performance liquid chromatography (HPLC). RESULTS: Resin based composites with well-dispersed organically modified MMT were successfully prepared. There were no significant weight loss differences shown by TGA within all samples. The DMA analysis showed that the introduction of clays have a beneficial effect in increasing the storage and elastic modulus of composites. Clay presence was shown to interfere with the blue light transmittance, affecting Vickers hardness and water sorption levels. The amount of released monomers measured from extracts was below expected levels for this type of materials and biological tests show satisfactory cell compatibility. SIGNIFICANCE: This paper reports the successful functionalization of MMT by a methacrylate group and further incorporation in experimental dental composites. Physical and biological results show a potential interest to the application of nanoclays into dental resin composites. PMID- 28094025 TI - Mechanical and microbiological properties and drug release modeling of an etch and-rinse adhesive containing copper nanoparticles. AB - OBJECTIVES: To evaluate the effect of addition of copper nanoparticles (CN) at different concentrations into a two-step etch-and-rinse (2-ER) adhesive on antimicrobial activity (AMA), copper release (CR), ultimate tensile strength (UTS), degree of conversion (DC), water sorption (WS), solubility (SO), as well as the immediate (IM) and 1-year resin-dentin bond strength (MUTBS) and nanoleakage (NL). METHODS: Seven adhesives were formulated according to the addition of CN (0, 0.0075, 0.015, 0.06, 0.1, 0.5 and 1wt%) in adhesive. The AMA was evaluated against Streptococcus mutans using agar diffusion assay. For CR, WS and SO, specimens were constructed and tested for 28 days. For UTS, specimens were tested after 24h and 28 days. For DC, specimens were constructed and tested after 24h by FTIR. After enamel removal, the ER was applied to dentin. After composite resin build-ups, specimens were sectioned to obtain resin-dentin sticks. For MUTBS and NL, specimens were tested after 24h and 1-year periods. All data were submitted to statistical analysis (alpha=0.05). RESULTS: The addition of CN provided AMA to the adhesives at all concentrations. Higher CR was observed in adhesives with higher concentration of CN. UTS, DC, WS and SO were not influenced. For MUTBS an increase was observed in 0.1 and 0.5% copper group. For NL, a significant decrease was observed in all groups in comparison with control group. After 1-year, no significant reductions of MUTBS and no significant increases of NL were observed for copper containing adhesives compared to the control group. SIGNIFICANCE: The addition of CN in concentrations up to 1wt% in the 2-ER adhesive may be an alternative to provide AMA and preserve the bonding to dentin, without reducing adhesives' mechanical properties evaluated. PMID- 28094026 TI - Nanoporous hydroxyapatite/sodium titanate bilayer on titanium implants for improved osteointegration. AB - OBJECTIVE: The aim of this study was to improve the strength and quality of the titanium-hydroxyapatite interface in order to prevent long-term failure of the implanted devices originating from coating delamination and to test it in an in vivo model. METHODS: Ti disks and dental commercial implants were etched in Kroll solution. Thermochemical treatments of the acid-etched titanium were combined with sol-gel hydroxyapatite (HA) coating processes to obtain a nanoporous hydroxyapatite/sodium titanate bilayer. The sodium titanate layer was created by incorporating sodium ions onto the Ti surface during a NaOH alkaline treatment and stabilized using a heat treatment. HA layer was added by dip-coating in a sol gel solution. The bioactivity was assessed in vitro with murine MC3T3-E1 and human SaOs-2 cells. Functional and histopathological evaluations of the coated Ti implants were performed at 22, 34 and 60days of implantation in a dog lower mandible model. RESULTS: Nanoporous hydroxyapatite/sodium titanate bilayer on titanium implants was sensitive neither to crack propagation nor to layer delamination. The in vitro results on murine MC3T3-E1 and human SaOs-2 cells confirm the advantage of this coating regarding the capacity of cell growth and differentiation. Signs of progressive bone incorporation, such as cancellous bone formed in contact with the implant over the existing compact bone, were notable as early as day 22. Overall, osteoconduction and osteointegration mean scores were higher for test implants compared to the controls at 22 and 34 days. SIGNIFICANCE: Nanoporous hydroxyapatite/sodium titanate bilayer improves the in vivo osteoconduction and osteointegration. It prevents the delamination during the screwing and it could increase HA-coated dental implant stability without adhesive failures. The combination of thermochemical treatments with dip coating is a low-cost strategy. PMID- 28094027 TI - Persistent Females and Compliant Males Coordinate Alarm Calling in Diana Monkeys. AB - Sexual dimorphisms in animal vocal behavior have been successfully explained by sexual selection theory (e.g., mammals [1-5]; birds [6, 7]; anurans [8, 9]), but this does not usually include alarm calls, which are thought to be the product of kin or individual selection (e.g., [10, 11]). Here, we present the results of playback experiments with wild Diana monkeys, a species with highly dimorphic predator-specific alarms, to investigate the communication strategies of males and females during predator encounters. First, we simulated predator presence by broadcasting vocalizations of their main predators, leopards or eagles. We found that males only produced predator-specific alarms after the females had produced theirs, in response to which the females ceased alarm calling. In a second experiment, we created congruent and incongruent situations, so that the calls of a predator were followed by playbacks of male or female alarms with a matching or mismatching referent. For congruent conditions, results were the same as in the first experiment. For incongruent conditions, however, the males always gave predator-specific alarms that referentially matched the females' calls, regardless of the previously displayed predator. In contrast, females always gave predator-specific alarms that matched the predator type, regardless of their own male's subsequent calls. Moreover, the females persistently continued to alarm call until their own male produced calls with the matching referent. Results show that males and females attend to the informational content of each other's alarm calls but prioritize them differently relative to an experienced external event, a likely reflection of different underlying selection pressures. PMID- 28094028 TI - Annual 10-Month Aerial Life Phase in the Common Swift Apus apus. AB - The common swift (Apus apus) is adapted to an aerial lifestyle, where food and nest material are captured in the air. Observations have prompted scientists to hypothesize that swifts stay airborne for their entire non-breeding period [1, 2], including migration into sub-Saharan Africa [3-5]. It is mainly juvenile common swifts that occasionally roost in trees or buildings before autumn migration when weather is bad [1, 6]. In contrast, the North American chimney swift (Chaetura pelagica) and Vaux's swift (C. vauxi) regularly settle to roost in places like chimneys and buildings during migration and winter [7, 8]. Observations of common swifts during the winter months are scarce, and roost sites have never been found in sub-Saharan Africa. In the breeding season, non breeding individuals usually spend the night airborne [9], whereas adult nesting birds roost in the nest [1]. We equipped common swifts with a micro data logger with an accelerometer to record flight activity (years 1-2) and with a light level sensor for geolocation (year 2). Our data show that swifts are airborne for >99% of the time during their 10-month non-breeding period; some individuals never settled, but occasional events of flight inactivity occurred in most individuals. Apparent flight activity was lower during the daytime than during the nighttime, most likely due to prolonged gliding episodes during the daytime when soaring in thermals. Our data also revealed that twilight ascents, previously observed during the summer [10], occur throughout the year. The results have important implications for understanding physiological adaptations to endure prolonged periods of flight, including the need to sleep while airborne. PMID- 28094029 TI - Nanostructures and Monolayers of Spheres Reduce Surface Reflections in Hyperiid Amphipods. AB - Transparent zooplankton and nekton are often nearly invisible when viewed under ambient light in the pelagic zone [1-3]. However, in this environment, where the light field is directional (and thus likely to cause reflections), and under the bioluminescent searchlights of potential predators, animals may be revealed by reflections from their body surface [4-7]. We investigated the cuticle surfaces of seven species of hyperiids (Crustacea; Amphipoda) using scanning electron microscopy and found two undocumented features that may reduce reflectance. We found that the legs of Cystisoma spp. (n = 5) are covered with an ordered array of nanoprotuberances 200 +/- 20 nm SD in height that function optically as a gradient refractive index material [6, 8, 9]. Additionally, we observed that Cystisoma and six other species of hyperiids are covered with a monolayer of homogenous spheres (diameters ranging from 52 +/- 7 nm SD on Cystisoma spp. to 320 +/- 15 nm SD on Phronima spp.). Optical modeling using effective medium theory and transfer matrix methods demonstrated that both the nanoprotuberances and the monolayers reduce reflectance by as much as 100-fold, depending on the wavelength and angle of the incident light and the thickness of the gradient layer. Even though we only consider surface reflectance and not internal light scattering, our study demonstrates that these nanoprotuberances and spheres can improve crypsis in a featureless habitat where the smallest reflection can render an animal vulnerable to visual predation. PMID- 28094030 TI - Glucocorticoid-induced leucine zipper protein regulates sodium and potassium balance in the distal nephron. AB - Glucocorticoid induced leucine zipper protein (GILZ) is an aldosterone-regulated protein that controls sodium transport in cultured kidney epithelial cells. Mice lacking GILZ have been reported previously to have electrolyte abnormalities. However, the mechanistic basis has not been explored. Here we provide evidence supporting a role for GILZ in modulating the balance of renal sodium and potassium excretion by regulating the sodium-chloride cotransporter (NCC) activity in the distal nephron. Gilz-/- mice have a higher plasma potassium concentration and lower fractional excretion of potassium than wild type mice. Furthermore, knockout mice are more sensitive to NCC inhibition by thiazides than are the wild type mice, and their phosphorylated NCC expression is higher. Despite increased NCC activity, knockout mice do not have higher blood pressure than wild type mice. However, during sodium deprivation, knockout mice come into sodium balance more quickly, than do the wild type, without a significant increase in plasma renin activity. Upon prolonged sodium restriction, knockout mice develop frank hyperkalemia. Finally, in HEK293T cells, exogenous GILZ inhibits NCC activity at least in part by inhibiting SPAK phosphorylation. Thus, GILZ promotes potassium secretion by inhibiting NCC and enhancing distal sodium delivery to the epithelial sodium channel. Additionally, Gilz-/- mice have features resembling familial hyperkalemic hypertension, a human disorder that manifests with hyperkalemia associated variably with hypertension. PMID- 28094031 TI - Patients receiving frequent hemodialysis have better health-related quality of life compared to patients receiving conventional hemodialysis. AB - Most patients with end-stage kidney disease value their health-related quality of life (HRQoL) and want to know how it will be affected by their dialysis modality. We extended the findings of two prior clinical trial reports to estimate the effects of frequent compared to conventional hemodialysis on additional measures of HRQoL. The Daily Trial randomly assigned 245 patients to receive frequent (six times per week) or conventional (three times per week) in-center hemodialysis. The Nocturnal Trial randomly assigned 87 patients to receive frequent nocturnal (six times per week) or conventional (three times per week) home hemodialysis. All patients were on conventional hemodialysis prior to randomization, with an average feeling thermometer score of 70 to 75 (a visual analog scale from 0 to 100 where 100 is perfect health), an average general health scale score of 40 to 47 (a score from 0 to 100 where 100 is perfect health), and an average dialysis session recovery time of 2 to 3 hours. Outcomes are reported as the between treatment group differences in one-year change in HRQoL measures and analyzed using linear mixed effects models. After one year in the Daily Trial, patients assigned to frequent in-center hemodialysis reported a higher feeling thermometer score, better general health, and a shorter recovery time after a dialysis session compared to standard thrice-weekly dialysis. After one year in the Nocturnal Trial, patients assigned to frequent home hemodialysis also reported a shorter recovery time after a dialysis session, but no statistical difference in their feeling thermometer or general health scores compared to standard home dialysis schedules. Thus, patients receiving day or nocturnal hemodialysis on average recovered approximately one hour earlier from a frequent compared to conventional hemodialysis session. Patients treated in an in-center dialysis facility reported better HRQoL with frequent compared to conventional hemodialysis. PMID- 28094032 TI - The airway approach to a neonate with Treacher Collins syndrome - Case report. AB - Neonates and small infants with syndromes characterized by the presence of craniofacial abnormalities may represent great challenges regarding the management of the airway. We describe the case of a 9-day-old neonate with Treacher Collins syndrome, in which a laryngeal mask was essential to improve the airway obstruction, ventilate the patient and serve as an airway conduit for a fiberoptic intubation. By presenting this case, we intend to show that in neonates with Treacher Collins syndrome, in whom difficulties ventilation and intubation are expected, a thoughtful airway management planning is mandatory. PMID- 28094033 TI - Vancomycin added to the wash solution of the cell-saver. Effect on bacterial contamination. AB - OBJECTIVES: The aim of this study is to test whether the addition of a low-dose of antibiotic (vancomycin) to the wash solution (saline) of the cell-saver reduces the incidence of bacterial contamination of the autologous red blood cell (RBCs) concentrate recovered. MATERIAL AND METHOD: Experimental, randomized, double-blind, parallel group study performed on 20 consecutive patients scheduled for posterior spinal fusion surgery. Intraoperative bleeding was processed through a cell-saver: HaemoLite(r) 2+, in which the RBCs were washed according to randomization group, with saline (control group) or saline+10MUg/ml-1 vancomycin (vanco group). Data regarding age, weight, processed and recovered volume, blood count, blood culture, and vancomycin concentration in RBCs concentrates obtained and incidence of fever after reinfusion were collected. RESULTS: Processed volume was 843+/-403ml and recovered volume 121+/-29ml, with haemoglobin concentration 10.4+/-5.0g/dl-1 and haematocrit 29.1+/-15.9% (mean+/-SD). Recovered RBC concentrate cultures were positive for coagulase-negative Staphylococcus in 5 cases (50%) of the control group while all cultures were negative in the vanco group (P=.016). The difference between the theoretical concentration of vancomycin administered and the concentration determined in the recovered RBC concentrate was 1.31MUg/ml-1 (95% CI 1.19 to 1.43; P=.074). CONCLUSIONS: The addition of vancomycin at a concentration of 10ug/ml-1 to the wash solution of the cell-saver achieved similar concentrations in the autologous blood concentrate recovered allowing for bacterial removal, with negative blood cultures in all cases. PMID- 28094034 TI - Dynamical Representation of Dominance Relationships in the Human Rostromedial Prefrontal Cortex. AB - Humans and other primates have evolved the ability to represent their status in the group's social hierarchy, which is essential for avoiding harm and accessing resources. Yet it remains unclear how the human brain learns dominance status and adjusts behavior accordingly during dynamic social interactions. Here we address this issue with a combination of fMRI and transcranial direct current stimulation (tDCS). In a first fMRI experiment, participants learned an implicit dominance hierarchy while playing a competitive game against three opponents of different skills. Neural activity in the rostromedial PFC (rmPFC) dynamically tracked and updated the dominance status of the opponents, whereas the ventromedial PFC and ventral striatum reacted specifically to competitive victories and defeats. In a second experiment, we applied anodal tDCS over the rmPFC to enhance neural excitability while subjects performed a similar competitive task. The stimulation enhanced the relative weight of victories over defeats in learning social dominance relationships and exacerbated the influence of one's own dominance over competitive strategies. Importantly, these tDCS effects were specific to trials in which subjects learned about dominance relationships, as they were not present for control choices associated with monetary incentives but no competitive feedback. Taken together, our findings elucidate the role of rmPFC computations in dominance learning and unravel a fundamental mechanism that governs the emergence and maintenance of social dominance relationships in humans. PMID- 28094035 TI - Extinction Generates Outcome-Specific Conditioned Inhibition. AB - Extinction involves altering a previously established predictive relationship between a cue and its outcome by repeatedly presenting that cue alone. Although it is widely accepted that extinction generates some form of inhibitory learning [1-4], direct evidence for this claim has been lacking, and the nature of the associative changes induced by extinction have, therefore, remained a matter of debate [5-8]. In the current experiments, we used a novel behavioral approach that we recently developed and that provides a direct measure of conditioned inhibition [9] to compare the influence of extinguished and non-extinguished cues on choice between goal-directed actions. Using this approach, we provide direct evidence that extinction generates outcome-specific conditioned inhibition. Furthermore, we demonstrate that this inhibitory learning is controlled by the infralimbic cortex (IL); inactivation of the IL using M4 DREADDs abolished outcome-specific inhibition and rendered the cue excitatory. Importantly, we found that context modulated this inhibition. Outside its extinction context, the cue was excitatory and functioned as a specific predictor of its previously associated outcome, biasing choice toward actions earning the same outcome. In its extinction context, however, the cue acted as a specific inhibitor and biased choice toward actions earning different outcomes. Context modulation of these excitatory and inhibitory memories was mediated by the dorsal hippocampus (HPC), suggesting that the HPC and IL act in concert to control the influence of conditioned inhibitors on choice. These findings demonstrate for the first time that extinction turns a cue into a net inhibitor that can influence choice via counterfactual action-outcome associations. PMID- 28094036 TI - Centriole Remodeling during Spermiogenesis in Drosophila. AB - The first cell of an animal (zygote) requires centrosomes that are assembled from paternally inherited centrioles and maternally inherited pericentriolar material (PCM) [1]. In some animals, sperm centrioles with typical ultrastructure are the origin of the first centrosomes in the zygote [2-4]. In other animals, however, sperm centrioles lose their proteins and are thought to be degenerated and non functional during spermiogenesis [5, 6]. Here, we show that the two sperm centrioles (the giant centriole [GC] and the proximal centriole-like structure [PCL]) in Drosophila melanogaster are remodeled during spermiogenesis through protein enrichment and ultrastructure modification in parallel to previously described centrosomal reduction [7]. We found that the ultrastructure of the matured sperm (spermatozoa) centrioles is modified dramatically and that the PCL does not resemble a typical centriole. We also describe a new phenomenon of Poc1 enrichment of the atypical centrioles in the spermatozoa. Using various mutants, protein expression during spermiogenesis, and RNAi knockdown of paternal Poc1, we found that paternal Poc1 enrichment is essential for the formation of centrioles during spermiogenesis and for the formation of centrosomes after fertilization in the zygote. Altogether, these findings demonstrate that the sperm centrioles are remodeled both in their protein composition and in ultrastructure, yet they are functional and are essential for normal embryogenesis in Drosophila. PMID- 28094037 TI - Identifying risk factors for occult lower extremity lymphedema using computed tomography in patients undergoing lymphadenectomy for gynecologic cancers. AB - OBJECTIVE: To identify risk factors for lower extremity lymphedema (LEL) using computed tomographic (CT) scan in patients undergoing lymphadenectomy for gynecologic cancers. METHODS: We retrospectively reviewed 511 consecutive gynecologic cancer patients undergoing lymphadenectomy. Mean difference (3.77+/ 3.14mm) of subcutaneous layer thicknesses between preoperative and postoperative 1-year CT scans of 106 patients with clinical LEL was used as an objective criterion for regrouping all the patients into those with mean difference >3.77mm and <=3.77mm. Risk factors for clinical LEL and significant increase of subcutaneous layer thickness on CT were evaluated using a logistic regression model. RESULTS: A total of 106 (20.7%) patients were clinically diagnosed with LEL by a physician. Total number of lymph nodes (LNs) retrieved >30 (Odds ratio [OR] 3.2; 95% Confidence interval [CI] 1.94-5.32; p<0.001) and adjuvant pelvic radiotherapy (OR 3.1; 95% CI 1.75-5.52; p<0.001) were risk factors for clinical LEL. One hundred-nineteen (23.3%) had subcutaneous layer thickness increase of >3.77mm. In addition to number of LNs retrieved >30 (OR 2.3; 95% CI 1.40-3.74; p=0.001) and adjuvant pelvic radiotherapy (OR 1.7; 95% CI 1.01-2.74; p=0.046), open surgery (OR 1.8; 95% CI 1.01-3.11; p=0.045), long operation time (OR 1.7; 95% CI 1.05-2.83; p=0.032), and no use of intermittent pneumatic compression (IPC) (OR 2.1; 95% CI 1.06-4.16; p=0.034) were risk factors for thick subcutaneous layer on postoperative CT. CONCLUSIONS: In addition to high LN retrieval and adjuvant pelvic radiotherapy, open surgery, long operation time, and no IPC use could be risk factors for occult LEL after lymphadenectomy in gynecologic cancers. PMID- 28094038 TI - Triaging HPV-positive women with p16/Ki-67 dual-stained cytology: Results from a sub-study nested into the ATHENA trial. AB - OBJECTIVES: In addition to genotyping for HPV16/18, dual-immunostaining for p16/Ki-67 has shown promise as a triage of HPV-positive women. We assessed the performance of p16/Ki-67 dual-stained cytology for triaging HPV-positive women undergoing primary HPV screening. METHODS: All women >=25years with valid cervical biopsy and cobas(r) HPV Test results from the cross-sectional phase of ATHENA who were referred to colposcopy (n=7727) were eligible for enrolment. p16/Ki-67 dual-stained cytology was retrospectively performed on residual cytologic material collected into a second liquid-based cytology vial during the ATHENA enrolment visit. The diagnostic performance of dual-stained cytology, with or without HPV16/18 genotyping, for the detection of biopsy-confirmed cervical intraepithelial neoplasia grade 3 or worse (CIN3+) was determined and compared to Pap cytology. Furthermore, the number of colposcopies required per CIN3+ detected was determined. RESULTS: Dual-stained cytology was significantly more sensitive than Pap cytology (74.9% vs. 51.9%; p<0.0001) for triaging HPV-positive women, whereas specificity was comparable (74.1% vs. 75.0%; p=0.3198). Referral of all HPV16/18 positive women combined with dual-stained cytology triage of women positive for 12 "other" HPV genotypes provided the highest sensitivity for CIN3+ (86.8%; 95% CI: 81.9-90.8). A similar strategy but using Pap cytology for the triage of women positive for 12 "other" HPV genotypes was less sensitive (78.2%; 95% CI: 72.5-83.2; p=0.0003), but required a similar number of colposcopies per CIN3+ detected. CONCLUSIONS: p16/Ki-67 dual-stained cytology, either alone or combined with HPV16/18 genotyping, represents a promising approach as a sensitive and efficient triage for colposcopy of HPV-positive women when primary HPV screening is utilized. PMID- 28094039 TI - Cisplatin can be safely administered to ovarian cancer patients with hypersensitivity to carboplatin. AB - OBJECTIVE: Hypersensitivity reactions (HSR) are frequently reported in patients rechallenged with carboplatin for recurrent ovarian cancer (ROC) and represent a critical issue, since discontinuation of the platinum-based therapy could affect prognosis. Several strategies to allow platinum rechallenge have been described, with controversial outcomes. The aim of this study is to illustrate a 10-year experience with cisplatin in patients with a previous HSR to carboplatin or at risk for allergy. METHODS: A retrospective review of all patients with platinum sensitive ROC retreated with carboplatin was performed between January 2007 and May 2016 at the Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples. RESULTS: Among 183 patients, 49 (26.8%) presented HSR to carboplatin, mainly during second line therapy. Mean number of cycles before HSR was 8 (range 3-17). G2, G3 and G4 reaction were detected in 83%, 15% and 2% of patients, respectively. In a multivariate analysis including age, hystotype, BRCA status, previous known HSR, and combination drug administered, only the type of carboplatin-based doublet used as 2nd line therapy was found to significantly affect HSR development, with a protective effect of PLD (pegylated liposomal doxorubicin) (p = 0.014, OR = 0.027). Thirty seven patients (77%) with a previous HSR to carboplatin were rechallenged with cisplatin. Treatment was generally well tolerated. 5 patients (13.1%) experienced mild HSR to cisplatin, successfully managed in all cases. 14 patients were treated with cisplatin even without a carboplatin-related HSR due to other allergies. Among these, only one developed HSR (7.1%). CONCLUSIONS: Cisplatin rechallenge is a feasible approach in patients experiencing HSR to carboplatin to maintain the beneficial effect of platinum while reducing hypersensitivity-related risks. PMID- 28094041 TI - Superstars: Assessing nutrient thresholds for enhanced larval success of Acanthaster planci, a review of the evidence. AB - Crown-of-thorns starfish, Acanthaster planci (COTS), predation is a major cause of coral reef decline, but the factors behind their population outbreaks remain unclear. Increased phytoplankton food resulting from eutrophication is suggested to enhance larval survival. We addressed the hypothesis that larval success is associated with particular chl-a levels in tightly controlled larval:algal conditions. We used chl-a conditions found on coral reefs (0.1-5.0MUgchl-aL-1), including nominal threshold levels for disproportionate larval success (>=1.0MUgchl-aL-1). High success to the juvenile occurred across an order of magnitude of chl-a concentrations (0.5-5.0MUgchl-aL-1), suggesting there may not be a narrow value for optimal success. Oligotrophic conditions (0.1MUgchl-aL-1) appeared to be a critical limit. With a review of the evidence, we suggest that opportunistic COTS larvae may be more resilient to low food levels than previously appreciated. Initiation of outbreak populations need not require eutrophic conditions. PMID- 28094040 TI - A phase 2 study of alisertib (MLN8237) in recurrent or persistent uterine leiomyosarcoma: An NRG Oncology/Gynecologic Oncology Group study 0231D. AB - OBJECTIVE: This two-stage Phase II study assessed the activity of single agent alisertib in patients with recurrent/persistent uterine leiomyosarcoma (uLMS). METHODS: Eligibility criteria included histologically-confirmed, recurrent or persistent uLMS, age>=18, 1-2 prior cytotoxic regimens, and RECIST version 1.1 measurable disease. The primary objective of the study was to evaluate the efficacy of alisertib through the frequency of patients with objective tumor responses and the frequency who survived event-free for at least 6months (EFS6). The endpoints for EFS were RECIST progression, death, or beginning a subsequent therapy. The null hypothesis jointly specified the probability of a patient experiencing a tumor response to less than or equal to 5% and the probability of a patient surviving event-free for at least 6months to less than or equal to 20%. A two-stage design was used with a target accrual of 23 patients for stage 1 and 47 pts. cumulative for stage 2. Confidence intervals do not correct for multiplicity. RESULTS: Twenty-three patients were enrolled with two patients excluded on central histology review, yielding 21 eligible patients. Median age was 61years. Prior treatment was either 1 cytotoxic regimen (71.4%) or 2 (28.6%). The most common treatment related AEs (grade 3 or worse) were anemia Hensley et al. (2008a) , leukopenia Hensley et al. (2008b) , neutropenia Maki et al. (2007) , thrombocytopenia Huang et al. (2012) , mucositis Hensley et al. (2008a) , diarrhea Huang et al. (2012) , and palmer-planter syndrome Zivanovic et al. (2012) . There were no objective responses (0%; 90% CI: 0-10.4%). Best response was stable disease (38.1%); 12 patients had progressive disease (57.1%). EFS6 was 0% (90% CI: 0-10.4%). Median PFS and OS were 1.7 (90% CI: 1.4-3.2) and 14.5months (90% CI: 7.6 - NA), respectively. CONCLUSION: Alisertib did not demonstrate clinically meaningful single agent activity in previously treated uLMS. PMID- 28094042 TI - Responses of the rotifer Brachionus plicatilis to flame retardant (BDE-47) stress. AB - A series of short-term toxicological tests were conducted on the rotifer Brachionus plicatilis to assess the toxicity of the flame retardant 2,2',4,4' tetrabrominated biphenyl ether (BDE-47). BDE-47 increased mortality, morphological damage, and altered population dynamics and fecundity of rotifer. Antioxidant enzymes were differentially changed to maintain the balance between antioxidant and pro-oxidant activity. However, with increases in the concentration of BDE-47, the metabolic and antioxidant activity decreased. Moreover, the reactive oxygen species (ROS) and malondialdehyde contents increased and the ratio between glutathione and glutathione-SH decreased, indicating oxidative stress. The addition of the ROS-inhibitor N-acetylcysteine alleviated the degree of damage and stimulated the activity of xenobiotic metabolizing and antioxidant system, which suggested that ROS were the most important loop in the stress response. PMID- 28094043 TI - Incidence and Clinical Course of Immune Reactions after Descemet Membrane Endothelial Keratoplasty: Retrospective Analysis of 1000 Consecutive Eyes. AB - PURPOSE: To analyze the incidence and clinical course of graft rejection episodes after Descemet membrane endothelial keratoplasty (DMEK). DESIGN: Retrospective analysis of a consecutive, interventional case series. PARTICIPANTS: One thousand eyes that underwent DMEK from July 2011 through August 2015 at the Department of Ophthalmology, University of Cologne. METHODS: All cases with follow-up of at least 1 month were included (mean follow-up, 18.5 months). Patients with a graft rejection episode were followed up for 1 additional year. MAIN OUTCOME MEASURES: Incidence of graft rejection, best spectacle-corrected visual acuity (BSCVA), central corneal thickness (CCT), endothelial cell density (ECD), and need for regraft. RESULTS: Nine hundred five cases met the inclusion criteria. A graft rejection episode developed in 12 patients (estimated probability of rejection at 1 year, 0.9%; at 2 years, 2.3%; at 4 years, 2.3%). At time of rejection, 9 of 12 patients had stopped corticosteroids. Five patients were symptomatic and 7 did not note the rejection episode. Intensified topical corticosteroid therapy was started immediately after diagnosis of rejection. Two eyes decompensated and required a regraft, whereas the remaining 10 eyes required no regraft (BSCVA, 0.27+/-0.28 logarithm of the minimum angle of resolution [logMAR]; CCT, 554.1+/ 39.1 MUm at last visit before rejection vs. BSCVA, 0.21+/-0.15 logMAR; CCT, 540.0+/-15.0 MUm 3 months after rejection). One year after the rejection episodes, BSCVA and CCT in these eyes remained unchanged when compared with the last visit before rejection (BSCVA, 0.15+/-0.11 logMAR; CCT, 533.8+/-26.0 MUm). Significant changes were observed for ECD values (1741+/-274.5 cells/mm2 at last visit before rejection vs. 1356+/-380.3 cells/mm2 after 3 months [P = 0.04] and 1290+/-359.0 cells/mm2 after 1 year [P = 0.01]). CONCLUSIONS: The risk for graft rejection after DMEK is low, and an even smaller minority requires a regraft. After intensified local corticosteroid therapy, most patients show stable visual acuity and CCT, although ECD decreases. The occurrence of immune reactions up to 2 years after surgery predominantly in patients not receiving corticosteroids supports the prolonged use of corticosteroids after DMEK. PMID- 28094044 TI - Diagnosis and Treatment of Acute Retinal Necrosis: A Report by the American Academy of Ophthalmology. AB - PURPOSE: To evaluate the available evidence in peer-reviewed publications about the diagnosis and treatment of acute retinal necrosis (ARN). METHODS: Literature searches of the PubMed and Cochrane Library databases were last conducted on July 27, 2016. The searches identified 216 unique citations, and 49 articles of possible clinical relevance were reviewed in full text. Of these 49 articles, 27 were deemed sufficiently relevant or of interest, and they were rated according to strength of evidence. An additional 6 articles were identified from the reference lists of these articles and included. All 33 studies were retrospective. RESULTS: Polymerase chain reaction (PCR) testing of aqueous or vitreous humor was positive for herpes simplex virus (HSV) or varicella zoster virus (VZV) in 79% to 100% of cases of suspected ARN. Aqueous and vitreous specimens are both sensitive and specific. There is level II and III evidence supporting the use of intravenous and oral antiviral therapy for the treatment of ARN. Data suggest that equivalent plasma drug levels of acyclovir can be achieved after administration of oral valacyclovir or intravenous acyclovir. There is level II and III evidence suggesting that the combination of intravitreal foscarnet and systemic antiviral therapy may have greater therapeutic efficacy than systemic therapy alone. The effectiveness of prophylactic laser or early pars plana vitrectomy (PPV) in preventing retinal detachment (RD) remains unclear. CONCLUSIONS: Polymerase chain reaction testing of ocular fluid is useful in supporting a clinical diagnosis of ARN, but treatment should not be delayed while awaiting PCR results. Initial oral or intravenous antiviral therapy is effective in treating ARN. The adjunctive use of intravitreal foscarnet may be more effective than systemic therapy alone. The role of prophylactic laser retinopexy or early PPV is unknown at this time. PMID- 28094045 TI - Quantification of User and Manufacturer Variabilities in Urinary Catheter Anchoring Balloon Inflation and Mitigation of Variability by Flow Resistance. AB - OBJECTIVE: To quantify user variability and manufacturer variability in urinary catheter anchoring balloon inflation pressure and to mitigate any significant variance by incorporating flow resistance into the anchoring balloon inflation process. METHODS: Inflation of a urinary catheter anchoring balloon was performed at atmospheric pressure by different users (n = 8) to investigate user variability. A calibrated pressure transducer measured inflation pressures, and a video extensometer measured balloon inflation profiles. Manufacturer variability was investigated by applying constant forces to the plunger of conventional syringes to mimic "heavy-," "intermediate-," and "light"-handed users for 3 brands of catheter. Flow restrictors of variable reduced cross-sectional areas were introduced to the outflow of the inflation syringes to investigate the effect of flow resistance on anchoring balloon inflation profiles. RESULTS: Variations in maximum inflation pressures (range: 75-355 kPa) were observed among the different users. There were no significant differences in maximum inflation pressure between brands at any of the 3 simulated hand forces (P = .97). Increasing the flow resistance significantly reduces the applicable inflation pressure of all hand forces (P < .001). Specifically, the difference in inflation pressure between heavy- and light-handed forces is reduced from over 405 kPa to under 65 kPa. Introducing flow resistance does not result in a significant difference in inflation pressure between brands (P = .254). CONCLUSION: There is significant user variability in urinary catheter balloon inflation pressure. This variation can be significantly reduced by introducing flow resistance to the inflation technique. PMID- 28094046 TI - Spatiotemporal variation of arbuscular mycorrhizal fungal colonization in olive (Olea europaea L.) roots across a broad mesic-xeric climatic gradient in North Africa. AB - This study aims to determine the spatiotemporal dynamics of root colonization and spore density of arbuscular mycorrhizal fungi (AMF) in the rhizosphere of olive trees (Olea europaea) with different plantation ages and under different climatic areas in Algeria. Soil and root samples were seasonally collected from three olive plantations of different ages. Other samples were carried out in productive olive orchards cultivated under a climatic gradient (desertic, semi-arid, subhumid, and humid). The olive varieties analysed in this study were Blanquette, Rougette, Chemlel and the wild-olive. Spore density, mycorrhization intensity (M%), spore diversity and the most probable number (MPN) were determined. Both the intensity of mycorrhizal colonization and spore density increased with the increase of seasonal precipitation and decreased with the increase of air temperature regardless of the climatic region or olive variety. The variety Rougette had the highest mycorrhizal levels in all plantation ages and climates. Spore community was composed of the genera Rhizophagus, Funneliformis, Glomus, Septoglomus, Gigaspora, Scutellospora and Entrophospora. The genus Glomus, with four species, predominated in all climate regions. Spores of Gigaspora sp. and Scutellospora sp. were the most abundant in desertic plantations. Statistical models indicated a positive relationship between spore density and M% during spring and winter in young seedlings and old plantations. A significant positive relationship was found between MPN and spore density under different climates. For a mycotrophic species, the rhizosphere of olive trees proved to be poor in mycorrhiza in terms of mycorrhizal colonization and numbers of the infective AMF propagules. PMID- 28094047 TI - Methanogenic biodegradation of paraffinic solvent hydrocarbons in two different oil sands tailings. AB - Microbial communities drive many biogeochemical processes in oil sands tailings and cause greenhouse gas emissions from tailings ponds. Paraffinic solvent (primarily C5-C6; n- and iso-alkanes) is used by some oil sands companies to aid bitumen extraction from oil sands ores. Residues of unrecovered solvent escape to tailings ponds during tailings deposition and sustain microbial metabolism. To investigate biodegradation of hydrocarbons in paraffinic solvent, mature fine tailings (MFT) collected from Albian and CNRL ponds were amended with paraffinic solvent at ~0.1wt% (final concentration: ~1000mgL-1) and incubated under methanogenic conditions for ~1600d. Albian and CNRL MFTs exhibited ~400 and ~800d lag phases, respectively after which n-alkanes (n-pentane and n-hexane) in the solvent were preferentially metabolized to methane over iso-alkanes in both MFTs. Among iso-alkanes, only 2-methylpentane was completely biodegraded whereas 2 methylbutane and 3-methylpentane were partially biodegraded probably through cometabolism. 16S rRNA gene pyrosequencing showed dominance of Anaerolineaceae and Methanosaetaceae in Albian MFT and Peptococcaceae and co-domination of "Candidatus Methanoregula" and Methanosaetaceae in CNRL MFT bacterial and archaeal communities, respectively, during active biodegradation of paraffinic solvent. The results are important for developing future strategies for tailings reclamation and management of greenhouse gas emissions. PMID- 28094048 TI - Optimization of the skimmed-milk flocculation method for recovery of adenovirus from sludge. AB - Return of treated sludge to the environment poses concerns and has stimulated the development of studies on viral monitoring in this matrix, in order to assess its potential risks for public health. Human adenovirus (HAdV) has been identified as a putative viral marker of faecal contamination due to its stability and resistance to the sewage treatment process. The aim of this study was to optimize the organic flocculation procedure in order to establish an appropriate methodology for HAdV recovery from sewage sludge samples. Four protocols (A-D) have been proposed, with changes in the initial sample dilution, in the stirring time and in the final concentration of skimmed-milk. A single sludge sample was obtained in Wastewater Treatment Plant (WWTP) and divided into aliquots. In each protocol, three aliquots were inoculated with HAdV and bacteriophage PP7 and a non-inoculated one was used as negative control. Viral load and recovery rate were determined by quantitative PCR. HAdV recovery rate varied between the protocols tested (p=0.016) and the best result was obtained through the protocol C. In order to confirm this result a field study with activated, thickened and digested sludge samples was carried out. Different types of sludge were obtained in two WWTPs and processed using protocol C. HAdV was detected in all samples, with a similar or higher viral load than those obtained with other concentration techniques already applied to sludge. Protocol C proved to be really efficient, with the advantage of showing low cost and practicability in routine laboratories. PMID- 28094050 TI - Corruption and use of antibiotics in regions of Europe. AB - The aim of this article is to investigate the association between corruption and antibiotic use at sub-national level. We explore the correlation between, on the one hand, two measures of corruption (prevalence of corruption in the health sector and prevalence of bribes in the society) at regional level from the European Quality of Government Index; and, on the other, the consumption of antibiotics in those European regions from a 2009 Special Euro Barometer. In a multivariate regression model, we control for potential confounders: purchasing power of standardized regional gross domestic product, inhabitants per medical doctor and age-standardized all-cause mortality rates. We find that there is a strong positive association between both measures of corruption (i.e. in the health sector, and in the society at large) and antibiotics use; and that this association is robust to the introduction of the control variables. These results support previous findings in the literature linking corruption to higher antibiotic use at cross-national level. We show that corruption does seem to account for some of the remarkable between-region variation in antibiotic consumption in Europe. PMID- 28094049 TI - EP4 receptor promotes invadopodia and invasion in human breast cancer. AB - The production of Prostaglandin E2 (PGE2) is elevated in human breast cancer cells. The abnormal expression of COX-2, which is involved in the synthesis of PGE2, was recently reported as a critical determinant for invasiveness of human breast cancer cells. Autocrine and paracrine PGE2-mediated stimulation of the PGE2 receptor EP4 transduces multiple signaling pathways leading to diverse patho physiological effects, including tumor cell invasion and metastasis. It is known that PGE2-induced EP4 activation can transactivate the intracellular signaling pathway of the epidermal growth factor receptor (EGFR). In malignant cancer cells, EGFR pathway activation promotes invadopodia protrusions, which further leads to degradation of the surrounding extracellular matrix (ECM). Despite the known influence of EP4 on the EGFR signaling pathway, the effect of EP4 stimulation on invadopodia formation in human breast cancer was never tested directly. Here we demonstrate the involvement of EP4 in invasion and its effect on invadopodia in breast cancer MDA-MB-231 cells using 2D invadopodia and 3D invasion in vitro assays as well as intravital microscopy. The results show that stimulation with the selective EP4 agonist CAY10598 or PGE2 promotes invadopodia mediated degradation of the ECM, as well as the invasion of breast cancer cells in in vitro models. The effect on matrix degradation can be abrogated via direct inhibition of EP4 signaling as well as via inhibition of EGFR tyrosine kinase, indicating that EP4-mediated effects on invadopodia-driven degradation are EGFR dependent. Finally, using xenograft mouse models, we show that short-term systemic treatment with CAY10598 results in a >9-fold increase in the number of invadopodia. These findings highlight the importance of further investigation on the role of EP4-EGFR crosstalk in invadopodia formation. PMID- 28094051 TI - Competition policy for health care provision in Portugal. AB - We review the role of competition among healthcare providers in Portugal, which has a public National Health Service (NHS) at the core of the health system. There is little competition among healthcare providers within the NHS. Competition among NHS primary care providers is hindered by excess demand (many residents in Portugal do not have a designated family doctor). Competition among NHS hospitals has been traditionally limited to cases of maximum guaranteed waiting time for surgery being exceeded. The Portuguese Competition Authority enforces competition law. It has focused on mergers between private hospitals and abuse of market power (including cartel cases) by private healthcare providers. The Healthcare Regulation Authority produced several reports on particular areas of activity by private healthcare providers. The main conclusion of these reviews was lack of conditions for effective competition, with the exception of dentistry. Within the NHS, the use of tendering procedures was able to create "competition for the market" in particular areas though it was not problem free. Details in the particular design adopted matter a lot. Overall, the scope for competition policy and for competition among healthcare providers to have a main role in a health system based on a public National Health Service seems limited, with more relevance to "competition for the market" situations than to "competition in the market". PMID- 28094052 TI - The association of cancer risks with pentachlorophenol exposure: Focusing on community population in the areas along certain section of Yangtze River in China. AB - Pentachlorophenol (PCP) was used in large quantities, and mainly for killing the intermediate host snails of schistosome in China, thereby resulting in ubiquitous PCP residue in the environment. However, studies considering the carcinogenicity of PCP for humans mainly focused on occupational workers, and the actual carcinogenicity of PCP for general population is uncertain. To investigate the association between cancer risks and PCP exposure in a community population, an ecological study was conducted in three contaminated areas along the Yangtze River. Standardized rate ratio (SRR) was calculated to represent the risk of cancer incidence, by using incidence in the low PCP exposure category as the reference group. A total of 15,962 cancer records were collected, and 76 water samples and 213 urine samples in three areas were examined. Our findings suggested that compared with the low PCP group, the high PCP group had significantly excessive incidences of various cancers related to different organs including lymph (SRR = 19.44, 95% CI = 15.00-25.19), blood (SRR = 17.24, 95% CI = 12.92-23.01), nasopharynx (SRR = 3.97, 95% CI = 3.75-4.21), gallbladder (SRR = 3.46, 95% CI = 3.09-3.87), pancreas (SRR = 3.41, 95% CI = 3.07-3.79), respiratory system (SRR = 3.41, 95% CI = 3.27-3.57) and liver (SRR = 3.31, 95% CI = 3.09 3.56). Taken together, our present study provides evidence that general community population exposed to high level of PCP exhibits a broader spectrum of increased cancer risks as compared to occupational groups. PMID- 28094053 TI - When the cows come home: occupational tinea barbae in a cattle farmer. PMID- 28094054 TI - Re: Prediction of Lymph Node Metastasis in Patients with Bladder Cancer Using Whole Transcriptome Gene Expression Signatures. PMID- 28094055 TI - Renal Cell Carcinoma with Isolated Lymph Node Involvement: Long-term Natural History and Predictors of Oncologic Outcomes Following Surgical Resection. AB - BACKGROUND: Renal cell carcinoma (RCC) with isolated lymph node (LN) involvement has historically been associated with poor prognosis. However, a subset of patients may experience long-term survival. OBJECTIVE: To examine the natural history of RCC with isolated LN involvement following surgical resection with long-term follow-up, and to evaluate clinicopathologic features associated with disease progression and survival. DESIGN, SETTING, AND PARTICIPANTS: A total of 138 patients with isolated pN1M0 RCC underwent partial or radical nephrectomy and LN dissection from 1980 to 2010. INTERVENTION: Partial or radical nephrectomy with LN dissection. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Metastasis free survival (MFS), cancer-specific survival (CSS), and overall survival (OS) were estimated using the Kaplan-Meier method. Associations between clinicopathologic features and oncologic outcomes were evaluated using Cox regression models. RESULTS AND LIMITATIONS: Median follow-up among survivors was 8.5 yr. The 5-yr and 10-yr MFS, CSS, and OS rates were 16% and 15%, 26% and 21%, and 25% and 15%, respectively. The median time to development of metastases was only 4.2 mo. On multivariable analysis, symptoms at presentation (hazard ratio [HR] 2.40; p=0.03), inferior vena cava tumor thrombus (HR 1.99; p=0.003), clear cell (HR 2.21; p=0.01) and collecting duct/not otherwise specified (HR 4.28; p<0.001) histologic subtypes, pT4 stage (HR 2.64; p=0.005), and coagulative tumor necrosis (HR 2.51; p<0.001) were independently associated with development of metastases. MFS rates at 1 yr after surgery were 71%, 63%, 33%, and 7% for patients with one, two, three, and four to five adverse features, respectively. Limitations include surgical selection bias. CONCLUSIONS: Although isolated pN1 disease portends a poor prognosis, a small subset of patients experience durable long-term survival after surgical resection of isolated lymphatic metastases. Adverse prognostic features may enhance patient risk stratification and facilitate multimodal management approaches. PATIENT SUMMARY: Although isolated lymph node metastases portend a poor prognosis, a small subset of patients experience long-term survival following surgical resection. PMID- 28094056 TI - Re: The Role of Adjuvant Radiotherapy in Pathologically Lymph Node Positive Prostate Cancer. PMID- 28094057 TI - Multiparametric Magnetic Resonance Imaging Targeted Biopsy for Early Detection of Prostate Cancer: All That Glitters Is Not Gold! PMID- 28094058 TI - Association between dietary patterns, cadmium intake and chronic kidney disease among adults. AB - BACKGROUND & AIMS: Almost one in ten Chinese adults has chronic kidney disease (CKD). However, the link between dietary patterns, dietary cadmium intake and CKD has not been studied in China. METHOD: Adults (n = 8429) in the China Health and Nutrition Survey who had at least one 3-day 24 h food record in combination with household food inventory in 1991, 1993, 1997, 2000, 2004, 2006, and 2009 and estimated glomerular filtration rate (eGFR) measured in 2009. Dietary pattern was identified using factor analysis. CKD was defined as eGFR <60 mL/min/1.73 m2. RESULTS: There were 641 (7.6%) cases of CKD in the sample. After adjustment for demographic, lifestyle factors (i.e. smoking, alcohol drinking, physical activity) and chronic conditions, the odds ratio (OR) for CKD was 4.05 (95%CI 2.91-5.63, p for trend <0.001) for extreme quartiles of estimated cumulative cadmium intake. A traditional southern dietary pattern (high intake of rice, pork, and vegetables, and low intake of wheat) was associated with more than four times increased prevalence of CKD (comparing extreme quartiles, OR 4.56, 95%CI 3.18-6.56). A modern dietary pattern (high intake of fruit, soy milk, egg, milk and deep fried products) was inversely associated with CKD (for extreme quartiles, OR 0.5, 95%CI 0.36-0.71). The association between dietary patterns and CKD were attenuated by cadmium intake. CONCLUSION: Traditional southern dietary pattern is positively associated, and modern dietary pattern is inversely associated, with CKD among Chinese adults. However, these associations can be partly attributed to cadmium contamination in parts of the food supply. PMID- 28094059 TI - Alteration of methylation status in the ATXN3 gene promoter region is linked to the SCA3/MJD. AB - DNA methylation has been acknowledged as one of the key epigenetic mechanisms involved in the regulation of gene expression and genomic functions. Alteration of the DNA methylation level has been linked to modification of the disease progression and instability regulation of certain disease-causing repeats in neurodegenerative diseases. In this study, blood samples collected from spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) patients versus control were used to explore the potential link of DNA methylation levels at ATXN3 gene promoter to the pathogenesis of SCA3/MJD. We found that the methylation levels in the ATXN3 promoter were significantly higher in SCA3/MJD patients relative to the controls. Furthermore, higher methylation levels were detected in the SCA3/MJD patients with earlier age at onset and the families with an intergenerational CAG repeats instability. In addition, the first CpG island of the ATXN3 promoter served as the main regulation region of DNA methylation. These findings suggested that an epigenetic change may contribute to the pathogenesis of the SCA3/MJD and provide potential therapeutic targets for CAG repeats-based diseases. PMID- 28094060 TI - Corrigendum to "Parenting very preterm infants and stress in Neonatal Intensive Care Units" [Early Hum. Dev. 101 (2016) 3-9]. PMID- 28094061 TI - Vitiligo-like lesions occurring in patients receiving anti-programmed cell death 1 therapies are clinically and biologically distinct from vitiligo. AB - BACKGROUND: The use of anti-programmed cell death (PD)-1 therapies in metastatic tumors is associated with cutaneous side effects including vitiligo-like lesions. OBJECTIVE: We sought to characterize clinically and biologically vitiligo-like lesions occurring in patients receiving anti-PD-1 therapies by studying a case series of 8 patients with metastatic tumors and 30 control subjects with vitiligo. METHODS: Eight patients receiving anti-PD-1 therapies with features of vitiligo-like lesions seen in our department were recruited. Clinical features and photographs were analyzed. For some patients, skin and blood samples were obtained. Results were compared with the vitiligo group. RESULTS: All patients developed lesions localized on photoexposed areas with a specific depigmentation pattern consisting of multiple flecked lesions without Koebner phenomenon. In contrast to vitiligo, patients receiving anti-PD-1 therapies who developed vitiligo-like lesions did not report any personal or family histories of vitiligo, thyroiditis, or other autoimmune disorders. Analysis of blood and skin samples revealed increased C-X-C motif ligand 10 levels in serum of patients developing vitiligo-like lesions, associated with skin infiltration of CD8 T cells expressing C-X-C motif receptor 3 and producing elevated levels of interferon-gamma and tumor necrosis factor-alfa. LIMITATIONS: This cross sectional study concerned a single center. CONCLUSIONS: Clinical and biological patterns of vitiligo-like lesions occurring in patients receiving anti-PD-1 therapies differ from vitiligo, suggesting a different mechanism. PMID- 28094062 TI - [Optic disc granuloma secondary to sarcoidosis]. AB - We report a case of optic disc granuloma due to sarcoidosis. A 64-year-old, caucasian female with a history of pulmonary sarcoidosis presented with a vision loss on her left eye. The ophthalmologic examination revealed a discrete optic disc infiltrate compatible with the diagnosis of optic disc granuloma. Fluorescein angiography showed diffusion and impregnation of the granuloma without vascularitis. The optical coherence tomography demonstrated a homogenous and isoreflective lesion at the optic disc. The patient recovered her visual acuity after systemic corticosteroid treatment. Isolated optic disc granuloma is a rare condition of ocular sarcoidosis. PMID- 28094063 TI - A change in landscape: Lessons learned from abandonment of ancient Wari agricultural terraces in Southern Peru. AB - Ancient agricultural terrace practices have survived for millennia, sustaining populations through extreme climatic shifts and political regime changes. In arid regions with abrupt relief such as Southern Peru, agricultural terracing is undergoing a resurgence, as has seen revitalization of once abandoned terrace and hydraulic systems. Wari terraces at Cerro Baul provide clues to past cultural practices. They also document sustainable farming practices by using resilient land management techniques which can help combat desertification and degradation of arable lands. Three abandoned Wari terrace systems were mapped using microtopographic methods, the erosion patterns examined, the states of preservation compared, and then the design contrasted with modern terracing practices in the Moquegua Valley. In order to negate the harmful effects of desertification, rehabilitation and reconstruction of these terraces using ancient knowledge and techniques may be necessary. Rehabilitation must be conducted with consideration for preservation of cultural patrimony that may be encountered within the terrace treads or riser structures. With future climatic shifts impacting vulnerable dryland areas more than others, the ability to resiliently respond to these changes may be found in the lessons learned from ancient farming techniques such as the Wari. PMID- 28094064 TI - Bioprospecting of antimicrobial activity of extracts of endophytic fungi from Bauhinia guianensis. AB - Antibiotic resistance results in higher medical costs, prolonged hospital stays and increased mortality and is rising to dangerously high levels in all parts of the world. Therefore, this study aims to search for new antimicrobial agents through bioprospecting of extracts of endophytic fungi from Bauhinia guianensis, a typical Amazonian plant used in combating infections. Seventeen (17) fungi were isolated and as result the methanolic extract of the fungus Exserohilum rostratum showed good activity against the bacteria tested. The polyketide monocerin was isolated by the chromatographic technique, identified by NMR and MS, showing broad antimicrobial spectrum. PMID- 28094065 TI - Risk factors for antimicrobial-resistant Neisseria gonorrhoeae and characteristics of patients infected with gonorrhea. AB - BACKGROUND: There are very few data available regarding risk factors associated with antibiotic resistant-Neisseria gonorrhoeae. METHODS: A study was conducted on 110 samples from 101 patients with gonococcal infection, in order to describe their characteristics and compare them with the antimicrobial susceptibility profile of their samples. RESULTS: An association was observed between resistant infections and heterosexual men, older age, concurrent sexually transmitted infection, and unsafe sexual behaviors. CONCLUSION: There is a need for improved data on the risk factors associated with antibiotic resistant gonococcal infection in order to identify risk groups, and to propose public health strategies to control this infection. PMID- 28094066 TI - Implementation of Elastography Score and Strain Ratio in Combination with B-Mode Ultrasound Avoids Unnecessary Biopsies of Breast Lesions. AB - The aim of this study was to evaluate whether the combination of B-mode ultrasound, elastography score (ES) and strain ratio (SR) improves diagnostic performance with respect to breast lesions. One hundred thirty lesions were prospectively evaluated by B-mode ultrasound and strain elastography, followed by fine-needle aspiration cytology/biopsy in 117 woman who were scheduled for regular breast BUS. The median ES (4.5 vs. 2.9, p < 0.001) and SR (4.9 vs. 2.3, p < 0.001) were significantly higher for malignant than for benign lesions. A sensitivity of 90.5% and specificity of 93.2% for the ES (cutoff point = 3.8) and a sensitivity of 87.5% and specificity of 87.6% for the SR (cutoff point = 3.5) were obtained. Elastography combined with B-mode ultrasound improved the specificity, accuracy and positive predictive value. Receiver operating characteristic curves yielded a higher value for the combined technique for diagnosis of breast lesions. Routine use of such a diagnostic algorithm could reduce the number of unnecessary biopsies. PMID- 28094068 TI - [Large vessel vasculitis with myelodysplastic syndrome: A rare association]. AB - INTRODUCTION: The vasculitis can be the consequence of malignancy: most often hematologic rather than solid tumors. The association between large vessels vasculitis and myelodysplastic syndrome is rare. CASE REPORT: A 55-year-old man experienced asthenia, fever, polyarthritis and inflammatory syndrome. Haematological investigations found a type 2 refractory anemia with excess blasts (RAEB-2) with discovery of severe anemia (Hb: 7,8g/dl) and thrombopenia (platelets: 40,000/mm3). Radiological examinations found thoracic aortitis and carotid vasculitis. Treatment in the form of steroids and azacitidine was instituted. The lack of control of both RAEB-2 and vasculitis was responsible for the death of the patient. CONCLUSION: Myelodysplastic syndrome and large vessels vasculitis is a rare but serious association disease. The lack of efficiency of corticosteroids seems to be common. Prognosis depends on the haematological treatment effectiveness. PMID- 28094067 TI - Differential Intensity Projection for Visualisation and Quantification of Plaque Neovascularisation in Contrast-Enhanced Ultrasound Images of Carotid Arteries. AB - Studies have reported that intraplaque neovascularisation (IPN) is closely correlated with plaque vulnerability. In this study, a new image processing approach, differential intensity projection (DIP), was developed to visualise and quantify IPN in contrast-enhanced non-linear ultrasound image sequences of carotid arteries. DIP used the difference between the local temporal maximum and the local temporal average signals to identify bubbles against tissue non-linear artefact and noise. The total absolute and relative areas occupied by bubbles within each plaque were calculated to quantify IPN. In vitro measurements on a laboratory phantom were made, followed by in vivo measurements in which 24 contrast-enhanced non-linear ultrasound image sequences of carotid arteries from 48 patients were selected and motion corrected. The results using DIP were compared with those obtained by maximum intensity projection (MIP) and visual assessment. The results indicated that DIP can significantly reduce non-linear propagation tissue artefacts and is much more specific in detecting bubble signals than MIP, being able to reveal microbubble signals that are buried in tissue artefacts in the corresponding MIP image. A good correlation was found between microvascular area (MVA) (r = 0.83, p < 0.001)/microvascular density (r = 0.77, p < 0.001) obtained using DIP and the corresponding expert visual grades, comparing favourably to r = 0.26 and 0.23 obtained using MIP on the same data. In conclusion, the proposed method exhibits great potential in quantification of IPN in contrast-enhanced ultrasound images of carotid arteries. PMID- 28094069 TI - Nobel prizes and the pancreatic knowledge. PMID- 28094070 TI - Endometriosis: Modern management of an ancient disease. PMID- 28094071 TI - Benefit of on nephrectomy for treating metastatic renal cell carcinoma. AB - INTRODUCTION: Systemic treatment for metastatic renal cell carcinoma (mRCC) has changed with the new therapies, and it is not clear if nephrectomy (NEP) has a survival benefit in this kind of patients. OBJECTIVE: To investigate if NEP associated to systemic treatment improves overall survival (OS) and progression free survival (PFS). MATERIAL AND METHODS: A retrospective, observational, descriptive study of 45 patients with diagnosis of mRCC between 2006-2014. Advanced cases with only palliative care were excluded, also patients with solitary metastasis who were managed with surgical resection. RESULTS: Finally 34 patients were treated with systemic treatment. Twenty-six also with surgery associated. Seventy percent were intermediate/low risk at the Motzer classification and>80% Karnofsky performance status. PFS was 7m. NEP improves PFS (10 vs. 4m). High risk Motzer decreased PFS (P<.001). The OS was 11.5m. Patients with Karnofsky performance status>80, intermediate or low risk Motzer treated with NEP and mTOR as second line treatment, increased the OS (14 vs. 3m, P=.0001; 14 vs. 6m, P=.001; and 9 vs. 5m, P=.003, respectively). In the multivariate analysis only NEP (P=0,006; HR 4.5) and intermediate/low risk at the Motzer classification(P=.020; HR 8.9) demonstrated significant improvement in OS. CONCLUSIONS: Patients treated with NEP associated to systemic treatment and with an intermediate/low risk in the Motzer classification had a better PFS and OS. The OS also improves in patients treated with mTOR in second line, and Karnofsky performance status>80%in the univariate study, but not in the multivariable one. PMID- 28094072 TI - Survey on graduate education in the Confederacion Americana de Urologia: Opinions and reality. AB - OBJECTIVE: Quality graduate medical training is a concern of Confederacion Americana de Urologia (CAU), the third largest urological society worldwide. It is important to analyse the diversity in the state training programmes and the feasibility and implications of conducting a common CAU programme. MATERIAL AND METHODS: A 20-item questionnaire was distributed to the directors of national societies who are members of the CAU concerning the graduate urological training in their institutions. RESULTS: A total of 28 presidents and expresidents representing 21 countries responded, the total number of independent states that constitute the confederation. In this setting, 664 residents start their training programme every year, in an area that treats 645.4 million inhabitants, with an active professional force of 16,752 specialists. We present data on the realities of the training (length of the programme, core curriculum) and occupation (job access, possible flow between countries) and on how accreditation and re certification of specialists in these countries are conducted. We also present the opinions on the feasibility of a joint CAU degree, as well as a number of its implications. CONCLUSIONS: The actual graduate training in the CAU setting is heterogeneous in its programmes and in its accreditation and re-certification methods. There is a strong desire to achieve joint degrees, except in Spain and Portugal. To enable joint certification, there will need to be intervention on numerous aspects and levels, redefining the desire for healthcare coverage in each country and considering the possible flow of specialists. PMID- 28094073 TI - Muscle function of the pelvic floor in healthy, puerperal women with pelvic floor dysfunction. AB - OBJECTIVES: To understand the function of the pelvic floor muscles (PFM) at different ages in healthy women and in puerperal women with pelvic floor dysfunctions (PFD) and to ascertain whether there are differences among them. MATERIAL AND METHODS: A descriptive cross-sectional study was conducted between June 2014 and September 2016 and included 177 women, 70 of whom had no symptoms of PFD, 53 primiparous mothers in late postpartum and 54 with PFD. The function of the PFM was measured through vaginal palpation (quality of the contraction); manometry (force); dynamometer (tone, strength, and response to stretching), and surface electromyography (neuromuscular activity and resistance). RESULTS: The healthy women showed superior values for PFM tone, maximum strength, neuromuscular activity and resistance than the puerperal mothers and the women with PFD (P<.01). The puerperal women and those with PFD showed similar functional PFM values (P>.05). The muscle function of the healthy women did not vary significantly with age, except in the case of tone, which was lower in the women older than 46 years (P=.004). CONCLUSIONS: Age and births decrease the baseline tone of the PFM in healthy women. Therefore, lower strength, resistance and neuromuscular activity appear to be the main difference between the PFM of women with PFD and the PFM of healthy women. PMID- 28094074 TI - Farewell to Prof. Jens Overgaard. PMID- 28094075 TI - Re-assessing the total burden of norovirus circulating in the United Kingdom population. AB - The second Infectious Intestinal Diseases study (IID2) estimated the incidence of norovirus in the UK at 47/1000 population (three million cases annually). Clinically significant norovirus was defined using a cycle threshold (ct) value of <30; a more stringent cut-off than used in diagnostic laboratories. The low infectious dose of norovirus means asymptomatic individuals potentially contribute to ongoing transmission. Using a less stringent but diagnostically relevant threshold increases the estimation of the population burden of norovirus infection by around 26% to 59/1000 person years (95% CI 52.32-64.98), equating to 3.7 million norovirus infections annually (3.3-4.1 million). With possible vaccines on the horizon for norovirus, having a good estimate of the total burden of norovirus infection, as well as symptomatic disease will be useful in helping to guide vaccination policy when candidate vaccines become available. PMID- 28094076 TI - Influenza vaccination in older people with diabetes and their household contacts. AB - BACKGROUND: People with diabetes are at a higher risk of influenza infections and severe complications. The vaccination of close contacts could offer indirect protection to people with diabetes; this is known as "herd immunity." The aim of this study is to investigate the vaccination rates of people with diabetes and their household contacts in Hong Kong. RESEARCH DESIGN AND METHODS: Face-to-face interviews with 158 patients diagnosed with Type 2 diabetes and aged ?65years were conducted in clinics. Telephone interviews were then conducted with 281 adult household contacts. RESULTS: Seasonal influenza vaccination rates were 54.5% and 27.4%, in people with diabetes and their contacts, respectively. The vaccination status of patients was not significantly associated with the vaccination of their household contacts (p=0.073). Among household contacts, children or the elderly, the partners or couples of patients, and those with more hours of daily contact, or with chronic conditions, were associated with higher vaccination rates. However, only age remained significant after adjusting for confounding factors in logistic regression models. CONCLUSIONS: The low vaccination rates of people with diabetes and their close contacts highlight the need to promote vaccination in susceptible populations and to educate the public about herd immunity. PMID- 28094077 TI - Human papillomavirus vaccine series completion in boys before and after recommendation for routine immunization. AB - BACKGROUND: Although the incidence of HPV-attributable cancers in males is rapidly increasing, HPV vaccine uptake in males remains poor. While quadrivalent human papillomavirus vaccine (4vHPV) series initiation in males increased following the Advisory Committee Immunization Practices (ACIP) male routine use recommendation, its impact on 4vHPV series completion in males at ACIP recommended intervals has not been evaluated in large male cohorts. We examined trends and correlates of 4vHPV completion since licensure in males in a large cohort of insured boys before and after the ACIP routine use recommendation. METHODS: We grouped data from electronic medical records of males aged 9-17years from Kaiser Permanente Southern California health plan who initiated 4vHPV into 3 cohorts by 4vHPV initiation date: licensure and ACIP permissive use: 2009-2010; addition of anal cancer indication: 2010-2011; ACIP routine use: 2011-2013. We estimated adjusted hazard ratios (AHRs) between patient and provider characteristics and vaccination using Marginal Cox proportional hazards models. RESULTS: Of 80,800 boys initiating 4vHPV, 24.3% completed the series within 12months with minimal differences across cohorts. Completion decreased with increasing age at initiation (13-17vs. 11-12year olds: AHR=0.85; 95% confidence interval [CI]=0.80, 0.89) and was greater among patients with a primary care provider (AHR=1.28, 95%CI=1.17, 1.41), influenza vaccine recipients (AHR=1.50, 95% CI=1.43, 1.57), and Asian/Pacific Islanders (AHR=1.07, 95% CI=1.00, 1.15), and lower among non-Hispanic Blacks (AHR=0.72, 95% CI=0.65, 0.80) and Hispanics (AHR=0.86, 95% CI=0.81, 0.90) compared to non-Hispanic Whites. CONCLUSIONS: Despite the ACIP routine use recommendation in males, 4vHPV series completion remained low. 4vHPV initiation at 11-12years and identification of a provider responsible for the adolescents' health care may increase 4vHPV series completion. Given the rapidly increasing incidence of HPV-related cancers in males, it is important to identify measures to increase HPV vaccine series completion, particularly among non-Hispanic Black and Hispanic males. PMID- 28094078 TI - Response to "Reassessing Claims of Non-inferiority of Daptomycin". PMID- 28094079 TI - A Stroke Mimic: Methotrexate-induced Neurotoxicity in the Emergency Department. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common form of childhood leukemia. The treatment of ALL involves multimodality therapy, and methotrexate (MTX) remains a mainstay of treatment. A complication of MTX therapy includes acute, subacute, and chronic neurotoxocity. Signs and symptoms may range from headaches, dizziness, and mood disorders to seizures and stroke-like symptoms. CASE REPORT: An 18-year-old woman with a history of ALL presented to the emergency department with acute onset of right-sided facial paralysis, right upper extremity flaccid paralysis, and right lower extremity weakness after receiving MTX therapy 3 days earlier. Diagnostic studies were unremarkable and the patient was treated with oral dextromethorphan for presumed MTX-induced neurotoxicity. The patient's symptoms began to improve within hours and she was discharged home within 48 hours with no neurologic deficits. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should be aware of this complication of MTX therapy given the sensitivity in regards to time with respect to cerebral vascular accidents. An awareness of this complication in the setting of the appropriate history and physical examination can lead to an accurate diagnosis and intervention and the avoidance of administering thrombolytics. PMID- 28094080 TI - Respectful Modeling: Addressing Uncertainty in Dynamic System Models for Molecular Biology. AB - Although there is still some skepticism in the biological community regarding the value and significance of quantitative computational modeling, important steps are continually being taken to enhance its accessibility and predictive power. We view these developments as essential components of an emerging 'respectful modeling' framework which has two key aims: (i) respecting the models themselves and facilitating the reproduction and update of modeling results by other scientists, and (ii) respecting the predictions of the models and rigorously quantifying the confidence associated with the modeling results. This respectful attitude will guide the design of higher-quality models and facilitate the use of models in modern applications such as engineering and manipulating microbial metabolism by synthetic biology. PMID- 28094081 TI - Emerging Human Fetuin A Assays for Biomedical Diagnostics. AB - Human fetuin A (HFA) plays a prominent pathophysiological role in numerous diseases and pathophysiological conditions with considerable biomedical significance; one example is the formation of calciprotein particles in osteoporosis and impaired calcium metabolisms. With impressive advances in in vitro diagnostic assays during the last decade, ELISAs have become a workhorse in routine clinical diagnostics. Recent diagnostic formats involve high-sensitivity immunoassay procedures, surface plasmon resonance, rapid immunoassay chemistries, signal enhancement, and smartphone detection. The current trend is toward fully integrated lab-on-chip platforms with smartphone readouts, enabling health-care practitioners and even patients to monitor pathological changes in biomarker levels. This review provides a critical analysis of advances made in HFA assays along with the challenges and future prospects. PMID- 28094082 TI - The LMA Fastrach(r) as a conduit for endotracheal intubation during simulated cardiopulmonary resuscitation. PMID- 28094083 TI - Unmasking evolutionary diversity among two closely related South African legless skink species (Acontinae: Acontias) using molecular data. AB - We examined species boundaries among two phylogenetically closely related and morphologically similar South African fossorial legless skink species, Acontias breviceps and Acontias gracilicauda. Samples of these two species were collected throughout their distribution ranges and sequenced for three DNA loci (two mitochondrial loci, 16S rRNA and cytochrome b (Cyt b), plus the nuclear locus prolactin). Phylogenetic relationships were determined using maximum parsimony, Bayesian inference and maximum likelihood analyses of the combined DNA sequence data set. The total evidence topology retrieved two paraphyletic clades in both Acontias species with strong statistical support. The phylogenetic results revealed that A. breviceps specimens from the Eastern Cape Province were basal (Clade 1), while the Highveld specimens of A. breviceps from the Mpumalanga Province (Clade 2) were retrieved as sister to A. gracilicauda (Clade 1). In addition, the A. gracilicauda specimens from the interior of the Northern Cape Province (Clade 2) were found embedded within the A. occidentalis species complex. These clades were characterised by marked sequence divergence for the Cyt b locus. Furthermore, no maternal or nuclear haplotypes were shared between clades within both A. breviceps and A. gracilicauda, alluding to genetic and reproductive isolation. The results provide overwhelming evidence to assign A. breviceps from the Mpumalanga Highveld to a novel species. Further sampling is required to accurately delineate species boundaries within A. gracilicauda. The conservation implications of our results are briefly discussed. PMID- 28094084 TI - Incontinence and psychological symptoms in individuals with Mowat-Wilson Syndrome. AB - BACKGROUND: Mowat-Wilson Syndrome (MWS) is caused by deletion/mutation of the ZEB2 gene on chromosome 2q22. MWS is characterized by a distinctive facial appearance, severe intellectual disability and other anomalies, e.g. seizures and/or Hirschsprung disease (HSCR). Most individuals have a sociable demeanor, but one third show psychological problems. AIMS: The aim was to investigate incontinence and psychological problems in MWS. METHODS AND PROCEDURES: 26 children (4-12 years), 13 teens (13-17 years) and 8 adults (>18years) were recruited through a MWS support group. The Parental Questionnaire: Enuresis/Urinary Incontinence, as well as the Developmental Behaviour Checklist (DBC) were completed by parents or care-givers. OUTCOMES AND RESULTS: 97.7% of persons with MWS had incontinence (nocturnal enuresis 74.4%; daytime urinary incontinence 76.2%; fecal incontinence 81.4%). Incontinence remained high over age groups (children 95.8%, teens 100%, adults 100%). 46.2% of children, 25% of teens and 37.5% of adults exceeded the clinical cut-off on the DBC. The ability to use the toilet for micturition improved with age. CONCLUSIONS AND IMPLICATIONS: MWS incontinence rates are very high. All had physical disabilities including anomalies of the genitourinary and gastrointestinal tract. Due to the high prevalence rates, a screening for incontinence and psychological problems in MWS is recommended. PMID- 28094085 TI - What is the most accurate lymph node staging method for perihilar cholangiocarcinoma? Comparison of UICC/AJCC pN stage, number of metastatic lymph nodes, lymph node ratio, and log odds of metastatic lymph nodes. AB - BACKGROUND: We compared the prognostic performance of the International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) 7th edition pN stage, number of metastatic LNs (MLNs), LN ratio (LNR), and log odds of MLNs (LODDS) in patients with perihilar cholangiocarcinoma (PCC) undergoing curative surgery in order to identify the best LN staging method. METHODS: Ninety-nine patients who underwent surgery with curative intent for PCC in a single tertiary hepatobiliary referral center were included in the study. Two approaches were used to evaluate and compare the predictive power of the different LN staging methods: one based on the estimation of variable importance with prediction error rate and the other based on the calculation of the receiver operating characteristic (ROC) curve. RESULTS: LN dissection was performed in 92 (92.9%) patients; 49 were UICC/AJCC pN0 (49.5%), 33 pN1 (33.3%), and 10 pN2 (10.1%). The median number of LNs retrieved was 8. The prediction error rate ranged from 42.7% for LODDS to 47.1% for UICC/AJCC pN stage. Moreover, LODDS was the variable with the highest area under the ROC curve (AUC) for prediction of 3-year survival (AUC = 0.71), followed by LNR (AUC = 0.60), number of MLNs (AUC = 0.59), and UICC/AJCC pN stage (AUC = 0.54). CONCLUSIONS: The number of MLNs, LNR, and LODDS appear to better predict survival than the UICC/AJCC pN stage in patients undergoing curative surgery for PCC. Moreover, LODDS seems to be the most accurate and predictive LN staging method. PMID- 28094086 TI - Differentiated and Medullary Thyroid Cancer: Surgical Management of Cervical Lymph Nodes. AB - Thyroid cancer metastasises to the central and lateral compartments of the neck frequently and early. The impact of nodal metastases on outcome is affected by the histological subtype of the primary tumour and the patient's age, as well as the size, number and location of those metastases. The impact of extranodal extension has recently been highlighted as an important prognosticating factor. Although clinically evident nodal disease in the lateral neck compartments has a significant impact on both survival and recurrence, microscopic metastases to the central or the lateral neck in well-differentiated thyroid cancer do not significantly affect outcome. Here we discuss the surgical management of neck metastases in well-differentiated and medullary thyroid carcinoma. PMID- 28094087 TI - [Management of jaundice in the newborn>=35 GW: From screening to follow-up after discharge. Guidelines for clinical practice]. AB - Jaundice due to unconjugated bilirubin is an everyday condition in the neonatal period because it results from the adaptation of bilirubin metabolism at this time of life. Hyperbilirubinemia has a potential neurotoxicity and although it most often resolves spontaneously, it can lead to acute and sometimes chronic encephalopathy. The latter condition is called kernicterus and induces severe and irreversible neurological sequelae. This rare complication is still reported in all countries throughout the world even if severe hyperbilirubinemia can be prevented and critical points points of failure in jaundice management are identified. Jaundice management are identified, jaundice is the most frequent symptom during the first days of life and after discharge from the maternity ward but also the major cause of readmission in the 15 first days of life. Therefore in the past 20 years, numerous countries have written national practical guidelines for the management of neonatal jaundice using various methodologies. Most of the time, the guidelines resulted from expert consensus more than from an evidence-based argument. The Societe francaise de neonatologie created a working group to provide the first French clinical guidelines for the management of jaundice in the near-term newborn (35 weeks and more). They were written following a physiopathological argument and taking into account both clinical risk factors for severe hyperbilirubinemia and interindividual variability in vulnerability to bilirubin neurotoxicity. Practical tools were also developed to facilitate implementation of the guidelines and are also included. PMID- 28094088 TI - Usefulness of multiparametric computerized tomography findings in the differential diagnosis of stroke mimics of epileptic origin: A preliminary study. AB - OBJECTIVE: Thirty percent of the patients for whom code stroke is activated have stroke mimics, the most common being epilepsy. Our purpose was to evaluate the usefulness of multiparametric CT for differentiating between seizure-related symptoms and vascular events. MATERIAL AND METHODS: We conducted a retrospective observational study; data were gathered prospectively during one year. We studied multiparametric CT images of patients admitted following code stroke activation and finally diagnosed with epilepsy. RESULTS: The study included a total of 11 patients; 36% were men and mean age was 74.5 years. Three patients had right hemisphere syndrome, 4 displayed left hemisphere syndrome, and the remaining 4 had isolated aphasia. Maximum time from symptom onset to multiparametric CT study was 8.16hours. Perfusion CT results were normal in 2 patients. Nine patients showed longer or shorter times to peak (Tmax); cerebral blood volume (CBV) and cerebral blood flow (CBF) maps varied. EEG was performed a maximum of 47.6hours after symptom onset. Four patients showed findings compatible with status epilepticus, 2 displayed focal epileptiform activity, and 5 showed post-ictal slowing ipsilateral to perfusion CT abnormalities. CONCLUSION: The most sensitive parameter for differentiating between stroke and epilepsy in our series was increased time to peak in multilobar cortical locations in the absence of large vessel occlusion and basal ganglia involvement. Multiparametric CT is a fast, readily available, and useful tool for the differential diagnosis of acute-onset neurological signs of epileptic origin in patients initially attended after code stroke activation. PMID- 28094089 TI - Use of emergency medical transport and impact on time to care in patients with ischaemic stroke. AB - INTRODUCTION: According to numerous studies, using emergency medical services (EMS) to transport stroke patients to hospitals decreases diagnostic and treatment delays. OBJECTIVES: To determine the frequency of use of EMS by stroke patients in Bizkaia (Spain), analyse the factors associated with using EMS, and study the impact of EMS on time to care. METHODS: We gathered data from 545 patients hospitalised for acute ischaemic stroke and recruited consecutively. Data were obtained from the patients' medical histories and interviews with the patients themselves or their companions. We studied the following variables: previous health status, stroke symptoms and severity (NIHSS), type of transport, and time to medical care. Univariate and multivariate analyses were performed to identify factors associated with use of EMS and care delays. RESULTS: Patients transported to hospital by the EMS accounted for 47.2% of the total. Greater stroke severity, arriving at the hospital at night, and poor functional status at baseline were found to be independently associated with use of EMS. Use of EMS was linked to earlier arrival at the hospital. Door-to-imaging times were shorter in the EMS group; however, this association disappeared after adjusting for stroke severity. Revascularisation was more frequent among patients transported by the EMS. CONCLUSIONS: EMS transport was associated with shorter prehospital delays. Effective health education programmes should be developed to promote EMS transport for patients with stroke symptoms. In-hospital stroke management should also be improved to reduce time to medical care. PMID- 28094090 TI - Biogas production from co-digestion of organic fraction of municipal solid waste and fruit and vegetable waste. AB - The anaerobic co-digestion of organic fraction of municipal solid waste (OFMSW) and fruit and vegetable waste (FVW) was evaluated in terms of biogas and methane yield, volatile solids (VS) removal rate and stability of the process. The batch experiment was conducted in mesophilic conditions (35 degrees C), with four different OFMSW/FVW ratios (VS basis) of 1/0, 1/1, 1/3, and 0/1. The methane yield from the co-digestion was higher than the mono-digestion for OFMSW and FVW. The optimal mixing ratio of OFMSW/FVW was found to be 1/3. The average cumulative biogas and methane yield in this condition was 493.8NmL/gVS and 396.6NmL/gVS, respectively, and the VS removal rate was 54.6%. Compared with the mono-digestion of OFMSW and FVW, the average increase in methane yield was 141% and 43.8%, respectively. PMID- 28094091 TI - Can MALDI-TOF Mass Spectrometry Reasonably Type Bacteria? AB - Bacterial typing is crucial to tackle the spread of bacterial pathogens but current methods are time-consuming and costly. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has been recently integrated into the microbiology laboratory workflow for a quick and low-cost microbial species identification. Independent research groups have successfully redirected the original function of this technology from their primary purpose to discriminate subgroups within pathogen species. However, identical bacterial subgroups could be identified by unrelated peaks by independent methods, thus limiting their robustness and exportability. We propose several guidelines that could improve the performance of MALDI-TOF MS-based typing methods for use as a first-line epidemiological tool. PMID- 28094092 TI - Step by Step, Cell by Cell: Quantification of the Bacterial Cell Cycle. AB - The Escherichia coli cell cycle is a classic, but we are still missing some of its essential aspects. The reason is that our knowledge is mostly based on population data, and our grasp of the behavior of single cells is still very limited. Today, new dynamic single-cell data promise to overcome this barrier. Existing data from single cells have already led to findings and hypotheses that challenge standard views, and have raised new questions. Here, we review these recent developments and propose that a systematic exploration of the correlation patterns between 'cell-cycle intervals' defined by key molecular events measured in many single cells could lead to a quantitative characterization of the cell cycle in terms of inherent stochasticity and homeostatic controls. PMID- 28094093 TI - AChiralPentagonalPolyhedralFramework forCharacterizingVirusCapsidStructures. AB - Recent developments of rational strategies for the design of antiviral therapies, including monoclonal antibodies (mAbs), have naturally relied extensively on available viral structural information. As new strategies continue to be developed, it is equally important to continue to refine our understanding and interpretation of viral structural data. There are known limitations to the traditional (Caspar-Klug) theory for describing virus capsid structures that involves subdividing a capsid into triangular subunits. In this context, we describe a more general polyhedral framework for describing virus capsid structures that is able to account for many of these limitations, including a more thorough characterization of intersubunit interfaces. Additionally, our use of pentagonal subunits instead of triangular ones accounts for the intrinsic chirality observed in all capsids. In conjunction with the existing theory, the framework presented here provides a more complete picture of a capsid's structure and therefore can help contribute to the development of more effective antiviral strategies. PMID- 28094094 TI - SIRA+P: Development and Testing. AB - OBJECTIVES: To describe the development of a new skin risk assessment scale called Skin Injury Risk Assessment and Prevention (SIRA+P) and to establish initial reliability and validity of the scale among patients ranging in age from birth, including pre-term, to adulthood, regardless of age or acuity of illness. STUDY DESIGN: The single-site study was a retrospective chart review to evaluate the measurement properties of SIRA+P. Charts of 385 patients of all ages and in all units (including the neonatal and pediatric intensive care units) of a free standing children's hospital were included. Concurrent validity was assessed with scales having previously established reliability and validity. For subjects <30days of age, the comparison scale was the Neonatal Skin Risk Assessment Scale (NSRAS); for subjects 31days through 17years, the Braden Q Scale (Braden Q) was used; and for subjects 18years and older, the Braden Scale (Braden) was used. Interrater reliability was examined using Intraclass Correlation Coefficients (ICC). Concurrent validity procedures compared SIRA+P with NSRAS, Braden Q, and Braden using Pearson Correlation Coefficients. RESULTS: Interrater reliability for SIRA+P was very high (0.878). SIRA+P strongly correlated with the NSRAS (0.725), the Braden Q (-0.634), and the Braden (-0.778). CONCLUSION: SIRA+P is designed to be used within the EHR and includes nursing decision support to guide pressure injury prevention interventions for specific skin integrity risks. SIRA+P has good interrater reliability, is valid across all age groups and accounts for device-related pressure. PMID- 28094096 TI - Component columella augmentation in cleft nose rhinoplasty: a preliminary study. AB - The purpose of this study was to evaluate the outcome of a component columella augmentation technique in cleft nose rhinoplasty. This prospective study included rhinoplasty procedures in bilateral cleft nose patients treated by component columella augmentation technique. After surgery, all patients were followed up daily for the first week, and then at 1 month and 6 months postoperative. The following four parameters were assessed: nasal tip projection, infratip lobule length, infratip lobule-to-base distance, and columella-labial angle. Thirteen rhinoplasty patients were included. Tip projection was increased (5.6+/-3.5mm) in all cases postoperatively (P<0.05); the increase was seen mostly in the lobule-to base length (4.5+/-0.4mm), with a minimal change in lobule length (1.1+/-3.6mm). Preoperative and postoperative lobule lengths were not statistically different (P>0.05). With this technique, it is not necessary to involve the upper and lower lips. Therefore, the non-aesthetic vertical scars and tissue distortion that may occur with local flaps are easily avoided. Compared to composite augmentation, each part of the deformity (cartilage and skin) is precisely and separately restored with this technique. PMID- 28094095 TI - Analysis of stereoselective drug interactions with serum proteins by high performance affinity chromatography: A historical perspective. AB - The interactions of drugs with serum proteins are often stereoselective and can affect the distribution, activity, toxicity and rate of excretion of these drugs in the body. A number of approaches based on affinity chromatography, and particularly high-performance affinity chromatography (HPAC), have been used as tools to study these interactions. This review describes the general principles of affinity chromatography and HPAC as related to their use in drug binding studies. The types of serum agents that have been examined with these methods are also discussed, including human serum albumin, alpha1-acid glycoprotein, and lipoproteins. This is followed by a description of the various formats based on affinity chromatography and HPAC that have been used to investigate drug interactions with serum proteins and the historical development for each of these formats. Specific techniques that are discussed include zonal elution, frontal analysis, and kinetic methods such as those that make use of band-broadening measurements, peak decay analysis, or ultrafast affinity extraction. PMID- 28094097 TI - Diverse genotypes of Bradyrhizobium nodulate herbaceous Chamaecrista (Moench) (Fabaceae, Caesalpinioideae) species in Brazil. AB - The genus Chamaecrista comprises more than 330 species which are mainly distributed across tropical America, especially in Brazil (256 spp.), the main center of radiation. In this study, nodulation of herbaceous Chamaecrista species that are commonly found growing in different vegetation types in the north eastern Brazilian state of Bahia was assessed together with the diversity of rhizobia isolated from their root nodules. Genetic characterization of the isolates was performed using molecular markers to examine the phylogeny of their "core" (16S rRNA, ITS, recA, glnII, dnaK and gyrB) and symbiosis-related (nifH, nodC) genomes. Nodule morphology, anatomy and ultrastructure were also examined, as was the capacity of the isolates to form nodules on Chamaecrista desvauxii and siratro (Macroptilium atropurpureum). Analysis of 16S rRNA gene sequences demonstrated that the isolates belonged to seven clusters within the genus Bradyrhizobium, and more detailed analyses using sequences of the ITS region and concatenated housekeeping genes grouped the Chamaecrista rhizobia by vegetation type and plant species. These analyses also suggested some potentially novel Bradyrhizobium species, which was corroborated by analyses of their nifH and nodC sequences, as these formed separated branches from all Bradyrhizobium type strains. All the 47 strains tested produced effective nodules on C. desvauxii but none on siratro. Chamaecrista nodules are herein described for the first time in detail: they are indeterminate and structurally similar to others described in the Caesalpinioideae, with infection threads in the invasion and nitrogen fixation zones, and with both infected and uninfected (interstitial) cells in the nitrogen fixation zone. PMID- 28094098 TI - Altered balance of epidermis-related chemokines in epidermolysis bullosa. AB - BACKGROUND: Epidermolysis bullosa (EB) is a congenital, refractory skin disease and there are no fundamental treatments. Recently, allogenic cell therapies are beginning to be applied as potential treatments, that are based on the concept that the allogenic cells can migrate into the skin and reconstitute the skin components. Although the mechanisms of cell migration into skin are not fully understood, chemokines are regarded as key factors in recruiting bone marrow derived cells. OBJECTIVES: Our study aims to elucidate the expression of chemokines in the EB patients. METHODS: We determined the expression of wound healing related chemokines in the sera, keratinocytes, and skin tissues of EB patients and compared them to those of healthy volunteers by enzyme-linked immunosorbent assays, quantitative reverse transcription PCR, and immunofluorescence staining. RESULTS: The serum levels of CXCL12 and HMGB1 were found to be significantly elevated in the EB patients. Conversely, the serum levels of CCL21 were found to be lower in the EB patients than in healthy controls. In addition, the serum levels of CXCL12 tended to increase and the serum levels of CCL27 tended to decrease with an increase in the affected body surface areas. To detect the origin of the circulating chemokines, we performed immunofluorescence staining. CCL21, CCL27, HMGB1 and CXCL12 were stained more broadly in the EB patient tissues than those in the control tissues. CONCLUSIONS: These results suggest that fluctuations in chemokine levels may contribute in a coordinated way to the wound-healing process and lend clues toward efficient cell therapies for EB. PMID- 28094099 TI - Association between -1082 A/G polymorphism in IL-10 and oral lichen planus: A meta-analysis. PMID- 28094100 TI - Inhibition of collagen production by ICG-001, a small molecule inhibitor for Wnt/beta-catenin signaling, in skin fibroblasts. PMID- 28094101 TI - Retinoic Acid and Immune Homeostasis: A Balancing Act. AB - In the immune system, the vitamin A metabolite retinoic acid (RA) is known for its role in inducing gut-homing molecules in T and B cells, inducing regulatory T cells (Tregs), and promoting tolerance. However, it was suggested that RA can have a broad spectrum of effector functions depending on the local microenvironment. Under specific conditions, RA can also promote an inflammatory environment. We discuss the dual role of RA in immune responses and how this might be regulated. Furthermore, we focus on the role of RA in autoimmune diseases and whether RA might be used as a therapeutic agent. PMID- 28094103 TI - Characterization of particulate matter binding peptides screened from phage display. AB - Particulate matter (PM), especially particulates with diameters of less than 2.5 MUm, can penetrate the alveolar region and increase the risk of respiratory diseases. This has stimulated research efforts to develop detection methods so that counter measures can be taken. In this study, four PM binding peptides were obtained by phage display and binding characteristics of these peptides were investigated using the peptide array. The strongest binding peptide, WQDFGAVRSTRS, displayed a binding property, measured in terms of spot intensity, 11.4 times higher than that of the negative control, AAAAA. Inductively coupled plasma mass spectrometry (ICPMS) analysis of the transition metal compounds in the PM bound to the peptide spots was performed, and two peptides showed higher binding towards Cu and Zn compounds in PM. These results suggest that the screened peptides could serve as an indicator of transition metal compounds, which are related to adverse health effects, contained in PM. PMID- 28094102 TI - Single-Cell Genomics: Approaches and Utility in Immunology. AB - Single-cell genomics offers powerful tools for studying immune cells, which make it possible to observe rare and intermediate cell states that cannot be resolved at the population level. Advances in computer science and single-cell sequencing technology have created a data-driven revolution in immunology. The challenge for immunologists is to harness computing and turn an avalanche of quantitative data into meaningful discovery of immunological principles, predictive models, and strategies for therapeutics. Here, we review the current literature on computational analysis of single-cell RNA-sequencing data and discuss underlying assumptions, methods, and applications in immunology, and highlight important directions for future research. PMID- 28094104 TI - Zolpidem in movement disorders after cardiac arrest. PMID- 28094105 TI - Sonographic alteration of substantia nigra is related to parkinsonism-predominant course of X-linked dystonia-parkinsonism. AB - INTRODUCTION: X-linked recessive dystonia-parkinsonism (XDP, DYT3) is highly prevalent in the Philippines and manifests with varying phenotype. We sought to evaluate the significance of transcranial brain sonography as a biomarker for parkinsonism-predominant phenotype. METHODS: 90 Filipino participants were enrolled into a cross-sectional study: 39 patients with XDP, 21 asymptomatic first-degree relatives of XDP patients, and 30 healthy control subjects. Echogenicity of the substantia nigra and the lenticular nuclei was digitally quantified. Brain sonography data were compared with video-based clinical assessment, genetic status and pedigree charts. RESULTS: The majority of patients had hyperechogenicity of the substantia nigra (79%) and/or the lenticular nuclei (81%). Disease duration correlated with echointensity of lenticular nuclei (Pearson test, r = 0.55, p = 0.029) but not substantia nigra (p = 0.31). Abnormal substantia-nigra hyperechogenicity was more frequent in patients with prominent parkinsonism (100%) compared to those without (68%; chi2 test, p = 0.035). The grading of substantia-nigra echogenicity (normal/increased) in patients was in all cases identical to that in their respective asymptomatic relatives. All patients with "familial" substantia-nigra normoechogenicity presented with a phenotype of predominant dystonia and only mild parkinsonism. In turn, "familial" substantia-nigra hyperechogenicity indicated a phenotype with moderate to severe parkinsonism (sensitivity, 100%; specificity, 67%; Fisher test, p = 0.021). CONCLUSION: Findings imply early alteration of the substantia nigra in XDP mutation carriers prone to develop parkinsonism. Thus, substantia-nigra hyperechogenicity may be regarded as a preclinical risk marker of parkinsonism predominant XDP. Furthermore, this biomarker is clustered in some families suggesting the existence of one or more genetic co-factors influencing the phenotype of the disease. PMID- 28094106 TI - Expanded phenotype and hippocampal involvement in a novel compound heterozygosity of adult PLA2G6 associated neurodegeneration (PARK14). PMID- 28094107 TI - Drug eruption caused by esomeprazole: A case report and mini-review. PMID- 28094108 TI - Analysis of primary treatment and prognosis of spontaneous urticaria. AB - BACKGROUND: The prognosis of spontaneous urticaria in association with early treatment remains unclear. In this study, we retrospectively studied the prognosis of acute spontaneous urticaria in relation to age and treatments in a local clinic of dermatology. METHODS: Out of 5000 patients who visited an office dermatology clinic, clinical records of patients with spontaneous urticaria were extracted. Their prognosis and the relation to age and treatments were analyzed by the Kaplan-Meier method and generalized Wilcoxon test. RESULTS: Among 386 patients diagnosed with spontaneous urticaria, 284 patients (73.6%) began treatments within a week after the onset. Their non-remission rates after one week, four weeks and one year from the onset were 26.8%, 15.0% and 6.7%, respectively. The non-remission rates of patients who were 20-years-old or younger by one year after the onset of urticaria, were significantly lower than those of patients older than 20-years-old. No apparent relationship between remission rates and sex or the use of steroids was detected. However, the non remission rates of urticaria treated with a standard dose of antihistamine were lower than that treated with additional medications. CONCLUSIONS: Most patients who began treatments within one week from the onset remitted quickly. However approximately 7% of them continued to suffer from symptoms for more than a year. Such prolongation tended to be seen among patients who required other medications in addition to a standard dose of antihistamine. PMID- 28094109 TI - Significant changes in the 6th edition of FACT-JACIE standards affecting apheresis facilities. AB - FACT-JACIE cellular therapy standards are being revised every 3years and currently in their 6th edition. Significant changes in the 6th edition of the standards that affect apheresis facilities participating in cellular therapy product collections are presented. PMID- 28094110 TI - Use of convalescent plasma in Ebola virus infection. AB - The recent Ebola virus epidemics which threatened three West African countries (Dec.2014-Apr.2016) has urged global collaborative health organizations and countries to set up measures to stop the infection and to treat patients, near half of them being at risk of death. Convalescent plasma-recovered from rescued West Africans-was considered a feasible therapeutic option. Efficacy was difficult to evaluate because of numerous unknowns (especially evolution of neutralizing antibodies), prior to the cessation of active transmission. This raises a large body of questions spanning epidemiological, virological, immunological but also ethical, sociological and anthropological aspects, alongside with public health concerns, in order to be better prepared to the next outbreak. This essay summarizes efforts made by a large number of groups worldwide, and attempts to address still unanswered questions on the benefit of specific versus non-specific plasma on altered-leaking-vascular endothelia in Ebola infection. PMID- 28094111 TI - Rupture of the stem cell bag before stem cell infusion: Evolving standard operating procedures. AB - The lives of recipients of peripheral blood progenitor cells (PBPC) depend upon the availability of PBPC. Rupture of stem cell bags does occur and can have devastating consequences. Each transplant center should agree on a rescue procedure and train its personnel to use it. We provide an example of such a procedure, and its update after the procedure was used for the first time. PMID- 28094112 TI - Extracorporeal photopheresis for bronchiolitis obliterans syndrome after allogeneic stem cell transplant: An emerging therapeutic approach? AB - Bronchiolitis obliterans syndrome (BOS) is the main manifestation of pulmonary GVHD. It has often a dramatic and fast evolution and current treatment (change or increase in immunosuppression, macrolides and inhaled therapy) is poor with high mortality rates. In this scenario, extracorporeal photopheresis (ECP) bursts as a new immunomodulatory approach with a different philosophical purpose. In fact, available data show that ECP treatment is intended to delay the inflammatory process and consequently respiratory lung function decline, rather than reverse the damage itself. Preliminary results reported in literature show that ECP may effectively improve/slow lung function decline in cGVHD patients with BOS after standard treatment failure. Further studies are needed to confirm the efficacy of ECP, assess the optimal schedule and consider it for early treatment. PMID- 28094114 TI - The quality of oncology nursing care: A cross sectional survey in three countries in Europe. AB - PURPOSE: The increase in patients diagnosed with and living with cancer calls for the provision of quality nursing care within this paradigm, one that can reflect the complex needs of the patient that cancer and its treatments induce. The study aimed to evaluate the quality of oncology nursing care, as perceived, by hospitalized cancer patients in three European countries. METHODS: This was a cross-sectional descriptive study. In-patients diagnosed with cancer were selected based on explicit inclusion and exclusion criteria. Data was collected with the Quality of Oncology Nursing Care Scale- QONCS, comprising of 34 items grouped in 5 domains. Sociodemographic data was also retrieved. RESULTS: The sample included 610 patients receiving care in 2 hospitals in Cyprus (n = 274), 1 hospital in Greece (n = 144) and 2 hospitals in the Czech Republic (n = 192). Statistically significant differences were found between the three countries and across all domains of the QONCS, with the exception of the spiritual and religious care (p = 0.136). Age and days of treatment produced statistically significant differences across all the domains of the QONCS, whilst gender did not produced any statistically significant differences (p ranged from (0.136 0.369). CONCLUSION: This is one of the first studies that provide evidence on the Quality of Nursing Care delivered to patients diagnosed with cancer in various European countries. Discrepancies were found between the participating countries. However, the provision of spiritual and religious care by the nurses received the lowest scores across the three participating countries. PMID- 28094116 TI - A qualitative study about experiences and emotions of emergency medical technicians and out-of-hospital emergency nurses after performing cardiopulmonary resuscitation resulting in death. AB - OBJECTIVE: To explore the experiences, emotions and coping skills among emergency medical technicians and emergency nurses after performing out-of-hospital cardiopulmonary resuscitation manoeuvres resulting in death. METHOD: An exploratory qualitative research was performed. Seven emergency medical technicians and six emergency nurses were selected by non-probability sampling among emergency medical system workers. The meetings took place up to information saturation, achieved after six individual interviews and a focal group. The meetings were then transcribed and a manual and inductive analysis of the contents performed. MAIN RESULTS: After a failed resuscitation several short and long-term reactions appear. They can be negatives, such as sadness or uncertainty, or positives, such as the feeling of having done everything possible to save the patient's life. Emotional stress increases when ambulance staff have to talk with the deceased's family or when the patient is a child. The workers don't know of a coping strategy other than talking about their emotions with their colleagues. CONCLUSIONS: Death after a failed resuscitation can be viewed as a traumatic experience for rescuers. Being in contact with the suffering of others is an emotional, stress-generating factor with direct repercussions on the working and personal lives of emergency staff. Nevertheless, structured coping techniques are not common among those professionals. PMID- 28094115 TI - Oxidative stress and antioxidant response in a thermotolerant yeast. AB - Stress tolerance is a key attribute that must be considered when using yeast cells for industrial applications. High temperature is one factor that can cause stress in yeast. High environmental temperature in particular may exert a natural selection pressure to evolve yeasts into thermotolerant strains. In the present study, three yeasts (Saccharomyces cerevisiae, MC4, and Kluyveromyces marxianus, OFF1 and SLP1) isolated from hot environments were exposed to increased temperatures and were then compared with a laboratory yeast strain. Their resistance to high temperature, oxidative stress, and antioxidant response were evaluated, along with the fatty acid composition of their cell membranes. The SLP1 strain showed a higher specific growth rate, biomass yield, and biomass volumetric productivity while also showing lower duplication time, reactive oxygen species (ROS) production, and lipid peroxidation. In addition, the SLP1 strain demonstrated more catalase activity after temperature was increased, and this strain also showed membranes enriched in saturated fatty acids. It is concluded that the SLP1 yeast strain is a thermotolerant yeast with less oxidative stress and a greater antioxidant response. Therefore, this strain could be used for fermentation at high temperatures. PMID- 28094117 TI - Maternal Weight after Childbirth versus Aging-Related Weight Changes. AB - BACKGROUND: Pregnancy weight gain is believed to contribute to female overweight and obesity. However, most studies do not account for the changes in body weight expected to occur as women age. We examined the long-term weight trajectory of childbearing women relative to weight progression that could be expected in the absence of pregnancy. METHODS: From the hospital records of 32,187 women with two births in Wisconsin during 2006 to 2013, we extracted the maternal weight at pregravid, delivery, and subsequent pregravid. We predicted the corresponding aging-progressed weights using a weight-for-age equation adjusted for sociodemographic variables. Nonparametric mixed effects models estimated the average maternal weight trajectory and the corresponding aging-related progression through 5 years after birth. RESULTS: The estimated aging-related progression predicted a gradual annual weight increase of 1.94 pounds (95% confidence interval 1.90-1.98), from 152.79 pounds at pregravid to 163.76 pounds by 5 years after birth. Actual maternal weight followed a sinusoidal pattern: increasing during gestation, decreasing during the first postbirth year, converging with the aging-related progression during the second postbirth year, and then increasing at 2.89 pounds (95% confidence interval 2.23-3.55) annually and diverging upward from the aging-related progression to 168.03 pounds by 5 years after birth. CONCLUSION: Pregnancy weight gain did not contribute to the aging-related trend, but lifestyle changes of parenthood may later exacerbate the long-term trend. PMID- 28094118 TI - Receipt of public assistance during childhood and hypertension risk in adulthood. AB - PURPOSE: We examined if receipt of public assistance during childhood lowered risk for hypertension by mid-life in a cohort of African Americans in the Southeastern United States. METHODS: We used multiple logistic regression models to assess the relationship between receipt of public assistance during childhood and adult hypertension among 405 male and 737 female adult participants enrolled between 1988 and 2001 in the Pitt County Study, a community-based prospective cohort study of African Americans in North Carolina. Statistical analyses were adjusted for child and adult sociodemographic measures as well as adult psychosocial and lifestyle factors. RESULTS: Women who grew up in economically disadvantaged families and who received public assistance during childhood had a 66% decreased odds of hypertension by mid-life compared with women similarly disadvantaged in childhood but who did not receive public assistance, odds ratio = 0.34; 95% confidence interval: 0.14-0.83. No association was observed for African American men. CONCLUSIONS: Receipt of anti-poverty federal assistance during childhood was associated with reduced risk for hypertension by mid-life among African American women. It is possible that social expenditures on public assistance programs for families in need could produce long-term health benefits for children. PMID- 28094119 TI - [Safety of repeat median sternotomy in the palliative treatment of patients with a univentricular heart]. AB - OBJECTIVE: To establish the morbidity and mortality of patients with univentricular hearts who underwent a repeat median sternotomy at the Instituto Nacional de Pediatria. METHOD: A retrospective review was performed on the clinical charts of all patients who underwent a repeat median sternotomy from 2001 to 2016. RESULTS: Sixty-five patients underwent 76 surgeries by repeat median sternotomy. Fifty-nine patients had a first repeat median sternotomy, with a mean age of 36 months (range: 4-176 months) and a mean weight of 12.2 kg (range: 3.2-21.5 kg). Forty patients had a Glenn procedure, and 19 patients had a Fontan procedure. There were 17 patients with a second repeat median sternotomy, with a mean age of 89 months (range 48-156 months), and a mean weight of 22.7 kg (14.4-41 kg). A Fontan procedure was performed on all these 17 patients. A section of the right coronary artery with electrocardiographic changes and a right atrium tear that caused hypotension occurred during first repeat sternotomy. An aortic tear occurred during a second repeat sternotomy with massive bleeding and subsequent death. This represents 3.9% of re-entry injuries. CONCLUSION: It is concluded that repeat median sternotomy is a safe procedure. PMID- 28094120 TI - Omalizumab-associated eosinophilic granulomatosis with polyangiitis (Churg Strauss syndrome). PMID- 28094121 TI - Mealtime behavior among parents and their young children with food allergy. AB - BACKGROUND: Food allergies are increasingly prevalent in the pediatric population. Balancing allergen avoidance with the promotion of healthy eating behaviors can be challenging for families. OBJECTIVE: To characterize mealtime behaviors among parents of young children with food allergy. METHODS: Seventy four parents of young children with food allergies (<=7 years of age) completed measures of mealtime behavior, perceptions of food allergy risk and severity, pediatric parenting stress, and food allergy-related quality of life. Mealtime behavior reports were compared with published data regarding typically developing children, young children with type 1 diabetes, and children with diagnosed feeding disorders (with or without related medical factors). RESULTS: Parents of young children with food allergies reported frequent mealtime concerns. Specifically, they reported significantly more mealtime behavioral concerns than typically developing peers, comparable mealtime behavioral concerns to young children with type 1 diabetes, and significantly fewer mealtime behavioral concerns than children with diagnosed feeding disorders. Parental mealtime concerns were positively correlated with other parent perceptions of food allergy, such as risk of allergen exposure, illness-related parenting stress, and food allergy-related quality of life. CONCLUSION: Young children with food allergy and their parents are more likely to exhibit mealtime behavioral concerns than typically developing peers and their parents. Future research should investigate the effect of food allergies and maladaptive mealtime behaviors on children's nutrition to provide clinical guidelines for parents who may benefit from psychosocial and/or nutritional support. PMID- 28094122 TI - Cardiac Remote Ischaemic Preconditioning: Mechanistic and Clinical Considerations. AB - Brief, non-harmful ischaemic insults to an organ remote from the heart, remote ischaemic preconditioning (RIPC), has been proposed to confer protection to the heart against ischaemia-reperfusion injury. While most clinical trials of RIPC during coronary interventions (PCI) suggest benefit, recent large, multicentre trials in coronary artery bypass surgery suggest a lack of efficacy. Mechanistically, RIPC most likely promotes the release of circulating factors which modulate multiple cellular pathways in the heart, promoting cell survival. This review explores potential mechanisms underlying RIPC and includes a contemporary evaluation of clinical studies in PCI and cardiac surgery, highlighting methodological differences which may explain discrepant findings between these two clinical groups. PMID- 28094123 TI - Myocardial and Serum Galectin-3 Expression Dynamics Marks Post-Myocardial Infarction Cardiac Remodelling. AB - BACKGROUND: Acute myocardial infarction (MI) causes significant changes in cardiac morphology and function. Galectin-3 is a novel and potentially therapeutically important mediator of cardiac remodelling. Myocardial and serum galectin-3 expression dynamics in response to the early cardiovascular outcomes after acute MI are not fully elucidated. METHODS: We first performed a comprehensive longitudinal microarray analyses in mice after acute MI. We then measured the serum levels of galectin-3 in a translational porcine model of coronary microembolism-induced post-ischaemic cardiac remodelling. We validated our pre-clinical studies in humans by measuring serum galectin-3 levels of 52 patients with acute ST-elevation MI (STEMI) and 11 healthy controls. We analysed galectin-3 data in relation to the development of major adverse cardiovascular outcomes (MACO). RESULTS: Of the 9,753 genes profiled at infarcted and remote myocardium at eight different time points, dynamic myocardial overexpression of galectin-3 mRNA was detected. In a pig model of diffuse myocardial damage and cardiac remodelling, galectin-3 localised to the areas of tissue damage and myocardial fibrosis, with proportionate increase of their serum galectin-3 expression levels. In humans, increased serum galectin-3 level was associated with in-hospital MACO. CONCLUSIONS: In this translational study, we demonstrated that galectin-3 is dynamically overexpressed in response to acute MI-induced cardiac remodelling. Elevated galectin-3 levels are associated with the development of in-hospital MACO. PMID- 28094124 TI - Quality control in QuantiFERON-TB gold in-tube for screening latent tuberculosis infection in health care workers. AB - QuantiFERON-TB gold in-tube has been used for screening latent tuberculosis infection in newly employed health care workers in Japan. There have been a few studies concerning quality control. We retrospectively analysed QuantiFERON-TB gold in-tube results in a hospital in Japan. Interferon-gamma values in three blood collection tubes for QuantiFERON-TB gold in-tube were analysed in association with the positivity rate. The data set consisted of health care workers aged 20-29 years during the 7 years between 2010 and 2016. The yearly QuantiFERON-TB gold in-tube positivity rate was 0.9%, 16.4%, 3.0%, 39.3%, 2.8%, 0.9% and 1.5%, and was extremely high in 2011 and 2013. The interferon-gamma values in the tuberculosis antigen tube were elevated in these two years, as indicated by higher median and wider interquartile range. The interferon-gamma value in the negative control tube was also higher in 2011. The higher interferon gamma values in collection tubes (tuberculosis antigen tube and/or negative control tube) resulted in higher QuantiFERON-TB gold in-tube positivity rate. The distribution of interferon-gamma in tuberculosis antigen tube and negative control tube, as evaluated by median and interquartile range, proved to be an effective index for the quality control of QuantiFERON-TB gold in-tube. PMID- 28094125 TI - Transcranial static magnetic field stimulation of M1 reduces corticospinal excitability without distorting sensorimotor integration in humans. PMID- 28094126 TI - Prevalence of Neuroendocrine Tumors in Patients With Cyanotic Congenital Heart Disease. PMID- 28094127 TI - Reply to: Catecholamine in Takotsubo syndrome. PMID- 28094128 TI - Lessons from contemporary trials of cardiovascular prevention and rehabilitation: A systematic review and meta-analysis. AB - BACKGROUND: Meta-analyses of cardiac rehabilitation trials up to 2010 showed a significant reduction in all-cause mortality but many of these trials were conducted before the modern management of acute coronary syndromes. METHODS: We undertook a meta-analysis of contemporary randomised controlled trials published in the period 2010 to 2015, including patients with other forms of atherosclerotic cardiovascular disease, to investigate the impact of cardiovascular prevention and rehabilitation on hard outcomes including survival. RESULTS: 18 trials randomising 7691 patients to cardiovascular prevention and rehabilitation or usual care were selected. All-cause mortality was not reduced (RR 1.00, 95% CI 0.88 to 1.14), but cardiovascular mortality was by 58% (95% CI 0.21, 0.88). Myocardial infarction was also reduced by 30% (95% CI 0.54, 0.91) and cerebrovascular events by 60% (95% CI 0.22, 0.74). Comprehensive programmes managing six or more risk factors reduced all-cause mortality in a subgroup analysis (RR 0.63, 95% CI 0.43, 0.93) but those managing less did not. In the three programmes that prescribed and monitored cardioprotective medications for blood pressure and lipids all-cause mortality was also reduced (RR 0.35, 95% CI 0.18, 0.70). CONCLUSIONS: Comprehensive prevention and rehabilitation programmes managing six or more risk factors, and those prescribing and monitoring medications within programmes to lower blood pressure and lipids, continue to reduce all-cause mortality. In addition, these comprehensive programmes not only reduced cardiovascular mortality and myocardial infarction but also, for the first time, cerebrovascular events, and all these outcomes across a broader spectrum of patients with atherosclerotic disease. PMID- 28094129 TI - Le-Compte maneuver in surgical correction of absent pulmonary valve. Does it improve severe bronchial compression? PMID- 28094130 TI - Acute systolic heart failure with normal admission BNP: clinical features and outcomes. AB - INTRODUCTION: The characteristics and outcomes of patients hospitalized with acute systolic heart failure (HF) and normal admission B-type natriuretic peptide (BNP) has not been previously explored. METHODS: Using the ESCAPE trial data, we compared patients with acute HF and left ventricular ejection fraction (LVEF) <=30% who have either normal or elevated BNP on the day of hospitalization. The study endpoints were 30-day and 6-month mortality, all-cause rehospitalization and rehospitalization for HF. RESULTS: Among 347 patients with acute systolic HF, 43 had normal (mean 50.6pg/mL) and 304 had elevated admission BNP (mean 1144pg/mL). Compared with patients with elevated BNP, those with normal admission BNP were younger (51.5 vs. 56.8years, P=0.01), with higher body mass index (33.6 vs. 28.7kg/m2, P<0.0001), lower frequency of ischemic etiology for heart disease (20.9% vs. 51.7%, P<0.001), lower blood urea nitrogen (29.1 vs. 36.3mg/dL, P=0.005) and creatinine (1.34 vs. 1.52mg/dL, P=0.038) levels, higher LVEF (25.5% vs. 19.1%, P=0.018), higher cardiac index (2.34 vs. 1.96, P=0.013), and better diastolic function evident by lower E/A ratio (1.73 vs. 2.67, P=0.001) and longer deceleration of E velocity (166 vs. 141ms, P=0.028). There was no difference between patients with normal or elevated admission BNP with regards to the degree of congestion. There were no differences between both groups in post-discharge hard endpoints such as 30-day (P=0.101) and 6-month (P=0.143) mortality, rehospitalization for any cause (P=0.992) or for HF (P=0.763). CONCLUSION: Patients hospitalized with acute systolic HF and normal admission BNP had no significant differences in the degree of congestion and post-discharge outcomes compared with those with elevated BNP. A normal BNP in this instance was not valuable for diagnostic or prognostic purposes. PMID- 28094131 TI - Prognostic significance of serial high-sensitivity troponin I measurements following acute cardiac decompensation-correlation with longer-term clinical outcomes and reverse remodelling. AB - BACKGROUND: This study investigated the correlation of levels of and changes in serial high-sensitivity cardiac troponin I (hsTnI) with subsequent clinical event rates and changes in cardiac morphology and function in patients hospitalized for acutely decompensated heart failure (ADHF). METHODS AND RESULTS: HsTnI levels were determined in 875 ADHF patients before discharge from hospital (baseline cohort) and clinical outcomes assessed after 180days. HsTnI was re-measured at 180days in 456/875 patients (follow-up cohort). Follow-up hsTnI values were grouped according to baseline hsTnI tertiles; echocardiographic changes from 0 180days and event rates from 180-540days were assessed in these subgroups. At baseline and 180-day follow-up, hsTnI levels were elevated (>0.06ng/mL) in 322/875 (37%) and 68/456 (15%) patients, respectively. At 180days, 85/875 patients (9.7%) had died (cardiovascular causes: 56/875 [6.4%]). Hazard ratios (HR) and 95% confidence intervals (CI) for all-cause and cardiovascular mortality (per two-fold hsTnI increase) were 1.2 (1.0-1.3; p=0.004) and 1.2 (1.1-1.4; p=0.001), respectively. In the follow-up cohort, 35/456 patients (7.7%) died between days 180 and 540 (cardiovascular death: 20/456, 4.4%). HsTnI was a significant predictor of cardiovascular re-hospitalization within 180-540days (HR 1.2, 95% CI 1.0-1.4; p=0.028). Patients with hsTnI in the lowest tertile at follow-up had more frequent and more pronounced reverse cardiac remodelling on echocardiography. CONCLUSIONS: Elevated baseline hsTnI was common and associated with adverse clinical outcomes. Changes in hsTnI from baseline to 180-day follow up predicted longer-term risk. Low or decreasing hsTnI was associated with better reverse cardiac remodelling and more favourable long-term outcomes. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN23325295. PMID- 28094132 TI - Cardiovascular maladaptation to exercise in young hypertensive patients. AB - BACKGROUND: Impairment of the adaptive mechanisms that increase cardiac output during exercise can translate to a reduced functional capacity. We investigated cardiovascular adaptation to exertion in asymptomatic hypertensive patients, aiming to identify the early signs of cardiac and vascular dysfunction. METHODS AND RESULTS: We enrolled 54 subjects: 30 patients (45.1+/-11.9years, 19 males) and 24 age-matched healthy controls (44.4+/-9.6years, 14 males). Speckle-tracking echocardiography (STE) and echo-tracking were performed at rest and during exertion to assess myocardial deformation and arterial stiffness. RESULTS: E/E' increased from rest to peak exercise more in patients than in controls (peak stage: p=0.024). Global longitudinal strain increased significantly from rest to peak stage in controls (p=0.011) whereas it remained unchanged in patients (p=0.777). Left atrial (LA) reservoir was significantly increased throughout the exercise only in controls (p=0.001) whereas it was almost unchanged in patients (p=0.293). LA stiffness was significantly higher in patients than in controls both at rest (p=0.023) and during exercise (p<0.001). Beta index and pulse wave velocity (PWV) increased during exercise in both groups, showing higher values in patients in each step. CONCLUSIONS: Our study showed a more pronounced maladaptation during exercise, with respect to rest, of the cardiovascular system with impaired cardiac-vessel coupling in hypertensive patients compared to healthy subjects. Exercise echocardiography implemented by STE and echo-tracking is invaluable in the early detection of these cardiovascular abnormalities. PMID- 28094134 TI - Cervical and Breast Cancer Screening After CARES: A Community Program for Immigrant and Marginalized Women. AB - INTRODUCTION: Marginalized populations such as immigrants and refugees are less likely to receive cancer screening. Cancer Awareness: Ready for Education and Screening (CARES), a multifaceted community-based program in Toronto, Canada, aimed to improve breast and cervical screening among marginalized women. This matched cohort study assessed the impact of CARES on cervical and mammography screening among under-screened/never screened (UNS) attendees. METHODS: Provincial administrative data collected from 1998 to 2014 and provided in 2015 were used to match CARES participants who were age eligible for screening to three controls matched for age, geography, and pre-education screening status. Dates of post-education Pap and mammography screening up to June 30, 2014 were determined. Analysis in 2016 compared screening uptake and time to screening for UNS participants and controls. RESULTS: From May 15, 2012 to October 31, 2013, a total of 1,993 women attended 145 educational sessions provided in 20 languages. Thirty-five percent (118/331) and 48% (99/206) of CARES participants who were age eligible for Pap and mammography, respectively, were UNS on the education date. Subsequently, 26% and 36% had Pap and mammography, respectively, versus 9% and 14% of UNS controls. ORs for screening within 8 months of follow-up among UNS CARES participants versus their matched controls were 5.1 (95% CI=2.4, 10.9) for Pap and 4.2 (95%=CI 2.3, 7.8) for mammography. Hazard ratios for Pap and mammography were 3.6 (95% CI=2.1, 6.1) and 3.2 (95% CI=2.0, 5.3), respectively. CONCLUSIONS: CARES' multifaceted intervention was successful in increasing Pap and mammography screening in this multiethnic under-screened population. PMID- 28094133 TI - Transgender Use of Cigarettes, Cigars, and E-Cigarettes in a National Study. AB - INTRODUCTION: Tobacco use among transgender adults continues to be an area of research with few reported findings. The limited literature indicates higher cigarette use among transgender adults, compared with the general population. This national study is the first to report on cigarettes, cigars, and e cigarettes by examining differences in transgender tobacco use independent of sexual orientation. METHODS: Data were collected in 2013 using a nationally cross sectional online survey of U.S. adults (cisgender, n=17,164; transgender, n=168) and analyzed in 2015. Past 30-day tobacco use point estimates and adjusted logistic regression while controlling for false discovery rate were reported for transgender and cisgender respondents. RESULTS: Transgender adults reported higher past 30-day use of any cigarette/cigar/e-cigarette product (39.7% vs 25.1%) and current use of cigarettes (35.5% vs 20.7%), cigars (26.8% vs 9.3%), and e-cigarettes (21.3% vs 5.0%) compared with cisgender adults (all p-values <=0.003). Transgender respondents had significantly higher odds of past 30-day tobacco product use for any cigarette/cigar/e-cigarette product (OR=1.97, 95% CI=1.25, 3.1), e-cigarettes (OR=5.15, 95% CI=3.36, 7.88), cigars (OR=3.56, 95% CI=2.27, 5.59), and cigarettes (OR=2.10, 95% CI=1.35, 3.28) versus cisgender respondents (all p-values <=0.0035). CONCLUSIONS: Transgender adults are at higher risk for tobacco use than cisgender adults and risk of specific product use varies by gender. This is the first U.S. national study to assess differences in use of various tobacco products using questions that specifically ask for gender identity separately from sexual orientation. This study provides data that can inform targeted interventions to promote transgender health. PMID- 28094135 TI - Diabetes Prevention Program Translation in the Veterans Health Administration. AB - INTRODUCTION: This clinical demonstration trial compared the effectiveness of the Veterans Affairs Diabetes Prevention Program (VA-DPP) with an evidence-based usual care weight management program (MOVE!(r)) in the Veterans Health Administration health system. DESIGN: Prospective, pragmatic, non-randomized comparative effectiveness study of two behavioral weight management interventions. SETTING/PARTICIPANTS: Obese/overweight Veterans with prediabetes were recruited from three geographically diverse VA sites between 2012 and 2014. INTERVENTION: VA-DPP included 22 group-based intensive lifestyle change sessions. MAIN OUTCOME MEASURES: Weight change at 6 and 12 months, hemoglobin A1c (HbA1c) at 12 months, and VA health expenditure changes at 15 months were assessed using VA electronic health record and claims data. Between- and within-group comparisons for weight and HbA1c were done using linear mixed-effects models controlling for age, gender, race/ethnicity, baseline outcome values, and site. Analyses were conducted in 2015-2016. RESULTS: A total of 387 participants enrolled (273 VA-DPP, 114 MOVE!). More VA-DPP participants completed at least one (73.3% VA-DPP vs 57.5% MOVE! p=0.002); four (57.5% VA-DPP vs 42.5% MOVE!, p=0.007); and eight or more sessions (42.5% VA-DPP vs 31% MOVE!, p=0.035). Weight loss from baseline was significant at both 6 (p<0.001) and 12 months (p<0.001) for VA-DPP participants, but only significant at 6 months for MOVE! participants (p=0.004). Between groups, there were significant differences in 6-month weight loss (-4.1 kg VA-DPP vs -1.9 kg MOVE!, p<0.001), but not 12-month weight loss ( 3.4 kg VA-DPP vs -2.0 kg MOVE!, p=0.16). There were no significant differences in HbA1c change or outpatient, inpatient, and total VA expenditures. CONCLUSIONS: VA DPP participants had higher participation rates and weight loss at 6 months, but similar weight, HbA1c, and health expenditures at 12 months compared to MOVE! PARTICIPANTS: Features of VA-DPP may help enhance the capability of MOVE! to reach a larger proportion of the served population and promote individual-level weight maintenance. PMID- 28094137 TI - The artificial pancreas-ready for prime time? PMID- 28094138 TI - New normoxic N-(Hydroxymethyl)acrylamide based polymer gel for 3D dosimetry in radiation therapy. AB - A novel composition of normoxic polymer gel dosimeters based on radiation-induced polymerization of N-(Hydroxymethyl)acrylamide (NHMA) is introduced in this study for 3D dosimetry for Quality Assurance (QA) in radiation therapy. Dosimeters were irradiated by 6, 10 and 18MV photon beams of a medical linear accelerator at various dose rates to doses of up to 20Gy. The dose response of polymer gel dosimeters was studied using nuclear magnetic resonance (NMR) spin-spin relaxation rate (R2) of hydrogen protons within the water molecule. Also, we measured gel response using absorption spectroscopy and found that this novel gel can be successfully utilized for both MRI- and OCT- (Optical Computed Tomography) based 3D dosimetry. We investigated dosimetric properties of six different compositions of the new NHMA-based gel in terms of dose rate, radiation beam quality and stability of dose-dependent polymerization after irradiation. We found no significant effects of these parameters on the novel gel dosimeter performance in both relaxation rate and absorbance measurements. PMID- 28094136 TI - Day-and-night glycaemic control with closed-loop insulin delivery versus conventional insulin pump therapy in free-living adults with well controlled type 1 diabetes: an open-label, randomised, crossover study. AB - BACKGROUND: Tight control of blood glucose concentration in people with type 1 diabetes predisposes to hypoglycaemia. We aimed to investigate whether day-and night hybrid closed-loop insulin delivery can improve glucose control while alleviating the risk of hypoglycaemia in adults with HbA1c below 7.5% (58 mmol/mol). METHODS: In this open-label, randomised, crossover study, we recruited adults (aged >=18 years) with type 1 diabetes and HbA1c below 7.5% from Addenbrooke's Hospital (Cambridge, UK) and Medical University of Graz (Graz, Austria). After a 2-4 week run-in period, participants were randomly assigned (1:1), using web-based randomly permuted blocks of four, to receive insulin via the day-and-night hybrid closed-loop system or usual pump therapy for 4 weeks, followed by a 2-4 week washout period and then the other intervention for 4 weeks. Treatment interventions were unsupervised and done under free-living conditions. During the closed-loop period, a model-predictive control algorithm directed insulin delivery, and prandial insulin delivery was calculated with a standard bolus wizard. The primary outcome was the proportion of time when sensor glucose concentration was in target range (3.9-10.0 mmol/L) over the 4 week study period. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02727231, and is completed. FINDINGS: Between March 21 and June 24, 2016, we recruited 31 participants, of whom 29 were randomised. One participant withdrew during the first closed-loop period because of dissatisfaction with study devices and glucose control. The proportion of time when sensor glucose concentration was in target range was 10.5 percentage points higher (95% CI 7.6-13.4; p<0.0001) during closed-loop delivery compared with usual pump therapy (65.6% [SD 8.1] when participants used usual pump therapy vs 76.2% [6.4] when they used closed-loop). Compared with usual pump therapy, closed loop delivery also reduced the proportion of time spent in hypoglycaemia: the proportion of time with glucose concentration below 3.5 mmol/L was reduced by 65% (53-74, p<0.0001) and below 2.8 mmol/L by 76% (59-86, p<0.0001). No episodes of serious hypoglycaemia or other serious adverse events occurred. INTERPRETATION: Use of day-and-night hybrid closed-loop insulin delivery under unsupervised, free living conditions for 4 weeks in adults with type 1 diabetes and HbA1c below 7.5% is safe and well tolerated, improves glucose control, and reduces hypoglycaemia burden. Larger and longer studies are warranted. FUNDING: Swiss National Science Foundation (P1BEP3_165297), JDRF, UK National Institute for Health Research Cambridge Biomedical Research Centre, and Wellcome Strategic Award (100574/Z/12/Z). PMID- 28094140 TI - Corrections. PMID- 28094139 TI - Theranostics in severe influenza. PMID- 28094141 TI - Intravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase 3 trial. AB - BACKGROUND: Neuraminidase inhibitors are effective for the treatment of acute uncomplicated influenza. However, there is an unmet need for intravenous treatment for patients admitted to hospital with severe influenza. We studied whether intravenous zanamivir was a suitable treatment in this setting. METHODS: In this international, randomised, double-blind, double-dummy, phase 3 trial, we recruited patients aged 16 years or older with severe influenza admitted to 97 hospitals from 26 countries. We randomly assigned patients (1:1:1 stratified by symptom onset <=4 days or 5-6 days) to receive 300 mg or 600 mg intravenous zanamivir, or standard-of-care (75 mg oral oseltamivir) twice a day for 5-10 days; patients were followed up for 28 days. The randomisation schedule, including stratification, was generated using GlaxoSmithKline's RandAll software. Patients, site study staff, and sponsor were masked to study treatment. The primary endpoint was time to clinical response-a composite of vital sign stabilisation and hospital discharge-in the influenza-positive population. The trial was powered to show an improvement of 1.5 days or greater with 600 mg intravenous zanamivir. Pharmacokinetic, safety, and virology endpoints were also assessed. This trial is registered with ClinicalTrials.gov, number NCT01231620. FINDINGS: Between Jan 15, 2011, and Feb 12, 2015, 626 patients were randomly assigned to receive 300 mg intravenous zanamivir (n=201), 600 mg intravenous zanamivir (n=209), or 75 mg oral oseltamivir (n=205) twice a day; 11 patients discontinued the study before receiving any study treatment. 488 (78%) of 626 patients had laboratory-confirmed influenza. Compared with a median time to clinical response of 5.14 days in the 600 mg intravenous zanamivir group, the median time to clinical response was 5.87 days (difference of -0.73 days, 95% CI 1.79 to 0.75; p=0.25) in the 300 mg intravenous zanamivir group and 5.63 days (difference of -0.48 days, 95% CI -2.11 to 0.97; p=0.39) in the oseltamivir group. Four patients with influenza A/H1N1pdm09 in the oseltamivir group developed H275Y resistance mutations. Adverse events were reported in 373 (61%) of treated patients and were similar across treatment groups; the most common adverse events (300 mg intravenous zanamivir, 600 mg intravenous zanamivir, oseltamivir) were diarrhoea (10 [5%], 15 [7%], 14 [7%]), respiratory failure (11 [5%], 14 [7%], 11 [5%]), and constipation (7 [3%], 13 [6%], 10 [5%]). 41 (7%) treated patients died during the study (15 [7%], 15 [7%], 11 [5%]); the most common causes of death were respiratory failure and septic shock. INTERPRETATION: Time to clinical response to intravenous zanamivir dosed at 600 mg was not superior to oseltamivir or 300 mg intravenous zanamivir. All treatments had a similar safety profile in hospitalised patients with severe influenza. FUNDING: GlaxoSmithKline. PMID- 28094142 TI - Epigenetic game theory and its application in plants: Comment on: "Epigenetic game theory: How to compute the epigenetic control of maternal-to-zygotic transition" by Qian Wang et al. PMID- 28094143 TI - Maturity as quantifier for physiological time: Comment on "Physics of metabolic organization" by Marko Jusup et al. PMID- 28094144 TI - More practical and gentler guides are required for non-mathematicians in ecotoxicology and beyond: Comment on "Physics of metabolic organization" by Marko Jusup et al. PMID- 28094145 TI - Constraints and DEB parameter estimation: Comment on: "Physics of metabolic organization" by Marko Jusup et al. PMID- 28094146 TI - The role of Dynamic Energy Budget theory in predictive modeling of stressor impacts on ecological systems: Comment on: "Physics of metabolic organization" by Marko Jusup et al. PMID- 28094147 TI - Integrating evolutionary game theory into epigenetic study of embryonic development: Comment on "Epigenetic game theory: How to compute the epigenetic control of maternal-to-zygotic transition" by Qian Wang et al. PMID- 28094148 TI - Epigenetic battle of the sexes: Comment on: "Epigenetic game theory: How to compute the epigenetic control of maternal-to-zygotic transition" by Qian Wang et al. PMID- 28094149 TI - The universality of the von Bertalanffy growth curve: Comment on: "Physics of metabolic organization" by Marko Jusup et al. PMID- 28094150 TI - Applications and extensions of epigenetic game theory: Comment on: "Epigenetic game theory: How to compute the epigenetic control of maternal-to-zygotic transition" by Qian Wang et al. PMID- 28094151 TI - Comparison of the BD MAX MRSA XT to the CepheidTM Xpert(r) MRSA assay for the molecular detection of methicillin-resistant Staphylococcus aureus from nasal swabs. AB - INTRODUCTION: Variation in MRSA genotypes may affect the sensitivity of molecular assays to detect this organism. METHODS: We compared 2 commonly used screening assays, the CepheidTM Xpert(r) MRSA and the BD MAXTM MRSA XT on consecutively obtained nasal swabs from 479 subjects. Specimens giving discordant results were subjected to additional microbiologic and molecular testing. RESULTS: Six hundred forty-two (97.6%) of the 658 test results were concordant. Of the 16 discordant results from 12 subjects, additional results suggested that 9 (60%) of the 15 MRSA XT assays were likely correct, and 6 (40%) of the 15 Xpert(r) assays were likely correct. One discordant result could not be resolved. A mecA dropout and novel mec right-extremity junction (MREJ) sites led to false-positive and negative results by Xpert(r). CONCLUSION: While both assays performed well, continued vigilance is needed to monitor for Staphylococcus aureus with novel MREJ sites, mecA dropouts, and mecC, leading to inaccurate results in screening assays. PMID- 28094152 TI - Use of 3D printer technology to facilitate surgical correction of a complex vascular anomaly with esophageal entrapment in a dog. AB - A 10 week old female intact Staffordshire terrier was presented with a total of five congenital cardio-thoracic vascular anomalies consisting of a patent ductus arteriosus (PDA) with an aneurysmic dilation, pulmonic stenosis, persistent right aortic arch, aberrant left subclavian artery and persistent left cranial vena cava. These abnormalities were identified with a combination of echocardiogram and computed tomography angiography (CTA). The abnormalities were associated with esophageal entrapment, regurgitation, and volume overload of the left heart with left atrial and ventricular enlargement. A 2 cm diameter aneurysmic dilation at the junction of the PDA, right aortic arch and aberrant left subclavian artery presented an unusual surgical challenge and precluded simple circumferential ligation and transection of the structure. A full scale three dimensional model of the heart and vasculature was constructed from the CTA and plasma sterilized. The model was used preoperatively to facilitate surgical planning and enhance intraoperative communication and coordination between the surgical and anesthesia teams. Intraoperatively the model facilitated spatial orientation, atraumatic vascular dissection, instrument sizing and positioning. A thoracoabdominal stapler was used to close the PDA aneurysm prior to transection. At the four month postoperative follow-up the patient was doing well. This is the first reported application of new imaging and modeling technology to enhance surgical planning when approaching correction of complex cardiovascular anomalies in a dog. PMID- 28094153 TI - Development and validation of a fast ionic liquid-based dispersive liquid-liquid microextraction procedure combined with LC-MS/MS analysis for the quantification of benzodiazepines and benzodiazepine-like hypnotics in whole blood. AB - To date, thorough clean-up of complex biological samples remains an essential part of the analytical process. The solid phase extraction (SPE) technique is the well-known standard, however, its main weaknesses are the labor-intensive and time-consuming protocols. In this respect, dispersive liquid-liquid microextractions (DLLME) seem to offer less complex and more efficient extraction procedures. Furthermore, ionic liquids (ILs) - liquid salts - are emerging as new promising extraction solvents, thanks to their non-flammable nature, negligible vapor pressure and easily adaptable physiochemical properties. In this study, we investigated whether ILs can be used as an extraction solvent in a DLLME procedure for the extraction of a broad range of benzodiazepines and benzodiazepine-like hypnotics in whole blood samples. 1.0mL whole blood was extracted using an optimized 30-min IL-based DLLME procedure, followed by LC ESI(+)-MS/MS analysis in scheduled MRM scan mode. The optimized analytical method was successfully validated for 7-aminoflunitrazepam, alprazolam, bromazepam, clobazam, clonazepam, clotiazepam, diazepam, estazolam, ethyl loflazepate, etizolam, flurazepam, lormetazepam, midazolam, oxazepam, prazepam, temazepam, triazolam, zolpidem and zopiclone. The method showed good selectivity for endogenous interferences based on 12 sources of blank whole blood. No benzodiazepine interferences were observed, except for clorazepate and nordiazepam, which were excluded from the quantitative method. Matrix-matched calibration curves were constructed covering the whole therapeutic range, including low toxic plasma concentrations. Accuracy and precision results met the proposed acceptance criteria for the vast majority of compounds, except for brotizolam, chlordiazepoxide, cloxazolam, flunitrazepam, loprazolam, lorazepam and nitrazepam, which can only be determined in a semi-quantitative way. Recoveries were within the range of 24.7%-127.2% and matrix effects were within 20.0%-92.6%. Both parameters were tested using 5 sources of whole blood and coefficients of variance were below 20%. Overall, the applicability of ILs as promising solvents for the extraction of benzodiazepines in whole blood samples has been proven. Moreover, a fast and easy IL-based DLLME procedure was developed for the quantification of 19 benzodiazepines and benzodiazepine-like hypnotics. PMID- 28094154 TI - Mandatory reporting for child protection in health settings and the rights of parents with disabilities. AB - This commentary considers the intersection of mandatory reporting in health settings and the public child protection system's treatment of parents with disabilities. Its impetus is the August 2015 technical assistance document issued jointly by the U.S. departments of Justice (DOJ) and Health and Human Services (HHS) that affirms the applicability of the ADA and Section 504 to child protection system (CPS) processes. The DOJ/HHS document speaks to actions of state child protection agencies and courts, without addressing the first step, mandatory reporting. Nonetheless, there are implications for how mandated reporters understand child risk in the presence of disability, and health settings are one venue where mandated reports initiate. This commentary seeks to provide medical professionals with greater understanding of the CPS process and its intersection with disability rights. It concludes that mandatory reporter training must include ADA principles for addressing disability so parents are not unnecessarily reported for investigation. PMID- 28094155 TI - Sustainable options for the utilization of solid residues from wine production. AB - The efficient use of solid organic waste materials is an issue of particular importance for the wine industry. This paper focuses on the valorization of grape marc, the major component of winery organic waste (60-70%). Two methods were designed and compared: combustion to generate electricity, and the pyrolysis for the production of bio-char, bio-oil, and bio-gas. Each of these processes was analysed to determine their economic and environmental viability. The flow sheeting software, ASPEN PLUS, was used to model the two cases. Data from the simulations was used to inform techno-economic and environmental analyses. Pyrolysis was found to be the superior method of utilizing grape marc from both economic and environmental perspectives. Both pyrolysis and combustion exploit the energy content of the waste, which is not recovered by the traditional treatments, composting or distillation. In addition to the production of energy, pyrolysis yielded 151kg of bio-char and 140kg of bio-oil per tonne of grape marc. These products may be used in place of fossil fuels, resulting in a net reduction of carbon dioxide emissions. However, the potential deleterious effects resulting from the replacement of the traditional treatments was not considered. Investment in either pyrolysis or combustion had a negligible impact on the price of the wine produced for wineries with an annual grape crush larger than 1000 tonnes. Composting has significant economic advantages in wineries with a small grape crush of less than 50 tonnes. PMID- 28094156 TI - Removal of toxic metals during biological treatment of landfill leachates. AB - Progressive implementation of the European Water Framework Directive has resulted in substantial changes in limits for discharges of heavy metals both to watercourses, and to sewer. The objective of this paper is to provide original, real, full-scale data obtained for removal of metals during aerobic biological leachate treatment, and also to report on studies carried out to look at further trace metal removal. Polishing technologies examined and investigated include; the incorporation of ultrafiltration (UF) membranes into biological treatment systems, the use of ion exchange, and of activated carbon polishing processes. Ultrafiltration was able to provide a 60 percent reduction in COD values in treated leachates, compared with COD values found in settled/clarified effluents. Removal rates for COD varied from 30.5 to 79.8 percent. Additionally, ultrafiltration of treated leachates significantly reduced both chromium and nickel concentrations of effluents by 61.6% and 34.3% respectively (median values). Despite mean reductions of chromium (9.7%) and nickel (13.7%) noted during the ion exchange trials, these results would not justify use of this technology for metals removal at full-scale. Further preliminary studies used pulverized activated carbon (PAC) polishing of UF effluents to demonstrate that significant (up to 80 per cent) removal of COD, TOC and heavy metals could readily be achieved by doses of up to 10g/l of suitable activated carbons. Additional evidence is provided that many trace metals are present not in ionic form, but as organic complexes; this is likely to make their removal to low levels more difficult and expensive. PMID- 28094157 TI - Stabilization of tannery sludge by co-treatment with aluminum anodizing sludge and phytotoxicity of end-products. AB - A global demand for efficient re-utilization of produced solid wastes, which is based on the principles of re-use and recycling, results to a circular economy, where one industry's waste becomes another's raw material and it can be used in a more efficient and sustainable way. In this study, the influence of a by-product addition, such as aluminum anodizing sludge, on tannery waste (air-dried sludge) stabilization was examined. The chemical characterization of tannery waste leachate, using the EN 12457-2 standard leaching test, reveals that tannery waste cannot be accepted even in landfills for hazardous wastes, according to the EU Decision 2003/33/EC. The stabilization of tannery waste was studied applying different ratios of tannery waste and aluminum anodizing sludge, i.e. 50:50, 60:40, 70:30 and 80:20 ratios respectively. Subsequently, the stabilization rate of the qualified as optimum homogenized mixture of 50:50 ratio was also tested during time (7, 15 and 30days). Moreover, this stabilized product was subjected to phytotoxicity tests using the Lepidium sativum, Sinapis alba and Sorghum saccharatum seeds. The experimental results showed that aluminum anodizing sludge managed to stabilize effectively chromium and organic content of tannery waste, which are the most problematic parameters influencing its subsequent disposal. As a result, tannery waste stabilized with the addition of aluminum anodizing sludge at 50:50 ratio can be accepted in non-hazardous waste landfills, as chromium and dissolved organic carbon concentrations in the respective leachate are below the relevant regulation limits, while the stabilized waste shows decreased phytotoxicity. PMID- 28094158 TI - The mass flow and proposed management of bisphenol A in selected Norwegian waste streams. AB - Current initiatives for waste-handling in a circular economy favor prevention and recycling over incineration or landfilling. However, the impact of such a transition on environmental emissions of contaminants like bisphenol A (BPA) during waste-handling is not fully understood. To address this, a material flow analysis (MFA) was constructed for selected waste categories in Norway, for which the amount recycled is expected to increase in the future; glass, vehicle, electronic, plastic and combustible waste. Combined, 92tons/y of BPA are disposed of via these waste categories in Norway, with 98.5% associated with plastic and electronic waste. During the model year 2011, the MFA showed that BPA in these waste categories was destroyed through incineration (60%), exported for recycling into new products (35%), stored in landfills (4%) or released into the environment (1%). Landfilling led to the greatest environmental emissions (up to 13% of landfilled BPA), and incinerating the smallest (0.001% of incinerated BPA). From modelling different waste management scenarios, the most effective way to reduce BPA emissions are to incinerate BPA-containing waste and avoid landfilling it. A comparison of environmental and human BPA concentrations with CoZMoMAN exposure model estimations suggested that waste emissions are an insignificant regional source. Nevertheless, from monitoring studies, landfill emissions can be a substantial local source of BPA. Regarding the transition to a circular economy, it is clear that disposing of less BPA-containing waste and less landfilling would lead to lower environmental emissions, but several uncertainties remain regarding emissions of BPA during recycling, particularly for paper and plastics. Future research should focus on the fate of BPA, as well as BPA alternatives, in emerging reuse and recycling processes, as part of the transition to a circular economy. PMID- 28094159 TI - Performance of polydimethylsiloxane membrane contactor process for selective hydrogen sulfide removal from biogas. AB - H2S in biogas affects the co-generation performance adversely by corroding some critical components within the engine and it has to be removed in order to improve the biogas quality. This work presents the use of polydimethylsiloxane (PDMS) membrane contactor for selective removal of H2S from the biogas. Experiments were carried out to evaluate the effects of different pH of absorption liquid, biogas flowrate and temperature on the absorption performances. The results revealed that at the lowest loading rate (91mg H2S/m2.h) more than 98% H2S and 59% CO2 absorption efficiencies were achieved. The CH4 content in the treated gas increased from 60 to 80% with nearly 5% CH4 loss. Increasing the pH (7-10) and loading rate (91-355mg H2S/m2.h) enhanced the H2S absorption capacity, and the maximum H2S/CO2 and H2S/CH4 selectivity factors were 2.5 and 58, respectively. Temperature played a key role in the process and lower temperature was beneficial for intensifying H2S absorption performance. The highest H2S fluxes at pH 10 and 7 were 3.4g/m2.d and 1.8g/m2.d with overall mass transfer coefficients of 6.91*10-6 and 4.99*10-6m/s, respectively. The results showed that moderately high H2S fluxes with low CH4 loss may be achieved by using a robust and cost-effective membrane based absorption process for desulfurization of biogas. A tubular PDMS membrane contactor was tested for the first time to remove H2S from biogas under slightly alkaline conditions and the suggested process could be a promising for real scale applications. PMID- 28094160 TI - A case of generalized lymphatic anomaly causing skull-base leakage and bacterial meningitis. AB - Generalized lymphatic anomaly is a multifocal lymphatic malformation that affects the skin, thoracic viscera, and bones. A 3year-old Japanese boy presented with right facial palsy due to cystic tumors in the ipsilateral petrous bone. Pericardial effusion had been found incidentally and generalized lymphatic anomaly had been diagnosed by pericardial biopsy. Petrous bone tumor had been followed up without surgery. At the age of seven he presented with fever and disturbance of consciousness, and bacterial meningitis due to Streptococcus pneumoniae was diagnosed. Computed tomography and magnetic resonance imaging revealed middle skull-base leakage due to lymphatic malformation. He achieved complete recovery under intensive care with antibiotics and mechanical ventilation. One year later, he presented with multiple cystic formations in bilateral femora. At the 3-year follow-up, the patient was healthy with no recurrence of meningitis and osteolytic lesions in the femora were non progressive. Computed tomography and magnetic resonance imaging are useful for demonstration of skull-base leakage by generalized lymphatic anomaly. We should consider generalized lymphatic anomaly among the differential diagnoses for skull base leakage. PMID- 28094161 TI - Disinhibition in children with attention-deficit/hyperactivity disorder: Changes in [oxy-Hb] on near-infrared spectroscopy during "rock, paper, scissors" task. AB - OBJECTIVE: Attention-deficit/hyperactivity disorder (AD/HD) is a common developmental disorder. Many reports have suggested that symptoms of AD/HD are related to frontal lobe dysfunctions, particularly disinhibition. However, measuring neurological findings with biomarkers during frontal functional tasks has sometimes been difficult in children with AD/HD. This study aimed to investigate frontal inhibitory function objectively in children with AD/HD during "rock, paper, scissors" (RPS) tasks, as a familiar game for Japanese children, using near-infrared spectroscopy (NIRS). SUBJECTS AND METHODS: Eighteen children with AD/HD were compared with 27 typically developing children (TDC). Children from each group were divided into two age groups: younger, 6-10years; and older, 11-16years. Changes in oxygenated hemoglobin [oxy-Hb] were measured in the prefrontal region using NIRS during a 'to lose' RPS task, in which subjects were asked to present the RPS signal that would lose in response to one of the three signals displayed randomly on a computer screen every 2.0s. RESULTS: The rate of correct performance with both TDC and AD/HD increased with age. Only in the older group, the rate of correct performance was significantly higher with TDC than with AD/HD. However, children with AD/HD in both age groups showed significantly lower [oxy-Hb] activity in the prefrontal region during the 'to lose' RPS task, particularly in the dorsolateral area. CONCLUSIONS: Our results suggest that prefrontal region activation during the 'to lose' RPS task could offer a biomarker for diagnosing AD/HD, and may help in the early treatment of AD/HD. PMID- 28094162 TI - Intrahepatic cholangiocarcinoma. AB - Cholangiocarcinoma, also referred to as cholangiocellular carcinoma (particularly in Japan), develops along the biliary tract. The tumor may be intra- or extrahepatic and have different features with specific treatments based on the site of origin. Guidelines for diagnosis and management of cholangiorcarcinoma, such as those proposed by EASL (European Association for the Study of the Liver)1 and the Mayo Clinic2 classify the tumor into intrahepatic, perihilar, and distal cholangiocarcinoma. There are three main macroscopic patterns of growth of cholangiocarcinoma: mass-forming, periductal-infiltrating and intraductal. A combination of mass-forming and periductal infiltrating tumors have been shown to have a poor prognosis.3 Intrahepatic cholangiocarcinoma (ICC) comprises two microscopic subtypes: bile duct and cholangiolar.4 The bile duct subtype has tall columnar cells that form large glands, whereas cholangiolar tumors are composed of cuboidal and low columnar cells. Patients with cholangiolar tumors, referred to as cholangiolocellular carcinoma, reportedly have a better 5-year survival rate than those with the bile duct type.4. PMID- 28094163 TI - Granulomatous & histiocytic dermatitides. AB - Granulomas of the skin may be classified in several ways. They are either infectious or non-infectious in character, and they contain areas of necrobiosis or necrosis, or not. Responsible infectious agents may be mycobacterial, fungal, treponemal, or parasitic organisms, and each case of granulomatous dermatitis should be assessed histochemically for those microbes. In the non-infectious group, examples of necrobiotic or necrotizing granulomas include granuloma annulare; necrobiosis lipoidica; rheumatoid nodule; and lupus miliaris disseminates faciei. Non-necrobiotic/necrotizing and non-infectious lesions are exemplified by sarcoidosis; foreign-body reactions; Melkersson-Rosenthal syndrome; Blau syndrome; elastolytic granuloma; lichenoid and granulomatous dermatitis; interstitial granulomatous dermatitis; cutaneous involvement by Crohn disease; granulomatous rosacea; and granulomatous pigmented purpura. Histiocytic dermatitides that do not feature granuloma formation are peculiar reactions to infection, such as cutaneous malakoplakia; leishmaniasis; histoplasmosis; lepromatous leprosy; rhinoscleroma; lymphogranuloma venereum; and granuloma inguinale. PMID- 28094164 TI - Disorders characterized by predominant or exclusive dermal inflammation. AB - Some cutaneous inflammatory disorders are typified by a predominant or exclusive localization in the dermis. They can be further subdivided by the principal cell types into lymphocytic, neutrophilic, and eosinophilic infiltrates, and mixtures of them are also seen in a proportion of cases. This review considers such conditions. Included among the lymphoid lesions are viral exanthems, pigmented purpuras, gyrate erythemas, polymorphous light eruption, lupus tumidus, and cutaneous lymphoid hyperplasia. Neutrophilic infiltrates are represented by infections, Sweet syndrome, pyoderma gangrenosum, and hidradenitis suppurativa, as well as a group of so-called "autoinflammatory" dermatitides comprising polymorphonuclear leukocytes. Eosinophil-dominated lesions include arthropod bite reactions, cutaneous parasitic infestations, the urticarial phase of bullous pemphigoid, Wells syndrome (eosinophilic cellulitis), hypereosinophilic syndrome, and Churg-Strauss disease. In other conditions, eosinophils are admixed with neutrophils in the corium, with or without small-vessel vasculitis. Exemplary disorders with those patterns include drug eruptions, chronic idiopathic urticaria, urticarial vasculitis, granuloma faciale, and Schnitzler syndrome (chronic urticarial with a monoclonal gammopathy). PMID- 28094165 TI - Psoriasiform dermatitides: A brief review. AB - Psoriasis vulgaris (PV)-the prototypical "psoriasiform" dermatitis-may assume a spectrum of histologic appearances, depending on whether it has been treated or not. Because of that relative lack of morphological uniformity, other skin disorders that feature epidermal acanthosis, with or without associated inflammation, may be confused diagnostically with PV. This brief review considers the clinicopathologic attributes of PV and its imitators, including chronic spongiotic dermatitides, lichen simplex chronicus, prurigo nodularis, pityriasis rubra pilaris, psoriasiform secondary syphilis, and Reiter syndrome. PMID- 28094166 TI - Carotid Stenting Prior to Coronary Bypass Surgery: An Updated Systematic Review and Meta-Analysis. AB - OBJECTIVES: The aim was to determine 30-day outcomes in patients with concurrent carotid and cardiac disease who underwent carotid artery stenting (CAS) followed by coronary artery bypass grafting (CABG). METHODS: This was a systematic review with searches of PubMed/Medline, Embase, and Cochrane databases. "Same-day" procedures involved CAS + CABG being performed on the same day, and "staged" interventions involved at least 1 day's delay between undergoing CAS and then CABG. RESULTS: There were 31 eligible studies (2727 patients), with 80% being neurologically asymptomatic with unilateral stenoses. Overall, the 30-day death/stroke rate was 7.9% (95% confidence interval [CI] 6.9-9.2), while death/stroke/MI was 8.8% (95% CI 7.3-10.5). Staged CAS + CABG was associated with 30-day death/stroke rate of 8.5% (95% CI 7.3-9.7) compared with 5.9% (95% CI 4.0 8.5) after "same-day" procedures. Outcomes following CAS + CABG in neurologically symptomatic patients were poorer, with procedural stroke rates of 15%. There were five antiplatelet (APRx) strategies: (a) no APRx (death/stroke/MI, 4.2%; no data on bleeding complications); (b) single APRx before CAS and CABG, then dual APRx after CABG (death/stroke/MI, 6.7%; 7.3% bleeding complications); (c) dual APRx pre-CAS down to one APRx pre-CABG (death/stroke/MI, 10.1%; 2.8% bleeding complications); (d) dual APRx pre-CAS, both stopped pre-CABG (death/stroke/MI, 14.4%); (e) dual APRx pre-CAS and continued through CABG (death/stroke/MI, 16%). There were insufficient data on bleeding complication in the last two strategies. CONCLUSIONS: In a cohort of predominantly asymptomatic patients with unilateral carotid stenoses, the 30-day rate of death/stroke was about 8%. Notwithstanding the effect of potential biases, this meta-analysis did not find evidence that outcomes after same-day CAS + CABG were higher than after staged interventions. However, outcomes were poorer in neurologically symptomatic patients. More data are required to establish the optimal antiplatelet strategy in patients undergoing same-day or staged CAS + CABG. PMID- 28094167 TI - Seizures and Antiseizure Medications are Important to Parents of Newborns With Seizures. AB - BACKGROUND: Neonatal seizures and antiseizure medications both have potentially serious consequences on the developing brain. As such, optimal treatment of neonatal seizures remains unclear. Moreover, little is known about parental experiences, concerns, or unanswered questions. We conducted an online survey to assess parental perspectives regarding neonatal seizures and their management, along with their suggestions for specific high priority research topics. METHODS: Parents whose children had neonatal seizures were recruited through social media support groups to complete an online survey. Respondents progressed through a tiered series of questions about their experiences with neonatal seizures and antiseizure medications. RESULTS: There were 126 eligible respondents. On a Likert scale, parents reported that neonatal seizures had a major effect on their families (median 10 of 10; interquartile range 3; n = 85). They also reported that antiseizure medications had a significant impact on their families (median 7 of 10; interquartile range 5.5; n = 75). The emotional impact of the uncertainty regarding seizures and medications was highlighted. Effects on neurodevelopment, continued seizures, and adverse effects of medications were some of the most commonly reported parental concerns and their highest priority research topics. CONCLUSIONS: Both neonatal seizures and the medications used to treat them contribute to parental worries and have major impact on families. Patient centered outcomes research should focus on the risk-benefit ratio of neonatal seizures and antiseizure medication. The emotional impact on parents related to the uncertainty regarding both immediate and long-term neonatal seizure management is important to address in the clinical setting. PMID- 28094168 TI - Clinical Epidemiology and Treatment of Febrile and Afebrile Convulsions With Mild Gastroenteritis: A Multicenter Study. AB - BACKGROUND: We investigated features and responses to treatment in patients with febrile and afebrile convulsions with mild gastroenteritis and characterized convulsions with rotavirus and norovirus gastroenteritis. METHODS: We conducted a prospective, observational study to evaluate patients with febrile and afebrile convulsions with mild gastroenteritis who were hospitalized between November 2011 and March 2014 at 13 facilities in the National Hospital Organization. We classified the patients into two groups: presence or absence of fever. We investigated the background, clinical and laboratory characteristics, viral antigen in stool, and efficacy of anticonvulsant drugs. RESULTS: Of 126 patients enrolled in this study, 50 were febrile (Fc group) and 76 were afebrile (aFc group). A family history of febrile seizures was significantly more frequent in the Fc group than in the aFc group (28.0% vs 9.2%, P = 0.005). Clinical characteristics were similar between the rotavirus and norovirus groups, but fever was significantly more frequent in the rotavirus group (46.2% vs 8.3%, P < 0.001). Serum sodium levels were significantly negatively related to the number of seizures in the aFc group (beta = -0.13; 95% confidence interval, -0.24, 0.03; P = 0.01). Carbamazepine was significantly more efficacious than diazepam suppositories in the aFc group (odds ratio = 49.3, 95% confidence interval, 2.35, 1037; P = 0.01). CONCLUSION: Febrile convulsions with mild gastroenteritis show characteristics of both febrile seizures and convulsions with mild gastroenteritis. Carbamazepine is optimal for convulsions with mild gastroenteritis. Clinical features of convulsions with rotavirus and norovirus gastroenteritis are similar, except for fever. Serum sodium levels may play a major role in the onset of convulsions with mild gastroenteritis. PMID- 28094169 TI - A 12-week randomized controlled trial of twice-daily intranasal oxytocin for social cognitive deficits in people with schizophrenia. AB - Social cognition is impaired in people with schizophrenia and these deficits are strongly correlated with social functioning. Oxytocin is a hypothalamic peptide that contributes to maternal infant bonding and has diverse pro-social effects in adults. This study tested the hypothesis that 12weeks of intranasal oxytocin will improve social cognitive function in outpatients with schizophrenia and schizoaffective disorder. Sixty-eight eligible participants were randomized to oxytocin (24IU twice daily) or placebo. Social cognitive function was assessed using the Emotion Recognition-40, Brune Theory of Mind, Reading the Mind in the Eyes test, Trustworthiness task and Ambiguous Intentions Hostility Questionnaire at baseline, 6weeks and 12weeks. In addition, social function was assessed using the Specific Levels of Functioning Scale and a role-play test, and psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Fifty-five participants completed the 12-week trial. The study found no evidence for a differential advantage of oxytocin over placebo on social cognition. Among secondary outcomes, there was a modest advantage for oxytocin over placebo on a component of social functioning, although there was also evidence that the placebo group outperformed the oxytocin group on the role-play task. No between-group differences emerged on measures of psychopathology in pre specified comparisons, but oxytocin showed significant within-group reduction in PANSS negative symptoms and significant between-group improvement in negative symptoms in the schizophrenia subgroup. Further testing is needed to clarify whether oxytocin has therapeutic potential for social cognitive deficits and/or negative symptoms in people with schizophrenia. PMID- 28094171 TI - The relationship of cognitive improvement after cognitive remediation with social functioning in patients with schizophrenia and severe cognitive deficits. AB - BACKGROUND: This study aims to examine the effects of change in neurocognition on functional outcomes and to examine predictors of change in social functions following a 12-week course of cognitive remediation in patients with schizophrenia and schizoaffective disorder with severe cognitive impairments. METHOD: Level of social functioning was assessed using a performance based measure of functional capacity (PSP) in patients prior to and after the completion of 12-week cognitive remediation treatment (CRT). Participants completed a neuropsychological battery (MCCB-MATRICS) and clinical measures at both time points. RESULTS: 63 subjects with a mean age of 41.4 (SD=12.2) and with 12.2years of education (SD=2.4) were enrolled. There were significant improvements in overall PSP score from baseline to endpoint (p=0.021) as well as in PSP domain A (socially useful activities) (p<=0.001), domain B (personal and social relationships) (p=0.009), and domain D (disturbing and aggressive behaviors) (p=0.003). There was a significant improvement in the composite MCCB score (p=0.020) and the Working Memory (p<0.046). Stepwise logistic regression yielded a significant association for baseline Visual Learning (Wald=6.537, p=0.011, OR=1.195), Speed of Processing (Wald=4.112, p=0.043, OR=0.850) and level of PANSS positive symptoms (Wald=4.087, p=0.043, OR=0.739) with PSP overall improvement. CONCLUSIONS: Faster speed of processing, better visual and verbal learning and less prominent positive symptoms were associated with greater functional improvement after a systematic cognitive intervention within a rehabilitative setting. PMID- 28094172 TI - Interval Changes in Myocardial Performance Index Predict Outcome in Severe Sepsis. AB - OBJECTIVES: Septic cardiomyopathy is a well-described consequence of septic shock and is associated with increased sepsis-related mortality. The myocardial performance index (MPI), a parameter derived from echocardiographic tissue Doppler measurements, allows for a more sensitive assessment of global cardiac function than do traditional metrics for cardiac function. The authors hypothesized that changes in left ventricular MPI in patients with severe sepsis would be associated with a higher 90-day mortality. DESIGN: Prospective, observational study. SETTING: Intensive care units of a tertiary medical center. PARTICIPANTS: The study comprised 47 patients admitted with new diagnoses of severe sepsis or septic shock. INTERVENTIONS: All patients underwent transthoracic echocardiograms with assessment of MPI at enrollment and 24 hours later. Hemodynamic data and information on sepsis-related mortality were collected. In the primary analysis, the association between change in MPI from enrollment to 24 hours and sepsis-related 90-day mortality was assessed. MEASUREMENTS AND MAIN RESULTS: Of the 47 patients enrolled, 30 demonstrated an improvement in MPI from 0 to 24 hours ("improved" group), and MPI worsened in the remaining 17 patients ("worsened" group). Despite no significant differences in ejection fraction or severity of illness, the median MPI at enrollment in the "improved" group was higher than baseline values in the "worsened" group (p = 0.005). A worsening MPI over the 24-hour study interval was associated with increased mortality at 90 days (p = 0.04), which remained significant (hazard ratio 3.72; 95% confidence interval 1.12-12.41; p = 0.03) after adjusting for severity of illness (Acute Physiology and Chronic Health Evaluation II score), intravenous fluids, and vasopressor use. CONCLUSIONS: In patients admitted to the intensive care unit with a diagnosis of severe sepsis or septic shock, a worsening MPI during the first 24 hours after intensive care unit admission was associated with higher 90-day mortality. PMID- 28094173 TI - A Rare Complication of Metastatic Osteosarcoma. PMID- 28094174 TI - Con: Atrial Fibrillation Prophylaxis Is Not Necessary in Patients Undergoing Major Thoracic Surgery. PMID- 28094175 TI - Septic Shock in Low-Cardiac-Output Patients With Heart and Lung Transplantation: Diagnosis and Management Dilemma. PMID- 28094170 TI - Common developmental genome deprogramming in schizophrenia - Role of Integrative Nuclear FGFR1 Signaling (INFS). AB - The watershed-hypothesis of schizophrenia asserts that over 200 different mutations dysregulate distinct pathways that converge on an unspecified common mechanism(s) that controls disease ontogeny. Consistent with this hypothesis, our RNA-sequencing of neuron committed cells (NCCs) differentiated from established iPSCs of 4 schizophrenia patients and 4 control subjects uncovered a dysregulated transcriptome of 1349 mRNAs common to all patients. Data reveals a global dysregulation of developmental genome, deconstruction of coordinated mRNA networks, and the formation of aberrant, new coordinated mRNA networks indicating a concerted action of the responsible factor(s). Sequencing of miRNA transcriptomes demonstrated an overexpression of 16 miRNAs and deconstruction of interactive miRNA-mRNA networks in schizophrenia NCCs. ChiPseq revealed that the nuclear (n) form of FGFR1, a pan-ontogenic regulator, is overexpressed in schizophrenia NCCs and overtargets dysregulated mRNA and miRNA genes. The nFGFR1 targeted 54% of all human gene promoters and 84.4% of schizophrenia dysregulated genes. The upregulated genes reside within major developmental pathways that control neurogenesis and neuron formation, whereas downregulated genes are involved in oligodendrogenesis. Our results indicate (i) an early (preneuronal) genomic etiology of schizophrenia, (ii) dysregulated genes and new coordinated gene networks are common to unrelated cases of schizophrenia, (iii) gene dysregulations are accompanied by increased nFGFR1-genome interactions, and (iv) modeling of increased nFGFR1 by an overexpression of a nFGFR1 lead to up or downregulation of selected genes as observed in schizophrenia NCCs. Together our results designate nFGFR1 signaling as a potential common dysregulated mechanism in investigated patients and potential therapeutic target in schizophrenia. PMID- 28094176 TI - Atrial Septal Defect in a Patient With a Mechanical Mitral Valve Prosthesis Undergoing Implantation of a Left Ventricular Assist Device: To Repair or Not to Repair. PMID- 28094177 TI - Cognitive Outcomes After Coronary Artery Bypass Grafting. PMID- 28094178 TI - "Efficacy and Safety of Fibrinogen Concentrate in Surgical Patients: A Meta analysis of Randomized Controlled Trials". PMID- 28094179 TI - Synthesis and antiviral evaluation of novel heteroarylpyrimidines analogs as HBV capsid effectors. AB - New modifications to the scaffold of previously reported HBV capsid assembly effectors such as BAY 41-4109, HAP-12 and GLS4 were explored. The anti-HBV activity in the HepAD38 system, and cytotoxicity profiles of each of the new compounds has been assessed. Among them, five new iodo- and bromo heteroarylpyrimidines analogs displayed anti-HBV activity in the low micromolar range. PMID- 28094180 TI - Antifungal activity of substituted aurones. AB - Novel antifungals are in high demand as there is a growing resistance to antifungals currently in use. In particular, opportunistic fungal infections caused by Candida spp. are on the rise with infections by this genus accounting for the most severe fungal infections following chemotherapy, implantation procedures, and in patients with HIV/AIDS. A series of simple aurone analogs were synthesized and screened for antifungal activity versus Candida spp. Several compounds displayed activity at 100MUM, with two having IC50 values below 20MUM for three species of Candida. One of the compounds tested here also exhibits anti biofilm activity for mid-maturation growth. PMID- 28094181 TI - The oxidative induction of DNA lesions in cancer cells by 5-thio-d-glucose and 6 thio-d-fructopyranose and their genotoxic effects. Part 3. AB - Thio-sugars have been described as potent inhibitors of cancer cell growth but the detailed mechanism of action remains unknown. Herein we investigated the mechanism of their anticancer action in the HeLa cell line. We investigated two thio-sugars: 5-thio-d-glucose (FCP1) and 6-thio-beta-d-fructopyranose (FCP2). We have observed that FCP1 as well as FCP2 clearly induced oxidative DNA lesions in cancer cells and increased the level of cellular ROS. A spin trap and antioxidants have decreased the level of DNA lesions induced by FCPs. FCPs also induced significant changes in the oxidative-stress gene expression. Therefore, we assume that ROS generation is correlated with the increased NOX5 expression by FCPs. Higher cyto- and genotoxicity of FCPs for HeLa cells in a low glucose environment suggested their role in the glucose metabolism. The data indicates that thio-sugars may become drug alternatives for the cancer treatment but such undertaking needs further studies. PMID- 28094182 TI - DNA-duplex linker for AFM-SELEX of DNA aptamer against human serum albumin. AB - DNA-duplex interactions in thymines and adenins are used as a linker for the novel methodology of Atomic Force Microscope-Systematic Evolution of Ligands by EXpotential enrichment (AFM-SELEX). This study used the hydrogen bonds in 10 mer of both thymines (T10) and adenines (A10). Initially, the interactive force in T10-A10 was measured by AFM, which returned an average interactive force of approximately 350pN. Based on this result, DNA aptamers against human serum albumin could be selected in the 4th round, and 15 different clones could be sequenced. The lowest dissociation constant of the selected aptamer was identified via surface plasmon resonance, and it proved to be identical to that of the commercial aptamer. Therefore, specific hydrogen bonds in DNA can be useful linkers for AFM-SELEX. PMID- 28094183 TI - Discovering novel 7-azaindole-based series as potent AXL kinase inhibitors. AB - AXL is a receptor tyrosine kinase that plays a key role in tumor growth and proliferation. The scientific community has validated AXL as therapeutic target in the treatment of cancers for several years now, and several AXL inhibitors have been developed but none of them are approved. In this context, we started to design new kinase inhibitors targeting AXL from the 7-azaindole scaffold well known to interact with the ATP binding site of the kinase. Focused screening and chemical diversification around 7-azaindole scaffold were developed, based on modeling studies and medicinal chemistry rational, leading to the discovery of a new family of hits with potent inhibitory activity against AXL. PMID- 28094184 TI - In vivo evaluation of IGF1R/IR PET ligand [18F]BMS-754807 in rodents. AB - In vivo evaluation of [18F]BMS-754807 binding in mice and rats using microPET and biodistribution methods is described herein. The radioligand shows consistent binding characteristics, in vivo, in both species. Early time frames of the microPET images and time activity curves of brain indicate poor penetration of the tracer across the blood brain barrier (BBB) in both species. However, microPET experiments in mice and rats show high binding of the radioligand outside the brain to heart, pancreas and muscle, the organs known for higher expression of IGF1R/1R. Biodistribution analysis 2h after injection of [18F]BMS 754807 in rats show negligible [18F]defluorination as reflected by the low bone uptake and clearance from blood. Overall, the data indicate that [18F]BMS-754807 can potentially be a radiotracer for the quantification of IGF1R/IR outside the brain using PET. PMID- 28094185 TI - Anticomplement triterpenoids from the roots of Ilex asprella. AB - Five new (1-5) and twenty-eight known (6-33) triterpenoids were isolated from the roots of Ilex asprella. The structures of the new compounds were elucidated by the detailed spectral analysis. The ursane and oleanane triterpenoids were found to show anticomplement activity with some structure-activity relationships. Several triterpenoids (1-3, 6-7) exhibited potent anticomplement activity with the CH50 and AP50 values of 0.058-0.131mg/mL and 0.080-0.444mg/mL, respectively. It was found that caffeoyl group could enhance activity remarkably, followed by coumaroyl and feruloyl group. The 28-carboxyl group was also important to anticomplement activity for the triterpenoids. However, the triterpenoids with lactone ring (4, 9-14) exhibited weak activity and triterpenoid glycosides (5, 23 33) showed no inhibition. The targets of several bioactive triterpenoids in complement activation cascade were identified as well. PMID- 28094187 TI - Midwives' perceptions and experiences of engaging fathers in perinatal services. AB - BACKGROUND: The active engagement of fathers in maternity care is associated with long-term benefits for the father, their partner, and their child. Midwives are ideally placed to engage fathers, but few studies have explored midwives' experiences of working with men. Therefore, the aim of this study was to describe midwives' perceptions and experiences of engaging fathers in perinatal services. METHOD: A multi-method approach was utilised. Registered midwives (N=106) providing perinatal services to families in Australia participated in an online survey. Of these, 13 also participated in semi-structured telephone interviews. Descriptive analyses summarised the online survey data. The interview data were coded using semantic thematic analysis. RESULTS: Survey results indicated that midwives unanimously agreed that engaging fathers is part of their role and acknowledged the importance of receiving education to develop knowledge and skills about fathers. Analysis of the telephone interviews led to the identification of a range of strategies, facilitators and barriers to engaging fathers in midwifery services. Some of these were related to characteristics of midwives, factors related specifically to fathers, and several external factors relating to organisational policies. CONCLUSIONS: Findings from this study could inform maternity health care policies, as well the development of resources, education and ongoing professional training for midwives to promote father inclusive practice. PMID- 28094186 TI - Nardonaphthalenones A and B from the roots and rhizomes of Nardostachys chinensis Batal. AB - Nardonaphthalenones A and B (1-2), one new apo-alpha-carotenone (3) and four new monoterpenoids (4, 8-9 and 11), along with six known compounds (5-7, 10, 12-13) were isolated from the dried roots and rhizomes of Nardostachys chinensis Batal. Their structures were elucidated by analysis of the spectroscopic data including NMR, HRESIMS and circular dichroism data. Furthermore, the serotonin transporter (SERT)-regulating activities of these isolates were evaluated, among them compound 3 showed the strongest enhancement activity while compound 12 showed a moderate inhibition activity on SERT. PMID- 28094188 TI - Prosthetic Valve Thrombosis in the Acute Phase of the Stroke: Relevance of Detection and Follow-Up. AB - BACKGROUND: Stroke may be the first symptom of prosthetic valve thrombosis (PVT); therefore, rapid diagnosis and therapy are crucial. We aimed to evaluate the prevalence, main predictors, and long-term clinical evolution of patients with PVT in the acute phase of stroke. METHODS: We studied consecutive acute ischemic stroke patients with prosthetic heart valves who underwent emergent transesophageal echocardiography (TEE) during a 5-year period. Two groups were defined depending on the presence of PVT (PVT or non-PVT groups). Baseline characteristics, TEE findings, and international normalized ratios (INRs) at the stroke event were registered. Follow-up visits and TEE control examinations were performed. RESULTS: Sixty-seven patients were registered. TEE was performed within the first week in 85% of patients (n = 57). PVT was diagnosed in 41.8% of cases (n = 28). Clinical severity and baseline INR level showed no differences when the PVT and non-PVT groups were compared. The presence of PVT was associated with the mitral valve location as compared with the aortic valve location (75% versus 25%, P = .003), the presence of spontaneous echocontrast (64.3% versus 35.9%, P = .022), and low ejection fraction (66.7% versus 32.7%, P = .019). The PVT group showed a trend toward higher percentage of recurrence (10.7% versus 2.5%, P = .102) in the follow up period (mean follow-up 25 months). CONCLUSIONS: The detection of PVT in the acute stroke phase was relevant, as the stroke recurrence rate was considerable. Therefore, all patients with prosthetic heart valve should undergo emergent TEE. PMID- 28094189 TI - Medicaid payer status is linked to increased rates of complications after treatment of proximal humerus fractures. AB - BACKGROUND: Low socioeconomic status and Medicaid insurance as a primary payer have been associated with major disparities in resource utilization and risk adjusted outcomes for patients undergoing total joint arthroplasty. With the expansion of Medicaid through the Affordable Care Act in 2014, examination of these disparities has become increasingly relevant for the treatment of proximal humerus fracture (PHF). METHODS: The Healthcare Cost and Utilization Project Nationwide Inpatient Sample database was used to identify patients who were treated for PHF from 2002 to 2012. Primary outcomes included treatment type, surgical fixation method, in-hospital complications, mean length of stay, and mean total charges for Medicaid patients vs. a matched privately insured cohort. In an effort to minimize confounding variables, each Medicaid patient was matched to a privately insured patient on the basis of gender, race, year of procedure, and age. RESULTS: Of the 678,831 patients treated with PHF, 4.9% (33,263) had Medicaid as the primary payer during the 10-year period. Medicaid patients were found to have a significantly higher risk (P < .05) of postoperative in-hospital complications, including postoperative infection (odds ratio [OR], 2.00 [1.37 2.93]), wound complications (OR, 1.69 [1.04-2.75]), and acute respiratory distress syndrome (OR, 1.34 [1.15-1.59]). CONCLUSIONS: Medicaid patients have a significantly higher risk for certain postoperative hospital complications and consume more resources after treatment for PHFs. Additional work is needed to understand the optimal treatment type for Medicaid patients and to understand the complex interplay between socioeconomic status and outcomes to ensure appropriate resource allocation and risk stratification. PMID- 28094190 TI - Three or more preoperative injections is the most significant risk factor for revision surgery after operative treatment of lateral epicondylitis: an analysis of 3863 patients. AB - BACKGROUND: This study was conducted to identify the rate of failure of operative treatment of lateral epicondylitis, defined as progression to ipsilateral revision surgery, and associated patient-specific risk factors for failure. METHODS: A national database was used to identify patients undergoing surgical treatment of lateral epicondylitis from 2005 to 2012. Patients undergoing concomitant procedures were excluded. Patients who then required subsequent ipsilateral extensor carpi radialis brevis debridement or release within 2 years were identified using similar methods. A multivariate binomial logistic regression analysis was used to evaluate patient-related risk factors for revision surgery. In addition, the number of preoperative injections (1, 2, or >=3) in the ipsilateral elbow was identified and included in the regression analysis. Adjusted odds ratios (OR) and 95% confidence intervals were calculated for each risk factor. RESULTS: Of 3863 patients who underwent operative treatment of lateral epicondylitis, 58 (1.5%) required ipsilateral revision surgery. Risk factors for revision surgery included age <65 years (OR, 2.95; P = .003), male gender (OR, 1.53; P = .017), morbid obesity (OR, 2.13; P = .002), tobacco use (OR, 1.87; P < .001), and inflammatory arthritis (OR, 1.79; P = .009). Having >=3 ipsilateral preoperative injections was the most significant risk factor (OR, 3.55; P < .001), whereas having 2 (OR, 1.44; P = .135) or 1 (OR, 1.15; P = .495) was not significant. CONCLUSIONS: The incidence of failure requiring revision surgery for lateral epicondylitis in the studied population is low (1.5%). Risk factors for revision surgery include younger age, male gender, morbid obesity, tobacco use, and inflammatory arthritis. The most significant risk factor for revision surgery is having >=3 ipsilateral preoperative injections. PMID- 28094191 TI - Functional results of bilateral reverse total shoulder arthroplasty. AB - BACKGROUND: The purpose of this study was to analyze a population of patients with bilateral reverse total shoulder arthroplasty (RTSA) to evaluate their ability to perform activities of daily living and personal hygiene tasks. METHODS: At a minimum 2-year follow-up, we retrospectively reviewed 50 patients (100 shoulders) with a mean age of 72 years who underwent staged bilateral RTSA. The average follow-up period was 61 months (range, 24-121 months), with a minimum 2-year follow-up after the second surgical procedure. Functional outcomes were assessed with American Shoulder and Elbow Surgeons, Simple Shoulder Test, and Short Form 12 (SF-12) scores. In addition, a unique questionnaire regarding personal hygiene habits and activities of daily living reliant on shoulder rotation was administered to all patients. RESULTS: Patients showed significant improvements in pain (mean improvement in visual analog scale score from 5.7 to 1.0, P < .001) and forward elevation (mean improvement from 71 degrees to 136 degrees , P < .001). Clinical outcome scores showed significant improvements: The mean American Shoulder and Elbow Surgeons score improved from 35.8 to 76.5 (P < .001), Simple Shoulder Test score improved from 2.4 to 8.0 (P < .001), SF-12 mental component subscore improved from 51.9 to 54.1 (P < .001), and SF-12 physical component subscore improved from 30.5 to 39.7 (P < .001). Internal and external rotation showed significant improvements (from 33 degrees to 53 degrees [P < .005] and from 27 degrees to 44 degrees [P < .001], respectively). All patients retained independence with personal hygiene and activities of daily living. Complications included prosthetic instability (3%), acromial fracture (5%), and periprosthetic joint infection (1%). The overall reoperation rate was 5%. CONCLUSIONS: Bilateral RTSA provides predictable pain relief and improved function. Hygiene practices are unaltered for most patients, and the other patients rapidly develop simple compensatory strategies and retain independence in activities of daily living. PMID- 28094192 TI - Risk factors for revision surgery following isolated ulnar nerve release at the cubital tunnel: a study of 25,977 cases. AB - BACKGROUND: The literature investigating risk factors for failure after decompression of the ulnar nerve at the elbow (cubital tunnel release [CuTR]) is limited. The purpose of this study was to identify risk factors for failure of isolated CuTR, defined as progression to subsequent ipsilateral revision surgery. METHODS: The 100% Medicare Standard Analytic Files from 2005 to 2012 were queried for patients undergoing CuTR. Patients undergoing any concomitant procedures were excluded. A multivariate binomial logistic regression analysis was used to evaluate patient-related risk factors for ipsilateral revision surgery. Adjusted odds ratios (ORs) and 95% confidence intervals were calculated for each risk factor. RESULTS: A total of 25,977 patients underwent primary CuTR, and 304 (1.4%) of those with >=2 years of follow-up required revision surgery. Although the rate of primary procedures is on the rise (P = .002), the revision rate remains steady (P = .148). Significant, independent risk factors for revision surgery included age <65 years (OR, 1.5; P < .001), obesity (OR, 1.3; P = .022), morbid obesity (OR, 1.3; P = .044), tobacco use (OR, 2.0; P < .001), diabetes (OR, 1.3; P = .011), hyperlipidemia (OR, 1.2; P = .015), chronic liver disease (OR, 1.6; P = .001), chronic anemia (OR, 1.6; P = .001), and hypercoagulable disorder (OR, 2.1; P = .001). CONCLUSIONS: The incidence of failure requiring ipsilateral revision surgery after CuTR remained steadily low (1.4%) during the study period. There are numerous patient-related risk factors that are independently associated with an increased risk for revision surgery, the most significant of which are tobacco use, younger age, hypercoagulable disorder, liver disease, and anemia. PMID- 28094193 TI - Factors associated with infection after reconstructive shoulder surgery for proximal humerus tumors. AB - BACKGROUND: The main reconstruction techniques for proximal humerus tumors include osteoarticular allografts (OAs), endoprostheses (EPs), or allograft prosthetic composites (APCs). A common complication is infection, and constructs involving the use of allografts are believed to be at a higher risk of infection. Literature comparing infection rates between different modalities of reconstruction is scarce and underpowered. The study purposes were (1) to determine and compare the prevalence of infection in patients who underwent reconstruction of the proximal humerus including OAs, EPs, and APCs; (2) to identify preoperative, perioperative, and postoperative predictors of infection that might be modifiable; and (3) to present our protocol of treatment in patients with superficial and deep infections. METHODS: We reviewed 150 patients of all ages with proximal humerus tumors treated by an OA, EP, or APC at 2 tertiary institutions. The prevalence of infection for each modality was calculated and compared between groups. We identified potential predictors of infection with stepwise backward multivariate Cox regression analysis. RESULTS: An infection developed in 19 patients (12%): 5 of 45 (11%) in the OA group, 12 of 85 (14%) in the EP group, and 2 of 20 (10%) in the APC group (P = .740). A lower preoperative hemoglobin blood level and low preoperative albumin blood level were independently associated with infection. CONCLUSIONS: We found similar infection rates compared with previously reported series. However, we did not identify a higher infection prevalence in constructs using allografts. Patients with a lower preoperative hemoglobin or albumin level are at higher risk of infection and should undergo optimization before surgery. PMID- 28094194 TI - MABp1 as a novel antibody treatment for advanced colorectal cancer: a randomised, double-blind, placebo-controlled, phase 3 study. AB - BACKGROUND: MABp1, an antibody that targets interleukin 1alpha, has been associated with antitumour activity and relief of debilitating symptoms in patients with advanced colorectal cancer. We sought to establish the effect of MABp1 with a new primary endpoint in patients with advanced colorectal cancer. METHODS: Eligible patients for the double-blind phase of this ongoing, placebo controlled, randomised, phase 3 trial, had metastatic or unresectable disease, Eastern Cooperative Oncology Group performance status score 1 or 2, systemic inflammation, weight loss, and other disease-related morbidities associated with poor prognosis, and were refractory to oxaliplatin and irinotecan. Patients were randomly assigned 2:1 to receive either MABp1 or placebo. Randomisation codes were obtained from a centrally held list via an interactive web response system. Patients received an intravenous infusion of 7.5 mg/kg MABp1 or placebo given every 2 weeks for 8 weeks. The primary endpoint was assessed in patients who received at least one dose of MABp1 or placebo (modified intention-to-treat population), and was a composite of stable or increased lean body mass and stability or improvement in two of three symptoms (pain, fatigue, or anorexia) at week 8 compared with baseline measurements. This study is registered with ClinicalTrials.gov, number NCT02138422. FINDINGS: Patients were enrolled between May 20, 2014, and Sept 2, 2015. The double-blind phase of the study was completed on Nov 3, 2015. Of 333 patients randomly assigned treatment, 207 received at least one dose of MABp1 and 102 at least one dose of placebo. 68 (33%) and 19 (19%) patients, respectively, achieved the primary endpoint (relative risk 1.76, 95% CI 1.12-2.77, p=0.0045). The most common grade 3-4 adverse events in the MABp1 group compared with in the placebo group were anaemia (eight [4%] of 207 vs five [5%] of 102 patients), increased concentration of alkaline phosphatase (nine [4%] vs two [2%]), fatigue (six [3%] vs seven [7%]), and increased concentration of aspartate aminotransferase (six [3%] vs two [2%]). After 8 weeks, 17 (8%) patients in the MABp1 group and 11 (11%) in the placebo group had died, but no death was judged to be related to treatment. The incidence of serious adverse events was not significantly different in the MABp1 group and placebo groups (47 [23%] vs 33 [32%], p=0.07). INTERPRETATION: The primary endpoint was a useful means of measuring clinical performance in patients. MABp1 might represent a new standard in the management of advanced colorectal cancer. FUNDING: XBiotech. PMID- 28094195 TI - Advanced colorectal cancer treatment options beyond standard systemic therapy. PMID- 28094196 TI - Is a negative prostate biopsy a risk factor for a prostate cancer related death? PMID- 28094197 TI - Another piece in the jigsaw of accelerated partial breast irradiation. PMID- 28094199 TI - Risk of prostate cancer diagnosis and mortality in men with a benign initial transrectal ultrasound-guided biopsy set: a population-based study. AB - BACKGROUND: The risk of missing prostate cancer in the transrectal ultrasound guided systematic biopsies of the prostate in men with suspected prostate cancer is a key problem in urological oncology. Repeat biopsy or MRI-guided biopsies have been suggested to increase sensitivity for diagnosis of prostate cancer, but the risk of disease-specific mortality in men who present with raised prostate specific antigen (PSA) concentration and a benign initial biopsy result remains unknown. We investigated the risk of overall and prostate cancer-specific mortality in men with a benign initial biopsy set. METHODS: Data were extracted from the Danish Prostate Cancer Registry-a population-based registry including all men undergoing histopathological assessment of prostate tissue. All men who were referred for transrectal ultrasound-guided biopsy for assessment of suspected prostate cancer between Jan 1, 1995, and Dec 31, 2011, in Denmark were eligible for inclusion. Follow-up data were obtained on April 28, 2015. The primary endpoint was the cumulative incidence of prostate cancer-specific mortality, analysed in a competing risk setting, with death from other causes as the competing event. FINDINGS: Between Jan 1, 1995, and Dec 31, 2011, 64 430 men were referred for transrectal ultrasound-guided biopsy, of whom 63 454 were eligible for inclusion. Median follow-up was 5.9 years (IQR 3.8-8.5) and the total follow-up time, from the enrolment of the first patient on Jan 1, 1995, until the extraction of causes of death on April 28, 2015, was 20 years. 10 407 (30%) of 35 159 men with malignant initial biopsy sets died from prostate cancer, compared with 541 (2%) of 27 181 men with benign initial biopsy sets. Estimated overall 20-year mortality was 76.1% (95% CI 73.0-79.2). In all men referred for transrectal ultrasound-guided biopsy, the cumulative incidence of prostate cancer specific mortality after 20 years was 25.6% (24.7-26.5) versus 50.5% (47.5-53.5) for mortality from other causes. In men with benign initial biopsy sets, the cumulative incidence of prostate cancer-specific mortality was 5.2% (3.9-6.5) versus 59.9% (55.2-64.6) for mortality from other causes. In men with PSA concentrations 10 MUg/L or lower and benign initial biopsy sets (2779 men), the cumulative incidence of prostate cancer-specific mortality was 0.7% (0.2-1.3). Cumulative incidence of prostate cancer specific mortality in men with benign initial biopsy sets was 3.6% (95% CI 0.1-7.2) for men with a PSA higher than 10 ng/mL but 20 ng/mL or less (855 men) and 17.6% (12.7-22.4) and for men with a PSA higher than 20 ng/mL (454 men). INTERPRETATION: The first systematic transrectal ultrasound-guided biopsy set holds important prognostic information. The 20-year risk of prostate cancer-specific mortality in men with benign initial results is low. Our findings question whether men with low PSA concentration and a benign initial biopsy set should undergo further diagnostic assessment in view of the high risk of mortality from other causes. FUNDING: Capital Region of Denmark's Fund for Health Research, Danish Cancer Society, Danish Association for Cancer Research, and Krista and Viggo Petersen's Foundation. PMID- 28094198 TI - Late side-effects and cosmetic results of accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation after breast conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: 5-year results of a randomised, controlled, phase 3 trial. AB - BACKGROUND: We previously confirmed the non-inferiority of accelerated partial breast irradiation (APBI) with interstitial brachytherapy in terms of local control and overall survival compared with whole-breast irradiation for patients with early-stage breast cancer who underwent breast-conserving surgery in a phase 3 randomised trial. Here, we present the 5-year late side-effects and cosmetic results of the trial. METHODS: We did this randomised, controlled, phase 3 trial at 16 centres in seven European countries. Women aged 40 years or older with stage 0-IIA breast cancer who underwent breast-conserving surgery with microscopically clear resection margins of at least 2 mm were randomly assigned 1:1, via an online interface, to receive either whole-breast irradiation of 50 Gy with a tumour-bed boost of 10 Gy or APBI with interstitial brachytherapy. Randomisation was stratified by study centre, menopausal status, and tumour type (invasive carcinoma vs ductal carcinoma in situ), with a block size of ten, according to an automated dynamic algorithm. Patients and investigators were not masked to treatment allocation. The primary endpoint of our initial analysis was ipsilateral local recurrence; here, we report the secondary endpoints of late side-effects and cosmesis. We analysed physician-scored late toxicities and patient-scored and physician-scored cosmetic results from the date of breast conserving surgery to the date of onset of event. Analysis was done according to treatment received (as-treated population). This trial is registered with ClinicalTrials.gov, number NCT00402519. FINDINGS: Between April 20, 2004, and July 30, 2009, we randomly assigned 1328 women to receive either whole-breast irradiation (n=673) or APBI with interstitial brachytherapy (n=655); 1184 patients comprised the as-treated population (551 in the whole-breast irradiation group and 633 in the APBI group). At a median follow-up of 6.6 years (IQR 5.8 7.6), no patients had any grade 4 toxities, and three (<1%) of 484 patients in the APBI group and seven (2%) of 393 in the whole-breast irradiation group had grade 3 late skin toxicity (p=0.16). No patients in the APBI group and two (<1%) in the whole-breast irradiation group developed grade 3 late subcutaneous tissue toxicity (p=0.10). The cumulative incidence of any late side-effect of grade 2 or worse at 5 years was 27.0% (95% CI 23.0-30.9) in the whole-breast irradiation group versus 23.3% (19.9-26.8) in the APBI group (p=0.12). The cumulative incidence of grade 2-3 late skin toxicity at 5 years was 10.7% (95% CI 8.0-13.4) in the whole-breast irradiation group versus 6.9% (4.8-9.0) in the APBI group (difference -3.8%, 95% CI -7.2 to 0.4; p=0.020). The cumulative risk of grade 2-3 late subcutaneous tissue side-effects at 5 years was 9.7% (95% CI 7.1-12.3) in the whole-breast irradiation group versus 12.0% (9.4-14.7) in the APBI group (difference 2.4%; 95% CI -1.4 to 6.1; p=0.28). The cumulative incidence of grade 2-3 breast pain was 11.9% (95% CI 9.0-14.7) after whole-breast irradiation versus 8.4% (6.1-10.6) after APBI (difference -3.5%; 95% CI -7.1 to 0.1; p=0.074). At 5 years' follow-up, according to the patients' view, 413 (91%) of 454 patients had excellent to good cosmetic results in the whole-breast irradiation group versus 498 (92%) of 541 patients in the APBI group (p=0.62); when judged by the physicians, 408 (90%) of 454 patients and 503 (93%) of 542 patients, respectively, had excellent to good cosmetic results (p=0.12). No treatment related deaths occurred, but six (15%) of 41 patients (three in each group) died from breast cancer, and 35 (85%) deaths (21 in the whole-breast irradiation group and 14 in the APBI group) were unrelated. INTERPRETATION: 5-year toxicity profiles and cosmetic results were similar in patients treated with breast conserving surgery followed by either APBI with interstitial brachytherapy or conventional whole-breast irradiation, with significantly fewer grade 2-3 late skin side-effects after APBI with interstitial brachytherapy. These findings provide further clinical evidence for the routine use of interstitial multicatheter brachytherapy-based APBI in the treatment of patients with low-risk breast cancer who opt for breast conservation. FUNDING: German Cancer Aid. PMID- 28094200 TI - Type I Interferon in Malaria: A Balancing Act. AB - Type I interferons (IFN-Is) can now be considered as the wedge that balances clinical protection to malaria. New studies recently highlighted a central role for IFN-Is in orchestrating an immunoregulatory network leading to the dampening of proinflammatory responses, expansion of type 1 regulatory (Tr1) cells, and restriction of humoral immunity during malaria blood stage infection. Plasmacytoid dendritic cells (pDCs) were identified as the major source of IFN Is. Here, we integrate the findings and provide a model for the mechanisms involved. PMID- 28094201 TI - Diagnosing Urogenital Schistosomiasis: Dealing with Diminishing Returns. AB - Urogenital schistosomiasis, caused by Schistosoma haematobium, is the most prevalent form of schistosomiasis affecting humans, and can result in severe bladder, kidney, ureteral, and genital pathologies. Chronic infection with S. haematobium has been linked with bladder cancer and increased risk for HIV infection. As mass drug administration with praziquantel increases in an attempt to transition from control to elimination of schistosomiasis, the need for updated, more sensitive diagnostic tools becomes more apparent, especially for use in areas of low infection intensity and for individuals with light infections. Here, we review established and investigational diagnostic tests utilized for urogenital schistosomiasis, highlighting new insights and recent advances. PMID- 28094202 TI - Engaging Early-Career Geriatric Mental Health Investigators as Associate Editorial Board Members. PMID- 28094203 TI - Implications of Differential Associations of Neuroticism Facets with Cognitive Function in Late-Life Depression. PMID- 28094204 TI - Microbial contamination of drinking water from risky tubewells situated in different hydrological regions of Bangladesh. AB - This study, conducted in 40 selected upazilas covering four hydrological regions of Bangladesh, aimed at determining the risk of selected shallow tubewells (depth<30m) used for drinking purpose (n=26,229). This was based on WHO's sanitary inspection guidelines and identifying the association of sanitary inspection indicators and risk scores with microbiological contamination of shallow tubewells. The main objective of the study was to observe the seasonal and regional differences of microbial contamination and finally reaching a conclusion about safe distance between tubewells and latrines by comparing the contamination of two tubewell categories (category-1: distance <=10m from nearest latrine; n=80 and category 2: distances 11-20m from nearest latrine; n=80) in different geographical contexts. About 62% of sampled tubewells were at medium to high risk according to WHO's sanitary inspection guidelines, while the situation was worst in south-west region. Microbiological contamination was significantly higher in sampled category-1 tubewells compared to category-2 tubewells, while the number of contaminated tubewells and level of contamination was higher during wet season. About 21% (CI95=12%-30%), 54% (CI95=43%-65%) and 58% (CI95=46%-69%) of water samples collected from category-1 tubewells were contaminated by E. coli, FC, and TC respectively during the wet season. The number of category-1 tubewells having E.coli was highest in the north-west (n=8) and north-central (n=4) region during wet season and dry season respectively, while the level of E.coli contamination in tubewell water (number of CFU/100ml of sample) was significantly higher in north-central region. However, the south-west region had the highest number of FC contaminated category-1 tubewells (n=16 & n=17; respectively during wet and dry season) and significantly a higher level of TC and FC in sampled Category-1 tubewells than north-west, north-central and south east region, mainly during wet season. Multivariate regression analysis could identified some sanitary inspection indicators, such as tubewell within <10m of latrine, platform absent/broken, pollution source (i.e. household's waste dumping point/poultry/dairy farm) within 10m of tubewell and unimproved sanitation facility which were significantly associated with presence of microbial contaminants in tubewell water (p<0.01). A tubewell with high risk level was associated with a higher chance of having FC and TC in tubewell water than a tubewell with a medium risk during wet season, but no such conclusion could be drawn in case of E.coli contamination. Construction of pit latrine in areas with high water table should be highly discouraged. Raised sealed pits or flush/pour flash to septic tank could be installed considering sanitary inspection criteria. Water should be treated before drinking. PMID- 28094205 TI - Legionnaires' disease at a medical center in southern Taiwan. AB - BACKGROUND/PURPOSE: Legionella pneumophila had been recognized as a pathogen for both healthcare-associated and community-acquired pneumonia. We aimed to evaluate clinical features and outcomes of patients with Legionnaires' disease at a tertiary medical center in southern Taiwan. METHODS: From January 2005 to December 2013, a retrospective study of adult cases of Legionnaires' disease was conducted in a 1200-bed tertiary hospital. Their medical records were reviewed for further evaluation and analysis. RESULTS: A total of 61 cases of Legionnaires' disease were identified during the study period. Their mean age was 61.1 years, with male predominance (43, 70.5%). Among them, 30 (49.2%) had healthcare-associated pneumonia (HCAP), 20 (32.8%) had community-acquired pneumonia, and notably 11 (18.0%) were caregivers. Patients with healthcare associated pneumonia tend to have higher Charlson comorbidity scores than those with community-acquired pneumonia (3.6+/-2.4 vs. 1.9+/-1.9, p=0.008) and caregivers (0.5+/-0.5, p<0.001). Six patients died, resulting in an in-hospital mortality rate of 9.8%. Underlying cancer (66.7% vs. 20.0%, p=0.028) and a higher Charlson comorbidity score (4.7+/-2.6 vs. 2.2+/-2.2, p=0.013) were related to a fatal outcome. CONCLUSION: L. pneumophila remains an important pathogen for pneumonia acquired from the community or associated with healthcare facility. Healthy caregivers may potentially be at risk for Legionella infection in certain clinical settings. PMID- 28094206 TI - Hepatocyte growth factor in physiology and infectious diseases. AB - Hepatocyte growth factor (HGF) is a pleiotropic cytokine composed of an alpha chain and a beta-chain, and these chains contain four kringle domains and a serine protease-like structure, respectively. The receptor for HGF was identified as the c-met proto-oncogene product of transmembrane receptor tyrosine kinase. HGF-induced signaling through the receptor Met provokes dynamic biological responses that support morphogenesis, regeneration, and the survival of various cells and tissues, which includes hepatocytes, renal tubular cells, and neurons. Characterization of tissue-specific Met knockout mice has further indicated that the HGF-Met system modulates immune cell functions and also plays an inhibitory role in the progression of chronic inflammation and fibrosis. However, the biological actions that are driven by the HGF-Met pathway all play a role in the acquisition of the malignant characteristics in tumor cells, such as invasion, metastasis, and drug resistance in the tumor microenvironment. Even though oncogenic Met signaling remains the major research focus, the HGF-Met axis has also been implicated in infectious diseases. Many pathogens try to utilize host HGF-Met system to establish comfortable environment for infection. Their strategies are not only simply change the expression level of HGF or Met, but also actively hijack HGF-Met system and deregulating Met signaling using their pathogenic factors. Consequently, the monitoring of HGF and Met expression, along with real-time detection of Met activation, can be a beneficial biomarker of these infectious diseases. Preclinical studies designed to address the therapeutic significance of HGF have been performed on injury/disease models, including acute tissue injury, chronic fibrosis, and cardiovascular and neurodegenerative diseases. Likewise, manipulating the HGF-Met system with complete control will lead to a tailor made treatment for those infectious diseases. PMID- 28094207 TI - Ebola virus disease sequelae: a challenge that is not going away. PMID- 28094209 TI - Simplified low-dose-rate infant total body irradiation. AB - PURPOSE: Low-dose-rate total body irradiation (LDR TBI) in infants possesses unique challenges because of the setup limitations imposed by anesthesia. We present an LDR TBI method with an anteroposterior/posteroanterior arrangement and dose rate < 10 cGy/minute for infants (thickness <14 cm) without the use of a beam attenuator. MATERIALS AND METHODS: The delivery used a 6 MV TrueBeam linear accelerator (Varian Medical Systems, Palo Alto, CA) with adjustable meterset rates below 100 MU/minute. A platform was constructed to support the patient 6 cm above the floor (~2 m from the source). A 40 * 40 cm2 field at isocenter along with a 45 degrees collimator rotation was used to achieve a maximum field width of approximately 113 cm at 2 m. The patient was positioned supine with head turned toward the patient's right side for the anteroposterior beam and prone with the head continuing to turn towards the patient's right side for the posteroanterior beam. A scattering plate with custom organ blocks was placed approximately 20 cm from the patient's skin surface. Output, depth-dose, surface dose, block transmission, and off-axis measurements were taken using solid water slabs, ion chambers, and film. RESULTS: The TrueBeam provides several options for this treatment geometry to deliver LDR TBI at less than 10 cGy/min by lowering the linear accelerator meterset rate below 100 MU/minute. This allowed for a compromise between dose rate and treatment time to be selected by the radiation oncology team without the use of a beam attenuator, thus improving patient safety. Depth-dose and off-axis measurements confirmed a dose distribution within +/-5% of the central-axis dose. A scattering plate distance of ~20 cm from the patient increases surface dose while allowing easy access to the patient during anesthesia. CONCLUSIONS: The method described is useful to pediatric radiation oncologists seeking to deliver LDR TBI to an infant patient. PMID- 28094208 TI - Multidisciplinary assessment of post-Ebola sequelae in Guinea (Postebogui): an observational cohort study. AB - BACKGROUND: The high number of survivors from the 2013-16 west African outbreak of Ebola virus disease (EVD) has raised several new issues: long-term clinical complications, psychosocial consequences, risks of EVD reactivation, and secondary transmission due to viral persistence in body fluids. We aimed to assess long-term clinical, psychosocial, and viral outcomes in EVD survivors in Guinea. METHODS: In this multidisciplinary observational cohort study, we recruited patients aged 1 year or more in four sites in Guinea (Donka National Hospital, Conakry; Macenta Prefectoral Hospital, Macenta; N'zerekore Regional Hospital, N'zerekore; and Forecariah Prefectoral Hospital, Forecariah) following discharge from any Ebola treatment centre in Guinea. Eligible patients had had laboratory-confirmed EVD and had then been declared clear of the virus in the blood. All consenting patients were included, with no exclusion criteria. Trained clinicians assessed patients at enrolment to the cohort, recording clinical symptoms and signs of depression. We did routine blood examinations and examined viral persistence in body fluids using RT-PCR. We did psychological evaluations using questionnaires developed for different age groups. Follow-up is planned to 2 years, and here we present findings at enrolment. FINDINGS: Between March 23, 2015, and July 11, 2016, we recruited 802 patients, of whom 360 (45%) were male, 442 (55%) were female; 158 (20%) were younger than 18 years. The median age was 28.4 years (range 1.0-79.9, IQR 19.4-39.8). The median delay after discharge was 350 days (IQR 223-491). The most frequent symptoms were general symptoms (324 [40%] patients), musculoskeletal pain (303 [38%]), headache (278 [35%]), depression (124 [17%] of 713 responses), abdominal pain (178 [22%]), and ocular disorders (142 [18%]). More adults than children had at least one clinical symptom (505 [78%] vs 101 [64%], p<0.0003), ocular complications (124 [19%] vs 18 [11%], p=0.0200), or musculoskeletal symptoms (274 [43%] vs 29 [18%], p<0.0001). A positive RT-PCR in semen was found in ten (5%) of 188 men, at a maximum of 548 days after disease onset. 204 (26%) of 793 patients reported stigmatisation. Ocular complications were more frequent at enrolment than at discharge (142 [18%] vs 61 [8%] patients). INTERPRETATION: Post-EVD symptoms can remain long after recovery and long-term viral persistence in semen is confirmed. The results justify calls for regular check-ups of survivors at least 18 months after recovery. FUNDING: INSERM/Reacting, the French Ebola Task Force, and Institut de Recherche pour le Developpement. PMID- 28094210 TI - Benefits of omitting primary site radiation therapy after transoral robotic surgery: Only time will tell. PMID- 28094211 TI - Likelihood of unacceptable normal tissue doses in breast cancer patients undergoing regional nodal irradiation in routine clinical practice. AB - PURPOSE: As indications for regional nodal irradiation (RNI) for breast cancer have expanded, so too has scrutiny over potential late toxicity from radiotherapy. This emphasizes the need for careful radiation treatment planning to maximize the therapeutic ratio. We sought to evaluate how often unacceptable doses (UDs) to organs at risk (OARs) occur and the associated factors for patients receiving RNI in daily practice. METHODS AND MATERIALS: Treatment records of patients who received RNI from February 2012 to May 2015 were studied. The NSABP B51/RTOG 1304 clinical dose-volume constraints for targets/OARs receiving RNI were used as the benchmark. Dose-volume histograms were analyzed for the rate of >=1 UD delivered to the following organs: heart, mean >5 Gy; ipsilateral lung, V20 >35%, V10 >60%, V5 >70%; contralateral lung (CL), V5 >15%; and contralateral breast, V4.1 >5%. Logistic regression was used to test the association between UDs to OAR and key variables. RESULTS: Two hundred three consecutive cases received RNI (105 left, 98 right), to the chest wall in 171 (84%) and to the internal mammary nodes in 170 (84%); 77.4% of cases met all OAR constraints. The most common OAR UDs were delivered to the contralateral breast (n = 32, 15.7%) and ipsilateral lung V5 (n = 22, 10.8%). On multivariate analysis, use of intensity modulated radiation therapy (odds ratio [OR], 64.7; 95% confidence interval, 20.8-201.5; P < .001) and use of nodal boost (OR, 5.5; 95% confidence interval, 1.1-27.1; P = .04), but not internal mammary node irradiation (OR, 2.7; P = .35) or reconstruction (OR, 0.62; P = .33), were independently associated with higher OAR UD rate. For 3-dimensional conformal radiation therapy plans, 7.9% had OAR UDs. CONCLUSION: The OAR UD rate with 3 dimensional conformal radiation therapy +/- deep inspiration breath-hold in routine clinical practice is low and not independently associated with internal mammary node irradiation or reconstruction presence. Women treated with intensity modulated radiation therapy had a significantly higher overall OAR UD rate, and clinicians should be aware of this as they initiate RNI treatment planning. PMID- 28094212 TI - Sparing of high retropharyngeal nodal basins in patients with unilateral oropharyngeal carcinoma treated with intensity modulated radiation therapy. AB - PURPOSE: The introduction of intensity modulated radiotherapy (IMRT) has facilitated dose painting and sparing of uninvolved/low-risk nodal basins in head and neck cancers. In oropharynx cancer (OPC), the need for elective coverage of uninvolved high contralateral retropharyngeal (RP) nodes and the risk associated with sparing this region remain unclear. We examined outcomes of OPC patients treated with IMRT and omission of contralateral high RP coverage. METHODS AND MATERIALS: We identified 102 OPC patients with cN0-N2b disease treated with definitive IMRT with or without concurrent chemotherapy between 2010 and 2013. The contralateral RP nodal basins superior to the vertebral level of C1 were omitted from the elective IMRT field for all patients. Of the 67 patients (66%) with p16 status available, 63 (94%) were p16+. We used the Kaplan-Meier method to estimate overall survival, as well as freedom from local failure, regional failure, distant failure, and retropharyngeal failure. RESULTS: The median follow up was 26.9 months (range, 3.0-59.9 months). There were no failures in the treated ipsilateral RP nodes or the spared contralateral high RP nodes in the entire cohort. In the p16+ cohort and the entire cohort, the 2-year rates of overall survival and freedom from local, regional, distant, and retropharyngeal failure were 98.0% and 95.1%, 98.1% and 97.7%, 96.4% and 96.7%, 98.1% and 95.1%, and 100% and 100%, respectively. CONCLUSIONS: Omission of contralateral high RP nodes in patients with p16+ OPC with unilateral disease is safe. PMID- 28094214 TI - Primary intraosseous adenoid cystic carcinoma of the mandible: a comprehensive review and analysis of four new cases with emphasis on morphologic, immunophenotypic, and molecular characteristics. AB - OBJECTIVE: To comprehensively review the clinical manifestations, imaging, diagnosis, treatment, and pathologic features of primary intraosseous adenoid cystic carcinoma (PIACC) of the mandible and analyze PIACC histopathology and molecular features in four cases. STUDY DESIGN: We reviewed the literature and retrospectively studied four cases of PIACC. RESULTS: The clinical and imaging findings of PIACC are similar to other malignant or borderline-malignant mandible tumors. The four cases of PIACC included three males and one female (aged between 41 and 58 years). The histopathologic features of the tumors resembled those of ACC. We observed abundant osteoclasts resorbing bone at the leading edge of the tumors characterized by solid structure histology but not by the cribriform subtype. Additionally, all four cases showed abnormalities in the MYB gene and high expression of MYB protein. All patients survived for the duration of follow up, and two patients had distant metastases (followed up for 3 to 36 months). CONCLUSIONS: PIACC is extremely rare and is often clinically misdiagnosed. Different histologic subtypes could show different mechanisms of invasion of the mandible. MYB gene and protein expression abnormalities can be used as indicators for the precise diagnosis of PIACC. PMID- 28094213 TI - Examination of the early wound healing process under different wound dressing conditions. AB - OBJECTIVE: Various types of wound-healing dressings have been used to assist in the healing of surgical wounds. We analyzed the wound-healing process in an animal model using different existing wound dressings. STUDY DESIGN: Full thickness defects were created using a biopsy punch on the backs of 7-week-old rats. The wounded areas were covered with NEOVEIL (polyglycolic acid [PGA]) or TERUDERMIS (collagen sponge [CS]) affixed using a rat jacket. The wound area, neo epithelium length, and alpha-smooth muscle actin (alpha-SMA) expression were evaluated and compared among the control, PGA, and CS groups. RESULTS: The wound areas in the control group on days 4 and 7 were significantly smaller than those in the PGA and CS groups. The expression of alpha-SMA in granulation tissue peaked on day 4 for all groups. The expression of alpha-SMA in the control group on days 4 and 7 after injury was greater than in the PGA and CS groups. However, there was no significant difference in the expression of alpha-SMA between the PGA and CS groups. CONCLUSIONS: In this study, PGA and CS suppressed wound contracture and reduced expression of alpha-SMA in wound areas. However, PGA and CS did not affect the neo-epithelium length at the wound site. PMID- 28094215 TI - Effect of decompression for patients with various jaw cysts based on a three dimensional computed tomography analysis. AB - OBJECTIVES: The aim of this study is to evaluate the effectiveness of decompression according to reduction parameters by measuring cystic volume changes using computed tomography (CT). STUDY DESIGN: We chose patients who had undergone decompression for a cystic lesion of the jaw at the Department of Oral and Maxillofacial Surgery in our dental hospital between 2006 and 2015. All patients had been examined by CT before and after decompression. We measured the volume of cystic lesions using the threshold method and evaluated the volumetric changes after decompression according to various parameters. RESULTS: The mean reduction rates of 46 cystic cases was 57.95%. There was a statistically significant difference in reduction rates by initial volume; the group with large initial volume reported higher reduction rates. CONCLUSION: Decompression is more effective in larger initial lesions when carried out more than 6 months. CT is an efficient method for evaluating the bony healing within the cyst cavity by measuring changes in cystic volume after decompression. However, due to its high cost and radiation dose, a comparative study using another diagnostic radiographic tool should be considered. PMID- 28094216 TI - Mild to moderate dysplasia at surgical margin is a significant indicator of survival in patients with oral cancer. AB - OBJECTIVE: The objective of this study was to investigate the significance of mild and moderate dysplasia at the surgical margin with regard to survival and locoregional recurrence. STUDY DESIGN: We investigated cases of primary oral squamous cell carcinoma with negative margins retrospectively from the database of a tertiary cancer hospital. All patients had been treated between January 2010 and December 2012, and margin dysplasia was investigated in a multivariate analysis for locoregional recurrence and overall survival. RESULTS: Of a total of 425 patients who fulfilled the inclusion criteria, 28 patients had mild dysplasia, and 29 patients had moderate dysplasia; median period of follow-up was 46.63 +/- 10.04 (standard deviation) months. Most of the patients with mild and moderate dysplasia in the margin were tobacco users (P = .007). Univariate analysis showed lower rates of survival among the patients with margin dysplasia (mild + moderate) (P = .043), and the multivariate cox regression revealed moderate dysplasia at the margin as an independent significant factor for survival (P < .0001) when adjusted with other cofounders. CONCLUSIONS: Patients with mild or moderate dysplasia at surgical margin were often tobacco users, and moderate dysplasia in the margin is an independent significant indicator for survival of patients with oral cancer in this single-institution, retrospective study. PMID- 28094217 TI - Development and validation of a quality-of-life questionnaire for patients with oral potentially malignant disorders. AB - OBJECTIVE: The aim of this study was to develop and evaluate the validity and reliability of a quality-of-life (QoL) questionnaire for patients with oral potentially malignant disorders (OPMDs). STUDY DESIGN: For item generation, 15 personal interviews and three focus group discussions were conducted with OPMD patients existing QoL questionnaires were reviewed, and inputs from specialist clinicians (n = 10) were considered. Data collected from patients were analyzed by using NVivo. This led to the identification of themes, item writing, scaling, item reduction, formatting, and pretesting of the newly developed questionnaire. The validity and reliability of the questionnaire were assessed in a separate sample of 300 patients (150 each of patients with OPMD and healthy individuals). RESULTS: Sixty items were generated from the qualitative data and by reviewing existing questionnaires. After item reduction, the final questionnaire comprised 20 questions, which could be categorized under four domains. Exploratory factor analysis revealed a four-factor structure conforming to the four domains. The OPMD QoL questionnaire exhibited good discriminant and convergent validity, with OPMD patients reporting poorer QoL compared with healthy individuals and correlating significantly with existing questionnaires designed for similar purposes respectively. CONCLUSIONS: Our OPMD QoL questionnaire was found to be valid and reliable. We recommend that it be applied in epidemiologic and treatment studies of these disorders. PMID- 28094218 TI - Cribriform adenocarcinoma of the soft palate with multiple lymph node metastasis and long-term follow-up. AB - INTRODUCTION: Cribriform adenocarcinoma of the tongue and minor salivary glands (CATMSG) is a recently described entity, with most cases previously published as polymorphous low-grade adenocarcinoma (PLGA). Typical cases share some main characteristics, such as oral sites (mainly tongue), regional lymph node metastasis, and morphology resembling solid and follicular variants of papillary thyroid carcinoma. OBJECTIVE: To present a CATMSG and emphasize the importance of reclassifying PLGAs with unusual behavior. CASE REPORT: A 78-year-old male presented with an ulcerated mass in the soft palate treated as PLGA. The patient developed 5 regional metastases over 11 years of follow-up, all diagnosed as PLGA. He died due to the disease, and because of the very aggressive behavior of PLGA, all histopathologic slides were revised and the tumor was reclassified as CATMSG. CONCLUSION: This report emphasizes the importance of reevaluating aggressive PLGA and contributes to a better understanding of CATMSG. PMID- 28094219 TI - 3,4-Dihydropyrimidinone-coumarin analogues as a new class of selective agent against S. aureus: Synthesis, biological evaluation and molecular modelling study. AB - Bacterial infections are increasingly difficult to combat as bacteria evolve resistance to antibiotic drugs and have severely compromised the arsenal of antibiotic drugs. On the other hand matrix metalloproteinases (MMPs) play a fundamental role in inflammation and extracellular matrix degradation in physiological and pathological conditions. In search of potent antibiotic, taking coumarin and dihydropyrimidinone as lead compound, a green, eco-friendly and efficient protocol has been developed and synthesized the dihydropyrimidin-2(1H) one/thione derivatives of coumarin 3/4 from substituted 4-formylcoumarins 2 and ethylacetoacetate using urea/thiourea in the presence of catalytic amount of ceric ammonium nitrate is reported. All the synthesized compounds were evaluated for their antibacterial activity against four bacterial strains by broth dilution method. The tested compounds have exhibited promising in vitro potency with low MIC values against the drug susceptive S. aureus strain with low MIC values ranging from 0.2 to 6.25MUg/mL. The in vivo anti-inflammatory potency of 3a-e and 4a-e by gelatin zymography is comparable to that of tetracycline. Molecular docking study performed for all the synthesized compounds with S. aureus DNA gyrase and results obtained were quite promising. PMID- 28094220 TI - Molecular docking, discovery, synthesis, and pharmacological properties of new 6 substituted-2-(3-phenoxyphenyl)-4-phenyl quinoline derivatives; an approach to developing potent DNA gyrase inhibitors/antibacterial agents. AB - Synthesis and molecular validation of 6-substituted-2-(3-phenoxyphenyl)-4 phenylquinoline derivatives (4a-h) as antibacterial/DNA gyrase inhibitors reported. Primarily, 6-substituted-2-(3-phenoxyphenyl)-4-phenylquinoline derivatives were docked into the active sites of DNA gyrase A&B, to ensure the binding mode of the compounds, and the results were superior on DNA gyrase A over DNA gyrase B. Based on this, S. aureus DNA gyrase A assay was proposed and executed. Most prominent DNA gyrase inhibition showed by 6-fluoro-2-(3 phenoxyphenyl)-4-phenylquinoline (4c), IC50 0.389MUg/mL; 2-(3-phenoxyphenyl)-4 phenylquinolin-6-ol (4e), IC50 0.328MUg/mL; and 5,7-dichloro-2-(3-phenoxyphenyl) 4-phenylquinolin-6-ol (4h), IC50 0.214MUg/mL which were substituted with fluorine (4F), nitrile (4CN), hydroxyl group (4OH) and dichloro-hydroxyl (3,5Cl, 4OH) groups in the quinoline scaffold. Antimicrobial activity on Gram-ve bacteria Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 424), and Gram+ve bacteria Staphylococcus aureus (MTCC 96) and Streptococcus pyogenes (MTCC 442) was evaluated. Excellent antibacterial activity showed by S. aureus and S. pyogenes which indicates the activity dominance of 6-substituted-2-(3 phenoxyphenyl)-4-phenylquinoline derivatives on Gram+ve bacteria rather than Gram ve. Subsequently, the cytotoxicity of 6-substituted-2-(3-phenoxyphenyl)-4 phenylquinoline derivatives was evaluated. Cytotoxicity results of MCF-7 (human breast cancer) and G361 (skin melanoma cancer) cell lines reveals that the 6 substituted-2-(3-phenoxyphenyl)-4-phenylquinoline derivatives are highly toxic to cancer cells. Predicted SAR, Lipinski's filter, Pharmacokinetic, and ADMET properties were also ensured the druggability probabilities of most favorable compounds among 6-substituted-2-(3-phenoxyphenyl)-4-phenylquinoline derivatives. PMID- 28094221 TI - Synthesis, biological evaluation and molecular docking analysis of 2-phenyl benzofuran-3-carboxamide derivatives as potential inhibitors of Staphylococcus aureus Sortase A. AB - In Gram-positive bacteria, Sortase A (Srt A) is a critical cysteine transpeptidase that is responsible for recognizing and assembling surface virulence proteins through the recognition of a LPXTG (leucine, proline, X, threonine, and glycine, where X is any amino acid) signal. Mutants lacking genes for Srt A attenuate infections without affecting microbial viability. Here a series of 2-phenyl-benzofuran-3-carboxamide derivatives were synthesized and identified as potent Srt A inhibitors. Activity assays revealed that multiple compounds exhibited excellent inhibitory activity against Srt A compared with known Sortase A inhibitor pHMB (IC50=130MUM). Structural activity relationships (SARs) demonstrated that the amide group at 3-position was essential for inhibitory activity. Replacement of the hydroxyl group at the 2-phenyl position of benzofuran with other substitutions such as a methoxyl, halogen or nitro group reduced the enzyme inhibitory activity in most cases. The compound Ia-22 was found to be the most potent inhibitor against the enzyme with an IC50 value of 30.8MUM. Molecular docking studies showed Ia-22 shared similar binding pattern with substrate LPXTG in the binding pocket of Srt A (PDB: 2KID) including i-butyl stretching, L-shape pattern kinking, and H-bond interaction with Srt A functional site residues Cys184, Trp194 and Arg197. PMID- 28094222 TI - Recent developments in the isolation, biological function, biosynthesis, and synthesis of phenazine natural products. AB - Phenazines are natural products which are produced by bacteria or by archaeal Methanosarcina species. The tricyclic ring system enables redox processes, which producing organisms use for oxidation of NADH or for the generation of reactive oxygen species (ROS), giving them advantages over other microorganisms. In this review we summarize the progress in the field since 2005 regarding the isolation of new phenazine natural products, new insights in their biological function, and particularly the now almost completely understood biosynthesis. The review is complemented by a description of new synthetic methods and total syntheses of phenazines. PMID- 28094223 TI - Anti-tuberculosis activity and structure-activity relationships of oxygenated tricyclic carbazole alkaloids and synthetic derivatives. AB - A series of 49 oxygenated tricyclic carbazole derivatives has been tested for inhibition of the growth of Mycobacterium tuberculosis and a mammalian cell line (vero cells). From this series, twelve carbazoles showed a significant anti-TB activity. The four most active compounds were the naturally occurring carbazole alkaloids clauszoline-M (45), murrayaline-C (41), carbalexin-C (27), and the synthetic carbazole derivative 22 with MIC90 values ranging from 1.5 to 3.7MUM. The active compounds were virtually nontoxic for the mammalian cell line in the concentration range up to 50MUM. PMID- 28094224 TI - Synthesis of pharmacologically important naphthoquinones and anticancer activity of 2-benzyllawsone through DNA topoisomerase-II inhibition. AB - Naphthoquinones are naturally occurring biologically active entities. Practical de novo syntheses of three naphthoquinones i.e. lawsone (1), lapachol (2), and beta-lapachone (3b) have been achieved from commercially available starting materials. The conversion of lapachol (2) to beta-lapachone (3b) was achieved through p-TSA/Iodine/BF3-etherate mediated regioselective cyclisation. Further, 2 alkyl and 2-benzyllawsone derivatives have been prepared as possible anticancer agents. Four derivatives exhibited significant anticancer activity and the best analogue i.e. compound 21a exhibited potential anticancer activity (IC50=5.2MUM) against FaDu cell line. Compound 21a induced apoptosis through activation of caspase pathway and exerted cell cycle arrest at S phase in FaDU cells. It also exhibited significant topoisomerase-II inhibition activity. Compound 21a was found to be safe in Swiss albino mice up to 1000mg/kg oral dose. PMID- 28094225 TI - [Oral methadone for the management of difficult to control pain in Fabry disease]. PMID- 28094226 TI - Relationship between age and cardiometabolic index in Japanese men and women. AB - BACKGROUND: Cardiometabolic index (CMI) is a new discriminator of the risk of diabetes and has been reported to be associated with the degree of atherosclerosis. However, it is unknown whether and how age influences CMI. METHODS: The subjects were Japanese men (n=35684) and women (n=18793) aged >=35 and <=70 years who had received periodic health examinations at workplaces. CMI and its association with diabetes were compared among different age groups in men and women. RESULTS: CMI was much higher in men than in women (median: 1.06 vs. 0.59). In men, CMI was significantly higher in the middle-aged (40-49 and 50-59 years) groups than in the youngest (35-39 years) and oldest (60-70 years) groups and was significantly higher in the oldest group than in the youngest group. In women, CMI tended to be higher with an increase of age, and log-transformed CMI was significantly correlated with age (Pearson's correlation coefficient: 0.235, p<0.01). Both in men and women, odds ratios of CMI (high vs. not high) for diabetes were significantly higher than the reference level in all of the age groups and tended to be lower with an increase of age. The above relationships among age, CMI and diabetes were also found in multivariate analyses adjusting for histories of smoking, alcohol drinking and regular exercise. CONCLUSIONS: Age influences CMI differently in men and women, and the association between CMI and diabetes became weaker with an increase of age both in men and women. PMID- 28094227 TI - The Effectiveness of the Braden Scale as a Tool for Identifying Nutrition Risk. PMID- 28094228 TI - Health Promotion in Practice-District Nurses' Experiences of Working with Health Promotion and Lifestyle Interventions Among Patients at Risk of Developing Cardiovascular Disease. AB - OBJECTIVE: Health Promotion Practice (HPP) has the objective to promote a healthier lifestyle and reduce the risk of disease. The aim of this study was to examine district nurses' experiences of working with health preventive actions among patients with risk factors for cardiovascular disease (CVD), and to identify facilitators and obstacles in HPP. DESIGN/SETTING: The study was carried out with a qualitative approach where individual semistructured interviews were performed with a total of 12 district nurses in primary care. Data transcripts were analyzed with a manifest content analysis. FINDINGS: Five categories were identified. Firstly, informants regarded HPP as the core essence of their work. Secondly, counseling and coaching were reported as crucial elements in working with HPP. Thirdly, informants identified tools such as motivational interviewing (MI) to facilitate HPP. In the fourth category facilitators and barriers of HPP appeared, consisting of both positive and negative attitudes and presence as well as lack of organizational culture and structure. Finally, some informants were dissatisfied with HPP and viewed it as compulsory or as a burden, while others were satisfied and experienced it as a stimulating challenge. CONCLUSION: This study identified that HPP is the core of the district nurses' work to promote a healthier lifestyle in individuals with CVD. Organizational structures and culture need to be improved in order to support district nurses to successfully work with HPP. To optimize health promotion and strengthen patients' self-care, it is recommended that HPP include holistic elements of care. PMID- 28094229 TI - Perceived Stress in Patients with Common Gastrointestinal Disorders: Associations with Quality of Life, Symptoms and Disease Management. AB - OBJECTIVE AND METHODS: Research supports relationships between stress and gastrointestinal (GI) symptoms and disorders. This pilot study assesses relationships between perceived stress, quality of life (QOL), and self-reported pain ratings as an indicator of symptom management in patients who self-reported gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD). RESULTS: In the full sample (n = 402) perceived stress positively correlated with depression (r = 0.76, P < .0001), fatigue (r = 0.38, P < .0001), sleep disturbance (r = 0.40, P < .0001), average pain (r = 0.26, P < .0001), and worst pain (r = 0.25, P < .0001). Higher perceived stress also correlated with lower mental health-related QOL. Similar correlations were found for the participants with GERD (n = 188), IBS (n = 132), and IBD (n = 82). Finally, there were significant correlations in the GERD cohort between perceived stress, and average pain (r = 0.34, P < .0001) and worst pain (r = 0.29, P < .0001), and in the IBD cohort between perceived stress, and average pain (r = 0.32, P < .0001), and worst pain (r = 0.35, P < .01). CONCLUSIONS: Perceived stress broadly correlated with QOL characteristics in patients with GERD, IBS, and IBD, and their overall QOL was significantly lower than the general population. Perceived stress also appeared to be an indicator of symptom management (self-reported pain ratings) in GERD and IBD, but not IBS. While future research using objective measures of stress and symptom/disease management is needed to confirm these associations, as well as to evaluate the ability of stress reduction interventions to improve perceived stress, QOL and disease management in these GI disorders, integrative medicine treatment programs would be most beneficial to study. PMID- 28094230 TI - Duelling Ontologies: Might Vitalism Offer Balance and Value? AB - This article is part of a project investigating chiropractors' beliefs on the role of vitalism in their philosophical and practice approaches and how that might contribute to addressing current epidemics of non-communicable diseases. It aims to present atomism, reductionism, materialism and mechanism as fundamental ontologies in biomedicine and to examine what role these might play in its struggle to deal with these epidemics; to present vitalism as a fundamental ontology existing in chiropractic along with these ontologies of biomedicine; and to discuss how imbalances in the use of these ontologies and practices stemming from them might be contributing to difficulties in addressing these epidemics. The use of more balanced approaches by chiropractors involving not only mechanistic biomedical ontologies but also an increased focus on vitalism might offer value in addressing these epidemics and should be investigated. PMID- 28094231 TI - Improving Efficiency Using Time-Driven Activity-Based Costing Methodology. AB - PURPOSE: The aim of this study was to increase efficiency in MR enterography using a time-driven activity-based costing methodology. METHODS: In February 2015, a multidisciplinary team was formed to identify the personnel, equipment, space, and supply costs of providing outpatient MR enterography. The team mapped the current state, completed observations, performed timings, and calculated costs associated with each element of the process. The team used Pareto charts to understand the highest cost and most time-consuming activities, brainstormed opportunities, and assessed impact. Plan-do-study-act cycles were developed to test the changes, and run charts were used to monitor progress. The process changes consisted of revising the workflow associated with the preparation and administration of glucagon, with completed implementation in November 2015. RESULTS: The time-driven activity-based costing methodology allowed the radiology department to develop a process to more accurately identify the costs of providing MR enterography. The primary process modification was reassigning responsibility for the administration of glucagon from nurses to technologists. After implementation, the improvements demonstrated success by reducing non-value added steps and cost by 13%, staff time by 16%, and patient process time by 17%. The saved process time was used to augment existing examination time slots to more accurately accommodate the entire enterographic examination. Anecdotal comments were captured to validate improved staff satisfaction within the multidisciplinary team. CONCLUSIONS: This process provided a successful outcome to address daily workflow frustrations that could not previously be improved. A multidisciplinary team was necessary to achieve success, in addition to the use of a structured problem-solving approach. PMID- 28094232 TI - Comparative evaluation of shear bond strength of metallic brackets bonded with two different bonding agents under dry conditions and with saliva contamination. AB - BACKGROUND: This study compared the shear bond strength of metallic brackets bonded with Single Bond and Assure bonding agents under dry and saliva contamination conditions. METHODS: Sixty sound premolar teeth were selected, and stainless-steel brackets were bonded on enamel surfaces with Single Bond and Assure bonding agents under dry condition or with saliva contamination. Shear bond strength values of brackets were measured in a universal testing machine. The adhesive remnant index scores were determined after debonding of the brackets under a stereomicroscope. One-way analysis of variance (ANOVA) was used to analyze bond strength. Two-by-two comparisons were made with post hoc Tukey tests (p<0.001). Frequencies of adhesive remnant index scores were analyzed by Kruskal Wallis test. RESULTS: Bond strength values of brackets to tooth structure were 9.29+/-8.56 MPa and 21.25+/-8.93 MPa with the use of Assure resin bonding agent under saliva-contamination and dry conditions, respectively. These values were 10.13+/-6.69 MPa and 14.09+/-6.6 MPa, respectively, under the same conditions with the use of Single Bond adhesive. Contamination with saliva resulted in a significant decrease in the bond strength of brackets to tooth structure with the application of Assure adhesive resin (p<0.001). There were no significant differences in the adhesive remnant index scores between the study groups. CONCLUSION: Application of Single Bond and Assure bonding agents resulted in adequate bond strength of brackets to tooth structures. Contamination with saliva significantly decreased the bond strength of Assure bonding agent compared with dry conditions. PMID- 28094233 TI - Association between the MTHFR C677T polymorphism, blood folate and vitamin B12 deficiency, and elevated serum total homocysteine in healthy individuals in Yunnan Province, China. AB - BACKGROUND: An increased serum total homocysteine (tHcy) concentration is typically associated with genetic defects involved in Hcy metabolism or related nutritional deficiencies. In this study, the combined effects of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and folate and vitamin B12 deficiency on serum total Hcy (tHcy) levels were evaluated in a healthy Chinese population in Yunnan Province, China. METHODS: The MTHFR C677T polymorphism was genotyped in 330 volunteers (164 men and 166 women) using polymerase chain reaction-restriction fragment length polymorphism analysis. Folate, vitamin B12, and tHcy concentrations were determined by corpuscle immune chemiluminescence assays. The tHcy concentration was determined using an enzymatic assay. RESULTS: Significant negative correlations (p<0.001) were observed between the serum levels of tHcy and folate (r=-0.252) and vitamin B12 (r=-0.243). Men had significantly higher serum tHcy concentrations than women (p<0.001). Individuals with the MTHFR TT genotype had significantly higher serum tHcy concentrations than individuals with the CC and CT genotypes (p<0.001). The folate level of red blood cells was significantly increased in individuals with the TT genotype than in individuals with the CC genotype (p<0.05). Moreover, in the low vitamin group, the serum tHcy level was significantly correlated with the levels of folate (r=-0.334, p=0.001) and vitamin B12 (r=-0.212, p=0.046). CONCLUSION: The MTHFR C677T polymorphism, folate deficiency, and B12 deficiency were significantly associated with elevated serum tHcy levels. Among these three factors, folate deficiency had the greatest contribution to the serum tHcy concentration, followed by (in order of decreasing effect) MTHFR C677T and vitamin B12 deficiency. Thus, folic acid and vitamin B12 supplementation could help prevent diseases associated with tHcy accumulation, especially in individuals with the MTHFR 677TT genotype. PMID- 28094234 TI - Association between preterm labor and genitourinary tract infections caused by Trichomonas vaginalis, Mycoplasma hominis, Gram-negative bacilli, and coryneforms. AB - BACKGROUND: Preterm labor (PTL) is responsible for most cases of neonatal death. In most of these cases, the causes of PTL have not been established although several risk factors have been described. Therefore, the aim of this study was to investigate risk factors for PTL before 37 gestational weeks among Egyptian women. METHODS: In this case-control study, 117 pregnant women without risk factors for PTL were chosen. The control group (n=45) had term labor (gestational weeks>=37 weeks), and the case group (n=72) had PTL (gestational weeks < 37 weeks). The two groups were screened for urinary and vaginal infections. The role of different demographic characteristics, patient history, and clinical signs were also investigated. RESULTS: Several risk factors were identified in this study, including age<20 years, nulliparity, previous abortion and previous preterm birth, menses vaginal bleeding, a vaginal pH>5, a positive whiff test, Trichomonas vaginalis infection, Mycoplasma hominis infection, coryneforms heavy vaginal growth, and any vaginal growth of Gram-negative bacilli. Urinary tract infection with any colony count was not associated with PTL. CONCLUSION: Our study demonstrated that the main risk factors for PTL were vaginal infection with T. vaginalis, M. hominis, coryneforms, and Gram-negative bacilli, and their determinants (vaginal pH>5, positive whiff test, heavy vaginal bleeding). Both young age (< 20 years) and poor obstetric history were also the risk factors. Therefore, screening for genitourinary tract infections is strongly recommended to be included in prenatal care. PMID- 28094235 TI - Corrigendum to "Increased BOLD Signals Elicited by High Gamma Auditory Stimulation of the Left Auditory Cortex in Acute State Schizophrenia" [EBioMedicine 12 (2016) 143-149]. PMID- 28094238 TI - Evaporating metal nanocrystal arrays. AB - Anodic aluminum oxide (AAO) substrates with a self-ordered triangular array of nanopores provide the means to fabricate multiple forms of nano materials, such as nanowires and nanoparticles. This study focuses on nanostructures that emerge in thin films of metals thermally evaporated onto the surface of AAO. Previous work showed that films of different evaporated metals assume dramatically different structures, e.g. an ordered triangular array of nearly monodisperse nanoparticles forms for lead (Pb) while a polycrystalline nanohoneycomb structure forms for silver (Ag). Here, we present investigations of the effects of substrate temperature and deposition angle that reveal the processes controlling the nano particle array formation. Our findings indicate that arrays form provided the grain nucleation density exceeds the pore density and the atomic mobility is high enough to promote grain coalescence. They introduce a method for producing films with anisotropic grain array structure. The results provide insight into the influence of substrate nano-morphology on thin film growth energetics and kinetics that can be harnessed for creating films with other novel nano-structures. PMID- 28094236 TI - Deficiency of PTP1B Attenuates Hypothalamic Inflammation via Activation of the JAK2-STAT3 Pathway in Microglia. AB - Protein tyrosine phosphatase 1B (PTP1B) regulates leptin signaling in hypothalamic neurons via the JAK2-STAT3 pathway. PTP1B has also been implicated in the regulation of inflammation in the periphery. However, the role of PTP1B in hypothalamic inflammation, which is induced by a high-fat diet (HFD), remains to be elucidated. Here, we showed that STAT3 phosphorylation (p-STAT3) was increased in microglia in the hypothalamic arcuate nucleus of PTP1B knock-out mice (KO) on a HFD, accompanied by decreased Tnf and increased Il10 mRNA expression in the hypothalamus compared to wild-type mice (WT). In hypothalamic organotypic cultures, incubation with TNFalpha led to increased p-STAT3, accompanied by decreased Tnf and increased Il10 mRNA expression, in KO compared to WT. Incubation with p-STAT3 inhibitors or microglial depletion eliminated the differences in inflammation between genotypes. These data indicate an important role of JAK2-STAT3 signaling negatively regulated by PTP1B in microglia, which attenuates hypothalamic inflammation under HFD conditions. PMID- 28094237 TI - A Multiplex Microsphere Immunoassay for Zika Virus Diagnosis. AB - Rapid and accurate diagnosis of infectious agents is essential for patient care, disease control, and countermeasure development. The present serologic diagnosis of Zika virus (ZIKV) infection relies mainly on IgM-capture ELISA which is confounded with the flaw of cross-reactivity among different flaviviruses. In this communication, we report a multiplex microsphere immunoassay (MIA) that captures the diagnostic power of viral envelope protein (that elicits robust, yet cross-reactive antibodies to other flaviviruses) and the differential power of viral nonstructural proteins NS1 and NS5 (that induce more virus-type specific antibodies). Using 153 patient specimens with known ZIKV and/or dengue virus (DENV; a closely related flavivirus) infections, we showed that (i) ZIKV envelope based MIA is equivalent or more sensitive than IgM-capture ELISA in diagnosing ZIKV infection, (ii) antibody responses to NS1 and NS5 proteins are more ZIKV specific than antibody response to envelope protein, (iii) inclusion of NS1 and NS5 in the MIA improves the diagnostic accuracy when compared with the MIA that uses envelope protein alone. The multiplex MIA achieves a rapid diagnosis (turnaround time<4h) and requires small specimen volume (10MUl) in a single reaction. This serologic assay could be developed for use in clinical diagnosis of ZIKV infection and for monitoring immune responses in vaccine trials. PMID- 28094239 TI - Performance variation due to stiffness in a tuna-inspired flexible foil model. AB - Tuna are fast, economical swimmers in part due to their stiff, high aspect ratio caudal fins and streamlined bodies. Previous studies using passive caudal fin models have suggested that while high aspect ratio tail shapes such as a tuna's generally perform well, tail performance cannot be determined from shape alone. In this study, we analyzed the swimming performance of tuna-tail-shaped hydrofoils of a wide range of stiffnesses, heave amplitudes, and frequencies to determine how stiffness and kinematics affect multiple swimming performance parameters for a single foil shape. We then compared the foil models' kinematics with published data from a live swimming tuna to determine how well the hydrofoil models could mimic fish kinematics. Foil kinematics over a wide range of motion programs generally showed a minimum lateral displacement at the narrowest part of the foil, and, immediately anterior to that, a local area of large lateral body displacement. These two kinematic patterns may enhance thrust in foils of intermediate stiffness. Stiffness and kinematics exhibited subtle interacting effects on hydrodynamic efficiency, with no one stiffness maximizing both thrust and efficiency. Foils of intermediate stiffnesses typically had the greatest coefficients of thrust at the highest heave amplitudes and frequencies. The comparison of foil kinematics with tuna kinematics showed that tuna motion is better approximated by a zero angle of attack foil motion program than by programs that do not incorporate pitch. These results indicate that open questions in biomechanics may be well served by foil models, given appropriate choice of model characteristics and control programs. Accurate replication of biological movements will require refinement of motion control programs and physical models, including the creation of models of variable stiffness. PMID- 28094240 TI - Ectopic bone formation by gel-derived bioactive glass-poly-L-lactide-co-glycolide composites in a rabbit muscle model. AB - In this study we aimed to assess the in vivo osteoinductive properties of two composite scaffolds made of PLGA (poly-L-lactide-co-glycolide) and two types of gel-derived bioactive glasses, namely a high silica S2 bioactive glass (S2-PLGA composites) or high lime A2 bioactive glass (A2-PLGA composites). To achieve that, the potential of the composites to induce ectopic bone formation in a rabbit muscle has been examined along with the control PLGA scaffold. Cylinder like scaffolds of 7 * 3 mm (width * height) were implanted into pouches created in the latissimus dorsi muscle of 18 New Zealand rabbits. The tissue sections were obtained at 6, 12 or 24 weeks post-surgery (six rabbits per each time point) and stained with hematoxylin-eosin. The process of wound healing, the formation of collagen-rich connective tissue and its transition to cartilage were examined by Sirius red and Alcian blue histological stainings. We also performed immunohistochemical verification of the presence of osteoblast- and osteoclast- like cells in the vicinity of the scaffolds. A typical foreign body reaction and wound healing process was observed for all implanted scaffolds. Osteoblast- and osteoclast-like cells were observed in the vicinity of the scaffolds as determined by the immunohistochemical staining for Osteocalcin, BMP-2 and Cathepsin K. Compared to plain PLGA scaffolds, numerous osteoblast-like cells were observed 12 weeks post implantation near the composites and the scaffolds gradually degraded as bone formation proceeded. S2-PLGA and A2-PLGA composites display osteoinductive properties in vivo. Furthermore, they are more effective at inducing ectopic bone formation in a rabbit muscle compared to plain PLGA. Thus these SBG-PLGA composite scaffolds have potential for clinical applications in dental and/or orthopedic-bone tissue engineering. PMID- 28094241 TI - Gelatin freeze casting of biomimetic titanium alloy with anisotropic and gradient pore structure. AB - Titanium is a material commonly used for dental and orthopaedic implants. However, due to large differences in properties between the titanium metal and the natural bone, stress shielding has been observed in the surrounding area, resulting in bone atrophy, and thus has raised concerns of the use of this material. Ideally implant materials should possess similar properties to the surrounding tissues in order to distribute the load as the joint would naturally, while also possessing a similar porous structure to the bone to enable interaction with the surrounding material. In this paper we report the formation of aligned porous titanium alloy scaffolds with the use of unidirectional freeze casting with a temperature gradient. The resulting scaffolds had a dense bottom part with sufficient strength for loading, while the top part remaining porous in order to allow bone growth in the scaffold and fully integrating with the surrounding tissue. The anisotropic nature of the pores within the titanium alloy samples were observed via micro computed tomography, where a gradient structure similar to bone was observed. The compressive strength of the fabricated scaffolds was found to be up to 427 MPa when measured with the pores aligned with the applied load, depending on the pore density. This is within the range of cortical bone. PMID- 28094242 TI - Wrinkle-free graphene electrodes in zinc tin oxide thin-film transistors for large area applications. AB - Wrinkle-free graphene was used to form the source-drain electrodes in thin film transistors based on a zinc tin oxide (ZTO) semiconductor. A 10 nm thick titanium adhesion layer was applied prior to transferring a conductive graphene film on top of it by chemical detachment. The formation of an interlayer oxide between titanium and graphene allows the achievement of uniform surface roughness over the entire substrate area. The resulting devices were thermally treated in ambient air, and a substantial decrease in field effect mobility is observed with increasing annealing temperature. The increase in electrical resistivity of the graphene film at higher annealing temperatures may have some influence, however the growth of the oxide interlayer at the ZTO/Ti boundary is suggested to be most influential, thereby inducing relatively high contact resistance. PMID- 28094243 TI - Linear and ultrafast nonlinear plasmonics of single nano-objects. AB - Single-particle optical investigations have greatly improved our understanding of the fundamental properties of nano-objects, avoiding the spurious inhomogeneous effects that affect ensemble experiments. Correlation with high-resolution imaging techniques providing morphological information (e.g. electron microscopy) allows a quantitative interpretation of the optical measurements by means of analytical models and numerical simulations. In this topical review, we first briefly recall the principles underlying some of the most commonly used single particle optical techniques: near-field, dark-field, spatial modulation and photothermal microscopies/spectroscopies. We then focus on the quantitative investigation of the surface plasmon resonance (SPR) of metallic nano-objects using linear and ultrafast optical techniques. While measured SPR positions and spectral areas are found in good agreement with predictions based on Maxwell's equations, SPR widths are strongly influenced by quantum confinement (or, from a classical standpoint, surface-induced electron scattering) and, for small nano objects, cannot be reproduced using the dielectric functions of bulk materials. Linear measurements on single nano-objects (silver nanospheres and gold nanorods) allow a quantification of the size and geometry dependences of these effects in confined metals. Addressing the ultrafast response of an individual nano-object is also a powerful tool to elucidate the physical mechanisms at the origin of their optical nonlinearities, and their electronic, vibrational and thermal relaxation processes. Experimental investigations of the dynamical response of gold nanorods are shown to be quantitatively modeled in terms of modifications of the metal dielectric function enhanced by plasmonic effects. Ultrafast spectroscopy can also be exploited to unveil hidden physical properties of more complex nanosystems. In this context, two-color femtosecond pump-probe experiments performed on individual bimetallic heterodimers are discussed in the last part of the review, demonstrating the existence of Fano interferences in the optical absorption of a gold nanoparticle under the influence of a nearby silver one. PMID- 28094244 TI - A bioinspired adaptive spider web. AB - This work presents an adaptive structure inspired by spider webs' behavior. To investigate the dynamic properties and performance of this system, numerical models are developed to examine the effects of pretension in radial strings, and Young's modulus, and damping ratio on the natural frequency and total energy of the system. An experimental study was conducted to validate theoretical results. Stepper motors controlled by a microcontroller are utilized to increase the pretension in the radial strings of the web in order to tune the web's energy absorption ability. It is demonstrated that the pretension, Young's modulus, and damping ratio in the radial strings can significantly affect the natural frequency and total energy of full and damaged webs. It is also shown that increasing the pretension in the radial strings compensates for the loss of stiffness due to the damaged strings. Finally, it is shown that controlling the pretension in radial strings can provide higher energy absorption capability for the spider web. PMID- 28094245 TI - External magnetic field dependent shift of superparamagnetic blocking temperature due to core/surface disordered spin interactions. AB - Although the blocking temperature of superparamagnetic nanoparticles (SPNPs) is crucial for various spintronics and biomedical applications, the precise determination of the blocking temperature is still not clear. Here, we present 'intrinsic' and 'extrinsic' characteristics of the blocking temperature in SPNP systems. In zero-field-cooled/field-cooled (ZFC-FC) curves, there was no shift of 'intrinsic blocking temperature' at different applied external (excitation) magnetic fields. However, 'extrinsic blocking temperature' shift is clearly dependent on the external (excitation) magnetic field. According to our newly proposed physical model, the 'intermediate spin layer' located between the core and surface disordered spin layers is primarily responsible for the physical nature of the shift of extrinsic blocking temperature. Our new findings offer possibilities for characterizing the thermally induced physical properties of SPNPs. Furthermore, these findings provide a new empirical approach to indirectly estimate the qualitative degree of the disordered surface spin status in SPNPs. PMID- 28094247 TI - Erratum: Fission and fusion scenarios for magnetic microswimmer clusters. PMID- 28094246 TI - Development of Sr-incorporated biphasic calcium phosphate bone cement. AB - To follow the design strategy of traditional biphasic calcium phosphate (BCP) ceramic, in the present study, strontium-doped biphasic calcium phosphate bone cement (Sr-BCPC) composites comprising Sr-beta-tricalcium phosphate (TCP)/Sr hydroxyapatite (HAP) had been prepared for the first time using Sr x -beta TCP/tetracalcium phosphate (TTCP) as a cement powder and diluted phosphoric acid as a cement liquid. The phase composition, setting time, compressive strength, washout resistance, in vitro degradation rate, microstructure evolutions, hydration dynamics and cytotoxicity of Sr-BCPC at various Sr contents were intensively investigated. It was found that the final cement product was composed of entangled Sr-HAP nano-needles and cobblestone-like Sr-beta-TCP sub-micron particles, and the weight percentages in the final cement product after hydration in simulated body fluid for 24 h were in the ranges of 60 wt%-70 wt% Sr-HAP and 30 wt%-40 wt% Sr-beta-TCP, respectively. Sr and the concentration of Sr exhibit significant effects on the phase compositions, compressive strength, setting time, in vitro degradation rate and cytotoxicity of the biphasic bone cement. In particular, the degradation rate increased considerably with the increase of the Sr-beta-TCP phase. It is anticipated that the introduction of the 'biphasic' design into calcium phosphate bone cements is an effective strategy to improve their degradation properties. PMID- 28094248 TI - Corrigendum: Tissue engineering of acellular vascular grafts capable of somatic growth in young lambs. PMID- 28094249 TI - Thermal engineering of FAPbI3 perovskite material via radiative thermal annealing and in situ XRD. AB - Lead halide perovskites have emerged as successful optoelectronic materials with high photovoltaic power conversion efficiencies and low material cost. However, substantial challenges remain in the scalability, stability and fundamental understanding of the materials. Here we present the application of radiative thermal annealing, an easily scalable processing method for synthesizing formamidinium lead iodide (FAPbI3) perovskite solar absorbers. Devices fabricated from films formed via radiative thermal annealing have equivalent efficiencies to those annealed using a conventional hotplate. By coupling results from in situ X ray diffraction using a radiative thermal annealing system with device performances, we mapped the processing phase space of FAPbI3 and corresponding device efficiencies. Our map of processing-structure-performance space suggests the commonly used FAPbI3 annealing time, 10 min at 170 degrees C, can be significantly reduced to 40 s at 170 degrees C without affecting the photovoltaic performance. The Johnson-Mehl-Avrami model was used to determine the activation energy for decomposition of FAPbI3 into PbI2. PMID- 28094250 TI - End-of-radiation PSA as a novel prognostic factor in patients undergoing definitive radiation and androgen deprivation therapy for prostate cancer. AB - BACKGROUND: In men undergoing definitive radiation for prostate cancer, it is unclear whether early biochemical response can provide additional prognostic value beyond pre-treatment risk stratification. METHODS: Prostate cancer patients consecutively treated with definitive radiation at our institution by a single provider from 1993 to 2006 and who had an end-of-radiation (EOR) PSA (n=688, median follow-up 11.2 years). We analyzed the association of an EOR PSA level, obtained during the last week of radiation, with survival outcomes. Multivariable adjusted cox proportional hazards models were constructed to assess associations between a detectable EOR PSA (defined as ?0.1 ng ml-1) and biochemical failure free survival (BFFS), metastasis-free survival (MFS), prostate cancer-specific survival (PCSS) and overall survival (OS). Kaplan-Meier survival curves were constructed, with stratification by EOR PSA. RESULTS: At the end of radiation, the PSA level was undetectable in 30% of patients. Men with a detectable EOR PSA experienced inferior 10-year BFFS (49.7% versus 64.4%, P<0.001), 10-year MFS (84.8% versus 92.0%, P=0.003), 10-year PCSS (94.3% versus 98.2%, P=0.007) and 10 year OS (75.8% versus 82.5%, P=0.01), as compared to men with an undetectable EOR PSA. Among National Comprehensive Care Network (NCCN) intermediate- and high-risk men who were treated with definitive radiation and androgen deprivation therapy (ADT), a detectable EOR PSA was more strongly associated with PCSS than initial NCCN risk level (EOR PSA: HR 5.89, 95% CI 2.37-14.65, P<0.001; NCCN risk level: HR 2.01, 95% CI 0.74-5.42, P=0.168). Main study limitations are retrospective study design and associated biases. CONCLUSIONS: EOR PSA was significantly associated with survival endpoints in men who received treatment with definitive radiation and ADT. Whether the EOR PSA can be used to modulate treatment intensity merits further investigation. PMID- 28094251 TI - Is prostate cancer stage migration continuing for black men in the PSA era? AB - BACKGROUND: In the United States, disease-specific mortality from prostate cancer (PC) is highest among black men. While the introduction of widespread PSA testing has been associated with a downward stage migration, whether this trend continues in the late PSA era and for black men is unknown. The objective of our study was to evaluate current PC stage migration patterns in the United States by race. METHODS: The Surveillance, Epidemiology and End Results (SEER) registry was queried to obtain all cases of PC reported between 2000 and 2013. Year of diagnosis was categorized into 2000-2003, 2004-2007, 2008-2010 and 2011-2013. Predictors of distant stage PC at diagnosis were determined using logistic regression adjusted for year of diagnosis, age at diagnosis, SEER region and race. RESULTS: A total of 791 184 PC cases were identified. The cohort comprised 78.9% (n=594 920) white and 14.1% (n=106 133) black men. The stage at diagnosis was 83.3% localized, 12.0% regional and 4.7% distant. Age-adjusted incidence demonstrated a steady decline for black men in all time groups while white men had a stable incidence of distant disease between 2000 and 2013. In univariate analysis, black men in the 2004-2007 (OR 0.86 (0.81-0.93)) and 2008-2010 cohorts (OR 0.85 (0.79-0.91)) were less likely to be diagnosed with metastatic PC as compared with the 2000-2003 baseline cohort. In multivariate analysis, the 2004 2007 black cohort was less likely to be diagnosed with distant PC (OR 0.90 (0.84 0.97)). This trend was not observed in white men who in multivariate analysis had an increased risk of distant PC in the 2004-2007 (OR 1.08 (1.04-1.11)), 2008-2010 (OR 1.22 (1.18-1.27)) and 2011-2013 (OR 1.65 (1.59-1.71)) groups. CONCLUSIONS: PC downward stage migration continues in black men but not in white men. Discontinuation of PSA-based screening for PC could disproportionately affect black men. PMID- 28094253 TI - Dynamical importance of van der Waals saddle and excited potential surface in C(1D)+D2 complex-forming reaction. AB - Encouraged by recent advances in revealing significant effects of van der Waals wells on reaction dynamics, many people assume that van der Waals wells are inevitable in chemical reactions. Here we find that the weak long-range forces cause van der Waals saddles in the prototypical C(1D)+D2 complex-forming reaction that have very different dynamical effects from van der Waals wells at low collision energies. Accurate quantum dynamics calculations on our highly accurate ab initio potential energy surfaces with van der Waals saddles yield cross sections in close agreement with crossed-beam experiments, whereas the same calculations on an earlier surface with van der Waals wells produce much smaller cross-sections at low energies. Further trajectory calculations reveal that the van der Waals saddle leads to a torsion then sideways insertion reaction mechanism, whereas the well suppresses reactivity. Quantum diffraction oscillations and sharp resonances are also predicted based on our ground- and excited-state potential energy surfaces. PMID- 28094254 TI - Describing polyhedral tilings and higher dimensional polytopes by sequence of their two-dimensional components. AB - Polyhedral tilings are often used to represent structures such as atoms in materials, grains in crystals, foams, galaxies in the universe, etc. In the previous paper, we have developed a theory to convert a way of how polyhedra are arranged to form a polyhedral tiling into a codeword (series of numbers) from which the original structure can be recovered. The previous theory is based on the idea of forming a polyhedral tiling by gluing together polyhedra face to face. In this paper, we show that the codeword contains redundant digits not needed for recovering the original structure, and develop a theory to reduce the redundancy. For this purpose, instead of polyhedra, we regard two-dimensional regions shared by faces of adjacent polyhedra as building blocks of a polyhedral tiling. Using the present method, the same information is represented by a shorter codeword whose length is reduced by up to the half of the original one. Shorter codewords are easier to handle for both humans and computers, and thus more useful to describe polyhedral tilings. By generalizing the idea of assembling two-dimensional components to higher dimensional polytopes, we develop a unified theory to represent polyhedral tilings and polytopes of different dimensions in the same light. PMID- 28094252 TI - A signature motif in LIM proteins mediates binding to checkpoint proteins and increases tumour radiosensitivity. AB - Tumour radiotherapy resistance involves the cell cycle pathway. CDC25 phosphatases are key cell cycle regulators. However, how CDC25 activity is precisely controlled remains largely unknown. Here, we show that LIM domain containing proteins, such as FHL1, increase inhibitory CDC25 phosphorylation by forming a complex with CHK2 and CDC25, and sequester CDC25 in the cytoplasm by forming another complex with 14-3-3 and CDC25, resulting in increased radioresistance in cancer cells. FHL1 expression, induced by ionizing irradiation in a SP1- and MLL1-dependent manner, positively correlates with radioresistance in cancer patients. We identify a cell-penetrating 11 amino-acid motif within LIM domains (eLIM) that is sufficient for binding CHK2 and CDC25, reducing the CHK2 CDC25 and CDC25-14-3-3 interaction and enhancing CDC25 activity and cancer radiosensitivity accompanied by mitotic catastrophe and apoptosis. Our results provide novel insight into molecular mechanisms underlying CDC25 activity regulation. LIM protein inhibition or use of eLIM may be new strategies for improving tumour radiosensitivity. PMID- 28094255 TI - Specific and Sensitive Isothermal Electrochemical Biosensor for Plant Pathogen DNA Detection with Colloidal Gold Nanoparticles as Probes. AB - Developing quick and sensitive molecular diagnostics for plant pathogen detection is challenging. Herein, a nanoparticle based electrochemical biosensor was developed for rapid and sensitive detection of plant pathogen DNA on disposable screen-printed carbon electrodes. This 60 min assay relied on the rapid isothermal amplification of target pathogen DNA sequences by recombinase polymerase amplification (RPA) followed by gold nanoparticle-based electrochemical assessment with differential pulse voltammetry (DPV). Our method was 10,000 times more sensitive than conventional polymerase chain reaction (PCR)/gel electrophoresis and could readily identify P. syringae infected plant samples even before the disease symptoms were visible. On the basis of the speed, sensitivity, simplicity and portability of the approach, we believe the method has potential as a rapid disease management solution for applications in agriculture diagnostics. PMID- 28094256 TI - Cymbiola nobilis shell: Toughening mechanisms in a crossed-lamellar structure. AB - Natural structural materials with intricate hierarchical architectures over several length scales exhibit excellent combinations of strength and toughness. Here we report the mechanical response of a crossed-lamellar structure in Cymbiola nobilis shell via stepwise compression tests, focusing on toughening mechanisms. At the lower loads microcracking is developed in the stacked direction, and channel cracking along with uncracked-ligament bridging and aragonite fiber bridging occurs in the tiled direction. At the higher loads the main mechanisms involve cracking deflection in the bridging lamellae in the tiled direction alongside step-like cracking in the stacked direction. A distinctive crack deflection in the form of "convex" paths occurs in alternative lamellae with respect to the channel cracks in the tiled direction. Furthermore, a barb like interlocking mechanism along with the uneven interfaces in the 1st-order aragonite lamellae is also observed. The unique arrangement of the crossed lamellar structure provides multiple interfaces which result in a complicated stress field ahead of the crack tip, hence increasing the toughness of shell. PMID- 28094259 TI - Immunotherapy: Glioblastoma regression obtained with CAR T cells. PMID- 28094257 TI - Pten is necessary for the quiescence and maintenance of adult muscle stem cells. AB - Satellite cells (SCs) are myogenic stem cells required for regeneration of adult skeletal muscles. A proper balance among quiescence, activation and differentiation is essential for long-term maintenance of SCs and their regenerative function. Here we show a function of Pten (phosphatase and tensin homologue) in quiescent SCs. Deletion of Pten in quiescent SCs leads to their spontaneous activation and premature differentiation without proliferation, resulting in depletion of SC pool and regenerative failure. However, prior to depletion, Pten-null activated SCs can transiently proliferate upon injury and regenerate injured muscles, but continually decline during regeneration, suggesting an inability to return to quiescence. Mechanistically, Pten deletion increases Akt phosphorylation, which induces cytoplasmic translocation of FoxO1 and suppression of Notch signalling. Accordingly, constitutive activation of Notch1 prevents SC depletion despite Pten deletion. Our findings delineate a critical function of Pten in maintaining SC quiescence and reveal an interaction between Pten and Notch signalling. PMID- 28094258 TI - Interfacial superconductivity in a bi-collinear antiferromagnetically ordered FeTe monolayer on a topological insulator. AB - The discovery of high-temperature superconductivity in Fe-based compounds triggered numerous investigations on the interplay between superconductivity and magnetism, and on the enhancement of transition temperatures through interface effects. It is widely believed that the emergence of optimal superconductivity is intimately linked to the suppression of long-range antiferromagnetic (AFM) order, although the exact microscopic picture remains elusive because of the lack of atomically resolved data. Here we present spin-polarized scanning tunnelling spectroscopy of ultrathin FeTe1-xSex (x=0, 0.5) films on bulk topological insulators. Surprisingly, we find an energy gap at the Fermi level, indicating superconducting correlations up to Tc~6 K for one unit cell FeTe grown on Bi2Te3, in contrast to the non-superconducting bulk FeTe. The gap spatially coexists with bi-collinear AFM order. This finding opens perspectives for theoretical studies of competing orders in Fe-based superconductors and for experimental investigations of exotic phases in superconducting layers on topological insulators. PMID- 28094260 TI - Targeted therapies: Selumetinib MEKing differences in NF1. PMID- 28094263 TI - Pancreatic cancer: Pancreatic cancer cells digest extracellular protein. PMID- 28094264 TI - First-line therapy for mCRC - the influence of primary tumour location on the therapeutic algorithm. PMID- 28094265 TI - Haematological cancer: Landmark survival achieved in MM. PMID- 28094261 TI - Beyond the margins: real-time detection of cancer using targeted fluorophores. AB - Over the past two decades, synergistic innovations in imaging technology have resulted in a revolution in which a range of biomedical applications are now benefiting from fluorescence imaging. Specifically, advances in fluorophore chemistry and imaging hardware, and the identification of targetable biomarkers have now positioned intraoperative fluorescence as a highly specific real-time detection modality for surgeons in oncology. In particular, the deeper tissue penetration and limited autofluorescence of near-infrared (NIR) fluorescence imaging improves the translational potential of this modality over visible-light fluorescence imaging. Rapid developments in fluorophores with improved characteristics, detection instrumentation, and targeting strategies led to the clinical testing in the early 2010s of the first targeted NIR fluorophores for intraoperative cancer detection. The foundations for the advances that underline this technology continue to be nurtured by the multidisciplinary collaboration of chemists, biologists, engineers, and clinicians. In this Review, we highlight the latest developments in NIR fluorophores, cancer-targeting strategies, and detection instrumentation for intraoperative cancer detection, and consider the unique challenges associated with their effective application in clinical settings. PMID- 28094266 TI - Cancer metabolism: a therapeutic perspective. PMID- 28094262 TI - Radiotherapy and immunotherapy: a beneficial liaison? AB - Investigations into the interaction between radiotherapy and the host immune system have uncovered new mechanisms that can potentially be exploited to improve the efficacy of radiotherapy. Radiation promotes the release of danger signals and chemokines that recruit inflammatory cells into the tumour microenvironment, including antigen-presenting cells that activate cytotoxic T-cell function. By contrast, radiation can attract immunosuppressive cells into the tumour microenvironment. In rare circumstances, the antitumour effect of radiotherapy has been observed outside of the radiation field, known as the abscopal effect. This phenomenon is proposed to have an immune origin and indicates that local radiotherapy elicits systemic effects. Herein, we highlight data that provide new mechanistic explanations for the success or failure of radiotherapy, and postulate how the combination of immune-modulation and radiation could tip the balance of the host immune response to promote cure. We use the concept of radiation- induced tumour equilibrium (RITE) as a starting point to discuss the mechanistic influence of immune-checkpoint therapies on radiotherapy efficacy. PMID- 28094267 TI - CNS cancer: Local chemotherapy favours antitumour immunity. PMID- 28094268 TI - Contribution of classical end-joining to PTEN inactivation in p53-mediated glioblastoma formation and drug-resistant survival. AB - DNA repair gene defects are found in virtually all human glioblastomas, but the genetic evidence for a direct role remains lacking. Here we demonstrate that combined inactivation of the XRCC4 non-homologous end-joining (NHEJ) DNA repair gene and p53 efficiently induces brain tumours with hallmark characteristics of human proneural/classical glioblastoma. The murine tumours exhibit PTEN loss of function instigated by reduced PTEN mRNA, and increased phosphorylated inactivation and stability as a consequence of aberrantly elevated CK2 provoked by p53 ablation and irrevocably deregulated by NHEJ inactivation. This results in DNA damage-resistant cytoplasmic PTEN and CK2 expression, and the attenuation of DNA repair genes. CK2 inhibition restores PTEN nuclear distribution and DNA repair activities and impairs tumour but not normal cell survival. These observations demonstrate that NHEJ contributes to p53-mediated glioblastoma suppression, and reveal a crucial role for PTEN in the early DNA damage signalling cascade, the inhibition of which promotes tumorigenicity and drug resistant survival. PMID- 28094269 TI - Dyslipidaemias: Cardiovascular effects of low Lp(a). PMID- 28094270 TI - Atherosclerosis in 2016: Advances in new therapeutic targets for atherosclerosis. PMID- 28094271 TI - Basic research: Cardioprotective benefits of dietary spermidine. PMID- 28094272 TI - Atherosclerosis: TREM1 in atherosclerosis development. PMID- 28094273 TI - Arrhythmias in 2016: Arrhythmia treatment - evidence catching up with technology. PMID- 28094274 TI - Folivory elicits a strong defense reaction in Catharanthus roseus: metabolomic and transcriptomic analyses reveal distinct local and systemic responses. AB - Plants deploy distinct secondary metabolisms to cope with environment pressure and to face bio-aggressors notably through the production of biologically active alkaloids. This metabolism-type is particularly elaborated in Catharanthus roseus that synthesizes more than a hundred different monoterpene indole alkaloids (MIAs). While the characterization of their biosynthetic pathway now reaches completion, still little is known about the role of MIAs during biotic attacks. As a consequence, we developed a new plant/herbivore interaction system by challenging C. roseus leaves with Manduca sexta larvae. Transcriptomic and metabolic analyses demonstrated that C. roseus respond to folivory by both local and systemic processes relying on the activation of specific gene sets and biosynthesis of distinct MIAs following jasmonate production. While a huge local accumulation of strictosidine was monitored in attacked leaves that could repel caterpillars through its protein reticulation properties, newly developed leaves displayed an increased biosynthesis of the toxic strictosidine-derived MIAs, vindoline and catharanthine, produced by up-regulation of MIA biosynthetic genes. In this context, leaf consumption resulted in a rapid death of caterpillars that could be linked to the MIA dimerization observed in intestinal tracts. Furthermore, this study also highlights the overall transcriptomic control of the plant defense processes occurring during herbivory. PMID- 28094275 TI - Sulfated Cyclocarya paliurus polysaccharides markedly attenuates inflammation and oxidative damage in lipopolysaccharide-treated macrophage cells and mice. AB - Natural polysaccharides and their modified derivatives are crucial supplements to the prevention of inflammation. This study aimed to evaluate the effect of sulfated modification on the anti-inflammatory and anti-oxidative activities of Cyclocarya paliurus polysaccharides (CP). A sulfated CP, S-CP1-4 was obtained using chlorosulfonic acid-pyridine method. The chemical components and FT-IR spectrum confirmed that sulfated group was synthesized to the polysaccharide chains successfully. S-CP1-4 was found to inhibit nitric oxide production, phagocytic activity and the release of interleukin (IL)-6 and IL-1beta in lipopolysaccharide-treated macrophage cells, RAW 264.7. S-CP1-4 significantly decreased the secretion of IL-6 and TNF-alpha and the thymus and spleen indexes, and increased the production of IL-10 in lipopolysaccharide-treated mice. S-CP1-4 could better protect the liver by inhibiting the activities of alanine aminotransferase and aspartate aminotransferase, and malondialdehyde level while increasing the superoxide dismutase activity and total anti-oxidative capacity. These results suggested that S-CP1-4 may be an effective anti-inflammatory agent, and sulfated modification may be a reliable method for the development of food supplements. PMID- 28094276 TI - B7-H3 participates in the development of Asthma by augmentation of the inflammatory response independent of TLR2 pathway. AB - B7-H3, a new member of the B7 superfamily, acts as both a T cell costimulator and coinhibitor. Recent studies identified B7-H3 plays a critical role in the development of asthma. But the definitive mechanism is not clear. In this study, we further report that B7-H3 participates in the development of OVA-induced asthma in a murine model. And study its mechanism through the vitro and vivo experiment. Exogenous administration of B7-H3 strongly amplified the inflammatory response and augmented proinflammatory cytokines in vitro and vivo. These B7-H3 associated proinflammatory effects were not dependent on TLR2 signaling, as airway inflammation, eosinophils infiltration and cytokins (IL-4, IL-5, IL-13 and IFN-gamma) augment were still amplified in TLR2-deficient mice after administrated recombinant mouse B7-H3. These results indicated an important role for B7-H3 in the development of Th1 and Th2 cells in a murine model of asthma and its proinflammatory effects are not dependent on TLR2 signaling. PMID- 28094277 TI - Peripheral arterial volume distensibility changes with applied external pressure: significant difference between arteries with different compliance. AB - This study aimed to quantify the different effect of external cuff pressure on arterial volume distensibility between peripheral arteries with different compliance. 30 healthy subjects were studied with the arm at two positions (0 degrees and 45 degrees from the horizontal level) to introduce different compliance of arteries. The electrocardiogram and finger and ear photoplethysmograms were recorded simultaneously under five external cuff pressures (0, 10, 20, 30 and 40 mmHg) on the whole arm to obtain arterial volume distensibility. With the applied external cuff pressures of 10, 20, 30 and 40 mmHg, the overall changes in arterial volume distensibility referred to those without external pressure were 0.010, 0.029, 0.054 and 0.108% per mmHg for the arm at the horizontal level, and 0.026, 0.071, 0.170 and 0.389% per mmHg for the arm at 45 degrees from the horizontal level, confirming the non-linearity between arterial volume distensibility and external pressure. More interestingly, the significant differences in arterial volume distensibility changes were observed between the two arm positions, which were 0.016, 0.043, 0.116 and 0.281% per mmHg (all P < 0.01). Our findings demonstrated that arterial volume distensibility of peripheral arm arteries increased with external pressure, with a greater effect for more compliant arteries. PMID- 28094278 TI - Persistent fibroblast growth factor 23 signalling in the parathyroid glands for secondary hyperparathyroidism in mice with chronic kidney disease. AB - Secondary hyperparathyroidism, in which parathyroid hormone (PTH) is excessively secreted in response to factors such as hyperphosphataemia, hypocalcaemia, and low 1,25-dihydroxyvitamin D (1,25(OH)2D) levels, is commonly observed in patients with chronic kidney disease (CKD), and is accompanied by high levels of fibroblast growth factor 23 (FGF23). However, the effect of FGF23 on the parathyroid glands (PG) remains controversial. To bind to FGF receptors, FGF23 requires alphaKlotho, which is highly expressed in the PG. Here, we examined the effects of Fgfr1-3, alphaKlotho, or Fgfr1-4 ablation specifically in the PG (conditional knockout, cKO). When mice with early to mid-stage CKD with and without cKO were compared, plasma concentrations of calcium, phosphate, FGF23, and 1,25(OH)2D did not change significantly. In contrast, plasma PTH levels, which were elevated in CKD mice, were significantly decreased in cKO mice. PG from CKD mice showed augmentation of cell proliferation, which was significantly suppressed by cKO. Parathyroid tissue cultured for 4 days showed upregulation of PTH secretion and cell proliferation in response to FGF23. Both these effects were inhibited by cKO. These findings suggest that FGF23 is a long-term inducer of parathyroid cell proliferation and PTH secretion, and is one cause of secondary hyperparathyroidism in CKD. PMID- 28094279 TI - Quantitative separation of the anisotropic magnetothermopower and planar Nernst effect by the rotation of an in-plane thermal gradient. AB - A thermal gradient as the driving force for spin currents plays a key role in spin caloritronics. In this field the spin Seebeck effect (SSE) is of major interest and was investigated in terms of in-plane thermal gradients inducing perpendicular spin currents (transverse SSE) and out-of-plane thermal gradients generating parallel spin currents (longitudinal SSE). Up to now all spincaloric experiments employ a spatially fixed thermal gradient. Thus, anisotropic measurements with respect to well defined crystallographic directions were not possible. Here we introduce a new experiment that allows not only the in-plane rotation of the external magnetic field, but also the rotation of an in-plane thermal gradient controlled by optical temperature detection. As a consequence, the anisotropic magnetothermopower and the planar Nernst effect in a permalloy thin film can be measured simultaneously. Thus, the angular dependence of the magnetothermopower with respect to the magnetization direction reveals a phase shift, that allows the quantitative separation of the thermopower, the anisotropic magnetothermopower and the planar Nernst effect. PMID- 28094280 TI - Accumulation and transformation of inorganic and organic arsenic in rice and role of thiol-complexation to restrict their translocation to shoot. AB - Environmental contamination of arsenic (As) and its accumulation in rice (Oryza sativa L.) is of serious human health concern. In planta speciation of As is an important tool to understand As metabolism in plants. In the present study, we investigated root to shoot As translocation and speciation in rice exposed to inorganic and methylated As. Arsenate (AsV) and methylarsonate (MAV) were efficiently reduced to arsenite (AsIII) and MAIII, respectively in rice root and shoot but no trivalent form of dimethylarsinate (DMAV) was detected. Further, up to 48 and 83% of root As in AsV and MAV exposed plants, respectively were complexed with various thiols showing up to 20 and 16 As species, respectively. Several mixed As- and MA-complexes with hydroxymethyl-phytochelatin, DesGly phytochelatin, hydroxymethyl-GSH and cysteine were identified in rice. Despite high complexation in roots, more As was translocated to shoots in MAV exposed plants than AsV, with shoot/root As transfer factor being in order DMAV > MAV > AsV. Moreover, in shoots 78% MAIII and 71% AsIII were present as weakly bound species which is alarming, as MAIII has been found to be more cytotoxic than AsIII for human and it could also be an important factor inducing straighthead (spikelet sterility disorder) in rice. PMID- 28094281 TI - Electrically tunable organic-inorganic hybrid polaritons with monolayer WS2. AB - Exciton-polaritons are quasiparticles consisting of a linear superposition of photonic and excitonic states, offering potential for nonlinear optical devices. The excitonic component of the polariton provides a finite Coulomb scattering cross section, such that the different types of exciton found in organic materials (Frenkel) and inorganic materials (Wannier-Mott) produce polaritons with different interparticle interaction strength. A hybrid polariton state with distinct excitons provides a potential technological route towards in situ control of nonlinear behaviour. Here we demonstrate a device in which hybrid polaritons are displayed at ambient temperatures, the excitonic component of which is part Frenkel and part Wannier-Mott, and in which the dominant exciton type can be switched with an applied voltage. The device consists of an open microcavity containing both organic dye and a monolayer of the transition metal dichalcogenide WS2. Our findings offer a perspective for electrically controlled nonlinear polariton devices at room temperature. PMID- 28094282 TI - Evidence of neofunctionalization after the duplication of the highly conserved Polycomb group gene Caf1-55 in the obscura group of Drosophila. AB - Drosophila CAF1-55 protein is a subunit of the Polycomb repressive complex PRC2 and other protein complexes. It is a multifunctional and evolutionarily conserved protein that participates in nucleosome assembly and remodelling, as well as in the epigenetic regulation of a large set of target genes. Here, we describe and analyze the duplication of Caf1-55 in the obscura group of Drosophila. Paralogs exhibited a strong asymmetry in evolutionary rates, which suggests that they have evolved according to a neofunctionalization process. During this process, the ancestral copy has been kept under steady purifying selection to retain the ancestral function and the derived copy (Caf1-55dup) that originated via a DNA mediated duplication event ~18 Mya, has been under clear episodic selection. Different maximum likelihood approaches confirmed the action of positive selection, in contrast to relaxed selection, on Caf1-55dup after the duplication. This adaptive process has also taken place more recently during the divergence of D. subobscura and D. guanche. The possible association of this duplication with a previously detected acceleration in the evolutionary rate of three CAF1-55 partners in PRC2 complexes is discussed. Finally, the timing and functional consequences of the Caf1-55 duplication is compared to other duplications of Polycomb genes. PMID- 28094283 TI - Adolescent Chronic Unpredictable Stress Exposure Is a Sensitive Window for Long Term Changes in Adult Behavior in Mice. AB - Adolescence is a time period in development when the brain undergoes substantial remodeling in response to the environment. To determine whether a stressful experience during adolescence affects adult behavior, we exposed adolescent male and female C57BL/6J mice to chronic unpredictable stress (CUS) for 12 days starting at postnatal day 28 (PND28). We also exposed adult male and female mice to CUS for 12 days beginning at PND70 to determine whether adolescence is a sensitive time period when stress can have long-lasting effects on behavior. Regardless of when mice were exposed to stress, they were all tested exactly 30 days later in the marble burying task, elevated zero maze, acoustic startle response, and forced swim test. Adolescent stress exposure increased anxiety-like behaviors in adult male and female mice and decreased acoustic startle response in a sex-dependent manner. However, adult stress exposure did not change anxiety or response to an acoustic tone in adult male or female mice as compared with nonstressed animals. Of interest, increased depression-like behavior in the forced swim test was observed in all mice, regardless of when the stress occurred. Gene expression analysis showed significant upregulation of corticotropin releasing factor receptor 2 (CrfR2) in the amygdala of males subjected to CUS during adolescence, but not in males that experienced CUS during adulthood. In contrast, females, regardless of when they were exposed to CUS, were not affected. These data support clinical evidence suggesting that early life stress may predispose individuals to increased anxiety and depression later in life. PMID- 28094284 TI - The Composition of Human Milk and Infant Faecal Microbiota Over the First Three Months of Life: A Pilot Study. AB - Human milk contains a diverse array of bioactives and is also a source of bacteria for the developing infant gut. The aim of this study was to characterize the bacterial communities in human milk and infant faeces over the first 3 months of life, in 10 mother-infant pairs. The presence of viable Bifidobacterium and Lactobacillus in human milk was also evaluated. MiSeq sequencing revealed a large diversity of the human milk microbiota, identifying over 207 bacterial genera in milk samples. The phyla Proteobacteria and Firmicutes and the genera Pseudomonas, Staphylococcus and Streptococcus were the predominant bacterial groups. A core of 12 genera represented 81% of the microbiota relative abundance in milk samples at week 1, 3 and 6, decreasing to 73% at week 12. Genera shared between infant faeces and human milk samples accounted for 70-88% of the total relative abundance in infant faecal samples, supporting the hypothesis of vertical transfer of bacteria from milk to the infant gut. In addition, identical strains of Bifidobacterium breve and Lactobacillus plantarum were isolated from the milk and faeces of one mother-infant pair. Vertical transfer of bacteria via breastfeeding may contribute to the initial establishment of the microbiota in the developing infant intestine. PMID- 28094285 TI - Urinary Exosomes Contain MicroRNAs Capable of Paracrine Modulation of Tubular Transporters in Kidney. AB - Exosomes derived from all nephron segments are present in human urine, where their functionality is incompletely understood. Most studies have focused on biomarker discovery rather than exosome function. Through sequencing we identified the miRNA repertoire of urinary exosomes from healthy volunteers; 276 mature miRNAs and 345 pre-miRNAs were identified (43%/7% of reads). Among the most abundant were members of the miR-10, miR-30 and let-7 families. Targets for the identified miRNAs were predicted using five different databases; genes encoding membrane transporters and their regulators were enriched, highlighting the possibility that these miRNAs could modulate key renal tubular functions in a paracrine manner. As proof of concept, cultured renal epithelial cells were exposed to urinary exosomes and cellular exosomal uptake was confirmed; thereafter, reduced levels of the potassium channel ROMK and kinases SGK1 and WNK1 were observed in a human collecting duct cell line, while SPAK was unaltered. In proximal tubular cells, mRNA levels of the amino acid transporter gene SLC38A2 were diminished and reflected in a significant decrement of its encoded protein SNAT2. Protein levels of the kinase SGK1 did not change. Thus we demonstrated a novel potential function for miRNA in urinary exosomes. PMID- 28094286 TI - Creating stable Floquet-Weyl semimetals by laser-driving of 3D Dirac materials. AB - Tuning and stabilizing topological states, such as Weyl semimetals, Dirac semimetals or topological insulators, is emerging as one of the major topics in materials science. Periodic driving of many-body systems offers a platform to design Floquet states of matter with tunable electronic properties on ultrafast timescales. Here we show by first principles calculations how femtosecond laser pulses with circularly polarized light can be used to switch between Weyl semimetal, Dirac semimetal and topological insulator states in a prototypical three-dimensional (3D) Dirac material, Na3Bi. Our findings are general and apply to any 3D Dirac semimetal. We discuss the concept of time-dependent bands and steering of Floquet-Weyl points and demonstrate how light can enhance topological protection against lattice perturbations. This work has potential practical implications for the ultrafast switching of materials properties, such as optical band gaps or anomalous magnetoresistance. PMID- 28094287 TI - Relaxation dynamics in the strong chalcogenide glass-former of Ge22Se78. AB - The enthalpy relaxation is performed in the glassy Ge22Se78 to understand the dynamic behaviors. The structure of the glass is examined by X-ray diffraction and Raman spectra. The dynamic parameters such as the fragility, stretching exponent and non-linear factor are determined. A low fragility of m = 27 is exhibited for the chalcogenide, however, the stretching exponent is found not to have a larger value. The enthalpy relaxation spectra are constructed for various glass formers, and a relationship between the fragility and the symmetry of the spectra is demonstrated. The dynamic results are used to evaluate the structure of the Ge22Se78 glass. PMID- 28094288 TI - Predator personality and prey behavioural predictability jointly determine foraging performance. AB - Predator-prey interactions play important roles in ecological communities. Personality, consistent inter-individual differences in behaviour, of predators, prey or both are known to influence inter-specific interactions. An individual may also behave differently under the same situation and the level of such variability may differ between individuals. Such intra-individual variability (IIV) or predictability may be a trait on which selection can also act. A few studies have revealed the joint effect of personality types of both predators and prey on predator foraging performance. However, how personality type and IIV of both predators and prey jointly influence predator foraging performance remains untested empirically. Here, we addressed this using a specialized spider-eating jumping spider, Portia labiata (Salticidae), as the predator, and a jumping spider, Cosmophasis umbratica, as the prey. We examined personality types and IIVs of both P. labiata and C. umbratica and used their inter- and intra individual behavioural variation as predictors of foraging performance (i.e., number of attempts to capture prey). Personality type and predictability had a joint effect on predator foraging performance. Aggressive predators performed better in capturing unpredictable (high IIV) prey than predictable (low IIV) prey, while docile predators demonstrated better performance when encountering predictable prey. This study highlights the importance of the joint effect of both predator and prey personality types and IIVs on predator-prey interactions. PMID- 28094289 TI - Analytically determined topological phase diagram of the proximity-induced gap in diffusive n-terminal Josephson junctions. AB - Multiterminal Josephson junctions have recently been proposed as a route to artificially mimic topological matter with the distinct advantage that its properties can be controlled via the superconducting phase difference, giving rise to Weyl points in 4-terminal geometries. A key goal is to accurately determine when the system makes a transition from a gapped to non-gapped state as a function of the phase differences in the system, the latter effectively playing the role of quasiparticle momenta in conventional topological matter. We here determine the proximity gap phase diagram of diffusive n-terminal Josephson junctions (), both numerically and analytically, by identifying a class of solutions to the Usadel equation at zero energy in the full proximity effect regime. We present an analytical equation which provides the phase diagram for an arbitrary number of terminals n. After briefly demonstrating the validity of the analytical approach in the previously studied 2- and 3-terminal cases, we focus on the 4-terminal case and map out the regimes where the electronic excitations in the system are gapped and non-gapped, respectively, demonstrating also in this case full agreement between the analytical and numerical approach. PMID- 28094290 TI - Protein arginine methyltransferase 1 (PRMT1) represses MHC II transcription in macrophages by methylating CIITA. AB - Efficient presentation of alien antigens triggers activation of T lymphocytes and robust host defense against invading pathogens. This pathophysiological process relies on the expression of major histocompatibility complex (MHC) molecules in antigen presenting cells such as macrophages. Aberrant MHC II transactivation plays a crucial role in the pathogenesis of atherosclerosis. Class II transactivator (CIITA) mediates MHC II induction by interferon gamma (IFN-gamma). CIITA activity can be fine-tuned at the post-translational level, but the mechanisms are not fully appreciated. We investigated the role of protein arginine methyltransferase 1 (PRMT1) in this process. We report here that CIITA interacted with PRMT1. IFN-gamma treatment down-regulated PRMT1 expression and attenuated PRMT1 binding on the MHC II promoter. Over-expression of PRMT1 repressed MHC II promoter activity while PRMT1 depletion enhanced MHC II transactivation. Mechanistically, PRMT1 methylated CIITA and promoted CIITA degradation. Therefore, our data reveal a previously unrecognized role for PRMT1 in suppressing CIITA-mediated MHC II transactivation. PMID- 28094291 TI - Differential Effects of Vitamins A and D on the Transcriptional Landscape of Human Monocytes during Infection. AB - Vitamin A and vitamin D are essential nutrients with a wide range of pleiotropic effects in humans. Beyond their well-documented roles in cellular differentiation, embryogenesis, tissue maintenance and bone/calcium homeostasis, both vitamins have attracted considerable attention due to their association with immunological traits. Nevertheless, our knowledge of their immunomodulatory potential during infection is restricted to single gene-centric studies, which do not reflect the complexity of immune processes. In the present study, we performed a comprehensive RNA-seq-based approach to define the whole immunomodulatory role of vitamins A and D during infection. Using human monocytes as host cells, we characterized the differential role of both vitamins upon infection with three different pathogens: Aspergillus fumigatus, Candida albicans and Escherichia coli. Both vitamins showed an unexpected ability to counteract the pathogen-induced transcriptional responses. Upon infection, we identified 346 and 176 immune-relevant genes that were regulated by atRA and vitD, respectively. This immunomodulatory activity was dependent on the inflammatory stimulus, allowing us to distinguish regulatory patterns which were specific for each stimulatory setting. Moreover, we explored possible direct and indirect mechanisms of vitamin-mediated regulation of the immune response. Our findings highlight the importance of vitamin-monitoring in critically ill patients. Moreover, our results underpin the potential of atRA and vitD as therapeutic options for anti-inflammatory treatment. PMID- 28094292 TI - Chromatin organization revealed by nanostructure of irradiation induced gammaH2AX, 53BP1 and Rad51 foci. AB - The spatial distribution of DSB repair factors gammaH2AX, 53BP1 and Rad51 in ionizing radiation induced foci (IRIF) in HeLa cells using super resolution STED nanoscopy after low and high linear energy transfer (LET) irradiation was investigated. 53BP1 and gammaH2AX form IRIF with same mean size of (540 +/- 40) nm after high LET irradiation while the size after low LET irradiation is significantly smaller. The IRIF of both repair factors show nanostructures with partial anti-correlation. These structures are related to domains formed within the chromatin territories marked by gammaH2AX while 53BP1 is mainly situated in the perichromatin region. The nanostructures have a mean size of (129 +/- 6) nm and are found to be irrespective of the applied LET and the labelled damage marker. In contrast, Rad51 shows no nanostructure and a mean size of (143 +/- 13) nm independent of LET. Although Rad51 is surrounded by 53BP1 it strongly anti correlates meaning an exclusion of 53BP1 next to DSB when decision for homologous DSB repair happened. PMID- 28094293 TI - The transmission potential of malaria-infected mosquitoes (An.gambiae-Keele, An.arabiensis-Ifakara) is altered by the vertebrate blood type they consume during parasite development. AB - The efficiency of malaria parasite development within mosquito vectors (sporogony) is a critical determinant of transmission. Sporogony is thought to be controlled by environmental conditions and mosquito/parasite genetic factors, with minimal contribution from mosquito behaviour during the period of parasite development. We tested this assumption by investigating whether successful sporogony of Plasmodium falciparum parasites through to human-infectious transmission stages is influenced by the host species upon which infected mosquitoes feed. Studies were conducted on two major African vector species that generally are found to differ in their innate host preferences: Anopheles arabiensis and An. gambiae sensu stricto. We show that the proportion of vectors developing transmissible infections (sporozoites) was influenced by the source of host blood consumed during sporogony. The direction of this effect was associated with the innate host preference of vectors: higher sporozoite prevalences were generated in the usually human-specialist An. gambiae s.s. feeding on human compared to cow blood, whereas the more zoophilic An. arabiensis had significantly higher prevalences after feeding on cow blood. The potential epidemiological implications of these results are discussed. PMID- 28094294 TI - Version 1.1 of the international spinal cord injury skin and thermoregulation function basic data set. AB - OBJECTIVE: To describe the changes made to the international spinal cord injury (SCI) skin and thermoregulation function basic data set in version 1.1. SETTING: International. METHODS: An international working group reviewed suggested changes to the international SCI skin and thermoregulation function basic data set version 1.0. These changes were discussed and the agreed changes were made. Subsequently, the recommended adjustments were circulated for review to the International Spinal Cord Society (ISCoS) Executive and Scientific Committees, the American Spinal Injury Association (ASIA) Board, around 40 national and international societies, and to interested individuals who had signed up wishing to have the opportunity to review. In addition, the suggested changes were displayed at the ISCoS and ASIA websites for at least a month for possible comments. RESULTS: The recommendation 'largest diameter, including undermining' is changed to: 'Largest undermining', and a description of how to measure this is inserted. The 'smallest opening diameter' is changed to: 'Width' as the maximum dimension perpendicular to the length axis. In the literature, there is a tendency to replace 'grades' or 'stages' with 'categories'; therefore, the word 'category' is used instead of 'grade' or 'stage'. CONCLUSIONS: Impracticable measurements have been adjusted and new terminology adopted. All are to be found on ISCoS website: http://www.iscos.org.uk/international-sci-skin-and thermoregulation-function-data-sets. PMID- 28094295 TI - Loss of PAFR prevents neuroinflammation and brain dysfunction after traumatic brain injury. AB - Traumatic brain injury (TBI) is a principal cause of death and disability worldwide, which is a major public health problem. Death caused by TBI accounts for a third of all damage related illnesses, which 75% TBI occurred in low and middle income countries. With the increasing use of motor vehicles, the incidence of TBI has been at a high level. The abnormal brain functions of TBI patients often show the acute and long-term neurological dysfunction, which mainly associated with the pathological process of malignant brain edema and neuroinflammation in the brain. Owing to the neuroinflammation lasts for months or even years after TBI, which is a pivotal causative factor that give rise to neurodegenerative disease at late stage of TBI. Studies have shown that platelet activating factor (PAF) inducing inflammatory reaction after TBI could not be ignored. The morphological and behavioral abnormalities after TBI in wild type mice are rescued by general knockout of PAFR gene that neuroinflammation responses and cognitive ability are improved. Our results thus define a key inflammatory molecule PAF that participates in the neuroinflammation and helps bring about cerebral dysfunction during the TBI acute phase. PMID- 28094296 TI - Hydrophobic Residues near the Bilin Chromophore-Binding Pocket Modulate Spectral Tuning of Insert-Cys Subfamily Cyanobacteriochromes. AB - Cyanobacteriochromes (CBCRs) are a subfamily of phytochrome photoreceptors found exclusively in photosynthetic cyanobacteria. Four CBCRs containing a second Cys in the insert region (insert-Cys) have been identified from the nonheterocystous cyanobacterium Microcoleus B353 (Mbr3854g4 and Mbl3738g2) and the nitrogen fixing, heterocystous cyanobacterium Nostoc punctiforme (NpF2164g3 and NpR1597g2). These insert-Cys CBCRs can sense light in the near-UV to orange range, but key residues responsible for tuning their colour sensitivity have not been reported. In the present study, near-UV/Green (UG) photosensors Mbr3854g4 (UG1) and Mbl3738g2 (UG2) were chosen for further spectroscopic analysis of their spectral sensitivity and tuning. Consistent with most dual-Cys CBCRs, both UGs formed a second thioether linkage to the phycocyanobilin (PCB) chromophore via the insert-Cys. This bond is subject to breakage and relinkage during forward and reverse photoconversions. Variations in residues equivalent to Phe that are in close contact with the PCB chromophore D-ring in canonical red/green CBCRs are responsible for tuning the light absorption peaks of both dark and photoproducts. This is the first time these key residues that govern light absorption in insert Cys family CBCRs have been identified and characterised. PMID- 28094298 TI - A new type of two-dimensional carbon crystal prepared from 1,3,5 trihydroxybenzene. AB - A new two-dimensional (2D) carbon crystal, different from graphene, has been prepared from 1,3,5-trihydroxybenzene, consisting of 4-carbon and 6-carbon rings in 1:1 ratio, named 4-6 carbophene by authors, in which all carbon atoms possess sp2 hybrid orbitals with some distortion, forming an extensive conjugated pi bonding planar structure. The angles between the three sigma-bonds of the carbon sp2 orbitals are roughly 120 degrees , 90 degrees , and 150 degrees . Each of the three non-adjacent sides of a 6C-ring is shared with a 4C-ring; and each of the two opposite sides of a 4C-ring is shared with a 6C-ring. Dodecagonal holes with a diameter of approximate 5.8 A are regularly located throughout the 2D carbon crystal. Even though the bond energies in 4-6 carbophene are weaker than those in the graphene, the new planar crystal is quite stable in ambient conditions. The 4 6 carbophene can be synthetized from 1,3,5-trihydroxybenzene or other benzene derivatives through dehydration and polymerization reactions, and may possess several possible patterns that form a family of 2D carbon crystals. A possible side reaction involving 1,3,5-trihydroxybenzene is also discussed, which may produce a carbon-oxygen two dimensional crystal. PMID- 28094297 TI - High-throughput quantitation of inorganic nanoparticle biodistribution at the single-cell level using mass cytometry. AB - Inorganic nanoparticles (NPs) are studied as drug carriers, radiosensitizers and imaging agents, and characterizing nanoparticle biodistribution is essential for evaluating their efficacy and safety. Tracking NPs at the single-cell level with current technologies is complicated by the lack of reliable methods to stably label particles over extended durations in vivo. Here we demonstrate that mass cytometry by time-of-flight provides a label-free approach for inorganic nanoparticle quantitation in cells. Furthermore, mass cytometry can enumerate AuNPs with a lower detection limit of ~10 AuNPs (3 nm core size) in a single cell with tandem multiparameter cellular phenotyping. Using the cellular distribution insights, we selected an amphiphilic surface ligand-coated AuNP that targeted myeloid dendritic cells in lymph nodes as a peptide antigen carrier, substantially increasing the efficacy of a model vaccine in a B16-OVA melanoma mouse model. This technology provides a powerful new level of insight into nanoparticle fate in vivo. PMID- 28094299 TI - Corrigendum: Critical exponents and scaling invariance in the absence of a critical point. PMID- 28094301 TI - The occurrence rate of acute-onset postoperative endophthalmitis after cataract surgery in Chinese small- and medium-scale departments of ophthalmology. AB - Endophthalmitis can be a devastating complication after cataract surgery. Therefore, this study sought to better understand the occurrence rate of acute onset postoperative endophthalmitis after cataract surgery in Chinese small and medium-scale departments of ophthalmology, as well as identify its risk factors and assess the treatment options. This investigation revealed 52 postoperative endophthalmitis cases in 46,185 operations at 30 hospitals from 2011 to 2013, at an occurrence rate of 0.11%. A small cataract surgery volume of less than 500 cases per year (OR 2.21; p = 0.006), the absence of 0.5% povidone iodine (PVP-I) irrigation (OR 1.73; p = 0.046), and intraoperative posterior capsular rupture (PCR) with vitreous loss (OR 4.40; p = 0.034) showed statistically significant associations with endophthalmitis in the multivariate analysis. The rate of culture positivity was 44.2%, with Staphylococcus epidermidis being the most common organism isolated in China. More than 40% of the endophthalmitis cases were treated with a nonstandard antibiotics regimen, and only 32.7% of these had a visual acuity of better than 20/40. We concluded that the occurrence rate of acute-onset endophthalmitis following cataract surgery in Chinese small and medium-scale departments of ophthalmology lags behind the level of developed countries, as well as Chinese top eye centers. Overall, the use of 0.5% PVP-I irrigation seemed to be an effective measure to reduce the risk of the development of postoperative endophthalmitis. PMID- 28094300 TI - Sequestration of PRMT1 and Nd1-L mRNA into ALS-linked FUS mutant R521C-positive aggregates contributes to neurite degeneration upon oxidative stress. AB - Mutations in fused in sarcoma (FUS), a DNA/RNA binding protein, are associated with familial amyotrophic lateral sclerosis (ALS). However, little is known about how ALS-causing mutations alter protein-protein and protein-RNA complexes and contribute to neurodegeneration. In this study, we identified protein arginine methyltransferase 1 (PRMT1) as a protein that more avidly associates with ALS linked FUS-R521C than with FUS-WT (wild type) or FUS-P525L using co immunoprecipitation and LC-MS analysis. Abnormal association between FUS-R521C and PRMT1 requires RNA, but not methyltransferase activity. PRMT1 was sequestered into cytosolic FUS-R521C-positive stress granule aggregates. Overexpression of PRMT1 rescued neurite degeneration caused by FUS-R521C upon oxidative stress, while loss of PRMT1 further accumulated FUS-positive aggregates and enhanced neurite degeneration. Furthermore, the mRNA of Nd1-L, an actin-stabilizing protein, was sequestered into the FUS-R521C/PRMT1 complex. Nd1-L overexpression rescued neurite shortening caused by FUS-R521C upon oxidative stress, while loss of Nd1-L further exacerbated neurite shortening. Altogether, these data suggest that the abnormal stable complex of FUS-R521C/PRMT1/Nd1-L mRNA could contribute to neurodegeneration upon oxidative stress. Overall, our study provides a novel pathogenic mechanism of the FUS mutation associated with abnormal protein-RNA complexes upon oxidative stress in ALS and provides insight into possible therapeutic targets for this pathology. PMID- 28094302 TI - Interfacial structures and energetics of the strengthening precipitate phase in creep-resistant Mg-Nd-based alloys. AB - The extraordinary creep-resistance of Mg-Nd-based alloys can be correlated to the formation of nanoscale-platelets of beta1-Mg3Nd precipitates, that grow along <110>Mg in bulk hcp-Mg and on dislocation lines. The growth kinetics of beta1 is sluggish even at high temperatures, and presumably occurs via vacancy migration. However, the rationale for the high-temperature stability of precipitate-matrix interfaces and observed growth direction is unknown, and may likely be related to the interfacial structure and excess energy. Therefore, we study two interfaces- {112}beta1/{100}Mg and {111}beta1/{110}Mg- that are commensurate with beta1/hcp Mg orientation relationship via first principles calculations. We find that beta1 acquires plate-like morphology to reduce small lattice strain via the formation of energetically favorable {112}beta1/{100}Mg interfaces, and predict that beta1 grows along <110>Mg on dislocation lines due to the migration of metastable {111}beta1/{110}Mg. Furthermore, electronic charge distribution of the two interfaces studied here indicated that interfacial-energy of coherent precipitates is sensitive to the population of distorted lattice sites, and their spatial extent in the vicinity of interfaces. Our results have implications for alloy design as they suggest that formation of beta1-like precipitates in the hcp Mg matrix will require well-bonded coherent interface along precipitate broad faces, while simultaneously destabilizing other interfaces. PMID- 28094304 TI - The different expression of TRPM7 and MagT1 impacts on the proliferation of colon carcinoma cells sensitive or resistant to doxorubicin. AB - The processes leading to anticancer drug resistance are not completely unraveled. To get insights into the underlying mechanisms, we compared colon carcinoma cells sensitive to doxorubicin with their resistant counterpart. We found that resistant cells are growth retarded, and show staminal and ultrastructural features profoundly different from sensitive cells. The resistant phenotype is accompanied by the upregulation of the magnesium transporter MagT1 and the downregulation of the ion channel kinase TRPM7. We demonstrate that the different amounts of TRPM7 and MagT1 account for the different proliferation rate of sensitive and resistant colon carcinoma cells. It remains to be verified whether they are also involved in the control of other "staminal" traits. PMID- 28094303 TI - Genetic Polymorphisms of rs3077 and rs9277535 in HLA-DP associated with Systemic lupus erythematosus in a Chinese population. AB - Although the SLE risk gene loci of HLA-DR and HLA-DQ within the major histocompatibility complex (MHC) region has been gradually revealed by recent Genome-Wide Association studies (GWAS), the association of HLA-DP polymorphisms with SLE was minimally reported. Considering that the variants in rs3077 and rs9277535 in the HLA-DP region could influence the immune response by affecting antigen presentation of HLA class II molecules to CD4+ T cells, the present study aimed to explore the role of HLA-DP polymorphisms in SLE. In total, samples from 335 SLE patients and 635 healthy controls were collected and genotyped by a polymerase chain reaction-high resolution melting (PCR-HRM) assay. A significant positive correlation was observed between the SNP rs3077, rs9277535 of HLA-DP and SLE susceptibility (rs3077, OR = 0.74, 95%CI = 0.60-0.91, P = 0.004; rs9277535, OR = 0.72, 95%CI = 0.59-0.88, P = 0.001). Rs3077 polymorphism was corelated to IL 17, INF-gamma and cutaneous vasculitis (P = 0.037, P = 0.020 and P = 0.006, respectively). Additionally, rs3077 AA genotype carriers showed lower concentration of inflammatory cytokines and lower cutaneous vasculitis incidence than did the other two genotype. No significant association was observed between rs9277535 and cytokines or any clinical features. In conclusion, HLA-DP polymorphisms (rs3077 and rs9277535) were associated with SLE susceptibility and the levels of some inflammatory cytokines in SLE patients. PMID- 28094305 TI - Association of the Intestinal Microbiome with the Development of Neovascular Age Related Macular Degeneration. AB - Age-related macular degeneration (AMD) is the most frequent cause of blindness in the elderly. There is evidence that nutrition, inflammation and genetic risk factors play an important role in the development of AMD. Recent studies suggest that the composition of the intestinal microbiome is associated with metabolic diseases through modulation of inflammation and host metabolism. To investigate whether compositional and functional alterations of the intestinal microbiome are associated with AMD, we sequenced the gut metagenomes of patients with AMD and controls. The genera Anaerotruncus and Oscillibacter as well as Ruminococcus torques and Eubacterium ventriosum were relatively enriched in patients with AMD, whereas Bacteroides eggerthii was enriched in controls. Patient's intestinal microbiomes were enriched in genes of the L-alanine fermentation, glutamate degradation and arginine biosynthesis pathways and decreased in genes of the fatty acid elongation pathway. These findings suggest that modifications in the intestinal microbiome are associated with AMD, inferring that this common sight threatening disease may be targeted by microbiome-altering interventions. PMID- 28094306 TI - Maternal diabetes modulates dental epithelial stem cells proliferation and self renewal in offspring through apurinic/apyrimidinicendonuclease 1-mediated DNA methylation. AB - Maternal gestational diabetes mellitus (GDM) has many adverse effects on the development of offspring. Aberrant DNA methylation is a potential mechanism associated with these effects. However, the effects of GDM on tooth development and the underlying mechanisms have not been thoroughly investigated. In the present study, a GDM rat model was established and incisor labial cervical loop tissue and dental epithelial stem cells (DESCs) were harvested from neonates of diabetic and control dams. GDM significantly suppressed incisor enamel formation and DESCs proliferation and self-renewal in offspring. Gene expression profiles showed that Apex1 was significantly downregulated in the offspring of diabetic dams. In vitro, gain and loss of function analyses showed that APEX1 was critical for DESCs proliferation and self-renewal and Oct4 and Nanog regulation via promoter methylation. In vivo, we confirmed that GDM resulted in significant downregulation of Oct4 and Nanog and hypermethylation of their promoters. Moreover, we found that APEX1 modulated DNA methylation by regulating DNMT1 expression through ERK and JNK signalling. In summary, our data suggest that GDM induced APEX1 downregulation increased DNMT1 expression, thereby inhibiting Oct4 and Nanog expression, through promoter hypermethylation, resulting in suppression of DESCs proliferation and self-renewal, as well as enamel formation. PMID- 28094307 TI - A transcriptome analysis focusing on inflammation-related genes of grass carp intestines following infection with Aeromonas hydrophila. AB - Inflammation is a protective response that is implicated in bacterial enteritis and other fish diseases. The inflammatory mechanisms behind Aeromonas hydrophila infections in fish remain poorly understood. In this study, we performed a de novo grass carp transcriptome assembly using Illumina's Solexa sequencing technique. On this basis we carried out a comparative analysis of intestinal transcriptomes from A. hydrophila-challenged and physiological saline solution (PSS/mock) -challenged fish, and 315 genes were up-regulated and 234 were down regulated in the intestines infected with A. hydrophila. The GO enrichment analysis indicated that the differentially expressed genes were enriched to 12, 4, and 8 GO terms in biological process, molecular function, and cellular component, respectively. A KEGG analysis showed that 549 DEGs were involved in 165 pathways. Moreover, 15 DEGs were selected for quantitative real-time PCR analysis to validate the RNA-seq data. The results confirmed the consistency of the expression levels between RNA-seq and qPCR data. In addition, a time-course analysis of the mRNA expression of 12 inflammatory genes further demonstrated that the intestinal inflammatory responses to A. hydrophila infection simultaneously modulated gene expression variations. The present study provides intestine-specific transcriptome data, allowing us to unravel the mechanisms of intestinal inflammation triggered by bacterial pathogens. PMID- 28094308 TI - Silicon availability modifies nutrient use efficiency and content, C:N:P stoichiometry, and productivity of winter wheat (Triticum aestivum L.). AB - Silicon (Si) is known as beneficial element for graminaceous plants. The importance of Si for plant functioning of cereals was recently emphasized. However, about the effect of Si availability on biomass production, grain yield, nutrient status and nutrient use efficiency for wheat (Triticum aestivum L.), as one of the most important crop plants worldwide, less is known so far. Consequently, we assessed the effect of a broad range of supply levels of amorphous SiO2 on wheat plant performance. Our results revealed that Si is readily taken up and accumulated basically in aboveground vegetative organs. Carbon (C) and phosphorus (P) status of plants were altered in response to varying Si supply. In bulk straw biomass C concentration decreased with increasing Si supply, while P concentration increased from slight limitation towards optimal nutrition. Thereby, aboveground biomass production increased at low to medium supply levels of silica whereas grain yield increased at medium supply level only. Nutrient use efficiency was improved by Si insofar that biomass production was enhanced at constant nitrogen (N) status of substrate and plants. Consequently, our findings imply fundamental influences of Si on C turnover, P availability and nitrogen use efficiency for wheat as a major staple crop. PMID- 28094309 TI - Blue Laser Diode Enables Underwater Communication at 12.4 Gbps. AB - To enable high-speed underwater wireless optical communication (UWOC) in tap water and seawater environments over long distances, a 450-nm blue GaN laser diode (LD) directly modulated by pre-leveled 16-quadrature amplitude modulation (QAM) orthogonal frequency division multiplexing (OFDM) data was employed to implement its maximal transmission capacity of up to 10 Gbps. The proposed UWOC in tap water provided a maximal allowable communication bit rate increase from 5.2 to 12.4 Gbps with the corresponding underwater transmission distance significantly reduced from 10.2 to 1.7 m, exhibiting a bit rate/distance decaying slope of -0.847 Gbps/m. When conducting the same type of UWOC in seawater, light scattering induced by impurities attenuated the blue laser power, thereby degrading the transmission with a slightly higher decay ratio of 0.941 Gbps/m. The blue LD based UWOC enables a 16-QAM OFDM bit rate of up to 7.2 Gbps for transmission in seawater more than 6.8 m. PMID- 28094310 TI - Rising temperatures may drive fishing-induced selection of low-performance phenotypes. AB - Climate warming is likely to interact with other stressors to challenge the physiological capacities and survival of phenotypes within populations. This may be especially true for the billions of fishes per year that undergo vigorous exercise prior to escaping or being intentionally released from fishing gear. Using adult coral grouper (Plectropomus leopardus), an important fisheries species throughout the Indo-Pacific, we show that population-level survival following vigorous exercise is increasingly compromised as temperatures increase from current-day levels (100-67% survival at 24-30 degrees C) to those projected for the end of the century (42% survival at 33 degrees C). Intriguingly, we demonstrate that high-performance individuals take longer to recover to a resting metabolic state and subsequently have lower survival in warm water compared with conspecifics that exercise less vigorously. Moreover, we show that post-exercise mortality of high-performance phenotypes manifests after 3-13 d at the current summer maximum (30 degrees C), while mortality at 33 degrees C occurs within 1.8-14.9 h. We propose that wild populations in a warming climate may become skewed towards low-performance phenotypes with ramifications for predator-prey interactions and community dynamics. Our findings highlight the susceptibility of phenotypic diversity to fishing activities and demonstrate a mechanism that may contribute to fishing-induced evolution in the face of ongoing climate change. PMID- 28094311 TI - Evidence of Microvascular Changes in the Retina following Kawasaki Disease. AB - It is unclear whether all children with Kawasaki disease (KD) have increased later cardiovascular risk. The retinal microvasculature reflects changes in the microcirculation and is associated with traditional cardiovascular risk factors and events. The aim of this study was to investigate retinal microvascular parameters in two populations of patients with previous KD and control participants. We performed case-control studies of 116 (57 patients and 59 control participants) Australian and 156 (78 patients and 78 control participants) Singaporean individuals, at least two years since their acute illness. Standardised retinal photographs were graded by trained technicians using a semi-automated software, which quantifies the retinal microvasculature (calibre, branching angle, fractal dimensions, and tortuosity). Retinal venules of Singaporean KD patients were 9.67 MUm (95% CI 4.87 to 14.51, p < 0.001) larger than control participants following correction for traditional cardiovascular risk factors. An incremental increase in the size of retinal venules in those with coronary artery abnormalities was observed. There was limited evidence that retinal venules were larger in Australian KD patients with coronary artery abnormalities compared to control participants (7.34 MUm, 95% CI 1.30 to 15.99, p = 0.10). Differences in retinal microvasculature were particularly evident in Singaporean KD patients. Larger retinal venules may reflect chronic inflammation and endothelial dysfunction, and are associated with coronary artery disease in adults. PMID- 28094312 TI - Unraveling the microbial processes of black band disease in corals through integrated genomics. AB - Coral disease outbreaks contribute to the ongoing degradation of reef ecosystems, however, microbial mechanisms underlying the onset and progression of most coral diseases are poorly understood. Black band disease (BBD) manifests as a cyanobacterial-dominated microbial mat that destroys coral tissues as it rapidly spreads over coral colonies. To elucidate BBD pathogenesis, we apply a comparative metagenomic and metatranscriptomic approach to identify taxonomic and functional changes within microbial lesions during in-situ development of BBD from a comparatively benign stage termed cyanobacterial patches. Results suggest that photosynthetic CO2-fixation in Cyanobacteria substantially enhances productivity of organic matter within the lesion during disease development. Photosynthates appear to subsequently promote sulfide-production by Deltaproteobacteria, facilitating the major virulence factor of BBD. Interestingly, our metagenome-enabled transcriptomic analysis reveals that BBD associated cyanobacteria have a putative mechanism that enables them to adapt to higher levels of hydrogen sulfide within lesions, underpinning the pivotal roles of the dominant cyanobacterium within the polymicrobial lesions during the onset of BBD. The current study presents sequence-based evidence derived from whole microbial communities that unravel the mechanism of development and progression of BBD. PMID- 28094313 TI - Comparison of Symptoms, Healthcare Utilization, and Treatment in Diagnosed and Undiagnosed Individuals With Diarrhea-Predominant Irritable Bowel Syndrome. AB - OBJECTIVES: Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by symptoms including abdominal pain and altered bowel function. Up to 75% of individuals with IBS may be undiagnosed. The aim of this study was to characterize symptoms, healthcare utilization, and treatments in populations with both diagnosed and undiagnosed IBS. METHODS: An online survey was conducted to compare gastrointestinal (GI) symptoms, healthcare visits, well-being, symptom management, and treatment satisfaction in individuals with and without medically diagnosed IBS (Rome III criteria). Symptom severity, disruptiveness, and treatment satisfaction were rated using a 7-point scale. Adjustments to daily life were determined by predefined survey responses. RESULTS: A total of 1,924 individuals with a history of GI symptoms were eligible and completed the survey. Of these, 1,094 individuals (56.9%) met the criteria for IBS; 830 individuals (43.1%) had no medical diagnosis of IBS despite meeting diagnostic criteria. Most participants received a diagnosis from either gastroenterologists (45%) or primary care physicians (42%). A greater percentage of diagnosed patients had severe GI symptoms (score >=6) vs. undiagnosed individuals (16% vs. 8%, respectively; P<0.05); diagnosed patients were more likely to report that GI symptoms adversely affected their quality of life. Approximately 40% of participants received IBS-related treatment from primary care physicians; 26% and 43% of diagnosed and undiagnosed individuals, respectively, were not receiving treatment for GI symptoms. CONCLUSIONS: Many individuals with IBS-related symptoms have not been medically diagnosed with IBS. IBS-related symptoms impact quality of life, yet more than one-third of individuals are not receiving treatment for IBS. PMID- 28094314 TI - Reassessment of Rebleeding Risk of Forrest IB (Oozing) Peptic Ulcer Bleeding in a Large International Randomized Trial. AB - OBJECTIVES: Our aims were to assess risks of early rebleeding after successful endoscopic hemostasis for Forrest oozing (FIB) peptic ulcer bleeding (PUBs) compared with other stigmata of recent hemorrhage (SRH). METHODS: These were post hoc multivariable analyses of a large, international, double-blind study (NCT00251979) of patients randomized to high-dose intravenous (IV) esomeprazole (PPI) or placebo for 72 h. Rebleeding rates of patients with PUB SRH treated with either PPI or placebo after successful endoscopic hemostasis were also compared. RESULTS: For patients treated with placebo for 72 h after successful endoscopic hemostasis, rebleed rates by SRH were spurting arterial bleeding (FIA) 22.5%, adherent clot (FIIB) 17.6%, non-bleeding visible vessel (FIIA) 11.3%, and oozing bleeding (FIB) 4.9%. Compared with FIB patients, FIA, FIIB, and FIIA had significantly greater risks of rebleeding with odds ratios (95% CI's) from 2.61 (1.05, 6.52) for FIIA to 6.66 (2.19, 20.26) for FIA. After hemostasis, PUB rebleeding rates for FIB patients at 72 h were similar with esomeprazole (5.4%) and placebo (4.9%), whereas rebleed rates for all other major SRH (FIA, FIIA, FIIB) were lower for PPI than placebo, but the treatment by SRH interaction test was not statistically significant. CONCLUSIONS: After successful endoscopic hemostasis, FIB patients had very low PUB rebleeding rates irrespective of PPI or placebo treatment. This implies that after successful endoscopic hemostasis the prognostic classification of FIB ulcers as a high-risk SRH and the recommendation to treat these with high-dose IV PPI's should be re-evaluated. PMID- 28094317 TI - Data mining of molecular dynamics data reveals Li diffusion characteristics in garnet Li7La3Zr2O12. AB - Understanding Li diffusion in solid conductors is essential for the next generation Li batteries. Here we show that density-based clustering of the trajectories computed using molecular dynamics simulations helps elucidate the Li diffusion mechanism within the Li7La3Zr2O12 (LLZO) crystal lattice. This unsupervised learning method recognizes lattice sites, is able to give the site type, and can identify Li hopping events. Results show that, while the cubic LLZO has a much higher hopping rate compared to its tetragonal counterpart, most of the Li hops in the cubic LLZO do not contribute to the diffusivity due to the dominance of back-and-forth type jumps. The hopping analysis and local Li configuration statistics give evidence that Li diffusivity in cubic LLZO is limited by the low vacancy concentration. The hopping statistics also shows uncorrelated Poisson-like diffusion for Li in the cubic LLZO, and correlated diffusion for Li in the tetragonal LLZO in the temporal scale. Further analysis of the spatio-temporal correlation using site-to-site mutual information confirms the weak site dependence of Li diffusion in the cubic LLZO as the origin for the uncorrelated diffusion. This work puts forward a perspective on combining machine learning and information theory to interpret results of molecular dynamics simulations. PMID- 28094315 TI - The usefulness of CorvisST Tonometry and the Ocular Response Analyzer to assess the progression of glaucoma. AB - Corneal Visualization Scheimpflug Technology (CST) and Ocular Response Analyzer (ORA) measurements were carried out in 105 eyes of 69 patients with primary open angle glaucoma. All patients had axial length (AL), central corneal thickness (CCT), intraocular pressure (IOP) with Goldmann applanation tonometry (GAT) and eight visual fields (VF)s with the Humphrey Field Analyzer. VF progression was summarized using a time trend analysis of mean total deviation (mTD) and the association between mTD progression rate and a number of ocular parameters (including CST and ORA measurements) was assessed using mixed linear regression analysis. The optimal model of VF progression selected based on the corrected Akaike Information Criteria (AICc) included ORA's corneal hysteresis (CH) parameter as well as a number of CST measurements: mTD progression rate = 1.2 0.070 * mean GAT + 0.090 * CH-1.5 * highest concavity deformation amplitude with CST + 9.4 * A1 deformation amplitude with CST-0.05 * A2 length with CST (AICc = 125.8). Eyes with corneas that experience deep indentation at the maximum deformation, shallow indentation at the first applanation and wide indentation at the second applanation in the CST measurement are more likely to experience faster rates of VF progression. PMID- 28094316 TI - Somatostatin receptor expression on von Hippel-Lindau-associated hemangioblastomas offers novel therapeutic target. AB - Von Hippel-Lindau (VHL)-associated hemangioblastomas (VHL-HB) arise in the central nervous system (CNS), and are a leading cause of morbidity and mortality in VHL disease. Currently, surgical resection is the most effective way to manage symptomatic VHL-HBs. Surgically unresectable VHL-HBs or those in frail patients are challenging problems. Therapies targeting oncologic and vascular endothelial growth factor (VEGF) pathways have failed to demonstrate tumor control. Our experience and previous reports on VHL-HB avidity to somatostatin analogues suggested somatostatin receptor (SSTR) expression in VHL-HBs, offering an alternative therapeutic strategy. We explored this possibility by demonstrating consistent histologic expression of SSTR1, 2a, 4, and 5 in VHL-HBs. We found that somatostatin analogue octreotide induces apoptosis in VHL-HB stromal cells in a dose-dependent fashion by BAX - caspase-3 pathway unrelated to canonical VHL pathway. When administered to a patient with unresectable symptomatic suprasellar hemangioblastoma, octreotide resulted in tumor volume reduction, symptom stabilization, and tumor cytopenia on repeat 68Ga-DOTA-TATE positron emission tomography (PET) within 6 months, suggesting tumor infarction. We conclude that VHL-HBs harbor multiple SSTR subtypes that offer actionable chemo-therapeutic strategy for management of symptomatic, unresectable tumors by somatostatin analogue therapy. PMID- 28094318 TI - Hydrogen reduction of molybdenum oxide at room temperature. AB - The color changes in chemo- and photochromic MoO3 used in sensors and in organic photovoltaic (OPV) cells can be traced back to intercalated hydrogen atoms stemming either from gaseous hydrogen dissociated at catalytic surfaces or from photocatalytically split water. In applications, the reversibility of the process is of utmost importance, and deterioration of the layer functionality due to side reactions is a critical challenge. Using the membrane approach for high-pressure XPS, we are able to follow the hydrogen reduction of MoO3 thin films using atomic hydrogen in a water free environment. Hydrogen intercalates into MoO3 forming HxMoO3, which slowly decomposes into MoO2 +1/2 H2O as evidenced by the fast reduction of Mo6+ into Mo5+ states and slow but simultaneous formation of Mo4+ states. We measure the decrease in oxygen/metal ratio in the thin film explaining the limited reversibility of hydrogen sensors based on transition metal oxides. The results also enlighten the recent debate on the mechanism of the high temperature hydrogen reduction of bulk molybdenum oxide. The specific mechanism is a result of the balance between the reduction by hydrogen and water formation, desorption of water as well as nucleation and growth of new phases. PMID- 28094320 TI - Improved motor performance in patients with acute stroke using the optimal individual attentional strategy. AB - It is believed that motor performance improves when individuals direct attention to movement outcome (external focus, EF) rather than to body movement itself (internal focus, IF). However, our previous study found that an optimal individual attentional strategy depended on motor imagery ability. We explored whether the individual motor imagery ability in stroke patients also affected the optimal attentional strategy for motor control. Individual motor imagery ability was determined as either kinesthetic- or visual-dominant by a questionnaire in 28 patients and 28 healthy-controls. Participants then performed a visuomotor task that required tracing a trajectory under three attentional conditions: no instruction (NI), attention to hand movement (IF), or attention to cursor movement (EF). Movement error in the stroke group strongly depended on individual modality dominance of motor imagery. Patients with kinesthetic dominance showed higher motor accuracy under the IF condition but with concomitantly lower velocity. Alternatively, patients with visual dominance showed improvements in both speed and accuracy under the EF condition. These results suggest that the optimal attentional strategy for improving motor accuracy in stroke rehabilitation differs according to the individual dominance of motor imagery. Our findings may contribute to the development of tailor-made pre-assessment and rehabilitation programs optimized for individual cognitive abilities. PMID- 28094319 TI - Helminth-induced Ly6Chi monocyte-derived alternatively activated macrophages suppress experimental autoimmune encephalomyelitis. AB - Helminths cause chronic infections and affect the immune response to unrelated inflammatory diseases. Although helminths have been used therapeutically to ameliorate inflammatory conditions, their anti-inflammatory properties are poorly understood. Alternatively activated macrophages (AAMphis) have been suggested as the anti-inflammatory effector cells during helminth infections. Here, we define the origin of AAMphis during infection with Taenia crassiceps, and their disease modulating activity on the Experimental Autoimmune Encephalomyelitis (EAE). Our data show two distinct populations of AAMphis, based on the expression of PD-L1 and PD-L2 molecules, resulting upon T. crassiceps infection. Adoptive transfer of Ly6C+ monocytes gave rise to PD-L1+/PD-L2+, but not PD-L1+/PD-L2- cells in T. crassiceps-infected mice, demonstrating that the PD-L1+/PD-L2+ subpopulation of AAMphis originates from blood monocytes. Furthermore, adoptive transfer of PD L1+/PD-L2+ AAMphis into EAE induced mice reduced disease incidence, delayed disease onset, and diminished the clinical disability, indicating the critical role of these cells in the regulation of autoimmune disorders. PMID- 28094321 TI - The reference frame of the tilt aftereffect measured by differential Pavlovian conditioning. AB - We used a differential Pavlovian conditioning paradigm to measure tilt aftereffect (TAE) strength. Gabor patches, rotated clockwise and anticlockwise, were used as conditioned stimuli (CSs), one of which (CS+) was followed by the unconditioned stimulus (UCS), whereas the other (CS-) appeared alone. The UCS was an air puff delivered to the left eye. In addition to the CS+ and CS-, the vertical test patch was also presented for the clockwise and anticlockwise adapters. The vertical patch was not followed by the UCS. After participants acquired differential conditioning, eyeblink conditioned responses (CRs) were observed for the vertical patch when it appeared to be tilted in the same direction as the CS+ owing to the TAE. The effect was observed not only when the adapter and test stimuli were presented in the same retinotopic position but also when they were presented in the same spatiotopic position, although spatiotopic TAE was weak-it occurred approximately half as often as the full effect. Furthermore, spatiotopic TAE decayed as the time after saccades increased, but did not decay as the time before saccades increased. These results suggest that the time before the performance of saccadic eye movements is needed to compute the spatiotopic representation. PMID- 28094322 TI - Rich structure in the correlation matrix spectra in non-equilibrium steady states. AB - It has been shown that, if a model displays long-range (power-law) spatial correlations, its equal-time correlation matrix will also have a power law tail in the distribution of its high-lying eigenvalues. The purpose of this paper is to show that the converse is generally incorrect: a power-law tail in the high lying eigenvalues of the correlation matrix may exist even in the absence of equal-time power law correlations in the initial model. We may therefore view the study of the eigenvalue distribution of the correlation matrix as a more powerful tool than the study of spatial Correlations, one which may in fact uncover structure, that would otherwise not be apparent. Specifically, we show that in the Totally Asymmetric Simple Exclusion Process, whereas there are no clearly visible correlations in the steady state, the eigenvalues of its correlation matrix exhibit a rich structure which we describe in detail. PMID- 28094323 TI - Gene set based association analyses for the WSSV resistance of Pacific white shrimp Litopenaeus vannamei. AB - White Spot Syndrome Virus (WSSV) is regarded as a virus with the strongest pathogenicity to shrimp. For the threshold trait such as disease resistance, marker assisted selection (MAS) was considered to be a more effective approach. In the present study, association analyses of single nucleotide polymorphisms (SNPs) located in a set of immune related genes were conducted to identify markers associated with WSSV resistance. SNPs were detected by bioinformatics analysis on RNA sequencing data generated by Illimina sequencing platform and Roche 454 sequencing technology. A total of 681 SNPs located in the exons of immune related genes were selected as candidate SNPs. Among these SNPs, 77 loci were genotyped in WSSV susceptible group and resistant group. Association analysis was performed based on logistic regression method under an additive and dominance model in GenABEL package. As a result, five SNPs showed associations with WSSV resistance at a significant level of 0.05. Besides, SNP-SNP interaction analysis was conducted. The combination of SNP loci in TRAF6, Cu/Zn SOD and nLvALF2 exhibited a significant effect on the WSSV resistance of shrimp. Gene expression analysis revealed that these SNPs might influence the expression of these immune-related genes. This study provides a useful method for performing MAS in shrimp. PMID- 28094325 TI - Measuring Orbital Angular Momentum (OAM) States of Vortex Beams with Annular Gratings. AB - Measuring orbital angular momentum (OAM) states of vortex beams is of great importance in diverse applications employing OAM-carrying vortex beams. We present a simple and efficient scheme to measure OAM states (i.e. topological charge values) of vortex beams with annular gratings. The magnitude of the topological charge value is determined by the number of dark fringes after diffraction, and the sign of the topological charge value is distinguished by the orientation of the diffraction pattern. We first theoretically study the diffraction patterns using both annular amplitude and phase gratings. The annular phase grating shows almost 10-dB better diffraction efficiency compared to the annular amplitude grating. We then experimentally demonstrate the OAM states measurement of vortex beams using annular phase grating. The scheme works well even for high-order vortex beams with topological charge value as high as +/- 25. We also experimentally show the evolution of diffraction patterns when slightly changing the fractional topological charge value of vortex beam from 0.1 to 1.0. In addition, the proposed scheme shows potential large tolerance of beam alignment during the OAM states measurement of vortex beams. PMID- 28094324 TI - Early-life adversity accelerates cellular ageing and affects adult inflammation: Experimental evidence from the European starling. AB - Early-life adversity is associated with accelerated cellular ageing during development and increased inflammation during adulthood. However, human studies can only establish correlation, not causation, and existing experimental animal approaches alter multiple components of early-life adversity simultaneously. We developed a novel hand-rearing paradigm in European starling nestlings (Sturnus vulgaris), in which we separately manipulated nutritional shortfall and begging effort for a period of 10 days. The experimental treatments accelerated erythrocyte telomere attrition and increased DNA damage measured in the juvenile period. For telomere attrition, amount of food and begging effort exerted additive effects. Only the combination of low food amount and high begging effort increased DNA damage. We then measured two markers of inflammation, high sensitivity C-reactive protein and interleukin-6, when the birds were adults. The experimental treatments affected both inflammatory markers, though the patterns were complex and different for each marker. The effect of the experimental treatments on adult interleukin-6 was partially mediated by increased juvenile DNA damage. Our results show that both nutritional input and begging effort in the nestling period affect cellular ageing and adult inflammation in the starling. However, the pattern of effects is different for different biomarkers measured at different time points. PMID- 28094326 TI - Remission of lymphoblastic leukaemia in an intravascular fluidic environment by pliable drug carrier with a sliding target ligand. AB - A polyrotaxane-based nanoconstruct with pliable structure carrying a chemotherapeutic drug was developed for targeting circulating lymphoblastic leukaemia cells in a fluidic environment of blood vessels in vivo. By introducing lymphoblast targeting aptamer DNA through cyclodextrin, threaded in poly(ethylene glycol) as polyrotaxane, target aptamer slides along the long polymeric chain and actively search for target ligand, leading to active targeting in dynamic fluidic system which is enhanced by up to 6-fold compared with that of control carriers with non-sliding targeting ligands. Moreover, the drug carrier was made stimuli responsive by employing i-motif DNA to selective releases of its payload at intracellular acidic condition. These combined features resulted in the effective remission of lymphoblastic leukaemia both in vitro and in dynamic blood vessels in vivo. PMID- 28094328 TI - Does a Strong El Nino Imply a Higher Predictability of Extreme Drought? AB - The devastating North China drought in the summer of 2015 was roughly captured by a dynamical seasonal climate forecast model with a good prediction of the 2015/16 big El Nino. This raises a question of whether strong El Ninos imply higher predictability of extreme droughts. Here we show that a strong El Nino does not necessarily result in an extreme drought, but it depends on whether the El Nino evolves synergistically with Eurasian spring snow cover reduction to trigger a positive summer Eurasian teleconnection (EU) pattern that favors anomalous northerly and air sinking over North China. The dynamical forecast model that only well represents the El Nino underpredicts the drought severity, while a dynamical-statistical forecasting approach that combines both the low- and high latitudes precursors is more skillful at long lead. In a warming future, the vanishing cryosphere should be better understood to improve predictability of extreme droughts. PMID- 28094327 TI - Rapid adaptation drives invasion of airway donor microbiota by Pseudomonas after lung transplantation. AB - In cystic fibrosis (CF) patients, chronic airway infection by Pseudomonas leads to progressive lung destruction ultimately requiring lung transplantation (LT). Following LT, CF-adapted Pseudomonas strains, potentially originating from the sinuses, may seed the allograft leading to infections and reduced allograft survival. We investigated whether CF-adapted Pseudomonas populations invade the donor microbiota and adapt to the non-CF allograft. We collected sequential Pseudomonas isolates and airway samples from a CF-lung transplant recipient during two years, and followed the dynamics of the microbiota and Pseudomonas populations. We show that Pseudomonas invaded the host microbiota within three days post-LT, in association with a reduction in richness and diversity. A dominant mucoid and hypermutator mutL lineage was replaced after 11 days by non mucoid strains. Despite antibiotic therapy, Pseudomonas dominated the allograft microbiota until day 95. We observed positive selection of pre-LT variants and the appearance of novel mutations. Phenotypic adaptation resulted in increased biofilm formation and swimming motility capacities. Pseudomonas was replaced after 95 days by a microbiota dominated by Actinobacillus. In conclusion, mucoid Pseudomonas adapted to the CF-lung remained able to invade the allograft. Selection of both pre-existing non-mucoid subpopulations and of novel phenotypic traits suggests rapid adaptation of Pseudomonas to the non-CF allograft. PMID- 28094331 TI - Prostate cancer: More metastases - incidence increased in the USA. PMID- 28094329 TI - Fumarase activity: an in vivo and in vitro biomarker for acute kidney injury. AB - Renal ischemia/reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), and at present, there is a lack of reliable biomarkers that can diagnose AKI and measure early progression because the commonly used methods cannot evaluate single-kidney IRI. Hyperpolarized [1,4-13C2]fumarate conversion to [1,4 13C2]malate by fumarase has been proposed as a measure of necrosis in rat tumor models and in chemically induced AKI rats. Here we show that the degradation of cell membranes in connection with necrosis leads to elevated fumarase activity in plasma and urine and secondly that hyperpolarized [1,4-13C2]malate production 24 h after reperfusion correlates with renal necrosis in a 40-min unilateral ischemic rat model. Fumarase activity screening on bio-fluids can detect injury severity, in bilateral as well as unilateral AKI models, differentiating moderate and severe AKI as well as short- and long-term AKI. Furthermore after verification of renal injury by bio-fluid analysis the precise injury location can be monitored by in vivo measurements of the fumarase activity non-invasively by hyperpolarized [1,4-13C]fumarate MR imaging. The combined in vitro and in vivo biomarker of AKI responds to the essential requirements for a new reliable biomarker of AKI. PMID- 28094332 TI - Bladder cancer: Genetic urinary biomarker panel is promising. PMID- 28094330 TI - Inhibition of Influenza A Virus Infection by Fucoidan Targeting Viral Neuraminidase and Cellular EGFR Pathway. AB - Development of novel anti-influenza A virus (IAV) drugs with high efficiency and low toxicity is critical for preparedness against influenza outbreaks. Herein, we investigated the anti-IAV activities and mechanisms of fucoidan in vitro and in vivo. The results showed that a fucoidan KW derived from brown algae Kjellmaniella crassifolia effectively blocked IAV infection in vitro with low toxicity. KW possessed broad anti-IAV spectrum and low tendency of induction of viral resistance, superior to the anti-IAV drug amantadine. KW was capable of inactivating virus particles before infection and blocked some stages after adsorption. KW could bind to viral neuraminidase (NA) and inhibit the activity of NA to block the release of IAV. KW also interfered with the activation of EGFR, PKCalpha, NF-kappaB, and Akt, and inhibited both IAV endocytosis and EGFR internalization in IAV-infected cells, suggesting that KW may also inhibit cellular EGFR pathway. Moreover, intranasal administration of KW markedly improved survival and decreased viral titers in IAV-infected mice. Therefore, fucoidan KW has the potential to be developed into a novel nasal drop or spray for prevention and treatment of influenza in the future. PMID- 28094333 TI - Penile cancer: Total glans resurfacing viable for all. PMID- 28094334 TI - Prostate cancer: The genomics of localized disease. PMID- 28094335 TI - Prostate cancer: An abiraterone ultraresponsive phenotype. PMID- 28094336 TI - Prevention: PFMT reduces the incidence of pelvic-organ-prolapse symptoms. PMID- 28094337 TI - Glatiramer acetate attenuates the activation of CD4+ T cells by modulating STAT1 and -3 signaling in glia. AB - Interactions between immune effector cells of the central nervous system appear to directly or indirectly influence the progress/regression of multiple sclerosis (MS). Here, we report that glial STAT1 and -3 are distinctively phosphorylated following the interaction of activated lymphocytes and glia, and this effect is significantly inhibited by glatiramer acetate (GA), a disease-modifying drug for MS. GA also reduces the activations of STAT1 and -3 by MS-associated stimuli such as IFNgamma or LPS in primary glia, but not neurons. Experiments in IFNgamma- and IFNgamma receptor-deficient mice revealed that GA-induced inhibitions of STAT signaling are independent of IFNgamma and its receptor. Interestingly, GA induces the expression levels of suppressor of cytokine signaling-1 and -3, representative negative regulators of STAT signaling in glia. We further found that GA attenuates the LPS-triggered enhancement of IL-2, a highly produced cytokine in patients with active MS, in CD4+ T cells co-cultured with glia, but not in CD4+ T cells alone. Collectively, these results provide that activation of glial STATs is an essential event in the interaction between glia and T cells, which is a possible underlying mechanism of GA action in MS. These findings provide an insight for the development of targeted therapies against MS. PMID- 28094340 TI - Lifetime prediction for organic coating under alternating hydrostatic pressure by artificial neural network. AB - A concept for prediction of organic coatings, based on the alternating hydrostatic pressure (AHP) accelerated tests, has been presented. An AHP accelerated test with different pressure values has been employed to evaluate coating degradation. And a back-propagation artificial neural network (BP-ANN) has been established to predict the service property and the service lifetime of coatings. The pressure value (P), immersion time (t) and service property (impedance modulus |Z|) are utilized as the parameters of the network. The average accuracies of the predicted service property and immersion time by the established network are 98.6% and 84.8%, respectively. The combination of accelerated test and prediction method by BP-ANN is promising to evaluate and predict coating property used in deep sea. PMID- 28094338 TI - Mitochondrial protein import - Functional analysis of the highly diverged Tom22 orthologue of Trypanosoma brucei. AB - The beta-barrel protein Tom40 and the alpha-helically anchored membrane protein Tom22 are the only universally conserved subunits of the protein translocase of the mitochondrial outer membrane (TOM). Tom22 has an N-terminal cytosolic and a C terminal intermembrane space domain. It occurs in two variants: one typified by the yeast protein which has a cytosolic domain containing a cluster of acidic residues, and a shorter variant typified by the plant protein that lacks this domain. Yeast-type Tom22 functions as a secondary protein import receptor and is also required for the stability of the TOM complex. Much less is known about the more widespread short variant of Tom22, which is also found in the parasitic protozoan Trypanosoma brucei. Here we show that the intermembrane space domain of trypanosomal Tom22 binds mitochondrial precursor proteins and that it is essential for normal growth and mitochondrial protein import. Moreover, complementation experiments indicate that the intermembrane space domain cannot be replaced by the corresponding regions of the yeast or plant Tom22 orthologues. Lack or replacement of the short cytosolic domain, however, does not interfere with protein function. Finally, we show that only the membrane-spanning domain of trypanosomal Tom22 is essential for assembly of the trypanosomal TOM complex analogue. PMID- 28094339 TI - Massive Effect on LncRNAs in Human Monocytes During Fungal and Bacterial Infections and in Response to Vitamins A and D. AB - Mycoses induced by C.albicans or A.fumigatus can cause important host damage either by deficient or exaggerated immune response. Regulation of chemokine and cytokine signaling plays a crucial role for an adequate inflammation, which can be modulated by vitamins A and D. Non-coding RNAs (ncRNAs) as transcription factors or cis-acting antisense RNAs are known to be involved in gene regulation. However, the processes during fungal infections and treatment with vitamins in terms of therapeutic impact are unknown. We show that in monocytes both vitamins regulate ncRNAs involved in amino acid metabolism and immune system processes using comprehensive RNA-Seq analyses. Compared to protein-coding genes, fungi and bacteria induced an expression change in relatively few ncRNAs, but with massive fold changes of up to 4000. We defined the landscape of long-ncRNAs (lncRNAs) in response to pathogens and observed variation in the isoforms composition for several lncRNA following infection and vitamin treatment. Most of the involved antisense RNAs are regulated and positively correlated with their sense protein coding genes. We investigated lncRNAs with stimulus specific immunomodulatory activity as potential marker genes: LINC00595, SBF2-AS1 (A.fumigatus) and RP11 588G21.2, RP11-394l13.1 (C.albicans) might be detectable in the early phase of infection and serve as therapeutic targets in the future. PMID- 28094341 TI - Ecological impact of a secondary bacterial symbiont on the clones of Sitobion avenae (Fabricius) (Hemiptera: Aphididae). AB - Many insects harbor heritable endosymbionts, whether obligatory or facultative, and the role of facultative endosymbionts in shaping the phenotype of these species has become increasingly important. However, little is known about whether micro-injected endosymbionts can have any effects on aphid clones, which was measured using various ecological parameters. We examined the effects between symbiotic treatments and the vital life history traits generated by Regiella insecticola on the life table parameters of Sitobion avenae. The results showed that R. insecticola can decrease the intrinsic rate of increase (r), the finite rate of increase (lambda) and birth rate and can increase the mean generation times (T) of S. avenae clones, suggesting that R. insecticola may decelerate the normal development of the hosts. No significant differences of these parameters were observed between the examined Sitobion avenae clones, and the symbiont treatment by genotype interaction affected only the net reproduction rate R0, pre adult duration and total longevity but not the other parameters. Additionally, a population projection showed that R. insecticola decelerated the growth of the S. avenae clones. The evocable effects of R. insecticola on the S. avenae clones may have significant ramifications for the control of S. avenae populations under field/natural conditions. PMID- 28094342 TI - Optimizing isothiocyanate formation during enzymatic glucosinolate breakdown by adjusting pH value, temperature and dilution in Brassica vegetables and Arabidopsis thaliana. AB - Consumption of glucosinolate-rich Brassicales vegetables is associated with a decreased risk of cancer with enzymatic hydrolysis of glucosinolates playing a key role. However, formation of health-promoting isothiocyanates is inhibited by the epithiospecifier protein in favour of nitriles and epithionitriles. Domestic processing conditions, such as changes in pH value, temperature or dilution, might also affect isothiocyanate formation. Therefore, the influences of these three factors were evaluated in accessions of Brassica rapa, Brassica oleracea, and Arabidopsis thaliana. Mathematical modelling was performed to determine optimal isothiocyanate formation conditions and to obtain knowledge on the kinetics of the reactions. At 22 degrees C and endogenous plant pH, nearly all investigated plants formed nitriles and epithionitriles instead of health promoting isothiocyanates. Response surface models, however, clearly demonstrated that upon change in pH to domestic acidic (pH 4) or basic pH values (pH 8), isothiocyanate formation considerably increases. While temperature also affects this process, the pH value has the greatest impact. Further, a kinetic model showed that isothiocyanate formation strongly increases due to dilution. Finally, the results show that isothiocyanate intake can be strongly increased by optimizing the conditions of preparation of Brassicales vegetables. PMID- 28094343 TI - T Oligo-Primed Polymerase Chain Reaction (TOP-PCR): A Robust Method for the Amplification of Minute DNA Fragments in Body Fluids. AB - Body fluid DNA sequencing is a powerful noninvasive approach for the diagnosis of genetic defects, infectious agents and diseases. The success relies on the quantity and quality of the DNA samples. However, numerous clinical samples are either at low quantity or of poor quality due to various reasons. To overcome these problems, we have developed T oligo-primed polymerase chain reaction (TOP PCR) for full-length nonselective amplification of minute quantity of DNA fragments. TOP-PCR adopts homogeneous "half adaptor" (HA), generated by annealing P oligo (carrying a phosphate group at the 5' end) and T oligo (carrying a T-tail at the 3' end), for efficient ligation to target DNA and subsequent PCR amplification primed by the T oligo alone. Using DNA samples from body fluids, we demonstrate that TOP-PCR recovers minute DNA fragments and maintains the DNA size profile, while enhancing the major molecular populations. Our results also showed that TOP-PCR is a superior method for detecting apoptosis and outperforms the method adopted by Illumina for DNA amplification. PMID- 28094344 TI - Estrogen related receptor is required for the testicular development and for the normal sperm axoneme/mitochondrial derivatives in Drosophila males. AB - Estrogen related receptors (ERRs), categorized as orphan nuclear receptors, are critical for energy homeostasis and somatic development. However, significance of ERRs in the development of reproductive organs/organelles/cells remain poorly understood, albeit their homology to estrogen receptors. In this context, here, we show that knockdown of ERR in the testes leads to improperly developed testes with mis-regulation of genes (aly, mia, bruce, bam, bgcn, fzo and eya) involved in spermatogenesis, resulting in reduced male fertility. The observed testicular deformity is consistent with the down-regulation of SOX-E group of gene (SOX100B) in Drosophila. We also show dispersion/disintegration of fusomes (microtubule based structures associated with endoplasmic reticulum derived vesicle, interconnecting spermatocytes) in ERR knockdown testes. A few ERR knockdown testes go through spermatogenesis but have significantly fewer sperm. Moreover, flagella of these sperm are defective with abnormal axoneme and severely reduced mitochondrial derivatives, suggesting a possible role for ERR in mitochondrial biogenesis, analogous to mammalian ERRalpha. Interestingly, similar knockdown of remaining seventeen nuclear receptors did not yield a detectable reproductive or developmental defect in Drosophila. These findings add newer dimensions to the functions envisaged for ERR and provide the foundation for deciphering the relevance of orphan nuclear receptors in ciliopathies and testicular dysgenesis. PMID- 28094345 TI - Bacterial plasmid-mediated quinolone resistance genes in aquatic environments in China. AB - Emerging antimicrobial resistance is a major threat to human's health in the 21st century. Understanding and combating this issue requires a full and unbiased assessment of the current status on the prevalence of antimicrobial resistance genes and their correlation with each other and bacterial groups. In aquatic environments that are known reservoirs for antimicrobial resistance genes, we were able to reach this goal on plasmid-mediated quinolone resistance (PMQR) genes that lead to resistance to quinolones and possibly also to the co-emergence of resistance to beta-lactams. Novel findings were made that qepA and aac-(6')-Ib genes that were previously regarded as similarly abundant with qnr genes are now dominant among PMQR genes in aquatic environments. Further statistical analysis suggested that the correlation between PMQR and beta-lactam resistance genes in the environment is still weak, that the correlations between antimicrobial resistance genes could be weakened by sufficient wastewater treatment, and that the prevalence of PMQR has been implicated in environmental, pathogenic, predatory, anaerobic, and more importantly, human symbiotic bacteria. This work provides a comprehensive analysis of PMQR genes in aquatic environments in Jinan, China, and provides information with which combat with the antimicrobial resistance problem may be fought. PMID- 28094346 TI - Development of interface-dominant bulk Cu/V nanolamellar composites by cross accumulative roll bonding. AB - Traditional nanostructured metals are inherently comprised of a high density of high-energy interfaces that make this class of materials not stable in extreme conditions. Therefore, high performance bulk nanostructured metals containing stable interfaces are highly desirable for extreme environments applications. Here, we reported an attractive bulk Cu/V nanolamellar composite that was successfully developed by integrating interface engineering and severe plastic deformation techniques. The layered morphology and ordered Cu/V interfaces remained stable with respect to continued rolling (total strain exceeding 12). Most importantly, for layer thickness of 25 nm, this bulk Cu/V nanocomposite simultaneously achieves high strength (hardness of 3.68 GPa) and outstanding thermal stability (up to 700 degrees C), which are quite difficult to realize simultaneously in traditional nanostructured materials. Such extraordinary property in our Cu/V nanocomposite is achieved via an extreme rolling process that creates extremely high density of stable Cu/V heterophase interfaces and low density of unstable grain boundaries. In addition, high temperature annealing result illustrates that Rayleigh instability is the dominant mechanism driving the onset of thermal instability after exposure to 800 degrees C. PMID- 28094347 TI - Endozoicomonas genomes reveal functional adaptation and plasticity in bacterial strains symbiotically associated with diverse marine hosts. AB - Endozoicomonas bacteria are globally distributed and often abundantly associated with diverse marine hosts including reef-building corals, yet their function remains unknown. In this study we generated novel Endozoicomonas genomes from single cells and metagenomes obtained directly from the corals Stylophora pistillata, Pocillopora verrucosa, and Acropora humilis. We then compared these culture-independent genomes to existing genomes of bacterial isolates acquired from a sponge, sea slug, and coral to examine the functional landscape of this enigmatic genus. Sequencing and analysis of single cells and metagenomes resulted in four novel genomes with 60-76% and 81-90% genome completeness, respectively. These data also confirmed that Endozoicomonas genomes are large and are not streamlined for an obligate endosymbiotic lifestyle, implying that they have free living stages. All genomes show an enrichment of genes associated with carbon sugar transport and utilization and protein secretion, potentially indicating that Endozoicomonas contribute to the cycling of carbohydrates and the provision of proteins to their respective hosts. Importantly, besides these commonalities, the genomes showed evidence for differential functional specificity and diversification, including genes for the production of amino acids. Given this metabolic diversity of Endozoicomonas we propose that different genotypes play disparate roles and have diversified in concert with their hosts. PMID- 28094348 TI - Weight of ABCB1 and POR genes on oral tacrolimus exposure in CYP3A5 nonexpressor pediatric patients with stable kidney transplant. AB - Tacrolimus (TAC) is highly effective for the prevention of acute organ rejection. However, its clinical use may be challenging due to its large interindividual pharmacokinetic variability, which can be partially explained by genetic variations in TAC-metabolizing enzymes and transporters. The aim of this study was to evaluate the influence of genetic and clinical factors on TAC pharmacokinetic variability in 21 stable pediatric renal transplant patients. This study was nested in a previous Prograf to Advagraf conversion clinical trial. CYP3A5, ABCB1 and two POR genotypes were assessed by real-time PCR. The impact on TAC pharmacokinetics of individual genetic variants on CYP3A5 nonexpressors was evaluated by genetic score. Explicative models for TAC AUC0 24h, Cmax and Cmin after Advagraf were developed by linear regression. The built genetic scores explain 13.7 and 26.5% of the total AUC0-24h and Cmin total variability, respectively. Patients genetic information should be considered to monitorizate and predict TAC exposure. PMID- 28094350 TI - Significantly enhanced creep resistance of low volume fraction in-situ TiBw/Ti6Al4V composites by architectured network reinforcements. AB - We present a new class of TiBw/Ti6Al4V composites with a network reinforcement architecture that exhibits a significant creep resistance compared to monolithic Ti6Al4V alloys. Creep tests performed at temperatures between 773 K and 923 K and stress range of 100 MPa-300 MPa indicate both a significant improvement of the composites creep resistance due to the network architecture made by the TiB whiskers (TiBw), and a decrease of the steady-state creep rates by augmenting the local volume fractions of TiBw in the network region. The deformation behavior is driven by a diffusion-controlled dislocation climb process. Moreover, the activation energies of these composites are significantly higher than that of Ti6Al4V alloys, indicating a higher creep resistance. The increase of the activation energy can be attributed to the TiBw architecture that severely impedes the movements of dislocation and grain boundary sliding and provides a tailoring of the stress transfer. These micromechanical mechanisms lead to a remarkable improvement of the creep resistance of these networked TiBw/Ti6Al4V composites featuring the special networked architecture. PMID- 28094349 TI - Proteomic and Carbonylation Profile Analysis at the Critical Node of Seed Ageing in Oryza sativa. AB - The critical node (CN), which is the transition from the plateau phase to the rapid decreasing phase of seed ageing, is extremely important for seed conservation. Although numerous studies have investigated the oxidative stress during seed ageing, information on the changes in protein abundance at the CN is limited. In this study, we aimed to investigate the abundance and carbonylation patterns of proteins at the CN of seed ageing in rice. The results showed that the germination rate of seeds decreased by less than 20% at the CN; however, the abundance of 112 proteins and the carbonylation levels of 68 proteins markedly changed, indicating oxidative damage. The abundance and activity of mitochondrial, glycolytic, and pentose phosphate pathway proteins were reduced; consequently, this negatively affected energy production and germination. Proteins related to defense, including antioxidant system and heat shock proteins, also reduced in abundance. Overall, energy metabolism was reduced at the CN, leading to a decrease in the antioxidant capacity, whereas seed storage proteins were up-regulated and carbonylated, indicating that the seed had a lower ability to utilize seed storage proteins for germination. Thus, the significant decrease in metabolic activities at the CN might accelerate the loss of seed viability. PMID- 28094351 TI - Nature, Nurture or Interacting Developmental Systems? Endophenotypes for learning systems bridge genes, language and development. PMID- 28094353 TI - Surfactant-free synthesis of three-dimensional nitrogen-doped hierarchically porous carbon and its application as an electrode modification material for simultaneous sensing of ascorbic acid, dopamine and uric acid. AB - Three-dimensional N-doped hierarchically porous carbon (3D NHPC) was synthesized successfully without using any surfactant or etching agent. This simple and effective synthesis method was accomplished by solvothermal synthesis followed by pyrolysis. The physical morphology and chemical composition of 3D NHPC were verified by scanning electron microscopy, nitrogen adsorption-desorption, and X ray photoelectron spectroscopy. Its structural studies reveal that it exhibits a micro-mesoporous hierarchical structure and contains C, O and N atoms forming different functional groups. The characterization also reveals that 3D NHPC has a Brunauer-Emmett-Teller (BET) surface area of 594.774 m2 g-1 and the micropore volume was calculated to be 0.192 cm3 g-1 using the t-plot method. Its catalytic activity was investigated by studying its application for simultaneous determination of ascorbic acid (AA), dopamine (DA) and uric acid (UA) by cyclic voltammetry and square-wave voltammetry at physiological pH. A 3D NHPC-modified glassy carbon electrode exhibits linear ranges from 0.05 to 14.50 MUM, 1.0 to 120.0 MUM, and 2.0 to 30.0 MUM for DA, AA and UA, respectively. It also exhibits low detection limits (0.02, 0.10, and 0.14 MUM for DA, AA, and UA, respectively), good reproducibility and stability. The urine sample analysis results show good recoveries ranging between 96.30% and 105.40%. PMID- 28094352 TI - Star-shaped copolymer grafted PEI and REDV as a gene carrier to improve migration of endothelial cells. AB - In this work, a biodegradable star-shaped copolymer poly(lactide-co-3(S)-methyl morpholine-2,5-dione)6 (Star-(PLMD)6) was synthesized via ring-opening polymerization (ROP), and subsequently a gene carrier Star-PLMD-g-PEI-g-PEG CREDVW was prepared by grafting polyethyleneimine (PEI), polyethylene glycol (PEG) and targeting peptide REDV onto Star-(PLMD)6. This gene carrier could form stable micelles to condense pEGFP-ZNF580 through electrostatic interaction. The resulting complexes were biocompatible and showed high efficiency in gene delivery. In addition, these complexes exhibited high selectivity for endothelial cells (ECs), high transfection efficiency and enhanced migration of ECs. The protein level of ZNF580 expression was significantly high (up to 85%), while the control group was only 51%. This combination of degradability, targeting ligand and star-structure strategy exhibits a significant advantage in transfection efficiency and migration of ECs. PMID- 28094354 TI - Accelerated room-temperature crystallization of ultrahigh-surface-area porous anatase titania by storing photogenerated electrons. AB - Room-temperature crystallization, a mild and energy-efficient process, shows important application potentials for developing functional materials. We significantly accelerated the crystallization of amorphous TiO2 at room temperature by storing photogenerated electrons and the resulting porous anatase titania exhibits ultrahigh surface areas up to 736 m2 g-1. PMID- 28094355 TI - Biopolymer-chitosan based supramolecular hydrogels as solid state electrolytes for electrochemical energy storage. AB - A biopolymer-chitosan based Supramolecular Hydrogel type solid state Electrolyte (SHE) is prepared via a simple and fast cross-linking between chitosan and Li+/Ag+. The obtained SHE itself shows high thermal stability and excellent flexible and mouldable properties. When integrated in an asymmetric supercapacitor with MnO2 as the positive electrode and active carbon as the negative electrode, it can survive more than 10 000 cycles with the areal capacity of 10 mF cm-2 at the 1.8 mA cm-2 current density. PMID- 28094356 TI - Morphology transition in helical tubules of a supramolecular gel driven by metal ions. AB - Our aim to access a particular chemical functionality on helical tubules has been achieved by the rational molecular design and synthesis of glucono-appended cardanol derivatives. For the first time, we report a chiral molecular packing with alpha-helical tubules, and chiral symmetry-breaking upon exposure to Cu2+ that generated the final ordered structure via an in situ morphological transition without undergoing any phase change. PMID- 28094357 TI - Kinetic analysis of non-isothermal solid-state reactions: multi-stage modeling without assumptions in the reaction mechanism. AB - A novel non-linear regression method for modeling non-isothermal thermogravimetric data is proposed. Experiments for several heating rates are analyzed simultaneously. The method is applicable to complex multi-stage processes when the number of stages is unknown. Prior knowledge of the type of kinetics is not required. The main idea is a consequent estimation of parameters when the overall model is successively changed from one level of modeling to another. At the first level, the Avrami-Erofeev functions are used. At the second level, the Sestak-Berggren functions are employed with the goal to broaden the overall model. The method is tested using both simulated and real-world data. A comparison of the proposed method with a recently published 'model-free' deconvolution method is presented. PMID- 28094358 TI - Ascorbate as a pro-oxidant: mild N-terminal modification with vinylboronic acids. AB - We describe divergent reactivity of vinylboronic acids for protein modification. In addition to previously reported copper-catalyzed backbone N-H modification, ascorbate in air mediates N-terminal functionalization with the same vinylboronate reagents. This mild and selective aqueous reactivity enables selective single-modification of the B chain of human insulin. PMID- 28094359 TI - Fused multifunctionalized dibenzoselenophenes from tetraynes. AB - The facile synthesis of fused multifunctionalized dibenzoselenophenes by a one pot-three-step cascade hexadehydro-Diels-Alder reaction of tetraynes is reported. The overall transformation involves the formation of four new C-C bonds and one new Caryl-Se bond and C-H activation via both intramolecular cyclization and intermolecular free radical reactions. PMID- 28094360 TI - Impact of morphology on polaron delocalization in a semicrystalline conjugated polymer. AB - We investigate the delocalization of holes in the semicrystalline conjugated polymer poly(2,5-bis(3-alkylthiophene-2-yl)thieno[3,2-b]thiophene) (PBTTT) by directly measuring the hyperfine coupling between photogenerated polarons and bound nuclear spins using electron nuclear double resonance spectroscopy. An extrapolation of the corresponding oligomer spectra reveals that charges tend to delocalize over 4.0-4.8 nm with delocalization strongly dependent on molecular order and crystallinity of the PBTTT polymer thin films. Density functional theory calculations of hyperfine couplings confirm that long-range corrected functionals appropriately describe the change in coupling strength with increasing oligomer size and agree well with the experimentally measured polymer limit. Our discussion presents general guidelines illustrating the various pitfalls and opportunities when deducing polaron localization lengths from hyperfine coupling spectra of conjugated polymers. PMID- 28094361 TI - Two different critical regimes enclosed in the Bean-Rodbell model and their implications for the field dependence and universal scaling of the magnetocaloric effect. AB - In the last few years power laws and universal scaling have been extensively used to study the field dependence of the magnitudes involved in the magnetocaloric effect of materials. They are key tools which allow us to compare the performing properties of different materials regardless of their nature, processing or experimental conditions during measurements. It was proved that power laws and universal scaling are a direct consequence of critical phenomena in the neighborhood of phase transitions. However, there remains some controversy about the reliability of these procedures. In this work we use the well-known Bean Rodbell model to confirm that these features are unmistakably related to the critical behavior of the continuous phase transitions. In this specific model, universal scaling occurs either at a purely mean field second order transition or at a tricritical point. Finally, we analyze in detail if the universal scaling is compatible with materials at the tricitical point, making a comprehensive comparison with available experimental data from the literature. We conclude that it is really difficult to know with full certainty if a sample really is in the tricritical regime. PMID- 28094362 TI - The crucial role of Mn spiral spin order in stabilizing the Dy-Mn exchange striction in multiferroic DyMnO3. AB - DyMnO3 hosts the less addressed duality of multiferroicity, owing to the Dy-Mn exchange striction and inverse Dzyaloshinskii-Moriya interaction between Mn spin pairs. Although the duality in DyMnO3 has been discussed earlier, there remains a question whether the Mn magnetic sublattice is necessarily multiferroic for generating the Dy-Mn exchange striction. In this work, we investigate the multiferroicity of Dy(Mn1-xFex)O3 (0 <= x <= 0.1) through detailed magnetic and ferroelectric characterization. It is found that Fe-doping continuously suppresses the independent Dy spin order but instead promotes the Dy-Mn(Fe) coupling. This coupling benefits the Dy-Mn(Fe) exchange striction which remarkably enhances the ferroelectric polarization at a low doping level (x <= 0.015), beyond which the Mn spiral spin order breaks down leading to collapse of the macroscopic polarization at x >= 0.05. This work discloses the crucial role of Mn spiral spin order in stabilizing the Dy-Mn exchange striction and thus highlights the duality of multiferroicity in DyMnO3. PMID- 28094363 TI - Photoassist-phosphorylated TiO2 as a catalyst for direct formation of 5 (hydroxymethyl)furfural from glucose. AB - Photo-assisted phosphorylation of an anatase TiO2 catalyst was examined to improve its catalytic performance for the direct production of 5 (hydroxymethyl)furfural (HMF), a versatile chemical platform, from glucose. In phosphorylation based on simple esterification between phosphoric acid and surface OH groups on anatase TiO2 with water-tolerant Lewis acid sites, the density of phosphates immobilized on TiO2 is limited to 2 phosphates nm-2, which limits selective HMF production. Phosphorylation of the TiO2 surface under fluorescent light irradiation increases the surface phosphate density to 50%, which is higher than the conventional limit, thus preventing the adsorption of hydrophilic glucose molecules on TiO2 and resulting in a more selective HMF production over photoassist-phosphorylated TiO2. PMID- 28094364 TI - Effect of electron spectral diffusion on static dynamic nuclear polarization at 7 Tesla. AB - Here, we present an integrated experimental and theoretical study of 1H dynamic nuclear polarization (DNP) of a frozen aqueous glass containing free radicals at 7 T, under static conditions and at temperatures ranging between 4 and 20 K. The DNP studies were performed with a home-built 200 GHz quasi-optics microwave bridge, powered by a tunable solid-state diode source. DNP using monochromatic and continuous wave (cw) irradiation applied to the electron paramagnetic resonance (EPR) spectrum of the radicals induces the transfer of polarization from the electron spins to the surrounding nuclei of the solvent and solutes in the frozen aqueous glass. In our systematic experimental study, the DNP enhanced 1H signals are monitored as a function of microwave frequency, microwave power, radical concentration, and temperature, and are interpreted with the help of electron spin-lattice relaxation times, experimental MW irradiation parameters, and the electron spectral diffusion (eSD) model introduced previously. This comprehensive experimental DNP study with mono-nitroxide radical spin probes was accompanied with theoretical calculations. Our results consistently demonstrate that eSD effects can be significant at 7 T under static DNP conditions, and can be systematically modulated by experimental conditions. PMID- 28094365 TI - Adsorbing the 3d-transition metal atoms to effectively modulate the electronic and magnetic behaviors of zigzag SiC nanoribbons. AB - On the basis of first-principles computations, we propose a simple and effective strategy through surface-adsorbing 3d-transition metal (TM) atoms, including Ti, Cr, Mn, Fe and Co, to modulate the electronic and magnetic behaviors of zigzag SiC nanoribbons (zSiCNRs), in view of the unique d electronic structures and intrinsic magnetic moments of TM atoms. It is revealed that like applying an electric field, the adsorption of these transition metal atoms can induce an evident change in the electrostatic potential of the substrate zSiCNRs owing to the electron transfer from the TM atom to the substrate. This can break the magnetic degeneracy of zSiCNRs and solely ferromagnetic (FM) or antiferromagnetic (AFM) metallicity and even intriguing FM or AFM half-metallicity can be observed in the TM-modified zSiCNR systems. Moreover, all these modified systems can exhibit considerably large adsorption energies ranging from -0.872 eV to -4.304 eV, indicating their considerably high structural stabilities. These intriguing findings will be advantageous for promoting excellent SiC-based nanomaterials in the practical application of spintronics and multifunctional nanodevices in the near future. PMID- 28094366 TI - Band gap opening in stanene induced by patterned B-N doping. AB - Stanene is a quantum spin Hall insulator and a promising material for electronic and optoelectronic devices. Density functional theory (DFT) calculations are performed to study the band gap opening in stanene by elemental mono-doping (B, N) and co-doping (B-N). Different patterned B-N co-doping is studied to change the electronic properties of stanene. A patterned B-N co-doping opens the band gap in stanene and its semiconducting nature persists under strain. Molecular dynamics (MD) simulations are performed to confirm the thermal stability of such a doped system. The stress-strain study indicates that such a doped system is as stable as pure stanene. Our work function calculations show that stanene and doped stanene have a lower work function than graphene and thus are promising materials for photocatalysts and electronic devices. PMID- 28094367 TI - Formation of carbon nanodots with different spin states in mechanically processed mixtures of ZnO with carbon nanoparticles: an electron paramagnetic resonance study. AB - Mixtures of zinc oxide with carbon nanoparticles, ZnO + xC (x = 0.1%, 1% and 3% by weight), were subjected to mechanical processing (MP) in a hermetically sealed grinding chamber. Using electron paramagnetic resonance (EPR) spectroscopy, we monitored the evolution of spin centers in CNPs. While the initial CNPs were EPR silent, their short-duration MP (tMP) gave rise to emergence of low-intensity carbon signal. Increasing the sample temperature at tMP > 9 min induced CNP oxidation, which lead to a dramatic increase in the intensity of C signal. The oxidation process also manifested itself in the appearance of a photoluminescence (PL) band at ~2.8 eV, which is characteristic for carbon nanodots with an average size of ~2.7 nm. A limited amount of oxygen in the grinding chamber lead to different ways of carbon nanodot oxidation, depending on carbon content in the samples, which in turn influenced the characteristics of C EPR signals observed. The number of spins calculated per one CNP (NSOP) was found to depend on carbon content in ZnO + xC samples. Based on a detailed analysis of EPR spectral lines, we suggest the existence of a broad variety of relaxation mechanisms for forming C paramagnetic centers. PMID- 28094368 TI - Tris(S,S-dioxide)-trithiasumanene: strong fluorescence and cocrystal with 1,2,6,7,10,11-hexabutoxytriphenylene. AB - Thiophene rings in trithiasumanene (1) are oxidized regioselectively to form tris(S,S-dioxide)-trithiasumanene (3). Compound 3 displays strong indigo fluorescence in both solution and the solid state, and forms a 1 : 1 cocrystal with HBT to give a yellow emission in crystalline form. PMID- 28094369 TI - Probing the electronic structures of Con (n = 1-5) clusters on gamma-Al2O3 surfaces using first-principles calculations. AB - The electronic structure of the oxide-supported nanoclusters based on metal support interactions including charge and spin reorganization plays a crucial role in the catalytic activity at the interface region. In this work, by using density functional theory periodic calculations, we theoretically investigated the stability, nucleation and electronic properties of cobalt clusters Con (n = 1 5) supported on gamma-Al2O3 surfaces including dehydrated (100) and hydrated (110) surfaces. In Con/gamma-Al2O3(100) (n = 1-5) and Con/gamma-Al2O3(110) (n = 1 and 2), the Con clusters prefer to adsorb on the surface. However, for Con/gamma Al2O3(110) (n = 3-5), the Con clusters bind to surface hydroxyl groups directly. Our results revealed that due to the metal-support interaction, small Co clusters strongly adsorb onto the surfaces. Nucleation energy disclosed that the critical cluster sizes are 4 and 3 for the dehydrated (100) and hydrated (110) surfaces, respectively, suggesting that the presence of gamma-Al2O3 surfaces remarkably affects and even prevents the sintering process of small Co clusters. More importantly, the charge analysis showed that both metal cluster and support play important roles in the charge state of clusters. PMID- 28094370 TI - Probing sub-nano level molecular packing and correlated positron annihilation characteristics of ionic cross-linked chitosan membranes using positron annihilation spectroscopy. AB - Chitosan, CS, cross-linked with bivalent palladium has shown enhanced mechanical and thermal properties depending on the transformation of the structure at a microscopic scale. In the present study, CS directly cross-linked by palladium cation membranes (CS-cr-PM) was prepared through a solution-casting method. Mobility of chitosan chains were greatly reduced after crosslinking, making a great reduction in the swelling ratio studied by a water-swelling degree measurement, which led to an improvement in molecular chain rigidity. In order to investigate the chain packing at the molecular level in the ionic cross-linked CS system, the structure of chemically-crosslinked CS is investigated by means of the combined use of wide angle X-ray diffraction (WAXD) and infrared measurements, and a combination of positron annihilation lifetime spectroscopy (PALS) and simultaneous coincidence Doppler broadening (CDB) spectroscopy offers coherent information on both the free-volume related sub-nano level molecular packing and the chemical surrounding of free volume nanoholes in CS-cr-PM as a function of palladium salt loading. The variations in the free volume size and size distribution have been determined through the ortho-positronium (o-Ps) lifetime and its lifetime distribution. The studies showed that a strong interaction between CS molecules and palladium cations results in the change in crystallinity in formed CS-cr-PM leading to variational chain packing density. Meanwhile, significant inhibition effects on positronium formation due to doping are observed, which could be interpreted in terms of the existence of chloride ions. Applications of positron annihilation spectroscopy to study the microstructure and correlated positron annihilation characteristics of an ionic cross-linked CS system are systematically discussed. PMID- 28094371 TI - Polarization independence of laser-induced nucleation in supersaturated aqueous urea solutions. AB - In a seminal report on laser-induced nucleation in aqueous supersaturated solutions (Phys. Rev. Lett., 1996, 77, 3475) it was noted that needle-shaped crystals of urea were aligned with the direction of the electric field of the linearly polarized laser pulse. The results gave rise to a new mechanism for control of crystal nucleation involving alignment of solute molecules (optical Kerr effect) now commonly known as non-photochemical laser-induced nucleation (NPLIN). Recent theoretical and experimental work has cast doubts on the optical Kerr effect mechanism. In the present letter we present results from digital imaging of urea-crystal growth immediately following laser-induced nucleation. Analysis of the data shows no statistically significant correlation between crystal angle and direction of linear polarization. The results overturn a long held result that has shaped theoretical and experimental studies of NPLIN. PMID- 28094372 TI - Theoretical studies on FGFR isoform selectivity of FGFR1/FGFR4 inhibitors by molecular dynamics simulations and free energy calculations. AB - The activation and overexpression of fibroblast growth factor receptors (FGFRs) are highly correlated with a variety of cancers. Most small molecule inhibitors of FGFRs selectively target FGFR1-3, but not FGFR4. Hence, designing highly selective inhibitors towards FGFR4 remains a great challenge because FGFR4 and FGFR1 have a high sequence identity. Recently, two small molecule inhibitors of FGFRs, ponatinib and AZD4547, have attracted huge attention. Ponatinib, a type II inhibitor, has high affinity towards FGFR1/4 isoforms, but AZD4547, a type I inhibitor of FGFR1, displays much reduced inhibition toward FGFR4. In this study, conventional molecular dynamics (MD) simulations, molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculations and umbrella sampling (US) simulations were carried out to reveal the principle of the binding preference of ponatinib and AZD4547 towards FGFR4/FGFR1. The results provided by MM/GBSA illustrate that ponatinib has similar binding affinities to FGFR4 and FGFR1, while AZD4547 has much stronger binding affinity to FGFR1 than to FGFR4. A comparison of the individual energy terms suggests that the selectivity of AZD4547 towards FGFR1 versus FGFR4 is primarily controlled by the variation of the van der Waals interactions. The US simulations reveal that the PMF profile of FGFR1/AZD4547 has more peaks and valleys compared with that of FGFR4/AZD4547, suggesting that the dissociation process of AZD4547 from FGFR1 are easily trapped into local minima. Moreover, it is observed that FGFR1/AZD4547 has much higher PMF depth than FGFR4/AZD4547, implying that it is more difficult for AZD4547 to escape from FGFR1 than from FGFR4. The physical principles provided by this study extend our understanding of the binding mechanisms and provide valuable guidance for the rational design of FGFR isoform selective inhibitors. PMID- 28094373 TI - Conformational dynamics and self-association of intrinsically disordered Huntingtin exon 1 in cells. AB - Huntington's disease is caused by a CAG trinucleotide expansion mutation in the Huntingtin gene that leads to an artificially long polyglutamine sequence in the Huntingtin protein. A key feature of the disease is the intracellular aggregation of the Huntingtin exon 1 protein (Httex1) into micrometer sized inclusion bodies. The aggregation process of Httex1 has been extensively studied in vitro, however, the crucial early events of nucleation and aggregation in the cell remain elusive. Here, we studied the conformational dynamics and self-association of Httex1 by in-cell experiments using laser-induced temperature jumps and analytical ultracentrifugation. Both short and long polyglutamine variants of Httex1 underwent an apparent temperature-induced conformational collapse. The temperature jumps generated a population of kinetically trapped species selectively for the longer polyglutamine variants of Httex1 proteins. Their occurrence correlated with the formation of inclusion bodies suggesting that such species trigger further self-association. PMID- 28094374 TI - Combined in- and ex situ studies of pyrazine adsorption into the aliphatic MOF Al CAU-13: structures, dynamics and correlations. AB - The intercalation of different pyrazines (pyrazine, methylpyrazine, 2,5 dimethylpyrazine, 2,3-dimethylpyrazine, trimethylpyrazine and tetramethylpyrazine) into the trans-1,4-cyclohexanedicarboxylate (CDC2-) based Al MOF [Al(OH)(CDC)], denoted as CAU-13, was investigated. The adsorption of the guest molecules into the flexible MOF was carried out from an aqueous solution or via vapour phase adsorption, starting with the hydrated narrow-pore form of the framework [Al(OH)(O2C-C6H10-CO2)].H2O (CAU-13-np). The obtained host-guest systems were characterised by thermogravimetry and vibrational spectroscopy and their crystal structures were elucidated using powder X-ray diffraction (PXRD) data. The crystal structures indicate that guest molecules forming hydrogen-bonds with the host framework (pyrazine, methylpyrazine and 2,5-dimethylpyrazine) induce a slight opening of the channels, resulting in a semi-open framework conformation (CAU-13-so). For the bulkier guests 2,3-dimethylpyrazine, trimethylpyrazine and tetramethylpyrazine, only van der Waals interactions can be observed between the host and the guest molecules and a large pore conformation is observed (CAU-13-lp). We carried out in situ PXRD studies using synchrotron radiation during the adsorption of the respective guest molecules from aqueous solutions with various concentrations and at different temperatures. In general, stronger host-guest interactions required milder adsorption conditions while harsher conditions nevertheless accelerated the conversion. The kinetic parameters for the intercalation of pyrazine indicate that the rate limiting step differs, depending on the intercalation temperature. PMID- 28094375 TI - Crystallization kinetics of cerium oxide nanoparticles formed by spontaneous, room-temperature hydrolysis of cerium(iv) ammonium nitrate in light and heavy water. AB - A stable sol of cerium oxide nanoparticles forms spontaneously when cerium(iv) ammonium nitrate (CAN) is dissolved in room-temperature water at mM concentrations. Electron microscopy experiments reveal the formation of highly crystalline cerium oxide particles several nm in diameter and suggest that they are formed from amorphous particles that are similar in size. Under the low pH conditions of the experiments, the nanoparticles form a stable dispersion and show no evidence of aggregation, even many months after synthesis. The absence of particles large enough to scatter light significantly makes it possible to observe the crystallization kinetics through dramatic changes in the UV-visible absorption spectra that occur during solution aging. Measurements show that the cerium oxide nanocrystals are formed roughly an order of magnitude more slowly in D2O than in H2O solution. This large solvent kinetic isotope effect (kH/kD ~ 10), which is reported here for the first time for the crystallization of a solid metal oxide phase, indicates a rate-determining proton transfer reaction, which is assigned to the conversion of hydroxy to oxo bridges. In D2O solution, the absorption per mole of cerium ions increases by over 400% at 290 nm as the weakly absorbing precursor phase is transformed into nanocrystalline cerium oxide. An isosbestic point is detected at 368 nm, and the absorption spectra can be modeled throughout aging by the sum of spectra of just two interconverting species. Preliminary ultrafast transient absorption experiments confirm that the optical properties of the amorphous precursors differ greatly from those of the final, nanocrystalline phase. Crystallization of CeO2 from CAN in water has much in common with the crystallization of iron oxides from iron(iii) salts, including the importance of non-classical nucleation and growth pathways. It is an outstanding system for studying the poorly understood events that cause molecularly solvated ions to self-assemble into nanocrystals, following hydrolysis. At the same time, the strong susceptibility of CAN to spontaneously form CeO2 nanocrystals under the mildest of reaction conditions indicates that caution is needed when working with this common sacrificial oxidant. PMID- 28094376 TI - Cyclopentadithiophene organic core in small molecule organic solar cells: morphological control of carrier recombination. AB - Two new planar and symmetrical A-D-A (electron acceptor-electron donor-electron acceptor) small molecules based on a commercial cyclopentadithiophene derivative have been synthesized for solution processed small molecule organic solar cells. The aim was to synthesise the molecules to be energetically identical (similar HOMO-LUMO energy levels) in order to assign the differences observed to changes in the film morphology or to differences in the interfacial recombination kinetics or both. Devices were electrically characterized under one sun simulated (1.5 AM G) conditions by determining current-voltage curves, light harvesting efficiencies and external quantum efficiencies. Moreover, time-resolved photo induced techniques such as photo-induced charge extraction and photo-induced transient photo-voltage were also performed. The results demonstrate that, despite having the same core, i.e. cyclopentadithiophene, the use of one hexyl chain instead of two in the organic molecule leads to a greater control of the molecular ordering using solvent vapour annealing techniques and also to better solar cell efficiency. PMID- 28094377 TI - Mechanistic insights into heterogeneous methane activation. AB - While natural gas is an abundant chemical fuel, its low volumetric energy density has prompted a search for catalysts able to transform methane into more useful chemicals. This search has often been aided through the use of transition state (TS) scaling relationships, which estimate methane activation TS energies as a linear function of a more easily calculated descriptor, such as final state energy, thus avoiding tedious TS energy calculations. It has been shown that methane can be activated via a radical or surface-stabilized pathway, both of which possess a unique TS scaling relationship. Herein, we present a simple model to aid in the prediction of methane activation barriers on heterogeneous catalysts. Analogous to the universal radical TS scaling relationship introduced in a previous publication, we show that a universal TS scaling relationship that transcends catalysts classes also seems to exist for surface-stabilized methane activation if the relevant final state energy is used. We demonstrate that this scaling relationship holds for several reducible and irreducible oxides, promoted metals, and sulfides. By combining the universal scaling relationships for both radical and surface-stabilized methane activation pathways, we show that catalyst reactivity must be considered in addition to catalyst geometry to obtain an accurate estimation for the TS energy. This model can yield fast and accurate predictions of methane activation barriers on a wide range of catalysts, thus accelerating the discovery of more active catalysts for methane conversion. PMID- 28094379 TI - Luminescent aryl-group eleven metal complexes. AB - Among the coinage metal complexes displaying luminescent properties, those bearing C-donor aryl ligands have an increasing part in the chemistry of these metals. These types of ligands confer a high kinetic and thermodynamic stability on the complexes, but they can also be involved in the photoluminescent behaviour of the complexes. The development of new aryl-containing complexes of group eleven metals, the study of their photoluminescent properties and their related properties and applications are discussed in this perspective. Among these, luminescent gold(i) and gold(iii) compounds are being intensively used for the development of new properties with potential applications such as, for instance, electroluminescence, triboluminescence, mechanochromism, aggregated induced emissions, quenching, luminescent liquid crystals, low molecular weight gelators and photocatalysts, among others. PMID- 28094378 TI - Synthesis and SMM behaviour of trinuclear versus dinuclear 3d-5f uranyl(v) cobalt(ii) cation-cation complexes. AB - Trinuclear versus dinuclear heterodimetallic UVO2+Co2+ complexes were selectively assembled via a cation-cation interaction by tuning the ligand. The trimeric complex 2, with a linear [Co-O[double bond, length as m-dash]U[double bond, length as m-dash]O-Co] core, exhibits magnetic exchange and slow relaxation with a reversal barrier of 30.5 +/- 0.9 K providing the first example of a U-Co exchange-coupled SMM. PMID- 28094380 TI - Crystallization and flow in active patch systems. AB - Based upon recent experiments in which Janus particles are made into active swimmers by illuminating them with laser light, we explore the effect of applying a light pattern on the sample, thereby creating activity inducing zones or active patches. We simulate a system of interacting Brownian diffusers that become active swimmers when moving inside an active patch and analyze the structure and dynamics of the ensuing stationary state. We find that, in some respects, the effect of spatially inhomogeneous activity is qualitatively similar to a temperature gradient. For asymmetric patches, however, this analogy breaks down because the ensuing stationary state is specific to partial active motion. PMID- 28094381 TI - Order of magnitude improvement of nano-contact spin torque nano-oscillator performance. AB - Spin torque nano-oscillators (STNO) represent a unique class of nano-scale microwave signal generators and offer a combination of intriguing properties, such as nano sized footprint, ultrafast modulation rates, and highly tunable microwave frequencies from 100 MHz to close to 100 GHz. However, their low output power and relatively high threshold current still limit their applicability and must be improved. In this study, we investigate the influence of the bottom Cu electrode thickness (tCu) in nano-contact STNOs based on Co/Cu/NiFe GMR stacks and with nano-contact diameters ranging from 60 to 500 nm. Increasing tCu from 10 to 70 nm results in a 40% reduction of the threshold current, an order of magnitude higher microwave output power, and close to two orders of magnitude better power conversion efficiency. Numerical simulations of the current distribution suggest that these dramatic improvements originate from a strongly reduced lateral current spread in the magneto-dynamically active region. PMID- 28094382 TI - The supercoiling state of DNA determines the handedness of both H3 and CENP-A nucleosomes. AB - Nucleosomes form the unit structure of the genome in eukaryotes, thereby constituting a fundamental tenet of chromatin biology. In canonical nucleosomes, DNA wraps around the histone octamer in a left-handed toroidal ramp. Here, in single-molecule magnetic tweezers studies of chaperone-assisted nucleosome assembly, we show that the handedness of the DNA wrapping around the nucleosome core is intrinsically ambidextrous, and depends on the pre-assembly supercoiling state of the DNA, i.e., it is not uniquely determined by the octameric histone core. Nucleosomes assembled onto negatively supercoiled DNA are found to exhibit a left-handed conformation, whereas assembly onto positively supercoiled DNA results in right-handed nucleosomes. This intrinsic flexibility to adopt both chiralities is observed both for canonical H3 nucleosomes, and for centromere specific variant CENP-A nucleosomes. These data support recent advances suggesting an intrinsic adaptability of the nucleosome, and provide insights into how nucleosomes might rapidly re-assemble after cellular processes that generate positive supercoiling in vivo. PMID- 28094384 TI - Foundation of correlation ellipsometry. AB - An experimental strategy for the detection of fluctuation dynamics at interfaces based on a combination of photon correlation spectroscopy (PCS) with a nulling ellipsometry scheme is investigated theoretically. The intensity description of ellipsometry measurements is generalized to PCS time correlation functions. The nulling ellipsometry procedure is applied for every lag time t of the correlation functions, to extract the dynamics connected to the coherent signal which contains the interface dynamics. The classical ellipsometry parameters Delta and tanPsi are generalized to functions and tan [capital Psi, Greek, tilde]Q(t). A suitable Siegert relation is derived and employed to show that either field correlation functions or intensity correlation functions after baseline subtraction can be used as the starting point for the nulling ellipsometry procedure. PMID- 28094385 TI - Towards an all-in fiber photodetector by directly bonding few-layer molybdenum disulfide to a fiber facet. AB - Although photodetectors based on two dimensional (2D) materials have been intensively studied, there are few reports of optical fiber compatible devices. Herein we successfully fabricated an all-in fiber photodetector (FPD) based on an end-face bonded with few-layer molybdenum disulfide (MoS2). Our FPD has a considerably high photo-responsivity of ~0.6 A W-1 at a bias voltage of 4 V and 0.01 A W-1 under the bias-free conditions. We believe that the proposed platform may provide a new strategy for the integration of 2D materials in fibers and realization of optoelectronic and sensing applications. PMID- 28094390 TI - Simultaneous measurement of the Young's modulus and the Poisson ratio of thin elastic layers. AB - The behavior of cells and tissue is greatly influenced by the mechanical properties of their environment. For studies on the interactions between cells and soft matrices, especially those applying traction force microscopy the characterization of the mechanical properties of thin substrate layers is essential. Various techniques to measure the elastic modulus are available. Methods to accurately measure the Poisson ratio of such substrates are rare and often imply either a combination of multiple techniques or additional equipment which is not needed for the actual biological studies. Here we describe a novel technique to measure both parameters, the Youngs's modulus and the Poisson ratio in a single experiment. The technique requires only a standard inverted epifluorescence microscope. As a model system, we chose cross-linked polyacrylamide and poly-N-isopropylacrylamide hydrogels which are known to obey Hooke's law. We place millimeter-sized steel spheres on the substrates which indent the surface. The data are evaluated using a previously published model which takes finite thickness effects of the substrate layer into account. We demonstrate experimentally for the first time that the application of the model allows the simultaneous determination of both the Young's modulus and the Poisson ratio. Since the method is easy to adapt and comes without the need of special equipment, we envision the technique to become a standard tool for the characterization of substrates for a wide range of investigations of cell and tissue behavior in various mechanical environments as well as other samples, including biological materials. PMID- 28094386 TI - A universal mechanism of the planar boron rotors B11-, B13+, B15+, and B19-: inner wheels rotating in pseudo-rotating outer bearings. AB - Planar boron clusters B11-, B13+, B15+, and B19- have been introduced recently as molecular Wankel motors or tank treads. Here we present a universal mechanism for these dynamically fluxional clusters; that is, they are molecular rotors with inner wheels that rotate almost freely in pseudo-rotating outer bearings, analogous to rotating molecules trapped in pseudo-rotating cages. This mechanism has significant quantum mechanical consequences: the global-minimum structures of the clusters have C2v symmetry, whereas the wheels rotating in pseudo-rotating bearings generate rosette-type shapes with D9h, D10h, D11h, and D13h symmetries. The related rotational/pseudo-rotational energies appear with characteristic band structures, effecting the dynamics. PMID- 28094391 TI - Advantages of an optical nanosensor system for the mechanistic analysis of a novel topoisomerase I targeting drug: a case study. AB - The continuous need for the development of new small molecule anti-cancer drugs calls for easily accessible sensor systems for measuring the effect of vast numbers of new drugs on their potential cellular targets. Here we demonstrate the use of an optical DNA biosensor to unravel the inhibitory mechanism of a member of a new family of small molecule human topoisomerase I inhibitors, the so-called indeno-1,5-naphthyridines. By analysing human topoisomerase I catalysis on the biosensor in the absence or presence of added drug complemented with a few traditional assays, we demonstrate that the investigated member of the indeno-1,5 naphthyridine family inhibited human topoisomerase I activity by blocking enzyme DNA dissociation. To our knowledge, this represents the first characterized example of a small molecule drug that inhibits a post-ligation step of catalysis. The elucidation of a completely new and rather surprising drug mechanism-of action using an optical real time sensor highlights the value of this assay system in the search for new topoisomerase I targeting small molecule drugs. PMID- 28094392 TI - 3D printing of self-assembling thermoresponsive nanoemulsions into hierarchical mesostructured hydrogels. AB - Spinodal decomposition and phase transitions have emerged as viable methods to generate a variety of bicontinuous materials. Here, we show that when arrested phase separation is coupled to the time scales involved in three-dimensional (3D) printing processes, hydrogels with multiple length scales spanning nanometers to millimeters can be printed with high fidelity. We use an oil-in-water nanoemulsion-based ink with rheological and photoreactive properties that satisfy the requirements of stereolithographic 3D printing. This ink is thermoresponsive and consists of poly(dimethyl siloxane) droplets suspended in an aqueous phase containing the surfactant sodium dodecyl sulfate and the cross-linker poly(ethylene glycol) dimethacrylate. Control of the hydrogel microstructure can be achieved in the printing process due to the rapid structural recovery of the nanoemulsions after large strain-rate yielding, as well as the shear thinning behavior that allows the ink to conform to the build platform of the printer. Wiper operations are used to ensure even spreading of the yield stress ink on the optical window between successive print steps. Post-processing of the printed samples is used to generate mesoporous hydrogels that serve as size-selective membranes. Our work demonstrates that nanoemulsions, which belong to a class of solution-based materials with flexible functionalities, can be printed into prototypes with complex shapes using a commercially available 3D printer with a few modifications. PMID- 28094393 TI - Correction: Copper(ii) catalyzed synthesis of novel helical luminescent benzo[4,5]imidazo[1,2-a][1,10]phenanthrolines via an intramolecular C-H amination reaction. AB - Correction for 'Copper(ii) catalyzed synthesis of novel helical luminescent benzo[4,5]imidazo[1,2-a][1,10]phenanthrolines via an intramolecular C-H amination reaction' by Ramon Borges da Silva, et al., Org. Biomol. Chem., 2017, DOI: 10.1039/c6ob02508k. PMID- 28094394 TI - Complete ultrafast charge carrier dynamics in photo-excited all-inorganic perovskite nanocrystals (CsPbX3). AB - Understanding the nature and dynamics of the photo-induced transients of all inorganic perovskite nanocrystals (NCs) is key to their exploitation in potential applications. In order to determine the nature of charge carriers, their deactivation pathways and dynamics, the photo-induced transients of CsPbBr3, CsPbBr2I, CsPbBr1.5I1.5 and CsPbI3 NCs are spectrally and temporally characterized employing a combination of femtosecond transient absorption (TA) and photoluminescence (PL) up-conversion techniques and global analysis of the data. The results provide distinct identities of the excitons and free charge carriers and distinguish the hot charge carriers from the cold ones. The carrier trapping is attributed to the electrons and their dynamics is unaffected in mixed halide perovskites. The excitation energy dependence of the TA dynamics suggests that the trap states are shallow in nature and mainly limited near the band-edge level. In mixed halide perovskites, an increase in the iodine content leads to hole trapping in a short time scale (<5 ps). The insights obtained from this study are likely to be helpful for tuning the photo-response of these substances and their better utilization in light-based applications. PMID- 28094396 TI - Nanostructuration of ionic liquids: impact on the cation mobility. A multi-scale study. AB - When probed at the macroscopic scale, Ionic Liquids (ILs) behave as highly dissociated (i.e. strong) electrolytes while, at the molecular scale, they show clear characteristics of weak ionic solutions. The multi-scale analysis we report in this paper reconciles these apparently at odds behaviors. We investigate by quasi-elastic neutron scattering (QENS) and neutron spin-echo (NSE), the nanometer/nanosecond dynamics of OMIM-BF4, an imidazolium-based IL showing strong nanostructuration. We also probe the same IL on the microscopic (MUm and ms) scale by pulsed field gradient NMR. To interpret the neutron data, we introduce a new physical model to account for the dynamics of the side-chains and for the diffusion of the whole molecule. This model describes the observables over the whole and unprecedented investigated spatial ([0.15-1.65] A-1) and time ([0.5 2000] ps) ranges. We arrive at a coherent and unified structural/dynamical description of the local cation dynamics: a localized motion within the IL nanometric domains is combined with a genuine long-range translational motion. The QENS, NSE and NMR experiments describe the same long-range translational process, but probed at different scales. The associated diffusion coefficients are more than one order of magnitude different. We show how this apparent discrepancy is a manifestation of the IL nanostructuration. PMID- 28094400 TI - Synthesis of 3-azabicyclo[3.1.0]hexane derivatives via palladium-catalyzed cyclopropanation of maleimides with N-tosylhydrazones: practical and facile access to CP-866,087. AB - A palladium-catalyzed cyclopropanation of internal alkenes with N-tosylhydrazones is presented. This gram-scale cyclopropanation reaction of maleimides provides a wide spectrum of 3-azabicyclo[3.1.0]hexane derivatives in high yields and diastereoselectivities. The major diastereoisomers could be easily isolated by chromatography on silica gel. This protocol provides a practical route to the mu opioid receptor antagonist CP-866,087. PMID- 28094402 TI - Mesoporous carbon nanoshells for high hydrophobic drug loading, multimodal optical imaging, controlled drug release, and synergistic therapy. AB - Loading and controlled release of sufficient hydrophobic drugs to tumor cells has been the bottleneck in chemotherapy for decades. Herein we report the development of a fluorescent and mesoporous carbon nanoshell (FMP-CNS) that exhibits a loading capacity for the hydrophobic drug paclitaxel (PTX) as high as ~80 wt% and releases the drug in a controllable fashion under NIR irradiation (825 nm) at an intensity of 1.5 W cm-2. The high drug loading is primarily attributed to its mesoporous structure and to the supramolecular pi-stacking between FMP-CNSs and PTX molecules. The FMP-CNS also exhibits wavelength-tunable and upconverted fluorescence properties and thus can serve as an optical marker for confocal, two photon, and near infrared (NIR) fluorescence imaging. Furthermore, our in vitro results indicate that FMP-CNSs demonstrate high therapeutic efficacy through the synergistic effect of combined chemo-photothermal treatment. In vivo studies demonstrate marked suppression of tumor growth in mice bearing rat C6 glioblastoma after administration with a single intratumoral injection of PTX loaded FMP-CNS. PMID- 28094404 TI - Excitation wavelength independent visible color emission of carbon dots. AB - Carbon dots (CDs) usually emit a strong blue light and excitation wavelength dependent long wavelength lights. This significantly limits their applications because one has to use a series of different excitation light sources to get different colors and the long wavelength emissions are usually very weak. We found that one type of CDs synthesized from p-phenylenediamine could emit various long wavelength lights (green to red) independent of the excitation wavelength when dispersed in different solvents. The photoluminescence quantum yields of the same CDs were 10-35% in different solvents for different color emissions. Based on this solvent-color effect, we further mixed the same CDs with different polymers to form solid CD films for various color emissions, and these film emissions were also excitation wavelength independent. Multicolor LEDs were demonstrated with the same CDs in solution and solid film states for color displays. PMID- 28094405 TI - Controlled and tunable design of polymer interface for immobilization of enzymes: does curvature matter? AB - Control and tuning of surface properties is indispensable for the programmed and rational design of materials. Particularly, polymeric brush-modified colloids can be used as carrier materials for enzyme immobilization. Although it is of prime importance to control the brush architecture, there is still a lack of systematic investigations concerning the impact of grafting density on the properties of the designed interface, as well as on the immobilization of biomolecules. In this work, we investigate the surface properties of polymer brushes with different grafting densities prepared using a "grafting from" approach on flat and on colloidal particle substrates by varying the density of initiator groups. In this way, we control and tune interfacial properties of the carrier material such as swelling, charge, adhesion as well as adsorption of laccase from Trametes versicolor on the grafted polyelectrolyte layer. We show that there is no direct transferability of the results received from planar to curved substrates regarding the swelling behavior in dependence on the grafting density. The maximum of swelling degree of PDMAEMA layers is achieved at 0.34 nm-2 and at 0.1 nm-2 grafting density for planar and curved particle substrates, respectively. The adhesion properties of the polymeric layer on both substrates are also strongly influenced by the grafting density, i.e. a decrease of the grafting density causes a transition from the adhesive to non-adhesive state. As proven by the cryo-TEM and AFM force distance measurements, an immobilization of laccase from Trametes versicolor causes a decrease of the polymer swelling and therefore leads to the changes in the surface morphology, charge and adhesion performance of final polymer-enzyme layer. Moreover, the higher effectiveness and activity of laccase were observed for the intermediate grafting densities which seem to be preferable over the maximum brush densities. PMID- 28094407 TI - C-H imidation: a distinct perspective of C-N bond formation. AB - The direct imidation strategy proficiently constructs C-N bonds and creates the useful amine functional group in the molecular template. This review briefly discusses the synthetic methods developed for the direct imidation of unactivated C(sp2/sp3/sp)-H bonds. Transition-metal catalysts, metal-free processes, and/or photo-induced methods are invariably employed for accomplishing C-H imidation transformations. The contents summarized herein would benefit the research community to use the C-H imidation reactions for broad synthetic applications and to unravel novel C-N bond forming processes. PMID- 28094408 TI - Large-area tungsten disulfide for ultrafast photonics. AB - Two-dimensional (2D) layered transition metal dichalcogenides (TMDs) have attracted significant interest in various optoelectronic applications due to their excellent nonlinear optical properties. One of the most important applications of TMDs is to be employed as an extraordinary optical modulation material (e.g., the saturable absorber (SA)) in ultrafast photonics. The main challenge arises while embedding TMDs into fiber laser systems to generate ultrafast pulse trains and thus constraints their practical applications. Herein, few-layered WS2 with a large-area was directly transferred on the facet of the pigtail and acted as a SA for erbium-doped fiber laser (EDFL) systems. In our study, WS2 SA exhibited remarkable nonlinear optical properties (e.g., modulation depth of 15.1% and saturable intensity of 157.6 MW cm-2) and was used for ultrafast pulse generation. The soliton pulses with remarkable performances (e.g., ultrashort pulse duration of 1.49 ps, high stability of 71.8 dB, and large pulse average output power of 62.5 mW) could be obtained in a telecommunication band. To the best of our knowledge, the average output power of the mode-locked pulse trains is the highest by employing TMD materials in fiber laser systems. These results indicate that atomically large-area WS2 could be used as excellent optical modulation materials in ultrafast photonics. PMID- 28094412 TI - Ultrasound-guided approach to the cervical articular process joints in horses: a validation of the technique in cadavers. AB - OBJECTIVES: To compare accuracy of the ultrasound-guided craniodorsal (CrD) approach with the dorsal (D) approach to the cervical articular process joints, and to evaluate the effect of the transducer, needle gauge, and operator experience. METHODS: Cervical articular process joints from 14 cadaveric neck specimens were injected using either a D or CrD approach, a linear (13 MHx) or microconvex transducer (10 MHz), and an 18 or 20 gauge needle, by an experienced or inexperienced operator. Injectate consisted of an iodinated contrast material solution. Time taken for injection, number of redirects, and retrieval of synovial fluid were recorded. Accuracy was assessed using a scoring system for contrast seen on computed tomography (CT). RESULTS: The successful performance of intra-articular injections of contrast detected by CT using the D (61/68) and CrD (57/64) approaches was comparable. No significant effect of approach, transducer or needle gauge was observed on injection accuracy, time taken to perform injection, or number of redirects. The 18 gauge needle had a positive correlation with retrieval of synovial fluid. A positive learning curve was observed for the inexperienced operator. CLINICAL RELEVANCE: Both approaches to the cervical articular process joints were highly accurate. Ultrasound-guided injection of the cervical articular process joints is an easily-learnt technique for an inexperienced veterinarian. Either approach may be employed in the field with a high level of accuracy, using widely available equipment. PMID- 28094413 TI - Electrical impedance tomography for lung ventilation monitoring of the dog. AB - BACKGROUND: Electrical impedance tomography (EIT) is a radiation free technique which takes advantage of the different electrical conductivities of different tissues. Its main field of application is lung ventilation monitoring. The aim of this prospective study was to evaluate the feasibility of collecting EIT information on a sample of dogs with different thoracic shapes under clinical conditions by connecting an electrode belt without fur clipping. MATERIAL AND METHODS: Fifteen pulmonary healthy dogs were anaesthetized, positioned in sternal recumbency and ventilated in a pressure-controlled mode at three different positive end-expiratory pressure levels (PEEP) of 0, 5 and 10 cmH2O for five breaths each, with a peak inspiratory pressure of 15 cmH2O. The impedance changes were recorded with a commercial EIT device applied around the thorax. Subsequently, the ventilation regime was repeated and a computed tomography scan (CT) of the same thoracic segment was performed for each PEEP level. The tidal volume (Vt) was recorded. For the collection of EIT data the sum of regional impedance changes was recorded. The impedance value of the entire lung (global) was recorded and the ventilated area was quartered into four regions of interest (ROI). In a CT image with the fewest adjacent organs, lung tissue was selected to obtain the mean value of lung radiodensitiy in Hounsfield-Units (HU) for the entire lung and for the four ROIs. RESULTS: EIT recordings via the electrode belt were possible without clipping. There was a significant correlation for the parameters of aeration as measured by EIT and CT for both the entire ventilated lung and the corresponding ROIs. The increasing PEEP resulted in a proportional increase of the impedance, and there was a negative correlation between EIT and Vt. The better ventilated dorsal ROIs could be identified using both EIT and CT. An intra-assay coefficient of variation showed a good reproducibility for lung ventilation in anaesthetized dogs in the EIT. DISCUSSION: The results show that EIT is a reliable method for evaluating the ventilation of dogs in a clinical setting. The accuracy of EIT might be improved by using a mesh corresponding to the different thoracic shapes of the dogs. PMID- 28094414 TI - Asymmetrical lumbosacral transitional vertebrae in dogs may promote asymmetrical hip joint development. AB - OBJECTIVES: This study examines the relationship between the morphology of the lumbosacral transitional vertebra (LTV) and asymmetrical development of the hip joints in dogs. METHODS: A total of 4000 dogs which had been consecutively scored for canine hip dysplasia were checked for the presence of a LTV. A LTV was noted in 138 dogs and classified depending on the morphology of the transverse processes and the degree of contact with the ilium. RESULTS: In dogs with an asymmetrical LTV, the hip joint was significantly more predisposed to subluxation and malformation on the side of the intermediate or sacral-like transverse process (p <0.01), on the side of the elevated pelvis (p <0.01), or when an asymmetrical LTV resulted in pelvic rotation on its long axis (p <0.01), whereas hip joint conformation was less affected on the side featuring a free transverse process (p <0.01). CLINICAL SIGNIFICANCE: The results support our hypothesis that an asymmetrical LTV favours pelvic rotation over its long axis, resulting in inadequate femoral head coverage by the acetabulum on one side. Inadequate coverage of the femoral head favours subluxation, malformation of the hip joint, and secondary osteoarthritis. Asymmetrical hip conformation may therefore be the sequela of a LTV and mask or aggravate genetically induced canine hip dysplasia. PMID- 28094415 TI - Outcome of nonunion fractures in dogs treated with fixation, compression resistant matrix, and recombinant human bone morphogenetic protein-2. AB - OBJECTIVES: To report the use of compression resistant matrix (CRM) infused with recombinant human bone morphogenetic protein (rhBMP-2) prospectively in the healing of nonunion long-bone fractures in dogs. METHODS: A longitudinal cohort of dogs that were presented with nonunion fractures were classified and treated with CRM soaked with rhBMP-2 and fracture fixation. They were followed with serial radiographs and evaluated for healing times and complications according to the time frame and definitions previously established for orthopaedic clinical cases. RESULTS: Eleven nonunion fractures in nine dogs were included. Median healing time was 10 weeks (range: 7-20 weeks). Major perioperative complications due to bandage morbidity were encountered in two of 11 limbs and resolved. All other complications were minor. They occurred perioperatively in eight of 11 limbs. Minor follow-up complications included short-term in one of two limbs, mid term in one of three, and long-term in four of five limbs. Nine limbs returned to full function and two limbs returned to acceptable function at the last follow up. CLINICAL SIGNIFICANCE: Nonunion fractures given a poor prognosis via standard of-care treatment were successfully repaired using CRM with rhBMP-2 accompanying fixation. These dogs, previously at high risk of failure, returned to full or acceptable function. PMID- 28094416 TI - Seasonal leukotrichia in a German shepherd dog. A case report. AB - Leukotrichia can be caused by a variety of metabolic and inflammatory diseases. Canine alopecia areata is a rare multifactorial benign non-scarring alopecia. This case report describes a seasonally recurrent leukotrichia associated with alopecia areata in a German shepherd dog. Important differential diagnoses were ruled out and histopathology finally confirmed the diagnosis of alopecia areata. Topical tacrolimus and hydrocortisone aceponate were ineffective. The cause for the seasonal character in this case remained undetermined. PMID- 28094417 TI - Evaluation of proximal and distal motor nerve conduction using the electrical root stimulation technique in the femoral and obturator nerves. AB - OBJECTIVES: This study aimed to investigate the adaptability of the electrical root stimulation technique by achieving normative data from the obturator and femoral nerves of healthy dogs. METHODS: For this purpose, two stimulations and recordings were performed on both the obturator and femoral nerves in 40 dogs (22 males and 18 females). Electrical root stimulation was applied via monopolar needle electrodes between the sixth to seventh and fifth to sixth lumbar interarcuate spaces to the obturator and femoral nerves, respectively. Muscle waves were recorded from the gracilis and sartorius muscles of the left and right pelvic limb. RESULTS: The proximal motor nerve conduction velocity was 60.89 +/- 3.93 m/s and 59.87 +/- 4.83 m/s in the obturator and femoral nerves, respectively. CLINICAL SIGNIFICANCE: Our results showed that electrical root stimulation could be a useful method to test the integrity of the roots of obturator and femoral nerves and their proximal parts. PMID- 28094418 TI - Comparative anatomy and biomechanical properties of atlantoaxial ligaments in equine, bovine, and canine cadaveric specimens. AB - OBJECTIVES: Atlantoaxial instability has been reported in humans, dogs, equids and ruminants. The functional role of the atlantoaxial ligaments has only been described rudimentarily in equids and ruminants. The goal of the present cadaveric study was to compare the anatomy between the different species and to comparatively assess the role of the stabilizing ligaments of the atlantoaxial joint under sagittal shear loading in canine, equine, and bovine cervical spines. METHODS: Three equine, bovine, and canine cadaveric specimens were investigated. Biomechanical testing was performed using a purpose built shear-testing device driven by a uniaxial servo-hydraulic testing machine. Three cycles in a dorsoventral direction with a constant quasi-static velocity of 0.2 mm/s up to a limiting force of 50 N (canine) or 250 N (bovine, equine), respectively, were performed for each specimen tested. Load and linear displacement were measured by the displacement sensor and load cell of the testing system at a sampling rate of 20 Hz. Tests were performed and the range of motion determined with both intact and transected atlantoaxial ligaments. RESULTS: The range of motion was significantly increased after transection of the ligaments only in the canine specimens. The bovine atlantoaxial joint was biomechanically more stable than in equids. CLINICAL SIGNIFICANCE: Species-specific anatomical and biomechanical differences of the atlantoaxial ligaments in canines, equids, and bovines were detected. The significance of these differences and their impact on the pathogenesis of atlantoaxial subluxations and subsequent treatment remain open questions. PMID- 28094419 TI - Postoperative computed tomography and low-field magnetic resonance imaging findings in dogs with degenerative lumbosacral stenosis treated by dorsal laminectomy. AB - OBJECTIVES: To describe postoperative computed tomography (CT) and magnetic resonance imaging (MRI) findings in dogs with degenerative lumbosacral stenosis (DLSS) treated by dorsal laminectomy and partial discectomy. METHODS: Prospective clinical case study of dogs diagnosed with and treated for DLSS. Surgical and clinical findings were described. Computed tomography and low field MRI findings pre- and postoperatively were described and graded. Clinical, CT and MRI examinations were performed four to 18 months after surgery. RESULTS: Eleven of 13 dogs were clinically improved and two dogs had unchanged clinical status postoperatively despite imaging signs of neural compression. Vacuum phenomenon, spondylosis, sclerosis of the seventh lumbar (L7) and first sacral (S1) vertebrae endplates and lumbosacral intervertebral joint osteoarthritis became more frequent in postoperative CT images. Postoperative MRI showed mild disc extrusions in five cases, and in all cases contrast enhancing non-discal tissue was present. All cases showed contrast enhancement of the L7 spinal nerves both pre- and postoperatively and seven had contrast enhancement of the lumbosacral intervertebral joints and paraspinal tissue postoperatively. Articular process fractures or fissures were noted in four dogs. CLINICAL SIGNIFICANCE: The study indicates that imaging signs of neural compression are common after DLSS surgery, even in dogs that have clinical improvement. Contrast enhancement of spinal nerves and soft tissues around the region of disc herniation is common both pre- and postoperatively and thus are unreliable criteria for identifying complications of the DLSS surgery. PMID- 28094420 TI - Evaluation of the optimal plate position for the fixation of supraglenoid tubercle fractures in warmbloods. AB - OBJECTIVES: To determine scapular cortex thickness, distal scapular bone density and describe the exact suprascapular nerve course to evaluate the best plate position for the fixation of supraglenoid tubercle fractures in horses. METHODS: Twelve equine cadaveric shoulders were examined with computed tomography. Computed tomography morphometry and density measurements (Hounsfield units [HU]) of the scapula were recorded. Statistical comparisons were made between the cranial and caudal aspects of the scapula. Dissection of each shoulder was performed and the suprascapular nerve course was described morphometrically and morphologically. RESULTS: The suprascapular nerve was found on the periosteum and embedded in connective tissue at the cranial aspect of the scapula. It ramified proximally and distally into the supraspinatus muscle, coursed caudolaterally at a median of 2 cm (1-2 cm) distal to the scapular spine and ramified proximally and distally into the infraspinatus muscle. The scapular cortex measurements (HU) cranially were significantly larger than caudally at most levels of the scapula. The bone density of the distal scapula cranially (651.3 +/- 104.2) was significantly lower than caudally (745.7 +/- 179.1). CLINICAL SIGNIFICANCE: For surgical access to the supraglenoid tubercle, knowledge of the anatomy is important. It is easiest to avoid the suprascapular nerve at the most cranial aspect of the scapula, where it has not yet ramified. For a stable fixation, knowledge of the characteristics of the equine scapula, such as scapular cortex thickness, is important. PMID- 28094421 TI - Biomechanical evaluation of simulated feline patellar fracture repairs. AB - OBJECTIVE: To investigate four techniques for stabilization of feline patellar fracture. METHODS: Feline cadaveric stifles with simulated patellar fracture were stabilized with one of four techniques: Group A - circumferential wire, group B - figure-of-eight wire, group C - combined figure-of-eight and circumferential wire, group D - pin and tension band wire. All repairs were subjected to a period of cyclic loading prior to load to failure testing. Experiments were recorded by video capture to determine load at failure and failure mode. Failure was defined as an opening of the fracture gap of 3 mm. RESULTS: Mean fracture gap opening (+/ SD) during peak loading after 1000 cycles was: group A with 1.66 mm (+/- 0.69), group B with 1.01 mm (+/- 0.45), group C with 0.81 mm (+/- 0.58), and group D with 0.65 mm (+/- 0.54). Groups C and D had significantly lower mean fracture gap opening after 1000 cycles when compared to group A (p <0.05). Mean loads (+/- SD) at failure were: group A with 171.4 N (+/- 62.2), group B with 208.7 N (+/- 20.7), group C with 288.2 N (+/- 62.5), and group D with 219.5 N (+/- 48.0). Group C had significantly higher mean load to failure than all other groups (p <0.05). There was no difference between other groups. In groups A, B and C the principle mode of failure was wire elongation and tearing of sutures through the retinaculae and periarticular soft tissues. In group D, the principle mode of failure was the pin pulling through the bone of the distal fragment. CONCLUSIONS: Combined figure-of-eight and circumferential wires may be useful for treatment of transverse feline patellar fracture. PMID- 28094422 TI - Predicting the need for trochleoplasty in canine patellar luxation using pre- and intra-operative assessments of trochlear depth. AB - OBJECTIVES: To evaluate the repeatability and reproducibility of ultrasonographic femoral trochlear depth measurements and to compare ultrasonographic and intra operative evaluations of femoral trochlear depth for predictive value in selecting trochleoplasty. METHODS: Repeatability and reproducibility of an ultrasonographic protocol were tested in a preclinical cadaveric study. Clinical patients undergoing corrective surgery for patellar luxation were evaluated preoperatively with ultrasound and intra-operatively using a depth gauge. Measurements were assessed for equivalence using linear regression, and agreement between decisions made based on these measurements assessed using Cohen's kappa. RESULTS: Although ultrasonographic and intra-operative measurements were in broad agreement, the prediction interval was too wide for clinical use. There was no significant agreement between predictions of the need for trochleoplasty using various cut-off values for the two measurements, nor between these and the surgeon's decision. CLINICAL SIGNIFICANCE: Based on our observations, use of ultrasound for evaluation of the femoral trochlea remains a largely qualitative assessment. A simpler and more direct objective measure of femoral trochlear adequacy is required for intra-operative use. PMID- 28094423 TI - Repeatability and accuracy testing of a weight distribution platform and comparison to a pressure sensitive walkway to assess static weight distribution. AB - OBJECTIVE: To evaluate the accuracy and repeatability of measurements collected using a weight distribution platform and a pressure sensitive walkway using an inanimate object with known weight distribution. METHODS: A custom-built jig with a range of weights was applied in a random order. Measurements were collected on both devices and compared to each other and to the known weight distribution. RESULTS: Weight distribution platform and pressure sensitive walkway measurements were highly correlated to each other (Pearson's correlation coefficient R = 0.98) and to actual weights (R = 0.99 for the weight distribution platform; 0.98 for the pressure sensitive walkway). Repeatability from day to day for both devices was greater than 0.99. For the weight distribution platform, the 95% confidence interval was +/- 2.5% from the true percentage and +/- 3.3% for the pressure sensitive walkway. The coefficient of variation (COV) was highest for both devices at the lightest weights (weight distribution platform 11.28%, pressure sensitive walkway 16.91%) and lowest with the heaviest weights (weight distribution platform 3.71%, pressure sensitive walkway 5.86%). CONCLUSION: Both the weight distribution platform and the pressure sensitive walkway provided accurate and consistent measures of weight distribution with no significant difference between devices. The rounded standard error was three percent for the weight distribution platform, and four percent for the pressure sensitive walkway. The higher variability when measuring the smallest weight suggests less accuracy at lower weights with both devices. CLINICAL SIGNIFICANCE: The weight distribution platform is a repeatable and accessible device to measure static weight distribution, and if proven the same in a clinical setting, it will be a valuable addition to current objective measures of limb use. PMID- 28094424 TI - Ex vivo torsional properties of a 2.5 mm veterinary interlocking nail system in canine femurs. Comparison with a 2.4 mm limited contact bone plate. AB - OBJECTIVE: To evaluate the torsional properties of the Targon(r) Vet Nail System (TVS) in small canine femurs and to compare these properties to those of the 2.4 mm LC-DCP(r) plates. METHODS: Thirty-six cadaveric femurs were allocated to three groups (n = 12). In all bones, points just distal to the lesser trochanter and just proximal to the fabellae were marked and a midshaft transverse osteotomy was performed. Group 1: bones were fixed with the 2.5 mm TVS with the bolts applied at the pre-identified marks. Group 2: A TVS system with 25% shorter inter-bolt distance was used. Group 3: A 7-hole 2.4 mm LC-DCP(r) plates were applied. All constructs were tested non-destructively for 10 cycles, followed by an acute torsion to failure. RESULTS: Torque at yield was 0.806 +/- 0.183 and 0.805 +/- 0.093 Nm for groups 1 and 2 and 1.737 +/- 0.461 Nm for group 3. Stiffness was 0.05 +/- 0.01, 0.05 +/- 0.007, and 0.14 +/- 0.015 Nm/ degrees for groups 1 to 3 respectively. Maximal angular displacement under cyclic loading was 16.6 degrees +/- 2.5 degrees , 15.6 degrees +/- 2.1 degrees , and 7.8 degrees +/- 1.06 degrees respectively. There was no significant difference for any of the parameters between groups 1 and 2. Both torque at yield and stiffness were significantly greater between group 3 and groups 1 and 2. CLINICAL SIGNIFICANCE: The TVS had approximately half the torsional strength and approximately 1/3 of the stiffness of the 2.4 mm bone plate. Slippage of the locking mechanism was probably the cause of the early failure. The system should be considered as a low strength and low-stiffness system when compared to bone plates. PMID- 28094425 TI - Learning Curve in Anatomo-Electrophysiological Correlations in Subthalamic Nucleus Stimulation. AB - AIM: Advances in neuroradiological planning techniques in deep brain stimulation have put the need for intraoperative electrophysiological monitoring into doubt. Moreover intraoperative monitoring prolongs surgical time and there is potential association between the use of microelectrodes and increased incidence of hemorrhagic complications. The aim of this study was to analyze the correlation between the anatomically planned trajectory and the final subthalamic electrode placement after electrophysiological monitoring in patients with Parkinson"s disease and its change with the increasing experience of the surgical team. MATERIAL AND METHODS: The trajectories of right (first implanted) and left electrodes were compared in the first 50 patients operated on (Group 1) and the next 50 patients (Group 2). RESULTS: In Group 1, 52% of central trajectories were on the right and 38% on the left; in Group 2, the percentage of central trajectories was 76% on the right and 78% on the left; the difference was statistically significant (p=0.021 and 0.001). The difference in the percentage of posterior trajectories reflecting brain shift between the right and left sides was statistically insignificant in Groups 1 (26% and 28%, p=0.999) and 2 (18% and 12%, p=0.549). The percentage of bilateral central electrodes was 14% and 62% in Groups 1 and 2, respectively. CONCLUSION: The correlation between anatomically planned trajectory and final electrode placement markedly improves with the number of patients. However the significant percentage of patients with final electrode trajectory differing from anatomically planned target supports the use of intraoperative monitoring. PMID- 28094426 TI - The Role of Cine Flow Magnetic Resonance Imaging in Patients with Chiari 0 Malformation. AB - AIM: To define the role of phase-contrast cine magnetic resonance imaging (MRI) in deciding the therapeutic strategy and underlying pathophysiology resulting in syrinx formation in patients with Chiari type 0 malformation. MATERIAL AND METHODS: Seven patients who were admitted to our clinic with the diagnosis of Chiari 0 malformation from January 2005 to July 2016 were enrolled in the study. All patients underwent a detailed preoperative neurological examination. Entire neuroaxis MRI and phase-contrast cine MRI were obtained preoperatively and postoperatively. RESULTS: Seven patients (5 female and 2 male) with Chiari type 0 malformation fulfilled the inclusion criteria. All of the patients had absent cine flow at the craniovertebral junction except two patients. These five patients underwent surgical interventions; suboccipital decompression and duraplasty. All of them showed both clinical and radiological improvement in the postoperative period. CONCLUSION: Cine flow MRI appears to be a useful tool in the management of patients with Chiari 0 malformation. There was a good correlation between the clinical presentation and cine flow preoperatively, and between clinical improvement and cine flow in the postoperative period. PMID- 28094427 TI - Minimalism in Art, Medical Science and Neurosurgery. AB - The word "minimalism" is a word derived from French the word "minimum". Whereas the lexical meaning of minimum is "the least or the smallest quantity necessary for something", its expression in mathematics can be described as "the lowest step a variable number can descend, least, minimal". Minimalism, which advocates an extreme simplicity of the artistic form, is a current in modern art and music whose origins go to 1960s and which features simplicity and objectivity. Although art, science and philosophy are different disciplines, they support each other from time to time, sometimes they intertwine and sometimes they copy each other. A periodic schools or teaching in one of them can take the others into itself, so, they proceed on their ways empowering each other. It is also true for the minimalism in art and the minimal invasive surgical approaches in science. Concepts like doing with less, avoiding unnecessary materials and reducing the number of the elements in order to increase the effect in the expression which are the main elements of the minimalism in art found their equivalents in medicine and neurosurgery. Their equivalents in medicine or neurosurgery have been to protect the physical integrity of the patient with less iatrogenic injury, minimum damage and the same therapeutic effect in the most effective way and to enable the patient to regain his health in the shortest span of time. As an anticipation, we can consider that the minimal approaches started by Richard Wollheim and Barbara Rose in art and Lars Leksell, Gazi Yasargil and other neurosurgeons in neurosurgery in the 1960s are the present day equivalents of the minimalist approaches perhaps unconsciously started by Kazimir Malevich in art and Victor Darwin L"Espinasse in neurosurgery in the early 1900s. We can also consider that they have developed interacting with each other, not by chance. PMID- 28094428 TI - Intraoperative Results and Postoperative Clinical Outcomes of Lumbar Microdiscectomy in Patients who Previously Received a Transforaminal Anterior Epidural Steroid Injection for Lumbar Radiculopathy. AB - AIM: To describe the intra- and postoperative results of patients who received a transforaminal anterior epidural steroid injection (TAESI) prior to lumbar microdiscectomy. MATERIAL AND METHODS: Sixty-four patients who did not improve after minimally invasive techniques (MIT) for lumbar radiculopathy were evaluated. Thirty-two of them treated with techniques other than TAESI and those receiving thrombolytic or anticoagulant drugs before microdiscectomy were excluded. We recorded the type of MIT, numbers of levels and injections, time interval between the last MIT and microdiscectomy, duration of surgery, amount of intraoperative blood loss, rate of incidental durotomy, postoperative infection, and visual analogue scale (VAS) scores for leg pain before and after microdiscectomy at 24 hours, and the 1st and 3rd months (Group 1). A total of 35 patients with no history of MIT or lumbar surgery who had undergone unilateral, single-level lumbar microdiscectomy at our clinic were randomly selected to be included in the control group (Group 2) and same parameters were recorded for the comparison of both groups. RESULTS: The mean duration of lumbar discectomy was 140 minutes, and the amount of average intraoperative blood loss was 227 cc in the study group (Group 1), and 65 minutes and 73 cc, respectively in the control group (Group 2)(p > 0.05). The comparison of VAS scores revealed that lumbar discectomy was still effective after TAESI (p=0.00). CONCLUSION: Although epidural steroid injection is an effective modality for the management of chronic pain, these patients should be informed preoperatively about the relatively long duration of surgery and the possible requirement for blood transfusion. PMID- 28094429 TI - A Comparison Between the Effectiveness of Full Outline of Unresponsiveness and Glasgow Coma Score at Neurosurgical Intensive Care Unit Patients. AB - AIM: To evaluate the effectiveness and the use of Glasgow Coma Score (GCS) and Full Outline of Unresponsiveness (FOUR) score by nurses in the follow-up and evaluation of patients admitted to the neurosurgical intensive care unit for cranial surgery or head trauma. MATERIAL and METHODS: The study was performed at a neurosurgical intensive care unit. Sample size was determined as 47 patients (a= 0.05, power= 0.95). The correlation coefficient less than 0.5 was accepted as weak. In the first 24 hours, Karnofsky Performance Scale was applied and the Acute Physiology and Chronic Health Evaluation II (APACHE II) Score calculated for patients who were admitted to the intensive care unit for cranial surgery or head trauma. Also FOUR and GCS were applied by two different nurses twice a day. Intraclass Correlation Coefficient, Pearson Correlation and Cronbach?s Alpha Security Index analyses were used to evaluate the data. RESULTS: Concordance was above 0.810 and correlation was above 0.837 between GCS and FOUR score evaluation results of nurses. Correlation of two different evaluation at every shift for GCS was 0.887, and for FOUR was 0.827 and above. Karnofsky Performance Scale correlation with FOUR and GCS scores of patients at admission and discharge from the intensive care unit was 0.709 and above. The correlation between APACHE II and FOUR was 0.851; between APACHE II and GCS 0.853. There was no difference between the evaluations of two scores and two nurses statistically. CONCLUSION: Concordance between nurses was found high both for GCS and FOUR. The FOUR score is as effective as GCS on the follow-up of patients who are managed in the neurosurgical intensive care units. PMID- 28094430 TI - Comparison of Sleep Quality and Sleepiness in Patients Operated for Pituitary Adenoma and in Healthy Individuals. AB - AIM: To investigate whether sleep quality and sleepiness of patients who undergo surgery for pituitary adenomas differ from healthy individuals. MATERIAL AND METHODS: Forty-four patients who were operated for pituitary adenomas and 44 healthy individuals, 88 subjects in total, were evaluated by a questionnaire. All questionnaires and scales were applied by the same researcher without the name of the participant in order to maintain consistency. Statistical analyses were conducted with the SPSS for Windows 23.00 package program. RESULTS: Of the 88 participants, 44 (50%) were patients who were operated for pituitary adenomas, while 44 (50%) were control subjects. 38 (43.2%) of the participants were male, 50 (56.8%) were female. The average age of the participants was 37 +/- 12.24 years. The best sleep quality was found in 41-50 years group (7 patients). In the control group, 23 patients (52.3%) had a sleep quality index above 5 and 21 patients (47.7%) had a value below 5. In the control group, 8 patients (21.2%) between 21-30 years were found to have poor sleep quality by age. CONCLUSION: Sleepiness and sleep quality have physiological, social and psychological effects on individuals. There is no statistically significant difference in sleep quality and sleepiness scales between patients operated for pituitary adenomas and healthy individuals. However, it is recommended that polysomnography should be used to examine these patients in more detail. PMID- 28094431 TI - Chordoma: Immunohistochemical Analysis of Brachury. AB - AIM: Chordomas are rare, slow growing but locally aggressive malignancies of the axial skeleton. Skull base chordomas, due to their intricate anatomical localization, pose significant challenges to managing physicians. In classical and chondroid chordomas, the disease course cannot be reliably determined using only morphological criteria. Brachyury (T Gene) was shown to play a central role in chordoma pathogenesis and several studies also showed that this gene also carries potential as a prognostic biomarker. This study aims to correlate Brachyury expression with the clinical course in surgically treated skull base chordomas. MATERIAL AND METHODS: Chordoma tumor samples from 14 patients with skull base chordomas, diagnosed using histopathological and immunohistochemistry criteria (epithelial membrane antigen (EMA), S100, pan cytokeratin (panCK)) were retrospectively analyzed for Brachyury expression using immunohistochemistry. Brachyury expression was graded using a 4 point semi-quantitative scoring system. Focal (grade II) and diffuse staining (grade III) were considered as overexpression. Patient recurrence-free survival and total survival were compared between Brachyury overexpressing and non-overexpressing groups using Kaplan-Meier survival analysis. RESULTS: Among the stained tumor samples, 85.7% were positive for brachyury expression. In both groups, there was one sample that was negative. We did not observe any significant difference among the groups for staining, grade and percentage of brachyury positive cells. CONCLUSION: Brachyury expression in tumor samples is not a sensitive indicator of prognosis in chordomas. PMID- 28094432 TI - Maltreatment-associated neurodevelopmental disorders: a co-twin control analysis. AB - BACKGROUND: Childhood maltreatment (CM) is strongly associated with psychiatric disorders in childhood and adulthood. Previous findings suggest that the association between CM and psychiatric disorders is partly causal and partly due to familial confounding, but few studies have investigated the mechanisms behind the association between CM and neurodevelopmental disorders (NDDs). Our objective was to determine whether maltreated children have an elevated number of NDDs and whether CM is a risk factor for an increased NDD 'load' and increased NDD symptoms when controlling for familial effects. METHODS: We used a cross sectional sample from a population-representative Swedish twin study, comprising 8,192 nine-year-old twins born in Sweden between 1997 and 2005. CM was defined as parent-reported exposure to emotional abuse/neglect, physical neglect, physical abuse, and/or sexual abuse. Four NDDs were measured with the Autism-Tics, AD/HD, and other comorbidities inventory. RESULTS: Maltreated children had a greater mean number of NDDs than nonmaltreated children. In a co-twin control design, CM discordant monozygotic twins did not differ significantly for their number of NDDs, suggesting that CM is not associated with an increased load of NDDs when genetic and shared environmental factors are taken into account. However, CM was associated with a small increase in symptoms of attention-deficit/hyperactivity disorder and autism spectrum disorder in CM-discordant MZ twins, although most of the covariance of CM with NDD symptoms was explained by common genetic effects. CONCLUSIONS: Maltreated children are at higher risk of having multiple NDDs. Our findings are, however, not consistent with the notion that CM causes the increased NDD load in maltreated children. Maltreated children should receive a full neurodevelopmental assessment, and clinicians should be aware that children with multiple NDDs are at higher risk of maltreatment. PMID- 28094433 TI - BMP15 "knockout-like" effect in familial premature ovarian insufficiency with persistent ovarian reserve. AB - Premature ovarian insufficiency (POI) affects 1% to 2% of women under 40 years. Bone morphogenetic protein 15 (BMP15) variants have been described in POI. We studied a family with 2 sisters compound heterozygous for deletions in the BMP15 gene on chromosome Xp11.22 yielding a human "knockout-like" effect: a c.151_152delGA deletion yielded a p.Glu51IlefsTer27 mutation transmitted by the hemizygous father and a c.189_198delAGGGCATTCAinsTG deletion/insertion yielded a p.Glu64AlafsTer12 mutation transmitted by the heterozygous mother. Both deletions resulted in frameshifts with premature stop codons at positions 78 and 76 in the proregion, precluding mature BMP15 production. One sister had primary amenorrhea and the other primo-secondary amenorrhea. No bone abnormality was observed. Despite streak ovaries devoid of follicles on ultrasonography, anti-Mullerian hormone (AMH) levels were low but detectable suggesting the presence of growing follicles. Five years later, AMH was undetectable in both sisters, 1 had received an egg donation. BMP15 did not seem critical for follicles to enter the growth phase. Genetic counselling should be performed and fertility preservation discussed before progressive loss of follicular reserve. The fertile heterozygous mother did not support previous reports of BMP15 haploinsufficiency and gene dosage in humans, as in bovine species. The hemizygous brother had asthenozoospermia, consistent with previous observations in bulls with a variant BMP15. PMID- 28094434 TI - The effect of remifentanil on propofol requirements to achieve loss of response to command vs. loss of response to pain. AB - When providing total intravenous anaesthesia, careful selection of end-points is required in titrating dose to effect during induction. Although propofol and remifentanil have predominantly different pharmacodynamic effects, they are seen to interact in achieving loss of consciousness and analgesia. To highlight these differences, we performed a double-blind, randomised controlled trial, comparing one group of patients receiving propofol alone (n = 42) with another group receiving remifentanil plus propofol (n = 46) as a target-controlled infusion of remifentanil (Minto; 3 ng.ml-1 ). Propofol was also titrated using a target controlled infusion (Marsh effect model) to produce loss of response to tactile and vocal stimuli, and subsequently to loss of response to pain. The effect-site concentration of propofol at which 50% of patients lost tactile/verbal response was 2.9 MUg.ml-1 in the propofol only group and 2.4 MUg.ml-1 in the remifentanil with propofol group. In contrast, loss of pain response occurred at 4.4 MUg.ml-1 in the propofol group, and 2.7 MUg.ml-1 in the remifentanil with propofol group, with correspondingly lower bispectral index values. Judicious use of analgesia in total intravenous anaesthesia can have a propofol-sparing effect and potentially minimise the suppression of brain electrical activity. . PMID- 28094435 TI - New interactions between tumor suppressor Fhit protein and a nonhydrolyzable analog of its AP4 A substrate. AB - Fragile histidine triad protein (Fhit) is a protein which primarily hydrolyses dinucleoside polyphosphates. To investigate possible interactions between the protein and a substrate, we used a nonhydrolyzable phosphorothioate analog of Ap4 A, containing 5-bromo-2'-deoxyuridine instead of one adenosine residue. Photocrosslinking, followed by LC-MS experiments, determined a complex in which the probe was covalently linked to the NDSIYEELQK peptide (residues 110-119). The peptide was located within the 'disordered' region, which is invisible in the known crystal structures of Fhit. This invisible and flexible part seems to play a role in the stabilization of the Fhit-substrate complex, which may be important for its tumor suppressor activity. PMID- 28094436 TI - Cartilage-hair hypoplasia with normal height in childhood-4 patients with a unique genotype. AB - The manifestations of cartilage-hair hypoplasia (CHH), a metaphyseal chondrodysplasia caused by RMRP mutations, include short stature, hypoplastic hair, immunodeficiency and increased risk of malignancies. Clinical features show significant variability. We report a patient with normal height until age 12.5 years (-1.6 SDS at 11 years) who was diagnosed with CHH at 14 years. RMRP sequencing revealed compound heterozygosity for g.70A>G mutation and a 10 nucleotide duplication at position -13 (TACTCTGTGA). Through the Finnish Skeletal Dysplasia Register, we identified 3 additional patients with identical genotype. Two of them also showed unusually mild growth failure (height SDS -1.6 at 14 years and -3.0 at 12 years, respectively). Three of the 4 patients suffered from recurrent infections; 1 developed progressive bronchiectasis and another died from aggressive lymphoma. Our findings expand the phenotypic variability in CHH to include normal childhood height. The milder growth retardation related to this particular genotype was not associated with less severe extra-skeletal manifestations, emphasizing the need for careful follow-up also in CHH patients with mild-skeletal manifestations. PMID- 28094438 TI - Environmental niche conservatism explains the accumulation of species richness in Mediterranean-hotspot plant genera. AB - The causes of exceptionally high plant diversity in Mediterranean-climate biodiversity hotspots are not fully understood. We asked whether a mechanism similar to the tropical niche conservatism hypothesis could explain the diversity of four large genera (Protea, Moraea, Banksia, and Hakea) with distributions within and adjacent to the Greater Cape Floristic Region (South Africa) or the Southwest Floristic Region (Australia). Using phylogenetic and spatial data we estimated the environmental niche of each species, and reconstructed the mode and dynamics of niche evolution, and the geographic history, of each genus. For three genera, there were strong positive relationships between the diversity of clades within a region and their inferred length of occupation of that region. Within genera, there was evidence for strong evolutionary constraint on niche axes associated with climatic seasonality and aridity, with different niche optima for hotspot and nonhotspot clades. Evolutionary transitions away from hotspots were associated with increases in niche breadth and elevated rates of niche evolution. Our results point to a process of "hotspot niche conservatism" whereby the accumulation of plant diversity in Mediterranean-type ecosystems results from longer time for speciation, with dispersal away from hotspots limited by narrow and phylogenetically conserved environmental niches. PMID- 28094437 TI - The deubiquitinating enzyme, ubiquitin-specific peptidase 50, regulates inflammasome activation by targeting the ASC adaptor protein. AB - NOD-like receptor family protein 3 (NLRP3)-mediated inflammasome activation promotes caspase-1-dependent production of interleukin-1beta (IL-1beta) and requires the adaptor protein ASC. Compared with the priming and activation mechanisms of the inflammasome signaling pathway, post-translational ubiquitination/deubiquitination mechanisms controlling inflammasome activation have not been clearly addressed. We here demonstrate that the deubiquitinating enzyme USP50 binds to the ASC protein and subsequently regulates the inflammasome signaling pathway by deubiquitinating the lysine 63-linked polyubiquitination of ASC. USP50 knockdown in human THP-1 cells and mouse bone marrow-derived macrophages shows a significant decrease in procaspase-1 cleavage, resulting in a reduced secretion of IL-1beta and interleukin-18 (IL-18) upon treatment with NLRP3 stimuli and a reduction in ASC speck formation and oligomerization. Thus, we elucidate a novel regulatory mechanism of the inflammasome signaling pathway mediated by the USP50 deubiquitinating enzyme. PMID- 28094439 TI - Adaptive evolution to novel predators facilitates the evolution of damselfly species range shifts. AB - Most species have evolved adaptations to reduce the chances of predation. In many cases, adaptations to coexist with one predator generate tradeoffs in the ability to live with other predators. Consequently, the ability to live with one predator may limit the geographic distributions of species, such that adaptive evolution to coexist with novel predators may facilitate range shifts. In a case study with Enallagma damselflies, we used a comparative phylogenetic approach to test the hypothesis that adaptive evolution to live with a novel predator facilitates range size shifts. Our results suggest that the evolution of Enallagma shifting from living in ancestral lakes with fish as top predators, to living in lakes with dragonflies as predators, may have facilitated an increase in their range sizes. This increased range size likely arose because lakes with dragonflies were widespread, but unavailable as a habitat throughout much of the evolutionary history of Enallagma because they were historically maladapted to coexist with dragonfly predators. Additionally, the traits that have evolved as defenses against dragonflies also likely enhanced damselfly dispersal abilities. While many factors underlie the evolutionary history of species ranges, these results suggest a role for the evolution of predator-prey interactions. PMID- 28094440 TI - Bidirectional communication between sensory neurons and osteoblasts in an in vitro coculture system. AB - Recent studies have revealed that the sensory nervous system is involved in bone metabolism. However, the mechanism of communication between neurons and osteoblasts is yet to be elucidated. In this study, we investigated the signaling pathways between sensory neurons of the dorsal root ganglion (DRG) and the osteoblast-like MC3T3-E1 cells using an in vitro coculture system. Our findings indicate that signal transduction from DRG-derived neurons to MC3T3-E1 cells is suppressed by antagonists of the AMPA receptor and the NK1 receptor. Conversely, signal transduction from MC3T3-E1 cells to DRG-derived neurons is suppressed by a P2X7 receptor antagonist. Our results suggest that these cells communicate with each other by exocytosis of glutamate, substance P in the efferent signal, and ATP in the afferent signal. PMID- 28094441 TI - Sex, drugs and rock and roll: tales from preterm fetal life. AB - Premature fetuses and babies are at greater risk of mortality and morbidity than their term counterparts. The underlying causes are multifactorial, but include exposure to hypoxia. Immaturity of organs and their functional control may impair the physiological defence responses to hypoxia and the preterm fetal responses, or lack thereof, to moderate hypoxia appear to support this concept. However, as this review demonstrates, despite immaturity, the preterm fetus responds to asphyxia in a qualitatively similar manner to that seen at term. This highlights the importance in understanding metabolism versus homeostatic threat when assessing fetal responses to adverse challenges such as hypoxia. Data are presented to show that the preterm fetal adaptation to asphyxia is triphasic in nature. Phase one represents the rapid institution of maximal defences, designed to maintain blood pressure and central perfusion at the expense of peripheral organs. Phase two is one of adaptive compensation. Controlled reperfusion partially offsets peripheral tissue oxygen debt, while maintaining sufficient vasoconstriction to limit the fall in perfusion. Phase three is about decompensation. Strikingly, the preterm fetus generally performs better during phases two and three, and can survive for longer without injury. Paradoxically, however, the ability to survive can lead to longer exposure to hypotension and hypoperfusion and thus potentially greater injury. The effects of fetal sex, inflammation and drugs on the triphasic adaptations are reviewed. Finally, the review highlights the need for more comprehensive studies to understand the complexity of perinatal physiology if we are to develop effective strategies to improve preterm outcomes. PMID- 28094442 TI - Identifying niche-mediated regulatory factors of stem cell phenotypic state: a systems biology approach. AB - Understanding how the cellular niche controls the stem cell phenotype is often hampered due to the complexity of variegated niche composition, its dynamics, and nonlinear stem cell-niche interactions. Here, we propose a systems biology view that considers stem cell-niche interactions as a many-body problem amenable to simplification by the concept of mean field approximation. This enables approximation of the niche effect on stem cells as a constant field that induces sustained activation/inhibition of specific stem cell signaling pathways in all stem cells within heterogeneous populations exhibiting the same phenotype (niche determinants). This view offers a new basis for the development of single cell based computational approaches for identifying niche determinants, which has potential applications in regenerative medicine and tissue engineering. PMID- 28094443 TI - Validity of simple clinical and biological parameters as screening tool for sickle cell anemia for referral to tertiary center in highly resource constraints. AB - BACKGROUND: In the Democratic Republic of Congo, the incidence of sickle cell anemia (SCA) is estimated around 40 000 neonates per year. However, it is notoriously difficult to perform conventional electrophoresis in all hospitals and laboratories, especially at peripheral levels and rural area. A panel of multiple clinical and laboratory features that would enhance sickle cell disease were assessed for the detection of the disease in highly resource-scarce settings. METHODS: A prospective study was conducted in Kinshasa. Venous blood samples were drawn from each study participant in order to determine the hematologic parameters, the peripheral smears, and the hemoglobin electrophoresis. We used Cohen's kappa statistic to examine the agreement of each variable and diagnosis of sickle cell disease. RESULTS: A total of 807 patients were screened for sickle cell disease. Among these 807 children, 36 (4.5%) were homozygous for Hb S disease. The presence of at least 8% erythroblasts (PPV: 91%, NPV: 99%, sensitivity: 83.3%, specificity: 99.6%, kappa value: .86) and sickle cells (PPV:100%, NPV: 98%, sensitivity: 50%, specificity: 100%, kappa value: .66) in the peripheral blood smear had an acceptable agreement for sickle cell disease. CONCLUSION: These two biological markers may guide the clinician in the decision-making to initiate the management of the children as a sickle cell patient, pending confirmation of the disease by electrophoresis techniques. PMID- 28094444 TI - The Current State of NAD+ -Dependent Histone Deacetylases (Sirtuins) as Novel Therapeutic Targets. AB - Sirtuins are NAD+ -dependent protein deacylases that cleave off acetyl, as well as other acyl groups, from the epsilon-amino group of lysines in histones and other substrate proteins. Seven sirtuin isotypes (Sirt1-7) have been identified in mammalian cells. As sirtuins are involved in the regulation of various physiological processes such as cell survival, cell cycle progression, apoptosis, DNA repair, cell metabolism, and caloric restriction, a dysregulation of their enzymatic activity has been associated with the pathogenesis of neoplastic, metabolic, infectious, and neurodegenerative diseases. Thus, sirtuins are promising targets for pharmaceutical intervention. Growing interest in a modulation of sirtuin activity has prompted the discovery of several small molecules, able to inhibit or activate certain sirtuin isotypes. Herein, we give an update to our previous review on the topic in this journal (Schemies, 2010), focusing on recent developments in sirtuin biology, sirtuin modulators, and their potential as novel therapeutic agents. PMID- 28094446 TI - Deep sequencing of a candidate region harboring the SOX9 gene for the canine XX disorder of sex development. AB - A disorder of sex development (DSD) in dogs with female sex chromosomes (78, XX), a lack of the SRY gene and the presence of testes or ovotestes is commonly diagnosed in numerous breeds. The molecular background of DSD is not fully recognized but has been linked to the copy number variation in the region harboring the SOX9 gene. We applied a genome-wide association study and targeted next-generation sequencing techniques to compare DSD and normal female dogs. The genome-wide association study did not indicate a significant chromosome region. Targeted next-generation sequencing of a 1.5-Mb region on canine chromosome 9 harboring the SOX9 gene revealed two putatively DSD-associated copy number variations 355 kb upstream and 691 kb downstream of SOX9, four blocks of low polymorphism and two blocks of an elevated heterozygosity. An initial next generation sequencing analysis showed an association with two SNPs, but validation in larger cohorts did not confirm this result. We identified a large homologous fragment (over 243.8 kb), named hfMAGI2, located upstream of SOX9, that overlaps a known copy number variation region. It shows a high sequence similarity with the 5' flanking region of the MAGI2 gene located on canine chromosome 18 that encodes a protein involved in ovary formation during early embryonic development. Our study showed that the identified copy number variation region located upstream of the SOX9 gene contains potential regulatory sequences (long non-coding RNA and hfMAGI2) and led to the assumption that a multiplication of this element may alter expression of the SOX9 gene, triggering the DSD phenotype. PMID- 28094447 TI - On the origins and genetic diversity of South American chickens: one step closer. AB - Local chicken populations are a major source of food in the rural areas of South America. However, very little is known about their genetic composition and diversity. Here, we analyzed five populations from South America to investigate their maternal genetic origin and diversity, hoping to mitigate the lack of information on local chicken populations from this region. We also included three populations of chicken from the Iberian Peninsula and one from Easter Island, which are potential sources of the first chickens introduced in South America. The obtained sequencing data from South American chickens indicate the presence of four haplogroups (A, B, E and D) that can be further subdivided into nine sub haplogroups. Of these, four (B1, D1a, E1a(b), E1b) were absent from local Iberian Peninsula chickens and one (D1a) was present only on Easter Island. The presence of the sub-haplogroups A1a(b) and E1a(b) in South America, previously only observed in Eastern Asia, and the significant population differentiation between Iberian Peninsula and South American populations, suggest a second maternal source of the extant genetic pool in South American chickens. PMID- 28094445 TI - Presynaptic inhibition of transient receptor potential vanilloid type 1 (TRPV1) receptors by noradrenaline in nociceptive neurons. AB - KEY POINTS: The transient receptor potential vanilloid type 1 (TRPV1) receptor is a polymodal molecular integrator in the pain pathway expressed in Adelta- and C fibre nociceptors and is responsible for the thermal hyperalgesia associated with inflammatory pain. Noradrenaline strongly inhibited the activity of TRPV1 channels in dorsal root ganglia neurons. The effect of noradrenaline was reproduced by clonidine and antagonized by yohimbine, consistent with contribution of alpha2 adrenergic receptors. The inhibitory effect of noradrenaline on TRPV1 channels was dependent on calcium influx and linked to calcium/calmodulin-dependent protein kinase II. In spinal cord slices, clonidine reduced the frequency of capsaicin-induced miniature EPSCs in the presence of tetrodotoxin and omega-conotoxin-MVIIC, consistent with inhibition of presynaptic TRPV1 channels by alpha2 adrenergic receptors. We suggest that modulation of presynaptic TRPV1 channels in nociceptive neurons by descending noradrenergic inputs may constitute a mechanism for noradrenaline to modulate incoming noxious stimuli in the dorsal horn of the spinal cord. ABSTRACT: The transient receptor potential vanilloid type 1 (TRPV1) receptor is a well-known contributor to nociceptor excitability. To address whether noradrenaline can down-regulate TRPV1 channel activity in nociceptors and reduce their synaptic transmission, the effects of noradrenaline and clonidine were tested on the capsaicin-activated current recorded from acutely dissociated small diameter (<27 MUm) dorsal root ganglia (DRG) neurons and on miniature (m)EPSCs recorded from large lamina I neurons in horizontal spinal cord slices. Noradrenaline or clonidine inhibited the capsaicin-activated current by ~60%, and the effect was reversed by yohimbine, confirming that it was mediated by activation of alpha2 adrenergic receptors. Similarly, clonidine reduced the frequency of capsaicin-induced mEPSCs by ~60%. Inhibition of capsaicin-activated current by noradrenaline was mediated by GTP binding proteins, and was highly dependent on calcium influx. The inhibitory effect of noradrenaline on the capsaicin-activated current was not affected either by blocking the activity of protein kinase A with H89, or by blocking the activity of protein kinase C with bisindolylmaleimide II. In contrast, when the calcium/calmodulin-dependent protein kinase II (CaMKII) was blocked with KN-93, the inhibitory effect of noradrenaline on the capsaicin activated current was greatly reduced, suggesting that activation of adrenergic receptors in DRG neurons is preferentially linked to CaMKII activity. We suggest that modulation of TRPV1 channels by noradrenaline in nociceptive neurons is a mechanism whereby noradrenaline may suppress incoming noxious stimuli at the primary synaptic afferents in the dorsal horn of the spinal cord. PMID- 28094448 TI - Human Antimicrobial Peptides in Bodily Fluids: Current Knowledge and Therapeutic Perspectives in the Postantibiotic Era. AB - Antimicrobial peptides (AMPs) are an integral part of the innate immune defense mechanism of many organisms. Due to the alarming increase of resistance to antimicrobial therapeutics, a growing interest in alternative antimicrobial agents has led to the exploitation of AMPs, both synthetic and isolated from natural sources. Thus, many peptide-based drugs have been the focus of increasing attention by many researchers not only in identifying novel AMPs, but in defining mechanisms of antimicrobial peptide activity as well. Herein, we review the available strategies for the identification of AMPs in human body fluids and their mechanism(s) of action. In addition, an overview of the distribution of AMPs across different human body fluids is provided, as well as its relation with microorganisms and infectious conditions. PMID- 28094450 TI - Relational Priming Based on a Multiplicative Schema for Whole Numbers and Fractions. AB - Why might it be (at least sometimes) beneficial for adults to process fractions componentially? Recent research has shown that college-educated adults can capitalize on the bipartite structure of the fraction notation, performing more successfully with fractions than with decimals in relational tasks, notably analogical reasoning. This study examined patterns of relational priming for problems with fractions in a task that required arithmetic computations. College students were asked to judge whether or not multiplication equations involving fractions were correct. Some equations served as structurally inverse primes for the equation that immediately followed it (e.g., 4 * 3/4 = 3 followed by 3 * 8/6 = 4). Students with relatively high math ability showed relational priming (speeded solution times to the second of two successive relationally related fraction equations) both with and without high perceptual similarity (Experiment 2). Students with relatively low math ability also showed priming, but only when the structurally inverse equation pairs were supported by high perceptual similarity between numbers (e.g., 4 * 3/4 = 3 followed by 3 * 4/3 = 4). Several additional experiments established boundary conditions on relational priming with fractions. These findings are interpreted in terms of componential processing of fractions in a relational multiplication context that takes advantage of their inherent connections to a multiplicative schema for whole numbers. PMID- 28094451 TI - Development of Diversity Arrays Technology markers as a tool for rapid genomic assessment in Nile tilapia, Oreochromis niloticus. AB - The development of genomic markers is described for Nile tilapia, Oreochromis niloticus, using the Diversity Arrays Technology (DArT) genotype-by-sequencing platform. A total of 13 215 single nucleotide polymorphism (SNP) markers and 12 490 silicoDArT (dominant) markers were identified from broodstock of two selective breeding programs [Genetically Improved Farmed Tilapia (GIFT) strain from Malaysia and the Abbassa strain from Egypt]. Over 10 000 SNPs were polymorphic in either strain, and 2985 and 3087 showed strain-specific polymorphisms for the GIFT and Abbassa strains respectively. We demonstrate the potential utility of these markers for rapid genomic screening and use in breeding programs. PMID- 28094449 TI - Genetic diversity and patterns of population structure in Creole goats from the Americas. AB - Biodiversity studies are more efficient when large numbers of breeds belonging to several countries are involved, as they allow for an in-depth analysis of the within- and between-breed components of genetic diversity. A set of 21 microsatellites was used to investigate the genetic composition of 24 Creole goat breeds (910 animals) from 10 countries to estimate levels of genetic variability, infer population structure and understand genetic relationships among populations across the American continent. Three commercial transboundary breeds were included in the analyses to investigate admixture with Creole goats. Overall, the genetic diversity of Creole populations (mean number of alleles = 5.82 +/- 1.14, observed heterozygosity = 0.585 +/- 0.074) was moderate and slightly lower than what was detected in other studies with breeds from other regions. The Bayesian clustering analysis without prior information on source populations identified 22 breed clusters. Three groups comprised more than one population, namely from Brazil (Azul and Grauna; Moxoto and Repartida) and Argentina (Long and shorthair Chilluda, Pampeana Colorada and Angora-type goat). Substructure was found in Criolla Paraguaya. When prior information on sample origin was considered, 92% of the individuals were assigned to the source population (threshold q >= 0.700). Creole breeds are well-differentiated entities (mean coefficient of genetic differentiation = 0.111 +/- 0.048, with the exception of isolated island populations). Dilution from admixture with commercial transboundary breeds appears to be negligible. Significant levels of inbreeding were detected (inbreeding coefficient > 0 in most Creole goat populations, P < 0.05). Our results provide a broad perspective on the extant genetic diversity of Creole goats, however further studies are needed to understand whether the observed geographical patterns of population structure may reflect the mode of goat colonization in the Americas. PMID- 28094452 TI - The dipteran parasitoid Exorista bombycis induces pro- and anti-oxidative reactions in the silkworm Bombyx mori: Enzymatic and genetic analysis. AB - Hymenopteran parasitoids inject various factors including polydnaviruses along with their eggs into their host insects that suppress host immunity reactions to the eggs and larvae. Less is known about the mechanisms evolved in dipteran parasitoids that suppress host immunity. Here we report that the dipteran, Exorista bombycis, parasitization leads to pro-oxidative reactions and activation of anti-oxidative enzymes in the silkworm Bombyx mori larva. We recorded increased activity of oxidase, superoxide dismutase, thioredoxin peroxidase, catalase, glutathione-S-transferase (GST), and peroxidases in the hemolymph plasma, hemocytes, and fat body collected from B. mori after E. bombycis parasitization. Microarray and qPCR showed differential expression of genes encoding pro- and anti-oxidant enzymes in the hemocytes. The significance of this work lies in increased understanding of dipteran parasitoid biology. PMID- 28094453 TI - Down-regulation of a chitin synthase a gene by RNA interference enhances pathogenicity of Beauveria bassiana ANU1 against Spodoptera exigua (HUBNER). AB - Chitin synthase (CHS) is an important enzymatic component, which is required for chitin formation in the cuticles and cuticular linings of other tissues in insects. CHSs have been divided into two classes, classes A and B, based on their amino acid sequence similarities and functions. Class A CHS (CHS-A) is specifically expressed in the epidermis and related ectodermal cells such as tracheal cells, while class B CHS (CHS-B) is expressed in gut epithelial cells that produce peritrophic matrices. In this study, we cloned the CHS-A gene from the beet armyworm, Spodoptera exigua (SeCHS-A). The SeCHS-A contains an open reading frame of 4,698 nucleotides, encoding a protein of 1,565 amino acids with a predicted molecular mass of approximately 177.8 kDa. The SeCHS-A mRNA was expressed in all developmental stages and specifically in the epidermis and tracheae tissue by quantitative real-time-PCR analysis. Expression of SeCHS-A gene was suppressed by feeding double-stranded RNA (dsCHS-A, 400 ng/larva) in the third instar larvae of S. exigua. Suppression of the SeCHS-A gene expression significantly increased 35% of mortality on pupation of S. exigua. Also, the third instar larvae fed with dsCHS-A significantly increased susceptibility to entomopathogenic fungi, Beauveria bassiana ANU1 at 3 days after treatment. These results suggest that the SeCHS-A gene plays an important role in development of S. exigua and RNA interference may apply to effective pest control with B. bassiana. PMID- 28094454 TI - Boosting the reserves: additive regulation of cardiac repolarisation. PMID- 28094455 TI - Body regions have an impact on the collagen/elastin index of the skin measured by non-invasive in vivo vertical two-photon microscopy. AB - It is known that the collagen and elastin fibre structures are changing with age. There is little knowledge about the influence of body area as these investigations have been limited for ethical reasons, so far. Thus, modified non invasive two-photon microscopy was used providing vertical optical sections of second harmonic generation and autofluorescence to calculate the collagen-to elastin ratio and its alterations depending on the investigated body site in vivo. The results of this study indicate that the impact of different body areas could be higher than the influence of age and should be considered in future studies. PMID- 28094456 TI - Waldenstrom macroglobulinemia: 2017 update on diagnosis, risk stratification, and management. AB - : Disease Overview: Waldenstrom macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. DIAGNOSIS: Presence of IgM monoclonal protein associated with >=10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients. Risk Stratification: Age, hemoglobin level, platelet count, beta2 microglobulin, and monoclonal IgM concentrations are characteristics required for prognosis. Risk Adapted Therapy: Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-based therapy is used in virtually all U.S. patients with WM and can be combined with bendamustine, an alkylating agent, or a proteosome inhibitor. Purine nucleoside analogues are widely used in Europe. The preferred Mayo Clinic nonstudy therapeutic induction is rituximab and bendamustine. Potential for stem cell transplantation should be considered in induction therapy selection. Management of Refractory Disease: Bortezomib, fludarabine, thalidomide, everolimus, ibrutinib, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in WM. Given WM's natural history, reduction of complications will be a priority for future treatment trials. Am. J. Hematol. 92:209-217, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28094457 TI - Granzyme A potentiates chemokine production in IL-17-stimulated keratinocytes. AB - Plaque psoriasis presents with focal skin inflammation, partially maintained by IL-17-mediated interactions between infiltrating epidermal T cells and activated keratinocytes. Here we show that the majority of lesional epidermal CD8 T cells express granzyme A, alone or in combination with IL-17. To assess proinflammatory properties of granzyme A in psoriasis, primary human keratinocytes were stimulated with granzyme A in the presence or absence of IL-17. Out of 33 analysed keratinocyte-derived inflammatory mediators, granzyme A potentiated IL 17-induced secretion of CXCL 1, CXCL 12 and CCL 4. Intriguingly, all three chemokines are implicated in psoriasis pathogenesis and are involved in recruitment of T cells, neutrophils and pDCs into inflamed tissues. Our results indicate that granzyme A produced by lesional CD8 T cells specifically increase the chemokine production from inflamed keratinocytes, thereby amplifying a chemotactic inflammatory loop that sustains psoriasis lesions. PMID- 28094459 TI - Investigation of Binding Behavior between Drug Molecule 5-Fluoracil and M4 L4 Type Tetrahedral Cages: Selectivity, Capture, and Release. AB - Two analogous M4 L4 -type tetrahedral cages (smaller: MOC-19; larger: MOC-22) were synthesized and investigated for their interactions with the anticancer drug 5-fluoracil (5-FU) by NMR spectroscopy, high-resolution electrospray-ionization mass spectrometry (HR-ESI-MS), and molecular simulation. The cage's size and window are of importance for the host-guest binding, and consequently the smaller MOC-19 with a more suitable size of cavity window was found to have much stronger hydrogen-bond interactions with 5-FU. The porous nanoparticles of MOC-19 exhibited outstanding behavior for the controlled release of 5-FU in a simulated human body with liquid phosphate-buffered saline solution. PMID- 28094458 TI - Inquiring about insomnia may facilitate diagnosis of depression in the primary care setting. AB - AIM: Depression is often undiagnosed in primary care. Asking about sleep status is much easier than asking about mood. This study was conducted to examine the relation between insomnia and depression. METHODS: New patients aged 35-64 years were recruited from internal medicine clinics in Japan. Self-administered questionnaires were employed. Depression was evaluated by the Zung Self-Rating Depression Scale and the Profile of Mood States. Sleep status was investigated using the Pittsburgh Sleep Quality Index. Likelihood ratios of insomnia for depression were calculated. To assess the relation between insomnia and depression independent of confounding factors, adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using multiple logistic regression analyses. RESULTS: Among 598 subjects, 153 (25.6%) were assessed as having depression. 'Very bad sleep quality, with difficulty falling asleep within 30 min >=3 times/week' showed a positive likelihood ratio of 20.36 (95%CI, 2.53-164) while 'not very good sleep quality' had a negative likelihood ratio of 0.32 (95%CI, 0.14-0.72). Adjusted for sex, age, underlying diseases, major life events, lifestyle habits, and relationship problems, significant OR for depression were observed for 'difficulty falling asleep within 30 min >=3 times/week' (OR, 2.53; 95%CI, 1.07-5.98), 'waking up in the middle of the night or early morning >=3 times/week' (OR, 3.09; 95%CI, 1.58-6.05), and 'fairly bad sleep quality' (OR, 3.65; 95%CI, 1.34-9.96). CONCLUSION: Inquiring about the weekly frequency of difficulty 'falling asleep within 30 min,' 'waking up in the middle of the night or early morning,' and 'sleep quality' may help to diagnose depression. PMID- 28094460 TI - N-Heterocyclic Carbene-Catalyzed Intramolecular Nucleophilic Substitution: Enantioselective Construction of All-Carbon Quaternary Stereocenters. AB - An efficient enantioselective N-heterocyclic carbene (NHC)-catalyzed intramolecular SN 2' nucleophilic substitution of aldehydes with (E/Z) trisubstituted allylic bromides was accomplished. A range of enantioenriched chromanones bearing an all-carbon quaternary stereocenter at the C3 position were prepared with up to 97 % yield and 98 % enantiomeric excess. The resulting vinyl and carbonyl groups in these products can be transformed into a variety of synthetically important building blocks. PMID- 28094461 TI - Comparison of the 32-item Hypomania Checklist, the 33-item Hypomania Checklist, and the Mood Disorders Questionnaire for bipolar disorder. AB - AIM: Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD) and hence reliable and culturally appropriate screening tools are needed. This study compared the 32-item Hypomania Checklist (HCL-32), the 33-item Hypomania Checklist (HCL-33), and the Mood Disorders Questionnaire (MDQ) for BD. METHODS: Altogether, 350 depressed patients were included. The HCL-32, HCL-33, and MDQ were completed by patients to identify manic and/or hypomanic symptoms. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve among the HCL-32, HCL-33, and MDQ for BD and MDD were calculated and compared, using cut-offs suggested by respective validation studies. RESULTS: Of the three scales, the MDQ had the highest sensitivity and NPV (sensitivity = 0.90, 0.81, and 0.90 for BD vs MDD, BD I vs MDD, and BD-II vs MDD, respectively; NPV = 0.78, 0.86, and 0.86 for BD vs MDD, BD-I vs MDD, and BD-II vs MDD, respectively), while the HCL-33 had the highest specificity and PPV (specificity = 0.74, 0.69, and 0.66 for BD vs MDD, BD I vs MDD, and BD-II vs MDD, respectively; PPV = 0.74, 0.55, and 0.56 for BD vs MDD, BD-I vs MDD, and BD-II vs MDD, respectively). CONCLUSION: Compared to both HCL scales, the MDQ had higher sensitivity and lower specificity in screening for BD. These results contradict previous findings in Western populations. As a screening instrument for BD in Chinese clinical settings, the MDQ appears to be appropriate. PMID- 28094462 TI - Orientation of the OmpF Porin in Planar Lipid Bilayers. AB - The outer-membrane protein OmpF is an abundant trimeric general diffusion porin that plays a central role in the transport of antibiotics and colicins across the outer membrane of E. coli. Individual OmpF trimers in planar lipid bilayers (PLBs) show one of two current-voltage asymmetries, thus implying that insertion occurs with either the periplasmic or the extracellular end first. A method for establishing the orientation of OmpF in PLB was developed, based on targeted covalent modification with membrane-impermeant reagents of peripheral cysteine residues introduced near the periplasmic or the extracellular entrance. By correlating the results of the modification experiments with measurements of current asymmetry or the sidedness of binding of the antibiotic enrofloxacin, OmpF orientation could be quickly determined in subsequent experiments under a variety of conditions. Our work will allow the precise interpretation of past and future studies of antibiotic permeation and protein translocation through OmpF and related porins. PMID- 28094463 TI - Network over-connectivity differentiates autism spectrum disorder from other developmental disorders in toddlers: A diffusion MRI study. AB - Advanced connectivity studies in toddlers with Autism Spectrum Disorder (ASD) are increasing and consistently reporting a disruption of brain connectivity. However, most of these studies compare ASD and typically developing subjects, thus providing little information on the specificity of the abnormalities detected in comparison with other developmental disorders (other-DD). We recruited subjects aged below 36 months who received a clinical diagnosis of Neurodevelopmental Disorder (32 ASD and 16 other-DD including intellectual disability and language disorder) according to DSM-IV TR. Structural and diffusion MRI were acquired to perform whole brain probabilistic and anatomically constrained tractography. Network connectivity matrices were built encoding the number of streamlines (DNUM ) and the tract-averaged fractional anisotropy (DFA ) values connecting each pair of cortical and subcortical regions. Network Based Statistics (NBS) was finally applied on the connectivity matrices to evaluate the network differences between the ASD and other-DD groups. The network differences resulted in an over-connectivity pattern (i.e., higher DNUM and DFA values) in the ASD group with a significance of P < 0.05. No contra-comparison results were found. The over-connectivity pattern in ASD occurred in networks primarily involving the fronto-temporal nodes, known to be crucial for social-skill development and basal ganglia, related to restricted and repetitive behaviours in ASD. To our knowledge, this is the first network-based diffusion study comparing toddlers with ASD and those with other-DD. Results indicate the detection of different connectivity patterns in ASD and other-DD at an age when clinical differential diagnosis is often challenging. Hum Brain Mapp 38:2333-2344, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28094464 TI - Test-retest reliability of functional connectivity networks during naturalistic fMRI paradigms. AB - Functional connectivity analysis has become a powerful tool for probing the human brain function and its breakdown in neuropsychiatry disorders. So far, most studies adopted resting-state paradigm to examine functional connectivity networks in the brain, thanks to its low demand and high tolerance that are essential for clinical studies. However, the test-retest reliability of resting state connectivity measures is moderate, potentially due to its low behavioral constraint. On the other hand, naturalistic neuroimaging paradigms, an emerging approach for cognitive neuroscience with high ecological validity, could potentially improve the reliability of functional connectivity measures. To test this hypothesis, we characterized the test-retest reliability of functional connectivity measures during a natural viewing condition, and benchmarked it against resting-state connectivity measures acquired within the same functional magnetic resonance imaging (fMRI) session. We found that the reliability of connectivity and graph theoretical measures of brain networks is significantly improved during natural viewing conditions over resting-state conditions, with an average increase of almost 50% across various connectivity measures. Not only sensory networks for audio-visual processing become more reliable, higher order brain networks, such as default mode and attention networks, but also appear to show higher reliability during natural viewing. Our results support the use of natural viewing paradigms in estimating functional connectivity of brain networks, and have important implications for clinical application of fMRI. Hum Brain Mapp 38:2226-2241, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28094465 TI - Determining the effective coverage of maternal and child health services in Kenya, using demographic and health survey data sets: tracking progress towards universal health coverage. AB - OBJECTIVES: Effective coverage (EC) is a measure of health systems' performance that combines need, use and quality indicators. This study aimed to assess the extent to which the Kenyan health system provides effective and equitable maternal and child health services, as a means of tracking the country's progress towards universal health coverage. METHODS AND RESULTS: The Demographic Health Surveys (2003, 2008-2009 and 2014) and Service Provision Assessment surveys (2004, 2010) were the main sources of data. Indicators of need, use and quality for eight maternal and child health interventions were aggregated across interventions and economic quintiles to compute EC. EC has increased from 26.7% in 2003 to 50.9% in 2014, but remains low for the majority of interventions. There is a reduction in economic inequalities in EC with the highest to lowest wealth quintile ratio decreasing from 2.41 in 2003 to 1.65 in 2014, but maternal health services remain highly inequitable. CONCLUSIONS: Effective coverage of key maternal and child health services remains low, indicating that individuals are not receiving the maximum possible health gain from existing health services. There is an urgent need to focus on the quality and reach of maternal and child health services in Kenya to achieve the goals of universal health coverage. PMID- 28094466 TI - Effects of beta-blockers on all-cause mortality in patients with type 2 diabetes and coronary heart disease. AB - AIMS: To assess whether the use of beta-blockers influences mortality and the incidence of major cardiovascular events in patients with diabetes and coronary heart disease (CHD). MATERIALS AND METHODS: Using data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial, we performed Cox proportional hazards analysis to assess the effects of beta-blockers on all-cause mortality in 2244 patients with type 2 diabetes who had stable CHD with and without a history of myocardial infarction (MI)/heart failure with reduced left ventricular ejection fraction (HFrEF). RESULTS: All-cause mortality in patients with MI/HFrEF was significantly lower in those receiving beta-blockers than in those not receiving beta-blockers (adjusted hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.37-0.98; P = .04), whereas that in patients without MI/HFrEF did not significantly differ (adjusted HR 0.91, 95% CI 0.76-1.32; P = .64). Among patients with MI/HFrEF, all-cause mortality in those who received intensive medical therapy alone for CHD was significantly lower in those on beta blockers than in those not on beta-blockers (adjusted HR 0.45, 95% CI 0.23-0.88; P = .02); however, mortality in patients who received early revascularization for CHD was not significantly lower in those on beta-blockers (adjusted HR 0.81, 95% CI 0.40-1.65; P = .57). The risk of major cardiovascular events in patients without MI/HFrEF was not significantly different between those on and those not on beta-blocker treatment. CONCLUSIONS: In patients with diabetes and CHD, the use of beta-blockers was effective in reducing all-cause mortality in those with MI/HFrEF but not in those without MI/HFrEF. PMID- 28094467 TI - Chemical Composition and Biological Activities of the Essential Oil from Leaves and Flowers of Pulicaria incisa sub. candolleana (Family Asteraceae). AB - The composition of the essential oil isolated from leaves and flowers of Pulicaria incisa sub. candolleana E. Gamal-Eldin, growing in Egypt, was analysed by GC and GC-MS. Forty-nine and 68 compounds were identified from the oils of the leaves and flowers accounting for 86.69 and 84.29%, respectively of the total detected constituents. Both leaves and flowers oils were characterized by the high content of carvotanacetone with 66.01, 50.87 and chrysanthenone 13.26, 24.3%, respectively. The cytotoxic activity of both essential oils was evaluated against hepatocellular carcinoma cell line HEPG-2, using MTT assay and vinblastine as a reference drug. Leaf oil showed higher activity with IC50 11.4 MUg/ml compared with 37.4 MUg/ml for flower oil. The antimicrobial activity of both oils was evaluated using agar well diffusion method towards two representatives for each of Gram positive and Gram negative bacteria as well as four representatives for fungi. The minimum inhibitory concentration of both essential oils against bacterial and fungal strains was obtained in the range of 0.49 - 15.63 MUg/ml. PMID- 28094468 TI - Long-term outcomes of transobturator tapes in women with stress urinary incontinence: E-TOT randomised controlled trial. AB - OBJECTIVE: To assess the long-term patient-reported outcomes and adverse events following surgery using transobturator tension-free vaginal tape (TO-TVT). DESIGN: Postal follow-up of the E-TOT randomised controlled trial (RCT). SETTING: A tertiary urogynaecology centre in the UK; all procedures took place in 2005 2007. POPULATION: A total of 341 women were randomised to receive either 'inside out' TVT-O (Ethicon Inc., Somerville, NJ, USA) or 'outside-in' TOT-ARIS (Coloplast Corp., Minneapolis, MN, USA) procedure. METHODS: Long-term follow-up (median 9 years) using validated symptom severity and quality-of-life (QoL) questionnaires. Statistical analysis was performed using spss 22.0 and GraphPad statistics 2014. MAIN OUTCOME MEASURES: The primary outcome was patient-reported success rate, defined as 'very much/much improved' on the Patient's Global Impression of Improvement (PGI-I) scale. Secondary outcomes included impact on women's QoL and sexual function, adverse events, and re-operations for stress urinary incontinence (SUI). RESULTS: The adjusted response rate was 67.8% and the median follow-up period was 9.2 years. The overall patient-reported success rate was 71.6%, with a further 14% reporting 'improvement', and there was no significant difference between inside-out and outside-in groups (P = 0.76; odds ratio, OR 0.8676; 95% confidence interval, 95% CI 0.4744-1.5865). The success rate showed a significant reduction compared with 1-year results (71.6 versus 80%; P = 0.004), but a clinically insignificant reduction when compared with the 3-year results (71.6 versus 73.1%). A total of 7.96% underwent further continence surgery, the tape extrusion/erosion rate was 4.5%, and groin pain/discomfort was reported in 4.32%, with only 1.4% requiring treatment. CONCLUSIONS: This is the largest and longest follow-up randomised trial of TO-TVT. TO-TVT is associated with 71.6% patient-reported success rate, 4% groin pain/discomfort, and 8% continence re-operation rate at a median of 9 years follow-up. The success rate is almost stable after 3 years. TWEETABLE ABSTRACT: The success rate for TO-TVT is 71% at 9 years, and is almost stable after 3 years; 8% required repeat surgery. PMID- 28094469 TI - Immunohistochemical assessment of glucagon-like peptide 1 receptor (GLP-1R) expression in the pancreas of patients with type 2 diabetes. AB - AIMS: Glucagon-like peptide-1 (GLP-1) is an incretin hormone which stimulates insulin release and inhibits glucagon secretion from the pancreas in a glucose dependent manner. Incretin-based therapies, consisting of GLP-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, are used for the treatment of type 2 diabetes (T2D). Immunohistochemical studies for GLP-1R expression have been hampered previously by the use of unspecific polyclonal antibodies. This study aimed to assess the expression levels of GLP-1R in a set of T2D donor samples obtained via nPOD. METHODS: This study used a new monoclonal antibody to assess GLP-1R expression in pancreatic tissue from 23 patients with T2D, including 7 with a DPP-4 inhibitor and 1 with a history of GLP-1R agonist treatment. A software-based automated image analysis algorithm was used for quantitating intensities and area fractions of GLP-1R positive compartments. RESULTS: The highest intensity GLP-1R immunostaining was seen in beta-cells in islets (average signal intensity, 76.1 [+/-8.1]). GLP-1R/insulin double-labelled single cells or small clusters of cells were also frequently located within or in close vicinity of ductal epithelium in all samples and with the same GLP-1R immunostaining intensity as found in beta-cells in islets. In the exocrine pancreas a large proportion of acinar cells expressed GLP-1R with a 3-fold lower intensity of immunoreactivity as compared to beta-cells (average signal intensity 25.5 [+/-3,3]). Our studies did not unequivocally demonstrate GLP-1R immunoreactivity on normal-appearing ductal epithelium. Pancreatic intraepithelial neoplasia (PanINs; a form of non-invasive pancreatic ductular neoplasia) was seen in most samples, and a minority of these expressed low levels of GLP-1R. CONCLUSION: These data confirm the ubiquity of early stage PanIN lesions in patients with T2D and do not support the hypothesis that incretin based therapies are associated with progression towards the more advanced stage PanIN lesions. PMID- 28094470 TI - Mechanistic Studies of Cyclohexene Oxide/CO2 Copolymerization by a Chromium(III) Pyridylamine-Bis(Phenolate) Complex. AB - Chromium(III) chlorido amine-bis(phenolate) complexes paired with nucleophilic co catalysts are a promising family of catalysts for the copolymerization of CO2 and epoxides to selectively produce polycarbonates with a very high degree of carbonate linkages. Single-component catalyst systems can be prepared, where the neutral nucleophile, 4-dimethylaminopyridine (DMAP), is coordinated to the metal site to provide a stable octahedral CrIII complex. These complexes possess the potential for both anionic (from the chlorido ligand) or neutral (DMAP) nucleophilic epoxide ring-opening during the proposed rate-determining initiation step. Concentration effect studies support a first-order dependence of the polymerization rate on the concentration of single-component catalyst. End-group analysis of polycarbonates by MALDI-TOF MS indicate the presence of predominantly DMAP-initiated chains as well as the occurrence of chain-transfer events resulting in ether linkages, likely from the presence of cyclohexene diol formed by the reaction of cyclohexene oxide and adventitious water. PMID- 28094471 TI - Cleanable Air Filter Transferring Moisture and Effectively Capturing PM2.5. AB - The lethal danger of particulate matter (PM) pollution on health leads to the development of challenging individual protection materials that should ideally exhibit a high PM2.5 purification efficiency, low air resistance, an important moisture-vapor transmission rate (MVTR), and an easy-to-clean property. Herein, a cleanable air filter able to rapidly transfer moisture and efficiently capture PM2.5 is designed by electrospinning superhydrophilic polyacrylonitrile/silicon dioxide fibers as the adsorption-desorption vector for moisture-vapor, and hydrophobic polyvinylidene fluoride fibers as the repellent components to avoid the formation of capillary water under high humidity. The desorption rate of water molecules increases from 10 to 18 mg min-1 , while the diameters of polyacrylonitrile fibers reduce from 1.02 to 0.14 um. Significantly, by introducing the hydroxyl on the surface of polyacrylonitrile nanofibers, rapid adsorption-desorption of the water molecules is observed. Moreover, by constructing a hydrophobic to super-hydrophilic gradient structure, the MVTR increases from 10 346 to 14 066 g m-2 d-1 . Interestingly, the prepared fibrous membranes is easy to clean. More importantly, benefiting from enhanced slip effect, the resultant fibrous membranes presented a low air resistance of 86 Pa. A field test in Shanghai shows that the air filter maintains stable PM2.5 purification efficiency of 99.99% at high MVTR during haze event. PMID- 28094473 TI - Transmeatal tympanoplasty of subtotal and anterior perforations: a single institution experience including 94 patients. PMID- 28094472 TI - Outpatient 60-hour day-and-night glucose control with dual-hormone artificial pancreas, single-hormone artificial pancreas, or sensor-augmented pump therapy in adults with type 1 diabetes: An open-label, randomised, crossover, controlled trial. AB - AIMS: To assess whether the dual-hormone (insulin and glucagon) artificial pancreas reduces hypoglycaemia compared to the single-hormone (insulin alone) artificial pancreas in outpatient settings during the day and night. MATERIAL AND METHODS: In a randomized, three-way, crossover trial we compared the dual-hormone artificial pancreas, the single-hormone artificial pancreas and sensor-augmented pump therapy (control) in 23 adults with type 1 diabetes. Each intervention was applied from 8 AM Day 1 to 8 PM Day 3 (60 hours) in outpatient free-living conditions. The primary outcome was time spent with sensor glucose levels below 4.0 mmol/L. A P value of less than .017 was regarded as significant. RESULTS: The median difference between the dual-hormone system and the single-hormone system was -2.3% (P = .072) for time spent below 4.0 mmol/L, -1.3% (P = .017) for time below 3.5 mmol/L, and -0.7% (P = .031) for time below 3.3 mmol/L. Both systems reduced (P < .017) hypoglycaemia below 4.0, 3.5 and 3.3 mmol/L compared to control therapy, but reductions were larger with the dual-hormone system than with the single-hormone system (medians -4.0% vs -3.4% for 4.0 mmol/L; -2.7% vs 2.2% for 3.5 mmol/L; and -2.2% vs -1.2% for 3.3 mmol/L). There were 34 hypoglycaemic events (<3.0 mmol/L for 20 minutes) with control therapy, 14 with the single-hormone system and 6 with the dual-hormone system. These differences in hypoglycaemia were observed while mean glucose level was low and comparable in all interventions (P = NS). CONCLUSIONS: The dual-hormone artificial pancreas had the lowest risk of hypoglycaemia, but the differences were not statistically significant. Larger studies are needed. PMID- 28094475 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 5/2017. PMID- 28094474 TI - Introduction: integrative molecular ecology is rapidly advancing the study of adaptation and speciation. PMID- 28094476 TI - DNA-Encoded Compound Libraries as Open Source: A Powerful Pathway to New Drugs. AB - "... We envisioned an iterative system where a unique DNA tag identifier that encoded the event was appended to each newly formed molecule. These vast collections of molecules are known today as DNA- encoded chemical libraries (DECLs), and allow scientists to do selections on the benchtop that previously required access to large and complex high-throughput screening centers ..." Read more in the Guest Editorial by Richard A. Lerner and Sydney Brenner. PMID- 28094477 TI - Effects of intravenous lidocaine, dexmedetomidine and their combination on postoperative pain and bowel function recovery after abdominal hysterectomy. AB - BACKGROUND: Intravenous (IV) lidocaine and dexmedetomidine have been shown to decrease postoperative pain, reduce analgesic consumption and facilitate return of bowel function. We investigated whether lidocaine combined with dexmedetomidine infusion was superior in controlling pain and recovery of bowel function. METHODS: A total of 240 women undergoing elective abdominal hysterectomy were randomly assigned into four groups: group CON received normal saline infusion, group LIDO received lidocaine infusion (1.5 mg/kg loading, 1.5 mg/kg/h infusion), group DEX received dexmedetomidine infusion (0.5 ug/kg loading, 0.4 ug/kg/h infusion) and group LIDO+DEX received lidocaine (1.5 mg/kg loading, 1.5 mg/kg/h infusion) and dexmedetomidine infusions (0.5 ug/kg loading, 0.4 ug/kg/h infusion). The primary outcome was visual analog pain scale (VAS) scores at 1, 4, 8, 12, 24, and 48 hours after surgery. The secondary outcomes included time to first bowel sounds and flatus, postoperative fentanyl requirement and perioperative propofol and remifentanil consumption. RESULTS: The VAS scores were significantly lower in groups LIDO and DEX at 4, 8, and 12 hours compared to group CON after surgery (P<0.01). The VAS scores were also significantly lower in group LIDO+DEX at 1, 4, 8, 12, and 24 hours compared to other three groups after surgery (P<0.01). Time to first bowel sounds and flatus was significantly shorter in groups LIDO and LIDO+DEX than groups CON and DEX (P<0.01). Postoperative fentanyl requirement was significantly lower in group LIDO at 1 and 4 hours and in group DEX at 1, 4, 8 hours compared to group CON after surgery (P<0.01). Postoperative fentanyl requirement was also significantly lower in group LIDO+DEX at 1, 4, 8, 12, 24 and 48 hours compared to other three groups after surgery (P<0.01). Propofol and remifentanil consumption was significantly lower in groups LIDO, DEX and LIDO+DEX compared to group CON (P<0.01). CONCLUSIONS: Lidocaine combined with dexmedetomidine infusion significantly improved postoperative pain and enhanced recovery of bowel function undergoing abdominal hysterectomy. PMID- 28094478 TI - Fluid management in cardiac surgery patients: pitfalls, challenges and solutions. AB - Fluid administration is a powerful tool for hemodynamic stabilization as it increases preload and improves cardiac function in fluid-responsive patients. However, there are various types of fluid to choose from. The use of colloids and crystalloids in non-cardiac Intensive Care Units (ICU) has been reported, showing controversial results. Many trials on sepsis in a non-cardiac ICU setting show that colloids, in particular hydroxyethyl starches and gelatins, might have a detrimental effect on kidney function, and on major outcomes such as mortality. Many small randomized clinical trials focusing on coagulation and bleeding show controversial results regarding fluid safety during the perioperative period in cardiac surgery, and in the cardiac ICU. No definitive data are available on the superiority of one fluid compared with another for fluid replacement after cardiac surgery. Only few data are available regarding the impact of fluids on kidney function in the cardiac ICU. On the other hand, there is much evidence showing that fluid administration requires strict protocols and close monitoring. Improved clinical outcomes are evident in protocols for goal-directed therapy. In conclusion, the application of a close monitoring and a pre-defined goal-directed protocol are far more important than the choice of a single fluid. This review examines the available evidence on fluid management in cardiac surgery and in the ICU, and analyzes the key steps of fluid strategy in these settings. PMID- 28094479 TI - Retromolar laryngoscopy: a randomized crossover vocal cords visualization study. AB - BACKGROUND: Vocal cords visualization is a major determinant for successful tracheal intubation. The aim of our study was to compare vocal cord visualization by using conventional direct laryngoscopy with retromolar direct laryngoscopy in patients with an existing retromolar gap at the right mandible. METHODS: We enrolled 100 adults needing endotracheal intubation for elective surgery. In each patient, the vocal cords were visualized and scored according to Cormack and Lehane with a Macintosh blade #3 for conventional technique and with a Miller blade #4 for the retromolar technique in a randomized sequence. Finally, tracheal intubation was performed primarily by conventional laryngoscopy and in the case of failing retromolar laryngoscopy was used as the rescue method. RESULTS: Overall 100 laryngoscopies with the conventional method and 100 laryngoscopies with the retromolar method were scored according to Cormack and Lehane. The retromolar technique achieved significant (P=0.000003) lower Cormack and Lehane scores compared to the conventional technique. In eleven patients, intubation by conventional laryngoscopy failed and seven of those patients were successfully intubated by the retromolar technique. A BURP-maneuver significantly improved vocal cord visualization during both methods. CONCLUSIONS: In summary, laryngoscopy via the retromolar method by using a Miller blade #4 lead to a significantly better vocal cord visualization compared to the conventional method performed with a Macintosh blade #3 in patients with an existing retromolar gap on the right side. PMID- 28094480 TI - Anesthetic complications during general anesthesia without intravenous access in pediatric ophthalmologic clinic: assessment of 5216 cases. AB - BACKGROUND: General anesthesia utilizing inhalational agents without intravenous (IV) access for minor procedures is controversial. Eliminating IV access increases efficiency and patient satisfaction; however, the ability to introduce rapid acting medications into the circulation during an unanticipated emergency becomes challenging. The objective of this study was to examine complication risk following pediatric ophthalmologic examinations under anesthesia (EUA) without IV placement. METHODS: A retrospective review of consecutive pediatric patients who underwent EUA for retinoblastoma management was performed from 2004 to 2014. The total number of anesthetics and elective IV placement were identified. Patient characteristics, length of the procedure, laryngeal mask airway (LMA) placement, and complications were also recorded. A survey of specialized ophthalmology institutions was performed in order to ascertain the state of standard practices. RESULTS: Over 10 years, 5216 anesthetics were identified. The mean age and weight of the patients were 2.7+/-2.0 years and 14.4+/-6.6 kg, respectively. In all, 298 elective IVs were placed (6%) and 4918 cases (94%) were performed without IV access. A total of 1687 (32%) anesthetics were administered with a laryngeal mask airway (LMA), of which 1389 (82%) did not have IV access. There were no deaths and no unplanned admissions. There were 8/5216 complications (0.153%) which all resolved safely. CONCLUSIONS: The current study shows that it is safe to perform EUA and procedures for the diagnosis and treatment of retinoblastoma in pediatric patients without securing IV access. All emergency post-complication IV placements were successful and no long-term sequelae were seen. PMID- 28094481 TI - Influence of the thoracic epidural anesthesia on the left ventricular function: an echocardiographic study. AB - BACKGROUND: Thoracic epidural anesthesia (TEA) is widely used for major surgery, but studies assessing its impact on left ventricular (LV) systolic and diastolic function are limited, and such studies have assessed patients already under general anesthesia and/or receiving volume expansion between examinations. METHODS: Observational study at a secondary university hospital including consecutive awake patients undergoing major abdominal surgery without significant pre-existing cardiac disease. Patients received a pre-emptive intravenous volume loading before epidural catheter placement with puncture between T6-T7 and T8-T9. Hemodynamic and trans-thoracic echocardiography (TTE) parameters were assessed before and after establishing TEA with a 10 mL bolus of 2% lidocaine. Changes in heart rate (HR), mean arterial pressure (MAP), stroke volume (SV), cardiac output (CO), LV systolic function (as evaluated by fractional shortening [FS]; ejection fraction [EF]; Simpson; S prime [S']), and LV diastolic function were recorded. RESULTS: Twenty-four awake patients were included. After TEA, HR, MAP, SV and CO significantly decreased (15.0%, 29.3%, 6.8% and 22%, respectively; all P<0.01); LV systolic function was also reduced by TEA (FS by 28%, EF-Simpson by 26%, S' by 15.3%, all P<0.001). TEA non-significantly reduced the incidence of diastolic dysfunction, from 65% (N.=15/23) to 43% (N.=10/23) patients (P=0.13) in the 23 complete diastolic function evaluations. CONCLUSIONS: The net effect of TEA in awake patients is a reduction of HR and LV systolic function, which results in a reduction of the CO and the MAP. The effect of TEA on LV diastolic function remains to be addressed by larger studies. PMID- 28094482 TI - Real-time ultrasound-guided spinal anesthesia in patients with predicted difficult anatomy. AB - BACKGROUND: There are limited reports of lumbar neuraxial blocks using real-time US in patients with predicted difficulties. We compared the number of attempts to perform spinal anesthesia using real-time US guidance versus landmark technique in patients meeting predefined criteria for difficult spinal anesthesia. We also compared procedure time, block success, patient satisfaction and difficulty scores between groups. METHODS: Following institutional review board approval patients scheduled for total hip or knee arthroplasty with expected difficulty to perform spinal anesthesia were included. Number of attempts, block time, success rate, patient satisfaction and difficulty scores were recorded and we conducted the Kruskal-Wallis non-parametric test of difference between the groups. RESULTS: Thirty-eight patients were enrolled and a total of 32 data sets was analyzed. For number of attempts, we observed no difference between the groups (P<0.83). The US group resulted in marginally higher time to block compared to the control (P<0.0653). The US group resulted in marginally higher satisfaction compared to the control group (P<0.09). The block success rate was 100% in both groups. Anesthesiologists rated the US group procedure more difficult than the control group (chi2=10.85, P<0.0010). CONCLUSIONS: This trial suggests that real-time US guidance for spinal anesthesia in challenging patients in comparison to the controlled group was completed in longer time, with lower needle insertion attempts, and higher patient satisfaction scores but without statistically significant differences. PMID- 28094483 TI - Italian validation of the Amsterdam Preoperative Anxiety and Information Scale. AB - BACKGROUND: Preoperative anxiety is usually experienced by patients awaiting surgical procedures and it can negatively impact patient's outcome. The Amsterdam Preoperative Anxiety and Information Scale (APAIS) is a questionnaire created to identify anxious patients and their need for information: it has been translated and validated in many languages because of its reliability and ease of completion. To date, no Italian version of the APAIS has been produced; our aim was to translate and validate the APAIS in Italian. METHODS: We produced an Italian version of the APAIS and we administered it to 110 patients undergoing elective surgery; we explored its structure by factor analysis and its reliability by Cronbach's alpha. We analyzed its external validity by confronting it to the Spielberg's State-Trait Anxiety Inventory (STAI). Sensitivity, specificity, and positive and negative predictive values of the Italian version of the APAIS were determined. RESULTS: The Italian version of the APAIS confirmed the original structure of the questionnaire and its internal consistency; it well correlated with the STAI-Y1, the subscale of the STAI which explore the anxiety "state." An APAIS score of 14 was found as best cutoff to distinguish anxious and non-anxious patients. CONCLUSIONS: The Italian translation of the APAIS showed psychometric properties similar to the original version. Its reliability and its efficiency make it a powerful tool even in Italian population to detect anxiety and need for information. PMID- 28094484 TI - A simplified screening tool to identify seriously ill patients in the Emergency Department for referral to a palliative care team. AB - BACKGROUND: The aims of this study were to evaluate the feasibility of an Emergency Department (ED)-initiated screening to identify seriously ill patients in need of palliative care (PC) and to develop a simplified screening tool (SST). METHODS: Eligible patients with known diagnosis of chronic heart, lung, liver, and kidney failures, progressive neurological diseases or advanced cancer, awaiting to be hospitalized after an ED visit, were assessed with the screening tool from the Italian Society of Anesthesia, Analgesia, Resuscitation, and Intensive Care (SIAARTI). RESULTS: Out of 1497 patients with an ED visit, 485 were hospitalized, and 257 of them met the inclusion criteria. Of 257 enrolled patients, 91 (35%) were identified as in need of PC. Comparing patients with 4 positive criteria to those with <4, the general clinical indicators more frequently positive were: >=1 admission within the last 12 months (P<0.001); hospital admission from or awaiting admission to health care services (HCS)/Hospice (P<0.001); cachexia (P<0.012); home oxygen use (P<0.001); dialysis (P<0.008). A SST was developed to identify patients in need of PC when a Palliative Performance Scale score <50 was present with at least one of the following indicators: >=1 admission within the last 12 months; hospital admission from HCS; awaiting admission to HCS/Hospice; dialysis; home oxygen use; non invasive ventilation. This SST showed a good agreement with the SIAARTI one as sensitivity (97.8%), specificity (92.8%), and accuracy (94.5%). CONCLUSIONS: Our study estimated that over one-third of the people with chronic diseases awaiting to be hospitalized after an ED visit were in need of PC and can be identified with this easy-to-use, non-disease-specific SST. PMID- 28094485 TI - Management of coagulopathy in the severely burned patient: a place for antifibrinolytic therapy? PMID- 28094486 TI - Understanding developmental hemostasis through the use of viscoelastic tests of whole blood coagulation. PMID- 28094487 TI - Blood doping at the Olympic Games. AB - INTRODUCTION: The objective of this paper was to review our knowledge of athletes who have, are believed to have or have attempted to engage in blood doping to enhance their performance at an Olympic Games. EVIDENCE ACQUISITION: The paper focused on the Games from Munich 1972 to London 2012 and the author had a medical role at each of the Olympics that is discussed. EVIDENCE SYNTHESIS: The study revealed that Olympic athletes have benefitted from manipulating their blood by re-infusion of autologous or infusion of homologous blood and by administering erythropoiesis stimulating agents, notably the three generations of erythropoietins. Fifty seven athletes have been sanctioned with 12 athletes forfeiting 17 Olympic medals including 12 gold medals because of blood doping. Until 1986, the infusion of blood was not prohibited in sport but considered unethical. Erythropoietin was prohibited by the International Olympic Committee's Medical Commission in 1990. CONCLUSIONS: There has been a change as to how Olympic athletes have enhanced performance by blood doping, commencing with blood infusion and later administering erythropoiesis stimulating agents and significant advances have occurred in detecting such misuse. Currently, the hematological component of World Anti-Doping Agency's athlete biological passport is an important but not infallible mechanism to identify athletes who cheat by blood doping. PMID- 28094488 TI - Effects of leg contrast strength training on sprint, agility and repeated change of direction performance in male soccer players. AB - BACKGROUND: Contrast training is a popular technique among individuals who are involved in dynamic sports, having as its goal an increase in dynamic muscular performance. It is characterized by the use of high and low loads in the same strength training session. The present investigation aimed to determine the effects of adding 8 weeks of contrast strength training (CSTP) to regular soccer practice in U-17 male soccer players during the competitive season. We hypothesized that CSTP would enhance their performance. METHODS: Subjects were divided randomly between a control group (CG, N.=12) and a contrast strength group (CSG, N.=19). The 2 groups trained together; controls followed the regular soccer program, which was replaced by a contrast strength training program for the experimental group. Performance was assessed before and after training, using 10 measures: 5-10-, 20- 30-, and 40-m sprints, a 4x5 m sprint (S4x5), a 9-3-6-3-9 m sprint with 180 degrees turns (S180), a 9-3-6-3-9 m sprint with backward and forward running (SBF), a Repeated-Shuttle-Sprint Ability Test (RSSA), and a Repeated Change of Direction Test (RCOD). RESULTS: CSG showed gains relative to controls in 5-m (P<0.000), 10-m (P<0.001), 20-m (P<0.001), 30-m (P<0.05) and 40-m (P<0.05) sprints. There were also significant gains in S180 degrees , SBF, and S4 x 5 agility tests (P<0.01), and all RCOD parameters (P<0.05) except RCOD-FI (P=0.055) but no significant change in any RSSA parameters. CONCLUSIONS: We conclude that biweekly contrast strength training can be commended to U-17 male soccer players as a means of improving many important components of athletic performance relative to standard in-season training. PMID- 28094489 TI - The sex-specific internal and external demands imposed on players during Ultimate Frisbee game-play. AB - BACKGROUND: Despite the growing popularity of Ultimate Frisbee (UF) across sexes, the game demands imposed on players have been predominately examined in males. This study aimed to compare the internal and external demands of UF game-play in males and females. METHODS: Male (N.=10) and female (N.=10) recreational UF players competed in separate sex-specific, indoor UF games. Internal responses (blood lactate concentration [BLa-], rating of perceived exertion [RPE], and heart rate [HR]) and external responses (direction-specific and total relative PlayerLoadTM [PL], and estimated equivalent distance [EED]) were measured. Data were analyzed using mixed ANOVAs with Cohen's effect sizes (d). RESULTS: During male game-play, significantly (P<0.01) higher BLa- (d=1.30, large), HR (d=0.40, small), PL (d=0.80-1.24, moderate-large), and EED (d=0.93, moderate) were apparent during the first half compared to the second half in males. During female game-play, a significantly (P<0.001) larger RPE (d=0.93, moderate) was evident during the second compared to the first half. In addition, females exhibited significantly (P<0.05) lower BLa- (d=1.43, large) in the first half and higher medio-lateral PL (d=1.10, moderate) in the second half compared to males. CONCLUSIONS: While similar global responses were observed between sexes across UF game-play, males experienced greater declines in physiological intensity and multi-directional activity than females. These data indicate overlap in game demands and training recommendations across sexes, with activity maintenance a focus, particularly in males. PMID- 28094490 TI - Urinary incontinence in women: non pharmacologic approaches and newer pharmacotherapies. An update. AB - Urinary incontinence is a widespread problem for women, with stress urinary incontinence (SUI) being the most common type. An updated review of PubMed literature using the following keywords was performed: "stress urinary incontinence", "women", "midurethral slings", "bulking agents", "pubovaginal slings", "retropubic suspension", "postoperative complications", and "treatment outcome". More recent publications, systematic reviews, and meta-analyses were given preference. The aging population will increase the demand for care of women with SUI. Patient evaluation should include a careful history of present illness, physical examination, and a discussion about their quality of life and goals of care. Behavioral modifications are considered first line therapy. For surgical treatment, bulking agents are a minimally invasive option with adequate short term cure rates. Both midurethral slings and pubovaginal slings have reported high rates of short and long term success and patient satisfaction. Retropubic suspension and artificial urinary sphincter are also treatment options in appropriately selected patients. The ultimate treatment decision will rely on an informed conversation between the physician and patient. PMID- 28094491 TI - The first-line treatment of Helicobacter pylori infection in Piedmont in the year 2017. PMID- 28094492 TI - Tuning the Surface Properties of Graphene Oxide by Surface-Initiated Polymerization of Epoxides: An Efficient Method for Enhancing Gas Separation. AB - Here, we describe an in situ approach for growing polyepoxides from the surfaces of graphene oxide (GO) using a surface-initiated polymerization reaction. The polymerization methodology is facile and general as a broad range of epoxides carrying various functional groups have been successfully polymerized by simply adding GO powders in the epoxide monomers. The resultant polyepoxide grafted GO are found to show enhanced dispersibility in various common solvents and to exhibit increased d-spacing between the basal planes. In particular, grafting poly(2,3-epoxy-1-propanol) (PEP) to GO results in a composite (i.e., GO-g-PEP) that is dispersible in water and miscible with polyether block amide, i.e., Pebax MH 1657. Preliminary studies have indicated the membranes prepared using Pebax/GO g-PEP composites exhibit enhanced CO2 permeabilities and selectivities in comparison to H2, O2, or N2. The excellent performance in gas separation is attributed to the layered structure of the GO-g-PEP sheets with enlarged d spacing and the functional groups present on the PEP chains grafted to the surfaces of GO sheets. PMID- 28094493 TI - Facile and Scalable Synthesis Method for High-Quality Few-Layer Graphene through Solution-Based Exfoliation of Graphite. AB - Here we describe a facile and scalable method for preparing defect-free graphene sheets exfoliated from graphite using the positively charged polyelectrolyte precursor poly(p-phenylenevinylene) (PPV-pre) as a stabilizer in an aqueous solution. The graphene exfoliated by PPV-pre was apparently stabilized in the solution as a form of graphene/PPV-pre (denoted to GPPV-pre), which remains in a homogeneous dispersion over a year. The thickness values of 300 selected 76% GPPV pre flakes ranged from 1 to 10 nm, corresponding to between one and a few layers of graphene in the lateral dimensions of 1 to 2 MUm. Furthermore, this approach was expected to yield a marked decrease in the density of defects in the electronic conjugation of graphene compared to that of graphene oxide (GO) obtained by Hummers' method. The positively charged GPPV-pre was employed to fabricate a poly(ethylene terephthalate) (PET) electrode layer-by-layer with negatively charged GO, yielding (GPPV-pre/GO)n film electrode. The PPV-pre and GO in the (GPPV-pre/GO)n films were simultaneously converted using hydroiodic acid vapor to fully conjugated PPV and reduced graphene oxide (RGO), respectively. The electrical conductivity of (GPPV/RGO)23 multilayer films was 483 S/cm, about three times greater than that of the (PPV/RGO)23 multilayer films (166 S/cm) comprising RGO (prepared by Hummers method). Furthermore, the superior electrical properties of GPPV were made evident, when comparing the capacitive performances of two supercapacitor systems; (polyaniline PANi/RGO)30/(GPPV/RGO)23/PET (volumetric capacitance = 216 F/cm3; energy density = 19 mWh/cm3; maximum power density = 498 W/cm3) and (PANi/RGO)30/(PPV/RGO)23/PET (152 F/cm3; 9 mWh/cm3; 80 W/cm3). PMID- 28094494 TI - Structural Evolution Induced by Interfacial Lattice Mismatch in Self-Organized YBa2Cu3O7-delta Nanocomposite Film. AB - Intriguing properties of self-organized nanocomposites of perovskite oxides are usually derived from the complex interface of constituent material phases. A sophisticated control of such a system is required for a broad range of energy and device applications, which demand a comprehensive understanding of the interface at the atomic scale. Here, we visualized and theoretically modeled the highly elastically strained nanorod, the interface region with misfit dislocations and heterointerface distortion, and the matrix with strain-induced oxygen vacancies in the self-organized YBa2Cu3O7-delta nanocomposite films with Ba perovskite nanorods. Large misfit strain was elastically accommodated in the nanocomposites, but since the elastic strain was mainly accommodated by the nanorods, the concentration of strain-induced oxygen vacancies was small enough for the matrix to keep high critical temperature (>85 K). The interfacial bonding distorted the atomic structure of YBa2Cu3O7-delta, but the thickness of distortion was limited to a few unit cells (less than the coherence length) due to the electron screening. The effect of volume fraction on elastic strain and the electron screening are crucial for strong vortex pinning without significant degradation of both the elementary pinning force and critical temperature in the nanocomposites. Thus, we comprehensively clarified the self-organized nanocomposite structure for on-demand control of superconductivity and oxide functionality in the nanocomposite engineering of perovskite oxides. PMID- 28094495 TI - Bacoside-A, an Indian Traditional-Medicine Substance, Inhibits beta-Amyloid Cytotoxicity, Fibrillation, and Membrane Interactions. AB - Bacoside-A, a family of compounds extracted from the Bacopa monniera plant, is a folk-medicinal substance believed to exhibit therapeutic properties, particularly enhancing cognitive functions and improving memory. We show that bacoside-A exerted significant inhibitory effects upon cytotoxicity, fibrillation, and particularly membrane interactions of amyloid-beta (1-42) (Abeta42), the peptide playing a prominent role in Alzeheimer's disease progression and toxicity. Specifically, preincubation of bacoside-A with Abeta42 significantly reduced cell toxicity and inhibited fibril formation both in buffer solution and, more significantly, in the presence of membrane vesicles. In parallel, spectroscopic and microscopic analyses reveal that bacoside-A blocked membrane interactions of Abeta42, while formation of Abeta42 oligomers was not disrupted. These interesting phenomena suggest that inhibition of Abeta42 oligomer assembly into mature fibrils, and blocking membrane interactions of the oligomers are likely the underlying factors for ameliorating amyloid toxicity by bacoside-A and its putative physiological benefits. PMID- 28094496 TI - Chemoproteomic Profiling of Acetanilide Herbicides Reveals Their Role in Inhibiting Fatty Acid Oxidation. AB - Acetanilide herbicides are among the most widely used pesticides in the United States, but their toxicological potential and mechanisms remain poorly understood. Here, we have used chemoproteomic platforms to map proteome-wide cysteine reactivity of acetochlor (AC), the most widely used acetanilide herbicide, in vivo in mice. We show that AC directly reacts with >20 protein targets in vivo in mouse liver, including the catalytic cysteines of several thiolase enzymes involved in mitochondrial and peroxisomal fatty acid oxidation. We show that the fatty acids that are not oxidized, due to impaired fatty acid oxidation, are instead diverted into other lipid pathways, resulting in heightened free fatty acids, triglycerides, cholesteryl esters, and other lipid species in the liver. Our findings show the utility of chemoproteomic approaches for identifying novel mechanisms of toxicity associated with environmental chemicals like acetanilide herbicides. PMID- 28094497 TI - An Approach To Fabricate PDMS Encapsulated All-Solid-State Advanced Asymmetric Supercapacitor Device with Vertically Aligned Hierarchical Zn-Fe-Co Ternary Oxide Nanowire and Nitrogen Doped Graphene Nanosheet for High Power Device Applications. AB - We highlight the design and fabrication of a polydimethylsiloxane (PDMS) encapsulated advanced all-solid-state asymmetric supercapacitor (ASC) device consisting of hierarchical mesoporous zinc-iron-cobalt ternary oxide (ZICO) nanowire coated nickel (Ni) foam (ZICO@Ni foam) as a promising positive electrode and nitrogen doped graphene coated Ni foam (N-G@Ni foam) as negative electrode in the presence of PVA-KOH gel electrolyte. Owing to outstanding electrochemical behavior and ultrahigh specific capacitance of ZICO (~ 2587.4 F/g at 1 A/g) and N G (550 F/g at 1 A/g) along with their mutual synergistic outputs, the assembled all-solid-state ASC device exhibits an outstanding energy density of ~40.5 Wh/kg accompanied by a remarkable long-term cycle stability with ~95% specific capacitance retention even after 5000 charge-discharge cycles. The exclusive hierarchical ZICO nanowires were synthesized by a facile two-step process comprising of a hydrothermal protocol followed by an annealing treatment on a quartz substrate. While Zn2+ gives the stability of the oxide system, Fe and Co ions provide better electronic conductivity and capacitive response under vigorous cyclic condition. The extraordinary performance of as-fabricated ASC device resembles its suitability for the construction of advanced energy storage devices in modern electronic industries. PMID- 28094498 TI - Barium Titanate Film Interfaces for Hybrid Composite Energy Harvesters. AB - Energy harvesting utilizing piezoelectric materials has become an attractive approach for converting mechanical energy into electrical power for low-power electronics. Structural composites are ideally suited for energy scavenging due to the large amount of mechanical energy they are subjected to. Here, a multifunctional composite with embedded sensing and energy harvesting is developed by integrating an active interface into carbon fiber reinforced polymer composites. By modifying the composite matrix, both rigid and flexible multifunctional composites are fabricated. Through electromechanical testing of a cantilever beam of the rigid composite, it reveals a power density of 217 pW/cc from only 1 g root-mean-square acceleration when excited at its resonant frequency of 47 Hz. Electromechanical sensor testing of the flexible multifunctional composite reveals an average voltage generation of 23.5 mV/g at its resonant frequency of 96 Hz. This research introduces a route for integrating nonstructural functionality into structural fiber composites by utilizing BaTiO3 coated woven carbon fiber fabrics with power scavenging and passive sensing capabilities. PMID- 28094499 TI - Organic Solar Cells with Controlled Nanostructures Based on Microphase Separation of Fullerene-Attached Thiophene-Selenophene Heteroblock Copolymers. AB - Heteroblock copolymers consisting of poly(3-hexylthiophene) and fullerene attached poly(3-alkylselenophene) (T-b-Se-PCBP) were synthesized for organic photovoltaic applications by quasi-living catalyst transfer polycondensation and subsequent conversion reactions. Characterization of the polymers confirmed the formation of well-defined diblock structures with high loading of the fullerene at the side chain (~40 wt %). Heteroblock copolymer cast as a thin film showed a clear microphase-separated nanostructure approximately 30 nm in repeating unit after thermal annealing, which is identical to the microphase-separated nanostructure of diblock copolymer consisting of poly(3-hexylthiophene) and fullerene-attached poly(3-alkylthiophene) (T-b-T-PCBP). These heteroblock copolymers provide an ideal platform for investigating the effects of nanostructures and interfacial energetics on the performance of organic photovoltaic devices. PMID- 28094500 TI - Chronic Mild Stress-Induced Alterations of Local Protein Synthesis: A Role for Cognitive Impairment. AB - Depression, a major cause of disability worldwide, is characterized by a complex and heterogeneous symptomatology. With this respect, cognitive deterioration represents a major problem that has a strong impact on a patient's function. Thus, within the context of a depressive phenotype, it is important to characterize the mechanisms that sustain cognitive dysfunctions and may represent an important target for pharmacological intervention. Here, using the chronic mild stress (CMS) paradigm of depression, we found that, independently from the anhedonic phenotype, CMS rats showed a deficit in the novel object recognition (NOR) test, which is associated with an inability to phosphorylate GluN2B subunit on Ser1303 and to activate the mTOR pathway. In agreement with the role of these systems in the control of local protein synthesis, we observed an increase phosphorylated eukaryotic elongation factor 2 (eEF2) in the crude synaptosomal fraction after the NOR test specifically in control animals. Since it has been demonstrated that peEF2 leads to the translation of specific mRNAs, we investigated if the gene-specific translational control depends on the presence of upstream open reading frame (uORF). Interestingly, we found a significant increase of oligophrenin-1 (2 uORFs) and of Bmal1 (7 uORFs) protein levels specifically in the control animals exposed to the NOR test. Our results demonstrated that the cognitive decline associated with stress exposure might be due to alterations in local protein translation of specific mRNAs, suggesting that a pharmacological intervention able to correct these defects might be useful in the improvement of deteriorated functions in patients with major depression and stress-related disorders. PMID- 28094501 TI - Artificial Cells: Synthetic Compartments with Life-like Functionality and Adaptivity. AB - Cells are highly advanced microreactors that form the basis of all life. Their fascinating complexity has inspired scientists to create analogs from synthetic and natural components using a bottom-up approach. The ultimate goal here is to assemble a fully man-made cell that displays functionality and adaptivity as advanced as that found in nature, which will not only provide insight into the fundamental processes in natural cells but also pave the way for new applications of such artificial cells. In this Account, we highlight our recent work and that of others on the construction of artificial cells. First, we will introduce the key features that characterize a living system; next, we will discuss how these have been imitated in artificial cells. First, compartmentalization is crucial to separate the inner chemical milieu from the external environment. Current state of-the-art artificial cells comprise subcompartments to mimic the hierarchical architecture of eukaryotic cells and tissue. Furthermore, synthetic gene circuits have been used to encode genetic information that creates complex behavior like pulses or feedback. Additionally, artificial cells have to reproduce to maintain a population. Controlled growth and fission of synthetic compartments have been demonstrated, but the extensive regulation of cell division in nature is still unmatched. Here, we also point out important challenges the field needs to overcome to realize its full potential. As artificial cells integrate increasing orders of functionality, maintaining a supporting metabolism that can regenerate key metabolites becomes crucial. Furthermore, life does not operate in isolation. Natural cells constantly sense their environment, exchange (chemical) signals, and can move toward a chemoattractant. Here, we specifically explore recent efforts to reproduce such adaptivity in artificial cells. For instance, synthetic compartments have been produced that can recruit proteins to the membrane upon an external stimulus or modulate their membrane composition and permeability to control their interaction with the environment. A next step would be the communication of artificial cells with either bacteria or another artificial cell. Indeed, examples of such primitive chemical signaling are presented. Finally, motility is important for many organisms and has, therefore, also been pursued in synthetic systems. Synthetic compartments that were designed to move in a directed, controlled manner have been assembled, and directed movement toward a chemical attractant is among one of the most life-like directions currently under research. Although the bottom-up construction of an artificial cell that can be truly considered "alive" is still an ambitious goal, the recent work discussed in this Account shows that this is an active field with contributions from diverse disciplines like materials chemistry and biochemistry. Notably, research during the past decade has already provided valuable insights into complex synthetic systems with life-like properties. In the future, artificial cells are thought to contribute to an increased understanding of processes in natural cells and provide opportunities to create smart, autonomous, cell-like materials. PMID- 28094502 TI - Highly Efficient Full-Color Thermally Activated Delayed Fluorescent Organic Light Emitting Diodes: Extremely Low Efficiency Roll-Off Utilizing a Host with Small Singlet-Triplet Splitting. AB - Numerous efforts have been devoted to boost the efficiency of thermally activated delayed fluorescence (TADF) devices; however, strategies to suppress the device efficiency roll-off are still in urgent need. Here, a general and effective approach to suppress the efficiency roll-off of TADF devices is proposed, that is, utilizing TADF materials as the hosts for TADF emitters. Bearing small singlet-triplet splitting (DeltaEST) with donor and acceptor units, TADF materials as the hosts possess the potential to achieve matched frontier energy levels with the adjacent transporting layers, facilitating balanced charge injection as well as bipolar charge transport mobilities beneficial to the balanced charges transportation. Furthermore, an enhanced Forster energy transfer from the host to the dopant can be anticipated, helpful to reduce the exciton concentration. Based on the principles, a new TADF material based on indeno[2,1 b]carbazole/1,3,5-triazin derivation is synthesized and used as the universal host for the full-color TADF devices. Remarkable low efficiency roll-off was achieved with above 90% of the maximum external quantum efficiencies (EQEmax's) maintained even at a brightness of 2000 cd/m2, along with EQEmax's of 23.2, 21.0, and 19.2% for orange, green, and sky-blue TADF devices, respectively. Through computational simulation, we identified the suppressed exciton annihilation rates compared with devices adopting conventional hosts. The state-of-the-art low efficiency roll-off of those TADF devices manifests the great potential of such host design strategy, paving an efficient strategy toward their practical application. PMID- 28094503 TI - Controlled Doping in Graphene Monolayers by Trapping Organic Molecules at the Graphene-Substrate Interface. AB - We report controlled doping in graphene monolayers through charge-transfer interaction by trapping selected organic molecules between graphene and underneath substrates. Controllability has been demonstrated in terms of shifts in Raman peaks and Dirac points in graphene monolayers. Under field effect transistor geometry, a shift in the Dirac point to the negative (positive) gate voltage region gives an inherent signature of n- (p-)type doping as a consequence of charge-transfer interaction between organic molecules and graphene. The proximity of organic molecules near the graphene surface as a result of trapping is evidenced by Raman and infrared spectroscopies. Density functional theory calculations corroborate the experimental results and also indicate charge transfer interaction between certain organic molecules and graphene sheets resulting p- (n-)type doping and reveals the donor and acceptor nature of molecules. Interaction between molecules and graphene has been discussed in terms of calculated Mulliken charge-transfer and binding energy as a function of optimized distance. PMID- 28094504 TI - 2-Fold Interpenetrating Bifunctional Cd-Metal-Organic Frameworks: Highly Selective Adsorption for CO2 and Sensitive Luminescent Sensing of Nitro Aromatic 2,4,6-Trinitrophenol. AB - A robust primitive diamond-type topology 3-D metal-organic framework (MOF) of {[Cd4(hbhdpy)2(bdc)3(DMA)2].(H2O)4}n (1, DMA = N,N-dimethylacetamide) was constructed from the planar secondary building units of the dinuclear cadmium clusters, Cd2(MU2-O)2, and two linear organic linkers of the new multidentate Schiff base of 4-(2-hydroxy-3-methoxy-benzyli-denehydrazino-carbonyl)-N-pyridin-4 yl-benzamide (Hhbhdpy) through the solvothermal reaction. 1 presents a 2-fold interpenetrating network along with confined narrow channels and rich acylamide groups as well as potential metal open sites for excellent selective CO2 uptake over CH4/N2 and high luminescent response for 2,4,6-trinitrophenol (TNP) in DMA solution under ambient conditions. With 2-amino-1,4-dicarboxy-benzene (H2bdc-NH2) replacing H2bdc, an amine-functionalized MOF of {[Cd4(hbhdpy)2(bdc-NH2)3 (DMA)2].(H2O)4}n (1-NH2) as an isomorphism of 1, was synthesized under the same reaction conditions. Compared with 1, the corresponding bifunctional features of 1-NH2 is more obvious. To the best of our knowledge, it is the first reported interpenetrating Cd-MOFs with highly sensitive luminescence response for TNP molecules combined with excellent selectivity for CO2/N2 and CO2/CH4. PMID- 28094505 TI - Self-Assembly and Disassembly of Amphiphilic Zwitterionic Perylenediimide Vesicles for Cell Membrane Imaging. AB - Animal cells have complicated dynamics of cell membrane structures which require desirable dyes for in vivo imaging. Here, an asymmetric amphiphilic zwitterionic perylenediimide (ZP) derivative has been constructed by introducing an octyl chain and a zwitterionic head to each imide position of perylenediimide chromophore. ZP could self-assemble into vesicles in aqueous solution. The aggregated ZP vesicles have been explored to image cell inner or surface membrane structures by a controlled disassembly process. After being taken up into cells, ZP vesicles disassemble into monomers and then incorporate into cell inner membranes. The vesicles can also disassemble in acid food and incorporate into cell surface membrane of gut cells. The research provides a new tool to label the complicated cell membrane structures with up to 3 days long-term labeling for life science applications. PMID- 28094506 TI - Superior Performance of Artificial Nacre Based on Graphene Oxide Nanosheets. AB - Natural nacre is well-known by its unique properties due to the well-recognized "bricks-and-mortar" structure. Inspired by the natural nacre, graphene oxide (GO) was reduced by dopamine with simultaneous coating by polydopamine (PDA) in aqueous solution to yield polydopamine-capped reduce GO (PDG). The artificial nacre nanocomposite materials of poly(vinyl alcohol) (PVA) and PDG presenting layered structure had been successfully constructed via a vacuum-assisted assembly process, in which PDG and PVA served as "bricks" and "mortar", respectively. A combination of hydrogen bonding, strong adhesion and friction between PDG nanosheets and PVA chains resulted in enhancements for mechanical properties. The tensile strength, elongation at break, and toughness of PDG-PVA nanocomposite reached to 327 +/- 19.3 MPa, 8 +/- 0.2%, and 13.0 +/- 0.7 MJ m-3, which is simultaneously 2.4, 8, and 7 times higher than that of nature nacre with 80-135 MPa, ~1%, and ~1.8 MJ m-3, respectively. More interestingly, the obtained nanocomposites demonstrated a high anisotropy of thermal conductivity (k?/k? ~ 380). Combined with superior mechanical properties and high anisotropy of thermal conductivity make these biomimetic materials promising candidates in aerospace, tissue engineering, and thermal management applications. PMID- 28094507 TI - Conjugated Polyelectrolyte Based Sensitive Detection and Removal of Antibiotics Tetracycline from Water. AB - A new conjugated polyelectrolyte poly[5,5'-(((2-phenyl-9H-fluorene-9,9 diyl)bis(hexane-6,1-diyl))bis(oxy))diisophthalate] sodium (PFPT) was synthesized via the palladium-catalyzed Suzuki cross-coupling polymerization method and successfully applied for the rapid, real time, and highly sensitive detection of antibiotics tetracycline (Tc) in 100% aqueous media via photoinduced electron transfer with detection limit in the ppb level. Remarkably, PFPT could also be applied for the trace analysis of Tc in serum samples having recoveries well in the range 92-97% with relative standard deviations (RSD) of 1.01-1.14%, confirming reliability of the present method for the analysis of Tc. Additionally, PFPT was blended with the abundant natural polysaccharide chitosan to form CS-PFPT composite films and developed as a biopolymer based membrane for the removal of Tc from water samples with a good adsorption capacity of 3.12 mg g 1, thus finding vital application in the treatment of antibiotic infested wastewater. PMID- 28094508 TI - Multiangular Rod-Shaped Na0.44MnO2 as Cathode Materials with High Rate and Long Life for Sodium-Ion Batteries. AB - The tunnel-structured Na0.44MnO2 is considered as a promising cathode material for sodium-ion batteries because of its unique three-dimensional crystal structure. Multiangular rod-shaped Na0.44MnO2 have been first synthesized via a reverse microemulsion method and investigated as high-rate and long-life cathode materials for Na-ion batteries. The microstructure and composition of prepared Na0.44MnO2 is highly related to the sintering temperature. This structure with suitable size increases the contact area between the material and the electrolyte and guarantees fast sodium-ion diffusion. The rods prepared at 850 degrees C maintain specific capacity of 72.8 mA h g-1 and capacity retention of 99.6% after 2000 cycles at a high current density of 1000 mA g-1. The as-designed multiangular Na0.44MnO2 provides new insight into the development of tunnel-type electrode materials and their application in rechargeable sodium-ion batteries. PMID- 28094509 TI - Harvesting Ambient Vibration Energy over a Wide Frequency Range for Self-Powered Electronics. AB - Vibration is one of the most common energy sources in ambient environment. Harvesting vibration energy is a promising route to sustainably drive small electronics. This work introduces an approach to scavenge vibrational energy over a wide frequency range as an exclusive power source for continuous operation of electronics. An elastic multiunit triboelectric nanogenerator (TENG) is rationally designed to efficiently harvest low-frequency vibration energy, which can provide a maximum instantaneous output power density of 102 W.m-3 at as low as 7 Hz and maintain its stable current outputs from 5 to 25 Hz. A self-charging power unit (SCPU) combining the TENG and a 10 mF supercapacitor gives a continuous direct current (DC) power delivery of 1.14 mW at a power management efficiency of 45.6% at 20 Hz. The performance of the SCPU can be further enhanced by a specially designed power management circuit, with a continuous DC power of 2 mW and power management efficiency of 60% at 7 Hz. Electronics such as a thermometer, hygrometer, and speedometer can be sustainably powered solely by the harvested vibration energy from a machine or riding bicycle. This approach has potential applications in self-powered systems for environment monitoring, machine safety, and transportation. PMID- 28094510 TI - Nanoporous-Gold-Based Electrode Morphology Libraries for Investigating Structure Property Relationships in Nucleic Acid Based Electrochemical Biosensors. AB - Nanoporous gold (np-Au) electrode coatings significantly enhance the performance of electrochemical nucleic acid biosensors because of their three-dimensional nanoscale network, high electrical conductivity, facile surface functionalization, and biocompatibility. Contrary to planar electrodes, the np-Au electrodes also exhibit sensitive detection in the presence of common biofouling media due to their porous structure. However, the pore size of the nanomatrix plays a critical role in dictating the extent of biomolecular capture and transport. Small pores perform better in the case of target detection in complex samples by filtering out the large nonspecific proteins. On the other hand, larger pores increase the accessibility of target nucleic acids in the nanoporous structure, enhancing the detection limits of the sensor at the expense of more interference from biofouling molecules. Here, we report a microfabricated np-Au multiple electrode array that displays a range of electrode morphologies on the same chip for identifying feature sizes that reduce the nonspecific adsorption of proteins but facilitate the permeation of target DNA molecules into the pores. We demonstrate the utility of the electrode morphology library in studying DNA functionalization and target detection in complex biological media with a special emphasis on revealing ranges of electrode morphologies that mutually enhance the limit of detection and biofouling resilience. We expect this technique to assist in the development of high-performance biosensors for point-of-care diagnostics and facilitate studies on the electrode structure-property relationships in potential applications ranging from neural electrodes to catalysts. PMID- 28094511 TI - Synthesis of Carboxylated-Graphenes by the Kolbe-Schmitt Process. AB - Graphene oxide is an oxidized form of graphene containing a large variety of oxygen groups. Although past models have suggested carboxylic acids to be present in significant amounts, recent evidence has shown otherwise. Toward the production of carboxyl-graphene, a synthetic method is presented herein based on the Kolbe-Schmitt process. A modified procedure of heating graphite oxide in the presence of a KOH/CaO mixture results in up to 11 atom % of carboxylic groups. The graphite oxide starting material and reaction temperature were investigated as two important factors, where a crumpled morphology of graphite oxide flakes and a lower 220 degrees C temperature preferentially led to greater carboxyl functionalization. Successful carboxylation caused a band gap opening of ~2.5 eV in the smallest carboxyl-graphene particles, which also demonstrated a yellow fluorescence under UV light unseen in its counterpart produced at 500 degrees C. These results are in good agreement with theoretical calculations showing band gap opening and spin polarization of impurity states. This demonstrates the current synthetic process as yet another approach toward tuning the physical properties of graphene. PMID- 28094512 TI - A Combined Spectroscopic/Molecular Dynamic Study for Investigating a Methyl Carboxylated PEI as a Potential Uranium Decorporation Agent. AB - Natural uranium has a very limited radioactive dose impact, but its chemical toxicity due to chronic exposure is still a matter of debate. Once inside the human body, the soluble uranium, under its uranyl form (U(VI)), is quickly removed from the blood system, partially excreted from the body, and partially retained in targeted organs, that is, the kidneys and bone matrix essentially. It is then crucial to remove or prevent the incorporation of uranium in these organs to limit the long-term chronic exposure. A lot of small chelating agents such as aminocarboxylates, catecholamides, and hydroxypyridonates have been developed so far. However, they suffer from poor selectivity and targeting abilities. Macromolecules and polymers are known to present a passive accumulation (size related), that is, the so-called enhanced permeability and retention effect, toward the main organs, which can be used as indirect targeting. Very interestingly, the methyl carboxylated polyethylenimine (PEI-MC) derivative has been described as a potent sequestering agent for heavy metals. It would be therefore an interesting candidate to evaluate as a new class of decorporation agents with passive targeting capabilities matching uranium preferential sequestering sites. In the present work, we explored the ability of a highly functionalized (89% rate) PEI-MC to uptake U(VI) close to physiological pH using a combination of analytical and spectroscopic techniques (inductively coupled plasma optical emission spectrometry (ICP-OES); extended X-ray absorption fine structure (EXAFS); and Fourier transformed infrared (FT-IR)) together with molecular dynamics (MD) simulation. A maximum loading of 0.47 mg U(VI) per milligram of PEI-MC was determined by ICP-OES measurements. From FT-IR data, a majority of monodentate coordination of the carboxylate functions of the PEI-MC seems to occur. From EXAFS and MD, a mix of mono and bidentate coordination mode was observed. Note that agreement between the EXAFS metrical parameters and MD radial distribution functions is remarkable. To the best of our knowledge, this is the first comprehensive structural study of a macromolecular PEI-based agent considered for uranium decorporation purposes. PMID- 28094513 TI - Native State Volume Fluctuations in Proteins as a Mechanism for Dynamic Allostery. AB - Allostery enables tight regulation of protein function in the cellular environment. Although existing models of allostery are firmly rooted in the current structure-function paradigm, the mechanistic basis for allostery in the absence of structural change remains unclear. In this study, we show that a typical globular protein is able to undergo significant changes in volume under native conditions while exhibiting no additional changes in protein structure. These native state volume fluctuations were found to correlate with changes in internal motions that were previously recognized as a source of allosteric entropy. This finding offers a novel mechanistic basis for allostery in the absence of canonical structural change. The unexpected observation that function can be derived from expanded, low density protein states has broad implications for our understanding of allostery and suggests that the general concept of the native state be expanded to allow for more variable physical dimensions with looser packing. PMID- 28094514 TI - Structural Model of the Tubular Assembly of the Rous Sarcoma Virus Capsid Protein. AB - The orthoretroviral capsid protein (CA) assembles into polymorphic capsids, whose architecture, assembly, and stability are still being investigated. The N terminal and C-terminal domains of CA (NTD and CTD, respectively) engage in both homotypic and heterotypic interactions to create the capsid. Hexameric turrets formed by the NTD decorate the majority of the capsid surface. We report nearly complete solid-state NMR (ssNMR) resonance assignments of Rous sarcoma virus (RSV) CA, assembled into hexamer tubes that mimic the authentic capsid. The ssNMR assignments show that, upon assembly, large conformational changes occur in loops connecting helices, as well as the short 310 helix initiating the CTD. The interdomain linker becomes statically disordered. Combining constraints from ssNMR and cryo-electron microscopy (cryo-EM), we establish an atomic resolution model of the RSV CA tubular assembly using molecular dynamics flexible fitting (MDFF) simulations. On the basis of comparison of this MDFF model with an earlier derived crystallographic model for the planar assembly, the induction of curvature into the RSV CA hexamer lattice arises predominantly from reconfiguration of the NTD-CTD and CTD trimer interfaces. The CTD dimer and CTD trimer interfaces are also intrinsically variable. Hence, deformation of the CA hexamer lattice results from the variable displacement of the CTDs that surround each hexameric turret. Pervasive H-bonding is found at all interdomain interfaces, which may contribute to their malleability. Finally, we find helices at the interfaces of HIV and RSV CA assemblies have very different contact angles, which may reflect differences in the capsid assembly pathway for these viruses. PMID- 28094515 TI - Nanoporous Materials for the Onboard Storage of Natural Gas. AB - Climate change, global warming, urban air pollution, energy supply uncertainty and depletion, and rising costs of conventional energy sources are, among others, potential socioeconomic threats that our community faces today. Transportation is one of the primary sectors contributing to oil consumption and global warming, and natural gas (NG) is considered to be a relatively clean transportation fuel that can significantly improve local air quality, reduce greenhouse-gas emissions, and decrease the energy dependency on oil sources. Internal combustion engines (ignited or compression) require only slight modifications for use with natural gas; rather, the main problem is the relatively short driving distance of natural-gas-powered vehicles due to the lack of an appropriate storage method for the gas, which has a low energy density. The U.S. Department of Energy (DOE) has set some targets for NG storage capacity to obtain a reasonable driving range in automotive applications, ruling out the option of storing methane at cryogenic temperatures. In recent years, both academia and industry have foreseen the storage of natural gas by adsorption (ANG) in porous materials, at relatively low pressures and ambient temperatures, as a solution to this difficult problem. This review presents recent developments in the search for novel porous materials with high methane storage capacities. Within this scenario, both carbon-based materials and metal-organic frameworks are considered to be the most promising materials for natural gas storage, as they exhibit properties such as large surface areas and micropore volumes, that favor a high adsorption capacity for natural gas. Recent advancements, technological issues, advantages, and drawbacks involved in natural gas storage in these two classes of materials are also summarized. Further, an overview of the recent developments and technical challenges in storing natural gas as hydrates in wetted porous carbon materials is also included. Finally, an analysis of design factors and technical issues that need to be considered before adapting vehicles to ANG technology is also presented. PMID- 28094516 TI - Designed DNA Crystal Habit Modifiers. AB - DNA is now one of the most widely used molecules for programmed self-assembly of discrete nanostructures. One of the long-standing goals of the DNA nanotechnology field has been the assembly of periodic, macroscopic 3D DNA crystals for controlled positioning of guest molecules to be used in a variety of applications. With continuing successes in assembling DNA crystals, there is an enhanced need to tailor macroscopic crystal properties-including morphology-to enable their integration into more complex systems. Here we describe the ability to alter and control crystal habits of a 3D DNA crystal formed by self-assembly of a DNA 13-mer. The introduction of "poison" oligonucleotides that specifically disrupt critical noncanonical base-pairing interactions in the crystal lattice leads to predictably modified crystal habits. We demonstrate that the poison oligomers can act as habit modifiers both during the initial crystallization and during growth of shell layers on a crystal macroseed. PMID- 28094517 TI - China Must Reduce Its Antibiotic Use. PMID- 28094518 TI - Conformational Effects of UV Light on DNA Origami. AB - The responses of DNA origami conformation to UV radiation of different wavelengths and doses are investigated. Short- and medium-wavelength UV light can cause photo-lesions in DNA origami. At moderate doses, the lesions do not cause any visible defects in the origami, nor do they significantly affect the hybridization capability. Instead, they help relieve the internal stress in the origami structure and restore it to the designed conformation. At high doses, staple dissociation increases which causes structural disintegration. Long wavelength UV does not show any effect on origami conformation by itself. We show that this UV range can be used in conjunction with photoactive molecules for photo-reconfiguration, while avoiding any damage to the DNA structures. PMID- 28094519 TI - Targeted Multiresidue Analysis of Veterinary Drugs in Milk-Based Powders Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). AB - An analytical method was developed and validated for the determination of 40 veterinary drugs in various milk-based powders. The method involves acetonitrile/water extraction, solid-phase filtration for lipid removal in fat containing matrices, and analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The limits of quantitation (LOQ) ranged from 0.02 to 82 ng/g. Acceptable recoveries (70-120%, RSD < 20%) were reached for 40 of 52 target compounds at three fortification levels in nonfat milk powder. Similar results were obtained for whole milk powder, milk protein concentrate, whey protein concentrate, and whey protein isolate. This new method will allow for better monitoring of a wide range of veterinary drugs in milk-based powders. PMID- 28094520 TI - Synthesis, Crystal Structure, Magnetic Properties, and Stability of the Manganese Rich "Mn3AlC" kappa Phase. AB - kappa-carbides of varying composition, seemingly responsible for age hardening in high-Al steel alloys, have been detected to precipitate both at grain boundaries and in the bulk grain of steels. Herein we report the bulk-phase synthesis of "Mn3AlC" by arc plasma sintering and rapid solidification. Single crystals have been found suitable for X-ray diffraction using Mo radiation and yield a lattice parameter of a = 3.875(2) A. We find a mixed occupation of the 1a position by Al and Mn, which, together with the C position being fully occupied, leads to the actual composition Mn3.1Al0.9C. Additional energy-dispersive X-ray-scanning electron microscopy measurements support the composition and corroborate the homogeneity. SQUID data collected on the polycrystalline ferromagnetic sample exhibit a Curie temperature of about 295 +/- 13 K and a soft magnetic behavior. The small but significant nonstoichiometry on 1a leads to a slightly larger lattice parameter, a higher electron count, and, thus, a lowered density of states at the Fermi level, indicative of increased phase stability. PMID- 28094521 TI - Titanium(III) Member of the Family of Trigonal Building Blocks with Scorpionate and Cyanide Ligands. AB - The titanium(III) cyanide compound [Et4N][Tp*Ti(CN)3] ([Et4N] = tetraethylamonium; Tp* = 3,5-dimethyltrispyrazolylhydroborate) is reported, which exhibits a trigonally distorted geometry. Magnetic data and ab initio calculations verified that the molecule is an S = 1/2 paramagnet and that it exhibits significant temperature-independent paramagnetism. PMID- 28094523 TI - Combining Agent-Based Modeling and Life Cycle Assessment for the Evaluation of Mobility Policies. PMID- 28094522 TI - Modulating the Primary and Secondary Coordination Spheres within a Series of CoII OH Complexes. AB - The interplay between the primary and secondary coordination spheres is crucial to determining the properties of transition metal complexes. To examine these effects, a series of trigonal bipyramidal Co-OH complexes have been prepared with tripodal ligands that control both coordination spheres. The ligands contain a combination of either urea or sulfonamide groups that control the primary coordination sphere through anionic donors in the trigonal plane and the secondary coordination sphere through intramolecular hydrogen bonds. Variations in the anion donor strengths were evaluated using electronic absorbance spectroscopy and a qualitative ligand field analysis to find that deprotonated urea donors are stronger field ligands than deprotonated sulfonamides. Structural variations were found in the CoII-O bond lengths that range from 1.953(4) to 2.051(3) A; this range in bond lengths were attributed to the differences in the intramolecular hydrogen bonds that surround the hydroxido ligand. A similar trend was observed between the hydrogen bonding networks and the vibrations of the O-H bonds. Attempts to isolate the corresponding CoIII-OH complexes were hampered by their instability at room temperature. PMID- 28094525 TI - Photocatalytic Color Switching of Transition Metal Hexacyanometalate Nanoparticles for High-Performance Light-Printable Rewritable Paper. AB - Developing efficient photoreversible color switching systems for constructing rewritable paper is of significant practical interest owing to the potential environmental benefits including forest conservation, pollution reduction, and resource sustainability. Here we report that the color change associated with the redox chemistry of nanoparticles of Prussian blue and its analogues could be integrated with the photocatalytic activity of TiO2 nanoparticles to construct a class of new photoreversible color switching systems, which can be conveniently utilized for fabricating ink-free, light printable rewritable paper with various working colors. The current system also addresses the phase separation issue of the previous organic dye-based color switching system so that it can be conveniently applied to the surface of conventional paper to produce an ink-free light printable rewritable paper that has the same feel and appearance as the conventional paper. With its additional advantages such as excellent scalability and outstanding rewriting performance (reversibility >80 times, legible time >5 days, and resolution >5 MUm), this novel system can serve as an eco-friendly alternative to regular paper in meeting the increasing global needs for environment protection and resource sustainability. PMID- 28094524 TI - Antimalarial Pyrido[1,2-a]benzimidazoles: Lead Optimization, Parasite Life Cycle Stage Profile, Mechanistic Evaluation, Killing Kinetics, and in Vivo Oral Efficacy in a Mouse Model. AB - Further structure-activity relationship (SAR) studies on the recently identified pyrido[1,2-a]benzimidazole (PBI) antimalarials have led to the identification of potent, metabolically stable compounds with improved in vivo oral efficacy in the P. berghei mouse model and additional activity against parasite liver and gametocyte stages, making them potential candidates for preclinical development. Inhibition of hemozoin formation possibly contributes to the mechanism of action. PMID- 28094526 TI - 1H NMR-Based Global Metabolic Studies of Pseudomonas aeruginosa upon Exposure of the Quorum Sensing Inhibitor Resveratrol. AB - Quorum sensing (QS) is a process of bacterial communication that has been a novel target for drug discovery. Pyocyanin quantification assay confirmed that resveratrol was an effective quorum sensing inhibitor (QSI) against Pseudomonas aeruginosa PAO1. In this study, the global metabolite changes of P. aeruginosa PAO1 exposed to QSI resveratrol were investigated by 1H NMR spectroscopy. A total of 40 metabolites containing amino acids, organic acid, organic amine, and energy storage compounds were identified. The changed metabolic profile indicated that resveratrol influenced pathways including oxidative stress, protein synthesis, and energy metabolism. Oxidative stress could upregulate the expression of genes related to QS in P. aeruginosa. It suggested that resveratrol could inhibit the QS systems in P. aeruginosa PAO1 by relieving oxidative stress due to its antioxidant activity. On the other hand, resveratrol could attenuate the pathogenicity of P. aeruginosa PAO1 by disturbing the TCA cycle so that anaerobic respiration could suppress the virulence because anaerobiosis could induce the loss of cytotoxicity regulated by QS in P. aeruginosa. These findings deepened our comprehending of the metabolic responses of P. aeruginosa PAO1 to resveratrol and pinpointed the possible underlying mechanism of resveratrol's inhibition effect on QS in P. aeruginosa PAO1. PMID- 28094527 TI - Binding and Inhibitory Effect of the Dyes Amaranth and Tartrazine on Amyloid Fibrillation in Lysozyme. AB - Interaction of two food colorant dyes, amaranth and tartrazine, with lysozyme was studied employing multiple biophysical techniques. The dyes exhibited hypochromic changes in the presence of lysozyme. The intrinsic fluorescence of lysozyme was quenched by both dyes; amaranth was a more efficient quencher than tartrazine. The equilibrium constant of amaranth was higher than that of tartarzine. From FRET analysis, the binding distances for amaranth and tartrazine were calculated to be 4.51 and 3.93 nm, respectively. The binding was found to be dominated by non-polyelectrolytic forces. Both dyes induced alterations in the microenvironment surrounding the tryptophan and tyrosine residues of the protein, with the alterations being comparatively higher for the tryptophans than the tyrosines. The interaction caused significant loss in the helicity of lysozyme, the change being higher with amaranth. The binding of both dyes was exothermic. The binding of amaranth was enthalpy driven, while that of tartrazine was predominantly entropy driven. Amaranth delayed lysozyme fibrillation at 25 MUM, while tartrazine had no effect even at 100 MUM. Nevertheless, both dyes had a significant inhibitory effect on fibrillogenesis. The present study explores the potential antiamyloidogenic property of these azo dyes used as food colorants. PMID- 28094528 TI - Noncontact Viscoelastic Measurement of Polymer Thin Films in a Liquid Medium Using Long-Needle Atomic Force Microscopy. AB - We report the noncontact measurement of the viscoelastic property of polymer thin films in a liquid medium using frequency-modulation atomic force microscopy with a newly developed long-needle probe. The probe contains a long vertical glass fiber with one end adhered to a cantilever beam and the other end with a sharp tip placed near the liquid-film interface. The nanoscale flow generated by the resonant oscillation of the needle tip provides a precise hydrodynamic force acting on the soft surface of the thin film. By accurately measuring the mechanical response of the thin film, we obtain the elastic and loss moduli of the thin film using the linear response theory of elastohydrodynamics. The experiment verifies the theory and demonstrates its applications. The technique can be used to accurately measure the viscoelastic property of soft surfaces, such as those made of polymers, nanobubbles, live cells, and tissues. PMID- 28094529 TI - Protonation Behavior of 1,1'-Bi-2-naphthol and Insights into Its Acid-Catalyzed Atropisomerization. AB - The behavior of 1,1'-bi-2-naphthol (BINOL) in variety of (super)acid media has been studied by NMR. The results are combined with the theoretical (DFT) study of the role of mono- and diprotonated forms of BINOL in the acid-catalyzed atropisomerization of this compound. It is demonstrated that the process of enantiomeric configuration exchange proceeds mainly via internal rotation around the C1(sp3)-C1'(sp3) bond in intermediates such as C1-monoprotonated keto or C1,C1'-diprotonated forms of BINOL, depending on the acidity level. PMID- 28094530 TI - Unexpected O-H Insertion of Rhodium-Azavinylcarbenes with N-Acylhydrazones: Divergent Synthesis of 3,6-Disubstituted- and 3,5,6-Trisubstituted-1,2,4 Triazines. AB - A practical and efficient method for divergent synthesis of 3,6-disubstituted- and 3,5,6-trisubstituted-1,2,4-triazines via unexpected rhodium-catalyzed O-H insertion/rearrangement/conditions-controlled intramolecular cyclization and oxidation reaction under mild conditions has been developed. Notably, it is the first example for the synthesis of 1,2,4-triazines with different substituted patterns via a common intermediate with excellent chemoselectivities by the reaction of N-acylhydrazones as aze-[3C] or [4C] synthons with N-sulfonyl-1,2,3 triazoles as aze-[2C] synthons. Furthermore, this method allows direct access to di(het)aryl ketone frameworks containing 1,2,4-triazine moiety for the first time, serving as a versatile building block for the synthesis of other useful heterocyclic skeletons, such as pyridine or pyridazinone-fused triazine in excellent yields. PMID- 28094531 TI - Cyanoform and Its Isomers. Relative Stabilities, Spectroscopic Features, and Rearrangements by Coupled Cluster and MCSCF-Based Methods. AB - Although an isolation of elusive tricyanomethane HC(CN)3 was recently reported, the existence of other HC4N3 species has yet to be confirmed. In this work, the relative stabilities, spectroscopic features, and rearrangements of tricyanomethane and its four isomers are examined using single- (CCSD(T), CCSD(T) F12) and multireference (MCSCF, MRPT2) methods. Tricyanomethane and dicyanoketenimine (NC)2CCNH, which are found to be the two most stable HC4N3 isomers lying within 9 kcal/mol, can be discriminated by their spectroscopic parameters. The predicted stepwise interconversion path relating HC(CN)3 and (NC)2CCNH features the HC4N3 species comprising the C-C-N ring moiety, with the largest barrier being associated with the initial H migration to one of the CN carbons. Adding a water molecule reduces the H migration barrier strongly and makes it possible to interconvert tricyanomethane to dicyanoketenimine in a "concerted" way. PMID- 28094533 TI - Animal experimentation: the statistics speak for themselves. PMID- 28094532 TI - Preclinical Comparison of Albumin-Binding Radiofolates: Impact of Linker Entities on the in Vitro and in Vivo Properties. AB - Tumor targeting with folic acid radioconjugates has been proposed as a promising strategy for radionuclide therapy of folate receptor alpha (FR)-positive cancer. Recently, it was shown that modification of radiofolates with an albumin-binding entity increased the tumor-to-kidney ratios of accumulated radioactivity in mice. The goal of this study was to evaluate the lead compound cm10 and compare it with new albumin-binding folate conjugates. Compound cm12 was designed with a long spacer consisting of a PEG-11 entity, and compound cm13 contained a short alkane chain between the albumin-binding moiety and folic acid. All of the derivatives were labeled with 177Lu (t1/2 = 6.65 days, Ebeta-,average = 134 keV; Egamma = 113 keV, 208 keV), a clinically established radionuclide for therapeutic purposes. The evaluation revealed that all of the albumin-binding radiofolates exhibited increased in vitro stability compared with the reference compound (177Lu-cm14) without albumin binder. Serum protein binding, determined with an ultrafiltration assay, was high (>88%) for the derivatives with albumin-binding entities. The FR binding affinity was in the same range (KD = 4.0-7.5 nM) for all of the radiofolates, independent of the albumin-binding entity and spacer length. FR specific uptake was proven in vitro using FR-positive KB tumor cells. In vivo studies with KB-tumor-bearing mice were performed in order to assess the tissue distribution profile of the novel radiofolates. 177Lu-cm13 showed high tumor uptake at late time points (13.3 +/- 2.94% IA/g, 48 h p.i.) and tumor-to-kidney ratios (0.59 +/- 0.03, 48 h p.i.) in the same range as 177Lu-cm10 (0.55 +/- 0.07, 48 h p.i.). However, the tumor-to-kidney ratio of 177Lu-cm12 (0.28 +/- 0.07, 48 h p.i.) was reduced compared with 177Lu-cm10 and 177Lu-cm13. The results of this study indicate that the spacer entity between folic acid and the albumin binder is of critical importance with regard to the tissue distribution profile of the radiofolate. The PEG spacer compromised the beneficial effects of the lead compound, but the design with a short alkane spacer appeared to be promising. Future studies will focus on the design of radiofolates with lipophilic and more rigid spacer entities, which may allow a further improvement of their tissue distribution profiles. PMID- 28094534 TI - In vitro assessment of skin irritation potential of surfactant-based formulations by using a 3-D skin reconstructed tissue model and cytokine response. AB - The personal care industry is focused on developing safe, more efficacious, and increasingly milder products, that are routinely undergoing preclinical and clinical testing before becoming available for consumer use on skin. In vitro systems based on skin reconstructed equivalents are now established for the preclinical assessment of product irritation potential and as alternative testing methods to the classic Draize rabbit skin irritation test. We have used the 3-D EpiDermTM model system to evaluate tissue viability and primary cytokine interleukin-1alpha release as a way to evaluate the potential dermal irritation of 224 non-ionic, amphoteric and/or anionic surfactant-containing formulations, or individual raw materials. As part of our testing programme, two representative benchmark materials with known clinical skin irritation potential were qualified through repeated testing, for use as references for the skin irritation evaluation of formulations containing new surfactant ingredients. We have established a correlation between the in vitro screening approach and clinical testing, and are continually expanding our database to enhance this correlation. This testing programme integrates the efforts of global manufacturers of personal care products that focus on the development of increasingly milder formulations to be applied to the skin, without the use of animal testing. PMID- 28094535 TI - Comparing the CORAL and Random Forest approaches for modelling the in vitro cytotoxicity of silica nanomaterials. AB - Nanotechnology is one of the most important technological developments of the 21st century. In silico methods to predict toxicity, such as quantitative structure-activity relationships (QSARs), promote the safe-by-design approach for the development of new materials, including nanomaterials. In this study, a set of cytotoxicity experimental data corresponding to 19 data points for silica nanomaterials were investigated, to compare the widely employed CORAL and Random Forest approaches in terms of their usefulness for developing so-called 'nano QSAR' models. 'External' leave-one-out cross-validation (LOO) analysis was performed, to validate the two different approaches. An analysis of variable importance measures and signed feature contributions for both algorithms was undertaken, in order to interpret the models developed. CORAL showed a more pronounced difference between the average coefficient of determination (R2) for training and for LOO (0.83 and 0.65 for training and LOO, respectively), compared to Random Forest (0.87 and 0.78 without bootstrap sampling, 0.90 and 0.78 with bootstrap sampling), which may be due to overfitting. With regard to the physicochemical properties of the nanomaterials, the aspect ratio and zeta potential were found to be the two most important variables for Random Forest, and the average feature contributions calculated for the corresponding descriptors were consistent with the clear trends observed in the data set: less negative zeta potential values and lower aspect ratio values were associated with higher cytotoxicity. In contrast, CORAL failed to capture these trends. PMID- 28094536 TI - The novel induction of retinal ganglion cell apoptosis in porcine organ culture by NMDA - an opportunity for the replacement of animals in experiments. AB - Some of the advantages of retina organ culture models include their efficient and easy handling and the ability to standardise relevant parameters. Additionally, when porcine eyes are obtained from the food industry, no animals are killed solely for research purposes. To induce retinal degeneration, a commonly used toxic substance, N-methyl-D-aspartate (NMDA), was applied to the cultures. To this end, organotypic cultures of porcine retinas were cultured and treated with different doses of NMDA (0 [control], 50, 100 and 200MUM) on day 2 for 48 hours. On day 7, the retinas were cryo-conserved for histological, Western blot and quantitative rt-PCR (qrt-PCR) analyses. NMDA treatment was found to significantly increase retinal ganglion cell (RGC) apoptosis in all the treated groups, without a profound RGC loss. In addition, the intrinsic apoptotic pathway was activated in the 50MUM and 100MUM NMDA groups, whereas induced nitric oxide synthase (iNOS) expression was increased in the 200MUM group. A slight microglial response was detectable, especially in the 100MUM group. NMDA treatment induced apoptosis, oxidative stress and a slight microglia activation. All these effects mimic a chronic slow progressive disease that especially affects RGCs, such as glaucoma. A particular advantage of this model is that mediators that can interact in the very early stages of the onset of RGC death, can be easily detected and potential therapies can be tested. PMID- 28094537 TI - Statistics of Scientific Procedures on Living Animals Great Britain 2015 - highlighting an ongoing upward trend in animal use and missed opportunities. AB - The Annual Statistics of Scientific Procedures on Living Animals Great Britain 2015 indicate that the Home Office were correct in recommending that caution should be exercised when interpreting the 2014 data as an apparent decline in animal experiments. The 2015 report shows that, as the changes to the format of the annual statistics have become more familiar and less problematic, there has been a re-emergence of the upward trend in animal research and testing in Great Britain. The 2015 statistics report an increase in animal procedures (up to 4,142,631) and in the number of animals used (up to 4,069,349). This represents 1% more than the totals in 2013, and a 7% increase on the procedures reported in 2014. This paper details an analysis of these most recent statistics, providing information on overall animal use and highlighting specific issues associated with genetically-altered animals, dogs and primates. It also reflects on areas of the new format that have previously been highlighted as being problematic, and concludes with a discussion about the use of animals in regulatory research and testing, and how there are significant missed opportunities for replacing some of the animal-based tests in this area. PMID- 28094538 TI - The Obesity Paradox in Colorectal Cancer Surgery: An Analysis of Korean Healthcare Big Data, 2012-2013. AB - Although it is well known that obesity increases the risk of colorectal cancer, several studies have recently suggested that those who are overweight or class one obese have better outcomes after surgery. However, the impact of obesity on the success of colorectal cancer surgery remains controversial. The medical records of patients diagnosed with colorectal cancer who were treated surgically from 2012 through 2013 were retrospectively analyzed. Data from a total of 36,740 patients were provided by the Healthcare Big Data Hub of the Korean Health Insurance Review & Assessment Service. Multivariate analyses suggested that hospital length of stay (LOS) was significantly associated with age, cancer stage, and body mass index. The odds ratios of spending more than 2 weeks in the hospital for the overweight or class-one obese groups compared to the normal weight group were 0.903 (95% confidence interval, 0.866-0.941) and 0.887 (95% confidence interval, 0.851-0.924), respectively, while that of the underweight group was 1.280 (95% confidence interval, 1.202-1.362). The "obesity paradox" applies to colorectal cancer, as indicated by decreased hospital LOS of overweight and obese patients. This result suggests that there is a protective effect of nutritional status in obese patients, which contributes to recovery from colorectal cancer surgery. PMID- 28094539 TI - Genetic diversity and population structure of castor (Ricinus communis L.) germplasm within the US collection assessed with EST-SSR markers. AB - Castor is an important oilseed crop and although its oil is inedible, it has multiple industrial and pharmaceutical applications. The entire US castor germplasm collection was previously screened for oil content and fatty acid composition, but its genetic diversity and population structure has not been determined. Based on the screening results of oil content, fatty acid composition, and country origins, 574 accessions were selected and genotyped with 22 polymorphic EST-SSR markers. The results from cluster analysis, population structure, and principal component analysis were consistent, and partitioned accessions into four subpopulations. Although there were certain levels of admixtures among groups, these clusters and subpopulations aligned with geographic origins. Both divergent and redundant accessions were identified in this study. The US castor germplasm collection encompasses a moderately high level of genetic diversity (pairwise dissimilarity coefficient = 0.53). The results obtained here will be useful for choosing accessions as parents to make crosses in breeding programs and prioritizing accessions for regeneration to improve germplasm management. A subset of 230 accessions was selected and will be planted in the field for establishing a core collection of the US castor germplasm. Further evaluation of the US castor germplasm collection is also discussed. PMID- 28094540 TI - Examining Mechanisms Underlying Fear-Control in the Extended Parallel Process Model. AB - This investigation sought to advance the extended parallel process model in important ways by testing associations among the strengths of efficacy and threat appeals with fear as well as two outcomes of fear-control processing, psychological reactance and message minimization. Within the context of print ads admonishing against noise-induced hearing loss (NIHL) and the fictitious Trepidosis virus, partial support was found for the additive model with no support for the multiplicative model. High efficacy appeals mitigated freedom threat perceptions across both contexts. Fear was positively associated with both freedom threat perceptions within the NIHL context and favorable attitudes for both NIHL and Trepidosis virus contexts. In line with psychological reactance theory, a freedom threat was positively associated with psychological reactance. Reactance, in turn, was positively associated with message minimization. The models supported reactance preceding message minimization across both message contexts. Both the theoretical and practical implications are discussed with an emphasis on future research opportunities within the fear-appeal literature. PMID- 28094542 TI - Power Distance, Uncertainty Avoidance, and the Effects of Source Credibility on Health Risk Message Compliance. AB - The present study aims to explore the relationship between perceived message source (spokesperson) credibility and message compliance in response to a health risk message. Based on an experiment in Ireland (n = 406) and Belgium (n = 410), we test how the relationship between source credibility and message compliance is mediated by perceived threat and efficacy of the message, and moderated by power distance and uncertainty avoidance. A source that is perceived as more credible is found to increase message compliance by increasing both the perceived message threat and efficacy. The indirect effect of source credibility on message compliance through perceived efficacy is stronger for individuals with lower power distance and higher uncertainty avoidance. PMID- 28094541 TI - Intestinal Proportion of Blautia sp. is Associated with Clinical Stage and Histoprognostic Grade in Patients with Early-Stage Breast Cancer. AB - Improving knowledge about breast cancer etiology is crucial in order to propose prevention strategies for this pathology. Gut microbiota is involved in numerous physiopathological situations including cancers. Although its potential involvement in breast cancer through the alteration of the enterohepatic circulation of estrogens and/or the metabolism of phytoestrogens has been discussed for some time, it remains to be demonstrated. The present study seeks to strengthen this hypothesis by identifying possible links between the fecal microbiota composition and clinical characteristics in breast cancer patients. Bacterial DNA was extracted from the feces of 31 patients with early-stage breast cancer and amplified by real-time polymerase chain reaction (qPCR), targeting 16S rRNA sequences specific to bacterial groups, and then analyzed in relation to clinical characteristics. The absolute numbers of total bacteria and of three bacterial groups (Firmicutes, Faecalibacterium prausnitzii, and Blautia) differed significantly according to the patient's body mass index. The percentage and the absolute numbers of certain bacterial groups, namely C. coccoides, F. prausnitzii, and Blautia, differed significantly according to the clinical stages and the histoprognostic grades. Our study highlighted that intestinal microbiota composition in these patients differs according to clinical characteristics and BMI. Further studies are required to clarify the link between breast cancer and intestinal microbiota. PMID- 28094543 TI - The Decision: A Creative Autoethnographic Account with Poetry. AB - This is the story of my decision to place my mother in a continuing-care facility. It is interwoven with the experiences of 32 residents of two continuing care communities. Their stories are presented as a poem, short conversation, and dramatic monologue. The poem describes what it means to be healthy. The short conversation elucidates the decision-making process of a couple and the monologue of a widow or single individual in moving to one of these facilities. PMID- 28094544 TI - Red Wine and Pomegranate Extracts Suppress Cured Meat Promotion of Colonic Mucin Depleted Foci in Carcinogen-Induced Rats. AB - Processed meat intake is carcinogenic to humans. We have shown that intake of a workshop-made cured meat with erythorbate promotes colon carcinogenesis in rats. We speculated that polyphenols could inhibit this effect by limitation of endogenous lipid peroxidation and nitrosation. Polyphenol-rich plant extracts were added to the workshop-made cured meat and given for 14 days to rats and 100 days to azoxymethane-induced rats to evaluate the inhibition of preneoplastic lesions. Colons of 100-d study were scored for precancerous lesions (mucin depleted foci, MDF), and biochemical end points of peroxidation and nitrosation were measured in urinary and fecal samples. In comparison with cured meat-fed rats, dried red wine, pomegranate extract, alpha-tocopherol added at one dose to cured meat and withdrawal of erythorbate significantly decreased the number of MDF per colon (but white grape and rosemary extracts did not). This protection was associated with the full suppression of fecal excretion of nitrosyl iron, suggesting that this nitroso compound might be a promoter of carcinogenesis. At optimized concentrations, the incorporation of these plant extracts in cured meat might reduce the risk of colorectal cancer associated with processed meat consumption. PMID- 28094545 TI - Electrochemical Analysis of Some Toxic Metals by Ion-Selective Electrodes. AB - An overview of potentiometric sensors that are capable of detecting toxic heavy metal ions in environmental samples is presented and discussed. Notwithstanding the tremendous work performed so far, it is obvious that still several limitations do exist in terms of selectivity, limits of detection, dynamic ranges, applicability to specific problems, and reversibility. A survey on important advances in potentiometric sensors with regard to high selectivity, lower detection limit, fast response time, and on-line environmental analysis is presented in this review article. [Supplemental materials are available for this article. Go to the publisher's online edition of Critical Reviews in Analytical Chemistry to view the free supplemental file.]. PMID- 28094546 TI - Letter from the Editor. PMID- 28094548 TI - The Progress in Electron Microscopy Studies of Particulate Matters to Be Used as a Standard Monitoring Method for Air Dust Pollution. AB - The present article reviews studies on air solid particles carried out with the use of electron microscopy. Particle analysis combining scanning and transmission electron microscopy (SEM and TEM) can be used to derive size-resolved information of the composition, mixing state, morphology, and complex refractive index of atmospheric aerosol particles. It seems that electron microscopy is more widely used in atmospheric particulate matter analysis, but the usage of this method is sometimes problematic. First of all, there is no standard methodology adapted for dust analysis, and it is difficult to compare the results coming from different laboratories. Nevertheless, it was shown that this method has potential to be used in the future as a standard monitoring procedure of air solid particles. PMID- 28094549 TI - Flavonoids as Analytical Reagents. AB - Compounds from the flavonoid family, while exhibiting a wide range of biological effects, are interesting reagents for analytical purposes as well. They form complexes with several p-, d-, and f-electron metals, which could be employed in the determination of these metal ions in different kinds of samples by various techniques. This article presents and discusses the application of flavonoid compounds as chromogenic agents in spectrophotometric and fluorometric detection, as complexing modifiers in solid phase extraction for preconcentration and separation of metal ions, and in adsorptive voltammetry for the determination of metals. Selected applications are included to illustrate the scope and limitations of the various approaches. PMID- 28094550 TI - Pharmacophore modelling, atom-based 3D-QSAR generation and virtual screening of molecules projected for mPGES-1 inhibitory activity. AB - COX-2 inhibitors exhibit anticancer effects in various cancer models but due to the adverse side effects associated with these inhibitors, targeting molecules downstream of COX-2 (such as mPGES-1) has been suggested. Even after calls for mPGES-1 inhibitor design, to date there are only a few published inhibitors targeting the enzyme and displaying anticancer activity. In the present study, we have deployed both ligand and structure-based drug design approaches to hunt novel drug-like candidates as mPGES-1 inhibitors. Fifty-four compounds with tested mPGES-1 inhibitory value were used to develop a model with four pharmacophoric features. 3D-QSAR studies were undertaken to check the robustness of the model. Statistical parameters such as r2 = 0.9924, q2 = 0.5761 and F test = 1139.7 indicated significant predictive ability of the proposed model. Our QSAR model exhibits sites where a hydrogen bond donor, hydrophobic group and the aromatic ring can be substituted so as to enhance the efficacy of the inhibitor. Furthermore, we used our validated pharmacophore model as a three-dimensional query to screen the FDA-approved Lopac database. Finally, five compounds were selected as potent mPGES-1 inhibitors on the basis of their docking energy and pharmacokinetic properties such as ADME and Lipinski rule of five. PMID- 28094551 TI - Effect of bovine lactoferrin on Chlamydia trachomatis infection and inflammation. AB - Chlamydia trachomatis is an obligate, intracellular pathogen responsible for the most common sexually transmitted bacterial disease worldwide, causing acute and chronic infections. The acute infection is susceptible to antibiotics, whereas the chronic one needs prolonged therapies, thus increasing the risk of developing antibiotic resistance. Novel alternative therapies are needed. The intracellular development of C. trachomatis requires essential nutrients, including iron. Iron chelating drugs inhibit C. trachomatis developmental cycle. Lactoferrin (Lf), a pleiotropic iron binding glycoprotein, could be a promising candidate against C. trachomatis infection. Similarly to the efficacy against other intracellular pathogens, bovine Lf (bLf) could both interfere with C. trachomatis entry into epithelial cells and exert an anti-inflammatory activity. In vitro and in vivo effects of bLf against C. trachomatis infectious and inflammatory process has been investigated. BLf inhibits C. trachomatis entry into host cells when incubated with cell monolayers before or at the moment of the infection and down regulates IL-6/IL-8 synthesized by infected cells. Six out of 7 pregnant women asymptomatically infected by C. trachomatis, after 30 days of bLf intravaginal administration, were negative for C. trachomatis and showed a decrease of cervical IL-6 levels. This is the first time that the bLf protective effect against C. trachomatis infection has been demonstrated. PMID- 28094552 TI - Glucose Metabolism in Cancer and Ischemia: Possible Therapeutic Consequences of the Warburg Effect. AB - The Warburg effect states that the main source of energy for cancer cells is not aerobic respiration, but glycolysis-even in normoxia. The shift from one to the other is governed by mutually counteracting enzymes: pyruvate dehydrogenase and pyruvate dehydrogenase kinase (PDK). Anaerobic metabolism of cancer cells promotes cell proliferation, local tissue immunosuppression, resistance to hypoxic conditions, and metastatic processes. By switching glucose back to oxidative metabolism, these effects might be reversed. This can be achieved using PDK inhibitors, such as dichloroacetate. Patients suffering from ischemic conditions might benefit from this effect. On the other hand, the beta-blockers (adrenergic beta-antagonists) often used in these patients appear to improve cancer-specific survival, and nonselective beta-blockers have been shown to promote glucose oxidation. Might there be a link? PMID- 28094553 TI - Burden of HIV, Syphilis, and Hepatitis B and C Among Inmates in a Prison State System in Mexico. AB - We studied the prevalence of HIV, syphilis, hepatitis B virus (HBV), and hepatitis C virus (HCV) infection and associated risk behaviors in the prison state system of Guanajuato, Mexico between September 2011 and February 2012. Blood samples were drawn from adult inmates in all State prisons who agreed to participate in this cross-sectional study. Data on risk behaviors were collected by using self-administered questionnaires. The prevalence of HIV, syphilis, HBV, and HCV infection was 0.6% [95% confidence interval (CI) = 0.2-1.1], 0.7% (95% CI = 0.4-1.0), 0.4 (95% CI = 0.04-0.74), and 4.8 (95% CI = 3.6-5.9), respectively. Female inmates had a higher prevalence of HIV (1.5% vs. 0.6%, p = .05), whereas male inmates had a higher prevalence of HCV (1% vs. 5%, p = .008). Twenty percent (n = 443, 95% CI = 15-26) of the participants were tattooed during incarceration, and most of them were tattooed with recycled materials. Around 60% (57%, 95% CI = 49-65) used drugs before incarceration, and 9.2% (n = 205) used injected drugs. During incarceration, 30% (95% CI = 23-39) used drugs and 43 continued injecting (20% of users). Consistent condom use was low among men before incarcerations but decreased by half during incarceration. The highest consistent condom use before incarceration was among men who have sex with men (MSM) (17.7%, 95% CI = 14-22), but it decreased (9%, 95% CI = 3-14) during incarceration. The prevalence of HIV, HBV, HCV, and syphilis in these inmates is higher than that of the local adult population. Most inmates had sex in prison, but few used condoms consistently. Access to condoms is apparently harder for MSM. Interventions to increase condom use, reduce use of shared or recycled materials for tattooing and injecting drugs, and treatment for drug abuse are needed. PMID- 28094554 TI - Impact of Phytochemicals and Dietary Patterns on Epigenome and Cancer. AB - Cancer remains one of the leading causes of death around the world. Initially it is recognized as a genetic disease, but now it is known to involve epigenetic abnormalities along with genetic alterations. Epigenetics refers to heritable changes that are not encoded in the DNA sequence itself, but play an important role in the control of gene expression. It includes changes in DNA methylation, histone modifications, and RNA interference. Although it is heritable, environmental factors such as diet could directly influence epigenetic mechanisms in humans. This article will focus on the role of dietary patterns and phytochemicals that have been demonstrated to influence the epigenome and more precisely histone and non-histone proteins modulation by acetylation that helps to induce apoptosis and phosphorylation inhibition, which counteracts with cells proliferation. Recent developments discussed here enhance our understanding of how dietary intervention could be beneficial in preventing or treating cancer and improving health outcomes. PMID- 28094555 TI - Loneliness and the risk of dementia among older Chinese adults: gender differences. AB - OBJECTIVE: The objective of this study was to examine whether loneliness was associated with the risk of developing dementia in Chinese older adults and whether the association was moderated by gender. METHOD: A 3-year cohort study was conducted using data from the 2008/2009 and 2011/2012 waves of the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Multiple logistic regression was used to analyze the relationship between loneliness and dementia. The interaction between loneliness and gender was also evaluated. RESULTS: At 3-year follow-up, 393 of the 7867 participants had dementia. Loneliness was associated with dementia (odds ratio (OR) = 1.31, 95% confidence interval (CI) = 1.11-1.56) after adjustment for sociodemographic characteristics, lifestyle, and baseline health status. A significant interaction between loneliness and gender was also found (OR = 0.81, 95% CI = 0.65-0.99). CONCLUSION: Loneliness increased the risk of developing dementia among people aged 65 years and older in China. Moreover, the effect of loneliness on dementia risk varied by gender. Specifically, men who felt lonely were more likely to suffer from dementia than women. PMID- 28094556 TI - How I Learned to Count. AB - This is a poem about surviving familial childhood sexual abuse and the healing I found through the beauty and spiritual growth of motherhood. PMID- 28094557 TI - Cigarette Initiation Among Chinese Male Teenagers in Early Smoking Interactions. AB - To collect in-depth information regarding cigarette initiation interactions in the early smoking experimentation among male youth in China, twenty focus groups with male teenagers (N = 165) were conducted. Focus group discussions indicated a high prevalence of cigarette initiation among peers, and such initiation often translated into immediate smoking. Of the identified cigarette initiation appeals, "face" and normative pressure appeals were the most difficult to reject. Upon first initiation attempts, more teenagers accepted cigarettes than rejected them. The reasons behind both cigarette initiation and acceptance primarily related to facilitating social interaction. Upon being rejected, initiating teenagers (agents) who insisted on offering cigarettes often gained compliance. Profiles of peer agents were constructed in this study. Key practical implications suggest simultaneously prioritizing efforts to reduce cigarette initiation and encouraging cigarette refusal. PMID- 28094558 TI - The Arts and Health Communication in Uganda: A Light Under the Table. AB - This qualitative interview study brings the voices of 27 public health leaders, health communication experts, and artists who work in public health in Uganda together to articulate the principles and practices that make the country a shining example of effective, evidence-based use of the arts for health communication. The specific aim of the study was to identify best practices, theoretical foundations, and other factors that contribute to the success of arts based health communication campaigns in Uganda. The study presents four primary themes related to use of the arts for health communication in Uganda: (1) the arts empower health communication; (2) the arts engage people emotionally; (3) effective programs are highly structured; and (4) professionalism is critical to program effectiveness. The findings suggest that the arts humanize, clarify, and empower health communication. The arts can attract attention and engage target populations, reduce hierarchical divisions and tensions that can challenge communication between health professionals and community members, make concepts clearer and more personally and culturally relevant, and communicate at an emotional level wherein concepts can be embodied and made actionable. The findings articulate why and how the arts are an effective means for health communication and can guide best practices. PMID- 28094559 TI - Sweet Temptations: How Does Reading a Fotonovela About Diabetes Affect Dutch Adults with Different Levels of Literacy? AB - Recent studies suggest that health-related fotonovelas-booklets that portray a dramatic story using photographs and captions-may be effective health communication tools, especially for readers with a low level of literacy. In this experiment, effects on knowledge and behavioral intentions were assessed of a fotonovela originally developed for a Latin-American audience. Dutch readers from a low literacy group (N = 89) and a high literacy group (N = 113) were randomly assigned to one of three conditions: a fotonovela condition (all captions translated into Dutch), a traditional brochure condition (also in Dutch), and a control condition. On knowledge about diabetes, participants in the fotonovela condition outperformed participants in both other conditions. This finding was consistent across literacy levels. On behavioral intentions, however, readers of the fotonovela did not score significantly higher than participants in the other conditions. We also evaluated hypotheses proposed in the Entertainment Overcoming Resistance Model (EORM; Moyer-Guse, 2008) on the possible mechanisms underlying persuasion through narratives. No support was found for the mechanisms proposed in the EORM. The outcomes of this study suggest that a fotonovela may be a valuable health education format for adults with varying levels of literacy, even if it was developed for a target group with a different cultural background. PMID- 28094560 TI - Systemic Metabolite Changes in Wild-type C57BL/6 Mice Fed Black Raspberries. AB - INTRODUCTION: Freeze-dried black raspberries (BRBs) elicit chemopreventive effects against colorectal cancer in humans and in rodents. The objective of this study was to investigate potential BRB-caused metabolite changes using wild-type (WT) C57BL/6 mice. METHODS AND RESULTS: WT mice were fed either control diet or control diet supplemented with 5% BRBs for 8 wk. A nontargeted metabolomic analysis was conducted on colonic mucosa, liver, and fecal specimens collected from both diet groups. BRBs significantly changed the levels of 41 colonic mucosa metabolites, 40 liver metabolites, and 34 fecal metabolites compared to control diet-fed mice. BRBs reduced 34 lipid metabolites in colonic mucosa and increased levels of amino acids in liver. One metabolite, 3-[3-(sulfooxy) phenyl] propanoic acid, might be a useful biomarker of BRB consumption. In addition, BRB powder was found to contain 30-fold higher levels of linolenate compared to control diets. Consistently, multiple omega-3 polyunsaturated fatty acids (omega-3 PUFAs), including stearidonate, docosapentaenoate (omega-3 DPA), eicosapentaenoate (EPA), and docosahexaenoate (DHA), were significantly elevated in livers of BRB-fed mice. CONCLUSION: The data from the current study suggest that BRBs produce systemic metabolite changes in multiple tissue matrices, supporting our hypothesis that BRBs may serve as both a chemopreventive agent and a beneficial dietary supplement. PMID- 28094561 TI - The perioperative dental screening and management of patients undergoing cardiothoracic, vascular surgery and other cardiovascular invasive procedures: A systematic review. AB - Background One controversial issue in the relationship between oral care and cardiovascular diseases is how and whether to manage oral infections prior to cardiovascular surgery or other cardiovascular invasive procedures. Design We designed a systematic review to assess the information available on three main questions. Is there an agreement on the need for dental evaluation and treatment before cardiovascular interventions? Are consistent clinical recommendations or protocols available? Is dental treatment prior to cardiovascular interventions effective? Methods A systematic electronic search of MEDLINE, Scopus and Web of Science was performed from the database inceptions up to 31 April 2016. Searches were performed using Boolean operators to combine medical subject headings and free text words. Because this review included a large, heterogeneous group of study designs and sources, the results were synthesised in a narrative approach. Results In total, 2447 studies were identified: 2099 (+241 duplicates) were excluded after screening; 107 were included for full-text assessment; 55 were excluded for not meeting the inclusion criteria; and 11 were not available. Thus, 44 studies meeting the inclusion criteria were analysed. We found that, for patients undergoing cardiovascular surgery, there is a general agreement on the need for screening and treatment of dental infections, but not on the protocols. We also found that there are conflicting indications on when and to what extent to perform the treatment and that the risk-to-benefit ratios for these treatments are controversial. Conclusion No satisfactory answers regarding dental care before cardiovascular invasive procedures are available. PMID- 28094563 TI - Dental Arch Relationships and Reverse Headgear Effects in Southern Chinese Patients with Unilateral Cleft Lip and Palate: A Retrospective Study. AB - OBJECTIVE: To evaluate the severity of the dental arch relationships and the treatment outcomes of reverse headgear (RHG) in southern Chinese patients with unilateral cleft lip and palate (UCLP). DESIGN: A retrospective study. SETTING: Faculty of Dentistry, The University of Hong Kong. PATIENTS: Thirty-eight UCLP patients with complete records. Among them, 14 were later treated with RHG (RHG group) and 24 were under review (non-RHG group) before definitive orthodontic or in conjunction with orthognathic surgery. INTERVENTIONS: Study models at T1 (aged 9.4 +/- 0.4 years old), prebone grafting and before any orthodontic treatment started; T2 (aged 11.3 +/- 0.6 years old), after bone grafting, and RHG treatment (RHG group) or under review (non-RHG group); and T3 (aged 15.3 +/- 3.2 years old), pretreatment of definitive orthodontic or in conjunction with orthognathic surgery. MAIN OUTCOME MEASURES: With satisfactory intra- and interexaminer agreement proven by the kappa value, the dental arch relationships of the study models at T1, T2, and T3 were assessed by a solo calibrated examiner using the GOSLON Yardstick. RESULTS: The median GOSLON score for southern Chinese patients with UCLP at T1 was 4.0. Sixty percent of the patients were categorized as "poor" at T1. RHG significantly improved dental arch relationships from T1 to T2, and the improvement was maintained until T3 assessed by the GOSLON Yardstick. CONCLUSIONS: The dental arch relationships in southern Chinese UCLP patients at 8 to 10 years old are unfavorable. RHG treatment shows positive effects in improving the dental arch relationships in UCLP patients, as assessed by the GOSLON Yardstick. PMID- 28094562 TI - Effects of Bisphosphonate Administration on Cleft Bone Graft in a Rat Model. AB - OBJECTIVE: Bone grafts in patients with cleft lip and palate can undergo a significant amount of resorption. The aim of this study was to investigate the effects of bisphosphonates (BPs) on the success of bone grafts in rats. DESIGN: Thirty-five female 15-week-old Fischer F344 Inbred rats were divided into the following experimental groups, each receiving bone grafts to repair an intraoral CSD: (1) Graft/saline: systemic administration of saline and (2) systemic administration of zoledronic acid immediately following surgery (graft/BP/T0), (3) 1 week postoperatively (graft/BP/T1), and (4) 3 weeks postoperatively (graft/BP/T2). As an additional control, the defect was left empty without bone graft. MAIN OUTCOME MEASURES: Microcomputed tomography and histologic analyses were performed in addition to evaluation of osteoclasts through tartrate resistant acid phosphatase staining. RESULTS: Bone volume fraction (bone volume/tissue volume) for the delayed BP treatment groups (graft/BP/T1 = 45.4% +/ 8.8%; graft/BP/T2 = 46.1% +/- 12.4%) were significantly greater than that for the graft/saline group (31.0% +/- 7.9%) and the graft/BP/T0 (27.6% +/- 5.9%) 6 weeks postoperatively (P < .05). Hematoxylin and eosin staining confirmed an evident increase in bone volume and fusion of defect margins with existing palatal bone in the graft/BP/T1 and graft/BP/T2 groups. The graft/BP/T0 group showed the lowest bone volume with signs of acute inflammation. CONCLUSIONS: Delayed BP administration following cleft bone graft surgery led to significant increase in bone volume and integration compared with saline controls. However, BP injection immediately after the surgery did not enhance bone volume, and rather, may negatively affect bone graft incorporation. PMID- 28094564 TI - Secondary Cleft Nasolabial Deformities: A New Classification System for Evaluation and Surgical Revision. AB - INTRODUCTION: Secondary or residual cleft lip and nasal deformities following primary unilateral or bilateral cleft lip repair are common. Many classification systems have been proposed to describe congenital cleft lip and palate deformities before repair. This article proposes a one-of-a-kind classification system for residual cleft deformities and describes its application to 136 cleft lip revision cases from cleft outreach missions worldwide. METHODS: Patients' demographics and deformities were classified preoperatively, and a database of the classification was created. Postoperatively, the type of surgery performed was added to the database and comparison was done using an independent t test. RESULTS: Kappa coefficient was 0.92 and showed excellent agreement between the type assigned preoperatively to the patient and the type of procedure done. CONCLUSIONS: This system proves to provide good descriptions of the deformities, is user friendly, facilitates the planning of the corrective surgical procedure, and enhances the communicative lingo between surgeons and members of cleft multidisciplinary care teams. It is broadly applicable in outreach missions with limited resources and cleft referral centers with considerable load. PMID- 28094565 TI - The Decline in HIV-1 Drug Resistance in Heavily Antiretroviral-Experienced Patients Is Associated with Optimized Prescriptions in a Treatment Roll-Out Program in Mexico. AB - A decrease in the rate of acquired antiretroviral (ARV) drug resistance (ADR) over time has been documented in high-income settings, but data on the determinants of this phenomenon are lacking. We tested the hypothesis that in heavily ARV-experienced patients in the Mexican ARV therapy (ART) roll-out program, the drop in ADR would be associated with changes in ARV drug usage. Genotypic resistance tests obtained from 974 HIV-infected patients with virological failure and at least 2 previously failed ARV regimens from throughout the country were analyzed for the presence of nucleos(t)ide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitor (PI) resistance-associated mutations (RAMs). Patients were divided into two groups according to their first ART start date: 488 patients initiated ART before mid-2003 (group 1) and 486 after mid-2003 (group 2). The rate of RAMs, median resistance score of several sentinel ARVs, and composition of ART drugs in patient's entire treatment history were compared between both groups. Patients in group 2 were less likely to have >3 thymidine analogue-associated mutations (TAMs) and >3 PI-mRAMs [adjusted odds ratio (aOR) = 0.37; 95% confidence interval (95% CI) = 0.25-0.54; p < .001 and aOR = 0.53; 95% CI = 0.36-0.77; p = .001, respectively] and had a significantly lower resistance score for zidovudine, tenofovir, ritonavir-boosted (r)-lopinavir, r-atazanavir, and r-darunavir than group 1 patients. A significantly lower proportion of patients in group 2 used monotherapy, bitherapy, thymidine analogue-containing regimens, nonboosted PI containing regimens, and low resistance barrier PI-containing regimens. In Mexican ARV-experienced patients, the occurrence of TAM and PI-mRAM has significantly declined over time. This can be explained by treatment optimization in the national ART roll-out program in recent years. PMID- 28094566 TI - Hepatitis C Virus Continuum of Care in the Interferon and Direct-Acting Agent Eras Among HIV-Coinfected Patients. PMID- 28094567 TI - A Vulnerable Age for the Introduction of Solid Foods in Pediatric Acute Lymphoblastic Leukemia. AB - BACKGROUND: There is little research concerning infant formula or the age at introduction to solid foods and pediatric acute lymphoblastic leukemia (ALL). The purpose of this case-control study was to estimate the association of age at introduction of solids and pediatric ALL. METHODS: 171 ALL cases aged 0-14 years were recruited at Texas Children's Cancer Center and matched on sex, age, and ethnicity to 342 population-based controls. Data were collected on infant feeding and known risk factors for ALL. Multivariable logistic regression was used to model the odds ratio of ALL by quartile of age at introduction of solids with the first/earliest quartile (0-4 months) as the reference group. RESULTS: In adjusted models, the odds ratio of ALL among children in quartile 3 (7-9 months) was 4.08, 95% confidence interval (CI) 1.42-11.71; for children in quartile 4 (>=10 months) the odds ratio (OR) was 6.03, 95% CI 2.06-17.72. For each additional month of milk formula feeding, the OR of ALL was 1.16, 95% CI 1.08-1.25. CONCLUSIONS: These results suggest a window when later introduction to solids is positively associated with ALL and recommend compliance with the American Academy of Pediatrics guidelines. PMID- 28094568 TI - Barcode-based species delimitation in the marine realm: a test using Hexanauplia (Multicrustacea: Thecostraca and Copepoda). AB - DNA barcoding has been used successfully for identifying specimens belonging to marine planktonic groups. However, the ability to delineate species within taxonomically diverse and widely distributed marine groups, such as the Copepoda and Thecostraca, remains largely untested. We investigate whether a cytochrome c oxidase subunit I (COI-5P) global pairwise sequence divergence threshold exists between intraspecific and interspecific divergences in the copepods plus the thecostracans (barnacles and allies). Using publicly accessible sequence data, we applied a graphical method to determine an optimal threshold value. With these thresholds, and using a newly generated planktonic marine data set, we quantify the degree of concordance using a bidirectional analysis and discuss different analytical methods for sequence-based species delimitation (e.g., BIN, ABGD, jMOTU, UPARSE, Mothur, PTP, and GMYC). Our results support a COI-5P threshold between 2.1% and 2.6% p-distance across methods for these crustacean taxa, yielding molecular groupings largely concordant with traditional, morphologically defined species. The adoption of internal methods for clustering verification enables rapid biodiversity studies and the exploration of unknown faunas using DNA barcoding. The approaches taken here for concordance assessment also provide a more quantitative comparison of clustering results (as contrasted with "success/failure" of barcoding), and we recommend their further consideration for barcoding studies. PMID- 28094569 TI - Dietary Fat Consumption and Non-Hodgkin's Lymphoma Risk: A Meta-analysis. AB - OBJECTIVE: Many studies suggest that high-fat diets are linked to the etiology of non-Hodgkin's lymphoma (NHL). However, the findings are inconsistent and therefore the association between fat and non-Hodgkin's lymphoma remains unclear. In this study, we aim to quantitatively assess the association between fat consumption and the risk for NHL. METHODS: We reviewed 221 published cohort and case-control studies that reported relative risk (RRs) and corresponding 95% confidence intervals (CIs) of NHL and fat intake using PubMed, Cochrane, EMBASE, and Google Scholar databases. A random-effects model computed summary risk estimates. RESULTS: Based on our literature search, 10 of 221 studies (two cohort and eight case-control studies) were relevant to this meta-analysis. There was a significant association between total fat consumption and increased risk of NHL (RR = 1.26; 95% CI: 1.12-1.42); in addition, subgroup analysis showed a significant correlation with diffuse large B-cell lymphoma (RR = 1.41; 95% CI: 1.08-1.84) but not with follicular lymphoma (RR = 1.21; 95% CI: 0.97-1.52), small lymphocytic lymphoma/chronic lymphocytic leukemia (RR = 0.91; 95% CI: 0.68-1.23), nor with T cell lymphoma (RR = 1.12; 95% CI: 0.60-2.09). The funnel plot revealed no evidence for publication bias. CONCLUSION: Total fat consumption, particularly animal fat, increases the risk for NHL. PMID- 28094570 TI - Antioxidant, Anti-inflammatory, and Genomic Stability Enhancement Effects of Zinc l-carnosine: A Potential Cancer Chemopreventive Agent? AB - Cancer is one of the major causes of death worldwide, and the incidence and mortality rates of cancer are expected to rise tremendously in the near future. Despite a better understanding of cancer biology and advancement in cancer management, current strategies in cancer treatment remain costly and ineffective. Hence, instead of putting more efforts to search for new cancer cures, attention has now been shifted to the development of cancer chemopreventive agents as a preventive measure for cancer formation. It is well known that neoplastic transformation of cells is multifactorial, and the occurrence of oxidative stress, chronic inflammation, and genomic instability events has been implicated in the carcinogenesis of cells. Zinc l-carnosine (ZnC), which is clinically used as gastric ulcer treatment in Japan, has been suggested to have the potential in preventing cancer development. Multiple studies have revealed that ZnC possesses potent antioxidant, anti-inflammatory, and genomic stability enhancement effects. Thus, this review provides some mechanistic insight into the antioxidant, anti inflammatory, and genomic stability enhancement effects of ZnC in relevance to its chemopreventive potential. PMID- 28094571 TI - Dietary Inflammatory Index and Risk of Colorectal Adenoma Recurrence: A Pooled Analysis. AB - No studies have evaluated the association between the dietary inflammatory index (DII) and colorectal adenoma recurrence. DII scores were calculated from a baseline food frequency questionnaire. Participants (n = 1727) were 40-80 years of age, enrolled in two Phase III clinical trials, who had >=1 colorectal adenoma(s) removed within 6 months of study registration, and a follow-up colonoscopy during the trial. Multiple logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). No statistically significant associations were found between DII and odds of colorectal adenoma recurrence [ORs (95% CIs) = 0.93 (0.73, 1.18) and 0.95 (0.73, 1.22)] for subjects in the second and third DII tertiles, respectively, compared to those in the lowest tertile (Ptrend = 0.72). No associations were found for recurrent colorectal adenoma characteristics, including advanced recurrent adenomas, large size, villous histology, or anatomic location. While our study did not support an association between a proinflammatory diet and colorectal adenoma recurrence, future studies are warranted to elucidate the role of a proinflammatory diet on the early stages of colorectal carcinogenesis. PMID- 28094572 TI - Lycopene in the Prevention of Radiation-Induced Esophagitis. AB - We aimed to research whether lycopene (L) could prevent radiation-induced acute esophageal toxicity in Wistar albino rats. 60 rats were placed in five groups as follows: control, L, radiotherapy (RT), L before RT (L + RT), and L before and after RT (L + RT + L). 6 mg/kg bw/day L was administered 7 days in the L group, 7 days before RT in the L + RT group, and 7 days before and after in the L + RT + L group. 35 Gy thoracic RT was performed. Serum L levels were measured, and the esophagi were evaluated histopathologically for intraepithelial degenerative changes-necrosis, vacuole formation, inflammation, regeneration-mitosis, and subepithelial bulla formation. L levels were significantly higher in the L receiving groups. All histopathologic results were significantly worse in the RT group than in the none-RT groups. The L + RT and the L + RT + L groups had better results than the RT group. Grade 2-3 degenerative changes-necrosis and vacuole formation were significantly lesser in the L + RT and the L + RT + L groups than those in the RT group. There was a trend toward decreased subepithelial bulla formation and inflammation in the L + RT and the L + RT + L groups compared to the RT group. Regeneration-mitosis was insignificantly lesser in the L + RT and significantly fewer in the L + RT + L groups than that in the RT group. PMID- 28094573 TI - Advanced gastric adenocarcinoma: optimizing therapy options. AB - INTRODUCTION: Gastric adenocarcinoma (GAC) is the fifth most common cancer and third leading cause of cancer related mortality worldwide. When localized, cure is achievable with surgery and adjunctive therapies in some patients, however, once advanced, GAC is not a curable condition. Only two targeted agents (trastuzumab and ramucirumab) have been approved and apatinib was approved only in China. Because of the heterogeneous nature of GAC, it is not possible to assess a standard therapeutic approach. Areas covered: In this review, we aimed to describe the optimal systemic therapy regimens for advanced GAC. A literature search was performed to identify all phase II-III studies about advanced GAC from PubMed, clinicaltrials.gov, American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) websites. Expert commentary: A combination of a platinum compound and a fluoropyrimidine is ideal as first line therapy. Trastuzumab should be added if the tumor is HER2 positive. In the second line setting, paclitaxel/ramucirumab is preferred over ramucirumab alone. Recently, two similar molecular classifications for GAC have been proposed. A better understanding of molecular and immune biology of GAC could identify new therapeutic targets. PMID- 28094574 TI - Inferring a role for methylation of intergenic DNA in the regulation of genes aberrantly expressed in precursor B-cell acute lymphoblastic leukemia. AB - A complete understanding of the mechanisms involved in the development of pre-B ALL is lacking. In this study, we integrated DNA methylation data and gene expression data to elucidate the impact of aberrant intergenic DNA methylation on gene expression in pre-B ALL. We found a subset of differentially methylated intergenic loci that were associated with altered gene expression in pre-B ALL patients. Notably, 84% of these regions were also bound by transcription factors (TF) known to play roles in differentiation and B-cell development in a lymphoblastoid cell line. Further, an overall downregulation of eRNA transcripts was observed in pre-B ALL patients and these transcripts were associated with the downregulation of putative target genes involved in B-cell migration, proliferation, and apoptosis. The identification of novel putative regulatory regions highlights the significance of intergenic DNA sequences and may contribute to the identification of new therapeutic targets for the treatment of pre-B ALL. PMID- 28094575 TI - Treatment approaches of hard-to-treat non-Hodgkin lymphomas. AB - INTRODUCTION: Even after recent advancements with monoclonal antibodies, antibody drug conjugates and immune therapies, relapsed and refractory lymphomas remain challenging to treat; and the definition and treatment approaches of hard-to treat lymphomas (HTL) continue to evolve. Areas covered: In this review, we will address HTL encompassing diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL) and peripheral T cell lymphomas (PTCL). DLBCL, which comprises 30 40% of non-Hodgkin lymphomas is a highly aggressive and heterogeneous malignancy, with primary refractory or relapsed disease remaining a therapeutic challenge. Similarly, early relapse within 2 years of primary treatment in the more indolent FL is associated with inferior outcomes. Finally, PTCL are universally aggressive and carry a poor prognosis. Expert commentary: Recently, novel antibodies, antibody drug conjugates, immunotherapies and cellular therapy (CAR therapy) have shown promising results in early phase clinical trials. These agents are changing the landscape of treatment of lymphomas and will be extremely important for improving outcomes of HTL. Importantly, revising current strict eligibility criteria for clinical trial participation is needed to help these patients benefit from these novel agents. PMID- 28094576 TI - Growth of Polypoidal Choroidal Vasculopathy Aligned to Choroidal Watershed Zone. PMID- 28094577 TI - Protective role of bentonite against aflatoxin B1- and ochratoxin A-induced immunotoxicity in broilers. AB - The present study was designed to investigate any ameliorative effects of bentonite (BN) against immuno-pathological alterations induced by dietary aflatoxin B1 (AFB1) or ochratoxin A (OTA) in broiler chicks. In one experiment, AFB1 (0.1, 0.2 or 0.6 mg/kg feed) was fed alone and par alley with bentonite clay (3.7 or 7.5 g/kg feed) to the broilers. In the second experiment, the broilers were given feed contaminated with OTA (0.15, 0.3 or 1.0 mg/kg feed) alone and in combination with bentonite clay (3.7, 7.5, or 15 g/kg feed). Experimental feedings were continued for 42 days. At various time points along the feeding schedule, immune system organ histologic status, as well as host humoral and cellular immune responses, were evaluated in all groups. The dietary addition of AFB1 and OTA alone significantly reduced immune responses in the birds as assessed by histological changes in the bursa of Fabricius and thymus, antibody responses to SRBC, in-vivo lympho-proliferative responses to Phytohemagglutinin-P (PHA-P) and, phagocytic function in situ. The dietary addition of BN significantly ameliorated the immunotoxicity of 0.1 and 0.2 mg/kg dietary AFB1, however with a level of 0.6 mg AFB1/kg only partial amelioration was seen. The co treatment of birds exposed to OTA with BN at all levels only partially alleviated deleterious effects on histology and immune responses. Taken together, the results here suggested to us that dietary addition of BN could help ameliorate AFB1-mediated immunotoxicities but could not afford such protection against OTA induced immune damage. PMID- 28094578 TI - Diversity and Inclusion in Occupational Therapy: Where We Are, Where We Must Go. AB - Diversity is a fundamental element of the AOTA Centennial Vision and a critical aspect for the visibility, growth, and sustainability of the occupational therapy profession. In this article, the authors suggest that, while the profession has been aware of the need for a diverse workforce and has taken steps to increase diversity and cultural competency, a more structured, comprehensive, and action oriented approach must be considered to address an issue which impacts professional roles and client engagement, satisfaction, and well-being. Informed by the value-added and mutual accommodation models of cultural diversity, the authors provide specific strategies and actions which promote diversity and inclusion at the personal, institutional/organizational, and professional levels. PMID- 28094579 TI - Expression Profile of the Integrin Receptor Subunits in the Guinea Pig Sclera. AB - PURPOSE: The ocular dimensional changes in myopia reflect increased scleral remodeling, and in high myopia, loss of scleral integrity leads to biomechanical weakening and continued scleral creep. As integrins, a type of cell surface receptors, have been linked to scleral remodeling, they represent potential targets for myopia therapies. As a first step, this study aimed to characterize the integrin subunits at the messenger RNA level in the sclera of the guinea pig, a more recently added but increasingly used animal model for myopia research. METHODS: Primers for alpha and beta integrin subunits were designed using NCBI/UCSC Genome Browser and Primer3 software tools. Total RNA was extracted from normal scleral tissue and isolated cultured scleral fibroblasts, as well as liver and lung, as reference tissues, all from guinea pig. cDNA was produced by reverse transcription, PCR was used to amplify products of predetermined sizes, and products were sequenced using standard methods. RESULTS: Guinea pig scleral tissue expressed all known integrin alpha subunits except alphaD and alphaE. The latter integrin subunits were also not expressed by cultured guinea pig scleral fibroblasts; however, their expression was confirmed in guinea pig liver. In addition, isolated cultured fibroblasts did not express integrin subunits alphaL, alphaM, and alphaX. This difference between results for cultured cells and intact sclera presumably reflects the presence in the latter of additional cell types. Both guinea pig scleral tissue and isolated scleral fibroblasts expressed all known integrin beta subunits. All results were verified through sequencing. CONCLUSION: The possible contributions of integrins to scleral remodeling make them plausible targets for myopia prevention. Data from this study will help guide future ex vivo and in vitro studies directed at understanding the relationship between scleral integrins and ocular growth regulation in the guinea pig model for myopia. PMID- 28094580 TI - Is walking symmetry important for ambulatory patients with spinal cord injury? AB - PURPOSE: To assess and compare the levels of walking symmetry in ambulatory participants with spinal cord injury (SCI) who had different degrees of lesion severity, levels of walking ability, and fall history. In addition, the study explored the relationship between the levels of walking symmetry and variables related to the ability of well-controlled walking of the participants. STUDY DESIGN: Cross-sectional study. METHODS: Sixty-six eligible participants were assessed and interviewed for levels of walking symmetry, walking speed, functional endurance, symmetrical lower limb support ability, balance control, and fall history over the last 6 months. RESULTS: Participants walked asymmetrically (85%) similar to those with unilateral impairments (i.e., patients with stroke and amputee, 79-93%). The levels of walking symmetry were significantly correlated to walking speed, functional endurance and balance ability of the participants (p < 0.05). The problem and correlation were particularly apparent in those with the history of multiple falls (79%, r = 0.613 0.765, p < 0.005) Conclusions: The findings confirm problems of asymmetrical walking and the importance of walking symmetry for the ability of well-controlled walking and a risk of multiple falls in ambulatory participants with SCI. Therefore, apart from the levels of independence, the improvement of walking symmetry is crucial for these individuals. Implications for Rehabilitation: Ambulatory individuals with spinal cord injury walked asymmetrically at the same level as those with unilateral impairments such as patients with stroke and amputee. Their levels of walking symmetry were significantly related to the ability of well-controlled walking, particularly in those with the history of multiple falls. The finding confirmed the importance of walking symmetry as a crucial parameter to detect walking improvement and fall risk reduction. Apart from the levels of independence, rehabilitation professionals also need to emphasize on the improvement of symmetrical walking for these patients. PMID- 28094581 TI - Early immunopathological events in acute model of mycobacterial hypersensitivity pneumonitis in mice. AB - Prolonged exposure to antigens of non-tuberculous mycobacteria species colonizing industrial metalworking fluid (MWF), particularly Mycobacterium immunogenum (MI), has been implicated in chronic forms of hypersensitivity pneumonitis (HP) in machinists based on epidemiology studies and long-term exposure of mouse models. However, a role of short-term acute exposure to these antigens has not been described in the context of acute forms of HP. This study investigated short-term acute exposure of mice to MI cell lysate (or live cell suspension) via oropharyngeal aspiration. The results showed there was a dose- and time-dependent increase (peaking at 2 h post-instillation) in lung immunological responses in terms of the pro- (TNFalpha, IL-6, IL-1beta) and anti-inflammatory (IL-10) cytokines. Bronchoalveolar lavage and histology showed neutrophils as the predominant infiltrating cell type, with lymphocytes <5% at all timepoints or concentrations. Granulomatous inflammation peaked between 8 and 24 h post exposure, and resolved by 96 h. Live bacterial challenge, typically encountered in real-world exposures, showed no significant differences from bacterial lysate except for induction of appreciable levels of interferon (IFN)-gamma, implying additional immunogenic potential. Collectively, the short-term mycobacterial challenge in mice led to a transient early immunopathologic response, with little adaptive immunity, which is consistent with events associated with human acute forms of HP. Screening of MWF-originated mycobacterial genotypes/variants (six of MI, four of M. chelonae, two of M. abscessus) showed both inter- and intra species differences, with MI genotype MJY10 being the most immunogenic. In conclusion, this study characterized the first short-term mycobacterial exposure mouse model that mimics acute HP in machinists; this could serve as a potentially useful model for rapid screening of field MWF-associated mycobacteria for routine and timely occupational risk assessment and for investigating early biomarkers and mechanisms of this understudied immune lung disease. PMID- 28094582 TI - Effects of arsenic on porcine dendritic cells in vitro. AB - Exposure to arsenic (As) is an ongoing, and in some places increasing, health problem. Still, however, the effects of As exposure on the immune system are not well understood. Dendritic cells (DC) are a critical immune cell that bridges the innate and adaptive immune systems. To determine the impact of inorganic (i)As exposure on DC, the effects of (geo)anthropogenically relevant levels of NaAsO2 on the function of porcine monocyte-derived DC (MoDC) were evaluated in an in vitro model. The results showed a low dose of iAs reduced the phagocytic capacity of MoDC. Furthermore, although surface expression of DC activation markers, such as major histocompatibility complex (MHC)-II, CD80/86, CD40 and CD25, were only slightly changed, MoDC T-cell proliferation-inducing capacity was remarkably diminished by iAs treatment. Additionally, iAs induced significant interleukin (IL)-6 secretion by MoDC after 12- or 24-h incubation, whereas IL-1beta secretion was only significantly up-regulated after 12 h. The secretion patterns of IL-8, tumor necrosis factor alpha (TNFalpha and IL-10 by iAs-treated MoDC were almost similar to that by mock-treated MoDC. Considering the broad roles of DC in immunobiology, this finding deepens the understanding of molecular mechanisms/functional consequences underpinning the immunopathology, inflammation, and increases in infection arising from As exposure. PMID- 28094583 TI - Signal detection activity on EudraVigilance data: analysis of the procedure and findings from an Italian Regional Centre for Pharmacovigilance. AB - BACKGROUND: In July 2012 a new European legislation (Directive 2010/84/EU and Regulation No. 1235/2010) regarding pharmacovigilance has become effective. It has boosted the activity of Signal Detection through a monthly analysis of potential safety signals on EudraVigilance (EV). Our aim is to describe the procedure of signal detection on EV data and to present results obtained by the our pharmacovigilance centre. METHOD: Data are extracted from EV database, which collects suspected Adverse Drug Reactions (ADRs) of medicinal products in Europe. We are appointed to supervise digoxin, nicardipine, delapril, manidipine and hydrochlorothiazide/ramipril. ADRs are coded through MedDRA Preferred Terms and collected in the electronic Reaction Monitoring Report (eRMR). Statistical analysis is based on the Proportional Reporting Ratio (PRR) as a measure of disproportionality. RESULTS: Up to April 2016 we have analyzed 45 eRMR for each drug. Two signals for nicardipine were submitted to the Pharmacovigilance Risk Assessment Committee of European Medicines Agency (EMA): acute pulmonary oedema (off-label use as tocolytic) and thrombocytopenia. CONCLUSIONS: Our experience shows the scientific and regulatory value of signal detection activity on EV data in order to continuously evaluate the benefit/risk profile of recent and older drugs. PMID- 28094584 TI - Cytoskeletal Alteration and Change of Retinal Nerve Fiber Layer Birefringence in Hypertensive Retina. AB - PURPOSE: Glaucoma damages the retinal nerve fiber layer (RNFL). Both RNFL thickness and retardance can be used to assess the damage, but birefringence, the ratio of retardance to thickness, is a property of the tissue itself. This study investigated the relationship between axonal cytoskeleton and RNFL birefringence in retinas with hypertensive damage. MATERIALS AND METHODS: High intraocular pressure (IOP) was induced unilaterally in rat eyes. RNFL retardance in isolated retinas was measured. Cytostructural organization and bundle thickness were evaluated by confocal imaging of immunohistochemical staining of the cytoskeletal components: microtubules (MTs), F-actin, and neurofilaments. Bundles with different appearances of MT stain were studied, and their birefringence was calculated at different radii from the optic nerve head (ONH) center. RESULTS: Forty bundles in eight normal retinas and 37 bundles in 10 treated retinas were examined. In normal retinas, the stain of axonal cytoskeleton was approximately uniform within bundles, and RNFL birefringence did not change along bundles. In treated retinas, elevation of IOP caused non-uniform alteration of axonal cytoskeleton across the retina, and distortion of axonal MTs was associated with decreased birefringence. The study further demonstrated that change of RNFL birefringence profiles along bundles can imply altered axonal cytoskeleton, suggesting that ultrastructural change of the RNFL can be inferred from clinical measurements of RNFL birefringence. The study also demonstrated that measuring RNFL birefringence profiles along bundles, instead of at a single location, may provide a more sensitive way to detect axonal ultrastructural change. CONCLUSIONS: Measurement of RNFL birefringence along bundles can provide estimation of cytoskeleton alteration and sensitive detection of glaucomatous damage. PMID- 28094585 TI - Relationship between Plasma Homocysteine Level and Glaucomatous Retinal Nerve Fiber Layer Defect. AB - AIMS: To investigate the association between plasma homocysteine levels and glaucomatous retinal nerve fiber layer (RNFL) defect in South Korean population. MATERIALS AND METHODS: This retrospective cross-sectional study included subjects who underwent screening at Kangbuk Samsung Hospital Health Screening Center between August 2012 and July 2013. Subjects underwent physical examination and provided samples for laboratory analysis of homocysteine. Subjects were divided equally into four quartiles (Qs) based on plasma homocysteine level. Digital fundus photographs of both eyes were obtained. Determination of glaucomatous disc appearance was based on criteria set forth by the International Society of Geographical and Epidemiological Ophthalmology and based on the appearance of the RNFL and optic disc. Multivariate logistic regression models were used to define elevated glaucoma risk with P < 0.2 on univariate analysis. RESULTS: A total of 78,049 subjects were included; 76,093 subjects were male, and 1956 subjects were female. When analyzed by gender, the mean homocysteine level in the male group with glaucomatous RNFL defects (11.05 +/- 3.80 umol/L) was higher than those without RNFL defects (10.81 +/- 4.12 umol/L (P = 0.000, chi2 test). Upon multifactorial logistic regression analysis adjusted for age, gender, creatinine, diabetes mellitus, hypertension, and hyperlipidemia, glaucomatous RNFL defects had a significant correlation with plasma homocysteine level. Based on the Q2 level, the odds ratio (OR) of Q3 was 1.267, while the OR of Q4 was 1.285 (95% CI = 1.067-1.505, 1.081-1.529, respectively, P for trend = 0.001). CONCLUSION: Our results suggest that homocysteine level is associated with the presence of glaucomatous RNFL defects. PMID- 28094586 TI - Perceptions of Occupational Therapists on the Patient Protection and Affordable Care Act: Five Years After Its Enactment. AB - This study explored the perceptions of occupational therapists regarding the impact and implications of the Patient Protection and Affordable Care Act (PPACA or ACA) on occupational therapy practice. Fifteen occupational therapists participated in an interview to answer open-ended questions related to their thoughts and perceptions regarding the impact and implications of the ACA on their practice. The participants were practicing in eight different states and worked in five different settings with clinical experience ranging from 3 to 38 years; their positions ranged from staff therapist to owner of a free-standing outpatient clinic. Qualitative content analysis was used to synthesize the interview transcripts. Results showed that therapists did not have sufficient knowledge on the various mandates and provisions of the ACA, or were uncertain about what implications the ACA would have on practice, with the ACA affecting some settings more than others. Data revealed the perceived impacts of the ACA on occupational therapy practice include greater attention on documenting outcome focused care, external accountability pressures on productivity, conscientiousness about clients' insurance coverage, uncertainty about collaborative care delivery, and survival of small businesses. Findings suggest training regarding knowledge about and implications of different elements of the ACA is needed as well as practices needing to promote the services that occupational therapists can provide to improve cost-effectiveness and outcomes in collaborative care environments. PMID- 28094587 TI - Applying theories to better understand socio-political challenges in implementing evidence-based work disability prevention strategies. AB - PURPOSE: This article explores and applies theories for analyzing socio-political aspects of implementation of work disability prevention (WDP) strategies. METHOD: For the analysis, theories from political science are explained and discussed in relation to case examples from three jurisdictions (Sweden, Brazil and Quebec). RESULTS: Implementation of WDP strategies may be studied through a conceptual framework that targets: (1) the institutional system in which policy-makers and other stakeholders reside; (2) the ambiguity and conflicts regarding what to do and how to do it; (3) the bounded rationality, path dependency and social systems of different stakeholders; and (4) coalitions formed by different stakeholders and power relations between them. In the case examples, the design of social insurance systems, the access to and infrastructure of healthcare systems, labor market policies, employers' level of responsibility, the regulatory environment, and the general knowledge of WDP issues among stakeholders played different roles in the implementation of policies based on scientific evidence. CONCLUSIONS: Future research may involve participatory approaches focusing on building coalitions and communities of practice with policy-makers and stakeholders, in order to build trust, facilitate cooperation, and to better promote evidence utilization. Implications for Rehabilitation Implementation of work disability prevention policies are subject to contextual influences from the socio-political setting and from relationships between stakeholders Stakeholders involved in implementing strategies are bound to act based on their interests and previous courses of action To promote research uptake on the policy level, stakeholders and researchers need to engage in collaboration and translational activities Political stakeholders at the government and community levels need to be more directly involved as partners in the production and utilization of evidence. PMID- 28094589 TI - Leucine-rich alpha2-glycoprotein as the acute-phase reactant to detect systemic juvenile idiopathic arthritis disease activity during anti-interleukin-6 blockade therapy: A case series. AB - OBJECTIVES: To assess the role of leucine-rich alpha2-glycoprotein (LRG) as a biomarker for monitoring systemic juvenile idiopathic arthritis (s-JIA) disease activity during interleukin (IL)-6 blockade treatment. METHODS: We serially measured serum LRG levels in four s-JIA patients treated with the anti-IL-6 receptor antibody tocilizumab and determined the correlation between clinical symptoms and other inflammatory biomarkers and proinflammatory cytokines, including IL-18, IL-6, neopterin, and tumor necrosis factor-alpha receptor type I and II. The serum levels of LRG and proinflammatory cytokines were determined using enzyme-linked immunosorbent assay. RESULTS: Serum LRG levels increased concomitantly with s-JIA disease flare-up and macrophage activation syndrome development. Furthermore, even in the clinically inactive phase, serum LRG levels were well above normal values. There were no correlations between serum LRG levels and indicators of s-JIA disease activity other than aspartate aminotransferase. There were significant positive correlations between serum LRG levels and proinflammatory cytokines. CONCLUSIONS: Serum LRG levels might be a unique and potential biomarker of s-JIA disease activity during IL-6 blockade treatment. PMID- 28094590 TI - Effects of Supernatants from Escherichia coli Nissle 1917 and Faecalibacterium prausnitzii on Intestinal Epithelial Cells and a Rat Model of 5-Fluorouracil Induced Mucositis. AB - Faecalibacterium prausnitzii (Fp) and Escherichia coli Nissle 1917 (EcN) are probiotics, which have been reported to ameliorate certain gastrointestinal disorders. We evaluated the effects of supernatants (SN) derived from Fp and EcN on 5-fluorouracil (5-FU)-treated intestinal cells and in a rat model of mucositis. In vitro: IEC-6, Caco-2, and T-84 cells were analyzed for viability and monolayer permeability. In vivo: Female dark agouti rats were gavaged with Fp or EcN SN and injected intraperitoneally with saline (control) or 5-FU to induce mucositis. Rats were euthanized and intestinal tissues collected for myeloperoxidase assay and histological analyses. In vitro: Caco-2 cell viability was further reduced when treated with Fp SN + 5-FU compared to 5-FU controls. In both Caco-2 and T-84 cells, Fp SN partially prevented the decrease in transepithelial electrical resistance (TER) caused by 5-FU administration. In vivo: 5-FU-injected rats administered Fp SN or EcN SN partly prevented body weight loss and normalized water intake compared to 5-FU controls. These results suggest a growth inhibitory mechanism of Fp SN action on transformed epithelial cells that could be mediated by effects on tight junctions. Factors derived from Fp SN and EcN SN could have a role in reducing the severity of intestinal mucositis. PMID- 28094591 TI - Algo Used by Homecare Nonoccupational Therapists Selecting Bathing Assistive Technology: Enhancing Standardization by Exploring Clinical Reasoning. AB - Algo is a clinical decision algorithm developed to support nonoccupational therapists in establishing assistive technology recommendations to enable physically disabled adults to perform their hygiene at home. This study aimed to explore the in-depth clinical reasoning of nonoccupational therapists using Algo to pinpoint the items leading to disagreements regarding recommendations. A multiple-case study was conducted with eight nonoccupational therapists trained to use Algo and filmed while using it with six standardized clients. Explicitation interviews were conducted for the conflicting recommendations. Identifying the key reasoning skills to develop in Algo users has led to three recommendations to enhance standardization with seniors. PMID- 28094592 TI - Association among Work-Related Musculoskeletal Disorders, Job Stress, and Job Attitude of Occupational Therapists. AB - This study was conducted to investigate the associations among work-related musculoskeletal disorders (WMSDs), job stress, and job attitude of occupational therapists in South Korea. Self-reporting questionnaires were distributed to 150 occupational therapists. Of the 128 occupational therapists who responded, 110 (85.9%) reported WMSDs affecting at least one body site. The most affected WMSDs site was the low back (26.8%), and the most reported number of body site affected by WMSDs was one (53.9%). As a result, there were significant differences in job stress and job attitude depending on the age, work experience, working hour, presence or absence of WMSDs, and number of site of pain. Factors influencing job attitude included job stress, the presence or absence of WMSDs and duration of pain. The results showed that the occurrence of WMSDs in occupational therapists was associated with increased job stress and negative job attitude. PMID- 28094593 TI - Erratum. PMID- 28094594 TI - Erratum. PMID- 28094596 TI - Comment On: Clinical Trial: Vitamin D3 Treatment in Crohn's Disease: A Randomized Double-Blind Placebo-Controlled Study. AB - BACKGROUND: Vitamin D has immune-regulatory functions in experimental colitis, and low vitamin D levels are present in Crohn's disease. METHODS: We performed a randomized double-blind placebo-controlled trial to assess the benefits of oral vitamin D3 treatment in Crohn's disease. We included 108 patients with Crohn's disease in remission, of which fourteen were excluded later. Patients were randomized to receive either 1200 IU vitamin D3 (n = 46) or placebo (n = 48) once daily during 12 months. The primary endpoint was clinical relapse. RESULTS: Oral vitamin D3 treatment with 1200 IU daily increased serum 25OHD from a mean of 69 nmol/L [standard deviation (s.d.) 31 nmol/L] to a mean of 96 nmol/L (s.d. 27 nmol/L) after 3 months (P < 0.001). The relapse rate was lower among patients treated with vitamin D3 (6/46 or 13%) among patients treated with placebo (14/48 or 29%), (P = 0.06). CONCLUSIONS: Oral supplementation with 1200 IE vitamin D3 significantly increased serum vitamin D levels and insignificantly reduced the risk of relapse from 29% to 13%, (P = 0.06). Given that vitamin D3 treatment might be effective in Crohn's disease, larger studies are required in order to elucidate this matter further. (Aliment Pharmacol Ther 2010;32:377-383.). PMID- 28094597 TI - Comment On: Maintenance of Remission in Inflammatory Bowel Disease Using Omega-3 Fatty Acids (Fish Oil): A Systematic Review and Meta-Analyses. AB - The objective was to systematically review the efficacy and safety of n-3 (omega 3 fatty acids, fish oil) for maintaining remission in Crohn's disease (CD) and ulcerative colitis (UC). Electronic databases were searched systematically for randomized controlled trials of n-3 for maintenance of remission in inflammatory bowel disease (IBD). Studies of patients of any age group who were in remission at the time of recruitment and were followed for at least 6 months were included. The primary outcome was relapse rate at the end of the follow-up period. Nine studies were eligible for inclusion; six studies of CD (n = 1039) and three of UC (n = 138). There was a statistically significant benefit for n-3 in CD (relative risk [RR] 0.77; 95% confidence interval [CI] 0.61-0.98); however, the studies were heterogeneous (I 2 = 58%). The absolute risk reduction was -0.14 (95% CI: 0.25 to -0.02). Opinions may vary on whether this is a clinically significant effect. Two well-done studies with a larger sample size reported no benefit. A sensitivity analysis excluding a small pediatric study resulted in the pooled RR being no longer statistically significant. A funnel plot analysis suggested publication bias for the smaller studies. For UC, there was no difference in the relapse rate between the n-3 and control groups (RR 1.02; 95% CI: 0.51-2.03). The pooled analysis showed a higher rate of diarrhea (RR 1.36; 95% CI: 1.01-1.84) and symptoms of the upper gastrointestinal tract (RR 1.96; 95% CI: 1.37-2.80) in the n-3 treatment group. There are insufficient data to recommend the use of omega-3 fatty acids for maintenance of remission in CD and UC. ( Inflamm Bowel Dis. 2011;17:336-345). PMID- 28094600 TI - Conversion Table-Conventional to SI Units. PMID- 28094601 TI - Recruiting newly referred lung cancer patients to a patient navigator intervention (PACO): lessons learnt from a pilot study. AB - OBJECTIVES: The incidence of and survival from lung cancer are associated with socioeconomic position, and disparities have been observed in both curative and palliative treatment for lung cancer. 'Patient navigation' is valuable in addressing health disparity, with timely treatment and transition to care. We conducted a pilot study to test the feasibility of a patient navigator program (PAtient COach) for newly diagnosed lung cancer. We present the trial, the findings from the pilot study and discuss factors that might have affected recruitment rates. MATERIAL AND METHODS: We invited 24 lung cancer patients referred for chemotherapy to the Oncology Department at Herlev University Hospital, Denmark, to participate in the pilot study. To be eligible, patients had to live alone, have no formal education beyond secondary school, have one or more comorbid conditions, have a performance status of 1 or 2 or be over 65 years of age. The patient navigators targeted four phases of treatment: planning, initiation, compliance and end of treatment. RESULTS: Six months after the start of the study, we had recruited only six patients, due mainly to inherent patient resistance and because only 50% of eligible patients were invited. Of the 18 patients who did not wish to participate, 13 agreed to fill in a baseline questionnaire. The most frequent reason given for not wanting to participate was a belief that a patient navigator would be of no benefit. CONCLUSIONS: The pilot study met a number of internal and external obstacles to patients' recruitment. The study provides insight into the barriers to recruitment of socially disadvantaged cancer patients to clinical trials and will inform future trial designs. PMID- 28094602 TI - North American Society for the Psychology of Sport and Physical Activity. PMID- 28094599 TI - Plasma 25-Hydroxyvitamin D3 Levels in Colorectal Cancer Patients and Associations with Physical Activity. AB - Physical activity (PA) and vitamin D are thought to affect colorectal cancer prognosis. The present study investigates associations between 25(OH)D3 and PA in prospectively followed colorectal cancer patients in the ColoCare study. At 6, 12, and 24 mo after surgery, patients donated a blood sample, wore an accelerometer for 10 consecutive days, and completed a PA questionnaire. Plasma 25-hydroxyvitamin D3 (25(OH)D3) levels were measured by high-performance liquid chromatography. We tested associations using partial correlations and multivariate linear regression analysis, adjusted for season, age, and body mass index. A total of 137 assessments of 25(OH)D3 levels and PA were conducted (58 at 6 mo, 51 at 12 mo, and 28 at 24 mo). More than 60% of the patients were vitamin D deficient (25(OH)D3 <=20 ng/ml), independent of study time point. At 6-mo follow up, accelerometry-based vigorous and moderate-to-vigorous PAs were positively associated with 25(OH)D3 levels (P = 0.04; P = 0.006,). PA together with season was a significant predictor of elevated 25(OH)D3 levels. Our results suggest that the majority of colorectal cancer patients may suffer from vitamin D deficiency. Engaging in PA may be an effective approach to increase their 25(OH)D3 levels. PMID- 28094603 TI - Lethal mechanisms in gastric volvulus. AB - A 55-year-old wheelchair-bound woman with severe cerebral palsy was found at autopsy to have marked distention of the stomach due to a volvulus. The stomach was viable, and filled with air and fluid and had pushed the left dome of the diaphragm upwards causing marked compression of the left lung with a mediastinal shift to the right (including the heart). There was no evidence of gastric perforation, ischaemic necrosis or peritonitis. Removal of the organ block revealed marked kyphoscoliosis. Histology confirmed the viability of the stomach and biochemistry showed no dehydration. Death in cases of acute gastric volvulus usually occurs because of compromise of the gastric blood supply resulting in ischaemic necrosis with distention from swallowed air and fluid resulting in perforation with lethal peritonitis. Hypovolaemic shock may also occur. However, the current case demonstrates an alternative lethal mechanism, that of respiratory compromise due to marked thoracic organ compression. PMID- 28094604 TI - North American Society for the Psychology of Sport and Physical Activity. PMID- 28094588 TI - Mechanisms and regulation of DNA replication initiation in eukaryotes. AB - Cellular DNA replication is initiated through the action of multiprotein complexes that recognize replication start sites in the chromosome (termed origins) and facilitate duplex DNA melting within these regions. In a typical cell cycle, initiation occurs only once per origin and each round of replication is tightly coupled to cell division. To avoid aberrant origin firing and re replication, eukaryotes tightly regulate two events in the initiation process: loading of the replicative helicase, MCM2-7, onto chromatin by the origin recognition complex (ORC), and subsequent activation of the helicase by its incorporation into a complex known as the CMG. Recent work has begun to reveal the details of an orchestrated and sequential exchange of initiation factors on DNA that give rise to a replication-competent complex, the replisome. Here, we review the molecular mechanisms that underpin eukaryotic DNA replication initiation - from selecting replication start sites to replicative helicase loading and activation - and describe how these events are often distinctly regulated across different eukaryotic model organisms. PMID- 28094606 TI - Trichinella Surveillance in Black Bears ( Ursus americanus ) from the Dehcho Region, Northwest Territories, Canada, 2002-15. AB - We used muscle digestion to test black bears ( Ursus americanus ) from the southwestern Northwest Territories, Canada, for Trichinella. Results showed a prevalence of 4.1%. Some bears had infection intensities of more than one larva per gram of muscle tissue; this level in meat is considered to pose a human consumption safety risk. PMID- 28094605 TI - Multiple protocadherins are expressed in brain microvascular endothelial cells and might play a role in tight junction protein regulation. AB - Protocadherins (Pcdhs) are a large family of cadherin-related molecules. They play a role in cell adhesion, cellular interactions, and development of the central nervous system. However, their expression and role in endothelial cells has not yet been characterized. Here, we examined the expression of selected clustered Pcdhs in endothelial cells from several vascular beds. We analyzed human and mouse brain microvascular endothelial cell (BMEC) lines and primary cells, mouse myocardial microvascular endothelial cell line, and human umbilical vein endothelial cells. We examined the mRNA and protein expression of selected Pcdhs using RT-PCR, Western blot, and immunostaining. A strong mRNA expression of Pcdhs was observed in all endothelial cells tested. At the protein level, Pcdhs gamma were detected using an antibody against the conserved C-terminal domain of Pcdhs-gamma or an antibody against PcdhgC3. Deletion of highly expressed PcdhgC3 led to differences in the tight junction protein expression and mRNA expression of Wnt/mTOR (mechanistic target of rapamycin) pathway genes as well as lower transendothelial electrical resistance. Staining of PcdhgC3 showed diffused cytoplasmic localization in mouse BMEC. Our results suggest that Pcdhs may play a critical role in the barrier-stabilizing pathways at the blood-brain barrier. PMID- 28094607 TI - Detection of the Amphibian Chytrid Fungus Batrachochytrium dendrobatidis in Museum Specimens of Andean Aquatic Birds: Implications for Pathogen Dispersal. AB - The occurrence of the pathogenic chytrid fungus Batrachochytrium dendrobatidis (Bd) in the feet of live waterfowl has been documented, but the potential role of birds as dispersers has not been studied. We report the presence of Bd in the feet of preserved aquatic birds in the Bolivian high Andes during the time of drastic amphibian declines in the country. We sampled 48 aquatic birds from the Bolivian Andes that were preserved in museum collections. Birds were sampled for the presence of Bd DNA by swabbing, taking small pieces of tissue from toe webbing, or both. We detected Bd by DNA using quantitative PCR in 42% of the birds sampled via toe tissue pieces. This method was significantly better than swabbing at detecting Bd from bird feet. We confirmed Bd presence by sequencing Bd -positive samples and found 91-98% homology with Bd sequences from GenBank. Our study confirms that aquatic birds can carry Bd and thus may serve as potential vectors of this pathogen across large distances and complex landscapes. In addition, we recommend using DNA from preserved birds as a novel source of data to test hypotheses on the spread of chytridiomycosis in amphibians. PMID- 28094608 TI - SURVEILLANCE FOR AVIAN INFLUENZA VIRUS IN WILD BIRDS IN POLAND, 2008-15. AB - We tested wild birds in Poland during 2008-15 for avian influenza virus (AIV). We took 10,312 swabs and feces samples from 6,314 live birds representing 12 orders and 84 bird species, mostly from orders Anseriformes and Charadriiformes, for testing and characterization by various PCR methods. From PCR-positive samples, we attempted to isolate and subtype the virus. The RNA of AIV was detected in 1.8% (95% confidence interval [CI], 1.5-2.1%) of birds represented by 48 Mallards ( Anas platyrhynchos ), 11 Mute Swans ( Cygnus olor ), 48 Common Teals ( Anas crecca ), three Black-headed Gulls (Chroicocephalus ridibundus), one Common Coot ( Fulica atra ), one Garganey (Spatula querquedula), and one unidentified bird species. Overall, the prevalence of AIV detection in Mallards and Mute Swans (the most frequently sampled species) was 2.0% (95% CI, 1.4-2.5%) and 0.5% (95% CI, 0.2-0.8%), respectively; the difference was statistically significant (P=0.000). Hemagglutinin subtypes from H1 to H13 were identified, including H5 and H7 low pathogenic AIV subtypes. Mallards and Common Teals harbored the greatest diversity of subtypes. We observed seasonality of viral detection in Mallards, with higher AIV prevalence in late summer and autumn than in winter and spring. In addition, two peaks in AIV prevalence in summer (August) and autumn (November) were demonstrated for Mallards. The prevalence of AIV in Mute Swans did not show any statistically significant seasonal patterns. PMID- 28094609 TI - Ecological Potential for Rabies Virus Transmission via Scavenging of Dead Bats by Mesocarnivores. AB - Multiple species of bats are reservoirs of rabies virus in the Americas and are occasionally the source of spillover infections into mesocarnivore species. Although rabies transmission generally is assumed to occur via bite, laboratory studies have demonstrated the potential for rabies transmission via ingestion of rabid animals. We investigated the ecological potential for this mode of transmission by assessing mesocarnivore scavenging behavior of dead bats in suburban habitats of Flagstaff, Arizona, US. In autumn 2013, summer 2014, and autumn 2015, we placed 104 rabies-negative bat carcasses either near buildings, in wildland areas, or in residential yards and then monitored them with trail cameras for 5 d. Overall, 52 (50%) bat carcasses were scavenged, with 39 (75%) of those scavenged by striped skunks ( Mephitis mephitis ). Within our study area, striped skunks had a higher ecological potential to contract rabies via ingestion of bat carcasses compared to other mesocarnivore species, due both to a greater number of encounters and a higher probability of ingestion per encounter (91%), and they were significantly more likely to approach bat carcasses in yards than in wildland areas. Raccoons ( Procyon lotor ) and gray foxes ( Urocyon cinereoargenteus ) had fewer encounters (nine and 13, respectively) and lower probability of ingesting bats (33% and 8%, respectively). PMID- 28094611 TI - 'Always go with your instincts'. AB - After qualifying as a registered nurse and sick children's nurse in the 1990s, Tracey Budding worked in variety of specialties, including orthopaedics, oncology and hospice care for adults and children, before specialising in neonatal care. She has been a modern matron on the neonatal unit at Birmingham Women's Hospital NHS Foundation Trust for 15 years. Ms Budding received the RCN Award of Merit for outstanding contribution and service to RCN members. PMID- 28094610 TI - Reference Intervals for Serum Biochemistries of Molting Pacific Black Brant ( Branta bernicla nigricans) in Northern Alaska, USA. AB - We determined reference intervals for nine serum biochemistries in samples from 329 molting, after-hatch-year, Pacific Black Brant ( Branta bernicla nigricans) in Alaska, US. Cholesterol and nonesterified fatty acids differed by sex, but no other differences were noted. PMID- 28094612 TI - Student essays. AB - I am proud to say I qualified in adult nursing this year with a 2:1 degree. I managed to achieve this while caring for two children and various pets and working part-time. PMID- 28094613 TI - We need our Admiral Nurses. AB - Despite the current emphasis on the importance of dementia care, it is disappointing to see Admiral Nurses falling victim to budget cuts (news online, 23 December). PMID- 28094614 TI - Psychotropic drugs increase risk of falls in nursing homes. AB - The prescription of psychotropic drugs is associated with a sharply higher risk of falling among residents of nursing homes. PMID- 28094615 TI - Female students more likely to have suicidal thoughts than males. AB - Interventions to prevent suicide among students should be designed separately for males and females, say UK researchers who studied more than 1,000 university students. PMID- 28094616 TI - Racket sports stave off death better than swimming or aerobics. AB - Racket sports, swimming and aerobics are associated with the best chance of staving off death, new study results suggest. PMID- 28094617 TI - Smokers under 50 have eightfold increased risk of heart attack. AB - People under the age of 50 who smoke are more than eight times as likely as non smokers to have a heart attack, a study found. PMID- 28094618 TI - Diabetes. AB - What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The CPD article provided an overview of diabetes. It outlined the differences between type 1 and type 2 diabetes, and included information about the diagnosis, causes and treatment of the condition. PMID- 28094620 TI - Seacole campaigner made a dame in honours list. AB - A trailblazing nurse who was a leading figure in the Mary Seacole statue campaign has been made a dame in the new year's honours. PMID- 28094622 TI - Cuts to CPD funding undermine nursing. AB - It is worrying that for 2016-17, Health Education England's (HEE) funding for continuing professional development has suffered significant cuts of up to 45%, with little discussion about strategic plans for CPD at a national level. PMID- 28094621 TI - The therapeutic bond is so powerful. AB - I was working on a medical ward for older people in my first year of training when a patient, whom I will call Joyce, was admitted following a fall. PMID- 28094623 TI - More care at home is the best way to meet patients' needs, says chief nurse. AB - The NHS needs to spend more money looking after people in their own homes rather than in hospitals, England's chief nursing officer has urged. PMID- 28094626 TI - Real-terms pay down almost 9% for nurses and midwives. AB - Nurses and midwives have seen their pay plummet almost 9% over the past five years, according to new research by the TUC, the national trade union centre. PMID- 28094624 TI - 'Siobhan has helped me regain a good quality of life with diabetes'. AB - I was diagnosed with type 1 diabetes, involving insulin dependence, some 40 years ago. PMID- 28094627 TI - Preventing falls in hospital. AB - Falls are the most frequent adverse event reported in hospitals, usually affecting older patients. Every year, more than 240,000 falls are reported in acute hospitals and mental health trusts in England and Wales, equivalent to more than 600 per day, according to the Royal College of Physicians (RCP). PMID- 28094628 TI - 'Staff want to address cultural issues, but don't know how'. AB - Katie de Freitas believes a greater awareness of cultures is crucial if clinicians are to meet the needs of patients and families. 'Cultural competency is a matter of quality and safety,' says the quality improvement lead at Great Ormond Street Hospital for Children NHS Foundation Trust (GOSH). 'It can help to bridge the gap between those providing care and those accessing services. PMID- 28094629 TI - Stories of George Michael's generosity and appreciation for nurses pour in. AB - Nurses have paid tribute to George Michael for championing the profession, and recalled how he once put on a concert especially for them. PMID- 28094630 TI - RCN Nurse of the Year 2016: 'Award win will open doors'. AB - 'The Nurse Awards have opened doors,' says Venetia Wynter-Blyth, RCN Nurse of the Year 2016. 'I cannot emphasise enough how many opportunities have been presented to us as a result of winning this award.' PMID- 28094631 TI - Stopping unnecessary deaths. AB - Cancer is a leading cause of death in the European Union. The European Commission has set goals for reducing cancer-related deaths by 15% in the next four years, and the World Health Assembly's global target is a 25% cut in premature non communicable mortality by 2025. PMID- 28094633 TI - Dying for a Drink: All You Need to Know to Beat the Booze (Second edition) Cantopher Tim Dying for a Drink: All You Need to Know to Beat the Booze (Second edition) 128pp L9.99 Sheldon Press 9781847094476 1847094473 [Formula: see text]. AB - This is an interesting and well-written book. The author has been thorough in his interpretation of alcohol addiction and has used humour and references to his own practice. PMID- 28094634 TI - My Pancreas. AB - This app has been designed for patients facing a diagnosis of pancreatic cancer. It acts as an information resource for family members, carers and friends. PMID- 28094635 TI - New year set to bring new routes into nursing. AB - In September, the first nursing degree apprentices are due to begin working on wards in England. This new cohort will combine degree-level training with working for at least four years. PMID- 28094637 TI - Praying for patients. AB - I feel sad for the nurse who was sacked for praying for a patient. Whatever happened to freedom of speech? What is wrong with offering to pray with patients? I pray this nurse finds a job where people appreciate her. PMID- 28094638 TI - How to remove an indwelling urinary catheter in female patients. AB - Rationale and key points This article aims to assist nurses to undertake the removal of an indwelling urinary catheter in female patients in a safe, timely, effective and patient-centred manner, while maintaining the patient's privacy and dignity. It is important for the nurse to be competent in undertaking this procedure, and to be aware of local and national policies on catheter removal. " Indwelling urinary catheters should be changed only when clinically necessary, or according to the manufacturer's guidelines. " Urinary catheters should be removed using sterile equipment. " The balloon of the indwelling catheter must be deflated before removal, and the catheter should be removed slowly to minimise trauma. Reflective activity 'How to' articles can help you update your practice and ensure it remains evidence-based. Apply this article to your practice. Reflect on and write a short account of: " How you think this article might change your practice when removing an indwelling urinary catheter. " How you could use this article to educate your colleagues. PMID- 28094639 TI - Chronic heart failure part 1: pathophysiology, signs and symptoms. AB - Chronic heart failure is a common and complex clinical syndrome that results from impaired cardiac relaxation or contraction. Patients with chronic heart failure may experience multiple debilitating symptoms, such as fatigue, pain, and peripheral oedema. However, breathlessness may be considered the most debilitating symptom. This is the first of two articles on chronic heart failure, and outlines the pathophysiology of the condition, its causes, assessment, and signs and symptoms. Part 2 will discuss the treatment and management of the condition, including pharmacological strategies, device implantation, lifestyle modification, cardiac rehabilitation and palliative care. PMID- 28094640 TI - Students should befriend their library staff. AB - The article 'How to write a perfect essay' (students, 7 December) advises readers to 'make the library your friend'. However, it is not the library that students or researchers need to befriend, it is the library staff. PMID- 28094641 TI - Women in Catholic countries are less likely to breastfeed. AB - Women in Western Catholic countries are less likely to breastfeed than those from predominantly Protestant nations, a study suggests. PMID- 28094644 TI - Why become a clinical nurse educator? AB - I have been a registered nurse in acute care for more than 30 years. Throughout that time, I have learned something new in my clinical practice every day. PMID- 28094646 TI - Retirement crisis warnings becoming a reality. AB - The figures are startling: the number of NHS staff applying to retire has surged by a quarter since 2012. The potential consequences are alarming; a serious shortage of nurses and other healthcare professionals now seems inevitable. PMID- 28094645 TI - Boarding school rules. AB - Ofsted inspects and regulates services that care for children and young people, including boarding facilities. Medication management is an integral part of caring for children in boarding schools, and robust systems must be in place to pass inspection. These systems must cover how medicines are dispensed, administered and stored at the facility, risk assessments, identifying which pupils can manage their own medicines and the individual health needs of boarders, so that care plans can be put in place for children with specific needs. PMID- 28094647 TI - Using drawings as a reflective tool to enhance communication in dementia care. AB - Communication skills training can be a valuable means of supporting professional and family carers of people with dementia. Most communication skills training programmes for those caring for people with dementia focus on dementia awareness and the technical aspects of communication, such as the pace and volume of the carer's speech. However, it is also important to examine what is conveyed about a carer's internal experience in their non-verbal interactions with people living with dementia. This article explores how drawings can be used to help carers to reflect on what is communicated and question any hidden assumptions. It discusses three case studies to demonstrate the complex dynamics that may be involved in interactions with people with dementia: the loss of shared memories, facing towards someone with dementia rather than away from them, and talking about issues that may be upsetting. Drawings provide a means for carers to access their unspoken thoughts and emotions, and can help them to improve their understanding of non-verbal interactions with people who have dementia. PMID- 28094648 TI - How to cope with staff shortages. AB - More than half of NHS trust leaders in England are worried that they do not have the staff numbers or skill mix they need to continue delivering high quality care, according to a recent survey by NHS Providers. This will not come as a surprise to nurses on the front line. PMID- 28094649 TI - Guidance on safe staffing shies away from set ratio. AB - The head of the Safe Staffing Alliance has said new draft guidance on nurse staffing on acute adult inpatient wards in England 'does not go far enough'. PMID- 28094650 TI - New education models must not take us back. AB - Last year was a landmark one for nursing. As well as celebrating 100 years since the RCN was founded, in 2016 we learned of changes that will shape the future of our profession. PMID- 28094651 TI - Get the most out of your practice placements. AB - Before each placement you are likely to experience a range of emotions. Along with the excitement of facing a new clinical environment may come fear, anxiety and self-doubt. These feelings are entirely normal and similar to what most people feel when starting a new job. PMID- 28094652 TI - Fresh warnings over nurse shortages. AB - Brexit and an ageing population could combine to worsen the existing shortage of nurses in England, researchers have warned. PMID- 28094653 TI - Associate move is about years of poor decisions, not improving care. AB - Physician associates, nursing associates - before long everyone will be associated with their job without being fully qualified to do it. Will we have associate managers? Associate MPs? The whole thing is quite odd. PMID- 28094654 TI - Protest for those caring for civilians in Syria. AB - UK nurses and doctors staged a 'die in' outside the Houses of Parliament to call for protection for healthcare workers caring for civilians caught up in the war in Syria. PMID- 28094656 TI - Readers' panel - Is the nursing associate role undermining graduate nurses? AB - Our experts consider a hot topic of the day. PMID- 28094657 TI - Surge in number of NHS staff applying to retire. AB - The number of NHS staff applying for retirement has surged by 25% over the past four years, Nursing Standard can reveal. PMID- 28094658 TI - Effects of Negative Affectivity and Odor Valence on Chemosensory and Symptom Perception and Perceived Ability to Focus on a Cognitive Task. AB - The aim was to gain understanding for the impact of negative affectivity (NA) and odor valance on perceptual aspects during low-level odorous exposure. Fifty-five young adults who were either relatively low or high in NA (anxiety, depression, and somatization) were randomized for exposure to either limonene (pleasant odor) or pyridine (unpleasant odor). In an exposure chamber, they took part in baseline, blank and stable exposure sessions, during which they rated odor intensity, impact on ability to focus on an imagined cognitive task, and intensity of symptoms. The results showed higher ratings of negative impact on ability to focus during exposure to the unpleasant odor compared with the pleasant odor, and an association between NA and symptom intensity, with 18% of the variance in symptom intensity explained by somatization. The association between NA and symptom intensity was found to be driven by the factor sex. These results imply (a) that prior findings of odorous exposure that interfere negatively with work performance may be due to impact of an unpleasant odor on ability to focus on cognitive tasks and (b) that there are associations between NA, sex, and symptoms that may partly be referred to attentiveness to and interpretation of bodily sensations. PMID- 28094659 TI - Current Literature: Standardization of IV Insulin Therapy Improves the Efficiency and Safety of Blood Glucose Control in Critically Ill Adults. AB - OBJECTIVE: Aggressive glycemic control improves mortality and morbidity in critically ill adults; however, implementation of such a strategy can be logistically difficult. This study evaluates the efficiency and safety of a nurse managed insulin protocol in critically ill adults. DESIGN: Combined retrospective prospective before-after cohort study. SETTING: Twenty-one bed medical/surgical intensive care unit (ICU) in a tertiary care hospital. PATIENTS: Two cohorts of 50 consecutive ICU patients requiring insulin infusions. INTERVENTION: Patients in the control cohort received insulin infusions titrated according to target blood glucose ranges and sliding scales at the physician's discretion. Patients in the interventional cohort received an insulin infusion adjusted using a standardized protocol targeting a blood glucose of 4.5 to 6.1 mmol/L (81 to 110 mg/dL). MEASUREMENTS AND MAIN RESULTS: Efficiency was measured by comparing the time to reach, and the time spent within, the target range between cohorts. Safety was assessed by comparing the incidence of severe hypoglycemia, the frequency of rescue dextrose administration, and the cumulative time that the infusion was held for hypoglycemia between cohorts. Patients in the interventional cohort reached their target more rapidly (11.3+/- 7.9 vs 16.4 +/- 12.6 hours; p = .028) and maintained their blood glucose within the target range longer (11.5 +/- 3.7 vs 7.1 +/- 5.0 hours/day; p < .001) than controls. The standardized protocol yielded a 4-fold reduction in the incidence of severe hypoglycemia (4 vs 16%; p = .046) and reduced the median frequency of dextrose rescue therapy (0 [0 to 0.91] vs 0.17 [0 to 1.2] episodes/patient per day; p = .01) as compared with controls. CONCLUSION: Standardization of intensive insulin therapy improves the efficiency and safety of glycemic control in critically ill adults. PMID- 28094661 TI - Diagnosis of pancreatic disease in feline platynosomosis. AB - Objectives Platynosomum species are cat-specific parasitic trematodes that parasitize the biliary ducts and gall bladder. Due to the common connection to the major duodenal papilla of the pancreas and common bile ducts in addition to the periductal proximity of the pancreas, it is possible that platynosomosis could cause pancreatitis. The objective of this study was to determine whether platynosomosis, a commonly diagnosed parasitic disease in cats on St Kitts, has any association with pancreatic disease. Methods To investigate this possibility, the pancreas of free-roaming cats with naturally acquired platynosomosis were evaluated via ultrasound, serum concentrations of feline pancreatic lipase (fPL), cobalamin, folate and feline trypsin-like immunoreactivity (fTLI) and histopathology. Twenty free-roaming, young adult, feral cats, positive for feline immunodeficiency virus, and diagnosed with Platynosomum species infection via fecal analysis were recruited. The liver, biliary system and pancreas were evaluated via ultrasonography during a short duration anesthesia. Serum concentrations of fPL, fTLI, folate and cobalamin were measured. Sections of the right limb, left limb and body of the pancreas were evaluated histopathologically using hematoxylin and eosin (H&E) stain. Results None of the cats had sufficient criteria to fulfill the ultrasonographic diagnosis of pancreatitis. One cat had an elevated fPL concentration in the range consistent with pancreatitis. Four cats had cobalamin deficiencies and 11 had abnormal folate concentration. The fTLI concentration was equivocal for the diagnosis of exocrine pancreatic insufficiency in one cat. With a single exception, histopathology changes, when present (n = 12), were mild, non-specific and predominantly characterized by lymphocytic infiltrates and fibrosis. The exception was a cat that presented a chronic interstitial and eosinophilic pancreatitis of slightly increased severity, likely the result of platynosomosis. Conclusions and relevance The results of this study suggest that platynosomosis rarely induces pancreatic damage in cats. With only one exception, chronic pancreatitis diagnosed in cats with fluke-induced cholangitis and cholangiohepatitis was subtle and interpreted as an incidental background lesion unrelated to platynosomosis. PMID- 28094662 TI - Clinical and psychological moderators of the effect of mindfulness-based cognitive therapy on persistent pain in women treated for primary breast cancer - explorative analyses from a randomized controlled trial. AB - BACKGROUND: Mindfulness-based intervention has been found efficacious in reducing persistent pain in women treated for breast cancer. Little, however, is known about possible moderators of the effect. We explored clinical and psychological moderators of the effect on pain intensity previously found in a randomized controlled trial of mindfulness-based cognitive therapy (MBCT) with women treated for breast cancer with persistent pain. MATERIAL AND METHODS: A total of 129 women treated for breast cancer reporting persistent pain were randomized to MBCT or a wait-list control. The primary outcome of pain intensity (11-point numeric rating scale) was measured at baseline, post-intervention, three, and six months follow-up. Proposed clinical moderators included age, axillary lymph node dissection (ALND), radiotherapy, and endocrine treatment. Psychological moderators included psychological distress [the Hospital Anxiety and Depression Scale (HADS)], the adult attachment dimensions anxiety and avoidance [the Experiences in Close Relationships Short Form (the ECR-SF)], and alexithymia [the Toronto Alexithymia Scale (TAS-20)]. Multi-level models were used to test moderation effects over time, i.e. time * group * moderator. RESULTS: Only attachment avoidance (p = 0.03, d = 0.36) emerged as a statistically significant moderator. Higher levels of attachment avoidance predicted a larger effect of MBCT in reducing pain intensity compared with lower levels attachment avoidance. None of the remaining psychological or clinical moderators reached statistical significance. However, based on the effect size, radiotherapy (p = 0.075, d = 0.49) was indicated as a possible clinical moderator of the effect, with radiotherapy being associated with a smaller effect of MBCT on pain intensity over time compared with no radiotherapy. CONCLUSION: Attachment avoidance, and potentially radiotherapy, may be clinically relevant factors for identifying the patients who may benefit most from MBCT as a pain intervention. Due to the exploratory nature of the analyses, the results should be considered preliminary. PMID- 28094663 TI - High pressure-low flow remodeling of the rat saphenous vein wall. AB - Objective To better understand factors that may play a role in the development of varicosities. Methods We induced combined flow-pressure disturbance in the saphenous system of the rat by performing chronic partial clipping of the main branch. Biomechanical and quantitative histological testing was undertaken. Results A rich microvenous network developed. Bloodflow decreased to 0.65 +/- 0.18 ul/s (control side, 3.5 +/- 1.4 ul/s) and pressure elevated to 6.8 +/- 0.7 mmHg (control side, 2.3 +/- 0.2 mmHg, p < 0.05). Involution of the wall and lumen was observed (16.5%, 28.7% and 35.5% reduction in outer diameter, wall thickness and wall mass respectively, p < 0.05). Elevated macrophage (CD68) and cell division (Ki67) activity was observed. Elastic tissue and smooth muscle actin became less concentrated in the inner medial layers. Conclusions Low-flow induced morphological shrinking of the lumen in veins may override pressure-induced morphological distension. Loosening of the force-bearing elements during flow induced wall remodeling may be an important pathological component in varicosity. PMID- 28094660 TI - Postoperative Bleeding and Associated Utilization following Tonsillectomy in Children. AB - Objective To assess posttonsillectomy hemorrhage (PTH), associated nonoperative readmissions/revisits, and reoperations in children. Data Sources MEDLINE, EMBASE, and the Cochrane Library. Review Methods Two investigators independently screened studies against predetermined criteria and extracted key data. Investigators independently assessed study risk of bias and the strength of the evidence of the body of literature. We calculated unadjusted pooled estimates of PTH frequency and conducted a Bayesian meta-analysis to estimate frequency of primary and secondary PTH and PTH-associated reoperation and revisits/readmissions by partial and total tonsillectomy and surgical approach. Results In meta-analysis, the frequency of primary and secondary PTH associated with total and partial tonsillectomy was <4% for any technique and with overlapping confidence bounds. Pooled frequencies of PTH were also <5% overall (4.2% for total tonsillectomy, 1.5% for partial tonsillectomy) in comparative studies. Fewer PTH episodes occurred with tonsillectomy for obstructive sleep disordered breathing than for throat infection. In meta-analysis, frequency of PTH-associated nonoperative revisits/readmission or reoperation ranged from 0.2% to 5.7% for total tonsillectomy and from 0.1% to 3.7% for partial tonsillectomy. At least 4 deaths were reported in case series including 1,778,342 children. Conclusions PTH occurred in roughly 4% of tonsillectomies in studies included in this review. Although studies typically did not report bleeding severity or amount, relatively few episodes of PTH necessitated reoperation for hemostasis. Nonetheless, tonsillectomy is not without risk of harm. Frequency of PTH across techniques was similar; thus, we cannot conclude that a given technique is superior. PMID- 28094664 TI - Feasibility and acceptability of active book clubs in cancer survivors - an explorative investigation. AB - BACKGROUND: While the increasing number of people surviving cancer is promising, the long-term health effects warrant broad, innovative interventions. We investigated the feasibility and acceptability of a 24-week intervention called 'Active Book Club' comprising audio book listening, pedometer walking and supervised book club meetings. MATERIAL AND METHODS: An exploratory and descriptive design was applied. Qualitative data included baseline and post intervention focus group interviews as well as post-intervention individual interviews. The study also included data on retention, attendance, and adherence. Seventeen self-referred cancer survivors with various oncological and sociodemographic backgrounds were included. RESULTS: Eight (47%) participants completed the entire intervention. Their median attendance at the book club meetings was eight [interquartile range (IQR) 6-9] of nine possible, and they reached the walking step goal in a median of 11 (IQR 7-12) of the first 12 weeks, and seven (IQR 1-10) of the last 12 weeks. The qualitative analysis revealed five themes including: Motivation and expectations (i.e. reasons for enrollment), Attentive listening (i.e. experiences of the audio book format), Affected by the story (i.e. experiences of the content of the books), Group involvement (i.e. experiences of the book club meetings) and Walking regularly (i.e. experiences of the walking program). Overall, findings revealed that while audio books may bring new meaning to physical activity and serve as a relief from own concerns, certain stories may affect some individuals negatively. The substantial dropout rate, however, suggested that modification is necessary and that patient involvement in choice of literature may be critical to enhance acceptability. CONCLUSION: The 'Active Book Club' represents a novel psychosocial intervention potentially supporting physical activity adoption and mental health in cancer survivors. However, several issues related to feasibility and acceptability including choice of literature genre, format and supervision of book club meetings need to be considered before larger scale clinical trials are initiated. PMID- 28094665 TI - FDG-PET reproducibility in tumor-bearing mice: comparing a traditional SUV approach with a tumor-to-brain tissue ratio approach. AB - BACKGROUND: Current [F-18]-fluorodeoxyglucose positron emission tomography (FDG PET) procedures in tumor-bearing mice typically includes fasting, anesthesia, and standardized uptake value (SUV)-based quantification. Such procedures may be inappropriate for prolonged multiscan experiments. We hypothesize that normalization of tumor FDG retention relative to a suitable reference tissue may improve accuracy as this method may be less susceptible to uncontrollable day-to day changes in blood glucose levels, physical activity, or unnoticed imperfect tail vein injections. MATERIAL AND METHODS: Fed non-anesthetized tumor-bearing mice were administered FDG intravenously (i.v.) or intraperitoneally (i.p.) and PET scanned on consecutive days using a Mediso nanoScan PET/magnetic resonance imaging (MRI). Reproducibility of various PET-deduced measures of tumor FDG retention, including normalization to FDG signal in reference organs and a conventional SUV approach, was evaluated. RESULTS: Day-to-day variability in i.v. injected mice was lower when tumor FDG retention was normalized to brain signal (T/B), compared to normalization to other tissues or when using SUV-based normalization. Assessment of tissue radioactivity in dissected tissues confirmed the validity of PET-derived T/B ratios. Mean T/B and SUV values were similar in i.v. and i.p. administered animals, but SUV normalization was more robust in the i.p. group than in the i.v. group. CONCLUSIONS: Multimodality scanners allow tissue delineation and normalization of tumor FDG uptake relative to reference tissues. Normalization to brain, but not liver or kidney, improved scan reproducibility considerably and was superior to traditional SUV quantification in i.v. tracer-injected animals. Day-to-day variability in SUV's was lower in i.p. than in i.v. injected animals, and i.p. injections may therefore be a valuable alternative in prolonged rodent studies, where repeated vein injections are undesirable. PMID- 28094667 TI - Corrigendum. PMID- 28094666 TI - Stage IV advanced diffuse large B-cell lymphoma in human immunodeficiency virus infection with achieving cure by using highly active antiretroviral therapy alone: a case report. AB - After the introduction of highly active antiretroviral therapy (HAART), there has been a decrease in the incidence of lymphoma among the HIV-infected population and also significantly improved survival rates. We describe a remarkable case of an HIV-infected patient with advanced stage IV diffuse large B-cell lymphoma (DLBCL), completely regressed with the use of HAART alone. He remained disease free for 6 years and he achieved cure without chemotherapy. Although several cases of low-grade lymphoma with complete regression were reported, we could not find any case of stage IV high-grade malignant lymphoma with HAART alone in complete remission for over 5 years from our review of the literature. This unique case shows the importance of HAART in improving survival and achieving cure in HIV-high-grade malignant lymphoma. PMID- 28094670 TI - CLINICAL NUTRITION WEEK 2006 NUTRITION PRACTICE POSTER ABSTRACTS. PMID- 28094672 TI - A Randomized Study Comparing the Effects of a Low-Carbohydrate Diet and a Conventional Diet on Lipoprotein Subfractions and C-reactive Protein Levels in Patients With Severe Obesity. AB - PURPOSE: To compare the effects of a low-carbohydrate diet and a conventional (fat- and calorie-restricted) diet on lipoprotein subfractions and inflammation in severely obese subjects. METHODS: We compared changes in lipoprotein subfractions and C-reactive protein levels in 78 severely obese subjects, including 86% with either diabetes or metabolic syndrome, who were randomly assigned to either a low-carbohydrate or conventional diet for 6 months. RESULTS: Subjects on a low-carbohydrate diet experienced a greater decrease in large very low-density lipoprotein (VLDL) levels (difference =-0.26 mg/dL, p = .03) but more frequently developed detectable chylomicrons (44% vs 22%, p = .04). Both diet groups experienced similar decreases in the number of low-density lipoprotein (LDL) particles (difference = -30 nmol/L, p = .74) and increases in large high density lipoprotein (HDL) concentrations (difference = 0.70 mg/dL, p = .63). Overall, C-reactive protein levels decreased modestly in both diet groups. However, patients with a high-risk baseline level (>3 mg/dL, n = 48) experienced a greater decrease in C-reactive protein levels on a low-carbohydrate diet (adjusted difference = -2 mg/dL, p = .005), independent of weight loss. CONCLUSIONS: In this 6-month study involving severely obese subjects, we found an overall favorable effect of a low-carbohydrate diet on lipoprotein subfractions and on inflammation in high-risk subjects. Both diets had similar effects on LDL and HDL subfractions. ( Am J Med. 2004;117:398-405.). PMID- 28094674 TI - Omega-3 Fatty Acids for the Prevention of Atrial Fibrillation After Coronary Artery Bypass Surgery: A Randomized, Controlled Trial. AB - OBJECTIVES: The aim of this study was to assess the efficacy of preoperative and postoperative treatment with omega-3 polyunsaturated fatty acids (PUFAs) in preventing the occurrence of atrial fibrillation (AF) after coronary artery bypass graft surgery (CABG). BACKGROUND: Postoperative AF is a common complication of CABG. There is growing clinical evidence that PUFAs have cardiac antiarrhythmic effects. METHODS: A total of 160 patients were prospectively randomized to a control group (81 patients, 13 female, 64.9 +/- 9.1 years) or PUFAs 2 g/day (79 patients, 11 female, 66.2 +/- 8.0 years) for at least 5 days before elective CABG and until the day of discharge from the hospital. The primary end point was the development of AF in the postoperative period. The secondary end point was the hospital length of stay after surgery. All end points were independently adjudicated by 2 cardiologists blinded to treatment assignment. RESULTS: The clinical and surgical characteristics of the patients in the 2 groups were similar. Postoperative AF developed in 27 patients of the control group (33.3%) and in 12 patients of the PUFAs group (15.2%) ( p = .013). There was no significant difference in the incidence of nonfatal postoperative complications, and postoperative mortality was similar in the PUFAs-treated patients (1.3%) vs controls (2.5%). After CABG, the PUFAs patients were hospitalized for significantly fewer days than controls (7.3 +/- 2.1 days vs 8.2 +/- 2.6 days, p = .017). CONCLUSIONS: This study first demonstrates that PUFA administration during hospitalization in patients undergoing CABG substantially reduced the incidence of postoperative AF (54.4%) and was associated with a shorter hospital stay. ( J Am Coll Cardiol. 2005;45:1723-1728.). PMID- 28094675 TI - Dietary Folate and Vitamin B12 Intake and Cognitive Decline Among Community Dwelling Older Persons. AB - BACKGROUND: Deficiencies in folate and vitamin B12 have been associated with neurodegenerative disease. OBJECTIVE: To examine the association between rates of age-related cognitive change and dietary intakes of folate and vitamin B12. DESIGN: Prospective study performed from 1993 to 2002. SETTING: Geographically defined biracial community in Chicago, Ill. PARTICIPANTS: A total of 3718 residents, 65 years and older, who completed 2 to 3 cognitive assessments and a food frequency questionnaire. MAIN OUTCOME MEASURE: Change in cognitive function measured at baseline and 3-year and 6-year follow-ups, using the average z score of 4 tests: the East Boston Tests of immediate and delayed recall, the Mini Mental State Examination, and the Symbol Digit Modalities Test. RESULTS: High folate intake was associated with a faster rate of cognitive decline in mixed models adjusted for multiple risk factors. The rate of cognitive decline among persons in the top fifth of total folate intake (median, 742 MUg/d) was more than twice that of those in the lowest fifth of intake (median, 186 MUg/d), a statistically significant difference of 0.02 standardized unit per year ( p = .002). A faster rate of cognitive decline was also associated with high folate intake from food ( p for trend = .04) and with folate vitamin supplementation of> 400 MUg/d compared with nonusers (beta = -.03, p < .001). High total B12 intake was associated with slower cognitive decline only among the oldest participants. CONCLUSIONS: High intake of folate may be associated with cognitive decline in older persons. These unexpected findings call for further study of the cognitive implications of high levels of dietary folate in older populations. ( Arch Neurol. 2005;62:641-645.). PMID- 28094677 TI - Costs of formal and informal care in the last year of life for patients in receipt of specialist palliative care. AB - BACKGROUND: Economic evaluation of palliative care has been slow to develop and the evidence base remains small. AIM: This article estimates formal and informal care costs in the last year of life for a sample of patients who received specialist palliative care in three different areas in Ireland. DESIGN: Formal care costs are calculated for community, specialist palliative care, acute hospital and other services. Where possible, a bottom-up approach is used, multiplying service utilisation by unit cost. Informal care is valued at the replacement cost of care. SETTING/PARTICIPANTS: Data on utilisation were collected during 215 'after death' telephone interviews with a person centrally involved in the care in the last year of life of decedents who received specialist palliative care in three areas in Ireland with varying levels of specialist palliative care. RESULTS: Mean total formal and informal costs in the last year of life do not vary significantly across the three areas. The components of formal costs, however, do vary across areas, particularly for hospital and specialist palliative care in the last 3 months of life. CONCLUSION: Costs in the last year of life for patients in receipt of specialist palliative care are considerable. Where inpatient hospice care is available, there are potential savings in hospital costs to offset specialist palliative care inpatient costs. Informal care accounts for a high proportion of costs during the last year of life in each area, underlining the important role of informal caregivers in palliative care. PMID- 28094678 TI - Orthotic treatment of positional brachycephaly associated with osteogenesis imperfecta. AB - BACKGROUND: Osteogenesis imperfecta is an inherited disorder of the connective tissue characterized primarily by fractures with no or small causal antecedents and extremely variable clinical presentation. The disorder requires a global and, therefore, multidisciplinary therapeutic approach that should aim, among other aspects, at the prevention and treatment of deformities resulting from osteogenesis imperfecta. Due to limitations related to bony deformities, it can be difficult to place these infants in a variety of positions that would help remediate skull deformities, so a cranial orthosis becomes the therapy of choice. The aim of this study was to demonstrate the results obtained during treatment with a cranial remolding orthosis (helmet) in babies with osteogenesis imperfecta. Case Description and Methods: For the first time in the scientific literature, this study describes the use of a cranial orthosis for the treatment of infants with osteogenesis imperfecta. Both children had severe asymmetrical brachycephaly documented by laser digital scanning and were submitted to treatment with a cranial remolding orthosis. Outcomes and Conclusion: The study showed that there was a significant improvement in cranial proportion and symmetry, with a reduction in the cephalic index at reevaluation. It is concluded that the orthotic therapy is an effective therapeutic modality to improve the proportion and minimize the asymmetry in children with osteogenesis imperfecta. Clinical relevance The clinical relevance of such a description is that children with osteogenesis imperfecta may have numerous deformities and minimizing them can be an important factor. This report showed a beneficial result as the orthotic therapy modality improved the proportions and minimized the asymmetry. This treatment offers too high levels of satisfaction to parents and brings these children closer to normal indices. PMID- 28094679 TI - A retrospective analysis of a pediatric tele-echocardiography service to treat, triage, and reduce trans-Pacific transport. AB - Introduction Tele-echocardiography can ensure prompt diagnosis and prevent the unnecessary transport of infants without critical congenital heart disease, particularly at isolated locations lacking access to tertiary care medical centers. Methods We retrospectively reviewed all infants who underwent tele echocardiography at a remote 16-bed level IIIB NICU from June 2005 to March 2014. Tele-echocardiograms were completed by cardiac sonographers in Okinawa, Japan, and transmitted asynchronously for review by pediatric cardiologists in Hawaii. Results During the study period 100 infants received 192 tele-echocardiograms: 46% of infants had tele-echocardiograms completed for suspected patent ductus arteriosus, 28% for suspected congenital heart disease, 12% for possible congenital heart disease in the setting of likely pulmonary hypertension, and 10% for possible congenital heart disease in the setting of other congenital anomalies. Of these, 17 patients were aeromedically evacuated for cardiac reasons; 12 patients were transported to Hawaii, while five patients with complex heart disease were transported directly to the United States mainland for interventional cardiac capabilities not available in Hawaii. Discussion This study demonstrates the use of tele-echocardiography to guide treatment, reduce long and potentially risky trans-Pacific transports, and triage transports to destination centers with the most appropriate cardiac capabilities. PMID- 28094680 TI - Changes in the corticospinal tract after wearing prosthesis in bilateral transtibial amputation. AB - BACKGROUND: After amputation, the brain is known to be reorganized especially in the primary motor cortex. We report a case to show changes in the corticospinal tract in a patient with serial bilateral transtibial amputations using diffusion tensor imaging. Case Description and Methods: A 78-year-old man had a transtibial amputation on his left side in 2008 and he underwent a right transtibial amputation in 2011. An initial brain magnetic resonance imaging with a diffusion tensor imaging was performed before starting rehabilitation on his right transtibial prosthesis, and a follow-up magnetic resonance imaging with diffusion tensor imaging was performed 2 years after this. Findings and Outcomes: In the initial diffusion tensor imaging, the number of fiber lines in his right corticospinal tract was larger than that in his left corticospinal tract. At follow-up diffusion tensor imaging, there was no definite difference in the number of fiber lines between both corticospinal tracts. CONCLUSION: We found that side-to-side corticospinal tract differences were equalized after using bilateral prostheses. Clinical relevance This case report suggests that diffusion tensor imaging tractography could be a useful method to understand corticomotor reorganization after using prosthesis in transtibial amputation. PMID- 28094681 TI - Relationship between body height and spatiotemporal parameters during a 100-m sprint in able-bodied and unilateral transtibial sprinters. AB - BACKGROUND: Although anthropometric factors could influence sprint performance in able-bodied sprinters, little is known about the relationships between these anthropometric factors and sprint performance in amputee sprinters. OBJECTIVES: To investigate the relationships between body height and spatiotemporal parameters of 100-m sprints in unilateral transtibial amputee and able-bodied sprinters. STUDY DESIGN: This is a cross-sectional study. METHODS: We analyzed elite-level 100-m races of 14 male unilateral transtibial amputee sprinters and 22 male able-bodied sprinters from publicly available Internet broadcasts. For each sprinter's run, the mean step length and frequency were determined using the number of steps in conjunction with the official race time. Furthermore, body height data for sprinters in both groups were obtained from publicly available resources. RESULTS: Linear relationships were found between body height and mean step length and frequency in able-bodied sprinters, respectively. However, there were no significant relationships between body height and spatiotemporal parameters in transtibial amputee sprinters. CONCLUSION: The results of this study suggest that the relationship between body height and spatiotemporal parameters during a 100-m sprint is not the same between unilateral transtibial amputees and able-bodied sprinters. Clinical relevance Understanding of the relationship between body height and spatiotemporal parameters during a 100-m sprint would provide important information that could be utilized for evaluating prosthetic sprint performance and coaching. PMID- 28094682 TI - Development, implementation and assessment of a concussion education programme for high school student-athletes. AB - Although experts have noted that adolescent athletes should be educated about concussions to improve their safety, there is no agreement on the most effective strategy to disseminate concussion education. The purpose of this study was to develop, implement and assess a concussion education programme. More precisely, four interactive oral presentations were delivered to high school student athletes (N = 35, Mage = 15.94, SD = 0.34) in a large urban centre. Participants completed a questionnaire at three time-points during the season to measure changes in their knowledge (CK) and attitudes (CA) of concussions, and focus group interviews were conducted following the concussion education programme. Questionnaire data revealed participants' post-intervention CK scores were higher than their pre-intervention scores. During the focus groups, the student-athletes said they acquired CK about the role of protective equipment and symptom variability, and in terms of CA, they intended to avoid dangerous in-game collisions in the future. Our study was the first to create and deliver a concussion education intervention across multiple time-points, and to use mixed methods in its assessment. These findings may be of interest to researchers, practitioners and stakeholders in sport who are invested in making the sport environment safer through concussion education and awareness. PMID- 28094686 TI - Northwestern University Flexible Subischial Vacuum Socket for persons with transfemoral amputation-Part 1: Description of technique. AB - BACKGROUND: Current transfemoral prosthetic sockets restrict function, lack comfort, and cause residual limb problems. Lower proximal trim lines are an appealing way to address this problem. Development of a more comfortable and possibly functional subischial socket may contribute to improving quality of life of persons with transfemoral amputation. OBJECTIVES: The purpose of this study was to (1) describe the design and fabrication of a new subischial socket and (2) describe efforts to teach this technique. STUDY DESIGN: Development project. METHODS: Socket development involved defining the following: subject and liner selection, residual limb evaluation, casting, positive mold rectification, check socket fitting, definitive socket fabrication, and troubleshooting of socket fit. Three hands-on workshops to teach the socket were piloted and attended by 30 certified prosthetists and their patient models. RESULTS: Patient models responded positively to the comfort, range of motion, and stability of the new socket while prosthetists described the technique as "straight forward, reproducible." CONCLUSION: To our knowledge, this is the first attempt to create a teachable subischial socket, and while it appears promising, more definitive evaluation is needed. Clinical relevance We developed the Northwestern University Flexible Subischial Vacuum (NU-FlexSIV) Socket as a more comfortable alternative to current transfemoral sockets and demonstrated that it could be taught successfully to prosthetists. PMID- 28094688 TI - President's message. PMID- 28094687 TI - Successful management of femoral trauma in a through-knee amputee with a previous malunited fracture: Implications and functional outcome. AB - BACKGROUND: After amputation patients are more likely to injure their residual limb. An injury of a previously amputated limb, especially if the residuum is not anatomically normal, poses a dilemma for management. Case Description and Methods: This case report discusses a femoral fracture sustained proximal to a through-knee amputation. Findings and outcomes: The fracture was at the site of a malunited fracture. A shortening osteotomy with bone graft was undertaken to improve alignment and prosthetic fit and remove poor-quality bone. This was stabilised using an intramedullary nail, supplemented with an anti-rotation plate. This fracture went on to uneventful union, and the patient was able to comfortably use a prosthesis with increased functionality compared with prior to the recent injury. DISCUSSION: This management enabled quick healing of the fracture without the need to resort to a more proximal amputation. CONCLUSION: In these unusual cases, careful planning is necessary to ensure all aspects of the problem is dealt with. Each case should be treated on its own merits. Clinical relevance This case demonstrates the difficulty in care of complex limb trauma and offers a solution for management of similar cases. Excellent results are possible when all surgical options are considered. PMID- 28094689 TI - Quantification of rectifications for the Northwestern University Flexible Sub Ischial Vacuum Socket. AB - BACKGROUND: The fit and function of a prosthetic socket depend on the prosthetist's ability to design the socket's shape to distribute load comfortably over the residual limb. We recently developed a sub-ischial socket for persons with transfemoral amputation: the Northwestern University Flexible Sub-Ischial Vacuum Socket. OBJECTIVE: This study aimed to quantify the rectifications required to fit the Northwestern University Flexible Sub-Ischial Vacuum Socket to teach the technique to prosthetists as well as provide a computer-aided design computer-aided manufacturing option. STUDY DESIGN: Development project. METHODS: A program was used to align scans of unrectified and rectified negative molds and calculate shape change as a result of rectification. Averaged rectifications were used to create a socket template, which was shared with a central fabrication facility engaged in provision of Northwestern University Flexible Sub-Ischial Vacuum Sockets to early clinical adopters. Feedback regarding quality of fitting was obtained. RESULTS: Rectification maps created from 30 cast pairs of successfully fit Northwestern University Flexible Sub-Ischial Vacuum Sockets confirmed that material was primarily removed from the positive mold in the proximal-lateral and posterior regions. The template was used to fabricate check sockets for 15 persons with transfemoral amputation. Feedback suggested that the template provided a reasonable initial fit with only minor adjustments. CONCLUSION: Rectification maps and template were used to facilitate teaching and central fabrication of the Northwestern University Flexible Sub-Ischial Vacuum Socket. Minor issues with quality of initial fit achieved with the template may be due to inability to adjust the template to patient characteristics (e.g. tissue type, limb shape) and/or the degree to which it represented a fully mature version of the technique. Clinical relevance Rectification maps help communicate an important step in the fabrication of the Northwestern University Flexible Sub Ischial Vacuum Socket facilitating dissemination of the technique, while the average template provides an alternative fabrication option via computer-aided design-computer-aided manufacturing and central fabrication. PMID- 28094690 TI - Letter to the Editor. PMID- 28094692 TI - Errata to "Side-by-Side Comparison of Field Monitoring Methods for Hot Bitumen Emission Exposures: The German BGIA Method 6305, the U.S. NIOSH Method 5042, and the Total Organic Matter Method" [JOEH 7:712-725, 2010]. PMID- 28094696 TI - The Biology of Carcinogen-Induced Hepatocyte Nodules and Related Liver Lesions in the Rats 1. AB - The only known sequence of tissue changes seen during liver cancer development involves microscopic foci or islands of altered hepatocytes, hepatocyte nodules, a subset of these nodules, the persistent nodules, nodules in nodules and ultimately hepatocellular carcinoma. The nodules show an array of architectural, fine ultrastructural, vascular, biochemical and physiological properties characteristic of this new population of hepatocytes. Despite their origin following initiation with a chemical carcinogen, the vast majority (98-99%) of nodules undergo a complex process of remodeling or redifferentiation to normal looking mature liver. A very small minority persist, continue to grow slowly and ultimately may act as a site of origin for new later precancerous nodules and metastasizing hepatocellular carcinoma. The basis for the different behaviour patterns, remodelling of the majority and persistence of the minority is not understood. Even though the vast majority of nodules do undergo remodelling and "disappear", it would be unwise at this time to ignore this key role of nodules in general in cancer development. PMID- 28094698 TI - The Use of In vivo Hepatic Initiation-Promotion Systems in Understanding the Hepatocarcinogenesis of Technical Grade Dinitrotoluene. AB - A 2 year bioassay sponsored by the Chemical Industry Institute of Toxicology demonstrated the potent hepatocarcinogenicity of technical grade dinitrotoluene (DNT) which contains 76% 2,4-DNT, 18% 2,6-DNT and less than 3% of each 2,3; 2,5; 3,4 and 3,5-DNT isomers. In contrast, a 2 year bioassay of 2,4-DNT sponsored by the National Cancer Institute did not result in the appearance of hepatic neoplasms above the spontaneous incidence. Using previously described in vivo hepatic initiation-promotion systems, an evaluation of the initiating and promoting activity of individual DNT isomers was undertaken to provide an understanding for the differences between the two bioassays. Weak hepatocyte initiating activity was identified in technical grade DNT and purified 2,6-DNT. In contrast, 2,3; 2,4; 2,5; 3,4 and 3,5 isomers had no detectable initiating activity. When fed following a diethylnitrosamine initiating regimen, technical grade DNT, purified 2,4 and 2,6-DNT isomers had demonstrable promoting activity. Therefore, the hepatic neoplasms resulting from technical grade DNT feeding apparently resulted from the initiating activity of 2,6-DNT followed by the promoting effect of both the 2,4 and 2,6-DNT isomers. The lack of hepatic neoplasms following chronic feeding of 2,4-DNT was apparently due to the lack of hepatic initiating activity. PMID- 28094700 TI - Liver Lesions from Sex Steroids. PMID- 28094701 TI - Human Liver Neoplasia and Steroid Exposure. AB - This study examines experience with over 250 liver tumors in young women. Most were oral contraceptive related. There were two distinct benign liver tumor types: focal nodular hyperplasia and liver cell adenoma. Six benign liver tumors were examined for estrogen receptors. They did not contain significant quantities of estrogen receptor, supporting experimental studies of an epigenetic origin. Multiple tumors occurred in about 20% of cases but did not change the favorable prognosis associated with benign tumors. The most significant source of morbidity and mortality was spontaneous hemorrhage or rupture. Twenty-three women in this series had hepatocellular carcinoma and the majority of these were associated with prolonged steroid usage. These malignant liver tumors occurred in young females without cirrhosis or other factors known to be associated with hepatic malignancy. Unlike "hepatocellular carcinomas" reported in males taking anabolic androgenic steroids, the tumors in females had a high rate of metastasis to a variety of organs. The risk of liver tumors in oral contraceptive users remains unknown, but must be very small since an estimated 150 million women worldwide and 40 million in the U.S.A. have used oral contraceptives. PMID- 28094707 TI - Hypolipidemics Hepatocarcinogenicity and Safety. PMID- 28094702 TI - Phenotypic Properties of Preneoplastic Rat Liver Lesions and Applications to Detection of Carcinogens and Tumor Promoters. AB - A variety of cellular lesions arise during liver carcinogenesis by chemicals in rats. The altered focus is a lesion of hepatocytes that occurs early in hepatocarcinogenesis and appears to give rise to both neoplastic nodules and carcinomas. Foci display numerous phenotypic abnormalities which together with nuclear abnormalities indicate that they are truly a new altered population. Using histochemical markers, the induction of foci can be measured as a quantitative index of hepatocarcinogenicity of genotoxic carcinogens. In addition, determination of the effect of agents on foci previously induced by genotoxic carcinogens can be used to assess the capacity of chemicals to act as liver tumor promoters. PMID- 28094708 TI - Sequential observation of pathomorphologic alterations in preneoplastic lesions during the promoting stage of hepatocarcinogenesis and the development of short term test system for hepatopromoters and hepatocarcinogens. AB - The aims of this study were 1) to observe the sequential development of hepatocellular carcinomas from preneoplastic lesions and to investigate hyperplastic (neoplastic) foci or nodules (HN) as an indicator of a preneoplastic population, and 2) to test the promoting effect of various agents and to study the dose-dependent effect of promoting agents in the induction of preneoplastic lesions in the rat liver. 1) F344 rats were injected with N-nitrosodiethylamine (DEN) and then given basal diet containing 2-acetylaminofluorene (2-AAF) or alpha hexachlorocyclohexane (alpha-HCH). Two-thirds partial hepatectomy (PH) was performed at the end of week 3. Animals were killed periodically for quantitative analysis of HN and for study of changes in blood supply to the lesions by method using a resin. In the liver of rats treated with 2-AAF after DEN, the number and area of HN were maximal in week 10, and then the number gradually decreased to week 50 (P < 0.001), whereas the area remained almost constant. In the group given alpha-HCH after DEN, the number of HN decreased temporarily in week 20 and then gradually increased, whereas the area of HN increased slowly throughout the experiment. Histological examination suggested that the decrease of HN after week 10 was due to degeneration of HN with their change to a spongy or cystic appearance, and that the degeneration resulted from circulatory disturbance. The number and area of these degenerating hyperplastic nodules (DHN) increased reciprocally to the decrease of HN with time until week 30. The number of hepatocellular carcinomas was maximal at week 40. The blood supply to the early hyperplastic nodules was mainly through the portal vein as with normal or surrounding liver tissue, but at a later stage HN and hepatocellular carcinomas were supplied with a blood mainly from the hepatic artery. Therefore, arterial blood supply seemed important for the persistence of HN and development of hepatocellular carcinoma. Most of the HN which appeared within the first 10 weeks were histochemically positive for gamma-glutamyl-transpeptidase (gamma-GT) activity. This experiment showed that detectable preneoplastic lesions measured as gamma-GT positive foci or HN were induced by exposure to promoting agents for 6 to 10 weeks after initiation with DEN. 2) In tests of the promoting activity and dose-dependent effect of various compounds, rats were injected intraperitoneally with DEN and given the test compounds for 6 to 10 weeks and then killed. PH was performed as in experiment 1. Potent hepatocarcinogens, such as 2-AAF, 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB), ethionine and N nitrosodimethylamine (DMN), induced a large number and area of HN or gamma-GT positive foci whereas weak ones, such as alpha-HCH, dieldrin, hormones and bile acids evoked less response. Both potent and weak carcinogens showed a clear dose dependent effect. A similar dose-dependent effect was also shown in the induction of hepatocellular carcinoma in a long-term experiment by continuous feeding of DMN. Non-hepatocarcinogens, such as N-ethylnitrosourea (ENU) and 3 methylcholanthrene (3-MC) induced them only in small numbers. PMID- 28094709 TI - Ultrastructure of altered hepatocytes induced by diethylnitrosamine (DENA). AB - Administration of diethylnitrosamine I.P. at dose level of 2 mg/kg five days a week to young Sprague-Dawley rats induced foci of altered hepatocytes entirely devoid of glucose-6-phosphatase and adenosine triphosphatase activity. Several weeks later, these foci developed hepatocellular carcinoma mostly of the trabecular type. Although these "preneoplastic" altered cells appeared as normal hepatocytes when examined in HE-sections, they were found to exhibit sites of dedifferentiation with ultrastructural features of hepatoma cells. Early morphological changes indicative of neoplastic transformation took place first as excessive storage of glycogen then as marked alterations at the surface membranes of such cells. Striking increase in coated pinocytotic vesicles appeared along the apposing cell membranes associated with loss of sinusoidal microvilli, protrusion of cytoplasmic blebs in the intercellular spaces, reduction or loss of desmosomes and obliteration of bile canaliculi. Subsequent changes were seen as dilation and disruption of the rough endoplasmic reticulum (RER), dispersal of ribosomes, proliferation and clustering of the smooth endoplasmic reticulum (SER), predominance of annulate lamellae, depletion of glycogen, enlargement of the Golgi cisterns and segregation of nucleolar elements. After 20 weeks, rats given DENA at a dose level of 25 mg/kg twice a week developed pronounced cirrhotic nodules in addition to multiple hepatocellular carcinoma. In contrast to the neoplastic nodules, the cirrhotic ones retained normal activity of glucose 6-phosphatase and adenosine triphosphatase and exhibited ultrastructural features typical of normal hepatocytes. PMID- 28094710 TI - Liver Tumors and Steroid Exposure. PMID- 28094711 TI - Initiation/promotion bioassay in rat liver: use of gamma glutamyltranspeptidase positive foci to indicate carcinogenic activity. AB - Gamma Glutamyltranspeptidase (GGTase)-positive foci have been used to indicate activity in an initiation/promotion bioassay in rat liver. This rat liver foci bioassay has been proposed for inclusion in tier 2 of a three tier decision tree approach to carcinogenesis testing where it would function to confirm carcinogenic activity. The assay was sensitive to hepatocarcinogens and some non hepatocarcinogens and was able to distinguish between tumor initiators and tumor promoters. The induction of GGTase-positive foci by methylating agents was associated with the formation of O6-methylguanine and not N-7 methylguanine, which would indicate a mutagenic origin for the foci. The foci once induced did not regress over the life time of the animal. Zonal induction of GGTase activity was induced by some promoters which confounded the scoring of foci incidence. The results to date indicate that the rat liver foci bioassay warrants further validation for inclusion in tier 2 and emphasizes the need to demonstrate the predictive and precursor relationship of GGTase-positive foci to cancer. PMID- 28094712 TI - Biological markers of preneoplastic foci and neoplastic nodules in rodent liver. AB - Foci of altered hepatocytes are regularly observed early during hepatocarcinogenesis in rodents. The abnormal hepatocytes may show a number of different phenotypes as characterized by various cytomorphological and cytochemical markers. The first appearance and the further development of the abnormal cell populations depend on the dose of the carcinogen given and on the duration of the carcinogenic treatment. According to cytochemical, morphometric and autoradiographic findings in rats receiving low doses (2-10% of the LD 50/kg bw/day) of hepatocarcinogens for limited periods ("stop" experiments), glycogenotic (clear or acidophilic) hepatocytes indicate the first step of the neoplastic cell transformation which can be detected by these methods at present. The glycogenotic cells undergo a characteristic metamorphosis and give rise to basophilic tumor cells poor in glycogen, but rich in ribosomes. Under extreme experimental conditions, such as a single or repeated application of higher doses of one or several chemical carcinogens a puzzling picture emerges which is "reversible" to a large extent after withdrawal of the respective compounds. This observation points to a phenotypic instability of the cellular changes induced in certain experimental systems. Foci of altered hepatocytes persisting after withdrawal of the carcinogenic compounds are considered preneoplastic lesions. They may transform into neoplastic nodules which are also persistent and share a number of cytomorphological and cytochemical markers with the focal lesions. The persistent nodules progress to hepatocarcinomas after lag periods of weeks or months. However, the foci may also progress to hepatocarcinomas without passing a nodular intermediate stage. The development of both neoplastic nodules and carcinomas from the preneoplastic glycogen storage foci can proceed independent of further administration of carcinogen. The sequence of cellular changes during hepatocarcinogenesis derived from the experimental results in rodents is strongly supported by observations in humans, especially by the increasing reports on the appearance of hepatic tumors in patients who suffer from inborn hepatic glycogenosis. PMID- 28094713 TI - Hypolipidemics Carcinogenicity and Extrapolation of Experimental Results for Human Safety Assessments. AB - Dyslipoproteinemias represent a group of disorders closely related to alterations of cholesterol and triglycerides. The alterations of these lipids are considered important risk factors in coronary heart disease and indicate the need for clinically effective and safe drugs. Hypolipidemic agent therapy, however, does not appear without risk since the administration of these agents is by necessity, on a long-term basis. In the conduct of animal safety studies with some hypolipidemics, hyperplastic nodules or tumors developed in the liver of rodents. Data from the literature seem to indicate that the tumor response in rodents varies with the type of hypolipidemic drug administered. This paper summarizes the studies with the new lipid-regulating agent gemfibrozil. Aside from conventional long-term studies in rodents, the ultrastructural aspects of the liver were analyzed in several species and genotoxicity assays and short-term tests for hepatocarcinogenicity were conducted. Thus, it was possible to obtain an overview of these biological phenomena in order to allow for safety extrapolations. The biological behavior of these liver nodules showed that gemfibrozil and clofibrate-induced hepatocytes had not undergone malignant transformation. Further, the phenomenon of peroxisome proliferation, a characteristic event that follows hypolipidemic administration in rodents, was not confirmed in primate or human liver. Peroxisome proliferation has been linked to the process of hepatocarcinogenesis in rodents, although genotoxicity assays were negative and initiation/promotion tests failed to elicit tumors or nodules in a system where hepatocarcinogens manifest their activity. Thus, hypolipidemics such as gemfibrozil or clofibrate may possess low tumorigenic potential with low risk due to the lack of correlation between these tests. Nevertheless, these agents are indicated for specific lipoprotein phenotype alteration with the resulting clinical benefits. PMID- 28094714 TI - Response of liver foci in rats to hepatic tumor promoters. AB - Putative preneoplastic foci (islands) of altered hepatocytes were induced by single doses of initiating hepatocarcinogens and identified by various histochemical and morphological markers. DNA synthesis, measured by 3H-thymidine and autoradiography, as well as mitotic activity were found to be higher in the foci than in normal hepatocytes. Without promotion this proliferative advantage is partially counterbalanced by reversion of altered cells to the normal phenotype and/or increased incidence of cell death by apoptosis, so that the islands show little growth. Prolonged administration of promoters such as phenobarbital, hexachlorocyclohexane etc. resulted in the appearance of more and larger foci, which exhibited steady growth. Island enlargement was due to an upsurge of cell proliferation (in the initial stage only) and to interference of the promoter with phenotypic reversion and/or apoptosis of island cells. Island multiplication during promotion was essentially due to induction of the histochemical marker (gamma-GT) in "latent" islands. Promoter withdrawal led to rapid reductions in size and number of foci suggesting that the effect of promoters on the phenotype of island cells is reversible under the conditions employed. Finally we offer the hypothesis that non-mutagenic compounds may produce liver tumors in experimental animals by promotion of "spontaneous" preneoplastic lesions. PMID- 28094717 TI - Hepatic Initiation-Promotion. PMID- 28094716 TI - Interpretation of Rodent Hepatocellular Proliferative Alterations and Hepatocellular Tumors in Chemical Safety Assessment 1 , 2. AB - Benign and malignant liver tumors have been frequently observed in National Cancer Institute/National Toxicology Program rodent carcinogenesis bioassays using Fischer 344 rats and B6C3F1 mice. A multilayered pathology review process enhances consistency and accuracy of the histologic diagnoses. All data, including statistically analyzed tumor prevalences, are ultimately reviewed by a multidisciplinary team of scientists for judgment regarding the carcinogenicity of the chemical. Rationale for interpretation of hepatocellular alterations is illustrated with results from the recently completed NCI/NTP bioassays of di(2 ethylhexyl)phthalate, C.I. Disperse Yellow 3, C.I. Solvent Yellow 14, and pentachloroethane. PMID- 28094718 TI - Experimental Diffuse Nodular Hepatic Hyperplasia. PMID- 28094720 TI - Hepatoproliferativ Changes in Rats. PMID- 28094719 TI - Chemically Induced Hepatocellular Proliferative Changes in the Rat Without Evidence of Neoplastic Transformation. AB - The hypothesis that hepatocellular proliferative changes give rise to autonomous, neoplastic lesions in rodents was tested in this study in which hepatoproliferative lesions induced in rats by feeding an experimental psychoactive drug, cyproximide, were examined at various times during the course of a 24 month study. A total of 610 male and female rats (Charles River Laboratories COBS(r)CD(r)(SD)BR, Wilmington, Mass.) were distributed into three groups. Each of two treatment groups contained 230 rats given 0.1% or 0.4% of cyproximide in the diet. One hundred and fifty rats were given a drug-free diet and served as controls. Five males and five females from each group were sacrificed for postmortem examination after 6, 12 and 20 months of drug diet feeding after which remaining rats were retained for recovery (nontreatment) periods of 18, 12 and 4 months, respectively. An additional 25 males and 25 females from each dose level were treated for 24 months and then sacrificed along with all surviving recovery and control rats. The results of this study demonstrated that the incidence of proliferative lesions was greater in the liver of treated rats (especially females) than in control rats; however, the incidence of hepatocellular neoplasms was the same in treated and control rats. PMID- 28094722 TI - The Epidemiology of Human Liver Tumors. AB - The epidemiology of primary liver cancer is reviewed in relation to associated lesions, e.g., cirrhosis, chronic hepatitis. Little data are available to permit evaluation of the frequency of many preneoplastic and precirrhotic lesions which per se carry a low mortality. The proportion of cirrhotic livers in which primary cancer develops varies between countries due to etiological differences. The major factors suspected of causing cirrhosis and cancer in man are: i) hepatitis B, ii) aflatoxin, and iii) alcohol. There is a miscellaneous group of hepatoproliferative disorders due to a wide range of agents which form a small proportion of the total liver problem in industrial and non-industrial states. In contrast to rodents, few liver carcinomas are related to industrial or occupational factors, apart from an association with alcoholism and low socioeconomic class. Data on benign hepatocellular proliferative lesions are inadequate, apart from steroid-induced adenomas. In contrast to rodent studies, primary liver cancers have not been associated in man with enzyme inducers, such as pesticides or drugs. In conclusion, apart from aflatoxin and hepatitis B, it has proven difficult to make valid comparisons between experimental models and human liver cancer and disease except in relation to morphological pathogenetic pathways. This discrepancy between high frequency or experimental carcinogens identified in rodents and the rarity of demonstrating similar effects due to chemical exposures in man merits further consideration. PMID- 28094723 TI - Sequential Morphological Changes in Aflatoxin B1-Induced Liver Tumors During Chronic Administration of Glutathione 1. AB - The sequential light microscopic changes in aflatoxin B1-induced liver tumors during chronic administration of glutathione were studied. The results suggest that necrosis of neoplastic hepatocytes plays an important role during the regression of tumor growth induced by glutathione. PMID- 28094726 TI - Choline Deficiency, Partial Hepatectomy, and Liver Tumors in Rats and Mice. AB - Choline deficiency (CD) increases susceptability of (he rat liver to a number of hepatocellular carcinogens with a wide diversity of structure and potency. While severe CD results in micronodular cirrhosis and enhanced tumor induction, even a mild deficiency, without cirrhosis is sufficient to result in the increased carcinogenic response. The effects of CD are in part mediated via modulation of microsomal and, possibly, cytosolic enzymes responsible for activation/deactivation of carcinogens. The B6C3F1 hybrid mouse is remarkably sensitive to initiation/promotion of liver tumors by many substances or conditions. Choline deficiency or partial hepatectomy alone, or in concert, markedly enhances liver tumor induction in the absence of any known carcinogen. These data indicate that the liver of this strain of mouse is "initiated" at or shortly after birth and can be promoted by non-carcinogenic substances or conditions. PMID- 28094727 TI - Biology of Liver Nodules. PMID- 28094728 TI - Liver Tumor Induction. AB - The significance of the development of nodular liver lesions in rodents following the administration of test agents raises several questions which could be placed in one of two general categories: diagnostic and interpretational. From a diagnostic point of view, the proper classification of liver tumors into a benign and malignant category has to be based on the direct correlation between the morphology and the biologic behavior of the lesions. Therefore, extreme care should be taken to separate the malignant tumors from the benign and the benign neoplasia from the hyperplasia. The substitution of the term "neoplastic nodule" for hyperplastic nodule in rats is misleading. Most of these nodules, when induced under special experimental conditions, may regress or remodel and thus they are not neoplastic in nature. Chronic carcinogenicity bioassays should include "stop" type of treatment leaving enough of the observational time to establish the fate of induced nodular lesions. The induction of histochemically changed foci can serve only as an indication of potential hepatocarcinogenicity and should not be equated with the induction of bona fide cancer. The biologic interpretation of nodular liver lesions, especially in mice, needs further scrutiny because these lesions have a tendency to develop spontaneously with high incidence in some strains. This characteristic then raises the question as to the mechanism by which various agents augment and/or accelerate the development of such tumors. Is this action primarily promoting or initiating in nature or does it represent the induction of tumors de novo? The answer to this dilemma may have a decisive bearing on carcinogenic risk assessment and the type of regulatory action, since the promoting agents possess a threshold effect and the promoted changes may regress following withdrawal of treatment. The interpretation of hepatocarcinogenesis is further complicated by the fact that several factors, such as sex hormonal environment, increased mitotic activity following an excessive loss of parenchymal cells, degree of caloric intake, enzymatic complement, and animals' age at the time of the exposure to a test agent, may influence the outcome of liver tumor development by modulating "initiation" and/or "promotion" of carcinogenesis. Broad fluctuation in the historic incidence of liver tumors further compounds the complexity of the proper bioassay interpretation. The specifically designed experiments may have the objective to explore predominantly the initiating or promoting effects of the agent. Such protocols should be used whenever necessary to differentiate between these two mechanisms of action. In the Caucasians, the "spontaneous" development of the primary hepatocellular tumors is rare. The majority of these tumors are malignant and rapidly fatal. According to some human pathologists, the benign variety of liver tumors is rare and it does not represent necessarily a premalignant stage in tumor development. Carcinoma of the liver may occur in infancy, especially in males before the age of 2 years. This suggests a genetic causation or carcinogenic exposure in utero. One of the geographic factors which significantly enhances the incidence of hepatocellular carcinoma in humans is exposure to aflatoxin B1 which is apparently potentiated by concurrent liver cirrhosis. Because many more agents have been found to be hepatocarcinogenic in mice and rats than in men, a question arises as to the direct relevance of rodent studies to humans. A balanced assessment of the carcinogenicity of the agent could only be reached in considering both the pharmacokinetics and the development of malignant neoplasia in other organs. In the case of positive carcinogenicity assessment, the outcome of the mutagenicity bioassays can suggest genic (genotoxic) or paragenic (epigenetic) mode of action in mammalian systems. PMID- 28094732 TI - Proliferative liver lesions and sex steroids in rats. AB - In standard two year tumorigenicity studies some gestagens, alone or in combination with an estrogen have been shown to produce proliferative liver lesions (PLL) in rats. Estrogens in general have not produced PLLs; for ethinyl estradiol the situation is equivocal. The steroids which increase the incidence of PLLs have not been shown to have the characteristics usually associated with classical hepatocarcinogens such as diethylnitrosamine (e.g. negative mutagenicity and cytoxicity, failure to bind covalently to DNA). Therefore, another mechanism must be assumed. A possible explanation is given by the ability demonstrated for a few steroids (mestranol alone or in combination with norethindrone, ethinylestradiol) to promote preneoplastic islands induced by diethylnitrosamine, resulting in an increase in tumor incidence over rats given only the carcinogen. Spontaneous preneoplastic islands in rats occur in various incidence in different strains and we have recently shown that their reaction to steroids-enhanced proliferation-is the same as the effect on preneoplastic islands produced by classical carcinogens. Sex steroids also enhance the growth or normal hepatocytes. It, therefore, seems reasonable to assume that sex steroids produce PLLs by acting on spontaneous preneoplastic lesions and not by the mechanisms usually associated with classical carcinogens. Extrapolating the incidence of PLLs in rats to a risk in humans may be highly misleading because of different pharmacokinetic patterns. Even in rats treated orally for two years with sex steroids dosed as multiples of the human contraceptive dose, resorption and biovailability may vary by a factor of 10 or more. It is, therefore, inappropriate to state that one sex steroid is more active in the production of PLLs than another, unless the data from pharmacokinetic studies are taken into account. Available evidence shows that sex steroids act as tumor promotors and enhance the growth of normal hepatocytes. It is extremely doubtful whether a sex steroid producing PLLs in the rat after two years of oral treatment can be classified as an initiating tumorigen for the rat. Substantial risk for humans cannot be inferred, because of the high incidence of spontaneous preneoplastic lesions in rats, and because of the very high sensitivity of the rat liver to a variety of chemically unrelated compounds including sex steroids. PMID- 28094735 TI - The Gelweave Valsalva Graft to Better Reconstruct the Anatomy of the Aortic Root. AB - The Bentall procedure introduced in 1968 represents an undisputed cure to treat multiple pathologies involving the aortic valve and the ascending thoracic aorta. Over the years, multiple modifications have been introduced as well as a standardized approach to the operation with the goal to prevent long-term adverse events. The Gelweave Valsalva graft provides a novel manner to more efficiently reconstruct the anatomy of the aortic root either with a valve-sparing procedure or with the implantation of a valved conduit (bioprosthesis or mechanical valve). The prosthesis holds three sections: the collar anchoring the valve; the skirt mimicking the Valsalva, which is suitable for the anastomoses with the coronary arteries; and the main body of the graft, which is designed to replace the ascending aorta. The Gelweave Valsalva graft allows the Bentall operation to be standardized, and it provides a potential for longer durability with reduced adverse events. PMID- 28094736 TI - Characterization of Patient Expectations and Satisfaction after Total Hip Arthroplasty. AB - We conducted a prospective multicenter study in which outcome-related expectations of 236 primary total hip arthroplasty patients were determined. Clinical surveys and radiographs were used to determine the relationship between postoperative level of patient satisfaction and patient-reported and radiographic outcomes. At 1 year, 82.6% of expectations were achieved, most of the time with high satisfaction (89.3%). Younger, lower body-mass index, male patients were more likely to expect the surgery to benefit "return to work" and "sexual function", whereas older, heavier patients, selected "elimination of assistive devices" and "independence in daily activities". The ability of the patient to meet their expectations fully did not correlate directly with level of satisfaction or clinical outcomes, suggesting limitations in current clinical surveys. The characterization of patient expectations is essential in providing patient-centered care. PMID- 28094737 TI - Osteoinductive Activity of DFDBA Materials versus Growth Factors on Gene Expression of MG-63 Cells: An In Vitro Study. AB - Guided bone regeneration using demineralized freeze-dried bone allograft (DFDBA) and growth factors (GFs) is a current goal in implant dentistry because of their potential osteoinductive abilities. Regarding controversial results, the purpose of this study was to compare the osteoinductivity of three different DFDBAs from two different banks with two different GFs: transforming growth factor-beta (TGF beta) and platelet-derived growth factor (PDGF). MG-63 osteoblast-like cells were exposed to two different concentration of commercial DFDBAs (10 and 20 mg/mL) and growth factors (5 and 10 ng/mL). Cell viability and proliferation were evaluated using a quantitative MTT assay (24 and 72 hours after treatment). For the assessment of cell differentiation, the expression of osteogenic marker genes was evaluated using quantitative real-time polymerase chain reaction 72 hours after treatment. Cell viability and proliferation in different concentrations of GFs was similar but significantly different in the DFDBA groups. Although water soluble materials released from DFDBAs reduced viability and even caused cytotoxicity (viability <70%) in first 24 hours after treatment, increased viability and proliferation were seen after 72 hours. Dose-dependent up regulation of osteocalcin (OC) was seen in the two DFDBA groups and in TGF-beta treated cells. In contrast, dose-dependent down-regulation of OC was seen in PDGF treated cells. The results show that induction of osteogenic differentiation (osteoinduction) at higher concentrations of DFDBAs (with the exception of one group) is more rapid than in the GF groups. In addition, TGF-beta at higher concentrations but PDGF at lower concentrations were associated with better results. PMID- 28094738 TI - A Cost-Effective Technique for Spinal Instrumentation in the Treatment of Adolescent Idiopathic Scoliosis. AB - Surgical treatment for adolescent idiopathic scoliosis (AIS) has evolved over the past decades to the point where instrumented arthrodesis with all pedicle screw and rod constructs is commonplace. Although these constructs provide superb correction and fixation, their financial burden is substantial. Here, we present a more cost-effective technique using a combination of pedicle screws (serving as the construct base), a sagittal precontoured unit rod, and sublaminar wires to provide segmental correction for the surgical treatment of AIS. Retrospective analyses of 42 patients treated with this construct were reviewed with a minimum 2-year follow-up. Correction in both coronal and sagittal planes was assessed radiographically and blood loss, operative time, complications, and cost were reviewed from hospital records. We conclude that this technique provides comparable correction to all pedicle screw constructs with similar blood loss and operative time, but with substantially decreased implant cost. The mean implant cost was $8910.83 +/- $184.26. PMID- 28094739 TI - Astym(r) Therapy for the Management of Recalcitrant Knee Joint Stiffness after Total Knee Arthroplasty. AB - Knee stiffness is a common complication after total knee arthroplasty (TKA). Despite studies published on the surgical management of reduced range of motion (ROM) after TKA, there is limited evidence on the nonoperative management of joint and soft tissue imbalances possibly contributing to reduced knee ROM. This report assesses changes in ROM, pain, function, and patellar tendon length after Astym(r) joint mobilization use. A 38-year-old male professional skier had a right TKA 3 months before presentation with 2 subsequent manipulations under anesthesia secondary to persistent knee stiffness. He had patellar baja on radiograph, a reduced arc of ROM, reduced patellar mobility and muscular extensibility, and pain to palpation along the patellar tendon. He had 12 visits of physical therapy with the use of Astym(r), patellar mobilization, and tibio femoral mobilizations with movement. The patient also used a customized knee device at home for prolonged knee extension stretching. The patient was treated for 12 visits, along with home use of customized bracing for knee extension. Significant improvements were seen in pain, function, and ROM. He returned to work full-time, ambulated prolonged distances, and negotiated stairs pain-free. He also demonstrated resolution of patellar baja radiographically. Conservative management of recalcitrant knee joint stiffness after primary TKA can be effective in restoring knee mobility and reducing pain and activity limitation. A multimodal approach using Astym(r) treatment, customized knee bracing, and targeted joint mobilization can be effective in resolving knee joint stiffness. PMID- 28094740 TI - Strength of Syndesmosis Fixation: Two TightRope versus One TightRope with Plate and-Screw Construct. AB - Injuries involving the distal tibiofibular syndesmosis can lead to critical destabilization of the ankle mortise. Although specific indications for operative fixation remain unclear, accurate reduction of the syndesmosis has been correlated with the best functional outcomes. The purpose of this study was to evaluate the maximum torque and rotation to failure after fixation with a novel construct. Seven pairs (14 ankles) of embalmed cadaveric lower legs, disarticulated at the knee, were obtained. Each pair was randomly assigned to receive either two TightRopes (Arthrex) or a plate-and-screw construct with one TightRope. All samples were mechanically tested in torsion to determine peak torque, torsional stiffness, and the maximum rotation angle at which failure occurred. Differences between the groups were compared using paired Student's t test. The maximum torque to failure after fixation was not significantly different between the two TightRopes (28.8 N*m; range, 7.3-49.7 N*m) and the one TightRope group (29.5 N*m; range, 9.2-44.9 N*m; p = 0.92). The maximum rotation to fracture after fixation was not significantly different between the two TightRopes (33.3 degrees; range, 21.6-57.0 degrees) and one TightRope group (38.6 degrees; range, 23.0-73.9 degrees). All specimens failed with the fracture of the fibula at the level of the inferior syndesmotic screw. The similar load to failure of the two TightRope and the one TightRope and plate-and-screw plate suggested similar stiffness between the two constructs. The addition of the plate may improve distribution of forces at the level of syndesmosis, reducing stress risers and decreasing the risk of failure, as demonstrated by a lower rotation to failure of the one TightRope with plate-and-screw construct. In addition, this construct is not likely to not be associated with any substantial cost increase. Further clinical studies may further elucidate the role of plate and/or TightRope augmentation to syndesmosis fixation. PMID- 28094741 TI - A Biomechanical Comparison of Different Tendon Repair Techniques. AB - Previous studies have examined multiple suture techniques for the repair of ruptured tendons. In this study, we investigated how the two- and four-stranded Krackow suture weave techniques compared with a novel Krackow/Bunnell suture technique. Our hypothesis was that the Krackow/Bunnell suture would have greater strength compared with the two- and four-stranded Krackow suture in terms of resistance to pullout from the muscle tendon. Thirty fresh bovine Achilles tendons were assigned randomly to three groups: (1) two-stranded Krackow, (2) fourstranded Krackow, and (3) the Krackow/Bunnell combination. After suture placement, all specimens were subjected to initial cyclic loading (0-200 N for 200 cycles) and then the tension to failure force defined as the pullout through the muscle tendon was evaluated. Significantly greater deformation before suture failure was seen in the Krackow/Bunnell group compared with the four-stranded Krackow construct (36.2 vs. 28.7 mm, p = 0.009), as well as greater energy required to rupture the suture (4635 vs. 3346 N/mm; p = 0.016). There was no significant difference with regard to the force to failure between the two groups (four-stranded Krackow vs. Krackow/Bunnell). The two-stranded Krackow was found to be inferior to both the four-stranded Krakow and the Krakow/Bunnell techniques with regard to load to failure. We have found that the Krackow/Bunnell suture technique is at least comparable to, if not superior to, the four-stranded Krackow technique with regard to deformation before suture failure and energy required to rupture the tendon. Therefore, the Krackow/Bunnell technique may be an optimal construct if the surgeon is concerned about suture pullout through the tendon; however, future studies evaluating this technique in the clinical setting are required before making any final conclusions for patient use. PMID- 28094742 TI - Upper Extremity Nerve Function and Pain in Human Volunteers with Narrow versus Wide Tourniquets. AB - Nerve injury is a serious potential complication associated with clinical use of tourniquets during surgery. A novel narrow, single-use silicon ring tourniquet has been introduced, which may cause less nerve compression and provide a larger field of surgical exposure than standard wide tourniquets. We investigated both types of tourniquets in the non-dominant proximal upper arm of 15 healthy human volunteers. Pain and neurological effects were assessed during 15 minute trials with each tourniquet applied 1 week apart without anesthesia according to the manufacturers' recommendations. Median nerve function was studied using the pressure-specified sensory device, an instrumented two-point discriminator, and pain was assessed by two validated instruments. Skin sores, redness, nerve damage, or neurological complications did not occur in either group. Subjects reported more pain with the narrow tourniquet; however, measurable effect on median nerve function was the same in both groups. Tourniquet application with the narrow device was more efficient, the device was easier to use, and larger surgical field exposure was obtained. We conclude that the sensory deficit with the use of narrow tourniquets is not greater than that observed with pneumatic/wide tourniquets. PMID- 28094743 TI - Relationship between Genetic Polymorphisms with Periodontitis and Peri Implantitis in the Iranian Population: A Literature Review. AB - Periodontitis is an infectious disease of the tooth-supporting tissues. Specific periodontal pathogens trigger inflammatory responses and result in progressive bone loss, which eventually leads to exfoliation of teeth. Periimplantitis is the destructive inflammatory process affecting the soft and hard tissues surrounding dental implants. The periodontal pathogens found around failing implants are very similar to those associated with various forms of periodontal diseases. Genetic susceptibility has been known to be an important risk factor for periodontitis and periimplantitis and there have been numerous studies evaluating this in different populations. Many gene polymorphisms may influence individual susceptibility to periodontitis and peri-implantitis. We conducted a review of the literature for gene polymorphisms associated with periodontitis and peri implantitis susceptibility in the Iranian population. A comprehensive search of the literature on human studies in English, published from January 2004 to February 2015 in PubMed database and Google scholar was performed using the key words "periodontitis," "peri-implantitis," "gene polymorphisms," and "Iranian population." Sixty-six studies were identified; 33 articles were excluded based on review of titles and abstracts. Thirty articles were eligible and had the full text evaluated. Further studies are needed to get more inclusive perception of the influence of gene polymorphisms in periodontitis and peri-implantitis. PMID- 28094744 TI - Genoprotective Capacity of Alternatively Cultivated Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes), Basidiocarps. AB - Ganoderma lucidum is traditionally used in Eastern medicine to preserve vitality, promote longevity, and treat disease. It possesses immunomodulatory, antitumor, antimicrobial, and antiaging activities, among others, but one of the most important is its antioxidant property, which is the basis for other effects, because free radicals trigger many diseases. The substrate commonly used for commercial cultivation of G. lucidum is not environmentally friendly nor economically justified, so there is a need to find new alternative substrates. The aim of this study was to analyze the effect of substrate composition on the bioactivity of G. lucidum basidiocarps. G. lucidum was cultivated on 2 different substrates: (1) a mixture of wheat straw, grapevine branches, and wheat bran, and (2) wheat straw. Commercial fruiting bodies, cultivated on oak sawdust, were used as the control. 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging ability, total phenols, and flavonoid content were determined spectrophotometrically to define the antioxidative potential of basidiocarp extracts. The comet test was performed to detect the degree of DNA damage in the cells that were exposed to G. lucidum extracts before and after the effect of oxidants. Higher antioxidative potential was observed for the extract of G. lucidum basidiocarps cultivated on wheat straw compared with that from the mixed substrate and especially with commercial ones. The alternatively cultivated basidiocarps also showed stronger antigenotoxic potential compared with commercial ones. The study showed that fruiting bodies produced on wheat straw, one of the most accessible and cheapest crop residues, are more potent antioxidant and antigenotoxic agents than commercially cultivated ones. PMID- 28094745 TI - Purification, Characterization, Antioxidation, and Antiaging Properties of Exopolysaccharides and Endopolysaccharides of the Royal Sun Medicinal Mushroom, Agaricus brasiliensis (Agaricomycetes). AB - Exopolysaccharides (ExPSs) and endopolysaccharides (EnPSs) were isolated from mycelia and culture medium of Agaricus brasiliensis. Four polysaccharide fractions (ExPS-1-2, ExPS-2, EnPS-1, and EnPS-2) were puri!fied from ExPSs and EnPSs using diethylaminoethyl anion exchange and a Sephadex G-100 gel filtration column, respectively, and their physicochemical properties were analyzed and evaluated to determine antioxidant activity. The results showed that rhamnose and mannose were the main monosaccharides of the polysaccharide fractions. ExPS-2 and EnPS-2 were acidic polysaccharide fractions and showed higher scavenging effects on 1,1-diphenyl-2-picryl- hydrazyl and hydroxyl radicals, and had higher reducing power in the in vitro antioxidant assays. In addition, the malondialdehyde contents, the total antioxidant capacity, and the alanine transaminase activity were also assessed to determine the antiaging effects; ExPSs showed more antiaging effects compared with EnPSs. The results suggest that polysaccharides extracted from A. brasiliensis have significant potential as natural antioxidants and antiaging agents. PMID- 28094746 TI - Effect of Polysaccharide from Cordyceps militaris (Ascomycetes) on Physical Fatigue Induced by Forced Swimming. AB - Cordyceps militaris is the one of the most important medicinal mushrooms, widely used in East Asian countries. Polysaccharide is considered to be the principal active component in C. militaris and has a wide range of biological and pharmacological properties. This study was undertaken to investigate the effect of polysaccharide from C. militaris (PCM) on physical fatigue induced in animals through a forced swimming test. The mice were divided into 4 groups receiving 28 days' treatment with drinking water (exercise control) or low-, medium-, and high dose PCM (40, 80, and 160 mg/kg/day, respectively). After 28 days, the mice were subjected to the forced swimming test; the exhaustive swimming time was measured and fatigue-related biochemical parameters, including serum lactic acid, urea nitrogen, creatine kinase, alanine aminotransferase, aspartate aminotransferase, superoxide dismutase, glutathi- one peroxidase, catalase, malondialdehyde, liver glycogen, and muscle glycogen, were analyzed. The results showed that PCM could significantly prolong the exhaustive swimming time of mice; decrease concentrations of serum lactic acid, urea nitrogen, creatine kinase, aspartate aminotransferase, alanine aminotransferase, and malondialdehyde; and increase liver and muscle glycogen contents and the concentrations of serum superoxide dismutase, glutathione per- oxidase, and catalase. The data suggest that PCM has an antifatigue effect, and it might become a new functional food or medicine for fatigue resistance. PMID- 28094747 TI - Investigation of the Tiger Milk Medicinal Mushroom, Lignosus rhinocerotis (Agaricomycetes), as an Antiulcer Agent. AB - The aim of this study was to determine the antiulcer activity of Lignosus rhinocerotis in rats. A total of 48 Sprague-Dawley rats were used in ethanol induced, aspirin-induced, and water immersion-restraint stress-induced ulcer models. Rats were equally divided into 4 groups for each model and orally administered 5 mL/kg distilled water, 20 mg/kg omeprazole, as well as 250 and 500 mg/kg of L. rhinocerotis powder. L. rhinocerotis powder at both 250 and 500 mg/kg doses demonstrated significant (P < 0.05) protection against gastric ulceration in all the induced ulcer models. Histological studies revealed severe damage and hemorrhage of gastric mucosa in the negative control group for all ulcer-induced models. The study suggests that L. rhinocerotis powder possesses dose-dependent antiulcer activity in the gastric mucosa, as ascertained grossly and histologically, compared with the negative control groups. PMID- 28094748 TI - Renoprotective Effects of Shout Camphor Medicinal Mushroom (Taiwanofungus camphorates, Basidiomycetes) Mycelia on Several Media in Mice with Chronic Kidney Disease. AB - Taiwanofungus camphoratus has been widely used in Taiwan as a folk medicine to prevent and treat liver diseases, diarrhea, abdominal pain, itchy skin, and hypertension. Recent studies have shown that T. camphoratus mycelia extracts exert anti-inflammatory and antioxidant effects on some types of renal disease, but the effect of T. camphoratus mycelia on chronic kidney disease (CKD) remains unclear. In this study we used the Bioresource Collection and Research Center (BCRC) medium and modified media (e.g., BCRC+A, HKS1, and HKS1+A media) to incubate T. camphorates mycelia and detect the feasible benefits of renal protection in mice with CKD. Five groups of mice with a partial nephrectomy (each mouse weighed approximately 30 g) received a daily administration of different media-treated T. camphoratus mycelia water solutions (3 mg dried mycelia dissolved in 0.3 mL water) by oral gavage for 30 days, while a control group received distilled water. The results show that progressive increased blood urea nitrogen and serum creatinine were significantly inhibited in the HKS1+A group on days 10 and 30. Plasma total protein was effectively increased in the HKS1 and HKS1+A groups. The BCRC and BCRC+A groups exhibited no obvious improvement in renal function. The results suggest that the HKS1+A medium provides the optimal effect in preventing the deterioration of kidney function and might have a renoprotective effect on CKD. PMID- 28094749 TI - High-Performance Liquid Chromatography Studies to Estimate Ergosterol Content at Different Developmental Stages of the Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes). AB - Ganoderma lucidum has been widely used as a source of potent nutraceutical products. This study was planned to identify and characterize the role of ergosterol in the developmental process of G. lucidum. Four strains of G. lucidum (GL-I-IV) showed a gradual increase in biomass (from 25.52 to 31.72 g) after 3 weeks of growth in mushroom complete medium broth, with maximum biomass observed for strain GL-III. Upon cultivation of G. lucidum strains on wheat straw supplemented with 5% wheat bran, maximum biological efficiency was recorded for the GL-I strain (31.23%), followed by GL-II (26.73%); the number of fruiting bodies were 927 and 693, each weighing 33.7 and 38.6 g, respectively. The amount of ergosterol in the Ganoderma test strains varied among the strains and at different developmental stages, namely, the vegetative mycelium, spawn run, pinhead, and fruiting body phases. The maximum ergosterol content was produced by the GL-I strain during the vegetative mycelium (4601 p.g/g) and reproductive fruiting body (7009 p.g/g) stages. However, strain GL-IV followed by strain GL-II exhibited maximum ergosterol content in the spawn run stage. The ergosterol content was better for GL-II at the pinhead stage. This report indicates that ergosterol content varies among the test strains. Moreover, it increases with each stage of the cultivation process, that is, from spawn run to pinhead to and fruiting body formation. PMID- 28094750 TI - Taxonomical Establishment and Compositional Studies of a New Cordyceps (Ascomycetes) Species from the Northwest Himalayas (India). AB - During a frequent survey in the northwest Indian Himalayan region, a new species Cordyceps macleodganensis-was encountered. This species is described on the basis of its macromorphological features, microscopic details, and internal transcribed spacer sequencing. This species showed only 90% resemblance to Cordyceps gracilis. The chemical composition of the mycelium showed protein (14.95 +/- 0.2%) and carbohydrates (59.21 +/- 3.8%) as the major nutrients. This species showed appreciable amounts of P-carotene, lycopene, phenolic compounds, polysaccharides, and flavonoids. Mycelial culture of this species showed higher effectiveness for ferric-reducing antioxidant power, DPPH radical scavenging activity, ferrous ion-chelating activity, and scavenging ability on superoxide anion-derived radicals, calculated by half-maximal effective concentrations. PMID- 28094751 TI - Downregulation of Ethylene Production Increases Mycelial Growth and Primordia Formation in the Button Culinary-Medicinal Mushroom, Agaricus bisporus (Agaricomycetes). AB - Ethylene biosynthesis and function in Agaricus bisporus (the button mushroom) remain uncertain. The enzyme activities of 1-aminocyclopropane-1-carboxylate (ACC) synthase (ACS) and ACC oxidase (ACO) were detectable in A. bisporus AS2796 and inhibited by alpha-aminooxyacetic acid and Co2+. We cloned and sequenced 2 ACS genes (Ab-ACS1 and Ab-ACS2) and 1 ACO gene (Ab-ACO) from the mushroom strain. Ab-ACS1 and Ab-ACS2 demonstrated low amino acid sequence similarity. Ab-ACO demonstrated an amino acid sequence completely identical to that of ACO1_AGABI from A. bisporus. Antisense ACO significantly reduced ACO gene expression level, ACO enzyme activity, and ethylene production in the mushroom transformants. The transformants grew faster than the wild-type strain in sterilized compost and normally formed primordia when cultivated in sterilized compost with the sterilized casing vermiculite, but the wild-type strain did not. Our results show that ethylene is synthesized in button mushrooms via the ACC pathway. Ethylene inhibited button mushroom mycelial growth and development. PMID- 28094752 TI - Production of Basidiomata and Ligninolytic Enzymes by the Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes), in Licuri (Syagrus coronata) Wastes in Brazil. AB - Ganoderma lucidum is a medicinal mushroom with different forms of bioactivity that has been used in popular medicine for centuries. This study aimed to test the application of agricultural wastes (fruit shells, leaves, and bracts) from the endemic Brazilian palm tree Syagrus coronata (licuri) as substrates for the production of G. lucidum basidiomata and ligninolytic enzymes via solid-state fermentation. The best culture conditions were the same for all substrates (pH 6.5, carbon-to-nitrogen ratio = 40, and temperature 30 degrees C) and were established from preliminary assays. The yield was not significantly different for bracts (33.53 g/kg) and leaves (37.48 g/kg), nor for the biological efficiency in these same substrates: bracts, 3.35%; leaves, 3.75%. The highest laccase (13.80 U/L) and manganese peroxidase (14.92 U/L) activities were achieved after 14 and 28 days of incubation, respectively, using bracts as the substrate. Licuri residues are then potential substrates to be used in the bioconversion process for mycelia, basidiomata, and ligninolytic enzyme production by G. lucidum. PMID- 28094753 TI - Quantifying cutaneous adverse effects of systemic glucocorticoids in patients with rheumatoid arthritis: a cross-sectional cohort study. AB - OBJECTIVES: EULAR guidelines state that adverse effects (AEs) of glucocorticoid (GC) therapy should be considered and discussed with the patient before treatment is initiated. However, reliable quantitative data, especially on cutaneous AEs of low-to-medium dose GCs are lacking. We performed a study assessing the occurrence of cutaneous AEs of GCs and its association with current and cumulative GC doses in patients with rheumatoid arthritis (RA). METHODS: In a cross-sectional study performed in 2 outpatient rheumatology centres, 381 RA patients were enrolled. They were classed into 4 groups, according their mean daily dose during the past 12 months: 0 mg (n=87), <5mg (n=108), 5-7.5 mg (n=130), and >7.5 mg (n=56) of prednisone equivalent. AEs of GC on the skin were assessed by physical examination using a predefined scoring system, and by patients' self-assessments. Data were analysed according GC dose categories and cumulative doses. RESULTS: Cushingoid habitus, easy bruising, skin atrophy, and impaired wound healing as reported by patients occurred significantly more frequently in those using a GC the past 12 months, compared to those not using a GC. At physicians' assessments, only Cushingoid habitus and ecchymosis were more prevalent in GC users. The prevalence of these AEs was statistically significantly positively associated with current and cumulative GC dose. There was low occurrence of abnormal stretch marks, acne, perioral dermatitis, alopecia and hirsutism, which were not correlated with GC use. CONCLUSIONS: Certain GC-associated cutaneous AEs are common in RA, but other AEs of GC occur infrequently at the low-to-medium GC doses used in RA. PMID- 28094755 TI - Profile of initial drug therapy in paediatric systemic lupus erythematosus in Finland, 2000-2007. PMID- 28094754 TI - Comparable therapeutic potential of umbilical cord mesenchymal stem cells in collagen-induced arthritis to TNF inhibitor or anti-CD20 treatment. AB - OBJECTIVES: The effects of mesenchymal stem cell (MSC) transplantation on established collagen-induced arthritis (CIA) were evaluated and compared to biologic therapies. METHODS: CIA was induced with the immunisation of type II collagen (CII) in DBA/1 mice. Human umbilical cord MSC, anti-TNF antibody, rhTNFR:Fc fusion protein and anti-CD20 antibody were respectively injected intraperitoneally into CIA mice. Arthritis severity was assessed by clinical and histological scoring. The frequencies of lymphocytes in spleen were analysed, and serum concentrations of cytokines and autoantibody to CII were also measured. The ability of MSC to regulate the balance of T helper cell subsets in CII stimulated CIA CD4+ T cells was assessed in vitro. RESULTS: MSC treatment significantly decreased the severity of arthritis, which was comparable to biologic treatments. All the treatments down-regulated Th1 subset. Except anti-CD20 all the treatments decreased Th17 subset. MSC treatment enhanced the proportion of regulatory T (Treg) cells and inhibited the generation of T follicular helper (Tfh) cells. The decrease in autoantibody level was detectable in all the treated groups. In vitro MSC induced Foxp3+ T cells, and down-regulated IL-17+, IFNgamma+ T cells and pathogenic IL-17+IFNgamma+ or IL-17+Foxp3+ T cells. MSC also reduced the secretion of IL-1beta, IL-6, IL-17 and TNF-alpha among collagen-specific T cells. CONCLUSIONS: MSC show comparable effects to the known biologic treatments and correct immune imbalance in CIA. MSC might provide a promising approach for the treatment of rheumatoid arthritis. PMID- 28094756 TI - Treatment modifying factors of biologics for psoriatic arthritis: a systematic review and Bayesian meta-regression. AB - OBJECTIVES: The aim of this study was to explore factors that modify treatment effects of non-conventional biologics versus placebo in patients with psoriatic arthritis. METHODS: A systematic literature review and meta-regression was conducted. The biologics included etanercept, infliximab, adalimumab, golimumab, certolizumab, ustekinumab, tocilizumab, anakinra, abatacept, rituximab, and secukinumab. Outcomes included American College of Rheumatology (ACR) 20 and 50, Psoriasis Area Severity Index (PASI) 75, and 36-Item Short Form Health Survey (SF 36) Physical and Mental Component Summaries (PCS and MCS). RESULTS: Twelve RCTs were eligible for meta-regression. Treatment effects for ACR-20 at 12 weeks were higher in trials with longer disease durations (OR=2.94), and lower in trials enrolling older patients (OR=0.48), and those recently published (OR=0.49). Treatment effects for ACR-50 at 12 weeks were higher in trials with more males (OR=2.27), but lower in trials with high prior anti-TNF use (OR=0.28) and recently published trials (OR=0.37). For PASI-75, trials with more male patients (24 weeks: OR=2.56), and with higher swollen and tender joint counts (12 weeks: OR=8.33; 24 weeks: OR=14.44) showed higher treatment effects, and trials with high prior anti-TNF use had lower effects (OR=0.41). Treatment effects for SF-36 PCS at 24 weeks were higher in trials with longer psoriasis disease durations (OR=2.95) and PsA disease durations (OR=4.76), and those published earlier (OR=4.19). CONCLUSIONS: Our analyses show that differences in baseline characteristics may explain some of the differences in response to biologics versus placebo across different trials. Accounting for these factors in future studies will likely be important. PMID- 28094757 TI - Which joints and why do rheumatologists scan in rheumatoid arthritis by ultrasonography? A real life experience. AB - OBJECTIVES: Ultrasonography (US) has been demonstrated to improve assessment of synovitis and disease activity in rheumatoid arthritis (RA). However, the utility and feasibility of US in RA in clinical practice in real life is not known. We aimed to investigate: i) the indications for performing US in RA in daily practice; and ii) whether the number of scanned joints varies according to the purpose. METHODS: Consecutive patients who had a US scan either for diagnosis or follow-up for RA from 5 centres were recruited. The sonographers were asked to mark the joints that had a US scan and grade their findings. Descriptive analysis was applied to find out the sites and the number of joints scanned and compared according to the indications of US. RESULTS: Two hundred consecutive patients were recruited. The most common indication was assessing disease activity (48.5%) followed by diagnosis (45.5 %). Wrists (66%) and MCPs (63.5) were the most frequently scanned joints followed by knees (26%), PIPs (20%). The number of joints scanned by US was significantly higher when performed for diagnostic purposes as compared to assessing disease activity and guidance for injections (p=0.001). CONCLUSIONS: The current data highlight differences between the numbers of joints for which that the clinician feels necessary to perform US in real life. This observation may be a guide when providing recommendations regarding which joints need to be scanned according to the indication. PMID- 28094758 TI - Exosomes isolated from serum of systemic sclerosis patients display alterations in their content of profibrotic and antifibrotic microRNA and induce a profibrotic phenotype in cultured normal dermal fibroblasts. AB - OBJECTIVES: Exosomes are lipid bilayer-bound microvesicles containing various macromolecules including numerous microRNA (miRNA). Exosomes mediate intercellular communication by fusing and releasing their macromolecular content into target cells. Here, we analysed the content of profibrotic and antifibrotic miRNAs in exosomes isolated from the serum of systemic sclerosis (SSc) patients and tested their ability to induce a profibrotic phenotype in normal human dermal fibroblasts in vitro. METHODS: Exosomes were isolated from serum from patients with limited cutaneous or diffuse cutaneous SSc and were characterised by Nanosight Particle Tracking Analysis, exosome antibody arrays, and transmission electron microscopy. The content of nine profibrotic and eighteen antifibrotic miRNA was assessed in the isolated exosomes by semiquantitative real time PCR. The effects of the isolated exosomes on cultured normal human dermal fibroblasts were assessed by real time PCR and Western blotting. RESULTS: The isolated serum exosomes displayed the expected exosome size and morphology and contained characteristic exosome proteins. Six profibrotic miRNAs were increased and ten antifibrotic miRNAs were decreased in SSc serum exosomes compared to normal serum exosomes. The levels of eight miRNA were significantly different between exosomes from limited and diffuse SSc. Exosomes isolated from both limited or diffuse SSc patients caused dose-dependent stimulation of profibrotic gene expression and type I collagen and fibronectin production and secretion in normal human dermal fibroblasts in vitro. CONCLUSIONS: Serum exosomes from SSc patients contain miRNA displaying a markedly profibrotic profile and induce a profibrotic phenotype in target normal fibroblasts in vitro suggesting a plausible mechanism for the extension of the fibrotic SSc process to non-affected tissues. PMID- 28094759 TI - Thymic findings before and after autologous stem cell transplantation for severe systemic sclerosis: a retrospective study using computed tomography in the pre- and post-transplantation setting. PMID- 28094760 TI - Treat-to-target biologic therapy in patients with rheumatoid arthritis is more efficacious and safe compared to delayed initiation of biologics: a real-world study. AB - OBJECTIVES: Rheumatoid arthritis (RA) is a chronic, devastating disease. Treat-to target strategy (T2T) more than the usual care, reduces disease activity by using aggressively all therapeutic options. The aim of the study was to evaluate our hypothesis that T2T strategy using biologic disease-modifying anti-rheumatic drugs (bDMARDs), when needed, is also safer than the usual care characterised by delayed initiation of bDMARDs. METHODS: Disease activity was regularly measured by DAS-28 until the end of treatment with the first bDMARD. All adverse events (AEs) and their severity were recorded. Cox proportional-hazards models were performed examining the association of treatment groups, with the risk of first AE. RESULTS: There were 113 patients in T2T and 250 patients in usual care group. The likelihood (adjusted hazard ratio, HR) of achieving remission or LDA was 71% higher in the T2T group than in the usual care group, as it has been already shown by others. The novel finding of our work was that AEs, including cancers, were less frequent in the T2T group with the corresponding HRs being less than 0.50 for serious AEs, infections and serious infections (significant or marginally non-significant results). There were 15 new cancer cases in usual care and 1 in T2T group (IR 1.99 vs. 0.4, p=0.027). CONCLUSIONS: Treat-to-target treatment with bDMARDs offers a safer, rapid and better long-term outcome to patients with RA. PMID- 28094762 TI - Persistent Mullerian Duct Syndrome with Transverse Testicular Ectopia: A Novel Anti-Mullerian Hormone Receptor Mutation. AB - Persistent Mullerian duct syndrome is the result of either anti-Mullerian hormone (AMH) deficiency or AMH receptor resistance. A long tubular structure was palpated during the physical examination of a 13-month-old male patient who had presented with bilateral undescended testes. At physical examination, the testes were not palpable. The patient's karyotype was XY, SRY (+), and his AMH level was 22 ng/mol. Structures suggestive of ovaries, a uterus, and fallopian tubes were observed during the laparoscopic examination of the ectopic testis. AMHR2 gene sequence analysis performed with a preliminary diagnosis of AMH receptor resistance revealed a previously unreported homozygous c.24G>A (p.W8X) mutation. The patient was assessed as a case of AMH receptor resistance. Orchiopexy was performed. PMID- 28094761 TI - Homeodomain protein Otp affects developmental neuropeptide switching in oxytocin neurons associated with a long-term effect on social behavior. AB - Proper response to stress and social stimuli depends on orchestrated development of hypothalamic neuronal circuits. Here we address the effects of the developmental transcription factor orthopedia (Otp) on hypothalamic development and function. We show that developmental mutations in the zebrafish paralogous gene otpa but not otpb affect both stress response and social preference. These behavioral phenotypes were associated with developmental alterations in oxytocinergic (OXT) neurons. Thus, otpa and otpb differentially regulate neuropeptide switching in a newly identified subset of OXT neurons that co express the corticotropin-releasing hormone (CRH). Single-cell analysis revealed that these neurons project mostly to the hindbrain and spinal cord. Ablation of this neuronal subset specifically reduced adult social preference without affecting stress behavior, thereby uncoupling the contribution of a specific OXT cluster to social behavior from the general otpa-/- deficits. Our findings reveal a new role for Otp in controlling developmental neuropeptide balance in a discrete OXT circuit whose disrupted development affects social behavior. PMID- 28094763 TI - Measuring the effect of femoral malrotation on knee joint biomechanics for total knee arthroplasty using computational simulation. AB - OBJECTIVES: Malrotation of the femoral component can result in post-operative complications in total knee arthroplasty (TKA), including patellar maltracking. Therefore, we used computational simulation to investigate the influence of femoral malrotation on contact stresses on the polyethylene (PE) insert and on the patellar button as well as on the forces on the collateral ligaments. MATERIALS AND METHODS: Validated finite element (FE) models, for internal and external malrotations from 0 degrees to 10 degrees with regard to the neutral position, were developed to evaluate the effect of malrotation on the femoral component in TKA. Femoral malrotation in TKA on the knee joint was simulated in walking stance-phase gait and squat loading conditions. RESULTS: Contact stress on the medial side of the PE insert increased with internal femoral malrotation and decreased with external femoral malrotation in both stance-phase gait and squat loading conditions. There was an opposite trend in the lateral side of the PE insert case. Contact stress on the patellar button increased with internal femoral malrotation and decreased with external femoral malrotation in both stance-phase gait and squat loading conditions. In particular, contact stress on the patellar button increased by 98% with internal malrotation of 10 degrees in the squat loading condition. The force on the medial collateral ligament (MCL) and the lateral collateral ligament (LCL) increased with internal and external femoral malrotations, respectively. CONCLUSIONS: These findings provide support for orthopaedic surgeons to determine a more accurate femoral component alignment in order to reduce post-operative PE problems.Cite this article: K-T. Kang, Y-G. Koh, J. Son, O-R. Kwon, C. Baek, S. H. Jung, K. K. Park. Measuring the effect of femoral malrotation on knee joint biomechanics for total knee arthroplasty using computational simulation. Bone Joint Res 2016;5:552-559. DOI: 10.1302/2046 3758.511.BJR-2016-0107.R1. PMID- 28094764 TI - Neuromorphic meets neuromechanics, part II: the role of fusimotor drive. AB - OBJECTIVE: We studied the fundamentals of muscle afferentation by building a Neuro-mechano-morphic system actuating a cadaveric finger. This system is a faithful implementation of the stretch reflex circuitry. It allowed the systematic exploration of the effects of different fusimotor drives to the muscle spindle on the closed-loop stretch reflex response. APPROACH: As in Part I of this work, sensory neurons conveyed proprioceptive information from muscle spindles (with static and dynamic fusimotor drive) to populations of alpha-motor neurons (with recruitment and rate coding properties). The motor commands were transformed into tendon forces by a Hill-type muscle model (with activation contraction dynamics) via brushless DC motors. Two independent afferented muscles emulated the forces of flexor digitorum profundus and the extensor indicis proprius muscles, forming an antagonist pair at the metacarpophalangeal joint of a cadaveric index finger. We measured the physical response to repetitions of bi directional ramp-and-hold rotational perturbations for 81 combinations of static and dynamic fusimotor drives, across four ramp velocities, and three levels of constant cortical drive to the alpha-motor neuron pool. MAIN RESULTS: We found that this system produced responses compatible with the physiological literature. Fusimotor and cortical drives had nonlinear effects on the reflex forces. In particular, only cortical drive affected the sensitivity of reflex forces to static fusimotor drive. In contrast, both static fusimotor and cortical drives reduced the sensitivity to dynamic fusimotor drive. Interestingly, realistic signal-dependent motor noise emerged naturally in our system without having been explicitly modeled. SIGNIFICANCE: We demonstrate that these fundamental features of spinal afferentation sufficed to produce muscle function. As such, our Neuro mechano-morphic system is a viable platform to study the spinal mechanisms for healthy muscle function-and its pathologies such as dystonia and spasticity. In addition, it is a working prototype of a robust biomorphic controller for compliant robotic limbs and exoskeletons. PMID- 28094765 TI - Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy. AB - Sensory neurons have the capacity to produce, release, and respond to acetylcholine (ACh), but the functional role of cholinergic systems in adult mammalian peripheral sensory nerves has not been established. Here, we have reported that neurite outgrowth from adult sensory neurons that were maintained under subsaturating neurotrophic factor conditions operates under cholinergic constraint that is mediated by muscarinic receptor-dependent regulation of mitochondrial function via AMPK. Sensory neurons from mice lacking the muscarinic ACh type 1 receptor (M1R) exhibited enhanced neurite outgrowth, confirming the role of M1R in tonic suppression of axonal plasticity. M1R-deficient mice made diabetic with streptozotocin were protected from physiological and structural indices of sensory neuropathy. Pharmacological blockade of M1R using specific or selective antagonists, pirenzepine, VU0255035, or muscarinic toxin 7 (MT7) activated AMPK and overcame diabetes-induced mitochondrial dysfunction in vitro and in vivo. These antimuscarinic drugs prevented or reversed indices of peripheral neuropathy, such as depletion of sensory nerve terminals, thermal hypoalgesia, and nerve conduction slowing in diverse rodent models of diabetes. Pirenzepine and MT7 also prevented peripheral neuropathy induced by the chemotherapeutic agents dichloroacetate and paclitaxel or HIV envelope protein gp120. As a variety of antimuscarinic drugs are approved for clinical use against other conditions, prompt translation of this therapeutic approach to clinical trials is feasible. PMID- 28094766 TI - Matriptase-mediated cleavage of EpCAM destabilizes claudins and dysregulates intestinal epithelial homeostasis. AB - Congenital tufting enteropathy (CTE) is a severe autosomal recessive human diarrheal disorder with characteristic intestinal epithelial dysplasia. CTE can be caused by mutations in genes encoding EpCAM, a putative adhesion molecule, and HAI-2, a cell surface protease inhibitor. A similar phenotype occurs in mice whose intestinal epithelial cells (IECs) fail to express the tight junction associated protein claudin-7. EpCAM stabilizes claudin-7 in IECs, and HAI-2 regulates the cell surface serine protease matriptase, a known modifier of intestinal epithelial physiology. Therefore, we hypothesized that HAI-2, matriptase, EpCAM, and claudin-7 were functionally linked. Herein we have demonstrated that active matriptase cleaves EpCAM after Arg80 and that loss of HAI-2 in IECs led to unrestrained matriptase activity and efficient cleavage of EpCAM. Cleavage of EpCAM decreased its ability to associate with claudin-7 and targeted it for internalization and lysosomal degradation in conjunction with claudin-7. CTE-associated HAI-2 mutant proteins exhibited reduced ability to inhibit matriptase and also failed to efficiently stabilize claudin-7 in IECs. These results identify EpCAM as a substrate of matriptase and link HAI-2, matriptase, EpCAM, and claudin-7 in a functionally important pathway that causes disease when it is dysregulated. PMID- 28094767 TI - Impaired SUMOylation of nuclear receptor LRH-1 promotes nonalcoholic fatty liver disease. AB - Hepatic steatosis is caused by metabolic imbalances that could be explained in part by an increase in de novo lipogenesis that results from increased sterol element binding protein 1 (SREBP-1) activity. The nuclear receptor liver receptor homolog 1 (LRH-1) is an important regulator of intermediary metabolism in the liver, but its role in regulating lipogenesis is not well understood. Here, we have assessed the contribution of LRH-1 SUMOylation to the development of nonalcoholic fatty liver disease (NAFLD). Mice expressing a SUMOylation-defective mutant of LRH-1 (LRH-1 K289R mice) developed NAFLD and early signs of nonalcoholic steatohepatitis (NASH) when challenged with a lipogenic, high-fat, high-sucrose diet. Moreover, we observed that the LRH-1 K289R mutation induced the expression of oxysterol binding protein-like 3 (OSBPL3), enhanced SREBP-1 processing, and promoted de novo lipogenesis. Mechanistically, we demonstrated that ectopic expression of OSBPL3 facilitates SREBP-1 processing in WT mice, while silencing hepatic Osbpl3 reverses the lipogenic phenotype of LRH-1 K289R mice. These findings suggest that compromised SUMOylation of LRH-1 promotes the development of NAFLD under lipogenic conditions through regulation of OSBPL3. PMID- 28094768 TI - BCL-W has a fundamental role in B cell survival and lymphomagenesis. AB - Compromised apoptotic signaling is a prerequisite for tumorigenesis. The design of effective therapies for cancer treatment depends on a comprehensive understanding of the mechanisms that govern cell survival. The antiapoptotic proteins of the BCL-2 family are key regulators of cell survival and are frequently overexpressed in malignancies, leading to increased cancer cell survival. Unlike BCL-2 and BCL-XL, the closest antiapoptotic relative BCL-W is required for spermatogenesis, but was considered dispensable for all other cell types. Here, however, we have exposed a critical role for BCL-W in B cell survival and lymphomagenesis. Loss of Bcl-w conferred sensitivity to growth factor deprivation-induced B cell apoptosis. Moreover, Bcl-w loss profoundly delayed MYC-mediated B cell lymphoma development due to increased MYC-induced B cell apoptosis. We also determined that MYC regulates BCL-W expression through its transcriptional regulation of specific miR. BCL-W expression was highly selected for in patient samples of Burkitt lymphoma (BL), with 88.5% expressing BCL-W. BCL-W knockdown in BL cell lines induced apoptosis, and its overexpression conferred resistance to BCL-2 family-targeting BH3 mimetics. Additionally, BCL-W was overexpressed in diffuse large B cell lymphoma and correlated with decreased patient survival. Collectively, our results reveal that BCL-W profoundly contributes to B cell lymphoma, and its expression could serve as a biomarker for diagnosis and aid in the development of better targeted therapies. PMID- 28094769 TI - iPSC-derived beta cells model diabetes due to glucokinase deficiency. PMID- 28094770 TI - Rapamycin-mediated mTOR inhibition uncouples HIV-1 latency reversal from cytokine associated toxicity. AB - Current strategies for HIV-1 eradication require the reactivation of latent HIV-1 in resting CD4+ T cells (rCD4s). Global T cell activation is a well-characterized means of inducing HIV-1 transcription, but is considered too toxic for clinical applications. Here, we have explored a strategy that involves a combination of immune activation and the immunosuppressive mTOR inhibitor rapamycin. In purified rCD4s from HIV-1-infected individuals on antiretroviral therapy, rapamycin treatment downregulated markers of toxicity, including proinflammatory cytokine release and cellular proliferation that were induced after potent T cell activation using alphaCD3/alphaCD28 antibodies. Using an ex vivo assay for HIV-1 mRNA, we demonstrated that despite this immunomodulatory effect, rapamycin did not affect HIV-1 gene expression induced by T cell activation in these rCD4s. In contrast, treating activated rCD4s with the immunosuppressant cyclosporin, a calcineurin inhibitor, robustly inhibited HIV-1 reactivation. Importantly, rapamycin treatment did not impair cytotoxic T lymphocyte (CTL) recognition and killing of infected cells. These findings raise the possibility of using rapamycin in conjunction with T cell-activating agents in HIV-1 cure strategies. PMID- 28094772 TI - Cardiac afferent activity modulates the expression of racial stereotypes. AB - Negative racial stereotypes tend to associate Black people with threat. This often leads to the misidentification of harmless objects as weapons held by a Black individual. Yet, little is known about how bodily states impact the expression of racial stereotyping. By tapping into the phasic activation of arterial baroreceptors, known to be associated with changes in the neural processing of fearful stimuli, we show activation of race-threat stereotypes synchronized with the cardiovascular cycle. Across two established tasks, stimuli depicting Black or White individuals were presented to coincide with either the cardiac systole or diastole. Results show increased race-driven misidentification of weapons during systole, when baroreceptor afferent firing is maximal, relative to diastole. Importantly, a third study examining the positive Black-athletic stereotypical association fails to demonstrate similar modulations by cardiac cycle. We identify a body-brain interaction wherein interoceptive cues can modulate threat appraisal and racially biased behaviour in context-dependent ways. PMID- 28094773 TI - Methane Emissions and Microbial Communities as Influenced by Dual Cropping of Azolla along with Early Rice. AB - Azolla caroliniana Willd. is widely used as a green manure accompanying rice, but its ecological importance remains unclear, except for its ability to fix nitrogen in association with cyanobacteria. To investigate the impacts of Azolla cultivation on methane emissions and environmental variables in paddy fields, we performed this study on the plain of Dongting Lake, China, in 2014. The results showed that the dual cropping of Azolla significantly suppressed the methane emissions from paddies, likely due to the increase in redox potential in the root region and dissolved oxygen concentration at the soil-water interface. Furthermore, the floodwater pH decreased in association with Azolla cultivation, which is also a factor significantly correlated with the decrease in methane emissions. An increase in methanotrophic bacteria population (pmoA gene copies) and a reduction in methanogenic archaea (16S rRNA gene copies) were observed in association with Azolla growth. During rice cultivation period, dual cropping of Azolla also intensified increasing trend of 1/Simpson of methanogens and significantly decreased species richness (Chao 1) and species diversity (1/Simpson, 1/D) of methanotrophs. These results clearly demonstrate the suppression of CH4 emissions by culturing Azolla and show the environmental and microbial responses in paddy soil under Azolla cultivation. PMID- 28094774 TI - Ab Initio Calculations of the N-N Bond Dissociation for the Gas-phase RDX and HMX. AB - NO2 fission is a vital factor for 1,3,5-Trinitroperhydro-1,3,5-triazine (RDX) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) decomposition. In this study, the geometry of the gas-phase RDX and HMX molecules was optimized, and the bond order and the bond dissociation energy of the N-N bonds were examined. Moreover, the rate constants of the gas-phase RDX and HMX conformers, concerning the N-N bond dissociation, were evaluated using the microcanonical variational transition state theory (MUVT). The calculation results have shown that HMX is more stable than RDX in terms of the N-N bond dissociation, and the conformers stability parameters were as follows: RDXaaa < RDXaae < HMX I < HMX II. In addition, for the RDX conformers, the N-N bond of the pseudo-equatorial positioning of the nitro group was more stable than the N-N bond of the axial positioning of the nitro group, while the results were opposite in the case of the HMX conformers. Moreover, it has been shown that the dissociation rate constant of the N-N bond is influenced by the temperature significantly, thus the rate constants were much lower (<10-10 s-1) when the temperature was less than 1000 K. PMID- 28094771 TI - Orphan Gpr182 suppresses ERK-mediated intestinal proliferation during regeneration and adenoma formation. AB - Orphan GPCRs provide an opportunity to identify potential pharmacological targets, yet their expression patterns and physiological functions remain challenging to elucidate. Here, we have used a genetically engineered knockin reporter mouse to map the expression pattern of the Gpr182 during development and adulthood. We observed that Gpr182 is expressed at the crypt base throughout the small intestine, where it is enriched in crypt base columnar stem cells, one of the most active stem cell populations in the body. Gpr182 knockdown had no effect on homeostatic intestinal proliferation in vivo, but led to marked increases in proliferation during intestinal regeneration following irradiation-induced injury. In the ApcMin mouse model, which forms spontaneous intestinal adenomas, reductions in Gpr182 led to more adenomas and decreased survival. Loss of Gpr182 enhanced organoid growth efficiency ex vivo in an EGF-dependent manner. Gpr182 reduction led to increased activation of ERK1/2 in basal and challenge models, demonstrating a potential role for this orphan GPCR in regulating the proliferative capacity of the intestine. Importantly, GPR182 expression was profoundly reduced in numerous human carcinomas, including colon adenocarcinoma. Together, these results implicate Gpr182 as a negative regulator of intestinal MAPK signaling-induced proliferation, particularly during regeneration and adenoma formation. PMID- 28094775 TI - Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems. AB - Because of its safe and effective protein expression profile, in vitro transcribed messenger RNA (IVT-mRNA) represents a promising candidate in the development of novel therapeutics for genetic diseases, vaccines or gene editing strategies, especially when its inherent shortcomings (for example, instability and immunogenicity) have been partially addressed via structural modifications. However, numerous unsolved technical difficulties in successful in vivo delivery of IVT-mRNA have greatly hindered the applications of IVT-mRNA in clinical development. Recent advances in nanotechnology and material science have yielded many promising nonviral delivery systems, some of which were able to efficiently facilitate targeted in vivo delivery of IVT-mRNA in safe and noninvasive manners. The diversity and flexibility of these delivery systems highlight the recent progress of IVT-mRNA-based therapy using nonviral vectors. In this review, we summarize recent advances of existing and emerging nonviral vector-based nanotechnologies for IVT-mRNA delivery and briefly summarize the interesting but rarely discussed applications on simultaneous delivery of IVT-mRNA with DNA. PMID- 28094776 TI - New Insights into Cooperative Binding of Homeodomain Transcription Factors PREP1 and PBX1 to DNA. AB - PREP1 and PBX1 are homeodomain (HD) transcription factors that play crucial roles in embryonic development. Here, we present the first biophysical characterization of a PREP1 HD, and the NMR spectroscopic study of its DNA binding pocket. The data show that residues flanking the HD participate in DNA binding. The kinetic parameters for DNA binding of individual PREP1 and PBX1 HDs, and of their combination, show that isolated PREP1 and PBX1 HDs bind to DNA in a cooperative manner. A novel PREP1 motif, flanking the HD at the C-terminus, is required for cooperativity. PMID- 28094777 TI - High resolution structural evidence suggests the Sarcoplasmic Reticulum forms microdomains with Acidic Stores (lysosomes) in the heart. AB - Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) stimulates calcium release from acidic stores such as lysosomes and is a highly potent calcium-mobilising second messenger. NAADP plays an important role in calcium signalling in the heart under basal conditions and following beta-adrenergic stress. Nevertheless, the spatial interaction of acidic stores with other parts of the calcium signalling apparatus in cardiac myocytes is unknown. We present evidence that lysosomes are intimately associated with the sarcoplasmic reticulum (SR) in ventricular myocytes; a median separation of 20 nm in 2D electron microscopy and 3.3 nm in 3D electron tomography indicates a genuine signalling microdomain between these organelles. Fourier analysis of immunolabelled lysosomes suggests a sarcomeric pattern (dominant wavelength 1.80 MUm). Furthermore, we show that lysosomes form close associations with mitochondria (median separation 6.2 nm in 3D studies) which may provide a basis for the recently-discovered role of NAADP in reperfusion-induced cell death. The trigger hypothesis for NAADP action proposes that calcium release from acidic stores subsequently acts to enhance calcium release from the SR. This work provides structural evidence in cardiac myocytes to indicate the formation of microdomains between acidic and SR calcium stores, supporting emerging interpretations of NAADP physiology and pharmacology in heart. PMID- 28094778 TI - Adipocyte Fatty Acid Binding Protein Potentiates Toxic Lipids-Induced Endoplasmic Reticulum Stress in Macrophages via Inhibition of Janus Kinase 2-dependent Autophagy. AB - Lipotoxicity is implicated in the pathogenesis of obesity-related inflammatory complications by promoting macrophage infiltration and activation. Endoplasmic reticulum (ER) stress and adipocyte fatty acid binding protein (A-FABP) play key roles in obesity and mediate inflammatory activity through similar signaling pathways. However, little is known about their interplay in lipid-induced inflammatory responses. Here, we showed that prolonged treatment of palmitic acid (PA) increased ER stress and expression of A-FABP, which was accompanied by reduced autophagic flux in macrophages. Over-expression of A-FABP impaired PA induced autophagy associating with enhanced ER stress and pro-inflammatory cytokine production, while genetic ablation or pharmacological inhibition of A FABP reversed the conditions. PA-induced expression of autophagy-related protein (Atg)7 was attenuated in A-FABP over-expressed macrophages, but was elevated in A FABP-deficient macrophages. Mechanistically, A-FABP potentiated the effects of PA by inhibition of Janus Kinase (JAK)2 activity, thus diminished PA-induced Atg7 expression contributing to impaired autophagy and further augmentation of ER stress. These findings suggest that A-FABP acts as autophagy inhibitor to instigate toxic lipids-induced ER stress through inhibition of JAK2-dependent autophagy, which in turn triggers inflammatory responses in macrophages. A-FABP JAK2 axis may represent an important pathological pathway contributing to obesity related inflammatory diseases. PMID- 28094779 TI - Suppression of colitis by adoptive transfer of helminth antigen-treated dendritic cells requires interleukin-4 receptor-alpha signaling. AB - Infection with helminth parasites has been explored as a treatment for autoimmune and inflammatory diseases. As helminth antigens have potent immunomodulation properties capable of inducing regulatory programs in a variety of cell types, transferring cells treated with helminth antigens represents a novel extension to helminth therapy. Previous work determined that transfer of bone marrow-derived dendritic cells (DC) pulsed with a crude extract of the tapeworm Hymenolepis diminuta (HD) can suppress colitis in recipient mice. The present study explored the mechanism of disease suppression and the importance of interleukin (IL)-4 signaling. Transfer of HD-DCs suppressed dinitrobenzene sulfonic acid (DNBS) induced colitis through activation of recipient IL-4 receptor-alpha. The transferred HD-DCs required IL-4Ralpha and the capacity to secrete IL-10 to drive IL-4 and IL-10 production and to suppress colitis in recipient mice. Treatment of DCs with IL-4 evokes an alternatively activated phenotype, but adoptive transfer of these cells did not affect the outcome of colitis. Collectively, these studies demonstrate the complexity between IL-4 and IL-10 in donor cells and recipient, and the requirement for parasite- and host-derived factors in this novel form of cell therapy. Thus IL-4Ralpha signaling is revealed as a pathway that could be exploited for helminth antigen cell-based therapy. PMID- 28094781 TI - Ultrastructure of sensilla of antennae and ovipositor of Sitotroga cerealella (Lepidoptera: Gelechiidae), and location of female sex pheromone gland. AB - The Angoumois grain moth, Sitotroga cerealella, is a serious pest of stored grains worldwide. Presently, the best effective control against the moth is to disrupt the sexual communication between sexes. Sexual communication in moths includes two processes in which females produce and release pheromones from the sex pheromone gland and males detect and respond to them with a relatively sophisticated olfactory system in their antennae. To better understand these processes, we studied the ultrastructure of antennal and ovipositor sensilla of S. cerealella and determined the location of the female sex pheromone gland. Seven types of antennal sensilla were identified on both sexes: sensilla trichodea, sensilla chaetica, sensilla coeloconica, sensilla styloconica, sensilla auricillica, sensilla squamiformia and Bohm bristles. Of these sensilla, the sensilla trichodea were significantly more abundant on male antennae than on those of females, suggesting that these sensilla may detect the sex pheromones. On the ovipositor, only sensilla chaetica of various lengths were found. The sexual gland was an eversible sac of glandular epithelium that was situated dorsally in the intersegmental membrane between the 8th and 9th abdominal segments. These results will lead to a better understanding of mate finding with sex pheromones for this worldwide pest species. PMID- 28094780 TI - Rapid acquisition of polymorphic virulence markers during adaptation of highly pathogenic avian influenza H5N8 virus in the mouse. AB - Emergence of a highly pathogenic avian influenza (HPAI) H5N8 virus in Asia and its spread to Europe and North America has caused great concern for human health. Although the H5N8 virus has been only moderately pathogenic to mammalian hosts, virulence can still increase. We evaluated the pathogenic potential of several H5N8 strains via the mouse-adaptation method. Two H5N8 viruses were sequentially passaged in BALB/c mice and plaque-purified from lung samples. The viruses rapidly obtained high virulence (MLD50, up to 0.5 log10 PFU/mL) within 5 passages. Sequence analysis revealed the acquisition of several virulence markers, including the novel marker P708S in PB1 gene. Combinations of markers synergistically enhanced viral replication and polymerase activity in human cell lines and virulence and multiorgan dissemination in mice. These results suggest that H5N8 viruses can rapidly acquire virulence markers in mammalian hosts; thus, rapid spread as well as repeated viral introduction into the hosts may significantly increase the risk of human infection and elevate pandemic potential. PMID- 28094782 TI - Cocaine Enhances DC to T-cell HIV-1 Transmission by Activating DC-SIGN/LARG/LSP1 Complex and Facilitating Infectious Synapse Formation. AB - DC-SIGN is a dendritic cell surface structure which participates in binding and transmission of HIV-1. Here, for the first time we demonstrate that cocaine induces over expression of DC-SIGN and significantly enhances virus transfer from DCs to T-cells by increasing the binding and internalization of HIV-1 in DCs. We found that cocaine activates a DC-SIGN mediated 'signalosome' complex by enhancing its association with LARG and LSP1. Further, LARG was observed to participate in DC-SIGN mediated internalization of HIV-1 in DCs. Intracellular trafficking studies of HIV-1 in cocaine treated DCs revealed increased co localization of HIV-1 with endosomal or multi vesicular body (MVB) markers such as CD81 and VPS4 and decreased co-localization with the phagolysomal marker LAMP1; this signified altered intracellular trafficking and decreased degradation of HIV-1 in cocaine treated DCs. Furthermore, we found that cocaine induced activation of LARG which in turn activated Rho A and the focal adhesion molecules FAK, Pyk2 and paxillin. This signaling cascade enhanced the formation of an infectious synapse between DCs and T-cells. Our study provides insight into the molecular mechanisms of cocaine's contribution to key components in HIV pathogenesis and highlights novel targets for interrupting the virus life cycle in substance using hosts. PMID- 28094783 TI - A novel spontaneous model of epithelial-mesenchymal transition (EMT) using a primary prostate cancer derived cell line demonstrating distinct stem-like characteristics. AB - Cells acquire the invasive and migratory properties necessary for the invasion metastasis cascade and the establishment of aggressive, metastatic disease by reactivating a latent embryonic programme: epithelial-to-mesenchymal transition (EMT). Herein, we report the development of a new, spontaneous model of EMT which involves four phenotypically distinct clones derived from a primary tumour derived human prostate cancer cell line (OPCT-1), and its use to explore relationships between EMT and the generation of cancer stem cells (CSCs) in prostate cancer. Expression of epithelial (E-cadherin) and mesenchymal markers (vimentin, fibronectin) revealed that two of the four clones were incapable of spontaneously activating EMT, whereas the others contained large populations of EMT-derived, vimentin-positive cells having spindle-like morphology. One of the two EMT-positive clones exhibited aggressive and stem cell-like characteristics, whereas the other was non-aggressive and showed no stem cell phenotype. One of the two EMT-negative clones exhibited aggressive stem cell-like properties, whereas the other was the least aggressive of all clones. These findings demonstrate the existence of distinct, aggressive CSC-like populations in prostate cancer, but, importantly, that not all cells having a potential for EMT exhibit stem cell-like properties. This unique model can be used to further interrogate the biology of EMT in prostate cancer. PMID- 28094784 TI - Targeted DNA sequencing and in situ mutation analysis using mobile phone microscopy. AB - Molecular diagnostics is typically outsourced to well-equipped centralized laboratories, often far from the patient. We developed molecular assays and portable optical imaging designs that permit on-site diagnostics with a cost effective mobile-phone-based multimodal microscope. We demonstrate that targeted next-generation DNA sequencing reactions and in situ point mutation detection assays in preserved tumour samples can be imaged and analysed using mobile phone microscopy, achieving a new milestone for tele-medicine technologies. PMID- 28094785 TI - High-resolution African population projections from radiative forcing and socio economic models, 2000 to 2100. AB - For its fifth assessment report, the Intergovernmental Panel on Climate Change divided future scenario projections (2005-2100) into two groups: Socio-Economic Pathways (SSPs) and Representative Concentration Pathways (RCPs). Each SSP has country-level urban and rural population projections, while the RCPs are based on radiative forcing caused by greenhouse gases, aerosols and associated land-use change. In order for these projections to be applicable in earth system models, SSP and RCP population projections must be at the same spatial scale. Thus, a gridded population dataset that takes into account both RCP-based urban fractions and SSP-based population projection is needed. To support this need, an annual (2000-2100) high resolution (approximately 1km at the equator) gridded population dataset conforming to both RCPs (urban land use) and SSPs (population) country level scenario data were created. PMID- 28094786 TI - Two replications of an investigation on empathy and utilitarian judgement across socioeconomic status. AB - Research by Cote, Piff, and Willer (2013) found that through the induction of empathy in an experimental condition, the association between socioeconomic status (SES) and utilitarian moral judgment was diminished. Participant self reported income interacted with experimental condition such that high SES participants who empathized with a disadvantaged group member redistributed fewer experimental dollars during an online task at the losing member's expense. This suggests that lower levels of empathy could help explain utilitarian decision making in high SES individuals. Two pre-registered, high-powered replications were conducted in order to assess the magnitude and reliability of this finding. While the first replication attempt failed to uncover the effect, the second attempt found a pattern consistent with the original study. A meta-analysis of the replication attempts with the original author's interaction effects was conducted. The confidence interval of the meta-analytic effect suggests that the true effect size may be as robust as reported by the original authors, or may be close to zero. Implications of the results found in the replication attempts are discussed. PMID- 28094787 TI - A dataset of human decision-making in teamwork management. AB - Today, most endeavours require teamwork by people with diverse skills and characteristics. In managing teamwork, decisions are often made under uncertainty and resource constraints. The strategies and the effectiveness of the strategies different people adopt to manage teamwork under different situations have not yet been fully explored, partially due to a lack of detailed large-scale data. In this paper, we describe a multi-faceted large-scale dataset to bridge this gap. It is derived from a game simulating complex project management processes. It presents the participants with different conditions in terms of team members' capabilities and task characteristics for them to exhibit their decision-making strategies. The dataset contains detailed data reflecting the decision situations, decision strategies, decision outcomes, and the emotional responses of 1,144 participants from diverse backgrounds. To our knowledge, this is the first dataset simultaneously covering these four facets of decision-making. With repeated measurements, the dataset may help establish baseline variability of decision-making in teamwork management, leading to more realistic decision theoretic models and more effective decision support approaches. PMID- 28094789 TI - Mate choice in fruit flies is rational and adaptive. AB - According to rational choice theory, beneficial preferences should lead individuals to sort available options into linear, transitive hierarchies, although the extent to which non-human animals behave rationally is unclear. Here we demonstrate that mate choice in the fruit fly Drosophila melanogaster results in the linear sorting of a set of diverse isogenic female lines, unambiguously demonstrating the hallmark of rational behaviour, transitivity. These rational choices are associated with direct benefits, enabling males to maximize offspring production. Furthermore, we demonstrate that female behaviours and cues act redundantly in mate detection and assessment, as rational mate choice largely persists when visual or chemical sensory modalities are impaired, but not when both are impaired. Transitivity in mate choice demonstrates that the quality of potential mates varies significantly among genotypes, and that males and females behave in such a way as to facilitate adaptive mate choice. PMID- 28094788 TI - Electronic control of gene expression and cell behaviour in Escherichia coli through redox signalling. AB - The ability to interconvert information between electronic and ionic modalities has transformed our ability to record and actuate biological function. Synthetic biology offers the potential to expand communication 'bandwidth' by using biomolecules and providing electrochemical access to redox-based cell signals and behaviours. While engineered cells have transmitted molecular information to electronic devices, the potential for bidirectional communication stands largely untapped. Here we present a simple electrogenetic device that uses redox biomolecules to carry electronic information to engineered bacterial cells in order to control transcription from a simple synthetic gene circuit. Electronic actuation of the native transcriptional regulator SoxR and transcription from the PsoxS promoter allows cell response that is quick, reversible and dependent on the amplitude and frequency of the imposed electronic signals. Further, induction of bacterial motility and population based cell-to-cell communication demonstrates the versatility of our approach and potential to drive intricate biological behaviours. PMID- 28094790 TI - Californium-252 neutron intracavity brachytherapy alone for T1N0 low-lying rectal adenocarcinoma: A definitive anal sphincter-preserving radiotherapy. AB - This study evaluated the 4-year results of 32 patients with T1N0 low-lying rectal adenocarcinoma treated solely with californium-252 (Cf-252) neutron intracavity brachytherapy (ICBT). Patients were solicited into the study from January 2008 to June 2011. All the patients had refused surgery or surgery was contraindicated. The patients were treated with Cf-252 neutron ICBT using a novel 3.5-cm diameter off-axis 4-channel intrarectal applicator designed by the authors. The dose reference point was defined on the mucosa surface, with a total dose of 55-62 Gy eq/4 f (13-16 Gy-eq/f/wk). All the patients completed the radiotherapy in accordance with our protocol. The rectal lesions regressed completely, and the acute rectal toxicity was mild (<=G2). The 4-year local control, overall survival, disease-free survival, and late complication (>=G2) rates were 96.9%, 90.6%, 87.5% and 15.6%, respectively. No severe late complication (>=G3) occurred. The mean follow-up was 56.1 +/- 16.0 months. At the end of last follow up, 29 patients remained alive. The mean survival time was 82.1 +/- 2.7 months. Cf-252 neutron ICBT administered as the sole treatment (without surgery) for patients with T1N0 low-lying rectal adenocarcinoma is effective with acceptable late complications. Our study and method offers a definitive anal sphincter preserving radiotherapy for T1N0 low-lying rectal adenocarcinoma patients. PMID- 28094791 TI - Weakening of annual temperature cycle over the Tibetan Plateau since the 1870s. AB - The annual cycle of extra-tropical surface air temperature is an important component of the Earth's climate system. Over the past decades, a reduced amplitude of this mode has been observed in some regions. Although attributed to anthropogenic forcing, it remains unclear when dampening of the annual cycle started. Here we use a residual series of tree-ring width and maximum latewood density from the Tibetan Plateau >4,000 m asl to reconstruct changes in temperature seasonality over the past three centuries. The new proxy evidence suggests that the onset of a decrease in summer-to-winter temperature difference over the Tibetan Plateau occurred in the 1870s. Our results imply that the influence of anthropogenic forcing on temperature seasonality might have started in the late nineteenth century, and that future human influence may further contribute to a weakening of the annual temperature cycle, with subsequent effects on ecosystem functioning and productivity. PMID- 28094792 TI - Identification of a Nuclear Respiratory Factor 1 Recognition Motif in the Apolipoprotein E Variant APOE4 linked to Alzheimer's Disease. AB - Alzheimer's disease affects tens of millions of people worldwide and its prevalence continues to rise. It is caused by a combination of a subject's heredity, environment, lifestyle, and medical condition. The most significant genetic risk factor for late onset Alzheimer's disease is a variant of the apolipoprotein E gene, APOE4. Here we show that the single nucleotide polymorphism rs429358 that defines APOE4 is located in a short sequence motif repeated several times within exon 4 of apolipoprotein E, reminiscent of the structure of transcriptional enhancers. A JASPAR database search predicts that the T to C transition in rs429358 generates a binding motif for nuclear respiratory factor NRF1. This site appears to be part of a binding site cluster for this transcription factor on exon 4 of APOE. This de novo NRF1 binding site has therefore the potential to affect the expression of multiple genes in its genomic vicinity. Our in silico analysis, suggesting a novel function for APOE4 at the DNA level, offers a potential mechanism for the observed tissue specific neurodegeneration and the role of environmental factors in Alzheimer's disease etiology. PMID- 28094793 TI - Caloric restriction improves health and survival of rhesus monkeys. AB - Caloric restriction (CR) without malnutrition extends lifespan and delays the onset of age-related disorders in most species but its impact in nonhuman primates has been controversial. In the late 1980s two parallel studies were initiated to determine the effect of CR in rhesus monkeys. The University of Wisconsin study reported a significant positive impact of CR on survival, but the National Institute on Aging study detected no significant survival effect. Here we present a direct comparison of longitudinal data from both studies including survival, bodyweight, food intake, fasting glucose levels and age-related morbidity. We describe differences in study design that could contribute to differences in outcomes, and we report species specificity in the impact of CR in terms of optimal onset and diet. Taken together these data confirm that health benefits of CR are conserved in monkeys and suggest that CR mechanisms are likely translatable to human health. PMID- 28094795 TI - Impacts of chemical gradients on microbial community structure. AB - Succession of redox processes is sometimes assumed to define a basic microbial community structure for ecosystems with oxygen gradients. In this paradigm, aerobic respiration, denitrification, fermentation and sulfate reduction proceed in a thermodynamically determined order, known as the 'redox tower'. Here, we investigated whether redox sorting of microbial processes explains microbial community structure at low-oxygen concentrations. We subjected a diverse microbial community sampled from a coastal marine sediment to 100 days of tidal cycling in a laboratory chemostat. Oxygen gradients (both in space and time) led to the assembly of a microbial community dominated by populations that each performed aerobic and anaerobic metabolism in parallel. This was shown by metagenomics, transcriptomics, proteomics and stable isotope incubations. Effective oxygen consumption combined with the formation of microaggregates sustained the activity of oxygen-sensitive anaerobic enzymes, leading to braiding of unsorted redox processes, within and between populations. Analyses of available metagenomic data sets indicated that the same ecological strategies might also be successful in some natural ecosystems. PMID- 28094796 TI - The evolution of no-cost resistance at sub-MIC concentrations of streptomycin in Streptomyces coelicolor. AB - At the high concentrations used in medicine, antibiotics exert strong selection on bacterial populations for the evolution of resistance. However, these lethal concentrations may not be representative of the concentrations bacteria face in soil, a recognition that has led to questions of the role of antibiotics in soil environments as well as the dynamics of resistance evolution during sublethal challenge. Here we examine the evolution of resistance to sub-minimal inhibitory concentrations (sub-MIC) of streptomycin in the filamentous soil bacterium Streptomyces coelicolor. First, we show that spontaneous resistance to streptomycin causes an average fitness deficit of ~21% in the absence of drugs; however, these costs are eliminated at concentrations as low as 1/10 the MIC of susceptible strains. Using experimental evolution, we next show that resistance to >MIC levels of streptomycin readily evolves when bacteria are exposed to sub MIC doses for 500 generations. Furthermore, the resistant clones that evolved at sub-MIC streptomycin concentrations carry no fitness cost. Whole-genome analyses reveal that evolved resistant clones fixed some of the same mutations as those isolated at high drug concentrations; however, all evolved clones carry additional mutations and some fixed mutations that either compensate for costly resistance or have no associated fitness costs. Our results broaden the conditions under which resistance can evolve in nature and suggest that rather than low-concentration antibiotics acting as signals, resistance evolves in response to antibiotics used as weapons. PMID- 28094797 TI - Whole genome sequencing data and de novo draft assemblies for 66 teleost species. AB - Teleost fishes comprise more than half of all vertebrate species, yet genomic data are only available for 0.2% of their diversity. Here, we present whole genome sequencing data for 66 new species of teleosts, vastly expanding the availability of genomic data for this important vertebrate group. We report on de novo assemblies based on low-coverage (9-39*) sequencing and present detailed methodology for all analyses. To facilitate further utilization of this data set, we present statistical analyses of the gene space completeness and verify the expected phylogenetic position of the sequenced genomes in a large mitogenomic context. We further present a nuclear marker set used for phylogenetic inference and evaluate each gene tree in relation to the species tree to test for homogeneity in the phylogenetic signal. Collectively, these analyses illustrate the robustness of this highly diverse data set and enable extensive reuse of the selected phylogenetic markers and the genomic data in general. This data set covers all major teleost lineages and provides unprecedented opportunities for comparative studies of teleosts. PMID- 28094798 TI - Stable isotopes in the atmospheric marine boundary layer water vapour over the Atlantic Ocean, 2012-2015. AB - The water vapour isotopic composition (1H216O, H218O and 1H2H16O) of the Atlantic marine boundary layer has been measured from 5 research vessels between 2012 and 2015. Using laser spectroscopy analysers, measurements have been carried out continuously on samples collected 10-20 meter above sea level. All the datasets have been carefully calibrated against the international VSMOW-SLAP scale following the same protocol to build a homogeneous dataset covering the Atlantic Ocean between 4 degrees S to 63 degrees N. In addition, standard meteorological variables have been measured continuously, including sea surface temperatures using calibrated Thermo-Salinograph for most cruises. All calibrated observations are provided with 15-minute resolution. We also provide 6-hourly data to allow easier comparisons with simulations from the isotope-enabled Global Circulation Models. In addition, backwards trajectories from the HYSPLIT model are supplied every 6-hours for the position of our measurements. PMID- 28094794 TI - Diversity and carbon storage across the tropical forest biome. AB - Tropical forests are global centres of biodiversity and carbon storage. Many tropical countries aspire to protect forest to fulfil biodiversity and climate mitigation policy targets, but the conservation strategies needed to achieve these two functions depend critically on the tropical forest tree diversity carbon storage relationship. Assessing this relationship is challenging due to the scarcity of inventories where carbon stocks in aboveground biomass and species identifications have been simultaneously and robustly quantified. Here, we compile a unique pan-tropical dataset of 360 plots located in structurally intact old-growth closed-canopy forest, surveyed using standardised methods, allowing a multi-scale evaluation of diversity-carbon relationships in tropical forests. Diversity-carbon relationships among all plots at 1 ha scale across the tropics are absent, and within continents are either weak (Asia) or absent (Amazonia, Africa). A weak positive relationship is detectable within 1 ha plots, indicating that diversity effects in tropical forests may be scale dependent. The absence of clear diversity-carbon relationships at scales relevant to conservation planning means that carbon-centred conservation strategies will inevitably miss many high diversity ecosystems. As tropical forests can have any combination of tree diversity and carbon stocks both require explicit consideration when optimising policies to manage tropical carbon and biodiversity. PMID- 28094799 TI - Activation of Wnt/beta-catenin signalling via GSK3 inhibitors direct differentiation of human adipose stem cells into functional hepatocytes. AB - The generation of hepatocytes that are derived from human adipose stem cells (hASCs) represents an alternative to human hepatocytes for individualized therapeutic and pharmaceutical applications. However, the mechanisms facilitating hepatocyte differentiation from hASCs are not well understood. Here, we show that upon exposure to glycogen synthase kinase 3 (GSK3) inhibitors alone, the expression of definitive endoderm specific genes GATA4, FOXA2, and SOX17 in hASCs significantly increased in a manner with activation of Wnt/beta-catenin signalling. Down regulation of the beta-catenin expression attenuates the effect of GSK3 inhibitors on the induction of these specific genes. The cells induced using GSK3 inhibitors were directed to differentiate synchronously into hepatocyte-like cells (HLCs) after further combinations of soluble factors by a reproducible three-stage method. Moreover, hASC-HLCs induced using GSK3 inhibitors possess low-density lipoprotein uptake, albumin secretion, and glycogen synthesis ability, express important drug-metabolizing cytochrome P450 (CYP450) enzymes, and demonstrate CYP450 activity. Therefore, our findings suggest that activation of Wnt/beta-catenin signalling via GSK3 inhibitors in definitive endoderm specification may represent an important mechanism mediating hASCs differentiated to functional hepatocyte. Furthermore, development of similar compounds may be useful for robust, potentially scalable and cost effective generation of functional hepatocytes for drug screening and predictive toxicology platforms. PMID- 28094800 TI - Relationship of hyposalivation and xerostomia in Mexican elderly with socioeconomic, sociodemographic and dental factors. AB - We determined the prevalence of hyposalivation and xerostomia in older Mexicans (>=60 years), and its relationship with diverse factors. A cross-sectional study was realized in elderly subjects from Pachuca, Mexico. Chewing-stimulated saliva was collected under standardized conditions and salivary flow was measured; subjects were considered to have hyposalivation if their stimulated salivary flow was less than 0.7 mL per minute. Xerostomia was evaluated by asking subjects 'Does your mouth feel dry?'. Hyposalivation was present in 59.7%, and xerostomia in 25.2% of subjects. 16.5% of subjects had both conditions. Xerostomia was present in 27.7% of subjects with hyposalivation and 21.4% of subjects without hyposalivation, but the difference was not significant (p > 0.05). Thus, 68.3% of older Mexicans had xerostomia and/or hyposalivation. Factors associated with hyposalivation were: using fewer devices in oral hygiene, lacking social benefits for retirement/pension, living in a public retirement home, brushing teeth less than twice a day and lacking teeth without dentures. None of the factors included in this study were associated with xerostomia. We concluded that several variables studied were associated with hyposalivation, but none for xerostomia. Additional research should examine the amount of hyposalivation and factors associated with hyposalivation especially in elderly with increased risk for hyposalivation. PMID- 28094801 TI - Electronegative LDL-mediated cardiac electrical remodeling in a rat model of chronic kidney disease. AB - The mechanisms underlying chronic kidney disease (CKD)-associated higher risks for life-threatening ventricular tachyarrhythmias remain poorly understood. In rats subjected to unilateral nephrectomy (UNx), we examined cardiac electrophysiological remodeling and relevant mechanisms predisposing to ventricular arrhythmias. Adult male Sprague-Dawley rats underwent UNx (n = 6) or sham (n = 6) operations. Eight weeks later, the UNx group had higher serum blood urea nitrogen and creatinine levels and a longer electrocardiographic QTc interval than did the sham group. Patch-clamp studies revealed epicardial (EPI) predominant prolongation of the action potential duration (APD) at 50% and 90% repolarization in UNx EPI cardiomyocytes compared to sham EPI cardiomyocytes. A significant reduction of the transient outward potassium current (Ito) in EPI but not in endocardial (ENDO) cardiomyocytes of UNx rats led to a decreased transmural gradient of Ito. The reduction of Ito currents in UNx EPI cardiomyocytes was secondary to downregulation of KChIP2 but not Kv4.2, Kv4.3, and Kv1.4 protein expression. Incubation of plasma electronegative low-density lipoprotein (LDL) from UNx rats with normal EPI and ENDO cardiomyocytes recapitulated the electrophysiological phenotype of UNx rats. In conclusion, CKD disrupts the physiological transmural gradient of Ito via downregulation of KChIP2 proteins in the EPI region, which may promote susceptibility to ventricular tachyarrhythmias. Electronegative LDL may underlie downregulation of KChIP2 in CKD. PMID- 28094802 TI - Extrinsic MAVS signaling is critical for Treg maintenance of Foxp3 expression following acute flavivirus infection. AB - Given the rapid spread of flaviviruses such as West Nile virus (WNV) and Zika virus, it is critical that we develop a complete understanding of the key mediators of an effective anti-viral response. We previously demonstrated that WNV infection of mice deficient in mitochondrial antiviral-signaling protein (MAVS), the signaling adaptor for RNA helicases such as RIG-I, resulted in increased death and dysregulated immunity, which correlated with a failure of Treg expansion following infection. Thus, we sought to determine if intrinsic MAVS signaling is required for participation of Tregs in anti-WNV immunity. Despite evidence of increased Treg cell division, Foxp3 expression was not stably maintained after WNV infection in MAVS-deficient mice. However, intrinsic MAVS signaling was dispensable for Treg proliferation and suppressive capacity. Further, we observed generation of an effective anti-WNV immune response when Tregs lacked MAVS, thereby demonstrating that Treg detection of the presence of WNV through the MAVS signaling pathway is not required for generation of effective immunity. Together, these data suggest that while MAVS signaling has a considerable impact on Treg identity, this effect is not mediated by intrinsic MAVS signaling but rather is likely an effect of the overproduction of pro inflammatory cytokines generated in MAVS-deficient mice after WNV infection. PMID- 28094803 TI - MiR-124 inhibits the migration and invasion of human hepatocellular carcinoma cells by suppressing integrin alphaV expression. AB - Tumor metastasis is the major cause of cancer-related death especially in human hepatocellular carcinoma (HCC). Although microRNAs have been implicated in tumor development, the roles of miR-124 in HCC metastasis are still not well understood. We conducted functional analysis in this study to investigate miR 124. We observed that miR-124 significantly retarded the wound healing and migration of HCC SMMC-7721 and BEL-7404 cells. Further analysis indicated miR-124 directly targeting the transcriptional factor Sp1 which is an important transcription factor for the integrin alphaV subunit gene transcription. Co transfection of miR-124 with the luciferase reporter containing Sp1 3' untranslated region (UTR) significantly suppressed the luciferase activities. While mutation of the binding site of miR-124 in Sp1 mRNA 3'UTR completely abrogated the suppression of miR-124. Overexpression of miR-124 resulted in robust downregulation of Sp1 and integrin alphaV expression at either mRNA or protein level. Ectopic expression of miR-124 in HCC dramatically repressed the wound healing and migration in vitro and tumor metastasis in mouse experiments. Our findings demonstrated that miR-124 played as an important role in regulation of integrin alphaV expression in HCC, and reintroduction of miR-124 might be an alternative therapeutic strategy for controlling integrin alphaV expression in HCC. PMID- 28094804 TI - Six Years in the Life of a Mother Bear - The Longest Continuous Heart Rate Recordings from a Free-Ranging Mammal. AB - Physiological monitoring of free-ranging wild animals is providing new insights into their adaptations to a changing environment. American black bears (Ursus americanus) are highly adaptable mammals, spending up to half the year hibernating, and the remainder of the year attempting to gain weight on a landscape with foods that vary seasonally and year to year. We recorded heart rate (HR) and corresponding activity of an adult female black bear over the course of six years, using an implanted monitor. Despite yearly differences in food, and an every-other year reproductive cycle, this bear exhibited remarkable consistency in HR and activity. HR increased for 12 weeks in spring, from minimal hibernation levels (mean 20-25 beats/minute [bpm]; min 10 bpm) to summer active levels (July daytime: mean 95 bpm). Timing was delayed following one cold winter. In August the bear switched from primarily diurnal to nocturnal, coincident with the availability of baits set by legal hunters. Activity in autumn was higher when the bear was with cubs. Birthing of cubs in January was identified by a transient increase in HR and activity. Long-term physiological and behavioral monitoring is valuable for understanding adaptations of free-ranging animals to climate change, food availability, and human-related stressors. PMID- 28094805 TI - The genome sequence of Barbarea vulgaris facilitates the study of ecological biochemistry. AB - The genus Barbarea has emerged as a model for evolution and ecology of plant defense compounds, due to its unusual glucosinolate profile and production of saponins, unique to the Brassicaceae. One species, B. vulgaris, includes two 'types', G-type and P-type that differ in trichome density, and their glucosinolate and saponin profiles. A key difference is the stereochemistry of hydroxylation of their common phenethylglucosinolate backbone, leading to epimeric glucobarbarins. Here we report a draft genome sequence of the G-type, and re-sequencing of the P-type for comparison. This enables us to identify candidate genes underlying glucosinolate diversity, trichome density, and study the genetics of biochemical variation for glucosinolate and saponins. B. vulgaris is resistant to the diamondback moth, and may be exploited for "dead-end" trap cropping where glucosinolates stimulate oviposition and saponins deter larvae to the extent that they die. The B. vulgaris genome will promote the study of mechanisms in ecological biochemistry to benefit crop resistance breeding. PMID- 28094807 TI - Antimicrobial Probiotics Reduce Salmonella enterica in Turkey Gastrointestinal Tracts. AB - Despite the arsenal of technologies employed to control foodborne nontyphoidal Salmonella (NTS), infections have not declined in decades. Poultry is the primary source of NTS outbreaks, as well as the fastest growing meat sector worldwide. With recent FDA rules for phasing-out antibiotics in animal production, pressure is mounting to develop new pathogen reduction strategies. We report on a technology to reduce Salmonella enteritidis in poultry. We engineered probiotic E. coli Nissle 1917, to express and secrete the antimicrobial peptide, Microcin J25. Using in vitro experiments and an animal model of 300 turkeys, we establish the efficacy of this technology. Salmonella more rapidly clear the ceca of birds administered the modified probiotic than other treatment groups. Approximately 97% lower Salmonella carriage is measured in a treated group, 14 days post Salmonella challenge. Probiotic bacteria are generally regarded as safe to consume, are bile-resistant and can plausibly be modified to produce a panoply of antimicrobial peptides now known. The reported systems may provide a foundation for platforms to launch antimicrobials against gastrointestinal tract pathogens, including ones that are multi-drug resistant. PMID- 28094806 TI - Plant toxin beta-ODAP activates integrin beta1 and focal adhesion: A critical pathway to cause neurolathyrism. AB - Neurolathyrism is a unique neurodegeneration disease caused by beta-N-oxalyl-L alpha, beta- diaminopropionic (beta-ODAP) present in grass pea seed (Lathyrus stativus L.) and its pathogenetic mechanism is unclear. This issue has become a critical restriction to take full advantage of drought-tolerant grass pea as an elite germplasm resource under climate change. We found that, in a human glioma cell line, beta-ODAP treatment decreased mitochondrial membrane potential, leading to outside release and overfall of Ca2+ from mitochondria to cellular matrix. Increased Ca2+ in cellular matrix activated the pathway of ECM, and brought about the overexpression of beta1 integrin on cytomembrane surface and the phosphorylation of focal adhesion kinase (FAK). The formation of high concentration of FA units on the cell microfilaments further induced overexpression of paxillin, and then inhibited cytoskeleton polymerization. This phenomenon turned to cause serious cell microfilaments distortion and ultimately cytoskeleton collapse. We also conducted qRT-PCR verification on RNA-sequence data using 8 randomly chosen genes of pathway enrichment, and confirmed that the data was statistically reliable. For the first time, we proposed a relatively complete signal pathway to neurolathyrism. This work would help open a new window to cure neurolathyrism, and fully utilize grass pea germplasm resource under climate change. PMID- 28094808 TI - Butterfly eyespot organiser: in vivo imaging of the prospective focal cells in pupal wing tissues. AB - Butterfly wing eyespot patterns are determined in pupal tissues by organisers located at the centre of the prospective eyespots. Nevertheless, organiser cells have not been examined cytochemically in vivo, partly due to technical difficulties. Here, we directly observed organiser cells in pupal forewing epithelium via an in vivo confocal fluorescent imaging technique, using 1-h post pupation pupae of the blue pansy butterfly, Junonia orithya. The prospective eyespot centre was indented from the plane of the ventral tissue surface. Three dimensional reconstruction images revealed that the apical portion of "focal cells" at the bottom of the eyespot indentation contained many mitochondria. The mitochondrial portion was connected with a "cell body" containing a nucleus. Most focal cells had globular nuclei and were vertically elongated, but cells in the wing basal region had flattened nuclei and were tilted toward the distal direction. Epithelial cells in any wing region had cytoneme-like horizontal processes. From 1 h to 10 h post-pupation, nuclear volume increased, suggesting DNA synthesis during this period. Morphological differences among cells in different regions may suggest that organiser cells are developmentally ahead of cells in other regions and that position-dependent heterochronic development is a general mechanism for constructing colour patterns in butterfly wings. PMID- 28094809 TI - Genome-wide identification, evolution and expression analysis of RING finger protein genes in Brassica rapa. AB - More and more RING finger genes were found to be implicated in various important biological processes. In the present study, a total of 731 RING domains in 715 predicted proteins were identified in Brassica rapa genome (AA, 2n = 20), which were further divided into eight types: RING-H2 (371), RING-HCa (215), RING-HCb (47), RING-v (44), RING-C2 (38), RING-D (10), RING-S/T (5) and RING-G (1). The 715 RING finger proteins were further classified into 51 groups according to the presence of additional domains. 700 RING finger protein genes were mapped to the 10 chromosomes of B. rapa with a range of 47 to 111 genes for each chromosome. 667 RING finger protein genes were expressed in at least one of the six tissues examined, indicating their involvement in various physiological and developmental processes in B. rapa. Hierarchical clustering analysis of RNA-seq data divided them into seven major groups, one of which includes 231 members preferentially expressed in leaf, and constitutes then a panel of gene candidates for studying the genetic and molecular mechanisms of leafy head traits in Brassica crops. Our results lay the foundation for further studies on the classification, evolution and putative functions of RING finger protein genes in Brassica species. PMID- 28094810 TI - Aberrant development of intrinsic brain activity in a rat model of caregiver maltreatment of offspring. AB - Caregiver maltreatment induces vulnerability to later-life psychopathology. Clinical and preclinical evidence suggest changes in prefrontal and limbic circuitry underlie this susceptibility. We examined this question using a rat model of maternal maltreatment and methods translated from humans, resting-state functional magnetic resonance imaging (R-fMRI). Rat pups were reared by mothers provided with insufficient or abundant bedding for nest building from postnatal (PN) days 8 to 12 and underwent behavioral assessments of affect-related behaviors (forced swim, sucrose preference and social interaction) in adolescence (PN45) and early adulthood (PN60). R-fMRI sessions were conducted under light anesthesia at both ages. Offspring reared with insufficient bedding (that is, maltreated) displayed enduring negative affective behaviors. Amygdala-prefrontal cortex (PFC) functional connectivity increased significantly from adolescence to adulthood in controls, but not in maltreated animals. We computed the fractional amplitude of low-frequency fluctuations (fALFF), an index of intrinsic brain activity, and found that fALFF in medial prefrontal cortex and anterior cingulate cortex (MPFC/ACC) increased significantly with age in controls but remained unchanged in maltreated animals during adolescence and adulthood. We used a seed based analysis to explore changes in functional connectivity between this region and the whole brain. Compared with controls, maltreated animals demonstrated reduced functional connectivity between MPFC/ACC and left caudate/putamen across both ages. Functional connectivity between MPFC/ACC and right caudate/putamen showed a group by age interaction: decreased in controls but increased in maltreated animals. These data suggest that maltreatment induces vulnerability to psychopathology and is associated with differential developmental trajectories of prefrontal and subcortical circuits underlying affect regulation. PMID- 28094811 TI - Brain connectivity changes occurring following cognitive behavioural therapy for psychosis predict long-term recovery. AB - Little is known about the psychobiological mechanisms of cognitive behavioural therapy for psychosis (CBTp) and which specific processes are key in predicting favourable long-term outcomes. Following theoretical models of psychosis, this proof-of-concept study investigated whether the long-term recovery path of CBTp completers can be predicted by the neural changes in threat-based social affective processing that occur during CBTp. We followed up 22 participants who had undergone a social affective processing task during functional magnetic resonance imaging along with self-report and clinician-administered symptom measures, before and after receiving CBTp. Monthly ratings of psychotic and affective symptoms were obtained retrospectively across 8 years since receiving CBTp, plus self-reported recovery at final follow-up. We investigated whether these long-term outcomes were predicted by CBTp-led changes in functional connections with dorsal prefrontal cortical and amygdala during the processing of threatening and prosocial facial affect. Although long-term psychotic symptoms were predicted by changes in prefrontal connections during prosocial facial affective processing, long-term affective symptoms were predicted by threat related amygdalo-inferior parietal lobule connectivity. Greater increases in dorsolateral prefrontal cortex connectivity with amygdala following CBTp also predicted higher subjective ratings of recovery at long-term follow-up. These findings show that reorganisation occurring at the neural level following psychological therapy can predict the subsequent recovery path of people with psychosis across 8 years. This novel methodology shows promise for further studies with larger sample size, which are needed to better examine the sensitivity of psychobiological processes, in comparison to existing clinical measures, in predicting long-term outcomes. PMID- 28094812 TI - Putative presynaptic dopamine dysregulation in schizophrenia is supported by molecular evidence from post-mortem human midbrain. AB - The dopamine hypothesis of schizophrenia posits that increased subcortical dopamine underpins psychosis. In vivo imaging studies indicate an increased presynaptic dopamine synthesis capacity in striatal terminals and cell bodies in the midbrain in schizophrenia; however, measures of the dopamine-synthesising enzyme, tyrosine hydroxylase (TH), have not identified consistent changes. We hypothesise that dopamine dysregulation in schizophrenia could result from changes in expression of dopamine synthesis enzymes, receptors, transporters or catabolic enzymes. Gene expression of 12 dopamine-related molecules was examined in post-mortem midbrain (28 antipsychotic-treated schizophrenia cases/29 controls) using quantitative PCR. TH and the synaptic dopamine transporter (DAT) proteins were examined in post-mortem midbrain (26 antipsychotic-treated schizophrenia cases per 27 controls) using immunoblotting. TH and aromatic acid decarboxylase (AADC) mRNA and TH protein were unchanged in the midbrain in schizophrenia compared with controls. Dopamine receptor D2 short, vesicular monoamine transporter (VMAT2) and DAT mRNAs were significantly decreased in schizophrenia, with no change in DRD3 mRNA, DRD3nf mRNA and DAT protein between diagnostic groups. However, DAT protein was significantly increased in putatively treatment-resistant cases of schizophrenia compared to putatively treatment responsive cases. Midbrain monoamine oxidase A (MAOA) mRNA was increased, whereas MAOB and catechol-O-methyl transferase mRNAs were unchanged in schizophrenia. We conclude that, whereas some mRNA changes are consistent with increased dopamine action (decreased DAT mRNA), others suggest reduced dopamine action (increased MAOA mRNA) in the midbrain in schizophrenia. Here, we identify a molecular signature of dopamine dysregulation in the midbrain in schizophrenia that mainly includes gene expression changes of molecules involved in dopamine synthesis and in regulating the time course of dopamine action. PMID- 28094814 TI - Meta-analysis reveals associations between genetic variation in the 5' and 3' regions of Neuregulin-1 and schizophrenia. AB - Genetic, post-mortem and neuroimaging studies repeatedly implicate neuregulin-1 (NRG1) as a critical component in the pathophysiology of schizophrenia. Although a number of risk haplotypes along with several genetic polymorphisms in the 5' and 3' regions of NRG1 have been linked with schizophrenia, results have been mixed. To reconcile these conflicting findings, we conducted a meta-analysis examining 22 polymorphisms and two haplotypes in NRG1 among 16 720 cases, 20 449 controls and 2157 family trios. We found significant associations for three polymorphisms (rs62510682, rs35753505 and 478B14-848) at the 5'-end and two (rs2954041 and rs10503929) near the 3'-end of NRG1. Population stratification effects were found for the rs35753505 and 478B14-848(4) polymorphisms. There was evidence of heterogeneity for all significant markers and the findings were robust to publication bias. No significant haplotype associations were found. Our results suggest genetic variation at the 5' and 3' ends of NRG1 are associated with schizophrenia and provide renewed justification for further investigation of NRG1's role in the pathophysiology of schizophrenia. PMID- 28094813 TI - A methylome-wide mQTL analysis reveals associations of methylation sites with GAD1 and HDAC3 SNPs and a general psychiatric risk score. AB - Genome-wide association studies have identified a number of single-nucleotide polymorphisms (SNPs) that are associated with psychiatric diseases. Increasing body of evidence suggests a complex connection of SNPs and the transcriptional and epigenetic regulation of gene expression, which is poorly understood. In the current study, we investigated the interplay between genetic risk variants, shifts in methylation and mRNA levels in whole blood from 223 adolescents distinguished by a risk for developing psychiatric disorders. We analyzed 37 SNPs previously associated with psychiatric diseases in relation to genome-wide DNA methylation levels using linear models, with Bonferroni correction and adjusting for cell-type composition. Associations between DNA methylation, mRNA levels and psychiatric disease risk evaluated by the Development and Well-Being Assessment (DAWBA) score were identified by robust linear models, Pearson's correlations and binary regression models. We detected five SNPs (in HCRTR1, GAD1, HADC3 and FKBP5) that were associated with eight CpG sites, validating five of these SNP CpG pairs. Three of these CpG sites, that is, cg01089319 (GAD1), cg01089249 (GAD1) and cg24137543 (DIAPH1), manifest in significant gene expression changes and overlap with active regulatory regions in chromatin states of brain tissues. Importantly, methylation levels at cg01089319 were associated with the DAWBA score in the discovery group. These results show how distinct SNPs linked with psychiatric diseases are associated with epigenetic shifts with relevance for gene expression. Our findings give a novel insight on how genetic variants may modulate risks for the development of psychiatric diseases. PMID- 28094815 TI - DRD2 co-expression network and a related polygenic index predict imaging, behavioral and clinical phenotypes linked to schizophrenia. AB - Genetic risk for schizophrenia (SCZ) is determined by many genetic loci whose compound biological effects are difficult to determine. We hypothesized that co expression pathways of SCZ risk genes are associated with system-level brain function and clinical phenotypes of SCZ. We examined genetic variants related to the dopamine D2 receptor gene DRD2 co-expression pathway and associated them with working memory (WM) behavior, the related brain activity and treatment response. Using two independent post-mortem prefrontal messenger RNA (mRNA) data sets (total N=249), we identified a DRD2 co-expression pathway enriched for SCZ risk genes. Next, we identified non-coding single-nucleotide polymorphisms (SNPs) associated with co-expression of this pathway. These SNPs were associated with regulatory genetic loci in the dorsolateral prefrontal cortex (P<0.05). We summarized their compound effect on co-expression into a Polygenic Co-expression Index (PCI), which predicted DRD2 pathway co-expression in both mRNA data sets (all P<0.05). We associated the PCI with brain activity during WM performance in two independent samples of healthy individuals (total N=368) and 29 patients with SCZ who performed the n-back task. Greater predicted DRD2 pathway prefrontal co expression was associated with greater prefrontal activity and longer WM reaction times (all corrected P<0.05), thus indicating inefficient WM processing. Blind prediction of treatment response to antipsychotics in two independent samples of patients with SCZ suggested better clinical course of patientswith greater PCI (total N=87; P<0.05). The findings on this DRD2 co-expression pathway are a proof of concept that gene co-expression can parse SCZ risk genes into biological pathways associated with intermediate phenotypes as well as with clinically meaningful information. PMID- 28094817 TI - Immune dysfunction and neuroinflammation in autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder with a complex pathogenesis. Many studies over the last four decades have recognized altered immune responses among individuals diagnosed with ASD. The purpose of this critical and comprehensive review is to examine the hypothesis that immune dysfunction is present more frequently, and it is related to ASD in humans. It was found that that often individuals diagnosed with ASD have alterations in immune cells such as T cells, B cells, monocytes, natural killer cells, and dendritic cells. Also, many individuals diagnosed with ASD have alterations in immunoglobulins and increased autoantibodies. Finally, an important portion of individuals diagnosed with ASD has elevated peripheral cytokines and chemokines and associated neuroinflammation. In conclusion, immune dysregulation and inflammation are important components of ASD diagnosis and are key components of the diagnosis and treatment of ASD. PMID- 28094816 TI - Methylation specific targeting of a chromatin remodeling complex from sponges to humans. AB - DNA cytosine methylation and methyl-cytosine binding domain (MBD) containing proteins are found throughout all vertebrate species studied to date. However, both the presence of DNA methylation and pattern of methylation varies among invertebrate species. Invertebrates generally have only a single MBD protein, MBD2/3, that does not always contain appropriate residues for selectively binding methylated DNA. Therefore, we sought to determine whether sponges, one of the most ancient extant metazoan lineages, possess an MBD2/3 capable of recognizing methylated DNA and recruiting the associated nucleosome remodeling and deacetylase (NuRD) complex. We find that Ephydatia muelleri has genes for each of the NuRD core components including an EmMBD2/3 that selectively binds methylated DNA. NMR analyses reveal a remarkably conserved binding mode, showing almost identical chemical shift changes between binding to methylated and unmethylated CpG dinucleotides. In addition, we find that EmMBD2/3 and EmGATAD2A/B proteins form a coiled-coil interaction known to be critical for the formation of NuRD. Finally, we show that knockdown of EmMBD2/3 expression disrupts normal cellular architecture and development of E. muelleri. These data support a model in which the MBD2/3 methylation-dependent functional role emerged with the earliest multicellular organisms and has been maintained to varying degrees across animal evolution. PMID- 28094818 TI - The physiology of blood platelets and changes of their biological activities in multiple sclerosis. AB - Increasing evidence indicates that blood platelets contribute to diverse processes that extend beyond hemostasis. Many of the same mechanisms that play a role in hemostasis and thrombosis facilitate platelets the participation in other physiological and pathological processes, particularly in the inflammation, the immune response and central nervous system disorders. Platelets are involved in pathophysiology of central nervous system diseases, especially in the pathogenesis of multiple sclerosis, but their role appears to be neglected. Platelets contribute to the inflammation and cooperate with immune cells in inflammatory and immune responses. These blood cells were identified in inflamed spinal cord and in the brain in chronic active lesions of multiple sclerosis and in the related animal models referred as Experimental Autoimmune Encephalomyelitis. This review summarizes recent insights in the platelet activation accompanied by the exocytosis of bioactive compounds stored in granules, formation of platelet microparticles, expression of specific membrane receptors, synthesis of numerous biomediators, generation of free radicals, and introduces the mechanisms by which activated platelets may be involved in the pathophysiology of multiple sclerosis. Understanding the role of platelets in multiple sclerosis may be essential for improved therapies. PMID- 28094819 TI - Age-dependent concomitant changes in synaptic dysfunction and GABAergic pathway in the APP/PS1 mouse model. AB - Synaptic dysfunction is a well-documented manifestation in animal models of Alzheimer's disease pathology. In this context, numerous studies have documented reduction in the functionality of synapses in various models. In addition, recent research has shed more light on increased excitability and its link to seizures and seizure-like activities in AD patients as well as in mouse models. These reports of hyperexcitability contradict the observed reduction in synaptic function and have been suggested to be as a result of the interplay between inhibitory and excitatory neuronal mechanism. The present study therefore investigates functional deficiency in the inhibitory system as complementary to the identified alterations in the glutamate excitatory pathway in AD. Since synaptic function deficit in AD is typically linked to progression/pathology of the disease, it is important to determine whether the deficits in the GABAergic system are functional and can be directly linked to the pattern of the disruption documented in the glutamate system. To build on previous research in this field, experiments were designed to determine if previously documented synaptic dysfunction in AD models is concomitantly observed with excitation/inhibition imbalance as suggested by observation of seizure and seizure-like pathology in such models. We report changes in synaptic function in aged APPPS1 mice not observable in the younger cohort. These changes in synaptic function are furthermore accompanied by alteration in the GABAergic neurotransmission. Thus, age-dependent alteration in the inhibitory/excitatory balance might underpin the symptomatic changes observed with the progression of Alzheimer's disease pathology including sleep disturbance and epileptic events. PMID- 28094820 TI - The effect of network template from normal subjects in the detection of network impairment. AB - This study aimed to provide a simple way to approach group differences by independent component analysis when researching functional connectivity changes of resting-state network in brain disorders. We used baseline resting state functional magnetic resonance imaging from the Alzheimer's disease neuroimaging initiative dataset and performed independent component analysis based on different kinds of subject selection, by including two downloaded templates and single-subject independent component analysis method. All conditions were used to calculate the functional connectivity of the default mode network, and to test group differences and evaluate correlation with cognitive measurements and hippocampal volume. The default mode network functional connectivity results most fitting clinical evaluations were from templates based on young healthy subjects and the worst results were from heterogeneous or more severe disease groups or single-subject independent component analysis method. Using independent component analysis network maps derived from normal young subjects to extract all individual functional connectivities provides significant correlations with clinical evaluations. PMID- 28094821 TI - Upregulation of CCL3/MIP-1alpha regulated by MAPKs and NF-kappaB mediates microglial inflammatory response in LPS-induced brain injury. AB - Growing evidence suggests that macrophage inflammatory protein (MIP)-1alpha (synonym CCL3) is upregulated in the neuroinflammatory processes initiated by some brain disorders, but its precise role and regulatory mechanism remain unclear. The present work aims to evaluate the role of CCL3/MIP-1alpha in lipopolysaccharide (LPS)-induced brain injury, and investigate whether the MAPKs and NF-kappaB regulate CCL3/MIP-1alpha expression. We firstly examined the patterns of CCL3/MIP-1alpha expression and phosphorylation of MAPKs in the brains of rats 6, 24, and 72 h after LPS administration. Additionally, LPS-treated rats were administered an anti-MIP-1alpha neutralizing antibody, and the microglial reaction and the expression of both cyclooxygenase-2 and inducible nitric oxide synthase (iNOS) were analyzed. We finally evaluated the effect of an inhibitor of P38 MAPK, an inhibitor of ERK1/2, or an inhibitor of NF-kappaB, on the levels of CCL3/MIP-1alpha protein and numbers of microglia in the brain. In the observation period, LPS induced CCL3/MIP-1alpha expression, which localized to OX-42-labeled microglia, leading to time-dependent increases in the phosphorylation of P38 MAPK and ERK1/2. The expression pattern of induced CCL3/MIP-1alpha was partly consistent with the phosphorylation of MAPKs (P38 MAPK, ERK1/2). Anti-MIP-1alpha attenuated microglial accumulation and the upregulation of cyclooxygenase-2 and iNOS. The inhibition of P38 MAPK, ERK1/2, or NF-kappaB signaling reduced the induced upregulation of CCL3/MIP-1alpha and the microglial accumulation. Our data suggest that upregulated CCL3/MIP-1alpha mediates the accumulation of microglia and the neuroinflammatory reaction, and its expression may be regulated by MAPKs and NF-kappaB in LPS-induced brain injury. PMID- 28094822 TI - Analysis of methionine synthase (rs1805087) gene polymorphism in autism patients in Northern Iran. AB - Autism is characterized by impairment in reciprocal communication and speech, repetitive behaviors, and social communication. The genetic and environmental factors play roles in the pathogenesis of autism. It was recently shown that the genes involved in the folate/homocysteine pathway may be risk factors for autistic children. One of the genes that may be the risk factor for autism is Methionine synthase (MTR). MTR is responsible for the regeneration of methionine from homocysteine. The aim of this study was to analyze the association of MTR A2756G gene polymorphism (rs1805087) and the risk of autism in a population in northern Iran. The prevalence of MTR A2756G polymorphism was determined in 108 children with autism and 130 controls in northern Iran. Genotypes and allele frequencies were determined in patients and controls by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The prevalence of genotype frequencies of AA, AG and GG in autistic children were 57.41%, 22.22% and 20.37%, respectively, while in controls were 61.54%, 32.31% and 6.15%, respectively. There was significant difference between the MTR polymorphism distribution in control and patient groups. The prevalence of allele frequencies of A and G in autistic children were 0.69 and 0.31, respectively and in controls were 0.78 and 0.22, respectively (P=0.03). The MTR G allele conferred a 1.6-fold increased risk to autism relative to the A allele (95% CI=1.06-2.41, P=0.02). The present study suggests that the G allele of MTR A2756G polymorphism is associated with an increased risk of autism. PMID- 28094823 TI - Anhedonia but not passive floating is an indicator of depressive-like behavior in two chronic stress paradigms. AB - Depression is the most common form of mental disability in the world. Depressive episodes may be precipitated by severe acute stressful events or by mild chronic stressors. Studies on the mechanisms of depression require both appropriate experimental models (most of them based on the exposure of animals to chronic stressors), and appropriate tests for assessment of depressive states. In this study male Wistar rats were exposed to two different chronic stress paradigms: an eight-week chronic unpredictable mild stress or a two-week combined chronic stress. The behavioral effects of stress were evaluated using sucrose preference, forced swim and open field tests. After the exposure to chronic unpredictable mild stress, anhedonia was developed, activity in the open field increased, while no changes in the duration of passive floating could be detected. After chronic combined stress, anhedonia was also evident, whereas behavior in the open field and forced swim test did not change. The levels of corticosterone in the blood and brain structures involved in stress-response did not differ from control in both experiments. The absence of significant changes in corticosterone levels and passive floating may be indicative of the adaptation of animals to chronic stress. Anhedonia appears to be a more sensitive indicator of depressive-like behavioral effects of chronic stress as compared to behavior in the forced swim or open field tests. PMID- 28094824 TI - Structural Neuroimaging in Polysubstance Users. AB - The simultaneous and/or concurrent use of licit and illicit substances (polysubstance use, PSU) is most common today. Structural magnetic resonance imaging (MRI) has been applied extensively to study individuals ostensibly using a single substance. These studies have produced a picture of regional gray matter and white matter alterations with each substance or class of substances. Very few studies measured regional brain morphometry in today's polysubstance users. This limited data suggest morphometric alterations with PSU that are not simply additive but often different from those of monosubstance users. Specifically, subcortical volume enlargements are observed that may be tied to mechanisms that also oppose volume reductions in cortical brain regions, thereby underestimating actual cortical atrophy. The complex actions of polysubstance use on brain structure and function need greater scrutiny with strong methodological approaches to inform more efficient treatment of polysubstance users. PMID- 28094825 TI - What people want in a prosthetic foot: A focus group study. PMID- 28094826 TI - Response to: Dittrich et al.: Non-Embryo-Destructive Extraction of Pluripotent Embryonic Stem Cells - Overlooked Legal Prohibitions, Professional Legal Consequences and Inconsistencies in Patent Law. AB - The publication of "Non-embryo-destructive Extraction of Pluripotent Embryonic Stem Cells: Implications for Regenerative Medicine and Reproductive Medicine" by Dittrich et al. in Geburtshilfe und Frauenheilkunde 2015; 75: 1239-1242 1 describes various possibilities which could result from the non-embryo destructive extraction of embryonic stem cells from human blastocysts. But implementing this method is more problematic, both legally and ethically, than the authors have represented it to be and is illegal in Germany. German patent DE 10 2004 062 184 on the non-embryo-destructive extraction of embryonic stem cells referred to by Dittrich et al. contravenes the higher-ranking case-law of the European Court of Justice. Ultimately, the non-embryo-destructive harvesting of embryonic stem cells with the aim of storing these cells for use in potential therapies as proposed by Dittrich et al. is prohibited in Germany and could lead to criminal prosecution. PMID- 28094828 TI - Highly sensitive and fast monolayer WS2 phototransistors realized by SnS nanosheet decoration. AB - Two-dimensional chalcogenide monolayers are strong candidates for next-generation flexible and transparent optoelectronics. Due to the intrinsic ultrathin thickness and limited optical absorption, however, their responsivity is normally low. Here we develop a simple and low-cost method to fabricate high-performance hybrid phototransistors of monolayer WS2 with significantly enhanced responsivity and an extended spectral response range, by virtue of surface decoration with liquid-phase exfoliated SnS nanosheets (NSs). The hybrid phototransistors show a much enhanced responsivity of ~2 A W-1 and an ultrahigh light/dark signal-to noise ratio of 106 under 457 nm excitation, exhibiting a significant increase of 3 orders of magnitude in responsivity and a 100 fold increase in signal-to-noise ratio, compared with pure WS2 devices. Our hybrid photodetectors also exhibit a respectable response speed, with a rise and decay time of 51 MUs and 98 MUs, respectively. After optimal surface decoration with narrow bandgap SnS NSs atop a monolayer WS2 channel, an emergent optical responsivity in the near infrared region (1064 nm) is also observed. PMID- 28094829 TI - News from Environmental Science: Processes & Impacts. PMID- 28094830 TI - Molecular electron acceptors for efficient fullerene-free organic solar cells. AB - Nowadays, organic solar cells (OSCs) with efficiencies over 10% have been achieved through the elaborate design of electron donors and fullerene acceptors. However, the drawbacks of fullerene acceptors, like poor absorption, limited chemical and energetic tunabilities, high-cost purification and morphological instability, have become the bottlenecks for the further improvement of OSCs. To overcome the mentioned shortages from fullerene, research studies on non fullerene electron acceptors have boomed. To date, the highest efficiency of fullerene-free OSCs has been pushed to be 12%, which surpasses that of fullerene based OSCs. In this perspective, we focus on summarizing the development of small molecule electron acceptors designed to replace the fullerene derivatives. Since it has been revealed that the search for matched donor:acceptor pairs is important for accomplishing high efficiencies, we therefore divide electron acceptors into several categories according to the donors used in fullerene-free OSCs. After the introduction of these acceptors, we outline the designing rules as well as perspectives for the development of non-fullerene acceptors. We believe that the development of non-fullerene electron acceptors will make organic photovoltaics closer to practical applications. PMID- 28094831 TI - [The child immunisation programme--effective but insufficient. Experiences from the Astrid Lindgren pediatric hospital, 2008-2013]. AB - The national Swedish immunisation programme includes vaccine against diphtheria, tetanus, polio, pertussis, Haemophilus influenzae type B, Pneumococcus as well as measles, mumps and rubella. Data were collected on hospital admissions for children 0- 17 years of age of vaccine-preventable diseases during 2008-2013 at Astrid Lindgren Children's Hospital, Stockholm. Patients were identified by discharge diagnosis codes as well as from the clinical microbiology laboratory. There were rare cases of measles and mumps, and only a few cases of invasive bacterial diseases. The dominating pathogens were influenza A and B, rotavirus and varicella zoster virus. Our national programme is effective, but vaccine preventable infections still cause significant morbidity in young children. An extended vaccine programme might significantly reduce the need of hospitalisations. PMID- 28094832 TI - [Prescribed drug use for bipolar disorder type I and II in clinical practice]. AB - Prescribed drug use for bipolar disorder type I and II in clinical practice Practice guidelines based on available evidence and clinical consensus are available for the treatment of bipolar disorder. We surveyed to which extent those guidelines are implemented in clinical practice in Sweden. We analysed pharmacological treatment in patients with bipolar disorder in 2015 using the national quality register for bipolar disorder (BipolaR). We compared bipolar disorder type I (BDI) with type bipolar disorder type II (BDII). The vast majority of patients were prescribed a mood stabilizer either as monotherapy or as a part of combination therapy (BDI 87%, BDII 83%, p<0.001). Whereas lithium was the most common mood stabilizer in type I (BDI 65%, BDII 40%, p<0.001), lamotrigine was the most common mood stabilizer in type II (BDI 18%, BDII 42%, p<0.001). Antidepressants were less common in BDI than BDII (35% vs. 53%, p<0.001). Antipsychotic drugs (first or second generation) were more frequently used in BDI than BDII (49% vs 35%, p<0.001). Central stimulants were rarely used (BDI 3.1%, BDII 6.6%, p<0.001). Combining a mood stabilizer with an antipsychotic drug was more common in BDI than BDII (27% vs. 12%, p<0.001), whereas combining a mood stabilizer with an antidepressant was less common in BDI than BDII (16% vs 28%, p<0.001). We conclude that most patients are prescribed mood stabilizers and that the differences between BDI and BDII are rational given the differences in clinical manifestations. The use of antidepressants is surprisingly high given the long-standing debate about the risk and effectiveness of this class in bipolar disorder. PMID- 28094834 TI - ? PMID- 28094833 TI - [First aid proposal for the TV lawyers' eczema]. PMID- 28094835 TI - [Sahlgrenska should take an "acid test"]. PMID- 28094836 TI - [Management theory in a new suit--or the emperor's new clothes]. PMID- 28094837 TI - [Should value-based care be introduced by consultants without scientific evidence?]. PMID- 28094838 TI - [Health care alarmists counteracts quality development]. PMID- 28094839 TI - Improved fluorescence assays to measure the defects associated with F508del-CFTR allow identification of new active compounds. AB - BACKGROUND AND PURPOSE: Cystic fibrosis (CF) is a debilitating disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which codes for a Cl-/HCO3 - channel. F508del, the most common CF-associated mutation, causes both gating and biogenesis defects in the CFTR protein. This paper describes the optimization of two fluorescence assays, capable of measuring CFTR function and cellular localization, and their use in a pilot drug screen. EXPERIMENTAL APPROACH: HEK293 cells expressing YFP-F508del-CFTR, in which halide sensitive YFP is tagged to the N-terminal of CFTR, were used to screen a small library of compounds based on the VX-770 scaffold. Cells expressing F508del-CFTR pHTomato, in which a pH sensor is tagged to the fourth extracellular loop of CFTR, were used to measure CFTR plasma membrane exposure following chronic treatment with the novel potentiators. KEY RESULTS: Active compounds with efficacy ~50% of VX-770, micromolar potency, and structurally distinct from VX 770 were identified in the screen. The F508del-CFTR-pHTomato assay suggests that the hit compound MS131A, unlike VX-770, does not decrease membrane exposure of F508del-CFTR. CONCLUSIONS AND IMPLICATIONS: Most known potentiators have a negative influence on F508del-CFTR biogenesis/stability, which means membrane exposure needs to be monitored early during the development of drugs targeting CFTR. The combined use of the two fluorescence assays described here provides a useful tool for the identification of improved potentiators and correctors. The assays could also prove useful for basic scientific investigations on F508del CFTR, and other CF-causing mutations. PMID- 28094840 TI - Hypertensive disorders in pregnancy and later dementia: a Swedish National Register Study. AB - INTRODUCTION: Our aim was to investigate the rate of vascular dementia and dementia in women with previous hypertensive disorders in pregnancy, since white matter lesions of the brain and cardiovascular disease are linked both to dementia and hypertensive disorders in pregnancy. MATERIAL AND METHODS: Prospective population-based registry study on all women giving birth in Sweden between 1973 and 1975 (284 598). Women with and without hypertensive disorders in pregnancy were identified by means of the Swedish Medical Birth Register and linked to the National Patient Register, where data on somatic disease later in life were obtained. International classification of disease was used. The Cox proportional hazard model was used to calculate hazard ratios for both groups and adjusted for possible confounders. Main outcome measures were in-hospital diagnosis of cardiovascular disease, vascular dementia and dementia. RESULTS: No increased risks were seen for vascular dementia or dementia after any hypertensive disorders in pregnancy. If broken down in specific diagnoses for hypertensive disease in pregnancy, adjusted risks for vascular dementia after hypertension and proteinuria during pregnancy the hazard ratio was 6.27 (95% CI 1.65-27.44). Higher risks for cardiovascular disease were confirmed. CONCLUSIONS: Because of the very low absolute risk, the wide confidence interval and risk of misclassification, our results on vascular dementia could be questioned. Considering the pathophysiology of preeclampsia, the findings of brain lesions and the increased risk for cardiovascular disease, the possibly increased risk for all kinds of dementia must be investigated in larger and more well-defined cohorts. PMID- 28094841 TI - Phase 2, randomized, double-blind study of pracinostat in combination with azacitidine in patients with untreated, higher-risk myelodysplastic syndromes. AB - BACKGROUND: The prognosis of patients with higher-risk myelodysplastic syndromes (MDS) remains poor despite available therapies. Histone deacetylase inhibitors have demonstrated activity in patients with MDS and in vitro synergy with azacitidine. METHODS: A phase 2 randomized, placebo-controlled clinical trial of azacitidine and pracinostat was conducted in patients who had International Prognostic Scoring System intermediate-2-risk or high-risk MDS. The primary endpoint was the complete response (CR) rate by cycle 6 of therapy. RESULTS: Of 102 randomized patients, there were 51 in the pracinostat group and 51 in the placebo group. The median age was 69 years. The CR rate by cycle 6 of therapy was 18% and 33% (P = .07) in the pracinostat and placebo groups, respectively. No significant differences in overall survival (median, 16 vs 19 months, respectively; hazard ratio, 1.21; 95% confidence interval, 0.66-2.23) or progression-free survival (11 vs 9 months, respectively; hazard ratio, 0.82; 95% confidence interval, 0.546-1.46) were observed between groups. Grade >=3 adverse events occurred more frequently in the pracinostat group (98% vs 74%), leading to more treatment discontinuations (20% vs 10%). CONCLUSIONS: The combination of azacitidine with pracinostat did not improve outcomes in patients with higher risk MDS. Higher rates of treatment discontinuation may partially explain these results, suggesting alternative dosing and schedules to improve tolerability may be required to determine the potential of the combination. Cancer 2017;123:994 1002. (c) 2016 American Cancer Society. PMID- 28094842 TI - Impact of microbial invasion of amniotic cavity and the type of microorganisms on short-term neonatal outcome in women with preterm labor and intact membranes. AB - INTRODUCTION: The objective of this study was to evaluate the impact of microbial invasion of the amniotic cavity and the type of microorganisms on pregnancy and short-term neonatal outcomes in women with preterm labor. MATERIAL AND METHODS: Prospective observational cohort study including women with preterm labor from 22.0 to 36.0 weeks. Microbial invasion of the amniotic cavity was defined based on amniotic fluid aerobic/anaerobic/mycoplasma cultures, and intra-amniotic inflammation on amniotic fluid interleukin-6 levels. Demographic data and pregnancy outcomes were compared among women exposed to microbial invasion of the amniotic cavity by Ureaplasma spp., women with microbial invasion of the amniotic cavity by other microorganisms, and a No-microbial invasion of the amniotic cavity/No-intra-amniotic inflammation group. The short-term neonatal outcome was evaluated in women delivering after 24.0 weeks. RESULTS: We included 228 women with preterm labor. Microbial invasion of the amniotic cavity occurred in 35% (80/228), 28% (22/80) being caused by Ureaplasma spp. Gestational age at admission and at delivery were significantly earlier and the rate of delivery at <24.0 weeks' gestation and of women who further developed clinical chorioamnionitis were significantly higher in women with microbial invasion of the amniotic cavity by microorganisms other than Ureaplasma spp. However, after 24 weeks, regardless of the microorganisms isolated, the short-term neonatal outcome was similar between women exposed to microbial invasion of the amniotic cavity and the No-microbial invasion of the amniotic cavity/No-intra-amniotic inflammation group when gestational age was considered. CONCLUSIONS: Microbial invasion of the amniotic cavity by microorganisms other than Ureaplasma spp. was associated with earlier gestational age at admission and at delivery, and a higher rate of preterm delivery <24.0 weeks and of women who developed clinical chorioamnionitis. However, we did not find differences in the short-term neonatal outcome between women exposed to microbial invasion of the amniotic cavity and the no-microbial invasion of the amniotic cavity/no-intra-amniotic inflammation group delivering after 24.0 weeks' gestation when adjusted by gestational age at delivery. PMID- 28094843 TI - Hypomethylating agents in combination with histone deacetylase inhibitors in higher risk myelodysplastic syndromes: Is there a light at the end of the tunnel? PMID- 28094844 TI - Local consolidative therapy may be beneficial in patients with oligometastatic non-small cell lung cancer. PMID- 28094845 TI - Five more years! Not everything changes. PMID- 28094846 TI - Chronic drug-induced effects on contractile motion properties and cardiac biomarkers in human induced pluripotent stem cell-derived cardiomyocytes. AB - BACKGROUND AND PURPOSE: In the pharmaceutical industry risk assessments of chronic cardiac safety liabilities are mostly performed during late stages of preclinical drug development using in vivo animal models. Here, we explored the potential of human induced pluripotent stem cell-derived cardiomyocytes (hiPS CMs) to detect chronic cardiac risks such as drug-induced cardiomyocyte toxicity. EXPERIMENTAL APPROACH: Video microscopy-based motion field imaging was applied to evaluate the chronic effect (over 72 h) of cardiotoxic drugs on the contractile motion of hiPS-CMs. In parallel, the release of cardiac troponin I (cTnI), heart fatty acid binding protein (FABP3) and N-terminal pro-brain natriuretic peptide (NT-proBNP) was analysed from cell medium, and transcriptional profiling of hiPS CMs was done at the end of the experiment. KEY RESULTS: Different cardiotoxic drugs altered the contractile motion properties of hiPS-CMs together with increasing the release of cardiac biomarkers. FABP3 and cTnI were shown to be potential surrogates to predict cardiotoxicity in hiPS-CMs, whereas NT-proBNP seemed to be a less valuable biomarker. Furthermore, drug-induced cardiotoxicity produced by chronic exposure of hiPS-CMs to arsenic trioxide, doxorubicin or panobinostat was associated with different profiles of changes in contractile parameters, biomarker release and transcriptional expression. CONCLUSION AND IMPLICATIONS: We have shown that a parallel assessment of motion field imaging derived contractile properties, release of biomarkers and transcriptional changes can detect diverse mechanisms of chronic drug-induced cardiac liabilities in hiPS CMs. Hence, hiPS-CMs could potentially improve and accelerate cardiovascular de risking of compounds at earlier stages of drug discovery. LINKED ARTICLES: This article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc. PMID- 28094847 TI - Increased regulatory T cell graft content is associated with improved outcome in haematopoietic stem cell transplantation: a systematic review. AB - Allogeneic haematopoietic stem cell transplant (HSCT) recipients are at increased risk of morbidity and mortality, often due to the development of acute or chronic graft-versus-host disease (GVHD). Low numbers or proportions of regulatory T cells (Tregs) have been reported in patients who develop GVHD. We undertook a systematic review of studies that reported the Treg composition of HSCT grafts in patients with haematological malignancies. Fourteen eligible studies were identified, eight of which stratified patients by Tregs (absolute dose or ratio to CD3+ or CD4+ cells). Meta-analyses showed that high levels of Tregs in the grafts were associated with improved overall survival [hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.23-0.74, P = 0.003, 2 studies], with a significant reduction in non-relapse mortality (HR 0.30, 95% CI 0.14-0.64, P = 0.002, 2 studies) and a reduced risk of acute GVHD (relative risk (RR) 0.59, 95% CI 0.40 0.89, P = 0.01, 6 studies). The consistency of these findings strongly suggests that the Treg composition of HSCT grafts has a powerful effect on the success of allogeneic HSCT. The major challenge is to translate these findings into better selection of allografts and future donors to provide a substantial improvement in allogeneic HSCT outcomes and practice. PMID- 28094848 TI - The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging. AB - The American Joint Committee on Cancer (AJCC) staging manual has become the benchmark for classifying patients with cancer, defining prognosis, and determining the best treatment approaches. Many view the primary role of the tumor, lymph node, metastasis (TNM) system as that of a standardized classification system for evaluating cancer at a population level in terms of the extent of disease, both at initial presentation and after surgical treatment, and the overall impact of improvements in cancer treatment. The rapid evolution of knowledge in cancer biology and the discovery and validation of biologic factors that predict cancer outcome and response to treatment with better accuracy have led some cancer experts to question the utility of a TNM-based approach in clinical care at an individualized patient level. In the Eighth Edition of the AJCC Cancer Staging Manual, the goal of including relevant, nonanatomic (including molecular) factors has been foremost, although changes are made only when there is strong evidence for inclusion. The editorial board viewed this iteration as a proactive effort to continue to build the important bridge from a "population-based" to a more "personalized" approach to patient classification, one that forms the conceptual framework and foundation of cancer staging in the era of precision molecular oncology. The AJCC promulgates best staging practices through each new edition in an effort to provide cancer care providers with a powerful, knowledge-based resource for the battle against cancer. In this commentary, the authors highlight the overall organizational and structural changes as well as "what's new" in the Eighth Edition. It is hoped that this information will provide the reader with a better understanding of the rationale behind the aggregate proposed changes and the exciting developments in the upcoming edition. CA Cancer J Clin 2017;67:93-99. (c) 2017 American Cancer Society. PMID- 28094849 TI - The "collimator monitoring fill factor" of a two-dimensional detector array, a measure of its ability to detect collimation errors. AB - PURPOSE: Two-dimensional detector arrays are routinely used for constancy checks and treatment plan verification in photon-beam radiotherapy. In addition to the spatial resolution of the dose profiles, the "coverage" of the radiation field with respect to the detection of any beam collimation deficiency appears as the second characteristic feature of a detector array. The here proposed "collimator monitoring fill factor" (CM fill factor) has been conceived to serve as a quantitative characteristic of this "coverage". METHODS: The CM fill factor is defined as the probability of a 2D array to detect any collimator position error. Therefore, it is represented by the ratio of the "sensitive area" of a single detector, in which collimator position errors are detectable, and the geometrical "cell area" associated with this detector within the array. Numerical values of the CM fill factor have been Monte Carlo simulated for 2D detector arrays equipped with air-vented ionization chambers, liquid-filled ionization chambers and diode detectors and were compared with the "FWHM fill factor" defined by Gago Arias et al. (2012). RESULTS: For arrays with vented ionization chambers, the differences between the CM fill factor and the FWHM fill factor are moderate, but occasionally the latter exceeds unity. For narrower detectors such as liquid filled ionization chambers and Si diodes and for small sampling distances, large differences between the FWHM fill factor and the CM fill factor have been observed. These differences can be explained by the shapes of the fluence response functions of these narrow detectors. CONCLUSIONS: A new parameter "collimator monitoring fill factor" (CM fill factor), applicable to quantitate the collimator position error detection probability of a 2D detector array, has been proposed. It is designed as a help in classifying the clinical performance of two-dimensional detector arrays in photon-beam radiotherapy. PMID- 28094850 TI - Discriminating solitary cysts from soft tissue lesions in mammography using a pretrained deep convolutional neural network. AB - PURPOSE: It is estimated that 7% of women in the western world will develop palpable breast cysts in their lifetime. Even though cysts have been correlated with risk of developing breast cancer, many of them are benign and do not require follow-up. We develop a method to discriminate benign solitary cysts from malignant masses in digital mammography. We think a system like this can have merit in the clinic as a decision aid or complementary to specialized modalities. METHODS: We employ a deep convolutional neural network (CNN) to classify cyst and mass patches. Deep CNNs have been shown to be powerful classifiers, but need a large amount of training data for which medical problems are often difficult to come by. The key contribution of this paper is that we show good performance can be obtained on a small dataset by pretraining the network on a large dataset of a related task. We subsequently investigate the following: (a) when a mammographic exam is performed, two different views of the same breast are recorded. We investigate the merit of combining the output of the classifier from these two views. (b) We evaluate the importance of the resolution of the patches fed to the network. (c) A method dubbed tissue augmentation is subsequently employed, where we extract normal tissue from normal patches and superimpose this onto the actual samples aiming for a classifier invariant to occluding tissue. (d) We combine the representation extracted using the deep CNN with our previously developed features. RESULTS: We show that using the proposed deep learning method, an area under the ROC curve (AUC) value of 0.80 can be obtained on a set of benign solitary cysts and malignant mass findings recalled in screening. We find that it works significantly better than our previously developed approach by comparing the AUC of the ROC using bootstrapping. By combining views, the results can be further improved, though this difference was not found to be significant. We find no significant difference between using a resolution of 100 versus 200 micron. The proposed tissue augmentations give a small improvement in performance, but this improvement was also not found to be significant. The final system obtained an AUC of 0.80 with 95% confidence interval [0.78, 0.83], calculated using bootstrapping. The system works best for lesions larger than 27 mm where it obtains an AUC value of 0.87. CONCLUSION: We have presented a computer-aided diagnosis (CADx) method to discriminate cysts from solid lesion in mammography using features from a deep CNN trained on a large set of mass candidates, obtaining an AUC of 0.80 on a set of diagnostic exams recalled from screening. We believe the system shows great potential and comes close to the performance of recently developed spectral mammography. We think the system can be further improved when more data and computational power becomes available. PMID- 28094851 TI - Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease. AB - BACKROUND: Sickle cell disease is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. Sickle cell disease can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Stroke affects around 10% of children with sickle cell anaemia (HbSS). Chronic blood transfusions may reduce the risk of vaso-occlusion and stroke by diluting the proportion of sickled cells in the circulation.This is an update of a Cochrane Review first published in 2002, and last updated in 2013. OBJECTIVES: To assess risks and benefits of chronic blood transfusion regimens in people with sickle cell disease for primary and secondary stroke prevention (excluding silent cerebral infarcts). SEARCH METHODS: We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 04 April 2016.We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register: 25 April 2016. SELECTION CRITERIA: Randomised controlled trials comparing red blood cell transfusions as prophylaxis for stroke in people with sickle cell disease to alternative or standard treatment. There were no restrictions by outcomes examined, language or publication status. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility and the risk of bias and extracted data. MAIN RESULTS: We included five trials (660 participants) published between 1998 and 2016. Four of these trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of sickle cell disease.Three trials compared regular red cell transfusions to standard care in primary prevention of stroke: two in children with no previous long-term transfusions; and one in children and adolescents on long-term transfusion.Two trials compared the drug hydroxyurea (hydroxycarbamide) and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children); and one in secondary prevention (children and adolescents).The quality of the evidence was very low to moderate across different outcomes according to GRADE methodology. This was due to the trials being at a high risk of bias due to lack of blinding, indirectness and imprecise outcome estimates. Red cell transfusions versus standard care Children with no previous long-term transfusionsLong-term transfusions probably reduce the incidence of clinical stroke in children with a higher risk of stroke (abnormal transcranial doppler velocities or previous history of silent cerebral infarct), risk ratio 0.12 (95% confidence interval 0.03 to 0.49) (two trials, 326 participants), moderate quality evidence.Long-term transfusions may: reduce the incidence of other sickle cell disease-related complications (acute chest syndrome, risk ratio 0.24 (95% confidence interval 0.12 to 0.48)) (two trials, 326 participants); increase quality of life (difference estimate -0.54, 95% confidence interval -0.92 to -0.17) (one trial, 166 participants); but make little or no difference to IQ scores (least square mean: 1.7, standard error 95% confidence interval -1.1 to 4.4) (one trial, 166 participants), low quality evidence.We are very uncertain whether long-term transfusions: reduce the risk of transient ischaemic attacks, Peto odds ratio 0.13 (95% confidence interval 0.01 to 2.11) (two trials, 323 participants); have any effect on all-cause mortality, no deaths reported (two trials, 326 participants); or increase the risk of alloimmunisation, risk ratio 3.16 (95% confidence interval 0.18 to 57.17) (one trial, 121 participants), very low quality evidence. Children and adolescents with previous long-term transfusions (one trial, 79 participants)We are very uncertain whether continuing long-term transfusions reduces the incidence of: stroke, risk ratio 0.22 (95% confidence interval 0.01 to 4.35); or all-cause mortality, Peto odds ratio 8.00 (95% confidence interval 0.16 to 404.12), very low quality evidence.Several review outcomes were only reported in one trial arm (sickle cell disease-related complications, alloimmunisation, transient ischaemic attacks).The trial did not report neurological impairment, or quality of life. Hydroxyurea and phlebotomy versus red cell transfusions and chelationNeither trial reported on neurological impairment, alloimmunisation, or quality of life. Primary prevention, children (one trial, 121 participants)Switching to hydroxyurea and phlebotomy may have little or no effect on liver iron concentrations, mean difference -1.80 mg Fe/g dry-weight liver (95% confidence interval -5.16 to 1.56), low quality evidence.We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: risk of stroke (no strokes); all-cause mortality (no deaths); transient ischaemic attacks, risk ratio 1.02 (95% confidence interval 0.21 to 4.84); or other sickle cell disease related complications (acute chest syndrome, risk ratio 2.03 (95% confidence interval 0.39 to 10.69)), very low quality evidence. Secondary prevention, children and adolescents (one trial, 133 participants)Switching to hydroxyurea and phlebotomy may: increase the risk of sickle cell disease-related serious adverse events, risk ratio 3.10 (95% confidence interval 1.42 to 6.75); but have little or no effect on median liver iron concentrations (hydroxyurea, 17.3 mg Fe/g dry-weight liver (interquartile range 10.0 to 30.6)); transfusion 17.3 mg Fe/g dry-weight liver (interquartile range 8.8 to 30.7), low quality evidence.We are very uncertain whether switching to hydroxyurea and phlebotomy: increases the risk of stroke, risk ratio 14.78 (95% confidence interval 0.86 to 253.66); or has any effect on all-cause mortality, Peto odds ratio 0.98 (95% confidence interval 0.06 to 15.92); or transient ischaemic attacks, risk ratio 0.66 (95% confidence interval 0.25 to 1.74), very low quality evidence. AUTHORS' CONCLUSIONS: There is no evidence for managing adults, or children who do not have HbSS sickle cell disease.In children who are at higher risk of stroke and have not had previous long-term transfusions, there is moderate quality evidence that long-term red cell transfusions reduce the risk of stroke, and low quality evidence they also reduce the risk of other sickle cell disease-related complications.In primary and secondary prevention of stroke there is low quality evidence that switching to hydroxyurea with phlebotomy has little or no effect on the liver iron concentration.In secondary prevention of stroke there is low-quality evidence that switching to hydroxyurea with phlebotomy increases the risk of sickle cell disease-related events.All other evidence in this review is of very low quality. PMID- 28094852 TI - The fluorescent foible of Heinz bodies. PMID- 28094853 TI - High dose-per-pulse electron beam dosimetry - A model to correct for the ion recombination in the Advanced Markus ionization chamber. AB - PURPOSE: The purpose of this work was to establish an empirical model of the ion recombination in the Advanced Markus ionization chamber for measurements in high dose rate/dose-per-pulse electron beams. In addition, we compared the observed ion recombination to calculations using the standard Boag two-voltage-analysis method, the more general theoretical Boag models, and the semiempirical general equation presented by Burns and McEwen. METHODS: Two independent methods were used to investigate the ion recombination: (a) Varying the grid tension of the linear accelerator (linac) gun (controls the linac output) and measuring the relative effect the grid tension has on the chamber response at different source to-surface distances (SSD). (b) Performing simultaneous dose measurements and comparing the dose-response, in beams with varying dose rate/dose-per-pulse, with the chamber together with dose rate/dose-per-pulse independent GafchromicTM EBT3 film. Three individual Advanced Markus chambers were used for the measurements with both methods. All measurements were performed in electron beams with varying mean dose rate, dose rate within pulse, and dose-per-pulse (10-2 <= mean dose rate <= 103 Gy/s, 102 <= mean dose rate within pulse <= 107 Gy/s, 10-4 <= dose per-pulse <= 101 Gy), which was achieved by independently varying the linac gun grid tension, and the SSD. RESULTS: The results demonstrate how the ion collection efficiency of the chamber decreased as the dose-per-pulse increased, and that the ion recombination was dependent on the dose-per-pulse rather than the dose rate, a behavior predicted by Boag theory. The general theoretical Boag models agreed well with the data over the entire investigated dose-per-pulse range, but only for a low polarizing chamber voltage (50 V). However, the two voltage-analysis method and the Burns & McEwen equation only agreed with the data at low dose-per-pulse values (<= 10-2 and <= 10-1 Gy, respectively). An empirical model of the ion recombination in the chamber was found by fitting a logistic function to the data. CONCLUSIONS: The ion collection efficiency of the Advanced Markus ionization chamber decreases for measurements in electron beams with increasingly higher dose-per-pulse. However, this chamber is still functional for dose measurements in beams with dose-per-pulse values up toward and above 10 Gy, if the ion recombination is taken into account. Our results show that existing models give a less-than-accurate description of the observed ion recombination. This motivates the use of the presented empirical model for measurements with the Advanced Markus chamber in high dose-per-pulse electron beams, as it enables accurate absorbed dose measurements (uncertainty estimation: 2.8-4.0%, k = 1). The model depends on the dose-per-pulse in the beam, and it is also influenced by the polarizing chamber voltage, with increasing ion recombination with a lowering of the voltage. PMID- 28094854 TI - Synthesis and antioxidant properties of caffeic acid corn bran arabinoxylan esters. AB - OBJECTIVE: As a potential of bioactive additives, corn bran arabinoxylan (CAX) was prominent in its probiotic benefits and immuno-enhancing activities. To improve the antioxidant ability of CAX, naturally occurring caffeic acid (CA) was covalently attached to CAX by esterification to generate caffeic acid corn bran arabinoxylan esters (CA-CAX) with various degrees of substitution (DS). METHODS: The structure of CA-CAX was analysed by NMR, and the DS was determined by HPLC. The antioxidant activity of CA-CAX was investigated on scavenging the 2,2' diphenyl-1-picrylhydrazyl (DPPH) radical and autoxidazing methyl linoleate, and an aqueous linolenic acid dispersion was also used as an in vitro test system to examine the inhibition effect of CA-CAX on the lipid peroxidation level after UV exposure. The ability of CA-CAX to prevent H2 O2 -induced oxidative damage of cell was studied by reducing MDA levels and increasing SOD and GSH-Px activities in human hepatocarcinoma (HepG2) cell. RESULTS: The results certificated that CA was linked to CAX successfully with various DS. Compared with CAX, the antioxidant capacity of CA-CAX was improved significantly and enhanced with the increasing concentration and DS. PMID- 28094855 TI - Technical Note: Dose distributions in the vicinity of high-density implants using 3D gel dosimeters. AB - PURPOSE: In this work, we develop a methodology for using Fricke gel dosimeters for dose distribution measurements surrounding high-density implants which circumvents artifact production by removing the obstruction during imaging. METHODS: Custom 3D printed molds were used to set cavities in Fricke gel phantoms to allow for the suspension of high-density implants in different geometries. This allowed for the metal valve extracted from a temporary tissue expander to be suspended during irradiation, and removed during optical-CT scanning. RESULTS: The removal of the metal implant and subsequent backfilling of the remaining cavity with optically matched fluid prior to dose evaluation enables accurate optical-CT scanning of the gel dosimeters. Results have shown very good agreement between measured and calculated doses within 2 mm from the surface of the implant. Slight deviations are present within 1 mm of the interface. CONCLUSIONS: Artifacts in the form of radial streaking, cold spots, and hot spots were all reduced using this technique, enabling the broader and more accurate use of optical-CT for the imaging of gels containing opaque objects. PMID- 28094856 TI - Percent depth doses and X-ray beam characterizations of a fluoroscopic system incorporating copper filtration. AB - PURPOSE: In this investigation, we sought to characterize X-ray beam qualities and quantitate percent depth dose (PDD) curves for fluoroscopic X-ray beams incorporating added copper (Cu) filtration, such as those commonly used in fluoroscopically guided interventions (FGI). The intended application of this research is for dosimetry in soft tissue from FGI procedures using these data. METHODS: All measurements in this study were acquired on a Siemens (Erlangen, Germany) Artis zeego fluoroscope. X-ray beam characteristics of first half-value layer (HVL), second HVL, homogeneity coefficients (HCs), backscatter factors (BSFs) and kVp accuracy and precision were determined to characterize the X-ray beams used for the PDD measurements. A scanning water tank was used to measure PDD curves for 60, 80, 100, and 120 kVp X-ray beams with Cu filtration thicknesses of 0.0, 0.1, 0.3, 0.6, and 0.9 mm at 11 cm, 22 cm, and 42 cm nominal fields of view, in water depths of 0 to 150 mm. RESULTS: X-ray beam characteristics of first HVLs and HCs differed from previous published research of fluoroscopic X-ray beam qualities without Cu filtration. PDDs for 60, 80, 100, and 120 kVp with 0 mm of Cu filtration were comparable to previous published research, accounting for differences in fluoroscopes, geometric orientation, type of ionization chamber, X-ray beam quality, and the water tank used for data collection. PDDs and X-ray beam characteristics for beam qualities with Cu filtration are presented, which have not been previously reported. CONCLUSIONS: The data sets of X-ray beam characteristics and PDDs presented in this study can be used to estimate organ or soft tissue doses at depth involving similar beam qualities or to compare with mathematical models. PMID- 28094857 TI - Use of Oncept melanoma vaccine in 69 canine oral malignant melanomas in the UK. AB - OBJECTIVES: Oral malignant melanomas carry a poor-to-guarded prognosis because of their local invasiveness and high metastatic propensity. The Oncept melanoma vaccine is licensed to treat dogs with stage II or III locally-controlled oral malignant melanoma and this retrospective study aimed to assess survival of affected dogs treated with the vaccine in the UK. MATERIAL AND METHODS: Medical records of dogs with histopathologically-confirmed oral malignant melanoma that received the vaccine as part of their treatment were evaluated. Survival analyses for potential prognostic factors were performed. RESULTS: Sixty-nine dogs were included; 56 dogs, staged I to III, and with previous locoregional therapy, had a median survival time of 455 days (95% CI: 324 to 586 days). Based on Kaplan-Meier survival analysis with associated log-rank testing, no significant prognostic factors were identified for this population. Of the 13 patients with macroscopic disease treated with vaccine alone or in combination therapy, eight showed clinical response. Three patients with stage IV oral malignant melanoma survived 171, 178 and 288 days from diagnosis. CLINICAL SIGNIFICANCE: Patients treated with the melanoma vaccine in our study had survival times similar to their counterparts receiving the vaccine in the USA. There were observed responses in patients with macroscopic disease and so the vaccine could be considered as palliative treatment in dogs with stage IV disease. PMID- 28094858 TI - Caudal mediastinal cystic lesion in a dog. PMID- 28094859 TI - Hair nicotine concentration measurement in cats and its relationship to owner reported environmental tobacco smoke exposure. AB - OBJECTIVES: To investigate the association between hair nicotine concentration in cats and owner-reported exposure to environmental tobacco smoke. MATERIALS AND METHODS: Owner questionnaires documented exposure. Nicotine was extracted from hair by sonification in methanol followed by hydrophilic interaction chromatography with mass spectrometry. Relationships between hair nicotine concentration and owner-reported exposure were examined using hypothesis-testing statistics and receiver operating characteristic curve analysis. RESULTS: The hair nicotine concentration of reportedly exposed cats was significantly higher than unexposed cats and groups of cats with different levels of exposure had significantly different median hair nicotine concentrations corresponding to exposure. A hair nicotine concentration of 0.1 ng/mg had a specificity of 98% (95% confidence interval: 83 to 100) and a sensitivity of 69% (95% confidence interval: 54 to 84) for detecting environmental tobacco smoke exposure. Outdoors access, coat colour, urban or rural environment and length of time living with the owner were not obviously associated with hair nicotine concentration. CLINICAL SIGNIFICANCE: Feline hair nicotine concentration appears strongly associated with owner-reported environmental tobacco smoke exposure. Feline hair nicotine concentration could therefore be used as a biomarker for tobacco smoke exposure, allowing future studies to assess whether exposed cats have an increased risk of specific diseases. PMID- 28094860 TI - TTA-Rapid in the treatment of the canine cruciate deficient stifle: short- and medium-term outcome. AB - OBJECTIVES: To evaluate complications, short- and medium-term outcomes following treatment of lameness associated with cranial cruciate ligament insufficiency in dogs using the "TTA-Rapid" technique. METHODS: Patient records from two veterinary clinics were retrospectively examined to collect data from cases treated over a period of 21 months. An owner postal questionnaire using a clinical metrology instrument (Liverpool Osteoarthritis in Dogs) evaluated medium term outcome of at least six months. RESULTS: In total 152 procedures were carried out in 141 dogs by two surgeons. Major complications, requiring further intervention, were identified in 11 (7%). Nine of these involved "late" meniscal injuries and two sustained tibial fractures postoperatively, one requiring internal fixation and the other external coaptation. The 3-month outcome was considered satisfactory in 99% of 135 procedures whilst the medium-term outcome (mean 16 months) was considered satisfactory in 86% of 108 dogs. CLINICAL SIGNIFICANCE: "TTA-Rapid" offers a treatment option for cranial cruciate deficient stifles with good short- and medium-term outcomes. The complication rate was low in our hands. PMID- 28094861 TI - Caudal vertebra transfer: treatment of radio-ulnar nonunion and severe bone shortening in a dog. PMID- 28094862 TI - Software platform for simulation of a prototype proton CT scanner. AB - PURPOSE: Proton computed tomography (pCT) is a promising imaging technique to substitute or at least complement x-ray CT for more accurate proton therapy treatment planning as it allows calculating directly proton relative stopping power from proton energy loss measurements. A proton CT scanner with a silicon based particle tracking system and a five-stage scintillating energy detector has been completed. In parallel a modular software platform was developed to characterize the performance of the proposed pCT. METHOD: The modular pCT software platform consists of (1) a Geant4-based simulation modeling the Loma Linda proton therapy beam line and the prototype proton CT scanner, (2) water equivalent path length (WEPL) calibration of the scintillating energy detector, and (3) image reconstruction algorithm for the reconstruction of the relative stopping power (RSP) of the scanned object. In this work, each component of the modular pCT software platform is described and validated with respect to experimental data and benchmarked against theoretical predictions. In particular, the RSP reconstruction was validated with both experimental scans, water column measurements, and theoretical calculations. RESULTS: The results show that the pCT software platform accurately reproduces the performance of the existing prototype pCT scanner with a RSP agreement between experimental and simulated values to better than 1.5%. CONCLUSIONS: The validated platform is a versatile tool for clinical proton CT performance and application studies in a virtual setting. The platform is flexible and can be modified to simulate not yet existing versions of pCT scanners and higher proton energies than those currently clinically available. PMID- 28094863 TI - Palatal morphology changes in post-stroke patients measured by geometric morphometrics. AB - This study aimed to describe longitudinal palatal shape changes in post-stroke patients when compared to a sample of healthy subjects through linear measurements and geometric morphometrics. The 3D palatal scanned models of seven stroke patients having a 1-year post-stroke follow-up were matched with seven control subjects of the same age group (range 50-87 years). Intercanine, intermolar distances and palatal height were measured. 3D images were also analysed through geometric morphometrics to assess changes in the shape of the palate from T0 to T1 (1 year after the stroke). Principal component analysis was used to describe shape morphology changes, and visual colour maps were used to qualitatively assess differences between T0 and T1. No changes were detected nor in linear measures neither in palatal shape in healthy subjects from T0 to T1. The palates of stroke patients showed no linear differences either. However, when visualising shape changes through colour maps, the lateral aspects of the palatal vault were slightly narrower in T1, with respect to T0 in stroke patients. This may be attributed to altered tongue function following the stroke. PMID- 28094864 TI - Quantifying the structural integrity of nanorod arrays. AB - Arrays of aligned nanorods oriented perpendicular to a support, which are accessible by top-down lithography or by means of shape-defining hard templates, have received increasing interest as sensor components, components for nanophotonics and nanoelectronics, substrates for tissue engineering, surfaces having specific adhesive or antiadhesive properties and as surfaces with customized wettability. Agglomeration of the nanorods deteriorates the performance of components based on nanorod arrays. A comprehensive body of literature deals with mechanical failure mechanisms of nanorods and design criteria for mechanically stable nanorod arrays. However, the structural integrity of nanorod arrays is commonly evaluated only visually and qualitatively. We use real-space analysis of microscopic images to quantify the fraction of condensed nanorods in nanorod arrays. We suggest the number of array elements apparent in the micrographs divided by the number of array elements a defect-free array would contain in the same area, referred to as integrity fraction, as a measure of structural array integrity. Reproducible procedures to determine the imaged number of array elements are introduced. Thus, quantitative comparisons of different nanorod arrays, or of one nanorod array at different stages of its use, are possible. Structural integrities of identical nanorod arrays differing only in the length of the nanorods are exemplarily analysed. PMID- 28094865 TI - Long-term side effects on the temporomandibular joints and oro-facial function in patients with obstructive sleep apnoea treated with a mandibular advancement device. AB - Patients with obstructive sleep apnoea (OSA) in long-term treatment with a mandibular advancement device (MAD) to increase the upper airway space may develop changes in the temporomandibular joint (TMJ) and the oro-facial function due to the protruded jaw position during sleep. The aim was to investigate the influence of long-term MAD treatment on the TMJs, oro-facial function and occlusion. This prospective study included 30 men and 13 women (median age 54) with OSA [Apnoea-Hypopnoea Index (AHI): 7-57]. They were examined with the Nordic Orofacial Test Screening (NOT-S), the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) and cone beam computed tomography (CBCT) of the TMJs. The examination was performed before MAD treatment (T0), and 3-6 months (T1, no CBCT), 1 year (T2) and 3 years (T3) after treatment start. The results were analysed as long term (T0-T3, n = 14) and short term (T0-T2, n = 24) by t test, Fisher's exact test and anova. Both long- and short-term analyses revealed a reduction in AHI (P < 0.002). Significant long term were increased scores in the NOT-S Interview (P < 0.045), reduced vertical overbite (P < 0.031) and increased jaw protrusive movement (P < 0.027). TMJ changes were found as joint sounds in terms of reciprocal clicking and crepitus, short term as a decrease and subsequent recurrence (P < 0.053; P < 0.037). No significant radiological changes were found. In conclusion, MAD treatment is beneficial to some OSA patients, but might induce changes in the TMJs, the oro-facial function and the occlusion. However, these changes seemed to be less harmful than previously reported with careful adaptation, control and follow-ups. PMID- 28094866 TI - Corticolimbic circuits in learning, memory, and disease. PMID- 28094867 TI - UVA-1 exposure in vivo leads to an IL-6 surge within the skin. AB - UVA-1 is a known promotor of skin ageing. Cytokines like IL-1alpha, Il-1beta or TNF-alpha, VEGF and IL-6 orchestrate UV effects, and IL-6 is furthermore an effector of UVA-induced photoageing. We investigated how fractionated UVA-1 doses influence the cytokine milieu and especially the IL-6 levels in the skin in vivo. In a study with 35 participants, we exposed previously unirradiated human skin to three UVA-1 irradiation regimes. Cytokine levels in interstitial skin fluid were measured up to 48 hours postexposure and compared to unirradiated control skin fluid. Our results show that IL-6 levels increased significantly after UVA-1 exposure at selected time points. The other candidates IL-1alpha, Il-1beta or TNF alpha and VEGF show no significant response after UVA-1 exposure in vivo. UVA-1 thus raises selectively IL-6 levels in vivo, a fact that underlines its role in photoageing and has potential implications for its modulatory effect on photoageing pathology. PMID- 28094868 TI - Biomaterials: A potential pathway to healing chronic wounds? AB - Chronic dermal wounds are a devastating problem, which disproportionally affect individuals with conditions such as diabetes, paralysis, or simply old age. These wounds are extremely challenging to treat due to a heterogeneous combination of causative factors, creating a substantial burden on healthcare systems worldwide. Despite their large impact, there is currently a startling lack of options for effectively treating the underlying biological changes that occur within the wounds. Biomaterials possess an enticing ability to provide new comprehensive approaches to healing these devastating wounds; advanced wound dressings are now being developed that enable the ability to coordinate temporal delivery of multiple therapeutics, protect sensitive biologics from degradation, and provide supportive matrices that encourage the growth of tissue. This positions biomaterials as a potential "conductor" of wound repair, allowing them to simultaneously address numerous barriers to healing, and in turn providing a promising pathway to innovative new technologies for driving successful healing. PMID- 28094869 TI - Loss of FAS/FASL signalling does not reduce apoptosis in Sharpin null mice. AB - Mice with mutations in SHANK-associated RH domain interactor (Sharpin) develop a hypereosinophilic auto-inflammatory disease known as chronic proliferative dermatitis. Affected mice have increased apoptosis in the keratinocytes of the skin, oesophagus and forestomach driven by extrinsic TNF receptor-mediated apoptotic signalling pathways. FAS receptor signalling is an extrinsic apoptotic signalling mechanism frequently involved in inflammatory skin diseases. Compound mutations in Sharpin and Fas or Fasl were created to determine whether these death domain proteins influenced the cutaneous phenotype in Sharpin null mice. Both Sharpin/Fas and Sharpin/Fasl compound mutant mice developed an auto inflammatory phenotype similar to that seen in Sharpin null mice, indicating that initiation of apoptosis by FAS signalling is likely not involved in the pathogenesis of this disease. PMID- 28094870 TI - Igf1r signalling acts on the anagen-to-catagen transition in the hair cycle. AB - Insulin-like growth factor 1 (Igf1) is important for skin development and homoeostasis. However, overexpression and inactivation studies have produced variable findings regarding its role in hair follicle (HF) biology. Here, we studied a conditional and inducible knockout of the Igf1 receptor (Igf1r) in keratin 15-expressing bulge cells. Deletion of Igf1r after the development of the skin appendages in K15-Igf1rKO mice showed no abnormalities in epidermal homoeostasis. Numbers of bulge cells were lower in K15-Igf1rKO mice than in controls, without consequences on wound healing, at least in young mice. K15 Igf1rKO HFs entered anagen phase earlier than controls and showed a delay in the anagen/catagen switch. The expression of Bmp-4 mRNA was inhibited in HFs from K15 Igf1rKO . MED1 transcription was impaired in the epidermis of K15-Igf1rKO mice. These findings suggest that Igf1r controls the hair cycle, partly through Bmp-4 activation. PMID- 28094872 TI - Niacinamide leave-on formulation provides long-lasting protection against bacteria in vivo. AB - Antimicrobial peptides (AMPs) form a part of the skin's innate immune system. Their primary activity is to provide antimicrobial benefits and hence protect from infections. AMPs that are present on human skin include psoriasin (S100A7), RNase 7, lysozyme, LL-37 and defensins. Niacinamide is a well-known cosmetic ingredient that has been used traditionally for multiple skin benefits. Recent data indicate that niacinamide treatment can boost AMPs in human gut epithelial cells and in neutrophils. Treatment with niacinamide in mice also provided protection from skin infections by enhancing AMPs. In this article, we find that treatment with niacinamide formulation provides long-lasting protection against bacteria, potentially through the activation of an AMP response. PMID- 28094871 TI - Divergence of cAMP signalling pathways mediating augmented nucleotide excision repair and pigment induction in melanocytes. AB - Loss-of-function melanocortin 1 receptor (MC1R) polymorphisms are common in UV sensitive fair-skinned individuals and are associated with blunted cAMP second messenger signalling and higher lifetime risk of melanoma because of diminished ability of melanocytes to cope with UV damage. cAMP signalling positions melanocytes to resist UV injury by upregulating synthesis of UV-blocking eumelanin pigment and by enhancing the repair of UV-induced DNA damage. cAMP enhances melanocyte nucleotide excision repair (NER), the genome maintenance pathway responsible for the removal of mutagenic UV photolesions, through cAMP activated protein kinase (protein kinase A)-mediated phosphorylation of the ataxia telangiectasia-mutated and Rad3-related (ATR) protein on the S435 residue. We investigated the interdependence of cAMP-mediated melanin upregulation and cAMP-enhanced DNA repair in primary human melanocytes and a melanoma cell line. We observed that the ATR-dependent molecular pathway linking cAMP signalling to the NER pathway is independent of MITF activation. Similarly, cAMP-mediated upregulation of pigment synthesis is independent of ATR, suggesting that the key molecular events driving MC1R-mediated enhancement of genome maintenance (eg PKA mediated phosphorylation of ATR) and MC1R-induced pigment induction (eg MITF activation) are distinct. PMID- 28094873 TI - Effects of adding whole-body vibration to routine day activity program on physical functioning in elderly with mild or moderate dementia: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effects of whole-body vibration (WBV) added to a routine activity program on lower limb strength, balance, and mobility among community-dwelling individuals with mild or moderate dementia, compared with the routine program alone. METHODS: Fifty-four older adults (40 women; mean (SD) age: 79.8 (6.1) years) with mild or moderate dementia were recruited from two daycare centers. The participants were randomly allocated to undergo a routine day activity program combined with WBV training (WBV at 30 Hz, 2-mm peak-to-peak amplitude) or the routine program only without WBV for 9 weeks (18 sessions). The primary outcome was functional mobility, measured using the timed up-and-go test. The following secondary outcomes were evaluated: Berg Balance Scale, Tinetti balance assessment, time to complete 5 repetitions of sit-to-stand, Quality of Life in Alzheimer's disease questionnaire, and Activities-specific Balance Confidence scale. The attendance rate and incidence of adverse events were also recorded. RESULTS: The attendance rate for the training was high (86.0%). The incidence of adverse events was low, with only two of the 27 participants in the WBV group reporting mild knee pain. While significant improvement in timed up-and go, Berg Balance Scale, and Tinetti balance score was found in both groups, none of the outcomes demonstrated a significant group by time interaction. CONCLUSIONS: WBV training is feasible and safe to use with people with mild or moderate dementia. However, it did not lead to further improvement in physical function and quality of life than the usual activity program provided at the daycare centers. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28094874 TI - Skin microbiome and acne vulgaris: Staphylococcus, a new actor in acne. AB - Propionibacterium acnes (P. acnes), the sebaceous gland and follicular keratinocytes are considered the three actors involved in the development of acne. This exploratory study investigated the characteristics of the skin microbiota in subjects with acne and determined microbiota changes after 28 days of application of erythromycin 4% or a dermocosmetic. Skin microbiota were collected under axenic conditions from comedones, papulo-pustular lesions and non lesional skin areas from subjects with mild to moderate acne according to the GEA grading using swabs. Samples were characterized using a high-throughput sequencing approach that targets a portion of the bacterial 16S rRNA gene. Overall, microbiota samples from 26 subjects showed an overabundance of Proteobacteria and Firmicutes and an under-representation of Actinobacteria. Staphylococci were more abundant on the surface of comedones, papules and pustules (P=.004 and P=.003 respectively) than on non-lesional skin. Their proportions increased significantly with acne severity (P<.05 between GEA-2 and GEA-3). Propionibacteria represented less than 2% of the bacteria on the skin surface. At Day 28, only the number of Actinobacteria had decreased with erythromycin while the dermocosmetic decreased also the number of Staphylococci. A significant reduction (P<.05) from Day 0 of comedones, papules and pustules with no significant difference between the products was observed. The bacterial diversity on all sampling areas was similar. The dermocosmetic decreased the number of Actinobacteria and Staphylococcus spp. after 28 days. Staphylococcus remained the predominant genus of the superficial skin microbiota. No significant reduction in Staphylococcus spp. was observed with the topical antibiotic. PMID- 28094875 TI - Neuroendocrinology of mast cells: Challenges and controversies. AB - Mast cells (MC) are hemotopoietically derived tissue immune cells that are ubiquitous in the body, including neuroendocrine organs such as the hypothalamus, pineal, pituitary, ovaries, pancreas and uterus where their action is not well understood. Mast cells have historically been associated with allergies because of their rich content of histamine and tryptase, but more recently with regulation of immunity and inflammation due to their synthesis and release of numerous cytokines and chemokines. Mast cells are located perivascularly and express numerous receptors for diverse ligands such as allergens, pathogens, neurotransmitters, neuropeptides and hormones including acetylcholine, calcitonin gene-related peptide (CGRP), corticosteroids, corticotropin-releasing hormone (CRH), beta-endorphin, epinephrine, 17beta-oestradiol, gonadotrophins, hemokinin A (HKA), leptin, melatonin, neurotensin (NT), parathyroid hormone (PTH), substance P (SP) and vasoactive intestinal peptide (VIP). Moreover, MC can synthesize and release most of their neurohormonal triggers, including adrenocorticotropin hormone (ACTH), CRH, endorphins, HKA, leptin, melatonin, NT, SP and VIP. Animal experiments have shown that diencephalic MC increase in number during courting in doves, while stimulation of brain and nasal MC leads to activation of the hypothalamic-pituitary-adrenal (HPA) axis. Recent evidence indicates that MC reactivity exhibits diurnal variations, and it is interesting that melatonin appears to regulate MC secretion. However, the way MC change their phenotype or secrete specific molecules selectively at different pathophysiological settings still remains unknown. Mast cells developed over 500 million years ago and may have served as the original prototype neuroimmunoendocrine cell and then evolved into a master regulator of such interactions, especially as most of the known diseases involve neuroinflammation that worsens with stress. PMID- 28094876 TI - Ultraviolet B irradiation increases keratin 1 and keratin 10 expressions in HaCaT keratinocytes via TRPV1 activation and ERK phosphorylation. AB - In this study, we characterized the effect of ultraviolet B (UVB) irradiation with or without epidermal growth factor (EGF) on the regulation of keratinocyte differentiation under physiological concentration of Ca2+ (1.8 mM). In addition, growth factor deprivation used to measure signal transduction and kinase phosphorylation in many studies is physiologically unreal. Therefore, 1% of serum was also included in all experiment. We found that UVB irradiation Ca2+ dependently induced morphological differentiation and increased keratin 1 and 10 (K1/K10) expressions. Both were inhibited by treatment of cells with EGF. In quiescent cells, phosphorylation of ERK was stimulated by acute EGF treatment, while it rapidly desensitized in chronic EGF treatment or 1% serum exposure. UVB irradiation-induced keratinocyte differentiation required Ca2+ influx through TRPV1. Ca2+ -dependent phosphorylation of ERK was responsible for the expression of K1/10. Cotreatment of cells with EGF during UVB irradiation inhibits the UVB irradiation-induced differentiation by desensitizing ERK phosphorylation. PMID- 28094877 TI - Hypothalamus Specific Re-Introduction of SNORD116 into Otherwise Snord116 Deficient Mice Increased Energy Expenditure. AB - The Snord116 gene cluster has been recognised as a critical contributor to the Prader-Willi syndrome (PWS), with mice lacking Snord116 displaying many classical PWS phenotypes, including low postnatal body weight, reduced bone mass and increased food intake. However, these mice do not develop obesity as a result of increased energy expenditure. To understand the physiological function of SNORD116 better and potentially rescue the altered metabolism of Snord116-/- mice, we used an adeno-associated viral (AAV) approach to reintroduce the product of the Snord116 gene into the hypothalamus in Snord116-/- mice at different ages. The results obtained show that mid-hypothalamic re-introduction of SNORD116 in 6 week-old Snord116-/- mice leads to significantly reduced body weight and weight gain, which is associated with elevated energy expenditure. Importantly, when the intervention targets other areas such as the anterior region of the hypothalamus or the reintroduction occurs in older mice, the positive effects on energy expenditure are diminished. These data indicate that the metabolic symptoms of PWS develop gradually and the Snord116 gene plays a critical role during this process. Furthermore, when we investigated the consequences of SNORD116 re introduction under conditions of thermoneutrality where the mild cold stress influences are avoided, we also observed a significant increase in energy expenditure. In conclusion, the rescue of mid-hypothalamic Snord116 deficiency in young Snord116 germline deletion mice increases energy expenditure, providing fundamental information contributing to potential virus-mediated genetic therapy in PWS. PMID- 28094878 TI - Characterization of cellulose degrading bacteria from the larval gut of the white grub beetle Lepidiota mansueta (Coleoptera: Scarabaeidae). AB - The goal of this study is to identify and characterize the cellulose degrading microorganisms in the larval gut of the white grub beetle, Lepidiota mansueta. Thirty bacterial strains were isolated and tested for cellulolytic activity using soluble carboxymethyl cellulose (CMC) degrading assays. Of these strains, five (FGB1, FB2, MB1, MB2, and HB1) degrade cellulose. Cellulolytic activity was determined based on formation of clear zone and cellulolytic index on CMC plate media. The highest cellulolytic index (2.14) was found in FGB1. Partial 16S rDNA sequencing, morphological, and biochemical tests were used to identify and characterize the five isolates, all Citrobacter sp. (Enterobacteriaceae). This study identifies new cellulose degrading microorganisms from the larval gut of L. mansueta. The significance of identifying these strains lies in possible application in cellulose degradation. PMID- 28094879 TI - Nutritional, inflammatory, and ecological correlates of maternal retinol allocation to breast milk in agro-pastoral Ariaal communities of northern Kenya. AB - OBJECTIVES: Vitamin A (VA) is an essential micronutrient required for a range of biological functions throughout life. VA deficiency (VAD) claims an estimated 1 million preschool children's lives annually. Human milk is enriched with VA (retinol) from the maternal blood, which originates from the hepatic reserve and dietary intake. Secreting retinol into milk will benefit the nursing infant through breast milk, but retaining retinol is also important for the maternal health. Previous studies found that the public health intervention of high-dose VA supplementation to lactating mothers did not significantly lower child mortality. The World Health Organization (WHO) recently acknowledged that our understanding about the principle of VA allocation within the maternal system and the secretion into milk is too incomplete to devise an effective intervention. METHODS: We present a secondary analysis of data collected among lactating mothers in VAD endemic northern Kenya (n = 171), examining nutritional, inflammatory, and ecological factors that might associate with maternal retinol allocation. Regression models were applied using the outcome milk-retinol allocation index: milk retinol/(milk retinol + serum retinol). RESULTS: Ten percent of the sample was identified as VAD. The average milk retinol concentration was 0.1 MUmo/L, grossly below what is considered minimally necessary for an infant (1 MUmol/L). VAD mothers and mothers with inflammation did not seem to compromise their milk retinol even though their serum retinol was lower than non-VAD and noninflammation mothers. Breast milk fat concentration positively correlated with milk retinol but not with serum retinol. CONCLUSIONS: This exploratory study contributes toward an understanding of maternal retinol allocation. PMID- 28094880 TI - Milk ejection patterns remain consistent during the first and second lactations. AB - OBJECTIVE: Milk ejection is a critical physiological process for successful lactation in humans and without it little milk can be removed. Individual milk ejection patterns have been shown to remain consistent between breasts at different lactation stages and using different vacuum patterns with an electric breast pump. Little is known about the milk ejection characteristics during the second lactation period in the same mother. The objective of this study was to examine milk ejection characteristics in the same woman over two lactations. METHODS: One mother took part in two pumping studies during consecutive lactations. One pumping study examined milk ejection characteristics during simultaneous breast expression during the first lactation. The second pumping study (second lactation) used two different pumping patterns. Three distinct milk ejections were measured during each pumping session. RESULTS: Measurements of milk flow were used to compare the duration and time taken to reach the peak of each milk ejection for two pumping sessions from each of the lactations. There were no significant differences in milk ejection characteristics between breasts, using different pumping patterns, or between lactations in this mother (P > .05). CONCLUSION: Milk ejection appears to be a physiological response that is consistent across consecutive lactations within the same mother. This suggests that milk ejection characteristics are established during or prior to the first lactation. The infant appears to have little influence on the milk ejection characteristics of the mother. PMID- 28094881 TI - Children with motor impairment related to cerebral palsy: Prevalence, severity and concurrent impairments in China. AB - AIM: Cerebral palsy (CP) is the most common cause of motor impairment in childhood. This study aimed to examine the prevalence, severity and concurrent impairments of CP-related motor impairment among Chinese children. METHODS: Children with CP-related motor impairment aged 0-17 years were identified through a national population-based survey based on World Health Organization International Classification of Functioning, Disability and Health. Logistic regression models allowing for weights were used to examine individual and family factors in relation to CP-related motor impairment. RESULTS: The weighted prevalence of CP-related motor impairment was 1.25 per 1000 children (95% confidence interval (CI): 1.16, 1.35) in China. Male children, children in multiples and in families where adults suffered from CP, were more likely to be affected by CP-related motor impairment. For mild, moderate, severe and extremely severe groups of motor impairment, weighted proportions of CP were 14.12% (95%CI: 11.70, 16.95), 20.35% (95%CI: 17.48, 23.56), 27.44% (95%CI: 24.25, 30.87) and 38.09% (95%CI: 34.55, 41.76), respectively; and weighted proportions of concurrent visual, hearing and cognitive impairment were 5.00% (95%CI: 3.59, 6.91), 6.98% (95%CI: 5.34, 9.08) and 71.06% (95%CI: 67.57, 74.31), respectively. CONCLUSIONS: Gender, multiple births and family adults with CP were significantly associated with CP-related motor impairment in Chinese children. Proportions of CP and concurrent impairments that increased with severity of motor impairment were observed. PMID- 28094882 TI - Association of cardiorespiratory fitness and adiposity with inflammatory biomarkers in young adults. AB - OBJECTIVES: Cardiorespiratory fitness (fitness) has been inversely associated with inflammation, but whether the association is attributed to fitness itself or lower levels of adiposity remains uncertain in young adults. The purpose of this study was to determine the association of fitness and adiposity with inflammation in young adults. METHODS: A cross-sectional study was conducted with 88 participants aged 20-34 years. Fitness was assessed by a submaximal treadmill walking test. Adiposity was assessed by body mass index (BMI) and waist circumference (WC). Inflammation was measured by plasma C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) levels using immunoassays. Biological data were log10 transformed. A separate multiple regression analysis was conducted with each inflammatory biomarker as a dependent variable. Covariates (sex, oral contraceptive use, and education level) were adjusted. RESULTS: Fitness was inversely associated with log10 CRP after adjustment for covariates but not after adjusting for BMI or WC. Fitness was inversely associated with log10 IL-6 after adjustment for WC and covariates (beta = -0.341, P = .049) but not after adjusting for BMI. Fitness * WC interaction (partial eta2 = 0.056, P = .033) indicated that high fitness was more strongly associated with low log10 IL-6 in young adults with high WC than those with low WC. CONCLUSIONS: Although adiposity has a stronger association than fitness with CRP and IL-6, higher levels of fitness could be essential for maintaining low levels of IL-6, especially in the presence of high levels of central adiposity. PMID- 28094883 TI - In silico prediction of Leishmania major-specific CD8+ epitopes. AB - Infections with Leishmania (L.) major induce protective IFN-gamma-dependent Th1/Tc1 immunity in C57BL/6 mice as well as in immunocompetent humans. Even though antigen-specific immunity provides lifelong immunity against reinfection, a vaccine against this pathogen does not yet exist. Here, we compared the results obtained from in silico predictions of murine CD8-specific L. major peptides using the algorithm SYFPEITHI with the number and predicted affinity of known proteins/peptides. Our results indicate that the majority of "immunodominant" epitopes of L. major have not been identified so far; thus, computer-based prediction algorithms may aid the development of an effective vaccine. PMID- 28094884 TI - Oxygen Delivery as a Limiting Factor in Modelling Dicopper(II) Oxidase Reactivity. AB - Deprotonation of ligand-appended alkoxyl groups in mononuclear copper(II) complexes of N,O ligands L1 and L2 , gave dinuclear complexes sharing symmetrical Cu2 O2 cores. Molecular structures of these mono- and binuclear complexes have been characterized by XRD, and their electronic structures by UV/Vis, 1 H NMR, EPR and DFT; moreover, catalytic performance as models of catechol oxidase was studied. The binuclear complexes with anti-ferromagnetically coupled copper(II) centers are moderately active in quinone formation from 3,5-di-tert-butyl catechol under the established conditions of oxygen saturation, but are strongly activated when additional dioxygen is administered during catalytic turnover. This unforeseen and unprecedented effect is attributed to increased maximum reaction rates vmax , whereas the substrate affinity KM remains unaffected. Oxygen administration is capable of (partially) removing limitations to turnover caused by product inhibition. Because product inhibition is generally accepted to be a major limitation of catechol oxidase models, we think that our observations will be applicable more widely. PMID- 28094885 TI - Free-Radical Carbocyanation of Olefins. AB - The free-radical three-component carbocyanation of electron-rich olefins was investigated with p-tosyl cyanide as cyanide source. The scope and limitations of the process were established by varying the nature of the alkene and radical precursor. Carbocyanation of chiral allylsilanes was shown to occur with high diastereocontrol, leading to syn beta-silyl nitriles. The origin of the stereocontrol was rationalized by a Felkin-Anh-type transition-state model. Finally, a tin-free carbocyanation process was also devised, based on the use of a new alkylsulfonyl cyanide incorporating both carbon fragments to be added across the olefinic pi system. PMID- 28094887 TI - Influence of Aggregation on the Structure and Fluorescent Properties of a Tetraphenylethylene Derivative: a Theoretical Study. AB - The case that aggregation has a large influence on the structure and fluorescent properties of 5-(4-(1,2,2-triphenylvinyl)phenyl)thiophene-2-carbaldehyde (P4 TA) is investigated in detail herein by employing quantum mechanics and molecular mechanics. Besides the isolated molecule, the aggregated molecule in water and in the crystalline state was studied by focusing on the comparison of photoelectronic properties, including the geometrical and electronic structures at ground and excited states, emission and internal conversation properties. For the aggregation state, the intermolecular interaction was used to explain the difference in structure, emission color and intensity of different polymorphs. The noticeable contribution from low-frequency region, corresponding to the four phenyl rings twisting vibration, to the Huang-Rhys factor and reorganization energy, as well as the possible potential energy surface crossing between S0 and S1 states for isolated molecules was considered as the reason of its aggregation induced emission (AIE) performance. Importantly, the aggregation process in water simulated at the same time helps us to have a deeper understanding of the AIE behavior of P4 TA, which also provides another perspective to explore the AIE phenomenon in theory. PMID- 28094888 TI - Association between body height and month of birth among women of European origin in northern and southern hemispheres. AB - OBJECTIVES: The purpose of this study was to examine the potential association between month of birth and body height among women in northern and southern hemispheres. METHODS: Body heights of adult women of European origin born between 1935 and 1981 who lived in Poland (N = 3,933) and in Australia (N = 1,118) were examined in relation to month of birth by analysis of variance. RESULTS: No association between month of birth and body height was observed in either Polish or Australian women. For Polish women, a clear, statistically significant secular trend in body height was confirmed for the analyzed period (P < .0001). No such trend occurred among the Australian women. CONCLUSIONS: Results do not confirm a significant association between month of birth and adult body height in women. It is, however, important to see a difference in secular trends, which was large in Polish women and nonexistent in Australian females. PMID- 28094886 TI - The parathyroid hormone family member TIP39 interacts with sarco/endoplasmic reticulum Ca2+ - ATPase activity by influencing calcium homoeostasis. AB - Darier disease (DD) is a genetic skin disease that is associated with mutations in the ATP2A2 gene encoding the type 2 sarco/endoplasmic reticulum (ER) Ca2+ - ATPase (SERCA2). Mutations of this gene result in alterations of calcium homoeostasis, abnormal epidermal adhesion and dyskeratosis. Silencing of ATP2A2 in monolayer cell culture of keratinocytes reduces desmoplakin expression at the borders of cells and impacts cell adhesion. Here, we report establishment of a three-dimensional (3D) epidermal model of DD and use this model to evaluate peptide therapy with tuberoinfundibular peptide of 39 residues (TIP39) to normalize calcium transport. Gene silencing of ATP2A2 in keratinocytes grown in a 3D model resulted in dyskeratosis, partial parakeratosis and suprabasal clefts that resembled the histological changes seen in skin biopsies from patients with DD. TIP39, a peptide recently identified as a regulator of keratinocyte calcium transport, was then applied to this ATP2A2-silenced 3D epidermal model. In normal keratinocytes, TIP39 increased [Ca2+ ]i through the inositol trisphosphate (IP3) receptor pathway and stimulated differentiation. In monolayer ATP2A2-silenced keratinocytes, although TIP39 increased cytosolic calcium from the ER, the response was incomplete compared with its control. TIP39 was observed to reduce intercellular clefts of the gene-silenced epidermal model but did not significantly upregulate keratinocyte differentiation genes such as keratin 10 and filaggrin. These findings indicate that TIP39 is a modulator of ER calcium signalling and may be used as a potential strategy for improving aspects of DD. PMID- 28094889 TI - Selective Electrochemical Bleaching of the Outer Leaflet of Fluorescently Labeled Giant Liposomes. AB - Electrochemistry and confocal fluorescence microscopy were successfully combined to selectively bleach and monitor the fluorescence of NBD (7-nitrobenz-2-oxa-1,3 diazole)-labeled phospholipids of giant liposomes. Three types of giant unilamellar vesicles have been investigated, the fluorescent phospholipids being localized either mainly on their outer-, inner-, or both inner/outer leaflets. We established that only the fluorescent lipids incorporated in the outer leaflet of the vesicles underwent electrochemical bleaching upon reduction. The relative fluorescence intensity decay was quantified all along the electrochemical extinction through an original fluorescence loss in electrobleaching (FLIE) assay. As expected, the reorganization of the fluorescent phospholipids followed diffusion-driven dynamics. This was also evidenced by comparison with fluorescence loss in photobleaching (FLIP) and the corresponding numerical model. The value of the lateral diffusion coefficient of phospholipids was found to be similar to that obtained by other methods reported in the literature. This versatile and selective bleaching procedure appears reliable to explore important biological and pharmacological issues. PMID- 28094890 TI - Three months of Western diet induces small intestinal mucosa alteration in TLR KO mice. AB - Several studies support the role of Western-style diet (WD) in inflammatory bowel disease (IBD). Toll-like receptors/NOD-like receptors (TLRs/NLRs) are important to maintain a healthy epithelium as well as inducing inflammation. Given that dietary factors influence IBD development, that epithelial dysfunction is thought to be involved in initiating intestinal inflammation and that TLR-NLR are involved in maintenance of the functionality of intestinal epithelium as well as in regulating inflammation, we decided to examine the role of TLR signals in the triggering events that lead to alteration of the small intestinal epithelium associated to consumption of WD. C57BL/6J mice deficient for TLR2, 4, 9, or NOD2 and wild-type (WT) were fed a WD or a standard diet for 3 months. The effects of WD on small intestinal samples were evaluated by histological and immunohistochemical analysis. After 3 months, WD modifies the morphology and the organization of the small intestine in TLR9 KO mice compared with WT mice and the others TLRs. The most interesting change involved the expression of proliferative and differentiation markers of WNT signaling, Ki67 and FzD5. Mice deficient in TLR2, 4, and NOD2 have a significant reduction in the proliferative cell numbers but do not show any signs of histological alterations. Our results suggest that TLR9 is an important protective factor in intestinal epithelial homeostasis and provide new insights into an unrecognized role of TLR9 signaling in the small intestinal mucosa dysfunction associated with WD. PMID- 28094891 TI - Collapse of human scalp microbiome network in dandruff and seborrhoeic dermatitis. AB - We investigate the relationship between scalp microbiota and dandruff/seborrhoeic dermatitis (D/SD), an unpleasant scalp disorder common in human populations. Bacterial and fungal community analyses on scalp of 102 Korean were performed by next-generation sequencing. Overall scalp microbiome composition significantly differed between normal and disease groups, and especially co-occurrence network of dominant members was breakdown in disease groups. These findings will provide novel insights into shifts of microbial community relevant to D/SD. PMID- 28094892 TI - Histological features of the vomeronasal organ in the giraffe, Giraffa camelopardalis. AB - The vomeronasal organ (VNO) that preferentially detects species-specific substances is diverse among animal species, and its morphological properties seem to reflect the ecological features of animals. This histological study of two female reticulated giraffes (Giraffa camelopardalis reticulata) found that the VNO is developed in giraffes. The lateral and medial regions of the vomeronasal lumen were covered with sensory and nonsensory epithelia, respectively. The vomeronasal glands were positive for periodic acid-Schiff and alcian blue (pH 2.5) stains. The VNO comprises several large veins like others in the order Cetartiodactyla, suggesting that these veins function in a pumping mechanism in this order. In addition, numerous thin-walled vessels located immediately beneath the epithelia covering the lumen entirely surrounded the vomeronasal lumen. This sponge-like structure might function as a specific secondary pump in giraffes. PMID- 28094893 TI - A comparison of skeletal maturity assessed by radiological and ultrasonic methods. AB - OBJECTIVES: The estimation of skeletal maturity is a useful tool in pediatric practice to determine the degree of delay or advancement in growth disorders and the effectiveness of treatment in conditions that influence linear growth. Skeletal maturity of children is commonly assessed using either Greulich-Pyle (GP) or Tanner-Whitehouse methods (TW2 and TW3). However, a less invasive ultrasonic method, that does not use ionizing radiation, has been suggested for use in epidemiological studies of skeletal maturity. The main purpose of the present study was to determine the accuracy of an ultrasonic method based on the GP maturity indicators compared to the standard GP radiographic method. METHODS: Skeletal maturity of 1502 healthy children, aged from 6 to 18 years, was estimated by quantitative ultrasound and compared to GP bone ages estimated from left hand and wrist radiographs of a subsample of 47 randomly selected participants. RESULTS: The ultrasonic bone age estimation demonstrated very strong correlations with all the radiological age estimations. The correlation coefficients ranged between 0.895 and 0.958, and the strongest correlation of ultrasonic skeletal maturity estimation was found with the Tanner-Whitehouse RUS method. The ultrasonic bone age estimation is suggested for use between the chronological ages of 8.5-16.0 years in boys and 7.5-15.0 years in girls. CONCLUSIONS: The ultrasonic bone age estimation is suggested for use in epidemiological surveys since the sensitivity for screening for not normal bone development is appropriate, at least within the 8-15 years age interval. PMID- 28094894 TI - Transmission electron microscopy method providing high resolution in the cell section without radiation damage. AB - Several new features of mitochondrial nucleoid and its surroundings in mammalian cells were described previously (Prachar, 2016). Very small details were observed using the improved transmission electron microscopy method, as described in the article. In the meantime, the method has again been improved to 2 A resolutions in the cell section. The method described in detail in the present work is documented on the same records that were published in lower resolution in the work Prachar (2016), enabling comparison of the achieved resolution with the previous one. New records are also presented, showing extremely high resolution and thus implying the importance of the method. Potential use of this method in different fields is suggested. PMID- 28094895 TI - A simple 2D composite image analysis technique for the crystal growth study of L ascorbic acid. AB - This work was destined for 2D crystal growth studies of L-ascorbic acid using the composite image analysis technique. Growth experiments on the L-ascorbic acid crystals were carried out by standard (optical) microscopy, laser diffraction analysis, and composite image analysis. For image analysis, the growth of L ascorbic acid crystals was captured as digital 2D RGB images, which were then processed to composite images. After processing, the crystal boundaries emerged as white lines against the black (cancelled) background. The crystal boundaries were well differentiated by peaks in the intensity graphs generated for the composite images. The lengths of crystal boundaries measured from the intensity graphs of composite images were in good agreement (correlation coefficient "r" = 0.99) with the lengths measured by standard microscopy. On the contrary, the lengths measured by laser diffraction were poorly correlated with both techniques. Therefore, the composite image analysis can replace the standard microscopy technique for the crystal growth studies of L-ascorbic acid. PMID- 28094896 TI - Characterisation of glufosinate resistance mechanisms in Eleusine indica. AB - BACKGROUND: An Eleusine indica population has evolved resistance to glufosinate, a major post-emergence herbicide of global agriculture. This population was analysed for target-site (glutamine synthetase) and non-target-site (glufosinate uptake, translocation and metabolism) resistance mechanisms. RESULTS: Glutamine synthetase (GS) activity extracted from susceptible (S) and resistant (R*) plants was equally sensitive to glufosinate inhibition, with IC50 values of 0.85 mm and 0.99 mm, respectively. The extractable GS activity was also similar in S and R* samples. Foliar uptake of [14 C]-glufosinate did not differ in S and R* plants, nor did glufosinate net uptake in leaf discs. Translocation of [14 C]-glufosinate into untreated shoots and roots was also similar in both populations, with 44% to 47% of the herbicide translocated out from the treated leaf 24 h after treatment. The HPLC and LC-MS analysis of glufosinate metabolism revealed no major metabolites in S or R* leaf tissue. CONCLUSIONS: Glufosinate resistance in this resistant population is not due to an insensitive GS, or increased activity, or altered glufosinate uptake and translocation, or enhanced glufosinate metabolism. Thus, target-site resistance is likely excluded and the exact resistance mechanism(s) remain to be determined. (c) 2017 Society of Chemical Industry. PMID- 28094897 TI - Cytology assessment can predict survival for patients with metastatic pancreatic neuroendocrine neoplasms. AB - BACKGROUND: Histological features and Ki-67 index have known usefulness in predicting prognosis and guiding therapy among patients with metastatic pancreatic neuroendocrine neoplasms. Fine-needle aspiration may offer advantages for Ki-67 assessment because the technique obtains highly cellular, well preserved specimens with the potential for broader tumor sampling. In the current study, the authors evaluated concordance for grade and differentiation between concurrent core needle biopsy and cytology preparations. Cytological features and grade then were correlated with survival. METHODS: Differentiation, grade by Ki 67 index, and correlation of these features with survival were compared between concurrent core needle biopsy and cytology specimens from 44 patients with metastatic pancreatic neuroendocrine neoplasms. RESULTS: Differentiation by cytology smear resulted in 38 cases of well (86%) and 6 cases of poor (14%) differentiation. Agreement for differentiation between smear and cell block, smear and core needle biopsy, and cell block and core needle biopsy was 88%, 94%, and 83%, respectively, and agreement for grade was 68%, 54%, and 22%, respectively. Cytology differentiation and cytology grade were found to be strong predictors of outcome with respective hazard ratios of 8.3 (95% confidence interval [95% CI], 3.1-22.1; P<.001) and 1.9 (95% CI, 1.2-2.9) for each ascending grade. The median disease-specific survival cytology projections were 121 months (95% CI, 57-185 months [estimated]) for grade 1, 45 months (95% CI, 29-87 months) for grade 2, and 19 months (95% CI, 1-44 months) for grade 3, with median survivals of 45 months and 3 months, respectively, for patients with well differentiated and poorly differentiated neuroendocrine tumors (P<.001). CONCLUSIONS: Grading of pancreatic neuroendocrine neoplasms on cytology may not correlate exactly with concurrent core needle biopsy, but cytology differentiation and grade are predictive of survival based on stage-adjusted analysis. Cancer Cytopathol 2017;125:188-196. (c) 2016 American Cancer Society. PMID- 28094898 TI - Polyelectrolyte Oil-Core Nanocarriers for Localized and Sustained Delivery of Daunorubicin to Colon Carcinoma MC38 Cells: The Case of Polysaccharide Multilayer Film in Relation to PEG-ylated Shell. AB - The authors examine properties of daunorubicin (DNR)-loaded oil-core multilayer nanocapsules prepared via layer-by-layer approach with different polyelectrolyte (PE) coatings such as a standard one (containing polysodium 4 styrenesulphonate/poly(diallyldimethyl-ammonium) chloride) and a polysaccharide based shell (dextran/chitosan), in regard to the outer layer of poly-l-glutamic acid (PGA) grafted with polyethylene glycol (PGA-g-PEG). The nanocarriers are obtained on a cationic nanoemulsion template (stabilized by dicephalic-type surfactant, N,N-bis[3,30-(trimethylammonio)propyl]-dodecanamide dimethylsulfate) and layered with the PE shell of different thicknesses resulting in average size of 150 nm in diameter (as shown by dynamic light scattering, scanning electron microscopy and cryogenic-transmission electron microscopy, and atomic force microscopy). The nanocapsules demonstrate efficient DNR encapsulation and its sustained release under physiological conditions or in the attendance of human serum albumin. The biocompatibility studies using colon carcinoma MC38 and macrophage P388D1 cell lines as well as human erythrocytes reveal that surface charge and outer PE layer type determine nanocarrier features that control their biological activity: protein adsorption, cellular internalization and localization, induction of apoptosis, and hemolytic activity. The investigations indicate that polysaccharide-coated nanocapsules present a considerable potential for application as efficient DNR delivery systems in chemotherapy of colon cancer as an alternative to nanocarriers with PEG-ylated shell. PMID- 28094899 TI - Identification of glyphosate resistance in Salsola tragus in north-eastern Oregon. AB - BACKGROUND: Farmers in the low-rainfall region of eastern Oregon rely on repeated applications of non-selective herbicides, predominately glyphosate, to control Salsola tragus in no-till fallow systems. Reports of poor glyphosate effectiveness have increased in recent years. Reduced efficacy is often attributed to dust, water stress, or generally poor growing conditions during application. Inadequate control also may be the result of the evolution of glyphosate resistance. Therefore, studies were undertaken to determine if glyphosate-resistant S. tragus populations occur in Oregon. RESULTS: Results from dose-response studies confirmed glyphosate resistance in three of 10 Oregon Salsola tragus populations. The ratio I50R /I50S from dose-response curves was, on average, 3.1 for the relative dry biomass per plant and 3.2 for the % of surviving plants per pot in these three populations. Plant mortality at recommended glyphosate doses for the resistant populations was less than 30% 3 weeks after treatment. CONCLUSIONS: Glyphosate resistance in S. tragus highlights the imperative need to diversify weed control strategies to preserve the longevity and sustainability of herbicides in semi-arid cropping systems of the Pacific Northwest. (c) 2017 Society of Chemical Industry. PMID- 28094901 TI - Characteristics of dust particles abraded from pesticide treated seeds: 1. Size distribution using different measuring techniques. AB - BACKGROUND: Particle size is one of the most important properties affecting the driftability and behaviour of dust particles abraded from pesticide dressed seeds during sowing. Three particle sizing techniques were used determine the particle size distribution of dust abraded from seeds from six different species. RESULTS: Important differences in dust particle size distribution between species were observed with the finest dust for rapeseed and the coarsest dust for barley. Wet laser diffraction and sonic sieving particle size results correlated well while micro-CT is able to deliver three-dimensional information and additional physical particle properties (shape, porosity). CONCLUSION: All particle sizing techniques have their (dis)advantages and none of them is able to perfectly describe the real size distribution of non-spherical particles. The particle size information gathered can be used in dust drift prediction models, risk assessment tools and will help to better understand the dust drift phenomenon. (c) 2017 Society of Chemical Industry. PMID- 28094900 TI - High-throughput precision measurement of subcellular localization in single cells. AB - To quantify visual and spatial information in single cells with a throughput of thousands of cells per second, we developed Subcellular Localization Assay (SLA). This adaptation of Proximity Ligation Assay expands the capabilities of flow cytometry to include data relating to localization of proteins to and within organelles. We used SLA to detect the nuclear import of transcription factors across cell subsets in complex samples. We further measured intranuclear re localization of target proteins across the cell cycle and upon DNA damage induction. SLA combines multiple single-cell methods to bring about a new dimension of inquiry and analysis in complex cell populations. (c) 2017 International Society for Advancement of Cytometry. PMID- 28094902 TI - Characteristics of dust particles abraded from pesticide treated seeds: 2. Density, porosity and chemical content. AB - BACKGROUND: Apart from particle size, drift of abraded seed particles during sowing is mainly affected by two other physical properties, viz. particle shape and envelope density. The impact of these abraded seed particles on the environment is highly dependable on their active ingredient content. In this study, the envelope density and chemical content of dust abraded from seeds was determined as a function of particle size for six seed species. RESULTS: Envelope density and active ingredient content both change as a function of particle size. Important differences in these physico-chemical properties were observed between the six species. Functions were fitted to the collected data to describe the physico-chemical properties as a function of particle size. CONCLUSION: The gathered physico-chemical information is essential for the computational fluid dynamics (CFD)-based dust drift prediction models and can be useful for other prediction models as well as for the ongoing risk assessment of active ingredients used for seed treatment on ecosystems and ecosystem-services. In addition, the results can help to better understand the dust drift phenomenon and to develop mitigation strategies. (c) 2017 Society of Chemical Industry. PMID- 28094903 TI - Evaluation of the efficacy of insecticidal coatings based on teflutrin and chlorpyrifos against Rhynchophorus ferrugineus. AB - BACKGROUND: The date palm (Phoenix dactylifera L.), an important economic resource for many nations worldwide, has recently been threatened by the presence of different insect pests, like the red palm weevil (RPW) Rhynchophorus ferrugineus. RESULTS: Two products, a glue (polyvinyl acetate) and an oil (raw linseed oil) were used as coatings and applied together with a repellent and two insecticides (teflutrin and chlorpyrifos) at different dosages on two species of palm (P. dactylifera and P. canariensis). Phytotoxic effects of the treatments were evaluated in a greenhouse on 260 potted palms (130 P. dactylifera and 130 P. canariensis) and no negative effects were observed. Afterwards, a trial lasting 400 days was carried out in a nursery located in Sicily (south Italy), treating 572 potted palm trees (286 P. dactylifera and 286 P. canariensis) with an average diameter at the base of 18-20 cm. After 400 days, 48% of the untreated palms were infested, while only 3% of date palms and 7% of Canary palms treated with insecticide at lower dosages were infested. CONCLUSIONS: The application of an insecticide-based coating is a good strategy to control and prevent the red palm weevil infestation, in particular on date palms. (c) 2017 Society of Chemical Industry. PMID- 28094904 TI - Hormetic effects of glyphosate on plants. AB - As all herbicides act on pathways or processes crucial to plants, in an inhibitory or stimulatory way, low rates of any herbicide might be used to modulate plant growth, development, or plant composition. Glyphosate is the most used herbicide in the world, and very low rates of this herbicide can stimulate plant growth, an effect called hormesis. Several studies have shown that glyphosate applications at low rates can increase plant growth, induce shikimic acid accumulation, increase photosynthesis and stomatal opening, increase seed production, and shorten the plant life cycle. Low rates of glyphosate applied to leaves have been reported to cause one or more of these effects in an expanding group of species. Under field conditions, pesticide rates are not uniform, causing some target organisms to receive rates that are low enough to cause hormesis. Until the present, low rates of glyphosate have not been recommended as a growth stimulant for crops, because the hormetic dose can vary considerably, depending on many factors. The objective of the present review is to summarize and analyze existing information about the hormetic effects of glyphosate on plants, thus contributing to understanding how glyphosate hormesis takes place and evaluating the potential use of glyphosate to stimulate plant growth. (c) 2017 Society of Chemical Industry. PMID- 28094905 TI - Abortion Incidence and Service Availability In the United States, 2014. AB - CONTEXT: National and state-level information about abortion incidence can help inform policies and programs intended to reduce levels of unintended pregnancy. METHODS: In 2015-2016, all U.S. facilities known or expected to have provided abortion services in 2013 or 2014 were surveyed. Data on the number of abortions were combined with population data to estimate national and state-level abortion rates. The number of abortion-providing facilities and changes since a similar 2011 survey were also assessed. The number and type of new abortion restrictions were examined in the states that had experienced the largest proportionate changes in clinics providing abortion services. RESULTS: In 2014, an estimated 926,200 abortions were performed in the United States, 12% fewer than in 2011; the 2014 abortion rate was 14.6 abortions per 1,000 women aged 15-44, representing a 14% decline over this period. The number of clinics providing abortions declined 6% between 2011 and 2014, and declines were steepest in the Midwest (22%) and the South (13%). Early medication abortions accounted for 31% of nonhospital abortions, up from 24% in 2011. Most states that experienced the largest proportionate declines in the number of clinics providing abortions had enacted one or more new restrictions during the study period, but reductions were not always associated with declines in abortion incidence. CONCLUSIONS: The relationship between abortion access, as measured by the number of clinics, and abortion rates is not straightforward. Further research is needed to understand the decline in abortion incidence. PMID- 28094906 TI - The Impact of Organizational Innovations in Nursing Homes on Staff Perceptions: A Secondary Data Analysis. AB - PURPOSE: The shift in nursing home care for patients with dementia from traditional task-driven environments towards patient-centered small-scale environments has implications for nursing practice. Information about its implications for nursing staff is lacking, and only a few studies have addressed staff perceptions. We sought to explore staff perceptions of required skills and to determine differences in job satisfaction, motivation, and job characteristics of staff working in both care settings. DESIGN: A secondary data analysis was conducted. The data source used was drawn from a larger study testing the effects of small-scale living (Verbeek et al., 2009). METHODS: Nursing staff working on a permanent basis and who were directly involved in care were eligible to participate in the study. Data on job satisfaction, motivation, and job characteristics of nursing staff working in typical small-scale and traditional care environments were derived using a questionnaire. Data were analyzed using descriptive statistics. Differences between nursing staff job satisfaction, motivation, and job characteristics were tested using multilinear regression analysis. FINDINGS: In total, 138 staff members were included (81 staff members working in traditional nursing home wards and 57 staff members working in small scale nursing home wards). The findings showed that in typical small-scale nursing homes, job satisfaction and job motivation were significantly higher compared to those in typical traditional nursing homes. Job autonomy and social support were also significantly higher, while job demands were significantly lower in these small-scale nursing homes. Social support was found to be the most significant predictor of job motivation and job satisfaction in both types of typical nursing homes. Nursing staff working in traditional care environments more often expressed the intention to switch to small-scale environments. CONCLUSIONS: Based on the findings of this study, it can be concluded that nursing homes environments differ substantially in experienced job satisfaction and job motivation. CLINICAL RELEVANCE: To enable a balanced work environment for nursing staff, a clear understanding of the relation between living environments and experienced job satisfaction among nursing staff is required. Since social support seems to be one of the key contributors to a supportive beneficial work climate, managers should focus on enabling this in daily nursing home care. PMID- 28094907 TI - Better Nurse Autonomy Decreases the Odds of 30-Day Mortality and Failure to Rescue. AB - RESEARCH PURPOSE: Autonomy is essential to professional nursing practice and is a core component of good nurse work environments. The primary objective of this study was to examine the relationship between nurse autonomy and 30-day mortality and failure to rescue (FTR) in a hospitalized surgical population. STUDY DESIGN: This study was a secondary analysis of cross-sectional data. It included data from three sources: patient discharge data from state administrative databases, a survey of nurses from four states, and the American Hospital Association annual survey from 2006-2007. METHODS: Survey responses from 20,684 staff nurses across 570 hospitals were aggregated to the hospital level to assess autonomy measured by a standardized scale. Logistic regression models were used to estimate the relationship between nurse autonomy and 30-day mortality and FTR. Patient comorbidities, surgery type, and other hospital characteristics were included as controls. FINDINGS: Greater nurse autonomy at the hospital level was significantly associated with lower odds of 30-day mortality and FTR for surgical patients even after accounting for patient risk and structural hospital characteristics. Each additional point on the nurse autonomy scale was associated with approximately 19% lower odds of 30-day mortality (p < .001) and 17% lower odds of failure to rescue (p < .01). CONCLUSIONS: Hospitals with lower levels of nurse autonomy place their surgical patients at an increased risk for mortality and FTR. CLINICAL RELEVANCE: Patients receiving care within institutions that promote high levels of nurse autonomy have a lower risk for death within 30 days and complications leading to death within 30 days. Hospitals can actively take steps to encourage nurse autonomy to positively influence patient outcomes. PMID- 28094908 TI - Improving Utilization of the Family History in the Electronic Health Record. AB - PURPOSE: The purpose of this article is to provide an overview of Family History in the Electronic Health Record and to identify opportunities to advance the contributions of nurses in obtaining, updating and assessing family history in order to improve the health of all individuals and populations. ORGANIZING CONSTRUCT: The article presents an overview of the obstacles to charting Family History within the Electronic Health Record and recommendations for using specific Family History tools and core Family History data sets. METHODS: Opportunities to advance nursing contributions in obtaining, updating, and assessing family history in order to improve the health of all individuals were identified. These opportunities are focused within the area of promoting the importance of communication within families and between healthcare providers to obtain, document, and update family histories. FINDINGS: Nurses can increase awareness of existing resources that can guide collection of a comprehensive and accurate family history and facilitate family discussions. In this paper, opportunities to advance nursing contributions in obtaining, updating, and assessing family history in order to improve the health of all individuals were identified. CONCLUSIONS: Aligned with the clinical preparation of nurses, family health should be used routinely by nurses for risk assessment and to help inform patient and family members on screening, health promotion, and disease prevention. The quality of family health information is critical in order to leverage the use of genomic healthcare information and derive new knowledge about disease biology, treatment efficacy, and drug safety. These actionable steps need to be performed in the context of promoting evidence-based applications of family history that will be essential for implementing personalized genomic healthcare approaches and disease prevention efforts. CLINICAL RELEVANCE: Family health history is one of the most important tools for identifying the risk of developing rare and chronic conditions, including cardiovascular disease, cancer, and diabetes, and represents an integration of disease risk from genetic, environmental, and behavioral/lifestyle factors. In fact, family history has long been recognized as a strong independent risk factor for disease and is the current best practice used in clinical practice to guide risk assessment. PMID- 28094909 TI - Integrated Working for Enhanced Health Care in English Nursing Homes. AB - BACKGROUND: The increasingly complex nature of care home residents' health status means that this population requires significant multidisciplinary team input from health services. To address this, a multisector and multiprofessional enhanced healthcare programme was implemented in nursing homes across Gateshead Council in Northern England. STUDY AIMS: To explore the views and experiences of practitioners, social care officers, and carers involved in the enhanced health care in care home programme, in order to develop understanding of the service delivery model and associated workforce needs for the provision of health care to older residents. METHODS: A qualitative constructivist methodology was adopted. The study had two stages. Stage 1 explored the experiences of the programme enhanced healthcare workforce through group, dyad, and individual interviews with 45 participants. Stage 2 involved two workshops with 28 participants to develop Stage 1 findings (data were collected during February-March 2016). Thematic and content analysis were applied. FINDINGS: The enhanced healthcare programme provides a whole system approach to the delivery of proactive and responsive care for nursing home residents. The service model enables information exchange across organizational and professional boundaries that support effective decision making and problem solving. CLINICAL RELEVANCE: Understanding of the processes and outcomes of a model of integrated health care between public and independent sector care home services for older people. PMID- 28094910 TI - Activated Carbon Fiber Paper Based Electrodes with High Electrocatalytic Activity for Vanadium Flow Batteries with Improved Power Density. AB - Vanadium flow batteries (VFBs) have received high attention for large-scale energy storage due to their advantages of flexibility design, long cycle life, high efficiency, and high safety. However, commercial progress of VFBs has so far been limited by its high cost induced by its low power density. Ultrathin carbon paper is believed to be a very promising electrode for VFB because it illustrates super-low ohmic polarization, however, is limited by its low electrocatalytic activity. In this paper, a kind of carbon paper (CP) with super-high electrocatalytic activity was fabricated via a universal and simple CO2 activation method. The porosity and oxygen functional groups can be easily tuned via this method. The charge transfer resistance (denoting the electrochemical polarization) of a VFB with CP electrode after CO2 activation decreased dramatically from 970 to 120 mOmegacm2. Accordingly, the energy efficiency of a VFB with activated carbon paper as the electrode increased by 13% as compared to one without activation and reaches nearly 80% when the current density is 140 mAcm-2. This paper provides an effective way to prepare high-performance porous carbon electrodes for VFBs and even for other battery systems. PMID- 28094911 TI - Codependence between Crystalline and Photovoltage Evolutions in P3HT:PCBM Solar Cells Probed with in-Operando GIWAXS. AB - We address the correlation between the crystalline state of photoactive materials in a model organic solar cell based on poly(3-hexylthiophene-2,5-diyl):phenyl-C60 butyric acid methyl ester (P3HT:PCBM) and the photovoltage in an in-operando investigation. I-V curves are simultaneously measured together with grazing incidence wide-angle X-ray scattering probing the crystalline state of the device active layer as a function of the operation time. The results show a high degree of correlation between open-circuit voltage VOC and the crystalline state of P3HT. PMID- 28094912 TI - Strong Strain Sensing Performance of Natural Rubber Nanocomposites. AB - A detail study concerning the strain (tensile) dependent electrical conductivity of elastomeric composites is reported in this present paper. Multiwall carbon nanotubes (CNT), conducting carbon black (CB), and their combinations were considered as conducting filler in cross-linked natural rubber matrix. The loadings of the fillers were considered from 3 to 11 phr (filler concentration close to their percolation threshold). Without hindering the elastic nature of the composite (reversible stretchability up to several 100%), the change of relative resistance, DeltaR/R0 (DeltaR is the change in the resistance with respect to strain and R0 is the initial resistance of the sample) of the CB filled composites was found to be as much as ~1300 at around 120% elongation. This value is much higher than any other reported values obtained from conducting polymeric composites. It was found that CNT offered a strong strain dependent character in the regime 100% to 150% elongation, whereas, the carbon black filled natural rubber showed strong strain dependencies at 50% to 100% elongation strain. The combination of two different fillers could be exploited to tailor and manipulate the sensing operating regime from 50% to 150% strain depending on the ratios of the two filler system. Additionally, after several loading-unloading cycles, the conductivity of the sample was very stable for CB filled system but for CNT filled system the conductivity of the sample was altered. This type of elastic materials could be used in structural health monitoring, sensors in different dynamic elastomeric parts like tires, valves, gaskets, engine mounts, etc. PMID- 28094914 TI - Confined Etching within 2D and 3D Colloidal Crystals for Tunable Nanostructured Templates: Local Environment Matters. AB - We report the isotropic etching of 2D and 3D polystyrene (PS) nanosphere hcp arrays using a benchtop O2 radio frequency plasma cleaner. Unexpectedly, this slow isotropic etching allows tuning of both particle diameter and shape. Due to a suppressed etching rate at the point of contact between the PS particles originating from their arrangement in 2D and 3D crystals, the spherical PS templates are converted into polyhedral structures with well-defined hexagonal cross sections in directions parallel and normal to the crystal c-axis. Additionally, we found that particles located at the edge (surface) of the hcp 2D (3D) crystals showed increased etch rates compared to those of the particles within the crystals. This indicates that 2D and 3D order affect how nanostructures chemically interact with their surroundings. This work also shows that the morphology of nanostructures periodically arranged in 2D and 3D supercrystals can be modified via gas-phase etching and programmed by the superlattice symmetry. To show the potential applications of this approach, we demonstrate the lithographic transfer of the PS template hexagonal cross section into Si substrates to generate Si nanowires with well-defined hexagonal cross sections using a combination of nanosphere lithography and metal-assisted chemical etching. PMID- 28094913 TI - Inhibition of Pax2 Transcription Activation with a Small Molecule that Targets the DNA Binding Domain. AB - The Pax gene family encodes DNA binding transcription factors that control critical steps in embryonic development and differentiation of specific cell lineages. Often, Pax proteins are re-expressed or ectopically expressed in cancer and other diseases of abnormal proliferation, making them attractive targets for tissue specific inhibition by small molecules. In this report, we used a homology model of the Pax2 paired domain and a virtual screen to identify small molecules that can inhibit binding of the paired domain to DNA and Pax2 mediated transcription activation. Candidates from the virtual screen were then confirmed in a cell based Pax2 transactivation assay. Subsequently, we tested analogs of these hits to identify a single compound that effectively blocked Pax2 activity and DNA binding with a Kd of 1.35-1.5 MUM. The compound, termed EG1, was used to inhibit embryonic kidney development, a process directly dependent on Pax2 activity. Furthermore, we show that EG1 can inhibit proliferation of Pax2 positive renal and ovarian cancer cell lines but has little effect on Pax2 negative cancer cells. These data confirm that small molecules targeting the DNA binding paired domain can be identified and may be good lead compounds for developing tissue and cell-type specific anticancer therapies. PMID- 28094915 TI - Ultrasensitive, Stretchable Strain Sensors Based on Fragmented Carbon Nanotube Papers. AB - The development of strain sensors featuring both ultra high sensitivity and high stretchability is still a challenge. We demonstrate that strain sensors based on fragmented single-walled carbon nanotube (SWCNT) paper embedded in poly(dimethylsiloxane) (PDMS) can sustain their sensitivity even at very high strain levels (with a gauge factor of over 107 at 50% strain). This record sensitivity is ascribed to the low initial electrical resistance (5-28 Omega) of the SWCNT paper and the wide change in resistance (up to 106 Omega) governed by the percolated network of SWCNT in the cracked region. The sensor response remains nearly unchanged after 10 000 strain cycles at 20% proving the robustness of this technology. This fragmentation based sensing system brings opportunities to engineer highly sensitive stretchable sensors. PMID- 28094916 TI - 3D Printing of Carbon Nanotubes-Based Microsupercapacitors. AB - A novel 3D printing procedure is presented for fabricating carbon-nanotubes (CNTs)-based microsupercapacitors. The 3D printer uses a CNTs ink slurry with a moderate solid content and prints a stream of continuous droplets. Appropriate control of a heated base is applied to facilitate the solvent removal and adhesion between printed layers and to improve the structure integrity without structure delamination or distortion upon drying. The 3D-printed electrodes for microsupercapacitors are characterized by SEM, laser scanning confocal microscope, and step profiler. Effect of process parameters on 3D printing is also studied. The final solid-state microsupercapacitors are assembled with the printed multilayer CNTs structures and poly(vinyl alcohol)-H3PO4 gel as the interdigitated microelectrodes and electrolyte. The electrochemical performance of 3D printed microsupercapacitors is also tested, showing a significant areal capacitance and excellent cycle stability. PMID- 28094917 TI - Tuning the Ignition Performance of a Microchip Initiator by Integrating Various Al/MoO3 Reactive Multilayer Films on a Semiconductor Bridge. AB - Reactive multilayer films (RMFs) can be integrated into semiconducting electronic structures with the use of microelectromechanical systems (MEMS) technology and represent potential applications in the advancement of microscale energy demanding systems. In this study, aluminum/molybdenum trioxide (Al/MoO3)-based RMFs with different modulation periods were integrated on a semiconductor bridge (SCB) using a combination of an image reversal lift-off process and magnetron sputtering technology. This produced an energetic semiconductor bridge (ESCB) chip initiator with controlled ignition performance. The effects of the Al/MoO3 RMFs with different modulation periods on ignition properties of the ESCB initiator were then systematically investigated in terms of flame duration, maximum flame area, and the reaction ratio of the RMFs. These microchip initiators achieved flame durations of 60-600 MUs, maximum flame areas of 2.85 17.61 mm2, and reaction ratios of ~14-100% (discharged with 47 MUF/30 V) by simply changing the modulation periods of the Al/MoO3 RMFs. This behavior was also consistent with a one-dimensional diffusion reaction model. The microchip initiator exhibited a high level of integration and proved to have tuned ignition performance, which can potentially be used in civilian and military applications. PMID- 28094918 TI - Mercury Wet Scavenging and Deposition Differences by Precipitation Type. AB - We analyze the effect of precipitation type on mercury wet deposition using a new database of individual rain events spanning the contiguous United States. Measurements from the Mercury Deposition Network (MDN) containing single rainfall events were identified and classified into six precipitation types. Mercury concentrations in surface precipitation follow a power law of precipitation depth that is modulated by precipitation system morphology. After controlling for precipitation depth, the highest mercury deposition occurs in supercell thunderstorms, with decreasing deposition in disorganized thunderstorms, quasi linear convective systems (QLCS), extratropical cyclones, light rain, and land falling tropical cyclones. Convective morphologies (supercells, disorganized, and QLCS) enhance wet deposition by a factor of at least 1.6 relative to nonconvective morphologies. Mercury wet deposition also varies by geographic region and season. After controlling for other factors, we find that mercury wet deposition is greater over high-elevation sites, seasonally during summer, and in convective precipitation. PMID- 28094919 TI - Synthesis of Three-Dimensional Nanoporous Li-Rich Layered Cathode Oxides for High Volumetric and Power Energy Density Lithium-Ion Batteries. AB - As rechargeable Li-ion batteries have expanded their applications into on-board energy storage for electric vehicles, the energy and power must be increased to meet the new demands. Li-rich layered oxides are one of the most promising candidate materials; however, it is very difficult to make them compatible with high volumetric energy density and power density. Here, we develop an innovative approach to synthesize three-dimensional (3D) nanoporous Li-rich layered oxides Li[Li0.144Ni0.136Co0.136Mn0.544]O2, directly occurring at deep chemical delithiation with carbon dioxide. It is found that the as-prepared material presents a micrometer-sized spherical structure that is typically composed of interconnected nanosized subunits with narrow distributed pores at 3.6 nm. As a result, this unique 3D micro-/nanostructure not only has a high tap density over 2.20 g cm-3 but also exhibits excellent rate capability (197.6 mA h g-1 at 1250 mA g-1) as an electrode. The excellent electrochemical performance is ascribed to the unique nanoporous micro-nanostructures, which facilitates the Li+ diffusion and enhances the structural stability of the Li-rich layered cathode materials. Our work offers a comprehensive designing strategy to construct 3D nanoporous Li rich layered oxides for both high volumetric energy density and power density in Li-ion batteries. PMID- 28094920 TI - Antifouling Thin-Film Composite Membranes by Controlled Architecture of Zwitterionic Polymer Brush Layer. AB - In this study, we demonstrate a highly antifouling thin-film composite (TFC) membrane by grafting a zwitterionic polymer brush via atom-transfer radical polymerization (ATRP), a controlled, environmentally benign chemical process. Initiator molecules for polymerization were immobilized on the membrane surface by bioinspired catechol chemistry, leading to the grafting of a dense zwitterionic polymer brush layer. Surface characterization revealed that the modified membrane exhibits reduced surface roughness, enhanced hydrophilicity, and lower surface charge. Chemical force microscopy demonstrated that the modified membrane displayed foulant-membrane interaction forces that were 1 order of magnitude smaller than those of the pristine TFC membrane. The excellent fouling resistance imparted by the zwitterionic brush layer was further demonstrated by significantly reduced adsorption of proteins and bacteria. In addition, forward osmosis fouling experiments with a feed solution containing a mixture of organic foulants (bovine-serum albumin, alginate, and natural organic matter) indicated that the modified membrane exhibited significantly lower water flux decline compared to the pristine TFC membrane. The controlled architecture of the zwitterionic polymer brush via ATRP has the potential for a facile antifouling modification of a wide range of water treatment membranes without compromising intrinsic transport properties. PMID- 28094921 TI - Uranium Redox Transformations after U(VI) Coprecipitation with Magnetite Nanoparticles. AB - Uranium redox states and speciation in magnetite nanoparticles coprecipitated with U(VI) for uranium loadings varying from 1000 to 10 000 ppm are investigated by X-ray absorption spectroscopy (XAS). It is demonstrated that the U M4 high energy resolution X-ray absorption near edge structure (HR-XANES) method is capable to clearly characterize U(IV), U(V), and U(VI) existing simultaneously in the same sample. The contributions of the three different uranium redox states are quantified with the iterative transformation factor analysis (ITFA) method. U L3 XAS and transmission electron microscopy (TEM) reveal that initially sorbed U(VI) species recrystallize to nonstoichiometric UO2+x nanoparticles within 147 days when stored under anoxic conditions. These U(IV) species oxidize again when exposed to air. U M4 HR-XANES data demonstrate strong contribution of U(V) at day 10 and that U(V) remains stable over 142 days under ambient conditions as shown for magnetite nanoparticles containing 1000 ppm U. U L3 XAS indicates that this U(V) species is protected from oxidation likely incorporated into octahedral magnetite sites. XAS results are supported by density functional theory (DFT) calculations. Further characterization of the samples include powder X-ray diffraction (pXRD), scanning electron microscopy (SEM) and Fe 2p X-ray photoelectron spectroscopy (XPS). PMID- 28094922 TI - Nano-Photoelectrochemical Cell Arrays with Spatially Isolated Oxidation and Reduction Channels. AB - Photoelectrochemical conversion of solar energy is explored for many diverse applications but suffers from poor efficiencies due to limited solar absorption, inadequate charge carrier separation, redox half-reactions occurring in close proximity, and/or long ion diffusion lengths. We have taken a drastically different approach to the design of photoelectrochemical cells (PECs) to spatially isolate reaction sites at the nanoscale to different materials and flow channels, suppressing carrier recombination and back-reaction of intermediates while shortening ion diffusion paths and, importantly, avoiding mixed product generation. We developed massively parallel nano-PECs composed of an array of open-ended carbon nanotubes (CNTs) with photoanodic reactions occurring on the outer walls, uniformly coated with titanium dioxide (TiO2), and photocathodic reactions occurring on the inner walls, decorated with platinum (Pt). We verified the redox reaction isolation by demonstrating selective photodeposition of manganese oxide on the outside and silver on the inside of the TiO2/CNT/Pt nanotubes. Further, the nano-PECs exhibit improved solar absorption and efficient charge transfer of photogenerated carriers to their respective redox sites, leading to a 1.8% photon-to-current conversion efficiency (a current density of 4.2 mA/cm2) under white-light irradiation. The design principles demonstrated can be readily adapted to myriads of photocatalysts for cost-effective solar utilization. PMID- 28094923 TI - Effect of E-waste Recycling on Urinary Metabolites of Organophosphate Flame Retardants and Plasticizers and Their Association with Oxidative Stress. AB - In this study, three chlorinated (Cl-mOPs) and five nonchlorinated (NCl-mOPs) organophosphate metabolites were determined in urine samples collected from participants living in an electronic waste (e-waste) dismantling area (n = 175) and two reference areas (rural, n = 29 and urban, n = 17) in southern China. Bis(2-chloroethyl) phosphate [BCEP, geometric mean (GM): 0.72 ng/mL] was the most abundant Cl-mOP, and diphenyl phosphate (DPHP, 0.55 ng/mL) was the most abundant NCl-mOP. The GM concentrations of mOPs in the e-waste dismantling sites were higher than those in the rural control site. These differences were significant for BCEP (p < 0.05) and DPHP (p < 0.01). Results suggested that e-waste dismantling activities contributed to human exposure to OPs. In the e-waste sites, the urinary concentrations of bis(2-chloro-isopropyl) phosphate (r = 0.484, p < 0.01), BCEP (r = 0.504, p < 0.01), dibutyl phosphate (r = 0.214, p < 0.05), and DPHP (r = 0.440, p < 0.01) were significantly increased as the concentration of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of DNA oxidative stress, increased. Our results also suggested that human exposure to OPs might be correlated with DNA oxidative stress for residents in e-waste dismantling areas. To our knowledge, this study is the first to report the urinary levels of mOPs in China and examine the association between OP exposure and 8-OHdG in humans. PMID- 28094924 TI - Reversible and Selective Encapsulation of Dextromethorphan and beta-Estradiol Using an Asymmetric Molecular Capsule Assembled via the Weak-Link Approach. AB - An allosterically regulated, asymmetric receptor featuring a binding cavity large enough to accommodate three-dimensional pharmaceutical guest molecules as opposed to planar, rigid aromatics, was synthesized via the Weak-Link Approach. This architecture is capable of switching between an expanded, flexible "open" configuration and a collapsed, rigid "closed" one. The structure of the molecular receptor can be completely modulated in situ through the use of simple ionic effectors, which reversibly control the coordination state of the Pt(II) metal hinges to open and close the molecular receptor. The substantial change in binding cavity size and electrostatic charge between the two configurations is used to explore the capture and release of two guest molecules, dextromethorphan and beta-estradiol, which are widely found as pollutants in groundwater. PMID- 28094925 TI - Retinal-Based Proton Pumping in the Near Infrared. AB - Proteorhodopsin (PR) and Gloeobacter rhodopsin (GR) are retinal-based light driven proton pumps that absorb visible light (maxima at 520-540 nm). Shifting the action spectra of these proton pumps beyond 700 nm would generate new prospects in optogenetics, membrane sensor technology, and complementation of oxygenic phototrophy. We therefore investigated the effect of red-shifting analogues of retinal, combined with red-shifting mutations, on the spectral properties and pump activity of the resulting pigments. We investigated a variety of analogues, including many novel ones. One of the novel analogues we tested, 3 methylamino-16-nor-1,2,3,4-didehydroretinal (MMAR), produced exciting results. This analogue red-shifted all of the rhodopsin variants tested, accompanied by a strong broadening of the absorbance band, tailing out to 850-950 nm. In particular, MMAR showed a strong synergistic effect with the PR-D212N,F234S double mutant, inducing an astonishing 200 nm red shift in the absorbance maximum. To our knowledge, this is by far the largest red shift reported for any retinal protein. Very importantly, all MMAR-containing holoproteins are the first rhodopsins retaining significant pump activity under near-infrared illumination (730 nm light-emitting diode). Such MMAR-based rhodopsin variants present very promising opportunities for further synthetic biology modification and for a variety of biotechnological and biophysical applications. PMID- 28094926 TI - The Room-Temperature Superionic Conductivity of Silver Iodide Nanoparticles under Pressure. AB - We performed variable-temperature synchrotron powder X-ray diffraction measurements and impedance spectroscopy under pressure for silver iodide (AgI) nanoparticles with a diameter of 11 nm. The superionic conducting alpha-phase of AgI nanoparticles was successfully stabilized down to at least 20 degrees C by applying a pressure of 0.18 GPa, whereas the transition temperature was 147 degrees C in bulk AgI at ambient pressure. To our knowledge, this is the first example of the alpha-phase of AgI existing stably at room temperature. PMID- 28094927 TI - Asymmetric Catalysis of the Carbonyl-Amine Condensation: Kinetic Resolution of Primary Amines. AB - A Bronsted acid catalyzed kinetic resolution of primary amines is described that is based on the condensation between an amine and a carbonyl compound. 1,3 Diketones react with racemic alpha-branched amines to furnish the corresponding enantioenriched enaminone and recovered starting material. Good to excellent enantioselectivity was observed with both aromatic and aliphatic primary amines. This process represents the first small-molecule catalyzed kinetic resolution of aliphatic amines. PMID- 28094928 TI - Efficient Charge Transport via DNA G-Quadruplexes. AB - The dynamics and efficiency of photoinduced charge transport has been investigated in DNA capped hairpins possessing a stilbenedicarboxamide (Sa) hole donor and stilbenediether (Sd) hole acceptor separated by DNA G-quadruplex structures possessing 2-to-4 tetrads by means of femtosecond and nanosecond transient absorption spectroscopy with global analysis. The results for the quadruplex structures are compared with those for the corresponding duplex structures having G-C base pairs in place of the G-tetrads. Following photoinduced charge separation to form a contact radical ion pair, hole transport to form the Sa-*/Sd+* charge-separated state is slower but more efficient for the quadruplex vs duplex structures. Thus, the G-quadruplex serves as an effective conduit for positive charge rather than as a hole trap when inserted into a duplex, as previously postulated. PMID- 28094929 TI - Effect of in Vitro Gastrointestinal Digestion on Encapsulated and Nonencapsulated Phenolic Compounds of Carob (Ceratonia siliqua L.) Pulp Extracts and Their Antioxidant Capacity. AB - To determine the effect of in vitro gastrointestinal digestion on the release and antioxidant capacity of encapsulated and nonencapsulated phenolics carob pulp extracts, unripe and ripe carob pulp extracts were microencapsulated with polycaprolactone via double emulsion/solvent evaporation technique. Microcapsules' characterization was performed using scanning electron microscopy and Fourier transform infrared spectrometry analysis. Total phenolics and flavonoids content and antioxidant activities (ORAC, DPPH, and FRAP) were evaluated after each digestion step. The release of phenolic acids and flavonoids was measured along the digestion process by HPLC-MS/MS analysis. The most important phenolics and flavonoids content as well as antioxidant activities were observed after gastric and intestinal phases for nonencapsulated and encapsulated extracts, respectively. The microencapsulation of carob polyphenols showed a protective effect against pH changes and enzymatic activities along digestion, thereby promoting a controlled release and targeted delivery of the encapsulated compound, which contributed to an increase in its bioaccessibility in the gut. PMID- 28094930 TI - Fe- and Ln-DOTAm-F12 Are Effective Paramagnetic Fluorine Contrast Agents for MRI in Water and Blood. AB - A series of fluorinated macrocyclic complexes, M-DOTAm-F12, where M is LaIII, EuIII, GdIII, TbIII, DyIII, HoIII, ErIII, TmIII, YbIII, and FeII, was synthesized, and their potential as fluorine magnetic resonance imaging (MRI) contrast agents was evaluated. The high water solubility of these complexes and the presence of a single fluorine NMR signal, two necessary parameters for in vivo MRI, are substantial advantages over currently used organic polyfluorocarbons and other reported paramagnetic 19F probes. Importantly, the sensitivity of the paramagnetic probes on a per fluorine basis is at least 1 order of magnitude higher than that of diamagnetic organic probes. This increased sensitivity is due to a substantial-up to 100-fold-decrease in the longitudinal relaxation time (T1) of the fluorine nuclei. The shorter T1 allows for a greater number of scans to be obtained in an equivalent time frame. The sensitivity of the fluorine probes is proportional to the T2/T1 ratio. In water, the optimal metal complexes for imaging applications are those containing HoIII and FeII, and to a lesser extent TmIII and YbIII. Whereas T1 of the lanthanide complexes are little affected by blood, the T2 are notably shorter in blood than in water. The sensitivity of Ln-DOTAm-F12 complexes is lower in blood than in water, such that the most sensitive complex in water, HoIII-DOTAm-F12, could not be detected in blood. TmIII yielded the most sensitive lanthanide fluorine probe in blood. Notably, the relaxation times of the fluorine nuclei of FeII-DOTAm-F12 are similar in water and in blood. That complex has the highest T2/T1 ratio (0.57) and the lowest limit of detection (300 MUM) in blood. The combination of high water solubility, single fluorine signal, and high T2/T1 of M-DOTAm-F12 facilitates the acquisition of three-dimensional magnetic resonance images. PMID- 28094931 TI - Observation of Internal Photoinduced Electron and Hole Separation in Hybrid Two Dimentional Perovskite Films. AB - Two-dimensional (2D) organolead halide perovskites are promising for various optoelectronic applications. Here we report a unique spontaneous charge (electron/hole) separation property in multilayered (BA)2(MA)n-1PbnI3n+1 (BA = CH3(CH2)3NH3+, MA = CH3NH3+) 2D perovskite films by studying the charge carrier dynamics using ultrafast transient absorption and photoluminescence spectroscopy. Surprisingly, the 2D perovskite films, although nominally prepared as "n = 4", are found to be mixture of multiple perovskite phases, with n = 2, 3, 4 and ~ infinity, that naturally align in the order of n along the direction perpendicular to the substrate. Driven by the band alignment between 2D perovskites phases, we observe consecutive photoinduced electron transfer from small-n to large-n phases and hole transfer in the opposite direction on hundreds of picoseconds inside the 2D film of ~358 nm thickness. This internal charge transfer efficiently separates electrons and holes to the upper and bottom surfaces of the films, which is a unique property beneficial for applications in photovoltaics and other optoelectronics devices. PMID- 28094932 TI - Series d-f Heteronuclear Metal-Organic Frameworks: Color Tunability and Luminescent Probe with Switchable Properties. AB - A series of five unique d-f heteronuclear luminescent metal-organic frameworks (MOFs) in an entangled polyrotaxane array and the light-harvesting block homonuclear zinc compound have been isolated successfully and characterized. The series of isostructural polymers feature 3,4-connected (4.82)(4.83.92)(6.8.9)2(6.92)(83) topology and high stability, exhibiting diverse void spaces. By taking advantage of the isostructural MOFs 2 and 3, the intensities of red and green emissions can be modulated by adjusting the ratios of EuIII and TbIII ions correspondingly, and white-light emission can be generated by a combination of different doped TbIII and EuIII concentrations. The Tb-Zn-based framework {[Tb3Zn6(bipy2)2(Hmimda)7 (H2O)3].5H2O}n (3; H3mimda = 2 methyl-1-H-imidazole-4,5-dicarboxylic acid and bipy = 4,4'-bipyridine) can detect trace MgII ion with relatively high sensitivity and selectivity. Dehydrated MOF 3a shows a remarkable emission quenching effect through the introduction of I2 solids. Further investigation indicates that it exhibits turn on/off switchable properties for small solvent molecules or heavy-metal ions. Steady/transient state near-IR luminescence properties for MOFs 1, 4, and 5 were investigated under visible-light excitation. PMID- 28094933 TI - Accurate Gas Phase Formation Enthalpies of Alloys and Refractories Decomposition Products. AB - Accurate gas phase formation enthalpies, DeltaHf, of metal oxides and halides are critical for the prediction of the stability of high temperature materials used in the aerospace and nuclear industries. Unfortunately, the experimental DeltaHf values of these compounds in the most used databases, such as the NIST-JANAF database, are often reported with large inaccuracy, while some other DeltaHf values clearly differ from the value predicted by CCSD(T) methods. To address this point, in this work we systematically predicted the DeltaHf values of a series of these compounds having a group 4, 6, or 14 metal. The DeltaHf values in question were derived within a composite Feller-Dixon-Peterson (FDP) scheme based protocol that combines the DLPNO-CCSD(T) enthalpy of ad hoc designed reactions and the experimental DeltaHf values of few reference complexes. In agreement with other theoretical studies, we predict the DeltaHf values for TiOCl2, TiOF2, GeF2, and SnF4 to be significantly different from the values tabulated in NIST-JANAF and other sources, which suggests that the tabulated experimental values are inaccurate. Similarly, the predicted DeltaHf values for HfCl2, HfBr2, HfI2, MoOF4, MoCl6, WOF4, WOCl4, GeO2, SnO2, PbBr4, PbI4, and PbO2 also clearly differ from the tabulated experimental values, again suggesting large inaccuracy in the experimental values. In the case when largely different experimental values are available, we point to the value that is in better agreement with our results. We expect the DeltaHf values reported in this work to be quite accurate, and thus, they might be used in thermodynamic calculations, because the effects from core correlation, relativistic effects, and basis set incompleteness were included in the DLPNO-CCSD(T) calculations. T1 and T2 values were thoroughly monitored as indicators of the quality of the reference Hartree-Fock orbitals (T1) and potential multireference character of the systems (T2). PMID- 28094934 TI - Donor-Acceptor Stabilized Tetra(silanimine). AB - The synthesis of an oligo(silanimine) is described. The reaction of the amidinato silylene [LSiN(SiMe3)2] (1, L = PhC(NtBu)2) with SiI4 in toluene afforded a mixture of the silanimine [LSi(I)NSiI3] (2), SiMe3I, and Si2I6. The mechanistic studies showed that 1 reacts with SiI4 to form the silyl ionic intermediate "{LSi(I)N(SiMe3)2}+{SiI3}-", which then eliminates SiMe3I and "SiI2" to form the silanimine intermediate "LSi(I)NSiMe3". It further undergoes a substitution with another molecule of SiI4 to form a mixture of 2 and SiMe3I. In addition, "SiI2" undergoes an oxidative addition with SiI4 to form Si2I6. Subsequently, compound 2 reacted with [LiN(SiMe3)Ar] to form the silanimine [LSi(I)NSiI2N(SiMe3)Ar] (6, Ar = 2,6-iPr2C6H3), which was then treated with KC8 to give the donor-acceptor stabilized tetra(silanimine) [LSiN(SiMe3)SiNAr]2 (7). It comprises four formal silanimine ">Si?N-" units, which are linked together. Compounds 2, 6, and 7 were characterized by NMR spectroscopy and X-ray crystallography. PMID- 28094935 TI - Sulfonic Group Functionalized Mixed Ligand Coordination Polymers: Synthesis, Characterization, Water Sorption, and Proton Conduction Studies. AB - Five sulfonic acid group functionalized mixed ligand coordination polymers (CPs), namely, {[Zn(bpeH)(5-sip)(H2O)].(H2O)}n (1), {[Cu(pyz)(5-Hsip)(H2O)2].(H2O)2}n (2), {[Cu(bpee)0.5(5-sip)(H2O)2].(H2O)4(bpeeH2)0.5}n (3), {[Cu(bpy)(5 Hsip)(H2O)].(H2O)2}n (4), and {[Cu(bpy)2(5-H2sip)2].(H2O)6}n (5) [where sip3- = 5 sulfoisophthalate; bpe = 4,4'-bispyridylethane; pyz = pyrazine; bpee = 4,4' bispyridylethylene; bpy = 4,4'-bipyridine], have been synthesized with varying different N,N'-donor linkers using slow diffusion techniques at room temperature. The CPs possess guest water filled 1D channels and noncoordinating sulfonic acid or coordinated sulfonate groups, which are interconnected by means of extended intermolecular H-bonding interaction, which supports the humidity dependent proton conductivity of the samples. Under 95% relative humidity (% RH), the CPs exhibit the temperature dependent proton conductivity which is maximum up to in the range of ~10-5-10-6 S cm-1 at 65 degrees C. In most of the cases, the framework shows activation energies with the value ranging from 0.35 to 0.54 eV, suggesting mostly the contribution of the Grotthuss mechanism of the proton conductivity. PMID- 28094936 TI - Computation of the Isotropic Hyperfine Coupling Constant: Efficiency and Insights from a New Approach Based on Wave Function Theory. AB - The present paper reports an original computational strategy for the computation of the isotropic hyperfine coupling constants (hcc). The algorithm proposed here is based on an approach recently introduced by some of the authors, namely, the first-order breathing orbital self-consistent field (FOBO-SCF). The approach is an almost parameter-free wave function method capable to accurately treat the spin delocalization together with the spin polarization effects while staying in a restricted formalism and avoiding spin contamination. The efficiency of the method is tested on a series of small radicals, among which four nitroxide radicals and the comparison with high-level ab initio methods show very encouraging results. On the basis of these results, the method is then applied to compute the hcc of a challenging system, namely, the DEPMPO-OOH radical in various conformations. The reference values obtained on such a large system allows us to validate a cheap computational method based on density functional theory (DFT). Another interesting feature of the model applied here is that it allows for the rationalization of the results according to a relatively simple scheme based on a two-step mechanism. More precisely, the results are analyzed in terms of two separated contributions: first the spin delocalization and then the spin polarization. PMID- 28094937 TI - Click Quantitative Mass Spectrometry Identifies PIWIL3 as a Mechanistic Target of RNA Interference Activator Enoxacin in Cancer Cells. AB - Enoxacin is a small molecule that stimulates RNA interference (RNAi) and acts as a growth inhibitor selectively in cancer but not in untransformed cells. Here, we used alkenox, a clickable enoxacin surrogate, coupled with quantitative mass spectrometry, to identify PIWIL3 as a mechanistic target of enoxacin. PIWIL3 is an Argonaute protein of the PIWI subfamily that is mainly expressed in the germline and that mediates RNAi through piRNAs. Our results suggest that cancer cells re-express PIWIL3 to repress RNAi through miRNAs and thus open a new opportunity for cancer-specific targeting. PMID- 28094938 TI - In Vitro and in Vivo Evaluation of Fully Substituted (5-(3-Ethoxy-3-oxopropynyl) 4-(ethoxycarbonyl)-1,2,3-triazolyl-glycosides as Original Nucleoside Analogues to Circumvent Resistance in Myeloid Malignancies. AB - A series of nucleoside analogues bearing a 1,4,5-trisubstituted-1,2,3-triazole aglycone was synthesized using a straightforward click/electrophilic addition or click/oxidative coupling tandem procedures. SAR analysis, using cell culture assays, led to the discovery of a series of compounds belonging to the 5-alkynyl 1,2,3-triazole family that exhibits potent antileukemic effects on several hematologic malignancies including chronic myeloid leukemia (CML) and myelodysplastic syndromes (MDS) either sensitive or resistant to their respective therapy. Compound 4a also proved efficient in vivo on mice xenografted with SKM1 R MDS cell line. Additionally, some insights in its mode of action revealed that this compound induced cell death by caspase and autophagy induction. PMID- 28094939 TI - Unimolecular Decomposition Mechanism of 1,2-Dioxetanedione: Concerted or Biradical? That is the Question! AB - Determination of the ground- and excited-state unimolecular decomposition mechanisms of 1,2-dioxetanedione gives a level of insight into bimolecular decomposition reactions of this kind for which some experimental results are reported. Although a few studies have put some effort to describe a biradical mechanism of this decomposition, there is still no systematic study that proves an existence of a biradical character. In the present study, state-of-the-art high-level multistate multiconfigurational reference second-order perturbation theory calculations are performed to describe the reaction mechanism of 1,2 dioxetanedione in detail. The calculations indicate that the decomposition of this four-membered ring peroxide containing two carbonyl carbon atoms occurs in concerted but not simultaneous fashion, so-called "merged", contrary to the case of unimolecular 1,2-dioxetane and 1,2-dioxetanone decompositions where biradical reaction pathways have been calculated. At the TS of the ground-state surface, the system enters an entropic trapping region, where four singlet and four triplet manifolds are degenerated, which can lead to the formation of triplet and singlet excited biradical species. However, these excited species have to overcome a second activation barrier for C-C bond cleavage for excited product formation, whereas the ground-state energy surface possesses only one TS. Thus our calculations indicate that the unimolecular decomposition of 1,2 dioxetanedione should not lead to efficient excited-state formation, in agreement with the lack of direct emission from the peroxyoxalate reaction. PMID- 28094941 TI - Impact of Turn Propensity on the Folding Rates of Z34C Protein: Implications for the Folding of Helix-Turn-Helix Motif. AB - The rate-limiting step for the folding of the helix-turn-helix (HTH) protein, Z34C, involves beta-turn region 20DPNL23. This reverse turn has been observed to be part of the transition state in the folding process for Z34C, influencing its folding rates. Molecular dynamics simulations were performed on this turn peptide and its two mutants, D20A and P21A, to study turn formation using GROMOS54A7 force field. We find that this region has a turn propensity of its own, and the highest turn propensity is observed for the wild-type, which correlates well with available experimental results. We also find that a slight unfavorable change in DeltaG turn folding causes a drastic change in the folding rates of HTH motif and a mechanistic interpretation is given. Implications of these observations for the folding of the HTH protein Z34C are discussed. PMID- 28094940 TI - High Electronic Conductance through Double-Helix DNA Molecules with Fullerene Anchoring Groups. AB - Determining the mechanism of charge transport through native DNA remains a challenge as different factors such as measuring conditions, molecule conformations, and choice of technique can significantly affect the final results. In this contribution, we have used a new approach to measure current flowing through isolated double-stranded DNA molecules, using fullerene groups to anchor the DNA to a gold substrate. Measurements were performed at room temperature in an inert environment using a conductive AFM technique. It is shown that the pi-stacked B-DNA structure is conserved on depositing the DNA. As a result, currents in the nanoampere range were obtained for voltages ranging between +/-1 V. These experimental results are supported by a theoretical model that suggests that a multistep hopping mechanism between delocalized domains is responsible for the long-range current flow through this specific type of DNA. PMID- 28094942 TI - Simulation of DBS, DBS-COOH, and DBS-CONHNH2 as Hydrogelators. AB - The organic gelator 1,3(R):2,4(S)-dibenzylidene-d-sorbitol (DBS) self-organizes to form a 3D network at relatively low concentrations in a variety of nonpolar organic solvents and polymer melt. DBS could be transformed into a hydrogelator by introduction of hydrophilic groups, which facilitate its self-assembly in an aqueous medium. In this work, we have investigated the hydrogelators DBS-COOH and DBS-CONHNH2 and the organogelator DBS by molecular modeling. We have used quantum mechanics (QM) to elucidate the preferred geometry of one molecule and a dimer of each of the gelators and molecular dynamics (MD) to simulate the pure gelators and their mixtures with water. The results of the simulation indicate that the interaction between DBS-COOH molecules is the strongest of the three and its water compatibility is the highest. Therefore, DBS-COOH seems to be a better hydrogelator than DBS-CONHNH2 and DBS. Intermolecular H-bonding interactions are formed between DBS, DBS-COOH, and DBS-CONHNH2 molecules as pure substances, and they dramatically decrease in the presence of water. In contrast, the intramolecular interactions increase in water. This result indicates that in aqueous environment the molecular structure tends to be more rigid and fixed in the preferred conformation. The most significant intramolecular interaction is formed between O3 acetal and H-O6 groups. Due to the H-bonds, DBS, DBS-COOH, and DBS-CONHNH2 molecules form a rigid structure similar to that of liquid crystal forming molecules, which might explain their tendency to create nanofibrils. It was found that the aromatic rings do not contribute significantly to the inter- and intramolecular interactions. Their main role is probably to stiffen the molecular structure. PMID- 28094943 TI - Exploitation of a Multienzymatic Stereoselective Cascade Process in the Synthesis of 2-Methyl-3-Substituted Tetrahydrofuran Precursors. AB - Enantiopure 2-methyl-3-substituted tetrahydrofurans are key precursors of several biologically active products (drugs, flavors, and agrochemicals). Thus, a stereocontrolled and efficient methodology for the obtainment of these synthons is highly desirable. We exploited a two-step multienzymatic stereoselective cascade reduction of alpha-bromo-alpha,beta-unsaturated ketones to give the corresponding bromohydrins in good yields, with high ee and de values. The cascade process is catalyzed by an ene-reductase and an alcohol dehydrogenase. Further manipulations of these bromohydrins, by two diastereodivergent routes, allowed the preparation of the tetrahydrofuran synthons. One route is based on a lipase catalyzed cleavage of the protecting group. The second route is characterized by a camphor sulfonic acid mediated isomerization of a beta hydroxyepoxide to give the tetrahydrofuran-2-ol. Finally, the synthesis of the most odorous and pleasant stereoisomer of the roasted meat aroma, i.e., (2S,3R)-2 methyl-3-thioacetate tetrahydrofuran, is reported as well. PMID- 28094944 TI - Solvent-Directed Switch of a Left-Handed 10/12-Helix into a Right-Handed 12/10 Helix in Mixed beta-Peptides. AB - Present study describes the synthesis and conformational analysis of beta peptides from C-linked carbo-beta-amino acids [beta-Caa(l)] with a d-lyxo furanoside side chain and beta-hGly in 1:1 alternation. NMR and CD investigations on peptides with an (S)-beta-Caa(l) monomer at the N-terminus revealed a right handed 10/12-mixed helix. An unprecedented solvent-directed "switch" both in helical pattern and handedness was observed when the sequence begins with a beta hGly residue instead of a (S)-beta-Caa(l) constituent. NMR studies on these peptides in chloroform indicated a left-handed 10/12-helix, while the CD spectrum in methanol inferred a right-handed secondary structure. The NMR data for these peptides in CD3OH showed the presence of a right-handed 12/10-helix. NMR investigations in acetonitrile indicated the coexistence of both helix types. Quantum chemical studies predicted a small energy difference of 0.3 kcal/mol between the two helix types, which may explain the possibility of solvent influence. Examples for a solvent-directed switch of both the H-bonding pattern and the handedness of foldamer helices are rare so far. A comparable solvent effect was not found in the corresponding peptides with (R)-beta-Caa(l) residues, where right-handed 12/10-helices are predominating. PMID- 28094945 TI - PdII/AgI-Catalyzed Room-Temperature Reaction of gamma-Hydroxy Lactams: Mechanism, Scope, and Antistaphylococcal Activity. AB - The present work reports a PdII/AgI-promoted amidoalkylation reaction involving various gamma-hydroxy lactams and C/O/S nucleophiles at room temperature. The dual mode of activation of both the electrophile and nucleophile by in situ generated catalytically active cationic PdII species facilitates the reaction at room temperature. Among the synthesized isoindoline derivatives, three compounds are found to be active against vancomycin and methicillin-resistant S. aureus strain with appreciable MIC values. PMID- 28094946 TI - Competing E2 and SN2 Mechanisms for the F- + CH3CH2I Reaction. AB - Anti-E2, syn-E2, inv-, and ret-SN2 reaction channels for the gas-phase reaction of F- + CH3CH2I were characterized with a variety of electronic structure calculations. Geometrical analysis confirmed synchronous E2-type transition states for the elimination of the current reaction, instead of nonconcerted processes through E1cb-like and E1-like mechanisms. Importantly, the controversy concerning the reactant complex for anti-E2 and inv-SN2 paths has been clarified in the present work. A positive barrier of +19.2 kcal/mol for ret-SN2 shows the least feasibility to occur at room temperature. Negative activation energies ( 16.9, -16.0, and -4.9 kcal/mol, respectively) for inv-SN2, anti-E2, and syn-E2 indicate that inv-SN2 and anti-E2 mechanisms significantly prevail over the eclipsed elimination. Varying the leaving group for a series of reactions F- + CH3CH2Y (Y = F, Cl, Br, and I) leads to monotonically decreasing barriers, which relates to the gradually looser TS structures following the order F > Cl > Br > I. The reactivity of each channel nearly holds unchanged except for the perturbation between anti-E2 and inv-SN2. RRKM calculation reveals that the reaction of the fluorine ion with ethyl iodide occurs predominately via anti-E2 elimination, and the inv-SN2 pathway is suppressed, although it is energetically favored. This phenomenon indicates that, in evaluating the competition between E2 and SN2 processes, the kinetic or dynamical factors may play a significant role. By comparison with benchmark CCSD(T) energies, MP2, CAM-B3LYP, and M06 methods are recommended to perform dynamics simulations of the title reaction. PMID- 28094947 TI - Synthesis of 2-Azulenyltetrathiafulvalenes by Palladium-Catalyzed Direct Arylation of 2-Chloroazulenes with Tetrathiafulvalene and Their Optical and Electrochemical Properties. AB - Tetrathiafulvalene (TTF) derivatives with 2-azulenyl substituents 5-11 were prepared by the palladium-catalyzed direct arylation reaction of 2-chloroazulenes with TTF in good yield. Photophysical properties of these compounds were investigated by UV-vis spectroscopy and theoretical calculations. Redox behavior of the novel azulene-substituted TTFs was examined by using cyclic voltammetry and differential pulse voltammetry, which revealed their multistep electrochemical oxidation and/or reduction properties. Moreover, these TTF derivatives showed significant spectral change in the visible region under the redox conditions. PMID- 28094948 TI - Liquid Cell Electron Microscopy of Nanoparticle Self-Assembly Driven by Solvent Drying. AB - Drying a colloidal solution of nanoparticles is a versatile method to construct self-assembled structures of nanoparticles. However, mechanistic understanding has mostly relied on empirical knowledge obtained from the final structures of self-assembly as relevant processes during solvent drying are likely kinetic and far from equilibrium. Here, we present in situ TEM studies of nanoparticle self assembly under various conditions, including the concentrations of the initial solution and the types of nanoparticles and substrates. The capability of tracking trajectories of individual nanoparticles enables us to understand the mechanisms of drying-mediated self-assembly at the single-nanoparticle level. Our results consistently show that a solvent boundary primarily affects nanoparticle motions and the resulting self-assembly processes regardless of different conditions. The solvent boundary drives nanoparticles to form two-dimensional assembly mainly through two pathways, transporting scattered nanoparticles by lateral dragging and flattening aggregated nanoparticles by vertical pressing. PMID- 28094949 TI - How High Concentrations of Proteins Stabilize the Amorphous State of Calcium Orthophosphate: A Solid-State Nuclear Magnetic Resonance (NMR) Study of the Casein Case. AB - Understanding how proteins stabilize amorphous calcium ortho-phosphate (ACP) phases is of great importance in biology and for pharmaceutical or food applications. Until now, most of the former investigations about ACP-protein stability and equilibrium were performed under conditions where ACP colloidal nanoclusters are surrounded by low to moderate concentrations of peptides or proteins (15-30 g L-1). As a result, the question of ACP-protein interactions in highly concentrated protein systems has clearly been overlooked, whereas it corresponds to actual industrial conditions such as drying or membrane filtration in the dairy industry for instance. In this study, the structure of an ACP phase is monitored in association with one model phosphorylated protein (casein) using solid-state nuclear magnetic resonance (ssNMR) under two conditions of high protein concentration (300 and 400 g L-1). At both concentrations and at 25 degrees C, it is found that the caseins maintain the mineral phase in an amorphous form with no detectable influence on its structure or size. Interestingly, and in both cases, a significant amount of the nonphosphorylated side chains interacts with ACP through hydrogen bonds. The number of these interacting side chains is found to be higher at the highest casein concentration. At 45 degrees C, which is a destabilizing temperature of ACP under protein-free conditions, the amorphous structure of the mineral phase is partially transformed at a casein concentration of 300 g L-1, while it remains almost intact at a casein concentration of 400 g L-1. Therefore, these results clearly indicate that increasing the concentration of proteins favors ACP-protein interactions and stabilizes the ACP clusters more efficiently. PMID- 28094950 TI - Capillary-Force-Induced Cold Welding in Silver-Nanowire-Based Flexible Transparent Electrodes. AB - Silver nanowire (AgNW) films have been studied as the most promising flexible transparent electrodes for flexible photoelectronics. The wire-wire junction resistance in the AgNW film is a critical parameter to the electrical performance, and several techniques of nanowelding or soldering have been reported to reduce the wire-wire junction resistance. However, these methods require either specific facilities, or additional materials as the "solder", and often have adverse effects to the AgNW film or substrate. In this study, we show that at the nanoscale, capillary force is a powerful driving force that can effectively cause self-limited cold welding of the wire-wire junction for AgNWs. The capillary-force-induced welding can be simply achieved by applying moisture on the AgNW film, without any technical support like the addition of materials or the use of specific facilities. The moisture-treated AgNW films exhibit a significant decrease in sheet resistance, but negligible changes in transparency. We have also demonstrated that this method is effective to heal damaged AgNW films of wearable electronics and can be conveniently performed not only indoors but also outdoors where technical support is often unavailable. The capillary force-based method may also be useful in the welding of other metal NWs, the fabrication of nanostructures, and smart assemblies for versatile flexible optoelectronic applications. PMID- 28094951 TI - Diabat Interpolation for Polymorph Free-Energy Differences. AB - Existing methods to compute free-energy differences between polymorphs use harmonic approximations, advanced non-Boltzmann bias sampling techniques, and/or multistage free-energy perturbations. This work demonstrates how Bennett's diabat interpolation method ( J. Comput. Phys. 1976, 22, 245 ) can be combined with energy gaps from lattice-switch Monte Carlo techniques ( Phys. Rev. E 2000, 61, 906 ) to swiftly estimate polymorph free-energy differences. The new method requires only two unbiased molecular dynamics simulations, one for each polymorph. To illustrate the new method, we compute the free-energy difference between face-centered cubic and body-centered cubic polymorphs for a Gaussian core solid. We discuss the justification for parabolic models of the free-energy diabats and similarities to methods that have been used in studies of electron transfer. PMID- 28094952 TI - Effect of an Enhanced Nose-to-Brain Delivery of Insulin on Mild and Progressive Memory Loss in the Senescence-Accelerated Mouse. AB - Insulin is now considered to be a new drug candidate for treating dementias, such as Alzheimer's disease, whose pathologies are linked to insulin resistance in the brain. Our recent work has clarified that a noncovalent strategy involving cell penetrating peptides (CPPs) can increase the direct transport of insulin from the nasal cavity into the brain parenchyma. The present study aimed to determine whether the brain insulin level increased by intranasal coadministration of insulin with the CPP penetratin has potential for treating dementia. The pharmacological actions of insulin were investigated at different stages of memory impairment using a senescence-accelerated mouse-prone 8 (SAMP8) model. The results of spatial learning tests suggested that chronic intranasal administration of insulin with l-penetratin to SAMP8 slowed the progression of memory loss in the early stage of memory impairment. However, contrary to expectations, this strategy using penetratin was ineffective in recovering the severe cognitive dysfunction in the progressive stage, which involves brain accumulation of amyloid beta (Abeta). Immunohistological examination of hippocampal regions of samples from SAMP8 in the progressive stage suggested that accelerated nose-to-brain insulin delivery had a partial neuroprotective function but unexpectedly increased Abeta plaque deposition in the hippocampus. These findings suggest that the efficient nose-to-brain delivery of insulin combined with noncovalent CPP strategy has different effects on dementia during the mild and progressive stages of cognitive dysfunction. PMID- 28094953 TI - Structure-Sensitive CO2 Electroreduction to Hydrocarbons on Ultrathin 5-fold Twinned Copper Nanowires. AB - Copper is uniquely active for the electrocatalytic reduction of carbon dioxide (CO2) to products beyond carbon monoxide, such as methane (CH4) and ethylene (C2H4). Therefore, understanding selectivity trends for CO2 electrocatalysis on copper surfaces is critical for developing more efficient catalysts for CO2 conversion to higher order products. Herein, we investigate the electrocatalytic activity of ultrathin (diameter ~20 nm) 5-fold twinned copper nanowires (Cu NWs) for CO2 reduction. These Cu NW catalysts were found to exhibit high CH4 selectivity over other carbon products, reaching 55% Faradaic efficiency (FE) at 1.25 V versus reversible hydrogen electrode while other products were produced with less than 5% FE. This selectivity was found to be sensitive to morphological changes in the nanowire catalyst observed over the course of electrolysis. Wrapping the wires with graphene oxide was found to be a successful strategy for preserving both the morphology and reaction selectivity of the Cu NWs. These results suggest that product selectivity on Cu NWs is highly dependent on morphological features and that hydrocarbon selectivity can be manipulated by structural evolution or the prevention thereof. PMID- 28094954 TI - Backbone Degradable N-(2-Hydroxypropyl)methacrylamide Copolymer Conjugates with Gemcitabine and Paclitaxel: Impact of Molecular Weight on Activity toward Human Ovarian Carcinoma Xenografts. AB - Degradable diblock and multiblock (tetrablock and hexablock) N-(2 hydroxypropyl)methacrylamide (HPMA) copolymer-gemcitabine (GEM) and -paclitaxel (PTX) conjugates were synthesized by reversible addition-fragmentation chain transter (RAFT) copolymerization followed by click reaction for preclinical investigation. The aim was to validate the hypothesis that long-circulating conjugates are needed to generate a sustained concentration gradient between vasculature and a solid tumor and result in significant anticancer effect. To evaluate the impact of molecular weight of the conjugates on treatment efficacy, diblock, tetrablock, and hexablock GEM and PTX conjugates were administered intravenously to nude mice bearing A2780 human ovarian xenografts. For GEM conjugates, triple doses with dosage 5 mg/kg were given on days 0, 7, and 14 (q7dx3), whereas a single dose regime with 20 mg/kg was applied on day 0 for PTX conjugates treatment. The most effective conjugates for each monotherapy were the diblock ones, 2P-GEM and 2P-PTX (Mw ~ 100 kDa). Increasing the Mw to 200 or 300 kDa resulted in decrease of activity most probably due to changes in the conformation of the macromolecule because of interaction of hydrophobic residues at side chain termini and formation of "unimer micelles". In addition to monotherapy, a sequential combination treatment of diblock PTX conjugate followed by GEM conjugate (2P-PTX/2P-GEM) was also performed, which showed the best tumor growth inhibition due to synergistic effect: complete remission was achieved after the first treatment cycle. However, because of low dose applied, tumor recurrence was observed 2 weeks after cease of treatment. To assess optimal route of administration, intraperitoneal (i.p.) application of 2P-GEM, 2P-PTX, and their combination was examined. The fact that the highest anticancer efficiency was achieved with diblock conjugates that can be synthesized in one scalable step bodes well for the translation into clinics. PMID- 28094955 TI - Using Diffusion To Characterize Interfacial Heterogeneity. AB - We report on the use of molecular diffusional motion over a range of length scales to characterize compositional heterogeneity in monolayer structures. This work focuses on the diffusional motion of perylene in two types of films supported on functionalized silica surfaces: single-component (stearic acid) and two-component (hydrocarbon/fluorocarbon) films. Langmuir-Blodgett (LB) monolayers were deposited directly on silica or were bound to surface-modified silica by means of metal ion complexation. The LB films were characterized by their pi-A isotherms and by Brewster angle microscopy (BAM) during formation and deposition. Chromophore mobility and monolayer structural heterogeneity were evaluated by comparing rotational diffusion data (fluorescence anisotropy decay imaging) and translational diffusion data (fluorescence recovery after photobleaching) on the same LB films. Our results indicate that the mobility of the chromophore depends sensitively on both metal ion identity and film composition. PMID- 28094956 TI - Radiolabeled R954 Derivatives for Imaging Bradykinin B1 Receptor Expression with Positron Emission Tomography. AB - Peptide receptors have emerged as promising targets for diagnosis and therapy. The aberrant overexpression of these receptors in different cancer subtypes allows for the adoption of new treatment strategies that complement conventional chemotherapies. Bradykinin B1 receptor (B1R) is a G protein-coupled receptor that is overexpressed in many cancers, with limited expression in healthy tissues. Previously, we developed 68Ga- and 18F-labeled derivatives of B1R antagonist peptides B9858 and B9958, and successfully targeted B1R-expressing tumor xenografts in vivo. R954 (Ac-Orn-Arg-Oic-Pro-Gly-alphaMePhe-Ser-d-2-Nal-Ile), a potent B1R antagonist, is reportedly more stable than B9858 against peptidase degradation. We evaluated two radiolabeled derivatives of R954 (68Ga-HTK01083 and 18F-HTK01146) for B1R PET imaging. Peptides were synthesized via solid phase strategy. Nonradioactive standards were obtain by reacting GaCl3 with DOTA-dPEG2 R954 and by clicking N-propargyl-N,N-dimethylammoniomethyl-trifluoroborate with azidoacetyl-dPEG2-R954. Binding affinity for B1R was determined by an in vitro competition binding assay. 68Ga-HTK01083 was obtained by incubating DOTA-dPEG2 R954 with 68GaCl3 under acidic conditions, while 18F-HTK01146 was prepared via an 18F-19F isotope exchange reaction. Biodistribution and imaging studies were conducted at 1 h postinjection (p.i.) in mice inoculated with B1R-expressing (B1R+) and B1R-nonexpressing (B1R-) cells. HTK01083 and HTK01146 bound B1R with good affinity (Ki = 30.5 and 24.8 nM, respectively). 68Ga/18F-labeled R954 were obtained on average in >=10% decay-corrected radiochemical yield with >99% radiochemical purity and >=52 GBq/MUmol specific activity. For both tracers, clearance was predominantly renal with minimal involvement of the hepatobiliary system. For PET images, B1R+ tumors, kidneys, and bladder were visible. At 1 h p.i., uptake in B1R+ tumor was comparable between 68Ga-HTK01083 (8.46 +/- 1.44%ID/g) and 18F-HTK01146 (9.25 +/- 0.69%ID/g). B1R+ tumor-to-blood and B1R+ tumor-to-muscle ratios were 6.32 +/- 1.44 and 20.7 +/- 3.58 for 68Ga-HTK01083, and 7.24 +/- 2.56 and 19.5 +/- 4.29 for 18F-HTK01146. Our results indicate R954 is a good lead sequence for optimization of B1R tracers for cancer imaging. PMID- 28094957 TI - Spatially Resolved Imaging on Photocarrier Generations and Band Alignments at Perovskite/PbI2 Heterointerfaces of Perovskite Solar Cells by Light-Modulated Scanning Tunneling Microscopy. AB - The presence of the PbI2 passivation layers at perovskite crystal grains has been found to considerably affect the charge carrier transport behaviors and device performance of perovskite solar cells. This work demonstrates the application of a novel light-modulated scanning tunneling microscopy (LM-STM) technique to reveal the interfacial electronic structures at the heterointerfaces between CH3NH3PbI3 perovskite crystals and PbI2 passivation layers of individual perovskite grains under light illumination. Most importantly, this technique enabled the first observation of spatially resolved mapping images of photoinduced interfacial band bending of valence bands and conduction bands and the photogenerated electron and hole carriers at the heterointerfaces of perovskite crystal grains. By systematically exploring the interfacial electronic structures of individual perovskite grains, enhanced charge separation and reduced back recombination were observed when an optimal design of interfacial PbI2 passivation layers consisting of a thickness less than 20 nm at perovskite crystal grains was applied. PMID- 28094958 TI - Magnetic Nanoparticle-Based Mechanical Stimulation for Restoration of Mechano Sensitive Ion Channel Equilibrium in Neural Networks. AB - Techniques offering remote control of neural activity with high spatiotemporal resolution and specificity are invaluable for deciphering the physiological roles of different classes of neurons in brain development and disease. Here, we first confirm that microfabricated substrates with enhanced magnetic field gradients allow for wireless stimulation of neural circuits dosed with magnetic nanoparticles using calcium indicator dyes. We also investigate the mechanism of mechano-transduction in this system and identify that N-type mechano-sensitive calcium ion channels play a key role in signal generation in response to magnetic force. We next applied this method for chronic stimulation of a fragile X syndrome (FXS) neural network model and found that magnetic force-based stimulation modulated the expression of mechano-sensitive ion channels which are out of equilibrium in a number of neurological diseases including FXS. This technique can serve as a tool for acute and chronic modulation of endogenous ion channel expression in neural circuits in a spatially localized manner to investigate a number of disease processes in the future. PMID- 28094960 TI - Tunable Length and Optical Properties of CsPbX3 (X = Cl, Br, I) Nanowires with a Few Unit Cells. AB - Perovskite nanostructures, both hybrid organo-metal and fully inorganic perovskites, have gained a lot of interest in the past few years for their intriguing optical properties in the visible region. We report on inorganic cesium lead bromide (CsPbBr3) nanowires (NWs) having quantum confined dimensions corresponding to 5 unit cells. The addition of various hydrohalic acids (HX, X = Cl, Br, I) was found to highly affect the NW length, composition, and optical properties. Hydrochloric (HCl) and hydroiodic (HI) acids mixed in the reaction solution influence the crystal structure and optical properties and shorten the NWs, while the hydrobromic acid (HBr) addition results solely in shorter NWs, without any structural change. The addition of HX increases the acidity of the reaction solution, resulting in protonation of the oleylamine ligands from oleylamine into oleyl-ammonium cations that behave similarly to Cs+ during crystallization. Therefore, the positions of the Cs+ at the growing surface of the NWs are taken by the oleyl-ammonium cations, thus blocking further growth in the favored direction. The emission of the NWs is tunable between ~423-505 nm and possesses a potential in the optoelectronic field. Moreover, electrical conductivity measurements of the NWs are discussed to give a new point of view regarding the conductivity of perovskite nanostructures. PMID- 28094959 TI - Noninvasive Targeted Transcranial Neuromodulation via Focused Ultrasound Gated Drug Release from Nanoemulsions. AB - Targeted, noninvasive neuromodulation of the brain of an otherwise awake subject could revolutionize both basic and clinical neuroscience. Toward this goal, we have developed nanoparticles that allow noninvasive uncaging of a neuromodulatory drug, in this case the small molecule anesthetic propofol, upon the application of focused ultrasound. These nanoparticles are composed of biodegradable and biocompatible constituents and are activated using sonication parameters that are readily achievable by current clinical transcranial focused ultrasound systems. These particles are potent enough that their activation can silence seizures in an acute rat seizure model. Notably, there is no evidence of brain parenchymal damage or blood-brain barrier opening with their use. Further development of these particles promises noninvasive, focal, and image-guided clinical neuromodulation along a variety of pharmacological axes. PMID- 28094961 TI - Enhancing the Sensing Properties of TiO2 Nanosheets with Exposed {001} Facets by a Hydrogenation and Sensing Mechanism. AB - Hydrogenation is successfully employed to improve sensing performances of the gas sensors based on TiO2 nanosheets with exposed {001} facets for the first time. The hydrogenated TiO2 nanosheets show a significantly higher response toward ethanol, acetone, triethylamine, or formaldehyde than the samples without hydrogenation, and the response further increases with an increase of the hydrogenation temperature. The excellent sensing performances are ascribed to an increase of the density of unsaturated Ti5c atoms on the {001} surface resulting from the hydrogenation process. The unsaturated Ti5c atoms are considered to serve as sensing reaction active sites. They can generate noncontributing (free) electrons and adsorb oxygen molecules, and the detailed sensing mechanism is described at atomic and molecule level. The hydrogenated strategy may be employed to enhance the sensing performances of other metal oxide sensors and catalytic reaction activities of catalyst. The concept of the surface unsaturated metal atoms serving as sensing reaction active sites not only deepens the understanding of the sensing reaction and catalytic reaction mechanism but also provides new insights into the design of advanced gas sensing materials, catalysts, and photoelectronic devices. PMID- 28094962 TI - Coumarin to Isocoumarin: One-Pot Synthesis of 3-Substituted Isocoumarins from 4 Hydroxycoumarins and Benzyne Precursors. AB - A novel transition-metal-free direct synthesis of 3-substituted isocoumarin from 4-hydroxycoumarin and a benzyne precursor is developed. This synthetic strategy proceeds via C-O and C-C bond cleavage as well as C-O and C-C bond formations in a single reaction vessel by simple treatment with CsF in the absence of catalyst. This methodology affords moderate to good yields of 3-substituted isocoumarins and is tolerant of a variety of functional groups including halide. PMID- 28094963 TI - Four-Step Total Synthesis of Selaginpulvilin D. AB - An extremely concise total synthesis of a potent phosphodiesterase-4 inhibitory natural product, selaginpulvilin D, is reported. The synthesis features a one pot, 3-fold electrophilic aromatic substitution sequence to assemble a 9,9 diarylfluorene core. The approach allows access to useful quantities of a selaginpulvilin natural product for the first time. PMID- 28094964 TI - Palladium(II)-Catalyzed Intramolecular Oxidative C-H/C-H Cross-Coupling Reaction of C3,N-Linked Biheterocycles: Rapid Access to Polycyclic Nitrogen Heterocycles. AB - A Pd(II)-catalyzed intramolecular oxidative C-H/C-H cross-coupling has been developed for the direct construction of valuable polycyclic heteroarene scaffolds. From a retrosynthetic point of view, the strategic formation of a C-C bond via C(sp2)-H/C(sp2)-H dehydrogenative coupling across C3,N-linked biheterocyclic precursors may be useful in de novo syntheses of indole-derived natural products and pharmaceuticals. The reaction exhibited good functional group/heterocycle tolerance, and a proposed mechanism involving an azoylpalladium complex is also supported. PMID- 28094965 TI - Taxodikaloids A and B, Two Dimeric Abietane-Type Diterpenoids from Taxodium ascendens Possessing an Oxazoline Ring Linkage. AB - Two dimeric diterpenoids, taxodikaloids A (1) and B (2), have been identified from the seeds of Taxodium ascendens. The diterpenoid structures were established on the basis of comprehensive spectroscopic analysis, and the absolute configuration of taxodikaloid A (1) was further confirmed by single-crystal X-ray diffraction. Both structures feature an unprecedented oxazoline ring linkage connecting two abietane diterpenoid monomers. A plausible biosynthetic pathway for compounds 1 and 2 is proposed. Both compounds show potential neuroprotective activity against Abeta25-35-induced damage in SH-SY5Y cells. PMID- 28094966 TI - Advanced Nitroso Aldol Reaction: Metal-Free Cross-Coupling of Anilines with Silyl Enol Ethers en Route to alpha-Amino Ketones. AB - A practical and step-economical nitroso aldol reaction has been developed based on metal-free direct cross-coupling of ready-stock anilines with silyl enol ethers at room temperature affording alpha-amino ketones in high yields (up to 82%). The protocol features a one-pot cascade of nitroso compound generation, selective C-N bond formation, and N-O bond cleavage using solely inexpensive and user-friendly Oxone and displays remarkable functional group tolerance. The method was further extended to prepare densely functionalized indoles that are otherwise difficult to synthesize. PMID- 28094968 TI - Computational Studies on Reaction Mechanism and Origins of Selectivities in Nickel-Catalyzed (2 + 2 + 2) Cycloadditions and Alkenylative Cyclizations of 1,6 Ene-Allenes and Alkenes. AB - The reaction mechanism and origins of ligand-controlled selectivity, regioselectivity, and stereoselectivity of Ni-catalyzed (2 + 2 + 2) cycloadditions and alkenylative cyclizations of 1,6-ene-allenes and alkenes were studied by using density functional theory. The catalytic cycle involves intermolecular oxidative coupling and an intramolecular concerted 1,4-addition step to afford a stable metallacycloheptane intermediate; these steps determine both the regioselectivity and stereoselectivity. Subsequent C-C reductive elimination leads to the cyclohexane product, whereas the beta-hydride elimination leads to the trans-diene product. The selectivity between (2 + 2 + 2) cycloadditions and alkenylative cyclizations is controlled by the ligand. Irrespective of the nature of the terminal substituents on the ene-allene and alkene, the P(o-tol)3 ligand always favors the C-C reductive elimination, resulting in the cyclohexane product. On the other hand, the flexibility of the PBu3 ligand means that electronic and steric factors play important roles. Electron-withdrawing groups such as CO2Me in the ene-allene terminal substituent induce obvious substrate-ligand repulsion and destabilize the C-C reductive elimination, giving rise to the trans-diene product. PMID- 28094967 TI - Remote C(sp3)-H Oxygenation of Protonated Aliphatic Amines with Potassium Persulfate. AB - This letter describes the development of a method for selective remote C(sp3)-H oxygenation of protonated aliphatic amines using aqueous potassium persulfate. Protonation serves to deactivate the proximal C(sp3)-H bonds of the amine substrates and also renders the amines soluble in the aqueous medium. These reactions proceed under relatively mild conditions (within 2 h at 80 degrees C with amine as limiting reagent) and do not require a transition metal catalyst. This method is applicable to a variety of types of C(sp3)-H bonds, including 3 degrees , 2 degrees , and benzylic C-H sites in primary, secondary, and tertiary amine substrates. PMID- 28094969 TI - Investigating Biogenetic Hypotheses of the Securinega Alkaloids: Enantioselective Total Syntheses of Secu'amamine E/ent-Virosine A and Bubbialine. AB - The synthesis of the Securinega alkaloid secu'amamine E (ent-virosine A) has been accomplished for the first time in 12 steps and 8.5% overall yield. In addition, bubbialine has been prepared and characterized. These two alkaloids and bubbialidine, all featuring an azabicyclo[2.2.2]octane core, were rearranged to their azabicyclo[3.2.1]octane congeners, a framework found in many Securinega alkaloids. These experiments suggest that azabicyclo[2.2.2]octane derivatives could serve as intermediates in the biosynthesis of the rearranged azabicyclo[3.2.1]octane products. PMID- 28094970 TI - Octagon to Square Wetting Area Transition of Water-Ethanol Droplets on a Micropyramid Substrate by Increasing Ethanol Concentration. AB - The wettability and evaporation of water-ethanol binary droplets on the substrate with micropyramid cavities are studied by controlling the initial ethanol concentrations. The droplets form octagonal initial wetting areas on the substrate. As the ethanol concentration increases, the side ratio of the initial wetting octagon increases from 1.5 at 0% ethanol concentration to 3.5 at 30% ethanol concentration. The increasing side ratio indicates that the wetting area transforms from an octagon to a square if we consider the octagon to be a square with its four corners cut. The droplets experience a pinning-depinning transition during evaporation. The pure water sessile droplet evaporation demonstrates three stages from the constant contact line (CCL) stage, and then the constant contact angle (CCA) stage, to the mixed stage. An additional mixed stage is found between the CCL and CCA stages in the evaporation of water-ethanol binary droplets due to the anisotropic depinning along the two different axes of symmetry of the octagonal wetting area. Droplet depinning occurs earlier on the patterned surface as the ethanol concentration increases. PMID- 28094971 TI - Predicting Nanoscale Dynamics of a Glass-Forming Liquid from Its Macroscopic Bulk Behavior and Vice Versa. AB - The properties of a molecular liquid confined at the nanometer length scale can be very distinct from the bulk. For that reason, the macro- and the nanoscopic behaviors of glass-forming liquids are regarded as two nonconnected realms, governed by their own rules. Here, we show that the glassy dynamics in molecular liquids confined to nanometer pores might obey the density scaling relation, rhogamma/T, just like in bulk fluids. Even more surprisingly, the same value of the scaling exponent gamma superposes the alpha-relaxation time measured at different state points in nanoscale confinement and upon increased pressure. We report this remarkable finding for van der Waals liquids tetramethyl-tetraphenyl trisiloxane (DC704) and polyphenyl ether (5PPE), considered as simple, single parameter liquids. Demonstrating that the density scaling idea can be fulfilled in both environments opens an exciting possibility to predict the dynamic features of the nanoconfined system close to its glass-transition temperature from the high-pressure studies of the bulk liquid. Likewise, we can describe the viscous liquid dynamics at any given combination of temperature and pressure based on analysis of its behavior in nanopores. PMID- 28094972 TI - Regioselective Construction of alpha,alpha-Disubstituted Allylic Amines by the Ruthenium-Catalyzed Allylic Amination of Tertiary Allylic Acetates. AB - The ruthenium-catalyzed regioselective allylic amination of tertiary allylic acetates with several types of amines has been accomplished. The reaction was effectively catalyzed by Cp*RuCl2/5,5'-dimethyl-2,2'-bipyridine or its related ruthenium catalyst systems, and alpha,alpha-disubstituted allylic amines were formed as a single regioisomer in moderate to high yields. PMID- 28094973 TI - Mild Functionalization of Tetraoxane Derivatives via Olefin Metathesis: Compatibility of Ruthenium Alkylidene Catalysts with Peroxides. AB - An easy and mild functionalization method of tetraoxane derivatives via olefin metathesis is reported. This reaction offers a new method to afford fully functionalized tetraoxanes in high yields. This method is also utilized in the functionalization of bioactive compounds. PMID- 28094975 TI - Endoribonuclease-Based Two-Component Repressor Systems for Tight Gene Expression Control in Plants. AB - Tight control and multifactorial regulation of gene expression are important challenges in genetic engineering and are critical for the development of regulatory circuits. Meeting these challenges will facilitate transgene expression regulation and support the fine-tuning of metabolic pathways to avoid the accumulation of undesired intermediates. By employing the endoribonuclease Csy4 and its recognition sequence from Pseudomonas aeruginosa and manipulating 5'UTR of mRNA, we developed a two-component expression-repression system to tightly control synthesis of transgene products. We demonstrated that this regulatory device was functional in monocotyledonous and dicotyledonous plant species, and showed that it can be used to repress transgene expression by >400 fold and to synchronize transgene repression. In addition to tissue-specific transgene repression, this system offers stimuli-dependent expression control. Using a bioinformatics approach, we identified 54 orthologous systems from various bacteria, and then validated in planta the activity for a few of those systems, demonstrating the potential diversity of such a two-component repressor system. PMID- 28094974 TI - Monitoring Dopamine Responses to Potassium Ion and Nomifensine by in Vivo Microdialysis with Online Liquid Chromatography at One-Minute Resolution. AB - Recently, our laboratory has demonstrated the technical feasibility of monitoring dopamine at 1 min temporal resolution with microdialysis and online liquid chromatography. Here, we monitor dopamine in the rat striatum during local delivery of high potassium/low sodium or nomifensine in awake-behaving rats. Microdialysis probes were implanted and perfused continuously with or without dexamethasone in the perfusion fluid for 4 days. Dexamethasone is an anti inflammatory agent that exhibits several positive effects on the apparent health of the brain tissue surrounding microdialysis probes. Dopamine was monitored 1 or 4 days after implantation under basal conditions, during 10 min applications of 60 mM or 100 mM K+, and during 15 min applications of 10 MUM nomifensine. High K+ and nomifensine were delivered locally by adding them to the microdialysis perfusion fluid using a computer-controlled, low-dead-volume six-port valve. Each day/K+/dexamethasone combination elicited specific dopamine responses. Dexamethasone treatment increased dopamine levels in basal dialysates (i.e., in the absence of K+ or nomifensine). Applications of 60 mM K+ evoked distinct responses on days one and four after probe implantation, depending upon the presence or absence of dexamethasone, consistent with dexamethasone's ability to mitigate the traumatic effect of probe implantation. Applications of 100 mM K+ evoked dramatic oscillations in dopamine levels that correlated with changes in the field potential at a metal electrode implanted adjacent to the microdialysis probe. This combination of results indicates the role of spreading depolarization in response to 100 mM K+. With 1 min temporal resolution, we find that it is possible to characterize the pharmacokinetics of the response to the local delivery of nomifensine. Overall, the findings reported here confirm the benefits arising from the ability to monitor dopamine via microdialysis at high sensitivity and at high temporal resolution. PMID- 28094976 TI - Breath Figure Micromolding Approach for Regulating the Microstructures of Polymeric Films for Triboelectric Nanogenerators. AB - A triboelectric nanogenerator (TENG) is an innovative kind of energy harvester recently developed on the basis of organic materials for converting mechanical energy into electricity through the combined use of the triboelectric effect and electrostatic induction. Polymeric materials and their microstructures play key roles in the generation, accumulation, and retainment of triboelectric charges, which decisively determines the final electric performance of TENGs. Herein we report a simple and efficient breath figure (BF) micromolding approach to rapidly regulate the surface microstructures of polymeric films for the assembly of TENGs. Honeycomb porous films with adjustable pore size and dimensional architectures were first prepared by the BF technique through simply adjusting the concentration of the polymer solution. They were then used as negative molds for straightforward synthesis of polydimethylsiloxane (PDMS) films with different microlens arrays (MLAs) and lens sizes, which were further assembled for TENGs to investigate the influence of film microstructures. All MLA-based TENGs were found to have an obviously enhanced electric performance in comparison with a flat-PDMS film-based TENG. Specifically, up to 3 times improvement in the electric performance can be achieved by the MLA-based TENG with optimal surface microstructures over flat-PDMS-film-based TENG under the same triggering conditions. A MLA-based TENG was further successfully used to harvest the waste mechanical energy generated by different human body motions, including finger tapping, hand clapping, and walking with a frequency ranging from 0.5 to 5.5 Hz. PMID- 28094977 TI - Crystallographic Mapping of Guided Nanowires by Second Harmonic Generation Polarimetry. AB - The growth of horizontal nanowires (NWs) guided by epitaxial and graphoepitaxial relations with the substrate is becoming increasingly attractive owing to the possibility of controlling their position, direction, and crystallographic orientation. In guided NWs, as opposed to the extensively characterized vertically grown NWs, there is an increasing need for understanding the relation between structure and properties, specifically the role of the epitaxial relation with the substrate. Furthermore, the uniformity of crystallographic orientation along guided NWs and over the substrate has yet to be checked. Here we perform highly sensitive second harmonic generation (SHG) polarimetry of polar and nonpolar guided ZnO NWs grown on R-plane and M-plane sapphire. We optically map large areas on the substrate in a nondestructive way and find that the crystallographic orientations of the guided NWs are highly selective and specific for each growth direction with respect to the substrate lattice. In addition, we perform SHG polarimetry along individual NWs and find that the crystallographic orientation is preserved along the NW in both polar and nonpolar NWs. While polar NWs show highly uniform SHG along their axis, nonpolar NWs show a significant change in the local nonlinear susceptibility along a few micrometers, reflected in a reduction of 40% in the ratio of the SHG along different crystal axes. We suggest that these differences may be related to strain accumulation along the nonpolar wires. We find SHG polarimetry to be a powerful tool to study both selectivity and uniformity of crystallographic orientations of guided NWs with different epitaxial relations. PMID- 28094978 TI - Phase Behavior and Self-Assembly of Perfectly Sequence-Defined and Monodisperse Multiblock Copolypeptides. AB - This paper investigates how the properties of multiblock copolypeptides can be tuned by their block architecture, defined by the size and distribution of blocks along the polymer chain. These parameters were explored by the precise, genetically encoded synthesis of recombinant elastin-like polypeptides (ELPs). A family of ELPs was synthesized in which the composition and length were conserved while the block length and distribution were varied, thus creating 11 ELPs with unique block architectures. To our knowledge, these polymers are unprecedented in their intricately and precisely varied architectures. ELPs exhibit lower critical solution temperature (LCST) behavior and micellar self-assembly, both of which impart easily measured physicochemical properties to the copolymers, providing insight into polymer hydrophobicity and self-assembly into higher order structures, as a function of solution temperature. Even subtle variation in block architecture changed the LCST phase behavior and morphology of these ELPs, measured by their temperature-triggered phase transition and nanoscale self assembly. Size and morphology of polypeptide micelles could be tuned solely by controlling the block architecture, thus demonstrating that when sequence can be precisely controlled, nanoscale self-assembly of polypeptides can be modulated by block architecture. PMID- 28094979 TI - Photoinduced Cross-Linking of Short Furan-Modified DNA on Surfaces. AB - We report for the first time the formation of site-specific interstrand cross linked (ICL) surface-immobilized furan-modified DNA duplexes via singlet oxygen. 1O2, necessary for effecting furan-mediated ICL formation, was produced in situ using methylene blue or a zinc phthalocyanine derivative (TT1) as a photosensitizer. Via surface plasmon resonance spectroscopy, we show that surface ICL was achieved, and a robust link formed that enhances the stability of the 12 mer duplex even after surface regeneration. The described method represents a novel platform technology based on surfaces with addressable and stable DNA duplexes requiring only short oligonucleotides. PMID- 28094981 TI - GW100: A Plane Wave Perspective for Small Molecules. AB - In a recent work, van Setten and co-workers have presented a carefully converged G0W0 study of 100 closed shell molecules [ J. Chem. Theory Comput. 2015 , 11 , 5665 - 5687 ]. For two different codes they found excellent agreement to within a few 10 meV if identical Gaussian basis sets were used. We inspect the same set of molecules using the projector augmented wave method and the Vienna ab initio simulation package (VASP). For the ionization potential, the basis set extrapolated plane wave results agree very well with the Gaussian basis sets, often reaching better than 50 meV agreement. In order to achieve this agreement, we correct for finite basis set errors as well as errors introduced by periodically repeated images. For positive electron affinities differences between Gaussian basis sets and VASP are slightly larger. We attribute this to larger basis set extrapolation errors for the Gaussian basis sets. For quasi particle (QP) resonances above the vacuum level, differences between VASP and Gaussian basis sets are, however, found to be substantial. This is tentatively explained by insufficient basis set convergence of the Gaussian type orbital calculations as exemplified for selected test cases. PMID- 28094980 TI - Fe-Catalyzed C-C Bond Construction from Olefins via Radicals. AB - This Article details the development of the iron-catalyzed conversion of olefins to radicals and their subsequent use in the construction of C-C bonds. Optimization of a reductive diene cyclization led to the development of an intermolecular cross-coupling of electronically-differentiated donor and acceptor olefins. Although the substitution on the donor olefins was initially limited to alkyl and aryl groups, additional efforts culminated in the expansion of the scope of the substitution to various heteroatom-based functionalities, providing a unified olefin reactivity. A vinyl sulfone acceptor olefin was developed, which allowed for the efficient synthesis of sulfone adducts that could be used as branch points for further diversification. Moreover, this reactivity was extended into an olefin-based Minisci reaction to functionalize heterocyclic scaffolds. Finally, mechanistic studies resulted in a more thorough understanding of the reaction, giving rise to the development of a more efficient second-generation set of olefin cross-coupling conditions. PMID- 28094982 TI - Bacterial Genome Editing via a Designed Toxin-Antitoxin Cassette. AB - Manipulating the bacterial genomes in an efficient manner is essential to biological and biotechnological research. Here, we reprogrammed the bacterial TA systems as the toxin counter-selectable cassette regulated by an antitoxin switch (TCCRAS) for genetic modifications in the extensively studied and utilized Gram positive bacteria, B. subtilis and Corynebacterium glutamicum. In the five characterized type II TA systems, the RelBE complex can specifically and efficiently regulate cell growth and death by the conditionally controlled antitoxin RelB switch, thereby serving as a novel counter-selectable cassette to establish the TCCRAS system. Using a single vector, such a system has been employed to perform in-frame deletion, functional knock-in, gene replacement, precise point mutation, large-scale insertion, and especially, deletion of the fragments up to 194.9 kb in B. subtilis. In addition, the biosynthesis of lycopene was first achieved in B. subtilis using TCCRAS to integrate a 5.4-kb fusion cluster ( P spac- crtI- crtE- crtB). The system was further adapted for gene knockdown and replacement, and large-scale deletion of the fragments up to 179.8 kb in C. glutamicum, with the mutation efficiencies increased by 0.8-1.0 fold compared to the conventional SacB method. TCCRAS thus holds promise as an effective and versatile genome-scale engineering technology for metabolic engineering and synthetic genomics research in a broad range of the Gram-positive bacteria. PMID- 28094983 TI - Hybrid and Constrained Resolution-of-Identity Techniques for Coulomb Integrals. AB - The introduction of auxiliary bases to approximate molecular orbital products has paved the way to significant savings in the evaluation of four-center two electron Coulomb integrals. We present a generalized dual space strategy that sheds a new light on variants over the standard density and Coulomb-fitting schemes, including the possibility of introducing minimization constraints. We improve in particular the charge- or multipole-preserving strategies introduced respectively by Baerends and Van Alsenoy that we compare to a simple scheme where the Coulomb metric is used for lowest angular momentum auxiliary orbitals only. We explore the merits of these approaches on the basis of extensive Hartree-Fock and MP2 calculations over a standard set of medium size molecules. PMID- 28094984 TI - A Generalized Grid-Based Fast Multipole Method for Integrating Helmholtz Kernels. AB - A grid-based fast multipole method (GB-FMM) for optimizing three-dimensional (3D) numerical molecular orbitals in the bubbles and cube double basis has been developed and implemented. The present GB-FMM method is a generalization of our recently published GB-FMM approach for numerically calculating electrostatic potentials and two-electron interaction energies. The orbital optimization is performed by integrating the Helmholtz kernel in the double basis. The steep part of the functions in the vicinity of the nuclei is represented by one-center bubbles functions, whereas the remaining cube part is expanded on an equidistant 3D grid. The integration of the bubbles part is treated by using one-center expansions of the Helmholtz kernel in spherical harmonics multiplied with modified spherical Bessel functions of the first and second kind, analogously to the numerical inward and outward integration approach for calculating two electron interaction potentials in atomic structure calculations. The expressions and algorithms for massively parallel calculations on general purpose graphics processing units (GPGPU) are described. The accuracy and the correctness of the implementation has been checked by performing Hartree-Fock self-consistent-field calculations (HF-SCF) on H2, H2O, and CO. Our calculations show that an accuracy of 10-4 to 10-7 Eh can be reached in HF-SCF calculations on general molecules. PMID- 28094985 TI - Beyond the Hofmeister Series: Ion-Specific Effects on Proteins and Their Biological Functions. AB - Ions differ in their ability to salt out proteins from solution as expressed in the lyotropic or Hofmeister series of cations and anions. Since its first formulation in 1888, this series has been invoked in a plethora of effects, going beyond the original salting out/salting in idea to include enzyme activities and the crystallization of proteins, as well as to processes not involving proteins like ion exchange, the surface tension of electrolytes, or bubble coalescence. Although it has been clear that the Hofmeister series is intimately connected to ion hydration in homogeneous and heterogeneous environments and to ion pairing, its molecular origin has not been fully understood. This situation could have been summarized as follows: Many chemists used the Hofmeister series as a mantra to put a label on ion-specific behavior in various environments, rather than to reach a molecular level understanding and, consequently, an ability to predict a particular effect of a given salt ion on proteins in solutions. In this Feature Article we show that the cationic and anionic Hofmeister series can now be rationalized primarily in terms of specific interactions of salt ions with the backbone and charged side chain groups at the protein surface in solution. At the same time, we demonstrate the limitations of separating Hofmeister effects into independent cationic and anionic contributions due to the electroneutrality condition, as well as specific ion pairing, leading to interactions of ions of opposite polarity. Finally, we outline the route beyond Hofmeister chemistry in the direction of understanding specific roles of ions in various biological functionalities, where generic Hofmeister-type interactions can be complemented or even overruled by particular steric arrangements in various ion binding sites. PMID- 28094986 TI - Improving Internal Cell Colonization of Porous Scaffolds with Chemical Gradients Produced by Plasma Assisted Approaches. AB - Cell colonization of the surrounding environment is a very significant process in both physiological and pathological events. In order to understand the tissue regeneration process and thereby provide guidance principles for designing new biomaterials, it is of paramount importance to study the cell colonization in the presence of physical, chemical, and biological cues. Flat "gradient" materials are generally used with this purpose. Three dimensional gradient scaffolds mimicking more precisely the situation in vivo are somewhat more complex to fabricate and characterize. Scaffolds for Tissue Engineering (TE) made of hydrophobic synthetic polymers do not allow good cell colonization: far from their periphery, in fact, internal cell colonization is usually low. In this research poly-epsilon caprolactone (PCL) scaffolds have been "decorated" with chemical gradients both on top and along their thickness by means of cold plasma processes, in order to improve cell colonization of their core. Plasma treatments with a mixture of argon and oxygen (Ar/O2), as well as plasma deposition of differently cross-linked poly(ethylene oxide) (PEO)-like coatings, have been performed. This study establishes that cross-linked PEO-like domains interspaced with native PCL ones deposited only on top of the scaffold (i.e., coating that penetrates less than 300 MUm inside the scaffold) are more effective in promoting cell colonization across the scaffolds than the other tested materials including superhydrophilic samples and that ones produced by tested double step approaches. Last but not least, one result of this research is that, in the case of plasma coatings with low deposition rates and porous materials with a low pore interconnectivity, it is possible to improve penetration of low pressure plasma active species inside the scaffold's core thorough a pretreatment of the porous materials (i.e., penetration up to 4500 mm far from topside). PMID- 28094987 TI - Crystal Engineering of Self-Assembled Porous Protein Materials in Living Cells. AB - Crystalline porous materials have been investigated for development of important applications in molecular storage, separations, and catalysis. The potential of protein crystals is increasing as they become better understood. Protein crystals have been regarded as porous materials because they present highly ordered 3D arrangements of protein molecules with high porosity and wide range of pore sizes. However, it remains difficult to functionalize protein crystals in living cells. Here, we report that polyhedra, a natural crystalline protein assembly of polyhedrin monomer (PhM) produced in insect cells infected by cypovirus, can be engineered to extend porous networks by deleting selected amino acid residues located on the intermolecular contact region of PhM. The adsorption rates and quantities of fluorescent dyes stored within the mutant crystals are increased relative to those of the wild-type polyhedra crystal (WTPhC) under both in vitro and in vivo conditions. These results provide a strategy for designing self assembled protein materials with applications in molecular recognition and storage of exogenous substances in living cell as well as an entry point for development of bioorthogonal chemistry and in vivo crystal structure analysis. PMID- 28094988 TI - Multireference Perturbation Theory with Cholesky Decomposition for the Density Matrix Renormalization Group. AB - We present a second-order N-electron valence state perturbation theory (NEVPT2) based on a density matrix renormalization group (DMRG) reference wave function that exploits a Cholesky decomposition of the two-electron repulsion integrals (CD-DMRG-NEVPT2). With a parameter-free multireference perturbation theory approach at hand, the latter allows us to efficiently describe static and dynamic correlation in large molecular systems. We demonstrate the applicability of CD DMRG-NEVPT2 for spin-state energetics of spin-crossover complexes involving calculations with more than 1000 atomic basis functions. We first assess, in a study of a heme model, the accuracy of the strongly and partially contracted variant of CD-DMRG-NEVPT2 before embarking on resolving a controversy about the spin ground state of a cobalt tropocoronand complex. PMID- 28094990 TI - Bridging the Gap between Dielectric Nanophotonics and the Visible Regime with Effectively Lossless Gallium Phosphide Antennas. AB - We present all-dielectric gallium phosphide (GaP) nanoantennas as an efficient nanophotonic platform for surface-enhanced second harmonic generation (SHG) and fluorescence (SEF), showing negligible losses in the visible range. Employing single GaP nanodisks, we observe an increase of more than 3 orders of magnitude in the SHG conversion signal in comparison with the bulk. This constitutes an SHG efficiency as large as 0.0002%, which is to the best of our knowledge the highest yet achieved value for a single nano-object in the optical region. Furthermore, we show that GaP dimers with 35 nm gap can enhance up to 3600 times the fluorescence emission of dyes located in the gap of the nanoantenna. This is accomplished by a fluorescence lifetime reduction of at least 22 times, accompanied by a high-intensity field confinement in the gap region. These results open new avenues for low-loss nanophotonics in the optical regime. PMID- 28094989 TI - "Bitter-Sweet" Polymeric Micelles Formed by Block Copolymers from Glucosamine and Cholic Acid. AB - Natural compounds glucosamine and cholic acid have been used to make acrylic monomers which are subsequently used to prepare amphiphilic block copolymers by reversible addition-fragmentation chain transfer (RAFT) polymerization. Despite the striking difference in polarity and solubility, three diblock copolymers consisting of glucosamine and cholic acid pendants with different hydrophilic and hydrophobic chain lengths have been synthesized without the use of protecting groups. They are shown to self-assemble into polymeric micelles with a "bitter" bile acid core and "sweet" sugar shell in aqueous solutions, as evidenced by dynamic light scattering and transmission electron microscopy. The critical micelle concentration varies with the hydrophobic/hydrophilic ratio, ranging from 0.62 to 1.31 mg/L. Longer chains of polymers induced the formation of larger micelles in range of 50-70 nm. These micelles can solubilize hydrophobic compounds such as Nile Red in aqueous solutions. Their loading capacity mainly depends upon the hydrophobic/hydrophilic ratio of the polymers, and may be also related to the length of the hydrophilic block. These polymeric micelles allowed for a 10-fold increase in the aqueous solubility of paclitaxel and showed no cytotoxicity below the concentration of 500 mg/L. Such properties make these polymeric micelles interesting reservoirs for hydrophobic molecules and drugs for biomedical applications. PMID- 28094991 TI - Polarization-Mediated Modulation of Electronic and Transport Properties of Hybrid MoS2-BaTiO3-SrRuO3 Tunnel Junctions. AB - Hybrid structures composed of ferroelectric thin films and functional two dimensional (2D) materials may exhibit unique characteristics and reveal new phenomena due to the cross-interface coupling between their intrinsic properties. In this report, we demonstrate a symbiotic interplay between spontaneous polarization of the ultrathin BaTiO3 ferroelectric film and conductivity of the adjacent molybdenum disulfide (MoS2) layer, a 2D narrow-bandgap semiconductor. Polarization-induced modulation of the electronic properties of MoS2 results in a giant tunneling electroresistance effect in the hybrid MoS2-BaTiO3-SrRuO3 ferroelectric tunnel junctions (FTJs) with an OFF-to-ON resistance ratio as high as 104, a 50-fold increase in comparison with the same type of FTJs with metal electrodes. The effect stems from the reversible accumulation-depletion of the majority carriers in the MoS2 electrode in response to ferroelectric switching, which alters the barrier at the MoS2-BaTiO3 interface. Continuous tunability of resistive states realized via stable sequential domain structures in BaTiO3 adds memristive functionality to the hybrid FTJs. The use of narrow band 2D semiconductors in conjunction with ferroelectric films provides a novel pathway for development of the electronic devices with enhanced performance. PMID- 28094992 TI - Measurement of Nanoplasmonic Field Enhancement with Ultrafast Photoemission. AB - Probing nanooptical near-fields is a major challenge in plasmonics. Here, we demonstrate an experimental method utilizing ultrafast photoemission from plasmonic nanostructures that is capable of probing the maximum nanoplasmonic field enhancement in any metallic surface environment. Directly measured field enhancement values for various samples are in good agreement with detailed finite difference time-domain simulations. These results establish ultrafast plasmonic photoelectrons as versatile probes for nanoplasmonic near-fields. PMID- 28094994 TI - Ag-Sn Bimetallic Catalyst with a Core-Shell Structure for CO2 Reduction. AB - Converting greenhouse gas carbon dioxide (CO2) to value-added chemicals is an appealing approach to tackle CO2 emission challenges. The chemical transformation of CO2 requires suitable catalysts that can lower the activation energy barrier, thus minimizing the energy penalty associated with the CO2 reduction reaction. First-row transition metals are potential candidates as catalysts for electrochemical CO2 reduction; however, their high oxygen affinity makes them easy to be oxidized, which could, in turn, strongly affect the catalytic properties of metal-based catalysts. In this work, we propose a strategy to synthesize Ag-Sn electrocatalysts with a core-shell nanostructure that contains a bimetallic core responsible for high electronic conductivity and an ultrathin partially oxidized shell for catalytic CO2 conversion. This concept was demonstrated by a series of Ag-Sn bimetallic electrocatalysts. At an optimal SnOx shell thickness of ~1.7 nm, the catalyst exhibited a high formate Faradaic efficiency of ~80% and a formate partial current density of ~16 mA cm-2 at -0.8 V vs RHE, a remarkable performance in comparison to state-of-the-art formate selective CO2 reduction catalysts. Density-functional theory calculations showed that oxygen vacancies on the SnO (101) surface are stable at highly negative potentials and crucial for CO2 activation. In addition, the adsorption energy of CO2- at these oxygen-vacant sites can be used as the descriptor for catalytic performance because of its linear correlation to OCHO* and COOH*, two critical intermediates for the HCOOH and CO formation pathways, respectively. The volcano like relationship between catalytic activity toward formate as a function of the bulk Sn concentration arises from the competing effects of favorable stabilization of OCHO* by lattice expansion and the electron conductivity loss due to the increased thickness of the SnOx layer. PMID- 28094993 TI - Biophysics of Artificially Expanded Genetic Information Systems. Thermodynamics of DNA Duplexes Containing Matches and Mismatches Involving 2-Amino-3 nitropyridin-6-one (Z) and Imidazo[1,2-a]-1,3,5-triazin-4(8H)one (P). AB - Synthetic nucleobases presenting non-Watson-Crick arrangements of hydrogen bond donor and acceptor groups can form additional nucleotide pairs that stabilize duplex DNA independent of the standard A:T and G:C pairs. The pair between 2 amino-3-nitropyridin-6-one 2'-deoxyriboside (presenting a {donor-donor-acceptor} hydrogen bonding pattern on the Watson-Crick face of the small component, trivially designated Z) and imidazo[1,2-a]-1,3,5-triazin-4(8H)one 2' deoxyriboside (presenting an {acceptor-acceptor-donor} hydrogen bonding pattern on the large component, trivially designated P) is one of these extra pairs for which a substantial amount of molecular biology has been developed. Here, we report the results of UV absorbance melting measurements and determine the energetics of binding of DNA strands containing Z and P to give short duplexes containing Z:P pairs as well as various mismatches comprising Z and P. All measurements were done at 1 M NaCl in buffer (10 mM Na cacodylate, 0.5 mM EDTA, pH 7.0). Thermodynamic parameters (DeltaH degrees , DeltaS degrees , and DeltaG degrees 37) for oligonucleotide hybridization were extracted. Consistent with the Watson-Crick model that considers both geometric and hydrogen bonding complementarity, the Z:P pair was found to contribute more to duplex stability than any mismatches involving either nonstandard nucleotide. Further, the Z:P pair is more stable than a C:G pair. The Z:G pair was found to be the most stable mismatch, forming either a deprotonated mismatched pair or a wobble base pair analogous to the stable T:G mismatch. The C:P pair is less stable, perhaps analogous to the wobble pair observed for C:O6-methyl-G, in which the pyrimidine is displaced into the minor groove. The Z:A and T:P mismatches are much less stable. Parameters for predicting the thermodynamics of oligonucleotides containing Z and P bases are provided. This represents the first case where this has been done for a synthetic genetic system. PMID- 28094995 TI - Photoluminescence Probing of Complex H2O Adsorption on InGaN/GaN Nanowires. AB - We demonstrate that the complex adsorption behavior of H2O on InGaN/GaN nanowire arrays is directly revealed by their ambient-dependent photoluminescence properties. Under low-humidity, ambient-temperature, and low-excitation-light conditions, H2O adsorbates cause a quenching of the photoluminescence. In contrast, for high humidity levels, elevated temperature, and high excitation intensity, H2O adsorbates act as efficient photoluminescence enhancers. We show that this behavior, which can only be detected due to the low operation temperature of the InGaN/GaN nanowires, can be explained on the basis of single H2O adsorbates forming surface recombination centers and multiple H2O adsorbates forming surface passivation layers. Reversible creation of such passivation layers is induced by the photoelectrochemical splitting of adsorbed water molecules and by the interaction of reactive H3O+ and OH- ions with photoactivated InGaN surfaces. Due to electronic coupling of adsorbing molecules with photoactivated surfaces, InGaN/GaN nanowires act as sensitive nanooptical probes for the analysis of photoelectrochemical surface processes. PMID- 28094997 TI - Combined Inkjet Printing and Infrared Sintering of Silver Nanoparticles using a Swathe-by-Swathe and Layer-by-Layer Approach for 3-Dimensional Structures. AB - Despite the advancement of additive manufacturing (AM)/3-dimensional (3D) printing, single-step fabrication of multifunctional parts using AM is limited. With the view of enabling multifunctional AM (MFAM), in this study, sintering of metal nanoparticles was performed to obtain conductivity for continuous line inkjet printing of electronics. This was achieved using a bespoke three dimensional (3D) inkjet-printing machine, JETx, capable of printing a range of materials and utilizing different post processing procedures to print multilayered 3D structures in a single manufacturing step. Multiple layers of silver were printed from an ink containing silver nanoparticles (AgNPs) and infrared sintered using a swathe-by-swathe (SS) and layer-by-layer sintering (LS) regime. The differences in the heat profile for the SS and LS was observed to influence the coalescence of the AgNPs. Void percentage of both SS and LS samples was higher toward the top layer than the bottom layer due to relatively less IR exposure in the top than the bottom. The results depicted a homogeneous microstructure for LS of AgNPs and showed less deformation compared to the SS. Electrical resistivity of the LS tracks (13.6 +/- 1 MUOmega cm) was lower than the SS tracks (22.5 +/- 1 MUOmega cm). This study recommends the use of LS method to sinter the AgNPs to obtain a conductive track in 25% less time than SS method for MFAM. PMID- 28094996 TI - Characterization of Protein-Excipient Microheterogeneity in Biopharmaceutical Solid-State Formulations by Confocal Fluorescence Microscopy. AB - Protein-stabilizer microheterogeneity is believed to influence long-term protein stability in solid-state biopharmaceutical formulations and its characterization is therefore essential for the rational design of stable formulations. However, the spatial distribution of the protein and the stabilizer in a solid-state formulation is, in general, difficult to characterize because of the lack of a functional, simple, and reliable characterization technique. We demonstrate the use of confocal fluorescence microscopy with fluorescently labeled monoclonal antibodies (mAbs) and antibody fragments (Fabs) to directly visualize three dimensional particle morphologies and protein distributions in dried biopharmaceutical formulations, without restrictions on processing conditions or the need for extensive data analysis. While industrially relevant lyophilization procedures of a model IgG1 mAb generally lead to uniform protein-excipient distribution, the method shows that specific spray-drying conditions lead to distinct protein-excipient segregation. Therefore, this method can enable more definitive optimization of formulation conditions than has previously been possible. PMID- 28094998 TI - Impulsive personality traits and alcohol use: Does sleeping help with thinking? AB - Both impulsivity and sleep disturbance have been associated with heavy alcohol use among young adults; yet studies to date have not examined their interactive effects. The current study aimed to determine if adequate sleep moderates the association between impulsive personality traits and alcohol use among young adults. College students (N = 568) who had been mandated to alcohol treatment following violation of campus alcohol policy provided information regarding alcohol use and related consequences, impulsive personality traits (measured using the UPPS Impulsive Behavior Scale), and perception of sleep adequacy as part of a larger intervention trial. Higher urgency, lower premeditation, and higher sensation-seeking predicted greater levels of alcohol consumption, while higher urgency predicted more alcohol-related consequences. As hypothesized, there was a significant interaction between premeditation and sleep adequacy in the prediction of drinks per week; in contrast to hypotheses, however, premeditation was associated with drinking only among those reporting adequate (rather than inadequate) sleep. Specifically, the tendency to premeditate was associated with less drinking among those who reported adequate sleep and was not associated with drinking among those reporting inadequate sleep. Sensation seeking and urgency are associated with greater alcohol involvement among young adults, regardless of sleep adequacy. Conversely, the ability to plan ahead and anticipate the consequences of one's behaviors (premeditation) is only protective against heavy drinking among individuals receiving adequate sleep. With replication, these findings may inform alcohol prevention and intervention efforts. (PsycINFO Database Record PMID- 28095000 TI - The challenge of abstract concepts. AB - concepts ("freedom") differ from concrete ones ("cat"), as they do not have a bounded, identifiable, and clearly perceivable referent. The way in which abstract concepts are represented has recently become a topic of intense debate, especially because of the spread of the embodied approach to cognition. Within this framework concepts derive their meaning from the same perception, motor, and emotional systems that are involved in online interaction with the world. Most of the evidence in favor of this view, however, has been gathered with regard to concrete concepts. Given the relevance of abstract concepts for higher-order cognition, we argue that being able to explain how they are represented is a crucial challenge that any theory of cognition needs to address. The aim of this article is to offer a critical review of the latest theories on abstract concepts, focusing on embodied ones. Starting with theories that question the distinction between abstract and concrete concepts, we review theories claiming that abstract concepts are grounded in metaphors, in situations and introspection, and in emotion. We then introduce multiple representation theories, according to which abstract concepts evoke both sensorimotor and linguistic information. We argue that the most promising approach is given by multiple representation views that combine an embodied perspective with the recognition of the importance of linguistic and social experience. We conclude by discussing whether or not a single theoretical framework might be able to explain all different varieties of abstract concepts. (PsycINFO Database Record PMID- 28094999 TI - Specificity of executive functioning and processing speed problems in common psychopathology. AB - OBJECTIVE: Interest continues in neuropsychological measures as cross-disorder intermediate phenotypes in understanding psychopathology. A central question concerns their specificity versus generalizability to particular forms of psychopathology, particularly for executive functioning (EF) and response speed. Three conceptual models examining these relationships were tested to clarify this picture at different levels in the diagnostic hierarchy. METHOD: Participants (total n = 641, age 18-60) yielded complete structured diagnostic interviews and a neuropsychological test battery comprising measures of executive function, processing speed, and IQ. Repeated measures multivariate analysis of variance, linear regression, and structural equation modeling (SEM) were used to test (a) a specificity model, which proposes that individual disorders are associated with component EF processes and speed; (b) a severity model, which proposes that the total number of comorbid disorders explain poor EF and/or slow speed; and (c) a higher-order dimensional model, which proposes that internalizing versus externalizing disorders are differentially related to EF or speed. RESULTS: EF effects were best explained by a specificity model, with distinct aspects of EF related to attention deficit hyperactivity disorder versus antisocial substance use disorders. Speed, on the other hand, emerged as a general indicator of externalizing psychopathology in the dimensional model, as well as overall severity of psychopathology in the severity model. CONCLUSIONS: Granular approaches are likely to be most productive for linking EF to psychopathology, whereas response speed has underused potential as an endophenotype for psychopathology liability. Results are discussed in terms of an integrated conceptualization of neuropsychological processes and putative neural systems involved in general and specific aspects of psychopathology. (PsycINFO Database Record PMID- 28095002 TI - The personality context of relational aggression: A Five-Factor Model profile analysis. AB - Relational aggression (RAgg) is a form of behavior intended to damage the victim's social status or interpersonal relationships through the use of purposeful interpersonal manipulation or social exclusion (Archer & Coyne, 2005). RAgg is impairing, stable, and largely defined by dysfunctional patterns of interpersonal interactions-all of which invokes comparisons to personality and, more specifically, personality pathology. Leveraging research using the Five Factor Model (FFM) in personality disorder (PD) work, the present study aims to understand the personality context of RAgg by applying this FFM profile approach in 2 ways: (a) by compiling a personality profile of RAgg based on a thorough review of the relevant literature and (b) by compiling a personality profile of RAgg based on expert ratings (N = 19). We then compared these profiles to each other and to existing personality profiles of Cluster B PDs to examine how RAgg fits into the personality space represented by Cluster B PDs. These analyses indicate that both FFM profiles of RAgg show substantial overlap with the FFM profile of narcissistic PD. The present study has important implications for bridging disjointed domains of research on personality pathology and RAgg and underscores the relevance of RAgg for early emergence of PD characteristics. (PsycINFO Database Record PMID- 28095001 TI - Callousness and affective face processing in adults: Behavioral and brain potential indicators. AB - The investigation of callous-unemotional (CU) traits has been central to contemporary research on child behavior problems, and served as the impetus for inclusion of a specifier for conduct disorder in the latest edition of the official psychiatric diagnostic system. Here, we report results from 2 studies that evaluated the construct validity of callousness as assessed in adults, by testing for affiliated deficits in behavioral and neural processing of fearful faces, as have been shown in youthful samples. We hypothesized that scores on an established measure of callousness would predict reduced recognition accuracy and diminished electocortical reactivity for fearful faces in adult participants. In Study 1, 66 undergraduate participants performed an emotion recognition task in which they viewed affective faces of different types and indicated the emotion expressed by each. In Study 2, electrocortical data were collected from 254 adult twins during viewing of fearful and neutral face stimuli, and scored for event related response components. Analyses of Study 1 data revealed that higher callousness was associated with decreased recognition accuracy for fearful faces specifically. In Study 2, callousness was associated with reduced amplitude of both N170 and P200 responses to fearful faces. Current findings demonstrate for the first time that callousness in adults is associated with both behavioral and physiological deficits in the processing of fearful faces. These findings support the validity of the CU construct with adults and highlight the possibility of a multidomain measurement framework for continued study of this important clinical construct. (PsycINFO Database Record PMID- 28095003 TI - Cocaine addiction as a homeostatic reinforcement learning disorder. AB - Drug addiction implicates both reward learning and homeostatic regulation mechanisms of the brain. This has stimulated 2 partially successful theoretical perspectives on addiction. Many important aspects of addiction, however, remain to be explained within a single, unified framework that integrates the 2 mechanisms. Building upon a recently developed homeostatic reinforcement learning theory, the authors focus on a key transition stage of addiction that is well modeled in animals, escalation of drug use, and propose a computational theory of cocaine addiction where cocaine reinforces behavior due to its rapid homeostatic corrective effect, whereas its chronic use induces slow and long-lasting changes in homeostatic setpoint. Simulations show that our new theory accounts for key behavioral and neurobiological features of addiction, most notably, escalation of cocaine use, drug-primed craving and relapse, individual differences underlying dose-response curves, and dopamine D2-receptor downregulation in addicts. The theory also generates unique predictions about cocaine self-administration behavior in rats that are confirmed by new experimental results. Viewing addiction as a homeostatic reinforcement learning disorder coherently explains many behavioral and neurobiological aspects of the transition to cocaine addiction, and suggests a new perspective toward understanding addiction. (PsycINFO Database Record PMID- 28095004 TI - "Self-critical perfectionism and depressive and anxious symptoms over 4 years: The mediating role of daily stress reactivity": Correction to Mandel et al. (2015). AB - Reports an error in "Self-critical perfectionism and depressive and anxious symptoms over 4 years: The mediating role of daily stress reactivity" by Tobey Mandel, David M. Dunkley and Molly Moroz (Journal of Counseling Psychology, 2015[Oct], Vol 62[4], 703-717). In the article, there were errors in Table 1. The corrected version of Table 1 appears in the erratum. (The following abstract of the original article appeared in record 2015-32534-001.) This study of 150 community adults examined heightened emotional reactivity to daily stress as a mediator in the relationships between self-critical (SC) perfectionism and depressive and anxious symptoms over a period of 4 years. Participants completed questionnaires assessing: perfectionism dimensions, general depressive symptoms (i.e., shared with anxiety), specific depressive symptoms (i.e., anhedonia), general anxious symptoms (i.e., shared with depression), and specific anxious symptoms (i.e., somatic anxious arousal) at Time 1; daily stress and affect (e.g., sadness, negative affect) for 14 consecutive days at Month 6 and Year 3; and depressive and anxious symptoms at Year 4. Path analyses indicated that SC perfectionism predicted daily stress-sadness reactivity (i.e., greater increases in sadness in response to increases in stress) across Month 6 and Year 3, which in turn explained why individuals with higher SC perfectionism had more general depressive symptoms, anhedonic depressive symptoms, and general anxious symptoms, respectively, 4 years later. In contrast, daily reactivity to stress with negative affect did not mediate the prospective relation between SC perfectionism and anhedonic depressive symptoms. Findings also demonstrated that higher mean levels of daily stress did not mediate the relationship between SC perfectionism and depressive and anxious symptoms 4 years later. These findings highlight the importance of targeting enduring heightened stress reactivity in order to reduce SC perfectionists' vulnerability to depressive and anxious symptoms over the long term. (PsycINFO Database Record PMID- 28095005 TI - Identifying stimuli that cue multiple responses triggers the congruency sequence effect independent of response conflict. AB - According to most accounts of executive control, resisting distraction requires enhancing task-relevant processing, reducing task-irrelevant processing, or both. Consistent with this view, the congruency effect in Stroop-like tasks-a putative measure of distraction-is often smaller after highly distracting incongruent trials than after less distracting congruent trials. Competing accounts of executive control, however, differ on which aspect of an incongruent trial triggers this congruency sequence effect (CSE). The activation-suppression account posits the activation of an incorrect response. In contrast, the response cueing account posits identifying stimuli that cue multiple responses. To distinguish between these accounts, we conducted 2 experiments involving a modified prime-probe task wherein participants respond to the distracter in occasional catch trials. We found that the CSE is triggered by identifying stimuli that cue multiple responses, rather than by the activation of an incorrect response. Further, we observed this effect while ruling out an alternative "response conflict" trigger. These findings are more consistent with the response cueing account than with the activation-suppression account. (PsycINFO Database Record PMID- 28095006 TI - Can the structure of motor variability predict learning rate? AB - Recent studies show that motor variability is actively regulated as an exploration tool to promote learning in reward-based tasks. However, its role in learning processes during error-based tasks, when a reduction of the motor variability is required to achieve good performance, is still unclear. In this study, we hypothesized that error-based learning not only depends on exploration but also on the individuals' ability to measure and predict the motor error. Previous studies identified a less auto-correlated motor variability as a higher ability to perform motion adjustments. Two experiments investigated the relationship between motor learning and variability, analyzing the long-range autocorrelation of the center of pressure fluctuations through the alpha score of a Detrended Fluctuation Analysis in balance tasks. In Experiment 1, we assessed the relationship between variability and learning rate using a standing balance task. Based on the results of this experiment, and to maximize learning, we performed a second experiment with a more difficult sitting balance task and increased practice. The learning rate of the 2 groups with similar balance performances but different alpha scores was compared. Individuals with a lower alpha score showed a higher learning rate. Because the alpha scores reveal how the motor output changes over time, instead of the magnitude of those changes, the higher learning rate is mainly linked to the higher error sensitivity rather than the exploration strategies. The results of this study highlight the relevance of the structure of output motor variability as a predictor of learning rate in error-based tasks. (PsycINFO Database Record PMID- 28095007 TI - Personality and behavior prediction and consistency across cultures: A multimethod study of Blacks and Whites in South Africa. AB - The cross-cultural universality of behavior's consistency and predictability from personality, assumed in trait models though challenged in cultural psychological models, has usually been operationalized in terms of beliefs and perceptions, and assessed using single-instance self-reports. In a multimethod study of actual behavior across a range of situations, we examined predictability and consistency in participants from the more collectivistic Black ethnic group and the more individualistic White group in South Africa. Participants completed personality questionnaires before the behavior measurements. In Study 1, 107 Black and 241 White students kept diaries for 21 days, recording their behaviors and the situations in which they had occurred. In Study 2, 57 Black and 52 White students were video-recorded in 12 situations in laboratory settings, and external observers scored their behaviors. Across both studies, behavior was predicted by personality on average equally well in the 2 groups, and equally well when using trait-adjective- and behavior-based personality measures. The few cultural differences in situational variability were not in line with individualism collectivism; however, subjective perceptions of variability, operationalized as dialectical beliefs, were more in line with individualism-collectivism: Blacks viewed their behavior as more variable than Whites. We propose drawing a distinction between subjective beliefs and objective behavior in the study of personality and culture. Larger cultural differences can be expected in beliefs and perceptions than in the links between personality and actual behavior. (PsycINFO Database Record PMID- 28095008 TI - Moving on or digging deeper: Regulatory mode and interpersonal conflict resolution. AB - Conflict resolution, in its most basic sense, requires movement and change between opposing motivational states. Although scholars and practitioners have long acknowledged this point, research has yet to investigate whether individual differences in the motivation for movement from state-to-state influence conflict resolution processes. Regulatory Mode Theory (RMT) describes this fundamental motivation as locomotion. RMT simultaneously describes an orthogonal motivational emphasis on assessment, a tendency for critical evaluation and comparison. We argue that this tendency, in the absence of a stronger motivation for locomotion, can obstruct peoples' propensity to reconcile. Five studies, using diverse measures and methods, found that the predominance of an individual's locomotion over assessment facilitates interpersonal conflict resolution. The first two studies present participants with hypothetical conflict scenarios to examine how chronic (Study 1) and experimentally induced (Study 2) individual differences in locomotion predominance influence the motivation to reconcile. The next two studies investigate this relation by way of participants' own conflict experiences, both through essay recall of previous conflict events (Study 3) and verbal narratives of ongoing conflict issues (Study 4). We then explore this association in the context of real-world conflict discussions between roommates (Study 5). Lastly, we examine results across these studies meta-analytically (Study 6). Overall, locomotion and assessment can inform lay theories of individual variation in the motivation to "move on" or "dig deeper" in conflict situations. We conclude by emphasizing the importance of using RMT to go beyond instrumental approaches to conflict resolution to understand fundamental individual motivations underlying its occurrence. (PsycINFO Database Record PMID- 28095009 TI - Cross-lingual neighborhood effects in generalized lexical decision and natural reading. AB - The present study assessed intra- and cross-lingual neighborhood effects, using both a generalized lexical decision task and an analysis of a large-scale bilingual eye-tracking corpus (Cop, Dirix, Drieghe, & Duyck, 2016). Using new neighborhood density and frequency measures, the general lexical decision task yielded an inhibitory cross-lingual neighborhood density effect on reading times of second language words, replicating van Heuven, Dijkstra, and Grainger (1998). Reaction times for native language words were not influenced by neighborhood density or frequency but error rates showed cross-lingual neighborhood effects depending on target word frequency. The large-scale eye movement corpus confirmed effects of cross-lingual neighborhood on natural reading, even though participants were reading a novel in a unilingual context. Especially second language reading and to a lesser extent native language reading were influenced by lexical candidates from the nontarget language, although these effects in natural reading were largely facilitatory. These results offer strong and direct support for bilingual word recognition models that assume language-independent lexical access. (PsycINFO Database Record PMID- 28095010 TI - Test expectancy and memory for important information. AB - Prior research suggests that learners study and remember information differently depending upon the type of test they expect to later receive. The current experiments investigate how testing expectations impact the study of and memory for valuable information. Participants studied lists of words ranging in value from 1 to 10 points with the goal being to maximize their score on a later memory test. Half of the participants were told to expect a recognition test after each list, whereas the other half were told to expect a recall test. After several lists of receiving tests congruent with expectations, participants studying for a recognition test instead received an unexpected recall test. In Experiment 1, participants who had studied for a recognition test recalled less of the valuable information than participants anticipating the recall format. These participants continued to attend less to item value on future (expected) recall tests than participants who had only ever experienced recall testing. When the recognition tests were made more demanding in Experiment 2, value-based recall improved relative to Experiment 1: though memory for the valuable information remained superior when participants studied with the expectation of having to recall the information, there were no longer significant differences after accounting for recall testing experience. Thus, recall-based testing encouraged strategic, value based encoding and enhanced retrieval of important information, whereas recognition testing in some cases limited value-based study and memory. These results extend prior work concerning the impact of testing expectations on memory, offering further insight into how people study important information. (PsycINFO Database Record PMID- 28095011 TI - Investigating developmental trajectories of morphemes as reading units in German. AB - The developmental trajectory of the use of morphemes is still unclear. We investigated the emergence of morphological effects on visual word recognition in German in a large sample across the complete course of reading acquisition in elementary school. To this end, we analyzed lexical decision data on a total of 1,152 words and pseudowords from a large cross-sectional sample of German children from the beginning of Grade 2 through 6, and a group of adults. We expand earlier evidence by (a) explicitly investigating processing differences between compounds, prefixes and suffixes, (b) taking into account vocabulary knowledge as an indicator for interindividual differences. Results imply that readers of German are sensitive to morphology in very early stages of reading acquisition with trajectories depending on morphological type and vocabulary knowledge. Facilitation from compound structure comes early in development, followed by facilitation from suffixes and prefixes later on in development. This indicates that stems and different types of affixes involve distinct processing mechanisms in beginning readers. Furthermore, children with higher vocabulary knowledge benefit earlier in development and to a greater extent from morphology. Our results specify the development and functional role of morphemes as reading units. (PsycINFO Database Record PMID- 28095012 TI - How our own speech rate influences our perception of others. AB - In conversation, our own speech and that of others follow each other in rapid succession. Effects of the surrounding context on speech perception are well documented but, despite the ubiquity of the sound of our own voice, it is unknown whether our own speech also influences our perception of other talkers. This study investigated context effects induced by our own speech through 6 experiments, specifically targeting rate normalization (i.e., perceiving phonetic segments relative to surrounding speech rate). Experiment 1 revealed that hearing prerecorded fast or slow context sentences altered the perception of ambiguous vowels, replicating earlier work. Experiment 2 demonstrated that talking at a fast or slow rate prior to target presentation also altered target perception, though the effect of preceding speech rate was reduced. Experiment 3 showed that silent talking (i.e., inner speech) at fast or slow rates did not modulate the perception of others, suggesting that the effect of self-produced speech rate in Experiment 2 arose through monitoring of the external speech signal. Experiment 4 demonstrated that, when participants were played back their own (fast/slow) speech, no reduction of the effect of preceding speech rate was observed, suggesting that the additional task of speech production may be responsible for the reduced effect in Experiment 2. Finally, Experiments 5 and 6 replicate Experiments 2 and 3 with new participant samples. Taken together, these results suggest that variation in speech production may induce variation in speech perception, thus carrying implications for our understanding of spoken communication in dialogue settings. (PsycINFO Database Record PMID- 28095013 TI - The tipping point of perceived change: Asymmetric thresholds in diagnosing improvement versus decline. AB - Change often emerges from a series of small doses. For example, a person may conclude that a happy relationship has eroded not from 1 obvious fight but from smaller unhappy signs that at some point "add up." Everyday fluctuations therefore create ambiguity about when they reflect substantive shifts versus mere noise. Ten studies reveal an asymmetry in this first point when people conclude "official" change: people demand less evidence to diagnose lasting decline than lasting improvement, despite similar evidential quality. This effect was pervasive and replicated across many domains and parameters. For example, a handful of poor grades, bad games, and gained pounds led participants to diagnose intellect, athleticism, and health as "officially" changed; yet corresponding positive signs were dismissed as fickle flukes (Studies 1a, 1b, and 1c). This further manifested in real-time reactions: participants interpreted the same graphs of change in the economy and public health as more meaningful if framed as depicting decline versus improvement (Study 2), and were more likely to gamble actual money on continued bad versus good luck (Study 3). Why? Effects held across self/other change, added/subtracted change, and intended/unintended change (Studies 4a, 4b, and 4c), suggesting a generalized negativity bias. Teasing this apart, we highlight a novel "entropy" component beyond standard accounts like risk aversion: good things seem more truly capable of losing their positive qualities than bad things seem capable of gaining them, rendering signs of decline to appear more immediately diagnostic (Studies 5 and 6). An asymmetric tipping point raises theoretical and practical implications for how people might inequitably react to smaller signs of change. (PsycINFO Database Record PMID- 28095014 TI - The ability to choose can increase satiation. AB - The ability to choose should let people create more enjoyable experiences. However, in a set of 5 studies, people who chose repeatedly during ongoing consumption exhibited a greater drop in enjoyment compared with those who received a series of random selections from the same set of liked stimuli. Process evidence indicated that choosing increased satiation because it triggered overall reflections on the repetitive nature of the ongoing consumption experience. Moderating evidence also supported our theoretical account as differences in satiation disappeared when nonchoosers were explicitly cued to think about repetition in the general sense, or when choosers made all of their choices before the onset of repeated consumption. Additional measures and analyses further established that choice set size, the difficulty of choosing, and other alternative accounts could not fully explain the pattern of effects. The paper closes with a discussion of the implications of these findings for understanding the causes of satiation, the consequences of choosing, and improving individuals' experiences. (PsycINFO Database Record PMID- 28095015 TI - Medicolegal-Malpractice and Ethical Issues in Radiology.Professional Liability (Malpractice) Insurance: Occurrence Versus Claims-Made. PMID- 28095017 TI - Spectrum of Xanthogranulomatous Processes in the Abdomen and Pelvis: A Pictorial Review of Infectious, Inflammatory, and Proliferative Responses. AB - OBJECTIVE: Xanthogranulomatous (XG) processes are rare inflammatory conditions with the characteristic pathologic feature of lipid-laden macrophages or histiocyte cells. Imaging findings are nonspecific and can simulate aggressive neoplastic processes. XG processes can be caused by infection, inflammation, histolytic process, or an inherited lysosomal disorder. XG infectious processes are mainly seen in cholecystitis and pyelonephritis, but several other organs can also be involved. Histiocytic processes can be divided into Langerhans and non Langerhans cell histiocytosis. The non-Langerhans cell histiocytosis entities include Erdheim-Chester disease, Rosai-Dorfman disease, juvenile xanthogranuloma, and hemophagocytic lymphohistiocytosis. The inherited lysosomal disorders resulting in XG processes include Nieman-Pick, Gaucher, and other lysosomal storage disorders. CONCLUSION: Radiologists need to be able to recognize features of xanthogranulomatous processes to help facilitate patient management. PMID- 28095018 TI - Hallway Conversations in PhysicsWhat Is the Typical Effective Dose From a Routine Eye-to-Thigh PET/CT Examination Assuming an Injected 18F-FDG Dose of 370 MBq? PMID- 28095016 TI - Renal Masses Detected on FDG PET/CT in Patients With Lymphoma: Imaging Features Differentiating Primary Renal Cell Carcinomas From Renal Lymphomatous Involvement. AB - OBJECTIVE: The purpose of this study is to analyze the 18F-FDG PET/CT features of solid renal masses detected in patients with lymphoma and to evaluate the ability of PET/CT to differentiate renal cell carcinoma (RCC) from renal lymphomatous involvement. MATERIALS AND METHODS: Thirty-six patients with solid renal masses on PET/CT performed for staging or follow-up of lymphoma were evaluated retrospectively. The features recorded for each renal mass included the following standardized uptake values (SUVs) on PET/CT: the maximum SUV (SUVmax), the mean SUV (SUVmean), the ratio of the SUVmax of the tumor to that of the normal kidney cortex, the ratio of the SUVmean of the tumor to that of the normal kidney cortex, the ratio of the SUVmax of the tumor to that of the normal liver, and the ratio of the SUVmean of the tumor to that of the normal liver. Renal mass size and margins (well defined vs infiltrative) and the presence of calcifications were evaluated on CT. Renal biopsy results were used as the reference standard. Relationships between imaging parameters and histopathologic findings were assessed. RESULTS: Of the 36 renal masses evaluated, 22 (61.1%) were RCCs and 14 (38.9%) were renal lymphomas. All SUV metrics were higher for renal lymphomas than for RCCs (p < 0.0001, for all). All renal lymphomas had an SUVmax higher than 5.98 g/mL (median, 10.99 g/mL), whereas all RCCs had an SUVmax lower than 5.26 g/mL (median, 2.91 g/mL). No statistically significant differences in mass size or margins were found between RCCs and renal lymphoma. CONCLUSION: PET/CT features may be useful for differentiating RCCs from renal involvement in patients with lymphoma with solid renal masses. PMID- 28095019 TI - Elbow Injuries in Adult Overhead Athletes. AB - OBJECTIVE: The purpose of this article is to review common elbow injuries found in overhead athletes with focus on mechanism, clinical features, imaging appearance, and treatment options. CONCLUSION: The overhead throwing motion subjects the elbow to a variety of complex forces, which places both osseous and soft-tissue structures at high risk for injury. PMID- 28095020 TI - Current Status of Ventilation-Perfusion Scintigraphy for Suspected Pulmonary Embolism. AB - OBJECTIVE: The purpose of this article is to outline recent progress made in ventilation-perfusion (V/Q) scintigraphy imaging techniques and the interpretation systems used for the diagnosis of pulmonary embolism (PE). Various state-of-the-art approaches that can be selected according to the needs dictated by the medical practice environment and specific patient groups are presented. CONCLUSION: Although advances in tomographic imaging have certainly improved the sensitivity of V/Q scans for the diagnosis of PE, they may lead to overdiagnosis by revealing small and clinically insignificant PEs. PMID- 28095021 TI - Reply to "Comment on 'Maximum-Intensity-Projection and Computer-Aided-Detection Algorithms as Stand-Alone Reader Devices in Lung Cancer Screening Using Different Dose Levels and Reconstruction Kernels'". PMID- 28095022 TI - Estimating Effective Dose of Radiation From Pediatric Cardiac CT Angiography Using a 64-MDCT Scanner: New Conversion Factors Relating Dose-Length Product to Effective Dose. AB - OBJECTIVE: The purpose of this study is to determine the conversion factors that enable accurate estimation of the effective dose (ED) used for cardiac 64-MDCT angiography performed for children. MATERIALS AND METHODS: Anthropomorphic phantoms representative of 1- and 10-year-old children, with 50 metal oxide semiconductor field-effect transistor dosimeters placed in organs, underwent scanning performed using a 64-MDCT scanner with different routine clinical cardiac scan modes and x-ray tube potentials. Organ doses were used to calculate the ED on the basis of weighting factors published in 1991 in International Commission on Radiological Protection (ICRP) publication 60 and in 2007 in ICRP publication 103. The EDs and the scanner-reported dose-length products were used to determine conversion factors for each scan mode. The effect of infant heart rate on the ED and the conversion factors was also assessed. RESULTS: The mean conversion factors calculated using the current definition of ED that appeared in ICRP publication 103 were as follows: 0.099 mSv . mGy-1 . cm-1, for the 1-year old phantom, and 0.049 mSv . mGy-1 . cm-1, for the 10-year-old phantom. These conversion factors were a mean of 37% higher than the corresponding conversion factors calculated using the older definition of ED that appeared in ICRP publication 60. Varying the heart rate did not influence the ED or the conversion factors. CONCLUSION: Conversion factors determined using the definition of ED in ICRP publication 103 and cardiac, rather than chest, scan coverage suggest that the radiation doses that children receive from cardiac CT performed using a contemporary 64-MDCT scanner are higher than the radiation doses previously reported when older chest conversion factors were used. Additional up-to-date pediatric cardiac CT conversion factors are required for use with other contemporary CT scanners and patients of different age ranges. PMID- 28095023 TI - Reply to "Vertebral Venous Congestion Mimicking Sclerotic Metastasis in the Absence of Venous Obstruction". PMID- 28095024 TI - Pathologic Subtypes of Ampullary Adenocarcinoma: Value of Ampullary MDCT for Noninvasive Preoperative Differentiation. AB - OBJECTIVE: The purpose of this study was to evaluate the utility of ampullary MDCT in the noninvasive, preoperative differentiation of pancreatobiliary and intestinal subtypes of ampullary adenocarcinoma. MATERIALS AND METHODS: This retrospective study included 32 patients (20 men, 12 women; age range, 41-81 years) with resected ampullary adenocarcinoma who underwent preoperative contrast enhanced ampullary MDCT. Two radiologists, blinded to pathologic diagnosis of adenocarcinoma subtype, evaluated the presence of seven MDCT features independently. MDCT findings and ampullary adenocarcinoma subtypes were correlated using chi-square and Fisher exact tests. Interobserver agreement was evaluated using the Cohen kappa statistic. RESULTS: When evaluated with ampullary MDCT, the intestinal and pancreatobiliary subtypes were significantly different in terms of lesion morphology (p < 0.0001), papillary shape (p < 0.0001), common bile duct (CBD) infiltration and dilatation (p = 0.003 and p = 0.0004, respectively), duodenopancreatic groove infiltration (p = 0.0009), and pancreaticoduodenal artery involvement (p = 0.004). Pancreatobiliary subtype tumors were more often infiltrative in morphology (18/18) and showed retracted papilla (14/18), CBD (18/18) and main pancreatic duct (MPD) infiltration (12/18), dilated CBD (18/18) and MPD (13/18), fixed duodenopancreatic groove appearance (15/18), and pancreaticoduodenal artery involvement (12/18). Intestinal subtype carcinomas were more frequently nodular (14/14) and had a bulging papilla (13/14), a free duodenopancreatic groove appearance (11/14), and no pancreaticoduodenal artery involvement (2/14). When all features were taken into account, MDCT showed sensitivity of 85.7% and specificity of 83.3% in differentiating intestinal and pancreatobiliary subtype tumors. Accuracy, positive predictive value, and negative predictive value of MDCT were 84.4%, 80%, and 88.2%, respectively. Interobserver agreement was almost perfect for the presence of each imaging feature (kappa > 0.8). CONCLUSION: Ampullary MDCT can be useful to differentiate pancreatobiliary and intestinal subtypes of ampullary adenocarcinoma preoperatively, provided the duodenum is optimally distended at imaging. PMID- 28095025 TI - The influence of personal protection equipment, occupant body size, and restraint system on the frontal impact responses of Hybrid III ATDs in tactical vehicles. AB - OBJECTIVE: Although advanced restraint systems, such as seat belt pretensioners and load limiters, can provide improved occupant protection in crashes, such technologies are currently not utilized in military vehicles. The design and use of military vehicles presents unique challenges to occupant safety-including differences in compartment geometry and occupant clothing and gear-that make direct application of optimal civilian restraint systems to military vehicles inappropriate. For military vehicle environments, finite element (FE) modeling can be used to assess various configurations of restraint systems and determine the optimal configuration that minimizes injury risk to the occupant. The models must, however, be validated against physical tests before implementation. The objective of this study was therefore to provide the data necessary for FE model validation by conducting sled tests using anthropomorphic test devices (ATDs). A secondary objective of this test series was to examine the influence of occupant body size (5th percentile female, 50th percentile male, and 95th percentile male), military gear (helmet/vest/tactical assault panels), seat belt type (3 point and 5-point), and advanced seat belt technologies (pretensioner and load limiter) on occupant kinematics and injury risk in frontal crashes. METHODS: In total, 20 frontal sled tests were conducted using a custom sled buck that was reconfigurable to represent both the driver and passenger compartments of a light tactical military vehicle. Tests were performed at a delta-V of 30 mph and a peak acceleration of 25 g. The sled tests used the Hybrid III 5th percentile female, 50th percentile male, and 95th percentile male ATDs outfitted with standard combat boots and advanced combat helmets. In some tests, the ATDs were outfitted with additional military gear, which included an improved outer tactical vest (IOTV), IOTV and squad automatic weapon (SAW) gunner with a tactical assault panel (TAP), or IOTV and rifleman with TAP. ATD kinematics and injury outcomes were determined for each test. RESULTS: Maximum excursions were generally greater in the 95th percentile male compared to the 50th percentile male ATD and in ATDs wearing TAP compared to ATDs without TAP. Pretensioners and load limiters were effective in decreasing excursions and injury measures, even when the ATD was outfitted in military gear. CONCLUSIONS: ATD injury response and kinematics are influenced by the size of the ATD, military gear, and restraint system. This study has provided important data for validating FE models of military occupants, which can be used for design optimization of military vehicle restraint systems. PMID- 28095026 TI - Self-regulation of driving speed among distracted drivers: An application of driver behavioral adaptation theory. AB - OBJECTIVE: The adaptive behavior of mobile phone-distracted drivers has been a topic of much discussion in the recent literature. Both simulator and naturalistic studies suggest that distracted drivers generally select lower driving speeds; however, speed adaptation is not observed among all drivers, and the mechanisms of speed selection are not well understood. The aim of this research was to apply a driver behavioral adaptation model to investigate the speed adaptation of mobile phone-distracted drivers. METHODS: The speed selection behavior of drivers was observed in 3 phone conditions including baseline (no conversation) and hands-free and handheld phone conversations in a high-fidelity driving simulator. Speed adaptation in each phone condition was modeled as a function of secondary task demand and self-reported personal/psychological characteristics with a system of seemingly unrelated equations (SURE) accounting for potential correlations due to repeated measures experiment design. RESULTS: Speed adaptation is similar between hands-free and handheld phone conditions, but the predictors of speed adaptation vary across the phone conditions. Though perceived workload of secondary task demand, self-efficacy, attitude toward safety, and driver demographics were significant predictors of speed adaptation in the handheld condition, drivers' familiarity with the hands-free interface, attitude toward safety, and sensation seeking were significant predictors in the hands-free condition. Drivers who reported more positive safety attitudes selected lower driving speeds while using phones. CONCLUSION: This research confirmed that behavioral adaptation models are suitable for explaining speed adaptation of mobile phone distracted drivers, and future research could be focused on further theoretical refinement. PMID- 28095027 TI - Severe and extensive traumatic axonal injury following minor and indirect head trauma. AB - OBJECTIVES: This study reports on a patient with mild traumatic brain injury (TBI) who showed severe and extensive traumatic axonal injury (TAI) of various neural tracts following minor and indirect head trauma, which was demonstrated by diffusion tensor tractography (DTT). CASE DESCRIPTION: A 26-year-old female patient suffered from indirect head trauma resulting from flexion-hyperextension injury after being hit from behind by a slowly moving car. At the time of head trauma, she felt tingling sensation on her four extremities; however, she did not experience loss of consciousness. At 5-day after onset, she began to experience tremor on the right leg and, subsequently, tremor had also developed in the left leg. At 8-days after onset, she could not even stand due to tremor of both legs and began to feel a tingling sensation on both legs. Since ~ 2 weeks after head trauma, myoclonus had developed mainly in the trunk. After 10-weeks after head trauma, when she started rehabilitation, she showed mild quadriparesis (4+/4+) with severe weakness of the proximal joint (shoulder/hip, 4-/4-), severe resting and intentional tremor, ataxic gait and severe myoclonus. CONCLUSIONS: Severe and extensive TAI of various neural tracts was demonstrated in a patient with mild TBI following minor and indirect head trauma, using DTT. PMID- 28095028 TI - Time Matters: Framing Antismoking Messages Using Current Smokers' Preexisting Perceptions of Temporal Distance to Smoking-Related Health Risks. AB - This study examined the effects of temporal framing used in messages about the future likelihood of developing smoking-related diseases on intention to quit smoking. Based on construal level theory (CLT), a causal model delineating the relationships among four variables-perceived temporal distance, personal relevance, perceived susceptibility, and behavioral intention-was proposed. The model was validated by an online experiment with a sample of 222 current smokers, revealing the effects of perceived temporal distance on behavioral intention via personal relevance and perceived susceptibility. Following the CLT-grounded model, the effects of different temporal frames (near future vs. distant future) on the four variables were tested. The near-future frame featured a risk perceived to be more temporally proximal (i.e., heart attack), and the distant future frame featured a risk perceived to be more temporally distant (i.e., larynx cancer) among current smokers. Participants exposed to the near-future frame reported significantly shorter perceived temporal distance, greater personal relevance and perceived susceptibility to the risk portrayed in the message, and greater intention to quit smoking than participants exposed to the distant-future frame. Implications for antismoking communications are discussed. PMID- 28095029 TI - Utilization of conventional neuroimaging following youth concussion. AB - BACKGROUND/OBJECTIVE: Conventional neuroimaging is not recommended for the routine diagnosis of concussion, but some patients with concussion undergo computed tomography (CT) or magnetic resonance imaging (MRI). The objective of this study was to explore the clinical factors that predict neuroimaging utilization in concussion. METHODS: Concussion-related CT and MRI data were analysed from 1953 patients, aged 10-19 years, who presented to a sports concussion clinic within 30 days of injury. RESULTS: The majority of CT scans (n = 193) were obtained during the acute concussion period (mean = 2.7 days post concussion), whereas MRI scans (n = 134) were ordered later during recovery (mean = 39.4 days post-concussion). Predictors of CT utilization included loss of consciousness, amnesia and vomiting (all p < 0.001). Prior concussion (p = 0.002) and continued participation in activity after injury (p = 0.03) predicted greater MRI utilization. Neuroimaging with either CT (p = 0.024, hazard ratio = 1.2) or MRI (p < 0.001, hazard ratio = 2.75) was associated with prolonged symptoms. Only 3.1% of CTs and 1.5% of MRIs demonstrated signs of traumatic brain injury. CONCLUSION: Several clinical factors predict neuroimaging utilization in patients with concussion. CT is generally used acutely, while MRI is used in the sub-acute and chronic post-concussion periods. In a sports concussion clinic, delayed neuroimaging has limited clinical yield. PMID- 28095030 TI - Green Tea Consumption and the Risk of Liver Cancer: A Meta-Analysis. AB - Green tea is a commonly consumed beverage in Asia and has been suggested to have anticarcinogenic properties. To date, epidemiological evidence of the effect of green tea consumption on liver cancer risk remains ambiguous. The aim of this meta-analysis is to evaluate the association between green tea consumption and the risk of liver cancer. The summary relative risk for the highest consumption (>=5 cups/day) of green tea on liver cancer incidence compared with nondrinkers was 0.62 (95% confidence interval: 0.49-0.79). We also found a trend that the incidence of liver cancer was reduced with the increasing years of green tea intake (significance at >20 yr). A significant dose-response association was found between green tea drinking and liver cancer risk. The downward trend was most obvious when the consumption of green tea increased up to about 4 cups/day. The results showed that the increasing green tea intake may have a preventive effect against liver cancer. PMID- 28095031 TI - The role of drug and alcohol use and the risk of motor vehicle crashes in Shiraz, Iran, 2014: A case-crossover study. AB - BACKGROUND: Traffic accidents and traffic-related injuries and mortality have become a major public health concern in Iran. This study aimed to examine the role of drug and alcohol use in motor vehicle accidents in Iran. METHODS: This case-crossover study was conducted on 441 drivers who survived a road traffic crash and were taken to the emergency department of Shahid Rajaee trauma hospital in Shiraz, southern Iran. Data were collected using checklists that included demographic characteristics and drug and alcohol use prior to driving. Alcohol and drug use was identified through self-report, and cannabis, morphine, and methamphetamine urine tests were used to confirm drug abuse among drivers. RESULTS: In total 17.9% of drivers reported using drugs (cannabis, opium, or metamphetamine) and 8.84% of drivers reported consuming alcohol prior to the collision. The crude odds ratios (ORs) for having a crash for opium, cannabis, and metamphetamine were 1.94 (95% interval confidence [CI], 1.11-3.38), 2.37 (95% CI, 1.03-5.42), 5.5 (95% CI, 1.21-24.81), respectively, and for all drugs was 3.83 (95% CI, 2.28-6.43). The OR for alcohol was 3.5 (95% CI, 1.73-7.06) based on self-report. CONCLUSION: Drug and alcohol use are increasing the risk of traffic crashes in Iran. Risk-reducing programs must be designed and implemented. PMID- 28095032 TI - The trajectories of overall disability in the first 5 years after moderate and severe traumatic brain injury. AB - PRIMARY OBJECTIVES: To assess longitudinal trajectories of overall disability after moderate-to-severe traumatic brain injury (TBI) and to examine whether those trajectories could be predicted by socio-demographic and injury characteristics. METHODS: Demographics and injury characteristics of 105 individuals with moderate-to-severe TBI were extracted from medical records. At the 1-, 2-, and 5-year follow-ups, TBI-related disability was assessed by the GOSE. A hierarchical linear model (HLM) was used to examine functional outcomes up to 5 years following injury and whether those outcomes could be predicted by: time, gender, age, relationship, education, employment pre-injury, occupation, GCS, cause of injury, length of post-traumatic amnesia (PTA), CT findings and injury severity score, as well as the interactions between each of these predictors and time. RESULTS: Higher GOSE trajectories (lower disability) were predicted by younger age at injury and shorter PTA, as well as by the interaction terms of time*PTA and time*employment. Those who had been employed at injury decreased in disability over time, while those who had been unemployed increased in disability. CONCLUSION: The study results support the view that individual factors generally outweigh injury-related factors as predictors of disability after TBI, except for PTA. PMID- 28095033 TI - Detection of the toughest: Pedestrian injury risk as a smooth function of age. AB - OBJECTIVE: Though it is common to refer to age-specific groups (e.g., children, adults, elderly), smooth trends conditional on age are mainly ignored in the literature. The present study examines the pedestrian injury risk in full-frontal pedestrian-to-passenger car accidents and incorporates age-in addition to collision speed and injury severity-as a plug-in parameter. METHODS: Recent work introduced a model for pedestrian injury risk functions using explicit formulae with easily interpretable model parameters. This model is expanded by pedestrian age as another model parameter. Using the German In-Depth Accident Study (GIDAS) to obtain age-specific risk proportions, the model parameters are fitted to the raw data and then smoothed by broken-line regression. RESULTS: The approach supplies explicit probabilities for pedestrian injury risk conditional on pedestrian age, collision speed, and injury severity under investigation. All results yield consistency to each other in the sense that risks for more severe injuries are less probable than those for less severe injuries. As a side product, the approach indicates specific ages at which the risk behavior fundamentally changes. These threshold values can be interpreted as the most robust ages for pedestrians. CONCLUSIONS: The obtained age-wise risk functions can be aggregated and adapted to any population. The presented approach is formulated in such general terms that in can be directly used for other data sets or additional parameters; for example, the pedestrian's sex. Thus far, no other study using age as a plug-in parameter can be found. PMID- 28095034 TI - Self-reported driving under the influence of alcohol and cannabis among Ontario students: Associations with graduated licensing, risk taking, and substance abuse. AB - OBJECTIVE: This article describes the patterns of self-reported driving under the influence of alcohol (DUIA) and driving under the influence of cannabis (DUIC) among licensed Ontario students in 2009 and examines their associations with graduated licensing, risk taking, and substance use problems for understanding DUIA and DUIC behaviors. Ontario's graduated licensing system requires new drivers to hold a G1 license for a minimum of 8 months and a G2 license for a minimum of 12 months before a full and unrestricted G license can be obtained. Among other restrictions, G1 drivers must maintain a 0 blood alcohol content (BAC), have an experienced driver in the passenger seat, not drive on any high speed expressways, and not drive between the hours of midnight and 5 a.m. A G2 license is more similar to a G license, with fewer restrictions. METHOD: This study analyzed data from the 2009 Ontario Student Drug Use and Health Survey (OSDUHS). The OSDUHS is a biennial population-based survey of students (grades 7 to 12) in Ontario, Canada. RESULTS: The results showed that 16.3% of licensed students in Ontario reported DUIC and 11.5% reported DUIA during the past year. After controlling for the effect of age, type of license emerged as a robust predictor for both DUIA and DUIC behavior, because students with a G2 and full license were significantly more likely to report DUIA and DUIC than drivers with a G1 license. Multivariate analyses suggested that risk-seeking behaviors were more important for understanding DUIA behavior than for DUIC behavior. Elevated problem indicators for alcohol and for cannabis were associated with DUIA and DUIC, respectively. CONCLUSIONS: Though much attention has been paid to drinking and driving among adolescents, this research shows that more Ontario students now report driving after cannabis use than after drinking alcohol. The results identify important correlates of both behaviors that may be useful for prevention purposes. PMID- 28095035 TI - Validation of a parametric finite element human femur model. AB - OBJECTIVE: Finite element (FE) models with geometry and material properties that are parametric with subject descriptors, such as age and body shape/size, are being developed to incorporate population variability into crash simulations. However, the validation methods currently being used with these parametric models do not assess whether model predictions are reasonable in the space over which the model is intended to be used. This study presents a parametric model of the femur and applies a unique validation paradigm to this parametric femur model that characterizes whether model predictions reproduce experimentally observed trends. METHODS: FE models of male and female femurs with geometries that are parametric with age, femur length, and body mass index (BMI) were developed based on existing statistical models that predict femur geometry. These parametric FE femur models were validated by comparing responses from combined loading tests of femoral shafts to simulation results from FE models of the corresponding femoral shafts whose geometry was predicted using the associated age, femur length, and BMI. The effects of subject variables on model responses were also compared with trends in the experimental data set by fitting similarly parameterized statistical models to both the results of the experimental data and the corresponding FE model results and then comparing fitted model coefficients for the experimental and predicted data sets. RESULTS: The average error in impact force at experimental failure for the parametric models was 5%. The coefficients of a statistical model fit to simulation data were within one standard error of the coefficients of a similarly parameterized model of the experimental data except for the age parameter, likely because material properties used in simulations were not varied with specimen age. In simulations to explore the effects of femur length, BMI, and age on impact response, only BMI significantly affected response for both men and women, with increasing BMI producing higher impact forces. CONCLUSIONS: Impactor forces from simulations, on average, matched experimental values at the time of failure. In addition, the simulations were able to match the trends in the experimental data set. PMID- 28095036 TI - Differentiation of Clear Cell Renal Cell Carcinoma From Other Renal Cortical Tumors by Use of a Quantitative Multiparametric MRI Approach. AB - OBJECTIVE: The purpose of this study was to develop a quantitative multiparametric MRI approach to differentiating clear cell renal cell carcinoma (RCC) from other renal cortical tumors. MATERIALS AND METHODS: This retrospective study included 119 patients with 124 histopathologically confirmed renal cortical tumors who underwent preoperative MRI including DWI, contrast-enhanced, and chemical-shift sequences before nephrectomy. Two radiologists independently assessed each tumor volumetrically, and apparent diffusion coefficient values, parameters from multiphasic contrast-enhanced MRI (peak enhancement, upslope, downslope, AUC), and chemical-shift indexes were calculated. Univariate and multivariable logistic regression analyses were performed to identify parameters associated with clear cell RCC. RESULTS: Interreader agreement was excellent (intraclass correlation coefficient, 0.815-0.994). The parameters apparent diffusion coefficient (reader 1 AUC, 0.804; reader 2, 0.807), peak enhancement (reader 1 AUC, 0.629; reader 2, 0.606), and downslope (reader 1 AUC, 0.575; reader 2, 0.561) were significantly associated with discriminating clear cell RCC from other renal cortical tumors. The combination of all three parameters further increased diagnostic accuracy (reader 1 AUC, 0.889; reader 2, 0.907; both p <= 0.001), yielding sensitivities of 0.897 for reader 1 and 0.897 for reader 2, and specificities of 0.762 for reader 1 and 0.738 for reader 2 in the identification of clear cell RCC. With maximized sensitivity, specificities of 0.429 and 0.262 were reached for readers 1 and 2, respectively. CONCLUSION: A quantitative multiparametric approach statistically significantly improves diagnostic performance in differentiating clear cell RCC from other renal cortical tumors. PMID- 28095037 TI - NONINVASIVE FOLLICULAR TUMOR WITH PAPILLARY-LIKE NUCLEAR FEATURES: NOT A TEMPEST IN A TEAPOT. AB - OBJECTIVE: Encapsulated non-invasive follicular variant papillary thyroid cancer (ENIFVPTC) has recently been retermed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This designation specifically omits the word "cancer" to encourage conservative treatment since patients with NIFTP tumors have been shown to derive no benefit from completion thyroidectomy or adjuvant radio-active iodine (RAI) therapy. METHODS: This was a retrospective study of consecutive cases of tumors from 2007 to 2015 that met pathologic criteria for NIFTP. The conservative management (CM) group included patients managed with lobectomy alone or appropriately indicated total thyroidectomy. Those included in the aggressive management (AM) group received either completion thyroidectomy or RAI or both. RESULTS: From 100 consecutive cases of ENIFVPTC reviewed, 40 NIFTP were included for the final analysis. Of these, 10 (27%) patients treated with initial lobectomy received completion thyroidectomy and 6 of 40 (16%) also received postsurgical adjuvant RAI. The mean per-patient cost of care in the AM group was $17,629 +/- 2,865, nearly twice the $8,637 +/- 309 costs in the CM group, and was largely driven by the cost of completion thyroidectomy and RAI. CONCLUSION: The term NIFTP has been recently promulgated to identify a type of thyroid neoplasm, formerly identified as a low-grade cancer, for which initial surgery represents adequate treatment. We believe that since the new NIFTP nomenclature intentionally omits the word "cancer," the clinical indolence of these tumors will be better appreciated, and cost savings will result from more conservative and appropriate clinical management. ABBREVIATIONS: AM = aggressive management CM = conservative management ENIFVPTC = encapsulated noninvasive form of FVPTC FVPTC = follicular variant of papillary thyroid carcinoma NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features PTC = papillary thyroid carcinoma PTMC = papillary thyroid microcarcinoma RAI = radio-active iodine US = ultrasound. PMID- 28095038 TI - PURE ANDROGEN-PRODUCING ADRENAL TUMOR: CLINICAL FEATURES AND PATHOGENESIS. AB - OBJECTIVE: Pure androgen-secreting adrenal tumors (PASATs) are extremely rare, most reports involving only a single case. This study examined 9 cases of PASAT, with an attempt to characterize its clinical features and to explore the pathogenesis. METHODS: Clinical data of 9 patients with PASAT were retrospectively reviewed. Immunostaining was conducted, and the aryl hydrocarbon receptor-interacting protein gene (AIP) was amplified and directly sequenced. RESULTS: The onset age of the patients ranged from 3.5 to 64 years. All 8 female patients had virilization, whereas the 7-year-old male patient presented with sexual precocity. Serum testosterone levels were elevated (4.1 to 52.3 nmol/L). Adrenal masses were detected and removed in all patients and histologically diagnosed as adrenocortical adenoma or carcinoma. Two patients had both PASATs and growth hormone (GH)-secreting pituitary adenomas (GH pituitary adenoma). Immunohistochemistry revealed nuclear immunoreactivity for p53 in 3 of 7 patients and nuclear immunoreactivity for cyclin D1 in 2 of 7 patients. Immunostaining of beta-catenin showed nuclear, cytoplasmic, and membrane immunoreactivity (2 of 7 patients) or merely cytoplasmic immunoreactivity (1 of 7 patients). The adrenocortical carcinoma showed positive staining for both p53 and cyclin D1 and a high Ki-67 index of 60%. Mutations p.Lys177Argfs*19 and p.Asp287Val in the AIP gene were identified in PASATs of the 2 patients with concomitant presence of GH pituitary adenoma. CONCLUSION: Clinical features of PASATs vary with gender and age of the patients. Abnormal p53 and beta-catenin expression might be involved in the tumorigenesis of these tumors. AIP mutations might be responsible for the concomitant presence of PASATs and GH pituitary adenoma. ABBREVIATIONS: ACA = adrenocortical adenoma ACC = adrenocortical carcinoma AIP = aryl hydrocarbon receptor-interacting protein DHEAS = dehydroepiandrosterone sulfate; GH growth hormone PASAT = pure androgen-secreting adrenal tumor. PMID- 28095039 TI - UPDATE ON A QUALITY INITIATIVE TO OVERCOME CLINICAL INERTIA IN THE POSTOPERATIVE CARE OF INPATIENTS WITH DIABETES MELLITUS. PMID- 28095040 TI - CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM - 2017 EXECUTIVE SUMMARY. AB - ABBREVIATIONS: A1C = hemoglobin A1C AACE = American Association of Clinical Endocrinologists ACCORD = Action to Control Cardiovascular Risk in Diabetes ACCORD BP = Action to Control Cardiovascular Risk in Diabetes Blood Pressure ACEI = angiotensin-converting enzyme inhibitor ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation AGI = alpha glucosidase inhibitor apo B = apolipoprotein B ASCVD = atherosclerotic cardiovascular disease BAS = bile acid sequestrant BMI = body mass index BP = blood pressure CHD = coronary heart disease CKD = chronic kidney disease CVD = cardiovascular disease DASH = Dietary Approaches to Stop Hypertension DPP-4 = dipeptidyl peptidase 4 eGFR = estimated glomerular filtration rate FDA = Food and Drug Administration GLP-1 = glucagon-like peptide 1 HDL-C = high-density lipoprotein cholesterol IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial LDL-C = low-density lipoprotein cholesterol LDL-P = low-density lipoprotein particle Look AHEAD = Look Action for Health in Diabetes NPH = neutral protamine Hagedorn OSA = obstructive sleep apnea SFU = sulfonylurea SGLT-2 = sodium glucose cotransporter-2 SMBG = self-monitoring of blood glucose T2D = type 2 diabetes TZD = thiazolidinedione VADT = Veterans Affairs Diabetes Trial. PMID- 28095041 TI - ORAL VERSUS TRANSDERMAL ESTROGEN IN TURNER SYNDROME: A SYSTEMATIC REVIEW AND META ANALYSIS. AB - OBJECTIVE: To conduct a systematic review and meta-analysis comparing transdermal estrogens (TDEs) versus oral estrogens (OEs) in Turner syndrome (TS). METHODS: Randomized trials and observational comparative studies with a minimal follow-up of 6 months for skeletal and metabolic outcomes and serum hormone changes were included. Outcomes were pooled with a random effects model and are reported as mean differences between OE and TDE groups and 95% confidence intervals (CIs). RESULTS: Of 845 candidate references, 4 studies were included. Both OEs and TDEs were associated with an increase in whole-body bone mineral density (BMD) z score, with TDE therapy displaying a greater increase. OEs were associated with higher fasting glucose and total cholesterol. Both OEs and TDEs reduced low density lipo-protein cholesterol (LDL-C) and increased high-density lipoprotein cholesterol (HDL-C), with OEs providing a more favorable effect. The use of 17 beta estradiol was associated with a higher total cholesterol and lower LDL-C than TDE. No statistically significant difference was found between OEs and TDEs in body mass index, fat mass, fat free mass, insulin-like growth factor 1, insulin-like growth factor binding protein 3, fasting insulin, triglycerides, estradiol, or estrone levels. CONCLUSION: In girls with TS, TDEs may be associated with a more beneficial effect on fasting glucose, cholesterol, and whole-body BMD. However, OEs have a more favorable impact on LDL-C and HDL-C. 17 beta estradiol has a more favorable effect on LDL-C. ABBREVIATIONS: BMI = body mass index BMD = bone mineral density CI = confidence interval HDL-C = high density lipo-protein-cholesterol IGF-1 = insulin-like growth factor 1 IGF-BP3 = insulin-like growth factor binding protein 3 LDL-C = low density lipoprotein cholesterol MD = mean difference OE = oral estrogen RCT = randomized controlled trial TDE = transdermal estrogen TS = Turner syndrome. PMID- 28095043 TI - SERUM INSULIN-LIKE GROWTH FACTOR 1 IN LEBANESE SCHOOLCHILDREN AND ITS RELATION TO VITAMIN D AND FERRITIN LEVELS. AB - OBJECTIVE: The aims of our study were to establish reference values for insulin like growth factor 1 (IGF-1) in Lebanese schoolchildren and to evaluate the relationship between IGF-1 and age, sex, body mass index (BMI), vitamin D, and ferritin. METHODS: This cross-sectional study included 952 Lebanese schoolchildren (495 boys and 457 girls) aged 8 to 18 years. Blood samples were taken from children attending 10 schools with different socio-economic status (SES). Chemiluminescent immunoassays were used for IGF-1, 25 hydroxyvitamin D (25(OH)D), testosterone, and ferritin measurements. RESULTS: The mean age was 13.46 +/- 2.80 with no significant difference according to sex. IGF-1 was correlated with age in both sexes (P<.0001); it was higher in girls compared to boys (P = .007) and peaked at the ages of 14 and 12 for boys and girls, respectively. For each age group, the median IGF-1 value was higher compared to the values provided by the kit. IGF-1 was significantly correlated with BMI in boys (r = 0.16, P<.0001) but not girls. In both sexes, IGF-1 was inversely correlated with 25(OH)D and ferritin values. After adjustment for age, BMI, and height, the correlation between IGF-1 and 25(OH)D disappeared, whereas the relationship with ferritin persisted (P<.001 for boys, P = .002 for girls). For both sexes, multivariate regression analysis revealed independent associations between IGF-1 and height, Tanner stage, and ferritin. An association was also noted in boys for BMI and testosterone. CONCLUSION: Our results showed higher and earlier peak IGF-1 values in the pediatric Lebanese population compared to western populations. In addition, an independent inverse relationship was observed between IGF-1 and ferritin. Further studies are needed to identify the reason(s) underlying these results. ABBREVIATIONS: BMI = body mass index CRP = C reactive protein CV = coefficient of variation GH = growth hormone IGF-1 = insulin-like growth factor 1 25(OH)D = 25 hydroxyvitamin D SES = socio-economic status TSH = thyroid-stimulating hormone. PMID- 28095042 TI - GAUGING THE EXTENT OF THYROIDECTOMY FOR INDETERMINATE THYROID NODULES: AN ONCOLOGIC PERSPECTIVE. AB - OBJECTIVE: Increasing emphasis is being placed on appropriateness of care and avoidance of over- and under-treatment. Indeterminate thyroid nodules (ITNs) present a particular risk for this problem because cancer found via diagnostic lobectomy (DL) often requires a completion thyroidectomy (CT). However, initial total thyroidectomy (TT) for benign ITN results in lifelong thyroid hormone replacement. We sought to measure the accuracy and factors associated with the extent of initial thyroidectomy for ITN. METHODS: We queried a single institution thyroid surgery database for all adult patients undergoing an initial operation for ITN. Multivariate logistic regression identified factors associated with either oncologic under- or overtreatment at initial operation. RESULTS: There were 639 patients with ITN. The median age was 52 (range, 18 to 93) years, 78.4% were female, and final pathology revealed a cancer >1 cm in 24.7%. The most common cytology was follicular neoplasm (45.1%) followed by Hurthle cell neoplasm (20.2%). CT or initial oncologic undertreatment was required in 58 patients (9.3%). Excluding those with goiters, 19.0% were treated with TT for benign final pathology. Multivariate analysis failed to identify any factor that independently predicted the need for CT. Female gender was associated with TT in benign disease (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0 to 4.5; P = .05). Age >45 years predicted correct initial use of DL (OR, 2.6; 95% CI, 1.2 to 5.7; P = .02). Suspicious for papillary thyroid carcinoma (OR, 5.7; 95% CI, 2.1 to 15.3; P<.01) and frozen section (OR, 9.7; 95% CI, 2.5 to 38.6; P<.01) were associated with oncologically appropriate initial TT. The highest frequency of CT occurred in patients with follicular lesion of undetermined significance (11.6%). TT for benign final pathology occurred most frequently in patients with a Hurthle cell neoplasm (24.8%). CONCLUSION: In patients with ITN, nearly 30% received an inappropriate extent of initial thyroidectomy from an oncologic standpoint. Tools to pre-operatively identify both benign and malignant disease can assist in the complex decision making to gauge the proper extent of initial surgery for ITN. ABBREVIATIONS: ATA = American Thyroid Association AUS = atypia of undetermined significance CI = confidence interval CT = completion thyroidectomy FLUS = follicular lesion of undetermined significance ITN = indeterminate thyroid nodule OR = odds ratio PTC = papillary thyroid carcinoma TT = total thyroidectomy. PMID- 28095044 TI - VITAMIN D BINDING PROTEIN AND 25-HYDROXYVITAMIN D LEVELS: EMERGING CLINICAL APPLICATIONS. AB - : The precursor of the active form of vitamin D, 25-hydroxyvitamin D (25(OH)D), is recognized as the optimal indicator of vitamin D status. Vitamin D3 undergoes conversion through a multitude of enzymatic reactions described within the paper, and vitamin D levels are dependent on many factors including the vitamin D binding protein (DBP). The free hormone hypothesis postulates that protein-bound hormones are not biologically available and that unbound hormones are biologically active. The majority of circulating 25(OH)D and 1,25 dihydroxyvitamin D is tightly bound to DBP and albumin, with less than 1% circulating in an unbound form. As a result, factors affecting DBP alter the interpretation of 25(OH)D levels. The aim of this review is to assess the current methodology used to measure total and free 25(OH)D, and DBP. Additionally, we analyze the effects of other endocrine hormones and disease processes on DBP levels and subsequently, the interpretation of 25(OH)D levels. ABBREVIATIONS: CF = cystic fibrosis DBP = vitamin D binding protein ELISA = enzyme-linked immunosorbent assay ESLD = end-stage liver disease HC = hormone contraceptives iPTH = intact parathyroid hormone LC-MS = liquid chromatography-mass spectrometry MS = multiple sclerosis 25(OH)D = 25-hydroxyvitamin D PHPT = primary hyperparathyroidism RIA = radioimmunoassay. PMID- 28095045 TI - WHAT IS THE CLINICAL ROLE OF ORAL LIQUID PREPARATIONS IN THE TREATMENT OF PATIENTS WITH HYPOTHYROIDISM? PMID- 28095046 TI - DOES VITAMIN D METABOLITE MEASUREMENT HELP PREDICT 25(OH)D CHANGE FOLLOWING VITAMIN D SUPPLEMENTATION? AB - OBJECTIVE: Variability in 25-hydroxyvitamin D (25(OH)D) change following vitamin D supplementation exists. Vitamin D metabolite measurement might assist in predicting 25(OH)D response and also contribute to defining vitamin D adequacy. This study assessed utility of vitamin D metabolite measurements to predict 25(OH)D response and explored the relationship between parathyroid hormone (PTH) and a "vitamin D composite index" comprised of the sum of serum 25(OH) D, cholecalciferol (vitamin D3) and 24,25 dihydroxyvitamin D (24,25(OH)2D). METHODS: Sixty-two postmenopausal women were randomized to daily vitamin D3 1,800 IU or placebo for 4 months. Blood was drawn at baseline and after 1 and 4 months. Serum 25(OH)D, vitamin D3, and 24,25(OH)2D were measured by liquid chromatography tandem mass spectroscopy. Free 25(OH)D and PTH were measured by enzyme-linked immunosorbent assay. Repeated measures analysis of variance and regression analyses were performed. RESULTS: Baseline 25(OH)D was positively correlated (P<.05) with vitamin D3, 24,25(OH)2D and free 25(OH) D. Daily vitamin D supplementation increased all metabolites (P<.001). Substantial individual variability in 25(OH) D change at 4 months was observed but was unrelated to baseline vitamin D3, 25(OH)D or 24,25(OH)2D. Only body mass index, body weight, and body fat mass was associated with 25(OH)D change at 4 months. The vitamin D composite score was associated with serum PTH, but this association was similar to that observed with 25(OH) D alone. CONCLUSION: This study does not support measurement of vitamin D metabolites in a composite index to assist in prediction of 25(OH)D response to supplementation. Overweight individuals have less robust 25(OH) D response to supplementation, but variability precludes prediction of the result following daily supplementation. ABBREVIATIONS: BMI = body mass index DXA = dual-energy X-ray absorptiometry LC-MS/MS = liquid chromatography tandem mass spectroscopy 25(OH)D = 25-hydroxyvitamin D 24,25(OH)2D = 24,25 dihydroxyvitamin D PTH = parathyroid hormone vitamin D3 = cholecalciferol. PMID- 28095047 TI - NIFTP: COMMENTARY ON AN EVOLVING ENTITY. PMID- 28095048 TI - AN APPROACH TO USING DATA MINING TO SUPPORT EARLY IDENTIFICATION OF ACROMEGALY. AB - OBJECTIVE: Data mining using insurance claims presents an opportunity to incorporate new analytic techniques in identifying rare conditions. This study aims to identify dyads of clinical conditions associated with acromegaly that may, with further validation and testing, be used to initially identify and diagnose this rare disease more accurately and efficiently. METHODS: This case control study used two claims databases to identify acromegaly patients (cases) (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]: 253.0) from 2008-2013. Each case was assigned two nonacromegaly controls (same age, gender, and region). Matched patients were randomly split into development and validation datasets. With expert clinician input, we isolated common associated conditions using ICD-9-CM codes. We identified all 2 way combinations of these conditions (dyads) and calculated the rate and risk relative (RR) to controls. Dyads meeting certain criteria (case rate >=5% [or >=1% if RR >=5] or observed RR > expected) were replicated in the validation dataset to confirm results. RESULTS: We identified 3,731 cases and 7,462 controls: mean age 41.8 (SD, 16.1) years, 51.8% female. A total of 32 and 38 dyads, reduced from 630, met study criteria. Among replicated dyads, case rates varied -15.9% (hypertension and metabolic disorder) to 0.6% (arthritis and menstrual abnormalities). The highest RRs (e.g., valvular insufficiency and colon polyps [RR, 13.5; rate, 0.7%]) also exceeded expected values. Replication showed similar RR direction and size. CONCLUSION: This novel analytic approach revealed several dyads that were significantly associated with an acromegaly diagnosis. Presence of high-risk condition pairs, if verified by a detailed data source (e.g., medical charts), may be incorporated into screening tools or serve as potential markers for physicians to consider an acromegaly diagnosis. ABBREVIATIONS: ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification ID = identification RR = relative risk. PMID- 28095049 TI - Visual Vignette. PMID- 28095050 TI - The Expressions of Klotho Family Genes in Human Ocular Tissues and in Anterior Lens Capsules of Age-Related Cataract. AB - PURPOSE: Klotho genes are expressed in limited tissues and have been found to be a pathogenic factor of age-related diseases in mammals, but their expressions and functions in human eyes are yet to be defined. This study was performed to investigate the expression of Klotho family genes in human ocular tissues and anterior lens capsules of age-related cataract. METHODS: Individual tissues were isolated from human eyeballs collected from Henan Eye Bank. Human anterior lens capsules were collected from cortical cataract patients during phacoemulsification with the informed consent. Real-time quantitative reverse transcription was performed to detect the mRNA expressions of alpha-Klotho, beta Klotho, gamma-Klotho, IGFR1, AKT, and ERK; Western blot analysis for detecting the expression of ERK1/2 and phosphor-ERK1/2 protein; and Pearson correlation analysis was performed to detect the relationship between Klotho genes and IGFR1, AKT or ERK genes. RESULTS: The expressions of alpha-, beta-, and gamma-Klotho mRNA were detected in human retina and optic nerve, but were not detected in iris, ciliary body, sclera, and choroid. Only alpha-and gamma-Klotho mRNA expressions were detected in the lens, and the expression levels were higher than that in the retina and optic nerve. The mRNA expressions of IGFR1 and AKT were not changed among the transparent and the opaque lens capsules. The mRNA expression of ERK was significantly decreased in the opaque lens capsule. Correlation analysis showed that the ERK mRNA expression was positively correlated with the expression of the gamma-Klotho gene. Western blot results showed a significant decrease of ERK1/2 and phosphor-ERK1/2 protein in opaque lens capsules. CONCLUSIONS: alpha- and gamma-Klotho genes express in the human retina, optic nerve, and lens. The beta-Klotho gene expresses only in retina and optic nerve. The gamma-Klotho gene may regulate human lens epithelial cells' function mainly by the MAPK/ERK1/2 signaling pathway. PMID- 28095051 TI - Improving personal self-advocacy skills for individuals with brain injury: A randomized pilot feasibility study. AB - OBJECTIVE: To investigate the feasibility of a self-advocacy intervention for individuals with acquired brain injury (ABI). DESIGN: Two-arm, parallel-design, randomized feasibility study. METHODS: Twelve participants, 1-year or more post ABI (TBI and cerebral vascular accident (CVA)), were randomized into treatment/control groups. The treatment group received a group intervention and workbook; the control group received the workbook only. Outcome measures, taken at baseline, post-treatment and 6-weeks follow-up, included the General Self Efficacy Scale (GSES), Satisfaction with Life Scale (SWLS) and Goal Attainment Scale (GAS) and two exploratory measures developed for the study: the Self Advocacy Scale (SAS) and the Personal Advocacy Activity Scale (PAAS). RESULTS: Participants were successfully recruited and treated per protocol. The treatment group exhibited improvements from baseline to post-treatment on all measures; the control group improved on the GSES and declined on all others. Both groups exhibited improvement on all measures at follow-up, except the PAAS, which declined. There were no significant group differences on non-parametric analysis at any assessment points; however, the magnitude of change at post-treatment approached significance for the SAS and PAAS. CONCLUSIONS: Initial feasibility for the methodology was demonstrated. Positive trends were noted. Further research could result in an evidence-based intervention to enhance self-advocacy post-ABI. PMID- 28095052 TI - Increased gamma connectivity during working memory retention following traumatic brain injury. AB - PRIMARY OBJECTIVE: Alterations to functional connectivity following a traumatic brain injury (TBI) may lead to impaired cognitive performance and major depressive disorder (MDD). In particular, functional gamma band connectivity is thought to reflect information binding important for working memory. The objective of this study was to determine whether altered functional gamma connectivity may be a factor in MDD following TBI (TBI-MDD). RESEARCH DESIGN: This study assessed individuals with TBI-MDD, as well as individuals with TBI alone and MDD alone using electroencephalographic recordings while participants performed a working memory task to assess differences in functional connectivity between these groups. METHODS AND PROCEDURES: Functional connectivity was compared using the debiased weighted phase lag index (wPLI). wPLI was measured from a group of healthy controls (n = 31), participants with MDD (n = 17), participants with TBI (n = 20) and participants with TBI-MDD (n = 15). MAIN OUTCOMES AND RESULTS: Contrary to the predictions, this study found both the groups with TBI and TBI-MDD showed higher gamma connectivity from posterior regions during WM retention. CONCLUSIONS: This may reflect dysfunctional functional connectivity in these groups, as a result of maladaptive neuroplastic reorganization. PMID- 28095054 TI - Adolescent Siblings of Individuals With and Without Intellectual and Developmental Disabilities: Self-Reported Empathy and Feelings About Their Brothers and Sisters. AB - Siblings of brothers or sisters with intellectual and developmental disabilities (IDD) are important but understudied family members. As many previous studies have relied on parent report of sibling outcomes, the use of sibling self-report is an important addition to the research. This study assessed the feelings of adolescent siblings toward their brothers or sisters with and without IDD, as well as broader aspects of sibling empathy. Data were collected via a national, online survey from 97 parent-sibling pairs. Siblings of individuals with IDD reported higher levels of anxiety toward the target child than did siblings of typically developing individuals. Sibling feelings toward the target child were related to both parental and target child factors, but only among families of individuals with IDD. PMID- 28095056 TI - Correlates of Adaptive Functioning in Minimally Verbal Children With Autism Spectrum Disorder. AB - Individuals with autism spectrum disorder (ASD) tend to have significant delays in adaptive functioning. In this study, the relationship between adaptive behavior and ASD symptomatology was investigated in minimally verbal, school-aged children with ASD (n = 333). Both the social affect (SA) and restricted and repetitive behavior (RRB) domains from the Autism Diagnostic Observation Schedule (ADOS) were analyzed in relation to adaptive skills. ADOS SA scores contributed unique variance to scores in each Vineland domain, though cognitive ability and age accounted for considerably more variance across domains. Results indicate that there is a significant, but small, association between social affect deficits and adaptive skills, challenging clinicians, educators, and caregivers to target adaptive skills in addition to more specific features of ASD. PMID- 28095057 TI - Age of Parental Concern, Diagnosis, and Service Initiation Among Children With Autism Spectrum Disorder. AB - Children with autism spectrum disorder (ASD) require substantial support to address the core symptoms of ASD and co-occurring behavioral/developmental conditions. This study explores the early diagnostic experiences of school-aged children with ASD using survey data from a large probability-based national sample. Multivariate linear regressions were used to examine age when parent reported developmental concern to doctor, received ASD diagnosis, and first obtained services. Children whose parents had concerns about their child's verbal communication reported earlier ages for all outcomes when compared to children of parents who did not have verbal communication concerns. Children whose parents had concerns about their child's nonverbal communication or unusual gestures/movements received an earlier diagnosis than children whose parents did not have these specific concerns. PMID- 28095058 TI - Efficacy of Peer Support Arrangements to Increase Peer Interaction and AAC Use. AB - Supporting interaction in inclusive settings between students with complex communication needs (CCN) and their peers requires careful planning and support. We used a multiple-probe-across-participants design to investigate the efficacy of collaborative planning and peer support arrangements to increase peer interaction in inclusive classrooms. Participants were four middle school students with CCN who had an intellectual disability and used an iPad with Proloquo2Go as augmentative and alternative communication (AAC). Educational teams comprised of a special educator, general educator, paraprofessional, and speech-language pathologist participated in collaborative planning for the intervention. For all four students, the intervention substantially increased communication to and from their peers. AAC use increased for one student. We offer implications for research and practice on supporting social interaction in general education settings. PMID- 28095059 TI - What's the Harm? Harms in Research With Adults With Intellectual Disability. AB - Scientific advances can improve the lives of adults with intellectual disability, yet concerns that research participation may impose harm impede scientific progress. What counts as harmful can be subjective and perceptions of harm may vary among stakeholders. We studied perspectives on the harmfulness of research events among adults with intellectual disability, family members and friends, disability service providers, researchers, and Institutional Review Board members. We found considerable variance. For example, adults with intellectual disability see exclusion from research as more harmful, but most psychosocial harms as less significant than others. All stakeholders agree that having someone else make the participation decision is harmful. Findings provide insights into the concept of harm and ethical research with adults with intellectual disability. PMID- 28095061 TI - Methods of Monitoring Training Load and Their Relationships to Changes in Fitness and Performance in Competitive Road Cyclists. AB - PURPOSE: To assess the dose-response relationships between different training load methods and aerobic fitness and performance in competitive road cyclists. METHODS: Training data from 15 well-trained competitive cyclists were collected during a 10-wk (December-March) preseason training period. Before and after the training period, participants underwent a laboratory incremental exercise test with gas-exchange and lactate measures and a performance assessment using an 8 min time trial (8MT). Internal training load was calculated using Banister TRIMP, Edwards TRIMP, individualized TRIMP (iTRIMP), Lucia TRIMP (luTRIMP), and session rating of perceived exertion (sRPE). External load was measured using Training Stress Score (TSS). RESULTS: Large to very large relationships (r = .54-.81) between training load and changes in submaximal fitness variables (power at 2 and 4 mmol/L) were observed for all training-load calculation methods. The strongest relationships with changes in aerobic fitness variables were observed for iTRIMP (r = .81 [95% CI .51-.93, r = .77 [95% CI .43-.92]) and TSS (r = .75 [95% CI .31 .93], r = .79 [95% CI .40-.94]). The strongest dose-response relationships with changes in the 8MT test were observed for iTRIMP (r = .63 [95% CI .17-.86]) and luTRIMP (r = .70 [95% CI .29-.89). CONCLUSIONS: Training-load quantification methods that integrate individual physiological characteristics have the strongest dose-response relationships, suggesting this to be an essential factor in the quantification of training load in cycling. PMID- 28095060 TI - Executive Functioning Mediates the Effect of Behavioral Problems on Depression in Mothers of Children With Developmental Disabilities. AB - The present investigation explored long-term relationships of behavioral symptoms of adolescents and adults with developmental disabilities with the mental health of their mothers. Fragile X premutation carrier mothers of an adolescent or adult child with fragile X syndrome (n = 95), and mothers of a grown child with autism (n = 213) were included. Behavioral symptoms at Time 1 were hypothesized to predict maternal depressive symptoms at Time 3 via maternal executive dysfunction at Time 2. Results provided support for the mediating pathway of executive dysfunction. Additionally, the association of behavioral symptoms with executive dysfunction differed across the two groups, suggesting that premutation carriers may be more susceptible to caregiving stress due to their genotype. PMID- 28095062 TI - MicroRNA-196a as a Potential Diagnostic Biomarker for Esophageal Squamous Cell Carcinoma. AB - We observed significant up-regulation of miR-196a in esophageal squamous cell carcinoma (ESCC) as compared with their adjacent normal tissue (p = .002). Receiver operating characteristics curve analysis confirmed the suitability of miR-196a as a potential tumor marker for diagnosis of ESCC. Furthermore, analysis of miR-196a levels in saliva samples determined an average of 27-fold up regulations in ESCC patients compared with healthy group. Our results suggest that salivary miR-196a may be a suitable noninvasive biomarker for diagnosis of ESCC. In addition, molecular pathway enrichment analysis of microRNA (miR)-196a determined focal adhesion, spliceosome and p53 signaling pathways as the most relevant pathways with miR-196a targetome. PMID- 28095063 TI - Early primary care follow-up after ED and hospital discharge - does it affect readmissions? AB - OBJECTIVES: After hospitalization, timely discharge follow-up has been linked to reduced readmissions in the heart failure population, but data from general inpatients has been mixed. The objective of this study was to determine if there was an association between completed follow-up appointments within 14 days of hospital discharge and 30-day readmission amongst primary care patients at an urban academic medical center. Index discharges included both inpatient and emergency room settings. A secondary objective was to identify patient factors associated with completed follow-up appointments within 14 days. METHODS: We conducted a retrospective review of primary care patients at an urban academic medical center who were discharged from either the emergency department (ED) or inpatient services at the Weill Cornell Medical Center/New York Presbyterian Hospital from 1 January 2014-31 December 2014. Cox proportional hazard models were used to identify the relationship between follow-up in primary care within 14 days and readmission within 30 days. Logistic regression was used to evaluate the association of patient factors with 14-day follow-up. RESULTS: Among 9,662 inpatient and ED discharges, multivariable analysis (adjusting for age, gender, race/ethnicity, insurance, number of diagnoses on problem list, length of stay, and discharge service) showed that follow-up with primary care within 14 days was not associated with a lower hazard of readmission within 30 days (HR = 0.78; 95% CI 0.56-1.09). A higher number of diagnoses on the problem list was associated with greater odds of follow-up for both inpatient and emergency department discharges (inpatient: HR = 1.03, 95% CI 1.02-1.04; ED: HR = 1.02, 95% CI 1.00 1.04). For inpatient discharges, each additional day in length of stay was associated with 3% lower odds of follow-up (HR = 0.97, 95% CI 0.96-0.99). CONCLUSION: Early follow-up within 14 days after discharge from general inpatient services was associated with a trend toward lower hazard of 30-day readmission though this finding was not significant. Future studies should focus on identifying additional cohorts of patients in which readmission is reduced by early follow-up, so that access to primary care appointments is not compromised. PMID- 28095064 TI - Adipokines induce catabolism of newly synthesized matrix in cartilage and meniscus tissues. AB - PURPOSE: Altered synovial levels of various adipokines (factors secreted by fat as well as other tissues) have been associated with osteoarthritis (OA) onset and progression. However, the metabolic effects of adipokines on joint tissues, in particular the fibrocartilaginous menisci, are not well understood. This study investigated effects of several adipokines on release of recently synthesized extracellular matrix in bovine cartilage and meniscus tissue explants. MATERIALS AND METHODS: After labeling newly synthesized proteins and sulfated glycosaminoglycans (sGAGs) with 3H-proline and 35S-sulfate, respectively; bovine cartilage and meniscus tissue explants were cultured for 6 days in basal medium (control) or media supplemented with adipokines (1 ug/ml of leptin, visfatin, adiponectin, or resistin) or 20 ng/ml interleukin-1 (IL-1). Release of radiolabel and sGAG to the media during culture and the final explant water, DNA, sGAG, and retained radiolabel were measured. Matrix metalloproteinase (MMP-2) and MMP-3 activities were assessed using gelatin and casein zymography, respectively. RESULTS: Water and DNA contents were not significantly altered by any treatment. Visfatin, adiponectin, resistin, and IL-1 stimulated sGAG release from meniscus, whereas only IL-1 stimulated sGAG release from cartilage. Release of 3H and 35S was stimulated not only by resistin and IL-1 in meniscus but also by IL-1 in cartilage. Retained 3H was unaltered by any treatment, while retained 35S was reduced by visfatin, resistin, and IL-1 in meniscus and by only IL-1 in cartilage. Resistin and IL-1 elevated active MMP-2 and total MMP-3 in meniscus, whereas cartilage MMP-3 activity was elevated by only IL-1. CONCLUSIONS: Resistin stimulated rapid and extensive catabolism of meniscus tissue, similar to IL-1, whereas adipokines minimally affected cartilage. Release of newly synthesized matrix was similar to overall release in both tissues. These observations provide further indications that meniscal tissue is more sensitive to pro-inflammatory factors than cartilage and also suggest further study of resistin's role in OA. PMID- 28095065 TI - Monitoring Fatigue Status in Elite Team-Sport Athletes: Implications for Practice. AB - The increase in competition demands in elite team sports over recent years has prompted much attention from researchers and practitioners to the monitoring of adaptation and fatigue in athletes. Monitoring fatigue and gaining an understanding of athlete status may also provide insights and beneficial information pertaining to player availability, injury, and illness risk. Traditional methods used to quantify recovery and fatigue in team sports, such as maximal physical-performance assessments, may not be feasible to detect variations in fatigue status throughout competitive periods. Faster, simpler, and nonexhaustive tests such as athlete self-report measures, autonomic nervous system response via heart-rate-derived indices, and to a lesser extent, jump protocols may serve as promising tools to quantify and establish fatigue status in elite team-sport athletes. The robust rationalization and precise detection of a meaningful fluctuation in these measures are of paramount importance for practitioners working alongside athletes and coaches on a daily basis. There are various methods for arriving at a minimal clinically important difference, but these have been rarely adopted by sport scientists and practitioners. The implementation of appropriate, reliable, and sensitive measures of fatigue can provide important information to key stakeholders in team-sport environments. Future research is required to investigate the sensitivity of these tools to fundamental indicators such as performance, injury, and illness. PMID- 28095066 TI - Association of Osteopontin Gene Polymorphisms with Colorectal Cancer. AB - We investigated the association of the Osteopontin (OPN) (rs9138 and rs1126616) polymorphisms with colorectal cancer (CRC). One hundred CRC patients and 112 healthy individuals were subjected to OPN (rs9138 and rs1126616) genotyping and measurement of OPN protein plasma level. The C allele of OPN rs1126616 and the CC haplotype were significantly higher in CRC patient (p = 0.036, 0.003, respectively). In females, the C allele of OPN rs9318 (A/C) polymorphism was significantly associated with increased CRC risk (p = 0.036). The plasma OPN level >104.35 ng/mL was significantly associated with CRC. Our findings suggest a significant role played by OPN (rs9138 and rs1126616) in colorectal carcinogenesis. PMID- 28095067 TI - Pacing Strategies and Metabolic Responses During 4-Minute Running Time Trials. AB - PURPOSE: The aim of the current study was to investigate pacing strategies and the distribution of physiological resources in best vs worst performances during a series of 4-min self-paced running time trials (RunTTs). METHODS: Five male and 5 female recreational runners (age 32 +/- 7 y) completed a submaximal ramp test and 5 RunTTs on a motor-driven treadmill fitted with a speed-controlling laser system. The supramaximal oxygen-uptake (VO2) demand was estimated by linear extrapolation from the submaximal relationship between VO2 and speed, enabling computation of the accumulated oxygen deficit. RESULTS: There were no significant differences between the 5 RunTTs for any of the performance, physiological, or subjective responses (P > .05). The trial-to-trial variability in pacing (ie, separate quarters) was typically low, with an average within-athlete coefficient of variation of 3.3%, being highest at the start and end of the 4 min. Total distance covered and distance covered over the first and last 2 min for best and worst performances were 1137 +/- 94 and 1090 +/- 89 (P < .001), 565 +/- 53 and 526 +/- 40 m (P = .002), and 572 +/- 47 and 565 +/- 54 m (P = .346), respectively. CONCLUSIONS: Negative pacing strategies were evident during both the best and the worst performances of the RunTT. Best performances were characterized by more aggressive pacing over the first 2 min compared with worst performances. In addition, the relatively low trial-to-trial variability in running speed suggests that pacing strategies are similar during a series of 4 min self-paced running time trials. PMID- 28095068 TI - Impact of telepharmacy services as a way to increase access to asthma care. AB - OBJECTIVE: To demonstrate that real-time, telepharmacy-based asthma educational services are feasible and to support the efforts of local primary care prescribers to improve patient outcomes. METHODS: The lead investigator (a pharmacist, physician assistant, and certified asthma educator) identified an independent community pharmacy with telehealth capabilities in a rural area with a high prevalence of asthma. Working with the pharmacy, an asthma education program was developed based on the National Asthma Education and Prevention Program guidelines. It consisted of three monthly education visits, with subsequent visits every three months for one year. The Asthma Control Test (ACT) was administered at baseline and at each visit to assess a patient's perception of asthma control. RESULTS: Eighteen of 20 patients (90%) with reversible airway disease completed all six visits in this year-long study. For the 18 patients, the mean ACT scores of 18 at baseline (initiation of intervention) did not meet the threshold for "well-controlled" asthma. By the third educational visit (3 months), 16 patients met ACT criteria for well-controlled asthma (mean score = 20), and they maintained control for the remaining 9-month follow-up period (ACT >= 21). Local prescribers authorized medication changes recommended by the asthma educator 20 times and also requested six direct consults with the asthma educator over the study period. CONCLUSION: Using the local community pharmacy as a vehicle to deliver asthma education services by telepharmacy was utilized by local prescribers. The findings show this is an effective means to engage patients to gain and maintain asthma control. PMID- 28095069 TI - The Evolution of Champion Cross-Country-Skier Training: From Lumberjacks to Professional Athletes. AB - Competitive cross-country (XC) skiing has traditions extending back to the mid 19th century and was included as a men's event in the first Winter Games in 1924. Since then, tremendous improvements in equipment, track preparation, and knowledge about training have prompted greater increases in XC-skiing speeds than in any other Olympic sport. In response, this commentary focuses on how the training of successful XC skiers has evolved, with interviews and training data from surviving Norwegian world and Olympic XC champions as primary sources. Before 1970, most male champion XC skiers were lumberjacks who ran or skied long distances to and from felling areas while working long days in the woods. In addition, they trained as much as possible, with increased intensity during the autumn, while less work but more ski-specific training and competitions were done during the winter. Until the 1970s, few XC skiers were women, whom coaches believed tolerated less training than men did. Today's XC skiers are less physically active, but the influence of both science and the systematic approaches of former athletes and coaches have gradually taught XC skiers to adopt smarter, more goal-oriented training practices. Although the very high VO2max of world-class XC skiers has remained the same since the 1960s, new events in modern XC skiing have additionally required superior upper-body power, high speed techniques, and tactical flexibility. These elements also emerge in the training of today's best skiers; women's physiological capacities and training routines especially seem to have improved dramatically. PMID- 28095070 TI - Player Responses to Match and Training Demands During an Intensified Fixture Schedule in Professional Rugby League: A Case Study. AB - Player loads and fatigue responses are reported in 15 professional rugby league players (24.3 +/- 3.8 y) during a period of intensified fixtures. Repeated measures of internal and external loads, perceived well-being, and jump flight time were recorded across 22 d, comprising 9 training sessions and matches on days 5, 12, 15, and 21 (player exposure: 3.6 +/- 0.6 matches). Mean training loads (session rating of perceived exertion * duration) between matches were 1177, 1083, 103, and 650 AU. Relative distance in match 1 (82 m/min) and match 4 (79 m/min) was very likely lower in match 2 (76 m/min) and likely higher in match 3 (86 m/min). High-intensity running (>=5.5 m/s) was likely to very likely lower than match 1 (5 m/min) in matches 2-4 (2, 4, and 3 m/min, respectively). Low intensity activity was likely to very likely lower than match 1 (78 m/min) in match 2 (74 m/min) and match 4 (73 m/min) but likely higher in match 3 (81 m/min). Accumulated accelerometer loads for matches 1-4 were 384, 473, 373, and 391 AU, respectively. Perceived well-being returned to baseline values (~21 AU) before all matches but was very likely to most likely lower the day after each match (~17 AU). Prematch jump flight times were likely to most likely lower across the period, with mean values of 0.66, 0.65, 0.62, and 0.64 s before matches 1-4, respectively. Across a 22-d cycle with fixture congestion, professional rugby league players experience cumulative neuromuscular fatigue and impaired match running performance. PMID- 28095071 TI - Mevalonate kinase deficiency associated with ataxia and retinitis pigmentosa in two brothers with MVK gene mutations. AB - PURPOSE: To report the clinical and molecular genetic findings in two brothers with retinitis pigmentosa (RP) and mevalonate kinase deficiency (MKD). METHODS: The brothers were examined clinically and with fundus autofluorescence, near infrared autofluorescence, and spectral domain optical coherence tomography. Targeted resequencing was done with a custom designed gene panel containing 78 genes associated with RP. Mutations were confirmed by direct Sanger sequencing. RESULTS: Both brothers, aged 46 and 47 years, were found to carry compound heterozygous mutations in the MVK gene (c.59A>C, c.1000G>A) encoding mevalonate kinase. They presented with severe ataxia, pseudophakia due to early onset cataract, and progressed retinitis pigmentosa. In one brother with cystoid macular edema, treatment with dorzolamide was beneficial. Serum IgD levels were markedly increased in both brothers and mevalonic acid blood and urine levels were markedly increased in the one brother who could be examined. The disease severity differed between the brothers-one had more severe ataxia and less severe visual deficiency compared to the other. CONCLUSION: MKD can be associated with RP and early onset cataract. Most MKD patients developing RP carry the (p.Ala334Thr) mutation. Macular edema can be treated using local dorzolamide. PMID- 28095072 TI - Parental coping, depressive symptoms, and children's asthma control and school attendance in low-income, racially, and ethnically diverse urban families. AB - OBJECTIVE: Low-income urban children of color are at elevated risk for poor asthma control. This cross-sectional study examined associations among parents' coping (primary control, secondary control, and disengagement), parental depressive symptoms, and children's asthma outcomes (asthma control and school attendance) in a predominantly low-income, racially/ethnically diverse sample of families. METHODS: Parents (N = 78; 90% female) of children (33% female; 46% Black; 38% Latino) aged 5-17 years (M = 9.5 years) reported on their own coping and depressive symptoms, their child's asthma control, and full and partial days of school missed due to asthma. RESULTS: Parents' secondary control coping (i.e., coping efforts to accommodate/adapt to asthma-related stressors) was negatively correlated, and disengagement coping (i.e. coping efforts to avoid/detach from stressors) was positively correlated, with their depressive symptoms. Secondary control coping was also correlated with fewer partial days of school missed. Primary control coping (i.e., coping efforts to change stressors) was not associated with depressive symptoms or asthma outcomes. Parents' depressive symptoms were also positively correlated with poorer asthma control and partial days of school missed. Regression models showed direct and indirect effects of secondary control and disengagement coping on asthma outcomes via depressive symptoms, after controlling for demographic factors. CONCLUSIONS: Parents' secondary control and disengagement coping are related to children's asthma outcomes. Secondary control coping may support parents' mental health and children's asthma control in low-income urban families. PMID- 28095073 TI - Preclinical and Potential Applications of Common Western Herbal Supplements as Complementary Treatment in Parkinson's Disease. AB - Parkinson's disease (PD) is a neurological disorder with a complex pathological etiology, which is not fully understood. Progression of PD may be the result of a buildup of iron in the substantia nigra, microglia-mediated neuroinflammation, dysfunctional mitochondria, or abnormal protein handling. Dopamine is the main neurotransmitter affected, but as the disease progresses, a decrease in all the brain's biogenic amines occurs. Current medication used in the treatment of PD aims to prevent the breakdown of dopamine or increase dopaminergic neurotransmission in the central nervous system. The complementary use of green tea (Camellia sinensis), red wine (Vitis vinifera), arctic root (Rhodiola rosea), and dwarf periwinkle (Vinca minor) may have a greater therapeutic effect than current pharmaceutical drugs, such as monoamine oxidase inhibitors or dopamine agonists alone. The bioactive components of these plants have been shown to have neuroprotective, antioxidant, anti-proteinopathies, neural-vasodilation, anti inflammatory, and iron chelating potential. They may treat the disease at the cellular level by decreasing microglia activation, attenuating damage from radical oxygen species, supporting correct protein folding, chelating iron, increasing the substantia nigra blood flow, and promoting dopaminergic cell growth. Although these alternative medicines appear to have potential, further human clinical trials need to be conducted to determine whether they could have a greater therapeutic effect than conventional medicines alone. PMID- 28095074 TI - Effects of Cycling Training at Imposed Low Cadences: A Systematic Review. AB - The present article reviews effects of training at low imposed cadences in cycling. The authors performed a systematic literature search of MEDLINE and SPORTDiscus up to April 2016 to identify potentially relevant articles. Based on the titles and abstracts of the identified articles, a subset of articles was selected for evaluation. These articles constituted original-research articles on adaptation to training at different imposed cadences in cycling. Seven articles were selected for evaluation. With regard to the terminology in the present article, low cadences are those below the freely chosen cadence. The rate of 80 rpm can, eg, be considered a low cadence if effort is maximal. On the other hand, the cadence has to be lower than 80 rpm (eg, 40-70 rpm) to be considered low if cycling is performed at low power output. The reason is that the choice of cadence depends on power output. In conclusion, there is presently no strong evidence for a benefit of training at low cadences. It can tentatively be recommended to consider including training bouts of cycling at low cadence at moderate to maximal intensity. The reason for the restrained recommendation is that some of the selected studies indicate no clear performance-enhancing effect of training at low cadence or even indicate a superior effect from training at freely chosen cadence. Furthermore, the selected studies are considerably dissimilar with respect to, eg, participant characteristics and to the applied training regimens. PMID- 28095075 TI - A Pilot Study Using Entropy as a Noninvasive Assessment of Running. AB - PURPOSE: Running performance is influenced by the interaction of biomechanical and physiological factors. Miniaturized accelerometers worn by athletes can be used to quantify mechanical aspects of running and as a noninvasive tool to assess training status and progression. The aim of this study was to define and validate a method to assess running regularity and allow the estimation of an individual's oxygen uptake (VO2) and/or blood lactate-[La]b-based on data collected with accelerometers and heart rate. METHODS: Male adolescent endurance athletes completed an incremental submaximal aerobic stage test where VO2 and [La]b were measured. The test was terminated when [La]b concentration at the end of the stage exceeded 4 mmol/L. Two wireless triaxial accelerometers were placed on participants' right shank and lower back throughout the test. The root mean square (RMS) and sample entropy (SampEn) were calculated for the vertical, mediolateral, and anteroposterior components of acceleration. RESULTS: There were significant positive correlations of acceleration and entropy variables with [La]b and VO2, with moderate to high coefficients (r = .43-.87). RMS of the shank acceleration was the most highly related with both physiological variables. When the accelerometer was attached on the trunk, SampEn of the vertical acceleration had the strongest relationship with VO2 (r = .76, P < .01). CONCLUSIONS: The described method analyzing running complexity may allow an assessment of gait variability, which noninvasively tracks VO2 and/or [La]b, allowing monitoring of fatigue or training readiness for trained adolescent individuals. PMID- 28095076 TI - Impaired Player-Coach Perceptions of Exertion and Recovery During Match Congestion. AB - : During intensified phases of competition, attunement of exertion and recovery is crucial to maintain performance. Although a mismatch between coach and player perceptions of training load is demonstrated, it is unknown if these discrepancies also exist for match exertion and recovery. PURPOSE: To determine match exertion and subsequent recovery and to investigate the extent to which the coach is able to estimate players' match exertion and recovery. METHODS: Rating of perceived exertion (RPE) and total quality of recovery (TQR) of 14 professional basketball players (age 26.7 +/- 3.8 y, height 197.2 +/- 9.1 cm, weight 100.3 +/- 15.2 kg, body fat 10.3% +/- 3.6%) were compared with observations of the coach. During an in-season phase of 15 matches within 6 wk, players gave RPEs after each match. TQR scores were filled out before the first training session after the match. The coach rated observed exertion (ROE) and recovery (TQ-OR) of the players. RESULTS: RPE was lower than ROE (15.6 +/- 2.3 and 16.1 +/- 1.4; P = .029). Furthermore, TQR was lower than TQ-OR (12.7 +/- 3.0 and 15.3 +/- 1.3; P < .001). Correlations between coach- and player-perceived exertion and recovery were r = .25 and r = .21, respectively. For recovery within 1 d the correlation was r = .68, but for recovery after 1-2 d no association existed. CONCLUSION: Players perceive match exertion as hard to very hard and subsequent recovery reasonable. The coach overestimates match exertion and underestimates degree of recovery. Correspondence between coach and players is thus not optimal. This mismatch potentially leads to inadequate planning of training sessions and decreases in performance during fixture congestion in basketball. PMID- 28095078 TI - Diagnosis, classification, and therapeutic interventions for sinopulmonary Aspergillosis. AB - INTRODUCTION: Sinopulmonary aspergillosis represents a diverse collection of allergic, invasive, and chronic sinus and respiratory conditions. These diseases can affect patients with and without immune impairment and in some cases may be life-threatening. Areas covered: We review the diagnosis, classification, and therapeutic options available to treat sinopulmonary aspergillosis and look ahead to emerging diagnostic and therapeutic options that may soon play an important role in clinical practice. Expert commentary: Histopathology and tissue culture remain the gold standard for the diagnosis of invasive sinopulmonary aspergillosis, but several new molecular detection methods have recently emerged, including various PCR-based platforms, MALDI-TOF, and lateral flow assays. We examine these methodologies as well as the barriers associated with the standardization, validation, and implementation. We also explore the pipeline of antifungal agents in development to treat sinopulmonary aspergillosis. PMID- 28095077 TI - Running Performance With Nutritive and Nonnutritive Sweetened Mouth Rinses. AB - : Using mouth rinse (MR) with carbohydrate during exercise has been shown to act as an ergogenic aid. PURPOSE: To investigate if nutritive or nonnutritive sweetened MR affects exercise performance and to assess the influence of sweetness intensity on endurance performance during a time trial (TT). METHODS: This randomized, single-blinded study had 4 treatment conditions. Sixteen subjects (9 men, 7 women) completed a 12.8-km TT 4 different times. During each TT, subjects mouth-rinsed and expectorated a different solution at time 0 and every 12.5% of the TT. The 4 MR solutions were sucrose (S) (sweet taste and provides energy of 4 kcal/g), a lower-intensity sucralose (S1:1) (artificial sweetener that provides no energy but tastes sweet), a higher-intensity sucralose (S100:1), and water as control (C). Completion times for each TT, heart rate (HR), and ratings of perceived exertion (RPE) were also recorded. RESULTS: Completion time for S was faster than for C (1:03:47 +/- 00:02:17 vs 1:06:56 +/- 00:02:18, respectively; P < .001) and showed a trend to be faster vs S100:1 (1:03:47 +/- 00:02:17 vs 1:05:38 +/- 00:02:12, respectively; P = .07). No other TT differences were found. Average HR showed a trend to be higher for S vs C (P = .08). The only difference in average or maximum RPE was for higher maximum RPE in C vs S1:1 (P = .02). CONCLUSION: A sweet-tasting MR did improve endurance performance compared with water in a significant manner (mean 4.5% improvement; 3+ min.); however, the presence of energy in the sweet MR appeared necessary since the artificial sweeteners did not improve performance more than water alone. PMID- 28095079 TI - The use of ultrasound in the study of articulatory properties of vowels in clear speech. AB - Although the acoustic properties of clear speech have been extensively studied, its underlying articulatory details have not been well understood. The purpose of the present study is twofold: To examine the specific articulatory processes of clear speech using ultrasound and to investigate whether and how the type of listener (hard of hearing, normal hearing) and the lexical property of words (frequency) interact in the production of clear speech. To this end, we examined productions of /alpha/, /ae/ and /u/ from 16 speakers of US English. Overall, our ultrasound results suggested that the tongue's highest point moved in a direction that exaggerated the three vowels' phonological features, resulting in an expanded articulatory vowel space for the hard-of-hearing listener and low frequency words. No interaction was found between the listener and word frequency, suggesting that the effects of word frequency hold constant across the two types of listeners. PMID- 28095080 TI - Missed opportunities to transition from nebulizers to inhalers during hospitalization for acute asthma: A multicenter observational study. AB - OBJECTIVE: Hospitalizations for acute asthma are thought to be highly preventable through the use of efficacious medications, though many patients have poor metered-dose inhaler (MDI) techniques, thus lessening these medications' real world effectiveness. Teaching MDI techniques during hospitalization may therefore lead to improved outcomes. However, MDIs may be underutilized to deliver short acting beta-agonists (SABAs) in the inpatient setting, despite equivalent efficacy to nebulizer delivery. We sought to characterize delivery methods of SABAs among hospitalized patients with acute asthma to understand if there are missed opportunities for self-management education. METHODS: In this secondary analysis of a cross-sectional 25-center chart review study of children and adults (ages 2-54 years) hospitalized for acute asthma across 18 states (2012-2013), we studied SABA therapy delivery methods during hospitalization and receipt of action plans and follow-up visits. Unadjusted associations were analyzed using chi-square, Fisher's exact, or Kruskal-Wallis tests. MEASUREMENTS AND MAIN RESULTS: Of 987 patients, 44% received only nebulizer-SABA (children 32% vs. adults 53%; p < 0.001) during hospitalization, and 55% (children 68% vs. adults 47%; p < 0.001) received any MDI-SABA during hospitalization. Children receiving only nebulizer- vs. MDI-SABA were significantly less likely to receive individualized action plans (p < 0.001). Compared to children, adults were overall less likely to receive written plans (47% vs. 78%, p < 0.001) or to have a follow-up appointment (38% vs. 59%, p < 0.001) at discharge. CONCLUSIONS: Opportunities exist to increase the delivery of MDI-SABA during hospitalization, particularly for adult inpatients with asthma. Further studies are needed to determine if increased use of MDI-delivered therapies improves patient education and outcomes. PMID- 28095081 TI - The Influence of Blood Removal on Pacing During a 4-Minute Cycling Time Trial. AB - PURPOSE: To examine the influence of manipulating aerobic contribution after whole-blood removal on pacing patterns, performance, and energy contribution during self-paced middle-distance cycling. METHODS: Seven male cyclists (33 +/- 8 y) completed an incremental cycling test followed 20 min later by a 4-min self paced cycling time trial (4MMP) on 6 separate occasions over 42 d. The initial 2 sessions acted as familiarization and baseline testing, after which 470 mL of blood was removed, with the remaining sessions performed 24 h, 7 d, 21 d, and 42 d after blood removal. During all 4MMP trials, power output, oxygen uptake, and aerobic and anaerobic contribution to power were determined. RESULTS: 4MMP average power output significantly decreased by 7% +/- 6%, 6% +/- 8%, and 4% +/- 6% at 24 h, 7 d, and 21 d after blood removal, respectively. Compared with baseline, aerobic contribution during the 4MMP was significantly reduced by 5% +/ 4%, 4% +/- 5%, and 4% +/- 10% at 24 h, 7 d, and 21 d, respectively. The rate of decline in power output on commencement of the 4MMP was significantly attenuated and was 76% +/- 20%, 72% +/- 24%, and 75% +/- 35% lower than baseline at 24 h, 21 d, and 42 d, respectively. CONCLUSION: Removal of 470 mL of blood reduces aerobic energy contribution, alters pacing patterns, and decreases performance during self-paced cycling. These findings indicate the importance of aerobic energy distribution during self-paced middle-distance events. PMID- 28095082 TI - Effect of Concussion on Performance of National Football League Players. AB - PURPOSE: Lingering neurologic injury after concussion may expose athletes to increased risk if return to play is premature. The authors explored whether on field performance after concussion is a marker of lingering neurologic injury. DESIGN: Retrospective cohort study on 1882 skill-position players who played in the National Football League (NFL) during 2007-2010. METHODS: Players with concussion based on the weekly injury report were compared with players with other head and neck injuries (controls) on measures of on-field performance using Football Outsiders' calculation of defense-adjusted yards above replacement (DYAR), a measure of a player's contribution controlling for game context. Changes in performance, relative to a player's baseline level of performance, were estimated before and after injury using fixed-effects models. RESULTS: The study included 140 concussed players and 57 controls. Players with concussion performed no better or worse than their baseline on return to play. However, a decline in DYAR relative to their prior performance was noted 2 wk and 1 wk before appearing on the injury report. Concussed players performed slightly better than controls in situations where they returned to play the same week as appearing on the injury report. CONCLUSIONS: On return, concussed NFL players performed at their baseline level of performance, suggesting that players have recovered from concussion. Decline in performance noted 2 wk and 1 wk before appearing on the injury report may suggest that concussion diagnosis was delayed or that concussion can be a multihit phenomenon. Athletic performance may be a novel tool for assessing concussion injury and recovery. PMID- 28095083 TI - Physiological Capacity and Training Routines of Elite Cross-Country Skiers: Approaching the Upper Limits of Human Endurance. AB - Cross-country (XC) skiing is one of the most demanding of endurance sports, involving protracted competitions on varying terrain employing a variety of skiing techniques that require upper- and/or lower-body work to different extents. Through more effective training and extensive improvements in equipment and track preparation, the speed of cross-country ski races has increased more than that of any other winter Olympic sport, and, in addition, new types of racing events have been introduced. To a certain extent this has altered the optimal physiological capacity required to win, and the training routines of successful skiers have evolved accordingly. The long-standing tradition of researchers working closely with XC-ski coaches and athletes to monitor progress, improve training, and refine skiing techniques has provided unique physiological insights revealing how these athletes are approaching the upper limits of human endurance. This review summarizes current scientific knowledge concerning the demands involved in elite XC skiing, as well as the physiological capacity and training routines of the best athletes. PMID- 28095084 TI - Changes on Walking During Street Crossing Situations and on Dorsiflexion Strength of Older Caribbean Americans After an Exercise Program: A Pilot Study. AB - The objective of this pilot study was to evaluate a 6-month exercise program completed by 10 older Caribbean Americans. Assessments were done at baseline and 3 and 6 months, and included walks on an instrumented mat at preferred speed, and during street crossing simulations with regular (10 s) and reduced time (5 s). There were no significant differences on preferred walking speed over time. Differences between the street crossing conditions were found only at 6 months. Significant changes over time among the assessments were found only during street crossing with reduced time. Street crossing with reduced time was the only walking condition sensitive to capture changes associated with participating in the exercise program. There was a significant increase in dorsiflexion strength overtime. At 6 months it was significantly higher than at baseline and 3 months. The program was feasible, acceptable, and had some positive effects on walking, knee flexion, and dorsiflexion strength. PMID- 28095085 TI - Building Community: Stakeholder Perspectives on Walking in Malls and Other Venues. AB - Mall walking has been a popular physical activity for decades. However, little is known about why mall managers support these programs or why adults choose to walk. Our study aim was to describe mall walking programs from the perspectives of walkers, managers, and leaders. Twenty-eight walkers, 16 walking program managers, and six walking program leaders from five states participated in a telephone or in-person semi-structured interview (N = 50). Interview guides were developed using a social-ecological model. Interviews were recorded, transcribed verbatim, and analyzed thematically. All informants indicated satisfaction with their program and environmental features. Differences in expectations were noted in that walkers wanted a safe, clean, and social place whereas managers and leaders felt a need to provide programmatic features. Given the favorable walking environments in malls, there is an opportunity for public health professionals, health care organizations, and providers of aging services to partner with malls to promote walking. PMID- 28095086 TI - Retinal findings and a novel TINF2 mutation in Revesz syndrome: Clinical and molecular correlations with pediatric retinal vasculopathies. AB - BACKGROUND: Revesz syndrome is a telomere disorder in the dyskeratosis congenita (DKC) spectrum characterized by exudative retinopathy, bone marrow failure, neuroradiographic abnormalities, and integumentary findings. MATERIALS/METHODS: We report the ophthalmologic findings, documented by examinations under anesthesia with clinical photography and fluorescein angiography, as well as the systemic manifestations and genetic and molecular testing, in identical twins with Revesz syndrome, and compare and contrast these features to those of other pediatric retinal vasculopathies. RESULTS: Both twins exhibited widespread avascularity and anomalous vasculature of the retinal periphery, retinal telangiectasias, and exudation. One twin developed a combination exudative/tractional/rhegmatogenous retinal detachment, while the other exhibited a focal collection of buds of retinal neovascularization. Both twins developed bone marrow failure and were found to have cerebellar hypoplasia and widespread cerebral calcifications. Telomere testing in lymphocytes and granulocytes revealed telomere length less than the 1st percentile for age, and gene sequencing revealed a novel mutation in the TINF2 gene, resulting in the T284P TIN2 protein variant. CONCLUSIONS: We report ophthalmic findings in twins with Revesz syndrome due to a previously unreported mutation in TINF2 and propose that phenotypic and molecular overlaps between DKC spectrum disorders and pediatric retinal vasculopathies may reflect a shared pathophysiologic basis. PMID- 28095088 TI - Modeling Longitudinal Relationships Between Habit and Physical Activity: Two Cross-Lagged Panel Design Studies in Older Adults. AB - These longitudinal studies in older adults targeted mediated relationships between habit and physical activity (PA). In The Netherlands two independent studies were conducted among 1976 (Study 1: Mage = 63.63, SD = 8.66, 30% functional limitations) and 2140 (Study 2: Mage = 62.75, SD = 8.57, 45% functional limitations) adults aged 50 years or older. Cross-lagged panel designs were applied to examine whether habit mediates the relationship between prior and later PA and whether PA simultaneously mediates the relationship between prior and later habit. Data on habit and PA were collected by means of questionnaires at baseline (t0) and at 6 (t1) and 12 (t2) months after baseline measurement. Results of structural equation modeling analyses were not unambiguous. Indications for the existence of both hypothesized mediation effects were found, but no clear, unequivocal pattern appeared. Somewhat more support was found for the PA-habit-PA path than for the habit-PA-habit path. More research is needed to draw more definitive conclusions. PMID- 28095087 TI - Binocular and Accommodative Characteristics in a Normal Population. AB - PURPOSE: To study binocular and accommodative characteristics and their associations with age and gender in an Iranian young adult population. METHODS: In this cross-sectional study, multistage cluster sampling was done from the students of Mashhad University of Medical Sciences. All participants had visual acuity, refraction, and cover tests followed by measurements of the near point of convergence (NPC), amplitude of accommodation (AA), monocular and binocular accommodative facility (MAF and BAF) using +/-2.00 diopter (D) flipper lenses, and negative and positive relative accommodation (NRA and PRA). Near and distance fusional vergence reserves were measured using prism bar, and near associated phoria was assessed using the Mallett unit. RESULTS: The mean age of the participants was 22.5+/-4.4 years (range: 18-35 years). The binocular and accommodative characteristics and their means in the studied sample included: mean distance dissociated phoria: 1.15 exophoria+/-2.04 prism diopters (PD), near dissociated phoria: 5.02 exophoria+/-4.74 PD, near associated phoria: 0.55 base in+/-1.02, gradient accommodative convergence/accommodation (AC/A) ratio: 4.66+/ 1.59, NPC: 5.27+/-3.60 cm, MAF: 11.33+/-5.58 cpm, BAF: 8.84+/-4.47 cpm, NRA: 2.08+/-0.33 D, PRA:-2.92+/-0.76 D, and AA: 11.14+/-2.6 D. In the multiple regression model including age and gender, near exophoria was significantly higher in men and levels of near base-out-break and near base-out-recovery were higher in females. Distance exophoria, distance base-in-break, distance base-in recovery, and NPC increased with age and near base-out-break, PRA, BAF, MAF, and AA significantly decreased with age. CONCLUSION: Studied indices in this study significantly differ from available guidelines and these differences must be considered when making diagnostic or therapeutic decisions. Certain indices can be affected by age and gender. PMID- 28095089 TI - Comparative data on SD-OCT for the retinal nerve fiber layer and retinal macular thickness in a large cohort with Marfan syndrome. AB - PURPOSE: To report the distribution of macular and optic nerve topography in the eyes of individuals with Marfan syndrome aged 8-56 years using spectral domain optical coherence tomography (SD-OCT). METHODS: Thirty-three patients with Marfan syndrome underwent a full eye examination including slit-lamp biomicroscopy, indirect ophthalmoscopy, and axial length measurement; and SD-OCT measurements of the retinal nerve fiber layer (RNFL) and macular thickness. RESULTS: For patients between the ages of 8 and 12 years, the average RNFL thickness is 98 +/- 9 MUm, the vertical cup to disc (C:D) ratio is 0.50 +/- 0.10, the central subfield thickness (CST) is 274 +/- 38 MUm, and the macular volume is 10.3 +/- 0.6 mm3. For patients between the ages of 13 and 17 years, the average RNFL is 86 +/- 16 MUm, the vertical C:D ratio is 0.35 +/- 0.20, the CST is 259 +/- 15 MUm, and the macular volume is 10.1 +/- 0.5 mm3. For patients 18 years or older, the average RNFL is 89 +/- 12 MUm, the vertical C:D ratio is 0.46 +/- 0.18, the CST is 262 +/ 20 MUm, and the macular volume is 10.2 +/- 0.4 mm3. When the average RNFL data are compared to a normative, age-adjusted database, 6 of 33 (18%) were thinner than the 5% limit. CONCLUSION: This study reports the distribution of SD-OCT data for patients with Marfan syndrome. Compared to a normative database, 18% of eyes with Marfan syndrome had RNFL thickness < 5% of the population. PMID- 28095090 TI - Associations between Rs4244285 and Rs762551 gene polymorphisms and age-related macular degeneration. AB - BACKGROUND: Age-related macular degeneration is the leading cause of blindness in elderly individuals in developed countries. The etiology and pathophysiology of age-related macular degeneration have not been elucidated yet. Knowing that the main pathological change of age-related macular degeneration is formation of drusen containing about 40% of lipids, there have been attempts to find associations between age-related macular degeneration and genes controlling lipid metabolism. PURPOSE: To determine the frequency of CYP2C19 (G681A) Rs4244285 and CYP1A2 (-163C>A) Rs762551 genotypes in patients with age-related macular degeneration. METHODS: The study enrolled 150 patients with early age-related macular degeneration and 296 age- and gender-matched healthy controls. The genotyping of Rs4244285 and Rs762551 was carried out by using the real-time polymerase chain reaction method. RESULTS: The CYP1A2 (-163C>A) Rs762551 C/C genotype was more frequently detected in patients with age-related macular degeneration than in the control group (32.7% vs. 21.6%, p = 0.011) and was associated with an increased risk of developing early age-related macular degeneration (OR = 1.759, 95% CI: 1.133-2.729; p = 0.012). The CYP1A2 (-163C>A) Rs762551 C/A genotype was more frequently documented in the control group compared with patients with age-related macular degeneration (46.3% vs. 30.7%, p = 0.002) and was associated with a decreased risk of having age-related macular degeneration (OR = 0.580. 95% CI: 0.362-0.929, p = 0.023) in the co-dominant model. CONCLUSION: The study showed that the CYP1A2 (-163C>A) Rs762551 C/C genotype was associated with an increased risk of age-related macular degeneration. PMID- 28095091 TI - Factors informing fear of reinjury after anterior cruciate ligament reconstruction. AB - OBJECTIVE: Fear of reinjury is associated with cessation of sport after anterior cruciate ligament (ACL) reconstruction despite normal postoperative knee function. The objective of this study is to describe factors informing athletes' experience of fear of reinjury post ACL reconstruction, in athletes who cited fear as the sole reason for not returning to their pre-injury level of sport. DESIGN: Mixed-methods study design of qualitative and a preliminary quantitative component. SETTING: A conveniently selected private hospital. PARTICIPANTS: Ten male and two female athletes, aged between 19 and 45 years, were eligible for the interview from 68 male and 32 female potential participants (age range 17-50) who underwent an ACL reconstruction using any graft type, excluding revision or multi ligament surgery. MAIN OUTCOME MEASURES: To explore factors informing fear of reinjury in participants citing fear of reinjury as the sole reason for not returning to sport, albeit normal knee function. RESULTS: From the participant interview, four themes emerged: undergoing the surgery and recovery again, nature of the pre-injury sport imposing risk of reinjury, personality traits, and social priorities. CONCLUSIONS: Clinicians should be aware of factors informing fear of reinjury post ACL reconstruction. Modifiable fears including pain, mode and length of rehabilitation and psychological factors should be considered during rehabilitation to potentially improve the return to sport rate. PMID- 28095093 TI - The effect of foot plantar massage on balance and functional reach in patients with type II diabetes. AB - OBJECTIVE: The aim of this study was to investigate the effect of manual foot plantar massage (classic and friction massage) on functional mobility level, balance, and functional reach in patients with type II diabetes mellitus (T2 DM). METHODS: A total of 38 subjects diagnosed with T2 DM were included in the study. A healthy control group could not be formed in this study. After the subjects' socio-demographic data were obtained, Timed Up & Go (TUG) Test, functional reach test (FRT), one-leg standing test with eyes open-closed, and Visual Analogue Scale (VAS) to measure foot pain intensity were performed. The results were also divided and assessed in three groups according to the ages of the individuals (40 54, 55-64, and 65 and over). RESULTS: As a result of statistical analysis, a difference was found in the values obtained from TUG, FRT, and one-leg standing test with eyes open and closed (p < 0.05). Following the massage, TUG values significantly decreased comparison with those before the massage, whereas the values of FRT and one-leg standing test with eyes open and closed significantly increased compared with those before the massage (p > 0.05). According to age groups, there were statistical differences (p < 0.05) between the TUG, one-leg standing test with eyes open and closed test values of the individuals before and after the massage. CONCLUSIONS: The results of our study indicated that application of plantar massage to patients with T2 DM caused an improvement in balance, functional mobility, and functional reach values. An increase in body balance and functional mobility may explain the improvement in TUG. Foot massage to be added to rehabilitation exercise programs of DM patients will be important in improving balance and mobility of patients. PMID- 28095092 TI - Ophthalmic artery chemosurgery for eyes with advanced retinoblastoma. AB - BACKGROUND: Surgical removal of one or both eyes has been the most common way to treat children with retinoblastoma worldwide for more than 100 years. Ophthalmic artery chemosurgery (OAC) was introduced 10 years ago and it has been used as an alternative to enucleation for eyes with advanced retinoblastoma. The purpose of this report is to analyze our 9-year experience treating advanced retinoblastoma eyes with OAC. MATERIALS AND METHODS: Single-arm retrospective study from a single center of 226 eyes with eyes of retinoblastoma patients with advanced intraocular disease defined as both Reese-Ellsworth (RE) "Va" or "Vb" and International Classification Retinoblastoma (ICRb) group "D" or "E" (COG Classification). Ocular survival, patient survival, second cancers, and electroretinography (ERG) were assessed. RESULTS: Ocular survival at five years for these advanced eyes was 70.2% (95% confidence interval, 57.3%-79.8%). When eyes were divided into groups either by RE classification or ICRb, no significant differences in ocular survival were seen. Ocular survival was significantly better in naive compared to non-naive eyes (80.2% vs 58.4%, p = 0.041). The ERG distribution was very similar before and after OAC treatment for the patient population that did not receive intravitreal chemotherapy. Three patients (1.5%) have developed metastatic retinoblastoma (previously reported) and were successfully treated (no deaths). CONCLUSION: Using OAC for advanced eyes (the majority of such eyes have been enucleated in the past) enables 70% 5-year ocular survival. Treated eyes have a similar ERG distribution before and after treatment. No patient has died of metastatic retinoblastoma. PMID- 28095094 TI - Female Age-Related Differences in Biomechanics and Muscle Activity During Descents on the Outstretched Arms. AB - The purposes of this study were to examine female age differences in: (1) upper extremity (UE) and trunk muscle activity, elbow joint moment, loading force, and UE energy absorption during a controlled forward body descent; and (2) UE muscle strength. Twenty young (mean 24.8 +/- 3.4 years) and 20 older (68.4 +/- 5.7 years) women were assessed via dynamometry for isometric, concentric, and eccentric UE strength and performed forward descents on force plates at three body lean angles (60 degrees , 45 degrees , and 30 degrees from horizontal). Significant differences (p < .05) were found for muscle strength, biomechanics, and muscle activity. Concentric UE strength averaged 15% lower in older women. At 30 degrees body lean, older women absorbed less energy. Older women had greater biceps brachii activation and less external oblique activation at all body lean angles. Age differences in muscle strength, activation, and energy absorption may contribute to fall-related injury risk. PMID- 28095096 TI - Corrigendum. PMID- 28095095 TI - Joint association of complement component 3 and CC-cytokine ligand2 (CCL2) or complement component 3 and CFH polymorphisms in age-related macular degeneration. AB - BACKGROUND: To determine the joint effect of complement component 3(C3 R102G) with CC-cytokine ligand2 (CCL2-2518) or complement factor H (CFH) Y402H polymorphisms on advanced age-related macular degeneration (AMD). METHODS: In this case-control study, 233 patients with advanced AMD and 159 unrelated healthy controls enrolled for evaluation. Selected polymorphisms were determined by polymerase chain reaction and restriction fragment length polymorphism. RESULTS: A combination of AA CCL2 (rs1024611) and GG C3 (R102G) genotypes resulted in a super-additivity of the risks: OR = 10.13, 95% CI 1.04-98.49, p = 0.04, adjusted OR = 7.74, 95% CI 0.71-84.75, p < 0.1, adjusted synergy indices: relative excess risk due to interaction (RERI) = 1.38, the attributable proportion due to interaction (AP) = 24.7% and the synergy index (S) = 1.43. Combination of at-risk genotypes of CFH Y402H and C3 R102G resulted in a strong super-additive risk: adjusted OR = 22.65, 95% CI 2.32-220.91, p = 0.007, adjusted AP = 90.4% and the S = 12.86. Attributable proportion of risk owing to C3-CCL2 and C3-CFH interaction calculated at 25% and 90% for advanced AMD. CONCLUSION: We have previously shown a strong association of C3 (R102G) and CFH Y402H with AMD whereas no association was found for CCL2-2518. This study enclosed strong synergistic association of risk genotypes of C3 and CFH Y402H with AMD. We also revealed synergistic influence of CCL2-2518 and the at-risk genotype of the C3 in AMD with an estimated AP = 50.9% (adjusted AP = 24.7%). Present findings show that CCL2-2518 polymorphism is not an innocent bystander in AMD susceptibility when combined with the at-risk genotype of C3 (R102G). PMID- 28095097 TI - Facilitating awareness of philosophy of science, ethics and communication through manual skills training in undergraduate education. AB - BACKGROUND: Professional health science education includes a common theoretical basis concerning the theory of science, ethics and communication. Former evaluations by first-year students of the bachelor physiotherapy program at Oslo and Akershus University College of Applied Sciences (HiOA) show that they find it hard to understand the relation between these particular topics and future professional practice. This challenge is the starting point for a pedagogical development project that aims to develop learning contexts that highlight the relevance of these theoretical concepts. AIM: The aim of the study is to explore and present findings on the value of using Sykegrep manual skills classes as an arena in which students can be encouraged to think about, reflect on and appreciate the role and value of the philosophical perspectives that inform their practice and contributes to practise knowledge. METHOD: A qualitative study with data collection through focus groups was performed and analyzed using thematic content analysis. Eighteen first-year undergraduate students, who had completed the manual skills course, participated in the study. FINDINGS: Analysis of the data yielded three categories of findings that can be associated with aspects of philosophy of science, ethics and communication. These are as follows: 1) preconceived understanding of physiotherapy; 2) body knowledge perspectives; and 3) relational aspects of interactions. Undergraduate students' understanding and experience of philosophy of science, ethics and communication may be facilitated by peer collaboration, reflection on intimacy and touch and the ethical aspects of interaction during manual skills training. CONCLUSION: Practical classes in Sykegrep provide a basis for students' discussions about the body as well as their experiences with the body in the collaborative learning context. The students' reflections on their expectations of manual skills in physiotherapy and experiences of touch and being touched can facilitate an awareness of philosophy of science, ethics and communication. IMPLICATIONS: Our study will be an incitement to further develop a manual skills teaching program that incorporates philosophy of science, ethics and communication in undergraduate education. PMID- 28095098 TI - Reduced penetrance in a large Caucasian pedigree with Stickler syndrome. AB - BACKGROUND: In a four-generation Caucasian family variably diagnosed with autosomal dominant (AD) Stickler or Wagner disease, commercial gene screening failed to identify a mutation in COL2A1 or VCAN. We utilized linkage mapping and exome sequencing to identify the causal variant. MATERIALS AND METHODS: Genomic DNA samples collected from 40 family members were analyzed. A whole-genome linkage scan was performed using Illumina HumanLinkage-24 BeadChip followed by two-point and multipoint linkage analyses using FASTLINK and MERLIN. Exome sequencing was performed on two affected individuals, followed by co-segregation analysis. RESULTS: Parametric multipoint linkage analysis using an AD inheritance model demonstrated HLOD scores > 2.00 at chromosomes 1p36.13-1p36.11 and 12q12 12q14.1. SIMWALK multipoint analysis replicated the peak in chromosome 12q (peak LOD = 1.975). FASTLINK two-point analysis highlighted several clustered chromosome 12q SNPs with HLOD > 1.0. Exome sequencing revealed a novel nonsense mutation (c.115C>T, p.Gln39*) in exon 2 of COL2A1 that is expected to result in nonsense-mediated decay of the RNA transcript. This mutation co-segregated with all clinically affected individuals and seven individuals who were clinically unaffected. CONCLUSIONS: The utility of combining traditional linkage mapping and exome sequencing is highlighted to identify gene mutations in large families displaying a Mendelian inheritance of disease. Historically, nonsense mutations in exon 2 of COL2A1 have been reported to cause a fully penetrant ocular-only Stickler phenotype with few or no systemic manifestations. We report a novel nonsense mutation in exon 2 of COL2A1 that displays incomplete penetrance and/or variable age of onset with extraocular manifestations. PMID- 28095099 TI - Efficacy of an Exercise and Nutritional Supplement Program on Physical Performance and Nutritional Status in Older Adults With Mobility Limitations Residing at Senior Living Facilities. AB - This cluster-randomized trial was designed to determine the efficacy of a 6-month exercise-nutritional supplement program (ENP) on physical function and nutritional status for older adults and the feasibility of implementing this program in a senior living setting. Twenty senior-living facilities were randomized to either a 3 day per week group-based ENP led by a trained facility staff member or a health education program (SAP). Participants (N = 121) completed a short physical performance battery, 400-m walk, handgrip strength test, and mini-nutrition assessment. 25-hydroxyvitamin D [25(OH)D], insulin-like growth-factor 1 (IGF-1), and activity level were also measured. The ENP did not significantly improve physical function or nutritional status compared with the SAP. Compared with baseline, participants in the ENP engaged in 39 min less physical activity per week at 6 months. Several facility characteristics hindered implementation of the ENP. This study highlights the complexity of implementing an evidence-based program in a field setting. PMID- 28095100 TI - Association of combined cigarette smoking and ARMS2/LOC387715 A69S polymorphisms with age-related macular degeneration: A meta-analysis. AB - PURPOSE: The age-related maculopathy susceptibility2 (ARMS2)/LOC387715 A69S (rs10490924) polymorphism and cigarette smoking have been shown to have significant association with AMD. In this meta-analysis we used the results of available association studies of combined ARMS2/LOC387715 genotypes and cigarette smoking with AMD to estimate the possible synergistic or multiplicative effects. METHODS: Heterogeneity of studies was evaluated using the Cochran Q-test and the I-square index. To compensate for the heterogeneity of the variables in the study we used a random effects model. Meta-analysis was performed using STATA. To estimate the additive or supra-additive effects, we calculated relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), synergy index (S), and multiplicative index (V). RESULTS: We could include four studies with 1982 AMD patients and 1797 control subjects. Considering the GG-no smoking as a reference line the meta-analysis result of AMD odds ratios for stratified combined factors was 3.05 (95% CI 2.32-4.02) for nonGG-no smoking, 2.24 (95% CI 1.39-3.63) for GG-smoking and 4.59 (95% CI 3.51-6.01) for nonGG smoking. The meta-analysis of synergy analysis revealed RERI = 2.01 (95% CI 1.01 3.25), AP = 0.40 (95% CI 0.22-0.54), S = 2.02 (95% CI 1.35-3.01), and V = 1.31 (95% CI 0.94-1.83). CONCLUSION: This analysis revealed the synergistic effect of these two factors indicating that there is a common pathway of ARMS2/LOC387715 and smoking in AMD pathogenesis which may be the complement system pathway. PMID- 28095101 TI - An immediate effect of axial neck rotation training with real time visual feedback using a smartphone inclinometer on improvement in axial neck rotation function. AB - OBJECTIVES: The purpose of this study was to compare the immediate effects of axial neck rotation training (Axi-NRT) with and without real-time visual feedback (VF) using a smartphone inclinometer on the range of motion (ROM) for axial neck rotation and the onset of compensatory neck lateral bending and extension during active neck rotation. METHODS: Twenty participants with restricted ROM for neck rotation but no neck pain (21.1 +/- 1.6 years and 8 males, 12 females) were recruited for Axi-NRT with VF, and twenty age- and gender-matched participants with restricted ROM for neck rotation were recruited for Axi-NRT without VF. Changes in ROM for neck rotation and the onset time of compensatory neck movement during active neck rotation were measured using an electromagnetic tracking system. RESULTS: Axi-NRT with VF was more effective in increasing ROM for neck rotation and decreasing and delaying the onset of compensatory neck movements during active neck rotation compared with Axi-NRT without VF. CONCLUSIONS: Repeated Axi-NRT using VF is useful to educate participants in maintaining the axis of the cervical spine and to increase ROM for axial neck rotation with less compensatory neck motion in participants with a restricted range of neck rotations. PMID- 28095103 TI - Corrigendum. PMID- 28095102 TI - Electromyographic analysis of gluteus maximus and hamstring activity during the supine resisted hip extension exercise versus supine unilateral bridge to neutral. AB - Hip extension strengthening exercises which maximize gluteus maximus contributions and minimize hamstring influences may be beneficial for persons with hip pain. This study's aim was to compare muscle activation of the gluteus maximus and hamstrings from healthy subjects during a supine resisted hip extension exercise versus supine unilateral bridge to neutral. Surface electromyographic (EMG) signals were obtained from the right gluteus maximus and hamstrings in 13 healthy male and 13 healthy female subjects. Maximum voluntary isometric contractions (MVICs) were collected to normalize data and permit meaningful comparisons across muscles. Peak median activation of the gluteus maximus was 33.8% MVIC for the bridge and 34.7% MVIC for the hip extension exercise, whereas peak median recruitment for hamstrings was 28.4% MVIC for the bridge and 51% MVIC for the hip extension exercise. The gluteus maximus to hamstrings ratio was compared between the two exercises using the Wilcoxon signed ranks test (alpha = 0.05). The ratio (p = 0.014) was greater in the supine unilateral bridge (median = 111.3%) than supine hip extension exercise (median = 59.2%), suggesting a reduction of hamstring recruitment in the unilateral bridge to neutral compared to the supine resisted hip extension exercise. The supine hip extension exercise demonstrated higher EMG activity of hamstrings in comparison with supine unilateral bridge and, therefore, may be less appropriate in subjects who need to increase gluteus maximus activation. PMID- 28095104 TI - The Relative Efficacy of Land-Based and Water-Based Exercise Training on Macro- and Microvascular Functions in Older Patients With Type 2 Diabetes. AB - Microvascular and macrovascular dysfunction plays an important role in the pathogenesis of diabetic vascular disease. Twenty-nine older patients with type 2 diabetes were randomly assigned into the land-based (LB; n = 14) or water-based (WB; n = 15) groups. Both groups completed supervised aerobic cycling exercises three times per week for 12 weeks. The WB group performed cycling exercise training in warm water (36 degrees C) immersed to the hip level. After 12 weeks, blood glucose concentration and insulin resistance did not change but hemoglobin A1c levels decreased (P < .05) in both groups. Plasma nitric oxide concentrations increased (P < .05) in both groups. Flow-mediated dilation in the popliteal artery increased and arterial stiffness decreased (P < .05) in both exercise groups. Indices of microvascular reactivity improved (P < .05) only in the WB group. The benefits of warm water-based training were similar in general, and superior in some measures, to the more established land-based cycling exercise. PMID- 28095106 TI - Gender Differences in Static and Dynamic Postural Stability of Soldiers in the Army's 101st Airborne Division (Air Assault). AB - CONTEXT: Postural stability is essential for injury prevention and performance. Differences between genders may affect training focus. OBJECTIVE: To examine static and dynamic postural stability in male and female soldiers. DESIGN: Descriptive laboratory study. SETTING: Biomechanics laboratory. PARTICIPANTS: 25 healthy female soldiers (26.4 +/- 5.3 y) and 25 healthy male soldiers (26.4 +/- 4.9 y) matched on physical demand rating and years of service from the Army's 101st Airborne Division (Air Assault). INTERVENTIONS: Each person underwent static and dynamic postural stability testing. MAIN OUTCOME MEASURES: Standard deviation of the ground reaction forces during static postural stability and the dynamic stability index for dynamic postural stability. RESULTS: Female soldiers had significantly better static postural stability than males but no differences were observed in dynamic postural stability. CONCLUSIONS: Postural stability is important for injury prevention, performance optimization, and tactical training. The differences observed in the current study may indicate the need for gender specific training emphasis on postural stability. PMID- 28095105 TI - Regular Latin Dancing and Health Education May Improve Cognition of Late Middle Aged and Older Latinos. AB - Disparities exist between Latinos and non-Latino Whites in cognitive function. Dance is culturally appropriate and challenges individuals physically and cognitively, yet the impact of regular dancing on cognitive function in older Latinos has not been examined. A two-group pilot trial was employed among inactive, older Latinos. Participants (N = 57) participated in the BAILAMOS(c) dance program or a health education program. Cognitive test scores were converted to z-scores and measures of global cognition and specific domains (executive function, episodic memory, working memory) were derived. Results revealed a group * time interaction for episodic memory (p < .05), such that the dance group showed greater improvement in episodic memory than the health education group. A main effect for time for global cognition (p < .05) was also demonstrated, with participants in both groups improving. Structured Latin dance programs can positively influence episodic memory, and participation in structured programs may improve overall cognition among older Latinos. PMID- 28095107 TI - Bioremediation of petroleum wastewater by hyper-phenol tolerant Bacillus cereus: Preliminary studies with laboratory-scale batch process. AB - Petroleum wastewater samples from oil refinery and oil exploration site were treated by hyper phenol-tolerant Bacillus cereus (AKG1 and AKG2) in laboratory scale batch process to assess their bioremediation efficacy. Quality of the treated wastewater samples were analyzed in terms of removal of chemical oxygen demand (COD), total organic carbon (TOC) and ammonium nitrogen content, and improvement of biological oxygen demand (BOD). Adaptation of these bacteria to the toxic environment through structural changes in their cell membranes was also highlighted. Among different combinations, the co-culture of AKG1 and AKG2 showed the best performance in degrading the wastewater samples. PMID- 28095108 TI - The Relationship Between 2-Dimensional Knee-Valgus Angles During Single-Leg Squat, Single-Leg-Land, and Drop-Jump Screening Tests. AB - CONTEXT: Injuries to the anterior cruciate ligament (ACL) and patellofemoral joint (PFJ) are a significant problem in female athletes. A number of screening tasks have been used in the literature to identify those at greatest risk of injury. To date, no study has examined the relationship in 2-dimensional (2D) knee valgus between common screening tasks to determine whether individuals exhibit similar movement patterns across tasks. OBJECTIVE: To establish whether frontal-plane projection angle (FPPA) during the single-leg squat (SLS), single leg land (SLL), and drop jump (DJ) are related. DESIGN: Cross-sectional study. SETTING: University laboratory. PARTICIPANTS: 52 national-league female football players and 36 national-league female basketball players. MAIN OUTCOME MEASURES: 2D FPPA during the SLS, SLL, and DJ screening tasks. RESULTS: Significant correlations were found between tasks. FPPA in the SLS was significantly correlated with SLL (r = .52) and DJ (r = .30), whereas FPPA in the SLL was also significantly correlated to DJ (r = .33). FPPA was significantly greater in the SLS than in the SLL (P < .001) and DJ (P < .001) and in the SLL than in the DJ (P < .001). CONCLUSION: The results showed that 2D FPPA is correlated across the SLS, SLL, and DJ tasks. However, significantly greater FPPA values in the unilateral tasks suggest that the DJ may not identify risk of injury in sports where primary injury mechanisms are during unilateral loading tasks. Therefore, it is recommended that both unilateral and bilateral tasks be included when screening for ACL and PFJ injury risk. PMID- 28095109 TI - Test-Retest Reliability and Practice Effects of the Stability Evaluation Test. AB - CONTEXT: Postural control plays an essential role in concussion evaluation. The Stability Evaluation Test (SET) aims to objectively analyze postural control by measuring sway velocity on the NeuroCom VSR portable force platform (Natus, San Carlos, CA). OBJECTIVE: To assess the test-retest reliability and practice effects of the SET protocol. DESIGN: Cohort. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: 50 healthy adults (20 men, 30 women, age 25.30 +/ 3.60 y, height 166.60+/- 12.80 cm, mass 68.80 +/- 13.90 kg). INTERVENTIONS: All participants completed 4 trials of the SET. Each trial consisted of six 20-s balance tests with eyes closed, under the following conditions: double-leg firm (DFi), single-leg firm (SFi), tandem firm (TFi), double-leg foam (DFo), single leg foam (SFo), and tandem foam (TFo). Each trial was separated by a 5-min seated rest period. MAIN OUTCOME MEASURES: The dependent variable was sway velocity (deg/s), with lower values indicating better balance. Sway velocity was recorded for each of the 6 conditions as well as a composite score for each trial. Test retest reliability was analyzed across 4 trials with intraclass correlation coefficients (ICCs). Practice effects analyzed with repeated measures analysis of variance, followed by Tukey post hoc comparisons for any significant main effects (P < .05). RESULTS: Sway-velocity reliability values were good to excellent: DFi (ICC = .88; 95%CI: .81, .92), SFi (ICC = .75; 95%CI: .61, .85), TFi (ICC = .84; 95%CI: .75, .90), DFo (ICC = .83; 95%CI: .74, .90), SFo (ICC = .82; 95%CI: .72, .89), TFo (ICC = .81; 95%CI: .69, .88), and composite score (ICC = .93; 95%CI: .88, .95). Significant practice effects (P < .05) were noted on the SFi, DFo, SFo, TFo conditions and composite scores. CONCLUSIONS: Our results suggest the SET has good to excellent reliability for the assessment of postural control in healthy adults. Due to the practice effects noted, a familiarization session is recommended (ie, all 6 conditions) before data are recorded. Future studies should evaluate injured patients to determine meaningful change scores during various injuries. PMID- 28095110 TI - The Effect of Following Clinical Practice Guidelines on the Pain and Disability Outcomes of Patients With Low Back Pain-A Critically Appraised Topic. AB - : Clinical Scenario: Health care clinicians are encouraged to practice according to the best available evidence for the purpose of improving patient outcomes. Clinical practice guidelines are one form of evidence that has been developed to enhance the care that patients receive for particular conditions. Low back pain is a common condition in rehabilitation medicine that places a significant financial burden on the healthcare system. Patients with low back pain often suffer great pain and disability that can last a long time, making effective and efficient care a priority. Several guidelines for the treatment of low back pain have been created; however, there is no consensus on whether following these guidelines will positively reduce the pain and disability experienced by patients. CLINICAL QUESTION: Does adherence to clinical practice guidelines for patients with nonspecific low back pain reduce pain and disability? Summary of Key Findings: A total of 4 studies of level 3 or higher were found. Four studies noted an improvement in disability following guidelines adherent care. Two studies reported greater reduction in pain with guideline adherent care and 2 did not. Clinical Bottom Line: Moderate evidence exists to support adherence to clinical practice guidelines to improve pain and disability ratings in patients with nonspecific low back pain. PMID- 28095111 TI - Increased Numb protein expression predicts poor clinical outcomes in esophageal squamous cell carcinoma patients. AB - Numb is a protein whose asymmetric segregation during cell division determines cell fate and has numerous functions relevant to multiple fields of study, including developmental neurobiology and cancer biology. Little is known about the role of Numb in esophageal squamous cell carcinoma (ESCC), the predominant histological esophageal carcinoma in Asian populations. In this study, we focused on the expression and biologic functions of Numb in the context of ESCC. From analysis of tissue microarrays with 212 patients, it was found that Numb was significantly upregulated in ESCC tissues compared with corresponding non cancerous tissues. Kaplan-Meier survival analysis suggests that higher expression of Numb was significantly associated with a high tumor recurrence (p = 0.015) and poor overall post-surgical survival (p = 0.016). Using multiple Cox regression, the expression of Numb was determined to be an independent predictor of poor prognosis. When siRNA was used to knockdown Numb in ESCC cell lines, there was a consistent increase in caspase-3 dependent apoptosis and inhibition of cellular proliferation, as well as downregulation of expression of the cancer stem cell markers Oct-4, SOX-2 and Nanog. In addition, downregulated Numb expression was not significantly associated with the migration of ESCC cells. These results indicate that Numb acts as an oncoprotein and has potential as a novel prognostic biomarker and therapeutic target in ESCC patients. PMID- 28095112 TI - Autogenous bone particle/titanium fiber composites for bone regeneration in a rabbit radius critical-size defect model. AB - PURPOSE: To explore the effects of autogenous bone particle/titanium fiber composites on repairing segmental bone defects in rabbits. MATERIALS AND METHODS: A model of bilateral radial bone defect was established in 36 New Zealand white rabbits which were randomly divided into 3 groups according to filling materials used for bilaterally defect treatment: in group C, 9 animal bone defect areas were prepared into simple bilateral radius bone defect (empty sham) as the control group; 27 rabbits were used in groups ABP and ABP-Ti. In group ABP, left defects were simply implanted with autogenous bone particles; meanwhile, group ABP-Ti animals had right defects implanted with autogenous bone particle/titanium fiber composites. Animals were sacrificed at 4, 8, and 12 weeks, respectively, after operation. RESULTS: Micro-CT showed that group C could not complete bone regeneration. Bone volume to tissue volume values in group ABP-Ti were better than group ABP. From histology and histomorphometry Groups ABP and ABP-Ti achieved bone repair, the bone formation of group ABP-Ti was better. The mechanical strength of group ABP-Ti was superior to that of other groups. CONCLUSIONS: These results confirmed the effectiveness of autologous bone particle/titanium fiber composites for promoting bone regeneration and mechanical strength. PMID- 28095113 TI - Quantitative analysis of cell surface antigen-antibody interaction using Gaussia princeps luciferase antibody fusion proteins. AB - Cell surface antigen-specific antibodies are of substantial diagnostic and therapeutic importance. The binding properties of such antibodies are usually evaluated by cell-free assays, in particular surface plasmon resonance (SPR) analysis, or flow cytometry. SPR analyses allow the detailed quantitative and dynamic evaluation of the binding properties of antibodies, but need purified, typically recombinantly produced antigens. It can, however, be difficult to produce the required antigen. Furthermore, cellular factors influencing the antigen-antibody interaction are not considered by this method. Flow cytometry based analyses do not have these limitations, but require elaborated calibration controls for absolute quantification of bound molecules. To overcome the limitations of SRP and flow cytometry in the characterization of cell surface antigen-specific antibodies, we developed Fn14-specific antibody 18D1 as an example of an antibody fusion protein format that includes the luciferase of Gaussia princeps (GpL), which enables very simple and highly sensitive cellular binding studies. We found that GpL-tagging of the C-terminus of the antibody light chain does not affect the interaction of 18D1-IgG1 with its antigen and Fc gamma receptors (FcgammaRs). In accordance with this, the GpL(LC-CT)-18D1-IgG1 antibody fusion protein showed basically the same FcgammaR-dependent agonistic properties as the parental 18D1 antibody. Similar results were obtained with isotype switch variants of 18D1 and antibodies specific for CD95, LTbetaR and CD40. In sum, we demonstrate that antibody GpL fusion proteins are easily manageable and versatile tools for the characterization of cell surface antigen antibody interactions that have the potential to considerably extend the instrumentarium for the evaluation of antibodies. PMID- 28095114 TI - Flowering time regulation by the CONSTANS-Like gene OsCOL10. AB - Plant flowering at the appropriate time is critical for reproductive success and influenced by a series of environmental factors such as photoperiod and temperature. A number of genes involved in photoperiodic flowering of have been cloned and their roles in modulating expression of the flowering genes have been characterized to a certain extent. However, much less is known about the pathway in transmitting the day length response signal(s) to induce transition to reproductive growth. Recently, we characterized a constitutive flowering repressor OsCOL10 encoding for a member of the CONSTANS-like (COL) family. Through transgenic analysis, we have showed that OsCOL10 repress flowering by reducing expression of the FT-like genes RFT1 and Hd3a through Ehd1. Moreover, we also showed that OsCOL10 acts downstream of Ghd7, a key LD-specific flowering repressor by reducing expression of Ehd1. Collectively, our finding identifies OsCOL10 functioning as a flowering-time repressor that links between Ghd7 and Ehd1 in rice. PMID- 28095115 TI - Working conditions and workplace health and safety promotion in home care: A mixed-method study from Swedish managers' perspectives. AB - Today, we can see a trend toward increased psychosocial strain at work among home care managers and staff. The aim of this study is to describe home care managers' views on their own psychosocial working conditions and on how to promote workplace health and safety in a municipality in northern Sweden. A mixed-methods design was used, including questionnaire and qualitative focus group data. The qualitative data were analyzed by manifest content analysis. The results indicate that most managers perceived increased variety in work and opportunities for development at work, but at the same time increased demands. The managers suggested that workplace health and safety could be improved by risk assessment and improved communication, a clear communication chain by a real as well as a virtual platform for communication. In summary, workplace health and safety could be improved by risk assessments and by a physical as well as a virtual platform for communication. PMID- 28095116 TI - Recent progress on the development of anisotropic gold nanoparticles: Design strategies and growth mechanism. AB - This review summarizes recent advances on design strategies for shape-controlled anisotropic gold nanoparticles. Detailed chemical mechanism has been discussed to understand the anisotropic growth. The effect of various chemical parameters and surface facets for the formation of different shaped anisotropic nanoparticles have been addressed. PMID- 28095117 TI - Parents' asthma information needs and preferences for school-based asthma support. AB - OBJECTIVES: This study sought to investigate parents' needs and preferences for school-based asthma support in Saudi Arabian primary schools. METHODS: Semi structured qualitative interviews were conducted in the period between November 2015 and February 2016, with a convenience sample that comprised Saudi parents and carers of children with asthma. Recruitment of participants was primarily driven through Saudi primary schools; passive snowballing and social networks were used to boost participation rates further. Interviews were audio-recorded, transcribed verbatim, translated and data were thematically organised using a latent content analysis approach. RESULTS: Twenty interviews were conducted. Six themes emerged from the interviews and were grouped into three major categories: (1) general asthma management issues; (2) school-based asthma management issues; and (3) communication dissatisfaction. Participants expressed concern at schools' social and physical environments and a lack of confidence in the ability of schools to manage their child's asthma, especially when their child was ill. Most of the participants advocated for staff training and school community engagement to improve the management of asthma in Saudi primary schools. CONCLUSION: This research clearly describes a need for school-based asthma support, including asthma-related policies, procedures and education on asthma and first aid in Saudi primary schools. PMID- 28095118 TI - Modeling and optimization of lime-based stabilization in high alkaline arsenic bearing sludges with a central composite design. AB - This study focuses on the modeling and optimization of lime-based stabilization in high alkaline arsenic-bearing sludges (HAABS) and describes the relationship between the arsenic leachate concentration (ALC) and stabilization parameters to develop a prediction model for obtaining the optimal process parameters and conditions. A central composite design (CCD) along with response surface methodology (RSM) was conducted to model and investigate the stabilization process with three independent variables: the Ca/As mole ratio, reaction time and liquid/solid ratio, along with their interactions. The obvious characteristic changes of the HAABS before and after stabilization were verified by X-ray diffraction (XRD), scanning electron microscopy (SEM), particle size distribution (PSD) and the community bureau of reference (BCR) sequential extraction procedure. A prediction model Y(ALC) with a statistically significant P-value <0.01 and high correlation coefficient R2 = 93.22% was obtained. The optimal parameters were successfully predicted by the model for the minimum ALC of 0.312 mg/L, which was validated with the experimental result (0.306 mg/L). The XRD, SEM and PSD results indicated that crystal calcium arsenate Ca5(AsO4)3OH and Ca4(OH)2(AsO4)2.4H2O formation played an important role in minimizing the ALC. The BCR sequential extraction results demonstrated that the treated HAABS were stable in a weak acidic environment for a short time but posed a potential environmental risk after a long time. The results clearly confirm that the proposed three-factor CCD is an effective approach for modeling the stabilization of HAABS. However, further solidification technology is suggested for use after lime-based stabilization treatment of arsenic-bearing sludges. PMID- 28095119 TI - Fecal Carriage of Extended-Spectrum beta-Lactamase-Producing Enterobacteriaceae Strains Is Associated with Worse Outcome in Patients Hospitalized in the Pediatric Oncology Unit of Beni-Messous Hospital in Algiers, Algeria. AB - OBJECTIVES: The current study aimed to investigate extended-spectrum beta lactamase-producing Enterobacteriaceae (ESBL-E) fecal carriage in children with different cancers admitted in the pediatric oncology unit of Beni-Messous Hospital (Algiers, Algeria). MATERIALS AND METHODS: Rectal swabs from children with cancer were sampled from February 2012 to May 2013 within 48 hours following their admission. After species identification and detection of ESBL production by double-disk synergy test (DD test), antibiotic susceptibility was determined by the standard disk diffusion method. Antibiotic resistance genes, including bla genes and plasmid-mediated quinolone resistance (PMQR) genes, were investigated by polymerase chain reaction (PCR). The phylogenetic grouping of Escherichia coli strains was determined by PCR. RESULTS: Of the 171 children studied, 93 (54%) were ESBL carriers. An antibiotic treatment for the last 3 months before admission (p = 0.01), hematological malignancies (p = 0.003), and death (p = 0.0003) were more frequent in the ESBL-E group than in the non-ESBL group. Multivariate analysis showed that hematological malignancies (odds ratio [OR]: 3.9; confidence interval [CI]: 1.1-14.1; p = 0.04) and ESBL-E carriage (OR: 6.2; CI: 1.7-22.00; p = 0.005) were two independent factors associated with increased risk of death. A total of 103 ESBL-E isolates were obtained. Klebsiella pneumoniae and E. coli isolates were the most frequently isolated. PCR amplification showed that all the isolates produced a CTX-M ESBL (CTX-M-15, CTX-M 14, and CTX-M-3). The PMQR genes detected were qnrB, qnrS, and aac(6')-Ib-cr. E. coli isolates were assigned to four major extraintestinal pathogenic E. coli phylogroups, including B2 and D. CONCLUSION: This study provides, for the first time, insight into epidemiology of the ESBL-E fecal carriage among children with cancer in Algeria. PMID- 28095120 TI - The bent conformation of poly(A)-binding protein induced by RNA-binding is required for its translational activation function. AB - A recent study revealed that poly(A)-binding protein (PABP) bound to poly(A) RNA exhibits a sharply bent configuration at the linker region between RNA recognition motif 2 (RRM2) and RRM3, whereas free PABP exhibits a highly flexible linear configuration. However, the physiological role of the bent structure of mRNA-bound PABP remains unknown. We investigated a role of the bent structure of PABP by constructing a PABP variant that fails to form the poly(A)-dependent bent structure but maintains its poly(A)-binding activity. We found that the bent structure of PABP/poly(A) complex is required for PABP's efficient interaction with eIF4G and eIF4G/eIF4E complex. Moreover, the mutant PABP had compromised translation activation function and failed to augment the formation of 80S translation initiation complex in an in vitro translation system. These results suggest that the bent conformation of PABP, which is induced by the interaction with 3' poly(A) tail, mediates poly(A)-dependent translation by facilitating the interaction with eIF4G and the eIF4G/eIF4E complex. The preferential binding of the eIF4G/eIF4E complex to the bent PABP/poly(A) complex seems to be a mechanism discriminating the mRNA-bound PABPs participating in translation from the idling mRNA-unbound PABPs. PMID- 28095121 TI - Toxicity of new pyrethroid in pest insects Asciamonuste and Diaphania hyalinata, predator Solenopsis saevissima and stingless bee Tetragonisca angustula. AB - There is increasing demand for new products for vegetable pest management. Thus, the aim of this study was to assess the toxicity of pyrethroids with acid moiety modifications to measure the insecticidal activity of these compounds on the lepidopteran vegetable pests Diaphania hyalinata (L.) (Lepidoptera: Pyralidae) and Asciamonuste (Latreille) (Lepidoptera: Pieridae) and evaluate their selectivity for the predatory ant Solenopsis saevissima (F. Smith) (Hymenoptera: Formicidae) and pollinator Tetragonisca angustula (Latreille) (Hymenoptera: Apidae: Meliponinae). Racemic mixtures of five new pyrethroids (30 ug molecule mg 1 insect body weight) resulted in high (100%) and rapid (stable LD50 after 12 h) mortality in D. hyalinata and A. monuste. In A. monuste, the trans-pyrethroid [12] isomer showed similar toxicity to permethrin. For D. hyalinata, the trans pyrethroid [9] isomer and cis-pyrethroid [10] isomer were as toxic as permethrin. Due to their low selectivity, these new pyrethroids should be applied on the basis of ecological selectivity principles to minimize impacts on nontarget organisms S. saevissima and T. angustula. PMID- 28095122 TI - Exome sequencing confirms ZNF408 mutations as a cause of familial retinitis pigmentosa. PMID- 28095123 TI - Seafood consumption habits of South Carolina shrimp baiters. AB - Shrimp baiting is a fishing technique used by many South Carolinians and has been regulated in the state since the late 1980s. A postcard survey was developed and included with 400 South Carolina Department of Natural Resources (SCDNR) annual surveys of registered shrimp baiters over a two-year period. The survey contained questions concerning frequency, portion size, baiting locations, and preparation techniques for shrimp as well as other species consumed and demographic information. An overall response rate of 37% was received. The majority of respondents were men over the age of 55 years. Charleston and Beaufort counties were the most common locations for shrimp baiting. Almost half (45.9%) of respondents reported eating locally caught shrimp at least 2-3 times per month. The most common portion size was 1/2 pound (8 oz. or 277 g), with 44.8% of respondents reporting this as their typical amount of shrimp ingested at one meal. Only 3.7% of respondents reported typically eating the whole shrimp, while all other respondents ingested shrimp with the head removed. The most commonly consumed species besides shrimp were blue crab, oysters, and flounder. According to the US Food and Drug Administration mercury (Hg) guidelines, the majority (97%) of our respondents were not at risk for consuming unsafe levels of Hg from locally caught shrimp. However, this does not take into account other local seafood eaten or other contaminants of concern. These consumption results may be used in conjunction with data on contaminant levels in shrimp to determine potential adverse health risks associated with consumption of locally caught shrimp. PMID- 28095124 TI - mlo-Based Resistance: An Apparently Universal "Weapon" to Defeat Powdery Mildew Disease. AB - Loss-of-function mutations of one or more of the appropriate Mildew resistance locus o (Mlo) genes are an apparently reliable "weapon" to protect plants from infection by powdery mildew fungi, as they confer durable broad-spectrum resistance. Originally detected as a natural mutation in an Ethiopian barley landrace, this so-called mlo-based resistance has been successfully employed in European barley agriculture for nearly four decades. More recently, mlo-mediated resistance was discovered to be inducible in virtually every plant species of economic or scientific relevance. By now, mlo resistance has been found (as natural mutants) or generated (by induced mutagenesis, gene silencing, and targeted or nontargeted gene knock-out) in a broad range of monocotyledonous and dicotyledonous plant species. Here, we review features of mlo resistance in barley, discuss approaches to identify the appropriate Mlo gene targets to induce mlo-based resistance, and consider the issue of pleiotropic effects often associated with mlo-mediated immunity, which can harm plant yield and quality. We portray mlo-based resistance as an apparently universal and effective weapon to defeat powdery mildew disease in a multitude of plant species. PMID- 28095125 TI - Nitrate in drinking water and risk of colorectal cancer in Yogyakarta, Indonesia. AB - Nitrate concentration in well water in Yogyakarta, Indonesia, and its surroundings tended to increase rapidly from time to time, and it may be associated with an elevated risk for several types of cancer. The purpose of this study was to examine the association between nitrate in drinking water and colorectal cancer (CRC) risk occurrence. A case-control study was conducted in Yogyakarta Special Province. Pathologically confirmed 75 CRC patients and 75 controls were consulted and their individual well water was sampled and examined for nitrate concentrations. Logistic regression analysis was conducted to establish the association between nitrate and CRC risk development. There was a significant correlation between nitrate in drinking water and CRC occurrence, and this value was relatively stable after being adjusted for protein intake, smoking history, age, and family history of cancer. These findings demonstrated that the risk of CRC development was fourfold among those with >10 years of nitrate exposure from well water compared with those with <=10 years of nitrate exposure. Consequently, a significant association between nitrate in drinking water and occurrence of CRC in Yogyakarta was established. PMID- 28095126 TI - The association between sensation seeking and e-cigarette use in Texas young adults: A cross-sectional study. AB - OBJECTIVE: To examine the associations between sensation seeking and ever and current e-cigarette use in Texas young adults (18-29 years old). Current cigarette use was examined as a potential effect modifier of the associations. PARTICIPANTS: Participants included college students enrolled in four-year and two-year colleges in four metropolitan areas in Texas (n = 5,418) who completed the survey between November 2014 and February 2015. METHODS: This cross-sectional study utilized mixed effects logistic regression to determine the associations between mean sensation seeking scores and ever and current e-cigarette use after controlling for covariates. RESULTS: After controlling for covariates, significant associations between sensation seeking and both ever and current e cigarette use were observed; however, these associations were significant for noncurrent smokers only (adjusted odds rations [AOR] = 1.55, 95% confidence interval (CI) = 1.39, 1.73; AOR = 1.82, 95% CI = 1.54, 2.15, respectively). CONCLUSIONS: Sensation seeking is an important factor in identifying college students who may be at increased risk for e-cigarette use behaviors. PMID- 28095127 TI - Association of the DNA repair SMUG1 rs3087404 polymorphism and its interaction with high sensitivity C-reactive protein for age-related macular degeneration in Iranian patients. AB - BACKGROUND: Age-related macular degeneration (AMD) is a complex disease and recently the role of DNA repairing genes in its susceptibility has been studied. It has been hypothesized that polymorphism in DNA repair system genes reduce the capacity to repair DNA damages which may lead to a greater susceptibility to AMD. C-reactive protein (CRP) production is shown to enhance inflammatory processes by increasing oxidative stress and inducing DNA damage. We planned to evaluate the possible association of SMUG1 variants and their possible interaction with high sensitivity CRP levels in AMD. MATERIALS AND METHODS: We included 500 case control samples consisting of 279 advanced type AMD patients and 221 genetically unrelated healthy controls enrolled for evaluation. Extracted-DNA samples were amplified to obtain fragments including the polymorphic region SMUG1 rs3087404. We calculated relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S) to clarify possible interaction of different genotypes and CRP levels for AMD. RESULTS: The distribution of the genotypes were not significantly different in the AMD patients compared to that of controls (p = 0.849). The allele frequency for SMUG1 was not different between study groups. No difference of SMUG1 polymorphism between case and control groups was evident in higher CRP levels (CRP>3mg/dl) compared with lower CRP levels. SMUG1/CRP synergy indices calculated as RERI = -0.12 and AP = -0.18 while S was not calculable. CONCLUSIONS: Our study showed that c.-31A/G-SMUG1 genotypes/alleles do not have any association with the occurrence or severity of advanced type AMD. There was no interaction of CRP levels and SMUG1 genotypes in AMD susceptibility. PMID- 28095128 TI - Safety and benefits of inhaled hypertonic saline following airway challenges with endotoxin and allergen in asthmatics. AB - OBJECTIVE: To determine whether induced sputum (IS) with hypertonic saline inhalation is safe to use in asthmatics within 24 hours of two commonly used airway challenges, namely endotoxin and dust mite allergen, and to assess whether IS can enhance mucociliary clearance (MCC) rates in asthmatics. METHODS: IS (three 7-minute inhalation periods of 3%, 4%, and 5% hypertonic saline) was employed before (N = 29) and within 24 hours of inhaled challenges with endotoxin (N = 13) and dust mite allergen (N = 12) in a cohort of mild to moderate asthmatics. Safety was assessed by lung function (Forced Expiratory Volume in 1 second; FEV1) and MCC was measured using a radiolabeled gamma scintigraphy method (Tcm99 sulfur colloid). IS was performed pre and post MCC. RESULTS: No significant lung function decrement was observed before or after inhaled challenges with endotoxin or dust mite allergen. IS significantly enhanced MCC rates before and after inhaled endotoxin challenge. CONCLUSION: Based on a small cohort, IS is safe to use in mild to moderate asthmatics before and within 24 hours of inhaled challenges with endotoxin and dust mite allergen. Furthermore, IS has beneficial effects on host defense function in asthmatics by enhancing MCC rates. PMID- 28095133 TI - Trauma exposure and disordered eating: A qualitative study. AB - Quantitative studies have demonstrated a positive association between trauma exposure and disordered eating. However, reasons for this relationship are unclear. We used qualitative methods to understand why some individuals exposed to trauma report disordered eating. We conducted five focus groups and two dyadic interviews between spring 2013 and fall 2014 with women at a Veterans Health Administration medical center (N = 20). Most participants were recruited from outpatient mental health clinics. Participants completed demographic and psychological questionnaires. Using thematic analysis of transcripts, we identified trauma and disordered eating-related themes. Most participants were women of color (55%), and many reported psychological symptoms (65%). The mean age was 48 years (SD = 15). Thematic analysis resulted in three themes. First, trauma can be associated with disordered eating, often in relation to negative affect and maladaptive thoughts. Second, disordered eating can provide short term, but not long-term, relief from trauma-related negative affect. Third, disordered eating can provide a mechanism to avoid unwanted attention from potential and past perpetrators of trauma. Trauma-related disordered eating, particularly in relation to sexual trauma, may have a distinct profile. Querying patients about causes of disordered eating when women report trauma histories may help clinicians ensure patients receive appropriate treatment. PMID- 28095134 TI - Physical and Occupational Therapy for a Teenager with Acute Flaccid Myelitis: A Case Report. AB - AIMS: The purpose of this case report is to describe the inpatient rehabilitation program of a 13-year-old boy with acute flaccid myelitis (AFM), specific to physical and occupational therapy examination, treatment, and outcomes. CASE DESCRIPTION: AFM is a rare, acute neurologic illness in children and young adults who present with weakness and/or paralysis of unknown etiology. The teenager was admitted to the program, dependent for all mobility and self-care. Interventions focused on range of motion, transfer training, self-care, power wheelchair mobility, and environmental adaptations. OUTCOMES: Weekly re-evaluations and the WeeFIM were used at admission and discharge to measure the teenager's progress. At discharge, the teenager had made small gains in his passive and active range of motion. He was independent in directing his care and able to drive his power wheelchair with supervision. DISCUSSION: Due to the scarcity of published data describing AFM, this report describes an individual's response to a rehabilitation program and will hopefully add to future research in order to provide patients and families with expectations for their recovery and ultimate level of function. PMID- 28095135 TI - Respirator Use Among US Farm Operators With Asthma: Results From the 2011 Farm and Ranch Safety Survey. AB - OBJECTIVE: The purpose of this study was to estimate the national prevalence of respirator use among farm operators with farm work-related asthma and factors associated with respirator use. METHODS: The authors examined the 2011 Farm and Ranch Safety Survey, a national survey collected from 11,210 actively farming farm operators in the United States. Adjusted prevalence ratios (aPORs) of respirator use were calculated by demographic characteristics, farm characteristics, asthma characteristics, and selected exposures and hazards. RESULTS: Among the estimated 2.2 million farm operators in 2011, 35.7% reported using a respirator in the past 12 months. Respirator use was significantly (P < .05) associated with age, marital status, sex, smoking status, farm value of sales, farm type, farm acreage, and geographic region. Operators who work with pesticides were 3.5 times more likely to use respirator than those who did not work with pesticides (P < .0001). Among those with current asthma, 60.8% of operators with farm work-related asthma used respirators compared with 44.4% of operators with non-farm work-related asthma (P = .03). Farm operators with farm work-related asthma who had an asthma attack at work were 11.3 times more likely to report respirator use than those who did not have an asthma attack at work (P = .03). CONCLUSIONS: Personal protective equipment, including respirators, is an approach to reducing respiratory exposures in agricultural settings, in particular among those with farm work-related asthma. Education for respirator use and evaluation for respirator tolerance should be considered. PMID- 28095136 TI - Homonationalism Before Homonationalism: Representations of Russia, Eastern Europe, and the Soviet Union in the U.S. Homophile Press, 1953-1964. AB - This essay focuses on representations of Russia, the Soviet Union, and Eastern Europe in U.S. homophile periodicals from 1953 to 1964. Extending the application of Jasbir Puar's concept of homonationalism to the Cold War period, the essay examines 128 articles and other items that were published in ONE, Mattachine Review, and The Ladder and demonstrates that these periodicals often engaged in homonationalist discourses when constructing the Russian, Soviet, and Eastern European "other." Negative constructions of these regions were sometimes used to affirm the political alignment of the homophile authors with the American nation. At other times, negative constructions were used in comparative assessments that critiqued both the United States and the Soviet and Eastern European regions. In contrast, positive constructions of Russian, Soviet, and Eastern European peoples and cultures were used as evidence that non-heteronormative desires and bodies had legitimate places in many "primitive" cultures and existed across all nations and periods. PMID- 28095137 TI - Diabetes mellitus and obesity in the French Caribbean: A special vulnerability for women? AB - The objective of this study was to analyze the prevalence, awareness, treatment, and control of diabetes and its risk factors among French Caribbean adults. This cross-sectional study included 18-74-year olds (N = 2252; 56.5 percent women) who underwent a heath examination in Guadeloupe during July-December 2014. Diabetes was defined as using antidiabetic treatment, or fasting glucose >=7 mmol/l, and glycated hemoglobin (HbA1c) >=6.5 percent; diabetes control was defined as HbA1c < 7 percent. Multilevel logistic regression was used. Diabetes prevalence was 8.2 percent for women and 5 percent for men (age-adjusted odds ratio [aOR] for women = 2.0; 95 percent confidence interval [CI]: 1.4-2.9). The proportion of women with diabetes who were aware of it was 84.5 versus 67.3 percent in men (aOR = 2.7; 95 percent CI: 1.2-6.2). Nearly, all diagnosed participants were being treated. In less than a third of diabetics in both sexes was diabetes control obtained. Most women (55.3 percent) had a waist circumference at or above the National Cholesterol Education Program thresholds versus 14 percent of men (aOR = 9.3; 95 percent CI: 7.5-11.7), which wholly accounted for excess diabetes in women. In women, obesity and diabetes were associated with low education and income. In this French Caribbean sample, abdominal obesity and diabetes affected more women. Diabetes was rarely controlled. A comprehensive women's health policy for the prevention of abdominal obesity and diabetes is needed. PMID- 28095139 TI - Corrigendum. PMID- 28095141 TI - An Old Problem: Aging and Skeletal-Muscle-Strain Injury. AB - : Clinical Scenario: Even though chronological aging is an inevitable phenomenological consequence occurring in every living organism, it is biological aging that may be the most significant factor challenging our quality of life. Development of functional limitations, resulting from improper maintenance and restoration of various organ systems, ultimately leads to reduced health and independence. Skeletal muscle is an organ system that, when challenged, is often injured in response to varying stimuli. Overt muscle-strain injury can be traumatic, clinically diagnosable, properly managed, and a remarkably common event, yet our contemporary understanding of how age and environmental stressors affect the initial and subsequent induction of injury and how the biological processes resulting from this event are modifiable and, eventually, lead to functional restoration and healing of skeletal muscle and adjacent tissues is presently unclear. Even though the secondary injury response to and recovery from "contraction-induced" skeletal-muscle injury are impaired with aging, there is no scientific consensus as to the exact mechanism responsible for this event. Given the multitude of investigative approaches, particular consideration given to the appropriateness of the muscle-injury model, or research paradigm, is critical so that outcomes may be physiologically relevant and translational. In this case, methods implementing stretch-shortening contractions, the most common form of muscle movements used by all mammals during physical movement, work, and activity, are highlighted. CLINICAL RELEVANCE: Understanding the fundamental evidence regarding how aging influences the responsivity of skeletal muscle to strain injury is vital for informing how clinicians approach and implement preventive strategies, as well as therapeutic interventions. From a practical perspective, maintaining or improving the overall health and tissue quality of skeletal muscle as one ages will positively affect skeletal muscle's safety threshold and responsivity, which may reduce incidence of injury, improve recovery time, and lessen overall fiscal burdens. PMID- 28095140 TI - PROM1 gene variations in Brazilian patients with macular dystrophy. AB - BACKGROUND: Although the pathogenicity of the prominin-1 (PROM1) gene has already been described as associated with autosomal dominant Stargardt disease, little is known about sequence variations in this gene. PURPOSE: The aim of this study was to evaluate PROM1 gene sequence variations in patients with macular dystrophy. MATERIAL AND METHODS: This retrospective study evaluated variations in the PROM1 gene detected by next-generation sequencing test in patients with macular dystrophy and Stargardt disease. RESULTS: Of 25 medical records of patients with Stargardt disease, three records of patients with PROM1 gene sequence variations were selected for the study. The p.Asp776Val and p.Asp829Asn variants were detected in cases 1 and 2, respectively, and predicted to be pathogenic; they were probably responsible for macular dystrophy in these patients. Case 3 showed a p.Ala643Gly variant in the PROM1 gene and a single variation in the ABCA4 gene, but molecular testing results were inconclusive. CONCLUSIONS: In cases of Stargardt disease, where molecular testing results are inconclusive for pathogenic variations in the ABCA4 gene, variations in the PROM1 gene may occur and be considered responsible for the disease in the molecular analysis. This study described three cases in which variations in PROM1 gene may play a role in the pathogenesis of macular dystrophy or be associated with both autosomal recessive and autosomal dominant inheritance. PMID- 28095138 TI - Leber congenital amaurosis, from darkness to light: An ode to Irene Maumenee. AB - This article is dedicated to Irene Hussels Maumenee, Professor of Human Genetics and Ophthalmology, Johns Hopkins' Wilmer Eye Institute, Ocular Genetics Fellowship director in 1994-1995. Leber congenital amaurosis (LCA) has almost come full circle, from a profound and molecularly uncharacterized form of congenital retinal blindness to one in which a large number of causative genes and disease pathways are known, and the world's first human retinal disease to be treated by gene therapy. Dr. Maumenee's insights, efforts, and leadership have contributed significantly to this remarkable scientific journey. In this manuscript, we present a short summary of the known LCA genes, LCA disease subtypes, and emerging treatment options. Our manuscript consolidates previous knowledge with current findings in an attempt to provide a more comprehensive understanding of LCA. PMID- 28095142 TI - Epidemiology of National Collegiate Athletic Association Women's Lacrosse Injuries, 2009-10 Through 2014-15. AB - CONTEXT: Participation in collegiate women's lacrosse has increased dramatically, but little recent epidemiological data exists regarding injuries. OBJECTIVE: Describe the epidemiology of National Collegiate Athletic Association (NCAA) women's lacrosse injuries during the 2009-10 through 2014-15 academic years. SETTING: Aggregate injury and exposure data collected from 40 women's lacrosse programs providing 83 team-seasons of data. PATIENTS OR OTHER PARTICIPANTS: Collegiate women's lacrosse student-athletes. INTERVENTION: Women's lacrosse data from the NCAA Injury Surveillance Program were analyzed. MAIN OUTCOME MEASURES: Injury rates; injury rate ratios; and injury proportions by body site, diagnosis, and injury mechanism were reported with 95% confidence intervals (CI). Time loss (TL) injuries resulted in participation restriction time of at least 24 hours. Nontime loss (NTL) injuries resulted in participation restriction time under 24 hours. RESULTS: There were 705 TL and NTL women's lacrosse injuries, resulting in an injury rate of 4.93/1000 athlete-exposures (AEs; 95% CI: 4.57-5.30). The TL and NTL injury rates were 2.18/1000 AE (95% CI: 1.93-2.42) and 2.64/1000 AE (95% CI: 2.37-2.90), respectively. Most injuries were to the lower extremity (competition: 64.4%; practice: 71.2%). Most injuries in competition were sprains (26.0%), contusions (19.6%), and strains (19.2%); most injuries in practice were strains (21.4%), sprains (18.1%), and inflammatory conditions (15.8%). Concussions comprised the highest proportion of head/face injuries (competition: 82.1%; practice: 54.5%). No eye injuries were reported. The highest proportion of injuries were player contact (27.4%) in competitions and noncontact (32.1%) in practices. Contact with the ball and stick comprised 21.5% of competition and 14.0% of practice injuries. CONCLUSIONS: This study is the most robust assessment of collegiate women's lacrosse injuries to date, utilizing surveillance data that includes both TL and NTL injuries. Over half of all injuries were NTL; inclusion of such injuries further highlights the breadth of injuries managed by team medical staff. PMID- 28095144 TI - Pancreatic Cancer Survival: Plasma Levels of 25-Hydroxyvitamin D and Smoking. PMID- 28095143 TI - "The Madness of the Carnival": Representations of Latin America and the Caribbean in the U.S. Homophile Press. AB - This essay examines representations of Latin America and the Caribbean in U.S. homophile periodicals from 1953 to 1964. The 120 items in ONE, Mattachine Review, and The Ladder that referenced this region depicted Latin America and the Caribbean as different from the United States in a number of ways, in particular as more sexually repressive or more sexually liberal. These representations typically conformed to the general homophile movement tendency to challenge U.S. anti-homosexual campaigns during the "Lavender Scare," while arguing for acceptance based on rights claims. The representations also were based on Cold War, colonial, racist, nationalist, and imperialist frameworks. The essay argues that although the magazines generally affirmed the dominant homophile discourses of respectability and domesticity, they also challenged these discourses by presenting Latin American and Caribbean cultures as gender-nonconforming and sexually promiscuous. PMID- 28095145 TI - Performance of Four Frailty Classifications in Older Patients With Cancer: Prospective Elderly Cancer Patients Cohort Study. AB - Purpose Frailty classifications of older patients with cancer have been developed to assist physicians in selecting cancer treatments and geriatric interventions. They have not been compared, and their performance in predicting outcomes has not been assessed. Our objectives were to assess agreement among four classifications and to compare their predictive performance in a large cohort of in- and outpatients with various cancers. Patients and Methods We prospectively included 1,021 patients age 70 years or older who had solid or hematologic malignancies and underwent a geriatric assessment in one of two French teaching hospitals between 2007 and 2012. Among them, 763 were assessed using four classifications: Balducci, International Society of Geriatric Oncology (SIOG) 1, SIOG2, and a latent class typology. Agreement was assessed using the kappa statistic. Outcomes were 1-year mortality and 6-month unscheduled admissions. Results All four classifications had good discrimination for 1-year mortality (C-index >= 0.70); discrimination was best with SIOG1. For 6-month unscheduled admissions, discrimination was good with all four classifications (C-index >= 0.70). For classification into three (fit, vulnerable, or frail) or two categories (fit v vulnerable or frail and fit or vulnerable v frail), agreement among the four classifications ranged from very poor (kappa <= 0.20) to good (0.60 < kappa <= 0.80). Agreement was best between SIOG1 and the latent class typology and between SIOG1 and Balducci. Conclusion These four frailty classifications have good prognostic performance among older in- and outpatients with various cancers. They may prove useful in decision making about cancer treatments and geriatric interventions and/or in stratifying older patients with cancer in clinical trials. PMID- 28095148 TI - Reply to A. Braillon. PMID- 28095146 TI - Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. AB - Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenstrom macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing. PMID- 28095147 TI - Management of Small Renal Masses: American Society of Clinical Oncology Clinical Practice Guideline. AB - Purpose To provide recommendations for the management options for patients with small renal masses (SRMs). Methods By using a literature search and prospectively defined study selection, we sought systematic reviews, meta-analyses, randomized clinical trials, prospective comparative observational studies, and retrospective studies published from 2000 through 2015. Outcomes included recurrence-free survival, disease-specific survival, and overall survival. Results Eighty-three studies, including 20 systematic reviews and 63 primary studies, met the eligibility criteria and form the evidentiary basis for the guideline recommendations. Recommendations On the basis of tumor-specific findings and competing risks of mortality, all patients with an SRM should be considered for a biopsy when the results may alter management. Active surveillance should be an initial management option for patients who have significant comorbidities and limited life expectancy. Partial nephrectomy (PN) for SRMs is the standard treatment that should be offered to all patients for whom an intervention is indicated and who possess a tumor that is amenable to this approach. Percutaneous thermal ablation should be considered an option if complete ablation can reliably be achieved. Radical nephrectomy for SRMs should only be reserved for patients who possess a tumor of significant complexity that is not amenable to PN or for whom PN may result in unacceptable morbidity even when performed at centers with expertise. Referral to a nephrologist should be considered if chronic kidney disease (estimated glomerular filtration rate < 45 mL/min/1.73 m2) or progressive chronic kidney disease occurs after treatment, especially if associated with proteinuria. PMID- 28095149 TI - Pertuzumab Use in the Adjuvant Setting: Why Not? PMID- 28095150 TI - Optimal Adjuvant Chemotherapy Regimens for Patients With Early-Stage Breast Cancer. PMID- 28095151 TI - Health-Related Quality of Life in Adolescent and Young Adult Patients With Cancer: A Longitudinal Study. AB - Purpose To examine changes in health-related quality of life (HRQoL) and its predictors during the first 2 years after initial cancer diagnosis in adolescent and young adult (AYA) patients with cancer. Patients and Methods A multicenter, longitudinal, prospective study was conducted among a diverse sample of AYA patients with cancer ages 15 to 39 years. One hundred seventy-six patients (75% response) completed a self-report measure of HRQoL (Short Form-36 [SF-36]) within the first 4 months after diagnosis and again 12 and 24 months later. Linear mixed models with random intercepts and slopes estimated changes in QoL. Results Recently diagnosed AYA patients with cancer had significantly worse physical component scale (PCS) scores (38.7 v 52.8; P < .001) and mental component scale (MCS) scores (42.9 v 48.9; P < .001) when compared with population norms. Significant improvements in PCS and MCS scores from baseline to 24-month follow up were observed; however, these increases were largest during the first 12 months. At the 24-month follow-up, AYA patients still had significantly lower PCS scores (48.0 v 52.8; P < .001) and MCS scores (45.8 v 48.9; P = .002) when compared with population norms. Multivariable analyses revealed that improvements in PCS and MCS scores were primarily a function of being off-treatment and being involved in school or work. PCS but not MCS scores were worse for AYA patients diagnosed with cancers with poorer prognoses. Conclusion Although HRQoL improved over time, it was still compromised 24 months after primary diagnosis. Given relatively little observed improvement in HRQoL during the 12- to 24-month period after diagnosis, AYA patients may benefit from supportive care interventions administered during the second year after diagnosis. PMID- 28095152 TI - Tailored Approaches to Induction Therapy for Acute Promyelocytic Leukemia. AB - The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. PMID- 28095154 TI - Radiation-Induced Heart Disease After Breast Cancer Treatment: How Big a Problem, and How Much Can-and Should-We Try to Reduce It? PMID- 28095153 TI - Reply to L. Moscetti. PMID- 28095155 TI - Understanding the Relationship Between Care Volume and Clinical Outcomes in Multiple Myeloma. PMID- 28095156 TI - Lung Cancer Risk Prediction Model Incorporating Lung Function: Development and Validation in the UK Biobank Prospective Cohort Study. AB - Purpose Several lung cancer risk prediction models have been developed, but none to date have assessed the predictive ability of lung function in a population based cohort. We sought to develop and internally validate a model incorporating lung function using data from the UK Biobank prospective cohort study. Methods This analysis included 502,321 participants without a previous diagnosis of lung cancer, predominantly between 40 and 70 years of age. We used flexible parametric survival models to estimate the 2-year probability of lung cancer, accounting for the competing risk of death. Models included predictors previously shown to be associated with lung cancer risk, including sex, variables related to smoking history and nicotine addiction, medical history, family history of lung cancer, and lung function (forced expiratory volume in 1 second [FEV1]). Results During accumulated follow-up of 1,469,518 person-years, there were 738 lung cancer diagnoses. A model incorporating all predictors had excellent discrimination (concordance (c)-statistic [95% CI] = 0.85 [0.82 to 0.87]). Internal validation suggested that the model will discriminate well when applied to new data (optimism-corrected c-statistic = 0.84). The full model, including FEV1, also had modestly superior discriminatory power than one that was designed solely on the basis of questionnaire variables (c-statistic = 0.84 [0.82 to 0.86]; optimism corrected c-statistic = 0.83; pFEV1 = 3.4 * 10-13). The full model had better discrimination than standard lung cancer screening eligibility criteria (c statistic = 0.66 [0.64 to 0.69]). Conclusion A risk prediction model that includes lung function has strong predictive ability, which could improve eligibility criteria for lung cancer screening programs. PMID- 28095158 TI - Are All Patients Truly Hormone Receptor Negative? PMID- 28095157 TI - At Sea. PMID- 28095159 TI - Validation and Modification of a Prediction Model for Acute Cardiac Events in Patients With Breast Cancer Treated With Radiotherapy Based on Three-Dimensional Dose Distributions to Cardiac Substructures. AB - Purpose A relationship between mean heart dose (MHD) and acute coronary event (ACE) rate was reported in a study of patients with breast cancer (BC). The main objective of our cohort study was to validate this relationship and investigate if other dose-distribution parameters are better predictors for ACEs than MHD. Patients and Methods The cohort consisted of 910 consecutive female patients with BC treated with radiotherapy (RT) after breast-conserving surgery. The primary end point was cumulative incidence of ACEs within 9 years of follow-up. Both MHD and various dose-distribution parameters of the cardiac substructures were collected from three-dimensional computed tomography planning data. Results The median MHD was 2.37 Gy (range, 0.51 to 15.25 Gy). The median follow-up time was 7.6 years (range, 0.1 to 10.1 years), during which 30 patients experienced an ACE. The cumulative incidence of ACE increased by 16.5% per Gy (95% CI, 0.6 to 35.0; P = .042). Analysis showed that the volume of the left ventricle receiving 5 Gy (LV-V5) was the most important prognostic dose-volume parameter. The most optimal multivariable normal tissue complication probability model for ACEs consisted of LV-V5, age, and weighted ACE risk score per patient (c-statistic, 0.83; 95% CI, 0.75 to 0.91). Conclusion A significant dose-effect relationship was found for ACEs within 9 years after RT. Using MHD, the relative increase per Gy was similar to that reported in the previous study. In addition, LV-V5 seemed to be a better predictor for ACEs than MHD. This study confirms the importance of reducing exposure of the heart to radiation to avoid excess risk of ACEs after radiotherapy for BC. PMID- 28095160 TI - Minimal Loss of Lifetime for Patients With Diffuse Large B-Cell Lymphoma in Remission and Event Free 24 Months After Treatment: A Danish Population-Based Study. AB - Purpose The general outlook for patients with diffuse large B-cell lymphoma (DLBCL) in first remission is important information for patients and for planning post-treatment follow-up. The purpose of this study was to evaluate the survival of patients with DLBCL in remission compared with a matched general population. Methods A total of 1,621 patients from the Danish Lymphoma Registry who were newly diagnosed with DLBCL between 2003 and 2011 were included in this study. All patients were >= 16 years of age at diagnosis and had achieved complete remission or complete remission unconfirmed after first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP like therapy. Results The 5-year post-treatment DLBCL survival was inferior to survival in the matched general population (78%; 95% CI, 76 to 80; v 87%; standardized mortality ratio, 1.75; P < .001). Excess mortality was present but reduced for patients achieving post-treatment event-free survival for 24 months (pEFS24; standardized mortality ratio, 1.27; P < .001). In age-stratified analyses, the survival of patients < 50 years of age was normalized to the general population after achieving pEFS24 ( P = .99). During the first 8 years after pEFS24, the average loss of lifetime was 0.31 mo/y (95% CI, 0.11 to 0.50 mo/y). Excess mortality diminished when analyzing death from lymphoma as competing event to death from other causes, suggesting that early and late relapse is responsible for increased mortality in patients with DLBCL. Conclusion Although this population-based study does not support complete normalization of survival for patients with DLBCL achieving pEFS24, the estimated loss of residual lifetime was low for patients in continuous remission 2 years after ending treatment. Therefore, pEFS24 is an appealing and relevant milestone for patient counseling and could be a surrogate end point in clinical trials. PMID- 28095161 TI - Reply to L. Del Mastro and A. Prat. PMID- 28095165 TI - Prevalence and Correlates of Misconduct Among Ethnically Diverse Adolescents of Native Hawaiian/Part-Hawaiian and Non-Hawaiian Ancestry. AB - BACKGROUND: Research on the prevalence and correlates of adolescent misconduct, arrests, and juvenile delinquency has been greatly neglected for the ethnically diverse adolescent groups in Hawai'i (i.e. Asian Americans, Pacific Islanders). AIMS: The aims of the present study are three-fold: (1) to determine whether there are differential rates of adolescent misconduct based on ethnicity, gender, and socioeconomic (SES) factors; (2) on an exploratory basis, to ascertain the demographic, social-cultural, psychological-psychiatric, and school-related correlates of misconduct, with some focus on cultural identification; and (3) to derive a parsimonious model of the correlates for an ethnically diverse group of adolescents by disentangling cultural identification from other variables including ethnicity. METHODS: Data were analyzed from the Native Hawaiian Mental Health Research Development Program, consisting of 2,732 Asian/Pacific Islander youths. Misconduct was operationally defined as 'was arrested or got in serious trouble with the law' within the past six months via adolescent self-report. Of added importance were the inclusion of a valid measure of Hawaiian cultural identification and actual school data. RESULTS: Significantly higher rates were obtained for Native Hawaiians, males, and adolescents whose main wage earners' educational attainment was at the high school level or less. Absences may be a more important marker for females than males in the prediction of arrests and serious trouble with the law. The most parsimonious model of self-reported arrests/serious trouble with the law consisted of four variables in the following order of importance: substance use, actual grade-point average, aggressive symptoms, and gender. CONCLUSION: This is one of the first major studies to examine the prevalence and risk-protective factors of misconduct for adolescents of Asian/Pacific Islander ancestry, and the first to include a valid measure of cultural identification and actual school data. The findings indicated that gender-specific prevention and intervention programs are needed. However, the issues are also complex whereby the use of substances, school performance, and aggression must be taken into account in deriving successful programs. The lack of sustained association between culturally based factors (e.g., ethnicity, Hawaiian cultural identifi-cation) and misconduct in the final parsimonious model suggested that the culturally based variables are not direct causes of misconduct, but rather correlates of misconduct that are over-shadowed by more substantive factors, such as substance use and academic performance, the latter being variables that must be addressed for youths across the United States. The present results reaffirmed the common correlates of misconduct across different ethnic groups. Further research is needed in the causal relationships among these important associations with misconduct. PMID- 28095167 TI - The Social Functioning Questionnaire: A Rapid and Robust Measure of Perceived Functioning. AB - BACKGROUND: The Social Functioning Questionnaire (SFQ), an eight-item selfreport scale (score range 0-24), was developed from the Social Functioning Schedule (SFS), a semi-structured interview which has been used primarily with non psychotic patients and has good test-retest and inter-rater reliability as well as construct validity. The SFQ was developed following the need for a quick assessment of perceived social function. AIMS: To give further details of old and new data sets from studies involving over 4000 subjects assessed with the SFQ illustrating its epidemiological and clinical associations. METHOD: New data were analysed from a national epidemiological study, a comparison of key-worker and subject versions of the SFQ, and reanalysis of data from three earlier clinical studies, of psychiatric emergencies, general practice psychiatric patients and those with recurrent psychotic illnesses. These data were examined further to determine their range, their relationship to other clinical measures, and change over time in clinical trials. RESULTS: The population mean score in 4164 subjects was 4.6 and the data from all studies suggested that a score of 10 or more indicated poor social functioning. Those presenting as psychiatric emergencies had the poorest social function (mean 11.4) and psychiatric patients from general practice the best function (mean 7.7) of the clinical populations. The eight item scores had a normal distribution in psychiatric populations and a skewed one in a normal population; scores were relatively stable over the short (weeks) and long term (months), and were high in the presence of acute mental health disturbance and personality disorder, giving support to the validity of the scale. The results from a UK sample of a randomly selected population specifically weighted for ethnic minorities showed similar social function across groups. PMID- 28095168 TI - Does Having a Culturally Competent Health Care Provider Affect the Patients' Experience or Satisfaction? A Critically Appraised Topic. AB - Clinical Scenario: The level of cultural competence of health care providers has been studied. However, limited scholarship has examined whether the cultural competence of the health care provider affects patient satisfaction. Focused Clinical Question: Does cultural competence of health care providers influence patient satisfaction with their experience with their provider? Summary of Key Findings: Having a culturally competent health care provider, or one who a patient perceives as culturally competent, does increase patient satisfaction. Clinical Bottom Line: Cultural competence in health care plays an important role in patients being satisfied with their providers, as well as patients willingly and actively participating in their treatment. Strength of Recommendation: Questions 1 to 5 and 9 of the critical appraisal skills program were answered "yes" for all studies in the critically appraised topic. Thus, the authors strongly support the findings. PMID- 28095169 TI - Examination of Knee Morphology After Secondary Ipsilateral ACL Injury Compared With Those That Have Not Been Reinjured: A Preliminary Study. AB - CONTEXT: Modifiable and nonmodifiable risk factors have been identified for sustaining a primary anterior cruciate ligament (ACL) injury; however, less research is available examining risk factors for a second injury. Identifying whether bony morphological factors are different (or more exaggerated) among those that experience a secondary ACL injury is critical to understanding if nonmodifiable risk factors are associated with a second injury. OBJECTIVE: To determine if bony morphology is different among those that experience a secondary ACL reinjury as compared with those that do not. DESIGN: Case-control. SETTING: University laboratory. PARTICIPANTS AND INTERVENTIONS: ACL participants were tracked after return to play following primary reconstruction, and if individuals experienced a second ipsilateral injury (ACLx2; n = 14, 8f/6m, 17.9 +/- 4.0 y), the primary clinical MRI was analyzed for bony morphological risk factors. ACLx2 participants were matched to individuals (sex, age, height, graft, gender, and activity level) that had undergone reconstruction but did not experience reinjury (ACLx1, n = 14, 8f/6m, 18.7 +/- 4.0 y). Ten controls were also enrolled (5m/5f, 20.8 +/- 3.9 y) for the purposes of comparing the authors' ACL data against healthy knees. MAIN OUTCOME MEASURES: Lateral and medial posterior tibial slopes (LPTS, MPTS), notch shape index (NSI), and medial tibial plateau depth of concavity (MDC). RESULTS: All ACL-reconstructed patients (combined ACLx1 and ACLx2 group) had a steeper LPTS than controls (d = 0.87, 95% CI 0.11-1.60, P = .023); however, no difference in LPTS was found between ACLx1 and ACLx2 (P > .05). No differences in MPTS, NSI, and MDC were found between all ACL participants (combined ACLx2 and ACLx1) and controls or between ACLx1 and ACLx2 (P > .05). CONCLUSIONS: Compared to healthy individuals, a steeper LPTS is a common bony abnormality in all ACL-injured participants. Individuals that go on to experience a second ipsilateral ACL injury do not have more exaggerated bony morphology than those that do not suggesting that differences in modifiable risk factors at return to play may contribute to reinjury. PMID- 28095170 TI - Financial Burden for Patients With Chronic Myeloid Leukemia Enrolled in Medicare Part D Taking Targeted Oral Anticancer Medications. AB - PURPOSE: The number of targeted oral anticancer medications (TOAMs) has grown rapidly in the past decade. The high cost of TOAMs raises concerns about the financial aspect of treatment, especially for patients enrolled in Medicare Part D plans because of the coverage gap. METHODS: We identified patients with chronic myeloid leukemia (CML) who were new TOAM users from the SEER registry data linked with Medicare Part D data, from years 2007 to 2012. We followed these patients throughout the calendar year when they started taking the TOAMs and examined their out-of-pocket (OOP) payments and gross drug costs, taking into account their benefit phase, plan type, and cost share group. RESULTS: We found that 726 (81%) of the 898 patients with CML who received TOAMs had reached the catastrophic phase of their Medicare Part D benefit within the year of medication initiation, with a large majority of patients reaching this phase in less than a month. Patients without subsidies showed a clear pattern of a spike in OOP payments when they began treatment with TOAMs. The OOP payment for patients with subsidies was substantially lower. The monthly gross drug costs were similar between patients with and without subsidies. CONCLUSION: Patients experience quick entry and exit from the coverage gap (also called the donut hole) as a result of the high price of TOAMs. Closing the donut hole will provide financial relief during the initial month(s) of treatment but will not completely eliminate the financial burden. PMID- 28095171 TI - Drug Interaction Database Sensitivity With Oral Antineoplastics: An Exploratory Analysis. AB - PURPOSE: Drug interactions are a concern in oncology with the shift toward oral antineoplastics (OAs). Using electronic databases to screen for drug interactions with OAs is a common practice. There is little literature to guide clinicians on the reliability of these systems with OAs. The primary objective of this study was to explore the sensitivity of commonly available drug interaction databases in detecting drug interactions with OAs. METHODS: A list of 20 drug interactions with OAs was developed by two Board-certified oncology pharmacists. The list included multiple types of drug interactions. The sensitivity in detecting these interactions by MicroMedex, Facts & Comparisons, Lexi-Interact, and Epocrates were evaluated. These databases were chosen based on their local availability and widespread use in practice. Drugs.com was evaluated as a surrogate for a patient accessible drug interaction database. The Cochran Q test was used to assess the sensitivity distribution across the five groups. RESULTS: Lexi-Interact and Drugs.com had a sensitivity of 95% for the 20 tested drug interaction pairs. Epocrates had a sensitivity of 90%, and both Micromedex and Facts & Comparisons had a sensitivity of 70%. There was a statistically significant difference ( P = .016) in the distribution across the databases in detecting clinically significant drug interactions. CONCLUSION: Commonly used databases for identifying drug interactions with oral antineoplastics vary significantly in their sensitivity. Clinicians should not rely on a single database and should consider using multiple resources as well as sound clinical judgment. Further work is needed in this area. PMID- 28095172 TI - Characterizing the Nature of Scan Results Discussions: Insights Into Why Patients Misunderstand Their Prognosis. AB - INTRODUCTION: Patients with incurable cancer have poor prognostic awareness. We present a detailed analysis of the dialogue between oncologists and patients in conversations with prognostic implications. METHODS: A total of 128 audio recorded encounters from a large multisite trial were obtained, and 64 involved scan results. We used conversation analysis, a qualitative method for studying human interaction, to analyze typical patterns and conversational devices. RESULTS: Four components consistently occurred in sequential order: symptom-talk, scan-talk, treatment-talk, and logistic-talk. Six of the encounters (19%) were identified as good news, 15 (45%) as stable news, and 12 (36%) as bad news. The visit duration varied by the type of news: good, 15 minutes (07:00-29:00); stable, 17 minutes (07:00-41:00); and bad, 20 minutes (07:00-28:00). Conversational devices were common, appearing in half of recordings. Treatment talk occupied 50% of bad-news encounters, 31% of good-news encounters, and 19% of stable-news encounters. Scan-talk occupied less than 10% of all conversations. There were only four instances of frank prognosis discussion. CONCLUSION: Oncologists and patients are complicit in constructing the typical encounter. Oncologists spend little time discussing scan results and the prognostic implications in favor of treatment-related talk. Conversational devices routinely help transition from scan-talk to detailed discussions about treatment options. We observed an opportunity to create prognosis-talk after scan-talk with a new conversational device, the question "Would you like to talk about what this means?" as the oncologist seeks permission to disclose prognostic information while ceding control to the patient. PMID- 28095173 TI - Performance of a Trigger Tool for Identifying Adverse Events in Oncology. AB - PURPOSE: Although patient safety is a priority in oncology, few tools measure adverse events (AEs) beyond treatment-related toxicities. The study objective was to assemble a set of clinical triggers in the medical record and assess the extent to which triggered events identified AEs. METHODS: We performed a retrospective cohort study to assess the performance of an oncology medical record screening tool at a comprehensive cancer center. The study cohort included 400 patients age 18 years or older diagnosed with breast (n = 128), colorectal (n = 136), or lung cancer (n = 136), observed as in- and outpatients for up to 1 year. RESULTS: We identified 790 triggers, or 1.98 triggers per patient (range, zero to 18 triggers). Three hundred four unique AEs were identified from medical record reviews and existing AE databases. The overall positive predictive value (PPV) of the original tool was 0.40 for total AEs and 0.15 for preventable or mitigable AEs. Examples of high-performing triggers included return to the operating room or interventional radiology within 30 days of surgery (PPV, 0.88 and 0.38 for total and preventable or mitigable AEs, respectively) and elevated blood glucose (> 250 mg/dL; PPV, 0.47 and 0.40 for total and preventable or mitigable AEs, respectively). The final modified tool included 49 triggers, with an overall PPV of 0.48 for total AEs and 0.18 for preventable or mitigable AEs. CONCLUSION: A valid medical record screening tool for AEs in oncology could offer a powerful new method for measuring and improving cancer care quality. Future improvements could optimize the tool's efficiency and create automated electronic triggers for use in real-time AE detection and mitigation algorithms. PMID- 28095174 TI - Medical Oncologists' Experiences in Using Genomic Testing for Lung and Colorectal Cancer Care. AB - PURPOSE: Genomic testing improves outcomes for many at-risk individuals and patients with cancer; however, little is known about how genomic testing for non small-cell lung cancer (NSCLC) and colorectal cancer (CRC) is used in clinical practice. PATIENTS AND METHODS: In 2012 to 2013, we surveyed medical oncologists who care for patients in diverse practice and health care settings across the United States about their use of guideline- and non-guideline-endorsed genetic tests. Multivariable regression models identified factors that are associated with greater test use. RESULTS: Of oncologists, 337 completed the survey (participation rate, 53%). Oncologists reported higher use of guideline-endorsed tests (eg, KRAS for CRC; EGFR for NSCLC) than non-guideline-endorsed tests (eg, Onco typeDX Colon; ERCC1 for NSCLC). Many oncologists reported having no patients with CRC who had mismatch repair and/or microsatellite instability (24%) or germline Lynch syndrome (32%) testing, and no patients with NSCLC who had ALK testing (11%). Of oncologists, 32% reported that five or fewer patients had KRAS and EGFR testing for CRC and NSCLC, respectively. Oncologists, rather than pathologists or surgeons, ordered the vast majority of tests. In multivariable analyses, fewer patients in nonprofit integrated health care delivery systems underwent testing than did patients in hospital or office-based single-specialty group settings (all P < .05). High patient volume and patient requests (CRC only) were also associated with higher test use (all P < .05). CONCLUSION: Genomic test use for CRC and NSCLC varies by test and practice characteristics. Research in specific clinical contexts is needed to determine whether the observed variation reflects appropriate or inappropriate care. One potential way to reduce unwanted variation would be to offer widespread reflexive testing by pathology for guideline-endorsed predictive somatic tests. PMID- 28095175 TI - Evaluation of the Droplet-Microarray Platform for High-Throughput Screening of Suspension Cells. AB - Phenotypic cell-based high-throughput screenings play a central role in drug discovery and toxicology. The main tendency in cell screenings is the increase of the throughput and decrease of reaction volume in order to accelerate the experiments, reduce the costs, and enable screenings of rare cells. Conventionally, cell-based assays are performed in microtiter plates, which exist in 96- to 1536-wells formats and cannot be further miniaturized. In addition, performing screenings of suspension cells is associated with risk of losing cell content during the staining procedures and incompatibility with high-content microscopy. Here, we evaluate the Droplet-Microarray screening platform for culturing, screening, and imaging of suspension cells. We demonstrate pipetting free cell seeding and proliferation of cells in individual droplets of 3-80 nL in volume. We developed a methodology to perform parallel treatment, staining, and fixation of suspension cells in individual droplets. Automated imaging of live suspension cells directly in the droplets combined with algorithms for pattern recognition for image analysis is demonstrated. We evaluated the developed methodology by performing a dose-response study with antineoplastic drugs. We believe that the DMA screening platform carries great potential to be adopted for broad spectrum of screenings of suspension cells. PMID- 28095176 TI - A Flexible Workflow for Automated Bioluminescent Kinase Selectivity Profiling. AB - Kinase profiling during drug discovery is a necessary process to confirm inhibitor selectivity and assess off-target activities. However, cost and logistical limitations prevent profiling activities from being performed in house. We describe the development of an automated and flexible kinase profiling workflow that combines ready-to-use kinase enzymes and substrates in convenient eight-tube strips, a bench-top liquid handling device, ADP-Glo Kinase Assay (Promega, Madison, WI) technology to quantify enzyme activity, and a multimode detection instrument. Automated methods were developed for kinase reactions and quantification reactions to be assembled on a Gilson (Middleton, WI) PIPETMAX, following standardized plate layouts for single- and multidose compound profiling. Pipetting protocols were customized at runtime based on user-provided information, including compound number, increment for compound titrations, and number of kinase families to use. After the automated liquid handling procedures, a GloMax Discover (Promega) microplate reader preloaded with SMART protocols was used for luminescence detection and automatic data analysis. The functionality of the automated workflow was evaluated with several compound-kinase combinations in single-dose or dose-response profiling formats. Known target-specific inhibitions were confirmed. Novel small molecule-kinase interactions, including off-target inhibitions, were identified and confirmed in secondary studies. By adopting this streamlined profiling process, researchers can quickly and efficiently profile compounds of interest on site. PMID- 28095177 TI - Integrated Colony Imaging, Analysis, and Selection Device for Regenerative Medicine. AB - Stem and progenitor cells derived from human tissues are being developed as cell sources for cell-based assays and therapies. However, tissue-derived stem and progenitor cells are heterogeneous. Differences in observed clones of stem cells likely reflect important aspects of the underlying state of the source cells, as well as future potency for cell therapies. This paper describes a colony analysis and picking device that provides quantitative analysis of heterogeneous cell populations and precise tools for cell picking for research or biomanufacturing applications. We describe an integrated robotic system that enables image acquisition and automated image analysis to be coupled with rapid automated selection of individual colonies in adherent cell cultures. Other automated systems have demonstrated feasibility with picking from semisolid media or off feeder layers. We demonstrate the capability to pick adherent bone-derived stem cells from tissue culture plastic. Cells are efficiently picked from a target site and transferred to a recipient well plate. Cells demonstrate viability and adherence and maintain biologic potential for surface markers CD73 and CD90 based on phase contrast and fluorescence imaging 6 days after transfer. Methods developed here can be applied to the study of other stem cell types and automated culture of cells. PMID- 28095178 TI - Current Trends in Multidrug Optimization. AB - The identification of effective and long-lasting cancer therapies still remains elusive, partially due to patient and tumor heterogeneity, acquired drug resistance, and single-drug dose-limiting toxicities. The use of drug combinations may help to overcome some limitations of current cancer therapies by challenging the robustness and redundancy of biological processes. However, effective drug combination optimization requires the careful consideration of numerous parameters. The complexity of this optimization problem is clearly nontrivial and likely requires the assistance of advanced heuristic optimization techniques. In the current review, we discuss the application of optimization techniques for the identification of optimal drug combinations. More specifically, we focus on the application of phenotype-based screening approaches in the field of cancer therapy. These methods are divided into three categories: (1) modeling methods, (2) model-free approaches based on biological search algorithms, and (3) merged approaches, particularly phenotypically driven network biology methods and computation network models relying on phenotypic data. In addition to a brief description of each approach, we include a critical discussion of the advantages and disadvantages of each method, with a strong focus on the limitations and considerations needed to successfully apply such methods in biological research. PMID- 28095179 TI - Development of Fully Automated Low-Cost Immunoassay System for Research Applications. AB - Enzyme-linked immunosorbent assay (ELISA) automation for routine operation in a small research environment would be very attractive. A portable fully automated low-cost immunoassay system was designed, developed, and evaluated with several protein analytes. It features disposable capillary columns as the reaction sites and uses real-time calibration for improved accuracy. It reduces the overall assay time to less than 75 min with the ability of easy adaptation of new testing targets. The running cost is extremely low due to the nature of automation, as well as reduced material requirements. Details about system configuration, components selection, disposable fabrication, system assembly, and operation are reported. The performance of the system was initially established with a rabbit immunoglobulin G (IgG) assay, and an example of assay adaptation with an interleukin 6 (IL6) assay is shown. This system is ideal for research use, but could work for broader testing applications with further optimization. PMID- 28095180 TI - An Introduction to the Special Issue: Contributions of Executive Function to Academic Skills. PMID- 28095181 TI - How tRNAs dictate nuclear codon reassignments: Only a few can capture non-cognate codons. AB - mRNA decoding by tRNAs and tRNA charging by aminoacyl-tRNA synthetases are biochemically separated processes that nevertheless in general involve the same nucleotides. The combination of charging and decoding determines the genetic code. Codon reassignment happens when a differently charged tRNA replaces a former cognate tRNA. The recent discovery of the polyphyly of the yeast CUG sense codon reassignment challenged previous mechanistic considerations and led to the proposal of the so-called tRNA loss driven codon reassignment hypothesis. Accordingly, codon capture is caused by loss of a tRNA or by mutations in the translation termination factor, subsequent reduction of the codon frequency through reduced translation fidelity and final appearance of a new cognate tRNA. Critical for codon capture are sequence and structure of the new tRNA, which must be compatible with recognition regions of aminoacyl-tRNA synthetases. The proposed hypothesis applies to all reported nuclear and organellar codon reassignments. PMID- 28095182 TI - Effect of intermittent aeration on microbial diversity in an intermittently aerated IFAS reactor treating municipal wastewater: A field study. AB - In the present study, the effect of three intermittent aeration (IA) cycles on treatment performance and microbial diversity was investigated in an integrated fixed film activated sludge (IFAS) reactor treating municipal wastewater. The results showed that IA strategies were able to achieve efficient removal of organics and nitrogen ranging between 90 and 95% and 70 and 80%, respectively, however the phosphorus removal was found to be inversely proportional to the duration of aeration off time in each IA cycle. The microscopic analysis revealed that the suspended and attached biomass had compact morphology and open floc structure, respectively. For each gram of volatile suspended solids, 165 and 148 mg of extracellular polymeric substances (EPS) were extracted from attached and suspended biomass, respectively, constituting carbohydrates (~24%), proteins (~31%), humic acids (~28%), DNA (~2%) and unknown substances (~12%). The microbial diversities of suspended biomass in IFAS reactor were investigated using culture-dependent approach, which confirmed the presence of Clostridium spp., Pseudomonas spp., Bacillus spp., Escherichia coli spp., Nitrosococcus spp., Streptococcus spp., Acinetobacter spp., Betaproteobacteria outliers, Klebsiella pneumoniae, Klebsiella aerogenes, Serratia marcescens, Micrococcus, Proteus vulgaris spp., Actinomycetes spp., and Actinobacteria including Micromonospora spp. and Streptomyces spp. Molecular tools for diversity analyses were used for ammonia and nitrite oxidizer identification, such as Nitrospira and Nitrosococcus species. Denitrifiers include the species of Pseudomonas, Betaproteobacteria and Flavobacterium. Acinetobacter, Betaproteobacteria and Gammaproteobacteria were responsible for the phosphorus removal in the present system. Overall, the system performed efficiently showing Proteobacteria (59%), Acinetobacter (12%) and Bacteroidetes (11%) as the dominant bacterial groups. However, the dominance of the bacterial diversity varied with the IA cycle time numerating the maximum percentage of bacterial species during IA1 phase i.e. 2.5 h aeration/0.5 h non aeration. PMID- 28095183 TI - Total mercury concentrations in white and striped Mullet (Mugil curema and M. cephalus) from a coastal lagoon in the SE Gulf of California. AB - The White and Striped mullets (Mugil curema and M. cephalus) are highly abundant and commercially important estuarine fish in northwest (NW) Mexico. Because of their feeding habits and habitat, they are likely to accumulate mercury (Hg) in their muscle and liver. The objectives of this study were to determine total Hg distribution in the tissues of interest, to correlate Hg levels between tissues and with length and weight of fish, to estimate the percentage weekly intake (PWI) of total Hg and methyl Hg (MeHg) through consumption of both mullet species, and to compare total Hg levels with mullets from other areas. The highest total Hg concentration (1.031 ug g-1 dry weight) was measured in liver of White mullet. In both species, the order of averaged Hg concentrations (M. curema liver 0.272, muscle 0.184; M. cephalus liver 0.211, muscle 0.129 ug g-1 dry weight) were liver>muscle. Correlations of Hg in muscle and liver with total weight of M. curema were significant. In M. cephalus, Hg levels in liver were significantly correlated with total length and weight. The PWI of THg (<4%) and MeHg (<10%) were not elevated for both species. Concentration of Hg in the studied mullets was comparable to levels in similar species from Mexican waters but lower than results in mugilids from other coastal areas. PMID- 28095184 TI - Ecotoxicological effects of larvicide used in the control of Aedes aegypti on nontarget organisms: Redefining the use of pyriproxyfen. AB - The continued widespread use of larvicides in Aedes aegypti control programs is still a necessary strategy, since there are no apparent efficient vaccines against arboviruses. However, chemical approaches may affect nontarget organisms and produce detrimental effects to environmental health. Therefore, the aim of this study was to conduct toxicity testing for pyriproxyfen at different concentrations using Daphnia magna and Artemia salina as model organisms to evaluate the ecotoxicological parameters. This study describes the toxicological effects of pyriproxyfen on both microcrustaceans, which are widely used in bioassays because of their sensitivity to changes in hydrosphere. Data demonstrated that the calculated EC50-48h value of pyriproxyfen was 2.5 MUg/for D. magna and A. salina; the no-observed-effect concentration (NOEC) and the lowest-observed-effect concentration (LOEC) of pyriproxyfen were found to be 0.63 and 1.25 MUg/L for Artemia salina and Daphnia magna, respectively. In chronic toxicity and reproduction tests on D. magna, a calculated CL50-7day (lethality on 50% of daphnids after 7 days of chronic test) and an EC50-21day (50% reduction in the reproductive output of parental daphnids after 21 days of exposure) higher than 1.25 MUg/L pyriproxyfen were observed. The time of first reproduction was significantly increased in D. magna after exposure to environmentally relevant concentrations of pyriproxyfen, but other reproduction parameters were not markedly altered. Environmental risk assessment revealed that pyriproxyfen is highly toxic for both branchiopods. Data demonstrated that pyriproxyfen may produce adverse effects on the aquatic ecosystem at concentrations required to control Ae. aegypti. PMID- 28095185 TI - Seasonal, age and sex fluctuations in aflatoxin B1 content in the liver and kidney of brown hares (Lepus europaeus Pall). AB - The goal of this study was to monitor the accumulation of aflatoxin B1 in the liver and kidney of brown hares (Lepus europaeus Pall) in the region of south western Slovakia. A total of 65 samples were involved for analysis by RIA method. Brown hares were divided into the groups according to age, sex and season (month). The sex was determined visually after shooting, and the age was assigned from dried eye lens. The average concentration of AFB1 in the liver of hares was 0.54 +/- 0.053 ug/kg, and lower values were measured in the kidney (0.41 +/- 0.038 ug/kg). The significantly (P < 0.05) higher values were found in winter months when compared to summer months. According to the age, juvenile animals showed significant higher accumulation of B1 in both organs than adults (P < 0.05). Wild animals can serve as a good model of real environmental contamination. Thus, monitoring of risk factors such as mycotoxins in the environment is important with regard to public health, as game animals constitute an important part of food chain for humans. PMID- 28095186 TI - Adaptable Categorization of Hands and Tools in Prosthesis Users. PMID- 28095187 TI - Fast extraction of polychlorinated dibenzo-p-dioxin and polychlorinated dibenzofuran in sewage sludge and soil samples. AB - The current environmental legislations recommend monitoring chemical contaminants such as polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans before the use of sewage sludge on the agricultural land. In this study, a solid liquid extraction with low-temperature purification (SLE-LTP) was optimized and validated to determine 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,3,7,8 tetrachlorodibenzofuran in sewage sludge and soil samples. The analyses were performed by gas chromatography-mass spectrometry operating in the selective ion mode (GC-MS-SIM). Acetonitrile:ethyl acetate 6.5:1.5 (v/v) was the best extraction phase, and the recoveries percentages were close to 100%. The linearity was demonstrated in the range of 1.25-25 ug L-1 of 1.25-20 ug L-1 for sewage sludge and soil, respectively. Matrix effect was proved for the two compounds and in the two matrices studied. Extraction percentages were between 78 and 109% and relative standard deviations <= 19%. The proposed method is faster than methods described in the literature because showed a few steps. The quantification limits (LOQ) in sewage sludge were 6.4 and 32 ng TEQ kg-1 for 2,3,7,8-TCDF and 2,3,7,8-TCDD, respectively. In soil, LOQs were 0.8 and 8.0 ng TEQ kg-1 for 2,3,7,8-TCDF and 2,3,7,8-TCDD, respectively. These values are lower than the maximum residue limits established by European Legislation. The method was applied to 22 agricultural soil samples from different Brazilian cities and 2,3,7,8-TCDF was detected in one of these samples. PMID- 28095189 TI - The unmet clinical need of novel antifungal drugs. PMID- 28095188 TI - miR-148a and miR-17-5p synergistically regulate milk TAG synthesis via PPARGC1A and PPARA in goat mammary epithelial cells. AB - MicroRNA (miRNA) are a class of '18-25' nt RNA molecules which regulate gene expression and play an important role in several biologic processes including fatty acid metabolism. Here we used S-Poly (T) and high-throughput sequencing to evaluate the expression of miRNA and mRNA during early-lactation and in the non lactating ("dry") period in goat mammary gland tissue. Results indicated that miR 148a, miR-17-5p, PPARGC1A and PPARA are highly expressed in the goat mammary gland in early-lactation and non-lactating periods. Utilizing a Luciferase reporter assay and Western Blot, PPARA, an important regulator of fatty acid oxidation, and PGC1a (PPARGC1A), a major regulator of fat metabolism, were demonstrated to be targets of miR-148a and miR-17-5p in goat mammary epithelial cells (GMECs). It was also revealed that miR-148a expression can regulate PPARA, and miR-17-5p represses PPARGC1A in GMECs. Furthermore, the overexpression of miR 148a and miR-17-5p promoted triacylglycerol (TAG) synthesis while the knockdown of miR-148a and miR-17-5p impaired TAG synthesis in GMEC. These findings underscore the importance of miR-148a and miR-17-5p as key components in the regulation of TAG synthesis. In addition, miR-148a cooperates with miR-17-5p to regulate fatty acid metabolism by repressing PPARGC1A and PPARA in GMECs. Further studies on the functional role of miRNAs in lipid metabolism of ruminant mammary cells seem warranted. PMID- 28095190 TI - "But Oh! What Tales": Portraying the Middle East in U.S. Homophile Periodicals of the 1950s and 1960s. AB - This essay examines Middle East representations in U.S. homophile periodicals from 1953 to 1964. The essay uses more than 120 Middle East-related items that were published in ONE, Mattachine Review, and The Ladder to address the periodicals' engagement with the region (particularly ancient history and biblical themes) and discuss the types of sexual "knowledge" that the homophile periodicals created about the region. It then assesses the role of periodicals as a genre in the creation of a transnational homophile community, showing both their potential for democratizing participation in this community and their limits. The essay argues that the periodicals made visible the process of assembling a homosexual identity and the fragmentary nature of the parts it strove to unify. Though the views of key U.S. homophile organizations became hegemonic in the international gay rights movement, the periodicals show a more complex, ambivalent, and contested process. PMID- 28095191 TI - Maximum Pseudolikelihood Estimation for Model-Based Clustering of Time Series Data. AB - Mixture of autoregressions (MoAR) models provide a model-based approach to the clustering of time series data. The maximum likelihood (ML) estimation of MoAR models requires evaluating products of large numbers of densities of normal random variables. In practical scenarios, these products converge to zero as the length of the time series increases, and thus the ML estimation of MoAR models becomes infeasible without the use of numerical tricks. We propose a maximum pseudolikelihood (MPL) estimation approach as an alternative to the use of numerical tricks. The MPL estimator is proved to be consistent and can be computed with an EM (expectation-maximization) algorithm. Simulations are used to assess the performance of the MPL estimator against that of the ML estimator in cases where the latter was able to be calculated. An application to the clustering of time series data arising from a resting state fMRI experiment is presented as a demonstration of the methodology. PMID- 28095192 TI - Spike-Centered Jitter Can Mistake Temporal Structure. AB - Jitter-type spike resampling methods are routinely applied in neurophysiology for detecting temporal structure in spike trains (point processes). Several variations have been proposed. The concern has been raised, based on numerical experiments involving Poisson spike processes, that such procedures can be conservative. We study the issue and find it can be resolved by reemphasizing the distinction between spike-centered (basic) jitter and interval jitter. Focusing on spiking processes with no temporal structure, interval jitter generates an exact hypothesis test, guaranteeing valid conclusions. In contrast, such a guarantee is not available for spike-centered jitter. We construct explicit examples in which spike-centered jitter hallucinates temporal structure, in the sense of exaggerated false-positive rates. Finally, we illustrate numerically that Poisson approximations to jitter computations, while computationally efficient, can also result in inaccurate hypothesis tests. We highlight the value of classical statistical frameworks for guiding the design and interpretation of spike resampling methods. PMID- 28095193 TI - Semisupervised, Multilabel, Multi-Instance Learning for Structured Data. AB - Many classification tasks require both labeling objects and determining label associations for parts of each object. Example applications include labeling segments of images or determining relevant parts of a text document when the training labels are available only at the image or document level. This task is usually referred to as multi-instance (MI) learning, where the learner typically receives a collection of labeled (or sometimes unlabeled) bags, each containing several segments (instances). We propose a semisupervised MI learning method for multilabel classification. Most MI learning methods treat instances in each bag as independent and identically distributed samples. However, in many practical applications, instances are related to each other and should not be considered independent. Our model discovers a latent low-dimensional space that captures structure within each bag. Further, unlike many other MI learning methods, which are primarily developed for binary classification, we model multiple classes jointly, thus also capturing possible dependencies between different classes. We develop our model within a semisupervised framework, which leverages both labeled and, typically, a larger set of unlabeled bags for training. We develop several efficient inference methods for our model. We first introduce a Markov chain Monte Carlo method for inference, which can handle arbitrary relations between bag labels and instance labels, including the standard hard-max MI assumption. We also develop an extension of our model that uses stochastic variational Bayes methods for inference, and thus scales better to massive data sets. Experiments show that our approach outperforms several MI learning and standard classification methods on both bag-level and instance-level label prediction. All code for replicating our experiments is available from https://github.com/hsoleimani/MLTM . PMID- 28095194 TI - Unifying Adversarial Training Algorithms with Data Gradient Regularization. AB - Many previous proposals for adversarial training of deep neural nets have included directly modifying the gradient, training on a mix of original and adversarial examples, using contractive penalties, and approximately optimizing constrained adversarial objective functions. In this article, we show that these proposals are actually all instances of optimizing a general, regularized objective we call DataGrad. Our proposed DataGrad framework, which can be viewed as a deep extension of the layerwise contractive autoencoder penalty, cleanly simplifies prior work and easily allows extensions such as adversarial training with multitask cues. In our experiments, we find that the deep gradient regularization of DataGrad (which also has L1 and L2 flavors of regularization) outperforms alternative forms of regularization, including classical L1, L2, and multitask, on both the original data set and adversarial sets. Furthermore, we find that combining multitask optimization with DataGrad adversarial training results in the most robust performance. PMID- 28095195 TI - Deep Learning with Dynamic Spiking Neurons and Fixed Feedback Weights. AB - Recent work in computer science has shown the power of deep learning driven by the backpropagation algorithm in networks of artificial neurons. But real neurons in the brain are different from most of these artificial ones in at least three crucial ways: they emit spikes rather than graded outputs, their inputs and outputs are related dynamically rather than by piecewise-smooth functions, and they have no known way to coordinate arrays of synapses in separate forward and feedback pathways so that they change simultaneously and identically, as they do in backpropagation. Given these differences, it is unlikely that current deep learning algorithms can operate in the brain, but we that show these problems can be solved by two simple devices: learning rules can approximate dynamic input output relations with piecewise-smooth functions, and a variation on the feedback alignment algorithm can train deep networks without having to coordinate forward and feedback synapses. Our results also show that deep spiking networks learn much better if each neuron computes an intracellular teaching signal that reflects that cell's nonlinearity. With this mechanism, networks of spiking neurons show useful learning in synapses at least nine layers upstream from the output cells and perform well compared to other spiking networks in the literature on the MNIST digit recognition task. PMID- 28095196 TI - Analysis of Online Composite Mirror Descent Algorithm. AB - We study the convergence of the online composite mirror descent algorithm, which involves a mirror map to reflect the geometry of the data and a convex objective function consisting of a loss and a regularizer possibly inducing sparsity. Our error analysis provides convergence rates in terms of properties of the strongly convex differentiable mirror map and the objective function. For a class of objective functions with Holder continuous gradients, the convergence rates of the excess (regularized) risk under polynomially decaying step sizes have the order [Formula: see text] after [Formula: see text] iterates. Our results improve the existing error analysis for the online composite mirror descent algorithm by avoiding averaging and removing boundedness assumptions, and they sharpen the existing convergence rates of the last iterate for online gradient descent without any boundedness assumptions. Our methodology mainly depends on a novel error decomposition in terms of an excess Bregman distance, refined analysis of self-bounding properties of the objective function, and the resulting one-step progress bounds. PMID- 28095197 TI - Solving Nonlinearly Separable Classifications in a Single-Layer Neural Network. AB - Since the work of Minsky and Papert ( 1969 ), it has been understood that single layer neural networks cannot solve nonlinearly separable classifications (i.e., XOR). We describe and test a novel divergent autoassociative architecture capable of solving nonlinearly separable classifications with a single layer of weights. The proposed network consists of class-specific linear autoassociators. The power of the model comes from treating classification problems as within-class feature prediction rather than directly optimizing a discriminant function. We show unprecedented learning capabilities for a simple, single-layer network (i.e., solving XOR) and demonstrate that the famous limitation in acquiring nonlinearly separable problems is not just about the need for a hidden layer; it is about the choice between directly predicting classes or learning to classify indirectly by predicting features. PMID- 28095198 TI - Effects of Small-World Rewiring Probability and Noisy Synaptic Conductivity on Slow Waves: Cortical Network. AB - Physiological rhythms play a critical role in the functional development of living beings. Many biological functions are executed with an interaction of rhythms produced by internal characteristics of scores of cells. While synchronized oscillations may be associated with normal brain functions, anomalies in these oscillations may cause or relate the emergence of some neurological or neuropsychological pathologies. This study was designed to investigate the effects of topological structure and synaptic conductivity noise on the spatial synchronization and temporal rhythmicity of the waves generated by cells in the network. Because of holding the ability of clustering and randomizing with change of parameters, small-world (SW) network topology was chosen. The oscillatory activity of network was tried out by manipulating an insulated SW, cortical network model whose morphology is very close to real world. According to the obtained results, it was observed that at the optimal probabilistic rates of conductivity noise and rewiring of SW, powerful synchronized oscillatory small waves are generated in relation to the internal dynamics of cells, which are in line with the network's input. These two parameters were observed to be quite effective on the excitation-inhibition balance of the network. Accordingly, it may be suggested that the topological dynamics of SW and noisy synaptic conductivity may be associated with the normal and abnormal development of neurobiological structure. PMID- 28095199 TI - Multiway Array Decomposition of EEG Spectrum: Implications of Its Stability for the Exploration of Large-Scale Brain Networks. AB - Multiway array decomposition methods have been shown to be promising statistical tools for identifying neural activity in the EEG spectrum. They blindly decompose the EEG spectrum into spatial-temporal-spectral patterns by taking into account inherent relationships among signals acquired at different frequencies and sensors. Our study evaluates the stability of spatial-temporal-spectral patterns derived by one particular method, parallel factor analysis (PARAFAC). We focused on patterns' stability over time and in population and divided the complete data set containing data from 50 healthy subjects into several subsets. Our results suggest that the patterns are highly stable in time, as well as among different subgroups of subjects. Further, we show with simultaneously acquired fMRI data that power fluctuations of some patterns have stable correspondence to hemodynamic fluctuations in large-scale brain networks. We did not find such correspondence for power fluctuations in standard frequency bands, the common way of dealing with EEG data. Altogether, our results suggest that PARAFAC is a suitable method for research in the field of large-scale brain networks and their manifestation in EEG signal. PMID- 28095200 TI - STDP-Compatible Approximation of Backpropagation in an Energy-Based Model. AB - We show that Langevin Markov chain Monte Carlo inference in an energy-based model with latent variables has the property that the early steps of inference, starting from a stationary point, correspond to propagating error gradients into internal layers, similar to backpropagation. The backpropagated error is with respect to output units that have received an outside driving force pushing them away from the stationary point. Backpropagated error gradients correspond to temporal derivatives with respect to the activation of hidden units. These lead to a weight update proportional to the product of the presynaptic firing rate and the temporal rate of change of the postsynaptic firing rate. Simulations and a theoretical argument suggest that this rate-based update rule is consistent with those associated with spike-timing-dependent plasticity. The ideas presented in this article could be an element of a theory for explaining how brains perform credit assignment in deep hierarchies as efficiently as backpropagation does, with neural computation corresponding to both approximate inference in continuous valued latent variables and error backpropagation, at the same time. PMID- 28095201 TI - Multisensory Bayesian Inference Depends on Synapse Maturation during Training: Theoretical Analysis and Neural Modeling Implementation. AB - Recent theoretical and experimental studies suggest that in multisensory conditions, the brain performs a near-optimal Bayesian estimate of external events, giving more weight to the more reliable stimuli. However, the neural mechanisms responsible for this behavior, and its progressive maturation in a multisensory environment, are still insufficiently understood. The aim of this letter is to analyze this problem with a neural network model of audiovisual integration, based on probabilistic population coding-the idea that a population of neurons can encode probability functions to perform Bayesian inference. The model consists of two chains of unisensory neurons (auditory and visual) topologically organized. They receive the corresponding input through a plastic receptive field and reciprocally exchange plastic cross-modal synapses, which encode the spatial co-occurrence of visual-auditory inputs. A third chain of multisensory neurons performs a simple sum of auditory and visual excitations. The work includes a theoretical part and a computer simulation study. We show how a simple rule for synapse learning (consisting of Hebbian reinforcement and a decay term) can be used during training to shrink the receptive fields and encode the unisensory likelihood functions. Hence, after training, each unisensory area realizes a maximum likelihood estimate of stimulus position (auditory or visual). In cross-modal conditions, the same learning rule can encode information on prior probability into the cross-modal synapses. Computer simulations confirm the theoretical results and show that the proposed network can realize a maximum likelihood estimate of auditory (or visual) positions in unimodal conditions and a Bayesian estimate, with moderate deviations from optimality, in cross-modal conditions. Furthermore, the model explains the ventriloquism illusion and, looking at the activity in the multimodal neurons, explains the automatic reweighting of auditory and visual inputs on a trial-by-trial basis, according to the reliability of the individual cues. PMID- 28095202 TI - Interpretation of the Precision Matrix and Its Application in Estimating Sparse Brain Connectivity during Sleep Spindles from Human Electrocorticography Recordings. AB - The correlation method from brain imaging has been used to estimate functional connectivity in the human brain. However, brain regions might show very high correlation even when the two regions are not directly connected due to the strong interaction of the two regions with common input from a third region. One previously proposed solution to this problem is to use a sparse regularized inverse covariance matrix or precision matrix (SRPM) assuming that the connectivity structure is sparse. This method yields partial correlations to measure strong direct interactions between pairs of regions while simultaneously removing the influence of the rest of the regions, thus identifying regions that are conditionally independent. To test our methods, we first demonstrated conditions under which the SRPM method could indeed find the true physical connection between a pair of nodes for a spring-mass example and an RC circuit example. The recovery of the connectivity structure using the SRPM method can be explained by energy models using the Boltzmann distribution. We then demonstrated the application of the SRPM method for estimating brain connectivity during stage 2 sleep spindles from human electrocorticography (ECoG) recordings using an [Formula: see text] electrode array. The ECoG recordings that we analyzed were from a 32-year-old male patient with long-standing pharmaco-resistant left temporal lobe complex partial epilepsy. Sleep spindles were automatically detected using delay differential analysis and then analyzed with SRPM and the Louvain method for community detection. We found spatially localized brain networks within and between neighboring cortical areas during spindles, in contrast to the case when sleep spindles were not present. PMID- 28095203 TI - Avoiding Optimal Mean l2,1-Norm Maximization-Based Robust PCA for Reconstruction. AB - Robust principal component analysis (PCA) is one of the most important dimension reduction techniques for handling high-dimensional data with outliers. However, most of the existing robust PCA presupposes that the mean of the data is zero and incorrectly utilizes the average of data as the optimal mean of robust PCA. In fact, this assumption holds only for the squared [Formula: see text]-norm-based traditional PCA. In this letter, we equivalently reformulate the objective of conventional PCA and learn the optimal projection directions by maximizing the sum of projected difference between each pair of instances based on [Formula: see text]-norm. The proposed method is robust to outliers and also invariant to rotation. More important, the reformulated objective not only automatically avoids the calculation of optimal mean and makes the assumption of centered data unnecessary, but also theoretically connects to the minimization of reconstruction error. To solve the proposed nonsmooth problem, we exploit an efficient optimization algorithm to soften the contributions from outliers by reweighting each data point iteratively. We theoretically analyze the convergence and computational complexity of the proposed algorithm. Extensive experimental results on several benchmark data sets illustrate the effectiveness and superiority of the proposed method. PMID- 28095204 TI - Democratizing LGBTQ History Online: Digitizing Public History in "U.S. Homophile Internationalism". AB - This article argues that the online archive and exhibit "U.S. Homophile Internationalism" effectively contributes to the democratizing effects that digital archives and online initiatives are having on the practice of history. "U.S. Homophile Internationalism" is an online archive of over 800 digitized articles, letters, advertisements, and other materials from the U.S. homophile press that reference six non-U.S. regions of the world. It also provides visitors with introductory regional essays, annotated bibliographies, and an interactive map feature. This essay weaves "U.S. Homophile Internationalism" into the debates in community-run LGBTQ archives regarding the digitization of archival materials and the possibilities presented by digital public history. In doing so, it outlines the structure and content of "U.S. Homophile Internationalism," highlighting how it increases the public accessibility of primary sources, encourages historical research on regions of the world that have not been adequately represented in LGBTQ history writing, and creates interactive components to support public engagements with the Web site. PMID- 28095205 TI - Imperial Queerness: The U.S. Homophile Press and Constructions of Sexualities in Asia and the Pacific, 1953-1964. AB - This essay examines the ways in which U.S. homophile magazines represented and constructed Asia and the Pacific from 1953 to 1964. Through an analysis of 209 items that referenced Asia and the Pacific in ONE, Mattachine Review, and the Ladder, the essay argues that U.S. homophiles referenced the region in three primary ways: first, to create relationships, allies, and exchanges with people living in the region; second, to highlight the inferiority of the East and superiority of the West; and, third, to reveal the cross-cultural and transhistorical nature of homosexuality. These references were influenced by Orientalism, colonialism, and the Cold War, which framed Asia and the Pacific as both sexually and culturally backward, but also as a potential tourist destination for gay men and lesbian women. PMID- 28095206 TI - Achieving Durable Resistance Against Plant Diseases: Scenario Analyses with a National-Scale Spatially Explicit Model for a Wind-Dispersed Plant Pathogen. AB - Genetic resistance in crops is a cornerstone of disease management in agriculture. Such genetic resistance is often rapidly broken due to selection for virulence in the pathogen population. Here, we ask whether there are strategies that can prolong the useful life of plant resistance genes. In a modeling study, we compared four deployment strategies: gene pyramiding, sequential use, simultaneous use, and a mixed strategy. We developed a spatially explicit model for France and parameterized it for the fungal pathogen Puccinia striiformis f. sp. tritici (causing wheat yellow rust) to test management strategies in a realistic spatial setting. We found that pyramiding two new resistance genes in one variety was the most durable solution only when the virulent genotype had to emerge by mutation. Deploying single-gene-resistant varieties concurrently with the pyramided variety eroded the durability of the gene pyramid. We found that continuation of deployment of varieties with broken-down resistance prolonged the useful life of simultaneous deployment of four single-gene-resistant varieties versus sequential use. However, when virulence was already present in the pathogen population, durability was low and none of the deployment strategies had effect. These results provide guidance on effective strategies for using resistance genes in crop protection practice. PMID- 28095207 TI - The Constitutive Endopolygalacturonase TvPG2 Regulates the Induction of Plant Systemic Resistance by Trichoderma virens. AB - Trichoderma spp. are opportunistic fungi some of which are commonly present in the rhizosphere. Several species, such as T. virens, are also efficient biocontrol agents against phytopathogenic fungi and exert beneficial effects on plants. These effects are the consequence of interactions between Trichoderma and plant roots, which trigger enhanced plant growth and induce plant resistance. We have previously shown that T. virens I10 expresses two endopolygalacturonase genes, tvpg1 and tvpg2, during the interaction with plant roots; tvpg1 is inducible while tvpg2 is constitutively transcribed. Using the same system, the tomato polygalacturonase-inhibitor gene Lepgip1 was induced at the same time as tvpg1. Here we show by gene disruption that TvPG2 performs a regulatory role on the inducible tvpg1 gene and in triggering the plant immune response. A tvpg2 knockout strain fails to transcribe the inducible tvpg1 gene in neither in vitro in inducing media containing pectin or plant cell walls, nor during the in vivo interaction with tomato roots. Likewise, the in vivo induction of Lepgip1 does not occur, and its defense against the pathogen Botrytis cinerea is significantly reduced. Our data prove the importance of a T. virens constitutively produced endopolygalacturonase in eliciting plant induced systemic resistance against pathogenic fungi. PMID- 28095208 TI - Tale of the Huanglongbing Disease Pyramid in the Context of the Citrus Microbiome. AB - The Huanglongbing (HLB) disease pyramid is composed of Liberibacters, psyllid vectors, citrus hosts, and the environment. The epidemiological outcomes for Liberibacter-associated plant diseases are collectively determined by the inherent relationships among plant-Liberibacters-psyllids, and how various environmental factors affect plant-Liberibacter-psyllid interactions. Citrus Liberibacter-psyllid interactions occur in a complex microbiome system. In this review, we focus on the progress in understanding the HLB disease pyramid, and how the microbiome affects the HLB disease pyramid including the interaction between HLB and the citrus microbiome; the interaction between Liberibacters and psyllids; the interaction between Liberibacters and gut microbiota in psyllids; and the effect of HLB on selected above- and belowground citrus pathogens. Their implications for HLB management are also discussed. PMID- 28095209 TI - Psychological factors influence the overlap syndrome in functional gastrointestinal disorders (FGIDs) among middle-aged women in South Korea. AB - This study investigated the psychological factors related to the overlap syndrome, i.e., multiple gastrointestinal conditions that are part of functional gastrointestinal disorders (FGIDs) in the same individual and potentially related to quality of life (QOL) among women aged 45-60 years (n = 627) in South Korea. The study was undertaken between July 2014 and March 2015. Depressive and anxiety symptoms were ascertained using the Center for Epidemiologic Studies Depression scale (CES-D) and the Beck Anxiety Inventory (BAI), respectively. Negative cognition and the cognitive triad were identified using the Automatic Thoughts Questionnaire-Negative (ATQ-N) and the Cognitive Triad Inventory (CTI), respectively. Resilience and QOL were assessed using the Connor-Davidson Resilience Scale (CD-RISC) and World Health Organization Quality of Life scale abbreviated version (WHOQOL-BREF). Women with the overlap syndrome had the highest CES-D (mean = 16.66 +/- 11.79, p < .001), BAI (mean = 17.46 +/- 12.67, p < .001), and ATQ-N scores (mean = 53.61 +/- 20.88, p < .001), followed by women with gastrointestinal disorders but without the overlap syndrome and healthy controls. Healthy controls had the highest WHOQOL-BREF score (mean = 77.69 +/- 12.53, p < .001). After stepwise selection, the final model explained 61.8 percent of the variance in QOL. Thus, depressive symptoms, anxiety, negative cognition, cognitive triad, and resilience were significantly related to QOL in women with the overlap syndrome. PMID- 28095210 TI - Fatal Incidents in Australia's Older Farmers (2001-2015). AB - OBJECTIVES: This study assesses nonintentional injury deaths of older farmers and the causal agents associated with these fatalities in Australia (2001-2015). It also explores approaches based on the hierarchy of risk controls to reduce fatalities and injuries in this cohort. METHODS: Data on farm-related incidents were sourced from the National Coroners Information System (NCIS) for the study period and coded. Rates were calculated and regression analyses completed to assess trends over time. RESULTS: Those in the 50+ years category (n = 610) accounted for 49.8% of all on-farm nonintentional injury deaths, with males (n = 566) dominating the cases. The annual mean was 40.66 cases (SD = 8.08) and the average rate 36/100,000. Trend analysis revealed a nonstatistically significant (P < 0.05) increase in cases over the period. Farm vehicles and machinery were responsible for almost two thirds of the fatal cases. CONCLUSION: Nonintentional fatality rates for older farmers have remained relatively unchanged for a significant period in Australia. There is a need to examine additional approaches that not only maintain the benefits of work activity for older farmers but also balance this against a safety perspective. PMID- 28095212 TI - Platelets - A fine balance. PMID- 28095211 TI - Social Networking in an Agricultural Research Center: Using Data to Enhance Outcomes. AB - The purpose of this article is to present a case study of one midwestern Agricultural Center (Ag Center) that used social network analysis (SNA) to (1) evaluate its collaborations with extramural stakeholders and (2) strategically plan for extending outreach for goal achievement. An evaluation team developed a data collection instrument based on SNA principles. It was administered to the Ag Center's intramural stakeholders (N = 9), who were asked to identify the key extramural stakeholders with whom they had collaborated within the previous 12 months. Additional questions about each extramural stakeholder helped to categorize them according to SNA network measures for degree of centrality, betweenness centrality, and closeness centrality. Findings showed the Ag Center had N = 305 extramural stakeholders. Most of these were other researchers and did not represent the diverse group of stakeholders that the Ag Center had targeted for engagement. Only a few of the intramural stakeholders had national or international connections. Findings were used to improve and diversify connections in order to leverage the Ag Center's expertise and ability to translate research into new best practices and policies. The SNA case study has implications for other evaluators and project directors looking for methodologies that can monitor networks in large science consortia and help leaders plan for translating research into practice and policies by networking with those who can influence such change. PMID- 28095213 TI - Editorial: Platelet Genomics and Disorders of Platelet Number and Function. PMID- 28095214 TI - Stretching Exercises for Subacromial Impingement Syndrome: Effects of 6-Week Program on Shoulder Tightness, Pain, and Disability Status. AB - CONTEXT: Increasing soft tissue flexibility and joint mobility is one of the important aims of studies to treat subacromial impingement syndrome (SIS). OBJECTIVE: The aim of this study was to investigate the effects of a stretching program on posterior capsule tightness, pectoralis minor tightness, pain severity, and disability status in SIS. DESIGN: Single-group pretest posttest design. SETTING: University outpatient clinic. PARTICIPANTS: 18 participants diagnosed with SIS (34.8+/-9.4 y, symptoms duration 5.8+/-4.9 months) were included in the study. INTERVENTION: The 6-week self-stretching program for pectoralis minor, posterior capsule, levator scapula, and latissimus dorsi was performed. MAIN OUTCOME MEASURES: Posterior capsule tightness, pectoralis minor tightness, pain severity (visual analog scale), and self-reported shoulder related pain and disability status (Shoulder Pain and Disability Index) were used to assess changes in flexibility and symptoms. RESULTS: Comparisons showed that there was significantly less posterior capsule and pectoralis minor tightness, less pain severity on activity and at night, and a lower disability score reported after the 6-week stretching program (P < 0.05). There was no statistically significant difference in pain severity at rest after the 6-week stretching program (P > 0.05). CONCLUSIONS: The findings of the study showed that flexibility, pain severity, and disability gains can be achieved with a 6-week stretching exercise training for participants with SIS. Therefore, shoulder girdle stretching exercises should be recommended early in shoulder rehabilitation program. PMID- 28095215 TI - Review: The role of angiotensin II AT1-receptors in the regulation of the cerebral blood flow and brain ischaemia. PMID- 28095216 TI - Review: Role of angiotensin in central regulation of sympathetic activity: effect of dietary sodium chloride. PMID- 28095217 TI - Persistent effect of treatment with candesartan cilexetil on blood pressure in spontaneously hypertensive rats. AB - We have investigated whether the angiotensin II type-1 (AT1) receptor antagonist, candesartan cilexetil, has a persistent effect on blood pressure even after withdrawal of treatment, as has been shown consistently for angiotensin converting enzyme inhibitors (ACE-1). Spontaneously hypertensive rats (SHR) were divided into four groups (n=16 per group) and treated with candesartan cilexetil (high-dose: 5 mg/kg/day; middle-dose: 1 mg/kg/day; low-dose: 0.5 mg/kg/day) or control from age four weeks to 20 weeks. Normotensive Wistar-Kyoto rats (WKY) were also investigated. The drug was given in the drinking water, the concentration adjusted for water consumption and rat weight. Blood pressure (BP) was measured regularly by the indirect tail-cuff method during the treatment period and after treatment, from age 20 weeks to 32 weeks. At age 20 weeks, candesartan treatment had caused a slight reduction in body weight, an increase in water consumption and a reduction in heart rate. During treatment, candesartan caused a dose-dependent reduction in BP. After withdrawal of treatment, BP increased but remained lower than that of untreated control SHR for the medium- and high-dose groups throughout the follow-up period, the reduction being 8-11% at the end of follow-up. At age 32 weeks, there was no significant difference between the three candesartan-treated groups. We conclude that treatment with the AT1-receptor antagonist candesartan has a modest persistent effect on BP after withdrawal of treatment. PMID- 28095218 TI - Review: Effect of combining angiotensin receptor blockers and ACE inhibitors on cardiovascular disease. PMID- 28095220 TI - Review: AT1-receptors in the central nervous system. PMID- 28095219 TI - Use of angiotensin II receptor blockers alone and in combination with other drugs: a large clinical experience trial. AB - Angiotensin II (Ang II) receptor blockers are the newest class of antihypertensive drugs to be developed. No large-scale clinical trials have been performed to evaluate their efficacy alone, or in combination with other drugs. A large-scale, eight week, open-label, non-placebo-controlled, single-arm trial evaluated the efficacy, tolerability and dose-response of candesartan cilexetil, 16-32 mg once-daily, either as monotherapy or as part of combination therapy, in a diverse hypertensive population in actual practice settings. 6465 patients with high blood pressure, of whom 52% were female and 16% African American, with a mean age of 58 years, were included. 5446 patients had essential hypertension and 1014 patients had isolated systolic hypertension. In order to be included in this study, patients had either untreated or uncontrolled hypertension (systolic blood pressure (SBP) 140-179 mmHg and/or diastolic blood pressure (DBP) 90-109 mmHg inclusive at baseline), despite a variety of other antihypertensive drugs. Of the 5156 patients with essential hypertension and at least one post baseline efficacy measurement, the mean pretreatment blood pressure (BP) was 156/97 mmHg. Candesartan cilexetil monotherapy reduced mean SBP/DBP by 18.0/12.2 mmHg. Similarly, in the 964 patients with isolated systolic hypertension and at least one post baseline efficacy measurement, candesartan cilexetil monotherapy reduced SBP/DBP from 158/81 by 16.5/4.5 mmHg. Candesartan cilexetil was similarly effective when employed as add-on therapy. When added to baseline antihypertensive medication in 51% of the patients with essential hypertension not achieving BP control, additional reduction in BP was achieved regardless of the background therapy, including diuretics (17.8/11.7 mmHg) calcium antagonists (16.6/11.2 mmHg), beta-blockers (16.5/10.4 mmHg), angiotensin-converting enzyme inhibitors (ACE-I) (15.3/10.0 mmHg), and alpha blockers (16.4/10.4 mmHg). Likewise, when candesartan cilexetil was used as add-on therapy in patients with isolated systolic hypertension, there was a consistent further reduction of mean SBP/DBP, regardless of the background therapy. Moreover, these monotherapeutic or add-on efficacy benefits were seen regardless of age (<65 or >65 years), gender, or race. Despite the open-label design of the study which enhances efficacy owing to the placebo effect, the Ang II receptor blocker, candesartan cilexetil either alone, or as an add-on therapy, is highly effective for assisting in the control of systolic and diastolic hypertension. PMID- 28095221 TI - Effects of low-dose candesartan on the rate of re-endothelialisation following vascular wound healing. AB - The wound healing response of the vascular wall to injury involves re endothelialisation of the denuded luminal surface and thickening of the intimal area (intimal hyperplasia), as expressed by the intimal-to-medial area ratio (I/M). Candesartan, at doses of 1 mg/kg/day or higher, has been reported to attenuate the intimal hyperplastic response. We tested the hypothesis that candesartan, at doses lower than those associated with attenuation of intimal hyperplasia, may affect re-endothelialisation. New Zealand White rabbits were subjected to balloon catheter injury to the thoracic aorta. Candesartan, at doses of 50, 100, and 500 ug/kg/day, was delivered via an Alzet pump placed in the abdomen one week prior to aortic injury. There was no attenuation of the hyperplastic response of the aortic wall. However, at 50 ug/kg/day the rate of reendothelialisation was significantly increased. These data suggest that candesartan may exhibit pleiotropic effects on vascular wound healing, in addition to the well-known effect of attenuating the development of intimal hyperplasia. PMID- 28095222 TI - Improvements of renal lesions and function by angiotensin and endothelin receptor antagonism in nitric oxide-deficient rats. AB - In previous studies, we have observed that antagonism of angiotensin or endothelin receptors prevented the development of nephroangio- and glomerulo sclerosis during hypertension by inhibiting collagen I gene synthesis, through a mechanism independent of systemic haemodynamics. The present study investigated whether treatment with angiotensin or endothelin receptor antagonists, given at doses that did not reduce blood pressure, could produce regression of renal sclerotic lesions and improve renal function during hypertension. Hypertension and renal vascular fibrosis were induced in rats by chronic inhibition of NO synthesis using NGnitro-L-arginine methyl ester (L-NAME). Systolic blood pressure gradually increased following L-NAME administration, reaching a plateau of 170 mmHg after four weeks of treatment. At the same time, urinary protein excretion and plasma creatinine concentration were increased ten- and three-fold compared with controls, respectively (p<0.001). This increase was accompanied by the appearance of sclerotic lesions within renal vessels and glomeruli, as evidenced by Masson's trichromic staining (sclerotic index 2.34+/-0.29 vs. 0.10+/-0.01 in L NAME four weeks and control, respectively, p<0.001). Thereafter, the L-NAME treatment was combined with either losartan (an AT1receptor antagonist), bosentan (an ETA/B antagonist), co-treatment with both agents, or vehicle for an additional period of four weeks. Blockade of AT1and/or ETA/B-receptors significantly reduced urinary protein excretion and plasma creatinine levels (p<0.01) and substantially improved renal vascular histology (sclerotic index 1.78+/-0.13, 1.57+/-0.22 and 1.85+/-0.15 respectively, p<0.01, vs. L-NAME eight week) without altering the L-NAME-induced increase of systolic pressure. These data indicate that angiotensin II and endothelin-1 participate in the mechanism(s) of renal vascular fibrosis by increasing extracellular matrix formation. Treatment with their respective receptor antagonists leads to the regression of renal vascular fibrosis and to the improvement of renal function by a common antifibrogenic mechanism that is independent of systemic haemodynamics. PMID- 28095223 TI - Candesartan prevents L-NAME-induced cardio-renal injury in spontaneously hypertensive rats beyond hypotensive effects. AB - Our goal was to assess the cardiovascular and renal protection afforded by angiotensin II type 1-receptor blockade against NG-nitro-L-arginine methyl ester (L-NAME)-exacerbated hypertension in young spontaneously hypertensive rats (SHR), in comparison with the antihypertensive drug, hydralazine. Male SHR were assigned to four groups (n=8 per group): no treatment (controls); L-NAME-treated group (20 mg/kg/day, 10 days, orally); co-treatment with L-NAME and hydralazine (15 mg/kg/day, by gavage); co-treatment with L-NAME and candesartan cilexetil (10 mg/kg/day, by gavage), i.e. at a dose that inhibited acute pressor responses to 5 20 ng angiotensin II. One animal died in the L-NAME group, and tail-cuff systolic blood pressure (SBP) increased significantly compared with controls to 201+/-5 mmHg. Albumin excretion increased 235-fold in L-NAME-treated rats. Heart weight index averaged 3.5+/-0.1 and 3.8+/-0.1 mg/g body weight (p<0.05) in control and L NAME rats, respectively, indicating moderate cardiac hypertrophy induced by L NAME. Preglomerular vascular lesions affected 63+/-6% of interlobular arteries and 10+/-2% of afferent arterioles (vs. 8+/-3 and 0.8+/-0.4% in controls, respectively). Hydralazine and candesartan cilexetil treatment similarly reduced SBP to 153+/-7, and 165+/-6 mmHg, respectively. However, candesartan provided more protection, in terms of no significant change in albuminuria (vs. 25-fold increase with hydralazine), regression of cardiac hypertrophy, frequency of vascular lesions and histological indices of renal injury maintained within control values. In conclusion, candesartan cilexetil prevented L-NAME-exacerbated hypertension and associated cardio-renal injury in young SHR, the beneficial effects exceeding those of hydralazine. PMID- 28095224 TI - Comparison of the AT1-receptor blockers candesartan, irbesartan and losartan for inhibiting renal microvascular constriction. AB - Angiotensin II (Ang II) type 1 (AT1) receptor blockers differ in their affinity for the AT1-receptor, suggesting a dissimilar potency for inhibiting Ang II induced vascular constriction. In the present study, we compared the effects of candesartan, irbesartan and losartan on the renal microvascular constriction to locally-formed Ang II, using isolated, perfused hydronephrotic rat kidneys. Addition of 1 nmol/L angiotensin I (Ang I, the precursor of Ang II) significantly reduced the diameters of interlobular arteries (ILAs; -47.6+/-2.6%), afferent arterioles (AAs; -43.6+/-2.3%) and efferent arterioles (EAs; -31.6+/-2.4%). Candesartan and irbesartan were more potent in antagonising the constriction to Ang I than losartan. By contrast, candesartan and irbesartan differed only slightly in potency. After a washing period of 60 minutes with drug-free medium, a second application of Ang I failed to induce vasoconstriction only in candesartan-treated kidneys. Pretreatment of hydronephrotic kidneys with candesartan, to further explore its antagonistic properties, shifted the dose response curves of Ang II approximately 2 log units to the right without reducing the maximal Ang II-induced constriction of ILAs, AAs or EAs. Additionally, dose response curves of Ang II were similar after short (10 minutes) and prolonged (60 minutes) preincubation with candesartan. Our findings indicate that candesartan and irbesartan are more potent inhibitors of renal microvascular constriction to locally-formed Ang II than losartan. The inhibitory effect of candesartan is more prolonged, suggesting a slow dissociation from the AT1-receptor. Additionally, candesartan was found to block the Ang II-induced constriction of renal microvessels in a surmountable manner. PMID- 28095225 TI - Angiotensin II blockade causes acute renal failure in eNOS-deficient mice. AB - Compared with wild-type mice, adult endothelial nitric oxide synthase (eNOS) knockout mice (eight months of age) have increased blood pressure (BP) (126+/-9 mmHg vs. 100+/-4 mmHg), and an increased renal vascular resistance (155+/-16 vs. 65+/-4 mmHg.min/ml). Renal vascular resistance responses to i.v. administration of noradrenaline were markedly enhanced in eNOS knockout mice. Glomerular filtration rate (GFR) of anaesthetised eNOS -/- mice was 324+/-57 ul/min gKW, significantly lower than the GFR of 761+/-126 ul/min.gKW in wild-type mice. AT1 receptor blockade with i.v. candesartan (1-1.5 mg/kg) reduced arterial blood pressure and renal vascular resistance, and increased renal blood flow (RBF) to about the same extent in wild-type and eNOS -/- mice. Candesartan did not alter GFR in wild-type mice (761+/-126 vs. 720+/-95 ul/min.gKW), but caused a marked decrease in GFR in eNOS -/- mice (324.5+/-75.2 vs. 77+/-18 ul/min.gKW). A similar reduction in GFR of eNOS deficient mice was also caused by angiotensin-converting enzyme (ACE) inhibition. Afferent arteriolar granularity, a measure of renal renin expression, was found to be reduced in eNOS -/- compared with wild-type mice. In chronically eNOS-deficient mice, angiotensin II (Ang II) is critical for maintaining glomerular filtration pressure and GFR, presumably through its effect on efferent arteriolar tone. PMID- 28095226 TI - Facilitative interaction between angiotensin II and oxidised LDL in cultured human coronary artery endothelial cells. AB - Background Several studies have shown that angiotensin II (Ang II) and oxidised low-density lipoprotein (ox-LDL) are critical factors in atherosclerosis. In this study, we examined the molecular basis of mutually facilitative interactions between Ang II and ox-LDL in human coronary artery endothelial cells (HCAECs). Methods and results We observed that incubation of cultured HCAECs with Ang II (10-12 to 10-6 M) for 24 hours caused a concentration-dependent increase in the expression of mRNA and protein of a specialised receptor for ox-LDL (LOX-1). These effects of Ang II were completely blocked by pretreatment of HCAECs with candesartan (10-6 M), a specific AT1-receptor blocker, but not by PD 123319 (10-6 M), a specific AT2-receptor blocker. On the other hand, incubation of HCAECs with ox-LDL (10 and 40 ug/ml) for 24 hours progressively upregulated AT1-, but not AT 2-, receptor mRNA and protein. Pretreatment of cells with the anti-oxidant alpha tocopherol (1-5 x 10-6 M) inhibited the upregulation of AT1-receptor expression induced by ox-LDL (p<0.05). To determine the significance of expression of AT1 receptors and LOX-1, we measured cell injury in response to Ang II and ox-LDL. Incubation of cells with both ox-LDL and Ang II synergistically increased cell injury, measured as cell viability and LDH release, compared with either ox-LDL or Ang II alone (both p<0.05). Alpha-tocopherol, as well as candesartan, attenuated cell injury in response to Ang II and ox-LDL (both p<0.05). Conclusions These observations show that Ang II upregulates a novel endothelial receptor for ox-LDL (LOX-1) gene expression and ox-LDL in turn upregulates Ang II AT 1receptor gene expression. This interaction between Ang II and ox-LDL further augments cell injury in HCAECs. These findings provide basis for the use of AT1 receptor blockers and anti-oxidants in designing therapy for atherosclerosis and myocardial ischaemia. PMID- 28095227 TI - The effect of high-dose angiotensin II receptor blockade beyond maximal recommended doses in reducing urinary protein excretion. AB - The optimal doses of angiotensin-converting enzyme inhibitors (ACE-I) and/or angiotensin II receptor blockers (ARBs) for maximal reduction in urinary protein excretion are not known. Moreover, beneficial effects from ARBs, such as tissue protection owing to a more complete blockade of the renin-angiotensin-aldosterone system (RAAS), may be independent of blood pressure-lowering by ARBs. In this investigation, we evaluated whether increasing the dose of candesartan cilexetil, in subjects already on the maximally-recommended FDA doses of 32 mg, would induce a further reduction in 24-hour urinary protein excretion in patients with heavy proteinuria (urinary protein excretion >1.5 g/day; mean 4.4+/-2 g/day). Ten patients were started on 16 or 32 mg of candesartan cilexetil daily. After 1-2 months of therapy, the dose was titrated upwards to 96 mg. In all subjects, there were further reductions in 24-hour urinary protein excretion when the dose was increased beyond the recommended 32 mg maximal dose. Increasing the dose of candesartan cilexetil to 96 mg was safe, as most subjects showed no changes in serum potassium and, as expected, only a slight increase (0.5-0.7 mg/dl) in serum creatinine. These data warrant further investigation, since some subjects may require higher doses of candesartan to achieve optimal regression of proteinuria. PMID- 28095228 TI - Prevention of atherosclerosis by specific AT1-receptor blockade with candesartan cilexetil. AB - Several studies indicate that blockade of the renin-angiotensin-aldosterone system (RAAS) can prevent atherosclerosis and vascular events, but the precise mechanisms involved are still unclear. In this study, we investigated the effect of the AT 1-receptor blocker, candesartan, in the prevention of atherosclerosis in Watanabe heritable hyperlipidaemic (WHHL) rabbits and also the effect of AT1 receptor blockade in the uptake of oxidised LDL by macrophage cell cultures. In the first set of experiments, 12 WHHL rabbits were randomly assigned to three groups: placebo, atenolol 5 mg/kg daily or candesartan 2 mg/kg daily for six months. Compared with controls and atenolol-treated rabbits, candesartan treatment resulted in a significant 50-60% reduction of atherosclerotic plaque formation and a 66% reduction in cholesterol accumulation in the thoracic aorta. Studies in macrophage cultures indicated that candesartan prevented uptake of oxidised LDL-(oxLDL)-cholesterol by cultured macrophages. Candesartan inhibited the uptake of oxLDL in a dose-dependent manner, reaching a maximum inhibition of 70% at concentrations of 5.6 ug/ml. Further studies in other animal models and well-designed trials in humans are warranted to further explore the role of AT1 receptor blockade in the prevention of atherosclerosis. PMID- 28095229 TI - Blockade of angiotensin AT1-receptors in the rostral ventrolateral medulla of spontaneously hypertensive rats reduces blood pressure and sympathetic nerve discharge. AB - Microinjections of angiotensin II (Ang II) into the rostral ventrolateral medulla (RVLM) induce a sympathetically-mediated increase in blood pressure (BP), through an interaction with AT1-receptors. Under basal conditions in anaesthetised animals, microinjections of AT 1-receptor antagonists into the RVLM have little, or no effect on BP, suggesting that the angiotensin input to this nucleus is not tonically active. In contrast, microinjections of AT1-receptor antagonists into the RVLM of sodium-deplete rats and TGR(mRen2)27 rats, induce a depressor response through sympatho-inhibition. This indicates that when the renin angiotensin system is activated, angiotensin can act in the RVLM to support sympathetic nerve discharge and BP. This study examined whether angiotensin inputs to the RVLM are activated in the spontaneously hypertensive rat - a pathophysiological model which displays increases in both brain angiotensin levels and sympathetic nerve activity. Bilateral microinjections of the AT 1 receptor antagonist candesartan cilexetil, (1 nmol in 100 nl), into the RVLM of the spontaneously hypertensive rat induced a significant decrease in lumbar sympathetic nerve discharge (-18+/-2%) and BP (140+/-6 to 115+/-6 mmHg). In contrast, similar microinjections in the Wistar-Kyoto (WKY) rat had no effect on BP or sympathetic nerve discharge. These results are interpreted to suggest that Ang II inputs to the RVLM are activated in the spontaneously hypertensive rat to maintain an elevated level of sympathetic nerve discharge, even in the face of increased BP. PMID- 28095230 TI - Development of salt-sensitive hypertension in a sensory denervated model: the underlying mechanisms. AB - We use a novel salt-sensitive hypertensive model recently developed in our laboratory. This model shows that neonatal degeneration of capsaicin-sensitive sensory nerves renders a rat responsive to a salt load with a significant rise in blood pressure (BP). To test the hypothesis that development of salt-sensitive hypertension in sensory denervated rats is mediated by abnormal regulation of both circulating and tissue renin-angiotensin systems (RAS), neonatal Wistar rats were given capsaicin, 50 mg/kg s.c., on the first and second days of life. Control rats were treated with vehicle solution. After the weaning period, male rats were divided into four groups and subjected to the following treatments for three weeks: control + high sodium diet (4%, CON-HS), capsaicin pretreatment + normal sodium diet (0.5%, CAP-NS), capsaicin pretreatment + high sodium diet (CAP HS), and capsaicin pretreatment + high sodium diet + candesartan cilexetil (10 mg/kg/per day, CAP-HS-CAN). Radioimmunoassay shows that plasma renin activity (ng/ml/hr, PRA) was higher in CAP-NS (2.58+/-0.17) than in CON-HS (0.14+/-0.03) and CAP-HS (0.74+/-0.15), and it was higher in CAP-HS than in CON-HS (p<0.05). Western blot analysis shows that expression of the angiotensin II (Ang II) type 1 (AT1) receptor in both the renal cortex and outer medulla was higher in CAP-HS than in CON-HS and CAP-NS rats (p<0.05). Expression of the Ang II type 2 (AT2) receptor in the renal cortex was higher in both CAP-HS and CAP-NS than in CON-HS rats (p<0.05), but there was no difference in AT2-receptor expression in the renal medulla between CAP-HS, CAP-NS, and CON-HS rats. Likewise, there was no difference in AT1-receptor expression in mesenteric resistance arteries between CAP-HS, CAP-NS, and CON-HS rats. In contrast, mesenteric AT2-receptor expression was lower in CAP-HS than in CAP-NS and CON-HS rats (p<0.05). Tail-cuff systolic BP (mmHg) shows that blockade of the AT1-receptor with candesartan prevents the development of hypertension in CAP-HS rats (by the end of the experiment, CON-HS, 122+/-3; CAP-NS, 118+/-10; CAP-HS, 169+/-9; CAP-HS-CAN, 129+/-2, p<0.05). Thus, both circulating and tissue RAS in sensory-denervated rats are abnormally regulated in response to a high-salt intake, which may contribute to increased salt sensitivity and account for the effectiveness of candesartan in lowering BP in this model. PMID- 28095231 TI - The renin-angiotensin system in obesity hypertension. PMID- 28095232 TI - Does protein binding modulate the effect of angiotensin II receptor antagonists? AB - Introduction Angiotensin II AT 1-receptor antagonists are highly bound to plasma proteins (>= 99%). With some antagonists, such as DuP-532, the protein binding was such that no efficacy of the drug could be demonstrated clinically. Whether protein binding interferes with the efficacy of other antagonists is not known. We have therefore investigated in vitro how plasma proteins may affect the antagonistic effect of different AT1-receptor antagonists. Methods A radio receptor binding assay was used to analyse the interaction between proteins and the ability of various angiotensin II (Ang II) antagonists to block AT1 receptors. In addition, the Biacore technology, a new technique which enables the real-time monitoring of binding events between two molecules, was used to evaluate the dissociation rate constants of five AT1-receptor antagonists from human serum albumin. Results The in vitro AT 1-antagonistic effects of different Ang II receptor antagonists were differentially affected by the presence of human plasma, with rightward shifts of the IC50 ranging from one to several orders of magnitude. The importance of the shift correlates with the dissociation rate constants of these drugs from albumin. Our experiments also show that the way that AT1-receptor antagonists bind to proteins differs from one compound to another. These results suggest that the interaction with plasma proteins appears to modulate the efficacy of some Ang II antagonists. Conclusion Although the high binding level of Ang II receptor antagonist to plasma proteins appears to be a feature common to this class of compounds, the kinetics and characteristics of this binding is of great importance. With some antagonists, protein binding interferes markedly with their efficacy to block AT1-receptors. PMID- 28095233 TI - Characterisation of angiotensin II receptors in isolated human subcutaneous resistance arteries. AB - Subcutaneous arteries have been used as a model for resistance arteries, which are potentially involved in enhanced blood pressure (BP) regulation in man. Angiotensin II (Ang II) is an important regulator of tone, acting via type 1 (AT1 ) and type 2 (AT2-) receptor subtypes. The aim of this study was to characterise the Ang II receptors in isolated human subcutaneous arteries, using pharmacological and molecular methods. Subcutaneous arteries were obtained from patients undergoing elective gut surgery and were carefully dissected from the abdominal wall. Cylindrical segments were mounted on two L-shaped metal prongs, one of which was connected to a force-displacement transducer for continuous recording of isometric tension. Concentration-response curves to Ang II were constructed in the presence and absence of various selective AT1-receptor antagonists, candesartan, EXP3174, irbesartan and losartan, and the AT2-receptor antagonist, PD 123319. Responses to Ang II were measured as increases in force (mN) and expressed as a percentage of the response to 60 mM of KCl. Ang II caused a concentration-dependent contraction (pEC50=9.45+/-0.48, Emax=120+/-13%). Candesartan and EXP3174 caused concentration-dependent depression of the Emax of Ang II without any major shift of pEC50. Losartan and irbesartan caused a significant, dose-dependent rightward shift of the Ang II contraction-response curve in human subcutaneous arteries. The results show that contractile responses of human subcutaneous arteries are mediated via the AT1-receptor. The AT1 receptor antagonists, candesartan and EXP3174, acted in an insurmountable manner, while losartan and irbesartan were surmountable AT1-receptor antagonists. The AT2 receptor antagonist, PD 123319, (10, 100 nM) had no effect on Ang II-induced contraction. This is supported by the positive identification of mRNA for the human AT 1-receptor by RT-PCR. PMID- 28095234 TI - Review: Lessons on renal function from transgenic mice lacking different angiotensin II receptors. PMID- 28095235 TI - Role of basic amino acids of the human angiotensin type 1 receptor in the binding of the non-peptide antagonist candesartan. AB - To explain the insurmountable/long-lasting binding of biphenyltetrazole containing AT1-receptor antagonists such as candesartan, to the human angiotensin II type 1-receptor, a model is proposed in which the basic amino acids Lys199 and Arg 167 of the receptor interact respectively with the carboxylate and the tetrazole group of the antagonists. To validate this model, we have investigated the impact of substitution of Lys199 by Ala or Gln and of Arg167 by Ala on the binding properties of [3H]candesartan and on competition binding by candesartan, EXP3174, irbesartan, losartan, angiotensin II (Ang II) and [Sar1 Ile8]angiotensin. Our results indicate that both amino acids play an important role in the AT1-receptor ligand binding. Whereas the negative charge of Lys 199 is involved in an ionic bond with the end-standing carboxylate group of the peptide ligands, its polarity also contributes to the non-peptide antagonist binding. Substitution of Arg167 by Ala completely abolished [3H]Ang II, as well as [3H] candesartan, binding. Whereas these results are in line with the proposed model, it cannot be excluded that both amino acid residues are important for the structural integrity of the AT1-receptor with respect to its ligand binding properties. PMID- 28095236 TI - Analysis of responses to angiotensin II in the mouse. AB - Responses to angiotensin II (Ang II) were investigated in anaesthetised CD1 mice. Injections of Ang II caused dose-related increases in systemic arterial pressure that were antagonised by candesartan. Responses to Ang II were not altered by PD 123319. At the lowest dose studied (20 ug/kg i.v.), the inhibitory effects of candesartan were competitive, whereas at the highest dose (100 ug/kg i.v.), the dose-response curve for Ang II was shifted to the right in a non-parallel manner. The inhibitory effects of candesartan were selective and were similar in animals pretreated with enalaprilat to reduce endogenous Ang II production. Pressor responses to Ang II were not altered by propranolol, phentolamine or atropine, but were enhanced by hexamethonium. Increases in total peripheral resistance were inhibited by the AT1-receptor antagonist (ARB) but were not altered by AT2 receptor, alpha- or beta-receptor antagonists. These results suggest that pressor responses to Ang II are mediated by AT 1-receptors, are buffered by the baroreceptors, are not modulated by effects on AT2receptors, and that activation of the sympathetic nervous system plays little role in mediating rapid haemodynamic responses to the peptide in anaesthetised mice. PMID- 28095237 TI - Candesartan abrogates G protein-coupled receptors agonist-induced MAPK activation and cardiac myocyte hypertrophy. AB - The renin-angiotensin-aldosterone system (RAAS) has been identified as a major contributor to the development of cardiac hypertrophy and the subsequent transition to heart failure. G protein-coupled receptors agonists such as angiotensin II (Ang II), endothelin-1 (ET-1) and phenylephrine (PE) have been implicated in hypertrophic responses in ventricular myocytes through the activation of several families of MAP kinases. In this study we examined the effect of candesartan, an Ang II type 1-(AT1)-receptor antagonist, on cardiac hypertrophy by using cultured neonatal rat cardiomyocytes. Stimulation with Ang II (100 nM), ET-1 (100 nM) or PE (1 uM) induced marked increases in [3H]Leucine incorporation (>= 50%), compatible with enhanced protein synthesis. The addition of candesartan abrogated the increase in [3H]Leucine incorporation in response not only to Ang II but also to ET-1 and PE. To elucidate the mechanisms involved in this antihypertrophic effect of candesartan, we studied the activation of p38 MAPK, extracellular signal-regulated kinases (ERK1/2) and stress-activated protein kinases (SAPKs). Ang II, ET-1 and PE increased the phosphorylation levels of ERK1/2, p54 SAPK and p46SAPK and p38 in a time-dependent manner. This activation was completely blocked in the case of Ang II by pretreatment with candesartan. ET-1-induced activation of ERKs, SAPKs and p38 was also partially, but significantly, reduced by candesartan. PE-induced activation of SAPKs, but not ERKs and p38, was also reduced by candesartan. These results suggest that the hypertrophic response to ET-1 and PE, along with Ang II, is dependent upon a functioning AT1-receptor and may be mediated by AT 1 activation of the MAP kinases. PMID- 28095238 TI - Cardioprotective effects of angiotensin II type 1 receptor blockade with candesartan after reperfused myocardial infarction: role of angiotensin II type 2 receptor. AB - To determine whether angiotensin II (Ang II) type 2 (AT2)-receptor activation associated with cardioprotection induced by Ang II type 1 (AT1)-receptor blockade during ischaemia-reperfusion (IR) might be reflected in increased AT 2-receptor, IP3-(1,4,5- inositol trisphosphate type 2) receptor and PKC-epsilon (protein kinase C-epsilon) proteins and tissue cGMP (cyclic guanosine monophosphate), we measured in vivo left ventricular (LV) systolic and diastolic function and remodelling (echocardiogram/Doppler) and haemodynamics, and ex vivo infarct size, AT1-/AT 2receptor, IP3-receptor and PKC-epsilon proteins (immunoblots) and cGMP (enzyme immunoassay) in dogs with reperfused anterior acute myocardial infarction (MI) (90-minute ischaemia, 120-minute reperfusion). Compared with controls (C, n=6) in vivo, candesartan (1 mg/kg i.v. over 30-minute pre-ischaemia, n=6) effectively inhibited the Ang II pressor response (Delta%, -14+/-22% vs. -80+/ 11, p<0.003) and decreased preload (122+/-35 vs. -2+/-16%, p<0.01), improved LV systolic ejection fraction (-29+/-4 vs. -11+/-5, p<0.03) and diastolic function (E/A ratio, -25+/-7 vs. 33+/-13, p<0.004), decreased the extent of LV asynergy (26+/-20 vs. -31+/-10% LV, p<0.05) and limited acute LV remodelling (expansion index 19+/-6 vs. -3+/-5, p<0.05; thinning ratio -22+/-2 vs. -4+/-2, p<0.0003). Ex vivo, candesartan decreased infarct size (55+/-2 vs. 27+/-2% risk, p<0.001) and increased infarct zone (IZ) AT2 -receptor protein by 8-fold (but not AT1-receptor protein), IP3-receptor protein by 12-fold, PKC-epsilon protein by 5-fold and cGMP by 40%. Cardioprotective effects of AT1-receptor blockade on acute IR injury, LV function, and remodelling may also involve AT 2-receptor activation and downstream signalling via IP3-receptor, PKC-epsilon and cGMP. PMID- 28095239 TI - Evidence for a cyclic AMP-dependent pathway in angiotensin AT1-receptor activation of human omental arteries. AB - Enhanced responses to vasoconstriction induced by neuropeptide Y and alpha2 adrenoceptor agonists have been seen following pharmacological activation of the adenylyl cyclase (AC) system. Since preliminary studies revealed only minor responses to angiotensin II (Ang II) in human omental arteries, we have investigated whether enhanced activity of AC may unravel further functional Ang II receptors. Human omental arteries were obtained in conjunction with elective gut surgery. After dissection of the vessel, the endothelium was removed by 10 sec of Triton X-100 treatment. Ring segments (1-2 mm long) were mounted on a myograph and studied. Ang II produced small contractions, 27+/-5% relative to the response elicited by 60 mM K+. However, enhanced Ang II (105+/-10%, p<0.001) responses were seen during AC activation by forskolin (0.1-1 uM). This enhanced contractile response to Ang II was not inhibited by the angiotensin II type 2 (AT2-receptor antagonist PD 123319 (0.1 uM), but was blocked in an insurmountable way by the angiotensin II type 1 (AT1)-receptor antagonist candesartan (1 nM) and in a surmountable manner by losartan (0.1 uM) and irbesartan (0.1 uM). Pertussis toxin (a Gi-protein blocker) and the protein kinase C inhibitor, RO31-8220 (0.01, 0.1 and 1 uM), markedly reduced this response, while the protein kinase A inhibitor, H89 (1, 10 uM), had no effect. RT-PCR provided evidence for the presence of mRNA for both AT1- and AT2-receptors. The results suggest that both a cAMP-dependent and a cAMP-independent mechanism are involved in the contractile responses to Ang II in human omental arteries and that both responses are mediated via the AT1-receptor. PMID- 28095240 TI - Reversal of cardiovascular remodelling with candesartan. AB - Cardiovascular remodelling, defined as ventricular and vascular hypertrophy together with fibrosis, characterises hypertension following inhibition of the production of the endogenous vasodilator, nitric oxide (NO). This study has determined whether the cardiovascular remodelling following chronic NO synthase inhibition can be reversed by administration of the selective angiotensin II AT1 receptor antagonist, candesartan. Male Wistar rats were treated with L nitroarginine methyl ester (L-NAME, 400 mg/l in drinking water) for eight weeks and with candesartan cilexetil (2 mg/kg/day by oral gavage) for the last four weeks. L-NAME-treated rats became hypertensive with systolic blood pressure increasing from 110+/-4 mmHg (control) to 170+/-10 mmHg. Rats developed left ventricular hypertrophy (control 1.70+/-0.06; L-NAME 2.10+/-0.04 mg/kg body wt) with markedly increased deposition of perivascular and interstitial collagen. Candesartan returned blood pressure, left ventricular weights and collagen deposition to control values. Echocardiographic assessment showed concentric hypertrophy with an increased fractional shortening; this was reversed by candesartan treatment. Heart failure was not evident. In the isolated Langendorff heart, diastolic stiffness increased in L-NAME-treated rats while the rate of increase in pressure (+dP/dt) increased after eight weeks only; candesartan reduced collagen deposition and normalised +dP/dt. In isolated left ventricular papillary muscles, the potency (negative log EC50) of noradrenaline as a positive inotropic compound was unchanged, (control 6.56+/-0.14); maximal increase in force before ectopic beats was reduced from 5.0+/-0.4 mN to 2.0+/-0.2 mN. Noradrenaline potency as a vasoconstrictor in thoracic aortic rings was unchanged, but maximal contraction was markedly reduced from 25.2+/-2.0 mN to 3.0+/-0.3 mN; this was partially reversed by candesartan treatment. Thus, chronic inhibition of NO production with L-NAME induces hypertension, hypertrophy and fibrosis with increased toxicity and significant decreases in vascular responses to noradrenaline. These changes were at least partially reversible by treatment with candesartan, implying a significant role of AT1-receptors in L-NAME-induced cardiovascular changes. PMID- 28095241 TI - Review: Gene targeting studies of angiotensin II type 1 (AT1) receptors. PMID- 28095242 TI - Regression of cardiac hypertrophy in the SHR by combined renin-angiotensin system blockade and dietary sodium restriction. AB - Altered operation of the renin-angiotensin-aldosterone system (RAAS) and dietary sodium intake have been identified as independent risk factors for cardiac hypertrophy. The way in which sodium intake and the operation of the renin angiotensin-aldosterone system interact in the pathogenesis of cardiac hypertrophy is poorly understood. The aims of this study were to investigate the cardiac effects of the renin-angiotensin system (RAS) blockade in the spontaneously hypertensive rat (SHR), using co-treatment with an angiotensin II receptor blocker (ARB) and an angiotensin-converting enzyme (ACE) inhibitor with different sodium intakes. Our experiments with SHR show that, at high levels of sodium intake (4.0%), aggressive RAS blockade treatment with candesartan (3 mg/kg) and perindopril (6 mg/kg) does not result in regression of cardiac hypertrophy. In contrast, RAS blockade coupled with reduced sodium diet (0.2%) significantly regresses cardiac hypertrophy, impairs animal growth and is associated with elevated plasma renin and dramatically suppressed plasma angiotensinogen levels. Histological analyses indicate that the differential effect of reduced sodium on heart growth during RAS blockade is not associated with any change in myocardial interstitial collagen, but reflects modification of cellular geometry. Dimensional measurements of enzymatically-isolated ventricular myocytes show that, in the RAS blocked, reduced sodium group, myocyte length and width were decreased by about 16-19% compared with myocytes from the high sodium treatment group. Our findings highlight the importance of 'titrating' sodium intake with combined RAS blockade in the clinical setting to optimise therapeutic benefit. PMID- 28095243 TI - Review: Promise of prevention and reversal of target organ involvement in hypertension. PMID- 28095244 TI - Candesartan decreases the sympatho-adrenal and hormonal response to isolation stress. AB - A change from group housing to isolation in unfamiliar metabolic cages represents, for rodents, a significant emotional stress. We studied the effect of candesartan, a peripheral and central angiotensin II AT1-receptor antagonist, on the hormonal and sympathetic response to acute isolation. We pretreated rats with 1 mg/kg/day candesartan for 13 days via subcutaneously implanted osmotic minipumps, followed by 24-hour isolation in individual metabolic cages. We measured brain, pituitary and adrenal angiotensin II (Ang II) receptor binding by quantitative autoradiography and adrenal hormones and catecholamines by RIA and HPLC. Isolation increased adrenal catecholamines, aldosterone and corticosterone, AT1-receptor binding in the zona glomerulosa and AT2-receptor binding in the adrenal medulla. Candesartan pretreatment decreased adrenal catecholamines, aldosterone and corticosterone, AT1-receptor binding in adrenal zona glomerulosa and medulla, pituitary gland and the hypothalamic paraventricular nucleus, and AT2-receptor binding in adrenal medulla, but increased AT2-receptor binding in zona glomerulosa. We conclude that peripheral and central AT1-receptor blockade with candesartan decreases the sympatho-adrenal and hormonal response to acute stress. Our results indicate that Ang II is an important stress hormone and suggest that blockade of the physiologically active AT 1-receptors could influence stress-related disorders. PMID- 28095245 TI - Distinctions between non-peptide angiotensin II AT1-receptor antagonists. AB - A far-reaching understanding of the molecular action mechanism of AT1-receptor antagonists (AIIAs) was obtained by using CHO cells expressing transfected human AT 1-receptors. In this model, direct [3H]-antagonist binding and inhibition of agonist-induced responses (inositol phosphate accumulation) can be measured under identical experimental conditions. Whereas preincubation with a surmountable AIIA (losartan) causes parallel shifts of the angiotensin II (Ang II) concentration response curve, insurmountable antagonists also cause partial (i.e., 30% for irbesartan, 50% for valsartan, 70% for EXP3174,) to almost complete (95% for candesartan) reductions of the maximal response. The main conclusions are that all investigated antagonists are competitive with respect to Ang II. They bind to a common or overlapping site on the receptor in a mutually exclusive way. Insurmountable inhibition is related to the slow dissociation rate of the antagonist-receptor complex (t 1/2 of 7 minutes for irbesartan, 17 minutes for valsartan, 30 minutes for EXP3174 and 120 minutes for candesartan). Antagonist bound AT1-receptors can adopt a fast and a slow reversible state. This is responsible for the partial nature of the insurmountable inhibition. The long lasting effect of candesartan, the active metabolite of candesartan cilexetil, in vascular smooth muscle contraction studies, as well as in in vivo experiments on rat and in clinical studies, is compatible with its slow dissociation from, and continuous recycling between AT1-receptors. This recycling, or 'rebinding' takes place because of the very high affinity of candesartan for the AT1-receptor. PMID- 28095246 TI - Review: Structural requirements for signalling and regulation of AT1-receptors. PMID- 28095247 TI - Review: AT 1-receptor blockade in experimental myocardial ischaemia/reperfusion. PMID- 28095248 TI - The role of angiotensin II and TGF-beta on the progression of chronic allograft nephropathy. AB - Chronic allograft nephropathy is the most prevalent cause of graft dysfunction and failure. Its pathogenesis and treatment remains poorly defined. The calcineurin inhibitors, cyclosporine and tacrolimus, may play a role in the progressive loss of renal function in patients with chronic allograft nephropathy. This effect may be either related to the direct stimulation of profibrogenic cytokines such as transforming growth factor (TGF-beta) or indirect mechanisms, through increases in blood pressure or alterations in either carbohydrate or lipid metabolism. Experimental studies have demonstrated that angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) can attenuate cyclosporine-mediated increases in TGF-beta production in renal tissue. Clinical studies have demonstrated that either cyclosporine or tacrolimus dose reduction may help reduce the rate of loss of renal function in patients with chronic allograft nephropathy. Moreover, other studies have demonstrated that a chronic reduction in the dose of cyclosporine in transplant patients can reduce serum TGF-beta levels. Treatment with an ARB can normalise the plasma levels of TGF-beta in renal transplant patients receiving cyclosporine. All these observations suggest that there may be a role of cyclosporine, and possibly tacrolimus, in worsening chronic allograft nephropathy through their effects on the renin-angiotensin-aldosterone system (RAAS) and TGF beta production. PMID- 28095249 TI - Relative antihypertensive and glomeruloprotective efficacies of enalapril and candesartan cilexetil in the remnant kidney model. AB - The present studies were performed to investigate whether the differences described between the two modalities for interruption of the renin-angiotensin aldosterone system (RAAS), angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin AT 1receptor antagonists (AIIA) result in differences in renoprotective efficacy in the rat remnant kidney model. Male Sprague-Dawley rats with an initial body weight of 225-300 g, underwent 5/6 renal ablation and had radiotransmitters installed for radiotelemetric blood pressure (BP) measurements, owing to the known limitations of periodic tail-cuff BP measurements to adequately reflect ambient BP profiles. After renal ablation surgery, the rats received no treatment (n=10); enalapril (n=11) or candesartan (n=9) after the first week, both administered initially at a dose of 50 mg/l of drinking water (~10 mg/kg). However, the dose of candesartan had to be reduced to 10-25 mg/l in 4/9 rats to avoid excessive hypotension. Both enalapril and candesartan produced significant reductions in average systolic BP during the subsequent approximately six weeks of observations as compared with untreated rats (187+/-4 mmHg, p<0.001), but candesartan was significantly more effective at these relative doses (121+/-3 vs. 133+/-4 mmHg, p<0.05). At approximately seven weeks, serum creatinine and proteinuria were measured before sacrifice for morphologic assessment of percentage glomerulosclerosis (GS). Despite the described differences between ACE-I and AIIA after acute administration, the percentage GS was reduced similarly by enalapril (down to 6.8+/-2.8%) and candesartan (down to 2.9+/-1.5%) as compared with untreated rats (37.2+/-4.3%). Moreover, GS in individual animals paralleled the BP reductions achieved. Proteinuria was reduced in parallel to the decrease in % GS. These data indicate that, at least in the 5/6 renal ablation model, RAAS blockade by either ACE-I or AIIA provides protection by BPdependent rather than BP-independent mechanisms. This may reflect the primarily hypertensive pathogenesis of GS in this model, and the fact that hypertension is also very angiotensin II-dependent in this model. Thus, these data suggest that models other than the 5/6 ablation model may be more appropriate to demonstrate the BP-independent protective effects of RAAS blockade. PMID- 28095250 TI - Review: Interaction among angiotensin II, nitric oxide and oxidative stress. PMID- 28095251 TI - Improvement of endothelial dysfunction in experimental heart failure by chronic RAAS-blockade: ACE-inhibition or AT1-receptor blockade? AB - Chronic heart failure (CHF) is associated with endothelial dysfunction. Activation of the renin-angiotensin-aldosterone system (RAAS) is believed to be important in the deterioration of endothelial dysfunction in CHF through stimulation of oxidative stress. Whereas angiotensin-converting enzyme inhibitors (ACE-I) improve endothelial function in CHF, the effects of angiotensin II AT1 receptor blockers (ARB) are less well established. Therefore we compared the effects of the ACE-I lisinopril vs. the ARB candesartan on endothelial dysfunction in a rat model of CHF. CHF was induced by myocardial infarction (MI) after coronary ligation. Two weeks after MI, daily treatment with lisinopril (2 mg/kg) or candesartan cilexetil (1.5 mg/kg) was started. After 13 weeks, rats were sacrificed and endothelial function was determined by measuring acetylcholine (ACh)-induced vasodilation in aortic rings, with selective presence of the nitric oxide synthase (NOS)-inhibitor NG-monomethyl-L-arginine (L-NMMA) to determine the contribution of nitric oxide (NO). ACh-induced vasodilation was attenuated in untreated MI (-50%) compared with control rats. This was in part due to an impaired contribution of NO (-49%). Lisinopril and candesartan cilexetil fully normalised ACh-induced dilation, including the part mediated by NO. Chronic RAAS-blockade with lisinopril and candesartan cilexetil normalised endothelial function in CHF in a comparable way. The effect of both treatments included the increase of the NO-mediated dilation, further indicating the important role of oxidative stress in the relationship between the RAAS and endothelial dysfunction in CHF. PMID- 28095252 TI - Review: The renin-angiotensin-aldosterone system, blockade and diabetic nephropathy. PMID- 28095253 TI - Lichen microalgae are sensitive to environmental concentrations of atrazine. AB - The identification of new organisms for environmental toxicology bioassays is currently a priority, since these tools are strongly limited by the ecological relevance of taxa used to study global change. Lichens are sensitive bioindicators of air quality and their microalgae are an untapped source for new low-cost miniaturized bioassays with ecological importance. In order to increase the availability of a wider range of taxa for bioassays, the sensitivity of two symbiotic lichen microalgae, Asterochloris erici and Trebouxia sp. TR9, to atrazine was evaluated. To achieve this goal, axenic cultures of these phycobionts in suspension were exposed to a range of environmental concentrations of the herbicide atrazine, a common water pollutant. Optical density and chlorophyll autofluorescence were used as endpoints of ecotoxicity and ecophysiology on cell suspensions. Results show that lichen microalgae show high sensitivity to very low doses of atrazine, being higher in Asterochloris erici than in Trebouxia sp. TR9. We conclude that environmental concentrations of atrazine could modify population dynamics probably through a shift in reproduction strategies of these organisms. This seminal work is a breakthrough in the use of lichen microalgae in the assessment of micropollution effects on biodiversity. PMID- 28095254 TI - Maternal psychological distress during pregnancy does not increase the risk for adverse birth outcomes. AB - Maternal psychological distress during pregnancy is a potential risk factor for various birth complications. This study aimed to explore psychological factors associated with adverse birth outcomes. Symptoms of psychological distress, individual characteristics, and medical complications were assessed at two time points antenatally in 285 women from Australia and New Zealand; birth outcomes were assessed postpartum, between January 2014 and September 2015. Hierarchical multiple regression analyses were conducted to examine the relation of psychological distress to adverse birth outcomes. Medical complications during pregnancy, such as serious infections, placental problems and preeclampsia, and antenatal cannabis use, were the factors most strongly associated with adverse birth outcomes, accounting for 22 percent of the total variance (p < .001). Symptoms of depression and/or anxiety, low social support, and low sense of coherence were not associated with birth complications. In unadjusted analyses, self-reported diagnosis of anxiety disorder during pregnancy and an orientation toward a Regulator mothering style were associated with adverse birth outcomes; however, after controlling for medical complications, these were no longer associated. Our study results indicate that antenatal depressive and/or anxiety symptoms were not independently associated with adverse birth outcomes, a reassuring finding for women who are already psychologically vulnerable during pregnancy. PMID- 28095255 TI - Effect of heroin use on changes of brain functions as measured by functional magnetic resonance imaging, a systematic review. AB - In this study the authors focus on reviewing imaging studies that used resting state functional magnetic resonance imaging for individuals with a history of heroin use. This review study compiled existing research addressing the effect of heroin use on decision making by reviewing available functional neuroimaging data. Systematic review of the literatures using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Eligible articles were retrieved through a computer-based MEDLINE and PsycINFO search from 1960 to December 2015 using the major medical subject headings "heroin, fMRI" (all fields). Only English language was included. Thirty-seven articles were initially included in the review. Sixteen were excluded because they did not meet the inclusion criteria. The results of 21 articles that met all the inclusion criteria were presented. Based on the 21 studies included in the current review, there is evidence that heroin use may have a direct and damaging effect on certain brain functions and that these changes may be associated with impulsive and unhealthy decision making. From the review of these studies, the authors understand that a longer duration of heroin use may be associated with more damaging effects on brain functions. The authors also understand that these brain changes could last long after abstinence, which may increase the risk of relapse to heroin use. More research is needed to create a biomarker map for patients with heroin use disorder that can be used to guide and assess response to treatment. PMID- 28095256 TI - Evaluation of a Psychomotor Vigilance Task for Touch Screen Devices. AB - OBJECTIVE: Our goals were to compare three techniques for performing a psychomotor vigilance task (PVT) on a touch screen device (fifth-generation iPod) and to determine the device latency. BACKGROUND: The PVT is a reaction-time test that is sensitive to sleep loss and circadian misalignment. Several PVT tests have been developed for touch screen devices, but unlike the standard PVT developed for laboratory use, these tests allow for touch responses to be recorded at any location on the device, with contact from any finger. In addition, touch screen devices exhibit latency in processing time between the touch response and the time registered by the device. METHOD: Thirteen participants completed a 5-min PVT on a touch screen device held in three positions (on a table with index finger, handheld portrait with index finger, handheld landscape with thumb). We compared reaction-time outcomes in each orientation condition using paired t tests. We recorded the first session using a high-speed video camera to determine the latency between the touch response and the documented response time. RESULTS: The participants had significantly faster reaction times in the landscape-oriented position using the thumb, compared with the portrait-oriented position using the index ( M = 224.13 and M = 244.26, p = .045). Using data from 1,241 unique touch events, we found a mean device latency of 68.53 ms that varied highly between individuals. CONCLUSION: Device orientation and device latency should be considered when using a touch screen version of a PVT. APPLICATION: Our findings apply to researchers administering touch screen versions of the PVT. PMID- 28095257 TI - Label-free affinity biosensor arrays: novel technology for molecular diagnostics. PMID- 28095258 TI - The safety of treatment options available for gout. AB - INTRODUCTION: Gout is the most common inflammatory arthritis in humans. Gout treatment includes rapid initiation of anti-inflammatory medications for acute attacks and chronically treating with urate lowering drugs as well as chronic anti-inflammatory prophylaxis. Areas covered: This review aims to provide an overview and discussion of the safety concerns of current treatment options available for gout. Expert opinion: Gout is a curable disease with appropriate treatment. The advent of new therapies provides encouraging opportunities to improve gout management. However, clinicians should be aware of some of the safety concerns of medications used to treat acute and chronic gout. When prescribing medications for gout one has to be mindful of the presence of comorbidities commonly affecting gout patients that may affect drug safety and efficacy, especially in the elderly and in patients treated with multiple drugs. The benefits of gout drugs, usually, outweigh their safety concerns. Studies are needed in gout patients with chronic kidney disease and/or cardiovascular disease, so that escalation of dosing /combination of anti-inflammatory drugs needed to suppress gouty inflammation as well as escalation of dosing/combination of urate lowering drugs needed to achieve target serum urate level will lead to better understanding of gout treatment safety issues. PMID- 28095259 TI - Impact of Skill-Based Approaches in Reducing Stigma in Primary Care Physicians: Results from a Double-Blind, Parallel-Cluster, Randomized Controlled Trial. AB - OBJECTIVE: Most interventions to reduce stigma in health professionals emphasize education and social contact-based strategies. We sought to evaluate a novel skill-based approach: the British Columbia Adult Mental Health Practice Support Program. We sought to determine the program's impact on primary care providers' stigma and their perceived confidence and comfort in providing care for mentally ill patients. We hypothesized that enhanced skills and increased comfort and confidence on the part of practitioners would lead to diminished social distance and stigmatization. Subsequently, we explored the program's impact on clinical outcomes and health care costs. These outcomes are reported separately, with reference to this article. METHODS: In a double-blind, cluster randomized controlled trial, 111 primary care physicians were assigned to intervention or control groups. A validated stigma assessment tool, the Opening Minds Scale for Health Care Providers (OMS-HC), was administered to both groups before and after training. Confidence and comfort were assessed using scales constructed from ad hoc items. RESULTS: In the primary analysis, no significant differences in stigma were found. However, a subscale assessing social distance showed significant improvement in the intervention group after adjustment for a variable (practice size) that was unequally distributed in the randomization. Significant increases in confidence and comfort in managing mental illness were observed among intervention group physicians. A positive correlation was found between increased levels of confidence/comfort and improvements in overall stigma, especially in men. CONCLUSIONS: This study provides some preliminary evidence of a positive impact on health care professionals' stigma through a skill-building approach to management of mild to moderate depression and anxiety in primary care. The intervention can be used as a primary vehicle for enhancing comfort and skills in health care providers and, ultimately, reducing an important dimension of stigma: preference for social distance. PMID- 28095260 TI - Differential Expression and Roles of Secreted Frizzled-Related Protein 5 and the Wingless Homolog Wnt5a in Periodontitis. AB - The Wingless/integrase-1 (Wnt) family of protein ligands and their functional antagonists, secreted frizzled-related proteins (sFRPs), regulate various biological processes ranging from embryonic development to immunity and inflammation. Wnt5a and sFRP5 comprise a typical ligand/antagonist pair, and the former molecule was recently detected at the messenger RNA (mRNA) level in human periodontitis. The main objective of this study was to investigate the interrelationship of expression of Wnt5a and sFRP5 in human periodontitis (as compared to health) and to determine their roles in inflammation and bone loss in an animal model. We detected both Wnt5a and sFRP5 mRNA in human gingiva, with Wnt5a dominating in diseased and sFRP5 in healthy tissue. Wnt5a and sFRP5 protein colocalized in the gingival epithelium, suggesting epithelial cell expression, which was confirmed in cultured human gingival epithelial cells (HGECs). The HGEC expression of Wnt5a and sFRP5 was differentially regulated by a proinflammatory stimulus (lipopolysaccharide [LPS] from Porphyromonas gingivalis) in a manner consistent with the clinical observations (i.e., LPS upregulated Wnt5a and downregulated sFRP5). In HGECs, exogenously added Wnt5a enhanced whereas sFRP5 inhibited LPS-induced inflammation, as monitored by interleukin 8 production. Consistent with this, local treatment with sFRP5 in mice subjected to ligature induced periodontitis inhibited inflammation and bone loss, correlating with decreased numbers of osteoclasts in bone tissue sections. As in humans, mouse periodontitis was associated with high expression of Wnt5a and low expression of sFRP5, although this profile was reversed after treatment with sFRP5. In conclusion, we demonstrated a novel reciprocal relationship between sFRP5 and Wnt5a expression in periodontal health and disease, paving the way to clinical investigation of the possibility of using the Wnt5a/sFRP5 ratio as a periodontitis biomarker. Moreover, we showed that sFRP5 blocks experimental periodontal inflammation and bone loss, suggesting a promising platform for the development of a new host modulation therapy in periodontitis. PMID- 28095261 TI - Serum alkaline phosphatase, a risk factor for non-alcoholic fatty liver, but only for women in their 30s and 40s: evidence from a large cohort study. AB - BACKGROUND: Several risk factors are able to predict non-alcoholic fatty liver (NAFL) development, but the predictive value of serum alkaline phosphatase (ALP) remains uncertain. Our aim is to investigate the association between serum ALP levels and NAFL. METHODS: 21,331 NAFL-free subjects were included. Sex-specific ALP quartiles (Q1 to Q4) were defined. With Q1 used as reference, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated across each quartile. RESULTS: After adjusting for confounding variables, values in Q2, Q3 and Q4 had HRs (95%CIs) of 1.16 (0.94-1.43), 1.38 (1.13-1.69), 1.51 (1.24-1.83) in females and 0.99 (0.90-1.09), 1.04 (0.95-1.14), 0.96 (0.87-1.05) in males, respectively. A subgroup analysis of age factors in females, from Q2 to Q4, adjusted HRs (95%CIs) were 1.31 (0.81-1.99), 1.86 (1.23-2.81), 2.44 (1.60-3.71) in their 30 s, 1.13 (0.83-1.54), 1.17 (0.85-1.62), 1.65 (1.22-2.25) in their 40 s, and 0.95 (0.51-1.78), 0.91 (0.52-1.62), 0.89 (0.53-1.52) in their 50 s. CONCLUSIONS: Higher serum ALP levels are considered a significant predictor for NAFL development in females aged 30 to 50. PMID- 28095262 TI - Biosimilars in Inflammatory Bowel Disease - Accumulating Clinical Evidence. AB - INTRODUCTION: Biologic antagonists to tumor necrosis factor alpha (TNF- alpha) are effective medications and have become well established in the treatment of both Crohn's disease and ulcerative colitis. Biosimilar medications, which are medications deemed to be equivalent to reference biologic products in terms of clinical effectiveness, safety, pharmacokinetic analysis, and immunogenicity, have now been approved in inflammatory bowel diseases (IBD) based on indication exploration from clinical data in alternate disease states. Clinicians use these products with caution secondary to lack of clinical experience. Areas Covered: The authors performed a literature search using the following keywords: CT-P13, biosimilar, adalimumab, infliximab, ABP 501, and inflammatory bowel disease. Bibliographies were also reviewed for pertinent articles. Articles pertaining to the clinical efficacy of biosimilars in IBD were included. Expert commentary: The phase 3 trials, which provided the clinical justification to bring TNF- alpha biosimilars to market, were in rheumatoid arthritis and ankylosing spondylitis; however, new clinical data suggests that biosimilar products have equivalent safety and efficacy to reference products in IBD. This has led to an increased acceptance amongst practicing gastroenterologists and a potential reduction in healthcare costs. PMID- 28095263 TI - Chemoprevention of colorectal cancer in inflammatory bowel disease. AB - INTRODUCTION: Patients with inflammatory bowel disease are at an increased risk of colorectal cancer when compared to the general population. Chronic inflammation is thought to be the underlying cause, and medications that reduce inflammation have the potential to reduce the risk of colorectal cancer. Areas covered: After conducting a PubMed search for relevant literature, we examined several classes of medications that have been studied as potential chemopreventive agents. These include 5-aminosalicylates, thiopurines, tumor necrosis factor antagonists, ursodeoxycholic acid, NSAIDs, and statins. Expert commentary: While each class of medications has some data to support its use in chemoprevention, the majority of the evidence in each case argues against the routine use of these medications solely for a chemopreventive benefit. PMID- 28095264 TI - Reply to G. Le Flahec et al. PMID- 28095265 TI - Reply to C.F. Hess et al. PMID- 28095266 TI - Reply to H.J.A. Adams et al and E.A. Hawkes et al. PMID- 28095267 TI - Survival After Early-Stage Breast Cancer of Women Previously Treated for Depression: A Nationwide Danish Cohort Study. AB - Purpose The aim of this nationwide, register-based cohort study was to determine whether women treated for depression before primary early-stage breast cancer are at increased risk for receiving treatment that is not in accordance with national guidelines and for poorer survival. Material and Methods We identified 45,325 women with early breast cancer diagnosed in Denmark from 1998 to 2011. Of these, 744 women (2%) had had a previous hospital contact (as an inpatient or outpatient) for depression and another 6,068 (13%) had been treated with antidepressants. Associations between previous treatment of depression and risk of receiving nonguideline treatment of breast cancer were assessed in multivariable logistic regression analyses. We compared the overall survival, breast cancer-specific survival, and risk of death by suicide of women who were and were not treated for depression before breast cancer in multivariable Cox regression analyses. Results Tumor stage did not indicate a delay in diagnosis of breast cancer in women previously treated for depression; however, those given antidepressants before breast cancer had a significantly increased risk of receiving nonguideline treatment (odds ratio, 1.14; 95% CI, 1.03 to 1.27) and significantly worse overall survival (hazard ratio, 1.21; 95% CI, 1.14 to 1.28) and breast cancer-specific survival (hazard ratio, 1.11; 95% CI, 1.03 to 1.20). Increased but nonsignificant estimated risks were also found for women with previous hospital contacts for depression. In subgroup analyses, the association of depression with poor survival was particularly strong among women who did not receive the indicated adjuvant systemic therapy. Conclusion Women previously treated for depression constitute a large subgroup of patients with breast cancer who are at risk for receiving nonguideline breast cancer treatment, which probably contributes to poorer overall and breast cancer-specific survival. PMID- 28095269 TI - Is Upfront Escalated BEACOPP for Advanced Hodgkin Lymphoma Becoming a Distant Memory? PMID- 28095268 TI - Impact of Increasing Age on Cause-Specific Mortality and Morbidity in Patients With Stage I Non-Small-Cell Lung Cancer: A Competing Risks Analysis. AB - Purpose To perform competing risks analysis and determine short- and long-term cancer- and noncancer-specific mortality and morbidity in patients who had undergone resection for stage I non-small-cell lung cancer (NSCLC). Patients and Methods Of 5,371 consecutive patients who had undergone curative-intent resection of primary lung cancer at our institution (2000 to 2011), 2,186 with pathologic stage I NSCLC were included in the analysis. All preoperative clinical variables known to affect outcomes were included in the analysis, specifically, Charlson comorbidity index, predicted postoperative (ppo) diffusing capacity of the lung for carbon monoxide, and ppo forced expiratory volume in 1 second. Cause-specific mortality analysis was performed with competing risks analysis. Results Of 2,186 patients, 1,532 (70.1%) were >= 65 years of age, including 638 (29.2%) >= 75 years of age. In patients < 65, 65 to 74, and >= 75 years of age, 5-year lung cancer-specific cumulative incidence of death (CID) was 7.5%, 10.7%, and 13.2%, respectively (overall, 10.4%); noncancer-specific CID was 1.8%, 4.9%, and 9.0%, respectively (overall, 5.3%). In patients >= 65 years of age, for up to 2.5 years after resection, noncancer-specific CID was higher than lung cancer-specific CID; the higher noncancer-specific, early-phase mortality was enhanced in patients >= 75 years of age than in those 65 to 74 years of age. Multivariable analysis showed that low ppo diffusing capacity of lung for carbon monoxide was an independent predictor of severe morbidity ( P < .001), 1-year mortality ( P < .001), and noncancer-specific mortality ( P < .001), whereas low ppo forced expiratory volume in 1 second was an independent predictor of lung cancer specific mortality ( P = .002). Conclusion In patients who undergo curative intent resection of stage I NSCLC, noncancer-specific mortality is a significant competing event, with an increasing impact as patient age increases. PMID- 28095270 TI - How Relevant Is Treatment-Related Infertility for Individual Treatment Selection in Hodgkin Lymphoma? PMID- 28095271 TI - Reply to G. Le Flahec et al. PMID- 28095272 TI - Reply to H.J.A. Adams et al, E.A. Hawkes et al, and C.F. Hess et al. PMID- 28095273 TI - Detection of Mismatch Repair Deficiency in Colorectal Cancers: Is It Really Time to Eliminate Immunohistochemistry? PMID- 28095275 TI - Tamoxifen Decreases Mortality, but How? PMID- 28095274 TI - Protein Intake and Breast Cancer Survival in the Nurses' Health Study. AB - Purpose Greater protein intake has been associated with better breast cancer survival in several prospective studies, including among 1,982 women in the Nurses' Health Study. We proposed to extend this previous finding. We hypothesized that protein, essential amino acid, branched-chain amino acid, and leucine intakes are associated with improved survival and that these associations are stronger in tumors expressing insulin receptor (IR). Patients and Methods We included 6,348 women diagnosed with stage I to III breast cancer between 1976 and 2004. There were 1,046 distant recurrences. Relative risks (RRs) and 95% CIs were calculated according to quintiles of updated postdiagnostic diet using adjusted Cox proportional hazards models based on follow-up until 2010. Results There was an inverse association between energy-adjusted protein intake and recurrence. Multivariable RRs for increasing quintiles of intake compared with the lowest were 0.95 (95% CI, 0.79 to 1.15), 0.92 (95% CI, 0.76 to 1.11), 0.75 (95% CI, 0.61 to 0.91), and 0.84 (95% CI, 0.69 to 1.03; trend P = .02). For animal protein intake, the RRs were 0.88 (95% CI, 0.73 to 1.06), 0.85 (95% CI, 0.70 to 1.02), 0.75 (95% CI, 0.62 to 0.92), and 0.78 (95% CI, 0.63 to 0.95; trend P = .003). Neither essential amino acids, branched-chain amino acids, nor any individual amino acid stood out as being the source of the association. The association also did not differ by IR status. There was no clear association with any protein containing foods. Conclusion We found a modest survival advantage with higher intake of protein, regardless of IR status. There was no clear mechanism for this association, although it is consistent with prior studies. Our data suggest that there is likely no advantage for women with a history of breast cancer in restricting protein intake or protein-containing foods. PMID- 28095276 TI - Predictive Value of Interim [18F]Fluorodeoxyglucose-Positron Emission Tomography in Advanced-Stage Hodgkin Lymphoma Is Not Well Established. PMID- 28095277 TI - Long-Term Follow-Up of the French Stop Imatinib (STIM1) Study in Patients With Chronic Myeloid Leukemia. AB - Purpose Imatinib (IM) can safely be discontinued in patients with chronic myeloid leukemia (CML) who have had undetectable minimal residual disease (UMRD) for at least 2 years. We report the final results of the Stop Imatinib (STIM1) study with a long follow-up. Patients and Methods IM was prospectively discontinued in 100 patients with CML with UMRD sustained for at least 2 years. Molecular recurrence (MR) was defined as positivity of BCR-ABL transcript in a quantitative reverse transcriptase polymerase chain reaction assay confirmed by a second analysis point that indicated an increase of one log in relation to the first analysis point at two successive assessments or loss of major molecular response at one point. Results The median molecular follow-up after treatment discontinuation was 77 months (range, 9 to 95 months). Sixty-one patients lost UMRD after a median of 2.5 months (range, 1 to 22 months), and one patient died with UMRD at 10 months. Molecular recurrence-free survival was 43% (95% CI, 33% to 52%) at 6 months and 38% (95% CI, 29% to 47%) at 60 months. Treatment was restarted in 57 of 61 patients with MR, and 55 patients achieved a second UMRD with a median time of 4 months (range, 1 to 16 months). None of the patients experienced a CML progression. Analyses of the characteristics of the study population identified that the Sokal risk score and duration of IM treatment were significantly associated with the probability of MR. Conclusion With a median follow-up of more than 6 years after treatment discontinuation, the STIM1 study demonstrates that IM can safely be discontinued in patients with a sustained deep molecular response with no late MR. PMID- 28095278 TI - Awareness of HIV Transmission Risks and Determinants of Sexual Behaviour: Descriptive and Multivariate Analyses among German Nursing Students. AB - BACKGROUND AND AIM: Nursing students play a crucial role in sexual health education. Evidence suggests, however, that nursing students had several gaps in their knowledge of HIV transmission. This study investigates how nursing students in Germany assess the potential risks of spreading HIV in defined situations and which factors influence the self-expressed sexual behaviour patterns of these students. METHODS: A standardized anonymous questionnaire was administered to a sample (N=617) of nursing students in 2008 and 2013. The survey was conducted during lessons, resulting in a response rate of 100%. RESULTS: For 17.4% of the students, assistance with personal hygiene was associated with higher HIV transmission risk. Also, changing dirty linen (17.6%) and physical examination (14.1%) were also noted similarly risky. The average age of first sexual intercourse was 15.5 years and the number of lifetime sexual partners was 4.3. The higher the average number of lifetime sexual partners, the higher the likelihood to use condoms only sometimes or never (OR 1.11). Forty students reported an unintended pregnancy. The likelihood to be unintentionally pregnant was six times higher among students aged 25 years or older (OR 6.16). CONCLUSIONS: The results clearly show that students overestimated HIV transmission risks in most of the situations encountered during health services provided by nurses, but overall sexual health behaviour indicated rather less risky behaviour. Nonetheless, the relatively high rate of unintended pregnancies is quite concerning. The findings underline the need for stronger integration of HIV and sexual education in the curricula of nursing schools in Germany. PMID- 28095279 TI - Overweight and Obesity in Italian Adolescents: Examined Prevalence and Socio Demographic Factors. AB - AIM: This study aimed to evaluate the prevalence of overweight and obesity derived from measured data of weight and height in a cross-sectional sample of adolescents in the Italian region of Lazio and to analyse their association with different socio-demographic factors. METHODS: The study was conducted in a representative sample of 15-16-year-old adolescents recruited in secondary schools between December 2011 and May 2012. 369 adolescents were investigated. Body weight, height and waist circumference were measured. The BMI of each subject was calculated, and the prevalence of overweight and obesity was determined by age and sex using the IOTF reference values and WHO growth standards. Waist circumference/height ratio (WC/Ht) was calculated and the subjects were classified using the cut-off of 0.5: WC/Ht>=0.5 and WC/Ht<0.5. Selected socio-demographic characteristics were assessed via questionnaire. RESULTS: The percentages of overweight and obesity were high, 15.4% and 7.9%, respectively, with significant difference between males and females (19.1% vs. 12.6% for overweight and 11.1% vs. 5.3% for obese) using the IOFT reference. The ratio WC/Ht>=0.5 was observed in 12.7% of the sample (all the obese and 29.8% of the overweight subjects). Multiple logistic regression analysis indicated that gender, school municipality, mother's employment status, and family structure had a significant effect on ponderal status (overweight/obesity vs. normal weight). CONCLUSION: These findings show a high prevalence of body weight excess associated with socio-demographic factors in the Italian sample investigated, and the need for effective public health interventions to combact obesity with particular attention to disadvantaged adolescents. PMID- 28095280 TI - Relative Importance of Traditional Risk Factors for Malignant Melanoma in the Czech Population. AB - AIM: The Czech Republic is one of the leading European countries in incident cases of malignant melanoma (MM), which is on the rise. The study objective was to assess the strength of associations between MM and the known generally accepted risk factors for MM in the population of the Czech Republic. METHODS: The study was designed as a case-control study where cases were incident cases of MM detected at the Department of Dermatology and Venereology of the Bulovka Hospital. Controls were selected from cancer-free patients admitted to departments other than Dermatology and Venereology. Validated questionnaires were used to collect demographic, epidemiological, and clinical data. RESULTS: The binary logistic model shows the main risk factors for MM: male, female (OR=0.292, 95% CI=0.175-0.486), a changed mole (OR=6.371, 95% CI=3.774-10.756), a history of skin cancer (OR=95.704, 95% CI=37.241-10.756), and sunbeds use (OR=3.594, 95% CI=1.288-10.028). Using sunscreen products was considered as a protective factor against MM (OR=0.253, 95% CI=0.137-0.466). CONCLUSION: The primary and secondary prevention increasingly emerges as a public health priority in the effort to reverse the negative trend in cases of MM and mortality from this disease in the Czech Republic. A prerequisite for an effective secondary prevention through screening is, among others, the identification of the population groups at highest risk for MM. PMID- 28095281 TI - Nurses' Attitudes toward Intervening with Smokers: Their Knowledge, Opinion and E Learning Impact. AB - BACKGROUND: Numbering about 90,000, nurses represent the largest group of health care providers in the Czech Republic. Therefore, nurses can make a significant impact in the treatment of tobacco dependence, particularly in applying brief interventions to smokers. METHODS: During 2014, 279 nurses from the Czech Republic participated in an e-learning education programme consisting of two Webcasts with additional web-based resources about smoking cessation in relation to health and treatment options in daily clinical practice, particularly regarding brief intervention methods. Before viewing the e-learning programme, and three months after viewing it, the nurses completed a questionnaire documenting their interventions with smokers and their knowledge, attitudes and opinions regarding nurses' roles in smoking cessation. RESULTS: The responses in all of the following categories significantly improved: usually/always asking patients about smoking from 58% to 69% (OR 1.62, CI=1.14-2.29, p=0.007); recommendations to stop smoking from 56% to 66% (OR 1.46, CI=1.03-2.06, p=0.03); assessing willingness to quit from 49% to 63% (OR 1.72, CI=1.23-2.42, p=0.002); assisting with cessation from 21% to 33% (OR 1.85, CI=1.26-2.71, p=0.002); and recommending a smoke-free home from 39% to 58% (OR 2.16, CI=1.54-3.04, p<0.001). The increase in arranging follow-up from 7% to 10% did not constitute a statistically significant improvement, however, this finding is understandable in relation to the status of nurses in the Czech Republic. However, nurses' confidence in helping smokers to quit smoking, their senses of responsibility and determining the appropriateness of these interventions remains inadequate. CONCLUSION: The nurses' brief intervention skills improved significantly after the completion of the e-learning programme, even though reservations remain among this group. The systematic education of nurses aimed at smoking cessation intervention and analyzing their motivation for treatment may contribute to improved nursing care, and thus lead to a reduction of smoking prevalence in the general population. PMID- 28095282 TI - Active Smoking and Associated Behavioural Risk Factors before and during Pregnancy - Prevalence and Attitudes among Newborns' Mothers in Mures County, Romania. AB - BACKGROUND AND AIM: Smoking before, during and after pregnancy leads to detrimental outcomes on maternal and foetal health and represents an important public health issue. This study aims to evaluate the prevalence and correlates of smoking before and during pregnancy in a sample of Romanian women. METHODS: A cross-sectional survey was conducted among mothers (N=1,278) in three maternity hospitals in Tirgu-Mures, Romania, immediately after childbirth, in 2014. We evaluated the prevalence of smoking before and during pregnancy and used binary logistic regression to assess the influence of socio-demographics and other health behaviour factors in three groups of women: non-smoking pregnant women, women who continued smoking during pregnancy, and smokers who quit during pregnancy. RESULTS: 30% of the interviewed mothers were smokers prior to pregnancy, of whom 43.3% continued smoking during pregnancy. Women with a family income of less than 100 Euro/month (OR=3.01, 95% CI: 1.02-8.83) and those who were unemployed (OR=13.2, 95% CI: 3.90-44.79) had increased odds of continued smoking versus quitting during pregancy in multivariable analyses. Women who continued smoking during pregnancy were also more likley to be of lower socioeconomic status than never smokers (OR=14.1, 95% CI: 4.97-39.6). CONCLUSIONS: A high percentage of women of reproductive age smoke and continue to smoke despite their knowledge about risks of smoking during pregnancy. Smoking prior to and during pregnancy is predominantly associated with lower socioeconomic status. Women with limited economic means should be a high priority target group for smoking cessation interventions. PMID- 28095283 TI - Substance Use among European Students: East - West Comparison between 1995 and 2011. AB - AIM: The aim of the study was to investigate long-term trends differences in student substance misuse between countries of former Eastern Bloc (FEB) and Western Europe (WEST). Overall data on student substance misuse gathered in five waves of the European School Survey Project on Alcohol and other Drugs (ESPAD) conducted between 1995 and 2011 were pooled and analysed. Findings were compared between FEB and WEST countries at the five time-points of data collection. METHODS: Over 396,000 of 16 years old students from thirteen FEB and thirteen WEST countries completed anonymous ESPAD questionnaires. The following data were compared by Wilcoxon test: proportion of students with experience of taking a legal drug at less than 13 years of age (early onset), regular tobacco use, emerging signs of alcohol abuse, and differences in prevalence of illegal drug use. RESULTS: Significant differences in selected variables were found in the early onset of legal and illegal drug use between FEB and WEST countries. On the contrary, no significant differences were present when several random samples from the pool of 26 participating countries were drawn and compared. This strengthens our confidence that the differences between FEB and WEST countries did not occur due to chance. CONCLUSIONS: Student drug use in FEB countries tended to follow the trends and patterns of legal and illegal drug use in WEST countries with some time lag. At the times of decline in use of both, legal and illegal substances in the WEST countries, the FEB countries were experiencing increase and later on stabilisation in drug use. The possible explanatory factors including the impact of profound political, cultural and socio-economic changes following the fall of the Iron Curtain in 1989 were discussed. The implications of these trends and suggestions for drug prevention strategies were outlined. PMID- 28095284 TI - Family Carers' Perspectives on Integrated Community Care in the Czech Republic. AB - AIM: The problem of family care for people dependent on another person has only recently become a focus of research. As demand for health and social services has not been adequately met by public service providers, growing attention has been given to informal care and the integration of families within systems of health and social care at the community level. This paper presents the results of a survey on informal carers' views and opinions under the current conditions of social support in the Czech Republic. The survey was based on theoretical concepts of caring societies, deinstitutionalization, refamilization, and integrated community care, and aimed to shed light on caring families' experiences and needs in the Czech Republic. METHODS: Family lay carers completed an original self-administered questionnaire. A convenient sample of 200 family carers was selected. RESULTS: The survey collected information about the most influential factors in determining whether the families continue to provide care for their relatives in the household. More than 50% of the caregivers provide care from moral and emotional reasons. Financial problems, risk of losing their jobs, and further deterioration of health of the person they care for emerged as key risk factors, but overall, determination among carers to continue providing care "at any cost" was high (53%). CONCLUSIONS: Involving local communities and services, e.g. general practitioners (GPs) to a greater extent in the coordination of various social and health services, and in support mechanisms at the juncture between informal and formal care would make it easier for family carers to continue providing long-term care. PMID- 28095285 TI - Urine Levels of Phthalate Metabolites and Bisphenol A in Relation to Main Metabolic Syndrome Components: Dyslipidemia, Hypertension and Type 2 Diabetes. A Pilot Study. AB - AIM: Human exposure to organic pollutants (some of them also called endocrine disruptors) can be associated with adverse metabolic health outcomes including type 2 diabetes. The goal of this study was to compare the urine levels of bisphenol A and phthalate metabolites in subgroups of patients with metabolic syndrome composed of patients with and without three important components of metabolic syndrome (hypertension, dyslipidemia and diabetes). METHODS: We have investigated 24 hr urine samples of 168 patients with metabolic syndrome from the Metabolic Outpatient Department of General University Hospital in Prague. Using standard metabolic syndrome criteria, we classified patients as dyslipidemic (n=87), hypertensive (n=96), and type 2 diabetic (n=58). Bisphenol A and 15 metabolites of phthalates were evaluated in relation to creatinine excretion. Samples were analysed with enzymatic cleavage of glucuronide using ultra-high performance liquid chromatography-electrospray ionization tandem mass spectrometry in one laboratory with external quality control. RESULTS: Four metabolites, mono-n-butyl phthalate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, and mono-(2-ethyl-5-carboxypentyl) phthalate showed significantly higher levels in diabetic compared to non-diabetic patients (p<0.001, p=0.002, p=0.002, and p=0.005, respectively). The differences remained significant after adjustment to hypertension, dyslipidemia, age, and BMI. No difference was found between either the hypertensive and non-hypertensive or dyslipidemic and non-dyslipidemic patients. There was no significant relation of bisphenol A level to diabetes, hypertension, dyslipidemia, age, and BMI. CONCLUSIONS: Urine levels of four phthalate metabolites were significantly higher in type 2 diabetics independently on specified predictors. Phthalate levels can be in relation to beta cell dysfunction in type 2 diabetic patients but this study is not able to show if the relation is causal. PMID- 28095286 TI - The Relations between Polycyclic Aromatic Hydrocarbons Exposure and 1-OHP Levels as a Biomarker of the Exposure. AB - BACKGROUND AND AIM: Polycyclic aromatic hydrocarbons (PAHs) are the products of incomplete combustion or pyrolysis of various organic materials. Their ubiquity in the environment leads to measurable levels of exposure. However, the exposure varies strongly between different regions in Europe. Some PAHs with four or more rings are suspected to be human carcinogens. Therefore, the occupational and/or environmental exposure to PAHs may cause a significant health risk. The aim of the study was to evaluate current levels of PAH exposure in defined groups of workers. METHODS: The industrial sites selected in this survey involved PAHs originating from coal tar pitch, carbon black, bitumen, and rubber fumes. Based on the historical data, the sites were expected to exhibit quantifiable levels of exposure to PAHs. The total study population consisted of 139 persons: 108 workers (85 males and 23 females) workers were occupationally exposed in aluminium production, the production of graphite electrodes, road construction, or the rubber forming industry and 31 control individuals in two groups. RESULTS: The highest concentrations - 8-hour time-weighted average (TWA) levels (sum of 16 components according to the EPA list), as expected, were found in the aluminium production plant (55.15 ug.m-3) and production of graphite electrodes (54.25 ug.m 3). The lowest concentrations were found in personal air samples of road construction workers (1.93 ug.m-3). The concentrations of 1-hydroxypyrene as a pyrene metabolite (1-OHP) in the urine of the exposed group of workers were found in levels 0.74 umol.mol-1 creatinine before the exposure and 2.27 umol.mol-1 creatinine after the exposure (arithmetic mean values). 1-OHP concentrations in post-shift urine samples were highly correlated with the total airborne PAHs concentrations and pyrene concentrations in air. The correlation coefficients (rS) between 1-OHP concentration and pyrene or total PAHs in air were 0.710 and 0.752 (p < 0.05). This statistical analysis confirmed the effect of the occupational exposure to PAHs and pyrene on body burden in workers. However, a modifying effect of gender, smoking habits, dietary intake, genetically modified metabolism, and the use of medication on the toxicokinetics of pyrene was not determined as significant. CONCLUSION: Based on the results a strong correlation between the concentration of 1-OHP in urine as an exposure biomarker and the concentration of pyrene or PAH was affirmed. PMID- 28095287 TI - Nanomaterials - a New and Former Public Health Issue. The Case of Slovakia. AB - Nanoparticles exist for a long time as both inorganic and organic parts of nature. Recently, massive expansion of nanotechnologies is evidenced, together with intentional production of new nanoparticles which have not been in contact with living organisms until now. Besides obvious positive aspects, potential threats related to their exposure should be taken into consideration. Unique physical-chemical properties of nanoparticles cause a high bioactivity following their intake (through air, ingestion and skin) and unrestricted spread in exposed organs. Primary effects of nanoparticles on cellular level represent oxidative stress and reactions leading to apoptosis, autophagocytosis and necrosis. Number of studies indicating contribution of nanoparticles to numerous disorders has been recently increasing. However, detailed mechanisms of health effects are not well known. Similarly, there is insufficient information on life cycle of nanoparticles in the environment. Research in this field as well as legislation is behind rapid development and use of nanotechnologies. Considering absence of mandatory exposure limits and other protective measures, nanomaterials represent a potential threat for population health. Recommendations and guidelines of international institutions can contribute to deal with situation, however, passing of effective legislation both on national and European level is urgently needed. PMID- 28095288 TI - Cytomegalovirus Immunoglobulin G Avidity Index among Blood Donors in Alexandria, Egypt. AB - BACKGROUND AND AIM: Transfusion transmitted diseases (TTD) are a major challenge to transfusion services all over the world. Cytomegalovirus (CMV) is considered one of the main viruses associated with blood transfusion. As CMV screening is not included in routine screening tests done for donated blood in blood banks in Egypt, the detection of CMV Immunoglobulin G (IgG) avidity needs to be tested for being a useful tool to diagnose recent infection among blood donors. The aim of this work was to study CMV IgG avidity index (AI) among blood donors. METHODS: A total of 88 blood samples were collected from the non-remunerated volunteer blood donors who attended the Alexandria Regional Blood Transfusion Centre. A quantitative enzyme linked immunosorbent assay for the avidity detection of the specific IgG antibodies to CMV in human serum samples was used. RESULTS: Eighty five studied blood donors (96.6%) were positive for CMV IgG. Eighty one donors (95.3%) showed high avidity (>45.0%). Regarding the remaining four CMV IgG positive donors; three had medium avidity (<45.0%) and only one had a low avidity of <25.0%. A moderate agreement of 42.4% was found between IgG concentration and avidity. CONCLUSIONS: CMV seroprevalence was found to be high among volunteer blood donors, where age and gender were statistically significant factors associated with CMV IgG concentration. The use of the avidity assay as a screening tool for CMV among blood donors is highly suggested. The exclusion of the low and medium AI units will ensure the availability of a safe stock of blood units, hence eliminating the risk of CMV transmission to vulnerable groups. PMID- 28095289 TI - Prevalence of HPV Infection in Croatian Men during a 12-year Period: a Comparative Study of External Genital and Urethral Swabs. AB - AIM: The aim of the study was to compare the prevalence and distribution of both low-risk and high-risk HPV infection of the urethra and outer genital region in Croatian men. Thus far there is a consensus that sampling the coronal sulcus and glans of the penis is essential for adequately assessing HPV status in men but less agreement is noted for urethral sampling. METHODS: External genital brushing and urethral swabs were taken from 1,342 men during a 12-year period and tested with the hc2 HPV DNA Test using Hybrid Capture 2 technology. RESULTS: The overall prevalence of male HPV infection in this study was 36.66%. Infection with high risk HPV types (44.72%) was significantly more frequent than infection with low risk HPV types (28.86%) or co-infection with both low-risk and high-risk HPV types (26.42%). HPV was more frequently demonstrated in the outer genital area (58.33%) when compared to the sole infection of the urethra (17.89%) or infection of both genital sites (23.78%). CONCLUSIONS: Results from this study indicate high prevalence of HPV infection in men and suggest that optimal sampling method for the testing of men is the combination of external genital and urethral swabs. Further research about the proper collection of biological samples and testing methods for HPV detection in men is necessary since our future end-goal is to implement standardized guidelines on sampling and diagnostic testing of males. PMID- 28095290 TI - Study of the Microbiological Quality of Bulgarian Bottled Water in Terms of Its Contamination with Pseudomonas Aeruginosa. AB - BACKGROUND: Due to the widespread use of bottled water, it is important from a hygienic point of view to ensure that these products have good quality and meet the requirements set out in regulations. METHODS AND RESULTS: In the period 2000 2013, a large-scale study (2,500 samples) was carried out on the quality of Bulgarian bottled water as per the microbiological parameters laid down in the European and Bulgarian legislation. Standard microbiological methods were applied. There is strong evidence that the most frequently isolated contaminant in these products was Pseudomonas aeruginosa. This agent was found in 274 samples out of a total of 2,500 analysed bottled waters. Because of the absolute prohibition of the presence of this microorganism in the finished product, the manufacturers should not allow their products with compromised quality to reach the market. They are obliged to check the quality of each batch by conducting an internal monitoring of production. When any inconsistencies are established in microbiological parameters, the producers must detect the critical point and apply more effective decontamination measures of the bottling lines. Given the importance of this fact for the health of consumers, the study also included determination of the antimicrobial resistance of P. aeruginosa strains isolated from Bulgarian bottled water. Ten strains of P. aeruginosa, isolated from bottled water and other water habitats in the environment, were tested for the effect of 13 antimicrobial agents by applying the Kirby-Bauer's method. CONCLUSIONS: The investigation found that Pseudomonas aeruginosa strains isolated from bottled water are sensitive to Ceftazidime, Amikacin, Ciprofloxacin, and Cefepime and one of them is resistant to Meropenem and Piperacillin. Another important conclusion is that there is no specific behaviour of P. aeruginosa strains originating from different sources to the test antimicrobials. The authors consider that drinking tap water is perhaps a more appropriate way for newborns, infants, elderly, and people with compromised immunity to satisfy thirst than using bottled water. PMID- 28095291 TI - Genotyping of Varicella Zoster Virus Clinical Isolates from the Czech Republic. PMID- 28095292 TI - Should Enteroviruses Be Monitored in Natural Recreational Waters? AB - Enteroviruses (EVs) infections occur worldwide. Although, infections by these viruses are often asymptomatic and go unnoticed, they can be shed in stool for several weeks. The EVs are associated with sporadic outbreaks and a wide range of clinical symptoms, occasionally accompanied with fatal consequences. Presently in the Slovak Republic (SR) recreational waters are tested only for bacterial indicators. Our aim was to monitor EVs in recreational waters. Water samples were collected during the years 2012-2014 from different recreational natural lakes in Central and West regions of SR. The samples were concentrated by centrifugation using the two-phase separation method recommended by the World Health Organization (WHO) used for EVs surveillance in the treated sewage waste water. Each of the two phases collected from the samples was analysed by polymerase chain reaction for detection of EVs and primary sequencing was done. Our study demonstrated presence of EVs in three localities consecutively for three years, indicating a probability of constant local source of faecal contamination. This is the first monitoring report on the occurrence of EVs in the natural recreational waters in SR. PMID- 28095294 TI - A novel SLC12A1 gene mutation associated with hyperparathyroidism, hypercalcemia, nephrogenic diabetes insipidus, and nephrocalcinosis in four patients. AB - Solute Carrier Family 12 member 1 (SLC12A1) gene encodes the sodium-potassium chloride co-transporter (NKCC2) at the apical membrane of the thick ascending loop of Henle (TAL). Bartter's syndrome (BS) type I is a rare, autosomal recessive, renal tubular disorder associated with mutation of the SLC12A1 gene. Presenting features include: hypokalemic metabolic alkalosis, hypercalciuria and nephrocalcinosis. The many allelic variants reported present with a spectrum of phenotypes, biochemical abnormalities and clinical severities. However, to date, only two reports have described hyperparathyroidism and hypercalcemia in patients with SLC12A1 gene mutations. We describe 4 patients with 4 novel mutation variants in the SLC12A1 gene (c.735C>G, c.1137del, c.2498-2499del, and c.1833delT) presenting with variable degrees of hyperparathyroidism, hypercalcemia, hypokalemic metabolic alkalosis, nephrocalcinosis, and nephrogenic diabetes insipidus. The link between calcium and parathyroid hormone abnormalities in patients with SLC12A1 mutations is unclear; the cases described suggest an association between primary hyperparathyroidism and loss of function mutation of SLC12A1, which may result in an aberrant threshold of the calcium sensing receptor at the level of the kidney. PMID- 28095293 TI - MAPK signaling promotes axonal degeneration by speeding the turnover of the axonal maintenance factor NMNAT2. AB - Injury-induced (Wallerian) axonal degeneration is regulated via the opposing actions of pro-degenerative factors such as SARM1 and a MAPK signal and pro survival factors, the most important of which is the NAD+ biosynthetic enzyme NMNAT2 that inhibits activation of the SARM1 pathway. Here we investigate the mechanism by which MAPK signaling facilitates axonal degeneration. We show that MAPK signaling promotes the turnover of the axonal survival factor NMNAT2 in cultured mammalian neurons as well as the Drosophila ortholog dNMNAT in motoneurons. The increased levels of NMNAT2 are required for the axonal protection caused by loss of MAPK signaling. Regulation of NMNAT2 by MAPK signaling does not require SARM1, and so cannot be downstream of SARM1. Hence, pro-degenerative MAPK signaling functions upstream of SARM1 by limiting the levels of the essential axonal survival factor NMNAT2 to promote injury-dependent SARM1 activation. These findings are consistent with a linear molecular pathway for the axonal degeneration program. PMID- 28095295 TI - Hematopoietic stem cell transplantation corrects osteopetrosis in a child carrying a novel homozygous mutation in the FERMT3 gene. AB - Osteopetrosis (OPT) is a rare skeletal disorder with phenotypic and genotypic heterogeneity: a variety of clinical features besides the bony defect may be present, and at least ten different genes are known to be involved in the disease pathogenesis. In the framework of this heterogeneity, we report the clinical description of a neonate, first child of consanguineous parents, who had osteoclast-rich osteopetrosis and bone marrow failure in early life, but no other usual classical features of infantile malignant OPT, such as visual or hearing impairments. Because of the severe presentation at birth, the patient received Hematopoietic Stem Cell Transplantation (HSCT) at 2months of age with successful outcome. Post-HSCT genetic investigation by means of exome sequencing identified a novel homozygous mutation in the Fermitin Family Member 3 (FERMT3) gene, which was predicted to disrupt the functionality of its protein product kindlin 3. Our report provides information relevant to physicians for recognizing patients with one of the rarest forms of infantile malignant OPT, and clearly demonstrates that HSCT cures kindlin 3 deficiency with severe phenotype. PMID- 28095297 TI - Dual estrogenic regulation of the nuclear progestin receptor and spermatogonial renewal during gilthead seabream (Sparus aurata) spermatogenesis. AB - Studies in teleosts suggest that progestins have crucial functions during early spermatogenesis. However, the role of the different progestin receptors in these mechanisms is poorly understood. In this work, we investigated the expression pattern and hormonal regulation of the classical nuclear progestin receptor (Pgr) in the gilthead seabream at three different stages of spermatogenesis: the resting (postspawning) phase, onset of spermatogenesis, and spermiation. Immunolocalization experiments using a seabream specific Pgr antibody revealed that the receptor was expressed in Sertoli and Leydig cells, and also in a subset of spermatogonia type A, throughout spermatogenesis. Short-term treatment of testis explants with 17beta-estradiol (E2) increased pgr mRNA expression at all stages, while the progestin 17alpha,20beta-dihydroxy-4-pregnen-3-one (17,20betaP) had the opposite effect. At the resting stage, Sertoli cell Pgr expression was positively correlated with the occurrence of proliferating spermatogonia type A in the tubules, and both processes were incremented in vitro by E2 likely through the estrogen receptor alpha (Era) expressed in Sertoli and Leydig cells. In contrast, treatment with 17,20betaP downregulated Pgr expression in somatic cells. The androgen 11-ketotestosterone (11-KT) upregulated pgr expression in Leydig cells and promoted the proliferation of mostly spermatogonia type B, but only during spermiation. No relationship between the changes in the cell type specific expression of the Pgr with the entry into meiosis of germ cells was found. These data suggest a differential steroid regulation of Pgr expression during seabream spermatogenesis and the potential interplay of the E2/Era and 17,20betaP/Pgr pathways for the maintenance of spermatogonial renewal rather than entry into meiosis. PMID- 28095298 TI - Molecular identification and genotyping of Trypanosoma cruzi DNA in autochthonous Chagas disease patients from Texas, USA. AB - The parasitic protozoan Trypanosoma cruzi, the causative agent of Chagas disease, is widely distributed throughout the Americas, from the southern United States (US) to northern Argentina, and infects at least 6 million people in endemic areas. Much remains unknown about the dynamics of T. cruzi transmission among mammals and triatomine vectors in sylvatic and peridomestic eco-epidemiological cycles, as well as of the risk of transmission to humans in the US. Identification of T. cruzi DTUs among locally-acquired cases is necessary for enhancing our diagnostic and clinical prognostic capacities, as well as to understand parasite transmission cycles. Blood samples from a cohort of 15 confirmed locally-acquired Chagas disease patients from Texas were used for genotyping T. cruzi. Conventional PCR using primers specific for the minicircle variable region of the kinetoplastid DNA (kDNA) and the highly repetitive genomic satellite DNA (satDNA) confirmed the presence of T. cruzi in 12/15 patients. Genotyping was based on the amplification of the intergenic region of the miniexon gene of T. cruzi and sequencing. Sequences were analyzed by BLAST and phylogenetic analysis by Maximum Likelihood method allowed the identification of non-TcI DTUs infection in six patients, which corresponded to DTUs TcII, TcV or TcVI, but not to TcIII or TcIV. Two of these six patients were also infected with a TcI DTU, indicating mixed infections in those individuals. Electrocardiographic abnormalities were seen among patients with single non-TcI and mixed infections of non-TcI and TcI DTUs. Our results indicate a greater diversity of T. cruzi DTUs circulating among autochthonous human Chagas disease cases in the southern US, including for the first time DTUs from the TcII-TcV-TcVI group. Furthermore, the DTUs infecting human patients in the US are capable of causing Chagasic cardiac disease, highlighting the importance of parasite detection in the population. PMID- 28095299 TI - African and Asian Zika virus strains differentially induce early antiviral responses in primary human astrocytes. AB - ZIKA virus (ZIKV) is a newly emerging arbovirus. Since its discovery 60years ago in Uganda, it has spread throughout the Pacific, Latin America and the Caribbean, emphasizing the capacity of ZIKV to spread to non-endemic regions worldwide. Although infection with ZIKV often leads to mild disease, its recent emergence in the Americas has coincided with an increase in adults developing Guillain-Barre syndrome and neurological complications in new-borns, such as congenital microcephaly. Many questions remain unanswered regarding the complications caused by different primary isolates of ZIKV. Here, we report the permissiveness of primary human astrocytes for two clinically relevant, Asian and African ZIKV strains and show that both isolates strongly induce antiviral immune responses in these cells albeit with markedly different kinetics. This study describes for the first time the specific antiviral gene expression in infected primary human astrocytes, the major glial cells within the central nervous system. PMID- 28095300 TI - Knockdown of CXCL14 disrupts neurovascular patterning during ocular development. AB - The C-X-C motif ligand 14 (CXCL14) is a recently discovered chemokine that is highly conserved in vertebrates and expressed in various embryonic and adult tissues. CXCL14 signaling has been implicated to function as an antiangiogenic and anticancer agent in adults. However, its function during development is unknown. We previously identified novel expression of CXCL14 mRNA in various ocular tissues during development. Here, we show that CXCL14 protein is expressed in the anterior eye at a critical time during neurovascular development and in the retina during neurogenesis. We report that RCAS-mediated knockdown of CXCL14 causes severe neural defects in the eye including precocious and excessive innervation of the cornea and iris. Absence of CXCL14 results in the malformation of the neural retina and misprojection of the retinal ganglion neurons. The ocular neural defects may be due to loss of CXCL12 modulation since recombinant CXCL14 diminishes CXCL12-induced axon growth in vitro. Furthermore, we show that knockdown of CXCL14 causes neovascularization of the cornea. Altogether, our results show for the first time that CXCL14 plays a critical role in modulating neurogenesis and inhibiting ectopic vascularization of the cornea during ocular development. PMID- 28095301 TI - Imaging the Photosystem I/Photosystem II chlorophyll ratio inside the leaf. AB - Oxygenic photosynthesis is driven by photosystems I (PSI) and II (PSII). In plants the number of chlorophylls of PSI versus PSII is adjusted to the light irradiance spectrum. On a timescale of days, this is regulated at the level of protein concentration. Instead, on a timescale of minutes, it is regulated by the dynamic association of light-harvesting complex II with either PSI or PSII. Thus far very diverse values have been reported for the PSI/PSII chlorophyll ratio, ranging from 0.54 to 1.4. The methods used require the isolation of chloroplasts and are time consuming. We present a fluorescence lifetime imaging approach that quantifies the PSI/PSII Chl ratio of chloroplasts directly in their natural leaf environment. In wild type Arabidopsis thaliana plants, grown under white light, the PSI/PSII chlorophyll ratio appeared to be 0.99+/-0.09 at the adaxial side and 0.83+/-0.05 at the abaxial side of the leaf. When these plants were acclimated to far red light for several days the PSI/PSII chlorophyll ratio decreased by more than a factor of 3 to compensate for the ineffective far red light absorption of PSII. This shows how plants optimize their light-harvesting capacity to the specific light conditions they encounter. Zooming in on single chloroplasts inside the leaf allowed to study the grana/stroma membrane network and their PSI/PSII chlorophyll ratios. The developed method will be useful to study dynamic processes in chloroplasts in intact leaves which involve changes in the grana and the stroma membranes such as state transitions. PMID- 28095302 TI - Internal evaluation of impregnation treatment of waterlogged wood; relation between concentration of internal materials and relaxation time using magnetic resonance imaging. AB - The purpose of this study is to clarify the degree of impregnation resulting from treatment of internal waterlogged wood samples using MRI. On a 1.5T MR scanner, T1 and T2 measurements were performed using inversion recovery and spin-echo sequences, respectively. The samples were cut waterlogged pieces of wood treated with various impregnation techniques which were divided into different concentrations of trehalose (C12H22O11) and polyethylene glycol (PEG; HO-(C2H4O)n H) solutions. Then these samples underwent impregnation treatment every two weeks. From the results, we found that the slope of the T1-concentration curve using linear fitting showed the value of the internal area for PEG to be higher than the external area; internal, -2.73ms/wt% (R2=0.880); external, -1.50ms/wt% (R2=0.887). Furthermore, the slope of the T1-concentration curve using linear fitting showed the values for trehalose to have almost no difference when comparing the internal and the external areas; internal, -2.79ms/wt% (R2=0.759); external, -3.02ms/wt% (R2=0.795). However, the slope of the T2-concentration curve using linear fitting for PEG showed that there was only a slight change between the internal and the external areas; internal, 0.26ms/wt% (R2=0.642); external, 0.18ms/wt% (R2=0.920). The slope of the T2-concentration curve did not show a change in linear relationship between the internal and the external areas; internal, 0.06ms/wt% (R2=0.175); external, -0.14ms/wt% (R2=0.043). In conclusion, using visualization of relaxation time T1, it is possible to obtain more detail information noninvasively concerning the state of impregnation treatment of internal waterlogged wood. PMID- 28095296 TI - Diverse role of survival motor neuron protein. AB - The multifunctional Survival Motor Neuron (SMN) protein is required for the survival of all organisms of the animal kingdom. SMN impacts various aspects of RNA metabolism through the formation and/or interaction with ribonucleoprotein (RNP) complexes. SMN regulates biogenesis of small nuclear RNPs, small nucleolar RNPs, small Cajal body-associated RNPs, signal recognition particles and telomerase. SMN also plays an important role in DNA repair, transcription, pre mRNA splicing, histone mRNA processing, translation, selenoprotein synthesis, macromolecular trafficking, stress granule formation, cell signaling and cytoskeleton maintenance. The tissue-specific requirement of SMN is dictated by the variety and the abundance of its interacting partners. Reduced expression of SMN causes spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. SMA displays a broad spectrum ranging from embryonic lethality to an adult onset. Aberrant expression and/or localization of SMN has also been associated with male infertility, inclusion body myositis, amyotrophic lateral sclerosis and osteoarthritis. This review provides a summary of various SMN functions with implications to a better understanding of SMA and other pathological conditions. PMID- 28095303 TI - Gd-DTPA-induced dynamic metabonomic changes in rat biofluids. AB - OBJECTIVES: The purposes of this study were (1) to detect the dynamic metabonomic changes induced by gadopentetate dimeglumine (Gd-DTPA) and (2) to investigate the potential metabolic disturbances associated with the pathogenesis of nephrogenic systemic fibrosis (NSF) at the early stage. METHODS: A nuclear magnetic resonance (NMR)-based metabolomics approach was used to investigate the urinary and serum metabolic changes induced by a single tail vein injection of Gd-DTPA (dosed at 2 and 5mmol/kg body weight) in rats. Urine and serum samples were collected on days 1, 2 and 7 after dosing. RESULTS: Metabolic responses of rats to Gd-DTPA administration were systematic involving changes in lipid metabolism, glucose metabolism, TCA cycle, amino acid metabolism and gut microbiota functions. Urinary and serum metabonomic recovery could be observed in both the 2 and 5mmol/kg body weight group, but the metabolic effects of high-dosed (5mmol/kg body weight) Gd-DTPA lasted longer. It is worth noting that hyperlipidemia was observed after Gd-DTPA injection, and nicotinate might play a role in the subsequent self-recovery of lipid metabolism. The disturbance of tyrosine, glutamate and gut microbiota metabolism might associate with the progression of NSF. CONCLUSION: These findings offered essential information about the metabolic changes induced by Gd-DTPA, and could be potentially important for investigating the pathogenesis of NSF at the early stage. Moreover, the recovery of rats administrated with Gd-DTPA may have implications in the treatment of early stage NSF. PMID- 28095304 TI - Adaptive significance of critical weight for metamorphosis in holometabolous insects. AB - Holometabolous insect larvae become committed to metamorphosis when they reach a critical weight. Although the physiological mechanisms involved in this process have been well-studied, the adaptive significance of the critical weight remains unclear. Here, we developed a life history model for holometabolous insects and evaluated it from the viewpoint of optimal energy allocation. We found that, without a priori assumptions about critical weight, the optimal growth schedule is always biphasic: larval tissues grow predominately until they reach a certain threshold, after which the imaginal tissues begin rapid growth, suggesting that the emergence of a critical weight as a phase-transition point is a natural consequence of optimal growth scheduling. Our model predicts the optimal timing of critical-weight attainment, in agreement with observations in phylogenetically distinct species. Furthermore, it also predicts the scaling of growth scheduling against environmental change, i.e., the relative value and timing of the critical weight should be constant, thus providing a general interpretation of observed phenotypic plasticity. This scaling relationship allows the classification of adaptive responses in critical weight into five possible types that reflect the ecological features of focal insects. In this manner, our theory and its consistency with experimental observations demonstrate the adaptive significance of critical weight. PMID- 28095305 TI - Fertility, kinship and the evolution of mass ideologies. AB - Traditional human societies are organised around kinship, and use kinship networks to generate large scale community projects. This is made possible by a combination of linguistic kin recognition, a uniquely human trait, which is mediated by the reliability of kin as collaborators. When effective fertility falls, this results in two simultaneous effects on social networks: there are fewer kin that can be relied on, and the limiting effect of the local kin clustering becomes stronger. To capture this phenomenon, we used a model of kinship lineages to build populations with a range of fertility levels combined with a behavioural synchrony model to measure the efficiency of collective action generated on kin networks within populations. Our findings suggest that, whenever effective cooperation depends on kinship, falling fertility creates a crisis when it results in too few kin to join the community project. We conclude that, when societies transition to small effective kin networks, due to falling fertility, increased relative distance to kin due to urbanisation or high mortality due to war or epidemics, they will be able to remain socially cohesive only if they replace disappearing kin networks with quasi-kin alternatives based on membership of guilds or clubs. PMID- 28095306 TI - The role of PTEN in regulation of hepatic macrophages activation and function in progression and reversal of liver fibrosis. AB - Activation of Kupffer cells (KCs) plays a pivotal role in the pathogenesis of liver fibrosis. The progression and reversal of CCl4-induced mouse liver fibrosis showed a mixed induction of hepatic classical (M1) and alternative (M2) macrophage markers. Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in modulating myeloid cell activation has recently been identified, its function in macrophage activation during hepatic fibrosis remains to be fully appreciated. In our study, PTEN expression of KCs was remarkably decreased in CCl4-induced mice but increased to a near-normal level in reversed mice. Moreover, PTEN was significantly decreased in IL4-induced RAW 264.7 cells in vitro and lower expression of PTEN was observed in M2 macrophages in vivo. In addition, loss- and gain-of-function studies suggested that PTEN regulates M2 macrophages polarization via activation of PI3K/Akt/STAT6 signaling, but had a limited effect on M1 macrophages polarization in vitro. Additionally, Ly294002, a chemical inhibitor of PI3K/Akt, could dramatically down-regulate the hallmarks of M2 macrophages. In conclusion, PTEN mediates macrophages activation by PI3K/Akt/STAT6 signaling pathway, which provides novel compelling evidences on the potential of PTEN in liver injury and opens new cellular target for the pharmacological therapy of liver fibrosis. PMID- 28095307 TI - Pre-exposure prophylaxis and antiretroviral treatment interventions with drug resistance. AB - We introduce a model for HIV/AIDS which can be utilized to assess the impact of combining pre-exposure prophylaxis (PrEP) and antiretroviral drugs (ARVs) use interventions (incorporating drug resistance). Mathematical and numerical analyses are carried out to investigate the effects of the combined controls in the presence of PrEP drug resistance. Our results predict a significant decrease in the number of new HIV infections when PrEP and ARVs are concurrently implemented at high levels. The results also reveal that PrEP drug resistance has the potential to slow down or reverse the effects of PrEP, especially at low efficacy levels. PMID- 28095308 TI - Lithium-induced malaise does not interfere with adaptation of the hypothalamic pituitary-adrenal axis to stress. AB - We have recently demonstrated that adaptation of the hypothalamic-pituitary adrenal (HPA) axis to repeated exposure to a stressor does not follow the rules of habituation and can be fully expressed after a single experience with severe stressors. In the present work we tested the hypothesis that adaptation could be impaired if animals experience malaise during initial exposure to the stressor. To this end, animals were allowed to drink saccharin for 30min before being exposed for 3h to immobilization on boards (IMO), a severe stressor; then they were given either saline or lithium ip after the first hour of IMO. Stress-naive rats followed exactly the same procedure except IMO. Exposure to IMO caused a strong activation of the HPA axis whereas the effect of lithium was modest. Both IMO and lithium administration resulted in conditioned taste aversion to saccharin when evaluated 4days later. When all animals were exposed to IMO 6days later, reduced HPA response and less impact on body weight was observed in the two groups previously exposed to IMO as compared with stress-naive rats. Therefore, lithium administration during the first IMO exposure did not affect adaptation of the HPA axis and weight gain. These results indicate that malaise per se only weakly activated the HPA axis and argue against the hypothesis that signs of physical malaise during exposure to the stressor could impair HPA adaptation. PMID- 28095309 TI - Microglia under psychosocial stressors along the aging trajectory: Consequences on neuronal circuits, behavior, and brain diseases. AB - Mounting evidence indicates the importance of microglia for proper brain development and function, as well as in complex stress-related neuropsychiatric disorders and cognitive decline along the aging trajectory. Considering that microglia are resident immune cells of the brain, a homeostatic maintenance of their effector functions that impact neuronal circuitry, such as phagocytosis and secretion of inflammatory factors, is critical to prevent the onset and progression of these pathological conditions. However, the molecular mechanisms by which microglial functions can be properly regulated under healthy and pathological conditions are still largely unknown. We aim to summarize recent progress regarding the effects of psychosocial stress and oxidative stress on microglial phenotypes, leading to neuroinflammation and impaired microglia synapse interactions, notably through our own studies of inbred mouse strains, and most importantly, to discuss about promising therapeutic strategies that take advantage of microglial functions to tackle such brain disorders in the context of adult psychosocial stress or aging-induced oxidative stress. PMID- 28095310 TI - Ilex paraguariensis supplementation may be an effective nutritional approach to modulate oxidative stress during perimenopause. AB - Perimenopause is a period in a woman's life that precedes menopause and is characterized by hormonal changes that result in increased oxidative stress. Since oxidative stress is associated with age-related diseases and perimenopausal symptoms including somato-vegetative manifestations, nutritional antioxidant supplementation may be an effective approach to minimizing this stress. Mate tea (MT) (Ilex paraguariensis), a typical and inexpensive beverage consumed in the Brazilian south-east, Argentina and Uruguay, increases antioxidant defense. We hypothesized that MT could minimize oxidative stress during perimenopause by modulating enzymatic antioxidant defense. To test this, we analyzed the lipid oxidative damage and antioxidant defense in erythrocytes and liver of rats, after MT treatment. Female Wistar rats (aged 16months) in proven perimenopause period received 20mg/kgBW/day of mate tea, by gavage (PM+MT group) or water (PM group). Female rats aged 4months (AD group) received water. Erythrocytes and liver were used to determine lipid oxidative damage, determined by malondialdehyde (MDA); superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) activities. Total plasma antioxidant capacity was examined by ferric reducing antioxidant power assay (FRAP) and estrogen by radioimmunoassay. MT increased FRAP and did not change estrogen levels. Increased SOD and GPx, and reduced MDA were observed in both tissues studied. Increased CAT activity was observed only in the liver. We confirmed the hypothesis that MT was capable of minimizing oxidative stress in this period of life by modulating antioxidant defense. PMID- 28095311 TI - Therapeutic drug monitoring - Key to personalized pharmacotherapy. PMID- 28095312 TI - Neural correlates of babyish adult face processing in men. AB - The morphological characteristics of an infant's face are collectively referred to as baby schema or babyishness. It has been well established that infant traits are implicitly projected, or overgeneralized, to adults with babyish facial features. However, few studies to date have investigated the neural underpinnings of such overgeneralization. In the present study, we addressed this issue by comparing neural activations elicited by baby-faced and mature-faced adult faces in men using fMRI. We found increased activations in clusters surrounding the bilateral insula, bilateral anterior cingulate cortex, and right inferior frontal gyrus, which have been previously linked to the processing of facial attractiveness and infant-related information. We also discovered increased activation in the left medial prefrontal cortex, which might be related to emotional or empathic responses directed towards baby-faced adults. The activated region also included the left premotor cortex, which presumably reflects an embodied response or approach motivation directed toward infant-related information. Furthermore, the activation level of the left caudate correlated with the salivary concentration of oxytocin. Taken together, these findings indicate that passive viewing of babyish adult faces induces increased responses in neural regions linked to facial attractiveness and infant-related information processing, and that these responses are partially influenced by oxytocinergic factors. PMID- 28095313 TI - Prefrontal mediation of emotion regulation in social anxiety disorder during laughter perception. AB - Social anxiety disorder (SAD) is characterized by negatively biased perception of social cues and deficits in emotion regulation. While negatively biased perception is thought to maintain social anxiety, emotion regulation represents an ability necessary to overcome both biased perception and social anxiety. Here, we used laughter as a social threat in a functional magnetic resonance imaging (fMRI) study to identify cerebral mediators linking SAD with attention and interpretation biases and their modification through cognitive emotion regulation in the form of reappraisal. We found that reappraisal abolished the negative laughter interpretation bias in SAD and that this process was directly mediated through activation patterns of the left dorsolateral prefrontal cortex (DLPFC) serving as a cerebral pivot between biased social perception and its normalization through reappraisal. Connectivity analyses revealed reduced prefrontal control over threat-processing sensory cortices (here: the temporal voice area) during cognitive emotion regulation in SAD. Our results indicate a central role for the left DLPFC in SAD which might represent a valuable target for future research on interventions either aiming to directly modulate cognitive emotion regulation in SAD or to evaluate its potential as physiological marker for psychotherapeutic interventions relying on emotion regulation. PMID- 28095314 TI - Cloning and expression characterization of peroxisome proliferator-activated receptors (PPARs) with their agonists, dietary lipids, and ambient salinity in rabbitfish Siganus canaliculatus. AB - Rabbitfish Siganus canaliculatus is the first marine teleost reported to have the ability of biosynthesizing C20-22 long-chain polyunsaturated fatty acids (LC PUFA) from C18 precursors, and thus provides a model for studying the regulatory mechanisms of LC-PUFA biosynthesis in teleosts. To investigate the possible roles of peroxisome proliferator-activated receptors (PPARs), critical transcription factors involved in the regulation of lipid metabolism, in the regulation of LC PUFA biosynthesis in rabbitfish, the PPAR genes were cloned and their expression characterization with PPAR agonists, dietary lipid resource, and ambient salinity were examined. Three cDNA sequences respectively encoding 477, 516 and 519 amino acids of PPARalpha, PPARbeta, and PPARgamma isoforms were obtained. PPARalpha exhibited a wide tissue expression with its highest levels in the heart and brain; PPARbeta was predominantly expressed in the gills, while PPARgamma was highly expressed in the intestine and gills. In rabbitfish primary hepatocytes, both the PPAR agonists 2-bromopalmitate (2-Bro) and fenofibrate (FF) increased the expression of PPARgamma, SREBP1c and Elovl5, whereas FF depressed the expression of Delta6/Delta5 Fad. Moreover, a higher hepatic PPARbeta expression was observed in fish fed diets with vegetable oils (VO) than that with fish oil (FO), in the former the expression of PPARalpha, PPARbeta, and PPARgamma were increased at the low ambient salinity (10ppt), where an increasing expression of Delta5/Delta6 Fad, Delta4 Fad and Elovl5 genes was previously reported. These results suggest that PPARs might be involved in the upregulation of LC-PUFA biosynthesis with dietary VO and low ambient salinity in rabbitfish. PMID- 28095315 TI - Cytoplasmic stress granules: Dynamic modulators of cell signaling and disease. AB - Stress granule (SG) assembly is a conserved cellular strategy to minimize stress related damage and promote cell survival. Beyond their fundamental role in the stress response, SGs have emerged as key players for human health. As such, SG assembly is associated with cancer, neurodegenerative disorders, ischemia, and virus infections. SGs and granule-related signaling circuits are therefore promising targets to improve therapeutic intervention for several diseases. This is clinically relevant, because pharmacological drugs can affect treatment outcome by modulating SG formation. As membraneless and highly dynamic compartments, SGs regulate translation, ribostasis and proteostasis. Moreover, they serve as signaling hubs that determine cell viability and stress recovery. Various compounds can modulate SG formation and dynamics. Rewiring cell signaling through SG manipulation thus represents a new strategy to control cell fate under various physiological and pathological conditions. PMID- 28095317 TI - Formulation of liposomes functionalized with Lotus lectin and effective in targeting highly proliferative cells. AB - BACKGROUND: Liposomes, used to improve the therapeutic index of new and established drugs, have advanced with the insertion of active targeting. The lectin from Lotus tetragonolobus (LTL), which binds glycans containing alpha-1,2 linked fucose, reveals surface regionalized glycoepitopes in highly proliferative cells not detectable in normally growing cells. In contrast, other lectins localize the corresponding glycoepitopes all over the cell surface. LTL also proved able to penetrate the cells by an unconventional uptake mechanism. METHODS: We used confocal laser microscopy to detect and localize LTL-positive glycoepitopes and lectin uptake in two cancer cell lines. We then constructed doxorubicin-loaded liposomes functionalized with LTL. Intracellular delivery of the drug was determined in vitro and in vivo by confocal and electron microscopy. RESULTS: We confirmed the specific localization of Lotus binding sites and the lectin uptake mechanism in the two cell lines and determined that LTL functionalized liposomes loaded with doxorubicin greatly increased intracellular delivery of the drug, compared to unmodified doxorubicin-loaded liposomes. The LTL-Dox-L mechanism of entry and drug delivery was different to that of Dox-L and other liposomal preparations. LTL-Dox-L entered the cells one by one in tiny tubules that never fused with lysosomes. LTL-Dox-L injected in mice with melanoma specifically delivered loaded Dox to the cytoplasm of tumor cells. CONCLUSIONS: Liposome functionalization with LTL promises to broaden the therapeutic potential of liposomal doxorubicin treatment, decreasing non-specific toxicity. GENERAL SIGNIFICANCE: Doxorubicin-LTL functionalized liposomes promise to be useful in the development of new cancer chemotherapy protocols. PMID- 28095316 TI - Rewiring protein synthesis: From natural to synthetic amino acids. AB - BACKGROUND: The protein synthesis machinery uses 22 natural amino acids as building blocks that faithfully decode the genetic information. Such fidelity is controlled at multiple steps and can be compromised in nature and in the laboratory to rewire protein synthesis with natural and synthetic amino acids. SCOPE OF REVIEW: This review summarizes the major quality control mechanisms during protein synthesis, including aminoacyl-tRNA synthetases, elongation factors, and the ribosome. We will discuss evolution and engineering of such components that allow incorporation of natural and synthetic amino acids at positions that deviate from the standard genetic code. MAJOR CONCLUSIONS: The protein synthesis machinery is highly selective, yet not fixed, for the correct amino acids that match the mRNA codons. Ambiguous translation of a codon with multiple amino acids or complete reassignment of a codon with a synthetic amino acid diversifies the proteome. GENERAL SIGNIFICANCE: Expanding the genetic code with synthetic amino acids through rewiring protein synthesis has broad applications in synthetic biology and chemical biology. Biochemical, structural, and genetic studies of the translational quality control mechanisms are not only crucial to understand the physiological role of translational fidelity and evolution of the genetic code, but also enable us to better design biological parts to expand the proteomes of synthetic organisms. This article is part of a Special Issue entitled "Biochemistry of Synthetic Biology - Recent Developments" Guest Editor: Dr. Ilka Heinemann and Dr. Patrick O'Donoghue. PMID- 28095319 TI - Autophagy and autoimmunity. AB - Autophagy is a highly conserved protein degradation pathway from yeasts to humans that is essential for removing protein aggregates and misfolded proteins in healthy cells. Recently, autophagy-related genes polymorphisms have been implicated in several autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, psoriasis, and multiple sclerosis. Numerous studies reveal autophagy and autophagy-related proteins also participate in immune regulation. Conditional deletions of autophagy-related proteins in mice have rendered protection from experimental autoimmune encephalomyelitis, and TNF-mediated joint destruction in animal models of multiple sclerosis and experimental arthritis respectively. As autophagy is strongly implicated in immune functions such as removal of intracellular bacteria, inflammatory cytokine secretion, antigen presentation, and lymphocyte development, in this review we summarized current understanding of the roles of autophagy and autophagy proteins in autoimmune diseases. PMID- 28095318 TI - Interoceptive modulation of neuroendocrine, emotional, and hypophagic responses to stress. AB - Periods of caloric deficit substantially attenuate many centrally mediated responses to acute stress, including neural drive to the hypothalamic-pituitary adrenal (HPA) axis, anxiety-like behavior, and stress-induced suppression of food intake (i.e., stress hypophagia). It is posited that this stress response plasticity supports food foraging and promotes intake during periods of negative energy balance, even in the face of other internal or external threats, thereby increasing the likelihood that energy stores are repleted. The mechanisms by which caloric deficit alters central stress responses, however, remain unclear. The caudal brainstem contains two distinct populations of stress-recruited neurons [i.e., noradrenergic neurons of the A2 cell group that co-express prolactin-releasing peptide (PrRP+ A2 neurons), and glucagon-like peptide 1 (GLP 1) neurons] that also are responsive to interoceptive feedback about feeding and metabolic status. A2/PrRP and GLP-1 neurons have been implicated anatomically and functionally in the central control of the HPA axis, anxiety-like behavior, and stress hypophagia. The current review summarizes a growing body of evidence that caloric deficits attenuate physiological and behavioral responses to acute stress as a consequence of reduced recruitment of PrRP+ A2 and hindbrain GLP-1 neurons, accompanied by reduced signaling to their brainstem, hypothalamic, and limbic forebrain targets. PMID- 28095320 TI - Lethal dysregulation of energy metabolism during embryonic vitamin E deficiency. AB - Vitamin E (alpha-tocopherol, VitE) was discovered in 1922 for its role in preventing embryonic mortality. We investigated the underlying mechanisms causing lethality using targeted metabolomics analyses of zebrafish VitE-deficient embryos over five days of development, which coincided with their increased morbidity and mortality. VitE deficiency resulted in peroxidation of docosahexaenoic acid (DHA), depleting DHA-containing phospholipids, especially phosphatidylcholine, which also caused choline depletion. This increased lipid peroxidation also increased NADPH oxidation, which depleted glucose by shunting it to the pentose phosphate pathway. VitE deficiency was associated with mitochondrial dysfunction with concomitant impairment of energy homeostasis. The observed morbidity and mortality outcomes could be attenuated, but not fully reversed, by glucose injection into VitE-deficient embryos at developmental day one. Thus, embryonic VitE deficiency in vertebrates leads to a metabolic reprogramming that adversely affects methyl donor status and cellular energy homeostasis with lethal outcomes. PMID- 28095321 TI - Cellulose: To depolymerize... or not to? AB - Oxidation of the primary OH groups in cellulose is a pivotal reaction both at lab and industrial scale, leading to the value-added products, i.e. oxidized cellulose which have tremendous applications in medicine, pharmacy and hi-tech industry. Moreover, the introduction of carboxyl moieties creates prerequisites for further cellulose functionalization through covalent attachment or electrostatic interactions, being an essential achievement designed to boost the area of cellulose-based nanomaterials fabrication. Various methods for the cellulose oxidation have been developed in the course of time, aiming the selective conversion of the OH groups. These methods use: nitrogen dioxide in chloroform, alkali metal nitrites and nitrates, strong acids alone or in combination with permanganates or sodium nitrite, ozone, and sodium periodate or lead (IV) tetraacetate. In the case of the last two reagents, cellulose dialdehydes derivatives are formed, which are further oxidized by sodium chlorite or hydrogen peroxide to form dicarboxyl groups. A major improvement in the cellulose oxidation was represented by the introduction of the stable nitroxyl radicals, such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO). However, a major impediment for the researchers working in this area is related with the severe depolymerisation occurred during the TEMPO-mediated conversion of CH2OH into COOH groups. On the other hand, the cellulose depolymerisation represent the key step, in the general effort of searching for alternative strategies to develop new renewable, carbon-neutral energy sources. In this connection, exploiting the biomass feed stocks to produce biofuel and other low molecular organic compounds, involves a high amount of research to improve the overall reaction conditions, limit the energy consumption, and to use benign reagents. This work is therefore focused on the parallelism between these two apparently antagonist processes involving cellulose, building a necessary bridge between them, thinking how the reported drawbacks of the TEMPO-mediated oxidation of cellulose are heading towards to the biomass valorisation, presenting why the apparently undesired side reactions could be turned into beneficial processes if they are correlated with the existing achievements of particular significance in the field of cellulose conversion into small organic compounds, aiming the general goal of pursuing for alternatives to replace the petroleum-based products in human life. PMID- 28095322 TI - Competent processing techniques for scaffolds in tissue engineering. AB - Engineering a functional tissue ex vivo requires a synchronized effort towards developing technologies for ECM mimicking scaffold and cultivating tissue specific cells in an integrated and controlled manner. Cell-interactive scaffolds in three dimensions (3D), designed and processed appropriately with an apt biomaterial to yield optimal porosity and mechanical strength is the key in tissue engineering (TE). In order to accomplish these facets in a 3D scaffold, multiple techniques and processes have been explored by researchers all over the world. New techniques offering reasonable flexibility to use blends of different materials for integrated tissue-specific mechanical strength and biocompatibility have an edge over conventional methods. They may allow a combinatorial approach with a mix of materials while incorporating multiple processing techniques for successful creation of tissue-specific ECM mimics. In this review, we analyze the material requirement from different TE perspectives, while discussing pros and cons of advanced fabrication techniques for scale-up manufacturing. PMID- 28095323 TI - Pattern recognitions receptors in immunodeficiency disorders. AB - Pattern recognition receptors (PRRs) recognize common microbial or host-derived macromolecules and have important roles in early activation and response of the immune system. Initiation of the innate immune response starts with the recognition of microbial structures called pathogen associated molecular patterns (PAMPs). Recognition of PAMPs is performed by germline-encoded receptors expressed mainly on immune cells termed pattern recognition receptors (PRRs). Several classes of pattern recognition receptors (PRRs) are involved in the pathogenesis of diseases, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and Nod-like receptors (NLRs). Patients with primary immune deficiencies (PIDs) affecting TLR signaling can elucidate the importance of these proteins in the human immune system. Defects in interleukin-1 receptor-associated kinase-4 and myeloid differentiation factor 88 (MyD88) lead to susceptibility to infections with bacteria, while mutations in nuclear factor-kappaB essential modulator (NEMO) and other downstream mediators generally induce broader susceptibility to bacteria, viruses, and fungi. In contrast, TLR3 signaling defects are associated with susceptibility to herpes simplex virus type 1 encephalitis. Other PIDs induce functional alterations of TLR signaling pathways, such as common variable immunodeficiency in which plasmacytoid dendritic cell defects enhance defective responses of B cells to shared TLR agonists. Altered TLR responses to TLR2 and 4 agonists are seen in chronic granulomatous disease (CGD) and X-linked agammaglobulinemia (XLA). Enhanced TLR responses, meanwhile, are seen for TLRs 5 and 9 in CGD, TLRs 4, 7/8, and 9 in XLA, TLRs 2 and 4 in hyper IgE syndrome (HIES), and for most TLRs in adenosine deaminase deficiency. In this review we provide the reader with an update on the role of TLRs and downstream signaling pathways in PID disorders. PMID- 28095324 TI - Formalin injection produces long-lasting hypersensitivity with characteristics of neuropathic pain. AB - The purpose of this study was to investigate whether 1%, 2% or 5% formalin injection produce hypersensitivity with characteristics of the neuropathic pain induced by spinal nerve injury. Formalin injection (1%, 2% and 5%) produced concentration-dependent long-lasting (at least 14 days) mechanical allodynia and hyperalgesia in both paws. Likewise, L5/L6 spinal nerve ligation induced allodynia and hyperalgesia in both paws. The intensity of hypersensitivity was greater in the ipsilateral than in the contralateral paw in all models. Systemic gabapentin or morphine completely reduced 1% formalin-induced hypersensitivity. In contrast, both drugs were not able to fully diminish 2-5% formalin- and nerve injury-induced hypersensitivity. Indomethacin produced a significant effect in the chronic 1% formalin test. Conversely, this drug did not modify 2 or 5% formalin- and nerve injury-induced hypersensitivity. Spinal nerve injury and 2 5%, but not 1%, formalin injection enhanced ATF3 protein expression and immunofluorescence in dorsal root ganglia (DRG) in a time-dependent manner. Furthermore, 2-5%, but not 1%, formalin injection or spinal nerve injury also enhanced alpha2delta-1 subunit protein levels in DRG. Our results suggest that 5% and, at lesser extent, 2% formalin injection produces long-lasting hypersensitivity with a pharmacological and molecular pattern that resembles neuropathic pain induced by spinal nerve ligation. PMID- 28095325 TI - Peroxisome proliferator-activated receptor gamma activation inhibits liver growth through miR-122-mediated downregulation of cMyc. AB - Although NR1C3 agonists inhibit cell growth, the molecular mechanism of their action has not been thoroughly characterized to date. A recent study demonstrated that NR1C3 can regulate miR-122 by binding to its promoter. Given that miR-122 can indirectly regulate cMyc-mediated promitogenic signaling by targeting E2f1, we hypothesized that NR1C3 activation inhibits hepatocyte proliferation through miR-122-mediated cMyc downregulation. In the present study, we examined if liver hyperplasia induced by a strong chemical mitogen for the liver, 1,4-bis[2-(3,5 dichloropyridyloxy)]benzene (TCPOBOP), which is an agonist of NR1I3, can be repressed by NR1C3 activation through miR-122 upregulation. Acute TCPOBOP treatment caused a significant increase in liver-to-body weight ratio. The liver mass increase was accompanied with miR-122 downregulation. ChIP assays demonstrated that TCPOBOP-activated NR1I3 accumulated on the DR1 site in the pri miR-122 promoter; and the NR1I3 accumulation is accompanied by a decrease in miR 122 and an increase in E2f1 and its transcription target cMyc. Rosiglitazone (Ros) treatment, which is an agonist of NR1C3, caused an opposite effect on liver to-body weight ratio. When Ros was given with TCPOBOP, it attenuated the inhibitory effect of TCPOBOP on miR-122. Moreover, Ros treatment inhibited the NR1I3 binding with the DR1 site in the pri-miR-122 promoter. Furthermore, the increase of miR-122 produced by Ros was correlated with the downregulation of its targets, E2f1 and cMyc. Thus, our finding demonstrated that the liver growth inhibitory effect of NR1C3 activation was at least partly related to the decrease of cMyc though the activation of miR-122 and the downregulation of E2f1. PMID- 28095326 TI - Additive antithrombotic effect of ASP6537, a selective cyclooxygenase (COX)-1 inhibitor, in combination with clopidogrel in guinea pigs. AB - Clopidogrel (Plavix(r), Sanofi-Aventis), the adenosine diphosphate P2Y12 receptor antagonist, is reported to be effective in the prevention of cardiovascular events and is often used in combination with aspirin, particularly in high-risk patients. ASP6537 is a reversible cyclooxygenase (COX)-1 inhibitor that is under investigation as an anti-platelet agent. First, we investigated the reversibility of the antiplatelet effect of ASP6537 and its interaction with ibuprofen to compare the usability of ASP6537 with that of aspirin. We then evaluated the antithrombotic effect of ASP6537 in combination with clopidogrel using a FeCl3 induced thrombosis model in guinea pigs. ASP6537 exerted reversible antiplatelet activity, and no pharmacodynamic interaction with ibuprofen was noted. When administered as monotherapy, ASP6537 exerted a significant antithrombotic effect at >=3mg/kg, while aspirin inhibited thrombosis at 100mg/kg. ASP6537 exerted significant additive effects in combination with clopidogrel, and the minimum antithrombotic dose was reduced by concomitant administration of clopidogrel. Our study showed that ASP6537 did not interact with ibuprofen and has clear additive effects in combination with clopidogrel. ASP6537 may therefore represent a promising antiplatelet agent for use in clinical settings in combination with clopidogrel. PMID- 28095327 TI - Proteomic and peptidomic analysis of human sweat with emphasis on proteolysis. AB - : Sweat is produced by eccrine and apocrine glands and represents a biological fluid with established roles in thermo-regulation and host infection defense. The composition of sweat is highly dynamic and alters significantly in various skin and other disorders. Therefore, in-depth profiling of sweat protein composition is expected to augment our understanding of the pathobiology of several skin diseases and may lead to the identification of useful sweat-based disease biomarkers. We here reported an in-depth analysis of the human sweat proteome and peptidome. Sweat was collected from healthy males and healthy females of ages 20 60years, following strenuous exercise. Two sweat pools were prepared (1 for males and 1 for females) and were subjected to sample preparation for mass spectrometric analysis. We identified a total of 861 unique proteins during our proteomic analysis and 32,818 endogenous peptides (corresponding to additional 1067 proteins) from our peptidomics workflow. As expected, the human skin was identified as the most abundant source of sweat proteins and peptides. Several skin proteases and protease inhibitors were identified in human sweat, highlighting the intense proteolytic activity of human skin. The presence of several antimicrobial peptides supports the functional roles of sweat in host defense and innate immunity. SIGNIFICANCE: Sweat is a skin-associated biological fluid, secreted by eccrine and apocrine glands, with essential function in body thermo-regulation and host infection defense. In the present study, we performed in-depth profiling of both sweat proteome and peptidome composition. Our data provide the most in-depth characterization of the skin's catalytic network present in sweat. For the first time, we brought to light novel peptides in human sweat that potentially have antimicrobial activity, which highlight the important role of this fluid in innate immunity. All these findings allow us to have a better understanding of the complex web of proteases in skin and may act as a platform for the future discovery of novel skin biomarkers. PMID- 28095328 TI - An integrated proteomic and transcriptomic analysis of perivitelline fluid proteins in a freshwater gastropod laying aerial eggs. AB - : Proteins of the egg perivitelline fluid (PVF) that surrounds the embryo are critical for embryonic development in many animals, but little is known about their identities. Using an integrated proteomic and transcriptomic approach, we identified 64 proteins from the PVF of Pomacea maculata, a freshwater snail adopting aerial oviposition. Proteins were classified into eight functional groups: major multifunctional perivitellin subunits, immune response, energy metabolism, protein degradation, oxidation-reduction, signaling and binding, transcription and translation, and others. Comparison of gene expression levels between tissues showed that 22 PVF genes were exclusively expressed in albumen gland, the female organ that secretes PVF. Base substitution analysis of PVF and housekeeping genes between P. maculata and its closely related species Pomacea canaliculata showed that the reproductive proteins had a higher mean evolutionary rate. Predicted 3D structures of selected PVF proteins showed that some nonsynonymous substitutions are located at or near the binding regions that may affect protein function. The proteome and sequence divergence analysis revealed a substantial amount of maternal investment in embryonic nutrition and defense, and higher adaptive selective pressure on PVF protein-coding genes when compared with housekeeping genes, providing insight into the adaptations associated with the unusual reproductive strategy in these mollusks. SIGNIFICANCE: There has been great interest in studying reproduction-related proteins as such studies may not only answer fundamental questions about speciation and evolution, but also solve practical problems of animal infertility and pest outbreak. Our study has demonstrated the effectiveness of an integrated proteomic and transcriptomic approach in understanding the heavy maternal investment of proteins in the eggs of a non-model snail, and how the reproductive proteins may have evolved during the transition from laying underwater eggs to aerial eggs. PMID- 28095329 TI - Comparing ancient DNA survival and proteome content in 69 archaeological cattle tooth and bone samples from multiple European sites. AB - : Ancient DNA (aDNA) is the most informative biomolecule extracted from skeletal remains at archaeological sites, but its survival is unpredictable and its extraction and analysis is time consuming, expensive and often fails. Several proposed methods for better understanding aDNA survival are based upon the characterisation of some aspect of protein survival, but these are typically non specific; proteomic analyses may offer an attractive method for understanding preservation processes. In this study, in-depth proteomic (LC-Orbitrap-MS/MS) analyses were carried out on 69 archaeological bovine bone and dentine samples from multiple European archaeological sites and compared with mitochondrial aDNA and amino acid racemisation (AAR) data. Comparisons of these data, including estimations of the relative abundances for seven selected non-collagenous proteins, indicate that the survival of aDNA in bone or dentine may correlate with the survival of some proteins, and that proteome complexity is a more useful predictor of aDNA survival than protein abundance or AAR. The lack of a strong correlation between the recovery of aDNA and the proteome abundance may indicate that the survival of aDNA is more closely linked to its ability to associate with bone hydroxyapatite crystals rather than to associate with proteins. SIGNIFICANCE: Ancient biomolecule survival remains poorly understood, even with great advancements in 'omics' technologies, both in genomics and proteomics. This study investigates the survival of ancient DNA in relation to that of proteins, taking into account proteome complexity and the relative protein abundances to improve our understanding of survival mechanisms. The results show that although protein abundance is not necessarily directly related to aDNA survival, proteome complexity appears to be. PMID- 28095330 TI - Usnic acid and atranorin exert selective cytostatic and anti-invasive effects on human prostate and melanoma cancer cells. AB - OBJECTIVES AND METHODS: Lichens are an interesting source of potential anti-tumor compounds, among which usnic acid and atranorin seem to be the most promising, but their impact on invasive potential of tumor cells has not yet been comprehensively addressed. The aim of the study was focused on the impact of the two lichen metabolites, on the viability (by Trypan blue test and fluoresceine diacetate and ethidium bromide assay), proliferation (cell counting in a Burker's chamber), apoptosis (flow cytometry analysis and Western blot) and motile activity (cell movement recording and image analysis) and actin cytoskeleton organization (immunofluorescent staining) of melanoma HTB-140, prostate cancers DU-145 and PC-3, normal human skin fibroblasts and prostate epithelial PNT2 cells, with special emphasis to their selectivity and versatility. RESULTS: Both compounds exerted strong inhibitory effects on cancer cell proliferation, migration and actin cytoskeleton organization, while their effect on apoptosis process was less relevant. The impact of usnic acid on the examined cancer cells was found more efficient in comparison to atranorin. Also, selective effect of both agents on tumor cells was observed. SIGNIFICANCE: The ability of usnic acid and atranorin to inhibit cancer cells motility may have future implications for development of new therapeutic strategies targeted at the interference with the metastatic cascade. PMID- 28095331 TI - The effect of combined avoidance and control training on implicit food evaluation and choice. AB - BACKGROUND: Continual exposure to food cues in the environment contributes to unhealthy eating behaviour. According to dual-process models, such behaviour is partly determined by automatic processing of unhealthy food cues (e.g., approach bias), which fails to be regulated by controlled processing (e.g., inhibitory control). The current study aimed to investigate the effect of combined avoidance and control training on implicit evaluation (liking), choice, and consumption of unhealthy snack food. METHOD: Participants were 240 undergraduate women who were randomly allocated to one of four experimental conditions of a 2 (avoidance training: training versus control) x 2 (control training: training versus control) between-subjects design. RESULTS: The combined training group had a more negative implicit evaluation of unhealthy food than either of the two training conditions alone or the control condition. In addition, participants trained to avoid unhealthy food cues subsequently made fewer unhealthy snack food choices. No significant group differences were found for food intake. LIMITATIONS: Participants were women generally of a healthy weight. Overweight or obese individuals may derive greater benefit from combined training. CONCLUSIONS: Results lend support to the theoretical predictions of dual-process models, as the combined training reduced implicit liking of unhealthy food. At a practical level, the findings have implications for the effectiveness of interventions targeting unhealthy eating behaviour. PMID- 28095332 TI - Signal and binding. II. Converting physico-chemical responses to macromolecule ligand interactions into thermodynamic binding isotherms. AB - Physico-chemical titration techniques are the most commonly used methods in characterizing molecular interactions. These methods are mainly based on spectroscopic, calorimetric, hydrodynamic, etc., measurements. However, truly quantitative physico-chemical methods are absolutely based on the determination of the relationship between the measured signal and the total average degree of binding in order to obtain meaningful interaction parameters. The relationship between the observed physico-chemical signal of whatever nature and the degree of binding must be determined and not assumed, based on some ad hoc intuitive relationship/model, leading to determination of the true binding isotherm. The quantitative methods reviewed and discussed here allow an experimenter to rigorously determine the degree of binding and the free ligand concentration, i.e., they lead to the construction of the thermodynamic binding isotherm in a model-independent fashion from physico-chemical titration curves. PMID- 28095333 TI - Effect of resveratrol on platelet aggregation by fibrinogen protection. AB - The effect of resveratrol (RSV) in inhibiting platelet adhesion and aggregation, as well as fibrinogen (FBG) conformational changes promoted by epinephrine (EP), were studied, by using complementary experimental techniques. NMR and IR spectroscopies were used to investigate possible protective effects by RSV towards FBG, in presence of EP. The protective effect of RSV towards FBG was highlighted by spin nuclear relaxation experiments that were interpreted for determining the thermodynamic equilibrium constants of FBG-EP interaction, and by infrared measurements, that showed EP-induced conformational changes of FBG. The ability of RSV in inhibiting platelet adhesion and aggregation promoted by EP was evaluated by scanning electron microscopy (SEM), measuring the platelet adhesion and aggregation degree, in comparison to data obtained for platelet aggregation in platelet rich plasma (PRP). The experimental combined approach pointed out that RSV is able to protect both FBG and platelets from the denaturant and aggregating action of EP at stress level concentration. PMID- 28095334 TI - Predictors and mediators of trait anger across the psychosis continuum: The role of attachment style, paranoia and social cognition. AB - Anger in the context of psychosis has a significant impact on treatment outcomes and serious implications for risk management. Understanding mechanisms underlying anger will improve interventions and inform strategies for prevention. This study is the first to examine the relationships between anger and key theoretical drivers across different phases of the psychosis continuum. A battery including measures of theory of mind, attachment, hostile attribution bias, paranoia and anger was administered to 174 participants (14 ultra-high risk, 20 first-episode, 20 established psychosis, 120 non-clinical participants). We tested the model that insecure attachment, paranoia, impaired theory of mind and hostile attribution bias would predict trait anger using multiple regression. Attachment avoidance, paranoia and hostile attribution bias were significantly associated with anger but attachment anxiety and theory of mind were not. Mediation analysis showed that paranoia partially mediated the relationship between avoidant attachment and anger but hostile attribution bias did not. Findings emphasise the importance of interventions targeting paranoia to reduce anger and the potential of preventive strategies focused on attachment relationships in early life or adulthood to reduce adult paranoia and anger. PMID- 28095335 TI - Guilt, shame and expressed emotion in carers of people with long-term mental health difficulties: A systematic review. AB - Expressed emotion (EE) is a global index of familial emotional climate, whose primary components are emotional over-involvement (EOI) and critical comments (CC)/hostility. There is a strong theoretical rationale for hypothesising that carers' guilt and shame may be differentially associated with their EOI and CC/hostility respectively. This systematic review investigates the magnitude of these theorised associations in carers of people with long-term mental health difficulties. Electronic searches (conducted in May 2016 across Medline, CINAHL, Embase, PsycINFO and ProQuest) were supplemented with iterative hand searches. Ten papers, reporting data from eight studies, were included. Risk of bias was assessed using a standardised checklist. Relevant data were extracted and synthesised narratively. EOI was positively associated with both guilt and shame, whereas CC/hostility was positively associated with shame. The strength of associations varied depending on whether or not guilt and shame were assessed within the context of the caring relationship. Based on these data, an argument can be made for the refinement, development and evaluation of systemic and individual interventions designed to target carers' guilt and shame. However, more research is needed to clarify the strength of these associations and their direction of effect before firm conclusions can be drawn. PMID- 28095336 TI - Psychiatric symptoms mediate the effects of neurological soft signs on functional outcomes in patients with chronic schizophrenia: A longitudinal path-analytic study. AB - Neurological soft signs (NSS) in motor coordination and sequencing occur in schizophrenia patients and are an intrinsic sign of the underlying neural dysfunctions. The present longitudinal study explored the relationships among NSS, psychiatric symptoms, and functional outcomes in 151 Chinese patients with chronic schizophrenia across a 6-month period. The participants completed neurological assessments at baseline (Time 1), psychiatric interviews at Time 1 and 3-month follow-up (Time 2), and self-report measures on daily functioning at 6-month follow-up (Time 3). Two possible (combined and cascading) path models were examined on predicting the functional outcomes. Direct and indirect effects of Time 1 NSS on Time 3 functional outcomes via Time 2 psychiatric symptoms were evaluated using path analysis under bootstrapping. Motor coordination and sequencing NSS did not have significant direct effects on functional outcomes. Motor coordination NSS exerted significant and negative indirect effects on functional outcomes via psychiatric symptoms. These results contribute to a better understanding of the determinants of functional outcomes by showing significant indirect pathways from motor coordination NSS to functional outcomes via psychiatric symptoms. That motor sequencing NSS did not affect functional outcomes either directly or indirectly may be explained by their trait marking features. PMID- 28095337 TI - Environment or beekeeping management: What explains better the prevalence of honey bee colonies with high levels of Varroa destructor? AB - Varroa destructor is one of the major threats to honey bee colonies. The mite abundance in the colonies is affected by environmental conditions as well as by beekeeping management. The aim of this study was to recognize the main drivers associated with autumn V. destructor infestation in honey bee colonies when different regions from Argentina are compared. A total of 361 colonies distributed in five Argentinean eco-regions were examined to evaluate Varroa mite infestation rate during autumn and Nosema sp. presence. Regions were different regarding annual temperature, precipitation and especially vegetation landscape. In addition, beekeeping management practices were obtained from a checklist questionnaire answered by the beekeepers. The prevalence of colonies with high infestation level was lower in semi-arid Chaco followed by humid and transition Chaco regions. Also, colonies that were positive for Nosema sp. showed a higher Varroa infestation rate. The "environmental" effect was stronger compared with the influence of secondary drivers associated with beekeeping activities. As well, a significant association between V. destructor infestation rates and Nosema presence was identified. Under contrasting natural conditions, environment seems a predominant driver on Varroa destructor infestation level in honey bee colonies. PMID- 28095338 TI - Docosahexaenoic acid attenuates LPS-stimulated inflammatory response by regulating the PPARgamma/NF-kappaB pathways in primary bovine mammary epithelial cells. AB - BACKGROUND: Docosahexaenoic acid (DHA) is a major dietary n-3 polyunsaturated fatty acid (n-3 PUFA) in fish oil, and has been reported to possess a number of biological properties, such as anti-inflammatory, antitumor and immune-regulatory properties. However, whether DHA exert anti-inflammatory effect on lipopolysaccharide (LPS)-induced mastitis remains unclear. In this study, we investigate the effect and underlying mechanisms of the effects of DHA on LPS stimulated primary bovine mammary epithelial cells (bMEC). METHODS: The experiment was divided into six groups as followed: control group, GW9662+LPS+DHA (100MUM) group, LPS and LPS+DHA (25, 50 and 100MUM) groups. bMEC were treated with DHA for 3h before LPS (200MUg/ml) stimulation, and incubated with the PPARgamma inhibitor GW9662 for 12h before DHA treatment. The mRNA levels of TNF alpha, IL-6 and IL-1beta were measured by quantitative real-time PCR (qRT-PCR). Western blot was employed for measuring the transcriptional activity of NF-kappaB and PPARgamma. RESULTS: Our results showed that DHA pretreatment significantly decreased the mRNA expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) in bMEC stimulated with LPS. Besides, DHA suppressed the phosphorylation of nuclear transcription factor kappaB (NF-kappaB) p65 and degradation inhibitor of NF-kappaBalpha (IkappaBalpha) in NF-kappaB signal pathway, and activated proliferator activated receptor gamma (PPARgamma). But, all those effects were obviously abolished by addition of GW9662, a specific inhibitor of PPARgamma. CONCLUSION: In conclusion, these results indicated that DHA may attenuate LPS-stimulated inflammatory response in bMEC by suppressing NF-kappaB activation through a mechanism partly dependent on PPARgamma activation. PMID- 28095340 TI - Body image in patients with mental disorders: Characteristics, associations with diagnosis and treatment outcome. AB - OBJECTIVE: Despite the increasing recognition in clinical practice of body image problems in other than appearance related mental disorders, the question remains how aspects of body image are affected in different disorders. The aim of this study was to measure body image in patients with a variety of mental disorders and to compare scores with those in the general population in order to obtain more insight in the relative disturbance of body image in the patients group compared to healthy controls. In a further exploration associations with self reported mental health, quality of life and empowerment were established as well as the changes in body image in patients over time. METHODS: 176 women and 91 men in regular psychiatric treatment completed the Dresden Body Image Questionnaire, the Outcome Questionnaire, the Manchester Short Assessment of Quality of Life and the Mental Health Confidence Scale. Measurements were repeated after four months. RESULTS: Patients with mental disorders, especially those with post-traumatic stress disorder (PTSD), scored significantly lower on body image, with large effect sizes, in comparison with the healthy controls. Scores of patients from different diagnostic groups varied across domains of body image, with body acceptance lowest in the group with eating disorders, and sexual fulfillment extremely low in PTSD. Vitality did not differ significantly between the various disorders. Gender differences were large for body acceptance and sexual fulfillment and small for vitality. Associations of body image with self-reported mental health, quality of life and empowerment were moderate to strong. After four months of treatment positive changes in body image were observed. CONCLUSIONS: Negative body image is a common problem occurring in most patients with mental disorders. Diagnosis-specific profiles emerge, with PTSD being the most affected disorder. Body acceptance and sexual fulfillment were the most differentiating aspects of body image between diagnoses. Changes in body image occur over the course of treatment. PMID- 28095339 TI - Preadolescent sensation seeking and early adolescent stress relate to at-risk adolescents' substance use by age 15. AB - BACKGROUND AND AIMS: Substance use during adolescence can lead to the development of substance use disorders and other psychosocial problems. These negative outcomes are especially likely for individuals who use substances at earlier ages and those who engage in heavier use during adolescence, behaviors which are both more common among youth at higher risk for developing a substance use disorder, such as those with a family history of substance use disorders (FH+). Factors such as increased sensation seeking and greater exposure to stressors among FH+ youth may influence these associations. Therefore, the aim of this study was to examine the relative and unique contributions of sensation seeking during preadolescence and exposure to stressors during early to mid-adolescence to cumulative substance use by mid-adolescence among FH+ youth. METHODS: A total of 167 mostly Hispanic FH+ youth (ages 12-15) who were participating in an ongoing longitudinal study were included in these analyses. Participants' data from biennial waves covering approximately 2.5years were used. Self-reported sensation seeking, exposure to stressors, and substance use were compared. RESULTS: Higher sensation seeking during preadolescence and greater exposure to stressors during early to mid-adolescence were both associated with substance use by age 15. These factors differentiated Substance Users from Non-Users, and also related to level of substance use. CONCLUSIONS: Elevated sensation seeking and exposure to stressors are both associated with substance use by age 15 among high-risk youth. Additionally, these factors can distinguish youth who develop heavier substance use during this important developmental period. PMID- 28095341 TI - Effect of the R119G mutation on human P5CR structure and its interactions with NAD: Insights derived from molecular dynamics simulation and free energy analysis. AB - Pyrroline-5-carboxylate reductase (P5CR), an enzyme with conserved housekeeping roles, is involved in the etiology of cutis laxa. While previous work has shown that the R119G point mutation in the P5CR protein is involved, the structural mechanism behind the pathology remains to be elucidated. In order to probe the role of the R119G mutation in cutis laxa, we performed molecular dynamics (MD) simulations, essential dynamics (ED) analysis, and Molecular mechanics Poisson Boltzmann surface area (MM-PBSA) binding free energy calculations on wild type (WT) and mutant P5CR-NAD complex. These MD simulations and ED analyses suggest that the R119G mutation decreases the flexibility of P5CR, specifically in the substrate binding pocket, which could decrease the kinetics of the cofactor entrance and egress. Furthermore, the MM-PBSA calculations suggest the R119G mutant has a lower cofactor binding affinity for NAD than WT. Our study provides insight into the possible role of the R119G mutation during interactions between P5CR and NAD, thus bettering our understanding of how the mutation promotes cutis laxa. PMID- 28095342 TI - Orthognathic surgery during breast cancer treatment-A case report. AB - INTRODUCTION: In recent years, patients with orthognathic surgery in middle-aged and elderly people have come to be a more frequent occurrence. Breast cancer is the most frequently diagnosed cancer in woman worldwide, and its prevalence rate is steadily increasing. PRESENTATION OF CASE: We report a case of a 47-year-old Japanese woman in whom left-side breast cancer (Stage 1) was unexpectedly found just before orthognathic surgery in April 2012. Breast-conserving surgery was performed (estrogen receptor+, progesterone receptor+, HER2 -, surgical margin+, sentinel lymph node +) that May. From June to August docetaxel (75mg/m2) and cyclophosphamide (600mg/m2) were administrated four times every 21days and thereafter radiotherapy (total 60Gy) was completed. The cancer surgeon declared the prognosis good and the patient had a strong desire to undergo orthognathic surgery, so in November we performed a bimaxillary osteotomy, and administration of tamoxifen began 6 weeks after the osteotomy. DISCUSSION: There are breast cancer cases in which the prognosis is sufficiently good for a planned orthognathic surgery to proceed. Good communication among surgeons and the patient is important. CONCLUSION: We experienced a case in which breast cancer was found just before the orthognathic surgery; we performed a bimaxillary osteotomy, including follow-up tamoxifen administration, during breast cancer treatment. PMID- 28095343 TI - Patient-tailored management of an asymptomatic massive substernal goiter presenting as brachiocephalic vein occlusion. Report of a case and review of sternotomy indications. AB - INTRODUCTION: Substernal goiters are characterized by the protrusion of at least 50% of the thyroid mass below the level of the thoracic inlet. Still their definition is controversial. CASE PRESENTATION: The case refers to a 44year old male who presented to our department due to swelling and a feeling of 'heaviness' of his left upper extremity for the past 6 months. CT scan revealed a massive substernal goiter extending to the great vessels. Intraoperatively, a median sternotomy was performed due to the size of the gland and the close adhesion of the isthmus and lower left thyroid lobe to the brachiocephalic vein. Resection of the gland revealed the vein to have a cord-like shape, leading to reduced venous return and upper extremity symptoms. Recovery was uneventful for the patient who was discharged on the 7th postoperative day. DISCUSSION: While most substernal goiters can be surgically managed through a cervical incision, there are cases in which a median sternotomy is indicated. Those cases include excessive gland size, thoracic pain, ectopic thyroid tissue and the extent of the goiter to the aortic arch. Median sternotomy is associated with a number of intra and postoperative complications, although when performed by an experienced surgeon, mortality and morbidity rates along with long-term recovery are not affected. CONCLUSSION: The lack of a uniform definition and variety of indications, lead to a patient tailored approach regarding the execution of sternotomy during surgical management of massive substernal goiters. PMID- 28095345 TI - Forensic assignment to geographic origin, a useful tool in seafood fraud control. AB - Seafood fraud is an economically motivated and widely spread problem encompassing drastic consequences in both public health and species conservation. In Northern Spain, only the first Atlantic salmon (Salmo salar) catch of the angling season (named Campanu) can be sold. In the year 2011, an angler denounced it on regional Court claiming that the Campanu (which was sold in 6000?) was fraudulent because it had been caught from another river than the fisherman ("the seller") stated. Here, we report the first judicial case of application of geographical genetic assignment in a fish species in Spain. In order to accomplish this, genetic assignments to their rivers of origin of the Campanu and another three following salmon catches of the angling season of the year 2011 were performed. A panel of eight microsatellite loci together with a comprehensive genetic baseline of the rivers of the region were employed. Results showed that the Campanu was the only case in which genetic assignment and fisherman declaration of the river of origin did not match. The methodology here employed showed to be very useful as a reinforcement of other evidences contributing to fight against seafood fraud in Courts. PMID- 28095344 TI - Concordance between maternal recall of birth complications and data from obstetrical records. AB - BACKGROUND: Prenatal complications are associated with poor outcomes in the offspring. Access to medical records is limited in the United States and investigators often rely on maternal report of prenatal complications. STUDY DESIGN AND AIMS: We tested concordance between maternal recall and birth records in a community-based sample of mothers participating in a longitudinal study in order to determine the accuracy of maternal recall of perinatal complications. SUBJECTS: Participants were 151 biological mothers, who were interviewed about gestational age at birth, birthweight, and the most commonly occurring birth complications: nuchal cord and meconium aspiration when the female child was on average 6years old, and for whom birth records were obtained. OUTCOME MEASURES: Concordance between reports was assessed using one-way random intra-class coefficients for continuous measures and kappa coefficients for dichotomous outcomes. Associations between maternal demographic and psychological factors and discrepancies also were tested. RESULTS: Concordance was excellent for continuously measured birthweight (ICC=0.85, p<0.001) and good for gestational age (ICC=0.68, p<0.001). Agreement was good for low birthweight (<2500g) (kappa=0.67, p<0.001), fair for preterm delivery (<37weeks gestation) (kappa=0.44, p<0.001), and poor for nuchal cord or meconium aspiration. Most discrepancies were characterized by presence according to birth record and absence according to maternal recall. Receipt of public assistance was associated with a decrease in discrepancy in report of nuchal cord. CONCLUSIONS: Concordance between maternal retrospective report and medical birth records varies across different types of perinatal events. There was little evidence that demographic or psychological factors increased the risk of discrepancies. Maternal recall based on continuous measures of perinatal factors may yield more valid data than dichotomous outcomes. PMID- 28095346 TI - Crystal structure, cytotoxicity and action mechanism of Zn(II)/Mn(II) complexes with isoquinoline ligands. AB - Four MU2-Cl bridged dinuclear metal complexes with isoquinoline ligands, (MPDQ)2Zn2Cl4 (1) (MPDQ=4.5-methylenedioxy-1-pyridinedihydroisoquinoline), (PYP)2Zn2Cl4 (2) (PYP=5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline), (MPDQ)2Mn2Cl4 (3),and (PYP)2Mn2Cl4 (4) were synthesized and characterized. All complexes exhibited strong proliferation inhibition activity against various cancer cells. The underlying molecular mechanisms through which they caused the cancer cell death were also elucidated. Induction of apoptosis in MGC-803 cells by complex 2 was evidenced by annexin V+/PI- detection and DiD/DAPI staining assay. Further investigation revealed that complex 2 was able to induce intrinsic pathway-dependent apoptosis in cancer cells by triggering DNA damage which was caused by the overproduction of reactive oxygen species. Based on these studies, we suggest that Zn(II) complexes containing isoquinoline ligands can be developed as candidates for anti-cancer chemotherapeutics. PMID- 28095347 TI - Using Experience-based Co-design with older patients, their families and staff to improve palliative care experiences in the Emergency Department: A reflective critique on the process and outcomes. AB - BACKGROUND: Increasing use of emergency departments among older patients with palliative needs has led to the development of several service-level interventions intended to improve care quality. There is little evidence of patient and family involvement in developmental processes, and little is known about the experiences of - and preferences for - palliative care delivery in this setting. Participatory action research seeking to enable collaborative working between patients and staff should enhance the impact of local quality improvement work but has not been widely implemented in such a complex setting. OBJECTIVES: To critique the feasibility of this methodology as a quality improvement intervention in complex healthcare settings, laying a foundation for future work. SETTING: an Emergency Department in a large teaching hospital in the United Kingdom. METHODS: Experience-based Co-design incorporating: 150h of nonparticipant observation; semi-structured interviews with 15 staff members about their experiences of palliative care delivery; 5 focus groups with 64 staff members to explore challenges in delivering palliative care; 10 filmed semi structured interviews with palliative care patients or their family members; a co design event involving staff, patients and family members. FINDINGS: the study successfully identified quality improvement priorities leading to changes in Emergency Department-palliative care processes. Further outputs were the creation of a patient-family-staff experience training DVD to encourage reflective discussion and the identification and application of generic design principles for improving palliative care in the Emergency Department. There were benefits and challenges associated with using Experience-based Co-design in this setting. Benefits included the flexibility of the approach, the high levels of engagement and responsiveness of patients, families and staff, and the impact of using filmed narrative interviews to enhance the 'voice' of seldom heard patients and families. Challenges included high levels of staff turnover during the 19 month project, significant time constraints in the Emergency Department and the ability of older patients and their families to fully participate in the co-design process. CONCLUSION: Experience-based Co-design is a useful approach for encouraging collaborative working between vulnerable patients, family and staff in complex healthcare environments. The flexibility of the approach allows the specific needs of participants to be accounted for, enabling fuller engagement with those who typically may not be invited to contribute to quality improvement work. Recommendations for future studies in this and similar settings include testing the 'accelerated' form of the approach and experimenting with alternative ways of increasing involvement of patients/families in the co-design phase. PMID- 28095348 TI - Immune transcriptome reveals the mincle C-type lectin receptor acts as a partial replacement for TLR4 in lipopolysaccharide-mediated inflammatory response in barramundi (Lates calcarifer). AB - Fish represent the most diverse and abundant extant vertebrate infraclass. They are also one of the earliest divergent phyla with adaptive immunity based on antigen recognition by MHC and immunoglobulin. The aquaculture industry, which currently provides more than half of the fish for human consumption globally, has successfully exploited the adaptive immune system of fish through mass vaccination programs. However, vaccination against highly diverse antigens, mostly carbohydrates, such as capsular polysaccharides and lipopolysaccharide (LPS) is challenging. Fish have a subdued innate response to LPS, but adaptive response is generally high and type-specific. To better understand the link between initial innate response and early onset of adaptive immunity to carbohydrate antigens in the perciform barramundi (Lates calcarifer), an immune transcriptome was prepared from pronephros and spleen following vaccination with LPS and peptidoglycan. From 163,661 transcripts derived by Illumina mRNA-Seq, most grouped in neuronal, endocrine or immune system categories, suggesting a close relationship between the three systems. Moreover, digestive enzyme transcripts in spleen appeared to be highly inducible in barramundi. Most of the known TLRs were transcribed in the barramundi spleen and HK transcriptome, with the notable exception of TLR4, which is primarily responsible for LPS recognition in mammals. Several C-type lectin receptors were also identified, including CD209, CD205, and CLEC4E (Mincle). As Mincle has been shown to bind LPS and is abundant on dendritic cells, its role in response to LPS in barramundi was further investigated. A high dose of LPS induced TNF-alpha expression via Mincle. However, IL-6 regulation, whilst still regulated in response to LPS, did not depend upon the Mincle pathway, suggesting other routes of activation. This study thus suggests that Mincle acts as a partial substitute for TLR4 in barramundi in the processing of LPS. PMID- 28095349 TI - Anti-inflammatory effects of ononin on lipopolysaccharide-stimulated RAW 264.7 cells. AB - Increasing evidence has shown that ononin, a major isoflavone, has anti inflammatory effects on lipopolysaccharide (LPS)-induced inflammation. However, the molecular mechanisms underlying the anti-inflammatory effects of ononin are still unclear. In the present study, we investigated these effects and the underlying mechanisms of ononin on LPS-induced inflammatory responses. Mouse RAW 264.7 cells were treated with 1MUg/mL LPS and 5, 25, 50, 100 or 150MUM ononin for 18h. Cell viability was assessed using MTT assays, and the production of nitric oxide (NO), prostaglandin E2 (PGE2) and the pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6 in cultures was examined by Griess and ELISA analyses. qRT-PCR was performed to detect the mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2). Mitogen-activated protein kinases (MAPKs) and nuclear transcription factor Kappa-B (NF-kappaB) signalling pathway-related proteins were assessed by western blot assays. The results showed that cell viability was not significantly affected by up to 100MUM ononin. The production of NO, PGE2 and the pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6 in the cultures, the mRNA expression of two major inflammatory mediators, COX-2 and iNOS, and the expression of phosphorylated IkappaB-alpha, ERK, JNK, and p38 MAPKs proteins in LPS-treated cells were significantly increased. These changes could be reversed by treatment with ononin in a concentration-dependent manner (P<0.05). The results suggest that ononin has anti-inflammatory effects on LPS induced inflammatory responses by inhibiting the NF-kappaB and MAPK pathways and may be a potential treatment for inflammation. PMID- 28095350 TI - Progressive multifocal leukoencephalopathy in a patient with systemic mastocytosis treated with cladribine. AB - BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic brain infection caused by the human polyomavirus JC (JCPyV). A particular problem with the drug cladribine seems to be prolonged suppression of the CD4+ T-cells, a well-known risk factor for PML. CASE DESCRIPTION: A 67-year old male presented with a 3-weeks history of unsteady gait, dysarthria and a dysfunctional right arm. Seven years earlier, he had been diagnosed with urticaria pigmentosa, and 2 years later aggressive systemic mastocytosis. Cladribine treatment was initiated and regarded effective, but the course was complicated with bouts of severe anemia and recurrent episodes of salmonella associated gastroenteritis. His lymphocyte count fell to 0.1*109/L at its lowest level, but gradually rose. Despite this, in the 6 month wake of the last dose of cladribine given, the patient experienced herpetic stomatitis, had CMV present in blood, and ultimately developed the neurological symptoms. An MRI scan revealed a lesion in the right cerebellar hemisphere compatible with PML, and PCR analysis of the CSF showed positive for JCPyV DNA with a load of 323 950 copies/ml. No pathological cells were seen on CSF flow cytometry. The CD4/CD8-ratio was 0.45 (160 CD4+ cells/mm3 and 360 CD8+ cells/mm3). The patient passed away 3 weeks later. CONCLUSION: PML may be the consequence of prolonged lymphopenia due to the use of cladribine. PMID- 28095351 TI - Level of Granzyme B-positive T-regulatory cells is a strong predictor biomarker of acute Graft-versus-host disease after day +30 after allo-HSCT. AB - Acute Graft-versus-host-disease (aGVHD), the major complication and one of the main causes of poor outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nowadays there are no widely accepted cell, plasma or another biomarker that can be used for aGVHD prediction. We hypothesized that a level of Granzyme B-positive T regulatory (GZMB-positive Treg) cells on day+30 after allo-HSCT could be the measure of immune response suppression and could predict aGVHD development after day +30. We applied a widespread and easy-to perform method of multicolor flow cytometry to measure level of GZMB-positive Treg cells. Levels of GZMB-positive Tregs on day +30 after allo-HSCT were significantly higher in those patients who never developed aGVHD in comparison with the other group of patient with aGVHD after day +30 (p=0.0229). We conclude that the level of GZMB-positive Treg cells is a strong predictor of acute Graft versus-host disease after day +30 after allo-HSCT. PMID- 28095352 TI - The relationship of REL proto-oncogene to pathobiology and chemoresistance in follicular and transformed follicular lymphoma. AB - Follicular lymphoma (FL) is a common type of indolent lymphoma that occasionally transforms to more aggressive B-cell lymphomas. These transformed follicular lymphomas (tFL) are often associated with chemoresistance whose mechanisms are currently unknown. REL, a proto-oncogene located on frequently amplified 2p16.1 p15 locus, promotes tumorigenesis in many cancer types through deregulation of the NF-kappaB pathway; however, its role in FL pathobiology or chemoresistance has not been addressed. Here, we evaluated REL gene copy number by q-PCR on FFPE FL tumor samples, and observed REL amplification in 30.4% of FL cases that was associated with weak elevation of transcript levels. PCR-Sanger analysis did not show any somatic mutation in FL tumors. In support of a marginal oncogenic role, a REL-transduced FL cell line was positively selected under limiting serum conditions. Interestingly, reanalysis of previously reported gene expression profiles revealed significant enrichment of DNA damage-induced repair and cell cycle arrest pathways in tFL tumors with high REL expression compared to those with low REL expression consistent with the critical role of c-REL in genotoxicity-induced NF-kappaB signaling, which was reported to lead to drug resistance. In addition to DNA damage repair genes such as ATM and BRCA1, anti apoptotic BCL2 was significantly elevated in REL-high FL and tFL tumors. Altogether these data suggest that other genes located in amplified 2p16.1-p15 locus may have more oncogenic role in FL etiology; however, high REL expression may be useful as a predictive biomarker of response to immunochemotherapy, and inhibition of c-REL may potentially sensitize resistant FL or tFL cells to chemotherapy. PMID- 28095353 TI - Liver alpha-amylase gene expression as an early obesity biomarker. AB - BACKGROUND: Obesity is a major health problem worldwide, for which preventive and therapeutic means are still needed. Alpha-amylase is a digestive enzyme whose inhibition has been targeted as a potential anti-obesity strategy. However, alpha amylase gene expression has not been particularly attended to, and in contrast with pancreatic and salivary amylases, fewer studies have focused on liver alpha amylase. The present study aimed at investigating the expression of alpha-amylase gene in obese and normal mice at RNA and protein level as well as acarbose effect on this gene expression in hepatocyte cell culture. METHODS: Control and case groups were fed by normal mouse pellet and high-fat diet respectively, during 8 weeks. After this period, serum biochemical parameters including glucose, cholesterol, triglycerides, AST, ALT and alpha-amylase were assayed. Liver alpha amylase gene was analyzed by real time PCR, and liver enzyme was assayed with Bernfeld and ELISA methods Hepatocyte cell culture derived from both group were also treated by acarbose and alpha-amylase activity and gene expression was analyzed by above mentioned methods. RESULTS: All biochemical factors showed an increase in obese mice, but the increase in ALT and AST were not statistically significant. Alpha-amylase levels were also increased in obese mice, both at RNA and protein level, while a decrease was seen in obese mice derived hepatocytes after acarbose treatment. CONCLUSIONS: Elevated liver alpha-amylase levels may be indicative of initial stages of obesity and the use of acarbose could be considered as a treatment of obesity which could be potentially effective at multiple levels. PMID- 28095354 TI - Heliangin inhibited lipopolysaccharide-induced inflammation through signaling NF kappaB pathway on LPS-induced RAW 264.7 cells. AB - The heliangin is a natural agent mainly isolated from Helianthus tuberosus L. (Asteraceae). In order to investigate the anti-inflammatory effect of heliangin, several typical models in vivo and in vitro were performed. The RAW264.7 mouse macrophages cells were employed in vitro and dexamethasone were conducted as positive. The cytotoxicity results of heliangin on RAW 264.7 cells provided the safety in vitro for further study. The mRNA of TNF-alpha, IL-6, iNOS and COX-2 were degraded under heliangin exposure in LPS-stimulated RAW 264.7 cells. The protein expression of iNOS, COX-2 were decreased via heliangin exposure in a dose dependent manner. Heliangin inhibited TNF-alpha, NO, IL-6 and PGE2 expression levels in macrophage cells lysate. The immunocytochemistry assay showed the fluorescence image of heliangin treatment intercepted the p65 translocation process from outside to inside of nuclei triggered by LPS. Moreover, we founded that MAPK and NF-kappaB signaling pathway play important roles in heliangin's activity on RAW264.7 cells. Secondly, the acute toxic study results of heliangin manifested the safety in vivo. Heliangin exerted anti-inflammation effect in a xylene-induced ear swelling in BALB/C mice and carrageenan-induced paw edema model in SD rats. The cytokines levels (TNF-alpha, IL-6 and PGE2) were decreased. The paw tissue immunochemistry assay demonstrated the IL-6 protein level changes in carrageenan-induced paw edema model under heliangin administration. PMID- 28095355 TI - Immune regulatory network in successful pregnancy and reproductive failures. AB - Maternal immune system must tolerate semiallogenic fetus to establish and maintain a successful pregnancy. Despite the existence of several strategies of trophoblast to avoid recognition by maternal leukocytes, maternal immune system may react against paternal alloantigenes. Leukocytes are important components in decidua. Not only T helper (Th)1/Th2 balance, but also regulatory T (Treg) cells play an important role in pregnancy. Although the frequency of Tregs is elevated during normal pregnancies, their frequency and function are reduced in reproductive defects such as recurrent miscarriage and preeclampsia. Tregs are not the sole population of suppressive cells in the decidua. It has recently been shown that regulatory B10 (Breg) cells participate in pregnancy through secretion of IL-10 cytokine. Myeloid derived suppressor cells (MDSCs) are immature developing precursors of innate myeloid cells that are increased in pregnant women, implying their possible function in pregnancy. Natural killer T (NKT) cells are also detected in mouse and human decidua. They can also affect the fetomaternal tolerance. In this review, we will discuss on the role of different immune regulatory cells including Treg, gammad T cell, Breg, MDSC, and NKT cells in pregnancy outcome. PMID- 28095356 TI - A systems pharmacology perspective to decipher the mechanism of action of Parangichakkai chooranam, a Siddha formulation for the treatment of psoriasis. AB - Psoriasis is a chronic relapsing immune mediated disorder of the skin. The disease presents itself with well featured clinical and histological characteristics however the aetiology of the disease still remains obscure. The current systemic therapies aim to eliminate the symptoms of disease rather than offering a complete cure. Parangichakkai chooranam (PC), a Siddha oral herbal formulation has been widely prescribed for the treatment of psoriasis. Though the medication is highly prescribed by the Siddha healers the mechanism of PC for the treatment of psoriasis remains to be elucidated. The current study utilizes an integrated systems pharmacology approach to decipher the mechanism of action of PC. The comprehensive network pharmacological approach resulted in the construction of a Compound-Target network which encloses 155 compounds and 583 protein targets. A Disease-Target network was constructed by assembling disease proteins and their partners. When the compound targets were mapped to the network their involvement as controllers of the disease and triggers of disease associated comorbidities were identified. A Target-Pathway network raised from the pathway enrichment analysis not only identified disease specific pathways but also the pathways mediating secondary complications such as skin hemostasis, wound healing, desquamation and itch. The present work sheds light on the mechanism of action of PC in treating psoriasis. This work not only highlights the pharmacological action of the formulation but also emphasis on safe herbal remedies offered by the Siddha medicinal system. PMID- 28095357 TI - Establishment of a fluorescence-based method to evaluate endocytosis of desialylated glycoproteins in vitro. AB - Insufficient sialylation can result in rapid clearance of therapeutic glycoproteins by intracellular degradation, which is mainly mediated by asialoglycoprotein receptors (ASGPRs) on hepatic cells. In contrast, for glycoproteins, a long half-life is often related to high level of terminal sialic acid. These could be extremely important for insufficient sialylated biomedicines in clinic, and development of therapeutic glycoproteins in laboratory. However, how the desialylated glycoproteins are removed and how to evaluate the ASGPRs mediated endocytosis in vitro needs further investigate. Herein we described an integrative characterization of ASGPRs in vitro to elucidate its endocytosis properties. The endocytosis was determined by a fluorescence-based quantization method. The results showed that the ASGPRs could bind to poorly sialylated glycoproteins including asialofetuin and low sialylated recombinant Factor VIIa with a relatively higher ASGPRs binding affinity, and induce a more rapid endocytosis in vitro. Moreover, the mechanism under the internalization of ASGPRs was also investigated, which was found to depend on clathrin and caveolin. Utilizing the relative fluorescence quantification can be suitable for measurement of insufficient sialylated glycoprotein endocytosis and quality control of therapeutic glycoproteins, which could be useful for the understanding of the development of therapeutic glycoproteins. PMID- 28095358 TI - Axial and torsional stiffness of pediatric prosthetic feet. AB - BACKGROUND: Prosthetic stiffness likely affects the walking biomechanics of toddlers and children with leg amputations, but the actual stiffness values for prostheses are not reported by manufacturers or in standardized testing procedures. AIM: We measured axial (kA) and torsional (kT) stiffness from four brands of pediatric prosthetic feet (Trulife, Kingsley Mfg. Co., TRS Incorporated, and College Park Industries) over a range of foot sizes. METHODS: We applied forces and torques onto prostheses with a materials testing machine that replicated those exhibited in vivo by using the kinetics measured from four non-amputee toddlers (2-3years) during walking. FINDINGS: Across brands, kA averaged 35.2kN/m during heel loading, was more stiff during midfoot loading (121.8kN/m, P<0.001) and less stiff during forefoot loading (11.8kN/m, P=0.013). kA was similar across brands with no statistically significant effect of prosthetic foot size, with the exception of the TRS feet. Plantarflexion torsional stiffness (kT1), was not statistically different across brands. For every 1cm increase in foot size, kT1 increased 0.16kN.m/rad (P<0.001). College Park prostheses had 4.54kN.m/rad lower dorsiflexion torsional stiffness (kT2) (P<0.001) compared to other brands. For every 1cm increase in foot size, the kT2 applied on the foot increased 0.63kN.m/rad. INTERPRETATION: The axial and torsional stiffness testing methods are reproducible and should be adopted by prosthetic foot manufacturers. Axial and torsional stiffness values of commercially available prosthetic feet should be publically reported to health practitioners to ensure evidence-based decisions and meet the specific needs of each patient with a leg amputation. PMID- 28095359 TI - Gait deviations associated with plantar heel pain: A systematic review. AB - BACKGROUND: Plantar heel pain is a common foot disorder associated with significant pain and gait-related disability. The aim of this systematic review was to identify gait deviations associated with plantar heel pain. METHODS: A systematic review of articles with quantitative gait variables in individuals with plantar heel pain was conducted using the CINAHL, MEDLINE, Scopus, and Embase databases. Methodological quality was assessed using the modified Downs and Black criteria and used along with the number of studies per gait variable to determine level of evidence. FINDINGS: Nineteen articles were included. There was strong evidence that stance phase duration is unchanged. There was moderate to strong evidence of decreased rearfoot center of pressure duration, impulse, and peak vertical ground reaction force at loading response. In compensation there was increased contact time of the midfoot and forefoot, increased midfoot and forefoot impulse, delayed time to the mid-stance vertical ground reaction force valley, and decreased peak force at terminal stance. The only quantitative measure of pronation/supination included limited evidence of increased medial forefoot and rearfoot inversion-eversion total mobility, and medial forefoot plantar flexion. INTERPRETATION: Studies included in this review identified specific foot and ankle gait deviations in individuals with plantar heel pain compared to asymptomatic cases or limbs. The variables identified in this review may be used to assist in identifying movement-related gait dysfunction for treatment decisions or as outcome measures of recovery. Additional research is needed to increase confidence and clinical relevance of gait variables used to assess and treat individuals with PHP. PMID- 28095360 TI - Enzyme-catalyzed Michael addition for the synthesis of warfarin and its determination via fluorescence quenching of l-tryptophan. AB - A sensitive fluorescence sensor for warfarin was proposed via quenching the fluorescence of l-tryptophan due to the interaction between warfarin and l tryptophan. Warfarin, as one of the most effective anticoagulants, was designed and synthesized via lipase from porcine pancreas (PPL) as a biocatalyst to catalyze the Michael addition of 4-hydroxycoumarin to alpha, beta-unsaturated enones in organic medium in the presence of water. Furthermore, the spectrofluorometry was used to detect the concentration of warfarin with a linear range and detection limit (3sigma/k) of 0.04-12.0MUmolL-1 (R2=0.994) and 0.01MUmolL-1, respectively. Herein, this was the first application of bio catalytic synthesis and fluorescence for the determination of warfarin. The proposed method was applied to determine warfarin of the drug in tablets with satisfactory results. PMID- 28095361 TI - Axial traction magnetic resonance imaging (MRI) of the glenohumeral joint in healthy volunteers: initial experience. AB - OBJECTIVE: Evaluate technical feasibility and potential applications of glenohumeral (GH) joint axial traction magnetic resonance imaging (MRI) in healthy volunteers. MATERIALS AND METHODS: Eleven shoulders were imaged in neutral and with 4kg axial traction at 3T. Quantitative measurements were assessed. RESULTS: Axial traction was well tolerated. There was statistically significant widening of the superior GH joint space (p=0.002) and acromial angle (p=0.017) with traction. Inter-rater agreement was high. CONCLUSION: GH joint axial traction MRI is technically feasible and well tolerated in volunteers. Traction of the capsule, widening of the superior GH joint space and acromial angle were observed. PMID- 28095362 TI - In vivo modulation of LPS induced leukotrienes generation and oxidative stress by sesame lignans. AB - The role of inflammation and oxidative stress is critical during onset of metabolic disorders and this has been sufficiently established in literature. In the present study, we evaluated the effects of sesamol and sesamin, two important bioactive molecules present in sesame oil, on the generation of inflammatory and oxidative stress factors in LPS injected rats. Sesamol and sesamin lowered LPS induced expression of cPLA2 (61 and 56%), 5-LOX (44 and 51%), BLT-1(32 and 35%) and LTC4 synthase (49 and 50%), respectively, in liver homogenate. The diminished serum LTB4 (53 and 64%) and LTC4 (67 and 44%) levels in sesamol and sesamin administered groups, respectively, were found to be concurrent with the observed decrease in the expression of cPLA2 and 5-LOX. The serum levels of TNF-alpha (29 and 19%), MCP-1 (44 and 57%) and IL-1beta (43 and 42%) were found to be reduced in sesamol and sesamin group, respectively, as given in parentheses, compared to LPS group. Sesamol and sesamin offered protection against LPS induced lipid peroxidation in both serum and liver. Sesamol, but not sesamin, significantly restored the loss of catalase and glutathione reductase activity due to LPS (P<.05). However, both sesamol and sesamin reverted SOD activities by 92 and 98%, respectively. Thus, oral supplementation of sesamol and sesamin beneficially modulated the inflammatory and oxidative stress markers, as observed in the present study, in LPS injected rats. Our report further advocates the potential use of sesamol and sesamin as an adjunct therapy wherein, inflammatory and oxidative stress is of major concern. PMID- 28095363 TI - Curcumin confers neuroprotection against alcohol-induced hippocampal neurodegeneration via CREB-BDNF pathway in rats. AB - BACKGROUND: Alcohol abuse causes severe damage to the brain neurons. Studies have reported the neuroprotective effects of curcumin against alcohol-induced neurodegeneration. However, the precise mechanism of action remains unclear. METHODS: Seventy rats were equally divided into 7 groups (10 rats per group). Group 1 received normal saline (0.7ml/rat) and group 2 received alcohol (2g/kg/day) for 21days. Groups 3, 4, 5 and 6 concurrently received alcohol (2g/kg/day) and curcumin (10, 20, 40 and 60mg/kg, respectively) for 21days. Animals in group 7 self- administered alcohol for 21days. Group 8 treated with curcumin (60mg/kg, i.p.) alone for 21days. Open Field Test (OFT) was used to investigate motor activity in rats. Hippocampal oxidative, antioxidative and inflammatory factors were evaluated. Furthermore, brain cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and brain derived neurotrophic factor (BDNF) levels were studied at gene level by reverse transcriptase polymerase chain reaction (RT-PCR). In addition, protein expression for BDNF, CREB, phosphorylated CREB (CREB-P), Bax and Bcl-2 was determined by western blotting. RESULT: Voluntary and involuntary administration of alcohol altered motor activity in OFT, and curcumin treatment inhibited this alcohol induced motor disturbance. Also, alcohol administration augmented lipid peroxidation, mitochondrial oxidized glutathione (GSSG), interleukin-1 beta (IL 1beta), tumor necrosis factor-alpha (TNF-alpha) and Bax levels in isolated hippocampal tissues. Furthermore, alcohol-induced significant reduction were observed in reduced form of glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) activities and CREB, BDNF and Bcl-2 levels. Also curcumin alone did not change the behavior and biochemical and molecular parameters. CONCLUSION: Curcumin can act as a neuroprotective agent against neurodegenerative effects of alcohol abuse, probably via activation of CREB-BDNF signaling pathway. PMID- 28095364 TI - Acute myeloid leukemia with myelodysplasia-related changes demonstrating mixed lineage phenotype. PMID- 28095365 TI - Barreloid Borders and Neuronal Activity Shape Panglial Gap Junction-Coupled Networks in the Mouse Thalamus. AB - The ventral posterior nucleus of the thalamus plays an important role in somatosensory information processing. It contains elongated cellular domains called barreloids, which are the structural basis for the somatotopic organization of vibrissae representation. So far, the organization of glial networks in these barreloid structures and its modulation by neuronal activity has not been studied. We have developed a method to visualize thalamic barreloid fields in acute slices. Combining electrophysiology, immunohistochemistry, and electroporation in transgenic mice with cell type-specific fluorescence labeling, we provide the first structure-function analyses of barreloidal glial gap junction networks. We observed coupled networks, which comprised both astrocytes and oligodendrocytes. The spread of tracers or a fluorescent glucose derivative through these networks was dependent on neuronal activity and limited by the barreloid borders, which were formed by uncoupled or weakly coupled oligodendrocytes. Neuronal somata were distributed homogeneously across barreloid fields with their processes running in parallel to the barreloid borders. Many astrocytes and oligodendrocytes were not part of the panglial networks. Thus, oligodendrocytes are the cellular elements limiting the communicating panglial network to a single barreloid, which might be important to ensure proper metabolic support to active neurons located within a particular vibrissae signaling pathway. PMID- 28095366 TI - Cryptosporidium hominis gene catalog: a resource for the selection of novel Cryptosporidium vaccine candidates. AB - Human cryptosporidiosis, caused primarily by Cryptosporidium hominis and a subset of Cryptosporidium parvum, is a major cause of moderate-to-severe diarrhea in children under 5 years of age in developing countries and can lead to nutritional stunting and death. Cryptosporidiosis is particularly severe and potentially lethal in immunocompromised hosts. Biological and technical challenges have impeded traditional vaccinology approaches to identify novel targets for the development of vaccines against C. hominis, the predominant species associated with human disease. We deemed that the existence of genomic resources for multiple species in the genus, including a much-improved genome assembly and annotation for C. hominis, makes a reverse vaccinology approach feasible. To this end, we sought to generate a searchable online resource, termed C. hominis gene catalog, which registers all C. hominis genes and their properties relevant for the identification and prioritization of candidate vaccine antigens, including physical attributes, properties related to antigenic potential and expression data. Using bioinformatic approaches, we identified ~400 C. hominis genes containing properties typical of surface-exposed antigens, such as predicted glycosylphosphatidylinositol (GPI)-anchor motifs, multiple transmembrane motifs and/or signal peptides targeting the encoded protein to the secretory pathway. This set can be narrowed further, e.g. by focusing on potential GPI-anchored proteins lacking homologs in the human genome, but with homologs in the other Cryptosporidium species for which genomic data are available, and with low amino acid polymorphism. Additional selection criteria related to recombinant expression and purification include minimizing predicted post-translation modifications and potential disulfide bonds. Forty proteins satisfying these criteria were selected from 3745 proteins in the updated C. hominis annotation. The immunogenic potential of a few of these is currently being tested.Database URL: http://cryptogc.igs.umaryland.edu. PMID- 28095367 TI - MicroRNAs are important regulators of drug resistance in colorectal cancer. AB - Despite of continuous development of cancer treatment over the past decades, drug resistance is still one of the major hurdles of effective therapy for advanced colorectal cancer (CRC) worldwide and the understanding of its underlying mechanisms remains limited. Data which have emerged suggests that many microRNAs (miRNAs) may contribute to drug resistance in CRC. Major findings on miRNA functions in drug resistance of CRC are systemically reviewed here, with the goal of providing new updates to broaden our comprehension of its mechanisms and evidence to utilize miRNAs as potential therapeutic targets for CRC treatment. PMID- 28095369 TI - Implanted muon spin spectroscopy on 2-O-adamantane: a model system that mimics the liquid[Formula: see text]glasslike transitions. AB - The transition taking place between two metastable phases in 2-O-adamantane, namely the [Formula: see text] cubic, rotator phase and the lower temperature P21/c, Z = 4 substitutionally disordered crystal is studied by means of muon spin rotation and relaxation techniques. Measurements carried out under zero, weak transverse and longitudinal fields reveal a temperature dependence of the relaxation parameters strikingly similar to those exhibited by structural glass[Formula: see text]liquid transitions (Bermejo et al 2004 Phys. Rev. B 70 214202; Cabrillo et al 2003 Phys. Rev. B 67 184201). The observed behaviour manifests itself as a square root singularity in the relaxation rates pointing towards some critical temperature which for amorphous systems is located some tens of degrees above that shown as the characteristic transition temperature if studied by thermodynamic means. The implications of such findings in the context of current theoretical approaches concerning the canonical liquid-glass transition are discussed. PMID- 28095370 TI - The B - L supersymmetric standard model with inverse seesaw at the large hadron collider. AB - We review the TeV scale B - L extension of the minimal supersymmetric standard model (BLSSM) where an inverse seesaw mechanism of light neutrino mass generation is naturally implemented and concentrate on its hallmark manifestations at the large hadron collider (LHC). PMID- 28095368 TI - Iron overload and altered iron metabolism in ovarian cancer. AB - Iron is an essential element required for many processes within the cell. Dysregulation in iron homeostasis due to iron overload is detrimental. This nutrient is postulated to contribute to the initiation of cancer; however, the mechanisms by which this occurs remain unclear. Defining how iron promotes the development of ovarian cancers from precursor lesions is essential for developing novel therapeutic strategies. In this review, we discuss (1) how iron overload conditions may initiate ovarian cancer development, (2) dysregulated iron metabolism in cancers, (3) the interplay between bacteria, iron, and cancer, and (4) chemotherapeutic strategies targeting iron metabolism in cancer patients. PMID- 28095371 TI - Implementation of transmission functions for an optimized three-terminal quantum dot heat engine. AB - We consider two modifications of a recently proposed three-terminal quantum dot heat engine. First, we investigate the necessity of the thermalization assumption, namely that electrons are always thermalized by inelastic processes when traveling across the cavity where the heat is supplied. Second, we analyze various arrangements of tunneling-coupled quantum dots in order to implement a transmission function that is superior to the Lorentzian transmission function of a single quantum dot. We show that the maximum power of the heat engine can be improved by about a factor of two, even for a small number of dots, by choosing an optimal structure. PMID- 28095373 TI - Comparison of "Lesion-by-Lesion" and Field Photodynamic Therapy in the Prevention of Actinic Keratoses: A Randomized, Split-Face, Single-Blind Pilot Study. AB - BACKGROUND: Actinic keratoses (AKs) are often treated separately, lesion by lesion. However, in the past years, AKs have been described as a field disease and not limited to single clinically apparent lesions. Treatment should therefore target an area of field change which may reduce the risk of development of further AKs, second tumours, and local recurrence. OBJECTIVE: The primary objective was to determine the number of new lesions at 9 months after methyl aminolevulinate photodynamic therapy (MAL-PDT). Secondary objectives were to determine the number of new lesions at 3 and 6 months after treatment and the percentage reduction of AKs from baseline at 3, 6, and 9 months after MAL-PDT. METHODS: This was a single-centre, prospective, randomized, split-face, investigator-blinded pilot study with a study duration of 1 year. The study population comprised patients with AKs on the face or scalp, with a maximum of 10 AKs on each side. One side was treated with 1 session of "lesion-by-lesion" MAL PDT (LT side) and the other side with 1 session of field MAL-PDT (FT side). RESULTS: At 9 months the FT demonstrated significantly fewer new lesions. At every time point during the follow-up, we found a significant reduction in the number of AKs in the LT as well as in the FT sides. After 3 and 6 months we did not observe significant differences between the sides. However, after 9 months, the LT area showed significantly fewer remaining AKs, whereas the FT area demonstrated significantly fewer new lesions. CONCLUSIONS: Field treatment results in significantly fewer new AK lesions compared with lesion-by-lesion treatment. PMID- 28095372 TI - Impaired Mitochondrial Respiration in Large Cerebral Arteries of Rats with Type 2 Diabetes. AB - Mitochondrial dysfunction has been suggested as a potential underlying cause of pathological conditions associated with type 2 diabetes (T2DM). We have previously shown that mitochondrial respiration and mitochondrial protein levels were similar in the large cerebral arteries of insulin-resistant Zucker obese rats and their lean controls. In this study, we extend our investigations into the mitochondrial dynamics of the cerebral vasculature of 14-week-old Zucker diabetic fatty obese (ZDFO) rats with early T2DM. Body weight and blood glucose levels were significantly higher in the ZDFO group, and basal mitochondrial respiration and proton leak were significantly decreased in the large cerebral arteries of the ZDFO rats compared with the lean controls (ZDFL). The expression of the mitochondrial proteins total manganese superoxide dismutase (MnSOD) and voltage-dependent anion channel (VDAC) were significantly lower in the cerebral microvessels, and acetylated MnSOD levels were significantly reduced in the large arteries of the ZDFO group. Additionally, superoxide production was significantly increased in the microvessels of the ZDFO group. Despite evidence of increased oxidative stress in ZDFO, exogenous SOD was not able to restore mitochondrial respiration in the ZDFO rats. Our results show, for the first time, that mitochondrial respiration and protein levels are compromised during the early stages of T2DM. PMID- 28095374 TI - Human Cytomegalovirus Infection in Nonimmunocompromised Patients: A Retrospective Analysis and Review of the Literature. AB - In a retrospective analysis of patients visiting the Outpatient Department of the Division of Infectious Diseases and Tropical Medicine over a period of 3 years, we found a high incidence of symptomatic nonsevere human cytomegalovirus (HCMV) infection in nonimmunocompromised patients. We present 11 symptomatic cases of HCMV infection in nonimmunocompromised patients with non-life-threatening symptoms like long-lasting depletion, fatigue, and subfebrile fever with or without muscular pain and arthralgia. Although the symptoms were not life threatening, all of the patients suffered a prolonged duration of the disease until improvement. These cases reinforce the important fact that HCMV infections in nonimmunocompromised patients are not always asymptomatic. Therefore, HCMV infection should always be included in the differential diagnosis of patients with unspecific signs of disease like depletion, subfebrile fever, and arthralgia. PMID- 28095375 TI - Disappearing in the Night: An Overview on Trade and Legislation of Night Monkeys in South and Central America. AB - The international trade in night monkeys (Aotus spp.), found throughout Central and South America, has been regulated by the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) since 1975. We present a quantitative analysis of this trade from all 9 range countries, over 4 decades, and compare domestic legislation to CITES regulations. Night monkeys were exported from 8 of the 9 habitat countries, totalling 5,968 live individuals and 7,098 specimens, with trade of live individuals declining over time. In terms of species, the most commonly traded was Aotus nancymaae (present in Brazil, Colombia, Peru) followed by A. vociferans (Brazil, Colombia, Ecuador, Peru) and A. zonalis (Colombia, Panama). There was no significant correlation between levels of trade and species' geographic range size or the number of countries in which a species occurs. Five countries have legislation that meets CITES requirements for implementation, whereas the other 4 countries' legislation showed deficiencies. Research conducted in Colombia, Peru, and Brazil suggests significant cross-border trade not captured in official international trade registers. Although international trade has diminished, current trends suggest that populations of rarer species may be under unsustainable pressure. Further research is needed to quantify real trade numbers occurring between habitat countries. PMID- 28095376 TI - Review of Decision-Making in Game Tasks in Elderly Participants with Alzheimer Disease and Mild Cognitive Impairment. AB - BACKGROUND: Changes in decision-making (DM) have recently been investigated in patients with Alzheimer disease (AD) or mild cognitive impairment (MCI). DM is highly relevant to everyday functioning and autonomy. It relies on several cognitive abilities, such as semantic and episodic memory, as well as aspects of executive functioning. We conducted a systematic review of DM in older adults with MCI and AD. SUMMARY: Only 5 studies whose main objective was to evaluate the DM performance were selected. The results extracted indicated that DM in ambiguity and in at-risk situations are both impaired in probable AD patients. MCI patients have difficulty making advantageous decisions under ambiguity and at risk, similar to patients with probable AD but they are less impaired. Key Messages: DM deficits may be a predictor of cognitive impairment and conversion to dementia and its potential clinical value should be further explored in longitudinal studies involving direct comparison between MCI and AD patients. PMID- 28095377 TI - Associations of Maternal Leptin with Neonatal Adiposity Differ according to Pregravid Weight. AB - BACKGROUND: During pregnancy, maternal circulating leptin is released by maternal adipose tissue and the placenta, and may have a role in fetal development. OBJECTIVES: We investigated maternal leptinemia and glycemia associations with neonatal adiposity, taking into account pregravid weight status. METHODS: We included 235 pregnant women from the Genetics of Glucose Regulation in Gestation and Growth prospective cohort with data: blood samples collected during the 2nd trimester, an oral glucose tolerance test (OGTT), and the measured leptin and glucose levels. As an integrated measure of maternal leptin exposure, we calculated the area under the curve for maternal leptin at the OGTT (AUCleptin). Within 72 h of delivery, we measured the triceps, biceps, subscapular, and suprailiac skinfold thicknesses (SFTs); the sum of these SFTs represented neonatal adiposity. We conducted a regression analysis to assess the maternal metabolic determinants of neonatal adiposity, adjusting for parity, smoking status, maternal triglyceride levels, gestational weight gain, placental weight, delivery mode, neonate sex, and gestational age at delivery. RESULTS: The pregravid BMI of the participating women was 23.3 (21.2-27.0). In the 2nd trimester, maternal AUCleptin was 1,292.0 (767.0-2,222.5) (ng * min)/mL, and fasting glucose levels were 4.2 +/- 0.4 mmol/L. At delivery, the neonatal sum of 4 SFTs was 17.9 +/- 3.3 mm. Higher maternal leptinemia was associated with higher neonatal adiposity (beta = 4.23 mm [SE = 1.77] per log-AUCleptin; p = 0.02) in mothers with a BMI >=25, independently of confounders and maternal glycemia, but not in mothers with a BMI <25. Higher maternal fasting glucose was associated with higher neonatal adiposity (beta = 0.88 mm [SE = 0.30] per SD glucose; p = 0.005) in mothers with a BMI <25, independently of confounders and maternal leptinemia. CONCLUSION: Maternal leptinemia may be associated with neonatal adiposity in offspring from overweight/obese mothers, independently of maternal glycemia. PMID- 28095378 TI - Advanced Neuroimaging Techniques in Pediatric Hydrocephalus. AB - From the early days of pneumoencephalography and ventriculography to the emerging technology of magnetic resonance diffusion tensor imaging (DTI) of the present day, neuroimaging has always been a critical tool in the diagnosis and treatment of pediatric hydrocephalus. There is accumulating evidence from both human and animal research suggesting that one of the major pathophysiological mechanisms underlying poor outcomes in these children is damage to vulnerable white matter (WM) structures in the brain as a result of ventricular enlargement and increased intracranial pressure. However, a clear understanding of these WM abnormalities and their implications on neurobehavioral outcomes in these patients is not well understood. To this end, DTI has recently been studied to allow noninvasive quantification of these abnormalities. Our review discusses the evolution of neuroimaging in pediatric hydrocephalus and focuses on the use of advanced imaging techniques, such as DTI, which is supported by a growing body of literature as a promising noninvasive imaging tool in the diagnosis and long-term management of this patient population. We conclude with a brief discussion on emerging techniques and experimental imaging. PMID- 28095379 TI - Diffusion Tensor Imaging Detects Occult Cerebellar Injury in Severe Neonatal Hypoxic-Ischemic Encephalopathy. AB - BACKGROUND: Despite the benefits of whole-body hypothermia therapy, many infants with hypoxic-ischemic encephalopathy (HIE) die or have significant long-term neurodevelopmental impairment. Prospectively identifying neonates at risk of poor outcome is essential but not straightforward. The cerebellum is not classically considered to be a brain region vulnerable to hypoxic-ischemic insults; recent literature suggests, however, that the cerebellum may be involved in neonatal HIE. In this study, we aimed to assess the microstructural integrity of cerebellar and linked supratentorial structures in neonates with HIE compared to neurologically healthy neonatal controls. METHODS: In this prospective cohort study, we performed a quantitative diffusion tensor imaging (DTI) analysis of the structural pathways of connectivity, which may be affected in neonatal cerebellar injury by measuring fractional anisotropy (FA) and mean diffusivity (MD) within the superior, middle, and inferior cerebellar peduncles, dentate nuclei, and thalami. All magnetic resonance imaging (MRI) studies were grouped into 4 categories of severity based on a qualitative evaluation of conventional and advanced MRI sequences. Multivariable linear regression analysis of cerebellar scalars of patients and controls was performed, controlling for gestational age, age at the time of MRI, and HIE severity. Spearman rank correlation was performed to correlate DTI scalars of the cerebellum and thalami. RESULTS: Fifty-seven (23 females, 40%) neonates with HIE and 12 (6 females, 50%) neonatal controls were included. There were 8 patients (14%) in HIE severity groups 3 and 4 (injury of the basal ganglia/thalamus and/or cortex). Based on a qualitative analysis of conventional and DTI images, no patients had evidence of cerebellar injury. No significant differences between patients and controls were found in the FA and MD scalars. However, FA values of the middle cerebellar peduncles (0.294 vs. 0.380, p < 0.001) and MD values of the superior cerebellar peduncles (0.920 vs. 1.007 * 10-3 mm/s2, p = 0.001) were significantly lower in patients with evidence of moderate or severe injury on MRI (categories 3 and 4) than in controls. In patients, cerebellar DTI scalars correlated positively with DTI scalars within the thalami. CONCLUSION: Our results suggest that infants with moderate-to-severe HIE may have occult injury of cerebellar white-matter tracts, which is not detectable by the qualitative analysis of neuroimaging data alone. Cerebellar DTI scalars correlate with thalamic measures, highlighting that cerebellar injury is unlikely to occur in isolation and may reflect the severity of HIE. The impact of concomitant cerebellar injury in HIE on long-term neurodevelopmental outcome warrants further study. PMID- 28095380 TI - Polycythemia Vera Management and Challenges in the Community Health Setting. AB - Patients with polycythemia vera (PV) experience shortened survival, increased risk of thromboembolic and hemorrhagic events, and burdensome symptoms. For all patients with PV, treatment with aspirin and hematocrit control with phlebotomy are recommended. In addition, patients with high-risk status or poor hematocrit control benefit from cytoreductive therapy with hydroxyurea, although approximately 1 in 4 patients develops resistance or intolerance. For patients who are resistant to or intolerant of hydroxyurea, studies have shown that ruxolitinib, a Janus kinase 1/2 inhibitor, provides hematocrit control, reduces spleen size, normalizes blood counts, and improves PV-related symptoms. For many patients, PV is managed in a community health setting, and it is important that community hematologists, oncologists, and internists are familiar with the contemporary management of PV to improve patient outcomes, including management for patients who present with unique health-care needs. This review provides an overview of current treatment options for patients with PV and discusses challenging circumstances encountered by community providers in the management of PV, including symptom assessment, identification of hydroxyurea resistance/intolerance, pregnancy, elective surgeries, concomitant immunosuppressants, and managing patients in areas with limited access to specialized hematologic care. PMID- 28095381 TI - A Single Oral Dose of Geranylgeranylacetone Upregulates Vascular Endothelial Growth Factor and Protects against Kainic Acid-Induced Neuronal Cell Death: Involvement of the Phosphatidylinositol-3 Kinase/Akt Pathway. AB - BACKGROUND: Previous studies demonstrated the cytoprotective effect of geranylgeranylacetone (GGA), a heat shock protein inducer, against ischemic insult or kainic acid (KA)-induced neuronal cell death. Phosphatidylinositol-3 kinase (PI3K)/Akt is thought to be an important factor that mediates neuroprotection. However, the signaling pathways in the brain in vivo after oral GGA administration remain unclear. METHODS: We measured and compared hippocampal neuron density to investigate the effect of GGA on KA-induced cell death in rats. We evaluated the effects of pretreatment with wortmannin (Wort), a specific PI3K inhibitor, on GGA-induced neuroprotection against KA-induced cell death. To clarify the relationship between PI3K/Akt activation and neuroprotection, we used immunoblot analysis to determine the amounts of p-Akt and vascular endothelial growth factor (VEGF) proteins present after GGA administration with or without Wort treatment. RESULTS: Neuroprotective effects of GGA (pretreatment with a single oral dose of GGA, 800 mg/kg, 48 h before KA injection) were prevented by Wort pretreatment, which indicates that the selective PI3K/Akt pathway may mediate the GGA-dependent protection. Oral GGA-induced p-Akt and VEGF, and GGA pretreatment enhanced KA-induced VEGF, both of which were prevented by Wort pretreatment. CONCLUSION: These results suggest that a single oral dose of GGA induces p-Akt and that GGA plays an important role in neuroprotection against KA induced neuronal cell death through VEGF induction. PMID- 28095382 TI - Examination of Anomalous World Experience: A Report on Reliability. AB - BACKGROUND: The EAWE (Examination of Anomalous World Experience) is a newly developed, semi-structured interview that aims to capture anomalies of subjectivity, common in schizophrenia spectrum disorders, that pertain to experiences of the lived world, including space, time, people, language, atmosphere, and certain existential attitudes. By contrast, previous empirical studies of subjective experience in schizophrenia have focused largely on disturbances in self-experience. AIM: To assess the reliability of the EAWE, including internal consistency and interrater reliability. SAMPLING AND METHODS: In the course of developing the EAWE, two distinct studies were conducted, one in the United States and the other in Slovenia. Thirteen patients diagnosed with schizophrenia spectrum or mood disorders were recruited for the US study. Fifteen such patients were recruited for the Slovenian study. Two live interviewers conducted the EAWE in the US. The Slovenian interviews were completed by one live interviewer with a second rater reviewing audiorecordings of the interview. Internal consistency and interrater reliability were calculated independently for each study, utilizing Cronbach's alpha, Spearman's rho, and Cohen's kappa. RESULTS: Each study yielded high internal consistency (Cronbach's alpha >0.82) and high interrater reliability for total EAWE scores (rho > 0.83; average kappa values were at least 0.78 for each study, with EAWE domain-specific kappa not lower than 0.73). CONCLUSION: The EAWE, containing world-oriented inquiries into anomalies in subjective experience, has adequate reliability for use in a clinical or research setting. PMID- 28095383 TI - Evaluation of Plasmatic Kisspetin-10 as a Biomarker for Malignancy and Subtype Differentiation in Small Renal Tumours. AB - OBJECTIVE: To evaluate Kisspeptin-10 (Kiss-10) in patients with small renal tumours (SRTs) and controls. MATERIAL AND METHODS: Kiss-10 was measured in preoperative plasma samples in a cohort of 143 patients with unilateral renal tumours smaller than or equal to 4 cm and 40 age-matched controls by a competitive ELISA test kit. The cohort of patients included 56 patients with clear cell renal cell carcinoma (ccRCC), 43 with papillary RCC (pRCC), 12 with chromophobe RCC (chRCC) and 32 with oncocytomas. RESULTS: Kiss-10 was detected in all patients and controls. SRT patients revealed significantly higher Kiss-10 levels than controls (mean value 10.04 vs. 6.37 pmol/l, p < 0.001). In SRT patients, Kiss-10 was detected at significantly different concentrations between the subgroups (p = 0.021). The highest concentration was observed in those with oncocytomas (11.50 pmol/) followed by chRCC, pRCC and ccRCC patients (9.89, 10.01 and 9.25 pmol/l, respectively). Receiver operating characteristic curve analyses revealed an area under the curve (AUC) of 0.82 for the comparison of all tumours vs. controls (p < 0.001) and an AUC of 0.671 for all malignant tumours vs. oncoytomas (p = 0.003). CONCLUSION: This study shows that Kiss-10 levels are significantly altered by malignancy and tumour subtypes even in patients with SRTs. Kiss-10 therefore deserves further attention as a plasmatic biomarker for renal tumours. PMID- 28095384 TI - A Case of Plasmablastic Lymphoma Achieving Complete Response and Durable Remission after Lenalidomide-Based Therapy. AB - BACKGROUND: Plasmablastic lymphoma (PBL) is an uncommon variant of diffuse large B-cell lymphoma that is characterized by its plasmacytoid features, aggressive tendencies, and frequent association with human immunodeficiency virus (HIV) infection or other immunocompromised states. Multi-agent, intensive chemotherapy regimens are recommended as first-line treatment by the National Comprehensive Cancer Network. However, the toxicity of these regimens is high and prognosis remains poor. CASE REPORT: We report a patient with HIV-negative PBL who achieved complete response and durable remission using a lenalidomide-based chemotherapy regimen as first-line therapy. CONCLUSION: Cyclophosphamide, lenalidomide, dexamethasone (CRD) may provide an alternative initial therapeutic option for patients with PBL who cannot tolerate the intensive chemotherapy regimens currently recommended. PMID- 28095385 TI - Early Cholecystectomy for Acute Cholecystitis in the Elderly Population: A Systematic Review and Meta-Analysis. AB - BACKGROUND: In the era of advanced surgical techniques and improved perioperative care, the willingness to perform emergency operations in elderly patients continues to increase. This systematic review aimed at assessing the clinical outcomes of early cholecystectomy in elderly patients with acute cholecystitis. METHODS: Medline, Embase, and Cochrane Library databases were systematically searched for studies reporting on early cholecystectomy for acute cholecystitis in patients aged >=70 years. The conversion rate, perioperative morbidity, and mortality were calculated using a random-effects model. RESULTS: Eight articles fell within the scope of this study. In total, 592 patients were identified. The mean age was 81 years. Early cholecystectomy was performed laparoscopically in 316 patients (53%) and open in 276 patients (47%). The procedure was associated with a conversion rate of 23% (95% CI 18.6-28.3), a perioperative morbidity of 24% (95% CI 20.5-27.5), and a mortality of 3.5% (95% CI 2.3-5.4). CONCLUSION: Early cholecystectomy seems to be a feasible treatment in elderly patients with acute cholecystitis. To reduce morbidity, patients who may benefit from surgery ought to be selected carefully. Future prospective studies should compare early cholecystectomy with alternative treatments to select the treatment that is most appropriate for elderly patients. PMID- 28095386 TI - In vitro Evaluation of the Cleansing Effect of a Monofilament Fiber Debridement Pad Compared to Gauze Swabs. AB - BACKGROUND: Removal of nonvital tissue is an accepted method to eradicate biofilms and to stimulate wound healing. Debridement using a monofilament polyester fiber pad has clinically been shown to be effective as well as pain and trauma free. METHODS: For in vitro determination of the cleansing capacity of this product compared to gauze swabs, a wound debridement model was used with glass plates coated with a bovine serum albumin solution, stained with hematoxylin. Both products were moistened and fixed to a weight connected to a regulated motor and were then pulled over the holding device with the coated glass plate under standardized conditions (power = 0.067 N/cm2, velocity = 1.6 cm/s). RESULTS: At a low coating concentration (0.5%) both products were equally effective, but at a high concentration (1.5%) cleansing did not occur after 5 wipes. When wiping the plates 15 times, the debridement pad cleansed significantly (p < 0.001) better than gauze. When consecutively wiping 4 coated plates with a single debridement pad or swab, the pad exhibited and maintained a significantly higher cleansing capacity while gauze quickly lost its effect. CONCLUSION: Our in vitro test results indicated a higher cleansing capacity of the debridement pad compared to gauze swabs. PMID- 28095387 TI - MRI of Cerebellar Infarction. AB - BACKGROUND: MRI is the imaging modality of choice for diagnosing brain infarction. Because of few or atypical clinical symptoms and a relatively low sensitivity of CT scans, many cerebellar infarctions may be detected only with MRI. With adequate recognition of cerebellar infarction on MRI and prompt initiation or optimisation of preventive therapeutic measures, more dramatic strokes may be avoided in selected cases. SUMMARY: We first briefly review the clinical presentation of cerebellar infarctions, followed by a short refresher on cerebellar anatomy and pathophysiological mechanisms of cerebellar infarcts. Then, we review the arterial cerebellar perfusion territories recently made visible with territorial arterial spin labeling (ASL), followed by a discussion and illustration of the MRI appearance of cerebellar infarcts in different stages. Similar to large cerebellar infarcts, recent studies investigating volumetric MRI datasets have now shown that small cerebellar infarcts occur in typical spatial patterns, knowledge of which may help in the diagnosis of even the smallest of cerebellar infarcts on MRI. Key Messages: MRI is the modality of choice for diagnosing cerebellar infarction. The posterior inferior cerebellar artery (PICA)-territories can be visualised with super-selective territorial ASL MRI. The PICA supplies at least the medial part of the posterior cerebellar surface. Anterior inferior cerebellar artery-infarcts can be mistaken for lateral PICA-infarcts. Small infarcts typically affect the cortex and often present as incidental cavities. Subacute cerebellar infarcts may be missed on imaging due to a phenomenon called "fogging." PMID- 28095388 TI - The Use of MitraClip for Symptomatic Patients with Hypertrophic Obstructive Cardiomyopathy. AB - OBJECTIVES: Current nonpharmacological therapies for symptomatic patients with hypertrophic obstructive cardiomyopathy (HOCM), including septal myectomy and alcohol septal ablation (ASA), carry significant risks for serious cardiac conduction abnormalities. We present a review of the currently available published data regarding the novel use of the relatively low-risk MitraClip(r) system in the treatment of symptomatic patients. METHODS: Data were collected from 4 separate studies on the use of the MitraClip on 15 symptomatic HOCM patients with systolic anterior motion (SAM) of the mitral valve apparatus. Information regarding the degree of mitral regurgitation (MR), left-ventricular outflow tract (LVOT) gradient, and NYHA class was consolidated. RESULTS: After MitraClip treatment, all patients had a resolution of SAM, a reduction in MR, and a reduction in the LVOT gradient from a mean of 75.8 +/- 39.7 to 11.0 +/- 5.6 mm Hg. Nearly all patients demonstrated improvements in symptoms by either new NYHA class designations or improved exercise tolerance. The procedure was not associated with conduction abnormalities or arrhythmias. CONCLUSION: MitraClip therapy may be a safe and effective treatment for symptomatic HOCM patients; it can help to avoid the potential risks associated with alternative therapies in high-risk surgical patients. PMID- 28095391 TI - Erratum. PMID- 28095390 TI - Hydrogen Sulfide Promotes Learning and Memory and Suppresses Proinflammatory Cytokines in Repetitive Febrile Seizures. AB - OBJECTIVE: Hydrogen sulfide (H2S), as a novel gasotransmitter, plays important roles in a number of physiological and pathological processes. Its effectiveness has been demonstrated in different types of brain disorders but not in repetitive febrile seizure (febrile status epilepticus; FSE) models. This study aims to test whether a donor of H2S sodium sulfhydrate (NaHS) is also effective for FSE in rats. METHODS: FSE was induced in rat pups on postnatal day 10 in water at 45.0 +/- 0.1 degrees C for 10 consecutive days with or without preadministration of NaHS. Following evaluation of the latency and duration of hyperthermic seizures, impairment in learning and memory was measured by the Morris water maze test. Moreover, alterations of the microglial response and the production of proinflammatory cytokines IL-1beta and TNF-alpha were calculated in the hippocampus. RESULTS: We found that NaHS significantly increased the latency and decreased the duration of hyperthermic seizures. Furthermore, NaHS-treated pups showed less impairment in learning and memory. In addition, NaHS inhibited FSE induced microglial responses and suppressed the production of IL-1beta and TNF alpha in the hippocampus. CONCLUSION: NaHS appears to be effective for the treatment of FSE in infants and children, in part due to its anti-inflammatory action. PMID- 28095392 TI - Binding versus Conventional Pancreaticojejunostomy in Preventing Postoperative Pancreatic Fistula: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The aim of this study was to compare the safety and efficacy of a new technology, binding pancreaticojejunostomy (BPJ), with conventional pancreaticojejunostomy (CPJ) after pancreaticoduodenectomy in preventing postoperative pancreatic fistula (POPF). METHODS: Randomized controlled trials and observational studies were retrieved from literature searches. Pooled OR with 95% CI for dichotomous variables and weighted mean difference with 95% CI for continuous variables were calculated. Fixed-effect and random-effect models as well as subgroup analysis were used for sensitivity analysis. RESULTS: No statistically significant differences were found in the incidence of POPF, delayed gastric emptying, postpancreatectomy hemorrhage, reoperation, morbidity, mortality, operation time, intraoperative blood loss, blood transfusion, and hospital stay between 2 groups. However, the total costs of hospitalization and ordinary stay were higher in BPJ group (?10,513 +/- ?6,536 vs. ?8,238 +/- ?4,687, p = 0.002; ?7,946 +/- ?5,023 vs. ?5,700 +/- ?2,902, p = 0.015, respectively). CONCLUSIONS: Our study showed BPJ was as safe as CPJ. However, no significant superiority was found in BPJ group regarding the incidence of POPF. The total costs of hospital stay were higher for patients undergoing BPJ. Surgeons can prefer to perform the digestive tract reconstruction of their choice. PMID- 28095393 TI - The Mechanism of Computed Tomography-Guided 125I Particle in Treating Lung Cancer. AB - BACKGROUND The incidence of malignant tumor has gradually increased. How to improve the survival and quality of life of patients who lose the opportunity for surgery or who are unwilling to receive surgery remains an obstacle. At present, 125I particle interstitial implant therapy has been applied in a variety of treatments of tumors. However, the mechanism of computed tomography (CT)-guided 125I particle therapy in lung cancer has not been fully elucidated. MATERIAL AND METHODS A total of 42 patients with advanced non-small cell lung cancer were retrospectively analyzed between January 2013 and December 2013, including 19 patients who received CT-guided 125I particle therapy and 23 patients who received chemotherapy. Curative effect and adverse reactions at 6 months and 12 months were compared and analyzed. A rabbit lung cancer VX2 model was treated by 125I particle implantation therapy under CT guidance. The change in tumor volume was detected. Tumor cell apoptosis was tested by flow cytometry. Bcl-2 and Bax expression were determined by real-time polymerase chain reaction (PCR) and Western blot. RESULTS 125I particle therapy obviously reduced tumor volume after 6 months and 12 months. It showed significantly higher efficiency (57.9%, 57.9%) and control (78.9%, 73.7%) than the rates of efficiency and control in the chemotherapy group (P<0.05). 125I particle implantation therapy markedly suppressed rabbit VX2 transplanted tumor cell proliferation, promoted tumor regression, induced tumor cell apoptosis, reduced Bcl-2 expression, and upregulated Bax expression level (P<0.05). CONCLUSIONS CT-guided 125I particle implantation therapy can inhibit tumor proliferation and growth by regulating the expression of apoptosis-related genes and proteins, which is a promising approach in lung cancer treatment. PMID- 28095394 TI - Loss of CUL4A expression is underlying cisplatin hypersensitivity in colorectal carcinoma cells with acquired trabectedin resistance. AB - BACKGROUND: Colorectal carcinoma (CRC) is the third most common cancer worldwide. Platinum-based anticancer compounds still constitute one mainstay of systemic CRC treatment despite limitations due to adverse effects and resistance development. Trabectedin has shown promising antitumor effects in CRC, however, again resistance development may occur. In this study, we aimed to develop strategies to circumvent or even exploit acquired trabectedin resistance in novel CRC treatment regimens. METHODS: Human HCT116 CRC cells were selected for acquired trabectedin resistance in vitro and characterised by cell biological as well as bioinformatic approaches. In vivo xenograft experiments were conducted. RESULTS: Selection of HCT116 cells for trabectedin resistance resulted in p53-independent hypersensitivity of the selected subline against cisplatin. Bioinformatic analyses of mRNA microarray data suggested deregulation of nucleotide excision repair and particularly loss of the ubiquitin ligase CUL4A in trabectedin selected cells. Indeed, transient knockdown of CUL4A sensitised parental HCT116 cells towards cisplatin. Trabectedin selected but not parental HCT116 xenografts were significantly responsive towards cisplatin treatment. CONCLUSIONS: Trabectedin selection-mediated CUL4A loss generates an Achilles heel in CRC cancer cells enabling effective cisplatin treatment. Hence, inclusion of trabectedin in cisplatin-containing cancer treatment regimens might cause profound synergism based on reciprocal resistance prevention. PMID- 28095395 TI - The burden of occupationally-related cutaneous malignant melanoma in Britain due to solar radiation. AB - BACKGROUND: Increasing evidence highlights the association of occupational exposure and cutaneous malignant melanoma (CMM). We estimated the burden of CMM and total skin cancer burden in Britain due to occupational solar radiation exposure. METHODS: Attributable fractions (AF) and numbers were estimated for CMM mortality and incidence using risk estimates from the published literature and national data sources for proportions exposed. We extended existing methods to account for the exposed population age structure. RESULTS: The estimated total AF for CMM is 2.0% (95% CI: 1.4-2.7%), giving 48 (95% CI: 33-64) deaths in (2012) and 241 (95% CI: 168-325) registrations (in 2011) attributable to occupational exposure to solar radiation. Higher exposure and larger numbers exposed led to much higher numbers for men than women. Industries of concern are construction, agriculture, public administration and defence, and land transport. CONCLUSIONS: These results emphasise the urgent need to develop appropriate strategies to reduce this burden. PMID- 28095396 TI - Tenascin-C and fibronectin expression divide early stage tongue cancer into low- and high-risk groups. AB - BACKGROUND: Oral tongue squamous cell carcinoma (OTSCC) metastasises early, especially to regional lymph nodes. There is an ongoing debate on which early stage (T1-T2N0) patients should be treated with elective neck dissection. We need prognosticators for early stage tongue cancer. METHODS: Mice immunisation with human mesenchymal stromal cells resulted in production of antibodies against tenascin-C (TNC) and fibronectin (FN), which were used to stain 178 (98 early stage), oral tongue squamous cell carcinoma samples. Tenascin-C and FN expression in the stroma (negative, moderate or abundant) and tumour cells (negative or positive) were assessed. Similar staining was obtained using corresponding commercial antibodies. RESULTS: Expression of TNC and FN in the stroma, but not in the tumour cells, proved to be excellent prognosticators both in all stages and in early stage cases. Among early stages, when stromal TNC was negative, the 5-year survival rate was 88%. Correspondingly, when FN was negative, no cancer deaths were observed. Five-year survival rates for abundant expression of TNC and FN were 43% and 25%, respectively. CONCLUSIONS: Stromal TNC and, especially, FN expressions differentiate patients into low- and high-risk groups. Surgery alone of early stage primary tumours might be adequate when stromal FN is negative. Aggressive treatments should be considered when both TNC and FN are abundant. PMID- 28095397 TI - A randomised phase II trial and feasibility study of palliative chemotherapy in frail or elderly patients with advanced gastroesophageal cancer (321GO). AB - BACKGROUND: Elderly patients are commonly under-represented in cancer clinical trials. The 321GO was undertaken in preparation for a definitive phase three trial assessing different chemotherapy regimens in a frail and/or elderly population with advanced gastroesophageal (GO) cancer. METHODS: Patients with advanced GO cancer considered unfit for conventional dose chemotherapy were randomly assigned in a 1 : 1 : 1 ratio to: epirubicin, oxaliplatin and capecitabine (EOX); oxaliplatin and capecitabine (OX); and capecitabine alone (X) (all 80% of full dose and unblinded). The primary end point was patient recruitment over an 18-month period. A registration study recorded treatment choice for all patients with advanced GO cancer at trial centres. RESULTS: A total of 313 patients were considered for palliative chemotherapy for GO cancer over the 18-month period: 115 received full dose treatment, 89 less than standard treatment or entered 321GO and 111 no treatment. Within 321GO, 55 patients were randomly assigned (19 to OX and X; 17 to EOX). Progression-free survival (PFS) for all patients was 4.4 months and by arm 5.4, 5.6 and 3.0 months for EOX, OX and X, respectively. The number of patients with a good overall treatment utility (OTU), a novel patient-centred endpoint, at 12 weeks was 3 (18%), 6 (32%) and 1 (6%) for EOX, OX and X, respectively. At 6 weeks, 22 patients (41%) had experienced a non-haematologic toxicity ?grade 3, most commonly lethargy or diarrhoea. The OTU was prognostic for overall survival in patients alive at week 12 (logrank test P=0.0001). CONCLUSIONS: It is feasible to recruit elderly and/or frail patients with advanced GO cancer to a randomised clinical trial. The OX is the preferred regimen for further study. Overall treatment utility shows promise as a comparator between treatment regimens for feasibility and randomised trials in the elderly and/or frail GO cancer population. PMID- 28095398 TI - Aurora B expression modulates paclitaxel response in non-small cell lung cancer. AB - BACKGROUND: Taxanes are mitotic poisons widely used in the treatment of non-small cell lung cancer (NSCLC), however, little is known about potential molecular modulators of response to these compounds. Aurora B (AURKB) is a critical regulator of the mitotic spindle assembly, previously shown overexpressed in NSCLC. Here we investigated the hypothesis that AURKB expression modulates the efficacy of taxanes in NSCLC cells. METHODS: AURKB mRNA expression was determined by qPCR in 132 frozen NSCLC tissues and nine NSCLC cell lines. Aurora B expression was knocked down in cell lines using multiple shRNA constructs. Barasertib was used to specifically inhibit AURKB activity, determined by the level of H3S10 phosphorylation. RESULTS: Frequent AURKB mRNA upregulation was observed in NSCLC tissues (P<0.0001), being more prominent in squamous carcinomas (P<0.0001). Aurora B expression in cell lines strongly correlated with sensitivity to both docetaxel (P=0.004) and paclitaxel (P=0.007). Aurora B knockdown derivatives consistently showed a dose-dependent association between low-AURKB expression and resistance to paclitaxel. Specific chemical inhibition of Aurora B activity also demonstrated a strong dose-dependent efficiency in triggering paclitaxel resistance. CONCLUSIONS: Aurora B activity is an important modulator of taxane response in NSCLC cells. This may lead to further insights into taxane sensitivity of NSCLC tumours. PMID- 28095399 TI - Evaluation of treatment-related mortality among paediatric cancer deaths: a population based analysis. AB - BACKGROUND: Objectives were to describe the proportion of deaths due to treatment related mortality (TRM) and to identify risk factors and probable causes of TRM among paediatric cancer deaths in a population-based cohort. METHODS: We included children with cancer ?18 years diagnosed and treated in Ontario who died between January 2003 and December 2012. Deaths were identified using a provincial registry, the Pediatric Oncology Group of Ontario Networked Information System. Probable causes of TRM were described. RESULTS: Among the 964 deaths identified, 821 were included. The median age at diagnosis was 6.6 years (range 0-18.8) and 51.8% had at least one relapse. Of the deaths examined, TRM occurred in 217/821 (26.4%) while 604/821 (73.6%) were due to progressive cancer. Deaths from TRM did not change over time. Using multiple regression, younger age, leukaemia diagnosis and absence of relapse were independently positively associated with TRM. The most common probable causes of TRM were respiratory, infection and haemorrhage. CONCLUSIONS: TRM was responsible for 26.4% of deaths in paediatric cancer. Underlying diagnosis, younger age and absence of relapse were associated with TRM and causes of TRM differed by diagnosis group. Future work should evaluate TRM rate and risk factors among newly diagnosed cancer patients. PMID- 28095400 TI - Computational Analysis of Residue Interaction Networks and Coevolutionary Relationships in the Hsp70 Chaperones: A Community-Hopping Model of Allosteric Regulation and Communication. AB - Allosteric interactions in the Hsp70 proteins are linked with their regulatory mechanisms and cellular functions. Despite significant progress in structural and functional characterization of the Hsp70 proteins fundamental questions concerning modularity of the allosteric interaction networks and hierarchy of signaling pathways in the Hsp70 chaperones remained largely unexplored and poorly understood. In this work, we proposed an integrated computational strategy that combined atomistic and coarse-grained simulations with coevolutionary analysis and network modeling of the residue interactions. A novel aspect of this work is the incorporation of dynamic residue correlations and coevolutionary residue dependencies in the construction of allosteric interaction networks and signaling pathways. We found that functional sites involved in allosteric regulation of Hsp70 may be characterized by structural stability, proximity to global hinge centers and local structural environment that is enriched by highly coevolving flexible residues. These specific characteristics may be necessary for regulation of allosteric structural transitions and could distinguish regulatory sites from nonfunctional conserved residues. The observed confluence of dynamics correlations and coevolutionary residue couplings with global networking features may determine modular organization of allosteric interactions and dictate localization of key mediating sites. Community analysis of the residue interaction networks revealed that concerted rearrangements of local interacting modules at the inter-domain interface may be responsible for global structural changes and a population shift in the DnaK chaperone. The inter-domain communities in the Hsp70 structures harbor the majority of regulatory residues involved in allosteric signaling, suggesting that these sites could be integral to the network organization and coordination of structural changes. Using a network-based formalism of allostery, we introduced a community-hopping model of allosteric communication. Atomistic reconstruction of signaling pathways in the DnaK structures captured a direction-specific mechanism and molecular details of signal transmission that are fully consistent with the mutagenesis experiments. The results of our study reconciled structural and functional experiments from a network-centric perspective by showing that global properties of the residue interaction networks and coevolutionary signatures may be linked with specificity and diversity of allosteric regulation mechanisms. PMID- 28095401 TI - The Nuclear Receptor HIZR-1 Uses Zinc as a Ligand to Mediate Homeostasis in Response to High Zinc. AB - Nuclear receptors were originally defined as endocrine sensors in humans, leading to the identification of the nuclear receptor superfamily. Despite intensive efforts, most nuclear receptors have no known ligand, suggesting new ligand classes remain to be discovered. Furthermore, nuclear receptors are encoded in the genomes of primitive organisms that lack endocrine signaling, suggesting the primordial function may have been environmental sensing. Here we describe a novel Caenorhabditis elegans nuclear receptor, HIZR-1, that is a high zinc sensor in an animal and the master regulator of high zinc homeostasis. The essential micronutrient zinc acts as a HIZR-1 ligand, and activated HIZR-1 increases transcription of genes that promote zinc efflux and storage. The results identify zinc as the first inorganic molecule to function as a physiological ligand for a nuclear receptor and direct environmental sensing as a novel function of nuclear receptors. PMID- 28095402 TI - A General Shear-Dependent Model for Thrombus Formation. AB - Modeling the transport, activation, and adhesion of platelets is crucial in predicting thrombus formation and growth following a thrombotic event in normal or pathological conditions. We propose a shear-dependent platelet adhesive model based on the Morse potential that is calibrated by existing in vivo and in vitro experimental data and can be used over a wide range of flow shear rates ([Formula: see text]). We introduce an Eulerian-Lagrangian model where hemodynamics is solved on a fixed Eulerian grid, while platelets are tracked using a Lagrangian framework. A force coupling method is introduced for bidirectional coupling of platelet motion with blood flow. Further, we couple the calibrated platelet aggregation model with a tissue-factor/contact pathway coagulation cascade, representing the relevant biology of thrombin generation and the subsequent fibrin deposition. The range of shear rates covered by the proposed model encompass venous and arterial thrombosis, ranging from low-shear rate conditions in abdominal aortic aneurysms and thoracic aortic dissections to thrombosis in stenotic arteries following plaque rupture, where local shear rates are extremely high. PMID- 28095403 TI - A Likelihood Approach for Real-Time Calibration of Stochastic Compartmental Epidemic Models. AB - Stochastic transmission dynamic models are especially useful for studying the early emergence of novel pathogens given the importance of chance events when the number of infectious individuals is small. However, methods for parameter estimation and prediction for these types of stochastic models remain limited. In this manuscript, we describe a calibration and prediction framework for stochastic compartmental transmission models of epidemics. The proposed method, Multiple Shooting for Stochastic systems (MSS), applies a linear noise approximation to describe the size of the fluctuations, and uses each new surveillance observation to update the belief about the true epidemic state. Using simulated outbreaks of a novel viral pathogen, we evaluate the accuracy of MSS for real-time parameter estimation and prediction during epidemics. We assume that weekly counts for the number of new diagnosed cases are available and serve as an imperfect proxy of incidence. We show that MSS produces accurate estimates of key epidemic parameters (i.e. mean duration of infectiousness, R0, and Reff) and can provide an accurate estimate of the unobserved number of infectious individuals during the course of an epidemic. MSS also allows for accurate prediction of the number and timing of future hospitalizations and the overall attack rate. We compare the performance of MSS to three state-of-the-art benchmark methods: 1) a likelihood approximation with an assumption of independent Poisson observations; 2) a particle filtering method; and 3) an ensemble Kalman filter method. We find that MSS significantly outperforms each of these three benchmark methods in the majority of epidemic scenarios tested. In summary, MSS is a promising method that may improve on current approaches for calibration and prediction using stochastic models of epidemics. PMID- 28095404 TI - Entropy Transfer between Residue Pairs and Allostery in Proteins: Quantifying Allosteric Communication in Ubiquitin. AB - It has recently been proposed by Gunasakaran et al. that allostery may be an intrinsic property of all proteins. Here, we develop a computational method that can determine and quantify allosteric activity in any given protein. Based on Schreiber's transfer entropy formulation, our approach leads to an information transfer landscape for the protein that shows the presence of entropy sinks and sources and explains how pairs of residues communicate with each other using entropy transfer. The model can identify the residues that drive the fluctuations of others. We apply the model to Ubiquitin, whose allosteric activity has not been emphasized until recently, and show that there are indeed systematic pathways of entropy and information transfer between residues that correlate well with the activities of the protein. We use 600 nanosecond molecular dynamics trajectories for Ubiquitin and its complex with human polymerase iota and evaluate entropy transfer between all pairs of residues of Ubiquitin and quantify the binding susceptibility changes upon complex formation. We explain the complex formation propensities of Ubiquitin in terms of entropy transfer. Important residues taking part in allosteric communication in Ubiquitin predicted by our approach are in agreement with results of NMR relaxation dispersion experiments. Finally, we show that time delayed correlation of fluctuations of two interacting residues possesses an intrinsic causality that tells which residue controls the interaction and which one is controlled. Our work shows that time delayed correlations, entropy transfer and causality are the required new concepts for explaining allosteric communication in proteins. PMID- 28095405 TI - Defining the Risk of Zika and Chikungunya Virus Transmission in Human Population Centers of the Eastern United States. AB - The recent spread of mosquito-transmitted viruses and associated disease to the Americas motivates a new, data-driven evaluation of risk in temperate population centers. Temperate regions are generally expected to pose low risk for significant mosquito-borne disease; however, the spread of the Asian tiger mosquito (Aedes albopictus) across densely populated urban areas has established a new landscape of risk. We use a model informed by field data to assess the conditions likely to facilitate local transmission of chikungunya and Zika viruses from an infected traveler to Ae. albopictus and then to other humans in USA cities with variable human densities and seasonality. Mosquito-borne disease occurs when specific combinations of conditions maximize virus-to-mosquito and mosquito-to-human contact rates. We develop a mathematical model that captures the epidemiology and is informed by current data on vector ecology from urban sites. The model demonstrates that under specific but realistic conditions, fifty percent of introductions by infectious travelers to a high human, high mosquito density city could initiate local transmission and 10% of the introductions could result in 100 or more people infected. Despite the propensity for Ae. albopictus to bite non-human vertebrates, we also demonstrate that local virus transmission and human outbreaks may occur when vectors feed from humans even just 40% of the time. Inclusion of human behavioral changes and mitigations were not incorporated into the models and would likely reduce predicted infections. This work demonstrates how a conditional series of non-average events can result in local arbovirus transmission and outbreaks of human disease, even in temperate cities. PMID- 28095406 TI - A Two-Locus Model of the Evolution of Insecticide Resistance to Inform and Optimise Public Health Insecticide Deployment Strategies. AB - We develop a flexible, two-locus model for the spread of insecticide resistance applicable to mosquito species that transmit human diseases such as malaria. The model allows differential exposure of males and females, allows them to encounter high or low concentrations of insecticide, and allows selection pressures and dominance values to differ depending on the concentration of insecticide encountered. We demonstrate its application by investigating the relative merits of sequential use of insecticides versus their deployment as a mixture to minimise the spread of resistance. We recover previously published results as subsets of this model and conduct a sensitivity analysis over an extensive parameter space to identify what circumstances favour mixtures over sequences. Both strategies lasted more than 500 mosquito generations (or about 40 years) in 24% of runs, while in those runs where resistance had spread to high levels by 500 generations, 56% favoured sequential use and 44% favoured mixtures. Mixtures are favoured when insecticide effectiveness (their ability to kill homozygous susceptible mosquitoes) is high and exposure (the proportion of mosquitoes that encounter the insecticide) is low. If insecticides do not reliably kill homozygous sensitive genotypes, it is likely that sequential deployment will be a more robust strategy. Resistance to an insecticide always spreads slower if that insecticide is used in a mixture although this may be insufficient to outperform sequential use: for example, a mixture may last 5 years while the two insecticides deployed individually may last 3 and 4 years giving an overall 'lifespan' of 7 years for sequential use. We emphasise that this paper is primarily about designing and implementing a flexible modelling strategy to investigate the spread of insecticide resistance in vector populations and demonstrate how our model can identify vector control strategies most likely to minimise the spread of insecticide resistance. PMID- 28095408 TI - Patient Safety Incidents Involving Sick Children in Primary Care in England and Wales: A Mixed Methods Analysis. AB - BACKGROUND: The UK performs poorly relative to other economically developed countries on numerous indicators of care quality for children. The contribution of iatrogenic harm to these outcomes is unclear. As primary care is the first point of healthcare contact for most children, we sought to investigate the safety of care provided to children in this setting. METHODS AND FINDINGS: We undertook a mixed methods investigation of reports of primary care patient safety incidents involving sick children from England and Wales' National Reporting and Learning System between 1 January 2005 and 1 December 2013. Two reviewers independently selected relevant incident reports meeting prespecified criteria, and then descriptively analyzed these reports to identify the most frequent and harmful incident types. This was followed by an in-depth thematic analysis of a purposive sample of reports to understand the reasons underpinning incidents. Key candidate areas for strengthening primary care provision and reducing the risks of systems failures were then identified through multidisciplinary discussions. Of 2,191 safety incidents identified from 2,178 reports, 30% (n = 658) were harmful, including 12 deaths and 41 cases of severe harm. The children involved in these incidents had respiratory conditions (n = 387; 18%), injuries (n = 289; 13%), nonspecific signs and symptoms, e.g., fever (n = 281; 13%), and gastrointestinal or genitourinary conditions (n = 268; 12%), among others. Priority areas for improvement included safer systems for medication provision in community pharmacies; triage processes to enable effective and timely assessment, diagnosis, and referral of acutely sick children attending out-of-hours services; and enhanced communication for robust safety netting between professionals and parents. The main limitations of this study result from underreporting of safety incidents and variable data quality. Our findings therefore require further exploration in longitudinal studies utilizing case review methods. CONCLUSIONS: This study highlights opportunities to reduce iatrogenic harm and avoidable child deaths. Globally, healthcare systems with primary-care-led models of delivery must now examine their existing practices to determine the prevalence and burden of these priority safety issues, and utilize improvement methods to achieve sustainable improvements in care quality. PMID- 28095409 TI - Sick Children Crying for Help: Fostering Adverse Event Reports. AB - In a Perspective, Gordon Schiff discusses the importance of appropriately analyzing adverse event reports. PMID- 28095407 TI - A Novel Imprinted Gene NUWA Controls Mitochondrial Function in Early Seed Development in Arabidopsis. AB - Imprinted genes display biased expression of paternal and maternal alleles and are only found in mammals and flowering plants. Compared to several hundred imprinted genes that are functionally characterized in mammals, very few imprinted genes were confirmed in plants and even fewer of them have been functionally investigated. Here, we report a new imprinted gene, NUWA, in plants. NUWA is an essential gene, because loss of its function resulted in reduced transmission through the female gametophyte and defective cell/nuclear proliferation in early Arabidopsis embryo and endosperm. NUWA is a maternally expressed imprinted gene, as only the maternal allele of NUWA is transcribed and translated from gametogenesis to the 16-cell globular embryo stage after fertilization, and the de novo transcription of the maternal allele of NUWA starts from the zygote stage. Different from other identified plant imprinted genes whose encoded proteins are mostly localized to the nucleus, the NUWA protein was localized to the mitochondria and was essential for mitochondria function. Our work uncovers a novel imprinted gene of a previously unidentified type, namely, a maternal-specific expressed nuclear gene with its encoded protein localizing to and controlling the function of the maternally inherited mitochondria. This reveals a unique mechanism of maternal control of the mitochondria and adds an extra layer of complexity to the regulation of nucleus organelle coordination during early plant development. PMID- 28095410 TI - Cardiomyocyte Regulation of Systemic Lipid Metabolism by the Apolipoprotein B Containing Lipoproteins in Drosophila. AB - The heart has emerged as an important organ in the regulation of systemic lipid homeostasis; however, the underlying mechanism remains poorly understood. Here, we show that Drosophila cardiomyocytes regulate systemic lipid metabolism by producing apolipoprotein B-containing lipoproteins (apoB-lipoproteins), essential lipid carriers that are so far known to be generated only in the fat body. In a Drosophila genetic screen, we discovered that when haplo-insufficient, microsomal triglyceride transfer protein (mtp), required for the biosynthesis of apoB lipoproteins, suppressed the development of diet-induced obesity. Tissue-specific inhibition of Mtp revealed that whereas knockdown of mtp only in the fat body decreases systemic triglyceride (TG) content on normal food diet (NFD) as expected, knockdown of mtp only in the cardiomyocytes also equally decreases systemic TG content on NFD, suggesting that the cardiomyocyte- and fat body derived apoB-lipoproteins serve similarly important roles in regulating whole body lipid metabolism. Unexpectedly, on high fat diet (HFD), knockdown of mtp in the cardiomyocytes, but not in fat body, protects against the gain in systemic TG levels. We further showed that inhibition of the Drosophila apoB homologue, apolipophorin or apoLpp, another gene essential for apoB-lipoprotein biosynthesis, affects systemic TG levels similarly to that of Mtp inhibition in the cardiomyocytes on NFD or HFD. Finally, we determined that HFD differentially alters Mtp and apoLpp expression in the cardiomyocytes versus the fat body, culminating in higher Mtp and apoLpp levels in the cardiomyocytes than in fat body and possibly underlying the predominant role of cardiomyocyte-derived apoB lipoproteins in lipid metabolic regulation. Our findings reveal a novel and significant function of heart-mediated apoB-lipoproteins in controlling lipid homeostasis. PMID- 28095411 TI - Optimal Management Strategies for Primary HPV Testing for Cervical Screening: Cost-Effectiveness Evaluation for the National Cervical Screening Program in Australia. AB - BACKGROUND: Several countries are implementing a transition to HPV testing for cervical screening in response to the introduction of HPV vaccination and evidence indicating that HPV screening is more effective than cytology. In Australia, a 2017 transition from 2-yearly conventional cytology in 18-20 to 69 years to 5-yearly primary HPV screening in 25 to 74 years will involve partial genotyping for HPV 16/18 with direct referral to colposcopy for this higher risk group. The objective of this study was to determine the optimal management of women positive for other high-risk HPV types (not 16/18) ('OHR HPV'). METHODS: We used a dynamic model of HPV transmission, vaccination, natural history and cervical screening to determine the optimal management of women positive for OHR HPV. We assumed cytology triage testing was used to inform management in this group and that those with high-grade cytology would be referred to colposcopy and those with negative cytology would receive 12-month surveillance. For those with OHR HPV and low-grade cytology (considered to be a single low-grade category in Australia incorporating ASC-US and LSIL), we evaluated (1) the 20-year risk of invasive cervical cancer assuming this group are referred for 12-month follow-up vs. colposcopy, and compared this to the risk in women with low-grade cytology under the current program (i.e. an accepted benchmark risk for 12-month follow-up in Australia); (2) the population-level impact of the whole program, assuming this group are referred to 12-month surveillance vs. colposcopy; and (3) the cost effectiveness of immediate colposcopy compared to 12-month follow-up. Evaluation was performed both for HPV-unvaccinated cohorts and cohorts offered vaccination (coverage ~72%). FINDINGS: The estimated 20-year risk of cervical cancer is <=1.0% at all ages if this group are referred to colposcopy vs. <=1.2% if followed-up in 12 months, both of which are lower than the <=2.6% benchmark risk in women with low-grade cytology in the current program (who are returned for 12 month follow-up). At the population level, immediate colposcopy referral provides an incremental 1-3% reduction in cervical cancer incidence and mortality compared with 12-month follow-up, but this is in the context of a predicted 24-36% reduction associated with the new HPV screening program compared to the current cytology-based program. Furthermore, immediate colposcopy substantially increases the predicted number of colposcopies, with >650 additional colposcopies required to avert each additional case of cervical cancer compared to 12-month follow-up. Compared to 12-month follow-up, immediate colposcopy has an incremental cost effectiveness ratio (ICER) of A$104,600/LYS (95%CrI:A$100,100-109,100) in unvaccinated women and A$117,100/LYS (95%CrI:A$112,300-122,000) in cohorts offered vaccination [Indicative willingness-to-pay threshold: A$50,000/LYS]. CONCLUSIONS: In primary HPV screening programs, partial genotyping for HPV16/18 or high-grade triage cytology in OHR HPV positive women can be used to refer the highest risk group to colposcopy, but 12-month follow-up for women with OHR HPV and low-grade cytology is associated with a low risk of developing cervical cancer. Direct referral to colposcopy for this group would be associated with a substantial increase in colposcopy referrals and the associated harms, and is also cost-ineffective; thus, 12-month surveillance for women with OHR HPV and low grade cytology provides the best balance between benefits, harms and cost effectiveness. PMID- 28095412 TI - Intensive versus Guideline Blood Pressure and Lipid Lowering in Patients with Previous Stroke: Main Results from the Pilot 'Prevention of Decline in Cognition after Stroke Trial' (PODCAST) Randomised Controlled Trial. AB - BACKGROUND: Stroke is associated with the development of cognitive impairment and dementia. We assessed the effect of intensive blood pressure (BP) and/or lipid lowering on cognitive outcomes in patients with recent stroke in a pilot trial. METHODS: In a multicentre, partial-factorial trial, patients with recent stroke, absence of dementia, and systolic BP (SBP) 125-170 mmHg were assigned randomly to at least 6 months of intensive (target SBP <125 mmHg) or guideline (target SBP <140 mmHg) BP lowering. The subset of patients with ischaemic stroke and total cholesterol 3.0-8.0 mmol/l were also assigned randomly to intensive (target LDL cholesterol <1.3 mmol/l) or guideline (target LDL-c <3.0 mmol/l) lipid lowering. The primary outcome was the Addenbrooke's Cognitive Examination-Revised (ACE-R). RESULTS: We enrolled 83 patients, mean age 74.0 (6.8) years, and median 4.5 months after stroke. The median follow-up was 24 months (range 1-48). Mean BP was significantly reduced with intensive compared to guideline treatment (difference 10.6/-5.5 mmHg; p<0.01), as was total/LDL-cholesterol with intensive lipid lowering compared to guideline (difference -0.54/-0.44 mmol/l; p<0.01). The ACE-R score during treatment did not differ for either treatment comparison; mean difference for BP lowering -3.6 (95% CI -9.7 to 2.4), and lipid lowering 4.4 (95% CI -2.1 to 10.9). However, intensive lipid lowering therapy was significantly associated with improved scores for ACE-R at 6 months, trail making A, modified Rankin Scale and Euro-Qol Visual Analogue Scale. There was no difference in rates of dementia or serious adverse events for either comparison. CONCLUSION: In patients with recent stroke and normal cognition, intensive BP and lipid lowering were feasible and safe, but did not alter cognition over two years. The association between intensive lipid lowering and improved scores for some secondary outcomes suggests further trials are warranted. TRIAL REGISTRATION: ISRCTN ISRCTN85562386. PMID- 28095413 TI - One-Month Global Longitudinal Strain Identifies Patients Who Will Develop Pacing Induced Left Ventricular Dysfunction over Time: The Pacing and Ventricular Dysfunction (PAVD) Study. AB - BACKGROUND: Predicting which individuals will have a decline in left ventricular (LV) function after pacemaker implantation remains an important challenge. We investigated whether LV global longitudinal strain (GLS), measured by 2D speckle tracking strain echocardiography, can identify patients at risk of pacing-induced left ventricular dysfunction (PIVD) or pacing-induced cardiomyopathy (PICMP). METHODS: Fifty-five patients with atrioventricular block and preserved LV function underwent dual-chamber pacemaker implantation and were followed with serial transthoracic echocardiography for 12 months for the development of PIVD (defined as a reduction in LV ejection fraction (LVEF) >=5 percentage points at 12 months) or PICMP (reduction in LVEF to <45%). RESULTS: At 12 months, 15 (27%) patients developed PIVD; of these, 4 patients developed PICMP. At one month, GLS was significantly lower in the 15 patients who subsequently developed PIVD, compared to those who did not (n = 40) (GLS -12.6 vs. -16.4 respectively; p = 0.022). When patients with PICMP were excluded, one month GLS was significantly reduced compared to baseline whereas LVEF was not. One-month GLS had high predictive accuracy for determining subsequent development of PIVD or PICMP (AUC = 0.80, optimal GLS threshold: <-14.5, sensitivity 82%, specificity 75%); and particularly PICMP (AUC = 0.86, optimal GLS threshold: <-13.5, sensitivity 100%, specificity 71%). CONCLUSIONS: GLS is a novel predictor of decline in LV systolic function following pacemaker implantation, with the potential to identify patients at risk of PIVD before measurable changes in LVEF are apparent. GLS measured one month after implantation has high predictive accuracy for identifying patients who later develop PIVD or PICMP. PMID- 28095414 TI - Mosquito-Disseminated Insecticide for Citywide Vector Control and Its Potential to Block Arbovirus Epidemics: Entomological Observations and Modeling Results from Amazonian Brazil. AB - BACKGROUND: Mosquito-borne viruses threaten public health worldwide. When the ratio of competent vectors to susceptible humans is low enough, the virus's basic reproductive number (R0) falls below 1.0 (each case generating, on average, <1.0 additional case) and the infection fades out from the population. Conventional mosquito control tactics, however, seldom yield R0 < 1.0. A promising alternative uses mosquitoes to disseminate a potent growth-regulator larvicide, pyriproxyfen (PPF), to aquatic larval habitats; this kills most mosquito juveniles and substantially reduces adult mosquito emergence. We tested mosquito-disseminated PPF in Manacapuru, a 60,000-inhabitant city (~650 ha) in Amazonian Brazil. METHODS AND FINDINGS: We sampled juvenile mosquitoes monthly in 100 dwellings over four periods in February 2014-January 2016: 12 baseline months, 5 mo of citywide PPF dissemination, 3 mo of focal PPF dissemination around Aedes-infested dwellings, and 3 mo after dissemination ended. We caught 19,434 juvenile mosquitoes (66% Aedes albopictus, 28% Ae. aegypti) in 8,271 trap-months. Using generalized linear mixed models, we estimated intervention effects on juvenile catch and adult emergence while adjusting for dwelling-level clustering, unequal sampling effort, and weather-related confounders. Following PPF dissemination, Aedes juvenile catch decreased by 79%-92% and juvenile mortality increased from 2%-7% to 80%-90%. Mean adult Aedes emergence fell from 1,077 per month (range 653 1,635) at baseline to 50.4 per month during PPF dissemination (range 2-117). Female Aedes emergence dropped by 96%-98%, such that the number of females emerging per person decreased to 0.06 females per person-month (range 0.002 0.129). Deterministic models predict, under plausible biological-epidemiological scenarios, that the R0 of typical Aedes-borne viruses would fall from 3-45 at baseline to 0.004-0.06 during PPF dissemination. The main limitations of our study were that it was a before-after trial lacking truly independent replicates and that we did not measure mosquito-borne virus transmission empirically. CONCLUSIONS: Mosquito-disseminated PPF has potential to block mosquito-borne virus transmission citywide, even under adverse scenarios. Our results signal new avenues for mosquito-borne disease prevention, likely including the effective control of Aedes-borne dengue, Zika, and chikungunya epidemics. Cluster randomized controlled trials will help determine whether mosquito-disseminated PPF can, as our findings suggest, develop into a major tool for improving global public health. PMID- 28095415 TI - KLK5 and KLK7 Ablation Fully Rescues Lethality of Netherton Syndrome-Like Phenotype. AB - Netherton syndrome (NS) is a severe skin disease caused by the loss of protease inhibitor LEKTI, which leads to the dysregulation of epidermal proteases and severe skin-barrier defects. KLK5 was proposed as a major protease in NS pathology, however its inactivation is not sufficient to rescue the lethal phenotype of LEKTI-deficient mice. In this study, we further elucidated the in vivo roles of the epidermal proteases in NS using a set of mouse models individually or simultaneously deficient for KLK5 and KLK7 on the genetic background of a novel NS-mouse model. We show that although the ablation of KLK5 or KLK7 is not sufficient to rescue the lethal effect of LEKTI-deficiency simultaneous deficiency of both KLKs completely rescues the epidermal barrier and the postnatal lethality allowing mice to reach adulthood with fully functional skin and normal hair growth. We report that not only KLK5 but also KLK7 plays an important role in the inflammation and defective differentiation in NS and KLK7 activity is not solely dependent on activation by KLK5. Altogether, these findings show that unregulated activities of KLK5 and KLK7 are responsible for NS development and both proteases should become targets for NS therapy. PMID- 28095416 TI - Meta-GWAS Accuracy and Power (MetaGAP) Calculator Shows that Hiding Heritability Is Partially Due to Imperfect Genetic Correlations across Studies. AB - Large-scale genome-wide association results are typically obtained from a fixed effects meta-analysis of GWAS summary statistics from multiple studies spanning different regions and/or time periods. This approach averages the estimated effects of genetic variants across studies. In case genetic effects are heterogeneous across studies, the statistical power of a GWAS and the predictive accuracy of polygenic scores are attenuated, contributing to the so-called 'missing heritability'. Here, we describe the online Meta-GWAS Accuracy and Power (MetaGAP) calculator (available at www.devlaming.eu) which quantifies this attenuation based on a novel multi-study framework. By means of simulation studies, we show that under a wide range of genetic architectures, the statistical power and predictive accuracy provided by this calculator are accurate. We compare the predictions from the MetaGAP calculator with actual results obtained in the GWAS literature. Specifically, we use genomic-relatedness matrix restricted maximum likelihood to estimate the SNP heritability and cross study genetic correlation of height, BMI, years of education, and self-rated health in three large samples. These estimates are used as input parameters for the MetaGAP calculator. Results from the calculator suggest that cross-study heterogeneity has led to attenuation of statistical power and predictive accuracy in recent large-scale GWAS efforts on these traits (e.g., for years of education, we estimate a relative loss of 51-62% in the number of genome-wide significant loci and a relative loss in polygenic score R2 of 36-38%). Hence, cross-study heterogeneity contributes to the missing heritability. PMID- 28095417 TI - Schistosoma mansoni Infection of Mice, Rats and Humans Elicits a Strong Antibody Response to a Limited Number of Reduction-Sensitive Epitopes on Five Major Tegumental Membrane Proteins. AB - Schistosomiasis is a major disease of the developing world for which no vaccine has been successfully commercialized. While numerous Schistosoma mansoni worm antigens have been identified that elicit antibody responses during natural infections, little is known as to the identities of the schistosome antigens that are most prominently recognized by antibodies generated through natural infection. Non-reducing western blots probed with serum from schistosome-infected mice, rats and humans on total extracts of larval or adult schistosomes revealed that a small number of antigen bands predominate in all cases. Recognition of each of these major bands was lost when the blots were run under reducing condition. We expressed a rationally selected group of schistosome tegumental membrane antigens in insect host cells, and used the membrane extracts of these cells to unambiguously identify the major antigens recognized by S. mansoni infected mouse, rat and human serum. These results revealed that a limited number of dominant, reduction-sensitive conformational epitopes on five major tegumental surface membrane proteins: SmTsp2, Sm23, Sm29, SmLy6B and SmLy6F, are primary targets of mouse, rat and human S. mansoni infection sera antibodies. We conclude that, Schistosoma mansoni infection of both permissive (mouse) and non-permissive (rat) rodent models, as well as humans, elicit a dominant antibody response recognizing a limited number of conformational epitopes on the same five tegumental membrane proteins. Thus it appears that neither infecting schistosomula nor mature adult schistosomes are substantively impacted by the robust circulating anti-tegumental antibody response they elicit to these antigens. Importantly, our data suggest a need to re-evaluate host immune responses to many schistosome antigens and has important implications regarding schistosome immune evasion mechanisms and schistosomiasis vaccine development. PMID- 28095418 TI - Novel Vector Control Approaches: The Future for Prevention of Zika Virus Transmission? AB - In a Perspective accompanying Abad-Franch and colleagues, Lorenz von Seidlein, Alexander Kekule, and Daniel Strickman discuss the importance of developing effective strategies to minimize mosquito-borne transmission of human diseases. PMID- 28095419 TI - PRC2 Represses Hormone-Induced Somatic Embryogenesis in Vegetative Tissue of Arabidopsis thaliana. AB - Many plant cells can be reprogrammed into a pluripotent state that allows ectopic organ development. Inducing totipotent states to stimulate somatic embryo (SE) development is, however, challenging due to insufficient understanding of molecular barriers that prevent somatic cell dedifferentiation. Here we show that Polycomb repressive complex 2 (PRC2)-activity imposes a barrier to hormone mediated transcriptional reprogramming towards somatic embryogenesis in vegetative tissue of Arabidopsis thaliana. We identify factors that enable SE development in PRC2-depleted shoot and root tissue and demonstrate that the establishment of embryogenic potential is marked by ectopic co-activation of crucial developmental regulators that specify shoot, root and embryo identity. Using inducible activation of PRC2 in PRC2-depleted cells, we demonstrate that transient reduction of PRC2 activity is sufficient for SE formation. We suggest that modulation of PRC2 activity in plant vegetative tissue combined with targeted activation of developmental pathways will open possibilities for novel approaches to cell reprogramming. PMID- 28095420 TI - Molecular Mechanism of Disease-Associated Mutations in the Pre-M1 Helix of NMDA Receptors and Potential Rescue Pharmacology. AB - N-methyl-D-aspartate receptors (NMDARs), ligand-gated ionotropic glutamate receptors, play key roles in normal brain development and various neurological disorders. Here we use standing variation data from the human population to assess which protein domains within NMDAR GluN1, GluN2A and GluN2B subunits show the strongest signal for being depleted of missense variants. We find that this includes the GluN2 pre-M1 helix and linker between the agonist-binding domain (ABD) and first transmembrane domain (M1). We then evaluate the functional changes of multiple missense mutations in the NMDAR pre-M1 helix found in children with epilepsy and developmental delay. We find mutant GluN1/GluN2A receptors exhibit prolonged glutamate response time course for channels containing 1 or 2 GluN2A-P552R subunits, and a slow rise time only for receptors with 2 mutant subunits, suggesting rearrangement of one GluN2A pre-M1 helix is sufficient for rapid activation. GluN2A-P552R and analogous mutations in other GluN subunits increased the agonist potency and slowed response time course, suggesting a functionally conserved role for this residue. Although there is no detectable change in surface expression or open probability for GluN2A-P552R, the prolonged response time course for receptors that contained GluN2A-P552R increased charge transfer for synaptic-like activation, which should promote excitotoxic damage. Transfection of cultured neurons with GluN2A-P552R prolonged EPSPs, and triggered pronounced dendritic swelling in addition to excitotoxicity, which were both attenuated by memantine. These data implicate the pre-M1 region in gating, provide insight into how different subunits contribute to gating, and suggest that mutations in the pre-M1 helix can compromise neuronal health. Evaluation of FDA-approved NMDAR inhibitors on the mutant NMDAR-mediated current response and neuronal damage provides a potential clinical path to treat individuals harboring similar mutations in NMDARs. PMID- 28095421 TI - Approximate Inference for Time-Varying Interactions and Macroscopic Dynamics of Neural Populations. AB - The models in statistical physics such as an Ising model offer a convenient way to characterize stationary activity of neural populations. Such stationary activity of neurons may be expected for recordings from in vitro slices or anesthetized animals. However, modeling activity of cortical circuitries of awake animals has been more challenging because both spike-rates and interactions can change according to sensory stimulation, behavior, or an internal state of the brain. Previous approaches modeling the dynamics of neural interactions suffer from computational cost; therefore, its application was limited to only a dozen neurons. Here by introducing multiple analytic approximation methods to a state space model of neural population activity, we make it possible to estimate dynamic pairwise interactions of up to 60 neurons. More specifically, we applied the pseudolikelihood approximation to the state-space model, and combined it with the Bethe or TAP mean-field approximation to make the sequential Bayesian estimation of the model parameters possible. The large-scale analysis allows us to investigate dynamics of macroscopic properties of neural circuitries underlying stimulus processing and behavior. We show that the model accurately estimates dynamics of network properties such as sparseness, entropy, and heat capacity by simulated data, and demonstrate utilities of these measures by analyzing activity of monkey V4 neurons as well as a simulated balanced network of spiking neurons. PMID- 28095422 TI - High-Throughput Carbon Substrate Profiling of Mycobacterium ulcerans Suggests Potential Environmental Reservoirs. AB - BACKGROUND: Mycobacterium ulcerans is a close derivative of Mycobacterium marinum and the agent of Buruli ulcer in some tropical countries. Epidemiological and environmental studies pointed towards stagnant water ecosystems as potential sources of M. ulcerans, yet the ultimate reservoirs remain elusive. We hypothesized that carbon substrate determination may help elucidating the spectrum of potential reservoirs. METHODOLOGY/PRINCIPAL FINDINGS: In a first step, high-throughput phenotype microarray Biolog was used to profile carbon substrates in one M. marinum and five M. ulcerans strains. A total of 131/190 (69%) carbon substrates were metabolized by at least one M. ulcerans strain, including 28/190 (15%) carbon substrates metabolized by all five M. ulcerans strains of which 21 substrates were also metabolized by M. marinum. In a second step, 131 carbon substrates were investigated, through a bibliographical search, for their known environmental sources including plants, fruits and vegetables, bacteria, algae, fungi, nematodes, mollusks, mammals, insects and the inanimate environment. This analysis yielded significant association of M. ulcerans with bacteria (p = 0.000), fungi (p = 0.001), algae (p = 0.003) and mollusks (p = 0.007). In a third step, the Medline database was cross-searched for bacteria, fungi, mollusks and algae as potential sources of carbon substrates metabolized by all tested M. ulcerans; it indicated that 57% of M. ulcerans substrates were associated with bacteria, 18% with alga, 11% with mollusks and 7% with fungi. CONCLUSIONS: This first report of high-throughput carbon substrate utilization by M. ulcerans would help designing media to isolate and grow this pathogen. Furthermore, the presented data suggest that potential M. ulcerans environmental reservoirs might be related to micro-habitats where bacteria, fungi, algae and mollusks are abundant. This should be followed by targeted investigations in Buruli ulcer endemic regions. PMID- 28095423 TI - Influences of Host Community Characteristics on Borrelia burgdorferi Infection Prevalence in Blacklegged Ticks. AB - Lyme disease is a major vector-borne bacterial disease in the USA. The disease is caused by Borrelia burgdorferi, and transmitted among hosts and humans, primarily by blacklegged ticks (Ixodes scapularis). The ~25 B. burgdorferi genotypes, based on genotypic variation of their outer surface protein C (ospC), can be phenotypically separated as strains that primarily cause human diseases-human invasive strains (HIS)-or those that rarely do. Additionally, the genotypes are non-randomly associated with host species. The goal of this study was to examine the extent to which phenotypic outcomes of B. burgdorferi could be explained by the host communities fed upon by blacklegged ticks. In 2006 and 2009, we determined the host community composition based on abundance estimates of the vertebrate hosts, and collected host-seeking nymphal ticks in 2007 and 2010 to determine the ospC genotypes within infected ticks. We regressed instances of B. burgdorferi phenotypes on site-specific characteristics of host communities by constructing Bayesian hierarchical models that properly handled missing data. The models provided quantitative support for the relevance of host composition on Lyme disease risk pertaining to B. burgdorferi prevalence (i.e. overall nymphal infection prevalence, or NIPAll) and HIS prevalence among the infected ticks (NIPHIS). In each year, NIPAll and NIPHIS was found to be associated with host relative abundances and diversity. For mice and chipmunks, the association with NIPAll was positive, but tended to be negative with NIPHIS in both years. However, the direction of association between shrew relative abundance with NIPAll or NIPHIS differed across the two years. And, diversity (H') had a negative association with NIPAll, but positive association with NIPHIS in both years. Our analyses highlight that the relationships between the relative abundances of three primary hosts and the community diversity with NIPAll, and NIPHIS, are variable in time and space, and that disease risk inference, based on the role of host community, changes when we examine risk overall or at the phenotypic level. Our discussion focuses on the observed relationships between prevalence and host community characteristics and how they substantiate the ecological understanding of phenotypic Lyme disease risk. PMID- 28095424 TI - Investigation of Inclusion Complex of Patchouli Alcohol with beta-Cyclodextrin. AB - The objective of this study was to improve the stability and water-solubility of patchouli alcohol by complexing with beta-cyclodextrin (beta-CD). The interactions between patchouli alcohol and beta-CD were characterized by differential scanning calorimetry (DSC), Fourier transformation-infrared (FT-IR) spectroscopy, powder X-ray diffraction (PXRD), and Scanning electron microscope (SEM), respectively. According to molecular modeling method, the enthalpy formation of host-guest illustrated the predominant configuration and the lowest value DeltabGo was -10.8174+/-1.9235 kcal/mol, suggesting the complex could reduce the energy of the system. The characterization analysis confirmed the formation of PA-CD inclusion complex, and the results indicated the advantage of the inclusion complex in stability and dissolution rates. These results identified PA-CD inclusion complex an effective way for the storage of PA, and better inclusion method still needed to be studied. PMID- 28095425 TI - Relationship between Clinical Parameters and Brain Structure in Sporadic Amyotrophic Lateral Sclerosis Patients According to Onset Type: A Voxel-Based Morphometric Study. AB - BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, phenotypically heterogeneous neurodegenerative disease affecting mainly the motor neuron system. The present voxel-based morphometry (VBM) study investigated whether patterns of brain atrophy differ among sporadic ALS subtypes. MATERIAL AND METHODS: Sporadic ALS patients (n = 62) with normal cognition and age-matched healthy controls (n = 57) were included in the study. ALS patients were divided into limb- and bulbar-onset groups according to clinical manifestations at symptom onset (n = 48 and 14, respectively). Clinical measures were ALS Functional Rating Scale-Revised (ALSFRS-R) score, disease duration, and forced vital capacity (FVC). Patterns of brain atrophy between ALS subgroups were compared by VBM. RESULTS: In limb-onset ALS patients, atrophy was largely confined to the motor cortex and adjacent pre- and postcentral regions. However, in the bulbar-onset group, affected regions were more widespread and included these same areas but also extended to the bilateral frontotemporal and left superior temporal and supramarginal gyri, and multiple regression analysis revealed that their ALSFRS-R scores were associated with extensive loss of gray matter while FVC was related to atrophy in subcortical regions of the left superior temporal gyrus. In limb-onset ALS patients, disease duration was related to the degree of atrophy in the motor and adjacent areas. CONCLUSION: Sporadic ALS subtypes show different patterns of brain atrophy. Neural networks related to limb and bulbar motor functions in each ALS subtype may underlie their distinct patterns of cerebral atrophy. That is, more extensive cortical and subcortical atrophy is correlated with greater ALSFRS-R severity and shorter disease duration in the bulbar-onset subtype and may explain the poor prognosis of these patients. PMID- 28095426 TI - Health Outcomes of Sarcopenia: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: The purpose of this study was to perform a systematic review to assess the short-, middle- and long-term consequences of sarcopenia. METHODS: Prospective studies assessing the consequences of sarcopenia were searched across different electronic databases (MEDLINE, EMBASE, EBM Reviews, Cochrane Database of Systematic Reviews, EBM Reviews ACP Journal Club, EBM Reviews DARE and AMED). Only studies that used the definition of the European Working Group on Sarcopenia in Older People to diagnose sarcopenia were included. Study selection and data extraction were performed by two independent reviewers. For outcomes reported by three or more studies, a meta-analysis was performed. The study results are expressed as odds ratios (OR) with 95% CI. RESULTS: Of the 772 references identified through the database search, 17 were included in this systematic review. The number of participants in the included studies ranged from 99 to 6658, and the duration of follow-up varied from 3 months to 9.8 years. Eleven out of 12 studies assessed the impact of sarcopenia on mortality. The results showed a higher rate of mortality among sarcopenic subjects (pooled OR of 3.596 (95% CI 2.96-4.37)). The effect was higher in people aged 79 years or older compared with younger subjects (p = 0.02). Sarcopenia is also associated with functional decline (pooled OR of 6 studies 3.03 (95% CI 1.80-5.12)), a higher rate of falls (2/2 studies found a significant association) and a higher incidence of hospitalizations (1/1 study). The impact of sarcopenia on the incidence of fractures and the length of hospital stay was less clear (only 1/2 studies showed an association for both outcomes). CONCLUSION: Sarcopenia is associated with several harmful outcomes, making this geriatric syndrome a real public health burden. PMID- 28095427 TI - Mobile Phones and Mental Well-Being: Initial Evidence Suggesting the Importance of Staying Connected to Family in Rural, Remote Communities in Uganda. AB - Due to the ubiquity of mobile phones around the globe, studies are beginning to analyze their influence on health. Prior work from developed countries highlights negative mental health outcomes related to overuse of mobile phones. However, there is little work on mental health impacts of mobile phone use or ownership in developing countries. This is an important gap to address because there are likely variations in mental health impacts of mobile phones between developing and developed countries, due to cultural nuances to phone use and distinct variations in financial models for obtaining mobile phone access in developing countries. To address this gap, this study analyzes survey data from 92 households in sparse, rural villages in Uganda to test two hypotheses about mobile phone ownership and mental health in a developing country context: (i) Mobile phone ownership is higher among more privileged groups, compared to less privileged groups (ie, wealth and ethnicity); and (ii) mobile phone ownership is positively associated with a culturally-relevant indicator of mental health, 'feelings of peace'. Results indicate that households with mobile phones had higher levels of wealth on average, yet no significant differences were detected by ethnicity. As hypothesized, mobile phone ownership was associated with increased mental well-being for persons without family nearby (in the District) (p = 0.038) after adjusting for wealth, ethnicity and amount of land for crops and land for grazing. Mobile phone ownership was not significantly associated with increased mental well-being for persons with family nearby. These findings are consistent with studies of mobile phone use in other sub-Saharan African countries which find that phones are important tools for social connection and are thus beneficial for maintaining family ties. One might infer then that this increased feeling of mental well-being for persons located farther from family stems from the ability to maintain family connections. These findings are quite different from work in developed countries where mobile phone use is a source of technology-related stress or technostress. PMID- 28095428 TI - Linking Ecology and Epidemiology to Understand Predictors of Multi-Host Responses to an Emerging Pathogen, the Amphibian Chytrid Fungus. AB - Variation in host responses to pathogens can have cascading effects on populations and communities when some individuals or groups of individuals display disproportionate vulnerability to infection or differ in their competence to transmit infection. The fungal pathogen, Batrachochytrium dendrobatidis (Bd) has been detected in almost 700 different amphibian species and is implicated in numerous global amphibian population declines. Identifying key hosts in the amphibian-Bd system-those who are at greatest risk or who pose the greatest risk for others-is challenging due in part to many extrinsic environmental factors driving spatiotemporal Bd distribution and context-dependent host responses to Bd in the wild. One way to improve predictive risk models and generate testable mechanistic hypotheses about vulnerability is to complement what we know about the spatial epidemiology of Bd with data collected through comparative experimental studies. We used standardized pathogen challenges to quantify amphibian survival and infection trajectories across 20 post-metamorphic North American species raised from eggs. We then incorporated trait-based models to investigate the predictive power of phylogenetic history, habitat use, and ecological and life history traits in explaining responses to Bd. True frogs (Ranidae) displayed the lowest infection intensities, whereas toads (Bufonidae) generally displayed the greatest levels of mortality after Bd exposure. Affiliation with ephemeral aquatic habitat and breadth of habitat use were strong predictors of vulnerability to and intensity of infection and several other traits including body size, lifespan, age at sexual maturity, and geographic range also appeared in top models explaining host responses to Bd. Several of the species examined are highly understudied with respect to Bd such that this study represents the first experimental susceptibility data. Combining insights gained from experimental studies with observations of landscape-level disease prevalence may help explain current and predict future pathogen dynamics in the Bd system. PMID- 28095429 TI - High Rates of Non-Tuberculous Mycobacteria Isolation in Mozambican Children with Presumptive Tuberculosis. AB - INTRODUCTION: Non-tuberculous mycobacteria (NTM) can cause disease which can be clinically and radiologically undistinguishable from tuberculosis (TB), posing a diagnostic and therapeutic challenge in high TB settings. We aim to describe the prevalence of NTM isolation and its clinical characteristics in children from rural Mozambique. METHODS: This study was part of a community TB incidence study in children <3 years of age. Gastric aspirate and induced sputum sampling were performed in all presumptive TB cases and processed for smear testing using fluorochrome staining and LED Microscopy, liquid and solid culture, and molecular identification by GenoType(r) Mycobacterium CM/AS assays. RESULTS: NTM were isolated in 26.3% (204/775) of children. The most prevalent NTM species was M. intracellulare (N = 128), followed by M. scrofulaceum (N = 35) and M. fortuitum (N = 9). Children with NTM were significantly less symptomatic and less likely to present with an abnormal chest radiograph than those with M. tuberculosis. NTM were present in 21.6% of follow-up samples and 25 children had the same species isolated from >=2 separate samples. All were considered clinically insignificant and none received specific treatment. Children with NTM isolates had equal all cause mortality and likelihood of TB treatment as those with negative culture although they were less likely to have TB ruled out. CONCLUSIONS: NTM isolation is frequent in presumptive TB cases but was not clinically significant in this patient cohort. However, it can contribute to TB misdiagnosis. Further studies are needed to understand the epidemiology and the clinical significance of NTM in children. PMID- 28095430 TI - Is Childhood Socioeconomic Status Independently Associated with Adult BMI after Accounting for Adult and Neighborhood Socioeconomic Status? AB - Childhood socioeconomic status (SES) is inversely associated with adult weight in high income countries. Whether the influence of childhood SES on adult weight is best described using a critical period model or an accumulation of risk model is not yet settled. This research tests whether childhood SES is associated with adult BMI and likelihood of obesity independent of adult socioeconomic status and neighborhood characteristics. Data on individual childhood and adult characteristics come from the Health and Retirement Study (N = 13,545). Data on neighborhood characteristics come from the 2000 Decennial Census and American Community Survey (2005-2009). In the fully adjusted models, perceived financial hardship before the age of sixteen and having a father who was unemployed are associated with higher BMI among males and, among females, paternal education remains associated with adult BMI. However, childhood SES is not associated with likelihood of obesity after fully adjusting for adult SES and neighborhood characteristics, suggesting that the direct effects of early childhood SES on BMI are small relative to the other factors associated with obesity in adulthood. PMID- 28095431 TI - Hair Measurements of Cortisol, DHEA, and DHEA to Cortisol Ratio as Biomarkers of Chronic Stress among People Living with HIV in China: Known-Group Validation. AB - BACKGROUND: Existing literature suggests that endocrine measures, including the steroid hormones of cortisol and Dehydroepiandrosterone (DHEA), as well as the DHEA to cortisol ratio in the human hair can be used as promising biomarkers of chronic stress among humans. However, data are limited regarding the validity of these measures as biomarkers of chronic stress among people living with HIV (PLWH), whose endocrine system or hypothalamic pituitary adrenal (HPA) axis may be affected by HIV infection and/or antiretroviral therapy (ART) medications. METHOD: Using hair sample data and self-reported survey from 60 PLWH in China, we examined the validity of three endocrine measures among Chinese PLWH using a known-groups validation strategy. High-stress group (n = 30) and low-stress group (n = 30) of PLWH were recruited through individual assessment interviews by a local licensed psychologist. The endocrine measures in hair were extracted and assessed by LC-APCI-MS/MS method. Both bivariate and multivariate analyses were conducted to examine the associations between the endocrine measures and the stress level, and to investigate if the associations differ by ART status. RESULTS: The levels of endocrine measures among Chinese PLWH were consistent with existing studies among PLWH. Generally, this pilot study confirmed the association between endocrine measures and chronic stress. The high stress group showed higher level hair cortisol and lower DHEA to cortisol ratio. The higher stress group also reported higher scores of stressful life events, perceived stress, anxiety and depression. Hair cortisol level was positively related to anxiety; DHEA was negatively associated with stressful life events; and the DHEA to cortisol ratio was positively related to stressful life events and perceived stress. ART did not affect the associations between the endocrine measures and stress level. CONCLUSIONS: Our findings suggest that hair cortisol and DHEA to cortisol ratio can be used as promising biomarkers of chronic stress among PLWH. Clarifying the role of steroid hormones in the psychoimmunology of PLWH may yield important implications for clinical practice and psychological intervention. PMID- 28095432 TI - Exploring Maternal Health Care-Seeking Behavior of Married Adolescent Girls in Bangladesh: A Social-Ecological Approach. AB - BACKGROUND: The huge proportion of child marriage contributes to high rates of pregnancies among adolescent girls in Bangladesh. Despite substantial progress in reducing maternal mortality in the last two decades, the rate of adolescent pregnancy remains high. The use of skilled maternal health services is still low in Bangladesh. Several quantitative studies described the use of skilled maternal health services among adolescent girls. So far, very little qualitative evidence exists about attitudes and practices related to maternal health. To fill this gap, we aimed at exploring maternal health care-seeking behavior of adolescent girls and their experiences related to pregnancy and delivery in Bangladesh. METHODS AND FINDINGS: A prospective qualitative study was conducted among thirty married adolescent girls from three Upazilas (sub-districts) of Rangpur district. They were interviewed in two subsequent phases (2014 and 2015). To triangulate and validate the data collected from these married adolescent girls, key informant interviews (KIIs) and focus group discussions (FGDs) were conducted with different stakeholders. Data analysis was guided by the Social-Ecological Model (SEM) including four levels of factors (individual, interpersonal and family, community and social, and organizational and health systems level) which influenced the maternal health care-seeking behavior of adolescent girls. While adolescent girls showed little decision making-autonomy, interpersonal and family level factors played an important role in their use of skilled maternal health services. In addition, community and social factors and as well as organizational and health systems factors shaped adolescent girls' maternal health care-seeking behavior. CONCLUSIONS: In order to improve the maternal health of adolescent girls, all four levels of factors of SEM should be taken into account while developing health interventions targeting adolescent girls. PMID- 28095433 TI - BJ-3105, a 6-Alkoxypyridin-3-ol Analog, Impairs T Cell Differentiation and Prevents Experimental Autoimmune Encephalomyelitis Disease Progression. AB - CD4+ T cells are essential in inflammation and autoimmune diseases. Interferon gamma (IFN-gamma) secreting T helper (Th1) and IL-17 secreting T helper (Th17) cells are critical for several autoimmune diseases. To assess the inhibitory effect of a given compound on autoimmune disease, we screened many compounds with an in vitro Th differentiation assay. BJ-3105, a 6-alkoxypyridin-3-ol analog, inhibited IFN-gamma and IL-17 production from polyclonal CD4+ T cells and ovalbumin (OVA)-specific CD4+ T cells which were activated by T cell receptor (TCR) engagement. BJ-3105 ameliorated the experimental autoimmune encephalomyelitis (EAE) model by reducing Th1 and Th17 generation. Notably, Th cell differentiation was significantly suppressed by BJ-3105 treatment without inhibiting in vitro proliferation of T cells or inducing programmed cell death. Mechanistically, BJ-3105 inhibited the phosphorylation of JAK and its downstream signal transducer and activator of transcription (STAT) that is critical for Th differentiation. These results demonstrated that BJ-3105 inhibits the phosphorylation of STAT in response to cytokine signals and subsequently suppressed the differentiation of Th cell responses. PMID- 28095434 TI - Field Evaluation of a High Throughput Loop Mediated Isothermal Amplification Test for the Detection of Asymptomatic Plasmodium Infections in Zanzibar. AB - BACKGROUND: New field applicable diagnostic tools are needed for highly sensitive detection of residual malaria infections in pre-elimination settings. Field performance of a high throughput DNA extraction system for loop mediated isothermal amplification (HTP-LAMP) was therefore evaluated for detecting malaria parasites among asymptomatic individuals in Zanzibar. METHODS: HTP-LAMP performance was evaluated against real-time PCR on 3008 paired blood samples collected on filter papers in a community-based survey in 2015. RESULTS: The PCR and HTP-LAMP determined malaria prevalences were 1.6% (95%CI 1.3-2.4) and 0.7% (95%CI 0.4-1.1), respectively. The sensitivity of HTP-LAMP compared to PCR was 40.8% (CI95% 27.0-55.8) and the specificity was 99.9% (CI95% 99.8-100). For the PCR positive samples, there was no statistically significant difference between the geometric mean parasite densities among the HTP-LAMP positive (2.5 p/MUL, range 0.2-770) and HTP-LAMP negative (1.4 p/MUL, range 0.1-7) samples (p = 0.088). Two lab technicians analysed up to 282 samples per day and the HTP-LAMP method was experienced as user friendly. CONCLUSIONS: Although field applicable, this high throughput format of LAMP as used here was not sensitive enough to be recommended for detection of asymptomatic low-density infections in areas like Zanzibar, approaching malaria elimination. PMID- 28095435 TI - Evaluation of a Silver-Embedded Ceramic Tablet as a Primary and Secondary Point of-Use Water Purification Technology in Limpopo Province, S. Africa. AB - The World Health Organization (WHO) recognizes point-of-use water treatment (PoUWT) technologies as effective means to improve water quality. This paper investigates long-term performance and social acceptance of a novel PoUWT technology, a silver-infused ceramic tablet, in Limpopo Province, South Africa. When placed in a water storage container, the silver-embedded ceramic tablet releases silver ions into water, thereby disinfecting microbial pathogens and leaving the water safe for human consumption. As a result of its simplicity and efficiency, the silver-embedded ceramic tablet can serve as a stand-alone PoUWT method and as a secondary PoUWT to improve exisitng PoUWT methods, such as ceramic water filters. In this paper, three PoUWT interventions were conducted to evaluate the silver-embedded ceramic tablet: (1) the silver-embedded ceramic tablet as a stand-alone PoUWT method, (2) ceramic water filters stand-alone, and (3) a filter-tablet combination. The filter-tablet combination evaluates the silver-embedded ceramic tablet as a secondary PoUWT method when placed in the lower reservoir of the ceramic water filter system to provide residual disinfection post-filtration. Samples were collected from 79 households over one year and analyzed for turbidity, total silver levels and coliform bacteria. Results show that the silver-embedded ceramic tablet effectively reduced total coliform bacteria (TC) and E. coli when used as a stand-alone PoUWT method and when used in combination with ceramic water filters. The silver-embedded ceramic tablet's performance as a stand-alone PoUWT method was comparable to current inexpensive, single-use PoUWT methods, demonstrating 100% and 75% median reduction in E. coli and TC, respectively, after two months of use. Overall, the the filter-tablet combination performed the best of the three interventions, providing a 100% average percent reduction in E. coli over one year. User surveys were also conducted and indicated that the silver-embedded ceramic tablet was simple to use and culturally appropriate. Also, silver levels in all treated water samples remained below 20 MUg/L, significantly lower than the drinking water standard of 100 MUg/L, making it safe for consumption. Long-term data demonstrates that the silver-embedded ceramic tablet has beneficial effects even after one year of use. This study demonstrates that the silver-embedded ceramic tablet can effectively improve water quality when used alone, or with ceramic water filters, to reduce rates of recontamination. Therefore, the tablet has the potential to provide a low-cost means to purify water in resource-limited settings. PMID- 28095436 TI - ArrayPitope: Automated Analysis of Amino Acid Substitutions for Peptide Microarray-Based Antibody Epitope Mapping. AB - Identification of epitopes targeted by antibodies (B cell epitopes) is of critical importance for the development of many diagnostic and therapeutic tools. For clinical usage, such epitopes must be extensively characterized in order to validate specificity and to document potential cross-reactivity. B cell epitopes are typically classified as either linear epitopes, i.e. short consecutive segments from the protein sequence or conformational epitopes adapted through native protein folding. Recent advances in high-density peptide microarrays enable high-throughput, high-resolution identification and characterization of linear B cell epitopes. Using exhaustive amino acid substitution analysis of peptides originating from target antigens, these microarrays can be used to address the specificity of polyclonal antibodies raised against such antigens containing hundreds of epitopes. However, the interpretation of the data provided in such large-scale screenings is far from trivial and in most cases it requires advanced computational and statistical skills. Here, we present an online application for automated identification of linear B cell epitopes, allowing the non-expert user to analyse peptide microarray data. The application takes as input quantitative peptide data of fully or partially substituted overlapping peptides from a given antigen sequence and identifies epitope residues (residues that are significantly affected by substitutions) and visualize the selectivity towards each residue by sequence logo plots. Demonstrating utility, the application was used to identify and address the antibody specificity of 18 linear epitope regions in Human Serum Albumin (HSA), using peptide microarray data consisting of fully substituted peptides spanning the entire sequence of HSA and incubated with polyclonal rabbit anti-HSA (and mouse anti-rabbit-Cy3). The application is made available at: www.cbs.dtu.dk/services/ArrayPitope. PMID- 28095437 TI - Relationship of Climatic and Forest Factors to Drought- and Heat-Induced Tree Mortality. AB - Tree mortality due to warming and drought is a critical aspect of forest ecosystem in responding to climate change. Spatial patterns of tree mortality induced by drought and its influencing factors, however, have yet to be documented at the global scale. We collected observations from 248 sites globally where trees have died due to drought and then assessed the effects of climatic and forest factors on the rate of tree mortality. The global mean annual mortality rate was 5.5%. The rate of tree mortality was significantly and negatively correlated with mean annual precipitation (P < 0.01). Tree mortality was lowest in tropical rainforests with mean annual precipitation >2000 mm and was severe in regions with mean annual precipitation <1000 mm. Mortality rates varied amongst species. The global annual rate of mortality was much higher for gymnosperms (7.1%) than angiosperms (4.8%) but did not differ significantly between evergreen (6.2%) and deciduous (6.1%) species. Stand age and wood density affected the mortality rate. Saplings (4.6%) had a higher mortality rate than mature trees (3.2%), and mortality rates significantly decreased with increasing wood density for all species (P < 0.01). We therefore concluded that the tree mortality around the globe varied with climatic and forest factors. The differences between tree species, wood density, stand density, and stand age should be considered when evaluating tree mortality at a large spatial scale during future climatic extremes. PMID- 28095438 TI - VH1 Family Immunoglobulin Repertoire Sequencing after Allogeneic Hematopoietic Stem Cell Transplantation. AB - After allogeneic hematopoietic stem cell transplantation (HSCT), recovery of humoral immunity is essential to protect from life-threatening infections. However, monitoring the humoral immune system after transplantation with standard techniques in the clinical routine is imprecise. Here, we performed sequencing of mononuclear bone marrow cells to characterize the VH1-repertoire of switched B cells of healthy volunteers and patients undergoing HSCT. Analysis of healthy bone marrow donors and patients showed virtually no clonally related sequences between individuals. Interestingly, clonally related sequences were present in pre- and post-transplantation bone marrow of patients undergoing HSCT for acute myeloid leukemia treatment. We consistently observed such related B cell clones, irrespective of conditioning regimen, donor source or time post transplantation. In general, repertoire diversity was lower in post-HSCT as compared to pre-HSCT samples. However, post-HSCT repertoires retained highly mutated sequences, despite immunosuppressive therapy and presence of T cell deficiency after HSCT. These observations identify key properties of the recovering B cell compartment and provide a conceptual framework for the surveillance of humoral immunity after allogeneic transplantation. PMID- 28095439 TI - Intracranial Injection of Dengue Virus Induces Interferon Stimulated Genes and CD8+ T Cell Infiltration by Sphingosine Kinase 1 Independent Pathways. AB - We have previously reported that the absence of sphingosine kinase 1 (SK1) affects both dengue virus (DENV) infection and innate immune responses in vitro. Here we aimed to define SK1-dependancy of DENV-induced disease and the associated innate responses in vivo. The lack of a reliable mouse model with a fully competent interferon response for DENV infection is a challenge, and here we use an experimental model of DENV infection in the brain of immunocompetent mice. Intracranial injection of DENV-2 into C57BL/6 mice induced body weight loss and neurological symptoms which was associated with a high level of DENV RNA in the brain. Body weight loss and DENV RNA level tended to be greater in SK1-/- compared with wildtype (WT) mice. Brain infection with DENV-2 is associated with the induction of interferon-beta (IFN-beta) and IFN-stimulated gene (ISG) expression including viperin, Ifi27l2a, IRF7, and CXCL10 without any significant differences between WT and SK1-/- mice. The SK2 and sphingosine-1-phosphate (S1P) levels in the brain were unchanged by DENV infection or the lack of SK1. Histological analysis demonstrated the presence of a cellular infiltrate in DENV infected brain with a significant increase in mRNA for CD8 but not CD4 suggesting this infiltrate is likely CD8+ but not CD4+ T-lymphocytes. This increase in T cell infiltration was not affected by the lack of SK1. Overall, DENV-infection in the brain induces IFN and T-cell responses but does not influence the SK/S1P axis. In contrast to our observations in vitro, SK1 has no major influence on these responses following DENV-infection in the mouse brain. PMID- 28095441 TI - Moving Model Test of High-Speed Train Aerodynamic Drag Based on Stagnation Pressure Measurements. AB - A moving model test method based on stagnation pressure measurements is proposed to measure the train aerodynamic drag coefficient. Because the front tip of a high-speed train has a high pressure area and because a stagnation point occurs in the center of this region, the pressure of the stagnation point is equal to the dynamic pressure of the sensor tube based on the obtained train velocity. The first derivation of the train velocity is taken to calculate the acceleration of the train model ejected by the moving model system without additional power. According to Newton's second law, the aerodynamic drag coefficient can be resolved through many tests at different train speeds selected within a relatively narrow range. Comparisons are conducted with wind tunnel tests and numerical simulations, and good agreement is obtained, with differences of less than 6.1%. Therefore, the moving model test method proposed in this paper is feasible and reliable. PMID- 28095440 TI - Comprehensive Maturity Onset Diabetes of the Young (MODY) Gene Screening in Pregnant Women with Diabetes in India. AB - Pregnant women with diabetes may have underlying beta cell dysfunction due to mutations/rare variants in genes associated with Maturity Onset Diabetes of the Young (MODY). MODY gene screening would reveal those women genetically predisposed and previously unrecognized with a monogenic form of diabetes for further clinical management, family screening and genetic counselling. However, there are minimal data available on MODY gene variants in pregnant women with diabetes from India. In this study, utilizing the Next generation sequencing (NGS) based protocol fifty subjects were screened for variants in a panel of thirteen MODY genes. Of these subjects 18% (9/50) were positive for definite or likely pathogenic or uncertain MODY variants. The majority of these variants was identified in subjects with autosomal dominant family history, of whom five were in women with pre-GDM and four with overt-GDM. The identified variants included one patient with HNF1A Ser3Cys, two PDX1 Glu224Lys, His94Gln, two NEUROD1 Glu59Gln, Phe318Ser, one INS Gly44Arg, one GCK, one ABCC8 Arg620Cys and one BLK Val418Met variants. In addition, three of the seven offspring screened were positive for the identified variant. These identified variants were further confirmed by Sanger sequencing. In conclusion, these findings in pregnant women with diabetes, imply that a proportion of GDM patients with autosomal dominant family history may have MODY. Further NGS based comprehensive studies with larger samples are required to confirm these finding. PMID- 28095442 TI - Cardiac Mean Electrical Axis in Thoroughbreds-Standardization by the Dubois Lead Positioning System. AB - BACKGROUND: Different methodologies for electrocardiographic acquisition in horses have been used since the first ECG recordings in equines were reported early in the last century. This study aimed to determine the best ECG electrodes positioning method and the most reliable calculation of mean cardiac axis (MEA) in equines. MATERIALS AND METHODS: We evaluated the electrocardiographic profile of 53 clinically healthy Thoroughbreds, 38 males and 15 females, with ages ranging 2-7 years old, all reared at the Sao Paulo Jockey Club, in Brazil. Two ECG tracings were recorded from each animal, one using the Dubois lead positioning system, the second using the base-apex method. QRS complex amplitudes were analyzed to obtain MEA values in the frontal plane for each of the two electrode positioning methods mentioned above, using two calculation approaches, the first by Tilley tables and the second by trigonometric calculation. Results were compared between the two methods. RESULTS: There was significant difference in cardiac axis values: MEA obtained by the Tilley tables was +135.1 degrees +/- 90.9 degrees vs. -81.1 degrees +/- 3.6 degrees (p<0.0001), and by trigonometric calculation it was -15.0 degrees +/- 11.3 degrees vs. -79.9 degrees +/- 7.4 degrees (p<0.0001), base-apex and Dubois, respectively. Furthermore, Dubois method presented small range of variation without statistical or clinical difference by either calculation mode, while there was a wide variation in the base-apex method. CONCLUSION: Dubois improved centralization of the Thoroughbreds' hearts, engendering what seems to be the real frontal plane. By either calculation mode, it was the most reliable methodology to obtain cardiac mean electrical axis in equines. PMID- 28095443 TI - Morphologic and Molecular Characterization of a Strain of Zika Virus Imported into Guangdong, China. AB - The recent outbreaks of Zika virus (ZIKV) disease have caused worldwide concerns. Guangdong province is one of the commercial centers in China and communicates frequently with the epidemic areas. To date, 65.2% of the ZIKV infection cases in China were imported via port of entry in Guangdong. The continuous surveillance of imported cases is crucial for the prevention and control of potential ZIKV infection outbreak in China. In this study, a strain of ZIKV was isolated from the serum of a 6-year-old child returning from Venezuela. The morphology of the ZIKV was analyzed in vivo and in vitro by electron microscopy, and clusters of virus particles were found in the loose cytoplasmic membrane structures. The genomic sequence of the isolated ZIKV was determined, and the alignment and phylogenetic analysis identified one unique amino acid substitution occurring in the non-structural protein 4B (NS4B), and the isolated virus belonged to the Asian lineage. PMID- 28095444 TI - The Role of DCT in HPV16 Infection of HaCaTs. AB - Persistent infection with high-risk human papillomavirus (HPV) genotype is a major factor leading to many human cancers. Mechanisms of HPV entry into host cells and genome trafficking towards the nucleus are incompletely understood. Dopachrome tautomerase (DCT) was identified as a cellular gene required for HPV infection in HeLa cells on a siRNA screen study. Here, we confirm that DCT knockdown significantly decreases HPV infection in the human keratinocyte HaCaT cells as was observed in HeLas. We investigated the effects of DCT knockdown and found that DCT depletion caused increased reactive oxygen species (ROS) levels, DNA damage and altered cell cycle in HaCaT cells. We observed increased viral DNA localization at the endoplasmic reticulum but an overall decrease in infection in DCT knockdown cells. This observation suggests that viral DNA might be retained in the ER due to altered cell cycle, and viral particles are incapable of further movement towards the nucleus in DCT knockdown cells. PMID- 28095445 TI - Cytosolic RNA:DNA Duplexes Generated by Endogenous Reverse Transcriptase Activity as Autonomous Inducers of Skin Inflammation in Psoriasis. AB - Psoriasis is a chronic skin disease of unknown aetiology. Recent studies suggested that a large amount of cytosolic DNA (cyDNA) in keratinocytes is breaking keratinocytes DNA tolerance and promotes self-sustained inflammation in the psoriatic lesion. We investigated the origin of this cyDNA. We show that, amongst all the possible DNA structures, the cyDNA could be present as RNA:DNA duplexes in keratinocytes. We further show that endogenous reverse transcriptase activities generate such duplexes and consequently activate the production of Th1 inflammatory cytokines. These observations open a new research avenue related to endogenous retroelements for the aetiology of psoriasis and probably of other human chronic inflammatory diseases. PMID- 28095446 TI - Neglected Intestinal Parasites, Malnutrition and Associated Key Factors: A Population Based Cross-Sectional Study among Indigenous Communities in Sarawak, Malaysia. AB - Intestinal parasitic infections (IPIs) have been recognized as one of the most significant causes of illness among disadvantaged communities. Many studies have been conducted on the prevalence of IPIs in Malaysia. However, these studies mostly focused on the indigenous groups in Peninsular Malaysia. The present study was conducted to provide the current baseline data on prevalence of IPIs, anaemia, malnutrition and associated risk factors among the indigenous communities in Sarawak, situation at northwest Borneo island of Malaysia. A cross sectional study was conducted among the longhouses communities. Stool samples were obtained and examined for the presence of IPIs using microscopy technique. Haemoglobin measurement was done using a portable haemoglobin analyzer. Malnutrition (i.e., stunting, underweight and wasting) was assessed using the WHO Anthro software. Statistical analysis was carried out using SPSS software. A total of 341participants took part in this study. The overall prevalence of IPIs was 57.5%. Multivariate analysis indicated that the absence of toilets (OR = 1.6; 95% CI = 1.1-2.7; p = 0.002) and close contact with animals (OR = 1.8; 95% CI = 1.3-2.9; p = 0.027) as significant predictors for IPIs. The incidence of anaemia was 36.4%. The incidence of underweight, wasting and stunting were 22.2%, 5.6% and 35.4%, respectively. Multivariate analysis demonstrated that low level of parental education attainment (OR = 1.9; 95% CI = 1.2-3.0; p = 0.006) was identified as significant predictor for anaemia. The incidence of wasting was significantly associated with mild anaemia (OR = 1.2; 95% CI = 0.9-1.7; p = 0.024). Low household income was identified as significant predictor for stunting (OR = 2.1; 95% CI = 9.8-22.2; p = 0.001) and underweight (OR = 1.9; 95% CI = 5.6 18.7; p = 0.037), respectively. Essentially, the present study highlighted that intestinal parasitic infections, anaemia and malnutrition are still prevalent among rural indigenous community in Sarawak. Improvement of socioeconomic status, periodic mass deworming, iron supplementation and health education program should be included in the control and prevention of public health strategies. PMID- 28095447 TI - Identification and Characterization of Single-Chain Antibodies that Specifically Bind GI Noroviruses. AB - Norovirus infections commonly lead to outbreaks of acute gastroenteritis and spread quickly, resulting in many health and economic challenges prior to diagnosis. Rapid and reliable diagnostic tests are therefore essential to identify infections and to guide the appropriate clinical responses at the point of-care. Existing tools, including RT-PCR and enzyme immunoassays, pose several limitations based on the significant time, equipment and expertise required to elicit results. Immunochromatographic assays available for use at the point-of care have poor sensitivity and specificity, especially for genogroup I noroviruses, thus requiring confirmation of results with more sensitive testing methods. Therefore, there is a clear need for novel reagents to help achieve quick and reliable results. In this study, we have identified two novel single chain antibodies (scFvs)-named NJT-R3-A2 and NJT-R3-A3-that effectively detect GI.1 and GI.7 virus-like particles (VLPs) through selection of a phage display library against the P-domain of the GI.1 major capsid protein. The limits of detection by each scFv for GI.1 and GI.7 are 0.1 and 0.2 ng, and 6.25 and 25 ng, respectively. They detect VLPs with strong specificity in multiple diagnostic formats, including ELISAs and membrane-based dot blots, and in the context of norovirus-negative stool suspensions. The scFvs also detect native virions effectively in norovirus-positive clinical stool samples. Purified scFvs bind to GI.1 and GI.7 VLPs with equilibrium constant (KD) values of 27 nM and 49 nM, respectively. Overall, the phage-based scFv reagents identified and characterized here show utility for detecting GI.1 and GI.7 noroviruses in multiple diagnostic assay formats with strong specificity and sensitivity, indicating promise for integration into existing point-of-care tests to improve future diagnostics. PMID- 28095448 TI - Distribution of Cathepsin K in Late Stage of Tooth Germ Development and Its Function in Degrading Enamel Matrix Proteins in Mouse. AB - Cathepsin K (CTSK) is a member of cysteine proteinase family, and is predominantly expressed in osteoclastsfor degradationof bone matrix proteins. Given the similarity in physical properties of bone and dental mineralized tissues, including enamel, dentin and cementum, CTSK is likely to take part in mineralization process during odontogenesis. On the other hand, patients with pycnodysostosis caused by mutations of the CTSK gene displayedmultipledental abnormalities, such as hypoplasia of the enamel, obliterated pulp chambers, hypercementosis and periodontal disease. Thereforeitis necessary to study the metabolic role of CTSK in tooth matrix proteins. In this study, BALB/c mice at embryonic day 18 (E18), post-natal day 1 (P1), P5, P10 and P20 were used (5 mice at each time point)for systematic analyses of CTSK expression in the late stage of tooth germ development. We found that CTSK was abundantly expressed in the ameloblasts during secretory and maturation stages (P5 and P10) by immunohistochemistry stainings.During dentinogenesis, the staining was also intense in the mineralization stage (P5 and P10),but not detectable in the early stage of dentin formation (P1) and after tooth eruption (P20).Furthermore, through zymography and digestion test in vitro, CTSK was proved to be capable of hydrolyzing Emdogain and also cleaving Amelogenininto multiple products. Our resultsshed lights on revealing new functions of CTSK and pathogenesis of pycnodysostosis in oral tissues. PMID- 28095449 TI - Does Antiplatelet Therapy during Bridging Thrombolysis Increase Rates of Intracerebral Hemorrhage in Stroke Patients? AB - BACKGROUND: Symptomatic intracerebral hemorrhage (sICH) after bridging thrombolysis for acute ischemic stroke is a devastating complication. We aimed to assess whether the additional administration of aspirin during endovascular intervention increases bleeding rates. METHODS: We retrospectively compared bleeding complications and outcome in stroke patients who received bridging thrombolysis with (tPA+ASA) and without (tPA-ASA) aspirin during endovascular intervention between November 2008 and March 2014. Furthermore, we analyzed bleeding complications and outcome in antiplatelet naive patients with those with prior or acute antiplatelet therapy. RESULTS: Baseline characteristics, previous medication, and dosage of rtPA did not differ between 50 tPA+ASA (39 aspirin naive, 11 preloaded) and 181 tPA-ASA patients (p>0.05). tPA+ASA patients had more often internal carotid artery (ICA) occlusion (p<0.001), large artery disease (p<0.001) and received more often acute stenting of the ICA (p<0.001). 10/180 (5.6%) tPA-ASA patients and 3/49 (6.1%) tPA+ASA patients suffered a sICH (p = 1.0). Rates of asymptomatic intracerebral hemorrhage, systemic bleeding complications and outcome did not differ between both groups (p>0.1). There were no differences in bleeding complications and mortality among 112 bridging patients with antiplatelet therapy (62 preloaded, 39 acute administration, 11 both) and 117 antiplatelet naive patients. In a logistic regression analysis, aspirin administration during endovascular procedure was not a predictor of sICH. CONCLUSION: Antiplatelet therapy before or during bridging thrombolysis in patients with acute ischemic stroke did not increase the risk of bleeding complications and had no impact on outcome. This finding has to be confirmed in larger studies. PMID- 28095450 TI - Non-Lytic Egression of Infectious Bursal Disease Virus (IBDV) Particles from Infected Cells. AB - Infectious bursal disease virus (IBDV), a member of the Birnaviridae family, is responsible for a devastating immunosuppressive disease affecting juvenile domestic chickens. IBDV particles are naked icosahedrons enclosing a bipartite double-stranded RNA genome harboring three open reading frames (ORF). One of these ORFs codes for VP5, a non-structural polypeptide dispensable for virus replication in tissue culture but essential for IBDV pathogenesis. Using two previously described recombinant viruses, whose genomes differ in a single nucleotide, expressing or not the VP5 polypeptide, we have analyzed the role of this polypeptide during the IBDV replication process. Here, we show that VP5 is not involved in house-keeping steps of the virus replication cycle; i.e. genome transcription/replication, protein translation and virus assembly. Although infection with the VP5 expressing and non-expressing viruses rendered similar intracellular infective progeny yields, striking differences were detected on the ability of their progenies to exiting infected cells. Experimental data shows that the bulk of the VP5-expressing virus progeny efficiently egresses infected cells during the early phase of the infection, when viral metabolism is peaking and virus-induced cell death rates are as yet minimal, as determined by qPCR, radioactive protein labeling and quantitative real-time cell death analyses. In contrast, the release of the VP5-deficient virus progeny is significantly abridged and associated to cell death. Taken together, data presented in this report show that IBDV uses a previously undescribed VP5-dependent non-lytic egress mechanism significantly enhancing the virus dissemination speed. Ultrastructural analyses revealed that newly assembled IBDV virions associate to a vesicular network apparently facilitating their trafficking from virus assembly factories to the extracellular milieu, and that this association requires the expression of the VP5 polypeptide. PMID- 28095451 TI - Comparing Human Metapneumovirus and Respiratory Syncytial Virus: Viral Co Detections, Genotypes and Risk Factors for Severe Disease. AB - BACKGROUND: It is unclarified as to whether viral co-detection and human metapneumovirus (HMPV) genotypes relate to clinical manifestations in children with HMPV and lower respiratory tract infection (LRTI), and if the clinical course and risk factors for severe LRTI differ between HMPV and respiratory syncytial virus (RSV). METHODS: We prospectively enrolled hospitalized children aged <16 years with LRTI from 2006 to 2015. Children were clinically examined, and nasopharyngeal aspirates were analyzed using semi-quantitative, real-time polymerase chain reaction tests for HMPV, RSV and 17 other pathogens. HMPV positive samples were genotyped. RESULTS: A total of 171 children had HMPV infection. HMPV-infected children with single virus (n = 106) and co-detections (n = 65) had similar clinical manifestations. No clinical differences were found between HMPV genotypes A (n = 67) and B (n = 80). The HMPV-infected children were older (median 17.2 months) than RSV-infected children (median 7.3 months, n = 859). Among single virus-infected children, no differences in age-adjusted LRTI diagnoses were found between HMPV and RSV. Age was an important factor for disease severity among single virus-infected children, where children <6 months old with HMPV had a milder disease than those with RSV, while in children 12-23 months old, the pattern was the opposite. In multivariable logistic regression analysis for each virus type, age >=12 months (HMPV), and age <6 months (RSV), prematurity, >=1 chronic disease and high viral loads of RSV, but not high HMPV viral loads, were risk factors for severe disease. CONCLUSIONS: Among hospitalized children with LRTI, HMPV manifests independently of viral co detections and HMPV genotypes. Disease severity in HMPV- and RSV-infected children varies in relation to age. A history of prematurity and chronic disease increases the risk of severe LRTI among HMPV- and RSV-infected children. PMID- 28095452 TI - Influence of Mechanical Circulatory Support on Endothelin Receptor Expression in Human Left Ventricular Myocardium from Patients with Dilated Cardiomyopathy (DCM). AB - BACKGROUND: In terminal failing hearts ventricular assist devices (VAD) are implanted as a bridge to transplantation. Endothelin receptor (ETR) antagonists are used for treatment of secondary pulmonary hypertension in VAD patients. However, the cardiac ETR regulation in human heart failure and during VAD support is incompletely understood. METHODS: In paired left ventricular samples of 12 dilated cardiomyopathy patients we investigated the density of endothelin A (ETA) and B (ETB) receptors before VAD implantation and after device removal. Left ventricular samples of 12 non-failing donor hearts served as control. Receptor quantification was performed by binding of [125I]-ET-1 in the presence of nonselective and ETA selective ETR ligands as competitors. Additionally, the ETR mRNA expression was analyzed using quantitative real-time-PCR. RESULTS: The mRNA of ETA but not ETB receptors was significantly elevated in heart failure, whereas total ETR density analyzed by radioligand binding was significantly reduced due to ETB receptor down regulation. ETA and ETB receptor density showed poor correlation to mRNA data (spearman correlation factor: 0.43 and 0.31, respectively). VAD support had no significant impact on the density of both receptors and on mRNA expression of ETA whereas ETB mRNA increased during VAD. A meta-analysis reveals that the ETA receptor regulation in human heart failure appears to depend on non-failing hearts. CONCLUSIONS: In deteriorating hearts of patients suffering from dilated cardiomyopathy the ETA receptor density is not changed whereas the ETB receptor is down regulated. The mRNA and the proteins of ETA and ETB show a weak correlation. Non-failing hearts might influence the interpretation of ETA receptor regulation. Mechanical unloading of the failing hearts has no impact on the myocardial ETR density. PMID- 28095453 TI - Bivalirudin versus Heparin plus Glycoprotein IIb/IIIa Inhibitors in Women Undergoing Percutaneous Coronary Intervention: A Meta-Analysis of Randomized Controlled Trials. AB - Bivalirudin has been shown to be safe and efficacious compared with heparin plus glycoprotein IIb/IIIa inhibitor (GPI) in patients undergoing percutaneous coronary intervention (PCI). Whether bivalirudin would have the beneficial effects in female patients undergoing PCI remains unknown. We searched the literature for randomized controlled trials that assessed bivalirudin versus heparin plus GPI therapy in female patients undergoing PCI. The primary efficacy end point was major adverse cardiovascular events (MACE) within 30 days. The secondary efficacy end points were 30-day incidence of all-cause mortality, myocardial infarction (MI), urgent/ischemia-driven revascularization of target vessel. The safety end point was major bleeding up to 30 days. A total of 4,501 female patients were included in five randomized trials. No significant difference in MACE emerged between bivalirudin and heparin plus GPI at 30 days (8.15% vs 8.76%, RR 0.94, 95% CI 0.77-1.16, P = .57). There were no significant differences in rates of mortality (1.28% vs 1.91%, RR 0.74, 95% CI 0.45-1.20, P = .22), MI (5.46% vs 5.25%, RR 1.02, 95% CI 0.79-1.32, p = .88), or target vessel revascularization (2.13% vs 1.65%, RR 1.43, 95% CI 0.88-2.30, P = .15). Compared with heparin plus GPI, bivalirudin was associated with a significant reduction in 30-day major bleeding (5.32% vs 9.20%, RR 0.58, 95% CI 0.47-0.72, P < .0001). In conclusion, bivalirudin is associated with a significant reduction in 30-day major bleeding without increased ischemic events compared with heparin plus GPI in female patients undergoing PCI. PMID- 28095454 TI - Non-Homologous End Joining and Homology Directed DNA Repair Frequency of Double Stranded Breaks Introduced by Genome Editing Reagents. AB - Genome editing using transcription-activator like effector nucleases or RNA guided nucleases allows one to precisely engineer desired changes within a given target sequence. The genome editing reagents introduce double stranded breaks (DSBs) at the target site which can then undergo DNA repair by non-homologous end joining (NHEJ) or homology directed recombination (HDR) when a template DNA molecule is available. NHEJ repair results in indel mutations at the target site. As PCR amplified products from mutant target regions are likely to exhibit different melting profiles than PCR products amplified from wild type target region, we designed a high resolution melting analysis (HRMA) for rapid identification of efficient genome editing reagents. We also designed TaqMan assays using probes situated across the cut site to discriminate wild type from mutant sequences present after genome editing. The experiments revealed that the sensitivity of the assays to detect NHEJ-mediated DNA repair could be enhanced by selection of transfected cells to reduce the contribution of unmodified genomic DNA from untransfected cells to the DNA melting profile. The presence of donor template DNA lacking the target sequence at the time of genome editing further enhanced the sensitivity of the assays for detection of mutant DNA molecules by excluding the wild-type sequences modified by HDR. A second TaqMan probe that bound to an adjacent site, outside of the primary target cut site, was used to directly determine the contribution of HDR to DNA repair in the presence of the donor template sequence. The TaqMan qPCR assay, designed to measure the contribution of NHEJ and HDR in DNA repair, corroborated the results from HRMA. The data indicated that genome editing reagents can produce DSBs at high efficiency in HEK293T cells but a significant proportion of these are likely masked by reversion to wild type as a result of HDR. Supplying a donor plasmid to provide a template for HDR (that eliminates a PCR amplifiable target) revealed these cryptic DSBs and facilitated the determination of the true efficacy of genome editing reagents. The results indicated that in HEK293T cells, approximately 40% of the DSBs introduced by genome editing, were available for participation in HDR. PMID- 28095455 TI - Novel Porcine Epidemic Diarrhea Virus (PEDV) Variants with Large Deletions in the Spike (S) Gene Coexist with PEDV Strains Possessing an Intact S Gene in Domestic Pigs in Japan: A New Disease Situation. AB - Since late 2013, after an absence of seven years, outbreaks of porcine epidemic diarrhea virus (PEDV) infection have reemerged and swept rapidly across Japan, resulting in significant economic losses. In this study, we report the emergence, mixed infection, and genetic characterization of 15 novel field PEDV variants with large genomic deletions. The sizes of deletion varied between 582 nt (194 aa) and 648 nt (216 aa) at positions 28-714 (10-238) on the S gene (protein). Among 17 PEDV samples isolated from individual pigs, all of them contained at least two distinct genotypes with large genomic deletions, and 94.1% of them were found to consist of strains with an intact S gene. These variants were found in eight primary and nine recurrent outbreaks, and they might be associated with persistent PEDV infection in the farms. Full-length S and ORF3 genes of eight variants derived from 2 samples were characterized. This is the first report of mixed infections caused by various genotypes of PEDV and would be important for the studies of viral isolation, pathogenesis, and molecular epidemiology of the disease. PMID- 28095456 TI - A Rasch Analysis of the Charcot-Marie-Tooth Neuropathy Score (CMTNS) in a Cohort of Charcot-Marie-Tooth Type 1A Patients. AB - The Charcot-Marie-Tooth Neuropathy Score (CMTNS) was developed as a main efficacy endpoint for application in clinical trials of Charcot-Marie-Tooth disease type 1A (CMT1A). However, the sensitivity of the CMTNS for measuring disease severity and progression in CMT1A patients has been questioned. Here, we applied a Rasch analysis in a French cohort of patients to evaluate the psychometrical properties of the CMTNS. Overall, our analysis supports the validity of the CMTNS for application to CMT1A patients though with some limitations such as certain items of the CMTNS being more suitable for moderate to severe forms of the disease, and some items being disordered. We suggest that additional items and/or categories be considered to better assess mild-to-moderate patients. PMID- 28095457 TI - Lysine Decarboxylase with an Enhanced Affinity for Pyridoxal 5-Phosphate by Disulfide Bond-Mediated Spatial Reconstitution. AB - Lysine decarboxylase (LDC) catalyzes the decarboxylation of l-lysine to produce cadaverine, an important industrial platform chemical for bio-based polyamides. However, due to high flexibility at the pyridoxal 5-phosphate (PLP) binding site, use of the enzyme for cadaverine production requires continuous supplement of large amounts of PLP. In order to develop an LDC enzyme from Selenomonas ruminantium (SrLDC) with an enhanced affinity for PLP, we introduced an internal disulfide bond between Ala225 and Thr302 residues with a desire to retain the PLP binding site in a closed conformation. The SrLDCA225C/T302C mutant showed a yellow color and the characteristic UV/Vis absorption peaks for enzymes with bound PLP, and exhibited three-fold enhanced PLP affinity compared with the wild type SrLDC. The mutant also exhibited a dramatically enhanced LDC activity and cadaverine conversion particularly under no or low PLP concentrations. Moreover, introduction of the disulfide bond rendered SrLDC more resistant to high pH and temperature. The formation of the introduced disulfide bond and the maintenance of the PLP binding site in the closed conformation were confirmed by determination of the crystal structure of the mutant. This study shows that disulfide bond-mediated spatial reconstitution can be a platform technology for development of enzymes with enhanced PLP affinity. PMID- 28095458 TI - Sub-Clinical Cognitive Decline and Resting Cerebral Blood Flow in Middle Aged Men. AB - BACKGROUND: Although dementia is associated with both global and regional cerebral blood flow (CBF) changes, little is known about cerebral perfusion in the early pre-clinical stages of cognitive decline preceding overt cognitive dysfunction. The aim of this study was to investigate the association of early sub-clinical cognitive decline with CBF. MATERIALS AND METHODS: The study participants were recruited from a cohort of Danish men born in 1953. Based on a regression model we selected men who performed better (Group A, n = 94) and poorer (Group B, n = 95) on cognitive testing at age 57 than expected from testing at age 20. Participants underwent supplementary cognitive testing, blood sampling and MRI including measurements of regional and global CBF. RESULTS: Regional CBF was lower in group B than in group A in the posterior cingulate gyrus and the precuneus. The associations were attenuated when corrected for global atrophy, but remained significant in regions of interest based analysis adjusting for regional gray matter volume and vascular risk factors. No influence of group on global CBF was observed. CONCLUSIONS: We conclude that early sub clinical cognitive decline is associated with reduced perfusion in the precuneus and posterior cingulate gyrus independently of regional atrophy and vascular risk factors, but cannot be statistically separated from an association with global atrophy. PMID- 28095460 TI - Fecal Fat Analyses in Chronic Pancreatitis Importance of Fat Ingestion before Stool Collection. AB - OBJECTIVE: Quantitative determination of fecal fat still is the gold standard for measuring malabsorption. We evaluated the importance of standardized food intake before and under the collection of feces. MATERIAL AND METHODS: In a project, evaluating patients with suspected chronic pancreatitis (CP) and healthy volunteers (HC), stools were collected for 72 hours coupled to registration of nutritional intake over five consecutive days. Patient groups were created by a modified Layer score, which includes imaging findings, clinical parameters and pancreas function testing. RESULTS: We found 12 patients with CP, 11 patients without CP and 13 healthy individuals in our database. Median fecal fat in CP patients was 12 g/day, in non-CP patients 5 g/day and in healthy controls 5 g/day. Median fat absorption coefficient was 81% in those with chronic pancreatitis, 92% in those without CP and 92% in healthy controls. Corresponding median fat intake was 65 g/day, 68 g/day and 81 g/day in the respective groups. Spearman Rank Order Correlation between fecal fat (g/d) and fat absorption coefficient in all study subjects (n = 36) was good (-0.88 (p<0.001)). When we stratified groups according to fat intake, correlation between fecal fat and fat absorption was also good (-0.86 to -0.95). CONCLUSION: In the diagnoses of fat malabsorption, calculating the ratio of fat absorption did not give additional information compared to fecal fat. PMID- 28095461 TI - The Impact of Antenatal Depression on Perinatal Outcomes in Australian Women. AB - BACKGROUND: In Australia, there is limited evidence on the impact of antenatal depression on perinatal outcomes. This study investigates the association between maternal depressive symptoms during pregnancy and key perinatal outcomes, including birth weight, gestational age at birth, breastfeeding indicators and postnatal depressive symptoms. METHOD: A retrospective cohort of mothers (N = 17,564) of all infants born in public health facilities within South Western Sydney Local Health District and Sydney Local Health District in 2014, in the state of New South Wales (NSW), Australia, was enumerated from routinely collected antenatal data to investigate the risk of adverse perinatal outcomes associated with maternal depressive symptoms during pregnancy. Antenatal depressive symptoms were measured using the Edinburgh Postnatal Depression Scale (EPDS). Logistic regression models that adjusted for confounders were conducted to determine associations between antenatal depressive symptoms and low birth weight, early gestational age at birth (<37 weeks), breast feeding indicators and postnatal depressive symptoms. RESULTS: The prevalence of maternal depressive symptoms during pregnancy was 7.0% in the cohort, and was significantly associated with postnatal depressive symptoms [Adjusted Odd Ratios (AOR) = 6.4, 95% CI: 4.8-8.7, P<0.001]. Antenatal depressive symptoms was associated with a higher odds of low birth weight [AOR = 1.7, 95% CI: 1.2-2.3, P = 0.003] and a gestational age at birth of <37 weeks [AOR = 1.3, 95% CI: 1.1-1.7, P = 0.018] compared to women who reported lower EPDS scores in antenatal period. Antenatal depressive symptoms were not strongly associated with non-exclusive breast feeding in the early postnatal period. CONCLUSION: Maternal depressive symptoms in the antenatal period are strongly associated with postnatal depressive symptoms and adverse perinatal outcomes in Australian infants. Early identification of antenatal and postnatal depressive symptoms, and referral for appropriate management could benefit not only the mother's mental health, but also the infant's health and development. PMID- 28095459 TI - Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach. AB - BACKGROUND: The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. METHODS AND FINDINGS: We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI related differential methylation at 83 CpGs that replicated across cohorts; BMI related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross sectional nature of the data limits definitive causal determination. CONCLUSIONS: We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases. PMID- 28095462 TI - Physiological Characterization and Comparative Transcriptome Analysis of White and Green Leaves of Ananas comosus var. bracteatus. AB - Leaf coloration is one of the most important and attractive characteristics of Ananas comosus var. bracteatus. The chimeric character is not stable during the in vitro tissue culturing. Many regenerated plants lost economic values for the loss of the chimeric character of leaves. In order to reveal the molecular mechanisms involved in the albino phenotype of the leaf cells, the physiological and transcriptional differences between complete white (CWh) and green (CGr) leaf cells of A. comosus var. bracteatus were analyzed. A total of 1,431 differentially expressed unigenes (DEGs) in CGr and CWh leaves were identified using RNA-seq. A comparison to the COG, GO and KEGG annotations revealed DEGs involved in chlorophyll biosynthesis, chloroplast development and photosynthesis. Furthermore, the measurement of main precursors of chlorophyll in the CWh leaves confirmed that the rate-limiting step in chlorophyll biosynthesis, and thus the cause of the albino phenotype of the white cells, was the conversion of pyrrole porphobilinogen (PBG) to uroporphyrinogen III (Uro III). The enzyme activity of porphobilinogen deaminase (PBGD) and uroporporphyrinogn III synthase (UROS), which catalyze the transition of PBG to Uro III, was significantly decreased in the CWh leaves. Our data showed the transcriptional differences between the CWh and CGr plants and characterized key steps in chlorophyll biosynthesis of the CWh leaves. These results contribute to our understanding of the mechanisms and regulation of pigment biosynthesis in the CWh leaf cells of A. comosus var. bracteatus. PMID- 28095463 TI - Brain Parenchymal Fraction in Healthy Adults-A Systematic Review of the Literature. AB - Brain atrophy is an important feature of many neurodegenerative disorders. It can be described in terms of change in the brain parenchymal fraction (BPF). In order to interpret the BPF in disease, knowledge on the BPF in healthy individuals is required. The aim of this study was to establish a normal range of values for the BPF of healthy individuals via a systematic review of the literature. The databases PubMed and Scopus were searched and 95 articles, including a total of 9269 individuals, were identified including the required data. We present values of BPF from healthy individuals stratified by age and post-processing method. The mean BPF correlated with mean age and there were significant differences in age adjusted mean BPF between methods. This study contributes to increased knowledge about BPF in healthy individuals, which may assist in the interpretation of BPF in the setting of disease. We highlight the differences between post-processing methods and the need for a consensus gold standard. PMID- 28095464 TI - Molecular Control of Innate Immune Response to Pseudomonas aeruginosa Infection by Intestinal let-7 in Caenorhabditis elegans. AB - The microRNA (miRNA) let-7 is an important miRNA identified in Caenorhabditis elegans and has been shown to be involved in the control of innate immunity. The underlying molecular mechanisms for let-7 regulation of innate immunity remain largely unclear. In this study, we investigated the molecular basis for intestinal let-7 in the regulation of innate immunity. Infection with Pseudomonas aeruginosa PA14 decreased let-7::GFP expression. Intestine- or neuron-specific activity of let-7 was required for its function in the regulation of innate immunity. During the control of innate immune response to P. aeruginosa PA14 infection, SDZ-24 was identified as a direct target for intestinal let-7. SDZ-24 was found to be predominantly expressed in the intestine, and P. aeruginosa PA14 infection increased SDZ-24::GFP expression. Intestinal let-7 regulated innate immune response to P. aeruginosa PA14 infection by suppressing both the expression and the function of SDZ-24. Knockout or RNA interference knockdown of sdz-24 dampened the resistance of let-7 mutant to P. aeruginosa PA14 infection. Intestinal overexpression of sdz-24 lacking 3'-UTR inhibited the susceptibility of nematodes overexpressing intestinal let-7 to P. aeruginosa PA14 infection. In contrast, we could observed the effects of intestinal let-7 on innate immunity in P. aeruginosa PA14 infected transgenic strain overexpressing sdz-24 containing 3' UTR. In the intestine, certain SDZ-24-mediated signaling cascades were formed for nematodes against the P. aeruginosa PA14 infection. Our results highlight the crucial role of intestinal miRNAs in the regulation of the innate immune response to pathogenic infection. PMID- 28095465 TI - Leishmania HASP and SHERP Genes Are Required for In Vivo Differentiation, Parasite Transmission and Virulence Attenuation in the Host. AB - Differentiation of extracellular Leishmania promastigotes within their sand fly vector, termed metacyclogenesis, is considered to be essential for parasites to regain mammalian host infectivity. Metacyclogenesis is accompanied by changes in the local parasite environment, including secretion of complex glycoconjugates within the promastigote secretory gel and colonization and degradation of the sand fly stomodeal valve. Deletion of the stage-regulated HASP and SHERP genes on chromosome 23 of Leishmania major is known to stall metacyclogenesis in the sand fly but not in in vitro culture. Here, parasite mutants deficient in specific genes within the HASP/SHERP chromosomal region have been used to investigate their role in metacyclogenesis, parasite transmission and establishment of infection. Metacyclogenesis was stalled in HASP/SHERP mutants in vivo and, although still capable of osmotaxis, these mutants failed to secrete promastigote secretory gel, correlating with a lack of parasite accumulation in the thoracic midgut and failure to colonise the stomodeal valve. These defects prevented parasite transmission to a new mammalian host. Sand fly midgut homogenates modulated parasite behaviour in vitro, suggesting a role for molecular interactions between parasite and vector in Leishmania development within the sand fly. For the first time, stage-regulated expression of the small HASPA proteins in Leishmania (Leishmania) has been demonstrated: HASPA2 is expressed only in extracellular promastigotes and HASPA1 only in intracellular amastigotes. Despite its lack of expression in amastigotes, replacement of HASPA2 into the null locus background delays onset of pathology in BALB/c mice. This HASPA2 dependent effect is reversed by HASPA1 gene addition, suggesting that the HASPAs may have a role in host immunomodulation. PMID- 28095466 TI - Substrate Stiffness Controls Osteoblastic and Chondrocytic Differentiation of Mesenchymal Stem Cells without Exogenous Stimuli. AB - Stem cell fate has been linked to the mechanical properties of their underlying substrate, affecting mechanoreceptors and ultimately leading to downstream biological response. Studies have used polymers to mimic the stiffness of extracellular matrix as well as of individual tissues and shown mesenchymal stem cells (MSCs) could be directed along specific lineages. In this study, we examined the role of stiffness in MSC differentiation to two closely related cell phenotypes: osteoblast and chondrocyte. We prepared four methyl acrylate/methyl methacrylate (MA/MMA) polymer surfaces with elastic moduli ranging from 0.1 MPa to 310 MPa by altering monomer concentration. MSCs were cultured in media without exogenous growth factors and their biological responses were compared to committed chondrocytes and osteoblasts. Both chondrogenic and osteogenic markers were elevated when MSCs were grown on substrates with stiffness <10 MPa. Like chondrocytes, MSCs on lower stiffness substrates showed elevated expression of ACAN, SOX9, and COL2 and proteoglycan content; COMP was elevated in MSCs but reduced in chondrocytes. Substrate stiffness altered levels of RUNX2 mRNA, alkaline phosphatase specific activity, osteocalcin, and osteoprotegerin in osteoblasts, decreasing levels on the least stiff substrate. Expression of integrin subunits alpha1, alpha2, alpha5, alphav, beta1, and beta3 changed in a stiffness- and cell type-dependent manner. Silencing of integrin subunit beta 1 (ITGB1) in MSCs abolished both osteoblastic and chondrogenic differentiation in response to substrate stiffness. Our results suggest that substrate stiffness is an important mediator of osteoblastic and chondrogenic differentiation, and integrin beta1 plays a pivotal role in this process. PMID- 28095467 TI - Phylogenetically Widespread Polyembryony in Cyclostome Bryozoans and the Protracted Asynchronous Release of Clonal Brood-Mates. AB - Polyembryony-the production of multiple cloned embryos from a single fertilised egg-is a seemingly paradoxical combination of reproductive modes that nevertheless persists in diverse taxa. We document features of polyembryony in the Cyclostomata (Bryozoa)-an ancient order of modular colonial marine invertebrates-that suggest a substantial reduction in the paradoxical nature of this enigmatic reproductive mode. Firstly, we provide molecular evidence for polyembryony in three exemplar species, supporting the widely cited inference that polyembryony characterises the entire order. Secondly, genotyping demonstrates protracted release of cloned offspring from the primary embryo in a given gonozooid (chamber for embryonic incubation), thus exposing the same genotype to changing environmental conditions over time. Finally, we confirm that each gonozooid produces a distinct genotype, with each primary embryo being the result of a separate fertilisation event. We hypothesise that the sustained release of one or a few genotypes against varying environmental conditions achieves levels of risk-spreading similar to those in organisms that release multiple, unique genotypes at a single time. We argue that polyembryony, specifically with the production of a large number of progeny per fertilisation event, has been favoured in the Cyclostomata over long geological periods. PMID- 28095468 TI - Evaluating Hospital-Based Surveillance for Outbreak Detection in Bangladesh: Analysis of Healthcare Utilization Data. AB - BACKGROUND: The International Health Regulations outline core requirements to ensure the detection of public health threats of international concern. Assessing the capacity of surveillance systems to detect these threats is crucial for evaluating a country's ability to meet these requirements. METHODS AND FINDINGS: We propose a framework to evaluate the sensitivity and representativeness of hospital-based surveillance and apply it to severe neurological infectious diseases and fatal respiratory infectious diseases in Bangladesh. We identified cases in selected communities within surveillance hospital catchment areas using key informant and house-to-house surveys and ascertained where cases had sought care. We estimated the probability of surveillance detecting different sized outbreaks by distance from the surveillance hospital and compared characteristics of cases identified in the community and cases attending surveillance hospitals. We estimated that surveillance detected 26% (95% CI 18%-33%) of severe neurological disease cases and 18% (95% CI 16%-21%) of fatal respiratory disease cases residing at 10 km distance from a surveillance hospital. Detection probabilities decreased markedly with distance. The probability of detecting small outbreaks (three cases) dropped below 50% at distances greater than 26 km for severe neurological disease and at distances greater than 7 km for fatal respiratory disease. Characteristics of cases attending surveillance hospitals were largely representative of all cases; however, neurological disease cases aged <5 y or from the lowest socioeconomic group and fatal respiratory disease cases aged >=60 y were underrepresented. Our estimates of outbreak detection rely on suspected cases that attend a surveillance hospital receiving laboratory confirmation of disease and being reported to the surveillance system. The extent to which this occurs will depend on disease characteristics (e.g., severity and symptom specificity) and surveillance resources. CONCLUSION: We present a new approach to evaluating the sensitivity and representativeness of hospital-based surveillance, making it possible to predict its ability to detect emerging threats. PMID- 28095469 TI - Characterization of Dof Transcription Factors and Their Responses to Osmotic Stress in Poplar (Populus trichocarpa). AB - The DNA-binding One Zinc Finger (Dof) genes are ubiquitous in many plant species and are especial transcription regulators that participate in plant growth, development and various procedures, including biotic and abiotic stress reactions. In this study, we identified 41 PtrDof members from Populus trichocarpa genomes and classified them into four groups. The conserved motifs and gene structures of some PtrDof genes belonging to the same subgroup were almost the same. The 41 PtrDof genes were dispersed on 18 of the 19 Populus chromosomes. Many key stress- or phytohormone-related cis-elements were discovered in the PtrDof gene promoter regions. Consequently, we undertook expression profiling of the PtrDof genes in leaves and roots in response to osmotic stress and abscisic acid. A total of seven genes (PtrDof14, 16, 25, 27, 28, 37 and 39) in the Populus Dof gene family were consistently upregulated at point in all time in the leaves and roots under osmotic and abscisic acid (ABA) stress. We observed that 12 PtrDof genes could be targeted by 15 miRNAs. Moreover, we mapped the cleavage site in PtrDof30 using the 5'RLM-RACE. The results showed that PtrDofs may have a role in resistance to abiotic stress in Populus trichocarpa. PMID- 28095471 TI - Prevalence and Risk Factors of Prehypertension and Hypertension in Southern China. AB - BACKGROUND: This study aimed to describe the prevalence and risk factors of prehypertension and hypertension in Jiangxi Province, China. Individuals with prehypertension frequently progress into hypertension and are at high risk of developing cardiovascular disease and stroke. METHODS: A cross-sectional survey of 15,296 participants (15 years or older) was conducted in Jiangxi Province, China, in 2013, using questionnaire forms and physical measurements. RESULTS: The prevalence of prehypertension and hypertension was 32.3% (39.2% in men and 27.6% in women) and 29.0% (30.1% in men and 28.2% in women), respectively. The awareness, treatment, and control rates among all hypertensive participants were 64.8%, 27.1%, and 12.6%, respectively. The prevalence of prehypertension in males declined with age, but the prevalence of hypertension increased in different genders. The prevalence of prehypertension and hypertension increased with increasing body mass index (BMI). The prevalence of prehypertension decreased, in parallel to an increase in the prevalence of hypertension, with increasing waist circumference (WC). A combination of WC and BMI was superior to individual indices in identifying hypertension. A multivariate logistic regression analysis indicated that increasing age, high BMI, high visceral adipose index, and high heart rate were risk factors for prehypertension and hypertension. The high body fat percentage was significantly associated with prehypertension. Living in an urban area, male sex, abdominal obesity, and menopause were correlated with hypertension. CONCLUSIONS: Prehypertension and hypertension are epidemic in southern China. Further studies are needed to explore an indicator that can represent the visceral fat accurately and has a close relationship with cardiovascular disease. PMID- 28095472 TI - Review of Participatory Epidemiology Practices in Animal Health (1980-2015) and Future Practice Directions. AB - In this study we combined an inventory of the major applications, geographic regions and diseases covered by participatory epidemiology (PE) activities in the field of animal health since 1980, together with an email discussion forum with PE practitioners from different regions of the world. The inventory included the search of peer-reviewed papers, master and technical reports, conference proceedings, manuals, training materials and projects. The search resulted in a low number of PE activity results until the year 2000, followed by a considerable increase (especially from 2012). Most of the identified activities were implemented in Africa and Asia, and focused on surveillance, disease survey and prioritization, and disease control. Seventy-nine PE practitioners working predominantly in Africa, Asia and Europe (29, 22 and 18 respectively) contributed to the email discussion forum. They proposed various modifications to the existing PE definition and discussed different issues related to the applicatoin of PE, its institutionalization for use in policy development, as well as the priorities for future development. The need to increase the number of PE trained people together with some methodological developments and the application of this methodology in developed countries, were some of the points highlighted during the forum. These factors stress the importance of further developing PE as a useful approach for engaging communities in addressing animal and related public health risks. PMID- 28095470 TI - Endogenous Semaphorin-7A Impedes Human Lung Fibroblast Differentiation. AB - Semaphorin-7A is a glycosylphosphatidylinositol-anchored protein, initially characterized as an axon guidance protein. Semaphorin-7A also contributes to immune cell regulation and may be an essential pro-fibrotic factor when expressed by non-fibroblast cell types (exogenous). In mouse models, semaphorin-7A was shown to be important for TGF-beta1-induced pulmonary fibrosis characterized by myofibroblast accumulation and extracellular matrix deposition, but the cell specific role of semaphorin-7A was not examined in fibroblasts. The purpose of this study is to determine semaphorin-7A expression by fibroblasts and to investigate the function of endogenously expressed semaphorin-7A in primary human lung fibroblasts (HLF). Herein, we show that non-fibrotic HLF expressed high levels of cell surface semaphorin-7A with little dependence on the percentage of serum or recombinant TGF-beta1. Semaphorin-7A siRNA strongly decreased semaphorin 7A mRNA expression and reduced cell surface semaphorin-7A. Reduction of semaphorin-7A induced increased proliferation and migration of non-fibrotic HLF. Also, independent of the presence of TGF-beta1, the decline of semaphorin-7A by siRNA was associated with increased alpha-smooth muscle actin production and gene expression of periostin, fibronectin, laminin, and serum response factor (SRF), indicating differentiation into a myofibroblast. Conversely, overexpression of semaphorin-7A in the NIH3T3 fibroblast cell line reduced the production of pro fibrotic markers. The inverse association between semaphorin-7A and pro-fibrotic fibroblast markers was further analyzed using HLF from idiopathic pulmonary fibrosis (IPF) (n = 6) and non-fibrotic (n = 7) lungs. Using these 13 fibroblast lines, we observed that semaphorin-7A and periostin expression were inversely correlated. In conclusion, our study indicates that endogenous semaphorin-7A in HLF plays a role in maintaining fibroblast homeostasis by preventing up regulation of pro-fibrotic genes. Therefore, endogenous and exogenous semaphorin 7A may have opposite effects on the fibroblast phenotype. PMID- 28095473 TI - The Asymmetric Cell Division Regulators Par3, Scribble and Pins/Gpsm2 Are Not Essential for Erythroid Development or Enucleation. AB - Erythroid enucleation is the process by which the future red blood cell disposes of its nucleus prior to entering the blood stream. This key event during red blood cell development has been likened to an asymmetric cell division (ACD), by which the enucleating erythroblast divides into two very different daughter cells of alternate molecular composition, a nucleated cell that will be removed by associated macrophages, and the reticulocyte that will mature to the definitive erythrocyte. Here we investigated gene expression of members of the Par, Scribble and Pins/Gpsm2 asymmetric cell division complexes in erythroid cells, and functionally tested their role in erythroid enucleation in vivo and ex vivo. Despite their roles in regulating ACD in other contexts, we found that these polarity regulators are not essential for erythroid enucleation, nor for erythroid development in vivo. Together our results put into question a role for cell polarity and asymmetric cell division in erythroid enucleation. PMID- 28095474 TI - Anti-Prion Screening for Acridine, Dextran, and Tannic Acid using Real Time Quaking Induced Conversion: A Comparison with PrPSc-Infected Cell Screening. AB - Prion propagation is mediated by the structural alteration of normal prion protein (PrPC) to generate pathogenic prion protein (PrPSc). To date, compounds for the inhibition of prion propagation have mainly been screened using PrPSc infected cells. Real time-quaking-induced conversion (RT-QuIC) is one alternative screening method. In this study, we assessed the propagation inhibition effects of known anti-prion compounds using RT-QuIC and compared the results with those from a PrPSc-infected cell assay. Compounds were applied to RT-QuIC reactions at 0 h or 22 h after prion propagation to determine whether they inhibited propagation or reduced amplified aggregates. RT-QuIC reactions in presence of acridine, dextran sulfate sodium (DSS), and tannic acid inhibited seeded aggregation with sporadic Creutzfeldt-Jakob disease at 0 h. After treatment at 22 h, amplified fluorescence was decreased in wells treated with either acridine or tannic acid. Compound activities were verified by western blot of RT-QuIC products and in a dye-independent conversion assay, the Multimer Detection System. Protease K-resistant PrPSc fragments (PrPres) were reduced by DSS and tannic acid in the PrPSc-infected cell assay. Importantly, these inhibitory effects were similar despite different treatment times (0 h versus 3 days). Consequentially, RT-QuIC enabled the more specific classification of compounds according to action (i.e., inhibition of prion propagation versus reduction of amplified aggregates). RT-QuIC addresses the limitations of cell-based screening methods and can be used to further aid our understanding of the mechanisms of action of anti-prion compounds. PMID- 28095475 TI - The Influence of Community Health Resources on Effectiveness and Sustainability of Community and Lay Health Worker Programs in Lower-Income Countries: A Systematic Review. AB - BACKGROUND: Despite the availability of practical knowledge and effective interventions required to reduce priority health problems in low-income countries, poor and vulnerable populations are often not reached. One possible solution to this problem is the use of Community or Lay Health Workers (CLHWs). So far, however, the development of sustainability in CLHW programs has failed and high attrition rates continue to pose a challenge. We propose that the roles and interests which support community health work should emerge directly from the way in which health is organized at community level. This review explores the evidence available to assess if increased levels of integration of community health resources in CLHW programs indeed lead to higher program effectiveness and sustainability. METHODS AND FINDINGS: This review includes peer-reviewed articles which meet three eligibility criteria: 1) specific focus on CLHWs or equivalent; 2) randomized, quasi-randomized, before/after methodology or substantial descriptive assessment; and 3) description of a community or peer intervention health program located in a low- or middle-income country. Literature searches using various article databases led to 2930 hits, of which 359 articles were classified. Of these, 32 articles were chosen for extensive review, complemented by analysis of the results of 15 other review studies. Analysis was conducted using an excel based data extraction form. Because results showed that no quantitative data was published, a descriptive synthesis was conducted. The review protocol was not proactively registered. Findings show minimal inclusion of even basic community level indicators, such as the degree to which the program is a community initiative, community input in the program or training, the background and history of CLHW recruits, and the role of the community in motivation and retention. Results show that of the 32 studies, only one includes one statistical measure of community integration. As a result of this lack of data we are unable to derive an evidence-based conclusion to our propositions. Instead, our results indicate a larger problem, namely the complete absence of indicators measuring community relationships with the programs studied. Studies pay attention only to gender and peer roles, along with limited demographic information about the recruits. The historicity of the health worker and the community s/he belongs to is absent in most studies reviewed. None of the studies discuss or test for the possibility that motivation emanates from the community. Only a few studies situate attrition and retention as an issue enabled by the community. The results were limited by a focus on low-income countries and English, peer-reviewed published articles only. CONCLUSION: Published, peer reviewed studies evaluating the effectiveness and sustainability of CLHW interventions in health programs have not yet adequately tested for the potential of utilizing existing community health roles or social networks for the development of effective and sustainable (retentive) CLHW programs. Community relationships are generally seen as a "black box" represented by an interchangeable CLHW labor unit. This disconnect from community relationships and resources may have led to a systematic and chronic undervaluing of community agency in explanations of programmatic effectiveness and sustainability. PMID- 28095476 TI - A Systematic Review of Ebola Treatment Trials to Assess the Extent to Which They Adhere to Ethical Guidelines. AB - BACKGROUND: Objective: To determine to what extent each trial met criteria specified in three research frameworks for ethical trial conduct. Design: Systematic review and narrative analysis. METHODS AND FINDINGS: Data sources: MEDBASE and EMBASE databases were searched using a specific search strategy. The Cochrane database for systematic reviews, the PROSPERO database and trial registries were examined. A grey literature search and citation search were also carried out. Eligibility criteria for selecting studies: Studies were included where the intervention was being used to treat Ebola in human subjects regardless of study design, comparator or outcome measured. Studies were eligible if they had taken place after the 21st March 2014. Unpublished as well as published studies were included. Included studies: Sixteen studies were included in the data synthesis. Data was extracted on study characteristics as well as any information relating to ten ethical areas of interest specified in the three research frameworks for ethical trial conduct and an additional criterion of whether the study received ethics approval from a research ethics committee. Synthesis of results: Eight studies were judged to fully comply with all eleven criteria. The other eight studies all had at least one criteria where there was not enough information available to draw any conclusions. In two studies there were ethical concerns regarding the information provided in relation to at least one ethical criteria. Description of the effect: One study did not receive ethical approval as the authors argued that treating approximately one hundred patients consecutively for compassionate reasons did not constitute a clinical trial. Furthermore, after the patients were treated, physicians in Sierra Leone did not release reports of treatment results and so study conclusions had to be made based on unpublished observations. In another study the risk-benefit ratio of the trial drug does not appear to be favourable and the pre-trial evidence base for its effectiveness against Ebola is speculative. CONCLUSIONS: Some limited and appropriate deviation from standard research expectations in disaster situations is increasingly accepted. However, this is not an excuse for poor ethics oversight and international regulations are in place which should not be ignored. New guidelines are needed that better define the boundaries between using medicines for compassionate use and conducting a clinical trial. Greater support should be offered for local research ethics committees in affected areas so that they can provide robust ethical review. Further systematic reviews should be carried out in epidemics of any novel infectious diseases to assess if comparable findings arise. PMID- 28095478 TI - Evaluating Silent Reading Performance with an Eye Tracking System in Patients with Glaucoma. AB - OBJECTIVE: To investigate the relationship between silent reading performance and visual field defects in patients with glaucoma using an eye tracking system. METHODS: Fifty glaucoma patients (Group G; mean age, 52.2 years, standard deviation: 11.4 years) and 20 normal controls (Group N; mean age, 46.9 years; standard deviation: 17.2 years) were included in the study. All participants in Group G had early to advanced glaucomatous visual field defects but better than 20/20 visual acuity in both eyes. Participants silently read Japanese articles written horizontally while the eye tracking system monitored and calculated reading duration per 100 characters, number of fixations per 100 characters, and mean fixation duration, which were compared with mean deviation and visual field index values from Humphrey visual field testing (24-2 and 10-2 Swedish interactive threshold algorithm standard) of the right versus left eye and the better versus worse eye. RESULTS: There was a statistically significant difference between Groups G and N in mean fixation duration (G, 233.4 msec; N, 215.7 msec; P = 0.010). Within Group G, significant correlations were observed between reading duration and 24-2 right mean deviation (rs = -0.280, P = 0.049), 24-2 right visual field index (rs = -0.306, P = 0.030), 24-2 worse visual field index (rs = -0.304, P = 0.032), and 10-2 worse mean deviation (rs = -0.326, P = 0.025). Significant correlations were observed between mean fixation duration and 10-2 left mean deviation (rs = -0.294, P = 0.045) and 10-2 worse mean deviation (rs = -0.306, P = 0.037), respectively. CONCLUSIONS: The severity of visual field defects may influence some aspects of reading performance. At least concerning silent reading, the visual field of the worse eye is an essential element of smoothness of reading. PMID- 28095477 TI - The Burden of Mental Disorders in the Eastern Mediterranean Region, 1990-2013. AB - The Eastern Mediterranean Region (EMR) is witnessing an increase in chronic disorders, including mental illness. With ongoing unrest, this is expected to rise. This is the first study to quantify the burden of mental disorders in the EMR. We used data from the Global Burden of Disease study (GBD) 2013. DALYs (disability-adjusted life years) allow assessment of both premature mortality (years of life lost-YLLs) and nonfatal outcomes (years lived with disability YLDs). DALYs are computed by adding YLLs and YLDs for each age-sex-country group. In 2013, mental disorders contributed to 5.6% of the total disease burden in the EMR (1894 DALYS/100,000 population): 2519 DALYS/100,000 (2590/100,000 males, 2426/100,000 females) in high-income countries, 1884 DALYS/100,000 (1618/100,000 males, 2157/100,000 females) in middle-income countries, 1607 DALYS/100,000 (1500/100,000 males, 1717/100,000 females) in low-income countries. Females had a greater proportion of burden due to mental disorders than did males of equivalent ages, except for those under 15 years of age. The highest proportion of DALYs occurred in the 25-49 age group, with a peak in the 35-39 years age group (5344 DALYs/100,000). The burden of mental disorders in EMR increased from 1726 DALYs/100,000 in 1990 to 1912 DALYs/100,000 in 2013 (10.8% increase). Within the mental disorders group in EMR, depressive disorders accounted for most DALYs, followed by anxiety disorders. Among EMR countries, Palestine had the largest burden of mental disorders. Nearly all EMR countries had a higher mental disorder burden compared to the global level. Our findings call for EMR ministries of health to increase provision of mental health services and to address the stigma of mental illness. Moreover, our results showing the accelerating burden of mental health are alarming as the region is seeing an increased level of instability. Indeed, mental health problems, if not properly addressed, will lead to an increased burden of diseases in the region. PMID- 28095479 TI - Central Role of IL-23 and IL-17 Producing Eosinophils as Immunomodulatory Effector Cells in Acute Pulmonary Aspergillosis and Allergic Asthma. AB - Aspergillus fumigatus causes invasive pulmonary disease in immunocompromised hosts and allergic asthma in atopic individuals. We studied the contribution of lung eosinophils to these fungal diseases. By in vivo intracellular cytokine staining and confocal microscopy, we observed that eosinophils act as local sources of IL-23 and IL-17. Remarkably, mice lacking eosinophils had a >95% reduction in the percentage of lung IL-23p19+ cells as well as markedly reduced IL-23 heterodimer in lung lavage fluid. Eosinophils killed A. fumigatus conidia in vivo. Eosinopenic mice had higher mortality rates, decreased recruitment of inflammatory monocytes, and decreased expansion of lung macrophages after challenge with conidia. All of these functions underscore a potential protective role for eosinophils in acute aspergillosis. Given the postulated role for IL-17 in asthma pathogenesis, we assessed whether eosinophils could act as sources of IL-23 and IL-17 in models where mice were sensitized to either A. fumigatus antigens or ovalbumin (OVA). We found IL-23p19+ IL-17AF+ eosinophils in both allergic models. Moreover, close to 95% of IL-23p19+ cells and >90% of IL-17AF+ cells were identified as eosinophils. These data establish a new paradigm in acute and allergic aspergillosis whereby eosinophils act not only as effector cells but also as immunomodulatory cells driving the IL-23/IL-17 axis and contributing to inflammatory cell recruitment. PMID- 28095481 TI - Correction: Variant Exported Blood-Stage Proteins Encoded by Plasmodium Multigene Families Are Expressed in Liver Stages Where They Are Exported into the Parasitophorous Vacuole. AB - [This corrects the article DOI: 10.1371/journal.ppat.1005917.]. PMID- 28095480 TI - Inference of Candidate Germline Mutator Loci in Humans from Genome-Wide Haplotype Data. AB - The rate of germline mutation varies widely between species but little is known about the extent of variation in the germline mutation rate between individuals of the same species. Here we demonstrate that an allele that increases the rate of germline mutation can result in a distinctive signature in the genomic region linked to the affected locus, characterized by a number of haplotypes with a locally high proportion of derived alleles, against a background of haplotypes carrying a typical proportion of derived alleles. We searched for this signature in human haplotype data from phase 3 of the 1000 Genomes Project and report a number of candidate mutator loci, several of which are located close to or within genes involved in DNA repair or the DNA damage response. To investigate whether mutator alleles remained active at any of these loci, we used de novo mutation counts from human parent-offspring trios in the 1000 Genomes and Genome of the Netherlands cohorts, looking for an elevated number of de novo mutations in the offspring of parents carrying a candidate mutator haplotype at each of these loci. We found some support for two of the candidate loci, including one locus just upstream of the BRSK2 gene, which is expressed in the testis and has been reported to be involved in the response to DNA damage. PMID- 28095482 TI - An Increase in Mean Platelet Volume/Platelet Count Ratio Is Associated with Vascular Access Failure in Hemodialysis Patients. AB - After stenosis of arteriovenous vascular access in hemodialysis patients, platelets play a crucial role in subsequent thrombus formation, leading to access failure. In a previous study, the mean platelet volume (MPV)/platelet count ratio, but not MPV alone, was shown to be an independent predictor of 4-year mortality after myocardial infarction. However, little is known about the potential influence of MPV/platelet count ratio on vascular access patency in hemodialysis patients. A total of 143 patients undergoing routine hemodialysis were recruited between January 2013 and February 2016. Vascular access failure (VAF) was defined as thrombosis or a decrease of greater than 50% of normal vessel diameter, requiring either surgical revision or percutaneous transluminal angioplasty. Cox proportional hazards model analysis ascertained that the change of MPV/platelet count ratio between baseline and 3 months [Delta(MPV/platelet count ratio)3mo-baseline] had prognostic value for VAF. Additionally, the changes of MPV/platelet count ratio over time were compared in patients with and without VAF by using linear mixed model analysis. Of the 143 patients, 38 (26.6%) were diagnosed with VAF. During a median follow-up of 26.9 months (interquartile range 13.0-36.0 months), Delta(MPV/platelet count ratio)3mo-baseline significantly increased in patients with VAF compared to that in patients without VAF [11.6 (6.3-19.0) vs. 0.8 (-1.8-4.0), P< 0.001]. In multivariate analysis, Delta(MPV/platelet ratio count)3mo-baseline was an independent predictor of VAF, after adjusting for age, sex, diabetes, hypertension, coronary artery disease, cerebrovascular disease, vascular access type, the presence of previous VAF, and antiplatelet drug use (hazard ratio, 1.15; 95% confidence interval, 1.10-1.21; P< 0.001). Moreover, a liner mixed model revealed that there was a significant increase of MPV/platelet count ratio over time in patients with VAF compared to those without VAF (P< 0.001). An increase in MPV/platelet count ratio over time was an independent risk factor for VAF. Therefore, continuous monitoring of the MPV/platelet count ratio may be useful to screen the risk of VAF in patients undergoing routine hemodialysis. PMID- 28095483 TI - Association between NF-kappaB Pathway Gene Variants and sICAM1 Levels in Taiwanese. AB - Intercellular adhesion molecule-1 (ICAM1) is crucial to the development and progression of atherosclerosis. Recent genome-wide association studies (GWAS) have revealed that single nucleotide polymorphisms (SNPs) in two of the nuclear factor-kappaB (NF-kappaB) pathway genes, NFKBIK and RELA, are associated with soluble ICAM1 (sICAM1) levels. However, neither of these two gene variants is found in the Asian populations. This study aimed to elucidate whether other candidate gene variants involved in the NF-kappaB pathway may be associated with sICAM1 levels in Taiwanese. After excluding carriers of the ICAM1 rs5491-T allele, three SNPs in the ICAM1 gene and eight SNPs in six of the NF-kappaB pathway genes (NFKB1, PDCD11, TNFAIP3, NKAPL, IKBKE, and PRKCB) were analyzed for their association with sICAM1 levels in 480 individuals. Our data showed that two SNPs, rs5498 of ICAM1 and rs1635 of NKAPL, were significantly associated with sICAM1 levels (P = 0.002 and 0.004, respectively) in the Taiwanese population. Using a multivariate analysis, rs5498 and rs1635 as well as the previously reported ABO genotypes and rs12051272 of the CDH13 gene were independently associated with sICAM1 levels (P = 0.001, 0.001, 0.006 and 0.031, respectively). An analysis with combined risk alleles of four candidate SNPs in the ICAM1, NKAPL, ABO, and CDH13 genes showed an increase in sICAM1 levels with added numbers of risk alleles and weighted genetic risk score. Our findings thus expanded the repertoire of gene variants responsible for the regulation of sICAM1 levels in the Asian populations. PMID- 28095484 TI - Experimental Diabetes Alters the Morphology and Nano-Structure of the Achilles Tendon. AB - Although of several studies that associate chronic hyperglycemia with tendinopathy, the connection between morphometric changes as witnessed by magnetic resonance (MR) images, nanostructural changes, and inflammatory markers have not yet been fully established. Therefore, the present study has as a hypothesis that the Achilles tendons of rats with diabetes mellitus (DM) exhibit structural changes. The animals were randomly divided into two experimental groups: Control Group (n = 06) injected with a vehicle (sodium citrate buffer solution) and Diabetic Group (n = 06) consisting of rats submitted to intraperitoneal administration of streptozotocin. MR was performed 24 days after the induction of diabetes and images were used for morphometry using ImageJ software. Morphology of the collagen fibers within tendons was examined using Atomic Force microscopy (AFM). An increase in the dimension of the coronal plane area was observed in the diabetic group (8.583 +/- 0.646 mm2/100g) when compared to the control group (4.823 +/- 0.267 mm2/100g) resulting in a significant difference (p = 0.003) upon evaluating the Achilles tendons. Similarly, our analysis found an increase in the size of the transverse section area in the diabetic group (1.328 +/- 0.103 mm2/100g) in comparison to the control group (0.940 +/- 0.01 mm2/100g) p = 0.021. The tendons of the diabetic group showed great irregularity in fiber bundles, including modified grain direction and jagged junctions and deformities in the form of collagen fibrils bulges. Despite the morphological changes observed in the Achilles tendon of diabetic animals, IL1 and TNF-alpha did not change. Our results suggest that DM promotes changes to the Achilles tendon with important structural modifications as seen by MR and AFM, excluding major inflammatory changes. PMID- 28095485 TI - Bordetella parapertussis Circumvents Neutrophil Extracellular Bactericidal Mechanisms. AB - B. parapertussis is a whooping cough etiological agent with the ability to evade the immune response induced by pertussis vaccines. We previously demonstrated that in the absence of opsonic antibodies B. parapertussis hampers phagocytosis by neutrophils and macrophages and, when phagocytosed, blocks intracellular killing by interfering with phagolysosomal fusion. But neutrophils can kill and/or immobilize extracellular bacteria through non-phagocytic mechanisms such as degranulation and neutrophil extracellular traps (NETs). In this study we demonstrated that B. parapertussis also has the ability to circumvent these two neutrophil extracellular bactericidal activities. The lack of neutrophil degranulation was found dependent on the O antigen that targets the bacteria to cell lipid rafts, eventually avoiding the fusion of nascent phagosomes with specific and azurophilic granules. IgG opsonization overcame this inhibition of neutrophil degranulation. We further observed that B. parapertussis did not induce NETs release in resting neutrophils and inhibited NETs formation in response to phorbol myristate acetate (PMA) stimulation by a mechanism dependent on adenylate cyclase toxin (CyaA)-mediated inhibition of reactive oxygen species (ROS) generation. Thus, B. parapertussis modulates neutrophil bactericidal activity through two different mechanisms, one related to the lack of proper NETs inducer stimuli and the other one related to an active inhibitory mechanism. Together with previous results these data suggest that B. parapertussis has the ability to subvert the main neutrophil bactericidal functions, inhibiting efficient clearance in non-immune hosts. PMID- 28095486 TI - Three-Dimensional Assessment of Temporomandibular Joint Using MRI-CBCT Image Registration. AB - PURPOSE: To introduce a new approach to reconstruct a 3D model of the TMJ using magnetic resonance imaging (MRI) and cone-beam computed tomography (CBCT) registered images, and to evaluate the intra-examiner reproducibility values of reconstructing the 3D models of the TMJ. METHODS: MRI and CBCT images of five patients (10 TMJs) were obtained. Multiple MRIs and CBCT images were registered using a mutual information based algorithm. The articular disc, condylar head and glenoid fossa were segmented at two different occasions, at least one-week apart, by one investigator, and 3D models were reconstructed. Differences between the segmentation at two occasions were automatically measured using the surface contours (Average Perpendicular Distance) and the volume overlap (Dice Similarity Index) of the 3D models. Descriptive analysis of the changes at 2 occasions, including means and standard deviation (SD) were reported to describe the intra examiner reproducibility. RESULTS: The automatic segmentation of the condyle revealed maximum distance change of 1.9+/-0.93 mm, similarity index of 98% and root mean squared distance of 0.1+/-0.08 mm, and the glenoid fossa revealed maximum distance change of 2+/-0.52 mm, similarity index of 96% and root mean squared distance of 0.2+/-0.04 mm. The manual segmentation of the articular disc revealed maximum distance change of 3.6+/-0.32 mm, similarity index of 80% and root mean squared distance of 0.3+/-0.1 mm. CONCLUSION: The MRI-CBCT registration provides a reliable tool to reconstruct 3D models of the TMJ's soft and hard tissues, allows quantification of the articular disc morphology and position changes with associated differences of the condylar head and glenoid fossa, and facilitates measuring tissue changes over time. PMID- 28095487 TI - DNA Metabarcoding of Amazonian Ichthyoplankton Swarms. AB - Tropical rainforests harbor extraordinary biodiversity. The Amazon basin is thought to hold 30% of all river fish species in the world. Information about the ecology, reproduction, and recruitment of most species is still lacking, thus hampering fisheries management and successful conservation strategies. One of the key understudied issues in the study of population dynamics is recruitment. Fish larval ecology in tropical biomes is still in its infancy owing to identification difficulties. Molecular techniques are very promising tools for the identification of larvae at the species level. However, one of their limits is obtaining individual sequences with large samples of larvae. To facilitate this task, we developed a new method based on the massive parallel sequencing capability of next generation sequencing (NGS) coupled with hybridization capture. We focused on the mitochondrial marker cytochrome oxidase I (COI). The results obtained using the new method were compared with individual larval sequencing. We validated the ability of the method to identify Amazonian catfish larvae at the species level and to estimate the relative abundance of species in batches of larvae. Finally, we applied the method and provided evidence for strong temporal variation in reproductive activity of catfish species in the Ucayali River in the Peruvian Amazon. This new time and cost effective method enables the acquisition of large datasets, paving the way for a finer understanding of reproductive dynamics and recruitment patterns of tropical fish species, with major implications for fisheries management and conservation. PMID- 28095488 TI - Metabolism of Seriola lalandi during Starvation as Revealed by Fatty Acid Analysis and Compound-Specific Analysis of Stable Isotopes within Amino Acids. AB - Fish starvation is defined as food deprivation for a long period of time, such that physiological processes become confined to basal metabolism. Starvation provides insights in physiological processes without interference from unknown factors in digestion and nutrient absorption occurring in fed state. Juveniles of amberjack Seriola lalandi were isotopically equilibrated to a formulated diet for 60 days. One treatment consisted of fish that continued to be fed and fish in the other treatment were not fed for 35 days. The isotopic signatures prior to the beginning of and after the starvation period, for fish in the starvation and control treatments, were analysed for lipid content, fatty acid composition and isotopic analysis of bulk (EA-IRMS) and of amino acids (compound specific isotope analysis, CSIA). There were three replicates for the starvation group. Fatty acid content in muscle and liver tissue before and after starvation was determined to calculate percent change. Results showed that crude lipid was the most used source of energy in most cases; the PUFAs and LC-PUFAs were highly conserved. According to the protein signature in bulk (delta15N) and per amino acid (delta13C and delta15N), in muscle tissue, protein synthesis did not appear to occur substantially during starvation, whereas in liver, increases in delta13C and delta15N indicate that protein turnover occurred, probably for metabolic routing to energy-yielding processes. As a result, isotopic values of delta15N in muscle tissue do not change, whereas CSIA net change occurred in the liver tissue. During the study period of 35 days, muscle protein was largely conserved, being neither replenished from amino acid pools in the plasma and liver nor catabolized. PMID- 28095489 TI - Transgenic Expression of the Anti-parasitic Factor TEP1 in the Malaria Mosquito Anopheles gambiae. AB - Mosquitoes genetically engineered to be resistant to Plasmodium parasites represent a promising novel approach in the fight against malaria. The insect immune system itself is a source of anti-parasitic genes potentially exploitable for transgenic designs. The Anopheles gambiae thioester containing protein 1 (TEP1) is a potent anti-parasitic protein. TEP1 is secreted and circulates in the mosquito hemolymph, where its activated cleaved form binds and eliminates malaria parasites. Here we investigated whether TEP1 can be used to create malaria resistant mosquitoes. Using a GFP reporter transgene, we determined that the fat body is the main site of TEP1 expression. We generated transgenic mosquitoes that express TEP1r, a potent refractory allele of TEP1, in the fat body and examined the activity of the transgenic protein in wild-type or TEP1 mutant genetic backgrounds. Transgenic TEP1r rescued loss-of-function mutations, but did not increase parasite resistance in the presence of a wild-type susceptible allele. Consistent with previous reports, TEP1 protein expressed from the transgene in the fat body was taken up by hemocytes upon a challenge with injected bacteria. Furthermore, although maturation of transgenic TEP1 into the cleaved form was impaired in one of the TEP1 mutant lines, it was still sufficient to reduce parasite numbers and induce parasite melanization. We also report here the first use of Transcription Activator Like Effectors (TALEs) in Anopheles gambiae to stimulate expression of endogenous TEP1. We found that artificial elevation of TEP1 expression remains moderate in vivo and that enhancement of endogenous TEP1 expression did not result in increased resistance to Plasmodium. Taken together, our results reveal the difficulty of artificially influencing TEP1-mediated Plasmodium resistance, and contribute to further our understanding of the molecular mechanisms underlying mosquito resistance to Plasmodium parasites. PMID- 28095490 TI - Costs and Tradeoffs of Resistance and Tolerance to Belowground Herbivory in Potato. AB - The success of sustainable crop production depends on our ability to select or create varieties that can allocate resources to both growth and defence. However, breeding efforts have emphasized increases in yields but have partially neglected defence traits against pests. Estimating the costs of multiple defences against tuber herbivores and the tradeoffs among them, as well as understanding the relationship between yield and multiple defences is still unknown but relevant to both basic and applied ecology. Using twenty commercial potato varieties available in Colombia and the tuber herbivore Tecia solanivora, we tested whether high yielding varieties show a reduction in three types of defence: constitutive and induced resistance, as well as tolerance. Specifically, we determined (1) the costs in terms of yield of all three defences, (2) the possible tradeoffs among them, and (3) if oviposition preference was related to the expression of these defences. We detected no costs in terms of yield of constitutive and induced resistance to tuber damage. We did, however, find evidence of costs of being able to tolerate tuber herbivory. While we found no tradeoffs among any of the estimated defences, there was a positive correlation between aboveground compensatory growth and tolerance in terms of tuber production, suggesting that after damage there are no shifts in the allocation of resources from aboveground to belowground biomass. Finally, we found that females laid more eggs on those varieties with the lowest level of constitutive resistance. In conclusion our findings suggest that in potatoes, breeding for higher yields has not caused any reduction in constitutive or induced resistance to tuber damage. This is not the case for tolerance where those varieties with higher yields are also less likely to tolerate tuber damage. Given the high incidence of tuber pests in Colombia, selecting for higher tolerance could allow for high productivity in the presence of herbivores. Finding mechanisms to decouple the tolerance response from yield should be a new priority in potato breeding in Colombia to guarantee a higher yield in both the presence and absence of herbivores. PMID- 28095491 TI - Pro-Inflammatory Cytokine Levels in HIV Infected and Uninfected Pregnant Women with and without Preeclampsia. AB - INTRODUCTION: Preeclampsia and HIV/AIDS are inflammatory conditions that contribute significantly to adverse maternal and foetal outcomes. The immune reconstitution effects of HAART on inflammatory mediators has not been adequately studied in pregnancy and may impact on the inflammatory cytokine network in women with co-morbid preeclampsia. Our study evaluated changes in pro-inflammatory cytokines IL-2, TNF-alpha, IFN-gamma and IL-6 in HIV infected preeclamptic women on HAART. METHODS: A prospective experimental study was conducted at Prince Mshiyeni Memorial Hospital between July 2013 and September 2014. One hundred and ninety three pregnant women were recruited into 4 groups: uninfected normotensive (50; 26%), infected normotensive (45; 23%), uninfected preeclamptic (53; 28%) and infected preeclamptic women (45; 23%). Serum levels of cytokines TNF-alpha, IFN- gamma, IL-2 and IL-6 were determined using commercially available kits and a Cytometric Bead Array (CBA). Comparative data was recorded and analysed descriptively. RESULTS: In the control groups (normotensive), significantly lower values were found in IL-2 (p = 0.010), TNF-alpha (p = 0.045), and IL-6 (p = 0.005); and a non-significant decrease was observed in IFN-gamma (p = 0.345) in HIV infected women on HAART compared to uninfected controls. In the experimental group (preeclamptic) women, significantly reduced levels were observed in IL-2 and TNF-alpha (p = 0.001; p = 0.000) and non-significant decreases were observed in IFN-gamma and IL-6 (p = 0.023; p = 0.086) in HIV infected women on HAART compared with uninfected preeclamptic women. Non-significant differences were observed between uninfected preeclamptic and normotensive women. CONCLUSION: In uncomplicated/normotensive pregnancies, HIV/HAART is associated with significant decreases in IL-2, TNF-alpha and IL-6, and in preeclamptic women significant decreases in IL-2 and TNF-alpha were observed. These findings suggest that HIV/HAART impacts on pro-inflammatory cytokines in women with co-morbid preeclampsia. This provides a platform for further research on immune reconstitution effects of HAART during pregnancy, and the development of potential immune modulation therapies for the management of preeclampsia. PMID- 28095492 TI - Growth Hormone Deficiency Is Associated with Worse Cardiac Function, Physical Performance, and Outcome in Chronic Heart Failure: Insights from the T.O.S.CA. GHD Study. AB - BACKGROUND: Although mounting evidence supports the concept that growth hormone (GH) deficiency (GHD) affects cardiovascular function, no study has systematically investigated its prevalence and role in a large cohort of chronic heart failure (CHF) patients. Aim of this study is to assess the prevalence of GHD in mild-to-moderate CHF and to explore clinical and functional correlates of GHD. METHODS: One-hundred thirty CHF patients underwent GH provocative test with GHRH+arginine and accordingly categorized into GH-deficiency (GHD, n = 88, age = 61.6+/-1.1 years, 68% men) and GH-sufficiency (GHS, n = 42, age = 63.6+/-1.5 years, 81% men) cohorts. Both groups received comprehensive cardiovascular examination and underwent Doppler echocardiography, cardiopulmonary exercise testing, and biochemical and hormonal assay. RESULTS: GHD was detected in roughly 30% of CHF patients. Compared to GHD, GHS patients showed smaller end-diastolic and end-systolic LV volumes (-28%, p = .008 and -24%, p = .015, respectively), lower LV end-systolic wall stress (-21%, p = .03), higher RV performance (+18% in RV area change, p = .03), lower estimated systolic pulmonary artery pressure ( 11%, p = .04), higher peak VO2 (+20%, p = .001) and increased ventilatory efficiency (-12% in VE/VCO2 slope, p = .002). After adjusting for clinical covariates (age, gender, and tertiles of LV ejection fraction, IGF-1, peak VO2, VE/VCO2 slope, and NT-proBNP), logistic multivariate analysis showed that peak VO2 (beta = -1.92, SE = 1.67, p = .03), VE/VCO2 slope (beta = 2.23, SE = 1.20, p = .02) and NT-proBNP (beta = 2.48, SE = 1.02, p = .016), were significantly associated with GHD status. Finally, compared to GHS, GHD cohort showed higher all-cause mortality at median follow-up of 3.5 years (40% vs. 25%, p < .001, respectively), independent of age, sex, NT-proBNP, peak VO2 and LVEF. CONCLUSIONS: GH deficiency identifies a subgroup of CHF patients characterized by impaired functional capacity, LV remodeling and elevated NT-proBNP levels. GHD is also associated with increased all-cause mortality. PMID- 28095494 TI - Correction: Prokaryotic soluble overexpression and purification of human VEGF165 by fusion to a maltose binding protein tag. AB - [This corrects the article DOI: 10.1371/journal.pone.0156296.]. PMID- 28095493 TI - Thoracic Temporal Subtraction Three Dimensional Computed Tomography (3D-CT): Screening for Vertebral Metastases of Primary Lung Cancers. AB - PURPOSE: We developed an original, computer-aided diagnosis (CAD) software that subtracts the initial thoracic vertebral three-dimensional computed tomography (3D-CT) image from the follow-up 3D-CT image. The aim of this study was to investigate the efficacy of this CAD software during screening for vertebral metastases on follow-up CT images of primary lung cancer patients. MATERIALS AND METHODS: The interpretation experiment included 30 sets of follow-up CT scans in primary lung cancer patients and was performed by two readers (readers A and B), who each had 2.5 years' experience reading CT images. In 395 vertebrae from C6 to L3, 46 vertebral metastases were identified as follows: osteolytic metastases (n = 17), osteoblastic metastases (n = 14), combined osteolytic and osteoblastic metastases (n = 6), and pathological fractures (n = 9). Thirty-six lesions were in the anterior component (vertebral body), and 10 lesions were in the posterior component (vertebral arch, transverse process, and spinous process). The area under the curve (AUC) by receiver operating characteristic (ROC) curve analysis and the sensitivity and specificity for detecting vertebral metastases were compared with and without CAD for each observer. RESULTS: Reader A detected 47 abnormalities on CT images without CAD, and 33 of them were true-positive metastatic lesions. Using CAD, reader A detected 57 abnormalities, and 38 were true positives. The sensitivity increased from 0.717 to 0.826, and on ROC curve analysis, AUC with CAD was significantly higher than that without CAD (0.849 vs. 0.902, p = 0.021). Reader B detected 40 abnormalities on CT images without CAD, and 36 of them were true-positive metastatic lesions. Using CAD, reader B detected 44 abnormalities, and 39 were true positives. The sensitivity increased from 0.783 to 0.848, and AUC with CAD was nonsignificantly higher than that without CAD (0.889 vs. 0.910, p = 0.341). Both readers detected more osteolytic and osteoblastic metastases with CAD than without CAD. CONCLUSION: Our temporal 3D-CT subtraction CAD software easily detected vertebral metastases on the follow up CT images of lung cancer patients regardless of the osteolytic or osteoblastic nature of the lesions. PMID- 28095495 TI - DNA Methylation Analysis of BRD1 Promoter Regions and the Schizophrenia rs138880 Risk Allele. AB - The bromodomain containing 1 gene, BRD1 is essential for embryogenesis and CNS development. It encodes a protein that participates in histone modifying complexes and thereby regulates the expression of a large number of genes. Genetic variants in the BRD1 locus show association with schizophrenia and bipolar disorder and risk alleles in the promoter region correlate with reduced BRD1 expression. Insights into the transcriptional regulation of BRD1 and the pathogenic mechanisms associated with BRD1 risk variants, however, remain sparse. By studying transcripts in human HeLa and SH-SY5Y cells we provide evidence for differences in relative expression of BRD1 transcripts with three alternative 5' UTRs (exon 1C, 1B, and 1A). We further show that expression of these transcript variants covaries negatively with DNA methylation proportions in their upstream promoter regions suggesting that promoter usage might be regulated by DNA methylation. In line with findings that the risk allele of the rs138880 SNP in the BRD1 promoter region correlates with reduced BRD1 expression, we find that it is also associated with moderate regional BRD1 promoter hypermethylation in both adipose tissue and blood. Importantly, we demonstrate by inspecting available DNA methylation and expression data that these regions undergo changes in methylation during fetal brain development and that differences in their methylation proportions in fetal compared to postnatal frontal cortex correlate significantly with BRD1 expression. These findings suggest that BRD1 may be dysregulated in both the developing and mature brain of risk allele carriers. Finally, we demonstrate that commonly used mood stabilizers Lithium, Valproate, and Carbamazepine affect the expression of BRD1 in SH-SY5Y cells. Altogether this study indicates a link between genetic risk and epigenetic dysregulation of BRD1 which raises interesting perspectives for targeting the mechanisms pharmacologically. PMID- 28095496 TI - Opportunities for Integrated Ecological Analysis across Inland Australia with Standardised Data from Ausplots Rangelands. AB - Australian rangelands ecosystems cover 81% of the continent but are understudied and continental-scale research has been limited in part by a lack of precise data that are standardised between jurisdictions. We present a new dataset from AusPlots Rangelands that enables integrative rangelands analysis due to its geographic scope and standardised methodology. The method provides data on vegetation and soils, enabling comparison of a suite of metrics including fractional vegetation cover, basal area, and species richness, diversity, and composition. Cover estimates are robust and repeatable, allowing comparisons among environments and detection of modest change. The 442 field plots presented here span a rainfall gradient of 129-1437 mm Mean annual precipitation with varying seasonality. Vegetation measurements include vouchered vascular plant species, growth form, basal area, height, cover and substrate type from 1010 point intercepts as well as systematically recorded absences, which are useful for predictive modelling and validation of remote sensing applications. Leaf and soil samples are sampled for downstream chemical and genomic analysis. We overview the sampling of vegetation parameters and environments, applying the data to the question of how species abundance distributions (SADs) vary over climatic gradients, a key question for the influence of environmental change on ecosystem processes. We found linear relationships between SAD shape and rainfall within grassland and shrubland communities, indicating more uneven abundance in deserts and suggesting relative abundance may shift as a consequence of climate change, resulting in altered diversity and ecosystem function. The standardised data of AusPlots enables such analyses at large spatial scales, and the testing of predictions through time with longitudinal sampling. In future, the AusPlots field program will be directed towards improving coverage of space, under represented environments, vegetation types and fauna and, increasingly, re sampling of established plots. Providing up-to-date data access methods to enhance re-use is also a priority. PMID- 28095497 TI - Replication-Coupled Recruitment of Viral and Cellular Factors to Herpes Simplex Virus Type 1 Replication Forks for the Maintenance and Expression of Viral Genomes. AB - Herpes simplex virus type 1 (HSV-1) infects over half the human population. Much of the infectious cycle occurs in the nucleus of cells where the virus has evolved mechanisms to manipulate host processes for the production of virus. The genome of HSV-1 is coordinately expressed, maintained, and replicated such that progeny virions are produced within 4-6 hours post infection. In this study, we selectively purify HSV-1 replication forks and associated proteins from virus infected cells and identify select viral and cellular replication, repair, and transcription factors that associate with viral replication forks. Pulse chase analyses and imaging studies reveal temporal and spatial dynamics between viral replication forks and associated proteins and demonstrate that several DNA repair complexes and key transcription factors are recruited to or near replication forks. Consistent with these observations we show that the initiation of viral DNA replication is sufficient to license late gene transcription. These data provide insight into mechanisms that couple HSV-1 DNA replication with transcription and repair for the coordinated expression and maintenance of the viral genome. PMID- 28095498 TI - Investigation of the Fusarium virguliforme Transcriptomes Induced during Infection of Soybean Roots Suggests that Enzymes with Hydrolytic Activities Could Play a Major Role in Root Necrosis. AB - Sudden death syndrome (SDS) is caused by the fungal pathogen, Fusarium virguliforme, and is a major threat to soybean production in North America. There are two major components of this disease: (i) root necrosis and (ii) foliar SDS. Root symptoms consist of root necrosis with vascular discoloration. Foliar SDS is characterized by interveinal chlorosis and leaf necrosis, and in severe cases by flower and pod abscission. A major toxin involved in initiating foliar SDS has been identified. Nothing is known about how root necrosis develops. In order to unravel the mechanisms used by the pathogen to cause root necrosis, the transcriptome of the pathogen in infected soybean root tissues of a susceptible cultivar, 'Essex', was investigated. The transcriptomes of the germinating conidia and mycelia were also examined. Of the 14,845 predicted F. virguliforme genes, we observed that 12,017 (81%) were expressed in germinating conidia and 12,208 (82%) in mycelia and 10,626 (72%) in infected soybean roots. Of the 10,626 genes induced in infected roots, 224 were transcribed only following infection. Expression of several infection-induced genes encoding enzymes with oxidation reduction properties suggests that degradation of antimicrobial compounds such as the phytoalexin, glyceollin, could be important in early stages of the root tissue infection. Enzymes with hydrolytic and catalytic activities could play an important role in establishing the necrotrophic phase. The expression of a large number of genes encoding enzymes with catalytic and hydrolytic activities during the late infection stages suggests that cell wall degradation could be involved in root necrosis and the establishment of the necrotrophic phase in this pathogen. PMID- 28095499 TI - Treatment with Riluzole Restores Normal Control of Soleus and Extensor Digitorum Longus Muscles during Locomotion in Adult Rats after Sciatic Nerve Crush at Birth. AB - The effects of sciatic nerve crush (SNC) and treatment with Riluzole on muscle activity during unrestrained locomotion were identified in an animal model by analysis of the EMG activity recorded from soleus (Sol) and extensor digitorum longus (EDL) muscles of both hindlimbs; in intact rats (IN) and in groups of rats treated for 14 days with saline (S) or Riluzole (R) after right limb nerve crush at the 1st (1S and 1R) or 2nd (2S and 2R) day after birth. Changes in the locomotor pattern of EMG activity were correlated with the numbers of survived motor units (MUs) identified in investigated muscles. S rats with 2-8 and 10-28 MUs that survived in Sol and EDL muscles respectively showed increases in the duration and duty factor of muscle EMG activity and a loss of correlation between the duty factors of muscle activity, and abnormal flexor-extensor co-activation 3 months after SNC. R rats with 5, 6 (Sol) and 15-29 MUs (EDL) developed almost normal EMG activity of both Sol and control EDL muscles, whereas EDL muscles with SNC showed a lack of recovery. R rats with 8 (Sol) and 23-33 (EDL) MUs developed almost normal EMG activities of all four muscles. A subgroup of S rats with a lack of recovery and R rats with almost complete recovery that had similar number of MUs (8 and 24-28 vs 8 and 23-26), showed that the number of MUs was not the only determinant of treatment effectiveness. The results demonstrated that rats with SNC failed to develop normal muscle activity due to malfunction of neuronal circuits attenuating EDL muscle activity during the stance phase, whereas treatment with Riluzole enabled almost normal EMG activity of Sol and EDL muscles during locomotor movement. PMID- 28095500 TI - SENP7 Potentiates cGAS Activation by Relieving SUMO-Mediated Inhibition of Cytosolic DNA Sensing. AB - Cyclic GMP-AMP (cGAMP) synthase (cGAS, a.k.a. MB21D1), a cytosolic DNA sensor, catalyzes formation of the second messenger 2'3'-cGAMP that activates the stimulator of interferon genes (STING) signaling. How the cGAS activity is modulated remains largely unknown. Here, we demonstrate that sentrin/SUMO specific protease 7 (SENP7) interacted with and potentiated cGAS activation. The small ubiquitin-like modifier (SUMO) was conjugated onto the lysine residues 335, 372 and 382 of cGAS, which suppressed its DNA-binding, oligomerization and nucleotidyl-transferase activities. SENP7 reversed this inhibition via catalyzing the cGAS de-SUMOylation. Consistently, silencing of SENP7 markedly impaired the IRF3-responsive gene expression induced by cGAS-STING axis. SENP7-knockdown mice were more susceptible to herpes simplex virus 1 (HSV-1) infection. SENP7 was significantly up-regulated in patients with SLE. Our study highlights the temporal modulation of the cGAS activity via dynamic SUMOylation, uncovering a novel mechanism for fine-tuning the STING signaling in innate immunity. PMID- 28095501 TI - Birth Weight and Its Relationship with the Cardiac Autonomic Balance in Healthy Children. AB - Several studies indicate that the fetal environment plays a significant role in the development of cardiometabolic disease later in life. However, a few studies present conflicting data about the correlation between birth weight and the impairment of cardiac autonomic modulation. The purpose of the present study was to provide further knowledge to elucidate this contradictory relationship. One hundred children aged 5 and 14 years had anthropometric parameters, body composition and blood pressure levels determined. Heart rate variability (HRV) was evaluated by heart rate monitoring, including measurements of both the time and frequency domains. The results showed inverse correlation between the HRV parameters with BMI (RMSSD: P = 0.047; PNN50: P = 0.021; HF: P = 0.041), systolic (RMSSD: P = 0.023; PNN50: P = 0.032) and diastolic (PNN50: P = 0.030) blood pressure levels. On the other hand, there were consistent positive correlations between the HRV parameters and birth weight (RMSSD: P = 0.001; PNN50: P = 0.001; HF: P = 0.002). To determine the effect of birth weight on HRV parameters, we perform multivariate linear regression analysis adjusted for potentially confounding factors (prematurity, gender, age, BMI, physical activity index and SBP levels). These findings were preserved even after adjusting for these confounders. Our results suggested that impaired cardiac autonomic modulation characterized by a reduction in the parasympathetic activity occurs in children with low birth weight. One possible interpretation for these data is that a vagal withdrawal, rather than a sympathetic overactivity, could precede the development of hypertension and other cardiometabolic diseases in children with low birth weight. However, long-term studies should be performed to investigate this possibility. PMID- 28095502 TI - Drosophila Genotype Influences Commensal Bacterial Levels. AB - Host genotype can influence the composition of the commensal bacterial community in some organisms. Composition, however, is only one parameter describing a microbial community. Here, we test whether a second parameter-abundance of bacteria-is a heritable trait by quantifying the presence of four commensal bacterial strains within 36 gnotobiotic inbred lines of Drosophila melanogaster. We find that D. melanogaster genotype exerts a significant effect on microbial levels within the fly. When introduced as monocultures into axenic flies, three of the four bacterial strains were reliably detected within the fly. The amounts of these different strains are strongly correlated, suggesting that the host regulates commensal bacteria through general, not bacteria-specific, means. While the correlation does not appear to be driven by simple variation in overall gut dimensions, a genetic association study suggests that variation in commensal bacterial load may largely be attributed to physical aspects of host cell growth and development. PMID- 28095503 TI - Detection of a Potential New Bartonella Species "Candidatus Bartonella rondoniensis" in Human Biting Kissing Bugs (Reduviidae; Triatominae). AB - BACKGROUND: Among the Reduviidae family, triatomines are giant blood-sucking bugs. They are well known in Central and South America where they transmit Trypanosoma cruzi to mammals, including humans, through their feces. This parasitic protozoan is the causative agent of Chagas disease, a major public health issue in endemic areas. Because of the medical and economic impact of Chagas disease, the presence of other arthropod-borne pathogens in triatomines was rarely investigated. METHODOLOGY/PRINCIPAL FINDINGS: In this study, seven triatomines species involved in the transmission of T. cruzi were molecularly screened for the presence of known pathogens generally associated with arthropods, such as Rickettsia, Bartonella, Anaplasmataceae, Borrelia species and Coxiella burnetii. Of all included triatomine species, only Eratyrus mucronatus specimens tested positive for Bartonella species for 56% of tested samples. A new genotype of Bartonella spp. was detected in 13/23 Eratyrus mucronatus specimens, an important vector of T. cruzi to humans. This bacterium was further characterized by sequencing fragments of the ftsZ, gltA and rpoB genes. Depending on the targeted gene, this agent shares 84% to 91% of identity with B. bacilliformis, the agent of Carrion's disease, a deadly sandfly-borne infectious disease endemic in South America. It is also closely related to animal pathogens such as B. bovis and B. chomelii. CONCLUSIONS: As E. mucronatus is an invasive species that occasionally feeds on humans, the presence of potentially pathogenic Bartonella-infected bugs could present another risk for human health, along with the T. cruzi issue. PMID- 28095504 TI - Cytoplasmic Localization of HTLV-1 HBZ Protein: A Biomarker of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). AB - HTLV-1 is the causative agent of a severe form of adult T cell leukemia/Lymphoma (ATL), and of a chronic progressive neuromyelopathy designated HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Two important HTLV-1-encoded proteins, Tax-1 and HBZ, play crucial roles in the generation and maintenance of the oncogenic process. Less information is instead available on the molecular and cellular mechanisms leading to HAM/TSP. More importantly, no single specific biomarker has been described that unambiguously define the status of HAM/TSP. Here we report for the first time the finding that HBZ, described until now as an exclusive nuclear protein both in chronically infected and in ATL cells, is instead exclusively localized in the cytoplasm of peripheral blood mononuclear cells (PBMC) from patients suffering of HAM/TSP. Interestingly, at the single cell level, HBZ and Tax-1 proteins are never found co-expressed in the same cell, suggesting the existence of mechanisms of expression uncoupling of these two important HTLV-1 viral products in HAM/TSP patients. Cells expressing cytoplasmic HBZ were almost exclusively found in the CD4+ T cell compartment that was not, at least in a representative HAM/TSP patient, expressing the CD25 marker. Less than 1 percent CD8+ T cells were fond positive for HBZ, while B cells and NK cells were found negative for HBZ in HAM/TSP patients. Our results identify the cytoplasmic localization of HBZ in HAM/TSP patient as a possible biomarker of this rather neglected tropical disease, and raise important hypotheses on the role of HBZ in the pathogenesis of the neuromyelopathy associated to HTLV-1 infection. PMID- 28095505 TI - Can Early Intervention Improve Maternal Well-Being? Evidence from a Randomized Controlled Trial. AB - OBJECTIVE: This study estimates the effect of a targeted early childhood intervention program on global and experienced measures of maternal well-being utilizing a randomized controlled trial design. The primary aim of the intervention is to improve children's school readiness skills by working directly with parents to improve their knowledge of child development and parenting behavior. One potential externality of the program is well-being benefits for parents given its direct focus on improving parental coping, self-efficacy, and problem solving skills, as well as generating an indirect effect on parental well being by targeting child developmental problems. METHODS: Participants from a socio-economically disadvantaged community are randomly assigned during pregnancy to an intensive 5-year home visiting parenting program or a control group. We estimate and compare treatment effects on multiple measures of global and experienced well-being using permutation testing to account for small sample size and a stepdown procedure to account for multiple testing. RESULTS: The intervention has no impact on global well-being as measured by life satisfaction and parenting stress or experienced negative affect using episodic reports derived from the Day Reconstruction Method (DRM). Treatment effects are observed on measures of experienced positive affect derived from the DRM and a measure of mood yesterday. CONCLUSION: The limited treatment effects suggest that early intervention programs may produce some improvements in experienced positive well being, but no effects on negative aspects of well-being. Different findings across measures may result as experienced measures of well-being avoid the cognitive biases that impinge upon global assessments. PMID- 28095506 TI - A Comparison of the Corrected Intraocular Pressure Obtained by the Corvis ST and Reichert 7CR Tonometers in Glaucoma Patients. AB - The purpose of the study was to investigate the accuracy of two corrected intraocular pressure (IOP) measurements by Corvis Scheimpflug Technology (CST) IOPpachy and by corneal-compensated IOP (IOPcc) using the Reichert 7CR (7CR) tonometers. We also investigated the effects of corneal anatomical and structural parameters on the IOP measurements. The participants included 90 primary open angle glaucoma patients. We assessed the IOP measurements, obtained by the CST, 7CR, and Goldmann applanation tonometer (GAT), using a paired t-test with Bonferroni correction, Bland-Altman plots, and multiple regression analyses. The 7CR-IOPcc gave the highest value (15.5 +/- 2.7 mmHg), followed by the 7CR-IOPg (13.7 +/- 3.1 mmHg), GAT-IOP (13.6 +/- 2.2 mmHg), CST-IOP (10.3 +/- 2.6 mmHg), and CST-IOPpachy (9.7 +/- 2.5 mmHg). The values of CST-IOPpachy were significantly lower than those obtained by the other IOP measurement methods (all, p < 0.01). The values of 7CR-IOPcc were significantly higher than those obtained by the other IOP measurement methods (all, p < 0.01). Bland-Altman plots showed a mean difference between the GAT-IOP and the other IOP measurements (CST IOP, CST-IOPpachy, 7CR-IOPg, and 7CR-IOPcc), which were -3.20, -3.82, 0.14, and 2.00 mmHg, respectively. The widths of the 95% limits of agreement between all pairs of IOP measurements were greater than 3 mmHg. With the exception of the 7CR IOPcc, all of the IOP variations were explained by regression coefficients involving gender, average corneal curvature, and central corneal thickness. The IOP values obtained by the GAT, CST, and 7CR were not interchangeable. Each new IOP measurement device that was corrected for ocular structure had its own limitations. PMID- 28095507 TI - Choline Deficiency Causes Colonic Type II Natural Killer T (NKT) Cell Loss and Alleviates Murine Colitis under Type I NKT Cell Deficiency. AB - Serum levels of choline and its derivatives are lower in patients with inflammatory bowel disease (IBD) than in healthy individuals. However, the effect of choline deficiency on the severity of colitis has not been investigated. In the present study, we investigated the role of choline deficiency in dextran sulfate sodium (DSS)-induced colitis in mice. Methionine-choline-deficient (MCD) diet lowered the levels of type II natural killer T (NKT) cells in the colonic lamina propria, peritoneal cavity, and mesenteric lymph nodes, and increased the levels of type II NKT cells in the livers of wild-type B6 mice compared with that in mice fed a control (CTR) diet. The gene expression pattern of the chemokine receptor CXCR6, which promotes NKT cell accumulation, varied between colon and liver in a manner dependent on the changes in the type II NKT cell levels. To examine the role of type II NKT cells in colitis under choline-deficient conditions, we assessed the severity of DSS-induced colitis in type I NKT cell deficient (Jalpha18-/-) or type I and type II NKT cell-deficient (CD1d-/-) mice fed the MCD or CTR diets. The MCD diet led to amelioration of inflammation, decreases in interferon (IFN)-gamma and interleukin (IL)-4 secretion, and a decrease in the number of IFN-gamma and IL-4-producing NKT cells in Jalpha18-/- mice but not in CD1d-/- mice. Finally, adaptive transfer of lymphocytes with type II NKT cells exacerbated DSS-induced colitis in Jalpha18-/- mice with MCD diet. These results suggest that choline deficiency causes proinflammatory type II NKT cell loss and alleviates DSS-induced colitis. Thus, inflammation in DSS-induced colitis under choline deficiency is caused by type II NKT cell-dependent mechanisms, including decreased type II NKT cell and proinflammatory cytokine levels. PMID- 28095508 TI - The Smc5/6 Complex Restricts HBV when Localized to ND10 without Inducing an Innate Immune Response and Is Counteracted by the HBV X Protein Shortly after Infection. AB - The structural maintenance of chromosome 5/6 complex (Smc5/6) is a restriction factor that represses hepatitis B virus (HBV) transcription. HBV counters this restriction by expressing HBV X protein (HBx), which targets Smc5/6 for degradation. However, the mechanism by which Smc5/6 suppresses HBV transcription and how HBx is initially expressed is not known. In this study we characterized viral kinetics and the host response during HBV infection of primary human hepatocytes (PHH) to address these unresolved questions. We determined that Smc5/6 localizes with Nuclear Domain 10 (ND10) in PHH. Co-localization has functional implications since depletion of ND10 structural components alters the nuclear distribution of Smc6 and induces HBV gene expression in the absence of HBx. We also found that HBV infection and replication does not induce a prominent global host transcriptional response in PHH, either shortly after infection when Smc5/6 is present, or at later times post-infection when Smc5/6 has been degraded. Notably, HBV and an HBx-negative virus establish high level infection in PHH without inducing expression of interferon-stimulated genes or production of interferons or other cytokines. Our study also revealed that Smc5/6 is degraded in the majority of infected PHH by the time cccDNA transcription could be detected and that HBx RNA is present in cell culture-derived virus preparations as well as HBV patient plasma. Collectively, these data indicate that Smc5/6 is an intrinsic antiviral restriction factor that suppresses HBV transcription when localized to ND10 without inducing a detectable innate immune response. Our data also suggest that HBx protein may be initially expressed by delivery of extracellular HBx RNA into HBV-infected cells. PMID- 28095509 TI - Body Mass Index at Accession and Incident Cardiometabolic Risk Factors in US Army Soldiers, 2001-2011. AB - Individuals entering US Army service are generally young and healthy, but many are overweight, which may impact cardiometabolic risk despite physical activity and fitness requirements. This analysis examines the association between Soldiers' BMI at accession and incident cardiometabolic risk factors (CRF) using longitudinal data from 731,014 Soldiers (17.0% female; age: 21.6 [3.9] years; BMI: 24.7 [3.8] kg/m2) who were assessed at Army accession, 2001-2011. CRF were defined as incident diagnoses through 2011, by ICD-9 code, of metabolic syndrome, glucose/insulin disorder, hypertension, dyslipidemia, or overweight/obesity (in those not initially overweight/obese). Multivariable-adjusted proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) between BMI categories at accession and CRF. Initially underweight (BMI<18.5 kg/m2) were 2.4% of Soldiers, 53.5% were normal weight (18.5-<25), 34.2% were overweight (25-<30), and 10.0% were obese (>=30). Mean age range at CRF diagnosis was 24-29 years old, with generally low CRF incidence: 228 with metabolic syndrome, 3,880 with a glucose/insulin disorder, 26,373 with hypertension, and 13,404 with dyslipidemia. Of the Soldiers who were not overweight or obese at accession, 5,361 were eventually diagnosed as overweight or obese. Relative to Soldiers who were normal weight at accession, those who were overweight or obese, respectively, had significantly higher risk of developing each CRF after multivariable adjustment (HR [95% CI]: metabolic syndrome: 4.13 [2.87-5.94], 13.36 [9.00-19.83]; glucose/insulin disorder: 1.39 [1.30-1.50], 2.76 [2.52-3.04]; hypertension: 1.85 [1.80-1.90], 3.31 [3.20-3.42]; dyslipidemia: 1.81 [1.75-1.89], 3.19 [3.04-3.35]). Risk of hypertension, dyslipidemia, and overweight/obesity in initially underweight Soldiers was 40%, 31%, and 79% lower, respectively, versus normal-weight Soldiers. BMI in early adulthood has important implications for cardiometabolic health, even within young, physically active populations. PMID- 28095510 TI - Screening and Identifying Antioxidative Components in Ginkgo biloba Pollen by DPPH-HPLC-PAD Coupled with HPLC-ESI-MS2. AB - The Ginkgo biloba is one of ancient trees that exists from billions of years ago, its leaf and nut are used as herbs and foods in China, while so far its pollen does not have any application except pollination. In order to evaluate the antioxidant activity of Ginkgo biloba pollen, and rapidly screen its antioxidative components, the 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging ability, total flavonoid, total phenol, and proanthocyanidin of Ginkgo biloba pollen were determined and compared with those of Ginkgo biloba leaf and nut, and the off-line DPPH-HPLC-PAD and HPLC-ESI-MS2 were applied for screening and identifying the antioxidant flavonoids in Ginkgo biloba pollen. The results showed that the DPPH scavenging ability of Ginkgo biloba pollen was much higher than Ginkgo biloba nut, but lower than Ginkgo biloba leaf, while the total content of flavonoid in Ginkgo biloba pollen was approximately 4.37 times higher than in Ginkgo biloba leaf. Further studies found that the major flavonol aglycone in Ginkgo biloba pollen was kaempferol, which accounted for 96.71% of the total aglycones (includes quercetin, kaempferol and isorhamnetin), and the main flavonoid components in Ginkgo biloba pollen were flavonoid glycosides. Finally, ten antioxidant peaks were screened and identified to be flavonoids (including kaempferol and nine flavonoid glycosides), so flavonoids were likely to be the main antioxidant components in GP, and among them, three novel kaempferol glycosides (peaks 1, 2, and 3) were found in Ginkgo biloba pollen for the first time, which had never been found in Ginkgo biloba. PMID- 28095512 TI - Models for Predicting the Biomass of Cunninghamialanceolata Trees and Stands in Southeastern China. AB - Using existing equations to estimate the biomass of a single tree or a forest stand still involves large uncertainties. In this study, we developed individual tree biomass models for Chinese Fir (Cunninghamia lanceolata.) stands in Fujian Province, southeast China, by using 74 previously established models that have been most commonly used to estimate tree biomass. We selected the best fit models and modified them. The results showed that the published model ln(B(Biomass)) = a + b * ln(D) + c * (ln(H))2 + d * (ln(H))3 + e * ln(WD) had the best fit for estimating the tree biomass of Chinese Fir stands. Furthermore, we observed that variables D(diameter at breast height), H (height), and WD(wood density)were significantly correlated with the total tree biomass estimation model. As a result, a natural logarithm structure gave the best estimates for the tree biomass structure. Finally, when a multi-step improvement on tree biomass model was performed, the tree biomass model with Tree volume(TV), WD and biomass wood density conversion factor (BECF),achieved the highest simulation accuracy, expressed as ln(TB) = -0.0703 + 0.9780 * ln(TV) + 0.0213 * ln(WD) + 1.0166 * ln(BECF). Therefore, when TV, WD and BECF were combined with tree biomass volume coefficient bi for Chinese Fir, the stand biomass (SB)model included both volume(SV) and coefficient bi variables of the stand as follows: bi = Exp( 0.0703+0.9780*ln(TV)+0.0213 * ln(WD)+1.0166*ln(BECF)). The stand biomass model is SB = SV/TV * bi. PMID- 28095511 TI - Epidemiology and Molecular Typing of Trypanosoma cruzi in Naturally-Infected Hound Dogs and Associated Triatomine Vectors in Texas, USA. AB - BACKGROUND: Trypanosoma cruzi is the etiologic agent of Chagas disease throughout the Americas. Few population-level studies have examined the epidemiology of canine infection and strain types of T. cruzi that infect canines in the USA. We conducted a cross-sectional study of T. cruzi infection in working hound dogs in south central Texas, including analysis of triatomine vectors collected within kennel environments. METHODOLOGY/PRINCIPLE FINDINGS: Paired IFA and Chagas Stat Pak serological testing showed an overall seroprevalence of 57.6% (n = 85), with significant variation across kennels. Dog age had a marginally significant effect on seropositivity, with one year of age increase associated with a 19.6% increase in odds of being seropositive (odds ratio 95% CI 0.996-1.435; p = 0.055). PCR analyses of blood revealed 17.4% of dogs harbored parasite DNA in their blood, including both seronegative and seropositive dogs. Molecular screening of organs from opportunistically sampled seropositive dogs revealed parasite DNA in heart, uterus, and mammary tissues. Strain-typing showed parasite discrete typing units (DTU) TcI and TcIV present in dog samples, including a co-occurrence of both DTUs in two individual dogs. Bloodmeal analysis of Triatoma gerstaeckeri and Triatoma sanguisuga insects collected from the kennels revealed exclusively dog DNA. Vector infection with T. cruzi was 80.6% (n = 36), in which T. gerstaeckeri disproportionately harbored TcI (p = 0.045) and T. sanguisuga disproportionately harbored TcIV (p = 0.029). Tracing infection status across dog litters showed some seropositive offspring of seronegative dams, suggesting infection of pups from local triatomine vectors rather than congenital transmission. CONCLUSIONS/SIGNIFICANCE: Canine kennels are high-risk environments for T. cruzi transmission, in which dogs likely serve as the predominant parasite reservoir. Disease and death of working dogs from Chagas disease is associated with unmeasured yet undoubtedly significant financial consequences because working dogs are highly trained and highly valued. PMID- 28095514 TI - Influence of Stepped Osteotomy on Primary Stability of Implants Inserted in Low Density Bone Sites: An In Vitro Study. AB - PURPOSE: The aims of this study were to evaluate the ability of a stepped osteotomy to improve dental implant primary stability in low-density bone sites and to investigate possible correlations between primary stability parameters. MATERIALS AND METHODS: The study was performed on fresh humid bovine bone classified as type III. The test group consisted of 30 Astra Tech EV implants inserted following the protocol provided by the manufacturer. The first control group consisted of 30 Astra Tech EV implants inserted in sites without the underpreparation of the apical portion. The second control group consisted of 30 Astra Tech TX implants inserted following the protocol provided by the manufacturer. Implant insertion was performed at the predetermined 30 rpm. The insertion torque data were recorded and exported as a curve; using a trapezoidal integration technique, the area underlying the curve was calculated: this area represents the variable torque work (VTW). Peak insertion torque (pIT) and resonance frequency analysis (RFA) were also recorded. RESULTS: A Mann-Whitney test showed that the mean VTW was significantly higher in the test group compared with the first control and second control groups; furthermore, statistical analysis showed that pIT also was significantly higher in the test group compared with the first and second control groups. Analyzing RFA values, only the difference between the test group and second control group showed statistical significance. Pearson correlation analysis showed a very strong positive correlation between pIT and VTW values in all groups; furthermore, it showed a positive correlation between pIT and RFA values and between VTW and RFA values only in the test group. CONCLUSION: Within the limitations of an in vitro study, the results show that stepped osteotomy can be a viable method to improve implant primary stability in low-density bone sites, and that, when a traditional osteotomy method is performed, RFA presents no correlation with pIT and VTW. PMID- 28095513 TI - Changes in Circulating B Cell Subsets Associated with Aging and Acute SIV Infection in Rhesus Macaques. AB - Aging and certain viral infections can negatively impact humoral responses in humans. To further develop the nonhuman primate (NHP) model for investigating B cell dynamics in human aging and infectious disease, a flow cytometric panel was developed to characterize circulating rhesus B cell subsets. Significant differences between human and macaque B cells included the proportions of cells within IgD+ and switched memory populations and a prominent CD21-CD27+ unswitched memory population detected only in macaques. We then utilized the expanded panel to analyze B cell alterations associated with aging and acute simian immunodeficiency virus (SIV) infection in the NHP model. In the aging study, distinct patterns of B cell subset frequencies were observed for macaques aged one to five years compared to those between ages 5 and 30 years. In the SIV infection study, B cell frequencies and absolute number were dramatically reduced following acute infection, but recovered within four weeks of infection. Thereafter, the frequencies of activated memory B cells progressively increased; these were significantly correlated with the magnitude of SIV-specific IgG responses, and coincided with impaired maturation of anti-SIV antibody avidity, as previously reported for HIV-1 infection. These observations further validate the NHP model for investigation of mechanisms responsible for B cells alterations associated with immunosenescence and infectious disease. PMID- 28095515 TI - Effects of Ultraviolet Photofunctionalization on Bone Augmentation and Integration Capabilities of Titanium Mesh and Implants. AB - PURPOSE: Ultraviolet (UV)-mediated photofunctionalization has earned considerable attention for the enhancement of the biologic capabilities of titanium. The effects of photofunctionalization on bone augmentation and gap closure were examined using titanium implants and mesh in a rat femur model. MATERIALS AND METHODS: An acid-etched titanium implant (4-mm length, 1-mm diameter) was placed in the gluteal tuberosity that resembles a knife-edge-like edentulous ridge. The lower half of the implant was located in a 2-mm-diameter defect created in the bone without cortical bone support; the upper half was exposed and covered with a titanium mesh to provide augmentation space. After 12 and 24 days of healing, specimens were subjected to microcomputed tomography (micro-CT)- and histology based bone morphometry in three zones of analysis: augmentation, cortical bone implant gap, and bone marrow. A biomechanical push-in test was performed to examine the strength of bone-implant integration. Photofunctionalization was performed by treating titanium implants and mesh with UV light for 12 minutes. RESULTS: Photofunctionalized titanium mesh and implants were hydrophilic, whereas untreated controls were hydrophobic. Bone volume was significantly greater in photofunctionalized implants and mesh than in untreated implants in all zones on days 12 and 24. Bone-to-implant contact of photofunctionalized implants was greater than that of untreated implants, not just in the bone marrow but also in the gap and augmented zones. The strength of osseointegration was three times greater for photofunctionalized implants than for untreated implants. CONCLUSION: Use of photofunctionalized titanium mesh and implants effectively enhanced vertical bone augmentation, cortical bone-implant gap closure, and osseointegration without innate bone support. PMID- 28095516 TI - Effect of Nanofeatured Topography on Ceria-Stabilized Zirconia/Alumina Nanocomposite on Osteogenesis and Osseointegration. AB - PURPOSE: The objective of this study was to evaluate the osteogenic and osseointegration capability of the Ce-tetragonal zirconia polycrystal (TZP)-based nanostructured zirconia/alumina composite (Ce-TZP/Al2O3) that was treated with hydrofluoric acid (HF). MATERIALS AND METHODS: Osteogenic MC3T3-E1 cells were cultured on acid-etched titanium (AETi) disks and Ce-TZP/Al2O3 disks without HF treatment (Zr[0%]), with 4% HF treatment (Zr[4%]), or with 55% HF treatment (Zr[55%]) for 24 hours, and biologic responses were compared among four conditions in vitro. Miniature implants of AETi and Zr(55%) were surgically placed in the femora of rats. Osseointegration was evaluated by a biomechanical push-in test after 2 and 4 weeks of healing. RESULTS: The surface of Zr(55%) rendered nanofeatured topography with a greater surface area and roughness, and extensive geographical undercut as ceria-zirconia crystal disappeared from the superficial layer and was similar to the surface morphology of biomineralized matrices. Culture studies showed that the attachment, proliferation, spread, and functional phenotypes of osteogenic cells, such as alkaline phosphatase activity and bone-related gene expression, were remarkably increased on the Zr(55%) surface. The strength of osseointegration measured using the biomechanical push in test in a rat model was stronger for Zr(55%) implants than for AETi implants by 1.6 fold. CONCLUSION: The nanostructured Ce-TZP/ Al2O3 surface substantially enhanced the osteogenic response in vitro and the osseointegration capability in vivo, which suggest its potential clinical application as a novel implant material. PMID- 28095517 TI - Radiographic Evaluation of Crestal Bone Level in Split-Crest and Immediate Implant Placement: Minimum 5-Year Follow-up. AB - PURPOSE: This study aimed to evaluate the radiographic bone level changes of implants positioned via the split-crest procedure both in the maxilla and mandible at a long-term follow-up. MATERIALS AND METHODS: Seventy-one patients were retrospectively enrolled in the study. The placement of 137 dental implants was performed in the edentulous premolar or molar region after a split-crest ridge expansion procedure. Implants followed a delayed loading protocol. Intraoral digital radiographs were performed at baseline, upon implant placement, at 70 days (following placement of the provisional prosthesis), and on a yearly basis during followup. Crestal bone levels were evaluated at the baseline, upon provisional prosthesis placement, at 12, 36, and 60 months, and at the long-term follow-up of healing from implant placement. RESULTS: The patients underwent a mean follow-up of 6.54 +/- 1.32 years, from which the implant survival rate was reported at 98.54%. Within the first year from implant placement, a bone loss resulted at a mean value of -1.11 +/- 0.44 mm. After almost 3 years from implant placement, a mean bone gain of +0.89 +/- 0.39 mm was reported, which was statistically significant compared with 12-month values (P < .05). From this point, bone levels remained stable, reporting similar values over time, with no significant differences (P > .05). CONCLUSION: A mean vertical bone gain of +0.89 +/- 0.39 mm was observed after almost 36 months after implant positioning. PMID- 28095518 TI - Long-Term Results of Peri-implant Conditions in Periodontally Compromised Patients Following Lateral Bone Augmentation. AB - PURPOSE: The aim of this retrospective study was to compare long-term (>= 5 years) outcomes of implants placed in patients treated for chronic periodontitis versus those placed in periodontally healthy patients. In both groups, the implants were placed in alveolar ridges that were laterally augmented with autogenous bone block grafts using a split bone block technique. MATERIALS AND METHODS: Two hundred ninety-two patients were screened in the course of supportive periodontal treatment examinations. Nonsmoking patients without any severe systemic diseases who had adhered to regular supportive periodontal treatment for a minimum of 5 years after undergoing autogenous lateral grafting (using the split bone block technique), implant placement, and prosthetic reconstructions were classified into two groups based on their presurgical status: periodontally healthy patients (PHP) and periodontally compromised patients (PCP). RESULTS: Clinical outcomes for 77 patients, 38 PHP and 39 PCP, were examined. All had been successfully treated for severe lateral atrophy and received a total of 241 endosseous implants between 2002 and 2008. At the final examination, mean bleeding on probing was 7.08% +/- 7.27% in PHP and 14.49% +/- 18.14% in PCP, a statistically significant difference. Significantly higher Plaque Index and more recession were associated with a narrow (< 2 mm) width of keratinized mucosa. CONCLUSION: Implants in alveolar ridges laterally augmented using a split bone block technique revealed similar clinical peri-implant conditions in both PHP and PCP. Using autogenous bone block grafts without biomaterials resulted in long-term peri-implant tissue stability. PMID- 28095519 TI - A Clinical Study Assessing the Influence of Anodized Titanium and Zirconium Dioxide Abutments and Peri-implant Soft Tissue Thickness on the Optical Outcome of Implant-Supported Lithium Disilicate Single Crowns. AB - PURPOSE: To assess the influence of anodized titanium and zirconium dioxide abutments and peri-implant soft tissue thickness on the optical outcome of implant-supported lithium disilicate single crowns. MATERIALS AND METHODS: Twenty patients with a missing maxillary single incisor, canine, or first premolar received an endosseous implant after a two-stage surgery protocol. After healing and soft tissue conditioning, peri-implant soft tissues were reproduced in the impression, and the thickness was measured. Customized abutments were made of titanium, gold-anodized titanium, pink-anodized titanium, and zirconium dioxide. The definitive prosthesis was a lithium disilicate crown stratified by feldsphatic porcelain. Customized abutments were screwed (35 Ncm), and the crown was temporarily placed on the abutment with a try-in paste. Color measurements were made using a spectrophotometer. CIELab color scale was employed following the formula: DeltaE = (DeltaL)2 + (Deltaa) 2 + (Deltab) 2. Data were analyzed using repeated-measures analysis of variance (ANOVA), Bonferroni and Pearson's correlation tests (alpha = .05). RESULTS: Abutment material type significantly affected the DeltaE values at both the peri-implant soft tissue (P = .0001) and coronal level (P = .001). The lowest DeltaE values were obtained with zirconia abutments at both soft tissue (6.06 +/- 3.2) and coronal level (5.76 +/- 2.9) compared with those of other abutments (soft tissue: 8.96 +/- 3.1 to 11.56 +/- 3.4; coronal: 8.66 +/- 6.1 to 10.42 +/- 6.3). Mean soft tissue thickness (1.63 +/ 0.64 mm) affected the DeltaE values at the peri-implant soft tissue level for only titanium and pink-anodized titanium abutments (P = .024 and P = .048, respectively). In all conditions, correlation coefficients between DeltaE and the abutment materials were higher for titanium (r = -0.544; P = .024) and the least for zirconia (r = -0.313; P = .238) and gold-anodized titanium (r = -0.393; P = .119) abutments. CONCLUSION: All abutment types demonstrated noticeable color difference at both the soft tissue and coronal levels. Zirconia abutments showed the lowest DeltaE values at both measurement zones. Soft tissue thickness did not affect the DeltaE values at the peri-implant soft tissue level. PMID- 28095520 TI - Dental Implants in the Elderly Population: A Long-Term Follow-up. AB - PURPOSE: The objectives of this study were to evaluate implant survival and success in the elderly population and to assess indicators and risk factors for success or failure of dental implants in older adults (aged 60 years and older). MATERIALS AND METHODS: This historical prospective study was developed from a cohort of patients born prior to 1950 who received dental implants in a single private dental office. Implant survival and marginal bone levels were recorded and analyzed with regard to different patient- and implant-related factors. RESULTS: The study examined 245 patient charts and 1,256 implants from one dental clinic. The mean age at the time of implant placement was 62.18 +/- 8.6 years. Smoking was reported by 9.4% of the cohort studied. The overall survival rate of the implants was 92.9%; 7.1% of the implants had failed. Marginal bone loss depicted by exposed threads was evident in 23.3% of the implants. Presenting with generalized periodontal disease and/or severe periodontal disease negatively influenced the survival probability of the implant. Implants placed in areas where bone augmentation was performed prior to or during implant surgery did not have the same longevity compared with those that did not have augmentation prior to implantation. CONCLUSION: The overall findings concluded that implants can be successfully placed in older adults. A variety of factors are involved in the long-term success of the implant, and special consideration should be taken prior to placing implants in older adults to limit the influence of those risk factors. PMID- 28095521 TI - Evaluation of Ultrashort and Longer Implants with Microrough Surfaces: Results of a 24- to 36-Month Prospective Study. AB - PURPOSE: The aim of this prospective study was to establish if ultrashort implants are a reliable therapeutic solution by evaluating their effect on mean crestal bone loss and assessing their survival and success rates. MATERIALS AND METHODS: Patients were treated using 6-, 9-, and 11-mm-long implants with sandblasted and acid-etched surfaces and fitted with fixed partial prostheses. Clinical and radiographic examinations were scheduled yearly. Data collected included the implant positioning site, implant length and diameter, peri-implant bone loss (PBL), and clinical and anatomical C/I ratios. RESULTS: One hundred eleven implants (6-mm-long, 30.6%) were positioned; two implants were lost before loading. During the 36-month followup, no other implants were lost (98.2% survival rate, 100% from loading), but four implants did not meet the criteria for success, due to excessive crestal bone loss, resulting in a 94.6% success rate, 96.3% from loading. Success rates and peri-implant bone loss were not significantly different among implants with different lengths. No correlation was observed between implant length and bone resorption. CONCLUSION: Six-millimeter long implants did not show different results in comparison with 9- and 11-mm-long implants. They can be considered a reliable solution for implant prosthetic rehabilitation and a dependable and minimally invasive therapeutic option in areas showing severe bone resorption. PMID- 28095522 TI - Correlation Between Resonance Frequency Analysis and Bone Quality Assessments at Dental Implant Recipient Sites. AB - PURPOSE: To evaluate whether primary implant stability could be used to predict bone quality, the association between the implant stability quotient (ISQ) value and the bone type at the implant site was evaluated. MATERIALS AND METHODS: Ninety-five implant sites in 50 patients were included. Bone type (categorized by Lekholm and Zarb) at the implant site was initially assessed using presurgical dental radiography. During the preparation of the implant site, a bone core specimen was carefully obtained. The bone type was assessed by tactile sensation during the drilling operation, according to the Misch criteria. The primary stability of the inserted implant was evaluated by resonance frequency analysis (RFA). The ISQ value was recorded. The bone core specimen was then examined by stereomicroscopy or microcomputed tomography (micro-CT), and the bone type was determined by the surface characteristics of the specimen, based on Lekholm and Zarb classification. Agreement between the bone quality assessed by the four methods (ie, presurgical radiography, tactile sensation, stereomicroscopy, and micro-CT) was tested by Cohen's kappa statistics, whereas the association between the ISQ value and the bone type was evaluated by the generalized linear regression model. RESULTS: The mean ISQ score was 72.6, and the score was significantly influenced by the maxillary or mandibular arch (P = .001). The bone type at the implant sites varied according to the assessment method. However, a significant influence of the arch was repeatedly noted when using radiography or tactile sensation. Among the four bone-quality assessment methods, a weak agreement existed only between stereomicroscopy and micro-CT, especially in the maxilla (kappa = 0.469). A negative association between the ISQ value and the bone type assessed by stereomicroscopy or by micro-CT was significant in the maxilla, but not in the mandible, after adjustments for sex, age, and right/left side (P = .013 and P = .027 for stereomicroscopy and micro-CT, respectively). CONCLUSION: The ISQ value was weakly associated with the bone type when assessed by stereomicroscopy or micro-CT in the maxilla. Caution is necessary if RFA is used as a tool to evaluate bone quality at the implant site, especially in the mandible. PMID- 28095523 TI - Effects of Titanium Surface Microtopography and Simvastatin on Growth and Osteogenic Differentiation of Human Mesenchymal Stem Cells in Estrogen-Deprived Cell Culture. AB - PURPOSE: This study aimed to investigate the effects of titanium surface topography and simvastatin on growth and osteogenic differentiation of human bone marrow stromal cells (hBMSCs) in estrogen-deprived (ED) cell culture. MATERIALS AND METHODS: Human BMSCs were seeded on cell culture plates, smooth-surface titanium (Ti) disks, and sandblasted with large grits and acid etched (SLA) surface Ti disks; and subsequently cultured in regular (fetal bovine serum [FBS]), ED, and ED-with 100 nM simvastatin (ED-SIM) culture media for 14 to 21 days. Live/dead cell staining, scanning electron microscope examination, and cell viability assay were performed to determine cell attachment, morphology, and growth. Expression levels of osteoblast-associated genes, Runx2 and bone sialoprotein and levels of alkaline phosphatase (ALP) activity, calcium content, and osteocalcin in culture media were measured to determine osteoblastic differentiation. Expression levels of bone morphogenetic protein-2 (BMP-2) were investigated to examine stimulating effects of simvastatin (n = 4 to 5, mean +/- SD). In vitro mineralization was verified by calcein staining. RESULTS: Human BMSCs exhibited different attachment and shapes on smooth and SLA titanium surfaces. Estrogen-deprived cell culture decreased cell attachment and growth, particularly on the SLA titanium surface, but cells were able to grow to reach confluence on day 21 in the ED-osteogenic (OS) culture medium. Promoting effects of the SLA titanium surface in ED-OS were significantly decreased. Simvastatin significantly increased osteogenic differentiation of human BMSCs on the SLA titanium surface in the ED-OS medium, and the promoting effects of simvastatin corresponded with the increasing of BMP-2 gene expression on the SLA titanium surface in ED-OS-SIM culture medium. CONCLUSION: The ED cell culture model provided a well-defined platform for investigating the effects of hormones and growth factors on cells and titanium surface interaction. Titanium, the SLA surface, and simvastatin synergistically promoted osteoblastic differentiation of hBMSCs in ED condition and might be useful to promote osteointegration in osteoporotic bone. PMID- 28095524 TI - Combination of Collagen Barrier Membrane with Enamel Matrix Derivative-Liquid Improves Osteoblast Adhesion and Differentiation. AB - PURPOSE: Collagen barrier membranes were first introduced to regenerative periodontal and oral surgery to prevent fast ingrowing soft tissues (ie, epithelium and connective tissue) into the defect space. More recent attempts have aimed at combining collagen membranes with various biologics/growth factors to speed up the healing process and improve the quality of regenerated tissues. Recently, a new formulation of enamel matrix derivative in a liquid carrier system (Osteogain) has demonstrated improved physico-chemical properties for the adsorption of enamel matrix derivative to facilitate protein adsorption to biomaterials. The aim of this pioneering study was to investigate the use of enamel matrix derivative in a liquid carrier system in combination with collagen barrier membranes for its ability to promote osteoblast cell behavior in vitro. MATERIALS AND METHODS: Undifferentiated mouse ST2 stromal bone marrow cells were seeded onto porcine-derived collagen membranes alone (control) or porcine membranes + enamel matrix derivative in a liquid carrier system. Control and enamel matrix derivative-coated membranes were compared for cell recruitment and cell adhesion at 8 hours; cell proliferation at 1, 3, and 5 days; and real-time polymerase chain reaction (PCR) at 3 and 14 days for genes encoding Runx2, collagen1alpha2, alkaline phosphatase, and bone sialoprotein. Furthermore, alizarin red staining was used to investigate mineralization. RESULTS: A significant increase in cell adhesion was observed at 8 hours for barrier membranes coated with enamel matrix derivative in a liquid carrier system, whereas no significant difference could be observed for cell proliferation or cell recruitment. Enamel matrix derivative in a liquid carrier system significantly increased alkaline phosphatase mRNA levels 2.5-fold and collagen1alpha2 levels 1.7-fold at 3 days, as well as bone sialoprotein levels twofold at 14 days postseeding. Furthermore, collagen membranes coated with enamel matrix derivative in a liquid carrier system demonstrated a sixfold increase in alizarin red staining at 14 days when compared with collagen membrane alone. CONCLUSION: The combination of enamel matrix derivative in a liquid carrier system with a barrier membrane significantly increased cell attachment, differentiation, and mineralization of osteoblasts in vitro. Future animal testing is required to fully characterize the additional benefits of combining enamel matrix derivative in a liquid carrier system with a barrier membrane for guided bone or tissue regeneration. PMID- 28095525 TI - Mechanism and Clinical Properties of StemBios Cell Therapy: Induction of Early Osseointegration in Novel Dental Implants. AB - PURPOSE: To examine early bone tissue healing in dental implants incorporating StemBios cell therapy. MATERIALS AND METHODS: SLAffinity samples were examined by scanning electron microscopy and atomic force microscopy. The clinical trial comprised 11 patients, who each received a dental implant in the mandible. Only one of these 11 patients received StemBios cell therapy in combination with the dental implant. The patients continued to be observed over a 4-month period after implantation using computed tomography and resonance frequency analysis. RESULTS: It was found that StemBios cell therapy promoted bone tissue healing in the case of the treated dental implant. The data indicated that stress altered more smoothly and declined faster in the patient who received the StemBios cell therapy than those without StemBios cell therapy over 4 months. CONCLUSION: A dental implant with SLAffinity surface treatment, in combination with StemBios cell therapy, significantly promoted bone tissue healing, especially at early osseointegration compared with that of implants without StemBios cell therapy when monitored over a 4-month period. PMID- 28095526 TI - Effects of Platform-Switching on Peri-implant Soft and Hard Tissue Outcomes: A Systematic Review and Meta-analysis. AB - PURPOSE: This systematic review and meta-analysis was aimed at evaluating the longitudinal effect of platform switching on implant survival rates as well as on soft and hard tissue outcomes. MATERIALS AND METHODS: An electronic search of the databases of the National Center for Biotechnology Information, PubMed, Ovid (MEDLINE), EMBASE, Web of Science, and Cochrane Collaboration Library was conducted in February 2015. Studies published in English with at least 10 human participants and a 12-month post-loading follow-up were included. Random effects meta-analyses of selected studies were applied to compare the primary and secondary outcomes of platform-switched (PS) and regular-platform (RP) implants, as well as the experimental designs and clinical outcomes. RESULTS: A total of 26 studies involving 1,511 PS implants and 1,123 RP implants were evaluated. Compared to RP implants, PS implants showed a slight increase in vertical marginal bone loss (VMBL) and pocket depth reduction (weighted mean differences were -0.23 mm and -0.20 mm, respectively). The PS implants had a mean VMBL of 0.36 +/- 0.15 mm within the first year of service. The meta-regression suggested a trend of decreased bone resorption at sites with thick soft tissues at baseline. CONCLUSION: This study suggested that platform switching may have an indirect protective effect on implant hard tissue outcomes. PMID- 28095527 TI - Satisfaction and Clinical Outcomes Among Patients with Immediately Loaded Mandibular Overdentures Supported by One or Two Dental Implants: Results of a 5 Year Prospective Randomized Clinical Trial. AB - PURPOSE: The purpose of this study was to evaluate patient satisfaction and clinical outcomes among subjects with mandibular overdentures supported by one or two immediately placed dental implants 5 years after loading. MATERIALS AND METHODS: Thirty-six subjects (16 men and 20 women) received one or two dental implants in the anterior mandible, and all implants were loaded the day of surgery. Subjects were scheduled for follow-up 3-, 6-, and 12 months after implant placement and thereafter annually for 4 more years. Patient satisfaction scores were measured with the Oral Health Impact Profile-EDENT (OHIPEDENT) questionnaire. RESULTS: Seventeen subjects (7 male and 10 female) with a mean age of 59.4 years (range, 44 to 74 years) were available for the 5-year follow-up examination. Nine subjects with 10 failing implants were excluded during the first year and nine subjects were lost to follow-up. No implants failed between the 12- and 60-month follow-up examinations, and the need for denture maintenance was low. Mean peri-implant bone change was 0.92 mm, and the Spearman test failed to show correlation between the insertion torque value and implant stability quotient. Patient satisfaction scores increased significantly when compared with baseline values and continued to be high for both groups, with no significant differences. CONCLUSION: Ten implants in nine subjects failed early, but no failures were observed after the 12-month examination. No significant differences were found between subjects in the two groups with respect to implant survival rates and peri-implant bone loss, and patient satisfaction scores continued to be high. Although patient satisfaction and implant success were high during the 12- to 60-month period, the results should be interpreted with caution because of the high number of failing implants and patients lost to follow-up. More research is needed to study outcomes of treatment with immediately loaded mandibular implant overdentures. PMID- 28095528 TI - The Role of Cutaneous Microbiota Harmony in Maintaining a Functional Skin Barrier. AB - The skin is constantly exposed to various endogenous and exogenous factors that may impact its barrier function at the physical, mechanical, immunological, and microbial levels. These factors have the potential to initiate or exacerbate a variety of inflammatory skin conditions, especially those associated with barrier dysfunction. The barrier function of the skin depends upon a symbiotic relationship between resident microbial communities and host tissue. This symbiosis results from complex signals involved in both the innate and adaptive immune responses. Recent research indicates that both bacterial diversity and the relative abundance of different microbes present on and in the skin, may contribute to skin barrier stability or dysfunction. The objectives of this review are to discuss the relationship between the skin microbiota and skin barrier function and to consider mechanisms that may help its preservation. J Drugs Dermatol. 2017;16(1):12-18.. PMID- 28095529 TI - Open-Label Study Evaluating the Anti-Aging Effects of a 3-Product, 2-Step Retinol Rejuvenation System Following 3 Months of Treatment in Subjects With Photodamage. AB - BACKGROUND: Photodamage to the skin occurs with exposure to sunlight (UVA or UVB) either intentionally or unintentionally, and can present in a variety of ways. It typically occurs on areas of chronic UV exposure, including the face, ears, and neck. METHODS: We evaluated the effects of a 3-product, 2-step retinol rejuvenation system containing an exfoliating cleanser, a 0.5% retinol emollient cream, and SPF 30 moisturizing sunscreen used daily for 3 months on the appearance of mild-to-moderate facial photodamage in female subjects. RESULTS: Significant improvements in facial appearance could be observed as early as 2 weeks, with continued improvement over the duration of the study. There were no adverse events reported that were related to study product and reports of cutaneous tolerability issues were rare. CONCLUSIONS: A 3-product, 2-step retinol rejuvenation system provides significant improvements in signs of photodamage and overall skin appearance, and is well-tolerated. J Drugs Dermatol. 2017;16(1):23-28.. PMID- 28095530 TI - The Anti-Aging Effects of Low Oxygen Tension Generated Multipotent Growth Factor Containing Serum. AB - Growth factors are a new category of ingredient found in modern cosmeceutical formulations. One novel method of obtaining cosmeceutical growth factors is the use of a bioreactor to culture neonatal broblasts on dextran microcarrier beads for 8 weeks under low oxygen tension (1-5%) mimicking embryonic conditions and eliminating the need for fetal bovine serum constituents in the final cosmetic material. This research evaluated the ingredient in a moisturizing vehicle on 40 females to determine its efficacy in improving overall facial skin appearance, as well as skin brightness, evenness, firmness, pore size, radiance, fine lines, coarse wrinkles, and blotchiness/ dispigmentation. Statistically significant improvement was seen in 90 days in skin hydration through corneometry, as well in global investigator and subject assessments. J Drugs Dermatol. 2017;16(1):30 34.. PMID- 28095531 TI - Future Applications of Deoxycholic Acid in Body Contouring. AB - Deoxycholic acid (KybellaTM, Allergan Pharmaceuticals, Irvine, CA) is a novel injectable treatment used for the cosmetic reduction of redundant submental fat. By inducing adipose cell lysis, the soft tissue alteration induces subsequent contour change and sharpening of the cervicomental angle.The safety and efficacy have been well established in several prospective clinical trials and subsequent FDA approval for this purpose. This has provided an effective and less invasive alternative to surgical liposuction with virtually no recovery time and less overall discomfort. Given its success for use in this context, a logical step would be to extrapolate to other regions of the body where cosmetic deformity is caused by excessive adipose tissue. In the current article, the authors propose potential options for further use in various targeted areas where subcutaneous fat may be amenable to reduction with deoxycholic acid injection, understanding that such uses would be off-label and require an understanding of the regional anatomy and possible complications. J Drugs Dermatol. 2017;16(1):43-46. PMID- 28095532 TI - 1060 nm Diode Hyperthermic Laser Lipolysis:The Latest in Non-Invasive Body Contouring. AB - Non-invasive body contouring is becoming increasingly popular in the United States. Using the 1060 nm diode laser to achieve hyperthermic temperatures within the adipose tissue with subsequent lipolysis is one of the most recent advancements in this field and is the first of its kind. This wavelength was carefully chosen to effectively target the unwanted adipocytes while sparing the overlying skin and adnexae. Appreciable results are achieved after a single treatment, and these results are comparable to other non-invasive technologies. The 25-minute procedure is well tolerated among patients, with no downtime required. This versatile system allows for treatment of multiple body sites, which can be customized for a particular patient's needs. Herein, we discuss in detail the mechanism of action, efficacy, and safety of 1060 nm diode hyperthermic laser lipolysis. Amongst the various body contouring modalities available today, the 1060 nm diode hyperthermic laser is a worthy addition providing a safe, quick, and effective non-invasive fat reduction option for patients. J Drugs Dermatol. 2017;16(1):48-52.. PMID- 28095533 TI - Neck Contouring and Treatment of Submental Adiposity. AB - There have been many recent and significant innovations to the cosmetic physician's repertoire for addressing excess submental fat and improving patients' neck contour. These new techniques include submental cryolipolysis, injectable chemical lipolysis, percutaneous radiofrequency, laser techniques, and liposuction with or without laser or power assistance. These modalities range from completely non-invasive to surgical procedures. Each technique has its own unique advantages, and limitations and as such, aesthetic practitioners should be familiar with the various indications to use each technique. Additionally, cost to the practice and patient are similarly varied across the different techniques. By increasing familiarity with the new procedures addressed herein, practices can better present a diverse range of treatment options for excess submental fat and neck fullness to the cosmetic patient. J Drugs Dermatol. 2017;16(1):54 57.. PMID- 28095534 TI - An Anatomical Approach to Evaluating and Treating Cellulite. AB - Cellulite is the common rippling or dimpling of skin of the thighs and buttocks of women, formed from a confluence of skin laxity, tethering fibrous septa, and fat herniation. We describe an anatomical approach to evaluating the cellulite patient and selecting the best treatment from among available non-invasive, minimally invasive, and invasive therapies. It is crucial to consider the anatomy of the patient and the morphology of cellulite while choosing a treatment. Diffuse rippling represents increased adiposity and/or increased skin laxity which may stand to benefit from lipolytic and skin tightening modalities. Dimpling represents tethering by fibrous septa which may stand to improve from subcision by minimally invasive devices such as Cell na. Patients with both morphologies may be treated with a combination of treatments or Cellulaze. Careful evaluation of the patient can help identify the best therapeutic strategy. J Drugs Dermatol. 2017;16(1):58-61.. PMID- 28095535 TI - A Systematic Review of Paradoxical Adipose Hyperplasia (PAH) Post-Cryolipolysis. AB - BACKGROUND: Body sculpting, or body contouring, is among the fastest growing areas in cosmetic dermatology. Cryolipolysis, or "fat freezing," was FDA-cleared (CoolSculpting System, ZELTIQ Aesthetics, Pleasanton, CA) initially in 2010 for fat removal of the anks, and subsequently received FDA-clearance for other anatomical locations. Over the past several years, there have been increasing published reports and physician discussion regarding paradoxical adipose hyperplasia (PAH) post-cryolipolysis, previously identified as a "rare" adverse effect. OBJECTIVE: To review published reports of PAH post-cryolipolysis, expand on previously proposed hypothesis of PAH, and provide rec- ommendations for prevention and treatment of PAH. METHODS AND MATERIALS: On July 26, 2016, we systematically searched the computerized medical bibliographic databases PubMed, EMBASE, Web of Science, and CINAHL with the search term "cryolipolysis." RESULTS: A total of 314 records were returned from our search terms and 10 records were found to be suitable for our review. We identi- ed a total of 16 cases of PAH post-cryolipolysis in the published literature. CONCLUSIONS: Based upon the published literature, we identi ed that the current incidence of PAH may be higher than previously re- ported. Although the pathoetiology of PAH is currently unknown, we hypothesize that some adipocytes may be "naturally selected" for survival due to their inherent tolerance to cryolipolysis. We believe that while cryolipolysis is an effective non-invasive treatment option for body contouring, physicians and patients should be aware of PAH as a potential adverse effect and treatment options. J Drugs Dermatol. 2017;16(1):62-67.. PMID- 28095536 TI - Improved Neocollagenesis and Skin Mechanical Properties After Injection of Diluted Calcium Hydroxylapatite in the Neck and Decolletage:A Pilot Study. AB - BACKGROUND: Calcium hydroxylapatite (CaHA; Radiesse (R)) provides safe and effective correction of moderate-to-deep lines, volume replacement, lift and contour, and induction of neocollagenesis and neoelastogenesis for improved skin quality. CaHA hyperdilution takes advantage of its skin-tightening properties without a volumizing effect. OBJECTIVE: To evaluate the collagen- and elastin stimulating effects of diluted CaHA in subjects with skin laxity in the neck and decolletage. METHODS: Twenty subjects with skin laxity in the neck and decolletage received multiple, linear, subdermal injections of CaHA diluted with preserved saline at baseline and 4 months: 1:2 dilution (normal skin), 1:4 dilution (thin skin), and 1:6 dilution (atrophic skin). Subjects also received deep subdermal injection of CaHA (~0.1 ml) of the same dilution in the peri auricular area for skin biopsy. Biopsy tissue was obtained at baseline, 4 months, and 7 months for immunohistochemical evaluation of neocollagenesis. Changes to skin mechanical properties were measured by ultrasound scanning and cutometry. Subject and investigator satisfaction was evaluated using the Global Aesthetic Improvement Scale. RESULTS: Immunohistochemical analysis of biopsy tissue demonstrated signi cant increases in collagen I expression at 4 months (P less than 0.05) and 7 months (P less than 0.00001) compared with baseline. Increases in collagen III levels were also significant at 4 months (P less than 0.00001); they declined by 7 months but remained above baseline. Staining for elastin and angiogenesis signi cantly increased at 4 months (P less than 0.05 and P less than 0.01, respectively) and 7 months (P less than 0.00001 for both) compared with baseline. Immunohistochemical data correlated with improvements in skin elasticity and pliability evaluated by cutometry, and with ultrasound-assessed increases in dermal thickness. Subject and investigator satisfaction was high, and the procedure was well tolerated. CONCLUSIONS: Injection of diluted CaHA is very effective for skin tightening of the neck and decolletage. J Drugs Dermatol. 2017;16(1):68-74.. PMID- 28095537 TI - Spotlight on the Use of Nitric Oxide in Dermatology: What Is It? What Does It Do? Can It Become an Important Addition to the Therapeutic Armamentarium for Skin Disease? AB - Nitric oxide (NO) is a diatomic gas that is synthesized within and released by multiple host cell types functioning to provide a variety of physiologic and homeostatic effects. Nitric oxide exhibits a variety of effects that relate significantly with outcomes that can provide therapeutic benefit if properly formulated and released. These include anti-inflammatory, immunomodulatory, antimicrobial, vasodilatory properties, and effects that are beneficial to wound healing. Lack of antibiotic resistance appears to be one major advantage of topically delivered NO. A specific topical formulation of NO has been developed that has been shown thus far in clinical studies to exhibit favorable efficacy and safety. This article provides a thorough review of the biologic effects of NO, discusses modes of action and potential pharmacologic benefits, and reviews currently available clinical data for acne. J Drugs Dermatol. 2017;16(1 Suppl 1):s4-10. PMID- 28095538 TI - Exogenous Factors in Skin Barrier Repair. AB - The stratum corneum (SC) is the skin's outermost layer and serves the primary function of acting as a shield to keep foreign matter out and to essential elements, such as moisture and water, in. Maintenance of this skin barrier is crucial to healthy functioning skin. A damaged or diseased skin barrier is vulnerable to infection, irritants, and allergens. The cornerstone of skin barrier regulation and repair is through the use of moisturizers. While healthcare providers and patients may underestimate the importance of moisturizers due to their lack of active ingredients, the benefit of a well planned moisturizer regimen for skin barrier regulation should not be discounted. Dermatologists should be comfortable prescribing and educating about over-the counter moisturizers to patients with skin barrier is- sues. A general understanding of basic moisturizer ingredients and formulations will aid the dermatologist in providing a personalized moisturizer regimen to their patients. J Drugs Dermatol. 2016;15(11):1289-1294.. PMID- 28095539 TI - A Proposed Method for Upper Eyelid and Infrabrow Tightening Using a Transcutaneous Temperature Controlled Radiofrequency Device With Opaque Plastic Eye Shields. AB - BACKGROUND: Laxity of the eyelid and periorbital area, a common manifestation of aging, is usually addressed via blepharoplasty and/ or fat transfer. Given the trend toward safer, less invasive treatments preferred by those patients reticent to undergo more invasive procedures, viable alternatives have been sought. Transcutaneous temperature controlled radiofrequency (TTCRF) integrates non- invasive super cial RF treatment with automatic temperature feedback control of energy deposition, as a stimulator of overall collagen remodeling; however, the globe of the eye is particularly sensitive to RF energy. The purpose of the study was to propose a method by which TTCRF and other non-ablative modalities could be used to treat eyelid and infrabrow laxity, with autoclavable opaque black haptic scleral contact lenses protecting the globe of the eye. METHODS: Subjects (n=40, 36 women and 4 men, age range, 33-72) with mild to moderate laxity of the eyelid and infrabrow were treated with TTCRF using black plastic eye shields (Oculoplastik, Montreal, Quebec, Canada) to protect the globe of the eye from heat and RF energy. With the shields in place subjects were treated with the 10 mm small monopolar emitter of the ThermiSmooth device (Thermi, Irving, Tex.), using small circular looping motions to safely elevate the temperature of target tissue to the therapeutically rel- evant range for approximately 6 minutes; tissue temperature was measured in real time using the device's forward-looking infrared imaging. RESULTS: No major adverse events were recorded. Treatment was safe and tolerable for all subjects. CONCLUSION: The use of autoclavable opaque black plastic eye shields provides a safe method of treating the upper eye lid and infrabrow using TTCRF. J Drugs Dermatol. 2016;15(11):1302-1305.. PMID- 28095540 TI - Multi-Center Pilot Study to Evaluate the Safety Profile of High Energy Fractionated Radiofrequency With Insulated Microneedles to Multiple Levels of the Dermis. AB - In this multi-center pilot study, the safety pro le of high intensity focused radiofrequency (RF) delivered to the dermis was evaluated for safety in the treatment of the aging neck and face. A newly designed insulated microneedle system delivers a signi cant coagulative thermal injury into the dermis while sparing the epidermis from RF injury. Thirty- ve healthy subjects from seven aesthetic practices were evaluated, and data from each were incorporated in this case report. The subjects received a single treatment using settings that delivered the highest RF energies suggested from the new recommended protocols. The depth of thermal delivery was adjusted before each pass and all subjects received a minimum of two to three passes to the treated areas. Before and after photographs along with adverse effects were recorded. This case report demonstrates the ability to deliver significant RF thermal injury to several layers of the dermis with insulated microneedles safely with little injury to the epidermis and minimum downtime. PMID- 28095541 TI - Safety and Efficacy Evaluation of Pulsed Dye Laser Treatment, CO2 Ablative Fractional Resurfacing, and Combined Treatment for Surgical Scar Clearance. AB - BACKGROUND & OBJECTIVE: Surgical scars are an unwanted sequela following surgical procedures. Several different treatment modalities and approaches are currently being employed to improve the cosmesis of surgical scars with each having varying degrees of success. The objective of this study was to assess the ef cacy and safety pulsed dye laser treatment, CO2 ablative fractional resurfacing, and a combined treatment with these two modalities for the cosmetic improvement of surgical scarring that occurred following the surgical removal of skin cancer from different anatomic areas. MATERIALS AND METHODS: Twenty-five patients with surgical scarring most frequently on the face following recent surgical excision of skin cancer with Mohs surgery were included in this multicenter, prospective clinical study. Patients were randomized into 4 treatment arms, namely, pulsed dye laser alone, CO2 laser alone, a combined treatment with these two modalities, and CO2 ablative fractional resurfacing on the same day of surgery to half of the scar, followed by a combined treatment with the two modalities to that half of the scar. Patients in each study arm received a total of 3-4 treatments, while those patients in Arm 4 underwent an additional treatment with CO2 laser immediately after surgery. Patients were followed up at 1 and 3 months after the final treatment session. RESULTS: No adverse events were seen. Significant improvements in the appearance of scars were achieved in all study arms, as as- sessed by the Vancouver Scar Scale and Global Evaluation Response scales, with the best clinical outcomes seen in those scars that underwent a combination treatment. All patients reported very high satisfaction from treatment. CONCLUSION: Both pulsed dye laser treatment and CO2 ablative fractional resurfacing, when used as a monotherapy, are safe and effective in the treatment and improvement of recent surgical scarring. When both of these modalities are used in combination, however, they appear to potentially have a synergistic effect and an accelerated outcome on the cosmesis of recent surgical scars. J Drugs Dermatol. 2016;15(11):1315-1319.. PMID- 28095542 TI - The Two Faces of Fractionated Photodynamic Therapy: Increasing Efficacy With Light Fractionation or Adjuvant Use of Fractional Laser Technology. AB - "Fractionated photodynamic therapy (PDT)" is a new term being used by dermatologists to describe advances in PDT technology including fractionated light or the adjuvant use of fractional lasers. Although dermatologists have used PDT since the early 1990s for the treatment of photodamage and precancerous lesions, newer developments in technology have allowed for the treatment of non melanoma skin cancers (NMSCs), in ammatory disorders, and even uses in the eld of anti-aging. Recent developments in fractionated light therapy have allowed for PDT with dark intervals and two-fold illumination schemes to increase cellular damage and apoptosis. Combining PDT with fractional laser technology has allowed for enhanced dermal penetration of topical photosensitizers including 5 aminolevulinic acid (ALA) and methyl aminolevulinate (MAL), as well as increased ef cacy of treatment. These advances in PDT technology will allow for increased convenience, decreased treatment time, only one application of topical photosensitizer, and decreased cost to the patient and dermatologist. J Drugs Dermatol. 2016;15(11):1324-1328.. PMID- 28095543 TI - Clinical Evaluation of Hair Removal Using an 810 nm Diode Laser With a Novel Scanning Device. AB - INTRODUCTION: Diode lasers are often considered as the gold standard preference for hair removal due to the deep penetration and ef- fective targeting of the hair follicle. A wide variety of diode lasers are available, which can differ in terms of their parameters (such as fluence, pulse duration, repetition rate, scanner, and cooling). OBJECTIVE: The objective of the study was to evaluate the safety and ef cacy of hair removal with an 810 nm novel scanning diode laser, up to six months after last treatment. METHODS: A scanning 810 nm diode laser was used for axillary hair removal of 14 female patients who received 3 treatments, 4 6 weeks apart. Follow-up on hair count was conducted 3 and 6 months after last treatment and compared to baseline hair count. RESULTS: No unexpected or signi cant adverse events were recorded. An average hair count reduction of 72.8% after 3 months and 67.6% 6 months after the last treatment is demonstrated. CONCLUSIONS: The examined 810 nm diode laser was proven to be safe and effective for hair removal. Results were sustained for 6 months after last treatment. Longer follow-up data are followed for further substantiation of the clinical effect. Scanning technology can provide for potentially faster and safer treatments. J Drugs Dermatol. 2016;15(11):1330-1333.. PMID- 28095544 TI - A Split-Face Assessment of the Synergistic Potential of Sequential Q-Switched Nd:YAG Laser and 1565 nm Fractional Nonablative Laser Treatment for Facial Rejuvenation in Fitzpatrick Skin Type II-V Patients. AB - Recent appreciation of the multifactorial pathophysiology of skin aging has led to increased use of parallel treatment regimens. This prospective, split-face, randomized study assessed the safety and efficacy of same-day sequential Q switched Nd:YAG laser and 1565 nm non-ablative fractional laser (SST) facial rejuvenation treatment in comparison to fractional non-ablative laser (NAFL) treatment only. Seventeen patients underwent three treatment sessions, conducted at 4-6-week intervals, in which SST treatment was delivered on a randomly selected side of the face followed by NAFL treatment on the contralateral side immediately thereafter. Immediate skin responses were assessed within 30 minutes of treatment, while wrinkle/elastosis scores, and skin tone and texture were evaluated 1, 3, and 6 months following the final treatment session. While SST and NAFL proved equally safe, SST was associated with signi cantly lower pain scores in all three treatment sessions. Both treatment regimens yielded signi cant improvements in wrinkle/elastosis scores, which were maintained throughout the 6 months of follow up. Physician-evaluated skin tone and patient ratings of skin texture and overall improvement of the SST-treated side were consistently higher than the contralateral NAFL-treated side. Histological analysis suggested a broader effect, alongside sparing of the outermost epidermal layer with the SST versus NAFL treatment. Although the SST regimen failed to demonstrate statistically signi cant clinical superiority over the NAFL regimen, the significantly lower pain levels, consistently higher physician and patient ratings following SST may justify its regular use as a skin rejuvenation technique. J Drugs Dermatol. 2016;15(11):1335-1342.. PMID- 28095545 TI - Real-time, High-resolution, In Vivo Characterization of Superficial Skin With Microscopy Using Ultraviolet Surface Excitation (MUSE). AB - BACKGROUND: Skin care products make up the largest part (36%) of the cosmetic market globally, of which the United States plays the largest role. In 2015, approximately 115 billion USD was spent globally on skin care products. Skin care products, in contradistinction to pharmaceuticals, are not strictly regulated by the FDA. A key factor for evaluation of a skin care product or topical drug is skin barrier function and effect on super cial skin. Thus, it is critical to have quantitative and qualitative methods to study the effects of skin care products on skin barrier and the super cial skin. Currently, no imaging method exists that can evaluate and track super cial skin changes visually in real-time. OBJECTIVE: To report using a novel imaging modality, Microscopy using Ultraviolet Surface Excitation (MUSE), to provide real-time, high- resolution, in vivo characterization of super cial skin and moisturizing properties of topical moisturizer, and to highlight key bene ts of using MUSE to visualize the super cial skin and serve as an excellent complementary tool to current quantitative methods. METHODS AND MATERIALS: The methodology of MUSE is based upon two main principles inherent to ultraviolet (UV) light and uorescent staining agents. In this study, the author's (JJ) index ngertip was imaged using the MUSE instrument without and with moisturizer. RESULTS: Dermatoglyphics of the fingertip consists of ridges (cristae super ciales) and grooves (sulci super ciales) proved to be straightforward to visualize at high resolution. Desquamation of superficial corneocytes and opening of an acrosyringium (the most superficial portion of eccrine ducts) were visualized in high-resolution. Post-application of a moisturizer, a uniform layer of moisturizer could be seen superficial to the corneocytes along the ridges and CONCLUSIONS: Real-time, high-resolution, in vivo characterization of super cial skin and moisturizing properties of moisturizer using MUSE is feasible. Its utility can be enhanced with downstream quantification using imaging software. J Drugs Dermatol. 2016;15(11):1344 1346.. PMID- 28095546 TI - Comparison of the Cutaneous Thermal Signatures Over Twenty-Four Hours With a Picosecond Alexandrite Laser Using a Flat or Fractional Optic. AB - INTRODUCTION: This study explored immediate heat signatures with different passing techniques and the delayed thermal data points with the picosecond Alexandrite laser with the 6mm at and fractional optic during and after treatment. We sought to clarify the im- mediate effects of heating and understand the thermal and short term clinical difference when using these optics. RESULTS: There were no immediate differences or a signi cant temperature rise with different passing techniques using the at or the fractional optic. However, after treatments a signi cant temperature elevation over 24 hours with manageable erythema was noted with the fractional optic. Only faint redness was appreciated with the at optic. CONCLUSION: The different passing methods with these optics did not result in a significant thermal change. However, the fractional optic produces a localized area of epidermal necrosis which results in a significant clinical and a delayed thermal effect. With multiple treatments over time, collagen, elastic tissue, and mucin is produced resulting in improvement of acne scars and photo-damaged skin. This process suggests that a well-placed epidermal injury can stimulate an inflammatory cascade with dermal remodeling. J Drugs Dermatol. 2016;15(11):1347-1352.. PMID- 28095547 TI - Prospective Internally Controlled Blind Reviewed Clinical Evaluation of Cryolipolysis Combined With Multipolar Radiofrequency andVaripulseTechnology for Enhanced Subject Results in Circumferential Fat Reduction and Skin Laxity of the Flanks. AB - BACKGROUND: Increasing demand for non-invasive skin tightening and body contouring procedures has led to several technological in- novations in energy based devices such as ultrasound, radiofrequency and cryolipolysis. An emerging trend in the eld is to evaluate whether combination therapies for skin laxity/body contouring using energy-based devices can deliver superior clinical results and patient satisfaction. As such, the objective of this prospective, internal-controlled, blind clinical study was to assess the safety and efficacy of cryolipolysis followed by multipolar radiofrequency with pulsed electromagnetic elds (PEMF) and adjustable pulsed suction for the treatment of skin laxity in the flanks. METHODS: Ten subjects with focal adiposities in the anks were enrolled in the study. All subjects received one session of cryolipolysis treatment and after randomization received two sessions of radiofrequency with PEMF (spaced two weeks apart), followed by another two sessions of radiofrequency with PEMF and adjustable pulsed suction (spaced two weeks apart). Clinical photography was used to monitor the subject's results at baseline, one week, three, and six months post treatment. Blinded reviewers and the treating inves- tigator assessed the clinical outcomes using the Global Aesthetic Improvement (GAI) scale. Side effects were recorded at every visit and patient satisfaction was noted at the one week, three and six-month follow-up using a 5-scale subject satisfaction assessment questionnaire. RESULTS: Analysis of the blinded investigator ratings demonstrated statistical significant enhanced skin laxity mean improvement of 1 grade on the GAI scale in subject treated with the combination treatment (cryolipolysis+RF/PEMF/suction) compared with the cryolipolysis treatment alone. The unblinded investigator GAI ratings also showed enhanced (20%) mean improvement of laxity in the combination treated subjects versus those receiving cryolipolysis alone. Over half of the participants reported satisfaction with both treatment results, but there was a 10% statistically significant higher satisfaction rating of the outcomes in the flank treated with the combination treatment. Procedures were well tolerated, side effects were transient and self-resolving and no unexpected adverse effects were reported for the duration of the study. CONCLUSION: The results of this study show that the combination of multipolar RF with PEMF/suction following cryolipolysis is a safe, effective, and painless approach to enhance skin tightening following fat reduction procedures in the flanks. J Drugs Dermatol. 2016;15(11):1354-1358.. PMID- 28095548 TI - Integrated Cooling-Vacuum-Assisted Non-Fractional 1540 nm Erbium:Glass Laser is Effective in Treating Acne Scars. AB - INTRODUCTION: Acne scars are a common result of in ammatory acne, affecting many patients worldwide. Among which, atrophic scars are the most prevalent form, presenting as dermal depressions caused by inflammatory degeneration of dermal collagen. Mid-infrared laser skin interaction is characterized by its modest absorption in water and nite penetration to the mid-dermis. Since collagen is a desirable laser target, 1540-nm wavelength is amenable for collagen remodeling within the depressed area of atrophic scars. OBJECTIVES: To evaluate the safety and efficacy of acne scars treatment using an integrated cooling-vacuum-assisted 1540 nm Erbium: Glass Laser. PATIENTS AND METHODS: This interventional prospective study included 25 volunteers (10 men, 15 women) with post acne atrophic scars. Patients were treated with a mid-infrared non-fractional 1540 nm Er:Glass laser (Alma Lasers Ltd. Caesarea, Israel) with integrat- ed cooling- vacuum assisted technology. Acne scars were exposed to 3 stacked laser pulses (400-600 mJ/pulse, 4 mm spot size, frequency of 3 Hz). Patients underwent 3-6 treatment sessions with a 2-3 week interval and were followed-up 1 month and 3 months after the last treatment. Clinical photographs were taken by high resolution digital camera before and after treatment. Clinical evaluation was performed by two independent dermatologists and results were graded on a scale of 0 (exacerbation) to 4 (76%-100% improvement). Patients' and physicians' satisfaction were also recorded (on a 1-5 scale). Pain perception and adverse effects were evaluated as well. RESULTS: Almost all patients (24/25) demonstrated a moderate to significant improvement. Average improvement was 3.9 and 4.1 points on the quartile scale used for outcome assessment 1 and 3 months following the last session, respectively. Patient satisfaction rate was 4.2. Side effects were minimal and transient: erythema, mild transient vesicles, and mild pain or inconvenience. CONCLUSION Cooling-Vacuum-Assisted mid-infrared non-fractional Er:Glass 1540 nm laser is safe and effective in the treatment of atrophic acne scars. J Drugs Dermatol. 2016;15(11):1359-1363.. PMID- 28095549 TI - Treatment of Facial Photodamage With Mass Market Topical Products vs Non-ablative Fractional Laser. AB - METHODS: In this split-face, evaluator-blinded study, 18 subjects were randomly assigned to receive either the SSR or NFL treatments on each side of the face. For the SSR facial sides subjects followed two morning-evening regimens. On the NFL sides subjects were treated 3 times with the 1927-nm laser at 4-week intervals. Three physician evaluators were asked to rate hyperpigmentation, global photoaging, and ne lines and wrinkles for each side of the face at baseline and at 3 months using a 5-point scale. RESULTS: The SSR and NFL treatments provided comparable results for each skin attribute. Improvement from baseline was signi - cant in both treatment programs for each skin attribute. The greatest 3-month improvement for both programs was in hyperpigmen- tation. For global photoaging and ne lines and wrinkles, positive responses were slightly greater in the NFL than in the SSR facial sides. Subject preference for the SSR over the NFL was greatest for ne lines around the eyes, ne lines around the mouth, smooth texture, radiant complexion, and overall improvement while the NFL was preferred for skin rmness and evenness. When the study was completed5 of 18 split-face subjects decided to undergo NFR laser treatment on the non laser treated side along with using the SSR product and 13 of the 18 subjects continued to use the SSR products to their full face after the study. CONCLUSION: The mass market skin care system of the present study provides improvement in hyperpigmentation, global photoaging, and ne lines and wrinkles comparable to that of a series of treatments with a non-ablative fractional laser. J Drugs Dermatol. 2016;15(11):1366-1372.. PMID- 28095550 TI - The Diagnostic Role of Optical Coherence Tomography (OCT) in Measuring the Depth of Burn and Traumatic Scars for More Accurate Laser Dosimetry: Pilot Study. AB - BACKGROUND: In recent decades, a number of optimal diagnostic technologies have emerged to assist in tissue visualization. Real-time monitoring of skin during laser therapies will help optimize laser parameters for more ef cient therapies. One of these technologies, optimal coherence tomography (OCT), may be used to help visualize burn and traumatic scars. When lasing severe scars, lasers have tunable pulse energies, which are made proportional to the scar thickness as estimated by palpation and the physician eye. This has historically been estimated by the clinician with no objective data. OCT is an emerging non invasive imaging technique that provides a cross-sectional image of tissue micro architecture from a depth of 0.7 - 1.5 mm. The signal intensity is related to the tissue optical scattering properties, which in turn is related to tissue constituents such as collagen density. Thus, OCT may provide an objective non invasive measurement of scar depth. STUDY: Thirty burn and traumatic scars were imaged with quality, traceable, and veri able OCT data from burn and trauma patients both pre- and post- laser therapy. OCT was rapid and ef cient (approximately 2 minutes) to scan skin to visualize real-time scar tissue in different areas of heterogenous scars. The OCT image of the scar was compared to that of normal tissue in order to identify scar tissue and estimate its depth. Laser parameters were then dialed to treat full thickness of the scar. RESULTS: Clinical and OCT correlation between atrophic versus hypertrophic scars was found. However, in most cases the clinicians underestimated the depth of the scar in the dermis. CONCLUSION: The treatment of burn and traumatic scars for both civilian and wounded warriors can be challenging. As these scars are often very deep, OCT allows for non-invasive examination of the thickness of the scar allowing the physician better accuracy for laser settings in the treatment for the full thickness of the scar tissue. J Drugs Dermatol. 2016;15(11):1375 1380.. PMID- 28095551 TI - Acne Treatment With 3-Step Broadband Light Protocol. AB - BACKGROUND AND OBJECTIVE: A new 3-step protocol using broadband light allows patients with moderate to severe in ammatory acne to avoid potential side effects of systemic acne treatments and the risks and uncertainties associated with laser and light treatments to date. The protocol also addresses acne scarring and, with appropriate modi cations, all skin types. METHODS: The protocol consists of 6 to 8 treatments performed with a single device that allows the user to select wavelength, spot size, uence, and pulse duration. Step 1 uses blue light with a large spot size and low uence to kill Propionibacterium acnes. Step 2 features red and yellow light with a smaller spot size and higher uence, which together exert anti-in ammatory effects and trigger neocollagenesis. Step 3 employs visible and infrared (IR) light with a high uence and 12-second pulse length, delivered with a constant motion technique, to enhance previous results while also targeting areas of frequent breakouts. RESULTS: Challenging cases treated with the protocol include a young adult female with a nearly decade-long history of in ammatory and cystic acne. Her skin remained clear more than 6 months post treatment. She reported her scarring reduction at 90%. Having treated more than 100 patients with the protocol, the author reports that approximately 80% of patients clear completely or achieve at least a 75% improvement in their in ammatory acne. Acne improvements start appearing 2 to 3 days after a treatment session. Red, purple, raised, or depressed acne scars less than 1 to 2 years old begin to fade 1 to 3 weeks post-treatment. CONCLUSION: The 3-step protocol is safe and effective for patients with moderate to severe in ammatory acne and acne scarring. J Drugs Dermatol. 2016;15(11):1382-1388.. PMID- 28095552 TI - A Prospective Split-Face Study of the Picosecond Alexandrite Laser With Specialized Lens Array for Facial Photoaging in Chinese. AB - BACKGROUND: A 755nm picosecond alexandrite laser with a diffractive lens array has been reported for the treatment of acne scar and photoaging with clinical ef cacy. In this study, we evaluated the application of the 755nm picosecond alexandrite laser with a diffractive lens array for facial photoaging in Chinese. MATERIALS AND METHODS: Ten subjects with moderate facial photoaging were enrolled in a prospective, evaluator-blinded, open-label, and split-face trial to assess the ef cacy and safety of the 755nm picosecond alexandrite laser with a diffractive lens array for facial photoaging. Each subject received a series of four treatment sessions on the right side of the face at two-week intervals. The left side of the face served as the control side. Blinded evaluation of baseline, pre-treatment, and two-month follow-up visit was performed by two independent dermatologists on a 5-point global photoaging scale (GPS) and a 6/8-point Asian photographic scale (APS). Adverse events and discomfort associated with the treatment were also assessed. RESULTS: Signi cant improvement in photoaged tissue was observed on the treated side of the face, with a mean GPS score decrease from 2.67 to 1.44 at the two-month follow-up visit. A greater improvement in wrinkles was observed (2.78 vs 1.89; P less than 0.05) when com- pared to the improvement in pigmentation (2.67 vs 2.11; P less than 0.05). No changes were observed on the control side. Treatment results improved gradually throughout the treatment program and continued to the two-month follow up. In addition, skin tightening was perceived in all subjects, and shallower nasolabial folds were observed in 60% of the subjects on the treated side of face. Moderate pain and transient erythema were observed as the two main discomforts associated with the treatment. CONCLUSIONS: The 755nm picosecond alexandrite laser with a diffractive lens array is efficacious and safe for rejuvenation of photodamaged facial tissue in Chinese. J Drugs Dermatol. 2016;15(11):1390-1396.. PMID- 28095553 TI - Evaluation of the Safety and Efficacy of a Low Fluence, Picopulsed, Alexandrite Laser in a Pico-Toning Technique With a Diffractive Lens Optic for the Treatment of Photodamage and Textural Improvement in "Off the Face" Applications. AB - BACKGROUND: The diffractive optic coupled with a picosecond pulsed alexandrite laser has been shown to effectively minimize pigmen- tation while improving the appearance of textural irregularities and rhytides. We evaluated the safety and ef cacy of the diffractive optic laser treatment for off of the face applications including the hands and decolletage in a pico-toning technique. STUDY: 20 healthy female patients (40-70 years of age) were treated with a picosecond pulsed alexandrite laser with a diffractive lens. 10 of the patients were enrolled in a prospective hand assessment study (20 hands) while the remaining 10 subjects were enrolled in an IRB approved study treating photodamage of the decolletage. Protocol for both groups included 4 treatments to the designated area with a picopulsed alexandrite laser with a diffractive lens on a 6mm handpiece delivering 0.71 j/cm2 with 10 hz repetition at 3 week intervals (+- 7 days) with follow up at 1 month and 3 months post fourth treatment using standardized digital photography. RESULTS: Statistically signi cant improvement in the overall appearance of pigmentation, texture and rhytides were recorded at each sub- sequent visit and at 1 and 3 months post the nal laser treatment. Clinical photographs were evaluated from baseline to the final photo at 3 months post last laser treatment by the treating physician, patient, and an independent evaluator. All hand subjects and chest subjects showed improvement in all 3 areas which were found to be statistically signi cant. No adverse events occurred in either study group. CONCLUSION: These study results show signi cant improvement in not only pigmentation, but in texture and rhytides in all subjects receiving pico-toning laser treatments to off of the face areas. The laser was well tolerated by all patients with no adverse effects. The use of a diffractive lens optic on a 6 mm xed spot size handpiece with a picopulsed alexandrite laser, in a pico-toning technique, provides a safe, low uence, yet effective treatment for not only pigment dyschromia but also textural irregularities and rhytides when treating the hands and decolletage. J Drugs Dermatol. 2016;15(11):1398-1401.. PMID- 28095554 TI - "Hands-Free" Noninvasive Body Contouring Devices: Review of Effectiveness and Patient Satisfaction. AB - The demand for body contouring is increasing rapidly and has generated the need for a variety of non-invasive body contouring devices. This review concentrates on three popular "hands-free" body contouring devices and analyzes their mechanism of action, as well as their evidence of safety and ef cacy. It also addresses some issues of usability from both the operators' and patients' point of view. J Drugs Dermatol. 2016;15(11):1402-1406.. PMID- 28095555 TI - Megasessions for Robotic Hair Restoration. AB - A robotic system can select and remove individual hair follicles from the donor area with great precision and without fatigue. This report describes the use of the robotic system in a megasession for hair restoration. Patients were instructed to cut their hair to 1.0 to 1.2 mm before surgery. The robot selected and removed 600 to 800 grafts per hour so the follicular units (FU)s could be transplanted manually to recipient sites. The robot arm consists of a sharp inner punch and a blunt outer punch which together separate FUs from the sur- rounding tissue. Stereoscopic cameras controlled by image processing software allow the system to identify the angle and direction of hair growth. The physician and one assistant control the harvesting with a hand-held remote control and computer monitor while the patient is positioned in an adjustable chair. When the robot has harvested all the FUs they are removed by technicians with small forceps. Hairline design, creation of recipient sites, and graft placement are performed manually by the physician. Clinical photographs before and after surgery show that patients experience excellent outcomes with the robotic megasession. Phy- sician fatigue during graft extraction is reduced because the robot performs the repetitive movements without fatigue. Variability of graft extraction is minimized because the robot's optical system can be programmed to choose the best FUs. The transection rate is reduced because the robot's graft extraction system uses two needles, a sharp one to piece the skin and a blunt needle to dissect the root without trauma. A robotic megasession for hair restoration is minimally invasive, does not result in linear scars in the donor area, and is associated with minimal fatigue and discomfort for both patient and physician. Healing is rapid and patients experience a high level of satisfaction with the results. J Drugs Dermatol. 2016;15(11):1407-1412.. PMID- 28095556 TI - Combination Therapy for Acne Scarring: Personal Experience and Clinical Suggestions. AB - Acne is one of the most prevalent skin conditions seen by dermatologists. The cosmetic sequelae of severe acne, including scarring and pigmentation, have a profound psychological impact on those in icted. Topical (eg, retinoids, antibiotics, dapsone, hydroxyacids) and oral treatments (eg, antibiotics and/or spironolactone) are often bene cial to control acne or in the instance of oral isotretinoin use, rid the acne permanently; however, these treatments have very little affect on the ultimate cosmetic outcome of the acne scarring and skin texture that results. Given the variety of scar types that can form and the variability of responses seen in various skin types and textures, treatment options are vast without appropriate guidelines for pathways that dictate best timing, combinations, and options in given clinical scenarios. Current treatment options include solo or combina- tions of energy-based (eg, laser, radiofrequency), chemical-based (eg, peels, TCA cross), surgical-based options (eg, subcision, punch excision), microneedling, and llers and/or fat injections. Most recently, fractional radiofrequency-based treatments have been used to improve acne scarring with less reported downtime as compared to lasers or chemical peels and the ability to treat darker or sensitive skin types with less risk of scarring or hyperpigmentation. In severe cystic ares, scarring treatments are often postposed till the acne is under control and in many instances this can limit the dermatologists ability to affect future cosmetic treatments. Based on personal experience of various clinical scenarios in a busy laser practice that treats a signi cant number of patients with acne scarring, fractional radiofrequency is an excellent choice for treating all forms of acne scars with minimal risk to patients, even those on concurrent treatments such as isotretinoin. Additionally, fractional radiofrequency can be used in combination with all other treatment options to speed the time to clinical improvement appreciated by the patient. Here we present personal experiences of combination treatments for acne scarring, pigmentation and textural issues, and suggest that fractional radiofrequency be considered a "gold standard" treatment of acne scarring in those with dark or sensitive skin types or those on concurrent isotretinoin. J Drugs Dermatol. 2016;15(11):1413-1419.. PMID- 28095557 TI - The Photodynamic Therapy Experience of a High Volume Laser and Dermatologic Surgery Center. AB - BACKGROUND: Photodynamic therapy (PDT) is an FDA approved treatment for actinic keratoses (AK's) although multiple off-label indi- cations are reported. Despite frequent use for AK's, no clear consensus exists regarding protocols for overall treatment parameters. METHODS: Retrospective chart review of 1,491 subjects who underwent PDT between 2007 and 2011 at a high volume laser surgery center. Demographic information, clinical history, treatment data, and subsequent diagnosis of skin cancers were recorded. An ex- ploratory subgroup analysis was performed for patients treated for AK and/or squamous cell carcinoma (SCC) that developed SCC or remained SCC-free one year after treatment. RESULTS: The most common indications for PDT were actinic keratoses (n=1404, 94.9%) then NMSC (n=45, 3.0%) The most common treatment site was the head and neck (n=1274, 86.1%). Blue light activation (405-420nm) was used more frequently than red light and visible light. (73.8% vs. 22.8% vs. 6.8%). The most commonly used photosensitizer was aminolevulinic acid (ALA) (98.6%, n=1456). Topical application (97.7% n=1437) of photosensitizer was used more frequently than intralesional administration (2.0%, n=29). 580 patients met subgroup analysis criteria. 66 developed SCC at treatment site (11%). Factors associated with developing SCC were older age, SCC history, Fitzpatrick skin-type 1, and sixty minute or less incubation times (P less than 0.05 for all factors). The SCC subgroup had a unique distribution of treatment sites (P less than.001). No statistically significant differences were observed for gender or wavelength. CONCLUSION: There are differences in protocols based on indication and location of lesion. Blue light is preferable for superFIcial lesions and red light for deeper lesions. Intralesional delivery is used more commonly for NMSC. Extremities require longer incubation times. PDT may be more effective with younger patients and longer than sixty-minute incubation times. PDT chemoprevention is independent of light source used. J Drugs Dermatol. 2016;15(11):1420-1426.. PMID- 28095558 TI - Clinical Evaluation of a 4% Hydroquinone + 1% Retinol Treatment Regimen for Improving Melasma and Photodamage in Fitzpatrick Skin Types III-VI. AB - The bene ts of monotherapy with hydroquinone for melasma and retinoids for photodamaged skin is well established. Here we report results of a hydroquinone skincare regimen designed for melasma treatment combined with a cosmetic retinol cream on subjects presenting with both melasma and facial photodamage in a 24 week study. Improvement in melasma and photodamage ef cacy pa- rameters of melasma pigmentation intensity and melasma area and severity index (MASI), as well as overall photodamage and mottled hyperpigmentation were found by week 4, the rst post-baseline time point. By week 8 signi cant improvements were also found in melasma disease severity assessment, tactile roughness, ne wrinkles, crepiness, actinic lentigines, and laxity. By week 18 signi cant reduction in coarse wrinkles was evident. Bene ts persisted through the study end on the panel of 31 subjects, with over 3/4 of par- ticipants demonstrating improvements in 10 of the 11 graded attributes. For the remaining attribute, coarse wrinkling, approximately 50% of the panel showed improvement. The regimen produced an average of "marked improvement" in melasma severity (51-75% improvement). Results of tolerance evaluations documented overall treatment mildness for a majority of the study participants. Subject questionnaires concur with high ratings of the study regimen for tolerability, ef cacy perception, product aesthetics and overall treat- ment satisfaction in subjects of Fitzpatrick Skin Type III-VI classi cation with melasma and photodamage in mild-to-moderate severity. J Drugs Dermatol. 2016;15(11):1435-1441.. PMID- 28095559 TI - Comparative Results in Treatment of Keloids With Intralesional 5-FU/Kenalog, 5 FU/Verapamil, Enalapril Alone,Verapamil Alone, and Laser: A Case Report and Review of the Literature. AB - BACKGROUND: The pathogenesis of keloids involves a hyperproliferative state due to molecular abnormalities, cellular driving pathways, such as TGF, VEGF, and the inactivation of proapoptotic genes. We reviewed the literature and compared various treatment combina- tions in the treatment of keloids in a one patient observation. METHODS AND MATERIALS: Treatment modalities consisted of: intralesional 5- uorouracil (5-FU)/triamcinolone (TMC), 5-FU/verapamil, enal- april alone, verapamil alone, and fractional carbon dioxide laser. Size, height, and softness of the keloid, pain, itching, and pain were assessed. RESULTS: 5-FU based treatments proved to be more ef cacious than the other modalities. 5-FU + TMC demonstrated the largest reduc- tion in keloid height and rmness. The greatest degree of scar softening and average size reduction was achieved with 5 FU/ TMC (80% and 70% reduction, respectively), followed by 5-FU/verapamil (50% and 33% reduction, respectively). The same combinations led to the greatest reduction in scar height (70% and 33%, respectively). All treatments led to resolution of pain and itching in the keloid. CONCLUSION: The favorable effects of the 5-FU + verapamil combination are new and deserve further exploration. J Drugs Dermatol. 2016;15(11):1442-1447.. PMID- 28095560 TI - Q-Switched Nd:YAG Laser Removal of Facial Amateur Tattoos in Patients With Fitzpatrick Type VI: Case Series. AB - INTRODUCTION: Q-switched neodymium:YAG (Nd:YAG) lasers are reported to be gold standard for laser tattoo removal. In particular, the Q-switched Nd:YAG laser at 1064 nm is widely recognized for the removal of blue/black amateur tattoos. However, treatment modalities in Fitzpatrick Type VI skin carry a greater risk of complications including alterations in pigmentation compared to fairer skin (Fitzpatrick Type I-IV skin). Therefore, the aim of this case series was to describe with the use of the Q-Switched Nd:YAG laser, the removal of carbon-based amateur tattoos on patients with Fitzpatrick Type VI skin as an effective and safe method. METHODS: Twenty- five patients with Fitzpatrick type VI skin, from Ethiopian origins, with facial tribal tattoos, were treated with the Q- Switched Nd:YAG laser at 1064 nm. Digital images were taken upon every treatment and the clearance rates of the tattoo was evalu- ated by imaging software. RESULTS: We observed an average tattoo clearance rate of 95% among the 45 facial tattoos in 25 patients presented in the case series with minimal pigmentary and textual changes evident. DISCUSSION: These positive aesthetic results have a signi cant psychosocial impact on the lives of those with Fitzpatrick Type VI skin, in particular the Ethiopian Jewish population. J Drugs Dermatol. 2016;15(11):1448-1452.. PMID- 28095561 TI - Self-Resolving Eruptive Keratoacanthomas After Full-Field Erbium Laser Resurfacing. AB - Keratoacanthoma (KA) is a subtype of squamous cell carcinoma whose development has been linked to excessive sun exposure, immunosuppression, and trauma. Given the rapidly expanding therapeutic armamentarium for anti-aging modalities in dermatology, reports of KA secondary to invasive cosmetic procedures are on the rise. We present a case of eruptive KAs after full- eld ablative Erbium:YAG 2940 nm laser resurfacing of the face that resolved with minimal intervention. This case demonstrates the potential for a rare yet signi cant laser complication that may warrant discussion during the consenting process. J Drugs Dermatol. 2016;15(11):1453-1455.. PMID- 28095562 TI - The Efficacy of Q-Switched ND:YAG 1064 nm Laser in Recalcitrant Macular Amyloidosis: A Case Report. AB - Macular amyloidosis typically presents as small, dusky-brown or greyish pigmented macules, the result of altered keratin deposition. Treatment of these hyperpigmented regions with topical and systemic therapies remains challenging, however Q-Switched neodymi- um-doped yttrium aluminum garnet (ND:YAG) laser has proven to be an effective treatment modality to reduce hyperpigmentation. In this case report we investigated the ef cacy of Q-Switched Nd:YAG laser treatment on a 34-year old woman with recalcitrant macular amyloidosis who failed to respond to over-the-counter bleaching creams. The patient was treated with 7 treatment sessions of Q- Switched Nd:YAG laser at one month intervals. According to our photographic analysis and patient self-assessment, the patient ap- peared to improve with each treatment session. Post-recurrence of the lesion after reaction to Triluma ( uocoinolone actetonide 0.01%, hydroquinone 4%, tretinoin 0.05%), the patient has been continuing to respond well to a second round of treatment with Q switched Nd:YAG laser at 1064 nm. J Drugs Dermatol. 2016;15(11):1456 1458.. PMID- 28095563 TI - Defining the Absorption Spectrum of the Skin After Application of a Popular Sunless Tanner, Dihydroxyacetone, Using Re ectance Photospectrometry. AB - Dihydroxyacetone (DHA) is a popular ingredient in sunless tanner and lotions. We sought to measure the absorption spectrum of hu- man skin after application of DHA. A male in his 30's applied DHA to one underarm once daily for seven days. Re ectance spectropho- tometry was performed on the treated and untreated side. The area treated with DHA revealed increased absorption in the 400-700 nm range. Compared to normal skin, the absorption spectrum of human skin after application of DHA is altered from 400-700 nm. Care should be taking with using lasers in these wavelengths on skin treated with DHA. J Drugs Dermatol. 2016;15(11):1459-1460.. PMID- 28095564 TI - Successful Treatment of Traumatic Onychodystrophy and Associated Pterygium Unguis With Fractionated Carbon Dioxide Laser: Case Report and Review of the Literature. AB - Onychodystrophy is a common, chronic malformation of the nail that is aesthetically displeasing and can signi cantly impact patient quality-of-life. Onychodystrophy can be associated with pterygium unguis that contributes to pain and appears as a V-shaped exten- sion of the proximal nail fold skin. Treatment options are limited, and topical or intralesional corticosteroids have minimal ef cacy and cause signi cant patient discomfort. Surgical revision of onychodystrophy is complex, and symptomatic or aesthetic improvements are difficult to achieve. There is limited published literature on laser treatment of noninfectious onychodystrophy or associated pterygium unguis. We present a case of a 68-year-old man with a 10-year history of painful traumatic onychodystrophy with associated pterygium unguis, who was successfully treated after three treatments of fractionated carbon dioxide (CO2) laser. Additionally, we review the medical literature on laser treatment of noninfectious onychodystrophy and pterygium unguis. To our knowledge, this is the first reported successful treatment of painful traumatic onychodystrophy and associated pterygium unguis using fractionated CO2 laser. We hope clinicians consider this treatment modality to relieve pain and improve aesthetics associated with traumatic onychodystrophy and associated pterygium unguis. We envision additional research investigating the mechanism of action of fractionated CO2 laser may con rm this treatment option for the management of traumatic onychodystrophy and associated pterygium unguis. J Drugs Dermatol. 2016;15(11):1461-1464.. PMID- 28095565 TI - Successful Treatment of Rhinophyma With Fractionated Carbon Dioxide (CO2) Laser in an African-American Man: Case Report and Review of Literature of Fractionated CO2 Laser Treatment of Rhinophyma. AB - Rhinophyma, a late complication of rosacea (phymatous subtype), is a chronic, progressive dermatological condition. The classic pre- sentation of rhinophyma is nodular, thickened skin over the distal nose, and is often accompanied by underlying erythema secondary to in ammation. Due to the unpleasant aesthetic and dis guring appearance, rhinophyma may be associated with a signi cant nega- tive psychosocial impact, resulting in decreased patient quality-of-life. Treatment of rhinophyma is challenging as topical and systemic pharmacotherapies have shown limited ef cacy. We present a case of a 39-year-old African-American male with long-standing, mild rhinophyma who was successfully treated with two sessions of fractionated carbon dioxide (CO2) laser. We also review the medical literature on fractionated CO2 laser treatment of rhinophyma. To the best of our knowledge, this is the rst report of successful treat- ment of rhinophyma using fractionated CO2 laser in an African-American man (Fitzpatrick VI). We believe that fractionated CO2 laser may be a safe and ef cacious treatment modality for rhinophyma in skin of color patients (Fitzpatrick IV-VI) and early intervention with fractionated CO2 laser to prevent rhinophyma worsening may yield better results than late intervention. J Drugs Dermatol. 2016;15(11):1465 1468.. PMID- 28095566 TI - Prospective Evaluation of the Safety and Efficacy of a 1060-nm Large Spot Size, Vacuum-Assisted Hair Removal Diode Laser System in Asian/Pacific Fitzpatrick's Skin Types IV-V Patients. AB - Laser-based photoepilation of dark skin types demands a delicate combination of appropriate light wavelengths and spot size to achieve optimal epidermal-to follicular energy absorption ratios. This prospective study assessed the axillary, arm, thigh, and back hair clearing ef cacy of the LightSheer In nity 1060 nm diode laser in 10 Fitzpatrick skin type IV-V patients. Each area was treated up to ve times, at 4-6-week intervals, after which immediate skin responses and adverse events were recorded. Hair count, color and coarseness were assessed before each treatment session, as well as 1, 3, and 6 months following the last session. Both patients and the treating physician rated the degree of improvement with time, and patients also ranked their satisfaction with the treatment outcome. Percent hair reduction from baseline gradually increased with treatment and peaked at 74.6%, 68.4%, and 65.7% for axillary, arm and thigh regions, respectively, 6 months following the last treatment session. Baseline hair growth patterns precluded effective selection of a representative area for hair counting. Patients satisfaction was consistently higher for axillary hair clearance rates, followed by thigh and arm responses. Throughout the follow-up period, the investigator rated 50-67% of the treated axillae as presenting "good" or "very good" hair clearance, and provided similar ratings for 67% of the treated thigh regions at both the 1 and 6 month follow-up sessions. Immediate responses to treatment were mild to moderate and short-lived and no incidents of brosis or scarring were reported. Taken together, the LightSheer In nity 1060 HS Handpiece provided for an ideal ef cacy-safety balance in treating dark-skinned patients, providing for long-term hair clearance with minimal downtime. J Drugs Dermatol. 2016;15(11):1427-1434. PMID- 28095567 TI - Evidence-Based Skincare: The Importance of Offering Moisturization, Relief, and Protection in Common Skin Disorders. AB - . PMID- 28095568 TI - Efficacy of a Moisturizing Foam in Skin Barrier Regeneration and Itch Relief in Subjects Prone to Atopic Dermatitis. AB - INTRODUCTION: Atopic dermatitis (AD) is characterized by impaired epidermal barrier with increased transepidermal water loss (TEWL). Scratching further compromises skin integrity, contributing to a cycle of inflammation. The objective of the present study was to investigate a topical anti-itch foam in improving skin barrier and itch. MATERIAL AND METHODS: A single center open study was performed on 26 adults previously diagnosed with AD but without active lesions. One leg was treated with a single application of an anti-itch foam. Dryness, scaling, roughness, cracking, and signs of scratching were assessed before, 6, and 24 hours after application. Skin hydration was measured at 24 hours. The same product was applied twice daily for 7.5 days to the other leg, and skin hydration and TEWL were measured at baseline and on days 2, 8, and 10. Pruritus was assessed by volunteers and by a dermatologist. RESULTS: A significant increase in skin moisture (P less than 0.001) was measured 6 hours after a single application. Scores of dryness, scaling, roughness (P less than 0.001) and cracking (P=0.002) were significantly improved up to 24 hours after a single application. After a 7.5-day repeated application period, the anti-itch foam significantly reduced TEWL (P less than 0.001) compared to baseline. Skin hydration significantly improved (P less than 0.001) in the same time period. 48 hours after the last application, these improvements remained significant (P less than 0.001). CONCLUSIONS: The anti-itch foam improved the skin barrier. It provided immediate relief of clinical signs of AD including pruritus. Moreover, it delivered a long-lasting moisturizing effect, comforting the skin, and improving overall skin condition. J Drugs Dermatol. 2016;15(suppl 11):s77 80.. PMID- 28095569 TI - Efficacy of a Hand Regimen in Skin Barrier Protection in Individuals With Occupational Irritant Contact Dermatitis. AB - BACKGROUND: Occupational irritant contact dermatitis (OICD) is a dif cult and hard to manage condition. It occurs more frequently in certain occupations where contact with harsh chemicals, use of alcohol-based disinfectants, and frequent hand washing heightens the risk. Treatment for OICD includes patient education in addition to physical, topical, and systemic therapies. OBJECTIVE: To review the pathogenesis and treatment options for OICD and evaluate the ef cacy of a selective skin-care regimen involv- ing a hand protectant cream alone as well as combined with a repair cream and speci c cleanser. MATERIALS AND METHODS: A single-center open study was performed comprising 42 healthy male and female adult volunteers prone to occupational irritant contact dermatitis due to frequent wet work or contact with detergents. Between day 0 and day 7, subjects applied a hand protectant cream as needed on both hands (at least twice daily). On days 7 to 14, subjects applied a hand protectant cream and cleanser as needed on both hands (at least twice daily) as well as a repair cream each evening. A diary log was given to each volunteer for application control and for a subjective evaluation of daily tolerability. RESULTS: In these subjects prone to occupational irritant contact dermatitis, the hand protectant cream applied during the initial 7-day period was effective in restoring the damaged skin barrier and improving the stratum corneum hydration. A regimen that combined the hand protectant and repair creams with a speci c cleanser during a further 7-day period allowed contin- ued improvement of skin hydration and additional clinical bene ts while respecting the skin barrier function. CONCLUSION: The results of this study support the use of a 3-step approach for patients who are at risk of repeated exposure to external irritants. J Drugs Dermatol. 2016;15(suppl 11):s81-85.. PMID- 28095570 TI - Efficacy of a Skin Condition-Adapted Solution for Xerosis and Itch Relief Associated With Aging. AB - In recent decades, the stratum corneum (SC), has been recognized for its multifunctional role in maintaining the homeostasis of the human epidermal barrier. A better understanding of the SC's ability to act as its own biosensor in detecting dysfunction and integrating restorative actions can help identify the origin of certain skin conditions. A more holistic understanding of the morphological changes of the SC during the natural aging process and how it deviates in disease states can help bring about new treatment strategies. Some important recent clinical studies point to new treatments and add to the existing body of research on corneobiology. These studies offer some explanation of and validation for the various ingredients incorporated into moisturizers and barrier repair devices aimed at treating pruritus and xerosis associated with the aging skin. J Drugs Dermatol. 2016;15(suppl 11):s91-94. PMID- 28095571 TI - Effectiveness of the "Mohs and Close Technique" in Increasing the Efficiency of a Mohs Micrographic Surgery. AB - INTRODUCTION: Mohs micrographic surgery (MMS) is successful and cost effective, but may be time consuming as patients are required to wait for final wound repair until margins are clear. We propose for selected cases the "Mohs and Close technique" (MCT), in which the defect is immediately repaired after tumor resection rather than waiting until margins are clear. METHODS: MCT was only performed on tumors that had clearly de ned borders, low risk histology, whose resulting defect after exci- sion required either a primary or partial closure, and whose repair wouldn't change to a different repair option if further stages of exci- sion were necessary. Tumor data was recorded for all cases. Time elapsed from tumor resection to completion of wound closure was recorded with and without performing MCT for comparable wounds. RESULTS: MCT was performed for 456 of 898 cases. Time required without MCT was significantly longer than with MCT when only one stage was performed (P<0.001). There was no statistical difference (P=0.3358) between the two separate techniques for cases which required 2 or more stages. CONCLUSION: MCT significantly reduces the time needed for selected Mohs cases that require only one stage of excision and therefore can increase the efficiency of MMS. J Drugs Dermatol. 2016;15(12):1481-1483. PMID- 28095572 TI - Development of a Clinical Pathway for Atopic Dermatitis Patients: A Case-Based Approach. AB - BACKGROUND: Atopic dermatitis (AD) is a common chronic skin condition, associated with significant patient morbidity. There are a myriad of excellent evidenced based guidelines to guide clinicians by an extensive review of all the available treatments. However, while well written and complete these papers may not always allow easy transition to clinical application. OBJECTIVE: The purpose of this paper was to develop a practical case-based approach for the treatment and maintenance of AD, enabling translation of guidelines into clinical care. METHODS: After literature searches, selected AD trials and recent existing guidelines were reviewed. Using a nominal group process for consensus, an expert panel of Canadian dermatologists determined the case features and corresponding treatments. RESULTS: A patient focused clinical pathway with 7 cases was developed. For each case scenario, treatment for mild, moderate, and severe disease was recommended. CONCLUSION: A practical case-based clinical pathway was developed for easy clinical application and optimal patient care. J Drugs Dermatol. 2016;15(12):1485-1494. PMID- 28095573 TI - Results of a Phase 2, Randomized,Vehicle-Controlled Study Evaluating the Efficacy,Tolerability, and Safety of Daily or Twice Daily SB204 for the Treatment of Acne Vulgaris. AB - OBJECTIVE: This randomized, double-blind, placebo-controlled, Phase 2 study compared efficacy, tolerability, and safety of SB204 once or twice daily to vehicle in the treatment of acne vulgaris. METHODS: Eligible subjects were to be between 12 and 40 years old, have facial acne vulgaris with 25 to 70 non inflammatory lesions, 20 to 40 inflammatory lesions, no more than 2 nodules, and a baseline Investigator's Global Assessment (IGA) score of moderate or severe. The co-primary efficacy endpoints were the absolute change in inflammatory and non-inflammatory lesion counts and IGA success rate (baseline to week 12). Safety assessments included reported adverse events (AEs), physical examinations, and laboratory testing. Tolerability was evaluated by the investigators based on the occurrence and severity of erythema, scaling, dryness, pruritus, and burning/stinging. RESULTS: A total of 213 subjects were randomized: 27 subjects to vehicle once daily; 29 subjects to vehicle twice daily; 53 subjects to SB204 2% twice daily; 52 subjects to SB204 4% once daily; and 52 subjects to SB204 4% twice daily. When compared to vehicle, treatment with all 3 SB204 regimens significantly reduced the absolute inflammatory lesion count and SB204 4% once daily reduced the absolute non-inflammatory lesion count. Treatment with SB204 4% once daily demonstrated a significant reduction in percent inflammatory lesions by week 4. There were no significant differences in the IGA success rates between groups at the end of treatment. All treatment regimens of SB204 were found to be safe and well tolerated. CONCLUSIONS: When compared to vehicle, SB204 2% and SB204 4% significantly decreased the absolute inflammatory lesion count and SB204 4% once daily also significantly decreased the absolute non-inflammatory lesion count in subjects with acne vulgaris treated for 12 weeks. Treatment with SB204 2% and 4% was found to be safe and well tolerated. J Drugs Dermatol. 2016;15(12):1496-1502. PMID- 28095574 TI - Managing Occupational Irritant Contact Dermatitis Using a Two-Step Skincare Regimen Designed to Prevent Skin Damage and Support Skin Recovery. AB - Occupational irritant contact dermatitis (ICD) affecting the hands is a common and difficult-to-manage condition. Occupations that necessitate contact with harsh chemicals, use of alcohol-based disinfectants, and frequent hand washing elevate the risk of ICD. Management strategies that do not adequately prevent accumulated damage and repair skin, can develop into chronic dermatoses which negatively impact work productivity and quality of life. A 2-step skin-care regimen (Excipial Daily Protection Hand Cream (EP) and Excipial Rapid Repair Hand Cream (ER), Galderma Laboratories, L.P.) has been developed as a daily-use management strategy to protect and repair vulnerable hands. The protective barrier cream is formulated with aluminum chlorohydrate and designed for pre exposure application to enhance the skin's natural protective barrier and minimize excessive moisture while wearing protective gloves. The repair cream, a lipid-rich formulation, is intended for post-exposure application to rehydrate and facilitate the skin's natural healing process. The results of 3 clinical studies highlighted in this review demonstrate how the use of a 2-step skin-care regimen offers a greater protective effect against ICD than the use of barrier cream alone, and also how the formulation of the barrier cream used in these studies helps minimize the occlusion effect caused by gloves and does not interfere with the antibacterial efficacy of an alcohol-based hand sanitizer. This 2-step skin-care regimen is effectively designed to manage and minimize the risk of ICD development in a variety of patients and provides clinicians an additional tool for helping patients manage ICD. J Drugs Dermatol. 2016;15(12):1504-1510. PMID- 28095575 TI - Review of Periorbital and Upper Face: Pertinent Anatomy, Aging, Injection Techniques, Prevention, and Management of Complications of Facial Fillers. AB - This paper aims to review articles related to facial fillers in the periorbital area, forehead, and temple. Anatomy, anatomical changes with aging, techniques of rejuvenation and facial harmonization with fillers are reviewed. Topics for complication prevention and management including knowledge of danger zones, timing of hyaluronidase injections, aspiration, definition a small aliquot, and thoughts about particle size are discussed. J Drugs Dermatol. 2016;15(12):1524 1531. PMID- 28095576 TI - Facial Contouring With Fillers, Neuromodulators, and Lipolysis to Achieve a Natural Look in Patients With Facial Fullness. AB - BACKGROUND: The desire for and use of nonsurgical injectable esthetic facial treatments is on a rise in Asia. Recent advances, including more versatile facial fillers, refined injection techniques, and adoption of a global facial approach, have in turn contributed to improved patient outcomes and increased patient satisfaction. The sought after nonsurgical treatments include the use of botulinum toxin, con- touring of the face with soft tissue fillers, and thinning of the face with injection lipolysis. AIM: To achieve a leaner, oval face shape with smooth contours. METHODS: A combination technique was applied, whereby narrowing of face was achieved with use of botulinum toxin, contouring with soft tissue llers, and thinning the face with injection lipolysis. Treatments were applied on 15 women aged between 25 and 40 years and observed with follow up for 12 weeks. Hyaluronic acid (HA)-based dermal fillers (Perlane, Voluma, and Juvederm), botulinum toxin type A (Botox), and a lipolytic solution of phosphatidylcholine with deoxycholate (Dermastabilion, Aesthetic Dermal, Spain) were used to achieve a natural look in these patients with a fuller appearance of the face. The procedure was performed to reduce the facial width using botulinum toxin type A and the reduction of submental and cheek fat by injecting lipolysis injection. RESULTS: All the women (n = 15) had edema for up to 2 weeks after undergoing lipolysis; however, two patients had edema for 3 weeks. After injecting the patient with botulinum toxin type A, no adverse event was observed; however, after using HA-based filler, one patient was observed to have bruising on the chin. CONCLUSION: Use of HA-based fillers, neuromodulators (botulinum toxin), and injectable lipolytics are well-tolerated and are effective nonsurgical modalities to achieve facial recontouring for slimming of the face. J Drugs Dermatol. 2016;15(12):1536-1542. PMID- 28095577 TI - Optimizing Injections of Poly-L-lactic Acid: The 6-Step Technique. AB - The authors present a reproducible and effective technique utilizing poly-L lactic acid for panfacial revolumization. The variable dilution ratios, reconstitution times, injection techniques and rates of nodule formation with poly-L-lactic acid can be intimidating to even experienced injectors. While there is no single cookie-cutter approach to facial volumization, this 6-step "Precise Sculpt" technique can be used as a template to reliably achieve optimal results while minimizing the risk of adverse events. J Drugs Dermatol. 2016;15(12):1550 1556. PMID- 28095578 TI - A Clinical Evaluation of a Next Generation, Non-Invasive, Selective Radiofrequency, Hands-Free, Body-Shaping Device. AB - OBJECTIVE: The aim of this study was to compare clinical outcomes of a noninvasive selective radiofrequency (RF) eld device (BTL Vanquish METM, BTL Industries Inc., Boston MA) with its predecessor (VanquishTM, BTL Industries Inc., Boston MA). The BTL Vanquish METM system has been thoroughly redesigned for more efficient, predictable and homogenous energy delivery to the targeted tissue. MATERIALS AND METHODS: In this multi-center study, 36 subjects with BMIs under 30 were randomly assigned to be treated in Group A (BTL Vanquish METM) or Group B (VanquishTM) in order to obtain a side by side comparison of the devices' ef cacies. Each subject re- ceived 4 weekly 45-minute treatments with the device determined by their group assignments. Measurements of subject's abdominal fat were taken prior to the first treatment and again four weeks after finishing the final treatment. RESULTS: The primary outcome was abdominal fat thickness reduction as measured by ultrasound one month following each subject's final treatment. Thirty four subjects completed the study. Two patients did not complete their treatments due to the reasons unrelated to the study (one from each group). Subjects in Group A treated with BTL Vanquish METM had an abdominal fat thickness reduction of 4.17 mm, or 29.46%, while subjects in Group B treated with VanquishTM had an abdominal fat thickness reduction of only 2.72 mm, or 15.21%. The 4 weekly treatments with BTL Vanquish METM in Group A produced a 53% higher reduction (4.17 mm vs 2.72 mm) of abdominal fat layer thickness than those in Group B. The standard deviation of ultrasound measurements in Groups A and B were 1.42mm and 2.21mm, respectively. Assuming a homogenous response across the entire treatment area, the volume of fat reduced was calculated by multiplying the average measured reduction in fat layer by the surface area of the treatment applicator (2100 cm2; 325.5 square inches). It was calculated that Group A patients lost an average of 0.876 liter (0.23 liquid gallon) of fat, while Group B patients lost 0.571 liter (0.15 liquid gallon) of fat. DISCUSSIONS AND CONCLUSIONS: The mean difference between the tested groups was statistically significant proving better outcomes in the Vanquish METM than its predecessor. Furthermore, the reduction in standard deviation of fat reduction measurements in Group A vs Group B is evidence that the Vanquish METM provides more consistent performance. J Drugs Dermatol. 2016;15(12):1557-1561. PMID- 28095579 TI - Development and Clinical Assessment of a Comprehensive Product for Pigmentation Control in Multiple Ethnic Populations. AB - BACKGROUND: Pigmentary changes in people of different ethnic origins are controlled by slight variations in key biological pathways leading to different outcomes from the same treatment. It is important to develop and test products for desired outcomes in varying ethnic populations. OBJECTIVES: To develop a comprehensive product (LYT2) that affects all major biological pathways controlling pigmentation and test for clinical efficacy and safety in different ethnic populations. METHODS: A thorough analysis of biological pathways was used to identify ingredient combinations for LYT2 that provided optimal melanin reduction in a 3-D skin model. Expression of four key genes for melanogenesis, TYR, TYRP-1, DCT, and MITF was analyzed by qPCR. Clinical study was conducted to compare the efficacy and tolerability of LYT2 against 4% hydroquinone (HQ). RESULTS: Average melanin suppression by LYT2 in 7 independent experiments was 45%. All four key genes show significant down- regulation of expression. LYT2 provided statistically significant reductions in mean overall hyperpigmentation grades as early as week 2 compared to baseline, with continued significant improvements through week 12 in all ethnic groups tested. CONCLUSION: We have successfully combined management of 6 categories of pathways related to melanogenesis: melanocyte activation, melanosome development, melanin production, melanin distribution, keratinocyte turnover, and barrier function to create a comprehensive HQ-free product. The outcome clearly shows greater pigmentation control with LYT2 compared to other HQ-free products in skin tissue models and earlier control in clinical studies compared to 4% HQ. Clinical study shows pigmentation control benefits of LYT2 in people of Caucasian, Hispanic, and African ethnic origins. J Drugs Dermatol. 2016;15(12):1562-1570. PMID- 28095580 TI - Split-Face Comparison of an Advanced Non-Hydroquinone Lightening Solution to 4% Hydroquinone. AB - INTRODUCTION: Hyperpigmentation is a primary concern for many cosmetic patients because of its high rate of occurrence and significant impact on perceived age. While 4% hydroquinone has been the gold-standard of treatment, there is a growing interest in non-hydroquinone solutions, however, many of these newer solutions fail to deliver equivalent improvement. METHODS: This double-blind, randomized, split-face study compares the effects of a new OTC non-hydroquinone lightening product (JM) to an available 4% hydroquinone lightening solution (OB) on the appearance of hyperpigmentation, texture, and ne lines and wrinkles. Comparisons were determined by both physician assessment and subject self-assessment at baseline, 4, 8, and 12 weeks. RESULTS: Physician assessment showed statistically equivalent improvement on both sides of the face with the JM side showing equivalent or superior average improvement in all assessed categories. Subject self-assessment showed a significant preference for the JM product over the 4% hydroquinone and a substantially higher perception of overall improvement over 4% hydroquinone (P=0.058). DISCUSSION: Physician assessment showed equal or superior average improvement in all measured categories with no statistically significant difference between the two sides. Subject self-assessment, however, showed a significant and growing preference toward the investigated JM product over the course of the study. Overall, the results of this study show the JM product to be equivalent if not superior to 4% hydroquinone for results and patient satisfaction. J Drugs Dermatol. 2016;15(12):1571-1577. PMID- 28095581 TI - Long-Term Adherence and Effectiveness of a Multicomponent Intervention for Community-Dwelling Overweight Thai Older Adults with Knee Osteoarthritis: 1-Year Follow Up. AB - Being overweight is a major risk factor for developing knee osteoarthritis (OA). The purpose of the current study was to: (a) determine participant adherence to a quadriceps exercise and weight management program after completion of the intervention; and (b) examine whether a quadriceps exercise and weight management program can reduce knee pain and improve knee function and weight loss in 40 community-dwelling overweight Thai older adults with knee OA at 6- and 12-month follow up. Twenty-nine (76.3%) participants completed at least 75% of the program. Two (5%) participants did not complete the program. In the intervention group, significant improvement was noted in knee range of motion at 6 and 12 months compared with baseline, and a significant reduction was noted in knee pain, time spent in the Timed Up and Go test, and body weight compared with baseline. These study variables, except for body weight, between the intervention group and control group were significantly different. This study highlights the benefit of long-term adherence to the multicomponent intervention for community dwelling overweight Thai older adults with knee OA. [Journal of Gerontological Nursing, 43(4), 40-48.]. PMID- 28095582 TI - Enhancing the ADMIT Me Tool for Care Transitions for Individuals With Alzheimer's Disease. AB - One of the goals of the National Plan to Address Alzheimer's Disease is to ensure safe care transitions. To facilitate safe and effective transitions from home to hospital, the ADMIT (Alzheimer's, Dementia, Memory Impaired Transitions) Me tool was developed and three focus groups were conducted with caregivers (n = 6), emergency department nurses (n = 6), and first responders (n = 14) to determine its usefulness and applicability to practice. Feedback was used to enhance the tool to reflect their needs. Each group expressed that the tool would help promote safety in care transitions. Using ADMIT Me, nurses can practice with clear communication and collaboration in care transitions, and provide patient centered care based on the behaviors and unique needs of the individual with dementia. [Journal of Gerontological Nursing, 43(5), 32-38.]. PMID- 28095583 TI - Is it My Job? The Role of RNs in the Assessment and Identification of Delirium in Hospitalized Older Adults: An Exploratory Qualitative Study. AB - Delirium is characterized by acute and fluctuating cognitive decline, which is often missed in older adults who are assumed to be experiencing age-related changes or dementia. Delirium affects up to 50% of hospitalized older adults. The aim of the current study was to (a) explore current practices of RNs in assessing and identifying delirium in hospitalized older adults and (b) inform new educational initiatives. Qualitative methods were adopted using eight semi structured group interviews with 24 RNs. Thematic analysis revealed a dichotomy in practice where RNs described delirium assessment and identification as (a) It's Not My Job, (b) It is My Job, and (c) It's Complex. The imperative to improve delirium assessment and identification to create safer and more caring health care environments means the current findings provide important evidence to build into practice and education strategies. The current authors have developed engaging educational interventions and begun implementation at the study site to develop delirium assessment and identification capacity, which moves clinicians beyond awareness and aims at practice adherence or the consistent application of evidence-based delirium assessment. [Journal of Gerontological Nursing, 43(4), 29 37.]. PMID- 28095584 TI - Creating a Dedicated Education Unit in Long-Term Care. AB - The number of older adults needing long-term care (LTC) may rise in future aging populations, necessitating an increase in the <1% of nurses currently certified in gerontological nursing. An innovative clinical model, the dedicated education unit (DEU), has been used globally with positive results. The purpose of the current review is to explore the DEU and its possible use in LTC settings, and identify if this clinical model increases nursing students' knowledge of the nursing role. Current literature, including a systematic review, is analyzed and rated for quality. Synthesis of findings show the DEU clinical model may increase student interest and knowledge of LTC nursing through collaboration with the practicing LTC nurse. More longitudinal studies are needed to determine the success of the DEU model as a long-term solution to this clinical problem. [Journal of Gerontological Nursing, 43 (5), 23-29.]. PMID- 28095585 TI - Clinical Nursing Leadership Education in Long-Term Care: Intervention Design and Evaluation. AB - The main objective of the current case study was to investigate the perceived leadership learning needs and feasibility of delivering leadership education to registered staff involved in direct care in long-term care (LTC) homes. The study was conducted in Ontario, Canada, and participants included RNs, registered practical nurses, and nursing administrators. Phase 1 bilingual web-based survey and bilingual focus group needs assessment data supported a preference for external training along with in-house mentoring to support sustainability. An intervention designed using insights gained from Phase 1 data was delivered via a 2-day, in-person workshop. Phases 2 and 3 evaluation survey data identified aspects of leadership training for LTC that require ongoing refinement. Findings suggest that communication skills and managing day-to-day nursing demands in the context of regulatory frameworks were areas of particular interest for leadership training in the LTC setting. [Journal of Gerontological Nursing, 43(4), 49-56.]. PMID- 28095586 TI - Antichlamydial Dimeric Indole Derivatives from Marine Actinomycete Rubrobacter radiotolerans. AB - Chlamydiae are widely distributed pathogens of human populations, which can lead to serious reproductive and other health problems. In our search for novel antichlamydial metabolites from marine derived-microorganisms, one new (1) and two known (2, 3) dimeric indole derivatives were isolated from the sponge-derived actinomycete Rubrobacter radiotolerans. The chemical structures of these metabolites were elucidated by NMR spectroscopic data as well as CD calculations. All three metabolites suppressed chlamydial growth in a concentration-dependent manner. Among them, compound 1 exhibited the most effective antichlamydial activity with IC50 values of 46.6 ~ 96.4 uM in the production of infectious progeny. Compounds appeared to target the mid-stage of the chlamydial developmental cycle by interfering with reticular body replication, but not directly inactivating the infectious elementary body. PMID- 28095587 TI - Quantitative Determination of Lactones in Piper methysticum (Kava-Kava) by Supercritical Fluid Chromatography. AB - A fast and validated supercritical fluid chromatography method for the quantitative determination of major lactones in Piper methysticum, a plant used against nervous anxiety, stress, and restlessness, was developed. The baseline separation of dihydrokavain, demethoxyyangonin, kavain, yangonin, dihydromethysticin, and methysticin was possible in less than 4 min on an Aquity UPC2 BEH 1.7 um column, in combination with a mobile phase comprising CO2 and methanol with diethylamine. The column temperature had a great impact on the results because only at 70 degrees C could kavain and yangonin be fully resolved. With correlation coefficients above 0.998, recovery rates between 95.9 and 104.1 % as well as limit of detection values below 1.5 ng on-column, the procedure fulfilled all validation requirements and was well suited for the quantitative analysis of commercial products containing P. methysticum root powder and/or extract. All of them contained the target analytes, however, the absolute content of lactones was quite variable. Accordingly, depending on the product, the total daily intake of lactones varied from 56 to 312 mg. Concerning speed, selectivity, and environmental friendly operation, this supercritical fluid chromatography approach surpasses all previously reported ones. PMID- 28095589 TI - Deciding with Thresholds: Importance Measures and Value of Information. AB - Risk-informed decision making is often accompanied by the specification of an acceptable level of risk. Such target level is compared against the value of a risk metric, usually computed through a probabilistic safety assessment model, to decide about the acceptability of a given design, the launch of a space mission, etc. Importance measures complement the decision process with information about the risk/safety significance of events. However, importance measures do not tell us whether the occurrence of an event can change the overarching decision. By linking value of information and importance measures for probabilistic risk assessment models, this work obtains a value-of-information-based importance measure that brings together the risk metric, risk importance measures, and the risk threshold in one expression. The new importance measure does not impose additional computational burden because it can be calculated from our knowledge of the risk achievement and risk reduction worth, and complements the insights delivered by these importance measures. Several properties are discussed, including the joint decision worth of basic event groups. The application to the large loss of coolant accident sequence of the Advanced Test Reactor helps us in illustrating the risk analysis insights. PMID- 28095588 TI - Potent effects of dioscin against pancreatic cancer via miR-149-3P-mediated inhibition of the Akt1 signalling pathway. AB - BACKGROUND AND PURPOSE: The aim of the present study was to investigate the effects and possible underlying mechanisms of dioscin against pancreatic cancer in vitro and in vivo. EXPERIMENTAL APPROACH: In vitro actions of dioscin on viability of ASPC-1 and PANC-1 cells, and in vivo effects to suppress the tumour growth of cell xenografts in nude mice were assessed. In addition, microRNA microarray analysis determined which microRNAs were affected by dioscin. The mechanisms underlying the actions of dioscin against pancreatic cancer were elucidated in terms of Akt1 and other proteins related to aopoptosis. KEY RESULTS: Dioscin markedly induced apoptosis and significantly suppressed the tumour growth of ASPC-1 and PANC-1 cell xenografts, in nude mice. Total of 107 microRNAs with differential changes were found, in which miR-149-3P targeted with Akt1 was markedly up-regulated by dioscin. Further studies showed that dioscin significantly down-regulated Akt1 levels, and thus induced cell apoptosis by increasing the levels of Bax, Apaf-1, cleaved caspase-3/9, cleaved PARP, suppressing Bcl-2 levels, and causing cytochrome c release. The effects of an inhibitor of miR-149-3P and of siRNA of testicular Akt1 suggested that dioscin showed excellent activity against pancreatic cancer via miR- 149-3P-mediated inhibition of Akt1 signalling pathway. CONCLUSIONS AND IMPLICATIONS: Collectively, these findings confirmed the potent effects of dioscin against pancreatic cancer and also provided novel insights into the mechanisms of the compound as a potential candidate for the treatment of pancreatic cancer. PMID- 28095590 TI - Cancer cachexia awareness, diagnosis, and treatment are lacking among oncology providers. PMID- 28095591 TI - A Critical Discussion and Practical Recommendations on Some Issues Relevant to the Nonprobabilistic Treatment of Uncertainty in Engineering Risk Assessment. AB - Models for the assessment of the risk of complex engineering systems are affected by uncertainties due to the randomness of several phenomena involved and the incomplete knowledge about some of the characteristics of the system. The objective of this article is to provide operative guidelines to handle some conceptual and technical issues related to the treatment of uncertainty in risk assessment for engineering practice. In particular, the following issues are addressed: (1) quantitative modeling and representation of uncertainty coherently with the information available on the system of interest; (2) propagation of the uncertainty from the input(s) to the output(s) of the system model; (3) (Bayesian) updating as new information on the system becomes available; and (4) modeling and representation of dependences among the input variables and parameters of the system model. Different approaches and methods are recommended for efficiently tackling each of issues (1)-(4) above; the tools considered are derived from both classical probability theory as well as alternative, nonfully probabilistic uncertainty representation frameworks (e.g., possibility theory). The recommendations drawn are supported by the results obtained in illustrative applications of literature. PMID- 28095592 TI - A Practical Approach to Address Uncertainty in Stakeholder Deliberations. AB - This article addresses the difficulties of incorporating uncertainty about consequence estimates as part of stakeholder deliberations involving multiple alternatives. Although every prediction of future consequences necessarily involves uncertainty, a large gap exists between common practices for addressing uncertainty in stakeholder deliberations and the procedures of prescriptive decision-aiding models advanced by risk and decision analysts. We review the treatment of uncertainty at four main phases of the deliberative process: with experts asked to describe possible consequences of competing alternatives, with stakeholders who function both as individuals and as members of coalitions, with the stakeholder committee composed of all stakeholders, and with decisionmakers. We develop and recommend a model that uses certainty equivalents as a theoretically robust and practical approach for helping diverse stakeholders to incorporate uncertainties when evaluating multiple-objective alternatives as part of public policy decisions. PMID- 28095593 TI - Automated face detection for occurrence and occupancy estimation in chimpanzees. AB - : Surveying endangered species is necessary to evaluate conservation effectiveness. Camera trapping and biometric computer vision are recent technological advances. They have impacted on the methods applicable to field surveys and these methods have gained significant momentum over the last decade. Yet, most researchers inspect footage manually and few studies have used automated semantic processing of video trap data from the field. The particular aim of this study is to evaluate methods that incorporate automated face detection technology as an aid to estimate site use of two chimpanzee communities based on camera trapping. As a comparative baseline we employ traditional manual inspection of footage. Our analysis focuses specifically on the basic parameter of occurrence where we assess the performance and practical value of chimpanzee face detection software. We found that the semi-automated data processing required only 2-4% of the time compared to the purely manual analysis. This is a non-negligible increase in efficiency that is critical when assessing the feasibility of camera trap occupancy surveys. Our evaluations suggest that our methodology estimates the proportion of sites used relatively reliably. Chimpanzees are mostly detected when they are present and when videos are filmed in high-resolution: the highest recall rate was 77%, for a false alarm rate of 2.8% for videos containing only chimpanzee frontal face views. Certainly, our study is only a first step for transferring face detection software from the lab into field application. Our results are promising and indicate that the current limitation of detecting chimpanzees in camera trap footage due to lack of suitable face views can be easily overcome on the level of field data collection, that is, by the combined placement of multiple high-resolution cameras facing reverse directions. This will enable to routinely conduct chimpanzee occupancy surveys based on camera trapping and semi-automated processing of footage. RESEARCH HIGHLIGHTS: Using semi-automated ape face detection technology for processing camera trap footage requires only 2-4% of the time compared to manual analysis and allows to estimate site use by chimpanzees relatively reliably. PMID- 28095594 TI - Mixed-Metal Tungsten Oxide Photoanode Materials Made by Pulsed-Laser in Liquids Synthesis. AB - Globally scalable sunlight-driven devices that convert solar energy into storable fuels will require efficient light absorbers that are made of non-precious elements. Suitable photoanode materials are yet to be discovered. Here we utilised the timesaving nature of pulsed-laser-in-liquids synthesis and prepared a series of neat and mixed-metal tungsten oxide photoanode materials to investigate the effect of ad-metals on optical and photocurrent generation properties. We obtained sub-MUm-sized materials with different colours from W, Al, Ta, or first-row transition metal targets in water or aqueous ammonium metatungstate solutions. We observed metastable polymorphs of WO3 and tungsten oxides with varying degrees of oxygen deficiency. Pulsed-laser in liquids synthesis of Ni in ammonium metatungstate solutions produce hollow spheres (with <=6 % Ni with respect to W). Photocurrent generation in strong aqueous acid is highest in mixed-metal tungsten oxide photoanode materials with around 5 % of iron or nickel. PMID- 28095595 TI - Critical Infrastructure Vulnerability to Spatially Localized Failures with Applications to Chinese Railway System. AB - This article studies a general type of initiating events in critical infrastructures, called spatially localized failures (SLFs), which are defined as the failure of a set of infrastructure components distributed in a spatially localized area due to damage sustained, while other components outside the area do not directly fail. These failures can be regarded as a special type of intentional attack, such as bomb or explosive assault, or a generalized modeling of the impact of localized natural hazards on large-scale systems. This article introduces three SLFs models: node centered SLFs, district-based SLFs, and circle shaped SLFs, and proposes a SLFs-induced vulnerability analysis method from three aspects: identification of critical locations, comparisons of infrastructure vulnerability to random failures, topologically localized failures and SLFs, and quantification of infrastructure information value. The proposed SLFs-induced vulnerability analysis method is finally applied to the Chinese railway system and can be also easily adapted to analyze other critical infrastructures for valuable protection suggestions. PMID- 28095596 TI - Analysis of Affordance, Time, and Adaptation in the Assessment of Industrial Control System Cybersecurity Risk. AB - Industrial control systems increasingly use standard communication protocols and are increasingly connected to public networks-creating substantial cybersecurity risks, especially when used in critical infrastructures such as electricity and water distribution systems. Methods of assessing risk in such systems have recognized for some time the way in which the strategies of potential adversaries and risk managers interact in defining the risk to which such systems are exposed. But it is also important to consider the adaptations of the systems' operators and other legitimate users to risk controls, adaptations that often appear to undermine these controls, or shift the risk from one part of a system to another. Unlike the case with adversarial risk analysis, the adaptations of system users are typically orthogonal to the objective of minimizing or maximizing risk in the system. We argue that this need to analyze potential adaptations to risk controls is true for risk problems more generally, and we develop a framework for incorporating such adaptations into an assessment process. The method is based on the principle of affordances, and we show how this can be incorporated in an iterative procedure based on raising the minimum period of risk materialization above some threshold. We apply the method in a case study of a small European utility provider and discuss the observations arising from this. PMID- 28095597 TI - Recollection Bias and Its Underpinnings: Lessons from Terrorism Risk Assessments. AB - Recollection bias is the phenomenon whereby people who observe a highly unexpected event hold current risk beliefs about a similar event that are no higher than their recollection of their prior beliefs. This article replicates and extends the authors' previous study of recollection bias in relation to individuals' perceptions of the risks of terrorism attacks. Over 60% of respondents in a national U.S. sample of over 900 adults believe that the current risk of a future terrorist attack by either an airplane or in a public setting is no higher than they recall having believed, respectively, before the 9/11 attack and before the Boston Marathon bombing. By contrast, a rational Bayesian model would update to a higher currently assessed risk of these previously uncontemplated events. Recollection bias is a persistent trait: individuals who exhibited this bias for the 9/11 attack exhibited it for the Boston Marathon bombing. Only one-fifth of respondents are free of any type of recollection bias. Recollection bias is negatively correlated with absolute levels of risk belief. Recollection bias in relation to highly unexpected terrorist events-the belief that perceived risks did not increase after the surprise occurrence-dampens support for a variety of anti-terrorism measures, controlling for the level of risk beliefs and demographic factors. Persistent recollection bias for both 9/11 and the Boston Marathon bombing is especially influential in diminishing support for protective policy measures, such as surveillance cameras in public places. Given that public attitudes influence policy, educating the public about risk is critical. PMID- 28095598 TI - Evaluating the Cost, Safety, and Proliferation Risks of Small Floating Nuclear Reactors. AB - It is hard to see how our energy system can be decarbonized if the world abandons nuclear power, but equally hard to introduce the technology in nonnuclear energy states. This is especially true in countries with limited technical, institutional, and regulatory capabilities, where safety and proliferation concerns are acute. Given the need to achieve serious emissions mitigation by mid century, and the multidecadal effort required to develop robust nuclear governance institutions, we must look to other models that might facilitate nuclear plant deployment while mitigating the technology's risks. One such deployment paradigm is the build-own-operate-return model. Because returning small land-based reactors containing spent fuel is infeasible, we evaluate the cost, safety, and proliferation risks of a system in which small modular reactors are manufactured in a factory, and then deployed to a customer nation on a floating platform. This floating small modular reactor would be owned and operated by a single entity and returned unopened to the developed state for refueling. We developed a decision model that allows for a comparison of floating and land-based alternatives considering key International Atomic Energy Agency plant-siting criteria. Abandoning onsite refueling is beneficial, and floating reactors built in a central facility can potentially reduce the risk of cost overruns and the consequences of accidents. However, if the floating platform must be built to military-grade specifications, then the cost would be much higher than a land-based system. The analysis tool presented is flexible, and can assist planners in determining the scope of risks and uncertainty associated with different deployment options. PMID- 28095599 TI - Minerals in the foods and diet of diademed sifakas: Are they nutritional challenges? AB - Minerals, though needed in small quantities, are essential to metabolic processes, and deficiencies can seriously threaten health, reproduction and survival. Despite this, few studies have measured mineral composition of wild primate foods and fewer have quantified mineral intake. Here we measured the concentration of nine minerals in 75 foods of diademed sifakas (Propithecus diadema; five groups) in habitats with varying levels of disturbance at Tsinjoarivo and estimated daily intakes using focal-animal feeding data and intake rates over one year. For six minerals (Ca, P, Na, Fe, Zn, and Cu), mean concentrations in foods fell short of the National Research Council's (NRC) recommendations for captive primates. Concentrations were highest in lianas, herbs, and epiphytes, and hemiparasites had exceptionally high Na. Leaves tended to have higher concentrations than fruits or flowers, but overlap was extensive. Mineral concentrations in daily diets varied little seasonally, but absolute intakes (g/day) were higher in the abundant season, due to the increase in food ingested. Disturbed habitat groups' diets had higher mineral concentrations for five minerals, but this translated into increased intakes only for Cu, as these groups ate less food overall. Overall, comparisons with percentage-based NRC recommendations suggests deficiencies, but this is contradicted by: (1) the fact that mass-specific intakes exceeded human recommendations, and (2) the lack of observed signs of deficiency. Ongoing efforts to quantify mineral consumption across wild primate populations and better understanding requirements on both a percentage and absolute basis will help in understanding effects on food selection, managing primate habitats and formulating captive diets. PMID- 28095600 TI - Human quarantine: Toward reducing infectious pressure on chimpanzees at the Tai Chimpanzee Project, Cote d'Ivoire. AB - Due to their genetic relatedness, great apes are highly susceptible to common human respiratory pathogens. Although most respiratory pathogens, such as human respiratory syncytial virus (HRSV) and human metapneumovirus (HMPV), rarely cause severe disease in healthy human adults, they are associated with considerable morbidity and mortality in wild great apes habituated to humans for research or tourism. To prevent pathogen transmission, most great ape projects have established a set of hygiene measures ranging from keeping a specific distance, to the use of surgical masks and establishment of quarantines. This study investigates the incidence of respiratory symptoms and human respiratory viruses in humans at a human-great ape interface, the Tai Chimpanzee Project (TCP) in Cote d'Ivoire, and consequently, the effectiveness of a 5-day quarantine designed to reduce the risk of potential exposure to human respiratory pathogens. To assess the impact of quarantine as a preventative measure, we monitored the quarantine process and tested 262 throat swabs for respiratory viruses, collected during quarantine over a period of 1 year. Although only 1 subject tested positive for a respiratory virus (HRSV), 17 subjects developed symptoms of infection while in quarantine and were subsequently kept from approaching the chimpanzees, preventing potential exposure in 18 cases. Our results suggest that quarantine-in combination with monitoring for symptoms-is effective in reducing the risk of potential pathogen exposure. This research contributes to our understanding of how endangered great apes can be protected from human-borne infectious disease. PMID- 28095601 TI - (Re) Defining Emerging Risks. AB - The concept of emergence in risk management can be seen as a revealing symptom of the increasing need for organizations to update their portfolio of risks and opportunities in a rapidly changing and highly competitive environment. Accordingly, the concept of emerging risks has been widely discussed in both scientific and business communities, with, however, a lack of agreement as to whether we should distinguish these risks from others and, if so, what should be the adopted approach for their governance. After reviewing a large set of definitions and conceptions of emerging risks, this article aims at exploring the existence of distinctive features allowing the characterization of a risk as emerging or not. First, we will demonstrate that the features used in the various definitions are ineffective to achieve this distinction. Furthermore, we will argue that all events and consequences associated with risks are or have been states of nature that emerged from complex interactions involving combinations of hazardous activities and stakes. Accordingly, emerging risks are no longer a specific category of risks; they are rather an early step in every risk life cycle that deserves specific governance approaches. PMID- 28095602 TI - Age and Adaptation: Stronger Decision Updating about Real World Risks in Older Age. AB - In later life, people are faced with a multitude of risky decisions that concern their health, finance, and personal security. Older adults often exercise caution in situations that involve risk. In this research, we asked whether older adults are also more responsive to warnings about potential risk. An answer to this question could reveal a factor underlying increased cautiousness in older age. In Study 1, participants decided whether they would engage in risky activities (e.g., using an ATM machine in the street) in four realistic scenarios about which participants could be expected to have relevant knowledge or experience. They then made posterior decisions after listening to audio extracts of real reports relevant to each activity. In Study 2, we explored the role that emotions play in decision updating. As in Study 1, participants made prior and posterior decisions, with the exception that for each scenario the reports were presented in their original audio format (high emotive) or in a written transcript format (low emotive). Following each posterior decision, participants indicated their emotional valence and arousal responses to the reports. In both studies, older adults engaged in fewer risky activities than younger adults, indicative of increased cautiousness in older age, and exhibited stronger decision updating in response to the reports. Older adults also showed stronger emotional responses to the reports, even though emotional responses did not differ for audio and written transcript formats. Finally, age differences in emotional responses to the reports accounted for age differences in decision updating. PMID- 28095603 TI - Review of Regulatory Emphasis on Transportation Safety in the United States, 2002 2009: Public versus Private Modes. AB - The U.S. Department of Transportation is responsible for implementing new safety improvements and regulations with the goal of ensuring limited funds are distributed to where they can have the greatest impact on safety. In this work, we conduct a study of new regulations and other reactions (such as recalls) to fatal accidents in several different modes of transportation implemented from 2002 to 2009. We find that in the safest modes of commercial aviation and bus transport, the amount of spending on new regulations is high in relation to the number of fatalities compared to the regulatory attention received by less safe modes of general aviation and private automobiles. Additionally, we study two major fatal accident investigations from commercial aviation and two major automotive recalls associated with fatal accidents. We find differences in the cost per expected fatality prevented for these reactions, with the airline accident investigations being more cost effective. Overall, we observe trends in both the automotive and aviation sectors that suggest that public transportation receives more regulatory attention than private transport. We also observe that the types of safety remedies utilized, regulation versus investigation, have varying levels of effectiveness in different transport modes. We suggest that these differences are indicative of increased public demand for safety in modes where a third party may be held responsible, even for those not participating in the transportation. These findings have important implications for the transportation industry, policymakers, and for estimating the public demand for safety in new transport modes. PMID- 28095604 TI - Vocal repertoire of free-ranging black howler monkeys' (Alouatta pigra): Call types, contexts, and sex-related contributions. AB - Alouatta species utter the most powerful primate vocalizations in the Neotropics and are well-known for their loud and long-lasting male howling bouts. However, the diversity of acoustic structures used in these howling bouts, as well as in non-howling contexts, and the relative contribution of the different group members to the entire vocal repertoire, needed to be explored further. This report provides the first detailed description of the vocal repertoire of black howler monkeys (Alouatta pigra), focusing on acoustic structures and contexts of emission of both loud and soft calls as well as on the contribution rate of males and females to the different call types. Three free-ranging social groups of black howler monkeys living in Palenque National Park, Mexico were monitored. We identified twelve acoustically discriminable call types, eight described previously and four described here for the first time. A few call types were systematically emitted either isolated or during howling bouts, but most of them could be heard in both calling contexts. Three call types were emitted only by females and two only by males. Adult males' call rates (for the seven shared call types) were higher than those of females but only when considering calls emitted within howling bouts. Our contextual analysis enabled us to divide call types into potential functional categories, according to their degree of contribution, to intra-group versus inter-group interactions and to neutral-positive versus negative situations. We then discussed how socio-ecological factors, notably sex differences in social behaviors, may explain the variability found in the vocal repertoire of this species and compared our findings with the literature on other primate species. PMID- 28095605 TI - Influence of Distribution of Animals between Dose Groups on Estimated Benchmark Dose and Animal Distress for Quantal Responses. AB - Increasingly, dose-response data are being evaluated with the benchmark dose (BMD) approach rather than by the less precise no-observed-adverse-effect-level (NOAEL) approach. However, the basis for designing animal experiments, using equally sized dose groups, is still primed for the NOAEL approach. The major objective here was to assess the impact of using dose groups of unequal size on both the quality of the BMD and overall animal distress. We examined study designs with a total number of 200 animals distributed in four dose groups employing quantal data generated by Monte Carlo simulations. Placing more animals at doses close to the targeted BMD provided an estimate of BMD that was slightly better than the standard design with equally sized dose groups. In situations involving a clear dose-response, this translates into fewer animals receiving high doses and thus less overall animal distress. Accordingly, in connection with risk and safety assessment, animal distress can potentially be reduced by distributing the animals appropriately between dose groups without decreasing the quality of the information obtained. PMID- 28095606 TI - Endothelin-1 and its receptors on haemorrhoidal tissue: a potential site for therapeutic intervention. AB - BACKGROUND AND PURPOSE: Haemorrhoids is a common anorectal condition affecting millions worldwide. We have studied the effect of endothelin-1 (ET-1) and the role of endothelin ETA and ETB receptors in haemorrhoid tissue. EXPERIMENTAL APPROACH: Protein expression of ET-1, ETA and ETB receptors were compared between haemorrhoids and normal rectal submucosa using Western blot analysis, with the localization of proteins determined by autoradiography and immunohistochemistry. Effects of ET-1 and sarafotoxin 6a on human colonic and rectal arteries and veins was assessed by wire myography and the involvement of receptor subtypes established by selective antagonists. KEY RESULTS: Dense binding of [125 I]-ET-1 to haemorrhoidal sections was reduced by selective receptor antagonists. A higher density of ETB than ETA receptors was found in haemorrhoidal, than in control rectal tissue and confirmed by Western blot analysis. ETA and ETB receptors were localized to smooth muscle of haemorrhoidal arteries and veins, with ETB receptors on the endothelium. Human colonic and rectal arteries and veins were similarly sensitive to ET-1 and affected by the ETA selective antagonist, but sarafotoxin S6a-induced contractions were more pronounced in veins and antagonized by a selective ETB receptor antagonist. CONCLUSIONS AND IMPLICATIONS: ETA and ETB receptors are present in human haemorrhoids with ETB receptors predominating. ETA receptors are activated by ET-1 to mediate a contraction in arteries and veins, but the latter are selectively activated by sarafotoxin S6a - a response that involves ETB receptors at low concentrations. Selective ETB agonists may have therapeutic potential to reduce congestion of the haemorrhoidal venous sinusoids. PMID- 28095607 TI - Heat shock protein 70 promotes coxsackievirus B3 translation initiation and elongation via Akt-mTORC1 pathway depending on activation of p70S6K and Cdc2. AB - We previously demonstrated that coxsackievirus B3 (CVB3) infection upregulated heat shock protein 70 (Hsp70) and promoted CVB3 multiplication. Here, we report the underlying mechanism by which Hsp70 enhances viral RNA translation. By using an Hsp70-overexpressing cell line infected with CVB3, we found that Hsp70 enhanced CVB3 VP1 translation at two stages. First, Hsp70 induced upregulation of VP1 translation at the initiation stage via upregulation of internal ribosome entry site trans-acting factor lupus autoantigen protein and activation of eIF4E binding protein 1, a cap-dependent translation suppressor. Second, we found that Hsp70 increased CVB3 VP1 translation by enhancing translation elongation. This was mediated by the Akt-mammalian target of rapamycin complex 1 signal cascade, which led to the activation of eukaryotic elongation factor 2 via p70S6K- and cell division cycle protein 2 homolog (Cdc2)-mediated phosphorylation and inactivation of eukaryotic elongation factor 2 kinase. We also determined the position of Cdc2 in this signal pathway, indicating that Cdc2 is regulated by mammalian target of rapamycin complex 1. This signal transduction pathway was validated using a number of specific pharmacological inhibitors, short interfering RNAs (siRNAs) and a dominant negative Akt plasmid. Because Hsp70 is a central component of the cellular network of molecular chaperones enhancing viral replication, these data may provide new strategies to limit this viral infection. PMID- 28095609 TI - Reply to Letter. PMID- 28095608 TI - ESX-1 and phthiocerol dimycocerosates of Mycobacterium tuberculosis act in concert to cause phagosomal rupture and host cell apoptosis. AB - Although phthiocerol dimycocerosates (DIM) are major virulence factors of Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, little is known about their mechanism of action. Localized in the outer membrane of mycobacterial pathogens, DIM are predicted to interact with host cell membranes. Interaction with eukaryotic membranes is a property shared with another virulence factor of Mtb, the early secretory antigenic target EsxA (also known as ESAT-6). This small protein, which is secreted by the type VII secretion system ESX-1 (T7SS/ESX-1), is involved in phagosomal rupture and cell death induced by virulent mycobacteria inside host phagocytes. In this work, by the use of several knock-out or knock-in mutants of Mtb or Mycobacterium bovis BCG strains and different cell biological assays, we present conclusive evidence that ESX-1 and DIM act in concert to induce phagosomal membrane damage and rupture in infected macrophages, ultimately leading to host cell apoptosis. These results identify an as yet unknown function for DIM in the infection process and open up a new research field for the study of the interaction of lipid and protein virulence factors of Mtb. PMID- 28095610 TI - Uveal schwannoma in a brown-eyed dog. AB - An eleven-year-old, female spayed Boxer dog was diagnosed with a uveal schwannoma (formerly known as the spindle cell tumor of the blue-eyed dog or SCTBED) despite having a uniformly brown iris. The patient presented to emergency for ocular discomfort, and the right globe was subsequently enucleated due to glaucoma and submitted for histopathology. Upon histopathologic evaluation, a uveal schwannoma was diagnosed and confirmed with immunohistochemical staining. Complete metastatic evaluation 1 and 6 months after initial presentation did not reveal evidence of metastasis, and the dog remains systemically healthy. This case represents a unique variant of uveal schwannoma and is relevant because although the vast majority of these tumors occur in blue-eyed dogs, clinicians should not completely rule out this tumor as a differential based on the iris color. PMID- 28095611 TI - Hypothesis: Gene-rich plastid genomes in red algae may be an outcome of nuclear genome reduction. AB - Red algae (Rhodophyta) putatively diverged from the eukaryote tree of life >1.2 billion years ago and are the source of plastids in the ecologically important diatoms, haptophytes, and dinoflagellates. In general, red algae contain the largest plastid gene inventory among all such organelles derived from primary, secondary, or additional rounds of endosymbiosis. In contrast, their nuclear gene inventory is reduced when compared to their putative sister lineage, the Viridiplantae, and other photosynthetic lineages. The latter is thought to have resulted from a phase of genome reduction that occurred in the stem lineage of Rhodophyta. A recent comparative analysis of a taxonomically broad collection of red algal and Viridiplantae plastid genomes demonstrates that the red algal ancestor encoded ~1.5* more plastid genes than Viridiplantae. This difference is primarily explained by more extensive endosymbiotic gene transfer (EGT) in the stem lineage of Viridiplantae, when compared to red algae. We postulate that limited EGT in Rhodophytes resulted from the countervailing force of ancient, and likely recurrent, nuclear genome reduction. In other words, the propensity for nuclear gene loss led to the retention of red algal plastid genes that would otherwise have undergone intracellular gene transfer to the nucleus. This hypothesis recognizes the primacy of nuclear genome evolution over that of plastids, which have no inherent control of their gene inventory and can change dramatically (e.g., secondarily non-photosynthetic eukaryotes, dinoflagellates) in response to selection acting on the host lineage. PMID- 28095613 TI - Xenopus egg extract to study regulation of genome-wide and locus-specific DNA replication. AB - Faithful DNA replication, coupled with accurate repair of DNA damage, is essential to maintain genome stability and relies on different DNA metabolism genes. Many of these genes are involved in the assembly of replication origins, in the coordination of DNA repair to protect replication forks progression in the presence of DNA damage and in the replication of repetitive chromatin regions. Some DNA metabolism genes are essential in higher eukaryotes, suggesting the existence of specialized mechanisms of repair and replication in organisms with complex genomes. The impact on cell survival of many of these genes has so far precluded in depth molecular analysis of their function. The cell-free Xenopus laevis egg extract represents an ideal system to overcome survival issues and to facilitate the biochemical study of replication-associated functions of essential proteins in vertebrate organisms. Here, we will discuss how Xenopus egg extracts have been used to study cellular and molecular processes, such as DNA replication and DNA repair. In particular, we will focus on innovative imaging and proteomic based experimental approaches to characterize the molecular function of a number of essential DNA metabolism factors involved in the duplication of complex vertebrate genomes. PMID- 28095612 TI - Xenopus laevis as a model system to study cytoskeletal dynamics during axon pathfinding. AB - The model system, Xenopus laevis, has been used in innumerable research studies and has contributed to the understanding of multiple cytoskeletal components, including actin, microtubules, and neurofilaments, during axon pathfinding. Xenopus developmental stages have been widely characterized, and the Xenopus genome has been sequenced, allowing gene expression modifications through exogenous molecules. Xenopus cell cultures are ideal for long periods of live imaging because they are easily obtained and maintained, and they do not require special culture conditions. In addition, Xenopus have relatively large growth cones, compared to other vertebrates, thus providing a suitable system for imaging cytoskeletal components. Therefore, X. laevis is an ideal model organism in which to study cytoskeletal dynamics during axon pathfinding. PMID- 28095614 TI - Over-the-scope clip closure for treatment of post-pancreaticogastrostomy pancreatic fistula: A case series. AB - BACKGROUND AND AIM: The over-the-scope clip (OTSC) system is a recently developed endoscopic device. In the last few years, it has been successfully used for severe bleeding or deep wall lesions, or perforations of the gastrointestinal (GI) tract. We hereby report a series of patients with post pancreaticogastrostomy pancreatic fistula in whom OTSC were used as endoscopic treatment. METHODS: From January 2012 to July 2015, we prospectively collected data on cases of postoperative pancreatic fistula. These patients underwent pancreaticoduodenectomy in a high-volume center of hepatobiliopancreatic surgery. After conservative management, OTSC closure was done by single skilled operators in anesthesiologist-assisted deep sedation. RESULTS: A total of seven patients were enrolled. According to the International Study Group of Pancreatic Surgery criteria, we observed grade B postoperative pancreatic fistula in all cases. All patients were treated with 12/6 t-type OTSC. In two cases, a second clip was successfully applied to a second site adjacent to the original closure site. In all cases, subsequent fluoroscopy showed no contrastographic spreading through the wall. There were no complications related to the procedure itself, not from the endoscopy point of view, nor from the anesthesiological perspective. There were no device malfunctions. Further clinical and endoscopic evaluation was made 8 weeks later and showed no fistula or anastomotic defect recurrence. No patients required additional endoscopic or interventional procedures. CONCLUSION: In consideration of clinical and technical success, OTSC placement in POPF seems to be effective, safe and technically relatively easy to carry out. PMID- 28095615 TI - The long-term population dynamics of common wasps in their native and invaded range. AB - Populations of introduced species are often thought to perform differently, or experience different population dynamics, in their introduced range compared to their native habitat. Differences between habitats in climate, competition or natural enemies may result in populations with varying density dependence and population dynamics. We examined the long-term population dynamics of the invasive common wasp, Vespula vulgaris, in its native range in England and its invaded range in New Zealand. We used 39 years of wasp density data from four sites in England, and 23 years of data from six sites in New Zealand. Wasp population time series was examined using partial rate correlation functions. Gompertz population models and multivariate autoregressive state-space (MARSS) models were fitted, incorporating climatic variation. Gompertz models successfully explained 59-66% of the variation in wasp abundance between years. Density dependence in wasp populations appeared to act similarly in both the native and invaded range, with wasp abundance in the previous year as the most important variable in predicting intrinsic rate of increase (r). No evidence of cyclic population dynamics was observed. Both the Gompertz and MARSS models highlighted the role of weather conditions in each country as significant predictors of annual wasp abundance. The temporal evolution of wasp populations at all sites was best modelled jointly using a single latent dynamic factor for local trends, with the inclusion of a latent spring weather covariate. That same parsimonious multivariate model structure was optimal in both the native and invaded range. Density dependence is overwhelmingly important in predicting wasp densities and 'wasp years' in both the native and invaded range. Spring weather conditions in both countries have a major influence, probably through their impact on wasp colony initiation and early development. The population dynamics in the native range and invaded range show no evidence of cyclic boom-and-bust dynamics. Invasive species may not exhibit different population dynamics despite considerable variation in abundances throughout their distribution. PMID- 28095616 TI - Using Xenopus to understand human disease and developmental disorders. AB - Model animals are crucial to biomedical research. Among the commonly used model animals, the amphibian, Xenopus, has had tremendous impact because of its unique experimental advantages, cost effectiveness, and close evolutionary relationship with mammals as a tetrapod. Over the past 50 years, the use of Xenopus has made possible many fundamental contributions to biomedicine, and it is a cornerstone of research in cell biology, developmental biology, evolutionary biology, immunology, molecular biology, neurobiology, and physiology. The prospects for Xenopus as an experimental system are excellent: Xenopus is uniquely well-suited for many contemporary approaches used to study fundamental biological and disease mechanisms. Moreover, recent advances in high throughput DNA sequencing, genome editing, proteomics, and pharmacological screening are easily applicable in Xenopus, enabling rapid functional genomics and human disease modeling at a systems level. PMID- 28095617 TI - Probing forebrain to hindbrain circuit functions in Xenopus. AB - The vertebrate hindbrain includes neural circuits that govern essential functions including breathing, blood pressure and heart rate. Hindbrain circuits also participate in generating rhythmic motor patterns for vocalization. In most tetrapods, sound production is powered by expiration and the circuitry underlying vocalization and respiration must be linked. Perception and arousal are also linked; acoustic features of social communication sounds-for example, a baby's cry-can drive autonomic responses. The close links between autonomic functions that are essential for life and vocal expression have been a major in vivo experimental challenge. Xenopus provides an opportunity to address this challenge using an ex vivo preparation: an isolated brain that generates vocal and breathing patterns. The isolated brain allows identification and manipulation of hindbrain vocal circuits as well as their activation by forebrain circuits that receive sensory input, initiate motor patterns and control arousal. Advances in imaging technologies, coupled to the production of Xenopus lines expressing genetically encoded calcium sensors, provide powerful tools for imaging neuronal patterns in the entire fictively behaving brain, a goal of the BRAIN Initiative. Comparisons of neural circuit activity across species (comparative neuromics) with distinctive vocal patterns can identify conserved features, and thereby reveal essential functional components. PMID- 28095618 TI - Genome-wide analysis of canonical Wnt target gene regulation in Xenopus tropicalis challenges beta-catenin paradigm. AB - Wnt/beta-catenin signaling is an important cell-to-cell signaling mechanism that controls gene expression during embryonic development and is critically implicated in human diseases. Developmental, cellular, and transcriptional responses to Wnt signaling are remarkably context-specific in different biological processes. While nuclear localization of beta-catenin is the key to activation of the Wnt/beta-catenin pathway and target gene expression, the molecular mechanisms of how the same Wnt/beta-catenin signaling pathway induces specific responses remain undetermined. Recent advances in high-throughput sequencing technologies and the availability of genome information for Xenopus tropicalis have enabled us to uncover a genome-wide view of Wnt/beta-catenin signaling in early vertebrate embryos, which challenges previous concepts about molecular mechanisms of Wnt target gene regulation. In this review, we summarize our experimental approaches, introduce the technologies we employed and focus on recent findings about Wnt target gene regulation from Xenopus research. We will also discuss potential functions of widespread beta-catenin binding in the genome that we discovered in this species. PMID- 28095619 TI - New recipes with CaMPARI for 'snapshots' of synaptic circuit activity. PMID- 28095620 TI - Tools for live imaging of active Rho GTPases in Xenopus. AB - Rho family GTPases are signaling molecules that orchestrate cytoskeletal dynamics in a variety of cellular processes. Because they effect localized changes to the cytoskeleton only in their active (GTP-bound) conformation, the ability to monitor the active state of Rho GTPases in space and time is critical for understanding their function. Here, we summarize popular tools used for live imaging of active Rho GTPases, outlining advantages and drawbacks of these approaches. Additionally, we highlight key features of the Xenopus laevis embryo that make it well-suited for epithelial cell biology and discuss how application of Rho activity reporters in the Xenopus laevis embryo led to the discovery of a novel phenomenon, junctional Rho flares. PMID- 28095621 TI - Targeted integration of genes in Xenopus tropicalis. AB - With the successful establishment of both targeted gene disruption and integration methods in the true diploid frog Xenopus tropicalis, this excellent vertebrate genetic model now is making a unique contribution to modelling human diseases. Here, we summarize our efforts on establishing homologous recombination mediated targeted integration in Xenopus tropicalis, the usefulness, and limitation of targeted integration via the homology-independent strategy, and future directions on how to further improve targeted gene integration in Xenopus tropicalis. PMID- 28095622 TI - TALENs and CRISPR/Cas9 fuel genetically engineered clinically relevant Xenopus tropicalis tumor models. AB - The targeted nuclease revolution (TALENs, CRISPR/Cas9) now allows Xenopus researchers to rapidly generate custom on-demand genetic knockout models. These novel methods to perform reverse genetics are unprecedented and are fueling a wide array of human disease models within the aquatic diploid model organism Xenopus tropicalis (X. tropicalis). This emerging technology review focuses on the tools to rapidly generate genetically engineered X. tropicalis models (GEXM), with a focus on establishment of genuine genetic and clinically relevant cancer models. We believe that due to particular advantageous characteristics, outlined within this review, GEXM will become a valuable alternative animal model for modeling human cancer. Furthermore, we provide perspectives of how GEXM will be used as a platform for elucidation of novel therapeutic targets and for preclinical drug validation. Finally, we also discuss some future prospects on how the recent expansions and adaptations of the CRISPR/Cas9 toolbox might influence and push forward X. tropicalis cancer research. PMID- 28095624 TI - 'It's good enough': Swedish general dental practitioners on reasons for accepting substandard root filling quality. AB - AIM: The concept of 'good enough' is central and necessary in the assessment of root filling quality. The aim was to explore the concept by analysing reasons and arguments for the acceptance or rejection of substandard root filling quality as reported by general dental practitioners (GDPs) in Sweden. METHODOLOGY: The study was designed as a qualitative and exploratory study based on seven videotaped focus group interviews analysed by means of qualitative content analysis. Thirty three GDPs employed in the Public Dental Health Service in Gothenburg, Sweden, participated (4-6 GDPs/interview). In all, nine predetermined questions were followed. Before each focus group, the participants received radiographs of 37 root fillings and were asked to assess the root filling quality. The three cases representing the most divergent assessments served as a basis for the discussion. The cases were presented without clinical information; the dentists would relate to the cases as being just root filled by themselves. RESULTS: The radiographs did not provide a sufficient basis for decisions on whether or not to accept the root filling. This study emphasized that dentists did not primarily look for these arguments in the technical details of the root filling per se, but instead, they considered selected features of the contextual situation. The GDPs constantly introduced relevant 'ad hoc considerations' to account for the decisions they made. These contextual considerations were related to aspects of pulpal and periapical disease, risks (e.g. technical complications) or to consumed resources (personal and/or economic). CONCLUSIONS: It was obvious that the concept of 'good enough' does not exist as a general formula ready to be applied in particular situations. Instead, it is necessarily and irremediably tied to contextual properties that emerge from case to case. PMID- 28095623 TI - Xenopus as a model for studies in mechanical stress and cell division. AB - We exist in a physical world, and cells within biological tissues must respond appropriately to both environmental forces and forces generated within the tissue to ensure normal development and homeostasis. Cell division is required for normal tissue growth and maintenance, but both the direction and rate of cell division must be tightly controlled to avoid diseases of over-proliferation such as cancer. Recent studies have shown that mechanical cues can cause mitotic entry and orient the mitotic spindle, suggesting that physical force could play a role in patterning tissue growth. However, to fully understand how mechanics guides cells in vivo, it is necessary to assess the interaction of mechanical strain and cell division in a whole tissue context. In this mini-review we first summarise the body of work linking mechanics and cell division, before looking at the advantages that the Xenopus embryo can offer as a model organism for understanding: (1) the mechanical environment during embryogenesis, and (2) factors important for cell division. Finally, we introduce a novel method for applying a reproducible strain to Xenopus embryonic tissue and assessing subsequent cell divisions. PMID- 28095625 TI - Potentiation of biological effects of mesenchymal stem cells in ischemic conditions by melatonin via upregulation of cellular prion protein expression. AB - Mesenchymal stem cells (MSCs) are promising candidates for stem cell-based therapy in ischemic diseases. However, ischemic injury induces pathophysiological conditions, such as oxidative stress and inflammation, which diminish therapeutic efficacy of MSC-based therapy by reducing survival and functionality of transplanted MSCs. To overcome this problem, we explored the effects of melatonin on the proliferation, resistance to oxidative stress, and immunomodulatory properties of MSCs. Treatment with melatonin enhanced MSC proliferation and self renewal via upregulation of cellular prion protein (PrPC ) expression. Melatonin diminished the extent of MSC apoptosis in oxidative stress conditions by regulating the levels of apoptosis-associated proteins, such as BCL-2, BAX, PARP 1, and caspase-3, in a PrPC -dependent manner. In addition, melatonin regulated the immunomodulatory effects of MSCs via the PrPC -IDO axis. In a murine hind limb ischemia model, melatonin-stimulated MSCs improved the blood flow perfusion, limb salvage, and vessel regeneration by lowering the extent of apoptosis of affected local cells and transplanted MSCs as well as by reducing infiltration of macrophages. These melatonin-mediated therapeutic effects were inhibited by silencing of PrPC expression. Our findings for the first time indicate that melatonin promotes MSC functionality and enhances MSC-mediated neovascularization in ischemic tissues through the upregulation of PrPC expression. In conclusion, melatonin-treated MSCs could provide a therapeutic strategy for vessel regeneration in ischemic disease, and the targeting of PrPC levels may prove instrumental for MSC-based therapies. PMID- 28095626 TI - HsfA1a upregulates melatonin biosynthesis to confer cadmium tolerance in tomato plants. AB - Melatonin regulates broad aspects of plant responses to various biotic and abiotic stresses, but the upstream regulation of melatonin biosynthesis by these stresses remains largely unknown. Herein, we demonstrate that transcription factor heat-shock factor A1a (HsfA1a) conferred cadmium (Cd) tolerance to tomato plants, in part through its positive role in inducing melatonin biosynthesis under Cd stress. Analysis of leaf phenotype, chlorophyll content, and photosynthetic efficiency revealed that silencing of the HsfA1a gene decreased Cd tolerance, whereas its overexpression enhanced plant tolerance to Cd. HsfA1a silenced plants exhibited reduced melatonin levels, and HsfA1a overexpression stimulated melatonin accumulation and the expression of the melatonin biosynthetic gene caffeic acid O-methyltransferase 1 (COMT1) under Cd stress. Both an in vitro electrophoretic mobility shift assay and in vivo chromatin immunoprecipitation coupled with qPCR analysis revealed that HsfA1a binds to the COMT1 gene promoter. Meanwhile, Cd stress induced the expression of heat-shock proteins (HSPs), which was compromised in HsfA1a-silenced plants and more robustly induced in HsfA1a-overexpressing plants under Cd stress. COMT1 silencing reduced HsfA1a-induced Cd tolerance and melatonin accumulation in HsfA1a overexpressing plants. Additionally, the HsfA1a-induced expression of HSPs was partially compromised in COMT1-silenced wild-type or HsfA1a-overexpressing plants under Cd stress. These results demonstrate that HsfA1a confers Cd tolerance by activating transcription of the COMT1 gene and inducing accumulation of melatonin that partially upregulates expression of HSPs. PMID- 28095627 TI - Melatonin regulates lipid metabolism in porcine oocytes. AB - It is being increasingly recognized that the processes of lipogenesis and lipolysis are important for providing an essential energy source during oocyte maturation and embryo development. Recent studies demonstrated that melatonin has a role in lipid metabolism regulation, including lipogenesis, lipolysis, and mitochondrial biogenesis. In this study, we attempted to investigate the effects of melatonin on lipid metabolism during porcine oocyte in vitro maturation. Melatonin treatment significantly enhanced the number of lipid droplets (LDs) and upregulated gene expression related to lipogenesis (ACACA, FASN, PPARgamma, and SREBF1). Oocytes treated with melatonin formed smaller LDs and abundantly expressed several genes associated with lipolysis, including ATGL, CGI-58, HSL, and PLIN2. Moreover, melatonin significantly increased the content of fatty acids, mitochondria, and ATP, as indicated by fluorescent staining. Concomitantly, melatonin treatment upregulated gene expression related to fatty acid beta-oxidation (CPT1a, CPT1b, CPT2, and ACADS) and mitochondrial biogenesis (PGC-1alpha, TFAM, and PRDX2). Overall, melatonin treatment not only altered both the morphology and amount of LDs, but also increased the content of fatty acids, mitochondria, and ATP. In addition, melatonin upregulated mRNA expression levels of lipogenesis, lipolysis, beta-oxidation, and mitochondrial biogenesis-related genes in porcine oocytes. These results indicated that melatonin promoted lipid metabolism and thereby provided an essential energy source for oocyte maturation and subsequent embryonic development. PMID- 28095628 TI - Sensitization from ketotifen fumarate in eye drops presenting as chronic conjunctivitis. PMID- 28095629 TI - Presence of allergens in the vehicles of Brazilian dermatological products. PMID- 28095630 TI - Oxidation products and the skin - the effect of hydroperoxides. PMID- 28095631 TI - Occupational allergic contact dermatitis caused by thebaine and oripavine. PMID- 28095633 TI - Allergic contact dermatitis caused by textile dyes mimicking atopic dermatitis. PMID- 28095632 TI - Severe intractable eyelid dermatitis probably caused by exposure to hydroperoxides of linalool in a heavily fragranced shampoo. PMID- 28095634 TI - Pragmatic management of (suspected allergic) diaper dermatitis. PMID- 28095635 TI - Allergic contact dermatitis caused by panthenol: a rare but relevant sensitizer. PMID- 28095636 TI - No contact allergy to acrylic acid and methacrylic acid in routinely tested dermatitis patients. PMID- 28095637 TI - Gene therapy for achromatopsia. AB - The present review summarizes the current status of achromatopsia (ACHM) gene therapy-related research activities and provides an outlook for their clinical application. ACHM is an inherited eye disease characterized by a congenital absence of cone photoreceptor function. As a consequence, ACHM is associated with strongly impaired daylight vision, photophobia, nystagmus and a lack of color discrimination. Currently, six genes have been linked to ACHM. Up to 80% of the patients carry mutations in the genes CNGA3 and CNGB3 encoding the two subunits of the cone cyclic nucleotide-gated channel. Various animal models of the disease have been established and their characterization has helped to increase our understanding of the pathophysiology associated with ACHM. With the advent of adeno-associated virus vectors as valuable gene delivery tools for retinal photoreceptors, a number of promising gene supplementation therapy programs have been initiated. In recent years, huge progress has been made towards bringing a curative treatment for ACHM into clinics. The first clinical trials are ongoing or will be launched soon and are expected to contribute important data on the safety and efficacy of ACHM gene supplementation therapy. PMID- 28095638 TI - Exploratory studies: a crucial step towards better hypothesis-driven confirmatory research in brain stimulation. PMID- 28095639 TI - Early involvement of lysosome dysfunction in the degeneration of cerebral cortical neurons caused by the lipid peroxidation product 4-hydroxynonenal. AB - Free radical-mediated oxidative damage to proteins, lipids, and DNA occurs in neurons during acute brain injuries and in neurodegenerative disorders. Membrane lipid peroxidation contributes to neuronal dysfunction and death, in part by disrupting neuronal ion homeostasis and cellular bioenergetics. Emerging findings suggest that 4-hydroxynonenal (HNE), an aldehyde produced during lipid peroxidation, impairs the function of various proteins involved in neuronal homeostasis. Here we tested the hypothesis that HNE impairs the cellular system that removes damaged proteins and organelles, the autophagy-lysosome pathway in rat primary cortical neurons. We found that HNE, at a concentration that causes apoptosis over a 48-72 h period, increases protein levels of LC3 II and p62 and within 1 and 4 h of exposure, respectively; LC3 II and p62 immunoreactive puncta were observed in the cytoplasm of HNE-treated neurons at 6 h. The extent of up regulation of p62 and LC3 II in response to HNE was not affected by co-treatment with the lysosome inhibitor bafilomycin A1, suggesting that the effects of HNE on autophagy were secondary to lysosome inhibition. Indeed, we found that neurons exposed to HNE exhibit elevated pH levels, and decreased protein substrate hydrolysis and cathepsin B activity. Neurons exposed to HNE also exhibited the accumulation of K63-linked polyubiquitinated proteins, which are substrates targeted for lysosomal degradation. Moreover, we found that the levels of LAMP2a and constitutively active heat-shock protein 70, and numbers of LAMP2a-positive lysosomes, are decreased in neurons exposed to HNE. Our findings demonstrate that the lipid peroxidation product HNE causes early impairment of lysosomes which may contribute to the accumulation of damaged and dysfunctional proteins and organelles and consequent neuronal death. Because impaired lysosome function is increasingly recognized as an early event in the neuronal death that occurs in neurodegenerative disorders, our findings suggest a role for HNE in such lysosomal dysfunction. PMID- 28095640 TI - Irradiation before and donor splenocyte infusion immediately after transplantation induce tolerance to lung, but not heart allografts in miniature swine. AB - Solid organs may differ in their potential to induce and maintain a state of donor-specific tolerance. Previously, we induced stable immunological tolerance in a lung transplantation model in miniature swine. Here, we wished to transfer this established protocol into a heart transplantation model in miniature swine. Heterotopic heart transplantation (HTX) was performed in four and left-sided lung transplantation (LTX) in seven minipigs from gender- and SLA-mismatched donors. All recipients received nonmyeloablative irradiation, donor splenocyte infusion and intravenous pharmacologic immunosuppression for 28 postoperative days. All transplanted hearts were rejected within 95 days. In contrast, four animals of the LTX group developed stable tolerance surviving beyond 500 days, and three further animals rejected 119, 239 and 360 days post-transplantation. In both groups, peripheral blood donor leucocyte chimerism peaked 1 h after reperfusion of the allograft. Importantly, the early chimerism level in the LTX group was significantly higher compared to the HTX group and remained detectable throughout the entire observation period. In conclusion, lungs and hearts vary in their potential to induce a state of tolerance after transplantation in a protocol with pre-operative recipient irradiation and donor splenocyte co-transplantation. This could be due to differential early levels of passenger leucocyte chimerism. PMID- 28095641 TI - Melatonin ameliorates alcohol-induced bile acid synthesis by enhancing miR-497 expression. AB - Alcoholic liver disease is a major cause of chronic liver disease worldwide, and cannabinoid receptor type 1 (CB1R) is involved in a diverse metabolic diseases. B cell translocation gene 2 (BTG2) and yin yang 1 (YY1) are a potent regulator of biological conditions. Melatonin plays a crucial role in regulating diverse physiological functions and metabolic homeostasis. MicroRNAs are key regulators of various biological processes. Herein, we demonstrate that melatonin improves bile acid synthesis in the liver of alcohol-fed mice by controlling miR-497 expression. The level of bile acid and the expression of Cb1r, Btg2, Yy1, and bile acid synthetic enzymes were significantly elevated in the livers of Lieber DeCarli alcohol-fed mice. The overexpression of Btg2 enhanced Yy1 gene expression and bile acid production, whereas disrupting the CB1R-BTG2-YY1 cascade protected against the bile acid synthesis caused by alcohol challenge. We identified an alcohol-mediated YY1 binding site on the cholesterol 7alpha-hydroxylase (Cyp7a1) gene promoter using promoter deletion analysis and chromatin immunoprecipitation assays. Notably, melatonin attenuated the alcohol-stimulated induction of Btg2, Yy1 mRNA levels and bile acid production by promoting miR-497. Overexpression of a miR-497 mimic dramatically diminished the increase of Btg2 and Yy1 gene expression as well as bile acid production by alcohol, whereas this phenomenon was reversed by miR-497 inhibitor. These results demonstrate that the upregulation of miR-497 by melatonin represses alcohol-induced bile acid synthesis by attenuating the BTG2-YY1 signaling pathway. The melatonin-miR497 signaling network may provide novel therapeutic targets for the treatment of hepatic metabolic dysfunction caused by the alcohol-dependent pathway. PMID- 28095643 TI - Seeing the future: using Xenopus to understand eye regeneration. AB - Studies of Xenopus eye development have contributed considerably to the understanding of vertebrate neurogenesis, including eye field specification, cell fate determination and identification of genes critical for eye formation. This knowledge has served as a solid foundation for cellular and molecular examinations of the robust regenerative capacity of the Xenopus eye. The retina, lens, and the optic nerve are capable of regeneration after injury in both larval and adult stages. Here, we discuss the current models for studying eye regeneration in Xenopus and their potential applications for providing insights into human eye diseases. As Xenopus has many of the same tools that are available for other regeneration models, we thus highlight the distinct strengths and versatility of this organism that make it especially suited for extrapolating and testing strategies aimed at promoting regeneration and repair in eye tissues. Furthermore, we outline a promising future for the use of new techniques and approaches to address outstanding questions in understanding eye regeneration. PMID- 28095642 TI - Maternal messages to live by: a personal historical perspective. AB - In the 1980s, the study of localized maternal mRNAs was just emerging as a new research area. Classic embryological studies had linked the inheritance of cytoplasmic domains with specific cell lineages, but the underlying molecular nature of these putative determinants remained a mystery. The model system Xenopus would play a pivotal role in the progress of this new field. In fact, the first localized maternal mRNA to be identified and cloned from any organism was Xenopus vg1, a TGF-beta family member. This seminal finding opened the door to many subsequent studies focused on how RNAs are localized and what functions they had in development. As the field moves into the future, Xenopus remains the system of choice for studies identifying RNA/protein transport particles and maternal RNAs through RNA-sequencing. PMID- 28095644 TI - Xenopus as a model organism to study heterotrimeric G-protein pathway during collective cell migration of neural crest. AB - Collective cell migration is essential in many fundamental aspects of normal development, like morphogenesis, organ formation, wound healing, and immune responses, as well as in the etiology of severe pathologies, like cancer metastasis. In spite of the huge amount of data accumulated on cell migration, such a complex process involves many molecular actors, some of which still remain to be functionally characterized. One of these signals is the heterotrimeric G protein pathway that has been studied mainly in gastrulation movements. Recently we have reported that Ric-8A, a GEF for Galpha proteins, plays an important role in neural crest migration in Xenopus development. Xenopus neural crest cells, a highly migratory embryonic cell population induced at the border of the neural plate that migrates extensively in order to differentiate in other tissues during development, have become a good model to understand the dynamics that regulate cell migration. In this review, we aim to provide sufficient evidence supporting how useful Xenopus model with its different tools, such as explants and transplants, paired with improved in vivo imaging techniques, will allow us to tackle the multiple signaling mechanisms involved in neural crest cell migration. PMID- 28095645 TI - What we can learn from a tadpole about ciliopathies and airway diseases: Using systems biology in Xenopus to study cilia and mucociliary epithelia. AB - Over the past years, the Xenopus embryo has emerged as an incredibly useful model organism for studying the formation and function of cilia and ciliated epithelia in vivo. This has led to a variety of findings elucidating the molecular mechanisms of ciliated cell specification, basal body biogenesis, cilia assembly, and ciliary motility. These findings also revealed the deep functional conservation of signaling, transcriptional, post-transcriptional, and protein networks employed in the formation and function of vertebrate ciliated cells. Therefore, Xenopus research can contribute crucial insights not only into developmental and cell biology, but also into the molecular mechanisms underlying cilia related diseases (ciliopathies) as well as diseases affecting the ciliated epithelium of the respiratory tract in humans (e.g., chronic lung diseases). Additionally, systems biology approaches including transcriptomics, genomics, and proteomics have been rapidly adapted for use in Xenopus, and broaden the applications for current and future translational biomedical research. This review aims to present the advantages of using Xenopus for cilia research, highlight some of the evolutionarily conserved key concepts and mechanisms of ciliated cell biology that were elucidated using the Xenopus model, and describe the potential for Xenopus research to address unresolved questions regarding the molecular mechanisms of ciliopathies and airway diseases. PMID- 28095646 TI - A frog's view of EphrinB signaling. AB - Cell-cell and cell-substrate adhesion are essential to the proper formation and maintenance of tissue patterns during development, and deregulation of these processes can lead to invasion and metastasis of cancer cells. Cell surface adhesion and signaling molecules are key players in both normal development and cancer progression. One set of cell surface proteins, the Eph receptor tyrosine kinases and their membrane-bound ligands, ephrins, are significant regulators of these processes. During embryonic development, the Eph/ephrin signaling system is involved in cell-cell contact events that result in cell sorting and boundary formation between receptor and ligand bearing cells. When migrating cells that display the membrane bound ligands or receptors come in contact with cells bearing the cognate partner, the response may be adhesion or repulsion, ultimately leading to the proper positioning of these cells. During cancer progression, the signaling between these receptor/ligand pairs is often deregulated, leading to increased invasion and metastasis. To gain mechanistic insight into the pathways that mediate Eph receptor and ephrin signaling we have relied upon a very tractable system, the frog Xenopus. This model system has proven to be extremely versatile, and represents a relatively quick and manipulable system to explore signaling events and the in vivo processes affected by these signals. PMID- 28095648 TI - AmphiBase: A new genomic resource for non-model amphibian species. AB - More than five thousand genes annotated in the recently published Xenopus laevis and Xenopus tropicalis genomes do not have a candidate orthologous counterpart in other vertebrate species. To determine whether these sequences represent genuine amphibian-specific genes or annotation errors, it is necessary to analyze them alongside sequences from other amphibian species. However, due to large genome sizes and an abundance of repeat sequences, there are limited numbers of gene sequences available from amphibian species other than Xenopus. AmphiBase is a new genomic resource covering non-model amphibian species, based on public domain transcriptome data and computational methods developed during the X. laevis genome project. Here, I review the current status of AmphiBase, including amphibian species with available transcriptome data or biological samples, and describe the challenges of building a comprehensive amphibian genomic resource in the absence of genomes. This mini-review will be informative for researchers interested in functional genomic experiments using amphibian model organisms, such as Xenopus and axolotl, and will assist in interpretation of results implicating "orphan genes." Additionally, this study highlights an opportunity for researchers working on non-model amphibian species to collaborate in their future efforts and develop amphibian genomic resources as a community. PMID- 28095647 TI - New-generation mass spectrometry expands the toolbox of cell and developmental biology. AB - Systems cell biology understanding of development requires characterization of all the molecules produced in the biological system. Decades of research and new generation sequencing provided functional information on key genes and transcripts. However, there is less information available on how differential gene expression translates into the domains of functionally important proteins, peptides, and metabolites, and how changes in these molecules impact development. Mass spectrometry (MS) is the current technology of choice for the detection and quantification of large numbers of proteins and metabolites, because it requires no use of antibodies, functional probes, or a priori knowledge of molecules produced in the system. This review focuses on recent technologies that have improved MS sensitivity for proteins and metabolites and enabled new functionalities to assess their temporal and spatial changes during vertebrate embryonic development. This review highlights case studies, in which new generation MS tools have enabled the study of hundreds-to-thousands of proteins and metabolites in tissues, cell populations, and single cells in model systems of vertebrate development, particularly the frog (Xenopus), zebrafish, and mouse. New-generation MS expands the toolbox of cell and developmental studies, raising exciting potentials to advance basic and translational research in the life sciences. PMID- 28095649 TI - The effect of mechanical stress on the proliferation, adipogenic differentiation and gene expression of human adipose-derived stem cells. AB - To allow for a better implementation of external volume expansion to clinical applications for soft tissue regeneration, it is necessary to comprehensively understand the underlying mechanisms. As human adipose-derived stem cells (hASCs) play a crucial role in soft tissue enlargement, we investigated the impact of cyclic stretch on gene expression, proliferation rate and adipogenic differentiation of these cells. After cyclic stretching, RNA was extracted and subjected to DNA microarray analysis and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Also, the expression of FABP4 mRNA was analysed by RT-qPCR to test whether mechanical stretch affected adipogenic differentiation of hASCs. The proliferation rate was assessed using the alamarBlue assay and Ki-67 staining. A cell cycle analysis was performed with flow cytometry and Western blot. We found that cyclic stretch significantly induced the expression of CYP1B1 mRNA. Furthermore, the adipogenic differentiation of hASCs was impaired, as was the proliferation. This was partly due to a decrease in extracellular signal-regulated kinase (ERK) 1/2 and histone H3 phosphorylation, suggesting a growth arrest in the G2 /M phase of the cell cycle. Enrichment analyses demonstrated that stretch-regulated genes were over represented in pathways and biological processes involved in extracellular matrix organization, vascular remodelling and responses to cell stress. Taken together, mechanical stress impaired both proliferation and adipogenic differentiation, but led to a tissue-remodelling phenotype of hASCs. These data suggest that extracellular matrix remodelling and neoangiogenesis may play a more important role in external volume expansion than proliferation and adipogenesis of hASCs. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28095650 TI - Bone tissue engineering in oral peri-implant defects in preclinical in vivo research: A systematic review and meta-analysis. AB - The regeneration and establishment of osseointegration within oral peri-implant bone defects remains a clinical challenge. Bone tissue engineering (BTE) is emerging as a promising alternative to autogenous and/or biomaterial-based bone grafting. The objective of this systematic review was to answer the focused question: in animal models, do cell-based BTE strategies enhance bone regeneration and/or implant osseointegration in experimental peri-implant defects, compared with grafting with autogenous bone or only biomaterial scaffolds? Electronic databases were searched for controlled animal studies reporting on peri-implant defects and implantation of mesenchymal stem cells (MSC) or other cells seeded on biomaterial scaffolds, following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Random effects meta-analyses were performed for the outcomes histomorphometric bone area fraction (BA) and bone-to-implant contact (BIC). Nineteen studies reporting on large animal models (dogs and sheep) were included. Experimental defects were created surgically (16 studies) or via ligature-induced peri implantitis (LIPI, three studies). In general, studies presented with an unclear to high risk of bias. In most studies, MSC were used in combination with alloplastic mineral phase or polymer scaffolds; no study directly compared cell loaded scaffolds vs. autogenous bone. In three studies, cells were also modified by ex vivo gene transfer of osteoinductive factors. The meta-analyses indicated statistically significant benefits in favour of: (a) cell-loaded vs. cell-free scaffolds [weighted mean differences (WMD) of 10.73-12.30% BA and 11.77-15.15% BIC] in canine surgical defect and LIPI models; and (b) gene-modified vs. unmodified cells (WMD of 29.44% BA and 16.50% BIC) in canine LIPI models. Overall, heterogeneity in the meta-analyses was high (I2 70-88%); considerable variation was observed among studies regarding the nature of cells and scaffolds used. In summary, bone regeneration and osseointegration in peri-implant defects are enhanced by the addition of osteogenic cells to biomaterial scaffolds. Although the direction of treatment outcome is clearly in favour of BTE strategies, due to the limited magnitude of treatment effect observed, no conclusive statements regarding the clinical benefit of such procedures for oral indications can yet be made. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28095651 TI - Transcriptional dynamics of tail regeneration in Xenopus tropicalis. AB - In contrast to humans, many amphibians are able to rapidly and completely regenerate complex tissues, including entire appendages. Following tail amputation, Xenopus tropicalis tadpoles quickly regenerate muscle, spinal cord, cartilage, vasculature and skin, all properly patterned in three dimensions. To better understand the molecular basis of this regenerative competence, we performed a transcriptional analysis of the first 72 h of tail regeneration using RNA-Seq. Our analysis refines the windows during which many key biological signaling processes act in regeneration, including embryonic patterning signals, immune responses, bioelectrical signaling and apoptosis. Our work provides a deep database for researchers interested in appendage regeneration, and points to new avenues for further study. PMID- 28095652 TI - Exosomal trafficking in Xenopus development. AB - Exosomes are small extracellular vesicles (EVs) secreted by many cell types in both normal and pathogenic circumstances. Because EVs, particularly exosomes, are known to transfer biologically active proteins, RNAs and lipids between cells, they have recently become the focus of intense interest as potential mediators of cell-cell communication, particularly in long-range and juxtacrine signaling events associated with adaptive immune function and progression of cancer. Among the EVs, exosomes appear particularly adapted for long-range delivery of cargoes between cells. Because of their association with disease states, the exciting potential for exosomes to serve as diagnostic biomarkers and as target-specific biomolecule delivery vehicles has stimulated a broad range of biomedical investigations to learn how exosomes are generated, what their cargoes are, and how they might be tailored for uptake by remote targets. Addressing these questions requires experimental models in which biochemically useful amounts of material can be harvested, gene expression easily manipulated, and interpretable biological assays developed. The early Xenopus embryo fulfills these model-system ideals in an in vivo context: during morphogenesis the embryo develops several large, fluid-filled extracellular compartments across which numerous tissue specifying signals must cross, and which are abundantly endowed with exosomes and other EVs. Importantly, certain surface-facing tissues avidly ingest EVs during gastrulation. Recent work has demonstrated that EVs can be isolated from these interstitial spaces in amounts suitable for proteomic and transcriptomic analysis. With its large numbers, great cell size, well-understood fate map, and tolerance of a variety of experimental approaches, the Xenopus embryo provides a unique opportunity to both understand and manipulate the basic cell biology of exosomal trafficking in the context of an intact organism. PMID- 28095653 TI - Efficacy of Korean Multipurpose Contact Lens Disinfecting Solutions against Acanthamoeba castellanii. AB - Acanthamoeba keratitis has been increasing in recent years. Main risk factors are contact lens wear and their cleaning solutions. Most contact lens wearers use multipurpose disinfecting solutions (MPDS) for cleansing and disinfecting microorganisms because of its convenience. We determined amoebicidal effects of MPDS made in Korea and their cytotoxicity on human corneal epithelium cells. Fifteen commercial MPDS (A to O) were tested for their amoebicidal effects on Acanthamoeba castellanii trophozoites and cysts by using a most probable number (MPN) technique. Among them, 7 kinds of MPDS showed little or no amoebicidal effects for 24 hr exposure. Solutions A, B, G, H, L, and O showed positive amoebicidal effects, and solutions M and N killed almost all trophozoites and cysts after 24 hr exposure. However, 50%-N solution showed 56% cytotoxicity on human corneal epithelial cells within 4 hr exposure, and 50%-O solution also showed 62% cytotoxicity on human cells within 4 hr exposure. Solution A did not show any cytotoxicity on human cells. These results revealed that most MPDS made in Korea were ineffective to kill Acanthamoeba. The solutions having amoebicidal activity also showed high levels of cytotoxicity on human corneal epithelial cells. New formulations for improved MPDS that are amoebicidal but safe for host cells are needed to prevent Acanthamoeba keratitis. PMID- 28095654 TI - Prevalence and Molecular Characterization of Intestinal Trichomonads in Pet Dogs in East China. AB - The trichomonad species Tritrichomonas foetus and Pentatrichomonas hominis were recently detected in the feces of dogs with diarrhea. However, little information is available on the prevalence and pathogenicity of these parasites in the canine population. Therefore, the aim of this study was to determine the prevalence and molecular characterization of trichomonads infecting pet dogs in Anhui and Zhejiang provinces, east China. In total, 315 pet dogs, with or without diarrhea, from 7 pet hospitals were included in this epidemiological survey. Microscopy and PCR detected P. hominis in 19.7% (62/315) and 31.4% (99/315) of fecal samples, respectively. T. foetus infection was detected in 0% (0/315) of samples with microscopy and in 0.6% (2/315) with PCR. The prevalence of P. hominis was significantly higher in young dogs (<=12 months) than in adult dogs (>12 months), and was significantly higher in diarrheic dogs (50.6%) than in non-diarrheic dogs (24.3%; P<0.05). Infection with T. foetus did not correlate with any risk factors evaluated in this study. A sequence analysis of the P. hominis PCR products showed minor allelic variations between our sequences and those of P. hominis strains from other hosts in different parts of the world. Type CC1 was the most common strain in dogs in east China. The internal transcribed spacer 1 (ITS1) 5.8S rRNA gene sequences from the 2 T. foetus isolates detected in this study displayed 100% identity and were homologous to the sequences of other strains isolated from domestic cats in other countries. PMID- 28095655 TI - Production of IL-1beta and Inflammasome with Up-Regulated Expressions of NOD-Like Receptor Related Genes in Toxoplasma gondii-Infected THP-1 Macrophages. AB - Toxoplasma gondii is an obligate intracellular parasite that stimulates production of high levels of proinflammatory cytokines, which are important for innate immunity. NLRs, i.e., nucleotide-binding oligomerization domain (NOD)-like receptors, play a crucial role as innate immune sensors and form multiprotein complexes called inflammasomes, which mediate caspase-1-dependent processing of pro-IL-1beta. To elucidate the role of inflammasome components in T. gondii infected THP-1 macrophages, we examined inflammasome-related gene expression and mechanisms of inflammasome-regulated cytokine IL-1beta secretion. The results revealed a significant upregulation of IL-1beta after T. gondii infection. T. gondii infection also upregulated the expression of inflammasome sensors, including NLRP1, NLRP3, NLRC4, NLRP6, NLRP8, NLRP13, AIM2, and NAIP, in a time dependent manner. The infection also upregulated inflammasome adaptor protein ASC and caspase-1 mRNA levels. From this study, we newly found that T. gondii infection regulates NLRC4, NLRP6, NLRP8, NLRP13, AIM2, and neuronal apoptosis inhibitor protein (NAIP) gene expressions in THP-1 macrophages and that the role of the inflammasome-related genes may be critical for mediating the innate immune responses to T. gondii infection. PMID- 28095656 TI - Dynamic Patterns of Systemic Innate Immunity and Inflammatory Associated Factors in Experimental Caprine Coccidiosis. AB - The present study was designed to assess the dynamic patterns of pro-inflammatory cytokines, including IFN-gamma, TNF-alpha, IL-4, IL-6, acute phase protein (alpha1-acid-glycoprotein, AGP), and an inflammation associated factor (adenosine deaminase; ADA) following experimental caprine coccidiosis. Ten kids aging from 2 to 4 months were infected orally with 5*104 sporulated oocysts and 10 animals served as controls. Blood samples were collected in both groups before infection and at days 3, 7, 14, 21, 28, and 35 post-infection (PI), and the levels of above mentioned factors were measured. IFN-gamma, TNF-alpha, IL-4, IL-6, AGP, and ADA activities were significantly higher in infected animals from day 7 PI (P<0.05). In conclusion, the circulatory levels of most systemic inflammatory markers, including pro-inflammatory cytokines (IFN-gamma, TNF-alpha, IL-4, IL-6), AGP, and ADA increased significantly starting from day 3 to day 7 PI in caprine coccidiosis. PMID- 28095657 TI - Characterization of Caveola-Vesicle Complexes (CVCs) Protein, PHIST/CVC-8195 in Plasmodium vivax. AB - Plasmodium vivax produces numerous caveola-vesicle complex (CVC) structures beneath the membrane of infected erythrocytes. Recently, a member helical interspersed subtelomeric (PHIST) superfamily protein, PcyPHIST/CVC-8195, was identified as CVCs-associated protein in Plasmodium cynomolgi and essential for survival of this parasite. Very little information has been documented to date about PHIST/CVC-8195 protein in P. vivax. In this study, the recombinant PvPHIST/CVC-8195 N and C termini were expressed, and immunoreactivity was assessed using confirmed vivax malaria patients sera by protein microarray. The subcellular localization of PvPHIST/CVC-8195 N and C termini in blood stage parasites was also determined. The antigenicity of recombinant PvPHIST/CVC-8195 N and C terminal proteins were analyzed by using serum samples from the Republic of Korea. The results showed that immunoreactivities to these proteins had 61% and 43% sensitivity and 96.9% and 93.8% specificity, respectively. The N terminal of PvPHIST/CVC-8195 which contains transmembrane domain and export motif (PEXEL; RxLxE/Q/D) produced CVCs location throughout the erythrocytic-stage parasites. However, no fluorescence was detected with antibodies against C terminal fragment of PvPHIST/CVC-8195. These results suggest that the PvPHIST/CVC-8195 is localized on the CVCs and may be immunogenic in natural infection of P. vivax. PMID- 28095658 TI - Therapeutic Assessment of Primaquine for Radical Cure of Plasmodium vivax Malaria at Primary and Tertiary Care Centres in Southwestern India. AB - Acquaintance is scanty on primaquine (PQ) efficacy and Plasmodium vivax recurrence in Udupi district, Karnataka, India. We assessed the efficacy of 14 days PQ regimen (0.25 mg/kg/day) to prevent P. vivax recurrence. Microscopically, aparasitemic adults (>=18 years) after acute vivax malaria on day 28 were re enrolled into 15 months' long follow-up study. A peripheral blood smear examination was performed with participants at every 1-2 month interval. A nested PCR test was performed to confirm the mono-infection with P. vivax. Of 114 participants, 28 (24.6%) recurred subsequently. The median (IQR) duration of the first recurrence was 3.1 (2.2-5.8) months which ranged from 1.2 to 15.1 months, including initial 28 days. Participants with history of vivax malaria had significantly higher risk of recurrence, with hazard ratio (HR) (95% CI) of 2.62 (1.24-5.54) (P=0.012). Severity of disease (11.4%, 13/114) was not associated (P=1.00) with recurrence. Of 28 recurrence cases, the nPCR proved that P. vivax mono-infection recurrence rate was at least 72.7% (16/22) at first recurrence. In Udupi district, PQ dose of 0.25 mg/kg/day over 14 days seems inadequate to prevent recurrence in substantial proportion of vivax malaria. Patients with a history of vivax malaria are at high risk of recurrences. PMID- 28095659 TI - Molecular Characterization of Nippostrongylus brasiliensis (Nematoda: Heligmosomatidae) from Mus musculus in India. AB - Mus musculus (Rodentia: Muridae) has generally been infected with a rodent hookworm Nippostrongylus brasiliensis. In this report, we present morphological and molecular identification of N. brasiliensis by light and scanning electron microscopy and PCR amplification of mitochondrial cytochrome c oxidase subunit 1 (cox1) gene and the protein sequences encoded by cox1 gene, respectively. Despite the use of N. brasiliensis in many biochemistry studies from India, their taxonomic identification was not fully understood, especially at the species level, and no molecular data is available in GenBank from India. Sequence analysis of cox1 gene in this study revealed that the present specimen showed close identity with the same species available in GenBank, confirming that the species is N. brasiliensis. This study represents the first record of molecular identification of N. brasiliensis from India and the protein structure to better understand the comparative phylogenetic characteristics. PMID- 28095660 TI - Draft Genome of Toxocara canis, a Pathogen Responsible for Visceral Larva Migrans. AB - This study aimed at constructing a draft genome of the adult female worm Toxocara canis using next-generation sequencing (NGS) and de novo assembly, as well as to find new genes after annotation using functional genomics tools. Using an NGS machine, we produced DNA read data of T. canis. The de novo assembly of the read data was performed using SOAPdenovo. RNA read data were assembled using Trinity. Structural annotation, homology search, functional annotation, classification of protein domains, and KEGG pathway analysis were carried out. Besides them, recently developed tools such as MAKER, PASA, Evidence Modeler, and Blast2GO were used. The scaffold DNA was obtained, the N50 was 108,950 bp, and the overall length was 341,776,187 bp. The N50 of the transcriptome was 940 bp, and its length was 53,046,952 bp. The GC content of the entire genome was 39.3%. The total number of genes was 20,178, and the total number of protein sequences was 22,358. Of the 22,358 protein sequences, 4,992 were newly observed in T. canis. Following proteins previously unknown were found: E3 ubiquitin-protein ligase cbl b and antigen T-cell receptor, zeta chain for T-cell and B-cell regulation; endoprotease bli-4 for cuticle metabolism; mucin 12Ea and polymorphic mucin variant C6/1/40r2.1 for mucin production; tropomodulin-family protein and ryanodine receptor calcium release channels for muscle movement. We were able to find new hypothetical polypeptides sequences unique to T. canis, and the findings of this study are capable of serving as a basis for extending our biological understanding of T. canis. PMID- 28095661 TI - Molecular Cloning and Characterization of a P38-Like Mitogen-Activated Protein Kinase from Echinococcus granulosus. AB - Cystic echinococcosis (CE) treatment urgently requires a novel drug. The p38 mitogen-activated protein kinases (MAPKs) are a family of Ser/Thr protein kinases, but still have to be characterized in Echinococcus granulosus. We identified a 1,107 bp cDNA encoding a 368 amino acid MAPK protein (Egp38) in E. granulosus. Egp38 exhibits 2 distinguishing features of p38-like kinases: a highly conserved T-X-Y motif and an activation loop segment. Structural homology modeling indicated a conserved structure among Egp38, EmMPK2, and H. sapiens p38alpha, implying a common binding mechanism for the ligand domain and downstream signal transduction processing similar to that described for p38alpha. Egp38 and its phosphorylated form are expressed in the E. granulosus larval stages vesicle and protoscolices during intermediate host infection of an intermediate host. Treatment of in vitro cultivated protoscolices with the p38 MAPK inhibitor ML3403 effectively suppressed Egp38 activity and led to significant protoscolices death within 5 days. Treatment of in vitro-cultivated protoscolices with TGF-beta1 effectively induced Egp38 phosphorylation. In summary, the MAPK, Egp38, was identified in E. granulosus, as an anti-CE drug target and participates in the interplay between the host and E. granulosus via human TGF-beta1. PMID- 28095662 TI - Factors Associated with Echinococcosis-Induced Perioperative Anaphylactic Shock. AB - This retrospective case-control study explored the factors associated with anaphylactic shock during surgery for cystic echinococcosis (CE) at the First Affiliated Hospital of Xinjiang Medical University between October 2008 and September 2013. Patients who suffered from anaphylactic shock (n=16) were age matched 3:1 to patients who did not (n=43). Multivariate analysis suggested that IL-4 levels (odds ratio=1.096; 95% confidence interval=1.015-1.185; P=0.02) and cyst size (odds ratio=3.028, 95% confidence interval=1.259-7.283, P=0.013) were independently associated with CE-induced perioperative anaphylactic shock. Using the receiver operating characteristic (ROC) curves and a cut-off value of 415.7 ng/ml, IL-4 showed an area under the ROC (AUC) of 0.926, sensitivity of 75.0%, and specificity of 97.7%. Using a cut-off value of 7.8 cm, cyst size showed an AUC of 0.828, sensitivity of 81.3%, and specificity of 76.7%. In conclusion, results suggest that levels of IL-4 and cyst size were independently associated with echinococcosis-induced perioperative anaphylactic shock. These results could help identifying patients with echinococcosis at risk of anaphylactic shock in whom appropriate prophylaxis could be undertaken. PMID- 28095663 TI - Morphology and Molecular Phylogeny of Raillietina spp. (Cestoda: Cyclophyllidea: Davaineidae) from Domestic Chickens in Thailand. AB - Raillietina species are prevalent in domestic chickens (Gallus gallus domesticus) in Phayao province, northern Thailand. Their infection may cause disease and death, which affects the public health and economic situation in chicken farms. The identification of Raillietina has been based on morphology and molecular analysis. In this study, morphological observations using light (LM) and scanning electron microscopies (SEM) coupled with molecular analysis of the internal transcribed spacer 2 (ITS2) region and the nicotinamide adenine dinucleotide dehydrogenase subunit 1 (ND1) gene were employed for precise identification and phylogenetic relationship studies of Raillietina spp. Four Raillietina species, including R. echinobothrida, R. tetragona, R. cesticillus, and Raillietina sp., were recovered in domestic chickens from 4 districts in Phayao province, Thailand. LM and SEM observations revealed differences in the morphology of the scolex, position of the genital pore, number of eggs per egg capsule, and rostellar opening surface structures in all 4 species. Phylogenetic relationships were found among the phylogenetic trees obtained by the maximum likelihood and distance-based neighbor-joining methods. ITS2 and ND1 sequence data recorded from Raillietina sp. appeared to be monophyletic. The query sequences of R. echinobothrida, R. tetragona, R. cesticillus, and Raillietina sp. were separated according to the different morphological characters. This study confirmed that morphological studies combined with molecular analyses can differentiate related species within the genus Raillietina in Thailand. PMID- 28095664 TI - Cutaneous Leishmaniasis of the Eyelids: A Case Series with Molecular Identification and Literature Review. AB - Cutaneous leishmaniasis (CL) is a protozoan disease which is endemic in Iran. It is transmitted by the Phlebotomus sand fly. The eyelid is rarely involved possibly because the movement of the lids impedes the sand fly from biting the skin in this region. Here, we report 6 rare cases of eyelid CL. The patients were diagnosed by skin scraping, culture, and PCR from the lesions. Skin scraping examination showed Leishmania spp. amastigotes in the cytoplasm of macrophages. Culture examination was positive for Leishmania spp. PCR was positive for Leishmania major and Leishmania tropica. The lesions were disguised as basal cell carcinoma, chalazion, hordeolum, and impetigo. The patients were treated with intramuscular meglumine antimoniate (20 mg/kg/day) for at least 3 weeks. They showed a dramatic response, and the lesions almost completely disappeared. We emphasized the importance of clinical and diagnostic features of lesions, characterized the phylogenetic relationship of isolated parasites, and reviewed the literature on ocular leishmaniasis. PMID- 28095665 TI - A Case of Cerebral Cysticercosis in Thailand. AB - Cysticercosis and sparganosis are not uncommon parasitic infections in the developing world. Central nervous system infection by both cestodes can present with neurological signs and symptoms, such as seizure and mass effect, including brain hernia. Early detection and accurate diagnosis can prevent a fatal outcome. Histological examinations of brain tissues can confirm the diagnosis of cerebral cysticercosis, which differs from sparganosis by the presence of a cavitated body. We report here a case of cerebral cysticercosis which has the similar clinical and imaging findings as sparganosis. PMID- 28095666 TI - Epidemiological Investigation of Asymptomatic Dogs with Leishmania Infection in Southwestern China Where Visceral Leishmaniasis is Intractable. AB - Heishui county, located in northwest Sichuan province, southwestern China, is an endemic area of zoonotic visceral leishmaniasis (VL) and is the most intractable area. VL is never destroyed in it. Asymptomatic dogs (Leishmania parasites have been diagnosed but clinically healthy) are considered to be a potential reservoir host in zoonotic VL area, and most can lead to infection of individuals, that is a new challenge for controlling VL in humans. The present study aimed to assess the Leishmania infection rate of asymptomatic dogs in Heishui county. Total 105 asymptomatic domestic dogs were gathered from 4 districts in Heishui county to investigate the infection rate with serological and molecular methods based on ELISA and kinetoplast minicircle DNA(kDNA) PCR, respectively. Out of 105 dogs, 44 (41.9%) were positive by more than 1 method; 21 (20.0%) were positive by ELISA, and 30 (28.6%) were positive by kDNA-PCR. Our study showed that Leishmania infection of domestic dogs which is clinically healthy is prevalent in the studied district, and the asymptomatic dogs infected by Leishmania may be the primary reason for the prevalence of visceral leishmaniasis in the area. PMID- 28095667 TI - Sequence Analysis of Mitochondrial Genome of Toxascaris leonina from a South China Tiger. AB - Toxascaris leonina is a common parasitic nematode of wild mammals and has significant impacts on the protection of rare wild animals. To analyze population genetic characteristics of T. leonina from South China tiger, its mitochondrial (mt) genome was sequenced. Its complete circular mt genome was 14,277 bp in length, including 12 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and 2 non coding regions. The nucleotide composition was biased toward A and T. The most common start codon and stop codon were TTG and TAG, and 4 genes ended with an incomplete stop codon. There were 13 intergenic regions ranging 1 to 10 bp in size. Phylogenetically, T. leonina from a South China tiger was close to canine T. leonina. This study reports for the first time a complete mt genome sequence of T. leonina from the South China tiger, and provides a scientific basis for studying the genetic diversity of nematodes between different hosts. PMID- 28095668 TI - Recovery of Oswaldotrema nacinovici from Whimbrels (Aves) in Korea. AB - Adult specimens of Oswaldotrema nacinovici (Digenea: Philophthalmidae) have been first identified in Korea from 2 migratory birds (whimbrels, Numenius phaeopus) which were found dead at a western seashore area near Gunsan. The worms were recovered in the intestine of these birds. The worms were morphologically characterized by a large ventral sucker in comparison to the oral sucker, an external seminal vesicle extending beyond the posterior margin of the ventral sucker, and conspicuous uterine seminal receptacle. It was noteworthy that metacercariae-like bodies were contained within the inflated regions of 2 ceca. Other intestinal trematode species found in whimbrels included Spelotrema pygmeum, Gynaecotyla squatarolae, Maritrema obstipum, and Himasthla megacotyle. Zoonotic potential of these trematode species should be taken into considerations. PMID- 28095669 TI - Complete Mitochondrial Genome of a Tongue Worm Armillifer agkistrodontis. AB - Armillifer agkistrodontis (Ichthyostraca: Pantastomida) is a parasitic pathogen, only reported in China, which can cause a zoonotic disease, pentastomiasis. A complete mitochondrial (mt) genome was 16,521 bp comprising 13 protein-coding genes (PCGs), 22 tRNA genes, 2 rRNA genes, and 1 non-coding region (NCR). A phylogenetic tree drawn with the concatenated amino acid sequences of the 6 conserved PCGs (atp6, cox1-3, and nad2) showed that A. agkistrodontis and Armillifer armillatus constituted a clade Pentastomida which was a sister group of the Branchiura. The complete mt genome sequence of A. agkistrodontis provides important genetic markers for both phylogenetic and epidemiological studies of pentastomids. PMID- 28095670 TI - Professor Chin-Thack Soh (1921-2016). PMID- 28095671 TI - Use of Calculated Physicochemical Properties to Enhance Quantitative Response When Using Charged Aerosol Detection. AB - Universal quantitative detection without the need for analyte reference standards would offer substantial benefits in many areas of analytical science. The quantitative capability of high-performance liquid chromatography (HPLC) with charged aerosol detection (CAD) was investigated for 50 compounds with a wide range of physical and chemical properties. It is widely believed that CAD is a mass detector. Quantification of the 50 compounds using a generic calibrant and mass calibration achieved an average error of 11.4% relative to 1H NMR. Correction factors are proposed that estimate the relative surface area of particles in the detector, taking into account the effects of the density and charge of analytes. Performing these corrections and quantifying with surface area calibration, rather than mass, shows considerably improved linearity and uniformity of detection, reducing the average error relative to 1H NMR to 7.1%. The accuracy of CAD quantification was most significantly improved for highly dense compounds, with traditional mass calibration showing an average error of 34.7% and the newly proposed surface area calibration showing an average error of 5.8%. PMID- 28095672 TI - Targeted Self-Healing by Magnetically Guiding Microcapsules. AB - Magnetically guided microcapsules are used to achieve self-healing with 1/10th of the healing components required using traditional self-healing approaches. Microcapsules are rendered responsive to magnetic fields by suspending magnetic nanoparticles in the core material. The nanoparticles are surface-modified to enable urea-formaldehyde encapsulation within a phenyl acetate core. Magnetic fields are used to guide the microcapsules to the expected fracture location in tapered double-cantilever beam (TDCB) epoxy specimens. This guiding method achieves an order of magnitude increase in local microcapsule concentration over controls, resulting in successful self-healing at microcapsule concentrations as low as 0.025 wt %. Additionally, the observed healing is both more consistent and significantly higher than that of control specimens, remaining relatively constant across all weight percentages tested. PMID- 28095673 TI - Comparative Study of Hepatotoxicity of Pyrrolizidine Alkaloids Retrorsine and Monocrotaline. AB - Many pyrrolizidine alkaloids (PAs) can cause liver injury in animals and humans. Different hepatotoxic PAs can produce similar hepatotoxic effects, but the degree of their toxicities may vary widely. Retrorsine (RTS) and monocrotaline (MCT) share the same core structure (retronecine) and similar metabolic activation pathway. RTS and MCT both produced liver injury, but the former was more hepatotoxic than the latter. Enzyme kinetic study demonstrated that the value of Vmax/Km for RTS was 5.5-fold larger than that of MCT. Additionally, RTS produced higher levels of pyrrole-glutathione (GSH) conjugates and protein covalent binding than MCT at the same dose. Furthermore, RTS induced significant hepatic GSH depletion but MCT did little. This comparative study provides clear evidence that the generation of the reactive pyrrolic intermediates plays a critical role in PA-induced hepatotoxicity. PMID- 28095674 TI - The "Century of Biology" and the Evolving Role of Medicinal Chemists in Neuroscience. AB - Society expects that the wave of contemporary new discoveries in biological sciences will soon lead to novel treatments for human diseases, including many devastating brain disorders. Historically, medicinal chemists have contributed to drug discovery teams in ways that synergize with those from their partner sciences, and help transform new knowledge into the ultimate tangible asset: a new drug. The optimal balance of resources and the right strategy to minimize the risk of late clinical failure may differ for different therapeutic indications. Recent progress in the oncology and neuroscience therapeutic areas is compared and contrasted, in particular looking at the biological target space and functional attributes of recently FDA-approved drugs and those in the late clinical pipeline. Medicinal chemists are poised to have major influence in neuroscience drug research, and examples of areas of potential impact are presented, together with a discussion of the soft skills they bring to their project teams and why they have been so impactful. PMID- 28095678 TI - Editors' Favorites of 2016. PMID- 28095675 TI - Elucidating Important Sites and the Mechanism for Amyloid Fibril Formation by Coarse-Grained Molecular Dynamics. AB - Fibrils formed by the beta-amyloid (Abeta) peptide play a central role in the development of Alzheimer's disease. In this study, the principles governing their growth and stability are investigated by analyzing canonical and replica-exchange molecular dynamics trajectories of Abeta(9-40) fibrils. In particular, an unstructured monomer was allowed to interact freely with an Abeta fibril template. Trajectories were generated with the coarse-grained united-residue force field, and one- and two-dimensional free-energy landscapes (FELs) along the backbone virtual-bond angle theta and backbone virtual-bond-dihedral angle gamma of each residue and principal components, respectively, were analyzed. Also, thermal unbinding (unfolding) of an Abeta peptide from the fibril template was investigated. These analyses enable us to illustrate the entire process of Abeta fibril elongation and to elucidate the key residues involved in it. Several different pathways were identified during the search for the fibril conformation by the monomer, which finally follows a dock-lock mechanism with two distinct locking stages. However, it was found that the correct binding, with native hydrogen bonds, of the free monomer to the fibril template at both stages is crucial for fibril elongation. In other words, if the monomer is incorrectly bound (with nonnative hydrogen bonds) to the fibril template during the first "docking" stage, it can remain attached to it for a long time before it dissociates and either attempts a different binding or allows another monomer to bind. This finding is consistent with an experimentally observed "stop-and-go" mechanism of fibril growth. PMID- 28095676 TI - Radiosynthesis and Evaluation of [11C]3-Hydroxycyclopent-1-enecarboxylic Acid as Potential PET Ligand for the High-Affinity gamma-Hydroxybutyric Acid Binding Sites. AB - gamma-Hydroxybutyric acid (GHB) is an endogenous neuroactive substance and proposed neurotransmitter with affinity for both low- and high-affinity binding sites. A radioligand with high and specific affinity toward the high-affinity GHB binding site would be a unique tool toward a more complete understanding of this population of binding sites. With its high specific affinity and monocarboxylate transporter (MCT1) mediated transport across the blood-brain barrier in pharmacological doses, 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) seems like a suitable PET radiotracer candidate. Here, we report the 11C-labeling and subsequent evaluation of [11C]HOCPCA in a domestic pig, as a PET-radioligand for visualization of the high-affinity GHB binding sites in the live pig brain. To investigate the regional binding of HOCPCA in pig brain prior to in vivo PET studies, in vitro quantitative autoradiography on sections of pig brain was performed using [3H]HOCPCA. In vivo evaluation of [11C]HOCPCA showed no brain uptake, possibly due to a limited uptake of HOCPCA by the MCT1 transporter at tracer doses of [11C]HOCPCA. PMID- 28095679 TI - Non-Naturally Occurring Small Molecule Microtubule-Stabilizing Agents: A Potential Tactic for CNS-Directed Therapies. AB - Several independent studies indicate that microtubule (MT)-stabilizing agents hold considerable promise as candidate therapeutics for a wide spectrum of conditions of the central nervous system (CNS), from brain tumors to spinal cord injury, as well as a number of neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobar degeneration, Parkinson's disease, and amyotrophic lateral sclerosis. Although the identification and development of candidate compounds for CNS-directed MT-stabilizing therapies has been a challenge in drug discovery for many years, a growing number of molecules have now been identified that exhibit both MT-stabilizing activity and brain penetration. In this Viewpoint, we will highlight the potential utility of MT-active triazolopyrimidines, phenylpyrimidines, and related classes of non-naturally occurring small molecules that exhibit favorable druglike properties, including brain penetration and oral bioavailability. The mode of action of these small molecules has not as yet been fully elucidated at the molecular level. However, based on all available data, compounds from these classes appear to act on MTs in a potentially unique manner. Further characterization of these molecules may have important ramifications for drug discovery, especially in the area of CNS diseases. PMID- 28095680 TI - Addition to "ITH14001, a CGP37157-Nimodipine Hybrid Designed to Regulate Calcium Homeostasis and Oxidative Stress, Exerts Neuroprotection in Cerebral Ischemia". PMID- 28095681 TI - Interfacing Inorganic Nanoparticles with Biology. PMID- 28095682 TI - Superparamagnetic Nanoparticles as High Efficiency Magnetic Resonance Imaging T2 Contrast Agent. AB - Nanoparticle-based magnetic resonance imaging T2 negative agents are of great interest, and much effort is devoted to increasing cell-loading capability while maintaining low cytotoxicity. Herein, two classes of mixed-ligand protected magnetic-responsive, bimetallic gold/iron nanoparticles (Au/Fe NPs) synthesized by a two-step method are presented. Their structure, surface composition, and magnetic properties are characterized. The two classes of sulfonated Au/Fe NPs, with an average diameter of 4 nm, have an average atomic ratio of Au to Fe equal to 7 or 8, which enables the Au/Fe NPs to be superparamagnetic with a blocking temperature of 56 K and 96 K. Furthermore, preliminary cellular studies reveal that both Au/Fe NPs show very limited toxicity. MRI phantom experiments show that r2/r1 ratio of Au/Fe NPs is as high as 670, leading to a 66% reduction in T2 relaxation time. These nanoparticles provide great versatility and potential for nanoparticle-based diagnostics and therapeutic applications and as imaging contrast agents. PMID- 28095683 TI - Colorimetric Detection of Staphylococcus aureus Contaminated Solutions without Purification. AB - Current water quality monitoring methods rely on growth-based measurements to detect fecal indicator bacteria, such as Escherichia coli and enterococci, and Staphylococcus aureus (S. aureus). These growth-based measurements, however, can take days to complete. This is a significant limitation in the evaluation of contaminated food and water sources. Various methods for selective in vitro detection of S. aureus have also been reported; however, these strategies, such as ELISA, agar-diffusion, PCR, or liquid chromatography-tandem mass spectrometry, all require overnight culturing or sophisticated instrumentation. There is a pressing need for a portable, simple diagnostic for S. aureus. Here, we demonstrate that oligonucleotide-functionalized gold nanoparticles (Oligo-AuNPs) can be designed to rapidly and selectively detect S. aureus with a colorimetric readout. We have functionalized a chemically modified 11-mer sequence onto AuNPs and have found that aggregation occurs in the presence of S. aureus supernantants. The particles can be stored as a lyophilized powder and reconstituted at time of use, and this has been tested in biologically relevant samples such as creek and ocean water. This approach requires minimal sample preparation and requires no extraneous instrumentation, leading to a rapid and simple diagnostic read-out that could be used in field tests to monitor food and water sources. PMID- 28095684 TI - Effect of the Protein Corona on Antibody-Antigen Binding in Nanoparticle Sandwich Immunoassays. AB - We investigated the effect of the protein corona on the function of nanoparticle (NP) antibody (Ab) conjugates in dipstick sandwich immunoassays. Ab specific for Zika virus nonstructural protein 1 (NS1) were conjugated to gold NPs, and another anti-NS1 Ab was immobilized onto the nitrocellulose membrane. Sandwich immunoassay formation was influenced by whether the strip was run in corona forming conditions, i.e., in human serum. Strips run in buffer or pure solutions of bovine serum albumin exhibited false positives, but those run in human serum did not. Serum pretreatment of the nitrocellulose also eliminated false positives. Corona formation around the NP-Ab in serum was faster than the immunoassay time scale. Langmuir binding analysis determined how the immobilized Ab affinity for the NP-Ab/NS1 was impacted by corona formation conditions, quantified as an effective dissociation constant, KDeff. Results show that corona formation mediates the specificity and sensitivity of the antibody-antigen interaction of Zika biomarkers in immunoassays, and plays a critical but beneficial role. PMID- 28095686 TI - Characterizing Self-Assembled Monolayers on Gold Nanoparticles. AB - A key aspect of nanoscience is to control the assembly of complex materials from a "bottom-up" approach. The self-assembly and self-organization of small ligands at the surface of nanoparticles represent a possible starting route for the preparation of (bio)nanomaterials with precise (bio)physical and (bio)chemical properties. However, surface characterization and elucidation of the structure properties relationship, essential to envisioning such control, remain challenging and are often poorly investigated. This Topical Review aims to discuss different levels of surface characterization, giving an overview of the experimental and computational approaches that are used to provide insights into the self-assembled monolayer with molecular details. The methods and strategies discussed focus on the characterization of self-assembled monolayers at the gold nanoparticle surface, but most of them could also be applied to other types of nanoparticles. PMID- 28095685 TI - Amphiphilic-Polymer-Guided Plasmonic Assemblies and Their Biomedical Applications. AB - Plasmonic nanostructures with unique physical and biological properties have attracted increased attention for potential biomedical applications. Polymers grafted on metal nanoparticle surface can be used as assembly regulating molecules to guide nanoparticles organize into ordered or hierarchical structures in solution, within condensed phases, or at interfaces. In this Topical Review, we will highlight recent efforts on self-assembly of gold nanoparticles coated with polymer brushes. How and what kind of polymer graft can be used to adjust nanoparticle interactions, to dictate interparticle orientation, and to determine assembled nanostructures will be discussed. Furthermore, the Topical Review will shed light on the physicochemical properties, including self-assembly behavior and kinetics, tunable localized surface plasmon resonance effect, enhanced surface enhanced Raman scattering, and other optical and thermal properties. The potential of self-assembled nanostructures for applications in different fields, especially in biomedicine, will also be elaborated. PMID- 28095687 TI - Patterned Poly(dopamine) Films for Enhanced Cell Adhesion. AB - Engineered materials that promote cell adhesion and cell growth are important in tissue engineering and regenerative medicine. In this work, we produced poly(dopamine) (PDA) films with engineered patterns for improved cell adhesion. The patterned films were synthesized via the polymerization of dopamine at the air-water interface of a floating bed of spherical particles. Subsequent dissolution of the particles yielded free-standing PDA films with tunable geometrical patterns. Our results show that these patterned PDA films significantly enhance the adhesion of both cancer cells and stem cells, thus showing promise as substrates for cell attachment for various biomedical applications. PMID- 28095688 TI - Effect of Gold Nanoparticle Size and Coating on Labeling Monocytes for CT Tracking. AB - With advances in cell therapies, interest in cell tracking techniques to monitor the migration, localization, and viability of these cells continues to grow. X ray computed tomography (CT) is a cornerstone of medical imaging but has been limited in cell tracking applications due to its low sensitivity toward contrast media. In this study, we investigate the role of size and surface functionality of gold nanoparticles for monocyte uptake to optimize the labeling of these cells for tracking in CT. We synthesized gold nanoparticles (AuNP) that range from 15 to 150 nm in diameter and examined several capping ligands, generating 44 distinct AuNP formulations. In vitro cytotoxicity and uptake experiments were performed with the RAW 264.7 monocyte cell line. The majority of formulations at each size were found to be biocompatible, with only certain 150 nm PEG functionalized particles reducing viability at high concentrations. High uptake of AuNP was found using small capping ligands with distal carboxylic acids (11 MUA and 16-MHA). Similar uptake values were found with intermediate sizes (50 and 75 nm) of AuNP when coated with 2000 MW poly(ethylene-glycol) carboxylic acid ligands (PCOOH). Low uptake values were observed with 15, 25, 100, and 150 nm PCOOH AuNP, revealing interplay between size and surface functionality. Transmission electron microscopy (TEM) and CT performed on cells revealed similar patterns of high gold uptake for 50 nm PCOOH and 75 nm PCOOH AuNP. These results demonstrate that highly negatively charged carboxylic acid coatings for AuNP provide the greatest internalization of AuNP in monocytes, with a complex dependency on size. PMID- 28095689 TI - Folate-Binding Protein Self-Aggregation Drives Agglomeration of Folic Acid Targeted Iron Oxide Nanoparticles. AB - Folate-conjugated nanomaterials have been widely investigated for drug and imaging-agent delivery. In this work, two folic acid (FA) conjugated iron oxide particles (IOP), a ~40 nm diameter FA-IOP and a ~450 nm diameter FA-IOP(FA SeraMag), were synthesized. Both particles aggregated in the presence of serum folate-binding protein (FBP) at physiological concentration and buffer conditions. Mixing 0.01% w/w FA-conjugated iron oxide particles with FBP-induced agglomeration generated an average hydrodynamic particle diameter of 3800 +/- 1100 nm for ~40 nm FA-IOP and 4030 +/- 1100 nm for FA-SeraMag as measured by dynamic light scattering (DLS). The presence of excess human serum albumin (HSA) (600 MUM) did not prevent agglomeration of the ~40 nm FA-IOP; however, it did inhibit agglomeration of FA-SeraMag. Atomic force microscopy measurement provided additional insight into particle morphology with the detection of individual particles in the agglomerate. This behavior is an example of a triggered cascade. A protein structural change is induced by FA binding, and the structural change favors aggregation of the ~4 nm diameter FBPs on the particle surface; this further triggers the agglomeration of both the ~40 and ~450 nm diameter IOPs. PMID- 28095690 TI - Fluorinated and Charged Hydrogenated Alkanethiolates Grafted on Gold: Expanding the Diversity of Mixed-Monolayer Nanoparticles for Biological Applications. AB - Low intrinsic toxicity, high solubility, and stability are important and necessary features of gold nanoparticles to be used in the biomedical field. In this context, charged nanoparticles proved to be very versatile, and among them charged mixed-monolayer gold nanoparticles, displaying monolayers with well defined morphologies, represent a paradigm. By using mixtures of hydrogenated and fluorinated thiols, the formation of monolayer domains may be brought to an extreme because of the immiscibility of fluorinated and hydrogenated chains. Following this rationale, mixed monolayer gold nanoparticles featuring ammonium, sulfonate, or carboxylic groups on their surface were prepared by using amphiphilic hydrogenated thiols and 1H,1H,2H,2H-perfluoro-alkanethiols. The toxicity of these systems was assessed in HeLa cells and was found to be, in general, low even for the cationic nanoparticles which usually show a high cytotoxicity and is comparable to that of homoligand gold nanoparticles displaying amphiphilic-charge neutral-hydrogenated or fluorinated thiolates in their monolayer. These properties make the mixed ligand monolayer gold nanoparticles an interesting new candidate for medical application. PMID- 28095691 TI - Micrometer-Scale Ion Current Rectification at Polyelectrolyte Brush-Modified Micropipets. AB - Here we report for the first time that ion current rectification (ICR) can be observed at the micrometer scale in symmetric electrolyte solution with polyimidazolium brush (PimB)-modified micropipets, which we call micrometer-scale ion current rectification (MICR). To qualitatively understand MICR, a three-layer model including a charged layer, an electrical double layer, and a bulk layer is proposed, which could also be extended to understanding ICR at the nanoscale. Based on this model, we propose that when charges in the charged layer are comparable with those in the bulk layer, ICR would occur regardless of whether the electrical double layers are overlapped. Finite element simulations based on the solution of Poisson and Nernst-Planck equations and in situ confocal laser scanning microscopy results qualitatively validate the experimental observations and the proposed three-layer model. Moreover, possible factors influencing MICR, including the length of PimB, electrolyte concentration, and the radius of the pipet, are investigated and discussed. This study successfully extends ICR to the micrometer scale and thus opens a new door to the development of ICR-based devices by taking advantage of ease-in-manipulation and designable surface chemistry of micropipets. PMID- 28095692 TI - Mechanochemistry of One-Dimensional Boron: Structural and Electronic Transitions. AB - Recent production of long carbyne chains, concurrent with advances in the synthesis of pure boron fullerenes and atom-thin layers, motivates an exploration of possible one-dimensional boron. By means of first-principles calculations, we find two isomers, two-atom wide ribbon and single-atom chain, linked by a tension driven (negative-pressure) transformation. We explore the stability and unusual properties of both phases, demonstrating mechanical stiffness on par with the highest-performing known nanomaterials, and a phase transition between stable 1D metal and an antiferromagnetic semiconductor, with the phase boundary effectively forming a stretchable 1D Schottky junction. In addition, the two-phase system can serve as a constant-tension nanospring with a well-calibrated tension defined by enthalpic balance of the phases. Progress in the synthesis of boron nanostructures suggests that the predicted unusual behaviors of 1D boron may find powerful applications in nanoscale electronics and/or mechanical devices. PMID- 28095693 TI - Solvation Dynamics in Liquid Water. III. Energy Fluxes and Structural Changes. AB - In previous installments it has been shown how a detailed analysis of energy fluxes induced by electronic excitation of a solute can provide a quantitative understanding of the dominant molecular energy flow channels characterizing solvation-and in particular, hydration- relaxation dynamics. Here this work and power approach is complemented with a detailed characterization of the changes induced by such energy fluxes. We first examine the water solvent's spatial and orientational distributions and the assorted energy fluxes in the various hydration shells of the solute to provide a molecular picture of the relaxation. The latter analysis is also used to address the issue of a possible "inverse snowball" effect, an ansatz concerning the time scales of the different hydration shells to reach equilibrium. We then establish a link between the instantaneous torque, exerted on the water solvent neighbors' principal rotational axes immediately after excitation and the final energy transferred into those librational motions, which are the dominant short-time energy receptor. PMID- 28095694 TI - Effect of a pH Gradient on the Protonation States of Cytochrome c Oxidase: A Continuum Electrostatics Study. AB - Cytochrome c oxidase (CcO) couples the reduction of dioxygen to water with transmembrane proton pumping, which leads to the generation of an electrochemical gradient. In this study we analyze how one of the components of the electrochemical gradient, the difference in pH across the membrane, or DeltapH, influences the protonation states of residues in CcO. We modified our continuum electrostatics/Monte Carlo (CE/MC) method in order to include the DeltapH and applied it to the study of CcO, in what is, to our best knowledge, the first CE/MC study of CcO in the presence of a pH gradient. The inclusion of a transmembrane pH gradient allows for the identification of residues whose titration behavior depends on the pH on both sides of the membrane. Among the several residues with unusual titration profiles, three are well-known key residues in the proton transfer process of CcO: E286I, Y288I, and K362I. All three residues have been previously identified as being critical for the catalytic or proton pumping functions of CcO. Our results suggest that when the pH gradient increases, these residues may be part of a regulatory mechanism to stem the proton flow. PMID- 28095695 TI - Frontier Molecular Orbital Contributions to Chlorination versus Hydroxylation Selectivity in the Non-Heme Iron Halogenase SyrB2. AB - The ability of an FeIV?O intermediate in SyrB2 to perform chlorination versus hydroxylation was computationally evaluated for different substrates that had been studied experimentally. The pi-trajectory for H atom abstraction (FeIV?O oriented perpendicular to the C-H bond of substrate) was found to lead to the S = 2 five-coordinate HO-FeIII-Cl complex with the C* of the substrate, pi-oriented relative to both the Cl- and the OH- ligands. From this ferric intermediate, hydroxylation is thermodynamically favored, but chlorination is intrinsically more reactive due to the energy splitting between two key redox-active dpi* frontier molecular orbitals (FMOs). The splitting is determined by the differential ligand field effect of Cl- versus OH- on the Fe center. This makes chlorination effectively competitive with hydroxylation. Chlorination versus hydroxylation selectivity is then determined by the orientation of the substrate with respect to the HO-Fe-Cl plane that controls either the Cl- or the OH- to rebound depending on the relative pi-overlap with the substrate C radical. The differential contribution of the two FMOs to chlorination versus hydroxylation selectivity in SyrB2 is related to a reaction mechanism that involves two asynchronous transfers: electron transfer from the substrate radical to the iron center followed by late ligand (Cl- or OH-) transfer to the substrate. PMID- 28095696 TI - Properties of Lanthanide Hydroxide Molecules Produced in Reactions of Lanthanide Atoms with H2O2 and H2 + O2 Mixtures: Roles of the +I, +II, +III, and +IV Oxidation States. AB - The reactions of laser-ablated lanthanide metal atoms with hydrogen peroxide or hydrogen plus oxygen mixtures have been studied experimentally in a solid argon matrix and theoretically with the ab initio MP2 and CCSD(T) methods. The Ln(OH)3 and Ln(OH)2 molecules and Ln(OH)2+ cations are the major products, and the reactions to form those hydroxides are predicted to be highly exothermic at the CCSD(T) level. Vibronic interactions are hypothesized to contribute to the abnormalities in deuterium shifts for Ln-OH(D) stretching modes for several hydroxides, consistent with CASSCF calculations. Additional new absorptions were assigned as HLnO or LnOH and OLnOH molecules. The tetrahydroxides of Ce, Pr, and Tb have also been observed. These reactive intermediates were identified from their matrix infrared spectra by using D2O2, HD, D2, 16,18O2, and 18O2 isotopic substitution, by matching observed frequencies with values calculated by electronic structure methods, and by following the trends observed in frequencies going through different lanthanide metal hydroxide series across the periodic table. The lanthanides are in the +II oxidation state for Ln(OH)2 and are in the +III oxidation state for Ln(OH)3 and Ln(OH)2+. PMID- 28095697 TI - Diazo Esters as Dienophiles in Intramolecular (4 + 2) Cycloadditions: Computational Explorations of Mechanism. AB - The first experimental examples of Diels-Alder (DA) reactions of diazo compounds as heterodienophiles with dienes have been studied with density functional theory (DFT) using the M06-2X functional. For comparison, the reactivities of diazo esters as dienophiles or 1,3-dipoles with 1,3-dienes in intermolecular model systems have been analyzed by the distortion/interaction model. The 1,3-dipolar cycloaddition is strongly favored for the intermolecular system. The intramolecular example is unique because the tether strongly favors the (4 + 2) cycloaddition. PMID- 28095698 TI - Evaluation of the Coupled Two-Dimensional Main Chain Torsional Potential in Modeling Intrinsically Disordered Proteins. AB - Intrinsically disordered proteins (IDPs) carry out crucial biological functions in essential biological processes of life. Because of the highly dynamic and conformationally heterogeneous nature of the disordered states of IDPs, molecular dynamics simulations are becoming an indispensable tool for the investigation of the conformational ensembles and dynamic properties of IDPs. Nevertheless, there is still no consensus on the most reliable force field in molecular dynamics simulations for IDPs hitherto. In this work, the recently proposed AMBER99SB2D force field is evaluated in modeling some disordered polypeptides and proteins by checking its ability to reproduce experimental NMR data. The results highlight that when the ildn side-chain corrections are included, AMBER99SB2D-ildn exhibits reliable results that agree with experiments compared with its predecessors, the AMBER14SB, AMBER99SB, AMBER99SB-ildn, and AMBER99SB2D force fields, and that decreasing the overall magnitude of protein-protein interactions in favor of protein-water interactions is a key ingredient behind the improvement. PMID- 28095700 TI - Nanohybrids consisting of magnetic nanoparticles and gold nanoclusters as effective peroxidase mimics and their application for colorimetric detection of glucose. AB - Although protein-stabilized gold nanoclusters (AuNCs) have gathered recent attention as biocompatible peroxidase mimics, their practical utility has been critically limited by the low catalytic activity. Here, the authors have developed a nanohybrid material to significantly enhance the catalytic activity of AuNCs by combining them with other inorganic enzyme mimetics, Fe3O4 magnetic nanoparticles (MNPs), through electrostatic attraction. Owing to the synergistic effect by incorporating AuNCs and MNPs, the constructed nanohybrids yielded highly enhanced catalytic activity and enabled rapid catalytic oxidation of 3,3',5,5'-tetramethylbenzidine substrate to produce a blue-colored solution in proportional to the amount of H2O2. Moreover, a highly sensitive and selective glucose biosensing strategy was developed based on the coupled catalytic action between glucose oxidase and the nanohybrids. Using this method, target glucose was successfully detected in a linear concentration range from 150 to 750 MUM with a detection limit as low as 100 MUM. Along with excellent linearity, high precision and reproducibility were achieved by employing real human blood serums, which enables its use for the reliable quantification of glucose in practical use. Based on these results, the authors anticipate that the nanohybrids consisting of MNPs and AuNCs can serve as potent peroxidase mimics for the detection of clinically important target molecules. PMID- 28095701 TI - Malignant bowel obstruction in advanced ovarian cancer. AB - AIM: Malignant bowel obstruction (MBO) in ovarian cancer is poorly understood. METHODS: This retrospective cohort study analyzed 129 patients with ovarian cancer and MBO. RESULTS: At presentation, 69 (53%) had platinum-resistant, 37 (29%) platinum-sensitive and 23 (18%) chemotherapy-naive disease. In patients receiving chemotherapy following the MBO episode, median overall survival (OS) was 107 days for chemotherapy-naive patients compared with 83 and 86 for platinum sensitive or platinum-resistant patients (p = 0.98). OS was inferior for best supportive care (45 days) compared with chemotherapy (152 days) or surgery (124 days; p < 0.001). The Manchester Bowel Obstruction Score using Eastern Cooperative Oncology Group and obstruction level discriminated patients by median OS of 181 days (neither) versus 98 days (one) versus 42 days (both; p < 0.01). CONCLUSION: The Manchester Bowel Obstruction Score may aide treatment stratification. PMID- 28095702 TI - Sleep problems and suicide associated with mood instability in the Adult Psychiatric Morbidity Survey, 2007. AB - OBJECTIVE: Mood instability is common in the general population. Mood instability is a precursor to mental illness and associated with a range of negative health outcomes. Sleep disturbance appears to be closely linked with mood instability. This study assesses the association between mood instability and sleep disturbance and the link with suicidal ideation and behaviour in a general population sample in England. METHOD: The Adult Psychiatric Morbidity Survey, 2007 collected detailed information about mental health symptoms and correlates in a representative sample of adult household residents living in England ( n = 7303). Mood instability was assessed using the Structured Clinical Interview for DSM-IV Axis-II. Sleep problems were defined as sleeping more than usual or less than usual during the past month. Other dependent variables included medication use and suicidal ideation and behaviour (response rate 57%). Generalized linear modelling was used to estimate the prevalence of mood instability and sleep problems. Logistic regression was used to estimate odds ratios. All estimates were weighted. RESULTS: The prevalence of mood instability was 14.7% (95% confidence interval [13.6%, 15.7%]). Sleep problems occurred in 69.8% (95% confidence interval: [66.6%, 73.1%]) of those with mood instability versus 37.6% (95% confidence interval: [36.2%, 39.1%]) of those without mood instability. The use of sedating and non-sedating medications did not influence the association. Sleep problems were significantly associated with suicidal ideation and behaviour even after adjusting for mood instability. CONCLUSION: Sleep problems are highly prevalent in the general population, particularly among those with mood instability. Sleep problems are strongly associated with suicidal ideation and behaviour. Treatments that target risk and maintenance factors that transcend diagnostic boundaries, such as therapies that target sleep disturbance, may be particularly valuable for preventing and addressing complications related to mood instability such as suicide. PMID- 28095703 TI - Outcomes of the Distal Metatarsal Dorsiflexion Osteotomy for Advanced Hallux Rigidus. AB - BACKGROUND: Hallux rigidus can be treated using several different methods and the best treatment option depends on the severity of degenerative changes of the metatarsophalangeal (MTP) joint. However, the ideal operative option for advanced hallux rigidus remains debatable. This prospective study was performed to evaluate the intermediate-term clinical outcomes of distal metatarsal osteotomy used as a joint-preserving method for the treatment of advanced hallux rigidus. METHODS: Forty-two cases (39 patients) were followed for more than 3 years after distal metatarsal dorsiflexion osteotomy for advanced hallux rigidus of grade III IV. Clinical evaluations included the American Orthopaedic Foot & Ankle Society (AOFAS) scores, Foot and Ankle Ability Measure (FAAM) scores, and patient subjective satisfaction scores. Range of motion (ROM) of great toe, complications, reoperation rates, width of the MTP joint space, and times to union were evaluated. RESULTS: Mean AOFAS hallux and mean FAAM scores significantly improved from 56.4 and 61.2 points preoperatively to 87.6 and 88.7 points at final follow-up, respectively ( P < .001). Grade III and IV groups had significantly different AOFAS and FAAM scores at final follow-up. Mean dorsiflexion of great toe significantly improved from 14.8 degrees preoperatively to 35.5 degrees at final follow-up ( P < .001). Mean patient satisfaction score at final follow-up was 92.8 points. There were 4 cases (9.5%) of subsequent fusion and 2 cases (4.8%) of transfer metatarsalgia. CONCLUSIONS: Distal metatarsal dorsiflexion osteotomy using bio-compression screws appears to be an effective operative option for grade III advanced hallux rigidus with viable cartilage on >50% of the first metatarsal articular surface, as it restored joint motion, provided reliable pain relief, and did not require implant removal. However, based on the unsatisfactory clinical results and the high rate of reoperation observed, the authors cannot recommend this operative method for the treatment of end-stage (grade IV) hallux rigidus. LEVEL OF EVIDENCE: Level IV, prospective case series. PMID- 28095704 TI - A pilot study examining the effects of priming headache illness schema on attentional engagement towards pain relief medication, in those with high and low medication treatment beliefs. AB - Few studies have assessed the underlying theoretical components of the Common Sense Model. Past studies have found, through implicit priming, that coping strategies are embedded within illness schema. Our aim was to evaluate the effect priming 'headache' illness schema upon attentional engagement to pain relief medication and to examine the interaction with illness treatment beliefs. Attentional engagement to the pain relief medication ('Paracetamol') was assessed using a 2 (primed vs. control) * 2 (strong belief in medication efficacy vs. weak belief in medication efficacy) design. During a grammatical decision task (identifying verbs/non-verbs), participants were randomised to receive a headache prime or a control. Response latency to the target word, 'Paracetamol' was the dependent variable. 'Paracetamol' treatment beliefs were determined using the brief illness perception questionnaire. Sixty-three participants completed the experiment. There was a significant interaction between illness-primed vs. control and high vs. low treatment efficacy of Paracetamol (p < .001), suggesting an attentional disengagement effect to the coping strategy in illness-primed participants whom held stronger treatment beliefs regarding the efficacy of Paracetamol. In summary, implicit illness schema activation may simultaneously activate embedded coping strategies, which appears to be moderated by specific illness beliefs. PMID- 28095705 TI - What's the story? A computational analysis of narrative competence in autism. AB - Individuals with autism spectrum disorder demonstrate narrative (i.e. storytelling) difficulties which can significantly impact their ability to form and maintain social relationships. However, existing research has not comprehensively documented these impairments in more open-ended, emotionally evocative situations common to daily interactions. Computational linguistic measures offer a promising complement to traditional hand-coding methods of narrative analysis and in this study were applied together with hand coding of narratives elicited with emotionally salient scenes from the Thematic Apperception Test. In total, 19 individuals with autism spectrum disorder and 14 typically developing controls were asked to tell stories about six images from the Thematic Apperception Test. Both structural and qualitative aspects of narrative were assessed using a hand-coding system and Latent Semantic Analysis, an automated computational measure of semantic similarity. Individuals with autism spectrum disorder demonstrated significant difficulties with the use of complex syntax to integrate their narratives and problems explaining characters' intentions. These and other key narrative skills were strongly related to narrative competence scores derived from Latent Semantic Analysis, which also distinguished the autism spectrum disorder group from controls. Together, results underscore key narrative impairments in autism spectrum disorder and support the promise of Latent Semantic Analysis as a valuable tool for the quantitative assessment of complex language abilities. PMID- 28095706 TI - Translation and pilot testing of a measure to assess hypertension self-care activities among Hispanics. AB - OBJECTIVE: Hispanics in the US have high rates of uncontrolled hypertension in comparison to non-Hispanic whites. This pilot study reports on the translation of a validated measure, the Hypertension Self-Care Activity Level Effects (H-SCALE), for use with Spanish speakers. The H-SCALE assesses Hispanics' adherence to lifestyle activities that contribute to primary and secondary risk reduction of high blood pressure. DESIGN: Cross-sectional data were collected from Hispanic primary care patients attending a free health clinic in Charlotte, NC. We performed basic psychometric tests and calculated descriptive statistics to assess adherence rates to recommended hypertension self-care behaviors. RESULTS: Participants were primarily female, under age 50 and had a high-school education or less; 48% were from Mexico. Internal consistency of all H-SCALE subscales was acceptable to good. Most participants were non-smokers (80%) and alcohol abstainers (85%). Participants had low adherence to weight management practices, physical activity and healthy eating habits. One-third of those with hypertension were adherent to medication regimens. CONCLUSION: The Spanish version of the H SCALE is a reliable and useful tool for clinicians working with Hispanic adults. Based on these findings, all adult Hispanics need lifestyle behavior counseling for primary and secondary prevention of hypertension and other chronic diseases. The H-SCALE can provide valuable information to clinical and public health practitioners focused on chronic disease prevention and management. PMID- 28095707 TI - Variations in mesothelioma mortality rates among migrants to Australia and Australian-born. AB - BACKGROUND: Australia's use and consumption of asbestos occurred at the same time as its immigration boom. Our objective was to investigate mesothelioma death rates among migrants and Australian-born between 1981 and 2012. METHODS: Australian national mesothelioma deaths from 1981 to 2002 and 2006 to 2012 together with national censuses from 1981 to 2011 were extracted and combined. Directly standardised rates and negative binomial regression were applied examining differences in mesothelioma death rates with regard to country of birth. RESULTS: Migrants from the UK and Ireland, Italy and Germany had significantly higher mesothelioma death rates than Australian-born; lower rates were observed among migrants from other countries. CONCLUSIONS: Our findings suggest there may have been differences in occupational health and safety between foreign and Australian-born. Because of changes in the demographics of migrants to Australia since the 1970s and changes in occupational circumstances over time, further comparisons of occupational-related health outcomes between foreign and Australian-born could identify potential occupational inequalities that may still exist today. PMID- 28095708 TI - Locational comparison of essential oils from selected conifers of Himachal Pradesh. AB - Nine samples of essential oil from needles of three conifers of Pinacea family namely Abies pindrow, Picea smithiana and Cedrus deodara collected from three different locations of Himachal Pradesh (India) were evaluated using gas chromatography and gas chromatography-mass spectrometry. A total of 31, 17 and 13 compounds were identified from essential oil of A. pindrow, P. smithiana and C. deodara, respectively. Among the characterised components, monoterpenoid hydrocarbons were predominated. alpha-Pinene, beta-pinene, beta-merycene, limonene and camphene were characterised as major components. Oil of C. deodara has significant effect of location on its oil composition. Principle component analysis on gas chromatographic data reveals variation in chemical composition which may be attributed to altitude and environmental conditions. PMID- 28095709 TI - Worldwide Trends of Urinary Stone Disease Treatment Over the Last Two Decades: A Systematic Review. AB - INTRODUCTION: Numerous studies have reported on regional or national trends of stone disease treatment. However, no article has yet examined the global trends of intervention for stone disease. METHODS AND MATERIALS: A systematic review of articles from 1996 to September 2016 for all English language articles reporting on trends of surgical treatment of stone disease was performed. Authors were contacted in the case of data not being clear. If the authors did not reply, data were estimated from graphs or tables. Results were analyzed using SPSS version 21, and trends were analyzed using linear regression. RESULTS: Our systematic review yielded 120 articles, of which 8 were included in the initial review. This reflected outcomes from six countries with available data: United Kingdom, United States, New Zealand, Australia, Canada, and Brazil. Overall ureteroscopy (URS) had a 251.8% increase in total number of treatments performed with the share of total treatments increasing by 17%. While the share of total treatments for percutaneous nephrolithotomy (PCNL) remained static, the share for extracorporeal shockwave lithotripsy and open surgery fell by 14.5% and 12%, respectively. There was significant linear regression between rising trends of total treatments year on year for URS (p < 0.001). CONCLUSION: In the last two decades, the share of total treatment for urolithiasis across the published literature has increased for URS, stable for PCNL, and decreased for lithotripsy and open surgery. PMID- 28095710 TI - The evolving role of chemotherapy in prostate cancer. AB - Despite extensive clinical research of different chemotherapy agents for more than three decades, the role of chemotherapy in prostate cancer was only established in 2004, after demonstrating a survival benefit with docetaxel in metastatic castration-resistant prostate cancer. 6 years later, second-line chemotherapy using cabazitaxel, after disease progression on docetaxel, demonstrated an additional survival improvement. Recently, docetaxel given alongside standard hormonal therapy in newly diagnosed advanced prostate cancer was found to lead to significantly improved patient outcomes. This article aims to cover the role of chemotherapy in prostate cancer and the latest developments. PMID- 28095711 TI - Systemic alkalinisation delays prostate cancer cell progression in TRAMP mice. AB - The microenvironment of solid tumours is extremely acidic and this condition arises since the precancerous stage. This acidic milieu could therefore provide a useful target for both prophylactic and therapeutic approaches. In TRAMP transgenic mice, an in vivo model of prostate adenocarcinoma (AC), oral administration of alkaline water was devoid of unwanted side effects, and when started from an early age was as effective as NaHCO3 in significantly delaying tumour progression, while when started when prostate tumours were already present, a nonstatistically significant trend in the same direction was detected. These findings indicate that the use of alkalinizing drugs should be considered for chemoprevention and, in association with standard chemotherapy, for treatment of human prostate AC. PMID- 28095713 TI - Disseminated eruptive granuloma annulare induced by levetiracetam. AB - Granuloma annulare (GA) is a benign, granulomatous cutaneous disease without clear etiology. Disseminated and drug induced granuloma annulare is a rare presentation. We present a 47-year-old woman with diffuse circular erythematous eruptions following treatment with levetiracetam. Her clinical and histopathological findings were compatible with the diagnosis of granuloma annulare. To the best of our knowledge, there is no previous report of this skin disease as a result of levetiracetam use. We report this case to highlight this antiepileptic drug as a possible etiologic agent in disseminated granuloma annulare. PMID- 28095712 TI - Current views on the potential for development of a HIV vaccine. AB - INTRODUCTION: Despite many recent advances in the HIV prevention landscape, an effective vaccine remains the most promising tool to end the HIV-1 pandemic. Areas covered: This review summarizes past HIV vaccine efficacy trials and current vaccine strategies as well as new approaches about to move into first-in human trials. Expert opinion: Despite many setbacks in early HIV vaccine efficacy trials, the success of RV144 has provided the glimmer of hope necessary to invigorate the vaccine field, and has led to the development of a large number of vaccine strategies aiming at inducing an array of different immune responses. The follow-up pox-protein trials, developed to replicate and enhance the polyfunctional antibody responses induced by the RV144 regimen, are already reaching efficacy trials, while a large body of work providing a more complete understanding of the development of broadly neutralizing antibodies is now being translated into immunogen design using several different strategies. T-cell based vaccines, fallen out of favor after Ad5-based trials showed increased infection rates in Ad5 seropositive vaccine recipients, are experiencing a comeback based in part on the promising results from non-human primate challenge studies using rhCMV-based immunogens. This diverse array of vaccine candidates may finally allow us to identify a broadly effective HIV vaccine able to contain the epidemic. PMID- 28095714 TI - Disease-related and drug-induced skin manifestations in inflammatory bowel disease. AB - INTRODUCTION: Skin manifestations are common in patients with inflammatory bowel diseases (IBD) and can be part of a concomitant illness with a shared genetic background, an extra-intestinal manifestation of the disease, or a drug side effect. Areas covered: We provide a practical overview of the epidemiology, pathogenesis, diagnosis, therapeutic approach and prognosis of the most frequent disease-related and drug-induced cutaneous manifestations in IBD, illustrated by cases encountered in our clinical practice. Among the most frequently encountered IBD-related lesions are erythema nodosum, pyoderma gangrenosum and Sweet's syndrome. Common skin manifestations with a strong association to TNF antagonists are local injection site reactions, psoriasiform lesions, cutaneous infections, vasculitides and lupus-like syndromes. In addition, we discuss the relation of thiopurines and TNF antagonists with the risk of skin cancer. Expert commentary: We hope this review will help caretakers involved in the management of IBD patients to recognize the lesions and to manage them in close collaboration with a dedicated dermatologist. PMID- 28095715 TI - An overview of aldehyde oxidase: an enzyme of emerging importance in novel drug discovery. AB - INTRODUCTION: Given the rising trend in medicinal chemistry strategy to reduce cytochrome P450-dependent metabolism, aldehyde oxidase (AOX) has recently gained increased attention in drug discovery programs and the number of drug candidates that are metabolized by AOX is steadily growing. Areas covered: Despite the emerging importance of AOX in drug discovery, there are certain major recognized problems associated with AOX-mediated metabolism of drugs. Intra- and inter species variations in AOX activity, the lack of reliable and predictive animal models using the common experimental animals, and failure in the predictions of in vivo metabolic activity of AOX using traditional in vitro methods are among these issues that are covered in this article. A comprehensive review of computational human AOX (hAOX) related studies are also provided. Expert opinion: Following the recent progress in the stem cell field, the authors recommend the application of organoids technology as an effective tool to solve the fundamental problems associated with the evaluation of AOX in drug discovery. The recent success in resolving the hAOX crystal structure can too be another valuable data source for the study of AOX-catalyzed metabolism of new drug candidates, using computer-aided drug discovery methods. PMID- 28095716 TI - CircRNAs: a regulator of cellular stress. AB - Circular RNAs (CircRNAs) were first identified as a viroid and later found to also be an endogenous RNA splicing product in eukaryotes. In recent years, a series of RNA-sequencing analyses from a diverse range of eukaryotes have shed new light on these eukaryotic circRNAs, revealing dynamic expression patterns in various developmental stages and physiological conditions. In this review, we focus on circRNAs implicated in stress response pathways and explore potential mechanisms underlying their regulation. To date, circRNAs have been shown to act as scaffolds in the assembly of protein complexes, sequester proteins from native subcellular localization, activate transcription of parental genes, inhibit RNA protein interactions, and function as regulators of microRNA activity. Although the mechanism modulating circRNA levels during stress remains unclear, circRNAs are shown to be regulated during biogenesis, degradation, and exportation. As circRNAs do not have 5' and 3' ends, there are no entry points for exoribonucleases to initiate degradation. Such inherent stability makes this class of RNA a strong candidate to maintain homeostasis in the face of environmental challenges. PMID- 28095718 TI - Key players associated with tuberization in potato: potential candidates for genetic engineering. AB - Tuberization in potato (Solanum tuberosum L.) is a complex biological phenomenon which is affected by several environmental cues, genetic factors and plant nutrition. Understanding the regulation of tuber induction is essential to devise strategies to improve tuber yield and quality. It is well established that short day photoperiods promote tuberization, whereas long days and high-temperatures inhibit or delay tuberization. Worldwide research on this complex biological process has yielded information on the important bio-molecules (proteins, RNAs, plant growth regulators) associated with the tuberization process in potato. Key proteins involved in the regulation of tuberization include StSP6A, POTH1, StBEL5, StPHYB, StCONSTANS, Sucrose transporter StSUT4, StSP5G, etc. Biomolecules that become transported from "source to sink" have also been suggested to be important signaling candidates regulating the tuberization process in potatos. Four molecules, namely StSP6A protein, StBEL5 RNA, miR172 and GAs, have been found to be the main candidates acting as mobile signals for tuberization. These biomolecules can be manipulated (overexpressed/inhibited) for improving the tuberization in commercial varieties/cultivars of potato. In this review, information about the genes/proteins and their mechanism of action associated with the tuberization process is discussed. PMID- 28095717 TI - Functional constituents of wild and cultivated Goji (L. barbarum L.) leaves: phytochemical characterization, biological profile, and computational studies. AB - Goji (Lycium barbarum L.) leaves are emphasized as a functional tea or as dietary supplements. The phenolic compound profile, antioxidant, enzyme inhibitory, antimicrobial, and antimutagenic activities of leaf extracts from two selected cultivars in comparison with wild-growing plants have been evaluated. HPLC DAD/ESI-ToF-MS analysis revealed the presence of phenolic acids and flavonoids with chlorogenic acid and rutin being the dominant compounds in the cultivated plants, whereas rutin and kaempeferol-3-O-rutinoside for wild growing ones. In particular, cv. Erma contained the highest amount of chlorogenic acid and showed a strong tyrosinase-inhibitory effect. Staphylococcus aureus, Listeria monocytogenes, and Penicillium funiculosum were the most sensitive strains when exposed to extracts from cultivated plants. Antimutagenic activity was evaluated by Ames' test. The tested extracts provided high protection against mutagenicity induced by 2-anthramine (2-AA) to Salmonella typhimurium strains TA 98 and TA 100 (max. inhibition (%) 88% and 74.2%, respectively). Overall, Goji leaves are a rich source of bioactive compounds with functional properties that need further risk/benefit evaluation when used in foods or health-promoting formulations. PMID- 28095719 TI - The importance of translatability in drug discovery. PMID- 28095720 TI - Baseline chromogranin A and its dynamics are prognostic markers in gastroenteropancreatic neuroendocrine tumors. AB - AIM: This study assessed whether absolute chromogranin A (CgA) values at various stages of treatment have prognostic value in patients with pancreatic and midgut neuroendocrine tumors, subjected to peptide receptor radionuclide therapy with 90Y-[DOTA0, D-Phe1, Tyr3]-octreotate. PATIENTS & METHODS: CgA was determined before peptide receptor radionuclide therapy, 6 weeks, 6, 12, 18 and 24 months after the last dose of 90Y-[DOTA0, D-Phe1, Tyr3]-octreotate. The primary end point was overall survival. RESULTS: Elevated baseline CgA concentrations and their relative increase within the first year of observation were unfavorable predictors of overall survival, but not progression. CONCLUSION: Even a single baseline measurement of CgA can be useful in establishing prognosis in this group, if this parameter exceeds its upper normal limit more than tenfold. PMID- 28095721 TI - A lateral dynamics of a wheelchair: identification and analysis of tire parameters. AB - In vehicle dynamics studies, the tire behaviour plays an important role in planar motion of the vehicle. Therefore, a correct representation of tire is a necessity. This paper describes a mathematical model for wheelchair tire based on the Magic Formula model. This model is widely used to represent forces and moments between the tire and the ground; however some experimental parameters must be determined. The purpose of this work is to identify the tire parameters for the wheelchair tire model, implementing them in a dynamic model of the wheelchair. For this, we developed an experimental test rig to measure the tires parameters for the lateral dynamics of a wheelchair. This dynamic model was made using a multi-body software and the wheelchair behaviour was analysed and discussed according to the tire parameters. The result of this work is one step further towards the understanding of wheelchair dynamics. PMID- 28095722 TI - Racial and ethnic differences in the relationship between antenatal stressful life events and postpartum depression among women in the United States: does provider communication on perinatal depression minimize the risk? AB - OBJECTIVE: Multi-state population-based studies exploring the racial/ethnic differences in the prevalence and correlates of postpartum depression (PPD), which affects 10-20% of women in the US, are rare. The aim of this study was to examine the racial/ethnic disparities in the relationship between antenatal stressful life events and PPD among US women and to explore whether antenatal health care provider communication on perinatal depression was associated with a lower risk. METHODS: Data from the 2009-2011 Pregnancy Risk Assessment Monitoring System (PRAMS) were used. For each racial/ethnic group, the distribution of PPD was compared according to different levels of the stressors and socio demographic, pre-pregnancy, antenatal, delivery, and neonatal characteristics. Multivariable logistic regression analyses were performed with PPD as the outcome and all variables that were significant in bivariate analyses as predictors. RESULTS: Eleven percent of 87,565 women met the criteria for PPD with the prevalence ranging from 7.9% among Asian/Pacific Islanders to 14% among American Indian/Alaska Natives. Irrespective of race/ethnicity, having many bills to pay and having more than usual arguments with husband/partner were risk factors for PPD. Among non-Hispanic black (NHB) women, having a husband/partner who did not want the pregnancy was associated with PPD (adjusted odds ratio [aOR]: 1.47; 95% confidence interval [CI]: 1.14, 1.90), and among non-Hispanic whites (NHWs), drug/drinking problems of someone close was associated with PPD (aOR: 1.37; 95% CI: 1.21, 1.55). Provider communication was inversely associated with PPD among NHWs (aOR: 0.77; 95% CI: 0.69, 0.85) and NHBs (aOR: 0.74; 95% CI: 0.60, 0.93). CONCLUSION: The protective effect of provider communication on PPD suggests the benefit of a simple conversation about perinatal depression during antenatal care. Furthermore, risk factors for PPD varied by race/ethnicity suggesting that these vulnerabilities should be taken into consideration in identifying women at risk for PPD. PMID- 28095723 TI - Increased long-term mortality after survival of invasive pneumococcal disease: a population-based study. AB - OBJECTIVES: We studied if patients surviving hospitalization for invasive pneumococcal disease (IPD) have an increased long-term mortality. METHODS: In this population-based case-control study, we assessed adults discharged from Aker University Hospital in Oslo, Norway, from 1993 to 2008 after surviving IPD. Mortality among the study population was compared to the general Norwegian population using standardized mortality ratios (SMR). Median follow-up time was 7.2 years (range 5 days to 21.1 years). Associated factors were also investigated. RESULTS: We assessed 372 patients of whom 184 patients died during the observation period. Mortality was increased for 10 years after surviving hospitalization for IPD. Patients aged 18-64 years had a one-year SMR of 18.8 (95% CI: 10.0-32.1) and a 10-year SMR of 6.0 (95% CI: 4.4-8.0). SMR for the first five years among patients with and without underlying conditions were 10.7 (95% CI: 7.0-15.5) and 2.8 (95% CI: 0.9-6.4), respectively. Patients older than 65 years had a one-year SMR of 1.8 (95% CI: 1.2-2.7) and a 10-year SMR of 1.6 (95% CI: 1.4-1.9). CONCLUSIONS: Patients surviving IPD had an increased long-term mortality compared to the general population. This was particularly pronounced in patients with known underlying conditions. These findings suggest that IPD is a negative prognostic marker, and that a closer follow-up of patients who have suffered IPD is warranted. PMID- 28095724 TI - Reverse hybrid total hip arthroplasty. AB - Background and purpose - The use of a cemented cup together with an uncemented stem in total hip arthroplasty (THA) has become popular in Norway and Sweden during the last decade. The results of this prosthetic concept, reverse hybrid THA, have been sparsely described. The Nordic Arthroplasty Register Association (NARA) has already published 2 papers describing results of reverse hybrid THAs in different age groups. Based on data collected over 2 additional years, we wanted to perform in depth analyses of not only the reverse hybrid concept but also of the different cup/stem combinations used. Patients and methods - From the NARA, we extracted data on reverse hybrid THAs from January 1, 2000 until December 31, 2013. 38,415 such hips were studied and compared with cemented THAs. The Kaplan-Meier method and Cox regression analyses were used to estimate the prosthesis survival and the relative risk of revision. The main endpoint was revision for any reason. We also performed specific analyses regarding the different reasons for revision and analyses regarding the cup/stem combinations used in more than 500 cases. Results - We found a higher rate of revision for reverse hybrids than for cemented THAs, with an adjusted relative risk of revision (RR) of 1.4 (95% CI: 1.3-1.5). At 10 years, the survival rate was 94% (CI: 94-95) for cemented THAs and 92% (95% CI: 92-93) for reverse hybrids. The results for the reverse hybrid THAs were inferior to those for cemented THAs in patients aged 55 years or more (RR =1.1, CI: 1.0-1.3; p < 0.05). We found a higher rate of early revision due to periprosthetic femoral fracture for reverse hybrids than for cemented THAs in patients aged 55 years or more (RR =3.1, CI: 2.2-4.5; p < 0.001). Interpretation - Reverse hybrid THAs had a slightly higher rate of revision than cemented THAs in patients aged 55 or more. The difference in survival was mainly caused by a higher incidence of early revision due to periprosthetic femoral fracture in the reversed hybrid THAs. PMID- 28095725 TI - Geospatial clustering in sugar-sweetened beverage consumption among Boston youth. AB - The objective was to detect geospatial clustering of sugar-sweetened beverage (SSB) intake in Boston adolescents (age = 16.3 +/- 1.3 years [range: 13-19]; female = 56.1%; White = 10.4%, Black = 42.6%, Hispanics = 32.4%, and others = 14.6%) using spatial scan statistics. We used data on self-reported SSB intake from the 2008 Boston Youth Survey Geospatial Dataset (n = 1292). Two binary variables were created: consumption of SSB (never versus any) on (1) soda and (2) other sugary drinks (e.g., lemonade). A Bernoulli spatial scan statistic was used to identify geospatial clusters of soda and other sugary drinks in unadjusted models and models adjusted for age, gender, and race/ethnicity. There was no statistically significant clustering of soda consumption in the unadjusted model. In contrast, a cluster of non-soda SSB consumption emerged in the middle of Boston (relative risk = 1.20, p = .005), indicating that adolescents within the cluster had a 20% higher probability of reporting non-soda SSB intake than outside the cluster. The cluster was no longer significant in the adjusted model, suggesting spatial variation in non-soda SSB drink intake correlates with the geographic distribution of students by race/ethnicity, age, and gender. PMID- 28095726 TI - Male professional footballers' experiences of mental health difficulties and help seeking. AB - OBJECTIVES: Male professional footballers (soccer) represent an at-risk population of developing mental health difficulties and not accessing professional support. One in four current footballers report mental health difficulties. Higher prevalence is reported after retirement. This qualitative study aimed to provide in-depth insight into male professional footballers' lived experiences of mental health difficulties and help-seeking. METHODS: Seven participants were interviewed. Data were analysed using interpretative phenomenological analysis. RESULTS: One superordinate theme emerged; 'Survival'. This related to survival in the professional football world, of mental health difficulties and after transition into the 'real world'. Six subordinate themes are explored alongside literature pertaining to male mental health, identity, injury, transition, and emotional development. Shame, stigma, fear and level of mental health literacy (knowledge of mental health and support) were barriers to help-seeking. CONCLUSION: Support for professional footballers' mental wellbeing requires improvement. Recommendations are made for future research, mental health education and support. PMID- 28095727 TI - Mentor mother support for mothers experiencing intimate partner violence in family practice: A qualitative study of three different perspectives on the facilitators and barriers of implementation. AB - BACKGROUND: Intimate partner violence (IPV) is highly prevalent and associated with physical and mental health problems. Mentor mother support is a low threshold intervention in family practice consisting of support by non professionals trained to support mothers experiencing IPV. A mentor mother support study showed reduced exposure to IPV and decreased symptoms of depression. OBJECTIVES: Identify factors determining implementation success of mentor mother support in family practice. METHODS: Individual interviews were conducted with 12 family physicians, 16 abused mothers and three mentor mothers. Four mentor mothers participated in a focus group. Qualitative content analysis was used to analyse the data. RESULTS: The identification and discussion of abuse is hindered by family physicians' attitudes because they considered mothers experiencing IPV as a difficult target group with a responsibility of their own to break out of their violent situation. Some family physicians doubted the partner's violence because he was known as a patient as well. Acceptance of mentor mother support is related to the readiness for change of mothers experiencing IPV. Mentor mothers facilitate acceptance and completion of their support by connecting as a friend who is equal and less threatening than professionals. CONCLUSION: To improve successful implementation of mentor mother support in primary care, we should focus on family physicians' attitudes towards IPV. To change these attitudes, we recommend continuous training of family physicians. By being paraprofessional friends, mentor mothers offer low threshold support that is complementary to professional support and should be embedded more widely in primary care. [Box: see text]. PMID- 28095728 TI - Dental Prophylaxis and Osteoradionecrosis: A Population-Based Study. AB - The aim of this study was to investigate the association of different dental prophylactic modalities and osteoradionecrosis (ORN) and determine the risk of ORN under different timing periods of scaling, with the use chlorhexidine mouth rinse after surgery and with different strategies of fluoride gel application in head and neck cancer (HNC) participants. A cohort of 18,231 HNC participants, including 941 ORN patients and 17,290 matched control cases, were enrolled from a Longitudinal Health Insurance Database for Catastrophic Illness Patients (LHID CIP) in Taiwan. Based on different dental prophylactic modalities before radiotherapy, including chlorhexidine mouth rinse, scaling, and fluoride gel, all HNC subjects were stratified into different groups. The Cox proportional hazard regression was used to compare ORN incidences under different dental prophylactic modalities. The results revealed that scaling and chlorhexidine mouth rinse were significantly related to ORN risk ( P = 0.004 and P < 0.0001). Chlorhexidine mouth rinse was highly correlated to ORN occurrence (hazard ratio [HR], 1.83 2.66), as exposure increased the risk by 2.43-fold among oral cancer patients, regardless of whether they had received major oral surgery or not. Oral cancer patients receiving scaling within 2 wk before radiotherapy increased their incidence of ORN by 1.28-fold compared with patients who had not undergone scaling within 6 mo. There is no significance of fluoride application for dental prophylaxis in increasing ORN occurrence. In conclusion, dental prophylaxis before radiotherapy is strongly correlated to ORN in HNC patients. Chlorhexidine exposure and dental scaling within 2 wk before radiotherapy is significantly related to ORN risk, especially in oral cancer patients. The use of 1.1% NaF topical application did not significantly increase the risk of ORN in HNC patients. An optimal dental prophylaxis protocol to reduce ORN should concern cancer location, cautious prescription of chlorhexidine mouth rinse, and proper timing of scaling. PMID- 28095729 TI - Impact of reactive oxygen species generation on Helicobacter pylori-related extragastric diseases: a hypothesis. AB - Helicobacter pylori (H. pylori) induces reactive oxygen species (ROS) production that contribute to pathogenesis of a variety of H. pylori-related gastric diseases, as shown in animal and human studies. Helicobacter pylori infection is also associated with variety of systemic extragastric diseases in which H. pylori related ROS production might also be involved in the pathogenesis of these systemic conditions. We proposed that Hp-related ROS may play a crucial role in the pathophysiology of Hp-related systemic diseases including Alzheimer's disease, multiple sclerosis, glaucoma and other relative neurodegenerative diseases, thereby suggesting introduction of relative ROS scavengers as therapeutic strategies against these diseases which are among the leading causes of disability and are associated with a large public health global burden. Moreover, we postulated that H. pylori-related ROS might also be involved in the pathogenesis of extragastric common malignancies, thereby suggesting that H. pylori eradication might inhibit the development or delay the progression of aforementioned diseases. However, large-scale future studies are warranted to elucidate the proposed pathophysiological mechanisms, including H. pylori-related ROS, involved in H. pylori-associated systemic and malignant conditions. PMID- 28095730 TI - Anaerobic biodegradation of spiramycin I and characterization of its new metabolites. AB - Activated sludge was used to treat the wastewater containing spiramycin I. Three new metabolites were isolated and identified, which produced by oxidation of C6 aldehyde, hydrolysis of C5-mycaminose-mycarose and macrolactone ring-open reaction of spiramycin I in anaerobic digestion. And their antimicrobial activities were inactivated. Our results indicated that anaerobic biodegradation metabolites of spiramycin I could not induce bacterial resistance in environment. PMID- 28095731 TI - N-Palmitoylethanolamine-Oxazoline as a New Therapeutic Strategy to Control Neuroinflammation: Neuroprotective Effects in Experimental Models of Spinal Cord and Brain Injury. AB - Modulation of N-acylethanolamine-hydrolyzing acid amidase (NAAA) represents a potential alternative strategy in the treatment of neuroinflammation. Recent studies showed that pharmacological modulation of NAAA could be achieved with the oxazoline of palmitoylethanolamide (PEA; PEA-OXA). The aim of this study was to evaluate the neuroprotective effects of PEA-OXA in the secondary neuroinflammatory events induced by spinal and brain trauma in mice. Animals were subjected to spinal cord and brain injury models and PEA-OXA (10 mg/kg) was administered both intraperitoneally and orally 1 h and 6 h after trauma. PEA-OXA treatment markedly reduced the histological alterations induced by spinal cord injury (SCI) and traumatic brain injury (TBI) and ameliorated the motor function and behavioral deficits, as well. In addition, the expression of neurotrophic factors, such as glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, and neurotrophin-3 were increased by PEA-OXA treatment. Moreover, PEA-OXA also significantly decreased glial fibrillary acidic protein hyperexpression, the nuclear translocation of nuclear factor (NF)-kappaB, phosphorylation of Ser536 on the NF-kappaB subunit p65, and degradation of IkappaB-alpha, as well as diminished the expression of pro-inflammatory mediators such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta. The modulation of intracellular NAAA by PEA-OXA treatment could thus represent a novel therapy to control neuroinflammatory conditions associated with SCI and TBI. PMID- 28095732 TI - An online survey of tobacco smoking cessation associated with naturalistic psychedelic use. AB - Data suggest psychedelics such as psilocybin and lysergic acid diethylamide (LSD) may hold therapeutic potential in the treatment of addictions, including tobacco dependence. This retrospective cross-sectional anonymous online survey characterized 358 individuals (52 females) who reported having quit or reduced smoking after ingesting a psychedelic in a non-laboratory setting ?1 year ago. On average, participants smoked 14 cigarettes/day for 8 years, and had five previous quit attempts before their psychedelic experience. Of the 358 participants, 38% reported continuous smoking cessation after psychedelic use (quitters). Among quitters, 74% reported >2 years' abstinence. Of the 358 participants, 28% reported a persisting reduction in smoking (reducers), from a mode of 300 cigarettes/month before, to a mode of 1 cigarette/month after the experience. Among reducers, 62% reported >2 years of reduced smoking. Finally, 34% of the 358 participants (relapsers) reported a temporary smoking reduction before returning to baseline smoking levels, with a mode time range to relapse of 3-6 months. Relapsers rated their psychedelic experience significantly lower in personal meaning and spiritual significance than both other groups. Participants across all groups reported less severe affective withdrawal symptoms (e.g. depression, craving) after psychedelic use compared with previous quit attempts, suggesting a potential mechanism of action for psychedelic-associated smoking cessation/reduction. Changes in life priorities/values were endorsed as the most important psychological factor associated with smoking cessation/reduction. Results suggest psychedelics may hold promise in treating tobacco addiction as potentially mediated by spiritual experience, changed priorities/values, and improved emotional regulation. PMID- 28095733 TI - Decoding Crucial LncRNAs Implicated in Neurogenesis and Neurological Disorders. AB - Unraveling transcriptional heterogeneity and the labyrinthine nature of neurodevelopment can probe insights into neuropsychiatric disorders. It is noteworthy that adult neurogenesis is restricted to the subventricular and subgranular zones of the brain. Recent studies suggest long non-coding RNAs (lncRNAs) as an avant-garde class of regulators implicated in neurodevelopment. But, paucity exists in the knowledge regarding lncRNAs in neurogenesis and their associations with neurodevelopmental defects. To address this, we extensively reviewed the existing literature databases as well as performed relevant in silico analysis. We utilized Allen Brain Atlas (ABA) differential search module and generated a catalogue of ~30,000 transcripts specific to the neurogenic zones, including coding and non-coding transcripts. To explore the existing lncRNAs reported in neurogenesis, we performed extensive literature mining and identified 392 lncRNAs. These degenerate lncRNAs were mapped onto the ABA transcript list leading to detection of 20 lncRNAs specific to neurogenic zones (Dentate gyrus/Lateral ventricle), among which 10 showed associations to several neurodevelopmental disorders following in-silico mapping onto brain disease databases like Simons Foundation Autism Research Initiative, AutDB, and lncRNADisease. Notably, using ABA correlation module, we could establish lncRNA to-mRNA coexpression networks for the above 10 candidate lncRNAs. Finally, pathway prediction revealed physical, biochemical, or regulatory interactions for nine lncRNAs. In addition, ABA differential search also revealed 54 novel significant lncRNAs from the null set (~30,000). Conclusively, this review represents an updated catalogue of lncRNAs in neurogenesis and neurological diseases, and overviews the field of OMICs-based data analysis for understanding lncRNome-based regulation in neurodevelopment. PMID- 28095734 TI - Entrapment efficiency of pyridoxine hydrochloride in unilamellar liposomes: experimental versus model-generated data. AB - The present study investigates the effect of the preparation method (four methods) and formulation additives (propylene glycol (PG) and cholesterol (CH)) on the entrapment efficiency (EE) of pyridoxine hydrochloride (vitamin B6 (VB6)), representing hydrophilic water-soluble low permeable vitamins, in unilamellar liposomes. The main aim is to compare determined EE with predicted values generated using a web-published, computational model. Results showed that among the different preparation methods, modified film hydration showed significantly higher EE (p < 0.05). With regard to formulation additives, PG (5% w/v) produced smaller vesicles size with narrow size distribution. Agreement between determined and model-generated EE values was more evident in formulae with narrow size distribution (polydispersity index (PdI) below 0.23). Formulae containing PG showed slightly higher determined than predicted EE values indicating vitamin phospholipid bilayer interaction. Meanwhile, agreement between determined and predicted EE was limited to VB6-to-phospholipid ratio below (1.2:2). The comparison provided further insight into the usefulness of the prediction model factors affecting agreement between determined and predicted EE data. PMID- 28095735 TI - Criterion validity of the D-KEFS color-word and verbal fluency switching paradigms following traumatic brain injury. AB - The present study was composed of two parts examining the clinical utility of the Delis-Kaplan Executive Function System (D-KEFS) Verbal Fluency and Color-Word subtests in traumatic brain injury (TBI). In the first part, the performance of 128 outpatients with mild to severe TBI on the Verbal Fluency and Color-Word subtests was examined in relation to two primary indicators of TBI severity: length of coma and the presence of intracranial lesions on neuroimaging through regression analysis. After controlling for education, ethnicity, and complicating premorbid and comorbid factors, length of coma predicted performance on the Color Word Inhibition/Switching subtest, whereas the presence of diffuse lesions was related to Verbal Fluency Category Switching performance. In the second part of this study, performance on the Category Switching and Inhibition/Switching subtests was compared between a group of 28 participants with moderate-to-severe TBI and demographically matched groups with mild-uncomplicated TBI (n = 28) and neurologically healthy control participants (n = 56). The moderate-to-severe TBI group performed significantly worse on both subtests than the mild-uncomplicated TBI and control groups, and the latter groups did not differ from each other on these subtests. Logistic regression analysis showed that the combined group classification accuracy of these subtests was 66.07%, with an area under the curve (AUC) of .70 and a likelihood ratio of 1.93. The findings provide modest support for the clinical utility of the Color-Word Inhibition/Switching subtest in the cognitive assessment of TBI, while also replicating prior research suggesting clinical utility of the Category Switching subtest in this population. PMID- 28095736 TI - Development of multifunctional foods. AB - Foods contain various biologically active substances with extent physiological effects. Among them, some substances, such as dietary fibers, polyunsaturated fatty acids, and antioxidants, exert multiple activities. In addition, combinational uses of some components, such as sesamin and alpha-tocopherol, enhance their biological effects each other. The expression of multiple effect leads to the production of multifunctional foods which prevent the occurrence of various diseases. Furthermore, synergic effects between biologically active substances allow us to decrease the dose of each component, which lead to the improvement of safety and reduction of production cost of multifunctional foods. To use these active components for human health, studies on their adsorption and transportation are important, since distribution of some components, such as tocotrienols, is limited to some tissues. In addition, extent safety studies are essential to use artificially synthesized substances such as 10t, 12c derivative of conjugated linoleic acid for human health. PMID- 28095737 TI - Induction, purification, and characterization of a thermo and pH stable laccase from Abortiporus biennis J2 and its application on the clarification of litchi juice. AB - A fungus J2 producing laccase with high yield was screened in soils and identified as Abortiporus biennis. The production of laccase was induced by 0.1 mM Cu2+, 0.1 mM tannic acid, and 0.5 M ethanol. The laccase from Abortiporus biennis J2 was purified to electrophoretic homogeneity by a couple of steps. The N-terminal amino acid sequence of the enzyme was AIGPTADLNISNADI. The properties of the purified laccase were investigated. The result showed the laccase from Abortiporus biennis J2 is a thermo and pH stable enzyme. The laccase activity was inhibited by Hg2+, Cd2+, Fe2+, Ag+, Cu2+, and Zn2+, while promoted by Mg2+, Mn2+ at 10 mM level. Purified laccase was used to the clarification of litchi juice. After treatment with this laccase, the phenolic content of litchi juice had been found to be greatly reduced along with an increase in the clarity of the juice. The result indicated the potential of this laccase for application in juice procession. PMID- 28095738 TI - Emotional Intelligence as an Evolutive Factor on Adult With ADHD. AB - OBJECTIVE: ADHD adults exhibit deficits in emotion recognition, regulation, and expression. Emotional intelligence (EI) correlates with better life performance and is considered a skill that can be learned and developed. The aim of this study was to assess EI development as ability in ADHD adults, considering the effect of comorbid psychiatric disorders and previous diagnosis of ADHD. METHOD: Participants ( n = 116) were distributed in four groups attending to current comorbidities and previous ADHD diagnosis, and administered the Mayer-Salovey Caruso Emotional Intelligence Test version 2.0 to assess their EI level. RESULTS: ADHD adults with comorbidity with no previous diagnosis had lower EI development than healthy controls and the rest of ADHD groups. In addition, ADHD severity in childhood or in adulthood did not influence the current EI level. CONCLUSION: EI development as a therapeutic approach could be of use in ADHD patients with comorbidities. PMID- 28095739 TI - Expression and localization of fibroblast growth factor (FGF)23 and Klotho in the spleen: its physiological and functional implications. AB - The FGF23-Klotho signaling axis is known to exert anti-aging effects via calcium phosphorus metabolism. In mice deficient in FGF23-Klotho signaling, however, the number of splenocytes is reduced. FGF23 is expressed in both bone and spleen, with regulation of its production differing in these organs. As FGF23-Klotho signaling may play an immunological role in the spleen, splenocytes in male C57BL/6J mice were assayed for expression of Klotho or FGF23 by flow cytometry and immunohistochemistry. Cells that expressed Klotho included CD45R/B220+ CD21/CD35+ CD1d+ CD43- marginal zone B cells. These cells also expressed FGF receptor 1, indicating that Klotho-positive B cells could respond to FGF23. Plasmacytoid dendritic cells (pDCs) with CD11c+ CD45R/B220+ CD11b- CD8alpha- were found to produce FGF23. Klotho-positive cells and FGF23-producing cells were present in close proximity to each other, suggesting that FGF23 produced by pDCs may act within a limited area. These findings indicate that FGF23-Klotho signaling could play a biological or immunological role in the spleen. PMID- 28095740 TI - Does a single session of reading literary fiction prime enhanced mentalising performance? Four replication experiments of Kidd and Castano (2013). AB - Prior experiments indicated that reading literary fiction improves mentalising performance relative to reading popular fiction, non-fiction, or not reading. However, the experiments had relatively small sample sizes and hence low statistical power. To address this limitation, the present authors conducted four high-powered replication experiments (combined N = 1006) testing the causal impact of reading literary fiction on mentalising. Relative to the original research, the present experiments used the same literary texts in the reading manipulation; the same mentalising task; and the same kind of participant samples. Moreover, one experiment was pre-registered as a direct replication. In none of the experiments did reading literary fiction have any effect on mentalising relative to control conditions. The results replicate earlier findings that familiarity with fiction is positively correlated with mentalising. Taken together, the present findings call into question whether a single session of reading fiction leads to immediate improvements in mentalising. PMID- 28095741 TI - Pullout performance comparison of novel expandable pedicle screw with expandable poly-ether-ether-ketone shells and cement-augmented pedicle screws. AB - Aim of this study is to assess the pullout performance of various pedicle screws in different test materials. Polyurethane foams (Grade 10 and Grade 40) produced in laboratory and bovine vertebrae were instrumented with normal, cannulated (cemented), novel expandable and normal (cemented) pedicle screws. Test samples were prepared according to the ASTM F543 standard testing protocols and surgical guidelines. To examine the screw placement and cement distribution, anteriosuperior and oblique radiographs were taken from each sample after insertion process was completed. Pullout tests were performed in an Instron 3369 testing device. Load versus displacement graphs were recorded and the ultimate pullout force was defined as the maximum load (pullout strength) sustained before failure of screw. Student's t-test was performed on each group whether the differences between pullout strength of pedicle screws were significant or not. While normal pedicle screws have the lowest pullout strength in all test materials, normal pedicle screws cemented with polymethylmethacrylate exhibit significantly higher pullout performance than others. For all test materials, there is a significant improvement in pullout strength of normal screws by augmentation. While novel expandable pedicle screws with expandable poly-ether ether-ketone shells exhibited lower pullout performance than normal screws cemented with polymethylmethacrylate, their pullout performances in all groups were higher than the ones of normal and cannulated pedicle screws. For all test materials, although cannulated pedicle screws exhibit higher pullout strength than normal pedicle screws, there are no significant differences between the two groups. The novel expandable pedicle screws with expandable poly-ether-ether ketone shells may be used instead of normal and cannulated pedicle screws cemented with polymethylmethacrylate due to their good performances. PMID- 28095742 TI - Lithium response in bipolar disorders and core clock genes expression. AB - OBJECTIVES: We examine whether the lithium response is associated with changes in the expression of core clock genes. METHODS: The effect of a therapeutic concentration of lithium (1 mM) on the expression levels of 17 circadian genes was examined in lymphoblastoid cell lines (LCLs) derived from two well characterized groups of bipolar disorder patients, defined as lithium non responders (NR, n = 20) or excellent responders (ER, n = 16). Quantitative real time PCR (qRT-PCR) was conducted at 2, 4 and 8 days (d2, d4 and d8) with and without lithium exposure. RESULTS: At d2, in ER only, BHLHE41, RORA, PER1, ARNTL, CRY2, BHLHE40 and CSNK1D were upregulated, whereas NR1D1 was downregulated. At d4, in ER only, CRY1 was downregulated. At d8, in NR only, GSK3beta was upregulated and DBP, TIMELESS and CRY1 were downregulated. Significant Group * Lithium interactions existed for NR1D1 at d2 (P = 0.02), and CRY1 at d4 (P = 0.02). Longitudinal analyses showed differential temporal evolutions between NR and ER (significant Time * Group interaction) for PER3, NR1D1, DBP, RORA, CSNK1D and TIMELESS; and a significant Time * Lithium interaction for NR1D1. Coexpression data analyses suggested distinct groups of circadian genes concurrently modulated by lithium. CONCLUSIONS: In LCLs, lithium influences expression of circadian genes with differences in amplitude and kinetics according to the patient's lithium response status. PMID- 28095744 TI - The effects of age on the learning and forgetting of primacy, middle, and recency components of a multi-trial word list. AB - The serial position effect reveals that recall of a supraspan list of words follows a predictable pattern, whereby words at the beginning (primacy) and end (recency) of a list are recalled more easily than words in the middle. This effect has typically been studied using single list-learning trials, but in neuropsychology, multi-trial list-learning tests are more commonly used. The current study examined trends in learning for primacy, middle, and recency effects across multiple trials in younger and older age cohorts. Participants were 158 volunteers, including 79 adults aged 17-36 ("younger" group) and 79 adults aged 54-89 years ("older" group). Each participant completed four learning trials and one delayed (5-10 min) recall trial from the Memory Assessment Scales. Scores were divided into primacy (first four words), middle (middle four words), and recency (final four words) scores for all trials. For list acquisition, mixed effects modeling examined the main effects of and interactions between learning slope (logarithmic), age group, and serial position. Rate of learning increased logarithmically over four trials and varied by serial position, with growth of middle and recency word acquisition increasing more rapidly than recall of primacy words; this interaction did not differ by age group. Delayed retention differed according to age group and serial position; both older and younger adults demonstrated similar retention for primacy words, but older adults showed reduced retention for middle and recency words. Although older adults acquired less information across learning trials, the reason for this reduced acquisition was related to initial learning, not to rate of learning over time. Older compared to younger adults were less efficient at transferring middle and recency words from short-term to long-term memory. PMID- 28095743 TI - Adult Murine Pancreatic Progenitors Require Epidermal Growth Factor and Nicotinamide for Self-Renewal and Differentiation in a Serum- and Conditioned Medium-Free Culture. AB - Adult pancreatic stem and progenitor cells may serve as an alternative source of insulin-secreting endocrine cells in cell replacement therapy for type 1 diabetes, but much remained unknown about these cells. We previously identified adult murine pancreatic progenitor-like cells that displayed in vitro self renewal and tri-lineage differentiation activities in a three-dimensional colony/organoid assay containing 1% methylcellulose and 5% Matrigel. However, the presence of other undefined culture components, such as serum and conditioned medium, has prevented a complete understanding of the signals required for progenitor cell growth. Here, we have established a serum-free, conditioned medium-free colony assay with the inclusion of seven defined factors: epidermal growth factor (EGF), R-Spondin 1 (RSPO1), Noggin, nicotinamide, exendin-4, activin B, and vascular endothelial growth factor (VEGF)-A. The requirements for colony growth were characterized and we found that EGF and nicotinamide were necessary and sufficient for the colony growth and long-term self-renewal of these progenitors. However, the seven factor (7F) culture medium better induced colony size and self-renewal in long-term culture than EGF plus nicotinamide alone. Individual 3-week-old colonies grown in the 7F culture medium expressed ductal, acinar, and endocrine lineage markers, suggesting that tri-lineage differentiation of the tri-potent progenitors was occurring without genetic manipulation. A delayed inhibition of Notch signaling using small molecules in 2 week-old cultures enhanced endocrine gene expression in 3-week-old colonies. This better-defined colony assay system will enable our and other laboratories for in depth mechanistic studies on the biology of these progenitor cells. PMID- 28095745 TI - Toward the definition of a new worst-case paradigm for the preclinical evaluation of posterior spine stabilization devices. AB - Mechanical reliability tests on posterior spine stabilization devices are based on standard F1717 by the American Society for Testing and Materials, which describes how to assemble the implant with vertebrae-like test blocks in a corpectomy model. A recent study proposed to revise the standard to describe the anatomical worst-case scenario, instead of the average one currently implemented, and introduce the unsupported screw length as a mechanical parameter. This article investigates the implications of such revisions on the endurance properties of an implant already on the market. Experimental fatigue tests demonstrate that the revision of F1717 standard leads to a reduction of 3.2 million cycles in the fatigue strength of the tested implant: this amount is comparable to the run-out number of cycles (5 million cycles) currently recommended. The numerical analysis, validated with static tests and strain gauges, supports the experimental findings and demonstrates that the stress on the implant may increase upon revision up to a 50% on the screw (most recurrent failure mode), with the unsupported screw length contributing alone up to 40%. The revision of ASTM F1717 standard would guarantee higher safety for the implant to test, potentially covering for a wider population of patients. PMID- 28095746 TI - Targeting of herbal bioactives through folate receptors: a novel concept to enhance intracellular drug delivery in cancer therapy. AB - Targeted drug delivery through folate receptor (FR) has emerged as a most biocompatible, target oriented, and non-immunogenic cargoes for the delivery of anticancer drugs. FRs are highly overexpressed in many tumor cells (like ovarian, lung, breast, kidney, brain, endometrial, and colon cancer), and targeting them through conjugates bearing specific ligand with encapsulated nanodrug moiety is undoubtedly, a promising approach toward tumor targeting. Folate, being an endogenous ligand, can be exploited well to affect various cellular events occurring during the progress of tumor, in a more natural and definite way. Thus, the aim of the review lies in summarizing the advancements taken place in the drug delivery system of different therapeutics through FRs and to refine its role as an endogenous ligand, in targeting of synthetic as well as natural bioactives. The review also provides an update on the patents received on the folate-based drug delivery system. PMID- 28095747 TI - Effects of roller massager on muscle recovery after exercise-induced muscle damage. AB - Two experiments (n = 10) were conducted to determine the effects of roller massager (RM) on ankle plantar flexor muscle recovery after exercise-induced muscle damage (EIMD). Experiment 1 examined both functional [i.e., ankle plantar flexion maximal isometric contraction and submaximal (30%) sustained force; ankle dorsiflexion maximal range of motion and resistance to stretch; and medial gastrocnemius pain pressure threshold] and morphological [cross-sectional area, thickness, fascicle length, and fascicle angle] variables, before and immediately, 1, 24, 48, and 72 h after an EIMD stimulus. Experiment 2 examined medial gastrocnemius deoxyhaemoglobin concentration kinetics before and 48 h after EIMD. Participants performed both experiments twice: with (RM) and without (no-roller massager; NRM) the application of a RM (6 * 45 s; 20-s rest between sets). RM intervention did not alter the functional impairment after EIMD, as well as the medial gastrocnemius morphology and oxygenation kinetics (P > 0.05). Although, an acute increase of ipsilateral (RM = + 19%, NRM = -5%, P = 0.032) and a strong tendency for contralateral (P = 0.095) medial gastrocnemius pain pressure threshold were observed. The present results suggest that a RM has no effect on plantar flexors performance, morphology, and oxygenation recovery after EIMD, except for muscle pain pressure threshold (i.e., a soreness). PMID- 28095748 TI - Myocardial Inactivation of Thyroid Hormones in Patients with Aortic Stenosis. AB - OBJECTIVE: The human heart expresses the type 2 deiodinase (D2) that activates thyroxine (T4) to triiodothyronine (T3). At the same time, the inactivating type 3 deiodinase (D3) has been found in a rat model of right ventricular hypertrophy. It is not known whether the human myocardium metabolizes thyroid hormone. This study examined myocardial thyroid hormone metabolism in patients with aortic valve stenosis (AS) undergoing aortic valve replacement and in patients with coronary artery disease (CAD) undergoing coronary artery bypass grafting surgery. METHODS: Myocardial thyroid hormone metabolism was assessed by analyzing the difference in serum thyroid hormone levels between the aortic root (incoming blood) and the coronary sinus (outgoing blood) of patients undergoing cardiac surgery. A total of 23 patients with AS and 35 patients with CAD were included. Patients received a pre-surgical echocardiogram, and pre-, during and post surgical thyroid hormone serum levels were collected in the myocardial and peripheral circulations. RESULTS: Patients with AS exhibited the expected left ventricle (LV) hypertrophy (i.e., 20-30% increase in LV posterior wall and interventricular septum thickness and ~10% increase in AS in LV diastolic diameter). Immediately before cardiopulmonary bypass, blood flowing through the AS myocardium exhibited a 4.6% reduction in T3 and 6.9% increase in rT3 levels, decreasing the serum T3/rT3 ratio by 9.6%. T4 and thyrotropin serum levels remained similar between the aortic root and coronary sinus. In contrast, no myocardial thyroid hormone metabolism was observed in CAD patients. Notably, the AS myocardium lost the ability to inactivate thyroid hormone after cardiopulmonary bypass, possibly due to myocardial stunning. CONCLUSIONS: There is accelerated thyroid hormone inactivation in the AS myocardium, which is likely the result of D3 expression. No evidence to suggest thyroid hormone activation in the myocardium was obtained in the present study. PMID- 28095750 TI - Effects of pre-germinated brown rice treatment high-fat diet-induced metabolic syndrome in C57BL/6J mice. AB - To investigate using pre-germinated brown rice (PGBR) to treat metabolic syndrome, we fed one group of mice standard-regular-diet (SRD) for 20 weeks and another group of mice high-fat-diet (HFD) for 16 weeks. We subdivided them into HFD group and HFD + PGBR group whose dietary carbohydrate was replaced with PGBR for 4 weeks. The HFD group gained more weight, had higher blood pressure, heart rate, blood glucose and lipids, liver levels of TG, feces TG and bile acid, lower adipose levels of adipocytokine, lower skeletal muscle IR, IRS-1, IRS-2, PI3 K, Akt/PKB, GLUT-1, GLUT-4, GCK and PPAR-gamma; higher liver SREBP-1, SCD-1, FAS, HMGCR, LDLR, CYP7alpha1 and PPAR-alpha, and higher adipose SREBP-1, SCD-1, FAS, and lower adipose PPAR-alpha and adiponectin. The HFD + PGBR group had clearly improved blood pressure, biochemical parameters and above proteins expressions. PGBR successful treatment of metabolic syndrome was achieved through improvements in glucose and lipid synthesis and metabolism. PMID- 28095749 TI - Obese adolescents with polycystic ovarian syndrome have elevated cardiovascular disease risk markers. AB - Women with polycystic ovarian syndrome (PCOS) have evidence of subclinical cardiovascular disease (CVD). However, insulin resistance, an important factor in the development of CVD in adults, is common in adolescents with PCOS, yet data in adolescents are limited. Therefore, we sought to measure insulin resistance and CVD markers in obese youth with and without PCOS. Thirty-six PCOS and 17 non-PCOS adolescent girls who were obese, sedentary, and non-hypertensive were recruited from clinics located within the Children's Hospital Colorado. Following 3 days of controlled diet and restricted exercise, fasting plasma samples were obtained prior to a hyperinsulinemic euglycemic clamp. PCOS girls were more insulin resistant than controls (glucose infusion rate 5.24+/-1.86 mg/kg/min vs 9.10+/ 2.69; p<0.001). Girls with PCOS had blood pressure in the normal range, but had greater carotid intima-media thickness (cIMT) (0.49+/-0.07 mm vs 0.44+/-0.06; p=0.038), beta stiffness index (5.1+/-1.3 U vs 4.4+/-0.9; p=0.037), and reduced arterial compliance (1.95+/-0.47 mm2/mmHg * 10-1 vs 2.13+/-0.43; p=0.047). PCOS girls had a normal mean lipid profile, yet had a more atherogenic lipoprotein cholesterol distribution and had persistent elevations of free fatty acids despite hyperinsulinemia (68+/-28 MUmol/mL vs 41+/-10; p=0.001), both potential contributors to CVD. Free fatty acid concentrations correlated best with all CVD markers. In summary, adolescent girls with PCOS have greater cIMT and stiffer arteries than girls without PCOS, perhaps related to altered lipid metabolism, even when clinical measures of blood pressure and cholesterol profiles are 'normal'. Therefore, management of adolescent PCOS should include assessment of CVD risk factor development. PMID- 28095752 TI - Isolation and identification of a humanTRPV1 activating compound from soy sauce. AB - Transient receptor potential vanilloid 1 (TRPV1) was identified as a receptor of capsaicin, which is a pungent ingredient in hot red peppers. Due to its relevance for nociception, a physiological and pharmacological study of TRPV1 has also been developed. Therefore, it is important to enrich scientific knowledge regarding the TRPV1 activating or inhibiting compounds. In this study, we fractionated soy sauce based on the human TRPV1 (hTRPV1) activity using column chromatography and purified 5-(9H-pyrido[3,4-b]indol-1-yl)-2-furanmethanol (perlolyrine) as an hTRPV1-activating compound. Additionally, perlolyrine activates the human transient receptor potential ankyrin 1 (hTRPA1). The EC50 of hTRPV1 and hTRPA1 were 2.87 and 1.67 MUmol L-1, respectively. HPLC quantification of soy sauces showed that they contain 2.22-12.13 MUmol L-1 of perlolyrine. The sensory evaluation revealed that perlolyrine has taste modification effect. The results of this study, for the first time, suggest that perlolyrine induces the activation of hTRPV1 and hTRPA1. PMID- 28095753 TI - A functional endonuclease Q exists in the bacterial domain: identification and characterization of endonuclease Q from Bacillus pumilus. AB - DNA base deamination occurs spontaneously under physiological conditions and is promoted by high temperature. Therefore, hyperthermophiles are expected to have efficient repair systems of the deaminated bases in their genomes. Endonuclease Q (EndoQ) was originally identified from the hyperthermophlic archaeon, Pyrococcus furiosus, as a hypoxanthine-specific endonuclease recently. Further biochemical analyses revealed that EndoQ also recognizes uracil, xanthine, and the AP site in DNA, and is probably involved in a specific repair process for damaged bases. Initial phylogenetic analysis showed that an EndoQ homolog is found only in the Thermococcales and some of the methanogens in Archaea, and is not present in most members of the domains Bacteria and Eukarya. A better understanding of the distribution of the EndoQ-mediated repair system is, therefore, of evolutionary interest. We showed here that an EndoQ-like polypeptide from Bacillus pumilus, belonging to the bacterial domain, is functional and has similar properties with the archaeal EndoQs. PMID- 28095751 TI - * CRISPR-Based Epigenome Editing of Cytokine Receptors for the Promotion of Cell Survival and Tissue Deposition in Inflammatory Environments. AB - Musculoskeletal diseases have been associated with inflammatory cytokine action, particularly action by TNF-alpha and IL-1beta. These inflammatory cytokines promote apoptosis and senescence of cells in diseased tissue and extracellular matrix breakdown. Stem cell-based therapies are being considered for the treatment of musculoskeletal diseases, but the presence of these inflammatory cytokines will have similar deleterious action on therapeutic cells delivered to these environments. Methods that prevent inflammatory-induced apoptosis and proinflammatory signaling, in cell and pathway-specific manners are needed. In this study we demonstrate the use of clustered regularly interspaced short palindromic repeats (CRISPR)-based epigenome editing to alter cell response to inflammatory environments by repressing inflammatory cytokine cell receptors, specifically TNFR1 and IL1R1. We targeted CRISPR/Cas9-based repressors to TNFR1 and IL1R1 gene regulatory elements in human adipose-derived stem cells (hADSCs) and investigated the functional outcomes of repression of these genes. Efficient signaling regulation was demonstrated in engineered hADSCs, as activity of the downstream transcription factor NF-kappaB was significantly reduced or maintained at baseline levels in the presence of TNF-alpha or IL-1beta. Pellet culture of undifferentiated hADSCs demonstrated improved survival in engineered hADSCs treated with TNF-alpha or IL-1beta, while having little effect on their immunomodulatory properties. Furthermore, engineered hADSCs demonstrated improved chondrogenic differentiation capacity in the presence of TNF-alpha or IL-1beta, as shown by superior production of glycosaminglycans in this inflammatory environment. Overall this work demonstrates a novel method for modulating cell response to inflammatory signaling that has applications in engineering cells delivered to inflammatory environments, and as a direct gene therapy to protect endogenous cells exposed to chronic inflammation, as observed in a broad spectrum of degenerative musculoskeletal pathology. PMID- 28095754 TI - Three-Dimensional Coculture of Meniscal Cells and Mesenchymal Stem Cells in Collagen Type I Hydrogel on a Small Intestinal Matrix-A Pilot Study Toward Equine Meniscus Tissue Engineering. AB - Meniscal injuries are the most frequently encountered soft tissue injuries in the equine stifle joint. Due to the inherent limited repair potential of meniscal tissue, meniscal injuries do not only affect the meniscus itself but also lead to impaired joint homeostasis and secondary osteoarthritis. The presented study compares 3D coculture constructs of primary equine mesenchymal stem cells (MSC) and meniscus cells (MC) seeded on three different scaffolds-a cell-laden collagen type I hydrogel (Col I gel), a tissue-derived small intestinal matrix scaffold (SIS-muc) and a combination thereof-for their qualification to be applied for meniscus tissue engineering. To investigate cell attachment of primary MC and MSC on SIS-muc matrix SEM pictures were performed. For molecular analysis, lyophilized samples of coculture constructs with different cell ratios (100% MC, 100% MSC, and 50% MC and 50% MSC, 20% MC, and 80% MSC) were digested and analyzed for DNA and GAG content. Active matrix remodeling of 3D coculture models was indicated by matrix metalloproteinases detection. For comparison of tissue engineered constructs with the histologic architecture of natural equine menisci, paired lateral and medial menisci of 15 horses representing different age groups were examined. A meniscus phenotype with promising similarity to native meniscus tissue in its GAG/DNA expression in addition to Col I, Col II, and Aggrecan production was achieved using a scaffold composed of Col I gel on SIS-muc combined with a coculture of MC and MSC. The results encourage further development of this scaffold-cell combination for meniscus tissue engineering. PMID- 28095755 TI - Changes in caregiver burden among informal caregivers of stroke patients in Mongolia. AB - BACKGROUND: Modern therapeutics and health care improvements prolong stroke patients' survival; however, the degree of disability remains high. Stroke survivors often require caregivers, particularly in the first year after the onset of the stroke. Longitudinal assessment of and factors associated with caregiver burden (CGB) among caregivers of stroke patients has been scarcely discussed. This study aimed to define the changes in CGB in the first year of caregiving among the caregivers of stroke patients and to identify associated factors. METHODS: A prospective, multi-centered observational study was conducted in nine public hospitals in Mongolia. We used the Montgomery CGB Scale for assessing CGB, and repeated the assessment after 1 year. Stroke patient characteristics were included in the analyses. Multinomial logistic regressions were conducted to analyze changes in CGB. RESULTS: A paired t-test analysis revealed that demand burden increased (from 12.61 to 11.50, p = 0.034), whereas stress burden decreased (from 10.69 to 11.60, p = 0.016). Although objective burden decreased, the difference was not significant. Factors associated with these changes in CGB were the caregiver's marital status, the caregiver's relationship with the patient, financial difficulties, and the patient's sex and dependency. DISCUSSION: The information on factors predicting changes in CGB in the first year of caregiving provided in this study suggests that social or financial support can assist in reducing CGB among the caregivers of post-stroke patients. PMID- 28095756 TI - Low-dose acute vanillin is beneficial against harmaline-induced tremors in rats. AB - OBJECTIVE: To study the effect of pretreatment with low doses of vanillin, a flavoring agent used as a food additive, on harmaline-induced tremor in rats. METHODS: Sprague Dawley rats (110 +/- 5 g) were divided into groups of six animals each. Vanillin (6.25 mg, 12.5 mg, and 25 mg/kg) was administered by gavage to different groups of rats, 30 minutes before the induction of tremor. Harmaline (10 mg/kg, i.p.) was used for the induction of tremor. The latency of onset, duration, tremor intensity, tremor index, and spontaneous locomotor activity were recorded. A separate batch of animals was used for the determination of serotonin (5HT) and 5 hydroxyindole acetic acid (5HIAA) levels in the brain. RESULTS: Harmaline treatment resulted in characteristic tremor that lasted for more than 2 hours and decreased the locomotor activity of rats. Pre treatment with vanillin significantly reduced the duration, intensity, and tremor index of harmaline-treated animals. Vanillin treatment also significantly attenuated harmaline-induced decrease in the locomotor activity. An increase in 5HT levels and the changes in 5HIAA/5HT ratio observed in harmaline treated rats were significantly corrected in vanillin pretreated animals. DISCUSSION: Vanillin in low doses reduces harmaline-induced tremor in rats, probably through its modulating effect on serotonin levels in the brain. These findings suggest a beneficial effect of vanillin in essential tremor. PMID- 28095757 TI - Ethical leadership outcomes in nursing. AB - BACKGROUND: Leadership style adopted by nursing managers is a key element in progress and development of nursing and quality of healthcare services received by the patients. In this regard, the role of ethical leadership is of utmost importance. OBJECTIVES: The objective of the study was to elaborate on the ethical leadership and its role in professional progress and growth of nurses in the light of work condition in health providing institutes. METHODS: The study was carried out as a qualitative study following conventional content analysis method. In total, 14 nursing faculty members and nursing managers at different levels were selected through purposive sampling method. Semi-structured interviews were used for data gathering. The data were analyzed using latent content analysis and constant comparison analysis. Ethical considerations: This study was conducted in accordance with ethical issues in research with human participants and national rules and regulations related to informed consent and confidentiality. The study was approved by the Committee of Ethics in Research at the Shahid Beheshti University of Medical Sciences in Tehran, Iran, under the code: sbmu.rec.1393.695 on 15 February 2015. FINDINGS: Five subcategories were obtained based on the analysis, which constituted two main categories including "all-inclusive satisfaction" and "productivity." Nursing leaders highlighted the point that their ethical behavior creates "inner satisfaction of the leader," "employees' job satisfaction," and "patients' satisfaction." Improvement of productivity was another outcome of ethical behavior of the leaders. This kind of behavior resulted in "providing better services" and "inspiring ethical behavior in the employees." It has great influence on progress and growth of the nursing profession. CONCLUSION: By creating an ethical climate, ethical leadership leads to positive and effective outcomes-for the patients as well as for the nurses and the leaders-and professional progress and development of the nursing profession. Therefore, an ethical work environment that supports nurses' progress and development can be developed by paying more attention to moralities in recruitment, teaching ethical values to the leaders, and using a systematic and objective approach to assess morality in the environment. PMID- 28095758 TI - Ethical difficulties in healthcare: A comparison between physicians and nurses AB - BACKGROUND: Advances in biomedical sciences, technologies and care practices have resulted in an increase in ethical problems and a resulting growth of difficulties encountered by health workers in their professional activity. OBJECTIVE: The main objective of this study was to analyse knowledge in the ethical field and experience with and the propensity for using ethics consultations by nurses and physicians. METHODS: Between March and June 2014, a cross-sectional observational study was conducted on a sample of 351 nurses and 128 physicians in four central Italian hospitals. For data collection, a semi structured questionnaire was used, consisting of 21 items divided into four sections exploring (1) demographic and occupational characteristics, (2) knowledge in the ethics field, (3) experience with ethical issues and (4) the propensity to use ethics consultation. Ethical considerations: Research ethics approval was obtained from the Italian Nurses Professional Board. RESULTS: The results show that both nurses and physicians are faced with ethically sensitive situations. Nurses were found to have better judgement concerning their own knowledge than physicians, but more physicians were found to have a deeper level of specific training in ethics issues. The propensity to ask for ethics consultations to address ethical issues was found to be significantly associated with the degree to which ethical issues have deepened (and the level of experience acquired in this field). CONCLUSION: The presence of a consulting service that can lead to shared choices may represent, together with basic and continuing education, a valid support for professional growth in the ethical field for both physicians and nurses. PMID- 28095759 TI - Living with end-stage renal disease. AB - BACKGROUND: Living with a renal disease often reduces quality of life because of the stress it entails. No attention has been paid to the moral challenges of living with renal disease. OBJECTIVES: To explore the moral challenges of living with a renal disease. RESEARCH DESIGN: A case study based on qualitative research. We used Walker's ethical framework combined with narrative ethics to analyse how negotiating care responsibilities lead to a new perspective on moral issues. Participants and research context: One case was chosen from 20 qualitative interviews with renal patients in the Netherlands. Ethical considerations: Several actions have been taken to ensure the informed consent, privacy, anonymity and confidentiality of the patient in this article. More details are offered in this article. The study has been conducted in line with the recommendations of the Medical Ethical Committee of the VU Medical Center. FINDINGS: A renal disease can force people to change their identity, relationships, values and responsibilities. The case study illustrates the moral challenges confronting renal patients. DISCUSSION AND CONCLUSION: Moral issues can be raised by the changes to identities, relationships, values and responsibilities caused by renal disease. Support services for renal patients and their relatives should pay more attention to these issues in order to promote self-management. PMID- 28095760 TI - Workplace justice and intention to leave the nursing profession. AB - BACKGROUND: Poor psychosocial work environments are considered critical factors of nurses' intention to leave their profession. Workplace injustice has been proven to increase the incidence of psychiatric morbidity among workers. However, few studies have directly investigated the effect of workplace justice on nurses' intention to leave their profession and the population attributable risk among nurses. OBJECTIVE: This study identified factors associated with workplace justice and nurses' intention to leave the profession. METHOD: A cross-sectional survey was conducted using a self-administered structured questionnaire. Approximately 10% of all secondary referral centers in Taiwan were stratified and randomly sampled. Multiple logistic regression and population attributable risks were preformed to assess the effect of workplace justice on nurses' intention to leave the nursing profession. Ethical considerations: This study was approved by the Research and Ethical Committee of National Taiwan University Hospital. Only nurses who consented to the study participated in the survey. RESULT: A total of 2268 nurses were recruited, of whom 1417 (62.5%) satisfactorily completed the questionnaire. The participants were classified and 342 (24.1%) of them were placed into the low workplace justice group. Nurses with low workplace justice had a higher intention of leaving the profession (adjusted odds ratio = 1.34, 95% confidence interval = 1.02-1.77). "Employees' opinions are influential in hospital's decision making" and "employees' performance is evaluated fairly" were the most influential factors of the participants' intention to quit. The adjusted population attributable risk was 3.7% for low workplace justice. CONCLUSION: This study has identified that workplace justice is a protective factor of nurses' leaving their current profession. A fair performance appraisal system and increased autonomy at work are warranted to dissuade nurses from leaving the nursing profession. PMID- 28095761 TI - The caring encounter in nursing. AB - BACKGROUND: The concept 'encounter' occurs in caring literature as a synonym for dialogue and relation describing deeper levels of interaction between patient and nurse. In nursing and caring research, the concept 'caring encounter' is often used without further reflection on the meaning of the concept. Encounters are, however, continuously taking place in the world of caring, which calls for a clarification of the concept. OBJECTIVES: This study is an analysis of the concept of caring encounter in nursing from the patients' and nurses' point of view. METHOD: Rodgers' evolutionary view guided the concept analysis within the theoretical perspective of caritative caring. DATA SOURCES: Peer-reviewed articles in English published between 1990 and 2014 were retrieved from the databases: CINAHL, PubMed, Web of Science, ScienceDirect (Elsevier), Springer Link, Primo Central (Ex Libris) and Academic Search Premier (EBSCO) using different combinations of encounter, caring and nursing as keywords. In all, 28 articles related to caring encounters were included in the analysis after applying inclusion and exclusion criteria. Ethical considerations: This study was conducted according to good scientific practice. RESULTS: Four antecedents to the caring encounter are found in the nurse's way of being: a reflective way of being; openness, sensitivity, empathy and ability to communicate; confidence, courage and professionalism; and showing respect and supporting dignity. The attributes are as follows: being there, uniqueness and mutuality. As a consequence, the caring encounter influences both patient and nurse. DISCUSSION AND CONCLUSION: The caring encounter is an encounter between two equal persons where one is nurse and the other is patient. They encounter in mutuality, in true presence, and both have allowed themselves to be the person they are. The results clarify the conceptual differences between relationship and caring communion as the mutuality in the caring encounter differs from the dependence on the other pronounced in the relationship. PMID- 28095762 TI - A moral profession. AB - BACKGROUND: Lack of compassion is claimed to result in poor and sometimes harmful nursing care. Developing strategies to encourage compassionate caring behaviours are important because there is evidence to suggest a connection between having a moral orientation such as compassion and resulting caring behaviour in practice. OBJECTIVE: This study aimed to articulate a clearer understanding of compassionate caring via nurse educators' selection and use of published texts and film. METHODOLOGY: This study employed discourse analysis. Participants and research context: A total of 41 nurse educators working in universities in the United Kingdom (n = 3), Ireland (n = 1) and Canada (n = 1) completed questionnaires on the narratives that shaped their understanding of care and compassion. FINDINGS: The desire to understand others and how to care compassionately characterised educators' choices. Most narratives were examples of kindness and compassion. A total of 17 emphasised the importance of connecting with others as a central component of compassionate caring, 10 identified the burden of caring, 24 identified themes of abandonment and of failure to see the suffering person and 15 narratives showed a discourse of only showing compassion to those 'deserving' often understood as the suffering person doing enough to help themselves. DISCUSSION: These findings are mostly consistent with work in moral philosophy emphasising the particular or context and perception or vision as well as the necessity of emotions. The narratives themselves are used by nurse educators to help explicate examples of caring and compassion (or its lack). CONCLUSION: To feel cared about people need to feel 'visible' as though they matter. Nurses need to be alert to problems that may arise if their 'moral vision' is influenced by ideas of desert and how much the patient is doing to help himself or herself. PMID- 28095763 TI - Effect of socks structures on plantar dynamic pressure distribution. AB - A major purpose of investigating the plantar pressure in patients with pain or those at risk for skin injury is to reduce the pressure below metatarsal heads, specially first and second metatarsal heads. The aim of this article is to evaluate the effects of the socks structures on the changes in plantar dynamic pressure. In this study, seven socks types with different structures for the sole area were produced. The Gaitview(r) AFA-50 system, a force plate, was used to measure the plantar dynamic pressure of 10 participants. The barefoot plantar dynamic pressure distribution was compared with the plantar dynamic pressure distribution with socks by two independent samples test on various zones of the foot and on different genders using SPSS software. Mann-Whitney tests were used to determine specific significant differences. The obtained results showed that the main trend was to redistribute the plantar dynamic pressure from the higher plantar pressure zones (toe and first through forth metatarsal bone regions) were decreased and as a result the plantar pressure toward the relatively lower pressure zones (fifth metatarsal bone and midfoot regions). In comparison with the barefoot condition, the cross miss structure reduced the mean pressure in the critical region of the foot (first metatarsal) for male and female subjects ( p < 0.05) and also the mock rib structure reduced the mean pressure for female subjects ( p < 0.05). In general, the results suggested wearing the socks because the socks make the plantar pressure redistributed from high to low plantar pressure zones. The results of this research indicated that wearing socks with cross miss and mock rib structures will reduce the mean plantar pressure values in forefoot area in comparison with the barefoot condition. PMID- 28095764 TI - Evaluation of the carotid artery stenosis based on minimization of mechanical energy loss of the blood flow. AB - BACKGROUND: Internal carotid artery stenosis requires an accurate risk assessment for the prevention of stroke. Although the internal carotid artery area stenosis ratio at the common carotid artery bifurcation can be used as one of the diagnostic methods of internal carotid artery stenosis, the accuracy of results would still depend on the measurement techniques. The purpose of this study is to propose a novel method to estimate the effect of internal carotid artery stenosis on the blood flow based on the concept of minimization of energy loss. METHODS: Eight internal carotid arteries from different medical centers were diagnosed as stenosed internal carotid arteries, as plaques were found at different locations on the vessel. A computational fluid dynamics solver was developed based on an open-source code (OpenFOAM) to test the flow ratio and energy loss of those stenosed internal carotid arteries. For comparison, a healthy internal carotid artery and an idealized internal carotid artery model have also been tested and compared with stenosed internal carotid artery in terms of flow ratio and energy loss. RESULTS: We found that at a given common carotid artery bifurcation, there must be a certain flow distribution in the internal carotid artery and external carotid artery, for which the total energy loss at the bifurcation is at a minimum; for a given common carotid artery flow rate, an irregular shaped plaque at the bifurcation constantly resulted in a large value of minimization of energy loss. Thus, minimization of energy loss can be used as an indicator for the estimation of internal carotid artery stenosis. PMID- 28095765 TI - Electrospun nanofibre bundles and yarns for tissue engineering applications: A review. AB - Nanofibre membranes produced through the electrospinning process have been studied extensively over the past decade for a number of high demand applications including use as tissue engineered scaffolds. Despite possessing desirable properties including high surface area to volume ratios and enhanced mechanical properties, they ultimately suffer from a lack of cellular infiltration. Variations on the process include the production of highly aligned filaments of electrospun fibres referred to as bundles and yarns. Nanofibre bundle and yarn based scaffolds have been shown to demonstrate superior cell infiltration rates compared to traditional electrospun nonwovens while also offering the capability to be incorporated into a wider array of post-processing technologies. In this review, fibre collection techniques currently employed within the literature for the fabrication of electrospun bundles and yarns along with their applications in the field of tissue engineering will be discussed. PMID- 28095766 TI - Clamping of fine Kirschner wires in external fixators. AB - In Ilizarov circular (ring) external fixators, fine Kirschner wires are used to fix the bone to the fixator. Clamping of the wires to the rings with different bolt torques has been studied. However, the relation between the bolt torque and the fixation load applied to the wire was not investigated. In this work, finite element method is used to address this problem. Here, a fully three-dimensional model of the wire fixation assembly was built, with geometric details like threads on the bolt to produce a realistic simulation of the clamping of the wire. Both cannulated and slotted bolt types were studied and values of 0.2, 0.25, 0.3 and 0.45 were used for coefficient of friction. A torque was applied to the nut while the ring section and bolt kept in place. The results for bolt load, nut rotation as well as axial and radial wire deformations were obtained. The results demonstrated a linear relation between the bolt load and the bolt torque. The coefficient of this relationship was shown to be inversely proportional to the coefficient of friction. For all results, the bolt load (N) was approximately 124 times the bolt torque (N m) divided by the friction coefficient. The results highlighted the difference between the cannulated and the slotted bolts in terms of their grip on the wire. PMID- 28095767 TI - In Vivo Quantification of the Deformations of the Femoropopliteal Segment: Percutaneous Transluminal Angioplasty vs Nitinol Stent Placement. AB - PURPOSE: To quantify the deformations of the femoropopliteal (FP) segment in patients undergoing endovascular revascularization and to compare the posttreatment deformations caused by primary nitinol stent implantation to those produced by percutaneous transluminal angioplasty (PTA). METHODS: Thirty-five patients (mean age 69+/-10 years; 20 men) scheduled for endovascular therapy were recruited for the study. During endovascular interventions, angiographic images were acquired with the legs straight and with a hip/knee flexion of 20 degrees /70 degrees . Image acquisition was performed before PTA for all patients, after PTA in 17 patients receiving this treatment only, and after primary stent implantation in the remaining 18 patients. A semiautomatic approach was used to reconstruct the 3-dimensional patient-specific artery models from 2-dimensional radiographs. Axial shortening and curvature changes in the arteries in vivo were calculated for the calcified, dilated, and stented regions, as well as the regions that were distal and proximal to the diseased and treated segments. RESULTS: Leg flexion resulted in shortening of the artery in all investigated FP segments. The dilated arteries exhibited greater shortening compared with their stented counterparts (post-PTA 7.6%+/-4.9%, poststent 3.2%+/-2.9%; p=0.004). Leg flexion also led to an increase in the curvatures of all the sections of the FP segment. While stented arteries had significantly higher curvature values than PTA within the regions proximal to the treated sections, the choice of the treatment method did not affect the curvature of the other segments. Despite this, 40% of the stented arteries exhibited kinking during leg flexion. CONCLUSION: The choice of the treatment method affects the postinterventional axial deformations of the FP segment but does not influence the curvature behavior. While PTA results in a more flexible artery, stents restrict the arteries' shortening capabilities. Depending on the anatomical position of the stents, this axial stiffening of the arteries may lead to chronic kinking, which may cause occlusions and, consequently, affect the long-term success of the procedure. PMID- 28095768 TI - True Competitor of Femoral Access for Iliac Endovascular Interventions: A Radial Appraisal. PMID- 28095769 TI - PCM-SABRE: a platform for benchmarking and comparing outcome prediction methods in precision cancer medicine. AB - BACKGROUND: Numerous publications attempt to predict cancer survival outcome from gene expression data using machine-learning methods. A direct comparison of these works is challenging for the following reasons: (1) inconsistent measures used to evaluate the performance of different models, and (2) incomplete specification of critical stages in the process of knowledge discovery. There is a need for a platform that would allow researchers to replicate previous works and to test the impact of changes in the knowledge discovery process on the accuracy of the induced models. RESULTS: We developed the PCM-SABRE platform, which supports the entire knowledge discovery process for cancer outcome analysis. PCM-SABRE was developed using KNIME. By using PCM-SABRE to reproduce the results of previously published works on breast cancer survival, we define a baseline for evaluating future attempts to predict cancer outcome with machine learning. We used PCM SABRE to replicate previous work that describe predictive models of breast cancer recurrence, and tested the performance of all possible combinations of feature selection methods and data mining algorithms that was used in either of the works. We reconstructed the work of Chou et al. observing similar trends - superior performance of Probabilistic Neural Network (PNN) and logistic regression (LR) algorithms and inconclusive impact of feature pre-selection with the decision tree algorithm on subsequent analysis. CONCLUSIONS: PCM-SABRE is a software tool that provides an intuitive environment for rapid development of predictive models in cancer precision medicine. PMID- 28095770 TI - The unique genomic landscape surrounding the EPSPS gene in glyphosate resistant Amaranthus palmeri: a repetitive path to resistance. AB - BACKGROUND: The expanding number and global distributions of herbicide resistant weedy species threaten food, fuel, fiber and bioproduct sustainability and agroecosystem longevity. Amongst the most competitive weeds, Amaranthus palmeri S. Wats has rapidly evolved resistance to glyphosate primarily through massive amplification and insertion of the 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene across the genome. Increased EPSPS gene copy numbers results in higher titers of the EPSPS enzyme, the target of glyphosate, and confers resistance to glyphosate treatment. To understand the genomic unit and mechanism of EPSPS gene copy number proliferation, we developed and used a bacterial artificial chromosome (BAC) library from a highly resistant biotype to sequence the local genomic landscape flanking the EPSPS gene. RESULTS: By sequencing overlapping BACs, a 297 kb sequence was generated, hereafter referred to as the "EPSPS cassette." This region included several putative genes, dense clusters of tandem and inverted repeats, putative helitron and autonomous replication sequences, and regulatory elements. Whole genome shotgun sequencing (WGS) of two biotypes exhibiting high and no resistance to glyphosate was performed to compare genomic representation across the EPSPS cassette. Mapping of sequences for both biotypes to the reference EPSPS cassette revealed significant differences in upstream and downstream sequences relative to EPSPS with regard to both repetitive units and coding content between these biotypes. The differences in sequence may have resulted from a compounded-building mechanism such as repetitive transpositional events. The association of putative helitron sequences with the cassette suggests a possible amplification and distribution mechanism. Flow cytometry revealed that the EPSPS cassette added measurable genomic content. CONCLUSIONS: The adoption of glyphosate resistant cropping systems in major crops such as corn, soybean, cotton and canola coupled with excessive use of glyphosate herbicide has led to evolved glyphosate resistance in several important weeds. In Amaranthus palmeri, the amplification of the EPSPS cassette, characterized by a complex array of repetitive elements and putative helitron sequences, suggests an adaptive structural genomic mechanism that drives amplification and distribution around the genome. The added genomic content not found in glyphosate sensitive plants may be driving evolution through genome expansion. PMID- 28095771 TI - The 100 most-cited articles on aortic dissection. AB - BACKGROUND: To identify and characterize the most frequently cited articles that have been published on aortic dissection. METHODS: A list of the 100 most frequently cited publications (T100) about aortic dissection was generated by performing a searching of the Science Citation Index--Expanded using "aortic dissection" as the search term. Basic information about the articles was recorded, including number of citations, journal title, journal impact factor, time since publication, first author's country, topic/subspecialty of the research, and publication type. RESULTS: We finally included 180 articles on aortic dissection, from which we identified the 100 most frequently cited articles (T100). The most frequently cited article received 1079 citations, while the least frequently cited article received 68 (mean140.5 citations per article). The T100 originated from 19 countries, with more than half of them originating from the USA (n = 97). The T100 articles were published from 1955 to 2013, with 79% published during the period 1990-2009. In addition, there were 40 different journals with Circulation having the most citations (n = 38). Regarding the article type, there were 21 basic and 140 clinical research articles, one meta analysis, and 18 review articles. Reviews had the highest mean number of citations (mean 235.5 citations per article). CONCLUSIONS: Our study provides a historical perspective on the progress of dissection research, and helps to identify the quality of the work, the discoveries made, and the trends steering the studies. PMID- 28095772 TI - Empirical assessment of analysis workflows for differential expression analysis of human samples using RNA-Seq. AB - BACKGROUND: RNA-Seq has supplanted microarrays as the preferred method of transcriptome-wide identification of differentially expressed genes. However, RNA Seq analysis is still rapidly evolving, with a large number of tools available for each of the three major processing steps: read alignment, expression modeling, and identification of differentially expressed genes. Although some studies have benchmarked these tools against gold standard gene expression sets, few have evaluated their performance in concert with one another. Additionally, there is a general lack of testing of such tools on real-world, physiologically relevant datasets, which often possess qualities not reflected in tightly controlled reference RNA samples or synthetic datasets. RESULTS: Here, we evaluate 219 combinatorial implementations of the most commonly used analysis tools for their impact on differential gene expression analysis by RNA-Seq. A test dataset was generated using highly purified human classical and nonclassical monocyte subsets from a clinical cohort, allowing us to evaluate the performance of 495 unique workflows, when accounting for differences in expression units and gene- versus transcript-level estimation. We find that the choice of methodologies leads to wide variation in the number of genes called significant, as well as in performance as gauged by precision and recall, calculated by comparing our RNA-Seq results to those from four previously published microarray and BeadChip analyses of the same cell populations. The method of differential gene expression identification exhibited the strongest impact on performance, with smaller impacts from the choice of read aligner and expression modeler. Many workflows were found to exhibit similar overall performance, but with differences in their calibration, with some biased toward higher precision and others toward higher recall. CONCLUSIONS: There is significant heterogeneity in the performance of RNA-Seq workflows to identify differentially expressed genes. Among the higher performing workflows, different workflows exhibit a precision/recall tradeoff, and the ultimate choice of workflow should take into consideration how the results will be used in subsequent applications. Our analyses highlight the performance characteristics of these workflows, and the data generated in this study could also serve as a useful resource for future development of software for RNA-Seq analysis. PMID- 28095773 TI - Dietary pea fiber increases diversity of colonic methanogens of pigs with a shift from Methanobrevibacter to Methanomassiliicoccus-like genus and change in numbers of three hydrogenotrophs. AB - BACKGROUND: Pea fiber (PF) is a potential fibrous supplement in swine production. The influence of dietary PF on microbial community in the colon of pigs remains largely unexplored. Methanogens in the hindgut of monogastric animals play important roles in degradation of dietary fibers and efficient removal of microbial metabolic end product H2. Understanding the impact of dietary PF on the structure of colonic methanogens may help understand the mechanisms of microbe mediated physiological functions of PF. This study investigated the influence of PF on the diversity and quantity and/or activity of colonic methanongens of piglets and finishing pigs. Four archaeal 16S rRNA clone libraries were constructed for piglets and finishers fed with control (Piglet-C and Finisher-C) or PF diet (Piglet-P and Finisher-P). RESULTS: There were 195, 190, 194 and 196 clones obtained from the library Piglet-C, Piglet-P, Finisher-C and Finisher-P, respectively, with corresponding 12, 11, 11 and 16 OTUs (operational taxonomic units). Significant differences of Shannon Index among the four libraries were found (P < 0.05). Libshuff analysis showed that the archaeal community structure among the four libraries were significantly different (P < 0.0001). The predominant methanogens shifted from Methanobrevibacter to Methanobrevibacter and Methanomassiliicoccus-like genus as a result of dietary PF. Supplementation of PF significantly increased the copy numbers of mcrA and dsrA genes (P < 0.05). CONCLUSIONS: Alteration of methanogenic community structure may lead to functional transition from utilization of H2/CO2 to employment of both H2/CO2 and methanol/CO2. Quantification of three functional genes (mcrA, dsrA and fhs) of methanogens, sulfate-reducing bacteria (SRB) and acetogens revealed that dietary PF also increased the activity of methanogens and SRB,probably associated with increased proportion of Methanomassiliicoccus luminyensis-species. Further study is required to examine the interaction between specific methanogens and SRB during fermentation of dietary PF. PMID- 28095774 TI - Multiple focal and macroreentrant left atrial tachycardias originating from a spontaneous scar at the contiguous aorta-left atrium area in a patient with hypertrophic cardiomyopathy: a case report. AB - BACKGROUND: Spontaneous scar-related left atrial tachycardia (AT) is a rare arrhythmia. We describe a patient with hypertrophic cardiomyopathy (HCM) who developed multiple, both focal and macroreentrant left ATs associated with a spontaneous scar located at the aorta-left atrium (LA) contiguous area. CASE PRESENTATION: A 65-year-old man with HCM complained of palpitations. Twelve-lead electrocardiogram showed narrow QRS tachycardia with 2:1 atrioventricular conduction. Two sessions of radiofrequency ablation (RFA) were required to eliminate all left ATs. In the first session, 3-dimensional electroanatomical mapping fused with the image constructed by multi-detector computed tomography showed a clockwise macroreentrant AT (AT1) associated with a low-voltage or dense scar area located along the aorta-LA contiguous area. AT1 was eliminated by RFA to the narrow isthmus with slow conduction velocity within the scar. Additional ATs (AT2-AT4) occurred 1 month after the first ablation. In the second session, AT2 and AT3 were identified as focal ATs with centrifugal propagation and few accompanying fragmentations, and AT4 as a macroreentrant AT with features similar to AT1. AT2 and AT3 were successfully eliminated by performing RFA to the earliest activation site, and AT4 was terminated by performing RFA to the narrow isthmus with slow conduction velocity. No ATs have recurred for 11 months after these RFAs. Interestingly, the substrate for all left ATs was associated with the aorta-LA contiguous area. CONCLUSION: To our knowledge, this is the first case of multiple, both focal and macroreentrant left ATs associated with a contiguous aorta-LA spontaneous scar area in a patient with HCM. PMID- 28095775 TI - ARA-PEPs: a repository of putative sORF-encoded peptides in Arabidopsis thaliana. AB - BACKGROUND: Many eukaryotic RNAs have been considered non-coding as they only contain short open reading frames (sORFs). However, there is increasing evidence for the translation of these sORFs into bioactive peptides with potent signaling, antimicrobial, developmental, antioxidant roles etc. Yet only a few peptides encoded by sORFs are annotated in the model organism Arabidopsis thaliana. RESULTS: To aid the functional annotation of these peptides, we have developed ARA-PEPs (available at http://www.biw.kuleuven.be/CSB/ARA-PEPs ), a repository of putative peptides encoded by sORFs in the A. thaliana genome starting from in house Tiling arrays, RNA-seq data and other publicly available datasets. ARA-PEPs currently lists 13,748 sORF-encoded peptides with transcriptional evidence. In addition to existing data, we have identified 100 novel transcriptionally active regions (TARs) that might encode 341 novel stress-induced peptides (SIPs). To aid in identification of bioactivity, we add functional annotation and sequence conservation to predicted peptides. CONCLUSION: To our knowledge, this is the largest repository of plant peptides encoded by sORFs with transcript evidence, publicly available and this resource will help scientists to effortlessly navigate the list of experimentally studied peptides, the experimental and computational evidence supporting the activity of these peptides and gain new perspectives for peptide discovery. PMID- 28095776 TI - Genetic and economic benefits of selection based on performance recording and genotyping in lower tiers of multi-tiered sheep breeding schemes. AB - BACKGROUND: Performance recording and genotyping in the multiplier tier of multi tiered sheep breeding schemes could potentially reduce the difference in the average genetic merit between nucleus and commercial flocks, and create additional economic benefits for the breeding structure. METHODS: The genetic change in a multiple-trait breeding objective was predicted for various selection strategies that included performance recording, parentage testing and genomic selection. A deterministic simulation model was used to predict selection differentials and the flow of genetic superiority through the different tiers. Cumulative discounted economic benefits were calculated based on trait gains achieved in each of the tiers and considering the extra revenue and associated costs of applying recording, genotyping and selection practices in the multiplier tier of the breeding scheme. RESULTS: Performance recording combined with genomic or parentage information in the multiplier tier reduced the genetic lag between the nucleus and commercial flock by 2 to 3 years. The overall economic benefits of improved performance in the commercial tier offset the costs of recording the multiplier. However, it took more than 18 years before the cumulative net present value of benefits offset the costs at current test prices. Strategies in which recorded multiplier ewes were selected as replacements for the nucleus flock did modestly increase profitability when compared to a closed nucleus structure. Applying genomic selection is the most beneficial strategy if testing costs can be reduced or by genotyping only a proportion of the selection candidates. When the cost of genotyping was reduced, scenarios that combine performance recording with genomic selection were more profitable and reached breakeven point about 10 years earlier. CONCLUSIONS: Economic benefits can be generated in multiplier flocks by implementing performance recording in conjunction with either DNA pedigree recording or genomic technology. These recording practices reduce the long genetic lag between the nucleus and commercial flocks in multi-tiered breeding programs. Under current genotyping costs, the time to breakeven was found to be generally very long, although this varied between strategies. Strategies using either genomic selection or DNA pedigree verification were found to be economically viable provided the price paid for the tests is lower than current prices, in the long-term. PMID- 28095777 TI - Random X-chromosome inactivation dynamics in vivo by single-cell RNA sequencing. AB - BACKGROUND: Random X-chromosome inactivation (rXCI) is important for the maintenance of normal somatic cell functions in female eutherian mammals. The dynamics of X-chromosome inactivation initiation has been widely studied by assessing embryonic stem cell differentiation in vitro. To investigate the phenomenon in vivo, we applied RNA sequencing to single cells from female embryos obtained from a natural intercrossing of two genetically distant mouse strains. Instead of artificially assigning the parental origin of the inactive X chromosome, the inactive X chromosomes in this study were randomly selected from the natural developmental periods and thus included both paternal and maternal origins. RESULTS: The rXCI stages of single cells from the same developmental stage showed heterogeneity. The high resolution of the rXCI dynamics was exhibited. The inactivation orders of X chromosomal genes were determined by their functions, expression levels, and locations; generally, the inactivation order did not exhibit a parental origin preference. New escape genes were identified. Ohno's hypothesis of dosage compensation was refuted by our post implantation stage data. CONCLUSIONS: We found the inactivation orders of X chromosomal genes were determined by their own properties. Generally, the inactivation order did not exhibit a parental origin preference. It provided insights into the gene silencing dynamics during rXCI in vivo. PMID- 28095778 TI - The pangenome of (Antarctic) Pseudoalteromonas bacteria: evolutionary and functional insights. AB - BACKGROUND: Pseudoalteromonas is a genus of ubiquitous marine bacteria used as model organisms to study the biological mechanisms involved in the adaptation to cold conditions. A remarkable feature shared by these bacteria is their ability to produce secondary metabolites with a strong antimicrobial and antitumor activity. Despite their biotechnological relevance, representatives of this genus are still lacking (with few exceptions) an extensive genomic characterization, including features involved in the evolution of secondary metabolites production. Indeed, biotechnological applications would greatly benefit from such analysis. RESULTS: Here, we analyzed the genomes of 38 strains belonging to different Pseudoalteromonas species and isolated from diverse ecological niches, including extreme ones (i.e. Antarctica). These sequences were used to reconstruct the largest Pseudoalteromonas pangenome computed so far, including also the two main groups of Pseudoalteromonas strains (pigmented and not pigmented strains). The downstream analyses were conducted to describe the genomic diversity, both at genus and group levels. This allowed highlighting a remarkable genomic heterogeneity, even for closely related strains. We drafted all the main evolutionary steps that led to the current structure and gene content of Pseudoalteromonas representatives. These, most likely, included an extensive genome reduction and a strong contribution of Horizontal Gene Transfer (HGT), which affected biotechnologically relevant gene sets and occurred in a strain specific fashion. Furthermore, this study also identified the genomic determinants related to some of the most interesting features of the Pseudoalteromonas representatives, such as the production of secondary metabolites, the adaptation to cold temperatures and the resistance to abiotic compounds. CONCLUSIONS: This study poses the bases for a comprehensive understanding of the evolutionary trajectories followed in time by this peculiar bacterial genus and for a focused exploitation of their biotechnological potential. PMID- 28095779 TI - Poly(ADP-ribose) polymerase inhibitors activate the p53 signaling pathway in neural stem/progenitor cells. AB - BACKGROUND: Poly(ADP-ribose) polymerase 1 (PARP-1), which catalyzes poly(ADP ribosyl)ation of proteins by using NAD+ as a substrate, plays a key role in several nuclear events, including DNA repair, replication, and transcription. Recently, PARP-1 was reported to participate in the somatic cell reprogramming process. Previously, we revealed a role for PARP-1 in the induction of neural apoptosis in a cellular model of cerebral ischemia and suggested the possible use of PARP inhibitors as a new therapeutic intervention. In the present study, we examined the effects of PARP inhibitors on neural stem/progenitor cells (NSPCs) of the mouse brain. RESULTS: PARP-1 was more abundant and demonstrated higher activity in NSPCs than in mouse embryonic fibroblasts. Treatment with PARP inhibitors suppressed the formation of neurospheres by NSPCs through the suppression of cell cycle progression and the induction of apoptosis. In order to identify the genes responsible for these effects, we investigated gene expression profiles by microarray analyses and found that several genes in the p53 signaling pathway were upregulated, including Cdkn1a, which is critical for cell cycle control, and Fas, Pidd, Pmaip1, and Bbc3, which are principal factors in the apoptosis pathway. Inhibition of poly(ADP-ribosyl)ation increased the levels of p53 protein, but not p53 mRNA, and enhanced the phosphorylation of p53 at Ser18. Experiments with specific inhibitors and also shRNA demonstrated that PARP-1, but not PARP-2, has a role in the regulation of p53. The effects of PARP inhibitors on NSPCs were not observed in Trp53 -/- NSPCs, suggesting a key role for p53 in these events. CONCLUSIONS: On the basis of the finding that PARP inhibitors facilitated the p53 signaling pathway, we propose that poly(ADP-ribosyl)ation contributes to the proliferation and self-renewal of NSPCs through the suppression of p53 activation. PMID- 28095781 TI - Link prediction in drug-target interactions network using similarity indices. AB - BACKGROUND: In silico drug-target interaction (DTI) prediction plays an integral role in drug repositioning: the discovery of new uses for existing drugs. One popular method of drug repositioning is network-based DTI prediction, which uses complex network theory to predict DTIs from a drug-target network. Currently, most network-based DTI prediction is based on machine learning - methods such as Restricted Boltzmann Machines (RBM) or Support Vector Machines (SVM). These methods require additional information about the characteristics of drugs, targets and DTIs, such as chemical structure, genome sequence, binding types, causes of interactions, etc., and do not perform satisfactorily when such information is unavailable. We propose a new, alternative method for DTI prediction that makes use of only network topology information attempting to solve this problem. RESULTS: We compare our method for DTI prediction against the well-known RBM approach. We show that when applied to the MATADOR database, our approach based on node neighborhoods yield higher precision for high-ranking predictions than RBM when no information regarding DTI types is available. CONCLUSION: This demonstrates that approaches purely based on network topology provide a more suitable approach to DTI prediction in the many real-life situations where little or no prior knowledge is available about the characteristics of drugs, targets, or their interactions. PMID- 28095780 TI - Effectiveness of medication review: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Medication review is often recommended to optimize medication use. In clinical practice it is mostly operationalized as an intervention without co interventions during a short term intervention period. However, most systematic reviews also included co-interventions and prolonged medication optimization interventions. Furthermore, most systematic reviews focused on specific patient groups (e.g. polypharmacy, elderly, hospitalized) and/or on specific outcome measures (e.g. hospital admissions and mortality). Therefore, the objective of this study is to assess the effectiveness of medication review as an isolated short-term intervention, irrespective of the patient population and the outcome measures used. METHODS: A literature search was performed in MEDLINE, EMBASE and Web of Science from their inception through September 2015. Randomized controlled trials (RCTs) with medication review as isolated short term intervention (<3 months) were included. There were no restrictions with regard to patient characteristics and outcome measures. One reviewer extracted and a second checked data. The risk of bias of studies was evaluated independently by two reviewers. A best evidence synthesis was conducted for every outcome measure used in more than one trial. In case of binary variables a meta-analysis was performed in addition to the best evidence synthesis, to quantify the effect. RESULTS: Thirty-one RCTs were included in this systematic review (55% low risk of bias). A best evidence synthesis was conducted for 22 outcome measures. No effect of medication review was found on clinical outcomes (mortality, hospital admissions/healthcare use, the number of patients falling, physical and cognitive functioning), except a decrease in the number of falls per patient. However, in a sensitivity analysis using a more stringent threshold for risk of bias, the conclusion for the effect on the number of falls changed to inconclusive. Furthermore no effect was found on quality of life and evidence was inconclusive about the effect on economical outcome measures. However, an effect was found on most drug-related problems: medication review resulted in a decrease in the number of drug-related problems, more changes in medication, more drugs with dosage decrease and a greater decrease or smaller increase of the number of drugs. CONCLUSIONS: An isolated medication review during a short term intervention period has an effect on most drug-related outcomes, minimal effect on clinical outcomes and no effect on quality of life. No conclusion can be drawn about the effect on economical outcome measures. Therefore, it should be considered to stop performing cross sectional medication reviews as standard care. PMID- 28095782 TI - Genome-scale transcriptional study of hybrid effects and regulatory divergence in an F1 hybrid Ruellia (Wild Petunias: Acanthaceae) and its parents. AB - BACKGROUND: New combinations of divergent genomes can give rise to novel genetic functions in resulting hybrid progeny. Such functions may yield opportunities for ecological divergence, contributing ultimately to reproductive isolation and evolutionary longevity of nascent hybrid lineages. In plants, the degree to which transgressive genotypes contribute to floral novelty remains a question of key interest. Here, we generated an F1 hybrid plant between the red-flowered Ruellia elegans and yellow flowered R. speciosa. RNA-seq technology was used to explore differential gene expression between the hybrid and its two parents, with emphasis on genetic elements involved in the production of floral anthocyanin pigments. RESULTS: The hybrid was purple flowered and produced novel floral delphinidin pigments not manufactured by either parent. We found that nearly a fifth of all 86,475 unigenes expressed were unique to the hybrid. The majority of hybrid unigenes (80.97%) showed a pattern of complete dominance to one parent or the other although this ratio was uneven, suggesting asymmetrical influence of parental genomes on the progeny transcriptome. However, 8.87% of all transcripts within the hybrid were expressed at significantly higher or lower mean levels than observed for either parent. A total of 28 unigenes coding putatively for eight core enzymes in the anthocyanin pathway were recovered, along with three candidate MYBs involved in anthocyanin regulation. CONCLUSION: Our results suggest that models of gene evolution that explain phenotypic novelty and hybrid establishment in plants may need to include transgressive effects. Additionally, our results lend insight into the potential for floral novelty that derives from unions of divergent genomes. These findings serve as a starting point to further investigate molecular mechanisms involved in flower color transitions in Ruellia. PMID- 28095783 TI - Genome-wide expression profiling in muscle and subcutaneous fat of lambs in response to the intake of concentrate supplemented with vitamin E. AB - BACKGROUND: The objective of this study was to acquire a broader, more comprehensive picture of the transcriptional changes in the L. Thoracis muscle (LT) and subcutaneous fat (SF) of lambs supplemented with vitamin E. Furthermore, we aimed to identify novel genes involved in the metabolism of vitamin E that might also be involved in meat quality. In the first treatment, seven lambs were fed a basal concentrate from weaning to slaughter (CON). In the second treatment, seven lambs received basal concentrate from weaning to 4.71 +/- 2.62 days and thereafter concentrate supplemented with 500 mg dl-alpha-tocopheryl acetate/kg (VE) during the last 33.28 +/- 1.07 days before slaughter. RESULTS: The addition of vitamin E to the diet increased the alpha-tocopherol muscle content and drastically diminished the lipid oxidation of meat. Gene expression profiles for treatments VE and CON were clearly separated from each other in the LT and SF. Vitamin E supplementation had a dramatic effect on subcutaneous fat gene expression, showing general up-regulation of significant genes, compared to CON treatment. In LT, vitamin E supplementation caused down-regulation of genes related to intracellular signaling cascade. Functional analysis of SF showed that vitamin E supplementation caused up-regulation of the lipid biosynthesis process, cholesterol, and sterol and steroid biosynthesis, and it down-regulated genes related to the stress response. CONCLUSIONS: Different gene expression patterns were found between the SF and LT, suggesting tissue specific responses to vitamin E supplementation. Our study enabled us to identify novel genes and metabolic pathways related to vitamin E metabolism that might be implicated in meat quality. Further exploration of these genes and vitamin E could lead to a better understanding of how vitamin E affects the oxidative process that occurs in manufactured meat products. PMID- 28095784 TI - Identification of a novel bovine enterovirus possessing highly divergent amino acid sequences in capsid protein. AB - BACKGROUND: Bovine enterovirus (BEV) belongs to the species Enterovirus E or F, genus Enterovirus and family Picornaviridae. Although numerous studies have identified BEVs in the feces of cattle with diarrhea, the pathogenicity of BEVs remains unclear. Previously, we reported the detection of novel kobu-like virus in calf feces, by metagenomics analysis. In the present study, we identified a novel BEV in diarrheal feces collected for that survey. Complete genome sequences were determined by deep sequencing in feces. Secondary RNA structure analysis of the 5' untranslated region (UTR), phylogenetic tree construction and pairwise identity analysis were conducted. RESULTS: The complete genome sequences of BEV were genetically distant from other EVs and the VP1 coding region contained novel and unique amino acid sequences. We named this strain as BEV AN12/Bos taurus/JPN/2014 (referred to as BEV-AN12). According to genome analysis, the genome length of this virus is 7414 nucleotides excluding the poly (A) tail and its genome consists of a 5'UTR, open reading frame encoding a single polyprotein, and 3'UTR. The results of secondary RNA structure analysis showed that in the 5'UTR, BEV-AN12 had an additional clover leaf structure and small stem loop structure, similarly to other BEVs. In pairwise identity analysis, BEV-AN12 showed high amino acid (aa) identities to Enterovirus F in the polyprotein, P2 and P3 regions (aa identity >=82.4%). Therefore, BEV-AN12 is closely related to Enterovirus F. However, aa sequences in the capsid protein regions, particularly the VP1 encoding region, showed significantly low aa identity to other viruses in genus Enterovirus (VP1 aa identity <=58.6%). In addition, BEV-AN12 branched separately from Enterovirus E and F in phylogenetic trees based on the aa sequences of P1 and VP1, although it clustered with Enterovirus F in trees based on sequences in the P2 and P3 genome region. CONCLUSIONS: We identified novel BEV possessing highly divergent aa sequences in the VP1 coding region in Japan. According to species definition, we proposed naming this strain as "Enterovirus K", which is a novel species within genus Enterovirus. Further genomic studies are needed to understand the pathogenicity of BEVs. PMID- 28095785 TI - Risk factors and medical costs for healthcare-associated carbapenem-resistant Escherichia coli infection among hospitalized patients in a Chinese teaching hospital. AB - BACKGROUND: The emergence and spread of Carbapenem-resistant Escherichia coli (CREC) is becoming a serious problem in Chinese hospitals, however, the data on this is scarce. Therefore, we investigate the risk factors for healthcare associated CREC infection and study the incidence, antibiotic resistance and medical costs of CREC infections in our hospital. METHODS: We conducted a retrospective, matched case-control-control, parallel study in a tertiary teaching hospital. Patients admitted between January 2012 and December 2015 were included in this study. For patients with healthcare-associated CREC infection, two matched subject groups were created; one group with healthcare-associated CSEC infection and the other group without infection. RESULTS: Multivariate conditional logistic regression analysis demonstrated that prior hospital stay (<6 months) (OR:3.96; 95%CI:1.26-12.42), tracheostomy (OR:2.24; 95%CI: 1.14 4.38), central venous catheter insertion (OR: 8.15; 95%CI: 2.31-28.72), carbapenem exposure (OR: 12.02; 95%CI: 1.52-95.4), urinary system disease (OR: 16.69; 95%CI: 3.01-89.76), low hemoglobin (OR: 2.83; 95%CI: 1.46-5.50), and high blood glucose are associated (OR: 7.01; 95%CI: 1.89-26.02) with CREC infection. Total costs (p = 0.00), medical examination costs (p = 0.00), medical test costs (p = 0.00), total drug costs (p = 0.00) and ant-infective drug costs (p = 0.00) for the CREC group were significantly higher than those for the no infection group. Medical examination costs (p = 0.03), total drug costs (p = 0.03), and anti-infective drug costs (p = 0.01) for the CREC group were significantly higher than for the CSEC group. Mortality in CREC group was significantly higher than the CSEC group (p = 0.01) and no infection group (p = 0.01). CONCLUSION: Many factors were discovered for acquisition of healthcare-associated CREC infection. CREC isolates were resistant to most antibiotics, and had some association with high financial burden and increased mortality. PMID- 28095786 TI - CTRC gene polymorphism (p.G60=; c.180 C > T) in acute pancreatitis. AB - BACKGROUND: The aim of the study was to determine the relationship between the presence of p.G60 = polymorphism (c.180C > T; rs497078) CTRC and the incidence together with the clinical course of acute pancreatitis (AP). METHODS: Two hundred ninety-nine people suffering from AP and 417 healthy volunteers were subjected to the study. DNA was isolated from blood samples. RESULTS: CTRC p.G60 = polymorphism (c.180C > T) occurred more frequently in the AP group (p = 0.015). The CT and TT genotype was found in 27.8% of the AP patients and in 19.9% of the healthy subjects (p = 0.017). No significant correlation was found between having the CT and TT genotype and the severity of the AP clinical course. In 6 patients (2%) with the CT genotype, a SPINK1 gene mutation was found, while in the control group it was found in 3 patients (0.7%), (p > 0.05). All patients with the present SPINK1 mutation with the CT genotype had a moderate or a severe course of the disease (p = 0.0007). CONCLUSIONS: CTRC polymorphism Hetero p.G60=; c.180C > T increases the risk of an AP occurrence and together with the SPINK 1 mutation, may be responsible for a more severe course of the disease. PMID- 28095787 TI - The effects of habitual functional training on physical functioning in patients after hip fracture: the protocol of the HIPFRAC study. AB - BACKGROUND: The survivors after hip fracture often report severe pain and loss of physical functioning. The poor outcomes cause negative impact on the person's physical functioning and quality of life and put a financial burden on society. Rehabilitation is important to improve physical functioning after hip fracture. To maintain the continuity in rehabilitation we have an assumption that it is of utmost importance to continue and progress the functional training that already started at the hospital, while the patients are transferred to short-term stays in a nursing home before they are returning to home. The aim presently is to examine the effects of a functional training program, initiated by the physiotherapist and performed by the nurses, on physical functioning while the patients are at short term stays in primary health care. METHODS/DESIGN: Inclusion and randomization will take place during hospital stay. All patients 65 years or above who have sustained a hip fracture are eligible, except if they have a score on Mini Mental State (MMS-E) of less than 15, could walk less than 10 m prior to the fracture, or are terminally ill. The intervention consists of additional functional training as part of the habitual daily routine during short term stays at nursing homes after discharge from hospital. The primary outcome is physical functioning measured by the Short Physical Performance Battery (SPPB). Secondary outcomes are Timed "Up & Go" (TUG), hand grip strength, activPAL accelerometer, and self-reported measures like new Mobility Score (NMS), Walking Habits, University of California Los Angeles (UCLA) activity scale, Fall efficacy scale (FES), EuroQol health status measure (EQ-5D-5 L), and pain. DISCUSSION: Issues related to internal and external validity in the study are discussed. The outline for the arguments in this protocol is organized according to the guidelines of the Medical Research Council (MRC) guidance on how to develop and evaluate complex interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT02780076 . PMID- 28095788 TI - Are interventions to increase the uptake of screening for cardiovascular disease risk factors effective? A systematic review and meta-analysis. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death globally. However, many individuals are unaware of their CVD risk factors. The objective of this systematic review is to determine the effectiveness of existing intervention strategies to increase uptake of CVD risk factors screening. METHODS: A systematic search was conducted through Pubmed, CINAHL, EMBASE and Cochrane Central Register of Controlled Trials. Additional articles were located through cross-checking of the references list and bibliography citations of the included studies and previous review papers. We included intervention studies with controlled or baseline comparison groups that were conducted in primary care practices or the community, targeted at adult populations (randomized controlled trials, non-randomized trials with controlled groups and pre- and post intervention studies). The interventions were targeted either at individuals, communities, health care professionals or the health-care system. The main outcome of interest was the relative risk (RR) of screening uptake rates due to the intervention. RESULTS: We included 21 studies in the meta-analysis. The risk of bias for randomization was low to medium in the randomized controlled trials, except for one, and high in the non-randomized trials. Two analyses were performed; optimistic (using the highest effect sizes) and pessimistic (using the lowest effect sizes). Overall, interventions were shown to increase the uptake of screening for CVD risk factors (RR 1.443; 95% CI 1.264 to 1.648 for pessimistic analysis and RR 1.680; 95% CI 1.420 to 1.988 for optimistic analysis). Effective interventions that increased screening participation included: use of physician reminders (RR ranged between 1.392; 95% CI 1.192 to 1.625, and 1.471; 95% CI 1.304 to 1.660), use of dedicated personnel (RR ranged between 1.510; 95% CI 1.014 to 2.247, and 2.536; 95% CI 1.297 to 4.960) and provision of financial incentives for screening (RR 1.462; 95% CI 1.068 to 2.000). Meta-regression analysis showed that the effect of CVD risk factors screening uptake was not associated with study design, types of population nor types of interventions. CONCLUSIONS: Interventions using physician reminders, using dedicated personnel to deliver screening, and provision of financial incentives were found to be effective in increasing CVD risk factors screening uptake. PMID- 28095789 TI - miRNA-338-3p/CDK4 signaling pathway suppressed hepatic stellate cell activation and proliferation. AB - BACKGROUND: Activated hepatic stellate cell (HSC) is the main fibrogenic cell type in the injured liver. miRNA plays an important role in activation and proliferation of HSC. METHODS: Our previous study examined the expression profiles of microRNAs in quiescent and activated HSC. Real-time PCR and western blot were used to detect the expression of Collagen type I (Col 1) and Alpha Smooth Muscle Actin (alpha-SMA). CCK-8 and Edu assay was used to measure the proliferation rate of HSC. Luciferase reporter gene assay was used to tested the binding between miR-338-3p and Cyclin-dependent kinase 4 (CDK4). RESULTS: We found overexpression of miR-338-3p could inhibit Col 1 and alpha-SMA, two major HSC activation markers, whereas miR-338-3p inhibitor could promote them. Besides, miR-338-3p overexpression could suppress the growth rate of HSC. Further, we found that CDK4, a pleiotropic signaling protein, was a direct target gene of miR 338-3p. Moreover, we found that overexpression of CDK4 could block the effects of miR-338-3p. CONCLUSIONS: We found miR-338-3p is an anti-fibrotic miRNA which inhibits cell activation and proliferation. Our findings suggest that miR-338 3p/CDK4 signaling pathway participates in the regulation of HSC activation and growth and may act as a novel target for further anti-fibrotic therapy. PMID- 28095790 TI - Comparison of loop-mediated isothermal amplification assay and smear microscopy with culture for the diagnostic accuracy of tuberculosis. AB - BACKGROUND: Tuberculosis (TB) caused by Mycobacterium tuberculosis is one of the leading causes of death from infectious diseases worldwide. Sputum smear microscopy remains the most widely available pulmonary TB diagnostic tool particularly in resource limited settings. A highly sensitive diagnostic with minimal infrastructure, cost and training is required. Hence, we assessed the diagnostic performance of Loop-mediated isothermal amplification (LAMP) assay in detecting M.tuberculosis infection in sputum sample compared to LED fluorescent smear microscopy and culture. METHOD: A cross-sectional study was conducted at the University of Gondar Hospital from June 01, 2015 to August 30, 2015. Pulmonary TB diagnosis using sputum LED fluorescence smear microscopy, TB-LAMP assay and culture were done. A descriptive analysis was used to determine demographic characteristics of the study participants. Analysis of sensitivity and specificity for smear microscopy and TB-LAMP compared with culture as a reference test was performed. Cohen's kappa was calculated as a measure of agreement between the tests. RESULTS: A total of 78 pulmonary presumptive TB patients sputum sample were analyzed. The overall sensitivity and specificity of LAMP were 75 and 98%, respectively. Among smear negative sputum samples, 33.3% sensitivity and 100% specificity of LAMP were observed. Smear microscopy showed 78.6% sensitivity and 98% specificity. LAMP and smear in series had sensitivity of 67.8% and specificity of 100%. LAMP and smear in parallel had sensitivity of 85.7% and specificity of 96%. The agreement between LAMP and fluorescent smear microscopy tests was very good (kappa = 0.83, P-value <=0.0001). CONCLUSIONS: TB LAMP showed similar specificity but a slightly lower sensitivity with LED fluorescence microscopy. The specificity of LAMP and smear microscopy in series was high. The sensitivity of LAMP was insufficient for smear negative sputum samples. PMID- 28095791 TI - A person-centred and thriving-promoting intervention in nursing homes - study protocol for the U-Age nursing home multi-centre, non-equivalent controlled group before-after trial. AB - BACKGROUND: The literature suggests that person-centred care can contribute to quality of life and wellbeing of nursing home residents, relatives and staff. However, there is sparse research evidence on how person-centred care can be operationalised and implemented in practice, and the extent to which it may promote wellbeing and satisfaction. Therefore, the U-Age nursing home study was initiated to deepen the understanding of how to integrate person-centred care into daily practice and to explore the effects and meanings of this. METHODS: The study aims to evaluate effects and meanings of a person-centred and thriving promoting intervention in nursing homes through a multi-centre, non-equivalent controlled group before-after trial design. Three nursing homes across three international sites have been allocated to a person-centred and thriving promoting intervention group, and three nursing homes have been allocated to an inert control group. Staff at intervention sites will participate in a 12-month interactive educational programme that operationalises thriving-promoting and person-centred care three dimensions: 1) Doing a little extra, 2) Developing a caring environment, and 3) Assessing and meeting highly prioritised psychosocial needs. A pedagogical framework will guide the intervention. The primary study endpoints are; residents' thriving, relatives' satisfaction with care and staff job satisfaction. Secondary endpoints are; resident, relative and staff experiences of the caring environment, relatives' experience of visiting their relative and the nursing home, as well as staff stress of conscience and perceived person-centredness of care. Data on study endpoints will be collected pre-intervention, post-intervention, and at a six-month follow up. Interviews will be conducted with relatives and staff to explore experiences and meanings of the intervention. DISCUSSION: The study is expected to provide evidence that can inform further research, policy and practice development on if and how person centred care may improve wellbeing, thriving and satisfaction for people who reside in, visit or work in nursing homes. The combination of quantitative and qualitative data will illuminate the operationalisation, effects and meaning of person-centred and thriving-promoting care. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov March 19, 2016, identifier NCT02714452 . PMID- 28095792 TI - Multi-contrast brain magnetic resonance image super-resolution using the local weight similarity. AB - BACKGROUND: Low-resolution images may be acquired in magnetic resonance imaging (MRI) due to limited data acquisition time or other physical constraints, and their resolutions can be improved with super-resolution methods. Since MRI can offer images of an object with different contrasts, e.g., T1-weighted or T2 weighted, the shared information between inter-contrast images can be used to benefit super-resolution. METHODS: In this study, an MRI image super-resolution approach to enhance in-plane resolution is proposed by exploring the statistical information estimated from another contrast MRI image that shares similar anatomical structures. We assume some edge structures are shown both in T1 weighted and T2-weighted MRI brain images acquired of the same subject, and the proposed approach aims to recover such kind of structures to generate a high resolution image from its low-resolution counterpart. RESULTS: The statistical information produces a local weight of image that are found to be nearly invariant to the image contrast and thus this weight can be used to transfer the shared information from one contrast to another. We analyze this property with comprehensive mathematics as well as numerical experiments. CONCLUSION: Experimental results demonstrate that the image quality of low-resolution images can be remarkably improved with the proposed method if this weight is borrowed from a high resolution image with another contrast. Multi-contrast MRI Image Super-resolution with Contrast-invariant Regression Weights. PMID- 28095793 TI - Genetic variation underlying renal uric acid excretion in Hispanic children: the Viva La Familia Study. AB - BACKGROUND: Reduced renal excretion of uric acid plays a significant role in the development of hyperuricemia and gout in adults. Hyperuricemia has been associated with chronic kidney disease and cardiovascular disease in children and adults. There are limited genome-wide association studies associating genetic polymorphisms with renal urate excretion measures. Therefore, we investigated the genetic factors that influence the excretion of uric acid and related indices in 768 Hispanic children of the Viva La Familia Study. METHODS: We performed a genome-wide association analysis for 24-h urinary excretion measures such as urinary uric acid/urinary creatinine ratio, uric acid clearance, fractional excretion of uric acid, and glomerular load of uric acid in SOLAR, while accounting for non-independence among family members. RESULTS: All renal urate excretion measures were significantly heritable (p <2 * 10-6) and ranged from 0.41 to 0.74. Empirical threshold for genome-wide significance was set at p <1 * 10-7. We observed a strong association (p < 8 * 10-8) of uric acid clearance with a single nucleotide polymorphism (SNP) in zinc finger protein 446 (ZNF446) (rs2033711 (A/G), MAF: 0.30). The minor allele (G) was associated with increased uric acid clearance. Also, we found suggestive associations of uric acid clearance with SNPs in ZNF324, ZNF584, and ZNF132 (in a 72 kb region of 19q13; p <1 * 10-6, MAFs: 0.28-0.31). CONCLUSION: For the first time, we showed the importance of 19q13 region in the regulation of renal urate excretion in Hispanic children. Our findings indicate differences in inherent genetic architecture and shared environmental risk factors between our cohort and other pediatric and adult populations. PMID- 28095794 TI - Development of an algorithm for phenotypic screening of carbapenemase-producing Enterobacteriaceae in the routine laboratory. AB - BACKGROUND: Carbapenemase-producing Enterobacteriaceae (CPE) are difficult to identify among carbapenem non-susceptible Enterobacteriaceae (NSE). We designed phenotypic strategies giving priority to high sensitivity for screening putative CPE before further testing. METHODS: Presence of carbapenemase-encoding genes in ertapenem NSE (MIC > 0.5 mg/l) consecutively isolated in 80 French laboratories between November 2011 and April 2012 was determined by the Check-MDR-CT103 array method. Using the Mueller-Hinton (MH) disk diffusion method, clinical diameter breakpoints of carbapenems other than ertapenem, piperazicillin+tazobactam, ticarcillin+clavulanate and cefepime as well as diameter cut-offs for these antibiotics and temocillin were evaluated alone or combined to determine their performances (sensitivity, specificity, positive and negative likelihood ratios) for identifying putative CPE among these ertapenem-NSE isolates. To increase the screening specificity, these antibiotics were also tested on cloxacillin containing MH when carbapenem NSE isolates belonged to species producing chromosomal cephalosporinase (AmpC) but Escherichia coli. RESULTS: Out of the 349 ertapenem NSE, 52 (14.9%) were CPE, including 39 producing OXA-48 group carbapenemase, eight KPC and five MBL. A screening strategy based on the following diameter cut offs, ticarcillin+clavulanate <15 mm, temocillin <15 mm, meropenem or imipenem <22 mm, and cefepime <26 mm, showed 100% sensitivity and 68.1% specificity with the better likelihood ratios combination. The specificity increased when a diameter cut-off <32 mm for imipenem (76.1%) or meropenem (78.8%) further tested on cloxacillin-containing MH was added to the previous strategy for AmpC-producing isolates. CONCLUSION: The proposed strategies that allowed for increasing the likelihood of CPE among ertapenem-NSE isolates should be considered as a surrogate for carbapenemase production before further CPE confirmatory testing. PMID- 28095795 TI - Intrathecal magnesium sulfate does not reduce the ED50 of intrathecal hyperbaric bupivacaine for cesarean delivery in healthy parturients: a prospective, double blinded, randomized dose-response trial using the sequential allocation method. AB - BACKGROUND: Addition of intrathecal magnesium sulfate to local anesthetics has been reported to potentiate spinal anesthesia and prolong analgesia in parturients. The current study was to determine whether intrathecal magnesium sulfate would reduce the dose of hyperbaric bupivacaine in spinal anesthesia with bupivacaine and sufentanil for cesarean delivery. METHODS: Sixty healthy parturients undergoing scheduled cesarean delivery were randomly assigned to receive spinal anesthesia with 0.5% hyperbaric bupivacaine and 5 MUg sufentanil with either 0.9% sodium chloride (Control group) or 50% magnesium sulfate (50 mg) (Magnesium group). Effective anesthesia was defined as a bilateral T5 sensory block level achieved within 10 min of intrathecal drug administration and no additional epidural anesthetic was required during surgery. Characteristic of spinal anesthesia and the incidence of side effects were observed. The ED50 for both groups was calculated using the Dixon and Massey formula. RESULTS: There was no significant difference in the ED50 of bupivacaine between the Magnesium group and the Control group (4.9 mg vs 4.7 mg) (P = 0.53). The duration of spinal anesthesia (183 min vs 148 min, P < 0.001) was longer, the consumption of fentanyl during the first 24 h postoperatively (343 MUg vs 550 MUg, P < 0.001) was lower in the Magnesium group than that in the Control group. CONCLUSIONS: Intrathecal magnesium sulfate (50 mg) did not reduce the dose requirement of intrathecal bupivacaine, but can extend the duration of spinal anesthesia with no obvious additional side effects. TRIAL REGISTRATION: This study was registered with Chinese Clinical Trial Registry (ChiCTR) on 15 Jul. 2014 and was given a trial ID number ChiCTR-TRC- 14004954 . PMID- 28095796 TI - A severe case of visceral leishmaniasis and liposomal amphotericin B treatment failure in an immunosuppressed patient 15 years after exposure. AB - BACKGROUND: Visceral leishmaniasis (VL) is a protozoan disease, which is responsible for 200.000-400.000 yearly infections worldwide. If left untreated, the fatality rate can be as high as 100% within 2 years. 90% of cases occur in just six countries: India, Bangladesh, Sudan, South Sudan, Ethiopia and Brazil. It is thus a disease rarely seen by physicians in Europe or North America. We report on the fatal case of VL in an 80-year-old immunosuppressed patient who presented with a latency of over 15 years after having visited an endemic region. This is the first report showing such extreme latency of VL in a European traveller. This case is furthermore unusual because it suggests primary treatment failure to liposomal amphotericin B. CASE PRESENTATION: An 80-year-old man who was on immunosuppressive treatment due to a non-specific inflammatory disease of the liver and kidney presented to our hospital with recurrent fever, fatigue and bloody diarrhoea. Histopathological analysis from a colon biopsy showed intracellular amastigotes. The diagnosis of VL was confirmed by polymerase-chain reaction (PCR) of the colon biopsy. PCR was also performed in plasma, a bronchopulmonary lavage, a lymph node, liver and bone marrow biopsy and proved L. donovani as causative species. The disseminated infection was unresponsive to treatment with liposomal amphotericin B as recommended in immunosuppressed individuals despite stopping immunosuppressive treatment. CONCLUSION: Imported cases of VL to non-endemic regions are increasing due to extensive international travel and migration. Furthermore, the increase of elderly patients and immunosuppressed individuals, secondary to HIV, post-transplant and chemotherapeutic agents, has resulted in an increase of VL also in endemic regions of Europe. It is thus important for physicians to be able to recognize the infection. This case also demonstrates treatment failure to amphotericin B, which was only a known problem in patients with HIV until now. The knowledge of this as a possible complication is important for specialists treating the disease. PMID- 28095797 TI - Cocaine/crack use is not associated with fibrosis progression measured by AST-to Platelet Ratio Index in HIV-HCV co-infected patients: a cohort study. AB - BACKGROUND: Cocaine and crack use has been associated with HIV and HCV infections, but its consequences on HCV progression have not been well established. We analyzed the impact of cocaine/crack use on liver fibrosis progression in a cohort of HIV-HCV co-infected patients. METHODS: A Canadian multicenter prospective cohort study followed 1238 HIV-HCV co-infected persons every 6 months between 2003 and 2013. Data were analyzed from 573 patients with positive HCV RNA, not on HCV treatment, without significant liver fibrosis (AST to-Platelet Ratio Index (APRI) <1.5) or history of end-stage liver disease at baseline, and having at least two study visits. Recent cocaine/crack use was defined as use within 6 months of cohort entry. Incidence rates of progression to significant fibrosis (APRI >= 1.5) were determined according to recent cocaine/crack use. Cox Proportional Hazards models were used to assess the association between time-updated cocaine/crack use and progression to APRI >= 1.5 adjusting for age, sex, HCV duration, baseline ln(APRI), and time-updated alcohol abuse, history of other drug use and CD4+ cell count. RESULTS: At baseline, 211 persons (37%) were recent cocaine/crack users and 501 (87%) ever used cocaine/crack. Recent users did not differ from non-recent users on gender, age, and CD4+ T-cell count. Over 1599 person-years of follow up (522 PY in recent users, 887 PY in previous users and 190 PY in never users),158 (28%) persons developed significant fibrosis (9.9/100 PY; 95% CI, 8.3-11.4); 56 (27%) recent users (10.7/100 PY; 7.9-13.5), 81 (28%) previous users (9.1/100 PY; 7.1-11.1), and 21 (29%) never users (11.1/100 PY; 6.3-15.8). There was no association between ever having used or time-updated cocaine/crack use and progression to APRI >= 1.5 (adjusted HR (95%CI): 0.96 (0.58, 1.57) and 0.88;(0.63-1.25), respectively). CONCLUSIONS: We could not find evidence that cocaine/crack use is associated with progression to advanced liver fibrosis in our prospective study of HIV-HCV co-infected patients. PMID- 28095798 TI - miR-27b inhibits fibroblast activation via targeting TGFbeta signaling pathway. AB - BACKGROUND: MicroRNAs are a group of small RNAs that regulate gene expression at the posttranscriptional level. They regulate almost every aspect of cellular processes. In this study, we investigated whether miR-27b regulates pulmonary fibroblast activation. RESULTS: We found that miR-27b was down-regulated in fibrotic lungs and fibroblasts from an experimental mouse model of pulmonary fibrosis. The overexpression of miR-27b with a lentiviral vector inhibited TGFbeta1-stimulated mRNA expression of collagens (COL1A1, COL3A1, and COL4A1) and alpha-smooth muscle actin, and protein expression of Col3A1 and alpha-smooth muscle actin in LL29 human pulmonary fibroblasts. miR-27b also reduced contractile activity of LL29. TGFbeta receptor 1 and SMAD2 were identified as the targets of miR-27b by 3'-untranslated region luciferase reporter and western blotting assays. CONCLUSIONS: Our results suggest that miR-27b is an anti fibrotic microRNA that inhibits fibroblast activation by targeting TGFbeta receptor 1 and SMAD2. This discovery may provide new targets for therapeutic interventions of idiopathic pulmonary fibrosis. PMID- 28095799 TI - MultiDataSet: an R package for encapsulating multiple data sets with application to omic data integration. AB - BACKGROUND: Reduction in the cost of genomic assays has generated large amounts of biomedical-related data. As a result, current studies perform multiple experiments in the same subjects. While Bioconductor's methods and classes implemented in different packages manage individual experiments, there is not a standard class to properly manage different omic datasets from the same subjects. In addition, most R/Bioconductor packages that have been designed to integrate and visualize biological data often use basic data structures with no clear general methods, such as subsetting or selecting samples. RESULTS: To cover this need, we have developed MultiDataSet, a new R class based on Bioconductor standards, designed to encapsulate multiple data sets. MultiDataSet deals with the usual difficulties of managing multiple and non-complete data sets while offering a simple and general way of subsetting features and selecting samples. We illustrate the use of MultiDataSet in three common situations: 1) performing integration analysis with third party packages; 2) creating new methods and functions for omic data integration; 3) encapsulating new unimplemented data from any biological experiment. CONCLUSIONS: MultiDataSet is a suitable class for data integration under R and Bioconductor framework. PMID- 28095800 TI - Diet, gonadal sex, and sex chromosome complement influence white adipose tissue miRNA expression. AB - BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression by targeting specific mRNA species for degradation or interfering with translation. Specific miRNAs are key regulators of adipogenesis, and are expressed at different levels in adipose tissue from lean and obese mice. The degree of lipid accumulation and distribution of white adipose tissue differs between males and females, and it is unknown whether sex differences in adipose tissue-specific miRNA expression may contribute to this dimorphism. Typically, sex differences are attributed to hormones secreted from ovaries or testes. However, the sex chromosome complement (XX versus XY) is also a determinant of sex differences and may regulate miRNA expression in adipocytes. RESULTS: To identify sex differences in adipose tissue miRNA expression and to understand the underlying mechanisms, we performed high-throughput miRNA sequencing in gonadal fat depots of the Four Core Genotypes mouse model. This model, which consists of XX female, XX male, XY female, and XY male mice, allowed us to assess independent effects of gonadal type (male vs. female) and sex chromosome complement (XX vs. XY) on miRNA expression profiles. We have also assessed the effects of a high fat diet on sex differences in adipose tissue miRNA profiles. We identified a male female effect on the overall miRNA expression profile in mice fed a chow diet, with a bias toward higher expression in male compared to female gonadal adipose tissue. This sex bias disappeared after gonadectomy, suggesting that circulating levels of gonadal secretions modulate the miRNA expression profile. After 16 weeks of high fat diet, the miRNA expression distribution was shifted toward higher expression in XY vs. XX adipose tissue. Principal component analysis revealed that high fat diet has a substantial effect on miRNA profile variance, while gonadal secretions and sex chromosome complement each have milder effects. CONCLUSIONS: Our results demonstrate that the overall miRNA expression profile in adipose tissue is influenced by gonadal hormones and the sex chromosome complement, and that expression profiles change in response to gonadectomy and high fat diet. Differential miRNA expression profiles may contribute to sex differences in adipose tissue gene expression, adipose tissue development, and diet-induced obesity. PMID- 28095801 TI - Providing lipid-based nutrient supplement during pregnancy does not reduce the risk of maternal P falciparum parasitaemia and reproductive tract infections: a randomised controlled trial. AB - BACKGROUND: Maternal infections are associated with maternal and foetal adverse outcomes. Nutrient supplementation during pregnancy may reduce the occurrence of infections by improving maternal immunity. We aimed to investigate the impact of small-quantity lipid-based nutrient supplement (SQ-LNS) on the occurrence of Plasmodium falciparum parasitaemia during pregnancy and trichomoniasis, vaginal candidiasis and urinary tract infection (UTI) after delivery. METHODS: Pregnant Malawian women enrolled in the iLiNS-DYAD trial receiving daily supplementation with SQ-LNS, multiple micronutrients (MMN) or iron & folic acid (IFA) from <20 gestation weeks (gw) were assessed for P. falciparum parasitaemia at 32 gw using rapid diagnostic testing (RDT), at 36 gw using polymerase chain reaction (PCR) and at delivery using both RDT and PCR; and at one week after delivery for trichomoniasis and vaginal candidiasis using wet mount microscopy and for UTI using urine dipstick analysis. The prevalence of each infection by intervention group was estimated at the prescribed time points and the global null hypothesis was tested using logistic regression. Adjusted analyses were performed using preselected covariates. RESULTS: The prevalence of P. falciparum parasitaemia was 10.7% at 32 gw, 9% at 36 gw, and 8.3% by RDT and 20.2% by PCR at delivery. After delivery the prevalence of trichomoniasis was 10.5%, vaginal candidiasis was 0.5%, and UTI was 3.1%. There were no differences between intervention groups in the prevalence of any of the infections. CONCLUSION: In this population, SQ-LNS did not influence the occurrence of maternal P. falciparum parasitaemia, trichomoniasis, vaginal candidiasis or UTI. TRIAL REGISTRATION: Identifier: NCT01239693 (10 November 2010). PMID- 28095802 TI - A case control study investigating factors associated with high infant death in Saiha district of Mizoram, India bordering Myanmar. AB - BACKGROUND: Infant mortality has dropped considerably in India over the last 5 years. A sharp contrast to this decline in national average of infant mortality is the rate recorded during 2014-2015 from the southernmost district of Saiha, Mizoram having a common international border with Myanmar. As this district specific rate (113 per 1000 live births) is 3 times higher compared to the national and state average, the present investigation was carried out to identify associated factors. METHODS: We examined secondary data made available by the national health mission, consulted with local community members and generated primary data through interviews. A case-control study design was followed. Mothers, who delivered a child during 2013-2015 and subsequently lost them due to infant death, formed the case group and controls were selected from same neighborhood as with case-mothers. The mother and child tracking system maintained by the district specific national health mission office was used for recruiting cases and controls. A total of 195 mothers were interviewed; 66 of them belonged to 'cases' and 129 were 'controls'. RESULTS: The mean age of the respondents was 27 years (median 27; SD +/- 5; minimum 17 & maximum 44). In uni variate analyses 'child delivery at home', 'low birth weight', 'non-attendance of school by mothers', 'completed standard of school education by mothers', 'both parents working', 'mothers receiving blood transfusion during last pregnancy', and 'fourth or more birth order during last pregnancy' were associated with infant deaths. Intriguingly, the number of daily kuhva (raw areca nut) intake during last pregnancy was significantly higher among case-mothers compared to controls. In conditional logistic regression, 'low birth weight' (adjusted OR (AOR) 14.7; 95% CI 2.1-101.8; p = 0.006), and 'consumption of 4 or more kuhva per day' (AOR 8; 95% CI 1.9-34.3; p = 0.005) were independently associated with infant-death-experiences. CONCLUSION: The present investigation merits due attention from policy makers and health planners for immediate improvement in peri-natal and neonatal care services in the remote district of Saiha. Need for further research exploring socio-behavioural issues around areca nut consumption and effects of interventions to reduce areca nut intake on maternal and children health are underscored. PMID- 28095803 TI - Increased glomerulonephritis recurrence after living related donation. AB - BACKGROUND: Kidney transplantation confers superior outcomes for patients with end stage kidney disease, and live donor kidneys associate with superior outcomes compared to deceased donor kidneys. Modern immunosuppression has improved rejection rates and transplant survival and, as a result, recurrence of glomerulonephritis has emerged as a major cause of allograft loss. However, many glomerulonephritides have significant genetic risk which may manifest through kidney intrinsic or systemic mechanisms. We hypothesise that heritable kidney intrinsic predisposition to glomerulonephritis will result in increased risk of glomerulonephritis recurrence in kidneys transplanted from genetically related donors. METHODS: We investigated the effect of living related donation on rates of recurrence and subsequent graft outcomes in 7236 patient from 28 years of ANZDATA transplant registry data. Data were analysed in R, using Kaplan Meier Survival analysis and adjusted analyses performed using Cox Proportional Hazards methods. A competing risk model was also analysed. RESULTS: Glomerulonephritis recurrence rates were significantly higher in living related donor grafts compared to either living unrelated or deceased donor grafts (p < 0 . 001). In IgA nephropathy, transplantation from living related donor kidneys demonstrated a 10 year recurrence rate of 16 . 7% compared to 7 . 1% in living unrelated donors and 9 . 2% in deceased donors (HR:1 . 7, 95% CI:1 . 26-2 . 26, p = 0 . 0005 for living related vs deceased donors). In focal segmental glomerulosclerosis, risk of recurrence at 10 years was 14 . 6% in living related donors compared to 10 . 8% in living unrelated donors and 6 . 6% in deceased donors (HR:2 . 2, 95% CI 1 . 34-3 . 64, p = 0 . 002) for living related vs deceased donors. Primary glomerulonephritis death censored graft survival was superior for living donor grafts, related or unrelated, compared to deceased donor grafts. CONCLUSIONS: We identified a significant increase in the risk of glomerulonephritis recurrence in IgA Nephropathy and Focal Segmental Glomerulosclerosis in living related donors compared to a deceased donors. PMID- 28095804 TI - Pulmonary manifestations in Niemann-Pick type C disease with mutations in NPC2 gene: case report and review of literature. AB - BACKGROUND: Niemann-Pick disease type C (NPC) is an inherited metabolic disorder; due to defect in cellular cholesterol trafficking. It is clinically a heterogeneous disease with variable age of onset with multiple organ systems being involved. NPC1 gene is involved in 95% cases where as remaining ~5% cases are linked with NPC2 gene. CASE PRESENTATION: Case-1, a 14-months-old female presented with recurrent respiratory distress, failure to thrive and hepatosplenomegaly. Lung biopsy was suggestive of alveolar proteinosis and liver biopsy confirmed foamy macrophages. Molecular analysis revealed homozygous mutation c.141C > A in exon 2 of NPC2 gene. Case-2, a 3-year-old male presented with dyspnoea and hepatomegaly noticed at 1 year of age. HRCT-scan of thoracic region showed consolidation with mediastinal lymphadenopathy. Broncho-alveolar lavage revealed moderate amount of foamy macrophages and bone marrow examination detected foam cells. Homozygous T > C transition in intron 1 of the NPC2 gene was identified. CONCLUSION: Our study demonstrates that NPC2 can present in early years of life with pulmonary complications like alveolar proteinosis and hepatosplenomegaly or hepatomegaly due to mutation in NPC2 gene. An early suspicion will help clinicians to clinch its diagnosis, management and genetic counselling. PMID- 28095805 TI - Vascular access placement in patients with chronic kidney disease Stages 4 and 5 attending an inner city nephrology clinic: a cohort study and survey of providers. AB - BACKGROUND: The majority of incident hemodialysis (HD) patients initiate dialysis via catheters. We sought to identify factors associated with initiating hemodialysis with a functioning arterio-venous (AV) access. METHODS: We conducted a retrospective chart review of all adult patients, age >18 years seeing a nephrologist with a diagnosis of CKD stage 4 or 5 during the study period between 06/01/2011 and 08/31/2013 to evaluate the placement of an AV access, initiation of dialysis and we conducted a survey of providers about the process. RESULTS: The 221 patients (56% female) in the study had median age of 66 years (interquartile range (IQR), 57-75) and were followed for a median of 1.26 years (IQR 0.6-1.68). At study entry, 81%had CKD stage 4 and 19% had CKD stage 5. By the end of study, 48 patients had initiated dialysis. Thirty-four of the patients started dialysis with a catheter (1 failed and 10 maturing AVFs), 9 with an AVF and 5 with an AVG. During the study period, 61 total AV accesses were placed (54 AVF and 7 AVG). A higher urinary protein/ creatinine ratio and a lower eGFR were associated with AV access placement and dialysis initiation. A greater number of nephrology visits were associated with AV access creation but not dialysis initiation. Hospitalizations and hospitalizations with an episode of acute kidney injury (AKI) were strongly associated with dialysis initiation (odds ratio (OR) 13.0 (95% confidence interval (CI) 2.3 to 73.3, p-value = 0.004) and OR 6.6 (95% CI 1.9 to 22.8, p-value = 0.003)). CONCLUSIONS: More frequent nephrology clinic visits for patients with a recent hospitalization may improve rates of placement of an AV access. A hospitalization with AKI is strongly associated with the need for dialysis initiation. Nephrologists may not be referring the correct patients to get an AV access surgery. PMID- 28095806 TI - Predictors of Mental Health Review Tribunal (MHRT) outcome in a forensic inpatient population: a prospective cohort study. AB - BACKGROUND: Previous studies have investigated factors associated with outcome at Mental Health Review Tribunals (MHRTs) in forensic psychiatric patients; however, dynamic variables such as treatment compliance and substance misuse have scarcely been examined, particularly in UK samples. We aimed to determine whether dynamic factors related to behaviour, cooperation with treatment, and activities on the ward were prospectively associated with outcome at MHRT. METHODS: At baseline, demographic, clinical, behavioural, and treatment-related factors were ascertained via electronic medical records and census forms completed by the patient's clinical team. Data on MHRTs (i.e., number attended, responsible clinician's recommendation, and outcome) were collected at a 2-year follow-up. Logistic regression analyses were performed to determine factors associated with outcome among those who attended a MHRT within the follow-up period. Of the 135 forensic inpatients examined at baseline, 79 patients (59%) attended a MHRT during the 2-year follow-up period and therefore comprised the study sample. Of these 79 patients included in the current study, 28 (35%) were subsequently discharged. RESULTS: In univariable analyses, unescorted community leave, responsible clinician's recommendation of discharge, and restricted Mental Health Act section were associated with a greater likelihood of discharge at MHRT; whilst inpatient aggression, a recent episode of acute illness, higher total score on the Historical Clinical Risk - 20 (HCR-20), higher HCR-20 clinical and risk scores, and agitated behaviour were negatively associated with discharge (p < 0.05). In multivariable analyses, HCR-20 clinical scale scores and physical violence independently predicted outcome at tribunal after controlling for other dynamic variables. CONCLUSION: By identifying dynamic factors associated with discharge at tribunal, the results have important implications for forensic psychiatric patients and their clinical teams. Our findings suggest that by reducing levels of agitated behaviour, verbal aggression, and physical violence on the ward, achieving unescorted community leave, and targeting specific items on the HCR-20 risk assessment tool, patients may be able to improve their changes of discharge at a MHRT. PMID- 28095808 TI - Associations between access to alcohol outlets and alcohol intake and depressive symptoms in women from socioeconomically disadvantaged neighbourhoods in Australia. AB - BACKGROUND: This study examined associations between alcohol outlet access and alcohol intake, depressive symptoms score and risk of depression among women residing in disadvantaged neighbourhoods in Victoria, Australia. METHODS: Data on depressive symptoms, alcohol intake and socio-demographic characteristics were obtained from a sample of 995 adult women from Victoria, Australia who were surveyed as part of the Resilience in Eating and Activity Despite Inequality (READI) study. The location of all licensed alcohol outlets in Victoria was obtained from the Victorian Commission for Gambling and Liquor Regulation. Participant and alcohol outlet addresses were geocoded to calculate individual alcohol outlet access, defined as the number of outlets (all and by sub-type) within 0.4 km and 3 km of participants' homes. Separate regression models with clustered standard errors were fitted to examine associations between access and alcohol intake according to national recommended limits for short- and long-term harm, frequency of consumption above long-term harm guidelines, depressive symptoms score and risk of depression. RESULTS: Odds of consumption within short term harm guidelines (<=4 drinks on any day) decreased with increasing access within 3 km, irrespective of outlet type. Typically, there was no evidence to support associations between access and consumption above long-term harm guidelines (>2 drinks on any day) unless considering frequency of consumption at this level where results showed decreased odds of 'don't drink' versus frequently drinking above long-term harm guidelines (i.e., >2 drinks at least once per week) with increasing access at either distance. Although there was no evidence of an association between any of the alcohol outlet access measures and depressive symptoms score, odds of being at risk of depression decreased with increasing access within 3 km. CONCLUSIONS: This study found some evidence to support an association between increasing alcohol outlet densities of all types and harmful levels of alcohol consumption, and the association appears to be dependent on the distance threshold considered, among women residing in socioeconomically disadvantaged neighbourhoods within Victoria, Australia. However, higher numbers of alcohol outlets appear to be associated with a slightly lower risk of depression, with further research needed to identify the direction and mechanisms underlying this unintuitive association. PMID- 28095809 TI - Taxing sugar-sweetened beverages: impact on overweight and obesity in Germany. AB - BACKGROUND: Consumption of sugar-sweetened beverages (SSBs) increases the risk of overweight and obesity. Taxing SSBs could decrease daily energy consumption and body weight. This model-based study evaluated the impact of a 20% SSB-sales tax on overweight and obesity in the context of Germany. METHODS: The population aged 15-79 years was modelled. Taxation was assumed to affect energy consumption via demand elasticities, which affected weight and BMI. Model-based analysis was performed to estimate the tax impact on BMI in different age, gender and income groups. RESULTS: Implementing a 20% SSB tax reduced energy consumption mainly in younger age groups, males, and those with low income. Taxation decreased the mean BMI in younger groups, with the largest decrease in those aged 20-29 years, while effects in groups 60 years or above were minimal. In absolute terms, taxation was estimated to avoid 1,028,000 (-3% relative reduction) overweight individuals and 479,000 obese individuals (-4%). Overweight decreased the most in males aged 20 29 years (408,000 fewer cases /-22%), the same applied for obesity (204,000/ 22%). CONCLUSIONS: An SSB tax could have significant impact on overweight and obesity, which could translate into substantial reductions of morbidity and mortality. PMID- 28095807 TI - Comparison of developmental milestone attainment in early treated HIV-infected infants versus HIV-unexposed infants: a prospective cohort study. AB - BACKGROUND: Infant HIV infection is associated with delayed milestone attainment. The extent to which effective antiretroviral therapy (ART) prevents these delays is not well defined. METHODS: Ages at attainment of milestones were compared between HIV-infected (initiated ART by age <5 months), and HIV-unexposed uninfected (HUU) infants. Kaplan Meier analyses were used to estimate and compare (log-rank tests) ages at milestones between groups. Adjusted analyses were performed using Cox proportional hazards models. RESULTS: Seventy-three HIV infected on ART (median enrollment age 3.7 months) and 92 HUU infants (median enrollment age 1.6 months) were followed prospectively. HIV-infected infants on ART had delays in developmental milestone attainment compared to HUU: median age at attainment of sitting with support, sitting unsupported, walking with support, walking unsupported, monosyllabic speech and throwing toys were each delayed (all p-values <0.0005). Compared with HUU, the subset of HIV-infected infants with both virologic suppression and immune recovery at 6 months had delays for speech (delay: 2.0 months; P = 0.0002) and trend to later walking unsupported. Among HIV infected infants with poor 6-month post-ART responses (lacking viral suppression and immune recovery) there were greater delays versus HUU for: walking unsupported (delay: 4.0 months; P = 0.0001) and speech (delay: 5.0 months; P < 0.0001). CONCLUSIONS: HIV infected infants with viral suppression on ART had better recovery of developmental milestones than those without suppression, however, deficits persisted compared to uninfected infants. Earlier ART may be required for optimized cognitive outcomes in perinatally HIV-infected infants. TRIAL REGISTRATION: NCT00428116 ; January 22, 2007. PMID- 28095810 TI - Neonatal screening for congenital adrenal hyperplasia in Southern Brazil: a population based study with 108,409 infants. AB - BACKGROUND: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder associated with inborn errors of steroid metabolism. 21-hydroxylase enzyme deficiency occurs in 90 to 95% of all cases of CAH, with accumulation of 17 hydroxyprogesterone (17-OHP). Early diagnosis of CAH based on newborn screening is possible before the development of symptoms and allows proper treatment, correct sex assignment, and reduced mortality rates. This study describes the results obtained in the first year of a public CAH screening program in the state of Rio Grande do Sul, Brazil. METHODS: We reviewed the screening database in search of babies with suspected CAH, that is, altered birth weight adjusted 17-OHP values at screening. The following data were analyzed for this population: screening 17-OHP values, retest 17-OHP values, serum 17-OHP values for those with confirmed CAH on retest, maternal and newborn data, and family history of CAH. For the screening program, 17-OHP levels are determined on dried blood spots obtained in filter paper with GSP solid phase time-resolved immunofluorescence. RESULTS: Of 108,409 newborns screened, eight were diagnosed with CAH (four males, four females). The incidence of CAH in the state was 1:13,551. Six cases were identified as classic salt-wasting CAH and two were cases of virilizing CAH. The positive predictive value (PPV) of the initial screening (before diagnostic confirmation) was 1.6%. The overall rate of false positive results was 0.47%. The number of false positive results was higher among newborns with birth weight < 2000 g. CONCLUSION: The present results support the need for CAH screening by the public health care system in the state, and show that the strategy adopted is adequate. PPV and false positive results were similar to those reported for other states of Brazil with similar ethnic backgrounds. PMID- 28095812 TI - Maternal sepsis complicating arabin cervical pessary placement for the prevention of preterm birth: a case report. AB - BACKGROUND: Preterm delivery is a major health problem and contributes to more than 50% of all neonatal and infant deaths. Recently, there has been a renewed interest in the use of cervical pessaries as a safe and effective intervention with few maternal side-effects for the prevention of preterm birth in both single and twin pregnancies. CASE PRESENTATION: A 43-year-old gravida 5, para 1 (previous preterm birth at 24 weeks) patient with an in vitro fertilization twin pregnancy had an Arabin cervical pessary placed at 19 weeks of pregnancy due to the presence of cervical funneling identified by ultrasound screening. She developed chorioamnionitis and sepsis and delivered at 21 3/7 weeks after extraction of the pessary. CONCLUSION: Severe maternal infection may complicate pessary treatment for the prevention of preterm birth. Careful follow-up is necessary in women with a cervical pessary during pregnancy, particularly when important funneling is present. PMID- 28095811 TI - An Integrated Recovery-oriented Model (IRM) for mental health services: evolution and challenges. AB - BACKGROUND: Over past decades, improvements in longer-term clinical and personal outcomes for individuals experiencing serious mental illness (SMI) have been moderate, although recovery has clearly been shown to be possible. Recovery experiences are inherently personal, and recovery can be complex and non-linear; however, there are a broad range of potential recovery contexts and contributors, both non-professional and professional. Ongoing refinement of recovery-oriented models for mental health (MH) services needs to be fostered. DISCUSSION: This descriptive paper outlines a service-wide Integrated Recovery-oriented Model (IRM) for MH services, designed to enhance personally valued health, wellbeing and social inclusion outcomes by increasing access to evidenced-based psychosocial interventions (EBIs) within a service context that supports recovery as both a process and an outcome. Evolution of the IRM is characterised as a series of five broad challenges, which draw together: relevant recovery perspectives; overall service delivery frameworks; psychiatric and psychosocial rehabilitation approaches and literature; our own clinical and service delivery experience; and implementation, evaluation and review strategies. The model revolves around the person's changing recovery needs, focusing on underlying processes and the service frameworks to support and reinforce hope as a primary catalyst for symptomatic and functional recovery. Within the IRM, clinical rehabilitation (CR) practices, processes and partnerships facilitate access to psychosocial EBIs to promote hope, recovery, self-agency and social inclusion. Core IRM components are detailed (remediation of functioning; collaborative restoration of skills and competencies; and active community reconnection), together with associated phases, processes, evaluation strategies, and an illustrative IRM scenario. The achievement of these goals requires ongoing collaboration with community organisations. CONCLUSIONS: Improved outcomes are achievable for people with a SMI. It is anticipated that the IRM will afford MH services an opportunity to validate hope, as a critical element for people with SMI in assuming responsibility and developing skills in self-agency and advocacy. Strengthening recovery-oriented practices and policies within MH services needs to occur in tandem with wide-ranging service evaluation strategies. PMID- 28095813 TI - Vocational rehabilitation for adults with psychotic disorders in a Scandinavian welfare society. AB - BACKGROUND: This study examined the outcomes of a vocational rehabilitation program (The Job Management Program, JUMP) for persons with psychotic disorders based on close collaboration between health and welfare services. METHODS: Participants (N = 148) with broad schizophrenia spectrum disorders (age 18-65) were recruited from six counties in Norway. Three counties were randomized to vocational rehabilitation augmented with cognitive behaviour therapy (CBT), while the remaining three counties were randomized to vocational rehabilitation augmented with cognitive remediation (CR). This paper compares the vocational activity of the total group of JUMP participants with a treatment as usual group (N = 341), and further examines differences between the two JUMP interventions. Employment status (working/not working) was registered at the time of inclusion and at the end of the intervention period. RESULTS: The total number of JUMP participants in any kind of vocational activity increased from 17 to 77% during the intervention. Of these, 8% had competitive employment, 36% had work placements in ordinary workplaces with social security benefits as their income, and 33% had sheltered work. The total number of working participants in the TAU group increased from 15.5 to 18.2%. The JUMP group showed significant improvements of positive (t = -2.33, p = 0.02) and general (t = -2.75, p = 0.007) symptoms of psychosis. Significant differences between the CBT and CR interventions were not demonstrated. CONCLUSIONS: The study supports existing evidence that the majority of persons with broad schizophrenia spectrum disorders can cope with some kind of work, given that internal and external barriers are reduced. Those who wish to work should be offered vocational rehabilitation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01139502 . Registered on 6 February 2010. PMID- 28095814 TI - Risk factors for aspiration pneumonia after definitive chemoradiotherapy or bio radiotherapy for locally advanced head and neck cancer: a monocentric case control study. AB - BACKGROUND: Chemoradiotherapy (CRT) and bio-radiotherapy (BRT) are recognized as standard therapies for head and neck cancer (HNC). Aspiration pneumonia after CRT or BRT is a common late adverse event. Our aim in this study was to evaluate the cause-specific incidence of aspiration pneumonia after CRT or BRT and to identify its clinical risk factors. METHODS: We performed a retrospective analysis of 305 patients with locally advanced HNC treated by CRT or BRT between August 2006 and April 2015. RESULTS: Of these 305 patients, 65 (21.3%) developed aspiration pneumonia after treatment. The median onset was 161 days after treatment. The two year cause-specific cumulative incidence by CRT or BRT was 21.0%. Multivariate analysis revealed five independent risk factors for aspiration pneumonia, namely, habitual alcoholic consumption, use of sleeping pills at the end of treatment, poor oral hygiene, hypoalbuminemia before treatment, and the coexistence of other malignancies. A predictive model using these risk factors and treatment efficacy was constructed, dividing patients into low- (0-2 predictive factors), moderate- (3-4 factors), and high-risk groups (5-6 factors), the two-year cumulative incidences of aspiration pneumonia of which were 3.0, 41.6, and 77.3%, respectively. Aspiration pneumonia tended to be associated with increased risk of death, although this was not statistically significant (multivariate-adjusted hazard ratio 1.39, P = 0.18). CONCLUSION: The cause-specific incidence and clinical risk factors for aspiration pneumonia after definitive CRT or BRT were investigated in patients with locally advanced HNC. Our predictive model may be useful for identifying patients at high risk for aspiration pneumonia. PMID- 28095815 TI - Assessment of the ecological bias of seven aggregate social deprivation indices. AB - BACKGROUND: In aggregate studies, ecological indices are used to study the influence of socioeconomic status on health. Their main limitation is ecological bias. This study assesses the misclassification of individual socioeconomic status in seven ecological indices. METHODS: Individual socioeconomic data for a random sample of 10,000 persons came from periodic health examinations conducted in 2006 in 11 French departments. Geographical data came from the 2007 census at the lowest geographical level available in France. The Receiver Operating Characteristics (ROC) curves, the areas under the curves (AUC) for each individual variable, and the distribution of deprived and non-deprived persons in quintiles of each aggregate score were analyzed. RESULTS: The aggregate indices studied are quite good "proxies" for individual deprivation (AUC close to 0.7), and they have similar performance. The indices are more efficient at measuring individual income than education or occupational category and are suitable for measuring of deprivation but not affluence. CONCLUSIONS: The study inventoried the aggregate indices available in France and evaluated their assessment of individual SES. PMID- 28095816 TI - Awareness and knowledge among internal medicine house-staff for dose adjustment of commonly used medications in patients with CKD. AB - BACKGROUND: Drug dosing errors result in adverse patient outcomes and are more common in patients with chronic kidney disease (CKD). As internists treat the majority of patients with CKD, we study if Internal Medicine house-staff have awareness and knowledge about the correct dosage of commonly used medications for those with CKD. METHODS: A cross-sectional survey was performed and included 341 participants. The outcomes were the awareness of whether a medication needs dose adjustment in patients with CKD and whether there was knowledge for the level of glomerular filtration rate (GFR) a medication needs to be adjusted. RESULTS: The overall pattern for all post-graduate year (PGY) groups in all medication classes was a lack of awareness and knowledge. For awareness, there were statistically significant increased mean differences for PGY2 and PGY3 as compared to PGY1 for allergy, endocrine, gastrointestinal, and rheumatologic medication classes but not for analgesic, cardiovascular, and neuropsychotropic medication classes. For knowledge, there were statistically significant increased mean differences for PGY2 and PGY3 as compared to PGY1 for allergy, cardiovascular, endocrine, and gastrointestinal, medication classes but not for analgesic, neuropsychotropic, and rheumatologic medication classes. CONCLUSIONS: Internal Medicine house-staff across all levels of training demonstrated poor awareness and knowledge for many medication classes in CKD patients. Internal Medicine house-staff should receive more nephrology exposure and formal didactic educational training during residency to better manage complex treatment regimens and prevent medication dosing errors. PMID- 28095817 TI - Changes in event-related potentials in patients with first-episode schizophrenia and their siblings. AB - BACKGROUND: This study aimed to explore the characteristics of event-related potentials induced by facial emotion recognition in patients with first-episode schizophrenia and in their siblings. METHODS: In this case-control study, 30 first-episode schizophrenia patients, 26 siblings, and 30 healthy controls were enrolled. They completed facial emotion recognition tasks from the Ekman Standard Faces Database as an induction for evoked potentials. Evoked potential data were obtained using a 64-channel electroencephalography system. Average evoked potential waveforms were computed from epochs for each stimulus type. The amplitudes and latency of the event-related potentials for P100 (positive potential 100 ms after stimulus onset), N170 (negative potential 170 ms after stimulus onset), and N250 (fronto-central peak) were investigated at O1, O2, P7, and P8 electrode locations. RESULTS: There were significant differences between the groups for P100 amplitude (F = 11.526, P < 0.001), electrode position (F = 450.592, P < 0.001), emotion (disgust vs. happiness vs. fear) (F = 1722.467, P < 0.001), and emotion intensity (low vs. moderate vs. high) (F = 1737.169, P < 0.001). Post hoc analysis showed significantly larger amplitudes in the schizophrenia group at the O1, O2, P7, and P8 electrode positions. There were no significant differences between the siblings of schizophrenia patients and the healthy controls. CONCLUSIONS: Patients with schizophrenia showed abnormalities in P100 amplitude, but similar results were not observed in their siblings. These results provide evidence of dysfunctional event-related potential patterns underlying facial emotion processing in patients with schizophrenia. P100 may be a characteristic index of schizophrenia. PMID- 28095818 TI - When parents won't vaccinate their children: a qualitative investigation of australian primary care providers' experiences. AB - BACKGROUND: Increasingly, the experiences and perceptions of parents who decline vaccination are the subject of investigation. However, the experiences of clinicians who encounter these parents in the course of their work has received little academic attention to date. This study aimed to understand the challenges faced and strategies used when general practitioners and immunising nurses encounter parents who choose not to vaccinate their children. METHODS: Primary care providers were recruited from regions identified through the Australian Childhood Immunisation Register (ACIR) as having higher than national average rates of registered objection to childhood vaccination. Interviews began with an exploration of provider experiences with parents who accept, are hesitant towards, and who decline vaccination. Participants were asked specifically about how they addressed any difficulties they encountered in their interactions. Thematic analysis focused on encounters with parents - challenges and strategies. RESULTS: Twenty-six general practitioners (GPs), community and practice nurses (PNs) were interviewed across two regions in NSW, Australia. Providers' sense of professional identity as health advocates and experts became conflicted in their encounters with vaccine objecting parents. Providers were dissatisfied when such consultations resulted in a 'therapeutic roadblock' whereby provider-parent communication came to a standstill. There were mixed views about being asked to sign forms exempting parents from vaccinating their children. These ranged from a belief that completing the forms rewarded parents for non-conformity to seeing it as a positive opportunity for engagement. Three common strategies were employed by providers to navigate through these challenges; 1) to explore and inform, 2) to mobilise clinical rapport and 3) to adopt a general principle to first do no harm to the therapeutic relationship. CONCLUSIONS: Many healthcare providers find consultations with vaccine objecting parents challenging and some, particularly more experienced providers, employ successful strategies to address this. Primary care providers, especially those more junior, could benefit from additional communication guidance to better the outcome and increase the efficiency of their interactions with such parents. PMID- 28095819 TI - ADHD, comorbid disorders and psychosocial functioning: How representative is a child cohort study? Findings from a national patient registry. AB - BACKGROUND: Cohort studies often report findings on children with Attention Deficit Hyperactivity Disorder (ADHD) but may be biased by self-selection. The representativeness of cohort studies needs to be investigated to determine whether their findings can be generalised to the general child population. The aim of the present study was to examine the representativeness of child ADHD in the Norwegian Mother and Child Cohort Study (MoBa). METHODS: The study population was children born between January 1, 2000 and December 31, 2008 registered with hyperkinetic disorders (hereafter ADHD) in the Norwegian Patient Registry during the years 2008-2013, and two groups of children with ADHD were identified in: 1. MoBa and 2. The general child population. We used the multiaxial International Classification of Diseases (ICD-10) and compared the proportions of comorbid disorders (axes I-III), abnormal psychosocial situations (axis V) and child global functioning (axis VI) between these two groups. We also compared the relative differences in the multiaxial classifications for boys and girls and for children with/without axis I comorbidity, respectively in these two groups of children with ADHD. RESULTS: A total of 11 119 children were registered with ADHD, with significantly fewer in MoBa (1.45%) than the general child population (2.11%), p < 0.0001. The proportions of comorbid axis I, II, and III disorders were low, with no significant group differences. Compared with the general child population with ADHD, children with ADHD in MoBa were registered with fewer abnormal psychosocial situations (axis V: t = 7.63, p < .0001; d = -.18) and better child global functioning (axis VI: t = 7.93, p < 0.0001; d = .17). When analysing relative differences in the two groups, essentially the same patterns were found for boys and girls and for children with/without axis I comorbidity. CONCLUSIONS: Self-selection was found to affect the proportions of ADHD, psychosocial adversity and child global functioning in the cohort. However, the differences from the general population were small. This indicates that studies on ADHD and multiaxial classifications in MoBa, as well as other cohort studies with similar self-selection biases, may have reasonable generalisability to the general child population. PMID- 28095820 TI - Microvascular invasion has limited clinical values in hepatocellular carcinoma patients at Barcelona Clinic Liver Cancer (BCLC) stages 0 or B. AB - BACKGROUND: Microvascular invasion (MVI) is recognized as a prognostic factor associated with poor outcome in hepatocellular carcinoma (HCC) patients after curative resection. It remains unclear, however, whether MVI can provide prognostic information for patients at a specific tumor stage. METHODS: Consecutive HCC patients who underwent curative resection in years of 2007 and 2008 (discovery cohort) were enrolled in this retrospective study. Patients were stratified by the Barcelona Clinic Liver Cancer (BCLC) staging system. The prognostic significance of MVI for overall survival (OS) and recurrence-free survival (RFS) was studied in each subgroup. The clinical significance of MVI was validated in another cohort of patients underwent curative surgery in the year of 2006 (validation cohort). RESULTS: Of the 1540 patients in the discovery cohort, 389 (25.3%) patients had detectable MVI. Occurrence rates of MVI in the BCLC stage 0, A, and B subgroups were 12.4, 26.2, and 34.4%, respectively. In univariate analysis, MVI was associated with poor OS and RFS (P < 0.001 for both) in HCC patients at stage A, with poor OS in patients at stage 0 (P = 0.028), and with poor RFS at stage B (P = 0.039). In multivariate analysis, MVI was an independent risk factor for OS (HR = 1.431, 95% CI, 1.163-1.761, P < 0.001) and RFS (HR = 1.400, 95% CI, 1.150-1.705, P = 0.001) in patients at stage A; and an independent risk factor for RFS (P = 0.043) in patients at stage B. A similar clinical significance of MVI was found in the validation cohort. CONCLUSIONS: MVI has limited prognostic value for HCC patients at BCLC stages 0 and B. For those at stage A, MVI was associated with patient survival and may help to select patients with high risk of disease recurrence. PMID- 28095821 TI - Weighing as a stand-alone intervention does not reduce excessive gestational weight gain compared to routine antenatal care: a systematic review and meta analysis of randomised controlled trials. AB - BACKGROUND: Excessive gestational weight gain is associated with short and long term adverse maternal and infant health outcomes, independent of pre-pregnancy body mass index. Weighing pregnant women as a stand-alone intervention during antenatal visits is suggested to reduce pregnancy weight gain. In the absence of effective interventions to reduce excessive gestational gain within the real world setting, this study aims to test if routine weighing as a stand-alone intervention can reduce total pregnancy weight gain and, in particular, excessive gestational weight gain. METHODS: A systematic review and meta-analysis of randomised controlled trials (RCTs) was conducted between November 2014 and January 2016, and reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Seven databases were searched. A priori eligibility criteria were applied to published literature by at least two independent reviewers. Studies considered methodologically rigorous, as per the Academy of Nutrition and Dietetics Quality Criteria Checklist for Primary Research, were included. Meta-analysis was conducted using fixed-effects models. RESULTS: A total of 5223 (non-duplicated) records were screened, resulting in two RCTs that were pooled for meta-analysis (n = 1068 randomised participants; n = 538 intervention, n = 534 control). No difference in total weight gain per week was observed between intervention and control groups (weighted mean difference (WMD) 0.00 kg/week, 95% confidence interval (CI) -0.03 to 0.02). There was also no reduction in excessive gestational weight gain between intervention and control, according to pre-pregnancy body mass index (BMI). However, total weight gain was lower in underweight women (n = 23, BMI <18.5 kg/m2) in the intervention compared to control group (-0.12 kg/week, 95% CI -0.23 to -0.01). No significant differences were observed for other pregnancy, birth and infant outcomes. CONCLUSION: Weighing as a stand-alone intervention is not worse nor better at reducing excessive gestational weight gain than routine antenatal care. PMID- 28095822 TI - Hyperuricemia increases the risk of acute kidney injury: a systematic review and meta-analysis. AB - BACKGROUND: Mounting evidence indicated that the elevated serum uric acid level was associated with an increased risk of acute kidney injury (AKI). Our goal was to systematically evaluate the correlation of serum uric acid (SUA) level and incidence of AKI by longitudinal cohort studies. METHODS: We searched electronic databases and the reference lists of relevant articles. 18 cohort studies with 75,200 patients were analyzed in this random-effect meta-analysis. Hyperuricemia was defined as SUA levels greater than 360-420 MUmol/L (6-7 mg/dl), which was various according to different studies. Data including serum uric acid, serum creatinine, and incidence of AKI and hospital mortality were summarized using random-effects meta-analysis. RESULTS: The hyperuricemia group significantly exerted a higher risk of AKI compared to the controls (odds ratio OR 2.24, 95% CI 1.76-2.86, p < 0.01). Furthermore, there is less difference of the pooled rate of AKI after cardiac surgery between hyperuricemia and control group (34.3% vs 29.7%, OR 1.24, 95% CI 0.96-1.60, p = 0.10), while the rates after PCI were much higher in hyperuricemia group than that in control group (16.0% vs 5.3%, OR 3.24, 95% CI 1.93-5.45, p < 0.01). In addition, there were significant differences in baseline renal function at admission between hyperuricemia and control groups in most of the included studies. The relationship between hyperuricemia and hospital mortality was not significant. The pooled pre-operative SUA levels were higher in AKI group than that in the non-AKI group. CONCLUSIONS: Elevated SUA level showed an increased risk for AKI in patients and measurements of SUA may help identify risks for AKI in these patients. PMID- 28095823 TI - Tobacco smoking policies in Australian alcohol and other drug treatment services, agreement between staff awareness and the written policy document. AB - BACKGROUND: Comprehensive smoke-free policy in the alcohol and other drug (AOD) setting provides an opportunity to reduce tobacco related harms among clients and staff. This study aimed to examine within AOD services: staff awareness of their service's smoking policy compared to the written policy document and staff and service factors associated with accurate awareness of a total ban and perceived enforcement of a total ban. METHODS: An audit of written tobacco smoking policy documents and an online cross-sectional survey of staff from 31 Australian AOD services. In addition, a contact at each service was interviewed to gather service-related data. RESULTS: Overall, 506 staff participated in the survey (response rate: 57%). Nearly half (46%) perceived their service had a total ban with 54% indicating that this policy was always enforced. Over one-third (37%) reported a partial ban with 48% indicating that this policy was always enforced. The audit of written policies revealed that 19 (61%) services had total bans, 11 (36%) had partial bans and 1 (3%) did not have a written smoking policy. Agreement between staff policy awareness and their service's written policy was moderate (Kappa 0.48) for a total ban and fair (Kappa 0.38) for a partial ban. Age (1 year increase) of staff was associated with higher odds of correctly identifying a total ban at their service. CONCLUSIONS: Tobacco smoking within Australian AOD services is mostly regulated by a written policy document. Staff policy awareness was modest and perceived policy enforcement was poor. PMID- 28095824 TI - Community-based health care is an essential component of a resilient health system: evidence from Ebola outbreak in Liberia. AB - BACKGROUND: Trained community health workers (CHW) enhance access to essential primary health care services in contexts where the health system lacks capacity to adequately deliver them. In Liberia, the Ebola outbreak further disrupted health system function. The objective of this study is to examine the value of a community-based health system in ensuring continued treatment of child illnesses during the outbreak and the role that CHWs had in Ebola prevention activities. METHODS: A descriptive observational study design used mixed methods to collect data from CHWs (structured survey, n = 60; focus group discussions, n = 16), government health facility workers and project staff. Monthly data on child diarrhea and pneumonia treatment were gathered from CHW case registers and local health facility records. RESULTS: Coverage for community-based treatment of child diarrhea and pneumonia continued throughout the outbreak in project areas. A slight decrease in cases treated during the height of the outbreak, from 50 to 28% of registers with at least one treatment per month, was attributed to directives not to touch others, lack of essential medicines and fear of contracting Ebola. In a climate of distrust, where health workers were reluctant to treat patients, sick people were afraid to self-identify and caregivers were afraid to take children to the clinic, CHWs were a trusted source of advice and Ebola prevention education. These findings reaffirm the value of recruiting and training local workers who are trusted by the community and understand the social and cultural complexities of this relationship. "No touch" integrated community case management (iCCM) guidelines distributed at the height of the outbreak gave CHWs renewed confidence in assessing and treating sick children. CONCLUSIONS: Investments in community-based health service delivery contributed to continued access to lifesaving treatment for child pneumonia and diarrhea during the Ebola outbreak, making communities more resilient when facility-based health services were impacted by the crisis. To maximize the effectiveness of these interventions during a crisis, proactive training of CHWs in infection prevention and "no touch" iCCM guidelines, strengthening drug supply chain management and finding alternative ways to provide supportive supervision when movements are restricted are recommended. PMID- 28095825 TI - No regrets: Young adult patients in psychiatry report positive reactions to biobank participation. AB - BACKGROUND: Research in vulnerable individuals must insure voluntariness and minimize negative reactions caused by participation. This study aimed to describe consent and completion rate in young psychiatric patients in relation to study components, degree of disability and to compare response to research participation in patients and controls. METHODS: Between 2012 and 2015, 463 patients with psychiatric disorders between the ages of 18-25 from the Dept. of General Psychiatry at Uppsala University Hospital and 105 controls were recruited to donate data and samples to a biobank. Consent and completion in relation to questionnaires, biological sampling of blood, saliva or feces, were monitored. Both groups were also asked about their perceived disability and how research participation affected them. RESULTS: Most patients who participated consented to and completed questionnaires and blood sampling. The majority also consented to saliva sampling, while less than half consented to collect feces. Of those who gave consent to saliva and feces only half completed the sampling. Both patients and controls reported high voluntariness and were positive to research participation. Within the patient group, those with greater perceived disability reported greater distress while participating in research, but there was no difference in consent or completion rates or level of regret. CONCLUSIONS: With the described information procedures, psychiatric patients, regardless of perceived disability, reported high voluntariness and did not regret participation in biobanking. Compared to questionnaires and blood sampling, given consent was reduced for feces and completion was lower for both saliva and feces sampling. PMID- 28095826 TI - Non-invasive respiratory support for infants with bronchiolitis: a national survey of practice. AB - BACKGROUND: Bronchiolitis is a common respiratory illness of early childhood. For most children it is a mild self-limiting disease but a small number of children develop respiratory failure. Nasal continuous positive airway pressure (nCPAP) has traditionally been used to provide non-invasive respiratory support in these children, but there is little clinical trial evidence to support its use. More recently, high-flow nasal cannula therapy (HFNC) has emerged as a novel respiratory support modality. Our study aims to describe current national practice and clinician preferences relating to use of non-invasive respiratory support (nCPAP and HFNC) in the management of infants (<12 months old) with acute bronchiolitis. METHODS: We performed a cross-sectional web-based survey of hospitals with inpatient paediatric facilities in England and Wales. Responses were elicited from one senior doctor and one senior nurse at each hospital. We analysed the proportion of hospitals using HFNC and nCPAP; clinical thresholds for their initiation; and clinician preferences regarding first-line support modality and future research. RESULTS: The survey was distributed to 117 of 171 eligible hospitals; 97 hospitals provided responses (response rate: 83%). The majority of hospitals were able to provide nCPAP (89/97, 91.7%) or HFNC (71/97, 73.2%); both were available at 65 hospitals (67%). nCPAP was more likely to be delivered in a ward setting in a general hospital, and in a high dependency setting in a tertiary centre. There were differences in the oxygenation and acidosis thresholds, and clinical triggers such as recurrent apnoeas or work of breathing that influenced clinical decisions, regarding when to start nCPAP or HFNC. More individual respondents with access to both modalities (74/106, 69.8%) would choose HFNC over nCPAP as their first-line treatment option in a deteriorating child with bronchiolitis. CONCLUSIONS: Despite lack of randomised trial evidence, nCPAP and HFNC are commonly used in British hospitals to support infants with acute bronchiolitis. HFNC appears to be currently the preferred first-line modality for non-invasive respiratory support due to perceived ease of use. PMID- 28095827 TI - Lessons learned from the London Exercise and Pregnant (LEAP) Smokers randomised controlled trial process evaluation: implications for the design of physical activity for smoking cessation interventions during pregnancy. AB - BACKGROUND: The challenges of delivering interventions for pregnant smokers have been poorly documented. Also, the process of promoting a physical activity intervention for pregnant smokers has not been previously recorded. This study describes the experiences of researchers conducting a randomised controlled trial of physical activity as an aid to smoking cessation during pregnancy and explores how the effectiveness of future interventions could be improved. METHODS: Two focus groups, with independent facilitators, were conducted with six researchers who had enrolled pregnant smokers in the LEAP trial, provided the interventions, and administered the research measures. Topics included recruitment, retention and how the physical activity intervention for pregnant smokers was delivered and how it was adapted when necessary to suit the women. The focus groups were audio recorded, transcribed verbatim and subjected to thematic analysis. RESULTS: Five themes emerged related to barriers or enablers to intervention delivery: (1) nature of the intervention; (2) personal characteristics of trial participants; (3) practical issues; (4) researchers' engagement with participants; (5) training and support needs. Researchers perceived that participants may have been deterred by the intensive and generic nature of the intervention and the need to simultaneously quit smoking and increase physical activity. Women also appeared hampered by pregnancy ailments, social deprivation, and poor mental health. Researchers observed that their status as health professionals was valued by participants but it was challenging to maintain contact with participants. Training and support needs were identified for dealing with pregnant teenagers, participants' friends and family, and post-natal return to smoking. CONCLUSIONS: Future exercise interventions for smoking cessation in pregnancy may benefit by increased tailoring of the intervention to the characteristics of the women, including their psychological profile, socio-economic background, pregnancy ailments and exercise preferences. Delivering an effective physical activity intervention for smoking cessation in pregnancy may require more comprehensive training for those delivering the intervention, particularly with regard to dealing with teenage smokers and smokers' friends and family, as well as for avoiding post-natal return to smoking. TRIAL REGISTRATION: ISRCTN48600346 , date of registration: 21/07/2008. PMID- 28095828 TI - Improved genome sequencing using an engineered transposase. AB - BACKGROUND: Next-generation sequencing (NGS) has transformed genomic research by reducing turnaround time and cost. However, no major breakthrough has been made in the upstream library preparation methods until the transposase-based Nextera method was invented. Nextera combines DNA fragmentation and barcoding in a single tube reaction and therefore enables a very fast workflow to sequencing-ready DNA libraries within a couple of hours. When compared to the traditional ligation based methods, transposed-based Nextera has a slight insertion bias. RESULTS: Here we present the discovery of a mutant transposase (Tn5-059) with a lowered GC insertion bias through protein engineering. We demonstrate Tn5-059 reduces AT dropout and increases uniformity of genome coverage in both bacterial genomes and human genome. We also observe higher library diversity generated by Tn5-059 when compared to Nextera v2 for human exomes, which leads to less sequencing and lower cost per genome. In addition, when used for human exomes, Tn5-059 delivers consistent library insert size over a range of input DNA, allowing up to a tenfold variance from the 50 ng input recommendation. CONCLUSIONS: Enhanced DNA input tolerance of Tn5-059 can translate to flexibility and robustness of workflow. DNA input tolerance together with superior uniformity of coverage and lower AT dropouts extend the applications of transposase based library preps. We discuss possible mechanisms of improvements in Tn5-059, and potential advantages of using the new mutant in varieties of applications including microbiome sequencing and chromatin profiling. PMID- 28095829 TI - A Middle Eastern journey of integrating Interprofessional Education into the healthcare curriculum: a SWOC analysis. AB - BACKGROUND: Interprofessional education (IPE) is an emerging concept in the Middle East with a number of health professional degree programs continually striving to meet international accreditation requirements to enhance the quality of education and ensure high standards are maintained. Using the College of Pharmacy at Qatar University (CPH QU) as a model, this article describes the IPE initiatives coordinated through the College's IPE Committee, with representation from fourteen programs at four Healthcare institutions: Qatar University; Weill Cornell Medical College in Qatar; the University of Calgary in Qatar; and the College of North Atlantic in Qatar. These activities are based on the model proposed by the University of British Columbia across the different pharmacy professional years. Learning objectives for these initiatives were selected from the IPE shared competency domains and competency statements developed for Qatar context. METHOD: A meeting with six faculty members, who have been instrumental to designing and executing the IPE activities in the previous 2 years, was convened. Faculty members reflected on IPE activities and collaborations with other participating programs. A structured SWOC (Strengths, Weaknesses, Opportunities, Challenges) framework was used to guide discussion. The discussion was recorded and notes were taken during the meeting. Raised points were categorized into each SWOC category for the final analysis. RESULTS: Implementation of IPE program is a major undertaking with a number of challenges that require invested time to overcome. This article highlights the importance of incorporating IPE into healthcare curricula to graduate students ready for collaborative practice in the workforce. Learning objectives for IPE initiatives need to be based on shared competency domains. When developing and implementing an IPE program it is necessary to align activities under a strong theoretical framework. This should be done under the leadership of an IPE steering group or committee to oversee the integration of IPE into the healthcare curriculum. CONCLUSION: The article presents many lessons learned through IPE implementation that are relevant to other academic institutions keen to incorporate IPE into their programs and also provides a successful model for integrating IPE into healthcare curricula. PMID- 28095830 TI - Kv7 voltage-activated potassium channel inhibitors reduce fluid resuscitation requirements after hemorrhagic shock in rats. AB - BACKGROUND: Recent evidence suggests that drugs targeting Kv7 channels could be used to modulate vascular function and blood pressure. Here, we studied whether Kv7 channel inhibitors can be utilized to stabilize hemodynamics and reduce resuscitation fluid requirements after hemorrhagic shock. METHODS: Anesthetized male Sprague-Dawley rats were instrumented with arterial and venous catheters for blood pressure monitoring, hemorrhage and fluid resuscitation. Series 1: Linopirdine (Kv7 channel blocker, 0.1-6 mg/kg) or retigabine (Kv7 channel activator, 0.1-12 mg/kg) were administered to normal animals. Series 2: Animals were hemorrhaged to a MAP of 25 mmHg for 30 min, followed by fluid resuscitation with normal saline (NS) to a MAP of 70 mmHg until t = 75 min. Animals were treated with single bolus injections of vehicle, linopirdine (1-6 mg/kg), XE-991 (structural analogue of linopirdine with higher potency for channel blockade, 1 mg/kg) prior to fluid resuscitation. Series 3: Animals were resuscitated with NS alone or NS supplemented with linopirdine (1.25-200 MUg/mL). Data were analyzed with 2-way ANOVA/Bonferroni post-hoc testing. RESULTS: Series 1: Linopirdine transiently (10-15 min) and dose-dependently increased MAP by up to 15%. Retigabine dose-dependently reduced MAP by up to 60%, which could be reverted with linopirdine. Series 2: Fluid requirements to maintain MAP at 70 mmHg were 65 +/- 34 mL/kg with vehicle, and 57 +/- 13 mL/kg, 22 +/- 8 mL/kg and 22 +/- 11 mL/kg with intravenous bolus injection of 1, 3 and 6 mg/kg linopirdine, respectively. XE-991 (1 mg/kg), reduced resuscitation requirements comparable to 3 mg/kg linopirdine. Series 3: When resuscitation was performed with linopirdine supplemented normal saline (NS), fluid requirements to stabilize MAP were 73 +/- 12 mL/kg with NS alone and 72 +/- 24, 61 +/- 20, 36 +/- 9 and 31 +/- 9 mL/kg with NS supplemented with 1.25, 6.25, 12.5 and 200 MUg/mL linopirdine, respectively. CONCLUSIONS: Our data suggest that Kv7 channel blockers could be used to stabilize blood pressure and reduce fluid resuscitation requirements after hemorrhagic shock. PMID- 28095831 TI - A follow-up study of airway symptoms and lung function among residents and workers 5.5 years after an oil tank explosion. AB - BACKGROUND: Assess if people who lived or worked in an area polluted after an oil tank explosion had persistent respiratory health impairment as compared to a non exposed population 5.5 years after the event. METHODS: A follow-up study 5.5 years after the explosion, 330 persons aged 18-67 years, compared lung function, lung function decline and airway symptoms among exposed persons (residents <6 km from the accident site or working in the industrial harbour at the time of the explosion) with a non-exposed group (residence >20 km away). Also men in the exposed group who had participated in accident related tasks (firefighting or clean-up of pollution) were compared with men who did not. Data were analysed using Poisson regression, adjusted for smoking, occupational exposure, atopy and age. RESULTS: Exposed men who had participated in accident related tasks had higher prevalence of lower airway symptoms after 5.5 years (n = 24 [73%]) than non-exposed men (28 [48%]), (adjusted relative risk 1.51 [95% confidence interval 1.07, 2.14]). Among men who participated in accident related tasks FEV1 decline was 48 mL per year, and 12 mL among men who did not (adjusted difference -34 mL per year [-67 mL, -1 mL]), and at follow-up FEV1/FVC ratio was 71.4 and 74.2% respectively, (adjusted difference -3.0% [-6.0, 0.0%]). CONCLUSION: Residents and workers had more airway symptoms and impaired lung function 5.5 years after an oil tank explosion, most significant for a group of men engaged in firefighting and clean-up of pollution after the accident. Public health authorities should be aware of long-term consequences after such accidents. PMID- 28095832 TI - Cost-effectiveness of using a motion-sensor biofeedback treatment approach for the management of sub-acute or chronic low back pain: economic evaluation alongside a randomised trial. AB - BACKGROUND: Low back pain is a common and costly condition internationally. There is high need to identify effective and economically efficient means for managing this problem. This study aimed to explore the cost-effectiveness of a novel motion-sensor biofeedback treatment approach in addition to guidelines-based care compared to guidelines-based care alone, from a societal perspective over a 12 month time horizon. METHOD: This was an incremental cost-effectiveness analysis conducted concurrently with a pilot, cluster randomized controlled trial. Health care resource use was collected using daily diaries and patient-self report at 3, 6 and 12 month follow-up assessments. Productivity was measured using industry classifications and participant self-reporting of ability to do their normal work with their present pain. Clinical effect was measured using the Patient Global Impression of Change measured at the 12 month follow-up assessment. Data were compared between groups using linear regression clustered by recruitment site. Bootstrap resampling was used to generate a visual representation of the 95% confidence interval for the incremental cost-effectiveness estimate. Two, one-way sensitivity analyses were undertaken to examine the robustness of findings to key assumptions. RESULT: There were n = 38 participants in the intervention group who completed the 12 month assessment and n = 45 in the control. The intervention group had greater use of trial-related medical and therapy resources [$477 per participant (95% CI: $447, $508)], but lower use of non-trial medical and therapy resources [$-53 per participant (95% CI: $-105, $-0)], and a greater improvement in productivity [$-5123 per participant (95% CI: $-10,174, $-72)]. Overall, the intervention dominated with a saving of $478,100 and an additional 41 participants self-rating as being very or much improved compared to the control. There was >99% confidence in this finding of dominance in both the primary and sensitivity analyses. CONCLUSIONS: The motion-sensor biofeedback treatment approach in addition to guidelines- based care appears to be both more clinically effective and economically efficient than guidelines- based care alone. This approach appears to be a viable means to manage low back pain and further research in this area should be a priority. TRIAL REGISTRATION: The randomised trial this research was based upon was prospectively registered on March 25th 2009 with the Australian New Zealand Clinical Trials Registry: ACTRN12609000157279 . PMID- 28095833 TI - Lifetime and 12-month prevalence of eating disorders amongst women in mid-life: a population-based study of diagnoses and risk factors. AB - BACKGROUND: Eating disorders (EDs) are common amongst women; however, no research has specifically investigated the lifetime/12-month prevalence of eating disorders amongst women in mid-life (i.e., fourth and fifth decade of life) and the relevant longitudinal risk factors. We aimed to investigate the lifetime and 12-month prevalence of EDs and lifetime health service use and to identify childhood, parenting, and personality risk factors. METHODS: This is a two-phase prevalence study, nested within an existing longitudinal community-based sample of women in mid-life. A total of 5658 women from the UK Avon Longitudinal Study of Parents and Children (ALSPAC; enrolled 20 years earlier) participated. ED diagnoses were obtained using validated structured interviews. Weighted analyses were carried out accounting for the two-phase methodology to obtain prevalence figures and to carry out risk factor regression analyses. RESULTS: By mid-life, 15.3% (95% confidence intervals, 13.5-17.4%) of women had met criteria for a lifetime ED. The 12-month prevalence of EDs was 3.6%. Childhood sexual abuse was prospectively associated with all binge/purge type disorders and an external locus of control was associated with binge-eating disorder. Better maternal care was protective for bulimia nervosa. Childhood life events and interpersonal sensitivity were associated with all EDs. CONCLUSIONS: By mid-life a significant proportion of women will experience an ED, and few women accessed healthcare. Active EDs are common in mid-life, both due to new onset and chronic disorders. Increased awareness of the full spectrum of EDs in this stage of life and adequate service provision is important. This is the first study to investigate childhood and personality risk factors for full threshold and sub-threshold EDs and to identify common predictors for full and sub-threshold EDs. Further research should clarify the role of preventable risk factors on both full and sub threshold EDs. PMID- 28095834 TI - Barriers to venipuncture-induced pain prevention in cancer patients: a qualitative study. AB - BACKGROUND: Procedural pain reduces the quality of life of cancer patients. Although there are recommendations for its prevention, there are some obstacles for its management. The purpose of this study was to analyze the barriers to procedural pain prophylaxis in cancer patients reflecting the views of the nurses. METHODS: We used qualitative methodology based on semi-structured interviews conducted with nurses, focusing on practices of venipuncture-induced and needle change for implantable central venous access port (ICVAP) pain management in cancer patients. A thematic analysis approach informed the data analysis. RESULTS: Interviews were conducted with 17 nurses. The study highlighted 4 main themes; technical and relational obstacles, nurses' professional recognition, the role of the team, and organizational issues. Participants understood the painful nature of venipuncture. Despite being aware of the benefits of the anesthetic patch, they did not utilize it in a systematic way. We identified several barriers at different levels: technical, relational and previous experience of incident pain. Several organizational issues were also highlighted (e.g. lack of protocol, lack of time). CONCLUSIONS: The prevention of venipuncture-induced cancer pain requires a structured training program, which should reflect the views of nurses in clinical practice. PMID- 28095835 TI - Antimicrobial activity of some plant materials used in Armenian traditional medicine. AB - BACKGROUND: Antibiotic resistance has become one of the major problems facing humanity. The need for new antimicrobials has been increased dramatically. Plants are considered as one of the most promising sources for new antimicrobials discovery. Despite relatively small area, Armenia has large diversity of flora with many endemic species. In Armenian folk medicine plant materials have been used to treat various microbial diseases since ancient times. The goal of our research was to evaluate antimicrobial efficiency of different parts of five wild plants species which are commonly used in Armenian traditional medicine. METHODS: Plant crude extracts were obtained with maceration technique using five solvents separately: distilled water, methanol, chloroform, acetone, and hexane. Agar well diffusion assay was used for initial evaluation of antimicrobial properties of plant materials against five bacterial and two yeast strains. Minimum inhibitory concentrations of the most active plant parts were determined by broth microdilution method. RESULTS: Crude extracts of all five tested plants expressed antimicrobial activity against at least four test strains at 500 MUg ml-1 concentration. Minimum inhibitory and bactericidal/fungicidal concentrations of selected plant parts were determined. Crude acetone and hexane extracts of Hypericum alpestre and acetone extract of Sanguisorba officinalis inhibited the growth of P. aeruginosa even at 64 MUg ml-1 concentration. Chloroform and acetone extracts of Sanguisorba officinalis exhibited cidal activity against P. aeruginosa till 256 MUg ml-1. Acetone was the most effective solvent for solubilizing antimicrobial compounds for almost all tested plant materials. CONCLUSIONS: Thus, antimicrobial activity of some medicinal plants used in Armenian traditional medicine was evaluated. Some of the plants had rather low minimum bacteriostatic/bactericidal concentrations and therefore they have prospective for further more inclusive studies. PMID- 28095836 TI - Physiotherapy clinical educators' perceptions of student fitness to practise. AB - BACKGROUND: Health professional students are expected to maintain Fitness to Practise (FTP) including clinical competence, professional behaviour and freedom from impairment (physical/mental health). FTP potentially affects students, clinicians and clients, yet the impact of supervising students across the spectrum of FTP issues remains relatively under-reported. This study describes clinical educators' perceptions of supporting students with FTP issues. METHODS: Between November 2012 and January 2013 an online survey was emailed to physiotherapy clinical educators from 34 sites across eight health services in Australia. The self-developed survey contained both closed and open ended questions. Demographic data and Likert scale responses were summarised using descriptive statistics. The hypotheses that years of clinical experience increased clinical educator confidence and comfort in supporting specific student FTP issues were explored with correlational analysis. Open text questions were analysed based on thematic analysis. RESULTS: Sixty-one percent of the 79 respondents reported supervising one or more students with FTP issues. Observed FTP concerns were clinical competence (76%), mental health (51%), professional behaviour (47%) and physical health (36%). Clinicians considered 52% (95% CI 38 66) of these issues avoidable through early disclosure, student and clinician education, maximising student competency prior to commencing placements, and human resources. Clinicians were confident and comfortable supporting clinical competence, professional behaviour and physical health issues but not mental health issues. Experience significantly increased confidence to support all FTP issues but not comfort. Student FTP issues affects the clinical educator role with 83% (95% CI 75-92) of clinicians reporting that work satisfaction was affected due to time pressures, emotional impact, lack of appreciation of educator time, quality of care conflict and a mismatch in role perception. Educators also considered that FTP issues affect service delivery and impact on those seeking health care. CONCLUSIONS: Strategies to support student FTP have potential to positively impact on students, clinicians and clients. Collaboration between these stakeholders is required, particularly in supporting mental health. Universities are strategically placed to implement appropriate support such as communication support. PMID- 28095837 TI - Enhancing the quality of life for palliative care cancer patients in Indonesia through family caregivers: a pilot study of basic skills training. AB - BACKGROUND: Palliative care in Indonesia is problematic because of cultural and socio-economic factors. Family in Indonesia is an integral part of caregiving process in inpatient and outpatient settings. However, most families are not adequately prepared to deliver basic care for their sick family member. This research is a pilot project aiming to evaluate how basic skills training (BST) given to family caregivers could enhance the quality of life (QoL) of palliative care cancer patients in Indonesia. METHODS: The study is a prospective quantitative with pre and post-test design. Thirty family caregivers of cancer patients were trained in basic skills including showering, washing hair, assisting for fecal and urinary elimination and oral care, as well as feeding at bedside. Patients' QoL were measured at baseline and 4 weeks after training using EORTC QLQ C30. Hypothesis testing was done using related samples Wilcoxon Signed Rank. A paired t-test and one-way ANOVA were used to check in which subgroups was the intervention more significant. RESULTS: The intervention showed a significant change in patients' global health status/QoL, emotional and social functioning, pain, fatigue, dyspnea, insomnia, appetite loss, constipation and financial hardship of the patients. Male patient's had a significant effect on global health status (qol) (p = 0.030); female patients had a significant effect on dyspnea (p = 0.050) and constipation (p = 0.038). Younger patients had a significant effect in global health status/QoL (p = 0.002). Patients between 45 and 54 years old had significant effect on financial issue (p = 0.039). Caregivers between 45 and 54 years old had significant effect on patients' dyspnea (p = 0.031). CONCLUSIONS: Basic skills training for family caregivers provided some changes in some aspects of QoL of palliative cancer patients. The intervention showed promises in maintaining the QoL of cancer patients considering socio-economic and cultural challenges in the provision of palliative care in Indonesia. PMID- 28095839 TI - Erratum to: Ceratonia siliqua pod extract ameliorates Schistosoma mansoni-induced liver fibrosis and oxidative stress. PMID- 28095838 TI - COMmunication with Families regarding ORgan and Tissue donation after death in intensive care (COMFORT): protocol for an intervention study. AB - BACKGROUND: Discussing deceased organ donation can be difficult not only for families but for health professionals who initiate and manage the conversations. It is well recognised that the methods of communication and communication skills of health professionals are key influences on decisions made by families regarding organ donation. METHODS: This multicentre study is being performed in nine intensive care units with follow-up conducted by the Organ and Tissue Donation Service in New South Wales (NSW) Australia. The control condition is pre intervention usual practice for at least six months before each site implements the intervention. The COMFORT intervention consists of six elements: family conversations regarding offers for organ donation to be led by a "designated requester"; family offers for donation are deferred to the designated requester; the offer of donation is separated from the end-of-life discussion that death is inevitable; it takes place within a structured family donation conversation using a "balanced" approach. Designated requesters may be intensivists, critical care nurses or social workers prepared by attending the three-day national "Family Donation Conversation" workshops, and the half-day NSW Simulation Program. The design is pre-post intervention to compare rates of family consent for organ donation six months before and under the intervention. Each ICU crosses from using the control to intervention condition after the site initiation visit. The primary endpoint is the consent rate for deceased organ donation calculated from 140 eligible next of kin families. Secondary endpoints are health professionals' adherence rates to core elements of the intervention; identification of predictors of family donation decision; and the proportion of families who regret their final donation decision at 90 days. DISCUSSION: The pragmatic design of this study may identify 'what works' in usual clinical settings when requesting organ donation in critical care areas, both in terms of changes in practice healthcare professionals are willing and able to adopt, and the effect this may have on desired outcomes. The findings of this study will be indicative of the potential benefits of the intervention and be relevant and transferrable to clinical settings in other states and countries. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12613000815763 (24 July 2013). ClinicalTrials.gov: NCT01922310 (14 August 2013) (retrospectively registered). PMID- 28095840 TI - Medical complexity and time to lung cancer treatment - a three-year retrospective chart review. AB - BACKGROUND: The time from a referral for suspected lung cancer is received at a hospital until treatment start has been defined as a quality indicator. Current Norwegian recommendation is that >=70% should start surgery or radiotherapy within 42 calendar days and systemic therapy within 35 days. However, delays can occur due to medical complexity. The aim of this study was to quantify the proportion of patients who started treatment within the recommended timeframes; and to assess the proportion of non-complex patients for which there were no good reasons for delays. METHODS: We performed a retrospective chart review of all patients diagnosed with lung cancer at a university hospital during 2011-2013. We defined "non-complex" patients as those who underwent <=1 tissue diagnostic procedure and had no delays due to comorbidity, intercurrent disease or complications to diagnostic procedures ("Medical delays") of more than three days. RESULTS: Four hundred forty-nine cases were analyzed; 142 (32%) had >1 tissue diagnostic procedures; 67 (15%) had medical delays >3 days; 262 (58%) were non-complex and 363 (81%) received treatment for lung cancer. Median number of days until surgery or radiotherapy was 48 (overall) and 41 (non-complex patients). The proportions who started surgery or radiotherapy within 42 days were 41% (overall) and 56% (non-complex). Corresponding numbers for systemic therapy were 29 days (overall) and 25 days (non-complex), and 64% (overall) and 80% (non-complex). CONCLUSION: Fewer lung cancer patients than desired started treatment within the recommended timeframes. Even among the least complex patients, too few patients received timely treatment. The reasons need to be identified and understood, and changes in the organization appear to be necessary in order to offer timely treatment to more patients. PMID- 28095842 TI - Cactus (Opuntia humifusa) water extract ameliorates loperamide-induced constipation in rats. AB - BACKGROUND: Korean cactus Cheonnyuncho (Opuntia humifusa) is rich in pectin, phenols, flavonoids, and minerals such as calcium and phosphorus. Some Koreans drink Cheonnyuncho juice prepared by grinding Cheonnyuncho with water. Cheonnyuncho is well known for its functional properties and antioxidant effects, but its effect on constipation has not been sufficiently studied. METHODS: Loperamide (2 mg/kg) was injected subcutaneously to induce constipation in rats. The animals were divided into four groups: a normal group (NOR), constipation control group (CON), and two constipation groups receiving the Cheonnyuncho extract (CE) at two different concentrations in drinking water, 3% (L-CE group) and 6% (H-CE group), for 25 days. RESULTS: The fecal pellet numbers of NOR and L CE were significantly increased from 35.67 +/- 2.09 (CON) to 50.60 +/- 1.38 and 46.50 +/- 2.91 after loperamide treatment, respectively (p < 0.05). The water content of fecal excretions was significantly enhanced in only the L-CE group (33.05 +/- 0.49%) compared to control (23.38 +/- 1.26%) (p < 0.05) after loperamide treatment. The oral intake of CE (L-CE and H-CE groups) significantly increased levels of the intestinal transit ratio (45.25 +/- 1.86% and 41.05 +/- 2.47%, respectively) compared to the CON group (32.15 +/- 2.05%) (p < 0.05). Treatment with the low concentration of CE significantly increased fecal levels of acetic, propionic, butyric, and valeric acids, as well as the total short chain fatty acid (SCFA) concentration. Histological analyses revealed that the thickness of the distal colon also increased in the CE-treated groups in a dose dependent manner. CONCLUSIONS: Constipation decreased when CE was fed to the rats. In particular, the fecal pellet number and water content, as well as histological parameters such as distal colon thickness, improved. The CE treatment also increased the fecal SCFA content. These results show that the extract of Cheonnyuncho (O. humifusa) alleviated the symptoms of loperamide induced constipation. PMID- 28095841 TI - Outcome following valve surgery in Australia: development of an enhanced database module. AB - BACKGROUND: Valvular heart disease, including rheumatic heart disease (RHD), is an important cause of heart disease globally. Management of advanced disease can include surgery and other interventions to repair or replace affected valves. This article summarises the methodology of a study that will incorporate enhanced data collection systems to provide additional insights into treatment choice and outcome for advanced valvular disease including that due to RHD. METHODS: An enhanced data collection system will be developed linking an existing Australian cardiac surgery registry to more detailed baseline co-morbidity, medication, echocardiographic and hospital separation data to identify predictors of morbidity and mortality outcome following valve surgery. DISCUSSION: This project aims to collect and incorporate more detailed information regarding pre and postoperative factors and subsequent morbidity. We will use this to provide additional insights into treatment choice and outcome. PMID- 28095843 TI - The tidal waves of connected health devices with healthcare applications: consequences on privacy and care management in European healthcare systems. AB - BACKGROUND: The market for Connected Health Devices (CHD) with healthcare applications is growing fast and should be worth several billion euros in turnover in the coming years. Their development will completely transform the organisation of our healthcare system, profoundly change the way patients are managed and revolutionizes disease prevention. MAIN BODY: The CHD with healthcare applications is a tidal wave that has societal impact calling into question the privacy of patients' personal and healthcare information and its protection in secure systems. Rather than trying to stop the use of CHD, we must channel the wave by clearly examining the advantages versus the risks and threats to the patients, and find counter-measures for implementation. The main difficulty is channeling the wave in a way that is acceptable to CHD developers who otherwise will bypass the rules, even if they can be sued for it. Therefore, it appears necessary to implement guidelines that can be used by all developers, defining the minimum requirement for assuring the security of patient privacy and healthcare management. CONCLUSION: In European Healthcare Systems, there is an imperative need for establishing security guidelines that CHD producers could use to ensure compliance, so that patient privacy and healthcare management is safeguarded. The aim would be to implement the guidelines a posteriori rather than a priori control so as not to hamper innovation. PMID- 28095844 TI - Barriers and facilitators of help-seeking among unemployed persons with mental health problems: a qualitative study. AB - BACKGROUND: Unemployed people with mental health problems often do not use mental health services and therefore do not benefit from available therapies. As unemployed individuals outside the healthcare system are a hard-to-reach group, barriers to and facilitators of mental health service use are poorly understood. The purpose of this study was to identify barriers to and facilitators of help seeking and service use based on experiences of unemployed people with mental health problems. METHODS: Fifteen qualitative semi-structured individual interviews were conducted with unemployed persons who reported mental health problems. Interview topics included individual experience with help-seeking and mental health service use with a focus on barriers and facilitators. Transcripts were analysed using qualitative content analysis and major themes were identified. RESULTS: Participants reported being treated as "different" within their social environment as well as by health care professionals because of their mental health problems, which resulted in a lack of self-esteem and avoidance of help-seeking. Interviewees associated negative attributes with help-seeking such as helplessness and weakness. They equated psychiatric medication with illegal drugs and worried about the risk of addiction. However, social support and a desire for change on the other hand increased the motivation to search for help. Employment agency staff were mostly perceived as supportive by individuals seeking mental health services. CONCLUSIONS: Unemployed individuals with mental health problems faced barriers and facilitators when seeking help on three different levels: (1) mental health literacy; (2) stigma and discrimination; and (3) structures and conditions of health care. Awareness and attitudes of health care professionals concerning mental health issues should be improved. Stigmatisation of people with mental illnesses should be reduced in health care settings. Training for employment agency staff concerning mental health problems and services is recommended. PMID- 28095845 TI - Relationship of diagnostic accuracy of renal cortical echogenicity with renal histopathology in dogs and cats, a quantitative study. AB - BACKGROUND: Renal cortical echogenicity is routinely evaluated during ultrasonographic investigation of the kidneys. Both in dog and cat previous ex vivo studies have revealed a poor correlation between renal echogenicity and corresponding lesions. The aim of this study was to establish the in-vivo relationship between renal cortical echogenicity and renal histopathology. RESULTS: Thirty-eight dogs and fifteen cats euthanized for critical medical conditions were included in the study. Ultrasonographic images of both kidneys were acquired ante mortem at standardized ultrasonographic settings. The echogenicity was quantified by means of Mean Gray Value (MGV) of the renal cortex measured with ImageJ. A complete histopathological examination of both kidneys was performed. Five kidneys were excluded because histopathology revealed neoplastic lesions. Only samples affected by tubular atrophy showed statistically different values in dog, and histopathology explained 13% of the total variance. MGV was not correlated neither to the degeneration nor to the inflammation scores. However, significant differences were identified between mildly and severely degenerated samples. Overall, the classification efficiency of MGV to detect renal lesions was poor with a sensitivity of 39% and a specificity of 86%. In cats, samples affected by both tubular vacuolar degeneration and interstitial nephritis were statistically different and histopathology explained 44% of the total variance. A linear correlation was evident between degeneration and MGV, whereas no correlation with inflammation was found. Statistically significant differences were evident only between normal and severely degenerated samples with a sensitivity of 54.17% and a specificity of 83.3% and MGV resulted scarce to discriminate renal lesions in this species. CONCLUSIONS: Renal cortical echogenicity shows low relevance in detecting chronic renal disease in dog whereas it results worth to identify severe renal damage in cat. PMID- 28095846 TI - Associations between degrees of task delegation and job satisfaction of general practitioners and their staff: a cross-sectional study. AB - BACKGROUND: In recent years, the healthcare system in the western world has undergone a structural development caused by changes in demography and pattern of disease. In order to maintain the healthcare system cost-effective, new tasks are placed in general practice urging the general practitioners to rethink the working structure without compromising the quality of care. However, there is a substantial variation in the degree to which general practitioners delegate tasks to their staff, and it is not known how these various degrees of task delegation influence the job satisfaction of general practitioners and their staff. METHODS: We performed a cross-sectional study based on two electronic questionnaires, one for general practitioners and one for their staff. Both questionnaires were divided into two parts, a part exploring the degree of task delegation regarding management of patients with chronic obstructive pulmonary disease in general practice and a part concerning the general job satisfaction and motivation to work. RESULTS: We found a significant association between perceived "maximal degree" of task delegation in management of patients with chronic obstructive pulmonary disease and the staff's overall job satisfaction. The odds ratio of the staff's satisfaction with the working environment displayed a tendency that there is also an association with "maximal degree" of task delegation. In the analysis of the general practitioners, the odds ratios of the results indicate that there is a tendency that "maximal degree" of task delegation is associated with overall job satisfaction, satisfaction with the challenges in work, and satisfaction with the working environment. CONCLUSIONS: We conclude that a high degree of task delegation is significantly associated with overall job satisfaction of the staff, and that there is a tendency that a high degree of task delegation is associated with the general practitioners' and the staff's satisfaction with the working environment as well as with general practitioners' overall job satisfaction and satisfaction with challenges in work. To qualify future delegation processes within general practice, further research could explore the reasons for our findings. PMID- 28095847 TI - The biomedical piglet: establishing reference intervals for haematology and clinical chemistry parameters of two age groups with and without iron supplementation. AB - BACKGROUND: The similarities between swine and humans in physiological and genomic patterns, and the great correlation in size and anatomy, make pigs extremely useful in preclinical studies. New-born piglets can represent a model for congenital and genetic diseases in new-born children. It is known that piglets may have significant differences in clinicopathological results compared to adult pigs. Therefore, adult laboratory reference intervals cannot be applied to piglets. The aim of this study was to compare haematological and chemical variables in piglets of two ages and determinate age-related reference intervals for commercial hybrid young pigs. Blood samples were collected under general anaesthesia from 130 animals divided into five- (P5) and 30- (P30) day-old piglets. Only P30 animals were treated with parenteral iron after birth. Samples were analysed using automated haematology (ADVIA 2120) and chemistry analysers, and age-related reference intervals were calculated. RESULTS: Significant higher values of RBC, Hb and HCT were observed in P30 animals when compared to P5, with an opposite trend for MCV. These results were associated with a reduction of the RBC regeneration process and the thrombopoietic response. The TSAT and TIBC were significantly higher in P30 compared to P5; however, piglets remained iron deficient compared to adult reference intervals reported previously. CONCLUSIONS: In conclusion, this paper emphasises the high variability occurring in clinicopathological variables between new-born and 30-day-old pigs, and between piglets and adult pigs. This study provides valuable reference data for piglets at precise ages and could be used in the future as historical control improving the Reduction in animal experiments, as suggested by the 3Rs principle. PMID- 28095848 TI - Laparoscopic versus open nephroureterectomy to treat localized and/or locally advanced upper tract urothelial carcinoma: oncological outcomes from a multicenter study. AB - BACKGROUND: Many studies have reported the oncological outcomes between open radical nephroureterectomy (ONU) and laparoscopic radical nephroureterectomy (LNU) of upper tract urothelial carcinoma (UTUC). However, few data have focused on the oncological outcomes of LNU in the subgroup of localized and/or locally advanced UTUC (T1-4/N0-X). The purpose of this study was to compare the oncological outcomes of LNU vs. ONU for the treatment in patients with T1-4/N0-X UTUC. METHODS: We collected and analyzed the data and clinical outcomes retrospectively for 265 patients who underwent radical nephroureterectomy for T1 4/N0-X UTUC between April 2000 and April 2013 at two Chinese tertiary hospitals. Survival was estimated using the Kaplan-Meier method. Cox's proportional hazards model was used for univariate and multivariate analysis. RESULTS: The mean patient age was 62.0 years and the median follow-up was 60.0 months. Of the 265 patients, 213 (80.4%) underwent conventional ONU, and 52 (19.6%) patients underwent LNU. The groups differed significantly in their presence of previous hydronephrosis, presence of previous bladder urothelial carcinoma, and management of distal ureter (P < 0.05). The predicted 5-year intravesical recurrence- free survival (RFS) (79% vs. 88%, P = 0.204), overall RFS (47% vs. 59%, P = 0.076), cancer-specific survival (CSS) (63% vs. 70%, P = 0.186), and overall survival (OS) (61% vs. 55%, P = 0.908) rates did not differ between the ONU and LNU groups. Multivariable Cox proportional regression analysis showed that surgical approach was not significantly associated with intravesical RFS (odds ratio [OR] 1.23, 95% confidence interval [CI] 0.46-3.65, P = 0.622), Overall RFS (OR 0.99, 95% CI 0.54-1.83, P = 0.974), CSS (OR 1.38, 95% CI 0.616-3.13, P = 0.444), or OS (OR 1.61, 95% CI 0.81-3.17, P = 0.17). CONCLUSIONS: The results of this retrospective study showed no statistically significant differences in intravesical RFS, overall RFS, CSS, or OS between the laparoscopy and the open groups. Thus, LNU can be an alternative to the open procedure for T1-4/N0-X UTUC. Further studies, including a multi-institutional, prospective study are required to confirm these findings. PMID- 28095849 TI - Simulated case management of home telemonitoring to assess the impact of different alert algorithms on work-load and clinical decisions. AB - BACKGROUND: Home telemonitoring (HTM) of chronic heart failure (HF) promises to improve care by timely indications when a patient's condition is worsening. Simple rules of sudden weight change have been demonstrated to generate many alerts with poor sensitivity. Trend alert algorithms and bio-impedance (a more sensitive marker of fluid change), should produce fewer false alerts and reduce workload. However, comparisons between such approaches on the decisions made and the time spent reviewing alerts has not been studied. METHODS: Using HTM data from an observational trial of 91 HF patients, a simulated telemonitoring station was created and used to present virtual caseloads to clinicians experienced with HF HTM systems. Clinicians were randomised to either a simple (i.e. an increase of 2 kg in the past 3 days) or advanced alert method (either a moving average weight algorithm or bio-impedance cumulative sum algorithm). RESULTS: In total 16 clinicians reviewed the caseloads, 8 randomised to a simple alert method and 8 to the advanced alert methods. Total time to review the caseloads was lower in the advanced arms than the simple arm (80 +/- 42 vs. 149 +/- 82 min) but agreements on actions between clinicians were low (Fleiss kappa 0.33 and 0.31) and despite having high sensitivity many alerts in the bio-impedance arm were not considered to need further action. CONCLUSION: Advanced alerting algorithms with higher specificity are likely to reduce the time spent by clinicians and increase the percentage of time spent on changes rated as most meaningful. Work is needed to present bio-impedance alerts in a manner which is intuitive for clinicians. PMID- 28095850 TI - Building system capacity for the integration of mental health at the level of primary care in Tunisia: a study protocol in global mental health. AB - BACKGROUND: In low- and middle-income countries (LMICs), addressing the high prevalence of mental disorders is a challenge given the limited number and unequal distribution of specialists, as well as scarce resources allocated to mental health. The Mental Health Gap Action Programme (mhGAP) and its accompanying Intervention Guide (IG), developed by the World Health Organization (WHO), aim to address this challenge by training non-specialists such as general practitioners (GPs) in mental health care. This trial aims to implement and evaluate an adapted version of the mhGAP-IG (version 1.0) offered to GPs in 2 governorates of Tunisia (i.e., Tunis and Sousse), in order to uncover important information regarding implementation process and study design before country-wide implementation and evaluation. METHODS/DESIGN: First, a systematic review will be conducted to explore types and effectiveness of mental health training programs offered to GPs around the world, with a specific focus on programs implemented and evaluated in LMICs. Second, a cluster randomized controlled trial (RCT) will be conducted to evaluate the effectiveness of the implemented training based on the mhGAP-IG (version 1.0). Third, multiple case study design will be used to explore how contextual factors impact the successful implementation of the training and desired outcomes. DISCUSSION: In Tunisia, an important need exists to further develop proximity health services and to address the growing mental health treatment gap. One solution is to train GPs in the detection, treatment, and management of mental health problems, given their strategic role in the healthcare system. This trial thus aims to implement and evaluate an adapted version of a training based on the mhGAP-IG (version 1.0) in Tunis and Sousse before country-wide implementation and evaluation. Several contributions are envisioned: adding to the growing evidence on the mhGAP and its accompanying guide, especially in French-speaking nations; building research capacity in Tunisia and more generally in LMICs by employing rigorous designs; evaluating an adapted version of the mhGAP-IG (version 1.0) on a sample of GPs; generating important information regarding implementation process and study design before country-wide implementation; and complimenting the trial results with implementation analysis, a priority in global mental health. PMID- 28095851 TI - Analytical method for calculation of deviations from intended dosages during multi-infusion. AB - BACKGROUND: In this paper, a new method is presented that combines mechanical compliance effects with Poiseuille flow and push-out effects ("dead volume") in one single mathematical framework for calculating dosing errors in multi-infusion set-ups. In contrast to existing numerical methods, our method produces explicit expressions that illustrate the mathematical dependencies of the dosing errors on hardware parameters and pump flow rate settings. METHODS: Our new approach uses the Z-transform to model the contents of the catheter, and after implementation in Mathematica (Wolfram), explicit expressions are produced automatically. Consistency of the resulting analytical expressions has been examined for limiting cases, and three types of in-vitro measurements have been performed to obtain a first experimental test of the validity of the theoretical results. RESULTS: The relative contribution of various factors affecting the dosing errors, such as the Poiseuille flow profile, resistance and internal volume of the catheter, mechanical compliance of the syringes and the various pump flow rate settings, can now be discerned clearly in the structure of the expressions generated by our method. The in-vitro experiments showed a standard deviation between theory and experiment of 14% for the delay time in the catheter, and of 13% for the time duration of the dosing error bolus. CONCLUSIONS: Our method provides insight and predictability in a large range of possible situations involving many variables and dependencies, which is potentially very useful for e.g. the development of a fast, bed-side tool ("calculator") that provides the clinician with a precise prediction of dosing errors and delay times interactively for many scenario's. The interactive nature of such a device has now been made feasible by the fact that, using our method, explicit expressions are available for these situations, as opposed to conventional time-consuming numerical simulations. PMID- 28095852 TI - The St. George's Respiratory Questionnaire as a prognostic factor in IPF. AB - BACKGROUND: It is unclear whether health related quality of life (HRQL) may have a predictive value for mortality in idiopathic pulmonary fibrosis (IPF). We investigated the relationship between HRQL assessed using the St. George's Respiratory Questionnaire (SGRQ) and survival time in patients with IPF, and tried to determine a clinical meaningful cut off value to predict poorer survival rates. METHODS: We retrospectively analyzed consecutive patients with IPF who underwent an initial evaluation from May 2007 to December 2012. The diagnosis of IPF was made according to the 2011 international consensus guidelines. We used Cox proportional hazard models to identify independent predictors for mortality rate in patients with IPF. RESULTS: We examined 182 eligible cases, average age was 66 years old, and 86% were male. Mean levels of percent predicted FVC, DLco, six-minute-walk test distance, and the SGRQ total score were around 80%, 58%, 580 m, and 34 points. On multivariate analysis, the SGRQ total score (hazard ratio [HR], 1.012; 95% confidence interval [CI] 1.001-1.023; P = .029) and percent predicted FVC (HR, 0.957; 95% CI 0.944-0.971, P < .001) were independent predictors for mortality rate. Moreover, a score higher than 30 points in the SGRQ total score showed higher mortality rate (HR, 2.047; 95% CI, 1.329-3.153; P = .001). CONCLUSIONS: The SGRQ total score was one of independent prognostic factors in patients with IPF. Total scores higher than 30 points were associated with higher mortality rates. TRIAL REGISTRATION: This study was retrospective, observational study, so it is not applicable. PMID- 28095853 TI - CRISPRi-mediated metabolic engineering of E. coli for O-methylated anthocyanin production. AB - BACKGROUND: Anthocyanins are a class of brightly colored, glycosylated flavonoid pigments that imbue their flower and fruit host tissues with hues of predominantly red, orange, purple, and blue. Although all anthocyanins exhibit pH responsive photochemical changes, distinct structural decorations on the core anthocyanin skeleton also cause dramatic color shifts, in addition to improved stabilities and unique pharmacological properties. In this work, we report for the first time the extension of the reconstituted plant anthocyanin pathway from (+)-catechin to O-methylated anthocyanins in a microbial production system, an effort which requires simultaneous co-option of the endogenous metabolites UDP glucose and S-adenosyl-L-methionine (SAM or AdoMet). RESULTS: Anthocyanin O methyltransferase (AOMT) orthologs from various plant sources were co-expressed in Escherichia coli with Petunia hybrida anthocyanidin synthase (PhANS) and Arabidopsis thaliana anthocyanidin 3-O-glucosyltransferase (At3GT). Vitis vinifera AOMT (VvAOMT1) and fragrant cyclamen 'Kaori-no-mai' AOMT (CkmOMT2) were found to be the most effective AOMTs for production of the 3'-O-methylated product peonidin 3-O-glucoside (P3G), attaining the highest titers at 2.4 and 2.7 mg/L, respectively. Following modulation of plasmid copy number and optimization of VvAOMT1 and CkmOMT2 expression conditions, production was further improved to 23 mg/L using VvAOMT1. Finally, CRISPRi was utilized to silence the transcriptional repressor MetJ in order to deregulate the methionine biosynthetic pathway and improve SAM availability for O-methylation of cyanidin 3-O-glucoside (C3G), the biosynthetic precursor to P3G. MetJ repression led to a final titer of 51 mg/L (56 mg/L upon scale-up to shake flask), representing a twofold improvement over the non-targeting CRISPRi control strain and 21-fold improvement overall. CONCLUSIONS: An E. coli strain was engineered for production of the specialty anthocyanin P3G using the abundant and comparatively inexpensive flavonol precursor, (+)-catechin. Furthermore, dCas9-mediated transcriptional repression of metJ alleviated a limiting SAM pool size, enhancing titers of the methylated anthocyanin product. While microbial production of P3G and other O methylated anthocyanin pigments will likely be valuable to the food industry as natural food and beverage colorants, we expect that the strain constructed here will also prove useful to the ornamental plant industry as a platform for evaluating putative anthocyanin O-methyltransferases in pursuit of bespoke flower pigment compositions. PMID- 28095854 TI - The effects of detraining and training on adipose tissue lipid droplet in obese mice after chronic high-fat diet. AB - BACKGROUND: It is well known that exercise promotes lipolysis by stimulating the lipid droplet (LD) signaling pathway. However, few studies have been conducted to examine the effect of detraining with high fat diet (HFD) and training effects after long-term HFD. Here, we investigated the effect of detraining and training on adipose tissue LD pathway in diet-induced obese mice after continuous HFD. METHODS: Seventy male C57BL/6 mice were randomly assigned into a Normal diet + Sedentary group (ND, n = 10) or a High-fat diet + Sedentary group (HF, n = 50); in the HF group, obesity was induced by a 45% fat chow for six weeks. For the subsequent eight weeks, the HF group was randomly subdivided into an HF (n = 30) or an HF + training group (HFT, n = 20), and the HFT group was subjected to treadmill training while on an HFD. Following this eight-week period, the HFT group stopped exercising (HFT-DT group, n = 10), and the mice in the HF group were randomly subdivided into an HF (n = 10) or an HF + training group (HF-T, n = 10). After training and detraining, abdominal visceral fat was obtained and analyzed by histological staining and western blot. RESULTS: Treadmill exercise decreased body weight and fat mass (P <0.05), and increased the levels of PKA, perilipin1, CGI-58, ATGL, and HSL (P <0.05) after eight weeks of training. Following eight weeks of detraining, the levels of PKA and HSL were decreased (P <0.05); however, exercise after chronic HFD increased the levels of PKA, perilipin1, CGI-58, ATGL, and HSL (P <0.05), and decreased body weight and fat mass (P <0.05). CONCLUSIONS: Regardless of dietary restrictions, exercise is an effective treatment for obesity, owing to the regulation of LD signaling proteins. Moreover, the effects of regular exercise after chronic HFD were similar to those of exercise in the absence of HFD. Therefore, although obesity is induced by chronic HFD, exercise without dietary change is sufficiently effective for obesity treatment regardless of the preceding HFD period. PMID- 28095855 TI - Meet us on the phone: mobile phone programs for adolescent sexual and reproductive health in low-to-middle income countries. AB - INTRODUCTION: mHealth as a technical area has seen increasing interest and promise from both developed and developing countries. While published research from higher income countries on mHealth solutions for adolescent sexual and reproductive health (SRH) is growing, there is much less documentation of SRH mHealth interventions for youth living in resource-poor settings. We conducted a global landscape analysis to answer the following research question: How are programs using mHealth interventions to improve adolescent SRH in low to middle income countries (LMICs)? METHODS: To obtain the latest information about mHealth programs targeting youth SRH, a global call for project resources was issued in 2014. Information about approximately 25 projects from LMICs was submitted. These projects were reviewed to confirm that mobile phones were utilized as a key communication media for the program, that youth ages 10-24 were a prime target audience, and that the program used mobile phone features beyond one-on-one phone calls between youth and health professionals. RESULTS: A total of 17 projects met our inclusion criteria. Most of these projects were based in Africa (67%), followed by Eurasia (26%) and Latin America (13%). The majority of projects used mHealth as a health promotion tool (82%) to facilitate knowledge sharing and behavior change to improve youth SRH. Other projects (18%) used mHealth as a way to link users to essential SRH services, including family planning counseling and services, medical abortion and post-abortion care, and HIV care and treatment. There was little variation in delivery methods for SRH content, as two-thirds of the projects (70%) relied on text messaging to transmit SRH information to youth. Several projects have been adapted and scaled to other countries. DISCUSSION: Findings suggest that mHealth interventions are becoming a more common method to connect youth to SRH information and services in LMICs, and evidence is emerging that mobile phones are an effective way to reach young people and to achieve knowledge and behavior change. More understanding is needed about the challenges of data privacy and phone access, especially among younger adolescents, and the role that mHealth solutions for adolescent SRH should play in health programming for young people. PMID- 28095856 TI - BAFF Index and CXCL13 levels in the cerebrospinal fluid associate respectively with intrathecal IgG synthesis and cortical atrophy in multiple sclerosis at clinical onset. AB - BACKGROUND: B lymphocytes are thought to play a relevant role in multiple sclerosis (MS) pathology. The in vivo analysis of intrathecally produced B cell related cytokines may help to clarify the mechanisms of B cell recruitment and immunoglobulin production within the central nervous system (CNS) in MS. METHODS: Paired cerebrospinal fluid (CSF) and serum specimens from 40 clinically isolated syndrome suggestive of MS or early-onset relapsing-remitting MS patients (CIS/eRRMS) and 17 healthy controls (HC) were analyzed for the intrathecal synthesis of IgG (quantitative formulae and IgG oligoclonal bands, IgGOB), CXCL13, BAFF, and IL-21. 3D-FLAIR, 3D-DIR, and 3D-T1 MRI sequences were applied to evaluate white matter (WM) and gray matter (GM) lesions and global cortical thickness (gCTh). RESULTS: Compared to HC, CIS/eRRMS having IgGOB (IgGOB+, 26 patients) had higher intrathecal IgG indexes (p < 0.01), lower values of BAFF Index (11.9 +/- 6.1 vs 17.5 +/- 5.2, p < 0.01), and higher CSF CXCL13 levels (27.7 +/- 33.5 vs 0.9 +/- 1.5, p < 0.005). In these patients, BAFF Index but not CSF CXCL13 levels inversely correlated with the intrathecal IgG synthesis (r > 0.5 and p < 0.05 for all correlations). CSF leukocyte counts were significantly higher in IgGOB+ compared to IgGOB- (p < 0.05) and HC (p < 0.01), and correlated to CSF CXCL13 concentrations (r 0.77, p < 0.001). The gCTh was significantly lower in patients with higher CSF CXCL13 levels (2.41 +/- 0.1 vs 2.49 +/- 0.1 mm, p < 0.05), while no difference in MRI parameters of WM and GM pathology was observed between IgGOB+ and IgGOB-. CONCLUSIONS: The intrathecal IgG synthesis inversely correlated with BAFF Index and showed no correlation with CSF CXCL13. These findings seem to indicate that intrathecally synthesized IgG are produced by long-term PCs that have entered the CNS from the peripheral blood, rather than produced by PCs developed in the meningeal follicle-like structures (FLS). In this study, CXCL13 identifies a subgroup of MS patients characterized by higher leukocyte counts in the CSF and early evidence of cortical thinning, further suggesting a role for this chemokine as a possible marker of disease severity. PMID- 28095857 TI - Real-time inverse kinematics for the upper limb: a model-based algorithm using segment orientations. AB - BACKGROUND: Model based analysis of human upper limb movements has key importance in understanding the motor control processes of our nervous system. Various simulation software packages have been developed over the years to perform model based analysis. These packages provide computationally intensive-and therefore off-line-solutions to calculate the anatomical joint angles from motion captured raw measurement data (also referred as inverse kinematics). In addition, recent developments in inertial motion sensing technology show that it may replace large, immobile and expensive optical systems with small, mobile and cheaper solutions in cases when a laboratory-free measurement setup is needed. The objective of the presented work is to extend the workflow of measurement and analysis of human arm movements with an algorithm that allows accurate and real time estimation of anatomical joint angles for a widely used OpenSim upper limb kinematic model when inertial sensors are used for movement recording. METHODS: The internal structure of the selected upper limb model is analyzed and used as the underlying platform for the development of the proposed algorithm. Based on this structure, a prototype marker set is constructed that facilitates the reconstruction of model-based joint angles using orientation data directly available from inertial measurement systems. The mathematical formulation of the reconstruction algorithm is presented along with the validation of the algorithm on various platforms, including embedded environments. RESULTS: Execution performance tables of the proposed algorithm show significant improvement on all tested platforms. Compared to OpenSim's Inverse Kinematics tool 50-15,000x speedup is achieved while maintaining numerical accuracy. CONCLUSIONS: The proposed algorithm is capable of real-time reconstruction of standardized anatomical joint angles even in embedded environments, establishing a new way for complex applications to take advantage of accurate and fast model-based inverse kinematics calculations. PMID- 28095859 TI - Vascular function in asthmatic children and adolescents. AB - BACKGROUND: Epidemiological studies have demonstrated an increased incidence of cardiovascular events in patients with bronchial asthma, but little is known about the relationship between asthma and vascular function. The purpose of this study was to evaluate endothelial function and arterial stiffness in children and adolescents with asthma. METHODS: A cross-sectional controlled study was designed. Measurements of endothelial function and arterial stiffness in asthmatic (13.6 +/- 0.6 years) and control groups (14.9 +/- 0.7 years) were taken by the non-invasive peripheral arterial tonometry (EndoPAT2000) determined by using the natural logarithm of the reactive hyperemia index (LnRHI) and the augmentation index (AIx@75%), respectively. Patients with asthma were also administered two questionnaires to evaluate asthma control and quality of life. Exercise functional capacity was evaluated using the Shuttle Walking Test (SWT). Only male participants were included in the present study. RESULTS: LnRHI and the walked distance during the SWT were similar between groups (p = 0.23 and p = 0.50, respectively). AIx@75% was significantly higher in the asthmatic group ( 7.75 +/- 1.7) compared to the control group (-15.25 +/- 1.8), p < 0.04. In the control group, the LnRHI correlated positively with baseline systolic blood pressure (r = 0.53, p = 0.02) and mean arterial pressure (r = 0.50, p = 0.03), age (r = 0.61, p = 0.007), weight (r = 0.63, p = 0.004) and height (r = 0.56, p = 0.015). Besides that LnRHI correlated with FVC (r = 0.69, p = 0.002), FEV1, (r = 0.53, p = 0.03) and negatively with Tiffeneau index (FEV1/FVC%, r = -0.49 p = 0.04). The LnRHI of the asthmatic group did not correlate with the different variables evaluated. CONCLUSION: The increased AIx@75% without changes in LnRHI in asthmatic patients could mean that an early detection of vascular impairment may precede endothelial dysfunction, and that different mechanisms may contribute to the pathogenesis and progression of cardiovascular events in this population. A large prospective and randomized controlled study should be done to evaluate the physiopathological mechanisms underlying the association between arterial stiffness and asthma. PMID- 28095858 TI - miR-4775 promotes colorectal cancer invasion and metastasis via the Smad7/TGFbeta mediated epithelial to mesenchymal transition. AB - BACKGROUND: Despite advancements in the diagnosis and treatment of colorectal cancer (CRC), many patients die because of tumor metastasis or recurrence. Therefore, identifying new prognostic markers and elucidating the mechanisms of CRC metastasis and recurrence will help to improve the prognosis of the disease. As dysregulation of microRNAs is strongly related to cancer progression, the aim of this study was to identify the role of miR-4775 in the prognosis of CRC patients and the underling mechanisms involved in CRC progression. METHODS: qPCR and in situ hybridization were used to evaluate the expression of miR-4775 in 544 pairs of paraffin-embedded normal and CRC tissues. Kaplan-Meier analysis with the log-rank test was used for survival analyses. Immunohistochemical staining was applied to investigate the expression of miR-4775-regulated Smad7/TGFbeta pathway associated markers. In vitro and in vivo invasion and metastasis assays were used to explore the function of miR-4775 in the progression of CRC. RESULTS: miR-4775 was identified as a high-risk factor for CRC metastasis and recurrence, with high levels predicting poor survival among the 544 studied CRC patients. Furthermore, high miR-4775 expression promoted the invasion of CRC cells as well as metastasis and the epithelial to mesenchymal transition (EMT) via Smad7-mediated activation of TGFbeta signaling both in vitro and in vivo. Downregulating miR-4775 or overexpressing Smad7 reversed the tumor-promoting roles of miR-4775/Smad7/TGFbeta in vitro and in vivo. CONCLUSION: miR-4775 promotes CRC metastasis and recurrence in a Smad7/TGFbeta signaling-dependent manner, providing a new therapeutic target for inhibiting the metastasis or recurrence of the disease. PMID- 28095861 TI - Challenges in conducting natural experiments in parks-lessons from the REVAMP study. AB - : Experimental evidence on the role of the built environment for promoting physical activity is important for informing how to create cities that promote active living. Parks provide opportunities for physical activity; however, there is little robust evidence on the impact of park refurbishment. Government agencies often modify parks, providing opportunities for natural experiment studies of these interventions. Such an opportunity was provided by the modification of a large park in Victoria, Australia in 2013 when the Recording and EValuating Activity in a Modified Park (REVAMP) study was established. Based on insights from the REVAMP study, this paper discusses challenges involved in conducting natural experiments in park settings, focussing on issues that may help design more effective future evaluations of the impact of park refurbishment. Natural experiments offer unique opportunities to evaluate the impact of large-scale changes to the built environment. They provide valuable data that might not otherwise be possible to gather, because of the costs associated with modification of the environment. However, factors beyond the control of the study team contribute to the complexity of both organising and conducting natural experiments, with potential flow-on effects to the quality of data. Therefore many extraneous factors need to be considered when designing, costing and conducting natural experiments; studies should identify opportunities to include key partners from the inception of the project, be flexible yet robust, and allow sufficient funding to accommodate unexpected changes in the research protocol. TRIAL REGISTRATION: Current controlled trial ISRCTN50745547 , registration date 11.1.2014. PMID- 28095862 TI - Different survival analysis methods for measuring long-term outcomes of Indigenous and non-Indigenous Australian cancer patients in the presence and absence of competing risks. AB - BACKGROUND: Net survival is the most common measure of cancer prognosis and has been used to study differentials in cancer survival between ethnic or racial population subgroups. However, net survival ignores competing risks of deaths and so provides incomplete prognostic information for cancer patients, and when comparing survival between populations with different all-cause mortality. Another prognosis measure, "crude probability of death", which takes competing risk of death into account, overcomes this limitation. Similar to net survival, it can be calculated using either life tables (using Cronin-Feuer method) or cause of death data (using Fine-Gray method). The aim of this study is two-fold: (1) to compare the multivariable results produced by different survival analysis methods; and (2) to compare the Cronin-Feuer with the Fine-Gray methods, in estimating the cancer and non-cancer death probability of both Indigenous and non Indigenous cancer patients and the Indigenous cancer disparities. METHODS: Cancer survival was investigated for 9,595 people (18.5% Indigenous) diagnosed with cancer in the Northern Territory of Australia between 1991 and 2009. The Cox proportional hazard model along with Poisson and Fine-Gray regression were used in the multivariable analysis. The crude probabilities of cancer and non-cancer methods were estimated in two ways: first, using cause of death data with the Fine-Gray method, and second, using life tables with the Cronin-Feuer method. RESULTS: Multivariable regression using the relative survival, cause-specific survival, and competing risk analysis produced similar results. In the presence of competing risks, the Cronin-Feuer method produced similar results to Fine-Gray in the estimation of cancer death probability (higher Indigenous cancer death probabilities for all cancers) and non-cancer death probabilities (higher Indigenous non-cancer death probabilities for all cancers except lung cancer and head and neck cancers). Cronin-Feuer estimated much lower non-cancer death probabilities than Fine-Gray for non-Indigenous patients with head and neck cancers and lung cancers (both smoking-related cancers). CONCLUSION: Despite the limitations of the Cronin-Feuer method, it is a reasonable alternative to the Fine-Gray method for assessing the Indigenous survival differential in the presence of competing risks when valid and reliable subgroup-specific life tables are available and cause of death data are unavailable or unreliable. PMID- 28095860 TI - Mouse models of atherosclerosis: a historical perspective and recent advances. AB - Atherosclerosis represents a significant cause of morbidity and mortality in both the developed and developing countries. Animal models of atherosclerosis have served as valuable tools for providing insights on its aetiology, pathophysiology and complications. They can be used for invasive interrogation of physiological function and provide a platform for testing the efficacy and safety of different pharmacological therapies. Compared to studies using human subjects, animal models have the advantages of being easier to manage, with controllable diet and environmental risk factors. Moreover, pathophysiological changes can be induced either genetically or pharmacologically to study the harmful effects of these interventions. There is no single ideal animal model, as different systems are suitable for different research objectives. A good understanding of the similarities and differences to humans enables effective extrapolation of data for translational application. In this article, we will examine the different mouse models for the study and elucidation of the pathophysiological mechanisms underlying atherosclerosis. We also review recent advances in the field, such as the role of oxidative stress in promoting endoplasmic reticulum stress, mitochondrial dysfunction and mitochondrial DNA damage, which can result in vascular inflammation and atherosclerosis. Finally, novel therapeutic approaches to reduce vascular damage caused by chronic inflammation using microRNA and nano medicine technology, are discussed. PMID- 28095863 TI - Dietary intake of n-3 PUFAs modifies the absorption, distribution and bioavailability of fatty acids in the mouse gastrointestinal tract. AB - BACKGROUND: Dietary polyunsaturated fatty acids (PUFAs), especially n-3 PUFAs, are important for human health. The intestinal tract, a location that is heavily colonized by microorganisms, is the main organ for absorbing fatty acids. METHODS: The purpose of this study was to analyze the effects of dietary n-3 and n-6 PUFAs on the distribution of different types of fatty acids and their bioavailability along the gut. Mice were fed for a week with experimental diets containing high n-3 or high n-6 fatty acid levels. Blood was collected at different time points, and after 7 days the mice were euthanized and their digestive tract was divided into 17 segments for fatty acids analyses. RESULTS: We found that supplementing n-3 fatty acids significantly changed the ratio of n 6/n-3 PUFAs, increased the bioavailability of n-3 PUFAs, and altered fatty acid distribution. In addition, in the n-3 diet group, the absorption of saturated fatty acids (SFAs) along the gut was found to be inhibited, which was confirmed by feeding the mice with a diet containing deuterium-labeled palmitic acid and stearic acid. CONCLUSION: These results show that a diet rich in n-3 PUFAs can significantly modify the distribution and bioavailability of fatty acids, and particularly, may block the absorption of SFAs in the mouse gastrointestinal (GI) tract. PMID- 28095865 TI - Engineered biosynthesis of milbemycins in the avermectin high-producing strain Streptomyces avermitilis. AB - BACKGROUND: Milbemycins, produced from Streptomyces hygroscopicus subsp. aureolacrimosus and Streptomyces bingchenggensis, are 16-membered macrolides that share structural similarity with avermectin produced from Streptomyces avermitilis. Milbemycins possess strong acaricidal, insecticidal, and anthelmintic activities but low toxicity. Due to the high commercial value of the milbemycins and increasing resistance to the avermectins and their derivatives, it is imperative to develop an efficient combinatorial biosynthesis system exploiting an overproduction host strain to produce the milbemycins and novel analogs in large quantities. RESULTS: The respective replacement of AveA1 and AveA3 (or module 7 in AveA3) of the avermectin polyketide synthase (PKS) in the avermectin high-producing strain S. avermitilis SA-01 with MilA1 and MilA3 (or module 7 in MilA3) of the milbemycin PKS resulted in the production of milbemycins A3, A4, and D in small amounts and their respective C5-O-methylated congener milbemycins B2, B3, and G as major products with total titers of approximately 292 mg/l. Subsequent inactivation of the C5-O-methyltransferase AveD led to a production of milbemycins A3/A4 (the main components of the commercial product milbemectin) in approximately 225 and 377 mg/l in the flask and 5 l fermenter culture, respectively, along with trace amounts of milbemycin D. CONCLUSIONS: We demonstrated that milbemycin biosynthesis can be engineered in the avermectin-producing S. avermitilis by combinatorial biosynthesis with only a slight decrease in its production level. Application of a similar strategy utilizing higher producing industrial strains will provide a more efficient combinatorial biosynthesis system based on S. avermitilis for further enhanced production of the milbemycins and their novel analogs with improved insecticidal potential. PMID- 28095864 TI - MicroRNA-141 enhances anoikis resistance in metastatic progression of ovarian cancer through targeting KLF12/Sp1/survivin axis. AB - BACKGROUND: Cancer metastasis is determined by the formation of the metastatic niche and the ability of cancer cells to adapt to microenvironmental stresses. Anoikis resistance is a fundamental feature of metastatic cancer cell survival during metastatic cancer progression. However, the mechanisms underlying anoikis resistance in ovarian cancer are still unclear. METHODS: Expressions of miRNA-141 and its downstream targets were evaluated by qPCR, Western blotting, Immunohistochemical (IHC) and in situ hybridization (ISH) assays. The luciferase assays were used to prove KLF12 as the downstream target of miR-141. The cDNA microarray and apoptotic protein arrays were used to identify the targets of miR 141 and KLF12. The competition of KLF12 and Sp1 on survivin promoter was examined by ChIP assay. IHC analysis on ovarian cancer tissue array was used to evaluate the expressions of KLF12 and miR-141 and to show the clinical relevance. The functional studies were performed by in vitro and in vivo tumorigenic assays. RESULTS: Enforced expression of miR-141 promotes, while knockdown of miR-141 expression inhibits, cell proliferation, anchorage-independent capacity, anoikis resistance, tumor growth and peritoneal metastases of ovarian cancer cells. Bioinformatics and functional analysis identified that Kruppel-related zinc finger protein AP-2rep (KLF12) is directly targeted by miR-141. Consistent with this finding, knockdown of KLF12 phenocopied the effects of miR-141 overexpression in ovarian cancer cells. In contrast, restoration of KLF12 in miR 141-expressing cells significantly attenuated anoikis resistance in ovarian cancer cells via interfering with Sp1-mediated survivin transcription, which inhibits the intrinsic apoptotic pathway and is crucial for ovarian cancer cell survival, anoikis resistance and peritoneal metastases. Immunohistochemical (IHC) and in situ hybridization (ISH) assays confirmed that miRNA-141 expression is inversely correlated with KLF12 expression and significantly associated with advanced ovarian cancers accompanied with distal metastases, underscoring the clinical relevance of our findings. CONCLUSIONS: Our data identify a novel signaling axis of miR-141/KLF12/Sp1/survivin in enhancing anoikis resistance and likely serves as a potential therapeutic target for metastatic ovarian cancer. PMID- 28095866 TI - Improvement of displacement estimation of breast tissue in ultrasound elastography using the monogenic signal. AB - BACKGROUND: In breast ultrasound elastography, tissues displacements estimation is obtained through a technique that follows the evolution of tissues under stress. However, during the acquisition of B-mode images, tissue displacements are often contaminated with multiplicative noise caused by changes in the speckle pattern in the tissue. Thus, the application of monogenic signal technique on the B-mode image in order to estimate displacement tissue, result in a presence of amplified noise in the deformation tissue image, which severely obscures the useful information. In this paper, we propose a new method based on the monogenic features, that is to improve the old monogenic signal (OMS) technique by improving the filtering step, so that the use of an effective denoising technique is enough to ensure a good estimation of displacement tissue. Our proposed method is based on the use of a robust filtering technique combined with the monogenic model. METHODS: Two models of phantom elasticity are used in our test validation sold by CIRS company. In-vivo testing was also performed on the sets of clinical B-mode images to 20 patients including malignant breast tumors. Shrinkage wavelets has been used to eliminate the noise according to the threshold, then a guided filter is introduced to completely filter the image, the monogenic model is used after excerpting the image feature and estimating analytically the displacement tissue. RESULTS: Accurate and excellent displacement estimation for breast tissue was observed in proposed method results. By adapting our proposed approach to breast B-mode images, we have shown that it demonstrated a higher performance for displacement estimation; it gives better values in term of standard deviation, higher contrast to noise ratio, greater peak signal-to-noise ratio, excellent structural similarity and much faster speed than OMS and B spline techniques. The results of the proposed model are encouraging, allowing quick and reliable estimations. CONCLUSION: Although the proposed approach is used in ultrasound domains, it has never been used in the estimation of the breast tissue displacement. In this context, our proposed approach could be a powerful diagnostic tool to be used in breast displacement estimation in ultrasound elastography. PMID- 28095867 TI - Effects of ablation depth and repair time on the corneal elastic modulus after laser in situ keratomileusis. AB - BACKGROUND: The biomechanical properties of the cornea should be taken into account in the refractive procedure in order to perform refractive surgery more accurately. The effects of the ablation depth and repair time on the elastic modulus of the rabbit cornea after laser in situ keratomileusis (LASIK) are still unclear. METHODS: In this study, LASIK was performed on New Zealand rabbits with different ablation depth (only typical LASIK flaps were created; residual stroma bed was 50 or 30% of the whole cornea thickness respectively). The animals without any treatment were served as normal controls. The corneal thickness was measured by ultrasonic pachymetry before animals were humanly killed after 7 or 28 days post-operatively. The corneal elastic modulus was measured by uniaxial tensile testing. A mathematical procedure considering the actual geometrics of the cornea was created to analyze the corneal elastic modulus. RESULTS: There were no obvious differences among all groups in the elastic modulus on after 7 days post-operatively. However, after 28th days post-operatively, there was a significant increase in the elastic modulus with 50 and 30% residual stroma bed; only the elastic modulus of the cornea with 30% residual stroma bed was significantly higher than that of 7 days. CONCLUSIONS: Changes in elastic modulus after LASIK suggest that this biomechanical effect may correlate with the ablation depth and repair time. PMID- 28095868 TI - PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression. AB - BACKGROUND: Lobular carcinoma in situ (LCIS) is a non-invasive breast lesion that is typically found incidentally on biopsy and is often associated with invasive lobular carcinoma (ILC). LCIS is considered by some to be a risk factor for future breast cancer rather than a true precursor lesion. The aim of this study was to identify genetic changes that could be used as biomarkers of progression of LCIS to invasive disease using cases of pure LCIS and comparing their genetic profiles to LCIS which presented contemporaneously with associated ILC, on the hypothesis that the latter represents LCIS that has already progressed. METHODS: Somatic copy number aberrations (SCNAs) were assessed by SNP array in three subgroups: pure LCIS, LCIS associated with ILC and the paired ILC. In addition exome sequencing was performed on seven fresh frozen samples of LCIS associated with ILC, to identify recurrent somatic mutations. RESULTS: The copy number profiles of pure LCIS and LCIS associated with ILC were almost identical. However, four SCNAs were more frequent in ILC than LCIS associated with ILC, including gain/amplification of CCND1. CCND1 protein over-expression assessed by immunohistochemical analysis in a second set of samples from 32 patients with pure LCIS and long-term follow up, was associated with invasive recurrence (P = 0.02, Fisher's exact test). Exome sequencing revealed that PIK3CA mutations were as frequent as CDH1 mutations in LCIS, but were not a useful biomarker of LCIS progression as they were as frequent in pure LCIS as in LCIS associated with ILC. We also observed heterogeneity of PIK3CA mutations and evidence of sub-clonal populations in LCIS irrespective of whether they were associated with ILC. CONCLUSIONS: Our data shows that pure LCIS and LCIS co-existing with ILC have very similar SCNA profiles, supporting the hypothesis that LCIS is a true precursor lesion. We have provided evidence that over-expression of CCND1 may identify a subgroup of patients with pure LCIS who are more likely to develop invasive disease, in contrast to PIK3CA mutations, which occur too early in lobular tumorigenesis to be informative. PMID- 28095869 TI - Macrophage Activation Syndrome: different mechanisms leading to a one clinical syndrome. AB - BACKGROUND: Macrophage activation syndrome (MAS) is a severe complication of rheumatic disease in childhood, particularly in systemic Juvenile Idiopathic Arthritis (sJIA). It is characterize by an uncontrolled activation and proliferation of T lymphocytes and macrophages. MAIN CONTENT: MAS is currently classified among the secondary or acquired forms of haemophagocytic lymphohistiocytosis (sHLH). The reason is that MAS shares clinical and laboratory features with primary genetic HLH (pHLH). In this context is conceivable that some of the pathogenic mechanisms of pHLH may be involved in other forms of HLH. Heterozygosity for mutations of genes involved in pHLH may lead to a cytotoxic defect and to a development of clinical overt disease. But other different contributors might be involved to the development of MAS such as infections or underlying inflammation. In MAS, the inflammatory status of the patient is a major contributor of the disease. Indeed, the majority of the MAS episodes occurs during active disease phases or at disease onset. In addition, recent evidence in animals and humans suggest that genetics may also play a major role in contributing to hyperinflammation and particularly to macrophages hyper responses. CONCLUSIONS: We hypothesize that HLH may be one unique clinical syndrome, to whose generation different mechanisms may contribute, and maintained by one final effector mechanism. PMID- 28095870 TI - Comparison of compressive forces caused by various cannulated cancellous screws used in arthroscopic ankle arthrodesis. AB - BACKGROUND: When performing arthroscopic ankle arthrodesis for end-stage ankle arthritis, internal fixation is performed using bone screws after appropriate preparation. However, optimal characteristics of bone screws have not been examined in terms of pressure force. Objective comparisons of bone-screw performance may provide information on procedures for arthroscopic ankle arthrodesis. The study objectives were to determine whether it was possible to measure compressive force changes using the newly developed device and to infer all screw characteristics from measurement results when used in actual surgeries. In addition, we performed experiments on cadavers to verify whether the experimental results could be applied to the joints of living subjects. METHODS: Three types of screws (S1, S2, and S3) were inserted into the unique measurement device, and the changes in pressure were measured for each 45 degrees turn. Changes in pressure and maximum pressure force were recorded after the application of the screws. After reaching the maximum pressure in the simulated bone, further screw rotations were accompanied by a gradual pressure decrease to 0 MPa. We also measured pressure changes in a similar manner by inserting a miniature pressure sensor into the talocrural joints of cadavers. RESULTS: The mean maximum pressure +/- standard deviation for S1, S2, and S3 were 0.832 +/- 0.164 MPa, 0.434 +/- 0.116 MPa, and 0.414 +/- 0.127 MPa, respectively. Pressure slopes to the maximum did not significantly differ between the screws in the simulated bone, and a subsequent pressure decrease to 0 MPa was significantly more rapid for S1 than for S2 and S3. Although pressure failure after the overtightening of screws was only observed in the simulated bone, patterns of pressure vs. rotation angle were similar in simulated and cadaveric bones. The pressure profile characteristics of three different screw types were determined. CONCLUSIONS: We were able to measure the compressive force changes using the newly developed device when the screws were inserted. On the basis of the measurement results, we were able to infer the characteristics of all screws when used in actual surgery. PMID- 28095871 TI - A systematic review of psychosocial therapies for children with rheumatic diseases. AB - BACKGROUND: To assess the quality of evidence for the effects of psychosocial therapies on pain and function in children with rheumatic diseases. METHODS: We conducted a literature search of MEDLINE and PsycINFO for randomized clinical trials of psychosocial interventions for pain and disability in children with rheumatic diseases from January 1969 to September 2015. Studies with a sample size less than 10 subjects were excluded. Study quality was assessed using the Jadad score. RESULTS: Five articles met inclusion criteria, for a total of 229 patients, aged 5 to 18 years. Two studies included children with fibromyalgia. Three studies included children with juvenile arthritis. Neither study in fibromyalgia reported the statistical significance of immediate between-group pre post changes in functioning or pain. One study examining the effects of an internet-based psychosocial intervention in children with juvenile arthritis reported significant differences in post-intervention pain scores (p = 0.03). However, 2 studies did not show improvements in pain scores among children with juvenile arthritis treated with psychosocial interventions vs. a wait-list control or vs. an active control (massage). No studies reported significant between-group differences for functional outcomes in children with juvenile arthritis. CONCLUSIONS: The available data were limited by the scarcity of randomized trials. Definite conclusions about the immediate effect of psychosocial interventions on pain and function in children with fibromyalgia could not be made because between-group comparisons of post-treatment change scores were not reported. For children with juvenile inflammatory arthritis, results of between-group comparisons for pain differed across studies, and analyses examining disability revealed no significant differences between groups. PMID- 28095872 TI - An unusual combined thymic carcinoma composed of squamous cell carcinoma and type AB thymoma: a rare case report. AB - BACKGROUND: Combined thymic carcinoma is a malignant neoplasm of the thymus recently added to the 4th edition of the World Health Organization (WHO) classification of tumors of the lung, pleura, thymus and heart. It involves at least one type of thymic carcinoma and another thymic epithelial tumor. The previously used term "combined thymic epithelial tumor" has been abandoned. CASE PRESENTATION: Here, we present an unusual case of combined thymic carcinoma of the thymus in a 44-year-old male who had suffered from fever, chest pain, chest tightness and shortness of breath. Magnetic resonance imaging (MRI) detected a mass approximately 6.4 cm * 4.2 cm in the anterior mediastinum, and a nonencapsulated tumor approximately 5.0 cm * 3.5 cm * 2.5 cm with an irregular shape was resected. The morphological features and the immunostaining pattern of the tumor revealed it to be an unusual combined thymic carcinoma consisting of type AB thymoma and squamous cell carcinoma. There were cysts of various sizes, some of which had crack-like structures, in the type AB thymoma area. A gradual transition could be seen between these structures and the squamous cell carcinoma, indicating that the carcinoma portion may have originated from the composition of the thymoma. CONCLUSIONS: Combined thymic carcinoma composed of type AB thymoma and squamous cell carcinoma is rare, and the carcinoma portion may have originated from epithelial structures in the type AB thymoma. PMID- 28095873 TI - Physical integrity and residual bio-efficacy of used LLINs in three cities of the South-West region of Cameroon 4 years after the first national mass-distribution campaign. AB - BACKGROUND: Long-lasting insecticidal nets (LLINs) are effective tools at reducing malaria transmission. In Cameroon, following the first national mass distribution campaign in 2011, there has been no follow up on the efficacy of LLINs distributed. The aim of this report is to assess the physical integrity and insecticidal potency of LLINs distributed in three cities with contrasting socio economic status (SES) and to evaluate the use and care for bed nets owned by individuals. METHODS: The study was conducted in Limbe, Tiko and Buea three localities in the Fako division of the South West Region of Cameroon. Tiko had the highest SES based on the type of building materials used, followed respectively by Limbe and Buea. The use and care for bed nets was assessed using a questionnaire, the physical state of bed nets evaluated following WHOPES recommendation for determining size of holes and the residual insecticidal activity of retrieved bed nets determined through a cone bioassay using susceptible strains of mosquitoes. RESULTS: Of the 241 households visited in Limbe (n = 81), Tiko (n = 80) and Buea (n = 80), 186 (77.2%) had LLINs, with no significant variations from the selected study locations. However, bed net coverage was not meeting World Health Organization standards (p < 0.0001). Six different brands of LLINs were recorded, and the majority were those provided by the NMCP through the 2011 national mass campaign or antenatal care programme. Based on the calculation of the Proportionate Hole Index (PHI) as indicator of physical integrity of nets, the proportion of nets classified as serviceable (versus too torn) differed statistically according to locations (p value = 0.04), with 63.8% in Tiko, 50% in Limbe and 47% in Buea. Of the 20 nets tested for their efficacy against susceptible strains of mosquito, 42.6% (3 nets) were optimally effective in Tiko, 57.4% (4), 16.7% (1) and 14.3% (1) were minimally effective in Tiko, Buea and Limbe respectively. Finally; 85.7% (6) and 83.3% (5) were not effective in Limbe and Buea. CONCLUSIONS: These findings pinpoint the need for more frequent replacement of LLINs especially for people with low SES and also the need for the promotion of good practices on the maintenance and washing of nets. PMID- 28095874 TI - Clinicopathological study of 9 cases of prostate cancer involving the rectal wall. AB - BACKGROUND: Prostate cancer involving the rectal wall is rare and may lead to diagnostic pitfalls. CASE PRESENTATION: Out of 9504 patients with rectal tumors between January 2003 and January 2015, 9 patients (elderly with a mean age of 74 years) with prostate cancer involving the rectal wall were clinically misdiagnosed with rectal cancer. The lesions were located in the rectum, and included 3 circumferential rectal masses, 1 ulceration lesion, 1 crater-like mass, and 4 protruding lesions. Specimens were acquired using biopsy, fine needle aspiration, or resection. The initial symptoms of these patients included rectal urgency, bowel obstruction, and lower gastrointestinal bleeding. Prostate-related symptoms were not obvious. Histologically, 2 cases showed cancer cell invasion in the mucosa, 1 showed transmural invasion from the mucosa to subserosal soft tissues, and 7 cases had submucosa and muscularis propria involvement. All the 9 cases had muscularis propria involvement. However, there were no intraepithelial neoplasias in the mucosal layer, which is reminiscent of rectal carcinoma. The tumors consisted of small-sized or foamy cells that formed acinus-like, duct like, and cribriform-like structures. We conducted histological staining and an immunohistochemical analysis for CDX-2, prostate-specific antigen (PSA), P504s, villin, carcinoembryonic antigen, CK-pan, cytokeratin 20, and Ki-67. All tumors were PSA and CK-pan positive, 5 of 9 tumors were P504s-positive, and all tumors were negative for the other markers. All patients underwent standard therapy for prostate cancer after the definitive pathological diagnosis. As of March 31, 2015, 8 patients were alive and 1 had died of prostate cancer 6 months posttreatment. CONCLUSIONS: Adenocarcinoma appearing in the rectal wall is not always rectal carcinoma. It is necessary to perform a differential diagnosis for prostate cancer in cases of rectal malignant tumors in elderly male patients. Any treatment should be postponed until the final definitive diagnosis is reached. PMID- 28095875 TI - Assessment of synthetic floral-based attractants and sugar baits to capture male and female Aedes aegypti (Diptera: Culicidae). AB - BACKGROUND: The viruses transmitted by Aedes aegypti, including dengue and Zika viruses, are rapidly expanding in geographic range and as a threat to public health. In response, control programs are increasingly turning to the use of sterile insect techniques resulting in a need to trap male Ae. aegypti to monitor the efficacy of the intervention. However, there is a lack of effective and cheap methods for trapping males. Thus, we attempted to exploit the physiological need to obtain energy from sugar feeding in order to passively capture male and female Ae. aegypti (nulliparous and gravid) in free-flight attraction assays. Candidate lures included previously identified floral-based (phenylacetaldehyde, linalool oxide, phenylethyl alcohol, and acetophenone) attractants and an attractive toxic sugar bait-based (ATSB) solution of guava and mango nectars. A free-flight attraction assay assessed the number of mosquitoes attracted to each candidate lure displayed individually. Then, a choice test was performed between the best performing lure and a water control displayed in Gravid Aedes Traps (GAT). RESULTS: Results from the attraction assays indicated that the ATSB solution of guava and mango nectars was the most promising lure candidate for males; unlike the floral-based attractants tested, it performed significantly better than the water control. Nulliparous and gravid females demonstrated no preference among the lures and water controls indicating a lack of attraction to floral-based attractants and sugar baits in a larger setting. Although the guava-mango ATSB lure was moderately attractive to males when presented directly (i.e. no need to enter a trap or other confinement), it failed to attract significantly more male, nulliparous female, or gravid female Ae. aegypti than water controls when presented inside a Gravid Aedes Trap. CONCLUSIONS: Our findings suggest that the use of volatile floral-based attractants and sugar mixtures that have been identified in the literature is not an effective lure by which to kill Ae. aegypti at ATSB stations nor capture them in the GAT. Future trapping efforts would likely be more successful if focused on more promising methods for capturing male and female Ae. aegypti. PMID- 28095876 TI - Multi-criteria decision analysis (MCDA): testing a proposed MCDA framework for orphan drugs. AB - BACKGROUND: Since the introduction of the orphan drugs legislation in Europe, it has been suggested that the general method of assessing drugs for reimbursement is not necessarily suitable for orphan drugs. The National Institute for Health and Clinical Excellence indicated that several criteria other than cost and efficacy could be considered in reimbursement decisions for orphan drugs. This study sought to explore the multi-criteria decision analysis (MCDA) framework proposed by (Orphanet J Rare Dis 7:74, 2012) to a range of orphan drugs, with a view to comparing the aggregate scores to the average annual cost per patient for each product, and thus establishing the merit of MCDA as a tool for assessing the value of orphan drugs in relation to their pricings. METHODS: An MCDA framework was developed using the nine criteria proposed by (Orphanet J Rare Dis 7:74, 2012) for the evaluation of orphan drugs, using the suggested numerical scoring system on a scale of 1 to 3 for each criterion. Correlations between the average annual cost of the drugs and aggregate MCDA scores were tested and plotted graphically. Different weightings for each of the attributes were also tested. A further analysis was conducted to test the impact of including the drug cost as an attribute in the aggregate index scores. RESULTS: In the drugs studied, the R 2, that statistically measures how close the data are to the fitted regression line was 0.79 suggesting a strong correlation between the drug scores and the average annual cost per patient. CONCLUSION: Despite several limitations of the proposed model, this quantitative study provided insight into using MCDA and its relationship to the average annual costs of the products. PMID- 28095877 TI - Deciphering composition and function of the root microbiome of a legume plant. AB - BACKGROUND: Diverse assemblages of microbes colonize plant roots and collectively function as a microbiome. Earlier work has characterized the root microbiomes of numerous plant species, but little information is available for legumes despite their key role in numerous ecosystems including agricultural systems. Legumes form a root nodule symbiosis with nitrogen-fixing Rhizobia bacteria and thereby account for large, natural nitrogen inputs into soils. Here, we describe the root bacteria microbiome of the legume Trifolium pratense combining culture-dependent and independent methods. For a functional understanding of individual microbiome members and their impact on plant growth, we began to inoculate root microbiome members alone or in combination to Trifolium roots. RESULTS: At a whole-root scale, Rhizobia bacteria accounted for ~70% of the root microbiome. Other enriched members included bacteria from the genera Pantoea, Sphingomonas, Novosphingobium, and Pelomonas. We built a reference stock of 200 bacteria isolates, and we found that they corresponded to ~20% of the abundant root microbiome members. We developed a microcosm system to conduct simplified microbiota inoculation experiments with plants. We observed that while an abundant root microbiome member reduced plant growth when inoculated alone, this negative effect was alleviated if this Flavobacterium was co-inoculated with other root microbiome members. CONCLUSIONS: The Trifolium root microbiome was dominated by nutrient-providing Rhizobia bacteria and enriched for bacteria from genera that may provide disease protection. First microbiota inoculation experiments indicated that individual community members can have plant growth compromising activities without being apparently pathogenic, and a more diverse root community can alleviate plant growth compromising activities of its individual members. A trait-based characterization of the reference stock bacteria will permit future microbiota manipulation experiments to decipher overall microbiome functioning and elucidate the biological mechanisms and interactions driving the observed effects. The presented reductionist experimental approach offers countless opportunities for future systematic and functional examinations of the plant root microbiome. PMID- 28095878 TI - Black-blood thrombus imaging (BTI): a contrast-free cardiovascular magnetic resonance approach for the diagnosis of non-acute deep vein thrombosis. AB - BACKGROUND: Deep vein thrombosis (DVT) is a common but elusive illness that can result in long-term disability or death. Accurate detection of thrombosis and assessment of its size and distribution are critical for treatment decision making. In the present study, we sought to develop and evaluate a cardiovascular magnetic resonance (CMR) black-blood thrombus imaging (BTI) technique, based on delay alternating with nutation for tailored excitation black-blood preparation and variable flip angle turbo-spin-echo readout, for the diagnosis of non-acute DVT. METHODS: This prospective study was approved by institutional review board and informed consent obtained from all subjects. BTI was first conducted in 11 healthy subjects for parameter optimization and then conducted in 18 non-acute DVT patients to evaluate its diagnostic performance. Two clinically used CMR techniques, contrast-enhanced CMR venography (CE-MRV) and three dimensional magnetization prepared rapid acquisition gradient echo (MPRAGE), were also conducted in all patients for comparison. All images obtained from patients were analyzed on a per-segment basis. Using the consensus diagnosis of CE-MRV as the reference, the sensitivity (SE), specificity (SP), positive and negative predictive values (PPV and NPV), and accuracy (ACC) of BTI and MPRAGE as well as their diagnostic agreement with CE-MRV were calculated. Besides, diagnostic confidence and interreader diagnostic agreement were evaluated for all three techniques. RESULTS: BTI with optimized parameters effectively nulled the venous blood flow signal and allowed directly visualizing the thrombus within the black blood lumen. Higher SE (90.4% vs 67.6%), SP (99.0% vs. 97.4%), PPV (95.4% vs. 85.6%), NPV (97.8% vs 92.9%) and ACC (97.4% vs. 91.8%) were obtained by BTI in comparison with MPRAGE. Good diagnostic confidence and excellent diagnostic and interreader agreements were achieved by BTI, which were superior to MPRAGE on detecting the chronic thrombus. CONCLUSION: BTI allows direct visualization of non-acute DVT within the dark venous lumen and has the potential to be a reliable diagnostic tool without the use of contrast medium. PMID- 28095879 TI - Treatment-seeking behaviour and barriers to service access for sexually transmitted diseases among men who have sex with men in China: a multicentre cross-sectional survey. AB - BACKGROUND: Delayed or inappropriate treatment for sexually transmitted diseases (STDs) increases the risk of HIV acquisition and may cause other harmful outcomes. However, studies on STD treatment-seeking behaviour and correlated factors in men who have sex with men (MSM) are scarce. This information is crucial for the promotion of STD treatment-seeking behaviour and reduction of HIV transmission among Chinese MSM. METHODS: During 2012-2013, a multicentre cross sectional study was conducted in 7 Chinese cities. Participants completed an interview-questionnaire and gave venous blood samples, which were then tested for antibodies to HIV, syphilis, and herpes simplex virus-2 (HSV-2). MSM who tested positive for syphilis/HSV-2 or had obvious STD-related symptoms within the last 12 months were defined as suspected STD-infected MSM. RESULTS: Of the 4 496 eligible MSM who completed this survey, 24.4% (1 096/4 496) were categorized as suspected STD-infected MSM. 35.7% (391/1 096) of these MSM with suspected STD infections sought STD treatment in clinics within the last 12 months. Among MSM who did not attend STD clinics for treatment, the prevalence of syphilis and HSV 2 was significantly higher; the HIV prevalence and incidence within this subpopulation reached as high as 14.5% and 12.2/100 person-years, respectively. Multivariate logistic regression analysis indicated that having 7-12 years of education (vs. <=6 years; aOR, 2.5; 95%CI, 1.0-6.1), >=13 years of education (vs. <=6 years: aOR, 2.8; 95%CI, 1.2-7.0), monthly income >500 USD (vs. <=500 USD: aOR, 1.5; 95%CI, 1.1-2.1), obvious STD-related symptoms within last 12 months (aOR, 5.3; 95%CI, 3.7-7.5), being HIV infected (aOR, 1.7; 95%CI, 1.1-2.6), currently syphilis infected (aOR, 0.6; 95%CI, 0.4-0.9) and HSV-2 infected (aOR, 0.6; 95%CI, 0.5-0.9) were independent correlates with seeking STD treatment in clinics among Chinese MSM. CONCLUSIONS: The high prevalence of STD infection coupled with a low proportion of individuals who exhibit appropriate treatment seeking behaviour create a high risk of a growing HIV epidemic among Chinese MSM. Models that prioritize better screening for and education about STDs should be urgently implemented, especially among low-income MSM. PMID- 28095880 TI - High-throughput expression of animal venom toxins in Escherichia coli to generate a large library of oxidized disulphide-reticulated peptides for drug discovery. AB - BACKGROUND: Animal venoms are complex molecular cocktails containing a wide range of biologically active disulphide-reticulated peptides that target, with high selectivity and efficacy, a variety of membrane receptors. Disulphide-reticulated peptides have evolved to display improved specificity, low immunogenicity and to show much higher resistance to degradation than linear peptides. These properties make venom peptides attractive candidates for drug development. However, recombinant expression of reticulated peptides containing disulphide bonds is challenging, especially when associated with the production of large libraries of bioactive molecules for drug screening. To date, as an alternative to artificial synthetic chemical libraries, no comprehensive recombinant libraries of natural venom peptides are accessible for high-throughput screening to identify novel therapeutics. RESULTS: In the accompanying paper an efficient system for the expression and purification of oxidized disulphide-reticulated venom peptides in Escherichia coli is described. Here we report the development of a high throughput automated platform, that could be adapted to the production of other families, to generate the largest ever library of recombinant venom peptides. The peptides were produced in the periplasm of E. coli using redox-active DsbC as a fusion tag, thus allowing the efficient formation of correctly folded disulphide bridges. TEV protease was used to remove fusion tags and recover the animal venom peptides in the native state. Globally, within nine months, out of a total of 4992 synthetic genes encoding a representative diversity of venom peptides, a library containing 2736 recombinant disulphide-reticulated peptides was generated. The data revealed that the animal venom peptides produced in the bacterial host were natively folded and, thus, are putatively biologically active. CONCLUSIONS: Overall this study reveals that high-throughput expression of animal venom peptides in E. coli can generate large libraries of recombinant disulphide-reticulated peptides of remarkable interest for drug discovery programs. PMID- 28095882 TI - The use of dose-escalated radiation for locally advanced non-small cell lung cancer in the U.S., 2004-2013. AB - PURPOSE/OBJECTIVES: The clinical effects of radiation dose-intensification in locally advanced non-small cell lung (NSCLCa) and other cancers are challenging to predict and are ideally studied in randomized trials. The purpose of this study was to assess the use of dose-escalated radiation for locally advanced NSCLCa in the U.S., 2004-2013, a period in which there were no published level 1 studies on dose-escalation. MATERIALS/METHODS: We performed analyses on two cancer registry databases with complementary strengths and weaknesses: the National Oncology Data Alliance (NODA) 2004-2013 and the National Cancer Database (NCDB) 2004-2012. We classified locally advanced patients according to the use of dose-escalation (>70 Gy). We used adjusted logistic regression to assess the association of year of treatment with dose-escalated radiation use in two periods representing time before and after the closure of a cooperative group trial (RTOG 0617) on dose-escalation: 2004-2010 and 2010-2013. To determine the year in which a significant change in dose could have been detected had dose been prospectively monitored within the NODA network, we compared the average annual radiation dose per year with the forecasted dose (average of the prior 3 years) adjusted for patient age and comorbidities. RESULTS: Within both the NODA and NCDB, use of dose-escalation increased from 2004 to 2010 (p < 0.0001) and decreased from 2010 to 2013 (p = 0.0018), even after controlling for potential confounders. Had the NODA network been monitoring radiation dose in this cohort, significant changes in average annual dose would have been detected at the end of 2008 and 2012. CONCLUSIONS: Patterns of radiation dosing in locally advanced NSCLCa changed in the U.S. in the absence of level 1 evidence. Monitoring radiation dose is feasible using an existing national cancer registry data collection infrastructure. PMID- 28095883 TI - Moderated online social therapy for carers of young people recovering from first episode psychosis: study protocol for a randomised controlled trial. AB - BACKGROUND: First-episode psychosis most often has its onset during late adolescence. In caring for the young person, families endure high levels of stress and depression. Meanwhile, the social networks of families often erode. Our group has previously shown that family cognitive behaviour therapy (CBT) leads to significantly improved perceived stress compared with specialist first episode treatment as usual; however, there are well-known barriers to the dissemination of effective family interventions. To address this, we have developed a novel online intervention entitled 'Altitudes' that fully integrates purpose-built online social networking, expert and peer moderation, and evidence based psychoeducation within a single application. The primary aim of this trial is to evaluate the effectiveness of Altitudes in reducing stress in carers over a 6-month period. METHODS/DESIGN: We describe here a single-blinded cluster randomised controlled trial (cRCT) with permutated blocks. The clusters comprise individual families. The two treatment conditions include Altitudes plus Specialist Treatment as Usual (STAU) and STAU alone. Altitudes involves participation in our novel online programme whereas STAU comprises specialist family work at the Early Psychosis Prevention and Intervention Centre (EPPIC), Melbourne, Australia. We aim to recruit 160 family members of young, 15-27 year old, patients registered for treatment for first-episode psychosis (FEP) at EPPIC. The design includes two assessment time points, namely, baseline and 6 month follow-up. The study is due for completion within 2 years including an 18 month recruitment period and a 6-month treatment phase. The primary outcome is carers' perceived stress at 6 months. Secondary outcome measures include a biomarker of stress, depressive symptoms, worry, substance use, loneliness, social support, satisfaction with life, and a range of measures that tap into coping resources. We seek to gain a dynamic picture of carer stress through our Smartphone Ecological Momentary Assessment (SEMA) tool. DISCUSSION: This is the first randomised controlled trial designed to evaluate an online intervention for carers of young people recovering from FEP. It has the potential to produce evidence in support of a highly novel, accessible, and cost-effective intervention to reduce stress in carers who are providing support to young people at a critical phase in their recovery from psychosis. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry, identifier: ACTRN12616000968471 . Retrospectively registered on 22 July 2016. PMID- 28095881 TI - Renal function in patients with non-dialysis chronic kidney disease receiving intravenous ferric carboxymaltose: an analysis of the randomized FIND-CKD trial. AB - BACKGROUND: Preclinical studies demonstrate renal proximal tubular injury after administration of some intravenous iron preparations but clinical data on renal effects of intravenous iron are sparse. METHODS: FIND-CKD was a 56-week, randomized, open-label, multicenter study in which patients with non-dialysis dependent chronic kidney disease (ND-CKD), anemia and iron deficiency without erythropoiesis-stimulating agent therapy received intravenous ferric carboxymaltose (FCM), targeting either higher (400-600 MUg/L) or lower (100-200 MUg/L) ferritin values, or oral iron. RESULTS: Mean (SD) eGFR at baseline was 34.9 (11.3), 32.8 (10.8) and 34.2 (12.3) mL/min/1.73 m2 in the high ferritin FCM (n = 97), low ferritin FCM (n = 89) and oral iron (n = 167) groups, respectively. Corresponding values at month 12 were 35.6 (13.8), 32.1 (12.7) and 33.4 (14.5) mL/min/1.73 m2. The pre-specified endpoint of mean (SE) change in eGFR from baseline to month 12 was +0.7 (0.9) mL/min/1.73 m2 with high ferritin FCM (p = 0.15 versus oral iron), -0.9 (0.9) mL/min/1.73 m2 with low ferritin FCM (p = 0.99 versus oral iron) and -0.9 (0.7) mL/min/1.73 m2 with oral iron. No significant association was detected between quartiles of FCM dose, change in ferritin or change in TSAT versus change in eGFR. Dialysis initiation was similar between groups. Renal adverse events were rare, with no indication of between-group differences. CONCLUSION: Intravenous FCM at doses that maintained ferritin levels of 100-200 MUg/L or 400-600 MUg/L did not negatively impact renal function (eGFR) in patients with ND-CKD over 12 months versus oral iron, and eGFR remained stable. These findings show no evidence of renal toxicity following intravenous FCM over a 1-year period. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT00994318 (first registration 12 October 2009). PMID- 28095884 TI - Optimal FSH usage in revascularization of allotransplanted ovarian tissue in mice. AB - BACKGROUD: Ovarian transplantation is a useful method for preserving the fertility of young women with cancer who undergo radiotherapy and chemotherapy. Follicle-stimulating hormone (FSH) is use to protect transplanted ovarian tissues from ischemia injury through promoting revascularization after transplantation, but the side effect of high level FSH is ovarian overstimulation leading to substantial follicular loss. In this study, we investigated the optimal usage of FSH on revascularization in the in vitro cultured ovarian tissues before and after transplantation. RESULTS: FSH mainly exhibited an additive response in the gene and protein expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and follicle stimulating hormone receptor (FSHR) with its raised concentrations (0.15 IU/ml, 0.30 IU/ml and 0.60 IU/ml) and prolonged treatment (3 h, 6 h, 12 h, 24 h). The concentrations with 0.60 IU/ml FSH could obviously promoted the expression of VEGF, bFGF and FSHR, but under this concentration FSH could also overstimulated the ovarian tissue leading to follicular loss. With the increase of culture time, the gene and protein expression of VEGF and bFGF both were up-regulated in all of the FSH added groups, but FSHR expression decreased when culture time exceeded 12 h. So we chose 0.30 IU/ml FSH added concentration and 6 h culture time as the FSH usage condition in functional revascularization verification experiment, and found that under this condition FSH promoted 2.5 times increase of vascular density in treated group than in control group after ovarian tissues transplantation. CONCLUSION: Ovarian intervention with 0.30 IU/ml FSH for 6 h is an optimal FSH usage condition which could accelerate the revascularization in the allotransplanted ovarian tissue and can not produce ovarian overstimulation. PMID- 28095885 TI - Symptoms of Attention Deficit Hyperactivity Disorder (ADHD) among adult eating disorder patients. AB - BACKGROUND: Very little is known about the prevalence of ADHD symptoms in Bulimia Nervosa and Binge Eating Disorder and even less in other eating disorders. This knowledge gap is of clinical importance since stimulant treatment is proven effective in Binge Eating Disorder and discussed as a treatment possibility for Bulimia Nervosa. The objective of this study was to explore the prevalence and types of self-reported ADHD symptoms in an unselected group of eating disorder patients assessed in a specialized eating disorder clinic. METHODS: In total 1165 adults with an eating disorder were assessed with a battery of standardized instruments, for measuring inter alia ADHD screening, demographic variables, eating disorder symptoms and psychiatric comorbidity. Chi-square tests were used for categorical variables and Kruskal-Wallis tests for continuous variables. RESULTS: Almost one third (31.3 %) of the patients scored above the screening cut off indicating a possible ADHD. The highest prevalence rates (35-37 %) were found in Bulimia Nervosa and Anorexia Nervosa bingeing/purging subtype, while Eating Disorder Not Otherwise Specified type 1-4 and Binge Eating Disorder patients reported slightly below average (26-31 %), and Anorexia Nervosa restricting subtype patients even lower (18 %). Presence of binge eating, purging, loss of control over eating and non-anorectic BMI were related to results indicating a possible ADHD. Psychiatric comorbidity correlated to ADHD symptoms without explaining the differences between eating disorder diagnoses. CONCLUSIONS: There is a high frequency of ADHD symptoms in patients with binge eating/purging eating disorders that motivates further studies, particularly concerning the effects of ADHD medication. The finding that the frequency of ADHD symptoms in anorexia nervosa with binge eating/purging is as high as in bulimia nervosa highlights the need also for this group. PMID- 28095886 TI - The dynamics of HIV transmission in out of school young heterosexual men in South Africa: a systematic scoping review protocol. AB - BACKGROUND: In South Africa, gender inequality dominated by males and heterosexual HIV epidemic are associated with high HIV infection. Underlying epidemiological and social determinants driving HIV acquisition and transmission are critical to understand the extent and complexity of sexual networks as primary mechanisms through which HIV is likely to spread. The aim of the study is to provide an overview of empiric evidence that links the complex interaction of risk of HIV infection in men. METHODS AND ANALYSIS: We will conduct a systematic scoping review to identify, describe, and map literature on the dynamics of HIV infection in men, and we will determine the quality of the studies reporting on the dynamics of HIV infections in men. Primary research articles, published in peer-reviewed journals, review articles, and gray literature that address the research question, will be included. We will search PubMed, Web of Knowledge, Science Direct, EBSCOhost, Google Scholar, World Health Organization library, and UNAIDS database. Reference lists and existing networks such as government organizations and conferences will also be included to source relevant literature. Two independent reviewers will extract data in parallel from all relevant search engines, using specific inclusion and exclusion criteria. A thematic content analysis will be used to present the narrative account of the reviews, using NVivo version 10. DISCUSSION: We anticipate finding relevant literature on the dynamics of HIV transmission in South African men. Once summarized, data will be useful to guide future research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016039489. PMID- 28095887 TI - Association between midlife health behaviours and transitions out of employment from midlife to early old age: Whitehall II cohort study. AB - BACKGROUND: It is important to determine whether unhealthy behaviours might influence transitions out of employment from midlife to old age, given the anticipated need for adults to work for longer. Our aim was to determine the association between repeated assessments of cigarette smoking, heavy/problem alcohol drinking, low physical activity and poor diet at midlife, in relation to work exit from midlife to old age. METHODS: Data from 7704 participants (5392 men) from the Whitehall II cohort study in employment at midlife were used to evaluate the association between unhealthy behaviours and a subsequent transition out of work during 22 years follow-up, using logistic regression models. RESULTS: Men who smoked cigarettes, consistently drank alcohol heavily, or reported problem drinking, were more likely to leave employment over follow-up. Women with a consistently poor diet were more likely to leave employment. Associations were stronger when the reason for leaving was health grounds, and stronger among those with persistently unhealthy behaviours over follow-up. The size of the effects were broadly equivalent to one advancing year of age on employment. Physical health functioning over follow-up only partly accounted for the associations with work exit, whereas physical and mental functioning accounted for most of the associations with work exit on health grounds. CONCLUSIONS: Unhealthy behaviours in midlife are associated with transitions out of employment into old age. Promoting healthy behaviours at midlife might support current policy initiatives aimed at extending working life. Future research should consider possible mechanisms that link behaviours to transitions out of employment, and consider sex differences in larger cohorts. PMID- 28095888 TI - Do patients prefer optimistic or cautious psychiatrists? An experimental study with new and long-term patients. AB - BACKGROUND: Patients seeking treatment may be assumed to prefer a psychiatrist who suggests a new treatment with confidence and optimism. Yet, this might not apply uniformly to all patients. In this study, we tested the hypothesis that new patients prefer psychiatrists who present treatments optimistically, whilst patients with longer-term experience of mental health care may rather prefer more cautious psychiatrists. METHODS: In an experimental study, we produced video clips of four psychiatrists, each suggesting a pharmacological and a psychological treatment once with optimism and once with caution. 100 'new' patients with less than 3 months experience of mental health care and 100 'long term' patients with more than one year of experience were shown a random selection of one video-clip from each psychiatrist, always including an optimistic and a cautious suggestion of each treatment. Patients rated their preferences for psychiatrists on Likert type scales. Differences in subgroups with different age (18-40 vs. 41-65 years), gender, school leaving age (<=16 vs. >16 years), and diagnosis (ICD 10 F2 vs. others) were explored. RESULTS: New patients preferred more optimistic treatment suggestions, whilst there was no preference among long-term patients. The interaction effect between preference for treatment presentations and experience of patients was significant (interaction p-value = 0.003). Findings in subgroups were similar. CONCLUSION: In line with the hypothesis, psychiatrists should suggest treatments with optimism to patients with little experience of mental health care. However, this rule does not apply to longer-term patients, who may have experienced treatment failures in the past. PMID- 28095889 TI - Evolution of gut microbiota composition from birth to 24 weeks in the INFANTMET Cohort. AB - BACKGROUND: The gut is the most extensively studied niche of the human microbiome. The aim of this study was to characterise the initial gut microbiota development of a cohort of breastfed infants (n = 192 ) from 1 to 24 weeks of age. METHODS: V4-V5 region 16S rRNA amplicon Illumina sequencing and, in parallel, bacteriological culture. The metabolomic profile of infant urine at 4 weeks of age was also examined by LC-MS. RESULTS: Full-term (FT), spontaneous vaginally delivered (SVD) infants' microbiota remained stable at both phylum and genus levels during the 24-week period examined. FT Caesarean section (CS) infants displayed an increased faecal abundance of Firmicutes (p < 0.01) and lower abundance of Actinobacteria (p < 0.001) after the first week of life compared to FT-SVD infants. FT-CS infants gradually progressed to harbouring a microbiota closely resembling FT-SVD (which remained stable) by week 8 of life, which was maintained at week 24. The gut microbiota of preterm (PT) infants displayed a significantly greater abundance of Proteobacteria compared to FT infants (p < 0.001) at week 1. Metabolomic analysis of urine at week 4 indicated PT-CS infants have a functionally different metabolite profile than FT (both CS and SVD) infants. Co-inertia analysis showed co-variation between the urine metabolome and the faecal microbiota of the infants. Tryptophan and tyrosine metabolic pathways, as well as fatty acid and bile acid metabolism, were found to be affected by delivery mode and gestational age. CONCLUSIONS: These findings confirm that mode of delivery and gestational age both have significant effects on early neonatal microbiota composition. There is also a significant difference between the metabolite profile of FT and PT infants. Prolonged breastfeeding was shown to have a significant effect on the microbiota composition of FT-CS infants at 24 weeks of age, but interestingly not on that of FT-SVD infants. Twins had more similar microbiota to one another than between two random infants, reflecting the influence of similarities in both host genetics and the environment on the microbiota. . PMID- 28095890 TI - Impact of diversity of Mycoplasma hyopneumoniae strains on lung lesions in slaughter pigs. AB - The importance of diversity of Mycoplasma hyopneumoniae (M. hyopneumoniae) strains is not yet fully known. This study investigated the genetic diversity of M. hyopneumoniae strains in ten pig herds, and assessed associations between the presence of different strains of M. hyopneumoniae and lung lesions at slaughter. Within each herd, three batches of slaughter pigs were investigated. At slaughter, from each batch, 20 post mortem bronchoalveolar lavage fluid samples were collected for multiple locus variable-number tandem repeat analysis (MLVA), and lung lesions (Mycoplasma-like lesions, fissures) were examined. Multivariable analyses including potential risk factors for respiratory disease were performed to assess associations between the number of different strains per batch (three categories: one strain, two-six strains, >=seven strains), and the lung lesions as outcome variables. In total, 135 different M. hyopneumoniae strains were found. The mean (min.-max.) number of different strains per batch were 7 (1-13). Batches with two-six strains or more than six strains had more severe Mycoplasma like lesions (P = 0.064 and P = 0.012, respectively), a higher prevalence of pneumonia [odds ratio (OR): 1.30, P = 0.33 and OR: 2.08, P = 0.012, respectively], and fissures (OR = 1.35, P = 0.094 and OR = 1.70, P = 0.007, respectively) compared to batches with only one strain. In conclusion, many different M. hyopneumoniae strains were found, and batches of slaughter pigs with different M. hyopneumoniae strains had a higher prevalence and severity of Mycoplasma-like lung lesions at slaughter, implying that reducing the number of different strains may lead to less lung lesions at slaughter and better respiratory health of the pigs. PMID- 28095891 TI - Factors associated with initiation and persistence of urate-lowering therapy. AB - BACKGROUND: Gout is the most common inflammatory arthritic disease and is caused by crystal deposition secondary to persistent hyperuricemia. Etiological treatment with urate-lowering therapy (ULT) has been available since the 1950s but previous studies have demonstrated suboptimal degree of treatment. In recent years we have seen recommendations for ULT earlier in the course of the disease, but there are few contemporary reports reflecting the current situation. Therefore we set out to investigate proportion receiving and persisting with ULT after gout diagnosis and predictors thereof. METHOD: A population-based cohort study using regional and national population-based registers. Cohort of patients (n = 7709) from western Sweden with incident gout aged 18 years and above from 2011 to 2013. An incident case of gout was defined as having been given a diagnosis of gout (ICD-10 M10, M14.0-14.1) not preceded by a gout diagnosis or a dispensation of ULT during the previous 5 years. Main outcome measures were cumulative incidence and predictors for start of, and persistence with, ULT in gout. RESULTS: Within the first year after first gout diagnosis, 32% received ULT. Male sex, presence of diabetes or cardiovascular comorbidity, reduced kidney function but not diagnosed "end-stage kidney failure" increased the likelihood of receiving ULT. Of those starting ULT a majority (75%) did not persist with ULT treatment within the first 2 years. Age <50 years, lack of comorbidities, and "normal kidney function" or "end-stage kidney failure" were associated with non persistence with ULT. CONCLUSIONS: Only a minority of patients received ULT and a majority of these did not persist with treatment over the next 2 years. However, the older patients with renal impairment and comorbidities, possibly suffering from a more severe gout disease, were more likely to receive and persist with treatment. There is thus still room for considerable improvement with regards to management of ULT in gout. PMID- 28095892 TI - Comparative effectiveness and cost-effectiveness of Chuna manual therapy versus conventional usual care for nonacute low back pain: study protocol for a pilot multicenter, pragmatic randomized controlled trial (pCRN study). AB - BACKGROUND: While Chuna manual therapy is a Korean manual therapy widely used primarily for low back pain (LBP)-related disorders in Korea, well-designed studies on the comparative effectiveness of Chuna manual therapy are scarce. METHODS/DESIGN: This study is the protocol for a three-armed, multicenter, pragmatic randomized controlled pilot trial. Sixty severe nonacute LBP patients (pain duration of at least 3 weeks, Numeric Rating Scale (NRS) >=5) will be recruited at four Korean medicine hospitals. Participants will be randomly allocated to the Chuna group (n = 20), usual care group (n = 20), or Chuna plus usual care group (n = 20) for 6 weeks of treatment. Usual care will consist of orally administered conventional medicine, physical therapy, and back pain care education. The trial will be conducted with outcome assessor and statistician blinding. The primary endpoint will be NRS of LBP at week 7 post randomization. Secondary outcomes include NRS of leg pain, the Oswestry Disability Index (ODI), the Patient Global Impression of Change (PGIC), the Credibility and Expectancy Questionnaire, lumbar range of motion (ROM), the EuroQol-5 Dimension (EQ-5D) health survey, the Health Utility Index III (HUI-III), and economic evaluation and safety data. Post-treatment follow-ups will be conducted at 1, 4, and 10 weeks after conclusion of treatment. DISCUSSION: This study will assess the comparative effectiveness of Chuna manual therapy compared to conventional usual care. Costs and effectiveness (utility) data will be analyzed for exploratory cost-effectiveness analysis. If this pilot study does not reach a definite conclusion due to its small sample size, these results will be used as preliminary results to calculate sample size for future large-scale clinical trials and contribute in the assessment of feasibility of a full-scale multicenter trial. TRIAL REGISTRATION: Clinical Research Information Service (CRIS), KCT0001850 . Registered on 17 March 2016. PMID- 28095893 TI - Clinical, biochemical and molecular characterization of Korean patients with mucolipidosis II/III and successful prenatal diagnosis. AB - BACKGROUND: Mucolipidosis types II and III (ML II/III) are autosomal recessive disorders caused by a deficiency in the lysosomal enzyme N-acetylglucosamine-1 phosphotransferase. We investigated the molecular genetic characteristics of the GNPTAB gene, which codes for the alpha/beta subunits of a phosphotransferase, in Korean ML II/III patients. We included prenatal tests and evaluated the spectrum of mutations in East Asian populations with ML II/III through a literature review. METHODS: Seven patients from six families were enrolled in the study including two prenatal tests using chorionic villi samples. A diagnosis of ML II/III was made based on clinical findings and increases in serum lysosomal enzyme levels. PCR and direct sequencing were performed to identify GNPTAB mutations. RESULTS: We found 14 mutant alleles including seven known mutations of c.2189delT (p.Leu730fs*7), c.1090C > T (p.Arg364*), c.2681G > A (p.Trp894*), c.3565C > T (p.Arg1189*), c.310C > T (p.Gln104*), c.1071G > A (p.Trp357*) and c.2574_2575delGA (p.Asn859Glnfs*2). Four were novel variants of unknown significance: c.992A > G (p.Tyr331Cys), c.2666 T > A (p.Leu889*), c.637-6 T > G (p.Thr213Phefs*11), and c.471_472delTT (p.Tyr158Serfs*8). Family studies revealed the probands to be compound heterozygotes. The fetuses carried the same GNPTAB mutations as the mucolipidosis II/III probands in the prenatal diagnosis. CONCLUSIONS: We identified GNPTAB mutations in all patients with ML II/III, but did not identify a hot spot in Korean patients. We successfully performed prenatal diagnosis using molecular investigation. PMID- 28095894 TI - What drives attitude towards telemedicine among families of pediatric patients? A survey. AB - BACKGROUND: Telemedicine has been recognized as a way to improve accessibility, quality, and efficiency of care. In view of the introduction of new telemedicine services, we conducted a survey through a self-administered questionnaire among families of children attending the Bambino Gesu Children's Hospital IRCCS, a tertiary care children's hospital located in Rome, Italy. METHODS: We investigated sociodemographic data, clinical information, technological profile, attitude towards telemedicine, perceived advantages of telemedicine, fears regarding telemedicine, willingness to use a smartphone app providing telemedicine services and willingness to use a televisit service. Through logistic regression, we explored the effect of sociodemographic and clinical variables and technological profile on willingness of using a telemedicine app and a televisit service. RESULTS: We enrolled a total of 751 families. Most patients had a high technological profile, 81% had at least one account on a social network. Whatsapp was the most popular messaging service (76%). Seventy two percent of patients would use an app for telemedicine services and 65% would perform a televisit. Owning a tablet was associated with both outcome variables - respectively: OR 2.216, 95% CI 1.358-3.616 (app) and OR 2.117, 95% CI 1.415-3.168 (televisit). Kind of hospitalization, diagnosis of a chronic disease, disease severity and distance from the health care center were not associated with the outcome variables. CONCLUSION: Families of pediatric patients with different clinical problems are keen to embark in telemedicine programs, independently from severity of disease or chronicity, and of distance from the hospital. PMID- 28095895 TI - Genome-wide SNP analysis using 2b-RAD sequencing identifies the candidate genes putatively associated with resistance to ivermectin in Haemonchus contortus. AB - BACKGROUND: The excessive and uncontrolled use of anthelmintics, e.g. ivermectin (IVM) for the treatment of livestock parasites has led to widespread resistance in gastrointestinal nematodes, such as Haemonchus contortus. There is an urgent need for better management of drug-use in nematode control and development of novel anthelmintics. Discovery and identification of anthelmintic resistance associate molecules/markers can provide a basis for rational anthelmintics-use and development of novel drugs. Recent studies have shown that ivermectin resistance in H. contortus is likely to be multi-genic in nature except for several genes coding for IVM target and efflux pump. However, no other IVM resistance-associated genes were characterized by conventional methods or strategies. In the present study we adopted a new strategy, i.e. using genome wide single nucleotide polymorphism (SNP) analysis based on 2b-RAD sequencing, for discovering SNPs markers across the genomes in both IVM susceptible and resistant isolates of H. contortus and identifying potential IVM resistance associated genes. RESULTS: We discovered 2962 and 2667 SNPs within both susceptible and resistant strains of H. contortus, respectively. A relative lower and similar genetic variations were observed within both resistant and susceptible strains (average pi values were equal to 0.1883 and 0.1953, respectively); whereas a high genetic variation was found across both strains (average pi value was equal to 0.3899). A significant differentiation across 2b RAD tags nucleotide sites was also observed between the two strains (average FST value was equal to 0.3076); the larger differences in average FST were observed at SNPs loci between coding and noncoding (including intronic) regions. Comparison between resistant and susceptible strains revealed that 208 SNPs loci exhibited significantly elevated FST values, 24 SNPs of those loci were located in the CDS regions of the nine genes and were likely to have signature of IVM directional selection. Seven of the nine candidate genes were predicted to code for some functional proteins such as potential IVM target and/or efflux pump proteins, component proteins of receptor complex in membrane on neuromuscular cells, and transcriptional regulation proteins. Those genes might be involved in resistance to IVM. CONCLUSIONS: Our data suggest that candidate genes putatively associated with resistance to IVM in H. contortus may be identified by genome wide SNP analysis using 2b-RAD sequencing. PMID- 28095896 TI - Screening for potential genes associated with bone overgrowth after mid-shaft femur fracture in a rat model. AB - BACKGROUND: We investigated the underlying molecular mechanisms of bone overgrowth after femoral fracture by using high-throughput bioinformatics approaches. METHODS: The gene expression profile of GSE3298 (accession number) was obtained from the Gene Expression Omnibus database. Sixteen femoral growth plate samples, including nine samples without fracture and seven fracture samples for seven time points, were used for analysis. The Limma package was applied to identify differentially expressed genes (DEGs) between fractured and intact samples. The DAVID online tool was used for Gene ontology functional and pathway enrichment analysis. A protein-protein interaction (PPI) network established by String software was used to identify interactions between significant DEGs, and network modules were detected using plug-in MCODE. Additionally, a transcription regulatory network was constructed based on the ENCODE Project and PPI network. RESULTS: A total of 680 DEGs were screened in fractured femoral growth plate samples compared with controls, including 238 up- and 442 down-regulated genes. These DEGs were significantly involved in the calcium signaling pathway and cancer pathway. A PPI network was constructed with 167 nodes and 233 edges, and module analysis demonstrated that CCL2, CSF2, NOS2, and DLC1 may stimulate bone overgrowth after femoral fracture via anti-apoptosis-related functions. A transcription regulatory network was constructed with 387 interacting pairs, and overlapping nodes were significantly enriched in intracellular signaling cascade and regulation of cell proliferation, among others. CONCLUSIONS: Bone overgrowth was associated with changes in the expression of identified DEGs such as CCL2, NOS2, CSF2, and DLC1 in the femoral head. They may be important in regulating bone overgrowth via the anti-apoptosis of osteoblasts. PMID- 28095897 TI - Efficacy of PermaNet(r) 3.0 and PermaNet(r) 2.0 nets against laboratory-reared and wild Anopheles gambiae sensu lato populations in northern Tanzania. AB - BACKGROUND: Mosquitoes have developed resistance against pyrethroids, the only class of insecticides approved for use on long-lasting insecticidal nets (LLINs). The present study sought to evaluate the efficacy of the pyrethroid synergist PermaNet(r) 3.0 LLIN versus the pyrethroid-only PermaNet(r) 2.0 LLIN, in an East African hut design in Lower Moshi, northern Tanzania. In this setting, resistance to pyrethroid insecticides has been identified in Anopheles gambiae mosquitoes. METHODS: Standard World Health Organization bioefficacy evaluations were conducted in both laboratory and experimental huts. Experimental hut evaluations were conducted in an area where there was presence of a population of highly pyrethroid-resistant An. arabiensis mosquitoes. All nets used were subjected to cone bioassays and then to experimental hut trials. Mosquito mortality, blood feeding inhibition and personal protection rate were compared between untreated nets, unwashed LLINs and LLINs that were washed 20 times. RESULTS: Both washed and unwashed PermaNet(r) 2.0 and PermaNet(r) 3.0 LLINs had knockdown and mortality rates of 100% against a susceptible strain of An. gambiae sensu stricto. The adjusted mortality rate of the wild mosquito population after use of the unwashed PermaNet(r) 3.0 and PermaNet(r) 2.0 nets was found to be higher than after use of the washed PermaNet(r) 2.0 and PermaNet(r) 3.0 nets. CONCLUSIONS: Given the increasing incidence of pyrethroid resistance in An. gambiae mosquitoes in Tanzania, we recommend that consideration is given to its distribution in areas with pyrethroid-resistant malaria vectors within the framework of a national insecticide-resistance management plan. PMID- 28095898 TI - Differences in RANTES and IL-6 levels among chronic rhinosinusitis patients with predominant gram-negative and gram-positive infection. AB - BACKGROUND: Bacteria are suspected players in the pathogenesis of chronic rhinosinusitis (CRS), yet their exact role is not understood. We investigated the effect of planktonic and biofilm of staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA) on the mucosa of CRS patients with gram-positive and gram negative infections by measuring the levels of IL-6 and RANTES, a chemokine with activity on eosinophils and T lymphocytes. METHODS: Ethmoid mucosa of six CRS patients with gram-positive bacteria on culture and five with gram-negative bacteria were compared to ethmoid mucosa of 8 control patients. The tissue explants were stimulated with SA and PA extracts in planktonic and biofilm form for 6 hours, then RANTES levels were measured by ELISA. RESULTS: Compared to the control group, CRS patients with gram-negative predominance demonstrated a significantly higher level of RANTES expression in response to all forms of bacterial stimuli (P-value <0.05). Patients with gram-positive predominance showed a higher level of RANTES compere to control group, however, this difference was not significant (P-value >0.05). CONCLUSIONS: The mucosa of CRS patients with gram-negative infections has a heightened innate immune response compared to controls and patients with gram-positive infections. It is possible that this response leads to the pathological eosinophilic inflammation seen in CRS. PMID- 28095899 TI - What is the relationship between type 2 diabetes mellitus status and the neuroradiological correlates of cerebral small vessel disease in adults? Protocol for a systematic review. AB - BACKGROUND: Cerebral small vessel disease (CSVD) is a common cause of stroke, dementia, and functional decline. In recent years, neuroradiologic correlates of CSVD have been identified. These imaging findings, best characterized on magnetic resonance imaging (MRI), include some combination of white matter hyperintensities, lacunes, cerebral microbleeds, enlarged perivascular spaces, and cerebral atrophy. Though some cohorts have reported that participants with type 2 diabetes mellitus (T2DM), an important risk factor for CSVD, may have a distinct neuroradiologic phenotype, this relationship is not well-characterized. Adults with diabetes mellitus have a two- to threefold higher incidence of ischemic stroke compared to controls and are an increasingly important population given global trends of increasing diabetes prevalence. This study aims to determine if adults with CSVD and T2DM have a distinct neuroradiologic phenotype. METHODS: A systematic search of the literature will be conducted to find articles that report the MRI features of CSVD in a cohort of participants including those with and without type 2 diabetes mellitus (T2DM). A number of databases will be searched including MEDLINE, Embase, CINAHL, and Web of Science. Proceedings and abstracts from key conferences will also be reviewed and relevant journals hand searched for additional papers. The references from selected papers will be scanned. Screening of potential articles, data extraction, and quality appraisal will be performed in duplicate by independent reviewers. Odds ratios and 95% confidence intervals for the presence versus absence of each neuroradiologic correlate of interest from each included study will be calculated. If sufficient homogeneity exists among studies, a meta-analysis will be performed for each neuroradiologic correlate of CSVD. If heterogeneity of studies precludes data pooling, results will be presented in narrative form. DISCUSSION: Determining whether a distinct neuroradiologic phenotype of CSVD exists in adults with T2DM will provide insight into the underlying mechanisms of CSVD and guide future research on therapeutic targets. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016046669. PMID- 28095900 TI - Post-stroke dementia - a comprehensive review. AB - Post-stroke dementia (PSD) or post-stroke cognitive impairment (PSCI) may affect up to one third of stroke survivors. Various definitions of PSCI and PSD have been described. We propose PSD as a label for any dementia following stroke in temporal relation. Various tools are available to screen and assess cognition, with few PSD-specific instruments. Choice will depend on purpose of assessment, with differing instruments needed for brief screening (e.g., Montreal Cognitive Assessment) or diagnostic formulation (e.g., NINDS VCI battery). A comprehensive evaluation should include assessment of pre-stroke cognition (e.g., using Informant Questionnaire for Cognitive Decline in the Elderly), mood (e.g., using Hospital Anxiety and Depression Scale), and functional consequences of cognitive impairments (e.g., using modified Rankin Scale). A large number of biomarkers for PSD, including indicators for genetic polymorphisms, biomarkers in the cerebrospinal fluid and in the serum, inflammatory mediators, and peripheral microRNA profiles have been proposed. Currently, no specific biomarkers have been proven to robustly discriminate vulnerable patients ('at risk brains') from those with better prognosis or to discriminate Alzheimer's disease dementia from PSD. Further, neuroimaging is an important diagnostic tool in PSD. The role of computerized tomography is limited to demonstrating type and location of the underlying primary lesion and indicating atrophy and severe white matter changes. Magnetic resonance imaging is the key neuroimaging modality and has high sensitivity and specificity for detecting pathological changes, including small vessel disease. Advanced multi-modal imaging includes diffusion tensor imaging for fiber tracking, by which changes in networks can be detected. Quantitative imaging of cerebral blood flow and metabolism by positron emission tomography can differentiate between vascular dementia and degenerative dementia and show the interaction between vascular and metabolic changes. Additionally, inflammatory changes after ischemia in the brain can be detected, which may play a role together with amyloid deposition in the development of PSD. Prevention of PSD can be achieved by prevention of stroke. As treatment strategies to inhibit the development and mitigate the course of PSD, lowering of blood pressure, statins, neuroprotective drugs, and anti-inflammatory agents have all been studied without convincing evidence of efficacy. Lifestyle interventions, physical activity, and cognitive training have been recently tested, but large controlled trials are still missing. PMID- 28095901 TI - Risk assessment tools to predict location of discharge and need for supportive services for medical patients after discharge from hospital: a systematic review protocol. AB - BACKGROUND: Patients who are discharged from hospital after an acute medical illness often have impaired function that prevents them from returning to their previous place of residence. Assessing each patient's post-discharge needs takes time and resources but is important in order to reduce unplanned readmissions and adverse events post-discharge. METHODS/DESIGN: We will conduct a systematic review to synthesize the evidence on prognostic models and their reported accuracy in predicting the location of discharge after a medical admission to an acute care hospital. We will perform searches in MEDLINE, EMBASE, CINAHL, and COCHRANE databases. Pre-defined study, population, and model characteristics will be reported. We will write a narrative summary of included studies. Methodological quality of the studies will be assessed using the QUIPS tool, and the quality of evidence will be evaluated using the GRADE tool. DISCUSSION: Early and accurate assessment of patient needs for supportive services after discharge has the potential to improve patient outcomes and health system efficiency. This systematic review will identify factors that can accurately predict location of discharge using existing tools and identify priority knowledge gaps to inform future research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016037144. PMID- 28095903 TI - Identification and application of anti-inflammatory compounds screening system based on RAW264.7 cells stably expressing NF-kappaB-dependent SEAP reporter gene. AB - BACKGROUND: NF-kappaB is one of the key transcription factors in the inflammatory response, transactivates a series of pro-inflammatory genes and is therefore regarded as an important target for anti-inflammatory drug screening. METHOD: We recombined the reporter gene vector with inserting the "neo" transcript into the vector pNF-kappaB-SEAP, made the reporter gene vector stable in a eukaryotic cell line. The recombinant reporter gene vector we named pNF-kappaB-SEAP-Neo was transfected into RAW264.7. We selected the transfected RAW264.7 cell line with G418 for 15 days and then get RAW264.7 cells stably expressing NF-kappaB dependent SEAP named as RAW264.7-pNF-kappaB-SEAP cells. We treated the RAW264.7 pNF-kappaB-SEAP cells with NF-kappaB agonists as LPS, PolyI:C and TNF-alpha, NF kappaB inhibitor as PDTC and BAY117085, in different concentrations and time points and tested the expression of the SEAP, constructed the drug screening system on the base of the RAW264.7-pNF-kappaB-SEAP cell line. 130 chemicals were screened with the drug screening system we constructed and one of these chemicals numbered w10 was found could inhibit the NF-kappaB significantly. At last, we verified the inhibition of w10 to expression of genes promoted with NF-kappaB in HepG2 and Hela, and to migration of Hela. RESULT: In this study, we established a drug screening system based on RAW264.7 cells that stably expressed the NF-kappaB dependent, SEAP reporter gene. To develop a standard method for drug screening using this reporter-gene cell line, the test approach of SEAP was optimized and basic conditions for drug screening were chosen. This included the initial cell number inoculated in a 96-well plate, the optimum agonist, inhibitor of NF-kappaB pathway and their concentrations during screening. Subsequently, 130 newly synthesized compounds were screened using the stable reporter-gene cell line. The anti-inflammatory effects of the candidate compounds obtained were further verified in 2 cancer cell lines. The results indicated that compound W10 (methyl 4-(4-(prop-2-yn-1-ylcarbamoyl) phenylcarbamoyl) benzoate) significantly inhibited SEAP production under the screening conditions. Further results confirmed that the precursor compound significantly inhibited the transcription of NF-kappaB target genes. CONCLUSION: In conclusion, RAW264.7 cells, stably expressing the NF kappaB-dependent SEAP-reporter gene, may provide a new, feasible, and efficient cellular drug-screening system. PMID- 28095902 TI - Identification of positive selection in genes is greatly improved by using experimentally informed site-specific models. AB - BACKGROUND: Sites of positive selection are identified by comparing observed evolutionary patterns to those expected under a null model for evolution in the absence of such selection. For protein-coding genes, the most common null model is that nonsynonymous and synonymous mutations fix at equal rates; this unrealistic model has limited power to detect many interesting forms of selection. RESULTS: I describe a new approach that uses a null model based on experimental measurements of a gene's site-specific amino-acid preferences generated by deep mutational scanning in the lab. This null model makes it possible to identify both diversifying selection for repeated amino-acid change and differential selection for mutations to amino acids that are unexpected given the measurements made in the lab. I show that this approach identifies sites of adaptive substitutions in four genes (lactamase, Gal4, influenza nucleoprotein, and influenza hemagglutinin) far better than a comparable method that simply compares the rates of nonsynonymous and synonymous substitutions. CONCLUSIONS: As rapid increases in biological data enable increasingly nuanced descriptions of the constraints on individual protein sites, approaches like the one here can improve our ability to identify many interesting forms of selection in natural sequences. REVIEWERS: This article was reviewed by Sebastian Maurer-Stroh, Olivier Tenaillon, and Tal Pupko. All three reviewers are members of the Biology Direct editorial board. PMID- 28095904 TI - Evaluation of the Tsima community mobilization intervention to improve engagement in HIV testing and care in South Africa: study protocol for a cluster randomized trial. AB - BACKGROUND: HIV transmission can be decreased substantially by reducing the burden of undiagnosed HIV infection and expanding early and consistent use of antiretroviral therapy (ART). Treatment as prevention (TasP) has been proposed as key to ending the HIV epidemic. To activate TasP in high prevalence countries, like South Africa, communities must be motivated to know their status, engage in care, and remain in care. Community mobilization (CM) has the potential to significantly increase uptake testing, linkage to and retention in care by addressing the primary social barriers to engagement with HIV care-including poor understanding of HIV care; fear and stigma associated with infection, clinic attendance and disclosure; lack of social support; and gender norms that deter men from accessing care. METHODS/DESIGN: Using a cluster randomized trial design, we are implementing a 3-year-theory-based CM intervention and comparing gains in HIV testing, linkage, and retention in care among individuals residing in 8 intervention communities to that of individuals residing in 7 control communities. Eligible communities include 15 villages within a health and demographic surveillance site (HDSS) in rural Mpumalanga, South Africa, that were not exposed to previous CM efforts. CM activities conducted in the 8 intervention villages map onto six mobilization domains that comprise the key components for community mobilization around HIV prevention. To evaluate the intervention, we will link a clinic-based electronic clinical tracking system in all area clinics to the HDSS longitudinal census data, thus creating an open, population-based cohort with over 30,000 18-49-year-old residents. We will estimate the marginal effect of the intervention on individual outcomes using generalized estimating equations. In addition, we will evaluate CM processes by conducting baseline and endline surveys among a random sample of 1200 community residents at each time point to monitor intervention exposure and community level change using validated measures of CM. DISCUSSION: Given the known importance of community social factors with regard to uptake of testing and HIV care, and the lack of rigorously evaluated community-level interventions effective in improving testing uptake, linkage and retention, the proposed study will yield much needed data to understand the potential of CM to improve the prevention and care cascade. Further, our work in developing a CM framework and domain measures will permit validation of a CM conceptual framework and process, which should prove valuable for community programming in Africa. TRIAL REGISTRATION: NCT02197793 Registered July 21, 2014. PMID- 28095905 TI - Imputing HIV treatment start dates from routine laboratory data in South Africa: a validation study. AB - BACKGROUND: Poor clinical record keeping hinders health systems monitoring and patient care in many low resource settings. We develop and validate a novel method to impute dates of antiretroviral treatment (ART) initiation from routine laboratory data in South Africa's public sector HIV program. This method will enable monitoring of the national ART program using real-time laboratory data, avoiding the error potential of chart review. METHODS: We developed an algorithm to impute ART start dates based on the date of a patient's "ART workup", i.e. the laboratory tests used to determine treatment readiness in national guidelines, and the time from ART workup to initiation based on clinical protocols (21 days). To validate the algorithm, we analyzed data from two large clinical HIV cohorts: Hlabisa HIV Treatment and Care Programme in rural KwaZulu-Natal; and Right to Care Cohort in urban Gauteng. Both cohorts contain known ART initiation dates and laboratory results imported directly from the National Health Laboratory Service. We assessed median time from ART workup to ART initiation and calculated sensitivity (SE), specificity (SP), positive predictive value (PPV), and negative predictive value (NPV) of our imputed start date vs. the true start date within a 6 month window. Heterogeneity was assessed across individual clinics and over time. RESULTS: We analyzed data from over 80,000 HIV-positive adults. Among patients who had a workup and initiated ART, median time to initiation was 16 days (IQR 7,31) in Hlabisa and 21 (IQR 8,43) in RTC cohort. Among patients with known ART start dates, SE of the imputed start date was 83% in Hlabisa and 88% in RTC, indicating this method accurately predicts ART start dates for about 85% of all ART initiators. In Hlabisa, PPV was 95%, indicating that for patients with a lab workup, true start dates were predicted with high accuracy. SP (100%) and NPV (92%) were also very high. CONCLUSIONS: Routine laboratory data can be used to infer ART initiation dates in South Africa's public sector. Where care is provided based on protocols, laboratory data can be used to monitor health systems performance and improve accuracy and completeness of clinical records. PMID- 28095906 TI - Cost of physician-led home visit care (Zaitaku care) compared with hospital care at the end of life in Japan. AB - BACKGROUND: Physician-led home visit care with medical teams (Zaitaku care) has been developed on a national scale to support those who wish to stay at home at the end of life, and promote a system of community-based integrated care in Japan. Medical care at the end of life can be expensive, and is an urgent socioeconomic issue for aging societies. However medical costs of physician-led home visits care have not been well studied. We compared the medical costs of Zaitaku care and hospital care at the end of life in a rapidly aging community in a rural area in Japan. METHODS: A cross-sectional study was performed to compare the total medical costs during patients' final days of life (30 days or less) between Zaitaku care and hospital care from September 2012 to August 2013 in Fukuoka Prefecture, Japan. RESULTS: Thirty four patients died at home under Zaitaku care, and 72 patients died in the hospital during this period. The average daily cost of care during the last 30 days did not differ significantly between the two groups. Although Zaitaku care costs were higher than hospital care costs in the short-term (?10 days, Zaitaku care $371.2 vs. Hospital care $202.0, p = 0.492), medical costs for Zaitaku care in the long-term care (?30 days) were less than that of hospital care ($155.8 vs. $187.4, p = 0.055). CONCLUSIONS: Medical costs of Zaitaku care were less compared with hospital care if incorporated early for long term care, but it was high if incorporated late for short term care. For long term care, medical costs for Zaitaku care was 16.7% less than for hospitalization at the end of life. This physician-led home visit care model should be an available option for patients who wish to die at home, and may be beneficial financially over time. PMID- 28095908 TI - Limiting treatment and shortening of life: data from a cross-sectional survey in Germany on frequencies, determinants and patients' involvement. AB - BACKGROUND: Limiting treatment forms part of practice in many fields of medicine. There is a scarcity of robust data from Germany. Therefore, in this paper, we report results of a survey among German physicians with a focus on frequencies, aspects of decision making and determinants of limiting treatment with expected or intended shortening of life. METHODS: Postal survey among a random sample of physicians working in the area of five German state chambers of physicians using a modified version of the questionnaire of the EURELD Consortium. Information requested referred to the patients who died most recently within the last 12 months. Logistic regression was performed to analyse associations between characteristics of physicians and patients regarding limitation of treatment with expected or intended shortening of life. RESULTS: As reported elsewhere, 734 physicians responded (response rate 36.9%) and of these, 174 (43.2%) reported a withholding and 144 (35.7%) a withdrawal of treatment. Eighty one physicians estimated that there was at least some shortening of life as a consequence. In 25.9% of these cases hastening death had been discussed with the patient at the time or immediately prior to this action. Types of treatment most frequently limited was artificial nutrition (n = 35). Bivariate analysis indicates that limitation of treatment with possible or intended shortening of life for patients aged > 75 years is performed significantly more often (p = 0.007, OR 1.848). There was significantly less limitation of treatment in patients who died from cancer compared to patients with other causes of death (p = 0.01, OR 0.486). There was no significant statistical association with physicians' religion, palliative care qualification or frequencies of limiting treatment. CONCLUSIONS: In comparison to recent research from other European countries, limitation of treatment with expected or intended shortening of life is frequently performed amongst the investigated sample. The role of clinical and non-medical aspects possibly relevant for physicians' decision about withholding or withdrawal of treatment with possible or intended shortening of life and reasons for non involvement of patients should be explored in more detail by means of mixed method and interdisciplinary empirical-ethical analysis. PMID- 28095907 TI - The Targeted SMAC Mimetic SW IV-134 is a strong enhancer of standard chemotherapy in pancreatic cancer. AB - BACKGROUND: Pancreatic cancer is a lethal malignancy that frequently acquires resistance to conventional chemotherapies often associated with overexpression of inhibitors of apoptosis proteins (IAPs). We have recently described a novel means to deliver second mitochondria-derived activator of caspases (SMAC) mimetics selectively to cancer cells employing the sigma-2 ligand/receptor interaction. The intrinsic death pathway agonist SMAC offers an excellent opportunity to counteract the anti-apoptotic activity of IAPs. SMAC mimetics have been used to sensitize several cancer types to chemotherapeutic agents but cancer-selective delivery and appropriate cellular localization have not yet been considered. In our current study, we tested the ability of the sigma-2/SMAC drug conjugate SW IV 134 to sensitize pancreatic cancer cells to gemcitabine. METHODS: Using the targeted SMAC mimetic SW IV-134, inhibition of the X-linked inhibitor of apoptosis proteins (XIAP) was induced pharmacologically and its impact on cell viability was studied alone and in combination with gemcitabine. Pathway analyses were performed by assessing caspase activation, PARP cleavage and membrane blebbing (Annexin-V), key components of apoptotic cell death. Single-agent treatment regimens were compared with combination therapy in a preclinical mouse model of pancreatic cancer. RESULTS: The sensitizing effect of XIAP interference toward gemcitabine was confirmed via pharmacological intervention using our recently designed, targeted SMAC mimetic SW IV-134 across a wide range of commonly used pancreatic cancer cell lines at concentrations where the individual drugs showed only minimal activity. On a mechanistic level, we identified involvement of key components of the apoptosis machinery during cell death execution. Furthermore, combination therapy proved superior in decreasing the tumor burden and extending the lives of the animals in a preclinical mouse model of pancreatic cancer. CONCLUSION: We believe that the strong sensitizing capacity of SW IV-134 in combination with clinically relevant doses of gemcitabine represents a promising treatment option that warrants clinical evaluation. PMID- 28095909 TI - Prevalence and genetic characterization of Cryptosporidium species and Giardia duodenalis in lambs in Oromia Special Zone, Central Ethiopia. AB - BACKGROUND: Cryptosporidium and Giardia duodenalis are gastro-intestinal parasites that infect human and animals worldwide. Both parasites share a broad host range and are believed to be zoonosis. The aim of this study was to identify the species of Cryptosporidium and assemblages of G. duodenalis in lambs and to elucidate their role in zoonotic transmission. RESULTS: A total of 389 fecal samples were collected from lambs and screened by microscopy and nested PCR targeting the small-subunit ribosomal RNA for Cryptosporidium; and the small subunit ribosomal RNA, triose phosphate isomerase, beta-giardin, and glutamate dehydrogenase genes for G. duodenalis. The prevalence of Cryptosporidium and G. duodenalis was 2.1% (8/389) and 2.6% (10/389), respectively. The infection rate at the three study sites ranged from 1.3 to 3.1% for Cryptosporidium and 1.6 to 3.9% for G. duodenalis; but variation was not statistically significant (p > 0.05). The finding also showed that there is no sex and age group associated difference in the occurrence of Cryptosporidium and G. duodenalis infections in lambs. Sequence analysis revealed that lambs were mono-infection with C. ubiquitum and G. duodenalis assemblage E. The analysis also indicated the presence of genetic variation within isolates of assemblage E; with 4 of them are novel genotypes at the small-subunit ribosomal RNA, beta-giardin, and glutamate dehydrogenase genes. CONCLUSION: The findings of the current study showed that lambs are capable of harboring C. ubiquitum and G. duodenalis assemblage E. This finding suggests that lambs might be sources for potentially zoonotic Cryptosporidium species. This was first molecular study in lambs and contributes to a better understanding of the epidemiology of Cryptosporidium and G. duodenalis in central Ethiopia. PMID- 28095910 TI - Profile of bioactive compounds in Nymphaea alba L. leaves growing in Egypt: hepatoprotective, antioxidant and anti-inflammatory activity. AB - BACKGROUND: Nymphaea alba L. represents an interesting field of study. Flowers have antioxidant and hepatoprotective effects, rhizomes constituents showed cytotoxic activity against liver cell carcinoma, while several Nymphaea species have been reported for their hepatoprotective effects. Leaves of N. alba have not been studied before. Therefore, in this study, in-depth characterization of the leaf phytoconstituents as well as its antioxidant and hepatoprotective activities have been performed where N. alba leaf extract was evaluated as a possible therapeutic alternative in hepatic disorders. METHODS: The aqueous ethanolic extract (AEE, 70%) was investigated for its polyphenolic content identified by high-resolution electrospray ionisation mass spectrometry (HRESI-MS/MS), while the petroleum ether fraction was saponified, and the lipid profile was analysed using gas liquid chromatography (GLC) analysis and compared with reference standards. The hepatoprotective activity of two doses of the extract (100 and 200 mg/kg; P.O.) for 5 days was evaluated against CCl4-induced hepatotoxicity in male Wistar albino rats, in comparison with silymarin. Liver function tests; aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGT) and total bilirubin were performed. Oxidative stress parameters; malondialdehyde (MDA), reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (TAC) as well as inflammatory mediator; tumour necrosis factor (TNF)-alpha were detected in the liver homogenate. Histopathological examination of the liver and immunohistochemical staining of caspase-3 were performed RESULTS: Fifty-three compounds were tentatively identified for the first time in N.alba leaf extract, where ellagitannins represent the main identified constituents. Nine hydrocarbons, two sterols and eleven fatty acids were identified in the petroleum ether extract where, palmitic acid and linolenic acids represented the major saturated and unsaturated fatty acid respectively. N.alba AEE significantly improved the liver function, oxidative stress parameters as well as TNF-alpha in addition to the amelioration of histopathological features of the liver and a profound decrease in caspase-3 expression. CONCLUSION: These results shed light on the hepatoprotective effect of N. alba that is comparable with that of silymarin. The antioxidant activities of N. alba extract in addition to the inhibition of crucial inflammatory mediator, as TNF-alpha, might be the possible hepatoprotective mechanisms. PMID- 28095912 TI - Study on expression of CDH4 in lung cancer. AB - BACKGROUND: The human CDH4 gene, which encodes the R-cadherin protein, has an important role in cell migration and cell adhesion, sorting, tissue morphogenesis, and tumor genesis. This study analyzed the relationship of CDH4 mRNA expression with lung cancer. METHODS: Real time PCR was applied to detect CDH4 mRNA transcription in 142 paired cases of lung cancer and noncancerous regions. RESULTS: No correlation was identified between CDH4 mRNA expression and gender, age, lymphnode metastasis, TNM stage, family history, smoking state, drinking state (P > 0.05), but grade and histotype (P < 0.05). The relative CDH4 mRNA value was remarkably decreased in lung cancer tissues compared with noncancerous tissues (P = 0.001). CONCLUSIONS: We found that CDH4 mRNA expression was associated with grade and histotype. What is more, the relative CDH4 mRNA value was decreased in the lung cancer tissues. Our results suggested that CDH4 might be a putative tumor suppressor gene (TSG) in lung cancer. PMID- 28095911 TI - Mistreatment of women during childbirth in Abuja, Nigeria: a qualitative study on perceptions and experiences of women and healthcare providers. AB - BACKGROUND: Global efforts have increased facility-based childbirth, but substantial barriers remain in some settings. In Nigeria, women report that poor provider attitudes influence their use of maternal health services. Evidence also suggests that women in Nigeria may experience mistreatment during childbirth; however, there is limited understanding of how and why mistreatment this occurs. This study uses qualitative methods to explore women and providers' experiences and perceptions of mistreatment during childbirth in two health facilities and catchment areas in Abuja, Nigeria. METHODS: In-depth interviews (IDIs) and focus group discussions (FGDs) were used with a purposive sample of women of reproductive age, midwives, doctors and facility administrators. Instruments were semi-structured discussion guides. Participants were asked about their experiences and perceptions of, and perceived factors influencing mistreatment during childbirth. Thematic analysis was used to synthesize findings into meaningful sub-themes, narrative text and illustrative quotations, which were interpreted within the context of this study and an existing typology of mistreatment during childbirth. RESULTS: Women and providers reported experiencing or witnessing physical abuse including slapping, physical restraint to a delivery bed, and detainment in the hospital and verbal abuse, such as shouting and threatening women with physical abuse. Women sometimes overcame tremendous barriers to reach a hospital, only to give birth on the floor, unattended by a provider. Participants identified three main factors contributing to mistreatment: poor provider attitudes, women's behavior, and health systems constraints. CONCLUSIONS: Moving forward, findings from this study must be communicated to key stakeholders at the study facilities. Measurement tools to assess how often mistreatment occurs and in what manner must be developed for monitoring and evaluation. Any intervention to prevent mistreatment will need to be multifaceted, and implementers should consider lessons learned from related interventions, such as increasing audit and feedback including from women, promoting labor companionship and encouraging stress-coping training for providers. PMID- 28095913 TI - Effects of a purified krill oil phospholipid rich in long-chain omega-3 fatty acids on cardiovascular disease risk factors in non-human primates with naturally occurring diabetes type-2 and dyslipidemia. AB - BACKGROUND: High serum levels of cholesterol, in particular low-density lipoprotein cholesterol, are considered a significant risk factor for development of cardiovascular disease. Therefore, rigorous treatment regimens with statins and other pharmaceuticals have been used extensively to reduce elevated cholesterol levels. Literature data have not clearly concluded whether long-chain omega-3 fatty acids reduce, increase or leave circulating cholesterol unaffected. In the present study a novel krill-oil derived preparation of omega-3 rich phospholipids, mainly phosphatidylcholine, was administered orally at increasing doses for 12 weeks to dyslipidemic non-human primates, and cholesterols and several other risk factors for cardiovascular disease were measured before, during and after treatment. METHODS: Six dyslipidemic non-human primates suffering from naturally occurring diabetes type-2 were included, three in a vehicle control group and three being treated with the omega-3 rich phospholipid preparation. The control and test items were given daily by gavage and the doses of the test item were 50, 150 and 450 mg phospholipids/kg/day. Each dose level was given for 4 weeks. Plasma concentrations of the omega-3 fatty acids were measured in connection with change in dose and the omega-3 index in erythrocytes was determined bi-weekly. Blood lipids, apolipoproteins and diabetes, inflammatory and safety biomarkers were determined either weekly, biweekly or every 4 weeks. For the blood lipids and apolipoproteins, control-adjusted mean values are presented while absolute values are presented for the other parameters. Due to the low number of animals in each group, no statistical analyses were done. RESULTS: The only detectable effects measured during dosing with the lowest dose were an increase in HDL-cholesterol and apolipoprotein A1. The intermediate and high doses decreased total cholesterol, LDL-cholesterol, apolipoprotein B100 and triglycerides and increased HDL-cholesterol and apolipoprotein A1. No effects were seen on the diabetes and inflammatory markers and on safety biomarkers. CONCLUSIONS: The results indicate that the omega-3 rich phospholipid preparation had a positive impact on cardiovascular disease risk factors by reducing total cholesterol, LDL-cholesterol and triglycerides and increasing HDL-cholesterol. These findings justify further investigations of this preparation in animal models of dyslipidemia and, provided the current findings are confirmed, in human trials. PMID- 28095914 TI - Vascular mapping of the retroauricular skin - proposal for a posterior superior surgical incision for transcutaneous bone-conduction hearing implants. AB - BACKGROUND: Passive transcutaneous osseointegrated hearing implant systems have become increasingly popular more recently. The area over the implant is vulnerable due to vibration and pressure from the externally worn sound processor. Good perfusion and neural integrity has the potential to reduce complications. The authors' objective was to determine the ideal surgical exposure to maintain perfusion and neural integrity and decrease surgical time as a result of reduced bleeding. METHODS: The vascular anatomy of the temporal parietal soft tissue was examined in a total of 50 subjects. Imaging diagnostics included magnetic resonance angiography in 12 and Doppler ultrasound in 25 healthy subjects to reveal the arterial network. Cadaver dissection of 13 subjects formed the control group. The prevalence of the arteries were statistically analyzed with sector analysis in the surgically relevant area. RESULTS: The main arterial branches of this region could be well identified with each method. Statistical analysis showed that the arterial pattern was similar in all subjects. The prevalence of major arteries is low in the upper posterior area though large in proximity to the auricle region. CONCLUSIONS: Diverse methods indicate the advantages of a posterior superior incision because the major arteries and nerves are at less risk of damage and best preserved. Although injury to these structures is rare, when it occurs, the distal flow is compromised and the peri-implant area is left intact. Hand-held Doppler is efficient and cost-effective in finding the best position for incision, if necessary, in subjects with a history of surgical stress to the retroauricular skin. TRIAL REGISTRATION: This was a non-interventional study. PMID- 28095915 TI - Development and validation of SEER (Seeking, Engaging with and Evaluating Research): a measure of policymakers' capacity to engage with and use research. AB - BACKGROUND: Capacity building strategies are widely used to increase the use of research in policy development. However, a lack of well-validated measures for policy contexts has hampered efforts to identify priorities for capacity building and to evaluate the impact of strategies. We aimed to address this gap by developing SEER (Seeking, Engaging with and Evaluating Research), a self-report measure of individual policymakers' capacity to engage with and use research. METHODS: We used the SPIRIT Action Framework to identify pertinent domains and guide development of items for measuring each domain. Scales covered (1) individual capacity to use research (confidence in using research, value placed on research, individual perceptions of the value their organisation places on research, supporting tools and systems), (2) actions taken to engage with research and researchers, and (3) use of research to inform policy (extent and type of research use). A sample of policymakers engaged in health policy development provided data to examine scale reliability (internal consistency, test-retest) and validity (relation to measures of similar concepts, relation to a measure of intention to use research, internal structure of the individual capacity scales). RESULTS: Response rates were 55% (150/272 people, 12 agencies) for the validity and internal consistency analyses, and 54% (57/105 people, 9 agencies) for test-retest reliability. The individual capacity scales demonstrated adequate internal consistency reliability (alpha coefficients > 0.7, all four scales) and test-retest reliability (intra-class correlation coefficients > 0.7 for three scales and 0.59 for fourth scale). Scores on individual capacity scales converged as predicted with measures of similar concepts (moderate correlations of > 0.4), and confirmatory factor analysis provided evidence that the scales measured related but distinct concepts. Items in each of these four scales related as predicted to concepts in the measurement model derived from the SPIRIT Action Framework. Evidence about the reliability and validity of the research engagement actions and research use scales was equivocal. CONCLUSIONS: Initial testing of SEER suggests that the four individual capacity scales may be used in policy settings to examine current capacity and identify areas for capacity building. The relation between capacity, research engagement actions and research use requires further investigation. PMID- 28095916 TI - Insecticide-treated net effectiveness at preventing Plasmodium falciparum infection varies by age and season. AB - BACKGROUND: After increasing coverage of malaria interventions, malaria prevalence remains high in Malawi. Previous studies focus on the impact of malaria interventions among children under 5 years old. However, in Malawi, the prevalence of infection is highest in school-aged children (SAC), ages 5 to 15 years. This study examined the interaction between age group and insecticide treated net (ITN) use for preventing individual and community-level infection in Malawi. METHODS: Six cross-sectional surveys were conducted in the rainy and dry seasons in southern Malawi from 2012 to 2014. Data were collected on household ITN usage and demographics. Blood samples for detection of Plasmodium falciparum infection were obtained from all household members present and over 6 months of age. Generalized linear mixed models were used to account for clustering at the household and community level. RESULTS: There were 17,538 observations from six surveys. The association between ITN use and infection varied by season in SAC, but not in other age groups. The adjusted odds ratio (OR) for infection comparing ITN users to non-users among SAC in the rainy season and dry season was 0.78 (95% CI 0.56, 1.10) and 0.51 (0.35, 0.74), respectively. The effect of ITN use did not differ between children under five and adults. Among all non-SACs the OR for infection was 0.78 (0.64, 0.95) in those who used ITNs compared to those that did not. Community net use did not protect against infection. CONCLUSIONS: Protection against infection with ITN use varies by age group and season. Individual estimates of protection are moderate and a community-level effect was not detected. Additional interventions to decrease malaria prevalence are needed in Malawi. PMID- 28095917 TI - Social and traditional practices and their implications for family planning: a participatory ethnographic study in Renk, South Sudan. AB - BACKGROUND: Understanding what determines family size is crucial for programmes that aim to provide family planning services during and after conflicts. Recent research found that development agents in post conflict settings do not necessarily take time to understand the context adequately, translate their context understanding into programming, or adjust programming in the light of changes. South Sudan, a country that has been suffering from war for almost 50 years, has one of the highest maternal death rates and the lowest contraceptive utilization rates in the world. METHODS: This research used Participatory Ethnographic Evaluation and Research (PEER) to provide a contextualised understanding of social and traditional practices and their implications for family planning. Fourteen women were recruited from 14 villages in Renk County in South Sudan in the period 2010-2012. They were trained to design research instruments, conduct interviews, collect narratives and stories and analyse data to identify, prioritize and address their maternal health concerns. RESULTS: As a result of wars, people are under pressure to increase their family sizes and thus increase the nation's population. This is to compensate for the men perished in war and the high child death rates. Large family size is regarded as a national obligation. Women are caught up in a vicious cycle of high fertility and a high rate of child mortality. Determinants of large family size include: 1) Social and cultural practices, 2) Clan lineage and 3) Compensation for loss of family members. Three strategies are used to increase family size: 1) Marry several women, 2) Husbands taking care of women, and 3) Financial stability. Consequences of big families include: 1) Financial burden, 2) Fear of losing children, 3) Borrowing children and 4) Husband shirking responsibility. CONCLUSION: The desire to have a big family will remain in South Sudan until families realise that their children will live longer, that their men will not be taken by the war, and that the costs of living will be met. In order to generate demand for family planning in South Sudan, priority should be given first to improve infant and child health. PMID- 28095918 TI - Anti-staphylococcal activity resulting from epithelial lining fluid (ELF) concentrations of amikacin inhale administered via the pulmonary drug delivery system. AB - BACKGROUND: Amikacin inhale (BAY41-6551), a unique drug-device combination of a specially formulated drug solution and a pulmonary drug delivery system device (AMK-I) is currently under phase III study as an adjunctive therapy to IV antibiotics for the treatment of Gram-negative pneumonia in mechanically ventilated patients. While the epidemiology of nosocomial pneumonia is predominated by Gram-negative pathogens such as Pseudomonas aeruginosa and the Enterobacteriaceae, Staphylococcus aureus is increasingly recognized as a pathogen of concern for these pulmonary based infections. Since the aminoglycosides are historically quite active against S. aureus the use of adjunctive AMK-I may enhance bacterial eradication. Herein, we aimed to characterize the in vitro pharmacodynamic (PD) profile of human-simulated ELF exposures of AMK-I against both methicillin-sensitive (MSSA) and -resistant (MRSA) S. aureus. METHODS: An in vitro model was used to simulate the resultant ELF pharmacokinetic profile of amikacin after the administration of AMK-I 400 mg q12h. The antibacterial activity of this regimen was tested against 7 S. aureus isolates that display MIC profiles encountered clinically (4 MRSA; MIC range 4 64, 3 MSSA; MIC range 8-16 mg/L). Experiments were conducted over 24 h and samples were taken throughout this period to assess the bacterial density in both control and treatments. RESULTS: The mean +/- SD inoculum 0 h bacterial density was 6.4 +/- 0.09 which increased to 8.6 +/- 0.19 log10 CFU/mL in the control models by the end of 24 h experiments. Simulated ELF concentrations of AMK-I resulted in a rapid, 5 log10 declined in CFU over the initial 12 h for all MRSA and MSSA isolates. After 12 h, all bacterial counts remained below the limit of detection (LOD, 1.7 log10 CFU/mL) and no regrowth was evident at the end of the study. CONCLUSION: AMK-I produced an ELF exposure profile that was rapidly bactericidal against S. aureus displaying typical MICs to amikacin irrespective of their phenotypic profile to methicillin. While the Gram-negative organisms are the target pathogens for AMK-I in the ongoing clinical trials, these data suggest that this adjunctive regimen may also have the potential to eradicate both MSSA and MRSA from lower airway which needs to be further evaluated in randomized controlled clinical trials. PMID- 28095919 TI - Ancient bacteria of the Otzi's microbiome: a genomic tale from the Copper Age. AB - BACKGROUND: Ancient microbiota information represents an important resource to evaluate bacterial evolution and to explore the biological spread of infectious diseases in history. The soft tissue of frozen mummified humans, such as the Tyrolean Iceman, has been shown to contain bacterial DNA that is suitable for population profiling of the prehistoric bacteria that colonized such ancient human hosts. RESULTS: Here, we performed a microbial cataloging of the distal gut microbiota of the Tyrolean Iceman, which highlights a predominant abundance of Clostridium and Pseudomonas species. Furthermore, in silico analyses allowed the reconstruction of the genome sequences of five ancient bacterial genomes, including apparent pathogenic ancestor strains of Clostridium perfringens and Pseudomonas veronii species present in the gut of the Tyrolean Iceman. CONCLUSIONS: Genomic analyses of the reconstructed C. perfringens chromosome clearly support the occurrence of a pathogenic profile consisting of virulence genes already existing in the ancient strain, thereby reinforcing the notion of a very early speciation of this taxon towards a pathogenic phenotype. In contrast, the evolutionary development of P. veronii appears to be characterized by the acquisition of antibiotic resistance genes in more recent times as well as an evolution towards an ecological niche outside of the (human) gastrointestinal tract. PMID- 28095920 TI - Accuracy of WHO immunological criteria in identifying virological failure among HIV-infected adults on First line antiretroviral therapy in Mwanza, North-western Tanzania. AB - BACKGROUND: Optimal HIV treatment monitoring remains a big challenge in resource limited settings. Guidelines recommend the use of clinical and immunological criteria in resource limited settings due to unavailability of viral load monitoring; however their utility is questionable. This study aimed at assessing the accuracy of immunological criteria in detecting treatment failure among HIV infected Tanzanian adults receiving first line ART. METHODS: A clinic based cross sectional study was conducted between February and July 2011 at Bugando Medical centre (BMC) HIV care and treatment clinic (CTC) involving HIV infected patients aged 18 years and above, receiving first line ART; followed up for at least 1 year. Viral load was tested for every enrolled patient. Standard WHO criteria were used to define immunological failure. Virological failure was defined as one viral load measurement of >5000 copies/ml and was used as a gold standard. A 2 * 2 table was used to assess the accuracy of immunological criteria in detecting treatment failure. RESULTS: A total of 274 HIV-infected adults were enrolled into the study. Out of these, 65.7% were females, the median age was 39 years (IQR 33 45), the median BMI 21.9 kg/m2 (IQR 19.7-24.0). Out of the 274 study participants 156 (56.9%) had immunological failure. Only 60 of the study participants (21.9%) had viral load >5000. Only 42 patients (70%) were found to have both immunological failure and virological failure. The sensitivity of immunological criteria in detecting treatment failure was 70%, specificity 46.7%, positive predictive and negative predictive values of 26.9 and 84.7% respectively. CONCLUSION: WHO immunological criteria have low sensitivity and positive predictive value for detecting treatment failure. Relying on CD4 counts for treatment monitoring would therefore lead to misclassifications of treatment failure that could result into unnecessary or delayed switch to second line ART. Access to viral load monitoring is important to avoid these misclassifications. PMID- 28095921 TI - Papillary fibroelastoma of the aortic valve presenting with chronic angina and acute stroke: a case report. AB - BACKGROUND: Papillary fibroelastomas are rare, benign cardiac tumors that are often found on cardiac valvular surfaces. Most are incidental discoveries during surgery or autopsy. The clinical presentation of fibroelastoma varies widely, ranging from clinically asymptomatic to severe thromboembolic events. CASE PRESENTATION: We report a case of 65-year-old white man diagnosed with scattered, bilateral acute cerebral hemisphere infarcts with a history of chronic angina. Transesophageal echocardiography identified a fibroelastoma on the right coronary cusp of the aortic leaflet. Cardiac catheterization revealed mild non-obstructive stenosis. We postulate that the etiology of his angina is related to the dynamic occlusion of his right coronary ostium by the fibroelastoma. CONCLUSIONS: To the best of our knowledge, this is the first case report describing a patient with a cardiac papillary fibroelastoma who presented with both chronic angina and acute stroke. PMID- 28095922 TI - Long noncoding RNA Braveheart promotes cardiogenic differentiation of mesenchymal stem cells in vitro. AB - BACKGROUND: Mesenchymal stem cells (MSCs) have limited potential of cardiogenic differentiation. In this study, we investigated the influence of long noncoding RNA Braveheart (lncRNA-Bvht) on cardiogenic differentiation of MSCs in vitro. METHODS: MSCs were obtained from C57BL/6 mice and cultured in vitro. Cells were divided into three groups: blank control, null vector control, and lncRNA-Bvht. All three groups experienced exposure to hypoxia (1% O2) and serum deprivation for 24 h, and 24 h of reoxygenation (20% O2). Cardiogenic differentiation was induced using 5-AZA for another 24 h. Normoxia (20% O2) was applied as a negative control during the whole process. Cardiogenic differentiation was assessed, and expressions of cardiac-specific transcription factors and epithelial-mesenchymal transition (EMT)-associated biomarkers were detected. Anti-mesoderm posterior1 (Mesp1) siRNA was transfected in order to block its expression, and relevant downstream molecules were examined. RESULTS: Compared with the blank control and null vector control groups, the lncRNA-Bvht group presented a higher percentage of differentiated cells of the cardiogenic phenotype in vitro both under the normal condition and after hypoxia/re-oxygenation. There was an increased level of cTnT and alpha-SA, and cardiac-specific transcription factors including Nkx2.5, Gata4, Gata6, and Isl-1 were significantly upregulated (P < 0.01). Expressions of EMT-associated genes including Snail, Twist and N-cadherin were much higher (P < 0.01). Mesp1 exhibited a distinct augmentation following lncRNA Bvht transfection. Expressions of relevant cardiac-specific transcription factors and EMT-associated genes all presented a converse alteration in the condition of Mesp1 inhibition prior to lncRNA-Bvht transfection. CONCLUSION: lncRNA-Bvht could efficiently promote MSCs transdifferentation into cells with the cardiogenic phenotype in vitro. It might function via enhancing the expressions of cardiac specific transcription factors and EMT-associated genes. Mesp1 could be a pivotal intermediary in the procedure. PMID- 28095924 TI - SONOlysis in prevention of Brain InfaRctions During Internal carotid Endarterectomy (SONOBIRDIE) trial - study protocol for a randomized controlled trial. AB - BACKGROUND: Carotid endarterectomy (CEA) is a beneficial procedure for selected patients with an internal carotid artery (ICA) stenosis. Surgical risk of CEA varies from between 2 and 15%. The aim of the study is to demonstrate the safety and effectiveness of sonolysis (continual transcranial Doppler monitoring, TCD) using a 2-MHz diagnostic probe with maximal diagnostic energy on the reduction of the incidence of stroke, transient ischemic attack (TIA) and brain infarction detected using magnetic resonance imaging (MRI) by the activation of the endogenous fibrinolytic system during CEA. METHODS/DESIGN: Design: a multicenter, randomized, double-blind, sham-controlled trial. SCOPE: international, multicenter trial for patients with at least 70% symptomatic or asymptomatic ICA stenosis undergoing CEA. INCLUSION CRITERIA: patients with symptomatic or asymptomatic ICA stenosis of at least 70% are candidates for CEA; a sufficient temporal bone window for TCD; aged 40-85 years, functionally independent; provision of signed informed consent. Randomization: consecutive patients will be assigned to the sonolysis or control (sham procedure) group by computer-generated 1:1 randomization. Prestudy calculations showed that a minimum of 704 patients in each group is needed to reach a significant difference with an alpha value of 0.05 (two-tailed) and a beta value of 0.8 assuming that 10% would be lost to follow-up or refuse to participate in the study (estimated 39 endpoints). ENDPOINTS: the primary endpoint is the incidence of stroke or TIA during 30 days after CEA and the incidence of new ischemic lesions on brain MRI performed 24 h after CEA in the sonolysis and control groups. Secondary endpoints are occurrence of death, any stroke, or myocardial infarction within 30 days, changes in cognitive functions 1 year post procedure related to pretreatment scores, and number of new lesions and occurrence of new lesions >=0.5 mL on post-procedural brain MRI. ANALYSIS: descriptive statistics and linear/logistic multiple regression models will be performed. Clinical relevance will be measured as relative risk reduction, absolute risk reduction and the number needed to treat. DISCUSSION: Reduction of the periprocedural complications of CEA using sonolysis as a widely available and cheap method may significantly increase the safety of CEA and extend the indication criteria for CEA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02398734 . Registered on 20 March 2015. PMID- 28095925 TI - The effect of cigarette smoking on the oral and nasal microbiota. AB - BACKGROUND: The goal of the study was to investigate whether cigarette smoking alters oral and nasal microbial diversity, composition, and structure. Twenty three current smokers and 20 never smokers were recruited. From each subject, nine samples including supra and subgingiva plaque scrapes, saliva, swabs from five soft oral tissue sites, and one nasal swab from both the anterior nares were collected. 16S rRNA V3-V4 region was sequenced for microbial profiles. RESULTS: We found that alpha diversity was lower in smokers than in nonsmokers in the buccal mucosa, but in other sample sites, microbial diversity and composition were not significantly different by smoking status. Microbial profiles differed significantly among eight oral sites. CONCLUSIONS: This study investigates the effect of cigarette smoking on different sites of the oral cavity and shows a potential effect of cigarette smoking on the buccal mucosa microbiota. The marked heterogeneity of the oral microbial ecosystem that we found may contribute to the stability of the oral microbiota in most sites when facing environmental perturbations such as that caused by cigarette smoking. PMID- 28095926 TI - Epidemiology of parainfluenza infection in England and Wales, 1998-2013: any evidence of change? AB - Human parainfluenza virus (HPIV) infections are one of the commonest causes of upper and lower respiratory tract infections. In order to determine if there have been any recent changes in HPIV epidemiology in England and Wales, laboratory surveillance data between 1998 and 2013 were analysed. The UK national laboratory surveillance database, LabBase, and the newly established laboratory-based virological surveillance system, the Respiratory DataMart System (RDMS), were used. Descriptive analysis was performed to examine the distribution of cases by year, age, sex and serotype, and to examine the overall temporal trend using the chi 2 test. A random-effects model was also employed to model the number of cases. Sixty-eight per cent of all HPIV detections were due to HPIV type 3 (HPIV 3). HPIV-3 infections were detected all year round but peaked annually between March and June. HPIV-1 and HPIV-2 circulated at lower levels accounting for 20% and 8%, respectively, peaking during the last quarter of the year with a biennial cycle. HPIV-4 was detected in smaller numbers, accounting for only 4% and also mainly observed in the last quarter of the year. However, in recent years, HPIV-4 detection has been reported much more commonly with an increase from 0% in 1998 to 3.7% in 2013. Although an overall higher proportion of HPIV infection was reported in infants (43.0%), a long-term decreasing trend in proportion in infants was observed. An increase was also observed in older age groups. Continuous surveillance will be important in tracking any future changes. PMID- 28095927 TI - Small alteration - big impacts: effects of small-scale riparian forest management on host-parasite dynamics in streams. AB - Environmental changes and ecological disturbances can have large and unpredictable effects on parasite dynamics. Increasing human impacts on freshwater ecosystems through land use may thus modify the distribution and abundance of parasites and have cascading effects on host populations. Here we tested the effects of small-scale riparian forest management on the nematode Cystidicoloides ephemeridarum and its insect intermediate host Ephemera danica in forested streams. We assessed the impacts of harvesting riparian trees on parasite prevalence and abundance concomitantly with host densities. We also looked at upstream and downstream reaches to document potential cascading effects on unaltered stream sections mediated by aerial dispersal of adult mayfly or downstream drift of E. danica larvae. We show that host densities and parasite levels (prevalence and abundance) increased significantly following riparian tree removal. Overall, parasite densities showed a 6- to 66-fold increase in harvested reaches compared to upstream, pristine reaches. Similar effects were also clear downstream of the disturbance. Thus, despite the small extent of riparian forest alteration along the study streams, both parasite and intermediate host were strongly affected. Small-scale riparian forest management may thus have large, unforeseen impacts on some aspects of freshwater ecosystem structure and functioning that are often ignored. Generally, understanding how human perturbations influence parasites is vital when trying to predict overall impacts on ecosystem structure and functioning, and how changes in infection dynamics may further affect host species. PMID- 28095928 TI - One hundred years of external approach medialisation thyroplasty. AB - It has been 100 years since Erwin Payr first developed an operation to improve the effects of a paralysed vocal fold, and operations based on this technique are still in use today. This technique, medialisation thyroplasty, aims to improve the symptoms caused by vocal fold palsy by realigning the lateralised vocal fold into the midline. Whilst the effects of vocal fold palsy were recognised in antiquity, it was only with the development of indirect laryngoscopy in the late nineteenth century that the vocal fold paralysis could be identified as an aetiology for poor phonation and dysphagia. Payr, in 1915, was the first to perform a recognisable form of medialisation thyroplasty, which was further developed in the early twentieth century, but medialisation thyroplasty did not begin to be widely used until the development of the modern technique by Isshiki et al., in 1974. Since then, medialisation thyroplasty has continued to be developed and is currently the most widely used technique for correcting the effects of vocal fold palsy. However, a wide array of therapeutic options is now available for vocal fold palsy and it is impossible to say whether or not medialisation thyroplasty will still be used in another 100 years. PMID- 28095929 TI - The provision of healthy food in a school tuck shop: does it influence primary school students' perceptions, attitudes and behaviours towards healthy eating? AB - OBJECTIVE: To investigate students' tuck shop buying behaviour, choices of lunchbox items and healthy eating perceptions and attitudes at a school with a nutritionally regulated tuck shop and a school with a conventional tuck shop. DESIGN: Mixed-methods research comprising a cross-sectional survey and focus groups. SETTING: Bloemfontein, South Africa. SUBJECTS: Randomly selected grade 2 to 7 students from a school with a nutritionally regulated tuck shop (school A; n 116) and a school with a conventional tuck shop (school B; n 141) completed a self-administered questionnaire about perceptions, attitudes, buying behaviours and lunchbox content. Six students per grade (n 72) in each school took part in focus group discussions to further explore concepts pertaining to healthy eating. RESULTS: In school A, older students had a negative attitude towards their 'healthy' tuck shop, while younger students were more positive. School B students were positive towards their conventional tuck shop. In both schools students wanted their tuck shop to allow them to choose from healthy and unhealthy items. School A students mostly bought slushies, iced lollies and baked samoosas, while school B students mostly bought sweets and crisps. The lunchboxes of school A students contained significantly (P<0.05) more healthy items but also significantly more unhealthy items. CONCLUSIONS: A single intervention such as having a nutritionally regulated tuck shop at a primary school cannot advance the healthy school food environment in its totality. A multi-pronged approach is recommended and awareness must be created among all role players, including parents who are responsible for preparing lunchboxes. PMID- 28095930 TI - Quantitative risk assessment of the introduction of rabies into Japan through the importation of dogs and cats worldwide. AB - Japan has been free from rabies since 1958. A strict import regimen has been adopted since 2004 consisting of identification of an animal with microchip, two time rabies vaccination, neutralizing antibody titration test and a waiting period of 180 days. The present study aims to quantitatively assess the risk of rabies introduction into Japan through the international importation of dogs and cats and hence provide evidence-based recommendations to strengthen the current rabies prevention system. A stochastic scenario tree model was developed and simulations were run using @RISK. The probability of infection in a single dog or cat imported into Japan is estimated to be 2.16 * 10-9 [90% prediction interval (PI) 6.65 * 10-11-6.48 * 10-9]. The number of years until the introduction of a rabies case is estimated to be 49 444 (90% PI 19 170-94 641) years. The current import regimen is effective in maintaining the very low risk of rabies introduction into Japan and responding to future changes including increases in import level and rabies prevalence in the world. However, non-compliance or smuggling activities could substantially increase the risk of rabies introduction. Therefore, policy amendment which could promote compliance is highly recommended. Scenario analysis demonstrated that the waiting period could be reduced to 90 days and the requirement for vaccination could be reduced to a single vaccination, but serological testing should not be stopped. PMID- 28095923 TI - NADPH oxidase in brain injury and neurodegenerative disorders. AB - Oxidative stress is a common denominator in the pathology of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, as well as in ischemic and traumatic brain injury. The brain is highly vulnerable to oxidative damage due to its high metabolic demand. However, therapies attempting to scavenge free radicals have shown little success. By shifting the focus to inhibit the generation of damaging free radicals, recent studies have identified NADPH oxidase as a major contributor to disease pathology. NADPH oxidase has the primary function to generate free radicals. In particular, there is growing evidence that the isoforms NOX1, NOX2, and NOX4 can be upregulated by a variety of neurodegenerative factors. The majority of recent studies have shown that genetic and pharmacological inhibition of NADPH oxidase enzymes are neuroprotective and able to reduce detrimental aspects of pathology following ischemic and traumatic brain injury, as well as in chronic neurodegenerative disorders. This review aims to summarize evidence supporting the role of NADPH oxidase in the pathology of these neurological disorders, explores pharmacological strategies of targeting this major oxidative stress pathway, and outlines obstacles that need to be overcome for successful translation of these therapies to the clinic. PMID- 28095931 TI - Anger Rumination Scale: Validation in Mexico. AB - The aim of the study was to assess the validity of the Anger Rumination Scale (ARS; Sukhodolsky, Golub, & Cromwell, 2001) in a Mexican sample (n = 700, M age = 38.6, SD = 12.42). Through confirmatory factor analysis and using modification indices, the four-factor structure of the original scale was replicated: angry afterthoughts, thoughts of revenge, angry memories, and understanding of causes. In addition, the four-factor model had better goodness of fit indices than rival models with three and two factors. Alpha reliabilities were acceptable (.72 .89). ARS results correlated with measures of state anger, trait anger, anger expression, and anger control (negatively); correlations were significant (ps < .001) ARS outcomes also correlated (ps < .001) with physical and verbal aggression, hostility, anger, and emotion suppression, suggesting convergent validity. Men reported more thoughts of revenge than women (p < .001; Eta squared = .026), but there was no evidence of gender differences on the other anger rumination scales, or in total scores. PMID- 28095932 TI - The role of marriage in criminal recidivism: a longitudinal and co-relative analysis. AB - AIMS: Marriage is associated with a reduced rate of criminal recidivism, but the underlying mechanisms have only partly been elucidated. We seek to clarify the nature of the association between marriage and recidivism and how that relationship may be moderated as a function of gender, deviance of spouse, a history of violence and familial risk. METHOD: We utilise a longitudinal cohort design consisting of Swedish men (n = 239 328) and women (n = 72 280), born between 1958 and 1986, who were convicted of at least one crime before age 20 and were not married prior to age 20. The analyses used Cox regression with marriage as a time-dependent covariate. We also perform co-relative analyses in sibling and first cousin pairs. RESULTS: Marriage after a first crime substantially reduces risk of recidivism in both males (hazard ratio (HR) with key covariates and 95% confidence intervals 0.55, 0.53-0.57) and females (HR = 0.38, 0.34-0.42), although the effect is stronger in females. Marriage to a deviant spouse increases recidivism rates in males. In males, a history of violent criminality and high familial risk, respectively, decrease and increase sensitivity to the protective effect of marriage on recidivism. Consistent with a causal effect of marriage on recidivism, marriage was associated with a decline in risk for criminal relapse comparable with that in the population in both male-male sibling pairs (raw HR = 0.53, 0.45-0.62) and cousin pairs (HR = 0.55, 0.47, 0.65) concordant for prior convictions. CONCLUSIONS: The protective effect of marriage on risk for criminal recidivism is likely largely causal and is of importance in both males and females. Those at high familial risk for criminal behaviour are more sensitive to the protective effects of marriage. PMID- 28095933 TI - Understanding Older Adults' Resilience During the Brisbane Floods: Social Capital, Life Experience, and Optimism. AB - OBJECTIVE: The purpose of this study was to explore how social capital or the impact of life and previous disaster experience facilitated resilience in older adults who experienced the 2011 and 2013 floods in Brisbane, Australia. METHODS: Data were drawn from in-depth interviews of 10 older adults from Brisbane who were evacuated in both the 2011 and 2013 floods. A combined qualitative approach drawing from the methods of constructivist grounded theory and narrative inquiry was applied and the data were analyzed by using (inductive) line-by-line and axial coding. RESULTS: The narratives of the older adults revealed a strong theme of resilience linked to social capital (bonding, bridging, and linking) and previous disaster experience. The results reflected the changing face of disaster management strategies and sources of social capital. CONCLUSIONS: Changes in disaster management polices (toward self-reliance) and more formalized sources of social capital highlight the need to build strong and healthy resilient communities that are capable of positively recovering from natural disasters. The results from this research emphasize the importance of initiatives that enhance social cohesion, trust, and social capital within local communities. (Disaster Med Public Health Preparedness. 2017;11:72-79). PMID- 28095934 TI - The Effect of Ambulance Staffing Models in a Metropolitan, Fire-Based EMS System. AB - : Introduction The staffing of ambulances with different levels of Emergency Medical Service (EMS) providers is a difficult decision with evidence being mixed on the benefit of each model. Hypothesis/Problem The objective of this study was to describe a pilot program evaluating alternative staffing on two ambulances utilizing the paramedic-basic (PB) model (staffed with one paramedic and one emergency medical technician[EMT]). METHODS: This was a retrospective study conducted from September 17, 2013 through December 31, 2013. The PB ambulances were compared to geographically matched ambulances staffed with paramedic paramedic (PP ambulances). One PP and one PB ambulance were based at Station A; one PP and one PB ambulance were based at Station B. The primary outcome was total on-scene time. Secondary outcomes included time-to-electrocardiogram (EKG), time-to-intravenous (IV) line insertion, IV-line success rate, and percentage of protocol violations. Inclusion criteria were all patients requesting prehospital services that were attended to by these teams. Patients were excluded if they were not attended to by the study ambulance vehicles. Descriptive statistics were reported as medians and interquartile ranges (IQR). Proportions were reported with 95% confidence intervals (CI). The Mann-Whitley U test was used for significance testing (P<.05). RESULTS: Median on-scene times at Station A for the PP ambulance were shorter than the PB ambulance team (PP: 10.1 minutes, IQR 6.0 15; PB: 13.0 minutes, IQR 8.1-18; P=.01). This finding also was noted at Station B (PP: 13.5 minutes, IQR 8.5-19; PB: 14.3 minutes, IQR 9.9-20; P=.01). There were no differences between PP and PB ambulance teams at Station A or Station B in time-to-EKG, time-to-IV insertion, IV success rate, and protocol violation rates. CONCLUSION: In the setting of a well-developed EMS system utilizing an all Advanced Life Support (ALS) response, this study suggests that PB ambulance teams may function well when compared to PP ambulances. Though longer scene times were observed, differences in time to ALS interventions and protocol violation rates were not different. Hybrid ambulance teams may be an effective staffing alternative, but decisions to use this model must address clinical and operational concerns. Cortez EJ , Panchal AR , Davis JE , Keseg DP . The effect of ambulance staffing models in a metropolitan, fire-based EMS system. Prehosp Disaster Med. 2017;32(2):175-179. PMID- 28095935 TI - Living well with chronic disease for those older adults living in the community. AB - BACKGROUND: Definitions of successful aging that incorporate dimensions of physical capacity and medical conditions are limited owing to the normative nature of experiencing medical conditions with age. We examine the capacity for older adults living in the community to live well with or without chronic disease as they age. METHOD: Participants (n = 1,001) were from the Melbourne Longitudinal Studies on Healthy Ageing (MELSHA) study who were aged 65+ years at baseline, were living in the community and followed for 16 years. RESULTS: Aging was associated with not living well (OR = 1.21; p < 0.001) and having a chronic disease (OR = 1.09; p < 0.001). There was increasing proportion of older adults not living well with chronic disease as they aged. Those not living well were at a substantial risk of death with (OR = 3.63; p < 0.001) or without (OR = 3.59; p < 0.001) chronic disease. DISCUSSION: The defining normative experience for older adults is that they are more likely to have a chronic disease and importantly not be living well with chronic disease as they age. However, it was the state of not living well that reflected the most substantial vulnerability for mortality, not chronic disease. PMID- 28095936 TI - How expensive is a cardioprotective diet? Analysis from the CRESSIDA study. AB - OBJECTIVE: To determine whether a cardioprotective dietary intervention based on UK dietary guidelines was more expensive than a conventional UK diet. DESIGN: Cost analysis of food records collected at baseline and after a 12-week dietary intervention of a cardioprotective diet v. conventional UK diet. SETTING: A randomized controlled dietary intervention study (CRESSIDA; ISRCTN 92382106) investigating the impact of following a diet consistent with UK dietary guidelines on CVD risk. SUBJECTS: Participants were healthy UK residents aged 40 70 years. A sub-sample of participants was randomly selected from those who completed the cardioprotective dietary intervention (n 20) or the conventional UK dietary intervention (n 20). RESULTS: Baseline diet costs did not differ between groups; mean daily food cost for all participants was L6.12 (sd L1.83). The intervention diets were not more expensive: at end point the mean daily cost of the cardioprotective diet was L6.43 (sd L2.05) v. the control diet which was L6.53 (sd L1.53; P=0.86). CONCLUSIONS: There was no evidence that consumption of a cardioprotective diet was more expensive than a conventional dietary pattern. Despite the perception that healthier foods are less affordable, these results suggest that cost may not be a barrier when modifying habitual intake and under tightly controlled trial conditions. The identification of specific food groups that may be a cost concern for individuals may be useful for tailoring interventions for CVD prevention for individuals and populations. PMID- 28095937 TI - Maternal gestational vitamin D supplementation and child health: looking to the future. PMID- 28095938 TI - Effect of the patient-to-patient communication model on dysphagia caused by total laryngectomy. AB - OBJECTIVE: The study aimed to evaluate the effect of a patient-to-patient communication model on dysphagia in laryngeal cancer patients after total laryngectomy. METHODS: Sixty-five patients who had undergone total laryngectomy were randomly divided into three groups: a routine communication group, a patient communication group (that received the patient-to-patient communication model) and a physician communication group. Questionnaires were used to compare quality of life and swallowing problems among all patient groups. RESULTS: The main factors causing dysphagia in total laryngectomy patients were related to fear and mental health. The patient communication group had improved visual analogue scale scores at one week after starting to eat. Quality of life in swallowing disorders questionnaire scores were significantly higher in the patient communication and physician communication groups than in the routine communication group. In addition, swallowing problems were much more severe in patients educated to high school level and above than in others. CONCLUSION: The patient-to-patient communication model can be used to resolve swallowing problems caused by psychological factors in total laryngectomy patients. PMID- 28095939 TI - Safe balloon sizing for endoscopic dilatation of subglottic stenosis in children. AB - OBJECTIVES: To describe our experience and provide guidelines for maximum safe balloon sizes according to age in children undergoing balloon dilatation. METHOD: A retrospective review was conducted of children undergoing balloon dilatation for subglottic stenosis in a paediatric tertiary unit between May 2006 and February 2016. RESULTS: A total of 166 patients underwent balloon dilatation. Mean ( +/- standard deviation) patient age was 4.5 +/- 3.99 years. The median balloon size was 8 mm, the median balloon inflation pressure was 10 atm, and the mean balloon inflation time was 65.1 +/- 18.6 seconds. No significant unexpected events occurred. The Pearson correlation co-efficient for the relationship between patient age and balloon size was 0.85 (p = 0.001), suggesting a strongly positive correlation. CONCLUSION: This study demonstrated that balloon dilatation is a safe procedure for airway stenosis. The results suggest using a balloon diameter that is equal to the outer diameter of the age-appropriate endotracheal tube +1 mm for the larynx and subglottis and +2 mm for the trachea. PMID- 28095940 TI - Neuroscience-based Nomenclature: improving clinical and scientific terminology in research and clinical psychopharmacology. PMID- 28095941 TI - Preparation for the end of life and life completion during late-stage lung cancer: An exploratory analysis. AB - OBJECTIVE: Our aim was to explore preparation for the end of life (EoL) and life closure among persons with advanced metastatic lung cancer. Understanding quality of life through the lens of preparation and completion is important since the trajectory of lung cancer can be relatively short, often leading to application of cancer-directed therapies near death without the opportunity for advance planning or palliative care. Clinical research is needed to understand the kinds of distress specific to older adults with advanced lung cancer that are amendable to palliative care interventions. METHOD: We employed an exploratory cross sectional design to examine psychosocial and existential concerns among a purposive sample (N = 30) of advanced lung cancer patients using the "end-of-life preparation" and "life completion" subscales of the Quality of Life at the End of Life (QUAL-E) questionnaire. Nonparametric methods were employed to analyze preparation, completion, global quality of life (QoL), and the associations among depressive symptoms, preparation, completion, and global QoL. RESULTS: Higher scores on life completion were associated with better global QoL, and with items related to transcendence, communicative acts, and interpersonal relationships demonstrating important contributions. The perception of being a future burden on family members was the greatest concern within the preparation domain. Depressive symptoms were not associated with preparation, completion, or global QoL. SIGNIFICANCE OF RESULTS: Psychosocial and existential issues contribute to QoL at the EoL among older adults with late-stage lung cancer during cancer-directed therapy, concurrent care, and hospice. The role of preparation, especially self perceived burden, merits further research early on in the oncological setting. The preparation and life completion subscales of the QUAL-E are feasible clinical tools for facilitating dyadic communication about sensitive topics in the palliative care setting. PMID- 28095942 TI - Association of neighbourhood food availability with the consumption of processed and ultra-processed food products by children in a city of Brazil: a multilevel analysis. AB - OBJECTIVE: To investigate the association between neighbourhood food availability and the consumption of ready-to-consume products (RCP), either processed or ultra processed, and unprocessed/minimally processed foods (UF-MPF) by children. DESIGN: Cross-sectional. 24 h Dietary recalls were collected from children from January 2010 to June 2011. Neighbourhood food availability data were collected from 672 food stores located within 500 m of participants' homes, using an adapted and validated instrument. Neighbourhood-level socio-economic status (SES) was obtained by calculating the mean years of household head's education level in each census tract covered by 500 m buffers. Foods that were consumed by children and/or available in the food stores were classified based on their degree of industrial processing. Multilevel random-effect models examined the association between neighbourhood food availability and children's diets. SETTING: Santos, Brazil. SUBJECTS: Children (n 513) under 10 years old (292 aged <6 years, 221 aged >=6 years). RESULTS: The availability of RCP in food stores was associated with increased RCP consumption (P<0.001) and decreased UF-MPF consumption (P<0.001). The consumption of UF-MPF was positively associated with neighbourhood level SES (P<0.01), but not with the availability of UF-MPF in the neighbourhood. CONCLUSIONS: Results suggest that food policies and interventions that aim to reduce RCP consumption in Santos and similar settings should focus on reducing the availability in food stores. The results also suggest that interventions should not only increase the availability of UF-MPF in lower-SES neighbourhoods, but should strive to make UF-MPF accessible within these environments. PMID- 28095943 TI - Sleep disturbances in caregivers of patients with advanced cancer: A systematic review. AB - OBJECTIVE: Sleep disturbances are a common issue for those who provide informal care to someone with a life-limiting condition. The negative consequences of poor sleep are well documented. The purpose of the present study was to determine the sleep patterns of caregivers of patients with advanced cancer. METHOD: An extensive systematic review of studies reporting empirical sleep data was undertaken in 2015 in accordance with the PRISMA Statement. A total of eight electronic databases were searched, with no date restrictions imposed. Additionally, a search of the bibliographies of the studies identified during the electronic search was conducted. Search terms included: "sleep," "insomnia," "sleep disturbance," "circadian rhythm," "caregiver," "carer," "advanced cancer," "palliative cancer," and MESH suggestions. The inclusion criteria required studies to be in English and to report primary qualitative and/or quantitative research that examined sleep in caregivers of patients with advanced cancer. Unpublished studies, conference papers, and dissertations were excluded. RESULTS: Overall, 10 studies met the inclusion criteria and were included in the review. Two major findings emerged from the data synthesis. First, at least 72% of caregivers reported moderate to severe sleep disturbance as measured by the Pittsburgh Sleep Quality Index. Second, objective measurement of caregivers' sleep identified that some caregivers experienced up to a 44% reduction in their total sleep time compared to the recommended eight hours. SIGNIFICANCE OF RESULTS: Reduction in total sleep time appears to be the biggest issue facing caregivers' sleep. Future studies need to explore the specific factors that cause these sleep disturbances and thus help to identify interventions to optimize sleep. PMID- 28095944 TI - Applications of the propensity score weighting method in psychogeriatric research: correcting selection bias and adjusting for confounders. AB - The propensity score (PS) weighting method is an analytic technique that has been applied in multiple fields for a number of purposes. Here, we discuss two common applications, which are (1) to correct for selection bias and (2) to adjust for confounding variables when estimating the effect of an exposure variable on the outcome of interest. PMID- 28095945 TI - Conflict monitoring and adaptation as reflected by N2 amplitude in obsessive compulsive disorder. AB - BACKGROUND: Feelings of doubt and perseverative behaviours are key symptoms of obsessive-compulsive disorder (OCD) and have been linked to hyperactive error and conflict signals in the brain. While enhanced neural correlates of error monitoring have been robustly shown, far less is known about conflict processing and adaptation in OCD. METHOD: We examined event-related potentials during conflict processing in 70 patients with OCD and 70 matched healthy comparison participants, focusing on the stimulus-locked N2 elicited in a flanker task. Conflict adaptation was evaluated by analysing sequential adjustments in N2 and behaviour, i.e. current conflict effects as a function of preceding conflict. RESULTS: Patients with OCD showed enhanced N2 amplitudes compared with healthy controls. Further, patients showed stronger conflict adaptation effects on reaction times and N2 amplitude. Thus, the effect of previous compatibility was larger in patients than in healthy participants as indicated by greater N2 adjustments in change trials (i.e. iC, cI). As a result of stronger conflict adaptation in patients, N2 amplitudes were comparable between groups in incompatible trials following incompatible trials. CONCLUSIONS: Larger N2 amplitudes and greater conflict adaptation in OCD point to enhanced conflict monitoring leading to increased recruitment of cognitive control in patients. This was most pronounced in change trials and was associated with stronger conflict adjustment in N2 and behaviour. Thus, hyperactive conflict monitoring in OCD may be beneficial in situations that require a high amount of control to resolve conflict, but may also reflect an effortful process that is linked to distress and symptoms of OCD. PMID- 28095947 TI - An Evaluation of Food as a Potential Source for Clostridium difficile Acquisition in Hospitalized Patients - CORRIGENDUM. PMID- 28095946 TI - Electroconvulsive therapy (ECT) for treating agitation in dementia (major neurocognitive disorder) - a promising option. AB - BACKGROUND: Agitation in patients with dementia increases caretaker burden, increases healthcare costs, and worsens the patient's quality of life. Antipsychotic medications, commonly used for the treatment of agitation in patients with dementia have a box warning from the FDA for elevated mortality risk. Electroconvulsive therapy (ECT) has made significant advances over the past several years, and is efficacious in treating a wide range of psychiatric conditions. We provide a systematic review of published literature regarding the efficacy of ECT for the treatment of agitation in patients with dementia (major neurocognitive disorder). METHODS: We searched PubMed, Medline, Google Scholar, UptoDate, Embase, and Cochrane for literature concerning ECT for treating agitation in dementia using the title search terms "ECT agitation dementia;" "ECT aggression dementia;" "ECT Behavior and Psychological Symptoms of Dementia;" and "ECT BPSD." The term "dementia" was also interchanged with "Major Neurocognitive Disorder." No time frame restriction was placed. We attempted to include all publications that were found to ensure a comprehensive review. We found 11 papers, with a total (N) of 216 patients. RESULTS: Limited to case reports, case series, retrospective chart review, retrospective case-control, and an open label prospective study, ECT has demonstrated promising results in decreasing agitation in patients with dementia. Patients who relapsed were found to benefit from maintenance ECT. CONCLUSIONS: Available studies are often limited by concomitant psychotropic medications, inconsistent use of objective rating scales, short follow-up, lack of a control group, small sample sizes, and publication bias. A future randomized controlled trial will pose ethical and methodological challenges. A randomized controlled trial must carefully consider the definition of usual care as a comparison group. Well-documented prospective studies and/or additional case series with explicit selection criteria, a wide range of outcome measures, and less selection bias of the study sample that may favor treatment response, is warranted. ECT may be a promising option for the treatment of aggression and agitation in patients with severe dementia who are refractory to other treatment options, but the limitations of available studies suggest that a cautious approach to future randomized controlled trials is warranted. PMID- 28095949 TI - AsMA: Science and Professional Practice. PMID- 28095950 TI - CT Coronary Angiography vs. Coronary Artery Calcium Scoring for the Occupational Assessment of Military Aircrew. AB - INTRODUCTION: To ensure flight safety military aircrew undergo regular clinical and occupational assessment. Coronary artery calcium scoring (CACS) has been established as an imaging modality to noninvasively assess coronary artery disease (CAD). CT coronary angiography (CTCA) potentially offers a more accurate assessment of CAD, but has not been formally assessed in military aircrew. This retrospective cohort study is designed to compare the theoretical differences in downstream investigations and occupational outcomes in aircrew with suspected CAD comparing CTCA with existing CACS pathways. METHOD: A 2-yr retrospective cohort study of consecutive UK military patients who underwent a CTCA and CACS was undertaken. Patient demographics, CTCA and CACS results, and initial and final occupational restrictions were analyzed comparing current UK, Canadian, and U.S. pathways. RESULTS: There were 44 patients who underwent CACS and CTCA. The commonest indication for a CTCA was a positive exercise ECG. Increasing CACS, stenosis severity, and stenosis burden were associated with significantly greater likelihood of occupational restriction (P = < 0.01). Following CTCA, 26/44 (59%) patients were found to have evidence of CAD, with 13/44 (30%) having at least a single vessel stenosis >=50%. All of these patients had subsequent occupational restrictions. Two patients with a calcium score <=10 had at least 1 single vessel stenosis >=50%. DISCUSSION: A CTCA pathway is potentially a better discriminator of CAD burden in aircrew when compared with CACS and may reduce downstream testing, allowing a more efficacious approach to CAD assessment in military aircrew.Parsons I, Pavitt C, Chamley R, d'Arcy J, Nicol E. CT coronary angiography vs. coronary artery calcium scoring for the occupational assessment of military aircrew. Aerosp Med Hum Perform. 2017; 88(2):76-81. PMID- 28095951 TI - Simulated Microgravity Effects on Nonsmall Cell Lung Cancer Cell Proliferation and Migration. AB - BACKGROUND: Despite improvements in medical technology, lung cancer metastasis remains a global health problem. The effects of microgravity on cell morphology, structure, functions, and their mechanisms have been widely studied; however, the biological effects of simulated microgravity on the interaction between cells and its eventual influence on the characteristics of cancer cells are yet to be discovered. We examined the effects of simulated microgravity on the metastatic ability of different lung cancer cells using a random positioning machine. METHODS: Human lung cancer cell lines of adenocarcinoma (A549) and squamous cell carcinoma (H1703) were cultured in a 3D clinostat system which was continuously rotated at 5 rpm for 36 h. The experimental and control group were cultured under identical conditions with the exception of clinorotation. RESULTS: Simulated microgravity had different effects on each lung cancer cell line. In A549 cells, the proliferation rate of the clinostat group (2.267 +/- 0.010) after exposure to microgravity did not differ from that of the control group (2.271 +/- 0.020). However, in H1703 cells, the proliferation rates of the clinostat group (0.534 +/ 0.021) was lower than that of the control group (1.082 +/- 0.021). The migratory ability of both A549 [remnant cell-free area: 33% (clinostat) vs. 78% (control)] and H1703 cells [40% (clinostat) vs. 68% (control)] were increased after exposure to microgravity. The results of the molecular changes in biomarkers after exposure to microgravity are preliminary. DISCUSSION: Simulated microgravity had different effects on the proliferation and migration of different lung cancer cell lines.Chung JH, Ahn CB, Son KH, Yi E, Son HS, Kim H-S, Lee SH. Simulated microgravity effects on nonsmall cell lung cancer cell proliferation and migration. Aerosp Med Hum Perform. 2017; 88(2):82-89. PMID- 28095952 TI - Neck and Shoulder Muscle Activation Among Experienced and Inexperienced Pilots in +Gz Exposure. AB - BACKGROUND: The aim of the present study was to compare differences in electromyography (EMG) activation of the neck and shoulder muscles between groups of inexperienced and experienced pilots during controlled +Gz exposure in a centrifuge. METHODS: The subjects were volunteer cadets (inexperienced group) and lieutenants (experienced group) undergoing their first centrifuge training. The first group did not have any high performance aircraft (HPA) experience, while the latter one had a 1-yr experience of intense flying of HPA. During the centrifuge run, EMG activity was recorded from the left and right shoulder, neck flexor, and neck extensor muscles. RESULTS: The pilots without HPA experience had significantly higher muscle activity in the neck flexor and extensor muscles during the last 5 s of the recorded period at G levels exceeding +7.4. DISCUSSION: Muscle activity in the neck and shoulder muscles was gradually higher among the whole study group with increasing +Gz forces. Because pilots without any HPA experience had significantly higher muscle activity than their counterparts with experience of HPA, we suppose that the experience of high +Gz forces might lead to lower muscle activation in the same flight mission.Honkanen T, Oksa J, Mantysaari MJ, Kyrolainen H, Avela J. Neck and shoulder muscle activation among experienced and inexperienced pilots in +Gz exposure. Aerosp Med Hum Perform. 2017; 88(2):90-95. PMID- 28095953 TI - Reported Back Pain in Army Aircrew in Relation to Airframe, Gender, Age, and Experience. AB - INTRODUCTION: Back pain has remained an issue of significance among aircraft crewmembers for decades, occurring in the majority of military helicopter pilots with potential deleterious effects on performance, safety, and operational readiness. This exploratory, correlational survey study was designed to evaluate the presence of patterns and relationships that may require further examination to understand causal factors. METHODS: The study population consisted of U.S. Army aviation crewmembers. Subjects (467) completed an anonymous survey, including questions regarding demographics, airframes, experience, pain history and severity, ergonomics, mitigation strategies, and duty limitations. RESULTS: Overall, 84.6% of participants reported back pain at some time during their flying career, with 77.8% reporting back pain in the last calendar year. Age was found to significantly correlate with earlier time to pain during flight, higher pain rating after flight, and occurrence of grounding. A stepwise linear regression model was used to explore the relationships between age, flight hours, and years of aviation experience, demonstrating age to be the significant variable accounting for the observed variance. Aircrew reported wear of combat related survival equipment and poor lumbar support to be the most notable contributors. DISCUSSION: Back pain rates were consistent with previous studies. The relationship of age to back pain in this study may highlight unique pathophysiological pathways that should be further investigated within an occupational context to better understand the etiologic role. Enhanced seated lumbar support and combat-related survival equipment remain relatively low cost/high-yield topics worthy of further investigation for exploiting efficient means to improve health, safety, and operational performance.Kelley AM, MacDonnell J, Grigley D, Campbell J, Gaydos SJ. Reported back pain in army aircrew in relation to airframe, gender, age, and experience. Aerosp Med Hum Perform. 2017; 88(2):96-103. PMID- 28095954 TI - Predicting Air Quality at First Ingress into Vehicles Visiting the International Space Station. AB - INTRODUCTION: NASA regularly performs ground-based offgas tests (OGTs), which allow prediction of accumulated volatile pollutant concentrations at first entry on orbit, on whole modules and vehicles scheduled to connect to the International Space Station (ISS). These data guide crew safety operations and allow for estimation of ISS air revitalization systems impact from additional pollutant load. Since volatiles released from vehicle, module, and payload materials can affect crew health and performance, prediction of first ingress air quality is important. METHODS: To assess whether toxicological risk is typically over or underpredicted, OGT and first ingress samples from 10 vehicles and modules were compared. Samples were analyzed by gas chromatography and gas chromatography-mass spectrometry. The rate of pollutant accumulation was extrapolated over time. Ratios of analytical values and Spacecraft Maximum Allowable Concentrations were used to predict total toxicity values (T-values) at first entry. Results were also compared by compound. RESULTS: Frequently overpredicted was 2-butanone (9/10), whereas propanal (6/10) and ethanol (8/10) were typically underpredicted, but T-values were not substantially affected. Ingress sample collection delay (estimated by octafluoropropane introduced from ISS atmosphere) and T-value prediction accuracy correlated well (R2 = 0.9008), highlighting the importance of immediate air sample collection and accounting for ISS air dilution. DISCUSSION: Importantly, T-value predictions were conservative 70% of the time. Results also suggest that T-values can be normalized to octafluoropropane levels to adjust for ISS air dilution at first ingress. Finally, OGT and ingress sampling has allowed small leaks in vehicle fluid systems to be recognized and addressed.Romoser AA, Scully RR, Limero TF, De Vera V, Cheng PF, Hand JJ, James JT, Ryder VE. Predicting air quality at first ingress into vehicles visiting the International Space Station. Aerosp Med Hum Perform. 2017; 88(2):104-113. PMID- 28095955 TI - Preconditioning to Reduce Decompression Stress in Scuba Divers. AB - BACKGROUND: Using ultrasound imaging, vascular gas emboli (VGE) are observed after asymptomatic scuba dives and are considered a key element in the potential development of decompression sickness (DCS). Diving is also accompanied with vascular dysfunction, as measured by flow-mediated dilation (FMD). Previous studies showed significant intersubject variability to VGE for the same diving exposure and demonstrated that VGE can be reduced with even a single pre-dive intervention. Several preconditioning methods have been reported recently, seemingly acting either on VGE quantity or on endothelial inflammatory markers. METHODS: Nine male divers who consistently showed VGE postdive performed a standardized deep pool dive (33 m/108 ft, 20 min in 33 degrees C water temperature) to investigate the effect of three different preconditioning interventions: heat exposure (a 30-min session of dry infrared sauna), whole-body vibration (a 30-min session on a vibration mattress), and dark chocolate ingestion (30 g of chocolate containing 86% cocoa). Dives were made one day per week and interventions were administered in a randomized order. RESULTS: These interventions were shown to selectively reduce VGE, FMD, or both compared to control dives. Vibration had an effect on VGE (39.54%, SEM 16.3%) but not on FMD postdive. Sauna had effects on both parameters (VGE: 26.64%, SEM 10.4%; FMD: 102.7%, SEM 2.1%), whereas chocolate only improved FMD (102.5%, SEM 1.7%). DISCUSSION: This experiment, which had the same subjects perform all control and preconditioning dives in wet but completely standardized diving conditions, demonstrates that endothelial dysfunction appears to not be solely related to VGE.Germonpre P, Balestra C. Preconditioning to reduce decompression stress in scuba divers. Aerosp Med Hum Perform. 2017; 88(2):114-120. PMID- 28095956 TI - Decelerations of Parachute Opening Shock in Skydivers. AB - INTRODUCTION: High prevalence of neck pain among skydivers is related to parachute opening shock (POS) exposure, but few investigations of POS deceleration have been made. Existing data incorporate equipment movements, limiting its representability of skydiver deceleration. This study aims to describe POS decelerations and compare human- with equipment-attached data. METHODS: Wearing two triaxial accelerometers placed on the skydiver (neck-sensor) and equipment (rig-sensor), 20 participants made 2 skydives each. Due to technical issues, data from 35 skydives made by 19 participants were collected. Missing data were replaced using data substitution techniques. Acceleration axes were defined as posterior to anterior (+ax), lateral right (+ay), and caudal to cranial (+az). Deceleration magnitude [amax (G)] and jerks (G . s-1) during POS were analyzed. RESULTS: Two distinct phases related to skydiver positioning and acceleration direction were observed: 1) the x-phase (characterized by -ax, rotating the skydiver); and 2) the z-phase (characterized by +az, skydiver vertically oriented). Compared to the rig-sensor, the neck-sensor yielded lower amax (3.16 G vs. 6.96 G) and jerk (56.3 G . s-1 vs. 149.0 G . s-1) during the x phase, and lower jerk (27.7 G . s-1 vs. 54.5 G . s-1) during the z-phase. DISCUSSION: The identified phases during POS should be considered in future neck pain preventive strategies. Accelerometer data differed, suggesting human-placed accelerometry to be more valid for measuring human acceleration.Gladh K, Lo Martire R, Ang BO, Lindholm P, Nilsson J, Westman A. Decelerations of parachute opening shock in skydivers. Aerosp Med Hum Perform. 2017; 88(2):121-127. PMID- 28095957 TI - Point-of-Care Ultrasound Utility and Potential for High Altitude Crew Recovery Missions. AB - INTRODUCTION: Flights to high altitude can lead to exposure and unique pathology not seen in normal commercial aviation. METHODS: This paper assesses the potential for point-of-care ultrasound to aid in management and disposition of injured crewmembers from a high altitude incident. This was accomplished through a systematic literature review regarding current diagnostic and therapeutic uses of ultrasound for injuries expected in high altitude free fall and parachuting. RESULTS: While current research supports its utility in diagnostics, therapeutic procedures, and triage decisions, little research has been done regarding its utility in high altitude specific pathology, but its potential has been demonstrated. DISCUSSION: An algorithm was created for use in high altitude missions, in the event of an emergency descent and traumatic landing for an unconscious and hypotensive pilot, to rule out most life threatening causes. Each endpoint includes disposition, allowing concise decision-making.Galdamez LA, Clark JB, Antonsen EL. Point-of-care ultrasound utility and potential for high altitude crew recovery missions. Aerosp Med Hum Perform. 2017; 88(2):128-136. PMID- 28095958 TI - Additive Effects of Sinusoidal Lower Body Negative Pressure on Cardiovascular Responses. AB - BACKGROUND: Sinusoidal lower body negative pressure (SLBNP) has been used to investigate the cardiovascular response to slow periodic changes in blood shifts, but measurements of slow fluctuations take a long time if measured for each period of SLBNP separately. Our study aimed to investigate whether the cardiovascular responses to superimposed SLBNP (S-SLBNP), which is expected to reduce the measurement time, are different from responses measured individually. METHODS: S-SLBNP was configured by superimposing two conventional SLBNPs (C SLBNP) at 180-s and 30-s periods in the pressure range from 0 to -25 mmHg. As the S-SLBNP has double the static load of C-SLBNP, we also used offset SLBNP (O SLBNP), which has the same static load level as S-SLBNP. Heart rate (HR), thoracic impedance (Z0), and mean arterial pressure (MAP) were measured from 11 male subjects. The transfer functions of gains from MAP to HR (Gain-HR/MAP) and from Z0 to HR (Gain-HR/Z0) were calculated as indexes of arterial baroreflex and cardiopulmonary baroreflex regulation of HR, respectively. RESULTS: The Gain HR/MAP in the 180-s period (2.11 +/- 0.17 bpm/mmHg; mean +/- SEM) was larger than that of the 30-s period (1.04 +/- 0.09 bpm/mmHg); however, there was no significant difference between the SLBNP conditions. The Gain-HR/Z0 in C-SLBNP (9.37 +/- 1.47 bpm/ohm) was smaller than that of the other conditions [18.46 +/- 2.45 bpm/ohm (O-SLBNP); 16.09 +/- 2.29 bpm/ohm (S-SLBNP)]. DISCUSSION: Using S SLBNP could reduce the measurement time needed to examine the arterial baroreflex. However, the cardiopulmonary baroreflex was modified by the static load of SLBNP.Ishibashi K, Oyama F, Yoshida H, Iwanaga K. Additive effects of sinusoidal lower body negative pressure on cardiovascular responses. Aerosp Med Hum Perform. 2017; 88(2):137-141. PMID- 28095959 TI - General Aviation Pilots Over 70 Years Old. AB - BACKGROUND: Currently it is not unusual for general aviation pilots in the United States to continue to fly beyond the age of 70, even into their 80s and 90s. Pilots have regular examinations according to protocols which do not specify special or additional requirements for pilots over 70 yr of age. Additionally, the third class medical reforms passed by the U.S. Senate on 15 July 2016 could potentially result in even less stringent medical certification requirements for general aviation pilots. METHODS: Accident rates, medical parameters, autopsy findings, and toxicological findings from the U.S. National Transportation Safety Board (NTSB) general aviation (GA) accident database were analyzed to assess potential risk factors with accident outcomes. RESULTS: During 2003-2012, there were 114 (113 men, 1 woman) general aviation fatal accidents involving pilots ages 70 to 92 yr. A combination of 3 or more drugs were found in 13 (13%) of deceased pilots. The most frequent drugs were first generation antihistamines and antidepressants represented the next highest proportion of possible performance affecting medications. CONCLUSION: This study indicates that there are critical medical factors that may contribute to fatal accidents among elderly pilots. Polypharmacy use should be taken into consideration, especially during periodic health examinations and fatal aviation investigations involving elderly pilots.Vuorio A, Asmayawati S, Budowle B, Griffiths R, Strandberg T, Kuoppala J, Sajantila A. General aviation pilots over 70 years old. Aerosp Med Hum Perform. 2017; 88(2):142-145. PMID- 28095960 TI - Medical Reasons for Loss of License in Norwegian Professional Pilots. AB - BACKGROUND: The aim of this study was to quantify causes of medical disqualification (groundings) of Norwegian commercial pilots for the period 2006 2010, and to compare our findings with former Norwegian studies on the subject to reveal possible changes in the disease spectrum over the last decades. We compared our data with previous studies for the periods 1982-1997 and 1997-2001, respectively. METHODS: The material was collected from the aeromedical section's archive. Files on all grounded pilots have been reviewed and classified by age group and diagnosis and grounding rates have been calculated. RESULTS: From the study population comprising 12,552 pilot-years for the years 2006-2010 inclusive, 85 pilots were permanently grounded, i.e., an average grounding rate of 6.8 per 1000 pilot-years. DISCUSSION: Compared with previous data there is a significant decrease in the disqualification rate due to cardiovascular conditions, while the disqualification rates due to ear, nose, and throat conditions and neurological conditions have both increased significantly.Hova JK, Thorheim L, Wagstaff AS. Medical reasons for loss of license in Norwegian professional pilots. Aerosp Med Hum Perform. 2017; 88(2):146-149. PMID- 28095961 TI - You're the Flight Surgeon. AB - Kahl CG. You're the flight surgeon: immunoglobulin A nephropathy. Aerosp Med Hum Perform. 2017; 88(2):150-153. PMID- 28095962 TI - Interview with Dr. Arnold S. Barer, a Soviet Space Medicine Pioneer. PMID- 28095964 TI - F-Wave Duration as a Specific and Sensitive Tool for the Diagnosis of Restless Legs Syndrome/Willis-Ekbom Disease. AB - STUDY OBJECTIVES: Restless legs syndrome, also known as Willis-Ekbom disease (RLS/WED), is a frequent condition, though its pathophysiology is not completely understood. The diagnosis of RLS/WED relies on clinical criteria, and the only instrumental tool, the suggested immobilization test, may lead to equivocal results. Recently, neurophysiological parameters related to F-wave duration have been proposed as a diagnostic aid. The aim of this study is to assess and compare the diagnostic values of these parameters in diagnosis of RLS/WED. METHODS: Fifteen women affected by primary RLS/WED and 17 age- and sex- matched healthy subjects. A complete electroneurographic evaluation, including nerve conduction studies (NCS), cutaneous silent period (CSP), and F-wave parameters, namely amplitude, F-wave duration (FWD), and the ratio between FWD and duration of the corresponding compound muscle action potential (FWD/CMAPD). RESULTS: No subject showed alterations of the NCS. However, FWD and FWD/CMAPD of both upper and lower limbs were significantly longer in patients than controls. Tibial FWD/CMAPD best discriminated RLS/WED patients from controls. A cutoff of 2.06 yielded a sensitivity of 69.2%, a specificity of 94.1%, a positive predictive power of 90%, and a negative predictive power of 80% (area under the curve = 0.817; 95% confidence interval = 0.674-0.959). The combination of ulnar or tibial FWD/CMAPD increases the sensitivity (85.7%) while slightly decreasing the specificity (87.5%, positive predictive value: 85.7%, negative predictive value: 87.5%). CONCLUSIONS: Lower limb FWD/CMAPD ratio may represent a supportive diagnostic tool, especially in cases of evening lower leg discomfort of unclear interpretation. PMID- 28095966 TI - Potential Underestimation of Sleep Apnea Severity by At-Home Kits: Rescoring In Laboratory Polysomnography Without Sleep Staging. AB - STUDY OBJECTIVES: Home sleep apnea testing (HSAT) is increasingly available for diagnosing obstructive sleep apnea (OSA). One key limitation of most HSAT involves the lack of sleep staging, such that the respiratory event index is calculated using the total recording time (TRT) rather than total sleep time (TST). METHODS: We performed a retrospective analysis of n = 838 diagnostic polysomnography (PSG) nights from our center; n = 444 with OSA (4% rule, apneahypopnea index (AHI) >= 5), and n = 394 with AHI < 5. We recalculated the AHI using time in bed (TIB) instead of TST, to assess the predicted underestimation risk of OSA severity. RESULTS: Of all the patients with OSA, 26.4% would be reclassified as having less severe or no OSA after recalculating the AHI using TIB rather than TST. Of the n = 275 with mild OSA, 18.5% would be reclassified as not having OSA. The risk of underestimation was higher in those with moderate or severe OSA. Of the n = 119 moderate OSA cases, 40.3% would be reclassified as mild, and of the n = 50 severe OSA cases, 36.0% would be reclassified as moderate. Age strongly correlated with the degree of underestimation of the AHI, because age was significantly correlated with time awake during PSG. CONCLUSIONS: The risk of sleep apnea underestimation is predicted to be substantial in a tertiary sleep center population. Phenotyping errors included risk of falsely negative results (from mild to normal), as well as category errors: moderate or severe moving to mild or moderate severity, respectively. Clinicians should recognize this underestimation limitation, which directly affects diagnostic phenotyping and thus therapeutic decisions. COMMENTARY: A commentary on this article appears in this issue on page 531. PMID- 28095965 TI - VAMONOS (Veterans Affairs' Metabolism, Obstructed and Non-Obstructed Sleep) Study: Effects of CPAP Therapy on Glucose Metabolism in Patients with Obstructive Sleep Apnea. AB - STUDY OBJECTIVES: Obstructive sleep apnea (OSA) and type 2 diabetes mellitus (T2DM) are prevalent disorders that pose increased risk of cardiovascular disease and death. The objective of this study was to clarify if continuous positive airway pressure (CPAP) therapy for OSA affects T2DM control and emergence. METHODS: Point-of-care, comparative effectiveness study; cross-sectional and longitudinal analyses. RESULTS: Our cohort included 928 consecutive patients; 13% were women; 36% were Caucasians and 61% African-Americans. OSA was diagnosed in approximately 738 patients and CPAP was initiated in 718 patients; median duration of therapy was 5 mo (25% to 75% interquartile range [IQR] 3-14). Patients with OSA used CPAP therapy for a median duration of 4.8 h, 34.5% of the nights. Adherence to CPAP was prespecified as follows: good (>= 70% nights and >= 4 h/night), excellent (>= 80% nights and >= 6 h/night) or outstanding (>= 90% of nights and 8 h/night). Based on objective data, good, excellent, and outstanding compliance were found in only 30%, 20%, and 6%, respectively. Three percent of subjects without CPAP follow-up and less than 4% of those nonadherent to CPAP therapy (based on the established criteria) developed incident T2DM. Incident T2DM developed in only 0.8% of those with good compliance and in none (0%) of those in the excellent and outstanding groups. During follow-up, median weight change was +0.3 kg (IQR -1.8 to 2.7). CONCLUSIONS: We found that an outstanding compliance to CPAP reduced fasting blood glucose in patients with OSA. Longitudinally, higher levels of therapeutic adherence may affect the rate of incident impaired fasting glucose, prediabetes, and T2DM, despite the observed weight gains. COMMENTARY: A commentary on this article appears in this issue on page 365. PMID- 28095968 TI - Catathrenia (Nocturnal Groaning): A Social Media Survey and State-of-the-Art Review. AB - STUDY OBJECTIVES: Catathrenia is an underrecognized nocturnal vocalization phenomenon that can be a source of perplexity to patients, bed partners, and medical providers. Catathrenia is distinct from both sleep talking (a parasomnia with loud talking during sleep) and snoring (noise due to vibration of upper airway soft tissues related to variations in airway resistance). The objective of this review is to provide an evidence-based resource to help the practitioner reliably evaluate and manage patients with this condition. METHODS: Data were gathered from: (1) PubMed, Scopus, Web of Science, and Google Scholar; and (2) catathrenia social media groups (Yahoo and Facebook). RESULTS: Data collected were (1) 15 case reports and 17 case series describing 191 patients with catathrenia; (2) questionnaires from 47 catathrenia subjects; (3) 5 audio files. CONCLUSIONS: Catathrenia is a noise produced during sleep (distinct from snoring) with identifiable harmonics, a computable main frequency, and high-decibel intensity that involves active adduction and vibration of the vocal cords during expiration. The quality of groaning in catathrenia is monotone, and often presents with a morose or sexual connotation, causing a significant social problem for patients. Although there is no association with risk of physical harm, catathrenia does present a significant disturbance to the bed partner and has been associated with subjective impairments to sleep quality, including unrefreshing sleep and fatigue. Polysomnography can be useful if performed properly to confirm the diagnosis and to evaluate for comorbid sleep disturbances, such as obstructive sleep apnea or parasomnia. Directions for further research could involve consideration of deep breathing exercises, yoga, meditation, or myofunctional therapy to help abate symptoms. PMID- 28095967 TI - Intravenous Immunoglobulin Therapy in Pediatric Narcolepsy: A Nonrandomized, Open Label, Controlled, Longitudinal Observational Study. AB - STUDY OBJECTIVES: Previous case reports of intravenous immunoglobulins (IVIg) in pediatric narcolepsy have shown contradictory results. METHODS: This was a nonrandomized, open-label, controlled, longitudinal observational study of IVIg use in pediatric narcolepsy with retrospective data collection from medical files obtained from a single pediatric national reference center for the treatment of narcolepsy in France. Of 56 consecutively referred patients with narcolepsy, 24 received IVIg (3 infusions administered at 1-mo intervals) in addition to standard care (psychostimulants and/or anticataplectic agents), and 32 continued on standard care alone (controls). RESULTS: For two patients in each group, medical files were unavailable. Of the 22 IVIg patients, all had cerebrospinal fluid (CSF) hypocretin <= 110 pg/mL and were HLA-DQB1*06:02 positive. Of the 30 control patients, 29 were HLA-DQB1*06:02 positive and of those with available CSF measurements, all 12 had hypocretin <= 110 pg/mL. Compared with control patients, IVIg patients had shorter disease duration, shorter latency to sleep onset, and more had received H1N1 vaccination. Mean (standard deviation) follow-up length was 2.4 (1.1) y in the IVIg group and 3.9 (1.7) y in controls. In multivariate adjusted linear mixed-effects analyses of change from baseline in Ullanlinna Narcolepsy Scale (UNS) scores, high baseline UNS, but not IVIg treatment, was associated with a reduction in narcolepsy symptoms. On time-to-event analysis, among patients with high baseline UNS scores, control patients achieved a UNS score < 14 (indicating remission) less rapidly than IVIg patients (adjusted hazard ratio 0.18; 95% confidence interval: 95% confidence interval: 0.03, 0.95; p = 0.043). Shorter or longer disease duration did not influence treatment response in any analysis. CONCLUSIONS: Overall, narcolepsy symptoms were not significantly reduced by IVIg. However, in patients with high baseline symptoms, a subset of IVIg-treated patients achieved remission more rapidly than control patients. COMMENTARY: A commentary on this article appears in this issue on page 363. PMID- 28095969 TI - Body Fat Distribution Ratios and Obstructive Sleep Apnea Severity in Youth With Obesity. AB - STUDY OBJECTIVES: Obesity and regional fat distribution, measured by neck fat mass percentage using dual-energy X-ray absorptiometry (DXA), correlate with obstructive sleep apnea (OSA) severity in adults. In obese children, neck-to waist-circumference ratio predicts OSA. This study examined associations between body fat percentage and distribution and sleep-disordered breathing (SDB) severity in obese youth, measured with DXA. METHODS: Cross-sectional retrospective study conducted at a tertiary children's hospital. Participants were aged 6 to 18 years with obesity (body mass index [BMI] > 99th percentile [BMI z-score 2.35] or > 95th percentile with comorbidity). They underwent polysomnography and DXA to quantify body fat percentage and distribution ratios (neck-to-abdominal fat percentage [NAF % ratio]). SDB was defined as apnea hypopnea index (AHI) > 5 and OSA as obstructive AHI (OAHI) > 1 event/h. Relationships of BMI z-score and NAF % ratio to log AHI and log OAHI were evaluated. RESULTS: Thirty individuals participated; 18 male; median age 14.1 years. Twenty-four individuals had BMI z-scores > 2.35. Ten had AHI > 5 events/h. NAF % ratio was significantly associated with log AHI in males and with log OAHI in all, whereas total fat mass percent was not. The association between log OAHI and NAF % ratio was significant in males, but not females. NAF % ratio was significantly associated with log OAHI in those with BMI z-score above 2.35. CONCLUSIONS: NAF % ratio was associated with OSA severity in males and youth with BMI > 99th percentile; however, total fat mass percentage was not, suggesting that body fat distribution is associated with OSA risk in youth. PMID- 28095970 TI - Cyclic Alternating Pattern Associated with Catathrenia and Bruxism in a 10-Year Old Patient. AB - ABSTRACT: Cyclic alternating pattern (CAP) is widely recognized as an expression of sleep instability in electroencephalogram activity during non-rapid eye movement sleep. We report a case with sequences of CAP followed by bruxism and catathrenia in a 10-y-old male patient with a diagnosis of attention deficit hyperactivity disorder in treatment with methylphenidate. We found CAP in 83.1% of all episodes of catathrenia, and the CAP rate was 12.8%. We propose to consider catathrenia as one of the sleep disorders that may be accompanied by CAP. PMID- 28095971 TI - Associations of Undiagnosed Obstructive Sleep Apnea and Excessive Daytime Sleepiness With Depression: An Australian Population Study. AB - STUDY OBJECTIVES: To determine whether undiagnosed obstructive sleep apnea (OSA) and/or excessive daytime sleepiness are associated with symptomatic depression in Australian men. METHODS: Participants were randomly selected, urban community dwelling men aged 40 to 88 years without a prior diagnosis of OSA. Clinically significant depressive symptoms were assessed using the Beck Depression Inventory 1A or Centre for Epidemiological Studies Depression Scale (2007-2010). A random sample of men (n = 788) undertook full at-home unattended polysomnography (Embletta X100, Broomfield, Colorado, United States) and completed the Epworth Sleepiness Scale questionnaire (2010-2012). RESULTS: Undiagnosed severe obstructive sleep apnea (apnea-hypopnea index >= 30 events/h) was associated with depressive symptoms (adjusted odds ratio = 1.98; 95% confidence interval [CI] 1.05-3.73; P = .036). However, a significant interaction was observed between obstructive sleep apnea and excessive daytime sleepiness (P = .03) such that individuals with OSA and excessive daytime sleepiness (Epworth Sleepiness Scale score of 10 or higher) exhibited the strongest associations with depression (mild moderate apnea: adjusted odd ratio = 3.86; 95% CI 1.87-7.95; severe apnea: adjusted odd ratio = 4.82; 95% CI 1.42-16.35) when compared to individuals without apnea. CONCLUSIONS: Depressive symptoms in men were associated with undiagnosed OSA in the community. It is important that clinicians and primary care practitioners consider screening for depression in men with severe OSA and for OSA in men with depression. Screening for depression should also be considered in men with excessive daytime sleepiness regardless of OSA severity. PMID- 28095974 TI - Urgent Need to Improve PAP Management: The Devil Is in Two (Fixable) Details. PMID- 28095973 TI - Impact of Obstructive Sleep Apnea and Its Treatments on Partners: A Literature Review. AB - STUDY OBJECTIVES: Many adults sleep with a significant other; thus, sleep disorder symptoms and treatments of one partner are likely to impact the other partner's health. A literature review was conducted to examine the impact of obstructive sleep apnea (OSA) and OSA treatments on partner-assessed sleep and daytime functioning and partner involvement in OSA treatment. METHODS: MEDLINE, EMBASE, and CINAHL searches yielded 38 pertinent quantitative and qualitative studies that described sleep and/or daytime functioning assessed in partners of patients with untreated OSA, sleep and/or daytime functioning assessed in partners who were referred for OSA treatment, including continuous positive airway pressure (CPAP) therapy, oral appliance (OA), or surgery, and/or associations between partner involvement and OSA treatment use. RESULTS: The majority of studies found untreated OSA to have a negative impact on partners' objective and subjective sleep and daytime functioning, in particular mood, quality of life, and relationship quality. Improvements in partner-assessed sleep quality were reported for CPAP, OA, and surgery. Conflicting results were reported for partners' mood, quality of life, daytime sleepiness, and relationship quality. Perceived partner support was associated with greater CPAP use. CONCLUSIONS: Symptoms associated with OSA can negatively impact partners' sleep and daytime functioning. Treatment of OSA with CPAP, OA, or surgery can have health benefits for not only patients but also partners. Collaborative partner involvement may be a useful strategy for interventions promoting CPAP adherence. PMID- 28095972 TI - Sex-Specific Difference in the Association Between Poor Sleep Quality and Abdominal Obesity in Rural Chinese: A Large Population-Based Study. AB - STUDY OBJECTIVES: Existing studies on sleep quality and associated obesity are inconsistent, and few studies have prospectively evaluated the association between sleep quality and abdominal obesity among Chinese individuals. To fill this void, the current study aimed to assess the association between sleep quality and abdominal obesity in a rural Chinese population. METHODS: A representative sample of 9,404 adults aged 20-93 years in northeastern China was selected between 2012 and 2013 by a multistage cluster and random sampling method. Sleep quality was evaluated by the Pittsburgh Sleep Quality Index (PSQI), where a score of 6 or higher indicated sleep disorder. Abdominal obesity was measured by waist circumference (WC), with abdominal obesity defined as WC > 90 cm for men and WC > 80 cm for women. RESULTS: Male participants with abdominal obesity had higher global PSQI scores in addition to higher subscores in almost all of the elements compared to normal values. The odds ratios of abdominal obesity among participants with sleep disorders were 1.64 (95% confidence interval [CI]: 1.39-1.95) and 1.14 (95% CI: 0.98-1.32) for males and females compared to the reference group. The risk in all sleep elements was significantly increased, with odds ratios ranging from 1.28 (95% CI: 1.08-1.51) to 5.81 (95% CI: 3.54-9.53) for males. The risk only in four elements was significantly increased, from 1.28 (95% CI: 1.12-1.47) to 2.27 (95% CI: 1.36-3.80) for females. CONCLUSIONS: Poor sleep quality was associated with abdominal obesity in Chinese. Furthermore, effects in males were larger than those in females. PMID- 28095975 TI - Sleep-Related Abnormal Sexual Behaviors (Sexsomnia) Successfully Treated With a Mandibular Advancement Device: A Case Report. AB - ABSTRACT: Sleep-related abnormal sexual behaviors (sexsomnia) are classified as a subtype of non-rapid eye movement sleep parasomnias. There are reported cases of control of sexsomnia with treatment of obstructive sleep apnea (OSA) with continuous positive airway pressure. We present a case of sexsomnia controlled with the treatment of OSA with a mandibular advancement device. PMID- 28095976 TI - Payer Perspective of the American Academy of Sleep Medicine Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia. PMID- 28095977 TI - Multidisciplinary Alternatives to CPAP Program for CPAP-Intolerant Patients. AB - ABSTRACT: Continuous positive airway pressure (CPAP) intolerance remains a persistent problem for many obstructive sleep apnea patients. Clinicians and researchers continue to search for other effective treatment modalities given the well-documented sequelae associated with untreated obstructive sleep apnea. A multidisciplinary "Alternatives to CPAP program" (ALT) can facilitate systematic evaluation of non-CPAP therapies appropriate for an individual patient. We review successful strategies and barriers encountered during implementation of an ALT at our institution. Creation of similar programs in private practice and academic settings can help medical, dental, and surgical sleep medicine specialists coordinate evaluation and treatment of CPAP-intolerant patients. PMID- 28095978 TI - Poor Quality Control of Over-the-Counter Melatonin: What They Say Is Often Not What You Get. PMID- 28095979 TI - A Step in the Right Direction: Moving Toward Increased Access to Insomnia Care. PMID- 28095980 TI - A Potential Alternative to Respiratory Inductance Plethysmography for Children? PMID- 28095981 TI - Man Versus Machine. PMID- 28095982 TI - What is the optimal radiotherapy schedule for limited stage small cell lung cancer? AB - Thoracic radiotherapy plays an important role in the treatment of limited disease SCLC. Best results are obtained with twice daily (BID) radiotherapy, starting early and given concurrently with chemotherapy. At ASCO, 2016, Faivre-Finn and colleagues presented the results of the CONVERT trial, comparing such a scheme with once daily radiotherapy to a higher dose. There was no statistically significant difference in survival between the two arms. Although the publication of the study is still awaited, this editorial puts the available data in perspective and draws some important conclusions. PMID- 28095983 TI - Application of close-packed structures in dental resin composites. AB - OBJECTIVE: The inorganic filler particles in dental resin composites serve to improve their mechanical properties and reduce polymerization shrinkage during their use. Efforts have been made in academia and industry to increase the filler particle content, but, few studies examine the theoretical basis for the maximum particle loading. METHODS: This work evaluates the packing of spherical particles in a close-packed state for highly loaded composites. RESULTS: Calculations show that for low dispersity particles, the maximum amount of particles is 74.05vol%, regardless of the particle size. This can be further improved by using a mix of large and small particles or by the use of non-spherical particles. For representative spherical particles with a diameter of 1000nm, two types of secondary particles with respective sizes of 414nm (dI) and 225nm (dII) are selected. The results show that after embedding secondary particles I & II into primary spherical particles, the packing factor is increased to 81.19% for the close-packed structures, which shows an improvement of 9.64%, compared to the 74.05% obtained only with primary spherical particles. This packing factor is also higher than either structure with the embedded secondary particles I or II. SIGNIFICANCE: Examples of these mixtures with different spherical particle sizes are shown as a theoretical estimation, serving as a guideline for the design and formulation of new dental resin composites with better properties and improved performance. PMID- 28095984 TI - Post-extubation stridor in the trauma ICU: Still a problem overly complex. PMID- 28095985 TI - Open preperitoneal groin hernia repair with mesh: A qualitative systematic review. AB - BACKGROUND: For the repair of inguinal hernias, several surgical methods have been presented where the purpose is to place a mesh in the preperitoneal plane through an open access. The aim of this systematic review was to describe preperitoneal repairs with emphasis on the technique. DATA SOURCES: A systematic review was conducted and reported according to the PRISMA statement. PubMed, Cochrane library and Embase were searched systematically. Studies were included if they provided clinical data with more than 30 days follow up following repair of an inguinal hernia with an open preperitoneal mesh technique. CONCLUSIONS: A total of 67 articles were included, describing nine different methods: Kugel, TREPP, TIPP, Onstep, Horton/Florence, Nyhus, Ugahary, Read, and Stoppa. In general, results regarding pain, recurrences and complications seem promising. It was not possible to conduct a meta-analysis. Open preperitoneal techniques with placement of a mesh through an open approach seem promising compared with the standard anterior techniques. This systematic review provides an overview of these techniques together with a description of surgical methods and clinical outcomes. PMID- 28095986 TI - Erratum to "Effects of Eph-ephrin mutations on pre-pulse inhibition in mice" [Physiology & Behavior 135, (2014) 232-236]. PMID- 28095987 TI - An anatomic risk model to screen post endovascular aneurysm repair patients for aneurysm sac enlargement. AB - BACKGROUND: Follow-up computed tomography angiography (CTA) scans add considerable postimplantation costs to endovascular aneurysm repairs (EVARs) of abdominal aortic aneurysms (AAAs). By building a risk model, we hope to identify patients at low risk for aneurysm sac enlargement to minimize unnecessary CTAs. METHODS: 895 consecutive patients who underwent EVAR for AAA were reviewed, of which 556 met inclusion criteria. A Probit model was created for aneurysm sac enlargement, with preoperative aneurysm morphology, patient demographics, and operative details as variables. RESULTS: Our final model included 287 patients and had a sensitivity of 100%, a specificity of 68.9%, and an accuracy of 70.4%. Ninety-nine (35%) of patients were assigned to the high-risk group, whereas 188 (65%) of patients were assigned to the low-risk group. Notably, regarding anatomic variables, our model reported that age, pulmonary comorbidities, aortic neck diameter, iliac artery length, and aneurysms were independent predictors of post-EVAR sac enlargement. With the exception of age, all statistically significant variables were qualitatively supported by prior literature. With regards to secondary outcomes, the high-risk group had significantly higher proportions of AAA-related deaths (5.1% versus 1.1%, P = 0.037) and Type 1 endoleaks (9.1% versus 3.2%, P = 0.033). CONCLUSIONS: Our model is a decent predictor of patients at low risk for post AAA EVAR aneurysm sac enlargement and associated complications. With additional validation and refinement, it could be applied to practices to cut down on the overall need for postimplantation CTA. PMID- 28095988 TI - Modern History of Medical Cannabis: From Widespread Use to Prohibitionism and Back. PMID- 28095989 TI - Prolonged K+ deficiency increases intracellular ATP, cell cycle arrest and cell death in renal tubular cells. AB - BACKGROUND: Chronic potassium (K+) deficiency can cause renal damage namely hypokalemic nephropathy with unclear pathogenic mechanisms. In the present study, we investigated expression and functional alterations in renal tubular cells induced by prolonged K+ deficiency. METHODS: MDCK cells were maintained in normal K+ (CNK) (K+=5.3mmol/L), low-K+ (CLK) (K+=2.5mmol/L), or K+-depleted (CKD) (K+=0mmol/L) medium for 10days (n=5 independent cultures/condition). Differentially expressed proteins were identified by a proteomics approach followed by various functional assays. RESULTS: Proteomic analysis revealed 46 proteins whose levels significantly differed among groups. The proteomic data were confirmed by Western blotting. Gene Ontology (GO) classification and protein network analysis revealed that majority of the altered proteins participated in metabolic process, whereas the rest involved in cellular component organization/biogenesis, cellular process (e.g., cell cycle, regulation of cell death), response to stress, and signal transduction. Interestingly, ATP measurement revealed that intracellular ATP production was increased in CLK and maximum in CKD. Flow cytometry showed cell cycle arrest at S-phase and G2/M-phase in CLK and CKD, respectively, consistent with cell proliferation and growth assays, which showed modest and marked degrees of delayed growth and prolonged doubling time in CLK and CKD, respectively. Cell death quantification also revealed modest and marked degrees of increased cell death in CLK and CKD, respectively. CONCLUSIONS: In conclusion, prolonged K+ deficiency increased intracellular ATP, cell cycle arrest and cell death in renal tubular cells, which might be responsible for mechanisms underlying the development of hypokalemic nephropathy. PMID- 28095990 TI - Treatment options to prevent diabetes in subjects with prediabetes: Efficacy, cost effectiveness and future outlook. PMID- 28095991 TI - Assessing environmental impacts of genetically modified plants on non-target organisms: The relevance of in planta studies. AB - In legal frameworks worldwide, genetically modified plants (GMPs) are subjected to pre-market environmental risk assessment (ERA) with the aim of identifying potential effects on the environment. In the European Union, the EFSA Guidance Document introduces the rationale that GMPs, as well as their newly produced metabolites, represent the potential stressor to be evaluated during ERA. As a consequence, during several phases of ERA for cultivation purposes, it is considered necessary to use whole plants or plant parts in experimental protocols. The importance of in planta studies as a strategy to address impacts of GMPs on non-target organisms is demonstrated, to evaluate both effects due to the intended modification in plant phenotype (e.g. expression of Cry proteins) and effects due to unintended modifications in plant phenotype resulting from the transformation process (e.g. due to somaclonal variations or pleiotropic effects). In planta tests are also necessary for GMPs in which newly expressed metabolites cannot easily be studied in vitro. This paper reviews the scientific literature supporting the choice of in planta studies as a fundamental tool in ERA of GMPs in cultivation dossiers; the evidence indicates they can realistically mimic the ecological relationships occurring in their receiving environments and provide important insights into the biology and sustainable management of GMPs. PMID- 28095992 TI - Changes in ecosystem carbon pool and soil CO2 flux following post-mine reclamation in dry tropical environment, India. AB - Open strip mining of coal results in loss of natural carbon (C) sink and increased emission of CO2 into the atmosphere. A field study was carried out at five revegetated coal mine lands (7, 8, 9, 10 and 11years) to assess the impact of the reclamation on soil properties, accretion of soil organic C (SOC) and nitrogen (N) stock, changes in ecosystem C pool and soil CO2 flux. We estimated the presence of C in the tree biomass, soils, litter and microbial biomass to determine the total C sequestration potential of the post mining reclaimed land. To determine the C sequestration of the reclaimed ecosystem, soil CO2 flux was measured along with the CO2 sequestration. Reclaimed mine soil (RMS) fertility increased along the age of reclamation and decreases with the soil depths that may be attributed to the change in mine soils characteristics and plant growth. After 7 to 11years of reclamation, SOC and N stocks increased two times. SOC sequestration (1.71MgCha-1year-1) and total ecosystem C pool (3.72MgCha-1year-1) increased with the age of reclamation (CO2 equivalent: 13.63MgCO2ha-1year-1). After 11years of reclamation, soil CO2 flux (2.36+/-0.95MUmolm-2s-1) was found four times higher than the natural forest soils (Shorea robusta Gaertn. F). The study shows that reclaimed mine land can act as a source/sink of CO2 in the terrestrial ecosystem and plays an important role to offset increased emission of CO2 in the atmosphere. PMID- 28095993 TI - Evaluation of the short-term fate and transport of chemicals of emerging concern during soil-aquifer treatment using select transformation products as intrinsic redox-sensitive tracers. AB - In this study, known products from oxic transformation of the X-ray contrast medium iopromide were introduced for the first time as intrinsic tracer for in situ characterization of the transition zone between oxic and suboxic conditions during the initial phase of soil-aquifer treatment (SAT). Two wet-dry cycles of a full-scale infiltration basin were monitored to characterize hydraulic retention times, redox conditions, removal of bulk organic parameters and the fate of chemicals of emerging concern (CECs). Tracer tests at the site showed an average hydraulic retention time of <20h before collection in drainage pipes located approximately 1.5m below surface. Dissolved oxygen at different depth rapidly depleted and only increased towards the end of the flooding event. Transformation of iopromide and all known intermediates to persistent transformation products (TPs) usually occurring during oxic biodegradation was very limited in samples from suction cups immediately underneath the basin. But transformation was complete in samples collected from the drainage outlet indicating that dissolved oxygen had been introduced to the system before sample collection in the combined drainage outlet. Similar to iopromide and its TPs, removal of several CECs (diclofenac, bezafibrate, mecoprop, TCEP) was inefficient after 90cm infiltration (<35%) but significantly enhanced in the combined drainage outlet (>80%). These results highlight that the analysis of iopromide along with its intermediates and persistent TPs can serve as a promising probing tool to determine overall efficiency of CEC biodegradation and to identify potential in situ oxygen limitations. PMID- 28095994 TI - Outcome of early stage cervical cancer patients treated according to a radiosurgical approach: Clinical results and prognostic factors. AB - OBJECTIVE: To report clinical results of a multimodal strategy based on preoperative brachytherapy followed with surgery in early stage cervical cancer. MATERIALS/METHODS: The outcome of consecutive patients receiving brachytherapy in our Institution for an early stage IB1-IIA1 invasive cervical cancer with risk factors (lymphovascular embols and/or tumor >2cm) between 2000 and 2013 was analyzed. The treatment consisted of preoperative low dose or pulse dose-rate utero-vaginal brachytherapy followed, 6-8weeks later, by a radical hysterectomy/bilateral salpingo-oophorectomy plus pelvic+/-para-aortic lymph node dissection. A postoperative chemoradiation was delivered in patients with histological evidence of lymph nodes metastases. RESULTS: 182 patients were identified. Histological examination of hysterectomy specimen showed the presence of a tumor residuum in 55 patients (30.2%). One patient (0.5%) had residual tumor cells in the parametria. With a median follow-up of 5.3years, 14 patients (7.7%) presented tumor relapse, including three (1.6%) local relapses. Five-year disease free survival (DFS) rate was 93.6% (95%CI: 91.6-95.6%). In log-rank analysis, presence of pelvic nodal metastases at time of lymphadenectomy (p=0.001) and tumor size >=3cm (p=0.003) correlated with a poorer DFS. Presence of a tumor residuum on hysterectomy specimen correlated with a higher risk of pelvic or para aortic failure (p=0.035). A time interval>10weeks between brachytherapy and surgery correlated with a higher risk of failure outside the pelvis (p=0.003). Significant postoperative complications were reported in 16 patients (8.8%). All delayed toxicities were mild to moderate. CONCLUSIONS: A preoperative brachytherapy is a safe and effective option in early stage cervical cancer. PMID- 28095995 TI - Pelvic floor reconstruction by modified rectus abdominis myoperitoneal (MRAM) flap after pelvic exenterations. AB - OBJECTIVE: To describe the technique and report experiences with pelvic floor reconstruction by modified rectus abdominis myoperitoneal (MRAM) flap after extensive pelvic procedures. METHODS: Surgical technique of MRAM harvest and transposition is carefully described. The patients in whom pelvic floor reconstruction with MRAM after either infralevator pelvic exenteration and/or extended lateral pelvic sidewall excision was carried out were enrolled into the study (MRAM group, n=16). Surgical data, post-operative morbidity, and disease status were retrospectively assessed. The results were compared with a historical cohort of patients, in whom an exenterative procedure without pelvic floor reconstruction was performed at the same institution (control group, n=24). RESULTS: Both groups were balanced in age, BMI, tumor types, and previous treatment. Substantially less patients from the MRAM group required reoperation within 60days of the surgery (25% vs. 50%) which was due to much lower rate of complications potentially related to empty pelvis syndrome (1 vs. 7 reoperations) (p=0.114). Late post-operative complication rate was substantially lower in the MRAM group (any grade: 79% vs. 44%; grade>=3: 37% vs. 6%) (p=0.041). The performance status 6months after the surgery was <=1 in the majority of patients in MRAM (81%) while in only 38% of patients from the control group (p=0.027). There was one incisional hernia in MRAM group while three cases were reported in the controls. CONCLUSIONS: Pelvic floor reconstruction by MRAM in patients after pelvic exenterative procedures is associated with a substantial decrease in postoperative complications that are potentially related to empty pelvis syndrome. PMID- 28095996 TI - Antenatal predictors of outcome in prenatally diagnosed congenital diaphragmatic hernia (CDH). AB - BACKGROUND: Pulmonary hypoplasia is the main cause of mortality in isolated congenital diaphragmatic hernia (CDH) and its prediction is paramount when counseling parents. We sought to identify antenatal parameters that predicted neonatal mortality in CDH. METHOD: Search was conducted in MEDLINE, EMBASE, Cochrane Database of Systematic reviews, PubMed, Scopus, and Web of Science on the ability of lung-to-head ratio (LHR), observed-to-expected LHR (o/e LHR), total fetal lung volume (TFLV), o/e TFLV, percentage predicted lung volume (PPLV) and degree of liver herniation to predict neonatal morbidity and mortality in fetuses with CDH. Primary outcome was perinatal survival and secondary was the use of extracorporeal membrane oxygenation (ECMO). RESULTS: Until April 2016, 1067 articles were found, of which 22 were included in our meta-analysis. This showed that the odds of survival with LHR <1.0 and liver herniation on ultrasound were 0.14 (CI 0.10-0.27) and 0.21 (CI 0.13-0.35) respectively. Mean LHR, o/e LHR, absolute TFLV, o/e TFLV, PPLV and liver herniation all predicted survival, however o/e LHR and o/e TFLV performed best in this prediction. When the longest diameter measurement method was used, the o/e TFLV (summary area under curve (AUC) 0.8) was slightly superior to o/e LHR (summary AUC 0.78). This difference disappeared when LHR was measured by the trace method. The most discriminatory threshold for O/E LHR and O/E TFLV was 25%. LHR <1 was predictive of extracorporeal life support (ECLS) use. CONCLUSION: O/E LHR, o/e TFLV (thresholds of 25%) and liver herniation are good predictors of mortality in CDH. LEVEL OF EVIDENCE: Level II Type of study: Systematic review and meta-analysis. PMID- 28095997 TI - Abnormal prefrontal and parietal activity linked to deficient active binding in working memory in schizophrenia. AB - Working memory deficits have been widely reported in schizophrenia, and may result from inefficient binding processes. These processes, and their neural correlates, remain understudied in schizophrenia. Thus, we designed an FMRI study aimed at investigating the neural correlates of both passive and active binding in working memory in schizophrenia. Nineteen patients with schizophrenia and 23 matched controls were recruited to perform a working memory binding task, in which they were instructed to memorize three letters and three spatial locations. In the passive binding condition, letters and spatial locations were directly presented as bound. Conversely, in the active binding condition, words and spatial locations were presented as separated, and participants were instructed to intentionally create associations between them. Patients exhibited a similar performance to the controls for the passive binding condition, but a significantly lower performance for the active binding. FMRI analyses revealed that this active binding deficit was related to aberrant activity in the posterior parietal cortex and the ventrolateral prefrontal cortex. This study provides initial evidence of a specific deficit for actively binding information in schizophrenia, which is linked to dysfunctions in the neural networks underlying attention, manipulation of information, and encoding strategies. Together, our results suggest that all these dysfunctions may be targets for neuromodulation interventions known to improve cognitive deficits in schizophrenia. PMID- 28095998 TI - The feasibility and clinical benefits of improving facial affect recognition impairments in schizophrenia: Systematic review and meta-analysis. AB - BACKGROUND: People diagnosed with schizophrenia have significant difficulty accurately recognising emotions expressed by others. This may generate anomalous experiences which, if misinterpreted, could contribute to experiences of social defeat, psychotic symptoms and reduced social functioning. It remains unclear whether this impairment is responsive to non-pharmacological intervention, or what the effect of modifying it is. METHODS: We did a systematic review and meta analysis to examine whether and to what extent facial affect recognition impairments can be improved by psychological intervention and, if so, whether this leads to improvements in psychotic symptoms and social functioning. RESULTS: A total of 8 randomised controlled trials (RCTs) consisting of 300 participants were included. Focused yet brief psychological interventions led to very large improvements in facial affect recognition ability in psychosis [k=8, N=300, g=1.26, 95% Confidence Interval (CI) 0.92, 1.60, I2 41%]. Early evidence suggests this may cause large improvements in social functioning (k=3, N=109, g=0.98, 95% CI 0.37, 1.36, I2 38%), but not psychotic symptoms. CONCLUSIONS: Facial affect recognition difficulties in schizophrenia are highly responsive to psychological interventions designed to improve them, and there is early evidence that this may lead to large gains in social functioning for this group - but not symptoms. A large-scale high-quality RCT with longer-term follow-up period is now required to overcome the limitations of the existing evidence. PMID- 28095999 TI - Challenges and strategies for conducting sensitive research with an Arab American population. AB - Recruiting minority groups such as Arab Americans (Ar-Am) for research studies has been challenging. To date no studies were found that explicitly addressed challenges to recruit Ar-Am for sensitive research. The purpose of this article is to present the challenges across three pilot studies that involved Ar-Am samples and the strategies that were implemented to overcome these challenges. The challenges faced with conducting studies with Ar-Am included difficulty for participants to express emotions, influence of male/female authority to consent for the study, lack of trust to disclose sensitive information, language barrier, and slow recruitment. Having bilingual female recruiters of Arabic descent, engaging the women's family members in the consent process, and addressing the sensitive topics in culturally appropriate language were effective strategies to overcome these challenges. These strategies might be helpful for other researchers who recruit Ar-Am for sensitive research. PMID- 28096000 TI - Effects of oral care with glutamine in preventing ventilator-associated pneumonia in neurosurgical intensive care unit patients. AB - PURPOSE: The study was designed as a randomized, controlled, experimental study aiming to determine the effects of oral care with glutamine in preventing ventilator-associated pneumonia in patients admitted to neurosurgical intensive care unit. METHODS: The universe consisted of patients who are admitted to neurosurgical intensive care unit between January 2014 and August 2015, while the sample consisted of 88 patients who fulfilled the inclusion criteria and were randomly selected. The study group received oral care with 5% glutamine, whereas the control group received oral care with 2% chlorhexidine gluconate solution. DATA COLLECTING TOOLS: All date was acquired using Patient Information Form, Acute Physiological and Chronic Health Evaluation scale (APACHE II), Beck Oral Assessment Scale (BOAS), Mucosal Plaque Score (MPS) and Clinical Pulmonary Infection Score (CPIS). One-way ANOVA test was used for comparing parameters with normal distribution between groups along with descriptive statistical methods. Kruskal-Wallis Test was used for comparing parameters without normal distribution between groups. RESULTS: In the control group, mean BOAS score was 9.33+/-1.8 mean MPS score was 3.68+/-0.87 and mean CPIS score was 4.07+/-1.78. In the study group, mean BOAS score was 10.16+/-2.78, mean MPS score was 3.93+/-1.04 and mean CPIS score was 3.78+/-2.25. There was no statistically significant difference in mean scores at 1st day, 3rd day, 5th day and discharge (p>0.05). However, BOAS, MPS, CPIS and APACHE II scores was significantly lower at discharge than 1st day in both groups. CONCLUSION: There was no significant difference in using 5% glutamine or 2% chlorhexidine gluconate solution for oral care for the prevention of ventilator-associated pneumonia. Similar studies with bigger sample size and longer term should be conducted for better results. PMID- 28096001 TI - Reliability and validity of the COPE Index among caregivers of disabled people. AB - AIM: To study the reliability and validity of the Carers of Older People in Europe (COPE) Index among caregivers of disabled people of different ages. METHODS: A cross-sectional design of Finnish caregivers (n=1117). Exploratory factor analysis (EFA) was performed separately on samples of three different age groups, and the internal consistencies of the subscales were investigated. RESULTS: Three factors were identified; Cronbach's alpha was 0.83-0.86 for negative impact and 0.77-0.78 for quality of support, indicating good internal consistency. The third factor, positive value, was less consistent across the age groups (alpha<0.66). CONCLUSIONS: The COPE Index is a valid and reliable screening tool to measure negative impact and quality of support of caregivers of disabled people. Further research is needed to develop the COPE Index to more precisely measure positive value of the caregiving process. PMID- 28096002 TI - Factors influencing the quality of life of patients with advanced cancer. AB - The present study aimed to determine the predictors of quality of life (QOL) of patients with advanced cancer. A cross-sectional study involving 494 patients with advanced cancer was conducted using the Memorial Symptom Assessment Scale Short Form, the Karnofsky Performance Status Scale, the World Health Organization Disability Assessment Schedule (Korean version), and the European Organization for Research and Treatment of Cancer Quality of Life Core 30. Regression analyses showed that physical and psychological symptoms significantly predicted the patients' QOL and explained 28.8% of the variance in QOL. Moreover, lack of energy was the patients' most prevalent symptom. The results of the present study will serve as fundamental data upon which the development of an intervention will be based so as to enhance the patients' QOL. Accordingly, an effective management of symptoms and performance maintenance should be considered in the future as key factors in providing support and establishing palliative care systems for patients with advanced cancer. PMID- 28096003 TI - Psychometric properties of the critical care family needs inventory-emergency department. AB - PURPOSE: The purpose of this study was to test the reliability and validity of the Turkish version of the Critical Care Family Needs Inventory-Emergency Department (CCFNI-ED) in Turkey. METHODS: This study used a cross-sectional survey design. The questionnaire was administered to 400 family members of patients with a critical illness in an emergency department. The 40-item English version of the CCFNI-ED was translated into Turkish following the standard back translation methodology. Confirmatory and exploratory factor analyses (CFA and EFA, respectively) were carried out using principal component analysis with varimax rotation to test the scale's construct validity. We used Cronbach's alpha to examine the CCFNI-ED's internal consistency reliability. RESULTS: The CFA failed to confirm the original Australian factor structure for our sample. The original scale was then modified based on the EFA and the best possible fitting model was obtained for the Turkish family member sample. The Cronbach's alpha of the modified scale was 0.91 and those for the subscales ranged from 0.68 to 0.87. CONCLUSIONS: The psychometric evaluation showed satisfactory validity and reliability estimates, supporting the use of the Turkish version of the CCFNI-ED with a sample of family members of critically ill patients in an emergency department. PMID- 28096004 TI - The effect of standard pain assessment on pain and analgesic consumption amount in patients undergoing arthroscopic shoulder surgery. AB - : Pain assessment has a key role in relief of the postoperative pain. In this study, we aimed to examine the effect of the Standard Pain Assessment Protocol (SPAP), which we developed based on acute pain guidelines, on pain level, and analgesic consumption. The study population consisted of a total of 101 patients who had arthroscopic shoulder surgery. The routine pain assessment was administered to the control group, while the SPAP was administered to the study group. The routine pain therapy of the clinic was administered to the subjects from both groups based on the pain assessment. Throughout the study, pain was assessed nearly two times more in the study group (p<0.001) and the mean pain levels were lower at 8th-11th hours in the study group (p<0.001). Pain assessment was not performed after 12th hour despite the severe pain in the control group, and, therefore, analgesia was administered at irregular intervals or was not administered at all. However, the hours of analgesic administration were found to be more regular according to the pain levels of the patients in the study group. In conclusion, the SPAP reduced the pain level by providing regular analgesia when used in combination with regular pain assessment. PERSPECTIVE: This article highlights the appropriate assessment for patients with surgical pain. In majority of literature on the subject, the authors emphasize the importance of Standard Pain Assessment Protocol to provide adequate pain relief. PMID- 28096005 TI - Effect of recorded male lullaby on physiologic response of neonates in NICU. AB - PURPOSE: Most infants in the NICU are exposed to sensory overloads and deprivations as part of their care. This study conducted to assess the effect of lullaby on physiologic response of neonates admitted to NICU. METHOD: This is a randomized double-blind intervention trial which was performed on 52 neonates in Jahrom (Iran) 2013-2014. The samples were randomly assigned into lullaby group and a control group (sampling was sequential and randomization was by lottery). Neonates in lullaby group (n=26) listened to male lullaby via headphones during 3days and daily for 20min. Headphones without sound were placed for the control group (n=26) during this period. Immediately before the intervention, 10min later, 20min after the start and 20min after the completion of it, changes in heart rate and oxygen saturation were recorded by heart monitor, then data were analyzed by software SPSS:V 21, Greenhouse-Geisser test, repeated measures and t test. RESULTS: The mean of Heart rate in secondday at 20th and 40th minutes in lullaby group were less than control and this differences were significant (respectively p=0.013, 0.026). Also the blood oxygen saturation levels on the first day at 20th minutes, secondday at 10th minutes-20th and 40th minutes and the third on 40min were significantly different among groups. CONCLUSION: Lullaby (male voice and without music) could significantly reduce heart rate and increase blood oxygen saturation of neonates. Future studies are required to make music as a part of evidence-based strategies to promote outcome of neonates in NICUs. PMID- 28096006 TI - Immunizations challenge healthcare personnel and affects immunization rates. AB - PURPOSE: This study measured 1. medical office immunization rates and 2. health care personnel competency in managing vaccine practices before and after evidence based immunization education was provided. METHOD: This descriptive study compared 32 family medicine and pediatric offices and 178 medical assistants, licensed practical nurses, registered nurses, nurse practitioners, and physicians in knowledge-based testing pre-education, post-education, and 12-months post education. Immunization rates were assessed before and 18-months post-education. RESULTS: Immunization rates increased 10.3% - 18months post-education; knowledge increased 7.8% - 12months post-education. Family medicine offices, licensed practical nurses, and medical assistants showed significant knowledge deficits before and 12-months post-education. All demographic groups scored less in storage/handling 12-months post-education. CONCLUSION: This study is one of the first studies to identify competency challenges in effective immunization delivery among medical assistants, licensed practical nurses, and family medicine offices. Formal and continuous education in immunization administration and storage/handling is recommended among these select groups. PMID- 28096007 TI - Health related quality of life and depressive symptoms among seropositive African Americans. AB - The primary aim of this descriptive correlational study was to determine which domains of health related quality of life (HRQOL) after controlling for demographic correlates predict depressive symptoms among N=70 seropositive African American men and women on Active Antiretroviral Therapy (ART). A demographic questionnaire, the Center for Epidemiological Studies Depression Scale (CESD-D), and the SF-36 Health Related Quality of Life (HRQOL) scale were administered. The regression analyses resulted in three models. The first model indicated that emotional well-being explained 38% of the variance in depressive symptoms (P=0.000) and in model two, emotional well-being and role limitations on emotional health explained 50% of the variance (P=0.000) and in the final and best fitting model emotional well-being, role limitations on emotional health and pain explained 53% of the variance in depressive symptoms (P=0.000) respectively. The findings underscore the need to explore the impact of HRQOL on mental health, and to also screen and treat seropositive African American men and women on (ART) for depressive symptoms. PMID- 28096008 TI - The effect of progressive muscle relaxation on glycated hemoglobin and health related quality of life in patients with type 2 diabetes mellitus. AB - AIM: This study aimed to evaluate the effect of Jacobson's progressive muscle relaxation (PMR) on glycated hemoglobin (HbA1c) levels and health-related quality of life (HRQoL) in patients with type 2 diabetes mellitus (DM). BACKGROUND: Due to relatively poor HRQoL in patients with type 2 DM, different stress reduction techniques was applied to improve physical and mental health in these patients. METHODS: This randomized controlled clinical trial was conducted at the Diabetes and Endocrinology Institute of Firoozgar Hospital, Tehran, Iran, between June and December 2015. Sixty-five patients with type 2 DM were randomly divided into the control (n=35) and PMR (n=30) groups. The patients of the control group only received the conventional care. The PMR group practiced Jacobson's PMR at home for 12 weeks and were monitored by the researcher's phone calls and patient's self-report list. For both groups, Iranian Diabetes Quality of Life Brief Clinical Inventory (IDQoL-BCI) questionnaire was completed and HbA1c levels were measured before and 12 weeks after study entry. RESULTS: The results showed that there were no significant differences in terms of HbA1c levels and HRQoL scores between the PMR and control groups 12 weeks after intervention. However, in the PMR group, the intervention led to a significant reduction in HbA1c levels (P=0.04) and a significant increase in total HRQoL score (P=0.045) and its psychosocial dimension (P=0.019). CONCLUSION: PMR had no significant impact on HbA1c levels and HRQoL in patients with type 2 DM. Further studies with larger sample size and longer follow-up are needed to improve QoL in patients with type 2 DM. PMID- 28096009 TI - Perceptions of dying well and distressing death by acute care nurses. AB - AIM: This study aims to identify perceptions of nurses practicing in four adult inpatient units regarding their actions to provide quality end of life care for dying patients, their definitions of dying well, and their symptoms of distress and actions they took for relief. BACKGROUND: Nurses caring for patients who are dying want them to have the best death possible; however, many nurses are not prepared for every death which may occur. METHODS: Qualitative questionnaire data were collected from 49 nurses on four adult inpatient nursing units to analyze nurse perceptions of distressing death and dying well. RESULTS: Three main concepts emerged describing the nurses' definition of dying well: emotional and spiritual support for the patient and family, patient and family control, and promotion of a peaceful environment. Eight categories of nursing actions to promote dying well were identified, which include communication with disciplinary team/nursing staff, provision of optimal physical care, demonstration of caring and compassion, supporting dignity in death for patient/family, education of patient/family to support dying well, emotional support for patient/family, advocacy for dying well, and fostering a peaceful environment. Symptoms of distress among nurses, and actions for relief were also indicated by participants. CONCLUSION: Future research is indicated to expand the sample to more hospitals and more disciplines. Administrators need to enhance their policies such as event debriefing or shifting workloads to support nurses caring for dying patients. They also need to offer nurses education in providing end of life care and how to become more resilient in the face of trauma. Nurses need to be aware of their symptoms and practices to relieve their stress such as crisis debriefing. They also need to seek education on how to educate patients and families about the process of dying and the value of comfort care. PMID- 28096010 TI - A pilot study of routine screening for distress by a nurse and psychologist in an outpatient haematological oncology clinic. AB - AIM: To explore the: 1) prevalence of distress, type of problems experienced by haematological patients, and referrals for supportive care; 2) effect of demographic and clinical variables on distress, and 3) effect on the time of health professionals conducting the screening in the ambulatory chemotherapy setting. METHODS: Participants completed the National Comprehensive Cancer Network Distress Thermometer and Problem List and had a follow-up screening discussion with a health professional. RESULTS: Of 68 participants, 40% reported significant distress (>=4) on the Distress Thermometer (mean 3.2, SD 2.4). All patients reported physical problems and 72% reported emotional problems-the major contributors to distress and to time spent with the health professional. Distress was unrelated to age, gender or cancer type. Patients were less likely to have significant distress at the end of treatment than at the beginning (OR=0.15, 95% CI: 0.03; 0.72,). Forty patients (59%) were referred to supportive services. The psychologist spent less time with patients compared to the nurse (18 vs 48min, p<0.001). The more emotional problems reported, the greater the time spent with the patient (rs=0.34, p=0.009). CONCLUSIONS: Nurses can appropriately screen for distress and address significant distress reported by haematology patients undergoing chemotherapy without over burdening the nurse or patient. PMID- 28096011 TI - A systematic nurse-led approach to withdrawal risk screening, prevention and treatment among inpatients with an alcohol use disorder in an ear, nose, throat and jaw surgery department-A formative evaluation. AB - INTRODUCTION: Among patients with head and neck cancer comorbid alcohol use disorder is frequent which contributes to higher risk of developing perioperative alcohol withdrawal syndrome/delirium or delirium due to medical conditions. Although guidelines emphasize prevention and treatment of alcohol withdrawal in hospitalized patients, a validated systematic approach for management of these patients is still lacking. Our aim was to formatively evaluate our newly developed systematic approach in view of nurses' adherence to screening patients for regular alcohol consumption and managing their withdrawal symptoms using the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised. METHODS: We conducted a formative evaluation to improve the project's design and performance and used a retrospective chart review in a consecutive sample of all adult inpatients with head and neck cancer being assigned for surgery in a university hospital. Our bundle of interventions consisted of nurses' screenings for regular alcohol consumption, withdrawal risk assessment, offering patients a substitution therapy, nurses' assessments of withdrawal symptoms and symptom oriented withdrawal management. Proximate endpoints were analyzed descriptively at each component of the bundle in terms of frequencies and severity of withdrawal symptoms, frequencies of nurses' and doctors' screenings and nurses' assessments performed as required. RESULTS: Between 2013 and 2014, 87 inpatients met inclusion criteria and screenings by doctors/ nurses revealed 49 alcohol consumers, where six screenings were omitted by nurses and six by doctors. Twenty one consumers were at risk and six of them developed an alcohol withdrawal syndrome. None of the 87 showed an alcohol withdrawal delirium, but five developed a delirium due to medical conditions. Nurses correctly conducted all preventive elements of the intervention bundle in 14 (58%) patients at risk but overall, only performed 50% of the required assessments. CONCLUSIONS: Although nurses safely managed patients' symptoms, nurses' adherence to the interventions was suboptimal and requires stronger leadership. PMID- 28096012 TI - Effects of music therapy and distraction cards on pain relief during phlebotomy in children. AB - AIM: To investigate three different distraction methods (distraction cards, listening to music, and distraction cards + music) on pain and anxiety relief in children during phlebotomy. METHODS: This study was a prospective, randomized, controlled trial. The sample consisted of children aged 7 to 12years who required blood tests. The children were randomized into four groups, distraction cards, music, distraction cards + music, and controls. Data were obtained through face to-face interviews with the children, their parents, and the observer before and after the procedure. The children's pain levels were assessed and reported by the parents and observers, and the children themselves who self-reported using Wong Baker FACES. The children's anxiety levels were also assessed using the Children's Fear Scale. RESULTS: Two hundred children (mean age: 9.01+/-2.35years) were included. No difference was found between the groups in the self, parent, and observer reported procedural pain levels (p=0.72, p=0.23, p=0.15, respectively). Furthermore, no significant differences were observed between groups in procedural child anxiety levels according to the parents and observer (p=0.092, p=0.096, respectively). CONCLUSIONS: Pain and anxiety relief was seen in all three methods during phlebotomy; however, no statistically significant difference was observed. PMID- 28096013 TI - Braden scale (ALB) for assessing pressure ulcer risk in hospital patients: A validity and reliability study. AB - PURPOSE: The inter-rater reliability of Braden Scale is not so good. We modified the Braden(ALB) scale by defining nutrition subscale based on serum albumin, then assessed it's the validity and reliability in hospital patients. METHODS: We designed a retrospective study for validity analysis, and a prospective study for reliability analysis. Receiver operating curve (ROC) and area under the curve (AUC) were used to evaluate the predictive validity. Intra-class correlation coefficient (ICC) was used to investigate the inter-rater reliability. RESULTS: Two thousand five hundred twenty-five patients were included for validity analysis, 76 patients (3.0%) developed pressure ulcer. Positive correlation was found between serum albumin and nutrition score in Braden scale (Spearman's coefficient 0.2203, P<0.0001). The AUCs for Braden scale and Braden(ALB) scale predicting pressure ulcer risk were 0.813 (95% CI 0.797-0.828; P<0.0001), and 0.859 (95% CI 0.845-0.872; P<0.0001), respectively. The Braden(ALB) scale was even more valid than the Braden scale (z=1.860, P=0.0628). In different age subgroups, the Braden(ALB) scale seems also more valid than the original Braden scale, but no statistically significant differences were found (P>0.05). The inter-rater reliability study showed the ICC-value for nutrition increased 45.9%, and increased 4.3% for total score. CONCLUSION: The Braden(ALB) scale has similar validity compared with the original Braden scale for in hospital patients. However, the inter-rater reliability was significantly increased. PMID- 28096015 TI - Association of medication errors with drug classifications, clinical units, and consequence of errors: Are they related? AB - Registered nurses (RNs) play an important role in safe medication administration and patient safety. This study examined a total of 1276 medication error (ME) incident reports made by RNs in hospital inpatient settings in the southwestern region of the United States. The most common drug class associated with MEs was cardiovascular drugs (24.7%). Among this class, anticoagulants had the most errors (11.3%). The antimicrobials was the second most common drug class associated with errors (19.1%) and vancomycin was the most common antimicrobial that caused errors in this category (6.1%). MEs occurred more frequently in the medical-surgical and intensive care units than any other hospital units. Ten percent of MEs reached the patients with harm and 11% reached the patients with increased monitoring. Understanding the contributing factors related to MEs, addressing and eliminating risk of errors across hospital units, and providing education and resources for nurses may help reduce MEs. PMID- 28096014 TI - A measure of facilitators and barriers to rapid response team activation. AB - PURPOSE: Poor patient outcomes and increased costs may be associated with underutilization of RRTs. The aim of this study was to develop and test an instrument that identifies specific facilitators and barriers to rapid response team (RRT) activation. METHODS: Using an exploratory design, we surveyed a convenience sample of 250 registered nurses (RNs) employed in five Illinois hospitals. Participants completed the online RRT Facilitators and Barriers Survey (RRT-FBS), a 36 item survey developed by the researchers. The survey contains two sections, facilitators and barriers. Items in the facilitators subscales described nursing unit culture, RRT knowledge, and RRT member characteristics. Items in the barriers subscales described nursing unit culture, RRT education, and RRT member characteristics. Item analyses were conducted through exploratory factor analyses; internal consistency estimates were obtained. Descriptive statistics were conducted on the demographic data to describe sample and setting characteristics. RESULTS: The final sample consisted of 202 nurses from four hospitals. We conducted an item analysis and were able to reduce the survey to 30 items with a secondary analysis. The full scale alpha was 0.752. Cronbach's alphas for subscales ranged from 0.770-0.897. CONCLUSIONS: Facilitators and barriers may vary across institutions. This scale shows promise for identifying facilitators and barriers to nurses' use of rapid response teams and may provide a foundation for interventional studies promoting RRT utilization. In addition, more frequent education, emphasizing the RRT process, may be an effective method to maintain high rates of RRT activation and increase confidence. PMID- 28096016 TI - The Peer Review Process Revisited. PMID- 28096017 TI - A survey of skin-to-skin contact with perinatal nurses. AB - OBJECTIVE: This study explored perinatal nurses' knowledge, attitudes and practices of SSC, to identify knowledge-practice gaps. STUDY DESIGN: A descriptive cross-sectional survey design was completed by 101 perinatal nurses. Descriptive statistics and ordered logistical regression were used to describe and compare nurses' responses. RESULTS: The participants strongly agreed that it is nurses' responsibility to advocate for SSC. Significant differences (p<0.01) were reported in provision of SSC with eligible infants between nurses within and between practice settings, education levels, year experience and age differences. Education levels significantly influenced attitudes and implementation of SSC. Perinatal nurses' responses about how difficult it is to initiate SSC changes were affected by years of nursing practice (p<0.04). CONCLUSIONS: Perinatal nurses strongly believe in SSC practices, yet additional training regarding SSC implementation is needed. Education levels, primary practice settings and years of practice appear to influence nurses' implementation of SSC. PMID- 28096018 TI - Understanding the distribution of A&E attendances and hospital admissions for the case managed population: A single case cross sectional study. AB - AIM: To describe the characteristics of case-managed patients presenting at accident and emergency (A & E) and to explore the distribution of their attendances and admissions. BACKGROUND: Recently, the UK Government announced extended-hours primary care provision in an effort to reduce the growing utilization of A & E. No evidence is available to understand the use of acute services by this high-risk patient group. METHOD: A cross-sectional design utilising routinely collected anonymsed A & E attendance and hospital admission data from 2010 to 2015. RESULTS: The case-managed population is typically 70years and older and most often arrive at A & E via emergency services and during the night (00:00-08:59). A large proportion are subsequently admitted having a statistically significant A & E conversion rate. No variables were predictive of admission. CONCLUSION: The high level of A&E conversion could indicate case managed patients are presenting appropriately with acute clinical need. However, inadequate provision in primary-care could drive decisions for admitting vulnerable patients. PMID- 28096019 TI - Tinker, tailor, deliberate. An ethnographic inquiry into the institutionalized practice of bar-coded medication administration technology by nurses. AB - AIM: Explore the practice of nurses working with bar-coded medication administration technology, to gain insight in the impact it has on their work. BACKGROUND: The widespread presumption of using Barcoded Medication Administration Technology (BCMA) is that it will effectively reduce the number of errors in the dispensing of medication to patients. However, it remains unclear whether this is the case in actual practice. METHOD: Two distinct but overlapping research methodologies of Institutional Ethnography and Praxeology were combined as a means to uncover the highly complex practice of BCMA by nurses. RESULTS: The implementation of BCMA creates a series of problems leading to nurses constantly tinkering with the technology. At the same time they are continuously deliberating the best ways of tailoring the BCMA to each of their patients. CONCLUSION: Although working with BCMA is often misconstrued as being mindless and automatic, conforming to the technology, this tinkering with BCMA in fact always entails thorough deliberation by nurses. PMID- 28096020 TI - Effectiveness of a psychoeducation program on the quality of life in patients with coronary heart disease: A clinical trial. AB - AIM: The present study was conducted to evaluate effectiveness of a psychoeducation program (PEP) on the quality of life in patients with coronary heart disease (CHD). BACKGROUND: CHD affects patients' quality of life. PEPs may be useful to help patients reach maximum functional health. METHODS: A pretest posttest controlled clinical trial was conducted on a study population of 70 CHD patients, who were selected through convenience sampling and randomly allocated to either the intervention or the control group. The MacNew Quality of Life Questionnaire in heart disease was completed by participants twice: first as a pretest, and then in a follow-up posttest. RESULTS: After the intervention, the quality of life (QOL) score was 157.97+/-25.51 in the intervention group and 105.03+/-8.38 in the control group, making for a significant difference (p<0. 05). CONCLUSION: Based on the findings, PEPs helped CHD patients improve their quality of life through reducing tension, relieving their negative emotions, and improving their social relationships. PMID- 28096021 TI - Body esteem is a mediator of the association between physical activity and depression in Korean adolescents. AB - PURPOSE: This study examined whether body-esteem would mediate the association between physical activity and depression in adolescents. METHODS: A total of 848 Korean high school students aged 15 to 18years completed a questionnaire on body esteem, physical activity recall, and depression. Path analysis was used to test mediating effects of body-esteem on the association between physical activity and depression. RESULTS: Girls showed a significantly higher level of depressive symptoms than boys. Boys showed significantly higher levels of physical activity and body-esteem than girls. Body-esteem mediated the relation of physical activity with depression. CONCLUSIONS: Physical activity might reduce the risk of depression in addition to supporting body-esteem in adolescents. Interventions that reinforce healthy body-esteem and encourage physical activity would help prevent depression in adolescents. Future studies should examine the effects of programs addressing physical activity and body-esteem among adolescents with depressive symptoms. PMID- 28096022 TI - The interaction of fatigue, physical activity, and health-related quality of life in adults with multiple sclerosis (MS) and cardiovascular disease (CVD). AB - In addition to the underlying health problems and disability associated with multiple sclerosis (MS) and cardiovascular disease (CVD), adults with each of these chronic illnesses are independently known to experience fatigue. While fatigue's influence on physical activity and health related quality of life (HRQOL) with each of these illnesses has been discussed, what is lacking is information on how fatigue impacts physical activity and health related quality of life, and ultimately self-management for adults with these conditions. Additionally, individuals may be unaware of the significance of maintaining optimal physical activity in order to maintain everyday function and self management. Thus, the purpose of this article is to discuss the complex effect of fatigue on physical activity and HRQOL among adults with MS and CVD, and to present potential self-management strategies. PMID- 28096023 TI - Communications with health professionals and psychological distress in family caregivers to cancer patients: A model based on stress-coping theory. AB - BACKGROUND: In cancer care settings, family caregivers often experience negative or little communication with the health professionals, and this negative communication and limited health-related information causes psychological distress in family caregivers to cancer patients. AIM: The first aim of this research is to investigate the relationship between communication with health professionals and psychological distress in family caregivers. The second aim is to investigate the mediating effects of self-efficacy in this hypothetical model. METHODS: A total of 1397 family caregivers were included in this research. A structural equation model was then applied, in order to examine the hypothesized model based on the stress-coping model. FINDINGS: More negative communication with health professionals was associated with higher psychological distress. Self efficacy in health information seeking significantly mediated the relationship between communication with health professionals and psychological distress. CONCLUSION: This study indicates that as a coping resource, self-efficacy in health information seeking, plays a significant role in reducing the effects of negative communication with health professionals on psychological distress in family caregivers. PMID- 28096024 TI - Improving satisfaction among established patients in a midwestern pain clinic. AB - BACKGROUND: A problem in many health care practices is deciding the appropriate appointment length for new and established patients. Patients become frustrated when there is inadequate time to have their needs met, yet when a patient's clinic time is spontaneously lengthened, the provider gets behind in schedule, causing delays and greater frustration for others. AIM: The aims of this evidence based project were to determine whether implementation of a flexible appointment system would improve the current scheduling process in a pain clinic by allowing complex patients the opportunity to schedule a longer clinic appointment and would improve patient satisfaction. DESIGN: This evidence-based practice innovation followed a program evaluation process using a descriptive, existing survey completed by clinic staff and patients. SETTING: A Midwestern pain clinic caring for patients with acute and chronic pain diagnoses. PARTICIPANTS: A convenience sample of 120 patients were surveyed before and after the process change. Thirteen staff members completed the survey on SurveyMonkey pre and post procedural change at the same intervals the patients were surveyed. RESULTS: Patients were more satisfied with the time that they spent in the exam room and the waiting room. The process change improved communication with staff and patients and provided an opportunity to discuss their concerns and health changes prior to their scheduled appointment. CONCLUSION: Allowing an option for flexible scheduling in appointment lengths provided an opportunity to meet patient needs, offer improved service, and improve patient-provider communication. PMID- 28096025 TI - The role of supervisor emotional support on individual job satisfaction: A multilevel analysis. AB - INTRODUCTION: Supervisor emotional support is a strong determinant of job satisfaction. There is no study examining the effect of supervisor emotional support at the group level on job satisfaction. Multilevel statistical techniques can help disentangle the effects of subjective assessments from those of group factors. AIM: The study's aim was to examine the moderating role of supervisor emotional support (group-level variable) on the relationship between work engagement and job satisfaction (individual-level variables). METHOD: A cross sectional study was performed in 39units from three Belgian hospitals. A total of 323 nurses completed a self-reported questionnaire. We carried out a multilevel analysis by using Hierarchical Linear Modeling. RESULTS: The results showed that the cross-level interaction was significant. Hence, at individual-level, the nurses with high levels of work engagement showed high levels of job satisfaction and this relationship was stronger when supervisor emotional support at group level was high. CONCLUSIONS: Contextual differences among groups had an impact on the form of the work engagement-job satisfaction relationship. This relationship between work engagement and job satisfaction is an individual and group level phenomenon. Ways to enhance emotional supervisor support include training supervisors in providing support and enhancing communication between nurses and supervisors. PMID- 28096026 TI - Clinical validation of the nursing outcome falls prevention behavior in people with stroke. AB - PURPOSE: To review the nursing outcome, Fall Prevention Behavior, and clinically validate its indicators in people with stroke. METHODS: A methodological study performed with 106 patients in two outpatient clinics, from July to September of 2013. Two pairs of trained nurses applied the NOC scale, one with and one without the use of operational definitions. The internal consistency, stability and difference between the medians obtained by nurses were compared within and between pairs. RESULTS: Most participants were men, elderly, with low education and income. Statistically significant differences were noted in twelve indicators. Five indicators had different means that were greater than the least significant difference. CONCLUSIONS: The indicators were statistically significant; the internal consistency was similar between the pairs and the intraclass correlation coefficient was more satisfactory in the pair that used the definitions. Thus, the construction of empirical referents and the clinical validation process makes the nursing indicators and outcomes more adequate for specific populations and provides an effective means to better evaluate the nursing actions. PMID- 28096027 TI - Work related musculoskeletal disorders in primary health care nurses. AB - BACKGROUND: Work related musculoskeletal disorders (WRMSDs) constitute a serious occupational health problem among registered nurses (RN) all around the world. Its prevalence is mainly associated with nurses' high physical demands that still remain poorly studied in primary health care (PHC). PURPOSE: To describe nurses' self-reported symptoms of WRMSDs (mainly discomfort and pain) in PHC, featuring the main work tasks that may have risk factors for its development. METHODS: A cross-sectional study was developed to identify self-reported WRMSD symptoms by nurses that worked on PHC in Portugal. Nurses answered an online Portuguese version of the Nordic Musculoskeletal Questionnaire (NMQ) (surveymonkey platform). Data was analyzed using the Statistical Package for the Social Science (SPSS17) program. Statistical analysis was based on descriptive statistics and associations with the chi2 test, Cramer's V, Mann-Whitney and Kruskal-Wallis test, with a significance level of 5%. RESULTS: A sample (n=409), mostly female (84.0%), showed a high prevalence of WRMSDs symptoms in the last 12months (89.0%). The lower back was the most affected body region (63.1%), followed by cervical, dorsal, shoulders and the wrist/hand. In the same period, absenteeism related to these complaints was high (51.4%) and strongly connected with standing work (48.8%), bending the trunk (42.3%), rotating the trunk (40.6%), applying force with hands or fingers (37.3%), sitting work (36.6%) and repetitive arm movement (34.3%). This study showed associations between the prevalence of WRMSDs symptoms in different body regions and some individual characteristics such as: gender, age, BMI, presence of other pathologies and regular physical exercise. CONCLUSIONS: This study indicates that, as in other areas of nursing practice, in PHC nurses are also exposed to risk factors that are linked with a high prevalence of WRMSDs symptoms. "Inadequate" and extreme postures sustained for prolonged periods and their repetitiveness will contribute to this occurrence. This shows the need to develop occupational prevention programs to curb this occupational health issue among PHC nurses. PMID- 28096028 TI - A psychometric examination of an instrument to measure the dimensions of Champion's Health Belief Model Scales for cervical cancer screening in women living with HIV. AB - PURPOSE: The purpose of this paper was to examine the psychometric properties of Champion's Health Belief Model Scales for cervical cancer and screening among women living with HIV. METHODS: A secondary data analysis was conducted using data from an exploratory cross-sectional study with a convenience sample of 300 women living with HIV receiving care at two HIV ambulatory care clinics in Florida. A 39-item adaptation of the Champion's Health Belief Model Scales was administered via paper and pencil. RESULTS: The authors used internal consistency measures, confirmatory factor analysis, and ordinal item response theory (IRT) techniques to examine the psychometric properties of the instrument. The 39-item instrument had adequate internal consistency and factor structure. However, the IRT analyses suggested that the instrument could be reduced to 24-items (61.5%), without loss of relevant information. CONCLUSION: A shortened 24-item instrument demonstrated good internal consistency among women living with HIV. Future work should include validating the properties of the reduced instrument in diverse samples of patients and conditions. PMID- 28096029 TI - Nurses' perspectives of a new individualized nursing care intervention for COPD patients in primary care settings: A mixed method study. AB - BACKGROUND: The major challenges in Chronic Obstructive Pulmonary Disease (COPD) care are guiding a patient in daily living with the consequences of the disease, reducing the impact of symptoms and improving Health Related Quality of Life (HRQoL). The new nurse-led COPD-Guidance, Research on an Illness Perception (COPD GRIP) intervention translates the evidence concerning illness perceptions and Health Related Quality of Life (HRQoL) into a practice nurse intervention. The aim is to explore the nurses' experiences with applying the new COPD-GRIP intervention. METHOD: An explanatory mixed-method study nested in a cluster randomized trial in primary care was conducted. Pre-intervention questionnaires were sent to all participating nurses (N=24) to identify expectations. Post intervention questionnaires identified experiences after applying the intervention followed by two focus groups to further extend exploration of findings. Questionnaires were analyzed by descriptive analyses. To identify themes the audio-taped and transcribed focus groups were independently coded by two researchers. RESULTS: The nurses described the intervention as a useful, structured and individualized tool to guide COPD patients in living with the consequences of COPD. Applying the intervention took less time than the nurses initially expected. The intervention enables to provide patient-centered care and to address patient needs. Barriers were encountered, especially in patients with a lower social economic status, in patients with a lower health literacy and in patients with other cultural backgrounds than the Dutch background. CONCLUSION: Nurses perceived the COPD-GRIP intervention as a feasible, individualized tool. According to the nurses, the intervention is a valuable improvement in the care for COPD patients. PMID- 28096030 TI - Game-based online antenatal breastfeeding education: A pilot. AB - AIM: The aim of this study was to evaluate the effect of the Healthy Moms intervention on antenatal breastfeeding self-efficacy and intention and to determine the feasibility of using an online game-based learning platform to deliver antenatal breastfeeding education. BACKGROUND: The Internet has potential for improving breastfeeding rates through improving women's access to antenatal breastfeeding education. METHODS: Twelve computer-based breastfeeding education modules were developed using an online learning platform. Changes in participants' breastfeeding self-efficacy and intention pre- and post intervention were measured using descriptive statistics and a one-way ANOVA. RESULTS: Of the 25 women submitting the pretest, four completed zero quests; seven, orientation only; eight, one to six breastfeeding quests; and six, 10 to 12 breastfeeding quests. No significant differences in breastfeeding self efficacy and intention were found among the groups. CONCLUSIONS: Online antenatal breastfeeding education is feasible; however, further research is warranted to determine if it can affect breastfeeding outcomes. PMID- 28096031 TI - The effect of nurse-led care on stability time in therapeutic range of INR in ischemic stroke patients receiving warfarin. AB - PURPOSE: The current study is designed in order to investigate the effect of nurse-led care (the supportive and educational measurements by nurses) on stability time in therapeutic range of INR in ischemic stroke patients receiving Warfarin. METHOD: In this quasi-experimental study, 80 ischemic stroke patients were investigated, 40 patients in experimental group and 40 in the control group referred to the nurse-based warfarin clinics affiliated to Shiraz University of Medical Sciences. The mean+/-SD duration of the intervention was 144+/-84days. The patients based on the percentage stability time in the therapeutic range of INR were classified into 3 groups of good control (>75%), medium control (60 75%), and poor control groups (<60%). The results were analyzed using qui-square and independent t-test according to these categories. RESULTS: 38 patients in the experimental group and 39 in the control group had the therapeutic range of INR 2 3. The percentage of the stability time in the therapeutic range of INR (mean+/ SD) in the experimental group was 64.08%+/-18.7 and in the control group it was 44.58%+/-25.12 (P<0.001). The percentage of total INRs within the therapeutic range was 52.5% in the experimental group and 40.6% in the control group (P=0.001). CONCLUSIONS: In conclusion, using the stroke prevention guidelines, thrombotic therapy protocols and familiarity with patients' diagnosis and risk factors in the experimental group led to more patients' stability time (The time that patients could remain stable within the INR therapeutic range) in their therapeutic range of INR as the best indicator of clinical performance. PMID- 28096032 TI - Creation of an intensive care unit and organizational changes in an adult emergency department: Impact on acute stroke management. AB - BACKGROUND AND PURPOSE: Following the reorganization of a University Medical Center onto a single campus, an Intensive Care Unit was created within the adult Emergency Department (ED ICU). We assessed the effects of these organizational changes on acute stroke management and the intravenous administration of recombinant tissue plasminogen activator (IV rtPA), as characterized by the thrombolysis rate, door-to-needle time (DNT) and outcome at 3months. METHODS: Between October 2013 and September 2015, we performed a retrospective, observational, single-center, comparative study of patients admitted for ischemic stroke and treated with IV rtPA during two 321-day periods (before and after the creation of the ED ICU). All patients with ischemic stroke were included. Multivariable logistic regression models were performed. The DNT was stratified according to a threshold of 60min. A favorable long-term outcome was defined as a modified Rankin score<=2 at 3months. RESULTS: A total of 1334 ischemic stroke patients were included. Among them, 101 patients received IV rtPA. The frequency of IV rtPA administration was 5.8% (39 out of 676) before the creation of the ED ICU, and 9.3% (62 out of 668) afterwards (odds ratio (OR) [95% confidence interval (CI)]: 1.67 [1.08-2.60]; p=0.02). Additionally, the DNT was shorter (OR [95%CI]: 4.30 [1.17-20.90]; p=0.04) and there was an improvement in the outcome (OR [95%CI]=1.30 [1.01-2.10]; p=0.045). CONCLUSION: Our results highlight the benefits of a separate ED ICU within conventional ED for acute stroke management, with a higher thrombolysis rate, reduced intrahospital delays and better safety. PMID- 28096033 TI - Transformations. AB - A patient with a serious illness continually refuses, postpones or avoids treatment until a conversation reveals essential contextual factors which change the physician's point of view. Once attended to, the patient also changes her attitude. PMID- 28096034 TI - Twelve months effect of self-referral to inpatient treatment on patient activation, recovery, symptoms and functioning: A randomized controlled study. AB - OBJECTIVE: To investigate the effect of having a contract for self-referral to inpatient treatment (SRIT) in patients with severe mental disorders. METHODS: A randomized controlled trial with 53 adult patients; 26 participants received a SRIT contract, which they could use to refer themselves into a Community Mental Health Centre up to five days for each referral without contacting a doctor in advance. Outcomes were assessed after 12 months with the self-report questionnaires Patient Activation Measure (PAM-13), Recovery Assessment Scale (RAS), and the Behavior and Symptom Identification Scale (BASIS-32) and analyzed using linear mixed and regression models. RESULTS: There was no significant effect on PAM-13 (estimated mean difference (emd) -0.41, 95% CI (CI):-7.49-6.67), nor on the RAS (emd 0.02, CI:-0.27-0.31) or BASIS-32 (0.09, CI:-0.28-0.45). An exploratory post hoc analysis showed effect of SRIT in those with low PAM below <=47 (p=0.049). CONCLUSION: There were no group differences after 12 months, but both groups maintained their baseline levels. PRACTICE IMPLICATIONS: SRIT contracts can be recommended as it supports the rights to self-determination, promote user participation in decision-making in own treatment without any indication of adverse effects. PMID- 28096035 TI - The role of health economics in the evaluation of surgery and operative technologies. AB - Dr Matthew Taylor is the director of York Health Economics Consortium and leads the Consortium's health technology assessment program. The work of York Health Economics Consortium involves empirical research in health economics for both the private and public sectors. Dr Taylor is the scientific lead for the National Institute for Health and Care Excellence (NICE) Economic and Methodological Unit and a former member of NICE's Public Health Advisory Committee. He is also managing director (Europe) of Minerva, an international network of health economics consultancies. PMID- 28096036 TI - A guide to the anti-innovation "pharmaphobia" narrative for the aspiring innovator. AB - Thomas P. Stossel is an American Cancer Society Professor of Medicine Emeritus at Harvard Medical School, Honorary Physician in the Hematology Division of Brigham & Women's Hospital, founding scientist of BioAegis Therapeutics, Visiting Scholar of The American Enterprise Institute and cofounder of Options for Children in Zambia. PMID- 28096037 TI - The future is here, but there is no reason to fear. AB - Nicole Fisher, MPP, PhD, is the founder and chief executive officer at HHR Strategies, a health care and human rights focused advising firm. Additionally, she is a senior policy advisor and expert on health economics, technology, and reform, specifically as they affect vulnerable populations. Nicole runs a health innovation and policy page at Forbes, highlighting and advising companies, ideas, and people that are changing the health landscape. She also is currently pursuing her PhD at the University of North Carolina in the Health Policy and Management Department. Her writing has appeared in many publications and her talks can be found on the United Nations website. Before pursuing her PhD in health policy, Nicole earned her Master's degree in Public Policy from the University of Chicago and her undergraduate degree from the University of Missouri. PMID- 28096038 TI - Kidney diseases and NOAC therapy: Is there a light at the end of the tunnel? PMID- 28096039 TI - The impact of emergency medical services in acute heart failure. AB - BACKGROUND: Real-life data on the role of emergency medical services (EMS) in acute heart failure (AHF) are scarce. Our aim was to describe prehospital treatment of AHF and to compare patients using EMS with self-presented, non-EMS patients. METHODS: Data were collected retrospectively from three university hospitals in Helsinki metropolitan area between July 1, 2012 and July 31, 2013. According to the use of EMS, patients were divided into EMS and non-EMS groups. RESULTS: The study included 873 AHF patients. One hundred were (11.5%) EMS and 773 (88.5%) non-EMS. EMS patients more often had comorbidities. Initial heart rate (HR) and peripheral oxygen saturation (SpO2) differed between EMS and non EMS patients; mean HR 89.2 (SD 22.5) vs. 83.7 (21.5)/min (p=0.02) and SpO2 90.3 (8.6) vs. 92.9 (6.6)% (p=0.01). However, on presentation to ED EMS patients' vital signs were similar to non-EMS patients'. On presentation to ED 46.0% were normotensive and 68.2% "warm and wet". Thirty-four percentage of EMS patients received prehospital medication. In-hospital mortality was 6.0% and 7.1% (p=0.84) and length of stay (LOS) 7.7 (7.0) and 8.5 (7.9) days (p=0.36) in EMS and non-EMS groups. CONCLUSION: The use of EMS and administration of prehospital medication was low. EMS patients had initially worse HR and SpO2 than non-EMS patients. However, EMS patients' signs improved and were similar on presentation to ED. There were no differences in in-hospital mortality and LOS. This underscores the need for equal attention to any AHF patient independent of the arrival mode. PMID- 28096040 TI - Calcium: A predictor of interventional treatment failure across all fields of cardiovascular medicine. AB - In this substudy of the ADAPT-DES trial Genereux et al. compared two years outcomes according to the presence or absence of coronary artery calcification (CAC) as assessed by coronary angiography. Coronary calcification was an independent predictor of interventional treatment failure and a higher incidence of both ischemic events and bleeding. The cohort with CAC was older with a higher prevalence of risk factors and comorbidities and an increased anatomical complexity of the target lesions, explaining only in part the worse outcome of the CAC population that persisted at multivariate analysis. Incomplete expansion and poor stent apposition, more frequent in calcified lesions, are predictive of target lesion failure and late stent thrombosis. The main limitation of the study is the use of angiography for CAC assessment with a likely major underestimation of CAC burden. Intravascular imaging might also help for a more accurate quantification of the CAC burden and characteristics, selecting the lesions in need of a calcium modification with atherectomy or lithotripsy before stent implantation. PMID- 28096041 TI - Advance Care Planning in Adults with Congenital Heart Disease: A Patient Priority. AB - BACKGROUND: Adult congenital heart disease (ACHD) patients with moderate or great defect complexity are at risk for premature death. Although early engagement in advance care planning (ACP) is recommended, previous research suggests that it seldom occurs. METHODS: This study investigated ACHD patient preferences for ACP and factors that impact preferences. ACHD patients completed an ACP preferences questionnaire, the Hospital Anxiety and Depression Scale and a measure of attachment styles. RESULTS: Of 152 ACHD patients (median age 33years, 50% female), 13% reported previous ACP discussions with providers and 21% had completed advance directives. On a 0-10 scale, the median rating for the importance of discussing ACP with providers was 7; 18years was identified as the most appropriate age to initiate this dialogue. Higher ratings for the importance of discussing ACP with providers was observed in patients who were female (p=0.03), had lower disease complexity (p=0.03), and had elevated anxiety symptoms (p=0.001); elevated anxiety remained significant in a multivariable model. Interest in receiving information about life expectancy (61% overall) was greater among patients with lower disease complexity (p=0.04) and a history of >=2 cardiac surgeries (p=0.01); disease complexity remained significant in a multivariable model. CONCLUSIONS: As a group, ACHD patients value the opportunity for ACP discussions and prefer earlier communication. Although some clinicians might avoid ACP discussions in patients who are generally more anxious or have less complex CHD, such avoidance does not appear to be warranted. PMID- 28096042 TI - Acute effect of intermittent and continuous aerobic exercise on release of cardiac troponin T in sedentary men. AB - BACKGROUND: Studies have shown that acute exercise can increase serum concentrations of cardiac biomarkers, including cardiac troponin T (cTnT). We investigated the acute effects of intermittent (IE) and continuous (CE) exercise at the same cardiac workload on myocardial necrosis biomarkers in sedentary men. METHODS: Eleven sedentary healthy men aged 22.3+/-1.9years completed the study. The subjects were divided into two groups and performed, in random order, IE (intensity alternating between 50% (2min) and 80% (1min) HRreserve) or CE (60% HRreserve). The study was designed as a single-blinded randomised crossover trial performed on two distinct experimental days separated by a 1-week washout period. Each session consisted of 40min of aerobic exercise, either IE or CE, on a treadmill. Blood samples were taken before (PRE), immediately after (POST) and 1h after (POST-1) each exercise session. RESULTS: hs-cTnT significantly increased immediately after exercise in both protocols and remained elevated at POST-1 (P<0.05). There was no significant difference between POST and POST-1 values(P>0.05). Neither CE nor IE caused any significant change in CK-MB (P>0.05). The results also showed that HR and RPP increased significantly following both exercise protocols (P=0.001). CONCLUSIONS: In summary, both CE and IE results in increased serum concentrations of hs-cTnT in sedentary men. However, this increase does not seem to be caused by the irreversible death of cardiomyocytes. CE resulted in a greater hs-cTnT concentration than IE. PMID- 28096043 TI - A simplified protocol for culture of murine neonatal cardiomyocytes on nanoscale keratin coated surfaces. AB - OBJECTIVE: We aim to develop a simple, efficient and cost-effective protocol for culturing the neonatal cardiomyocytes using keratin derived from human hair, which can be used for studying cardiac hypertrophy in vitro. METHODS: Keratin was extracted from human hair and applied as nanoscale coating onto the culture dishes. Physical parameters such as surface morphology and roughness of the coating were studied by SEM and AFM. Cardiomyocyte specific markers were assessed by immunofluorescence. Signaling pathways activated in hypertrophy were analyzed by western blotting and changes in the expression of fetal genes were analyzed by qPCR. The changes in the calcium fluxes were observed microscopically using Fluo 4. RESULTS: Keratin coated surfaces displayed a uniform coating and comparable roughness across dishes. Our optimized protocol for isolating cardiomyocytes yielded up to ~106 cells per heart. Characterization of cardiomyocytes with specific markers revealed that they can attach, grow and show spontaneous contractions on keratin-coated substrates similar to fibronectin-coated surfaces. Phenylephrine (PE) treated cardiomyocytes grown on keratin-coated substrates exhibited increased cell size, sarcomere organization and perinuclear ANP expression indicating the development of cardiac hypertrophy. In addition, we observed increased activation of Akt and ERK pathways, induction of the fetal genes and increased protein synthesis upon PE treatment, which are characteristics of cardiomyocyte hypertrophy. The protocol was extended to mouse cardiomyocytes and found to show similar results upon examination. CONCLUSION: We demonstrate that keratin can act as an efficient yet cost effective alternative substrate for the attachment, growth and differentiation of neonatal murine cardiomyocytes. PMID- 28096044 TI - Use of transesophageal echocardiography and contrast echocardiography in the evaluation of cardiac masses. AB - OBJECTIVES: To determine whether the combination of transesophageal echocardiography (TEE) and contrast echocardiography (CE) accurately diagnose suspected cardiac masses using large sample data. METHODS: Patients with cardiac masses undergoing surgical treatment were enrolled in this study. Routine transthoracic echocardiography (TTE) and TEE examinations were carried out, and CE examinations were carried out when needed. All patients' clinical data and imaging features were retrospectively reviewed. Surgery and histopathology served as the gold standard for diagnosing cardiac masses. RESULTS: A total of 252 consecutive patients were included in this study. Sixteen patients were lost to follow-up and were excluded from the study. The combinations of TEE and CE yielded the correct pathologic diagnosis in 225 of 230 patients (97.8%), while CT yielded the correct pathologic diagnosis in 122 of 141 patients (86.5%), p<0.01. TEE yielded the correct pathologic diagnosis in 219 of 226 patients (96.9%), and CE yielded the correct pathologic diagnosis in 45 of 48 patients (93.8%). TTE alone yielded the correct pathologic diagnosis in 163 of 236 patients (69.1%), p<0.001 for all. TEE imaging provided detailed and precise information regarding cardiovascular morphology, anatomy, hemodynamics and function, and CE provided information regarding tissue characteristics without subjecting patients to radiation exposure. CONCLUSIONS: The combination of TEE and CE is feasible for the detection of suspected cardiac masses, especially in diagnosing and differentiating between benign and malignant lesions. PMID- 28096045 TI - Early detection of left ventricular dysfunction in first-degree relatives of diabetic patients by myocardial deformation imaging: The role of endothelial glycocalyx damage. AB - BACKGROUND: First-degree relatives of type-2 diabetes patients (FDR) present insulin resistance. We investigated whether FDR and dysglycaemic subjects demonstrate abnormal endothelial glycocalyx and LV deformation during postprandial hyperglycemia. METHODS: We studied 40 FDR with normal oral glucose test (OGTT), 40 subjects with abnormal OGTT (dysglycaemic) and 20 subjects with normal OGTT without parental history of diabetes (normoglycaemic). At 0 and 120min of OGTT we measured: a) LV longitudinal strain (LS) of subendocardial, mid myocardial and subepicardial layers, global LS (GLS), peak twisting (pTw), untwisting velocity (pUtwVel), by speckle tracking echocardiography b) perfused boundary region (PBR) of the sublingual arterial microvessels; high PBR values represent reduced glycocalyx thickness. Insulin resistance was evaluated using insulin sensitivity index (ISI). RESULTS: ISI was related with baseline PBR, GLS and pTw in all subjects (p<0.05). Compared to normoglycaemics, FDR and dysglycaemics had higher PBR, lower ISI, GLS (-18.4+/-2.6 and -16.8+/-2.0 vs. 19.2+/-2.4%), subendocardial LS (-19.0+/-4.2 and -17.9+/-3.0 vs. -20.1+/-3.4%), pTw (14.4+/-4.4 and 15.6+/-6.4 vs. 16.9+/-6.5deg) and pUtwVel (p<0.05 for all comparisons). A GLS<-18% identified FDR with LV dysfunction (p=0.016). Post-OGTT, GLS and the subendocardial LS decreased while pTw and pUtwVel increased in FDR and dysglycaemics (p<0.05) indicating prevalence of the motion of the subepicardial over a dysfunctioning subendocardial myocardial helix. Increased PBR was related with impaired deformation markers at baseline and 120min of OGTT (p<0.05). CONCLUSION: First-degree relatives and dysglycaemics have reduced glycocalyx thickness related with impaired LV longitudinal, twisting-untwisting function. Postprandial hyperglycemia when combined with insulin resistance causes LV longitudinal dysfunction leading to increased LV twisting. PMID- 28096046 TI - Worse late-phase survival after elective endovascular than open surgical repair for intact abdominal aortic aneurysm. AB - OBJECTIVES: To determine whether follow-up survival is better after elective endovascular aneurysm repair (EVAR) than open surgical repair (OSR) for intact abdominal aortic aneurysm (AAA), we combined 5-year survival curves themselves of EVAR and OSR in randomized controlled trials (RCTs) and propensity-score matched (PSM) studies. METHODS: Eligible studies were RCTs or PSM studies of elective EVAR versus OSR enrolling patients with intact AAA and reporting 5-year (at least) survival curves. Data regarding detailed inclusion criteria, duration of follow-up, and survival curves were abstracted from each individual study. In case of crossing of the combined survival curves, a pooled late-phase (between the crossing time and 5years) hazard ratio (HR) for all-cause mortality was calculated. RESULTS: Our search identified 7 eligible studies (including 2 RCTs and 5 PSM studies) enrolling a total of 92,333 patients with AAA assigned to EVAR or OSR. Pooled survival rates after EVAR and OSR were 98.1% and 96.1 at 1month, 94.2% and 93.1% at 1year, 85.1% and 86.8% at 3years, and 75.8% and 78.8% at 5years, respectively. The survival curves crossed at 1.8years with the survival rate of 90.5%. A pooled late-phase (between 1.8years and 5years) HR for calculated from data of the combined survival curves significantly favored OSR (1.29, 95% confidence interval, 1.24 to 1.35; p<0.00001). CONCLUSIONS: For intact AAA, although survival was better immediately after elective EVAR than OSR, the survival curves crossed at 1.8years. Thereafter until 5years, survival was worse after EVAR than OSR. PMID- 28096048 TI - Introduction to inflammatory dermatoses: Histological clues for the practicing pathologist. PMID- 28096047 TI - Cellular basis of angiotensin-(1-7)-induced augmentation of left ventricular functional performance in heart failure. AB - BACKGROUND: Angiotensin-(1-7) [Ang-(1-7)] exhibits cardiovascular effects opposite those of angiotensin II (Ang II), thus providing protection against heart disease. However, how Ang-(1-7) imparts cardioprotection is unclear, and its direct cardiac effects are controversial. Whether heart failure (HF) alters cardiac contractile responses to Ang-(1-7) remains undetermined. We tested the hypothesis that in HF, Ang-(1-7) may produce positive modulation on [Ca2+]i regulation, enhancing left ventricular (LV) and myocyte contraction and relaxation via Ang-(1-7) Mas receptor coupled with nitric oxide (NO)/bradykinin (BK)-mediated mechanism. METHODS AND RESULTS: We measured LV contractility changes after Ang-(1-7) (650ng/kg, iv) and compared myocyte functional and [Ca2+]i transient ([Ca2+]iT) responses to Ang-(1-7) superfusion in 24 normal rats and 34 rats with isoproterenol-induced HF (3months after 170mg/kg, s.q. for 2days). To assess the mechanisms of altered HF responses to Ang-(1-7), subsets of HF myocytes were pretreated to inhibit NO synthase (L-NAME), BK (HOE-140), and Mas receptor (A-779) followed with Ang-(1-7). In normal rats, Ang-(1-7) produced no significant changes in LV and myocyte function. In HF rats, Ang-(1-7) significantly augmented LV contractility and relaxation with increased EES (51%), but decreased tau compared to baseline. Ang-(1-7) also significantly increased myocyte contraction (dL/dtmax, 30%), relaxation (dR/dtmax, 41%), and [Ca2+]iT. L NAME increased, HOE-140 decreased, and A-779 prevented HF myocyte contractile responses to Ang-(1-7). CONCLUSIONS: In a rat model of HF, Ang-(1-7) increases [Ca2+]iT, and produces positive inotropic and lusitropic effects in the LV and myocytes. These effects are mediated by the Mas receptor and involve activation of NO/BK pathways. PMID- 28096049 TI - Monoenergetic reconstructions for imaging of coronary artery stents using spectral detector CT: In-vitro experience and comparison to conventional images. AB - PURPOSE: Accurate assessment of coronary stents using non-invasive CT imaging remains challenging despite new stent materials and improvements in CT technology. Virtual monoenergetic (monoE) images reconstructed from dual energy CT acquisitions potentially decrease artifacts caused by coronary stents. A novel spectral detector technology provides monoE and conventional images simultaneously for all conducted scans. The purpose of our study was to systematically investigate the influence of different monoE reconstructions on the visualization of coronary stent lumen in comparison to conventional images. METHOD AND MATERIALS: Ten different coronary stents (diameter 3.0 mm) embedded in plastic tubes filled with contrast agent (500 HU) were scanned with a 128-row spectral detector CT (IQon, Philips, 120 kV, 125 mAs). Images were reconstructed (0.67 mm slice thickness, 0.35 mm increment) with a stent-specific conventional reconstruction kernel and 6 different monoE settings (60, 70, 80, 90, 100, 150 keV). Image quality for each stent and reconstruction was quantified using established parameters: image noise (standard deviation (SD) within a standardized ROI), in-stent attenuation difference (mean attenuation difference between stented and non-stented lumen) and visible lumen diameter (mean visible diameter of the stented tube). RESULTS: Image noise was significantly lower in all monoE data dets compared to conventional images (conventional: 13.41, 60 keV: 11.62, 70 keV: 11.67, 80 keV: 11.69, 90 keV: 11.71, 100 keV: 11.75, 150 keV: 11.80 HU SD; p < 0.01). The in-stent attenuation difference was significantly smaller in monoE data with higher keV levels than in conventional images (conventional: 148.18, 60 keV: 154.13 p = 0.036, 70 keV: 143.43 p = 0.109, 80 keV: 137.25 p = 0.052, 90 keV: 133.02 p = 0.043, 100 keV: 130.12 p = 0.039, 150 keV: 123.99 HU p = 0.035). The visible lumen diameter was significantly greater in monoE data with higher keV levels than in conventional images (conventional: 0.65, 60 keV: 0.68 p = 0.542, 70 keV: 0.71 p = 0.053, 80 keV: 0.74 p < 0.01, 90 keV: 0.77 p < 0.01, 100 keV: 0.82 p < 0.01, 150 keV: 0.87 mm p < 0.01). CONCLUSION: In comparison to conventional CT images, well-established parameters for objective assessment of CT image quality for coronary stents are significantly improved by utilization of monoE reconstructions with adequate keV levels derived from data acquired on a novel spectral detector CT platform. PMID- 28096050 TI - [Incidence of accidental exposure to blood and body fluids among healthcare professionals in a community hospital]. AB - OBJECTIVE: To determine the annual incidence of healthcare professionals' accidental exposure to blood and body fluids in a community hospital and describe their characteristics, associated situations and follow-up. METHOD: A longitudinal, retrospective study of biological accidents voluntarily reported on a yearly basis by exposed healthcare professionals at Fundacio Hospital de l'Esperit Sant (in Santa Coloma de Gramenet, Barcelona, Spain), between 2005 and 2014. A descriptive analysis of the variables related to the exposed professional, the exposure itself, its production mechanism and the source patient was conducted. The rate of exposure was calculated per 100 occupied beds and by job category. RESULTS: 318 exposures were reported; 89.62% were percutaneous and the remainder were non-intact skin or mucous contamination. The mean percutaneous exposure incidence rate from 2005 to 2014 was 17.6 per 100 occupied beds/year (limits 10.3 in 2013 and 24.5 in 2005). Doctors were exposed to the greatest risk (5.29 exposures per 100 doctors). Over 50% occurred in a surgical setting. 44.2% of exposed healthcare professionals had been working at the centre for 1 year or less on average. Puncture was the most common percutaneous lesion. No cases of occupational viral transmission were reported. CONCLUSIONS: The rate of percutaneous exposure reported in this hospital fluctuated significantly throughout the analysis period. Risk of exposure is related to job category, work experience, the setting and the activity performed. PMID- 28096052 TI - Population data of 15 autosomal STR loci in Chinese Han population from Yangjiang, Southern China. PMID- 28096051 TI - Transitions of care: Medication-related barriers identified by low socioeconomic patients of a federally qualified health center following hospital discharge. AB - This article describes a qualitative research study using a semi-structured interview process to describe barriers surrounding medication access, use, and adherence for recently discharged patients of a federally qualified health center. Common themes which emerged were: 1) Team assumptions regarding patient plans to access or appropriately use discharge medications negatively impact adherence; 2) Unmet expectation for care coordination between primary care physician (PCP) and hospital; 3) Disconnect between patients and health care workers leads to disengagement; and 4) Lack of personal contact hinders access to services. PMID- 28096053 TI - A Potential New Therapeutic Approach to DMD: PKC Theta Inhibition. PMID- 28096054 TI - Glycogen storage disease type Ia mice with less than 2% of normal hepatic glucose 6-phosphatase-alpha activity restored are at risk of developing hepatic tumors. AB - Glycogen storage disease type Ia (GSD-Ia), characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA) and carcinoma (HCC), is caused by a deficiency in glucose-6-phosphatase-alpha (G6Pase-alpha or G6PC). We have previously shown that G6pc-/- mice receiving gene transfer mediated by rAAV-G6PC, a recombinant adeno-associated virus (rAAV) vector expressing G6Pase alpha, and expressing 3-63% of normal hepatic G6Pase-alpha activity maintain glucose homeostasis and do not develop HCA/HCC. However, the threshold of hepatic G6Pase-alpha activity required to prevent tumor formation remained unknown. In this study, we constructed rAAV-co-G6PC, a rAAV vector expressing a codon optimized (co) G6Pase-alpha and showed that rAAV-co-G6PC was more efficacious than rAAV-G6PC in directing hepatic G6Pase-alpha expression. Over an 88-week study, we showed that both rAAV-G6PC- and rAAV-co-G6PC-treated G6pc-/- mice expressing 3-33% of normal hepatic G6Pase-alpha activity (AAV mice) maintained glucose homeostasis, lacked HCA/HCC, and were protected against age-related obesity and insulin resistance. Of the eleven rAAV-G6PC/rAAV-co-G6PC-treated G6pc /- mice harboring 0.9-2.4% of normal hepatic G6Pase-alpha activity (AAV-low mice), 3 expressing 0.9-1.3% of normal hepatic G6Pase-alpha activity developed HCA/HCC, while 8 did not (AAV-low-NT). Finally, we showed that the AAV-low-NT mice exhibited a phenotype indistinguishable from that of AAV mice expressing >=3% of normal hepatic G6Pase-alpha activity. The results establish the threshold of hepatic G6Pase-alpha activity required to prevent HCA/HCC and show that GSD-Ia mice harboring <2% of normal hepatic G6Pase-alpha activity are at risk of tumor development. PMID- 28096056 TI - Common issues in the management of patients in the waiting list and after liver transplantation. AB - The present document contains the recommendations of an expert panel of transplant hepatologists, appointed by the Italian Association for the Study of the Liver (AISF), on how to manage the most common aspects of liver transplantation: the topics covered include: new treatments for HCV in patients on the waiting list for liver transplantation; antiviral treatments in patients with HCV recurrence after liver transplantation; prophylaxis for HBV recurrence after liver transplantation; indications for liver transplantation in alcoholic liver disease; and Immunosuppressive therapy. The statements on each topic were approved by participants at the AISF Transplant Hepatologist Expert Meeting (organized by the Permanent Committee on Liver Transplantation in Mondello on 4-5 October 2015), and are graded according to the Oxford classification of levels of evidence. PMID- 28096055 TI - An Ancient Family of RNA-Binding Proteins: Still Important! AB - RNA-binding proteins are important modulators of mRNA stability, a crucial process that determines the ultimate cellular levels of mRNAs and their encoded proteins. The tristetraprolin (TTP) family of RNA-binding proteins appeared early in the evolution of eukaryotes, and has persisted in modern eukaryotes. The domain structures and biochemical functions of family members from widely divergent lineages are remarkably similar, but their mRNA 'targets' can be very different, even in closely related species. Recent gene knockout studies in species as distantly related as plants, flies, yeasts, and mice have demonstrated crucial roles for these proteins in a wide variety of physiological processes. Inflammatory and hematopoietic phenotypes in mice have suggested potential therapeutic approaches for analogous human disorders. PMID- 28096057 TI - The five-year survival rate after endoscopic submucosal dissection for superficial esophageal squamous cell neoplasia. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is a widely accepted procedure for superficial esophageal squamous cell neoplasia (ESCN) because of a high complete resection rate. However, there were a few reports about the long-term outcomes of these patients due to short follow-up periods. AIMS: We aimed to evaluate the 5-year survival after ESD for superficial ESCN. METHODS: This was a retrospective cohort study performed at a single institution. Between 2006 and 2009, 94 patients with superficial ESCN underwent ESD. Eighty-three patients (93.3%) who had completed an extended period of observation of at least 5 years were enrolled. The main outcomes were the 5-year survival rates. The secondary outcomes were the cumulative incidence rate of metachronous ESCN, and the clinical outcomes. RESULTS: The 5-year relative overall survival rate was 99.0%, whereas the cause specific survival rate was 100% during 72.9 months of median follow up period. Subgroup analysis showed that the 5year survival of patients with EP/LPM and MM/SM1 (submucosal invasion <=200MUm) were 100% and 89.0%, respectively. The cumulative incidence rate of metachronous ESCN at 5 years was 16.8%. CONCLUSION: ESD for superficial ESCN is a curative treatment with a favorable 5-year survival rate. PMID- 28096058 TI - Anemia at the time of diagnosis of inflammatory bowel disease: Prevalence and associated factors in adolescent and adult patients. AB - BACKGROUND: The prevalence, characteristic and determinants of anemia, at the time of inflammatory bowel disease (IBD) diagnosis have yet to be fully elucidated. METHODS: Retrospective cross-sectional study. Analytical data and disease characteristics obtained upon diagnosis of 1278 IBD patients [Crohn's disease/ulcerative colitis (CD/UC): 718/560] were collected. RESULTS: Anemia was present in 41.2% of patients at diagnosis (47% and 33.8% of CD and UC patients, respectively; p<0.001), being severe in 5.5%. Iron deficiency anemia represented 69.6% of cases, with no differences between CD and UC. Female sex was the strongest risk factor for anemia in both CD and UC (OR 7.11; 95%CI 4.18-12.10 and 6.55; 95%CI 3.39-12.63, respectively), followed by elevated (>=2mg/dL) C-reactive protein (OR 4.08; 95%CI 2.39-6.97 and 4.58; 95%CI 2.26-9.27, respectively). Current smoking was a risk factor for anemia in CD (OR 2.23; 95%CI 1.24-4.02), but a protective one in UC (OR 0.36; 95%CI 0.14-0.92). A penetrating CD behavior increased the risk of anemia (OR 3.34; 95%CI 1.36-8.21); in UC, anemia increased with disease extension (E2+E3) (OR 1.80; 95%CI 1.13-2.86). CONCLUSIONS: Female sex and disease activity are major determinants of anemia at IBD diagnosis. Anemia is associated with disease behavior in CD and with disease extension in UC. PMID- 28096059 TI - Clinical utility of the SMSA grading tool for the management of colonic neoplastic lesions. AB - BACKGROUND: Whilst polyp size has been traditionally used as a predictor of the complexity of endoscopic resection, the influence of other factors is increasingly recognised. The SMSA grading system takes into account polyp Site, Morphology, Size and Access, with higher scores correlating with increased technical difficulty. AIMS: To evaluate whether the SMSA grading tool correlates with endoscopic and clinical outcomes. METHODS: This retrospective study was conducted at two high volume centres in the United Kingdom and Italy. All polyps identified at colonoscopy were included in this study and classified as per the SMSA grading system. RESULTS: A total of 1668 lesions were resected in 1016 patients. There was a positive correlation between increasing SMSA level and the inability to resect lesions "en bloc" (p<0.001). Histologically complete clearance was higher in the lower SMSA groups (p<0.0001). Additional endoscopic therapies, were more commonly required with the higher SMSA groups to achieve histological clearance (p<0.0001). Moreover, advanced histology in resection specimens and procedural complications were significantly less common in SMSA level 1 lesions compared to level 3 or 4 lesions (p<0.0001). CONCLUSIONS: The SMSA grading tool is a useful predictor of outcome following the resection of colonic neoplastic lesions. PMID- 28096060 TI - Nutritional status and bioelectrical phase angle assessment in adult Crohn disease patients receiving anti-TNFalpha therapy. AB - BACKGROUND: Altered body composition is frequently observed in Crohn's disease (CD) patients. AIMS: To investigate the nutritional status, and the effect of different therapeutic regimes in adult CD patients. METHODS: Fat free mass (FFM) and BIA-derived phase angle (PhA) were assessed in 45 CD patients, 22 on conventional therapy (CT) and 23 on maintenance therapy with infliximab (MT). Nutritional status was also assessed in 12 CD patients before and following the induction protocol with infliximab. BIA data of CD patients were compared with those of 20 healthy asymptomatic volunteers. In CD patients C Reactive Protein (CRP) and albuminaemia dosage were obtained. RESULTS: The mean values of PhA and of FFM were significantly lower in CT patients when compared with control group and MT patients. Following infliximab treatment FFM increased, although not significantly, while mean phase angle value significantly increased from 4.6+/ 0.3 to 6.2+/-0.4 (p<0.05). CRP was significantly lower in MT patients compared to that in CT patients. CONCLUSION: CD patients on conventional therapy showed a lower FFM and a lower mean phase angle score compared to those on infliximab therapy. Following infliximab treatment the mean phase angle score normalized. PhA is a reliable nutritional indicator in IBD patients and could be considered as an additional tool for assessing response to treatment. PMID- 28096061 TI - Connexin37 deficiency alters organic bone matrix, cortical bone geometry, and increases Wnt/beta-catenin signaling. AB - Deletion of connexin (Cx) 37 in mice leads to increased cancellous bone mass due to defective osteoclast differentiation. Paradoxically; however, Cx37-deficient mice exhibit reduced cortical thickness accompanied by higher bone strength, suggesting a contribution of Cx37 to bone matrix composition. Thus, we investigated whether global deletion of Cx37 alters the composition of organic bone extracellular matrix. Five-month-old Cx37-/- mice exhibited increased marrow cavity area, and periosteal and endocortical bone surface resulting in higher total area in tibia compared to Cx37+/+ control mice. Deletion of Cx37 increased genes involved in collagen maturation (loxl3 and loxl4) and glycosaminoglycans- (chsy1, chpf and has3) proteoglycans- associated genes (biglycan and decorin). In addition, expression of type II collagen assessed by immunostaining was increased by 82% whereas collagen maturity by picrosirius-polarizarion tended to be reduced (p=0.071). Expression of glycosaminoglycans by histochemistry was decreased, whereas immunostaining revealed that biglycan was unchanged and decorin was slightly increased in Cx37-/- bone sections. Consistent with these in vivo findings, MLO-Y4 osteocytic cells silenced for Cx37 gene exhibited increased mRNA levels for collagen synthesis (col1a1 and col3a1) and collagen maturation (lox, loxl1 and loxl2 genes). Furthermore, mechanistic studies showed Wnt/beta-catenin activation in MLO-Y4 osteocytic cells, L5 vertebra, and authentic calvaria derived osteocytes isolated by fluorescent-activated cell sorter. Our findings demonstrate that altered profile of the bone matrix components in Cx37-deficient mice acts in favor of higher resistance to fracture in long bones. PMID- 28096062 TI - Combat Casualty Care improvement: A quality process. PMID- 28096063 TI - Chest trauma: First 48hours management. AB - Chest trauma remains an issue for health services for both severe and apparently mild trauma management. Severe chest trauma is associated with high mortality and is considered liable for 25% of mortality in multiple traumas. Moreover, mild trauma is also associated with significant morbidity especially in patients with preexisting conditions. Thus, whatever the severity, a fast-acting strategy must be organized. At this time, there are no guidelines available from scientific societies. These expert recommendations aim to establish guidelines for chest trauma management in both prehospital an in hospital settings, for the first 48hours. The "Societe francaise d'anesthesie reanimation" and the "Societe francaise de medecine d'urgence" worked together on the 7 following questions: (1) criteria defining severity and for appropriate hospital referral; (2) diagnosis strategy in both pre- and in-hospital settings; (3) indications and guidelines for ventilatory support; (4) management of analgesia; (5) indications and guidelines for chest tube placement; (6) surgical and endovascular repair indications in blunt chest trauma; (7) definition, medical and surgical specificity of penetrating chest trauma. For each question, prespecified "crucial" (and sometimes also "important") outcomes were identified by the panel of experts because it mattered for patients. We rated evidence across studies for these specific clinical outcomes. After a systematic Grade(r) approach, we defined 60 recommendations. Each recommendation has been evaluated by all the experts according to the DELPHI method. PMID- 28096064 TI - Evaluation of financial burden following complications after major surgery in France: Potential return after perioperative goal-directed therapy. AB - OBJECTIVE: Perioperative goal-directed therapy (PGDT) has been demonstrated to improve postoperative outcomes and reduce the length of hospital stays. The objective of our analysis was to evaluate the cost of complications, derived from French hospital payments, and calculate the potential cost savings and length of hospital stay reductions. METHODS: The billing of 2388 patients who underwent scheduled high-risk surgery (i.e. major abdominal, gynaecologic, urological, vascular, and orthopaedic interventions) over three years was retrospectively collected from three French hospitals (one public-teaching, one public, and one private hospital). A relationship between mortality, length of hospital stays, cost/patient, and severity scores, based mainly on postoperative complications but also on preoperative clinical status, were analysed. Statistical analysis was performed using Student's t-tests or Wilcoxon tests. RESULTS: Our analyses determined that a severity score of 3 or 4 was associated with complications in 90% of cases and this represented 36% of patients who, compared with those with a score of 1 or 2, were associated with significantly increased costs (? 8205+/ 3335 to ? 22,081+/-16,090; P<0.001, delta of ? 13,876) and a prolonged length of hospital stay (mean of 10 to 27 days; P<0.001, delta of 17 days). According to estimates for complications avoided by PGDT, there was a projected reduction in average healthcare costs of between ? 854 and ? 1458 per patient and a reduction in total hospital bed days from 1755 to 4423 over three years. Based on French National data (47,000 high risk surgeries per year), the potential financial savings ranged from ? 40M to ? 68M, not including the costs of PGDT and its implementation. CONCLUSION: Our analysis demonstrates that patients with complications are significantly more expensive to care for than those without complications. In our model, it was projected that implementing PGDT during high risk surgery may significantly reduce healthcare costs and the length of hospital stays in France while probably improving patient access to care and reducing waiting times for procedures. PMID- 28096065 TI - Patient-Specific Predictive Modeling Using Random Forests: An Observational Study for the Critically Ill. AB - BACKGROUND: With a large-scale electronic health record repository, it is feasible to build a customized patient outcome prediction model specifically for a given patient. This approach involves identifying past patients who are similar to the present patient and using their data to train a personalized predictive model. Our previous work investigated a cosine-similarity patient similarity metric (PSM) for such patient-specific predictive modeling. OBJECTIVE: The objective of the study is to investigate the random forest (RF) proximity measure as a PSM in the context of personalized mortality prediction for intensive care unit (ICU) patients. METHODS: A total of 17,152 ICU admissions were extracted from the Multiparameter Intelligent Monitoring in Intensive Care II database. A number of predictor variables were extracted from the first 24 hours in the ICU. Outcome to be predicted was 30-day mortality. A patient-specific predictive model was trained for each ICU admission using an RF PSM inspired by the RF proximity measure. Death counting, logistic regression, decision tree, and RF models were studied with a hard threshold applied to RF PSM values to only include the M most similar patients in model training, where M was varied. In addition, case specific random forests (CSRFs), which uses RF proximity for weighted bootstrapping, were trained. RESULTS: Compared to our previous study that investigated a cosine similarity PSM, the RF PSM resulted in superior or comparable predictive performance. RF and CSRF exhibited the best performances (in terms of mean area under the receiver operating characteristic curve [95% confidence interval], RF: 0.839 [0.835-0.844]; CSRF: 0.832 [0.821-0.843]). RF and CSRF did not benefit from personalization via the use of the RF PSM, while the other models did. CONCLUSIONS: The RF PSM led to good mortality prediction performance for several predictive models, although it failed to induce improved performance in RF and CSRF. The distinction between predictor and similarity variables is an important issue arising from the present study. RFs present a promising method for patient-specific outcome prediction. PMID- 28096066 TI - "Happiness Inventors": Informing Positive Computing Technologies Through Participatory Design With Children. AB - BACKGROUND: Positive psychological interventions for children have typically focused on direct adaptations of interventions developed for adults. As the community moves toward designing positive computing technologies to support child well-being, it is important to use a more participatory process that directly engages children's voices. OBJECTIVE: Our objectives were, through a participatory design study, to understand children's interpretations of positive psychology concepts, as well as their perspectives on technologies that are best suited to enhance their engagement with practice of well-being skills. METHODS: We addressed these questions through a content analysis of 434 design ideas, 51 sketches, and 8 prototype and videos, which emerged from a 14-session cooperative inquiry study with 12 child "happiness inventors." The study was part of a summer learning camp held at the children's middle school, which focused on teaching the invention process, teaching well-being skills drawn from positive psychology and related areas (gratitude, mindfulness, and problem solving), and iterating design ideas for technologies to support these skills. RESULTS: The children's ideas and prototypes revealed specific facets of how they interpreted gratitude (as thanking, being positive, and doing good things), mindfulness (as externally representing thought and emotions, controlling those thoughts and emotions, getting through unpleasant things, and avoiding forgetting something), and problem solving (as preventing bad decisions, seeking alternative solutions, and not dwelling on unproductive thoughts). This process also revealed that children emphasized particular technologies in their solutions. While desktop or laptop solutions were notably lacking, other ideas were roughly evenly distributed between mobile apps and embodied computing technologies (toys, wearables, etc). We also report on desired functionalities and approaches to engagement in the children's ideas, such as a notable emphasis on representing and responding to internal states. CONCLUSIONS: Our findings point to promising directions for the design of positive computing technologies targeted at children, with particular emphases on the perspectives, technologies, engagement approaches, and functionalities that appealed to the children in our study. The dual focus of the study on teaching skills while designing technologies is a novel methodology in the design of positive computing technologies intended to increase child well being. PMID- 28096067 TI - Assessing the Quality, Feasibility, and Efficacy of Electronic Patient Platforms Designed to Support Adolescents and Young Adults With Cancer: A Systematic Review Protocol. AB - BACKGROUND: A range of innovative websites, mobile technologies, eHealth and mHealth platforms have emerged to support adolescents and young adults (AYAs) with cancer. Previous reviews have identified these various applications and solutions, but no review has summarized the quality, feasibility, and efficacy of existing patient platforms (inclusive of websites, mobile technologies, mHealth and eHealth platforms) developed specifically for young people with cancer. OBJECTIVE: This paper describes the design of a protocol to conduct a review of published studies or reports which describe or report on an existing platform designed specifically for AYAs who have had a cancer diagnosis. METHODS: A search string was developed using a variety of key words and Medical Subject Heading and applied to bibliographic databases. General data (sample characteristics, patient platform development, design and, if applicable, pilot testing outcomes) will be extracted from reports and studies. Drawing on a previously developed coding schematic, the identified patient platforms will be coded for mode of delivery into (1) automated functions, (2) communicative functions, and (3) use of supplementary modes. An adapted version of the Mobile App Rating Scale (MARS) will be used to assess the of quality of each identified patient platform. The methodological quality of included studies will be assessed using the Quality Assessment Criteria for Evaluating Primary Research Papers from a Variety of Fields (QualSyst). Both authors will independently screen eligible studies for final inclusion and will both be responsible for data extraction and appraisal. Data will be synthesized narratively to provide an overview of identified patient platforms. RESULTS: The review began in October 2016 and is currently in progress. The review paper will be submitted for peer-review and publication in the summer of 2017. CONCLUSIONS: This review will be unique in its focus on assessing, where possible, the quality and efficacy of patient platforms for adolescents and young adults diagnosed with cancer. Results generated from this review will provide an invaluable insight into the utility of modern technology in supporting young people with cancer. PMID- 28096068 TI - Perceived and Performed eHealth Literacy: Survey and Simulated Performance Test. AB - BACKGROUND: Electronic health (eHealth) literacy of consumers is essential in order to improve information and communication technology (ICT) use for health purposes by ordinary citizens. However, performed eHealth literacy is seldom studied. Therefore, the present study assessed perceived and performed eHealth literacy using the recent conceptualization of health literacy skills. OBJECTIVE: The aim of this paper was to examine the association between perceived and performed eHealth literacies. METHODS: In total, 82 Israeli adults participated in the study, all 50 years and older, with a mean age of 67 (SD 11). Of the participants, 60% (49/82) were women and 72% (59/82) had a post-secondary education. The participants were first surveyed and then tested in a computer simulation of health-related Internet tasks. Performed, perceived (eHealth Literacy Scale, eHEALS), and evaluated eHealth literacy were assessed, and performed eHealth literacy was also recorded and re-evaluated later. Performance was scored for successful completion of tasks, and was also assessed by two researchers for motivation, confidence, and amount of help provided. RESULTS: The skills of accessing, understanding, appraising, applying, and generating new information had decreasing successful completion rates. Generating new information was least correlated with other skills. Perceived and performed eHealth literacies were moderately correlated (r=.34, P=.01) while facets of performance (ie, digital literacy and eHealth literacy) were highly correlated (r=.82, P<.001). Participants low and high in performed eHealth literacy were significantly different: low performers were older and had used the Internet for less time, required more assistance, and were less confident in their conduct than high performers. CONCLUSIONS: The moderate association between perceived and performed eHealth literacy indicates that the latter should be assessed separately. In as much, the assessment of performed eHealth literacy in clinical settings should entail the structuring of tasks as well as shortening and automatizing the assessment. PMID- 28096069 TI - Newspaper response to the back pain myth busting advice: bruising but helpful. PMID- 28096070 TI - A Comparative Study of Tower of London Scoring Systems and Normative Data. AB - Objective: Tower of London (ToL) is a planning ability task that includes multiple versions. The original ToL was developed by Shallice together with two scoring systems (ToL-SS). Another two ToL-SS were proposed by Anderson et al. and Krikorian et al. The purpose of this study is to provide normative data for four ToL-SS and explore the effects of demographic variables on ToL performance. Furthermore, we aimed to determine the discriminative validity of these ToL-SS in clinical samples. Method: Four groups were included in the study: a normative sample of healthy adults (HC; n = 298); patients with Parkinson's disease with mild cognitive impairment (PD-MCI; n = 52) and without cognitive impairment (PD ND; n = 57); and patients with schizophrenia (SCH; n = 28). The effects of demographic variables on ToL-SS were examined in the HC group. Between-groups comparisons of ToL-SS were conducted using regression analysis with dummy codes. Results: All four ToL-SS were not significantly affected by age, whereas the effect of gender and education is not consistent. ToL-SS significantly (p < .05) differentiate HC from PD-MCI and SCH. Cohen's effect size coefficients d range from 0.68 to 1.29. Internal consistency coefficients (Cronbach's alpha) of ToL-SS range from 0.33 to 0.60. Conclusions: Despite poor to questionable internal consistency of ToL-SS, the discriminative validity and clinical utility for assessing planning deficits in PD-MCI and SCH are high. This study provides normative standards for all four ToL-SS on an adult population for use in clinical practice. PMID- 28096071 TI - Clinical benefit of vedolizumab on articular manifestations in patients with active spondyloarthritis associated with inflammatory bowel disease. PMID- 28096072 TI - Response to eLetter: 'Infections in giant cell arteritis and therapeutic implications' by Moiseev et al. PMID- 28096073 TI - Woman dies after infection with bacteria resistant to all antibiotics available in US. PMID- 28096074 TI - Notions of similarity for systems biology models. PMID- 28096075 TI - hppRNA-a Snakemake-based handy parameter-free pipeline for RNA-Seq analysis of numerous samples. AB - RNA-Seq technology has been gradually becoming a routine approach for characterizing the properties of transcriptome in terms of organisms, cell types and conditions and consequently a big burden has been put on the facet of data analysis, which calls for an easy-to-learn workflow to cope with the increased demands from a large number of laboratories across the world. We report a one-in all solution called hppRNA, composed of four scenarios such as pre-mapping, core workflow, post-mapping and sequence variation detection, written by a series of individual Perl and R scripts, counting on well-established and preinstalled software, irrespective of single-end or paired-end, unstranded or stranded sequencing method. It features six independent core-workflows comprising the state-of-the-art technology with dozens of popular cutting-edge tools such as Tophat-Cufflink-Cuffdiff, Subread-featureCounts-DESeq2, STAR-RSEM-EBSeq, Bowtie eXpress-edgeR, kallisto-sleuth, HISAT-StringTie-Ballgown, and embeds itself in Snakemake, which is a modern pipeline management system. The core function of this pipeline is turning the raw fastq files into gene/isoform expression matrix and differentially expressed genes or isoforms as well as the identification of fusion genes, single nucleotide polymorphisms, long noncoding RNAs and circular RNAs. Last but not least, this pipeline is specifically designed for performing the systematic analysis on a huge set of samples in one go, ideally for the researchers who intend to deploy the pipeline on their local servers. The scripts as well as the user manual are freely available at https://sourceforge.net/projects/hpprna/. PMID- 28096076 TI - A landscape of synthetic viable interactions in cancer. AB - Synthetic viability, which is defined as the combination of gene alterations that can rescue the lethal effects of a single gene alteration, may represent a mechanism by which cancer cells resist targeted drugs. Approaches to detect synthetic viable (SV) interactions in cancer genome to investigate drug resistance are still scarce. Here, we present a computational method to detect synthetic viability-induced drug resistance (SVDR) by integrating the multidimensional data sets, including copy number alteration, whole-exome mutation, expression profile and clinical data. SVDR comprehensively characterized the landscape of SV interactions across 8580 tumors in 32 cancer types by integrating The Cancer Genome Atlas data, small hairpin RNA-based functional experimental data and yeast genetic interaction data. We revealed that the SV interactions are favorable to cells and can predict clinical prognosis for cancer patients, which were robustly observed in an independent data set. By integrating the cancer pharmacogenomics data sets from Cancer Cell Line Encyclopedia (CCLE) and Broad Cancer Therapeutics Response Portal, we have demonstrated that SVDR enables drug resistance prediction and exhibits high reliability between two databases. To our knowledge, SVDR is the first genome scale data-driven approach for the identification of SV interactions related to drug resistance in cancer cells. This data-driven approach lays the foundation for identifying the genomic markers to predict drug resistance and successfully infers the potential drug combination for anti-cancer therapy. PMID- 28096078 TI - How to prevent the microvascular complications of type 2 diabetes beyond glucose control. AB - Microvascular complications (retinopathy, nephropathy, and neuropathy) affect hundreds of millions of patients with type 2 diabetes. They usually affect people with longstanding or uncontrolled disease, but they can also be present at diagnosis or in those yet to have a diagnosis made. The presentation and progression of these complications can lead to loss of visual, renal, and neurologic functions, impaired mobility and cognition, poor quality of life, limitations for employment and productivity, and increased costs for the patient and society. If left uncontrolled or untreated, they lead to irreversible damage and even death. This review focuses on the primary and secondary prevention of diabetic microvascular complications in patients with type 2 diabetes, beyond glycemic control. Interventions discussed include standard of care interventions supported by guidelines from major organizations, as well as additional proposed interventions that are supported by research published in the past decade. High level evidence sources such as systematic reviews and large, multicenter randomized clinical trials have been prioritized. Smaller trials were included where high quality evidence was unavailable. PMID- 28096079 TI - Exercise therapy versus arthroscopic partial meniscectomy for degenerative meniscal tear in middle aged patients: randomised controlled trial with two year follow-up. PMID- 28096080 TI - FTO genotype and weight loss: systematic review and meta-analysis of 9563 individual participant data from eight randomised controlled trials. PMID- 28096082 TI - The ties that bind. PMID- 28096081 TI - Mice with hyperbilirubinemia due to Gilbert's syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARalpha. AB - Gilbert's syndrome in humans is derived from a polymorphism (TA repeat) in the hepatic UGT1A1 gene that results in decreased conjugation and increased levels of unconjugated bilirubin. Recently, we have shown that bilirubin binds directly to the fat-burning nuclear peroxisome proliferator-activated receptor-alpha (PPARalpha). Additionally, we have shown that serine 73 phosphorylation [Ser(P)73] of PPARalpha decreases activity by reducing its protein levels and transcriptional activity. The aim of this study was to determine whether humanized mice with the Gilbert's polymorphism (HuUGT*28) have increased PPARalpha activation and reduced hepatic fat accumulation. To determine whether humanized mice with Gilbert's mutation (HuUGT*28) have reduced hepatic lipids, we placed them and C57BL/6J control mice on a high-fat (60%) diet for 36 wk. Body weights, fat and lean mass, and fasting blood glucose and insulin levels were measured every 6 wk throughout the investigation. At the end of the study, hepatic lipid content was measured and PPARalpha regulated genes as well as immunostaining of Ser(P)73 PPARalpha from liver sections. The HuUGT*28 mice had increased serum bilirubin, lean body mass, decreased fat mass, and hepatic lipid content as well as lower serum glucose and insulin levels. Also, the HuUGT*28 mice had reduced Ser(P)73 PPARalpha immunostaining in livers and increased PPARalpha transcriptional activity compared with controls. A chronic but mild endogenous increase in unconjugated hyperbiliubinemia protects against hepatic steatosis through a reduction in Ser(P)73 PPARalpha, causing an increase in PPARalpha transcriptional activity. PMID- 28096083 TI - LRSSL: predict and interpret drug-disease associations based on data integration using sparse subspace learning. AB - Motivation: : Exploring the potential curative effects of drugs is crucial for effective drug development. Previous studies have indicated that integration of multiple types of information could be conducive to discovering novel indications of drugs. However, how to efficiently identify the mechanism behind drug-disease associations while integrating data from different sources remains a challenging problem. Results: : In this research, we present a novel method for indication prediction of both new drugs and approved drugs. This method is based on Laplacian regularized sparse subspace learning (LRSSL), which integrates drug chemical information, drug target domain information and target annotation information. Experimental results show that the proposed method outperforms several recent approaches for predicting drug-disease associations. Some drug therapeutic effects predicted by the method could be validated by database records or literatures. Moreover, with L1-norm constraint, important drug features have been extracted from multiple drug feature profiles. Case studies suggest that the extracted drug features could be beneficial to interpretation of the predicted results. Availability and Implementation: https://github.com/LiangXujun/LRSSL. Contact: proteomics@csu.edu.cn. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28096084 TI - TimesVector: a vectorized clustering approach to the analysis of time series transcriptome data from multiple phenotypes. AB - Motivation: Identifying biologically meaningful gene expression patterns from time series gene expression data is important to understand the underlying biological mechanisms. To identify significantly perturbed gene sets between different phenotypes, analysis of time series transcriptome data requires consideration of time and sample dimensions. Thus, the analysis of such time series data seeks to search gene sets that exhibit similar or different expression patterns between two or more sample conditions, constituting the three dimensional data, i.e. gene-time-condition. Computational complexity for analyzing such data is very high, compared to the already difficult NP-hard two dimensional biclustering algorithms. Because of this challenge, traditional time series clustering algorithms are designed to capture co-expressed genes with similar expression pattern in two sample conditions. Results: We present a triclustering algorithm, TimesVector, specifically designed for clustering three dimensional time series data to capture distinctively similar or different gene expression patterns between two or more sample conditions. TimesVector identifies clusters with distinctive expression patterns in three steps: (i) dimension reduction and clustering of time-condition concatenated vectors, (ii) post processing clusters for detecting similar and distinct expression patterns and (iii) rescuing genes from unclassified clusters. Using four sets of time series gene expression data, generated by both microarray and high throughput sequencing platforms, we demonstrated that TimesVector successfully detected biologically meaningful clusters of high quality. TimesVector improved the clustering quality compared to existing triclustering tools and only TimesVector detected clusters with differential expression patterns across conditions successfully. Availability and Implementation: The TimesVector software is available at http://biohealth.snu.ac.kr/software/TimesVector/. Contact: sunkim.bioinfo@snu.ac.kr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28096085 TI - Improved orthology inference with Hieranoid 2. AB - Motivation: The initial step in many orthology inference methods is the computationally demanding establishment of all pairwise protein similarities across all analysed proteomes. The quadratic scaling with proteomes has become a major bottleneck. A remedy is offered by the Hieranoid algorithm which reduces the complexity to linear by hierarchically aggregating ortholog groups from InParanoid along a species tree. Results: We have further developed the Hieranoid algorithm in many ways. Major improvements have been made to the construction of multiple sequence alignments and consensus sequences. Hieranoid version 2 was evaluated with standard benchmarks that reveal a dramatic increase in the coverage/accuracy tradeoff over version 1, such that it now compares favourably with the best methods. The new parallelized cluster mode allows Hieranoid to be run on large data sets in a much shorter timespan than InParanoid, yet at similar accuracy. Contact: mateusz.kaduk@scilifelab.se. Availability and Implementation: Perl code freely available at http://hieranoid.sbc.su.se/ . Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28096088 TI - How I treat acquired aplastic anemia. AB - Acquired severe aplastic anemia (SAA) is a rare hematologic disease associated with significant morbidity and mortality. Immune destruction of hemopoietic stem cells plays an important role in pathogenesis, as shown by successful treatment with immunosuppressive agents, leading to transfusion independence or complete recovery of peripheral blood counts in a proportion of patients. Growth factors can be combined with immunosuppressive therapy (IST) and may improve response rates, as recently shown with thrombopoietin analogs. Anabolic steroids may still play a role in combination with IST. The problem with IST is failure to respond and the development of late clonal disorders. Bone marrow transplantation (BMT) is the other therapeutic option: a matched sibling donor remains the best choice. For patients lacking a matched family donor, unrelated donors can be readily found, although mostly for patients of Caucasian origin. Other BMT options include unrelated cord blood or mismatched family donors. Acute and chronic graft versus-host disease remain important complications of BMT. Patient age is a strong predictor of outcome for both IST and BMT, and must be considered when designing therapeutic strategies. Early diagnosis and treatment, as well as long term monitoring, remain crucial steps for successful treatment of SAA. PMID- 28096087 TI - Diffuse large B-cell lymphoma genotyping on the liquid biopsy. AB - Accessible and real-time genotyping for diagnostic, prognostic, or treatment purposes is increasingly impelling in diffuse large B-cell lymphoma (DLBCL). Cell free DNA (cfDNA) is shed into the blood by tumor cells undergoing apoptosis and can be used as source of tumor DNA for the identification of DLBCL mutations, clonal evolution, and genetic mechanisms of resistance. In this study, we aimed at tracking the basal DLBCL genetic profile and its modification upon treatment using plasma cfDNA. Ultra-deep targeted next generation sequencing of pretreatment plasma cfDNA from DLBCL patients correctly discovered DLBCL associated mutations that were represented in >20% of the alleles of the tumor biopsy with >90% sensitivity and ~100% specificity. Plasma cfDNA genotyping also allowed for the recovery of mutations that were undetectable in the tissue biopsy, conceivably because, due to spatial tumor heterogeneity, they were restricted to clones that were anatomically distant from the biopsy site. Longitudinal analysis of plasma samples collected under rituximab cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP) chemotherapy showed a rapid clearance of DLBCL mutations from cfDNA among responding patients. Conversely, among patients who were resistant to R-CHOP, basal DLBCL mutations did not disappear from cfDNA. In addition, among treatment-resistant patients, new mutations were acquired in cfDNA that marked resistant clones selected during the clonal evolution. These results demonstrate that cfDNA genotyping of DLBCL is as accurate as genotyping of the diagnostic biopsy to detect clonally represented somatic tumor mutations and is a real-time and noninvasive approach to tracking clonal evolution and the emergence of treatment-resistant clones. PMID- 28096086 TI - Platelets activate a pathogenic response to blood-stage Plasmodium infection but not a protective immune response. AB - Clinical studies indicate that thrombocytopenia correlates with the development of severe falciparum malaria, suggesting that platelets either contribute to control of parasite replication, possibly as innate parasite killer cells or function in eliciting pathogenesis. Removal of platelets by anti-CD41 mAb treatment, platelet inhibition by aspirin, and adoptive transfer of wild-type (WT) platelets to CD40-KO mice, which do not control parasite replication, resulted in similar parasitemia compared with control mice. Human platelets at a physiologic ratio of 1 platelet to 9 red blood cells (RBCs) did not inhibit the in vitro development or replication of blood-stage Plasmodium falciparum The percentage of Plasmodium-infected (iRBCs) with bound platelets during the ascending parasitemia in Plasmodium chabaudi- and Plasmodium berghei-infected mice and the 48-hour in vitro cycle of P falciparum was <10%. P chabaudi and P berghei iRBCs with apoptotic parasites (TdT+) exhibited minimal platelet binding (<5%), which was similar to nonapoptotic iRBCs. These findings collectively indicate platelets do not kill bloodstage Plasmodium at physiologically relevant effector-to-target ratios. P chabaudi primary and secondary parasitemia was similar in mice depleted of platelets by mAb-injection just before infection, indicating that activation of the protective immune response does not require platelets. In contrast to the lack of an effect on parasite replication, adoptive transfer of WT platelets to CD40-KO mice, which are resistant to experimental cerebral malaria, partially restored experimental cerebral malaria mortality and symptoms in CD40-KO recipients, indicating platelets elicit pathogenesis and platelet CD40 is a key molecule. PMID- 28096089 TI - Tolerogenic interactions between CD8+ dendritic cells and NKT cells prevent rejection of bone marrow and organ grafts. AB - The combination of total lymphoid irradiation and anti-T-cell antibodies safely induces immune tolerance to combined hematopoietic cell and organ allografts in humans. Our mouse model required host natural killer T (NKT) cells to induce tolerance. Because NKT cells normally depend on signals from CD8+ dendritic cells (DCs) for their activation, we used the mouse model to test the hypothesis that, after lymphoid irradiation, host CD8+ DCs play a requisite role in tolerance induction through interactions with NKT cells. Selective deficiency of either CD8+ DCs or NKT cells abrogated chimerism and organ graft acceptance. After radiation, the CD8+ DCs increased expression of surface molecules required for NKT and apoptotic cell interactions and developed suppressive immune functions, including production of indoleamine 2,3-deoxygenase. Injection of naive mice with apoptotic spleen cells generated by irradiation led to DC changes similar to those induced by lymphoid radiation, suggesting that apoptotic body ingestion by CD8+ DCs initiates tolerance induction. Tolerogenic CD8+ DCs induced the development of tolerogenic NKT cells with a marked T helper 2 cell bias that, in turn, regulated the differentiation of the DCs and suppressed rejection of the transplants. Thus, reciprocal interactions between CD8+ DCs and invariant NKT cells are required for tolerance induction in this system that was translated into a successful clinical protocol. PMID- 28096090 TI - How I manage ibrutinib-refractory chronic lymphocytic leukemia. AB - The introduction of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib has dramatically changed the management of chronic lymphocytic leukemia (CLL). Although responses have been durable in the majority of patients, relapses do occur, especially in the high-risk patient population. Most relapses occur as the result of acquired mutations in BTK and PLCG2, which may facilitate success with alternative targeted therapies. As outcomes after ibrutinib relapse have been reported to be poor, specific strategies are needed for this patient population. Here, I discuss the diagnosis and management of ibrutinib-refractory CLL. The focus will be on common clinical scenarios that can be mistaken for relapse and how to accurately determine which patients are relapsing. Because there is no established standard of care, I discuss currently available options for standard therapy and existing clinical data. I also discuss new agents with the potential to be effective in patients refractory to ibrutinib. Finally, I discuss strategies for long-term disease control in this patient population. PMID- 28096092 TI - Initiation of acute graft-versus-host disease by angiogenesis. AB - The inhibition of inflammation-associated angiogenesis ameliorates inflammatory diseases by reducing the recruitment of tissue-infiltrating leukocytes. However, it is not known if angiogenesis has an active role during the initiation of inflammation or if it is merely a secondary effect occurring in response to stimuli by tissue-infiltrating leukocytes. Here, we show that angiogenesis precedes leukocyte infiltration in experimental models of inflammatory bowel disease and acute graft-versus-host disease (GVHD). We found that angiogenesis occurred as early as day+2 after allogeneic transplantation mainly in GVHD typical target organs skin, liver, and intestines, whereas no angiogenic changes appeared due to conditioning or syngeneic transplantation. The initiation phase of angiogenesis was not associated with classical endothelial cell (EC) activation signs, such as Vegfa/VEGFR1+2 upregulation or increased adhesion molecule expression. During early GVHD at day+2, we found significant metabolic and cytoskeleton changes in target organ ECs in gene array and proteomic analyses. These modifications have significant functional consequences as indicated by profoundly higher deformation in real-time deformability cytometry. Our results demonstrate that metabolic changes trigger alterations in cell mechanics, leading to enhanced migratory and proliferative potential of ECs during the initiation of inflammation. Our study adds evidence to the hypothesis that angiogenesis is involved in the initiation of tissue inflammation during GVHD. PMID- 28096093 TI - Lymphangiogenesis is a feature of acute GVHD, and VEGFR-3 inhibition protects against experimental GVHD. AB - Lymph vessels play a crucial role in immune reactions in health and disease. In oncology the inhibition of lymphangiogenesis is an established therapeutic concept for reducing metastatic spreading of tumor cells. During allogeneic tissue transplantation, the inhibition of lymphangiogenesis has been successfully used to attenuate graft rejection. Despite its critical importance for tumor growth, alloimmune responses, and inflammation, the role of lymphangiogenesis has not been investigated during allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that acute graft-versus-host disease (aGVHD) is associated with lymphangiogenesis in murine allo-HSCT models as well as in patient intestinal biopsies. Inhibition of aGVHD-associated lymphangiogenesis by monoclonal antibodies against vascular endothelial growth factor receptor 3 (VEGFR-3) ameliorated aGVHD and improved survival in murine models. The administration of anti-VEGFR-3 antibodies did not interfere with hematopoietic engraftment and improved immune reconstitution in allo-HSCT recipients with aGVHD. Anti-VEGFR-3 therapy had no significant impact on growth of malignant lymphoma after allo-HSCT. We conclude that aGVHD is associated with lymphangiogenesis in intestinal lesions and in lymph nodes. Our data show that anti-VEGFR-3 treatment ameliorates lethal aGVHD and identifies the lymphatic vasculature as a novel therapeutic target in the setting of allo-HSCT. PMID- 28096091 TI - Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel. AB - An international expert panel, active within the European Society for Blood and Marrow Transplantation, European LeukemiaNet, Blood and Marrow Transplant Clinical Trial Group, and the International Myelodysplastic Syndromes Foundation developed recommendations for allogeneic hematopoietic stem cell transplantation (HSCT) in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Disease risks scored according to the revised International Prognostic Scoring System (IPSS-R) and presence of comorbidity graded according to the HCT Comorbidity Index (HCT-CI) were recognized as relevant clinical variables for HSCT eligibility. Fit patients with higher-risk IPSS-R and those with lower-risk IPSS-R with poor-risk genetic features, profound cytopenias, and high transfusion burden are candidates for HSCT. Patients with a very high MDS transplantation risk score, based on combination of advanced age, high HCT-CI, very poor-risk cytogenetic and molecular features, and high IPSS-R score have a low chance of cure with standard HSCT and consideration should be given to treating these patients in investigational studies. Cytoreductive therapy prior to HSCT is advised for patients with >=10% bone marrow myeloblasts. Evidence from prospective randomized clinical trials does not provide support for specific recommendations on the optimal high intensity conditioning regimen. For patients with contraindications to high-intensity preparative regimens, reduced intensity conditioning should be considered. Optimal timing of HSCT requires careful evaluation of the available effective nontransplant strategies. Prophylactic donor lymphocyte infusion (DLI) strategies are recommended in patients at high risk of relapse after HSCT. Immune modulation by DLI strategies or second HSCT is advised if relapse occurs beyond 6 months after HSCT. PMID- 28096094 TI - Platelet CD34 expression and alpha/delta-granule abnormalities in GFI1B- and RUNX1-related familial bleeding disorders. PMID- 28096096 TI - Political crisis in the NHS. PMID- 28096097 TI - Eating disorders are more prevalent than expected in women during midlife, study finds. PMID- 28096095 TI - Functional role and therapeutic targeting of p21-activated kinase 4 in multiple myeloma. AB - Dysregulated oncogenic serine/threonine kinases play a pathological role in diverse forms of malignancies, including multiple myeloma (MM), and thus represent potential therapeutic targets. Here, we evaluated the biological and functional role of p21-activated kinase 4 (PAK4) and its potential as a new target in MM for clinical applications. PAK4 promoted MM cell growth and survival via activation of MM survival signaling pathways, including the MEK-extracellular signal-regulated kinase pathway. Furthermore, treatment with orally bioavailable PAK4 allosteric modulator (KPT-9274) significantly impacted MM cell growth and survival in a large panel of MM cell lines and primary MM cells alone and in the presence of bone marrow microenvironment. Intriguingly, we have identified FGFR3 as a novel binding partner of PAK4 and observed significant activity of KPT-9274 against t(4;14)-positive MM cells. This set of data supports PAK4 as an oncogene in myeloma and provide the rationale for the clinical evaluation of PAK4 modulator in myeloma. PMID- 28096098 TI - Avoiding Untimely Implantable Cardioverter/Defibrillator Implantation by Intensified Heart Failure Therapy Optimization Supported by the Wearable Cardioverter/Defibrillator-The PROLONG Study. AB - BACKGROUND: Optimal timing of implantation of an implantable cardioverter/defibrillator (ICD) after newly diagnosed heart failure is unclear given that late reverse remodelling may occur. We aimed to analyze left ventricular ejection fraction (LVEF) after diagnosis of an LVEF <=35% during optimization of heart failure drug therapy. METHODS AND RESULTS: One hundred fifty-six patients with newly diagnosed LVEF <=35% receiving a wearable cardioverter/defibrillator (WCD) were analyzed. WCD was prescribed for 3 months until first re-evaluation. Indications for prolongation of WCD wearing period instead of ICD implantation were: (1) LVEF at 3-month visit 30% to 35%; (2) increase in LVEF of >=5% compared to the last visit; and (3) nonoptimized heart failure medication. Mean LVEF was 24+/-7% at diagnosis and 39+/-11% at last follow-up (mean, 12+/-10 months). Whereas 88 patients presented a primary preventive ICD indication (LVEF <=35%) at 3-month follow-up, only 58 showed a persistent primary preventive ICD indication at last follow-up. This delayed improvement in LVEF was related to nonischemic origin of cardiomyopathy, New York Heart Association functional class at baseline, heart rate, better LVEF after 3 months, and higher dosages of mineralocorticoid receptor antagonist. Twelve appropriate WCD shocks for ventricular tachycardia/ventricular fibrillation occurred in 11 patients. Two patients suffered from ventricular tachycardia/ventricular fibrillation beyond 3 months after diagnosis. CONCLUSIONS: A relevant proportion of patients with newly diagnosed heart failure shows recovery of LVEF >35% beyond 3 months after initiation of heart failure therapy. To avoid untimely ICD implantation, prolongation of WCD period should be considered in these patients to prevent sudden cardiac death while allowing left ventricular reverse remodeling during intensified drug therapy. PMID- 28096099 TI - High-Saturated-Fat Diet Increases Circulating Angiotensin-Converting Enzyme, Which Is Enhanced by the rs4343 Polymorphism Defining Persons at Risk of Nutrient Dependent Increases of Blood Pressure. AB - BACKGROUND: Angiotensin-converting enzyme (ACE) plays a major role in blood pressure regulation and cardiovascular homeostasis. Contrary to the assumption that ACE levels are stable, circulating ACE has been shown to be altered in obesity and weight loss. We sought to examine effects of a high-saturated-fat (HF) diet on ACE within the NUtriGenomic Analysis in Twins (NUGAT) study. METHODS AND RESULTS: Forty-six healthy and nonobese twin pairs initially consumed a carbohydrate-rich, low-fat diet over a period of 6 weeks to standardize for nutritional behavior prior to the study, followed by 6 weeks of HF diet under isocaloric conditions. After 6 weeks of HF diet, circulating ACE concentrations increased by 15% (P=1.6*10-30), accompanied by an increased ACE gene expression in adipose tissue (P=3.8*10-6). Stratification by ACE rs4343, a proxy for the ACE insertion/deletion polymorphism (I/D), revealed that homozygous carriers (GG) of the variant had higher baseline ACE concentrations (P=7.5*10-8) and additionally showed a 2-fold increase in ACE concentrations in response to the HF diet as compared to non- or heterozygous carriers (AA/AG, P=2*10-6). GG carriers also responded with higher systolic blood pressure as compared to AA/AG carriers (P=0.008). The strong gene-diet interaction was confirmed in a second independent, cross-sectional cohort, the Metabolic Syndrome Berlin Potsdam (MeSyBePo) study. CONCLUSIONS: The HF-diet-induced increase of ACE serum concentrations reveals ACE to be a potential molecular link between dietary fat intake and hypertension and cardiovascular disease (CVD). The GG genotype of the ACE rs4343 polymorphism represents a robust nutrigenetic marker for an unfavorable response to high-saturated-fat diets. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01631123. PMID- 28096101 TI - Advancing child health research in the UK: the Royal College of Paediatrics and Child Health Infants' Children's and Young People's Research Charter. PMID- 28096100 TI - Efficacy and Safety of Apixaban Compared With Warfarin in Patients With Atrial Fibrillation and Peripheral Artery Disease: Insights From the ARISTOTLE Trial. AB - BACKGROUND: We studied (1) the rates of stroke or systemic embolism and bleeding in patients with atrial fibrillation and peripheral artery disease (PAD) and (2) the efficacy and safety of apixaban versus warfarin in patients with atrial fibrillation with and without PAD. METHODS AND RESULTS: The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin for stroke/systemic embolism prevention; 884 (4.9%) patients had PAD at baseline. Patients with PAD had higher unadjusted rates of stroke and systemic embolism (hazard ratio [HR] 1.73, 95% CI 1.22-2.45; P=0.002) and major bleeding (HR 1.34, 95% CI 1.00-1.81; P=0.05), but after adjustment, no differences existed in rates of stroke and systemic embolism (HR 1.32, 95% CI 0.93-1.88; P=0.12) and major bleeding (HR 1.03, 95% CI 0.76-1.40; P=0.83) compared with patients without PAD. The risk of stroke or systemic embolism was similar in patients assigned to apixaban and warfarin with PAD (HR 0.63, 95% CI 0.32-1.25) and without PAD (HR 0.80, 95% CI 0.66-0.96; interaction P=0.52). Patients with PAD did not have a statistically significant reduction in major or clinically relevant nonmajor bleeding with apixaban compared with warfarin (HR 1.05, 95% CI 0.69-1.58), whereas those without PAD had a statistically significant reduction (HR 0.65, 95% CI 0.58-0.73; interaction P=0.03). CONCLUSIONS: Patients with PAD in ARISTOTLE had a higher crude risk of stroke or systemic embolism compared with patients without PAD that was not present after adjustment. The benefits of apixaban versus warfarin for stroke and systemic embolism were similar in patients with and without PAD. These findings highlight the need to optimize the treatment of patients with atrial fibrillation and PAD. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984. PMID- 28096102 TI - NIHR Clinical Research Networks: what they do and how they help paediatric research. AB - This review provides paediatricians with an update on the new structure of the National Institute for Health Research's (NIHR) Clinical Research Network (CRN): Children and its role within the wider NIHR infrastructure. The network supports delivery of high-quality research within the NHS in England and supports researchers, through provision of staff and resources, with feasibility, site set up, patient recruitment and study management. Since 2013, over 80% of commercial contract studies running within the UK sat within the UKCRN Portfolio. Of the diverse, increasing portfolio of studies supported by the network, many studies are interventional, with 33% being randomised controlled studies. Recruitment to studies supported by the network through the Children's Portfolio has consistently improved. Over 200 000 participants have been recruited to the Children's Portfolio studies to date, and there are currently approximately 500 studies open to recruitment. The CRN: Children has successfully involved patients and the public in all aspects of study design and delivery, including through the work of Generation R. Challenges remain in conducting paediatric research and the network is committed to supporting Children's research and further building on its achievements to date. Education and engagement of paediatricians within the network and research is important to further improving quality and delivery of paediatric research. PMID- 28096103 TI - Failure and success in severe gastrointestinal disease complicating neurodisability: who is at the end of the line? PMID- 28096104 TI - Recent developments in the surgical management of paediatric epilepsy. AB - Among the 1% of children affected by epilepsy, failure of pharmacological therapy and early age of seizure onset can lead to worse long-term cognitive outcomes, mental health disorders and impaired functional status. Surgical management often improves functional and cognitive outcomes in children with medically refractory epilepsy, especially when seizure remission is achieved. However, surgery remains underused in children with drug-resistant epilepsy, creating a large treatment gap. Several recent innovations have led to considerable improvement in surgical technique, including the recent development of minimally invasive diagnostic and therapeutic techniques such as stereotactic EEG, transcranial magnetic stimulation, MRI-guided laser ablation, as well as novel paradigms of neurostimulation. This article discusses the current landscape of surgical innovation in the management of paediatric epilepsy, leading to a paradigm shift towards minimally invasive therapy and closing the treatment gap in children suffering from drug-resistant seizures. PMID- 28096105 TI - The value of paediatric assessment in historic child sexual abuse. AB - INTRODUCTION: A perception exists that there are few benefits of a paediatric assessment in historic child sexual abuse (CSA), as the likelihood of finding forensic evidence is low. AIM: To determine the value of a comprehensive paediatric assessment in a dedicated clinic for children and young people who present following suspicion or allegation of historic CSA. METHOD: All children with suspected or alleged historic CSA, defined as >7 days after the last episode of sexual assault in pubertal girls, or >3 days for prepubertal girls and all boys, were assessed in a specialised paediatric clinic. Clinic data were collected prospectively between October 2009 and November 2014 and through retrospective case note review. RESULTS: Among the 249 children who presented with possible historic CSA, ages ranged from 0 to 17 years (median 7, SD 4.3). Of these children, 141 (57%) had a medical concern(s) related to the referral reason, 78 (31%) had an unrelated medical concern(s) and 55 (22%) had emotional or behavioural concerns requiring onward referral, while 18 (7%) children had physical signs supportive of CSA. Findings referable to social care were identified in 26 cases (10%), the police in 6 cases and 15 (6%) parents required professional help for anxiety symptoms. CONCLUSIONS: This study highlights the value of a comprehensive paediatric assessment in a dedicated clinic for cases of suspected or alleged historic CSA, by identifying a broad variety of unmet health needs in this group. The findings have important implications for the child, their families and the multiagency team. PMID- 28096106 TI - Non-accidental injury or congenital infection? PMID- 28096107 TI - The polio endgame: rationale behind the change in immunisation. AB - The decades long effort to eradicate polio is nearing the final stages and oral polio vaccine (OPV) is much to thank for this success. As cases of wild poliovirus continue to dwindle, cases of paralysis associated with OPV itself have become a concern. As type-2 poliovirus (one of three) has been certified eradicated and a large proportion of OPV-related paralysis is caused by the type 2 component of OPV, the World Health Assembly endorsed the phased withdrawal of OPV and the introduction of inactivated polio vaccine (IPV) into routine immunisation schedules as a crucial step in the polio endgame plan. The rapid pace of IPV scale-up and uptake required adequate supply, planning, advocacy, training and operational readiness. Similarly, the synchronised switch from trivalent OPV (all three types) to bivalent OPV (types 1 and 3) involved an unprecedented level of global coordination and country commitment. The important shift in vaccination policy seen through global IPV introduction and OPV withdrawal represents an historical milestone reached in the polio eradication effort. PMID- 28096108 TI - Reasons for drug policy reform: prohibition enables systemic human rights abuses and undermines public health. PMID- 28096110 TI - Bra Sizing and the Plastic Surgery Herd Effect: Are Breast Augmentation Patients Getting Accurate Information? AB - BACKGROUND: Bra sizing is a common method to preoperatively select implants for breast augmentation; however, no series has analyzed the accuracy of this modality postoperatively. Alternatively, previous investigations have validated the accuracy and utility of three-dimensional (3D) imaging for preoperative simulation in breast augmentation. OBJECTIVES: This investigation utilizes 3D analysis to determine if preoperative bra sizing provides equivocal information compared to surgical 3D simulation for patient education and planning prior to a breast augmentation. METHODS: During primary breast augmentation consultation, patients received preoperative 3D images and associated simulations. Sizers, equivocal to the implants chosen in the simulation, were placed in a surgical bra, and 3D images were repeated. Volumetric and contour analyses were compared between the surgical simulation and the bra/sizer image. All patients used a surgical bra and smooth, round silicone sizers (average volume, 302 cc; range, 265-339 cc). RESULTS: Seven patients (14 breasts) underwent analysis and comparison. The mean bra/sizer volume image was 22.3% greater than the preoperative simulated breast image. The mean absolute difference of all surface points between the two breast images was 9.25 mm (range, 5.98-11.96 mm; standard deviation, 8.59). The maximum anterior displacement of the bra image from the simulated image was 19.52 mm, centered at the upper pole; the maximum posterior displacement was 25.49 mm, centered at the lower pole. CONCLUSIONS: In comparison to 3D simulation, preoperative bra sizing overestimates postoperative volume, and upper pole fullness and underestimates lower pole projection. This investigation outlines some deficiencies of bra sizing and offers solutions for clinical management in primary breast augmentation. LEVEL OF EVIDENCE 2. PMID- 28096109 TI - Financial ties of principal investigators and randomized controlled trial outcomes: cross sectional study. AB - OBJECTIVE: To examine the association between the presence of individual principal investigators' financial ties to the manufacturer of the study drug and the trial's outcomes after accounting for source of research funding. DESIGN: Cross sectional study of randomized controlled trials (RCTs). SETTING: Studies published in "core clinical" journals, as identified by Medline, between 1 January 2013 and 31 December 2013. PARTICIPANTS: Random sample of RCTs focused on drug efficacy. MAIN OUTCOME MEASURE: Association between financial ties of principal investigators and study outcome. RESULTS: A total of 190 papers describing 195 studies met inclusion criteria. Financial ties between principal investigators and the pharmaceutical industry were present in 132 (67.7%) studies. Of 397 principal investigators, 231 (58%) had financial ties and 166 (42%) did not. Of all principal investigators, 156 (39%) reported advisor/consultancy payments, 81 (20%) reported speakers' fees, 81 (20%) reported unspecified financial ties, 52 (13%) reported honorariums, 52 (13%) reported employee relationships, 52 (13%) reported travel fees, 41 (10%) reported stock ownership, and 20 (5%) reported having a patent related to the study drug. The prevalence of financial ties of principal investigators was 76% (103/136) among positive studies and 49% (29/59) among negative studies. In unadjusted analyses, the presence of a financial tie was associated with a positive study outcome (odds ratio 3.23, 95% confidence interval 1.7 to 6.1). In the primary multivariate analysis, a financial tie was significantly associated with positive RCT outcome after adjustment for the study funding source (odds ratio 3.57 (1.7 to 7.7). The secondary analysis controlled for additional RCT characteristics such as study phase, sample size, country of first authors, specialty, trial registration, study design, type of analysis, comparator, and outcome measure. These characteristics did not appreciably affect the relation between financial ties and study outcomes (odds ratio 3.37, 1.4 to 7.9). CONCLUSIONS: Financial ties of principal investigators were independently associated with positive clinical trial results. These findings may be suggestive of bias in the evidence base. PMID- 28096111 TI - Commentary on: A Retrospective Study of the Psychological Outcomes of Labiaplasty. PMID- 28096112 TI - Caring for the "crash-landers". PMID- 28096113 TI - BMA calls for urgent meeting with prime minister to discuss NHS crisis. PMID- 28096114 TI - Bar code app aims to cut sugar intake. PMID- 28096115 TI - Australian medical college fights accusations of misconduct in presidential election. PMID- 28096116 TI - Commentary on: Lower Eyelid Retraction Surgery Without Internal Spacer Graft. PMID- 28096117 TI - Commentary on: An Anatomical Analysis of the Supratrochlear Artery: Considerations in Facial Filler Injections and Preventing Vision Loss. PMID- 28096118 TI - Commentary on: Is Office-Based Surgery Safe? Comparing Outcomes of 183,914 Aesthetic Surgical Procedures Across Different Types of Accredited Facilities. PMID- 28096119 TI - Commentary on: Exposure to Tumescent Solution Significantly Increases Phosphorylation of Perilipin in Adipocytes. PMID- 28096122 TI - Reasons for drug policy reform: people who use drugs are denied evidence based treatment. PMID- 28096123 TI - Current Evidence on the Association of Dietary Patterns and Bone Health: A Scoping Review. AB - Nutrition is an important modifiable factor that affects bone health. Diet is a complex mixture of nutrients and foods that correlate or interact with each other. Dietary pattern approaches take into account contributions from various aspects of diet. Findings from dietary pattern studies could complement those from single-nutrient and food studies on bone health. In this study we aimed to conduct a scoping review of the literature that assessed the impact of dietary patterns (derived with the use of both a priori and data-driven approaches) on bone outcomes, including bone mineral status, bone biomarkers, osteoporosis, and fracture risk. We retrieved 49 human studies up to June 2016 from the PubMed, Embase, and CINAHL databases. Most of these studies used a data-driven method, especially factor analysis, to derive dietary patterns. Several studies examined adherence to a variety of the a priori dietary indexes, including the Mediterranean diet score, the Healthy Eating Index (HEI), and the Alternative Healthy Eating Index (AHEI). The bone mineral density (BMD) diet score was developed to measure adherence to a dietary pattern beneficial to bone mineral density. Findings revealed a beneficial impact of higher adherence to a "healthy" dietary pattern derived using a data-driven method, the Mediterranean diet, HEI, AHEI, Dietary Diversity Score, Diet Quality Index-International, BMD Diet Score, Healthy Diet Indicator, and Korean Diet Score, on bone. In contrast, the "Western" dietary pattern and those featuring some aspects of an unhealthy diet were associated inversely with bone health. In both a priori and data-driven dietary pattern studies, a dietary pattern that emphasized the intake of fruit, vegetables, whole grains, poultry and fish, nuts and legumes, and low-fat dairy products and de-emphasized the intake of soft drinks, fried foods, meat and processed products, sweets and desserts, and refined grains showed a beneficial impact on bone health. Overall, adherence to a healthy dietary pattern consisting of the above-mentioned food groups can improve bone mineral status and decrease osteoporosis and fracture risk. PMID- 28096124 TI - Nutritional Considerations for Healthy Aging and Reduction in Age-Related Chronic Disease. AB - A projected doubling in the global population of people aged >=60 y by the year 2050 has major health and economic implications, especially in developing regions. Burdens of unhealthy aging associated with chronic noncommunicable and other age-related diseases may be largely preventable with lifestyle modification, including diet. However, as adults age they become at risk of "nutritional frailty," which can compromise their ability to meet nutritional requirements at a time when specific nutrient needs may be high. This review highlights the role of nutrition science in promoting healthy aging and in improving the prognosis in cases of age-related diseases. It serves to identify key knowledge gaps and implementation challenges to support adequate nutrition for healthy aging, including applicability of metrics used in body-composition and diet adequacy for older adults and mechanisms to reduce nutritional frailty and to promote diet resilience. This review also discusses management recommendations for several leading chronic conditions common in aging populations, including cognitive decline and dementia, sarcopenia, and compromised immunity to infectious disease. The role of health systems in incorporating nutrition care routinely for those aged >=60 y and living independently and current actions to address nutritional status before hospitalization and the development of disease are discussed. PMID- 28096125 TI - Dietary Supplements and Risk of Cause-Specific Death, Cardiovascular Disease, and Cancer: A Systematic Review and Meta-Analysis of Primary Prevention Trials. AB - Our aim was to assess the efficacy of dietary supplements in the primary prevention of cause-specific death, cardiovascular disease (CVD), and cancer by using meta-analytical approaches. Electronic and hand searches were performed until August 2016. Inclusion criteria were as follows: 1) minimum intervention period of 12 mo; 2) primary prevention trials; 3) mean age >=18 y; 4) interventions included vitamins, fatty acids, minerals, supplements containing combinations of vitamins and minerals, protein, fiber, prebiotics, and probiotics; and 5) primary outcome of all-cause mortality and secondary outcomes of mortality or incidence from CVD or cancer. Pooled effects across studies were estimated by using random-effects meta-analysis. Overall, 49 trials (69 reports) including 287,304 participants met the inclusion criteria. Thirty-two trials were judged as low risk-, 15 trials as moderate risk-, and 2 trials as high risk-of bias studies. Supplements containing vitamin E (RR: 0.88; 95% CI: 0.80, 0.96) significantly reduced cardiovascular mortality risk, whereas supplements with folic acid reduced the risk of CVD (RR: 0.81; 95% CI: 0.70, 0.94). Vitamins D, C, and K; selenium; zinc; magnesium; and eicosapentaenoic acid showed no significant risk reduction for any of the outcomes. On the contrary, vitamin A was linked to an increased cancer risk (RR: 1.16; 95% CI: 1.00, 1.35). Supplements with beta carotene showed no significant effect; however, in the subgroup with beta carotene given singly, an increased risk of all-cause mortality by 6% (RR: 1.06; 95% CI: 1.02, 1.10) was observed. Taken together, we found insufficient evidence to support the use of dietary supplements in the primary prevention of cause specific death, incidence of CVD, and incidence of cancer. The application of some supplements generated small beneficial effects; however, the heterogeneous types and doses of supplements limit the generalizability to the overall population. PMID- 28096126 TI - The Age-Related Eye Disease 2 Study: Micronutrients in the Treatment of Macular Degeneration. AB - Age-related macular degeneration (AMD) is one of the leading causes of vision loss in the elderly. With an increasingly aged population worldwide, the need for the prevention of AMD is rising. Multiple studies investigating AMD with the use of animal models and cell culture have identified oxidative stress-related retinal damage as an important contributing factor. In general, diet is an excellent source of the antioxidants, vitamins, and minerals necessary for healthy living; moreover, the general public is often receptive to recommendations made by physicians and health care workers regarding diet and supplements as a means of empowering themselves to avoid common and worrisome ailments such as AMD, which has made epidemiologists and clinicians enthusiastic about dietary intervention studies. A wide variety of nutrients, such as minerals, vitamins, omega-3 (n-3) fatty acids, and various carotenoids, have been associated with reducing the risk of AMD. Initial results from the Age-Related Eye Disease Study (AREDS) indicated that supplementation with antioxidants (beta carotene and vitamins C and E) and zinc was associated with a reduced risk of AMD progression. The AREDS2 follow-up study, designed to improve upon the earlier formulation, tested the addition of lutein, zeaxanthin, and omega-3 fatty acids. In this review, we examine the science behind the nutritional factors included in these interventional studies and the reasons for considering their inclusion to lower the rate of AMD progression. PMID- 28096127 TI - Formation of Fructose-Mediated Advanced Glycation End Products and Their Roles in Metabolic and Inflammatory Diseases. AB - Fructose is associated with the biochemical alterations that promote the development of metabolic syndrome (MetS), nonalcoholic fatty liver disease, and type 2 diabetes. Its consumption has increased in parallel with MetS. It is metabolized by the liver, where it stimulates de novo lipogenesis. The triglycerides synthesized lead to hepatic insulin resistance and dyslipidemia. Fructose-derived advanced glycation end products (AGEs) may be involved via the Maillard reaction. Fructose has not been a main focus of glycation research because of the difficulty in measuring its adducts, and, more importantly, because although it is 10 times more reactive than glucose, its plasma concentration is only 1% of that of glucose. In this focused review, I summarize exogenous and endogenous fructose metabolism, fructose glycation, and in vitro, animal, and human data. Fructose is elevated in several tissues of diabetic patients where the polyol pathway is active, reaching the same order of magnitude as glucose. It is plausible that the high reactivity of fructose, directly or via its metabolites, may contribute to the formation of intracellular AGEs and to vascular complications. The evidence, however, is still unconvincing. Two areas that have been overlooked so far and should be actively explored include the following: 1) enteral formation of fructose AGEs, generating an inflammatory response to the receptor for AGEs (which may explain the strong association between fructose consumption and asthma, chronic bronchitis, and arthritis); and 2) inactivation of hepatic AMP-activated protein kinase by a fructose-mediated increase in methylglyoxal flux (perpetuating lipogenesis, fatty liver, and insulin resistance). If proven correct, these mechanisms would put the fructose mediated Maillard reaction in the limelight again as a contributing factor in chronic inflammatory diseases and MetS. PMID- 28096128 TI - A Systematic Review of Methods to Assess Children's Diets in the School Context. AB - To evaluate the impact of school-based nutrition interventions, accurate and reliable methods are needed to assess what children eat at school. The primary objective of this study was to systematically review methodological evidence on the relative accuracy and reliability of dietary assessment methods used in the school context. The secondary objective was to assess the frequency of methods and analytical approaches used in studies reporting in-school dietary outcomes. Three health databases were searched for full-text English-language studies. Twenty-two methodological studies were reviewed. For school meal recalls, the majority of studies (n = 8 of 12) reported poor accuracy when accuracy was measured by using frequencies of misreported foods. However, when energy report rates were used as a measure of accuracy, studies suggested that children were able to accurately report energy intake as a group. Results regarding the accuracy of food-frequency questionnaires (FFQs) and food records (FRs) were promising but limited to a single study each. Meal observations offered consistently good interrater reliability across all studies reviewed (n = 11). Studies reporting in-school dietary outcomes (n = 47) used a broad range of methods, but the most frequently used methods included weighed FRs (n = 12), school meal recalls (n = 10), meal observations by trained raters (n = 8), and estimated FRs (n = 7). The range of dietary components was greater among studies relying on school meal recalls and FRs than among studies using FFQs. Overall, few studies have measured the accuracy of dietary assessment methods in the school context. Understanding the methodological characteristics associated with dietary instruments is vital for improving the quality of the evidence used to inform and evaluate the impact of school-based nutrition policies and programs. PMID- 28096129 TI - Current Knowledge of Necrotizing Enterocolitis in Preterm Infants and the Impact of Different Types of Enteral Nutrition Products. AB - Preterm infants are extremely vulnerable to a range of morbidities and mortality. Underdeveloped cardiac, respiratory, gastrointestinal, and immune systems in the preterm period increase the risk of necrotizing enterocolitis (NEC), a serious disease of the gut. NEC affects 5-12% of very-low birth-weight infants, leads to surgery in 20-40% of cases, and is fatal in 25-50% of cases. There are multiple factors that may contribute to NEC, but the exact cause is not yet fully understood. Severe cases can result in intestinal resection or death, and the health care costs average >$300,000/infant when surgical management is required. Different types of nutrition may affect the onset or progression of NEC. Several studies have indicated that bovine milk-based infant formulas lead to a higher incidence of NEC in preterm infants than does human milk (HM). However, it is not clear why HM is linked to a lower incidence of NEC or why some infants fed an exclusively HM diet still develop NEC. An area that has not been thoroughly explored is the use of semielemental or elemental formulas. These specialty formulas are easy to digest and absorb in the gut and may be an effective nutritional intervention for reducing the risk of NEC. This review summarizes what is known about the factors that contribute to the onset and progression of NEC, discusses its health care cost implications, and explores the impact that different formulas and HM have on this disease. PMID- 28096131 TI - Nutrition, microRNAs, and Human Health. AB - MicroRNAs (miRs) hybridize with complementary sequences in mRNA and silence genes by destabilizing mRNA or preventing translation of mRNA. Over 60% of human protein-coding genes are regulated by miRs, and 1881 high-confidence miRs are encoded in the human genome. Evidence suggests that miRs not only are synthesized endogenously, but also might be obtained from dietary sources, and that food compounds alter the expression of endogenous miR genes. The main food matrices for studies of biological activity of dietary miRs include plant foods and cow milk. Encapsulation of miRs in exosomes and exosome-like particles confers protection against RNA degradation and creates a pathway for intestinal and vascular endothelial transport by endocytosis, as well as delivery to peripheral tissues. Evidence suggests that the amount of miRs absorbed from nutritionally relevant quantities of foods is sufficient to elicit biological effects, and that endogenous synthesis of miRs is insufficient to compensate for dietary miR depletion and rescue wild-type phenotypes. In addition, nutrition alters the expression of endogenous miR genes, thereby compounding the effects of nutrition miR interactions in gene regulation and disease diagnosis in liquid biopsies. For example, food components and dietary preferences may modulate serum miR profiles that may influence biological processes. The complex crosstalk between nutrition, miRs, and gene targets poses a challenge to gene network analysis and studies of human disease. Novel pipelines and databases have been developed recently, including a dietary miR database for archiving reported miRs in 15 dietary resources. miRs derived from diet and endogenous synthesis have been implicated in physiologic and pathologic conditions, including those linked with nutrition and metabolism. In fact, several miRs are actively regulated in response to overnutrition and tissue inflammation, and are involved in facilitating the development of chronic inflammation by modulating tissue-infiltrated immune cell function. PMID- 28096130 TI - Early-Life Nutrition and Neurodevelopment: Use of the Piglet as a Translational Model. AB - Optimal nutrition early in life is critical to ensure proper structural and functional development of infant organ systems. Although pediatric nutrition historically has emphasized research on the relation between nutrition, growth rates, and gastrointestinal maturation, efforts increasingly have focused on how nutrition influences neurodevelopment. The provision of human milk is considered the gold standard in pediatric nutrition; thus, there is interest in understanding how functional nutrients and bioactive components in milk may modulate developmental processes. The piglet has emerged as an important translational model for studying neurodevelopmental outcomes influenced by pediatric nutrition. Given the comparable nutritional requirements and strikingly similar brain developmental patterns between young pigs and humans, the piglet is being used increasingly in developmental nutritional neuroscience studies. The piglet primarily has been used to assess the effects of dietary fatty acids and their accretion in the brain throughout neurodevelopment. However, recent research indicates that other dietary components, including choline, iron, cholesterol, gangliosides, and sialic acid, among other compounds, also affect neurodevelopment in the pig model. Moreover, novel analytical techniques, including but not limited to MRI, behavioral assessments, and molecular quantification, allow for a more holistic understanding of how nutrition affects neurodevelopmental patterns. By combining early-life nutritional interventions with innovative analytical approaches, opportunities abound to quantify factors affecting neurodevelopmental trajectories in the neonate. This review discusses research using the translational pig model with primary emphasis on early-life nutrition interventions assessing neurodevelopment outcomes, while also discussing nutritionally-sensitive methods to characterize brain maturation. PMID- 28096132 TI - Innovative Techniques for Evaluating Behavioral Nutrition Interventions. AB - Assessing outcomes and the impact from behavioral nutrition interventions has remained challenging because of the lack of methods available beyond traditional nutrition assessment tools and techniques. With the current high global obesity and related chronic disease rates, novel methods to evaluate the impact of behavioral nutrition-based interventions are much needed. The objective of this narrative review is to describe and review the current status of knowledge as it relates to 4 different innovative methods or tools to assess behavioral nutrition interventions. Methods reviewed include 1) the assessment of stress and stress responsiveness to enhance the evaluation of nutrition interventions, 2) eye tracking technology in nutritional interventions, 3) smartphone biosensors to assess nutrition and health-related outcomes, and 4) skin carotenoid measurements to assess fruit and vegetable intake. Specifically, the novel use of functional magnetic resonance imaging, by characterizing the brain's responsiveness to an intervention, can help researchers develop programs with greater efficacy. Similarly, if eye-tracking technology can enable researchers to get a better sense as to how participants view materials, the materials may be better tailored to create an optimal impact. The latter 2 techniques reviewed, smartphone biosensors and methods to detect skin carotenoids, can provide the research community with portable, effective, nonbiased ways to assess dietary intake and quality and more in the field. The information gained from using these types of methodologies can improve the efficacy and assessment of behavior-based nutrition interventions. PMID- 28096134 TI - Nutritionally Nonessential Amino Acids: A Misnomer in Nutritional Sciences. PMID- 28096137 TI - Introduction to the Yogurt in Nutrition Initiative at the First Symposium of Yogurt in Mexico: The Balanced Diet Initiative. AB - In some European countries, yogurt consumption is common. However, such consumption is not common in Latin America, particularly in Mexico, partially because of the lack of a cultural tradition of consuming yogurt. Moreover, we also know that little information about the health benefits associated with yogurt consumption has been provided to the Mexican population. Thus, there is an immediate need to provide, at least to the nutrition community in the country, current scientific evidence about the health benefits of yogurt, with the aim that yogurt be included as part of the functional foods recommended to the population. Currently, extensive research has been conducted to investigate the mechanisms through which yogurt generates beneficial effects. Gut microbiota appear to be an important factor that can be modified by dietary prebiotics, as well as probiotics such as yogurt. The prevention or attenuation of gut microbiota dysbiosis is now associated with improvements observed in individuals with metabolic syndrome and cardiovascular disease. Thus, it is important to establish guidelines for the consumption of dairy products, including yogurt. Such guidelines are necessary to increase the consumption of dairy products in Mexico and other countries. PMID- 28096133 TI - Regulation of the Iron Homeostatic Hormone Hepcidin. AB - Iron is required for many biological processes but is also toxic in excess; thus, body iron balance is maintained through sophisticated regulatory mechanisms. The lack of a regulated iron excretory mechanism means that body iron balance is controlled at the level of absorption from the diet. Iron absorption is regulated by the hepatic peptide hormone hepcidin. Hepcidin also controls iron release from cells that recycle or store iron, thus regulating plasma iron concentrations. Hepcidin exerts its effects through its receptor, the cellular iron exporter ferroportin. Important regulators of hepcidin, and therefore of systemic iron homeostasis, include plasma iron concentrations, body iron stores, infection and inflammation, and erythropoiesis. Disturbances in the regulation of hepcidin contribute to the pathogenesis of many iron disorders: hepcidin deficiency causes iron overload in hereditary hemochromatosis and nontransfused beta-thalassemia, whereas overproduction of hepcidin is associated with iron-restricted anemias seen in patients with chronic kidney disease, chronic inflammatory diseases, some cancers, and inherited iron-refractory iron deficiency anemia. This review summarizes our current understanding of the molecular mechanisms and signaling pathways involved in the control of hepcidin synthesis in the liver, a principal determinant of plasma hepcidin concentrations. PMID- 28096138 TI - Associations between Yogurt Consumption and Weight Gain and Risk of Obesity and Metabolic Syndrome: A Systematic Review. AB - The role of yogurt consumption in the risk of developing overweight, obesity, or metabolic syndrome has been the subject of epidemiologic studies over the last 10 y. A comprehensive literature search on MEDLINE and ISI Web of Knowledge from 1966 through June 2016 was conducted to examine the relation between yogurt consumption and weight gain, as well as the risk of overweight, obesity, or metabolic syndrome, in prospective cohort studies. Ten articles met all the inclusion criteria and were included in our systematic review. Of the 10 cohort studies, 3 analyzed the relation between yogurt consumption and the risk of overweight or obesity, 8 analyzed changes in waist circumference or weight changes, 3 studied the association with the risk of developing metabolic syndrome, and 1 studied the probability of abdominal obesity reversion. Although an inverse association between yogurt consumption and the risk of developing overweight or obesity was not fully consistent or always statistically significant, all studies but one showed in their point estimates inverse associations between yogurt consumption and changes in waist circumference, changes in weight, risk of overweight or obesity, and risk of metabolic syndrome during follow-up, although not all estimates were statistically significant (2 studies). Prospective cohort studies consistently suggested that yogurt consumption may contribute to a reduction in adiposity indexes and the risk of metabolic syndrome. Therefore, there is a need for more prospective studies and high-quality randomized clinical trials to confirm this apparent inverse association. PMID- 28096139 TI - Potential Health Benefits of Combining Yogurt and Fruits Based on Their Probiotic and Prebiotic Properties. AB - Fruit and yogurt have been identified individually as indicators of healthy dietary patterns. Fruits are relatively low in energy density and are an excellent source of antioxidants and prebiotic fibers and polyphenols, which can promote digestive health. Yogurt, on the other hand, is a nutrient-dense food that is a good source of dairy protein, calcium, magnesium, vitamin B-12, conjugated linoleic acid, and other key fatty acids. In addition, it contains beneficial bacterial cultures, making it a potential source of probiotics. Yogurt's unique fermented food matrix provides added health benefits by enhancing nutrient absorption and digestion. Combining the intake of yogurt and fruit could provide probiotics, prebiotics, high-quality protein, important fatty acids, and a mixture of vitamins and minerals that have the potential to exert synergistic effects on health. Yogurt consumption has been associated with reduced weight gain and a lower incidence of type 2 diabetes, whereas fruits have established effects on reducing the risk of cardiovascular disease. Yogurt and fruits can be eaten together and may exert combined health benefits through potential prebiotic and probiotic effects. Furthermore, substituting high-energy, nutrient-deficient snacks with fruit and yogurt could reduce the intake of high-calorie obesogenic foods. In light of the positive cardiometabolic impacts of fruit and yogurt and their association with healthy dietary patterns, there is sufficient evidence to warrant further exploration into the potential synergistic health benefits of a combined intake of fruit and yogurt. PMID- 28096140 TI - Setting the Lipid Component of the Diet: A Work in Process. AB - Some of the most relevant yet controversial issues in nutrition are those surrounding the guidelines on quality and quantity of dietary fat in the prevention and treatment of cardiovascular diseases and coronary heart diseases. Conflicting evidence questions the credibility of the previous dietary guidelines, particularly the quality of the evidence on which these recommendations were based. It is therefore important to explore the changes that have occurred in these guidelines and their influence on the adoption of different dietary patterns over time. In this review, we summarize the evolution of the fat component of the dietary guidelines, discuss controversial aspects, and highlight the areas in which additional evidence is still needed. Over the years, the scientific community has shown an obsession for calories in a diet instead of focusing on the quality of the food that makes up the diet. This is why certain authors have identified the importance of evaluating a diet focusing on diet patterns, rather than single isolated nutrients. This approach has been proposed in the most recent Dietary Guidelines for Americans. PMID- 28096144 TI - Oxidative Stress Participates in the Associations Between Serum Uric Acid and Albuminuria in the Obesity. PMID- 28096145 TI - Association of Household Wealth Index, Educational Status, and Social Capital with Hypertension Awareness, Treatment, and Control in South Asia. AB - OBJECTIVE: Hypertension control rates are low in South Asia. To determine association of measures of socioeconomic status (wealth, education, and social capital) with hypertension awareness, treatment, and control among urban and rural subjects in these countries we performed the present study. METHODS: We enrolled 33,423 subjects aged 35-70 years (women 56%, rural 53%, low-education status 51%, low household wealth 25%, low-social capital 33%) in 150 communities in India, Pakistan, and Bangladesh during 2003-2009. Prevalence of hypertension and its awareness, treatment, and control status and their association with wealth, education, and social capital were determined. RESULTS: Age-, sex-, and location-adjusted prevalence of hypertension in men was 31.5% (23.9-40.2%) and women was 32.6% (24.9-41.5%) with variations in prevalence across study sites (urban 30-56%, rural 11-43%). Prevalence was significantly greater in urban locations, older subjects, and participants with more wealth, greater education, and lower social capital index. Hypertension awareness was in 40.4% (urban 45.9, rural 32.5), treatment in 31.9% (urban 37.6, rural 23.6), and control in 12.9% (urban 15.4, rural 9.3). Control was lower in men and younger subjects. Hypertension awareness, treatment, and control were significantly lower, respectively, in lowest vs. highest wealth index tertile (26.2 vs. 50.6%, 16.9 vs. 44.0%, and 6.9 vs. 17.3%, P < 0.001) and lowest vs. highest educational status tertile (31.2 vs. 48.4%, 21.8 vs. 42.1%, and 7.8 vs. 19.2%, P < 0.001) while insignificant differences were observed in lowest vs. highest social capital index (38.2 vs. 36.1%, 35.1 vs. 27.8%, and 12.5 vs. 9.1%). CONCLUSIONS: This study shows low hypertension awareness, treatment, and control in South Asia. Lower wealth and educational status are important in low hypertension awareness, treatment, and control. PMID- 28096141 TI - The Role of the Novel Lipokine Palmitoleic Acid in Health and Disease. AB - The monounsaturated fatty acid palmitoleate (palmitoleic acid) is one of the most abundant fatty acids in serum and tissues, particularly adipose tissue and liver. Its endogenous production by stearoyl-CoA desaturase 1 gives rise to its cis isoform, cis-palmitoleate. Although trans-palmitoleate is also synthesized in humans, it is mainly found as an exogenous source in ruminant fat and dairy products. Recently, palmitoleate was considered to be a lipokine based on evidence demonstrating its release from adipose tissue and its metabolic effects on distant organs. After this finding, research has been performed to determine whether palmitoleate has beneficial effects on metabolism and to elucidate the underlying mechanisms. Thus, the aim of this work was to review the current status of knowledge about palmitoleate, its metabolism, and its influence on metabolic abnormalities. Results have shown mixed cardiovascular effects, direct or inverse correlations with obesity, and hepatosteatosis, but a significant amelioration or prevention of insulin resistance and diabetes. Finally, the induction of palmitoleate release from adipose tissue, dietary intake, and its supplementation are all interventions with a potential impact on certain metabolic diseases. PMID- 28096147 TI - Hemodynamic Biomarker-Initiated Anticipation Medicine in the Future Management of Hypertension. PMID- 28096146 TI - Long-Term Exposure to NO2 and Ozone and Hypertension Incidence in the Black Women's Health Study. AB - BACKGROUND: Evidence shows that exposure to air pollutants can increase blood pressure in the short and long term. Some studies show higher levels of hypertension prevalence in areas of high pollution. Few data exist on the association of air pollution with hypertension incidence. The purpose of the present study was to prospectively assess the associations of the traffic-related nitrogen dioxide (NO2) and of ozone with the incidence of hypertension in the Black Women's Health Study (BWHS), a large cohort study of African American women. METHODS: We used Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CI) for hypertension associated with exposure to NO2 and ozone among 33,771 BWHS participants. NO2 and ozone levels at participant residential locations were estimated with validated models. RESULTS: From 1995 to 2011, 9,570 incident cases of hypertension occurred in a total of 348,154 person-years (median follow-up time, 11 years). The multivariable HRs per interquartile range of NO2 (9.7 ppb) and ozone (6.7 ppb) were 0.92 (95% CI = 0.86, 0.98) and 1.09 (95% CI = 1.00, 1.18). CONCLUSIONS: In this large cohort of African American women, higher ozone levels were associated with an increase in hypertension incidence. Higher NO2 levels were not associated with greater hypertension incidence; indeed, incidence was lower at higher NO2 levels. PMID- 28096143 TI - Methodological Challenges in Studies Examining the Effects of Breakfast on Cognitive Performance and Appetite in Children and Adolescents. AB - Breakfast is purported to confer a number of benefits on diet quality, health, appetite regulation, and cognitive performance. However, new evidence has challenged the long-held belief that breakfast is the most important meal of the day. This review aims to provide a comprehensive discussion of the key methodological challenges and considerations in studies assessing the effect of breakfast on cognitive performance and appetite control, along with recommendations for future research. This review focuses on the myriad challenges involved in studying children and adolescents specifically. Key methodological challenges and considerations include study design and location, sampling and sample section, choice of objective cognitive tests, choice of objective and subjective appetite measures, merits of providing a fixed breakfast compared with ad libitum, assessment and definition of habitual breakfast consumption, transparency of treatment condition, difficulty of isolating the direct effects of breakfast consumption, untangling acute and chronic effects, and influence of confounding variables. These methodological challenges have hampered a clear substantiation of the potential positive effects of breakfast on cognition and appetite control and contributed to the debate questioning the notion that breakfast is the most important meal of the day. PMID- 28096148 TI - Uric Acid and New Onset Left Ventricular Hypertrophy: Findings From the PAMELA Population. AB - BACKGROUND: The association between serum uric acid (SUA) and left ventricular hypertrophy (LVH) is controversial and the ability of SUA in predicting incident LVH remains unsettled. Thus, we evaluated the relationship of SUA with new-onset echocardiographic LVH over a 10-year period in subjects of the general population enrolled in the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study. METHODS: The study included 960 subjects with normal LV mass index (LVMI) at baseline echocardiographic evaluation and a readable echocardiogram at the end of follow-up. Cut-points for LVH were derived from reference values of the healthy fraction of the PAMELA population. RESULTS: Over a 10-year period, 258 participants (26.9%) progressed to LVH. The incidence of new-onset LVH increased from the lowest (23%) to intermediate (25%) and the highest baseline SUA tertile (32%). After adjusting for confounders (not including body mass index (BMI)), each 1 mg/dl increase in SUA entailed a 26% higher risk of incident LVH. Adjusted odd ratio of LVH risk in the highest SUA tertile was 96% higher than in the lowest tertile (odds ratio (OR) = 1.966, 95% CI = 1.158-3.339, P = 0.0123). Correction for BMI reduced the magnitude and statistical significance of ORs. CONCLUSIONS: The study shows that SUA is a predictor of long-term echocardiographic changes from normal LVMI to LVH in a community sample. Thus, life-style and pharmacologic measures aimed to reduce SUA levels may concur to preventing LVH development in the general population. PMID- 28096149 TI - Uric Acid and Left Ventricular Hypertrophy: A Potentially New Modifiable Target? PMID- 28096151 TI - Response to Letter to the Editor entitled Oxidative Stress Participates in the Associations Between Serum Uric Acid and Albuminuria in Obesity. PMID- 28096150 TI - Hemodynamic Determinants of the Short-Term Blood Pressure Variability: Differential Roles of Arterial Stiffness and Wave Reflection. AB - BACKGROUND: A high 24-hour ambulatory diastolic (DBP) but not systolic (SBP) blood pressure variability (BPV) is significantly predictive of long-term cardiovascular mortality in untreated hypertensive subjects, independent of office or 24-hour SBP. The present study was aimed to investigate hemodynamic factors that are independently associated with systolic and diastolic BPV from the 24-hour ambulatory blood pressure monitoring (ABPM). METHODS: A cohort of 624 normotensive and 633 untreated hypertensive participants with baseline ABPM was drawn from a community-based survey. BPV was assessed by the read-to-read average real variability of the 24-hour SBP and DBP (ARVs and ARVd, respectively). Hemodynamic variables including total peripheral resistance (TPR), carotid femoral pulse wave velocity (cf-PWV), and amplitudes of the decomposed forward (Pf) and backward (Pb) carotid pressure waves were analyzed. RESULTS: In multivariable analyses, hemodynamic variables independently associated with 24 hour SBP were 24-hour heart rate (HR), TPR, cf-PWV, Pf, and Pb (model r2 = 0.535). Hemodynamic factors independently associated with ARV were 24-hour HR, Pf, and Pb for ARVs, and 24-hour HR, cf-PWV, Pf, and Pb for ARVd (model R2 = 0.345 and 0.220, respectively). Addition of 24-hour SBP to the ARV models only slightly improved variance explained by the models (R2 = 0.383 and 0.224, respectively). Pb accounted for >50% of total variance of ARVs and ARVd, whereas cf-PWV was a minor determinant of ARVd (<5% of total variance). CONCLUSIONS: ARVd was associated with fewer hemodynamic variables than to 24-hour SBP. Among those hemodynamic variables wave reflection but not arterial stiffness had the dominant independent association with ARV. PMID- 28096152 TI - BclI Glucocorticoid Receptor Polymorphism in Relation to Arterial Stiffening and Cardiac Structure and Function: The Hoorn and CODAM Studies. AB - BACKGROUND: Chronic glucocorticoid excess is associated with arterial stiffening and cardiac dysfunction. The BclI glucocorticoid receptor (GR) polymorphism increases GR sensitivity and is associated with a higher body mass index (BMI) and some proxies for cardiovascular disease (CVD). Whether BclI influences arterial stiffening and cardiac dysfunction is currently unknown. Therefore, the aim of the present study was to investigate the association of the BclI polymorphism with arterial stiffening and cardiac structure and function. METHODS: We conducted an observational cohort study, combining 2 cohort studies designed to investigate genetic and metabolic determinants of CVD. We genotyped 1,124 individuals (age: 64.7 +/- 8.5 years) from the Hoorn study and Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study for BclI. Several arterial stiffening indices of the carotid (Hoorn and CODAM study), brachial and femoral artery and the carotid-femoral pulse wave velocity (Hoorn study only) were determined. In addition, in the Hoorn study, we determined several variables of cardiac structure and function. RESULTS: We identified 155 homozygous carriers (GG), 498 heterozygous carriers (CG), and 471 noncarriers (CC) of the BclI polymorphism. BclI genotypes did not display significant differences in variables of arterial stiffening (e.g., carotid distensibility coefficient (DC): 12.41 +/- 5.37 vs. 12.87 +/- 5.55 10-3/kPa [mean +/- SD]; P = 0.38; homozygous vs. noncarriers). In addition, no clear differences in estimates of cardiac structure and function were found. CONCLUSIONS: Even though BclI is associated with a higher BMI and some proxies of CVD, our results do not support the concept that BclI carrier status is associated with greater arterial stiffening or cardiac dysfunction. PMID- 28096153 TI - Plasmidic qnr Genes Confer Clinical Resistance to Ciprofloxacin under Urinary Tract Physiological Conditions. AB - Escherichia coli variants expressing plasmid-mediated qnr genes are usually susceptible to fluoroquinolones by standard susceptibility testing. Here we show that, under specific urinary tract physiological conditions, susceptible laboratory and clinical strains harboring qnr determinants become fully resistant to ciprofloxacin (CIP). Therefore, physiological conditions, mainly urine pH values, should be considered when performing susceptibility testing of CIP activity against E. coli in treating urinary tract infection (UTI) and for selecting appropriate antibiotics for UTI treatment. PMID- 28096154 TI - Influence of rhlR and lasR on Polymyxin Pharmacodynamics in Pseudomonas aeruginosa and Implications for Quorum Sensing Inhibition with Azithromycin. AB - The impact of quorum sensing on polymyxin and azithromycin pharmacodynamics was assessed in Pseudomonas aeruginosa PAO1 and an isogenic rhlR/lasR double knockout. For polymyxin B, greater killing against the rhlR/lasR knockout than against PAO1 was observed at 108 CFU/ml (polymyxin B half-maximal effective concentration [EC50], 5.61 versus 12.5 mg/liter, respectively; P < 0.005). Polymyxin B combined with azithromycin (256 mg/liter) was synergistic against each strain, significantly reducing the respective polymyxin B EC50 compared to those with monotherapy (P < 0.005), and is a promising strategy by which to combat P. aeruginosa. PMID- 28096155 TI - Inhibition of the beta-Lactamase BlaMab by Avibactam Improves the In Vitro and In Vivo Efficacy of Imipenem against Mycobacterium abscessus. AB - Mycobacterium abscessus pulmonary infections are treated with a macrolide (clarithromycin or azithromycin), an aminoglycoside (amikacin), and a beta-lactam (cefoxitin or imipenem). The triple combination is used without any beta lactamase inhibitor, even though Mabscessus produces the broad-spectrum beta lactamase BlaMab We determine whether inhibition of BlaMab by avibactam improves the activity of imipenem against M. abscessus The bactericidal activity of drug combinations was assayed in broth and in human macrophages. The in vivo efficacy of the drugs was tested by monitoring the survival of infected zebrafish embryos. The level of BlaMab production in broth and in macrophages was compared by quantitative reverse transcription-PCR and Western blotting. The triple combination of imipenem (8 or 32 MUg/ml), amikacin (32 MUg/ml), and avibactam (4 MUg/ml) was bactericidal in broth (<0.1% survival), with 3.2- and 4.3-log10 reductions in the number of CFU being achieved at 72 h when imipenem was used at 8 and 32 MUg/ml, respectively. The triple combination achieved significant intracellular killing, with the bacterial survival rates being 54% and 7% with the low (8 MUg/ml) and high (32 MUg/ml) dosages of imipenem, respectively. In vivo inhibition of BlaMab by avibactam improved the survival of zebrafish embryos treated with imipenem. Expression of the gene encoding BlaMab was induced (20 fold) in the infected macrophages. Inhibition of BlaMab by avibactam improved the efficacy of imipenem against M. abscessusin vitro, in macrophages, and in zebrafish embryos, indicating that this beta-lactamase inhibitor should be clinically evaluated. The in vitro evaluation of imipenem may underestimate the impact of BlaMab, since the production of the beta-lactamase is inducible in macrophages. PMID- 28096156 TI - Bacterium-Derived Cell-Penetrating Peptides Deliver Gentamicin To Kill Intracellular Pathogens. AB - Commonly used antimicrobials show poor cellular uptake and often have limited access to intracellular targets, resulting in low antimicrobial activity against intracellular pathogens. An efficient delivery system to transport these drugs to the intracellular site of action is needed. Cell-penetrating peptides (CPPs) mediate the internalization of biologically active molecules into the cytoplasm. Here, we characterized two CPPs, alpha1H and alpha2H, derived from the Yersinia enterocolitica YopM effector protein. These CPPs, as well as Tat (trans-activator of transcription) from HIV-1, were used to deliver the antibiotic gentamicin to target intracellular bacteria. The YopM-derived CPPs penetrated different endothelial and epithelial cells to the same extent as Tat. CPPs were covalently conjugated to gentamicin, and CPP-gentamicin conjugates were used to target infected cells to kill multiple intracellular Gram-negative pathogenic bacteria, including Escherichia coli K1, Salmonella enterica serovar Typhimurium, and Shigella flexneri Taken together, CPPs show great potential as delivery vehicles for antimicrobial agents and may contribute to the generation of new therapeutic tools to treat infectious diseases caused by intracellular pathogens. PMID- 28096157 TI - Resistance to Thiacetazone Derivatives Active against Mycobacterium abscessus Involves Mutations in the MmpL5 Transcriptional Repressor MAB_4384. AB - Available chemotherapeutic options are very limited against Mycobacterium abscessus, which imparts a particular challenge in the treatment of cystic fibrosis (CF) patients infected with this rapidly growing mycobacterium. New drugs are urgently needed against this emerging pathogen, but the discovery of active chemotypes has not been performed intensively. Interestingly, however, the repurposing of thiacetazone (TAC), a drug once used to treat tuberculosis, has increased following the deciphering of its mechanism of action and the detection of significantly more potent analogues. We therefore report studies performed on a library of 38 TAC-related derivatives previously evaluated for their antitubercular activity. Several compounds, including D6, D15, and D17, were found to exhibit potent activity in vitro against M. abscessus, Mycobacterium massiliense, and Mycobacterium bolletii clinical isolates from CF and non-CF patients. Similar to TAC in Mycobacterium tuberculosis, the three analogues act as prodrugs in M. abscessus, requiring bioactivation by the EthA enzyme, MAB_0985. Importantly, mutations in the transcriptional TetR repressor MAB_4384, with concomitant upregulation of the divergently oriented adjacent genes encoding an MmpS5/MmpL5 efflux pump system, accounted for high cross-resistance levels among all three compounds. Overall, this study uncovered a new mechanism of drug resistance in M. abscessus and demonstrated that simple structural optimization of the TAC scaffold can lead to the development of new drug candidates against M. abscessus infections. PMID- 28096158 TI - Peak Measurement for Vancomycin AUC Estimation in Obese Adults Improves Precision and Lowers Bias. AB - Vancomycin area under the curve (AUC) estimates may be skewed in obese adults due to weight-dependent pharmacokinetic parameters. We demonstrate that peak and trough measurements reduce bias and improve the precision of vancomycin AUC estimates in obese adults (n = 75) and validate this in an independent cohort (n = 31). The precision and mean percent bias of Bayesian vancomycin AUC estimates are comparable between covariate-dependent (R2 = 0.774, 3.55%) and covariate independent (R2 = 0.804, 3.28%) models when peaks and troughs are measured but not when measurements are restricted to troughs only (R2 = 0.557, 15.5%). PMID- 28096159 TI - Genome Analysis of the Carbapenem- and Colistin-Resistant Escherichia coli Isolate NRZ14408 Reveals Horizontal Gene Transfer Pathways towards Panresistance and Enhanced Virulence. PMID- 28096160 TI - Determinants of Antibacterial Spectrum and Resistance Potential of the Elongation Factor G Inhibitor Argyrin B in Key Gram-Negative Pathogens. AB - Argyrins are natural products with antibacterial activity against Gram-negative pathogens, such as Pseudomonas aeruginosa, Burkholderia multivorans, and Stenotrophomonas maltophilia We previously showed that argyrin B targets elongation factor G (FusA). Here, we show that argyrin B activity against P. aeruginosa PAO1 (MIC = 8 MUg/ml) was not affected by deletion of the MexAB-OprM, MexXY-OprM, MexCD-OprJ, or MexEF-OprN efflux pump. However, argyrin B induced expression of MexXY, causing slight but reproducible antagonism with the MexXY substrate antibiotic ciprofloxacin. Argyrin B activity against Escherichia coli increased in a strain with nine tolC efflux pump partner genes deleted. Complementation experiments showed that argyrin was effluxed by AcrAB, AcrEF, and MdtFX. Argyrin B was inactive against Acinetobacter baumannii Differences between A. baumannii and P. aeruginosa FusA proteins at key residues for argyrin B interaction implied that natural target sequence variation impacted antibacterial activity. Consistent with this, expression of the sensitive P. aeruginosa FusA1 protein in A. baumannii conferred argyrin susceptibility, whereas resistant variants did not. Argyrin B was active against S. maltophilia (MIC = 4 MUg/ml). Spontaneous resistance occurred at high frequency in the bacterium (circa 10-7), mediated by mutational inactivation of fusA1 rather than by amino acid substitutions in the target binding region. This strongly suggested that resistance occurred at high frequency through loss of the sensitive FusA1, leaving an alternate argyrin-insensitive elongation factor. Supporting this, an additional fusA-like gene (fusA2) is present in S. maltophilia that was strongly upregulated in response to mutational loss of fusA1. PMID- 28096161 TI - Perifosine Mechanisms of Action in Leishmania Species. AB - Here the mechanism by which perifosine induced cell death in Leishmania donovani and Leishmania amazonensis is described. The drug reduced Leishmania mitochondrial membrane potential and decreased cellular ATP levels while increasing phosphatidylserine externalization. Perifosine did not increase membrane permeabilization. We also found that the drug inhibited the phosphorylation of Akt in the parasites. These results highlight the potential use of perifosine as an alternative to miltefosine against Leishmania. PMID- 28096163 TI - Large-Scale Evaluation of In Vitro Amphotericin B, Triazole, and Echinocandin Activity against Coccidioides Species from U.S. Institutions. AB - Large-scale testing of Coccidioides isolates has not been performed, and the frequency of clinical isolates with elevated amphotericin B or triazole MICs has not been evaluated. Coccidioides isolates (n = 581) underwent antifungal susceptibility testing. Elevated MIC values were observed for fluconazole (>=16 MUg/ml, 37.3% of isolates; >=32 MUg/ml, 7.9% of isolates), itraconazole (>=2 MUg/ml, 1.0% of isolates), posaconazole (>=1 MUg/ml, 1.0% of isolates), and voriconazole (>=2 MUg/ml, 1.2% of isolates). However, mold-active triazoles exhibited low MICs for the majority of isolates tested. Additional correlation with patient outcomes to determine the relevance of elevated MICs in Coccidioides isolates is needed. PMID- 28096162 TI - Impact of Extended Duration of Artesunate Treatment on Parasitological Outcome in a Cytocidal Murine Malaria Model. AB - Artemisinin-based combination therapies are a key pillar in global malaria control and are recommended as a first-line Plasmodium falciparum treatment. They rely upon a rapid 4-log-unit reduction in parasitemia by artemisinin compounds with a short half-life and the killing of remaining parasites by a partner compound with a longer half-life. Current treatment guidelines stipulate giving three 24-h-interval doses or six 12-h-interval doses over a 3-day period. Due to the short half-life of artesunate and artemether, almost all of the resulting cytocidal activity is confined within a single 48-h asexual P. falciparum cycle. Here, we utilized a luciferase reporter, Plasmodium berghei ANKA, in a cytocidal model in which treatment was initiated at high parasitemia, allowing us to monitor a greater than 3-log-unit reduction in parasite density, as well as 30 day survival. In this study, we demonstrated that increasing the artesunate duration from spanning one asexual cycle to spanning three asexual cycles while keeping the total dose constant results in enhanced cytocidal activity. Single daily artesunate doses at 50 mg/kg of body weight over 7 days were the minimum necessary for curative monotherapy. In combination with a single sub-human equivalent dose of the partner drug amodiaquine or piperaquine, the three-asexual cycle artesunate duration was able to cure 75% and 100% of mice, respectively, whereas 0% and 33% cures were achieved with the single-asexual-cycle artesunate duration. In summary, cytocidal activity of the artemisinin compounds, such as artesunate, can be improved solely by altering the dosing duration. PMID- 28096164 TI - Pharmacodynamics of Ceftaroline plus Ampicillin against Enterococcus faecalis in an In Vitro Pharmacokinetic/Pharmacodynamic Model of Simulated Endocardial Vegetations. AB - The combination of ampicillin plus ceftaroline has been suggested to be more reliably synergistic against Enterococcus faecalis than ampicillin plus ceftriaxone using time-kill methods. The purpose of this study was to determine if this trend persists in a two-compartment model of simulated endocardial vegetations (SEV) using clinically relevant pharmacokinetic exposures of these antimicrobials. Three clinically derived E. faecalis strains were included in the study. The MICs of study antimicrobials were determined by broth microdilution. Simulations of ampicillin (2 g every 4 h [q4h]; maximum concentration of drug in serum [Cmax], 72.4 mg/liter; half-life [t1/2], 1.9 h), ceftaroline-fosamil (600 mg q8h; Cmax, 21.3 mg/liter; t1/2, 2.66 h), ceftriaxone (Cmax, 257 mg/liter; t1/2, 8 h), and ampicillin plus ceftaroline and ampicillin plus ceftriaxone were evaluated against 3 strains of E. faecalis isolated from patients with endocarditis in an in vitro PK/PD SEV model over 72 h, with a starting inoculum of ~9 log10 CFU/g. All strains were susceptible to ampicillin (MIC, <=2 mg/liter). Ceftaroline MICs varied from 2 to 16 mg/liter. All strains had ceftriaxone MICs of 256 mg/liter. W04 and W151 exhibited high-level aminoglycoside resistance but W07 did not. Ampicillin plus ceftaroline resulted in significantly greater reductions in CFU per gram by 72 h than ampicillin for all strains (P <= 0.025) than ampicillin plus ceftriaxone for W04 (P = 0.019) but not W07 or W151 (P >= 0.15). A 4-fold increase in ampicillin MIC was observed for W07 at 72 h, but this was prevented by the addition of ceftaroline or ceftriaxone. The combination of ampicillin plus ceftaroline appears to be at least as efficacious as ampicillin plus ceftriaxone and may lead to improved activity against some strains of E. faecalis, but these differences may be small and the clinical significance should not be overestimated. PMID- 28096165 TI - In Vitro Activity of Ceftolozane-Tazobactam against Multidrug-Resistant Nonfermenting Gram-Negative Bacilli Isolated from Patients with Cystic Fibrosis. AB - Ceftolozane-tazobactam was tested against 58 multidrug-resistant nonfermenting Gram-negative bacilli (35 Pseudomonas aeruginosa, 11 Achromobacter xylosoxydans, and 12 Stenotrophomonas maltophilia isolates) isolated from cystic fibrosis patients and was compared to ceftolozane alone, ceftazidime, meropenem, and piperacillin-tazobactam. Ceftolozane-tazobactam was the most active agent against P. aeruginosa but was inactive against A. xylosoxydans and S. maltophilia In time kill experiments, ceftolozane-tazobactam had complete bactericidal activity against 2/6 clinical isolates (33%). PMID- 28096166 TI - Role of Renal Drug Exposure in Polymyxin B-Induced Nephrotoxicity. AB - Despite dose-limiting nephrotoxic potentials, polymyxin B has reemerged as the last line of therapy against multidrug-resistant Gram-negative bacterial infections. However, the handling of polymyxin B by the kidneys is still not thoroughly understood. The objectives of this study were to evaluate the impact of renal polymyxin B exposure on nephrotoxicity and to explore the role of megalin in renal drug accumulation. Sprague-Dawley rats (225 to 250 g) were divided into three dosing groups, and polymyxin B was administered (5 mg/kg, 10 mg/kg, and 20 mg/kg) subcutaneously once daily. The onset of nephrotoxicity over 7 days and renal drug concentrations 24 h after the first dose were assessed. The effects of sodium maleate (400 mg/kg intraperitoneally) on megalin homeostasis were evaluated by determining the urinary megalin concentration and electron microscopic study of renal tissue. The serum/renal pharmacokinetics of polymyxin B were assessed in megalin-shedding rats. The onset of nephrotoxicity was correlated with the daily dose of polymyxin B. Renal polymyxin B concentrations were found to be 3.6 +/- 0.4 MUg/g, 9.9 +/- 1.5 MUg/g, and 21.7 +/- 4.8 MUg/g in the 5-mg/kg, 10-mg/kg, and 20-mg/kg dosing groups, respectively. In megalin shedding rats, the serum pharmacokinetics of polymyxin B remained unchanged, but the renal exposure was attenuated by 40% compared to that of control rats. The onset of polymyxin B-induced nephrotoxicity is correlated with the renal drug exposure. In addition, megalin appears to play a pivotal role in the renal accumulation of polymyxin B, which might contribute to nephrotoxicity. PMID- 28096167 TI - Chemical Fingerprint of Dachaihu Granule and Its Chemical Correlation Between Raw Herbs. AB - To develop a method to overall evaluate the quality of Dachaihu Granule (DCHG), high-performance liquid chromatography coupled with diode array detector was used to establish chemical fingerprint of DCHG. The correlation between the formula and its raw herbs was also evaluated. According to the retention time of standard components, chemical fingerprint of DCHG was developed and a total of 21 constituents were characterized. The separation was performed on a Kromasil C18 column (250 mm * 4.6 mm i.d. with 5.0 MUm particle size) with a linear gradient elution of acetonitrile and water with 0.05% phosphoric acid. Precision, stability and repeatability of the method were validated. The developed method was subsequently applied to evaluate 15 batches of DCHG using similarity analysis, principal component analysis and partial least squares discriminate analysis. PMID- 28096169 TI - Correction to: Procedural and Long-Term Outcomes of Bioresorbable Scaffolds Versus Drug-Eluting Stents in Chronic Total Occlusions: The BONITO Registry (Bioresorbable Scaffolds Versus Drug-Eluting Stents in Chronic Total Occlusions). PMID- 28096168 TI - SK channel enhancers attenuate Ca2+-dependent arrhythmia in hypertrophic hearts by regulating mito-ROS-dependent oxidation and activity of RyR. AB - Aims: Plasmamembrane small conductance Ca2+-activated K+ (SK) channels were implicated in ventricular arrhythmias in infarcted and failing hearts. Recently, SK channels were detected in the inner mitochondria membrane (IMM) (mSK), and their activation protected from acute ischaemia-reperfusion injury by reducing intracellular levels of reactive oxygen species (ROS). We hypothesized that mSK play an important role in regulating mitochondrial function in chronic cardiac diseases. We investigated the role of mSK channels in Ca2+-dependent ventricular arrhythmia using rat model of cardiac hypertrophy induced by banding of the ascending aorta thoracic aortic banding (TAB). Methods and results: Dual Ca2+ and membrane potential optical mapping of whole hearts derived from TAB rats revealed that membrane-permeable SK enhancer NS309 (2 MUM) improved aberrant Ca2+ homeostasis and abolished VT/VF induced by beta-adrenergic stimulation. Using whole cell patch-clamp and confocal Ca2+ imaging of cardiomyocytes derived from TAB hearts (TCMs) we found that membrane-permeable SK enhancers NS309 and CyPPA (10 MUM) attenuated frequency of spontaneous Ca2+ waves and delayed afterdepolarizations. Furthermore, mSK inhibition enhanced (UCL-1684, 1 MUM); while activation reduced mitochondrial ROS production in TCMs measured with MitoSOX. Protein oxidation assays demonstrated that increased oxidation of ryanodine receptors (RyRs) in TCMs was reversed by SK enhancers. Experiments in permeabilized TCMs showed that SK enhancers restored SR Ca2+ content, suggestive of substantial improvement in RyR function. Conclusion: These data suggest that enhancement of mSK channels in hypertrophic rat hearts protects from Ca2+ dependent arrhythmia and suggest that the protection is mediated via decreased mitochondrial ROS and subsequent decreased oxidation of reactive cysteines in RyR, which ultimately leads to stabilization of RyR-mediated Ca2+ release. PMID- 28096172 TI - Still too little transparency among guideline writers and others. PMID- 28096171 TI - How well do we currently care for our dying patients in acute hospitals: the views of the bereaved relatives? AB - BACKGROUND: The National Care of the Dying Audit-Hospitals (NCDAH) is used as a method to evaluate care for dying patients in England. An additional component to the 2013/2014 audit was the Local Survey of Bereaved Relatives Views using the 'Care Of the Dying Evaluation' (CODE) questionnaire. AIM: Within the context of the NCDAH audit, to evaluate quality of care provided to dying patients and their families in acute hospitals from the perspective of bereaved relatives. DESIGN: Postbereavement survey to bereaved relatives. SETTING/PARTICIPANTS: For acute hospitals wishing to participate, consecutive 'expected' adult deaths occurring between 1 May and 30 June 2013 were identified and the CODE questionnaire was sent to the next-of-kin. RESULTS: From 3414 eligible next-of-kin, 95 (2.8%) were excluded due to being involved in a complaint procedure and 1006 (29.5%) due to insufficient next-of-kin details. From the remaining 2313 potential participants, 858 returned a completed CODE questionnaire (37.1% response rate). Generally, symptoms were perceived to be well controlled with 769 (91%) participants reporting that either no pain was present or only there 'some of the time'. Unmet information needs, however, was a recognised area for improvement, for example, 230 (29%) reporting having a discussion about hydration would have been beneficial. CONCLUSIONS: Adopting a postbereavement survey to NCDAH appears to be feasible, acceptable and a valuable addition. On the whole, the majority of participants reported good or excellent care. A small but significant minority, however, perceived poor quality of patient care with clear and timely communication urgently needed. PMID- 28096173 TI - Commentary: Working better, not harder. PMID- 28096177 TI - PM vows to improve "dangerously disregarded" mental healthcare. PMID- 28096176 TI - Reduced all-cause mortality with antipsychotics and antidepressants compared to increased all-cause mortality with benzodiazepines in patients with schizophrenia observed in naturalistic treatment settings. PMID- 28096174 TI - Anti-Folate Receptor-alpha IgE but not IgG Recruits Macrophages to Attack Tumors via TNFalpha/MCP-1 Signaling. AB - IgE antibodies are key mediators of antiparasitic immune responses, but their potential for cancer treatment via antibody-dependent cell-mediated cytotoxicity (ADCC) has been little studied. Recently, tumor antigen-specific IgEs were reported to restrict cancer cell growth by engaging high-affinity Fc receptors on monocytes and macrophages; however, the underlying therapeutic mechanisms were undefined and in vivo proof of concept was limited. Here, an immunocompetent rat model was designed to recapitulate the human IgE-Fcepsilon receptor system for cancer studies. We also generated rat IgE and IgG mAbs specific for the folate receptor (FRalpha), which is expressed widely on human ovarian tumors, along with a syngeneic rat tumor model expressing human FRalpha. Compared with IgG, anti FRalpha IgE reduced lung metastases. This effect was associated with increased intratumoral infiltration by TNFalpha+ and CD80+ macrophages plus elevated TNFalpha and the macrophage chemoattractant MCP-1 in lung bronchoalveolar lavage fluid. Increased levels of TNFalpha and MCP-1 correlated with IgE-mediated tumor cytotoxicity by human monocytes and with longer patient survival in clinical specimens of ovarian cancer. Monocytes responded to IgE but not IgG exposure by upregulating TNFalpha, which in turn induced MCP-1 production by monocytes and tumor cells to promote a monocyte chemotactic response. Conversely, blocking TNFalpha receptor signaling abrogated induction of MCP-1, implicating it in the antitumor effects of IgE. Overall, these findings show how antitumor IgE reprograms monocytes and macrophages in the tumor microenvironment, encouraging the clinical use of IgE antibody technology to attack cancer beyond the present exclusive reliance on IgG. Cancer Res; 77(5); 1127-41. (c)2017 AACR. PMID- 28096178 TI - NHS in 2017: A medical profession in step with today's NHS? PMID- 28096179 TI - Dbf4-dependent kinase and the Rtt107 scaffold promote Mus81-Mms4 resolvase activation during mitosis. AB - DNA repair by homologous recombination is under stringent cell cycle control. This includes the last step of the reaction, disentanglement of DNA joint molecules (JMs). Previous work has established that JM resolving nucleases are activated specifically at the onset of mitosis. In case of budding yeast Mus81 Mms4, this cell cycle stage-specific activation is known to depend on phosphorylation by CDK and Cdc5 kinases. Here, we show that a third cell cycle kinase, Cdc7-Dbf4 (DDK), targets Mus81-Mms4 in conjunction with Cdc5-both kinases bind to as well as phosphorylate Mus81-Mms4 in an interdependent manner. Moreover, DDK-mediated phosphorylation of Mms4 is strictly required for Mus81 activation in mitosis, establishing DDK as a novel regulator of homologous recombination. The scaffold protein Rtt107, which binds the Mus81-Mms4 complex, interacts with Cdc7 and thereby targets DDK and Cdc5 to the complex enabling full Mus81 activation. Therefore, Mus81 activation in mitosis involves at least three cell cycle kinases, CDK, Cdc5 and DDK Furthermore, tethering of the kinases in a stable complex with Mus81 is critical for efficient JM resolution. PMID- 28096181 TI - Long-term (8-10 years) outcomes after biodegradable polymer-coated biolimus eluting stent implantation. AB - OBJECTIVE: Efficacy and safety data on biodegradable polymer-coated biolimus eluting stent (BP-BES) are currently limited to 5 years. We evaluated longer term (8-10 years) clinical and angiographic outcomes after BP-BES implantation. METHODS: Between 2005 and 2008, 243 patients (301 lesions) underwent BP-BES implantation. The primary clinical outcome measure was defined as any target lesion revascularisation (TLR). Absolute serial angiographic studies without any concomitant TLR within 2 years after the procedure were performed in 55 patients (65 lesions) at postprocedure, mid-term (within 1 year), late term (between 1 and 2 years) and very late term (beyond 2 years). RESULTS: The median follow-up duration was 9.4 years (IQR 8.2-10.2 years). The 8-year cumulative incidence of any TLR was 20.3%. The increase rate was approximately 7% per year in the first 2 years, but decelerated to approximately 1.2% per year beyond 2 years after the procedure. The minimal lumen diameter significantly decreased from postprocedure (2.63+/-0.44 mm) to mid-term (2.43+/-0.59 mm, p=0.002) and from late term (2.27+/ 0.63 mm) to very late term (1.98+/-0.73 mm, p=0.002). The 8-year cumulative incidences of definite or probable stent thrombosis (ST) and major bleeding (Bleeding Academic Research Consortium (BARC) >=3) were 0.5% and 12.0%, respectively. Definite ST was none within 10 years in the entire cohort. CONCLUSIONS: The long-term clinical outcomes after BP-BES implantation were favourable, although angiographic late progression of luminal narrowing did not reach a plateau. The incidence of ST remained notably low, whereas that of major bleeding gradually increased. PMID- 28096180 TI - Nutrient sensing and TOR signaling in yeast and mammals. AB - Coordinating cell growth with nutrient availability is critical for cell survival. The evolutionarily conserved TOR (target of rapamycin) controls cell growth in response to nutrients, in particular amino acids. As a central controller of cell growth, mTOR (mammalian TOR) is implicated in several disorders, including cancer, obesity, and diabetes. Here, we review how nutrient availability is sensed and transduced to TOR in budding yeast and mammals. A better understanding of how nutrient availability is transduced to TOR may allow novel strategies in the treatment for mTOR-related diseases. PMID- 28096182 TI - Treatment of locally advanced prostate cancer (Stage T3). AB - Objective: Formerly, locally advanced prostate cancer exhibited poorly prognosis. In the late 1990s, new surgical and radiation technologies were introduced in combination with androgen deprivation. To evaluate respective strategies, outcomes were examined. Patients and methods: Between 2001 and 2010, 224 patients with T3N0M0 (10.9% of all prostate cancer cases) were treated with prostatectomy, external beam radiation therapy with/without androgen deprivation or hormone alone. Complete records were obtained by the end of 2015. Results: Operation group first started without adjuvant treatment and prostate-specific antigen (PSA) relapse occurred in 39% of cases. Radiation therapy group was alternatively divided into two subgroups, that received either monotherapy or combination with androgen deprivation, and PSA relapse rates were 65 and 16%, respectively. High rates of PSA relapse in both the operation and radiation therapy groups were observed in patients without adjuvant therapy, but after relapse androgen deprivation proceeded favorable outcomes. In the radiation subgroups, PSA relapse rates were different, but both subsequent survival rates were the same. This may be due to the effect of androgen deprivation after relapse, indicating effect of delayed therapy. PSA relapse rate in the hormone therapy group was 25% and after relapse, patients applied to treatment with other hormonal and anticancer drugs. Overall survival rates were 91, 88 and 67% in the operation, radiation therapy and hormone therapy groups, respectively. Conclusion: Aggressive treatment with short-term androgen deprivation for locally advanced prostate cancer could be beneficial and not harmful when suitable candidates are selected. Delayed androgen deprivation was effective for no adjuvant patients after PSA relapse. PMID- 28096183 TI - Pneumococcal Neuraminidase A (NanA) Promotes Biofilm Formation and Synergizes with Influenza A Virus in Nasal Colonization and Middle Ear Infection. AB - Even in the vaccine era, Streptococcus pneumoniae (the pneumococcus) remains a leading cause of otitis media, a significant public health burden, in large part because of the high prevalence of nasal colonization with the pneumococcus in children. The primary pneumococcal neuraminidase, NanA, which is a sialidase that catalyzes the cleavage of terminal sialic acids from host glycoconjugates, is involved in both of these processes. Coinfection with influenza A virus, which also expresses a neuraminidase, exacerbates nasal colonization and disease by S. pneumoniae, in part via the synergistic contributions of the viral neuraminidase. The specific role of its pneumococcal counterpart, NanA, in this interaction, however, is less well understood. We demonstrate in a mouse model that NanA deficient pneumococci are impaired in their ability to cause both nasal colonization and middle ear infection. Coinfection with neuraminidase-expressing influenza virus and S. pneumoniae potentiates both colonization and infection but not to wild-type levels, suggesting an intrinsic role of NanA. Using in vitro models, we show that while NanA contributes to both epithelial adherence and biofilm viability, its effect on the latter is actually independent of its sialidase activity. These data indicate that NanA contributes both enzymatically and nonenzymatically to pneumococcal pathogenesis and, as such, suggest that it is not a redundant bystander during coinfection with influenza A virus. Rather, its expression is required for the full synergism between these two pathogens. PMID- 28096184 TI - The modern role of transoesophageal echocardiography in the assessment of valvular pathologies. AB - Despite significant advancements in the field of cardiovascular imaging, transoesophageal echocardiography remains the key imaging modality in the management of valvular pathologies. This paper provides echocardiographers with an overview of the modern role of TOE in the diagnosis and management of valvular disease. We describe how the introduction of 3D techniques has changed detection and grading of valvular pathologies and concentrate on its role as a monitoring tool in interventional cardiology. In addition, we focus on the echocardiographic and Doppler techniques used in the assessment of prosthetic valves, and provide guidance for evaluation of prosthetic valves. Finally, we summarise quantitative methods used for the assessment of valvular stenosis and regurgitation and highlight the key areas where echocardiography remains superior over other novel imaging modalities. PMID- 28096185 TI - Transcriptomic profiling of purified patient-derived dopamine neurons identifies convergent perturbations and therapeutics for Parkinson's disease. AB - While induced pluripotent stem cell (iPSC) technologies enable the study of inaccessible patient cell types, cellular heterogeneity can confound the comparison of gene expression profiles between iPSC-derived cell lines. Here, we purified iPSC-derived human dopaminergic neurons (DaNs) using the intracellular marker, tyrosine hydroxylase. Once purified, the transcriptomic profiles of iPSC derived DaNs appear remarkably similar to profiles obtained from mature post mortem DaNs. Comparison of the profiles of purified iPSC-derived DaNs derived from Parkinson's disease (PD) patients carrying LRRK2 G2019S variants to controls identified significant functional convergence amongst differentially-expressed (DE) genes. The PD LRRK2-G2019S associated profile was positively matched with expression changes induced by the Parkinsonian neurotoxin rotenone and opposed by those induced by clioquinol, a compound with demonstrated therapeutic efficacy in multiple PD models. No functional convergence amongst DE genes was observed following a similar comparison using non-purified iPSC-derived DaN-containing populations, with cellular heterogeneity appearing a greater confound than genotypic background. PMID- 28096186 TI - Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma. AB - The intratumor microenvironment generates phenotypically distinct but interconvertible malignant cell subpopulations that fuel metastatic spread and therapeutic resistance. Whether different microenvironmental cues impose invasive or therapy-resistant phenotypes via a common mechanism is unknown. In melanoma, low expression of the lineage survival oncogene microphthalmia-associated transcription factor (MITF) correlates with invasion, senescence, and drug resistance. However, how MITF is suppressed in vivo and how MITF-low cells in tumors escape senescence are poorly understood. Here we show that microenvironmental cues, including inflammation-mediated resistance to adoptive T cell immunotherapy, transcriptionally repress MITF via ATF4 in response to inhibition of translation initiation factor eIF2B. ATF4, a key transcription mediator of the integrated stress response, also activates AXL and suppresses senescence to impose the MITF-low/AXL-high drug-resistant phenotype observed in human tumors. However, unexpectedly, without translation reprogramming an ATF4 high/MITF-low state is insufficient to drive invasion. Importantly, translation reprogramming dramatically enhances tumorigenesis and is linked to a previously unexplained gene expression program associated with anti-PD-1 immunotherapy resistance. Since we show that inhibition of eIF2B also drives neural crest migration and yeast invasiveness, our results suggest that translation reprogramming, an evolutionarily conserved starvation response, has been hijacked by microenvironmental stress signals in melanoma to drive phenotypic plasticity and invasion and determine therapeutic outcome. PMID- 28096187 TI - GPRASP2, a novel causative gene mutated in an X-linked recessive syndromic hearing loss. AB - BACKGROUND: A substantial amount of nuclear genes have been identified to be implicated in genetic hearing loss, while X-linked hearing loss is genetically heterogeneous and relatively infrequent. OBJECTIVE: To identify the causative gene mutation in a five-generation Chinese family with an X-linked recessive syndromic hearing loss (SHL). METHODS: Targeted X-chromosome exome sequencing was conducted, and cosegregation analysis was performed in the members of the affected family. The in silico and expression studies were also performed. RESULTS: A 2-bp missense mutation (c.1717_1718GC>AA, p.A573N) in the G protein coupled receptor associated sorting protein 2 (GPRASP2) gene was identified in four hemizygous male patients and two heterozygous female carriers, which was cosegregated with the clinical phenotypes in this family. In silico analysis supported that this gene mutation is functionally deleterious, and it was detected that homologous Gprasp2 was highly expressed in multiple structures of the mouse cochlea, which suggested that GPRASP2 might be the genetic cause for the described disease phenotypes. CONCLUSIONS: This study presented a novel X linked SHL combined with unique and unrecognised clinical features, and a missense variation of GPRASP2 was first identified to be implicated in X-linked SHL. PMID- 28096188 TI - Extracellular Signal-Regulated Kinases 1 and 2 Phosphorylate Gab2 To Promote a Negative-Feedback Loop That Attenuates Phosphoinositide 3-Kinase/Akt Signaling. AB - The scaffolding adapter protein Gab2 (Grb2-associated binder) promotes cell proliferation, survival, and motility by engaging several signaling pathways downstream of growth factor and cytokine receptors. In particular, Gab2 plays essential roles in mast cells, as it is required for phosphoinositide 3-kinase (PI3K) activation in response to Kit and the high-affinity IgE receptor. While the positive role of Gab2 in PI3K signaling is well documented, very little is known about the mechanisms that attenuate its function. Here we show that Gab2 becomes phosphorylated on multiple proline-directed sites upon stimulation of the Ras/extracellular signal-regulated kinase (ERK) signaling pathway. We demonstrate that ERK1 and ERK2 interact with Gab2 via a novel docking motif, which is required for subsequent Gab2 phosphorylation in response to ERK1/2 activation. We identified four ERK1/2-dependent phosphorylation sites in Gab2 that prevent the recruitment of the p85 regulatory subunit of PI3K. Using bone marrow-derived mast cells to study Gab2-dependent signaling, we found that the inhibition of ERK1/2 activity promotes Akt signaling in response to Kit and the high-affinity IgE receptor. Together, our results indicate that ERK1/2 participates in a negative feedback loop that attenuates PI3K/Akt signaling in response to various agonists. PMID- 28096189 TI - Suppressor of Overexpression of CO 1 Negatively Regulates Dark-Induced Leaf Degreening and Senescence by Directly Repressing Pheophytinase and Other Senescence-Associated Genes in Arabidopsis. AB - Although the biochemical pathway of chlorophyll (Chl) degradation has been largely elucidated, how Chl is rapidly yet coordinately degraded during leaf senescence remains elusive. Pheophytinase (PPH) is the enzyme for catalyzing the removal of the phytol group from pheophytin a, and PPH expression is significantly induced during leaf senescence. To elucidate the transcriptional regulation of PPH, we used a yeast (Saccharomyces cerevisiae) one-hybrid system to screen for its trans-regulators. SUPPRESSOR OF OVEREXPRESSION OF CO 1 (SOC1), a key flowering pathway integrator, was initially identified as one of the putative trans-regulators of PPH After dark treatment, leaves of an SOC1 knockdown mutant (soc1-6) showed an accelerated yellowing phenotype, whereas those of SOC1-overexpressing lines exhibited a partial stay-green phenotype. SOC1 and PPH expression showed a negative correlation during leaf senescence. Substantially, SOC1 protein could bind specifically to the CArG box of the PPH promoter in vitro and in vivo, and overexpression of SOC1 significantly inhibited the transcriptional activity of the PPH promoter in Arabidopsis (Arabidopsis thaliana) protoplasts. Importantly, soc1-6 pph-1 (a PPH knockout mutant) double mutant displayed a stay-green phenotype similar to that of pph-1 during dark treatment. These results demonstrated that SOC1 inhibits Chl degradation via negatively regulating PPH expression. In addition, measurement of the Chl content and the maximum photochemical efficiency of photosystem II of soc1-6 and SOC1-OE leaves after dark treatment suggested that SOC1 also negatively regulates the general senescence process. Seven SENESCENCE-ASSOCIATED GENES (SAGs) were thereafter identified as its potential target genes, and NONYELLOWING1 and SAG113 were experimentally confirmed. Together, we reveal that SOC1 represses dark induced leaf Chl degradation and senescence in general in Arabidopsis. PMID- 28096190 TI - Gain-of-Function Mutants of the Cytokinin Receptors AHK2 and AHK3 Regulate Plant Organ Size, Flowering Time and Plant Longevity. AB - The phytohormone cytokinin is a regulator of numerous processes in plants. In Arabidopsis (Arabidopsis thaliana), the cytokinin signal is perceived by three membrane-located receptors named ARABIDOPSIS HISTIDINE KINASE2 (AHK2), AHK3, and AHK4/CRE1. How the signal is transmitted across the membrane is an entirely unknown process. The three receptors have been shown to operate mostly in a redundant fashion, and very few specific roles have been attributed to single receptors. Using a forward genetic approach, we isolated constitutively active gain-of-function variants of the AHK2 and AHK3 genes, named repressor of cytokinin deficiency2 (rock2) and rock3, respectively. It is hypothesized that the structural changes caused by these mutations in the sensory and adjacent transmembrane domains emulate the structural changes caused by cytokinin binding, resulting in domain motion propagating the signal across the membrane. Detailed analysis of lines carrying rock2 and rock3 alleles revealed how plants respond to locally enhanced cytokinin signaling. Early flowering time, a prolonged reproductive growth phase, and, thereby, increased seed yield suggest that cytokinin regulates various aspects of reproductive growth. In particular, it counteracts the global proliferative arrest, a correlative inhibition of maternal growth by seeds, an as yet unknown activity of the hormone. PMID- 28096193 TI - Announcing Additional Leadership in Plant Biology. PMID- 28096191 TI - Allosteric modulation of the substrate specificity of acyl-CoA wax alcohol acyltransferase 2. AB - The esterification of alcohols with fatty acids is a universal mechanism to form inert storage forms of sterols, di- and triacylglycerols, and retinoids. In ocular tissues, formation of retinyl esters is an essential step in the enzymatic regeneration of the visual chromophore (11-cis-retinal). Acyl-CoA wax alcohol acyltransferase 2 (AWAT2), also known as multifunctional O-acyltransferase (MFAT), is an integral membrane enzyme with a broad substrate specificity that has been shown to preferentially esterify 11-cis-retinol and thus contribute to formation of a readily available pool of cis retinoids in the eye. However, the mechanism by which this promiscuous enzyme can gain substrate specificity is unknown. Here, we provide evidence for an allosteric modulation of the enzymatic activity by 11-cis retinoids. This regulation is independent from cellular retinaldehyde-binding protein (CRALBP), the major cis-retinoid binding protein. This positive-feedback regulation leads to decreased esterification rates for 9 cis, 13-cis, or all-trans retinols and thus enables preferential synthesis of 11 cis-retinyl esters. Finally, electron microscopy analyses of the purified enzyme indicate that this allosteric effect does not result from formation of functional oligomers. Altogether, these data provide the experimental basis for understanding regulation of AWAT2 substrate specificity. PMID- 28096192 TI - Integrated Physiological, Proteomic, and Metabolomic Analysis of Ultra Violet (UV) Stress Responses and Adaptation Mechanisms in Pinus radiata. AB - Globally expected changes in environmental conditions, especially the increase of UV irradiation, necessitate extending our knowledge of the mechanisms mediating tree species adaptation to this stress. This is crucial for designing new strategies to maintain future forest productivity. Studies focused on environmentally realistic dosages of UV irradiation in forest species are scarce. Pinus spp. are commercially relevant trees and not much is known about their adaptation to UV. In this work, UV treatment and recovery of Pinus radiata plants with dosages mimicking future scenarios, based on current models of UV radiation, were performed in a time-dependent manner. The combined metabolome and proteome analysis were complemented with measurements of + physiological parameters and gene expression. Sparse PLS analysis revealed complex molecular interaction networks of molecular and physiological data. Early responses prevented phototoxicity by reducing photosystem activity and the electron transfer chain together with the accumulation of photoprotectors and photorespiration. Apart from the reduction in photosynthesis as consequence of the direct UV damage on the photosystems, the primary metabolism was rearranged to deal with the oxidative stress while minimizing ROS production. New protein kinases and proteases related to signaling, coordination, and regulation of UV stress responses were revealed. All these processes demonstrate a complex molecular interaction network extending the current knowledge on UV-stress adaptation in pine. PMID- 28096194 TI - Autologous Cell Therapy for Peripheral Arterial Disease: Systematic Review and Meta-Analysis of Randomized, Nonrandomized, and Noncontrolled Studies. AB - RATIONALE: Critical limb ischemia is a life-threatening complication of peripheral arterial disease. In patients who are ineligible for revascularization procedures, there are few therapeutic alternatives, leading to amputations and death. OBJECTIVE: To provide a systematic review of the literature and a meta analysis of studies evaluating safety and efficacy of autologous cell therapy for intractable peripheral arterial disease/critical limb ischemia. METHODS AND RESULTS: We retrieved 19 randomized controlled trials (837 patients), 7 nonrandomized trials (338 patients), and 41 noncontrolled studies (1177 patients). The primary outcome was major amputation. Heterogeneity was high, and publication bias could not be excluded. Despite these limitations, the primary analysis (all randomized controlled trials) showed that cell therapy reduced the risk of amputation by 37%, improved amputation-free survival by 18%, and improved wound healing by 59%, without affecting mortality. Cell therapy significantly increased ankle brachial index, increased transcutaneous oxygen tension, and reduced rest pain. The secondary analysis (all controlled trials; n=1175 patients) shows that there may be potential to avoid ~1 amputation/year for every 2 patients successfully treated. The tertiary analysis (all studies; n=2332 patients) precisely estimated the changes in ankle brachial index, transcutaneous oxygen tension, rest pain, and walking capacity after cell therapy. Intramuscular implantation appeared more effective than intra-arterial infusion, and mobilized peripheral blood mononuclear cells may outperform bone marrow-mononuclear cells and mesenchymal stem cells. Amputation rate was improved more in trials wherein the prevalence of diabetes mellitus was high. Cell therapy was not associated with severe adverse events. Remarkably, efficacy of cell therapy on all end points was no longer significant in placebo-controlled randomized controlled trials and disappeared in randomized controlled trials with a low risk of bias. CONCLUSIONS: Although this meta-analysis highlights the need for more high quality placebo-controlled trials, equipoise may no longer be guaranteed because autologous cell therapy has the potential to modify the natural history of intractable critical limb ischemia. PMID- 28096197 TI - Measles Vaccination for International Airport Workers. PMID- 28096196 TI - Craniospinal irradiation using helical tomotherapy for central nervous system tumors. AB - The aim of this study was to describe early and late toxicity, survival and local control in 45 patients with primary brain tumors treated with helical tomotherapy craniospinal irradiation (HT-CSI). From 2006 to 2014, 45 patients with central nervous system malignancies were treated with HT-CSI. The most common tumors were medulloblastoma in 20 patients, ependymoma in 10 patients, intracranial germinoma (ICG) in 7 patients, and primitive neuroectodermal tumor in 4 patients. Hematological toxicity during treatment included leukopenia Grades 1-4 (6.7%, 33.3%, 37.8% and 17.8%, respectively), anemia Grades 1-4 (44.4%, 22.2%, 22.2% and 0%, respectively) and thrombocytopenia Grades 1-4 (51.1%, 15.6%, 15.6% and 6.7%, respectively). The most common acute toxicities were nausea, vomiting, fatigue, loss of appetite, alopecia and neurotoxicity. No Grade 3 or higher late toxicity occurred. The overall 3- and 5-year survival rates were 80% and 70%, respectively. Survival for the main tumor entities included 3- and 5-year survival rates of 80% and 70%, respectively, for patients with medulloblastoma, 70% for both in patients with ependymoma, and 100% for both in patients with ICG. Relapse occurred in 11 patients (24.4%): 10 with local and 1 with multifocal relapse. One patient experienced a secondary cancer. M-status and the results of the re-evaluation at the end of treatment were significantly related to survival. Survival after HT-CSI was in line with the existing literature, and acute treatment-induced toxicity resolved quickly. Compared with conventional radiotherapy, HT offers benefits such as avoiding gaps and junctions, sparing organs, and better and more homogeneous dose distribution and coverage of the target volume. PMID- 28096195 TI - Multifunctional Mitochondrial Epac1 Controls Myocardial Cell Death. AB - RATIONALE: Although the second messenger cyclic AMP (cAMP) is physiologically beneficial in the heart, it largely contributes to cardiac disease progression when dysregulated. Current evidence suggests that cAMP is produced within mitochondria. However, mitochondrial cAMP signaling and its involvement in cardiac pathophysiology are far from being understood. OBJECTIVE: To investigate the role of MitEpac1 (mitochondrial exchange protein directly activated by cAMP 1) in ischemia/reperfusion injury. METHODS AND RESULTS: We show that Epac1 (exchange protein directly activated by cAMP 1) genetic ablation (Epac1-/-) protects against experimental myocardial ischemia/reperfusion injury with reduced infarct size and cardiomyocyte apoptosis. As observed in vivo, Epac1 inhibition prevents hypoxia/reoxygenation-induced adult cardiomyocyte apoptosis. Interestingly, a deleted form of Epac1 in its mitochondrial-targeting sequence protects against hypoxia/reoxygenation-induced cell death. Mechanistically, Epac1 favors Ca2+ exchange between the endoplasmic reticulum and the mitochondrion, by increasing interaction with a macromolecular complex composed of the VDAC1 (voltage-dependent anion channel 1), the GRP75 (chaperone glucose-regulated protein 75), and the IP3R1 (inositol-1,4,5-triphosphate receptor 1), leading to mitochondrial Ca2+ overload and opening of the mitochondrial permeability transition pore. In addition, our findings demonstrate that MitEpac1 inhibits isocitrate dehydrogenase 2 via the mitochondrial recruitment of CaMKII (Ca2+/calmodulin-dependent protein kinase II), which decreases nicotinamide adenine dinucleotide phosphate hydrogen synthesis, thereby, reducing the antioxidant capabilities of the cardiomyocyte. CONCLUSIONS: Our results reveal the existence, within mitochondria, of different cAMP-Epac1 microdomains that control myocardial cell death. In addition, our findings suggest Epac1 as a promising target for the treatment of ischemia-induced myocardial damage. PMID- 28096198 TI - Comparison of Triage Strategies for HPV-Positive Women: Canadian Cervical Cancer Screening Trial Results. AB - Background: High-risk human papillomavirus (HR-HPV) testing has become a preferred cervical cancer screening strategy in some countries due to its superior sensitivity over cytology-based methods for identifying cervical intraepithelial neoplasia of grade 2 or worse (CIN2+). Improved sensitivity has been accompanied by reductions in specificity and concerns regarding overscreening and overtreatment of women with transient or nonprogressing HR-HPV infections. Triage of HR-HPV+ women to colposcopy is, thus, warranted for appropriate management and treatment.Methods: Using data from the Canadian Cervical Cancer Screening Trial (CCCaST), we compared the performance of cytology and HR-HPV strategies to detect CIN2+ among HR-HPV+ women (age, 30-69 years). Colposcopy referral rates and performance gains from adding other HR-HPV genotypes to HPV16/18+ triage were also evaluated.Results: A strategy referring all women HPV16/18+ and HPV16/18-, but with atypical squamous cells of undetermined significance or worse cytology (ASC-US+) had the highest sensitivity [82.5%; 95% confidence interval (CI), 70.9%-91.0%] but yielded the highest colposcopy referral rate. HPV16/18+ triage was the next most sensitive strategy (64.1%; 95% CI, 51.1%-75.7%). Low-grade squamous intraepithelial lesion or worse cytology (LSIL+) triage yielded a low sensitivity (32.8%; 95% CI, 21.9%-45.4%) but had the most favorable specificity (93.6%; 95% CI, 91.0%-95.6%), positive predictive value (41.5%; 95% CI, 28.1%-55.9%), and colposcopy referral rate of strategies examined. HPV viral load triage strategies did not perform optimally overall. Inclusion of HR-HPV genotypes 31 and 52 to HPV16/18+ triage provided the highest sensitivities.Conclusion: Concerns surrounding HPV-based screening can be effectively mitigated via triage.Impact: Balancing the benefits of HPV-based primary cervical screening with informed management recommendations for HR-HPV+ women may decide the success of its widening utilization. Cancer Epidemiol Biomarkers Prev; 26(6); 923-9. (c)2017 AACR. PMID- 28096199 TI - Trends in Radiation Therapy among Cancer Survivors in the United States, 2000 2030. AB - Background: Although the number of cancer survivors has increased substantially over the past several decades, the composition of survivors treated with radiotherapy is not well defined. Radiotherapy carries unique long-term toxicity risks for cancer survivors. This study describes the current estimates and future projections of the epidemiology of 5-year cancer survivors who receive radiation therapy.Methods: We used cancer incidence and survival data from the Surveillance, Epidemiology, and End-Results (SEER) database linked to U.S. Census data to estimate the number of 5-year cancer survivors treated with radiation between 2000 and 2030. Future projections assumed continuing incidence and survival trends based on historical rates.Results: In 2016, there were an estimated 3.05 million cancer survivors treated with radiation, accounting for 29% of all cancer survivors. The number of radiation-treated cancer survivors is projected to reach 3.38 million by 2020 and 4.17 million by 2030. In 2016, breast (40%) and prostate cancer (23%) composed the majority of radiation-treated survivors, followed by head and neck cancer (5.8%), lymphoma (5.6%), uterine (3.9%), and rectal cancer (3.8%). The percentage of 70 years or older radiation treated survivors steadily increased between 2000 and 2030.Conclusions: The next several years are projected to see a large increase in the number of cancer survivors treated with radiation.Impact: This group of cancer survivors has unique needs given the long-term risks of radiation, and increased research and awareness are required to optimize health of this growing population. Cancer Epidemiol Biomarkers Prev; 26(6); 963-70. (c)2017 AACR. PMID- 28096200 TI - Family History of Breast Cancer, Breast Density, and Breast Cancer Risk in a U.S. Breast Cancer Screening Population. AB - Background: The utility of incorporating detailed family history into breast cancer risk prediction hinges on its independent contribution to breast cancer risk. We evaluated associations between detailed family history and breast cancer risk while accounting for breast density.Methods: We followed 222,019 participants ages 35 to 74 in the Breast Cancer Surveillance Consortium, of whom 2,456 developed invasive breast cancer. We calculated standardized breast cancer risks within joint strata of breast density and simple (1st-degree female relative) or detailed (first-degree, second-degree, or first- and second-degree female relative) breast cancer family history. We fit log-binomial models to estimate age-specific breast cancer associations for simple and detailed family history, accounting for breast density.Results: Simple first-degree family history was associated with increased breast cancer risk compared with no first degree history [Risk ratio (RR), 1.5; 95% confidence interval (CI), 1.0-2.1 at age 40; RR, 1.5; 95% CI, 1.3-1.7 at age 50; RR, 1.4; 95% CI, 1.2-1.6 at age 60; RR, 1.3; 95% CI, 1.1-1.5 at age 70). Breast cancer associations with detailed family history were strongest for women with first- and second-degree family history compared with no history (RR, 1.9; 95% CI, 1.1-3.2 at age 40); this association weakened in higher age groups (RR, 1.2; 95% CI, 0.88-1.5 at age 70). Associations did not change substantially when adjusted for breast density.Conclusions: Even with adjustment for breast density, a history of breast cancer in both first- and second-degree relatives is more strongly associated with breast cancer than simple first-degree family history.Impact: Future efforts to improve breast cancer risk prediction models should evaluate detailed family history as a risk factor. Cancer Epidemiol Biomarkers Prev; 26(6); 938-44. (c)2017 AACR. PMID- 28096201 TI - Serum C-peptide, Total and High Molecular Weight Adiponectin, and Pancreatic Cancer: Do Associations Differ by Smoking? AB - Background: Studies examining associations between circulating concentrations of C-peptide and total adiponectin, two biomarkers related to obesity and insulin secretion and sensitivity and pancreatic ductal adenocarcinoma (PDA) risk have shown inconsistent results and included limited numbers of smokers.Methods: We examined associations of these biomarkers and high molecular weight (HMW) adiponectin with PDA, overall, and by smoking status. We conducted a pooled nested case-control analysis in 3 cohorts (Prostate, Lung, Colorectal, and Ovarian Cancer Trial, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, and Cancer Prevention Study-II), with 758 cases (435 current smokers) and 1,052 controls (531 smokers) matched by cohort, age, sex, race, blood draw date and follow-up time. We used conditional logistic regression adjusted for age, smoking, diabetes, and body mass index to calculate ORs and 95% confidence intervals (CI).Results: Circulating C-peptide concentration was not associated with PDA in never or former smokers, but was inversely associated with PDA in current smokers (per SD OR = 0.67; 95% CI, 0.54-0.84; Pinteraction = 0.005). HMW adiponectin was inversely associated with PDA in never smokers (OR = 0.43; 95% CI, 0.23-0.81), not associated in former smokers, and positively associated in smokers (OR = 1.23; 95% CI, 1.04-1.45; Pinteraction = 0.009). Total adiponectin was not associated with PDA in nonsmokers or current smokers.Conclusions: Associations of biomarkers of insulin secretion and sensitivity with PDA differ by smoking status. Smoking-induced pancreatic damage may explain the associations in smokers while mechanisms related to insulin resistance associations in nonsmokers.Impact: Future studies of these biomarkers and PDA should examine results by smoking status. Cancer Epidemiol Biomarkers Prev; 26(6); 914-22. (c)2017 AACR. PMID- 28096202 TI - HASF (C3orf58) is a novel ligand of the insulin-like growth factor 1 receptor. AB - We have recently shown that hypoxia and Akt-induced stem cell factor (HASF) protects the heart from ischemia-induced damage and promotes cardiomyocyte proliferation. While we have identified certain signaling pathways responsible for these protective effects, the receptor mediating these effects was unknown. Here, we undertook studies to identify the HASF receptor. A yeast two-hybrid screen identified a partial fragment of insulin-like growth factor 1 receptor (IGF1R) as a binding partner of HASF. Subsequent co-immunoprecipitation experiments showed that HASF bound to full-length IGF1R. Binding assays revealed a high affinity of HASF for IGF1R. The treatment of neonatal ventricular cardiomyocytes with HASF resulted in the phosphorylation of IGF1R and other proteins known to be involved in IGF1R-mediated signaling pathways. HASF-mediated ERK activation was abrogated by IGF1R pharmacological inhibitors and siRNAs that targeted IGF1R. However, siRNA-mediated knockdown of either IGF2R or the insulin receptor had no effect on HASF-induced cell signaling. Additionally, pharmacologic inhibition of IGF1R impeded HASF's ability to induce cardiomyocyte proliferation. Finally, we documented that in vivo deletion of the IGF1R completely abolished the ability of HASF to promote cardiomyocyte proliferation in an overexpression mouse model providing further evidence in vivo that the IGF1R is the functional receptor for HASF. PMID- 28096203 TI - Hospital Variation in Functional Recovery After Stroke. AB - BACKGROUND: Functional status is a key patient-centric outcome, but there are little data on whether functional recovery post-stroke varies among hospitals. This study examined the distribution of functional status 3 months after stroke, determined whether these outcomes vary among hospitals, and identified hospital characteristics associated with better (or worse) functional outcomes. METHODS AND RESULTS: Observational analysis of the AVAIL study (Adherence Evaluation After Ischemic Stroke-Longitudinal) included 2083 ischemic stroke patients enrolled from 82 US hospitals participating in Get With The Guidelines-Stroke and AVAIL. The primary outcome was dependence or death at 3 months (modified Rankin Scale [mRS] score of 3-6). Secondary outcomes included functional dependence (mRS score of 3-5), disabled (mRS score of 2-5), and mRS evaluated as a continuous score. By 3 months post-discharge, 36.5% of patients were functionally dependent or dead. Rates of dependence or death varied widely by discharging hospitals (range: 0%-67%). After risk adjustment, patients had lower rates of 3-month dependence or death when treated at teaching hospitals (odds ratio, 0.72; 95% confidence interval, 0.54-0.96) and certified primary stroke centers (odds ratio, 0.69; 95% confidence interval, 0.53-0.91). In contrast, a composite measure of hospital-level adherence to acute stroke care performance metrics, stroke volume, and bed size was not associated with downstream patient functional status. Findings were robust across mRS end points and sensitivity analyses. CONCLUSIONS: One third of acute ischemic stroke patients were functionally dependent or dead 3 months postacute stroke; functional recovery rates varied considerably among hospitals, supporting the need to better determine which care processes can maximize functional outcomes. PMID- 28096204 TI - Atrial Fibrillation Diagnosis Timing, Ambulatory ECG Monitoring Utilization, and Risk of Recurrent Stroke. AB - BACKGROUND: The risk of recurrence after an initial ischemic stroke or transient ischemic attack (TIA) may be impacted by undiagnosed atrial fibrillation (AF). We therefore assessed the impact of AF diagnosis and timing on stroke/TIA recurrence rates in a large real-world sample of patients. METHODS AND RESULTS: Using commercial claims data (Truven Health Analytics MarketScan), we performed a retrospective cohort study of patients with an index stroke or TIA event recorded in years 2008 through 2011. Patients were characterized by baseline oral anticoagulation, CHADS2 and CHA2DS2-VASc scores, AF diagnosis and timing with respect to the index stroke, and presence or absence of post-index ambulatory cardiac monitoring. The primary outcome was the recurrence of an ischemic stroke or TIA. Of 179 160 patients (age 67+/-16.2 years; 53.7% female), the Kaplan-Meier estimate for stroke/TIA recurrence within 1 year was 10.6%. Not having oral anticoagulation prescribed at baseline and having AF first diagnosed >7 days post stroke (late AF) was highly associated with recurrent stroke/TIA (hazard ratio, 2.0; 95% confidence interval, 1.9-2.1). Among patients with at least 1 year of follow-up, only 2.6% and 9.7% had ambulatory ECG monitoring in the 7 days and 12 months post-stroke, respectively. CONCLUSIONS: AF diagnosed after stroke is an important hallmark of recurrent stroke risk. Increasing the low utilization of cardiac monitoring after stroke could identify undiagnosed AF earlier, leading to appropriate oral anticoagulation treatment and a reduction in stroke/TIA recurrence. PMID- 28096205 TI - Effect of Prepublication Results on Trends in Prescribing of Antihypertensive Medication: Impact of the ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Disease Endpoints) Trial on Aliskiren Prescribing. PMID- 28096206 TI - Racial and Ethnic Differences in Antihypertensive Medication Use and Blood Pressure Control Among US Adults With Hypertension: The National Health and Nutrition Examination Survey, 2003 to 2012. AB - BACKGROUND: A key to reduce and eradicate racial disparities in hypertension outcomes is to understand their causes. We aimed at evaluating racial differences in antihypertensive drug utilization patterns and blood pressure control by insurance status, age, sex, and presence of comorbidities. METHODS AND RESULTS: A total of 8796 hypertensive individuals >=18 years of age were identified from the National Health and Nutrition Examination Survey (2003-2012) in a repeated cross sectional study. During the study period, all 3 racial groups (whites, blacks, and Hispanics) experienced substantial increase in hypertension treatment and control. The overall treatment rates were 73.9% (95% confidence interval [CI], 71.6%-76.2%), 70.8% (95% CI, 68.6%-73.0%), and 60.7% (95% CI, 57.0%-64.3%) and hypertension control rates were 42.9% (95% CI, 40.5%-45.2%), 36.9% (95% CI, 34.7% 39.2%), and 31.2% (95% CI, 28.6%-33.9%) for whites, blacks, and Hispanics, respectively. When stratified by insurance status, blacks (odds ratio, 0.74 [95% CI, 0.64-0.86] for insured and 0.59 [95% CI, 0.36-0.94] for uninsured) and Hispanics (odds ratio, 0.74 [95% CI, 0.60-0.91] for insured and 0.58 [95% CI, 0.36-0.94] for uninsured) persistently had lower rates of hypertension control compared with whites. Racial disparities also persisted in subgroups stratified by age (>=60 and <60 years of age) and presence of comorbidities but worsened among patients <60 years of age. CONCLUSIONS: Black and Hispanic patients had poorer hypertension control compared with whites, and these differences were more pronounced in younger and uninsured patients. Although black patients received more intensive antihypertensive therapy, Hispanics were undertreated. Future studies should further explore all aspects of these disparities to improve cardiovascular outcomes. PMID- 28096207 TI - Use of Strategies to Improve Door-to-Needle Times With Tissue-Type Plasminogen Activator in Acute Ischemic Stroke in Clinical Practice: Findings from Target: Stroke. AB - BACKGROUND: The implementation of Target: Stroke Phase I, the first stage of the American Heart Association's national quality improvement initiative to accelerate door-to-needle (DTN) times, was associated with an average 15-minute reduction in DTN times. TARGET: Stroke phase II was launched in April 2014 with a goal of promoting further reduction in treatment times for tissue-type plasminogen activator (tPA) administration. METHODS AND RESULTS: We conducted a second survey of Get With The Guidelines-Stroke hospitals regarding strategies used to reduce delays after Target: Stroke and quantify their association with DTN times. A total of 16 901 ischemic stroke patients were treated with intravenous tPA within 4.5 hours of symptom onset from 888 surveyed hospitals between June 2014 and April 2015. The patient-level median DTN time was 56 minutes (interquartile range, 42-75), with 59.3% of patients receiving intravenous tPA within 60 minutes and 30.4% within 45 minutes after hospital arrival. Most hospitals reported routinely using a majority of Target: Stroke key practice strategies, although direct transport of patients to computed tomographic/magenetic resonance imaging scanner, premix of tPA ahead of time, initiation of tPA in brain imaging suite, and prompt data feedback to emergency medical services providers were used less frequently. Overall, we identified 16 strategies associated with significant reductions in DTN times. Combined, a total of 20 minutes (95% confidence intervals 15-25 minutes) could be saved if all strategies were implemented. CONCLUSIONS: Get With The Guidelines-Stroke hospitals have initiated a majority of Target: Stroke-recommended strategies to reduce DTN times in acute ischemic stroke. Nevertheless, certain strategies were infrequently practiced and represent a potential immediate target for further improvements. PMID- 28096208 TI - Improving Door-to-Needle Times for Acute Ischemic Stroke: Effect of Rapid Patient Registration, Moving Directly to Computed Tomography, and Giving Alteplase at the Computed Tomography Scanner. AB - BACKGROUND: The effectiveness of specific systems changes to reduce DTN (door-to needle) time has not been fully evaluated. We analyzed the impact of 4 specific DTN time reduction strategies implemented prospectively in a staggered fashion. METHODS AND RESULTS: The HASTE (Hurry Acute Stroke Treatment and Evaluation) project was implemented in 3 phases at a single academic medical center. In HASTE I (June 6, 2012 to June 5, 2013), baseline performance was analyzed. In HASTE II (June 6, 2013 to January 24, 2015), 3 changes were implemented: (1) a STAT stroke protocol to prenotify the stroke team about incoming stroke patients; (2) administering alteplase at the computed tomography (CT) scanner; and (3) registering the patient as unknown to allow immediate order entry. In HASTE III (January 25, 2015 to June 29, 2015), we implemented a process to bring the patient directly to CT on the emergency medical services stretcher. Log transformed DTN time was modeled. Data from 350 consecutive alteplase-treated patients were analyzed. Multivariable regression showed the following factors to be significant: giving alteplase in the CT (32% decrease in DTN time, 95% confidence interval [CI] 38%-55%), stretcher to CT (30% decrease in DTN time, 95% CI 16%-42%), patient registered as unknown (12% decrease in DTN time, 95% CI 3% 20%), STAT stroke protocol (11% decrease in DTN time, 95% CI 1%-20%), and stroke severity (National Institutes of Health Stroke Scale score 6-8: 19% decrease in DTN time, 95% CI 6%-31%; National Institutes of Health Stroke Scale score >8: 27% decrease in DTN time, 95% CI 17%-37%). CONCLUSIONS: Taking the patient to CT on the emergency medical services stretcher, registering the patient as unknown, STAT stroke protocol, and administering alteplase in CT are associated with lower DTN time. PMID- 28096209 TI - Use of Mixed Methods Research in Research on Coronary Artery Disease, Diabetes Mellitus, and Hypertension: A Scoping Review. AB - BACKGROUND: Mixed methods research, the use of both qualitative and quantitative methods within 1 program of study, is becoming increasingly popular to allow investigators to explore patient experiences (qualitative) and also measure outcomes (quantitative). Coronary artery disease and its risk factors are some of the most studied conditions; however, the extent to which mixed methods studies are being conducted in these content areas is unknown. We sought to comprehensively describe the characteristics of published mixed methods studies on coronary artery disease and major risk factors (diabetes mellitus and hypertension). METHODS AND RESULTS: We conducted a scoping review of the literature indexed in PubMed, Medline, EMBASE, and CINAHL. We identified 811 abstracts for screening, of which 254 articles underwent full-text review and 97 reports of 81 studies met criteria for inclusion. The majority of studies in this area were conducted in the past 10 years by nurse researchers from the United States and United Kingdom. Diabetes mellitus was the most common content area for mixed methods investigation (compared with coronary artery disease and hypertension). Most authors described their rationale for using mixed methods as complementarity and did not describe study priority or how they reconciled differences in methodological paradigms. Some mixed methods study designs were more commonly used than others, including concurrent timing and integration at the interpretation stage. Qualitative strands were most commonly descriptive studies using interviews for data collection. Quantitative strands were most commonly cross-sectional observational studies, which relied heavily on self report data such as surveys and scales. CONCLUSIONS: Although mixed methods research is becoming increasingly popular in the area of coronary artery disease and its risk factors, many of the more advanced mixed methods, qualitative, and quantitative techniques have not been commonly used in these areas. PMID- 28096210 TI - Pace of Progress in Stroke Thrombolysis: Are Hospitals Running To Stand Still? PMID- 28096211 TI - Primate embryogenesis predicts the hallmarks of human naive pluripotency. AB - Naive pluripotent mouse embryonic stem cells (ESCs) resemble the preimplantation epiblast and efficiently contribute to chimaeras. Primate ESCs correspond to the postimplantation embryo and fail to resume development in chimaeric assays. Recent data suggest that human ESCs can be 'reset' to an earlier developmental stage, but their functional capacity remains ill defined. Here, we discuss how the naive state is inherently linked to preimplantation epiblast identity in the embryo. We hypothesise that distinctive features of primate development provide stringent criteria to evaluate naive pluripotency in human and other primate cells. Based on our hypothesis, we define 12 key hallmarks of naive pluripotency, five of which are specific to primates. These hallmarks may serve as a functional framework to assess human naive ESCs. PMID- 28096213 TI - Endothelial cell regulation of salivary gland epithelial patterning. AB - Perfusion-independent regulation of epithelial pattern formation by the vasculature during organ development and regeneration is of considerable interest for application in restoring organ function. During murine submandibular salivary gland development, the vasculature co-develops with the epithelium during branching morphogenesis; however, it is not known whether the vasculature has instructive effects on the epithelium. Using pharmacological inhibitors and siRNA knockdown in embryonic organ explants, we determined that VEGFR2-dependent signaling is required for salivary gland epithelial patterning. To test directly for a requirement for endothelial cells in instructive epithelial patterning, we developed a novel ex vivo cell fractionation/reconstitution assay. Immuno depletion of CD31+ endothelial cells in this assay confirmed a requirement for endothelial cells in epithelial patterning of the gland. Depletion of endothelial cells or inhibition of VEGFR2 signaling in organ explants caused an aberrant increase in cells expressing the ductal proteins K19 and K7, with a reduction in Kit+ progenitor cells in the endbuds of reconstituted glands. Addition of exogenous endothelial cells to reconstituted glands restored epithelial patterning, as did supplementation with the endothelial cell-regulated mesenchymal factors IGFBP2 and IGFBP3. Our results demonstrate that endothelial cells promote expansion of Kit+ progenitor cells and suppress premature ductal differentiation in early developing embryonic submandibular salivary gland buds. PMID- 28096212 TI - Planar cell polarity in moving cells: think globally, act locally. AB - The planar cell polarity (PCP) pathway is best known for its role in polarizing epithelial cells within the plane of a tissue but it also plays a role in a range of cell migration events during development. The mechanism by which the PCP pathway polarizes stationary epithelial cells is well characterized, but how PCP signaling functions to regulate more dynamic cell behaviors during directed cell migration is much less understood. Here, we review recent discoveries regarding the localization of PCP proteins in migrating cells and their impact on the cell biology of collective and individual cell migratory behaviors. PMID- 28096214 TI - Cartilage to bone transformation during fracture healing is coordinated by the invading vasculature and induction of the core pluripotency genes. AB - Fractures heal predominantly through the process of endochondral ossification. The classic model of endochondral ossification holds that chondrocytes mature to hypertrophy, undergo apoptosis and new bone forms by invading osteoprogenitors. However, recent data demonstrate that chondrocytes transdifferentiate to osteoblasts in the growth plate and during regeneration, yet the mechanism(s) regulating this process remain unknown. Here, we show a spatially-dependent phenotypic overlap between hypertrophic chondrocytes and osteoblasts at the chondro-osseous border in the fracture callus, in a region we define as the transition zone (TZ). Hypertrophic chondrocytes in the TZ activate expression of the pluripotency factors [Sox2, Oct4 (Pou5f1), Nanog], and conditional knock-out of Sox2 during fracture healing results in reduction of the fracture callus and a delay in conversion of cartilage to bone. The signal(s) triggering expression of the pluripotency genes are unknown, but we demonstrate that endothelial cell conditioned medium upregulates these genes in ex vivo fracture cultures, supporting histological evidence that transdifferentiation occurs adjacent to the vasculature. Elucidating the cellular and molecular mechanisms underlying fracture repair is important for understanding why some fractures fail to heal and for developing novel therapeutic interventions. PMID- 28096215 TI - Brassinosteroid signaling directs formative cell divisions and protophloem differentiation in Arabidopsis root meristems. AB - Brassinosteroids (BRs) trigger an intracellular signaling cascade through its receptors BR INSENSITIVE 1 (BRI1), BRI1-LIKE 1 (BRL1) and BRL3. Recent studies suggest that BR-independent inputs related to vascular differentiation, for instance root protophloem development, modulate downstream BR signaling components. Here, we report that protophloem sieve element differentiation is indeed impaired in bri1 brl1 brl3 mutants, although this effect might not be mediated by canonical downstream BR signaling components. We also found that their small meristem size is entirely explained by reduced cell elongation, which is, however, accompanied by supernumerary formative cell divisions in the radial dimension. Thus, reduced cell expansion in conjunction with growth retardation, because of the need to accommodate supernumerary formative divisions, can account for the overall short root phenotype of BR signaling mutants. Tissue-specific re addition of BRI1 activity partially rescued subsets of these defects through partly cell-autonomous, partly non-cell-autonomous effects. However, protophloem specific BRI1 expression essentially rescued all major bri1 brl1 brl3 root meristem phenotypes. Our data suggest that BR perception in the protophloem is sufficient to systemically convey BR action in the root meristem context. PMID- 28096216 TI - Basal filopodia and vascular mechanical stress organize fibronectin into pillars bridging the mesoderm-endoderm gap. AB - Cells may exchange information with other cells and tissues by exerting forces on the extracellular matrix (ECM). Fibronectin (FN) is an important ECM component that forms fibrils through cell contacts and creates directionally biased geometry. Here, we demonstrate that FN is deposited as pillars between widely separated germ layers, namely the somitic mesoderm and the endoderm, in quail embryos. Alongside the FN pillars, long filopodia protrude from the basal surfaces of somite epithelial cells. Loss-of-function of Ena/VASP, alpha5beta1 integrins or talin in the somitic cells abolished the FN pillars, indicating that FN pillar formation is dependent on the basal filopodia through these molecules. The basal filopodia and FN pillars are also necessary for proper somite morphogenesis. We identified a new mechanism contributing to FN pillar formation by focusing on cyclic expansion of adjacent dorsal aorta. Maintenance of the directional alignment of the FN pillars depends on pulsatile blood flow through the dorsal aortae. These results suggest that the FN pillars are specifically established through filopodia-mediated and pulsating force-related mechanisms. PMID- 28096217 TI - High-throughput analysis reveals novel maternal germline RNAs crucial for primordial germ cell preservation and proper migration. AB - During oogenesis, hundreds of maternal RNAs are selectively localized to the animal or vegetal pole, including determinants of somatic and germline fates. Although microarray analysis has identified localized determinants, it is not comprehensive and is limited to known transcripts. Here, we utilized high throughput RNA-sequencing analysis to comprehensively interrogate animal and vegetal pole RNAs in the fully grown Xenopus laevis oocyte. We identified 411 (198 annotated) and 27 (15 annotated) enriched mRNAs at the vegetal and animal pole, respectively. Ninety were novel mRNAs over 4-fold enriched at the vegetal pole and six were over 10-fold enriched at the animal pole. Unlike mRNAs, microRNAs were not asymmetrically distributed. Whole-mount in situ hybridization confirmed that all 17 selected mRNAs were localized. Biological function and network analysis of vegetally enriched transcripts identified protein-modifying enzymes, receptors, ligands, RNA-binding proteins, transcription factors and co factors with five defining hubs linking 47 genes in a network. Initial functional studies of maternal vegetally localized mRNAs show that sox7 plays a novel and important role in primordial germ cell (PGC) development and that ephrinB1 (efnb1) is required for proper PGC migration. We propose potential pathways operating at the vegetal pole that highlight where future investigations might be most fruitful. PMID- 28096221 TI - Efficient CRISPR/Cas9-assisted gene targeting enables rapid and precise genetic manipulation of mammalian neural stem cells. AB - Mammalian neural stem cell (NSC) lines provide a tractable model for discovery across stem cell and developmental biology, regenerative medicine and neuroscience. They can be derived from foetal or adult germinal tissues and continuously propagated in vitro as adherent monolayers. NSCs are clonally expandable, genetically stable, and easily transfectable - experimental attributes compatible with targeted genetic manipulations. However, gene targeting, which is crucial for functional studies of embryonic stem cells, has not been exploited to date in NSC lines. Here, we deploy CRISPR/Cas9 technology to demonstrate a variety of sophisticated genetic modifications via gene targeting in both mouse and human NSC lines, including: (1) efficient targeted transgene insertion at safe harbour loci (Rosa26 and AAVS1); (2) biallelic knockout of neurodevelopmental transcription factor genes; (3) simple knock-in of epitope tags and fluorescent reporters (e.g. Sox2-V5 and Sox2-mCherry); and (4) engineering of glioma mutations (TP53 deletion; H3F3A point mutations). These resources and optimised methods enable facile and scalable genome editing in mammalian NSCs, providing significant new opportunities for functional genetic analysis. PMID- 28096224 TI - Supra and infratentorial ectopic schwannoma mimicking a meningioma. AB - We report the case of a supra and infratentorial ectopic schwannoma, mimicking a meningioma, that was surgically resected on a 75-year-old man, with a history of progressive visual loss and headaches. MRI was in favour of an occipital, cystic, tentorial-based meningioma extending to the posterior fossa, with signs of intratumoral haemorrhage. This is a unique case because of the rare type of lesion, in a very atypical location, completely unexpected by the preoperative imaging analysis, and to the best of our knowledge it is the oldest patient reported in the literature with this kind of tumour. PMID- 28096225 TI - Not so patchy story of attempted suicide...leading to 24 hours of deep sleep and survival! AB - Here, we present a somewhat unusual suicide attempt where, despite an unbelievable overdose with transdermal fentanyl patches, the patient survived. The patient-a woman aged 70 years, who has suffered from chronic back pain despite starting transdermal fentanyl patches in 2007. The unconventional method of attempted suicide was based on online research into deaths from fentanyl patch toxicity. She had gradually accumulated 100 ug fentanyl patches from repeat prescriptions, applying 14 patches with fatal intent, alongside 2 45 mg mirtazapine tablets, and concurrent therapeutic doses of tramadol and morphine sulfate oral solution. However, after 24 hours, she awoke from a deep sleep to the sound of the telephone ringing, somewhat amazed her drastic efforts had failed. During admission to Great Western hospital, she was seen by liaison psychiatry and subsequently transferred to the care of the pain management team, to which she had already been referred. PMID- 28096223 TI - Combination Therapy With Exenatide Plus Pioglitazone Versus Basal/Bolus Insulin in Patients With Poorly Controlled Type 2 Diabetes on Sulfonylurea Plus Metformin: The Qatar Study. AB - OBJECTIVE: The Qatar Study was designed to examine the efficacy of combination therapy with exenatide plus pioglitazone versus basal/bolus insulin in patients with long-standing poorly controlled type 2 diabetes mellitus (T2DM) on metformin plus a sulfonylurea. RESEARCH DESIGN AND METHODS: The study randomized 231 patients with poorly controlled (HbA1c >7.5%, 58 mmol/mol) T2DM on a sulfonylurea plus metformin to receive 1) pioglitazone plus weekly exenatide (combination therapy) or 2) basal plus prandial insulin (insulin therapy) to maintain HbA1c <7.0% (53 mmol/mol). RESULTS: After a mean follow-up of 12 months, combination therapy caused a robust decrease in HbA1c from 10.0 +/- 0.6% (86 +/- 5.2 mmol/mol) at baseline to 6.1 +/- 0.1% (43 +/- 0.7 mmol/mol) compared with 7.1 +/- 0.1% (54 +/- 0.8 mmol/mol) in subjects receiving insulin therapy. Combination therapy was effective in lowering the HbA1c independent of sex, ethnicity, BMI, or baseline HbA1c. Subjects in the insulin therapy group experienced significantly greater weight gain and a threefold higher rate of hypoglycemia than patients in the combination therapy group. CONCLUSIONS: Combination exenatide/pioglitazone therapy is a very effective and safe therapeutic option in patients with long-standing poorly controlled T2DM on metformin plus a sulfonylurea. PMID- 28096222 TI - First Infant Formula Type and Risk of Islet Autoimmunity in The Environmental Determinants of Diabetes in the Young (TEDDY) Study. AB - OBJECTIVE: Studies on the introduction of infant formulas and its effect on the risk of islet autoimmunity and type 1 diabetes (T1D) have yielded inconsistent results. We investigated whether the introduction of formula based on hydrolyzed cow's milk as the first formula is associated with reduced islet autoimmunity risk in a large prospective cohort. RESEARCH DESIGN AND METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively monitors 8,676 children at increased genetic risk for T1D. Autoantibodies to insulin, GAD65, and IA2 were measured regularly to define islet autoimmunity. Information on formula feeding was collected by questionnaires at 3 months of age. RESULTS: In survival analyses, after adjustment for family history with T1D, HLA genotype, sex, country, delivery mode, breast-feeding >=3 months, and seasonality of birth, we observed no significant association with islet autoimmunity in infants who received extensively hydrolyzed compared with nonhydrolyzed cow's milk-based formula as the first formula during the first 3 months (adjusted hazard ratio 1.38 [95% CI 0.95; 2.01]), and a significantly increased risk for extensively hydrolyzed formula introduced during the first 7 days (adjusted hazard ratio 1.57 [1.04; 2.38]). Using a partially hydrolyzed or other formula as the first formula, or no formula, was not associated with islet autoimmunity risk. CONCLUSIONS: These results add to the existing evidence that islet autoimmunity risk is not reduced, and may be increased, by using hydrolyzed compared with nonhydrolyzed cow's milk-based infant formula as the first formula in infants at increased genetic risk for T1D. PMID- 28096226 TI - Disseminated adenovirus infection causing severe ARDS. AB - A previously healthy young man with a rare genetic condition presented with severe acute respiratory distress syndrome secondary to pneumonia with septic shock. He did not improve with conventional therapy for his known causal organism thus prompting further workup. He was found to be profoundly immunosuppressed raising our suspicion for atypical organisms. A bronchoalveolar lavage sample was positive via PCR for adenovirus which we suspect exacerbated a pre-existing bacterial pneumonia and led to a severe and non-responsive respiratory failure. His serum adenovirus load was markedly elevated. Treatment was started once the diagnosis of disseminated adenovirus infection was made; however, at that time patient was suffering from refractory hypoxaemia, respiratory acidosis, right heart failure and septic shock. Despite maximal supportive measures our patient ultimately expired over the course of 6 days. PMID- 28096227 TI - Atypical presentation of Bezold's and Citelli's abscesses, with recollection following an incomplete postoperative course of antibiotics. AB - Bezold's and Citelli's abscesses are rare complications of otitis media. We present a case of a 44-year-old Eastern European man, with a history of recurrent otitis media, who was admitted to hospital with mastoiditis and initially treated with antibiotics. Despite clinical improvement, a CT scan showed mastoiditis with Bezold's and Citelli's abscesses. The patient underwent a myringotomy and grommet insertion, in addition to a cortical mastoidectomy and curettage of the neck abscesses. After a good recovery, he was discharged home. However, likely due to the language barrier, he did not complete a course of antibiotics as prescribed, and the abscess re-collected, necessitating a re-admission and re-operation. This report illustrates the importance of considering rare features of a common disease in the differential, and of communication in ensuring compliance. PMID- 28096228 TI - Ingestion of cylindrical batteries and its management. AB - In contrast to the ingestion of coin batteries, the ingestion of cylindrical batteries is an uncommon medical presentation. Owing to their larger size, cylindrical battery ingestion can lead to serious complications including intestinal haemorrhage, bowel obstruction, bowel perforation, peritonitis and even death. We discuss the case of a 17-year-old girl who presented after swallowing three cylindrical batteries. Her medical history included depression and previous battery ingestion that required surgical removal. During this presentation however, these ingested batteries were removed endoscopically at oesophagogastroduodenoscopy and ileocolonoscopy. The patient was subsequently discharged without complication. This paper discusses the complications and management of cylindrical battery ingestion. PMID- 28096229 TI - Disseminated melioidosis in the head and neck. AB - A 35-year-old man was admitted to an intensive care unit with unilateral facial swelling and septic shock after multiple presentations to the emergency department with non-specific unilateral pain over the parotid area. A CT scan of his neck showed diffuse right-sided facial soft tissue infection, mastoid effusion and temporal lobe cerebritis. The upper lobes of his lungs had cannonball lesions that were suggestive of septic lung metastases. Blood cultures and ear canal swabs were positive for Burkholderia pseudomallei The temporal lobe cerebritis eventually developed into an abscess, necessitating a cortical mastoidectomy, craniectomy and temporal lobectomy. After the surgical interventions, antibiotic therapy was continued for a further 6 months. The patient remained well and had no signs of recurrence up to 7 months after the initial presentation. PMID- 28096230 TI - Haemodialysis in acute paracetamol poisoning. AB - A woman aged 23 years presented late with clinical and biochemical features of a life-threatening paracetamol (acetaminophen) overdose. Despite instigating N acetylcysteine treatment, due to evidence of mitochondrial dysfunction together with an exceedingly high paracetamol level, the decision was made to dialyse the patient acutely to remove the parent drug. This was highly effective, and with on going supportive care, the patient made a full recovery without the need for transplantation. This case highlights the role of extracorporeal therapy as a treatment option in selected cases of paracetamol overdose, consistent with the international guidelines. PMID- 28096231 TI - Roles of 5-lipoxygenase and cyclooxygenase-2 in the biosynthesis of hemiketals E2 and D2 by activated human leukocytes. AB - The 2 hemiketal (HK) eicosanoids HKD2 and HKE2 are the major products of the biosynthetic crossover of the 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) pathways. HKs result from the rearrangement of a di-endoperoxide intermediate formed in the COX-2-dependent oxygenation of 5S-hydroxyeicosatetraenoic acid (5S HETE). We analyzed HK biosynthesis in human leukocytes stimulated ex vivo and defined the biosynthetic roles of 5-LOX and COX-2, using inhibitors and incubations with exogenous substrates. Activation of leukocytes with LPS followed by treatment with the calcium ionophore A23187 resulted in the formation of PGE2, 5-HETE, and LTB4 as the principal metabolites of COX-2 and 5-LOX, respectively. The formation of HKD2 and HKE2 was highest after 15 min LPS treatment, and at that time, levels were similar to PGE2, but less than 5-HETE and LTB4 The time course of HK formation paralleled that of 5-HETE and LTB4, implying the availability of the 5S-HETE substrate as a limiting factor in biosynthesis rather than expression levels of COX-2. Specific inhibitors of COX-2 and 5-LOX decreased formation of HKD2 and HKE2 Platelets did not form HKs from exogenous 5S-HETE, implying that COX-1 is not involved. HKs are early products during an inflammatory event and require cells that express 5-LOX and COX-2 for their biosynthesis.-Gimenez-Bastida, J. A., Shibata, T., Uchida, K., Schneider, C. Roles of 5-lipoxygenase and cyclooxygenase-2 in the biosynthesis of hemiketals E2 and D2 by activated human leukocytes. PMID- 28096232 TI - PR-957, a selective inhibitor of immunoproteasome subunit low-MW polypeptide 7, attenuates experimental autoimmune neuritis by suppressing Th17-cell differentiation and regulating cytokine production. AB - Experimental autoimmune neuritis (EAN) is a CD4+ T-cell-mediated autoimmune inflammatory demyelinating disease of the peripheral nervous system. It has been replicated in an animal model of human inflammatory demyelinating polyradiculoneuropathy, Guillain-Barre syndrome. In this study, we evaluated the therapeutic efficacy of a selective inhibitor of the immunoproteasome subunit, low-MW polypeptide 7 (PR-957) in rats with EAN. Our results showed that PR-957 significantly delayed onset day, reduced severity and shortened duration of EAN, and alleviated demyelination and inflammatory infiltration in sciatic nerves. In addition to significantly regulating expression of the cytokine profile, PR-957 treatment down-regulated the proportion of proinflammatory T-helper (Th)17 cells in sciatic nerves and spleens of rats with EAN. Data presented show the role of PR-957 in the signal transducer and activator of transcription 3 (STAT3) pathway. PR-957 not only decreased expression of IL-6 and IL-23 but also led to down regulation of STAT3 phosphorylation in CD4+ T cells. Regulation of the STAT3 pathway led to a reduction in retinoid-related orphan nuclear receptor gamma t and IL-17 production. Furthermore, reduction of STAT3 phosphorylation may have directly suppressed Th17-cell differentiation. Therefore, our study demonstrates that PR-957 could potently alleviate inflammation in rats with EAN and that it may be a likely candidate for treating Guillain-Barre syndrome.-Liu, H., Wan, C., Ding, Y., Han, R., He, Y., Xiao, J., Hao, J. PR-957, a selective inhibitor of immunoproteasome subunit low-MW polypeptide 7, attenuates experimental autoimmune neuritis by suppressing Th17-cell differentiation and regulating cytokine production. PMID- 28096233 TI - Role of the constant region domain in the structural diversity of human antibody light chains. AB - Issues regarding the structural diversity (heterogeneity) of an antibody molecule have been the subject of discussion along with the development of antibody drugs. Research on heterogeneity has been extensive in recent years, but no clear solution has been reached. Heterogeneity is also observed in catalytic antibody kappa light chains (CLs). In this study, we investigated how the constant region domain of CLs concerns structural diversity because it is a simple and good example for elucidating heterogeneity. By means of cation-exchange chromatography, SDS-PAGE, and 2-dimensional electrophoresis for the CL, multimolecular forms consisting of different electrical charges and molecular sizes coexisted in the solution, resulting in the similar heterogeneity of the full length of CLs. The addition of copper ion could cause the multimolecular forms to change to monomolecular forms. Copper ion contributed greatly to the enrichment of the dimer form of CL and the homogenization of the differently charged CLs. Two molecules of the CL protein bound one copper ion. The binding affinity of the ion was 48.0 MUM-1 Several divalent metal ions were examined, but only zinc showed a similar effect.-Hifumi, E., Taguchi, H., Kato, R., Uda, T. Role of the constant region domain in the structural diversity of human antibody light chains. PMID- 28096234 TI - Glutamate oxaloacetate transaminase enables anaplerotic refilling of TCA cycle intermediates in stroke-affected brain. AB - Ischemic stroke results in excessive release of glutamate, which contributes to neuronal cell death. Here, we test the hypothesis that otherwise neurotoxic glutamate can be productively metabolized by glutamate oxaloacetate transaminase (GOT) to maintain cellular energetics and protect the brain from ischemic stroke injury. The GOT-dependent metabolism of glutamate was studied in primary neural cells and in stroke-affected C57-BL6 mice using magnetic resonance spectroscopy and GC-MS. Extracellular Glu sustained cell viability under hypoglycemic conditions and increased GOT-mediated metabolism in vitro Correction of stroke induced hypoxia using supplemental oxygen in vivo lowered Glu levels as measured by 1H magnetic resonance spectroscopy. GOT knockdown abrogated this effect and caused ATP loss in the stroke-affected brain. GOT overexpression increased anaplerotic refilling of tricarboxylic acid cycle intermediates in mouse brain during ischemic stroke. Furthermore, GOT overexpression not only reduced ischemic stroke lesion volume but also attenuated neurodegeneration and improved poststroke sensorimotor function. Taken together, our results support a new paradigm that GOT enables metabolism of otherwise neurotoxic extracellular Glu through a truncated tricarboxylic acid cycle under hypoglycemic conditions.-Rink, C., Gnyawali, S., Stewart, R., Teplitsky, S., Harris, H., Roy, S., Sen, C. K., Khanna, S. Glutamate oxaloacetate transaminase enables anaplerotic refilling of TCA cycle intermediates in stroke-affected brain. PMID- 28096237 TI - The Human Microbiome and Cancer. AB - Recent scientific advances have significantly contributed to our understanding of the complex connection between the microbiome and cancer. Our bodies are continuously exposed to microbial cells, both resident and transient, as well as their byproducts, including toxic metabolites. Circulation of toxic metabolites may contribute to cancer onset or progression at locations distant from where a particular microbe resides. Moreover, microbes may migrate to other locations in the human body and become associated with tumor development. Several case-control metagenomics studies suggest that dysbiosis in the commensal microbiota is also associated with inflammatory disorders and various cancer types throughout the body. Although the microbiome influences carcinogenesis through mechanisms independent of inflammation and immune system, the most recognizable link is between the microbiome and cancer via the immune system, as the resident microbiota plays an essential role in activating, training, and modulating the host immune response. Immunologic dysregulation is likely to provide mechanistic explanations as to how our microbiome influences cancer development and cancer therapies. In this review, we discuss recent developments in understanding the human gut microbiome's relationship with cancer and the feasibility of developing novel cancer diagnostics based on microbiome profiles. Cancer Prev Res; 10(4); 226-34. (c)2017 AACR. PMID- 28096235 TI - Role of cardiotrophin-1 in the regulation of metabolic circadian rhythms and adipose core clock genes in mice and characterization of 24-h circulating CT-1 profiles in normal-weight and overweight/obese subjects. AB - Cardiotrophin (CT)-1 is a regulator of glucose and lipid homeostasis. In the present study, we analyzed whether CT-1 also acts to peripherally regulate metabolic rhythms and adipose tissue core clock genes in mice. Moreover, the circadian pattern of plasma CT-1 levels was evaluated in normal-weight and overweight subjects. The circadian rhythmicity of oxygen consumption rate (Vo2) was disrupted in aged obese CT-1-deficient (CT-1-/-) mice (12 mo). Although circadian rhythms of Vo2 were conserved in young lean CT-1-/- mice (2 mo), CT-1 deficiency caused a phase shift of the acrophase. Most of the clock genes studied (Clock, Bmal1, and Per2) displayed a circadian rhythm in adipose tissue of both wild-type (WT) and CT-1-/- mice. However, the pattern was altered in CT-1-/- mice toward a lower percentage of the rhythm or lower amplitude, especially for Bmal1 and Clock. Moreover, CT-1 mRNA levels in adipose tissue showed significant circadian fluctuations in young WT mice. In humans, CT-1 plasma profile exhibited a 24-h circadian rhythm in normal-weight but not in overweight subjects. The 24-h pattern of CT-1 was characterized by a pronounced increase during the night (from 02:00 to 08:00). These observations suggest a potential role for CT-1 in the regulation of metabolic circadian rhythms.-Lopez-Yoldi, M., Stanhope, K. L., Garaulet, M., Chen, X. G., Marcos-Gomez, B., Carrasco-Benso, M. P., Santa Maria, E. M., Escote, X., Lee, V., Nunez, M. V., Medici, V., Martinez-Anso, E., Sainz, N., Huerta, A. E., Laiglesia, L. M., Prieto, J., Martinez, J. A., Bustos, M., Havel, P. J., Moreno-Aliaga, M. J. Role of cardiotrophin-1 in the regulation of metabolic circadian rhythms and adipose core clock genes in mice and characterization of 24-h circulating CT-1 profiles in normal-weight and overweight/obese subjects. PMID- 28096236 TI - Inhibitory Effects of gamma- and delta-Tocopherols on Estrogen-Stimulated Breast Cancer In Vitro and In Vivo. AB - Estrogens have been implicated as complete carcinogens for breast and other tissues through mechanisms involving increased cell proliferation, oxidative stress, and DNA damage. Because of their potent antioxidant activity and other effects, tocopherols have been shown to exert antitumor activities in various cancers. However, limited information is available on the effect of different forms of tocopherols in estrogen-mediated breast cancer. To address this, we examined the effects of alpha-, gamma-, and delta-tocopherols as well as a natural gamma-tocopherol-rich mixture of tocopherols, gamma-TmT, on estrogen stimulated MCF-7 cells in vitro and in vivo For the in vivo studies, MCF-7 cells were injected into the mammary fat pad of immunodeficient mice previously implanted with estrogen pellets. Mice were then administered diets containing 0.2% alpha-, gamma-, delta-tocopherol, or gamma-TmT for 5 weeks. Treatment with alpha-, gamma-, delta-tocopherols, and gamma-TmT reduced tumor volumes by 29% (P < 0.05), 45% (P < 0.05), 41% (P < 0.05), and 58% (P < 0.01), as well as tumor weights by 20%, 37% (P < 0.05), 39% (P < 0.05), and 52% (P < 0.05), respectively. gamma- and delta-tocopherols and gamma-TmT inhibited the expression of cell proliferation-related genes such as cyclin D1 and c-Myc, and estrogen-related genes such as TFF/pS2, cathepsin D, and progesterone receptor in estrogen stimulated MCF-7 cells in vitro Further, gamma- and delta-tocopherols decreased the levels of estrogen-induced oxidative stress and nitrosative stress markers, 8 hydroxy-2'-deoxyguanosine and nitrotyrosine, as well as the DNA damage marker, gamma-H2AX. Our results suggest that gamma- and delta-tocopherols and the gamma tocopherol-rich mixture are effective natural agents for the prevention and treatment of estrogen-mediated breast cancer. Cancer Prev Res; 10(3); 188-97. (c)2017 AACR. PMID- 28096238 TI - Activation of TRPA1 Channel by Antibacterial Agent Triclosan Induces VEGF Secretion in Human Prostate Cancer Stromal Cells. AB - Accruing evidence indicates that exposure to environmental compounds may adversely affect human health and promote carcinogenesis. Triclosan (TCS), an antimicrobial agent widely used as a preservative in personal care products, has been shown to act as an endocrine disruptor in hormone-dependent tissues. Here, we demonstrate a new molecular mechanism by which TCS stimulates the secretion by human prostate cancer stromal cells of vascular endothelial growth factor (VEGF), a factor known to promote tumor growth. This mechanism involves an increase in intracellular calcium levels due to the direct activation of a membrane ion channel. Using calcium imaging and electrophysiology techniques, we show for the first time that environmentally relevant concentrations of TCS activate a cation channel of the TRP family, TRPA1 (Transient Receptor Potential Ankirin 1), in primary cultured human prostate cancer stromal cells. The TCS-induced TRPA1 activation increased basal calcium in stromal cells and stimulated the secretion of VEGF and epithelial cells proliferation. Interestingly, immunofluorescence labeling performed on formalin-fixed paraffin-embedded prostate tissues showed an exclusive expression of the TRPA1 channel in prostate cancer stromal cells. Our data demonstrate an impact of the environmental factor TCS on the tumor microenvironment interactions, by activating a tumor stroma-specific TRPA1 ion channel. Cancer Prev Res; 10(3); 177-87. (c)2017 AACR. PMID- 28096239 TI - Skin-to-skin care in preterm infants receiving respiratory support does not lead to physiological instability. AB - OBJECTIVE: Providing skin-to-skin care (SSC) to preterm infants is standard practice in many neonatal intensive care units. There are conflicting reports on the stability of oxygen saturation (SpO2) during SSC, which may create a barrier to a wider implementation of SSC to infants receiving respiratory support. Regional cerebral oxygenation (rcO2) measured using near-infrared spectroscopy can serve as a surrogate parameter for cerebral oxygen delivery and consumption. We hypothesised that rcO2 during SSC would be similar to standard care in preterm infants receiving respiratory support. DESIGN: Prospective observational non inferiority study. SETTING: Single tertiary perinatal centre in Australia. PATIENTS: Forty preterm infants (median (IQR) of 27.6 (26.0-28.9) weeks' gestation) receiving respiratory support were studied on day 8 (5-18). INTERVENTIONS: Ninety minutes of SSC, with infants in incubators acting as their own control. Parents and caregivers were blinded to the measurements. MAIN OUTCOME MEASURES: Mean difference in rcO2 between SSC and incubator care; as well as heart rate (HR), SpO2, fraction of inspired oxygen (FiO2) and temperature, were compared using a paired t-test. RESULTS: rcO2 was similar during SSC (mean (SD) 74.9 (6.5)%)% compared with incubator care (74.7 (6.1)%, mean difference (95% CI) 0.2 (-0.8 to 1.1)%, p=0.71). No clinically important differences in HR, SpO2, FiO2 or temperature were observed in the whole cohort and by mode of respiratory support (endotracheal tube mechanical ventilation, continuous positive airway pressure and high-flow nasal cannulae). CONCLUSIONS: Cerebral oxygenation and other physiological measurements in ventilated preterm infants did not differ between SSC and incubator care. TRIAL REGISTRATION NUMBER: 12615000959572. PMID- 28096240 TI - Coevolution of Leukemia and Host Immune Cells in Chronic Lymphocytic Leukemia. AB - Cumulative studies on the dissection of changes in driver genetic lesions in cancer across the course of the disease have provided powerful insights into the adaptive mechanisms of tumors in response to the selective pressures of therapy and environmental changes. In particular, the advent of next-generation sequencing (NGS)-based technologies and its implementation for the large-scale comprehensive analyses of cancers have greatly advanced our understanding of cancer as a complex dynamic system wherein genetically distinct subclones interact and compete during tumor evolution. Aside from genetic evolution arising from interactions intrinsic to the cell subpopulations within tumors, it is increasingly appreciated that reciprocal interactions between the tumor cell and cellular constituents of the microenvironment further exert selective pressures on specific clones that can impact the balance between tumor immunity and immunologic evasion and escape. Herein, we review the evidence supporting these concepts, with a particular focus on chronic lymphocytic leukemia (CLL), a disease that has been highly amenable to genomic interrogation and studies of clonal heterogeneity and evolution. Better knowledge of the basis for immune escape has an important clinical impact on prognostic stratification and on the pursuit of new therapeutic opportunities. PMID- 28096241 TI - The Chromodomain Helicase DNA-Binding Chromatin Remodelers: Family Traits that Protect from and Promote Cancer. AB - A plethora of mutations in chromatin regulators in diverse human cancers is emerging, attesting to the pivotal role of chromatin dynamics in tumorigenesis. A recurrent theme is inactivation of the chromodomain helicase DNA-binding (CHD) family of proteins-ATP-dependent chromatin remodelers that govern the cellular machinery's access to DNA, thereby controlling fundamental processes, including transcription, proliferation, and DNA damage repair. This review highlights what is currently known about how genetic and epigenetic perturbation of CHD proteins and the pathways that they regulate set the stage for cancer, providing new insight for designing more effective anti-cancer therapies. PMID- 28096243 TI - Fused in Sarcoma Neuropathology in Neurodegenerative Disease. AB - Abnormal intracellular accumulation of the fused in sarcoma (FUS) protein is the characteristic pathological feature of cases of familial amyotrophic lateral sclerosis (ALS) caused by FUS mutations (ALS-FUS) and several uncommon disorders that may present with sporadic frontotemporal dementia (FTLD-FUS). Although these findings provide further support for the concept that ALS and FTD are closely related clinical syndromes with an overlapping molecular basis, important differences in the pathological features and results from experimental models indicate that ALS-FUS and FTLD-FUS have distinct pathogenic mechanisms. PMID- 28096242 TI - Developing Therapeutics for PrP Prion Diseases. AB - The prototypical PrP prion diseases are invariably fatal, and the search for agents to treat them spans more than 30 years, with limited success. However, in the last few years, the application of high-throughput screening, medicinal chemistry, and pharmacokinetic optimization has led to important advances. The PrP prion inoculation paradigm provides a robust assay for testing therapeutic efficacy, and a dozen compounds have been reported that lead to meaningful extension in survival of prion-infected mice. Here, we review the history and recent progress in the field, focusing on studies validated in animal models. Based on screens in cells infected with mouse-passaged PrP prions, orally available compounds were generated that double or even triple the survival of mice infected with the same prion strain. Unfortunately, no compounds have yet shown efficacy against human prions. Nevertheless, the speed of the recent advances brings hope that an effective therapeutic can be developed. A successful treatment for any neurodegenerative disease would be a major achievement, and the growing understanding that the more common neurodegenerative diseases, including Alzheimer's and Parkinson's, progress by an analogous prion mechanism serves to highlight the importance of antiprion therapeutics. PMID- 28096244 TI - Experimental Models of Inherited PrP Prion Diseases. AB - The inherited prion protein (PrP) prion disorders, which include familial Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, and fatal familial insomnia, constitute ~10%-15% of all PrP prion disease cases in humans. Attempts to generate animal models of these disorders using transgenic mice expressing mutant PrP have produced variable results. Although many lines of mice develop spontaneous signs of neurological illness with accompanying prion disease specific neuropathological changes, others do not. Furthermore, demonstrating the presence of protease-resistant PrP species and prion infectivity-two of the hallmarks of the PrP prion disorders-in the brains of spontaneously sick mice has proven particularly challenging. Here, we review the progress that has been made toward developing accurate mouse models of the inherited PrP prion disorders. PMID- 28096246 TI - Chronic Traumatic Encephalopathy: Is Latency in Symptom Onset Explained by Tau Propagation? AB - Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive mild brain trauma. CTE, previously termed "dementia pugilistica," has been identified in American football, ice hockey, baseball, rugby and soccer players, boxers, wrestlers, and military personnel exposed to blast and other traumatic brain injuries. There is often a long latency period between an individual's exposure to repetitive brain trauma and the clinical symptoms of CTE. The pathology of CTE is characterized by a progression from isolated focal perivascular hyperphosphorylated tau lesions in the cerebral cortex to a widespread tauopathy that involves diffuse cortical and medial temporal lobe regions. We hypothesize that the spread of tau from focal perivascular lesions to a widespread tauopathy occurs as a result of intraneuronal and intrasynaptic prion-like protein templating, as well as tau secretion and propagation along glymphatic and cerebrospinal fluid pathways. PMID- 28096245 TI - Prion-Like Characteristics of Polyglutamine-Containing Proteins. AB - Transmissible spongiform encephalopathies are infectious neurodegenerative diseases caused by the conversion of prion protein (PrP) into a self-replicating conformation that spreads via templated conversion of natively folded PrP molecules within or between cells. Recent studies provide compelling evidence that prion-like behavior is a general property of most protein aggregates associated with neurodegenerative diseases. Many of these disorders are associated with spontaneous protein aggregation, but genetic mutations can increase the aggregation propensity of specific proteins, including expansion of polyglutamine (polyQ) tracts, which is causative of nine inherited neurodegenerative diseases. Aggregates formed by polyQ-expanded huntingtin (Htt) in Huntington's disease can transfer between cells and seed the aggregation of cytoplasmic wild-type Htt in a prion-like manner. Additionally, prion-like properties of glutamine-rich proteins underlie nonpathological processes in yeast and higher eukaryotes. Here, we review current evidence supporting prion-like characteristics of polyQ and glutamine-rich proteins. PMID- 28096247 TI - Order Matters: The Order of Somatic Mutations Influences Cancer Evolution. AB - Cancers evolve as a consequence of multiple somatic lesions, with competition between subclones and sequential subclonal evolution. Some driver mutations arise either early or late in the evolution of different individual tumors, suggesting that the final malignant properties of a subclone reflect the sum of mutations acquired rather than the order in which they arose. However, very little is known about the cellular consequences of altering the order in which mutations are acquired. Recent studies of human myeloproliferative neoplasms show that the order in which individual mutations are acquired has a dramatic impact on the cell biological and molecular properties of tumor-initiating cells. Differences in clinical presentation, complications, and response to targeted therapy were all observed and implicate mutation order as an important player in cancer biology. These observations represent the first demonstration that the order of mutation acquisition influences stem and progenitor cell behavior and clonal evolution in any cancer. Thus far, the impact of different mutation orders has only been studied in hematological malignancies, and analogous studies of solid cancers are now required. PMID- 28096249 TI - Natural language processing to extract symptoms of severe mental illness from clinical text: the Clinical Record Interactive Search Comprehensive Data Extraction (CRIS-CODE) project. AB - OBJECTIVES: We sought to use natural language processing to develop a suite of language models to capture key symptoms of severe mental illness (SMI) from clinical text, to facilitate the secondary use of mental healthcare data in research. DESIGN: Development and validation of information extraction applications for ascertaining symptoms of SMI in routine mental health records using the Clinical Record Interactive Search (CRIS) data resource; description of their distribution in a corpus of discharge summaries. SETTING: Electronic records from a large mental healthcare provider serving a geographic catchment of 1.2 million residents in four boroughs of south London, UK. PARTICIPANTS: The distribution of derived symptoms was described in 23 128 discharge summaries from 7962 patients who had received an SMI diagnosis, and 13 496 discharge summaries from 7575 patients who had received a non-SMI diagnosis. OUTCOME MEASURES: Fifty SMI symptoms were identified by a team of psychiatrists for extraction based on salience and linguistic consistency in records, broadly categorised under positive, negative, disorganisation, manic and catatonic subgroups. Text models for each symptom were generated using the TextHunter tool and the CRIS database. RESULTS: We extracted data for 46 symptoms with a median F1 score of 0.88. Four symptom models performed poorly and were excluded. From the corpus of discharge summaries, it was possible to extract symptomatology in 87% of patients with SMI and 60% of patients with non-SMI diagnosis. CONCLUSIONS: This work demonstrates the possibility of automatically extracting a broad range of SMI symptoms from English text discharge summaries for patients with an SMI diagnosis. Descriptive data also indicated that most symptoms cut across diagnoses, rather than being restricted to particular groups. PMID- 28096250 TI - Clinical management of unruptured intracranial aneurysm in Germany: a nationwide observational study over a 5-year period (2005-2009). AB - OBJECTIVES: Our aim was to provide nationwide age-standardised rates (ASR) on the usage of endovascular coiling and neurosurgical clipping for unruptured intracranial aneurysm (UIA) treatment in Germany. SETTING: Nationwide observational study using the Diagnosis-Related-Groups (DRG) statistics for the years 2005-2009 (overall 83 million hospitalisations). PARTICIPANTS: From 2005 to 2009, overall 39 155 hospitalisations with a diagnosis of UIA occurred in Germany. PRIMARY OUTCOME MEASURES: Age-specific and age-standardised hospitalisation rates for UIA with the midyear population of Germany in 2007 as the standard. RESULTS: Of the 10 221 hospitalisations with UIA during the observation period, 6098 (59.7%) and 4123 (40.3%) included coiling and clipping, respectively. Overall hospitalisation rates for UIA increased by 39.5% (95% CI 24.7% to 56.0%) and 50.4% (95% CI 39.6% to 62.1%) among men and women, respectively. In 2005, the ASR per 100 000 person years for coiling was 0.7 (95% CI 0.62 to 0.78) for men and 1.7 (95% CI 1.58 to 1.82) for women. In 2009, the ASR was 1.0 (95% CI 0.90 to 1.10) and 2.4 (95% CI 2.24 to 2.56), respectively. Similarly, the ASR for clipping in 2005 amounted to 0.6 (95% CI 0.52 to 0.68) for men and 1.1 (95% CI 1.00 to 1.20) for women. These rates increased in 2009 to 0.8 (95% CI 0.72 to 0.88) and 1.7 (95% CI 1.58 to 1.82), respectively. We observed a marked geographical variation of ASR for coiling and less pronounced for clipping. For the federal state of Saarland, the ASR for coiling was 5.64 (95% CI 4.76 to 6.52) compared with 0.68 (95% CI 0.48 to 0.88; per 100 000 person years) in Saxony-Anhalt, whereas, ASR for clipping were highest in Rhineland-Palatinate (2.48, 95% CI 2.17 to 4.75) and lowest in Saxony-Anhalt (0.52, 95% CI 0.34 to 0.70). CONCLUSIONS: To the best of our knowledge, we presented the first representative, nationwide analysis of the clinical management of UIA in Germany. The ASR increased markedly and showed substantial geographical variation among federal states for all treatment modalities during the observation period. PMID- 28096251 TI - Healthcare resource consumption for intermittent urinary catheterisation: cost effectiveness of hydrophilic catheters and budget impact analyses. AB - OBJECTIVES: This study presents a cost-effectiveness analysis comparing hydrophilic coated to uncoated catheters for patients performing urinary intermittent catheterisation. A national budget impact analysis is also included to evaluate the impact of intermittent catheterisation for management of bladder dysfunctions over a period of 5 years. DESIGN: A Markov model (lifetime horizon, 1 year cycle length) was developed to project health outcomes (life years and quality-adjusted life years) and economic consequences related to patients using hydrophilic coated or uncoated catheters. The model was populated with catheter related clinical efficacy data retrieved from randomised controlled trials and quality-of-life data (utility weights) from the literature. Cost data (EUR, 2015) were estimated on the basis of healthcare resource consumption derived from an e survey addressed to key opinion leaders in the field. SETTING: Italian Healthcare Service perspective. POPULATION: Patients with spinal cord injury performing intermittent urinary catheterisation in the home setting. MAIN OUTCOME MEASURES: Incremental cost-effectiveness and cost-utility ratios (ICER and ICUR) of hydrophilic coated versus uncoated catheters and associated healthcare budget impact. RESULTS: The base-case ICER and ICUR associated with hydrophilic coated catheters were ?20 761 and ?24 405, respectively. This implies that hydrophilic coated catheters are likely to be cost-effective in comparison to uncoated ones, as proposed Italian threshold values range between ?25 000 and ?66 400. Considering a market share at year 5 of 89% hydrophilic catheters and 11% uncoated catheters, the additional cost for Italy is approximately ?12 million in the next 5 years (current market share scenario for year 0: 80% hydrophilic catheters and 20% uncoated catheters). CONCLUSIONS: Considered over a lifetime, hydrophilic coated catheters are potentially a cost-effective choice in comparison to uncoated ones. These findings can assist policymakers in evaluating intermittent catheterisation in patients with spinal cord injury. PMID- 28096252 TI - Understanding the importance of therapeutic relationships in the development of self-management behaviours during cancer rehabilitation: a qualitative research protocol. AB - INTRODUCTION: Cancer is a growing health, social and economic problem. 1 in 3 people in the UK will develop cancer in their lifetime. With survival rates rising to over 50%, the long-term needs of cancer survivors are of growing importance. Cancer rehabilitation is tailored to address the physical or psychosocial decline in ability to engage in daily activities. Its use is supported by high-quality international, multicentre research. Incorporating strategies for self-management behaviour development into rehabilitation can prepare individuals for cancer survivorship. However, healthcare professionals will need to adjust their therapeutic interactions accordingly. Research is yet to clarify the impact of the therapeutic relationship on rehabilitation outcomes in cancer. This study aims to explore the impact of therapeutic relationships on self-management behaviours after cancer. METHODS AND ANALYSIS: This qualitative study aims to understand cancer rehabilitation participants' beliefs regarding the importance of therapeutic relationships in developing self-management behaviours. A sample representative of a local cancer rehabilitation cohort will be asked to complete a semistructured interview to identify their perspectives on the importance of therapeutic relationships in cancer rehabilitation. Data obtained from the interviews will be analysed, coded and entered into a Delphi questionnaire for circulation to a local cancer rehabilitation population to determine if the views expressed by the interviewees are supported by group consensus. ETHICS AND DISSEMINATION: This study was approved by Wales Research Ethics Committee 6 (15/WA/0331) in April 2016. Findings will be disseminated through the first author's doctoral thesis; peer-reviewed journals; local, national and international conference presentations; and public events involving research participants and the general public. PMID- 28096253 TI - Generic prognostic factors for musculoskeletal pain in primary care: a systematic review. AB - OBJECTIVES: To summarise the evidence for generic prognostic factors across a range of musculoskeletal (MSK) conditions. SETTING: primary care. METHODS AND OUTCOMES: Comprehensive systematic literature review. MEDLINE, CINAHL, PsychINFO and EMBASE were searched for prospective cohort studies, based in primary care (search period-inception to December 2015). Studies were included if they reported on adults consulting with MSK conditions and provided data on associations between baseline characteristics (prognostic factors) and outcome. A prognostic factor was identified as generic when significantly associated with any outcome for 2 or more different MSK conditions. Evidence synthesis focused on consistency of findings and study quality. RESULTS: 14 682 citations were identified and 78 studies were included (involving more than 48 000 participants with 18 different outcome domains). 51 studies were on spinal pain/back pain/low back pain, 12 on neck/shoulder/arm pain, 3 on knee pain, 3 on hip pain and 9 on multisite pain/widespread pain. Total quality scores ranged from 5 to 14 (mean 11) and 65 studies (83%) scored 9 or more. Out of a total of 78 different prognostic factors for which data were provided, the following factors are considered to be generic prognostic factors for MSK conditions: widespread pain, high functional disability, somatisation, high pain intensity and presence of previous pain episodes. In addition, consistent evidence was found for use of pain medications not to be associated with outcome, suggesting that this factor is not a generic prognostic factor for MSK conditions. CONCLUSIONS: This large review provides new evidence for generic prognostic factors for MSK conditions in primary care. Such factors include pain intensity, widespread pain, high functional disability, somatisation and movement restriction. This information can be used to screen and select patients for targeted treatment in clinical research as well as to inform the management of MSK conditions in primary care. PMID- 28096254 TI - Factors predicting antibiotic prescription and referral to hospital for children with respiratory symptoms: secondary analysis of a randomised controlled study at out-of-hours services in primary care. AB - OBJECTIVES: Acute respiratory infections and fever among children are highly prevalent in primary care. It is challenging to distinguish between viral and bacterial infections. Norway has a relatively low prescription rate of antibiotics, but it is still regarded as too high as the antimicrobial resistance is increasing. The aim of the study was to identify predictors for prescribing antibiotics or referral to hospital among children. DESIGN: Secondary analysis of a randomised controlled study. SETTING: 4 out-of-hours services and 1 paediatric emergency clinic in Norwegian primary care. PARTICIPANTS: 401 children aged 0-6 years with respiratory symptoms and/or fever visiting the out-of-hours services. OUTCOMES: 2 main outcome variables were registered: antibiotic prescription and referral to hospital. RESULTS: The total prescription rate of antibiotics was 23%, phenoxymethylpenicillin was used in 67% of the cases. Findings on ear examination (OR 4.62; 95% CI 2.35 to 9.10), parents' assessment that the child has a bacterial infection (OR 2.45; 95% CI 1.17 to 5.13) and a C reactive protein (CRP) value >20 mg/L (OR 3.57; 95% CI 1.43 to 8.83) were significantly associated with prescription of antibiotics. Vomiting in the past 24 hours was negatively associated with prescription (OR 0.26; 95% CI 0.13 to 0.53). The main predictors significantly associated with referral to hospital were respiratory rate (OR 1.07; 95% CI 1.03 to 1.12), oxygen saturation <95% (OR 3.39; 95% CI 1.02 to 11.23), signs on auscultation (OR 5.57; 95% CI 1.96 to 15.84) and the parents' assessment before the consultation that the child needs hospitalisation (OR 414; 95% CI 26 to 6624). CONCLUSIONS: CRP values >20 mg/L, findings on ear examination, use of paracetamol and no vomiting in the past 24 hours were significantly associated with antibiotic prescription. Affected respiration was a predictor for referral to hospital. The parents' assessment was also significantly associated with the outcomes. TRIAL REGISTRATION NUMBER: NCT02496559; Results. PMID- 28096255 TI - SheppHeartCABG trial-comprehensive early rehabilitation after coronary artery bypass grafting: a protocol for a randomised clinical trial. AB - INTRODUCTION: Patients undergoing coronary artery bypass graft surgery often experience a range of symptoms. Studies indicate that non-pharmacological interventions such as exercise training and psychoeducation have a positive physiological and psychological effect in early outpatient rehabilitation. The SheppHeartCABG trial will investigate the effect of early comprehensive rehabilitation in early phase rehabilitation versus usual care. The aim of this paper is to present the protocol for the SheppHeartCABG trial. METHODS/ANALYSIS: SheppHeartCABG is an investigator-initiated randomised clinical superiority trial with blinded outcome assessment, employing 1:1 central randomisation to rehabilitation plus usual care versus usual care alone. On the basis of a sample size calculation, 326 patients undergoing coronary artery bypass grafting will be included from two clinical sites. All patients receive usual care and patients allocated to the experimental intervention follow 4 weeks rehabilitation consisting of an exercise programme, psycho-educative consultations and a compact mindfulness programme. The primary outcome is physical function measured by the 6 min walk test. The secondary outcomes are mental health and physical activity measured by the Medical Outcome Study Short Form (SF-12), anxiety and depression measured by the Hospital Anxiety and Depression Scale questionnaire, physical, emotional and global scores by the HeartQoL questionnaire, sleep measured by the Pittsburgh Sleep Quality Index, pain measured by the Orebro Musculoskeletal Screening Questionnaire and muscle endurance measured by the sit-to-stand test. A number of explorative analyses will also be conducted. ETHICS AND DISSEMINATION: SheppHeartCABG is approved by the regional ethics committee (no. H-4-2014-109) and the Danish Data Protection Agency (no. 30-1309) and is performed in accordance with good clinical practice and the Declaration of Helsinki in its latest form. Positive, neutral and negative results of the trial will be submitted to international peer-reviewed journals. Furthermore, results will be presented at national and international conferences relevant to the subject fields. TRIAL REGISTRATION NUMBER: NCT02290262; pre-results. PMID- 28096256 TI - Chronic symptoms in a representative sample of community-dwelling older people: a cross-sectional study in Switzerland. AB - OBJECTIVES: The burden of multiple diagnoses is well documented in older people, but less is known about chronic symptoms, many of which are even not brought to medical attention. This study aimed to determine the prevalence of chronic symptoms, their relationships with disability in basic activities of daily living (BADL) and quality of life (QoL), and their public health impact. DESIGN: A large cross-sectional population-based study. SETTING: Community in 2 regions of French speaking Switzerland. PARTICIPANTS: Community-dwelling older adults aged 68 years and older in 2011 (N=5300). OUTCOMES: Disability in BADL defined as difficulty or help needed with any of dressing, bathing, eating, getting in/out of bed or an arm chair, and using the toilet. Overall QoL dichotomised as favourable (ie, excellent or very good) or unfavourable (ie, good, fair or poor). Disturbance by any of the following 14 chronic symptoms for at least 6 months: joint pain, back pain, chest pain, dyspnoea, persistent cough, swollen legs, memory gaps, difficulty concentrating, difficulty making decisions, dizziness/vertigo, skin problems, stomach/intestine problems, urinary incontinence and impaired sexual life. RESULTS: Only 17.1% of participants did not report being disturbed by any of these chronic symptoms. Weighted prevalence ranged from 3.1% (chest pain) to 47.7% (joint pain). Most chronic symptoms were significantly associated with disability in BADL or unfavourable QoL, with substantial gender differences. The number of chronic symptoms was significantly associated with disability in BADL and unfavourable QoL, with gradients suggesting dose-response relationships. Joint pain and back pain had the highest population attributable fractions. CONCLUSIONS: Chronic symptoms are highly prevalent in older people, and are associated with disability in BADL and unfavourable QoL, particularly when multiple chronic symptoms co-occur. Owing to their high public health impact, musculoskeletal chronic symptoms represent good targets for preventive interventions. PMID- 28096257 TI - Inhibition of Gastric Inhibitory Polypeptide Receptor Signaling in Adipose Tissue Reduces Insulin Resistance and Hepatic Steatosis in High-Fat Diet-Fed Mice. AB - Gastric inhibitory polypeptide receptor (GIPR) directly induces energy accumulation in adipose tissue in vitro. However, the importance of the direct effect of GIPR signaling on adipose tissue in vivo remains unclear. In the current study, we generated adipose tissue-specific GIPR knockout (GIPRadipo-/-) mice and investigated the direct actions of GIP in adipose tissue. Under high-fat diet (HFD)-fed conditions, GIPRadipo-/- mice had significantly lower body weight and lean body mass compared with those in floxed GIPR (GIPRfl/fl) mice, although the fat volume was not significantly different between the two groups. Interestingly, insulin resistance, liver weight, and hepatic steatosis were reduced in HFD-fed GIPRadipo-/- mice. Plasma levels of interleukin-6 (IL-6), a proinflammatory cytokine that induces insulin resistance, were reduced in HFD-fed GIPRadipo-/- mice compared with those in HFD-fed GIPRfl/fl mice. Suppressor of cytokine signaling 3 (SOCS3) signaling is located downstream of the IL-6 receptor and is associated with insulin resistance and hepatic steatosis. Expression levels of SOCS3 mRNA were significantly lower in adipose and liver tissues of HFD fed GIPRadipo-/- mice compared with those of HFD-fed GIPRfl/fl mice. Thus, GIPR signaling in adipose tissue plays a critical role in HFD-induced insulin resistance and hepatic steatosis in vivo, which may involve IL-6 signaling. PMID- 28096259 TI - Bariatric Surgery Enhances Splanchnic Vascular Responses in Patients With Type 2 Diabetes. AB - Bariatric surgery results in notable weight loss and alleviates hyperglycemia in patients with type 2 diabetes (T2D). We aimed to characterize the vascular effects of a mixed meal and infusion of exogenous glucose-dependent insulinotropic polypeptide (GIP) in the splanchnic region in 10 obese patients with T2D before and after bariatric surgery and in 10 lean control subjects. The experiments were carried out on two separate days. Pancreatic and intestinal blood flow (BF) were measured at baseline, 20 min, and 50 min with 15O-water by using positron emission tomography and MRI. Before surgery, pancreatic and intestinal BF responses to a mixed meal did not differ between obese and lean control subjects. Compared with presurgery, the mixed meal induced a greater increase in plasma glucose, insulin, and GIP concentrations after surgery, which was accompanied by a marked augmentation of pancreatic and intestinal BF responses. GIP infusion decreased pancreatic but increased small intestinal BF similarly in all groups both before and after surgery. Taken together, these results demonstrate that bariatric surgery leads to enhanced splanchnic vascular responses as a likely consequence of rapid glucose appearance and GIP hypersecretion. PMID- 28096261 TI - Tuning Collective Cell Migration by Cell-Cell Junction Regulation. AB - Collective cell migration critically depends on cell-cell interactions coupled to a dynamic actin cytoskeleton. Important cell-cell adhesion receptor systems implicated in controlling collective movements include cadherins, immunoglobulin superfamily members (L1CAM, NCAM, ALCAM), Ephrin/Eph receptors, Slit/Robo, connexins and integrins, and an adaptive array of intracellular adapter and signaling proteins. Depending on molecular composition and signaling context, cell-cell junctions adapt their shape and stability, and this gradual junction plasticity enables different types of collective cell movements such as epithelial sheet and cluster migration, branching morphogenesis and sprouting, collective network migration, as well as coordinated individual-cell migration and streaming. Thereby, plasticity of cell-cell junction composition and turnover defines the type of collective movements in epithelial, mesenchymal, neuronal, and immune cells, and defines migration coordination, anchorage, and cell dissociation. We here review cell-cell adhesion systems and their functions in different types of collective cell migration as key regulators of collective plasticity. PMID- 28096258 TI - Regulation of Glucose Uptake and Enteroendocrine Function by the Intestinal Epithelial Insulin Receptor. AB - Insulin receptors (IRs) and IGF-I receptors (IGF-IR) are major regulators of metabolism and cell growth throughout the body; however, their roles in the intestine remain controversial. Here we show that genetic ablation of the IR or IGF-IR in intestinal epithelial cells of mice does not impair intestinal growth or development or the composition of the gut microbiome. However, the loss of IRs alters intestinal epithelial gene expression, especially in pathways related to glucose uptake and metabolism. More importantly, the loss of IRs reduces intestinal glucose uptake. As a result, mice lacking the IR in intestinal epithelium retain normal glucose tolerance during aging compared with controls, which show an age-dependent decline in glucose tolerance. Loss of the IR also results in a reduction of glucose-dependent insulinotropic polypeptide (GIP) expression from enteroendocrine K-cells and decreased GIP release in vivo after glucose ingestion but has no effect on glucagon-like peptide 1 expression or secretion. Thus, the IR in the intestinal epithelium plays important roles in intestinal gene expression, glucose uptake, and GIP production, which may contribute to pathophysiological changes in individuals with diabetes, metabolic syndrome, and other insulin-resistant states. PMID- 28096260 TI - FGF21 Mediates the Thermogenic and Insulin-Sensitizing Effects of Dietary Methionine Restriction but Not Its Effects on Hepatic Lipid Metabolism. AB - Dietary methionine restriction (MR) produces a rapid and persistent remodeling of white adipose tissue (WAT), an increase in energy expenditure (EE), and enhancement of insulin sensitivity. Recent work established that hepatic expression of FGF21 is robustly increased by MR. Fgf21-/- mice were used to test whether FGF21 is an essential mediator of the physiological effects of dietary MR. The MR-induced increase in energy intake and EE and activation of thermogenesis in WAT and brown adipose tissue were lost in Fgf21-/- mice. However, dietary MR produced a comparable reduction in body weight and adiposity in both genotypes because of a negative effect of MR on energy intake in Fgf21-/- mice. Despite the similar loss in weight, dietary MR produced a more significant increase in in vivo insulin sensitivity in wild-type than in Fgf21-/- mice, particularly in heart and inguinal WAT. In contrast, the ability of MR to regulate lipogenic and integrated stress response genes in liver was not compromised in Fgf21-/- mice. Collectively, these findings illustrate that FGF21 is a critical mediator of the effects of dietary MR on EE, remodeling of WAT, and increased insulin sensitivity but not of its effects on hepatic gene expression. PMID- 28096262 TI - Cilia and Obesity. AB - The ciliopathies Bardet-Biedl syndrome and Alstrom syndrome cause obesity. How ciliary dysfunction leads to obesity has remained mysterious, partly because of a lack of understanding of the physiological roles of primary cilia in the organs and pathways involved in the regulation of metabolism and energy homeostasis. Historically, the study of rare monogenetic disorders that present with obesity has informed our molecular understanding of the mechanisms involved in nonsyndromic forms of obesity. Here, we present a framework, based on genetic studies in mice and humans, of the molecular and cellular pathways underlying long-term regulation of energy homeostasis. We focus on recent progress linking these pathways to the function of the primary cilia with a particular emphasis on the roles of neuronal primary cilia in the regulation of satiety. PMID- 28096263 TI - Integration of Cadherin Adhesion and Cytoskeleton at Adherens Junctions. AB - The cadherin-catenin adhesion complex is the key component of the intercellular adherens junction (AJ) that contributes both to tissue stability and dynamic cell movements in epithelial and nonepithelial tissues. The cadherin adhesion complex bridges neighboring cells and the actin-myosin cytoskeleton, and thereby contributes to mechanical coupling between cells which drives many morphogenetic events and tissue repair. Mechanotransduction at cadherin adhesions enables cells to sense, signal, and respond to physical changes in their environment. Central to this process is the dynamic link of the complex to actin filaments (F-actin), themselves structurally dynamic and subject to tension generated by myosin II motors. We discuss in this review recent breakthroughs in understanding molecular and cellular aspects of the organization of the core cadherin-catenin complex in adherens junctions, its association to F-actin, its mechanosensitive regulation, and dynamics. PMID- 28096264 TI - Adherens Junctions on the Move-Membrane Trafficking of E-Cadherin. AB - Cadherin-based adherens junctions are conserved structures that mediate epithelial cell-cell adhesion in invertebrates and vertebrates. Despite their pivotal function in epithelial integrity, adherens junctions show a remarkable plasticity that is a prerequisite for tissue architecture and morphogenesis. Epithelial cadherin (E-cadherin) is continuously turned over and undergoes cycles of endocytosis, sorting and recycling back to the plasma membrane. Mammalian cell culture and genetically tractable model systems such as Drosophila have revealed conserved, but also distinct, mechanisms in the regulation of E-cadherin membrane trafficking. Here, we discuss our current knowledge about molecules and mechanisms controlling endocytosis, sorting and recycling of E-cadherin during junctional remodeling. PMID- 28096265 TI - Prion Properties of SOD1 in Amyotrophic Lateral Sclerosis and Potential Therapy. AB - Amyotrophic lateral sclerosis (ALS) is a devastating and rapidly progressive neurodegenerative disease caused by the deterioration of motor neurons. The first symptoms of ALS always begin at a focal but variable site and consistently spread to neighboring regions, suggesting that neurodegeneration in ALS is an orderly and propagating process. Like other neurodegenerative diseases, misfolding of a specific protein is central to ALS. SOD1, the major constituent of the protein deposits in some familial and sporadic forms of ALS, propagates its misfolded conformation like prions, providing a plausible molecular basis for the focality and spreading of muscle weakness in ALS. Because protein misfolding is a common cause of diverse neurodegenerative diseases, strategies aimed at boosting a cell's ability to cope with misfolded proteins could lead to therapeutics to combat these devastating age-related proteinopathies. PMID- 28096266 TI - Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics. AB - Adherens junctions (AJs) and desmosomes connect the actin and keratin filament networks of adjacent cells into a mechanical unit. Whereas AJs function in mechanosensing and in transducing mechanical forces between the plasma membrane and the actomyosin cytoskeleton, desmosomes and intermediate filaments (IFs) provide mechanical stability required to maintain tissue architecture and integrity when the tissues are exposed to mechanical stress. Desmosomes are essential for stable intercellular cohesion, whereas keratins determine cell mechanics but are not involved in generating tension. Here, we summarize the current knowledge of the role of IFs and desmosomes in tissue mechanics and discuss whether the desmosome-keratin scaffold might be actively involved in mechanosensing and in the conversion of chemical signals into mechanical strength. PMID- 28096267 TI - Toward the Atomic Structure of PrPSc. AB - In this review, we detail our current knowledge of PrPSc structure on the basis of structural and computational studies. We discuss the progress toward an atomic resolution description of PrPSc and results from the broader field of amyloid studies that may further inform our knowledge of this structure. Moreover, we summarize work that investigates the role of PrPSc structure in its toxicity, transmissibility, and species specificity. We look forward to an atomic model of PrPSc, which is expected to bring diagnostics and/or therapeutics to the field of prion disease. PMID- 28096268 TI - The TGF-beta Family in Caenorhabditis elegans. AB - Transforming growth factor beta (TGF-beta) and related ligands have potent effects on an enormous diversity of biological functions in all animals examined. Because of the strong conservation of TGF-beta family ligand functions and signaling mechanisms, studies from multiple animal systems have yielded complementary and synergistic insights. In the nematode Caenorhabditis elegans, early studies were instrumental in the elucidation of TGF-beta family signaling mechanisms. Current studies in C. elegans continue to identify new functions for the TGF-beta family in this organism as well as new conserved mechanisms of regulation. PMID- 28096269 TI - Differentiation between Radiation Necrosis and Tumor Progression Using Chemical Exchange Saturation Transfer. AB - Purpose: Stereotactic radiosurgery (SRS) is a common treatment used in patients with brain metastases and is associated with high rates of local control, however, at the risk of radiation necrosis. It is difficult to differentiate radiation necrosis from tumor progression using conventional MRI, making it a major diagnostic dilemma for practitioners. This prospective study investigated whether chemical exchange saturation transfer (CEST) was able to differentiate these two conditions.Experimental Design: Sixteen patients with brain metastases who had been previously treated with SRS were included. Average time between SRS and evaluation was 12.6 months. Lesion type was determined by pathology in 9 patients and the other 7 were clinically followed. CEST imaging was performed on a 3T Philips scanner and the following CEST metrics were measured: amide proton transfer (APT), magnetization transfer (MT), magnetization transfer ratio (MTR), and area under the curve for CEST peaks corresponding to amide and nuclear Overhauser effect (NOE).Results: Five lesions were classified as progressing tumor and 11 were classified as radiation necrosis (using histopathologic confirmation and radiographic follow-up). The best separation was obtained by NOEMTR (NOEMTR,necrosis = 8.9 +/- 0.9%, NOEMTR,progression = 12.6 +/- 1.6%, P < 0.0001) and AmideMTR (AmideMTR,necrosis = 8.2 +/- 1.0%, AmideMTR,progression = 12.0 +/- 1.9%, P < 0.0001). MT (MTnecrosis = 4.7 +/- 1.0%, MTprogression = 6.7 +/ 1.7%, P = 0.009) and NOEAUC (NOEAUC,necrosis = 4.3 +/- 2.0% Hz, NOEAUC,progression = 7.2 +/- 1.9% Hz, P = 0.019) provided statistically significant separation but with higher P values.Conclusions: CEST was capable of differentiating radiation necrosis from tumor progression in brain metastases. Both NOEMTR and AmideMTR provided statistically significant separation of the two cohorts. However, APT was unable to differentiate the two groups. Clin Cancer Res; 23(14); 3667-75. (c)2017 AACR. PMID- 28096270 TI - Mutation-Enrichment Next-Generation Sequencing for Quantitative Detection of KRAS Mutations in Urine Cell-Free DNA from Patients with Advanced Cancers. AB - Purpose: Tumor-derived cell-free DNA (cfDNA) from urine of patients with cancer offers noninvasive biological material for detection of cancer-related molecular abnormalities such as mutations in Exon 2 of KRASExperimental Design: A quantitative, mutation-enrichment next-generation sequencing test for detecting KRASG12/G13 mutations in urine cfDNA was developed, and results were compared with clinical testing of archival tumor tissue and plasma cfDNA from patients with advanced cancer.Results: With 90 to 110 mL of urine, the KRASG12/G13 cfDNA test had an analytical sensitivity of 0.002% to 0.006% mutant copies in wild-type background. In 71 patients, the concordance between urine cfDNA and tumor was 73% (sensitivity, 63%; specificity, 96%) for all patients and 89% (sensitivity, 80%; specificity, 100%) for patients with urine samples of 90 to 110 mL. Patients had significantly fewer KRASG12/G13 copies in urine cfDNA during systemic therapy than at baseline or disease progression (P = 0.002). Compared with no changes or increases in urine cfDNA KRASG12/G13 copies during therapy, decreases in these measures were associated with longer median time to treatment failure (P = 0.03).Conclusions: A quantitative, mutation-enrichment next-generation sequencing test for detecting KRASG12/G13 mutations in urine cfDNA had good concordance with testing of archival tumor tissue. Changes in mutated urine cfDNA were associated with time to treatment failure. Clin Cancer Res; 23(14); 3657-66. (c)2017 AACR. PMID- 28096271 TI - In Hepatocellular Carcinoma miR-221 Modulates Sorafenib Resistance through Inhibition of Caspase-3-Mediated Apoptosis. AB - Purpose: The aberrant expression of miR-221 is a hallmark of human cancers, including hepatocellular carcinoma (HCC), and its involvement in drug resistance, together with a proved in vivo efficacy of anti-miR-221 molecules, strengthen its role as an attractive target candidate in the oncologic field. The discovery of biomarkers predicting the response to treatments represents a clinical challenge in the personalized treatment era. This study aimed to investigate the possible role of miR-221 as a circulating biomarker in HCC patients undergoing sorafenib treatment as well as to evaluate its contribution to sorafenib resistance in advanced HCC.Experimental Design: A chemically induced HCC rat model and a xenograft mouse model, together with HCC-derived cell lines were employed to analyze miR-221 modulation by Sorafenib treatment. Data from the functional analysis were validated in tissue samples from surgically resected HCCs. The variation of circulating miR-221 levels in relation to Sorafenib treatment were assayed in the animal models and in two independent cohorts of patients with advanced HCC.Results: MiR-221 over-expression was associated with Sorafenib resistance in two HCC animal models and caspase-3 was identified as its target gene, driving miR-221 anti-apoptotic activity following Sorafenib administration. Lower pre-treatment miR-221 serum levels were found in patients subsequently experiencing response to Sorafenib and an increase of circulating miR-221 at the two months assessment was observed in responder patients.Conclusions: MiR-221 might represent a candidate biomarker of likelihood of response to Sorafenib in HCC patients to be tested in future studies. Caspase-3 modulation by miR-221 participates to Sorafenib resistance. Clin Cancer Res; 23(14); 3953-65. (c)2017 AACR. PMID- 28096272 TI - Antileukemia Efficacy and Mechanisms of Action of SL-101, a Novel Anti-CD123 Antibody Conjugate, in Acute Myeloid Leukemia. AB - Purpose: The persistence of leukemia stem cells (LSC)-containing cells after induction therapy may contribute to minimal residual disease (MRD) and relapse in acute myeloid leukemia (AML). We investigated the clinical relevance of CD34+CD123+ LSC-containing cells and antileukemia potency of a novel antibody conjugate SL-101 in targeting CD123+ LSCs.Experimental Methods and Results: In a retrospective study on 86 newly diagnosed AML patients, we demonstrated that a higher proportion of CD34+CD123+ LSC-containing cells in remission was associated with persistent MRD and predicted shorter relapse-free survival in patients with poor-risk cytogenetics. Using flow cytometry, we explored the potential benefit of therapeutic targeting of CD34+CD38-CD123+ cells by SL-101, a novel antibody conjugate comprising an anti-CD123 single-chain Fv fused to Pseudomonas exotoxin A The antileukemia potency of SL-101 was determined by the expression levels of CD123 antigen in a panel of AML cell lines. Colony-forming assay established that SL-101 strongly and selectively suppressed the function of leukemic progenitors while sparing normal counterparts. The internalization, protein synthesis inhibition, and flow cytometry assays revealed the mechanisms underlying the cytotoxic activities of SL-101 involved rapid and efficient internalization of antibody, sustained inhibition of protein synthesis, induction of apoptosis, and blockade of IL3-induced p-STAT5 and p-AKT signaling pathways. In a patient derived xenograft model using NSG mice, the repopulating capacity of LSCs pretreated with SL-101 in vitro was significantly impaired.Conclusions: Our data define the mechanisms by which SL-101 targets AML and warrant further investigation of the clinical application of SL-101 and other CD123-targeting strategies in AML. Clin Cancer Res; 23(13); 3385-95. (c)2017 AACR. PMID- 28096274 TI - Infectious Diseases Society of America Position Statement on Telehealth and Telemedicine as Applied to the Practice of Infectious Diseases. AB - The use of telehealth and telemedicine offers powerful tools for delivering clinical care, conducting medical research, and enhancing access to infectious diseases physicians. The Infectious Diseases Society of America (IDSA) has prepared a position statement to educate members on the use of telehealth and telemedicine technologies. The development of telehealth and telemedicine programs requires the consideration of several issues such as HIPAA, state and local licensure requirements, credentialing and privileging, scope of care, quality, and responsibility and liability. IDSA supports appropriate use of telehealth and telemedicine to provide timely, cost-effective specialty care to resource-limited populations. PMID- 28096275 TI - Persistent Mouth Ulceration in a Renal Allograft Recipient. PMID- 28096273 TI - Mortalin promotes cell proliferation and epithelial mesenchymal transition of intrahepatic cholangiocarcinoma cells in vitro. AB - AIMS: The prognosis of patients with intrahepatic cholangiocarcinoma (ICC) remains poor in terms of overall survival (OS) and recurrence rate. Mortalin, a stress chaperone, has been reported to be involved in carcinogenesis and metastasis. However, its role in ICC has not been defined. METHODS: Mortalin expression in tumour samples from patients with ICC was examined by Western blot and immunohistochemistry, and correlation between its expression and clinicopathological features was assessed. In addition, invasion, migration proliferation and apoptosis, and the expression of epithelial-mesenchymal transition (EMT)-related markers in ICC cells were assessed after mortalin depletion. Finally, the prognostic significance of mortalin in patients with ICC was further evaluated by Kaplan-Meier and Cox regression analysis. RESULTS: We provide evidence that expression of mortalin in human ICC tissues is higher than that in matched peritumoural tissues. The interference of mortalin expression inhibited the proliferation and invasion of ICC cells in vitro. Mechanistically, inhibition of mortalin expression in ICC cells upregulated E-cadherin expression and decreased vimentin and snail expression. Clinically, a high level of mortalin in ICC samples was associated with loss of E-cadherin, and increased expression of vimentin and snail. Patients with ICC and high mortalin expression had a shorter OS and a higher recurrence rate. Multivariate analysis revealed that mortalin overexpression was an independent prognostic indicator for patients with ICC. CONCLUSIONS: Mortalin may promote cell proliferation and invasion via induction of EMT of ICC cells. A high level of mortalin may be used as a prognostic biomarker and therapeutic target for patients with ICC. PMID- 28096276 TI - Persistent Mouth Ulceration in a Renal Allograft Recipient. PMID- 28096279 TI - A framework of comfort for practice: An integrative review identifying the multiple influences on patients' experience of comfort in healthcare settings. AB - Purpose: Comfort is central to patient experience but the concept of comfort is poorly defined. This review aims to develop a framework representing patients' complex perspective of comfort to inform practice and guide initiatives to improve the quality of healthcare. Data sources: CINAHL, MEDLINE Complete, PsycINFO and Google Scholar (November 2016); reference lists of included publications. Study selection: Qualitative and theoretical studies advancing knowledge about the concept of comfort in healthcare settings. Studies rated for methodological quality and relevance to patients' perspectives. Data extraction: Data on design, methods, features of the concept of comfort, influences on patients' comfort. Data were systematically coded and categorized using Framework method. Results of data synthesis: Sixty-two studies (14 theoretical and 48 qualitative) were included. Qualitative studies explored patient and staff perspectives in varying healthcare settings including hospice, emergency departments, paediatric, medical and surgical wards and residential care for the elderly. From patients' perspective, comfort is multidimensional, characterized by relief from physical discomfort and feeling positive and strengthened in one's ability to cope with the challenges of illness, injury and disability. Different factors are important to different individuals. We identified 10 areas of influence within four interrelated levels: patients' use of self-comforting strategies; family presence; staff actions and behaviours; and environmental factors. Conclusion: Our data provide new insights into the nature of comfort as a highly personal and contextual experience influenced in different individuals by different factors that we have classified into a framework to guide practice and quality improvement initiatives. PMID- 28096280 TI - Consumer satisfaction with tertiary healthcare in China: findings from the 2015 China National Patient Survey. AB - Objective: This study aims to develop understanding of Chinese patient satisfaction with tertiary hospitals. Design: The study draws on data collected from the 2015 China National Patient Survey. A Likert five-point scale was used to formulate the questionnaires. Descriptive analysis and logistic regression analysis were conducted. Setting: A structured questionnaire was used by 1432 interviewers to interview 27 475 outpatients and 19 938 inpatients in 136 tertiary hospitals from 31 provinces. Participants: Outpatients in the dispensing area and inpatients in the discharging area were randomly interviewed. Main Outcome Measure(s): Key domains of the questionnaire include the layout of service functions, environment maintenance, process management, quality of care, humane care and the patient-doctor relationship. Within each domain, several indicators were set, and each indicator was given a statement. Results: The overall satisfaction scores are 4.42 +/- 0.68 and 4.67 +/- 0.62 for outpatient and inpatient, respectively. The domains with highest satisfaction are 'diagnosis and treatment' for outpatient and 'nursing care' for inpatient. Outpatients were least satisfied with long waiting time, while inpatients were least satisfied with the food. The strongest predictor of overall satisfaction appears to be 'patient-doctor relationship' for both outpatients (OR = 3.53, 95% CI: 3.17-3.92) and inpatients (OR = 7.34, 95% CI: 5.55-9.70). Conclusions: Chinese hospitals need to pay more attention to offering more humane care to patients, hospital environment and process management improvement, reducing waiting times for seeing doctors and outpatient testing, and improving amenity services such as better food in the wards. PMID- 28096281 TI - De-freezing frozen patient management. AB - Objective: To compare the effectiveness of two methods in encouraging the consideration of a leap from one patient management routine to another: (i) real time review of the facts by an external medical team (ii) implementation of the 're-thinking-protocol' ('de-Freezing') by both treating and external medical teams. Design: Students accompanied doctors, nurses and patients as non interrupting observers. When an obvious gap between the expected and actual findings occurred, it was discussed four times: by two teams (treating team, external medical team) in two discussion modes (real-time review, de-Freezing questionnaire). The students then recorded if a leap was considered for each discussion. Setting: The study was conducted in the emergency department of the Baruch Padeh Medical Centre, Poriya, Israel. Participants: All patients were included during times when both medical teams (treating, external) were present. Intervention(s): During 14 periods of 5-7 h each, 459 patients were sampled. In 183 patients, 200 gaps were discovered. Results: The external team considered a leap 76 times, compared with 47 by the treating team (P < 0.001). Using the de Freezing-protocol, the treating team considered a leap 133 times. Interestingly, even the external team benefited from the de-Freezing protocol and considered a leap 140 times (NS compared to the treating team). Conclusions: While the importance of timely leaping from one patient management routine to another is emphasized in the training of physicians, medical teams too often fail to do so. The de-Freezing-protocol inexpensively encourages the consideration of a leap beyond what is evoked by the involvement of an external team. The protocol is applicable to all medical processes and should be incorporated into medical practice and education. PMID- 28096282 TI - The effect of mTOR inhibitors on respiratory infections in lymphangioleiomyomatosis. AB - Lymphangioleiomyomatosis (LAM) is a destructive cystic lung disease. Mammalian target of rapamycin (mTOR) inhibitors are the primary treatment for LAM but it is unknown whether these immunosuppressing medications increase the risk for or the severity of respiratory infections in LAM patients.We searched multiple databases for original articles that reported the rate of respiratory infections in LAM patients treated with mTOR inhibitors or placebo. We calculated incidence rates for respiratory infections in these groups and incidence rate ratios for respiratory infections and severe respiratory infections in mTOR inhibitors treated versus placebo treated patients.11 studies were included. There were 294 patients in the treatment groups and 93 patients in the placebo groups. Among subjects in placebo arms, the incidence rate of respiratory infections was 58.8 per 100 patient-years (95% CI 35.3-82.3 per 100 patient-years). The incidence rate ratio (IRR) for respiratory infection among treated subjects was 0.71 (95% CI 0.50-1.02; p=0.06 compared to placebo subjects). The IRR for severe respiratory infections among treated subjects was 1.56 (95% CI 0.43-8.55; p=0.52).We found that respiratory infections are common in patients with LAM. Importantly, treatment with mTOR inhibitors does not increase the incidence of these infections and may be protective. PMID- 28096283 TI - LABA/LAMA combination in COPD: a meta-analysis on the duration of treatment. AB - When there are no randomised clinical trials directly comparing all relevant treatment options, an indirect treatment comparison via meta-analysis of the available clinical evidence is an acceptable alternative. However, meta-analyses may be very misleading if not adequately performed. Here, we propose and validate a simple and effective approach to meta-analysis for exploring the effectiveness of long-acting beta2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations in chronic obstructive pulmonary disease.14 articles with 20 329 patients (combinations n=9292; monocomponents n=11 037) were included in this study. LABA/LAMA combinations were always more effective than the monocomponents in terms of the improvement in trough forced expiratory volume in 1 s, transition dyspnoea index and St George's Respiratory Questionnaire scores after 3, 6 and 12 months of treatment. No significant publication bias was identified. Significant discrepancies with previous network meta-analyses have been found, with overall differences ranging from 26.7% to 43.3%.Results from previous network meta-analyses were misleading because no adequate attention was given to formulating the review question, specifying eligibility criteria, correctly identifying studies, collecting appropriate information and deciding what it would be pharmacologically relevant to analyse. The real gradient of effectiveness of LABA/LAMA fixed-dose combinations remains an unmet medical need; however, it can be investigated indirectly using a high-quality meta-analytic approach. PMID- 28096284 TI - Pulmonary vascular and cardiac impairment in interstitial lung disease. AB - Pulmonary vascular and cardiac impairment is increasingly appreciated as a major adverse factor in the natural history of interstitial lung disease. This clinically orientated review focuses on the current concepts in the pathogenesis, pathophysiology and implications of the detrimental sequence of increased pulmonary vascular resistance, pre-capillary pulmonary hypertension and right heart failure in interstitial lung disease, and provides guidance on its management. PMID- 28096285 TI - Epoprostenol and pulmonary arterial hypertension: 20 years of clinical experience. AB - Epoprostenol was the first therapy to be approved for the treatment of pulmonary arterial hypertension (PAH). In the 20 years since the introduction of this prostacyclin analogue, the outlook for patients with PAH has improved, with survival rates now double those from the era before the development of disease specific treatments. Today, there are a large amount of data on the clinical role of prostacyclin treatments and a body of evidence attesting the efficacy of epoprostenol in improving exercise capacity, key haemodynamic parameters and PAH symptoms, as well as in reducing mortality. The place of epoprostenol in the therapeutic management of PAH continues to evolve, with the development of new formulations and use in combination with other drug classes. In this review, we provide a historical perspective on the first 20 years of epoprostenol, a therapy that led to evidence-based study of PAH-specific treatments and the subsequent expansion of treatment options for PAH. PMID- 28096286 TI - Diagnosis of primary ciliary dyskinesia: potential options for resource-limited countries. AB - Primary ciliary dyskinesia is a genetic disease of ciliary function leading to chronic upper and lower respiratory tract symptoms. The diagnosis is frequently overlooked because the symptoms are nonspecific and the knowledge about the disease in the primary care setting is poor. Additionally, none of the available tests is accurate enough to be used in isolation. These tests are expensive, and need sophisticated equipment and expertise to analyse and interpret results; diagnosis is therefore only available at highly specialised centres. The diagnosis is particularly challenging in countries with limited resources due to the lack of such costly equipment and expertise.In this review, we discuss the importance of early and accurate diagnosis especially for countries where the disease is clinically prevalent but diagnostic tests are lacking. We review the diagnostic tests available in specialised centres (nasal nitric oxide, high-speed video microscopy, transmission electron microscopy, immunofluorescence and genetics). We then consider modifications that might be considered in less well resourced countries whilst maintaining acceptable accuracy. PMID- 28096287 TI - Prediction models for exacerbations in patients with COPD. AB - Personalised medicine aims to tailor medical decisions to the individual patient. A possible approach is to stratify patients according to the risk of adverse outcomes such as exacerbations in chronic obstructive pulmonary disease (COPD). Risk-stratified approaches are particularly attractive for drugs like inhaled corticosteroids or phosphodiesterase-4 inhibitors that reduce exacerbations but are associated with harms. However, it is currently not clear which models are best to predict exacerbations in patients with COPD. Therefore, our aim was to identify and critically appraise studies on models that predict exacerbations in COPD patients. Out of 1382 studies, 25 studies with 27 prediction models were included. The prediction models showed great heterogeneity in terms of number and type of predictors, time horizon, statistical methods and measures of prediction model performance. Only two out of 25 studies validated the developed model, and only one out of 27 models provided estimates of individual exacerbation risk, only three out of 27 prediction models used high-quality statistical approaches for model development and evaluation. Overall, none of the existing models fulfilled the requirements for risk-stratified treatment to personalise COPD care. A more harmonised approach to develop and validate high- quality prediction models is needed to move personalised COPD medicine forward. PMID- 28096288 TI - Mid-regional pro-atrial natriuretic peptide to predict clinical course in heart failure patients undergoing cardiac resynchronization therapy. AB - Aims: Cardiac resynchronization therapy (CRT) induces reverse cardiac remodelling in heart failure (HF), but many patients receiving CRT remain non-responders. This study assessed the role of amino-terminal-pro-B-type natriuretic peptide (NT proBNP), mid-regional-pro-atrial natriuretic peptide (MR-proANP), and mid regional-pro-adrenomedullin (MR-proADM) at the time of device implantation to predict favourable clinical course (CRT response and/or risk of MACE) in HF patients receiving CRT. Methods and results: A total of 137 HF patients were prospectively included. Blood was drawn from the coronary sinus (CS) at CRT implantation, and from a peripheral vein (PV) simultaneously and after 6 months. Clinical CRT response at 6 months and major adverse cardiovascular events (MACE) at 2 years were assessed. Baseline PV-levels of MR-proANP (202 vs. 318 pmol/L, P = 0.009) and MR-proADM (843 vs. 1112 pmol/L, P = 0.02) were lower in CRT responders compared with non-responders. At 6 months, CRT responders showed a decrease in MR-proANP levels, compared with an increase in non-responders (-32 vs. +7 pmol/L, P = 0.02). During the same period, NT-proBNP decreased by a similar way in responders and non-responders, while MR-proADM was unchanged in both groups. High baseline MR-proANP, either in PV (OR 0.41, 95% CI 0.24-0.71, P = 0.002) or CS (OR 0.32, 95% CI 0.15-0.70, P = 0.005) was associated with reduced likelihood of CRT response. Furthermore, PV and CS levels of NT-proBNP, MR proANP, and MR-proADM were all associated with increased risk of 2-year MACE (all P < 0.01). Conclusion: Mid-regional-pro-atrial natriuretic peptide may assist prediction of clinical course in HF patients undergoing CRT implantation. Low circulating MR-proANP at the time of device implantation is associated with CRT response and more favourable outcome. PMID- 28096289 TI - Left juxtaposed right atrial appendage suspected on a plain chest radiograph. PMID- 28096291 TI - Correction: Preventing tumor escape by targeting a post-proteasomal trimming independent epitope. PMID- 28096290 TI - The epidermal polarity protein Par3 is a non-cell autonomous suppressor of malignant melanoma. AB - Melanoma, an aggressive skin malignancy with increasing lifetime risk, originates from melanocytes (MCs) that are in close contact with surrounding epidermal keratinocytes (KCs). How the epidermal microenvironment controls melanomagenesis remains poorly understood. In this study, we identify an unexpected non-cell autonomous role of epidermal polarity proteins, molecular determinants of cytoarchitecture, in malignant melanoma. Epidermal Par3 inactivation in mice promotes MC dedifferentiation, motility, and hyperplasia and, in an autochthonous melanoma model, results in increased tumor formation and lung metastasis. KC specific Par3 loss up-regulates surface P-cadherin that is essential to promote MC proliferation and phenotypic switch toward dedifferentiation. In agreement, low epidermal PAR3 and high P-cadherin expression correlate with human melanoma progression, whereas elevated P-cadherin levels are associated with reduced survival of melanoma patients, implying that this mechanism also drives human disease. Collectively, our data show that reduced KC Par3 function fosters a permissive P-cadherin-dependent niche for MC transformation, invasion, and metastasis. This reveals a previously unrecognized extrinsic tumor-suppressive mechanism, whereby epithelial polarity proteins dictate the cytoarchitecture and fate of other tissue-resident cells to suppress their malignant outgrowth. PMID- 28096292 TI - Regulation of kidney development by the Mdm2/Mdm4-p53 axis. AB - While p53 activity is required for tumour suppression, unconstrained p53 activity on the other hand is detrimental to the organism, resulting in inappropriate cellular death or proliferation defects. Unimpeded p53 activity is lethal in the developing embryo, underlining the need for maintaining a tight control on p53 activity during this period. The critical role of the negative regulators of p53, Mdm2 and Mdm4, in vertebrate development came to light by fatal disruption of embryogenesis that was observed with Mdm2 and Mdm4 gene deletions in mice. Embryonic lethality was rescued only by superimposing p53 removal. Here we summarize the contribution of the Mdm2/Mdm4-p53 axis that occurs at multiple steps of kidney development. Conditional, cell type-specific deletions reveal distinct functions of these proteins in renal morphogenesis. The severe impact on the renal phenotype from targeted gene deletions underscores the critical role played by the Mdm2/Mdm4-p53 nexus on nephrogenesis, and emphasizes the need to monitor patients with aberrations in this pathway for kidney function defects and associated cardiovascular dysfunction. PMID- 28096293 TI - The role of MDM2 and MDM4 in breast cancer development and prevention. AB - The major cause of death from breast cancer is not the primary tumour, but relapsing, drug-resistant, metastatic disease. Identifying factors that contribute to aggressive cancer offers important leads for therapy. Inherent defence against carcinogens depends on the individual molecular make-up of each person. Important molecular determinants of these responses are under the control of the mouse double minute (MDM) family: comprised of the proteins MDM2 and MDM4. In normal, healthy adult cells, the MDM family functions to critically regulate measured, cellular responses to stress and subsequent recovery. Proper function of the MDM family is vital for normal breast development, but also for preserving genomic fidelity. The MDM family members are best characterized for their negative regulation of the major tumour suppressor p53 to modulate stress responses. Their impact on other cellular regulators is emerging. Inappropriately elevated protein levels of the MDM family are highly associated with an increased risk of cancer incidence. Exploration of the MDM family members as cancer therapeutic targets is relevant for designing tailored anti-cancer treatments, but successful approaches must strategically consider the impact on both the target cancer and adjacent healthy cells and tissues. This review focuses on recent findings pertaining to the role of the MDM family in normal and malignant breast cells. PMID- 28096294 TI - Mouse modelling of the MDM2/MDMX-p53 signalling axis. AB - It is evident that p53 activity is critical for tumour prevention and stress response through its transcriptional activation of genes affecting cellular senescence, apoptosis, cellular metabolism, and DNA repair. The regulation of p53 is highly complex, and MDM2 and MDMX are thought to be critical for deciding the fate of p53, both through inhibitory binding and post-translational modification. Many mouse models have been generated to study the regulation of p53 in vivo, and they have altered our interpretations of how p53 is regulated by MDM2 and MDMX. Although MDM2 is absolutely required for p53 regulation, certain functions are dispensable under unstressed conditions, including the ability of MDM2 to degrade p53. MDMX, on the other hand, may only be required in select situations, like embryogenesis. These models have also clarified how cellular stress signals modify the p53-inhibiting activities of MDM2 and MDMX in vivo. It is clear that more work will need to be performed to further understand the contexts for each of these signals and the requirements of various MDM2 and MDMX functions. Here, we will discuss what we have learned from mouse modelling of MDM2 and MDMX and underscore the ways in which these models could inform future therapies. PMID- 28096295 TI - Does selection for short sleep duration explain human vulnerability to Alzheimer's disease? AB - Compared with other primates, humans sleep less and have a much higher prevalence of Alzheimer 's disease (AD) pathology. This article reviews evidence relevant to the hypothesis that natural selection for shorter sleep time in humans has compromised the efficacy of physiological mechanisms that protect against AD during sleep. In particular, the glymphatic system drains interstitial fluid from the brain, removing extra-cellular amyloid beta (eAbeta) twice as fast during sleep. In addition, melatonin - a peptide hormone that increases markedly during sleep - is an effective antioxidant that inhibits the polymerization of soluble eAbeta into insoluble amyloid fibrils that are associated with AD. Sleep deprivation increases plaque formation and AD, which itself disrupts sleep, potentially creating a positive feedback cycle. These and other physiological benefits of sleep may be compromised by short sleep durations. Our hypothesis highlights possible long-term side effects of medications that reduce sleep, and may lead to potential new strategies for preventing and treating AD. PMID- 28096296 TI - A Critical Asthma Standardized Clinical and Management Plan Reduces Duration of Critical Asthma Therapy. AB - BACKGROUND AND OBJECTIVE: Reduction of critical asthma management time can reduce intensive care utilization. The goal of this study was to determine whether a Critical Asthma Standardized Clinical Assessment and Management Plan (SCAMP) can decrease length of critical asthma management time. METHODS: This retrospective study compared critical asthma management times in children managed before and after implementation of a Critical Asthma SCAMP. The SCAMP used an asthma severity score management scheme to guide stepwise escalation and weaning of therapies. The SCAMP guided therapy until continuous albuterol nebulization (CAN) was weaned to intermittent albuterol every 2 hours (q2h). Because the SCAMP was part of a quality improvement initiative in which all patients received a standardized therapy, informed consent was waived. The study was conducted in Medicine ICU and Intermediate Care Units in a tertiary care freestanding children's hospital. Children >=2 years of age who had CAN initiated in the emergency department and were admitted to the Division of Medicine Critical Care with status asthmaticus were included. The time to q2h dosing from initiation of CAN was compared between the baseline and SCAMP cohorts. Adverse events were compared. The Mann-Whitney test was used for analysis; P values <.05 were considered statistically significant. RESULTS: There were 150 baseline and 123 SCAMP patients eligible for analysis. There was a decrease in median time to q2h dosing after the SCAMP (baseline, 21.6 hours [interquartile range, 3.2-32.3 hours]; SCAMP, 14.2 hours [interquartile range, 9.0-23.1 hours]; P < .01). There were no differences in adverse events or readmissions. CONCLUSIONS: A Critical Asthma SCAMP was effective in decreasing time on continuous albuterol. PMID- 28096297 TI - Frontline Science: Tumor necrosis factor-alpha stimulation and priming of human neutrophil granule exocytosis. AB - Neutrophil granule exocytosis plays an important role in innate and adaptive immune responses. The present study examined TNF-alpha stimulation or priming of exocytosis of the 4 neutrophil granule subsets. TNF-alpha stimulated exocytosis of secretory vesicles and gelatinase granules and primed specific and azurophilic granule exocytosis to fMLF stimulation. Both stimulation and priming of exocytosis by TNF-alpha were dependent on p38 MAPK activity. Bioinformatic analysis of 1115 neutrophil proteins identified by mass spectrometry as being phosphorylated by TNF-alpha exposure found that actin cytoskeleton regulation was a major biologic function. A role for p38 MAPK regulation of the actin cytoskeleton was confirmed experimentally. Thirteen phosphoproteins regulated secretory vesicle quantity, formation, or release, 4 of which-Raf1, myristoylated alanine-rich protein kinase C (PKC) substrate (MARCKS), Abelson murine leukemia interactor 1 (ABI1), and myosin VI-were targets of the p38 MAPK pathway. Pharmacologic inhibition of Raf1 reduced stimulated exocytosis of gelatinase granules and priming of specific granule exocytosis. We conclude that differential regulation of exocytosis by TNF-alpha involves the actin cytoskeleton and is a necessary component for priming of the 2 major neutrophil antimicrobial defense mechanisms: oxygen radical generation and release of toxic granule contents. PMID- 28096298 TI - MFG-E8-derived peptide attenuates adhesion and migration of immune cells to endothelial cells. AB - Milk fat globule-epidermal growth factor-factor 8 (MFG-E8) plays an immunomodulatory role in inflammatory diseases. MFG-E8-derived short peptide (MSP68) greatly reduces neutrophil infiltration and injury in the lung during sepsis. In this study, we examined the effect of MSP68 on chemotaxis of various immune cells and its regulatory mechanism. Bone marrow-derived neutrophils (BMDNs) from C57BL/6 mice, human monocyte THP-1 cell line, and human T lymphocyte Jurkat cell line were used for adhesion and migration assays using a Transwell method in the presence of MSP68. Treatment with MSP68 significantly inhibited the BMDN and THP-1 cell but not Jurkat cell adhesion on the TNF-alpha-stimulated pulmonary artery endothelial cell (PAEC) monolayer dose-dependently. MSP68 also significantly reduced BMDN adhesion on VCAM-1-coated wells dose dependently. Surface plasmon resonance (SPR) analysis revealed that MSP68 efficiently recognized integrin alpha4beta1 (receptor for VCAM-1) at the dissociation constant (KD) of 1.53 * 10-7 M. These findings implicate that MSP68 prevents neutrophil adhesion to the activated endothelial cells by interfering with the binding between integrin alpha4beta1 on neutrophils and VCAM-1 on endothelial cells. Moreover, MSP68 significantly attenuated the migration of BMDN and THP-1 cells but not Jurkat cells to their chemoattractants. Pretreatment with MSP68 inhibited the transmigration of BMDNs across the PAECs toward chemoattractants, fMLP, MIP-2, and complement fragment 5a (C5a) dose-dependently. Finally, we identified that the activation of p38 MAPK in BMDNs by fMLP was inhibited by MSP68. Thus, MSP68 attenuates extravasation of immune cells through the endothelial cell lining into inflamed tissue, implicating MSP68 to be a novel, therapeutic agent for inflammatory diseases caused by excessive immune cell infiltration. PMID- 28096299 TI - Exosomes from eosinophils autoregulate and promote eosinophil functions. AB - Eosinophils are able to secrete exosomes that have an undefined role in asthma pathogenesis. We hypothesized that exosomes released by eosinophils autoregulate and promote eosinophil function. Eosinophils of patients with asthma (n = 58) and healthy volunteers (n = 16) were purified from peripheral blood, and exosomes were isolated and quantified from eosinophils of the asthmatic and healthy populations. Apoptosis, adhesion, adhesion molecules expression, and migration assays were performed with eosinophils in the presence or absence of exosomes from healthy and asthmatic individuals. Reactive oxygen species (ROS) were evaluated by flow cytometry with an intracellular fluorescent probe and nitric oxide (NO) and a colorimetric kit. In addition, exosomal proteins were analyzed by mass spectrometry. Eosinophil-derived exosomes induced an increase in NO and ROS production on eosinophils. Moreover, exosomes could act as a chemotactic factor on eosinophils, and they produced an increase in cell adhesion, giving rise to a specific augmentation of adhesion molecules, such as ICAM-1 and integrin alpha2. Protein content between exosomes from healthy and asthmatic individuals seems to be similar in both groups. In conclusion, we found that exosomes from the eosinophils of patients with asthma could modify several specific eosinophil functions related to asthma pathogenesis and that they could contribute fundamentally to the development and maintenance of asthma. PMID- 28096300 TI - Enhanced suppression of polyclonal CD8+25+ regulatory T cells via exosomal arming of antigen-specific peptide/MHC complexes. AB - Compared with CD4+25+ regulatory T cells (Tregs), the mechanisms for natural, polyclonal CD8+25+ Treg immune suppression have been significantly less studied. We previously showed that polyclonal T cells can acquire antigen-specific targeting activity through arming with exosomal peptide-MHC (pMHC). In this study, we assessed the suppressive effect of CD8+25+ Tregs or CD8+25+ Tregs armed with ovalbumin (OVA)-specific exosomes on other immune cells and OVA-specific dendritic cell (DCOVA)-stimulated antitumor immunity. We demonstrate that CD8+25+ Tregs inhibit T cell proliferation in vitro in a cell contact-dependent fashion but independent of the expression of immunosuppressive IL-10, TGF-beta, and CTLA 4. CD8+25+ Tregs anergize naive T cells upon stimulation by up-regulating T cell anergy-associated Egr2 and down-regulating IL-2 production. Tregs also anergize DCs by preventing DC maturation through the down-regulation of Iab, CD80, CD86, and inflammatory cytokines, leading to defects in T cell stimulation. Moreover, CD8+25+ Tregs inhibit CTLs through inducing CTL death via perforin-mediated apoptosis and through reducing effector CTL cytotoxic activity via down regulating CTL perforin-production and degranulation. In addition, we show that CD8+25+ Tregs suppress DCOVA-stimulated CTL responses in priming and effector phases and inhibit immunity against OVA-expressing CCLOVA lung cancer. Remarkably, polyclonal CD8+25+ Tregs armed with OVA-specific exosomal pMHC class II (pMHC-II), or pMHC class-I (pMHC-I) complexes exert their enhanced inhibition of CTL responses in the priming and the effector phases, respectively. Taken together, our investigation reveals that assigning antigen specificity to nonspecific polyclonal CD8+25+ Tregs for enhanced immune suppression can be achieved through exosomal pMHC arming. This principle may have a great effect on Treg-mediated immunotherapy of autoimmune diseases. PMID- 28096301 TI - Phosphoinositol 3-phosphate acts as a timer for reactive oxygen species production in the phagosome. AB - Production of reactive oxygen species (ROS) in the phagosome by the NADPH oxidase is critical for mammalian immune defense against microbial infections and phosphoinositides are important regulators in this process. Phosphoinositol 3 phosphate (PI(3)P) regulates ROS production at the phagosome via p40phox by an unknown mechanism. This study tested the hypothesis that PI(3)P controls ROS production by regulating the presence of p40phox and p67phox at the phagosomal membrane. Pharmacologic inhibition of PI(3)P synthesis at the phagosome decreased the ROS production both in differentiated PLB-985 cells and human neutrophils. It also releases p67phox, the key cytosolic subunit of the oxidase, and p40phox from the phagosome. The knockdown of the PI(3)P phosphatase MTM1 or Rubicon or both increases the level of PI(3)P at the phagosome. That increase enhances ROS production inside the phagosome and triggers an extended accumulation of p67phox at the phagosome. Furthermore, the overexpression of MTM1 at the phagosomal membrane induces the disappearance of PI(3)P from the phagosome and prevents sustained ROS production. In conclusion, PI(3)P, indeed, regulates ROS production by maintaining p40phox and p67phox at the phagosomal membrane. PMID- 28096302 TI - Postmortem and Toxicological Findings in a Series of Furanylfentanyl-Related Deaths. AB - Over the course of 4 months in 2015 and 2016, a cluster of seven fatal intoxications involving the opioid-analogue furanylfentanyl occurred in Sweden; toxicological analysis showed presence of furanylfentanyl either as the only drug or in combination with other illicit substances. Previous publications have only reported non-lethal furanylfentanyl intoxications. In the cases presented here, furanylfentanyl intoxication-alone or in combination with other drugs-was determined to be the cause of death by the responsible pathologist. All victims were young (24-37 years old) males, five of which had a well-documented history of drug abuse. Femoral blood concentration of furanylfentanyl ranged from 0.41 ng/g to 2.47 ng/g blood. Five cases presented a complex panel of drugs of abuse and prescription drugs. Moreover, in five cases the concurrent presence of pregabalin corroborates previous observations indicating pregabalin as a possible contributing factor in polydrug intoxications. We conclude that it is difficult to establish a specific lethal concentration of furanylfentanyl, due to incompletely known effects of possible pharmacokinetic and pharmacodynamic interactions with other drugs, as well as to the unknown degree of tolerance to opioids. We suggest that a full toxicological screening-to assess the possibility of drug interactions-together with segmental hair analysis regarding opioids-to estimate the level of opioid tolerance-be carried out to assist in the interpretation of cases involving synthetic opioids such as furanylfentanyl. PMID- 28096303 TI - Down-Regulation of EPAS1 Transcription and Genetic Adaptation of Tibetans to High Altitude Hypoxia. AB - Tibetans are well adapted to the hypoxic environments at high altitude, yet the molecular mechanism of this adaptation remains elusive. We reported comprehensive genetic and functional analyses of EPAS1, a gene encoding hypoxia inducible factor 2alpha (HIF-2alpha) with the strongest signal of selection in previous genome-wide scans of Tibetans. We showed that the Tibetan-enriched EPAS1 variants down-regulate expression in human umbilical endothelial cells and placentas. Heterozygous EPAS1 knockout mice display blunted physiological responses to chronic hypoxia, mirroring the situation in Tibetans. Furthermore, we found that the Tibetan version of EPAS1 is not only associated with the relatively low hemoglobin level as a polycythemia protectant, but also is associated with a low pulmonary vasoconstriction response in Tibetans. We propose that the down regulation of EPAS1 contributes to the molecular basis of Tibetans' adaption to high-altitude hypoxia. PMID- 28096304 TI - Antibiotic Cycling and Antibiotic Mixing: Which One Best Mitigates Antibiotic Resistance? AB - : Can we exploit our burgeoning understanding of molecular evolution to slow the progress of drug resistance? One role of an infection clinician is exactly that: to foresee trajectories to resistance during antibiotic treatment and to hinder that evolutionary course. But can this be done at a hospital-wide scale? Clinicians and theoreticians tried to when they proposed two conflicting behavioral strategies that are expected to curb resistance evolution in the clinic, these are known as "antibiotic cycling" and "antibiotic mixing." However, the accumulated data from clinical trials, now approaching 4 million patient days of treatment, is too variable for cycling or mixing to be deemed successful. The former implements the restriction and prioritization of different antibiotics at different times in hospitals in a manner said to "cycle" between them. In antibiotic mixing, appropriate antibiotics are allocated to patients but randomly. Mixing results in no correlation, in time or across patients, in the drugs used for treatment which is why theorists saw this as an optimal behavioral strategy. So while cycling and mixing were proposed as ways of controlling evolution, we show there is good reason why clinical datasets cannot choose between them: by re-examining the theoretical literature we show prior support for the theoretical optimality of mixing was misplaced. Our analysis is consistent with a pattern emerging in data: neither cycling or mixing is a priori better than the other at mitigating selection for antibiotic resistance in the clinic. Key words: : antibiotic cycling, antibiotic mixing, optimal control, stochastic models. PMID- 28096305 TI - Epithelial expression and function of trypsin-3 in irritable bowel syndrome. AB - OBJECTIVES: Proteases are key mediators of pain and altered enteric neuronal signalling, although the types and sources of these important intestinal mediators are unknown. We hypothesised that intestinal epithelium is a major source of trypsin-like activity in patients with IBS and this activity signals to primary afferent and enteric nerves and induces visceral hypersensitivity. DESIGN: Trypsin-like activity was determined in tissues from patients with IBS and in supernatants of Caco-2 cells stimulated or not. These supernatants were also applied to cultures of primary afferents. mRNA isoforms of trypsin (PRSS1, 2 and 3) were detected by reverse transcription-PCR, and trypsin-3 protein expression was studied by western blot analysis and immunohistochemistry. Electrophysiological recordings and Ca2+ imaging in response to trypsin-3 were performed in mouse primary afferent and in human submucosal neurons, respectively. Visceromotor response to colorectal distension was recorded in mice administered intracolonically with trypsin-3. RESULTS: We showed that stimulated intestinal epithelial cells released trypsin-like activity specifically from the basolateral side. This activity was able to activate sensory neurons. In colons of patients with IBS, increased trypsin-like activity was associated with the epithelium. We identified that trypsin-3 was the only form of trypsin upregulated in stimulated intestinal epithelial cells and in tissues from patients with IBS. Trypsin-3 was able to signal to human submucosal enteric neurons and mouse sensory neurons, and to induce visceral hypersensitivity in vivo, all by a protease-activated receptor-2-dependent mechanism. CONCLUSIONS: In IBS, the intestinal epithelium produces and releases the active protease trypsin-3, which is able to signal to enteric neurons and to induce visceral hypersensitivity. PMID- 28096307 TI - 'He would by no means risque his Reputation': patient and doctor shame in Daniel Turner's De Morbis Cutaneis (1714) and Syphilis (1717). AB - This article offers a historical corollary to the examination of shame in medical practice by considering the negotiation of shame in the treatment of a stigmatised disease at a time in which surgeons themselves occupied a highly ambivalent social position. It will focus on case studies provided by Daniel Turner (1667-1741), prominent surgeon and later member of the College of Physicians, in his textbooks De Morbis Cutaneis. A Treatise of Diseases Incident to the Skin (1714) and Syphilis. A Practical Dissertation on the Venereal Disease (1717). Turner demonstrates an awareness of the precarious position of both the surgeon and the syphilitic, and devotes significant portions of his text to advising the trainee surgeon on how to manage patients' reticence over disclosure of symptoms, expectations for cure and impudence towards medical authority. In turn, the trainee must manage his own reputation as a moral and medical authority who can treat all distempers, yet without condoning or facilitating the shameful behaviours associated with a sexual disease. Furthermore, shaming plays a key role in enabling Turner to fashion an ideal patient whose successful cure will both respond to and build the surgeon's medical authority and that of the medical field in general. PMID- 28096306 TI - National multicentre audit of pregnancy status in general surgery admissions in Scotland. AB - BACKGROUND: Documentation of pregnancy status (PS) is an integral component of the assessment of women of reproductive age when admitted to hospital. Our aim was to determine how accurately PS was documented in a multicentre audit of female admissions to general surgery. METHODS: A prospective multicentre audit of elective and emergency admissions was performed in 18 Scottish centres between 08:00 on 11 May 2015 and 07:59 on 25 May 2015. The lower age limit was the minimum age for admission to the adult surgical ward and the upper age limit was 55 years. RESULTS: There were 2743 admissions, with 612 (22.3%) women of reproductive age. After 82 exclusions, the final total was 530: 169 (31.9%) elective and 361 (68.1%) emergency. Documentation of PS was achieved in 274 (51.7%) cases: 52 (30.8%) elective and 222 (61.5%) emergency. In 318 (88.1%) of the emergency admissions, the patient had abdominal pain. Of these, 211 (65.1%) had a documented PS. The possibility of pregnancy was established in 237 (44.7%) cases. DISCUSSION: Establishing the possibility of pregnancy before surgery is poor, particularly in the elective setting. Objective documentation of PS in the emergency setting in those with abdominal pain is also poor. Our study highlights an important safety issue in the management of female patients. We advocate electronic storage of pregnancy test results and new guidelines to cover both elective and emergency surgery. PS should form part of the pre-theatre safety brief and checklist. PMID- 28096308 TI - (Re)Building a Kidney. AB - (Re)Building a Kidney is a National Institute of Diabetes and Digestive and Kidney Diseases-led consortium to optimize approaches for the isolation, expansion, and differentiation of appropriate kidney cell types and the integration of these cells into complex structures that replicate human kidney function. The ultimate goals of the consortium are two-fold: to develop and implement strategies for in vitro engineering of replacement kidney tissue, and to devise strategies to stimulate regeneration of nephrons in situ to restore failing kidney function. Projects within the consortium will answer fundamental questions regarding human gene expression in the developing kidney, essential signaling crosstalk between distinct cell types of the developing kidney, how to derive the many cell types of the kidney through directed differentiation of human pluripotent stem cells, which bioengineering or scaffolding strategies have the most potential for kidney tissue formation, and basic parameters of the regenerative response to injury. As these projects progress, the consortium will incorporate systematic investigations in physiologic function of in vitro and in vivo differentiated kidney tissue, strategies for engraftment in experimental animals, and development of therapeutic approaches to activate innate reparative responses. PMID- 28096311 TI - The Comparison of Health Status Between Male and Female Medical Radiation Workers in China. AB - To assess the health statue of chronically exposed Chinese medical radiation workers. A cross-sectional study of 530 medical radiation workers in a city of China was conducted to document the health status and the monitored annually absorbed doses. Long-term and low-dose radiation exposure can affect a number of health indicators in the individuals, which covered the cardiovascular system, hematologic system, ophthalmology, liver and kidney's functions, chromosome aberration and micronucleus. The differences in the health status between male and female individuals were associated with job types and exposed years of service. The monitored doses of individuals were lower than the limit value of the national standard. The health status in chronically exposed individuals demonstrated some gender difference associated with length of exposure and work type. This study provides some evidence to understand the health status of medical radiation workers in China and have the potentially to inform screening and clinical diagnosis. PMID- 28096310 TI - Characterization of the dTDP-Fuc3N and dTDP-Qui3N biosynthetic pathways in Campylobacter jejuni 81116. AB - The Gram-negative bacterium Campylobacter jejuni 81116 (Penner serotype HS:6) has a class E lipooligosaccharide (LOS) biosynthesis locus containing 19 genes, which encode for 11 putative glycosyltransferases, 1 lipid A acyltransferase and 7 enzymes thought to be involved in the biosynthesis of dideoxyhexosamine (ddHexN) moieties. Although the LOS outer core structure of C. jejuni 81116 is still unknown, recent mass spectrometry analyses suggest that it contains acetylated forms of two ddHexN residues. For this investigation, five of the genes encoding enzymes reportedly involved in the biosyntheses of these sugar residues were examined, rmlA, rmlB, wlaRA, wlaRB and wlaRG. Specifically, these genes were cloned and expressed in Escherichia coli, and the corresponding enzymes were purified and tested for biochemical activity. Here we present data demonstrating that RmlA functions as a glucose-1-phosphate thymidylyltransferase and that RmlB is a thymidine diphosphate (dTDP)-glucose 4,6-dehydratase. We also show, through nuclear magnetic resonance spectroscopy and mass spectrometry analyses, that WlaRG, when utilized in coupled assays with either WlaRA or WlaRB and dTDP-4-keto 6-deoxyglucose, results in the production of either dTDP-3-amino-3,6-dideoxy-d galactose (dTDP-Fuc3N) or dTDP-3-amino-3,6-dideoxy-d-glucose (dTDP-Qui3N), respectively. In addition, the X-ray crystallographic structures of the 3,4 ketoisomerases, WlaRA and WlaRB, were determined to 2.14 and 2.0 A resolutions, respectively. Taken together, the data reported herein demonstrate that C. jejuni 81116 utilizes five enzymes to synthesize dTDP-Fuc3N or dTDP-Qui3N and that WlaRG, an aminotransferase, can function on sugars with differing stereochemistry about their C-4' carbons. Importantly, the data reveal that C. jejuni 81116 has the ability to synthesize two isomeric ddHexN forms. PMID- 28096312 TI - Analysis of Thermoluminescence Glow Curves using Derivatives of different Orders. AB - The suitability of the second derivative method for locating component peaks in complex thermoluminescence (TL) glow curves has been investigated in this work by considering both numerically simulated and experimental TL peaks. This technique is useful to acquire knowledge of the number of component peaks in a complex TL curve which in turn serves as a basic information before applying the deconvolution technique to the glow curve. To check the consistency of the results so obtained, we have also applied the first derivative technique to TL glow curves. It is well-known that kinetic order formalism fails for saturated TL peaks with heavy retrapping. Such peaks are usually broad and, to the best of our knowledge, have not yet been observed experimentally. The present derivative technique has been used to detect whether such broad peaks are truly single or not by considering a number of numerically simulated saturated glow curves with heavy retrapping where the conventional peak shape method fails. In all the cases considered here, the second derivative technique proves to be a potential candidate for estimating the number of peaks and their respective locations in a complex TL glow curve. PMID- 28096309 TI - Anti-Factor B and Anti-C3b Autoantibodies in C3 Glomerulopathy and Ig-Associated Membranoproliferative GN. AB - In C3 glomerulopathy (C3G), the alternative pathway of complement is frequently overactivated by autoantibodies that stabilize the C3 convertase C3bBb. Anti-C3b and anti-factor B (anti-FB) IgG have been reported in three patients with C3G. We screened a cohort of 141 patients with C3G and Ig-associated membranoproliferative GN (Ig-MPGN) for anti-FB and anti-C3b autoantibodies using ELISA. We identified seven patients with anti-FB IgG, three patients with anti C3b IgG, and five patients with anti-FB and anti-C3b IgG. Of these 15 patients, ten were diagnosed with Ig-MPGN. Among those patients with available data, 92% had a nephrotic syndrome, 64% had AKI, and 67% had a documented infection. Patients negative for anti-C3b and anti-FB IgG had much lower rates of infection (17 [25%] patients with C3G and one [10%] patient with Ig-MPGN). After 48 months, four of 15 (26%) positive patients had developed ESRD or died. All 15 patients had high plasma Bb levels, six (40%) patients had low levels of C3, and nine (60%) patients had high levels of soluble C5b9. In vitro, IgG purified from patients with anti-FB Abs selectively enhanced C3 convertase activity; IgG from patients with anti-C3b/anti-FB Abs enhanced C3 and C5 cleavage. IgG from patients with anti-C3b Abs stabilized C3bBb and perturbed C3b binding to complement receptor 1 but did not perturb binding to factor H. In conclusion, the prevalence of anti-C3b/anti-FB Abs and alternative pathway activation is similar in Ig-MPGN and C3G, suggesting similar pathogenic mechanisms. Identification of the underlying defect in Ig-MPGN could lead to improved treatment. PMID- 28096313 TI - Opportunities to Reduce CT Radiation Exposure, Experience Over 5 Years at the NIH Clinical Center. AB - Our current study was undertaken in order to compare CT exposures during various dose-reduction initiatives at the National Institutes of Health Clinical center, to show trends in exposure reduction over a 5-y period, and to provide benchmarks that other facilities may use. Using an in-house extraction tool (Radiation Exposure Extraction Engine), we derived CT exposure data from Digital Imaging and Communications in Medicine (DICOM) headers over 5 y. We present parameters used and compare most common exams between 2010 and 2015. During a period of exposure reduction initiatives, data of 79 396 exams from nine CT scanners on 87 scan protocols were analyzed. Adult chest exposures were reduced 53% and chest, abdomen and pelvis exams were reduced 43% (p < 0.001). Only extremity exams did not show significantly reduced exposure. Collecting data over several years allowed us to confirm and compare several initiatives. We demonstrated significant exposure reductions during continued reduction efforts on common exams. Our results may provide benchmarks for similar centers. PMID- 28096314 TI - Exposure to Recycled Uranium Contaminants in Gaseous Diffusion Plants. AB - As part of an ongoing study of health effects in a pooled cohort of gaseous diffusion plant workers, organ dose from internal exposure to uranium was evaluated. Due to the introduction of recycled uranium into the plants, there was also potential for exposure to radiologically significant levels of 99Tc, 237Np and 238,239Pu. In the evaluation of dose response, these radionuclide exposures could confound the effect of internal uranium. Using urine bioassay data for study subjects reported in facility records, intakes and absorbed dose to bone surface, red bone marrow and kidneys were estimated as these organs were associated with a priori outcomes of interest. Additionally, 99Tc intakes and doses were calculated using a new systemic model for technetium and compared to intakes and doses calculated using the current model recommended by the International Commission on Radiological Protection. Organ absorbed doses for the transuranics were significant compared to uranium doses; however, 99Tc doses calculated using the new systemic model were significant as well. Use of the new model resulted in an increase in 99Tc-related absorbed organ dose of a factor of 8 (red bone marrow) to 30 (bone surface). PMID- 28096315 TI - Experimental Optimization of Exposure Index and Quality of Service in Wlan Networks. AB - This paper presents the first real-life optimization of the Exposure Index (EI). A genetic optimization algorithm is developed and applied to three real-life Wireless Local Area Network scenarios in an experimental testbed. The optimization accounts for downlink, uplink and uplink of other users, for realistic duty cycles, and ensures a sufficient Quality of Service to all users. EI reductions up to 97.5% compared to a reference configuration can be achieved in a downlink-only scenario, in combination with an improved Quality of Service. Due to the dominance of uplink exposure and the lack of WiFi power control, no optimizations are possible in scenarios that also consider uplink traffic. However, future deployments that do implement WiFi power control can be successfully optimized, with EI reductions up to 86% compared to a reference configuration and an EI that is 278 times lower than optimized configurations under the absence of power control. PMID- 28096316 TI - BAY 11-7082 inhibits the NF-kappaB and NLRP3 inflammasome pathways and protects against IMQ-induced psoriasis. AB - BAY 11-7082 antagonizes I-kappaB kinase-beta preventing nuclear translocation of nuclear factor-kappaB (NF-kappaB); it also inhibits NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation. NF-kappaB is involved in psoriasis, whereas the role of NLRP3 is controversial. We investigated BAY 11 7082 effects in an experimental model of psoriasis-like dermatitis. Psoriasis like lesions were induced by a topical application of imiquimod (IMQ) cream (62.5 mg/day) on the shaved back skin of C57BL/6 and NLRP3 knockout (KO) mice for 7 consecutive days. Sham psoriasis animals were challenged with Vaseline cream. Sham and IMQ animals were randomized to receive BAY 11-7082 (20 mg/kg/i.p.) or its vehicle (100 MUl/i.p of 0.9% NaCl). Skin of IMQ animals developed erythema, scales, thickening and epidermal acanthosis. IMQ skin samples showed increased expression of pNF-kappaB and NLRP3 activation. BAY 11-7082 blunted epidermal thickness, acanthosis and inflammatory infiltrate. BAY 11-7082 reduced pNF kappaB, NLRP3, tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and IL-1beta expression, blunted the phosphorylation of signal transducer and activators of transcription 3 (STAT3) and decreased IL-23 levels. In addition, BAY 11-7082 reawakened the apoptotic machinery. NLRP3 KO animals showed a reduced total histological score but persistent mild acanthosis, dermal thickness and expression of pNF-kappaB and pSTAT3, following IMQ application. Our data suggest that BAY 11-7082 might represent an interesting approach for the management of psoriasis-like dermatitis depending on the dual inhibition of NF-kappaB and NLRP3. PMID- 28096319 TI - Rotator cuff impingement associated with Type III acromial morphology in a young athlete-a case for early imaging. AB - Down-sloped or hooked acromion morphologies may cause bony encroachment on the soft tissues of the subacromial space, predisposing to shoulder impingement syndrome. Of the latter, a hooked or Type III acromion (T3A) has also been linked to rotator cuff (RC) pathology. However, as bony acromial impingement is typically thought to occur over the age of 40, its occurrence in younger shoulder athletes presenting with shoulder pain, impingement and RC pathology may be overlooked. This case serves to illustrate the occurrence of T3A in a younger shoulder athlete, and the importance of early imaging in achieving diagnostic accuracy. Appropriate surgical referrals are patients with subacromial impingement syndrome refractory to 3-6 months of appropriate conservative treatment. Surgery may be particularly beneficial in patients with a T3A. PMID- 28096318 TI - Bone marrow mesenchymal stem cells inhibit dendritic cells differentiation and maturation by microRNA-23b. AB - Research on regulation and its mechanism of bone marrow mesenchymal stem cells (BMSCs) on dendritic cells (DCs), which is the initiating factor in immune response has applicable clinical value. Although BMSCs have a significant regulatory effect on the maturation of DCs, its molecular mechanism is still unclear. BMSCs and DCs, were co-cultured by different concentration ratios. Flow cytometry was used to detect the expression of DC markers (CD83, CD11c). Quantitative reverse transcription PCR (qRT-PCR) was used to measure the expression of related genes in RNA level. Expression of the target proteins was detected with using Western blot assay. miRNA inhibitor and miRNA mimic were used to suppress and up-regulate the expression of the target gene. In this research, our results demonstrated that BMSCs notably inhibited maturation of DCs in the co culture system of BMSCs and DCs and confirmed that this inhibition is due to overexpression of miR-23b Furthermore, this research found that miR-23b overexpression inhibited the expression of p50/p65, thus blocked the activation of the NF-kappaB pathway. In conclusion, BMSCs affected the activation of NF kappaB pathway through miR-23b overexpression resulting in inhibition of the maturation and differentiation of DCs. PMID- 28096320 TI - Streptococcus gordonii-a rare cause of prosthetic joint infection in a total hip replacement. AB - A 69-year-old female with a history of bilateral total hip replacements presented with rigors, fever and sudden onset left groin pain. A pelvic X-ray showed well fixed implants. Blood results revealed a leucocytosis (white cell count 22.3 * 109 l-1) and elevated C-reactive protein (211 mg/l). Ultrasound-guided aspiration of her left hip grew Streptococcus gordonii No source infection could be identified apart from a new chronic sinus infection in a left upper incisor. Following a discussion with the patient a 6-week course of intravenous ceftriaxone was started and was successful in normalizing her inflammatory markers. She was placed on long-term suppressive amoxicillin following this. Her suppressive antibiotic therapy was complicated by the development of a clostridium difficile infection and her antibiotics were changed to doxycycline. At 1-year follow-up, she was asymptomatic with no further episodes of groin pain or fever. PMID- 28096321 TI - Synchronous single-port access laparoscopic right hemicolectomy and laparoscopic assisted vaginal hysterectomy with bilateral salpingo-oophorectomy. AB - Laparoscopic surgery through a single incision is gaining popularity with different stakeholders. The advantages of improved cosmetics, decreased postoperative pain and blood loss continue to attract patients from different surgical fields. Multidisciplinary approach to different surgical entities through a single incision has just been introduced. We report the first case of a synchronous single-port access (SPA) laparoscopic right hemicolectomy and laparoscopic-assisted vaginal hysterectomy with bilateral salpingo-oophorectomy through a single incision above the umbilicus in a 48-year-old female with ascending colon mass and uterine mass with good postoperative outcomes. SPA laparoscopic surgery is feasible for multidisciplinary approach in resectable tumors. PMID- 28096317 TI - Modelling the molecular mechanisms of aging. AB - The aging process is driven at the cellular level by random molecular damage that slowly accumulates with age. Although cells possess mechanisms to repair or remove damage, they are not 100% efficient and their efficiency declines with age. There are many molecular mechanisms involved and exogenous factors such as stress also contribute to the aging process. The complexity of the aging process has stimulated the use of computational modelling in order to increase our understanding of the system, test hypotheses and make testable predictions. As many different mechanisms are involved, a wide range of models have been developed. This paper gives an overview of the types of models that have been developed, the range of tools used, modelling standards and discusses many specific examples of models that have been grouped according to the main mechanisms that they address. We conclude by discussing the opportunities and challenges for future modelling in this field. PMID- 28096322 TI - Enterobius vermicularis presentation during laparoscopic cholecystectomy. AB - Enterobius vermicularis infection is uncommon in adults, compared to children, and rarely causes significant illness. Adult infection is usually colonic in nature and found incidentally at colonoscopy. Worm migration to other tissues is rare. We here-in describe the case of a 73-year-old woman found to have biliary tree E. vermicularis-an as yet undescribed site of migration. PMID- 28096323 TI - Pyoderma gangrenosum following complex reconstruction of a large-scale lower limb defect by combined Parascapular and latissimus dorsi flap. AB - A female patient with a critical soft tissue defect after elective knee replacement surgery was transferred to our department for reconstruction. As wounds were rapidly progressing, necrotizing fasciitis was initially suspected but eventually ruled out by histopathological analysis. A 50 * 15 cm defect was then reconstructed by means of a combined Parascapular and latissimus dorsi flap before, a couple days later, the patient developed tender pustules and ulcers involving the flap as well as the donor site. Attempts of excising necrotic areas not only continued to fail but seemed to worsen the patient's wound and overall condition. Eventually, pyoderma gangrenosum (PG) was diagnosed and local and systemic therapy was initiated but treatment proved to be challenging and insufficient at first. Being an extremely aggressive disease, early diagnosis is crucial and PG should always be suspected when rapidly progressive ulceration on surgical sites is observed. PMID- 28096324 TI - Totally laparoscopic liver resection for colorectal metastasis located in Segment 7 in a patient with situs inversus totalis. AB - Situs inversus totalis (SIT) is a congenital condition consisting of a mirror image of transposition of the abdominal and thoracic organs occurring in about 1:5000 to 1:10 000 adults. We report on a 60-year-old male with a single colorectal liver metastasis in the Segment 7. The patients underwent a totally laparoscopic sub-segmentectomy. Intraoperative approach on a reverse posterior segment was difficult because of left-sided position of the liver. Postoperative course was uneventful and the patient was discharged after 5 days. To our knowledge, only a few cases of open liver resections in patients with SIT have been published. This is, therefore, the first case of laparoscopic liver resection for colorectal liver metastasis in a patient with SIT. We provide the readers with useful tips to perform minimally invasive liver surgery in such patients. PMID- 28096325 TI - Saphenous vein patch for correction of anomalous origin of the right coronary artery from the left main coronary artery. AB - Anomalous origin of the coronary arteries is a rare congenital heart defect that may lead to disturbed life style, myocardial infarction and sudden death. This report describes a young lady with the right coronary artery arising from the left main coronary artery, which was confirmed by coronary angiography and corrected surgically using saphenous vein patch. PMID- 28096326 TI - A rare presentation of an acute appendicitis. AB - Paraumbilical hernia sac usually contains omentum, bowel loop and rarely appendicular epiploicae, metastatic deposits and vermiform appendix. Presentation of acute appendicitis in a paraumbilical hernia is rare and limited to few case reports in the literature. Herein, we would like to report a case of a successfully treated acute appendicitis presenting in a paraumbilical hernia in an 84-year-old lady with 6-month follow-up. PMID- 28096327 TI - Pneumatosis coli causing pneumoperitoneum. AB - This is a case of a 54-year-old gentleman who presented to an outside hospital emergency department with lower abdominal pain. Computed tomography imaging showed a small amount of intraperitoneal free air and cystic pneumatosis coli. He was admitted, managed conservatively with intravenous antibiotics, and then discharged home after his symptoms improved. Elective laparoscopic sigmoid colectomy was subsequently performed with intraoperative findings of partial sigmoid volvulus and extensive pneumatosis coli of the sigmoid colon. Pneumoperitoneum was determined to be from ruptured intramural cysts. The etiology of pneumatosis coli was likely from chronic sigmoid volvulus. PMID- 28096328 TI - Dynamic PIN-FORMED auxin efflux carrier phosphorylation at the plasma membrane controls auxin efflux-dependent growth. AB - The directional distribution of the phytohormone auxin is essential for plant development. Directional auxin transport is mediated by the polarly distributed PIN-FORMED (PIN) auxin efflux carriers. We have previously shown that efficient PIN1-mediated auxin efflux requires activation through phosphorylation at the four serines S1-S4 in Arabidopsis thaliana The Brefeldin A (BFA)-sensitive D6 PROTEIN KINASE (D6PK) and the BFA-insensitive PINOID (PID) phosphorylate and activate PIN1 through phosphorylation at all four phosphosites. PID, but not D6PK, can also induce PIN1 polarity shifts, seemingly through phosphorylation at S1-S3. The differential effects of D6PK and PID on PIN1 polarity had so far been attributed to their differential phosphosite preference for the four PIN1 phosphosites. We have mapped PIN1 phosphorylation at S1-S4 in situ using phosphosite-specific antibodies. We detected phosphorylation at PIN1 phosphosites at the basal (rootward) as well as the apical (shootward) plasma membrane in different root cell types, in embryos, and shoot apical meristems. Thereby, PIN1 phosphorylation at all phosphosites generally followed the predominant PIN1 distribution but was not restricted to specific polar sides of the cells. PIN1 phosphorylation at the basal and apical plasma membrane was differentially sensitive to BFA treatments, suggesting the involvement of different protein kinases or trafficking mechanisms in PIN1 phosphorylation control. We conclude that phosphosite preferences are not sufficient to explain the differential effects of D6PK and PID on PIN1 polarity, and suggest that a more complex model is needed to explain the effects of PID. PMID- 28096329 TI - Tissue dual RNA-seq allows fast discovery of infection-specific functions and riboregulators shaping host-pathogen transcriptomes. AB - Pathogenic bacteria need to rapidly adjust their virulence and fitness program to prevent eradication by the host. So far, underlying adaptation processes that drive pathogenesis have mostly been studied in vitro, neglecting the true complexity of host-induced stimuli acting on the invading pathogen. In this study, we developed an unbiased experimental approach that allows simultaneous monitoring of genome-wide infection-linked transcriptional alterations of the host and colonizing extracellular pathogens. Using this tool for Yersinia pseudotuberculosis-infected lymphatic tissues, we revealed numerous alterations of host transcripts associated with inflammatory and acute-phase responses, coagulative activities, and transition metal ion sequestration, highlighting that the immune response is dominated by infiltrating neutrophils and elicits a mixed TH17/TH1 response. In consequence, the pathogen's response is mainly directed to prevent phagocytic attacks. Yersinia up-regulates the gene and expression dose of the antiphagocytic type III secretion system (T3SS) and induces functions counteracting neutrophil-induced ion deprivation, radical stress, and nutritional restraints. Several conserved bacterial riboregulators were identified that impacted this response. The strongest influence on virulence was found for the loss of the carbon storage regulator (Csr) system, which is shown to be essential for the up-regulation of the T3SS on host cell contact. In summary, our established approach provides a powerful tool for the discovery of infection specific stimuli, induced host and pathogen responses, and underlying regulatory processes. PMID- 28096330 TI - Spectroscopic evidence for bulk-band inversion and three-dimensional massive Dirac fermions in ZrTe5. AB - Three-dimensional topological insulators (3D TIs) represent states of quantum matters in which surface states are protected by time-reversal symmetry and an inversion occurs between bulk conduction and valence bands. However, the bulk band inversion, which is intimately tied to the topologically nontrivial nature of 3D Tis, has rarely been investigated by experiments. Besides, 3D massive Dirac fermions with nearly linear band dispersions were seldom observed in TIs. Recently, a van der Waals crystal, ZrTe5, was theoretically predicted to be a TI. Here, we report an infrared transmission study of a high-mobility [~33,000 cm2/(V ? s)] multilayer ZrTe5 flake at magnetic fields (B) up to 35 T. Our observation of a linear relationship between the zero-magnetic-field optical absorption and the photon energy, a bandgap of ~10 meV and a [Formula: see text] dependence of the Landau level (LL) transition energies at low magnetic fields demonstrates 3D massive Dirac fermions with nearly linear band dispersions in this system. More importantly, the reemergence of the intra-LL transitions at magnetic fields higher than 17 T reveals the energy cross between the two zeroth LLs, which reflects the inversion between the bulk conduction and valence bands. Our results not only provide spectroscopic evidence for the TI state in ZrTe5 but also open up a new avenue for fundamental studies of Dirac fermions in van der Waals materials. PMID- 28096331 TI - One-step design of a stable variant of the malaria invasion protein RH5 for use as a vaccine immunogen. AB - Many promising vaccine candidates from pathogenic viruses, bacteria, and parasites are unstable and cannot be produced cheaply for clinical use. For instance, Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is essential for erythrocyte invasion, is highly conserved among field isolates, and elicits antibodies that neutralize in vitro and protect in an animal model, making it a leading malaria vaccine candidate. However, functional RH5 is only expressible in eukaryotic systems and exhibits moderate temperature tolerance, limiting its usefulness in hot and low-income countries where malaria prevails. Current approaches to immunogen stabilization involve iterative application of rational or semirational design, random mutagenesis, and biochemical characterization. Typically, each round of optimization yields minor improvement in stability, and multiple rounds are required. In contrast, we developed a one step design strategy using phylogenetic analysis and Rosetta atomistic calculations to design PfRH5 variants with improved packing and surface polarity. To demonstrate the robustness of this approach, we tested three PfRH5 designs, all of which showed improved stability relative to wild type. The best, bearing 18 mutations relative to PfRH5, expressed in a folded form in bacteria at >1 mg of protein per L of culture, and had 10-15 degrees C higher thermal tolerance than wild type, while also retaining ligand binding and immunogenic properties indistinguishable from wild type, proving its value as an immunogen for a future generation of vaccines against the malaria blood stage. We envision that this efficient computational stability design methodology will also be used to enhance the biophysical properties of other recalcitrant vaccine candidates from emerging pathogens. PMID- 28096332 TI - Human NF-kappaB repressing factor acts as a stress-regulated switch for ribosomal RNA processing and nucleolar homeostasis surveillance. AB - The nucleolus, a dynamic nuclear compartment long regarded as the cell ribosome factory, is emerging as an important player in the regulation of cell survival and recovery from stress. In larger eukaryotes, the stress-induced transcriptional response is mediated by a family of heat-shock transcription factors. Among these, HSF1, considered the master regulator of stress-induced transcriptional responses, controls the expression of cytoprotective heat shock proteins (HSPs), molecular chaperones/cochaperones constituting a major component of the cell protein quality control machinery essential to circumvent stress induced degradation and aggregation of misfolded proteins. Herein we identify human NF-kappaB repressing factor (NKRF) as a nucleolar HSP essential for nucleolus homeostasis and cell survival under proteotoxic stress. NKRF acts as a thermosensor translocating from the nucleolus to the nucleoplasm during heat stress; nucleolar pools are replenished during recovery upon HSF1-mediated NKRF resynthesis. Silencing experiments demonstrate that NKRF is an unconventional HSP crucial for correct ribosomal RNA (rRNA) processing and preventing aberrant rRNA precursors and discarded fragment accumulation. These effects are mediated by NKRF interaction with the 5'-to-3' exoribonuclease XRN2, a key coordinator of multiple pre-rRNA cleavages, driving mature rRNA formation and discarded rRNA decay. Under stress conditions, NKRF directs XRN2 nucleolus/nucleoplasm trafficking, controlling 5'-to-3' exoribonuclease nucleolar levels and regulating rRNA processing. Our study reveals a different aspect of rRNA biogenesis control in human cells and sheds light on a sophisticated mechanism of nucleolar homeostasis surveillance during stress. PMID- 28096333 TI - Biophysical properties of the clinical-stage antibody landscape. AB - Antibodies are a highly successful class of biological drugs, with over 50 such molecules approved for therapeutic use and hundreds more currently in clinical development. Improvements in technology for the discovery and optimization of high-potency antibodies have greatly increased the chances for finding binding molecules with desired biological properties; however, achieving drug-like properties at the same time is an additional requirement that is receiving increased attention. In this work, we attempt to quantify the historical limits of acceptability for multiple biophysical metrics of "developability." Amino acid sequences from 137 antibodies in advanced clinical stages, including 48 approved for therapeutic use, were collected and used to construct isotype-matched IgG1 antibodies, which were then expressed in mammalian cells. The resulting material for each source antibody was evaluated in a dozen biophysical property assays. The distributions of the observed metrics are used to empirically define boundaries of drug-like behavior that can represent practical guidelines for future antibody drug candidates. PMID- 28096334 TI - Role of CCT chaperonin in the disassembly of mitotic checkpoint complexes. AB - The mitotic checkpoint system prevents premature separation of sister chromatids in mitosis and thus ensures the fidelity of chromosome segregation. When this checkpoint is active, a mitotic checkpoint complex (MCC), composed of the checkpoint proteins Mad2, BubR1, Bub3, and Cdc20, is assembled. MCC inhibits the ubiquitin ligase anaphase promoting complex/cyclosome (APC/C), whose action is necessary for anaphase initiation. When the checkpoint signal is turned off, MCC is disassembled, a process required for exit from checkpoint-arrested state. Different moieties of MCC are disassembled by different ATP-requiring processes. Previous work showed that Mad2 is released from MCC by the joint action of the TRIP13 AAA-ATPase and the Mad2-binding protein p31comet Now we have isolated from extracts of HeLa cells an ATP-dependent factor that releases Cdc20 from MCC and identified it as chaperonin containing TCP1 or TCP1-Ring complex (CCT/TRiC chaperonin), a complex known to function in protein folding. Bacterially expressed CCT5 chaperonin subunits, which form biologically active homooligomers [Sergeeva, et al. (2013) J Biol Chem 288(24):17734-17744], also promote the disassembly of MCC. CCT chaperonin further binds and disassembles subcomplexes of MCC that lack Mad2. Thus, the combined action of CCT chaperonin with that of TRIP13 ATPase promotes the complete disassembly of MCC, necessary for the inactivation of the mitotic checkpoint. PMID- 28096335 TI - Myofibril breakdown during atrophy is a delayed response requiring the transcription factor PAX4 and desmin depolymerization. AB - A hallmark of muscle atrophy is the excessive degradation of myofibrillar proteins primarily by the ubiquitin proteasome system. In mice, during the rapid muscle atrophy induced by fasting, the desmin cytoskeleton and the attached Z band-bound thin filaments are degraded after ubiquitination by the ubiquitin ligase tripartite motif-containing protein 32 (Trim32). To study the order of events leading to myofibril destruction, we investigated the slower atrophy induced by denervation (disuse). We show that myofibril breakdown is a two-phase process involving the initial disassembly of desmin filaments by Trim32, which leads to the later myofibril breakdown by enzymes, whose expression is increased by the paired box 4 (PAX4) transcription factor. After denervation of mouse tibialis anterior muscles, phosphorylation and Trim32-dependent ubiquitination of desmin filaments increased rapidly and stimulated their gradual depolymerization (unlike their rapid degradation during fasting). Trim32 down-regulation attenuated the loss of desmin and myofibrillar proteins and reduced atrophy. Although myofibrils and desmin filaments were intact at 7 d after denervation, inducing the dissociation of desmin filaments caused an accumulation of ubiquitinated proteins and rapid destruction of myofibrils. The myofibril breakdown normally observed at 14 d after denervation required not only dissociation of desmin filaments, but also gene induction by PAX4. Down regulation of PAX4 or its target gene encoding the p97/VCP ATPase reduced myofibril disassembly and degradation on denervation or fasting. Thus, during atrophy, the initial loss of desmin is critical for the subsequent myofibril destruction, and over time, myofibrillar proteins become more susceptible to PAX4 induced enzymes that promote proteolysis. PMID- 28096336 TI - beta-Catenin haploinsufficiency promotes mammary tumorigenesis in an ErbB2 positive basal breast cancer model. AB - Aberrant activation of beta-catenin through its activity as a transcription factor has been observed in a large proportion of human malignancies. Despite the improved understanding of the beta-catenin signaling pathway over the past three decades, attempts to develop therapies targeting beta-catenin remain challenging, and none of these targeted therapies have advanced to the clinic. In this study, we show that part of the challenge in antagonizing beta-catenin is caused by its dual functionality as a cell adhesion molecule and a signaling molecule. In a mouse model of basal ErbB2 receptor tyrosine kinase 2 (ErbB2)-positive breast cancer (ErbB2KI), which exhibits aberrant beta-catenin nuclear signaling, beta catenin haploinsufficiency induced aggressive tumor formation and metastasis by promoting the disruption of adherens junctions, dedifferentiation, and an epithelial to mesenchymal transition (EMT) transcriptional program. In contrast to the accelerated tumor onset observed in the haploid-insufficient ErbB2 tumors, deletion of both beta-catenin alleles in the ErbB2KI model had only a minor impact on tumor onset that further correlated with the retention of normal adherens junctions. We further showed that retention of adherens junctional integrity was caused by the up-regulation of the closely related family member plakoglobin (gamma-catenin) that maintained both adherens junctions and the activation of Wnt target genes. In contrast to the ErbB2KI basal tumor model, modulation of beta-catenin levels had no appreciable impact on tumor onset in an ErbB2-driven model of luminal breast cancer [murine mammary tumor virus promoter (MMTV-NIC)]. These observations argue that the balance of junctional and nuclear beta-catenin activity has a profound impact on tumor progression in this basal model of ErbB2-positive breast cancer. PMID- 28096337 TI - Stress granule-associated protein G3BP2 regulates breast tumor initiation. AB - Breast tumors contain tumorigenic cancer cells, termed "tumor-initiating cells" (TICs), which are capable of both replenishing themselves and giving rise to populations of nontumorigenic breast cancer cells (non-TICs). However, the molecular mechanisms responsible for breast tumor initiation remain poorly understood. Here we describe a chemical screening strategy to identify small molecules that enhance the effect of chemotherapeutic agents on TIC-enriched breast cancer cells. We identified proteins that interact with the lead compound C108, including the stress granule-associated protein, GTPase-activating protein (SH3 domain)-binding protein 2, G3BP2. G3BP2 regulates breast tumor initiation through the stabilization of Squamous cell carcinoma antigen recognized by T cells 3 (SART3) mRNA, which leads to increased expression of the pluripotency transcription factors Octamer-binding protein 4 (Oct-4) and Nanog Homeobox (Nanog). Our findings suggest that G3BP2 is important for the process of breast cancer initiation. Furthermore, these data suggest a possible connection between stress granule formation and tumor initiation in breast cancer cells. PMID- 28096338 TI - Mitochondrial fusion dynamics is robust in the heart and depends on calcium oscillations and contractile activity. AB - Mitochondrial fusion is thought to be important for supporting cardiac contractility, but is hardly detectable in cultured cardiomyocytes and is difficult to directly evaluate in the heart. We overcame this obstacle through in vivo adenoviral transduction with matrix-targeted photoactivatable GFP and confocal microscopy. Imaging in whole rat hearts indicated mitochondrial network formation and fusion activity in ventricular cardiomyocytes. Promptly after isolation, cardiomyocytes showed extensive mitochondrial connectivity and fusion, which decayed in culture (at 24-48 h). Fusion manifested both as rapid content mixing events between adjacent organelles and slower events between both neighboring and distant mitochondria. Loss of fusion in culture likely results from the decline in calcium oscillations/contractile activity and mitofusin 1 (Mfn1), because (i) verapamil suppressed both contraction and mitochondrial fusion, (ii) after spontaneous contraction or short-term field stimulation fusion activity increased in cardiomyocytes, and (iii) ryanodine receptor-2-mediated calcium oscillations increased fusion activity in HEK293 cells and complementing changes occurred in Mfn1. Weakened cardiac contractility in vivo in alcoholic animals is also associated with depressed mitochondrial fusion. Thus, attenuated mitochondrial fusion might contribute to the pathogenesis of cardiomyopathy. PMID- 28096339 TI - Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism. AB - Cholesterol is important for normal brain function. The brain synthesizes its own cholesterol, presumably in astrocytes. We have previously shown that diabetes results in decreased brain cholesterol synthesis by a reduction in sterol regulatory element-binding protein 2 (SREBP2)-regulated transcription. Here we show that coculture of control astrocytes with neurons enhances neurite outgrowth, and this is reduced with SREBP2 knockdown astrocytes. In vivo, mice with knockout of SREBP2 in astrocytes have impaired brain development and behavioral and motor defects. These mice also have altered energy balance, altered body composition, and a shift in metabolism toward carbohydrate oxidation driven by increased glucose oxidation by the brain. Thus, SREBP2-mediated cholesterol synthesis in astrocytes plays an important role in brain and neuronal development and function, and altered brain cholesterol synthesis may contribute to the interaction between metabolic diseases, such as diabetes and altered brain function. PMID- 28096340 TI - Evolution of antibiotic resistance is linked to any genetic mechanism affecting bacterial duration of carriage. AB - Understanding how changes in antibiotic consumption affect the prevalence of antibiotic resistance in bacterial pathogens is important for public health. In a number of bacterial species, including Streptococcus pneumoniae, the prevalence of resistance has remained relatively stable despite prolonged selection pressure from antibiotics. The evolutionary processes allowing the robust coexistence of antibiotic sensitive and resistant strains are not fully understood. While allelic diversity can be maintained at a locus by direct balancing selection, there is no evidence for such selection acting in the case of resistance. In this work, we propose a mechanism for maintaining coexistence at the resistance locus: linkage to a second locus that is under balancing selection and that modulates the fitness effect of resistance. We show that duration of carriage plays such a role, with long duration of carriage increasing the fitness advantage gained from resistance. We therefore predict that resistance will be more common in strains with a long duration of carriage and that mechanisms maintaining diversity in duration of carriage will also maintain diversity in antibiotic resistance. We test these predictions in S. pneumoniae and find that the duration of carriage of a serotype is indeed positively correlated with the prevalence of resistance in that serotype. These findings suggest heterogeneity in duration of carriage is a partial explanation for the coexistence of sensitive and resistant strains and that factors determining bacterial duration of carriage will also affect the prevalence of resistance. PMID- 28096342 TI - Eight-coordinate fluoride in a silicate double-four-ring. AB - Fluoride, nature's smallest anion, is capable of covalently coordinating to eight silicon atoms. The setting is a simple and common motif in zeolite chemistry: the box-shaped silicate double-four-ring (D4R). Fluoride seeks its center. It is the strain of box deformation that keeps fluoride in the middle of the box, and freezes what would be a transition state in its absence. Hypervalent bonding ensues. Fluoride's compactness works to its advantage in stabilizing the cage; chloride, bromide, and iodide do not bring about stabilization due to greater steric repulsion with the box frame. The combination of strain and hypervalent bonding, and the way they work in concert to yield this unusual case of multiple hypervalence, has potential for extension to a broader range of solid-state compounds. PMID- 28096341 TI - Harmonic template neurons in primate auditory cortex underlying complex sound processing. AB - Harmonicity is a fundamental element of music, speech, and animal vocalizations. How the auditory system extracts harmonic structures embedded in complex sounds and uses them to form a coherent unitary entity is not fully understood. Despite the prevalence of sounds rich in harmonic structures in our everyday hearing environment, it has remained largely unknown what neural mechanisms are used by the primate auditory cortex to extract these biologically important acoustic structures. In this study, we discovered a unique class of harmonic template neurons in the core region of auditory cortex of a highly vocal New World primate, the common marmoset (Callithrix jacchus), across the entire hearing frequency range. Marmosets have a rich vocal repertoire and a similar hearing range to that of humans. Responses of these neurons show nonlinear facilitation to harmonic complex sounds over inharmonic sounds, selectivity for particular harmonic structures beyond two-tone combinations, and sensitivity to harmonic number and spectral regularity. Our findings suggest that the harmonic template neurons in auditory cortex may play an important role in processing sounds with harmonic structures, such as animal vocalizations, human speech, and music. PMID- 28096343 TI - Profile of David J. Thouless, J. Michael Kosterlitz, and F. Duncan M. Haldane, 2016 Nobel Laureates in Physics. PMID- 28096344 TI - Atrial natriuretic peptide regulates adipose tissue accumulation in adult atria. AB - The abundance of epicardial adipose tissue (EAT) is associated with atrial fibrillation (AF), the most frequent cardiac arrhythmia. However, both the origin and the factors involved in EAT expansion are unknown. Here, we found that adult human atrial epicardial cells were highly adipogenic through an epithelial mesenchymal transition both in vitro and in vivo. In a genetic lineage tracing the WT1CreERT2+/-RosatdT+/- mouse model subjected to a high-fat diet, adipocytes of atrial EAT derived from a subset of epicardial progenitors. Atrial myocardium secretome induces the adipogenic differentiation of adult mesenchymal epicardium derived cells by modulating the balance between mesenchymal Wingless-type Mouse Mammary Tumor Virus integration site family, member 10B (Wnt10b)/beta-catenin and adipogenic ERK/MAPK signaling pathways. The adipogenic property of the atrial secretome was enhanced in AF patients. The atrial natriuretic peptide secreted by atrial myocytes is a major adipogenic factor operating at a low concentration by binding to its natriuretic peptide receptor A (NPRA) receptor and, in turn, by activating a cGMP-dependent pathway. Hence, our data indicate cross-talk between EAT expansion and mechanical function of the atrial myocardium. PMID- 28096345 TI - The NBS-LRR architectures of plant R-proteins and metazoan NLRs evolved in independent events. AB - There are intriguing parallels between plants and animals, with respect to the structures of their innate immune receptors, that suggest universal principles of innate immunity. The cytosolic nucleotide binding site-leucine rich repeat (NBS LRR) resistance proteins of plants (R-proteins) and the so-called NOD-like receptors of animals (NLRs) share a domain architecture that includes a STAND (signal transduction ATPases with numerous domains) family NTPase followed by a series of LRRs, suggesting inheritance from a common ancestor with that architecture. Focusing on the STAND NTPases of plant R-proteins, animal NLRs, and their homologs that represent the NB-ARC (nucleotide-binding adaptor shared by APAF-1, certain R gene products and CED-4) and NACHT (named for NAIP, CIIA, HET E, and TEP1) subfamilies of the STAND NTPases, we analyzed the phylogenetic distribution of the NBS-LRR domain architecture, used maximum-likelihood methods to infer a phylogeny of the NTPase domains of R-proteins, and reconstructed the domain structure of the protein containing the common ancestor of the STAND NTPase domain of R-proteins and NLRs. Our analyses reject monophyly of plant R proteins and NLRs and suggest that the protein containing the last common ancestor of the STAND NTPases of plant R-proteins and animal NLRs (and, by extension, all NB-ARC and NACHT domains) possessed a domain structure that included a STAND NTPase paired with a series of tetratricopeptide repeats. These analyses reject the hypothesis that the domain architecture of R-proteins and NLRs was inherited from a common ancestor and instead suggest the domain architecture evolved at least twice. It remains unclear whether the NBS-LRR architectures were innovations of plants and animals themselves or were acquired by one or both lineages through horizontal gene transfer. PMID- 28096346 TI - Conserved GTPase LepA (Elongation Factor 4) functions in biogenesis of the 30S subunit of the 70S ribosome. AB - The physiological role of LepA, a paralog of EF-G found in all bacteria, has been a mystery for decades. Here, we show that LepA functions in ribosome biogenesis. In cells lacking LepA, immature 30S particles accumulate. Four proteins are specifically underrepresented in these particles-S3, S10, S14, and S21-all of which bind late in the assembly process and contribute to the folding of the 3' domain of 16S rRNA. Processing of 16S rRNA is also delayed in the mutant strain, as indicated by increased levels of precursor 17S rRNA in assembly intermediates. Mutation DeltalepA confers a synthetic growth phenotype in absence of RsgA, another GTPase, well known to act in 30S subunit assembly. Analysis of the DeltarsgA strain reveals accumulation of intermediates that resemble those seen in the absence of LepA. These data suggest that RsgA and LepA play partially redundant roles to ensure efficient 30S assembly. PMID- 28096347 TI - Human transposon insertion profiling: Analysis, visualization and identification of somatic LINE-1 insertions in ovarian cancer. AB - Mammalian genomes are replete with interspersed repeats reflecting the activity of transposable elements. These mobile DNAs are self-propagating, and their continued transposition is a source of both heritable structural variation as well as somatic mutation in human genomes. Tailored approaches to map these sequences are useful to identify insertion alleles. Here, we describe in detail a strategy to amplify and sequence long interspersed element-1 (LINE-1, L1) retrotransposon insertions selectively in the human genome, transposon insertion profiling by next-generation sequencing (TIPseq). We also report the development of a machine-learning-based computational pipeline, TIPseqHunter, to identify insertion sites with high precision and reliability. We demonstrate the utility of this approach to detect somatic retrotransposition events in high-grade ovarian serous carcinoma. PMID- 28096348 TI - Transcriptomic, proteomic, and metabolomic landscape of positional memory in the caudal fin of zebrafish. AB - Regeneration requires cells to regulate proliferation and patterning according to their spatial position. Positional memory is a property that enables regenerating cells to recall spatial information from the uninjured tissue. Positional memory is hypothesized to rely on gradients of molecules, few of which have been identified. Here, we quantified the global abundance of transcripts, proteins, and metabolites along the proximodistal axis of caudal fins of uninjured and regenerating adult zebrafish. Using this approach, we uncovered complex overlapping expression patterns for hundreds of molecules involved in diverse cellular functions, including development, bioelectric signaling, and amino acid and lipid metabolism. Moreover, 32 genes differentially expressed at the RNA level had concomitant differential expression of the encoded proteins. Thus, the identification of proximodistal differences in levels of RNAs, proteins, and metabolites will facilitate future functional studies of positional memory during appendage regeneration. PMID- 28096349 TI - Structure of eukaryotic CMG helicase at a replication fork and implications to replisome architecture and origin initiation. AB - The eukaryotic CMG (Cdc45, Mcm2-7, GINS) helicase consists of the Mcm2-7 hexameric ring along with five accessory factors. The Mcm2-7 heterohexamer, like other hexameric helicases, is shaped like a ring with two tiers, an N-tier ring composed of the N-terminal domains, and a C-tier of C-terminal domains; the C tier contains the motor. In principle, either tier could translocate ahead of the other during movement on DNA. We have used cryo-EM single-particle 3D reconstruction to solve the structure of CMG in complex with a DNA fork. The duplex stem penetrates into the central channel of the N-tier and the unwound leading single-strand DNA traverses the channel through the N-tier into the C tier motor, 5'-3' through CMG. Therefore, the N-tier ring is pushed ahead by the C-tier ring during CMG translocation, opposite the currently accepted polarity. The polarity of the N-tier ahead of the C-tier places the leading Pol epsilon below CMG and Pol alpha-primase at the top of CMG at the replication fork. Surprisingly, the new N-tier to C-tier polarity of translocation reveals an unforeseen quality-control mechanism at the origin. Thus, upon assembly of head to-head CMGs that encircle double-stranded DNA at the origin, the two CMGs must pass one another to leave the origin and both must remodel onto opposite strands of single-stranded DNA to do so. We propose that head-to-head motors may generate energy that underlies initial melting at the origin. PMID- 28096350 TI - Combating Parkinson's disease-associated toxicity by modulating proteostasis. PMID- 28096352 TI - Recognition of protein-linked glycans as a determinant of peptidase activity. AB - The vast majority of proteins are posttranslationally altered, with the addition of covalently linked sugars (glycosylation) being one of the most abundant modifications. However, despite the hydrolysis of protein peptide bonds by peptidases being a process essential to all life on Earth, the fundamental details of how peptidases accommodate posttranslational modifications, including glycosylation, has not been addressed. Through biochemical analyses and X-ray crystallographic structures we show that to hydrolyze their substrates, three structurally related metallopeptidases require the specific recognition of O linked glycan modifications via carbohydrate-specific subsites immediately adjacent to their peptidase catalytic machinery. The three peptidases showed selectivity for different glycans, revealing protein-specific adaptations to particular glycan modifications, yet always cleaved the peptide bond immediately preceding the glycosylated residue. This insight builds upon the paradigm of how peptidases recognize substrates and provides a molecular understanding of glycoprotein degradation. PMID- 28096351 TI - Uncovering hidden variation in polyploid wheat. AB - Comprehensive reverse genetic resources, which have been key to understanding gene function in diploid model organisms, are missing in many polyploid crops. Young polyploid species such as wheat, which was domesticated less than 10,000 y ago, have high levels of sequence identity among subgenomes that mask the effects of recessive alleles. Such redundancy reduces the probability of selection of favorable mutations during natural or human selection, but also allows wheat to tolerate high densities of induced mutations. Here we exploited this property to sequence and catalog more than 10 million mutations in the protein-coding regions of 2,735 mutant lines of tetraploid and hexaploid wheat. We detected, on average, 2,705 and 5,351 mutations per tetraploid and hexaploid line, respectively, which resulted in 35-40 mutations per kb in each population. With these mutation densities, we identified an average of 23-24 missense and truncation alleles per gene, with at least one truncation or deleterious missense mutation in more than 90% of the captured wheat genes per population. This public collection of mutant seed stocks and sequence data enables rapid identification of mutations in the different copies of the wheat genes, which can be combined to uncover previously hidden variation. Polyploidy is a central phenomenon in plant evolution, and many crop species have undergone recent genome duplication events. Therefore, the general strategy and methods developed herein can benefit other polyploid crops. PMID- 28096353 TI - High Coulombic efficiency aluminum-ion battery using an AlCl3-urea ionic liquid analog electrolyte. AB - In recent years, impressive advances in harvesting renewable energy have led to a pressing demand for the complimentary energy storage technology. Here, a high Coulombic efficiency (~99.7%) Al battery is developed using earth-abundant aluminum as the anode, graphite as the cathode, and a cheap ionic liquid analog electrolyte made from a mixture of AlCl3 and urea in a 1.3:1 molar ratio. The battery displays discharge voltage plateaus around 1.9 and 1.5 V (average discharge = 1.73 V) and yielded a specific cathode capacity of ~73 mAh g-1 at a current density of 100 mA g-1 (~1.4 C). High Coulombic efficiency over a range of charge-discharge rates and stability over ~150-200 cycles was easily demonstrated. In situ Raman spectroscopy clearly showed chloroaluminate anion intercalation/deintercalation of graphite (positive electrode) during charge discharge and suggested the formation of a stage 2 graphite intercalation compound when fully charged. Raman spectroscopy and NMR suggested the existence of AlCl4-, Al2Cl7- anions and [AlCl2.(urea)n]+ cations in the AlCl3/urea electrolyte when an excess of AlCl3 was present. Aluminum deposition therefore proceeded through two pathways, one involving Al2Cl7- anions and the other involving [AlCl2.(urea)n]+ cations. This battery is a promising prospect for a future high-performance, low-cost energy storage device. PMID- 28096354 TI - Loss of GET pathway orthologs in Arabidopsis thaliana causes root hair growth defects and affects SNARE abundance. AB - Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins are key players in cellular trafficking and coordinate vital cellular processes, such as cytokinesis, pathogen defense, and ion transport regulation. With few exceptions, SNAREs are tail-anchored (TA) proteins, bearing a C-terminal hydrophobic domain that is essential for their membrane integration. Recently, the Guided Entry of Tail-anchored proteins (GET) pathway was described in mammalian and yeast cells that serve as a blueprint of TA protein insertion [Schuldiner M, et al. (2008) Cell 134(4):634-645; Stefanovic S, Hegde RS (2007) Cell 128(6):1147-1159]. This pathway consists of six proteins, with the cytosolic ATPase GET3 chaperoning the newly synthesized TA protein posttranslationally from the ribosome to the endoplasmic reticulum (ER) membrane. Structural and biochemical insights confirmed the potential of pathway components to facilitate membrane insertion, but the physiological significance in multicellular organisms remains to be resolved. Our phylogenetic analysis of 37 GET3 orthologs from 18 different species revealed the presence of two different GET3 clades. We identified and analyzed GET pathway components in Arabidopsis thaliana and found reduced root hair elongation in Atget lines, possibly as a result of reduced SNARE biogenesis. Overexpression of AtGET3a in a receptor knockout (KO) results in severe growth defects, suggesting presence of alternative insertion pathways while highlighting an intricate involvement for the GET pathway in cellular homeostasis of plants. PMID- 28096355 TI - A natural product inhibits the initiation of alpha-synuclein aggregation and suppresses its toxicity. AB - The self-assembly of alpha-synuclein is closely associated with Parkinson's disease and related syndromes. We show that squalamine, a natural product with known anticancer and antiviral activity, dramatically affects alpha-synuclein aggregation in vitro and in vivo. We elucidate the mechanism of action of squalamine by investigating its interaction with lipid vesicles, which are known to stimulate nucleation, and find that this compound displaces alpha-synuclein from the surfaces of such vesicles, thereby blocking the first steps in its aggregation process. We also show that squalamine almost completely suppresses the toxicity of alpha-synuclein oligomers in human neuroblastoma cells by inhibiting their interactions with lipid membranes. We further examine the effects of squalamine in a Caenorhabditis elegans strain overexpressing alpha synuclein, observing a dramatic reduction of alpha-synuclein aggregation and an almost complete elimination of muscle paralysis. These findings suggest that squalamine could be a means of therapeutic intervention in Parkinson's disease and related conditions. PMID- 28096356 TI - Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner. AB - Necroptosis is a physiological cell suicide mechanism initiated by receptor interacting protein kinase-3 (RIPK3) phosphorylation of mixed-lineage kinase domain-like protein (MLKL), which results in disruption of the plasma membrane. Necroptotic cell lysis, and resultant release of proinflammatory mediators, is thought to cause inflammation in necroptotic disease models. However, we previously showed that MLKL signaling can also promote inflammation by activating the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome to recruit the adaptor protein apoptosis-associated speck like protein containing a caspase activation and recruitment domain (ASC) and trigger caspase-1 processing of the proinflammatory cytokine IL-1beta. Here, we provide evidence that MLKL-induced activation of NLRP3 requires (i) the death effector four-helical bundle of MLKL, (ii) oligomerization and association of MLKL with cellular membranes, and (iii) a reduction in intracellular potassium concentration. Although genetic or pharmacological targeting of NLRP3 or caspase 1 prevented MLKL-induced IL-1beta secretion, they did not prevent necroptotic cell death. Gasdermin D (GSDMD), the pore-forming caspase-1 substrate required for efficient NLRP3-triggered pyroptosis and IL-1beta release, was not essential for MLKL-dependent death or IL-1beta secretion. Imaging of MLKL-dependent ASC speck formation demonstrated that necroptotic stimuli activate NLRP3 cell intrinsically, indicating that MLKL-induced NLRP3 inflammasome formation and IL 1beta cleavage occur before cell lysis. Furthermore, we show that necroptotic activation of NLRP3, but not necroptotic cell death alone, is necessary for the activation of NF-kappaB in healthy bystander cells. Collectively, these results demonstrate the potential importance of NLRP3 inflammasome activity as a driving force for inflammation in MLKL-dependent diseases. PMID- 28096357 TI - Prion replication without host adaptation during interspecies transmissions. AB - Adaptation of prions to new species is thought to reflect the capacity of the host-encoded cellular form of the prion protein (PrPC) to selectively propagate optimized prion conformations from larger ensembles generated in the species of origin. Here we describe an alternate replicative process, termed nonadaptive prion amplification (NAPA), in which dominant conformers bypass this requirement during particular interspecies transmissions. To model susceptibility of horses to prions, we produced transgenic (Tg) mice expressing cognate PrPC Although disease transmission to only a subset of infected TgEq indicated a significant barrier to EqPrPC conversion, the resulting horse prions unexpectedly failed to cause disease upon further passage to TgEq. TgD expressing deer PrPC was similarly refractory to deer prions from diseased TgD infected with mink prions. In both cases, the resulting prions transmitted to mice expressing PrPC from the species of prion origin, demonstrating that transmission barrier eradication of the originating prions was ephemeral and adaptation superficial in TgEq and TgD. Horse prions produced in vitro by protein misfolding cyclic amplification of mouse prions using horse PrPC also failed to infect TgEq but retained tropism for wild-type mice. Concordant patterns of neuropathology and prion deposition in susceptible mice infected with NAPA prions and the corresponding prion of origin confirmed preservation of strain properties. The comparable responses of both prion types to guanidine hydrochloride denaturation indicated this occurs because NAPA precludes selection of novel prion conformations. Our findings provide insights into mechanisms regulating interspecies prion transmission and a framework to reconcile puzzling epidemiological features of certain prion disorders. PMID- 28096358 TI - Repair shielding of platinum-DNA lesions in testicular germ cell tumors by high mobility group box protein 4 imparts cisplatin hypersensitivity. AB - Cisplatin is the most commonly used anticancer drug for the treatment of testicular germ cell tumors (TGCTs). The hypersensitivity of TGCTs to cisplatin is a subject of widespread interest. Here, we show that high-mobility group box protein 4 (HMGB4), a protein preferentially expressed in testes, uniquely blocks excision repair of cisplatin-DNA adducts, 1,2-intrastrand cross-links, to potentiate the sensitivity of TGCTs to cisplatin therapy. We used CRISPR/Cas9 mediated gene editing to knockout the HMGB4 gene in a testicular human embryonic carcinoma and examined cellular responses. We find that loss of HMGB4 elicits resistance to cisplatin as evidenced by cell proliferation and apoptosis assays. We demonstrate that HMGB4 specifically inhibits repair of the major cisplatin-DNA adducts in TGCT cells by using the human TGCT excision repair system. Our findings also reveal characteristic HMGB4-dependent differences in cell cycle progression following cisplatin treatment. Collectively, these data provide convincing evidence that HMGB4 plays a major role in sensitizing TGCTs to cisplatin, consistent with shielding of platinum-DNA adducts from excision repair. PMID- 28096359 TI - alpha-Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering dopaminergic cell death via AMPK hyperactivation. AB - The abnormal aggregation of fibrillar alpha-synuclein in Lewy bodies plays a critical role in the pathogenesis of Parkinson's disease. However, the molecular mechanisms regulating alpha-synuclein pathological effects are incompletely understood. Here we show that alpha-synuclein binds phosphoinositide-3 kinase enhancer L (PIKE-L) in a phosphorylation-dependent manner and sequesters it in Lewy bodies, leading to dopaminergic cell death via AMP-activated protein kinase (AMPK) hyperactivation. alpha-Synuclein interacts with PIKE-L, an AMPK inhibitory binding partner, and this action is increased by S129 phosphorylation through AMPK and is decreased by Y125 phosphorylation via Src family kinase Fyn. A pleckstrin homology (PH) domain in PIKE-L directly binds alpha-synuclein and antagonizes its aggregation. Accordingly, PIKE-L overexpression decreases dopaminergic cell death elicited by 1-methyl-4-phenylpyridinium (MPP+), whereas PIKE-L knockdown elevates alpha-synuclein oligomerization and cell death. The overexpression of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or alpha synuclein induces greater dopaminergic cell loss and more severe motor defects in PIKE-KO and Fyn-KO mice than in wild-type mice, and these effects are attenuated by the expression of dominant-negative AMPK. Hence, our findings demonstrate that alpha-synuclein neutralizes PIKE-L's neuroprotective actions in synucleinopathies, triggering dopaminergic neuronal death by hyperactivating AMPK. PMID- 28096361 TI - Thermal-driven domain and cargo transport in lipid membranes. AB - Domain migration is observed on the surface of ternary giant unilamellar vesicles held in a temperature gradient in conditions where they exhibit coexistence of two liquid phases. The migration localizes domains to the hot side of the vesicle, regardless of whether the domain is composed of the more ordered or disordered phase and regardless of the proximity to chamber boundaries. The distribution of domains is explored for domains that coarsen and for those held apart due to long-range repulsions. After considering several potential mechanisms for the migration, including the temperature preferences for each lipid, the favored curvature for each phase, and the thermophoretic flow around the vesicle, we show that observations are consistent with the general process of minimizing the system's line tension energy, because of the lowering of line interface energy closer to mixing. DNA strands, attached to the lipid bilayer with cholesterol anchors, act as an exemplar "cargo," demonstrating that the directed motion of domains toward higher temperatures provides a route to relocate species that preferentially reside in the domains. PMID- 28096360 TI - Measurement of cortical elasticity in Drosophila melanogaster embryos using ferrofluids. AB - Many models of morphogenesis are forced to assume specific mechanical properties of cells, because the actual mechanical properties of living tissues are largely unknown. Here, we measure the rheology of epithelial cells in the cellularizing Drosophila embryo by injecting magnetic particles and studying their response to external actuation. We establish that, on timescales relevant to epithelial morphogenesis, the cytoplasm is predominantly viscous, whereas the cellular cortex is elastic. The timescale of elastic stress relaxation has a lower bound of 4 min, which is comparable to the time required for internalization of the ventral furrow during gastrulation. The cytoplasm was measured to be ~103-fold as viscous as water. We show that elasticity depends on the actin cytoskeleton and conclude by discussing how these results relate to existing mechanical models of morphogenesis. PMID- 28096362 TI - Catalytic oxidation of Li2S on the surface of metal sulfides for Li-S batteries. AB - Polysulfide binding and trapping to prevent dissolution into the electrolyte by a variety of materials has been well studied in Li-S batteries. Here we discover that some of those materials can play an important role as an activation catalyst to facilitate oxidation of the discharge product, Li2S, back to the charge product, sulfur. Combining theoretical calculations and experimental design, we select a series of metal sulfides as a model system to identify the key parameters in determining the energy barrier for Li2S oxidation and polysulfide adsorption. We demonstrate that the Li2S decomposition energy barrier is associated with the binding between isolated Li ions and the sulfur in sulfides; this is the main reason that sulfide materials can induce lower overpotential compared with commonly used carbon materials. Fundamental understanding of this reaction process is a crucial step toward rational design and screening of materials to achieve high reversible capacity and long cycle life in Li-S batteries. PMID- 28096364 TI - Bilateral recruitment of prefrontal cortex in working memory is associated with task demand but not with age. AB - Elderly adults may master challenging cognitive demands by additionally recruiting the cross-hemispheric counterparts of otherwise unilaterally engaged brain regions, a strategy that seems to be at odds with the notion of lateralized functions in cerebral cortex. We wondered whether bilateral activation might be a general coping strategy that is independent of age, task content and brain region. While using functional magnetic resonance imaging (fMRI), we pushed young and old subjects to their working memory (WM) capacity limits in verbal, spatial, and object domains. Then, we compared the fMRI signal reflecting WM maintenance between hemispheric counterparts of various task-relevant cerebral regions that are known to exhibit lateralization. Whereas language-related areas kept their lateralized activation pattern independent of age in difficult tasks, we observed bilaterality in dorsolateral and anterior prefrontal cortex across WM domains and age groups. In summary, the additional recruitment of cross-hemispheric counterparts seems to be an age-independent domain-general strategy to master cognitive challenges. This phenomenon is largely confined to prefrontal cortex, which is arguably less specialized and more flexible than other parts of the brain. PMID- 28096363 TI - An RNA-based signature enables high specificity detection of circulating tumor cells in hepatocellular carcinoma. AB - Circulating tumor cells (CTCs) are shed into the bloodstream by invasive cancers, but the difficulty inherent in identifying these rare cells by microscopy has precluded their routine use in monitoring or screening for cancer. We recently described a high-throughput microfluidic CTC-iChip, which efficiently depletes hematopoietic cells from blood specimens and enriches for CTCs with well preserved RNA. Application of RNA-based digital PCR to detect CTC-derived signatures may thus enable highly accurate tissue lineage-based cancer detection in blood specimens. As proof of principle, we examined hepatocellular carcinoma (HCC), a cancer that is derived from liver cells bearing a unique gene expression profile. After identifying a digital signature of 10 liver-specific transcripts, we used a cross-validated logistic regression model to identify the presence of HCC-derived CTCs in nine of 16 (56%) untreated patients with HCC versus one of 31 (3%) patients with nonmalignant liver disease at risk for developing HCC (P < 0.0001). Positive CTC scores declined in treated patients: Nine of 32 (28%) patients receiving therapy and only one of 15 (7%) patients who had undergone curative-intent ablation, surgery, or liver transplantation were positive. RNA based digital CTC scoring was not correlated with the standard HCC serum protein marker alpha fetoprotein (P = 0.57). Modeling the sequential use of these two orthogonal markers for liver cancer screening in patients with high-risk cirrhosis generates positive and negative predictive values of 80% and 86%, respectively. Thus, digital RNA quantitation constitutes a sensitive and specific CTC readout, enabling high-throughput clinical applications, such as noninvasive screening for HCC in populations where viral hepatitis and cirrhosis are prevalent. PMID- 28096366 TI - Iron isotopes reveal distinct dissolved iron sources and pathways in the intermediate versus deep Southern Ocean. AB - As an essential micronutrient, iron plays a key role in oceanic biogeochemistry. It is therefore linked to the global carbon cycle and climate. Here, we report a dissolved iron (DFe) isotope section in the South Atlantic and Southern Ocean. Throughout the section, a striking DFe isotope minimum (light iron) is observed at intermediate depths (200-1,300 m), contrasting with heavier isotopic composition in deep waters. This unambiguously demonstrates distinct DFe sources and processes dominating the iron cycle in the intermediate and deep layers, a feature impossible to see with only iron concentration data largely used thus far in chemical oceanography. At intermediate depths, the data suggest that the dominant DFe sources are linked to organic matter remineralization, either in the water column or at continental margins. In deeper layers, however, abiotic non reductive release of Fe (desorption, dissolution) from particulate iron-notably lithogenic-likely dominates. These results go against the common but oversimplified view that remineralization of organic matter is the major pathway releasing DFe throughout the water column in the open ocean. They suggest that the oceanic iron cycle, and therefore oceanic primary production and climate, could be more sensitive than previously thought to continental erosion (providing lithogenic particles to the ocean), particle transport within the ocean, dissolved/particle interactions, and deep water upwelling. These processes could also impact the cycles of other elements, including nutrients. PMID- 28096365 TI - Unlocking Tn3-family transposase activity in vitro unveils an asymetric pathway for transposome assembly. AB - The Tn3 family is a widespread group of replicative transposons that are notorious for their contribution to the dissemination of antibiotic resistance and the emergence of multiresistant pathogens worldwide. The TnpA transposase of these elements catalyzes DNA breakage and rejoining reactions required for transposition. It also is responsible for target immunity, a phenomenon that prevents multiple insertions of the transposon into the same genomic region. However, the molecular mechanisms whereby TnpA acts in both processes remain unknown. Here, we have developed sensitive biochemical assays for the TnpA transposase of the Tn3-family transposon Tn4430 and used these assays to characterize previously isolated TnpA mutants that are selectively affected in immunity. Compared with wild-type TnpA, these mutants exhibit deregulated activities. They spontaneously assemble a unique asymmetric synaptic complex in which one TnpA molecule simultaneously binds two transposon ends. In this complex, TnpA is in an activated state competent for DNA cleavage and strand transfer. Wild-type TnpA can form this complex only on precleaved ends mimicking the initial step of transposition. The data suggest that transposition is controlled at an early stage of transpososome assembly, before DNA cleavage, and that mutations affecting immunity have unlocked TnpA by stabilizing the protein in a monomeric activated synaptic configuration. We propose an asymmetric pathway for coupling active transpososome assembly with proper target recruitment and discuss this model with respect to possible immunity mechanisms. PMID- 28096367 TI - Zero-index structures as an alternative platform for quantum optics. AB - Vacuum fluctuations are one of the most distinctive aspects of quantum optics, being the trigger of multiple nonclassical phenomena. Thus, platforms like resonant cavities and photonic crystals that enable the inhibition and manipulation of vacuum fluctuations have been key to our ability to control light matter interactions (e.g., the decay of quantum emitters). Here, we theoretically demonstrate that vacuum fluctuations may be naturally inhibited within bodies immersed in epsilon-and-mu-near-zero (EMNZ) media, while they can also be selectively excited via bound eigenmodes. Therefore, zero-index structures are proposed as an alternative platform to manipulate the decay of quantum emitters, possibly leading to the exploration of qualitatively different dynamics. For example, a direct modulation of the vacuum Rabi frequency is obtained by deforming the EMNZ region without detuning a bound eigenmode. Ideas for the possible implementation of these concepts using synthetic implementations based on structural dispersion are also proposed. PMID- 28096368 TI - Elemental sulfur aerosol-forming mechanism. AB - Elemental sulfur aerosols are ubiquitous in the atmospheres of Venus, ancient Earth, and Mars. There is now an evolving body of evidence suggesting that these aerosols have also played a role in the evolution of early life on Earth. However, the exact details of their formation mechanism remain an open question. The present theoretical calculations suggest a chemical mechanism that takes advantage of the interaction between sulfur oxides, SOn (n = 1, 2, 3) and hydrogen sulfide (nH2S), resulting in the efficient formation of a Sn+1 particle. Interestingly, the SOn + nH2S -> Sn+1 + nH2O reactions occur via low-energy pathways under water or sulfuric acid catalysis. Once the Sn+1 particles are formed, they may further nucleate to form larger polysulfur aerosols, thus providing a chemical framework for understanding the formation mechanism of S0 aerosols in different environments. PMID- 28096369 TI - Reply to Datchi et al.: Recovered phase CO2-V at low temperature and a newly predicted 3D-extended CO2 phase. PMID- 28096370 TI - Polymeric phase V of carbon dioxide has not been recovered at ambient pressure and has a unique structure. PMID- 28096371 TI - COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells. AB - In recent years, it has been established that programmed cell death protein ligand 1 (PD-L1)-mediated inhibition of activated PD-1+ T lymphocytes plays a major role in tumor escape from immune system during cancer progression. Lately, the anti-PD-L1 and -PD-1 immune therapies have become an important tool for treatment of advanced human cancers, including bladder cancer. However, the underlying mechanisms of PD-L1 expression in cancer are not fully understood. We found that coculture of murine bone marrow cells with bladder tumor cells promoted strong expression of PD-L1 in bone marrow-derived myeloid cells. Tumor induced expression of PD-L1 was limited to F4/80+ macrophages and Ly-6C+ myeloid derived suppressor cells. These PD-L1-expressing cells were immunosuppressive and were capable of eliminating CD8 T cells in vitro. Tumor-infiltrating PD-L1+ cells isolated from tumor-bearing mice also exerted morphology of tumor-associated macrophages and expressed high levels of prostaglandin E2 (PGE2)-forming enzymes microsomal PGE2 synthase 1 (mPGES1) and COX2. Inhibition of PGE2 formation, using pharmacologic mPGES1 and COX2 inhibitors or genetic overexpression of PGE2 degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), resulted in reduced PD-L1 expression. Together, our study demonstrates that the COX2/mPGES1/PGE2 pathway involved in the regulation of PD-L1 expression in tumor infiltrating myeloid cells and, therefore, reprogramming of PGE2 metabolism in tumor microenvironment provides an opportunity to reduce immune suppression in tumor host. PMID- 28096372 TI - Helical structure, stability, and dynamics in human apolipoprotein E3 and E4 by hydrogen exchange and mass spectrometry. AB - Apolipoprotein E (apoE) plays a critical role in cholesterol transport in both peripheral circulation and brain. Human apoE is a polymorphic 299-residue protein in which the less common E4 isoform differs from the major E3 isoform only by a C112R substitution. ApoE4 interacts with lipoprotein particles and with the amyloid-beta peptide, and it is associated with increased incidence of cardiovascular and Alzheimer's disease. To understand the structural basis for the differences between apoE3 and E4 functionality, we used hydrogen-deuterium exchange coupled with a fragment separation method and mass spectrometric analysis to compare their secondary structures at near amino acid resolution. We determined the positions, dynamics, and stabilities of the helical segments in these two proteins, in their normal tetrameric state and in mutation-induced monomeric mutants. Consistent with prior X-ray crystallography and NMR results, the N-terminal domain contains four alpha-helices, 20 to 30 amino acids long. The C-terminal domain is relatively unstructured in the monomeric state but forms an alpha-helix ~70 residues long in the self-associated tetrameric state. Helix stabilities are relatively low, 4 kcal/mol to 5 kcal/mol, consistent with flexibility and facile reversible unfolding. Secondary structure in the tetrameric apoE3 and E4 isoforms is similar except that some helical segments in apoE4 spanning residues 12 to 20 and 204 to 210 are unfolded. These conformational differences result from the C112R substitution in the N-terminal helix bundle and likely relate to a reduced ability of apoE4 to form tetramers, thereby increasing the concentration of functional apoE4 monomers, which gives rise to its higher lipid binding compared with apoE3. PMID- 28096373 TI - Pathogen-mediated manipulation of arthropod microbiota to promote infection. AB - Arthropods transmit diverse infectious agents; however, the ways microbes influence their vector to enhance colonization are poorly understood. Ixodes scapularis ticks harbor numerous human pathogens, including Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis. We now demonstrate that A. phagocytophilum modifies the I. scapularis microbiota to more efficiently infect the tick. A. phagocytophilum induces ticks to express Ixodes scapularis antifreeze glycoprotein (iafgp), which encodes a protein with several properties, including the ability to alter bacterial biofilm formation. IAFGP thereby perturbs the tick gut microbiota, which influences the integrity of the peritrophic matrix and gut barrier-critical obstacles for Anaplasma colonization. Mechanistically, IAFGP binds the terminal d-alanine residue of the pentapeptide chain of bacterial peptidoglycan, resulting in altered permeability and the capacity of bacteria to form biofilms. These data elucidate the molecular mechanisms by which a human pathogen appropriates an arthropod antibacterial protein to alter the gut microbiota and more effectively colonize the vector. PMID- 28096374 TI - Phylogenetic analysis of the human antibody repertoire reveals quantitative signatures of immune senescence and aging. AB - The elderly have reduced humoral immunity, as manifested by increased susceptibility to infections and impaired vaccine responses. To investigate the effects of aging on B-cell receptor (BCR) repertoire evolution during an immunological challenge, we used a phylogenetic distance metric to analyze Ig heavy-chain transcript sequences in both young and elderly individuals before and after influenza vaccination. We determined that BCR repertoires become increasingly specialized over a span of decades, but less plastic. In 50% of the elderly individuals, a large space in the repertoire was occupied by a small number of recall lineages that did not decline during vaccine response and contained hypermutated IgD+ B cells. Relative to their younger counterparts, older subjects demonstrated a contracted naive repertoire and diminished intralineage diversification, signifying a reduced substrate for mounting novel responses and decreased fine-tuning of BCR specificities by somatic hypermutation. Furthermore, a larger proportion of the repertoire exhibited premature stop codons in some elderly subjects, indicating that aging may negatively affect the ability of B cells to discriminate between functional and nonfunctional receptors. Finally, we observed a decreased incidence of radical mutations compared with conservative mutations in elderly subjects' vaccine responses, which suggests that accumulating original antigenic sin may be limiting the accessible space for paratope evolution. Our findings shed light on the complex interplay of environmental and gerontological factors affecting immune senescence, and provide direct molecular characterization of the effects of senescence on the immune repertoire. PMID- 28096375 TI - Do guanidinium and tetrapropylammonium ions specifically interact with aromatic amino acid side chains? AB - Many ions are known to affect the activity, stability, and structural integrity of proteins. Although this effect can be generally attributed to ion-induced changes in forces that govern protein folding, delineating the underlying mechanism of action still remains challenging because it requires assessment of all relevant interactions, such as ion-protein, ion-water, and ion-ion interactions. Herein, we use two unnatural aromatic amino acids and several spectroscopic techniques to examine whether guanidinium chloride, one of the most commonly used protein denaturants, and tetrapropylammonium chloride can specifically interact with aromatic side chains. Our results show that tetrapropylammonium, but not guanidinium, can preferentially accumulate around aromatic residues and that tetrapropylammonium undergoes a transition at ~1.3 M to form aggregates. We find that similar to ionic micelles, on one hand, such aggregates can disrupt native hydrophobic interactions, and on the other hand, they can promote alpha-helix formation in certain peptides. PMID- 28096376 TI - Myosin-driven transport network in plants. AB - We investigate the myosin XI-driven transport network in Arabidopsis using protein-protein interaction, subcellular localization, gene knockout, and bioinformatics analyses. The two major groups of nodes in this network are myosins XI and their membrane-anchored receptors (MyoB) that, together, drive endomembrane trafficking and cytoplasmic streaming in the plant cells. The network shows high node connectivity and is dominated by generalists, with a smaller fraction of more specialized myosins and receptors. We show that interaction with myosins and association with motile vesicles are common properties of the MyoB family receptors. We identify previously uncharacterized myosin-binding proteins, putative myosin adaptors that belong to two unrelated families, with four members each (MadA and MadB). Surprisingly, MadA1 localizes to the nucleus and is rapidly transported to the cytoplasm, suggesting the existence of myosin XI-driven nucleocytoplasmic trafficking. In contrast, MadA2 and MadA3, as well as MadB1, partition between the cytosolic pools of motile endomembrane vesicles that colocalize with myosin XI-K and diffuse material that does not. Gene knockout analysis shows that MadB1-4 contribute to polarized root hair growth, phenocopying myosins, whereas MadA1-4 are redundant for this process. Phylogenetic analysis reveals congruent evolutionary histories of the myosin XI, MyoB, MadA, and MadB families. All these gene families emerged in green algae and show concurrent expansions via serial duplication in flowering plants. Thus, the myosin XI transport network increased in complexity and robustness concomitantly with the land colonization by flowering plants and, by inference, could have been a major contributor to this process. PMID- 28096377 TI - Comparative genomics reveals convergent evolution between the bamboo-eating giant and red pandas. AB - Phenotypic convergence between distantly related taxa often mirrors adaptation to similar selective pressures and may be driven by genetic convergence. The giant panda (Ailuropoda melanoleuca) and red panda (Ailurus fulgens) belong to different families in the order Carnivora, but both have evolved a specialized bamboo diet and adaptive pseudothumb, representing a classic model of convergent evolution. However, the genetic bases of these morphological and physiological convergences remain unknown. Through de novo sequencing the red panda genome and improving the giant panda genome assembly with added data, we identified genomic signatures of convergent evolution. Limb development genes DYNC2H1 and PCNT have undergone adaptive convergence and may be important candidate genes for pseudothumb development. As evolutionary responses to a bamboo diet, adaptive convergence has occurred in genes involved in the digestion and utilization of bamboo nutrients such as essential amino acids, fatty acids, and vitamins. Similarly, the umami taste receptor gene TAS1R1 has been pseudogenized in both pandas. These findings offer insights into genetic convergence mechanisms underlying phenotypic convergence and adaptation to a specialized bamboo diet. PMID- 28096378 TI - Biosynthesis of the microtubule-destabilizing diterpene pseudolaric acid B from golden larch involves an unusual diterpene synthase. AB - The diversity of small molecules formed via plant diterpene metabolism offers a rich source of known and potentially new biopharmaceuticals. Among these, the microtubule-destabilizing activity of pseudolaric acid B (PAB) holds promise for new anticancer agents. PAB is found, perhaps uniquely, in the coniferous tree golden larch (Pseudolarix amabilis, Pxa). Here we describe the discovery and mechanistic analysis of golden larch terpene synthase 8 (PxaTPS8), an unusual diterpene synthase (diTPS) that catalyzes the first committed step in PAB biosynthesis. Mining of the golden larch root transcriptome revealed a large TPS family, including the monofunctional class I diTPS PxaTPS8, which converts geranylgeranyl diphosphate into a previously unknown 5,7-fused bicyclic diterpene, coined "pseudolaratriene." Combined NMR and quantum chemical analysis verified the structure of pseudolaratriene, and co-occurrence with PxaTPS8 and PAB in P amabilis tissues supports the intermediacy of pseudolaratriene in PAB metabolism. Although PxaTPS8 adopts the typical three-domain structure of diTPSs, sequence phylogeny places the enzyme with two-domain TPSs of mono- and sesqui terpene biosynthesis. Site-directed mutagenesis of PxaTPS8 revealed several catalytic residues that, together with quantum chemical calculations, suggested a substantial divergence of PxaTPS8 from other TPSs leading to a distinct carbocation-driven reaction mechanism en route to the 5,7-trans-fused bicyclic pseudolaratriene scaffold. PxaTPS8 expression in microbial and plant hosts provided proof of concept for metabolic engineering of pseudolaratriene. PMID- 28096379 TI - Molecular mechanism underlying juvenile hormone-mediated repression of precocious larval-adult metamorphosis. AB - Juvenile hormone (JH) represses precocious metamorphosis of larval to pupal and adult transitions in holometabolous insects. The early JH-inducible gene Kruppel homolog 1 (Kr-h1) plays a key role in the repression of metamorphosis as a mediator of JH action. Previous studies demonstrated that Kr-h1 inhibits precocious larval-pupal transition in immature larva via direct transcriptional repression of the pupal specifier Broad-Complex (BR-C). JH was recently reported to repress the adult specifier gene Ecdysone-induced protein 93F (E93); however, its mechanism of action remains unclear. Here, we found that JH suppressed ecdysone-inducible E93 expression in the epidermis of the silkworm Bombyx mori and in a B. mori cell line. Reporter assays in the cell line revealed that the JH dependent suppression was mediated by Kr-h1. Genome-wide ChIP-seq analysis identified a consensus Kr-h1 binding site (KBS, 14 bp) located in the E93 promoter region, and EMSA confirmed that Kr-h1 directly binds to the KBS. Moreover, we identified a C-terminal conserved domain in Kr-h1 essential for the transcriptional repression of E93 Based on these results, we propose a mechanism in which JH-inducible Kr-h1 directly binds to the KBS site upstream of the E93 locus to repress its transcription in a cell-autonomous manner, thereby preventing larva from bypassing the pupal stage and progressing to precocious adult development. These findings help to elucidate the molecular mechanisms regulating the metamorphic genetic network, including the functional significance of Kr-h1, BR-C, and E93 in holometabolous insect metamorphosis. PMID- 28096380 TI - In situ structure of trypanosomal ATP synthase dimer reveals a unique arrangement of catalytic subunits. AB - We used electron cryotomography and subtomogram averaging to determine the in situ structures of mitochondrial ATP synthase dimers from two organisms belonging to the phylum euglenozoa: Trypanosoma brucei, a lethal human parasite, and Euglena gracilis, a photosynthetic protist. At a resolution of 32.5 A and 27.5 A, respectively, the two structures clearly exhibit a noncanonical F1 head, in which the catalytic (alphabeta)3 assembly forms a triangular pyramid rather than the pseudo-sixfold ring arrangement typical of all other ATP synthases investigated so far. Fitting of known X-ray structures reveals that this unusual geometry results from a phylum-specific cleavage of the alpha subunit, in which the C terminal alphaC fragments are displaced by ~20 A and rotated by ~30 degrees from their expected positions. In this location, the alphaC fragment is unable to form the conserved catalytic interface that was thought to be essential for ATP synthesis, and cannot convert gamma-subunit rotation into the conformational changes implicit in rotary catalysis. The new arrangement of catalytic subunits suggests that the mechanism of ATP generation by rotary ATPases is less strictly conserved than has been generally assumed. The ATP synthases of these organisms present a unique model system for discerning the individual contributions of the alpha and beta subunits to the fundamental process of ATP synthesis. PMID- 28096381 TI - Scene-selective coding by single neurons in the human parahippocampal cortex. AB - Imaging, electrophysiological, and lesion studies have shown a relationship between the parahippocampal cortex (PHC) and the processing of spatial scenes. Our present knowledge of PHC, however, is restricted to the macroscopic properties and dynamics of bulk tissue; the behavior and selectivity of single parahippocampal neurons remains largely unknown. In this study, we analyzed responses from 630 parahippocampal neurons in 24 neurosurgical patients during visual stimulus presentation. We found a spatially clustered subpopulation of scene-selective units with an associated event-related field potential. These units form a population code that is more distributed for scenes than for other stimulus categories, and less sparse than elsewhere in the medial temporal lobe. Our electrophysiological findings provide insight into how individual units give rise to the population response observed with functional imaging in the parahippocampal place area. PMID- 28096382 TI - Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. AB - Although immunotherapy by PD-1 blockade has dramatically improved the survival rate of cancer patients, further improvement in efficacy is required to reduce the fraction of less sensitive patients. In mouse models of PD-1 blockade therapy, we found that tumor-reactive cytotoxic T lymphocytes (CTLs) in draining lymph nodes (DLNs) carry increased mitochondrial mass and more reactive oxygen species (ROS). We show that ROS generation by ROS precursors or indirectly by mitochondrial uncouplers synergized the tumoricidal activity of PD-1 blockade by expansion of effector/memory CTLs in DLNs and within the tumor. These CTLs carry not only the activation of mechanistic target of rapamycin (mTOR) and AMP activated protein kinase (AMPK) but also an increment of their downstream transcription factors such as PPAR-gamma coactivator 1alpha (PGC-1alpha) and T bet. Furthermore, direct activators of mTOR, AMPK, or PGC-1alpha also synergized the PD-1 blockade therapy whereas none of above-mentioned chemicals alone had any effects on tumor growth. These findings will pave a way to developing novel combinatorial therapies with PD-1 blockade. PMID- 28096383 TI - Fragility of the provision of local public goods to private and collective risks. AB - Smallholder agricultural systems, strongly dependent on water resources and investments in shared infrastructure, make a significant contribution to food security in developing countries. These communities are being increasingly integrated into the global economy and are exposed to new global climate-related risks that may affect their willingness to cooperate in community-level collective action problems. We performed field experiments on public goods with private and collective risks in 118 small-scale rice-producing communities in four countries. Our results indicate that increasing the integration of those communities with the broader economic system is associated with lower investments in public goods when facing collective risks. These findings indicate that local public good provision may be negatively affected by collective risks, especially in communities more integrated with the market economy. PMID- 28096384 TI - Holocene ENSO-related cyclic storms recorded by magnetic minerals in speleothems of central China. AB - Extreme hydrologic events such as storms and floods have the potential to severely impact modern human society. However, the frequency of storms and their underlying mechanisms are limited by a paucity of suitable proxies, especially in inland areas. Here we present a record of speleothem magnetic minerals to reconstruct paleoprecipitation, including storms, in the eastern Asian monsoon area over the last 8.6 ky. The geophysical parameter IRMsoft-flux represents the flux of soil-derived magnetic minerals preserved in stalagmite HS4, which we correlate with rainfall amount and intensity. IRMsoft-flux exhibits relatively higher values before 6.7 ky and after 3.4 ky and lower values in the intervening period, consistent with regional hydrological changes observed in independent records. Abrupt enhancements in the flux of pedogenic magnetite in the stalagmite agree well with the timing of known regional paleofloods and with equatorial El Nino-Southern Oscillation (ENSO) patterns, documenting the occurrence of ENSO related storms in the Holocene. Spectral power analyses reveal that the storms occur on a significant 500-y cycle, coincident with periodic solar activity and ENSO variance, showing that reinforced (subdued) storms in central China correspond to reduced (increased) solar activity and amplified (damped) ENSO. Thus, the magnetic minerals in speleothem HS4 preserve a record of the cyclic storms controlled by the coupled atmosphere-oceanic circulation driven by solar activity. PMID- 28096385 TI - Correction for Melo et al., Small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing. PMID- 28096386 TI - Molecular imaging of biological systems with a clickable dye in the broad 800- to 1,700-nm near-infrared window. AB - Fluorescence imaging multiplicity of biological systems is an area of intense focus, currently limited to fluorescence channels in the visible and first near infrared (NIR-I; ~700-900 nm) spectral regions. The development of conjugatable fluorophores with longer wavelength emission is highly desired to afford more targeting channels, reduce background autofluorescence, and achieve deeper tissue imaging depths. We have developed NIR-II (1,000-1,700 nm) molecular imaging agents with a bright NIR-II fluorophore through high-efficiency click chemistry to specific molecular antibodies. Relying on buoyant density differences during density gradient ultracentrifugation separations, highly pure NIR-II fluorophore antibody conjugates emitting ~1,100 nm were obtained for use as molecular specific NIR-II probes. This facilitated 3D staining of ~170-MUm histological brain tissues sections on a home-built confocal microscope, demonstrating multicolor molecular imaging across both the NIR-I and NIR-II windows (800-1,700 nm). PMID- 28096387 TI - Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease. AB - Although it has been known for more than 60 years that the cause of sickle cell disease is polymerization of a hemoglobin mutant, hydroxyurea is the only drug approved for treatment by the US Food and Drug Administration. This drug, however, is only partially successful, and the discovery of additional drugs that inhibit fiber formation has been hampered by the lack of a sensitive and quantitative cellular assay. Here, we describe such a method in a 96-well plate format that is based on laser-induced polymerization in sickle trait cells and robust, automated image analysis to detect the precise time at which fibers distort ("sickle") the cells. With this kinetic method, we show that small increases in cell volume to reduce the hemoglobin concentration can result in therapeutic increases in the delay time prior to fiber formation. We also show that, of the two drugs (AES103 and GBT440) in clinical trials that inhibit polymerization by increasing oxygen affinity, one of them (GBT440) also inhibits sickling in the absence of oxygen by two additional mechanisms. PMID- 28096388 TI - Competition of calcified calmodulin N lobe and PIP2 to an LQT mutation site in Kv7.1 channel. AB - Voltage-gated potassium 7.1 (Kv7.1) channel and KCNE1 protein coassembly forms the slow potassium current IKS that repolarizes the cardiac action potential. The physiological importance of the IKS channel is underscored by the existence of mutations in human Kv7.1 and KCNE1 genes, which cause cardiac arrhythmias, such as the long-QT syndrome (LQT) and atrial fibrillation. The proximal Kv7.1 C terminus (CT) binds calmodulin (CaM) and phosphatidylinositol-4,5-bisphosphate (PIP2), but the role of CaM in channel function is still unclear, and its possible interaction with PIP2 is unknown. Our recent crystallographic study showed that CaM embraces helices A and B with the apo C lobe and calcified N lobe, respectively. Here, we reveal the competition of PIP2 and the calcified CaM N lobe to a previously unidentified site in Kv7.1 helix B, also known to harbor an LQT mutation. Protein pulldown, molecular docking, molecular dynamics simulations, and patch-clamp recordings indicate that residues K526 and K527 in Kv7.1 helix B form a critical site where CaM competes with PIP2 to stabilize the channel open state. Data indicate that both PIP2 and Ca2+-CaM perform the same function on IKS channel gating by producing a left shift in the voltage dependence of activation. The LQT mutant K526E revealed a severely impaired channel function with a right shift in the voltage dependence of activation, a reduced current density, and insensitivity to gating modulation by Ca2+-CaM. The results suggest that, after receptor-mediated PIP2 depletion and increased cytosolic Ca2+, calcified CaM N lobe interacts with helix B in place of PIP2 to limit excessive IKS current inhibition. PMID- 28096389 TI - Ontogenetic and life history trait changes associated with convergent ecological specializations in extinct ungulate mammals. AB - Investigating life history traits in mammals is crucial to understand their survival in changing environments. However, these parameters are hard to estimate in a macroevolutionary context. Here we show that the use of dental ontogenetic parameters can provide clues to better understand the adaptive nature of phenotypic traits in extinct species such as South American notoungulates. This recently extinct order of mammals evolved in a context of important geological, climatic, and environmental variations. Interestingly, notoungulates were mostly herbivorous and acquired high-crowned teeth very early in their evolutionary history. We focused on the variations in crown height, dental eruption pattern, and associated body mass of 69 notoungulate taxa, placed in their phylogenetic and geological contexts. We showed that notoungulates evolved higher crowns several times between 45 and 20 Ma, independently of the variation in body mass. Interestingly, the independent acquisitions of ever-growing teeth were systematically accompanied by eruption of molars faster than permanent premolars. These repeated associations of dental innovations have never been documented for other mammals and raise questions on their significance and causal relationships. We suggest that these correlated changes could originate from ontogenetic adjustments favored by structural constraints, and may indicate accelerated life histories. Complementarily, these more durable and efficient dentitions could be selected to cope with important ingestions of abrasive particles in the context of intensified volcanism and increasing aridity. This study demonstrates that assessing both life history and ecological traits allows a better knowledge of the specializations of extinct mammals that evolved under strong environmental constraints. PMID- 28096390 TI - Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance. AB - Maternal microchimerism (MMc) has been associated with development of allospecific transplant tolerance, antitumor immunity, and cross-generational reproductive fitness, but its mode of action is unknown. We found in a murine model that MMc caused exposure to the noninherited maternal antigens in all offspring, but in some, MMc magnitude was enough to cause membrane alloantigen acquisition (mAAQ; "cross-dressing") of host dendritic cells (DCs). Extracellular vesicle (EV)-enriched serum fractions from mAAQ+, but not from non-mAAQ, mice reproduced the DC cross-dressing phenomenon in vitro. In vivo, mAAQ was associated with increased expression of immune modulators PD-L1 (programmed death ligand 1) and CD86 by myeloid DCs (mDCs) and decreased presentation of allopeptide+self-MHC complexes, along with increased PD-L1, on plasmacytoid DCs (pDCs). Remarkably, both serum EV-enriched fractions and membrane microdomains containing the acquired MHC alloantigens included CD86, but completely excluded PD-L1. In contrast, EV-enriched fractions and microdomains containing allopeptide+self-MHC did not exclude PD-L1. Adoptive transfer of allospecific transgenic CD4 T cells revealed a "split tolerance" status in mAAQ+ mice: T cells recognizing intact acquired MHC alloantigens proliferated, whereas those responding to allopeptide+self-MHC did not. Using isolated pDCs and mDCs for in vitro culture with allopeptide+self-MHC-specific CD4 T cells, we could replicate their normal activation in non-mAAQ mice, and PD-L1-dependent anergy in mAAQ+ hosts. We propose that EVs provide a physiologic link between microchimerism and split tolerance, with implications for tumor immunity, transplantation, autoimmunity, and reproductive success. PMID- 28096391 TI - Network-based integration of systems genetics data reveals pathways associated with lignocellulosic biomass accumulation and processing. AB - As a consequence of their remarkable adaptability, fast growth, and superior wood properties, eucalypt tree plantations have emerged as key renewable feedstocks (over 20 million ha globally) for the production of pulp, paper, bioenergy, and other lignocellulosic products. However, most biomass properties such as growth, wood density, and wood chemistry are complex traits that are hard to improve in long-lived perennials. Systems genetics, a process of harnessing multiple levels of component trait information (e.g., transcript, protein, and metabolite variation) in populations that vary in complex traits, has proven effective for dissecting the genetics and biology of such traits. We have applied a network based data integration (NBDI) method for a systems-level analysis of genes, processes and pathways underlying biomass and bioenergy-related traits using a segregating Eucalyptus hybrid population. We show that the integrative approach can link biologically meaningful sets of genes to complex traits and at the same time reveal the molecular basis of trait variation. Gene sets identified for related woody biomass traits were found to share regulatory loci, cluster in network neighborhoods, and exhibit enrichment for molecular functions such as xylan metabolism and cell wall development. These findings offer a framework for identifying the molecular underpinnings of complex biomass and bioprocessing related traits. A more thorough understanding of the molecular basis of plant biomass traits should provide additional opportunities for the establishment of a sustainable bio-based economy. PMID- 28096393 TI - Utility-value intervention with parents increases students' STEM preparation and career pursuit. AB - During high school, developing competence in science, technology, engineering, and mathematics (STEM) is critically important as preparation to pursue STEM careers, yet students in the United States lag behind other countries, ranking 35th in mathematics and 27th in science achievement internationally. Given the importance of STEM careers as drivers of modern economies, this deficiency in preparation for STEM careers threatens the United States' continued economic progress. In the present study, we evaluated the long-term effects of a theory based intervention designed to help parents convey the importance of mathematics and science courses to their high-school-aged children. A prior report on this intervention showed that it promoted STEM course-taking in high school; in the current follow-up study, we found that the intervention improved mathematics and science standardized test scores on a college preparatory examination (ACT) for adolescents by 12 percentile points. Greater high-school STEM preparation (STEM course-taking and ACT scores) was associated with increased STEM career pursuit (i.e., STEM career interest, the number of college STEM courses, and students' attitudes toward STEM) 5 y after the intervention. These results suggest that the intervention can affect STEM career pursuit indirectly by increasing high-school STEM preparation. This finding underscores the importance of targeting high school STEM preparation to increase STEM career pursuit. Overall, these findings demonstrate that a motivational intervention with parents can have important effects on STEM preparation in high school, as well as downstream effects on STEM career pursuit 5 y later. PMID- 28096392 TI - Continual renewal and replication of persistent Leishmania major parasites in concomitantly immune hosts. AB - In most natural infections or after recovery, small numbers of Leishmania parasites remain indefinitely in the host. Persistent parasites play a vital role in protective immunity against disease pathology upon reinfection through the process of concomitant immunity, as well as in transmission and reactivation, yet are poorly understood. A key question is whether persistent parasites undergo replication, and we devised several approaches to probe the small numbers in persistent infections. We find two populations of persistent Leishmania major: one rapidly replicating, similar to parasites in acute infections, and another showing little evidence of replication. Persistent Leishmania were not found in "safe" immunoprivileged cell types, instead residing in macrophages and DCs, ~60% of which expressed inducible nitric oxide synthase (iNOS). Remarkably, parasites within iNOS+ cells showed normal morphology and genome integrity and labeled comparably with BrdU to parasites within iNOS- cells, suggesting that these parasites may be unexpectedly resistant to NO. Nonetheless, because persistent parasite numbers remain roughly constant over time, their replication implies that ongoing destruction likewise occurs. Similar results were obtained with the attenuated lpg2- mutant, a convenient model that rapidly enters a persistent state without inducing pathology due to loss of the Golgi GDP mannose transporter. These data shed light on Leishmania persistence and concomitant immunity, suggesting a model wherein a parasite reservoir repopulates itself indefinitely, whereas some progeny are terminated in antigen-presenting cells, thereby stimulating immunity. This model may be relevant to understanding immunity to other persistent pathogen infections. PMID- 28096394 TI - Elucidating the mechanism of fluorinated extender unit loading for improved production of fluorine-containing polyketides. AB - Polyketides are a large family of bioactive natural products synthesized by polyketide synthase (PKS) enzyme complexes predominantly from acetate and propionate. Given the structural diversity of compounds produced using these two simple building blocks, there has been longstanding interest in engineering the incorporation of alternative extender units. We have been investigating the mechanism of fluorinated monomer insertion by three of the six different modules of the PKS involved in erythromycin biosynthesis (6-deoxyerythronolide B synthase, DEBS) to begin understanding the contribution of different steps, such as enzyme acylation, transacylation, C-C bond formation, and chain transfer, to the overall selectivity and efficiency of this process. In these studies, we observe that inactivation of a cis-acyltransferase (AT) domain to circumvent its native extender unit preference leads concurrently to a change of mechanism in which chain extension with fluorine-substituted extender units switches largely to an acyl carrier protein (ACP)-independent mode. This result suggests that the covalent linkage between the growing polyketide chain and the enzyme is lost in these cases, which would limit efficient chain elongation after insertion of a fluorinated monomer. However, use of a standalone trans-acting AT to complement modules with catalytically deficient AT domains leads to enzyme acylation with the fluoromalonyl-CoA extender unit. Formation of the canonical ACP-linked intermediate with fluoromalonyl-CoA allows insertion of fluorinated extender units at 43% of the yield of the wild-type system while also amplifying product yield in single chain-extension experiments and enabling multiple chain extensions to form multiply fluorinated products. PMID- 28096395 TI - Genomic analysis reveals major determinants of cis-regulatory variation in Capsella grandiflora. AB - Understanding the causes of cis-regulatory variation is a long-standing aim in evolutionary biology. Although cis-regulatory variation has long been considered important for adaptation, we still have a limited understanding of the selective importance and genomic determinants of standing cis-regulatory variation. To address these questions, we studied the prevalence, genomic determinants, and selective forces shaping cis-regulatory variation in the outcrossing plant Capsella grandiflora We first identified a set of 1,010 genes with common cis regulatory variation using analyses of allele-specific expression (ASE). Population genomic analyses of whole-genome sequences from 32 individuals showed that genes with common cis-regulatory variation (i) are under weaker purifying selection and (ii) undergo less frequent positive selection than other genes. We further identified genomic determinants of cis-regulatory variation. Gene body methylation (gbM) was a major factor constraining cis-regulatory variation, whereas presence of nearby transposable elements (TEs) and tissue specificity of expression increased the odds of ASE. Our results suggest that most common cis regulatory variation in C. grandiflora is under weak purifying selection, and that gene-specific functional constraints are more important for the maintenance of cis-regulatory variation than genome-scale variation in the intensity of selection. Our results agree with previous findings that suggest TE silencing affects nearby gene expression, and provide evidence for a link between gbM and cis-regulatory constraint, possibly reflecting greater dosage sensitivity of body methylated genes. Given the extensive conservation of gbM in flowering plants, this suggests that gbM could be an important predictor of cis-regulatory variation in a wide range of plant species. PMID- 28096396 TI - Tuning the ion selectivity of two-pore channels. AB - Organellar two-pore channels (TPCs) contain two copies of a Shaker-like six transmembrane (6-TM) domain in each subunit and are ubiquitously expressed in plants and animals. Interestingly, plant and animal TPCs share high sequence similarity in the filter region, yet exhibit drastically different ion selectivity. Plant TPC1 functions as a nonselective cation channel on the vacuole membrane, whereas mammalian TPC channels have been shown to be endo/lysosomal Na+ selective or Ca2+-release channels. In this study, we performed systematic characterization of the ion selectivity of TPC1 from Arabidopsis thaliana (AtTPC1) and compared its selectivity with the selectivity of human TPC2 (HsTPC2). We demonstrate that AtTPC1 is selective for Ca2+ over Na+, but nonselective among monovalent cations (Li+, Na+, and K+). Our results also confirm that HsTPC2 is a Na+-selective channel activated by phosphatidylinositol 3,5-bisphosphate. Guided by our recent structure of AtTPC1, we converted AtTPC1 to a Na+-selective channel by mimicking the selectivity filter of HsTPC2 and identified key residues in the TPC filters that differentiate the selectivity between AtTPC1 and HsTPC2. Furthermore, the structure of the Na+-selective AtTPC1 mutant elucidates the structural basis for Na+ selectivity in mammalian TPCs. PMID- 28096397 TI - Correction for Roberts et al., Evolution of South Atlantic density and chemical stratification across the last deglaciation. PMID- 28096398 TI - Correction for Lorenzi et al., Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA. PMID- 28096399 TI - Antiviral screening identifies adenosine analogs targeting the endogenous dsRNA Leishmania RNA virus 1 (LRV1) pathogenicity factor. AB - The endogenous double-stranded RNA (dsRNA) virus Leishmaniavirus (LRV1) has been implicated as a pathogenicity factor for leishmaniasis in rodent models and human disease, and associated with drug-treatment failures in Leishmania braziliensis and Leishmania guyanensis infections. Thus, methods targeting LRV1 could have therapeutic benefit. Here we screened a panel of antivirals for parasite and LRV1 inhibition, focusing on nucleoside analogs to capitalize on the highly active salvage pathways of Leishmania, which are purine auxotrophs. Applying a capsid flow cytometry assay, we identified two 2'-C-methyladenosine analogs showing selective inhibition of LRV1. Treatment resulted in loss of LRV1 with first-order kinetics, as expected for random virus segregation, and elimination within six cell doublings, consistent with a measured LRV1 copy number of about 15. Viral loss was specific to antiviral nucleoside treatment and not induced by growth inhibitors, in contrast to fungal dsRNA viruses. Comparisons of drug-treated LRV1+ and LRV1- lines recapitulated LRV1-dependent pathology and parasite replication in mouse infections, and cytokine secretion in macrophage infections. Agents targeting Totiviridae have not been described previously, nor are there many examples of inhibitors acting against dsRNA viruses more generally. The compounds identified here provide a key proof-of-principle in support of further studies identifying efficacious antivirals for use in in vivo studies of LRV1 mediated virulence. PMID- 28096400 TI - Defining recovery neurobiology of injured spinal cord by synthetic matrix assisted hMSC implantation. AB - Mesenchymal stromal stem cells (MSCs) isolated from adult tissues offer tangible potential for regenerative medicine, given their feasibility for autologous transplantation. MSC research shows encouraging results in experimental stroke, amyotrophic lateral sclerosis, and neurotrauma models. However, further translational progress has been hampered by poor MSC graft survival, jeopardizing cellular and molecular bases for neural repair in vivo. We have devised an adult human bone marrow MSC (hMSC) delivery formula by investigating molecular events involving hMSCs incorporated in a uniquely designed poly(lactic-co-glycolic) acid scaffold, a clinically safe polymer, following inflammatory exposures in a dorsal root ganglion organotypic coculture system. Also, in rat T9-T10 hemisection spinal cord injury (SCI), we demonstrated that the tailored scaffolding maintained hMSC stemness, engraftment, and led to robust motosensory improvement, neuropathic pain and tissue damage mitigation, and myelin preservation. The scaffolded nontransdifferentiated hMSCs exerted multimodal effects of neurotrophism, angiogenesis, neurogenesis, antiautoimmunity, and antiinflammation. Hindlimb locomotion was restored by reestablished integrity of submidbrain circuits of serotonergic reticulospinal innervation at lumbar levels, the propriospinal projection network, neuromuscular junction, and central pattern generator, providing a platform for investigating molecular events underlying the repair impact of nondifferentiated hMSCs. Our approach enabled investigation of recovery neurobiology components for injured adult mammalian spinal cord that are different from those involved in normal neural function. The uncovered neural circuits and their molecular and cellular targets offer a biological underpinning for development of clinical rehabilitation therapies to treat disabilities and complications of SCI. PMID- 28096401 TI - Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications. AB - Macrophage activation is a critical step in host responses during bacterial infections. Ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine metabolism, has been well studied in epithelial cells and is known to have essential roles in many different cellular functions. However, its role in regulating macrophage function during bacterial infections is not well characterized. We demonstrate that macrophage-derived ODC is a critical regulator of M1 macrophage activation during both Helicobacter pylori and Citrobacter rodentium infection. Myeloid-specific Odc deletion significantly increased gastric and colonic inflammation, respectively, and enhanced M1 activation. Add back of putrescine, the product of ODC, reversed the increased macrophage activation, indicating that ODC and putrescine are regulators of macrophage function. Odc-deficient macrophages had increased histone 3, lysine 4 (H3K4) monomethylation, and H3K9 acetylation, accompanied by decreased H3K9 di/trimethylation both in vivo and ex vivo in primary macrophages. These alterations in chromatin structure directly resulted in up-regulated gene transcription, especially M1 gene expression. Thus, ODC in macrophages tempers antimicrobial, M1 macrophage responses during bacterial infections through histone modifications and altered euchromatin formation, leading to the persistence and pathogenesis of these organisms. PMID- 28096402 TI - Establishment of expression-state boundaries by Rif1 and Taz1 in fission yeast. AB - The Shelterin component Rif1 has emerged as a global regulator of the replication timing program in all eukaryotes examined to date, possibly by modulating the 3D organization of the genome. In fission yeast a second Shelterin component, Taz1, might share similar functions. Here, we identified unexpected properties for Rif1 and Taz1 by conducting high-throughput genetic screens designed to identify cis- and trans-acting factors capable of creating heterochromatin-euchromatin boundaries in fission yeast. The preponderance of cis-acting elements identified in the screens originated from genomic loci bound by Taz1 and associated with origins of replication whose firing is repressed by Taz1 and Rif1. Boundary formation and gene silencing by these elements required Taz1 and Rif1 and coincided with altered replication timing in the region. Thus, small chromosomal elements sensitive to Taz1 and Rif1 (STAR) could simultaneously regulate gene expression and DNA replication over a large domain, at the edge of which they established a heterochromatin-euchromatin boundary. Taz1, Rif1, and Rif1 associated protein phosphatases Sds21 and Dis2 were each sufficient to establish a boundary when tethered to DNA. Moreover, efficient boundary formation required the amino-terminal domain of the Mcm4 replicative helicase onto which the antagonistic activities of the replication-promoting Dbf4-dependent kinase and Rif1-recruited phosphatases are believed to converge to control replication origin firing. Altogether these observations provide an insight into a coordinated control of DNA replication and organization of the genome into expression domains. PMID- 28096403 TI - Crystal structure of Pistol, a class of self-cleaving ribozyme. AB - Small self-cleaving ribozymes have been discovered in all evolutionary domains of life. They can catalyze site-specific RNA cleavage, and as a result, they have relevance in gene regulation. Comparative genomic analysis has led to the discovery of a new class of small self-cleaving ribozymes named Pistol. We report the crystal structure of Pistol at 2.97-A resolution. Our results suggest that the Pistol ribozyme self-cleavage mechanism likely uses a guanine base in the active site pocket to carry out the phosphoester transfer reaction. The guanine G40 is in close proximity to serve as the general base for activating the nucleophile by deprotonating the 2'-hydroxyl to initiate the reaction (phosphoester transfer). Furthermore, G40 can also establish hydrogen bonding interactions with the nonbridging oxygen of the scissile phosphate. The proximity of G32 to the O5' leaving group suggests that G32 may putatively serve as the general acid. The RNA structure of Pistol also contains A-minor interactions, which seem to be important to maintain its tertiary structure and compact fold. Our findings expand the repertoire of ribozyme structures and highlight the conserved evolutionary mechanism used by ribozymes for catalysis. PMID- 28096404 TI - TORC1-dependent sumoylation of Rpc82 promotes RNA polymerase III assembly and activity. AB - Maintaining cellular homeostasis under changing nutrient conditions is essential for the growth and development of all organisms. The mechanisms that maintain homeostasis upon loss of nutrient supply are not well understood. By mapping the SUMO proteome in Saccharomyces cerevisiae, we discovered a specific set of differentially sumoylated proteins mainly involved in transcription. RNA polymerase III (RNAPIII) components, including Rpc53, Rpc82, and Ret1, are particularly prominent nutrient-dependent SUMO targets. Nitrogen starvation, as well as direct inhibition of the master nutrient response regulator target of rapamycin complex 1 (TORC1), results in rapid desumoylation of these proteins, which is reflected by loss of SUMO at tRNA genes. TORC1-dependent sumoylation of Rpc82 in particular is required for robust tRNA transcription. Mechanistically, sumoylation of Rpc82 is important for assembly of the RNAPIII holoenzyme and recruitment of Rpc82 to tRNA genes. In conclusion, our data show that TORC1 dependent sumoylation of Rpc82 bolsters the transcriptional capacity of RNAPIII under optimal growth conditions. PMID- 28096405 TI - Selenium isotopes record extensive marine suboxia during the Great Oxidation Event. AB - It has been proposed that an "oxygen overshoot" occurred during the early Paleoproterozoic Great Oxidation Event (GOE) in association with the extreme positive carbon isotopic excursion known as the Lomagundi Event. Moreover, it has also been suggested that environmental oxygen levels then crashed to very low levels during the subsequent extremely negative Shunga-Francevillian carbon isotopic anomaly. These redox fluctuations could have profoundly influenced the course of eukaryotic evolution, as eukaryotes have several metabolic processes that are obligately aerobic. Here we investigate the magnitude of these proposed oxygen perturbations using selenium (Se) geochemistry, which is sensitive to redox transitions across suboxic conditions. We find that delta82/78Se values in offshore shales show a positive excursion from 2.32 Ga until 2.1 Ga (mean +1.03 +/- 0.670/00). Selenium abundances and Se/TOC (total organic carbon) ratios similarly show a peak during this interval. Together these data suggest that during the GOE there was pervasive suboxia in near-shore environments, allowing nonquantitative Se reduction to drive the residual Se oxyanions isotopically heavy. This implies O2 levels of >0.4 MUM in these settings. Unlike in the late Neoproterozoic and Phanerozoic, when negative delta82/78Se values are observed in offshore environments, only a single formation, evidently the shallowest, shows evidence of negative delta82/78Se. This suggests that there was no upwelling of Se oxyanions from an oxic deep-ocean reservoir, which is consistent with previous estimates that the deep ocean remained anoxic throughout the GOE. The abrupt decline in delta82/78Se and Se/TOC values during the subsequent Shunga Francevillian anomaly indicates a widespread decrease in surface oxygenation. PMID- 28096406 TI - Shifting diets and the rise of male-biased inequality on the Central Plains of China during Eastern Zhou. AB - Farming domesticated millets, tending pigs, and hunting constituted the core of human subsistence strategies during Neolithic Yangshao (5000-2900 BC). Introduction of wheat and barley as well as the addition of domesticated herbivores during the Late Neolithic (~2600-1900 BC) led to restructuring of ancient Chinese subsistence strategies. This study documents a dietary shift from indigenous millets to the newly introduced cereals in northcentral China during the Bronze Age Eastern Zhou Dynasty (771-221 BC) based on stable isotope analysis of human and animal bone samples. Our results show that this change affected females to a greater degree than males. We find that consumption of the newly introduced cereals was associated with less consumption of animal products and a higher rate of skeletal stress markers among females. We hypothesized that the observed separation of dietary signatures between males and females marks the rise of male-biased inequality in early China. We test this hypothesis by comparing Eastern Zhou human skeletal data with those from Neolithic Yangshao archaeological contexts. We find no evidence of male-female inequality in early farming communities. The presence of male-biased inequality in Eastern Zhou society is supported by increased body height difference between the sexes as well as the greater wealth of male burials. PMID- 28096407 TI - Development of chronic allergic responses by dampening Bcl6-mediated suppressor activity in memory T helper 2 cells. AB - Mice deficient in the transcriptional repressor B-cell CLL/lymphoma 6 (Bcl6) exhibit similar T helper 2 (TH2) immune responses as patients with allergic diseases. However, the molecular mechanisms underlying Bcl6-directed regulation of TH2 cytokine genes remain unclear. We identified multiple Bcl6/STAT binding sites (BSs) in TH2 cytokine gene loci. We found that Bcl6 is modestly associated with the BSs, and it had no significant effect on cytokine production in newly differentiated TH2 cells. Contrarily, in memory TH2 (mTH2) cells derived from adaptively transferred TH2 effectors, Bcl6 outcompeted STAT5 for binding to TH2 cytokine gene loci, particularly Interleukin4 (Il4) loci, and attenuated GATA binding protein 3 (GATA3) binding to highly conserved intron enhancer regions in mTH2 cells. Bcl6 suppressed cytokine production epigenetically in mTH2 cells to negatively tune histone acetylation at TH2 cytokine gene loci, including Il4 loci. In addition, IL-33, a pro-TH2 cytokine, diminished Bcl6's association with loci to which GATA3 recruitment was inversely augmented, resulting in altered IL 4, but not IL-5 and IL-13, production in mTH2 cells but no altered production in newly differentiated TH2 cells. Use of a murine asthma model that generates high levels of pro-TH2 cytokines, such as IL-33, suggested that the suppressive function of Bcl6 in mTH2 cells is abolished in severe asthma. These findings indicate a role of the interaction between TH2-promoting factors and Bcl6 in promoting appropriate IL-4 production in mTH2 cells and suggest that chronic allergic diseases involve the TH2-promoting factor-mediated functional breakdown of Bcl6, resulting in allergy exacerbation. PMID- 28096408 TI - Rhythm judgments reveal a frequency asymmetry in the perception and neural coding of sound synchrony. AB - In modern Western music, melody is commonly conveyed by pitch changes in the highest-register voice, whereas meter or rhythm is often carried by instruments with lower pitches. An intriguing and recently suggested possibility is that the custom of assigning rhythmic functions to lower-pitch instruments may have emerged because of fundamental properties of the auditory system that result in superior time encoding for low pitches. Here we compare rhythm and synchrony perception between low- and high-frequency tones, using both behavioral and EEG techniques. Both methods were consistent in showing no superiority in time encoding for low over high frequencies. However, listeners were consistently more sensitive to timing differences between two nearly synchronous tones when the high-frequency tone followed the low-frequency tone than vice versa. The results demonstrate no superiority of low frequencies in timing judgments but reveal a robust asymmetry in the perception and neural coding of synchrony that reflects greater tolerance for delays of low- relative to high-frequency sounds than vice versa. We propose that this asymmetry exists to compensate for inherent and variable time delays in cochlear processing, as well as the acoustical properties of sound sources in the natural environment, thereby providing veridical perceptual experiences of simultaneity. PMID- 28096409 TI - Field-scale experiments reveal persistent yield gaps in low-input and organic cropping systems. AB - Knowledge of production-system performance is largely based on observations at the experimental plot scale. Although yield gaps between plot-scale and field scale research are widely acknowledged, their extent and persistence have not been experimentally examined in a systematic manner. At a site in southwest Michigan, we conducted a 6-y experiment to test the accuracy with which plot scale crop-yield results can inform field-scale conclusions. We compared conventional versus alternative, that is, reduced-input and biologically based organic, management practices for a corn-soybean-wheat rotation in a randomized complete block-design experiment, using 27 commercial-size agricultural fields. Nearby plot-scale experiments (0.02-ha to 1.0-ha plots) provided a comparison of plot versus field performance. We found that plot-scale yields well matched field scale yields for conventional management but not for alternative systems. For all three crops, at the plot scale, reduced-input and conventional managements produced similar yields; at the field scale, reduced-input yields were lower than conventional. For soybeans at the plot scale, biological and conventional managements produced similar yields; at the field scale, biological yielded less than conventional. For corn, biological management produced lower yields than conventional in both plot- and field-scale experiments. Wheat yields appeared to be less affected by the experimental scale than corn and soybean. Conventional management was more resilient to field-scale challenges than alternative practices, which were more dependent on timely management interventions; in particular, mechanical weed control. Results underscore the need for much wider adoption of field-scale experimentation when assessing new technologies and production-system performance, especially as related to closing yield gaps in organic farming and in low-resourced systems typical of much of the developing world. PMID- 28096410 TI - Selection against variants in the genome associated with educational attainment. AB - Epidemiological and genetic association studies show that genetics play an important role in the attainment of education. Here, we investigate the effect of this genetic component on the reproductive history of 109,120 Icelanders and the consequent impact on the gene pool over time. We show that an educational attainment polygenic score, POLYEDU, constructed from results of a recent study is associated with delayed reproduction (P < 10-100) and fewer children overall. The effect is stronger for women and remains highly significant after adjusting for educational attainment. Based on 129,808 Icelanders born between 1910 and 1990, we find that the average POLYEDU has been declining at a rate of ~0.010 standard units per decade, which is substantial on an evolutionary timescale. Most importantly, because POLYEDU only captures a fraction of the overall underlying genetic component the latter could be declining at a rate that is two to three times faster. PMID- 28096411 TI - Hepatitis E virus ORF3 is a functional ion channel required for release of infectious particles. AB - Hepatitis E virus (HEV) is the leading cause of enterically transmitted viral hepatitis globally. Of HEV's three ORFs, the function of ORF3 has remained elusive. Here, we demonstrate that via homophilic interactions ORF3 forms multimeric complexes associated with intracellular endoplasmic reticulum (ER) derived membranes. HEV ORF3 shares several structural features with class I viroporins, and the function of HEV ORF3 can be maintained by replacing it with the well-characterized viroporin influenza A virus (IAV) matrix-2 protein. ORF3's ion channel function is further evidenced by its ability to mediate ionic currents when expressed in Xenopus laevis oocytes. Furthermore, we identified several positions in ORF3 critical for its formation of multimeric complexes, ion channel activity, and, ultimately, release of infectious particles. Collectively, our data demonstrate a previously undescribed function of HEV ORF3 as a viroporin, which may serve as an attractive target in developing direct-acting antivirals. PMID- 28096413 TI - Modeling the role of voyaging in the coastal spread of the Early Neolithic in the West Mediterranean. AB - The earliest dates for the West Mediterranean Neolithic indicate that it expanded across 2,500 km in about 300 y. Such a fast spread is held to be mainly due to a demic process driven by dispersal along coastal routes. Here, we model the Neolithic spread in the region by focusing on the role of voyaging to understand better the core elements that produced the observed pattern of dates. We also explore the effect of cultural interaction with Mesolithic populations living along the coast. The simulation study shows that (i) sea travel is required to obtain reasonable predictions, with a minimum sea-travel range of 300 km per generation; (ii) leapfrog coastal dispersals yield the best results (quantitatively and qualitatively); and (iii) interaction with Mesolithic people can assist the spread, but long-range voyaging is still needed to explain the archaeological pattern. PMID- 28096412 TI - Transmembrane protein 108 is required for glutamatergic transmission in dentate gyrus. AB - Neurotransmission in dentate gyrus (DG) is critical for spatial coding, learning memory, and emotion processing. Although DG dysfunction is implicated in psychiatric disorders, including schizophrenia, underlying pathological mechanisms remain unclear. Here we report that transmembrane protein 108 (Tmem108), a novel schizophrenia susceptibility gene, is highly enriched in DG granule neurons and its expression increased at the postnatal period critical for DG development. Tmem108 is specifically expressed in the nervous system and enriched in the postsynaptic density fraction. Tmem108-deficient neurons form fewer and smaller spines, suggesting that Tmem108 is required for spine formation and maturation. In agreement, excitatory postsynaptic currents of DG granule neurons were decreased in Tmem108 mutant mice, indicating a hypofunction of glutamatergic activity. Further cell biological studies indicate that Tmem108 is necessary for surface expression of AMPA receptors. Tmem108-deficient mice display compromised sensorimotor gating and cognitive function. Together, these observations indicate that Tmem108 plays a critical role in regulating spine development and excitatory transmission in DG granule neurons. When Tmem108 is mutated, mice displayed excitatory/inhibitory imbalance and behavioral deficits relevant to schizophrenia, revealing potential pathophysiological mechanisms of schizophrenia. PMID- 28096414 TI - Profile of Jean-Pierre Sauvage, Sir J. Fraser Stoddart, and Bernard L. Feringa, 2016 Nobel Laureates in Chemistry. PMID- 28096415 TI - Increased mitochondrial nanotunneling activity, induced by calcium imbalance, affects intermitochondrial matrix exchanges. AB - Exchanges of matrix contents are essential to the maintenance of mitochondria. Cardiac mitochondrial exchange matrix content in two ways: by direct contact with neighboring mitochondria and over longer distances. The latter mode is supported by thin tubular protrusions, called nanotunnels, that contact other mitochondria at relatively long distances. Here, we report that cardiac myocytes of heterozygous mice carrying a catecholaminergic polymorphic ventricular tachycardia-linked RyR2 mutation (A4860G) show a unique and unusual mitochondrial response: a significantly increased frequency of nanotunnel extensions. The mutation induces Ca2+ imbalance by depressing RyR2 channel activity during excitation-contraction coupling, resulting in random bursts of Ca2+ release probably due to Ca2+ overload in the sarcoplasmic reticulum. We took advantage of the increased nanotunnel frequency in RyR2A4860G+/- cardiomyocytes to investigate and accurately define the ultrastructure of these mitochondrial extensions and to reconstruct the overall 3D distribution of nanotunnels using electron tomography. Additionally, to define the effects of communication via nanotunnels, we evaluated the intermitochondrial exchanges of matrix-targeted soluble fluorescent proteins, mtDsRed and photoactivable mtPA-GFP, in isolated cardiomyocytes by confocal microscopy. A direct comparison between exchanges occurring at short and long distances directly demonstrates that communication via nanotunnels is slower. PMID- 28096416 TI - Infrastructure mitigates the sensitivity of child growth to local agriculture and rainfall in Nepal and Uganda. AB - This paper investigates linear growth and weight gain among 11,946 children below the age of 5 y in Nepal and Uganda, testing the hypothesis that child growth is sensitive to precipitation during key periods in a child's early life. The paper also tests the importance of the economic and physical environments in which children reside. Outcomes are not completely explained by agricultural performance or the observed characteristics of children or their households. Associations between height-for-age z-score (HAZ) and weight-for-height z-score (WHZ) and rainfall are generally positive, but patterns are heterogeneous. At the mean, an increase of 1 SD in agricultural season rainfall is associated with a 0.05- to 0.25-point higher z-score, which translates into increases of roughly 4 13% for HAZ and 1-7% for WHZ. Nutrition sensitivity to rainfall is greater in Nepal, where rainfall is lower on average and wider ranging, than in Uganda. Health and transport infrastructure help to buffer children from the deleterious nutritional effects of precipitation shortfalls, underscoring the role of broadly based economic development in promoting child nutrition. PMID- 28096417 TI - Phosphorylation by PKC and PKA regulate the kinase activity and downstream signaling of WNK4. AB - With-no-lysine kinase 4 (WNK4) regulates electrolyte homeostasis and blood pressure. WNK4 phosphorylates the kinases SPAK (Ste20-related proline alanine rich kinase) and OSR1 (oxidative stress responsive kinase), which then phosphorylate and activate the renal Na-Cl cotransporter (NCC). WNK4 levels are regulated by binding to Kelch-like 3, targeting WNK4 for ubiquitylation and degradation. Phosphorylation of Kelch-like 3 by PKC or PKA downstream of AngII or vasopressin signaling, respectively, abrogates binding. We tested whether these pathways also affect WNK4 phosphorylation and activity. By tandem mass spectrometry and use of phosphosite-specific antibodies, we identified five WNK4 sites (S47, S64, S1169, S1180, S1196) that are phosphorylated downstream of AngII signaling in cultured cells and in vitro by PKC and PKA. Phosphorylation at S64 and S1196 promoted phosphorylation of the WNK4 kinase T-loop at S332, which is required for kinase activation, and increased phosphorylation of SPAK. Volume depletion induced phosphorylation of these sites in vivo, predominantly in the distal convoluted tubule. Thus, AngII, in addition to increasing WNK4 levels, also modulates WNK4 kinase activity via phosphorylation of sites outside the kinase domain. PMID- 28096418 TI - Multi-institute analysis of carbapenem resistance reveals remarkable diversity, unexplained mechanisms, and limited clonal outbreaks. AB - Carbapenem-resistant Enterobacteriaceae (CRE) are among the most severe threats to the antibiotic era. Multiple different species can exhibit resistance due to many different mechanisms, and many different mobile elements are capable of transferring resistance between lineages. We prospectively sampled CRE from hospitalized patients from three Boston-area hospitals, together with a collection of CRE from a single California hospital, to define the frequency and characteristics of outbreaks and determine whether there is evidence for transfer of strains within and between hospitals and the frequency with which resistance is transferred between lineages or species. We found eight species exhibiting resistance, with the majority of our sample being the sequence type 258 (ST258) lineage of Klebsiella pneumoniae There was very little evidence of extensive hospital outbreaks, but a great deal of variation in resistance mechanisms and the genomic backgrounds carrying these mechanisms. Local transmission was evident in clear phylogeographic structure between the samples from the two coasts. The most common resistance mechanisms were KPC (K. pneumoniae carbapenemases) beta lactamases encoded by blaKPC2, blaKPC3, and blaKPC4, which were transferred between strains and species by seven distinct subgroups of the Tn4401 element. We also found evidence for previously unrecognized resistance mechanisms that produced resistance when transformed into a susceptible genomic background. The extensive variation, together with evidence of transmission beyond limited clonal outbreaks, points to multiple unsampled transmission chains throughout the continuum of care, including asymptomatic carriage and transmission of CRE. This finding suggests that to control this threat, we need an aggressive approach to surveillance and isolation. PMID- 28096419 TI - Stromal cues regulate the pancreatic cancer epigenome and metabolome. AB - A fibroinflammatory stromal reaction cooperates with oncogenic signaling to influence pancreatic ductal adenocarcinoma (PDAC) initiation, progression, and therapeutic outcome, yet the mechanistic underpinning of this crosstalk remains poorly understood. Here we show that stromal cues elicit an adaptive response in the cancer cell including the rapid mobilization of a transcriptional network implicated in accelerated growth, along with anabolic changes of an altered metabolome. The close overlap of stroma-induced changes in vitro with those previously shown to be regulated by oncogenic Kras in vivo suggests that oncogenic Kras signaling-a hallmark and key driver of PDAC-is contingent on stromal inputs. Mechanistically, stroma-activated cancer cells show widespread increases in histone acetylation at transcriptionally enhanced genes, implicating the PDAC epigenome as a presumptive point of convergence between these pathways and a potential therapeutic target. Notably, inhibition of the bromodomain and extraterminal (BET) family of epigenetic readers, and of Bromodomain-containing protein 2 (BRD2) in particular, blocks stroma-inducible transcriptional regulation in vitro and tumor progression in vivo. Our work suggests the existence of a molecular "AND-gate" such that tumor activation is the consequence of mutant Kras and stromal cues, providing insight into the role of the tumor microenvironment in the origin and treatment of Ras-driven tumors. PMID- 28096420 TI - Drivers of Rift Valley fever epidemics in Madagascar. AB - Rift Valley fever (RVF) is a vector-borne viral disease widespread in Africa. The primary cycle involves mosquitoes and wild and domestic ruminant hosts. Humans are usually contaminated after contact with infected ruminants. As many environmental, agricultural, epidemiological, and anthropogenic factors are implicated in RVF spread, the multidisciplinary One Health approach was needed to identify the drivers of RVF epidemics in Madagascar. We examined the environmental patterns associated with these epidemics, comparing human and ruminant serological data with environmental and cattle-trade data. In contrast to East Africa, environmental drivers did not trigger the epidemics: They only modulated local Rift Valley fever virus (RVFV) transmission in ruminants. Instead, RVFV was introduced through ruminant trade and subsequent movement of cattle between trade hubs caused its long-distance spread within the country. Contact with cattle brought in from infected districts was associated with higher infection risk in slaughterhouse workers. The finding that anthropogenic rather than environmental factors are the main drivers of RVF infection in humans can be used to design better prevention and early detection in the case of RVF resurgence in the region. PMID- 28096421 TI - RFamide-related peptide-3 (RFRP-3) suppresses sexual maturation in a eusocial mammal. AB - Neuroendocrine mechanisms underlying social inhibition of puberty are not well understood. Here, we use a model exhibiting the most profound case of pubertal suppression among mammals to explore a role for RFamide-related peptide-3 [RFRP 3; mammalian ortholog to gonadotropin-inhibitory hormone (GnIH)] in neuroendocrine control of reproductive development. Naked mole rats (NMRs) live in sizable colonies where breeding is monopolized by two to four dominant animals, and no other members exhibit signs of puberty throughout their lives unless they are removed from the colony. Because of its inhibitory action on the reproductive axis in other vertebrates, we investigated the role of RFRP-3 in social reproductive suppression in NMRs. We report that RFRP-3 immunofluorescence expression patterns and RFRP-3/GnRH cross-talk are largely conserved in the NMR brain, with the exception of the unique presence of RFRP-3 cell bodies in the arcuate nucleus (Arc). Immunofluorescence comparisons revealed that central expression of RFRP-3 is altered by reproductive status, with RFRP-3 immunoreactivity enhanced in the paraventricular nucleus, dorsomedial nucleus, and Arc of reproductively quiescent NMRs. We further observed that exogenous RFRP 3 suppresses gonadal steroidogenesis and mating behavior in NMRs given the opportunity to undergo puberty. Together, our findings establish a role for RFRP 3 in preserving reproductive immaturity, and challenge the view that stimulatory peptides are the ultimate gatekeepers of puberty. PMID- 28096422 TI - Hydrogen isotope fractionation in methane plasma. AB - The hydrogen isotope ratio (D/H) is commonly used to reconstruct the chemical processes at the origin of water and organic compounds in the early solar system. On the one hand, the large enrichments in deuterium of the insoluble organic matter (IOM) isolated from the carbonaceous meteorites are interpreted as a heritage of the interstellar medium or resulting from ion-molecule reactions taking place in the diffuse part of the protosolar nebula. On the other hand, the molecular structure of this IOM suggests that organic radicals have played a central role in a gas-phase organosynthesis. So as to reproduce this type of chemistry between organic radicals, experiments based on a microwave plasma of CH4 have been performed. They yielded a black organic residue in which ion microprobe analyses revealed hydrogen isotopic anomalies at a submicrometric spatial resolution. They likely reflect differences in the D/H ratios between the various CHx radicals whose polymerization is at the origin of the IOM. These isotopic heterogeneities, usually referred to as hot and cold spots, are commensurable with those observed in meteorite IOM. As a consequence, the appearance of organic radicals in the ionized regions of the disk surrounding the Sun during its formation may have triggered the formation of organic compounds. PMID- 28096423 TI - Trogocytosis of peptide-MHC class II complexes from dendritic cells confers antigen-presenting ability on basophils. AB - Th2 immunity plays important roles in both protective and allergic responses. Nevertheless, the nature of antigen-presenting cells responsible for Th2 cell differentiation remains ill-defined compared with the nature of the cells responsible for Th1 and Th17 cell differentiation. Basophils have attracted attention as a producer of Th2-inducing cytokine IL-4, whereas their MHC class II (MHC-II) expression and function as antigen-presenting cells are matters of considerable controversy. Here we revisited the MHC-II expression on basophils and explored its functional relevance in Th2 cell differentiation. Basophils generated in vitro from bone marrow cells in culture with IL-3 plus GM-CSF displayed MHC-II on the cell surface, whereas those generated in culture with IL 3 alone did not. Of note, these MHC-II-expressing basophils showed little or no transcription of the corresponding MHC-II gene. The GM-CSF addition to culture expanded dendritic cells (DCs) other than basophils. Coculture of basophils and DCs revealed that basophils acquired peptide-MHC-II complexes from DCs via cell contact-dependent trogocytosis. The acquired complexes, together with CD86, enabled basophils to stimulate peptide-specific T cells, leading to their proliferation and IL-4 production, indicating that basophils can function as antigen-presenting cells for Th2 cell differentiation. Transfer of MHC-II from DCs to basophils was also detected in draining lymph nodes of mice with atopic dermatitis-like skin inflammation. Thus, the present study defined the mechanism by which basophils display MHC-II on the cell surface and appears to reconcile some discrepancies observed in previous studies. PMID- 28096424 TI - alpha-Actinin/titin interaction: A dynamic and mechanically stable cluster of bonds in the muscle Z-disk. AB - Stable anchoring of titin within the muscle Z-disk is essential for preserving muscle integrity during passive stretching. One of the main candidates for anchoring titin in the Z-disk is the actin cross-linker alpha-actinin. The calmodulin-like domain of alpha-actinin binds to the Z-repeats of titin. However, the mechanical and kinetic properties of this important interaction are still unknown. Here, we use a dual-beam optical tweezers assay to study the mechanics of this interaction at the single-molecule level. A single interaction of alpha actinin and titin turns out to be surprisingly weak if force is applied. Depending on the direction of force application, the unbinding forces can more than triple. Our results suggest a model where multiple alpha-actinin/Z-repeat interactions cooperate to ensure long-term stable titin anchoring while allowing the individual components to exchange dynamically. PMID- 28096426 TI - Correction to "Berberine Reverses Epithelial-to-Mesenchymal Transition and Inhibits Metastasis and Tumor-Induced Angiogenesis in Human Cervical Cancer Cells". PMID- 28096425 TI - Correction to "Antibody Tracking Demonstrates Cell Type-Specific and Ligand Independent Internalization of Guanylyl Cyclase A and Natriuretic Peptide Receptor C". PMID- 28096427 TI - Influence of fatiguing noise on auditory evoked responses to stimuli of various levels in a beluga whale, Delphinapterus leucas. AB - The negative impact of man-made noise on the hearing of odontocetes has attracted considerable recent attention. In the majority of studies, permanent or temporary reductions in sensitivity, known as permanent or temporary threshold shift (PTS or TTS, respectively), have been investigated. In the present study, the effects of a fatiguing sound on the hearing of a beluga whale, Delphinapterus leucas, within a wide range of levels of test signals was investigated. The fatiguing noise was half-octave band-limited noise centered at 32 kHz. Post-exposure effects of this noise on the evoked responses to test stimuli (rhythmic pip trains with a 45-kHz center frequency) at various levels (from threshold to 60 dB above threshold) were measured. For baseline (pre-exposure) responses, the magnitude-versus-level function featured a segment of steep magnitude dependence on level (up to 30 dB above threshold) that was followed by a plateau segment that featured little dependence on level (30 to 55 dB above threshold). Post exposure, the function shifted upward along the level scale. The shift was 23 dB at the threshold and up to 33 dB at the supra-threshold level. Owing to the plateau in the magnitude-versus-level function, post-exposure suppression of responses depended on the stimulus level such that higher levels corresponded to less suppression. The experimental data may be modeled based on the compressive non-linearity of the cochlea. According to the model, post-exposure responses of the cochlea to high-level stimuli are minimally suppressed compared with the pre exposure responses, despite a substantially increased threshold. PMID- 28096428 TI - A statistical approach to understanding reproductive isolation in two sympatric species of tree crickets. AB - In acoustically communicating animals, reproductive isolation between sympatric species is usually maintained through species-specific calls. This requires that the receiver be tuned to the conspecific signal. Mapping the response space of the receiver onto the signal space of the conspecific investigates this tuning. A combinatorial approach to investigating the response space is more informative as the influence on the receiver of the interactions between the features is also elucidated. However, most studies have examined individual preference functions rather than the multivariate response space. We studied the maintenance of reproductive isolation between two sympatric tree cricket species (Oecanthus henryi and Oecanthus indicus) through the temporal features of the calls. Individual response functions were determined experimentally for O. henryi, the results from which were combined in a statistical framework to generate a multivariate quantitative receiver response space. The predicted response was higher for the signals of the conspecific than for signals of the sympatric heterospecific, indicating maintenance of reproductive isolation through songs. The model allows prediction of response to untested combinations of temporal features as well as delineation of the evolutionary constraints on the signal space. The model can also be used to predict the response of O. henryi to other heterospecific signals, making it a useful tool for the study of the evolution and maintenance of reproductive isolation via long-range acoustic signals. PMID- 28096429 TI - Lombard effect onset times reveal the speed of vocal plasticity in a songbird. AB - Animals that use vocal signals to communicate often compensate for interference and masking from background noise by raising the amplitude of their vocalisations. This response has been termed the Lombard effect. However, despite more than a century of research, little is known how quickly animals can adjust the amplitude of their vocalisations after the onset of noise. The ability to respond quickly to increases in noise levels would allow animals to avoid signal masking and ensure their calls continue to be heard, even if they are interrupted by sudden bursts of high-amplitude noise. We tested how quickly singing male canaries (Serinus canaria) exhibit the Lombard effect by exposing them to short playbacks of white noise and measuring the speed of their responses. We show that canaries exhibit the Lombard effect in as little as 300 ms after the onset of noise and are also able to increase the amplitude of their songs mid-song and mid phrase without pausing. Our results demonstrate high vocal plasticity in this species and suggest that birds are able to adjust the amplitude of their vocalisations very rapidly to ensure they can still be heard even during sudden changes in background noise levels. PMID- 28096430 TI - Testing hypotheses about individual variation in plasma corticosterone in free living salamanders. AB - In vertebrates, many responses to stress as well as homeostatic maintenance of basal metabolism are regulated by plasma glucocorticoid hormones (GCs). Despite having crucial functions, levels of GCs are typically variable among individuals. We examined the contribution of several physiological factors to individual variation in plasma corticosterone (CORT) and the number of corticotropin releasing hormone (CRH) neurons in the magnocellular preoptic area of the brain in free-living Allegheny Mountain dusky salamanders. We addressed three hypotheses: the current-condition hypothesis, the facilitation hypothesis and the trade-off hypothesis. Differential white blood cell count was identified as a strong contributor to individual variation in baseline CORT, stress-induced CORT and the number of CRH neurons. In contrast, we found no relationship between CORT (or CRH) and body condition, energy stores or reproductive investment, providing no support for the current-condition hypothesis or the trade-off hypothesis involving reproduction. Because of the difficulties of interpreting the functional consequences of variation in differential white blood cell counts, we were unable to distinguish between the facilitation hypothesis or the trade-off hypothesis related to immune function. However, the strong association between differential white blood cell count and hypothalamic-pituitary-adrenal/interrenal (HPA/I) activation suggests that a more thorough examination of immune profiles is critical to understanding variation in HPA/I activation. PMID- 28096431 TI - Activation of respiratory muscles does not occur during cold-submergence in bullfrogs, Lithobates catesbeianus. AB - Semiaquatic frogs may not breathe air for several months because they overwinter in ice-covered ponds. In contrast to many vertebrates that experience decreased motor performance after inactivity, bullfrogs, Lithobates catesbeianus, retain functional respiratory motor processes following cold-submergence. Unlike mammalian hibernators with unloaded limb muscles and inactive locomotor systems, respiratory mechanics of frogs counterintuitively allow for ventilatory maneuvers when submerged. Thus, we hypothesized that bullfrogs generate respiratory motor patterns during cold-submergence to avoid disuse and preserve motor performance. Accordingly, we measured activity of respiratory muscles (buccal floor compressor and glottal dilator) via electromyography in freely behaving bullfrogs at 20 and 2 degrees C. Although we confirm that ventilation cycles occur underwater at 20 degrees C, bullfrogs did not activate either respiratory muscle when submerged acutely or chronically at 2 degrees C. We conclude that cold-submerged bullfrogs endure respiratory motor inactivity, implying that other mechanisms, excluding underwater muscle activation, maintain a functional respiratory motor system throughout overwintering. PMID- 28096432 TI - Effects of activity, genetic selection and their interaction on muscle metabolic capacities and organ masses in mice. AB - Chronic voluntary exercise elevates total daily energy expenditure and food consumption, potentially resulting in organ compensation supporting nutrient extraction/utilization. Additionally, species with naturally higher daily energy expenditure often have larger processing organs, which may represent genetic differences and/or phenotypic plasticity. We tested for possible adaptive changes in organ masses of four replicate lines of house mice selected (37 generations) for high running (HR) compared with four non-selected control (C) lines. Females were housed with or without wheel access for 13-14 weeks beginning at 53-60 days of age. In addition to organ compensation, chronic activity may also require an elevated aerobic capacity. Therefore, we also measured hematocrit and both citrate synthase activity and myoglobin concentration in heart and gastrocnemius. Both selection (HR versus C) and activity (wheels versus no wheels) significantly affected morphological and biochemical traits. For example, with body mass as a covariate, mice from HR lines had significantly higher hematocrit and larger ventricles, with more myoglobin. Wheel access lengthened the small intestine, increased relative ventricle and kidney size, and increased skeletal muscle citrate synthase activity and myoglobin concentration. As compared with C lines, HR mice had greater training effects for ventricle mass, hematocrit, large intestine length and gastrocnemius citrate synthase activity. For ventricle and gastrocnemius citrate synthase activity, the greater training was quantitatively explainable as a result of greater wheel running (i.e. 'more pain, more gain'). For hematocrit and large intestine length, differences were not related to amount of wheel running and instead indicate inherently greater adaptive plasticity in HR lines. PMID- 28096433 TI - Sex differences in the development of prolactinoma in mice overexpressing hCGbeta: role of TGFbeta1. AB - Female transgenic mice that overexpress the human chorionic gonadotrophin beta subunit (hCGbeta+) develop prolactinomas, whereas hCGbeta+ males do not. The high levels of circulating hCG induce massive luteinization in the ovary of hCGbeta+ females, and progesterone becomes the primary steroid hormone produced, but estradiol remains at physiological level. The involvement of high levels of progesterone in lactotroph proliferation is not clearly understood; hence, the pathogenesis of prolactinomas in hCGbeta+ females remains unclear. TGFbeta1 is an inhibitor of lactotroph function, and the reduced TGFbeta1 activity found in prolactinomas has been proposed to be involved in tumor development. The aim of the present work was to study the role of TGFbeta1 in the gender-specific development of prolactinomas in hCGbeta+ mice. We compared the expression of different components of the pituitary TGFbeta1 system in males and females in this model. We found reduced TGFbeta1 levels, reduced expression of TGFbeta1 target genes, TGFbeta1 receptors, Ltbp1, Smad4 and Smad7 in hCGbeta+ female pituitaries. However, no differences were found between the transgenic and wild type male pituitaries. We postulate that decreased pituitary TGFbeta1 activity in hCGbeta+ females is involved in the development of prolactinomas. In fact, we demonstrated that an in vivo treatment carried out for increasing pituitary TGFbeta1 activity, was successful in reducing the prolactinoma development, and the hyperprolactinemia in hCGbeta+ females. Moreover, the stronger TGFbeta1 system found in males could protect them from excessive lactotroph proliferation. Sex differences in the regulation of the pituitary TGFbeta1 system could explain gender differences in the incidence of prolactinoma. PMID- 28096434 TI - Precocious glucocorticoid exposure reduces skeletal muscle satellite cells in the fetal rat. AB - Perinatal skeletal muscle growth rates are a function of protein and myonuclear accretion. Precocious exposure of the fetus to glucocorticoids (GLC) in utero impairs muscle growth. Reduced muscle protein synthesis rates contribute to this response, but the consequences for myonuclear hyperplasia are unknown. To test the hypothesis that blunting of Pax7+ muscle progenitor cell proliferative activity by GLC in vivo also contributes to reduced fetal muscle growth, pregnant rats were administered dexamethasone (DEX: 1 mg/L drinking water) from embryonic day (ED) 13 to ED21. Their responses were compared to pair-fed (PF) and ad libitum-fed controls (CON). Bromodeoxyuridine (BrdU) was administered before delivery to measure myonuclear accretion. Fetal hind limb and diaphragm muscles were collected at term and analyzed for myofiber cross-sectional area (CSA), total and BrdU+ myonuclei, Pax7+ nuclei, MyoD and myogenin protein and mRNA abundance and myosin heavy chain (MyHC) isoform composition. Mean fiber CSA, myonuclei/myofiber and Pax7+ nuclei/myofiber ratios were reduced in DEX compared to those in CON and PF muscles; CSA/myonucleus, BrdU+/total myonuclei and BrdU+ myonuclei/Pax7+ nuclei were similar among groups. Myogenin abundance was reduced and MyHC-slow was increased in DEX fetuses. The data are consistent with GLC inhibition of muscle progenitor cell proliferation limiting satellite cell and myonuclear accretion. The response of PF-fed compared to CON muscles indicated that decreased food consumption by DEX dams contributed to the smaller myofiber CSA but did not affect Pax7+ nuclear accretion. Thus, the effect on satellite cell reserve and myonuclear number also contributes to the blunting of fetal muscle growth by GLC. PMID- 28096435 TI - Regulation of aldosterone secretion by mineralocorticoid receptor-mediated signaling. AB - We posit the existence of a paracrine/autocrine negative feedback loop, mediated by the mineralocorticoid receptor (MR), regulating aldosterone secretion. To assess this hypothesis, we asked whether altering MR activity in zona glomerulosa (ZG) cells affects aldosterone production. To this end, we studied ex vivo ZG cells isolated from male Wistar rats fed chow containing either high (1.6% Na+ (HS)) or low (0.03% Na+ (LS)) amount of sodium. Western blot analyses demonstrated that MR was present in both the ZG and zona fasciculata/zona reticularis (ZF/ZR/ZR). In ZG cells isolated from rats on LS chow, MR activation by fludrocortisone produced a 20% and 60% reduction in aldosterone secretion basally and in response to angiotensin II (ANGII) stimulation, respectively. Corticosterone secretion was increased in these cells suggesting that aldosterone synthase activity was being reduced by fludrocortisone. In contrast, canrenoic acid, an MR antagonist, enhanced aldosterone production by up to 30% both basally and in response to ANGII. Similar responses were observed in ZG cells from rats fed HS. Modulating glucocorticoid receptor (GR) activity did not alter aldosterone production by ZG cells; however, altering GR activity did modify corticosterone production from ZF/ZR/ZR cells both basally and in response to adrenocorticotropic hormone (ACTH). Additionally, activating the MR in ZF/ZR/ZR cells strikingly reduced corticosterone secretion. In summary, these data support the hypothesis that negative ultra-short feedback loops regulate adrenal steroidogenesis. In the ZG, aldosterone secretion is regulated by the MR, but not the GR, an effect that appears to be secondary to a change in aldosterone synthase activity. PMID- 28096436 TI - Angiotensin II induces differential insulin action in rat skeletal muscle. AB - Angiotensin II (ANGII) is reportedly involved in the development of skeletal muscle insulin resistance. The present investigation evaluated the effects of two ANGII doses on the phenotypic characteristics of insulin resistance syndrome and insulin action and signaling in rat skeletal muscle. Male Sprague-Dawley rats were infused with either saline (SHAM) or ANGII at a commonly used pressor dose (100 ng/kg/min; ANGII-100) or a higher pressor dose (500 ng/kg/min; ANGII-500) via osmotic minipumps for 14 days. We demonstrated that ANGII-100-infused rats exhibited the phenotypic features of non-obese insulin resistance syndrome, including hypertension, impaired glucose tolerance and insulin resistance of glucose uptake in the soleus muscle, whereas ANGII-500-treated rats exhibited diabetes-like symptoms, such as post-prandial hyperglycemia, impaired insulin secretion and hypertriglyceridemia. At the cellular level, insulin-stimulated glucose uptake in the soleus muscle of the ANGII-100 group was 33% lower (P < 0.05) than that in the SHAM group and was associated with increased insulin stimulated IRS-1 Ser307 and decreased Akt Ser473 and AS160 Thr642 phosphorylation and GLUT-4 expression. However, ANGII-500 infusion did not induce skeletal muscle insulin resistance or impair insulin signaling elements as initially anticipated. Moreover, we found that insulin-stimulated glucose uptake in the ANGII-500 group was accompanied by the enhanced expression of ACE2 and MasR proteins, which are the key elements in the non-classical pathway of the renin-angiotensin system. Collectively, this study demonstrates for the first time that chronic infusion with these two pressor doses of ANGII induced differential metabolic responses at both the systemic and skeletal muscle levels. PMID- 28096437 TI - Phase Angle Predicts Arterial Stiffness and Vascular Calcification in Peritoneal Dialysis Patients. AB - OBJECTIVES: Fluid overload (FO) is frequently present in peritoneal dialysis (PD) patients and is associated with markers of malnutrition, inflammation, and atherosclerosis/calcification (MIAC) syndrome. We examined the relationships in stable PD patients between phase angle (PhA) and the spectrum of uremic vasculopathy including vascular calcification and arterial stiffness and between PhA and changes in serum fetuin-A levels. METHODS: Sixty-one stable adult PD patients were evaluated in a cross-sectional study (ST1). Phase angle was measured by multifrequency bioimpedance analysis (InbodyS10, Biospace, Korea) at 50 kHz. Augmentation index (AI), a surrogate marker of arterial stiffness, was assessed by digital pulse amplitude tonometry (Endo PAT, Itamar Medical, Caesarea, Israel). Vascular calcification was assessed by simplified calcification score (SCS). Serum fetuin-A levels were measured by ELISA (Thermo scientific; Waltham, MA, USA). Serum albumin was used as a nutritional marker, and serum C-reactive protein (CRP) was used as an inflammatory marker. The same assessments were carried out longitudinally (ST2) in the first 33 patients who completed 1 year of evaluation in ST1. RESULTS: In ST1, patients with PhA < 6 degrees had higher CRP levels, AI, and SCS and lower serum albumin and fetuin-A levels, in comparison with patients with PhA >= 6 degrees . In addition, PhA was a predictor of both AI (beta = -0.351, p = 0.023) and SCS >= 3 (EXP (B) = 0.243, p = 0.005). In ST2, the increase of PhA over time was associated with decreases in both AI (r = -0.378, p = 0.042) and CRP levels (r = -0.426, p = 0.021), as well as with the increase in serum fetuin-A levels (r = 0.411, p = 0.030). CONCLUSIONS: Phase angle predicts both arterial stiffness and vascular calcification in stable PD patients. PMID- 28096438 TI - Infection Prophylaxis in Peritoneal Dialysis Patients: Results from an Australia/New Zealand Survey. AB - ? BACKGROUND: Clinical practice guidelines aim to reduce the rates of peritoneal dialysis (PD)-related infections, a common complication of PD in end-stage kidney disease patients. We describe the clinical practices used by Australian and New Zealand nephrologists to prevent PD-related infections in PD patients. ? METHODS: A survey of PD practices in relation to the use of antibiotic and antifungal prophylaxis in PD patients was conducted of practicing nephrologists identified via the Australia and New Zealand Society of Nephrology (ANZSN) membership in 2013. ? RESULTS: Of 333 nephrologists approached, 133 (39.9%) participated. Overall, 127 (95.5%) nephrologists prescribed antibiotics at the time of Tenckhoff catheter insertion, 85 (63.9%) routinely screened for nasal S. aureus carriage, with 76 (88.4%) reporting they treated S. aureus carriers with mupirocin ointment. Following Tenckhoff catheter insertion, 79 (59.4%) prescribed mupirocin ointment at the exit site or intranasally, and 93 (69.9%) nephrologists routinely prescribed a course of oral antifungal agent whenever their PD patients were given a course of antibiotics. ? CONCLUSIONS: Although the majority of nephrologists prescribe antibiotics at the time of Tenckhoff catheter insertion, less than 70% routinely prescribe mupirocin ointment and/or prophylactic antifungal therapy. This variation in practice in Australia and New Zealand may contribute to the disparity in PD-related infection rates that is seen between units. PMID- 28096439 TI - The 24-Month Changes in Body Fat Mass and Adipokines in Patients Starting Peritoneal Dialysis. AB - ? BACKGROUND: Peritoneal dialysis (PD) is characterized by a gain in fat mass. The fat tissue is a complex endocrine organ that releases various adipokines. In this study, we prospectively examined serial changes of fat composition and adipokines in patients undergoing PD. ? METHODS: Body composition was assessed by computed tomography (CT). Nutrition status and adipokines (leptin, adiponectin, interleukin [IL]-6, and tumor necrosis factor [TNF]-alpha) were assessed on the 7th day and 6 months, 12 months, and 24 months after the start of PD. ? RESULTS: Fifty-four patients (28 men), with a mean age of 53.2 +/- 13.2 years, were enrolled. Baseline fat mass, especially subcutaneous fat mass, was correlated with baseline leptin (rho = 0.612), adiponetin (rho = -0.477), and interleukin-6 (IL-6) (rho = 0.391). Visceral fat mass was correlated with leptin (rho = 0.545) and adiponectin (rho = -0.514). Baseline adiponectin was negatively correlated with baseline leptin (rho = -0.363). While body weight and leptin increased during the 24 months, serum adiponectin decreased in that period. The changes in visceral and subcutaneous fat mass were greater in the first 12 months and 6 months, respectively. There was no difference in IL-6 and TNF-alpha. Eight patients died during the follow-up period (mean 47.4 months). Twenty-seven patients continued PD. Increased baseline and serial change of IL-6 level were risk factors for mortality. After adjusting for age, sex, diabetes mellitus (DM), and coronary vascular disease (CVD), the significance of the IL-6 level disappeared. ? CONCLUSIONS: Baseline subcutaneous fat in patients starting PD is correlated with baseline adipokine levels rather than visceral fat. The increase in subcutaneous fat was greatest in the first 6 months. While leptin and adiponectin increased and decreased respectively, IL-6 did not change in the first 24 months. PMID- 28096440 TI - TNF Signaling in Peritoneal Mesothelial Cells: Pivotal Role of cFLIPL. AB - ? BACKGROUND: Peritoneal dialysis (PD) coincides with high concentrations of proinflammatory cytokines, such as tumor necrosis factor (TNF), in the peritoneal cavity. During treatment, chronic inflammatory processes lead to damage of the peritoneal membrane and a subsequent ultrafiltration failure. Human peritoneal mesothelial cells (HPMCs) play a central role as mediators and targets of PD related inflammatory changes. Although TNF Receptor 1 (TNFR1) is expressed in high numbers on the cells, TNF-induced apoptosis is inhibited. Here, the underlying molecular mechanisms of TNFR1 signaling in HPMCs are investigated. ? METHODS: Human peritoneal mesothelial cells were isolated from the omentum of healthy donors and the dialysis solution of PD patients. Flow cytometry was applied to determine cell surface expression of TNFR1 on HPMCS from healthy donors in absence or presence of TNF or PD fluid (PDF) and were compared to TNFR1 expression on cells from PD patients. To investigate TNFR1-mediated signaling, HPMCs were treated with PDF or TNF, and expression patterns of proteins involved in the TNFR1 signaling pathway were assessed by western blot. ? RESULTS: Incubation with PDF led to a significant up-regulation of TNFR1 on the cell surface correlating with elevated TNFR1 numbers on HPMCs from PD patients. Investigations of underlying molecular mechanisms of TNFR1 signaling showed that PDF affects TNFR1 signaling at the proapoptotic signaling pathway by upregulation of IkappaBalpha and downregulation of cFLIPL. In contrast, TNF exclusively induces the activation of NFkappaB by an increase of phosphorylated IkappaBalpha. ? CONCLUSIONS: Novel and relevant insights into the mechanisms of TNFR1-mediated signaling in HPMCs with an impact on our understanding of PD-associated damage of the peritoneal membrane are shown. PMID- 28096441 TI - Improved Outcome of Enteric Peritonitis in Peritoneal Dialysis Patients Aged 50 Years and Older with Temporary Discontinuation of Peritoneal Dialysis and Intravenous Meropenem. AB - ? BACKGROUND: Peritonitis is a major cause of morbidity, mortality, and technique failure in peritoneal dialysis (PD) patients, especially when caused by enteric microorganisms (EM). We have implemented a treatment protocol specifically aimed at improving the outcome in EM peritonitis. The adapted protocol was applied in all PD patients 50 years and older presenting with peritonitis who were considered to be at risk of EM peritonitis and involves 3 interventions: 1) temporary discontinuation of PD without removing the catheter (peritoneal rest), 2) intravenous meropenem, and 3) meropenem intracatheter as lock (Mero-PerRest protocol). ? METHODS: In this observational study, we compared the outcome of 203 peritonitis episodes in 71 patients treated with the Mero-PerRest protocol, with 217 episodes in 104 patients treated with a more traditional intraperitoneal gentamicin-rifampicin-based regimen. ? RESULTS: In EM peritonitis episodes, the Mero-PerRest protocol resulted in a higher primary cure rate (90.0% vs 65.3%, adjusted odds ratio [OR] 4.54 [95% confidence interval (CI) 1.46 - 14.15]) and better technique survival (90.0% vs 69.4%, adjusted OR 3.41 [95% CI 1.07 - 10.87]). This effect was most distinct in patients with polymicrobial EM peritonitis (cure rate 87.5% vs 34.8%, p = 0.0003). Interestingly, primary cure rate (95.6% vs 84.7%, adjusted OR 3.92 [95% CI 1.37 - 11.19]) and technique survival (95.6% vs 85.6%, adjusted OR 3.60 [95% CI 1.25 - 10.32]) were also excellent in non-EM peritonitis episodes. Patient survival did not differ significantly. ? CONCLUSION: The poor outcome of peritonitis caused by EM in PD patients aged 50 years and older could be improved by applying a treatment protocol involving temporary discontinuation of PD without catheter removal and intravenous and intracatheter meropenem. PMID- 28096442 TI - Kinetic Modeling of Incremental Ambulatory Peritoneal Dialysis Exchanges. AB - ? BACKGROUND: Incremental peritoneal dialysis (PD), the gradual introduction of dialysate exchanges at less than full-dose therapy, has been infrequently described in clinical reports. One concern with less than full-dose dialysis is whether urea clearance targets are achievable with an incremental regimen. In this report, we used a large database of PD patients, across all membrane transport types, and performed urea kinetic modeling determinations of possible incremental regimens for an individual membrane type. ? METHODS: Using a modified 3-pore model of peritoneal transport, various incremental manual continuous ambulatory PD (CAPD) exchanges employing glucose and/or icodextrin were evaluated. Peritoneal urea clearances from those simulations were added to residual kidney urea clearance for patients with various glomerular filtration rates (GFRs), and the total weekly urea clearance was then compared to the total weekly urea Kt/V target of 1.7. All 4 peritoneal membrane types were modeled. For each simulated prescription, net ultrafiltration and carbohydrate absorption were also calculated. ? RESULTS: Incremental CAPD regimens of 2 exchanges a day met adequacy targets if the GFR was 6 mL/min/1.73 m2 in all membrane types. For regimens employing 3 exchanges a day, Kt/V targets were achieved at GFR levels of 4 to 5 mL/min/1.73 m2 in high transporters to low transporters but higher tonicity 2.5% glucose solutions or icodextrin were required in some regimens. ? CONCLUSIONS: This work demonstrates that with incremental CAPD regimens, urea kinetic targets are achievable in most new starts to PD with residual kidney function. Incremental PD may be a less intrusive, better accepted initial treatment regime and a cost-effective way to initiate chronic dialysis in the incident patient. The key role of intrinsic kidney function in incremental regimens is highlighted in this analysis and would warrant conscientious monitoring. PMID- 28096443 TI - Stem-loop RNA labeling can affect nuclear and cytoplasmic mRNA processing. AB - The binding of sequence-specific RNA-interacting proteins, such as the bacteriophage MS2 or PP7 coat proteins, to their corresponding target sequences has been extremely useful and widely used to visualize single mRNAs in vivo. However, introduction of MS2 stem-loops into yeast mRNAs has recently been shown to lead to the accumulation of RNA fragments, suggesting that the loops impair mRNA decay. This result was questioned, because fragment occurrence was mainly assessed using ensemble methods, and their cellular localization and its implications had not been addressed on a single transcript level. Here, we demonstrate that the introduction of either MS2 stem-loops (MS2SL) or PP7 stem loops (PP7SL) can affect the processing and subcellular localization of mRNA. We use single-molecule fluorescence in situ hybridization (smFISH) to determine the localization of three independent mRNAs tagged with the stem-loop labeling systems in glucose-rich and glucose starvation conditions. Transcripts containing MS2SL or PP7SL display aberrant localization in both the nucleus and the cytoplasm. These defects are most prominent in glucose starvation conditions, with nuclear mRNA processing being altered and stem-loop fragments abnormally enriching in processing bodies (PBs). The mislocalization of SL-containing RNAs is independent of the presence of the MS2 or PP7 coat protein (MCP or PCP). PMID- 28096444 TI - Single-molecule FRET-Rosetta reveals RNA structural rearrangements during human telomerase catalysis. AB - Maintenance of telomeres by telomerase permits continuous proliferation of rapidly dividing cells, including the majority of human cancers. Despite its direct biomedical significance, the architecture of the human telomerase complex remains unknown. Generating homogeneous telomerase samples has presented a significant barrier to developing improved structural models. Here we pair single molecule Forster resonance energy transfer (smFRET) measurements with Rosetta modeling to map the conformations of the essential telomerase RNA core domain within the active ribonucleoprotein. FRET-guided modeling places the essential pseudoknot fold distal to the active site on a protein surface comprising the C terminal element, a domain that shares structural homology with canonical polymerase thumb domains. An independently solved medium-resolution structure of Tetrahymena telomerase provides a blind test of our modeling methodology and sheds light on the structural homology of this domain across diverse organisms. Our smFRET-Rosetta models reveal nanometer-scale rearrangements within the RNA core domain during catalysis. Taken together, our FRET data and pseudoatomic molecular models permit us to propose a possible mechanism for how RNA core domain rearrangement is coupled to template hybrid elongation. PMID- 28096445 TI - Unraveling the stereochemical and dynamic aspects of the catalytic site of bacterial peptidyl-tRNA hydrolase. AB - Bacterial peptidyl-tRNA hydrolase (Pth; EC 3.1.1.29) hydrolyzes the peptidyl tRNAs accumulated in the cytoplasm and thereby prevents cell death by alleviating tRNA starvation. X-ray and NMR studies of Vibrio cholerae Pth (VcPth) and mutants of its key residues involved in catalysis show that the activity and selectivity of the protein depends on the stereochemistry and dynamics of residues H24, D97, N118, and N14. D97-H24 interaction is critical for activity because it increases the nucleophilicity of H24. The N118 and N14 have orthogonally competing interactions with H24, both of which reduce the nucleophilicity of H24 and are likely to be offset by positioning of a peptidyl-tRNA substrate. The region proximal to H24 and the lid region exhibit slow motions that may assist in accommodating the substrate. Helix alpha3 exhibits a slow wobble with intermediate time scale motions of its N-cap residue N118, which may work as a flypaper to position the scissile ester bond of the substrate. Overall, the dynamics of interactions between the side chains of N14, H24, D97, and N118, control the catalysis of substrate by this enzyme. PMID- 28096446 TI - Rpn (YhgA-Like) Proteins of Escherichia coli K-12 and Their Contribution to RecA Independent Horizontal Transfer. AB - Bacteria use a variety of DNA-mobilizing enzymes to facilitate environmental niche adaptation via horizontal gene transfer. This has led to real-world problems, like the spread of antibiotic resistance, yet many mobilization proteins remain undefined. In the study described here, we investigated the uncharacterized family of YhgA-like transposase_31 (Pfam PF04754) proteins. Our primary focus was the genetic and biochemical properties of the five Escherichia coli K-12 members of this family, which we designate RpnA to RpnE, where Rpn represents recombination-promoting nuclease. We employed a conjugal system developed by our lab that demanded RecA-independent recombination following transfer of chromosomal DNA. Overexpression of RpnA (YhgA), RpnB (YfcI), RpnC (YadD), and RpnD (YjiP) increased RecA-independent recombination, reduced cell viability, and induced the expression of reporter of DNA damage. For the exemplar of the family, RpnA, mutational changes in proposed catalytic residues reduced or abolished all three phenotypes in concert. In vitro, RpnA displayed magnesium dependent, calcium-stimulated DNA endonuclease activity with little, if any, sequence specificity and a preference for double-strand cleavage. We propose that Rpn/YhgA-like family nucleases can participate in gene acquisition processes.IMPORTANCE Bacteria adapt to new environments by obtaining new genes from other bacteria. Here, we characterize a set of genes that can promote the acquisition process by a novel mechanism. Genome comparisons had suggested the horizontal spread of the genes for the YhgA-like family of proteins through bacteria. Although annotated as transposase_31, no member of the family has previously been characterized experimentally. We show that four Escherichia coli K-12 paralogs contribute to a novel RecA-independent recombination mechanism in vivo For RpnA, we demonstrate in vitro action as a magnesium-dependent, calcium stimulated nonspecific DNA endonuclease. The cleavage products are capable of providing priming sites for DNA polymerase, which can enable DNA joining by primer-template switching. PMID- 28096447 TI - PBP1B Glycosyltransferase and Transpeptidase Activities Play Different Essential Roles during the De Novo Regeneration of Rod Morphology in Escherichia coli. AB - Peptidoglycan is a vital component of nearly all cell wall-bearing bacteria and is a valuable target for antibacterial therapy. However, despite decades of work, there remain important gaps in understanding how this macromolecule is synthesized and molded into a three-dimensional structure that imparts specific morphologies to individual cells. Here, we investigated the particularly enigmatic area of how peptidoglycan is synthesized and shaped during the first stages of creating cell shape de novo, that is, in the absence of a preexisting template. We found that when lysozyme-induced (LI) spheroplasts of Escherichia coli were allowed to resynthesize peptidoglycan, the cells divided first and then elongated to recreate a normal rod-shaped morphology. Penicillin binding protein 1B (PBP1B) was critical for the first stage of this recovery process. PBP1B synthesized peptidoglycan de novo, and this synthesis required that PBP1B interact with the outer membrane lipoprotein LpoB. Surprisingly, when LpoB was localized improperly to the inner membrane, recovering spheroplasts synthesized peptidoglycan and divided but then propagated as amorphous spheroidal cells, suggesting that the regeneration of a normal rod shape depends on a particular spatial interaction. Similarly, spheroplasts carrying a PBP1B variant lacking transpeptidase activity or those in which PBP1A was overproduced could synthesize new peptidoglycan and divide but then grew as oddly shaped spheroids. We conclude that de novo cell wall synthesis requires the glycosyltransferase activity of PBP1B but that PBP1B transpeptidase activity is needed to assemble cell walls with wild-type morphology.IMPORTANCE Bacterial cell wall peptidoglycan is synthesized and modified by penicillin binding proteins (PBPs), which are targeted by about half of all currently prescribed antibiotics, including penicillin and its derivatives. Because antibiotic resistance is rising, it has become increasingly urgent that we fill the gaps in our knowledge about how PBPs create and assemble this protective wall. We report here that PBP1B plays an essential role in synthesizing peptidoglycan in the absence of a preexisting template: its glycosyltransferase activity is responsible for de novo synthesis, while its transpeptidase activity is required to construct cell walls of a specific shape. These results highlight the importance of this enzyme and distinguish its biological roles from those of other PBPs and peptidoglycan synthases. PMID- 28096448 TI - Loss-of-Function Mutations in HspR Rescue the Growth Defect of a Mycobacterium tuberculosis Proteasome Accessory Factor E (pafE) Mutant. AB - Mycobacterium tuberculosis uses a proteasome to degrade proteins by both ATP dependent and -independent pathways. While much has been learned about ATP dependent degradation, relatively little is understood about the ATP-independent pathway, which is controlled by Mycobacterium tuberculosisproteasome accessory factor E (PafE). Recently, we found that a Mycobacterium tuberculosispafE mutant has slowed growth in vitro and is sensitive to killing by heat stress. However, we did not know if these phenotypes were caused by an inability to degrade the PafE-proteasome substrate HspR (heat shock protein repressor), an inability to degrade any damaged or misfolded proteins, or a defect in another protein quality control pathway. To address this question, we characterized pafE suppressor mutants that grew similarly to pafE+ bacteria under normal culture conditions. All but one suppressor mutant analyzed contained mutations that inactivated HspR function, demonstrating that the slowed growth and heat shock sensitivity of a pafE mutant were caused primarily by the inability of the proteasome to degrade HspR.IMPORTANCEMycobacterium tuberculosis encodes a proteasome that is highly similar to eukaryotic proteasomes and is required for virulence. We recently discovered a proteasome cofactor, PafE, which is required for the normal growth, heat shock resistance, and full virulence of M. tuberculosis In this study, we demonstrate that PafE influences this phenotype primarily by promoting the expression of protein chaperone genes that are necessary for surviving proteotoxic stress. PMID- 28096449 TI - Specific Glucoside Transporters Influence Septal Structure and Function in the Filamentous, Heterocyst-Forming Cyanobacterium Anabaena sp. Strain PCC 7120. AB - When deprived of combined nitrogen, some filamentous cyanobacteria contain two cell types: vegetative cells that fix CO2 through oxygenic photosynthesis and heterocysts that are specialized in N2 fixation. In the diazotrophic filament, the vegetative cells provide the heterocysts with reduced carbon (mainly in the form of sucrose) and heterocysts provide the vegetative cells with combined nitrogen. Septal junctions traverse peptidoglycan through structures known as nanopores and appear to mediate intercellular molecular transfer that can be traced with fluorescent markers, including the sucrose analog esculin (a coumarin glucoside) that is incorporated into the cells. Uptake of esculin by the model heterocyst-forming cyanobacterium Anabaena sp. strain PCC 7120 was inhibited by the alpha-glucosides sucrose and maltose. Analysis of Anabaena mutants identified components of three glucoside transporters that move esculin into the cells: GlsC (Alr4781) and GlsP (All0261) are an ATP-binding subunit and a permease subunit of two different ABC transporters, respectively, and HepP (All1711) is a major facilitator superfamily (MFS) protein that was shown previously to be involved in formation of the heterocyst envelope. Transfer of fluorescent markers (especially calcein) between vegetative cells of Anabaena was impaired by mutation of glucoside transporter genes. GlsP and HepP interact in bacterial two-hybrid assays with the septal junction-related protein SepJ, and GlsC was found to be necessary for the formation of a normal number of septal peptidoglycan nanopores and for normal subcellular localization of SepJ. Therefore, beyond their possible role in nutrient uptake in Anabaena, glucoside transporters influence the structure and function of septal junctions.IMPORTANCE Heterocyst-forming cyanobacteria have the ability to perform oxygenic photosynthesis and to assimilate atmospheric CO2 and N2 These organisms grow as filaments that fix these gases specifically in vegetative cells and heterocysts, respectively. For the filaments to grow, these types of cells exchange nutrients, including sucrose, which serves as a source of reducing power and of carbon skeletons for the heterocysts. Movement of sucrose between cells in the filament takes place through septal junctions and has been traced with a fluorescent sucrose analog, esculin, that can be taken up by the cells. Here, we identified alpha-glucoside transporters of Anabaena that mediate uptake of esculin and, notably, influence septal structure and the function of septal junctions. PMID- 28096450 TI - Analysis of genome instability biomarkers in children with non-syndromic orofacial clefts. AB - The non-syndromic cleft lip and/or palate (NSCL/P) is a common birth defect caused by a combination of genetic and environmental factors. The possible role of genome instability on NSCL/P patient needs more investigation, since DNA metabolism is an essential cellular function to keep cells with normal genotypes and gene expression patterns according to tissue specificities, which is critical during embryo development because it requires sensitive regulation of cell proliferation, apoptosis and differentiation. Thus, genome stability is ultimately essential to maintain a healthy life. The aim of this study was to assess the frequency of genome instability biomarkers and their relationship with NSCL/P. Cytokinesis-block micronucleus assay was performed to estimate the biomarkers frequency and gene expression was analyzed by the transcriptogram in order to further explore the role of genome instability and other biological processes in this birth defect. The NSCL/P patients had higher baseline frequency of micronucleus, nuclear buds and nucleoplasmic bridges (P < 0.001) than the control group. Moreover, new nuclear morphologies (fused, circular and horseshoe) was detected in the patients' cells analyzed, possibly indicating that chronic folic acid deficiency is interfering in their genome instability. Children with clefts had 2.3 times more risk to have high micronuclei frequency (P = 0.043) according to binary logistic regression. The high genomic instability in children with oral clefts suggests that misrepaired double strand breaks in DNA that create micronuclei representing a significant factor in NSCL/P development. This study was published in 52nd EUROTOX Abstract Book. PMID- 28096452 TI - M-INK, a novel tool for visualizing melanosomes and melanocores. AB - Melanosome transfer from melanocytes to surrounding keratinocytes is one of the crucial but less well-characterized steps in the process of skin pigmentation. Although several markers have generally been used to detect melanosomes in melanocytes, no suitable markers for melanosomes that have been transferred into keratinocytes have ever been reported. The melanocore-interacting Kif1c-tail (M INK) probe we developed and reported here specifically recognizes melanocores and thus makes visualizing melanosomes that have been incorporated into keratinocytes possible even in a fluorescent field. M-INK staining makes it possible to reconstruct 3D images of melanosome-containing keratinocytes, and thereby precisely localize melanosomes in keratinocytes. PMID- 28096451 TI - Quantitative relationships between lacZ mutant frequency and DNA adduct frequency in MutaTMMouse tissues and cultured cells exposed to 3-nitrobenzanthrone. AB - The frequency of stable DNA adducts in a target tissue can be used to assess biologically effective dose; however, the utility of the metric in a risk assessment context depends on the likelihood that the DNA damage will be manifested as mutation. Previously, we employed the MutaTMMouse system to examine the induction of lacZ mutants and DNA adducts following exposure to the well studied mutagenic carcinogen 3-nitrobenzanthrone (3-NBA). In this follow-up work, we examined the empirical relationships between total adduct frequency and mutant frequency (MF) in tissues and cultured cells following acute 3-NBA exposure. The results show a significant induction of DNA damage and lacZ mutants in liver, colon and bone marrow, as well as FE1 pulmonary epithelial cells. In contrast, lung and small intestine samples had low, but significantly elevated adduct levels, with no significant increases in lacZ MF. Additional analyses showed a significant relationship between the mutagenic efficiency of total adducts, measured as the slope of the relationships between MF and total adduct frequency, and tissue-specific mitotic index (MI). The lack of mutation response in lung, in contrast to the high in vitro MF in FE-1 lung cells, is likely related to the 100 fold difference in MI. The lack of small intestine mutagenic response may be related to limited metabolic capacity, differences in DNA repair, and /or chemically induced apoptosis that has been observed for other potent mutagens. The results indicate that interpretation of adduct frequency values in a risk assessment context can be improved by considering the MI of the target tissue; however, more generalised interpretation is hampered by tissue-specific variations in metabolic capacity and damage processing. The work provides a proof of principle regarding the use of the MutaTMMouse system to critically examine the health risks associated with tissue-specific adduct loads. PMID- 28096453 TI - Programmable formation of catalytic RNA triangles and squares by assembling modular RNA enzymes. AB - RNA is a biopolymer that is attractive for constructing nano-scale objects with complex structures. Three-dimensional (3D) structures of naturally occurring RNAs often have modular architectures. The 3D structure of a group I (GI) ribozyme from Tetrahymena has a typical modular architecture, which can be separated into two structural modules (DeltaP5 and P5abc). The fully active ribozyme can be reconstructed by assembling the two separately prepared modules through highly specific and strong assembly between DeltaP5 ribozyme and P5abc RNA. Such non covalent assembly of the two modules allows the design of polygonal RNA nano structures. Through rational redesign of the parent GI ribozyme, we constructed variant GI ribozymes as unit RNAs for polygonal-shaped (closed) oligomers with catalytic activity. Programmed trimerization and tetramerization of the unit RNAs afforded catalytically active nano-sized RNA triangles and squares, the structures of which were directly observed by atomic force microscopy (AFM). PMID- 28096454 TI - Mitochondrial function is required for extracellular ATP-induced NLRP3 inflammasome activation. AB - The NLRP3 inflammasome plays a critical role in the processing and release of inflammatory cytokines, such as interleukin-1beta (IL-1beta) and IL-18. Accumulating evidence suggests that mitochondria are common mediators of NLRP3 inflammasome activation induced by a wide range of inflammatory stimuli; however, the precise role of mitochondria is still not fully understood. Here, we show that mitochondrial function is required for extracellular ATP-induced NLRP3 inflammasome activation. Extracellular ATP induced the loss of mitochondrial membrane potential and mitochondrial fragmentation in a different manner than other stimuli in primary mouse macrophages. CCCP, an uncoupler and antimycin A, an inhibitor of the mitochondrial electron transport chain, inhibited IL-1beta release induced by ATP but not by other stimuli. CCCP did not inhibit the ATP induced generation of reactive oxygen species and cell death, both of which are known to promote IL-1beta release, but did inhibit the ATP-induced activation of caspase-1, a component of the NLRP3 inflammasome. These results suggest that mitochondrial function is required somewhat specifically for ATP-induced NLRP3 inflammasome activation. In contrast to many previous reports that dysfunctional mitochondria promote NLRP3 inflammasome activation, the function of intact mitochondria appears to be required for NLRP3 inflammasome activation, depending on the stimulus. PMID- 28096455 TI - Multicenter prospective study on device-associated infection rates and bacterial resistance in intensive care units of Venezuela: International Nosocomial Infection Control Consortium (INICC) findings. AB - BACKGROUND: Device-associated healthcare-acquired infections (DA-HAI) pose a threat to patient safety in the intensive care unit (ICU). METHODS: A DA-HAI surveillance study was conducted by the International Nosocomial Infection Control Consortium (INICC) in two adult medical/surgical ICUs at two hospitals in Caracas, Venezuela, in different periods from March 2008 to April 2015, using the US Centers for Disease Control and Prevention's National Healthcare Safety Network (CDC/NHSN) definitions and criteria, and INICC methods. RESULTS: We followed 1041 ICU patients for 4632 bed days. Central line-associated bloodstream infection (CLABSI) rate was 5.1 per 1000 central line days, ventilator-associated pneumonia (VAP) rate was 7.2 per 1000 mechanical ventilator days, and catheter associated urinary tract infection (CAUTI) rate was 3.9 per 1000 urinary catheter days, all similar to or lower than INICC rates (4.9 [CLABSI]; 16.5 [VAP]; 5.3 [CAUTI]), and higher than CDC/NHSN rates (0.8 [CLABSI]; 1.1 [VAP]; and 1.3 [CAUTI]). Device utilization ratios were higher than INICC and CDC/NHSN rates, except for urinary catheter, which was similar to INICC. Extra length of stay was 8 days for patients with CLABSI, 9.6 for VAP and 5.7 days for CAUTI. Additional crude mortality was 3.0% for CLABSI, 4.4% for VAP, and 16.9% for CAUTI. CONCLUSIONS: DA-HAI rates in our ICUs are higher than CDC/NSHN's and similar to or lower than INICC international rates. PMID- 28096456 TI - Antibody-Conjugated, DNA-Based Nanocarriers Intercalated with Doxorubicin Eliminate Myofibroblasts in Explants of Human Lens Tissue. AB - Posterior capsule opacification (PCO) occurs in some adults and most children following cataract surgery. The fibrotic form of PCO arises, in part, from migratory, contractile myofibroblasts that deform the lens capsule and impair vision. In short-term cultures of human anterior lens tissue, myofibroblasts emerge from Myo/Nog cells that are identified with the G8 monoclonal antibody and by their expression of the MyoD transcription factor and bone morphogenetic protein inhibitor noggin. In this study, we tested the hypothesis that targeted depletion of Myo/Nog cells with the G8 monoclonal antibody (mAb) conjugated to three-dimensional DNA nanocarriers intercalated with doxorubicin (G8:3DNA:Dox) would prevent the accumulation of myofibroblasts in long-term, serum- and growth factor-free cultures of human lens tissue obtained by capsulorhexis. The mAb:nanocarrier complex was internalized into acidic compartments of the cell. G8:3DNA:Dox killed nearly all Myo/Nog cells without affecting the lens epithelial cells. In 30-day cultures, all G8-positive cells expressed noggin, and subpopulations had synthesized MyoD, sarcomeric myosin, and alpha smooth muscle actin (alpha-SMA). Myo/Nog cells responded to scratching of the lens epithelium by accumulating around the edges of the wound. Treatment with two doses of G8:3DNA:Dox completely eliminated G8+/alpha-SMA+ cells throughout the explant. These experiments demonstrate that Myo/Nog cells are the source of myofibroblasts in long-term cultures of anterior human lens tissue and mAb:3DNA nanocarriers specifically and effectively deliver cytotoxic cargo to a subpopulation of cells without off-target effects. G8:3DNA:Dox has the potential to reduce PCO following cataract surgery. PMID- 28096457 TI - The predictive value of serum S100A9 and response to etanercept is not confirmed in a large UK rheumatoid arthritis cohort. AB - Objective: The aim was to correlate protein concentrations of S100A9 in pretreatment serum samples with response to the tumour-necrosis factor (TNF) inhibitor drugs etanercept in a large UK replication cohort. Methods: Pretreatment serum samples from patients with RA (n = 236) about to commence treatment with etanercept had S100A9 serum concentration measured using an ELISA. Following the experimental procedure, S100A9 concentrations were analysed with respect to EULAR response. Results: No evidence of association between S100A9 concentration and EULAR response to the TNF-inhibitor biologic drug etanercept was observed following multinomial logistic regression analysis (non-responder vs moderate responder, P = 0.957; and non-responder vs good responder, P = 0.316). Furthermore, no significant associations were observed when correlating pretreatment S100A9 concentrations with clinical parameters of disease activity (P > 0.05). Conclusion: In the largest replication cohort conducted to date, no evidence for association was observed to support the use of S100A9 as a clinical biomarker predictive of response to the TNF-inhibitor biologic drug etanercept. PMID- 28096458 TI - More severe disease and slower recovery in younger patients with anti-3-hydroxy-3 methylglutaryl-coenzyme A reductase-associated autoimmune myopathy. AB - Objective: To study disease severity and response to therapy in a large cohort of patients with anti-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) associated myositis. Methods: Muscle strength, creatine kinase levels and treatments were assessed in anti-HMGCR-positive patients at each clinical visit. Univariate and multivariate analyses were used to analyse the influence of clinical characteristics on strength and the change in strength over time. Whole exome sequencing was performed in a subset of patients. Results: . Among 50 patients followed for ?2 years, only 22 (44%) reached full strength with immunosuppressive therapy; even among those with full strength, 55% continued to have CK levels in excess of 500 IU/l and only three could be tapered off immunosuppressive therapy. Both univariate and multivariate analysis showed that patients who were older at disease onset were stronger at all time points (P < 0.001) and improved faster (P < 0.008) than younger patients; a history of statin exposure was not independently associated with the improvement rate. Younger patients were more likely to have refractory disease (P = 0.02) than older patients. Among eight refractory patients with DNA available for testing, whole exome sequencing did not reveal pathogenic mutations in known dystrophy genes. The risk of cancer was not increased in anti-HMGCR myositis patients compared with the general population. Conclusions: Anti-HMGCR myositis is usually a chronic disease requiring long-term immunosuppression. Although younger patients had more severe disease and a worse prognosis than older patients, they did not have evidence of a known co-existing muscular dystrophy to explain their persistent, and sometimes progressive, muscle weakness. PMID- 28096459 TI - Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by gamma-Secretase and Amyloid-beta Peptide Production. AB - Recent evidence suggests involvement of biometal homeostasis in the pathological mechanisms in Alzheimer's disease (AD). For example, increased intracellular copper or zinc has been linked to a reduction in secreted levels of the AD causing amyloid-beta peptide (Abeta). However, little is known about whether these biometals modulate the generation of Abeta. In the present study we demonstrate in both cell-free and cell-based assays that zinc and copper regulate Abeta production by distinct molecular mechanisms affecting the processing by gamma-secretase of its Abeta precursor protein substrate APP-C99. We found that Zn2+ induces APP-C99 dimerization, which prevents its cleavage by gamma-secretase and Abeta production, with an IC50 value of 15 MUm Importantly, at this concentration, Zn2+ also drastically raised the production of the aggregation prone Abeta43 found in the senile plaques of AD brains and elevated the Abeta43:Abeta40 ratio, a promising biomarker for neurotoxicity and AD. We further demonstrate that the APP-C99 histidine residues His-6, His-13, and His-14 control the Zn2+-dependent APP-C99 dimerization and inhibition of Abeta production, whereas the increased Abeta43:Abeta40 ratio is substrate dimerization-independent and involves the known Zn2+ binding lysine Lys-28 residue that orientates the APP C99 transmembrane domain within the lipid bilayer. Unlike zinc, copper inhibited Abeta production by directly targeting the subunits presenilin and nicastrin in the gamma-secretase complex. Altogether, our data demonstrate that zinc and copper differentially modulate Abeta production. They further suggest that dimerization of APP-C99 or the specific targeting of individual residues regulating the production of the long, toxic Abeta species, may offer two therapeutic strategies for preventing AD. PMID- 28096460 TI - Occupancy of the Zinc-binding Site by Transition Metals Decreases the Substrate Affinity of the Human Dopamine Transporter by an Allosteric Mechanism. AB - The human dopamine transporter (DAT) has a tetrahedral Zn2+-binding site. Zn2+ binding sites are also recognized by other first-row transition metals. Excessive accumulation of manganese or of copper can lead to parkinsonism because of dopamine deficiency. Accordingly, we examined the effect of Mn2+, Co2+, Ni2+, and Cu2+ on transport-associated currents through DAT and DAT-H193K, a mutant with a disrupted Zn2+-binding site. All transition metals except Mn2+ modulated the transport cycle of wild-type DAT with affinities in the low micromolar range. In this concentration range, they were devoid of any action on DAT-H193K. The active transition metals reduced the affinity of DAT for dopamine. The affinity shift was most pronounced for Cu2+, followed by Ni2+ and Zn2+ (= Co2+). The extent of the affinity shift and the reciprocal effect of substrate on metal affinity accounted for the different modes of action: Ni2+ and Cu2+ uniformly stimulated and inhibited, respectively, the substrate-induced steady-state currents through DAT. In contrast, Zn2+ elicited biphasic effects on transport, i.e. stimulation at 1 MUm and inhibition at 10 MUm A kinetic model that posited preferential binding of transition metal ions to the outward-facing apo state of DAT and a reciprocal interaction of dopamine and transition metals recapitulated all experimental findings. Allosteric activation of DAT via the Zn2+-binding site may be of interest to restore transport in loss-of-function mutants. PMID- 28096461 TI - Differential Contribution of Transmembrane Domains IV, V, VI, and VII to Human Angiotensin II Type 1 Receptor Homomer Formation. AB - G protein-coupled receptors (GPCRs) play an important role in drug therapy and represent one of the largest families of drug targets. The angiotensin II type 1 receptor (AT1R) is notable as it has a central role in the treatment of cardiovascular disease. Blockade of AT1R signaling has been shown to alleviate hypertension and improve outcomes in patients with heart failure. Despite this, it has become apparent that our initial understanding of AT1R signaling is oversimplified. There is considerable evidence to suggest that AT1R signaling is highly modified in the presence of receptor-receptor interactions, but there is very little structural data available to explain this phenomenon even with the recent elucidation of the AT1R crystal structure. The current study investigates the involvement of transmembrane domains in AT1R homomer assembly with the goal of identifying hydrophobic interfaces that contribute to receptor-receptor affinity. A recently published crystal structure of the AT1R was used to guide site-directed mutagenesis of outward-facing hydrophobic residues within the transmembrane region of the AT1R. Bioluminescence resonance energy transfer was employed to analyze how receptor mutation affects the assembly of AT1R homomers with a specific focus on hydrophobic residues. Mutations within transmembrane domains IV, V, VI, and VII had no effect on angiotensin-mediated beta-arrestin1 recruitment; however, they exhibited differential effects on the assembly of AT1R into oligomeric complexes. Our results demonstrate the importance of hydrophobic amino acids at the AT1R transmembrane interface and provide the first glimpse of the requirements for AT1R complex assembly. PMID- 28096462 TI - Unique Contributions of an Arginine Side Chain to Ligand Recognition in a Glutamate-gated Chloride Channel. AB - Glutamate recognition by neurotransmitter receptors often relies on Arg residues in the binding site, leading to the assumption that charge-charge interactions underlie ligand recognition. However, assessing the precise chemical contribution of Arg side chains to protein function and pharmacology has proven to be exceedingly difficult in such large and complex proteins. Using the in vivo nonsense suppression approach, we report the first successful incorporation of the isosteric, titratable Arg analog, canavanine, into a neurotransmitter receptor in a living cell, utilizing a glutamate-gated chloride channel from the nematode Haemonchus contortus Our data unveil a surprisingly small contribution of charge at a conserved arginine side chain previously suggested to form a salt bridge with the ligand, glutamate. Instead, our data show that Arg contributes crucially to ligand sensitivity via a hydrogen bond network, where Arg interacts both with agonist and with a conserved Thr side chain within the receptor. Together, the data provide a new explanation for the reliance of neurotransmitter receptors on Arg side chains and highlight the exceptional capacity of unnatural amino acid incorporation for increasing our understanding of ligand recognition. PMID- 28096463 TI - DENEDDYLASE1 Protein Counters Automodification of Neddylating Enzymes to Maintain NEDD8 Protein Homeostasis in Arabidopsis. AB - In eukaryotes, the conjugation of the ubiquitin-like protein NEDD8 onto protein targets is an important post-translational modification. The best understood neddylation targets are the cullins, scaffold subunits of E3 ubiquitin ligases, where neddylation as well as deneddylation, facilitated by the protease activity of the CSN (COP9 signalosome), are required to control ubiquitin ligase assembly, function, and ultimately substrate degradation. Little is known about the role of other deneddylating enzymes besides CSN and the role of neddylation and deneddylation of their substrates. We previously characterized Arabidopsis thaliana mutants with defects in the conserved NEDD8-specific protease DEN1 (DENEDDYLASE1). These mutants display only subtle growth phenotypes despite the strong accumulation of a broad range of neddylated proteins. Specifically, we identified AXR1 (AUXIN-RESISTANT1), a subunit of the heterodimeric NAE (E1 NEDD8 ACTIVATING ENZYME), as highly neddylated in den1 mutants. Here, we examined the mechanism and consequences of AXR1 neddylation in more detail. We find that AXR1 as well as other neddylation enzymes are autoneddylated at multiple lysines. NAE autoneddylation can be linked to reduced NCE (E2 NEDD8-CONJUGATING ENZYME) NEDD8 thioester levels, either by critically reducing the pool of free NEDD8 or by reducing NAE activity. In planta, increasing NEDD8 gene dosage is sufficient to suppress den1 mutant phenotypes. We therefore suggest that DEN1 serves to recover diverted NEDD8 moieties from autoneddylated NAE subunits, and possibly also other neddylated proteins, to maintain NEDD8 pathway activity toward other NEDD8 dependent processes such as cullin E3 ligase regulation. PMID- 28096464 TI - Functional Transformation of C-reactive Protein by Hydrogen Peroxide. AB - C-reactive protein (CRP) is present at sites of inflammation including amyloid plaques, atherosclerotic lesions, and arthritic joints. CRP, in its native pentameric structural conformation, binds to cells and molecules that have exposed phosphocholine (PCh) groups. CRP, in its non-native pentameric structural conformation, binds to a variety of deposited, denatured, and aggregated proteins, in addition to binding to PCh-containing substances. In this study, we investigated the effects of H2O2, a prototypical reactive oxygen species that is also present at sites of inflammation, on the ligand recognition function of CRP. Controlled H2O2 treatment of native CRP did not monomerize CRP and did not affect the PCh binding activity of CRP. In solid phase ELISA-based ligand binding assays, purified pentameric H2O2-treated CRP bound to a number of immobilized proteins including oxidized LDL, IgG, amyloid beta peptide 1-42, C4b-binding protein, and factor H, in a CRP concentration- and ligand concentration-dependent manner. Using oxidized LDL as a representative protein ligand for H2O2-treated CRP, we found that the binding occurred in a Ca2+-independent manner and did not involve the PCh-binding site of CRP. We conclude that H2O2 is a biological modifier of the structure and ligand recognition function of CRP. Overall, the data suggest that the ligand recognition function of CRP is dependent on the presence of an inflammatory microenvironment. We hypothesize that one of the functions of CRP at sites of inflammation is to sense the inflammatory microenvironment, change its own structure in response but remain pentameric, and then bind to pathogenic proteins deposited at those sites. PMID- 28096465 TI - Sequences within the C Terminus of the Metabotropic Glutamate Receptor 5 (mGluR5) Are Responsible for Inner Nuclear Membrane Localization. AB - Traditionally, G-protein-coupled receptors (GPCR) are thought to be located on the cell surface where they transmit extracellular signals to the cytoplasm. However, recent studies indicate that some GPCRs are also localized to various subcellular compartments such as the nucleus where they appear required for various biological functions. For example, the metabotropic glutamate receptor 5 (mGluR5) is concentrated at the inner nuclear membrane (INM) where it mediates Ca2+ changes in the nucleoplasm by coupling with Gq/11 Here, we identified a region within the C-terminal domain (amino acids 852-876) that is necessary and sufficient for INM localization of the receptor. Because these sequences do not correspond to known nuclear localization signal motifs, they represent a new motif for INM trafficking. mGluR5 is also trafficked to the plasma membrane where it undergoes re-cycling/degradation in a separate receptor pool, one that does not interact with the nuclear mGluR5 pool. Finally, our data suggest that once at the INM, mGluR5 is stably retained via interactions with chromatin. Thus, mGluR5 is perfectly positioned to regulate nucleoplasmic Ca2+in situ. PMID- 28096466 TI - A Phosphoproteomic Screen Identifies a Guanine Nucleotide Exchange Factor for Rab3A Protein as a Mitogen-activated Protein (MAP) Kinase Phosphatase-5-regulated MAP Kinase Target in Interleukin 6 (IL-6) Secretion and Myogenesis. AB - The mitogen-activated protein kinases (MAPKs) have been shown to regulate skeletal muscle function. Previously, we showed that MAPK phosphatase-5 (MKP-5) negatively regulates myogenesis and regeneration of skeletal muscle through inhibition of p38 MAPK and c-Jun N-terminal kinase (JNK). However, the identity and contribution of MKP-5-regulated MAPK targets in the control of skeletal muscle function and regenerative myogenesis have not been established. To identify MKP-5-regulated MAPK substrates in skeletal muscle, we performed a global differential phospho-MAPK substrate screen in regenerating skeletal muscles of wild type and MKP-5-deficient mice. We discovered a novel MKP-5 regulated MAPK substrate called guanine nucleotide exchange factor for Rab3A (GRAB) that was hyperphosphorylated on a phospho-MAPK motif in skeletal muscle of MKP-5-deficient mice. GRAB was found to be phosphorylated by JNK on serine 169. Myoblasts overexpressing a phosphorylation-defective mutant of GRAB containing a mutation at Ser-169 to Ala-169 (GRAB-S169A) inhibited the ability of C2C12 myoblasts to differentiate. We found that GRAB phosphorylation at Ser-169 was required for the secretion of the promyogenic cytokine interleukin 6 (IL-6). Consistent with this observation, MKP-5-deficient mice exhibited increased circulating IL-6 expression as compared with wild type mice. Collectively, these data demonstrate a novel mechanism whereby MKP-5-mediated regulation of JNK negatively regulates phosphorylation of GRAB, which subsequently controls secretion of IL-6. These data support the notion that MKP-5 serves as a negative regulator of MAPK-dependent signaling of critical skeletal muscle signaling pathways. PMID- 28096467 TI - miR-21-mediated Radioresistance Occurs via Promoting Repair of DNA Double Strand Breaks. AB - miR-21, as an oncogene that overexpresses in most human tumors, is involved in radioresistance; however, the mechanism remains unclear. Here, we demonstrate that miR-21-mediated radioresistance occurs through promoting repair of DNA double strand breaks, which includes facilitating both non-homologous end-joining (NHEJ) and homologous recombination repair (HRR). The miR-21-promoted NHEJ occurs through targeting GSK3B (a novel target of miR-21), which affects the CRY2/PP5 pathway and in turn increases DNA-PKcs activity. The miR-21-promoted HRR occurs through targeting both GSK3B and CDC25A (a known target of miR-21), which neutralizes the effects of targeting GSK3B-induced CDC25A increase because GSK3B promotes degradation of both CDC25A and cyclin D1, but CDC25A and cyclin D1 have an opposite effect on HRR. A negative correlation of expression levels between miR-21 and GSK3beta exists in a subset of human tumors. Our results not only elucidate miR-21-mediated radioresistance, but also provide potential new targets for improving radiotherapy. PMID- 28096469 TI - Super-resolution Visualization of Caveola Deformation in Response to Osmotic Stress. AB - Caveolae are protein-dense plasma membrane domains structurally composed of caveolin-1 or -3 along with other proteins. Our previous studies have shown that caveolae enhance calcium signals generated through the Galphaq/phospholipase Cbeta signaling pathway and that subjecting cells to hypo-osmotic stress reverses this enhancement. In this study, we have used super-resolution fluorescence microscopy supplemented by fluorescence correlation studies to determine the structural factors that underlie this behavior. We find similar and significant population of Galphaq and one of its receptors, bradykinin type 2 receptor (B2R), as well as a significant population of Galphai and its coupled beta2-adrenergic receptor (betaAR), are localized to caveola domains. Although mild osmotic stress deforms caveolae and alters interactions between the caveolae and these proteins, the general structure and the localization of caveola components remain largely unchanged. This deformation eliminates the ability of caveolae to stabilize calcium signals mediated through Galphaq-B2R, but does not affect cAMP signals mediated through Galphai and betaAR. Structurally, we find that mild osmotic stress corresponding roughly to a pressure of 3.82 newtons/m2 increases the domain diameter by ~30% and increases the fluorescence intensity in the center of the domain mouth suggesting a flattening of the invagination. Approximate calculations show that caveolae in muscle tissue have the strength to handle the stress of muscle movement. PMID- 28096468 TI - O-Linked N-Acetylglucosamine (O-GlcNAc) Expression Levels Epigenetically Regulate Colon Cancer Tumorigenesis by Affecting the Cancer Stem Cell Compartment via Modulating Expression of Transcriptional Factor MYBL1. AB - To study the regulation of colorectal adenocarcinoma progression by O-GlcNAc, we have focused on the O-GlcNAc-mediated epigenetic regulation of human colon cancer stem cells (CCSC). Xenograft tumors from colon tumor cells with O-linked N acetylglucosamine transferase (OGT) knockdown grew significantly slower than those formed from control cells, indicating a reduced proliferation of tumor cells due to inhibition of OGT expression. Significant reduction of the CCSC population was observed in the tumor cells after OGT knockdown, whereas tumor cells treated with the O-GlcNAcase inhibitor showed an increased CCSC population, indicating that O-GlcNAc levels regulated the CCSC compartment. When grown in suspension, tumor cells with OGT knockdown showed a reduced ability to form tumorspheres, indicating a reduced self-renewal of CCSC due to reduced levels of O-GlcNAc. ChIP-sequencing experiments using an anti-O-GlcNAc antibody revealed significant chromatin enrichment of O-GlcNAc-modified proteins at the promoter of the transcription factor MYBL1, which was also characterized by the presence of H3K27me3. RNA-sequencing analysis showed an increased expression of MYBL1 in tumor cells with OGT knockdown. Forced overexpression of MYBL1 led to a reduced population of CCSC and tumor growth in vivo, similar to the effects of OGT silencing. Moreover, two CpG islands near the transcription start site of MYBL1 were identified, and O-GlcNAc levels regulated their methylation status. These results strongly argue that O-GlcNAc epigenetically regulates MYBL1, functioning similarly to H3K27me3. The aberrant CCSC compartment observed after modulating O GlcNAc levels is therefore likely to result, at least in part, from the epigenetic regulation of MYBL1 expression by O-GlcNAc, thereby significantly affecting tumor progression. PMID- 28096470 TI - Dampened Amphetamine-Stimulated Behavior and Altered Dopamine Transporter Function in the Absence of Brain GDNF. AB - Midbrain dopamine neuron dysfunction contributes to various psychiatric and neurological diseases, including drug addiction and Parkinson's disease. Because of its well established dopaminotrophic effects, the therapeutic potential of glial cell line-derived neurotrophic factor (GDNF) has been studied extensively in various disorders with disturbed dopamine homeostasis. However, the outcomes from preclinical and clinical studies vary, highlighting a need for a better understanding of the physiological role of GDNF on striatal dopaminergic function. Nevertheless, the current lack of appropriate animal models has limited this understanding. Therefore, we have generated novel mouse models to study conditional Gdnf deletion in the CNS during embryonic development and reduction of striatal GDNF levels in adult mice via AAV-Cre delivery. We found that both of these mice have reduced amphetamine-induced locomotor response and striatal dopamine efflux. Embryonic GDNF deletion in the CNS did not affect striatal dopamine levels or dopamine release, but dopamine reuptake was increased due to increased levels of both total and synaptic membrane-associated dopamine transporters. Collectively, these results suggest that endogenous GDNF plays an important role in regulating the function of dopamine transporters in the striatum.SIGNIFICANCE STATEMENT Delivery of ectopic glial cell line-derived neurotrophic factor (GDNF) promotes the function, plasticity, and survival of midbrain dopaminergic neurons, the dysfunction of which contributes to various neurological and psychiatric diseases. However, how the deletion or reduction of GDNF in the CNS affects the function of dopaminergic neurons has remained unknown. Using conditional Gdnf knock-out mice, we found that endogenous GDNF affects striatal dopamine homeostasis and regulates amphetamine-induced behaviors by regulating the level and function of dopamine transporters. These data regarding the physiological role of GDNF are relevant in the context of neurological and neurodegenerative diseases that involve changes in dopamine transporter function. PMID- 28096471 TI - Resolving the Brainstem Contributions to Attentional Analgesia. AB - Previous human imaging studies manipulating attention or expectancy have identified the periaqueductal gray (PAG) as a key brainstem structure implicated in endogenous analgesia. However, animal studies indicate that PAG analgesia is mediated largely via caudal brainstem structures, such as the rostral ventromedial medulla (RVM) and locus coeruleus (LC). To identify their involvement in endogenous analgesia, we used brainstem optimized, whole-brain imaging to record responses to concurrent thermal stimulation (left forearm) and visual attention tasks of titrated difficulty in 20 healthy subjects. The PAG, LC, and RVM were anatomically discriminated using a probabilistic atlas. Pain ratings disclosed the anticipated analgesic interaction between task difficulty and pain intensity (p < 0.001). Main effects of noxious thermal stimulation were observed across several brain regions, including operculoinsular, primary somatosensory, and cingulate cortices, whereas hard task difficulty was represented in anterior insular, parietal, and prefrontal cortices. Permutation testing within the brainstem nuclei revealed the following: main effects of task in dorsal PAG and right LC; and main effect of temperature in RVM and a task * temperature interaction in right LC. Intrasubject regression revealed a distributed network of supratentorial brain regions and the RVM whose activity was linearly related to pain intensity. Intersubject analgesia scores correlated to activity within a distinct region of the RVM alone. These results identify distinct roles for a brainstem triumvirate in attentional analgesia: with the PAG activated by attentional load; specific RVM regions showing pronociceptive and antinociceptive processes (in line with previous animal studies); and the LC showing lateralized activity during conflicting attentional demands.SIGNIFICANCE STATEMENT Attention modulates pain intensity, and human studies have identified roles for a network of forebrain structures plus the periaqueductal gray (PAG). Animal data indicate that the PAG acts via caudal brainstem structures to control nociception. We investigated this issue within an attentional analgesia paradigm with brainstem-optimized fMRI and analysis using a probabilistic brainstem atlas. We find pain intensity encoding in several forebrain structures, including the insula and attentional activation of the PAG. Discrete regions of the rostral ventromedial medulla bidirectionally influence pain perception, and locus coeruleus activity mirrors the interaction between attention and nociception. This approach has enabled the resolution of contributions from a hub of key brainstem structures to endogenous analgesia. PMID- 28096472 TI - Myosin VI facilitates connexin 43 gap junction accretion. AB - In this study, we demonstrate myosin VI enrichment at Cx43 (also known as GJA1) containing gap junctions (GJs) in heart tissue, primary cardiomyocytes and cell culture models. In primary cardiac tissue and in fibroblasts from the myosin VI null mouse as well as in tissue culture cells transfected with siRNA against myosin VI, we observe reduced GJ plaque size with a concomitant reduction in intercellular communication, as shown by fluorescence recovery after photobleaching (FRAP) and a new method of selective calcein administration. Analysis of the molecular role of myosin VI in Cx43 trafficking indicates that myosin VI is dispensable for the delivery of Cx43 to the cell surface and connexon movement in the plasma membrane. Furthermore, we cannot corroborate clathrin or Dab2 localization at gap junctions and we do not observe a function for the myosin-VI-Dab2 complex in clathrin-dependent endocytosis of annular gap junctions. Instead, we found that myosin VI was localized at the edge of Cx43 plaques by using total internal reflection fluorescence (TIRF) microscopy and use FRAP to identify a plaque accretion defect as the primary manifestation of myosin VI loss in Cx43 homeostasis. A fuller understanding of this derangement may explain the cardiomyopathy or gliosis associated with the loss of myosin VI. PMID- 28096473 TI - Vimentin intermediate filaments control actin stress fiber assembly through GEF H1 and RhoA. AB - The actin and intermediate filament cytoskeletons contribute to numerous cellular processes, including morphogenesis, cytokinesis and migration. These two cytoskeletal systems associate with each other, but the underlying mechanisms of this interaction are incompletely understood. Here, we show that inactivation of vimentin leads to increased actin stress fiber assembly and contractility, and consequent elevation of myosin light chain phosphorylation and stabilization of tropomyosin-4.2 (see Geeves et al., 2015). The vimentin-knockout phenotypes can be rescued by re-expression of wild-type vimentin, but not by the non-filamentous 'unit length form' vimentin, demonstrating that intact vimentin intermediate filaments are required to facilitate the effects on the actin cytoskeleton. Finally, we provide evidence that the effects of vimentin on stress fibers are mediated by activation of RhoA through its guanine nucleotide exchange factor GEF H1 (also known as ARHGEF2). Vimentin depletion induces phosphorylation of the microtubule-associated GEF-H1 on Ser886, and thereby promotes RhoA activity and actin stress fiber assembly. Taken together, these data reveal a new mechanism by which intermediate filaments regulate contractile actomyosin bundles, and may explain why elevated vimentin expression levels correlate with increased migration and invasion of cancer cells. PMID- 28096474 TI - JunB regulates angiogenesis and neurovascular parallel alignment in mouse embryonic skin. AB - Blood vessels and nerve fibers are often closely arranged in parallel throughout the body. Therefore, neurovascular interactions have been suggested to be important for the development of vascular networks. However, the molecular mechanisms and genes regulating this process remain unclear. In the present study, we investigated the genes that are activated in endothelial cells (ECs) following interactions with neurons during vascular development. Microarray analyses of human primary microvascular ECs co-cultured with mouse primary dorsal root ganglion cells showed that JunB is strongly upregulated in ECs by neurovascular interactions. Furthermore, the forced expression of JunB in ECs stimulated a tip-like cell formation and angiogenesis in vitro and induced vascular endothelial growth factor A (VEGFA) and the pro-angiogenic integrin subunit ITGB3 expression. Moreover, in vivo knockdown of JunB in ECs from developing mouse limb skin considerably decreased the parallel alignments of blood vessels and nerve fibers. Taken together, the present data demonstrates for the first time that JunB plays an important role in the formation of embryonic vascular networks. These results contribute to the molecular understanding of neurovascular interactions during embryonic vascular development. PMID- 28096476 TI - Accuracy of Oxygen Consumption and Carbon Dioxide Elimination Measurements in 2 Breath-by-Breath Devices. AB - BACKGROUND: Although accurate quantification of oxygen consumption (VO2 ) and carbon dioxide elimination (VCO2 ) provides important insights into a patient's nutritional and hemodynamic status, few devices exist to accurately measure these parameters in children. Therefore, we assessed the accuracy and agreement of 2 devices currently on the market using a pediatric in vitro model of gas exchange. METHODS: We utilized a Huszczuk simulation model, which simulates oxygen consumption and carbon dioxide production using gas dilution, to examine the accuracy of two FDA-cleared respiratory modules (E-COVX and E-sCAiOVX-00). VO2 and VCO2 were set at 20, 40, 60, and 100 mL/min, ranges typical for infant and pediatric patients. Bland-Altman analysis was used to calculate the bias and limits of agreement of each device relative to simulated values for VO2 and VCO2 . RESULTS: The E-COVX mean percentage bias (limits of agreement) was -26.3% ( 36.1 to -16.6%) and -39.3% (-47.5 to -31.1%) for VO2 and VCO2 , respectively. The mean bias (limits of agreement) for the E-aCAiOVX-00 was -0.5% (-13.3 to 12.3%) and -6.0% (-13.8 to 1.7%) for VO2 and VCO2 , respectively. CONCLUSIONS: The E COVX demonstrated bias and limits of agreement that were not clinically acceptable; therefore, application of this module to pediatric patients would not be recommended. The new module, E-sCAiOVX, demonstrated acceptable bias and limits of agreement for the VO2 and VCO2 in the range 40-100 mL/min (which corresponds to patients in the range of ~5-16 kg). PMID- 28096475 TI - Stress-specific differences in assembly and composition of stress granules and related foci. AB - Cells have developed different mechanisms to respond to stress, including the formation of cytoplasmic foci known as stress granules (SGs). SGs are dynamic and formed as a result of stress-induced inhibition of translation. Despite enormous interest in SGs due to their contribution to the pathogenesis of several human diseases, many aspects of SG formation are poorly understood. SGs induced by different stresses are generally assumed to be uniform, although some studies suggest that different SG subtypes and SG-like cytoplasmic foci exist. Here, we investigated the molecular mechanisms of SG assembly and characterized their composition when induced by various stresses. Our data revealed stress-specific differences in composition, assembly and dynamics of SGs and SG-like cytoplasmic foci. Using a set of genetically modified haploid human cells, we determined the molecular circuitry of stress-specific translation inhibition upstream of SG formation and its relation to cell survival. Finally, our studies characterize cytoplasmic stress-induced foci related to, but distinct from, canonical SGs, and also introduce haploid cells as a valuable resource to study RNA granules and translation control mechanisms. PMID- 28096477 TI - The Future of Respiratory Care: Results of a New York State Survey of Respiratory Therapists. AB - BACKGROUND: In the current health-care environment, respiratory care may need to make significant changes to academic preparation and clinical practice. The purpose of this research was to assess current needs of respiratory therapists (RTs) in New York State and to understand how RTs perceive their future clinical and academic roles. METHODS: This study employed a descriptive, cross-sectional non-experimental design. Between October and December 2014, a 32-item online survey was distributed via e-mail to the 2,170 members of the New York State Society of Respiratory Care. Descriptive statistics were used to summarize responses, and bivariate analyses were assessed using Kruskal-Wallis and Mann Whitney U tests. RESULTS: The response rate was 22% and resulted in 435 valid surveys returned. Seventy percent of 415 respondents agreed that the practice of respiratory care is at risk of losing practitioners. The most important incentive for retention of practitioners in the field was professional growth and an expanded scope of clinical practice. Specifically, the most important of these roles was gaining the ability to assess patients, develop a plan of care, and receive reimbursement for services. Sixty-four percent of 415 respondents strongly agreed that the minimum academic standard for RTs should be raised to the baccalaureate level. Of 415 respondents, the majority (78%) agreed that it is important for therapists to remain in the profession and to be an active member of the American Association for Respiratory Care (83%). CONCLUSIONS: These data are useful to the profession, notably for academic programs that must meet the need for a more highly prepared and skilled workforce. The findings emphasize that viability of the profession in the current health-care environment calls for the evolution of a more autonomous RT who can be reimbursed for services and obtain salaries that are competitive with other health professions. PMID- 28096478 TI - Demographic, procedural and 30-day safety results from the WEB Intra-saccular Therapy Study (WEB-IT). AB - INTRODUCTION: The Woven EndoBridge (WEB) represents a novel intrasaccular therapeutic option for the treatment of intracranial wide-necked bifurcation aneurysms (WNBAs). The WEB-IT Study is a pivotal Investigational Device Exemption (IDE) study to determine the safety and effectiveness of the WEB device for the treatment of WNBAs located in the anterior and posterior intracranial circulations. We present the patient demographics, procedural characteristics, and 30-day adverse event data for the US WEB-IT study. METHODS: WEB-IT is a prospective multicenter single-arm interventional study conducted at 25 US and 6 international centers. The study enrolled 150 adults with WNBAs of the anterior and posterior intracranial circulations. All patients were intended to receive a WEB device delivered via standard endovascular neurosurgical embolization techniques. The study was conducted under Good Clinical Practices and included independent adjudication effectiveness outcomes and all adverse events. RESULTS: One hundred and fifty patients enrolled at 27 investigational sites underwent attempted treatment with the WEB. Mean age was 59 years (range 29-79) and 110 (73.3%) of the patients were female. Treated aneurysms were located at the basilar apex (n=59, 39.3%), middle cerebral artery bifurcation (n=45, 30%), anterior communicating artery (n=40, 26.7%), and internal carotid artery terminus (n=6, 4%). Average aneurysm size was 6.4 mm (range 3.6-11.4) with a mean neck size of 4.8 mm (range 2.0-8.2, mean dome to neck ratio 1.34). Nine patients presented with ruptured aneurysms. Of the enrolled patients, 98.7% were treated successfully with WEB devices. Mean+/-SD fluoroscopy time was 30.2+/-15.7 min. One primary safety event (PSE) (0.7%)-a delayed parenchymal hemorrhage 22 days after treatment-occurred between the index procedure and 30-day follow-up. In addition to the single PSE, there were seven (4.7%) minor ischemic strokes (5 resolved without sequelae and 2 had a modified Rankin Scale score of 1 at 30 days), five (2.7%) transient ischemic attacks, and two (1.3%) minor subarachnoid hemorrhages, which did not meet the prospectively established criteria for PSEs. CONCLUSIONS: The WEB device can be used to treat WNBAs with a high level of procedural safety and a high degree of technical success. TRIAL REGISTRATION NUMBER: NCT02191618; Pre-results. PMID- 28096480 TI - Chronic tophaceous gout. PMID- 28096479 TI - IGF-1 Receptor Modulates FoxO1-Mediated Tamoxifen Response in Breast Cancer Cells. AB - Tamoxifen is a common adjuvant treatment for estrogen receptor (ER)alpha-positive patients with breast cancer; however, acquired resistance abrogates the efficacy of this therapeutic approach. We recently demonstrated that G protein-coupled estrogen receptor 1 (GPER1) mediates tamoxifen action in breast cancer cells by inducing insulin-like growth factor-binding protein-1 (IGFBP-1) to inhibit IGF-1 dependent signaling. To determine whether dysregulation of IGFBP-1 induction is associated with tamoxifen resistance, IGFBP-1 transcription was measured in tamoxifen-resistant MCF-7 cells (TamR) after tamoxifen (Tam) treatment. IGFBP-1 transcription was not stimulated in tamoxifen-treated TamR cells whereas decreased expression of FoxO1, a known modulator of IGFBP-1, was observed. Exogenous expression of FoxO1 rescued the ability of tamoxifen to induce IGFBP-1 transcription in TamR cells. As decreased IGF-1R expression is observed in tamoxifen-resistant cells, the requirement for IGF-1R expression on tamoxifen stimulated IGFBP-1 transcription was investigated. In TamR and SK-BR-3 cells, both characterized by low IGF-1R levels, exogenous IGF-1R expression increased FoxO1 levels and IGFBP-1 expression, whereas IGF-1R knockdown in MCF-7 cells decreased tamoxifen-stimulated IGFBP-1 transcription. Interestingly, both 17beta estradiol (E2)-stimulated ERalpha phosphorylation and progesterone receptor (PR) expression were altered in TamR. PR is a transcription factor known to modulate FoxO1 transcription. In addition, IGF-1R knockdown decreased FoxO1 protein levels in MCF-7 cells. Furthermore, IGF-1R or FoxO1 knockdown inhibited the ability of tamoxifen to induce IGFBP-1 transcription and tamoxifen sensitivity in MCF-7 cells. These data provide a molecular mechanistic connection between IGF-1R expression and the FoxO1-mediated mechanism of tamoxifen action in breast cancer cells.Implications: Loss of IGF-1R expression is associated with decreased tamoxifen efficacy in patients with breast cancer and the development of tamoxifen resistance. This contribution identifies potential molecular mechanisms of altered tamoxifen sensitivity in breast cancer cells resulting from decreased IGF-1R expression. Mol Cancer Res; 15(4); 489-97. (c)2017 AACR. PMID- 28096481 TI - Successful removal of multiple long foreign bodies: an unusual neck hyperextension technique. PMID- 28096482 TI - Chronic disease management interventions for people with chronic kidney disease in primary care: a systematic review and meta-analysis. AB - Background: Primary care providers manage the majority of patients with chronic kidney disease (CKD), although the most effective chronic disease management (CDM) strategies for these patients are unknown. We assessed the efficacy of CDM interventions used by primary care providers managing patients with CKD. Methods: The Medline, Embase and Cochrane Central databases were systematically searched (inception to November 2014) for randomized controlled trials (RCTs) assessing education-based and computer-assisted CDM interventions targeting primary care providers managing patients with CKD in the community. The efficacy of CDM interventions was assessed using quality indicators [use of angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), proteinuria measurement and achievement of blood pressure (BP) targets] and clinical outcomes (change in BP and glomerular filtration rate). Two independent reviewers evaluated studies for inclusion, quality and extracted data. Random effects models were used to estimate pooled odds ratios (ORs) and weighted mean differences for outcomes of interest. Results: Five studies (188 clinics; 494 physicians; 42 852 patients with CKD) were included. Two studies compared computer-assisted intervention strategies with usual care, two studies compared education-based intervention strategies with computer-assisted intervention strategies and one study compared both these intervention strategies with usual care. Compared with usual care, computer-assisted CDM interventions did not increase the likelihood of ACEI/ARB use among patients with CKD {pooled OR 1.00 [95% confidence interval (CI) 0.83-1.21]; I2 = 0.0%}. Similarly, education related CDM interventions did not increase the likelihood of ACEI/ARB use compared with computer-assisted CDM interventions [pooled OR 1.12 (95% CI 0.77 1.64); I2 = 0.0%]. Inconsistencies in reporting methods limited further pooling of data. Conclusions: To date, there have been very few randomized trials testing CDM interventions targeting primary care providers with the goal of improving care of people with CKD. Those conducted to date have shown minimal impact, suggesting that other strategies, or multifaceted interventions, may be required to enhance care for patients with CKD in the community. PMID- 28096483 TI - The Gut Microbiome of the Vector Lutzomyia longipalpis Is Essential for Survival of Leishmania infantum. AB - : The vector-borne disease leishmaniasis, caused by Leishmania species protozoa, is transmitted to humans by phlebotomine sand flies. Development of Leishmania to infective metacyclic promastigotes in the insect gut, a process termed metacyclogenesis, is an essential prerequisite for transmission. Based on the hypothesis that vector gut microbiota influence the development of virulent parasites, we sequenced midgut microbiomes in the sand fly Lutzomyia longipalpis with or without Leishmania infantum infection. Sucrose-fed sand flies contained a highly diverse, stable midgut microbiome. Blood feeding caused a decrease in microbial richness that eventually recovered. However, bacterial richness progressively decreased in L. infantum-infected sand flies. Acetobacteraceae spp. became dominant and numbers of Pseudomonadaceae spp. diminished coordinately as the parasite underwent metacyclogenesis and parasite numbers increased. Importantly, antibiotic-mediated perturbation of the midgut microbiome rendered sand flies unable to support parasite growth and metacyclogenesis. Together, these data suggest that the sand fly midgut microbiome is a critical factor for Leishmania growth and differentiation to its infective state prior to disease transmission. IMPORTANCE: Leishmania infantum, a parasitic protozoan causing fatal visceral leishmaniasis, is transmitted to humans through the bite of the sand fly Lutzomyia longipalpis Development of the parasite to its virulent metacyclic state occurs in the sand fly gut. In this study, the microbiota within the Lu. longipalpis midgut was delineated by 16S ribosomal DNA (rDNA) sequencing, revealing a highly diverse community composition that lost diversity as parasites developed to their metacyclic state and increased in abundance in infected flies. Perturbing sand fly gut microbiota with an antibiotic cocktail, which alone had no effect on either the parasite or the fly, arrested both the development of virulent parasites and parasite expansion. These findings indicate the importance of bacterial commensals within the insect vector for the development of virulent pathogens, and raise the possibility that impairing the microbial composition within the vector might represent a novel approach to control of vector-borne diseases. PMID- 28096484 TI - Evolutionary Dynamics of Pandemic Methicillin-Sensitive Staphylococcus aureus ST398 and Its International Spread via Routes of Human Migration. AB - : Methicillin-susceptible Staphylococcus aureus (MSSA) accounts for the majority of S. aureus infections globally, and yet surprisingly little is known about its clonal evolution. We applied comparative whole-genome sequencing (WGS) analyses to epidemiologically and geographically diverse ST398-MSSA, a pandemic lineage affecting both humans and livestock. Bayesian phylogenetic analysis predicted divergence of human-associated ST398-MSSA ~40 years ago. Isolates from Midwestern pigs and veterinarians differed substantially from those in New York City (NYC). Pig ST398 strains contained a large region of recombination representing imports from multiple sequence types (STs). Phylogeographic analyses supported the spread of ST398-MSSA along local cultural and migratory links between parts of the Caribbean, North America, and France, respectively. Applying pairwise single nucleotide polymorphism (SNP) distances as a measure of genetic relatedness between isolates, we observed that ST398 not only clustered in households but also frequently extended across local social networks. Isolates collected from environmental surfaces reflected the full diversity of colonizing individuals, highlighting their potentially critical role as reservoirs for transmission and diversification. Strikingly, we observed high within-host SNP variability compared to our previous studies on the dominant methicillin-resistant Staphylococcus aureus (MRSA) clone USA300. Our data indicate that the dynamics of colonization, persistence, and transmission differ substantially between USA300 MRSA and ST398-MSSA. Taken together, our study reveals local and international routes of transmission for a major MSSA clone, indicating key impacts of recombination and mutation on genetic diversification and highlighting important ecological differences from epidemic USA300. Our study demonstrates extensive local and international routes of transmission for a major MSSA clone despite the lack of substantial antibiotic resistance. IMPORTANCE: Unlike methicillin resistant Staphylococcus aureus (MRSA), surprisingly little is known about the clonal evolution of methicillin-susceptible S. aureus (MSSA), although these strains account for the majority of S. aureus infections. To better understand how MSSA spreads and becomes established in communities, we applied comparative bacterial whole-genome sequencing to pandemic ST398-MSSA, a clone of clinical importance affecting humans and livestock in different geographic regions. Phylogeographic analyses identified that ST398-MSSA spread along local cultural and migratory links between parts of the Caribbean, North America, and France, respectively. We observed high within-host SNP variability compared to our previous studies on the dominant MRSA clone USA300. Our data indicate that the dynamics of colonization, persistence, and transmission differ substantially between USA300 MRSA and ST398 MSSA. PMID- 28096485 TI - Murine Cytomegalovirus Deubiquitinase Regulates Viral Chemokine Levels To Control Inflammation and Pathogenesis. AB - : Maintaining control over inflammatory processes represents a paradox for viral pathogens. Although many viruses induce host inflammatory responses to facilitate infection, control is necessary to avoid overactivation. One way is through the manipulation of proinflammatory chemokine levels, both host and viral. Murine cytomegalovirus (MCMV), a model betaherpesvirus, encodes a viral C-C chemokine, MCK2, which promotes host inflammatory responses and incorporates into virions to facilitate viral dissemination. Here, we show that the activity of M48, the conserved MCMV deubiquitinating enzyme (DUB), regulates MCK2 levels during infection. Inactivation of M48 DUB activity results in viral attenuation and exacerbates virally induced, MCK2-dependent inflammatory responses. M48 DUB activity also influences MCK2 incorporation into virions. Importantly, attenuation of DUB-mutant virus acute replication in vitro and in vivo is largely ameliorated by targeted deletion of MCK2. Thus, uncontrolled MCK2 levels appear to mediate DUB-mutant virus attenuation in specific tissues or cell types. This demonstrates that MCMV M48 DUB activity plays a previously unappreciated role in controlling MCK2 levels, thereby managing MCK2-dependent processes. These findings reveal a novel intrinsic control mechanism of virally induced inflammation and support the identification of betaherpesvirus DUBs as possible new targets for antiviral therapies. IMPORTANCE: Human cytomegalovirus infections represent a tremendous burden not only to those afflicted but also to health care systems worldwide. As cytomegalovirus infections are a leading cause of nongenetic sensory loss and neurodevelopmental delay, it is imperative that valuable model systems exist in order that we might understand what viral factors contribute to replication and pathogenesis. Currently, the only approved drug treatments against CMV infection are nucleoside analogues, to which some strains have become resistant. Understanding unique viral enzymatic contributions to infections will allow the development of novel pharmacological therapies. Here, we show that M48, the conserved MCMV deubiquitinase, is critical for MCMV replication in mice and demonstrate that attenuation is due to deregulated production of a viral proinflammatory chemokine. The deubiquitinases of both human and murine CMV represent structurally unique DUBs and are therefore attractive targets for pharmacological intervention. Continued research into the substrates of these DUBs will lend additional insight into their potential as targets. PMID- 28096486 TI - Phage-Derived Protein Induces Increased Platelet Activation and Is Associated with Mortality in Patients with Invasive Pneumococcal Disease. AB - : To improve our understanding about the severity of invasive pneumococcal disease (IPD), we investigated the association between the genotype of Streptococcus pneumoniae and disease outcomes for 349 bacteremic patients. A pneumococcal genome-wide association study (GWAS) demonstrated a strong correlation between 30-day mortality and the presence of the phage-derived gene pblB, encoding a platelet-binding protein whose effects on platelet activation were previously unknown. Platelets are increasingly recognized as key players of the innate immune system, and in sepsis, excessive platelet activation contributes to microvascular obstruction, tissue hypoperfusion, and finally multiorgan failure, leading to mortality. Our in vitro studies revealed that pblB expression was induced by fluoroquinolones but not by the beta-lactam antibiotic penicillin G. Subsequently, we determined pblB induction and platelet activation by incubating whole blood with the wild type or a pblB knockout mutant in the presence or absence of antibiotics commonly administered to our patient cohort. pblB-dependent enhancement of platelet activation, as measured by increased expression of the alpha-granule protein P-selectin, the binding of fibrinogen to the activated alphaIIbbeta3 receptor, and the formation of platelet-monocyte complex occurred irrespective of antibiotic exposure. In conclusion, the presence of pblB on the pneumococcal chromosome potentially leads to increased mortality in patients with an invasive S. pneumoniae infection, which may be explained by enhanced platelet activation. This study highlights the clinical utility of a bacterial GWAS, followed by functional characterization, to identify bacterial factors involved in disease severity. IMPORTANCE: The exact mechanisms causing mortality in invasive pneumococcal disease (IPD) patients are not completely understood. We examined 349 patients with IPD and found in a bacterial genome wide association study (GWAS) that the presence of the phage-derived gene pblB was associated with mortality in the first 30 days after hospitalization. Although pblB has been extensively studied in Streptococcus mitis, its consequence for the interaction between platelets and Streptococcus pneumoniae is largely unknown. Platelets are important in immunity and inflammation, and excessive platelet activation contributes to microvascular obstruction and multiorgan failure, leading to mortality. We therefore developed this study to assess whether the expression of pblB might increase the risk of death for IPD patients through its effect on enhanced platelet activation. This study also shows the value of integrating extensive bacterial genomics and clinical data in predicting and understanding pathogen virulence, which in turn will help to improve prognosis and therapy. PMID- 28096487 TI - A Clostridium difficile-Specific, Gel-Forming Protein Required for Optimal Spore Germination. AB - : Clostridium difficile is a Gram-positive spore-forming obligate anaerobe that is a leading cause of antibiotic-associated diarrhea worldwide. In order for C. difficile to initiate infection, its aerotolerant spore form must germinate in the gut of mammalian hosts. While almost all spore-forming organisms use transmembrane germinant receptors to trigger germination, C. difficile uses the pseudoprotease CspC to sense bile salt germinants. CspC activates the related subtilisin-like protease CspB, which then proteolytically activates the cortex hydrolase SleC. Activated SleC degrades the protective spore cortex layer, a step that is essential for germination to proceed. Since CspC incorporation into spores also depends on CspA, a related pseudoprotease domain, Csp family proteins play a critical role in germination. However, how Csps are incorporated into spores remains unknown. In this study, we demonstrate that incorporation of the CspC, CspB, and CspA germination regulators into spores depends on CD0311 (renamed GerG), a previously uncharacterized hypothetical protein. The reduced levels of Csps in gerG spores correlate with reduced responsiveness to bile salt germinants and increased germination heterogeneity in single-spore germination assays. Interestingly, asparagine-rich repeat sequences in GerG's central region facilitate spontaneous gel formation in vitro even though they are dispensable for GerG-mediated control of germination. Since GerG is found exclusively in C. difficile, our results suggest that exploiting GerG function could represent a promising avenue for developing C. difficile-specific anti-infective therapies. IMPORTANCE: The spore-forming bacterium Clostridium difficile is a leading cause of health care-associated infections. While a subset of antibiotics can treat C. difficile infections (CDIs), the primary determinant of CDI disease susceptibility is prior antibiotic exposure, since it reduces the colonization resistance conferred by a diverse microflora. Thus, therapies that minimize perturbations to the gut microbiome should be more effective at reducing CDIs and their recurrence, the main source of disease complications. Given that spore germination is essential for C. difficile to initiate infection and that C. difficile uses a unique pathway to initiate germination, methods that inhibit distinct elements of germination could selectively prevent C. difficile disease recurrence. Here, we identify GerG as a C. difficile-specific protein that controls the incorporation of germinant signaling proteins into spores. Since gerG mutant spores exhibit germination defects and are less responsive to germinant, GerG may represent a promising target for developing therapeutics against CDI. PMID- 28096488 TI - Novel "Superspreader" Bacteriophages Promote Horizontal Gene Transfer by Transformation. AB - : Bacteriophages infect an estimated 1023 to 1025 bacterial cells each second, many of which carry physiologically relevant plasmids (e.g., those encoding antibiotic resistance). However, even though phage-plasmid interactions occur on a massive scale and have potentially significant evolutionary, ecological, and biomedical implications, plasmid fate upon phage infection and lysis has not been investigated to date. Here we show that a subset of the natural lytic phage population, which we dub "superspreaders," releases substantial amounts of intact, transformable plasmid DNA upon lysis, thereby promoting horizontal gene transfer by transformation. Two novel Escherichia coli phage superspreaders, SUSP1 and SUSP2, liberated four evolutionarily distinct plasmids with equal efficiency, including two close relatives of prominent antibiotic resistance vectors in natural environments. SUSP2 also mediated the extensive lateral transfer of antibiotic resistance in unbiased communities of soil bacteria from Maryland and Wyoming. Furthermore, the addition of SUSP2 to cocultures of kanamycin-resistant E. coli and kanamycin-sensitive Bacillus sp. bacteria resulted in roughly 1,000-fold more kanamycin-resistant Bacillus sp. bacteria than arose in phage-free controls. Unlike many other lytic phages, neither SUSP1 nor SUSP2 encodes homologs to known hydrolytic endonucleases, suggesting a simple potential mechanism underlying the superspreading phenotype. Consistent with this model, the deletion of endonuclease IV and the nucleoid-disrupting protein ndd from coliphage T4, a phage known to extensively degrade chromosomal DNA, significantly increased its ability to promote plasmid transformation. Taken together, our results suggest that phage superspreaders may play key roles in microbial evolution and ecology but should be avoided in phage therapy and other medical applications. IMPORTANCE: Bacteriophages (phages), viruses that infect bacteria, are the planet's most numerous biological entities and kill vast numbers of bacteria in natural environments. Many of these bacteria carry plasmids, extrachromosomal DNA elements that frequently encode antibiotic resistance. However, it is largely unknown whether plasmids are destroyed during phage infection or released intact upon phage lysis, whereupon their encoded resistance could be acquired and manifested by other bacteria (transformation). Because phages are being developed to combat antibiotic-resistant bacteria and because transformation is a principal form of horizontal gene transfer, this question has important implications for biomedicine and microbial evolution alike. Here we report the isolation and characterization of two novel Escherichia coli phages, dubbed "superspreaders," that promote extensive plasmid transformation and efficiently disperse antibiotic resistance genes. Our work suggests that phage superspreaders are not suitable for use in medicine but may help drive bacterial evolution in natural environments. PMID- 28096489 TI - Induced Packaging of Cellular MicroRNAs into HIV-1 Virions Can Inhibit Infectivity. AB - : Analysis of the incorporation of cellular microRNAs (miRNAs) into highly purified HIV-1 virions revealed that this largely, but not entirely, mirrored the level of miRNA expression in the producer CD4+ T cells. Specifically, of the 58 cellular miRNAs detected at significant levels in the producer cells, only 5 were found in virions at a level 2- to 4-fold higher than that predicted on the basis of random cytoplasmic sampling. Of note, these included two miRNAs, miR-155 and miR-92a, that were reported previously to at least weakly bind HIV-1 transcripts. To test whether miRNA binding to the HIV-1 genome can induce virion incorporation, artificial miRNA target sites were introduced into the viral genome and a 10- to 40-fold increase in the packaging of the cognate miRNAs into virions was then observed, leading to the recruitment of up to 1.6 miRNA copies per virion. Importantly, this high level of incorporation significantly inhibited HIV-1 virion infectivity. These results suggest that target sites for cellular miRNAs can inhibit RNA virus replication at two distinct steps, i.e., during infection and during viral gene expression, thus explaining why a range of different RNA viruses appear to have evolved to avoid cellular miRNA binding to their genome. IMPORTANCE: The genomes of RNA viruses have the potential to interact with cellular miRNAs, which could lead to their incorporation into virions, with unknown effects on virion function. Here, it is demonstrated that wild-type HIV-1 virions essentially randomly incorporate low levels of the miRNAs expressed by infected cells. However, the specific incorporation of high levels of individual cellular miRNAs can be induced by insertion of cognate target sites into the viral genome. Of note, this results in a modest but significant inhibition of virion infectivity. These data imply that cellular miRNAs have the potential to inhibit viral replication by interfering with not only viral mRNA function but also virion infectivity. PMID- 28096490 TI - Comprehensive Essentiality Analysis of the Mycobacterium tuberculosis Genome via Saturating Transposon Mutagenesis. AB - : For decades, identifying the regions of a bacterial chromosome that are necessary for viability has relied on mapping integration sites in libraries of random transposon mutants to find loci that are unable to sustain insertion. To date, these studies have analyzed subsaturated libraries, necessitating the application of statistical methods to estimate the likelihood that a gap in transposon coverage is the result of biological selection and not the stochasticity of insertion. As a result, the essentiality of many genomic features, particularly small ones, could not be reliably assessed. We sought to overcome this limitation by creating a completely saturated transposon library in Mycobacterium tuberculosis In assessing the composition of this highly saturated library by deep sequencing, we discovered that a previously unknown sequence bias of the Himar1 element rendered approximately 9% of potential TA dinucleotide insertion sites less permissible for insertion. We used a hidden Markov model of essentiality that accounted for this unanticipated bias, allowing us to confidently evaluate the essentiality of features that contained as few as 2 TA sites, including open reading frames (ORF), experimentally identified noncoding RNAs, methylation sites, and promoters. In addition, several essential regions that did not correspond to known features were identified, suggesting uncharacterized functions that are necessary for growth. This work provides an authoritative catalog of essential regions of the M. tuberculosis genome and a statistical framework for applying saturating mutagenesis to other bacteria. IMPORTANCE: Sequencing of transposon-insertion mutant libraries has become a widely used tool for probing the functions of genes under various conditions. The Himar1 transposon is generally believed to insert with equal probabilities at all TA dinucleotides, and therefore its absence in a mutant library is taken to indicate biological selection against the corresponding mutant. Through sequencing of a saturated Himar1 library, we found evidence that TA dinucleotides are not equally permissive for insertion. The insertion bias was observed in multiple prokaryotes and influences the statistical interpretation of transposon insertion (TnSeq) data and characterization of essential genomic regions. Using these insights, we analyzed a fully saturated TnSeq library for M. tuberculosis, enabling us to generate a comprehensive catalog of in vitro essentiality, including ORFs smaller than those found in any previous study, small (noncoding) RNAs (sRNAs), promoters, and other genomic features. PMID- 28096491 TI - Expressing the Geobacter metallireducens PilA in Geobacter sulfurreducens Yields Pili with Exceptional Conductivity. AB - : The electrically conductive pili (e-pili) of Geobacter sulfurreducens serve as a model for a novel strategy for long-range extracellular electron transfer. e pili are also a new class of bioelectronic materials. However, the only other Geobacter pili previously studied, which were from G. uraniireducens, were poorly conductive. In order to obtain more information on the range of pili conductivities in Geobacter species, the pili of G. metallireducens were investigated. Heterologously expressing the PilA gene of G. metallireducens in G. sulfurreducens yielded a G. sulfurreducens strain, designated strain MP, that produced abundant pili. Strain MP exhibited phenotypes consistent with the presence of e-pili, such as high rates of Fe(III) oxide reduction and high current densities on graphite anodes. Individual pili prepared at physiologically relevant pH 7 had conductivities of 277 +/- 18.9 S/cm (mean +/- standard deviation), which is 5,000-fold higher than the conductivity of G. sulfurreducens pili at pH 7 and nearly 1 million-fold higher than the conductivity of G. uraniireducens pili at the same pH. A potential explanation for the higher conductivity of the G. metallireducens pili is their greater density of aromatic amino acids, which are known to be important components in electron transport along the length of the pilus. The G. metallireducens pili represent the most highly conductive pili found to date and suggest strategies for designing synthetic pili with even higher conductivities. IMPORTANCE: e-pili are a remarkable electrically conductive material that can be sustainably produced without harsh chemical processes from renewable feedstocks and that contain no toxic components in the final product. Thus, e-pili offer an unprecedented potential for developing novel materials, electronic devices, and sensors for diverse applications with a new "green" technology. Increasing e-pili conductivity will even further expand their potential applications. A proven strategy is to design synthetic e-pili that contain tryptophan, an aromatic amino acid not found in previously studied e-pili. The studies reported here demonstrate that a productive alternative approach is to search more broadly in the microbial world. Surprisingly, even though G. metallireducens and G. sulfurreducens are closely related, the conductivities of their e-pili differ by more than 3 orders of magnitude. The ability to produce e-pili with high conductivity without generating a genetically modified product enhances the attractiveness of this novel electronic material. PMID- 28096492 TI - Identification of Glutaminyl Cyclase Genes Involved in Pyroglutamate Modification of Fungal Lignocellulolytic Enzymes. AB - : The breakdown of plant biomass to simple sugars is essential for the production of second-generation biofuels and high-value bioproducts. Currently, enzymes produced from filamentous fungi are used for deconstructing plant cell wall polysaccharides into fermentable sugars for biorefinery applications. A post translational N-terminal pyroglutamate modification observed in some of these enzymes occurs when N-terminal glutamine or glutamate is cyclized to form a five membered ring. This modification has been shown to confer resistance to thermal denaturation for CBH-1 and EG-1 cellulases. In mammalian cells, the formation of pyroglutamate is catalyzed by glutaminyl cyclases. Using the model filamentous fungus Neurospora crassa, we identified two genes (qc-1 and qc-2) that encode proteins homologous to mammalian glutaminyl cyclases. We show that qc-1 and qc-2 are essential for catalyzing the formation of an N-terminal pyroglutamate on CBH 1 and GH5-1. CBH-1 and GH5-1 produced in a Deltaqc-1 Deltaqc-2 mutant, and thus lacking the N-terminal pyroglutamate modification, showed greater sensitivity to thermal denaturation, and for GH5-1, susceptibility to proteolytic cleavage. QC-1 and QC-2 are endoplasmic reticulum (ER)-localized proteins. The pyroglutamate modification is predicted to occur in a number of additional fungal proteins that have diverse functions. The identification of glutaminyl cyclases in fungi may have implications for production of lignocellulolytic enzymes, heterologous expression, and biotechnological applications revolving around protein stability. IMPORTANCE: Pyroglutamate modification is the post-translational conversion of N terminal glutamine or glutamate into a cyclized amino acid derivative. This modification is well studied in animal systems but poorly explored in fungal systems. In Neurospora crassa, we show that this modification takes place in the ER and is catalyzed by two well-conserved enzymes, ubiquitously conserved throughout the fungal kingdom. We demonstrate that the modification is important for the structural stability and aminopeptidase resistance of CBH-1 and GH5-1, two important cellulase enzymes utilized in industrial plant cell wall deconstruction. Many additional fungal proteins predicted in the genome of N. crassa and other filamentous fungi are predicted to carry an N-terminal pyroglutamate modification. Pyroglutamate addition may also be a useful way to stabilize secreted proteins and peptides, which can be easily produced in fungal production systems. PMID- 28096493 TI - Combining standard clinical blood values for improving survival prediction in patients with newly diagnosed brain metastases-development and validation of the LabBM score. AB - Background: We aimed to investigate the potential of standard hematologic and serum biochemical parameters to provide an independent and substantial contribution to the prediction of survival in patients with newly diagnosed brain metastases (BM). Methods: Hemoglobin, white blood cell count, platelet count, serum albumin, creatinine, lactate dehydrogenase (LDH), and C-reactive protein (CRP) were assessed at diagnosis of BM in a discovery cohort of 1200 cancer patients. A multivariable Cox regression model was used to derive the LabBM score. The LabBM score was externally validated in an independent cohort consisting of 366 patients. Results: Hemoglobin below lower limit of normal (ULN; HR: 1.51; P < .001), and CRP >ULN (HR: 1.52; P < .001) were associated with survival in a multivariable Cox regression model and were included in the calculation of the LabBM score. Multivariable analysis including the LabBM score and graded prognostic assessment class revealed an independent and significant association of the LabBM score with overall survival (OS) (HR: 1.42; 95% CI: 1.29 1.57; P < .001). The strong and independent association of LabBM score (HR: 1.93; 95% CI: 1.54-2.42) with OS prognosis was confirmed in the validation cohort. Conclusion: Standard clinical blood parameters, combined in the easy-to-calculate LabBM score, provide strong and independent prognostic information in patients with BM. The LabBM score is an objective, inexpensive, and reproducible tool to plan clinical management strategies in BM patients and to improve patient selection and stratification for clinical trials. PMID- 28096494 TI - Reproductive performance primarily depends on the female genotype in a two factorial breeding experiment using high-fertility mouse lines. AB - Mouse models showing an improved fertility phenotype are barely described in the literature. In the present study, we further characterized two outbred mouse models that have been selected for the phenotype 'high fertility' for more than 177 generations (fertility lines (FL) 1 and 2). In order to delineate the impact of males and females on fertility parameters, we performed a two-factorial breeding experiment by mating males and females of the three different genotypes (FL1, FL2, unselected control (Ctrl)) in all 9 possible combinations. Reproductive performance, such as number of offspring per litter or total birth weight of the entire pup, mainly depends on the female genotype. Although the reproductive performance of FL1 and FL2 is very similar, their phenotypes differ. FL2 animals of both genders are larger compared to FL1 and control animals. Females of the control line delivered offspring earlier compared to FL1 and FL2 dams. Males of FL1 are the lightest and the only ones who gained weight during the two weeks mating period. To address whether this effect is correlated with differing serum androgen levels, we measured the concentrations of testosterone, dehydroepiandrosterone, 4-androstenedione, androstanediol and dihydrotestosterone in males of all three lines by GC-MS. We measured serum testosterone between 5.0 and 6.4 ng/mL, whereas the concentrations of the other androgens were at least one order of magnitude lower, with no significant differences between the lines. Our data indicate that reproductive outcome largely depends on the genotype of the female in a two-factorial breeding experiment and supports previous findings that the phenotype 'high fertility' is warranted by using different physiological strategies. PMID- 28096496 TI - A reminder of extinction reduces relapse in an animal model of voluntary behavior. AB - One experiment with rats explored whether an extinction-cue prevents the recovery of extinguished lever-pressing responses. Initially, rats were trained to perform one instrumental response (R1) for food in Context A, and a different instrumental response (R2) in Context B. Then, responses were extinguished each in the alternate context (R1 in Context B; R2 in Context A). For one group, extinction of both responses was conducted in the presence of an extinction-cue, whereas in a second group, the extinction-cue only accompanied extinction of R1. During a final test, we observed that returning the rats to the initial acquisition context renewed performance and that response recovery was attenuated in the presence of the cue that accompanied extinction of the response. The impact of the extinction-cue, however, was not transferred to the response that has been extinguished without the cue. Our results are consistent with the idea that extinction established an inhibitory cue-response association. PMID- 28096495 TI - Memory disrupting effects of nonmuscle myosin II inhibition depend on the class of abused drug and brain region. AB - Depolymerizing actin in the amygdala through nonmuscle myosin II inhibition (NMIIi) produces a selective, lasting, and retrieval-independent disruption of the storage of methamphetamine-associated memories. Here we report a similar disruption of memories associated with amphetamine, but not cocaine or morphine, by NMIIi. Reconsolidation appeared to be disrupted with cocaine. Unlike in the amygdala, methamphetamine-associated memory storage was not disrupted by NMIIi in the hippocampus, nucleus accumbens, or orbitofrontal cortex. NMIIi in the hippocampus did appear to disrupt reconsolidation. Identification of the unique mechanisms responsible for NMII-mediated, amygdala-dependent disruption of memory storage associated with the amphetamine class may enable induction of retrieval independent vulnerability to other pathological memories. PMID- 28096497 TI - BDNF regains function in hippocampal long-term potentiation deficits caused by diencephalic damage. AB - Thiamine deficiency (TD), commonly associated with chronic alcoholism, leads to diencephalic damage, hippocampal dysfunction, and spatial learning and memory deficits. We show a decrease in the magnitude of long-term potentiation (LTP) and paired-pulse facilitation (PPF) at CA3-CA1 synapses, independent of sex, following diencephalic damage induced by TD in rats. Thus, despite a lack of extensive hippocampal cell loss, diencephalic brain damage down-regulates plastic processes within the hippocampus, likely contributing to impaired hippocampal dependent behaviors. However, both measures of hippocampal plasticity (LTP, PPF) were restored with brain-derived neurotrophic factor (BDNF), revealing an avenue for neural and behavioral recovery following diencephalic damage. PMID- 28096498 TI - Differential changes in hippocampal CaMKII and GluA1 activity after memory training involving different levels of adaptive forgetting. AB - Phosphorylation of CaMKII and AMPA receptor GluA1 subunit has been shown to play a major role in hippocampal-dependent long-term/reference memory (RM) and in the expression of long-term synaptic potentiation (LTP). In contrast, it has been proposed that dephosphorylation of these proteins could be involved in the opposite phenomenon of hippocampal long-term synaptic depression (LTD) and in adaptive forgetting. Adaptive forgetting allows interfering old memories to be forgotten to give new ones the opportunity to be stored in memory, and in particular in short-term/working memory (WM) that was shown to be very sensitive to proactive interference. To determine the role of CaMKII and GluA1 in adaptive forgetting, we adopted a comparative approach to assess the relative quantity and phosphorylation state of these proteins in the brain of rats trained in one of three radial maze paradigms: a RM task, a WM task involving a high level of adaptive forgetting, or a WM involving a low level of adaptive forgetting. Surprisingly, Western blot analyses revealed that training in a WM task involving a high level of adaptive forgetting specifically increased the expression of AMPA receptor GluA1 subunit and the activity of CaMKII in the dentate gyrus. These results highlight that WM with proactive interference involves mechanisms of synaptic plasticity selectively in the dentate gyrus. PMID- 28096499 TI - When eye movements express memory for old and new scenes in the absence of awareness and independent of hippocampus. AB - Eye movements can reflect memory. For example, participants make fewer fixations and sample fewer regions when viewing old versus new scenes (the repetition effect). It is unclear whether the repetition effect requires that participants have knowledge (awareness) of the old-new status of the scenes or if it can occur independent of knowledge about old-new status. It is also unclear whether the repetition effect is hippocampus-dependent or hippocampus-independent. A complication is that testing conscious memory for the scenes might interfere with the expression of unconscious (unaware), experience-dependent eye movements. In experiment 1, 75 volunteers freely viewed old and new scenes without knowledge that memory for the scenes would later be tested. Participants then made memory judgments and confidence judgments for each scene during a surprise recognition memory test. Participants exhibited the repetition effect regardless of the accuracy or confidence associated with their memory judgments (i.e., the repetition effect was independent of their awareness of the old-new status of each scene). In experiment 2, five memory-impaired patients with medial temporal lobe damage and six controls also viewed old and new scenes without expectation of memory testing. Both groups exhibited the repetition effect, even though the patients were impaired at recognizing which scenes were old and which were new. Thus, when participants viewed scenes without expectation of memory testing, eye movements associated with old and new scenes reflected unconscious, hippocampus independent memory. These findings are consistent with the formulation that, when memory is expressed independent of awareness, memory is hippocampus-independent. PMID- 28096501 TI - Science and Culture: Searching for shared inspiration, artists head to the world's largest science experiment. PMID- 28096502 TI - Core Concept: How nonequilibrium thermodynamics speaks to the mystery of life. PMID- 28096504 TI - Opportunity for marine fisheries reform in China. AB - China's 13th Five-Year Plan, launched in March 2016, provides a sound policy platform for the protection of marine ecosystems and the restoration of capture fisheries within China's exclusive economic zone. What distinguishes China among many other countries striving for marine fisheries reform is its size-accounting for almost one-fifth of global catch volume-and the unique cultural context of its economic and resource management. In this paper, we trace the history of Chinese government priorities, policies, and outcomes related to marine fisheries since the 1978 Economic Reform, and examine how the current leadership's agenda for "ecological civilization" could successfully transform marine resource management in the coming years. We show how China, like many other countries, has experienced a decline in the average trophic level of its capture fisheries during the past few decades, and how its policy design, implementation, and enforcement have influenced the status of its wild fish stocks. To reverse the trend in declining fish stocks, the government is introducing a series of new programs for sustainable fisheries and aquaculture, with greater traceability and accountability in marine resource management and area controls on coastal development. As impressive as these new plans are on paper, we conclude that serious institutional reforms will be needed to achieve a true paradigm shift in marine fisheries management in China. In particular, we recommend new institutions for science-based fisheries management, secure fishing access, policy consistency across provinces, educational programs for fisheries managers, and increasing public access to scientific data. PMID- 28096506 TI - Targeting TNFR2, an immune checkpoint stimulator and oncoprotein, is a promising treatment for cancer. AB - Tumor necrosis factor receptor 2 (TNFR2) is expressed both by some cancer cells and by tumor-infiltrating immunosuppressive CD4+FoxP3+ regulatory T cells (Tregs). TNFR2 stimulates the activation and proliferation of Tregs, a major checkpoint of antitumor immune responses, and promotes cancer cell survival and tumor growth. In this issue of Science Signaling, Torrey et al found that dominant antagonistic antibodies against human TNFR2 may be a potential therapy for ovarian cancer patients by simultaneously suppressing Treg activity and inducing the death of the cancer cells. PMID- 28096509 TI - Translational complex for differentiation. AB - NAT1 interacts with a subset of eukaryotic translation initiation factors to enable expression of transcripts required for stem cell differentiation signals. PMID- 28096507 TI - De novo phosphorylation and conformational opening of the tyrosine kinase Lck act in concert to initiate T cell receptor signaling. AB - The enzymatic activity of the Src family tyrosine kinase p56Lck (Lck) is tightly controlled by differential phosphorylation of two tyrosine residues, Tyr394 and Tyr505 Phosphorylation of Tyr394 and the conformational opening of Lck are believed to activate the kinase, whereas Tyr505 phosphorylation is thought to generate a closed, inactive conformation of Lck. We investigated whether the conformation of Lck and its phosphorylation state act in concert to regulate the initiation of T cell receptor (TCR) signaling. With a sensitive biosensor, we used fluorescence lifetime imaging microscopy (FLIM) to investigate the conformations of wild-type Lck and its phosphorylation-deficient mutants Y394F and Y505F and the double mutant Y394F/Y505F in unstimulated T cells and after TCR stimulation. With this approach, we separated the conformational changes of Lck from the phosphorylation state of its regulatory tyrosines. We showed that the conformational opening of Lck alone was insufficient to initiate signaling events in T cells. Rather, Lck additionally required phosphorylation of Tyr394 to induce T cell activation. Consistent with the FLIM measurements, an optimized immunofluorescence microscopy protocol revealed that the TCR-stimulated phosphorylation of Lck at Tyr394 occurred preferentially at the plasma membrane of Jurkat cells and primary human T cells. Our study supports the hypothesis that T cell activation through the TCR complex is accompanied by the de novo activation of Lck and that phosphorylation of Tyr394 plays a role in Lck function that goes beyond inducing an open conformation of the kinase. PMID- 28096505 TI - The neuropilin 2 isoform NRP2b uniquely supports TGFbeta-mediated progression in lung cancer. AB - Neuropilins (NRP1 and NRP2) are co-receptors for heparin-binding growth factors and class 3 semaphorins. Different isoforms of NRP1 and NRP2 are produced by alternative splicing. We found that in non-small cell lung cancer (NSCLC) cell lines, transforming growth factor-beta (TGFbeta) signaling preferentially increased the abundance of NRP2b. NRP2b and NRP2a differ only in their carboxyl terminal regions. Although the presence of NRP2b inhibited cultured cell proliferation and primary tumor growth, NRP2b enhanced cellular migration, invasion into Matrigel, and tumorsphere formation in cultured cells in response to TGFbeta signaling and promoted metastasis in xenograft mouse models. These effects of overexpressed NRP2b contrast with the effects of overexpressed NRP2a. Hepatocyte growth factor (HGF)-induced phosphorylation of the kinase AKT was specifically promoted by NRP2b, whereas inhibiting the HGF receptor MET attenuated NRP2b-dependent cell migration. Unlike NRP2a, NRP2b did not bind the PDZ domain scaffolding protein GAIP carboxyl terminus-interacting protein (GIPC1) and only weakly recruited phosphatase and tensin homolog (PTEN), potentially explaining the difference between NRP2b-mediated and NRP2a-mediated effects. Analysis of NSCLC patient tumors showed that NRP2b abundance correlated with that of the immune cell checkpoint receptor ligand PD-L1 as well as with epithelial-to mesenchymal transition (EMT) phenotypes in the tumors, acquired resistance to epidermal growth factor receptor (EGFR) inhibitors, disease progression, and poor survival in patients. NRP2b knockdown attenuated the acquisition of resistance to the EGFR inhibitor gefitinib in cultured NSCLC cells. Thus, in NSCLC, NRP2b contributed to the oncogenic response to TGFbeta and correlated with tumor progression in patients. PMID- 28096510 TI - B cells prevent preterm labor. AB - Premature labor and consequent neonatal mortality may be prevented by stimulating the expression of PIBF1 in uterine B cells. PMID- 28096513 TI - Targeting TNFR2 with antagonistic antibodies inhibits proliferation of ovarian cancer cells and tumor-associated Tregs. AB - Major barriers to cancer therapy include the lack of selective inhibitors of regulatory T cells (Tregs) and the lack of broadly applicable ways to directly target tumors through frequently expressed surface oncogenes. Tumor necrosis factor receptor 2 (TNFR2) is an attractive target protein because of its restricted abundance to highly immunosuppressive Tregs and oncogenic presence on human tumors. We characterized the effect of TNFR2 inhibition using antagonistic antibodies. In culture-based assays, we found that two TNFR2 antagonists inhibited Treg proliferation, reduced soluble TNFR2 secretion from normal cells, and enabled T effector cell expansion. The antagonistic activity occurred in the presence of added TNF, a natural TNFR2 agonist. These TNFR2 antibodies killed Tregs isolated from ovarian cancer ascites more potently than it killed Tregs from healthy donor samples, suggesting that these antibodies may have specificity for the tumor microenvironment. The TNFR2 antagonists also killed OVCAR3 ovarian cancer cells, which have abundant surface TNFR2. The antibodies stabilized antiparallel dimers in cell surface TNFR2 that rendered the receptor unable to activate the nuclear factor kappaB pathway and trigger cell proliferation. Our data suggest that, by targeting tumor cells and immunosuppressive tumor associated Tregs, antagonistic TNFR2 antibodies may be an effective treatment for cancers positive for TNFR2. PMID- 28096514 TI - Tonsillectomy for Obstructive Sleep-Disordered Breathing: A Meta-analysis. AB - CONTEXT: The effectiveness of tonsillectomy or adenotonsillectomy (hereafter, "tonsillectomy") for obstructive sleep-disordered breathing (OSDB) compared with watchful waiting with supportive care is poorly understood. OBJECTIVE: To compare sleep, cognitive or behavioral, and health outcomes of tonsillectomy versus watchful waiting with supportive care in children with OSDB. DATA SOURCES: Medline, Embase, and the Cochrane Library. STUDY SELECTION: Two investigators independently screened studies against predetermined criteria. DATA EXTRACTION: Two investigators independently extracted key data. Investigators independently assessed study risk of bias and the strength of the evidence of the body of literature. Investigators synthesized data qualitatively and meta-analyzed apnea hypopnea index (AHI) scores. RESULTS: We included 11 studies. Relative to watchful waiting, most studies reported better sleep-related outcomes in children who had a tonsillectomy. In 5 studies including children with polysomnography confirmed OSDB, AHI scores improved more in children receiving tonsillectomy versus surgery. A meta-analysis of 3 studies showed a 4.8-point improvement in the AHI in children who underwent tonsillectomy compared with no surgery. Sleep related quality of life and negative behaviors (eg, anxiety and emotional lability) also improved more among children who had a tonsillectomy. Changes in executive function were not significantly different. The length of follow-up in studies was generally <12 months. LIMITATIONS: Few studies fully categorized populations in terms of severity of OSDB; outcome measures were heterogeneous; and the durability of outcomes beyond 12 months is not known. CONCLUSIONS: Tonsillectomy can produce short-term improvement in sleep outcomes compared with no surgery in children with OSDB. Understanding of longer-term outcomes or effects in subpopulations is lacking. PMID- 28096515 TI - Tonsillectomy Versus Watchful Waiting for Recurrent Throat Infection: A Systematic Review. AB - CONTEXT: The effectiveness of tonsillectomy or adenotonsillectomy ("tonsillectomy") for recurrent throat infection compared with watchful waiting is uncertain. OBJECTIVE: To compare sleep, cognitive, behavioral, and health outcomes of tonsillectomy versus watchful waiting in children with recurrent throat infections. DATA SOURCES: MEDLINE, Embase, and the Cochrane Library. STUDY SELECTION: Two investigators independently screened studies against predetermined criteria. DATA EXTRACTION: One investigator extracted data with review by a second. Investigators independently assessed risk of bias and strength of evidence (SOE) and confidence in the estimate of effects. RESULTS: Seven studies including children with >=3 infections in the previous 1 to 3 years addressed this question. In studies reporting baseline data, number of infections/sore throats decreased from baseline in both groups, with greater decreases in sore throat days, clinician contacts, diagnosed group A streptococcal infections, and school absences in tonsillectomized children in the short term (<12 months). Quality of life was not markedly different between groups at any time point. LIMITATIONS: Few studies fully categorized infection/sore throat severity; attrition was high. CONCLUSIONS: Throat infections, utilization, and school absences improved in the first postsurgical year in tonsillectomized children versus children not receiving surgery. Benefits did not persist over time; longer term outcomes are limited. SOE is moderate for reduction in short-term throat infections and insufficient for longer-term reduction. SOE is low for no difference in longer-term streptococcal infection reduction. SOE is low for utilization and missed school reduction in the short term, low for no difference in longer-term missed school, and low for no differences in quality of life. PMID- 28096517 TI - The nucleoside analog clitocine is a potent and efficacious readthrough agent. AB - Nonsense mutations resulting in a premature stop codon in an open reading frame occur in critical tumor suppressor genes in a large number of the most common forms of cancers and are known to cause or contribute to the progression of disease. Low molecular weight compounds that induce readthrough of nonsense mutations offer a new means of treating patients with genetic disorders or cancers resulting from nonsense mutations. We have identified the nucleoside analog clitocine as a potent and efficacious suppressor of nonsense mutations. We determined that incorporation of clitocine into RNA during transcription is a prerequisite for its readthrough activity; the presence of clitocine in the third position of a premature stop codon directly induces readthrough. We demonstrate that clitocine can induce the production of p53 protein in cells harboring p53 nonsense-mutated alleles. In these cells, clitocine restored production of full length and functional p53 as evidenced by induced transcriptional activation of downstream p53 target genes, progression of cells into apoptosis, and impeded growth of nonsense-containing human ovarian cancer tumors in xenograft tumor models. Thus, clitocine induces readthrough of nonsense mutations by a previously undescribed mechanism and represents a novel therapeutic modality to treat cancers and genetic diseases caused by nonsense mutations. PMID- 28096518 TI - Structural basis for guanidine sensing by the ykkC family of riboswitches. AB - Regulation of gene expression by cis-encoded riboswitches is a prevalent theme in bacteria. Of the hundreds of riboswitch families identified, the majority of them remain as orphans, without a clear ligand assignment. The ykkC orphan family was recently characterized as guanidine-sensing riboswitches. Herein we present a 2.3 A crystal structure of the guanidine-bound ykkC riboswitch from Dickeya dadantii The riboswitch folds into a boot-shaped structure, with a coaxially stacked P1/P2 stem forming the boot, and a 3'-P3 stem-loop forming the heel. Sophisticated base pairing and cross-helix tertiary contacts give rise to the ligand-binding pocket between the boot and the heel. The guanidine is recognized in its positively charged guanidinium form, in its sp2 hybridization state, through a network of coplanar hydrogen bonds and by a cation-pi stacking contact on top of a conserved guanosine residue. Disruption of these contacts resulted in severe guanidinium binding defects. These results provide the structural basis for specific guanidine sensing by ykkC riboswitches and pave the way for a deeper understanding of guanidine detoxification-a previously unappreciated aspect of bacterial physiology. PMID- 28096516 TI - Newborn Sequencing in Genomic Medicine and Public Health. AB - The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening. PMID- 28096519 TI - The nuclear poly(A) binding protein of mammals, but not of fission yeast, participates in mRNA polyadenylation. AB - The nuclear poly(A) binding protein (PABPN1) has been suggested, on the basis of biochemical evidence, to play a role in mRNA polyadenylation by strongly increasing the processivity of poly(A) polymerase. While experiments in metazoans have tended to support such a role, the results were not unequivocal, and genetic data show that the S. pombe ortholog of PABPN1, Pab2, is not involved in mRNA polyadenylation. The specific model in which PABPN1 increases the rate of poly(A) tail elongation has never been examined in vivo. Here, we have used 4-thiouridine pulse-labeling to examine the lengths of newly synthesized poly(A) tails in human cells. Knockdown of PABPN1 strongly reduced the synthesis of full-length tails of ~250 nucleotides, as predicted from biochemical data. We have also purified S. pombe Pab2 and the S. pombe poly(A) polymerase, Pla1, and examined their in vitro activities. Whereas PABPN1 strongly increases the activity of its cognate poly(A) polymerase in vitro, Pab2 was unable to stimulate Pla1 to any significant extent. Thus, in vitro and in vivo data are consistent in supporting a role of PABPN1 but not S. pombe Pab2 in the polyadenylation of mRNA precursors. PMID- 28096520 TI - Differences in Prevalence of Lymphovascular Invasion among Early Gastric Cancers between Korea and Japan. AB - Background/Aims: The presence of invasion is a diagnostic criterion of early gastric cancer (EGC) in Korea, whereas diagnosis in Japan is based on enlarged nuclei and prominent nucleoli. Moreover, the depth of invasion is the location of cancer cell infiltration in Korea, whereas it is the location of lymphovascular invasion (LVI) or cancer cell infiltration in Japan. We evaluated the characteristics of EGC with LVI to uncover the effects of different diagnostic criteria. Methods: Consecutive T1-stage EGC patients who underwent complete resection were included after endoscopic or surgical resection. The presence of LVI was evaluated. Results: LVI was present in 112 of 1,089 T1-stage EGC patients. LVI was associated with depth of invasion (p<0.001) and age (p=0.017). The prevalence of LVI in mucosal cancer was significantly higher in Korea (p<0.001), whereas that of submucosal cancer was higher in Japan (p=0.024). For mucosal EGC types, LVI was positively correlated with diagnostic criteria applied in Korea (p=0.017). For submucosal EGC types, LVI was positively correlated with Japanese criteria (p=0.001) and old age (p=0.045). Conclusions: The higher prevalence of LVI for mucosal EGC in Korea and for submucosal EGC in Japan indicates that different diagnostic criteria should be considered when reading publications from other countries. PMID- 28096521 TI - Decreased Esophageal Sensitivity to Acid in Morbidly Obese Patients: A Cause for Concern? AB - Background/Aims: To evaluate esophageal sensitivity to acid between morbidly obese (MO) patients and non-MO controls with abnormal esophageal acid exposure. Methods: We conducted a cross-sectional study of 58 patients: 30 MO (cases) and 28 non-MO (controls). Esophageal symptoms and esophageal sensitivity to 0.1 M hydrochloric acid solution (Bernstein test) were compared between MO and non-MO patients with a prior diagnosis of abnormal esophageal acid exposure. Results: MO patients were less symptomatic than non-MO controls (14% vs 96%; odds ratio [OR], 0.006; 95% confidence interval [CI], 0.001 to 0.075; p=0.000). MO patients were more likely to present with decreased esophageal sensitivity to the instillation of acid than non-MO controls (57% vs 14%; OR, 8; 95% CI, 1.79 to 35.74; p=0.009). Subgroup analysis revealed no differences in esophageal sensitivity in MO patients with and without abnormal esophageal acid exposure (43% vs 31%; p=0.707). Conclusions: Silent gastroesophageal reflux disease (GERD) is common among MO individuals, likely due to decreased esophageal sensitivity to acid. The absence of typical GERD symptoms in these patients may delay discovery of precancerous conditions, such as Barrett's esophagus. We believe that these patients may require a more aggressive diagnostic work-up to rule out the presence of silent GERD. PMID- 28096523 TI - X-ray imaging of spin currents and magnetisation dynamics at the nanoscale. AB - Understanding how spins move in time and space is the aim of both fundamental and applied research in modern magnetism. Over the past three decades, research in this field has led to technological advances that have had a major impact on our society, while improving the understanding of the fundamentals of spin physics. However, important questions still remain unanswered, because it is experimentally challenging to directly observe spins and their motion with a combined high spatial and temporal resolution. In this article, we present an overview of the recent advances in x-ray microscopy that allow researchers to directly watch spins move in time and space at the microscopically relevant scales. We discuss scanning x-ray transmission microscopy (STXM) at resonant soft x-ray edges, which is available at most modern synchrotron light sources. This technique measures magnetic contrast through the x-ray magnetic circular dichroism (XMCD) effect at the resonant absorption edges, while focusing the x ray radiation at the nanometre scale, and using the intrinsic pulsed structure of synchrotron-generated x-rays to create time-resolved images of magnetism at the nanoscale. In particular, we discuss how the presence of spin currents can be detected by imaging spin accumulation, and how the magnetisation dynamics in thin ferromagnetic films can be directly imaged. We discuss how a direct look at the phenomena allows for a deeper understanding of the the physics at play, that is not accessible to other, more indirect techniques. Finally, we present an overview of the exciting opportunities that lie ahead to further understand the fundamentals of novel spin physics, opportunities offered by the appearance of diffraction limited storage rings and free electron lasers. PMID- 28096524 TI - A Case of Seronegative Limbic Encephalitis with Multiple Sclerosis: A Possible Overlapping Syndrome. AB - BACKGROUND Autoimmune encephalitis might coexist in patients with autoimmune demyelinating disorders. CASE REPORT We report on a case of a 45-year-old female multiple sclerosis (MS) patient presenting with acute onset short-term memory loss, altered mental status, inflammatory cerebrospinal fluid (CSF) findings and an MRI lesion on the left temporal lobe. An extensive panel for neuronal autoantibodies proved negative. Neuropsychological symptoms gave a prompt response to immunotherapy but nevertheless control MRI showed left hippocampal atrophy. CONCLUSIONS Several recent reports of concurrent emergence of autoimmune encephalitis and MS suggest a common mechanism for these disorders. Since autoimmune encephalitis and MS share certain common CSF and neuroimaging findings, an increased understanding of overlapping autoimmune brain disorders is required to avoid misdiagnosis especially in antibody negative autoimmune encephalitis cases. PMID- 28096522 TI - Control of Food Intake by Gastrointestinal Peptides: Mechanisms of Action and Possible Modulation in the Treatment of Obesity. AB - This review focuses on the control of appetite by food intake-regulatory peptides secreted from the gastrointestinal tract, namely cholecystokinin, glucagon-like peptide 1, peptide YY, ghrelin, and the recently discovered nesfatin-1 via the gut-brain axis. Additionally, we describe the impact of external factors such as intake of different nutrients or stress on the secretion of gastrointestinal peptides. Finally, we highlight possible conservative-physical activity and pharmacotherapy-treatment strategies for obesity as well as surgical techniques such as deep brain stimulation and bariatric surgery also altering these peptidergic pathways. PMID- 28096525 TI - Toll-Like Receptor 4 Signaling in High Mobility Group Box-1 Protein 1 Mediated the Suppression of Regulatory T-Cells. AB - BACKGROUND Treg cells play a central role in the suppression of immune response, and their suppressive capacity can be modulated by toll-like receptor (TLR) ligands. However, the detailed pathway of TLR ligand modulation is still unknown. The present study aimed to evaluate the effect of the high mobility group box-1 protein 1 (HMGB1) and lipopolysaccharide (LPS) on Treg cells through TLR4 signaling. MATERIAL AND METHODS Treg cells were purified from healthy human peripheral blood mononuclear cells (PBMCs) by magnetic-bead activity cell sorting (MACS), blocked by anti-TLR4 monoclonal antibody, and then incubated with different concentration of LPS or HMGB1. The level of gene expression of IL 1beta, IL-10, IFN-gamma, and TGF-beta were detected using quantitative real-time polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA), and the proliferation of Treg cells after treating by LPS and HMGB1 was analyzed by flow cytometry. The NF-kappaB expression in Treg cells was examined by Western blotting. RESULTS LPS treated CD4 CD25 Treg cells directly increased the expression of IL-1b and IL-10 and decreased the expression of IFN-gamma and TGF beta. However, HMGB1 treatment resulted in a marked decreased expression of IL 1beta, IL-10, IFN-gamma, and TGF-beta. The proliferation of CD4+ T cells was significantly inhibited by Treg cells in the LPS treatment group, but weaken in the HMGB1 treatment group. These data suggest that HMGB1 and LPS stimulation could downregulate the expression NF-kappaB p65 in cytoplasmic proteins and increase the expression in nuclear proteins, thus leading to modulation of IL 1beta, IL-10, IFN-gamma, and TGF-beta expression; moreover, the suppressive function of Treg cells could be regulated by TLR4. CONCLUSIONS TLR4 signaling in HMGB1 mediated the suppressive function of Treg cells through the activation of the NF-kappaB pathway. PMID- 28096527 TI - DNA repair: Histones have got to go. PMID- 28096528 TI - Testing the Gateway Hypothesis. PMID- 28096529 TI - Genetic screens: Combining CRISPR perturbations and RNA-seq. PMID- 28096526 TI - Telomeres in cancer: tumour suppression and genome instability. AB - The shortening of human telomeres has two opposing effects during cancer development. On the one hand, telomere shortening can exert a tumour-suppressive effect through the proliferation arrest induced by activating the kinases ATM and ATR at unprotected chromosome ends. On the other hand, loss of telomere protection can lead to telomere crisis, which is a state of extensive genome instability that can promote cancer progression. Recent data, reviewed here, provide new evidence for the telomere tumour suppressor pathway and has revealed that telomere crisis can induce numerous cancer-relevant changes, including chromothripsis, kataegis and tetraploidization. PMID- 28096530 TI - Associations between body mass index-related genetic variants and adult body composition: The Fenland cohort study. AB - BACKGROUND/OBJECTIVE: Body mass index (BMI) is a surrogate measure of adiposity but does not distinguish fat from lean or bone mass. The genetic determinants of BMI are thought to predominantly influence adiposity but this has not been confirmed. Here we characterise the association between BMI-related genetic variants and body composition in adults. SUBJECTS/METHODS: Among 9667 adults aged 29-64 years from the Fenland study, a genetic risk score for BMI (BMI-GRS) was calculated for each individual as the weighted sum of BMI-increasing alleles across 96 reported BMI-related variants. Associations between the BMI-GRS and body composition, estimated by dual-energy X-ray absorptiometry (DXA) scans, were examined using age-adjusted linear regression models, separately by sex. RESULTS: The BMI-GRS was positively associated with all fat, lean and bone variables. Across body regions, associations of the greatest magnitude were observed for adiposity variables, for example, for each s.d. increase in BMI-GRS predicted BMI, we observed a 0.90 s.d. (95% confidence interval (CI): 0.71, 1.09) increase in total fat mass for men (P=3.75 * 10-21) and a 0.96 s.d. (95% CI: 0.77, 1.16) increase for women (P=6.12 * 10-22). Associations of intermediate magnitude were observed with lean variables, for example, total lean mass: men: 0.68 s.d. (95% CI: 0.49, 0.86; P=1.91 * 10-12); women: 0.85 s.d. (95% CI: 0.65, 1.04; P=2.66 * 10-17) and of a lower magnitude with bone variables, for example, total bone mass: men: 0.39 s.d. (95% CI: 0.20, 0.58; P=5.69 * 10-5); women: 0.45 s.d. (95% CI: 0.26, 0.65; P=3.96 * 106). Nominally significant associations with BMI were observed for 28 single-nucleotide polymorphisms. All 28 were positively associated with fat mass and 13 showed adipose-specific effects. CONCLUSIONS: In adults, genetic susceptibility to elevated BMI influences adiposity more than lean or bone mass. This mirrors the association between BMI and body composition. The BMI-GRS can be used to model the effects of measured BMI and adiposity on health and other outcomes. PMID- 28096532 TI - A sensitive and specific point-of-care detection assay for Zaire Ebola virus. PMID- 28096531 TI - The first imported case of Rift Valley fever in China reveals a genetic reassortment of different viral lineages. AB - We report the first imported case of Rift Valley fever (RVF) in China. The patient returned from Angola, a non-epidemic country, with an infection of a new reassortant from different lineages of Rift Valley fever viruses (RVFVs). The patient developed multiorgan dysfunction and gradually recovered with continuous renal replacement therapy and a short regimen of methylprednisolone treatment. The disordered cytokines and chemokines in the plasma of the patient revealed hypercytokinemia, but the levels of protective cytokines were low upon admission and fluctuated as the disease improved. Whole-genome sequencing and phylogenetic analysis revealed that the imported strain was a reassortant comprising the L and M genes from lineage E and the S gene from lineage A. This case highlights that RVFV had undergone genetic reassortment, which could potentially alter its biological properties, cause large outbreaks and pose a serious threat to global public health as well as the livestock breeding industry. PMID- 28096533 TI - Impact of pretreatment characteristics and salvage strategy on outcome in patients with relapsed acute myeloid leukemia. PMID- 28096534 TI - Novel therapeutic approach to improve hematopoiesis in low risk MDS by targeting MDSCs with the Fc-engineered CD33 antibody BI 836858. AB - We recently reported that the accumulation of myeloid-derived suppressor cells (MDSC), defined as CD33+HLA-DR-Lin-, has a direct role in the pathogenesis of myelodysplastic syndrome (MDS). In particular, CD33 is strongly expressed in MDSC isolated from patients with MDS where it has an important role in MDSC-mediated hematopoietic suppressive function through its activation by S100A9. Therefore, we tested whether blocking this interaction with a fully human, Fc-engineered monoclonal antibody against CD33 (BI 836858) suppresses CD33-mediated signal transduction and improves the bone marrow microenvironment in MDS. We observed that BI 836858 can reduce MDSC by antibody-dependent cellular cytotoxicity, which correlated with increases in granule mobilization and cell death. BI 836858 can also block CD33 downstream signaling preventing immune-suppressive cytokine secretion, which correlates with a significant increase in the formation of CFU GM and BFU-E colonies. Activation of the CD33 pathway can cause reactive oxygen species (ROS)-induced genomic instability but BI 836858 reduced both ROS and the levels of double strand breaks and adducts (measured by comet assay and gammaH2AX). This work provides the ground for the development of a novel group of therapies for MDS aimed at MDSC and their disease-promoting properties with the goal of improving hematopoiesis in patients. PMID- 28096536 TI - Germline IKAROS mutation associated with primary immunodeficiency that progressed to T-cell acute lymphoblastic leukemia. PMID- 28096537 TI - JAK2-V617F activates beta1-integrin-mediated adhesion of granulocytes to vascular cell adhesion molecule 1. PMID- 28096538 TI - Pancreatic cancer: Pancreatic tumours derive amino acids via extracellular protein uptake. PMID- 28096535 TI - Genetics of ancestry-specific risk for relapse in acute lymphoblastic leukemia. AB - The causes of individual relapses in children with acute lymphoblastic leukemia (ALL) remain incompletely understood. We evaluated the contribution of germline genetic factors to relapse in 2225 children treated on Children's Oncology Group trial AALL0232. We identified 302 germline single-nucleotide polymorphisms (SNPs) associated with relapse after adjusting for treatment and ancestry and 715 additional SNPs associated with relapse in an ancestry-specific manner. We tested for replication of these relapse-associated SNPs in external data sets of antileukemic drug pharmacokinetics and pharmacodynamics and an independent clinical cohort. 224 SNPs were associated with rapid drug clearance or drug resistance, and 32 were replicated in the independent cohort. The adverse risk associated with black and Hispanic ancestries was attenuated by addition of the 4 SNPs most strongly associated with relapse in these populations (for blacks: model without SNPs hazard ratio (HR)=2.32, P=2.27 * 10-4, model with SNPs HR=1.07, P=0.79; for Hispanics: model without SNPs HR=1.7, P=8.23 * 10-5, model with SNPs HR=1.31, P=0.065). Relapse SNPs associated with asparaginase resistance or allergy were overrepresented among SNPs associated with relapse in the more asparaginase intensive treatment arm (20/54 in Capizzi-methorexate arm vs 8/54 in high-dose methotrexate arm, P=0.015). Inherited genetic variation contributes to race-specific and treatment-specific relapse risk. PMID- 28096539 TI - Development: Modelling human stomach development with gastric organoids. PMID- 28096540 TI - Alcoholic liver disease: Alcoholic hepatitis: a warning for prednisolone and infection risk? PMID- 28096542 TI - Liquid biopsy in 2016: Circulating tumour cells and cell-free DNA in gastrointestinal cancer. PMID- 28096543 TI - Therapy: Experimental portal hypertension - pinning hopes on FXR agonists? PMID- 28096541 TI - The mucosal immune system: master regulator of bidirectional gut-brain communications. AB - Communication between the brain and gut is not one-way, but a bidirectional highway whereby reciprocal signals between the two organ systems are exchanged to coordinate function. The messengers of this complex dialogue include neural, metabolic, endocrine and immune mediators responsive to diverse environmental cues, including nutrients and components of the intestinal microbiota (microbiota gut-brain axis). We are now starting to understand how perturbation of these systems affects transition between health and disease. The pathological repercussions of disordered gut-brain dialogue are probably especially pertinent in functional gastrointestinal diseases, including IBS and functional dyspepsia. New insights into these pathways might lead to novel treatment strategies in these common gastrointestinal diseases. In this Review, we consider the role of the immune system as the gatekeeper and master regulator of brain-gut and gut brain communications. Although adaptive immunity (T cells in particular) participates in this process, there is an emerging role for cells of the innate immune compartment (including innate lymphoid cells and cells of the mononuclear phagocyte system). We will also consider how these key immune cells interact with the specific components of the enteric and central nervous systems, and rapidly respond to environmental variables, including the microbiota, to alter gut homeostasis. PMID- 28096544 TI - Simamycin (5'-O-geranyluridine): a new prenylated nucleoside from Streptomyces sp. AB - A new nucleoside modified by prenylation, simamycin (1), was isolated from the culture broth of a soil-derived Streptomyces sp. Its structure was determined by spectroscopic analysis and chemical synthesis as 5'-O-geranyluridine. Compound 1 induced differentiation of preadipocytes into matured adipocytes. PMID- 28096545 TI - Thiazomycin, nocathiacin and analogs show strong activity against clinical strains of drug-resistant Mycobacterium tuberculosis. AB - Thiazolyl peptides are a class of natural products with potent Gram-positive antibacterial activities. Lack of aqueous solubility precluded this class of compounds from advancing to clinical evaluations. Nocathiacins and thiazomycins are sub-classes of thiazolyl peptides that are endowed with structural features amenable for chemical modifications. Semi-synthetic modifications of nocathiacin led to a series of analogs with improved water solubility, while retaining potency and antibacterial spectrum. We studied the activities of a selection of two natural products (nocathiacin and thiazomycin) as well as seven polar semi synthetic analogs against twenty clinical strains of Mycobacterium tuberculosis with MDR phenotypes. Two compounds show useful activity against H37Rv strain with MIC values ?1 MUM, two (?0.5 MUm) and three (?10 MUm). These two derivatives showed MIC values ?2.5 MUm against most of the 20 MDR strains regardless their resistance profile. Specifically, these lack cross-resistance to rifampicin, isoniazid and moxifloxacin. PMID- 28096546 TI - MA026, an anti-hepatitis C virus compound, opens tight junctions of the epithelial cell membrane. AB - MA026 is an antiviral natural compound against hepatitis C virus (HCV). It was recently reported that MA026 binds claudin-1 (CLDN1) and inhibits HCV infection. Although CLDN1 is an important component of tight junctions (TJ) in the epithelial cell layer, the effects of MA026 on the TJ barrier function remained to be revealed. Here we report that MA026 irreversibly opens the TJ. MA026 irreversibly increased FD4 permeability and decreased transepithelial electrical resistance (TER) for at least 5 h. Although MA026 increased Ca2+ influx in layered MDCKII cells, the Ca2+ influx was less than that of capsaicin, a reversible TJ opener. Moreover, MA026 did not induce the dephosphorylation of cofilin and reorganization of F-actin structure. Although the mechanism is left to be disclosed, these results suggest that MA026 is a novel irreversible TJ opener probably by targeting CLDN1. PMID- 28096547 TI - Trachyspic acid 19-butyl ester, a new inhibitor of Plk1 polo box domain-dependent recognition from uncharacterized fungus RKGS-F2684. PMID- 28096548 TI - The synthesis and evaluation of the antiproliferative activity of deacidified GEX1A analogues. AB - GEX1A/herboxidiene (1) is a natural product isolated from Streptomyces sp. and has been reported to target the pre-mRNA splicing process. Although 1 was shown to have antitumor activity in vivo, weight loss was observed in mice when 1 was consecutively administered. We assumed that the carboxylic acid moiety was one of the causes of this toxicity. In this study, a series of amide, carbamate and urea analogues of 1 were synthesized and their antiproliferative activity was evaluated in vitro. The synthesis of urea analogues featured Curtius rearrangement following amine treatment with the one-pot procedure from 1. Furthermore, a structure-activity relationship study of the urea analogues revealed that the pharmacologically preferable basic side chains were acceptable and that compound 9g was equipotent to parent 1. These basic urea analogues would be promising leads for the development of novel antitumor agents. PMID- 28096550 TI - The ups and downs of drug discovery: the early history of Fidaxomicin. AB - The path from antibiotic compound discovery to the market is marked by many potholes and its negotiation is often dependent on luck and persistence. Perhaps the prime example of this is the case of the development of tiacumicin B to Fidaxomicin, where both parameters were critical and the path was particularly circuitous. PMID- 28096549 TI - Decatamariic acid, a new mitochondrial respiration inhibitor discovered by pesticidal screening using drug-sensitive Saccharomyces cerevisiae. AB - A new decalin, decatamariic acid, was isolated from a cultured broth of the fungus Aspergillus tamarii FKI-6817. Its absolute configuration was elucidated by NMR and electronic circular dichroism. Decatamariic acid (10 MUM) elicited ~50% inhibition of the ATP production in mitochondria isolated from wild-type Saccharomyces cerevisiae without affecting the activities of respiratory enzymes. The action manner of this compound may be interesting as a possible seed for new pesticides. PMID- 28096551 TI - The natural evolution of idiophatic epimacular membrane. AB - BACKGROUND AND AIMS: Epiretinal membrane (ERM) refers to a semi-translucent tissue layer found on the inner surface of the retina especially in older people. Surgical treatment remains controversial, optimal timing for such treatment is difficult to determine and data on the natural evolution of this disorder are limited. In this study we evaluated the natural course of idiopathic epimacular membrane in 49 patients (53 eyes). MATERIALS AND METHODS: Retrospective evaluation of a group of 49 patients (53 eyes) with idiopathic epimacular membrane confirmed by biomicroscopy, photography and optical coherence tomography (OCT). RESULTS: Patient age ranged from 51-85 years (median 72). The average follow-up was 21.3 months (+/- 14). Between the initial and final best corrected visual acuity (BCVA) there was no statistically significant difference although there was a significant tendency to decrease in BCVA (Spearman P=0.05) during the follow-up. Initial BCVA correlated with initial central retinal thickness (CRT), final CRT, final volume, and age. The final BCVA significantly correlated with all parameters measured. CONCLUSION: BCVA during follow-up tended to decrease: difference of starting BCVA and final BCVA values depending on the time of monitoring is significant. This we attribute to a slow gradual progression of macular changes. But, initial and final BCVA measurements were not substantially different at the end. Thus, in the absence of any clear signs of ERM progression, we can safely postpone the decision whether to perform PPV. PMID- 28096552 TI - Novel missense variant of CACNA1A gene in a Slovak family with episodic ataxia type 2. AB - INTRODUCTION: Episodic ataxias (EAs) are rare dominantly inherited neurological disorders characterized by recurrent episodes of ataxia lasting minutes to hours. The most common subtype is EA type 2 (EA2) caused by pathogenic variants of calcium voltage-gated channel subunit alpha1 A gene (CACNA1A) on chromosome 19p13. SUBJECTS AND METHODS: We examined a Slovak three-generation family. Genomic DNA of the family members was extracted from peripheral blood and amplified by polymerase chain reaction. CACNA1A variants were screened by Sanger sequencing. RESULTS: We identified four family members with recurrent episodes of ataxia. Complex differential diagnosis was performed. Genetic analysis with direct sequencing revealed a novel heterozygous variant of CACNA1A - c.5264A>G (p.Glu1755Gly) located in the pore loop of domain IV of calcium channel alpha-1A subunit. CONCLUSION: We identified a novel missense variant of a voltage dependent P/Q-type calcium channel alpha-1A subunit in a Slovak three-generation family with recurrent episodes of ataxia. The heterozygous missense variant resulted in changing a highly conserved glutamic acid within the pore loop of domain IV. PMID- 28096553 TI - Outstanding contribution of British medicine to child health in Sudan. PMID- 28096554 TI - Launching of the MRCPCH Clinical Examination in Khartoum, Sudan. PMID- 28096555 TI - WHO/UNICEF recommended therapeutic food versus home based therapeutic food in the management of severe acute malnutrition: A randomized controlled trial. AB - Malnutrition is a major public health problem especially in the developing countries. The objective of the study was to compare WHO/UNICEF recommended therapeutic food with home based therapeutic food in the management of severe acute malnutrition. It was a randomized controlled trial at tertiary care level hospital with nutritional rehabilitation centre. Children (6 month to 5 years) having severe acute malnutrition were included in the study. Group A (n=74 children) was given WHO recommended therapeutic food and group B (n=75 children) was given home based therapeutic food. The mean rate of weight gain, gain in height and increase in mid-upper arm circumference were significantly higher (p<0.05) in the group received home based therapeutic food. Mean duration to achieve target weight was 21.44+/-3.33 days in group A and 16.28+/-2.11 days in group B (p15 min) for patients under the care of clinical anesthesia (CA) residents. We also sought to identify factors from resident training, medical history, anesthetic use, and anesthesia staffing, which affect emergence. MATERIAL AND METHODS: In this single center, historical cohort study, perioperative information management systems provided data for surgical cases under resident care at a tertiary care center in the United States from 2006 to 2008. Using multiple logistic regression, the effects of variables on emergence was analyzed. RESULTS: Of 7687 cases under the care of 27 residents, the incidence of prolonged emergence was 13.9%. Emergence prolongation decreased by month in training for 1st-year (CA-1) residents (r2 = 0.7, P < 0.001), but not for CA-2 and CA-3 residents. Mean patient emergence time differed among 27 residents (P < 0.01 for 58.4% or 205/351 paired comparisons). In a model restricted to 1st-year residents, patient male gender, American Society of Anesthesiologists (ASA) physical status >II, emergency surgical case, operative duration >=2 h, and paralytic agent use were associated with higher frequency of prolonged emergence, while sevoflurane or desflurane use was associated with lower frequency. Attending anesthesiologist handoff was not associated with longer emergence. CONCLUSION: Incidence of prolonged emergence from general anesthesia differed significantly among trainees, by resident training duration, and for patients with ASA >II. PMID- 28096574 TI - Awareness during general anesthesia: An Indian viewpoint. AB - BACKGROUND AND AIMS: The incidence of intra-operative awareness with explicit recall in the Western world has been reported to be between 0.1% and 0.2% in the general surgical population and up to 1-2% of patients at high risk for this complication. Awareness in the Indian population has never been studied; we therefore wanted to detect the incidence of awareness in patients who were at high risk of experiencing awareness during surgery in our population. MATERIAL AND METHODS: We conducted a prospective single-center observational study at a 600-bedded tertiary cancer care referral hospital. We recruited adult patients posted for major cancer surgery who were considered to be at high risk for awareness. These patients were interviewed at three time-points using the structured modified Brice interview questionnaire. The primary outcome studied was the incidence of definite intra-operative awareness. RESULTS: A total of 934 patients were included in the final analysis of which none reported awareness. Using the rule of three (Hanley and Lippman-Hand) we conclude that the upper 95% confidence interval for the incidence of awareness in this population is <1 in 300 (0.33%). CONCLUSION: Awareness under anesthesia is a distressing complication with a potential for long-term psychological consequences, and every effort should be undertaken to prevent it. It is reassuring though that our data in Indian cancer patients at high risk for intra-operative awareness suggests that it is an uncommon occurrence. PMID- 28096575 TI - The effect of epidural dexmedetomidine on oxygenation and shunt fraction in patients undergoing thoracotomy and one lung ventilation: A randomized controlled study. AB - BACKGROUND AND AIMS: Role of epidural dexmedetomidine in providing analgesia is well documented, but its effect on oxygenation and shunt fraction is not well established. We studied the hypothesis that epidural dexmedetomidine may improve oxygenation and shunt fraction during one-lung ventilation (OLV). MATERIAL AND METHODS: After taking Institutional Ethics Committee approval, sixty patients undergoing thoracotomy and OLV were randomized to receive epidural ropivacaine with saline (RS group) or epidural ropivacaine with dexmedetomidine (RD group). Group RS received 7 ml of ropivacaine 0.5% with 1.5 ml normal saline (NS) bolus while RD group received 7 ml of 0.5% ropivacaine with 1 mcg/kg dexmedetomidine reconstituted in 1.5 ml NS. This was followed by infusion of 5 ml/h of 0.5% ropivacaine in RS group and 5 ml/h of 0.5% ropivacaine containing 0.2 mcg/kg of dexmedetomidine in RD group. Arterial and central venous blood gas parameters were obtained 15 minutes after intubation during two lung ventilation (TLV15), 15 and 45 min after OLV (OLV15, OLV45) and 15 minutes after reinstitution of two lung ventilation (ReTLV). RESULTS: RD group had better oxygenation (254.2 +/- 72.3 mmHg, 240.60 +/- 59.26 mmHg) as compared to RS group (215.2 +/- 64.3 mmHg, 190.7 +/- 61.48 mmHg) at OLV15 (P - 0.04) and OLV45 (P - 0.004) respectively. Shunt fraction in RD group was (30.31 +/- 7.89%, 33.76 +/- 8.89%) and (35.14 +/- 7.58%, 39.57 +/- 13.03%) in RS group at OLV15 and OLV45, respectively. The increase in the shunt fraction from TLV15 was significantly greater in RS group than RD group both at OLV15 (P - 0.03) and OLV45 (P - 0.03). The sevoflurane and fentanyl requirement was lower in RD group. CONCLUSION: Epidural dexmedetomidine improves oxygenation and reduces shunt fraction during OLV, in patients undergoing thoracotomy. It also reduces intraoperative anesthetic and analgesic requirement. PMID- 28096576 TI - Role of edaravone in managemant of septic peritonitis. AB - BACKGROUND AND AIMS: Sepsis is a complex rapidly progressive infectious disease that remain a major cause of morbidity and mortality in surgical patients and trauma victims. Edaravone a novel free radical scavenger was approved in 2001 in Japan for treatment of acute cerebral and myocardial infarction. Hence, in this work we attempt to evaluate its role in cases of septic peritonitis (SP). MATERIAL AND METHODS: This is a prospective randomized observer-blinded study carried out in surgical Intensive Care Unit (ICU) after approval by Hospital Ethical Committee. After admission to ICU patients were randomly divided into two groups of thirty patients each-Group (C): Control group managed according to the routine protocol of sepsis and Group (E): Edaravone treated SP managed according to the routine protocol of sepsis + edaravone at dose of 30 mg/12 h intravenous infusion for 2 weeks. All patients were monitored for invasive blood pressure, central venous pressure, heart rate, temperature, urine output, total fluid balance, and routine investigation. Blood sample was taken weekly for 2 weeks to measure the following parameters: Nuclear transcription factor kappa B activity (NFKB), mitogen-activated protein kinase (MAPK), heat shock protein 72 (HSP 72) and total antioxidant capacity (TAC). RESULTS: There was significant decrease (P < 0.05) in serum level of NFKB, MAPK in Group E in comparison with Group C. While serum level of HSP 72 and TAC showed significant increase (P < 0.05) in Group E compared with Group C with better outcome. CONCLUSION: SP treatment with edaravone could significantly improve the inflammatory and oxidative states with better patient outcomes. PMID- 28096577 TI - The effect of atrial natriuretic peptide infusion on intestinal injury in septic shock. AB - BACKGROUND AND AIMS: The aim of this study is to assess the effect of atrial natriuretic peptide (ANP) on intestinal ischemia-reperfusion injury in septic shock. MATERIAL AND METHODS: A prospective randomized controlled, observer blinded study was carried out in surgical Intensive Care Unit (ICU), University Hospital. Forty adult patients in septic shock were randomly divided into two groups, control group (Group C) received normal saline and ANP group (Group A) patients received ANP in the form of 1.5 mg vial added to 250 ml solvent in plastic bag (1 ml = 6 micg) given at 2 mcg/kg intravenous bolus over 1 min followed by 0.01 mcg/kg/min for 24 h. The primary outcome measurements were blood marker of intestinal hypoperfusion in form of intestinal fatty acid binding protein (I-FABP), malondialdehyde (MDA), myloperoxidase enzyme activity (MPO), protein carbonyl (PC), and glutathione peroxidase activity (GPA) measured before start of ANP infusion, 6 h, 12 h, and 24 h after start of infusion. The secondary outcome measurements were the duration of noradrenaline infusion, duration of ICU stay, hospital mortality rate, and complications related to ANP. RESULTS: In comparison with Group C, Group A showed a significant decrease (P < 0.05) in serum level of MPO, MDA, PC, and I-FABP, with a significant increase (P < 0.05) in serum level of GPA, 6 h, 12 h, and 24 h after the start of ANP infusion. There was significant decrease (P < 0.05) in mean duration of noradrenaline infusion, the length of ICU stay and mortality rate in Group A in comparison with Group C. In Group A, seven patients had mean arterial blood pressure < 65 mmHg but respond to volume resuscitation, three patients serum sodium was 125-130 mmol/L. CONCLUSION: In cases of septic shock, concomitant administration of ANP with noradrenaline may have a protective effect against intestinal injury through a decrease in the level of intestinal hypoperfusion owing to its anti-inflammatory and antioxidant effect. PMID- 28096578 TI - The effect of pregabalin and s-ketamine in total knee arthroplasty patients: A randomized trial. AB - BACKGROUND AND AIMS: Pain reduction is important for rehabilitation after total knee arthroplasty. Intra- and peri-articular infiltration with local anesthetics may be an alternative to commonly used locoregional techniques. Adding pregabalin orally and s-ketamine intravenously may further reduce postoperative pain. MATERIAL AND METHODS: This prospective, randomized, double-blind, placebo controlled study compared two methods of perioperative analgesia. Control patients received a standardized multimodal postoperative analgesic regime of paracetamol, diclofenac, and piritramide-patient-controlled analgesia, including ropivacaine knee infiltration during surgery. The study group received pregabalin orally and s-ketamine intravenously as an additional medication to the standard multimodal regimen. The control group received placebo. RESULTS: The study group showed lower piritramide consumption during the first 24 h (P: 0.043), but with more side effects such as diplopia and dizziness. CONCLUSION: Addition of pregabalin and s-ketamine resulted in lower piritramide consumption during the first 24 h postoperatively. However, more investigation on benefits versus side effects of this medication is required. PMID- 28096579 TI - Intrathecal ropivacaine with or without tramadol for lower limb orthopedic surgeries. AB - BACKGROUND AND AIM: Preservative free tramadol has been used as an adjuvant to intrathecal bupivacaine. However, the effect of the addition of tramadol on intrathecal isobaric ropivacaine has never been studied. MATERIAL AND METHODS: This prospective, randomized, double-blind study was conducted in 50 adult male American Society of Anesthesiologists grade I or II patients, aged 18-60 years, being operated for unilateral femur fractures. An epidural catheter was inserted in L2-L3 interspace and subarachnoid block was given in L3-L4 space. The patients were randomized to receive 0.5 mL normal saline (group R) or 0.5 mL (25 mg) preservative free tramadol (group RT) with 2.5 mL of 0.75% intrathecal ropivacaine. Hemodynamic parameters, sensory level, motor block, sedation and side-effects were recorded. Statistical analysis was done using Student's t-test, Chi-square test, Fischer's exact test and repeated measures ANOVA. RESULTS: The time of sensory block onset was 9.2 +/- 4.9 min and 8.6 +/- 5.3 min (P = 0.714) in group R and group RT, respectively. The motor block onset was also comparable in both the groups (P = 0.112). The duration of sensory block was 147.2 +/- 37.4 min in group R and 160.4 +/- 40.9 min in group RT (P = 0.252). The median maximum block height achieved in both the groups was T6 and the time to achieve the maximum block was also comparable statistically (P = 0.301). CONCLUSION: The addition of intrathecal tramadol 25 mg to the isobaric ropivacaine does not alter the block characteristics produced by intrathecal ropivacaine alone. PMID- 28096580 TI - Randomized double-blind comparison of remifentanil and alfentanil in patients undergoing laparoscopic cholecystectomy using total intravenous anesthesia. AB - BACKGROUND AND AIMS: To compare the use of remifentanil and alfentanil to suppress intraoperative adrenergic response of pain and the influence of these drugs on the recovery profile in patients undergoing laparoscopic cholecystectomy using a total intravenous anesthesia (TIVA) technique. MATERIAL AND METHODS: One hundred patients undergoing elective laparoscopic cholecystectomy were randomized to be managed with either remifentanil (group R) or alfentanil (group A). During general anesthesia, we evaluated adrenergic responses to intubation to first surgical incision and over the surgical procedure. We also recorded time to first spontaneous breathing, time to successful ventilation, time to respond to verbal orders, and time to extubation. RESULTS: The R group reported a significantly lower number of responses to intubation and responses to first surgical incision (14% vs. 30%; P = 0.013 and 8% vs. 18%; P = 0,037, respectively). The event of one or more responses during the surgical procedure was also lower in the R group (56% vs. 70%; P = 0.017). Hypertensive response to surgical stimuli during the procedure was lower in the R group as well as a lower frequency of tachycardia episodes in this group (34% vs. 56%; P = 0.033 and 28% vs. 44%; P = 0.041, respectively). No differences were found between groups relating to the percentage of hypotensive episodes and no episodes of bradycardia were appreciated. Both groups were similar relating to recovery times: time to the first spontaneous breathing, time to successful ventilation, time to respond to verbal orders, and time to extubation. CONCLUSION: Remifentanil showed a more stable hemodynamic response during the surgery compared with the use of alfentanil in anesthetized patients undergoing laparoscopic cholecystectomy using TIVA. Both opioids, alfentanil and remifentanil, have a similar recovery profile, and they do not delay time to awakening. PMID- 28096581 TI - Role of preemptive tapentadol in reduction of postoperative analgesic requirements after laparoscopic cholecystectomy. AB - BACKGROUND AND AIMS: Poorly managed acute postoperative pain may result in prolonged morbidity. Various pharmacotherapies have targeted this, but research on an ideal preemptive analgesic continues, taking into account drug-related side effects. Considering the better tolerability profile of tapentadol, we assessed its role as a preemptive analgesic in the reduction of postoperative analgesic requirements, after laparoscopic cholecystectomy. MATERIAL AND METHODS: In a prospective-double-blinded fashion, sixty patients posted for above surgery, were randomized to receive tablet tapentadol 75 mg (Group A) or starch tablets (Group B) orally, an hour before induction of general anesthesia. Perioperative analgesic requirement, time to first analgesia, pain, and sedation score were compared for first 24 h during the postoperative period and analyzed by one-way analysis of variance test. A P < 0.05 was considered significant. RESULTS: Sixty patients were analyzed. The perioperative analgesic requirement was significantly lower in Group A. Verbal numerical score was significantly lower in Group A at the time point, immediately after shifting the patient to the postanesthesia care unit. Ramsay sedation scores were similar between the groups. No major side effects were observed except for nausea and vomiting in 26 cases (10 in Group A, 16 in Group B). CONCLUSION: Single preemptive oral dose of tapentadol (75 mg) is effective in reducing perioperative analgesic requirements and acute postoperative pain, without added side effects. It could be an appropriate preemptive analgesic, subjected to future trials concentrating upon its dose response effects. PMID- 28096582 TI - Comparison of different regimens of intravenous dexmedetomidine on duration of subarachnoid block. AB - BACKGROUND AND AIMS: Many studies have studied the effect of intravenous dexmedetomidine on the prolongation of the duration of the subarachnoid block (SAB). These studies had administered dexmedetomidine using different regimens. This study was designed to find out the suitable regimen with maximum advantages and minimum disadvantages. MATERIAL AND METHODS: Ninety-three ASA 1 and 2 patients scheduled to undergo surgeries under SAB were randomly allocated into three groups namely B, M, and BM. After SAB, Group B received 0.5 MUg/kg of dexmedetomidine bolus over 15 min, Group M received 0.5 MUg/kg/h of dexmedetomidine infusion until the end of surgery, Group BM received both bolus and infusion. RESULTS: The time to achieve T10 sensory level (SL) was significantly faster in the Groups B and BM than in the Group M. Maximum block height achieved was T4 and was same in all the groups. The Time to achieve maximum SL and Bromage 3 was comparable in all groups. The two-segment regression time and time to reach Bromage 0 was significantly higher in Groups M and BM than Group B. The time for a first request of analgesia was similar in Groups M and BM. The maximum sedation attained in all groups was Ramsay Sedation Score of 3. Side effects such as bradycardia, hypotension, and desaturation were comparable between the groups. CONCLUSION: We conclude that the continuous infusion of dexmedetomidine results in more advantages than just a bolus dose. Therefore, we suggest using only the maintenance dose of intravenous dexmedetomidine after subarachnoid blockade for prolonging the duration and achieving sedation. PMID- 28096583 TI - Addition of clonidine to bupivacaine in transversus abdominis plane block prolongs postoperative analgesia after cesarean section. AB - BACKGROUND AND AIMS: The aim was to compare duration of postoperative analgesia with addition of clonidine to bupivacaine in bilateral transversus abdominis plane (TAP) block after lower segment cesarean section (LSCS). MATERIAL AND METHODS: One hundred American Society of Anesthesiologists (ASA) grade I and II pregnant patients undergoing LSCS under spinal anesthesia were randomly divided to receive either 20 ml bupivacaine 0.25% (Group B; n = 50) or 20 ml bupivacaine+1ug/kg clonidine bilaterally (Group BC; n = 50) in TAP block in a double-blind fashion. The total duration of analgesia, patient satisfaction score, total requirement of analgesics in the first 24 h, and the side effects of clonidine such as sedation, dryness of mouth, hypotension, and bradycardia were observed. P < 0.05 was taken as significant. RESULTS: In 99 patients analyzed, TAP block failed in five patients. Duration of analgesia was significantly longer in Group BC (17.8 +/- 3.7 h) compared to Group B (7.3 +/- 1.2 h; P < 0.01). Mean consumption of diclofenac was 150 mg and 65.4 mg in Groups B and BC (P < 0.01), respectively. All patients in Group BC were extremely satisfied (P < 0.01) while those in Group B were satisfied. Thirteen patients (28%) in Group BC were sedated but arousable (P = 0.01) compared to none in Group B. In Group BC, 19 patients complained of dry mouth compared to 13 in Group B (P = 0.121). None of the patients experienced hypotension or bradycardia. CONCLUSION: Addition of clonidine 1 MUg/kg to 20 ml bupivacaine 0.25% in TAP block bilaterally for cesarean section significantly increases the duration of postoperative analgesia, decreases postoperative analgesic requirement, and increases maternal comfort compared to 20 ml of bupivacaine 0.25% alone. PMID- 28096584 TI - Randomized controlled study comparing the hemodynamic response to laryngoscopy and endotracheal intubation with McCoy, Macintosh, and C-MAC laryngoscopes in adult patients. AB - BACKGROUND AND AIMS: Earlier studies have shown that the type of laryngoscope blade influences the degree of hemodynamic response to endotracheal intubation. The aim of the study was to evaluate the hemodynamic response to oral endotracheal intubation with C-MAC laryngoscopy and McCoy laryngoscopy compared to that of Macintosh laryngoscopy in adult patients under general anesthesia. MATERIAL AND METHODS: This is a prospective randomized parallel group study. Ninety American Society of Anesthesiologists I patients were randomly allotted into three groups. Group A - Macintosh laryngoscopy (control group). Group B - laryngoscopy with McCoy laryngoscope. Group C - laryngoscopy with C-MAC video laryngoscope. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were monitored at baseline (just before induction), just before intubation (T0), 1 min (T1), 3 min (T3), 5 min (T5), and 10 min (T10) after intubation. Intergroup comparison of study parameters was done by unpaired sample t-test for normal data and Mann-Whitney U test for skewed data. For within-group comparison, the repeated measures of ANOVA for normal data and Friedman followed by Wilcoxon signed rank test for skewed data were performed. RESULTS: In C-MAC group, the HR was significantly higher than the Macintosh group at 3 min after intubation, whereas SBP, DBP, and MAP were significantly higher at 1 min. McCoy group showed a similar response compared to Macintosh group at all time intervals. CONCLUSION: C-MAC video laryngoscope has a comparatively greater hemodynamic response than Macintosh laryngoscope. PMID- 28096585 TI - Comparison of three insertion techniques of ProSeal laryngeal mask airway: A randomized clinical trial. AB - BACKGROUND AND AIMS: We aimed to compare three techniques for insertion of ProSeal laryngeal mask airway (PLMA). MATERIAL AND METHODS: Two hundred ten patients (American Society of Anaethesiologists I-II, aged 18-60 years) undergoing general anesthesia using the PLMA as an airway management device were randomly allocated to digital (D), rotational (R), or pharyngoscopic (P) techniques. In the D group (n = 70), the PLMA insertion was performed by using digital manipulation. In the R group (n = 70), the PLMA was inserted into the mouth, rotated anticlockwise through 90 degrees and advanced into the hypopharynx. In the P group (n = 70), the PLMA was inserted after gentle pharyngoscopy using laryngoscope. Success rate at the first attempt, insertion time, airway manipulations required, and postoperative complications were noted. RESULTS: Insertion at first attempt was more successful with P technique than the R and D groups (100% vs. 98.5% vs. 81.4% respectively, P < 0.01). Insertion time was shortest for the P group which was statistically significant compared to the group D (P < 0.001), but comparable with the R group. None of the patients required manipulation in the P group compared to the group R (P = 0.04) and D (P < 0.001). Blood staining (group P = 2.8% vs. group R = 2.8% vs. group D = 22%, P < 0.0001) and sore throat (group P = 0% vs. group R = 6.9% vs. group D = 16.7%, both: P < 0.005) were lower with the pharyngoscopic technique. CONCLUSION: We conclude that the pharyngoscopic technique for PLMA insertion is more successful with lower incidence of complications (mucosal bleeding and sore throat). PMID- 28096586 TI - Comparison of intubating laryngeal mask airway and fiberoptic bronchoscopy for endotracheal intubation in patients undergoing cervical discectomy. AB - BACKGROUND AND AIMS: Direct laryngoscopy is hazardous in patients with cervical posterior intervertebral disc prolapse (PIVD) as it may worsen the existing cord compression. To achieve smooth intubation, many adjuncts such as fiberoptic bronchoscope (FOB), video laryngoscopes, lighted stylets, and intubating laryngeal mask airways (ILMAs) are available. However, there is a paucity of literature comparing ILMA with fiberoptic intubation in patients with PIVD. Hence, this study was designed to compare the effectiveness of ILMA technique with FOB to accomplish endotracheal intubation in patients undergoing cervical discectomy. MATERIAL AND METHODS: Sixty patients of age group 20-60 years, of American Society of Anesthesiologists status I or II, were enrolled in this prospective and randomized study. They were allocated to one of the two groups, ILMA group and FOB group. The patients were intubated orally using either equipment, after dexmedetomidine premedication and induction of general anesthesia. Chi-square and Fisher exact tests were used to find the significance of study parameters on a categorical scale. Paired samples t-test and Student's t test were used to find the significance of study parameters on a continuous scale. Significance was assessed at 5% level of significance. RESULTS: Bronchoscopy was a faster method of securing airway as compared with ILMA (38.13 +/- 11.52 vs. 29.83 +/- 13.75 s). Tracheal intubation was successful in all 60 patients (100%), belonging to both groups. CONCLUSION: ILMA and FOB were comparable with regards to ease of intubation in terms of time, the number of attempts and hemodynamic stability. PMID- 28096587 TI - Is dedicating an ultrasound machine to regional anesthesia an economically viable option? AB - BACKGROUND AND AIMS: The cost effectiveness of ultrasound-guided regional anesthesia is an issue which requires discussion. Based on our experience, we hypothesized that this is an economically viable option. MATERIAL AND METHODS: In this retrospective study, we included 90 patients who underwent upper extremity surgeries in our institute solely under ultrasound (USG)-guided brachial plexus blocks in a year. The cost of the block was derived by adding the cost of the material and drugs used for the block. This cost was subtracted from the cost that otherwise would have been incurred for general anesthesia (GA) of similar duration. This cost difference or benefit per case was then used to calculate the duration in years required to recover the cost of the ultrasound machine. STATISTICS: Data were analyzed using SPSS 15.0. Analysis of variance was applied to compare mean benefits as per surgery, block, and duration. Ninety-five percent confidence interval for mean were calculated. Level of significance was taken as P = 0.05. RESULTS: There were significant economic benefits using ultrasound guidance as compared to GA. Benefits differed significantly as per the type of surgery, type of block, and duration of the surgery. With the cost benefit that we have obtained, the cost of USG machine can be recovered in about 3 years. CONCLUSION: USG regional anesthesia is an economically viable concept. The cost benefit increases with the duration of a given surgery and increases with the number of blocks. PMID- 28096588 TI - Prolonged coma after anesthesia. PMID- 28096589 TI - Water-cooled radiofrequency neuroablation for sacroiliac joint dysfunctional pain. AB - Sacroiliac (SI) joint dysfunction is a common source of chronic low-back pain. Recent evidences from different parts of the world suggest that cooled radiofrequency (RF) neuroablation of sacral nerves supplying SI joints has superior pain alleviating properties than available existing treatment options for SI joint dysfunctional pain. A 35-year-old male had intractable bilateral SI joint pain (numeric rating scale [NRS] - 9/10) with poor treatment response to intra-articular steroid therapy. Bilateral water cooled = RF was applied for neuroablation of nerves supplying both SI joints. Postprocedure pain intensity was 5/10 and after 7 days it was 2/10. On 18th-month follow-up, he is pain free except for mild pain (NRS 2/10) on occasional extreme twisting of the back. This case attempts to highlight that sacral neuroablation based on cooled RF technique can be a long lasting remedial option for chronic SI joint pain unresponsive to conventional treatment. PMID- 28096590 TI - Posterior cerebral stroke: An unusual cause of postoperative bilateral sensorineural hearing loss after laparoscopic surgery. PMID- 28096591 TI - Factitious reading by gas monitor. PMID- 28096592 TI - Intrathoracic bronchial intubation: A feasible option to manage life-threatening hypoxia in a neonate. PMID- 28096593 TI - Emergency craniotomy in Glanzmann thrombasthenia: Anesthetic management and brief review of literature. PMID- 28096595 TI - Hyperventilation syndrome after general anesthesia: Our experience. PMID- 28096594 TI - Lateral position... beware! PMID- 28096596 TI - Hydatidiform mole with uncontrolled hyperthyroidism: An anesthetic challenge. PMID- 28096597 TI - Cardiac arrest after tramadol injection in a polytrauma patient. PMID- 28096598 TI - Cognitive function test: Is preanesthesia checkup complete without this? PMID- 28096599 TI - Do we need bronchoscopy during percutaneous tracheostomy? PMID- 28096600 TI - Lower tidal volumes through ProSeal laryngeal mask airway as compared to endotracheal tube? PMID- 28096601 TI - Video laryngoscope aids in the assessment of vocal cord paralysis due to recurrent laryngeal nerve injury after thyroid surgery. PMID- 28096602 TI - Surface plasmon resonance based biosensor: A new platform for rapid diagnosis of livestock diseases. AB - Surface plasmon resonance (SPR) based biosensors are the most advanced and developed optical label-free biosensor technique used for powerful detection with vast applications in environmental protection, biotechnology, medical diagnostics, drug screening, food safety, and security as well in livestock sector. The livestock sector which contributes the largest economy of India, harbors many bacterial, viral, and fungal diseases impacting a great loss to the production and productive potential which is a major concern in both small and large ruminants. Hence, an accurate, sensitive, and rapid diagnosis is required for prevention of these above-mentioned diseases. SPR based biosensor assay may fulfill the above characteristics which lead to a greater platform for rapid diagnosis of different livestock diseases. Hence, this review may give a detail idea about the principle, recent development of SPR based biosensor techniques and its application in livestock sector. PMID- 28096603 TI - Gastrointestinal nematode larvae in the grazing land of cattle in Guwahati, Assam. AB - AIM: To know the prevalence of gastrointestinal nematode larvae (L3) in the grazing land of cattle in Guwahati, Kamrup district, Assam. MATERIALS AND METHODS: Pastures were collected and examined for the presence of nematode larvae (L3) from six localities of Guwahati at monthly interval from August 2012 to July 2013. The counted larvae were then expressed as per kg dry matter of herbage (L3/kg DM). RESULTS: Examination of pastures revealed presence of nematode larvae (L3) in pastures throughout the year which varied from 4.5 L3/kg DM in January to a maximum of 106.33 L3/kg DM in August. The L3 of Haemonchus contortus, Trichostrongylus spp., Oesophagostomum spp., Cooperia spp., and Mecistocirrus spp. were recovered from pastures. The average pasture larval burden (PLB) was 34.75+/-3.48 L3/kg DM. Season-wise PLB revealed the presence of 23.89+/-3.01, 67.54+/-5.41, 26.67+/-1.92, and 7.28+/-0.89 L3/kg DM during pre-monsoon, monsoon, post-monsoon, and winter seasons, respectively. Monsoon season has significant (p<0.05) effect on PLB. However, analysis of variance of different locations with respect to season revealed that there was no significant difference but season wise it was highly significant (p<0.01). Pearson correlation of environmental variables (temperature, relative humidity, and rainfall) with PLB revealed correlation was statistically significant with rainfall (p<0.05). CONCLUSION: This study reveals the presence of five nematode larvae (L3) in the pastures of Guwahati, Assam throughout the year, statistically significant during monsoon season. PMID- 28096604 TI - Ocimum sanctum Linn. stimulate the expression of choline acetyltransferase on the human cerebral microvascular endothelial cells. AB - AIM: This research was conducted to identify the expression of choline acetyltransferase (ChAT) in human cerebral microvascular endothelial cells (HCMECs) and to clarify the capability of Ocimum sanctum Linn. ethanolic extract to stimulate the presence of ChAT in the aging HCMECs. MATERIALS AND METHODS: In this study, we perform an in vitro analysis some in the presence of an ethanolic extract of O. sanctum Linn. as a stimulator for the ChAT expression. HCMECs are divided become two groups, the first is in low passage cells as a model of young aged and the second is in a high passage as a model of aging. Furthermore to analysis the expression of ChAT without and with extract treatments, immunocytochemistry and flow cytometry analysis were performed. In addition, ChAT sandwich enzyme-linked immunosorbent assay is developed to detect the increasing activity of the ChAT under normal, and aging HCMECs on the condition treated and untreated cells. RESULTS: In our in vitro models using HCMECs, we found that ChAT is expressed throughout intracytoplasmic areas. On the status of aging, the ethanolic extract from O. sanctum Linn. is capable to stimulate and restore the expression of ChAT. The increasing of ChAT expression is in line with the increasing activity of this enzyme on the aging treated HCMECs. CONCLUSIONS: Our observation indicates that HCMECs is one of the noncholinergic cells which is produced ChAT. The administrated of O. sanctum Linn. ethanolic extract may stimulate and restore the expression of ChAT on the deteriorating cells of HCMECs, thus its may give nerve protection and help the production of acetylcholine. PMID- 28096605 TI - Molecular and epidemiological updates on cystic echinococcosis infecting water buffaloes from Egypt. AB - AIM: Cystic echinococcosis (CE) represents a serious parasitic disease at both animal and public health levels. The majority of reports negated the CE infection in buffaloes from Egypt; however, one study illustrated their infection with G6 genotype (camel strain). The present work contributed to update the epidemiological and molecular knowledge about CE infecting this economically important animal for better understanding of its role in maintaining the Echinococcus life cycle. MATERIALS AND METHODS: A total of 120 slaughtered water buffaloes at Mansoura abattoir, Dakahlia province, Egypt, were inspected for the existence of hydatid cysts. Cysts location and fertility were examined. Five out of 27 revealed cysts were tested molecularly using both cytochrome C oxidase subunit 1 and nicotinamide adenine dinucleotide hydrogen subunit 1 (nadh1) genes. RESULTS: Low prevalence (4.2%) as well as considerably low fertility rate (14.8%) of buffaloes CE was noted. G1 genotype (common sheep strain) was revealed from the five examined cysts. At the level of nadh1 partial sequences, a globally singleton G1 haplotype was reported. CONCLUSION: This the first report about the G1 infection in buffaloes from Egypt. This study proposed the minimized role of this animal in echinococcosis transmission. These findings could provide preliminary data for the local control of this disease. PMID- 28096606 TI - Phylogenetic analysis of glycoprotein B gene sequences of bovine herpesvirus 1 isolates from India reveals the predominance of subtype 1.1. AB - AIM: This study was conducted for the isolation and molecular characterization of bovine herpesvirus 1 (BoHV-1) isolated from the nasal and vaginal swabs collected from naturally infected cattle showing clinical symptoms of the respiratory disease. MATERIALS AND METHODS: Isolation of BoHV-1 virus performed on clinical samples collected from 65 cattle from five states of India. The BoHV-1 isolates were further confirmed by polymerase chain reaction (PCR) using primers specific for glycoprotein B (gB) genomic region. PCR amplification was performed using previously published gB gene-specific primer pairs. gB PCR amplicons obtained from all isolates were sequenced, and phylogenetic analysis was performed using software. RESULTS: A total of 12 samples were found positive in cell culture isolation. 11 isolates showed the visible cytopathic effect on Madin-Darby bovine kidney after 72 h. Partial sequence analysis of gB gene of all isolates revealed 99.0-100% homology between them. All isolates showed 99.2-99.8% homology with Cooper stain. CONCLUSION: BoHV-1.1 is the predominant circulating subtype of BoHV in India, and all isolates have homology with Cooper stain. PMID- 28096608 TI - Effect of Aegle marmelos and Murraya koenigii in treatment of delayed pubertal buffaloes heifers. AB - AIM: This study aims to study the estrus induction, ovulation, and conception rate of delayed puberty in buffaloes heifers by feeding a herbal plants Aegle marmelos (bael/bili/bhel leaf) and Murraya koenigii (Curry leaf). MATERIALS AND METHODS: Totally, 24 buffalo heifers with delayed puberty were selected for the present study and divided randomly in four equal groups (n=6). Before experiment, all animals were dewormed with albendazole at 10 mg/kg body weight to prevent them from the stress of parasitism. In the present experiment, four group taken and Group I (n=6) treated with A. marmelos, Group II (n=6) treated with M. koenigii, Group III (n=6) treated with mixture of A. marmelos and M. koenigii and fed for 9 days. Group IV (n=6) considered as control and fed with concentrate only. The blood samples were collected from all the animals on day 0 (before treatment), 4, 9 (during treatment), on the day of estrus and day 8 after the onset of estrus. The 10 ml blood was collected from the jugular vein of all the experimental animals for estimation of serum calcium, inorganic phosphorus, and progesterone (P4). The estrus response, ovulation, conception rate along with serum calcium, inorganic phosphorus, and progesterone level were determined by the standard protocol. RESULTS: From Group III 4 heifers, from Group II 3 heifers, and from Group I and IV (Control) 2 heifers each, exhibited the estrus. The estrus response was recorded as 33.33%, 50.00%, 75.00%, and 33.33% in Group I, Group II, Group III, and Group IV, respectively. In treatment Group III, serum calcium found significantly more (p<0.05) on day 8 post-estrus as compared to other groups at a similar interval. Inorganic phosphorus and progesterone show no significant difference between groups. The ovulation and conception rates are comparatively better in Group III (75%) buffalo heifers than other groups. CONCLUSION: Herbal supplementation of A. marmelos and M. koenigii in combination, as well as M. koenigii alone, were found effective in fertility improvement in delayed pubertal buffalo heifers by increasing ovulation and conception rate. PMID- 28096607 TI - Diagnosis and management of bovine babesiosis outbreaks in cattle in Punjab state. AB - AIM: The aim of the present study was to diagnose severe outbreaks of bovine babesiosis in Punjab state, in the year 2015 and to suggest control and preventive measures to animal owners. MATERIALS AND METHODS: Mortality of animals was recorded in two cattle herd comprising a total of 465 cattle in Sangrur (n=125) and Faridkot (n=340) districts. There was a history of purchase of animals at one farm. 23 blood samples were collected from diseased (n=15) and healthy animals (n=8) for hematological analysis, parasitological, and polymerase chain reaction (PCR)-based diagnosis. Ticks were also collected from animals for identification. RESULTS: Out of 465 cattle at risk, 28 were critically ill and 14 died of disease with morbidity, mortality, and case fatality rate of 6.02%, 3.01%, and 50.00%, respectively. Clinical signs and necropsy findings were suggestive of babesiosis. Ticks collected from both the outbreaks were identified as Rhipicephalus (Boophilus) microplus. Thin blood smears from infected animals (especially with clinical sign of hemoglobinuria) were found positive for Babesia bigemina organisms; however, molecular diagnosis (PCR) further confirmed the disease. Animals were successfully treated with diminazene aceturate, hematinics, and antipyretics. CONCLUSIONS: Two fatal outbreaks of babesiosis in cattle were diagnosed with application of conventional parasitological, hematological, and molecular diagnostic techniques. PCR was found to be far more sensitive in detecting the disease, especially in latent infections. Animal owners were advised to follow quarantine measures before mixing new animals in the herd and strategic acaricidal treatments for effective tick control. PMID- 28096609 TI - Studies on alterations of clinical and hemato-biochemical parameters before and after treatment in calves naturally infected with theileriosis. AB - AIM: The aim was to determine hemato-biochemical alterations and to determine the better treatment of theileriosis in naturally infected calves. MATERIALS AND METHODS: A total of 74 Holstein crossbred calves below 6 months of age, of either sex were included for present investigation in Bikaner. Based on the clinical examinations and laboratory results, 20 calves included for hemato-biochemical studies (before and after treatment) and divided into two groups (having 10 calves each). RESULTS: The clinical examination of these calves revealed weakness, ticks infestations, high fever above 104 degrees F, pronounced swelling of prescapular, prefemoral, parotid lymph nodes, loss of elasticity of skin, anemia, lacrimal discharges, pulpy cornea, tachycardia, and dyspnea. There was highly significant decrease (p<0.01) in hemoglobin, total erythrocyte count, packed cell volume and total leukocyte count, serum glucose, total protein, globulin and albumin level and highly significant increase in aspartate aminotransferase and alanine aminotransferase level as compared to healthy control animals in Group I and II. The animals of Group II treated with buparvaquone along with single blood transfusion shows better recovery then animals of Group I treated with bupavaqone and hematinic. CONCLUSIONS: Significant changes were found in hemato-biochemical parameters in theileria affected calves before treatment as compare to healthy control calves. Significant improvement was observed in hemato-biochemical parameters in buparvaquone and single blood transfusion treated calves as compare to another group, so it is concluded that buparvaquone and single blood transfusion is better combination for treatment of theileriosis. PMID- 28096610 TI - Investigation of body and udder skin surface temperature differentials as an early indicator of mastitis in Holstein Friesian crossbred cows using digital infrared thermography technique. AB - AIM: The objective of this study was to investigate the ability of infrared thermography (IRT) technique and its interrelationship with conventional mastitis indicators for the early detection of mastitis in Holstein Friesian (HF) crossbred cows. MATERIALS AND METHODS: A total of 76 quarters of lactating HF crossbred (Bos indicus * Bos taurus) cows (n=19) were monitored for body temperature (i.e., eye temperature) and udder skin surface temperature (USST) before milking using forward-looking infrared (FLIR) i5 camera. Milk samples were collected from each quarter and screened for mastitis using Somatic Cell Count (SCC), Electrical Conductivity (EC), and California mastitis test. Thermographic images were analyzed using FLIR Quick Report 1.2 image analysis software. Data on body and USST were compiled and analyzed statistically using SPSS 16.0 and Sigmaplot 11. RESULTS: The mean+/-standard deviation (SD) body (37.23+/-0.08 degrees C) and USST (37.22+/-0.04 degrees C) of non-mastitic cow did not differ significantly; however, the mean USST of the mastitis-affected quarters were significantly higher than the body temperature and USST of unaffected quarters (p<0.001). The mean+/-SD USST of the subclinical mastitis (SCM) and clinical mastitis-affected quarters were 38.08+/-0.17 degrees C and 38.25+/-0.33 degrees C, respectively, which is 0.72 and 1.05 degrees C higher than the USST temperature of unaffected quarters. The USST was positively correlated with EC (r=0.95) and SCC (r=0.93). The receiver operating characteristic curve analysis revealed a higher sensitivity for USST in early prediction of SCM with a cut-off value of >37.61 degrees C. CONCLUSION: It is concluded that infrared thermal imaging technique could be used as a potential noninvasive, quick cow-side diagnostic technique for screening and early detection of SCM and clinical mastitis in crossbred cows. PMID- 28096611 TI - Recent advances in role of chromium and its antioxidant combinations in poultry nutrition: A review. AB - Poultry is reared in open side houses in most of the tropical countries, which results in huge temperature variation in shed causing stress resulting in increased demand of antioxidant supplementation. Since cooling of poultry houses or environment control is very expensive, thus methods focused on nutritional modifications appears to be the much logical approach. Stress increases mineral and vitamin mobilization from tissues and their excretion. Effect of some minerals and vitamin supplements such as chromium (Cr) and ascorbic acid to elevate the negative effects of environmental stress is well documented. Cr functions as an antioxidant and its deficiency are said to disrupt carbohydrate and protein metabolism. Cr has been utilized for weight gain, to improve feed conversion ratio, increase relative organ weight, muscle development, decrease cholesterol, increase high-density lipoprotein cholesterol, and improve nutrient digestion. Therefore, the present review discusses the beneficial aspects of Cr with its effect in different doses and antioxidant combinations to explore and promote its optimum utilization in poultry nutrition and production. PMID- 28096612 TI - Effect of feeding Acacia nilotica pod meal on hematobiochemical profile and fecal egg count in goats. AB - AIM: This study was conducted to observe the effect of feeding Acacia nilotica pod meal on hematobiochemical profile and gastrointestinal parasitic load in growing goats. MATERIALS AND METHODS: To experiment was conducted for a period of 3-month on 24 male goats (31/2 month old, average body weight [BW] 6.50+/-1.50 kg), distributed into four groups of six animals each. The experimental animals were fed graded level of A. nilotica pod meal (0%, 10%, 20% and 30%) mixed in concentrate mixture equivalent to tannin concentration of 0%, 1.91%, 3.82% and 5.73% in the total mixed ration I, II, III and IV, respectively, but ad libitum measured quantity of green sorghum fodder (Sorghum bicolor) feeding. The blood samples were collected from experimental goats during the feeding experiment for the examination of different hematological indices and serum biochemical profile to know the overall health status of animals and standard method was followed to analyze the samples. Fecal sample was collected directly from the anus of goats by inserting middle finger and kept the samples in labeled polythene bag. Further fresh sample was processed and examined by McMaster Technique for eggs per gram and oocysts per gram. It gives accurate information regarding severity of infection. RESULTS: The feeding of babul pod meal did not address significant changes about the hematological parameters among various treatment groups. The lymphocyte count was significantly higher (p=0.07) in T3 group as compared to control and increase with increase in level of babul pod meal in the diet. Blood urea nitrogen (BUN) level was 4.86 and 6.59% lower in T1 and T2 group as compared to control and inversely proportional with level of supplement in ration. The decrease in BUN reflected good dietary protein metabolism happened in animals supplemented with babul pod meal. Serum creatinine level was significantly lower (p<0.01) in T2 group as compared to control. The creatinine level was 20.17% lower in T2 group as compared to control. Haemonchus and Coccidian egg count was significantly reduced (p<0.01) in T2 and T3 group followed with T1 as compared to control group. CONCLUSION: The metabolic status of the animal was not affected with the supplementation of babul pod meal, however, lower serum creatinine level and remarkable reduction in nematode, as well as protozoan egg count in the treatment group, showed good health impact of babul pod. PMID- 28096613 TI - Immunotoxic effect of thiamethoxam in immunized mice with Brucella abortus cultural filtrate antigen. AB - AIM: This study was planned for determination the toxic effect of thiamethoxam (TMX) in immunized mice with Brucella abortus culture filtrate antigen (CFBAgs) (as a vaccine) and its role of TMX on decrease activity of B. abortus antigen on eliciting of humoral and cellular immunity. MATERIALS AND METHODS: To achieve these goals 60 female mice were used, 7-8 weeks age, they were divided equally into three groups (20 in each group) and treated as follows: 1st group: Mice were immunized with CFBAgs intraperitoneally in two doses, 2 weeks intervals with (protein concentration 2 mg?ml), 2nd group: Mice immunized as in the 1st group and was administrated orally with 1/10 lethal dose 50% of TMX (83.7 mg/kg B.W.) for 4 weeks daily, 3rd group was administrated orally with 0.3 ml normal saline served as a control group. At day 28 post immunization (PI) delayed type hypersensitivity (skin test) was done, and serum samples were collected at day 30 (PI) for detection of passive hemagglutination test (PHA); interferon gamma (IFN gamma) which was done by enzyme-linked immunosorbent assay test in addition to phagocytes assay. RESULTS: The results of skin test post injection with soluble antigen of B. abortus intradermally showed a high significantly mean values at p<=0.05 of footpad skin thickness in the 1st group of mice which recorded (0.51+/ 0.002 mm) as compared with the 2nd group of mice which showed (0.08+/-0.002 mm) after 24 h; the mean values of skin thickness were declined in the 1st mice (0.46+/-0.002) and 2nd mice (0.070+/-0.001) at 48 h; control group showed a negative results. These results were agreed with results of serum levels of IFN gamma (pg/ml) that showed that a significant increase the vaccinated 1st group (406.36+/-1.52), than those values in the 2nd group (151.61+/-0.89) and negative result in 3rd group (46.47+/-0.60), in addition to results of PHA test which showed a significant increase in antibody titer in the 1st group (139+/-12.16) with low level of serum antibody in the 2nd group (7.66+/-0.33). Phagocytic ratio results in the 1st group showed an increase to reach (18.55+/-0.44) than a ratio in the 2nd group (13.24+/-0.32) and the control group (5.46+/-0.25). CONCLUSION: It was concluded that TMX induced suppression of humoral and cellular immune responses in immunized mice with CFBAgs. PMID- 28096614 TI - Evidence of hemolysis in pigs infected with highly virulent African swine fever virus. AB - AIM: The research was conducted to understand more profoundly the pathogenetic aspects of the acute form of the African swine fever (ASF). MATERIALS AND METHODS: A total of 10 pigs were inoculated with ASF virus (ASFV) (genotype II) in the study of the red blood cells (RBCs), blood and urine biochemistry in the dynamics of disease. RESULTS: The major hematological differences observed in ASFV infected pigs were that the mean corpuscular volume, mean corpuscular hemoglobin, and hematocrits were significantly decreased compared to controls, and the levels of erythropoietin were significantly increased. Also were detected the trends of decrease in RBC count at terminal stages of ASF. Analysis of blood biochemistry revealed that during ASF development, besides bilirubinemia significantly elevated levels of lactate dehydrogenase, and aspartate aminotransferase were detected. Analysis of urine biochemistry revealed the presence of bilirubinuria, proteinuria during ASF development. Proteinuria, especially at late stages of the disease reflects a severe kidney damage possible glomerulonefritis. CONCLUSION: The results of this study indicate the characteristics of developing hemolytic anemia observed in acute ASF (genotype II). PMID- 28096615 TI - Molecular characterization of field infectious bursal disease virus isolates from Nigeria. AB - AIM: To characterize field isolates of infectious bursal disease virus (IBDV) from outbreaks in nine states in Nigeria through reverse transcription polymerase chain reaction (RT-PCR) and sequence analysis of portions of the VP2 and VP1 genes and to determine the presence or absence of reassortant viruses. MATERIALS AND METHODS: A total of 377 bursa samples were collected from 201 suspected IBD outbreaks during 2009 to 2014 from nine states in Nigeria. Samples were subjected to RT-PCR using VP2 and VP1 gene specific primers, and the resulting PCR products were sequenced. RESULTS: A total of 143 samples were positive for IBDV by RT-PCR. These assays amplified a 743 bp fragment from nt 701 to 1444 in the IBDV VP2 hypervariable region (hvVP2) of segment A and a 722 bp fragment from nt 168 to 889 in the VP1 gene of segment B. RT-PCR products were sequenced, aligned and compared with reference IBDV sequences obtained from GenBank. All but one hvVP2 sequence showed similarity to very virulent IBDV (vvIBDV) reference strains, yet only 3 of the VP1 67 VP1 sequences showed similarity to the VP1 gene of vvIBDV. Phylogenetic analysis revealed a new lineage of Nigerian reassortant IBDV strains. CONCLUSION: Phylogenetic analysis of partial sequences of genome segment A and B of IBDV in Nigeria confirmed the existence of vvIBDV in Nigeria. In addition, we noted the existence of reassortant IBDV strains with novel triplet amino acid motifs at positions 145, 146 and 147 in the reassorted Nigerian IBDV. PMID- 28096616 TI - Intravenous administration of puppy deciduous teeth stem cells in degenerative valve disease. AB - AIM: The objective of this study is to investigate the improvement of heart function in dogs with chronic valvular heart disease after puppy deciduous teeth stem cells (pDSCs) administration. MATERIALS AND METHODS: 20 client-owned dogs with degenerative valvular heart disease underwent multiple intravenous injections of allogeneic pDSCs. Dogs were randomly assigned to two groups: (i) Control group (n=10) with standard treatment for heart failure and (ii) group with standard treatment and multiple administrations of pDSCs (n=10). Electrocardiography, complete transthoracic echocardiography, thoracic radiography, and blood pressure were recorded before and after pDSCs injections for 15, 30 and 60 days. RESULTS: Post pDSCs injection showed measurable improvement in left ventricular ejection fraction, American College of Veterinary Internal Medicine (ACVIM) functional class significantly improved and improved quality of life scores were observed. In the control group, there were no significant enhancements in heart function or ACVIM class. CONCLUSIONS: This finding suggests that pDSCs could be a supplement for valvular heart disease treatment. PMID- 28096618 TI - Evaluation of sperm recovered after slaughter from cauda epididymides of red Sokoto bucks. AB - AIM: Viable spermatozoa could be recovered from the cauda epididymides for the purpose of preservation of genetic material of male animals with desirable traits and for use in reproductive biotechnology. The aim of this study was to determine the effect of storage time on testicular and epididymal biometry, sperm reserves and epididymal sperm characteristics of red Sokoto bucks post mortem. MATERIALS AND METHODS: Testes-epididymides were collected immediately after slaughter of mature red Sokoto bucks and transported in ice chest to the laboratory. The samples were either processed immediately or stored at 5 degrees C in refrigerator for 24, 48 h and then processed. The testes and epididymides were measured and weighed. Sperm motility, concentration, livability, morphology, intact acrosome, and sperm reserves from different treatment groups including control were evaluated and means (+/-standard error of mean) were recorded. RESULTS: There was no significant difference (p>0.05) in the testicular and epididymal dimensions determined between the means of the groups. Percent sperm motility and viability decreased significantly (p<0.05) after 24 h from 69.00+/ 0.46 and 71.27+/-0.50% to 50.60+/-0.48 and 60.47+/-0.70% at 48 h, respectively. Significant decreases (p<0.05) in epididymal sperm concentration and intact acrosome from 2.86+/-0.08 and 92.87+/-0.39 at 0 to 24 h of storage, respectively, were observed. CONCLUSION: The results of this study suggest that spermatozoa recovered from the epididymides of red Sokoto bucks were viable after storage for up to 48 h. Furthermore, this finding offers some hope that epididymal sperm recovered post-mortem can be used in assisted reproductive technologies. PMID- 28096617 TI - Phenotypic and genotypic characterization of locally isolated Salmonella strains used in preparation of Salmonella antigens in Egypt. AB - AIM: This work was conducted to study the phenotypic and genotypic characterization of locally isolated Salmonella strains (Salmonella Pullorum, Salmonella Enteritidis, and Salmonella Typhimurium) from poultry used in the preparation of Salmonella antigens in Egypt. MATERIALS AND METHODS: The phenotypic characterization of Salmonella strains was done using standard microbiological, biochemical, and serological techniques. Molecular identification was done using different sets of primers on different genes using different polymerase chain reaction (PCR) techniques. RESULTS: The phenotypic characterization of Salmonella strains was confirmed. Molecular identification revealed detection of 284 bp fragment of InvA gene in all studied Salmonella strains. Furthermore, multiplex PCR was used for more confirmation of being Salmonella spp., generally at 429 bp as well as genotyping of Salmonella Typhimurium and Salmonella Enteritidis at 559 and 312 bp, respectively, in one reaction. CONCLUSION: The locally isolated field Salmonella strains were confirmed phenotypically and genotypically to be Salmonella Enteritidis, and Salmonella Typhimurium and could be used for the preparation of Salmonella antigens. PMID- 28096619 TI - Detection, identification, and differentiation of sheep pox virus and goat pox virus from clinical cases in Giza Governorate, Egypt. AB - AIM: To isolate, identify, and differentiate Capripoxviruses (CaPV) (sheep pox virus and goat pox virus) infections by egg inoculation, transmission electron microscopy (TEM), and 30 kDa RNA polymerase subunit gene-based polymerase chain reaction (PCR) (RPO30) in clinically affected animals in Hawamdia township of Giza Governorate, Egypt. MATERIALS AND METHODS: A total of 37 scab samples were collected from clinically suspected field cases of sheep pox and goat pox. These samples were collected during (2014-2015) during different outbreaks of sheep pox and goat pox from Hawamdia township of Giza Governorate, Egypt. The samples were subjected to egg inoculation, TEM, and (RPO30) gene-based PCR. By using the egg inoculation: Previously prepared 37 scab samples (n=23 sheep and n=14 goats) were inoculated on the chorioallantoic membrane of specific pathogen free (SPF) embryonated chicken eggs (12 days old age). In the presence of the suitable percentage of humidity and candling, the inoculated eggs were incubated at 37 degrees C. By using the TEM: Samples showed positive pock lesions on the chorioallantoic membranes, were fixed in glutaraldehyde, then processed and sectioned for TEM. Using the (RPO30) gene-based PCR assay, 30 of positive samples after egg inoculation (n=19 sheep and n=11 goats) were screened. RESULTS: Using the egg inoculation, a characteristic pock lesions for poxviruses were seen in 30/37 (n=19 sheep and n=11 goats) (81.08%). Using the TEM, examination of the positive samples after egg inoculation revealed positive result in 23/30 (n=15 sheep and n=8 goats) (76.66%). The positive results represented by the presence of negatively stained oval-shape virus particles. Using the (RPO30) gene-based PCR assay, out of 30 total of positive samples after egg inoculation (n=19 sheep and n=11 goats) were screened, 27 (90%) samples (n=17 sheep and n=10 goats) were positive. The given band sizes of sheep and goats were 172 and 152 bp, respectively. CONCLUSION: PCR assay depended on RPO30 gene can be used lonely for the detection, identification, and differentiation of CaPVs. RPO30 gene-based PCR assay in combination with gene sequencing helps in molecular epidemiological studies of CaPV infection. PMID- 28096620 TI - Epidural analgesia in cattle, buffalo, and camels. AB - Epidural analgesia is commonly used in large animals. It is an easy, cheap, and effective technique used to prevent or control pain during surgeries involving the tail, anus, vulva, perineum, caudal udder, scrotum, and upper hind limbs. The objectives of this article were to comprehensively review and summarize all scientific data available in the literature on new techniques and drugs or drug combinations used for epidural anesthesia in cattle, camel, and buffalo. Only articles published between 2006 and 2016 were included in the review. The most common sites for epidural administration in cattle, camels, and buffalos were the sacrococcygeal intervertebral space (S5-Co1) and first intercoccygeal intervertebral space (Co1-Co2). The most frequently used drugs and dosages were lidocaine (0.22-0.5 mg/kg), bupivacaine (0.125 mg/kg), ropivacaine (0.11 mg/kg), xylazine (0.05 mg/kg), medetomidine (15 ug/kg), romifidine (30-50 ug/kg), ketamine (0.3-2.5 mg/kg), tramadol (1 mg/kg), and neostigmine (10 ug/kg), and the clinical applications, clinical effects, recommendations, and side effects were discussed. PMID- 28096621 TI - Multiple infections of Anaplasma platys variants in Philippine dogs. AB - AIM: Anaplasma platys, the causative agent of infectious canine cyclic thrombocytopenia, is a tick-borne pathogen that also has been implicated as potentially zoonotic. To provide molecular evidence on the multiple infections of A. platys variants in Philippine dogs. MATERIALS AND METHODS: DNA fragments of A. platys from infected dogs in the Philippines were molecularly characterized. For screening, 25 dogs suspected to have canine anaplasmosis were tested using a 16S rRNA-based nested polymerase chain reaction (PCR). Infection was confirmed by sequencing of positive amplicons. Second round PCR targeting a longer 16S rRNA fragment was subsequently performed on the first round PCR amplicons of the positive samples. Further characterization using the heat-shock operon (groEL) gene was also performed on the A. platys-positive samples. RESULTS: 10 16S rRNA sequences were obtained and found 99.6-100% identical to each other and 99.6 99.7% identical to the closest registered A. platys sequences. On the other hand, 36 groEL clone sequences were obtained and found to be 85.1-99.8% identical with each other and 85.0-88.9% identical to the closest previously registered A. platys sequences. Four dogs were found coinfected with 2-3 groEL variant sequences. Phylogenetic analyses suggest that the detected A. platys in the Philippines may represent unique variants. CONCLUSION: A. platys variants were detected in Philippine dogs. Coinfection of different A. platys variants in dogs was also demonstrated. The present study may indicate the potential genetic diversity of A. platys in the country. PMID- 28096622 TI - Survey on Sarcocystis in bovine carcasses slaughtered at the municipal abattoir of El-Kharga, Egypt. AB - AIM: The main objectives of this study were to determine the incidence of Sarcocystis sp. infection in cattle and buffalo carcasses slaughtered at El Kharga abattoir, New Valley Governorate, Egypt. MATERIALS AND METHODS: The slaughtered animals were daily inspected for Sarcocystis macrocysts through a year (2015). Macroscopic Sarcocystis was detected from a total of 2120 cattle and buffalo carcasses. In addition, 100 meat samples were collected from female cattle and buffalo (50 each) and were examined microscopically for sarcocystosis. RESULTS: The overall incidence of Sarcocystis macrocyst among bovine carcasses was 159/2120 (7.5%). Total incidence in cattle was 149/2000 (7.45%), whereas it was 10/120 (8.33%) in buffalo carcasses. Concerning gender, the overall prevalence of Sarcocystis infection was 127/1790 (7.09%) in male and 32/330 (9.69%) in females bovine carcasses. The highest detection rate of Sarcocystis lesions was from the esophagus (76.3%) followed by throat muscles (35.3%), tongue (33.8%), and diaphragm muscles (18.71%). Macrocysts from cattle were identified to Sarcocystis hirsuta, whereas Sarcocystis fusiformis was identified from buffalo carcasses. By microscopic examination, 18 (36%) of 50 female cattle carcasses harbor Sarcocystis sp., whereas 11 (22%) of buffalo carcasses were harbored Sarcocystis microcysts. CONCLUSION: A high incidence of Sarcocystis infection was detected among slaughtered bovines in El-Kharga abattoir, Egypt. Sarcocystis macrocysts were a higher incidence in female elder animals macrocysts were identified to S. hirsuta in cattle and S. fusiformis in buffaloes. Sarcocystosis constitute a major cause of economic losses at El-Kharga abattoir. Beef meat may carry health risks to consumers. PMID- 28096623 TI - Estrus induction and fertility response following different treatment protocols in Murrah buffaloes under field conditions. AB - AIM: The aim of this study was to evaluate the efficacy of three different treatment protocols for estrus induction and conception rate in postpartum anestrus buffaloes during breeding season under field conditions. MATERIALS AND METHODS: The 47 postpartum anestrus buffaloes of the 2nd to 6th parity were divided into three groups. Group 1 (n=16): Buffaloes received cosynch treatment, that is, buserelin acetate 10 ug on day 0 and 9, cloprostenol 500 ug on day 7 followed by fixed-time artificial insemination (FTAI) at the time of second buserelin acetate and 24 h later. Group 2 (n=15): Buffaloes received norgestomet ear implant subcutaneously for 9 days, estradiol benzoate 2 mg on the day of implant insertion (day 0), pregnant mare serum gonadotropin (PMSG) 400 IU and cloprostenol 500 ug on day 9 followed by AI at 48 and 72 h after implant removal. Group 3 (Cosynch-plus, n=16): Buffaloes received Cosynch protocol as per Group 1 except an additional injection of PMSG 400 IU (i.m.) was given 3 days before the start of protocol and FTAI done at the same time of Group 1. Pregnancy diagnosis was performed after 45 days of AI. RESULTS: The estrus induction response following the treatment was 81.3%, 100%, and 93.7% in Group 1, 2, and 3, respectively. The buffaloes of Group 1, 2, and 3 expressed intense (38.4%, 60% and 46.6%, respectively) and moderate estrus (46.1%, 26.6%, and 40%, respectively). The conception rates in Group 1, 2, and 3, at FTAI and overall including subsequent estrus were 37.5% and 62.5%, 53.3%, and 66.6%, 56.3%, and 75%, respectively. CONCLUSION: All the three treatment protocols can be effectively used for induction of estrus with acceptable conception rate in postpartum anestrus buffaloes during breeding season under field conditions. However, Cosynch-plus (similar to Cosynch protocol except addition of PMSG, 400 IU 3 days before the start of first buserelin acetate administration) protocol results comparatively better pregnancy rate. PMID- 28096624 TI - Genetic variability and discrimination of low doses of Toxocara spp. from public areas soil inferred by loop-mediated isothermal amplification assay as a field friendly molecular tool. AB - ABSTRACT: Aim: One of the main diagnostic problems of conventional polymerase chain reaction (PCR) is indiscrimination of low parasitic loads in soil samples. The aim of this study is to determine the genetic diversity and identification of Toxocara spp. from public areas soil inferred by loop-mediated isothermal amplification (LAMP) assay. MATERIALS AND METHODS: A total of 180 soil samples were collected from various streets and public parks of northwest Iran. The DNA of recovered Toxocara eggs were extracted and amplified by PCR and LAMP following ZnSO4 flotation technique. The amplicons of internal transcribed spacer-2 gene were sequenced to reveal the heterogeneity traits of Toxocara spp. In addition, Toxocara canis sequences of southwest Iran were directly retrieved to compare gene flow between two distinct populations. RESULTS: Toxocara spp. eggs were found in 57, 14 and 77 of soil samples using the microscopy, PCR and LAMP (detection limit 1-3 eggs/200 g soil), respectively. 7.7% of isolates were identified as T. canis by PCR method, while LAMP was able to detect 27.2%, 15.5% and 12.2% as Toxocara cati, T. canis and mixed infections, respectively. The kappa coefficient between LAMP and microscopy indicated a strong agreement (0.765) but indicated a faint agreement among LAMP-PCR (0.203) and PCR-microscopy (0.308) methods. A pairwise fixation index (Fst) as a degree of gene flow was generally low (0.02156) among Toxocara populations of northwest and southwest Iran. CONCLUSIONS: The statistically significant Fst value indicates that the T. canis populations are not genetically well differentiated between northwest and southwest Iran. This shows that here is possibly an epidemiological drift due to the transfer of alleles. The LAMP assay because of its shorter reaction time, more sensitivity, and simultaneous detection of environmental contamination to be appears as valuable field diagnosis compared to PCR. Therefore, the detection of low Toxocara spp. loads from public area soils will help to expand epidemiological understanding of toxocariasis and establishing preventive strategies in resource-limited endemic of Iran. PMID- 28096625 TI - The effect of dietary supplementation of salts of organic acid on production performance of laying hens. AB - AIM: An experiment was conducted to evaluate the effect of supplementing different levels of salts of organic acid in the laying hen's diet on their production performance and egg quality parameters during a period of 16-week. MATERIALS AND METHODS: A total of 140 white leghorn laying hens at 24 weeks of age were randomly distributed to seven dietary treatment groups, i.e. T1 (control), T2 (0.5% sodium-butyrate), T3 (1.0% sodium-butyrate), T4 (1.5% sodium butyrate), T5 (0.5% calcium-propionate), T6 (1.0% calcium-propionate) and T7 (1.5% calcium-propionate) consisting of 5 replications of 4 birds each in each treatment and housed in individual cages from 24 to 40 weeks of age. Feed intake, percent hen-day egg production, egg weight, egg mass production, feed conversion ratio (FCR), and economics of supplementation of salts of organic acids in layers' ration were evaluated. RESULTS: The dietary supplementation of salts of organic acids did not significantly affect the feed intake (g/day/hen) and body weight gain (g). Different levels of supplementation significantly (p<0.05) improved production performance (percent hen-day egg production and egg mass production) as compared to control group. FCR in terms of feed intake (kg) per dozen eggs was lowest (1.83+/-0.05) in T4 and feed intake (kg) per kg egg mass was lowest (2.87+/-0.05) in T5 as comparison to control (T1) group. Salts of organic acids supplementation resulted in significant (p<0.05) improvement in FCR. Egg weight was significantly (p<0.05) increased at 0.5% level of salts of organic acids in the diet. The cumulative mean values of feed cost per dozen egg production were Rs. 44.14, 42.40, 42.85, 43.26, 42.57, 43.29 and 43.56 in treatment groups T1, T2, T3, T4, T5, T6 and T7, respectively, and reduction in feed cost per kg egg mass production for Rs. 0.52 and 0.99 in groups T2 and T5, respectively, in comparison to T1 group. CONCLUSIONS: It can be concluded that supplementation of salts of organic acids may improve persistency of lay, egg weight, and FCR. From economical point of view, egg production was more profitable at 0.5% level of sodium butyrate and 0.5% level of calcium propionate which reduced the feed cost per dozen eggs and per kg egg mass production without affecting the egg quality. PMID- 28096626 TI - Effect of intrapartum fetal stress associated with obstetrical interventions on viability and survivability of canine neonates. AB - AIM: This study was conducted with the objective of identifying and evaluating intrapartum fetal stress in connection with the type of delivery in bitches. MATERIALS AND METHODS: A total of 26 bitches between 1 and 5 years, belonging to 10 different breeds were evaluated. Bitches were subjected to detailed clinico gynecological examination based on history. Neonatal stress associated with spontaneous whelping (SW), assisted whelping (AW), and emergency cesarean section (EC) was evaluated using umbilical vein lactate (UL) estimation by collecting the blood from umbilical vein. RESULTS: A high umbilical vein lactate value was associated with fetal distress. The mean umbilical lactate value was highest in EC (12.54+/-0.8 mmol/L) followed by AW (8.86+/-0.9 mmol/L) and the lowest value was found in SW (7.56+/-0.58 mmol/L). A significant increase (p<0.05) in umbilical lactate level was observed in EC group of canine neonates compared with AW and SW groups. Overall mean umbilical lactate values of neonates which died within 24 h (13.31+/-1.08 mmol/L) and the neonates which survived beyond 24 h (8.87+/-0.55 mmol/L) differed significantly at 5% level. CONCLUSION: Immediate identification of neonatal distress by use of umbilical vein lactate estimation is helpful for the clinician to undertake resuscitation or medical therapy to ensure better neonatal survivability. PMID- 28096627 TI - Altered oxidative stress and carbohydrate metabolism in canine mammary tumors. AB - AIM: Mammary tumors are the most prevalent type of neoplasms in canines. Even though cancer induced metabolic alterations are well established, the clinical data describing the metabolic profiles of animal tumors is not available. Hence, our present investigation was carried out with the aim of studying changes in carbohydrate metabolism along with the level of oxidative stress in canine mammary tumors. MATERIALS AND METHODS: Fresh mammary tumor tissues along with the adjacent healthy tissues were collected from the college surgical ward. The levels of thiobarbituric acid reactive substances (TBARS), glutathione, protein, hexose, hexokinase, glucose-6-phosphatase, fructose-1, 6-bisphosphatase, and glucose-6-phosphate dehydrogenase (G6PD) were analyzed in all the tissues. The results were analyzed statistically. RESULTS: More than two-fold increase in TBARS and three-fold increase in glutathione levels were observed in neoplastic tissues. Hexokinase activity and hexose concentration (175%) was found to be increased, whereas glucose-6-phosphatase (33%), fructose-1, 6-bisphosphatase (42%), and G6PD (5 fold) activities were reduced in tumor mass compared to control. CONCLUSION: Finally, it was revealed that lipid peroxidation was increased with differentially altered carbohydrate metabolism in canine mammary tumors. PMID- 28096628 TI - Eco matters; In & Out. PMID- 28096629 TI - Induced pluripotent stem cells as a cellular model for studying Down Syndrome. AB - Down Syndrome (DS), or Trisomy 21 Syndrome, is one of the most common genetic diseases. It is a chromosomal abnormality caused by a duplication of chromosome 21. DS patients show the presence of a third copy (or a partial third copy) of chromosome 21 (trisomy), as result of meiotic errors. These patients suffer of many health problems, such as intellectual disability, congenital heart disease, duodenal stenosis, Alzheimer's disease, leukemia, immune system deficiencies, muscle hypotonia and motor disorders. About one in 1000 babies born each year are affected by DS. Alterations in the dosage of genes located on chromosome 21 (also called HSA21) are responsible for the DS phenotype. However, the molecular pathogenic mechanisms of DS triggering are still not understood; newest evidences suggest the involvement of epigenetic mechanisms. For obvious ethical reasons, studies performed on DS patients, as well as on human trisomic tissues are limited. Some authors have proposed mouse models of this syndrome. However, not all the features of the syndrome are represented. Stem cells are considered the future of molecular and regenerative medicine. Several types of stem cells could provide a valid approach to offer a potential treatment for some untreatable human diseases. Stem cells also represent a valid system to develop new cell based drugs and/or a model to study molecular disease pathways. Among stem cell types, patient-derived induced pluripotent stem (iPS) cells offer some advantages for cell and tissue replacement, engineering and studying: self-renewal capacity, pluripotency and ease of accessibility to donor tissues. These cells can be reprogrammed into completely different cellular types. They are derived from adult somatic cells via reprogramming with ectopic expression of four transcription factors (Oct3/4, Sox2, c-Myc and Klf4; or, Oct3/4, Sox2, Nanog, and Lin28). By reprogramming cells from DS patients, it is possible to obtain new tissue with the same genetic background, offering a valuable tool for studying this genetic disease and to design customized patient-specific stem cell therapies. PMID- 28096630 TI - New Trends in Heart Regeneration: A Review. AB - In this review, we focus on new approaches that could lead to the regeneration of heart muscle and the restoration of cardiac muscle function derived from newly formed cardiomyocytes. Various strategies for the production of cardiomyocytes from embryonic stem cells, induced pluripotent stem cells, adult bone marrow stem cells and cardiac spheres from human heart biopsies are described. Pathological conditions which lead to atherosclerosis and coronary artery disease often are followed by myocardial infarction causing myocardial cell death. After cell death, there is very little self-regeneration of the cardiac muscle tissue, which is replaced by non-contractile connective tissue, thus weakening the ability of the heart muscle to contract fully and leading to heart failure. A number of experimental research approaches to stimulate heart muscle regeneration with the hope of regaining normal or near normal heart function in the damaged heart muscle have been attempted. Some of these very interesting studies have used a variety of stem cell types in combination with potential cardiogenic differentiation factors in an attempt to promote differentiation of new cardiac muscle for possible future use in the clinical treatment of patients who have suffered heart muscle damage from acute myocardial infarctions or related cardiovascular diseases. Although progress has been made in recent years relative to promoting the differentiation of cardiac muscle tissue from non-muscle cells, much work remains to be done for this technology to be used routinely in translational clinical medicine to treat patients with damaged heart muscle tissue and return such individuals to pre-heart-attack activity levels. PMID- 28096631 TI - Randomized controlled trial comparing hyaluronic acid, platelet-rich plasma and the combination of both in the treatment of mild and moderate osteoarthritis of the knee. AB - Objective: This study aims at evaluating the clinical effects of Platelet Rich Plasma (PRP) and Hyaluronic Acid (HA) as individual treatments for mild to moderate Osteoarthritis (OA) and it also examines the potential synergistic effects of PRP in combination with HA. Research continues to emerge examining the potential therapeutic efficacy of HA and PRP as autologous injectable treatments for joint arthritis. However, there is a paucity of research investigating the effects of combining HA and PRP on pain and functional status in patients with OA. Design: In this multi-center, randomized, controlled, double blind, prospective trial, 105 patients with mild to moderate knee osteoarthritis, who met the study criteria, were randomly allocated to one of three interventions: HA (n=36), PRP (n=36), or HA+PRP (n=33). Each patient received 3 intra-articular knee injections of their assigned substance, with 2 week intervals between each injection. Clinical outcomes were evaluated using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and Visual Analogue Scale (VAS) questionnaire at baseline and after 1,3,6 and 12 months. Results: The study showed that the PRP group have significant reduction in VAS scores at 1 (p= 0.003), 3 (p= 0.0001), 6 (p= 0.0001) and 12 (p= 0.000) months when compared to HA. In addition, the PRP group illustrated greater improvement in WOMAC physical activity scale at 12 months (p= 0.008) when compared to the HA group. Combining HA and PRP resulted in a significant decreases in pain (p=0.0001) and functional limitation (p=0.0001) when compared to HA alone at 1 year post treatment; and significantly increased physical function at 1 (p=0.0004) and 3 (p=.011) months when compared to PRP alone. Conclusion: The findings of the study support the use of autologous PRP as an effective treatment of mild to moderate knee osteoarthritis. It also shows that the combination of HA and PRP resulted to better outcomes than HA alone up to 1 year and PRP alone up to 3 months. Furthermore, the results suggest that combination of PRP and HA could potentially provide better functional outcomes in the first 30 days after treatment with both PRP and HA alone. PMID- 28096632 TI - Compatibility of Porous Chitosan Scaffold with the Attachment and Proliferation of human Adipose-Derived Stem Cells In Vitro. AB - Adipose-derived stem cells (ASCs) have potential applications in the repair and regeneration of various tissues and organs. The use of various scaffold materials as an excellent template for mimicking the extracellular matrix to induce the attachment and proliferation of different cell types has always been of interest in the field of tissue engineering because ideal biomaterials are in great demand. Chitosan, a marine polysaccharide, have wide clinical applications and it acts as a promising scaffold for cell migration and proliferation. ASCs, with their multi-differentiation potential, and chitosan, with its great biocompatibility with ASCs, were investigated in the present study. ASCs were isolated and were characterized by two different methods: immunocytochemistry and flow cytometry, using the mesenchymal stem cell markers CD90, CD105, CD73 and CD29. The ASCs were then induced to differentiate into adipogenic, osteogenic and chondrogenic lineages. These ASCs were incorporated into a porous chitosan scaffold (PCS), and their structural morphology was studied using a scanning electron microscope and hematoxylin and eosin staining. The proliferation rate of the ASCs on the PCS was assessed using a PrestoBlue viability assay. The results indicated that the PCS provides an excellent template for the adhesion and proliferation of ASCs. Thus, this study revealed that PCS is a promising biomaterial for inducing the proliferation of ASCs, which could lead to successful tissue reconstruction in the field of tissue engineering. PMID- 28096633 TI - Mesenchymal stem cells-seeded bio-ceramic construct for bone regeneration in large critical-size bone defect in rabbit. AB - Bone marrow derived mesenchymal stem cells (BMSC) represent an attractive cell population for tissue engineering purpose. The objective of this study was to determine whether the addition of recombinant human bone morphogenetic protein (rhBMP-2) and insulin-like growth factor (IGF-1) to a silica-coated calcium hydroxyapatite (HASi) - rabbit bone marrow derived mesenchymal stem cell (rBMSC) construct promoted bone healing in a large segmental bone defect beyond standard critical -size radial defects (15mm) in rabbits. An extensively large 30mm long radial ostectomy was performed unilaterally in thirty rabbits divided equally in five groups. Defects were filled with a HASi scaffold only (group B); HASi scaffold seeded with rBMSC (group C); HASi scaffold seeded with rBMSC along with rhBMP-2 and IGF-1 in groups D and E respectively. The same number of rBMSC (five million cells) and concentration of growth factors rhBMP-2 (50ug) and IGF-1 (50ug) was again injected at the site of bone defect after 15 days of surgery in their respective groups. An empty defect served as the control group (group A). Radiographically, bone healing was evaluated at 7, 15, 30, 45, 60 and 90 days post implantation. Histological qualitative analysis with microCT (u-CT), haematoxylin and eosin (H & E) and Masson's trichrome staining were performed 90 days after implantation. All rhBMP-2-added constructs induced the formation of well-differentiated mineralized woven bone surrounding the HASi scaffolds and bridging bone/implant interfaces as early as eight weeks after surgery. Bone regeneration appeared to develop earlier with the rhBMP-2 constructs than with the IGF-1 added construct. Constructs without any rhBMP-2 or IGF-1 showed osteoconductive properties limited to the bone junctions without bone ingrowths within the implantation site. In conclusion, the addition of rhBMP-2 to a HASi scaffold could promote bone generation in a large critical-size-defect. PMID- 28096634 TI - Intraventricular Transplantation of Autologous Bone Marrow Mesenchymal Stem Cells via Ommaya Reservoir in Persistent Vegetative State Patients after Haemorrhagic Stroke: Report of Two Cases & Review of the Literature. AB - Background: One of the most devastating diseases, stroke, is a leading cause of death and disability worldwide with severe emotional and economic consequences. The purpose of this article is mainly to report the effect of intraventricular transplantation via an Ommaya reservoir using autologous bone marrow mesenchymal stem cells (BM-MSCs) in haemorrhagic stroke patients. Case Presentations: Two patients, aged 51 and 52, bearing sequels of haemorrhagic stroke were managed by intraventricular transplantation of BM-MSCs obtained from their own bone marrow. Before the procedure, both patients were bedridden, tracheostomised, on nasogastric (NG) tube feeding and in hemiparesis. The cells were transplanted intraventricularly (20 x 106 cells/2.5 ml) using an Ommaya reservoir, and then repeated transplantations were done after 1 and 2 months consecutively. The safety and efficacy of the procedures were evaluated 3, 6 and 12 months after treatment. The National Institute of Health Stroke Scale (NIHSS) was used to evaluate the patients' neurological status before and after treatment. No adverse events derived from the procedures or transplants were observed in the one-year follow-up period, and the neurological status of both patients improved after treatment. Conclusions: Our report demonstrates that the intraventricular transplantation of BM-MSCs via an Ommaya reservoir is safe and it improves the neurological status of post-haemorrhagic stroke patients. The repeated transplantation procedure is easier and safer to perform via a subcutaneously implanted Ommaya reservoir. Key Words: Haemorrhagic stroke, bone marrow mesenchymal stem cells (BM-MSCs), intraventricular transplantation. PMID- 28096635 TI - Metaniche session 2016: Tailor-made sensors for rapid Therapeutic Drug Monitoring Interactions between Biomaterial Physicists, Chemical Engineers and Clinicians for successful translation of technologies in Healthcare. PMID- 28096636 TI - Opportunistic salpingectomy: Remove the tubes and save the ovaries. PMID- 28096637 TI - Prevalence of female sexual dysfunction among Indian fertile females. AB - BACKGROUND: Female sexual dysfunction (FSD) is described as difficulty experienced by a female during any stage of a normal sexual activity including physical pleasure, desire, arousal, or orgasm. There are various factors responsible for FSD including psychological status of a person, gynecological or medical problems, long use of certain drugs, and social beliefs. OBJECTIVES: To study the prevalence and various factors associated with FSD. MATERIALS AND METHODS: Study Design - This study design was a cross-sectional observational study conducted at Tertiary Care Centre, in Ahmedabad from June 2015 to March 2016. Sample Size - One hundred and fifty-three fertile females in reproductive age group (20-47 years) were included in the study. Written and informed consent was obtained from all the females. Methods - FSD was assessed with a detailed 19 item female sexual function index questionnaire. All six domains of sexual dysfunction, i.e., desire, arousal, lubrication, orgasm, satisfaction, and pain were studied. Various associated factors such as gynecological or psychological problems were also studied. Exclusion - Infertile patients were excluded from the study. RESULTS: The prevalence of FSD was 55.55% among 153 fertile females. FSD was more prevalent in the age group of 26-30 years and with duration of marriage >16 years. FSD was also more common in females with middle education and those belonging to upper middle socioeconomic status. Psychological stress was significantly associated with FSD. CONCLUSION: It is right of every female to lead healthy sexual life as it is key to happiness in marriage. Females with FSD can be managed with proper counseling and treating the underlying etiology. PMID- 28096638 TI - Coexisting genital malignancies with tuberculosis: A case series with review of literature. AB - OBJECTIVE: To study a case series of genital malignancies coexisting with genital tuberculosis. MATERIALS AND METHODS: A series of three cases with known genital malignancies were found to have coexisting genital tuberculosis on subsequent workup. RESULTS: First case was a 45 years old lady who underwent staging laparotomy for ovarian cancer. On histopathology examination, there was coexisting tuberculosis with papillary serous carcinoma. Second case was 53 years old postmenopausal lady who underwent extrafascial hysterectomy along with pelvic lymph node dissection. Histopathology showed tubercular changes along with endometrial malignancy. Third patient was a 50 years old postmenopausal lady with stage IIA carcinoma of cervix. She underwent radical hysterectomy and histopathology revealed tubercular changes in pelvic lymph nodes. All patients were given antitubercular therapy for 9 months in postoperative period along with adjuvant therapy. CONCLUSION: Although diagnosed as an incidental finding in the case series, genital tuberculosis may present in patients with malignancies as a result of immunosupression. PMID- 28096639 TI - Association between serum 25-hydroxyvitamin D levels and bone mineral density in normal postmenopausal women. AB - AIM: This study was conducted with the objective of assessing serum 25 hydroxyvitamin D (25(OH)D) in postmenopausal women (PMW), to detect osteopenia or osteoporosis in PMW and to establish a correlation between serum 25(OH)D levels and bone mineral density (BMD). MATERIALS AND METHODS: A total of 100 healthy PMW were selected, and a prospective observational study was conducted to correlate the BMD with serum 25(OH)D levels. Their laboratory investigations along with serum 25(OH)D levels were done. Their BMD was assessed with dual-energy X-ray absorptiometry at lumbar spine and neck of femur; T-scores were derived. Correlation analysis was done to investigate the relationship between serum 25(OH)D levels and BMD. RESULTS: The proportion of osteoporosis at the hip was 31.9% in deficient group, 16.1% in insufficient, and 18.2% in sufficient group and at lumbar spine, it was 27.7%, 16.1%, and 22.7%, respectively. Forty-seven percent of PMW had deficient (<20 ng/ml) serum 25(OH)D levels and 31% had insufficiency. T-score at hip in deficient group was -2.05 +/- 0.25, and in an insufficient group, it was -1.79 +/- 0.13; T-score at lumbar spine was -1.92 +/- 0.12 and -1.79 +/- 0.12, respectively, but both were not statistically significant. Osteoporosis was seen in 24%, osteopenia in 55% at hip level and 23% and 59% respectively at lumbar spine. There was no association between serum 25(OH)D levels and BMD neither at hip nor at lumbar spine (P = 0.51 and P = 0.79 respectively). CONCLUSION: In this study, among our cohort of patients there was no correlation between serum 25(OH)D levels and BMD. However, Vitamin D deficiency coexists with low BMD. Vitamin D insufficiency is a common risk factor for osteoporosis associated with increased bone remodeling and low bone mass. PMID- 28096640 TI - Prevalence of metabolic syndrome in pre- and post-menopausal women: A prospective study from apex institute of North India. AB - BACKGROUND: The metabolic syndrome (MS) (syndrome X, insulin resistance syndrome) is a constellation of metabolic abnormalities and a complex predisease state that predicts future development of type 2 diabetes mellitus and cardiovascular disease. Menopausal transition and postmenopausal state are considered as a vulnerable period for developing MS, and this increased risk has been attributed to decreasing estrogen levels with an increasing risk of insulin resistance following menopause. AIMS AND OBJECTIVES: This study aimed to determine the prevalence of MS and its components in pre- and post-menopausal women from North India. METHODOLOGY: This is a cross-sectional study of 350 women in the age group of 45-55 years attending gynecology clinic in a tertiary center of North India. Details of sociodemographic data, menopausal history, reproductive, and medical profile were obtained. Then, waist circumference, body mass index (BMI), and blood pressure were recorded. A venous blood sample was collected for fasting blood glucose, triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. MS was defined according to the modified National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS: The mean age was 49.09 +/- 2.2 years in premenopausal and 49.54 +/- 2.8 years in postmenopausal women. The prevalence of MS in the study group was 62.6%. Occurrence of MS was higher in older and obese women. Abnormal waist circumference was the most prevalent component (87%) of MS and in terms of odd ratio, correlation was highest for BMI followed by total cholesterol and waist-hip ratio. CONCLUSION: We should target obesity and deranged lipid profile by bringing out changes in lifestyle and dietary habits to decrease the higher prevalence of MS and the risk of cardiovascular diseases. PMID- 28096641 TI - Assessment of periodontal health status in postmenopausal women visiting dental hospital from in and around Meerut city: Cross-sectional observational study. AB - BACKGROUND: Puberty, menses, pregnancy, and menopause are the different phases of a woman's life which have a varied influence on oral health. During the menopause, women go through biological and endocrine changes, particularly in their sex steroid hormone production which affects their health. Because the oral mucosa contains estrogen receptors, variations in hormone levels can be seen directly in the oral cavity leading to a few oral conditions and diseases seen more frequently during postmenopausal years. OBJECTIVE: The objective of this study is to assess periodontal health status in postmenopausal women in and around Meerut city. MATERIALS AND METHODS: The study sample comprised ninety postmenopausal women. History of menopause was recorded, and the dental examinations were done by measuring the following parameters of periodontal health: plaque index (PI), gingival index (GI), bleeding on probing (BOP), pocket probing depth, and Russell's periodontal index. The collected data were subjected to statistical analyses. RESULTS AND CONCLUSION: In the study group, mean age was 55 years, mean missing teeth were 10.3, mean duration of menopause was 9.23. Eleven percent females were completely edentulous, and 5 females had never brushed. Mean PI-s was 1.99, mean GI-s was 1.74, mean BOP was 52.85, and mean Russell's periodontal index was 4.34. Eleven patients were at the initial stages of destructive periodontal disease, 34 had established destructive periodontal disease while thirty patients had the terminal periodontal disease. These findings suggest that females after menopause are at a risk of developing destructive periodontal disease if proper oral hygiene practices are not followed. PMID- 28096642 TI - Awareness of osteoporosis in postmenopausal Indian women: An evaluation of Osteoporosis Health Belief Scale. AB - CONTEXT: The level of awareness about osteoporosis in postmenopausal women who are the common sufferers. AIMS: This study aims to evaluate the level of awareness in postmenopausal women using the Osteoporosis Health Belief Scale (OHBS). SETTINGS AND DESIGN: Osteoporosis has emerged as a common health problem in geriatric population. A proactive role needs to be played for preventing its consequences. Before initiating any preventive measures, an evaluation of awareness level of the target population is necessary. The questionnaire-based study design was used for this study. SUBJECTS AND METHODS: A questionnaire (OHBS)-based study in 100 postmenopausal women in Chandigarh was conducted. The bone mineral density (BMD) was measured in each case by dual energy X-ray absorptiometry. Height, weight, and body mass index (BMI) of the participants were noted. STATISTICAL ANALYSIS USED: Statistical analysis was conducted to evaluate any correlation between the various components of the OHBS and the BMD. RESULTS: No statistically significant difference was noted in the seven component parameters of OHBS among the normal, osteopenic, and osteoporotic women suggesting that the health belief regarding susceptibility is not much different between the three groups of the study population. A statistically significant difference between the mean BMI of normal and osteoporotic population was noted. CONCLUSIONS: The results show that there is a great deficit in the awareness level of postmenopausal Indian women regarding osteoporosis. Most of the women were unaware of the condition and the means to prevent it. The study emphasizes that health care professionals have lot of ground to cover to decrease the incidence of osteoporosis and its associated health problem. PMID- 28096643 TI - Intestinal obstruction associated with ovarian remnant in postmenopausal female. AB - Ovarian remnant syndrome (ORS) is a rare condition, in which the ovarian tissue is inadvertently left behind after difficult oophorectomy. The most common preexisting conditions associated for this complication include endometriosis, pelvic inflammatory disease, and prior abdominal surgery as in these conditions, removal of ovarian tissue becomes difficult. This is likely due to the presence of the dense fibrotic adhesions between an ovary and the surrounding structures. This residual ovarian tissue can become functional and cystic. A 56-year-old multigravida postmenopausal female was diagnosed with intestinal obstruction. She had multiple abdominal surgeries in the past, including cholecystectomy, appendectomy, hysterectomy, and bilateral salpingo-oophorectomy. Patient underwent exploratory laparotomy. Intraoperatively, extensive adhesions and scarring of bowel wall were present and approximately 15 cm proximal to the terminal ileum, a small bowel mesenteric nodule was present. Histopathology of the mesenteric nodule was consistent with the diagnosis of overian remnant. ORS can be prevented with careful resection of the entire ovarian tissue during the difficulty oophorectomy so that no ovarian tissue is left behind. PMID- 28096644 TI - Postmenopausal hyperandrogenism of ovarian origin: A clinicopathologic study of five cases. AB - In postmenopausal women presenting with virilization and elevated testosterone levels, laparoscopic salpingo-oophorectomy should be considered after exclusion of adrenal causes. A clinicopathological study was conducted among those women who presented with features of hyperandrogenism in our postmenopausal clinic over a period of 2 years. Relevant past medical and surgical histories were elicited. Basic hormonal evaluation and radiological imaging were done. Laparoscopic bilateral salpingo-oophorectomy was done. Six weeks postoperatively, serum testosterone was undetectable with significant clinical improvement. There was no recurrence of symptoms during the follow-up period of 2 years. Treatment of postmenopausal women with hyperandrogenism and virilization with laparoscopic bilateral salpingo-oophorectomy is effective if she has no pronounced ovarian enlargement or adrenal tumor on imaging. An extensive endocrine testing and a detailed search for metastatic disease may be unnecessary. PMID- 28096645 TI - Peri and post-menopausal women with complex adnexal masses, ascites, and raised CA-125: Is it ovarian cancer or tuberculosis? AB - Pelvic and peritoneal tuberculosis may resemble advanced ovarian cancer due to the presence of ascites, complex adnexal masses, peritoneal deposits and raised CA-125 level, especially in peri- and postmenopausal women. Other common features among women with these two conditions are abdominal pain and distension, weight loss and reduced appetite. As the treatment of pelvic-peritoneal tuberculosis is completely different from that of ovarian cancer, it is important to reach a correct diagnosis. Sometimes women with pelvic-peritoneal tuberculosis may be subjected to a laparotomy for suspected ovarian cancer which is likely to increase their morbidity. In the present article, we report ten women in the peri and post-menopausal age group where this diagnostic dilemma arose of whom seven were diagnosed only after a laparotomy had been performed for suspected ovarian cancer due to adnexal masses with ascites and raised CA-125 level. Ascitic fluid showing lymphocytic predominance, raised ADA level and absence of malignant cells are pointers to consider the possibility of pelvic- peritoneal tuberculosis, especially in endemic countries like India. In such situations, an effort should be made to obtain a cytological or histopathological diagnosis of either condition by ultrasound guided needle biopsy or laparoscopically obtained biopsy rather that proceeding with laparotomy for suspected ovarian cancer. PMID- 28096647 TI - Bayesian ABC-MCMC Classification of Liquid Chromatography-Mass Spectrometry Data. AB - Proteomics promises to revolutionize cancer treatment and prevention by facilitating the discovery of molecular biomarkers. Progress has been impeded, however, by the small-sample, high-dimensional nature of proteomic data. We propose the application of a Bayesian approach to address this issue in classification of proteomic profiles generated by liquid chromatography-mass spectrometry (LC-MS). Our approach relies on a previously proposed model of the LC-MS experiment, as well as on the theory of the optimal Bayesian classifier (OBC). Computation of the OBC requires the combination of a likelihood-free methodology called approximate Bayesian computation (ABC) as well as Markov chain Monte Carlo (MCMC) sampling. Numerical experiments using synthetic LC-MS data based on an actual human proteome indicate that the proposed ABC-MCMC classification rule outperforms classical methods such as support vector machines, linear discriminant analysis, and 3-nearest neighbor classification rules in the case when sample size is small or the number of selected proteins used to classify is large. PMID- 28096646 TI - Commensal Viruses of Mosquitoes: Host Restriction, Transmission, and Interaction with Arboviral Pathogens. AB - Recent advances in virus detection strategies and deep sequencing technologies have enabled the identification of a multitude of new viruses that persistently infect mosquitoes but do not infect vertebrates. These are usually referred to as insect-specific viruses (ISVs). These novel viruses have generated considerable interest in their modes of transmission, persistence in mosquito populations, the mechanisms that restrict their host range to mosquitoes, and their interactions with pathogens transmissible by the same mosquito. In this article, we discuss studies in our laboratory and others that demonstrate that many ISVs are efficiently transmitted directly from the female mosquito to their progeny via infected eggs, and, moreover, that persistent infection of mosquito cell cultures or whole mosquitoes with ISVs can restrict subsequent infection, replication, and transmission of some mosquito-borne viral pathogens. This suggests that some ISVs may act as natural regulators of arboviral transmission. We also discuss viral and host factors that may be responsible for their host restriction. PMID- 28096649 TI - CURRENT DEVELOPMENTS IN DRUG ELUTING DEVICES: Introductory Editorial: Drug Eluting Stents or Drug-Eluting Grafts? Insights from Proteomic Analysis. PMID- 28096648 TI - Identification of Genetic and Epigenetic Variants Associated with Breast Cancer Prognosis by Integrative Bioinformatics Analysis. AB - INTRODUCTION: Breast cancer being a multifaceted disease constitutes a wide spectrum of histological and molecular variability in tumors. However, the task for the identification of these variances is complicated by the interplay between inherited genetic and epigenetic aberrations. Therefore, this study provides an extrapolate outlook to the sinister partnership between DNA methylation and single-nucleotide polymorphisms (SNPs) in relevance to the identification of prognostic markers in breast cancer. The effect of these SNPs on methylation is defined as methylation quantitative trait loci (meQTL). MATERIALS AND METHODS: We developed a novel method to identify prognostic gene signatures for breast cancer by integrating genomic and epigenomic data. This is based on the hypothesis that multiple sources of evidence pointing to the same gene or pathway are likely to lead to reduced false positives. We also apply random resampling to reduce overfitting noise by dividing samples into training and testing data sets. Specifically, the common samples between Illumina 450 DNA methylation, Affymetrix SNP array, and clinical data sets obtained from the Cancer Genome Atlas (TCGA) for breast invasive carcinoma (BRCA) were randomly divided into training and test models. An intensive statistical analysis based on log-rank test and Cox proportional hazard model has established a significant association between differential methylation and the stratification of breast cancer patients into high- and low-risk groups, respectively. RESULTS: The comprehensive assessment based on the conjoint effect of CpG-SNP pair has guided in delaminating the breast cancer patients into the high- and low-risk groups. In particular, the most significant association was found with respect to cg05370838-rs2230576, cg00956490-rs940453, and cg11340537-rs2640785 CpG-SNP pairs. These CpG-SNP pairs were strongly associated with differential expression of ADAM8, CREB5, and EXPH5 genes, respectively. Besides, the exclusive effect of SNPs such as rs10101376, rs140679, and rs1538146 also hold significant prognostic determinant. CONCLUSIONS: Thus, the analysis based on DNA methylation and SNPs have resulted in the identification of novel susceptible loci that hold prognostic relevance in breast cancer. PMID- 28096650 TI - Refractive and visual outcomes after Keraring intrastromal corneal ring segment implantation for keratoconus assisted by femtosecond laser at 6 months follow-up. AB - PURPOSE: We attempted to evaluate the efficacy of femtosecond laser-assisted intrastromal corneal ring segment implantation in patients with keratoconus (KC). PATIENTS AND METHODS: A retrospective interventional consecutive clinical study was conducted on patients with KC who were treated with femtosecond laser Keraring implantation. All procedures were performed at Ebsar Eye Center in the period from January 5, 2015, to February 28, 2016. RESULTS: Thirty eyes of 20 patients were included in this study. The mean age of patients was 27.43+/-3.57 years. Eleven patients (55%) were female and nine patients (45%) were male. Keraring segments were successfully implanted in all eyes. There were no complications or need for ring repositioning. The follow-up period was 6 months postoperatively. There was a significant improvement in the mean logarithm of the minimum angle of resolution (LogMAR) of uncorrected visual acuity (UCVA) after Keraring segment implantation from 1.5+/-0.23 preoperatively to 0.54+/-0.16 at 6 months postoperatively (P=0.001). The preoperative mean LogMAR of best-corrected visual acuity (BCVA) was 0.85+/-0.17. At 1 month postoperatively, it was 0.35+/ 0.15; at 3 months postoperatively, it was 0.26+/-0.11, and at 6 months postoperatively, it was 0.14+/-0.07 (P=0.001). The mean preoperative maximum keratometric value for 3 mm pupil in diopters (K max) significantly decreased from 55.85+/-5.44 preoperatively (N=30) to 44.05+/-1.64 D at 6 months postoperatively (P=0.001). There was a statistically significant reduction in the mean preoperative spherical equivalent from -5.43+/-1.76 D preoperatively to 2.43+/-0.95 D at 6 months postoperatively. No statistically significant differences were detected between 1 and 3 months of follow-up regarding the visual and refractive outcomes. CONCLUSION: Analysis of the outcomes after Keraring ICRS implantation showed a significant postoperative corneal flattening with a subsequent increase in UCVA and BCVA. Using the femtosecond laser for tunnel creation made the procedure easy and fast with an accurate precise depth of implantation and reduced the risk of operative and postoperative complications. PMID- 28096651 TI - Effects of 3% diquafosol sodium ophthalmic solution on higher-order aberrations in patients diagnosed with dry eye after cataract surgery. AB - PURPOSE: To evaluate the effects of diquafosol sodium ophthalmic solution 3% (DQS) and artificial tears (AT) on higher-order aberrations (HOAs) in patients with dry eye after cataract surgery. DESIGN: This was a post hoc analysis of a previously conducted randomized clinical study. METHODS: Fifty-nine eyes from 42 patients (17 males and 25 females, aged 72.6+/-8.0 years) with verified or suspected dry eye at 4 weeks after cataract surgery were evaluated. The dry eye patients were randomly assigned to receive DQS or AT for 4 weeks. Tear breakup time (BUT), corneal and conjunctival fluorescein staining scores, and HOAs were analyzed before and after instillation. HOAs were measured consecutively for 10 seconds with a wavefront analyzer. Average HOAs, HOA fluctuations (fluctuation index [FI]) and changes in HOAs (stability index [SI]) were compared within and between the two groups. RESULTS: After 4 weeks of instillation, BUT significantly increased (P=0.001) compared with preinstillation values in the DQS group, but not in the AT group. This increase in BUT in the DQS group was significantly greater than in the AT group (P=0.014). Corneal and conjunctival fluorescein staining scores after instillation significantly improved compared with preinstillation values in the DQS group (P=0.018). In HOAs, the cornea aberration changed from an upward curve (a sawtooth pattern) to an almost constant value (a stable pattern) in the DQS group, but not in the AT group. In FI and SI, there were no significant changes in either group; however, FI and SI were significantly lower in the DQS group than in the AT group (both, P=0.004). CONCLUSION: The dry eye patients after cataract surgery had a visual dysfunction in HOAs. DQS is effective to treat dry eye disease after cataract surgery with improvement of visual function. PMID- 28096652 TI - Erratum: Macular morphology and response to ranibizumab treatment in patients with wet age-related macular degeneration [Corrigendum]. AB - [This corrects the article on p. 1117 in vol. 10, PMID: 27366051.]. PMID- 28096653 TI - Applicability of automatic spectral domain optical coherence tomography for glaucoma mass screening. AB - PURPOSE: To perform a preliminary evaluation of the applicability of automatic spectral domain optical coherence tomography (ASD-OCT) for glaucoma mass screening in a population-based setting. METHODS: Information using ASD-OCT (thicknesses of the macular retinal nerve fiber layer [mRNFL], disc retinal nerve fiber layer [dRNFL], ganglion cell layer [GCL] + inner plexiform layer [IPL]; GCL+, and ganglion cell complex [GCL + IPL + RNFL; GCL++]) was obtained from 245 eyes of 123 glaucomatous subjects and 1,454 eyes of 727 normal subjects. For all four measurements, each grid was scored as follows: 2= within 95% of the normal database; 1= within 5%; and 0= within 1%. The sums of each grid (mRNFLs, dRNFLs, GCL+s, and GCL++s) were used as indicators. The effectiveness was estimated by the area under the receiver operating characteristic curve (AUC-ROC). The appropriate algorithm was then applied to 10,145 eyes of 5,088 subjects from the general population (mean age: 50.1+/-10.3 years). RESULTS: AUC-ROC of mRNFLs, dRNFLs, GCL+s, and GCL++s was 0.927 (95% confidence interval [CI] =0.903-0.950), 0.919 (95% CI =0.899-0.940), 0.972 (95% CI =0.958-0.986), and 0.972 (95% CI =0.957-0.986), respectively. The discriminant analysis demonstrated that the canonical correlation coefficients of mRNFLs, dRNFLs, GCL+s, and dGCL++s were 0.07, 0.255, 0.661, and 0.207, respectively. AUC-ROC of the discriminant value was 0.971 (95% CI =0.956-0.986). The sensitivity/specificity using GCL+s (cutoff =160) was 81.6%/99.9%. This algorithm was applied to the general population, and 1,658 eyes (16.3%) were found to be positive for glaucoma. CONCLUSION: In the case-control setting, ASD-OCT showed a relatively high performance, and the thickness of the GCL + IPL was the best predictor. However, further prospective studies are needed, in which the results of this study are compared to the general population, because the false-positive rate of glaucoma seems to be high. PMID- 28096654 TI - Comparison of Visian toric collamer lens and toric acrylic intraocular lens implantation for the treatment of myopia with astigmatism. AB - PURPOSE: To compare the efficacy and outcome of phakic toric implantable collamer lens (TICL) and refractive clear lens extraction with AcrySof Toric intraocular lens (TIOL) implantation for the treatment of myopic astigmatism. PATIENTS AND METHODS: This study assessed eyes with myopic astigmatism >-1 D and <=-4 D with a spherical equivalent >10 D or <10 D if the patients were unsuitable for corneal refractive surgery. These eyes were divided into group A, in which Visian Toric ICLTM Phakic TICL was implanted, and group B, which involved clear lens extraction with implantation of an AcrySof IQ toric SN60T3-9TM IOL. The outcome and complications were evaluated. RESULTS: This study enrolled 63 eyes of 38 patients with a follow-up period of at least 6 months. The mean postoperative spherical equivalent was -0.19+/-0.31 D in group A and -0.21+/-0.28 D in group B (P=0.69). The mean postoperative cylinder value was -0.46+/-0.53 D in group A and -0.32+/-0.41 D in group B (P=0.35). Postoperative cylinder was <1 D in 76.47% and 79.31% of eyes in groups A and B, respectively. The mean endothelial cell count was reduced by 4.32% in group A and by 5.32% in group B (P=0.003). The mean postoperative intraocular pressure increased insignificantly in group A (P=0.22) and reduced significantly in group B (P=0.004). The complication rate was 11.76% in group A and 6.90% in group B. CONCLUSION: Both procedures showed predictable results and good visual results. However, the loss of accommodation and risk of retinal complications in the TIOL group suggest that the use of TICL for myopic astigmatism is a better choice in younger patients. PMID- 28096655 TI - Reversibility of retinal ischemia due to central retinal artery occlusion by hyperbaric oxygen. AB - PURPOSE: Ischemic retinal damage can be reversed by hyperbaric oxygen therapy (HBOT) as long as irreversible infarction damage has not developed. However, the time window till irreversible damage develops is still unknown. The study aim was to evaluate the effect of HBOT and determine possible markers for irreversible retinal damage. MATERIALS AND METHODS: Retrospective analysis of 225 patients treated with HBOT for central retinal artery occlusion (CRAO) in 1999-2015. One hundred and twenty-eight patients fulfilled inclusion/exclusion criteria: age >18 years, symptoms <20 hours, and best-corrected visual acuity (BCVA) <0.5 logMAR. RESULTS: Time delay from symptoms to treatment was 7.8+/-3.8 hours. The BCVA was significantly improved after HBOT, from 2.14+/-0.50 to 1.61+/-0.78 (P<0.0001). The proportion of patients with clinically meaningful visual improvement was significantly higher in patients without cherry-red spot (CRS) compared to patients with CRS at presentation (86.0% vs 57.6%, P<0.0001). The percentage of patients with final BCVA better than 1.0 was also significantly higher in patients without CRS vs patients with CRS at presentation (61.0% vs 7.1%, P<0.0001). There was no correlation between CRS and the time from symptoms. HBOT was found to be safe, and only 5.5% of patients had minor, reversible, adverse events. CONCLUSION: HBOT is an effective treatment for non-arteritic CRAO as long as CRS has not formed. The fundus findings, rather than the time delay, should be used as a marker for irreversible damage. PMID- 28096656 TI - Analysis of pramipexole dose-response relationships in Parkinson's disease. AB - BACKGROUND: Pramipexole (PPX), a non-ergot dopamine receptor agonist, is a first line treatment for Parkinson's disease (PD). A critical dose level above which a better benefit-to-harm ratio exists has not been examined. METHODS: Chinese PD patients (n=464) were retrospectively analyzed by PPX maintenance dose, PD stage, combined levodopa dose, and baseline tremor contribution. The sum score of Baseline Activities of Daily Living (part II) and Motor Examination (III) of the Unified Parkinson's Disease Rating Scale (UPDRS II+III) was used as a covariate for final score adjustment. RESULTS: Sustained-release (SR) and immediate-release (IR) PPX showed similar efficacy based on score changes at 18 weeks, with comparable tolerability. Approximately two-third of patients received PPX at >=1.5 mg/d, and one fourth of patients had >=20% tremor contribution to UPDRS II+III. After treatment, patients receiving PPX >=1.5 mg/d showed better improvement in UPDRS II+III scores (P=0.0025), with similar trends with the IR and SR formulations. Patients with >=20% tremor contribution showed better improvement in UPDRS II+III scores (P=0.0017). No differences were seen based on PD stage or combined levodopa dose. The overall proportions of adverse events (AEs) were similar. More patients discontinued because of intolerable side effects, and more investigator-defined drug-related AEs were recorded in the <1.5 mg/d subgroup. CONCLUSION: UPDRS II+III improvement was better with PPX >=1.5 than with <1.5 mg/d in Chinese PD patients after 18 weeks of treatment, with similar trends seen with IR and SR formulations. The frequency of AEs in PPX >=1.5 and <1.5 mg/d subgroups was similar. PMID- 28096657 TI - Vitamin D deficiency and the risk of tuberculosis: a meta-analysis. AB - BACKGROUND AND AIM: To conduct meta-analyses of all published studies on various aspects of association between vitamin D and tuberculosis (TB). METHODS: PubMed and Web of Knowledge were searched for all properly controlled studies on vitamin D and TB. Pooled odds ratio, mean difference or standardized mean difference, and its corresponding 95% confidence interval were calculated with the Cochrane Review Manager 5.3. RESULTS: A significantly lower vitamin D level was found in TB patients vs controls; vitamin D deficiency (VDD) was associated with an increased risk of TB, although such an association was lacking in the African population and in the human immunodeficiency virus-infected African population. A significantly lower vitamin D level was found in human immunodeficiency virus-TB coinfected African patients receiving antiretroviral treatment who developed TB associated immune reconstitution inflammatory syndrome vs those who did not develop TB-associated immune reconstitution inflammatory syndrome. VDD was associated with an increased risk of developing active TB in those subjects with latent TB infection and with an increased risk of tuberculin skin test conversion/TB infection conversion, and the trend toward a lower vitamin D level in active TB patients vs latent TB infection subjects did not reach statistical significance, indicating that VDD was more likely a risk factor than a consequence of TB. This concept was further strengthened by our result that anti TB treatment did not affect vitamin D level in TB patients receiving the treatment. CONCLUSION: Our analyses revealed an association between vitamin D and TB. VDD is more likely a risk factor for TB than its consequence. More studies are needed to determine whether vitamin D supplementation is beneficial to TB prevention and treatment. PMID- 28096660 TI - Erratum: A triazole derivative elicits autophagic clearance of polyglutamine aggregation in neuronal cells [Corrigendum]. AB - [This corrects the article on p. 2947 in vol. 10.]. PMID- 28096658 TI - Anticancer and anti-inflammatory activities of girinimbine isolated from Murraya koenigii. AB - Therapy that directly targets apoptosis and/or inflammation could be highly effective for the treatment of cancer. Murraya koenigii is an edible herb that has been traditionally used for cancer treatment as well as inflammation. Here, we describe that girinimbine, a carbazole alkaloid isolated from M. koenigii, induced apoptosis and inhibited inflammation in vitro as well as in vivo. Induction of apoptosis in human colon cancer cells (HT-29) by girinimbine revealed decreased cell viability in HT-29, whereas there was no cytotoxic effect on normal colon cells. Changes in mitochondrial membrane potential, nuclear condensation, cell permeability, and cytochrome c translocation in girinimbine treated HT-29 cells demonstrated involvement of mitochondria in apoptosis. Early phase apoptosis was shown in both acridine orange/propidium iodide and annexin V results. Girinimbine treatment also resulted in an induction of G0/G1 phase arrest which was further corroborated with the upregulation of two cyclin dependent kinase proteins, p21 and p27. Girinimbine treatment activated apoptosis through the intrinsic pathway by activation of caspases 3 and 9 as well as cleaved caspases 3 and 9 which ended by triggering the execution pathway. Moreover, apoptosis was confirmed by downregulation of Bcl-2 and upregulation of Bax in girinimbine-treated cells. In addition, the key tumor suppressor protein, p53, was seen to be considerably upregulated upon girinimbine treatment. Induction of apoptosis by girinimbine was also evidenced in vivo in zebrafish embryos, with results demonstrating significant distribution of apoptotic cells in embryos after a 24-hour treatment period. Meanwhile, anti-inflammatory action was evidenced by the significant dose-dependent girinimbine inhibition of nitric oxide production in lipopolysaccharide/interferon-gamma-induced cells along with significant inhibition of nuclear factor-kappa B translocation from the cytoplasm to nucleus in stimulated RAW 264.7 cells. Girinimbine was also shown to have considerable antioxidant activity whereby 20 MUg/mL of girinimbine was equivalent to 82.17+/-1.88 MUM of Trolox. In mice with carrageenan-induced peritonitis, oral pretreatment with girinimbine helped limit total leukocyte migration (mainly of neutrophils), and reduced pro-inflammatory cytokine levels (interleukin-1beta and tumor necrosis factor-alpha) in the peritoneal fluid. These findings strongly suggest that girinimbine could act as a chemopreventive and/or chemotherapeutic agent by inducing apoptosis while suppressing inflammation. There is a potential for girinimbine to be further investigated for its applicability in treating early stages of cancer. PMID- 28096659 TI - Effects of multiple-dose ponesimod, a selective S1P1 receptor modulator, on lymphocyte subsets in healthy humans. AB - This study investigated the effects of ponesimod, a selective S1P1 receptor modulator, on T lymphocyte subsets in 16 healthy subjects. Lymphocyte subset proportions and absolute numbers were determined at baseline and on Day 10, after once-daily administration of ponesimod (10 mg, 20 mg, and 40 mg each consecutively for 3 days) or placebo (ratio 3:1). The overall change from baseline in lymphocyte count was -1,292+/-340*106 cells/L and 275+/-486*106 cells/L in ponesimod- and placebo-treated subjects, respectively. This included a decrease in both T and B lymphocytes following ponesimod treatment. A decrease in naive CD4+ T cells (CD45RA+CCR7+) from baseline was observed only after ponesimod treatment (-113+/-98*106 cells/L, placebo: 0+/-18*106 cells/L). The number of T cytotoxic (CD3+CD8+) and T-helper (CD3+CD4+) cells was significantly altered following ponesimod treatment compared with placebo. Furthermore, ponesimod treatment resulted in marked decreases in CD4+ T-central memory (CD45RA-CCR7+) cells (-437+/-164*106 cells/L) and CD4+ T-effector memory (CD45RA-CCR7-) cells ( 131+/-57*106 cells/L). In addition, ponesimod treatment led to a decrease of 228+/-90*106 cells/L of gut-homing T cells (CLA-integrin beta7+). In contrast, when compared with placebo, CD8+ T-effector memory and natural killer (NK) cells were not significantly reduced following multiple-dose administration of ponesimod. In summary, ponesimod treatment led to a marked reduction in overall T and B cells. Further investigations revealed that the number of CD4+ cells was dramatically reduced, whereas CD8+ and NK cells were less affected, allowing the body to preserve critical viral-clearing functions. PMID- 28096661 TI - Patient knowledge on reporting adverse drug reactions in Poland. AB - AIM: The aim of the study was to assess patient knowledge on reporting of adverse drug reactions. MATERIALS AND METHODS: A prospective study was conducted among 200 patients. The study was based on an original survey composed of 15 single- and multiple-choice questions. The study involved individuals who have experienced adverse reactions as well as individuals who have never experienced any adverse reactions; people over the age of 18; literate; residing in Mazowieckie Voivodeship, who have not been diagnosed with any disease that could compromise their logical thinking skills. RESULTS: The respondents who lived in the city had a greater knowledge compared to the respondents who lived in the countryside (Pearson's chi2=47.70, P=0.0013). The respondents who lived in the city were also more statistically likely to provide a correct answer to the question about the type of adverse reactions to be reported (Pearson's chi2=50.66, P=0.012). Statistically significant associations were found between the place of residence of the respondents and the correct answer to the question about the data that must be included in the report on adverse reactions (Pearson's chi2=11.7, P<0.0001). PMID- 28096662 TI - Synthetic nanoparticles of bovine serum albumin with entrapped salicylic acid. AB - Bovine serum albumin (BSA) is highly water soluble and binds drugs or inorganic substances noncovalently for their effective delivery to various affected areas of the body. Due to the well-defined structure of the protein, containing charged amino acids, albumin nanoparticles (NPs) may allow electrostatic adsorption of negatively or positively charged molecules, such that substantial amounts of drug can be incorporated within the particle, due to different albumin-binding sites. During the synthesis procedure, pH changes significantly. This variation modifies the net charge on the surface of the protein, varying the size and behavior of NPs as the drug delivery system. In this study, the synthesis of BSA NPs, by a desolvation process, was studied with salicylic acid (SA) as the active agent. SA and salicylates are components of various plants and have been used for medication with anti-inflammatory, antibacterial, and antifungal properties. However, when administered orally to adults (usual dose provided by the manufacturer), there is 50% decomposition of salicylates. Thus, there has been a search for some time to develop new systems to improve the bioavailability of SA and salicylates in the human body. Taking this into account, during synthesis, the pH was varied (5.4, 7.4, and 9) to evaluate its influence on the size and release of SA of the formed NPs. The samples were analyzed using field-emission scanning electron microscopy, transmission electron microscopy, Fourier transform infrared, zeta potential, and dynamic light scattering. Through fluorescence, it was possible to analyze the release of SA in vitro in phosphate-buffered saline solution. The results of chemical morphology characterization and in vitro release studies indicated the potential use of these NPs as drug carriers in biological systems requiring a fast release of SA. PMID- 28096663 TI - Pressure ulcers in palliative ward patients: hyponatremia and low blood pressure as indicators of risk. AB - BACKGROUND: Prevention strategies for pressure ulcer formation remain critical in patients with an advanced illness. We analyzed factors associated with the development of pressure ulcers in patients hospitalized in a palliative care ward setting. PATIENTS AND METHODS: This study was a retrospective analysis of 329 consecutive patients with a mean age (+/- standard deviation) of 70.4+/-11.8 years (range: 30-96 years, median 70.0 years; 55.3% women), who were admitted to the Palliative Care Department between July 2012 and May 2014. RESULTS: Patients were hospitalized for mean of 24.8+/-31.4 days (1-310 days, median 14 days). A total of 256 patients (77.8%) died in the ward and 73 patients (22.2%) were discharged. Two hundred and six patients (62.6%) did not develop pressure ulcers during their stay in the ward, 84 patients (25.5%) were admitted with pressure ulcers, and 39 patients (11.9%) developed pressure ulcers in the ward. Four factors assessed at admission appear to predict the development of pressure ulcers in the multivariate logistic regression model: Waterlow score (odds ratio [OR] =1.140, 95% confidence interval [CI] =1.057-1.229, P=0.001), transfer from other hospital wards (OR =2.938, 95% CI =1.339-6.448, P=0.007), hemoglobin level (OR =0.814, 95% CI =0.693-0.956, P=0.012), and systolic blood pressure (OR =0.976, 95% CI =0.955-0.997, P=0.023). Five other factors assessed during hospitalization appear to be associated with pressure ulcer development: mean evening body temperature (OR =3.830, 95% CI =1.729-8.486, P=0.001), mean Waterlow score (OR =1.194, 95% CI =1.092-1.306, P<0.001), the lowest recorded sodium concentration (OR =0.880, 95% CI =0.814-0.951, P=0.001), mean systolic blood pressure (OR =0.956, 95% CI =0.929-0.984, P=0.003), and the lowest recorded hemoglobin level (OR =0.803, 95% CI =0.672-0.960, P=0.016). CONCLUSION: Hyponatremia and low blood pressure may contribute to the formation of pressure ulcers in patients with an advanced illness. PMID- 28096664 TI - Predictors of outcomes following reablement in community-dwelling older adults. AB - BACKGROUND: Reablement is a rehabilitation intervention for community-dwelling older adults, which has recently been implemented in several countries. Its purpose is to improve functional ability in daily occupations (everyday activities) perceived as important by the older person. Performance and satisfaction with performance in everyday life are the major outcomes of reablement. However, the evidence base concerning which factors predict better outcomes and who receives the greatest benefit in reablement is lacking. OBJECTIVE: The objective of this study was to determine the potential factors that predict occupational performance and satisfaction with that performance at 10 weeks follow-up. METHODS: The sample in this study was derived from a nationwide clinical controlled trial evaluating the effects of reablement in Norway and consisted of 712 participants living in 34 municipalities. Multiple linear regression was used to investigate possible predictors of occupational performance (COPM-P) and satisfaction with that performance (COPM-S) at 10 weeks follow-up based on the Canadian Occupational Performance Measure (COPM). RESULTS: The results indicate that the factors that significantly predicted better COPM-P and COPM-S outcomes at 10 weeks follow-up were higher baseline scores of COPM-P and COPM-S respectively, female sex, having a fracture as the major health condition and high motivation for rehabilitation. Conversely, the factors that significantly predicted poorer COPM-P and COPM-S outcomes were having a neurological disease other than stroke, having dizziness/balance problems as the major health condition and having pain/discomfort. In addition, having anxiety/depression was a predictor of poorer COPM-P outcomes. The two regression models explained 38.3% and 38.8% of the total variance of the dependent variables of occupational performance and satisfaction with that performance, respectively. CONCLUSION: The results indicate that diagnosis, functional level, sex and motivation are significant predictors of outcomes following reablement. PMID- 28096665 TI - Gender differences in partners of patients with COPD and their perceptions about the patients. AB - BACKGROUND/OBJECTIVES: Chronic obstructive pulmonary disease (COPD) not only affects patients but also their partners. Gender-related differences in patients with COPD are known, for instance regarding symptoms and quality of life. Yet, research regarding gender differences in partners of patients with COPD has been conducted to a lesser extent, and most research focused on female partners. We aimed to investigate differences between male and female partners of patients with COPD regarding their own characteristics and their perceptions of patients' characteristics. DESIGN: Cross-sectional study. SETTING: Four hospitals in the Netherlands. PARTICIPANTS: One hundred and eighty-eight patient-partner couples were included in this cross-sectional study. MEASUREMENTS: General and clinical characteristics, health status, care dependency, symptoms of anxiety and depression, social support, caregiver burden, and coping styles were assessed during a home visit. RESULTS: Female partners had more symptoms of anxiety and a worse health status than male partners. Social support and caregiver burden were comparable, but coping styles differed between male and female partners. Female partners thought that male patients were less care dependent and had more symptoms of depression, while these gender differences did not exist in patients themselves. CONCLUSION: Health care providers should pay attention to the needs of all partners of patients with COPD, but female partners in particular. Obtaining an extensive overview of the patient-partner couple, including coping styles, health status, symptoms of anxiety, and caregiver burden, is necessary to be able to support the couple as effectively as possible. PMID- 28096666 TI - Barriers and facilitators influencing self-management among COPD patients: a mixed methods exploration in primary and affiliated specialist care. AB - Self-management is becoming increasingly important in COPD health care although it remains difficult to embed self-management into routine clinical care. The implementation of self-management is understood as a complex interaction at the level of patient, health care provider (HCP), and health system. Nonetheless there is still a poor understanding of the barriers and effective facilitators. Comprehension of these determinants can have significant implications in optimizing self-management implementation and give further directions for the development of self-management interventions. Data were collected among COPD patients (N=46) and their HCPs (N=11) in three general practices and their collaborating affiliated hospitals. Mixed methods exploration of the data was conducted and collected by interviews, video-recorded consultations (N=50), and questionnaires on consultation skills. Influencing determinants were monitored by 1) interaction and communication between the patient and HCP, 2) visible and invisible competencies of both the patient and the HCP, and 3) degree of embedding self-management into the health care system. Video observations showed little emphasis on effective behavioral change and follow-up of given lifestyle advice during consultation. A strong presence of COPD assessment and monitoring negatively affects the patient-centered communication. Both patients and HCPs experience difficulties in defining personalized goals. The satisfaction of both patients and HCPs concerning patient centeredness during consultation was measured by the patient feedback questionnaire on consultation skills. The patients scored high (84.3% maximum score) and differed from the HCPs (26.5% maximum score). Although the patient-centered approach accentuating self management is one of the dominant paradigms in modern medicine, our observations show several influencing determinants causing difficulties in daily practice implementation. This research is a first step unravelling the determinants of self-management leading to a better understanding. PMID- 28096667 TI - Hyaluronan-modified superparamagnetic iron oxide nanoparticles for bimodal breast cancer imaging and photothermal therapy. AB - Theranostic nanoparticles with both imaging and therapeutic abilities are highly promising in successful diagnosis and treatment of the most devastating cancers. In this study, the dual-modal imaging and photothermal effect of hyaluronan (HA) modified superparamagnetic iron oxide nanoparticles (HA-SPIONs), which was developed in a previous study, were investigated for CD44 HA receptor overexpressing breast cancer in both in vitro and in vivo experiments. Heat is found to be rapidly generated by near-infrared laser range irradiation of HA SPIONs. When incubated with CD44 HA receptor-overexpressing MDA-MB-231 cells in vitro, HA-SPIONs exhibited significant specific cellular uptake and specific accumulation confirmed by Prussian blue staining. The in vitro and in vivo results of magnetic resonance imaging and photothermal ablation demonstrated that HA-SPIONs exhibited significant negative contrast enhancement on T2-weighted magnetic resonance imaging and photothermal effect targeted CD44 HA receptor overexpressing breast cancer. All these results indicated that HA-SPIONs have great potential for effective diagnosis and treatment of cancer. PMID- 28096668 TI - Impact of nanostructured thin ZnO film in ultraviolet protection. AB - Nanoscale ZnO is one of the best choices for ultraviolet (UV) protection, not only because of its antimicrobial properties but also due to its potential application for UV preservation. However, the behavior of nanostructured thin ZnO films and long-term effects of UV-radiation exposure have not been studied yet. In this study, we investigated the UV-protection ability of sol gel-derived thin ZnO films after different exposure times. Scanning electron microscopy, atomic force microscopy, and UV-visible optical spectroscopy were carried out to study the structure and optical properties of the ZnO films as a function of the UV irradiation time. The results obtained showed that the prepared thin ZnO films were somewhat transparent under the visible wavelength region and protective against UV radiation. The UV-protection factor was 50+ for the prepared samples, indicating that they were excellent UV protectors. The deposited thin ZnO films demonstrated promising antibacterial potential and significant light absorbance in the UV range. The experimental results suggest that the synthesized samples have potential for applications in the health care field. PMID- 28096669 TI - Nanocoating with plant-derived pectins activates osteoblast response in vitro. AB - A new strategy to improve osseointegration of implants is to stimulate adhesion of bone cells, bone matrix formation, and mineralization at the implant surface by modifying surface coating on the nanoscale level. Plant-derived pectins have been proposed as potential candidates for surface nanocoating of orthopedic and dental titanium implants due to 1) their osteogenic stimulation of osteoblasts to mineralize and 2) their ability to control pectin structural changes. The aim of this study was to evaluate in vitro the impact of the nanoscale plant-derived pectin Rhamnogalacturonan-I (RG-I) from potato on the osteogenic response of murine osteoblasts. RG-I from potato pulps was isolated, structurally modified, or left unmodified. Tissue culture plates were either coated with modified RG-I or unmodified RG-I or - as a control - left uncoated. The effect of nanocoating on mice osteoblast-like cells MC3T3-E1 and primary murine osteoblast with regard to proliferation, osteogenic response in terms of mineralization, and gene expression of Runt-related transcription factor 2 (Runx2), alkaline phosphate (Alpl), osteocalcin (Bglap), alpha-1 type I collagen (Col1a1), and receptor activator of NF-kappaB ligand (Rankl) were analyzed after 3, 7, 14, and 21 days, respectively. Nanocoating with pectin RG-Is increased proliferation and mineralization of MC3T3-E1 and primary osteoblast as compared to osteoblasts cultured without nanocoating. Moreover, osteogenic transcriptional response of osteoblasts was induced by nanocoating in terms of gene induction of Runx2, Alpl, Bglap, and Col1a1 in a time-dependent manner - of note - to the highest extent under the PA-coating condition. In contrast, Rankl expression was initially reduced by nanocoating in MC3T3-E1 or remained unaltered in primary osteoblast as compared to the uncoated controls. Our results showed that nanocoating of implants with modified RG-I beneficially 1) supports osteogenesis, 2) has the capacity to improve osseointegration of implants, and is therefore 3) a potential candidate for nanocoating of bone implants. PMID- 28096670 TI - Lung-targeting drug delivery system of baicalin-loaded nanoliposomes: development, biodistribution in rabbits, and pharmacodynamics in nude mice bearing orthotopic human lung cancer. AB - The present study aims to develop a kind of novel nanoliposomes for the lung targeting delivery system of baicalin as a Chinese medicine monomer. Baicalin loaded nanoliposomes were prepared by the effervescent dispersion and lyophilized techniques. Baicalin-loaded nanoliposomes had an average particle size of 131.7+/ 11.7 nm with 0.19+/-0.02 polydispersity index, 82.8%+/-1.24% entrapment efficiency and 90.47%+/-0.93% of yield and sustaining drug release effect over 24 h and were stable for 12 months at least. In vitro no hemolytic activity was observed for the experimental drug concentration. After intravenous administration of baicalin-loaded nanoliposomes to rabbits, drug concentration in the lungs was the highest among the tested organs at all time points and was significantly higher than that of its solution. For the targeting parameters, the relative intake rate and the ratio of peak concentration of lung were 4.837 and 2.789, respectively. Compared with plasma, liver, spleen, and kidney, the ratios of targeting efficacy (Te)liposomes to (Te)injection of lung were increased by a factor of 14.131, 1.893, 3.357, and 3.470, respectively. Furthermore, the results showed that the baicalin-loaded nanoliposomes did not induce lung injury. Importantly, baicalin-loaded nanoliposomes showed better antitumor therapeutic efficacy in the nude mice bearing orthotopic human lung cancer with the median survival time of blank liposomes (11.40+/-0.16 days), baicalin solution (17.30+/ 0.47 days), and baicalin-loaded nanoliposomes (25.90+/-0.53 days). Therefore, the liposome is a promising drug carrier with an excellent lung-targeting property and therapeutic effect for the treatment of lung disease, such as lung cancer. PMID- 28096671 TI - Local mild hypothermia therapy as an augmentation strategy for minimally invasive surgery of hypertensive intracerebral hemorrhage: a meta-analysis of randomized clinical trials. AB - BACKGROUND: Previous studies reported that the mild hypothermia therapy (MHT) could significantly improve the clinical outcomes for patients with hypertensive intracerebral hemorrhage (HICH). Therefore, this meta-analysis was conducted to systematically assess whether the addition of local MHT (LMHT) could significantly improve the efficacy of minimally invasive surgery (MIS) in treating HICH. METHODS: Randomized clinical trials on the combined application of MIS and LMHT (MIS+LMHT) vs MIS alone for treating HICH were searched up to September 2016 in databases. Response rate and mortality rate were the primary outcomes, and the neurologic function and Barthel index were the secondary outcomes. Side effects were also analyzed. RESULTS: Totally, 28 studies composed of 2,325 patients were included to compare the efficacy of MIS+LMHT to MIS alone. The therapeutic effects of MIS+LMHT were significantly better than MIS alone. The pooled odds ratio of response rate and mortality rate was 2.68 (95% confidence interval [CI]=2.22-3.24) and 0.43 (95% CI=0.32-0.57), respectively. In addition, the MIS+LMHT led to a significantly better improvement in the neurologic function and activities of daily living. The incidence of pneumonia was similar between the two treatment methods. CONCLUSION: These results indicated that compared to MIS alone, the MIS+LMHT could be more effective for the acute treatment of patients with HICH. This treatment modality should be further explored and optimized. PMID- 28096672 TI - A biopsychological review of gambling disorder. AB - The present review is an overview of previous experimental work on biopsychological aspects of gambling disorder. It includes the topics 1) gambling disorder from the neuroimaging and electroencephalography (EEG) perspective, 2) cognitive, executive functioning, and neuropsychological aspects of gambling disorder, and 3) rodent models of gambling disorder. Penalties and losses in gambling can differ in terms of brain activity. Also, specific patterns of brain activity, brain anatomical traits, EEG responses, and cognitive and executive performance can discriminate pathological gamblers from nonpathological gamblers. Also, pathological gamblers can display dysfunction in such brain areas as the insula, frontal lobe, and orbitofrontal cortex. Pathological gambling is a heterogeneous disorder that can vary depending on the severity of cognition, the style of gambling (strategic or not), the prospect of recovery, proneness to relapse, and proneness to treatment withdrawal. Finally, based on rodent models of gambling, the appropriateness of gambling decision is influenced by the presence of cues, the activity of dopamine receptors, and the activity of some brain areas (infralimbic, prelimbic, or rostral agranular insular cortex). Pathological gamblers differed in terms of frontoparietal brain activation compared to nonpathological gamblers (if winning or losing a game). Pathological gamblers had dysfunctional EEG activity. The severity of gambling was linked to the magnification and content of cognitive distortions. The insula was fundamental in the distortion of cognitions linked to result analysis during gambling activity. PMID- 28096673 TI - Apathy and intrinsic functional connectivity networks in amnestic mild cognitive impairment. AB - BACKGROUND: Although several prior works reported that apathy is associated with conversion to Alzheimer's disease in individuals with amnestic mild cognitive impairment (aMCI), effects of apathy on the functional connectivity (FC) of the brain remain unclear. In this study, we assessed the pattern of association between apathy and default mode network (DMN), salience network and central executive network (CEN) in aMCI subjects. METHODS: Fifty subjects with aMCI and 50 controls (CONs) participated in this study. They underwent clinical assessments and magnetic resonance imaging for the structural and resting-state scan. We explored the patterns of association between apathy inventory (IA) total score and the whole-brain voxel-wise FCs of the DMN, salience network and CEN in aMCI subjects. RESULTS: We observed that the FCs of the DMN were less and those of CEN were more in the aMCI group than the CON group. Total IA score was negatively correlated with FCs of the anterior cingulate within the DMN, and positively correlated with FCs of the middle frontal, inferior frontal, and supramarginal gyrus within the CEN in the aMCI group. CONCLUSION: Our findings suggest that distinctive patterns of association between apathy and FCs in the DMN and CEN in the aMCI group might reflect the putative role of functional network change in the development of apathy in aMCI. PMID- 28096674 TI - Alterations of white matter fractional anisotropy in unmedicated obsessive compulsive disorder. AB - BACKGROUND: Abnormalities in white matter (WM) have previously been reported in patients with obsessive-compulsive disorder (OCD). However, there was some inconsistency in the results obtained for altered regions of WM. The aim of this study was to investigate fractional anisotropy (FA) in the WM of the whole brain in patients with OCD by using diffusion tensor imaging (DTI). METHODS: In total, 28 unmedicated patients with OCD and 28 healthy volunteers underwent DTI scan. A voxel-based analysis was used to compare FA values in WM of the two groups at a voxel threshold of P<0.005 with an extent threshold of k>72 voxels (P<0.05; Alphasim correction). Subsequently, correlation analysis was conducted in order to find the correlation between the mean FA values in significantly altered brain regions and Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores of the OCD patients. RESULTS: Compared with healthy volunteers, the OCD patients had lower FA value in the left lingual gyrus, right midbrain, and right precuneus. There were no regions with significantly higher FA values in OCD patients compared with healthy volunteers. The mean FA values in the above regions (left lingual, r=0.019, P=0.923; right midbrain, r=-0.208, P=0.289; and right precuneus, r= 0.273, P=0.161) had no significant correlation with the Y-BOCS scores of the OCD patients. CONCLUSION: The findings of this study suggest that alterations in WM of the left lingual gyrus, right midbrain, and right precuneus are associated with the pathophysiology mechanism of OCD, and these microstructural alterations do not correlate with symptom severity of OCD. PMID- 28096675 TI - The role of heme oxygenase-1 (HO-1) in the regulation of inflammatory reaction, neuronal cell proliferation and apoptosis in rats after intracerebral hemorrhage (ICH). AB - OBJECTIVE: To investigate the role of heme oxygenase-1 (HO-1) in the regulation of inflammatory reaction, neuronal cell proliferation and apoptosis in rats after intracerebral hemorrhage (ICH). METHODS: Thirty-six adult Sprague Dawley (SD) male rats were randomly divided into sham operation, ICH and zinc protoporphyrin (ZPP) group. Rats (except for the sham operation group) were given 50 MUL stereotactic injection of autologous blood from the femoral artery into the caudate nucleus, to establish an ICH model. In addition, rats in the ZPP group were given 10 mg/kg intraperitoneal injection of ZPP. At day 3 postoperative, neurobehavioral changes and brain water content were evaluated, brain tissue HO-1 expression was detected with immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR), brain tissue apoptosis was evaluated with TUNEL method, Caspase 3, Caspase 8 and Caspase 9 activity were detected with colorimetric method, level of TNF-alpha, IL-1beta, IL-6 and IL-8 were measured with the enzyme-linked immunosorbent assay (ELISA), while Bcl-2, Bax, p-NF-kappaB p65 and p-IkappaBalpha protein expression were detected with Western blot. RESULTS: ICH group compared to sham operation: HO-1 positive rate and mRNA expression were increased, neurological deficit score and cell apoptosis rate were increased, Caspase 3, Caspase 8 and Caspase 9 activity were increased, level of TNF-alpha, IL-1beta, IL-6 and IL-8 were increased, Bcl-2 expression was downregulated, Bax, p-NF-kappaB p65 and p-IkappaBalpha expression were upregulated. The differences were statistically significant (P<0.01). ZPP group compared to ICH: HO-1 positive rate and mRNA expression were decreased, neurological deficit score and cell apoptosis rate were decreased, Caspase 3, Caspase 8, Caspase 9 activity were decreased, level of TNF-alpha, IL-1beta, IL-6 and IL-8 were decreased, Bcl-2 expression was upregulated, Bax, p-NF-kappaB p65 and p-IkappaBalpha expression were downregulated, and the differences were statistically significant (P<0.01). CONCLUSION: HO-1 inhibitor, ZPP does have a protective effect on ICH rats. This might be due to its inhibition to the inflammatory reaction and neuronal cell apoptosis. PMID- 28096676 TI - Aripiprazole augmentation in managing comorbid obsessive-compulsive disorder and bipolar disorder: a case with suicidal attempts. AB - Comorbid obsessive-compulsive disorder (OCD) and bipolar disorder (BD) have long been an intractable problem in clinical practice. The increased risk of manic/hypomanic switch hinders the use of antidepressants for managing coexisting OCD symptoms in BD patients. We herein present a case of a patient with BD-OCD comorbidity, who was successfully treated with mood stabilizers and aripiprazole augmentation. The young female patient reported recurrent depressive episodes and aggravating compulsive behaviors before hospitalization. Of note, the patient repetitively attempted suicide and reported dangerous driving because of intolerable mental sufferings. The preexisting depressive episode and OCD symptoms prompted the use of paroxetine, which consequently triggered the manic switching. Her diagnosis was revised into bipolar I disorder. Minimal response with mood stabilizers prompted the addition of aripiprazole (a daily dose of 10 mg), which helped to achieve significant remission in emotional and obsessive compulsive symptoms. This case highlights the appealing efficacy of a small dose of aripiprazole augmentation for treating BD-OCD comorbidity. Well-designed clinical trials are warranted to verify the current findings. PMID- 28096677 TI - Long-term bicycle riding ameliorates the depression of the patients undergoing hemodialysis by affecting the levels of interleukin-6 and interleukin-18. AB - PURPOSE: Hemodialysis patients with depression have a higher risk of death and hospitalization. Although there is pharmacological management for the depression of hemodialysis patients, the adverse effect of the drug limits the use. The nonpharmacological way, bicycle riding, may be an effective way for the therapy of the depression in hemodialysis patients. However, the underlying mechanism of this relationship is still not fully explained, while interleukin-6 (IL-6) and interleukin-18 (IL-18) are associated with depression and exercise. Thus, the effects of bicycle riding on the levels of the interleukin were explored. PARTICIPANTS AND METHODS: One hundred and eighty-nine patients with chronic hemodialysis were selected and randomly assigned to three groups of medicine (MG, received 20-mg escitalopram daily), medicine and aerobic exercise (MAG, received 20-mg escitalopram daily and bicycle riding six times weekly), and only aerobic exercise (AG, received 20-mg placebo daily and bicycle riding six times weekly). The whole experiment lasted for 18 weeks. The quality of life (36-Item Short Form Health Survey) and depression severity according to criteria in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition [DSM-IV] were measured before and at the end of this study. The serum levels of IL-6 and IL-18 were measured by an enzyme-linked immunosorbent assay kit. RESULTS: The quality of life was improved and depression severity was reduced significantly in the MAG and AG groups when compared with the MG group (P<0.05). Serum levels of IL-6 and IL-18 were the highest in the MG group, moderate in the MAG group and the lowest in AG group. On the other hand, the serum levels of IL-6 and IL-18 were closely associated with depression scores (P<0.05). CONCLUSION: Aerobic exercise improves the quality of life and ameliorates the depression severity of the patients undergoing hemodialysis by affecting the levels of IL-6 and IL-18. Bicycle riding is a potential way for the depression therapy of the patients with chronic hemodialysis. PMID- 28096678 TI - Risperidone improves interpersonal perception and executive function in patients with schizophrenia. AB - OBJECTIVE: To investigate whether risperidone improves social cognitive impairments and executive dysfunction in people with schizophrenia. METHODS: Fifty-six patients who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, diagnostic criteria for schizophrenia were allocated to a risperidone treatment group (RTG, n=28) and a typical antipsychotic treatment group (TATG, n=28). Twenty-eight healthy volunteers were recruited as the normal control group (NCG). The Positive and Negative Syndrome Scale, Interpersonal Perception Task-15 (IPT-15), and Wisconsin Card Sorting Test (WCST) were rated at baseline and after 4 and 12 weeks of treatment with risperidone or typical antipsychotics. RESULTS: Risperidone and typical antipsychotics decreased Positive and Negative Syndrome Scale scores for total psychopathology and positive and negative symptoms. At baseline, in the IPT-15, total scores and five factor scores, as well as the number of categories completed and the percentage of conceptual level responses, were significantly lower in the RTG and TATG than in the NCG, whereas total response errors, perseverative errors, and failure to maintain set were significantly higher in the patient groups than in the NCG. Repeated measures analysis of variance revealed a significant main effect of time period (baseline, 4 weeks, and 12 weeks) for IPT-15 scores and WCST performances, and significant interactions for time period * group (RTG and TATG). Multivariate analysis of variance showed no significant differences between the RTG and TATG on IPT-15 scores at 4 weeks, but there were significant differences between these two groups at 12 weeks. Significant differences were also found between the RTG and TATG on WCST performances at 4 and 12 weeks. CONCLUSION: Individuals with schizophrenia have impairments in social cognitive and executive function, which might be improved by risperidone. PMID- 28096679 TI - A Phase II single-arm trial of palonosetron for the prevention of acute and delayed chemotherapy-induced nausea and vomiting in malignant glioma patients receiving multidose irinotecan in combination with bevacizumab. AB - PURPOSE: Given that the prognosis of recurrent malignant glioma (MG) remains poor, improving quality of life (QoL) through symptom management is important. Meta-analyses establishing antiemetic guidelines have demonstrated the superiority of palonosetron (PAL) over older 5-hydroxytryptamine 3-receptor antagonists in chemotherapy-induced nausea and vomiting (CINV) prevention, but excluded patients with gliomas. Irinotecan plus bevacizumab is a treatment frequently used in MG, but is associated with low (55%) CINV complete response (CR; no emesis or use of rescue antiemetic) with commonly prescribed ondansetron. A single-arm Phase II trial was conducted in MG patients to determine the efficacy of intravenous PAL (0.25 mg) and dexamethasone (DEX; 10 mg) received in conjunction with biweekly irinotecan-bevacizumab treatment. The primary end point was the proportion of subjects achieving acute CINV CR (no emesis or antiemetic <=24 hours postchemotherapy). Secondary end points included delayed CINV CR (days 2-5), overall CINV CR (days 1-5), and QoL, fatigue, and toxicity. MATERIALS AND METHODS: A two-stage design of 160 patients was planned to differentiate between CINV CR of 55% and 65% after each dose of PAL-DEX. Validated surveys assessed fatigue and QoL. RESULTS: A total of 63 patients were enrolled, after which enrollment was terminated due to slow accrual; 52 patients were evaluable for the primary outcome of acute CINV CR. Following PAL-DEX dose administrations 1-3, acute CINV CR rates were 62%, 68%, and 70%; delayed CINV CR rates were 62%, 66%, and 70%, and overall CINV CR rates were 47%, 57%, and 62%, respectively. Compared to baseline, there was a clinically meaningful increase in fatigue during acute and overall phases, but not in the delayed phase. There were no grade >=3 PAL-DEX treatment-related toxicities. CONCLUSION: Data suggest that PAL-DEX is effective in preventing CINV in MG patients, which ultimately maintains the QoL of patients with glioma. PMID- 28096680 TI - Safety, Efficacy, and Patient Acceptability of Everolimus in the Treatment of Breast Cancer. AB - Everolimus combined with exemestane is an important treatment option for patients suffering from estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer (ABC) who have been previously treated with a nonsteroidal aromatase inhibitor (NSAI). After presentation of phase III registration trial BOLERO-2, several phase IIIb trials have been started to evaluate this regimen in a more real-world setting. Here, we review the efficacy and safety data published or presented at selected international meetings. These studies confirmed the outcome observed in the BOLERO-2 trial. Patient acceptance rate is also discussed by focusing on the permanent everolimus discontinuation rate in these trials. Factors influencing the safety profile are also reported, including the impact of age. The optimal sequence of combined therapy approaches associating targeted and endocrine therapy (ET) has yet to be determined as new treatment options such as cyclin-dependent kinase inhibitors become available. However, everolimus-exemestane remains an important treatment option with a major impact on progression-free survival (PFS) and an acceptable safety profile. PMID- 28096681 TI - The relatives' voice: how do relatives experience participation in reablement? A qualitative study. AB - BACKGROUND: Reablement is an early and time-limited home-based model of rehabilitation intervention with an emphasis on intensive, goal-oriented, and multidisciplinary assistance for persons experiencing functional decline. When rehabilitation in general takes place in the person's own home, in contrast to an institution, relatives may have larger responsibilities in helping and supporting the family member. Although there is evidence, showing that family caregivers, such as spouses and children, experience burdens and demanding situations related to their caregiving role, there are currently few publications exploring relatives' experiences of participating in reablement. The aim of our study was to explore and describe how relatives in a community setting in Norway experienced participation in the reablement process. METHODS: Six relatives participated in semi-structured interviews. Qualitative systematic text condensation was used as the analysis strategy. RESULTS: Five themes emerged that summarized the relatives' experiences with reablement: 1) a wish to give and receive information, wish to be involved; 2) wish to be a resource in reablement process; 3) conflicting expectations; 4) have more free time to themselves; and 5) a lack of follow-up programs. CONCLUSION: Our findings highlight the involvement and collaborative process between health professionals, older adults, and relatives and have practical significance for health care services. To advance collaborative practices, the municipal health and social care services should consider establishing a system or a routine to foster this collaboration in reablement. Follow-up programs should be included. PMID- 28096682 TI - Decreased miR-503 expression in gastric cancer is inversely correlated with serum carcinoembryonic antigen and acts as a potential prognostic and diagnostic biomarker. AB - BACKGROUND: Altered expression of miR-503 has been linked to human carcinogenesis. In this present study, we aimed to detect the potential for miR 503 as a novel biomarker for gastric cancer (GC) patients. MATERIALS AND METHODS: The relative mRNA level of miR-503 in serum and tissue of 68 GC patients and serum of 32 healthy volunteers was determined by real-time reverse transcription quantitative polymerase chain reaction. RESULTS: The miR-503 level was significantly lower in the tissue and serum of GC than their counterparts (all P<0.01). Downregulation of miR-503 was found to be corrected with more aggressive tumor. Patients in the high-miR-503 group showed significantly better overall survival compared to the low-miR-503 group (P=0.021). The serum miR-503 level in GC was inversely correlated with carcinoembryonic antigen (CEA) (r=-0.624, P<0.001). Furthermore, the area under the receiver operating characteristic curve for miR-503 discriminating GC patients from healthy individuals was 0.889 (P=0.006), with a sensitivity of 96.8% and a specificity of 79.4%, higher than that of CEA (area under the receiver operating characteristic curve =0.681, P=0.048). CONCLUSION: The present study suggests that the expression level of miR 503 may serve as prognostic and diagnostic biomarker for GC. PMID- 28096683 TI - Clinicopathological and immunohistochemical features of lung invasive mucinous adenocarcinoma based on computed tomography findings. AB - BACKGROUND: We performed an analysis to clarify differences in clinicopathological and molecular features of lung invasive mucinous adenocarcinoma (IMA) based on computed tomography (CT) findings and their impact on prognosis. PATIENTS AND METHODS: On the basis of CT findings, we divided lung IMA into three subtypes: solid, bubbling, and pneumonic. We then investigated differences in clinicopathological characteristics, prognosis, and the expressions of well-identified biomarkers, including cyclooxygenase-2 (Cox-2), excision repair cross-complementation group 1 (ERCC1), ribonucleotide reductase M1 (RRM1), class III beta-tubulin, thymidylate synthase (TS), secreted protein acidic and rich in cysteine (SPARC), programmed cell death-1 ligand-1 (PD-L1), and epidermal growth factor receptor mutation, among the three subtypes. RESULTS: A total of 29 patients with resected lung IMA were analyzed. Compared with the solid or bubbling type, the pneumonic type had a higher proportion of symptoms, a larger tumor size, a higher pathological stage, and a significantly worse prognosis. The immunohistochemical findings tended to show high expression of RRM1, class III beta-tubulin, and Cox-2 in the tumor and of SPARC in the stroma, but not of ERCC1, TS, and PD-L1 in the tumor. None of the biomarkers with high expression levels in the tumor were prognostic biomarkers, but the expression of SPARC in the stroma was correlated with a poor outcome. CONCLUSION: Clinical and pathological features, in conjunction with molecular data, indicate that IMA should be divided into different subgroups. In our results, the pneumonic type was correlated with a significantly worse outcome. Further studies should be performed to confirm our conclusion and to explore its molecular implications. PMID- 28096685 TI - The role of microRNA-21 in predicting brain metastases from non-small cell lung cancer. AB - OBJECTIVE: This study aimed at exploring the role of microRNA-21 (miR-21) in predicting brain metastases (BM) from non-small cell lung cancer (NSCLC). METHODS: A total of 132 NSCLC patients, including 68 patients with BM and 64 patients without BM, were included in the study. NSCLC cells were collected and assigned to the inhibitor (IN) group, the mock group, and the negative control (NC) group. The quantitative real-time polymerase chain reaction assay was used to detect the miR-21 expression. Cell proliferation, migration, invasion, and apoptosis were detected by colony-forming assay, MTT assay, transwell assay, and flow cytometry, respectively. Angiogenesis was measured by endothelial cell tube formation assay. RESULTS: The miR-21 expression was higher in NSCLC patients with BM than in those without BM. The miR-21 expression in the IN group was lower than that in the NC and mock groups. Compared with the NC and mock groups, the values of optical density (OD) and the colony-forming number decreased in the IN group. Compared with the NC and mock groups, cell invasion and migration abilities significantly reduced in the IN group. The IN group had higher apoptosis rate than the NC and mock groups. The tube length was shorter and the number of junction points was less in the IN group in comparison to the NC and mock groups. CONCLUSION: miR-21 might be a potential biomarker for the development of BM in NSCLC patients and could promote the proliferation, migration, invasion, and angiogenesis of NSCLC cells. PMID- 28096684 TI - Pediatric papillary thyroid cancer: current management challenges. AB - Although with a standardized incidence of 0.54 cases per 100,000 persons, differentiated thyroid cancer (DTC) is a rare disease in children and adolescents, it nonetheless concerns ~1.4% of all pediatric malignancies. Furthermore, its incidence is rising. Due to the rarity and long survival of pediatric DTC patients, in most areas of treatment little evidence exists. Treatment of pediatric DTC is therefore littered with controversies, many questions therefore remain open regarding the optimal management of pediatric papillary thyroid cancer (PTC), and many challenges remain unsolved. In the present review, we aim to provide an overview of these challenging areas of patient and disease management in pediatric PTC patients. Data on diagnosis, surgery, radionuclide, and endocrine therapy are discussed, and the controversies therein are highlighted. PMID- 28096686 TI - Peptide consensus sequence determination for the enhancement of the antimicrobial activity and selectivity of antimicrobial peptides. AB - The rise of multidrug-resistant bacteria is causing a serious threat to the world's human population. Recent reports have identified bacterial strains displaying pan drug resistance against antibiotics and generating fears among medical health specialists that humanity is on the dawn of entering a post antibiotics era. Global research is currently focused on expanding the lifetime of current antibiotics and the development of new antimicrobial agents to tackle the problem of antimicrobial resistance. In the present study, we designed a novel consensus peptide named "Pepcon" through peptide consensus sequence determination among members of a highly homologous group of scorpion antimicrobial peptides. Members of this group were found to possess moderate antimicrobial activity with significant toxicity against mammalian cells. The aim of our design method was to generate a novel peptide with an enhanced antimicrobial potency and selectivity against microbial rather than mammalian cells. The results of our study revealed that the consensus peptide displayed potent antibacterial activities against a broad range of Gram-positive and Gram negative bacteria. Our membrane permeation studies displayed that the peptide efficiently induced membrane damage and consequently led to cell death through the process of cell lysis. The microbial DNA binding assay of the peptide was found to be very weak suggesting that the peptide is not targeting the microbial DNA. Pepcon induced minimal cytotoxicity at the antimicrobial concentrations as the hemolytic activity was found to be zero at the minimal inhibitory concentrations (MICs). The results of our study demonstrate that the consensus peptide design strategy is efficient in generating peptides. PMID- 28096687 TI - Coaching and barriers to weight loss: an integrative review. AB - INTRODUCTION: Coaching is proposed to raise a patient's awareness and responsibility for their health behaviour change by transforming the professional patient relationship. OBJECTIVE: To review the scientific literature on how coaching can assist in weight loss and improve a patient's state of health. METHODOLOGY: An integrative literature search was performed using PubMed, Latin American and Caribbean Literature in Health Sciences, and Scientific Electronic Library Online. We selected articles that were published in Portuguese, English, and Spanish over the last 10 years. Data analysis was performed using a validated data collection instrument. RESULTS: Among the 289 articles identified in the search, 276 were excluded because they did not address the leading research question, their full texts were not available on the Internet, or they were duplicate publications. Therefore, for the analysis, we selected 13 articles that we classified as randomized clinical studies (46.15%; n=6), cohort studies (30.76%; n=4), cross-sectional studies (7.69%; n=1), case studies (7.69%; n=1), and review articles (7.69%; n=1). Joint intervention (combined in-person and telecoaching sessions) constituted the majority of session types. The use of technical coaching was superior in reducing anthropometric measurements and increasing the levels of motivation and personal satisfaction compared with formal health education alone. CONCLUSION: Coaching is an efficient, cost effective method for combining formal education and treatment of health in the weight-loss process. Additional randomized studies are needed to demonstrate its effectiveness with respect to chronic disease indicators. PMID- 28096688 TI - Extreme leukocytosis and leukemoid reaction associated with the lung sarcomatoid carcinoma: an unusual case report. AB - PURPOSE: To report a rare case of extreme leukocytosis and leukemoid reaction associated with lung sarcomatoid carcinoma (LSC) and increase people's awareness of the disease. PATIENTS AND METHODS: A 58-year-old male patient was diagnosed with LSC; however, after the end of the second course of chemotherapy, his white blood cells increased gradually without fever or use of medications such as granulocyte colony-stimulating factor and steroids. A bone marrow biopsy then confirmed it to be a leukemoid reaction. RESULTS: The patient died of multiple organ failure 2 months after being diagnosed with leukocytosis. CONCLUSION: LSC associated with leukemoid reaction is very rare and the prognosis is poor. When a patient's white blood cells are extremely elevated, we should think of the possible causes of the tumor itself and identify it with other diseases. However, more data and evidence are still needed to find an effective adjuvant therapy for these patients. PMID- 28096689 TI - Influence of exercise on visceral pain: an explorative study in healthy volunteers. AB - BACKGROUND AND OBJECTIVES: Contradictory results have been found about the effect of different exercise modalities on pain. The aim of this study was to investigate the early effects of aerobic and isometric exercise on different types of experimental pain, including visceral pain, compared to an active control condition. METHODS: Fifteen healthy subjects (6 women, mean [standard deviation] age 25 [6.5] years) completed 3 interventions consisting of 20 minutes of aerobic cycling, 12 minutes of isometric knee extension and a deep breathing procedure as active control. At baseline and after each intervention, psychophysical tests were performed, including electrical stimulation of the esophagus, pressure pain thresholds and the cold pressor test as a measure for conditioned pain modulation. Participants completed the Medical Outcome Study Short-Form 36 and State-Trait Anxiety Inventory prior to the experiments. Data were analyzed using two-way repeated measures analysis of variance. RESULTS: No significant differences were found for the psychophysical tests after the interventions, compared to baseline pain tests and the control condition. CONCLUSION: No hypoalgesic effect of aerobic and isometric exercise was found. The evidence for exercise-induced hypoalgesia appears to be not as consistent as initially thought, and caution is recommended when interpreting the effects of exercise on pain. PMID- 28096690 TI - The relationship between findings on magnetic resonance imaging and previous history of low back pain. AB - The objective of this study was to evaluate the relationship between magnetic resonance imaging (MRI) findings and previous low back pain (LBP) in participants without current LBP. Current LBP was defined as LBP during the past month. Previous LBP was defined as a history of medical consultation for LBP. Ninety-one participants without current LBP were included. Sagittal T2-weighted MRI was used to assess the intervertebral space from T12/L1 to L5/S1. These images were classified into five grades based on the Pfirrmann grading system. Furthermore, we evaluated the presence of disk bulging, high-intensity zone, and spondylolisthesis. We compared the MRI findings between groups with (27 participants) and without (64 participants) previous LBP without current LBP. Intraobserver and interobserver kappa values were evaluated. Participants had an average age of 34.9 years; 47 were female and 44 were male; and their average body mass index was 21.8 kg/m2. Compared to the group of participants without previous LBP, the group of participants with previous LBP had a significantly higher incidence of disk degeneration such as a Pfirrmann grade >=3, disk bulging, and high-intensity zone in the analyses adjusted by age and sex. There were no significant differences in spondylolisthesis between the groups. An odds ratio of >10 was only found for Pfirrmann grade >=3, ie, a Pfirrmann grade >=3 was strongly associated with a history of previous LBP in participants without current LBP. PMID- 28096691 TI - Pain acceptance potentially mediates the relationship between pain catastrophizing and post-surgery outcomes among compensated lumbar fusion patients. AB - PURPOSE: Chronic low back pain is highly prevalent and often treatment recalcitrant condition, particularly among workers' compensation patients. There is a need to identify psychological factors that may predispose such patients to pain chronicity. The primary aim of this study was to examine whether pain acceptance potentially mediated the relationship between pain catastrophizing and post-surgical outcomes in a sample of compensated lumbar fusion patients. PATIENTS AND METHODS: Patients insured with the Workers Compensation Fund of Utah and who were at least 2 years post-lumbar fusion surgery completed an outcome survey. These data were obtained from a prior retrospective-cohort study that administered measures of pain catastrophizing, pain acceptance, mental and physical health, and disability. RESULTS: Of the 101 patients who completed the outcome survey, 75.2% were male with a mean age of 42.42 years and predominantly identified as White (97.0%). The majority of the participants had a posterior lumbar interbody fusion surgery. Pain acceptance, including activity engagement and pain willingness, was significantly correlated with better physical health and mental health, and lower disability rates. Pain catastrophizing was inversely correlated with measures of pain acceptance (activity engagement r=-0.67, p<0.01, pain willingness r=-0.73, p<0.01) as well as the outcome measures: mental health, physical health, and disability. Pain acceptance significantly mediated the relationship between pain catastrophizing and both mental and physical health and also the relationship between pain catastrophizing and disability. CONCLUSION: This study demonstrated that the relationship between pain catastrophizing and negative patient outcomes was potentially mediated by pain acceptance. Understanding this mediating relationship offers insight into how pain acceptance may play a protective role in patients' pain and disability and has potential implications for pain treatments. PMID- 28096692 TI - Huge Left Atrial Myxoma and Concomitant Silent Coronary Artery Disease in a Young Man. AB - Severe but silent coronary artery disease may rarely exist in young patients with a low-risk profile but with a family history of coronary artery disease. We describe the case of a 33-year-old Caucasian male with progressive shortness of breath caused by a huge left atrial myxoma who was diagnosed to have significant coronary artery disease in the preoperative assessment. After investigations, the patient underwent resection of the left atrial tumor and coronary artery bypass grafting (CABG) with a successful outcome. Even in the case of a young male, it may be prudent to investigate silent coronary artery disease in the presence of cardiovascular risk factors and family history of coronary artery disease. The learning objective of this case is to debate about the usefulness of a preoperative coronary study even in the young population with cardiac nonischemic pathologies (ie, valve pathology, cardiac tumors, etc.). PMID- 28096693 TI - Gastric and colon metastasis from breast cancer: case report, review of the literature, and possible underlying mechanisms. AB - Gastrointestinal metastases from breast cancer are not common. We present a 58 year-old female diagnosed with lobular breast cancer some years before whose relapses were gastric and colonic mucosal. Simultaneous metastases are extremely rare. To our knowledge, no cases of initial dual affectation have been reported. The patient also showed gastritis by Helicobacter pylori. Invasive lobular breast carcinoma is the most frequent special type of breast cancer and carries some specific molecular alterations such as loss of expression of E-cadherin. Although underlying mechanisms of metastasization are not entirely known, chemokines as well as inflammatory events seem to be implicated in this process. Interaction between chemokines and their receptors frequently induces cell migration. We hypothesize that H. pylori, inflammatory cells, and chemokines may create a favorable environment attracting tumor cells. PMID- 28096694 TI - Luteolin inhibits lung metastasis, cell migration, and viability of triple negative breast cancer cells. AB - Most breast cancer-related deaths from triple-negative breast cancer (TNBC) occur following metastasis of cancer cells and development of tumors at secondary sites. Because TNBCs lack the three receptors targeted by current chemotherapeutic regimens, they are typically treated with extremely aggressive and highly toxic non-targeted treatment strategies. Women with TNBC frequently develop metastatic lesions originating from drug-resistant residual cells and have poor prognosis. For this reason, novel therapeutic strategies that are safer and more effective are sought. Luteolin (LU) is a naturally occurring, non-toxic plant compound that has proven effective against several types of cancer. With this in mind, we conducted in vivo and in vitro studies to determine whether LU might suppress metastasis of TNBC. In an in vivo mouse metastasis model, LU suppressed metastasis of human MDA-MB-435 and MDA-MB-231 (4175) LM2 TNBC cells to the lungs. In in vitro assays, LU inhibited cell migration and viability of MDA MB-435 and MDA-MB-231 (4175) LM2 cells. Further, LU induced apoptosis in MDA-MB 231 (4175) LM2 cells. Relatively low levels (10 uM) of LU significantly inhibited vascular endothelial growth factor (VEGF) secretion in MDA-MB-231 (4175) LM2 cells, suggesting that it has the ability to suppress a potent angiogenic and cell survival factor. In addition, migration of MDA-MB-231 (4175) LM2 cells was inhibited upon exposure to an antibody against the VEGF receptor, KDR, but not by exposure to a VEGF165 antibody. Collectively, these data suggest that the anti metastatic properties of LU may, in part, be due to its ability to block VEGF production and KDR-mediated activity, thereby inhibiting tumor cell migration. These studies suggest that LU deserves further investigation as a potential treatment option for women with TNBC. PMID- 28096695 TI - Hysterosalpingo-foam sonography: patient selection and perspectives. AB - We present an overview of the common types of tubal patency tests, with a focus on hysterosalpingo-foam sonography (HyFoSy). Current evidence suggests that HyFoSy is an accurate alternative to X-ray hysterosalpingography (HSG) for outpatient tubal evaluation in women who are at low risk for tubal disease. It may be superior to saline hysterosalpingo-contrast sonography (HyCoSy) in excluding tubal occlusion. A hyperechogenic medium may enhance contrast visualization and enable clearer delineation of tubal anatomy. This may enhance confidence in the diagnosis of tubal patency, reduce false occlusion results, and improve the diagnostic yield of the test. It would be reasonable to deduce that HyFoSy would have similar performance characteristics as HyCoSy with other positive contrast agents. The available evidence supports the accuracy of HyFoSy compared to other forms of tubal investigation. We suggest a decision-making pathway based on the most current professional recommendations and available evidence. However, in this article, we do not provide a definitive exposition of the methods used for investigating tubal patency. Rather, we explore the contexts in which the various investigations are most and least suitable, and identify their strengths and limitations. Finally, we also discuss challenges encountered when performing tubal contrast sonography in clinical practice, including the problem of false occlusion results. PMID- 28096696 TI - Tidal breathing patterns derived from structured light plethysmography in COPD patients compared with healthy subjects. AB - PURPOSE: Differences in tidal breathing patterns have been reported between patients with chronic obstructive pulmonary disease (COPD) and healthy individuals using traditional measurement techniques. This feasibility study examined whether structured light plethysmography (SLP) - a noncontact, light based technique - could also detect differences in tidal breathing patterns between patients with COPD and healthy subjects. PATIENTS AND METHODS: A 5 min period of tidal (quiet) breathing was recorded in each patient with COPD (n=31) and each healthy subject (n=31), matched for age, body mass index, and sex. For every participant, the median and interquartile range (IQR; denoting within subject variability) of 12 tidal breathing parameters were calculated. Individual data were then combined by cohort and summarized by its median and IQR. RESULTS: After correction for multiple comparisons, inspiratory time (median tI) and its variability (IQR of tI) were lower in patients with COPD (p<0.001 and p<0.01, respectively) as were ratios derived from tI (tI/tE and tI/tTot, both p<0.01) and their variability (p<0.01 and p<0.05, respectively). IE50SLP (the ratio of inspiratory to expiratory flow at 50% tidal volume calculated from the SLP signal) was higher (p<0.001) in COPD while SLP-derived time to reach peak tidal expiratory flow over expiratory time (median tPTEFSLP/tE) was shorter (p<0.01) and considerably less variable (p<0.001). Thoraco-abdominal asynchrony was increased (p<0.05) in COPD. CONCLUSION: These early observations suggest that, like traditional techniques, SLP is able to detect different breathing patterns in COPD patients compared with subjects with no respiratory disease. This provides support for further investigation into the potential uses of SLP in assessing clinical conditions and interventions. PMID- 28096697 TI - miR-486-3p, miR-139-5p, and miR-21 as Biomarkers for the Detection of Oral Tongue Squamous Cell Carcinoma. AB - Oral tongue squamous cell carcinoma (TSCC) is a complex disease with extensive genetic and epigenetic defects, including microRNA deregulation. The aims of the present study were to test the feasibility of performing the microRNA profiling analysis on archived TSCC specimens and to assess the potential diagnostic utility of the identified microRNA biomarkers for the detection of TSCC. TaqMan array-based microRNA profiling analysis was performed on 10 archived TSCC samples and their matching normal tissues. A panel of 12 differentially expressed microRNAs was identified. Eight of these differentially expressed microRNAs were validated in an independent sample set. A random forest (RF) classification model was built with miR-486-3p, miR-139-5p, and miR-21, and it was able to detect TSCC with a sensitivity of 100% and a specificity of 86.7% (overall error rate = 6.7%). As such, this study demonstrated the utility of the archived clinical specimens for microRNA biomarker discovery. The feasibility of using microRNA biomarkers (miR-486-3p, miR-139-5p, and miR-21) for the detection of TSCC was confirmed. PMID- 28096699 TI - The Major Role of IK1 in Mechanisms of Rotor Drift in the Atria: A Computational Study. AB - Maintenance of paroxysmal atrial fibrillation (AF) by fast rotors in the left atrium (LA) or at the pulmonary veins (PVs) is not fully understood. This review describes the role of the heterogeneous distribution of transmembrane currents in the PVs and LA junction (PV-LAJ) in the localization of rotors in the PVs. Experimentally observed heterogeneities in IK1, IKs, IKr, Ito, and ICaL in the PV LAJ were incorporated into models of human atrial kinetics to simulate various conditions and investigate rotor drifting mechanisms. Spatial gradients in the currents resulted in shorter action potential duration, less negative minimum diastolic potential, slower upstroke and conduction velocity for rotors in the PV region than in the LA. Rotors under such conditions drifted toward the PV and stabilized at the less excitable region. Our simulations suggest that IK1 heterogeneity is dominant in determining the drift direction through its impact on the excitability gradient. These results provide a novel framework for understanding the complex dynamics of rotors in AF. PMID- 28096698 TI - Burkitt lymphoma in adolescents and young adults: management challenges. AB - About one-half of all Burkitt lymphoma (BL) patients are younger than 40 years, and one-third belong to the adolescent and young adult (AYA) subset, defined by an age between 15 and 25-40 years, based on selection criteria used in different reports. BL is an aggressive B-cell neoplasm displaying highly characteristic clinico-diagnostic features, the biologic hallmark of which is a translocation involving immunoglobulin and c-MYC genes. It presents as sporadic, endemic, or epidemic disease. Endemicity is pathogenetically linked to an imbalance of the immune system which occurs in African children infected by malaria parasites and Epstein-Barr virus, while the epidemic form strictly follows the pattern of infection by HIV. BL shows propensity to extranodal involvement of abdominal organs, bone marrow, and central nervous system, and can cause severe metabolic and renal impairment. Nevertheless, BL is highly responsive to specifically designed short-intensive, rotational multiagent chemotherapy programs, empowered by the anti-CD20 monoclonal antibody rituximab. When carefully applied with appropriate supportive measures, these modern programs achieve a cure rate of approximately 90% in the average AYA patient, irrespective of clinical stage, which is the best result achievable in any aggressive lymphoid malignancy to date. The challenges ahead concern the following: optimization of management in underdeveloped countries, with reduction of diagnostic and referral-for-care intervals, and the applicability of currently curative regimens; the development of lower intensity but equally effective treatments for frail or immunocompromised patients at risk of death by complications; the identification of very high-risk patients through positron-emission tomography and minimal residual disease assays; and the assessment in these and the few refractory/relapsed ones of new monoclonals (ofatumumab, blinatumomab, inotuzumab ozogamicin) and new molecules targeting c-MYC and key proliferative steps of B cell malignancies. PMID- 28096700 TI - Sequential Combination Chemotherapy of Dacarbazine (DTIC) with Carboplatin and Paclitaxel for Patients with Metastatic Mucosal Melanoma of Nasal Cavity and Paranasal Sinuses. AB - By the recent introduction of molecular targeting drugs against BRAF mutation and immune checkpoint inhibitors, the prognosis of patients with melanoma in advanced stage is now improving, but still in the minority. Mucosal melanoma lacks the BRAF mutations, and hence conventional chemotherapeutic regimens must be improved. We have conventionally used dacarbazine (DTIC) for patients with metastatic mucosal melanoma. However, the efficacy of DTIC in patients with metastatic mucosal melanoma has been limited. Therefore, we explored other possibilities to improve the prognosis of patients suffering from metastatic mucosal melanoma. In this communication, we present a retrospective analysis of the sequential combination chemotherapy of DTIC with carboplatin and paclitaxel (CP) for metastatic mucosal melanoma of nasal cavity and paranasal sinuses. The objective response rate of seven patients is 14.3% by RECIST 1.1 and the overall survival (OS) is 12.5 months. These data indicate that the sequential combination chemotherapy of DTIC with CP could be an option for patients with metastatic mucosal melanoma of nasal cavity and paranasal sinuses who are currently ending into dismal prognosis. PMID- 28096701 TI - Metreleptin Treatment in Three Patients with Generalized Lipodystrophy. AB - Generalized lipodystrophy (GL) is a rare inherited or acquired disease characterized by widespread loss of subcutaneous fat, leading to leptin deficiency, ectopic fat deposition, and severe metabolic abnormalities. Previous studies have shown the benefit of leptin replacement (metreleptin) in ameliorating metabolic complications, but little is known about the experience of metreleptin treatment outside of a research setting. We report on post-marketing clinical experience with metreleptin therapy in three patients with GL and marked hypoleptinemia, uncontrolled diabetes, and hypertriglyceridemia. After metreleptin treatment for 12-168 weeks, the mean glycated hemoglobin decreased from 10.9% to 5.8%, and serum triglycerides were normalized (a mean decline of 90%). These benefits were observed within weeks of starting therapy, were durable, and were accompanied by subjective improvements in quality of life, decreased need for concomitant medications, and no significant adverse effects. Metreleptin was safe and effective in normalizing certain severe metabolic abnormalities in the clinic setting. PMID- 28096702 TI - Early Benefits of a Starter Formula Enriched in Prebiotics and Probiotics on the Gut Microbiota of Healthy Infants Born to HIV+ Mothers: A Randomized Double-Blind Controlled Trial. AB - The gut microbiota of infants is shaped by both the mode of delivery and the type of feeding. The gut of vaginally and cesarean-delivered infants is colonized at different rates and with different bacterial species, leading to differences in the gut microbial composition, which may persist up to 6 months. In a multicenter, randomized, controlled, double-blind trial conducted in South Africa, we tested the effect of a formula supplemented with a prebiotic (a mixture of bovine milk-derived oligosaccharides [BMOS] generated from whey permeate and containing galactooligosaccharides and milk oligosaccharides such as 3'- and 6'-sialyllactose) and the probiotic Bifidobacterium animalis subsp. lactis (B. lactis) strain CNCM I-3446 on the bifidobacteria levels in the gut of infants born vaginally or via cesarean section in early life. Additionally, the safety of the new formulation was evaluated. A total of 430 healthy, full-term infants born to HIV-positive mothers who had elected to feed their child beginning from birth (<=3 days old) exclusively with formula were randomized into this multicenter trial of four parallel groups. A total of 421 infants who had any study formula intake were included in the full analysis set (FAS). The first two groups consisted of cesarean-delivered infants assigned to the Test formula (n = 92) (a starter infant formula [IF] containing BMOS at a total oligosaccharide concentration of 5.8 +/- 1.0 g/100 g of powder formula [8 g/L in the reconstituted formula] + B. lactis [1 * 107 colony-forming units {cfu}/g]) or a Control IF (n = 101); the second two groups consisted of vaginally delivered infants randomized to the same Test (n = 115) or Control (n = 113) formulas from the time of enrollment to 6 months. The primary efficacy outcome was fecal bifidobacteria count at 10 days, and the primary safety outcome was daily weight gain (g/d) between 10 days and 4 months. At 10 days, fecal bifidobacteria counts were significantly higher in the Test formula than in the Control formula group among infants with cesarean birth (median [range] log: 9.41 [6.30-10.94] cfu/g versus 6.30 [6.30-10.51] cfu/g; P = 0.002) but not among those with vaginal birth (median [range] log: 10.06 [5.93-10.77] cfu/g versus 9.85 [6.15-10.79] cfu/g; P = 0.126). The lower bound of the two-sided 95% confidence interval of the difference in the mean daily weight gain between the Test and Control formula groups was more than -3 g/d in both the vaginally and cesarean-delivered infants, indicating that growth in the Test formula-fed infants was not inferior to that of Control formula-fed infants. At 10 days and 4 weeks, the fecal pH of infants fed the Test formula was significantly lower than in those fed the Control formula, irrespective of mode of delivery: for vaginal delivery: 4.93 versus 5.59; P < 0.001 (10 days) and 5.01 versus 5.71; P < 0.001 (4 weeks); for cesarean delivery: 5.14 versus 5.65, P = 0.009 (10 days) and 5.06 versus 5.75, P < 0.001 (4 weeks). At 3 months, this acidification effect only persisted among cesarean born infants. IF supplemented with the prebiotic BMOS and probiotic B. lactis induced a strong bifidogenic effect in both delivering modes, but more explicitly correcting the low bifidobacteria level found in cesarean-born infants from birth. The supplemented IF lowered the fecal pH and improved the fecal microbiota in both normal and cesarean-delivered infants. The use of bifidobacteria as a probiotic even in infants who are immunologically at risk is safe and well tolerated. PMID- 28096703 TI - Progesterone for Luteal Phase Support in In Vitro Fertilization: Comparison of Vaginal and Rectal Pessaries to Vaginal Capsules: A Randomized Controlled Study. AB - BACKGROUND: In IVF, Luteal phase support is usually performed using vaginal progesterone. A part of patients using this route reports being uncomfortable with this route. We tried to study whether the rectal route could be an effective alternative and associated with less discomfort. PATIENTS AND METHODS: A prospective randomized controlled study. All patient were eligible for IVF treatment for infertility. After oocyte pickup, 186 patients were allocated to one the following protocols for luteal phase support: (i) rectal pessaries group: natural progesterone pessaries administered rectally 200 mg three times a day, (ii) vaginal pessaries group: natural progesterone pessaries administered vaginally 200 mg three times a day), and (iii) vaginal capsules group: natural micronized progesterone capsules administered vaginally 200 mg three times a day. On the day of pregnancy test, patients were asked to fill in a questionnaire conducted by an investigator in order to assess the tolerability and side effects of the LPS treatment taken. The primary endpoint was the occurrence of perineal irritation. RESULTS: Fifty eight patients were assigned to the rectal pessaries group, 68 patients to the vaginal pessaries group, and 60 patients to the vaginal capsules group. All patients adhered to their allocated treatment. Implantation and clinical pregnancy rates per transfer did not differ between the three groups. Perineal irritation, which was our primary endpoint, was the same for all the three groups (respectively 1.7 % versus 5.9 % versus 11.7%). Regarding the other side effects, more patients experienced constipation and flatulence with the rectal route, whereas more patients reported vaginal discharge in the vaginal capsules group. CONCLUSION: Rectal administration for luteal phase support is effective and well accepted alternative to vaginal route. PMID- 28096704 TI - Neonatal resuscitation: advances in training and practice. AB - Each year in the US, some four hundred thousand newborns need help breathing when they are born. Due to the frequent need for resuscitation at birth, it is vital to have evidence-based care guidelines and to provide effective neonatal resuscitation training. Every five years, the International Liaison Committee on Resuscitation (ILCOR) reviews the science of neonatal resuscitation. In the US, the American Heart Association (AHA) develops treatment guidelines based on the ILCOR science review, and the Neonatal Resuscitation Program (NRP) translates the AHA guidelines into an educational curriculum. In this report, we review recent advances in neonatal resuscitation training and practice. We begin with a review of the new 7th edition NRP training curriculum. Then, we examine key changes to the 2015 AHA neonatal resuscitation guidelines. The four components of the NRP curriculum reviewed here include eSim(r), Performance Skills Stations, Integrated Skills Station, and Simulation and Debriefing. The key changes to the AHA neonatal resuscitation guidelines reviewed include initial steps of newborn care, positive-pressure ventilation, endotracheal intubation and use of laryngeal mask, chest compressions, medications, resuscitation of preterm newborns, and ethics and end-of-life care. We hope this report provides a succinct review of recent advances in neonatal resuscitation. PMID- 28096705 TI - Situational judgment tests reliably measure professional attributes important for clinical practice. AB - Over the course of more than 40 years, international research has consistently shown situational judgment tests (SJTs) to be a reliable and valid selection method for assessing a range of professional attributes. However, SJTs still represent a relatively new selection method within the medical profession, and as such it is to be expected that applicant reactions will vary. In this Expert Opinion piece, we respond to Najim et al's article "The situational judgement test: a student's worst nightmare" by highlighting three key clarifications. We outline that 1) the UK Foundation Programme's SJT deliberately measures only a subset (five) of the nine professional attributes important for the role of Foundation Trainee doctor, 2) these attributes are measured in addition to academic attainment, and 3) the SJT represents a cost-effective approach to selection rather than attempting to interview approximately 8,000 candidates each year, which would be logistically impossible. We present these points to inform future research and encourage debate, and conclude that the SJT is an appropriate and fair measurement method to be used as one part of selection to the UK Foundation Programme. PMID- 28096706 TI - Balancing standardized testing with personalized training in surgery. AB - Students pursuing a medical career in the US are subject to standardized testing at regular intervals. These standardized tests not only quantify the milestones students have already achieved, but also define the path for future achievements. The purpose of these examinations is to help students become self-directed, lifelong learners - an essential attribute of a medical professional. However, whether preparing for these examinations actually makes students such disciplined learners needs to be examined. Especially during residency training with its limited time and unpredictable exposure, trainees must learn in the most efficient way for their learning styles, and thus develop attributes that will be helpful to them in their medical career. In this review, we propose that a personalized, learner-centered approach tailored to residents' educational needs and preferences can not only fulfill learning interests and objectives but also serve as a time-efficient and cost-effective approach for graduate medical education. PMID- 28096707 TI - Simulation-based medical education to improve intrinsic motivation in medical students. PMID- 28096708 TI - Evaluating medical students' proficiency with a handheld ophthalmoscope: a pilot study. AB - INTRODUCTION: Historically, testing medical students' skills using a handheld ophthalmoscope has been difficult to do objectively. Many programs train students using plastic models of the eye which are a very limited fidelity simulator of a real human eye. This makes it difficult to be sure that actual proficiency is attained given the differences between the various models and actual patients. The purpose of this article is to introduce a method of testing where a medical student must match a patient with his/her fundus photo, ensuring objective evaluation as well as developing skills on real patients which are more likely to transfer into clinical practice directly. PRESENTATION OF CASE: Fundus photos from standardized patients (SPs) were obtained using a retinal camera and placed into a grid using proprietary software. Medical students were then asked to examine a SP and attempt to match the patient to his/her fundus photo in the grid. RESULTS: Of the 33 medical students tested, only 10 were able to match the SP's eye to the correct photo in the grid. The average time to correct selection was 175 seconds, and the successful students rated their confidence level at 27.5% (average). The incorrect selection took less time, averaging 118 seconds, yet yielded a higher student-reported confidence level at 34.8% (average). The only noteworthy predictor of success (p<0.05) was the student's age (p=0.02). CONCLUSION: It may be determined that there is an apparent gap in the ophthalmoscopy training of the students tested. It may also be of concern that students who selected the incorrect photo were more confident in their selections than students who chose the correct photo. More training may be necessary to close this gap, and future studies should attempt to establish continuing protocols in multiple centers. PMID- 28096709 TI - Communication pitfalls of traditional history and physical write-up documentation. AB - BACKGROUND: An unofficial standardized "write-up" outline is commonly used for documenting history and physical examinations, giving oral presentations, and teaching clinical skills. Despite general acceptance, there is an apparent discrepancy between the way clinical encounters are conducted and how they are documented. METHODS: Fifteen medical school websites were randomly selected from search-engine generated lists. One example of a history and physical write-up from each of six sites, one teaching outline from each of nine additional sites, and recommendations for documentation made in two commonly used textbooks were compared for similarities and differences. RESULTS: Except for minor variations in documenting background information, all sampled materials utilized the same standardized format. When the examiners' early perceptions of the patients' degree of illness or level of distress were described, they were categorized as "general appearance" within the physical findings. Contrary to clinical practice, none of the examples or recommendations documented these early perceptions before chief concerns and history were presented. DISCUSSION: An examiner's initial perceptions of a patient's affect, degree of illness, and level of distress can influence the content of the history, triage decisions, and prioritization of likely diagnoses. When chief concerns and history are shared without benefit of this information, erroneous assumptions and miscommunications can result. CONCLUSION: This survey confirms common use of a standardized outline for documenting, communicating, and teaching history-taking and physical examination protocol. The present outline shares early observations out of clinical sequence and may provide inadequate context for accurate interpretation of chief concerns and history. Corrective actions include modifying the documentation sequence to conform to clinical practice and teaching contextual methodology for sharing patient information. PMID- 28096710 TI - Navigating Uncertainty: Health Professionals' Knowledge, Skill, and Confidence in Assessing and Managing Pain in Children with Profound Cognitive Impairment. AB - There is limited evidence to underpin the assessment and management of pain in children with profound cognitive impairment and these children are vulnerable to poor pain assessment and management. Health professionals working with children with profound cognitive impairment from a single paediatric tertiary referral centre in England were interviewed to explore how they develop and acquire knowledge and skills to assess and manage pain in children with cognitive impairment. The interviews were transcribed and subjected to thematic analysis. Nineteen health professionals representing different professional groups and different levels of experience participated in the study. A metatheme "navigating uncertainty; deficits in knowledge and skills" and two core themes "framing as different and teasing things out" and "the settling and unsettling presence of parents" were identified. Uncertainty about aspects of assessing and managing the pain of children with cognitive impairment tended to erode professional confidence and many discussed deficits in their skill and knowledge set. Uncertainty was managed through engaging with other health professionals and the child's parents. Most health professionals stated they would welcome more education and training although many felt that this input should be clinical and not classroom oriented. PMID- 28096711 TI - Effectiveness of High Intensity Laser Therapy for Reduction of Pain in Knee Osteoarthritis. AB - Introduction. Osteoarthritis is the most common type of arthritis. It is the main cause of chronic musculoskeletal pain and disability among the elderly population. Aim. This is a pilot, randomized clinical study about the effect of high intensity laser therapy in patients with osteoarthritis of the knee (OA of the knee). Material and Method. 72 patients (aged between 39 and 83 years) with (clinically and radiographically proved) OA of the knee were included in the study. They were randomized in two groups: therapeutic (test) one (n = 37, 65,11 +/- 1,40 (mean +/- SD) years old; patients were treated with HILT) and control group (n = 35, 64,71 +/- 1,98; patients receive sham laser). Both groups had seven sessions of treatment. VAS and dolorimetry were used for assessment of pain before and after the therapy. Pedobarometric analysis (static and dynamic) was used to assess comparatively the contact surface area and maximum pressure under the heel. Results. Pain levels measured by VAS and dolorimetry decreased significantly in the therapeutic group after seven days of treatment (p< 0,001). Conclusion. The results after seven days of treatment show more intensive and cumulative effect after the application of high intensity laser therapy in comparison to sham laser. This is the reason why HILT can be a method of choice in the treatment of gonarthrosis. PMID- 28096713 TI - Expanding Horizons in Cancer Imaging. PMID- 28096714 TI - Evolving Cancer Classification in the Era of Personalized Medicine: A Primer for Radiologists. AB - Traditionally tumors were classified based on anatomic location but now specific genetic mutations in cancers are leading to treatment of tumors with molecular targeted therapies. This has led to a paradigm shift in the classification and treatment of cancer. Tumors treated with molecular targeted therapies often show morphological changes rather than change in size and are associated with class specific and drug specific toxicities, different from those encountered with conventional chemotherapeutic agents. It is important for the radiologists to be familiar with the new cancer classification and the various treatment strategies employed, in order to effectively communicate and participate in the multi disciplinary care. In this paper we will focus on lung cancer as a prototype of the new molecular classification. PMID- 28096715 TI - Radiology Consultation in the Era of Precision Oncology: A Review of Consultation Models and Services in the Tertiary Setting. AB - The purpose of the article is to describe the various radiology consultation models in the Era of Precision Medicine. Since the inception of our specialty, radiologists have served as consultants to physicians of various disciplines. A variety of radiology consultation services have been described in the literature, including clinical decision support, patient-centric, subspecialty interpretation, and/or some combination of these. In oncology care in particular, case complexity often merits open dialogue with clinical providers. To explore the utility and impact of radiology consultation services in the academic setting, this article will further describe existing consultation models and the circumstances that precipitated their development. The hybrid model successful at our tertiary cancer center is discussed. In addition, the contributions of a consultant radiologist in breast cancer care are reviewed as the archetype of radiology consultation services provided to oncology practitioners. PMID- 28096716 TI - Molecular Targeted Therapy in Modern Oncology: Imaging Assessment of Treatment Response and Toxicities. AB - Oncology is a rapidly evolving field with a shift toward personalized cancer treatment. The use of therapies targeted to the molecular features of individual tumors and the tumor microenvironment has become much more common. In this review, anti-angiogenic and other molecular targeted therapies are discussed, with a focus on typical and atypical response patterns and imaging manifestations of drug toxicities. PMID- 28096717 TI - Immune-Checkpoint Inhibitors in the Era of Precision Medicine: What Radiologists Should Know. AB - Over the past five years immune-checkpoint inhibitors have dramatically changed the therapeutic landscape of advanced solid and hematologic malignancies. The currently approved immune-checkpoint inhibitors include antibodies to cytotoxic T lymphocyte antigen-4, programmed cell death (PD-1), and programmed cell death ligand (PD-L1 and PD-L2). Response to immune-checkpoint inhibitors is evaluated on imaging using the immune-related response criteria. Activation of immune system results in a unique toxicity profile termed immune-related adverse events. This article will review the molecular mechanism, clinical applications, imaging of immune-related response patterns and adverse events associated with immune checkpoint inhibitors. PMID- 28096718 TI - Diffuse Large B-Cell Lymphoma in the Era of Precision Oncology: How Imaging Is Helpful. AB - Diffuse large B cell lymphoma (DLBCL) is the most common histological subtype of Non-Hodgkin's lymphoma. As treatments continues to evolve, so do imaging strategies, and positron emission tomography (PET) has emerged as the most important imaging tool to guide oncologists in the diagnosis, staging, response assessment, relapse/recurrence detection,and therapeutic decision making of DLBCL. Other imaging modalities including magnetic resonance imaging (MRI), computed tomography (CT), ultrasound, and conventional radiography are also used in the evaluation of lymphoma. MRI is useful for nervous system and musculoskeletal system involvement and is emerging as a radiation free alternative to PET/CT. This article provides a comprehensive review of both the functional and morphological imaging modalities, available in the management of DLBCL. PMID- 28096719 TI - T-Cell Non-Hodgkin Lymphomas: Spectrum of Disease and the Role of Imaging in the Management of Common Subtypes. AB - T-cell non-Hodgkin lymphomas (NHLs) are biologically diverse, uncommon malignancies characterized by a spectrum of imaging findings according to subtype. The purpose of this review is to describe the common subtypes of T-cell NHL, highlight important differences between cutaneous, various peripheral and precursor subtypes, and summarize imaging features and the role of imaging in the management of this diverse set of diseases. PMID- 28096720 TI - Update on Gastrointestinal Stromal Tumors for Radiologists. AB - The management of gastrointestinal stromal tumors (GISTs) has evolved significantly in the last two decades due to better understanding of their biologic behavior as well as development of molecular targeted therapies. GISTs with exon 11 mutation respond to imatinib whereas GISTs with exon 9 or succinate dehydrogenase subunit mutations do not. Risk stratification models have enabled stratifying GISTs according to risk of recurrence and choosing patients who may benefit from adjuvant therapy. Assessing response to targeted therapies in GIST using conventional response criteria has several potential pitfalls leading to search for alternate response criteria based on changes in tumor attenuation, volume, metabolic and functional parameters. Surveillance of patients with GIST in the adjuvant setting is important for timely detection of recurrences. PMID- 28096721 TI - Current Concepts in Non-Gastrointestinal Stromal Tumor Soft Tissue Sarcomas: A Primer for Radiologists. AB - Non-gastrointestinal stromal tumor (GIST) soft tissue sarcomas (STSs) are a heterogeneous group of neoplasms whose classification and management continues to evolve with better understanding of their biologic behavior. The 2013 World Health Organization (WHO) has revised their classification based on new immunohistochemical and cytogenetic data. In this article, we will provide a brief overview of the revised WHO classification of soft tissue tumors, discuss in detail the radiology and management of the two most common adult non-GIST STS, namely liposarcoma and leiomyosarcoma, and review some of the emerging histology driven targeted therapies in non-GIST STS, focusing on the role of the radiologist. PMID- 28096722 TI - Evidence-Based Cancer Imaging. AB - With the advances in the field of oncology, imaging is increasingly used in the follow-up of cancer patients, leading to concerns about over-utilization. Therefore, it has become imperative to make imaging more evidence-based, efficient, cost-effective and equitable. This review explores the strategies and tools to make diagnostic imaging more evidence-based, mainly in the context of follow-up of cancer patients. PMID- 28096723 TI - Myocardial T1 and T2 Mapping: Techniques and Clinical Applications. AB - Cardiac magnetic resonance (CMR) imaging is widely used in various medical fields related to cardiovascular diseases. Rapid technological innovations in magnetic resonance imaging in recent times have resulted in the development of new techniques for CMR imaging. T1 and T2 image mapping sequences enable the direct quantification of T1, T2, and extracellular volume fraction (ECV) values of the myocardium, leading to the progressive integration of these sequences into routine CMR settings. Currently, T1, T2, and ECV values are being recognized as not only robust biomarkers for diagnosis of cardiomyopathies, but also predictive factors for treatment monitoring and prognosis. In this study, we have reviewed various T1 and T2 mapping sequence techniques and their clinical applications. PMID- 28096724 TI - Essential Items for Structured Reporting of Rectal Cancer MRI: 2016 Consensus Recommendation from the Korean Society of Abdominal Radiology. AB - High-resolution rectal MRI plays a crucial role in evaluating rectal cancer by providing multiple prognostic findings and imaging features that guide proper patient management. Quality reporting is critical for accurate effective communication of the information among multiple disciplines, for which a systematic structured approach is beneficial. Existing guides on reporting of rectal MRI are divergent on some issues, largely reflecting the differences in overall management of rectal cancer patients between the United States and Europe. The Korean Society of Abdominal Radiology (KSAR) study group for rectal cancer has developed an expert consensus recommendation regarding essential items for structured reporting of rectal cancer MRI using a modified Delphi method. This recommendation aims at presenting an up-to-date, evidence-based, practical, structured reporting template that can be readily adopted in daily clinical practice. In addition, a thorough explanation of the clinical and scientific rationale underlying the reporting items and their formats is provided. This KSAR recommendation may serve as a useful tool to help achieve more standardized optimal care for rectal cancer patients using rectal MRI. PMID- 28096725 TI - Added Value of Contrast-Enhanced Ultrasound on Biopsies of Focal Hepatic Lesions Invisible on Fusion Imaging Guidance. AB - OBJECTIVE: To assess whether contrast-enhanced ultrasonography (CEUS) with Sonazoid can improve the lesion conspicuity and feasibility of percutaneous biopsies for focal hepatic lesions invisible on fusion imaging of real-time ultrasonography (US) with computed tomography/magnetic resonance images, and evaluate its impact on clinical decision making. MATERIALS AND METHODS: The Institutional Review Board approved this retrospective study. Between June 2013 and January 2015, 711 US-guided percutaneous biopsies were performed for focal hepatic lesions. Biopsies were performed using CEUS for guidance if lesions were invisible on fusion imaging. We retrospectively evaluated the number of target lesions initially invisible on fusion imaging that became visible after applying CEUS, using a 4-point scale. Technical success rates of biopsies were evaluated based on histopathological results. In addition, the occurrence of changes in clinical decision making was assessed. RESULTS: Among 711 patients, 16 patients (2.3%) were included in the study. The median size of target lesions was 1.1 cm (range, 0.5-1.9 cm) in pre-procedural imaging. After CEUS, 15 of 16 (93.8%) focal hepatic lesions were visualized. The conspicuity score was significantly increased after adding CEUS, as compared to that on fusion imaging (p < 0.001). The technical success rate of biopsy was 87.6% (14/16). After biopsy, there were changes in clinical decision making for 11 of 16 patients (68.8%). CONCLUSION: The addition of CEUS could improve the conspicuity of focal hepatic lesions invisible on fusion imaging. This dual guidance using CEUS and fusion imaging may affect patient management via changes in clinical decision-making. PMID- 28096726 TI - Diffusion-Weighted MR Enterography to Monitor Bowel Inflammation after Medical Therapy in Crohn's Disease: A Prospective Longitudinal Study. AB - OBJECTIVE: To prospectively evaluate the performance of diffusion-weighted imaging (DWI) to monitor bowel inflammation after medical therapy for Crohn's disease (CD). MATERIALS AND METHODS: Before and following 1-2 years of medical therapy, between October 2012 and May 2015, 18 randomly selected adult CD patients (male:female, 13:5; mean age +/- SD, 25.8 +/- 7.9 years at the time of enrollment) prospectively underwent MR enterography (MRE) including DWI (b = 900 s/mm2) and ileocolonoscopy. Thirty-seven prospectively defined index lesions (one contiguous endoscopy-confirmed inflamed area chosen from each inflamed anatomical bowel segment; 1-4 index lesions per patient; median, 2 lesions) were assessed on pre- and post-treatment MRE and endoscopy. Visual assessment of treatment responses on DWI in 4 categories including complete remission and reduced, unchanged or increased inflammation, and measurements of changes in apparent diffusion coefficient (DeltaADC), i.e., pre-treatment-post-treatment, were performed by 2 independent readers. Endoscopic findings and CD MRI activity index (CDMI) obtained using conventional MRE served as reference standards. RESULTS: DeltaADC significantly differed between improved (i.e., complete remission and reduced inflammation) and unimproved (i.e., unchanged or increased inflammation) lesions: mean +/- SD (* 10-3 mm2/s) of -0.65 +/- 0.58 vs. 0.06 +/- 0.15 for reader 1 (p = 0.022) and -0.68 +/- 0.56 vs. 0.10 +/- 0.26 for reader 2 (p = 0.025). DWI accuracy for diagnosing complete remission or improved inflammation ranged from 76% (28/37) to 84% (31/37). A significant negative correlation was noted between DeltaADC and DeltaCDMI for both readers with correlation coefficients of -0.438 and -0.461, respectively (p < 0.05). CONCLUSION: DWI is potentially a feasible tool to monitor quantitatively and qualitatively bowel inflammation of CD after medical treatment. PMID- 28096727 TI - New Radiofrequency Device to Reduce Bleeding after Core Needle Biopsy: Experimental Study in a Porcine Liver Model. AB - OBJECTIVE: To evaluate the in vivo efficiency of the biopsy tract radiofrequency ablation for hemostasis after core biopsy of the liver in a porcine liver model, including situations with bleeding tendency and a larger (16-gauge) core needle. MATERIALS AND METHODS: A preliminary study was performed using one pig to determine optimal ablation parameters. For the main experiment, four pigs were assigned to different groups according to heparinization use and biopsy needle caliber. In each pig, 14 control (without tract ablation) and 14 experimental (tract ablation) ultrasound-guided core biopsies were performed using either an 18- or 16-gauge needle. Post-biopsy bleeding amounts were measured by soaking up the blood for five minutes. The results were compared using the Mann-Whitney U test. RESULTS: The optimal parameters for biopsy tract ablation were determined as a 2-cm active tip electrode set at 40-watt with a tip temperature of 70-80C. The bleeding amounts in all experimental groups were smaller than those in the controls; however they were significant in the non-heparinized pig biopsied with an 18-gauge needle and in two heparinized pigs (p < 0.001). In the heparinized pigs, the mean blood loss in the experimental group was 3.5% and 13.5% of the controls biopsied with an 18- and 16-gauge needle, respectively. CONCLUSION: Radiofrequency ablation of hepatic core biopsy tract ablation may reduce post biopsy bleeding even under bleeding tendency and using a larger core needle, according to the result from in vivo porcine model experiments. PMID- 28096728 TI - High-resolution Imaging of Neural Anatomy and Pathology of the Neck. AB - The neck has intricately connected neural structures, including cervical and brachial plexi, the sympathetic system, lower cranial nerves, and their branches. Except for brachial plexus, there has been little research regarding the normal imaging appearance or corresponding pathologies of neural structures in the neck. The development in imaging techniques with better spatial resolution and signal to-noise ratio has made it possible to see many tiny nerves to predict complications related to image-guided procedures and to better assess treatment response, especially in the management of oncology patients. The purposes of this review is to present imaging-based anatomy of major nerves in the neck and explain their relevant clinical significance according to representative pathologies of regarded nerves in the neck. PMID- 28096729 TI - Advanced MRI for Pediatric Brain Tumors with Emphasis on Clinical Benefits. AB - Conventional anatomic brain MRI is often limited in evaluating pediatric brain tumors, the most common solid tumors and a leading cause of death in children. Advanced brain MRI techniques have great potential to improve diagnostic performance in children with brain tumors and overcome diagnostic pitfalls resulting from diverse tumor pathologies as well as nonspecific or overlapped imaging findings. Advanced MRI techniques used for evaluating pediatric brain tumors include diffusion-weighted imaging, diffusion tensor imaging, functional MRI, perfusion imaging, spectroscopy, susceptibility-weighted imaging, and chemical exchange saturation transfer imaging. Because pediatric brain tumors differ from adult counterparts in various aspects, MRI protocols should be designed to achieve maximal clinical benefits in pediatric brain tumors. In this study, we review advanced MRI techniques and interpretation algorithms for pediatric brain tumors. PMID- 28096730 TI - Methodology for Developing Evidence-Based Clinical Imaging Guidelines: Joint Recommendations by Korean Society of Radiology and National Evidence-Based Healthcare Collaborating Agency. AB - This paper is a summary of the methodology including protocol used to develop evidence-based clinical imaging guidelines (CIGs) in Korea, led by the Korean Society of Radiology and the National Evidence-based Healthcare Collaborating Agency. This is the first protocol to reflect the process of developing diagnostic guidelines in Korea. The development protocol is largely divided into the following sections: set-up, process of adaptation, and finalization. The working group is composed of clinical imaging experts, and the developmental committee is composed of multidisciplinary experts to validate the methodology. The Korean CIGs will continue to develop based on this protocol, and these guidelines will act for decision supporting tools for clinicians as well as reduce medical radiation exposure. PMID- 28096732 TI - Estimation of T2* Relaxation Time of Breast Cancer: Correlation with Clinical, Imaging and Pathological Features. AB - OBJECTIVE: The purpose of this study was to estimate the T2* relaxation time in breast cancer, and to evaluate the association between the T2* value with clinical-imaging-pathological features of breast cancer. MATERIALS AND METHODS: Between January 2011 and July 2013, 107 consecutive women with 107 breast cancers underwent multi-echo T2*-weighted imaging on a 3T clinical magnetic resonance imaging system. The Student's t test and one-way analysis of variance were used to compare the T2* values of cancer for different groups, based on the clinical imaging-pathological features. In addition, multiple linear regression analysis was performed to find independent predictive factors associated with the T2* values. RESULTS: Of the 107 breast cancers, 92 were invasive and 15 were ductal carcinoma in situ (DCIS). The mean T2* value of invasive cancers was significantly longer than that of DCIS (p = 0.029). Signal intensity on T2 weighted imaging (T2WI) and histologic grade of invasive breast cancers showed significant correlation with T2* relaxation time in univariate and multivariate analysis. Breast cancer groups with higher signal intensity on T2WI showed longer T2* relaxation time (p = 0.005). Cancer groups with higher histologic grade showed longer T2* relaxation time (p = 0.017). CONCLUSION: The T2* value is significantly longer in invasive cancer than in DCIS. In invasive cancers, T2* relaxation time is significantly longer in higher histologic grades and high signal intensity on T2WI. Based on these preliminary data, quantitative T2* mapping has the potential to be useful in the characterization of breast cancer. PMID- 28096731 TI - Core Needle Biopsy of the Thyroid: 2016 Consensus Statement and Recommendations from Korean Society of Thyroid Radiology. AB - Core needle biopsy (CNB) has been suggested as a complementary diagnostic method to fine-needle aspiration in patients with thyroid nodules. Many recent CNB studies have suggested a more advanced role for CNB, but there are still no guidelines on its use. Therefore, the Task Force Committee of the Korean Society of Thyroid Radiology has developed the present consensus statement and recommendations for the role of CNB in the diagnosis of thyroid nodules. These recommendations are based on evidence from the current literature and expert consensus. PMID- 28096733 TI - Diagnosis of Nerve Root Compromise of the Lumbar Spine: Evaluation of the Performance of Three-dimensional Isotropic T2-weighted Turbo Spin-Echo SPACE Sequence at 3T. AB - OBJECTIVE: To explore the performance of three-dimensional (3D) isotropic T2 weighted turbo spin-echo (TSE) sampling perfection with application optimized contrasts using different flip angle evolution (SPACE) sequence on a 3T system, for the evaluation of nerve root compromise by disc herniation or stenosis from central to extraforaminal location of the lumbar spine, when used alone or in combination with conventional two-dimensional (2D) TSE sequence. MATERIALS AND METHODS: Thirty-seven patients who had undergone 3T spine MRI including 2D and 3D sequences, and had subsequent spine surgery for nerve root compromise at a total of 39 nerve levels, were analyzed. A total of 78 nerve roots (48 symptomatic and 30 asymptomatic sites) were graded (0 to 3) using different MRI sets of 2D, 3D (axial plus sagittal), 3D (all planes), and combination of 2D and 3D sequences, with respect to the nerve root compromise caused by posterior disc herniations, lateral recess stenoses, neural foraminal stenoses, or extraforaminal disc herniations; grading was done independently by two readers. Diagnostic performance was compared between different imaging sets using the receiver operating characteristics (ROC) curve analysis. RESULTS: There were no statistically significant differences (p = 0.203 to > 0.999) in the ROC curve area between the imaging sets for both readers 1 and 2, except for combined 2D and 3D (0.843) vs. 2D (0.802) for reader 1 (p = 0.035), and combined 2D and 3D (0.820) vs. 3D including all planes (0.765) for reader 2 (p = 0.049). CONCLUSION: The performance of 3D isotropic T2-weighted TSE sequence of the lumbar spine, whether axial plus sagittal images, or all planes of images, was not significantly different from that of 2D TSE sequences, for the evaluation of nerve root compromise of the lumbar spine. Combining 2D and 3D might possibly improve the diagnostic accuracy compared with either one. PMID- 28096734 TI - Chest CT Features of Cystic Fibrosis in Korea: Comparison with Non-Cystic Fibrosis Diseases. AB - OBJECTIVE: Cystic fibrosis (CF) is a rare congenital disease in Korea, and its clinical and imaging findings are unclear. The objective of our study was to describe the clinical and CT features of CF in Korea and compare its features with those of other diseases mimicking CF. MATERIALS AND METHODS: From November 1994 to December 2014, a presumptive diagnosis of CF was made in 23 patients based on clinical or radiological examination. After the exclusion of 10 patients without diagnostic confirmation, 13 patients were included in the study. A diagnosis of CF was made with the CF gene study. CT findings were evaluated for the presence and distribution of parenchymal abnormalities including bronchiectasis, tree-in-bud (TIB) pattern, mucus plugging, consolidation, and mosaic attenuation. RESULTS: Of the 13 patients, 7 (median age, 15 years) were confirmed as CF, 4 (median age, 19 years) had primary ciliary dyskinesia, 1 had bronchiectasis of unknown cause, and 1 had chronic asthma. CT of patients with CF showed bilateral bronchiectasis, TIB pattern, mosaic attenuation, and mucus plugging in all patients, with upper lung predominance (57%). In CT of the non-CF patients, bilateral bronchiectasis, TIB pattern, mosaic attenuation, and mucus plugging were also predominant features, with lower lung predominance (50%). CONCLUSION: Korean patients with CF showed bilateral bronchiectasis, cellular bronchiolitis, mucus plugging, and mosaic attenuation, which overlapped with those of non-CF patients. CF gene study is recommended for the definitive diagnosis of CF in patients with these clinical and imaging features. PMID- 28096735 TI - Volatile Fatty Acids Production from Codigestion of Food Waste and Sewage Sludge Based on beta-Cyclodextrins and Alkaline Treatments. AB - Volatile fatty acids (VFAs) are preferred valuable resources, which can be produced from anaerobic digestion process. This study presents a novel technology using beta-cyclodextrins (beta-CD) pretreatment integrated alkaline method to enhance VFAs production from codigestion of food waste and sewage sludge. Experiment results showed that optimized ratio of food waste to sewage sludge was 3 : 2 because it provided adequate organic substance and seed microorganisms. Based on this optimized ratio, the integrated treatment of alkaline pH 10 and beta-CD addition (0.2 g/g TS) performed the best enhancement on VFAs production, and the maximum VFAs production was 8631.7 mg/L which was 6.13, 1.38, and 1.57 times higher than that of control, initial pH 10, and 0.2 g beta-CD/g TS treatment, respectively. Furthermore, the hydrolysis rate of protein and polysaccharides was greatly improved in integration treatment, which was 1.18 3.45 times higher than that of other tests. Though the VFAs production and hydrolysis of polymeric organics were highly enhanced, the primary bacterial communities with different treatments did not show substantial differences. PMID- 28096736 TI - Marine Subsurface Microbial Community Shifts Across a Hydrothermal Gradient in Okinawa Trough Sediments. AB - Sediments within the Okinawa back-arc basin overlay a subsurface hydrothermal network, creating intense temperature gradients with sediment depth and potential limits for microbial diversity. We investigated taxonomic changes across 45 m of recovered core with a temperature gradient of 3 degrees C/m from the dynamic Iheya North Hydrothermal System. The interval transitions sharply from low temperature marine mud to hydrothermally altered clay at 10 meters below seafloor (mbsf). Here, we present taxonomic results from an analysis of the 16S rRNA gene that support a conceptual model in which common marine subsurface taxa persist into the subsurface, while high temperature adapted archaeal taxa show localized peaks in abundances in the hydrothermal clay horizons. Specifically, the bacterial phylum Chloroflexi accounts for a major proportion of the total microbial community within the upper 10 mbsf, whereas high temperature archaea (Terrestrial Hot Spring Crenarchaeotic Group and methanotrophic archaea) appear in varying local abundances in deeper, hydrothermal clay horizons with higher in situ temperatures (up to 55 degrees C, 15 mbsf). In addition, geochemical evidence suggests that methanotrophy may be occurring in various horizons. There is also relict DNA (i.e., DNA preserved after cell death) that persists in horizons where the conditions suitable for microbial communities have ceased. PMID- 28096737 TI - Implementation of evidence on the nurse-patient relationship in psychiatric wards through a mixed method design: study protocol. AB - BACKGROUND: Psychiatric nurses are aware of the importance of the therapeutic relationship in psychiatric units. Nevertheless, a review of the scientific evidence indicates that theoretical knowledge alone is insufficient to establish an adequate therapeutic alliance. Therefore, strategies are required to promote changes to enhance the establishment of the working relationship. The aims of the study are to generate changes in how nurses establish the therapeutic relationship in acute psychiatric units, based on participative action research and to evaluate the effectiveness of the implementation of evidence through this method. METHODS/DESIGN: The study will use a mixed method design. Qualitative methodology, through participative action research, will be employed to implement scientific evidence on the therapeutic relationship. A quasi-experimental, one group, pre-test/post-test design will also be used to quantitatively measure the effectiveness of the implementation of the evidence. Participants will consist of nurses and patients from two psychiatric units in Barcelona. Nurses will be selected by theoretical sampling, and patients assigned to each nurses will be selected by consecutive sampling. Qualitative data will be gathered through discussion groups and field diaries. Quantitative data will be collected through the Working Alliance Inventory and the Interpersonal Reactivity Index. Qualitative data will be analysed through the technique of content analysis and quantitative data through descriptive and inferential statistics. DISCUSSION: This study will help to understand the process of change in a nursing team working in an inpatient psychiatric ward and will allow nurses to generate knowledge, identify difficulties, and establish strategies to implement change, as well as to assess whether the quality of the care they provide shows a qualitative improvement. PMID- 28096739 TI - Being critical and constructive: a guide to peer reviewing for librarians. PMID- 28096738 TI - Clinical management, expectations, and satisfaction of patients with moderate to severe allergic rhinoconjunctivitis treated with SQ-standardized grass-allergen tablet under routine clinical practice conditions in Spain. AB - BACKGROUND: Sublingual immunotherapy has been proven as a well-tolerated and effective treatment for allergic rhinitis. Within this type of treatment, GRAZAX(r) is the most documented product in terms of safety and efficacy. The objective of this study was to identify the patients' expectations and level of treatment satisfaction, as well as the clinical management of patients with moderate/severe allergic rhinoconjunctivitis treated with GRAZAX(r). METHODS: This was a non-interventional, observational, multi-centre, open-label study involving a total of 131 adult patients aged 18-66 years with confirmed diagnosis of grass-allergy and initiated treatment with GRAZAX(r) between June 2010 and April 2011. RESULTS: In the pollen season after starting treatment, 56.6% of patients stated that their symptoms were much less/less intense, 86% needed less symptomatic medication for control of their symptoms, and 74.4% manifested to have improved (quite/a lot) as regards their allergic disease since treatment was initiated as compared with previous grass pollen season. The patient satisfaction with GRAZAX(r) was measured using a visual analogue scale (VAS) between 0 (minimum satisfaction) and 100 (maximum satisfaction) comprising five different items: effectiveness, tolerability, cost, convenience and overall satisfaction. The results obtained for each item were [mean (SD)]: 74.7 (18.1), 70.3 (36.1), 39.3 (25.8), 86.2 (12.6), 78.4 (15.8) respectively. The patient's level of satisfaction is highly influenced, especially in terms of assessment of effectiveness, tolerability and convenience, by the information provided by the specialist. CONCLUSIONS: In summary, it can be concluded that improved communication leads to increased patient knowledge, greater patient compliance, and increased patient satisfaction. PMID- 28096740 TI - Unanswered clinical questions: a survey of specialists and primary care providers. AB - OBJECTIVE: With the myriad of cases presented to clinicians every day at our integrated academic health system, clinical questions are bound to arise. Clinicians need to recognize these knowledge gaps and act on them. However, for many reasons, clinicians might not seek answers to these questions. Our goal was to investigate the rationale and process behind these unanswered clinical questions. Subsequently, we explored the use of biomedical information resources among specialists and primary care providers and identified ways to promote more informed clinical decision making. METHODS: We conducted a survey to assess how practitioners identify and respond to information gaps, their background knowledge of search tools and strategies, and their usage of and comfort level with technology. RESULTS: Most of the 292 respondents encountered clinical questions at least a few times per week. While the vast majority often or always pursued answers, time was the biggest barrier for not following through on questions. Most respondents did not have any formal training in searching databases, were unaware of many digital resources, and indicated a need for resources and services that could be provided at the point of care. CONCLUSIONS: While the reasons for unanswered clinical questions varied, thoughtful review of the responses suggested that a combination of educational strategies, embedded librarian services, and technology applications could help providers pursue answers to their clinical questions, enhance patient safety, and contribute to patient-based, self-directed learning. PMID- 28096742 TI - Collection-based analysis of selected medical libraries in the Philippines using Doody's Core Titles. AB - OBJECTIVES: This study assessed the book collection of five selected medical libraries in the Philippines, based on Doodys' Essential Purchase List for basic sciences and clinical medicine, to compare the match and non-match titles among libraries, to determine the strong and weak disciplines of each library, and to explore the factors that contributed to the percentage of match and non-match titles. METHOD: List checking was employed as the method of research. RESULTS: Among the medical libraries, De La Salle Health Sciences Institute and University of Santo Tomas had the highest percentage of match titles, whereas Ateneo School of Medicine and Public Health had the lowest percentage of match titles. University of the Philippines Manila had the highest percentage of near-match titles. CONCLUSION: De La Salle Health Sciences Institute and University of Santo Tomas had sound medical collections based on Doody's Core Titles. Collectively, the medical libraries shared common collection development priorities, as evidenced by similarities in strong areas. Library budget and the role of the library director in book selection were among the factors that could contribute to a high percentage of match titles. PMID- 28096741 TI - A day in the life of third-year medical students: using an ethnographic method to understand information seeking and use. AB - OBJECTIVE: The authors undertook this project to learn how third-year medical students seek and use information in the course of daily activities, especially activities conducted in clinical settings in a variety of institutions. METHODS: We recruited sixty-eight third-year undergraduate medical school students to create a mapping diary of a day that included clinical activities. We conducted semi-structured interviews based on the mapping diaries. Using content and thematic analyses of the resulting interview transcripts, we developed an ethnographic case study for each participant. RESULTS: In the studied sample, we identified a broad range of information resources used for personal, clinical, and educational use. Participants relied heavily on technology throughout their day, including desktop computers, smart phones, handheld tablets, and laptops. Time management was a pervasive theme in the interviews, with participants squeezing in time to study for exams wherever and whenever they could. Selection of a particular information resource or technology to use was governed largely by the convenience of using that resource or technology. When obstacles were encountered, workarounds might be sought, but in many cases, the resource or technology would be abandoned in favor of a more convenient solution. Convenience was also a consideration in choosing spaces to use for clinical duties or for study, with specific considerations of available technology, proximity to clinical areas, and security for belongings contributing to choices made. CONCLUSIONS: Some of our results align with those of other recent studies of information use among medical students, residents, and practicing physicians. In particular, the fast-paced clinical setting favors use of information resources that are fast and easy to use. We demonstrated that the methods used are suitable to better understand clinicians' discovery and use of information. PMID- 28096743 TI - Meeting at the crossroads: collaboration between information technology departments and health sciences libraries. AB - OBJECTIVE: The purposes of this survey were to determine the nature and extent of collaboration between health sciences libraries and their information technology (IT) departments, to identify strengths and issues connected to this relationship, and to provide examples demonstrating exceptional collaborative success. METHODS: A fourteen-question survey was sent to a broad selection of health care and academic libraries through a variety of email discussion lists and was limited to one response per institution. Convenience sampling was used to collect the responses. RESULTS: An overwhelming majority of libraries described the relationship with their IT departments as good or excellent, and there were a variety of creative joint initiatives underway. Opportunities exist for continued and expanded library/IT collaboration. CONCLUSIONS: Good quality relationships between libraries and their IT departments are essential due to the interconnected nature of their services, and fortunately, this appears to be the norm at a variety of institutions. Mutual respect, open communication, realization of each department's mission, and responsiveness to each other's needs are part of what makes these relationships successful, which in turn leads to successful collaborative ventures that bode well for the future of both services. PMID- 28096744 TI - Measuring the health literacy of the Upper Midwest. AB - OBJECTIVES: Health literacy-the ability to obtain, process, and understand basic health information-is a major determinant of an individual's overall health and health care utilization. In this project, the authors examined predictors of health literacy levels, including numeracy and graphic literacy, among an adult population in the Upper Midwest. METHODS: The research was conducted at the Minnesota State Fair. Three previously validated scales were used to assess health literacy: Newest Vital Sign, the General Health Numeracy Test, and questions from Galesic and Garcia-Retamero's Graph Literacy Scale. Demographic information-such as age, educational attainment, zip code, and other potential predictors and modifiers-was collected. Multivariate linear regression was conducted to examine the independent effects of educational attainment, race, ethnicity, gender, and rural or urban location on overall health literacy and scores on each of the individual instruments. RESULTS: A total of 353 Upper Midwest residents completed the survey, with the majority being white, college educated, and from an urban area. Having a graduate or professional degree or being under the age of 21 were associated with increased health literacy scores, while having a high school diploma or some high school education, being Asian American, or being American Indian/Alaska Native were associated with lower health literacy scores. CONCLUSION: Advanced health literacy skills, including the ability to calculate and compare information, were problematic even in well educated populations. Understanding numerical and graphical information was found to be particularly difficult, and more research is needed to understand these deficits and how best to address them. PMID- 28096745 TI - Your teaching strategy matters: how engagement impacts application in health information literacy instruction. AB - OBJECTIVE: The purpose of this study was to compare two pedagogical methods, active learning and passive instruction, to determine which is more useful in helping students to achieve the learning outcomes in a one-hour research skills instructional session. METHODS: Two groups of high school students attended an instructional session to learn about consumer health resources and strategies to enhance their searching skills. The first group received passive instruction, and the second engaged in active learning. We assessed both groups' learning using 2 methods with differing complexity. A total of 59 students attended the instructional sessions (passive instruction, n=28; active learning, n=31). RESULTS: We found that the active learning group scored more favorably in four assessment categories. CONCLUSIONS: Active learning may help students engage with and develop a meaningful understanding of several resources in a single session. Moreover, when using a complex teaching strategy, librarians should be mindful to gauge learning using an equally complex assessment method. PMID- 28096746 TI - From English to Chinese, Japanese, and Russian: extending research visibility with language translations of a conference slide presentation. AB - OBJECTIVE: The research demonstrates that a conference slide presentation translated into non-English languages reaches significantly larger and different audiences than an English presentation alone. METHODS: The slides of a presentation from the Medical Library Association annual meeting were translated from English to Chinese, Japanese, and Russian and posted along with the English version to SlideShare, an open slide-hosting website. View counts, traffic sources, and geographic origins of the traffic for each language version were tracked over a twenty-two-month period. RESULTS: Total view counts for all 4 language versions amounted to 3,357 views, with the Chinese version accounting for 71% of the total views. The trends in view counts over time for the Japanese, Russian, and English versions were similar, with high interest at the beginning and a rapid drop and low level of viewing activity thereafter. The pattern of view counts for the Chinese version departed considerably from the other language versions, with very low activity at the beginning but a sharp rise 10 months later. This increase in activity was related to access to the presentations via a Taiwanese website that embedded the SlideShare website code. CONCLUSIONS: Language translation can be a difficult and time-consuming task. However, translation of a conference slide presentation with limited text is an achievable activity and engages an international audience for information that is often not noticed or lost. Although English is by far the primary language of science and other disciplines, it is not necessarily the first or preferred language of global researchers. By offering appropriate language versions, the authors of presentations can expand the reach of their work. PMID- 28096747 TI - Implementing a 3D printing service in a biomedical library. AB - Three-dimensional (3D) printing is opening new opportunities in biomedicine by enabling creative problem solving, faster prototyping of ideas, advances in tissue engineering, and customized patient solutions. The National Institutes of Health (NIH) Library purchased a Makerbot Replicator 2 3D printer to give scientists a chance to try out this technology. To launch the service, the library offered training, conducted a survey on service model preferences, and tracked usage and class attendance. 3D printing was very popular, with new lab equipment prototypes being the most common model type. Most survey respondents indicated they would use the service again and be willing to pay for models. There was high interest in training for 3D modeling, which has a steep learning curve. 3D printers also require significant care and repairs. NIH scientists are using 3D printing to improve their research, and it is opening new avenues for problem solving in labs. Several scientists found the 3D printer so helpful they bought one for their labs. Having a printer in a central and open location like a library can help scientists, doctors, and students learn how to use this technology in their work. PMID- 28096748 TI - Questioning reliability assessments of health information on social media. AB - This narrative review examines assessments of the reliability of online health information retrieved through social media to ascertain whether health information accessed or disseminated through social media should be evaluated differently than other online health information. Several medical, library and information science, and interdisciplinary databases were searched using terms relating to social media, reliability, and health information. While social media's increasing role in health information consumption is recognized, studies are dominated by investigations of traditional (i.e., non-social media) sites. To more richly assess constructions of reliability when using social media for health information, future research must focus on health consumers' unique contexts, virtual relationships, and degrees of trust within their social networks. PMID- 28096750 TI - The research life cycle and the health sciences librarian: responding to change in scholarly communication. PMID- 28096751 TI - Reviewing retrieved references for inclusion in systematic reviews using EndNote. PMID- 28096749 TI - Evidence-based information needs of public health workers: a systematized review. AB - OBJECTIVE: This study assessed public health workers' evidence-based information needs, based on a review of the literature using a systematic search strategy. This study is based on a thesis project conducted as part of the author's master's in public health coursework and is considered a systematized review. METHODS: Four databases were searched for English-language articles published between 2005 and 2015: PubMed, Web of Science, Library Literature & Information Science Index, and Library, Information Science & Technology Abstracts (LISTA). Studies were excluded if there was no primary data collection, the population in the study was not identified as public health workers, "information" was not defined according to specific criteria, or evidence-based information and public health workers were not the major focus. Studies included in the final analysis underwent data extraction, critical appraisal using CASP and STROBE checklists, and thematic analysis. RESULTS: Thirty-three research studies were identified in the search, including twenty-one using quantitative methods and twelve using qualitative methods. Critical appraisal revealed many potential biases, particularly in the validity of research. Thematic analysis revealed five common themes: (1) definition of information needs, (2) current information-seeking behavior and use, (3) definition of evidence-based information, (4) barriers to information needs, and (5) public health-specific issues. CONCLUSIONS: Recommendations are given for how librarians can increase the use of evidence based information in public health research, practice, and policy making. Further research using rigorous methodologies and transparent reporting practices in a wider variety of settings is needed to further evaluate public health workers' information needs. PMID- 28096752 TI - We can be heroes: MLA's leadership journey(s). AB - OBJECTIVE: Are there key attributes of leaders? Extrovert versus introvert? Charismatic? Detail oriented? Visionary? How do past leaders of the Medical Library Association (MLA) stack up? What leadership skills will MLA's leaders need in a complex information future? Leadership attributes of MLA's past and current presidents were studied to determine the common characteristics shared among these leaders. An examination of the leadership literature identified critical leadership characteristics essential to successful future leaders. MLA's past, current, and future leadership development efforts were examined. Finally, all members were encouraged to consider leadership with a small "l" and become leaders based on their own strengths, interests, and environments. METHODS: A text analysis was performed on past presidential profiles, the past twenty-five years of MLA presidents were surveyed, and conversations with MLA's current presidents were held to determine commonalities among leadership characteristics. These were compared and contrasted with characteristics in the current leadership literature regarding the qualities of future leaders. RESULTS: The text analysis of past presidential profiles was not particularly revelatory regarding leadership qualities of early MLA presidents although several generalized traits emerged including collaborative traits; management traits such as effectiveness and efficiency, innovation, and vision; personal traits such as humor and energy; and finally, a passion for the work were revealed. These aligned with traits identified in the survey of the past twenty-five years of MLA presidents and with the thoughts of the president-elect, president, and past president. Additional qualities identified were communication skills, political acumen, creativity, courage, and respect for the opinions and concerns of all members. MLA's current leadership programs were reviewed in the context of examining traits needed by leaders of the future. A lack of focus on the needs of middle managers and the development of individual leadership skills was identified. CONCLUSIONS: As an organization, MLA should focus on leadership development in contrast to management training to prepare members as leaders in careers and work that may be vastly different than current situations. Equipping members with the skills enabling them to lead and thrive in these diverse situations, whether as the heads of programs or middle managers, or exploring and empowering individual leadership development while maintaining a passion for the profession, will be essential. PMID- 28096754 TI - Correction. AB - [This corrects the article on p. 242 in vol. 104.]. PMID- 28096753 TI - History matters. PMID- 28096755 TI - Correction. AB - [This corrects the article on p. 315 in vol. 104, PMID: 27822156.]. PMID- 28096756 TI - 116th Annual Meeting, Medical Library Association, Inc., Toronto, ON, Canada, May 15-20, 2015. PMID- 28096757 TI - Effects of ingesting a pre-workout dietary supplement with and without synephrine for 8 weeks on training adaptations in resistance-trained males. AB - BACKGROUND: The purpose of this study was to examine whether ingesting a pre workout dietary supplement (PWS) with and without synephrine (S) during training affects training responses in resistance-trained males. METHODS: Resistance trained males (N = 80) were randomly assigned to supplement their diet in a double-blind manner with either a flavored placebo (PLA); a PWS containing beta alanine (3 g), creatine nitrate as a salt (2 g), arginine alpha-ketoglutarate (2 g), N-Acetyl-L-Tyrosine (300 mg), caffeine (284 mg), Mucuna pruiriens extract standardized for 15% L-Dopa (15 mg), Vitamin C as Ascorbic Acid (500 mg), niacin (60 mg), folate as folic acid (50 mg), and Vitamin B12 as Methylcobalamin (70 mg); or, the PWS supplement with Citrus aurantium extract containing 20 mg of synephrine (PWS + S) once per day for 8-weeks during training. Participants donated a fasting blood sample and had body composition (DXA), resting heart rate and blood pressure, cognitive function (Stroop Test), readiness to perform, bench and leg press 1 RM, and Wingate anaerobic capacity assessments determined a 0, 4, and 8-weeks of standardized training. Data were analyzed by MANOVA with repeated measures. Performance and cognitive function data were analyzed using baseline values as covariates as well as mean changes from baseline with 95% confidence intervals (CI). Blood chemistry data were also analyzed using Chi-square analysis. RESULTS: Although significant time effects were seen, no statistically significant overall MANOVA Wilks' Lambda interactions were observed among groups for body composition, resting heart and blood pressure, readiness to perform questions, 1RM strength, anaerobic sprint capacity, or blood chemistry panels. MANOVA univariate analysis and analysis of changes from baseline with 95% CI revealed some evidence that cognitive function and 1RM strength were increased to a greater degree in the PWS and/or PWS + S groups after 4- and/or 8-weeks compared to PLA responses. However, there was no evidence that PWS + S promoted greater overall training adaptations compared to the PWS group. Dietary supplementation of PWS and PWS + S did not increase the incidence of reported side effects or significantly affect the number of blood values above clinical norms compared to PLA. CONCLUSION: Results provide some evidence that 4-weeks of PWS and/or PWS + S supplementation can improve some indices of cognitive function and exercise performance during resistance-training without significant side effects in apparently health males. However, these effects were similar to PLA responses after 8-weeks of supplementation and inclusion of synephrine did not promote additive benefits. TRIAL REGISTRATION: This trial (NCT02999581) was retrospectively registered on December 16th 2016. PMID- 28096759 TI - The Role of Metals in the Reaction Catalyzed by Metal-Ion-Independent Bacillary RNase. AB - Extracellular enzymes of intestinal microbiota are the key agents that affect functional activity of the body as they directly interact with epithelial and immune cells. Several species of the Bacillus genus, like Bacillus pumilus, a common producer of extracellular RNase binase, can populate the intestinal microbiome as a colonizing organism. Without involving metal ions as cofactors, binase depolymerizes RNA by cleaving the 3',5'-phosphodiester bond and generates 2',3'-cyclic guanosine phosphates in the first stage of a catalytic reaction. Maintained in the reaction mixture for more than one hour, such messengers can affect the human intestinal microflora and the human body. In the present study, we found that the rate of 2',3'-cGMP was growing in the presence of transition metals that stabilized the RNA structure. At the same time, transition metal ions only marginally reduced the amount of 2',3'-cGMP, blocking binase recognition sites of guanine at N7 of nucleophilic purine bases. PMID- 28096758 TI - Effects of acute ingestion of a pre-workout dietary supplement with and without p synephrine on resting energy expenditure, cognitive function and exercise performance. AB - BACKGROUND: The purpose of this study was to examine the effects of acute ingestion of a pre-workout dietary supplement (PWS) with and without p-synephrine (S) on perceptions of readiness to perform, cognitive function, exercise performance, and markers of safety. METHODS: In a randomized, double-blind, and counterbalanced manner; 25 healthy and recreationally active male and female participants ingested a flavored maltodextrin placebo (PLA), a PWS containing beta-alanine (3 g), creatine nitrate as a salt (2 g), arginine alpha ketoglutarate (2 g), N-Acetyl-L-Tyrosine (300 mg), caffeine (284 mg), Mucuna pruiriens extract standardized for 15% L-Dopa (15 mg), Vitamin C as Ascorbic Acid (500 mg), niacin (60 mg), folate as folic acid (50 mg), and Vitamin B12 as Methylcobalamin (70 mg) with 2 g of maltodextrin and flavoring; or, the PWS with Citrus aurantium (PWS + S) extract standardized for 30% p-synephrine (20 mg). Participants had heart rate (HR), blood pressure, resting energy expenditure (REE), 12-lead electrocardiograms (ECG), perceptions about readiness to perform, cognitive function (Stroop Color-Word test), bench and leg press performance (2 sets of 10 repetitions at 70% of 1RM and 1 set to failure), and Wingate anaerobic capacity (WAC) sprint performance determined as well as donated blood samples prior to and/or following exercise/supplementation. Data were analyzed by MANOVA with repeated measures as well as mean changes from baseline with 95% confidence intervals (CI). RESULTS: No clinically significant differences were observed among treatments in HR, blood pressure, ECG, or general clinical blood panels. There was evidence that PWS and PWS + S ingestion promoted greater changes in REE responses. Participants reported higher perception of optimism about performance and vigor and energy with PWS and PWS + S ingestion and there was evidence that PWS and PWS + S improved changes in cognitive function scores from baseline to a greater degree than PLA after 1 or 2 h. However, the scores in the PWS + S treatment did not exceed PLA or PWS responses at any data point. No statistically significant differences were observed among treatments in total bench press lifting volume, leg press lifting volume or WAC sprint performance. CONCLUSIONS: Within the confines of this study, ingestion of PWS and/or PWS + S prior to exercise appears to be well-tolerated when consumed by young, healthy individuals. The primary effects appear to be to increase REE responses and improve perceptions about readiness to perform and cognitive function with limited to no effects on muscular endurance and WAC. The addition of 20 mg of p synephrine to the PWS provided limited to no additive benefits. TRIAL REGISTRATION: This trial (NCT02952014) was retrospectively registered on September 13th 2016. PMID- 28096760 TI - Analysis of genetic diversity of Tunisian caprifig (Ficus carica L.) accessions using simple sequence repeat (SSR) markers. AB - BACKGROUND: The common fig (Ficus carica L.) is a gynodioecious species with two sexual forms: male trees (caprifigs) with male and female flowers and female trees that produce only female flowers that will result in the edible fig syconium. In this study the genetic diversity of 20 Tunisian accessions of caprifig is analyzed using SSR markers previously developed for this crop. RESULTS: The results revealed that the 13 pairs of primers used amplified a total of 37 alleles in the accessions studied. The number of alleles per locus ranged from two to six, with a mean value of 2.85 alleles per locus. Observed and expected heterozygosities showed mean values of 0.33 and 0.29 respectively. UPGMA cluster analysis and Principal Component Analysis grouped the caprifig accessions analyzed in three groups. CONCLUSION: The results obtained show a low genetic diversity in the Tunisian accessions of caprifig studied and, in spite of analyzing samples from different geographic regions, no clear groupings based on geographical origin are observed suggesting widespread exchange of caprifig plant material through vegetative propagation among different areas in Tunisia. PMID- 28096761 TI - Resurrection of Hereditas, a journal with almost 100 years of tradition. PMID- 28096762 TI - The Trp719Arg polymorphism of the KIF6 gene and coronary heart disease risk: systematic review and meta-analysis. AB - BACKGROUND: Genetic factors play an important role in the pathogenesis of coronary heart disease (CHD). Kinesin-like protein 6 (KIF6) is a new candidate gene for CHD, since it has been identified as a potential risk factor. The aim of this study was to perform a systematic review and meta-analysis of previously published association studies between the Trp719Arg polymorphism of KIF6 and the development of CHD. METHODS: Studies and abstracts investigating the relationship between the Trp719Arg polymorphism of KIF6 and subsequent risk for development of CHD were reviewed. Electronic search from Pubmed and EBSCO databases was performed between 1993 and 2014 to identify studies that fulfilled the inclusion criteria. To analyze the association we used the models: allelic, additive, dominant and recessive. Moreover, we conducted a sub-analysis by populations using the same four models. RESULTS: Twenty-three studies were included in the meta-analysis. The Trp719Arg polymorphism showed a significant association with CHD when the analysis comprised the population with myocardial infarction (MI) and the additive genetic model was used. Moreover, this polymorphism showed a protective association with CHD when the analysis comprised the whole population using the recessive genetic model. CONCLUSIONS: Our findings indicate that the Trp719Arg polymorphism of the KIF6 gene is an important risk factor for developing MI and that allele 719Arg may have a protective association to present CHD in all populations. PROSPERO REGISTRATION: CRD42015024602. PMID- 28096763 TI - A preliminary phylogeny of the South African Lentulidae. AB - BACKGROUND: The grasshopper family Lentulidae is endemic to eastern and southern Africa, with its center of diversity situated in South Africa, the highest diversity being found in the Cape Floristic Region, which is one of the global biodiversity hotspots. The family consists of 35 genera sorted in two subfamilies. This study provides first insights into the phylogeny of Lentulidae. Two mitochondrial genes (12S and NDS) were sequenced and the phylogeny was inferred through Maximum Likelihood and Bayesian Inference. RESULTS: Our results indicate that the current classification into the subfamilies Lentulinae and Shelforditinae may be incorrect as Uvarovidium, Leatettix (Shelforditinae) and Devylderia (Lentulinae) clustered together in one main clade, while Betiscoides, Basutacris and Gymnidium (all Lentulinae) formed the second main clade. The genera Uvarovidium and Leatettix, which had been assigned to the Acrididae (subfamily Hemiacridinae) in the past, grouped within the Lentulidae, confirming their current assignment to this family. The East African Usambilla group is likely to represent a sister clade to the south African Lentula and Eremidium. Diversification patterns in the genus Devylderia and Betiscoides suggest a higher number of species than currently known. CONCLUSIONS: Our phylogeny is not in line with the current systematics of Lentulidae, suggesting that a broader sampling and a study of the genitalia would be useful to clarify the taxonomy. Furthermore, some genera (particularly Betiscoides and Devylderia) are in need of taxonomic revision, as the number of species within these genera is likely to be higher than the current taxonomy suggests. PMID- 28096764 TI - Leptin receptor gene polymorphisms and morbid obesity in Mexican patients. AB - BACKGROUND: Human obesity is due to a complex interaction among environmental, behavioral, developmental and genetic factors, including the interaction of leptin (LEP) and leptin receptor (LEPR). Several LEPR mutations and polymorphisms have been described in patients with early onset severe obesity and hyperphagic eating behavior; however, some contradictory findings have also been reported. In the present study we explored the association of six LEPR gene polymorphisms in patients with morbid obesity. FINDINGS: Twenty eight patients with morbid obesity and 56 non-obese Mexican Mestizo individuals were included. Typing of rs1137100, rs1137101, rs1805134, Ser492Thr, rs1805094 and rs1805096 LEPR polymorphisms was performed by PCR and allele specific hybridization. The LEPR Ser492Thr polymorphism was monomorphic with the presence of only the Ser492Thr-G allele. Allele C and genotype T/C for rs1805134 polymorphism were associated with susceptibility to morbid obesity (p = 0.02 and p = 0.03, respectively). No association was observed with any haplotype. Linkage disequilibrium (LD) showed that five polymorphisms (rs1137100, rs1137101, rs1805134, rs1805094 and rs1805096) were in absolute (D' = 1) but none in perfect (r2 = 1) LD. CONCLUSIONS: Our results suggest that rs1805134 polymorphism could be involved in the development of morbid obesity, whilst none of the alleles of the LEPR gene, rs1137100, rs1137101, rs1805094 and rs1805096 were associated as risk factors. However, more studies are necessary to confirm or reject this hypothesis. PMID- 28096765 TI - Cloning and characterization of an ABA-independent DREB transcription factor gene, HcDREB2, in Hemarthria compressa. AB - BACKGROUND: Hemarthria compressa is a stoloniferous perennial tropical forage grass with a wide geographic distribution; however, environmental stress has a great influence on its growth. The DREB transcription factor family genes contains candidate genes for improving plant stress tolerance. RESULTS: From cold treated H. compressa plants, a putative DREB2 gene (HcDREB2) was cloned using the RACE-PCR method. HcDREB2 was 1296 bp in length and encoded a putative protein 264 amino acid residues long. HcDREB2 shared the highest sequence identity with DREB2 in sorghum. The expression of HcDREB2 was independent of ABA treatment, but inducible by low temperatures as well as drought and high salinity treatments. Yeast one-hybrid assays showed that HcDREB2 directly bound the DRE cis-acting element to transactivate the expression of the downstream reporter genes. CONCLUSIONS: HcDREB2, a stress-inducible but ABA-independent transcription factor gene, can transactivate downstream genes by binding to the DRE cis-element. The current results are a foundation for making use of this stress tolerance gene in future H. compressa studies. PMID- 28096766 TI - Genetic variation, population structure and linkage disequilibrium in Switchgrass with ISSR, SCoT and EST-SSR markers. AB - BACKGROUND: To evaluate genetic variation, population structure, and the extent of linkage disequilibrium (LD), 134 switchgrass (Panicum virgatum L.) samples were analyzed with 51 markers, including 16 ISSRs, 20 SCoTs, and 15 EST-SSRs. RESULTS: In this study, a high level of genetic variation was observed in the switchgrass samples and they had an average Nei's gene diversity index (H) of 0.311. A total of 793 bands were obtained, of which 708 (89.28 %) were polymorphic. Using a parameter marker index (MI), the efficiency of the three types of markers (ISSR, SCoT, and EST-SSR) in the study were compared and we found that SCoT had a higher marker efficiency than the other two markers. The 134 switchgrass samples could be divided into two sub-populations based on STRUCTURE, UPGMA clustering, and principal coordinate analyses (PCA), and upland and lowland ecotypes could be separated by UPGMA clustering and PCA analyses. Linkage disequilibrium analysis revealed an average r2 of 0.035 across all 51 markers, indicating a trend of higher LD in sub-population 2 than that in sub population 1 (P < 0.01). CONCLUSIONS: The population structure revealed in this study will guide the design of future association studies using these switchgrass samples. PMID- 28096767 TI - Assessment of genetic diversity in Nordic timothy (Phleum pratense L.). AB - BACKGROUND: Timothy (Phleum pratense L.), a cool-season hexaploid perennial, is the most important forage grass species in Nordic countries. Earlier analyses of genetic diversity in a collection of 96 genebank accessions of timothy with SSR markers demonstrated high levels of diversity but could not resolve population structure. Therefore, we examined a subset of 51 accessions with REMAP markers, which are based on retrotransposons, and compared the diversity results with those obtained with SSR markers. RESULTS: Using four primer combinations, 533 REMAP markers were analyzed, compared with 464 polymorphic alleles in the 13 SSR loci previously. The average marker index, which describes information obtained per experiment (per primer combination or locus) was over six times higher with REMAPs. Most of the variation found was within accessions, with somewhat less, 89 %, for REMAPs, than for SSR, with 93 %. CONCLUSIONS: SSRs revealed differences in the level of diversity slightly better than REMAPs but neither marker type could reveal any clear clustering of accessions based on countries, vegetation zones, or different cultivar types. In our study, reliable evaluation of SSR allele dosages was not possible, so each allele had to be handled as a dominant marker. SSR and REMAP, which report from different mechanisms of generating genetic diversity and from different genomic regions, together indicate a lack of population structure. Taken together, this likely reflects the outcrossing and hexaploid nature of timothy rather than failures of either marker system. PMID- 28096768 TI - eRFSVM: a hybrid classifier to predict enhancers-integrating random forests with support vector machines. AB - BACKGROUND: Enhancers are tissue specific distal regulation elements, playing vital roles in gene regulation and expression. The prediction and identification of enhancers are important but challenging issues for bioinformatics studies. Existing computational methods, mostly single classifiers, can only predict the transcriptional coactivator EP300 based enhancers and show low generalization performance. RESULTS: We built a hybrid classifier called eRFSVM in this study, using random forests as a base classifier, and support vector machines as a main classifier. eRFSVM integrated two components as eRFSVM-ENCODE and eRFSVM-FANTOM5 with diverse features and labels. The base classifier trained datasets from a single tissue or cell with random forests. The main classifier made the final decision by support vector machines algorithm, with the predicting results of base classifiers as inputs. For eRFSVM-ENCODE, we trained datasets from cell lines including Gm12878, Hep, H1-hesc and Huvec, using ChIP-Seq datasets as features and EP300 based enhancers as labels. We tested eRFSVM-ENCODE on K562 dataset, and resulted in a predicting precision of 83.69 %, which was much better than existing classifiers. For eRFSVM-FANTOM5, with enhancers identified by RNA in FANTOM5 project as labels, the precision, recall, F-score and accuracy were 86.17 %, 36.06 %, 50.84 % and 93.38 % using eRFSVM, increasing 23.24 % (69.92 %), 97.05 % (18.30 %), 76.90 % (28.74 %), 4.69 % (89.20 %) than the existing algorithm, respectively. CONCLUSIONS: All these results demonstrated that eRFSVM was a better classifier in predicting both EP300 based and FAMTOM5 RNAs based enhancers. PMID- 28096769 TI - Assessment of diversity and genetic relationships of Neonectria ditissima: the causal agent of fruit tree canker. AB - BACKGROUND: Neonectria ditissima is one of the most important fungal pathogens of apple trees, where it causes fruit tree canker. Information about the amount and partitioning of genetic variation of this fungus could be helpful for improving orchard management strategies and for breeding apple cultivars with high levels of genetically determined resistance. In this study single-spore Neonectria isolates originating from both the same and from different perithecia, apple cultivars and apple orchards in Sweden and Belgium, were evaluated for AFLP- and SSR-based genetic similarity and for mating system. RESULTS: Seven SSR loci produced a total of 31 alleles with an average of 4 alleles per locus, while 11 AFLP primer combinations produced an average of 35 fragments per primer combination and 71 % polymorphic fragments. An AFLP-based analysis of molecular variance (AMOVA) revealed that 89 % of the variation was found within orchards and 11 % between orchards. Genetic similarity among the studied isolates was illustrated with a principal coordinate analyseis (PCoA) and a dendrogram. AFLP based Jaccard's similarity coefficients were the highest when single-ascospore isolates obtained from the same perithecium were compared, medium-high for isolates from different perithecia on the same tree, and lowest when isolates from different trees were compared. CONCLUSIONS: Based on the results of PCoA and AMOVA analysis, isolates from the same or geographically close orchards did not group together. Since AFLP profiles differed also when single-ascospore isolates from the same perithecium were compared, the mating system of N. ditissima is most likely heterothallic. PMID- 28096770 TI - Genetic structure of Mount Huang honey bee (Apis cerana) populations: evidence from microsatellite polymorphism. AB - BACKGROUND: The Mount Huang eastern honey bees (Apis cerana) are an endemic population, which is well adapted to the local agricultural and ecological environment. In this study, the genetic structure of seven eastern honey bees (A. cerana) populations from Mount Huang in China were analyzed by SSR (simple sequence repeat) markers. RESULTS: The results revealed that 16 pairs of primers used amplified a total of 143 alleles. The number of alleles per locus ranged from 6 to 13, with a mean value of 8.94 alleles per locus. Observed and expected heterozygosities showed mean values of 0.446 and 0.831 respectively. UPGMA cluster analysis grouped seven eastern honey bees in three groups. CONCLUSION: The results obtained show a high genetic diversity in the honey bee populations studied in Mount Huang, and high differentiation among all the populations, suggesting that scarce exchange of honey bee species happened in Mount Huang. Our study demonstrated that the Mount Huang honey bee populations still have a natural genome worth being protected for conservation. PMID- 28096772 TI - Genetic diversity and occurrence of the F129L substitutions among isolates of Alternaria solani in south-eastern Sweden. AB - BACKGROUND: Early blight, caused by the fungus Alternaria solani, occurs on potato mainly in the south-eastern part of Sweden, but also in other parts of the country. The aim of this study was to investigate the genetic diversity of A. solani populations from different potato growing regions in south-eastern Sweden using AFLP marker analysis. In addition, the cultured isolates were examined for substitutions in the gene encoding cytochrome b, associated with loss of sensitivity against QoI fungicides. RESULTS: Nei's gene diversity index for the Swedish populations of A. solani revealed a gene diversity of up to 0.20. Also genetic differentiation was observed among populations of A. solani from different locations in south-eastern Sweden. The mitochondrial genotype of the isolates of A. solani was determined and both known genotypes, GI (genotype 1) and GII (genotype 2), were found among the isolates. The occurrence of the F129L substitution associated with a loss of sensitivity to strobilurins was confirmed among the GII isolates. In vitro conidial germination tests verified that isolates containing the F129L substitution had reduced sensitivity to azoxystrobin and, at a lower extent, to pyraclostrobin. CONCLUSIONS: Genetic diversity was relatively high among isolates of A. solani in south-eastern part of Sweden. F129L substitutions, leading to reduced sensitivity to strobilurins, have been established in field populations, which may have implications for the future efficacy of QoI fungicides. PMID- 28096771 TI - Insight into the genetic variability analysis and cultivar identification of tall fescue by using SSR markers. AB - BACKGROUND: Genetic diversity of 19 forage-type and 2 turf-type cultivars of tall fescue (Festuca arundinacea Schreb.) was revealed using SSR markers in an attempt to explore the genetic relationships among them, and examine potential use of SSR markers to identify cultivars by bulked samples. RESULTS: A total of 227 clear band was scored with 14 SSR primers and out of which 201 (88.6 %) were found polymorphic. The percentage of polymorphic bands (PPB) per primer pair varied from 62.5 to 100 % with an average of 86.9 %. The polymorphism information content (PIC) value ranged from 0.116 to 0.347 with an average of 0.257 and the highest PIC value (0.347) was noticed for primer NFA040 followed by NFA113 (0.346) whereas the highest discriminating power (D) of 1 was shown in NFA037 and LMgSSR02-01C. A Neighbor-joining dendrogram and the principal component analysis identified six major clusters and grouped the cultivars in agreement with their breeding histories. STRUCTURE analysis divided these cultivars into 3 sub-clades which correspond to distance based groupings. CONCLUSION: These findings indicates that SSR markers by bulking strategy are a useful tool to measure genetic diversity among tall fescue cultivars and could be used to supplement morphological data for plant variety protection. PMID- 28096773 TI - Whole genome SNP typing to investigate methicillin-resistant Staphylococcus aureus carriage in a health-care provider as the source of multiple surgical site infections. AB - BACKGROUND: Prevention of nosocomial transmission of infections is a central responsibility in the healthcare environment, and accurate identification of transmission events presents the first challenge. Phylogenetic analysis based on whole genome sequencing provides a high-resolution approach for accurately relating isolates to one another, allowing precise identification or exclusion of transmission events and sources for nearly all cases. We sequenced 24 methicillin resistant Staphylococcus aureus (MRSA) genomes to retrospectively investigate a suspected point source of three surgical site infections (SSIs) that occurred over a one-year period. The source of transmission was believed to be a surgical team member colonized with MRSA, involved in all surgeries preceding the SSI cases, who was subsequently decolonized. Genetic relatedness among isolates was determined using whole genome single nucleotide polymorphism (SNP) data. RESULTS: Whole genome SNP typing (WGST) revealed 283 informative SNPs between the surgical team member's isolate and the closest SSI isolate. The second isolate was 286 and the third was thousands of SNPs different, indicating the nasal carriage strain from the surgical team member was not the source of the SSIs. Given the mutation rates estimated for S. aureus, none of the SSI isolates share a common ancestor within the past 16 years, further discounting any common point source for these infections. The decolonization procedures and resources spent on the point source infection control could have been prevented if WGST was performed at the time of the suspected transmission, instead of retrospectively. CONCLUSIONS: Whole genome sequence analysis is an ideal method to exclude isolates involved in transmission events and nosocomial outbreaks, and coupling this method with epidemiological data can determine if a transmission event occurred. These methods promise to direct infection control resources more appropriately. PMID- 28096774 TI - Efficient callus formation and plant regeneration are heritable characters in sugar beet (Beta vulgaris L.). AB - BACKGROUND: Obtaining dedifferentiated cells (callus) that can regenerate into whole plants is not always feasible for many plant species. Sugar beet is known to be recalcitrant for dedifferentiation and plant regeneration. These difficulties were major obstacles for obtaining transgenic sugar beets through an Agrobacterium-mediated transformation procedure. The sugar beet line 'NK-219mm-O' is an exceptional line that forms callus efficiently and is easy to regenerate, but the inheritance of these characters was unknown. Another concern was whether these characters could coexist with an annual habitat that makes it possible to breed short life-cycle sugar beet suitable for molecular genetic analysis. FINDINGS: Five sugar beet lines including NK-219mm-O were crossed with each other and subjected to in vitro culture to form callus. F1s with a NK-219mm-O background generally formed callus efficiently compared to the others, indicating that efficient callus formation is heritable. The regeneration potential was examined based on the phenotypes of calli after placement on regeneration medium. Five phenotypes were observed, of which two phenotypes regenerated shoots or somatic embryo-like structures. Vascular differentiation was evident in regenerable calli, whereas non-regenerable calli lacked normally developed vascular tissues. In a half-diallel cross, the callus-formation efficiency and the regeneration potential of reciprocal F1s progeny having a NK-219mm-O background were high. Finally, we crossed NK-219mm-O with an annual line that had a poor in vitro performance. The callus-formation efficiency and the regeneration potential of reciprocal F1 were high. The regenerated plants showed an annual habitat. CONCLUSIONS: Efficient callus formation and the high plant regeneration potential of NK-219mm-O were inherited and expressed in the F1. The annual habitat does not impair these high in vitro performances. PMID- 28096776 TI - A C-banded karyotype of mitotic chromosomes in diploid purple coneflower (Echinacea purpurea L.). AB - BACKGROUND: Aneuploid ermpglasm is an important resource for genetic studies and identification of individual chromosomes in the cells of the aneuploid is an important step. The karyotype has already been established for purple coneflower (Echinacea purpurea L.), but due to the high similarity in the morphology of several pairs of chromosomes in this species, it cannot be used to identify individual chromosomes in its own complement. The objectives of this study are to develop and evaluate the Giemsa C-banding technique for the purpose of identifying the individual chromosomes in Echinacea purpurea. RESULTS: The established karyotype with C-bands showed that all the 11 pairs of chromosomes possessed centromeric bands. Telomeric bands appeared most frequently in almost all the chromosomes with only two exceptions, the short arm of the chromosome 9 and the long arm of the chromosome 10. Intercalary bands were found mainly in the long arm of some chromosomes with only two exceptions, the chromosomes 1 and 2 that had intercalary bands on both arms. The chromosome 4 was the only chromosome where intercalary bands were absent. CONCLUSIONS: Chromosomes in E. purpurea could be stained with Giemsa to bear C-bands. By classifying the chromosomes into groups and judging the C-bands, each chromosome could be identified. The methods established in this study might be used for the identification of chromosome constitution in aneuploid E. purpurea created in a breeding program. PMID- 28096775 TI - Effect on the expression of drd2 and drd3 after neonatal lesion in the lymphocytes, nucleus accumbens, hippocampus and prefrontal cortex: comparative analysis between juvenile and adult Wistar rats. AB - BACKGROUND: Neonatal lesion in the ventral hippocampus (NLVH) is a validated animal model to study schizophrenia from a neurodevelopmental perspective. This animal model is also used to investigate how neonatal lesions may alter the genetic expression of dopaminergic receptors. The present study compares mRNA expression levels of dopamine receptors (drd2 and drd3) in lymphocytes and brain of NLVH animals at two different age stages: young and adult. METHODS: The NLVH procedure was performed on 20 male Wistar rats at postnatal days 5-7. The mRNA expression levels of drd2 and drd3 genes in lymphocytes, nucleus accumbens, hippocampus and prefrontal cortex were measured and analyzed at postnatal days 45 and 90. The results were compared and contrasted with respective sham groups. RESULTS: In lymphocytes, only in NLVH-adult group we observed drd2 mRNA expression, while drd2 mRNA expression was not observed in the NLVH-juvenile rats; on the other hand, the drd3 mRNA expression did not show significant statistical differences. In hippocampus no differences were observed between drd2 mRNA or drd3 mRNA expression when comparing juvenile/adult shams with NLVH groups. In the prefrontal area, a decrease in drd2 mRNA expression levels were observed in the NLVH-adult group (F(1,3) = 52.83, p = 0,005) in comparison to the sham-adult group. Finally, in the nucleus accumbens, a strong decrease of drd3 mRNA expression was observed in the NLVH-adult group in comparison to the sham adult group (F(1,3) = 123,2, p < 0.001). CONCLUSIONS: Our results show that differences in drd2 and drd3 mRNA levels in NLVH-adults are patent when compared to the sham-adult group or with the NLVH-juvenile group. These findings suggest that the expression levels may be regulated during adulthood, leading to behavioral and neurochemical changes related to schizophrenia. Therefore, more studies are necessary to determine the role of dopamine receptors as possible molecular markers for neurodevelopmental changes associated with schizophrenia. PMID- 28096777 TI - Negative frequency dependent selection on sympatric mtDNA haplotypes in Drosophila subobscura. AB - BACKGROUND: Recent experimental evidence for selection on mitochondrial DNA (mtDNA) has prompted the question as to what processes act to maintain within population variation in mtDNA. Balancing selection though negative frequency dependent selection (NFDS) among sympatric haplotypes is a possibility, but direct empirical evidence for this is very scarce. FINDINGS: We extend the previous findings of a multi-generation replicated cage experiment in Drosophila subobscura, where mtDNA polymorphism was maintained in a laboratory setting. First, we use a set of Monte Carlo simulations to show that the haplotype frequency dynamics observed are inconsistent with genetic drift alone and most closely match those expected under NFDS. Second, we show that haplotype frequency changes over time were significantly different from those expected under either genetic drift or positive selection but were consistent with those expected under NFSD. CONCLUSIONS: Collectively, our analyses provide novel support for NFDS on mtDNA haplotypes, suggesting that mtDNA polymorphism may at least in part be maintained by balancing selection also in natural populations. We very briefly discuss the possible mechanisms that might be involved. PMID- 28096778 TI - PineElm_SSRdb: a microsatellite marker database identified from genomic, chloroplast, mitochondrial and EST sequences of pineapple (Ananas comosus (L.) Merrill). AB - BACKGROUND: Simple Sequence Repeats or microsatellites are resourceful molecular genetic markers. There are only few reports of SSR identification and development in pineapple. Complete genome sequence of pineapple available in the public domain can be used to develop numerous novel SSRs. Therefore, an attempt was made to identify SSRs from genomic, chloroplast, mitochondrial and EST sequences of pineapple which will help in deciphering genetic makeup of its germplasm resources. RESULTS: A total of 359511 SSRs were identified in pineapple (356385 from genome sequence, 45 from chloroplast sequence, 249 in mitochondrial sequence and 2832 from EST sequences). The list of EST-SSR markers and their details are available in the database. CONCLUSIONS: PineElm_SSRdb is an open source database available for non-commercial academic purpose at http://app.bioelm.com/ with a mapping tool which can develop circular maps of selected marker set. This database will be of immense use to breeders, researchers and graduates working on Ananas spp. and to others working on cross-species transferability of markers, investigating diversity, mapping and DNA fingerprinting. PMID- 28096779 TI - Transcriptome analysis of genes involved in anthocyanins biosynthesis and transport in berries of black and white spine grapes (Vitis davidii). AB - BACKGROUND: The color of berry skin is an important economic trait for grape and is essentially determined by the components and content of anthocyanins. The fruit color of Chinese wild grapes is generally black, and the profile of anthocyanins in Chinese wild grapes is significantly different from that of Vitis vinifera. However, V. davidii is the only species that possesses white berry varieties among Chinese wild grape species. Thus, we performed a transcriptomic analysis to compare the difference of transcriptional level in black and white V. davidii, in order to find some key genes that are related to anthocyanins accumulation in V. davidii. RESULTS: The results of anthocyanins detection revealed that 3,5-O-diglucoside anthocyanins is the predominant anthocyanins in V. davidii. It showed obvious differences from V. vinifera in the profile of the composition of anthocyanins. The transcriptome sequencing by Illumina mRNA-Seq technology generated an average of 57 million 100-base pair clean reads from each sample. Differential gene expression analysis revealed thousands of differential expression genes (DEGs) in the pairwise comparison of different fruit developmental stages between and within black and white V. davidii. After the analysis of functional category enrichment and differential expression patterns of DEGs, 46 genes were selected as the candidate genes. Some genes have been reported as being related to anthocyanins accumulation, and some genes were newly found in our study as probably being related to anthocyanins accumulation. We inferred that 3AT (VIT_03s0017g00870) played an important role in anthocyanin acylation, GST4 (VIT_04s0079g00690) and AM2 (VIT_16s0050g00910) played important roles in anthocyanins transport in V. davidii. The expression of some selected DEGs was further confirmed by quantitative real-time PCR (qRT-PCR). CONCLUSIONS: The present study investigated the transcriptomic profiles of berry skin from black and white spine grapes at three fruit developmental stages by Illumina mRNA Seq technology. It revealed the variety specificity of anthocyanins accumulation in V. davidi at the transcriptional level. The data reported here will provide a valuable resource for understanding anthocyanins accumulation in grapes, especially in V. davidii. PMID- 28096780 TI - Molecular breeding of a novel orange-brown tomato fruit with enhanced beta carotene and chlorophyll accumulation. AB - BACKGROUND: Tomatoes provide a significant dietary source of the carotenoids, lycopene and beta-carotene. During ripening, carotenoid accumulation determines the fruit colors while chlorophyll degradation. These traits have been, and continue to be, a significant focus for plant breeding efforts. Previous work has found strong evidence for a relationship between CYC-B gene expression and the orange color of fleshy fruit. Other work has identified a point mutation in SGR that impedes chlorophyll degradation and causes brown flesh color to be retained in some tomato varieties. METHODS: We crossed two inbred lines, KNY2 (orange) and KNB1 (brown) and evaluated the relationship between these genes for their effect on fruit color. Phenotypes of F2 generation plants were analyzed and a novel 'orange-brown' fruit color was identified. RESULTS: We confirm two SNPs, one in CYC-B and another in SGR gene sequence, associated with segregation of 'orange brown' fruit color in F2 generation. The carotenoid and chlorophyll content of a fleshy fruit was assessed across the different phenotypes and showed a strong correlation with expression pattern of carotenoid biosynthesis genes and SGR function. The orange-brown fruit has high beta-carotene and chlorophyll. Our results provide valuable information for breeders to develop tomato fruit of a novel color using molecular markers. PMID- 28096781 TI - A replication study of schizophrenia-related rare copy number variations in a Han Southern Chinese population. AB - BACKGROUND: Schizophrenia (SCZ) is a common, complex and severe psychiatric disorder associated with many different genetic and environmental risk factors. Evidence from genetic studies has revealed the role of genome structural variations, specifically copy number variants (CNVs), in the etiology of SCZ. Nevertheless, the occurrence of CNVs and their relation to SCZ has remained relatively unstudied in the diverse Han Chinese population. RESULTS: We used a case/control paradigm, including 476 cases and 1023 controls. All samples were genotyped using the Axiom(r) Exome Genotyping Arrays. Four CNVs, including two deletions and two duplications, were detected in this study. Notably, the 16p11.2 duplication from 29.3 Mb to 29.6 Mb was detected in four cases (0.84%) and one control (0.098%) (p = 0.0377). CONCLUSIONS: The results highlight the potential role of these deletions and duplications in the development of SCZ. Clearly, larger sample sized studies are needed for a careful localization of these CNVs and to possibly detect more deletions and/or duplications, associated with the development of SCZ in the Han Chinese population. PMID- 28096782 TI - Automatic liver segmentation on Computed Tomography using random walkers for treatment planning. AB - Segmentation of the liver from Computed Tomography (CT) volumes plays an important role during the choice of treatment strategies for liver diseases. Despite lots of attention, liver segmentation remains a challenging task due to the lack of visible edges on most boundaries of the liver coupled with high variability of both intensity patterns and anatomical appearances with all these difficulties becoming more prominent in pathological livers. To achieve a more accurate segmentation, a random walker based framework is proposed that can segment contrast-enhanced livers CT images with great accuracy and speed. Based on the location of the right lung lobe, the liver dome is automatically detected thus eliminating the need for manual initialization. The computational requirements are further minimized utilizing rib-caged area segmentation, the liver is then extracted by utilizing random walker method. The proposed method was able to achieve one of the highest accuracies reported in the literature against a mixed healthy and pathological liver dataset compared to other segmentation methods with an overlap error of 4.47 % and dice similarity coefficient of 0.94 while it showed exceptional accuracy on segmenting the pathological livers with an overlap error of 5.95 % and dice similarity coefficient of 0.91. PMID- 28096783 TI - Quantification of rutin in rat's brain by UHPLC/ESI-Q-TOF-MS/MS after intranasal administration of rutin loaded chitosan nanoparticles. AB - Rutin (RT), an antioxidant drug, has been utilized to treat cerebral ischemia hence a sensitive quantification method for estimation of RT in brain homogenate is necessary to develop. This study aims to prepare RT loaded Chitosan Nanoparticles (RT-CS-NPs) develop and validate ultra-high performance liquid chromatography-electrospray ionization-synapt mass spectrometric method Synapt Mass Spectrometry (Synapt MS) (UHPLC/ESI-QTOF-MS/MS) for quantification of RT in brain homogenate from Wistar rat. The process of chromatographic separation was carried out on Waters ACQUITY UPLCTM with the components of separation in detail as; column: BEH C-18 with dimension as 2.1 mm*100 mm and particle size 1.7 um, mobile phase: acetonitrile (85 % v/v/v): 2 mM ammonium formate (15 % v/v/v): formic acid (0.1 % v/v/v) and flow rate: 0.25 mL/min. Liquid-liquid extraction method (LLE), in mixture, i.e. ethyl acetate:acetonitrile, was considered to optimize the recovery of analyte from the brain homogenate of Wistar rat. Over a total run time of 5 minutes, the elution time for RT and internal standard (IS), i.e. Tolbutamide, observed was 2.67 and 2.82 min respectively whereas the transition observed for RT and IS was at m/z 611.1023/303.1071 and 271.1263/155.1073, respectively. Results, regarding various processes and parameters studied for RT as summarized, established a linear dynamic range over a concentration range of 1.00 ng/mL - 1000.0 ng/mL with r2; 0.9991+/-0.0010. Accuracy for intra and inter-assay in terms of % CV revealed a range of 0.45- 2.11 whereas lower limit of detection (LOD) and quantitation (LOQ) observed was 0.09 ng/mL and 0.142 ng/mL, respectively. The analyte stability as well as method specificity and accuracy, i.e. recovery > 86 %, supports the idea for application of current developed method in order to quantify and evaluate the RT-loaded-CS NPs for RT determination in brain homogenate after intranasal drug delivery. PMID- 28096784 TI - Segmenting breast cancerous regions in thermal images using fuzzy active contours. AB - Breast cancer is the main cause of death among young women in developing countries. The human body temperature carries critical medical information related to the overall body status. Abnormal rise in total and regional body temperature is a natural symptom in diagnosing many diseases. Thermal imaging (Thermography) utilizes infrared beams which are fast, non-invasive, and non contact and the output created images by this technique are flexible and useful to monitor the temperature of the human body. In some clinical studies and biopsy tests, it is necessary for the clinician to know the extent of the cancerous area. In such cases, the thermal image is very useful. In the same line, to detect the cancerous tissue core, thermal imaging is beneficial. This paper presents a fully automated approach to detect the thermal edge and core of the cancerous area in thermography images. In order to evaluate the proposed method, 60 patients with an average age of 44/9 were chosen. These cases were suspected of breast tissue disease. These patients referred to Tehran Imam Khomeini Imaging Center. Clinical examinations such as ultrasound, biopsy, questionnaire, and eventually thermography were done precisely on these individuals. Finally, the proposed model is applied for segmenting the proved abnormal area in thermal images. The proposed model is based on a fuzzy active contour designed by fuzzy logic. The presented method can segment cancerous tissue areas from its borders in thermal images of the breast area. In order to evaluate the proposed algorithm, Hausdorff and mean distance between manual and automatic method were used. Estimation of distance was conducted to accurately separate the thermal core and edge. Hausdorff distance between the proposed and the manual method for thermal core and edge was 0.4719 +/- 0.4389, 0.3171 +/- 0.1056 mm respectively, and the average distance between the proposed and the manual method for core and thermal edge was 0.0845 +/- 0.0619, 0.0710 +/- 0.0381 mm respectively. Furthermore, the sensitivity in recognizing the thermal pattern in breast tissue masses is 85 % and its accuracy is 91.98 %.A thermal imaging system has been proposed that is able to recognize abnormal breast tissue masses. This system utilizes fuzzy active contours to extract the abnormal regions automatically. PMID- 28096786 TI - Apple as a source of dietary phytonutrients: an update on the potential health benefits of apple. PMID- 28096785 TI - Nutrients as novel therapeutic approaches for metabolic disturbances in polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders among women. This disease is characterized by infertility, menstrual dysfunction, and hyperandrogenism. Also, PCOS is often associated with hyperlipidemia and impaired glucose tolerance, conditions that are associated with cardiovascular disorder, type 2 diabetes, cancer and hypertension. Evidence supports that some nutrients may affect the hormonal and metabolic disturbances of PCOS. Here in this study, we aimed to review the available literature that assessed the nutrients such as inostol, isoflavonids, resveratrol, vitamin D, and PUFA (polyunsaturated fatty acids), known to influence the hormonal and metabolic disturbances of PCOS, along with the strategies and future directions of nutrient supplementations in such patients. PMID- 28096787 TI - Current potential health benefits of sulforaphane. PMID- 28096788 TI - Current trends in the treatment of hepatitis C: interventions to avoid adverse effects and increase effectiveness of anti-HCV drugs. AB - Viral hepatitis, an inflammatory liver disease, is caused by various genotypes of hepatitis C viruses (HCV). Hepatitis C slowly sprouts into fibrosis, which progresses to cirrhosis. Over a prolonged period of time compensated cirrhosis can advance to decompensated cirrhosis culminating in hepatic failure and death. Conventional treatment of HCV involves the administration of interferons. However, association of interferon with the adverse drug reactions led to the development of novel anti-HCV drugs given as monotherapy or in combination with the other drugs. Advances in drug delivery systems (DDS) improved the pharmacokinetic profile and stability of drugs, ameliorated tissue damages on extravasation and increased the targeting of affected sites. Liposomes and lipid based vehicles have been employed with polyethylene glycol (PEG) so as to stabilize the formulations as PEG drug complex. Sofosbuvir, a novel anti-HCV drug, is administered as monotherapy or in combination with daclatasvir, ledipasivir, protease inhibitors, ribavirin and interferon for the treatment of HCV genotypes 1, 2 and 3. These drug combinations are highly effective in eradicating the interferon resistance, recurrent HCV infection in liver transplant, concurrent HIV infection and preventing interferon related adverse effects. Further investigations to improve drug targeting and identification of new drug targets are highly warranted due to the rapid emergence of drug resistance in HCV. PMID- 28096789 TI - Genotoxic and cytotoxic action potential of Terminalia citrina, a medicinal plant of ethnopharmacological significance. AB - Most herbal medicines utilized in complementary and alternative medicine lack safety evaluation setting our lives under unwarranted risks. Present study comprised of genotoxic and cytotoxic appraisal of Terminalia citrina fruits which are used as a folklore medicine for treatment of various ailments. Aqueous and ethanolic extracts of T. citrina fruit extracts were evaluated for the presence of different phytochemicals. Genotoxic potential of both the extract of T. citrina was assessed through Ames reverse mutagenicity assay in Salmonella TA 100 and 102 strains. Cytotoxic potential of T. citrina was determined in baby hamster kidney cell line (BHK-21). Statistical analysis was carried out by ANOVA following post hoc test. Phytochemical analysis showed the presence of alkaloids, carbohydrates, phenolic compounds, tannins, catechins and saponins. It was revealed that both the extracts of T. citrina exhibited significant mutagenicity in tester strains. Ethanolic extract showed higher mutagenicity in TA 100 strain, whereas aqueous extract of T. citrina exhibited higher mutagenicity in TA 102 strain than TA 100. Both the extracts of T. citrina showed dose-dependent mutagenicity. Fifty percent cell viability was exhibited by 260 and 545 ug/mL of ethanolic and aqueous extracts respectively. This study concludes that the ethanolic and aqueous fruit extracts of T. citrina may not be safe owing to their mutagenic and cytotoxic potential and it necessitates further investigation regarding its safety evaluation. PMID- 28096790 TI - Isolation, characterization and hypolipidemic activity of ferulic acid in high fat-diet-induced hyperlipidemia in laboratory rats. AB - Prosopis cineraria (L.) Druce (Leguminosae) (syn. Prosopis spicigera L.) has antidiabetic and antioxidant potential. Earlier we reported its hypolipidemic activity obtained from ethanol extract (ET-PCF). Object of this work was to isolate ferulic acid (FA) from ET-PCF and evaluate hypolipidemic activity against high-fat diet (HFD)-induced hyperlipidemic laboratory rats. ET-PCF was subjected to flash column chromatography to isolate FA. The chemical structure of the isolated compound was elucidated by UV, IR, 1H NMR,13C NMR and LC-MS. Further, the antihyperlipidemic effect of FA (10, 20 and 40 mg/kg, p.o.) in HFD-induced hyperlipidemic rats was investigated. Hyperlipidemia was induced in male Sprague Dawley rats by feeding with HFD for 60 days. Lipid parameters such as total cholesterol (TC), Low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) levels were measured in serum and hepatic tissue. Hepatic oxido-nitrosative stress (SOD, GSH, MDA and NO) were also determined. Histological evaluation of liver tissue was carried out. The structure of the isolated compound was characterized based on spectral data and confirmed as FA. HFD induced an alteration in serum, and hepatic lipid profile (triglyceride, cholesterol, HDL, and LDL) was significantly restored (p < 0.001) by administration of FA (20 and 40 mg/kg, p.o.). The elevated level of oxido-nitrosative stress in liver was significantly reduced (p < 0.001) by FA (20 and 40 mg/kg, p.o.). Histological aberration induced in the liver after HFD ingestion were restored by FA administration. Ferulic acid isolated from ET-PCF showed hypolipidemic effects in HFD-induced hyperlipidemic rats via modulation of elevated oxido-nitrosative stress. PMID- 28096791 TI - Physicochemical analyses of a bioactive 4-aminoantipyrine analogue - synthesis, crystal structure, solid state interactions, antibacterial, conformational and docking studies. AB - A novel Schiff base derivative of 4-aminoantipyrine, that is, (E)-4-(2 methoxybenzylideneamino)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one (MBA-dMPP), was synthesized and characterized by FT-IR, 1H-NMR, and EI-MS. Single-crystal X ray diffraction data revealed MBA-dMPP adopts a trans configuration around its central C=N double bond, and forms orthorhombic crystals. XRD revealed that MBA dMPP possess two different planes, in which the pyrazolone and benzylidene groups attached to C9 of the pyrazolone ring are almost coplanar and the phenyl ring connected to the N1 atom of the pyrazolone moiety lies in another plane. The intermolecular, host-guest C-H...O, C-H...N, and C-H...C van der Waals interactions were found to form a 3D network and confer stability to the MBA-dMPP crystal structure. The quantitative and qualitative solid state behaviors of MBA dMPP were subjected to 3D Hirshfeld surface analysis and 2D fingerprint plotting. Reciprocal H...H contacts contributed most (52.9 %) to the Hirshfeld surface, followed by C...H/H...C contacts (30.2 %), whereas, O...H/H...O and N...H/H...N interactions contributed 15.5 % to the Hirshfeld surface. Electrostatic potentials were mapped over the Hirshfeld surface to analyze electrostatic complementarities within the MBA-dMPP crystal. In addition, geometrical descriptors were also analyzed to the extent of surface interactions. MBA-dMPP was also investigated for in vitro antibacterial activity against Gram-positive and Gram-negative bacterial strains, and showed highest activity against Bacillus cereus (MIC = 12.5 MUg mL-1) and Salmonellatythimurium (MIC = 50 MUg mL-1). In silico screening was conducted by docking MBA-dMPP on the active site of S12 bacterial protein (an important therapeutic target of antibacterial agents) and its binding properties were compared with those of ciprofloxacin. Moreover, a field points map of MBA-dMPP ligand was studied to determine electrostatic and van der Waals forces, hydrophobic potentials, and positions involved in ligand receptor interactions. Finally, the torsion energies of crystal structure and optimized and bioactive conformers of MBA-dMPP were compared to predict its bioactive conformation. PMID- 28096792 TI - First reported case of Haemoglobin-M Hyde Park in a Malay family living in Malaysia. AB - Haemoglobin (Hb)-M Hyde Park, also known as Hb-M Akita is a rare type of hereditary Hb M due to autosomal dominant mutation of CAC>TAC on codon 92 of beta globin gene resulting in the replacement of histidine by tyrosine on beta globin chain. This variant Hb has a tendency to form methaemoglobin (metHb). The iron ion in metHb is oxidized to ferric (Fe3+) which is unable to carry oxygen and the patients manifest as cyanosis clinically. A 9-year-old Malay girl was incidentally found to be cyanotic when she presented to a health clinic. Laboratory investigations revealed raised methaemoglobin levels and Hb analysis findings were consistent with Hb-M Hyde Park. beta gene sequencing confirmed a point mutation of CAC>TAC on codon 92 in one of the beta genes. The family study done on the individuals with cyanosis showed similar findings. A diagnosis of heterozygous Hb-M Hyde Park was made. Patients with this variant Hb usually presented with cyanosis with mild haemolysis and maybe misdiagnosed as congenital heart disease. No further treatment is needed as patients are relatively asymptomatic. Although the disease is harmless in the heterozygous carriers but the offspring of the carriers may suffer severe haemolytic anaemia when the offspring also inherit other beta haemoglobinopathies/thalassemia. This can happen due to high prevalence of beta thalassemia carrier (3.5-4 %) found in Malaysia. At the time of writing, this is the first case of hereditary Hb-M Hyde Park diagnosed in a Malay family living in Malaysia. PMID- 28096794 TI - Tobacco use patterns, knowledge, attitudes towards tobacco and availability of tobacco control training among school personnel from a rural area in Poland. AB - BACKGROUND: Tobacco-free school environment as well as non-smoking teachers and school personnel provide positive role models for children and young people. In Poland, smoking should be banned in colleges, schools, educational establishments and educational care facilities. However, for the existing law to be effective, awareness of all people in school curriculum and enforcement of the law are crucial. The aim of the study was to evaluate tobacco use patterns, knowledge and attitudes towards tobacco as well as availability of tobacco control training among school personnel in a rural area in Poland. Moreover, compliance with tobacco control policies and their enforcement were assessed. METHODS: The study was carried out in Piotrkowski district between November 2014 and May 2015 in accordance with the Global School Personnel Survey (GSPS) methodology. Sixty schools participated in the survey (92% of the schools from the region) with involvement of 1044 teachers and 500 non-teaching staff (the response rate - 83.1%). The multivariate linear regression analyses were applied to study factors linked to the need for anti-tobacco training dedicated to the youth and teachers' knowledge as well as activities to educate the students about tobacco use and its prevention. RESULTS: About 24% of the school personnel were current and 9% were ex-smokers. Significantly more teachers than the non-teaching staff indicated that the schools had a policy prohibiting tobacco use among students. In addition, 6% of the study participants indicated everyday violations of the tobacco control policy by the school personnel. More than 80% of the teaching personnel indicated the need for training dedicated to the youth to prevent their tobacco use. In the multivariate linear regression model, longer duration of working experience predicted higher levels of knowledge and more activities performed to teach the youth about tobacco use and its prevention. The smokers comparing to the non-smokers perceived the need for anti- tobacco training among the youth less strongly. CONCLUSIONS: In order to make it possible for the inhabitants of Piotrkowski district to work and learn in tobacco smoke free environment there is an urgent need for taking actions aiming at increasing effectiveness of enforcing applicable tobacco control regulations in educational units. The necessity for systematic training dedicated to the youth to prevent their tobacco use, including accurate preparation of teachers, also needs to be highlighted. PMID- 28096793 TI - Efficacy of antioxidant in idiopathic pulmonary fibrosis: A systematic review and meta-analysis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic oxido-inflammatory disorder of the lung. Oxidative stress is widely recognized as a central feature of IPF. Antioxidant therapy has been proposed as an effective treatment for IPF. An array of clinical trials describing the therapeutic impact of these drugs have been reporting albeit with conflicting evidence points. We performed a meta-analysis of trials in which efficacy of antioxidant therapy was compared with control in IPF. Systematic literature search was conducted in PubMed, EMBASE, the Cochrane Library, CPCI-S (Conference Proceedings Citation Index-Science), ICTRP (International Clinical Trials Registry Platform), and Google Scholar till June 2016 by two independent researchers. Various outcomes such as changes in pulmonary function tests (change in vital capacity [DeltaVC], change in forced vital capacity [DeltaFVC], change in percentage of predicted vital capacity [Delta%VC], and change in percentage of predicted carbon monoxide diffusing capacity [Delta%DLco]), changes in 6 minutes walking test distance (Delta6MWT), rates of adverse events, and rates of death, were included. All statistical analyses were performed using RevMan V.5.3. Twelve studies (n = 1062) were identified that used antioxidants (N-acetylcysteine and lecithinized superoxide dismutase) as a treatment for IPF. Overall, there was no association of antioxidant therapy with DeltaFVC (SMD = 0.27, 95% CI:-0.07 to 0.61; P = 0.12), DeltaFVC (%) (SMD = -0.10, 95% CI:-0.56 to 0.36; P = 0.66) and 6MWT (SMD = -0.04, 95% CI:-0.11 to 0.20; P = 0.59) in IPF patients. However, combined antioxidant therapy was found to be associated with %VC (SMD = 0.37, 95% CI: 0.09 to 0.64; P = 0.008) and Delta%DLco (SMD = 0.15, 95% CI: 0.00 to 0.29; P = 0.05) in IPF patients. Strong evidence was obtained that the antioxidants increased adverse effects adverse events (OR = 1.56, 95% CI: 0.75 to 3.24; P = 0.23) but it did not associate mortality (OR = 0.96, 95% CI: 0.44 to 2.11; P = 0.92). The use of significant clinical heterogeneity, low statistical power, high dropout rates, duration of follow-ups, and dosing regimens of antioxidant agents. Combined antioxidant therapy seems to be a safe and effective therapy for IPF patients which provides a more beneficial effect in terms of VC, and DLco rather than monotherapy. Further randomized controlled trials with homogeneous outcome measures are needed. PMID- 28096795 TI - Editorial: In vivo Imaging in Pharmacological Research. PMID- 28096796 TI - Neuroendocrinology of a Male-Specific Pattern for Depression Linked to Alcohol Use Disorder and Suicidal Behavior. AB - Epidemiological studies show low rates of diagnosed depression in men compared to women. At the same time, high rates of alcohol use disorders (AUDs) and completed suicide are found among men. These data suggest that a male-specific pattern for depression may exist that is linked to AUDs and suicidal behavior. To date, no underlying neuroendocrine model for this specific pattern of male depression has been suggested. In this paper, we integrate findings related to this specific pattern of depression with underlying steroid secretion patterns, polymorphisms, and methylation profiles of key genes in order to detail an original neuroendocrine model of male-specific depression. Low circulating levels of sex steroids seem to increase the vulnerability for male depression, while concomitant high levels of glucocorticoids further intensify this vulnerability. Interactions of hypothalamus-pituitary-gonadal (HPG) and hypothalamus-pituitary adrenocortical (HPA) axis-related hormones seem to be highly relevant for a male specific pattern of depression linked to AUDs and suicidal behavior. Moreover, genetic variants and the epigenetic profiles of the androgen receptor gene, well known depression related genes, and HPA axis-related genes were shown to further interact with men's steroid secretion and thus may further contribute to the proposed male-specific pattern for depression. This mini-review points out the multilevel interactions between the HPG and HPA axis for a male-specific pattern of depression linked to AUDs and suicidal behavior. An integration of multilevel interactions within the three-hit concept of vulnerability and resilience concludes the review. PMID- 28096797 TI - Do Affective Variables Make a Difference in Consumers Behavior Toward Mobile Advertising? AB - Research into permission-based mobile marketing is increasingly common due to the widespread adoption of mobile technology and its use as a communication channel. Yet few studies have attempted to analyze the factors that determine attitudes toward mobile advertising while simultaneously considering: the links among them and consumers' intentions, behavior, and/or cognitive and affective variables simultaneously. The present research therefore sought to deepen understanding of the antecedents and consequences of attitudes toward permission-based mobile advertising. More specifically, it sought to identify the antecedents of attitudes toward mobile advertising and the bridges between these attitudes and consumers' intentions upon receiving advertising on their mobile devices. To this end, a causal model was proposed and tested with a sample of 612 mobile phone users that was collected from a panel of Spanish adults who receive advertising on their mobile phones in the form of SMS text messages. The structural model used was validated using the partial least squares (PLS) regression technique. The results show that the greatest influence was that exerted by positive emotions on feelings, suggesting that positive emotions have an indirect effect on attitude toward mobile advertising. This influence was even greater than their direct effect. Another important, though less powerful, effect was the influence of attitude on behavioral intentions to receive mobile advertising. In contrast, the influence of cognitive variables on attitude was less relevant. PMID- 28096798 TI - Building the Case for Insulin-Like Growth Factor Receptor-I Involvement in Thyroid-Associated Ophthalmopathy. AB - The pathogenesis of orbital Graves' disease (GD), a process known as thyroid associated ophthalmopathy (TAO), remains incompletely understood. The thyrotropin receptor (TSHR) represents the central autoantigen involved in GD and has been proposed as the thyroid antigen shared with the orbit that could explain the infiltration of immune cells into tissues surrounding the eye. Another cell surface protein, insulin-like growth factor-I receptor (IGF-IR), has recently been proposed as a second antigen that participates in TAO by virtue of its interactions with anti-IGF-IR antibodies generated in GD, its apparent physical and functional complex formation with TSHR, and its necessary involvement in TSHR post-receptor signaling. The proposal that IGF-IR is involved in TAO has provoked substantial debate. Furthermore, several studies from different laboratory groups, each using different experimental models, have yielded conflicting results. In this article, we attempt to summarize the biological characteristics of IGF-IR and TSHR. We also review the evidence supporting and refuting the postulate that IGF-IR is a self-antigen in GD and that it plays a potentially important role in TAO. The putative involvement of IGF-IR in disease pathogenesis carries substantial clinical implications. Specifically, blocking this receptor with monoclonal antibodies can dramatically attenuate the induction by TSH and pathogenic antibodies generated in GD of proinflammatory genes in cultured orbital fibroblasts and fibrocytes. These cell types appear critical to the development of TAO. These observations have led to the conduct of a now-completed multicenter therapeutic trial of a fully human monoclonal anti-IGF-IR blocking antibody in moderate to severe, active TAO. PMID- 28096799 TI - Spread of Botrytis cinerea Strains with Multiple Fungicide Resistance in German Horticulture. AB - Botrytis cinerea is a major plant pathogen, causing gray mold rot in a variety of cultures. Repeated fungicide applications are common but have resulted in the development of fungal populations with resistance to one or more fungicides. In this study, we have monitored fungicide resistance frequencies and the occurrence of multiple resistance in Botrytis isolates from raspberries, strawberries, grapes, stone fruits and ornamental flowers in Germany in 2010 to 2015. High frequencies of resistance to all classes of botryticides was common in all cultures, and isolates with multiple fungicide resistance represented a major part of the populations. A monitoring in a raspberry field over six seasons revealed a continuous increase in resistance frequencies and the emergence of multiresistant Botrytis strains. In a cherry orchard and a vineyard, evidence of the immigration of multiresistant strains from the outside was obtained. Inoculation experiments with fungicide-treated leaves in the laboratory and with strawberry plants cultivated in the greenhouse or outdoors revealed a nearly complete loss of fungicide efficacy against multiresistant strains. B. cinerea field strains carrying multiple resistance mutations against all classes of site specific fungicides were found to show similar fitness as sensitive field strains under laboratory conditions, based on their vegetative growth, reproduction, stress resistance, virulence and competitiveness in mixed infection experiments. Our data indicate an alarming increase in the occurrence of multiresistance in B. cinerea populations from different cultures, which presents a major threat to the chemical control of gray mold. PMID- 28096800 TI - Interferon-Induced Transmembrane Protein 3 Inhibits Hantaan Virus Infection, and Its Single Nucleotide Polymorphism rs12252 Influences the Severity of Hemorrhagic Fever with Renal Syndrome. AB - Hantaan virus (HTNV) causes hemorrhagic fever with renal syndrome (HFRS). Previous studies have identified interferon-induced transmembrane proteins (IFITMs) as an interferon-stimulated gene family. However, the role of IFITMs in HTNV infection is unclear. In this study, we observed that IFITM3 single nucleotide polymorphisms (SNP) rs12252 C allele and CC genotype associated with the disease severity and HTNV load in the plasma of HFRS patients. In vitro experiments showed that the truncated protein produced by the rs12252 C allele exhibited an impaired anti-HTNV activity. We also proved that IFITM3 was able to inhibit HTNV infection in both HUVEC and A549 cells by overexpression and RNAi assays, likely via a mechanism of inhibiting virus entry demonstrated by binding and entry assay. Localization of IFITM3 in late endosomes was also observed. In addition, we demonstrated that the transcription of IFITM3 is negatively regulated by an lncRNA negative regulator of interferon response (NRIR). Taken together, we conclude that IFITM3, negatively regulated by NRIR, inhibits HTNV infection, and its SNP rs12252 correlates with the plasma HTNV load and the disease severity of patients with HFRS. PMID- 28096801 TI - Protective Effects of Platycodin D on Lipopolysaccharide-Induced Acute Lung Injury by Activating LXRalpha-ABCA1 Signaling Pathway. AB - The purpose of this study was to investigate the protective effects of platycodin D (PLD) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and clarify the possible mechanism. An LPS-induced ALI model was used to confirm the anti inflammatory activity of PLD in vivo. The A549 lung epithelial cells were used to investigate the molecular mechanism and targets of PLD in vitro. In vivo, the results showed that PLD significantly attenuated lung histopathologic changes, myeloperoxidase activity, and pro-inflammatory cytokines levels, including TNF alpha, IL-1beta, and IL-6. In vitro, PLD inhibited LPS-induced IL-6 and IL-8 production in LPS-stimulated A549 lung epithelial cells. Western blot analysis showed that PLD suppressed LPS-induced NF-kappaB and IRF3 activation. Moreover, PLD did not act though affecting the expression of TLR4. We also showed that PLD disrupted the formation of lipid rafts by depleting cholesterol and prevented LPS induced TLR4 trafficking to lipid rafts, thereby blocking LPS-induced inflammatory response. Finally, PLD activated LXRalpha-ABCA1-dependent cholesterol efflux. Knockdown of LXRalpha abrogated the anti-inflammatory effects of PLD. The anti-inflammatory effects of PLD was associated with upregulation of the LXRalpha-ABCA1 pathway, which resulted in disrupting lipid rafts by depleting cholesterol and reducing translocation of TLR4 to lipid rafts. PMID- 28096802 TI - A Regulatory miRNA-mRNA Network Is Associated with Tissue Repair Induced by Mesenchymal Stromal Cells in Acute Kidney Injury. AB - Mesenchymal stromal cells (MSCs) orchestrate tissue repair by releasing cell derived microvesicles (MVs), which, presumably by small RNA species, modulate global gene expression. The knowledge of miRNA/mRNA signatures linked to a reparative status may elucidate some of the molecular events associated with MSC protection. Here, we used a model of cisplatin-induced kidney injury (acute kidney injury) to assess how MSCs or MVs could restore tissue function. MSCs and MVs presented similar protective effects, which were evidenced in vivo and in vitro by modulating apoptosis, inflammation, oxidative stress, and a set of prosurvival molecules. In addition, we observed that miRNAs (i.e., miR-880, miR 141, miR-377, and miR-21) were modulated, thereby showing active participation on regenerative process. Subsequently, we identified that MSC regulates a particular miRNA subset which mRNA targets are associated with Wnt/TGF-beta, fibrosis, and epithelial-mesenchymal transition signaling pathways. Our results suggest that MSCs release MVs that transcriptionally reprogram injured cells, thereby modulating a specific miRNA-mRNA network. PMID- 28096803 TI - Host and Viral Modulation of RIG-I-Mediated Antiviral Immunity. AB - Innate immunity is the first line of defense against invading pathogens. Rapid and efficient detection of pathogen-associated molecular patterns via pattern recognition receptors is essential for the host to mount defensive and protective responses. Retinoic acid-inducible gene-I (RIG-I) is critical in triggering antiviral and inflammatory responses for the control of viral replication in response to cytoplasmic virus-specific RNA structures. Upon viral RNA recognition, RIG-I recruits the mitochondrial adaptor protein mitochondrial antiviral signaling protein, which leads to a signaling cascade that coordinates the induction of type I interferons (IFNs), as well as a large variety of antiviral interferon-stimulated genes. The RIG-I activation is tightly regulated via various posttranslational modifications for the prevention of aberrant innate immune signaling. By contrast, viruses have evolved mechanisms of evasion, such as sequestrating viral structures from RIG-I detections and targeting receptor or signaling molecules for degradation. These virus-host interactions have broadened our understanding of viral pathogenesis and provided insights into the function of the RIG-I pathway. In this review, we summarize the recent advances regarding RIG-I pathogen recognition and signaling transduction, cell-intrinsic control of RIG-I activation, and the viral antagonism of RIG-I signaling. PMID- 28096805 TI - Improving of Rice Blast Resistances in Japonica by Pyramiding Major R Genes. AB - Rice blast, caused by the fungal pathogen Magnaporthe oryzae, is a major constraint to rice production worldwide. In this study, we developed monogenic near-isogenic lines (NILs) NIL Pi9, NIL Pizt , and NIL Pi54 carrying genes Pi9, Pizt, and Pi54, respectively, by marker assisted backcross breeding using 07GY31 as the japonica genetic background with good agronomic traits. Polygene pyramid lines (PPLs) PPL Pi9+Pi54 combining Pi9 with Pi54, and PPL Pizt+Pi54 combining Pizt with Pi54 were then developed using corresponding NILs with genetic background recovery rates of more than 97%. Compared to 07GY31, the above NILs and PPLs exhibited significantly enhanced resistance frequencies (RFs) for both leaf and panicle blasts. RFs of both PPLs for leaf blast were somewhat higher than those of their own parental NILs, respectively, and PPL Pizt+Pi54 exhibited higher RF for panicle blast than NIL Pizt and NIL Pi54 (P < 0.001), hinting an additive effect on the resistance. However, PPL Pi9+Pi54 exhibited lower RF for panicle blast than NIL Pi9 (P < 0.001), failing to realize an additive effect. PPL Pizt+Pi54 showed higher resistant level for panicle blast and better additive effects on the resistance than PPL Pi9+Pi54. It was suggested that major R genes interacted with each other in a way more complex than additive effect in determining panicle blast resistance levels. Genotyping by sequencing analysis and extreme-phenotype genome-wide association study further confirmed the above results. Moreover, data showed that pyramiding multiple resistance genes did not affect the performance of basic agronomic traits. So the way to enhance levels of leaf and panicle blast resistances for rice breeding in this study is effective and may serve as a reference for breeders. Key Message: Resistant levels of rice blast is resulted from different combinations of major R genes, PPL Pizt+Pi54 showed higher resistant level and better additive effects on the panicle blast resistance than PPL Pi9+Pi54. PMID- 28096804 TI - Divide, Conquer, and Sense: CD8+CD28- T Cells in Perspective. AB - Understanding the rationale for the generation of a pool of highly differentiated effector memory CD8+ T cells displaying a weakened capacity to scrutinize for peptides complexed with major histocompatibility class I molecules via their T cell receptor, lacking the "signal 2" CD28 receptor, and yet expressing a highly diverse array of innate receptors, from natural killer receptors, interleukin receptors, and damage-associated molecular pattern receptors, among others, is one of the most challenging issues in contemporary human immunology. The prevalence of these differentiated CD8+ T cells, also known as CD8+CD28-, CD8+KIR+, NK-like CD8+ T cells, or innate CD8+ T cells, in non-lymphoid organs and tissues, in peripheral blood of healthy elderly, namely centenarians, but also in stressful and chronic inflammatory conditions suggests that they are not merely end-of-the-line dysfunctional cells. These experienced CD8+ T cells are highly diverse and capable of sensing a variety of TCR-independent signals, which enables them to respond and fine-tune tissue homeostasis. PMID- 28096808 TI - Recent Advances in Microwave Imaging for Breast Cancer Detection. AB - Breast cancer is a disease that occurs most often in female cancer patients. Early detection can significantly reduce the mortality rate. Microwave breast imaging, which is noninvasive and harmless to human, offers a promising alternative method to mammography. This paper presents a review of recent advances in microwave imaging for breast cancer detection. We conclude by introducing new research on a microwave imaging system with time-domain measurement that achieves short measurement time and low system cost. In the time domain measurement system, scan time would take less than 1 sec, and it does not require very expensive equipment such as VNA. PMID- 28096806 TI - A Systems Approach Implicates a Brain Mitochondrial Oxidative Homeostasis Co expression Network in Genetic Vulnerability to Alcohol Withdrawal. AB - Genetic factors significantly affect vulnerability to alcohol dependence (alcoholism). We previously identified quantitative trait loci on distal mouse chromosome 1 with large effects on predisposition to alcohol physiological dependence and associated withdrawal following both chronic and acute alcohol exposure in mice (Alcdp1 and Alcw1, respectively). We fine-mapped these loci to a 1.1-1.7 Mb interval syntenic with human 1q23.2-23.3. Alcw1/Alcdp1 interval genes show remarkable genetic variation among mice derived from the C57BL/6J and DBA/2J strains, the two most widely studied genetic animal models for alcohol-related traits. Here, we report the creation of a novel recombinant Alcw1/Alcdp1 congenic model (R2) in which the Alcw1/Alcdp1 interval from a donor C57BL/6J strain is introgressed onto a uniform, inbred DBA/2J genetic background. As expected, R2 mice demonstrate significantly less severe alcohol withdrawal compared to wild type littermates. Additionally, comparing R2 and background strain animals, as well as reciprocal congenic (R8) and appropriate background strain animals, we assessed Alcw1/Alcdp1 dependent brain gene expression using microarray and quantitative PCR analyses. To our knowledge this includes the first Weighted Gene Co-expression Network Analysis using reciprocal congenic models. Importantly, this allows detection of co-expression patterns limited to one or common to both genetic backgrounds with high or low predisposition to alcohol withdrawal severity. The gene expression patterns (modules) in common contain genes related to oxidative phosphorylation, building upon human and animal model studies that implicate involvement of oxidative phosphorylation in alcohol use disorders (AUDs). Finally, we demonstrate that administration of N-acetylcysteine, an FDA approved antioxidant, significantly reduces symptoms of alcohol withdrawal (convulsions) in mice, thus validating a phenotypic role for this network. Taken together, these studies support the importance of mitochondrial oxidative homeostasis in alcohol withdrawal and identify this network as a valuable therapeutic target in human AUDs. PMID- 28096809 TI - Low-Rank Linear Dynamical Systems for Motor Imagery EEG. AB - The common spatial pattern (CSP) and other spatiospectral feature extraction methods have become the most effective and successful approaches to solve the problem of motor imagery electroencephalography (MI-EEG) pattern recognition from multichannel neural activity in recent years. However, these methods need a lot of preprocessing and postprocessing such as filtering, demean, and spatiospectral feature fusion, which influence the classification accuracy easily. In this paper, we utilize linear dynamical systems (LDSs) for EEG signals feature extraction and classification. LDSs model has lots of advantages such as simultaneous spatial and temporal feature matrix generation, free of preprocessing or postprocessing, and low cost. Furthermore, a low-rank matrix decomposition approach is introduced to get rid of noise and resting state component in order to improve the robustness of the system. Then, we propose a low-rank LDSs algorithm to decompose feature subspace of LDSs on finite Grassmannian and obtain a better performance. Extensive experiments are carried out on public dataset from "BCI Competition III Dataset IVa" and "BCI Competition IV Database 2a." The results show that our proposed three methods yield higher accuracies compared with prevailing approaches such as CSP and CSSP. PMID- 28096807 TI - Incorporating Colour Information for Computer-Aided Diagnosis of Melanoma from Dermoscopy Images: A Retrospective Survey and Critical Analysis. AB - Cutaneous melanoma is the most life-threatening form of skin cancer. Although advanced melanoma is often considered as incurable, if detected and excised early, the prognosis is promising. Today, clinicians use computer vision in an increasing number of applications to aid early detection of melanoma through dermatological image analysis (dermoscopy images, in particular). Colour assessment is essential for the clinical diagnosis of skin cancers. Due to this diagnostic importance, many studies have either focused on or employed colour features as a constituent part of their skin lesion analysis systems. These studies range from using low-level colour features, such as simple statistical measures of colours occurring in the lesion, to availing themselves of high-level semantic features such as the presence of blue-white veil, globules, or colour variegation in the lesion. This paper provides a retrospective survey and critical analysis of contributions in this research direction. PMID- 28096810 TI - Duodenal Rare Neuroendocrine Tumor: Clinicopathological Characteristics of Patients with Gangliocytic Paraganglioma. AB - Gangliocytic paraganglioma (GP) has been regarded as a rare benign tumor that commonly arises from the second part of the duodenum. As GP does not exhibit either prominent mitotic activity or Ki-67 immunoreactivity, it is often misdiagnosed as neuroendocrine tumor (NET) G1. However, the prognosis might be better in patients with GP than in those with NET G1. Therefore, it is important to differentiate GP from NET G1. Moreover, our previous study indicated that GP accounts for a substantial, constant percentage of duodenal NETs. In the present article, we describe up-to-date data on the clinicopathological characteristics of GP and on the immunohistochemical findings that can help differentiate GP from NET G1, as largely revealed in our new and larger literature survey and recent multi-institutional retrospective study. Furthermore, we would like to refer to differential diagnosis and clinical management of this tumor and provide intriguing information about the risk factors for lymph node metastasis on GP. PMID- 28096811 TI - Cerebral Hemodynamics and Cognitive Function in Cirrhotic Patients with Hepatic Encephalopathy. AB - : Aims. To investigate cerebral hemodynamics in cirrhotic patients with HE and to observe effects of treatment in cerebral hemodynamics and correlations among ammonia, cerebral hemodynamics, and cognitive function. Methods. There were four groups: healthy controls (group 1), cirrhosis without HE (group 2), cirrhosis with MHE (group 3), and cirrhosis with OHE (group 4). Ammonia and cerebral hemodynamics (by TCD) were assessed. Patients in group 3 were subsequently randomized to two subgroups: the control (group A) and the treated (group B, treated with lactulose for two months), and they were retested for ammonia and TCD after treatment. RESULTS: Ammonia, Vm , Vd , PI, and RI were statistically different before treatment, and ammonia, PI, and RI levels paralleled the severity of HE (P < 0.05). In group B, Vd increased and ammonia, PI, and RI declined following treatment (P < 0.05), while there were no differences in group A (P > 0.05). Correlations were found between ammonia and Vd , PI, RI, NCT-A, and DST and also found between Vd , PI, RI, and NCT-A and DST (P < 0.05). Conclusions. This study revealed that cerebral hemodynamics were related to the severity of HE and cerebral autoregulation was impaired. There were tight correlations among ammonia, cerebral hemodynamics, and cognitive function, and, following treatment, cerebral hemodynamics improved. PMID- 28096812 TI - Does Leaving the Biopsy Needle in Povidone-Iodine Solution Reduce Infective Complications after Biopsy? AB - Aim. The aim of this study is to evaluate whether leaving the biopsy needle used during prostate needle biopsy in 10% povidone-iodine (betadine) solution affects the infectious complications forming after biopsy. Material and Method. This study retrospectively evaluated the data of 176 patients with prostate biopsy performed between December 2012 and April 2014. Patients in Group 1 (n = 89) were given ofloxacin as a prophylactic antibiotic before biopsy. Patients in Group 2 (n = 87) had the biopsy needle left in povidone-iodine solution for 1 minute before each use, in addition to antibiotic prophylaxis. The two groups were compared in terms of infective complications developing after biopsy. Results were analyzed using the Mann-Whitney U test and Fisher's exact test. Results. The distribution of infective complications after biopsy according to group was as follows. Group 1, not using betadine, had 15.7% fever, 13.5% hospital stay, 12.4% urinary retention, 10.1% prostatitis, and 5.6% sepsis. The distribution of the same complications in Group 2 using betadine was identified as 5.7% fever, 4.6% hospital stay, 3.4% urinary retention, 2.3% prostatitis, and 0% sepsis. The use of betadine was found to significantly reduce the infectious complications after biopsy compared to the control group (p < 0.05). Conclusion. At the end of this study leaving the prostate needle in povidone-iodine solution before each use during prostate biopsy was found to reduce the infective complications and hospital stay after biopsy. PMID- 28096813 TI - Corrigendum to "Structural Stability, Transitions, and Interactions within SoxYZCD-Thiosulphate from Sulfurimonas denitrificans: An In Silico Molecular Outlook for Maintaining Environmental Sulphur Cycle". AB - [This corrects the article DOI: 10.1155/2016/8683713.]. PMID- 28096814 TI - Hyaluromycin, a Novel Hyaluronidase Inhibitor, Attenuates Pancreatic Cancer Cell Migration and Proliferation. AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by accelerated production and degradation of hyaluronan (HA), a major component of extracellular matrix involved in the malignant phenotype of cancer. In particular, increased hyaluronidase (HYAL) activity plays a critical role in cancer progression, at least in part, by producing low-molecular-weight- (LMW-) HA or small fragments of HA, suggesting HYAL as a target for cancer treatment. Hyaluromycin, a new member of the rubromycin family of antibiotics, was isolated from the culture extract of a marine-derived Streptomyces hyaluromycini as a HYAL inhibitor. We investigated the antitumor effects of hyaluromycin in PDAC cells. We examined the effects of hyaluromycin on the proliferation and migration of PDAC cells. To elucidate the mechanisms underlying the effect of hyaluromycin on PDAC cells, we examined the concentration of LMW-HA in the conditioned media after treating PDAC cells with hyaluromycin. We demonstrate that hyaluromycin inhibits proliferation and migration of PDAC cells. We also found that these antitumor effects of hyaluromycin were associated with a decreased concentration of LMW-HA and a decreased phosphorylation of ribosomal protein S6. Our results suggest that hyaluromycin is a promising new drug against this highly aggressive neoplasm. PMID- 28096815 TI - Accuracy of Multiple Pour Cast from Various Elastomer Impression Methods. AB - The accurate duplicate cast obtained from a single impression reduces the profession clinical time, patient inconvenience, and extra material cost. The stainless steel working cast model assembly consisting of two abutments and one pontic area was fabricated. Two sets of six each custom aluminum trays were fabricated, with five mm spacer and two mm spacer. The impression methods evaluated during the study were additional silicone putty reline (two steps), heavy-light body (one step), monophase (one step), and polyether (one step). Type IV gypsum casts were poured at the interval of one hour, 12 hours, 24 hours, and 48 hours. The resultant cast was measured with traveling microscope for the comparative dimensional accuracy. The data obtained were subjected to Analysis of Variance test at significance level <0.05. The die obtained from two-step putty reline impression techniques had the percentage of variation for the height -0.36 to -0.97%, while diameter was increased by 0.40-0.90%. The values for one-step heavy-light body impression dies, additional silicone monophase impressions, and polyether were -0.73 to -1.21%, -1.34%, and -1.46% for the height and 0.50-0.80%, 1.20%, and -1.30% for the width, respectively. PMID- 28096816 TI - Optimization of the Medium for the Production of Extracellular Amylase by the Pseudomonas stutzeri ISL B5 Isolated from Municipal Solid Waste. AB - The management of municipal solid waste is one of the major problems of the present world. The use of microbial enzymes for sustainable management of the solid waste is the need of the time. In the present study, we have isolated a potent amylase producing strain (ISL B5) from municipal solid waste. The strain was identified as Pseudomonas stutzeri (P. stutzeri) both biochemically and by 16S rDNA sequencing. The optimization studies revealed that the strain ISL B5 exhibited maximum activity in the liquid media containing 2% starch (2.77 U/ml), 0.8% peptone (2.77 U/ml), and 0.001% Ca2+ ion (2.49 U/ml) under the pH 7.5 (2.59 U/ml), temperature 40 degrees C (2.63 U/ml), and 25 h of incubation period (2.49 U/ml). The highest activity of crude enzyme has also been optimized at the pH 8 (2.49 U/ml). PMID- 28096817 TI - Heralding Extramedullary Blast Crisis: Horner's Syndrome with Brachial Plexopathy in a Patient with Chronic Myelogenous Leukemia. AB - Chronic myelogenous leukemia (CML) blast crisis is an ominous clinical event that is challenging to treat. This can develop at extramedullary sites rarely and is defined as the infiltration of blasts outside the bone marrow irrespective of proliferation of blasts within the bone marrow. We aim to report an unusual clinical presentation characterized by Horner's syndrome, ipsilateral arm weakness, and cervical lymphadenopathy as the first signs of extramedullary blast crisis in a CML patient. To the best of our knowledge, the extramedullary locations involving the brachial plexus along with cervicothoracic paraspinal chloroma have not been previously reported in the literature. PMID- 28096818 TI - Associated Factors to Seroprevalence of Ehrlichia spp. in Dogs of Quintana Roo, Mexico. AB - The objective of this study was to determine the seroprevalence to Ehrlichia spp. in dogs from Xcalak, Quintana Roo, Mexico, and the associated factors. Serum samples were obtained from 118 dogs and used in an indirect immunofluorescent assay test for the detection of antibodies against Ehrlichia spp. A questionnaire was used to obtain information about possible variables associated with seroprevalence. These variables were analyzed through Chi2 test and logistic regression. Dog seroprevalence of antibodies against Ehrlichia spp. was 64% (75/118). Fifty-two percent (61/118) of dogs had tick infestation which was identified as Rhipicephalus sanguineus sensu lato. Anemia was observed in 36% of dogs. Leucopenia (2.5%), thrombocytopenia (70%), and hemorrhage (14%) were also observed. Thirty-one percent (23/75) of dogs with anemia, 4% (3/75) of dogs with leucopenia, 80% (60/75) of dogs with thrombocytopenia, 17% (13/75) of dogs with hemorrhages, and 59% (44/75) of dogs with ticks were positive for Ehrlichia spp. antibodies. The factors associated with seroprevalence were age (1-3 and >3 years old, OR = 7.77 and OR = 15.39, resp.), tick infestation (OR = 3.13), and thrombocytopenia (OR = 3.36). In conclusion, seroprevalence of Ehrlichia spp. was high in the community of Xcalak and its associated factors were age, tick infestation, and thrombocytopenia. PMID- 28096819 TI - Urinary Schistosomiasis among Children in Murbai and Surbai Communities of Ardo Kola Local Government Area, Taraba State, Nigeria. AB - Background. This cross-sectional study was conducted to determine the prevalence, intensity of infection, and risk factors associated with urinary schistosomiasis among children in Murbai and Surbai communities of Ardo-Kola Local Government Area (LGA), Taraba State, Nigeria. Methods. Urine samples were analysed by the standard filtration technique using 10 ml syringe, Swinnex polypropylene filter holder (13 mm diameter), and polycarbonate membrane filters (12 MUm porosity). Sociodemographic data and water contact activities were collated from children using structured questionnaires. Results. A point prevalence of 58.54% was reported out of the urine samples examined. Males were significantly more infected than their female counterparts (71.15% versus 43.66%, chi2 = 89.12, p = 0.000). The age-related prevalence showed 6-10 and 11-15 years significantly infected with 78.70% and 73.02%, respectively (chi2 = 89.12, p = 0.000). Light intensity of infection, 62.51%, was significantly higher than heavy intensity, 37.48%, among the infected children (chi2 = 365.8, p = 0.000). Water contact activities such as fishing (OR = 4.01, CI = 3.04-5.61, p = 0.000), rice farming (OR = 4.01, CI = 2.96-5.36, p = 0.000), and dry season farming (OR = 4.78, CI = 3.68-6.22, p = 0.000) were the risk factors exposing children to infection in the area. Conclusion. There is an urgent need to undertake a large scale deworming control programme using praziquantel in the area. PMID- 28096820 TI - Increase in the Risk of Respiratory Disorders in Adults and Children Related to Crop-Growing in Niger. AB - Background and Objective. Environmental factors are an increasing concern for respiratory health in developing countries. The objective of this study was to investigate whether Nigerien people living in cultivated areas have more respiratory symptoms than those living in pastoral areas. Method. A cross sectional study was conducted in 2013 in two populations during the rainy season when land is cultivated. Environmental factors including pesticide use and respiratory symptoms were collected in adults and children during face-to-face interviews. Multivariate analysis between exposures and symptoms was performed in children and in adults separately. Results. The study included 471 adults and 229 children. Overall, none of the households reported the use of pesticides for agricultural purposes. However, 87.2% reported the use of insecticides at home. Multivariate analysis showed that people living in agricultural areas compared to those in pastoral areas had an increased risk of respiratory symptoms in adults (wheezing, dyspnea, sudden shortness of breath, and cough without fever) and in children (cough without fever). The use of insecticides showed no effect on respiratory symptoms after adjustment. Conclusion. This first epidemiological study on the environment and respiratory health conducted in Niger demonstrates a significant relationship between respiratory manifestations and the agricultural characteristics of the living area. However only the effect of insecticides in the home on respiratory health was observed. PMID- 28096821 TI - Comment on "A Cluster of Three Cases of Hantavirus Pulmonary Syndrome among Canadian Military Personnel". PMID- 28096822 TI - Molecular Detection of Anaplasma spp. and Ehrlichia spp. in Ruminants from Twelve Provinces of China. AB - Anaplasma spp. and Ehrlichia spp. are tick-transmitted bacteria that are of significant economic importance as they can infect large and small ruminants and also people. There is little information on anaplasmosis and ehrlichiosis in ruminants in China. 16S rRNA FRET-qPCRs were used to screen convenience whole blood samples from 2,240 domestic ruminants in 12 provinces of China for Anaplasma spp. and Ehrlichia spp. Positive samples were further analyzed with a standard PCR for the gltA. Anaplasma spp. DNA was detected in the sheep (11.7%; 13/111), goats (81.8%; 219/270), cattle (13.2%; 241/1,830), and water buffaloes (6.9%; 2/29). Ehrlichia spp. DNA was detected in sheep (1.8%; 2/111), goats (1.1%; 3/270), and cattle (3.6%; 65/1830) but not in water buffaloes (0/29). Sequencing of gltA PCR products showed that A. marginale, A. ovis, Ehrlichia canis, and Ehrlichia sp. (JX629807) were present in ruminants from China, while the 16S rRNA FRET-qPCR sequence data indicated that there might also be A. platys, A. phagocytophilum, Anaplasma sp. BL126-13 (KJ410243), and Anaplasma sp. JC3-6 (KM227012). Our study shows that domestic ruminants from China are not uncommonly infected with a variety of Anaplasma spp. and Ehrlichia spp. PMID- 28096823 TI - Comparison of del Nido cardioplegia and St. Thomas Hospital solution - two types of cardioplegia in adult cardiac surgery. AB - INTRODUCTION: St. Thomas' cardioplegic solution No. 2 (ST), although most widely used in adult cardiac surgery, needs to be given at short intervals, causing additional myocardial injury. AIM: To determine whether del Nido (DN) cardioplegia, with longer periods of arrest, provides equivalent myocardial protection as compared to ST. MATERIAL AND METHODS: The study population comprised 100 patients who underwent elective coronary artery bypass grafting (CABG) or double valve replacement (DVR) surgery between January 2015 and January 2016. The patients were divided into two groups based on the type of cardioplegia administered during surgery: 1) intermittent ST (ST, n = 50) and 2) DN cardioplegia (DN, n = 50). We compared the aortic cross clamp (CC) and cardiopulmonary bypass (CPB) times, number of intra-operative DC shocks required, and postoperative changes in left ventricular ejection fraction (LVEF) in the two groups. RESULTS: The aortic cross clamp and bypass times were shorter with DN (110.15 +/-36.84 vs. 133.56 +/-35.66 and 158.60 +/-39.92 vs. 179.81 +/-42.36 min respectively, p < 0.05). Fewer cardioplegia doses were required in the DN group vs. the ST group (1.38 +/-0.59 vs. 4.15 +/-1.26; p = 0.001), while a single cardioplegia dose was given to 35 DN patients (70%) vs. 0 ST patients (p < 0.001). Postoperative LVEF was better preserved in the DN group. CONCLUSIONS: The use of DN leads to shorter cross clamp and CPB times, reduces cardioplegia dosage, and provides potentially better myocardial protection in terms of LVEF preservation, with a safety profile comparable to ST cardioplegia. PMID- 28096824 TI - Extended myectomy in the treatment of patients with hypertrophic obstructive cardiomyopathy. AB - INTRODUCTION: Partial resection of the septal muscle is a well-established and effective method of surgical treatment for patients with hypertrophic obstructive cardiomyopathy (HOCM). The procedure is characterized by a low operative mortality rate and long-term clinical improvement that has been confirmed in numerous publications. Mitral insufficiency in patients with HOCM is mostly functional due to the effect of systolic anterior motion (SAM). AIM: To present the early results of surgical treatment provided to HOCM patients and to compare the effectiveness of two surgical procedures: isolated myectomy and myectomy combined with mitral valve replacement. MATERIAL AND METHODS: The study analyzed a group of 49 patients (20 women) with HOCM who underwent surgical treatment between 2012 and 2015. Isolated myectomy was performed in 67.25% (n = 33) of patients, myectomy combined with mitral valve replacement in 30.61% (n = 15), and 1 (2.04%) patient underwent myectomy combined with mitral valvuloplasty (papillary muscle repositioning). RESULTS: A greater reduction of the left ventricular outflow tract (LVOT) gradient was observed in the population with concomitant mitral valve replacement in comparison to patients after isolated myectomy; the difference was statistically significant (p = 0.020). No significant correlation was observed between residual SAM and the grade of mitral regurgitation (p = 0.699) or between residual SAM and the LVOT gradient (p = 0.280). CONCLUSIONS: Surgical myectomy is a well-established, effective method of reducing increased LVOT gradients in patients with HOCM. Additional mitral valve replacement may be associated with greater reductions of the LVOT gradient in the early postoperative period. Valve replacement should be considered in patients with concomitant mitral valve degeneration and patients with narrowed left ventricular cavities. PMID- 28096825 TI - Determination of the value of glycated hemoglobin HbA1c and fructosamine in assessing the risk of perioperative complications after cardiac surgery in patients with type 2 diabetes. AB - INTRODUCTION: Patients with diabetes have a worse postoperative course and longer length of hospital stay after surgery. A good indicator of proper long-term (3 months) glycemic control is glycated hemoglobin (HbA1c), and fructosamine in the short term (2-3 weeks). AIM: To determine the degree of glycemic control evaluated preoperatively by HbA1c and/or fructosamine influence on the postoperative course of patients with diabetes undergoing coronary artery bypass grafting (CABG) in 2014-2015. MATERIAL AND METHODS: Before the operation HbA1c (N < 7.0) and fructosamine (N < 280 umol/l) were measured and depending on the results the respondents were divided into 4 groups: group I (n = 46) - normal both parameters; group II (n = 22) - high both values; group III (n = 4) - normal fructosamine/HbA1c high; group IV (n = 33) - high HbA1c/fructosamine normal. Statistical analysis was performed using the t-test assuming p < 0.05 to be statistically significant. RESULTS: One hundred and five patients were treated by CABG/OPCAB (39 female, 66 males). The mean age was 65.7 +/-7.3, HbA1c: 7.23 +/ 1.2%, fructosamine: 261.8 +/-43.8. There was no difference in the incidence of other postoperative complications between the two groups. CONCLUSIONS: Glycated hemoglobin and fructosamine levels to a similar extent define the risk of perioperative complications in patients undergoing cardiac surgery. In patients in whom there is a need to quickly compensate for elevated blood glucose consider enabling determination of fructosamine. PMID- 28096826 TI - POL-TAVI - Polish Registry of Transcatheter Aortic Valve Implantation - simple tool, great value, rationale and design. AB - Aortic stenosis (AS) is the most common valvular heart disease in adults in Europe and North America. Management of AS patients depends on accurate diagnosis of the cause and stage of the disease process: the first and definitive therapeutic choice for a growing number of elderly patients with symptomatic AS is surgical treatment. In patients not eligible for surgery, transcatheter aortic valve implantation (TAVI) constitutes a safe and effective alternative. As an innovative, costly method of treatment, it requires however careful monitoring of its course, documenting its early and long-term results, and assessment of its safety and medical-economic cost-effectiveness. A medical registry seems to be an excellent tool to perform such analysis. The aim of this paper is to present the design and rationale for creation of the first National Cardiac-Cardiac Surgical Registry of Percutaneous Aortic Valve Treatment POL-TAVI, to describe its genesis and to highlight its key assumptions and aims. Despite its recent beginnings, the POL-TAVI Registry has already demonstrated its value and usability in monitoring and assessment of TAVI procedures, leading to further improvement and development of this new method in Poland. It constitutes an important and valuable tool for patients, the medical community and the payer. PMID- 28096827 TI - Lung exposure during simultaneous myocardial revascularization and lung surgery through median sternotomy. AB - Coronary artery disease is a frequent comorbidity in patients undergoing major thoracic surgery. Simultaneous operations eliminate the necessity of a second operation and, more importantly, minimize the delay in compulsory postoperative oncological therapy. We describe a relaxing incision in the contralateral pericardium, which allows for simple displacement of the heart. This maneuver improves exposure of the pulmonary hilum and middle mediastinum on the side of resection. PMID- 28096828 TI - Intramural esophageal tumors. AB - INTRODUCTION: Intramural esophageal tumors (IET) are located between unchanged mucous membrane and muscularis mucosae. They can be both benign and malignant. AIM: To evaluate diagnostic and therapeutic difficulties of IET. MATERIAL AND METHODS: During the years 2010-2015, 11 patients with IET were treated in our clinic. Diagnostics included gastroscopy, computed tomography of the chest, endoscopic ultrasound (EUS) guided fine needle biopsy, and positron emission tomography (PET) of the esophagus in cases with no histopathological confirmation. RESULTS: Based on the conducted analysis we diagnosed 1 case of gastrointestinal stromal tumor (GIST), 1 case of adenocarcinoma, and 2 cases of esophageal cysts. In another 7 cases radiological images resembled leiomyoma but with no histopathological confirmation. Esophagectomy was performed in 2 cases of malignant tumors and 1 case of a large benign tumor. In other cases surgical enucleation of tumors was performed. Postoperatively we diagnosed 6 cases of leiomyoma, 1 case of schwannoma, 2 esophageal cysts, 1 case of GIST and 1 of esophageal cancer. CONCLUSIONS: Intramural esophageal tumors is a very diverse group of tumors, both malignant and benign. In every case of IET we should seek histopathological conformation. Treatment of IET depends on localization, size and histopathological type of lesion. PMID- 28096829 TI - Is it possible to standardize the treatment of primary spontaneous pneumothorax? Part 1: etiology, symptoms, diagnostics, minimally invasive treatment. AB - The authors of this report present the history of primary spontaneous pneumothorax (PSP) treatment, its etiology, clinical symptoms, and diagnostic methodology. Further, they discuss minimally invasive methods of treating PSP such as thoracentesis and chemical pleurodesis. They discuss the pros and cons of each method, emphasizing that, according to the international recommendations, they should be used as the first line of treatment for PSP. PMID- 28096830 TI - Is it possible to standardize the treatment of primary spontaneous pneumothorax? Part 2: surgical methods of treatment. AB - The present report provides a detailed description of the surgical methods for primary spontaneous pneumothorax (PSP) treatment, from open surgery (thoracotomy) to minimally invasive procedures (video-assisted thoracoscopic surgery - VATS). It describes the methods of preventing pneumothorax recurrence, including partial or complete resection of the parietal pleura and chemical pleurodesis with VATS. The pros and cons of each method are presented. The paper also discusses new techniques for diagnosing pneumothorax, such as fluorescein-enhanced autofluorescence thoracoscopy (FEAT) and infrared thoracoscopy. Finally, the authors propose their own algorithm for the treatment of PSP. PMID- 28096831 TI - Predeployed aortic extension cuff (kilt) in EVAR with hostile neck anatomy using Endurant II system: preliminary results. AB - INTRODUCTION: Various modifications of standard endovascular aortic aneurysm repair (EVAR) have been developed to solve the problem of difficult neck anatomy. AIM: The authors propose the implantation of a predeployed extension cuff (kilt) using on-shelf Endurant II elements. In a vast majority of cases, the proposed method provides a solution for the hostile neck problem using standard Endurant II elements available in all centers performing subrenal EVAR procedures. MATERIAL AND METHODS: The early outcomes of kilt implantation were evaluated in 11 patients (three with ruptured abdominal aortic aneurysms, one symptomatic) in 2 vascular centers in Silesia (Poland). All patients presented with hostile neck anatomy defined as neck length < 10 mm, diameter > 28 mm, angulation > 60 degrees , mural thrombus or calcium > 2 mm in thickness or > 180 degrees circumference. RESULTS: No intraoperative type I endoleak or device migration was observed. Two perioperative deaths occurred in patients in a severe condition with ruptured aneurysms. One case of type III endoleak was managed by the implantation of an additional iliac extension with complete endoleak sealing. CONCLUSIONS: The proposed method seems to be effective in early endoleak prevention in patients with hostile neck anatomy undergoing EVAR procedures; however, studies with long term follow-up are needed. PMID- 28096832 TI - Perioperative care in elderly cardiac surgery patients. AB - INTRODUCTION: Surgery is an extreme physiological stress for the elderly. Aging is inevitably associated with irreversible and progressive cellular degeneration. Patients above 75 years of age are characterized by impaired responses to operative stress and a very narrow safety margin. AIM: To evaluate perioperative complications in patients aged >= 75 years who underwent cardiac surgery in comparison to outcomes in younger patients. MATERIAL AND METHODS: The study was conducted at the Silesian Centre for Heart Diseases in Zabrze in 2009-2014 after a standard of perioperative care in seniors was implemented to reduce complications, in particular to decrease the duration of mechanical ventilation and reduce postoperative delirium. The study group included 1446 patients. RESULTS: The mean duration of mechanical ventilation was 13.8 h in patients aged >= 75 years and did not differ significantly compared to younger patients. In hospital mortality among seniors was 3.8%, a value significantly higher than that observed among patients younger than 75 years of age. Patients aged >= 75 years undergoing cardiac surgery have significantly more concomitant conditions involving other organs, which affects treatment outcomes (duration of hospital stay, mortality). CONCLUSIONS: The implementation of a standard of perioperative care in this age group reduced the duration of mechanical ventilation and lowered the rate of postoperative delirium. PMID- 28096833 TI - Utility of serum concentration of protein S100 at admission to the medical intensive care unit in prediction of permanent neurological injury. AB - INTRODUCTION: Admission to the intensive care unit (ICU) may be preceded by dramatic events leading to permanent neurological injury. Plasma S100 protein levels are proved to be clinically useful in predicting neurological outcome following cardiac arrest. It is unclear, however, whether this may be extrapolated to a broader population of ICU patients. AIM: To assess the utility of plasma S100 protein in predicting death, permanent neurological damage, or unfavourable outcome at admission to the intensive care unit. MATERIAL AND METHODS: The concentration of plasma S100 protein was established in 102 patients on admission to the ICU, regardless of their neurological status and the reason for admission. The majority of patients were admitted with various cardiac diseases, excluding trauma patients. The patients were classified into three groups with the following binary outcomes: permanent neurological deficit or restoration of consciousness; unfavourable outcome (death or survival with permanent neurological deficit) or favourable outcome; and death or survival. RESULTS: Plasma S100 protein levels at admission facilitated the identification of patients who later developed a permanent neurological deficit or regained consciousness (p < 0.0001). All patients with plasma S100 protein over 0.532 MUg/l at ICU admission either developed a permanent neurological deficit or had an unfavourable outcome (death or survival with permanent neurological deficit). However, sensitivity for this cut-off value was only 48% and 40%, respectively. CONCLUSIONS: Plasma S100 protein levels over 0.532 MUg/l are specific but not sensitive for both permanent neurological deficit and unfavourable outcome when assessed in a heterogeneous population at admission to the ICU. PMID- 28096836 TI - Coronary artery spasm following on-pump coronary artery bypass grafting with 20 months follow-up. AB - We report on a 69-year-old woman who demonstrated native coronary artery and grafted vessel spasm following on-pump coronary artery bypass grafting (CABG). Despite intraaortic balloon pump (IABP) insertion, electrocardiogram (ECG) abnormalities did not disappear. Emergency coronary angiography (CAG) was performed. The patient was successfully treated with systemic and intracoronary injection of vasodilator agents. ECG changes disappeared, with normalized and stable hemodynamic function. Intraaortic balloon pump was maintained for 48 h. The patient was discharged in good clinical condition. Coronary artery spasm (CAS) may result in life-threatening arrhythmias, circulatory collapse or death. The etiology of CAS is multifactorial and includes heart manipulation, exogenous vasoconstrictors, stress-related catecholamine release, hypoxia and oxidative stress. Postoperative CAS is most commonly manifested by ST-segment elevation and circulatory collapse without specific causes. The gold standard for revealing CAS is CAG. Infusion of vasodilators combined with IABP is adequate in most instances, but extracorporeal membrane oxygenation has been necessary for more extensive or resistant coronary spasm. PMID- 28096835 TI - Left atrial appendage mass: is it always a thrombus? AB - Myxoma is the most common benign tumor of the heart, but it is very rare for it to originate from the left atrial appendage. Distinguishing between a mass, a thrombus, and a tumor in the body of the left atrium with preoperative transthoracic or transesophageal echocardiography is very difficult, even more so in patients with mitral valve disease and chronic atrial fibrillation. A 50-year old male patient was admitted for surgery with the diagnosis of mitral stenosis and chronic atrial fibrillation. Transesophageal echocardiography demonstrated a mass attached to the wall of the left atrial appendage. Histopathological examination of the mass showed an image compatible with a myxoma. We hereby describe a case of a left atrial appendage myxoma mimicking a left atrial appendage thrombus. PMID- 28096834 TI - Does the APACHE II score predict performance of activities of daily living in patients discharged from a weaning center? AB - INTRODUCTION: Data regarding the functional status of patients after prolonged mechanical ventilation are scarce, and little is known about its clinical predictors. AIM: To investigate whether the Acute Physiology and Chronic Health Evaluation (APACHE) II score on admission may predict performance in activities of daily living on discharge from a weaning center. MATERIAL AND METHODS: All consecutive patients admitted between January 1, 2012 and December 31, 2013 were enrolled (n = 130). During this period, 15 subjects died, and 115 were successfully discharged (34 women; 81 men). APACHE II was calculated based on the worst values taken during the first 24 hours after admission. On discharge, the Barthel Index (BI) and its extended version, the Early Rehabilitation Barthel Index (ERBI), were assessed. RESULTS: Median BI was 20 points (IQR 5; 40), and ERBI was 20 points (-50; 40). There was no correlation between APACHE II and either BI (R = -0.07; p = 0.47) or ERBI (R = -0.07; p = 0.44). APACHE II predicted the need for assistance with bathing (AUROC = 0.833; p < 0.001), grooming (AUROC = 0.823; p < 0.001), toilet use (AUROC = 0.887; p < 0.001), and urination (AUROC = 0.658; p = 0.04). APACHE II had no impact on any ERBI items associated with ventilator weaning, including the need of further mechanical ventilation (AUROC = 0.534; p = 0.65) or tracheostomy (AUROC = 0.544; p = 0.42). CONCLUSIONS: Although APACHE II cannot predict the overall functional status in patients discharged from a weaning center, it helps identify subjects who will need support with bathing, grooming, and toilet use. The APACHE II score is inadequate to predict performance in activities associated with further respiratory support. PMID- 28096837 TI - Sutureless aortic valve and mitral valve repair in redo cases - really an off label approach? AB - Sutureless aortic valve replacement (AVR) was developed as an alternative treatment option to conventional open-heart surgery and transcatheter aortic valve implantation for "gray zone" patients. The need for concurrent mitral valve surgery is generally viewed as a contraindication to sutureless AVR. The purpose of this brief paper is to report our experiences with sutureless valves in patients after previous cardiac procedures with degenerated aortic bioprostheses and concomitant mitral valve disease. PMID- 28096838 TI - A rare case of myocardial bridge involving left anterior descending, obtuse marginal and ramus intermediate coronary arteries. AB - Myocardial bridging, a congenital coronary anomaly, is a cluster of myocardial fibers crossing over the epicardial coronary arteries. It is most frequently seen in the left anterior descending artery (LAD), and rarely involves the circumflex (CX) and right coronary artery (RCA). We report a patient with an unusual coronary bridge crossing over the left anterior descending, obtuse marginal and ramus intermediate branches. The patient presented with exercise-induced angina pectoris that was relieved with medical therapy. PMID- 28096839 TI - Thoracoscopic resection of a bronchogenic cyst in a 17-year-old girl. AB - Bronchogenic cysts comprise approximately 6% of mediastinal tumors in children. The treatment consists in surgical resection of the cyst. The authors present the case of a 17-year-old girl who was accidentally diagnosed with a mediastinal cyst. The patient was successfully treated with thoracoscopic surgery with good early and late clinical outcomes. PMID- 28096840 TI - Video-assisted thoracoscopic surgery (VATS) right upper lobectomy for non-small cell lung cancer with an azygos lobe. AB - Although it is not a pathologically significant entity, cases of azygos lobe (AL) are interesting due to the difficulty of performing video-assisted thoracoscopic surgery (VATS) procedures in the affected patients and the presence of a congenital malformation. Currently, videothoracoscopic surgery has advanced to such a level that most thoracic procedures can be performed with video assistance. However, some technical difficulties may arise in cases with anatomical anomalies such as AL. This report presents the case of a patient with an azygos lobe who underwent videothoracoscopic lung resection due to the presence of non-small-cell lung carcinoma in the upper lobe of the right lung. PMID- 28096841 TI - Retroperitoneal tumor: giant cavernous hemangioma - case presentation and literature review. AB - Retroperitoneal hemangiomas are very rare. This paper presents the case of a 71 year-old female patient with giant cavernous hemangioma of the retroperitoneum who underwent surgical treatment for abdominal pain and left lower limb edema. Interventional staged treatment with percutaneous transcatheter arterial embolization prior to surgery was considered. Radical resection of the tumor was performed, which caused the symptoms to abate. Additionally a literature review of cases involving cavernous hemangioma in the retroperitoneal space is presented. No description of retroperitoneal cavernous hemangioma originating from the bowel was found in the analyzed reports. PMID- 28096842 TI - Purple, stiff lesions resembling varicose veins on lower limb: certainly consider Kaposi sarcoma. AB - Kaposi's sarcoma (KS) typically presents multiple cutaneous lesions of the lower extremities. Lesions can rarely mimic varicose veins without venous insufficiency, vascular or stasis ulcers. As the initial diagnosis of KS is generally determined clinically, a high index of suspicion and palpation of lesions are necessary for all patients with atypical presentations of varicose like lesions of lower extremities. Tissue biopsy with histological analysis is essential for all uncertain lesions. This is a case of KS occurring in a 79-year old man who presented with indurated vascular plaques resembling varicose veins on the right foot. PMID- 28096843 TI - Left atrial myxoma in a patient with a biventricular pacemaker. AB - Myxomas make up about 50% of benign cardiac neoplasms. The most common location is within the left atrium. At the initial stage they do not exhibit any specific clinical symptoms, so they are often diagnosed by accident or during examinations recommended for other reasons. Here we present a case of left atrium myxoma in a patient (a man, age 68 years) with a dual chamber pacemaker. The myxoma did not reveal any clinical symptoms and was discovered in echocardiography during routine diagnostic examination preceding pacemaker implantation. The literature search made by the authors showed that this is the first recorded case of myxoma in a patient after the implantation of a biventricular pacemaker. PMID- 28096844 TI - Influence of an extended education program on the knowledge of cardiovascular risk factors among subjects undergoing rehabilitation following acute coronary syndrome. AB - INTRODUCTION: Health education is a component of complex cardiac rehabilitation (CCR). AIM: To evaluate the influence of an authorial extended educational program on the knowledge of cardiovascular risk factors among subjects undergoing early in-hospital rehabilitation following acute coronary syndrome treated with percutaneous intervention. MATERIAL AND METHODS: This prospective study covered 205 consecutive subjects (153 men and 52 women, aged 62 +/-9 years) undergoing CCR. They were randomly allocated to the control group (105 patients receiving standard education during CCR) or the study group (100 patients participating in the extended education program). The extended education program was conducted in the 2nd and 3rd week of CCR and included a package of educational materials and additional lectures. RESULTS: Knowledge of basic rules for secondary cardiac prevention was better in the study group, both on admission and after CCR. Notwithstanding, a positive influence of the extended educational program was found with regard to awareness of recommended blood pressure levels and blood lipid profile (improvement of 15-20% in the study group). At baseline, the knowledge of risk factors was comparable between the groups (the percentage of correct questionnaire answers was 50 +/-17% among the controls vs. 49 +/-16% in the study group; p = 0.77), but improved significantly after education (52 +/-17% among controls vs. 58 +/-19% in the study group; p = 0.009) and remained better in the study group after a 3-month follow-up (56 +/-19% among controls vs. 64 +/ 19% in the study group). CONCLUSIONS: Extended education during CCR significantly improves the knowledge of cardiovascular risk factors in patients after acute coronary syndrome. PMID- 28096846 TI - Dr. Denton Cooley (1920-2016). In memory of. PMID- 28096845 TI - Cognitive impairment after sudden cardiac arrest. AB - AIM: To evaluate the incidence and severity of the impairment of selected cognitive functions in patients after sudden cardiac arrest (SCA) in comparison to patients after myocardial infarction without SCA and healthy subjects and to analyze the influence of sociodemographic and clinical parameters and the duration of cardiac arrest on the presence and severity of the described disorders. MATERIAL AND METHODS: The study group comprised 30 cardiac arrest survivors, the reference group comprised 31 survivors of myocardial infarction without cardiac arrest, and the control group comprised 30 healthy subjects. The Mini-Mental State Examination (MMSE), the Digit Span test from the Wechsler Adult Intelligence Scale, Lauretta Bender's Visual-Motor Gestalt Test, and the Benton Visual Retention Test (BVRT) were used to assess the presence of cognitive impairment. An original questionnaire developed by the author was used for overall mental state assessment. RESULTS: The Bender test demonstrated a significant difference in the presence and severity of visual-motor skills between the study group and the control group, while BVRT and MMSE revealed increased incidence of cognitive impairment in the study group. The Bender and BVRT (D/D)/SS (version D, method D, scaled score) scales indicated cognitive impairment in 53.3% of these patients, while the BVRT (C/A)/SS test indicated cognitive impairment in 40%. For the reference group, the values were 32.3% and 12.9%, respectively. No correlation was found between the severity of cognitive impairment and the duration of cardiac arrest. CONCLUSIONS: Impairment of visual motor skills, short-term visual memory, concentration, and visual-motor coordination occurs much more frequently and is more severe in individuals after SCA than in healthy individuals. Impairment of memory trace storage and recall after delay occurs more frequently in patients after SCA than in patients after myocardial infarction without cardiac arrest and in healthy individuals. SCA duration did not have any influence on the severity of the described disorders. PMID- 28096847 TI - Transfusion-Transmitted Malaria in Iran: A Narrative Review Article. AB - BACKGROUND: Malaria is the most important transfusion-transmitted infection (TTI) in worldwide after viral hepatitis and human immunodeficiency virus (HIV) infection. The main objective of the present study was to review and evaluate the transmission of malaria via blood transfusion in Iran. METHODS: A literature search was done without time limitation in the electronic databases as follows: PubMed, Scopus, Google Scholar, Web of Science, Science Direct, scientific information database (SID), Magiran, IranMedex and Irandoc. The searches were limited to the published papers to English and Persian languages. RESULTS: Six papers were eligible. From 1963 to 1983, 344 cases of Transfusion-transmitted malaria (TTM) had been reported from different provinces of Iran. The most prevalent species of involved Plasmodium in investigated cases of TTM was Plasmodium malariae (79.24%). The screening results of 1,135 blood donors for malaria were negative by microscopic examination of peripheral blood smears and rapid diagnostic test (RDT) methods. CONCLUSION: Lack of TTM report from Iran in the last three decades indicates that the screening of blood donors through interviewing (donor selection) may be effective in the prevention of the occurrence of transfusion-transmitted malaria. PMID- 28096848 TI - Immunogenicity and Efficacy of Live L. tarentolae Expressing KMP11-NTGP96-GFP Fusion as a Vaccine Candidate against Experimental Visceral Leishmaniasis Caused by L. infantum. AB - BACKGROUND: The aim of present study was to evaluate the protective efficacy of live recombinant L. tarentolae expressing KMP11-NTGP96-GFP fusion as candidates for live engineered recombinant vaccine against visceral leishmaniasis in BALB/c mice. METHODS: KMP-11 and NT-GP96 genes cloned into the pJET1.2/blunt cloning vector and then into pEGFP-N1 expression vector. The KMP-11, NT-GP96 and GFP fused in pEGFP-N1 and subcloned into Leishmanian pLEXSY-neo vector. Finally this construct was transferred to L. tarentolae by electroporation. Tranfection was confirmed by SDS-PAGE, WESTERN blot, flowcytometry and RT-PCR. Protective efficacy of this construct was evaluated as a vaccine candidate against visceral leishmaniasis. Parasite burden, humoral and cellular immune responses were assessed before and at 4 weeks after challenge. RESULTS: KMP- NT-Gp96-GFP Fusion was cloned successfully into pLEXSY -neo vector and this construct successfully transferred to L. tarentolae. Finding indicated that immunization with L. tarentolae tarentolae-KMP11-NTGP96-GFP provides significant protection against visceral leishmaniasis and was able to induce an increased expression of IFN gamma and IgG2a. Following challenge, a reduced parasite load in the spleen of the KMP11-NTGP96-GFP immunized group was detected. CONCLUSION: The present study is the first to use a combination of a Leishmania antigen with an immunologic antigen in live recombinant L. tarentolae and results suggest that L. tarentolae KMP11-NTGP96-GFP could be considered as a potential tool in vaccination against visceral leishmaniasis and this vaccination strategy could provide a potent rout for future vaccine development. PMID- 28096849 TI - Assessment of the Effects of Extremely Low Frequency Electromagnetic Fields on Toxoplasma gondii. AB - BACKGROUND: The effects of extremely low frequency electromagnetic fields (ELF EMF) on Toxoplasma gondii have not been explained yet. The aim of this study was to assess the possible effects of ELF-EMF on growth, survival time and viability of Toxoplasma gondii. In addition, the life span of Toxoplasma infected animals was investigated. METHODS: Sixty adult male BALB/c mice were used for in vivo and in vivo experiments in Laboratory of Biopyhsics and Parasitology of Medical Faculty, Adnan Menderes University, Turkey, in 2010. During in vivo experiments, pulsed and continuous EMFs were applied for 5 d to the infected mice. During in vivo experiments, pulsed and continuous EMF was applied to the tachyzoites within peritoneal exudates for 8 h/d at 4 degrees C and the tachyzoites were then injected to mice. In both experiments, the number of T. gondii in peritoneal exudates was counted and T. gondii protein bands patterns were investigated with polyacrylamide gel electrophoresis and Western Blotting. RESULTS: Pulsed and continuous EMF exposure reduced the number of T. gondii tachyzoites in comparison to controls. However, no statistically significant differences were observed at the patterns of protein bands among the samples. CONCLUSION: EMF exposure induces a decrease in the number of T. gondii. Further studies are required to understand the mechanism of EMF on intracellular parasites. PMID- 28096850 TI - Expression Analysis of Multiple Genes May Involve in Antimony Resistance among Leishmania major Clinical Isolates from Fars Province, Central Iran. AB - BACKGROUND: Treatment of Cutaneous Leishmaniasis (CL) is being faced with serious difficulties in Fars Province, due to emerging of resistance against meglumine antimonite (Glucantime(r)). In this context, determining some biomarkers for drug sensitivity monitoring seems to be highly essential. Different studies have been carried out to decipher the genes might be involved in antimony resistant phenotype in Leishmania spp. Here, we selected three genes: AQP (as drug transporter), TDR-1-1(as drug activator), and gamma-GCS (inducing reduction environment) for comparative expression analysis on clinical resistant and sensitive isolates of L. major. METHODS: The clinical isolates of L. major were collected from CL patients referred to Valfajr Health Center, Shiraz from Oct 2011 to Feb 2012. The susceptibility test was performed to confirm drug sensitivity of strains in vitro as well. Then, the gene expression analysis was performed by quantitative real-time PCR using SYBR(r) Green. RESULTS: By comparison of expression level between strains, up regulation of gamma-GCS gene and down regulation of AQP gene were observed in resistant strains compared to the sensitive isolates; however, down regulation of AQP was not statistically specific. Analysis of TDR-1-1 gene unexpectedly showed a high level of expression in the non-responsive cases. CONCLUSION: The gamma-GCS, at least, can be considered as a suitable molecular marker for screening antimony sensitivity in clinical isolates, although AQP and TDR-1-1gene seem not to be reliable resistant markers. PMID- 28096851 TI - Acetylcholinesterase Inhibitor Improves Learning and Memory Impairment Induced by Toxoplasma gondii Infection. AB - BACKGROUND: Here, we established the mouse models of chronic toxoplasmosis by T. gondii Tehran strain to provide a good understanding about defining the possible association between T. gondii exposure and learning and memory impairments. Moreover, as secondary objective of the present study, we hypothesized whether administration of an acetylcholinesterase (AChE) inhibitor could reduce learning and memory impairments induced by T. gondii infection. METHODS: Twenty-four male BALB/c mice were used to establishment of latent toxoplasmosis. The animal model of Toxoplasma infection was established by the intraperitoneal inoculation of 20 25 tissue cysts from Tehran strain of T. gondii. Donepezil (2 mg/kg) an AChE inhibitor to treat Alzheimer disease was injected intraperitoneally once a day for two weeks starting from post-infection day 90. Morris water maze (MWM) task was used to assay spatial learning and short term spatial memory in all groups. One-way ANOVA with Tukey's post-hoc test was used to assess differences between experimental groups. P<0.05 was considered statistically significant. RESULTS: Toxoplasma infection impaired spatial leaning and short term spatial memory of the infected BALB/c mice, whereas donepezil, an AChE inhibitor, improved impairments induced by Toxoplasma infection. CONCLUSION: T. gondii infection through increasing AChE reduces the level of Acetylcholine (Ach) and consequently affects learning and memory activity in infected hosts, whereas, donepezil as an AChE inhibitor improves these impairments by restoring ACh levels at synapses of neurons in brain. PMID- 28096852 TI - Echinococcus granulosus Sensu Stricto in Dogs and Jackals from Caspian Sea Region, Northern Iran. AB - BACKGROUND: The aim of the present study was genotyping of Echinococcus granulosus isolates from dogs and jackals in Mazandaran Province, northern Iran, and using partial sequence of the mitochondrial cytochrome c oxidase subunit 1 gene (cox1). METHODS: E. granulosus isolates (n = 15) were collected from 42 stray dogs and 16 jackals found in south of the Caspian Sea in northern Iran. After morphological study, the isolates were genetically characterized using consensus sequences (366bp) of the cox1 gene. Phylogenetic analysis of cox1 nucleotide sequence data was performed using a Bayesian Inference approach. RESULTS: Four different sequences were observed among the isolates. Two genotypes [G1 (66.7%) and G3 (33.3%)] were identified among the isolates. The G1 sequences indicated three sequence profiles. One profile (Maz1) had 100% homology with reference sequence (AN: KP339045). Two other profiles, designated Maz2 and Maz3, had 99% homology with the G1 genotype (ANs: KP339046 and KP339047). A G3 sequence designated Maz4 showed 100% homology with a G3 reference sequence (AN: KP339048). CONCLUSION: The occurrence of the G1 genotype of E. granulosus sensu stricto as a frequent genotype in dogs is emphasized. This study established the first molecular characterization of E. granulosus in the province. PMID- 28096853 TI - Microsporidial Spores in Fecal Samples of Some Domesticated Animals Living in Giza, Egypt. AB - BACKGROUND: The aim of the present work was to investigate the prevalence and species of intestinal microsporidiosis among animals in Giza, Egypt. METHODS: A total of 869 animal fecal samples were collected from domesticated animals (dogs, cats, rabbits, cattle, buffaloes, sheep, goats, donkeys and pigs) living in Giza, Egypt. Spores of microsporidia were concentrated from collected samples by centrifugation and finally stained with modified trichrome (MT) stain to detect microsporidial spores. Microsporidial spores in microscopically-positive samples were molecularly confirmed and identified using species-specific primers. RESULTS: Spores of microsporidia were microscopically detected in 17.0% of the examined animal fecal samples. The highest and lowest rates of infection with intestinal microsporidia were recorded in dogs (33.3%) and buffaloes (6.9%), respectively. Molecularly, the obtained microsporidial spores were classified as Enterocytozoon bieneusi and E. intestinalis. Dual infection with both identified species was observed in fecal samples from buffalo, rabbit, goat, cat, pig and dog. CONCLUSION: Domestic animals may play a role in dissemination of intestinal microsporidiosis in the environment. Examined animals were infected with E. bieneusi in a higher percentage than E. intestinalis. PMID- 28096854 TI - Social Network Analysis of Iranian Researchers on Medical Parasitology: A 41 Year Co-Authorship Survey. AB - BACKGROUND: The aim of this study was to survey the Iranian Parasitology researchers' performance, and analyse and visualize the scientific outputs of their co-authorship network. METHODS: This study was conducted using scientometric method and social network analysis (SNA). The data extracted from the Web of Science (WoS) databases in July 10th 2014. Totally, 1048 documents of all types in research area of Parasitology during 1972-2013 by Iranian researches retrieved. The co-authorship map was drawn utilizing NETDRAW, Coauthor.exe, and UCINET softwares and was analysed based on SNA measures. RESULTS: The researchers' co-authorship network consisted of 78 authors and its density degree is 0.57. "Mohebali" ranked top in all of centrality measures. The most of the publications were related to 2012, "Mohebali" with about 9% of all documents was the Iranian most prolific author in Parasitology field. The Iranian researches have published mostly (266 documents) in "Iranian Journal of Parasitology", and the most of the documents belong to "Tropical Medicine" subject field. The most of Iranian researchers' scientific cooperation was performed with England and United States. CONCLUSION: Bringing forth density degree (is 0.57) showed that this network has an almost medium density. Indeed, the authors have had relations in moderate level with each other in the network. The findings of this study can be identified aspects of scientific collaboration, and help policy makers of Parasitology field research. PMID- 28096855 TI - Helminth Infections of Meriones persicus (Persian Jird), Mus musculus (House Mice) and Cricetulus migratorius (Grey Hamster): A Cross-Sectional Study in Meshkin-Shahr District, Northwest Iran. AB - BACKGROUND: Rodents have important role as reservoirs of different parasites. The aim of this study was to determine helminth parasites of abundant rodents in Meshkin-Shahr, Ardabil Province northwest Iran. METHODS: From April 2014 to March 2015; 205 rodents including 118 Meriones persicus, 63 Mus musculus and 24 Cricetulus migratorius were collected, using live traps. All rodents were dissected and their different tissues examined for infectivity with helminth parasites. RESULTS: Overall, 74.2% of rodents were infected with helminth parasites. The rate of infectivity in M. persicus, M. musculus and C. migratorius was 82.2%, 61.9%, 66.7%, respectively. In general, among all 205 rodents, the species and infection rates of helminthes were as follows: Nematoda: Trichuris sp. (46.8%), Capillaria hepatica (18.1%), Syphacia frederici (14.2%), Aspicularis tetraptera (3.4%), Trichuris rhombomidis (2%), Heligmosomom sp. (2%), Streptopharagus kuntzi (0.5%), Spiruridae gen. sp. (0.5%); Cestoda: Hymenolepis nana fraterna (16.6%) Hymenolepis diminuta (7.3%) tetratiridium of Mesocestoides sp. (1%), Paranoplocephala sp. (0.5%), Cysticercus fasciolaris (0.5%), Taenia endothoracicus larva (0.5%), and Acanthocephala: Moniliformis moniliformis (18.5%). CONCLUSIONS: Variable species of helminthes circulate in the rodents of the study area. Presence of several zoonotic species highlights the potential risk of infections for public health. PMID- 28096856 TI - Epidemiological Survey of Bovine Thelaziosis in Southeastern of Iran. AB - BACKGROUND: This study aimed at investigating the prevalence and risk factors of bovine thelaziosis, performed in the southeast of Iran, an endemic area for Iranian Sistani cattle. METHODS: Between September 2012 to October 2014, 1924 cattle, Sistani breed (n= 1235) and Brahman breed (n=689) of all sex and age groups collected from Sistan and Baluchestan Province were examined using visual observation of the eyes by flushing the conjunctival sac and lachrymal duct with sterile saline solution. RESULTS: The overall prevalence for thelaziosis was 50 of 1924 cows (2. 6%; 95% CI: 1. 9-3. 3%), with significant higher prevalence of infection in Sistani breed than in Brahman breed (3. 15% vs 1. 59%). Sixty adult worms (84. 5% of females and 15. 5% of males) were collected from the conjunctiva of the infected cattle: Thelazia gulosa (50/60, 83. 3%) was the most represented species followed by Thelazia. rhodesi (10/60, 16. 7%). The number of worms collected per cow ranged from one to seven (average +/- standard deviation: 2. 08 +/- 1. 49). Worms were gathered from cows throughout all months of the year. The difference in the seasonal variations of prevalence and the intensity of infection were significant, however, no significant correlation between prevalence, sex and age of cattle was noted. CONCLUSION: Bovine thelaziosis needs special attention by veterinarians in the differential diagnosis of ocular manifestations and considering its impact on cattle production. PMID- 28096857 TI - The Effect of Fluphenazine and Thioridazine on Toxoplasma gondii In Vivo. AB - BACKGROUND: Toxoplasma gondii is the most common parasite causing latent cerebral infections in human. It has been shown that some anti-psychotic drugs are able to inhibit the proliferation of the parasite in in vitro study. There is very limited data regarding the inhibitory effect of anti-psychotics on Toxoplasma in in vivo. In this study, we evaluated anti-Toxoplasma activity of fluphenazine and thioridazine drugs on T. gondii in mice. METHODS: Mice were divided into six groups: Control, sesame as vehicle, thioridazine 10 mg/kg, thioridazine 20 mg/kg, fluphenazine 0.06 mg/kg and fluphenazine 0.6 mg/kg. They were inoculated intraperitoneally with brain suspension containing tissue cysts of T. gondii Tehran strain. Two months after inoculation, the number of cysts in crushed smears of mice brain were counted microscopically and considered as an indicator of anti-Toxoplasma activity. This work has conducted in Qazvin, central Iran, 2014. RESULTS: Our study showed that fluphenazine and thioridazine could not significantly inhibit the brain cystogenesis of T. gondii in mice. However, the number of brain cysts was less at higher dose compared to lower doses for both drugs. CONCLUSION: Further studies need to clear the mechanism of different structure of anti-psychotic drugs on activity of Toxoplasma. PMID- 28096858 TI - Prevalence of Intestinal Parasitic Infections in Jiroft, Kerman Province, Iran. AB - BACKGROUND: Intestinal parasitic infections have a worldwide distribution. High prevalence of intestinal parasitic infections in individuals with low socioeconomic status and environmental conditions was found. No study has ever been conducted on the prevalence of these infections in Jiroft. Therefore, in this study prevalence of intestinal parasitic infections was evaluated in Jiroft, Kerman Province, Iran. METHODS: A total of 1060 individuals from rural and urban areas of Jiroft were sampled accidentally, during 2013-2014. Fresh stool samples were collected from all individuals and examined by formalin ether concentration and agar plate culture. Direct examination was performed on watery samples. RESULTS: Out of 1060 individuals, 563 (53.1%) and 497 (46.9%) people were from rural and urban areas, respectively. In general, 297 individuals (28%) were infected with intestinal parasites. The prevalence of infection for protozoa and helminthes infections were 27.4% and 1.8%, respectively. The most prevalent protozoans were Blastocystis hominis (13.7%) and Giardia lamblia (7.8%), and that of helminth was Hymenolepis nana (1.1%). CONCLUSION: Intestinal protozoan parasites were more prevalent than helminth parasites. Source of water supply and personal hygiene were important factors in the distribution of parasites in the study area. PMID- 28096860 TI - Determination of Asymptomatic Malaria among Afghani and Pakistani Immigrants and Native Population in South of Kerman Province, Iran. AB - BACKGROUND: This study was proposed to monitor the situation of asymptomatic malaria among the native population and Afghani and Pakistani immigrants in Kahnooj and Ghale-Ganj districts from Kerman Province, Southeastern Iran. METHODS: A number of 180 and 120 individuals from Kahnooj and Ghale-Ganj respectively were registered and considered based on a cross-sectional surveillance method. From 300 registered cases, 200 individuals (66.7%) were selected among Afghani and Pakistani immigrants and the rest (33.3%) were native resident individuals. All samples were processed with employing microscopical examination, Rapid Diagnostic Tests (RDTs) and Semi- nested Multiplex PCR techniques. RESULTS: None of the samples collected from native residents showed any malaria parasite, but among Afghani immigrants, one asymptomatic vivax malaria was detected in a 12 yr old girl with 280 parasites per microliter of blood. Moreover, one symptomatic vivax malaria was detected from a Pakistani immigrant with 47560 parasites per microliter of blood. All results obtained via microscopical method, confirmed by RDTs and PCR techniques. CONCLUSION: To achieve the malaria elimination program different studies are needed that to be performed. Monitoring the asymptomatic malaria in all over the malaria endemic areas especially among the immigrant individuals is the most crucial necessity. PMID- 28096859 TI - Occurrence and Intensity of Anisakid Nematode Larvae in Some Commercially Important Fish Species in Persian Gulf. AB - BACKGROUND: Anisakid nematodes are common parasites of fish, mammals, fish-eating birds, and reptiles with a worldwide distribution, causing diseases in human, fish and important economic losses. METHODS: A preliminary epidemiological study was carried out on Anisakid nematodes larvae in some commercially important fish species to evaluate the anisakid nematode larvae from greater lizardfish, (Saurida tumbil), Japanese thread fin bream (Nemipterus japonicus), crocodile longtom (Tylosurus crocodilus crocodiles) and longfin trevally (Carangoides armatus) from the Persian Gulf of Iran. RESULTS: The collected larvae were identified mainly as the third larval stage (L3) of Hysterothylacium larval type A, B and C, Anisakis sp., Raphidascaris sp., Pseudoterranova sp. and Philometra sp. (Nematoda: Philometridae). The prevalence of Anisakid larvae infection of examined fishes was 97.2% in N. japonicus, 90.3% in S. tumbil, 20.5% in crocodile longtom and 5.5% in longfin trevally. Anisakis type III for the first time was different from Anisakis type I and Anisakis type II. DISCUSSION: Zoonotic anisakids by high prevalence in edible fish could be a health hazard for people. So health practices should be considered in these areas. PMID- 28096861 TI - 5.8S rRNA Sequence and Secondary Structure in Parabronema skrjabini and Related Habronematidae Species. AB - BACKGROUND: Genomic DNA was isolated from Parabronema skrjabini. rRNA region was amplified and sequenced. METHODS: The RNA secondary structure was predicted using mfold software ( http://mfold.rit.albany.edu ). The secondary structure with bulge, hairpins, helices, interior, external and multi loops was predicted for 5.8srDNA of our sequence of P. skrjabini and a sequence of P. skrjabini and two species of Habronema (H. microstoma and H. muscae) in GenBank. RNA motifs were predicted by MEME program version 4.10.2. RESULTS: The length of 5.8S rRNA sequence for P. skrjabini#1, P. skrjabini#2, H. microstoma and H. muscae was 158, 156, 127 and 127bp, and the DG required for the formation of the secondary structure was -70.50, -56.40, -41.50 and -41.40 kcal/Mol, respectively. Common structural elements were initially recognized with the help of mfold by screening for thermodynamically optimal and suboptimal secondary structures (default settings, with T = 37 degrees C). The energy levels of the presumptive secondary structures were then calculated with mfold at the DNA level. Both motifs and the sequence of P. skrjabini#1 were completely different from the other analyzed samples. This difference might be due to the differences in host and geographical area. CONCLUSION: This is the first molecular study of P. skrjabini in sheep, which could be further used in the structure modeling across Habronematidae. PMID- 28096862 TI - Does Nosema ceranae Wipe Out Nosema apis in Turkey? AB - BACKGROUND: The aim of this study was to determine the prevalence of the Nosema ceranae and Nosema apis among apiaries using both spore counts and multiplex PCR and the replacement of N. apis by N. ceranae in some regions of Turkey. METHODS: A hundred honey bee samples were collected from 99 apiaries in 11 different locations in 2011-2012 in Turkey. Nosema infection degree from collected samples was determined using light microscope and molecular detection of Nosema spp. (N. ceranae and N. apis) was performed using specific primers by multiplex PCR. RESULTS: N. ceranae was only found spores in sampling areas using molecular diagnosis. N. apis was not detected in whole sampling areas using both techniques. There are no Nosema spores detected in Konya one location using two techniques. The nucleotide sequences from amplification products of the Nosema infested honeybee samples were (98%) identical with the sequence of N. ceranae for many countries deposited in the GenBank database in this study. CONCLUSION: The present study illustrated that N. ceranae is the only spores for sampled areas in 2011-2012. The study could also indicate that N. ceranae has been replaced instead of N. apis in Turkey. In addition, the prevalence of N. ceranae and two microsporodia spores effects on honey bee colonies in Turkey were needed to determine with intensive sampling, periodically. PMID- 28096863 TI - Seroepidemiological Study of Toxocariasis in the Owners of Domestic Cats and Dogs in Mashhad, Northeastern Iran. AB - BACKGROUND: Toxocariasis is the clinical terms applied to infection of human with Ascarid nematodes in the order Ascaridida, named Toxocara canis and T. cati. Because in recent years in Iran many people desire to keep pets (cats and dogs), and lacking of seroepidemiological study of toxocariasis in Mashhad, we decided to determine the seroprevalence of toxocariasis among people who own cats and dogs in comparison with control group. METHODS: A serological study for detection antibodies to Toxocara in two groups (93 cat and dog owners and 93 healthy people as control group) was conducted from Feb 2013 to Dec 2013. An ELISA method was employed using determination of IgG antibodies against Toxocara. The serum samples were evaluated for anti-Toxocara antibody, using ELISA technique at Parasitology and Immunology Lab of Imam Reza Hospital of Mashhad. Using a questionnaire, epidemiological factors associated with infection were examined. Data were analyzed using Chi-square test. RESULTS: The seroprevalence of Toxocara antibodies in the pet owners and control group was respectively 20.43% and 1.07%. 47.3% of pet owners were female. CONCLUSION: Presented data showed the significant difference between seroprevalence of toxocariasis among pet owners and control group. Education of society and in particular pet owners consisting of preventing contamination of the environment with Toxocara eggs is advised. PMID- 28096864 TI - Feline Dirofilariosis Due to Dirofilaria immitis in Meshkin Shahr District, Northwestern Iran. AB - BACKGROUND: Dirofilaria immitis is a common nematode of the cardiovascular system, which infects carnivores all over the world. The infection is prevalent in dogs, but in cats and human is rare. Dirofilariosis is transmitted by mosquitoes. Cats are accidental hosts and are naturally resistant to the infection, compared to the dogs. Mild infection can cause severe illness in cats and may lead to death, so it is clinically important to diagnose the disease. METHODS: In the present study, 103 stray cats were collected from Meshkin Shahr district, Aradabil Province, northwestern Iran that is an endemic area for canine dirofilariosis. Blood samples were prepared from the saphenous vein of each cat and were examined for the presence of microfilariae by the modified Knott test. RESULTS: A 2 yr old male cat (0.97%) was microfilaremic. The cat was subjected to necropsy and 4 adult D. immitis (2 male and 2 female worms) were found in the right ventricle of the heart. PCR was then carried out and D. immitis was confirmed. CONCLUSION: Cats and other carnivores in Meshkin Shahr district are at risk of infection due to the high activity of vectors in this climate and it is important to follow up the infection in this area. PMID- 28096865 TI - Cardiac Hydatid Cyst without Liver Involvement: A Case Report. AB - Hydatid disease is a rare parasitic disease, which mainly involves liver then lung tissues. Cardiac involvement is very rare, especially when there is not hepatic involvement. We describe a 47-year-old woman with a history of a lung hydatid cyst who was referred to Rajaei Heart Center, Tehran, Iran in 2012. Her chest computed tomographic scan showed a cardiac mass. Echocardiographic examination illustrated a large, well-defined heterogeneous mass (4.5 * 2.5 cm) in the roof of the right atrium with attachment to the crista terminalis without compressive effect on the inferior and superior venae cavae. The patient was candidate for open-heart surgery via median sternotomy. A cystic mass was observed in the lateral aspect of the right atrial wall. After an injection of hypertonic normal saline into the cystic lesion, the mass was excised totally. The right atrial defect was reconstructed with autologous pericardium. The patient was discharged from the hospital in good condition. Histological examination confirmed the diagnosis of the hydatid cyst. PMID- 28096866 TI - Disseminated Strongyloidiasis in an Iranian Immunocompromised Patient: A Case Report. AB - Strongyloides stercoralis is a soil-transmitted helminth (STH) widespread in various part of the world. A 78-yr-old peasant diabetic female from Mazandaran Province northern Iran, was admitted to Infection Department of the Razi Hospital in city of Qaemshahr, north of Iran complaining about abdominal skin rash, pruritus, itching, anorexia, nausea, vomiting, dysuria and cough. This patient had cutaneous migration effects of S. stercoralis larvae in her abdominal skin (larva currents and urticaria). Lung CT without contrast demonstrate s bilateral diffuse ground glass opacity draws attention. Upper gastrointestinal endoscopy revealed gastro esophageal reflux with antral gastritis. Duodenal endoscopy showed unusual mucosa and a biopsy from it sent to the pathology laboratory. Histopathology of duodenal bulb and duodenum biopsy showed mild villous atrophy and S. stercoralis infection. The patient was treated with albendazole and clinical sings improved completely after treatment. Strongyloidiasis should be carefully considered by clinicians who practice in endemic areas. Clinicians must keep a high level of skepticism for patients from endemic area. PMID- 28096867 TI - Nasal Nosocomial Myiasis Infection Caused by Chrysomya bezziana (Diptera: Calliphoridae) Following the Septicemia: A Case Report. AB - A 74 yr old woman from Gonabad, southern part of Khorasan Razavi Province of Iran was admitted to a Hospital of Gonabad, because of respiratory distress, exertional dyspnea and fever. Close contact with domestic animals, history of chronic obstructive pulmonary disease (COPD), and completely resolved pulmonary tuberculosis (TB) in remote past, were notable parts of her past medical history. Due to clinical, paraclinical and radiographic findings and because of recent hospitalization, she was admitted to internal medicine ward with the diagnosis of health care associated pneumonia (HCAP). Despite the application of broad spectrum antibiotics and appropriate supportive care, she had a poor response to the treatment. During the daily visit in Intensive Care Unit (ICU), numerous white larvae were detected in both nostrils. Further investigation of oropharynx and tracheal tube aspiration, showed no more larvae in mentioned parts. An hour later, nasal spontaneous bleeding occurred. Otorhinolaryngology consultation was performed and led to surgical procedure. In ENT examination, there were numerous larvae and massive clot formation in both inferior meatuses and distal nasal septum perforation. Thirty-seven extracted larvae were transferred to Medical Entomology lab by vial 70% ethanol and 5 live larvae for rearing. After precise investigation by aid of light microscopy, the larvae were identified as Chrysomya bezziana. Due to discovered 2nd larvae stage and duration of hospitalization, this infestation was identified as nasal myiasis. PMID- 28096869 TI - Short-Term Psychiatric Rehabilitation in Major Depressive and Bipolar Disorders: Neuropsychological-Psychosocial Outcomes. AB - OBJECTIVE: Our pilot study aims to investigate the efficacy of a Short-Term (4 weeks) Psychiatric Rehabilitation Program (S-T PsyRP), without specific cognitive remediation trainings, on the neuropsychological performance and psychosocial functioning of inpatients with Major Depressive Disorder (MDD) or Bipolar Disorder (BD). Published studies with similar aims are lacking. METHODS: Fifty three inpatients with MDD and 27 with BD (type I/II) were included. The S-T PsyRP was usually performed as clinical practice at Villa San Benedetto Menni Hospital and included a variety of activities aimed at promoting personal autonomies, interpersonal/social skills, and self-care. At the beginning and the end of the hospitalization we evaluated: neuropsychological performance (cognitive tests on verbal/visual working memory, attention, visual-constructive ability, language fluency, and comprehension); psychosocial functioning by the Rehabilitation Areas Form (RAF, handbook VADO); illness severity by the Brief Psychiatric Rating Scale (BPRS). Repeated-measure ANOVA and Pearson's linear correlation were used. RESULTS: We found significant improvement (p<0.01) in all the neuropsychological tests except for one, in 4 out of 6 RAF psychosocial areas ("involvement in ward activities", "autonomies", "self-care", and "self-management of health") and in clinical symptoms severity. No associations were found between the amelioration of clinical symptoms and neuropsychological or psychosocial improvement. CONCLUSION: A S-T PsyRP without specific cognitive remediation trainings may improve several cognitive/functional domains in MDD or BD inpatients, probably by offering opportunities to engage in demanding problem-solving conditions and cognitively stimulating activities. PMID- 28096868 TI - Comparisons of Subthreshold Versus Full Posttraumatic Stress Disorder Distinguished by Subjective Functional Impairment Among Train Drivers: A Population-Based Nationwide Study in South Korea. AB - OBJECTIVE: Subthreshold posttraumatic stress disorder (SPTSD), a condition that meets the full symptomatic criteria of posttraumatic stress disorder (PTSD) without subjective functional impairment, has yet to be fully investigated. In this study, we aimed to determine the prevalence and characteristics of SPTSD. METHODS: The web-based survey including psychiatric diagnosis and experience of human error was conducted in actively working train drivers in South Korea. RESULTS: Of the 4,634 subjects, 103 (2.23%) were categorized as full PTSD and 322 (6.96%) were categorized as having SPTSD. Individuals with full PTSD showed higher impulsivity and anxiety compared to those with SPTSD and those without PTSD, while those with SPTSD had more frequent clinically meaningful depression, posttraumatic stress, and alcohol and nicotine dependence and significant human error. CONCLUSION: Despite not qualifying as a subjective functional disability, SPTSD still had significant psychiatric symptoms. More clinical attentions need to be given to the diagnosis and treatment of SPTSD. PMID- 28096870 TI - The Economic Crisis in Greece and Its Impact on the Seasonality of Suicides in the Athens Greater Area. AB - OBJECTIVE: The economic crisis and the implementation of austerity measures in Greece lead to significant socioeconomic changes. The effects of the crisis were mainly felt by the Greek population during the years 2011 and 2012. This study aimed to investigate the impact of Greece's economic crisis on the seasonality of suicides in the Athens Greater Area. METHODS: Data were collected for all recorded cases of suicides committed over a 5-year period (from 2008 to 2012) from the Athens Department of Forensic Medicine. Two sub-periods were studied in relation to the economic crisis: 2008-2010 and 2011-2012. Seasonality was estimated with the Poison regression variant of the circular normal distribution. RESULTS: Suicide seasonality appeared significant during 2008-2010 (relative risk, RR=1.36) and strengthened in the years 2011-2012 (RR=1.69), when the impact of the austerity measures was increasingly being felt by the Greek society. Regarding the latter sub-period, seasonality was established for males (RR=1.75), individuals aged 45 years or more (RR=1.75) and suicide by hanging (RR=1.96). CONCLUSION: The economic crisis in Greece, especially in the period during its effects had a significant impact on the population's economic condition, seems to have strengthened the seasonality of suicides, while a noteworthy suicide risk of 96% was revealed for suicides by hanging (peak in early June). PMID- 28096871 TI - The Structured Clinical Interview for DSM-5 Internet Gaming Disorder: Development and Validation for Diagnosing IGD in Adolescents. AB - OBJECTIVE: This study aimed to develop and validate a Structured Clinical Interview for Internet Gaming Disorder (SCI-IGD) in adolescents. METHODS: First, we generated preliminary items of the SCI-IGD based on the information from the DSM-5 literature reviews and expert consultations. Next, a total of 236 adolescents, from both community and clinical settings, were recruited to evaluate the psychometric properties of the SCI-IGD. RESULTS: First, the SCI-IGD was found to be consistent over the time period of about one month. Second, diagnostic concordances between the SCI-IGD and clinician's diagnostic impression were good to excellent. The Likelihood Ratio Positive and the Likelihood Ratio Negative estimates for the diagnosis of SCI-IGD were 10.93 and 0.35, respectively, indicating that SCI-IGD was 'very useful test' for identifying the presence of IGD and 'useful test' for identifying the absence of IGD. Third, SCI IGD could identify disordered gamers from non-disordered gamers. CONCLUSION: The implications and limitations of the study are also discussed. PMID- 28096872 TI - Reliability and Validity of the Beck Depression Inventory-II among Korean Adolescents. AB - OBJECTIVE: The Beck Depression Inventory-II (BDI-II) is one of the most popular scales for evaluating the severity of depression in adolescents as well as adults. The prevalence of depression increases during adolescence, and it has shown a rapid increase with occurrence at an earlier age and a tendency to continue into adulthood. Data from an adolescent nonclinical sample provides us more information related to depressive symptoms as potential risk factors. The current study was designed to two objectives: 1) to analyze the reliability and validity the BDI-II among Korean adolescents and 2) to evaluate the factorial structure in a Korean nonclinical adolescent sample. METHODS: The participants included 1072 adolescent boys and girls. We assessed the internal consistency, corrected item-total correlation, and the convergent validity of the BDI-II. We also performed confirmatory factor analyses to determine the internal structure of the BDI-II for Korean adolescents using Mplus 6.1. RESULTS: The Cronbach's alpha for the BDI-II total score was 0.89. The correlation between the BDI-II and the PHQ-9 was strong (r=0.75), and anxiety-related measures were 0.68 and 0.71, which were also in the high range. Among the five different factor structures, the modified three-factor model demonstrated the best overall fit. CONCLUSION: The BDI-II is a reliable tool for measuring the severity of depressive symptoms in Korean adolescents. Therefore, the findings can provide basic information for examining the prevalence rate, intervention strategies for depression in adolescents. PMID- 28096873 TI - The Relationship between Childhood Trauma and Suicidal Ideation: Role of Maltreatment and Potential Mediators. AB - OBJECTIVE: Childhood trauma is recognized as an important risk factor in suicidal ideation, however it is not fully understood how the different types of childhood maltreatment influence suicidal ideation nor what variables mediate the relationship between childhood trauma and suicidal ideation. This study examined the path from childhood trauma to suicidal ideation, including potential mediators. METHODS: A sample of 211 healthy adults completed the Childhood Trauma Questionnaire (CTQ), Beck scale for Suicidal Ideation (BSI), Functional Social Support Questionnaire (FSSQ) and Hospital Anxiety and Depression Scale (HADS). Path analysis was used to investigate the relationship among study variables. RESULTS: Of the several types of childhood maltreatment we considered, only childhood sexual abuse directly predicted suicidal ideation (beta=0.215, p=0.001). Childhood physical abuse (beta=0.049, 95% confidence interval: 0.011 0.109) and childhood emotional abuse (beta=0.042, 95% confidence interval: 0.001 0.107) indirectly predicted suicidal ideation through their association with anxiety. Childhood neglect indirectly predicted suicidal ideation through association with perceived social support (beta=0.085, 95% confidence interval: 0.041-0.154). CONCLUSION: Our results confirmed that childhood sexual abuse is a strong predictor of suicidal ideation. Perceived social support mediated the relationship between suicidal ideation and neglect. Anxiety fully mediated the relationship between suicidal ideation and both physical abuse and emotional abuse. Interventions to reduce suicidal ideation among survivors of childhood trauma should focus on anxiety symptoms and attempt to increase their social support. PMID- 28096875 TI - Sensory Processing Disorders are Associated with Duration of Current Episode and Severity of Side Effects. AB - OBJECTIVE: Longer duration of untreated illness, longer duration of current episode, and the severity of medication side effects may negatively impact on the perceived disability and psychosocial impairment of patients with major affective and anxiety disorders. Studies also suggested the involvement of sensory perception in emotional and psychopathological processes. The present study aimed to examine the relationship between Sensory Processing Disorders (SPD), duration of untreated illness and current illness episode, and the severity of side effects related to psychoactive medications. METHODS: The sample included 178 participants with an age ranging from 17 to 85 years (mean=53.84+/-15.55). Participants were diagnosed with unipolar Major Depressive Disorder (MDD) (50%), Bipolar Disorder (BD) (33.7%), and Anxiety disorders (16.3%). They completed a socio-demographic questionnaire, the Udvalg for Kliniske Undersogelser (UKU), and Adolescent/Adult Sensory Profile (AASP) questionnaire. RESULTS: Longer duration of current episode correlated with greater registration of sensory input and lower avoidance from sensory input among unipolar patients; with lower registration of sensory input, and higher tendency for sensory sensitivity/avoidance among bipolar participants; with lower sensory sensitivity/avoidance among anxiety participants, respectively. Also, mean UKU total scores correlated with lower sensory sensitivity among bipolar individuals. CONCLUSION: SPD expressed in either hypo/hyper sensitivity may serve to clinically characterize subjects with major affective and anxiety disorders. PMID- 28096876 TI - Effectiveness of Electroconvulsive Therapy Augmentation on Clozapine-Resistant Schizophrenia. AB - OBJECTIVE: This retrospective case series study of the effectiveness of electroconvulsive therapy (ECT) augmentation on clozapine-resistant schizophrenia was conducted by EMR review. METHODS: Clozapine-resistance was defined as persistent psychotic symptoms despite at least 12 weeks of clozapine administration with blood levels over 350 ng/mL in order to rule out pseudo resistance. Seven in-patients who were taking clozapine and treated with ECT were selected. We analyzed the psychopathology and subscales changed by ECT. RESULTS: The average number of ECT sessions was 13.4 (+/-4.6). Total Positive and Negative Syndrome Scale (PANSS) score was significantly reduced by 17.9 (+/-12.8) points (p=0.0384) on average, which represented a reduction of 25.5% (+/-14.3). 71.4% (5/7) of patients were identified as clinical remission, with at least a 20% reduction in PANSS score. PANSS reduction was associated with number of ECT sessions, stimulus level in the final session, and blood clozapine levels before ECT. However, the negative subscale on the PANSS were not reduced by ECT in any patient. We did not observe any persistent adverse cognitive effects. CONCLUSION: This study supports that ECT augmentation on clozapine-resistant schizophrenia reveals clinically effective and safe. Further research should be done involving a larger number of patients to investigate the effectiveness of clozapine/ECT combination therapy. PMID- 28096874 TI - Prevalence of Metabolic Syndrome in Patients with Schizophrenia in Korea: A Multicenter Nationwide Cross-Sectional Study. AB - OBJECTIVE: We designed a nationwide study with limited exclusion criteria to investigate the prevalence of metabolic syndrome (MetS) in Korea and its relationship with antipsychotic medications. METHODS: This multicenter, cross sectional, and observational study included patients diagnosed with schizophrenia or schizoaffective disorder. Sixteen hospitals enrolled 845 patients aged 18 to 65 years prescribed any antipsychotic medication between August 2011 and August 2013. MetS was diagnosed using the criteria of the modified Adult Treatment Panel III of the National Cholesterol Education Program with the Korean abdominal obesity definition (waist circumference >=85 cm in women, >=90 cm in men). RESULTS: The prevalence of MetS in all patients was 36.5% and was significantly higher in men than women (men, 40.8%; women, 32.2%) and was significantly correlated with age [odds ratio (OR) 1.02] and duration of illness (OR 1.03). The prevalence of MetS across antipsychotic drugs in the major monotherapy group was as follows: 18.8% for quetiapine, 22.0% for aripiprazole, 33.3% for both amisulpride and paliperidone, 34.0% for olanzapine, 35% for risperidone, 39.4% for haloperidol, and 44.7% for clozapine. CONCLUSION: The prevalence of MetS is very high in patients with schizophrenia or schizoaffective disorder. Screening and monitoring of MetS is also strongly recommended. PMID- 28096877 TI - Efficacy and Safety of Bitopertin in Patients with Schizophrenia and Predominant Negative Symptoms: Subgroup Analysis of Japanese Patients from the Global Randomized Phase 2 Trial. AB - OBJECTIVE: The aim of the present study was to perform a subgroup analysis of data from a phase II global, multi-center, randomized, double-blind, placebo controlled study to evaluate the efficacy and safety of bitopertin, a glycine reuptake inhibitor that activates N-methyl-D-aspartate receptors by increasing the concentration of glycine in the synaptic cleft, in Japanese and non-Japanese patients with schizophrenia and predominant negative symptoms. METHODS: Patients with schizophrenia and predominant negative symptoms on one or two antipsychotic drugs, including atypical antipsychotic drugs (olanzapine, risperidone, quetiapine, aripiprazole, and paliperidone) as the primary treatment, received bitopertin (10, 30, or 60 mg/day) or placebo once daily for 8 weeks as an add-on treatment. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS) negative symptom factor score (NSFS). RESULTS: The efficacy of bitopertin (10 mg and 30 mg) was similar between Japanese and non-Japanese patients. In the bitopertin 60-mg group, no difference from the placebo group was observed in Japanese or non-Japanese patients. The response to placebo was lower in Japanese patients, and there was a trend towards a greater difference in the change in PANSS NSFS between the placebo group and the 10-mg and 30-mg groups among Japanese patients. The safety profile of bitopertin was favorable in Japanese and non-Japanese patients. CONCLUSION: According to this subgroup analysis from a global phase II study of bitopertin, there was no difference in terms of efficacy and safety between Japanese and non-Japanese patients. PMID- 28096878 TI - Reversion of BDNF, Akt and CREB in Hippocampus of Chronic Unpredictable Stress Induced Rats: Effects of Phytochemical, Bacopa Monnieri. AB - OBJECTIVE: The aims of the present study were to explore the behavioural effects and to understand the possible mode of action of Bacopa monnieri extract (BME) on chronic unpredictable stress (CUS) induced depressive model and the biochemical alterations such as brain derived neurotrophic factor (BDNF), Akt, cyclic-AMP response element binding (CREB) protein level in the hippocampus of rats. METHODS: We examined the effects of chronic administration of BME on CUS exposed rats for 28 days. Behavioural changes were assessed by sucrose consumption and open field test to assess the effect of BME on CUS-induced depression. The mechanisms underlying antidepressant like action of BME was further evaluated by measuring levels of BDNF, Akt, and CREB in the hippocampus of rat brain and compared with the standard tricyclic antidepressant drug imipramine (20 mg/kg body weight). RESULTS: Exposure to CUS for 28 days produced depression-like behavior in rats, as indicated by significant decreases in sucrose consumption, locomotor activity including decreased BDNF, Akt and CREB levels in the hippocampus. Daily administration of BME at a dose of (80 mg/kg body weight) significantly reverses the behavioral alteration and restored the normal level of BDNF, total and phospho-Akt, total and phospho CREB in the hippocampus of CUS induced rats as compared to vehicle treated control rats. CONCLUSION: These findings suggest that BME ameliorates CUS induced behavioural depression in rats and that can be used as a potent therapeutic agent in treating depressive like behavior. PMID- 28096879 TI - Association between Mitofusin 2 Gene Polymorphisms and Late-Onset Alzheimer's Disease in the Korean Population. AB - OBJECTIVE: Mitochondrial dysfunction is a prominent and early feature of Alzheimer's disease (AD). The morphologic changes observed in the AD brain could be caused by a failure of mitochondrial fusion mechanisms. The aim of this study was to investigate whether genetic polymorphisms of two genes involved in mitochondrial fusion mechanisms, optic atrophy 1 (OPA1) and mitofusin 2 (MFN2), were associated with AD in the Korean population by analyzing genotypes and allele frequencies. METHODS: One coding single nucleotide polymorphism (SNP) in the MFN2, rs1042837, and two coding SNPs in the OPA1, rs7624750 and rs9851685, were compared between 165 patients with AD (83 men and 82 women, mean age 72.3+/ 4.41) and 186 healthy control subjects (82 men and 104 women, mean age 76.5+/ 5.98). RESULTS: Among these three SNPs, rs1042837 showed statistically significant differences in allele frequency, and genotype frequency in the co dominant 1 model and in the dominant model. CONCLUSION: These results suggest that the rs1042837 polymorphism in MFN2 may be involved in the pathogenesis of AD. PMID- 28096880 TI - Genetic Polymorphism of 1019C/G (rs6295) Promoter of Serotonin 1A Receptor and Catechol-O-Methyltransferase in Panic Disorder. AB - OBJECTIVE: Family and twin studies have suggested genetic liability for panic disorder (PD) and therefore we sought to determine the role of noradrenergic and serotonergic candidate genes for susceptibility for PD in a Japanese population. METHODS: In this age- and gender-matched case-control study involving 119 PD patients and 119 healthy controls, we examined the genotype distributions and allele frequencies of the serotonin transporter gene linked polymorphic region (5 HTTLPR), -1019C/G (rs6295) promoter polymorphism of the serotonin receptor 1A (5 HT1A), and catechol-O-methyltransferase (COMT) gene polymorphism (rs4680) and their association with PD. RESULTS: No significant differences were evident in the allele frequencies or genotype distributions of the COMT (rs4680), 5-HTTLPR polymorphisms or the -1019C/G (rs6295) promoter polymorphism of 5-HT1A between PD patients and controls. Although there were no significant associations of these polymorphisms with in subgroups of PD patients differentiated by gender or in subgroup comorbid with agoraphobia (AP), significant difference was observed in genotype distributions of the -1019C/G (rs6295) promoter polymorphism of 5-HT1A between PD patients without AP and controls (p=0.047). CONCLUSION: In this association study, the 1019C/G (rs6295) promoter polymorphism of the 5-HT1A receptor G/G genotype was associated with PD without AP in a Japanese population. PMID- 28096881 TI - Design and Methodology of the Korean Early Psychosis Cohort Study. AB - The present study details the rationale and methodology of the Korean Early Psychosis Cohort Study (KEPS), which is a clinical cohort investigation of first episode psychosis patients from a Korean population. The KEPS is a prospective naturalistic observational cohort study that follows the participants for at least 2 years. This study includes patients between 18 and 45 years of age who fulfill the criteria for one of schizophrenia spectrum and other psychotic disorders according to the diagnostic criteria of DSM-5. Early psychosis is defined as first episode patients who received antipsychotic treatment for fewer than 4 consecutive weeks after the onset of illness or stabilized patients in the early stages of the disorder whose duration of illness was less than 2 years from the initiation of antipsychotic treatment. The primary outcome measures are treatment response, remission, recovery, and relapse. Additionally, several laboratory tests are conducted and a variety of objective and subjective psychiatric measures assessing early life trauma, lifestyle pattern, and social and cognitive functioning are administered. This long-term prospective cohort study may contribute to the development of early intervention strategies and the improvement of long-term outcomes in patients with schizophrenia. PMID- 28096882 TI - Design and Methods of the Mood Disorder Cohort Research Consortium (MDCRC) Study. AB - The Mood Disorder Cohort Research Consortium (MDCRC) study is designed as a naturalistic observational prospective cohort study for early-onset mood disorders (major depressive disorders, bipolar disorders type 1 and 2) in South Korea. The study subjects consist of two populations: 1) patients with mood disorders under 25 years old and 2) patients with mood disorders within 2 years of treatment under 35 years old. After successful screening, the subjects are evaluated using baseline assessments and serial follow-up assessments at 3-month intervals. Between the follow-up assessments, subjects are dictated to check their own daily mood status before bedtime using the eMood chart application or a paper mood diary. At the regular visits every 3 months, inter-visit assessments are evaluated based on daily mood charts and interviews with patients. In addition to the daily mood chart, sleep quality, inter-visit major and minor mood episodes, stressful life events, and medical usage pattern with medical expenses are also assessed. Genomic DNA from blood is obtained for genomic analyses. From the MDCRC study, the clinical course, prognosis, and related factors of early onset mood disorders can be clarified. The MDCRC is also able to facilitate translational research for mood disorders and provide a resource for the convergence study of mood disorders. PMID- 28096883 TI - Reconsidering Clinical Staging Model: A Case of Genetic High Risk for Schizophrenia. AB - The clinical staging model is considered a useful and practical method not only in dealing with the early stage of psychosis overcoming the debate about diagnostic boundaries but also in emerging mood disorder. However, its one limitation is that it cannot discriminate the heterogeneity of individuals at clinical high risk for psychosis, but lumps them all together. Even a healthy offspring of schizophrenia can eventually show clinical symptoms and progress to schizophrenia under the influence of genetic vulnerability and environmental stress even after the peak age of onset of schizophrenia. Therefore, individuals with genetic liability of schizophrenia may require a more intensive intervention than recommended by the staging model based on current clinical status. PMID- 28096884 TI - Immunomodulatory Efficacy of Standardized Annona muricata (Graviola) Leaf Extract via Activation of Mitogen-Activated Protein Kinase Pathways in RAW 264.7 Macrophages. AB - Annona muricata, commonly known as Graviola, has been utilized as a traditional medicine to treat various human diseases. The aim of this study was to examine the immune-enhancing activity of Graviola leaf extracts in RAW 264.7 macrophage cells. Active ingredients in Graviola leaf extracts (GE) were identified as kaempferol-3-O-rutinoside and quercetin-3-O-rutinoside by LC-MS/MS. When treated with steam or 50% ethanol GE, cell morphology was altered due to initiation of cell differentiation. While the cell viability was not altered by the steam GE, it was reduced by the ethanol GE. Both steam and ethanol GE induced the transcriptional expression of cytokines, including tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta, but only the steam extract upregulated inducible nitric oxide synthase (iNOS). In consistence with mRNA expression, the production of TNF-alpha and nitrite was elevated by both steam and ethanol extracts of Graviola leaves. This is mainly due to activation of mitogen activated protein (MAP) kinase signaling pathways. These results suggest that Graviola leaves enhance immunity by activation of the MAP kinase pathways. These bioactive properties of Graviola indicate its potential as a health-promoting ingredient to boost the immune system. PMID- 28096885 TI - Spatholobus suberectus Column Extract Inhibits Estrogen Receptor Positive Breast Cancer via Suppressing ER MAPK PI3K/AKT Pathway. AB - Although Chinese herbal compounds have long been alternatively applied for cancer treatment in China, their treatment effects have not been sufficiently investigated. The Chinese herb Spatholobus suberectus is commonly prescribed to cancer patients. HPLC analysis has shown that the main components of Spatholobus suberectus are flavonoids that can be classified as phytoestrogens, having a structure similar to estrogen. This study was designed to investigate the effects of Spatholobus suberectus column extract (SSCE) on the estrogen receptor-positive (ER+) breast cancer cell line MCF-7 and its possible molecular mechanism. In our study, MTT assay was performed to evaluate cell viability. The results show that SSCE (80, 160, and 320 MUg/ml) significantly decreased the viability of MCF-7 cells. SSCE also triggered apoptosis, arrested the cell cycle at the G0/G1 phase, and inhibited cell migration. A dual-luciferase reporter system showed that SSCE suppressed intranuclear p-ER activity; Western blot analysis confirmed the repressed expression of phosphorylated-ER alpha (p-ERalpha), ERK1/2, p-ERK1/2, AKT, p-AKT, p-mTOR, PI3K, and p-PI3K, indicating that SSCE suppressed the MAPK PI3K/AKT signaling pathway. Collectively, our results suggest that SSCE causes apoptosis, an arrest in the G0/G1 phase, and a decrease in migration in ER+ MCF-7 cells via hypoactivity of the ER and suppression of the MAPK PI3K/AKT pathway. PMID- 28096886 TI - Fermented Chinese Formula Shuan-Tong-Ling Protects Brain Microvascular Endothelial Cells against Oxidative Stress Injury. AB - Fermented Chinese formula Shuan-Tong-Ling (STL), composed of fourteen medicinal herbs, was an experiential formula by Dr. Zhigang Mei for treating vascular encephalopathy, but the underlying mechanisms remained unknown. In this study, we aimed to investigate the protective effects of fermented STL on hydrogen peroxide (H2O2-) induced injury in rat brain microvascular endothelial cells (BMECs) and the possible mechanisms. Cultured BMECs were treated with H2O2, STL, or nicotinamide (NAM, a SIRT1 inhibitor). Then, 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl-2H-tetrazolium bromide (MTT) assay was employed to detect cell proliferation and senescence-associated beta-galactosidase (SA-beta-gal) was used to examine cell senescence. Cell nuclei were observed by 4',6-diamidino-2 phenylindole. Additionally, changes in reactive oxygen species (ROS), superoxide dismutase (SOD), and glutathione (GSH) levels were measured. Expression of SIRT1, p21, and PGC-1alpha was determined by western blot. Cell proliferation significantly increased with STL treatment in a dose-dependent manner. H2O2 treatment could intensify cell senescence and nuclei splitting or pyknosis. With STL treatment, the reduced ROS level was accompanied by increased SOD and GSH activity. Further assays showed upregulation of SIRT1 and PGC-1alpha and downregulation of p21 after STL treatment. The results revealed that STL could protect BMECs against oxidative stress injury at least partially through the SIRT1 pathway. PMID- 28096887 TI - Thylakoids reduce body fat and fat cell size by binding to dietary fat making it less available for absorption in high-fat fed mice. AB - BACKGROUND: Dietary thylakoids derived from spinach have beneficial effects on body fat accumulation and blood lipids as demonstrated in humans and rodents. Important mechanisms established include delayed fat digestion in the intestine, without causing steatorrhea, and increased fatty acid oxidation in intestinal cells. The objective of our study was to elucidate if increased fecal fat excretion is an important mechanism to normalize adipose tissue metabolism during high-fat feeding in mice supplemented with thylakoids. METHODS: Mice were randomized to receive HFD or thylHFD for 14 days (n = 14 for the control group and 16 for the thylakoid group). The effect of thylakoids on body fat distribution, faecal and liver fat content, and adipose tissue metabolism was investigated following high-fat feeding. RESULTS: Thylakoid supplementation for 14 days caused an increased faecal fat content without compensatory eating compared to control. As a result, thylakoid treated animals had reduced fat mass depots and reduced liver fat accumulation compared to control. The size distribution of adipocytes isolated from visceral adipose tissue was narrowed and the cell size decreased. Adipocytes isolated from thylakoid-treated mice displayed a significantly increased lipogenesis, and protein expression of peroxisome proliferator-activated receptor gamma (PPARgamma), down-stream target FAS, as well as transcription factor coactivators PGC1-alpha and LPIN-1 were upregulated in adipose tissue from thylakoid-fed mice. CONCLUSIONS: Together, these data suggest that thylakoid supplementation reduces body fat and fat cell size by binding to dietary fat and increasing its fecal excretion, thus reducing dietary fat available for absorption. PMID- 28096888 TI - Sociocultural factors influencing breastfeeding practices in two slums in Nairobi, Kenya. AB - BACKGROUND: Despite numerous interventions promoting optimal breastfeeding practices in Kenya, pockets of suboptimal breastfeeding practices are documented in Kenya's urban slums. This paper describes cultural and social beliefs and practices that influence breastfeeding in two urban slums in Nairobi, Kenya. METHODS: Qualitative data were collected in Korogocho and Viwandani slums through 10 focus group discussions and 19 in-depth interviews with pregnant, breastfeeding women and community health volunteers and 11 key-informant interviews with community leaders. Interviews were audiotaped, transcribed verbatim, coded in NVIVO and analyzed thematically. RESULTS: Social and cultural beliefs and practices that result to suboptimal breastfeeding practices were highlighted including; considering colostrum as 'dirty' or 'curdled milk', a curse 'bad omen' associated with breastfeeding while engaging in extra marital affairs, a fear of the 'evil eye' (malevolent glare which is believed to be a curse associated with witchcraft) when breastfeeding in public and breastfeeding being associated with sagging breasts. Positive social and cultural beliefs were also identified including the association of breast milk with intellectual development and good child health. The beliefs and practices were learnt mainly from spouses, close relatives and peers. CONCLUSION: Interventions promoting behavior change with regards to breastfeeding should focus on dispelling the beliefs and practices that result to suboptimal breastfeeding practices and to build on the positive ones, while involving spouses and other family members as they are important sources of information on breastfeeding. TRIAL REGISTRATION: ISRCTN83692672: December 2013 (retrospectively registered). PMID- 28096889 TI - Detection of Doppler Microembolic Signals Using High Order Statistics. AB - Robust detection of the smallest circulating cerebral microemboli is an efficient way of preventing strokes, which is second cause of mortality worldwide. Transcranial Doppler ultrasound is widely considered the most convenient system for the detection of microemboli. The most common standard detection is achieved through the Doppler energy signal and depends on an empirically set constant threshold. On the other hand, in the past few years, higher order statistics have been an extensive field of research as they represent descriptive statistics that can be used to detect signal outliers. In this study, we propose new types of microembolic detectors based on the windowed calculation of the third moment skewness and fourth moment kurtosis of the energy signal. During energy embolus free periods the distribution of the energy is not altered and the skewness and kurtosis signals do not exhibit any peak values. In the presence of emboli, the energy distribution is distorted and the skewness and kurtosis signals exhibit peaks, corresponding to the latter emboli. Applied on real signals, the detection of microemboli through the skewness and kurtosis signals outperformed the detection through standard methods. The sensitivities and specificities reached 78% and 91% and 80% and 90% for the skewness and kurtosis detectors, respectively. PMID- 28096890 TI - Defining the Optimal Region of Interest for Hyperemia Grading in the Bulbar Conjunctiva. AB - Conjunctival hyperemia or conjunctival redness is a symptom that can be associated with a broad group of ocular diseases. Its levels of severity are represented by standard photographic charts that are visually compared with the patient's eye. This way, the hyperemia diagnosis becomes a nonrepeatable task that depends on the experience of the grader. To solve this problem, we have proposed a computer-aided methodology that comprises three main stages: the segmentation of the conjunctiva, the extraction of features in this region based on colour and the presence of blood vessels, and, finally, the transformation of these features into grading scale values by means of regression techniques. However, the conjunctival segmentation can be slightly inaccurate mainly due to illumination issues. In this work, we analyse the relevance of different features with respect to their location within the conjunctiva in order to delimit a reliable region of interest for the grading. The results show that the automatic procedure behaves like an expert using only a limited region of interest within the conjunctiva. PMID- 28096891 TI - Phantom Validation of Tc-99m Absolute Quantification in a SPECT/CT Commercial Device. AB - Aim. Similar to PET, absolute quantitative imaging is becoming available in commercial SPECT/CT devices. This study's goal was to assess quantitative accuracy of activity recovery as a function of image reconstruction parameters and count statistics in a variety of phantoms. Materials and Methods. We performed quantitative 99mTc-SPECT/CT acquisitions (Siemens Symbia Intevo, Erlangen, Germany) of a uniform cylindrical, NEMA/IEC, and an anthropomorphic abdominal phantom. Background activity concentrations tested ranged: 2-80 kBq/mL. SPECT acquisitions used 120 projections (20 s/projection). Reconstructions were performed with the proprietary iterative conjugate gradient algorithm. NEMA phantom reconstructions were obtained as a function of the iteration number (range: 4-48). Recovery coefficients, hot contrast, relative lung error (NEMA phantom), and image noise were assessed. Results. In all cases, absolute activity and activity concentration were measured within 10% of the expected value. Recovery coefficients and hot contrast in hot inserts did not vary appreciably with count statistics. RC converged at 16 iterations for insert size > 22 mm. Relative lung errors were comparable to PET levels indicating the efficient integration of attenuation and scatter corrections with adequate detector modeling. Conclusions. The tested device provided accurate activity recovery within 10% of correct values; these performances are comparable to current generation PET/CT systems. PMID- 28096892 TI - Investigating Mutations to Reduce Huntingtin Aggregation by Increasing Htt-N Terminal Stability and Weakening Interactions with PolyQ Domain. AB - Huntington's disease is a fatal autosomal genetic disorder characterized by an expanded glutamine-coding CAG repeat sequence in the huntingtin (Htt) exon 1 gene. The Htt protein associated with the disease misfolds into toxic oligomers and aggregate fibril structures. Competing models for the misfolding and aggregation phenomena have suggested the role of the Htt-N-terminal region and the CAG trinucleotide repeats (polyQ domain) in affecting aggregation propensities and misfolding. In particular, one model suggests a correlation between structural stability and the emergence of toxic oligomers, whereas a second model proposes that molecular interactions with the extended polyQ domain increase aggregation propensity. In this paper, we computationally explore the potential to reduce Htt aggregation by addressing the aggregation causes outlined in both models. We investigate the mutation landscape of the Htt-N-terminal region and explore amino acid residue mutations that affect its structural stability and hydrophobic interactions with the polyQ domain. Out of the millions of 3-point mutation combinations that we explored, the (L4K E12K K15E) was the most promising mutation combination that addressed aggregation causes in both models. The mutant structure exhibited extreme alpha-helical stability, low amyloidogenicity potential, a hydrophobic residue replacement, and removal of a solvent-inaccessible intermolecular side chain that assists oligomerization. PMID- 28096893 TI - Determining Cutoff Point of Ensemble Trees Based on Sample Size in Predicting Clinical Dose with DNA Microarray Data. AB - Background/Aim. Evaluating the success of dose prediction based on genetic or clinical data has substantially advanced recently. The aim of this study is to predict various clinical dose values from DNA gene expression datasets using data mining techniques. Materials and Methods. Eleven real gene expression datasets containing dose values were included. First, important genes for dose prediction were selected using iterative sure independence screening. Then, the performances of regression trees (RTs), support vector regression (SVR), RT bagging, SVR bagging, and RT boosting were examined. Results. The results demonstrated that a regression-based feature selection method substantially reduced the number of irrelevant genes from raw datasets. Overall, the best prediction performance in nine of 11 datasets was achieved using SVR; the second most accurate performance was provided using a gradient-boosting machine (GBM). Conclusion. Analysis of various dose values based on microarray gene expression data identified common genes found in our study and the referenced studies. According to our findings, SVR and GBM can be good predictors of dose-gene datasets. Another result of the study was to identify the sample size of n = 25 as a cutoff point for RT bagging to outperform a single RT. PMID- 28096894 TI - A Novel Sample Selection Strategy for Imbalanced Data of Biomedical Event Extraction with Joint Scoring Mechanism. AB - Biomedical event extraction is an important and difficult task in bioinformatics. With the rapid growth of biomedical literature, the extraction of complex events from unstructured text has attracted more attention. However, the annotated biomedical corpus is highly imbalanced, which affects the performance of the classification algorithms. In this study, a sample selection algorithm based on sequential pattern is proposed to filter negative samples in the training phase. Considering the joint information between the trigger and argument of multiargument events, we extract triplets of multiargument events directly using a support vector machine classifier. A joint scoring mechanism, which is based on sentence similarity and importance of trigger in the training data, is used to correct the predicted results. Experimental results indicate that the proposed method can extract events efficiently. PMID- 28096895 TI - Towards the Design of a Patient-Specific Virtual Tumour. AB - The design of a patient-specific virtual tumour is an important step towards Personalized Medicine. However this requires to capture the description of many key events of tumour development, including angiogenesis, matrix remodelling, hypoxia, and cell state heterogeneity that will all influence the tumour growth kinetics and degree of tumour invasiveness. To that end, an integrated hybrid and multiscale approach has been developed based on data acquired on a preclinical mouse model as a proof of concept. Fluorescence imaging is exploited to build case-specific virtual tumours. Numerical simulations show that the virtual tumour matches the characteristics and spatiotemporal evolution of its real counterpart. We achieved this by combining image analysis and physiological modelling to accurately described the evolution of different tumour cases over a month. The development of such models is essential since a dedicated virtual tumour would be the perfect tool to identify the optimum therapeutic strategies that would make Personalized Medicine truly reachable and achievable. PMID- 28096896 TI - Registration and Summation of Respiratory-Gated or Breath-Hold PET Images Based on Deformation Estimation of Lung from CT Image. AB - Lung motion due to respiration causes image degradation in medical imaging, especially in nuclear medicine which requires long acquisition times. We have developed a method for image correction between the respiratory-gated (RG) PET images in different respiration phases or breath-hold (BH) PET images in an inconsistent respiration phase. In the method, the RG or BH-PET images in different respiration phases are deformed under two criteria: similarity of the image intensity distribution and smoothness of the estimated motion vector field (MVF). However, only these criteria may cause unnatural motion estimation of lung. In this paper, assuming the use of a PET-CT scanner, we add another criterion that is the similarity for the motion direction estimated from inhalation and exhalation CT images. The proposed method was first applied to a numerical phantom XCAT with tumors and then applied to BH-PET image data for seven patients. The resultant tumor contrasts and the estimated motion vector fields were compared with those obtained by our previous method. Through those experiments we confirmed that the proposed method can provide an improved and more stable image quality for both RG and BH-PET images. PMID- 28096897 TI - The impact of organisational change and fiscal restraint on organisational culture. AB - BACKGROUND: Strategies to implement evidence-based practice have highlighted the bidirectional relationship of organisational change on organisational culture. The present study examined changes in perceptions of organisational culture in two community mental health services implementing cognitive therapies into routine psychosis care over 3 years. During the time of the study there were a number of shared planned and unplanned changes that the mental health services had to accommodate. One service, Metro South, had the additional challenge of embarking on a major organisational restructure. METHODS: A survey of organisational culture was administered to clinical staff of each service at yearly intervals over the 3 years. RESULTS: At baseline assessment there was no significant difference between the two services in organisational culture. At the midpoint assessment, which was conducted at the time the Metro South restructure was operationalized, there were less positive ratings of organisational culture recorded in Metro South compared to the other service. Organisational culture returned to near-baseline levels at endpoint assessment. CONCLUSIONS: These findings are consistent with the literature that organisational culture is relatively robust and resilient. It is also consistent with the literature that, at any one time, a service or organisation may have a finite capacity to absorb change. Consequently this limitation needs to be taken into account in the timing and planning of major service reform where possible. The results also extend the literature, insofar as external factors with a high impact on the operation of an organisation may impact upon organisational culture albeit temporarily. PMID- 28096898 TI - Characteristics of adolescents frequently restrained in acute psychiatric units in Norway: a nationwide study. AB - BACKGROUND: The use of restraints in adolescent psychiatric settings requires particular professional, ethical, and legal considerations. The purpose of this study was to investigate whether the number of restraint episodes per patient was related to any of several characteristics of the adolescents. METHODS: In this nationwide study, we included all adolescents restrained during the period 2008 2010 (N = 267) in Norwegian adolescent acute psychiatric inpatient units. They constitute 6.5% of the adolescents hospitalized in these units in the same period of time. We collected data on the number of restraint episodes they experienced during the study period; Poisson regression was then used to analyze the impact of gender, social, mental health, and treatment characteristics on the frequency of restraint. We developed a risk index for the likelihood of experiencing multiple restraint episodes. RESULTS: We found a skewed distribution of restraint episodes in which a small group (18%) of restrained adolescents experienced a majority (77%) of the restraint episodes. A large percentage of the restrained adolescents (36%) experienced only one restraint episode. Risk factors for multiple restraint episodes were female gender, lower psychosocial functioning (Children's Global Assessment Scale below 35), more and longer admissions, and concomitant use of pharmacological restraint. Except for gender, we used these variables to develop a risk index that was moderately associated with multiple restraint episodes. CONCLUSIONS: As a small group of patients accounted for a large percentage of the restraint episodes, future research should further investigate the reasons for and consequences of multiple restraint episodes in patients at acute adolescent psychiatric units, and evaluate preventive approaches targeted to reduce their risk for experiencing restraint. PMID- 28096899 TI - Why do surgeons continue to perform unnecessary surgery? PMID- 28096901 TI - Exploring musculoskeletal injuries in the podiatry profession: an international cross sectional study. AB - BACKGROUND: Workplace injury is an international costly burden. Health care workers are an essential component to managing musculoskeletal disorders, however in doing this, they may increase their own susceptibility. While there is substantial evidence about work-related musculoskeletal disorders across the health workforce, understanding risk factors in specific occupational groups, such as podiatry, is limited. The primary aim of this study was to determine the prevalence and intensity of work related low back pain in podiatrists. METHODS: This was an international cross-sectional survey targeting podiatrists in Australia, New Zealand and the United Kingdom. The survey had two components; general demographic variables and variables relating to general musculoskeletal pain in general or podiatry work-related musculoskeletal pain. Multivariable regression analyses were used to identify factors associated with musculoskeletal stiffness and pain and low back pain intensity. Thematic analysis was used to group comments podiatrists made about their musculoskeletal health. RESULTS: There were 948 survey responses (5% of Australian, New Zealand and United Kingdom registered podiatrists). There were 719 (76%) podiatrists reporting musculoskeletal pain as a result of their work practices throughout their career. The majority of injuries reported were in the first five years of practice (n = 320, 45%). The body area reported as being the location of the most significant injury was the low back (203 of 705 responses, 29%). Being female (p < 0.001) and working in private practice (p = 0.003) was associated with musculoskeletal pain or stiffness in the past 12 months. There were no variables associated with pain or stiffness in the past four weeks. Being female was the only variable associated with higher pain (p = 0.018). There were four main themes to workplace musculoskeletal pain: 1. Organisational and procedural responses to injury, 2. Giving up work, taking time off, reducing hours, 3. Maintaining good musculoskeletal health and 4. Environmental change. CONCLUSIONS: The postures that podiatrists hold while treating patients appear to impact on musculoskeletal pain and stiffness. Recently graduated and female podiatrists are at higher risk of injury. There is a need for the profession to consider how they move and take care of their own musculoskeletal health. PMID- 28096900 TI - MS_HistoneDB, a manually curated resource for proteomic analysis of human and mouse histones. AB - BACKGROUND: Histones and histone variants are essential components of the nuclear chromatin. While mass spectrometry has opened a large window to their characterization and functional studies, their identification from proteomic data remains challenging. Indeed, the current interpretation of mass spectrometry data relies on public databases which are either not exhaustive (Swiss-Prot) or contain many redundant entries (UniProtKB or NCBI). Currently, no protein database is ideally suited for the analysis of histones and the complex array of mammalian histone variants. RESULTS: We propose two proteomics-oriented manually curated databases for mouse and human histone variants. We manually curated >1700 gene, transcript and protein entries to produce a non-redundant list of 83 mouse and 85 human histones. These entries were annotated in accordance with the current nomenclature and unified with the "HistoneDB2.0 with Variants" database. This resource is provided in a format that can be directly read by programs used for mass spectrometry data interpretation. In addition, it was used to interpret mass spectrometry data acquired on histones extracted from mouse testis. Several histone variants, which had so far only been inferred by homology or detected at the RNA level, were detected by mass spectrometry, confirming the existence of their protein form. CONCLUSIONS: Mouse and human histone entries were collected from different databases and subsequently curated to produce a non-redundant protein-centric resource, MS_HistoneDB. It is dedicated to the proteomic study of histones in mouse and human and will hopefully facilitate the identification and functional study of histone variants. PMID- 28096902 TI - Functional characterization of the active Mutator-like transposable element, Muta1 from the mosquito Aedes aegypti. AB - BACKGROUND: Mutator-like transposable elements (MULEs) are widespread with members in fungi, plants, and animals. Most of the research on the MULE superfamily has focused on plant MULEs where they were discovered and where some are extremely active and have significant impact on genome structure. The maize MuDR element has been widely used as a tool for both forward and reverse genetic studies because of its high transposition rate and preference for targeting genic regions. However, despite being widespread, only a few active MULEs have been identified, and only one, the rice Os3378, has demonstrated activity in a non host organism. RESULTS: Here we report the identification of potentially active MULEs in the mosquito Aedes aegypti. We demonstrate that one of these, Muta1, is capable of excision and reinsertion in a yeast transposition assay. Element reinsertion generated either 8 bp or 9 bp target site duplications (TSDs) with no apparent sequence preference. Mutagenesis analysis of donor site TSDs in the yeast assay indicates that their presence is important for precise excision and enhanced transposition. Site directed mutagenesis of the putative DDE catalytic motif and other conserved residues in the transposase protein abolished transposition activity. CONCLUSIONS: Collectively, our data indicates that the Muta1 transposase of Ae. aegypti can efficiently catalyze both excision and reinsertion reactions in yeast. Mutagenesis analysis reveals that several conserved amino acids, including the DDE triad, play important roles in transposase function. In addition, donor site TSD also impacts the transposition of Muta1. PMID- 28096903 TI - Anxiety and depression symptoms among women attending group-based patient education courses for hereditary breast and ovarian cancer. AB - BACKGROUND: Women carrying BRCA-mutations are facing significant challenges, including decision making regarding surveillance and risk-reducing surgery. They often report that they are left alone with these important decisions. In order to enhance the genetic counselling session we organized a group-based patient education (GPE) course for women with BRCA-mutations. The study aims were to characterize women attending a group-based patient education (GPE) course for hereditary breast and ovarian cancer, consider the usefulness of the course, evaluate symptoms of anxiety and depression among the participants, and finally investigate whether their levels of anxiety and depression changed from before to after the course session. METHODS: A prospective study was conducted. Two weeks before (T1) and 2 weeks after (T2) attending the GPE-course the participants received questionnaires by mail. We collected information on demographic- and medical variables, anxiety and depression using Hospital Anxiety and Depression Scale (HADS), self-efficacy using The Bergen Genetic Counseling Self-Efficacy scale (BGCSES) and coping style using the Threatening Medical Situations Inventory (TMSI). A total of N = 100 (77% response rate) women participated at baseline and 75 (58% response rate) also completed post-course assessment. RESULTS: The mean level of anxiety symptoms was elevated among participants but decreased significantly during follow-up. Lower anxiety symptom levels were associated with "longer time since disclosure of gene test result", "higher levels of self-efficacy" and having experienced "loss of a close relative due to breast or ovarian cancer". Lower depression symptom levels were associated with "higher levels of education" and "loss of a close relative due to breast or ovarian cancer". CONCLUSION: The women in this study seemed to benefit from the GPE course. Women newly diagnosed with a BRCA mutation who reported lower levels of self-efficacy and lower levels of education were more vulnerable. These women need special attention. PMID- 28096904 TI - Magnetic Resonance Imaging (MRI) Characterization of Perianal Fistulous Disease in a Rural Based Tertiary Hospital of North India. AB - BACKGROUND: To diagnose and characterize the perianal fistulous disease using Magnetic resonance imaging (MRI) in a hilly and rural area of North India. MATERIAL/METHODS: This prospective hospital based study was conducted for a period of one year from April 2014 to April 2015 in the departments of Radiodiagnosis and Surgery of our institute. A total of 50 consecutive patients presenting with perianal fistulous disease fulfilling the inclusion and exclusion criteria were included in the study and taken up for MRI. The perianal fistulae were classified according to St James University hospital classification and tracks were assessed with regard to anatomical plane, length, ramifications, abscess formation, enteric communication, external cutaneous opening, enhancement and suprasphincteric extension. Surgical correlation was done in 31 patients who opted for surgical treatment. Rest of the 19 patients preferred alternative medicine for treatment or chose to postpone their surgery. RESULTS: The disease was much more prevalent in males in comparison to females with male to female ratio of 24:1. Grade 4 was the most common type of fistula (34%) while Grade 5 was the least common type (4%).MRI showed a high sensitivity of 93.7% and positive predictive value (PPV) of 96.7% when correlated with surgical findings. A substantial number of patients (38%) preferred alternative medicine or non surgical form of treatment. CONCLUSIONS: MRI is a very sensitive modality for the evaluation of perianal fistula. In our study group, the disease predominantly affected middle aged men. Ramifications and abscesses were commonly seen, affecting nearly half of the patients and majority of the patients had active fistulous tracks with posteriorly located enteric opening. Overall, transsphincteric fistulae were most common. Significant number of patients avoided surgery or showed preference for non surgical treatment. PMID- 28096905 TI - Metastasis of Renal Clear Cell Carcinoma to Thyroid Gland Mimicking Adenomatous Goiter. AB - BACKGROUND: Renal cell carcinoma is an interesting tumor due to its unpredictable behavior. Common metastatic sites of renal cell carcinoma are the lungs, lymph nodes, bones and liver. Concurrent thyroid metastasis of clear cell carcinoma is uncommon but it can appear as a rapidly growing cervical, painless nodular mass. CASE REPORT: We report a case of a 56-year-old male patient with clear cell renal carcinoma confirmed on a histopathological examination. The patient noticed a rapidly growing mass in the thyroid region when receiving medical anticancer therapy. Because of that, gray-scale thyroid ultrasonography and a fine-needle aspiration biopsy were performed. The histopathological examinationof the biopsy specimen revealed a lesion composed of malignant epithelial cells compatible with metastasis of renal carcinoma. CONCLUSIONS: In patients with with a history of RCC, both past and present, a thyroid mass, especially co-existing with an adenomatous goiter, should prompt a work-up for thyroid metastasis. PMID- 28096906 TI - Relapsing-Remitting Severe Bickerstaff's Brainstem Encephalitis - Case Report and Literature Review. AB - BACKGROUND: Bickerstaff's brainstem encephalitis (BBE) is a very rare disease of the central nervous system. Aetiology of the disease is auto-immunological. However, it is not entirely understood. Clinically BBE manifests in progressive ophthalmoplegia, ataxia and consciousness disturbances. Clinical symptoms are usually preceded by an unidentified infection of the upper respiratory tract. Usually, the disease has one phase, but individual relapses have also been described. Despite quite severe clinical symptoms, the prognosis is usually good. CASE REPORT: The article presents a case of a patient with relapsing-remitting severe BBE. The case is presented due to the relapsing-remitting clinical course of the disease that resulted in patient's death, rarely described in the literature. We also present the results of subsequent MR scans in the course of the disease, so far described only in individual reports. It is also the first report in the world's literature presenting the results of series of MR spectroscopy (MRS) examinations in the course of BBE. CONCLUSIONS: MR examination is an important component in BBE diagnostics, allowing to differentiate atypical cases and place them under special supervision due to the possibility of the severe clinical course. MR also facilitates differentiation between Miller-Fisher Syndrome (MFS) and BBE in cases of diagnostic doubts. Adding MRS and MRI to the protocol allows us to define the nature of morphological changes more accurately in patients with suspected or diagnosed BBE. PMID- 28096907 TI - Thinking outside of the pelvis: Managing chronic urological pain. PMID- 28096909 TI - Further thoughts on transition of care for spina bifida patients: Experiences in BC. PMID- 28096908 TI - Is there a manpower crisis looming for Canadian urology? PMID- 28096910 TI - Exploring the business of urology: Conflict resolution and negotiation. PMID- 28096911 TI - Depression and catastrophizing predict suicidal ideation in tertiary care patients with interstitial cystitis/bladder pain syndrome. AB - INTRODUCTION: We sought to evaluate psychosocial factors as predictors of suicidal ideation (SI) in a tertiary care outpatient sample of women suffering from interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: The patients are women managed at tertiary care centres (n=190). Controls were recruited from the community (n=117). Both groups completed questionnaires on demographics, pain (McGill Pain Questionnaire), IC/BPS symptoms, and psychological variables. Univariate and multivariate hierarchical regression modelling was conducted to examine the strength of associations and unique effects of psychosocial variables on patient SI. RESULTS: Compared to 6% in healthy controls, 23% of patients endorsed SI in the past two weeks. Correlations between SI, depression, and catastrophizing across controls and cases show that for controls, SI is associated with greater pain (0.31; p<0.01) and depression only (0.59; p<0.01). For tertiary care centre cases, SI is associated with pain (0.24; p<0.01), depression (0.64; p<0.01), and catastrophizing (0.35; p<0.01). Regression analyses indicated that psychosocial variables accounted for a significant amount of variance over and above IC/BPS symptoms. Catastrophizing (i.e., helplessness) about pain and depression were significant univariate predictors of SI, but only depression predicted SI in multivariable analyses. CONCLUSIONS: Limitations of this study include its cross-sectional design and primarily correlation-based statistics. The present study is the first to implicate multiple psychosocial risk factors over and above IC/BPS-specific symptoms and patient pain experience in SI in women with IC/BPS. Depression in particular is uniquely important in predicting suicidality. These results support a multidisciplinary, proactive approach to IC/BPS involving not only treatment of disease symptoms, but also early detection/treatment of associated psychosocial problems. PMID- 28096912 TI - Mortality trends and the impact of lymphadenectomy on survival for renal cell carcinoma patients with distant metastasis. AB - INTRODUCTION: Current treatment paradigms for metastatic renal cell carcinoma (mRCC) invoke a combination of surgical and systemic therapies. We sought to quantify trends in mortality and performance of lymphadenectomy, as well as impact on survival for patients with mRCC. METHODS: The Surveillance, Epidemiology, and End Results registry (SEER) (1988-2011) identified patients with mRCC. Kaplan-Meier curves and Cox proportional hazards models with competing risks regression were employed to assess survival. RESULTS: 15 060 patients with mRCC were identified, with 6316 (41.9%) undergoing cytoreductive nephrectomy. Mean number of lymph nodes removed was 6.2, with mean 3.3 positive nodes among 1018 (43.9%) patients with positive nodes. Median overall survival (OS) increased from seven to 11 months (1999-2010), and finding a positive node decreased median cancer survival from 22 to nine months. Cancer-specific survival (CSS) showed significant decreases in mortality after 2005 (hazard ratio [HR] 0.71 [0.60-0.83] comparing 2010 to 1990). Lymphadenectomy was associated with decreased OS (HR 1.10 [1.03-1.16]; p=0.002) due to decreased CSS (HR 1.10 [1.04-1.17]; p<0.001) without increase in other-cause mortality (HR 0.94 [0.79-1.11]; p=0.455). However, more extensive lymphadenectomy >=3 lymph nodes removed did not significantly impact OS or CSS. Number of positive lymph nodes was associated with decreased CSS. CONCLUSIONS: mRCC continues to carry a poor prognosis, but current treatment paradigms have led to modest improvements in OS and CSS in recent years. Lymphadenectomy was found to play a prognostic rather than therapeutic role in the management of mRCC. The performance of lymphadenectomy should be limited based on clinical judgment and better incorporated into randomized trials of new systemic therapies to identify scenarios where implementation may improve survival. PMID- 28096913 TI - Rethinking lymph node metastasis and cytoreductive nephrectomy. PMID- 28096914 TI - Benefits of surgeon-controlled fluoroscopy outweigh concerns. PMID- 28096915 TI - The impact of prior urethral sling on artificial urinary sphincter outcomes. AB - INTRODUCTION: We sought to evaluate device outcomes in men who underwent primary artificial urinary sphincter (AUS) placement after failed male urethral sling (MUS). METHODS: We performed a retrospective chart review of 990 men who underwent an AUS procedure between 2003 and 2014. Of these, 540 were primary AUS placements, including 30 (5.5%) with a history of MUS. AUS revisions and explantations were compared between men stratified by the presence of prior sling. Hazard ratios (HR) adjusting for competing risks were used to determine the association with prior sling and AUS outcomes (infection/erosion, urethral atrophy, and mechanical malfunction), while overall device failure was estimated using Kaplan-Meier and Cox-regression analysis. RESULTS: There was no significant difference in age, body mass index, prior prostatectomy, or pelvic radiation when stratified by history of MUS. However, patients with a history of MUS were more likely to have undergone prior collagen injection (p=0.01). On univariate and multivariate analysis, prior MUS was not associated with device failure (HR 1.54; p=0.27). Three-year overall device survival did not significantly differ between those with and without prior MUS (70% vs. 85%; p=0.21). Also, there were no significant differences in the incidence of device infection/erosion, mechanical malfunction, and urethral atrophy. CONCLUSIONS: AUS remains a viable treatment option for men with persistent or recurrent stress urinary incontinence after MUS. However, while not statistically significant, we identified a trend towards lower three-year device outcomes in patients with prior urethral sling. These findings indicate the need for longer-term studies to determine if slings pose an increased hazard. PMID- 28096916 TI - An audit of referral and treatment patterns of high-risk prostate cancer patients in Alberta. AB - INTRODUCTION: We aimed to determine the impact of clinical practice guidelines (CPG) on rates of radiation oncologist (RO) referral, androgen-deprivation therapy (ADT), radiation therapy (RT), and radical prostatectomy (RP) in patients with high-risk prostate cancer (HR-PCa). METHODS: All men >18 years, diagnosed with PCa in 2005 and 2012 were identified from the Alberta Cancer Registry. Patient age, aggregated clinical risk group (ACRG) score, Gleason score (GS), pre treatment prostate-specific antigen (PSA), RO referral, and treatment received were extracted from electronic medical records. Logistic regression modelling was used to examine associations between RO referral rates and relevant factors. RESULTS: HR-PCa was diagnosed in 261 of 1792 patients in 2005 and 435 of 2148 in 2012. Median age and ACRG scores were similar in both years (p>0.05). The rate of patients with PSA >20 were 67% and 57% in 2005 and 2012, respectively (p=0.004). GS <=6 was found in 13% vs. 5% of patients, GS 7 in 27% vs. 24%, and GS >=8 in 59% vs. 71% in 2005 and 2012, respectively (p<0.001). In 2005, RO referral rate was 68% compared to 56% in 2012 (p=0.001), use of RT + ADT was 53% compared to 32% (p<0.001), and RP rate was 9% vs. 17% (p=0.002). On regression analysis, older age, 2012 year of diagnosis and higher PSA were associated with decreased RO referral rates (odds ratios [OR] 0.49, 95% confidence interval [CI] 0.39-0.61; OR 0.51, 95% CI 0.34-0.76; and OR 0.64, 95% CI 0.39-0.61), respectively [p<0.001]). CONCLUSIONS: Since CPG creation in 2005, RO referral rates and ADT + RT use declined and RP rates increased, which demonstrates a need to improve adherence to CPG in the HR-PCa population. PMID- 28096917 TI - Assessment of histopathological features of needle biopsy in recurrent prostate cancer following salvage high-intensity focused ultrasound. AB - INTRODUCTION: Local recurrence of prostate cancer (PCa) following radiotherapy may be treated with curative intent using salvage high-intensity focused ultrasound (s-HIFU). The interpretation of needle core biopsy specimens following s-HIFU is a daunting task, even for experienced pathologists. We describe various histopathological features encountered in biopsy specimens following whole-gland s-HIFU in one of the largest descriptive studies to date. METHODS: Fifty-five patients with biopsy-proven localized radio-recurrent PCa underwent s-HIFU and transrectal ultrasound (TRUS)-guided prostatic needle biopsies at 180 days post treatment. All biopsies were reviewed by two genitourinary pathologists. RESULTS: PCa was detected in 11 (24%) biopsies. Radiation therapy-associated changes were identified in all cases. Additional findings included extensive coagulative stromal necrosis (100%), smudgy chromatin of cancer nuclei (82%), and markedly enlarged bizarre nuclei in the residual cancer (55%). Gleason grade assignment was possible in 10 (91%) of these biopsies and concordance of Gleason grading between pre- and post-therapy specimens was observed in six (60%) cases. CONCLUSIONS: The histological interpretation of needle biopsies following salvage HIFU is challenging and requires an understanding of the histopathological changes associated with this procedure in both tumoural and non-tumoural prostatic tissue. Accurate interpretation of the morphological changes following s-HIFU is instrumental for optimization of clinical decision-making and treatment planning in recurrent PCa. PMID- 28096918 TI - Perioperative outcomes following radical prostatectomy for patients with disseminated cancer: An analysis of the National Surgical Quality Improvement Program database. AB - INTRODUCTION: We sought to determine whether patients undergoing radical prostatectomy (RP) in the context of disseminated cancer have higher 30-day complications. METHODS: We conducted a retrospective cohort study of the National Surgical Quality Improvement Program (NSQIP) database. Men undergoing RP (from January 1, 2005 to December 31, 2014) for prostate cancer were identified and stratified by presence (n=97) or absence (n=27 868) of disseminated cancer. The primary outcome was major complications (death, re-operation, cardiac or neurologic events) within 30 days of surgery. Secondary outcomes included pulmonary, infectious, venous thromboembolic, and bleeding complications; prolonged length of stay; and concomitant procedures (bowel-related, cystectomy, urinary diversion, and major ureteric reconstruction). Odds ratios (OR) for each complication were calculated using univariable logistic regression. RESULTS: We did not identify a difference in major complication rates (OR 2.26, 95% confidence interval [CI] 0.71-7.16). Patients with disseminated cancer had increased risk of venous thromboembolic events (OR 3.30, 95% CI 1.04-10.48) and transfusion (OR 2.45, 95% CI 1.18-5.05), but similar odds of pulmonary and infectious complications and length of stay. Bowel procedures were rare, however, a significantly higher proportion of patients with disseminated cancer required bowel procedures (2.1% vs. 0.3%; p=0.03). Patients with disseminated cancer undergoing RP had greater comorbidities and higher predicted probability of morbidity and mortality. This study is limited by its retrospective design, lack of cancer-specific variables, and prostatectomy-specific complications. CONCLUSIONS: RP in the context of disseminated cancer may be associated with increased perioperative complications. Caution should be exercised in embarking on this practice outside of clinical trials. PMID- 28096920 TI - The impact of day of surgery on the length of stay for major urological procedures. AB - INTRODUCTION: Surgery performed later in the week has been associated with longer length of stay (LOS). The aim of this study was to assess if the day of the surgery impacted the LOS for two major urological procedures in a tertiary referral university teaching hospital. METHODS: A retrospective review was performed of two major urological procedures consecutively performed by a single surgeon in our unit from March 2012 to December 2015. Patient demographics, histopathological characteristics, operative details, and LOS were obtained from the patients' medical records. Procedures performed on Monday or Tuesday were defined as early in the week and procedures performed on Wednesday, Thursday, or Friday were defined as late in the week. RESULTS: During the study period, 140 open radical prostatectomy (ORP) and 42 open partial nephrectomy (OPN) procedures were performed. There was a significant difference in median LOS for major urological procedures performed early in the week compared to late in the week (3 [3-4] days vs. 4 [4-5] days; p= 0.0001). There was a significant difference in median LOS for ORP performed early in the week compared to late in the week (3 [3 4] days vs. 4 [4-5] days; p= 0.0004). There was a similar significant difference in OPN performed early in the week compared to late in the week (4 [3-5.5] days vs. 5 [4-5] days; p= 0.029). CONCLUSIONS: The day of surgery impacts LOS for major urological procedures. Major procedures should be performed early in the week, when it is feasible to facilitate prompt safe discharge and better use of hospital resources. PMID- 28096921 TI - A sequential comparison of postoperative voiding function between two different transobturator sling procedures. AB - INTRODUCTION: We evaluated sequential postoperative voiding function of two types of sling procedures (Monarc(r) and ALIGN(r)) in patients with stress urinary incontinence. METHODS: Ninety-one women diagnosed with urodynamic stress incontinence were randomly assigned to the study. All enrolled patients underwent Monarc or ALIGN procedure. They were postoperatively evaluated at one day, one week, one month, three months, 12 months, and 24 months. The voiding function was evaluated with uroflowmetry and post-void residual urine. Patients were asked if voiding had changed after surgery and had to complete the incontinence quality of life scale (I-QoL) questionnaire at 12 months. RESULTS: The Monarc (n=47) and ALIGN (n=44) groups had similar demographic characteristics. The maximal flow rate (Qmax) was significantly decreased on the first day after surgery and gradually increased during the following weeks. Comparing the two groups at one week, the ALIGN group had a significantly decreased Qmax than the Monarc group (17.6 +/- 5.2 vs. 20.7 +/- 5.0; p=0.004). However, at one, three, 12, and 24 months, there were no significant differences between the two groups. CONCLUSIONS: This study demonstrated that an absorbable tensioning suture in the Monarc mesh could increase Qmax compared to ALIGN at one week after surgery. An absorbable tensioning suture may reduce the risk of an early postoperative voiding dysfunction compared to other meshes that do not have this. PMID- 28096922 TI - Relationship between Gleason score and apparent diffusion coefficients of diffusion-weighted magnetic resonance imaging in prostate cancer patients. AB - INTRODUCTION: We assessed the correlation between the apparent diffusion coefficient (ADC) and pathological Gleason score (GS) of prostate cancer patients. METHODS: A total of 125 patients who underwent multiparametric magnetic resonance imaging before radical prostatectomy for prostate cancer were included in this study. ADC values were compared with different GS. We used receiver operating characteristic analysis and determined the ADC cutoff value to differentiate tumours with a GS of 6 from those with a GS >=7. RESULTS: We identified 34 patients (27.2%) with a GS of 6; 33 patients (26.4%) with a GS of 7; 22 patients (17.6%) with a GS of 8; and 36 patients (28.8%) with a GS of >=9. The mean ADC value for disease with a GS of 6 was 0.914 +/- 0.161 *10-3 mm2/s; GS of 7: 0.741 +/- 0.164 *10-3 mm2/s; GS of 8: 0.679 +/- 0.130 *10-3 mm2/s; and GS of >=9: 0.593 +/- 0.089 *10-3 mm2/s. An ADC value of 0.830 *10-3mm2/s was the best cutoff value to identify prostate cancer with a GS of 6. CONCLUSIONS: We observed an inverse relationship between GS and ADC value. Moreover, a cutoff ADC value may help differentiate disease with a GS of 6 from disease with a GS >=7. PMID- 28096923 TI - Role of neutrophil-to-lymphocyte ratio in prediction of Gleason score upgrading and disease upstaging in low-risk prostate cancer patients eligible for active surveillance. AB - INTRODUCTION: Active surveillance (AS) is an option for management of low-risk prostate cancer (PCa). However, grade and stage progression is an important consideration. Neutrophil-to-lymphocyte ratio (NLR) is a useful marker of cancer related inflammation. In this study, we aimed to identify the roles of neutrophil count (NC), lymphocyte count (LC), and NLR to predict Gleason score (GS) upgrading, disease upstaging, and biochemical recurrence rates (BCR) in low-risk PCa patients. METHODS: We retrospectively evaluated data of 210 low-risk PCa patients eligible for AS, but who underwent radical prostatectomy. The roles of NC, LC, and NLR on the GS upgrading, disease upstaging, and BCR rates were investigated. Univariate and multivariate models were used to determine the effect of these parameters. RESULTS: There were 104 and 106 patients in the NLR <2.5 and NLR >=2.5 groups, respectively. GS upgrading in the NLR >=2.5 group was more common than in the NLR<2.5 group (p=0.04). The NLR >=2.5 group had significantly higher GS (8-10; p=0.03). With regard to NLR, the groups were found to have similar rates of disease upstaging (9/104 in NLR <2.5 vs. 16/106 in NLR >=2.5; p=0.200). BCR rates were also significantly different between groups (p=0.033). NC an LC were not found to be associated with GS upgrading, disease upstaging, or BCR. CONCLUSIONS: NLR is a predictor of GS upgrading and BCR, but not disease upstaging in patients with low-risk PCa. Furthermore, higher NLR was found to be associated with higher GS PCa. NLR is a cost-effective and easily accessible tool that can be used in the decision-making process for treatment of low-risk PCa cases. PMID- 28096919 TI - CUA guideline on the evaluation and medical management of the kidney stone patient - 2016 update. PMID- 28096924 TI - Scrotal recurrence of germ cell tumour in a non-violated scrotum. AB - Testicular cancer is the most common cancer diagnosis in males aged 15-30 years. For over a century, radical inguinal orchiectomy has been the standard of care for initial treatment of testicular cancer. This approach is preferred over trans scrotal interventions, in an effort to avoid tumour seeding, spermatic cord invasion, and disturbance to lymphatic drainage. Scrotal violation is defined as any trans-scrotal intervention that may impact spread of disease in testicular cancer, including scrotal orchiectomy, fine-needle aspiration, and testicular biopsy. Studies have shown statistically significant differences in local recurrence rates between patients who undergo the standard inguinal surgical approach and cases with scrotal violation. Over 95% of testicular cancers are curative, often with surgery alone. Recurrence of disease is divided into two categories: local and distant sites. Local recurrence of testicular cancer involves the scrotal and inguinal regions, including superficial inguinal lymph nodes. More commonly, local recurrence is seen in cases of testicular cancer with scrotal violation. We describe a case of local recurrence of testicular cancer in a non-violated scrotum, a finding that has not been previously reported in the literature. PMID- 28096925 TI - Penile metastasis from primary transitional cell carcinoma of the bladder sparing the urethra. AB - Metastatic involvement of the penis is relatively infrequent. Metastasis of transitional cell carcinoma (TCC) is extremely rare. We report a case of bladder TCC with metastases to the penis that spares the urethra - a finding that, to the best of our knowledge, has not been previously reported. Of the documented mechanisms of metastatic transmission to the penis, we suspect the cause was retrograde lymphatic spread. In our case, a 59-year-old male presented to our clinic initially with phimosis and later developed gross hematuria. Subsequent cystoscopy noted the appearance of tumour extending into the prostate, as well as the appearance of extensive TCC throughout the bladder. Following transurethral resection of prostate and bladder tissue, which demonstrated high-grade urothelial carcinoma, the patient underwent a radical cystoprostatectomy. A year later, he developed worsening gross hematuria and we noted the appearance of primary penile squamous cell malignancy. He then underwent a partial penectomy. The histopathology evaluation result from the partial penectomy revealed infiltration of TCC in the glans penis, as well as invasion into the corpus spongiosum, with sparing of the urethra. PMID- 28096926 TI - Congenital anterior urethral diverticulum presenting as a scrotal mass in a two year-old child. AB - Here, we describe a case of congenital anterior urethral diverticulum (CAUD) in a two-year-old boy, who presented with right inguinoscrotal swelling that mimicked a spermatic cord cyst or hydrocele. Accurate diagnosis was made intraoperatively by retrograde urethrography. Open diverticulectomy and primary urethroplasty were performed for its management. The clinical presentation, diagnosis, and the management of this rare condition is discussed. PMID- 28096927 TI - Sclerosing epithelioid fibrosarcoma metastasizing to the penile shaft. AB - We present the case of a 50-year-old man with a periurethral mass. He was previously known for sclerosing epithelioid fibrosarcoma (SEF) of the left foot, having an amputation for local recurrence with >2 cm negative margins. A solid periurethral mass was surgically excised seven months later, yielding the diagnosis of metastatic SEF. This is the first documented metastasis of SEF to the penis. These sarcomas have proven difficult to treat, with high recurrence rates despite a multimodal approach. PMID- 28096928 TI - Spontaneous uretero-sigmoid fistula secondary to calculus. AB - A 25-year-old man was referred to the urology department after a subacute history of left back pain, burning micturition associated with pneumaturia and fecaluria. Ultrasonography was performed showing hydronephrosis, and plain film radiography demonstrated a long vertical left pelvic calculi. Uro-computed tomography (CT) combined with a water enema CT showed a 10 cm long calculus with the cranial extremity fistulating the sigmoidal wall. Surgical treatment included left nephroureterectomy and sigmoidectomy with a colorectal anastomosis. Postoperative course was uneventful. PMID- 28096929 TI - Tremendous non-progressed chromophobe renal cell carcinoma for eight years performed by laparoscope. AB - The prognostic role of chromophobe renal cell carcinoma (ChRCC) is still controversial. Here, we report on a patient who lived with tremendous non progressed renal malignant tumour for eight years. The 32-year-old patient presented to our hospital with a huge renal tumour. Computed tomography (CT) scan showed a tumour 12 cm in diameter at the upper pole of the right kidney. Trans abdominal laparoscopic right radical nephrectomy was performed. Histopathological examination confirmed this tumour to be a ChRCC. The phenomenon of long-term non progressed renal malignant tumour will help us further understand the characteristics of ChRCC. PMID- 28096930 TI - Management of adult concealed penis using a meshed, split-thickness skin graft. AB - INTRODUCTION: Concealed penis (CP) is a rare problem faced by urologists and plastic surgeons. CP occurs secondary to trauma, obesity, or infection. Surgical treatment is individualized and based on patient and provider variables. We aim to review our recent experience using meshed split-thickness skin grafting (STSG) for CP management. METHODS: A retrospective review was performed on patients who underwent STSG for CP at our institution. Records were reviewed for demographic, operative, and postoperative variables. Preoperative and postoperative photos were obtained to monitor cosmetic results. RESULTS: Eleven patients underwent CP release with meshed STSG placement. All cases showed improved functional phallic length and good cosmetic results, regardless of etiology. CONCLUSIONS: STSG is a viable option for penile coverage for management of this difficult-to-treat CP population. This primary or salvage modality offers excellent cosmetic results and may be used following prior reconstructive attempts. PMID- 28096931 TI - ? PMID- 28096933 TI - The association of male pattern baldness and risk of cancer and high-grade disease among men presenting for prostate biopsy. AB - INTRODUCTION: Androgens have been implicated in both male pattern baldness (MPB) and prostate cancer (PCa). We set out to prospectively determine if men with independently assessed MPB are at higher risk for PCa at biopsy and determine if any grade associations exist. METHODS: We prospectively enrolled 394 eligible patients presenting for prostate biopsy and independently determined their MPB pattern using the validated modified Norwood classification system (0: no balding; 1: frontal balding; 2: mild vertex balding; 3: moderate vertex balding; 4: sever vertex balding). Univariate and multivariable models, including Norwood score, age, prostate-specific antigen, and digital rectal examination abnormalities, were calculated for the outcomes of cancer and high-grade disease (Gleason >6). C-statistics analyses of our models were then compared with and without MPB pattern for marginal utility. RESULTS: Norwood patterns were increasingly associated with cancer and high-grade disease with a dose-effect (p for trend <0.001 on univariate and multivariable analyses for cancer and p=0.001 and p=0.0036 for high-grade disease on univariate and multivariable analyses, respectively). On multivariable analyses, trends still held, with all patients exhibiting Norwood scale 3 and 4 at increased risk for cancer. In predicting risk of high-grade disease, only patients with Norwood pattern 4 exhibited an increased risk. CONCLUSIONS: MPB appears to be a strong and independent risk factor for both cancer and high-grade disease for men presenting for prostate biopsy. Ours could be superior to marketed costly genetic tests. Further research is needed to understand the biology behind this observation and to incorporate these findings into clinical decision-making. PMID- 28096934 TI - First-line treatment options in metastatic renal cell cancer. AB - The introduction of targeted therapy a decade ago revolutionized the treatment of metastatic renal cell carcinoma (mRCC). The current standard of care focuses on the inhibition of angiogenesis through the targeting of the vascular endothelial growth factor receptor (VEGFR) and the mammalian target of rapamycin (mTOR). Currently recommended first-line treatments in Canada include sunitinib, pazopanib, and temsirolimus. With the heterogeneity of mRCC disease, the choice of treatment is driven largely by prognostic factors. PMID- 28096932 TI - Contemporary agents in the management of metastatic castration-resistant prostate cancer. AB - Docetaxel-based chemotherapy has been the standard of care for metastatic castration-resistant prostate cancer (mCRPC) since 2004. Over the past few years, there has been a significant paradigm shift in the treatment landscape of this disease. A deeper understanding of prostate cancer biology, along with the development of novel agents has created hope towards treating chemotherapy-naive and resistant disease. Following the implementation of docetaxel as the first line therapy for mCRPC, five novel therapies have demonstrated survival benefit in mCRPC. Cabazitaxel, abiraterone acetate, and enzalutamide are three agents recently approved for the treatment of mCRPC, having shown overall survival benefit in patients previously treated with docetaxel, while both abiraterone acetate and enzalutamide have also shown promise in the pre-docetaxel setting. Sipuleucel-T has shown overall survival benefit in asymptomatic mCRPC, while radium-223 provides survival benefit to patients with mCRPC who are symptomatic from their skeletal metastases in both docetaxel-naive patients and post docetaxel patients. Denosumab, an anti-RANKL antibody, has been approved for the prevention of skeletal-related events in patients with prostate cancer bone metastases. This review examines the phase 3 trials supporting the use of theses novel agents in the treatment of mCRPC. While these agents provide incremental increases in patient survival, further study to determine the best choice, combination, and/or sequencing of administration is still necessary. PMID- 28096935 TI - Practical first-line management of renal cell carcinoma in a community practice. AB - Sunitinib is an oral receptor tyrosine kinase inhibitor (TKI) that targets signalling by vascular endothelial growth factor receptors (VEGFRs). The standard sunitinib dosing schedule for metastatic renal cell carcinoma (mRCC) is 50 mg for four weeks (28 days) of treatment, followed by a two-week (14-day) break from treatment (four/two schedule). However, this schedule is associated with toxicities that can limit the patient's health-related quality of life (HRQOL) and impede treatment compliance. Given the generally incurable nature of mRCC and the toxicity associated with therapy, treatment strategies should focus on achieving long-term response, preserving HRQOL, and minimizing treatment-related toxicity. The William Osler Cancer Clinic in Brampton, ON, has instituted an alternative schedule of sunitinib treatment as our standard dosing strategy, involving two weeks of treatment, followed by a one-week break (two/one schedule), to minimize toxicity and improve HRQOL among their patients with mRCC. PMID- 28096936 TI - Treatment options in advanced renal cell carcinoma after first-line treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors. AB - Targeted therapy for metastatic renal cell carcinoma (mRCC) was introduced a decade ago and since then, a number of therapeutic options have been developed. Vascular endothelial growth factor-targeted therapy is the widely accepted first line option for mRCC. After progression, treatment in the second-line setting has typically been with either axitinib or everolimus. However, with the advent of several new agents demonstrating efficacy in the second-line setting, including nivolumab, cabozantinib, and the combination of lenvatinib and everolimus, the treatment paradigm has shifted toward these novel therapies with improved patient outcomes. PMID- 28096937 TI - Sunitinib side effects as surrogate biomarkers of efficacy. AB - With the proliferation of treatment options for the management of metastatic renal cell carcinoma (mRCC) over the past decade, predictive markers of response to therapy are becoming increasingly important. Sunitinib is commonly used in the first-line treatment of mRCC. Common mechanism-based adverse events, including hypertension, hypothyroidism, hand-foot syndrome, and neutropenia, have been explored as potential biomarkers of the clinical efficacy of sunitinib in mRCC and are reviewed in this article. PMID- 28096938 TI - Sunitinib toxicity management - a practical approach. AB - This article summarizes the adverse events (AEs) of sunitinib that are commonly encountered in a community oncology practice, and provides practical recommendations for their management based on the available literature and on the author's own experience. PMID- 28096939 TI - Can individualized sunitinib dose and schedule changes optimize outcomes for kidney cancer patients? AB - The recommended starting dose and schedule for sunitinib is 50 mg daily for 28 days, followed by a 14-day break with significant dose reductions to 37.5 mg (75% of starting dose), and then 25 mg (50% of starting dose) on the same schedule (four/two schedule). There are several reasons why these dose and scheduling recommendations may not be optimal for most patients, as outlined below. PMID- 28096940 TI - The next 10 years: Challenges for the future and overcoming resistance to targeted therapies for renal cell carcinoma. AB - The introduction of targeted therapies over the past 10 years revolutionized the treatment of metastatic renal cell carcinoma (mRCC). The next 10 years hold promise for even greater expansion of the therapeutic armamentarium for mRCC. A number of recently completed and ongoing trials have explored the use of antivascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors in the adjuvant setting, the use of predictive biomarkers to guide personalized medicine, as well as new systemic treatments and combination therapies for mRCC. PMID- 28096942 TI - Plant-Derived Antioxidants in Disease Prevention. PMID- 28096941 TI - Transport of biomolecules to binding partners displayed on the surface of microbeads arrayed in traps in a microfluidic cell. AB - Arrays of probe molecules integrated into a microfluidic cell are utilized as analytical tools to screen the binding interactions of the displayed probes against a target molecule. These assay platforms are useful in enzyme or antibody discovery, clinical diagnostics, and biosensing, as their ultraminiaturized design allows for high sensitivity and reduced consumption of reagents and target. We study here a platform in which the probes are first grafted to microbeads which are then arrayed in the microfluidic cell by capture in a trapping course. We examine a course which consists of V-shaped, half-open enclosures, and study theoretically and experimentally target mass transfer to the surface probes. Target binding is a two step process of diffusion across streamlines which convect the target over the microbead surface, and kinetic conjugation to the surface probes. Finite element simulations are obtained to calculate the target surface concentration as a function of time. For slow convection, large diffusive gradients build around the microbead and the trap, decreasing the overall binding rate. For rapid convection, thin diffusion boundary layers develop along the microbead surface and within the trap, increasing the binding rate to the idealized limit of untrapped microbeads in a channel. Experiments are undertaken using the binding of a target, fluorescently labeled NeutrAvidin, to its binding partner biotin, on the microbead surface. With the simulations as a guide, we identify convective flow rates which minimize diffusion barriers so that the transport rate is only kinetically determined and measure the rate constant. PMID- 28096944 TI - Assessment of the changes in alveolar bone quality after fixed orthodontic therapy: A trabecular structure analysis. AB - Background. Tooth displacement changes the periodontium. The aim of orthodontic treatment is desired tooth movement with minimum side effects on the alveolar bone quality. The aim of the present study was to assess changes of alveolar trabeculation in children, young adults and adults and the two genders. Methods. In this cross-sectional study, 63 patients who had been treated in Department of Orthodontics, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran, were chosen with convenient sampling method. They were divided into three groups based on their age. Their digitized panoramic radiographs (PRs) were evaluated at six interdental sites from the mesial aspect of the mandibular second molars to the distal aspect of the mandibular first premolars using a visual index. The trabeculation pattern was assigned as either dense (score 3), dense-sparse (score 2) or sparse (score 1). Data were imported to SPSS. Mean of the scores before treatment (score B) and mean of them after treatment (score A) were compared for each group with paired t-test. Changes between score B and sore A of the groups were compared using one-way ANOVA and post hoc tests. Results. Mean score A was significantly higher than mean score B in children (P = 0.001). In contrast, mean score A was significantly lower than mean score B in young adults (P = 0.003). Conclusion. Orthodontists should be cautious when treating young adults and adults regarding the probable, yet possibly temporary, negative effects of orthodontic therapy on the alveolar bone quality. PMID- 28096943 TI - Nitric Oxide: Exploring the Contextual Link with Alzheimer's Disease. AB - Neuronal inflammation is a systematically organized physiological step often triggered to counteract an invading pathogen or to rid the body of damaged and/or dead cellular debris. At the crux of this inflammatory response is the deployment of nonneuronal cells: microglia, astrocytes, and blood-derived macrophages. Glial cells secrete a host of bioactive molecules, which include proinflammatory factors and nitric oxide (NO). From immunomodulation to neuromodulation, NO is a renowned modulator of vast physiological systems. It essentially mediates these physiological effects by interacting with cyclic GMP (cGMP) leading to the regulation of intracellular calcium ions. NO regulates the release of proinflammatory molecules, interacts with ROS leading to the formation of reactive nitrogen species (RNS), and targets vital organelles such as mitochondria, ultimately causing cellular death, a hallmark of many neurodegenerative diseases. AD is an enervating neurodegenerative disorder with an obscure etiology. Because of accumulating experimental data continually highlighting the role of NO in neuroinflammation and AD progression, we explore the most recent data to highlight in detail newly investigated molecular mechanisms in which NO becomes relevant in neuronal inflammation and oxidative stress-associated neurodegeneration in the CNS as well as lay down up-to-date knowledge regarding therapeutic approaches targeting NO. PMID- 28096945 TI - FT-Raman spectroscopic characterization of enamel surfaces irradiated with Nd:YAG and Er:YAG lasers. AB - Background. Despite recent advances in dental caries prevention, caries is common and remains a serious health problem. Laser irradiation is one of the most common methods in preventive measures in recent years. Raman spectroscopy technique is utilized to study the microcrystalline structure of dental enamel. In this study, FT-Raman spectroscopy was used to evaluate chemical changes in enamel structure irradiated with Nd:YAG and Er:YAG lasers. Methods. We used 15 freshly-extracted, non-carious, human molars that were treated as follows: No treatment was carried out in group A (control group); Group B was irradiated with Er:YAG laser for 10 seconds under air and water spray; and Group C was irradiated with Nd:YAG laser for 10 seconds under air and water spray. After treatment, the samples were analyzed by FT-Raman spectroscopy. Results. The carbonate content evaluation with regard to the integrated area under the curve (1065/960 cm-1) exhibited a significant reduction in its ratio in groups B and C. The organic content (2935/960 cm-1) area exhibited a significant decrease after laser irradiation in group B and C. Conclusion. The results showed that the mineral and organic matrices of enamel structure were affected by laser irradiation; therefore, it might be a suitable method for caries prevention. PMID- 28096946 TI - Effect of different bleaching strategies on microhardness of a silorane-based composite resin. AB - Background. Dentists' awareness of the effects of bleaching agents on the surface and mechanical properties of restorative materials is of utmost importance. Therefore, this in vitro study was undertaken to investigate the effects of different bleaching strategies on the microhardness of a silorane-based composite resin. Methods. Eighty samples of a silorane-based composite resin (measuring 4 mm in diameter and 2 mm in thickness) were prepared within acrylic molds. The samples were polished and randomly assigned to 4 groups (n=20). Group 1 (controls) were stored in distilled water for 2 weeks. The samples in group 2 underwent a bleaching procedure with 15% carbamide peroxide for two weeks two hours daily. The samples in group 3 were bleached with 35% hydrogen peroxide twice 5 days apart for 30 minutes each time. The samples in group 4 underwent a bleaching procedure with light-activated 35% hydrogen peroxide under LED light once for 40 minutes. Then the microhardness of the samples was determined using Vickers method. Data were analyzed with one-way ANOVA and post hoc Tukey tests (P < 0.05). Results. All the bleaching agents significantly decreased microhardness compared to the control group (P < 0.05). In addition, there were significant differences in microhardness between groups 2 and 4 (P = 0.001) and between groups 3 and 4 (P<0.001). However, no significant differences were detected in microhardness between groups 2 and 3 (P > 0.05). Conclusion. Bleaching agents decreased microhardness of silorane-based composite resin restorations, the magnitude of which depending on the bleaching strategy used. PMID- 28096947 TI - Antibacterial efficacy of AH Plus and AH26 sealers mixed with amoxicillin, triple antibiotic paste and nanosilver. AB - Background. Elimination of bacteria from the root canal system is one of the aims of endodontic treatment; hence the incorporation of antibiotics into sealers can increase their antimicrobial efficacy. The aim of the present study was to determine the in vitro antimicrobial effects of AH26 and AH Plus sealers mixed with amoxicillin, triple antibiotic paste and nanosilver on Enterococcus faecalis. Methods. In this experiment, amoxicillin, triple antibiotic paste and nanosilver powder were added at 10% of the total sealer weight to AH26 and AH Plus sealers and then cultured freshly or after 1, 3, and 7 days with suspension of E. faecalis for 24 hours. The zones of growth inhibition for E. faecalis were evaluated in each group. Results. Incorporation of nanosilver did not increase antibacterial effects of the sealers. Sealers combined with amoxicillin exhibited the highest antibacterial efficacy in fresh condition. In the set specimens, the results demonstrated that the mixture of sealers and triple antibiotic pastes exhibited the greatest antibacterial efficacy. Conclusion. Amoxicillin and triple antibiotic paste significantly improved the antibacterial properties of AH Plus and AH26 sealers. Such properties decreased with time, but the use of sealer amoxicillin/triple paste combination was still superior to using sealers alone or in combination with nanosilver. PMID- 28096948 TI - Efficacy of Hypozalix spray and propolis mouthwash for prevention of chemotherapy induced oral mucositis in leukemic patients: A double-blind randomized clinical trial. AB - Background. Oral mucositis is the chief complication of head and neck chemotherapy. This study was conducted to evaluate Hypozalix artificial saliva and propolis mouthwash efficacy for the prevention of chemotherapy-induced oral mucositis in leukemic patients. Methods. The present double-blind clinical trial was carried out on 72 patients undergoing chemotherapy. The patients were assigned to 3 groups. In the control group, CHX mouthwash and fluconazole were used by the subjects. In groups 1 and 2, Hypozalix and propolis mouthwashes were added to the combination therapy used in the control group. The results were compared between the three groups after 14 days. Results. Mean score A was significantly higher than mean score B in children (P = 0.001). In contrast, mean score A was significantly lower than mean score B in young adults (P = 0.003). Conclusion. Use of Hypozalix spray or propolis mouthwash in association with CHX mouthwash and fluconazole simultaneously at the start of chemotherapy resulted in a decrease in chemotherapy complications after 14 days. In many cases the use of propolis mouthwash yielded better results and the patients exhibited a greater tendency to continue to use it. PMID- 28096950 TI - Evaluation of mast cell counts and microvessel density in reactive lesions of the oral cavity. AB - Background. Reliable immunohistochemical assays to assess the definitive role of mast cells (MCs) and angiogenesis in the pathogenesis of oral reactive lesions are generally not available. The aim of the present study was to evaluate mast cell counts (MCC) and microvessel density (MVD) in oral reactive lesions and determine the correlation between MCC and MVD. Methods. Seventy-five cases of reactive lesions of the oral cavity, including pyogenic granuloma, fibroma, peripheral giant cell granuloma, inflammatory fibrous hyperplasia, peripheral ossifying fibroma (15 for each category) were immunohisto-chemically stained with MC tryptase and CD31. Fifteen cases of normal gingival tissue were considered as the control group. The mean MCC and MVD in superficial and deep connective tissues were assessed and total MCC and MVD was computed for each lesion. Results . Statistically significant differences were observed in MCC and MVD between the study groups (P < 0.001). MC tryptase and CD31 expression increased in the superficial connective tissue of each lesion in comparison to the deep con nective tissue. A significant negative correlation was not found between MCC and MVD in oral reactive lesions (P < 0.001, r = -0.458). Conclusion. Although MCs were present in the reactive lesions of the oral cavity, a direct correlation between MCC and MVD was not found in these lesions. Therefore, a significant interaction between MCs and endothelial cells and an active role for MCs in the growth of oral reactive lesions was not found in this study. PMID- 28096949 TI - Association between anxiety, obesity and periodontal disease in smokers and non smokers: A cross-sectional study. AB - Background. Psychological stress is known to be a relevant risk factor for many inflammatory conditions, including periodontal disease. A few studies have probed the relationship between obesity and periodontal disease. Therefore this cross sectional study was aimed to examine the relationship between psychological stress and obesity and periodontal disease in smokers and non-smokers. Methods. The participants included 90 patients, equally divided into three groups of non smokers and periodontally healthy, non-smokers and smokers with untreated moderate-to-severe chronic periodontitis. Socioeconomic data, psychosocial measurements, physical parameters and clinical findings of PPD, CAL, PI and GI were recorded. Results. The clinical parameters were assessed for three groups in three different anxiety levels of mild, moderate and severe. Intra-group comparison of PPD and CAL in the three anxiety levels showed increased periodontal destruction with an increase in anxiety levels, the results being statistically highly significant for PPD differences in smokers (P < 0.0001). The mean differences in PPD and CAL in severe anxiety levels between smokers and non smokers were 0.68 mm and 0.70 mm and both the findings were statistically significant. The mean PPD and CAL in smoker and non-smoker groups in obese patients was higher as compared to non-obese patients and the differences were highly significant (P < 0.001). Conclusion. The results of our study indicated a positive and strong correlation between anxiety, obesity and periodontal disease in smokers and non-smokers. Smoking appears to further attenuate this association. PMID- 28096951 TI - Evaluation of changes in anthropometric indexes due to intermaxillary fixation following facial fractures. AB - Background. One of the treatment modalities for facial fractures is closed reduction technique, but treatment with intermaxillary fixation (IMF) interferes with normal nutrition, and malnutrition can affect the patient's recovery. Anthropometric measurements such as skinfold thickness and body mass index (BMI) are universal indexes for diagnosing malnutrition. Therefore, in this study we explain how treatment with IMF changes the anthropometric indexes. Methods. In this study 60 patients were treated with 4 weeks of IMF. Skinfold thickness and BMI of these patients were measured and compared before and after the treatment. Results. Patients' weight, BMI and skinfold thickness decreased during the IMF period, and this decrease was statistically significant (P < 0.01). Conclusion. Although no severe and acute malnutrition was seen among our patients, IMF led to mild to moderate malnutrition in some cases, making it necessary to use nutritional supplements. PMID- 28096952 TI - The effect of irrigating solutions on the apical sealing ability of MTA Fillapex and Adseal root canal sealers. AB - Background. Maximum sealing ability or adhesion of endodontic sealers can be achieved after effective removal of the smear layer. Endodontic irrigants assist in adequate removal of the smear layer, improving the retention mechanism. The aim of this study was to evaluate the effect of two different root canal irrigation solutions (5.25% NaOCl followed by 17% EDTA and QMix) on the apical sealing ability of two different root canal sealers (MTA Fillapex and Adseal). Methods. Forty-six single-canal teeth were divided into 4 experimental groups of 10 teeth each and a positive and negative group of 3 teeth each. The root canals were prepared using step-back technique. The teeth in groups 1 and 2 were irrigated with 5.25% NaOCl followed by 17% EDTA and the teeth in groups 3 and 4 were irrigated with QMix. Finally all the teeth were flushed with sterile saline and dried using paper points. Obturation was accomplished by gutta-percha using lateral condensation technique. MTA Fillapex sealer was used in groups 1 and 3 whereas Adseal was used in groups 2 and 4. Dye penetration method was used to evaluate apical leakage. Data were analyzed with Kruskal-Wallis and Mann-Whitney U tests using SPSS 14. Statistical significance was set at P < 0.05. Results. Group 3 showed maximum amount of apical leakage (3.7+/-0.3 mm) whereas group 2 exhibited the least amount of apical leakage (2.1 +/- 0.4 mm) among all the experimental groups. Significant differences were found in the amount of apical leakage between all the groups (P = 0.00001). Conclusion. Within the limitations of this study, 5.25% sodium hypochlorite followed by 17% EDTA and Adseal resulted in the best apical seal. PMID- 28096953 TI - Determining the distance from the lingual frenum anterior attachment to the lower incisors' incisal edges. AB - Background. Occlusal rims are used to determine the jaw relationships in the transverse and vertical dimensions and estimate the inter-occlusal distance in edentulous patients. It is important to find ways to determine the height and shape of the occlusal rims correctly. This study was undertaken to determine the exact distance from the oral cavity floor to the incisal edges of mandibular incisors to serve as a guide for adjusting the height of the mandibular occlusal rim. Methods. Forty patients were selected and special trays were fabricated to prepare accurate stone casts on which the measurements were made at 0.01-mm accuracy. Two marks were placed on the casts at the incisal edges of mandibular incisors and at anterior attachment of lingual frenum. Then the distance between these two marks was determined on the vertical spindle of a surveyor using a digital Vernier measuring tool and recorded. Results. The results showed that the mean and standard deviation of the distances between the oral cavity floor and the incisal edges of lower incisors were 14.35 +/- 1.68 mm, with a range of 10.2 17.02 mm. The mean distances in males and females were 15.42 +/- 0.97 and 13.28 +/- 1.57 mm, respectively. T-test showed significant differences in this distance between males and females, with greater distances in males. Conclusion. The distance between the oral cavity floor and the incisal edges of mandibular incisors at anterior attachment of lingual frenum might be a proper criterion for the initial adjustment of occlusal rims. PMID- 28096954 TI - HIV stigma: perceptions from HIV-positive and HIV-negative patients in a community dental clinic. AB - Background. In the medical sense, stigma has been defined as the collection of negative attitudes and beliefs that are directed at people living with a particular condition or disease process. A cohort study was conducted to explore the HIV stigma that is perceived by HIV-positive individuals versus that perceived by the general population within a community-based dental clinic. Methods. Two separate and independent cross-sectional surveys, the Berger Stigma Scale and the Rutgers-Modified Berger Stigma Scale, were employed in order to analyze the stigma factors of an HIV-positive population versus an HIV-negative general population, respectively. The HIV stigma factors studied included personalized stigma, disclosure concerns, negative self-image, and concern with public attitudes. Results. The total stigma scale scores for the studied HIV positive population were significantly lower than the total stigma scale scores for the studied HIV-negative population (P < 0.05). Conclusion. Interestingly, there is a misplaced expectation by the general population that HIV-positive individuals experience more stigma than the HIV-positive population in the clinic actually reported. Interventions to reduce HIV stigma should be an integral component of comprehensive care for all patients. PMID- 28096955 TI - Environmental and perceived stress in Australian dental undergraduates: Preliminary outcomes. AB - Background. Dental students have reported a high prevalence of psychological stress and the causes are associated with the challenging dental environmental and demographic factors. This study aimed to conduct a preliminary investigation on dental students' stress status, using a sample of first-to-third-year Bachelor of Dental Surgery students in an Australian university. Special interests included causes of dental environmental stress and access to help services. Methods. A sample of 145 students was surveyed with a modified Dental Environmental Survey and Depression Anxiety Stress Scale in 2014. The participants' demographic information was also collected. Results. The response rate was 95.4%. Second-year (P = 0.042), third-year (P < 0.001) and employed students (P = 0.027) were more likely to report stress resulting from transition to clinical learning. Third-year students were more often stressed about communicating and approaching staff (P = 0.023) as well as different opinions between staff (P < 0.001) and reduced holidays (P < 0.001). Students that were younger than 21 years of age (P = 0.001), that were first years (P < 0.001), and that were not in a relationship (P = 0.010) more often found difficulty of course work stressful. Students who were not in a relationship more often considered learning manual dexterity a source of stress (P = 0.034). Students previously seeking professional help were more likely to be stressed (P = 0.010). Conclusion. Causes of dental environment stress varied among years of study and demographic backgrounds. Professional support to stressed students should be enhanced. Further investigation is indicated. PMID- 28096956 TI - Erratum to: Effect of non-surgical periodontal treatment on transferrin serum levels in patients with chronic periodontitis. AB - [This corrects the article DOI: 10.15171/joddd.2016.027.]. PMID- 28096958 TI - Survival, proliferation, and migration of human meningioma stem-like cells in a nanopeptide scaffold. AB - OBJECTIVES: In order to grow cells in a three-dimensional (3D) microenvironment, self-assembling peptides, such as PuraMatrix, have emerged with potential to mimic the extracellular matrix. The aim of the present study was to investigate the influence of the self-assembling peptide on the morphology, survival, proliferation rate, migration potential, and differentiation of human meningioma stem-like cells (hMgSCs). MATERIALS AND METHODS: The efficacy of a novel method for placing hMgSCs in PuraMatrix (the injection approach) was compared to the encapsulation and surface plating methods. In addition, we designed a new method for measurement of migration distance in 3D cultivation of hMgSCs in PuraMatrix. RESULTS: Our results revealed that hMgSCs have the ability to form spheres in stem cell culture condition. These meningioma cells expressed GFAP, CD133, vimentin, and nestin. Using the injection method, a higher proliferation rate of the hMgSCs was observed after seven days of culture. Furthermore, the novel migration assay was able to measure the migration of a single cell alone in 3D environment. CONCLUSION: The results indicate the injection method as an efficient technique for culturing hMgSCs in PuraMatrix. Furthermore, the novel migration assay enables us to evaluate the migration of hMgSCs. PMID- 28096957 TI - Cinnamon effects on metabolic syndrome: a review based on its mechanisms. AB - OBJECTIVES: Nowadays, cardiovascular diseases (CVDs) are the major risk factors of death globally. One of the most undeniable reasons of CVDs is metabolic syndrome (MetS). MetS is defined as a complex of diseases including insulin resistance, hyperglycemia, obesity, high blood pressure and dyslipidemia. The use of complementary medicine such as traditional herbal species can be effective in treatment of MetS's complications. Cinnamomum verum (family Lauraceae) is a medicinal global plant which has been used daily by people all over the world. Positive effects of cinnamon in reducing blood pressure, plasma glucose, obesity and ameliorating dyslipidemia which represented in traditional medicine introduced it as probable decreasing MetS's complications agent. The aim of this review was to investigate the mechanisms of C. verum in reducing the MetS's complications and CVDs risk factors. MATERIALS AND METHODS: Various databases such as PubMed, Science Direct, Scopus, Web of Science, Google Scholar and Persian Websites such as www.sid.ir with keywords search of cinnamon, cinnamomum, cinnamaldehyde, atherogenic, hypertension, hyperglycemia, insulin resistance, obesity and dyslipidemia have been included in this search. RESULTS: Clinical data and mechanisms of action of C. verum and its active ingredients that have been shown in this review indicated that cinnamon has protective effects against MetS's aspects in various ways. CONCLUSION: The use of this plant can be effective in reducing MetS's complications and its morbidity and mortality. PMID- 28096959 TI - The effect of aminoguanidine on sperm motility and mitochondrial membrane potential in varicocelized rats. AB - OBJECTIVES: Increased levels of nitric oxide (NO) in the testicular veins of people suffering from varicocele have already been reported. However, the role of NO-synthase (NOS) isozymes and their inhibitors have not been extensively studied. We aimed to evaluate the inhibitory effects of aminoguanidine (AG), on sperm motility, vitality, and mitochondrial membrane potential (MMP) in varicocelized rats. MATERIALS AND METHODS: Twenty fore male Wister rats were divided into control, sham, varicocele, and treatment groups. Varicocele and treatment groups underwent partial ligation of left renal vein. Rats in the sham group underwent the same procedures as the varicocele group with the exception of vein ligation. 10 weeks after varicocele induction, sperm parameters were evaluated in all groups. The treatment group received 50 mg/kg AG injection daily for 10 weeks after which they were sacrificed prior to assessment of the parameters. Sperm viability and MMP were assessed by flow cytometry using propidium iodide (PI) and rhodamine 123 (Rh123), respectively. RESULTS: The results of this study show a decrease in sperm viability, motility and MMP in the varicocele group compared with the other groups. After AG injection, we observed that all the parameters were significantly enhanced in the treatment group compared with the other groups. Rh123 staining revealed a positive relation between MMP and sperm motility, whereas PI staining showed a positive relation between sperm motility and viability. CONCLUSION: The findings of our study show that AG improves sperm motility and MMP, and thus, might be useful in the management of varicocele-related infertility. PMID- 28096960 TI - Estrogen agonist genistein differentially influences the cognitive and motor disorders in an ovariectomized animal model of Parkinsonism. AB - OBJECTIVES: Parkinson's disease (PD) is a progressive neurological disorder associated with motor disabilities and cognitive dysfunction as well. Evidence indicates that PD occurs less frequently in women than men, confirming a role for steroid hormones in protection of dopaminergic nigrostriatal neurons. It is reported that soy genistein, an estrogen agonist phytoestrogen, display neuroprotective effects against neuronal death. In this study we evaluated the effect of genistein in animal models of Parkinsonism (P) and Parkinsonism + ovariectomized (OP). MATERIALS AND METHODS: The experiments were carried out on the control, P and OP animals. Learning and memory abilities were evaluated using Morris water maze. The latency and speed of locating the platform were measured as cognitive indices. Motor behaviors were assessed by testing the animals in rota rod and the latency to fall from the rod was scored. RESULTS: We found that Parkinsonism leads to the cognitive and motor disabilities; ovariectomy intensified these disorders. Whereas genistein treatment improved the maze performances in both P and OP animals it failed to influence the kinetic problems. Genistein displayed a neuroprotective effect on dopaminergic neurons. CONCLUSION: Positive impact of genistein on the spatial learning and memory may reflect its effects on the nigrostriatal pathway and striatum. Nevertheless, ineffectiveness of genistein on the motor disorders, despite its neuroprotective impacts, led us to conclude that the cognitive improvement by genistein may also contribute to its effects in other areas of brain. PMID- 28096961 TI - Polysaccharide from Sepia esculenta ink and cisplatin inhibit synergistically proliferation and metastasis of triple-negative breast cancer MDA-MB-231 cells. AB - OBJECTIVES: This paper aims to investigate synergistic inhibition of polysaccharide from Sepia esculenta ink (SIP), a newly isolated marine polysaccharide in our laboratory, on breast cancer MDA-MB-231 cells exposed to cisplatin. MATERIALS AND METHODS: Cell viability of MDA-MB-231 cells was determined by CCK 8 assay. Median-effect concentration was analyzed using Chou Talalay method that was also subjected to determine cell inhibition ratio and combined index, as well as interaction between SIP and cisplatin. Proliferation and migration abilities were detected with plate colony formation assay and cell wound scratch assay, respectively. Expression of MMP-2 and MMP-9 proteins was measured with Western blot assay. RESULTS: Data showed that SIP not only suppressed proliferation and migration of MDA-MB-231 cells, and expression of MMP 2 and MMP-9 proteins, also promoted inhibition of cisplatin on proliferation, migration and MMPs expression of MDA-MB-231 cells, which indicates synergy inhibition of drug combination of SIP and cisplatin on breast cancer cells. The median-effect concentrations of cisplatin and SIP were 4.9 and 1659.6 MUg/ml, respectively. Whereas the concentration of combination drug was 158.5 MUg/ml. The data indicated that drug combination can decrease dosages of the two single agents, especially the usual dosage of cisplatin. CONCLUSION: This research demonstrated that SIP repressed proliferation and metastasis of MDA-MB-231 cells and promoted anticancer effect of cisplatin on the breast cancer cells. The data suggested that SIP is a potential natural drug that can be used as an auxiliary medicine alongside chemotherapy in treating breast cancer. PMID- 28096962 TI - Extra virgin olive oil in maternal diet increases osteogenic genes expression, but high amounts have deleterious effects on bones in mice offspring at adolescence. AB - OBJECTIVES: Maternal high-fat diet has been shown to have deleterious effects on the offspring bones. However, there is no study to assess the effects of type and amount of maternal dietary oil in an isocaloric diet, with focus on extra virgin olive oil (EVOO). The objective of the current study was to test the hypothesis that type of maternal dietary oil has more effects than its amount in an isocaloric diet during gestation and lactation on bone genes expression in offspring in adolescence. MATERIALS AND METHODS: Virgin female C57BL/6 mice were impregnated and fed either the AIN 93G diet (received 16% of calories as soybean oil, as a control diet, or EVOO) or a high fat AIN 93G diet (received 45% of calories as soybean oil or EVOO) from the time of vaginal plug confirmation until offspring's weaning. RESULTS: After adjusting for the amount of oils, osteoprotegerin/receptor activator of nuclear factor NF-kappaB ligand (OPG/RANK L) and OPG expressions were 6.1- and 2.8-folds higher in offspring born to EVOO compared with soybean oil-fed mothers. OPG, beta-catenin, and OPG/RANK-L expression were 88%, 94%, and 70% lower in offspring born to the 45% oil-fed mothers compared with the 16% group. In contrast, peroxisome proliferator activated receptor gamma-2 (PPARgamma2) gene expression was higher in the 45% oil group, adjusted for the types of oil. CONCLUSION: Maternal EVOO consumption, but not soybean oil increased osteoblastic gene expression, and high amounts of both oils decreased osteoblastic and increased adipogenic genes expression in adolescent offspring. PMID- 28096963 TI - Effect of A-769662, a direct AMPK activator, on Tlr-4 expression and activity in mice heart tissue. AB - OBJECTIVES: TLR-4 activates a number of inflammatory signaling pathways. Also, AMPK could be involved in anti-inflammatory signaling. The aim of this study was to identify whether stimulation of AMPK could inhibit LPS-induced Tlr-4 gene expression in mice hearts. MATERIALS AND METHODS: Heart AMPK activity and/or Tlr 4 expression was stimulated in different mice groups, using respectively IP injection of A-769662 (10 mg/kg) and LPS (2 mg/kg) or a combination of both agents. Moreover, compound-C (20 mg/kg), as an AMPK antagonist, was intraperitoneally co-administrated with both A-769662 and LPS in another group to investigate the role of AMPK activity on Tlr-4 regulation. After 8 hr, in addition to peripheral neutrophil cell count, myocardial p-AMPK, p-ACC as well as MyD88 protein contents and Tlr-4 expression was assessed by Western blotting and real-time qRT-PCR, respectively. TNF-alpha and IL-6 expression levels were also determined by ELISA. RESULTS: LPS induced heart Tlr-4 expression (P<0.001) associating with an increase in the myocardial MyD88 protein content (P<0.001), elevation of heart TNF-alpha (P<0.01) and IL-6 (P<0.05) concentrations, and rise in the peripheral neutrophil cell count (P<0.001). Administration of A-769662 decreased LPS-induced Tlr-4 expression (P<0.01) and alleviated peripheral neutrophil cell count (P<0.01). The inhibitory effect of A-769662 on LPS-induced Tlr-4 expression was reversed by antagonizing AMPK with compound-C (P<0.001) which reduced p-AMPK (P<0.05) and p-ACC (P<0.01) myocardial protein contents in the LPS+A-769662 group. CONCLUSION: This study demonstrated that activation of AMPK, by A-769662 agent, could inhibit Tlr-4 expression and activity, suggesting a link between AMPK and Tlr-4 in heart tissue. PMID- 28096964 TI - G-CSF for mobilizing transplanted bone marrow stem cells in rat model of Parkinson's disease. AB - OBJECTIVES: Granulocyte-colony stimulating factor (G-CSF) is used in clinical practice for the treatment of neutropenia and to stimulate generation of hematopoietic stem cells in bone marrow donors. In the present study, the ability of G-CSF in mobilizing exogenous bone marrow stem cells (BMSCs) from peripheral blood into the brain was tested. We for the first time injected a small amount of BMSCs through the tail vein. MATERIALS AND METHODS: We choose 25 male Wistar rats (200-250 g) were lesioned by 6-OHDA injected into the left substantia nigra, pars compacta (SNpc). G-CSF (70 ug/kg/day) was given from the 7th day after lesion for five days. The BMSCs (2*105) were injected through the dorsal tail vein on the 7th day after lesion. RESULTS: The number of rotations was significantly lower in the stem cell therapy group than in the control group. In the third test in the received G-CSF and G-CSF+stem cells groups, animals displayed significant behavioral recovery compared with the control group (P<0.05). There was a significant difference in the average of dopaminergic neurons in SNpc between the control group and G-CSF and G-CS+stem cells groups. We didn't detect any labeling stem cells in SNpc. CONCLUSION: G-CSF can't mobilize low amounts of exogenous BMSCs from the blood stream to injured SNpc. But G-CSF (70 ug/kg) is more neuroprotective than BMSCs (2*105 number[w1] of BMSCs). Results of our study suggest that G-CSF alone is more neuroprotective than BMSCs. PMID- 28096965 TI - Molecular typing of nosocomial Staphylococcus aureus strains associated to biofilm based on the coagulase and protein A gene polymorphisms. AB - OBJECTIVES: Staphylococcus aureus is an important bacterial pathogen responsible for a variety numbers of nosocomial and community acquired infections. Biofilm formation is regarded as an important factor in the establishment of S. aureus infection. The contribution of the genetic background of S. aureus to biofilm formation is poorly understood. The aim of the present work was to genotype S. aureus strains associated to biofilm based on the coagulase and protein A genes and to evaluate the association between the genetic background and the biofilm forming ability of clinical S. aureus isolates. MATERIALS AND METHODS: A total number of 100 S. aureus were isolated from nosocomial infections and biofilm formation capability was investigated using phenotypic assay and molecular detection of biofilm associated genes. The strains were genotyped based on coagulase (coa) and protein A (spa) gene polymorphisms using restriction fragments length polymorphism-polymerase chain reaction (RFLP-PCR). RESULTS: RFLP PCR of coa gene generated two types and three subtypes. Amplification of spa gene resulted in two banding patterns and their restriction digestion generated three subtypes. The combined coa and spa RFLP patterns generated nine genotypes (G1 G9). The genotypes G4 and G1 were the most prevalent (32.1% and 24.3%, respectively). CONCLUSION: High clonal diversity of S. aureus strains able to produce biofilm was observed. Biofilm formation correlates with the spa and coa clonal lineage in our population and testing for multiple gene polymorphisms could be employed for local epidemiologic purposes. PMID- 28096966 TI - MicroRNA-297a regulates vascular calcification by targeting fibroblast growth factor 23. AB - OBJECTIVES: Vascular calcification is one the major characteristics in patients with various types of chronic inflammatory disorders. MiRNAs have been shown to be involved in many normal biological functions as well as diseases; however, their role in vascular calcification has not received much attention. MATERIALS AND METHODS: In the current study, we built a vascular calcification rat model using vitamin D3 plus nicotine and analyzed miRNA expression profile by miRNA chip assay. Potential target of one selected miRNA with sharpest variation in expression were predicted by both PicTar and TargetScan. The impact of the selected miRNA on the expression of the potential target on both mRNA and protein levels were measured by RT-PCR and Western blot, respectively. RESULTS: Our results identified 16 dysregulated miRNAs, among which miR-297a showed the sharpest variation. Further analysis focusing on miR-297a revealed that fibroblast growth factor 23 (FGF23) was a potential target of miR297a. Measurement of FGF23 and its regulator Klotho on both mRNA and protein levels demonstrated that FGF23 was significantly increased while Klotho was decreased in rats with vascular calcification. CONCLUSION: Our results indicated that FGF23 was target of miR-297a and decreased miR-297a in vascular calcification lead to the increase of FGF23, which together with Klotho might enhance vascular calcification. The findings of this study could provide valuable information for the understanding of mechanisms underlying miR-dependent vascular calcification as well as potential treatment target for the disease. PMID- 28096967 TI - Volatile compounds analysis and antioxidant, antimicrobial and cytotoxic activities of Mindium laevigatum. AB - OBJECTIVES: Mindium laevigatum is an endemic plant of Iran and Turkey and is widely used as blood purifier, antiasthma and antidyspnea in traditional medicine. Chemical composition of volatile materials of the plant and its antioxidant, antimicrobial and cytotoxic activities were reported in this study. MATERIALS AND METHODS: Simultaneous distillation-extraction (SDE) and GC-Mass-FID analysis were used for the plant volatile materials chemical composition identification and quantification. Several antioxidant tests including DPPH radical scavenging, hydrogen peroxide scavenging, reducing power determination, beta-carotene-linoleic acid and total phenolic content tests were used for antioxidant activity evaluation. Antimicrobial and anticancer activities were also estimated using microbial strains, cancer cell lines and brine shrimp larva. RESULT: s: GC-Mass-FID analysis of volatile samples showed a total of 74 compounds of which palmitic acid (7.4-33.7%), linoleic acid (6.6-18.6%), heneicosane (1.3-9.6%) and myristic acid (1.4-6.0%) were detected as main volatile components. Moderate to good results were recorded for the plant in beta carotene-linoleic acid test. Total phenolic content of the extracts as gallic acid equivalents were estimated in the range of 15.7 to 79.6 MUg/mg. Some microbial strains showed moderate sensitivities to plant extracts. Brine shrimp lethality test and cytotoxic cancer cell line assays showed mild cytotoxic activities for the plant. CONCLUSION: Moderate to good antioxidant activities in beta-carotene-linoleic acid test and presence of considerable amounts of unsaturated hydrocarbons may explain the plant traditional use in asthma and dyspnea. These findings also candidate it as a good choice for investigating its possible modern medical applications. PMID- 28096968 TI - A novel atheroprotective role of MF59-like adjuvant when co-administered with CETP vaccine in rabbit model of atherosclerosis. AB - OBJECTIVES: In this study, for the first time, MF59 adjuvant was used to develop a cholesteryl ester transfer protein (CETP) vaccine. The efficacy of the vaccine was compared with the efficacy of CETP vaccine formulated with Alum/CpG, the formulation that its immunogenicity has been already demonstrated in rabbit and mice. MATERIALS AND METHODS: Tetanus toxoid- CETP peptide (TT-CETP) was mixed with Alum/CpG or MF59-like and administered subcutaneously for total five times in rabbit model of atherosclerosis. Anti-TT-CETP specific antibody, CETP activity in sera and mRNA level of cytokine IL-4 and IFN-gamma in peripheral mononuclear cells were determined. Therapeutic response was also examined by tracking serum lipoprotein levels and pathologic observation of atherosclerotic lesions at aortic site. RESULTS: More anti-TT-CETP antibody was found in Alum/CpG vaccinated rabbits compared to buffer (P<0.001). Antibody induced by MF59-like formulation was not significantly higher than buffer. CETP activity and lipoprotein levels were not significantly different between vaccinated and control rabbits. The mRNA level of IL-4 was significantly lower than buffer while, IFN-gamma gene expression was significantly higher in both vaccinated groups. Atherosclerosis thickness grade of aorta was dramatically lower than buffer (P<0.01) in both vaccinated groups. CONCLUSION: It is concluded that MF59-adjuvanted CETP vaccine showed anti-atherosclerosis properties, but the protective effect could not be directly attributed to the immune response induced by anti TT-CETP antibody and CETP inhibition. Further studies are needed to explain the anti-atherosclerosis properties of MF59 in the presence of TT-CETP peptide. PMID- 28096969 TI - Dendrosomal nanocurcumin and p53 overexpression synergistically trigger apoptosis in glioblastoma cells. AB - OBJECTIVES: Glioblastoma is the most lethal tumor of the central nervous system. Here, we aimed to evaluate the effects of exogenous delivery of p53 and a nanoformulation of curcumin called dendrosomal curcumin (DNC), alone and in combination, on glioblastoma tumor cells. MATERIALS AND METHODS: MTT assay was exploited to measure the viability of U87-MG cells against DNC treatment. Cells were separately subjected to DNC treatment and transfected with p53-containing vector and then were co-exposed to DNC and p53 overexpression[A GA1][B2]. Annexin V-FLUOS staining followed by flow cytometry and real-time PCR were applied to examine apoptosis and analyze the expression levels of the genes involved in cell cycle and oncogenesis, respectively. RESULTS: The results of cell viability assay through MTT indicated that DNC inhibits the proliferation of U87-MG cells in a time- and dose-dependent manner. Apoptosis evaluation revealed that p53 overexpression accompanied by DNC treatment can act in a synergistic manner to significantly enhance the number of apoptotic cells (90%) compared with their application alone (15% and 38% for p53 overexpression and DNC, respectively). Also, real-time PCR data showed that the concomitant exposure of cells to both DNC and p53 overexpression leads to an enhanced expression of GADD45 and a reduced expression of NF-kappaB and c-Myc. CONCLUSION: The findings of the current study suggest that our combination strategy, which merges two detached gene (p53) and drug (curcumin) delivery systems into an integrated platform, may represent huge potential as a novel and efficient modality for glioblastoma treatment. PMID- 28096970 TI - Inhibition of Akt phosphorylation attenuates resistance to TNF-alpha cytotoxic effects in MCF-7 cells, but not in their doxorubicin resistant derivatives. AB - OBJECTIVES: Acquisition of TNF-alpha resistance plays role in the onset and growth of malignant tumors. Previous studies have demonstrated that MCF-7 cell line and its doxorubicin resistant variant MCF-7/Adr are resistant against the cytotoxic effects of TNF-alpha. In this study, we investigated the role of Akt activation in resistance of MCF-7 and MCF-7/Adr against TNF-alpha cytotoxicity. MATERIALS AND METHODS: The role of Akt activation in TNF-alpha cytotoxicity was investigated by MTT cell viability assay following treatment of the cells with the chemical inhibitor of Akt activation with or without TNF-alpha treatment. Phosphorylation of Akt at Ser473 before and after 72 hr TNF-alpha treatment was also determined by western blot. RESULTS: TNF-alpha treatment led to enhancement of Akt Ser473 phosphorylation. Treatment of MCF-7 cells with TNF-alpha along with Akt-inhibitor agent, tricribine, attenuated Akt Ser473 phosphorylation and sensitized these cells to the cytotoxic effects of TNF-alpha in a dose and time dependent manner while tricribine treatment did not cause any significant cytotoxicity in MCF-7/Adr cells alone or in combination with TNF-alpha. CONCLUSION: These results demonstrate that Akt phosphorylation plays pivotal role in the resistance of MCF-7 cells against TNF-alpha-induced cytotoxicity while it might play no significant role in the resistance of MCF-7/Adr cells against TNF alpha. PMID- 28096971 TI - Carthamus tinctorius L. ameliorates brain injury followed by cerebral ischemia reperfusion in rats by antioxidative and anti-inflammatory mechanisms. AB - OBJECTIVES: Carthamus tinctorius L. (CT) or safflower is widely used in traditional Chinese medicine. This study investigated the effects of CT extract (CTE) on ischemia-reperfusion (I/R) brain injury and elucidated the underlying mechanism. MATERIALS AND METHODS: The I/R model was conducted by occlusion of both common carotid arteries and right middle cerebral artery for 90 min followed by 24 hr reperfusion in Sprague-Dawley rats. CTE (0.2-0.6 g/kg) was administered intraperitoneally before and during ischemia, and during reperfusion period. The cerebral infarction area, neurological deficit scores, free radicals (lucigenin chemiluminescence counts) and pro-inflammatory cytokines expression were measured. RESULTS: Pretreatment and treatment with CTE significantly reduced the cerebral infarction area and neurological deficits. CTE (0.4 g/kg) also reduced blood levels of free radicals and expression of tumor necrosis factor-alpha and interleukin-1beta in the cerebral infarction area. CONCLUSION: The reduction in I/R cerebral infarction caused by CTE is possibly associated with its antioxidation and anti-inflammatory properties. PMID- 28096972 TI - Objects Versus Shadows as Influences on Perceived Object Motion. AB - The motion trajectory of an object's cast shadow has been shown to alter the perceived trajectory of a casting object, an effect that holds even if the cast shadow appears unrealistic. This raises the question of whether a cast shadow per se is necessary for this influence, a question that has been studied only with stationary targets. We examined the relative influence of a shadow and a spherical object on the perceived motion trajectory of an identical spherical object, using a paradigm similar to Kersten, Mamassian, and Knill's ball-in-box animation. We recorded both depth and height estimates of the perceived end-point of the target trajectory as a function of various target and context trajectories. Both shadows and objects significantly influenced the perceived trajectory of the target, though the influence of the shadow was overall stronger. We conjecture that the influence of the object reveals the assumption that similar objects moving at the same speed and in similar directions are perceived to move within the same plane, a plane subject to a fronto-parallel bias. PMID- 28096973 TI - A fission yeast cell-based system for multidrug resistant HIV-1 proteases. AB - BACKGROUND: HIV-1 protease (PR) is an essential enzyme for viral production. Thus, PR inhibitors (PIs) are the most effective class of anti-HIV drugs. However, the main challenge to the successful use of PI drugs in patient treatment is the emergence of multidrug resistant PRs (mdrPRs). This study aimed to develop a fission yeast cell-based system for rapid testing of new PIs that combat mdrPRs. RESULTS: Three mdrPRs were isolated from HIV-infected patients that carried seven (M7PR), ten (M10PR) and eleven (M11PR) PR gene mutations, respectively. They were cloned and expressed in fission yeast under an inducible promoter to allow the measurement of PR-specific proteolysis and drug resistance. The results showed that all three mdrPRs maintained their abilities to proteolyze HIV viral substrates (MA?CA and p6) and to confer drug resistance. Production of these proteins in the fission yeast caused cell growth inhibition, oxidative stress and altered mitochondrial morphologies that led to cell death. Five investigational PIs were used to test the utility of the established yeast system with an FDA-approved PI drug Darunavir (DRV) as control. All six compounds suppressed the wildtype PR (wtPR) and the M7PR-mediated activities. However, none of them were able to suppress the M10PR or the M11PR. CONCLUSIONS: The three clinically isolated mdrPRs maintained their viral proteolytic activities and drug resistance in the fission yeast. Furthermore, those viral mdrPR activities were coupled with the induction of growth inhibition and cell death, which could be used to test the PI activities. Indeed, the five investigational PIs and DRV suppressed the wtPR in fission yeast as they did in mammalian cells. Significantly, two of the high level mdrPRs (M10PR and M11PR) were resistant to all of the existing PI drugs including DRV. This observation underscores the importance of continued searching for new PIs against mdrPRs. PMID- 28096975 TI - A prospective survey of Pseudomonas aeruginosa colonization and infection in the intensive care unit. AB - BACKGROUND: Pseudomonas aeruginosa (PA) surveillance may improve empiric antimicrobial therapy, since colonizing strains frequently cause infections. This colonization may be 'endogenous' or 'exogenous', and the source determines infection control measures. We prospectively investigated the sources of PA, the clinical impact of PA colonization upon admission and the dynamics of colonization at different body sites throughout the intensive care unit stay. METHODS: Intensive care patients were screened on admission and weekly from the pharynx, endotracheal aspirate, rectum and urine. Molecular typing was performed using Enterobacterial Repetitive Intergenic Consensus Polymerase Chain reaction (ERIC-PCR). RESULTS: Between November 2014 and January 2015, 34 patients were included. Thirteen (38%) were colonized on admission, and were at a higher risk for PA-related clinical infection (Hazard Ratio = 14.6, p = 0.0002). Strains were often patient-specific, site-specific and site-persistent. Sixteen out of 17 (94%) clinical isolates were identical to strains found concurrently or previously on screening cultures from the same patient, and none were unique. Ventilator associated pneumonia-related strains were identical to endotracheal aspirates and pharynx screening (87-75% of cases). No clinical case was found among patients with repeated negative screening. CONCLUSION: PA origin in this non-outbreak setting was mainly 'endogenous' and PA-strains were generally patient- and site-specific, especially in the gastrointestinal tract. While prediction of ventilator associated pneumonia-related PA-strain by screening was fair, the negative predictive value of screening was very high. PMID- 28096974 TI - Mortality, hospital days and treatment costs of current and reduced sugar consumption in Israel. AB - BACKGROUND: Consumption of sugar causes tooth decay, overweight and obesity related morbidities. This paper in response to the Minister of Health's request, provides estimates of the mortality, morbidity and health care costs attributable to sugar consumption in Israel along with the effects of reducing sugar consumption. METHODS: Gender specific relative risks of many diseases from overweight (25 < =BMI < 30) and obesity (BMI > =30) were applied to the national gender specific prevalence rates of overweight and obesity in order to calculate the population attributable fraction (PAF) from overweight and obesity. National expenditure on these related diseases was calculated by applying disease-specific data from a recent Canadian study to estimates of disease specific general hospital expenditures in Israel. Disease specific costs attributable to overweight and obesity were estimated from the product of these expenditures and PAF. In addition national costs of treating caries in persons under 18 years of age from sugar were calculated. Similar calculations were made to estimate the burden from sugar in terms of mortality and hospital utilisation. A recent UK modelling study was used to estimate the effect of a national program to reduce calorific consumption of sugar from 12.45 to 10% in 5 years. RESULTS: Conditions associated with overweight or obesity accounted annually for 6402 deaths (95% CI 3296-8760) and 268,009 hospital days. Dental costs attributable to sugar consumption were 264 million NIS. In total, obesity, overweight and sugar consumption accounted for 2449 million in direct treatment costs (0.21% of GDP), rising to 4027 million (0.35% of GDP) when indirect costs were included. A national program of reducing energy from sugar consumption from 12.45 to 10% over 5 years is considered have a very feasible short-term goal. Even if the program does not impose taxes on sugar consumption, this would save 778 million NIS as well as 1184 lives. CONCLUSION: Sugar consumption causes a huge monetary and mortality burden. Estimates of potential decreases in this burden justify the current prioritisation given by the health minister of creating and implementing a national program to reduce sugar consumption, which is likely to be cost-saving (ie: averted treatment costs will exceed intervention costs). PMID- 28096976 TI - Effect of handrubbing using locally-manufactured alcohol-based handrubs in paediatric wards in Harare, Zimbabwe. AB - We assessed bacterial contamination of hands of adults present in paediatric wards in two tertiary-care hospitals in Harare, Zimbabwe and the microbiologic efficacy of locally-manufactured alcohol-based hand rub (ABHR). During unannounced visits, samples were collected using hand-print and hand-rinse methods. Samples were collected from 152 individuals (16 nurses, 10 doctors, 28 students, 86 parents/guardians, 12 others). Contamination of hands with Gram negative bacteria was found in 91% of adults tested with a mean of 14.6 CFU (hand rinse method; IQR 3-65), representing a high risk for transmission of pathogens potentially leading to nosocomial infections. A single application of ABHR under controlled conditions achieved an average of 82% (or 0.72 log) reduction in detectable counts. Amongst 49 Enterobacteriaceae isolates from hands, 53% were resistant to gentamicin and 63% were resistant to cefpodoxime. Use of ABHR represents an attractive intervention for reducing nosocomial infections in this setting. PMID- 28096977 TI - High rates of multidrug resistance among uropathogenic Escherichia coli in children and analyses of ESBL producers from Nepal. AB - BACKGROUND: Emergence of Extended-spectrum beta-lactamase producing Escherichia coli causing urinary tract infections (UTI) among pediatric patients is an increasing problem worldwide. However, very little is known about pediatric urinary tract infections and antimicrobial resistance trend from Nepal. This study was conducted to assess the current antibiotic resistance rate and ESBL production among uropathogenic Escherichia coli in pediatric patients of a tertiary care teaching hospital of Nepal. METHODS: A total of 5,484 urinary tract specimens from children suspected with UTI attending a teaching hospital of Nepal over a period of one year were processed for the isolation of bacterial pathogens and their antimicrobial susceptibility testing. Escherichia coli (n = 739), the predominant isolate in pediatric UTI, was further selected for the detection of ESBL-production by phenotypic combination disk diffusion test. RESULTS: Incidence of urinary tract infection among pediatric patients was found to be 19.68% and E coli (68.4%) was leading pathogen involved. Out of 739 E coli isolates, 64.9% were multidrug resistant (MDR) and 5% were extensively drug resistant (XDR). Extended spectrum beta lactamase (ESBL) was detected in 288 (38.9%) of the E coli isolates. CONCLUSION: Alarming rate of drug resistance among pediatric uropathogens and high rate of ESBL-producing E. coli was observed. It is extremely necessary to routinely investigate the drug resistance among all isolates and formulate strict antibiotics prescription policy in our country. PMID- 28096978 TI - Carriage of antibiotic-resistant Enterobacteriaceae in hospitalised children in tertiary hospitals in Harare, Zimbabwe. AB - BACKGROUND: Extended-spectrum beta-lactamase-producing and gentamicin resistant Enterobacteriaceae are increasingly recognised as a major cause of infection in low-income countries. We assessed the prevalence of gastrointestinal carriage of these bacteria in hospitalised children in Harare, Zimbabwe. METHODS: We conducted a cohort study in paediatric inpatients at two tertiary-referral hospitals between May and July 2015. Rectal swabs and faecal samples were collected within 24 h of admission and further follow-up samples were collected on alternate days during hospitalization. Disc-based, selective and enrichment methods were used to detect carriage of these two forms of resistance. Standard methods were used to confirm resistance status and determine the susceptibility of resistant isolates to other commonly-used antibiotics. RESULTS: One hundred and sixty four paediatric inpatient admissions (median age = 1.0 year, IQR = 0.2 2.2years) were enrolled, and an average of 1.9 faecal samples per patient were collected. On admission, 68/164 (41%) patients had both ESBL and gentamicin resistant Enterobacteriaceae detected, 18 (11%) had ESBL only, 17 (10%) had gentamicin resistance only and 61 (37%) had negative screening for both forms of resistance. During hospitalisation, 32/164 (20%) patients were found to have a type of resistant organism which was not present in their admission sample. We found that faecal samples and use of a selective enrichment broth enhanced the detection of resistant organisms. Amongst resistant bacteria isolated, there were high levels of resistance to ciprofloxacin and chloramphenicol, but not ertapenem. CONCLUSIONS: More than half of children had enteric carriage of a clinically-relevant form of antibiotic resistance on admission to public-sector hospitals in urban Zimbabwe. Additionally, a fifth of children acquired a further form of resistance during hospitalisation. Urgent action is needed to tackle the spread of antibiotic resistant enteric bacteria in African hospitals. PMID- 28096980 TI - Genetic and prenatal findings in two Japanese patients with Schinzel-Giedion syndrome. AB - We report two Japanese patients with Schinzel-Giedion syndrome. When polyhydramnios is observed, additional fetal findings such as overlapping fingers, hydrocephalus, hydronephrosis, and very characteristic facial appearance comprising high, prominent forehead, hypertelorism, and depressed nasal root may suggest Schinzel-Giedion syndrome. PMID- 28096979 TI - Bibliometric analysis of worldwide publications on multi-, extensively, and totally drug - resistant tuberculosis (2006-2015). AB - BACKGROUND: The year 2015 marked the end of United Nations Millennium Development Goals which was aimed at halting and reversing worldwide tuberculosis (TB). The emergence of drug resistance is a major challenge for worldwide TB control. The aim of this study was to give a bibliometric overview of publications on multi-, extensively, and totally drug-resistant TB. METHODS: Scopus database was used to retrieve articles on multidrug resistant (MDR), extensively drug-resistant (XDR), and totally drug-resistant (TDR) tuberculosis for the study period (2006-2015). The number of publications, top productive countries and institutions, citation analysis, co-authorships, international collaboration, active authors, and active journals were retrieved and analyzed. RESULTS: A total of 2260 journal articles were retrieved. The mean +/- SD citations per article was 7.04 +/- 16.0. The h index of retrieved data was 76. The number of publications showed a three - fold increase over the study period compared with less than two - fold increase in tuberculosis research during the same study period. Stratified by number of publications, the United States of America ranked first while Switzerland ranked first in productivity per 100 million people, and South Africa ranked first in productivity stratified per one trillion Gross Domestic Product. Three of the High Burden Countries (HBC) MDR-TB (India, China, and South Africa) were present in top productive countries. High percentage of international collaboration was seen among most HBC MDR-TB. Except for Plos One journal, most active journals in publishing articles on MDR, XDR, TDR-TB were in infection - related fields and in general medicine. Top 20 cited articles were published in prestigious journal such as Lancet and New England Journal of Medicine. The themes in top 20 cited articles were diverse, ranging from molecular biology, diagnostic tools, co infection with HIV, and results of new anti-TB drugs. CONCLUSION: Publications on MDR, XDR and TDR - TB are increasing in the past decade. International collaboration was common. Many low resourced African and Asian countries will benefit from research leading to new diagnostic and screening technology of TB. The exchange of expertise, ideas and technology is of paramount importance in this field. PMID- 28096981 TI - Experience of Mowat-Wilson syndrome prenatal diagnosis for a Chinese family. AB - Mowat-Wilson syndrome (MWS) is a complex developmental disorder. We report the first prenatal diagnosis provided for a family in mainland China after identifying the causal mutation for the proband. Special focus on MWS-related organs during prenatal ultrasound scan is described which is extremely important for genetic counseling of parents. PMID- 28096982 TI - The birth and rise of a craniopharyngioma: the radiological evolution of an incidental craniopharyngioma detected on serial MRI during medical treatment of a macroprolactinoma. AB - This case demonstrates the rare coexistence of a prolactinoma with craniopharyngioma and documents its radiological growth. This case suggests that patients with pituitary neoplasms should be followed closely and although prolactinomas can often be managed medically, a coexistent other lesion may require surgery for histological assessment and to reduce mass effect. PMID- 28096983 TI - PDE3 inhibition with enoximone as first-line therapy for severe persistent pulmonary hypertension of the newborn during neonatal transport: a case report. AB - Severe Persistent pulmonary hypertension of the newborn (PPHN) can be effectively treated with a PDE3 inhibitor as first-line treatment during neonatal transport when iNO is not readily available. Starting iNO as soon as possible is strongly advised because of the complementary actions of both therapeutics. PMID- 28096984 TI - Chryseobacterium indologenes, a possible emergent organism resistant to carbapenem antimicrobials after stem cell transplantation. AB - A 64-year-old female was diagnosed with adult T-cell leukemia/lymphoma. She then underwent an unrelated allogeneic bone marrow transplantation with a reduced intensity regimen. She achieved engraftment followed by HHV-6 encephalopathy. This was complicated by Chryseobacterium indologenes pneumonia. Chryseobacterium indologenes is now a possible emergent organism resistant to carbapenem after transplantation. PMID- 28096985 TI - Radioactive seed localization of renal cell carcinoma in a patient with Von Hippel-Lindau disease. AB - This report describes the case of a patient, who had successful radioactive seed localization (RSL) performed to improve the identification and excision of a renal cell carcinoma. RSL is a new method of preoperative localization, which can ease the surgical procedure, minimize tissue trauma, and ultimately benefit the patient. PMID- 28096986 TI - Extracorporeal membrane oxygenation rescue in adolescent with bronchiolitis obliterans-organizing pneumonia like Wegener's granulomatosis. AB - We report a 17-year-old woman with bronchiolitis obliterans-organizing pneumonia (BOOP)-like granulomatosis with polyangiitis developing severe airway obliterations. Pending age, phase and grade of autoimmune treatment, and offering ECMO treatment may be crucial for survival but occasionally preface futility. ECMO-treated patient with BOOP-like GPA has never been described before. PMID- 28096987 TI - Therapeutic plasma exchange: a second-line treatment for brodifacoum poisoning following an anaphylactoid reaction to vitamin K. AB - Vitamin K1 is the first-line therapy to brodifacoum poisoning. Anaphylactoid reactions may occur anytime during intravenous administration of vitamin K1 injection. Vitamin K1 must be ceased when anaphylactoid reactions emerge, and therapeutic plasma exchange could be a second-line option. PMID- 28096988 TI - Successful outcome of three patients with sickle-cell disease and fat embolism syndrome treated with intensive exchange transfusion. AB - Fat embolism syndrome (FES) is a rare complication of sickle-cell disease (SCD) associated with extremely high mortality rates. It affects predominantly non-SS patients and those with previously mild disease. Rapid institution of exchange transfusion with an aim to reduce HbS to very low levels as soon as FES is suspected can be life-saving. PMID- 28096989 TI - Successful treatment of severe baclofen toxicosis initially refractory to conventional treatment. AB - After ingesting a dose of baclofen thought to be lethal, a patient with severe neurologic signs was successfully managed despite initially being refractory to treatment. Patients with persistent neurologic abnormalities may still have an excellent prognosis despite lack of initial response. Additionally, we present a potential case of benzodiazepine withdrawal. PMID- 28096990 TI - Extensive cutaneous metastases of pancreatic adenocarcinoma: a case report and review of the literature. AB - Herein, we present the case of a patient with pancreatic cancer and nonumbilical cutaneous metastasis. Patients with pancreatic adenocarcinomas can develop extensive cutaneous metastases involving not only abdominal skin but also other unusual sites such as the scrotum. PMID- 28096991 TI - Premature pubarche in a child with abnormal 3beta-hydroxysteroid dehydrogenase function and Klinefelter syndrome: the intriguing relationship between androgen deficiency and excess. AB - Disorders of androgen excess may coexist with disorders of androgen deficiency, such as Klinefelter syndrome, and can create diagnostic and therapeutic challenges. PMID- 28096992 TI - Development of myasthenia gravis 8 years after interstitial lung disease associated with antisynthetase (anti-EJ antibody) syndrome. AB - Patients with antisynthetase-positive interstitial lung disease (ILD) alone sometimes develop myositis during follow-up, but myasthenia gravis (MG) overlapping on antisynthetase syndrome is unusual. A 56-year-old woman with ILD and anti-EJ antibody treated for 8 years developed MG. Physicians should consider myositis and MG when patients develop muscle symptoms during follow-up. PMID- 28096993 TI - Like Father, Like Daughter-inherited cutis aplasia occurring in a family with Marfan syndrome: a case report. AB - We present the case of a newborn with co-occurrence of Marfan syndrome and aplasia cutis congenita (ACC) and a family history significant for Marfan syndrome and ACC in the father. This case details a previously unreported mutation in Marfan syndrome and describes a novel coinheritance of Marfan syndrome and ACC. PMID- 28096994 TI - Multiple liver abscesses and bacteremia caused by Streptococcus constellatus infection: a case report. AB - The Streptococcus milleri group (SMG) comprises commensal mucosal bacteria. Pyogenic liver abscesses due to hematogenous SMG infection are rare but can be observed even in healthy patients. In such cases, physicians should consider the existence of primary lesions that allow penetration of the SMG. PMID- 28096995 TI - Response to ibrutinib in chronic lymphocytic leukemia improves in quality with time. AB - Unlike chemoimmunotherapy regimens, which are given for a defined period, ibrutinib, a first-in-class Bruton's kinase inhibitor, allows most patients with CLL to remain on treatment for an extended period. Our experience, supported by sequential CT scan images, suggests that long-term ibrutinib promotes a high response rate that improves in quality with time. PMID- 28096996 TI - Recurrent haemoptysis as a symptom of severe pulmonary vein stenosis-a rare complication of catheter ablation in atrial fibrillation. AB - A pulmonary vein stenosis is a known adverse event of catheter ablation in atrial fibrillation. However, it should be considered due to high frequency of such procedures. Haemoptysis, a symptom of severe stenosis, is often misdiagnosed as other different diseases. We present a case report of a 52-year-old patient with recurrent haemoptysis, dyspnoea, and fatigue, which turned out to be complication after catheter ablation. Successful treatment with drug-eluting stent (DES) was implemented with vast clinical improvement and follow-up. PMID- 28096997 TI - Bronchial tree-shaped mucous plug in cystic fibrosis: imaging-guided management. AB - We report the case of a 17-year-old boy with cystic fibrosis (CF) who presented with persistent cough; after starting intravenous antibiotics for Pseudomonas aeruginosa he underwent a computed tomography (CT) scan of the chest. CT revealed extensive consolidation in the right lower lobe with relative bronchus obstruction; the cause of bronchial obstruction was detected in the mediastinal window, corresponding to a bronchial tree-shaped, thick, tenacious mucous plug. This was extracted 48 h after unresponsive bronchial washing and endobronchial instillation of rhDNAse, using foreign-body forceps, with subsequent resolution of cough. This case, which is the second report of plastic bronchitis in CF, was resolved by mechanical removal of the mucous plug, suggesting that a careful observation of CT imaging may guide intervention aimed at resolution of atelectasis. PMID- 28096998 TI - Treatment with nintedanib for acute exacerbation of idiopathic pulmonary fibrosis. AB - There is currently no effective treatment for acute exacerbation of idiopathic pulmonary fibrosis (IPF). We herein report the case of a patient with acute exacerbation of IPF which was treated with nintedanib, an intracellular inhibitor of tyrosine kinases, and showed improvement of the condition. An 84-year-old man with IPF was admitted to our hospital because of dry cough and worsening of dyspnoea within last 1 month. He presented with hypoxemia, and chest high resolution computed tomography (HRCT) revealed new, bilateral multifocal ground glass opacities superimposed on the background of lung fibrosis. After exclusion of alternative causes, acute exacerbation of IPF was diagnosed and we started treatment with nintedanib of 300 mg/day. This resulted in the gradual improvement of his condition and HRCT findings without administering antibiotics or corticosteroids. Serum Krebs von den Lungen-6 and surfactant protein D levels increased at acute exacerbation and subsequently decreased. This case suggests that nintedanib therapy may have possible benefits in acute exacerbation of IPF. PMID- 28096999 TI - Decreasing skeletal muscle as a risk factor for mortality in elderly patients with sepsis: a retrospective cohort study. AB - BACKGROUND: Older patients account for the majority of patients with sepsis. The objective of this study was to determine if decreased skeletal muscle mass is associated with outcomes in elderly patients with sepsis. METHODS: Patients (60 years and older) who were admitted to a tertiary medical center intensive care unit with a primary diagnosis of sepsis between January 2012 and February 2016 were included. Patients who had not undergone abdominal computed tomography on the day of admission, had cardiopulmonary arrest on arrival, or had iliopsoas abscess were excluded from the analyses. Cross-sectional muscle area at the 3rd lumber vertebra was quantified, and the relation to in-hospital mortality was analyzed. Multivariable logistic regression analysis that included sex and APACHE II score as explanatory variables was performed. The optimal cutoff value to define decreased muscle mass (sarcopenia) was calculated using receiver operating characteristic curve analysis, and the odds ratio for in-hospital mortality was determined. RESULTS: There were 150 elderly patients with sepsis (median age, 75 years) enrolled; in-hospital mortality and median APACHE II score were 38.7 and 24%, respectively. The skeletal muscle area of deceased patients was significantly lower than that of the survival group (P < 0.001). The multivariable logistic regression analysis demonstrated that decreased muscle mass was significantly associated with increased mortality (odds ratio = 0.94, 95% confidence interval = 0.90 to 0.97, P < 0.001). The optimal cutoff value of skeletal muscle area to predict in-hospital mortality was 45.2 cm2 for men and 39.0 cm2 for women. With these cutoff values, the adjusted odds ratio for decreased muscle area was 3.27 (95% CI, 1.61 to 6.63, P = 0.001). CONCLUSIONS: Less skeletal muscle mass is associated with higher in-hospital mortality in elderly patients with sepsis. The results of this study suggest that identifying patients with low muscularity contributes to better stratification in this population. PMID- 28097000 TI - Biased small-molecule ligands for selective inhibition of HIV-1 cell entry via CCR5. AB - Since the discovery of HIV's use of CCR5 as the primary coreceptor in fusion, the focus on developing small-molecule receptor antagonists for inhibition hereof has only resulted in one single drug, Maraviroc. We therefore investigated the possibility of using small-molecule CCR5 agonists as HIV-1 fusion inhibitors. A virus-free cell-based fusion reporter assay, based on mixing "effector cells" (expressing HIV Env and luciferase activator) with "target cells" (expressing CD4, CCR5 wild type or a selection of well-described mutations, and luciferase reporter), was used as fusion readout. Receptor expression was evaluated by ELISA and fluorescence microscopy. On CCR5 WT, Maraviroc and Aplaviroc inhibited fusion with high potencies (EC 50 values of 91 and 501 nM, respectively), whereas removal of key residues for both antagonists (Glu283Ala) or Maraviroc alone (Tyr251Ala) prevented fusion inhibition, establishing this assay as suitable for screening of HIV entry inhibitors. Both ligands inhibited HIV fusion on signaling deficient CCR5 mutations (Tyr244Ala and Trp248Ala). Moreover, the steric hindrance CCR5 mutation (Gly286Phe) impaired fusion, presumably by a direct hindrance of gp120 interaction. Finally, the efficacy switch mutation (Leu203Phe) - converting small-molecule antagonists/inverse agonists to full agonists biased toward G-protein activation - uncovered that also small-molecule agonists can function as direct HIV-1 cell entry inhibitors. Importantly, no agonist-induced receptor internalization was observed for this mutation. Our studies of the pharmacodynamic requirements for HIV-1 fusion inhibitors highlight the possibility of future development of biased ligands with selective targeting of the HIV-CCR5 interaction without interfering with the normal functionality of CCR5. PMID- 28097001 TI - MAG-DPA curbs inflammatory biomarkers and pharmacological reactivity in cytokine triggered hyperresponsive airway models. AB - Bronchial inflammation contributes to a sustained elevation of airway hyperresponsiveness (AHR) in asthma. Conversely, omega-3 fatty acid derivatives have been shown to resolve inflammation in various tissues. Thus, the effects of docosapentaenoic acid monoacylglyceride (MAG-DPA) were assessed on inflammatory markers and reactivity of human distal bronchi as well as in a cultured model of guinea pig tracheal rings. Human bronchi were dissected and cultured for 48 h with 10 ng/mL TNF-alpha or IL-13. Guinea pig tracheas were maintained in organ culture for 72 h which was previously shown to trigger spontaneous AHR. All tissues were treated with increasing concentrations of MAG-DPA (0.1, 0.3, and 1 MUmol/L). Pharmacomechanical reactivity, Ca2+ sensitivity, and western blot analysis for specific phosphoproteins and transcription factors were performed to assess the effects of both cytokines, alone or in combination with MAG-DPA, on human and guinea pig airway preparations. Although 0.1 MUmol/L MAG-DPA did not significantly reduce inflammatory biomarkers, the higher concentrations of MAG DPA (0.3 and 1 MUmol/L) blunted the activation of the TNF-alpha/NF kappaB pathway and abolished COX-2 expression in human and guinea pig tissues. Moreover, 0.3 and 1 MUmol/L MAG-DPA consistently decreased the Ca2+ sensitivity and pharmacological reactivity of cultured bronchial explants. Furthermore, in human bronchi, IL-13 stimulated phosphorylation of CPI-17 was reversed by 1 MUmol/L MAG-DPA. This effect was further amplified in the presence of 100 MUmol/L aspirin. MAG-DPA mediates antiphlogistic effects by increasing the resolution of inflammation, while resetting Ca2+ sensitivity and contractile reactivity. PMID- 28097002 TI - AmBisome Induced Avascular Necrosis of the Alae of the Nose of a very young girl suffering from Kala-azar - a Case Report. AB - Although liposomal amphotericin B (AmBisome) is considered as the first-line treatment for New Kala-azar, there is not enough evidence on the dosage formulation in children and its effect on them. Being considered as the safest drug for treatment of Kala-azar, this case of AmBisome-induced avascular necrosis now gives rise to the question; whether it is actually safe enough and if a dosage modification is needed in case of children. This so far, to the best of our knowledge, is the first instance of such severe adverse event due to AmBisome administration. PMID- 28097003 TI - Application of a systems pharmacology model for translational prediction of hERG mediated QTc prolongation. AB - Drug-induced QTc interval prolongation (Delta QTc) is a main surrogate for proarrhythmic risk assessment. A higher in vivo than in vitro potency for hERG mediated QTc prolongation has been suggested. Also, in vivo between-species and patient populations' sensitivity to drug-induced QTc prolongation seems to differ. Here, a systems pharmacology model integrating preclinical in vitro (hERG binding) and in vivo (conscious dog Delta QTc) data of three hERG blockers (dofetilide, sotalol, moxifloxacin) was applied (1) to compare the operational efficacy of the three drugs in vivo and (2) to quantify dog-human differences in sensitivity to drug-induced QTc prolongation (for dofetilide only). Scaling parameters for translational in vivo extrapolation of drug effects were derived based on the assumption of system-specific myocardial ion channel densities and transduction of ion channel block: the operational efficacy (transduction of hERG block) in dogs was drug specific (1-19% hERG block corresponded to >=10 msec Delta QTc). System-specific maximal achievable Delta QTc was estimated to 28% from baseline in both dog and human, while %hERG block leading to half-maximal effects was 58% lower in human, suggesting a higher contribution of hERG-mediated potassium current to cardiac repolarization. These results suggest that differences in sensitivity to drug-induced QTc prolongation may be well explained by drug- and system-specific differences in operational efficacy (transduction of hERG block), consistent with experimental reports. The proposed scaling approach may thus assist the translational risk assessment of QTc prolongation in different species and patient populations, if mediated by the hERG channel. PMID- 28097005 TI - The cardioprotective efficacy of TVP1022 against ischemia/reperfusion injury and cardiac remodeling in rats. AB - Following acute myocardial infarction (MI), early and successful reperfusion is the most effective strategy for reducing infarct size and improving the clinical outcome. However, immediate restoration of blood flow to the ischemic zone results in myocardial damage, defined as "reperfusion-injury". Whereas we previously reported that TVP1022 (the S-isomer of rasagiline, FDA-approved anti Parkinson drug) decreased infarct size 24 h post ischemia reperfusion (I/R) in rats, in this study we investigated the chronic cardioprotective efficacy of TVP1022 14 days post-I/R. To simulate the clinical settings of acute MI followed by reperfusion therapy, we employed a rat model of left anterior descending artery occlusion for 30 min followed by reperfusion and a follow-up for 14 days. TVP1022 was initially administered postocclusion-prereperfusion, followed by chronic daily administrations. Cardiac performance and remodeling were evaluated using customary and advanced echocardiographic methods, hemodynamic measurements by Millar Mikro-Tip(r) catheter, and histopathological techniques. TVP1022 administration markedly decreased the remodeling process as illustrated by attenuation of left ventricular enlargement and cardiac hypertrophy (both at the whole heart and the cellular level). Furthermore, TVP1022 inhibited cardiac fibrosis and reduced ventricular BNP levels. Functionally, TVP1022 treatment preserved cardiac wall motion. Specifically, the echocardiographic and most of the direct hemodynamic measures were pronouncedly improved by TVP1022. Collectively, these findings indicate that TVP1022 provides prominent cardioprotection against I/R injury and post-MI remodeling in this I/R model. PMID- 28097004 TI - Rifampicin decreases exposure to sublingual buprenorphine in healthy subjects. AB - Buprenorphine is mainly metabolized by the cytochrome P450 (CYP) 3A4 enzyme. The aim of this study was to evaluate the role of first-pass metabolism in the interaction of rifampicin and analgesic doses of buprenorphine. A four-session paired cross-over study design was used. Twelve subjects ingested either 600 mg oral rifampicin or placebo once daily in a randomized order for 7 days. In the first part of the study, subjects were given 0.6-mg (placebo phase) or 0.8-mg (rifampicin phase) buprenorphine sublingually on day 7. In the second part of the study, subjects received 0.4-mg buprenorphine intravenously. Plasma concentrations of buprenorphine and urine concentrations of buprenorphine and its primary metabolite norbuprenorphine were measured over 18 h. Adverse effects were recorded. Rifampicin decreased the mean area under the dose-corrected plasma concentration-time curve (AUC 0-18) of sublingual buprenorphine by 25% (geometric mean ratio (GMR): 0.75; 90% confidence interval (CI) of GMR: 0.60, 0.93) and tended to decrease the bioavailability of sublingual buprenorphine, from 22% to 16% (P = 0.31). Plasma concentrations of intravenously administered buprenorphine were not influenced by rifampicin. The amount of norbuprenorphine excreted in the urine was decreased by 65% (P < 0.001) and 52% (P < 0.001) after sublingual and intravenous administration, respectively, by rifampicin. Adverse effects were frequent. Rifampicin decreases the exposure to sublingual but not intravenous buprenorphine. This can be mainly explained by an enhancement of CYP3A-mediated first-pass metabolism, which sublingual buprenorphine only partially bypasses. Concomitant use of rifampicin and low-dose sublingual buprenorphine may compromise the analgesic effect of buprenorphine. PMID- 28097006 TI - Contribution of Sigma-1 receptor to cytoprotective effect of afobazole. AB - Anxiolytic afobazole (5-Ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihidrochloride) has pronounced ligand properties toward Sigma-1 receptor (sigma1 receptor,SigmaR1) and MT 3 receptors. Our previous work demonstrated that afobazole possess cytoprotective effect in the in vitro model of menadione genotoxicity (Woods et al. 1997) through interaction with MT 3 receptor (Kadnikov et al. 2014). Present study utilized previously described models to address the contribution of SigmaR1 to cytoprotective action of afobazole. The reduction in afobazole cytoprotective effect observed after preincubation of cell suspension with selective SigmaR1 antagonist BD-1047 revealed an important contribution of SigmaR1 in afobazole-mediated effect. We confirmed our observation using selective SigmaR1 agonist PRE-084. We conclude that pronounced cytoprotective effect of afobazole over PRE-084 is likely achieved by additive SigmaR1 and MT 3 mediated effects. PMID- 28097007 TI - Safety assessment in rats and dogs of Acoustic Cluster Therapy, a novel concept for ultrasound mediated, targeted drug delivery. AB - Acoustic Cluster Therapy (ACT) represents a novel concept for targeted drug delivery. Ultrasound is applied to activate intravenously administered free flowing clusters of microbubbles and microdroplets within the target pathology, depositing 20-30 MUm large bubbles in the microvasculature for 5-10 min. Further application of ultrasound induces biomechanical effects which increase vascular permeability and enhance localized extravasation of coadministered drugs. Herein we report investigations done to assess the preclinical safety of ACT, using doses up to 1 mL/kg (3 MUL perfluoromethyl-cyclopentane/kg). In dogs, half the animals were exposed to ultrasound activation in the heart for 1 min, no ultrasound was applied in the other half. Posttreatment observation time was 24 h. Clinical signs, ophthalmoscopy, clinical pathology, macro-, and microscopy were used as endpoints. No differences between groups with and without ultrasound activation were observed. Short-lasting leukopenia and thrombocytopenia, possibly secondary to a slight and short-lasting increase in plasma histamine and complement split products, were the only effects noted. In rats ACT was activated in the liver for 5 min. Histopathology and clinical chemistry parameters remained unchanged. Lastly, rats were treated with ACT activated in the heart and thereafter placed on a rotarod for evaluation of motor coordination. No differences were observed between animals treated with ACT and controls. In conclusion, ACT appeared safe at dose-levels up to 1 mL/kg and with activation either in the heart or the liver. These results, together with positive efficacy data upon coinjection with cytotoxic compounds encourage further preclinical safety studies with the objective of entering subsequent clinical trials. PMID- 28097008 TI - Preclinical findings predicting efficacy and side-effect profile of LY2940094, an antagonist of nociceptin receptors. AB - Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide whose receptor is designated ORL1 or nociceptin receptor (NOP). We utilized a potent, selective, and orally bioavailable antagonist with documented engagement with NOP receptors in vivo to assess antidepressant- and anxiolytic-related pharmacological effects of NOP receptor blockade along with measures of cognitive and motor impingement. LY2940094 ([2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4' piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol) displayed antidepressant-like behavioral effects in the forced-swim test in mice, an effect absent in NOP -/- mice. LY2940094 also augmented the behavioral effect of fluoxetine without changing target occupancies (NOP and serotonin reuptake transporter [SERT]). LY2940094 did not have effects under a differential reinforcement of low rate schedule. Although anxiolytic-like effects were not observed in some animal models (conditioned suppression, 4-plate test, novelty suppressed feeding), LY2940094 had effects like that of anxiolytic drugs in three assays: fear-conditioned freezing in mice, stress-induced increases in cerebellar cGMP in mice, and stress-induced hyperthermia in rats. These are the first reports of anxiolytic-like activity with a systemically viable NOP receptor antagonist. LY2940094 did not disrupt performance in either a 5-choice serial reaction time or delayed matching-to-position assay. LY2940094 was also not an activator or suppressor of locomotion in rodents nor did it induce failures of rotarod performance. These data suggest that LY2940094 has unique antidepressant- and anxiolytic-related pharmacological effects in rodents. Clinical proof of concept data on this molecule in depressed patients have been reported elsewhere. PMID- 28097010 TI - Corrigendum. AB - [This corrects the article DOI: 10.1002/prp2.248.]. PMID- 28097009 TI - Statin utilisation in a real-world setting: a retrospective analysis in relation to arterial and cardiovascular autonomic function. AB - Randomized trials suggest that statin treatment may lower blood pressure and influence cardiovascular autonomic function (CVAF), but the impact of duration of usage, discontinuation, and adherence to this therapy is unknown. We examined these issues with regard to blood pressure (BP)-related variables in a large, population-based study. Participants were 4942 adults (58% male; aged 50-84 years): 2179 on statin treatment and 2763 untreated. Days of utilization, adherence (proportion of days covered >=0.8), and discontinuation (non-use for >=30 days immediately prior to BP measurement) of three statins (atorvastatin, pravastatin, and simvastatin) over a period of up to 2 years was monitored retrospectively from electronic databases. Systolic BP (SBP), diastolic BP (DBP), augmentation index, excess pressure, reservoir pressure, and CVAF (pulse rate and BP variability) parameters were calculated from aortic pressure waveforms derived from suprasystolic brachial measurement. Days of statin treatment had inverse relationships with pulse rate variability parameters in cardiac arrhythmic participants (20-25% lower than in statin non-users) and with most arterial function parameters in everyone. For example, compared to untreated participants, those treated for >=659 days had 3.0 mmHg lower aortic SBP (P < 0.01). Discontinuation was associated with higher brachial DBP and aortic DBP (for both, beta = 2.0 mmHg, P = 0.008). Compared to non-adherent statin users, adherent users had lower levels of brachial SBP, brachial DBP, aortic DBP, aortic SBP, and peak reservoir pressure (beta = -1.4 to -2.6 mmHg). In conclusion, in a real world setting, statin-therapy duration, non-discontinuation and adherence associate inversely with BP variables and, in cardiac arrhythmias, CVAF parameters. PMID- 28097011 TI - A selective GPR40 (FFAR1) agonist LY2881835 provides immediate and durable glucose control in rodent models of type 2 diabetes. AB - LY2881835 is a selective, potent, and efficacious GPR40 agonist. The objective of the studies described here was to examine the pharmacological properties of LY2881835 in preclinical models of T2D. Significant increases in insulin secretion were detected when LY2881835 was tested in primary islets from WT mice but not in islets from GPR40 KO mice. Furthermore, LY2881835 potentiated glucose stimulated insulin secretion in normal lean mice. Acute administration of LY2881835 lowered glucose during OGTTs in WT mice but not in GPR40 KO mice. These findings demonstrate that LY2881835 induces GPR40-mediated activity ex vivo and in vivo. LY2881835 was administered orally at 10 mg/kg to diet-induced obese (DIO) mice (an early model of T2D due to insulin resistance) for 14 days. Statistically significant reductions in glucose were seen during OGTTs performed on days 1 and 15. When a study was done for 3 weeks in Zucker fa/fa rats, a rat model of insulin resistance, normalization of blood glucose levels equivalent to those seen in lean rats was observed. A similar study was performed in streptozotocin (STZ)-treated DIO mice to explore glucose control in a late model of T2D. In this model, pancreatic insulin content was reduced ~80% due to STZ treatment plus the mice were insulin resistant due to their high fat diet. Glucose AUCs were significantly reduced during OGTTs done on days 1, 7, and 14 compared to control mice. In conclusion, these results demonstrate that LY2881835 functions as a GPR40-specific insulin secretagogue mediating immediate and durable glucose control in rodent models of early- and late-stage T2D. PMID- 28097012 TI - Pharmacokinetics and pharmacodynamics of antibiotics in critically ill acute kidney injury patients. AB - Sepsis is the most common cause of death in critically ill patients and is associated with multiorgan failure, including acute kidney injury (AKI). This situation can require acute renal support and increase mortality. Therefore, it is essential to administer antimicrobials in doses that achieve adequate serum levels, avoiding both overdosing and drug toxicity as well as underdosing and the risk of antibiotic resistance and higher mortality. Currently, there are no validated guidelines on antibiotic dose adjustments in septic patients with AKI. The current recommendations were extrapolated from studies conducted in noncritical patients with end-stage chronic kidney disease receiving chronic renal replacement therapy. This study aimed to review and discuss the complexity of this issue, considering several factors related to drug metabolism, the characteristics of critically ill patients, the properties of antimicrobial drugs and dialysis methods. PMID- 28097013 TI - Randomised, double-blind, clinical investigation to compare orlistat 60 milligram and a customized polyglucosamine, two treatment methods for the management of overweight and obesity. AB - BACKGROUND: The efficacy of a non-prescription drug to support weight loss programs has yet to be compared. This clinical trial investigates the comparability of orlistat 60 milligram (mg) and polyglucosamine. METHODS: Sixty four overweight or obese subjects were included in a two-center double-blind study. One center was in Germany [center 1] and the other was in Italy [center 2]. The subjects (26 in center 1 and 38 in center 2) were recommended to follow a calorie deficit of about 2000 kilojoules/day and to increase their physical activity to 3 metabolic equivalent hours (MET h)/day. In both centers, subjects were randomized to receive polyglucosamine (2 tablets x 2) or orlistat (1 capsule x 3) for a period of 12 weeks. Weight loss was considered as a main variable together with the reduction of 5 per cent (%) of body weight (5R). Body Mass Index (BMI) and waist circumference (WC) were taken as secondary variables. RESULTS: A significant difference in weight loss between the two groups was shown, 6.7 +/- 3.14 kilogram (kg) in group polyglucosamine versus 4.8 +/- 2.24 kg in group orlistat (t test p < 0.05) respectively; BMI and WC reduction were also more consistent with polyglucosamine treatment than with orlistat treatment (t test p < 0.05). No significant difference was found in the number of subjects who achieved 5R (70% for polyglucosamine and 55% for orlistat group; chi square p > 0.05). The administration of polyglucosamine following energy restriction and increase in physical activity reduces body weight, BMI and WC more efficiently than orlistat. CONCLUSIONS: Even though both groups were instructed to adopt a calorie restricted diet together with increased physical activity an additional weight loss in the polyglucosamine group of 1.6 kilogram (kg) compared to the orlistat group (6.2 +/- 3.46 versus 4.6 +/- 2.36 kg) in both centers was seen despite the higher consumption of carbohydrates in Italy (center 2). A typical Italian diet is usually high in carbohydrate content whereas Germans tend to consume meals with higher fat content. This leads to the assumption that polyglucosamine limits both fat and carbohydrate absorption which would explain the comparable effective weight reduction in the Italian participants. TRIAL REGISTRATION: Trial registration at ClinicalTrials.gov NCT02529631, registered on Aug 19, 2015 retrospectively registered. PMID- 28097014 TI - Development and evaluation of a formula for predicting introduction of medication self-management in stroke patients in the Kaifukuki rehabilitation ward. AB - BACKGROUND: Medication self-management in stroke patients is important to prevent further progression of disease and incidence of side effects. The purpose of this study was to create a formula for predicting medication self-management introduction in stroke patients using functional independence measure items and patient data, including medication-related information. METHODS: This was a retrospective analysis of 104 patients (cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage) discharged from the Kaifukuki rehabilitation ward at Showa University Fujigaoka Rehabilitation Hospital from January to December 2012. Multivariate analysis was performed to develop a formula for predicting achievement of medication self-management. RESULTS: Of the 104 patients, 39 (37.5%) achieved medication self-management. In the logistic regression analysis, number of drugs, age, walk/wheelchair mobility FIM, and memory FIM were extracted as significant factors independently contributing to achievement of medication self-management (p < 0.05). The prediction formula was [4.404 - 0.229 * number of drugs at admission + 0.470 * walk/wheelchair mobility FIM at admission + 0.416 * memory FIM at admission - 0.112 * age]. CONCLUSIONS: In the future, this formula may be used as an index to predict success of medication self-management in stroke patients. PMID- 28097015 TI - Co-administration of dexamethasone increases severity and accelerates onset day of neutropenia in bladder cancer patients on methotrexate, vinblastine, adriamycin and cisplatin chemotherapy: a retrospective cohort study. AB - BACKGROUND: Bladder cancer patients receiving methotrexate, vinblastine, adriamycin and cisplatin (MVAC) chemotherapy are co-administered with dexamethasone as an anti-emetic. We examined whether or not dexamethasone affects the severity and onset day of MVAC-induced severe neutropenia. METHODS: This was a retrospective study of bladder cancer patients treated with MVAC chemotherapy with or without dexamethasone as an antiemetic at Kanazawa University Hospital during January 2005 - December 2009. Patients were categorized into three groups; no dexamethasone use (Dex (-)), dexamethasone on day 2 (Dex 1 day), and dexamethasone on days 2, 3 and 4 (Dex multiday). We evaluated the incidence of grade 3/4 neutropenia and the day of onset of first severe neutropenic episode during the first course of MVAC chemotherapy. Logistic regression was used to investigate whether co-administration of dexamethasone was a risk factor for severe neutropenia. RESULTS: Episodes of grade 3/4 neutropenia occurred in 3 out of 6 (50.0%), 11 out of 12 (91.7%) and 6 out of 6 (100%) patients in the Dex (-), Dex 1 day, and Dex multiday groups, respectively. The appearance day of first severe neutropenia in the Dex multiday group (13.2 +/- 1.0) was significantly accelerated compared to the Dex (-) group (17.7 +/- 2.1). Univariate logistic regression analysis revealed that dexamethasone is a risk factor for severe neutropenia (OR 17.0; 95%CI: 1.3-223.1). CONCLUSIONS: Co-administration of dexamethasone for anti-emesis brings forward the first appearance of neutropenia, and increases the severity of neutropenia, in bladder cancer patients receiving MVAC chemotherapy. PMID- 28097016 TI - Smoking treatment optimisation in pharmacies (STOP): a cluster randomised pilot trial of a training intervention. AB - BACKGROUND: UK government policy aims to strengthen the role of community pharmacies in health promotion. Thus, we conducted feasibility studies for an intervention to enhance delivery of the NHS Smoking Cessation Service. METHODS: The overall aims were to assess acceptability and feasibility of conducting the intervention in community pharmacies and piloting this with a cluster randomised trial. Specific objectives were (1) to estimate likely participation rates of pharmacies and stop smoking advisors, (2) to establish the potential impact of the training intervention on throughput and retention of smokers in smoking services, (3) to establish potential impact on smoking cessation outcomes, (4) to optimise logistics for conducting a cluster randomised trial in the next phase of the research programme and (5) to consider the feasibility of collecting pharmacy and service user data. In this cluster randomised parallel group pilot trial, 12 community pharmacies in East London were allocated to intervention or usual practice using simple randomisation (allocation ratio 2:1). Data were analysed descriptively. RESULTS: Twelve of 54 (22.2%, 95% CI 12.0% to 35.6%) pharmacies and 20 of 23 (87.0%, 95% CI 66.4% to 97.2%) advisors invited, agreed to participate. Over 5 months, 302 smokers in intervention pharmacies (mean per pharmacy 43.1, 95% CI: -4.3 to 90.5) and 319 in usual practice pharmacies (mean per pharmacy 79.8, 95% CI: 19.0 to 140.5) joined the service. 51 of 621 smokers (6.3% in intervention vs 10.0% in usual practice) consented to provide additional data on smoking cessation. 17 of 19 smokers that consented were retained at 4 weeks in intervention arm (89.5%, 95% CI: 66.9% to 98.7%) and 24 of 32 in usual practice (75.0%, 95% CI: 56.6% to 88.5%). 10 of 19 in the intervention arm (52.6%, 95% CI: 28.9% to 75.6%) stopped smoking compared to 7 of 32 in usual practice arm (21.9%, 95% CI: 9.3% to 40.0%). The pilot was useful in providing insights on how best to conduct the definitive trial and shortcomings of our present logistical arrangements, including feasibility of collecting pharmacy and service user data. CONCLUSIONS: Recruitment rates show that the main trial is feasible, and the results suggest that the intervention may improve retention and quit rates in smoking cessation services. We gained insights on how best to conduct the definitive trial which will proceed as planned. PMID- 28097017 TI - Study of myoblast differentiation using multi-dimensional scaffolds consisting of nano and micropatterns. AB - BACKGROUND: The topographical cue is major influence on skeletal muscle cell culture because the structure is highly organized and consists of long parallel bundles of multinucleated myotubes that are formed by differentiation and fusion of myoblast satellite cells. In this technical report, we fabricated a multiscale scaffold using electrospinning and poly (ethylene glycol) (PEG) hydrogel micropatterns to monitor the cell behaviors on nano- and micro-alignment combined scaffolds with different combinations of angles. RESULTS: We fabricated multiscale scaffolds that provide biocompatible and extracellular matrix (ECM) mimetic environments via electrospun nanofiber and PEG hydrogel micro patterning. MTT assays demonstrated an almost four-fold increase in the proliferation rate during the 7 days of cell culture for all of the experimental groups. Cell orientation and elongation were measured to confirm the myogenic potential. On the aligned fibrous scaffolds, more than 90% of the cells were dispersed +/- 20 degrees of the fiber orientation. To determine cell elongation, we monitored nuclei aspect ratios. On a random nanofiber, the cells demonstrated an aspect ratio of 1.33, but on perpendicular and parallel nanofibers, the aspect ratio was greater than 2. Myosin heavy chain (MHC) expression was significantly higher i) on parallel compared to random fibers, ii) the 100 MUm compared to the 200 MUm line pattern. We confirmed the disparate trends of myotube formation that can be provoked through multi-dimensional scaffolds. CONCLUSION: We studied more favorable environments that induce cell alignment and elongation for myogenesis by combining nano- and micro-scale patterns. The fabricated system can serve as a novel multi-dimensional platform to study in vitro cell behaviors. PMID- 28097018 TI - Effect of Vision Therapy on Accommodation in Myopic Chinese Children. AB - Introduction. We evaluated the effectiveness of office-based accommodative/vergence therapy (OBAVT) with home reinforcement to improve accommodative function in myopic children with poor accommodative response. Methods. This was a prospective unmasked pilot study. 14 Chinese myopic children aged 8 to 12 years with at least 1 D of lag of accommodation were enrolled. All subjects received 12 weeks of 60-minute office-based accommodative/vergence therapy (OBAVT) with home reinforcement. Primary outcome measure was the change in monocular lag of accommodation from baseline visit to 12-week visit measured by Shinnipon open-field autorefractor. Secondary outcome measures were the changes in accommodative amplitude and monocular accommodative facility. Results. All participants completed the study. The lag of accommodation at baseline visit was 1.29 +/- 0.21 D and it was reduced to 0.84 +/- 0.19 D at 12-week visit. This difference (-0.46 +/- 0.22 D; 95% confidence interval: -0.33 to -0.58 D) is statistically significant (p < 0.0001). OBAVT also increased the amplitude and facility by 3.66 +/- 3.36 D (p = 0.0013; 95% confidence interval: 1.72 to 5.60 D) and 10.9 +/- 4.8 cpm (p < 0.0001; 95% confidence interval: 8.1 to 13.6 cpm), respectively. Conclusion. Standardized 12 weeks of OBAVT with home reinforcement is able to significantly reduce monocular lag of accommodation and increase monocular accommodative amplitude and facility. A randomized clinical trial designed to investigate the effect of vision therapy on myopia progression is warranted. PMID- 28097019 TI - A Community-Based Assessment of Hypertension and Some Other Cardiovascular Disease Risk Factors in Ngaoundere, Cameroon. AB - Background and Objective. Cardiovascular diseases are primary causes of death worldwide with well documented risk factors whose varying impacts added to the complexity in CVD management dictate the need for region-specific studies. We aimed at investigating the interactions between CVD risk factors and hypertension in Ngaoundere. Methods. A cross-sectional survey was carried out from March to August 2014. Sociodemographic, fasting blood glucose, blood pressure, and anthropometric data were recorded. Statistical analyses were carried out using SAS software version 9.1. Results. 700 adults resident in Ngaoundere for at least two years consented and were included in the survey. Abdominal obesity, physical inactivity, and hypertension were the dominant risk factors recording 51.1%, 35.4%, and 20.4%, respectively. The prevalence of hyperglycaemia, tobacco consumption, obesity, and alcohol consumption was 5.6%, 8.3%, 9.6%, and 18.1%, respectively. Advanced age, hyperglycaemia, a divorced marital status, and alcohol consumption were independent determinants of high blood pressure. Conclusion. Physical inactivity, abdominal obesity, and hypertension were the most prevalent CVD risk factors, and the role of advanced age and hyperglycaemia in the occurrence of high blood pressure was reiterated. Health programs need to focus on effective screening, prevention, and control of CVDs in the Adamawa Region and Cameroon at large. PMID- 28097020 TI - Renal Urotensin II System Plays Roles in the Regulation of Blood Pressure in Dahl Salt-Resistant Rat. AB - Introduction. Dahl salt-resistant (SR) animal models are similar to peritoneal dialysis patients with fluid volumes overload with normal blood pressure in hemodynamic profiles. We will verify the roles of UII in the regulation of blood pressure in these animal models. Methodology. The Dahl salt-sensitive (SS) and SR rats and UII receptor gene knocked out (KO) mice were placed on a high-salt diet. Renal tissues were performed for the expression of UII in Dahl groups. Results. After high-salt diet for 6 weeks, the systolic blood pressure (SBP) in SR group was significantly lower, accompanied with higher urinary UII levels, higher 24 hour urinary sodium excretion, and higher urinary creatinine clearance in the SR rats in comparison to SS group. The expressions of UII and UT were both upregulated in the kidney tissues of SR group in comparison to SS group (P < 0.05). After high-salt diet for 8 weeks, the SBP of the KO group is significantly higher than that of the wild type group. Conclusion. We first demonstrate that renal UII system can play important roles in the regulation of blood pressure in Dahl SR rats which can be highly correlated to its effect on renal tubular sodium absorption. PMID- 28097021 TI - Downregulation of PGC-1alpha Prevents the Beneficial Effect of EET-Heme Oxygenase 1 on Mitochondrial Integrity and Associated Metabolic Function in Obese Mice. AB - Background/Objectives. Obesity and metabolic syndrome and associated adiposity are a systemic condition characterized by increased mitochondrial dysfunction, inflammation, and inhibition of antioxidant genes, HO-1, and EETs levels. We postulate that EETs attenuate adiposity by stimulating mitochondrial function and induction of HO-1 via activation of PGC-1alpha in adipose and hepatic tissue. Methods. Cultured murine adipocytes and mice fed a high fat (HF) diet were used to assess the functional relationship among EETs, PGC-1alpha, HO-1, and mitochondrial signaling using an EET-agonist (EET-A) and PGC-1alpha-deficient cells and mice using lentiviral PGC-1alpha(sh). Results. EET-A is a potent inducer of PGC-1alpha, HO-1, mitochondrial biogenesis (cytochrome oxidase subunits 1 and 4 and SIRT3), fusion proteins (Mfn 1/2 and OPA1) and fission proteins (DRP1 and FIS1) (p < 0.05), fasting glucose, BW, and blood pressure. These beneficial effects were prevented by administration of lenti-PGC 1alpha(sh). EET-A administration prevented HF diet induced mitochondrial and dysfunction in adipose tissue and restored VO2 effects that were abrogated in PGC 1alpha-deficient mice. Conclusion. EET is identified as an upstream positive regulator of PGC-1alpha that leads to increased HO-1, decreased BW and fasting blood glucose and increased insulin receptor phosphorylation, that is, increased insulin sensitivity and mitochondrial integrity, and possible use of EET-agonist for treatment of obesity and metabolic syndrome. PMID- 28097022 TI - From Blank Canvas to Masterwork: Creating a Professional Practice Model at a Magnet Hospital. AB - Objective. The purpose of this study was to engage registered nurses (RNs) in the creation of a Professional Practice Model (PPM). Background. PPMs are essential as the philosophical underpinnings for nursing practice. The study institution created a new PPM utilizing the voice of their RNs. Methods. Qualitative inquiry with focus groups was conducted to explore RNs values and beliefs about their professional practice. Constant-comparative analysis was used to code data and identify domains. Results. The 92 RN participants represented diverse roles and practice settings. The four domains identified were caring, knowing, navigating, and leading. Conclusions. Nurse leaders face the challenge of assisting nurses in articulating their practice using a common voice. In this study, nurses described their identity, their roles, and how they envisioned nursing should be practiced. The results align with the ANCC Magnet(r) Model, ANA standards, and important foundational and organization specific documents. PMID- 28097023 TI - Impact of the Implementation of New WHO Diagnostic Criteria for Gestational Diabetes Mellitus on Prevalence and Perinatal Outcomes: A Population-Based Study. AB - Objectives. To determine the impact of the implementation of new WHO diagnostic criteria for gestational diabetes mellitus (GDM) on prevalence, predictors, and perinatal outcomes in Croatian population. Methods. A cross-sectional study was performed using data from medical birth certificates collected in 2010 and 2014. Data collected include age, height, and weight before and at the end of pregnancy, while perinatal outcome was assessed by onset of labor, mode of delivery, and Apgar score. Results. A total of 81.748 deliveries and 83.198 newborns were analysed. Prevalence of GDM increased from 2.2% in 2010 to 4.7% in 2014. GDM was a significant predictor of low Apgar score (OR 1.656), labor induction (OR 2.068), and caesarean section (OR 1.567) in 2010, while in 2014 GD was predictive for labor induction (OR 1.715) and caesarean section (OR 1.458) only. Age was predictive for labor induction only in 2014 and for caesarean section in both years, while BMI before pregnancy was predictive for all observed perinatal outcomes in both years. Conclusions. Despite implementation of new guidelines, GDM remains burdened with increased risk of labor induction and caesarean section, but no longer with low Apgar score, while BMI remains an important predictor for all three perinatal outcomes. PMID- 28097025 TI - Epidural Catheter Migration in a Patient with Severe Spinal Stenosis. AB - Establishment of appropriate neuraxial catheter positioning is typically a straightforward procedural undertaking. It can, however, lead to deception of even the most experienced clinician and occur despite the most meticulous attention to detail. Written and verbal consent were obtained from the patient to prepare, discuss, and publish this case report; we describe the occurrence of what we believe was the intraoperative migration of an epidural catheter in the setting of significant tissue changes resulting from a previous spinal fusion. PMID- 28097024 TI - Synchronized Progression of Prestin Expression and Auditory Brainstem Response during Postnatal Development in Rats. AB - Prestin is the motor protein expressed in the cochlear outer hair cells (OHCs) of mammalian inner ear. The electromotility of OHCs driven by prestin is responsible for the cochlear amplification which is required for normal hearing in adult animals. Postnatal expression of prestin and activity of OHCs may contribute to the maturation of hearing in rodents. However, the temporal and spatial expression of prestin in cochlea during the development is not well characterized. In the present study, we examined the expression and function of prestin from the OHCs in apical, middle, and basal turns of the cochleae of postnatal rats. Prestin first appeared at postnatal day 6 (P6) for basal turn, P7 in middle turn, and P9 for apical turn of cochlea. The expression level increased progressively over the next few days and by P14 reached the mature level for all three segments. By comparison with the time course of the development of auditory brainstem response for different frequencies, our data reveal that prestin expression synchronized with the hearing development. The present study suggests that the onset time of hearing may require the expression of prestin and is determined by the mature function of OHCs. PMID- 28097026 TI - Excision of Mucocele Using Diode Laser in Lower Lip. AB - Mucoceles are nonneoplastic cystic lesions of major and minor salivary glands which result from the accumulation of mucus. These lesions are most commonly seen in children. Though usually these lesions can be treated by local surgical excision, in our case, to avoid intraoperative surgical complications like bleeding and edema and to enable better healing, excision was done using a diode laser in the wavelength of 940 nm. PMID- 28097027 TI - Regional Odontodysplasia with Generalised Enamel Defect. AB - Regional odontodysplasia (ROD) is uncommon developmental anomaly, which tends to be localised and involves the ectodermal and mesodermal tooth components. A five year-old female was referred to Department of Child Dental Health at the Leeds Dental Institute regarding malformed primary teeth. On examination 64, 74, and 72 had localised hypomineralized enamel defect. The crown of 55 was broken down with only the root remaining below the gingival level. 54 has a yellowish brown discolouration with rough irregular surface. The upper anterior teeth show mild enamel opacity. Radiographically, 55 and 54 had thin radioopaque contour, showing poor distinction between the enamel and dentine and the classic feature of a wide pulp chamber. 15, 16, and 17 were developmentally delayed and were displaying the characteristic "ghost appearance." Comprehensive dental care was done under local anaesthesia and it included extraction of the primary molars affected by ROD, stainless steel crown on 64, and caries prevention program. Fifteen months following the initial assessment the patient's oral condition remains stable and she is under regular follow-up at the department. Paediatric dentists should be aware of this anomaly as it involves both dentitions and usually requires multidisciplinary care. PMID- 28097028 TI - Hirayama Disease: A Rare Disease with Unusual Features. AB - Hirayama disease, also known as monomelic amyotrophy (MMA), is a rare cervical myelopathy that manifests itself as a self-limited, asymmetrical, slowly progressive atrophic weakness of the forearms and hands predominantly in young males. The forward displacement of the posterior dura of the lower cervical dural canal during neck flexion has been postulated to lead to lower cervical cord atrophy with asymmetric flattening. We report a case of Hirayama disease in a 25 year-old Indian man presenting with gradually progressive asymmetrical weakness and wasting of both hands and forearms along with unusual features of autonomic dysfunction and upper motor neuron lesion. PMID- 28097029 TI - Successful Closed Reduction of a Lateral Elbow Dislocation. AB - In this report, we present a case of lateral elbow dislocation treated with closed reduction. Lateral elbow dislocation is rare, and a closed reduction is reported with even less frequency. The reduction can be hindered by swelling and soft tissue interposition, and we describe the use of a nonoperative reduction technique performed under mild sedation with early physiotherapy to avoid joint stiffness. No additional complication was observed, and the normal range of elbow movement and function was obtained by early physiotherapy. PMID- 28097030 TI - A Foregut Duplication Cyst of the Stomach in Association with a Gastrointestinal Stromal Tumor and a Leiomyoma: A Case Report. AB - Objectives. Duplication cysts are rare benign lesions usually arising in the gastrointestinal tract. We report a case of a 52-year-old woman with an incidental gastric mass found on computed tomography during a pregraft workup for a familial cardiomyopathy. Methods. The mass was completely excised by partial gastrectomy and gross examination revealed a cystic lesion containing two small solid nodules in its wall. Microscopic evaluation and immunohistochemistry study were performed to further characterize the cyst and the nodules. A comprehensive literature review of the NCBI database PubMed was also carried out. Results. While the cyst was diagnosed as a foregut duplication cyst, the solid nodules proved to be concomitant gastrointestinal stromal tumor (GIST) and leiomyoma. Both morphologic features and immunohistochemistry stains, including CD117, smooth muscle actin, and CD34 supported the diagnosis. Clinical course was benign and the patient had no clinical evidence of relapse ten months following the surgical procedure. The literature search did not reveal any other published case of a foregut duplication cyst presenting in combination with a GIST and a leiomyoma. Conclusions. To our knowledge, this is the first case of a composite lesion comprising a foregut duplication cyst of the stomach along with a leiomyoma and a GIST. PMID- 28097031 TI - Diffuse Gallium-67 Accumulation in the Left Atrial Wall Detected Using SPECT/CT Fusion Images. AB - Gallium-67 scintigraphy is useful for detecting active inflammation. We show a 66 year-old female patient with atrial fibrillation and diffuse thickening of the left atrial wall due to acute myocarditis, who presented diffuse abnormal accumulation of gallium-67 in the left atrium on single photon emission computed tomography/computed tomography (SPECT/CT) fusion images. In the second gallium-67 scan 2 months after the first scintigraphy, the abnormal accumulation in the heart was no longer visible. Gallium-67 SPECT/CT images helped understanding the disease condition that temporary inflammation in the left atrium caused atrial fibrillation. PMID- 28097032 TI - Abdominal Pain in the Female Patient: A Case of Concurrent Acute Appendicitis and Ruptured Endometrioma. AB - General surgeons are often asked to evaluate acute abdominal pain which has an expanded differential diagnosis in women of childbearing age. Acute appendicitis accounts for many surgical emergencies as a common cause of nongynecologic pelvic pain. In some rare instances, acute appendicitis has been shown to occur simultaneously with a variety of gynecologic diseases. We report a case of concurrent acute appendicitis and ruptured ovarian endometrioma. PMID- 28097033 TI - A Case Report of Bilateral Adrenal Sarcomatoid Carcinoma. AB - Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy. Sarcomatoid adrenal carcinoma is even more aggressive type of ACC. Bilateral malignant adrenal tumors are extremely rare except for those that represent metastasis from an extra-adrenal organ. Here we report a 53-year-old woman who presented with abdominal pain and weight loss. Abdominal computed tomography revealed bilateral adrenal masses and a mass in her liver. Surgical specimens showed pleomorphic tumor cells with epithelial and spindle cell morphology and immunohistochemical staining was compatible with sarcomatoid carcinoma. Sarcomatoid adrenal carcinoma should be kept in mind during the management of bilateral adrenal masses. PMID- 28097034 TI - Blowhole Colostomy for Clostridium difficile-Associated Toxic Megacolon. AB - We present the case of a 58-year-old man who underwent urgent blowhole colostomy for toxic megacolon (TM) secondary to Clostridium difficile infection (CDI). This infection occurred under antibiotic coverage with amoxicillin-clavulanic acid, four days after laparoscopic sigmoidectomy in our hospital. Although prospective clinical research regarding the surgical management of TM is lacking, decompressive procedures like blowhole colostomy are reported to carry a high risk of postoperative morbidity and mortality and are widely regarded as obsolete. Subtotal or total colectomy with end ileostomy is currently considered the procedure of choice. After presenting our case, we discuss the literature available on the subject to argue that the scarce evidence on the optimal surgical treatment for TM is primarily based on TM associated with inflammatory bowel diseases (IBD) and that there might be a rationale for considering minimally invasive procedures like blowhole colostomy for CDI-associated TM. PMID- 28097035 TI - Flare-Up Diverticulitis in the Terminal Ileum in Short Interval after Conservative Therapy: Report of a Case. AB - Diverticulitis in the terminal ileum is uncommon. Past reports suggested that conservative therapy may be feasible to treat terminal ileum diverticulitis without perforation; however, there is no consensus on the therapeutic strategy for small bowel diverticulitis. We present a 37-year-old man who was referred to our hospital for sudden onset of abdominal pain and nausea. He was diagnosed with diverticulitis in the terminal ileum by computed tomography (CT). Tazobactam/piperacillin hydrate (18 g/day) was administered. The antibiotic treatment was maintained for 7 days, and the symptoms disappeared after the treatment. Thirty-eight days after antibiotic therapy, he noticed severe abdominal pain again. He was diagnosed with diverticulitis in terminal ileum which was flare-up of inflammation. He was given antibiotic therapy again. Nine days after antibiotic therapy, laparoscopy assisted right hemicolectomy and resection of 20 cm of terminal ileum were performed. Histopathology report confirmed multiple ileal diverticulitis. He was discharged from our hospital 12 days after the surgery. Colonoscopy was performed two months after the surgery and it revealed no finding suggesting inflammatory bowel disease. Surgical treatment should be taken into account as a potential treatment option to manage the diverticulitis in the terminal ileum even though it is not perforated. PMID- 28097036 TI - Urinary Obstruction of Transplanted Kidney Caused by Uterine Adenomyosis and 2 Year Posthysterectomy Psoas Abscess in Conjunction with Transplanted Kidney. AB - Urinary obstruction of the transplanted kidney caused by uterine leiomyoma is an extremely rare condition. To the best of our knowledge, there are only two reports in English literature. Psoas abscess secondary to renal graft pyelonephritis is also uncommon. We present this unusual case and its treatment course. A 43-year-old female presented with renal dysfunction. She was started on peritoneal dialysis from the age of 26 years and received kidney transplantation from her mother (living donor) at the age of 27 years. Computed tomography (CT) revealed right hydronephrosis and a large uterine mass compressing the distal ureter of the transplanted kidney. After a simple total hysterectomy, her renal function improved. Two years following the hysterectomy, she experienced painful urination, fever, right abdominal pain, and right lower limb pain. CT and T2 weighed magnetic resonance imaging of her pelvis demonstrated right psoas abscess in conjunction with transplanted kidney. She was treated with broad-spectrum antibiotics alone, which resulted in a good response. Urinary obstruction of the transplanted kidney caused by uterine leiomyoma is an extremely rare condition. Psoas abscess secondary to transplanted kidney pyelonephritis is also rare. We should keep these rare diseases in mind when treating such cases. PMID- 28097038 TI - Quantitative Analysis in Combination with Fingerprint Technology and Chemometric Analysis Applied for Evaluating Six Species of Wild Paris Using UHPLC-UV-MS. AB - A fast method was developed by ultra high performance liquid chromatography (UHPLC) for simultaneous determination of polyphyllin I and polyphyllin II. Chemometric analyses including principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) based on UHPLC chromatography were used to evaluate 38 batches from six species of Paris. Variable importance of projection was applied to select important peaks. Meanwhile, similarity analysis of UHPLC fingerprint was used to evaluate the sample of Paris polyphylla yunnanensis (PPY) and P. axialis (PA). The results indicated that the total content of saponins in PPY and PA collected from Baoshan City of Yunnan Province above 8.07 mg/g was stronger than that from other areas of the rest of species. PLS-DA showed better performance than PCA with regard to classifying the samples. Retention time during 20-27 minutes of UHPLC was screened as significant peak for distinguishing Paris of different species and original geography. All of PPY and PA with similarity value were more than 0.80. It indicated that quantitative analysis combined with chemometric and similarity analyses could evaluate the different species of Paris effectively and comprehensively. PMID- 28097039 TI - The Concept of Wind in Traditional Chinese Medicine. AB - The use of folk medicine has been widely embraced in many developed countries under the name of traditional, complementary and alternative medicine (TCAM) and is now becoming the mainstream in the UK and the rest of Europe, as well as in North America and Australia. Diversity, easy accessibility, broad continuity, relatively low cost, base levels of technological inputs, fewer side effects, and growing economic importance are some of the positive features of folk medicine. In this framework, a critical need exists to introduce the practice of folk medicine into public healthcare if the goal of reformed access to healthcare facilities is to be achieved. The amount of information available to public health practitioners about traditional medicine concepts and the utilization of that information are inadequate and pose many problems for the delivery of primary healthcare globally. Different societies have evolved various forms of indigenous perceptions that are captured under the broad concept of folk medicine, e.g., Persian, Chinese, Grecian, and African folk medicines, which explain the lack of universally accepted definitions of terms. Thus, the exchange of information on the diverse forms of folk medicine needs to be facilitated. Various concepts of Wind are found in books on traditional medicine, and many of those go beyond the boundaries established in old manuscripts and are not easily understood. This study intends to provide information, context, and guidance for the collection of all important information on the different concepts of Wind and for their simplification. This new vision for understanding earlier Chinese medicine will benefit public health specialists, traditional and complementary medicine practitioners, and those who are interested in historical medicine by providing a theoretical basis for the traditional medicines and the acupuncture that is used to eliminate Wind in order to treat various diseases. PMID- 28097037 TI - Nonmedical Use of Antihistaminergic Anxiolytics and Other Prescription Drugs among Persons with Opioid Dependence. AB - Background. Nonmedical prescription drug use (NMPDU) is an increasing problem, insufficiently studied among people in opioid maintenance treatment (OMT). This study investigates the prevalence of and factors associated with NMPDU for drug classes insufficiently described in opioid-dependent populations, including antihistaminergic anxiolytics and central stimulants. Methods. Study participants were recruited at two OMT clinics in Malmo, Sweden, between October 2014 and December 2015 (N = 73) and interviewed about their use, motivations for use, and acquisition and administration of prescription drugs. Results. The majority of the sample reported lifetime NMPDU: 60% for benzodiazepine-like hypnotics (z drugs), 21% for pregabalin, 19% for stimulants, and 12%-15% for antihistaminergic anxiolytics. Lower age was associated with nonmedical benzodiazepine use (Adjusted Odds Ratio = 0.89; 95% Confidence Interval = 0.82-0.97). Illicit acquisition was reported by 61% of people using z-drugs, 46% of people using pregabalin, and 38% of people using prescription stimulants, but only by 6-10% of people using antihistaminergic anxiolytics. Conclusions. The substantial nonmedical use of pregabalin, z-drugs, and prescription stimulants found in this study suggests that clinicians should prescribe these drugs with great caution. Nonmedical use of antihistaminergic anxiolytics does not seem to be a clinical issue among people in OMT in a Swedish setting, but we propose future studies to monitor their use. PMID- 28097040 TI - Effects of Inhalable Microparticles of Seonpyejeongcheon-Tang in an Asthma Mouse Model: - Effects of Microparticles of SJT. AB - OBJECTIVES: Allergic asthma generally presents with symptoms of wheezing, coughing, breathlessness, and airway inflammation. Seonpyejeongcheon-tang (SJT) consists of 12 herbs. It originated from Jeongcheon-tang (JT), also known as Ding chuan-tang, composed of 7 herbs, in She-sheng-zhong-miao-fang. This study aimed to evaluate the effects of local delivery of SJT via inhalable microparticles in an asthma mouse model. METHODS: Microparticles containing SJT were produced by spray-drying with leucine as an excipient. SJT microparticles were evaluated with respect to their aerodynamic properties, in vitro cytotoxicity, in vivo toxicity, and therapeutic effects on ovalbumin (OVA)-induced asthma in comparison with orally-administered SJT. RESULTS: SJT microparticles provided desirable aerodynamic properties (fine particle fraction of 48.9% +/- 6.4% and mass median aerodynamic diameter of 3.7 +/- 0.3 MUm). SJT microparticles did not show any cytotoxicity against RAW 264.7 macrophages at concentrations of 0.01 - 3 mg/mL. Inhaled SJT microparticles decreased the levels of IL-4, IL-5, IL-13, IL-17A, eotaxin and OVA-IgE in bronchoalveolar lavage fluid (BALF) in mice with OVA induced asthma. These effects were verified by histological evaluation of the levels of infiltration of inflammatory cells and collagen, destructions of alveoli and bronchioles, and hyperplasia of goblet cells in lung tissues. The effects of SJT microparticles in the asthma model were equivalent to those of orally-administered SJT extract. CONCLUSION: This study suggests that SJT is a promising agent for inhalation therapy for patients with asthma. PMID- 28097041 TI - Effect of Catechins, Green tea Extract and Methylxanthines in Combination with Gentamicin Against Staphylococcus aureus and Pseudomonas aeruginosa: - Combination therapy against resistant bacteria. AB - OBJECTIVES: Bacterial resistant infections have become a global health challenge and threaten the society's health. Thus, an urgent need exists to find ways to combat resistant pathogens. One promising approach to overcoming bacterial resistance is the use of herbal products. Green tea catechins, the major green tea polyphenols, show antimicrobial activity against resistant pathogens. The present study aimed to investigate the effect of catechins, green tea extract, and methylxanthines in combination with gentamicin against standard and clinical isolates of Staphylococcus aureus (S. aureus) and the standard strain of Pseudomonas aeruginosa (P. aeruginosa). METHODS: The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) values of different agents against bacterial strains were determined. The interactions of green tea extract, epigallate catechin, epigallocatechin gallate, two types of methylxanthine, caffeine, and theophylline with gentamicin were studied in vitro by using a checkerboard method and calculating the fraction inhibitory concentration index (FICI). RESULTS: The MICs of gentamicin against bacterial strains were in the range of 0.312 - 320 MUg/mL. The MIC values of both types of catechins were 62.5 - 250 MUg/ mL. Green tea extract showed insufficient antibacterial activity when used alone. Methylxanthines had no intrinsic inhibitory activity against any of the bacterial strains tested. When green tea extract and catechins were combined with gentamicin, the MIC values of gentamicin against the standard strains and a clinical isolate were reduced, and synergistic activities were observed (FICI < 1). A combination of caffeine with gentamicin did not alter the MIC values of gentamicin. CONCLUSION: The results of the present study revealed that green tea extract and catechins potentiated the antimicrobial action of gentamicin against some clinical isolates of S. aureus and standard P. aeruginosa strains. Therefore, combinations of gentamicin with these natural compounds might be a promising approach to combat microbial resistance. PMID- 28097043 TI - Single-Dose Intramuscular Toxicity of Mahwangcheonoh Pharmacopuncture in a Rat Model: - Toxicity of Mahwangcheonoh Pharmacopuncture in SD Rats. AB - OBJECTIVES: This study was conducted to analyze the single-dose toxicity and the safety of Mahwangcheonoh pharmacopuncture extracts. METHODS: Six-week-old Sprague Dawley rats were used for this study. Doses of Mahwangcheonoh pharmacopuncture extracts were set at 0.25 mL (low-dose), 0.5 mL (medium-dose) and 1.0 mL (high dose) for the test groups. A dose of 1.0 mL of normal saline solution was set for the control group. During 14 days, general symptoms, mortalities, and changes in hematology, blood biochemistry and histopathology of all rats were observed. RESULTS: No death was observed in all test groups. Any abnormal symptom was not observed in all of the groups. No significant changes in weight between the control group and the test groups were observed. In addition, no significant differences in the hematology signs, the blood biochemistry levels and the histopathological signs related to the Mahwangcheonoh pharmacopuncture extracts injection were observed. CONCLUSION: The findings of this study indicate that Mahwangcheonoh pharmacopuncture at doses of 1.0 mL or less may be consider safe and non-toxic. So, it can be used for therapy of obesity sufficiently. But further studies on this subject must be performed to confirm and verify this conclusion. PMID- 28097042 TI - The Relaxant Activity of Safranal in Isolated Rat Aortas is Mediated Predominantly via an Endothelium-Independent Mechanism: -Vasodilatory mechanism of safranal. AB - OBJECTIVES: Safranal is a pharmacologically active component of saffron and is responsible for the unique aroma of saffron. The hypotensive effect of safranal has been shown in previous studies. This study evaluates the mechanism for the vasodilatory effects induced by safranal on isolated rat aortas. METHODS: To study the vasodilatory effects of safranal (0.2, 0.4 and 0.8 mM), we contracted isolated rat thoracic aorta rings by using 10-6-M phenylephrine (PE) or 80-mM KCl. Dimethyl sulfoxide (DMSO) was used as a control. The vasodilatory effect of safranal was also evaluated both on intact and denuded endothelium aortic rings. Furthermore, to study the role of nitric oxide and prostacyclin in the relaxation induced by safranal, we incubated the aortic rings by using L-NAME (10-6 M) or indomethacin (10-5 M), each for 20 minutes. RESULTS: Safranal induced relaxation in endothelium-intact aortic rings precontracted by using PE or KCl in a concentration-dependent manner, with a maximum relaxation of more than 100%. The relaxant activity of safranal was not eliminated by incubating the aortic rings with L-NAME (EC50 = 0.29 vs. EC50 = 0.43) or with indomethacin (EC50 = 0.29 vs. EC50 = 0.35), where EC50 is the half maximal effective concentration. Also, the vasodilatory activity of safranal was not modified by endothelial removal. CONCLUSION: This study indicated that relaxant activity of safranal is mediated predominantly through an endothelium- independent mechanism. PMID- 28097044 TI - Study on the Single Dose Toxicity of ShinEumHur Pharmacopuncture Injected into the Muscles of Rats. AB - OBJECTIVES: This study was carried out to analyze the single dose toxicity of ShinEumHur (SEH) pharmacopuncture injected into the muscles of Sprague-Dawley rats. METHODS: The SEH pharmacopuncture was made in a clean room at the Korean Pharmacopuncture Institute (K-GMP). After the mixing process with sterile distilled water had been completed, the pH was controlled to between 7.0 and 7.5. All experiments were conducted at Biotoxtech, an institution authorized to perform non-clinical studies under the Good Laboratory Practice (GLP) regulations. Sprague-Dawley rats were chosen for the pilot study. Doses of SEH pharmacopuncture, 0.25, 0.5 and 1.0 mL, were administered to the experimental groups, and a dose of normal saline solution, 1.0 mL, was administered to the control group. We examined the survival rate, weights, clinical signs, mean hematology parameters, mean clinical chemistry, necropsy and histopathological findings. This study was conducted under the approval of the Institutional Animal Ethics Committee. RESULTS: No deaths or abnormalities occurred in any of the four groups. No significant changes in weight, hematological parameters or clinical chemistry between the control group and the experimental groups were observed. To check for abnormalities in organs and tissues, we used microscopy to examine representative histological sections of each specified organ; the results showed no significant differences in any of the organs or tissues. CONCLUSION: The above findings suggest that treatment with SEH pharmacopuncture is relatively safe. Further studies on this subject are needed to yield more concrete evidence. PMID- 28097045 TI - Homeopathy - A Safe, Much Less Expensive, Non-Invasive, Viable Alternative for the Treatment of Patients Suffering from Loss of Lumbar Lordosis. AB - OBJECTIVES: Loss of lumbar lordosis causing pain and curvature of the vertebral skeleton to one side is a relatively uncommon disease. To our knowledge, successful treatment of loss of lumbar lordosis with any potentized homeopathic drug diluted above Avogadro's limit (that is, above a potency of 12C) has not been documented so far. In this communication, we intend to document a relatively rare case of loss of lumbar lordosis with osteophytic lippings, disc desiccation, and protrusion, causing a narrowing of secondary spinal canal and a bilateral neural foramina, leading to vertebral column curvature with acute pain in an adolescent boy. METHODS: The patient had undergone treatment with orthodox Western medicines, but did not get any relief from, or cure of, the ailment; finally, surgery was recommended. The patient's family brought the patient to the Khuda-Bukhsh Homeopathic Benevolent Foundation where a charitable clinic is run every Friday with the active participation of four qualified homeopathic doctors. A holistic method of homeopathic treatment was adopted by taking into consideration all symptoms and selecting the proper remedy by consulting the homeopathic repertory, mainly of Kent. RESULTS: The symptoms were effectively treated with different potencies of a single homeopathic drug, Calcarea phos. X ray and magnetic resonance imaging (MRI) supported recovery and a change in the skeletal curvature that was accompanied by removal of pain and other acute symptoms of the ailment. CONCLUSION: Homeopathy can be a safe, much less expensive, non-invasive, and viable alternative for the treatment of such cases. PMID- 28097046 TI - Molecular classification of tissue from a transformed non-Hogkin's lymphoma case with unexpected long-time remission. AB - BACKGROUND: The concept of precision medicine in cancer includes individual molecular studies to predict clinical outcomes. In the present N = 1 case we retrospectively have analysed lymphoma tissue by exome sequencing and global gene expression in a patient with unexpected long-term remission following relaps. The goals were to phenotype the diagnostic and relapsed lymphoma tissue and evaluate its pattern. Furthermore, to identify mutations available for targeted therapy and expression of genes to predict specific drug effects by resistance gene signatures (REGS) for R-CHOP as described at http://www.hemaclass.org. We expected that such a study could generate therapeutic information and a frame for future individual evaluation of molecular resistance detected at clinical relapse. CASE PRESENTATION: The patient was diagnosed with a transformed high grade non-Hodgkin lymphoma stage III and treated with conventional R-CHOP [rituximab (R), cyclophosphamide (C), doxorubicin (H), vincristine (O) and prednisone (P)]. Unfortunately, she suffered from severe toxicity but recovered during the following 6 months' remission until biopsy-verified relapse. The patient refused second-line combination chemotherapy, but accepted 3 months' palliation with R and chlorambucil. Unexpectedly, she obtained continuous complete remission and is at present >9 years after primary diagnosis. Molecular studies and data evaluation by principal component analysis, mutation screening and copy number variations of the primary and relapsed tumor, identified a pattern of branched lymphoma evolution, most likely diverging from an in situ follicular lymphoma. Accordingly, the primary diagnosed transformed lymphoma was classified as a diffuse large B cell lymphoma (DLBCL) of the GCB/centrocytic subtype by "cell of origin BAGS" assignment and R sensitive and C, H, O and P resistant by "drug specific REGS" assignment. The relapsed DLBCL was classified as NC/memory subtype and R, C, H sensitive but O and P resistant. CONCLUSIONS: Thorough analysis of the tumor DNA and RNA documented a branched evolution of the two clinical diagnosed tFL, most likely transformed from an unknown in situ lymphoma. Classification of the malignant tissue for drug-specific resistance did not explain the unexpected long-term remission and potential cure. However, it is tempting to consider the anti-CD20 immunotherapy as the curative intervention in the two independent tumors of this case. PMID- 28097047 TI - Quantifying the ON and OFF Contributions to the Flash ERG with the Discrete Wavelet Transform. AB - PURPOSE: Discrete wavelet transform (DWT) analyses suggest that the 20- and 40-Hz components of the short-flash photopic electroretinogram (ERG) are closely related to the ON and OFF pathways, respectively. With the DWT, we examined how the ERG ON and OFF components are modulated by the stimulus intensity and/or duration. METHODS: Discrete wavelet transform descriptors (20, 40 Hz and 40:20-Hz ratio) were extracted from ERGs evoked to 25 combinations of flash durations (150 5 ms) and strengths (0.8-2.8 log cd.m-2). RESULTS: In ERGs evoked to the 150-ms stimulus (to separate the ON and OFF ERGs), the 40:20-Hz ratio of ON ERGs (mean +/- SD: 0.49 +/- 0.04) was significantly smaller (P < 0.05) than that of OFF ERGs (1.71 +/- 0.18) owing to a significantly (P < 0.05) higher contribution of the 20 and 40 Hz components to the ON and OFF ERGs, respectively. With brighter stimuli, the ON and OFF components increased similarly (P < 0.05). While progressively shorter flashes had no impact (P > 0.05) on the ON component, it exponentially enhanced (P < 0.05) the OFF component. CONCLUSIONS: Discrete wavelet transform allows for an accurate determination of ON and OFF retinal pathways even in ERGs evoked to a short flash. To our knowledge, the significant OFF facilitatory effect evidenced with shorter stimuli has not previously been reported. TRANSLATIONAL RELEVANCE: The DWT approach should offer a rapid, easy, and reproducible approach to retrospectively and prospectively evaluate the function of the retinal ON and OFF pathways using the standard (short-flash duration) clinical ERG stimulus. PMID- 28097048 TI - Effects of grazing intensity and the use of veterinary medical products on dung beetle biodiversity in the sub-mountainous landscape of Central Italy. AB - Grazing extensification and intensification are among the main problems affecting European grasslands. We analyze the impact of grazing intensity (low and moderate) and the use of veterinary medical products (VMPs) on the dung beetle community in the province of Pesaro-Urbino (Italy). Grazing intensity is a key factor in explaining the diversity of dung beetles. In the case of the alpha diversity component, sites with a low level of grazing activity-related in a previous step to the subsequent abandonment of traditional farming-is characterized by a loss of species richness (q = 0) and a reduction in alpha diversity at the levels q = 1 and q = 2. In the case of beta diversity, sites with a different grazing intensity show remarkable differences in terms of the composition of their species assemblages. The use of VMPs is another important factor in explaining changes in dung beetle diversity. In sites with a traditional use of VMPs, a significant loss of species richness and biomass is observed, as is a notable effect on beta diversity. In addition, the absence of indicator species in sites with a historical use of VMPs corroborates the hypothesis that these substances have a ubiquitous effect on dung beetles. However, the interaction between grazing activity and VMPs when it comes to explaining changes in dung beetle diversity is less significant (or is not significant) than the main effects (each factor separately) for alpha diversity, biomass and species composition. This may be explained if we consider that both factors affect the various species differently. In other words, the reduction in dung availability affects several larger species more than it does very small species, although this does not imply that the former are more susceptible to injury caused by the ingestion of dung contaminated with VMPs. Finally, in order to prevent negative consequences for dung beetle diversity, we propose the maintenance of a moderate grazing intensity and the rational use of VMPs. It is our view that organic management can prevent excessive extensification while providing an economic stimulus to the sector. Simultaneously, it can also prevent the abuse of VMPs. PMID- 28097049 TI - Sharing refuges on arid islands: ecological and social influence on aggregation behaviour of wall geckos. AB - BACKGROUND: The extent of social behaviour among reptiles is underappreciated. Two types of aggregations are recognized in lizards: ecological and social, i.e., related to the attraction to a site or to animals of the same species, respectively. As most lizards are territorial, aggregations increase the probability of aggressive interactions among individuals, a density-dependent behaviour. METHODS: After some spurious observations of aggregation behaviour in the endemic Cabo Verde nocturnal gecko Tarentola substituta, we conducted a field based study in order to thoroughly characterize it. We sampled 48 transects and 40 10 * 10 m quadrats on Sao Vicente Island to describe the incidence, size and composition of aggregations and to study the effect of gecko and refuge density, plus refuge quality, on refuge sharing. We hypothesize that when density of animals and scarcity of high-quality refuges is higher, lizards have increased probability of aggregating. We also predict a consistent pattern of size and composition of groups (male-female pairs, only one adult male per group) throughout the year if there is a selected behaviour to avoid agonistic interactions, and low thermal advantage to aggregating individuals. RESULTS: We present one of the first evidences of aggregation for Phyllodactylidae geckos. We found that T. substituta forms aggregations around 30-40% of the time, and that refuges are almost always shared by a female-male pair, sometimes with a juvenile, probably a mechanism to avoid aggressive interactions. We also observed that refuge sharing is dependent on refuge quality, as medium-large (thermally more stable and positively selected) rocks are shared much more frequently than small ones, but independent of adult sizes. Refuge sharing is also directly related to the density of geckos and inversely related to the density of high quality refuges. We found no relation between body temperatures of geckos and refuge sharing when controlling the effect of rock/air temperature, suggesting that huddling does not improve thermoregulation. DISCUSSION: Our results suggest that in this harsh environment (rocks reach 46 degrees C) aggregation incidence is mainly driven by an ecological factor (scarcity of high-quality refuges) and its intersexual composition by social factors (avoidance of agonistic interactions by males, and possible increased reproductive success of the pair). This study sheds some light on the little explored gecko aggregation behaviour and other studies should follow. PMID- 28097050 TI - Microbial communities mediating algal detritus turnover under anaerobic conditions. AB - BACKGROUND: Algae encompass a wide array of photosynthetic organisms that are ubiquitously distributed in aquatic and terrestrial habitats. Algal species often bloom in aquatic ecosystems, providing a significant autochthonous carbon input to the deeper anoxic layers in stratified water bodies. In addition, various algal species have been touted as promising candidates for anaerobic biogas production from biomass. Surprisingly, in spite of its ecological and economic relevance, the microbial community involved in algal detritus turnover under anaerobic conditions remains largely unexplored. RESULTS: Here, we characterized the microbial communities mediating the degradation of Chlorella vulgaris (Chlorophyta), Chara sp. strain IWP1 (Charophyceae), and kelp Ascophyllum nodosum (phylum Phaeophyceae), using sediments from an anaerobic spring (Zodlteone spring, OK; ZDT), sludge from a secondary digester in a local wastewater treatment plant (Stillwater, OK; WWT), and deeper anoxic layers from a seasonally stratified lake (Grand Lake O' the Cherokees, OK; GL) as inoculum sources. Within all enrichments, the majority of algal biomass was metabolized within 13-16 weeks, and the process was accompanied by an increase in cell numbers and a decrease in community diversity. Community surveys based on the V4 region of the 16S rRNA gene identified different lineages belonging to the phyla Bacteroidetes, Proteobacteria (alpha, delta, gamma, and epsilon classes), Spirochaetes, and Firmicutes that were selectively abundant under various substrate and inoculum conditions. Within all kelp enrichments, the microbial communities structures at the conclusion of the experiment were highly similar regardless of the enrichment source, and were dominated by the genus Clostridium, or family Veillonellaceae within the Firmicutes. In all other enrichments the final microbial community was dependent on the inoculum source, rather than the type of algae utilized as substrate. Lineages enriched included the uncultured groups VadinBC27 and WCHB1 69 within the Bacteroidetes, genus Spirochaeta and the uncultured group SHA-4 within Spirochaetes, Ruminococcaceae, Lachnospiraceae, Yongiibacter, Geosporobacter, and Acidaminobacter within the Firmicutes, and genera Kluyvera, Pantoea, Edwardsiella and Aeromonas, and Buttiauxella within the Gamma Proteobaceteria order Enterobacteriales. CONCLUSIONS: Our results represent the first systematic survey of microbial communities mediating turnover of algal biomass under anaerobic conditions, and highlights the diversity of lineages putatively involved in the degradation process. PMID- 28097051 TI - CTLA-4 polymorphisms associate with breast cancer susceptibility in Asians: a meta-analysis. AB - Previous studies have investigated the association between cytotoxic T-lymphocyte antigen-4 (CTLA-4) polymorphisms and breast cancer susceptibility, but the results remained inconsistent. Therefore, we evaluated the relationship between four common CTLA-4 polymorphisms and breast cancer risk by a meta-analysis, aiming to derive a comprehensive and precise conclusion. We searched EMBASE, Pubmed, Web of Science, CNKI, and Wanfang databases until July 18th, 2016. Finally, ten eligible studies involving 4,544 breast cancer patients and 4,515 cancer-free controls were included; all these studies were from Asia. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the breast cancer risk in five genetic models. The results indicated that the CTLA-4 +49A>G (rs231775) polymorphism had a significant association with decreased breast cancer risk in allelic, homozygous, dominant and recessive models. Also, the +6230G>A (rs3087243) polymorphism reduced breast cancer risk especially in the Chinese population under homozygous and recessive models. In contrast, the 1661A>G (rs4553808) polymorphism increased breast cancer risk in allelic, heterozygous and dominant models, whereas -1722 T>C (rs733618) did not relate to breast cancer risk. In conclusion, CTLA-4 polymorphisms significantly associate with breast cancer susceptibility in Asian populations, and different gene loci may have different effects on breast cancer development. Further large-scale studies including multi-racial populations are required to confirm our findings. PMID- 28097052 TI - Population dynamics of epidemic and endemic states of drug-resistance emergence in infectious diseases. AB - The emergence and spread of drug-resistance during treatment of many infectious diseases continue to degrade our ability to control and mitigate infection outcomes using therapeutic measures. While the coverage and efficacy of treatment remain key factors in the population dynamics of resistance, the timing for the start of the treatment in infectious individuals can significantly influence such dynamics. We developed a between-host disease transmission model to investigate the short-term (epidemic) and long-term (endemic) states of infections caused by two competing pathogen subtypes, namely the wild-type and resistant-type, when the probability of developing resistance is a function of delay in start of the treatment. We characterize the behaviour of disease equilibria and obtain a condition to minimize the fraction of population infectious at the endemic state in terms of probability of developing resistance and its transmission fitness. For the short-term epidemic dynamics, we illustrate that depending on the likelihood of resistance development at the time of treatment initiation, the same epidemic size may be achieved with different delays in start of the treatment, which may correspond to significantly different treatment coverages. Our results demonstrate that early initiation of treatment may not necessarily be the optimal strategy for curtailing the incidence of resistance or the overall disease burden. The risk of developing drug-resistance in-host remains an important factor in the management of resistance in the population. PMID- 28097053 TI - In vitro effect of direct current electrical stimulation on rat mesenchymal stem cells. AB - BACKGROUND: Electrical stimulation (ES) has been successfully used to treat bone defects clinically. Recently, both cellular and molecular approaches have demonstrated that ES can change cell behavior such as migration, proliferation and differentiation. METHODS: In the present study we exposed rat bone marrow- (BM-) and adipose tissue- (AT-) derived mesenchymal stem cells (MSCs) to direct current electrical stimulation (DC ES) and assessed temporal changes in osteogenic differentiation. We applied 100 mV/mm of DC ES for 1 h per day for three, seven and 14 days to cells cultivated in osteogenic differentiation medium and assessed viability and calcium deposition at the different time points. In addition, expression of osteogenic genes, Runx2, Osteopontin, and Col1A2 was assessed in BM- and AT-derived MSCs at the different time points. RESULTS: Results showed that ES changed osteogenic gene expression patterns in both BM- and AT-MSCs, and these changes differed between the two groups. In BM-MSCs, ES caused a significant increase in mRNA levels of Runx2, Osteopontin and Col1A2 at day 7, while in AT-MSCs, the increase in Runx2 and Osteopontin expression were observed after 14 days of ES. DISCUSSION: This study shows that rat bone marrow- and adipose tissue-derived stem cells react differently to electrical stimuli, an observation that could be important for application of electrical stimulation in tissue engineering. PMID- 28097054 TI - Hydrogel scaffolds promote neural gene expression and structural reorganization in human astrocyte cultures. AB - Biomaterial scaffolds have the potential to enhance neuronal development and regeneration. Understanding the genetic responses of astrocytes and neurons to biomaterials could facilitate the development of synthetic environments that enable the specification of neural tissue organization with engineered scaffolds. In this study, we used high throughput transcriptomic and imaging methods to determine the impact of a hydrogel, PuraMatrixTM, on human glial cells in vitro. Parallel studies were undertaken with cells grown in a monolayer environment on tissue culture polystyrene. When the Normal Human Astrocyte (NHA) cell line is grown in a hydrogel matrix environment, the glial cells adopt a structural organization that resembles that of neuronal-glial cocultures, where neurons form clusters that are distinct from the surrounding glia. Statistical analysis of next generation RNA sequencing data uncovered a set of genes that are differentially expressed in the monolayer and matrix hydrogel environments. Functional analysis demonstrated that hydrogel-upregulated genes can be grouped into three broad categories: neuronal differentiation and/or neural plasticity, response to neural insult, and sensory perception. Our results demonstrate that hydrogel biomaterials have the potential to transform human glial cell identity, and may have applications in the repair of damaged brain tissue. PMID- 28097055 TI - Comprehensive transcriptome analysis provides new insights into nutritional strategies and phylogenetic relationships of chrysophytes. AB - BACKGROUND: Chrysophytes are protist model species in ecology and ecophysiology and important grazers of bacteria-sized microorganisms and primary producers. However, they have not yet been investigated in detail at the molecular level, and no genomic and only little transcriptomic information is available. Chrysophytes exhibit different trophic modes: while phototrophic chrysophytes perform only photosynthesis, mixotrophs can gain carbon from bacterial food as well as from photosynthesis, and heterotrophs solely feed on bacteria-sized microorganisms. Recent phylogenies and megasystematics demonstrate an immense complexity of eukaryotic diversity with numerous transitions between phototrophic and heterotrophic organisms. The question we aim to answer is how the diverse nutritional strategies, accompanied or brought about by a reduction of the plasmid and size reduction in heterotrophic strains, affect physiology and molecular processes. RESULTS: We sequenced the mRNA of 18 chrysophyte strains on the Illumina HiSeq platform and analysed the transcriptomes to determine relations between the trophic mode (mixotrophic vs. heterotrophic) and gene expression. We observed an enrichment of genes for photosynthesis, porphyrin and chlorophyll metabolism for phototrophic and mixotrophic strains that can perform photosynthesis. Genes involved in nutrient absorption, environmental information processing and various transporters (e.g., monosaccharide, peptide, lipid transporters) were present or highly expressed only in heterotrophic strains that have to sense, digest and absorb bacterial food. We furthermore present a transcriptome-based alignment-free phylogeny construction approach using transcripts assembled from short reads to determine the evolutionary relationships between the strains and the possible influence of nutritional strategies on the reconstructed phylogeny. We discuss the resulting phylogenies in comparison to those from established approaches based on ribosomal RNA and orthologous genes. Finally, we make functionally annotated reference transcriptomes of each strain available to the community, significantly enhancing publicly available data on Chrysophyceae. CONCLUSIONS: Our study is the first comprehensive transcriptomic characterisation of a diverse set of Chrysophyceaen strains. In addition, we showcase the possibility of inferring phylogenies from assembled transcriptomes using an alignment-free approach. The raw and functionally annotated data we provide will prove beneficial for further examination of the diversity within this taxon. Our molecular characterisation of different trophic modes presents a first such example. PMID- 28097056 TI - Rhea: a transparent and modular R pipeline for microbial profiling based on 16S rRNA gene amplicons. AB - The importance of 16S rRNA gene amplicon profiles for understanding the influence of microbes in a variety of environments coupled with the steep reduction in sequencing costs led to a surge of microbial sequencing projects. The expanding crowd of scientists and clinicians wanting to make use of sequencing datasets can choose among a range of multipurpose software platforms, the use of which can be intimidating for non-expert users. Among available pipeline options for high throughput 16S rRNA gene analysis, the R programming language and software environment for statistical computing stands out for its power and increased flexibility, and the possibility to adhere to most recent best practices and to adjust to individual project needs. Here we present the Rhea pipeline, a set of R scripts that encode a series of well-documented choices for the downstream analysis of Operational Taxonomic Units (OTUs) tables, including normalization steps, alpha- and beta-diversity analysis, taxonomic composition, statistical comparisons, and calculation of correlations. Rhea is primarily a straightforward starting point for beginners, but can also be a framework for advanced users who can modify and expand the tool. As the community standards evolve, Rhea will adapt to always represent the current state-of-the-art in microbial profiles analysis in the clear and comprehensive way allowed by the R language. Rhea scripts and documentation are freely available at https://lagkouvardos.github.io/Rhea. PMID- 28097057 TI - A gene expression study of dorso-ventrally restricted pigment pattern in adult fins of Neolamprologus meeli, an African cichlid species. AB - Fish color patterns are among the most diverse phenotypic traits found in the animal kingdom. Understanding the molecular and cellular mechanisms that control in chromatophore distribution and pigmentation underlying this diversity is a major goal in developmental and evolutionary biology, which has predominantly been pursued in the zebrafish model system. Here, we apply results from zebrafish work to study a naturally occurring color pattern phenotype in the fins of an African cichlid species from Lake Tanganyika. The cichlid fish Neolamprologus meeli displays a distinct dorsal color pattern, with black and white stripes along the edges of the dorsal fin and of the dorsal half of the caudal fin, corresponding with differences in melanophore density. To elucidate the molecular mechanisms controlling the differences in dorsal and ventral color patterning in the fins, we quantitatively assessed the expression of 15 candidate target genes involved in adult zebrafish pigmentation and stripe formation. For reference gene validation, we screened the expression stability of seven widely expressed genes across the investigated tissue samples and identified tbp as appropriate reference. Relative expression levels of the candidate target genes were compared between the dorsal, striped fin regions and the corresponding uniform, grey colored regions in the anal and ventral caudal fin. Dorso-ventral expression differences, with elevated levels in both white and black stripes, were observed in two genes, the melanosome protein coding gene pmel and in igsf11, which affects melanophore adhesion, migration and survival. Next, we predicted potential shared upstream regulators of pmel and igsf11. Testing the expression patterns of six predicted transcriptions factors revealed dorso-ventral expression difference of irf1 and significant, negative expression correlation of irf1 with both pmel and igsf11. Based on these results, we propose pmel, igsf11 and irf1 as likely components of the genetic mechanism controlling distinct dorso ventral color patterns in N. meeli fins. PMID- 28097058 TI - Determining virus-host interactions and glycerol metabolism profiles in geographically diverse solar salterns with metagenomics. AB - Solar salterns are excellent model ecosystems for studying virus-microbial interactions because of their low microbial diversity, environmental stability, and high viral density. By using the power of CRISPR spacers to link viruses to their prokaryotic hosts, we explored virus-host interactions in geographically diverse salterns. Using taxonomic profiling, we identified hosts such as archaeal Haloquadratum, Halorubrum, and Haloarcula and bacterial Salinibacter, and we found that community composition related to not only salinity but also local environmental dynamics. Characterizing glycerol metabolism genes in these metagenomes suggested Halorubrum and Haloquadratum possess most dihydroxyacetone kinase genes while Salinibacter possesses most glycerol-3-phosphate dehydrogenase genes. Using two different methods, we detected fewer CRISPR spacers in Haloquadratum-dominated compared with Halobacteriaceae-dominated saltern metagenomes. After CRISPR detection, spacers were aligned against haloviral genomes to map virus to host. While most alignments for each saltern metagenome linked viruses to Haloquadratum walsbyi, there were also alignments indicating interactions with the low abundance taxa Haloarcula and Haloferax. Further examination of the dinucleotide and trinucleotide usage differences between paired viruses and their hosts confirmed viruses and hosts had similar nucleotide usage signatures. Detection of cas genes in the salterns supported the possibility of CRISPR activity. Taken together, our studies suggest similar virus host interactions exist in different solar salterns and that the glycerol metabolism gene dihydroxyacetone kinase is associated with Haloquadratum and Halorubrum. PMID- 28097059 TI - The complete chloroplast genome sequence of an endemic monotypic genus Hagenia (Rosaceae): structural comparative analysis, gene content and microsatellite detection. AB - Hagenia is an endangered monotypic genus endemic to the topical mountains of Africa. The only species, Hagenia abyssinica (Bruce) J.F. Gmel, is an important medicinal plant producing bioactive compounds that have been traditionally used by African communities as a remedy for gastrointestinal ailments in both humans and animals. Complete chloroplast genomes have been applied in resolving phylogenetic relationships within plant families. We employed high-throughput sequencing technologies to determine the complete chloroplast genome sequence of H. abyssinica. The genome is a circular molecule of 154,961 base pairs (bp), with a pair of Inverted Repeats (IR) 25,971 bp each, separated by two single copies; a large (LSC, 84,320 bp) and a small single copy (SSC, 18,696). H. abyssinica's chloroplast genome has a 37.1% GC content and encodes 112 unique genes, 78 of which code for proteins, 30 are tRNA genes and four are rRNA genes. A comparative analysis with twenty other species, sequenced to-date from the family Rosaceae, revealed similarities in structural organization, gene content and arrangement. The observed size differences are attributed to the contraction/expansion of the inverted repeats. The translational initiation factor gene (infA) which had been previously reported in other chloroplast genomes was conspicuously missing in H. abyssinica. A total of 172 microsatellites and 49 large repeat sequences were detected in the chloroplast genome. A Maximum Likelihood analyses of 71 protein coding genes placed Hagenia in Rosoideae. The availability of a complete chloroplast genome, the first in the Sanguisorbeae tribe, is beneficial for further molecular studies on taxonomic and phylogenomic resolution within the Rosaceae family. PMID- 28097060 TI - Why choose Random Forest to predict rare species distribution with few samples in large undersampled areas? Three Asian crane species models provide supporting evidence. AB - Species distribution models (SDMs) have become an essential tool in ecology, biogeography, evolution and, more recently, in conservation biology. How to generalize species distributions in large undersampled areas, especially with few samples, is a fundamental issue of SDMs. In order to explore this issue, we used the best available presence records for the Hooded Crane (Grus monacha, n = 33), White-naped Crane (Grus vipio, n = 40), and Black-necked Crane (Grus nigricollis, n = 75) in China as three case studies, employing four powerful and commonly used machine learning algorithms to map the breeding distributions of the three species: TreeNet (Stochastic Gradient Boosting, Boosted Regression Tree Model), Random Forest, CART (Classification and Regression Tree) and Maxent (Maximum Entropy Models). In addition, we developed an ensemble forecast by averaging predicted probability of the above four models results. Commonly used model performance metrics (Area under ROC (AUC) and true skill statistic (TSS)) were employed to evaluate model accuracy. The latest satellite tracking data and compiled literature data were used as two independent testing datasets to confront model predictions. We found Random Forest demonstrated the best performance for the most assessment method, provided a better model fit to the testing data, and achieved better species range maps for each crane species in undersampled areas. Random Forest has been generally available for more than 20 years and has been known to perform extremely well in ecological predictions. However, while increasingly on the rise, its potential is still widely underused in conservation, (spatial) ecological applications and for inference. Our results show that it informs ecological and biogeographical theories as well as being suitable for conservation applications, specifically when the study area is undersampled. This method helps to save model-selection time and effort, and allows robust and rapid assessments and decisions for efficient conservation. PMID- 28097061 TI - Contrasting molecular and morphological evidence for the identification of an anomalous Buteo: a cautionary tale for hybrid diagnosis. AB - An adult Buteo was found dead as a road-kill south of Sacramento, California, and was thought to represent the first state record of the eastern Red-shouldered Hawk (B. lineatus lineatus;). It is now a specimen in the Museum of Wildlife and Fisheries Biology (WFB 4816) at the University of California, Davis. We examined this specimen and found that many of its plumage characters differed from all other adult Red-shouldered Hawks examined, including nominate adults. Plumage markings and measurements were intermediate between Red-tailed Hawk (Buteo jamaicensis, ssp calurus) and Red-shouldered Hawk (ssp elegans), leading us to hypothesize that the bird was a hybrid. However, mtDNA sequences and nuDNA microsatellites proved definitively that the bird was a Red-shouldered Hawk, most likely of eastern origin. This case illustrates that apparent hybrids or apparent vagrants could be individuals with anomalous phenotypes caused by rare genetic variation or novel epigenetic effects. PMID- 28097062 TI - Diversity and distribution of the Caddisflies (Insecta: Trichoptera) of Ecuador. AB - BACKGROUND: Aquatic insects and other freshwater animals are some of the most threatened forms of life on Earth. Caddisflies (Trichoptera) are highly biodiverse in the Neotropics and occupy a wide variety of freshwater habitats. In Andean countries, including Ecuador, knowledge of the aquatic biota is limited, and there is a great need for baseline data on the species found in these countries. Here we present the first list of Trichoptera known from Ecuador, a country that harbors two global biodiversity "hotspots." METHODS: We conducted a literature review of species previously reported from Ecuador and supplemented these data with material we collected during five recent field inventories from about 40 localities spanning both hotspots. Using species presence data for each Ecuadorian province, we calculated the CHAO 2 species estimator to obtain the minimum species richness for the country. RESULTS: We recorded 310 species, including 48 new records from our own field inventories for the country. CHAO 2 calculations showed that only 54% of the species have been found. Hydroptilidae and Hydropsychidae were the most species rich families. We report the family Xiphocentronidae for the first time from Ecuador as well as several new records of genera from different families. DISCUSSION: As in the neighboring Andean countries of Colombia and Peru, it is common to find undescribed species of caddisflies. There are vast areas of Ecuador and the northern Andes that are completely unexplored, and we expect that hundreds of new species are yet to be discovered. PMID- 28097063 TI - Interferon-gamma responses to Plasmodium falciparum vaccine candidate antigens decrease in the absence of malaria transmission. AB - BACKGROUND: Malaria elimination campaigns are planned or active in many countries. The effects of malaria elimination on immune responses such as antigen specific IFN- gamma responses are not well characterized. METHODS: IFN- gamma responses to the P. falciparum antigens circumsporozoite protein, liver stage antigen-1, thrombospondin-related adhesive protein, apical membrane antigen-1, MB2, and merozoite surface protein-1 were tested by ELISA in 243 individuals in highland Kenya in April 2008, October 2008, and April 2009, after a one-year period of interrupted malaria transmission from April 2007 to March 2008. RESULTS: While one individual (0.4%) tested positive for P. falciparum by PCR inOctober 2008 and another two (0.9%) tested positive in April 2009, no clinical malaria cases were detected during weekly visits. Levels of IFN-gamma to all antigens decreased significantly from April 2008 to April 2009 (all P < 0.001). DISCUSSION: Naturally acquired IFN- gamma responses to P. falciparum antigensare short-lived in the absence of repeated P. falciparum infection. Even short periods of malaria interruption may significantly decrease IFN-gamma responses to P. falciparum antigens. PMID- 28097064 TI - Phalangeal joints kinematics during ostrich (Struthio camelus) locomotion. AB - The ostrich is a highly cursorial bipedal land animal with a permanently elevated metatarsophalangeal joint supported by only two toes. Although locomotor kinematics in walking and running ostriches have been examined, these studies have been largely limited to above the metatarsophalangeal joint. In this study, kinematic data of all major toe joints were collected from gaits with double support (slow walking) to running during stance period in a semi-natural setup with two selected cooperative ostriches. Statistical analyses were conducted to investigate the effect of locomotor gait on toe joint kinematics. The MTP3 and MTP4 joints exhibit the largest range of motion whereas the first phalangeal joint of the 4th toe shows the largest motion variability. The interphalangeal joints of the 3rd and 4th toes present very similar motion patterns over stance phases of slow walking and running. However, the motion patterns of the MTP3 and MTP4 joints and the vertical displacement of the metatarsophalangeal joint are significantly different during running and slow walking. Because of the biomechanical requirements, osctriches are likely to select the inverted pendulum gait at low speeds and the bouncing gait at high speeds to improve movement performance and energy economy. Interestingly, the motions of the MTP3 and MTP4 joints are highly synchronized from slow to fast locomotion. This strongly suggests that the 3rd and 4th toes really work as an "integrated system" with the 3rd toe as the main load bearing element whilst the 4th toe as the complementary load sharing element with a primary role to ensure the lateral stability of the permanently elevated metatarsophalangeal joint. PMID- 28097065 TI - Upregulation of NOXA by 10-Hydroxycamptothecin plays a key role in inducing fibroblasts apoptosis and reducing epidural fibrosis. AB - The fibrosis that develops following laminectomy or discectomy often causes serious complications, and the proliferation of fibroblasts is thought to be the major cause of epidural fibrosis. 10-Hydroxycamptothecin (HCPT) has been proven to be efficient in preventing epidural fibrosis, but the exact mechanism is still unclear. NOXA is a significant regulator of cell apoptosis, which has been reported to be beneficial in the treatment of fibrosis. We performed a series of experiments, both in vitro and in vivo, to explore the intrinsic mechanism of HCPT that underlies the induction of apoptosis in fibroblasts, and also to investigate whether HCPT has positive effects on epidural fibrosis following laminectomy in rats. Fibroblasts were cultured in vitro and stimulated by varying concentrations of HCPT (0, 1, 2, 4 ug/ml) for various durations (0, 24, 48, 72 h); the effect of HCPT in inducing the apoptosis of fibroblasts was investigated via Western blots and TUNEL assay. Our results showed that HCPT could induce apoptosis in fibroblasts and up-regulate the expression of NOXA. Following the knockdown of NOXA in fibroblasts, the results of Western blot analysis showed that the level of apoptotic markers, such as cleaved-PARP and Bax, was decreased. The results from the TUNEL assay also showed a decreased rate of apoptosis in NOXA-knocked down fibroblasts. For the in vivo studies, we performed a laminectomy at the L1-L2 levels in rats and applied HCPT of different concentrations (0.2, 0.1, 0.05 mg/ml and saline) locally; the macroscopic histological assessment, hydroxyproline content analysis and histological staining were performed to evaluate the effect of HCPT on reducing epidural fibrosis. The TUNEL assay in epidural tissues showed that HCPT could obviously induce apoptosis in fibroblasts in a dose-dependent manner. Also, immunohistochemical staining showed that the expression of NOXA increased as the concentrations of HCPT increased. Our findings are the first to demonstrate that upregulation of NOXA by HCPT plays a key role in inducing fibroblast apoptosis and in reducing epidural fibrosis. These findings might provide a potential therapeutic target for preventing epidural fibrosis following laminectomy. PMID- 28097066 TI - Henricia djakonovi sp. nov. (Echinodermata, Echinasteridae): a new sea star species from the Sea of Japan. AB - A new sea star species, H. djakonovi sp.n., was discovered in Rudnaya Bay in the Sea of Japan. This is a sympatric species of the well-known and common species Henricia pseudoleviuscula Djakonov, 1958. Both species are similar in body size and proportions, shape of skeletal plates, and life coloration, which distinguishes them from the other Henricia species inhabiting the Sea of Japan. Nevertheless, these species can be distinguished by their abactinal spines: in both species, they are short and barrel-like, but the new species is the only Henricia species in Russian waters of the Pacific that possesses such spines with a massive, smooth, bullet-like tip. The spines in H. pseudoleviuscula are crowned with a variable number of well-developed thorns. About half (<50%) of the abactinal pseudopaxillae in the new species are oval, not crescent-shaped as in H. pseudoleviuscula. PMID- 28097067 TI - Anatomical mechanism of spontaneous recovery in regions caudal to thoracic spinal cord injury lesions in rats. AB - BACKGROUND: The nerve fibre circuits around a lesion play a major role in the spontaneous recovery process after spinal cord hemisection in rats. The aim of the present study was to answer the following question: in the re-control process, do all spinal cord nerves below the lesion site participate, or do the spinal cord nerves of only one vertebral segment have a role in repair? METHODS: First we made a T7 spinal cord hemisection in 50 rats. Eight weeks later, they were divided into three groups based on distinct second operations at T7: ipsilateral hemisection operation, contralateral hemisection, or transection. We then tested recovery of hindlimbs for another eight weeks. The first step was to confirm the lesion had role or not in the spontaneous recovery process. Secondly, we performed T7 spinal cord hemisections in 125 rats. Eight weeks later, we performed a second single hemisection on the ipsilateral side at T8-T12 and then tested hindlimb recovery for another six weeks. RESULTS: In the first part, the Basso, Beattie, Bresnahan (BBB) scores and the electrophysiology tests of both hindlimbs weren't significantly different after the second hemisection of the ipsilateral side. In the second part, the closer the second hemisection was to T12, the more substantial the resulting impairment in BBB score tests and prolonged latency periods. CONCLUSIONS: The nerve regeneration from the lesion area after hemisection has no effect on spontaneous recovery of the spinal cord. Repair is carried out by all vertebrae caudal and ipsilateral to the lesion, with T12 being most important. PMID- 28097068 TI - Hepatic fibrosis and factors associated with liver stiffness in HIV mono-infected individuals. AB - BACKGROUND: Liver disease has become an important cause of morbidity and mortality even in those HIV-infected individuals who are devoid of hepatitis virus co-infection. The aim of this study was to evaluate the degree of hepatic fibrosis and the role of associated factors using liver stiffness measurement in HIV mono-infected patients without significant alcohol intake. METHODS: We performed a cross-sectional study of 101 HIV mono-infected patients recruited prospectively from March 1, 2014 to October 30, 2014 at the Center for HIV, St Istvan and St Laszlo Hospital, Budapest, Hungary. To determine hepatic fibrosis, liver stiffness was measured with transient elastography. Demographic, immunologic and other clinical parameters were collected to establish a multivariate model. Bayesian Model Averaging (BMA) was performed to identify predictors of liver stiffness. RESULTS: Liver stiffness ranged from 3.0-34.3 kPa, with a median value of 5.1 kPa (IQR 1.7). BMA provided a very high support for age (Posterior Effect Probability-PEP: 84.5%), moderate for BMI (PEP: 49.3%), CD4/8 ratio (PEP: 44.2%) and lipodystrophy (PEP: 44.0%). For all remaining variables, the model rather provides evidence against their effect. These results overall suggest that age and BMI have a positive association with LS, while CD4/8 ratio and lipodystrophy are negatively associated. DISCUSSION: Our findings shed light on the possible importance of ageing, overweight and HIV-induced immune dysregulation in the development of liver fibrosis in the HIV-infected population. Nonetheless, further controlled studies are warranted to clarify causal relations. PMID- 28097069 TI - Italian and Swedish adolescents: differences and associations in subjective well being and psychological well-being. AB - BACKGROUND: One important aspect of subjective judgments about one's well-being (i.e., subjective well-being: life satisfaction, positive affect, and negative affect) is that cultural features, such as, nationality seem to shape cognitive judgments about the "the ideal life." In this comparative study we examined differences in subjective well-being and psychological well-being between Italian and Swedish adolescents and tested if the relationship between the three constructs of subjective well-being (i.e., satisfaction with life, positive affect, and negative affect) and psychological well-being was moderated by the adolescents' nationality. METHOD: Italian (n = 255) and Swedish (n = 277) adolescents answered to the Satisfaction with Life Scale, the Positive Affect Negative Affect Schedule, and Ryff's Scales of Psychological Well-Being. Differences between samples were tested using a Multiple Analysis of Variance. We also conducted a multiple group analysis (Italy and Sweden) using Structural Equation Modelling to investigate the relationship between all three subjective well-being constructs and psychological well-being. RESULTS: Italian adolescents scored significantly higher in satisfaction with life than Swedish adolescents. Additionally, across countries, girls scored significantly higher in negative affect than boys. In both countries, all three constructs of subjective well being were significantly associated to adolescents' psychological well-being. Nevertheless, while the effect of the relationship between affect and psychological well-being was almost the same across countries, life satisfaction was more strongly related to psychological well-being among Swedish adolescents. CONCLUSIONS: The present study shows that there are larger variations between these two cultures in the cognitive construct of subjective well-being than in the affective construct. Accordingly, associations between the cognitive component, not the affective component, of subjective well-being and psychological well-being differ between countries as well. PMID- 28097070 TI - Sponge exhalent seawater contains a unique chemical profile of dissolved organic matter. AB - Sponges are efficient filter feeders, removing significant portions of particulate and dissolved organic matter (POM, DOM) from the water column. While the assimilation and respiration of POM and DOM by sponges and their abundant microbial symbiont communities have received much attention, there is virtually no information on the impact of sponge holobiont metabolism on the composition of DOM at a molecular-level. We applied untargeted and targeted metabolomics techniques to characterize DOM in seawater samples prior to entering the sponge (inhalant reef water), in samples exiting the sponge (exhalent seawater), and in samples collected just outside the reef area (off reef seawater). Samples were collected from two sponge species, Ircinia campana and Spheciospongia vesparium, on a near-shore hard bottom reef in the Florida Keys. Metabolic profiles generated from untargeted metabolomics analysis indicated that many more compounds were enhanced in the exhalent samples than in the inhalant samples. Targeted metabolomics analysis revealed differences in diversity and concentration of metabolites between exhalent and off reef seawater. For example, most of the nucleosides were enriched in the exhalent seawater, while the aromatic amino acids, caffeine and the nucleoside xanthosine were elevated in the off reef water samples. Although the metabolic profile of the exhalent seawater was unique, the impact of sponge metabolism on the overall reef DOM profile was spatially limited in our study. There were also no significant differences in the metabolic profiles of exhalent water between the two sponge species, potentially indicating that there is a characteristic DOM profile in the exhalent seawater of Caribbean sponges. Additional work is needed to determine whether the impact of sponge DOM is greater in habitats with higher sponge cover and diversity. This work provides the first insight into the molecular-level impact of sponge holobiont metabolism on reef DOM and establishes a foundation for future experimental studies addressing the influence of sponge-derived DOM on chemical and ecological processes in coral reef ecosystems. PMID- 28097071 TI - The fishing and natural mortality of large, piscivorous Bull Trout and Rainbow Trout in Kootenay Lake, British Columbia (2008-2013). AB - BACKGROUND: Estimates of fishing and natural mortality are important for understanding, and ultimately managing, commercial and recreational fisheries. High reward tags with fixed station acoustic telemetry provides a promising approach to monitoring mortality rates in large lake recreational fisheries. Kootenay Lake is a large lake which supports an important recreational fishery for large Bull Trout and Rainbow Trout. METHODS: Between 2008 and 2013, 88 large (>=500 mm) Bull Trout and 149 large (>=500 mm) Rainbow Trout were marked with an acoustic transmitter and/or high reward ($100) anchor tags in Kootenay Lake. The subsequent detections and angler recaptures were analysed using a Bayesian individual state-space Cormack-Jolly-Seber (CJS) survival model with indicator variable selection. RESULTS: The final CJS survival model estimated that the annual interval probability of being recaptured by an angler was 0.17 (95% CRI [0.11-0.23]) for Bull Trout and 0.14 (95% CRI [0.09-0.19]) for Rainbow Trout. The annual interval survival probability for Bull Trout was estimated to have declined from 0.91 (95% CRI [0.76-0.97]) in 2009 to just 0.46 (95% CRI [0.24 0.76]) in 2013. Rainbow Trout survival was most strongly affected by spawning. The annual interval survival probability was 0.77 (95% CRI [0.68-0.85]) for a non spawning Rainbow Trout compared to 0.41 (95% CRI [0.30-0.53]) for a spawner. The probability of spawning increased with the fork length for both species and decreased over the course of the study for Rainbow Trout. DISCUSSION: Fishing mortality was relatively low and constant while natural mortality was relatively high and variable. The results indicate that angler effort is not the primary driver of short-term population fluctations in the Rainbow Trout abundance. Variation in the probability of Rainbow Trout spawning suggests that the spring escapement at the outflow of Trout Lake may be a less reliable index of abundance than previously assumed. Multi-species stock assessment models need to account for the fact that large Bull Trout are more abundant than large Rainbow Trout in Kootenay Lake. PMID- 28097072 TI - Aggregations and parental care in the Early Triassic basal cynodonts Galesaurus planiceps and Thrinaxodon liorhinus. AB - Non-mammaliaform cynodonts gave rise to mammals but the reproductive biology of this extinct group is still poorly known. Two exceptional fossils of Galesaurus planiceps and Thrinaxodon liorhinus, consisting of juveniles closely associated with an adult, were briefly described more than 50 years ago as examples of parental care in non-mammaliaform cynodonts. However, these two Early Triassic fossils have largely been excluded from recent discussions of parental care in the fossil record. Here we re-analyse these fossils in the context of an extensive survey of other aggregations found in these two basal cynodont taxa. Our analysis revealed six other unequivocal cases of aggregations in Thrinaxodon, with examples of same-age aggregations among immature or adult individuals as well as mixed-age aggregations between subadult and adult individuals. In contrast, only one additional aggregation of Galesauruswas identified. Taking this comprehensive survey into account, the two previously described cases of parental care in Galesaurus and Thrinaxodon are substantiated. The juveniles are the smallest specimens known for each taxon, and the size difference between the adult and the two associated juveniles is the largest found for any of the aggregations. The juveniles of Thrinaxodon are approximately only 37% of the associated adult size; whereas in Galesaurus, the young are at least 60% of the associated adult size. In each case, the two juvenile individuals are similar in size, suggesting they were from the same clutch. Even though parental care was present in both Galesaurus and Thrinaxodon, intraspecific aggregations were much more common in Thrinaxodon, suggesting it regularly lived in aggregations consisting of both similar and different aged individuals. PMID- 28097073 TI - Handling stress may confound murine gut microbiota studies. AB - BACKGROUND: Accumulating evidence indicates interactions between human milk composition, particularly sugars (human milk oligosaccharides or HMO), the gut microbiota of human infants, and behavioral effects. Some HMO secreted in human milk are unable to be endogenously digested by the human infant but are able to be metabolized by certain species of gut microbiota, including Bifidobacterium longum subsp. infantis (B. infantis), a species sensitive to host stress (Bailey & Coe, 2004). Exposure to gut bacteria like B. infantisduring critical neurodevelopment windows in early life appears to have behavioral consequences; however, environmental, physical, and social stress during this period can also have behavioral and microbial consequences. While rodent models are a useful method for determining causal relationships between HMO, gut microbiota, and behavior, murine studies of gut microbiota usually employ oral gavage, a technique stressful to the mouse. Our aim was to develop a less-invasive technique for HMO administration to remove the potential confound of gavage stress. Under the hypothesis that stress affects gut microbiota, particularly B. infantis, we predicted the pups receiving a prebiotic solution in a less-invasive manner would have the highest amount of Bifidobacteria in their gut. METHODS: This study was designed to test two methods, active and passive, of solution administration to mice and the effects on their gut microbiome. Neonatal C57BL/6J mice housed in a specific-pathogen free facility received increasing doses of fructooligosaccharide (FOS) solution or deionized, distilled water. Gastrointestinal (GI) tracts were collected from five dams, six sires, and 41 pups over four time points. Seven fecal pellets from unhandled pups and two pellets from unhandled dams were also collected. Qualitative real-time polymerase chain reaction (qRT-PCR) was used to quantify and compare the amount of Bifidobacterium, Bacteroides, Bacteroidetes, and Firmicutes. RESULTS: Our results demonstrate a significant difference between the amount of Firmicutes in pups receiving water passively and those receiving FOS actively (p-value = 0.009). Additionally, we found significant differences between the fecal microbiota from handled and non-handled mouse pups. DISCUSSION: From our results, we conclude even handling pups for experimental purposes, without gavage, may induce enough stress to alter the murine gut microbiota profile. We suggest further studies to examine potential stress effects on gut microbiota caused by experimental techniques. Stress from experimental techniques may need to be accounted for in future gut microbiota studies. PMID- 28097075 TI - Effects of an 8-week yoga program on sustained attention and discrimination function in children with attention deficit hyperactivity disorder. AB - This study investigated whether a yoga exercise intervention influenced the sustained attention and discrimination function in children with ADHD. Forty-nine participants (mean age = 10.50 years) were assigned to either a yoga exercise or a control group. Participants were given the Visual Pursuit Test and Determination Test prior to and after an eight-week exercise intervention (twice per week, 40 min per session) or a control intervention. Significant improvements in accuracy rate and reaction time of the two tests were observed over time in the exercise group compared with the control group. These findings suggest that alternative therapies such as yoga exercises can be complementary to behavioral interventions for children with attention and inhibition problems. Schools and parents of children with ADHD should consider alternatives for maximizing the opportunities that children with ADHD can engage in structured yoga exercises. PMID- 28097076 TI - A critical issue in model-based inference for studying trait-based community assembly and a solution. AB - Statistical testing of trait-environment association from data is a challenge as there is no common unit of observation: the trait is observed on species, the environment on sites and the mediating abundance on species-site combinations. A number of correlation-based methods, such as the community weighted trait means method (CWM), the fourth-corner correlation method and the multivariate method RLQ, have been proposed to estimate such trait-environment associations. In these methods, valid statistical testing proceeds by performing two separate resampling tests, one site-based and the other species-based and by assessing significance by the largest of the two p-values (the pmax test). Recently, regression-based methods using generalized linear models (GLM) have been proposed as a promising alternative with statistical inference via site-based resampling. We investigated the performance of this new approach along with approaches that mimicked the pmax test using GLM instead of fourth-corner. By simulation using models with additional random variation in the species response to the environment, the site based resampling tests using GLM are shown to have severely inflated type I error, of up to 90%, when the nominal level is set as 5%. In addition, predictive modelling of such data using site-based cross-validation very often identified trait-environment interactions that had no predictive value. The problem that we identify is not an "omitted variable bias" problem as it occurs even when the additional random variation is independent of the observed trait and environment data. Instead, it is a problem of ignoring a random effect. In the same simulations, the GLM-based pmax test controlled the type I error in all models proposed so far in this context, but still gave slightly inflated error in more complex models that included both missing (but important) traits and missing (but important) environmental variables. For screening the importance of single trait environment combinations, the fourth-corner test is shown to give almost the same results as the GLM-based tests in far less computing time. PMID- 28097074 TI - Resources available for autism research in the big data era: a systematic review. AB - Recently, there has been a move encouraged by many stakeholders towards generating big, open data in many areas of research. One area where big, open data is particularly valuable is in research relating to complex heterogeneous disorders such as Autism Spectrum Disorder (ASD). The inconsistencies of findings and the great heterogeneity of ASD necessitate the use of big and open data to tackle important challenges such as understanding and defining the heterogeneity and potential subtypes of ASD. To this end, a number of initiatives have been established that aim to develop big and/or open data resources for autism research. In order to provide a useful data reference for autism researchers, a systematic search for ASD data resources was conducted using the Scopus database, the Google search engine, and the pages on 'recommended repositories' by key journals, and the findings were translated into a comprehensive list focused on ASD data. The aim of this review is to systematically search for all available ASD data resources providing the following data types: phenotypic, neuroimaging, human brain connectivity matrices, human brain statistical maps, biospecimens, and ASD participant recruitment. A total of 33 resources were found containing different types of data from varying numbers of participants. Description of the data available from each data resource, and links to each resource is provided. Moreover, key implications are addressed and underrepresented areas of data are identified. PMID- 28097077 TI - A Case of Umbilical Endometriosis: Villar's Nodule. AB - Umbilical endometriosis is a fairly rare clinical entity with unclear pathogenesis. We report the case of a 27-year-old woman who presented with a painful umbilical mass and discharge. Imaging performed was inconclusive, and surgical excision of the site with margins revealed endometriosis on microscopic examination. The incidence of umbilical endometriosis, its pathogenesis, clinical manifestations, workup, and management are discussed. PMID- 28097078 TI - The Human Central Canal of the Spinal Cord: A Comprehensive Review of its Anatomy, Embryology, Molecular Development, Variants, and Pathology. AB - The human central canal of the spinal cord is often overlooked. However, with advancements in imaging quality, this structure can be visualized in more detail than ever before. Therefore, a timely review of this part of the cord seemed warranted. Using standard search engines, a literature review was performed for the development, anatomy, and pathology involving the central canal. Clinicians who treat patients with issues near the spine or interpret imaging of the spinal cord should be familiar with the morphology and variants of the central canal. PMID- 28097079 TI - Symptomatic Unilateral Spondylolysis Associated With Nonspondylolytic Lateral Clefts in Adults: Review of an Infrequently Reported Pathology. AB - Nonspondylolytic lateral clefts of the lumbar neural arch (laminolysis and pediculolysis) are rare pathologies that usually occur consequent to repetitive stress injuries in patients with unilateral spondylolysis. These lesions are different from the usual bilateral spondylolytic defects, and their management depends upon the chronicity and the type of bony defect. We hereby discuss the verdict of current literature on underlying pathomechanics and ideal management guidelines of these rare lesions. PMID- 28097080 TI - Immunoglobulin M Nephropathy in a Patient with Wilson's Disease. AB - Immunoglobulin M nephropathy (IgMN) is characterized by the deposition of immunoglobulin M in a dominant distribution in the renal glomeruli. Primary immunoglobulin M nephropathy is diagnosed after consistent light microscopy (LM), immunofluorescence (IF), electron microscopy (EM) results, and exclusion of known systemic disorders causing immunoglobulin M deposition in the glomeruli. The secondary disease has been reported with a few conditions though it has never been reported with any primary disease of the liver. We report the case of an adolescent male patient who presented with nausea, vomiting, diarrhea, and worsening anasarca. He was found to have nephrotic-range proteinuria that did not respond to conventional corticosteroid treatment. He was subjected to a renal biopsy which revealed a diagnosis of immunoglobulin M nephropathy. His liver function tests were deranged and an ultrasound scan of the abdomen revealed a coarse irregular liver. Workup revealed elevated urine copper excretion and a low ceruloplasmin level. He was diagnosed as a case of Wilson's disease and started on penicillamine and pyridoxine. He was also started on intravenous cyclophosphamide for the corticosteroid-resistant nephrotic syndrome to which he responded remarkably well. His edema settled, proteinuria resolved, and liver functions normalized. Currently, he is in remission and enjoying good health. To the best of our knowledge, we report the first known association between IgM nephropathy and Wilson's disease. It is presently not clear if causation can necessarily be established. This may be the result of defective IgM clearance by the liver or an altered metabolism of the antibody or immune complexes, as with hepatic-associated immunoglobulin M (IgM) nephropathy. Further studies are needed to elucidate the exact mechanism of this disease. PMID- 28097081 TI - B-Cell Lymphoma in the Tricuspid Valve. AB - Lymphoma can involve any organ or tissue that contains lymphoid tissue and the heart is no exception. A few prior case reports have described lymphoma encasing a coronary artery or involving one or more cardiac valves. We present a rare case of diffuse large B-cell lymphoma (DLBCL) involving the tricuspid valve and right coronary artery diagnosed on coronary CT angiography. The clinical and imaging characteristics of cardiac lymphoma are discussed. PMID- 28097082 TI - A Review of Colorectal Cancer Detection Modalities, Stool DNA, and Fecal Immunochemistry Testing in Adults Over the Age of 50. AB - Colorectal cancer (CRC) is the third leading cause of cancer death in the United States. Recently, more focus has been placed on developing effective screening tools to detect the presence of both precancerous and cancerous lesions present in the colon and rectum. Colonoscopy has been well established as the gold standard of the colon and rectal cancer screening. However, not all patients are willing to undergo a colonoscopy due to the procedure's invasive nature. Non invasive screening methods have been developed to appeal to patients who refuse colonoscopy. Fecal occult blood tests have long been used by physicians, in addition to colonoscopy, in an effort to screen for CRC. New screening methods, such as fecal immunochemical test (FIT) and stool DNA (sDNA) testing, have been developed as a more sensitive screening measure to attempt to accurately screen patients who have precancerous or cancerous colorectal lesions. This article compares CRC screening techniques through literature review in order to determine which tests offer the most sensitive detection of CRC and precancerous lesions in average-risk adults over the age of 50 years old. Through this review, it can be seen that sDNA is more sensitive than FIT in detecting all stages of CRC, as well as precancerous lesions. PMID- 28097083 TI - Recurrent Squamous Cell Carcinoma of the Eyelid Presenting as Trigeminal Neuralgia. AB - This paper describes two patients with squamous cell carcinoma (SCC) of the periocular and periorbital skin who presented with trigeminal neuralgia. Both patients had previous cutaneous SCC of the scalp treated successfully with surgical resection but later presented with neuro-ophthalmic findings suggesting perineural invasion (PNI) of SCC. PNI of SCC in the periocular skin or orbit can lead to devastating effects if malignant cells seed into the orbit and adjacent cranial nerves as our two patients developed an orbital apex syndrome. Patients with a history of SCC of the scalp and forehead who later develop neuro ophthalmological deficits or patients with persistent ocular symptoms should, in particular, be followed with a low threshold for cutaneous SCC or PNI of recurrent disease. SCC metastasizing into the periocular tissues and orbit by neural invasion is rare and carries a poor prognosis. The urgency for a prompt diagnosis and evaluation by a multidisciplinary team is warranted to prevent untoward outcomes of this skin cancer. PMID- 28097084 TI - The calcium-dependent protein kinase (CDPK) and CDPK-related kinase gene families in Hevea brasiliensis-comparison with five other plant species in structure, evolution, and expression. AB - Calcium-dependent protein kinases (CDPKs or CPKs) play important roles in various physiological processes of plants, including growth and development, stress responses and hormone signaling. Although the CDPK gene family has been characterized in several model plants, little is known about this gene family in Hevea brasiliensis (the Para rubber tree). Here, we characterize the entire H. brasiliensis CDPK and CDPK-related kinase (CRK) gene families comprising 30 CDPK genes (HbCPK1 to 30) and nine CRK genes (HbCRK1 to 9). Structure and phylogeny analyses of these CDPK and CRK genes demonstrate evolutionary conservation in these gene families across H. brasiliensis and other plant species. The expression of HbCPK and HbCRK genes was investigated via Solexa sequencing in a range of experimental conditions (different tissues, phases of leaf development, ethylene treatment, and various abiotic stresses). The results suggest that HbCPK and HbCRK genes are important components in growth, development, and stress responses of H. brasiliensis. Parallel studies on the CDPK and CRK gene families were also extended to five other plant species (Arabidopsis thaliana, Oryza sativa, Populus trichocarpa, Manihot esculenta, and Ricinus communis). The CDPK and CRK genes from different plant species that exhibit similar expression patterns tend to cluster together, suggesting a coevolution of gene structure and expression behavior in higher plants. The results serve as a foundation to further functional studies of these gene families in H. brasiliensis as well as in the whole plant kingdom. PMID- 28097085 TI - Interaction with adenylate cyclase toxin from Bordetella pertussis affects the metal binding properties of calmodulin. AB - Adenylate cyclase toxin domain (CyaA-ACD) is a calmodulin (CaM)-dependent adenylate cyclase involved in Bordetella pertussis pathogenesis. Calcium (Ca2+) and magnesium (Mg2+) concentrations impact CaM-dependent CyaA-ACD activation, but the structural mechanisms remain unclear. In this study, NMR, dynamic light scattering, and native PAGE were used to probe Mg2+-induced transitions in CaM's conformation in the presence of CyaA-ACD. Mg2+ binding was localized to sites I and II, while sites III and IV remained Ca2+ loaded when CaM was bound to CyaA ACD. 2Mg2+/2Ca2+-loaded CaM/CyaA-ACD was elongated, whereas mutation of site I altered global complex conformation. These data suggest that CyaA-ACD interaction moderates CaM's Ca2+- and Mg2+-binding capabilities, which may contribute to pathobiology. PMID- 28097086 TI - Liver X receptor agonist T0901317 reverses resistance of A549 human lung cancer cells to EGFR-TKI treatment. AB - Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is effective in lung cancer patients carrying sensitive EGFR mutations. In this study, we investigated if liver X receptor (LXR) agonist T0901317 could reverse the resistance of lung cancer cell lines A549 and H1650 to EGFR-TKI treatment. We found that T0901317 could make natural EGFR-TKI-resistant A549 human lung cancer cells sensitive to EGFR-TKI treatment and that this was dependent on LXRbeta expression. However, T0901317 does not have a similar effect on another natural EGFR-TKI-resistant cell line H1650. PMID- 28097087 TI - Identification of the vascular endothelial growth factor signalling pathway by quantitative proteomic analysis of rat condylar cartilage. AB - Angiogenesis mediated by vascular endothelial growth factor (VEGF) is known to play an important role in regulating cartilage remodelling and endochondral ossification. However, the details of how VEGF signalling mechanisms affect condyle remodelling in response to alterations in functional loading remains unclear. To explore this, eighty 16-day-old male SD rats were divided into two equal groups which were fed either a soft/powdery diet or a hard diet for 4 weeks; the stiffness of the diet results in alteration of mastication force and hence temporomandibular joint (TMJ) development. We performed a proteomic analysis of rat condylar cartilage using isobaric tags for relative and absolute quantification (iTRAQ) labelling, followed by 2D nano-high performance liquid chromatography and MALDI-TOF/time-of-flight technology. After protein identification, we used biological information analysis to identify the differentially expressed proteins associated with the VEGF signalling pathway. Among the identified differentially expressed proteins, we found VEGF signalling mainly via the p44/42 MAPK and p38 mitogen-activated protein kinase (MAPK) pathways in condylar cartilage, including VEGFD, VGFR2, KPCB, KPCT, KPCZ, ARAF, RASN, PLCG2, PLCG1, JUN and M3K12. Furthermore, four representative protein candidates, VEGF, p38 MAPK and p44/42 MAPK/phospho-p44/42 MAPK, were confirmed by immunohistochemical staining and western blot. Our data suggest that VEGF might play an important role in TMJ development and remodelling in response to alterations in functional loading through the p44/42 MAPK and p38 MAPK signalling pathway. This study provides new clues to the understanding of the signalling mechanism responsible for VEGF production in response to different masticatory functions at the protein level. PMID- 28097088 TI - Icariin ameliorates IgA nephropathy by inhibition of nuclear factor kappa b/Nlrp3 pathway. AB - Immunoglobulin A nephropathy (IgAN) is the most frequent form of glomerulonephritis, which is characterized by glomerular proliferation and renal inflammation. Icariin is a flavonoid from the Chinese herb Epimedium, and its anti-inflammatory effect has been reported. This study aimed to investigate the effects of icariin on the renal damage in IgAN rats and the mechanisms behind these effects. IgAN model was established in Sprague-Dawley rats by oral and intravenous immunization with bovine gamma-globulin for 12 weeks, and rats were treated with icariin from 12 to 18 weeks. At the end of experimental period, kidneys, urine, and blood samples were collected for further analysis. Our results showed that icariin ameliorated the increase in the levels of proteinuria, serum creatinine, and urea nitrogen without severe side effects. IgAN rats exhibited significantly increased IgA deposition, mesangial matrix expansion, and glomerular fibrosis, while icariin treatment markedly attenuated these alterations. Moreover, treatment with icariin also dramatically blocked nuclear factor kappa b (NF-kappaB) nuclear translocation and Nlrp3 inflammasome activation in IgAN rats, leading to reduced downstream proinflammatory cytokines production. Mechanistically, we found that icariin treatment inhibited IKKbeta and IkappaBalpha phosphorylation and IkappaBalpha degradation in IgAN rats. Our data demonstrate that icariin ameliorates renal damage in IgAN rats via inhibition of NF-kappaB-mediated Nlrp3 inflammasome activation. These findings provide insight into an application of icariin for the treatment of IgAN disease, and represent a novel mechanism behind these effects. PMID- 28097089 TI - Selective inhibition of phosphodiesterases 4, 5 and 9 induces HSP20 phosphorylation and attenuates amyloid beta 1-42-mediated cytotoxicity. AB - Phosphodiesterase (PDE) inhibitors are currently under evaluation as agents that may facilitate the improvement of cognitive impairment associated with Alzheimer's disease. Our aim was to determine whether inhibitors of PDEs 4, 5 and 9 could alleviate the cytotoxic effects of amyloid beta 1-42 (Abeta1-42) via a mechanism involving the small heatshock protein HSP20. We show that inhibition of PDEs 4, 5 and 9 but not 3 induces the phosphorylation of HSP20 which, in turn, increases the colocalisation between the chaperone and Abeta1-42 to significantly decrease the toxic effect of the peptide. We conclude that inhibition of PDE9 is most effective to combat Abeta1-42 cytotoxicity in our cell model. PMID- 28097090 TI - A comparative study of the degradation of yeast cyclins Cln1 and Cln2. AB - The yeast cyclins Cln1 and Cln2 are very similar in both sequence and function, but some differences in their functionality and localization have been recently described. The control of Cln1 and Cln2 cellular levels is crucial for proper cell cycle initiation. In this work, we analyzed the degradation patterns of Cln1 and Cln2 in order to further investigate the possible differences between them. Both cyclins show the same half-life but, while Cln2 degradation depends on ubiquitin ligases SCFGrr1 and SCFCdc4, Cln1 is affected only by SCFGrr1. Degradation analysis of chimeric cyclins, constructed by combining fragments from Cln1 and Cln2, identifies the N-terminal sequence of the proteins as responsible of the cyclin degradation pattern. In particular, the N-terminal region of Cln2 is required to mediate degradation by SCFCdc4. This region is involved in nuclear import of Cln1 and Cln2, which suggests that differences in degradation may be due to differences in localization. Moreover, a comparison of the cyclins that differ only in the presence of the Cln2 nuclear export signal indicates a greater instability of exported cyclins, thus reinforcing the idea that cyclin stability is influenced by their localization. PMID- 28097091 TI - Evaluation of novel protease inhibitors against darunavir-resistant variants of HIV type 1. AB - HIV disease became a manageable chronic disease since combination antiretroviral therapy (cART) was introduced as the standard treatment regimen. However, the emergence of drug-resistant viruses is a major problem associated with cART. A phenotypic drug susceptibility test using a lentiviral vector was established and applied to evaluate new protease inhibitors (PIs). Lentiviral vectors representing a wild-type (WT-lentivector) and darunavir (DRV)-resistant HIV type 1 (HIV-1) (DRV r-lentivector) were generated. Nine clinically approved protease inhibitors (PIs) inhibited the transduction ability of WT-lentivector similar to their inhibitory effects on the replication of WT HIV-1. Three new PIs reduced the transduction ability of WT- and DRV r-lentivector, suggesting that these PIs may be the candidates as novel antiretroviral drugs against drug-resistant variants of HIV-1. PMID- 28097092 TI - Comparative interactomics for virus-human protein-protein interactions: DNA viruses versus RNA viruses. AB - Viruses are obligatory intracellular pathogens and completely depend on their hosts for survival and reproduction. The strategies adopted by viruses to exploit host cell processes and to evade host immune systems during infections may differ largely with the type of the viral genetic material. An improved understanding of these viral infection mechanisms is only possible through a better understanding of the pathogen-host interactions (PHIs) that enable viruses to enter into the host cells and manipulate the cellular mechanisms to their own advantage. Experimentally-verified protein-protein interaction (PPI) data of pathogen-host systems only became available at large scale within the last decade. In this study, we comparatively analyzed the current PHI networks belonging to DNA and RNA viruses and their human host, to get insights into the infection strategies used by these viral groups. We investigated the functional properties of human proteins in the PHI networks, to observe and compare the attack strategies of DNA and RNA viruses. We observed that DNA viruses are able to attack both human cellular and metabolic processes simultaneously during infections. On the other hand, RNA viruses preferentially interact with human proteins functioning in specific cellular processes as well as in intracellular transport and localization within the cell. Observing virus-targeted human proteins, we propose heterogeneous nuclear ribonucleoproteins and transporter proteins as potential antiviral therapeutic targets. The observed common and specific infection mechanisms in terms of viral strategies to attack human proteins may provide crucial information for further design of broad and specific next-generation antiviral therapeutics. PMID- 28097093 TI - Vascular endothelial growth factor suppresses TNFSF15 production in endothelial cells by stimulating miR-31 and miR-20a expression via activation of Akt and Erk signals. AB - Tumor necrosis factor superfamily-15 (TNFSF15; VEGI; TL1A) is a negative modulator of angiogenesis for blood vessel homeostasis and is produced by endothelial cells in a mature vasculature. It is known to be downregulated by vascular endothelial growth factor (VEGF), a major regulator of neovascularization but the mechanism of this interaction is unclear. Here we report that VEGF is able to stimulate the production of two microRNAs, miR-20a and miR-31, which directly target the 3'-UTR of TNFSF15. Additionally, we show that two VEGF-stimulated cell growth signals, Erk and Akt, are responsible for promoting the expression of miR-20a and miR-31. Treatment of human umbilical vein endothelial cells (HUVECs) with Akt inhibitor LY294002 results in diminished miR 20a and miR-31 production, while Erk inhibitor U0126 prevented VEGF-stimulated expression of miR-20a but not that of miR-31. Furthermore, inactivation of either Erk or Akt signals restores TNFSF15 gene expression. In an angiogenesis assay, elevated miR-20a or miR-31 levels in HUVECs leads to enhancement of capillary like tubule formation in vitro, whereas lowered miR-20a and miR-31 levels results in an inhibition. These findings are consistent with the view that miR-20a and miR-31 mediate VEGF-induced downregulation of TNFSF15. Targeting these microRNA molecules may therefore provide an effective approach to inhibit angiogenesis. PMID- 28097094 TI - Corrigendum. AB - [This corrects the article DOI: 10.1002/2211-5463.12131.]. PMID- 28097095 TI - Limited Knowledge of Acetaminophen in Patients with Liver Disease. AB - Background and Aims: Unintentional acetaminophen overdose remains the leading cause of acute liver failure in the United States. Patients with underlying liver disease are at higher risk of poor outcomes from acetaminophen overdose. Limited knowledge of acetaminophen may be a preventable contributor to elevated rates of overdose and thus acute liver failure. The purpose of this study is to assess knowledge of acetaminophen dosing and presence of acetaminophen in common combination products in patients with liver disease. Methods: We performed a cross-sectional study of patients with liver disease at the Pfleger Liver Institute at the University of California, Los Angeles between June 2015 and August 2016. Patients completed a demographic questionnaire and an acetaminophen knowledge survey. Additional information was obtained from the medical record. Results: Of 401 patients with liver disease, 30 (15.7%) were able to correctly identify that people without liver disease can safely take up to 4 g/day of acetaminophen. The majority of patients (79.9%-86.8%) did not know that Norco(r) (hydrocone/acetaminophen), Vicodin(r) (hydrocone/acetaminophen) and Percocet(r) (oxycodone/acetaminophen) contained acetaminophen. Only 45.3% of the patients knew that Tylenol(r) #3 contained acetaminophen. Conclusions: We conclude that patients with liver disease have critically low levels of knowledge of acetaminophen, putting them at risk both of acetaminophen overdose, as well as undermedication, and inadequate management of chronic pain. We recommend an increase in education efforts regarding acetaminophen dosage and its safety in the setting of liver disease. Increasing education for those at risk of low acetaminophen knowledge is essential to minimizing acetaminophen overdose rates and optimizing pain management. PMID- 28097096 TI - Impact of Different Embolic Agents for Transarterial Chemoembolization (TACE) Procedures on Systemic Vascular Endothelial Growth Factor (VEGF) Levels. AB - Background and Aims: Intermediate stage hepatocellular carcinoma (HCC) can be treated by transarterial chemoembolization (TACE). However, there appear to be side effects, such as induction of proangiogenic factors, e.g. vascular endothelial growth factor (VEGF), which have been shown to be associated with a poor prognosis. This prospective study was designed to compare serum VEGF level response after TACE with different embolic agents in patients with HCC. Methods: Patients were assigned to one of three different TACE regimens: degradable starch microspheres (DSM) TACE, drug-eluting bead (DEBDOX) TACE or Lipiodol TACE (cTACE). All patients received 50 mg doxorubicin/m2 body surface area (BSA) during TACE. Serum VEGF levels were assessed before TACE treatment, 24 h post treatment and 4 weeks later. Results: Twenty-two patients with 30 TACE treatments were enrolled. Compared to baseline VEGF levels, a marked increase was observed for 24 h post-TACE (164% of baseline level) and during the 4-week follow-up (170% of baseline level) only for the cTACE arm (p < 0.05). In contrast, the increase of serum VEGF levels were only 114% and 123% for DEBDOX and 121% and 124% for DSM, respectively. Conclusions: Conventional TACE using Lipiodol shows marked increase in blood levels of the proangiogenic factor VEGF, while DEBDOX and DSM TACE induce only a moderate VEGF response. PMID- 28097097 TI - miR-29a Promotes Lipid Droplet and Triglyceride Formation in HCV Infection by Inducing Expression of SREBP-1c and CAV1. AB - Aims: To examine the regulation of SREBP-1c and CAV1 by microRNA-29a (miR-29a) in cells infected with hepatitis C virus (HCV) in an attempt to control HCV-induced non-alcoholic fatty liver disease. Methods: In order to examine the manipulation of SREBP-1c and CAV1 by miR-29a, oleic acid (OA)-treated JFH-I-infected Huh-7 cells were used. OA was added 24 h post-transfection and gene expression was investigated by qRT-PCR at 48 h post treatment. The functional impact of the observed alteration in SREBP-1c and CAV1 expression was analyzed by examining lipid droplet (LD) and triglyceride (TG) content at 72 h post-OA treatment using light microscopy and spectrophotometry, respectively. Viral load was quantified by qRT-PCR at 72 h post-transfection. Results: OA treatment induced the expression of miR-29a and SREBP-1c, as compared to untreated cells. Forced miR 29a expression led to a significant up-regulation of SREBP-1c as well as CAV1 compared to mock untransfected cells. Ectopic expression of miR-29a resulted in a marked increase in LDs and their respective TGs, while miR-29a antagomirs decreased both the LD and TG content compared to mock untransfected cells. Moreover, forcing the expression of miR-29a in JFH-1 HCV-infected Huh-7 cells resulted in 53% reduction in viral titers compared to mock untransfected Huh-7 cells. Conclusion: Inducing miR-29a expression significantly induces SREBP-1c and CAV1 expression, thereby increasing LDs as well as their respective TGs. Nonetheless, forcing the expression of miR-29a resulted in reduction of HCV RNA levels in Huh-7 cells. PMID- 28097098 TI - miR-34a: Multiple Opposing Targets and One Destiny in Hepatocellular Carcinoma. AB - Background and Aims: The role of miR-34a in hepatocellular carcinoma (HCC) is controversial and several unresolved issues remain, including its expression pattern and relevance to tumor etiology, tumor stage and prognosis, and finally, its impact on apoptosis. Methods: miR-34a expression was assessed in hepatitis C virus (HCV)-induced non-metastatic HCC tissues by RT-Q-PCR. Huh-7 cells were transfected with miR-34a mimics and the impact of miR-34a was examined on 84 pro apoptotic/anti-apoptotic genes using PCR array; its net effect was tested on cell viability via MTT assay. Results: miR-34a expression was up-regulated in HCC tissues. Moreover, miR-34a induced a large set of pro-apoptotic/anti-apoptotic genes, with a net result of triggering apoptosis and repressing cell viability. Conclusions: HCC-related differential expression of miR-34a could be etiology based or stage-specific, and low expression of miR-34a may predict poor prognosis. This study's findings also emphasize the role of miR-34a in apoptosis. PMID- 28097099 TI - Comparison of Vitamin D Levels in Naive, Treated, and Inactive Carriers with Chronic Hepatitis B Virus. AB - Background and Aims: During recent years, the relationship between vitamin D levels and chronic hepatitis B (CHB) infection has attracted many researchers' attention. However, the results relating to the association of vitamin D levels and HBV infection have been conflicting and there remains a lack of knowledge about the effects of antiviral treatments on vitamin D level. Methods: Eighty four patients with CHB were assessed and divided into three groups: inactive carriers (n = 28), treated (n = 34), and new (treatment-naive) cases (n = 22). Thirty-two healthy controls (HCs) were included to enable comparison with the CHB groups. The levels of vitamin D3 were measured and statistically compared among the various groups. Results: Male subjects had higher levels of vitamin D3 (41.25 vs 28.85, p < 0.01). No association was found among any of the groups when compared with the HC group. Despite the significant association, the HCs demonstrated a higher level of vitamin D3, which was lower in the treated group, the inactive carrier group, and the new cases group (new case [29.82] < inactive carrier [32.91] < treated [39.56] < control [44.88]). The HBV DNA levels were not associated with vitamin D3 levels in the inactive carriers (p = 0.171), the treated groups (p = 0.192), and the new cases (p = 0.369). Moreover, the alanine transaminase and aspartate transaminase levels were not associated with vitamin D3 levels for any of the HBV-infected groups. Conclusions: Vitamin D3 contributes to the clinical statues of CHB patients. There is also a possible correlation between clinically healthy CHB patients and vitamin D3 level. PMID- 28097100 TI - Hepatitis C Virus: A Review of Treatment Guidelines, Cost-effectiveness, and Access to Therapy. AB - Hepatitis C virus (HCV) infection remains a significant medical concern in the United States and around the world. It is still one of the leading causes of chronic liver disease, and, for more than 20 years, there has been little progress in the treatment of HCV infection. The advent of direct-acting antivirals (DAAs) initiated the era of high efficacy and well-tolerated medications with high cure rates. The efficacy of these medications has prompted many professional societies around the world to update their treatment guidelines to include DAAs as first-line treatment. Guidelines by the American Association for the Study of Liver Disease/Infectious Disease Society of America, World Health Organization, Asian-Pacific Association for the Study of Liver and the European Association for the Study of Liver have all incorporated DAAs into their treatment guidelines. Despite the promising data supporting these medications, however, their cost represents a limiting factor to their use, even though studies have shown DAAs to be cost-effective. In addition to the expense of these medications and limited resources, there are many barriers preventing patients from receiving this potentially life-saving treatment. In order to overcome these barriers, these issues need to be recognized and addressed. PMID- 28097101 TI - Novel Treatment of Hepatitis C Virus Infection for Patients with Renal Impairment. AB - Prevalence of hepatitis C virus (HCV) infection is high in patients with end stage renal dysfunction, including patients undergoing hemodialysis (HD). The HCV infection itself can cause glomerulonephritis and puts individuals at increased risk of developing end-stage renal disease; fortunately, successful HCV eradication sometimes restore HCV-related renal dysfunction. Moreover, the prognosis of dialysis patients infected with HCV is significantly worse and the renal allograft survival in HCV-infected patients is also worse than in dialysis patients without HCV infection. If life prognosis is favorable, therefore, anti HCV therapy is strongly recommended for HCV-infected patients with severe renal dysfunction. The standard therapy for HCV-infected patients with severe renal dysfunction has historically been interferon-based therapy. However, this therapy remains ineffective in achieving high, sustained viral response rates and the rate of adverse events and treatment discontinuation due to treatment-induced adverse events continues to be high in patients with severe renal dysfunction. Safe and effective anti-HCV therapies are urgently needed, and crucial, for patients with severe renal dysfunction. Recently, direct-acting antivirals (DAAs) that specifically target viral proteins have been developed, and these targets include the NS3, NS5A, and NS5B of HCV. Clinical trials have revealed high efficacy and safety of the DAA-based therapies, but patients with severe renal dysfunction were not included in the majority of these trials. However, several recent reports have shown high efficacy and safety for some regimens of DAA combination therapy for HCV-infected patients with severe renal dysfunction. In this review, we discuss novel treatments for HCV-infected patients with severe renal dysfunction and the pharmacokinetics of these drugs. PMID- 28097102 TI - Mechanisms of Accelerated Liver Fibrosis Progression during HIV Infection. AB - With the introduction of antiretroviral therapy (ART), a dramatic reduction in HIV-related morbidity and mortality has been observed. However, it is now becoming increasingly clear that liver-related complications, particularly rapid fibrosis development from ART as well as from the chronic HIV infection itself, are of serious concern to HIV patients. The pathophysiology of liver fibrosis in patients with HIV is a multifactorial process whereby persistent viral replication, and bacterial translocation lead to chronic immune activation and inflammation, which ART is unable to fully suppress, promoting production of fibrinogenic mediators and fibrosis. In addition, mitochondrial toxicity, triggered by both ART and HIV, contributes to intrahepatic damage, which is even more severe in patients co-infected with viral hepatitis. In recent years, new insights into the mechanisms of accelerated fibrosis and liver disease progression in HIV has been obtained, and these are detailed and discussed in this review. PMID- 28097103 TI - Efficacy and Safety of Daclatasvir in Hepatitis C: An Overview. AB - Hepatitis C virus (HCV) infection is a growing public health concern, with 184 million people infected worldwide. During the past decade, interferon has been the backbone of HCV treatment, even though it remains far from ideal. The latest development of the new direct antivirals has drastically changed the treatment approach for chronic hepatitis C (CHC). Inhibitors of the HCV NS5A region have garnered remarkable interest among treating physicians, due to their high potency and favourable safety profile. In particular, treatment with daclatasvir (DCV) has yielded high rates of vriologic response in patients infected with genotype (Gt) 1 and Gt 3, when used in combination with other antivirals of a different class, such as sofosbuvir. Although few data are available for DCV treatment of the other Gts, the results in patients with Gt 2 and Gt 4 infection appear promising, as do those for unique patient populations. NS5A-resistant viral variants can pre-exist or emerge after treatment failure for the HCV NS5A inhibitors. Nonetheless, DCV-resistant viral variants continue to be sensitive to interferon and other classes of antivirals such as NS3/4A and NS5B inhibitors. Herein, we aimed to provide an overview of the current knowledge about DCV in the treatment of CHC. PMID- 28097104 TI - Massive Hemolysis Causing Renal Failure in Acute Hepatitis E Infection. AB - Acute viral hepatitis is usually a self-limiting illness. However, it can lead to complications that can be life-threatening, such as acute liver failure. Glucose 6 phosphate dehydrogenase (G6PD) deficiency in the setting of acute viral hepatitis can lead to a massive hemolysis, manifesting as acute kidney injury and markedly raised bilirubin levels; although cases are rare. Here, we report such a case. The patient had a viral hepatitis E infection and presented with kidney injury requiring dialysis. Examination showed very high mixed hyperbilirubinemia due to massive intravascular hemolysis. The patient experienced a long, protracted course of illness, requiring renal replacement therapy with other supportive management, which led to improvement over a period of four weeks. This case highlights the importance of recognizing associated hemolysis in a patient with viral hepatitis who presents with very high bilirubin levels or associated kidney injury. Such patients will require aggressive supportive care with prompt fluid and electrolyte management. PMID- 28097106 TI - Postmeal triglyceridemia and variability of HbA1c and postmeal glycemia were predictors of annual decline in estimated glomerular filtration rate in type 2 diabetic patients with different stages of nephropathy. AB - BACKGROUND: This study examined associations of annual glycemic variability and postprandial dysmetabolism with annual decline in estimated glomerular filtration rate (eGFR) in type 2 diabetic patients with different stages of nephropathy. METHODS: Intrapersonal mean and coefficient of variation (CV) of HbA1c, fasting and postmeal concentrations of plasma glucose (FPG and PMPG, respectively) and serum triglycerides (FTG and PMTG, respectively) during the first 12 months after enrollment were calculated in a cohort of 168 type 2 diabetic patients: 53 with optimal albumin/creatinine ratio (ACR < 10 mg/g), 62 with high normal ACR (10-29 mg/g) and 53 with elevated ACR (?30 mg/g). Annual changes in eGFR were computed using 52 (median) creatinine measurements obtained over a median follow-up of 6.0 years. Multivariate linear regressions assessed the independent correlates of changes in eGFR. RESULTS: Kidney function declined faster in patients with high normal and elevated ACR (-1.47 and -2.01 ml/min/1.73 m2/year, respectively) compared to patients with optimal ACR (0.08 ml/min/1.73 m2/year, p < 0.05). In patients with high normal ACR, age (standardized beta,-0.30,p = 0.01), CV-HbA1c (standardized beta,-0.66,p < 0.001) and CV-PMPG (standardized beta,-0.27,p = 0.01) was associated with annual eGFR decline independently of mean HbA1c and PMPG, sex, BMI, waist circumference, diabetes duration and therapy, means and CVs of FPG and systolic blood pressure, baseline eGFR, log ACR and uses of anti hypertensive medications (R2 = 0.47). In patients with elevated ACR, PMTG (standardized beta,-0.408, p = 0.007) was associated with annual eGFR decline (R2 = 0.15). CONCLUSIONS: Consistency of glycemic control and management of postprandial glycemia and lipidemia are important to preserve kidney function in type 2 diabetic patients. PMID- 28097107 TI - Surgical resection of localized hepatocellular carcinoma: patient selection and special consideration. AB - Localized hepatocellular carcinoma (HCC) refers to a solitary or few tumors located within either the left or right hemiliver without evidence of bilobar or extrahepatic spread. This term encompasses a heterogeneous morphology with no regard to stage of prognosis of the disease. Surgical resection remains the mainstay of curative treatment for the localized HCC. Various biochemical and radiological tests constitute an indispensible part of preoperative assessment. Emergence of laparoscopic hepatectomy has brought liver resection into a new era. Improved understanding of the pathophysiology of HCC allows more aggressive surgical resection without compromising outcomes. New insights into the management of special situations, such as ruptured HCC, pyogenic transformation of HCC, and HCC with portal vein tumor thrombus, rekindle the hopes of curative resection in these terminal events. Amalgamating salvage liver transplantation into the surgical management of resectable HCC has revolutionized the treatment paradigm of this deadly disease. PMID- 28097108 TI - The Current Concepts of Total Hip Arthroplasty. PMID- 28097109 TI - Accuracy and Reliability of Preoperative On-screen Templating Using Digital Radiographs for Total Hip Arthroplasty. AB - PURPOSE: Preoperative on-screen templating is a method of using acetate templates on digital images. The aim of the present study was to evaluate the accuracy, intra- and interobserver reliabilities of preoperative on-screen templating using digital radiographs for total hip arthroplasty (THA). MATERIALS AND METHODS: Two hundred patients with hip disease who were treated with primary cementless THA were retrospectively evaluated. The accuracy of on-screen templating was assessed by comparing the predicted prosthesis sizes with the actual sizes used operatively. The inter- and intraobserver reliabilities of the templating results were also evaluated. RESULTS: The prosthesis prediction accuracy within +/-one size was 96.6% for the cup size and 97.8% for the stem size. The inter- and intraobserver reliabilities for the implant size were substantial (kappa>0.70). The intra- and interobserver reliabilities for the leg length discrepancy and femoral offset difference using the intraclass correlation coefficient ranged from 0.89 to 0.97. CONCLUSION: Preoperative on-screen templating using digital radiographs showed substantial accuracy and reliability for implant prediction. It is an effective method for predicting the size of implant, correcting the leg length discrepancy and restoring the femoral offset. PMID- 28097110 TI - Comparative Study of Bipolar Hemiarthroplasty for Femur Neck Fractures Treated with Cemented versus Cementless Stem. AB - PURPOSE: To compare and analyze clinical and radiologic outcomes of cemented versus cementless bipolar hemiarthroplasty for treatment of femur neck fractures. MATERIALS AND METHODS: A total of 180 patients aged 65 years and over older who underwent bipolar hemiarthroplasty for treatment of displaced femur neck fractures (Garden stage III, IV) from March 2009 to February 2014 were included in this study. Among the 180 patients, 115 were treated with cemented stems and 65 patients with cementless stems. Clinical outcomes assessed were: i) postoperative ambulatory status, ii) inguinal and thigh pain, and iii) complications. The radiologic outcome was femoral stem subsidence measured using postoperative simple X-ray. RESULTS: The cemented group had significantly lower occurrence of complications (postoperative infection, P=0.04) compared to the cementless group. There was no significant difference in postoperative ambulatory status, inguinal and thigh pain, and femoral stem subsidence. CONCLUSION: For patients undergoing bipolar hemiarthroplasty, other than complications, there was no statistically significant difference in clinical or radiologic outcomes in our study. Selective use of cemented stem in bipolar hemiarthroplasty may be a desirable treatment method for patients with poor bone quality and higher risk of infections. PMID- 28097111 TI - Fucntional and Radiological Outcome of Surgical Management of Acetabular Fractures in Tertiary Care Hospital. AB - PURPOSE: Acetabular fractures are mainly caused by trauma and the incidence is rising in developing countries. Initially these fractures were managed conservatively, due to lack of specialized and dedicated acetabulum surgery centres. Our aim is to study the radiological and functional outcomes of surgical management of acetabular fractures in tertiary care hospital. MATERIALS AND METHODS: Total 50 patients were enrolled. The patients with acetabular fractures were enrolled between the years 2012 to 2014. Patients were evaluated clinically with Harris hip score (HHS) and radiologically with Matta outcome grading. The factors examined include age, gender, fracture pattern, time between injury and surgery, initial displacement and quality of reduction on the final outcome. RESULTS: There were 34 males and 16 females. Mean age was 44.20+/-11.65 years while mean duration of stay was 9.28+/-2.36 days. Duration of follow-up was 24 months. Most common mechanism of injury was motor vehicle accident (n=37, 74.0%). Open reduction and internal fixation of fractures were performed using reconstruction plates. Mean HHS at 24 months was 82.36+/-8.55. The clinical outcome was acceptable (excellent or good) in 35 (70.0%) cases and not acceptable (fair or poor) in 15 (30.0%) cases. The radiological outcome was anatomical in 39 (78.0%) cases, congruent in 5 (10.0%) cases, incongruent in 6 (12.0%) cases. CONCLUSION: Study results indicated that mechanism of injury, time between injury and surgery, initial degree of displacement and quality of reduction had significant effect on functional as well as radiological outcome. PMID- 28097112 TI - Surgical Results of the Cephalomedullary Nail for the Femoral Intertrochanteric Fracture: Comparison between Non-experienced Surgeons and Experienced Surgeon. AB - PURPOSE: Cephalomedullary nail (CM nail) in the treatment of femoral intertrochanteric fractures is in the lime light in recent years. The purpose of this study is to compare surgical outcomes between experienced surgeon and non experienced surgeons in respect of CM nail for femoral intertrochanteric fractures. MATERIALS AND METHODS: The 129 patients underwent CM nail for femoral intertrochanteric fracture more than six months of follow-up from April 2011 to March 2014 in Seoul Medical Center (Seoul, Korea) were participated in this study. For this study, group A consisted of experienced surgeons who performed more than 500 times of CM nail, and group B consisted of non-experienced surgeons who performed less than 50 times of CM nail. Clinical and radiologic outcomes, complications and the need for reoperation between both groups were compared in the study. RESULTS: According to clinical result, both the mean operation time and transfusion volume were significantly longer and greater in group B (P<0.05). In the radiologic outcomes, adequacy of reduction, tip-apex distance and numbers of case placed in the Cleveland zones 5, 6 and 8; there was no statistical difference between both groups. Moreover, rate of complication and reoperation had same results as radiologic outcomes. CONCLUSION: There was no significant difference with statistical data in complications from CM nail for femoral intertrochanteric fractures between experienced surgeon and non-experienced surgeon. Although the operation time and transfusion volume were significantly longer and greater in the case of operation by non-experienced surgeon, satisfactory performance was seen in the complications and the need for reoperation. PMID- 28097113 TI - Clinical and Functional Outcomes of Treatment for Type A1 Intertrochanteric Femoral Fracture in Elderly Patients: Comparison of Dynamic Hip Screw and Proximal Femoral Nail Antirotation. AB - PURPOSE: We aimed to evaluate and compare the clinical and functional outcomes of dynamic hip screw (DHS) and proximal femoral nail antirotation (PFNA) treatment of AO type 1 intertrochanteric fractures in elderly patients. MATERIALS AND METHODS: We retrospectively reviewed 194 consecutive patients with type A1 intertrochanteric femoral fractures who were treated with DHS (n=113) or PFNA (n=81). We evaluated operation time, intraoperative blood loss, and functional outcomes, walking ability, and the Barthel activities index. Fracture union, sliding of hip screw, proximal femur shortening, and presence of complications were assessed radiologically at relevant follow-up intervals. RESULTS: The mean operation time and blood loss were significantly lower for the PFNA group, but walking ability and Barthel index decreased to a similar extent for both groups. However, patients in the DHS group complained of significantly more pain (P=0.049). Although there were no significant differences between the two groups with respect to the time until fracture union was achieved, patients in the DHS group exhibited a higher extent of proximal femoral shortening and sliding of the hip screw. Differences about hip screw sliding and proximal femur shortening within each subgroup were not significant. CONCLUSION: Compared to DHS treatment, PFNA treatment of type A1 intertrochanteric fractures is associated with reduced blood loss, shorter operation time, and less severe pain after surgery. Additionally, sliding of the hip screw and proximal femur shortening are expected to occur more frequently after DHS. PMID- 28097114 TI - Bilateral Idiopathic Chondrolysis of the Hip in an Adult: A Case Report and Review of the Literature. AB - Idiopathic chondrolysis of the hip usually develops in adolescents and is a disease characterized by gradual degenerative changes of the hyaline cartilage surrounding the head of the femur. It eventually decreases the hip joint space and causes limitations in the hip joint range of motion due to pain. The authors had experienced an unusual case of bilateral idiopathic chondrolysis of the hip in an 54 year-old male; thus, we report the treatment results and literature reviews in this case report. PMID- 28097115 TI - Granulomatous Lung Disease: A Novel Complication following Metallosis from Hip Arthroplasty. AB - A case of a female patient with local and systemic complications of metallosis, following catastrophic wear of a revised hip arthroplasty, is presented. The patient had a history of a fractured ceramic-on-ceramic implant, exchanged with a metal-on-polyethylene prosthesis. Systemic complications included sarcoidosis like reactions, presenting as granulomatous lung disease, along with chorioretinitis, erythema nodosum, and cardiomyopathy. High local and circulating cobalt and chromium levels established the diagnosis. The patient underwent extensive debridement and implant revision. One year postoperatively, she had no respiratory symptoms or functional impairment. Local and systemic complications of metallosis after hip arthroplasty should be promptly recognized and treated operatively. PMID- 28097116 TI - Kikuchi-Fujimoto Disease Misdiagnosed as Relapse of the Infection after Treatment of Periprosthetic Hip Joint Infection. AB - Periprosthetic joint infection (PJI) of the hip can be difficult to treat and can lead to a number of problems including: i) severe functional decline of the hip joint and ii) increasing financial burden for patients due to long treatment periods and the need for repeated surgical interventions. Because there is risk of inadequate control of infection or relapse of a preexisting infection following the treatment of PJI through surgery, it is important to closely observe clinical symptoms such as systemic fever. Kikuchi-Fujimoto disease is usually a self-limiting disease characterized by fever and cervical lymphadenopathy. We report one case of Kikuchi-Fujimoto disease, with literatures review, that was mistaken for an infection relapse after surgical treatment of the PJI due to sustained fever postoperatively. PMID- 28097117 TI - Cobalt Intoxication Heart Failure after Revision Total Hip Replacement for Ceramic Head Fracture: A Case Report. AB - In 1960s, toxic heart failure due to cobalt poisoning was firstly reported from Canadian industrial worker. Following development of bearing materials in hip arthroplasties, using cobalt-chrome alloy in bearing surface, there were rarely reported of systemic affect toxic cobaltism include toxic heart failure due to articulation wear in Western countries. It could be happened more easily by third body wear from ceramic particle especially revision total hip replacement (THR) surgery using cobalt-chrome alloy following ceramic articulation breakage which index surgery performed by ceramic on ceramic bearing. In Korea, due to many surgeons prefer ceramic on ceramic bearing in THR compared to Western countries, it might be more important issue within a time. However in our knowledge, there was no previous report about cobalt poisoning heart failure in Korea. It is still very rare and hard to diagnose cobalt intoxication heart failure after THR, so we report a case of fatal heart failure caused by cobalt intoxication after revision THR in 53-year old man who successfully underwent re-revision THR. PMID- 28097118 TI - Femur Neck Fracture in a Young Marfan Syndrome Patient. AB - Marfan syndrome is an autosomal dominant and could decrease bone mineral density. So patients with Marfan syndrome could vulnerable to trauma in old ages. We present the first report, to the best of our knowledge, of a rare fracture of the femoral neck with a minor traumatic history in a juvenile Marfan syndrome patient whose physis is still open. Although the patient is young, her bone mineral density was low and the geometry of femur is changed like old ages. The femur neck fracture in children is very rare and only caused by high energy trauma, we concluded that the Marfan syndrome makes the bone weaker in young age and preventative medications to avoid fractures in younger Marfan syndrome patients are necessary in early ages. PMID- 28097119 TI - Overfat and Underfat: New Terms and Definitions Long Overdue. AB - For the first time in human history, the number of obese people worldwide now exceeds those who are underweight. However, it is possible that there is an even more serious problem-an overfat pandemic comprised of people who exhibit metabolic health impairments associated with excess fat mass relative to lean body mass. Many overfat individuals, however, are not necessarily classified clinically as overweight or obese, despite the common use of body mass index as the clinical classifier of obesity and overweight. The well-documented obesity epidemic may merely be the tip of the overfat iceberg. The counterpart to the overfat condition is the underfat state, also a common and dangerous health circumstance associated with chronic illness and starvation. Currently (and paradoxically), high rates of obesity and overweight development coexist with undernutrition in developing countries. Studies in cognitive linguistics suggest that accurate, useful, and unintimidating terminology regarding abnormal body fat conditions could help increase a person's awareness of their situation, helping the process of implementing prevention and simple remedies. Our contention is that promoting the terms "overfat" and "underfat" to describe body composition states to the point where they enter into common usage may help in creating substantive improvements in world health. PMID- 28097120 TI - Barriers and Facilitators toward HIV Testing and Health Perceptions among African American Men Who Have Sex with Women at a South Side Chicago Community Health Center: A Pilot Study. AB - In the United States, African-Americans' (AAs) HIV infection rates are higher than any other racial group, and AA men who have sex with women (MSW) are a significant proportion of new cases. There is little research into AA MSW HIV/AIDS knowledge, barriers, and facilitators of HIV testing in Chicago. We enrolled a convenience sample of AA MSW from a community health clinic who completed self-administered surveys assessing HIV knowledge and testing-related barriers and facilitators. The survey was a combination of questions from several validated instruments, and additional questions were written based on key informant interviews with social scientists to tailor the questionnaire for AA men living on the South Side of Chicago. We recruited 20 AA MSW (mean age 47.4 years). Sixty-five percent had incomes <$10,000/year, 30% were insured, and 50% had post-secondary education. Despite low socioeconomic status, their HIV literacy was relatively high. The identified major barriers to testing were low perceived HIV risk, concerns over privacy, and external stigma at testing sites. Future efforts should focus on educating AA MSW on actual risk for HIV and address issues of privacy and stigma at testing sites. PMID- 28097122 TI - Proactive Risk Assessments and the Continuity of Business Principles: Perspectives on This Novel, Combined Approach to Develop Guidance for the Permitted Movement of Agricultural Products during a Foot-and-Mouth Disease Outbreak in the United States. AB - Animal diseases such as foot-and-mouth disease (FMD) have the potential to severely impact food animal production systems. Paradoxically, the collateral damage associated with the outbreak response may create a larger threat to the food supply, social stability, and economic viability of rural communities than the disease itself. When FMD occurs in domestic animals, most developed countries will implement strict movement controls in the area surrounding the infected farm(s). Historically, stopping all animal movements has been considered one of the most effective ways to control FMD and stop disease spread. However, stopping all movements in an area comes at a cost, as there are often uninfected herds and flocks within the control area. The inability to harvest uninfected animals and move their products to processing interrupts the food supply chain and has the potential to result in an enormous waste of safe, nutritious animal products, and create animal welfare situations. In addition, these adverse effects may negatively impact agriculture businesses and the related economy. Effective disease control measures and the security of the food supply thus require a balanced approach based on science and practicality. Evaluating the risks associated with the movement of live animals and products before an outbreak happens provides valuable insights for risk management plans. These plans can optimize animal and product movements while preventing disease spread. Food security benefits from emergency response plans that both control the disease and keep our food system functional. Therefore, emergency response plans must aim to minimize the unintended negative consequence to farmers, food processors, rural communities, and ultimately consumers. PMID- 28097121 TI - The Gastrointestinal Tract as a Key Target Organ for the Health-Promoting Effects of Dietary Proanthocyanidins. AB - Proanthocyanidins (PACs) are polymers of flavan-3-ols abundant in many vegetable foods and beverages widely consumed in the human diet. There is increasing evidence supporting the beneficial impact of dietary PACs in the prevention and nutritional management of non-communicable chronic diseases. It is considered that PACs with a degree of polymerization >3 remain unabsorbed in the gastrointestinal (GI) tract and accumulate in the colonic lumen. Accordingly, the GI tract may be considered as a key organ for the healthy-promoting effects of dietary PACs. PACs form non-specific complexes with salivary proteins in mouth, originating the sensation of astringency, and with dietary proteins, pancreatic enzymes, and nutrient transporters in the intestinal lumen, decreasing the digestion and absorption of carbohydrates, proteins, and lipids. They also exert antimicrobial activities, interfering with cariogenic or ulcerogenic pathogens in the mouth (Streptococcus mutans) and stomach (Helicobacter pylori), respectively. Through their antioxidant and antiinflammatory properties, PACs decrease inflammatory processes in animal model of gastric and colonic inflammation. Interestingly, they exert prebiotic activities, stimulating the growth of Lactobacillus spp. and Bifidobacterium spp. as well as some butyrate-producing bacteria in the colon. Finally, PACs are also metabolized by the gut microbiota, producing metabolites, mainly aromatic acids and valerolactones, which accumulate in the colon and/or are absorbed into the bloodstream. Accordingly, these compounds could display biological activities on the colonic epithelium or in extra-intestinal tissues and, therefore, contribute to part of the beneficial effects of dietary PACs. PMID- 28097123 TI - The Power of CRISPR-Cas9-Induced Genome Editing to Speed Up Plant Breeding. AB - Genome editing with engineered nucleases enabling site-directed sequence modifications bears a great potential for advanced plant breeding and crop protection. Remarkably, the RNA-guided endonuclease technology (RGEN) based on the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR associated protein 9 (Cas9) is an extremely powerful and easy tool that revolutionizes both basic research and plant breeding. Here, we review the major technical advances and recent applications of the CRISPR-Cas9 system for manipulation of model and crop plant genomes. We also discuss the future prospects of this technology in molecular plant breeding. PMID- 28097124 TI - Transcriptome Sequencing of Gynostemma pentaphyllum to Identify Genes and Enzymes Involved in Triterpenoid Biosynthesis. AB - G. pentaphyllum (Gynostemma pentaphyllum), a creeping herbaceous perennial with many important medicinal properties, is widely distributed in Asia. Gypenosides (triterpenoid saponins), the main effective components of G. pentaphyllum, are well studied. FPS (farnesyl pyrophosphate synthase), SS (squalene synthase), and SE (squalene epoxidase) are the main enzymes involved in the synthesis of triterpenoid saponins. Considering the important medicinal functions of G. pentaphyllum, it is necessary to investigate the transcriptomic information of G. pentaphyllum to facilitate future studies of transcriptional regulation. After sequencing G. pentaphyllum, we obtained 50,654,708 unigenes. Next, we used RPKM (reads per kilobases per million reads) to calculate expression of the unigenes and we performed comparison of our data to that contained in five common databases to annotate different aspects of the unigenes. Finally, we noticed that FPS, SS, and SE showed differential expression of enzymes in DESeq. Leaves showed the highest expression of FPS, SS, and SE relative to the other two tissues. Our research provides transcriptomic information of G. pentaphyllum in its natural environment and we found consistency in unigene expression, enzymes expression (FPS, SS, and SE), and the distribution of gypenosides content in G. pentaphyllum. Our results will enable future related studies of G. pentaphyllum. PMID- 28097125 TI - Bioinformatics Analysis of the Human Surfaceome Reveals New Targets for a Variety of Tumor Types. AB - It is estimated that 10 to 20% of all genes in the human genome encode cell surface proteins and due to their subcellular localization these proteins represent excellent targets for cancer diagnosis and therapeutics. Therefore, a precise characterization of the surfaceome set in different types of tumor is needed. Using TCGA data from 15 different tumor types and a new method to identify cancer genes, the S-score, we identified several potential therapeutic targets within the surfaceome set. This allowed us to expand a previous analysis from us and provided a clear characterization of the human surfaceome in the tumor landscape. Moreover, we present evidence that a three-gene set-WNT5A, CNGA2, and IGSF9B-can be used as a signature associated with shorter survival in breast cancer patients. The data made available here will help the community to develop more efficient diagnostic and therapeutic tools for a variety of tumor types. PMID- 28097127 TI - Translational Molecular Imaging Computing: Advances in Theories and Applications. PMID- 28097126 TI - Inhibitor of Nicotinamide Phosphoribosyltransferase Sensitizes Glioblastoma Cells to Temozolomide via Activating ROS/JNK Signaling Pathway. AB - Overcoming temozolomide (TMZ) resistance is a great challenge in glioblastoma (GBM) treatment. Nicotinamide phosphoribosyltransferase (NAMPT) is a rate limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide and has a crucial role in cancer cell metabolism. In this study, we investigated whether FK866 and CHS828, two specific NAMPT inhibitors, could sensitize GBM cells to TMZ. Low doses of FK866 and CHS828 (5 nM and 10 nM, resp.) alone did not significantly decrease cell viability in U251-MG and T98 GBM cells. However, they significantly increased the antitumor action of TMZ in these cells. In U251-MG cells, administration of NAMPT inhibitors increased the TMZ (100 MUM)-induced apoptosis and LDH release from GBM cells. NAMPT inhibitors remarkably enhanced the activities of caspase-1, caspase-3, and caspase-9. Moreover, NAMPT inhibitors increased reactive oxygen species (ROS) production and superoxide anion level but reduced the SOD activity and total antioxidative capacity in GBM cells. Treatment of NAMPT inhibitors increased phosphorylation of c-Jun and JNK. Administration of JNK inhibitor SP600125 or ROS scavenger tocopherol with TMZ and NAMPT inhibitors substantially attenuated the sensitization of NAMPT inhibitor on TMZ antitumor action. Our data indicate a potential value of NAMPT inhibitors in combined use with TMZ for GBM treatment. PMID- 28097128 TI - Vowel Imagery Decoding toward Silent Speech BCI Using Extreme Learning Machine with Electroencephalogram. AB - The purpose of this study is to classify EEG data on imagined speech in a single trial. We recorded EEG data while five subjects imagined different vowels, /a/, /e/, /i/, /o/, and /u/. We divided each single trial dataset into thirty segments and extracted features (mean, variance, standard deviation, and skewness) from all segments. To reduce the dimension of the feature vector, we applied a feature selection algorithm based on the sparse regression model. These features were classified using a support vector machine with a radial basis function kernel, an extreme learning machine, and two variants of an extreme learning machine with different kernels. Because each single trial consisted of thirty segments, our algorithm decided the label of the single trial by selecting the most frequent output among the outputs of the thirty segments. As a result, we observed that the extreme learning machine and its variants achieved better classification rates than the support vector machine with a radial basis function kernel and linear discrimination analysis. Thus, our results suggested that EEG responses to imagined speech could be successfully classified in a single trial using an extreme learning machine with a radial basis function and linear kernel. This study with classification of imagined speech might contribute to the development of silent speech BCI systems. PMID- 28097129 TI - Structure Prior Effects in Bayesian Approaches of Quantitative Susceptibility Mapping. AB - Quantitative susceptibility mapping (QSM) has shown its potential for anatomical and functional MRI, as it can quantify, for in vivo tissues, magnetic biomarkers and contrast agents which have differential susceptibilities to the surroundings substances. For reconstructing the QSM with a single orientation, various methods have been proposed to identify a unique solution for the susceptibility map. Bayesian QSM approach is the major type which uses various regularization terms, such as a piece-wise constant, a smooth, a sparse, or a morphological prior. Six QSM algorithms with or without structure prior are systematically discussed to address the structure prior effects. The methods are evaluated using simulations, phantom experiments with the given susceptibility, and human brain data. The accuracy and image quality of QSM were increased when using structure prior in the simulation and phantom compared to same regularization term without it, respectively. The image quality of QSM method using the structure prior is better comparing, respectively, to the method without it by either sharpening the image or reducing streaking artifacts in vivo. The structure priors improve the performance of the various QSMs using regularized minimization including L1, L2, and TV norm. PMID- 28097130 TI - Establishment of a Novel Simplified Surgical Model of Acute Liver Failure in the Cynomolgus Monkey. AB - Models using large animals that are suitable for studying artificial liver support system (ALSS) are urgently needed. Presently available acute liver failure (ALF) models mainly involve pigs or dogs. Establishment of current surgical ALF models (hepatectomy/devascularization) requires either very good surgical skills or multistep processes-even multiple stages of surgery. Therefore, it is necessary to develop a simplified surgical method. Here we report a novel simplified surgical ALF model using cynomolgus monkeys. Six monkeys underwent portal-right renal venous shunt combined with common bile duct ligation and transection (PRRS + CBDLT). Postoperatively, the monkeys had progressively increased listlessness, loss of appetite, and obvious jaundice. Blood biochemistry levels (Amm, ALT, AST, TBiL, DBiL, ALP, LDH, CK, and Cr) and prothrombin time (PT) were significantly increased (all P < 0.01) and albumin (ALB) was markedly reduced (P < 0.01) compared with baseline values. Histological examination of liver specimens on postoperative day 10 revealed cholestasis and inflammation. PRRS + CBDLT produced ALF that closely correlated with clinical situations. Compared with other surgical or drug ALF models, ours was simplified and animals were hemodynamically stable. This model could provide a good platform for further research on ALSS, especially regarding their detoxification functions. PMID- 28097131 TI - Genome-Wide Identification of Long Noncoding RNAs in Human Intervertebral Disc Degeneration by RNA Sequencing. AB - Long noncoding RNAs (lncRNAs) are emerging as crucial players in a myriad of biological processes. However, the precise mechanism and functions of most lncRNAs are poorly characterized. In this study, we presented genome-wide identification of lncRNAs in the patients with intervertebral disc degeneration (IDD) and spinal cord injury (control) using RNA sequencing (RNA-seq). A total of 124.6 million raw reads were yielded using Hiseq 2500 platform and approximately 88% clean reads could be aligned to human reference genome in both IDD and control groups. RNA-seq profiling indicated that 1,854 lncRNAs were differentially expressed (log2 fold change >= 1 or <=-1, p < 0.05), in which 1,530 could potentially target 6,386 genes via cis-regulatory effects. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis for these target genes suggested that lncRNAs were involved in diverse pathways, such as lysosome, focal adhesion, and MAPK signaling. In addition, a competing endogenous RNA (ceRNA) network was constructed for analyzing the function of lncRNAs. Further, quantitative real time PCR (qRT-PCR) was used to confirm the differentially expressed lncRNAs and ceRNA network. In conclusion, our results present the first global identification of lncRNAs in IDD and may provide candidate diagnostic biomarkers for IDD treatment. PMID- 28097132 TI - Knowledge of the Disease, Perceived Social Support, and Cognitive Appraisals in Women with Urinary Incontinence. AB - Social support and knowledge of the disease have been shown to facilitate adaptation to a chronic disease. However, the adaptation process is not fully understood. We hypothesized that these factors can contribute to better adaptation to the disease through their impact on disease-related cognitive appraisal. To analyze the links between social support and the knowledge of the disease, on one hand, and disease-related appraisals, on the other hand, one hundred fifty-eight women with stress UI, aged 32 to 79, took part in the study. Questionnaire measures of knowledge of UI, social support, and disease-related appraisals were used in the study. The level of knowledge correlated significantly negatively with the appraisal of the disease as Harm. The global level of social support correlated significantly positively with three disease related appraisals: Profit, Challenge, and Value. Four subgroups of patients with different constellations of social support and knowledge of the disease were identified in cluster analysis and were demonstrated to differ significantly on four disease-related appraisals: Profit, Challenge, Harm, and Value. Different cognitive appraisals of UI may be specifically related to social support and knowledge of the disease, with social support affective positive disease-related appraisals, and the knowledge affecting the appraisal of Harm. PMID- 28097134 TI - Natural Therapies for Cardiovascular Diseases. PMID- 28097133 TI - Morphokinetic Characteristics and Developmental Potential of In Vitro Cultured Embryos from Natural Cycles in Patients with Poor Ovarian Response. AB - Background. Patients with poor ovarian response to ovarian hyperstimulation represent an interesting group for studying the impact of embryo cleavage irregularities on clinical outcome since all embryos, regardless of their quality, are usually transferred to the uterus. The aim of our study was to follow the morphokinetics of fertilized oocytes from natural cycles in poor responders. Methods. Zygotes from 53 cycles were cultured in vitro for 3 days. The morphokinetics of their development and transfer outcomes were retrospectively analyzed for the normally and irregularly cleaved embryos. Results. Of all embryos, 30.2% had single and 20.8% multiple cleavage irregularities with the following prevalence: developmental arrest 30.2%, direct cleavage to more than two cells 24.5%, chaotic cleavage 13.2%, and reverse cleavage 11.3%. These embryos had longer pronuclear phases, first cytokinesis, second embryo cell cycles, and less synchronized divisions. The transfer of normally developing embryos resulted in an implantation rate of 30.8% and a delivery rate of 23.1%, but irregularly cleaved embryos did not implant. Conclusions. The use of time-lapse microscopy in poor responder patients identified embryos with cleavage abnormalities that are related with no or extremely low implantation potential. Gained information about embryo quality is important for counselling patients about their expectations. PMID- 28097135 TI - Significance of "Not Detected but Amplified" Results by Real-Time PCR Method for HPV DNA Detection. AB - Human papillomavirus (HPV) infection is an important etiologic factor in cervical carcinogenesis. Various HPV DNA detection methods have been evaluated for clinicopathological level. For the specimens with normal cytological finding, discrepancies among the detection methods were frequently found and adequate interpretation can be difficult. 6,322 clinical specimens were submitted and evaluated for real-time PCR and Hybrid Capture 2 (HC2). 573 positive or "Not Detected but Amplified" (NDBA) specimens by real-time PCR were additionally tested using genetic analyzer. For the reliability of real-time PCR, 325 retests were performed. Optimal cut-off cycle threshold (CT ) value was evaluated also. 78.7% of submitted specimens showed normal or nonspecific cytological finding. The distributions of HPV types by real-time PCR were not different between positive and NDBA cases. For positive cases by fragment analysis, concordance rates with real-time PCR and HC2 were 94.2% and 84.2%. In NDBA cases, fragment analysis and real-time PCR showed identical results in 77.0% and HC2 revealed 27.6% of concordance with fragment analysis. Optimal cut-off CT value was different for HPV types. NDBA results in real-time PCR should be regarded as equivocal, not negative. The adjustment of cut-off CT value for HPV types will be helpful for the appropriate result interpretation. PMID- 28097137 TI - Do Mechanical and Physicochemical Properties of Orthodontic NiTi Wires Remain Stable In Vivo? AB - Introduction and Aim. Exceptional properties of the NiTi archwires may be jeopardized by the oral cavity; thus its long-term effect on the mechanical and physiochemical properties of NiTi archwires was the aim of work. Material and Methods. Study group comprised sixty 0.016 * 0.022 NiTi archwires from the same manufacturer evaluated (group A) after the first 12 weeks of orthodontic treatment. 30 mm long pieces cut off from each wire prior to insertion formed the control group B. Obeying the strict rules of randomization, all samples were subjected to microscopic evaluation and nanoindentation test. Results. Both groups displayed substantial presence of nonmetallic inclusions. Heterogeneity of the structure and its alteration after usage were found in groups B and A, respectively. Conclusions. Long-term, reliable prediction of biomechanics of NiTi wires in vivo is impossible, especially new archwires from the same vendor display different physiochemical properties. Moreover, manufacturers have to decrease contamination in the production process in order to minimize risk of mutual negative influence of nickel-titanium archwires and oral environment. PMID- 28097136 TI - Intrapulpal Thermal Changes during Setting Reaction of Glass Carbomer(r) Using Thermocure Lamp. AB - Objectives. To measure the temperature increase induced during thermocure lamp setting reaction of glass carbomer and to compare it with those induced by visible light curing of a resin-modified glass ionomer and a polyacid-modified composite resin in primary and permanent teeth. Materials and Methods. Nonretentive class I cavities were prepared in extracted primary and permanent molars. Glass carbomer (GC) was placed in the cavity and set at 60 degrees C for 60 sn using a special thermocure lamp. Resin-modified glass ionomer (RMGIC) and polyacid-modified composite resin (PMCR) were placed in the cavities and polymerized with an LED curing unit. Temperature increases during setting reactions were measured with a J-type thermocouple wire connected to a data logger. Data were examined using two-way analysis of variance and Tukey's honestly significant difference tests. Results. The use of GC resulted in temperature changes of 5.17 +/- 0.92 degrees C and 5.32 +/- 0.90 degrees C in primary and permanent teeth, respectively (p > 0.05). Temperature increases were greatest in the GC group, differing significantly from those in the PMCR group (p < 0.05). Conclusion. Temperature increases during polymerization and setting reactions of the materials were below the critical value in all groups. No difference was observed between primary and permanent teeth, regardless of the material used. PMID- 28097138 TI - Pulmonary Function and Arterial Stiffness in Chronic Heart Failure. AB - Arterial stiffness contributes to heart failure and is decreased by angiotensin receptor blockers (ARBs). This cross-sectional study aimed to assess associations of lung function and ARB with arterial stiffness in patients with chronic heart failure. 354 outpatients (168 males; 186 females; 68.2 +/- 7.2 years old) with chronic heart failure were evaluated. Lung function parameters, including forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and FEV1 to FVC ratio (FEV1/FVC), were assessed. The cardio-ankle vascular index (CAVI) was used to estimate arterial stiffness. Unadjusted correlation analyses revealed a positive association of CAVI with ARB but not ACEI, and a negative correlation with FEV1 (r = -0.2987, p < 0.0001). Multiple stepwise regression analyses showed that ARB and FEV1 (p < 0.0001) were independent predicting factors for CAVI. These findings suggest that reduced pulmonary function is associated with increased CAVI. Pulmonary function protection could be used to improve the prognosis in heart failure, but additional studies are necessary. PMID- 28097139 TI - Optimal Control Model of Tumor Treatment with Oncolytic Virus and MEK Inhibitor. AB - Tumors are a serious threat to human health. The oncolytic virus is a kind of tumor killer virus which can infect and lyse cancer cells and spread through the tumor, while leaving normal cells largely unharmed. Mathematical models can help us to understand the tumor-virus dynamics and find better treatment strategies. This paper gives a new mathematical model of tumor therapy with oncolytic virus and MEK inhibitor. Stable analysis was given. Because mitogen-activated protein kinase (MEK) can not only lead to greater oncolytic virus infection into cancer cells, but also limit the replication of the virus, in order to provide the best dosage of MEK inhibitors and balance the positive and negative effect of the inhibitors, we put forward an optimal control problem of the inhibitor. The optimal strategies are given by theory and simulation. PMID- 28097141 TI - Emodin Inhibits the Epithelial to Mesenchymal Transition of Epithelial Ovarian Cancer Cells via ILK/GSK-3beta/Slug Signaling Pathway. AB - Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Despite the anticancer capabilities of emodin observed in many cancers, including EOC, the underlying molecular mechanism remains to be elucidated. A crucial link has been discovered between the acquisition of metastatic traits and the epithelial-mesenchymal transition (EMT). The present study aimed to determine whether emodin could inhibit the EMT of EOC cells and explore the underlying mechanism. The CCK-8 assay and transwell assay showed that emodin effectively repressed the abilities of proliferation, invasion, and migration in A2780 and SK OV-3 cells. The Western blot showed that emodin upregulated epithelial markers (E cadherin and Claudin) while it downregulated mesenchymal markers (N-cadherin and Vimentin) and transcription factor (Slug) in a dose-dependent fashion. After transfection of siRNA-Slug, both Slug and N-cadherin were downregulated in EOC cells while E-cadherin was upregulated, which was intensified by emodin. Besides, emodin decreased the expression of ILK, p-GSK-3beta, beta-catenin, and Slug. Transfection of siRNA-ILK also achieved the same effects, which was further strengthened by following emodin treatment. Nevertheless, SB216763, an inhibitor of GSK-3beta, could reverse the effects of emodin except for ILK expression. These findings suggest that emodin inhibited the EMT of EOC cells via ILK/GSK 3beta/Slug signaling pathway. PMID- 28097142 TI - Evaluation of Two Methods for Determination of CD64 as a Diagnostic Marker of Infection in Critically Ill Adults. AB - Objectives. Diagnostic markers of infection have had little innovation over the last few decades. CD64, a marker expressed on the surface of neutrophils, may have utility for this purpose. Methods. This study was conducted in an adult intensive care unit (ICU) in Sao Paulo, Brazil, with 89 patients. We evaluated CD64 in patients with documented or clinically diagnosed infection (infection group) and controls (patients without any evidence of infection) by two different methodologies: method #1, an in house assay, and method #2, the commercial kit Leuko64 (Trillium Diagnostics). Results. CD64 displayed good discriminating power with a 91.2% sensitivity (95% CI 90.7-91.6%) for detecting infection. The commercial kit (Leuko64) demonstrated higher specificity (87.3%) compared with method #1 as well as better accuracy (88.8%). Conclusions. CD64 seems to be a promising marker of infection in the intensive care setting, with Leuko64 showing a slight advantage. PMID- 28097140 TI - Function, Role, and Clinical Application of MicroRNAs in Vascular Aging. AB - Vascular aging, a specific type of organic aging, is related to age-dependent changes in the vasculature, including atherosclerotic plaques, arterial stiffness, fibrosis, and increased intimal thickening. Vascular aging could influence the threshold, process, and severity of various cardiovascular diseases, thus making it one of the most important risk factors in the high mortality of cardiovascular diseases. As endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are the main cell biological basis of these pathology changes of the vasculature, the structure and function of ECs and VSMCs play a key role in vascular aging. MicroRNAs (miRNAs), small noncoding RNAs, have been shown to regulate the expression of multiple messenger RNAs (mRNAs) posttranscriptionally, contributing to many crucial aspects of cell biology. Recently, miRNAs with functions associated with aging or aging-related diseases have been studied. In this review, we will summarize the reported role of miRNAs in the process of vascular aging with special emphasis on EC and VSMC functions. In addition, the potential application of miRNAs to clinical practice for the diagnosis and treatment of cardiovascular diseases will also be discussed. PMID- 28097143 TI - Analysis of Polyphenolic Compounds in Extracts from Leaves of Some Malus domestica Cultivars: Antiradical and Antimicrobial Analysis of These Extracts. AB - In this study, methanol, ethyl acetate, water extracts, and precipitate were obtained from leaves of Malus domestica cultivars: Golden delicious, Jonagold, Elstar, Ligol, and Mutsu. Antiradical activity of these extracts was measured using the ABTS+? radical, and antimicrobial activity was measured with the disk diffusion method. Phenolic compounds were measured with the colorimetric method and identified with high performance liquid chromatography (HPLC). The highest antiradical activity was observed for the Jonagold variety, and in particular strong activity was noted for ethyl acetate extracts. Antimicrobial activity was observed against strains of Staphylococcus aureus, Enterococcus faecalis, and the fungus Candida glabrata. Particularly susceptible to the extracts activity appeared to be Staphylococcus aureus, but the growth of Candida glabrata was inhibited in the presence of ethyl acetate extracts. With the HPLC method we identified a high amount of phloridzin (above 500 mg per g of ethyl acetate extracts), lower amounts of hyperoside, isoquercitrin, and quercitrin, and traces of p-hydroxybenzoic and chlorogenic acids. The contribution of phloridzin to antiradical activity of methanol and ethyl acetate extracts was very high (above 90%). In water extract the contribution of phloridzin was between 38.9 and 55.2%, chlorogenic acid 22.7 and 36.1%, and hyperoside 12.2 and 13.3%. PMID- 28097144 TI - Remote Postconditioning Alone and Combined with Hypothermia Improved Postresuscitation Cardiac and Neurological Outcomes in Swine. AB - Objective. Previously, we demonstrated that remote ischemic postconditioning (RIpostC) improved postresuscitation myocardial and cerebral functions in rat. Here, we investigated the effects of RIpostC alone and combined with therapeutic hypothermia (TH) on cardiac and neurological outcomes after CPR in swine. Methods. Twenty-one pigs were subjected to 10 mins of VF and then 5 mins of CPR. The animals were randomized to receive RIpostC alone, or its combination with TH, or sham control. RIpostC was induced by 4 cycles of limb ischemia followed by reperfusion. TH was implemented by surface cooling to reach a temperature of 32 34 degrees C. Results. During 72 hrs after resuscitation, lower level of cardiac troponin I and greater stroke volume and global ejection fraction were observed in animals that received RIpostC when compared to the control. RIpostC also decreased serum levels of neuron-specific enolase and S100B and increased neurologic alertness score after resuscitation. The combination of RIpostC and TH resulted in greater improvement in cardiac and neurological outcomes than RIpostC alone. Conclusion. RIpostC was conducive to improving postresuscitation myocardial and cerebral functions and reducing their organ injuries. Its combination with TH further enhanced its protective effects. PMID- 28097145 TI - Depression and HIV Risk Behaviors among Female Sex Workers in Guangdong, China: A Multicenter Cross-Sectional Study. AB - Background. Our study aimed to assess the burden of depression and evaluate factors associated with depression and status of HIV risk behaviors among female sex workers (FSWs) in Guangdong, China. Method. We recruited FSWs from massage parlors, saunas, restaurants, hotels, hair salons, and streets in Guangdong, China, in 2014. Information on demographic characteristics, HIV testing history, and sexual behaviors was collected using a questionnaire. A blood sample was collected to test for HIV, syphilis, and HCV. A participant was defined as being depressed if she obtained 6 points or above using the 12-item General Health Questionnaire. Results. Among the 653 participants, 41.7% were 21-30 years old and 43.6% married. Overall, 52.4% were found to be depressed. FSWs who had correct syphilis related knowledge [aOR = 1.45; 95% CI: 1.04-2.03] and had primary sex partner (1.63, 1.14-2.33) were more likely to be depressed. FSWs who did not use a condom during their last sex with the primary sex partner were less likely to be depressed (0.47, 0.31-0.71). Conclusion. Our study observed high level of depression and HIV risk behaviors among Chinese FSWs. Future interventions should integrate mental health services in comprehensive interventions to prevent depression among Chinese FSWs. PMID- 28097146 TI - Versatility of Approximating Single-Particle Electron Microscopy Density Maps Using Pseudoatoms and Approximation-Accuracy Control. AB - Three-dimensional Gaussian functions have been shown useful in representing electron microscopy (EM) density maps for studying macromolecular structure and dynamics. Methods that require setting a desired number of Gaussian functions or a maximum number of iterations may result in suboptimal representations of the structure. An alternative is to set a desired error of approximation of the given EM map and then optimize the number of Gaussian functions to achieve this approximation error. In this article, we review different applications of such an approach that uses spherical Gaussian functions of fixed standard deviation, referred to as pseudoatoms. Some of these applications use EM-map normal mode analysis (NMA) with elastic network model (ENM) (applications such as predicting conformational changes of macromolecular complexes or exploring actual conformational changes by normal-mode-based analysis of experimental data) while some other do not use NMA (denoising of EM density maps). In applications based on NMA and ENM, the advantage of using pseudoatoms in EM-map coarse-grain models is that the ENM springs are easily assigned among neighboring grains thanks to their spherical shape and uniformed size. EM-map denoising based on the map coarse-graining was so far only shown using pseudoatoms as grains. PMID- 28097147 TI - Pharmacological Evaluation of Chrozophora tinctoria as Wound Healing Potential in Diabetic Rat's Model. AB - Objective. The study was designed to evaluate pharmacological potential of hydroalcoholic leaves extract of Chrozophora tinctoria intended for wound healing in diabetic rats' model. Methods. The method used to evaluate the pharmacological potential of hydroalcoholic leave extract was physical incision rat model. In this model, cutting of the skin and/or other tissues with a sharp blade has been made and the rapid disruption of tissue integrity with minimal collateral damage was observed shortly. Animals used in the study were divided into four groups that consist of six animals in each group. Group I serves as normal control, Group II serves as disease control, Group III was used as standard treatment (Povidone iodine 50 mg/kg b.w.), and Group IV was used for test drug (C. tinctoria 50 mg/kg b.w.). Result. The hydroalcoholic leave extract of Chrozophora tinctoria has been significantly observed to heal the wound (98%) in diabetic rats within 21 days, while standard drug (Povidone iodine) healed the wound about 95% in the same condition. The oral dose (50 mg/kg b.w.) of Chrozophora tinctoria was also found to improve the elevated blood glucose level in comparison to disease control group, which increased after the oral administration of Streptozotocin. Conclusion. The Chrozophora tinctoria has significant wound healing potential in the animal having physically damaged tissue in diabetic condition. PMID- 28097148 TI - Exercise Physiology, Cognitive Function, and Physiologic Alterations in Extreme Conditions 2016. PMID- 28097149 TI - Benefit of Leukocyte- and Platelet-Rich Plasma in Operative Wound Closure in Oral and Maxillofacial Surgery. AB - This article reports the influence of an autologous leukocyte- and platelet-rich plasma (L-PRP) injection as a minimally invasive method on supporting wound healing processes after a mandibular odontogenic cystectomy and double mandibular fracture fixation. 113 patients were enrolled into a control group (received no L PRP injection) and 102 patients were enrolled into an L-PRP group with an oral mucosa incision. 18 patients after a double mandibular fracture were operated on using 2 external submandibular approaches receiving no fluids in the right site (a control group) and an L-PRP injection in the left incision (L-PRP group). Clinical observations showed that the oral mucosa healed faster in patients treated with L-PRP, in comparison to cases where inductive biomaterial was not added. Pain at the L-PRP injection site was relieved within few hours after an operation in patients with double mandibular fractures. However, there were no differences observed in the progression of the healing process. L-PRP possesses inductive properties that could stimulate healing processes and it seems to be one of the most promising methods in the future for the treatment of soft tissue defects. PMID- 28097150 TI - A Naphthalenic Derivative ND-1 Inhibits Thrombus Formation by Interfering the Binding of Fibrinogen to Integrin alphaIIbbeta3. AB - Integrin alphaIIbbeta3 plays a crucial role in the process of platelet aggregation. Three integrin alphaIIbbeta3 antagonists (abciximab, eptifibatide, and tirofiban) have been approved by FDA for clinical use. Unfortunately, they all showed severe side effects such as thrombocytopenia and bleeding risk. Thus, researches on the development of more effective and safer antiplatelet agents are needed. In this manuscript we reported a novel naphthalenic derivative compound ND-1 with potent antithrombotic effect and lower bleeding risk. ND-1 inhibited ADP-, collagen-, thrombin-, and U46619-induced platelet aggregation with IC50 values of 1.29, 14.46, 12.84, and 40.24 MUM, respectively. Mechanism studies indicated that ND-1 inhibited the binding of fibrinogen to integrin alphaIIbbeta3 in a dose-dependent manner with an IC50 value of 3.12 MUM. ND-1 inhibited P selectin expression induced by ADP, collagen, thrombin, and U46619 on the surface of platelets. Additionally, this compound reduced platelets spreading to the immobilized fibrinogen. In vivo, ND-1 potently decreased thrombus formation in an arteriovenous shunt thrombosis model in rats and slightly prolonged bleeding time in a tail cutting model in mice. Taken together, our results reveal that ND-1 is a novel antagonist of alphaIIbbeta3 with strong antithrombotic effect and lower bleeding risk. PMID- 28097152 TI - Corrigendum to "Transmission Model of Hepatitis B Virus with the Migration Effect". AB - [This corrects the article DOI: 10.1155/2013/150681.]. PMID- 28097151 TI - Identification of Potential Key lncRNAs and Genes Associated with Aging Based on Microarray Data of Adipocytes from Mice. AB - Objective. This study aimed to screen potential crucial lncRNAs and genes involved in aging. Methods. The data of 9 peripheral white adipocytes, respectively, taken from male C57BL/6J mice (6 months, 14 months, and 18 months of age) in GSE25905 were used in this study. Differentially time series expressed lncRNA genes (DE-lncRNAs) and mRNA genes (DEGs) were identified. After cluster analysis of lncRNAs expression pattern, target genes of DE-lncRNAs were predicted from the DEGs, and functional analysis for target genes was conducted. Results. A total of 8301 time series-related DEGs and 43 time series-related DE-lncRNAs were identified. Among them, 41 DE-lncRNAs targeted 1880 DEGs. The DEGs positively regulated by DE-lncRNAs were mainly related to the development of blood vessel and the pathways of cholesterol biosynthesis and elastic fibre formation. Furthermore, the DEGs negatively regulated by DE-lncRNAs were correlated with protein metabolism. Conclusion. These DE-lncRNAs and DEGs are potentially involved in the process of aging. PMID- 28097153 TI - Effects of Renal Ischemic Postconditioning on Myocardial Ultrastructural Organization and Myocardial Expression of Bcl-2/Bax in Rabbits. AB - We investigated the cardioprotective effect of renal ischemic postconditioning (RI-PostC) and its mechanisms in a rabbit model. Rabbits underwent 60 min of left anterior descending coronary artery occlusion (LADO) and 6 h of reperfusion. The ischemia-reperfusion (IR) group underwent LADO and reperfusion only. In the RI PostC group, the left renal artery underwent 3 cycles of occlusion for 30 seconds and release for 30 seconds, before the coronary artery was reperfused. In the RI PostC + GF109203X group, the rabbits received 0.05 mg/kg GF109203X (protein kinase C inhibitor) intravenously for 10 min followed by RI-PostC. Light microscopy and electron microscopy demonstrated that the RI-PostC group showed less pronounced changes, a smaller infarct region, and less apoptosis than the other two groups. Bcl-2 and Bax protein expression did not differ between the IR and RI-PostC + GF109203X groups. However, in the RI-PostC group, Bcl-2 protein expression was significantly higher and Bax protein expression was significantly lower than in the other two groups (P < 0.05). Changes in heart rate and mean arterial pressure were also smaller in the RI-PostC group than in the other two groups. These results indicate that RI-PostC can ameliorate myocardial ischemia reperfusion injury and increase the Bcl-2/Bax ratio through a mechanism involving protein kinase C. PMID- 28097154 TI - A Comparative Chemical Study of Calcium Silicate-Containing and Epoxy Resin-Based Root Canal Sealers. AB - Objective. The present study assessed the chemical elements in two novel calcium silicate-containing root canal sealers, BioRoot RCS and Well-Root ST, compared to a calcium silicate-containing root canal sealer that has been on the market for several years, MTA Fillapex, and epoxy resin-based sealer AHPlus. Material and Methods. The sealers were mixed and manipulated according to the manufacturers' instructions. Twelve cylindrical molds (inner diameter 4 mm; height 3 mm) were placed on a glass petri dish and packed with the materials. The dish was transferred to an incubator. After 72 h the molds were examined by scanning electron microscopy and energy dispersive X-ray microanalysis. Results. BioRoot RCS and Well-Root ST had high peaks of calcium, zirconium, oxygen, carbon, silicon, and chlorine. Well-Root ST also had sodium, magnesium, aluminum, and titanium peaks. MTA Fillapex and AHPlus had carbon, oxygen, calcium, titanium, and bismuth peaks. A silicon peak was also observed for MTA Fillapex, and zirconium and tungsten peaks for AHPlus. Conclusion. BioRoot RSC had the highest degree of purity. The clinical implication of metals contained in the other sealers needs to be investigated. PMID- 28097155 TI - Potential Involvement of Type I Interferon Signaling in Immunotherapy in Seasonal Allergic Rhinitis. AB - Specific immunotherapy (SIT) reverses the symptoms of seasonal allergic rhinitis (SAR) in most patients. Recent studies report type I interferons shifting the balance between type I T helper cell (Th1) and type II T helper cells (Th2) towards Th2 dominance by inhibiting the differentiation of naive T cells into Th1 cells. As SIT is thought to cause a shift towards Th1 dominance, we hypothesized that SIT would alter interferon type I signaling. To test this, allergen and diluent challenged CD4+ T cells from healthy controls and patients from different time points were analyzed. The initial experiments focused on signature genes of the pathway and found complex changes following immunotherapy, which were consistent with our hypothesis. As interferon signaling involves multiple genes, expression profiling studies were performed, showing altered expression of the pathway. These findings require validation in a larger group of patients in further studies. PMID- 28097156 TI - Metabolic Syndrome and Selective Inflammatory Markers in Psoriatic Patients. AB - The presented article studies the role of selected inflammatory and anti inflammatory serum markers of psoriatic patients in the pathogenesis of metabolic syndrome (MS) and psoriasis. The study is based on the comparison between the group of psoriatic patients (74) and the control group (65). We found significantly higher BMI (p < 0.05) and diastolic blood pressure (p < 0.05) in the psoriatic patients. The values of waist circumference and BMI were significantly higher (p < 0.05) in the male patients compared to the men in the control group. The analysis revealed significantly higher CRP (p < 0.001), Lp PLA2 (p < 0.001), leptin (p < 0.01), and resistin (p < 0.01) levels in the psoriatic patients. Significantly higher levels of CRP (p < 0.01), Lp-PLA2 (p < 0.001), leptin (p < 0.01), and resistin (p < 0.05) were found in the patients with MS compared to the controls with MS. The level of adiponectin was significantly lower (p < 0.01) in the patients with MS. Finally, we found significantly higher level of Lp-PLA2 (p < 0.001) in the group of patients without MS compared to the controls without MS. In conclusion, observed inflammatory and anti-inflammatory markers (CRP, adiponectin, leptin, resistin, and Lp-PLA2) are involved in both pathogenesis of MS and pathogenesis of psoriasis. The level of Lp-PLA2 indicates the presence of subclinical atherosclerosis (cardiovascular risk) in psoriatic patients. PMID- 28097157 TI - NK-DC Crosstalk in Immunity to Microbial Infection. AB - The interaction between natural killer (NK) cell and dendritic cell (DC), two important cellular components of innate immunity, started to be elucidated in the last years. The crosstalk between NK cells and DC, which leads to NK cell activation, DC maturation, or apoptosis, involves cell-cell contacts and soluble factors. This interaction either in the periphery or in the secondary lymphoid organs acts as a key player linking innate and adaptive immune responses to microbial stimuli. This review focuses on the mechanisms of NK-DC interaction and their relevance in antimicrobial responses. We specifically aim to emphasize the ability of various microbial infections to differently influence NK-DC crosstalk thereby contributing to distinct adaptive immune response. PMID- 28097160 TI - Contribution to the molecular systematics of the genus Capoeta from the south Caspian Sea basin using mitochondrial cytochrome b sequences (Teleostei: Cyprinidae). AB - Traditionally, Capoeta populations from the southern Caspian Sea basin have been considered as Capoeta capoeta gracilis. Study on the phylogenetic relationship of Capoeta species using mitochondrial cytochrome b gene sequences show that Capoeta population from the southern Caspian Sea basin is distinct species and receive well support (posterior probability of 100%). Based on the tree topologies obtained from Bayesian and Maximum Likelihood methods, three main groups for the studied Capoeta were detected: Clade I) Capoeta trutta group (the Mesopotamian Capoeta group) including closely related taxa (e.g. trutta, turani, barroisi) characterized by having numerous irregular black spots on the dorsal half of the body. This clade was the sister group to all other Capoeta species and its separation occurred very early in evolution possess, so we considered it as O ld Evolutionary Group. Clade II) comprises highly diversified and widespread group, Capoeta damascina complex group (small scale capoeta group), the Anatolian Iranian group (e.g. banarescui, buhsei, damascina, saadii), characterized by small scales and plain body (absence of irregular black spots on the dorsal half of the body, except in some juveniles) with significantly later speciation event so called Young Evolutionary Group. Clade III) Capoeta capoeta complex group (large scale capoeta group, the Aralo-Caspian group) comprises very closely related taxa characterized by large scales and plain body (absence of irregular black spots on the dorsal half of the body) distributed in Aralo-Caspian water bodies (capoeta, ekmekciae, heratensis, gracilis, sevangi) that has been recently diverged and could be considered as Very Young Evolutionary Group. PMID- 28097161 TI - Effects of extremely low-frequency electromagnetic field on expression levels of some antioxidant genes in human MCF-7 cells. AB - In the past three decades, study on the biological effects of extremely low frequency electromagnetic fields (ELF-EMFs) has been of interest to scientists. Although the exact mechanism of its effect is not fully understood, free radical processes has been proposed as a possible mechanism. This study was designed to evaluate the effect of 50-Hz EMFs on the mRNA levels of seven antioxidant genes (CAT, SOD1, SOD2, GSTO1, GSTM3, MSGT1, and MSGT3) in human MCF-7 cells. The EMF exposure patterns were: 1) 5 min field-on/5 min filed-off, 2) 15 min field-on/15 min field-off, 3) 30 min field-on continuously. In all three exposure conditions we tried to have total exposure time of 30 minutes. Control cultures were located in the exposure apparatus when the power was off. The experiments were done at two field intensities; 0.25 mT and 0.50 mT. The RNA extraction was done at two times; immediately post exposure and two hours post exposure. The mRNA levels were determined using quantitative real-time polymerase chain reaction. MTT assay for three exposure conditions in the two field intensities represented no cytotoxic effect on MCF-7 cells. Statistical comparison showed a significant difference between 0.25 mT and 0.50 mT intensities for "the 15 min field-on/15 min field-off condition" (Fisher's exact test, P=0.041), indicating that at 0.50 mT intensity field, the number of down-regulated and/or up-regulated genes increased compared with the other ones. However, there is no statistical significant difference between the field intensities for the two others EMF exposure conditions. PMID- 28097162 TI - Antioxidant activity of polyphenolic myricetin in vitro cell- free and cell-based systems. AB - Myricetin (Myc) is one of the most important flavonoids in diet due to its abundance in foods with the highest antioxidant activity. The antioxidant activity of Myc was studied in cell-free and cell-based systems to evaluate the ROS protection efficiency of Myc. The studies were based on the assessment of reducing power of Myc according to ferric ion reduction and intracellular ROS level measurement by assaying the cellular fluorescence intensity using dichlorodihydrofluorescein (DCF) probe as an indicator for ROS in cells. Moreover, the antitoxic capability of Myc was assessed using MTT method. Data indicated that intracellular ROS are highly toxic and applying low concentration of Myc not only inhibited cellular ROS production but also was accompanying with the protection of cells against the highly toxic and the lethal effects of peroxide compounds. Because of strong correlation between cellular ROS and their cell toxic properties, the higher antioxidant potency of Myc in cell medium resulted in effectively blocking intracellular ROS and protecting cell death. This property is achieved by the help of high polar solubility and cell membrane permeability of Myc. PMID- 28097163 TI - Genetic polymorphisms in the promoter region of catalase gene, creates new potential PAX-6 and STAT4 response elements. AB - Catalase (CAT, OMIM: 115500) is an endogenous antioxidant enzyme and genetic variations in the regulatory regions of the CAT gene may alter the CAT enzyme activity and subsequently may alter the risk of oxidative stress related disease. In this study, potential influence(s) of the A-21T (rs7943316) and C-262T (rs1001179) genetic polymorphisms in the CAT promoter region, using the ALGGEN PROMO.v8.3 online software were analyzed. Our findings show that the A allele at the -21 position creates a new potential binding site for PAX-6 and the T allele at the -262 position changes the TFII-I binding site into STAT4 response element. The PAX-6 and STAT4 are the multifunctional and enhancing transcription factors. PMID- 28097159 TI - IgE-Related Chronic Diseases and Anti-IgE-Based Treatments. AB - IgE is an immunoglobulin that plays a central role in acute allergic reactions and chronic inflammatory allergic diseases. The development of a drug able to neutralize this antibody represents a breakthrough in the treatment of inflammatory pathologies with a probable allergic basis. This review focuses on IgE-related chronic diseases, such as allergic asthma and chronic urticaria (CU), and on the role of the anti-IgE monoclonal antibody, omalizumab, in their treatment. We also assess the off-label use of omalizumab for other pathologies associated with IgE and report the latest findings concerning this drug and other new related drugs. To date, omalizumab has only been approved for severe allergic asthma and unresponsive chronic urticaria treatments. In allergic asthma, omalizumab has demonstrated its efficacy in reducing the dose of inhaled corticosteroids required by patients, decreasing the number of asthma exacerbations, and limiting the effect on airway remodeling. In CU, omalizumab treatment rapidly improves symptoms and in some cases achieves complete disease remission. In systemic mastocytosis, omalizumab also improves symptoms and its prophylactic use to prevent anaphylactic reactions has also been discussed. In other pathologies such as atopic dermatitis, food allergy, allergic rhinitis, nasal polyposis, and keratoconjunctivitis, omalizumab significantly improves clinical manifestations. Omalizumab acts in two ways: by sequestering free IgE and by accelerating the dissociation of the IgE-Fcepsilon receptor I complex. PMID- 28097158 TI - Osteopontin Bridging Innate and Adaptive Immunity in Autoimmune Diseases. AB - Osteopontin (OPN) regulates the immune response at multiple levels. Physiologically, it regulates the host response to infections by driving T helper (Th) polarization and acting on both innate and adaptive immunity; pathologically, it contributes to the development of immune-mediated and inflammatory diseases. In some cases, the mechanisms of these effects have been described, but many aspects of the OPN function remain elusive. This is in part ascribable to the fact that OPN is a complex molecule with several posttranslational modifications and it may act as either an immobilized protein of the extracellular matrix or a soluble cytokine or an intracytoplasmic molecule by binding to a wide variety of molecules including crystals of calcium phosphate, several cell surface receptors, and intracytoplasmic molecules. This review describes the OPN structure, isoforms, and functions and its role in regulating the crosstalk between innate and adaptive immunity in autoimmune diseases. PMID- 28097164 TI - Molecular characterization and construction of an infectious clone of a pepper isolate of Beet curly top Iran virus. AB - Geminiviruses cause curly top disease, in dicotyledonous plants which constrains host crop production. Beet curly top Iran virus (BCTIV) is a widespread Becurtovirus (family Geminiviridae) in numerous areas within Iran. In this study, we isolated and analyzed a full-length genomic DNA of a new variant of BCTIV from pepper crops in the Kaftark region, east of Shiraz (proposed acronym: BCTIV-Kaf [IR: Kaf:2016:Pepper]). Infected pepper plants showed shortening of internodes, severe interveinal chlorosis, upward leaf rolling and leaf curling. Sequence and phylogenetic analysis showed this BCTIV variant grouped with sugar beet isolates of BCTIV and has the highest similarity to a sugar beet BCTIV isolate from Negar town in Kerman province, Iran. It was more distantly related to a bean isolate of BCTIV from northeast region of Iran. A tandem repeat partial dimmer of BCTIV was constructed and found to be infectious in pepper, tomato and Nicotiana benthamiana plants. Results of this study indicated that BCTIV-Kaf is a new variant of BCTIV infecting pepper plants in Shiraz and that geographic location rather than the type of host plant has more effect on genetic diversity of BCTIV in Iran. PMID- 28097165 TI - In silico comparison of Iranian HIV -1 envelop glycoprotein with five nearby countries. AB - HIV-1 envelope (env) glycoprotein mediates an important role in entry of the virus into the susceptible target cells. As env glycoprotein of HIV-1 is highly variable in the different geographical regions, in the present study, different properties of this protein in Iran are compared with five nearby countries. The sequences of HIV-1 env glycoproteins of Iran, Afghanistan, Russia, Turkey, Pakistan and Saudi Arabia databases were collected from databases. Amino acid composition and physical and chemical properties of the proteins from these countries were studied using Protparam and COPid tools. Receiver-operating characteristic (ROC) curve analysis and Support Vector Machine (SVM) were used to evaluate association between the properties of HIV-1 env glycoprotein of Iran with five nearby countries. The results verify that amino acid composition and four physical and chemical properties (molecular weight, isoelectric point, Aliphatic Index, and grand average of hydropathicity) of HIV-1 env protein in Iran and Russia were not significantly different. In conclusion, the results indicate that in silico techniques provide valuable information for comparing HIV 1 envelop glycoprotein in different geographical locations. PMID- 28097166 TI - Molecular characterization of Pasteurella multocida isolates obtained from poultry, ruminant, cats and dogs using RAPD and REP-PCR analysis. AB - In the present study, Randomly Amplified Polymorphic DNA (RAPD) and Repetitive Extragenic Palindromic sequence-based Polymerase Chain Reaction (REP- PCR) were used to characterize 131 isolates of Pasteurella multocida, originating from different healthy and diseased animal species obtained from several geographical regions of Iran. The RAPD and REP-PCR generated amplified products in the range of 300 to 3400 bp and 200 to 2850 bp, respectively. Among all of the P. multocida isolates, cluster analysis revealed that 63 clusters and nine untypable isolates and 81 clusters and six untypable isolates were produced with RAPD and REP-PCR methods, respectively. The results indicated that the REP-PCR method showed a slightly higher level of discrimination power in differentiating of P. multocida isolates as compared with RAPD. The results showed that a considerable level of genetic diversity exists among P. multocida isolates even in the isolates with the same animal or geographical origins. There was no host- and region-specific pattern. In addition, the isolates obtained from the healthy and diseased animal did not reveal any correlation genotypic profiles, which could be supported by the hypothesis that P. multocida is a strictly opportunistic pathogen. In conclusion, because of a large amount of genetic heterogeneity in the P. multocida isolates, Pasteurellosis may be caused by different clones in the same herd or animal. PMID- 28097167 TI - Expression, purification and kinetic characterization of recombinant benzoate dioxygenase from Rhodococcus ruber UKMP-5M. AB - In this study, benzoate dioxygenase from Rhodococcus ruber UKMP-5M was catalyzed by oxidating the benzene ring to catechol and other derivatives. The benzoate dioxygenase (benA gene) from Rhodococcus ruber UKMP-5M was then expressed, purified, characterized, The benA gene was amplified (642 bp), and the product was cloned into a pGEM-T vector. The recombinant plasmid pGEMT-benA was digested by double restriction enzymes BamHI and HindIII to construct plasmid pET28b-benA and was then ligated into Escherichia coli BL21 (DE3). The recombinant E. coli was induced with 0.5 mM isopropyl beta-D-thiogalactoside (IPTG) at 22C to produce benzoate dioxygenase. The enzyme was then purified by ion exchange chromatography after 8 purification folds. The resulting product was 25 kDa, determined by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting. Benzoate dioxygenase activity was found to be 6.54 U/mL and the optimal pH and temperature were 8.5 and 25 degrees C, respectively. Maximum velocity (Vmax) and Michaelis constant (Km) were 7.36 U/mL and 5.58 uM, respectively. The end metabolite from the benzoate dioxygenase reaction was cyclohexane dione, which was determined by gas chromatography mass spectrometry (GC-MS). PMID- 28097168 TI - Purification and biochemical properties of a thermostable, haloalkaline cellulase from Bacillus licheniformis AMF-07 and its application for hydrolysis of different cellulosic substrates to bioethanol production. AB - A thermophilic strain AMF-07, hydrolyzing carboxymethylcellulose (CMC) was isolated from Kerman hot spring and was identified as Bacillus licheniformis based on 16S rRNA sequence homology. The carboxymethylcellulase (CMCase) enzyme produced by the B. licheniformis was purified by (NH4)2SO4 precipitation, ion exchange and gel filtration chromatography. The purified enzyme gave a single band on SDS- PAGE with a molecular weight of 37 kDa. The CMCase enzyme was highly active and stable over broad ranges of temperature (40-80oC), pH (6.0-10.0) and NaCl concentration (10-25%) with an optimum at 70oC, pH 9.0 and 20% NaCl, which showed excellent thermostable, alkali-stable and halostable properties. Moreover, it displayed high activity in the presence of cyclohexane (134%) and chloroform (120%). Saccharification of rice bran and wheat bran by the CMCase enzyme resulted in respective yields of 24 and 32 g L-1 reducing sugars. The enzymatic hydrolysates of rice bran were then used as the substrate for ethanol production by Saccharomyces cerevisiae. Fermentation of cellulosic hydrolysate using S. cerevisiae, reached maximum ethanol production about 0.125 g g-1 dry substrate (pretreated wheat bran). Thus, the purified cellulase from B. licheniformis AMF 07 utilizing lignocellulosic biomass could be greatly useful to develop industrial processes. PMID- 28097169 TI - Molecular characterization of Argulus bengalensis and Argulus siamensis (Crustacea: Argulidae) infecting the cultured carps in West Bengal, India using 18S rRNA gene sequences. AB - The present study characterized Argulus spp. infecting the cultured carps using 18S rRNA gene sequences, estimated the genetic similarity among Argulus spp. and established their phylogenetic relationship. Of the 320 fish samples screened, 34 fish (10.6%) had Argulus infection. The parasitic frequency index (PFI) was observed to be high (20%) in Hypophthalmichthys molitrix and Labeo bata. The frequency of infection was high in September (PFI: 17%) and October (PFI: 12.9%). The 18S rRNA sequences of five A. bengalensis (KF583878, KF192316, KM016968, KM016969, and KM016970) and one A. siamensis (KF583879) of this study showed genetic heterogeneity and exhibited 77-99% homology among the 18S rRNA gene sequences of Argulus spp. of NCBI GenBank database. Among the Indian Argulus spp. the sequence homology was 87-100%. Evolutionary pair-wise distances between Indian Argulus spp. and other Argulus spp. ranged from 0 to 20.20%. In the phylogenetic tree, all the crustaceans were clustered together as a separate clade with two distinct lineages. The lineage-1 comprised exclusive of Branchiura (Argulus spp.). All Argulus bengalensis clustered together and A. siamensis (KF583879) was closely related to Argulus sp. JN558648. The results of the present study provided baseline data for future work on population structure analysis of Indian Argulus species. PMID- 28097170 TI - Microsatellite (SSR) amplification by PCR usually led to polymorphic bands: Evidence which shows replication slippage occurs in extend or nascent DNA strands. AB - Microsatellites or simple sequence repeats (SSRs) are very effective molecular markers in population genetics, genome mapping, taxonomic study and other large scale studies. Variation in number of tandem repeats within microsatellite refers to simple sequence length polymorphism (SSLP); but there are a few studies that are showed SSRs replication slippage may be occurred during in vitro amplification which are produced 'stutter products' differing in length from the main products. The purpose of this study is introducing a reliable method to realize SSRs replication slippage. At first, three unique primers designed to amplify SSRs loci in the great gerbil (Rhombomys opimus) by PCR. Crush and soak method used to isolate interesting DNA bands from polyacrylamide gel. PCR products analyzed using by sequencing methods. Our study has been shown that Taq DNA polymerase slipped during microsatellite in vitro amplification which led to insertion or deletion of repeats in sense or antisense DNA strands. It is produced amplified fragments with various lengths in gel electrophoresis showed as 'stutter bands'. Thus, in population studies by SSRs markers recommend that replication slippage effects and stutter bands have been considered. PMID- 28097171 TI - Structural insights into the effects of charge-reversal substitutions at the surface of horseradish peroxidase. AB - Horseradish peroxidase (HRP), has gained significant interests in biotechnology, especially in biosensor field and diagnostic test kits. Hence, its solvent exposed lysine residues 174, 232, and 241 have been frequently modified with the aim of improving its stability and catalytic efficiency. In this computational study, we investigated the effects of Lys-to-Glu substitutions on HRP structure to model charge-reversal manipulations at the enzyme surface. Simulation results implied that upon these substitutions, the number of stable hydrogen bonds and alpha-helical content of HRP are increased and the proximal Ca2+ binding pocket becomes more integrated. The results revealed that although Glu174-heme hydrogen bond is lost after mutation, formation of a new hydrogen bonding network contributes to the stability of heme-protein linkage. Together, it may be concluded that these substitutions enhance the stability of the protein moiety as well as the heme-protein non-covalent interactions. In the enzyme active site, we observed increased accessibility of peroxide binding site and heme prosthetic group to the peroxide and aromatic substrates, respectively. Results also demonstrated that the bottleneck entry of the peroxide-binding site has become wider and more flexible upon substitutions. Moreover, the hydrophobic patch functioning as a binding site or trap for reducing aromatic substrates is more extended in mutated enzyme. These observations suggest that the reactivity of the enzyme to its substrates has increased. Together, the results of this simulation study could provide possible structural clues to explain those experimental observations in which the protein stability achieved upon manipulation of charge distribution on protein surface. PMID- 28097172 TI - Transcript levels of phytoene desaturase gene in Dunaliella salina Teod. as affected by PbS nanoparticles and light intensity. AB - Phytoene synthase (Psy) and Phytoene desaturase (Pds) are the first two regulatory enzymes in the carotenoids biosynthetic pathway. The genes Psy and Pds are under transcriptional control in many photosynthetic organisms. In the present study, using quantitative real time- PCR (qRT-PCR), the effects of uncoated and gum-Arabic coated PbS nanoparticles (GA-coated PbS NPs) and light intensity on the mRNA levels of Pds were investigated. Relative to mRNA level of Pds at 100 umol photon m-2 s-1 light intensity (control culture), 2.2-fold increase in transcript levels occurred after 12 h of exposure to higher light intensity, which is significantly (P<0.05) different compared to control. After 48 h of exposure, the mRNA level of Pds was reduced to that in control. This indicates that light intensity regulates Pds at the mRNA level. In the presence of uncoated and GA-coated PbS NPs, the transcript levels of Pds were decreased over time, with uncoated PbS NPs having more inhibitory effects on mRNA levels compared to GA- coated PbS NPs. This shows that PbS NPs have adverse effects on transcription or post transcriptional processing and coating nanoparticles with biopolymers reduces their toxicity to organisms. Being under control, it seems that genetic manipulation of Pds may result in increased biotechnological production of carotenoids by D. salina. PMID- 28097173 TI - Contributing Factors to High-Risk Sexual Behaviors among Iranian Adolescent Girls: A Systematic Review. AB - BACKGROUND: Adolescence is a period of overwhelming changes and challenges, which expose the adolescents to high-risk behaviors. Risky sexual relationship is one of these behaviors that entails physical risks and psychosocial harms. Various factors have been recognized to shape sexual behaviors in adolescents. This paper is an attempt to investigate the factors contributing to high-risk sexual behaviors in Iranian adolescent girls. METHODS: A literature review of the research published by Iranian authors, in Farsi or English language in local and foreign journals, was conducted using PubMed, Science Direct, Scopus, Scientific Information Database (SID), IranMedex, IranDoc, and Google Scholar. The search in each database included all the years covered at that time using keywords such as "sexual, adolescents, and Iran", and continued using other keywords such as "sexual behavior, high-risk behavior, sexual risk and reproductive behavior" individually and in combination. RESULTS: Sixteen published articles were identified. Factors contributing to high-risk sexual behaviors in girls can be divided into four general groups including personal, family, peer, school and community. CONCLUSION: Regarding the identified risk and protective factors, appropriate individual, family and school-based interventions can be designed and implemented to strengthen protective factors. While individual and family factors are considered more in research, factors related to peers, school and community have received less attention. Since social values, beliefs and norms are important factors in formation of sexual behaviors, further research regarding these factors is suggested. PMID- 28097174 TI - Uncertainty, the Overbearing Lived Experience of the Elderly People Undergoing Hemodialysis: A Qualitative Study. AB - BACKGROUND: The chronic kidney disease is a major health concern. The number of the elderly people with chronic renal failure has increased across the world. Dialysis is an appropriate therapy for the elderly, but it involves certain challenges. The present paper reports uncertainty as part of the elderly experiences of living with hemodialysis. METHODS: This qualitative study applied Max van Manen interpretative phenomenological analysis to explain and explore experiences of the elderly with hemodialysis. Given the study inclusion criteria, data were collected using in-depth unstructured interviews with nine elderly undergoing hemodialysis, and then analyzed according to Van Manen 6-stage methodological approach. RESULTS: One of the most important findings emerging in the main study was "uncertainty", which can be important and noteworthy, given other aspects of the elderly life (loneliness, despair, comorbidity of diseases, disability, and mental and psychosocial problems). Uncertainty about the future is the most psychological concerns of people undergoing hemodialysis. CONCLUSION: The results obtained are indicative of the importance of paying attention to a major aspect in the life of the elderly undergoing hemodialysis, uncertainty. A positive outlook can be created in the elderly through education and increased knowledge about the disease, treatment and complications. PMID- 28097175 TI - Socioeconomic Status and Satisfaction with Public Healthcare System in Iran. AB - BACKGROUND: The users' satisfaction is a method for evaluating the efficacy of healthcare system. We aimed to evaluate the association between the users' socioeconomic status (SES) and satisfaction with the healthcare system in Shiraz, Iran. METHODS: This cross-sectional study was conducted from December, 2013 to March, 2014, in Shiraz, Iran. 3400 households were recruited by multi-stage cluster random sampling. Information about demographic, insurance status, and users' satisfaction was derived from face-to-face interviews. Satisfaction with healthcare system was assessed by using 5-point Likert scale statements, which ranged from "very dissatisfied" to "very satisfied". All statistical analyses were performed using SPSS-21. RESULTS: Overall, 1.6% (55) of the respondents were very satisfied, while 6% (203) were very dissatisfied with healthcare system. Participants were classified into high SES (26.3%), middle SES (47.9%) and low SES (25.8%). It was discovered that the better the SES, the more frequent were the respondents dissatisfied with healthcare system (P<0.001). Also, dissatisfied respondents were significantly older (P=0.036). Moreover, women were more dissatisfied with healthcare system (P=0.005). Also, dissatisfied respondents had significantly a higher level of education than satisfied ones (P<0.001). Furthermore, logistic regression revealed that age (P=0.04), marital status (P=0.01), insurance status (P<0.001), SES (P<0.001), and having supplemental insurance (P=0.02) were determinant factors of satisfaction with healthcare system. CONCLUSION: This study demonstrated that users' sex, age, educational level, and SES were related to dissatisfaction with healthcare system. Meanwhile, clients' age, SES, insurance status and marital status were recognized as determinant factors. PMID- 28097176 TI - A Comparison between the Quality of Life and Mental Health of Patients with Hypothyroidism and Normal People Referred to Motahari Clinic of Shiraz University of Medical Sciences. AB - BACKGROUND: Hypothyroidism is a condition caused by a decrease in the thyroid gland hormones. This disease is very common at all age ranges. Regarding its long term therapeutic procedure, this disease can affect the quality of life and the mental health of the patients. The present study aimed to compare the quality of life and mental health in hypothyroid patients and normal people. METHODS: This descriptive-analytic investigation was performed using convenience sampling on 95 patients with hypothyroidism and 95 normal cases referring to Motahari clinic between October 2014 and August 2015. Data were collected through General Health Questionnaire (consisted of 4 fields; physical signs, anxiety, social function disorder, depression) and Quality of life Questionnaires. Data were analyzed using Independent t- test, Pearson correlation coefficient and Variance analysis. P-values<0.05 were considered as significant. RESULTS: Both control (normal) and test (patient) groups were matched in demographic characteristics in this study (P>0.001). The results showed that there was no significant difference between the quality of life of patients and that of the normal people (test and control groups) (P>0.001). But the comparison of mental health level of patients (59.70) and normal people (48.68) showed a significant difference at all aspects (P<0.001). CONCLUSION: Considering and improving the mental health status of such patients can be positively effective in their treatment procedure. Considering this key point in a country like Iran with rich religious backgrounds can be useful in designing self-care and therapeutic programs and even for all people. PMID- 28097177 TI - Spirituality: A Panacea for Patients Coping with Heart Failure. AB - BACKGROUND: Many patients with heart failure grapple with related problems that threaten their feeling of well-being and quality of life. Patients look for ways to cope with the new situation. The present study aimed to explore religious coping from the perspective of patients with heart failure. METHODS: This qualitative study used the content analysis of the semi-structured interviews. The data were collected from 18 participants referring to training hospitals in Kerman University of Medical Sciences in southeastern Iran. The data were analyzed using Lundman and Graneheim qualitative content analysis. RESULTS: The main theme of "Spiritual coping, a dominant strategy" was extracted with two categories: 1- "religious belief" having the sub-categories of "inner faith" and "search of meaning" 2- "connection to God as the supreme power" with sub categories of "seeking healing through supplication and rituals", "worship as a barrier to the flood of problems", and "submission to and trust in God". CONCLUSION: The findings suggest that a spiritual strategy helps the patients effectively to cope with heart failure. Patients learn to use religious beliefs and faith to accept the reality of the disease and its stages and to manage their condition with patience, tolerance, and hope calmly and confidently for a bright future. PMID- 28097178 TI - Antecedents of Coping with the Disease in Patients with Multiple Sclerosis: A Qualitative Content Analysis. AB - BACKGROUND: Due to many physical and mental disorders that occur in multiple sclerosis patients, identifying the factors affecting coping based on the experiences of patients using qualitative study is essential to improve their quality of life. This study was conducted to explore the antecedents of coping with the disease in patients with multiple sclerosis. METHODS: This is a qualitative study conducted on 11 patients with multiple sclerosis in 2015 in Tehran, Iran. These patients were selected based on purposive sampling. Data were collected using semi-structured and in-depth interviews and coded. These data were analyzed using the conventional content analysis. The rigor of qualitative data using the criteria proposed by Guba and Lincoln were assessed. RESULTS: Five main categories were revealed: (1) social support, (2) lenience, (3) reliance on faith, (4) knowledge of multiple sclerosis and modeling, and (5) economic and environmental situation. Each category had several distinct sub-categories. CONCLUSIONS: The results of this study showed that coping with multiple sclerosis is a complex, multidimensional and contextual concept that is affected by various factors in relation to the context of Iran. The findings of the study can provide the healthcare professionals with deeper recognition and understanding of these antecedents to improve successful coping in Iranian patients suffering from multiple sclerosis. PMID- 28097179 TI - The Comparison of Two Types of Relaxation Techniques on Postoperative State Anxiety in Candidates for The Mastectomy Surgery: A Randomized Controlled Clinical Trial. AB - BACKGROUND: Anxiety among patients after surgery can affect their physiological and psychological well-being. The aim of this study was to investigate and compare the effects of Benson's relaxation and rhythmic breathing techniques on postoperative anxiety in candidates for the mastectomy surgery. METHODS: This randomized controlled clinical trial study was conducted with ninety patients in 2013. The patients were hospitalized for the mastectomy surgery in three surgical wards in a teaching hospital, Tehran, Iran. They were randomly assigned into three groups: Benson's relaxation including the cognitive relaxation technique type, rhythmic breathing including the somatic relaxation technique type and control groups. According to the Davidson and Schwartz multi-process theory, the Benson's relaxation and the rhythmic breathing techniques have cognitive and somatic effects, respectively. One day before the surgery, the patients in the intervention groups were trained regarding relaxation and breathing techniques and were asked to perform the techniques under the supervision of the researcher in the night before the surgery. The cognitive somatic anxiety questionnaire was used to measure anxiety before the intervention and half an hour after recovery of consciousness after the surgery. Descriptive and inferential statistics were used for data analysis via the SPSS v.21 software. RESULTS: There were no statistically significant differences between the groups in terms of demographic characteristics. The application of both techniques reduced the level of patients' anxiety after the surgery. The patients in the Benson's relaxation technique group reported only the relief of somatic anxiety. However, the breathing technique patients reported a reduction in both cognitive and somatic anxiety. CONCLUSION: The Benson's relaxation and rhythmic breathing techniques can reduce postoperative anxiety in patients after the mastectomy surgery. Trial Registration Number: IRCT2014042017350N1. PMID- 28097180 TI - The Role of Nurses in Coping Process of Family Caregivers of Vegetative Patients: A Qualitative Study. AB - BACKGROUND: Vegetative state (VS) occurs through return of the brain stem after coma state. After hospital discharge, responsibility of caring for VS patients is transferred to their families, which causes a high burden on them. Nurses have an important role in helping the family caregivers to meet their needs and cope with difficulties. To explore the role of nurses during coping process of family caregivers of VS patients. METHODS: This study is a part of a larger qualitative study which was performed in Kerman province, Iran during 2014- 2015. Purposive and theoretical sampling was used. 14 caregivers participated in the study. Data were gathered using face-to-face in-depth interviews and managed by MAXQDA 10 software. Analysis was done through constant Comparative Method. RESULTS: Three themes of "nurse as a pursuer teacher", "nurse as a compassionate caregiver", and "nurse as a supporter" were derived from analysis that represent various roles of a nurse in the coping process of family caregivers of vegetative patients during the care process. CONCLUSION: Nurses can play an effective role in improving the caregivers' well-being by considering the importance of training at discharge time and during home care, helping families in providing care and support them during care process. PMID- 28097181 TI - Social Well-Being and Related Factors in Students of School of Nursing and Midwifery. AB - BACKGROUND: According to the World Health Organization viewpoint, social well being is an important dimension of health along with physical and mental aspects. Evaluation of social well-being is necessary in students, especially in medical sciences students due to future responsibility as health care professionals. The present study attempted to investigate the level of social well-being, five domains of it (like actualization, integration, contribution), and some related factors in the school of nursing and midwifery students. METHODS: This cross sectional study was carried out between Julys to December 2015 and comprised 346 students in the school of nursing and midwifery in Shiraz University of Medical Sciences, Shiraz, Iran. Social well-being, socio-demographic status and physical activity were measured by valid questionnaires. Univariate linear regression analysis, multiple imputation method, ANOVA and independent sample t-test were used as different statistical methods. The P values less than 0.05 were considered as statistically significant. RESULTS: The mean score of social well being was 50. The minimum and maximum scores of social well-being were 20 to 100. Married students had higher social well-being than single students in univariate linear regression (Beta: 2.111, 95% CI: (0.387 to 3.738), P=0.017). Also, social integration had higher scores in married students (P=0.015). Social actualization was higher in male students (P=0.015); on the other hand, social contribution was higher in female students (P=0.026). CONCLUSION: The results of our study showed that social well-being status of students in this research was not satisfactory. Designing and conducting programs for promotion of social well-being, for example preparing facilities for marriage of students, can be helpful. Evaluation of social well-being in students of other schools with multicenter studies seems to be useful. PMID- 28097182 TI - The Role of Mass Media in Iranian Youth's Premarital Sexual Relationships: A Qualitative Study. AB - BACKGROUND: Youth's sexual behaviors have various consequences such as unwanted pregnancy, acquired immunodeficiency syndrome and sexually transmitted infections. Little information is available about the impact of mass media in the development of premarital sexual relationships. This study aimed to explore the role of mass media on premarital sexual relationships among Iranian youth. METHODS: This qualitative study was conducted with 26 single boys and girls aged 18-24 years who were living in Isfahan, Iran and have already been started their sexual relationships. Also, 12 other participants who were involved in such an experience were recruited in this study. Data was collected using semi-structured interviews and the observation of youth's sexual interactions in different fields. Conventional content analysis method was used for data analysis. RESULTS: Three main categories were developed: "foreigner media as the role model", "the ease of access to sexual contents and materials" and "the ease of interactions and relationships with the opposite sex". CONCLUSION: The prominent role of mass media in the formation of premarital sexual relationships was described in this study. This issue needs to be taken into consideration by policy makers for taking necessary actions for reducing the impact of mass media on the youth's engagement in premarital sexual relationships. PMID- 28097183 TI - Local Anesthesia for Percutaneous Thoracic Endovascular Aortic Repair. AB - BACKGROUND: Thoracic endovascular aortic repair (TEVAR) requires large-bore vascular access due to the considerable diameters of the endoprosthesis and delivery device. The preclose technique preceding endograft delivery has opened the door for an evolved access strategy. In addition, treatment under local anesthesia offers the advantage of optimal neuromonitoring. The goal of this study was to analyze the efficacy and safety of percutaneous TEVAR under local anesthesia. METHODS: All patients undergoing TEVAR in an elective setting at the Antwerp University Hospital between June 2012 and June 2015 were prospectively entered into an endovascular database. This database was queried for demographics, procedural details, and access-related complications. All patients underwent a percutaneous approach with the Perclose Proglide under local anesthesia. RESULTS: This review identified 34 patients in whom 37 percutaneous TEVAR procedures were completed under local anesthesia. All patients experienced adequate analgesia, and no conversions to general anesthesia were implemented. The mean size of the arteriotomy was 23.8 +/- 1.3 French (F). The number of Proglide deployments was 80, with an 8% rate of failure on deployment. There were no conversions to surgical cutdown, and adequate hemostasis was obtained in all procedures. The incidence of postprocedural access-related complications was 3%. CONCLUSION: Local anesthesia for percutaneous TEVAR can be performed safely and effectively. The percutaneous approach facilitates local anesthesia, which provides the added benefit of early recognition of neurologic complications while maintaining a low risk of access-related complications despite the need for large bore vascular access. PMID- 28097184 TI - KIF6 719Arg Genetic Variant and Risk for Thoracic Aortic Dissection. AB - BACKGROUND: Carriers of the 719Arg variant in KIF6, compared with noncarriers, have been reported to be at greater risk for coronary heart disease (CHD) in six prospective studies. Because CHD, thoracic aortic dissection, and nondissection thoracic aortic aneurysm share some risk factors and aspects of pathophysiology, we investigated whether carriers of the 719Arg variant also have greater odds of thoracic aortic dissection or nondissected thoracic aortic aneurysm than noncarriers. METHODS: We genotyped 140 thoracic aortic dissection cases, 497 nondissection thoracic aortic aneurysm cases, and 275 disease-free controls collected in the United States, Hungary, and Greece and investigated the association between KIF6 719Arg carrier status and thoracic aortic dissection, and between KIF6 719Arg carrier status and nondissection thoracic aortic aneurysm, using logistic regression models adjusted for age, sex, hypertension, smoking, and country. RESULTS: The odds of aortic dissection were two-fold greater in KIF6 719Arg carriers compared with noncarriers (odds ratio (OR) 2.14, 95% confidence interval (CI) 1.18-3.9). To account for the potential of concomitant CHD to confound the association between the KIF6 719Arg and thoracic aortic dissection, we repeated the analysis after removing subjects with concomitant CHD; the estimates for association of KIF6 719Arg carrier status remained essentially the same (OR 2.04, 95% CI 1.11-3.77). In contrast, KIF6 719Arg carrier status was not associated with risk for nondissection thoracic aortic aneurysm. CONCLUSIONS: We observed an association of the KIF6 719Arg genetic variant with thoracic aortic dissection in this multicenter case-control study. This association may enhance our management of patients with thoracic aortic disease. PMID- 28097185 TI - Immediate Improvement in Severe Mitral Regurgitation After Aortic Valve Replacement for Severe Aortic Insufficiency. AB - A 57-year-old male with ascending aortic aneurysm, severe aortic regurgitation, and severe mitral regurgitation (MR) underwent ascending aortic replacement and aortic valve replacement. MR in this patient with normal mitral valve morphology was considered secondary to aortic valve incompetency. Consequently, a surgical approach to restore aortic valve function was adopted with successful MR resolution. This case report demonstrates the possibility of reversing early functional mitral regurgitation without surgically approaching the mitral valve. PMID- 28097186 TI - Unusual Management of Thoracic Aortic Injury After Spinal Instrumentation: Just Glue It! AB - We report the cases of two patients who presented with screw misplacement following spinal surgery. Both benefited from unusual vascular surgical management with removal of the material and injection of biological glue facing the injury, with uneventful postoperative courses. PMID- 28097187 TI - Intraoperative Epiaortic Ultrasound for Traumatic Pseudoaneurysm of the Ascending Aorta. AB - Epiaortic ultrasound is an imaging modality that is commonly used to evaluate the ascending aorta for atheroma and other mural lesions during elective cardiac surgery. Its use in contained aortic rupture has not been established. We present a case of thoracic trauma with contained pseudoaneurysm of the ascending aorta. At operation, the precise location of the aortic tear could not be identified by visual inspection, manual palpation, or transesophageal echocardiography. Epiaortic ultrasound was employed and the aortic defect was identified and successfully repaired. This intraoperative imaging modality may play an increasing role in the identification of aortic pathology when visual inspection and other intraoperative imaging is insufficient. PMID- 28097188 TI - The Migration of Air into the Aorta from a Pneumothorax in a Patient with a Penetrating Injury of the Aorta. AB - A tree fell on the back of a 77-year-old male. A postmortem computed tomographic pan scan revealed systemic air embolism, multiple rib fractures with a penetrating injury to the aorta, pneumohemothorax, and air in the aorta. A massive amount of air entered the site of a penetrating injury of the aorta. This unique case adds one more cause to the list of documented etiologies of air in the aorta. PMID- 28097189 TI - Is the Sac Waiting to Rupture? Sinus of Valsalva Aneurysm. AB - Completely asymptomatic sinus of Valsalva aneurysms are rare entities, and there is no consensus regarding their management. We present the case of a patient who underwent atrial septal defect device closure at 5 years of age and was lost to follow-up, then presented 6 years later with unruptured sinus of Valsalva aneurysm and was closely followed. The aneurysm eventually ruptured and was successfully operated on with good outcomes. PMID- 28097190 TI - Chronic Type A Aortic Dissection and Giant Aortic Root Aneurysm After Aortic Valve Replacement. AB - We describe the case of a 61-year-old male with a giant aortic root aneurysm associated with chronic aortic Type A dissection. The patient had been operated on 16 years before due to aortic annuloectasia with mechanical valve replacement. The patient underwent revision aortic surgery with a Bentall-De Bono operation with Svensson modification, using a #21 On-X Valsalva mechanical valve conduit. The postoperative course was uneventful. PMID- 28097191 TI - Page for the General Public. PMID- 28097192 TI - List of Upcoming Meetings. PMID- 28097193 TI - Axillary Versus Femoral Arterial Cannulation During Repair of Type A Aortic Dissection?: An Old Problem Seeking New Solutions. AB - BACKGROUND: The goal of this study was to compare early postoperative outcomes and actuarial-free survival between patients who underwent repair of acute Type A aortic dissection with axillary or femoral artery cannulation. METHODS: A total of 305 patients from five academic medical centers underwent acute Type A aortic dissection repair via axillary (n = 107) or femoral (n = 198) artery cannulation between January 2000 and December 2010. Major morbidity, operative mortality, and 5-year actuarial survival were compared between groups. Multivariate logistic regression was used to determine predictors of operative mortality, and Cox regression hazard ratios were calculated to determine predictors of long-term mortality. RESULTS: Operative mortality was not influenced by cannulation site (16% for axillary cannulation vs. 19% for femoral cannulation, p = 0.64). In multivariate logistic regression analysis, hemodynamic instability (p < 0.001) and prolonged cardiopulmonary bypass time (>200 min; p = 0.05) emerged as independent predictors of operative mortality. Stroke rates were comparable between the two techniques (14% for axillary and 17% for femoral cannulation, p = 0.52). Five-year actuarial survival was comparable between the groups (55.1% for axillary and 65.7% for femoral cannulation, p = 0.36). In Cox regression analysis, predictors of long-term mortality were: age (p < 0.001), stroke (p < 0.001), prolonged cardiopulmonary bypass time (p = 0.001), hemodynamic instability (p = 0.002), and renal failure (p = 0.001). CONCLUSIONS: The outcomes of femoral versus axillary arterial cannulation in patients with acute Type A aortic dissection are comparable. The choice of arterial cannulation site should be individualized based on different patient risk profiles. PMID- 28097194 TI - The Mystery of the Z-Score. AB - Reliable methods for measuring the thoracic aorta are critical for determining treatment strategies in aneurysmal disease. Z-scores are a pragmatic alternative to raw diameter sizes commonly used in adult medicine. They are particularly valuable in the pediatric population, who undergo rapid changes in physical development. The advantage of the Z-score is its inclusion of body surface area (BSA) in determining whether an aorta is within normal size limits. Therefore, Z scores allow us to determine whether true pathology exists, which can be challenging in growing children. In addition, Z-scores allow for thoughtful interpretation of aortic size in different genders, ethnicities, and geographical regions. Despite the advantages of using Z-scores, there are limitations. These include intra- and inter-observer bias, measurement error, and variations between alternative Z-score nomograms and BSA equations. Furthermore, it is unclear how Z scores change in the normal population over time, which is essential when interpreting serial values. Guidelines for measuring aortic parameters have been developed by the American Society of Echocardiography Pediatric and Congenital Heart Disease Council, which may reduce measurement bias when calculating Z scores for the aortic root. In addition, web-based Z-score calculators have been developed to aid in efficient Z-score calculations. Despite these advances, clinicians must be mindful of the limitations of Z-scores, especially when used to demonstrate beneficial treatment effect. This review looks to unravel the mystery of the Z-score, with a focus on the thoracic aorta. Here, we will discuss how Z-scores are calculated and the limitations of their use. PMID- 28097195 TI - Rapidly Expanding Infectious Aortic Aneurysm Caused by Perforated Colon Cancer. AB - A 50-year-old male smoker presented with a perforated colon cancer and underwent an extended right colectomy. Feculent peritonitis was treated with empiric antibiotics. Postoperatively he developed severe back pain and rising leukocytosis. Serial computed tomography revealed a rapidly expanding infrarenal aortic aneurysm. He was urgently treated with extra-anatomic bypasses and aortic resection. No organisms grew from the resected aortic wall. He was discharged in stable condition, and the ileostomy was reversed 9 months later. PMID- 28097196 TI - Chimney Technique with Nellix EndoVascular Aneurysm Sealing System in a Patient with Single Kidney and Juxtarenal Abdominal Aortic Aneurysm. AB - We present a saccular asymptomatic juxtarenal abdominal aortic aneurysm in a 70 year-old male with a very short left renal artery supplying the only kidney. The case was successfully treated with the Nellix EndoVascular Aneurysm Sealing system combined with a chimney technique. PMID- 28097197 TI - Early Coronary Thrombosis without ST-Segment Elevation Following Repair of Acute Aortic Dissection. AB - Acute coronary thrombosis after emergent surgery for acute Type A aortic dissection is a rare event that can remain undiagnosed in absence of typical electrocardiogram readings. We report a case of left anterior descending artery thrombosis without ST-segment elevation three days after surgical repair, which was successfully treated with angioplasty and stenting. PMID- 28097198 TI - Intimal Sarcoma of the Descending Aorta Mimicking Aortitis. AB - We describe a 74-year-old male patient with an intimal sarcoma of the descending aorta mimicking aortitis. The patient presented with lower back pain, fever, and increased C-reactive protein, erythrocyte sedimentation rate, and immunoglobulin G4 (IgG4) serum levels, together with Staphylococcus epidermidis-positive blood cultures. These findings, together with evidence of a 49-mm pseudoaneurysm of the descending thoracic aorta, caused us to suspect aortitis. However, postoperative histology and immunohistochemistry demonstrated the presence of an intimal aortic sarcoma. At the 8-month follow-up, local recurrence of the neoplasm and lung metastases were noted. PMID- 28097199 TI - Long-Term Survival After Composite Mechanical Aortic Root Replacement. AB - This report describes the long-term follow-up of the repair of a giant ascending aneurysm using a composite graft with a mechanical valve. PMID- 28097200 TI - Page for the General Public. PMID- 28097201 TI - List of Upcoming Meetings. PMID- 28097202 TI - Distinct effects of obesity and puberty on risk and age at onset of pediatric MS. AB - OBJECTIVE: The aim of this study was to examine the relative contributions of body mass index (BMI) and pubertal measures for risk and age of onset of pediatric MS. METHODS: Case-control study of 254 (63% female) MS cases (onset<18 years of age) and 420 (49% female) controls conducted at 14 U.S. Pediatric MS Centers. Sex- and age-stratified BMI percentiles were calculated using CDC growth charts from height and weight measured at enrollment for controls, and within 1 year of onset for MS cases. Sex-stratified associations between MS risk and age at symptom onset with both BMI and pubertal factors were estimated controlling for race and ethnicity. RESULTS: Only 11% of girls and 15% of boys were prepubertal (Tanner stage I) at MS onset. 80% of girls had onset of MS after menarche. BMI percentiles were higher in MS cases versus controls (girls: P < 0.001; boys: P = 0.018). BMI was associated with odds of MS in multivariate models in postpubertal girls (OR = 1.60, 95% confidence interval [CI]: 1.12, 2.27, P = 0.009) and boys (OR = 1.43, 95% CI: 1.08, 1.88, P = 0.011). In girls with MS onset after menarche, higher BMI was associated with younger age at first symptoms (P = 0.031). Younger menarche was associated with stronger effects of BMI through mediation and interaction analysis. In pubertal/postpubertal boys, 89% of whom were obese/overweight, earlier sexual maturity was associated with earlier onset of MS (P < 0.001). INTERPRETATION: Higher BMI in early adolescence is a risk factor for MS in girls and boys. Earlier age at sexual maturity contributes to earlier age at MS onset, particularly in association with obesity. PMID- 28097203 TI - Staged anticonvulsant screening for chronic epilepsy. AB - OBJECTIVE: Current anticonvulsant screening programs are based on seizures evoked in normal animals. One-third of epileptic patients do not respond to the anticonvulsants discovered with these models. We evaluated a tiered program based on chronic epilepsy and spontaneous seizures, with compounds advancing from high throughput in vitro models to low-throughput in vivo models. METHODS: Epileptogenesis in organotypic hippocampal slice cultures was quantified by lactate production and lactate dehydrogenase release into culture media as rapid assays for seizure-like activity and cell death, respectively. Compounds that reduced these biochemical measures were retested with in vitro electrophysiological confirmation (i.e., second stage). The third stage involved crossover testing in the kainate model of chronic epilepsy, with blinded analysis of spontaneous seizures after continuous electrographic recordings. RESULTS: We screened 407 compound-concentration combinations. The cyclooxygenase inhibitor, celecoxib, had no effect on seizures evoked in normal brain tissue but demonstrated robust antiseizure activity in all tested models of chronic epilepsy. INTERPRETATION: The use of organotypic hippocampal cultures, where epileptogenesis occurs on a compressed time scale, and where seizure-like activity and seizure-induced cell death can be easily quantified with biomarker assays, allowed us to circumvent the throughput limitations of in vivo chronic epilepsy models. Ability to rapidly screen compounds in a chronic model of epilepsy allowed us to find an anticonvulsant that would be missed by screening in acute models. PMID- 28097204 TI - Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases. AB - OBJECTIVES: We assessed the current genetic evidence for the involvement of various cell types and tissue types in the etiology of neurodegenerative diseases, especially in relation to the neuroinflammatory hypothesis of neurodegenerative diseases. METHODS: We obtained large-scale genome-wide association study (GWAS) summary statistics from Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). We used multiple sclerosis (MS), an autoimmune disease of the central nervous system, as a positive control. We applied stratified LD score regression to determine if functional marks for cell type and tissue activity, and gene-set lists were enriched for genetic heritability. We compared our results to those from two gene set enrichment methods (Ingenuity Pathway Analysis and enrichr). RESULTS: There were no significant heritability enrichments for annotations marking genes active within brain regions, but there were significant heritability enrichments for annotations marking genes active within cell types that form part of both the innate and adaptive immune systems. We found this for MS (as expected) and also for AD and PD. The strongest signals were from the adaptive immune system (e.g., T cells) for PD, and from both the adaptive (e.g., T cells) and innate (e.g., CD14: a marker for monocytes, and CD15: a marker for neutrophils) immune systems for AD. Annotations from the liver were also significant for AD. Pathway analysis provided complementary results. INTERPRETATION: For AD and PD, we found significant enrichment of heritability in annotations marking gene activity in immune cells. PMID- 28097205 TI - Impact of tau and amyloid burden on glucose metabolism in Alzheimer's disease. AB - In a multimodal PET imaging approach, we determined the differential contribution of neurofibrillary tangles (measured with [18F]AV-1451) and beta-amyloid burden (measured with [11C]PiB) on degree of neurodegeneration (i.e., glucose metabolism measured with [18F]FDG-PET) in patients with Alzheimer's disease. Across brain regions, we observed an interactive effect of beta-amyloid burden and tau deposition on glucose metabolism which was most pronounced in the parietal lobe. Elevated beta-amyloid burden was associated with a stronger influence of tau accumulation on glucose metabolism. Our data provide the first in vivo insights into the differential contribution of Abeta and tau to neurodegeneration in Alzheimer's disease. PMID- 28097206 TI - [18F]AV-1451 PET in behavioral variant frontotemporal dementia due to MAPT mutation. AB - The validation of tau radioligands could improve the diagnosis of frontotemporal lobar degeneration and the assessment of disease-modifying therapies. Here, we demonstrate that binding of the tau radioligand [18F]AV-1451 was significantly abnormal in both magnitude and distribution in a patient with familial frontotemporal dementia due to a MAPT 10 + 16C>T gene mutation, recapitulating the pattern of neuropathology seen in her father. Given the genetic diagnosis and the non-Alzheimer's pathology, these findings suggest that [18F]AV-1451 might be a useful biomarker in primary tauopathies. Largerscale in vivo and post-mortem studies will be needed to assess the technique's specificity. PMID- 28097207 TI - Upper arm and cardiac magnetic resonance imaging in Duchenne muscular dystrophy. AB - We analyzed quantitative maps of T1 and T2 relaxation times and muscle fat fraction measurements in magnetic resonance imaging of the upper arm skeletal muscles and heart in ambulatory boys with Duchenne muscular dystrophy and age range-matched healthy volunteer boys. The cardiac-optimized sequences detected fatty infiltration and edema in the upper arm skeletal muscles but not the myocardium in these Duchenne muscular dystrophy boys who had normal ejection fraction. Imaging the heart and skeletal muscle using the same magnetic resonance imaging methods during a single scan may be useful in assessing relative disease status and therapeutic response in clinical trials of Duchenne muscular dystrophy. PMID- 28097208 TI - Muscle synergies after stroke are correlated with perilesional high gamma. AB - Movements can be factored into modules termed "muscle synergies". After stroke, abnormal synergies are linked to impaired movements; however, their neural basis is not understood. In a single subject, we examined how electrocorticography signals from the perilesional cortex were associated with synergies. The measured synergies contained a mix of both normal and abnormal patterns and were remarkably similar to those described in past work. Interestingly, we found that both normal and abnormal synergies were correlated with perilesional high gamma. Given the link between high gamma and cortical spiking, our results suggest that perilesional spiking may organize synergies after stroke. PMID- 28097209 TI - Fluorescence-guided resection of brain tumor: review of the significance of intraoperative quantification of protoporphyrin IX fluorescence. AB - Surgical removal of tumor mass is a common approach in the management of brain tumors. However, the precise delineation of normal tissue from tumor tissue for a complete resection of tumor mass in brain tumor surgery remains a difficult task for neurosurgeons. Aminolevulinic acid (ALA)-mediated exgogenous fluorescence of protoporphyrin IX (PpIX) is a sensitive approach for tumor imaging. Recent studies suggest that the use of ALA/PpIX-mediated fluorescence-guided resection (FGR) or fluorescence-guided surgery can enable more accurate and complete resection of brain tumors, especially when used in quantitative fashion. This review will highlight the current progress in PpIX-mediated FGR and discuss technical challenges in intraoperative quantification of intracellular PpIX fluorescence during FGR of brain tumor. PMID- 28097210 TI - Preclinical positron emission tomography scanner based on a monolithic annulus of scintillator: initial design study. AB - Positron emission tomography (PET) scanners designed for imaging of small animals have transformed translational research by reducing the necessity to invasively monitor physiology and disease progression. Virtually all of these scanners are based on the use of pixelated detector modules arranged in rings. This design, while generally successful, has some limitations. Specifically, use of discrete detector modules to construct PET scanners reduces detection sensitivity and can introduce artifacts in reconstructed images, requiring the use of correction methods. To address these challenges, and facilitate measurement of photon depth of-interaction in the detector, we investigated a small animal PET scanner (called AnnPET) based on a monolithic annulus of scintillator. The scanner was created by placing 12 flat facets around the outer surface of the scintillator to accommodate placement of silicon photomultiplier arrays. Its performance characteristics were explored using Monte Carlo simulations and sections of the NEMA NU4-2008 protocol. Results from this study revealed that AnnPET's reconstructed spatial resolution is predicted to be [Formula: see text] full width at half maximum in the radial, tangential, and axial directions. Peak detection sensitivity is predicted to be 10.1%. Images of simulated phantoms (mini-hot rod and mouse whole body) yielded promising results, indicating the potential of this system for enhancing PET imaging of small animals. PMID- 28097211 TI - New-generation small animal positron emission tomography system for molecular imaging. AB - The next generation of discoveries in molecular imaging requires positron emission tomography (PET) systems with high spatial resolution and high sensitivity to visualize and quantify low concentrations of molecular probes. The goal of this work is to assemble and explore such a system. We use cadmium zinc telluride (CZT) to achieve high spatial resolution, three-dimensional interaction positioning, and excellent energy resolution. The CZT crystals are arranged in an edge-on configuration with a minimum gap of [Formula: see text] in a four-sided panel geometry to achieve superior photon sensitivity. The developed CZT detectors and readout electronics were scaled up to complete significant portions of the final PET system. The steering electrode bias and the amplitude of the analog signals for time measurement were optimized to improve performance. The energy resolution (at 511 keV) over 468 channels is [Formula: see text] full width-at-half-maximum (FWHM). The spatial resolution is [Formula: see text] FWHM. The time resolution of six CZT crystals in coincidence with six other CZT crystals is 37 ns. With high energy and spatial resolution and the relatively low random rate for small animal imaging, this system shows promise to be very useful for molecular imaging studies. PMID- 28097212 TI - Feasibility of reduced-dose three-dimensional/four-dimensional-digital subtraction angiogram using a weighted edge preserving filter. AB - A conventional three-dimensional/four-dimensional (3D/4D) digital subtraction angiogram (DSA) requires two rotational acquisitions (mask and fill) to compute the log-subtracted projections that are used to reconstruct a 3D/4D volume. Since all of the vascular information is contained in the fill acquisition, it is hypothesized that it is possible to reduce the x-ray dose of the mask acquisition substantially and still obtain subtracted projections adequate to reconstruct a 3D/4D volume with noise level comparable to a full-dose acquisition. A full-dose mask and fill acquisition were acquired from a clinical study to provide a known full-dose reference reconstruction. Gaussian noise was added to the mask acquisition to simulate a mask acquisition acquired at 10% relative dose. Noise in the low-dose mask projections was reduced with a weighted edge preserving filter designed to preserve bony edges while suppressing noise. Two-dimensional (2D) log-subtracted projections were computed from the filtered low-dose mask and full-dose fill projections, and then 3D/4D-DSA reconstruction algorithms were applied. Additional bilateral filtering was applied to the 3D volumes. The signal to-noise ratio measured in the filtered 3D/4D-DSA volumes was compared to the full-dose case. The average ratio of filtered low-dose SNR to full-dose SNR was 0.856 for the 3D-DSA and 0.849 for the 4D-DSA, indicating that the method is a feasible approach to restoring SNR in DSA scans acquired with a low-dose mask. The method was also tested in a phantom study with full-dose fill and 22%-dose mask. PMID- 28097213 TI - Fully automated quantitative cephalometry using convolutional neural networks. AB - Quantitative cephalometry plays an essential role in clinical diagnosis, treatment, and surgery. Development of fully automated techniques for these procedures is important to enable consistently accurate computerized analyses. We study the application of deep convolutional neural networks (CNNs) for fully automated quantitative cephalometry for the first time. The proposed framework utilizes CNNs for detection of landmarks that describe the anatomy of the depicted patient and yield quantitative estimation of pathologies in the jaws and skull base regions. We use a publicly available cephalometric x-ray image dataset to train CNNs for recognition of landmark appearance patterns. CNNs are trained to output probabilistic estimations of different landmark locations, which are combined using a shape-based model. We evaluate the overall framework on the test set and compare with other proposed techniques. We use the estimated landmark locations to assess anatomically relevant measurements and classify them into different anatomical types. Overall, our results demonstrate high anatomical landmark detection accuracy ([Formula: see text] to 2% higher success detection rate for a 2-mm range compared with the top benchmarks in the literature) and high anatomical type classification accuracy ([Formula: see text] average classification accuracy for test set). We demonstrate that CNNs, which merely input raw image patches, are promising for accurate quantitative cephalometry. PMID- 28097214 TI - Location- and lesion-dependent estimation of mammographic background tissue complexity. AB - We specify a notion of perceived background tissue complexity (BTC) that varies with lesion shape, lesion size, and lesion location in the image. We propose four unsupervised BTC estimators based on: perceived pre and postlesion similarity of images, lesion border analysis (LBA; conspicuous lesion should be brighter than its surround), tissue anomaly detection, and local energy. The latter two are existing methods adapted for location- and lesion-dependent BTC estimation. For evaluation, we ask human observers to measure BTC (threshold visibility amplitude of a given lesion inserted) at specified locations in a mammogram. As expected, both human measured and computationally estimated BTC vary with lesion shape, size, and location. BTCs measured by different human observers are correlated ([Formula: see text]). BTC estimators are correlated to each other ([Formula: see text]) and less so to human observers ([Formula: see text]). With change in lesion shape or size, LBA estimated BTC changes in the same direction as human measured BTC. Proposed estimators can be generalized to other modalities (e.g., breast tomosynthesis) and used as-is or customized to a specific human observer, to construct BTC-aware model observers with applications, such as optimization of contrast-enhanced medical imaging systems and creation of a diversified image dataset with characteristics of a desired population. PMID- 28097215 TI - An ambiguity principle for assigning protein structural domains. AB - Ambiguity is the quality of being open to several interpretations. For an image, it arises when the contained elements can be delimited in two or more distinct ways, which may cause confusion. We postulate that it also applies to the analysis of protein three-dimensional structure, which consists in dividing the molecule into subunits called domains. Because different definitions of what constitutes a domain can be used to partition a given structure, the same protein may have different but equally valid domain annotations. However, knowledge and experience generally displace our ability to accept more than one way to decompose the structure of an object-in this case, a protein. This human bias in structure analysis is particularly harmful because it leads to ignoring potential avenues of research. We present an automated method capable of producing multiple alternative decompositions of protein structure (web server and source code available at www.dsimb.inserm.fr/sword/). Our innovative algorithm assigns structural domains through the hierarchical merging of protein units, which are evolutionarily preserved substructures that describe protein architecture at an intermediate level, between domain and secondary structure. To validate the use of these protein units for decomposing protein structures into domains, we set up an extensive benchmark made of expert annotations of structural domains and including state-of-the-art domain parsing algorithms. The relevance of our "multipartitioning" approach is shown through numerous examples of applications covering protein function, evolution, folding, and structure prediction. Finally, we introduce a measure for the structural ambiguity of protein molecules. PMID- 28097216 TI - The last frontiers of wilderness: Tracking loss of intact forest landscapes from 2000 to 2013. AB - An intact forest landscape (IFL) is a seamless mosaic of forest and naturally treeless ecosystems with no remotely detected signs of human activity and a minimum area of 500 km2. IFLs are critical for stabilizing terrestrial carbon storage, harboring biodiversity, regulating hydrological regimes, and providing other ecosystem functions. Although the remaining IFLs comprise only 20% of tropical forest area, they account for 40% of the total aboveground tropical forest carbon. We show that global IFL extent has been reduced by 7.2% since the year 2000. An increasing rate of global IFL area reduction was found, largely driven by the tripling of IFL tropical forest loss in 2011-2013 compared to that in 2001-2003. Industrial logging, agricultural expansion, fire, and mining/resource extraction were the primary causes of IFL area reduction. Protected areas (International Union for Conservation of Nature categories I to III) were found to have a positive effect in slowing the reduction of IFL area from timber harvesting but were less effective in limiting agricultural expansion. The certification of logging concessions under responsible management had a negligible impact on slowing IFL fragmentation in the Congo Basin. Fragmentation of IFLs by logging and establishment of roads and other infrastructure initiates a cascade of changes that lead to landscape transformation and loss of conservation values. Given that only 12% of the global IFL area is protected, our results illustrate the need for planning and investment in carbon sequestration and biodiversity conservation efforts that target the most valuable remaining forests, as identified using the IFL approach. PMID- 28097217 TI - Amylose recognition and ring-size determination of amylomaltase. AB - Starch is a major carbon and energy source throughout all kingdoms of life. It consists of two carbohydrate polymers, branched amylopectin and linear amylose, which are sparingly soluble in water. Hence, the enzymatic breakdown by glycoside hydrolases (GHs) is of great biological and societal importance. Amylomaltases (AMs) are GHs specialized in the hydrolysis of alpha-1,4-linked sugar chains such as amylose. They are able to catalyze an intramolecular transglycosylation of a bound sugar chain yielding polymeric sugar rings, the cycloamyloses (CAs), consisting of 20 to 100 glucose units. Despite a wealth of data on short oligosaccharide binding to GHs, no structural evidence is available for their interaction with polymeric substrates that better represent the natural polysaccharide. We have determined the crystal structure of Thermus aquaticus AM in complex with a 34-meric CA-one of the largest carbohydrates resolved by x-ray crystallography and a mimic of the natural polymeric amylose substrate. In total, 15 glucose residues interact with the protein in an extended crevice with a length of more than 40 A. A modified succinimide, derived from aspartate, mediates protein-sugar interactions, suggesting a biological role for this nonstandard amino acid. The structure, together with functional assays, provides unique insights into the interaction of GHs with their polymeric substrate and reveals a molecular ruler mechanism for minimal ring-size determination of CA products. PMID- 28097218 TI - Energy penetration into arrays of aligned nanowires irradiated with relativistic intensities: Scaling to terabar pressures. AB - Ultrahigh-energy density (UHED) matter, characterized by energy densities >1 * 108 J cm-3 and pressures greater than a gigabar, is encountered in the center of stars and inertial confinement fusion capsules driven by the world's largest lasers. Similar conditions can be obtained with compact, ultrahigh contrast, femtosecond lasers focused to relativistic intensities onto targets composed of aligned nanowire arrays. We report the measurement of the key physical process in determining the energy density deposited in high-aspect-ratio nanowire array plasmas: the energy penetration. By monitoring the x-ray emission from buried Co tracer segments in Ni nanowire arrays irradiated at an intensity of 4 * 1019 W cm 2, we demonstrate energy penetration depths of several micrometers, leading to UHED plasmas of that size. Relativistic three-dimensional particle-in-cell simulations, validated by these measurements, predict that irradiation of nanostructures at intensities of >1 * 1022 W cm-2 will lead to a virtually unexplored extreme UHED plasma regime characterized by energy densities in excess of 8 * 1010 J cm-3, equivalent to a pressure of 0.35 Tbar. PMID- 28097219 TI - Key role of the dopamine D4 receptor in the modulation of corticostriatal glutamatergic neurotransmission. AB - Polymorphic variants of the dopamine D4 receptor gene (DRD4) have been repeatedly associated with numerous neuropsychiatric disorders. Yet, the functional role of the D4 receptor and the functional differences of the products of DRD4 polymorphic variants remained enigmatic. Immunohistochemical and optogenetic microdialysis experiments were performed in knock-in mice expressing a D4 receptor with the long intracellular domain of a human DRD4 polymorphic variant associated with attention deficit hyperactivity disorder (ADHD). When compared with the wild-type mouse D4 receptor, the expanded intracellular domain of the humanized D4 receptor conferred a gain of function, blunting methamphetamine induced cortical activation and optogenetic and methamphetamine-induced corticostriatal glutamate release. The results demonstrate a key role of the D4 receptor in the modulation of corticostriatal glutamatergic neurotransmission. Furthermore, these data imply that enhanced D4 receptor-mediated dopaminergic control of corticostriatal transmission constitutes a vulnerability factor of ADHD and other neuropsychiatric disorders. PMID- 28097220 TI - Slab temperature controls on the Tonga double seismic zone and slab mantle dehydration. AB - Double seismic zones are two-layered distributions of intermediate-depth earthquakes that provide insight into the thermomechanical state of subducting slabs. We present new precise hypocenters of intermediate-depth earthquakes in the Tonga subduction zone obtained using data from local island-based, ocean bottom, and global seismographs. The results show a downdip compressional upper plane and a downdip tensional lower plane with a separation of about 30 km. The double seismic zone in Tonga extends to a depth of about 300 km, deeper than in any other subduction system. This is due to the lower slab temperatures resulting from faster subduction, as indicated by a global trend toward deeper double seismic zones in colder slabs. In addition, a line of high seismicity in the upper plane is observed at a depth of 160 to 280 km, which shallows southward as the convergence rate decreases. Thermal modeling shows that the earthquakes in this "seismic belt" occur at various pressures but at a nearly constant temperature, highlighting the important role of temperature in triggering intermediate-depth earthquakes. This seismic belt may correspond to regions where the subducting mantle first reaches a temperature of ~500 degrees C, implying that metamorphic dehydration of mantle minerals in the slab provides water to enhance faulting. PMID- 28097221 TI - Electrospun core-shell microfiber separator with thermal-triggered flame retardant properties for lithium-ion batteries. AB - Although the energy densities of batteries continue to increase, safety problems (for example, fires and explosions) associated with the use of highly flammable liquid organic electrolytes remain a big issue, significantly hindering further practical applications of the next generation of high-energy batteries. We have fabricated a novel "smart" nonwoven electrospun separator with thermal-triggered flame-retardant properties for lithium-ion batteries. The encapsulation of a flame retardant inside a protective polymer shell has prevented direct dissolution of the retardant agent into the electrolyte, which would otherwise have negative effects on battery performance. During thermal runaway of the lithium-ion battery, the protective polymer shell would melt, triggered by the increased temperature, and the flame retardant would be released, thus effectively suppressing the combustion of the highly flammable electrolytes. PMID- 28097222 TI - Early formation of the Moon 4.51 billion years ago. AB - Establishing the age of the Moon is critical to understanding solar system evolution and the formation of rocky planets, including Earth. However, despite its importance, the age of the Moon has never been accurately determined. We present uranium-lead dating of Apollo 14 zircon fragments that yield highly precise, concordant ages, demonstrating that they are robust against postcrystallization isotopic disturbances. Hafnium isotopic analyses of the same fragments show extremely low initial 176Hf/177Hf ratios corrected for cosmic ray exposure that are near the solar system initial value. Our data indicate differentiation of the lunar crust by 4.51 billion years, indicating the formation of the Moon within the first ~60 million years after the birth of the solar system. PMID- 28097223 TI - ABCA7 loss-of-function variants, expression, and neurologic disease risk. AB - OBJECTIVE: To investigate and characterize putative "loss-of-function" (LOF) adenosine triphosphate-binding cassette, subfamily A member 7 (ABCA7) mutations reported to associate with Alzheimer disease (AD) risk. METHODS: We genotyped 6 previously reported ABCA7 putative LOF variants in 1,465 participants with AD, 381 participants with other neuropathologies (non-AD), and 1,043 controls and assessed the overall mutational burden for association with different diagnosis groups. We measured brain ABCA7 protein and messenger RNA (mRNA) levels using Western blot and quantitative PCR, respectively, in 11 carriers of the 3 most common variants, and sequenced all 47 ABCA7 exons in these participants to screen for other coding variants. RESULTS: At least one of the investigated variants was identified in 45 participants with late-onset Alzheimer disease, 12 participants with other neuropathologies, and 11 elderly controls. Association analysis revealed a significantly higher burden of these variants in participants with AD (p = 5.00E-04) and those with other neuropathologies (p = 8.60E-03) when compared with controls. Concurrent analysis of brain ABCA7 mRNA and protein revealed lower protein but not mRNA in p.L1403fs carriers, lower mRNA but not protein in p.E709fs carriers, and additional deleterious mutations in some c.5570+5G>C carriers. CONCLUSIONS: Our results suggest that LOF may not be a common mechanism for these ABCA7 variants and expand the list of neurologic diseases enriched for them. PMID- 28097224 TI - Everolimus does not prevent Lafora body formation in murine Lafora disease. PMID- 28097225 TI - Centrally involved X-linked Charcot-Marie-Tooth disease presenting as a stroke mimic. PMID- 28097226 TI - IFITM1 targets HIV-1 latently infected cells for antibody-dependent cytolysis. AB - HIV-1 persistence in latent reservoirs during antiretroviral therapy (ART) is the main obstacle to virus eradication. To date, there is no marker that adequately identifies latently infected CD4+ T cells in vivo. Using a well-established ex vivo model, we generated latently infected CD4+ T cells and identified interferon induced transmembrane protein 1 (IFITM1), a transmembrane antiviral factor, as being overexpressed in latently infected cells. By targeting IFITM1, we showed the efficient and specific killing of a latently infected cell line and CD4+ T cells from ART-suppressed patients through antibody-dependent cytolysis. We hypothesize that IFITM1 could mark natural reservoirs, identifying an immune target for killing of latently infected cells. These novel insights could be explored to develop clinical therapeutic approaches to effectively eradicate HIV 1. PMID- 28097227 TI - A xenogeneic-free system generating functional human gut organoids from pluripotent stem cells. AB - Functional intestines are composed of cell types from all 3 primary germ layers and are generated through a highly orchestrated and serial developmental process. Directed differentiation of human pluripotent stem cells (hPSCs) has been shown to yield gut-specific cell types; however, these structures do not reproduce critical functional interactions between cell types of different germ layers. Here, we developed a simple protocol for the generation of mature functional intestinal organoids from hPSCs under xenogeneic-free conditions. The stem cell derived gut organoids produced here were found to contain distinct types of intestinal cells, including enterocytes, goblet cells, Paneth cells, and enteroendocrine cells, that were derived from all 3 germ layers; moreover, they demonstrated intestinal functions, including peptide absorption, and showed innervated bowel movements in response to stimulation with histamine and anticholinergic drugs. Importantly, the gut organoids obtained using this xenogeneic-free system could be stably maintained in culture for prolonged periods and were successfully engrafted in vivo. Our xenogeneic-free approach for generating gut organoids from hPSCs provides a platform for studying human intestinal diseases and for pharmacological testing. PMID- 28097228 TI - Kappa opioid receptor signaling protects cartilage tissue against posttraumatic degeneration. AB - Osteoarthritis is the most common form of arthritis, and pain relief with opioid like drugs is a commonly used therapeutic for osteoarthritic patients. Recent studies published by our group showed that the kappa opioid receptor (KOR) is highly expressed during human development in joint-forming cells. However, the precise role of this receptor in the skeletal system remains elusive. The main aim of the current study was to investigate the role of KOR signaling in synovial and cartilaginous tissues in pathological conditions. Our data demonstrate that KOR null mice exhibit accelerated cartilage degeneration after injury when compared with WT mice. Activation of KOR signaling increased the expression of anabolic enzymes and inhibited cartilage catabolism and degeneration in response to proinflammatory cytokines such as TNF-alpha. In addition, selective KOR agonists increased joint lubrication via the activation of cAMP/CREB signaling in chondrocytes and synovial cells. Taken together, these results demonstrate direct effects of KOR agonists on cartilage and synovial cells and reveals a protective effect of KOR signaling against cartilage degeneration after injury. In addition to pain control, local administration of dynorphin or other KOR agonist represents an attractive therapeutic approach in patients with early stages of osteoarthritis. PMID- 28097229 TI - Anti-SIRPalpha antibodies as a potential new tool for cancer immunotherapy. AB - Tumor cells are thought to evade immune surveillance through interaction with immune cells. Much recent attention has focused on the modification of immune responses as a basis for new cancer treatments. SIRPalpha is an Ig superfamily protein that inhibits phagocytosis in macrophages upon interaction with its ligand CD47 expressed on the surface of target cells. Here, we show that SIRPalpha is highly expressed in human renal cell carcinoma and melanoma. Furthermore, an anti-SIRPalpha Ab that blocks the interaction with CD47 markedly suppressed tumor formation by renal cell carcinoma or melanoma cells in immunocompetent syngeneic mice. This inhibitory effect of the Ab appeared to be mediated by dual mechanisms: direct induction of Ab-dependent cellular phagocytosis of tumor cells by macrophages and blockade of CD47-SIRPalpha signaling that negatively regulates such phagocytosis. The antitumor effect of the Ab was greatly attenuated by selective depletion not only of macrophages but also of NK cells or CD8+ T cells. In addition, the anti-SIRPalpha Ab also enhances the inhibitory effects of Abs against CD20 and programmed cell death 1 (PD-1) on tumor formation in mice injected with SIRPalpha-nonexpressing tumor cells. Anti-SIRPalpha Abs thus warrant further study as a potential new therapy for a broad range of cancers. PMID- 28097230 TI - Protection against Plasmodium falciparum malaria by PfSPZ Vaccine. AB - BACKGROUND: A radiation-attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) malaria vaccine, PfSPZ Vaccine, protected 6 of 6 subjects (100%) against homologous Pf (same strain as in the vaccine) controlled human malaria infection (CHMI) 3 weeks after 5 doses administered intravenously. The next step was to assess protective efficacy against heterologous Pf (different from Pf in the vaccine), after fewer doses, and at 24 weeks. METHODS: The trial assessed tolerability, safety, immunogenicity, and protective efficacy of direct venous inoculation (DVI) of 3 or 5 doses of PfSPZ Vaccine in non-immune subjects. RESULTS: Three weeks after final immunization, 5 doses of 2.7 * 105 PfSPZ protected 12 of 13 recipients (92.3% [95% CI: 48.0, 99.8]) against homologous CHMI and 4 of 5 (80.0% [10.4, 99.5]) against heterologous CHMI; 3 doses of 4.5 * 105 PfSPZ protected 13 of 15 (86.7% [35.9, 98.3]) against homologous CHMI. Twenty four weeks after final immunization, the 5-dose regimen protected 7 of 10 (70.0% [17.3, 93.3]) against homologous and 1 of 10 (10.0% [-35.8, 45.6]) against heterologous CHMI; the 3-dose regimen protected 8 of 14 (57.1% [21.5, 76.6]) against homologous CHMI. All 22 controls developed Pf parasitemia. PfSPZ Vaccine was well tolerated, safe, and easy to administer. No antibody or T cell responses correlated with protection. CONCLUSIONS: We have demonstrated for the first time to our knowledge that PfSPZ Vaccine can protect against a 3-week heterologous CHMI in a limited group of malaria-naive adult subjects. A 3-dose regimen protected against both 3-week and 24-week homologous CHMI (87% and 57%, respectively) in this population. These results provide a foundation for developing an optimized immunization regimen for preventing malaria. TRIAL REGISTRATION: ClinicalTrials.gov NCT02215707. FUNDING: Support was provided through the US Army Medical Research and Development Command, Military Infectious Diseases Research Program, and the Naval Medical Research Center's Advanced Medical Development Program. PMID- 28097231 TI - Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation. AB - BACKGROUND: Protein disulfide isomerase (PDI) is required for thrombus formation. We previously demonstrated that glycosylated quercetin flavonoids such as isoquercetin inhibit PDI activity and thrombus formation in animal models, but whether extracellular PDI represents a viable anticoagulant target in humans and how its inhibition affects blood coagulation remain unknown. METHODS: We evaluated effects of oral administration of isoquercetin on platelet-dependent thrombin generation in healthy subjects and patients with persistently elevated anti-phospholipid antibodies. RESULTS: Following oral administration of 1,000 mg isoquercetin to healthy adults, the measured peak plasma quercetin concentration (9.2 MUM) exceeded its IC50 for inhibition of PDI by isoquercetin in vitro (2.5 +/- 0.4 MUM). Platelet-dependent thrombin generation decreased by 51% in the healthy volunteers compared with baseline (P = 0.0004) and by 64% in the anti phospholipid antibody cohort (P = 0.015) following isoquercetin ingestion. To understand how PDI affects thrombin generation, we evaluated substrates of PDI identified using an unbiased mechanistic-based substrate trapping approach. These studies identified platelet factor V as a PDI substrate. Isoquercetin blocked both platelet factor Va and thrombin generation with an IC50 of ~5 MUM. Inhibition of PDI by isoquercetin ingestion resulted in a 53% decrease in the generation of platelet factor Va (P = 0.001). Isoquercetin-mediated inhibition was reversed with addition of exogenous factor Va. CONCLUSION: These studies show that oral administration of isoquercetin inhibits PDI activity in plasma and diminishes platelet-dependent thrombin generation predominantly by blocking the generation of platelet factor Va. These pharmacodynamic and mechanistic observations represent an important step in the development of a novel class of antithrombotic agents targeting PDI. TRIAL REGISTRATION: Clinicaltrials.gov (NCT01722669) FUNDING: National Heart, Lung, and Blood Institute (U54 HL112302) and Quercegen Pharma. PMID- 28097232 TI - Vps34 regulates myofibril proteostasis to prevent hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is a common heart disease with a prevalence of 1 in 500 in the general population. Several mutations in genes encoding cardiac proteins have been found in HCM patients, but these changes do not predict occurrence or prognosis and the molecular mechanisms underlying HCM remain largely elusive. Here we show that cardiac expression of vacuolar protein sorting 34 (Vps34) is reduced in a subset of HCM patients. In a mouse model, muscle specific loss of Vps34 led to HCM-like manifestations and sudden death. Vps34 deficient hearts exhibited abnormal histopathologies, including myofibrillar disarray and aggregates containing alphaB-crystallin (CryAB). These features result from a block in the ESCRT-mediated proteolysis that normally degrades K63 polyubiquitinated CryAB. CryAB deposition was also found in myocardial specimens from a subset of HCM patients whose hearts showed decreased Vps34. Our results identify disruption of the previously unknown Vps34-CryAB axis as a potentially novel etiology of HCM. PMID- 28097233 TI - Ectonucleotidase CD39-driven control of postinfarction myocardial repair and rupture. AB - Mechanical complications of myocardial infarction (MI) are often fatal. Little is known about endogenous factors that predispose to myocardial rupture after MI. Ectonucleoside triphosphate diphosphohydrolase (CD39) could be a critical mediator of propensity to myocardial rupture after MI due to its role in modulating inflammation and thrombosis. Using a model of permanent coronary artery ligation, rupture was virtually abrogated in cd39-/- mice versus cd39+/+ controls, with elevated fibrin and collagen deposition and marked neutrophil and macrophage influx. Macrophages were found to display increased surface expression of CD301 and CD206, marking a reparative phenotype, driven by increased extracellular ATP and IL-4 in the infarcted myocardium of cd39-/- mice. A myeloid specific CD39-knockout mouse also demonstrated protection from rupture, with an attenuated rupture phenotype, suggesting that complete ablation of CD39 provides the greatest degree of protection in this model. Absence of CD39, either globally or in a myeloid lineage-restricted fashion, skews the phenotype toward alternatively activated (reparative) macrophage infiltration following MI. These studies reveal a previously unrecognized and unexpected role of endogenous CD39 to skew macrophage phenotype and promote a propensity to myocardial rupture after MI. PMID- 28097234 TI - Kruppel-like factor4 regulates PRDM1 expression through binding to an autoimmune risk allele. AB - A SNP identified as rs548234, which is found in PRDM1, the gene that encodes BLIMP1, is a risk allele associated with systemic lupus erythematosus (SLE). BLIMP1 expression was reported to be decreased in women with the PRDM1 rs548234 risk allele compared with women with the nonrisk allele in monocyte-derived DCs (MO-DCs). In this study, we demonstrate that BLIMP1 expression is regulated by the binding of Kruppel-like factor 4 (KLF4) to the risk SNP. KLF4 is highly expressed in MO-DCs but undetectable in B cells, consistent with the lack of altered expression of BLIMP1 in B cells from risk SNP carriers. Female rs548234 risk allele carriers, but not nonrisk allele carriers, exhibited decreased levels of BLIMP1 in MO-DCs, showing that the regulatory function of KLF4 is influenced by the risk allele. In addition, KLF4 directly recruits histone deacetylases (HDAC4, HDAC6, and HDAC7), established negative regulators of gene expression. Finally, the knock down of KLF4 expression reversed the inhibitory effects of the risk SNP on promoter activity and BLIMP1 expression. Therefore, the binding of KLF4 and the subsequent recruitment of HDACs represent a mechanism for reduced BLIMP1 expression in MO-DCs bearing the SLE risk allele rs548234. PMID- 28097236 TI - Lung vaso-occlusion in sickle cell disease mediated by arteriolar neutrophil platelet microemboli. AB - In patients with sickle cell disease (SCD), the polymerization of intraerythrocytic hemoglobin S promotes downstream vaso-occlusive events in the microvasculature. While vaso-occlusion is known to occur in the lung, often in the context of systemic vaso-occlusive crisis and the acute chest syndrome, the pathophysiological mechanisms that incite lung injury are unknown. We used intravital microscopy of the lung in transgenic humanized SCD mice to monitor acute vaso-occlusive events following an acute dose of systemic lipopolysaccharide sufficient to trigger events in SCD but not control mice. We observed cellular microembolism of precapillary pulmonary arteriolar bottlenecks by neutrophil-platelet aggregates. Blood from SCD patients was next studied under flow in an in vitro microfluidic system. Similar to the pulmonary circulation, circulating platelets nucleated around arrested neutrophils, translating to a greater number and duration of neutrophil-platelet interactions compared with normal human blood. Inhibition of platelet P-selectin with function-blocking antibody attenuated the neutrophil-platelet interactions in SCD patient blood in vitro and resolved pulmonary arteriole microembolism in SCD mice in vivo. These results establish the relevance of neutrophil-platelet aggregate formation in lung arterioles in promoting lung vaso-occlusion in SCD and highlight the therapeutic potential of targeting platelet adhesion molecules to prevent acute chest syndrome. PMID- 28097235 TI - A patient-derived-xenograft platform to study BRCA-deficient ovarian cancers. AB - Approximately 50% of high-grade serous ovarian cancers (HGSOCs) have defects in genes involved in homologous recombination (HR) (i.e., BRCA1/2). Preclinical models to optimize therapeutic strategies for HR-deficient (HRD) HGSOC are lacking. We developed a preclinical platform for HRD HGSOCs that includes primary tumor cultures, patient-derived xenografts (PDXs), and molecular imaging. Models were characterized by immunohistochemistry, targeted sequencing, and reverse phase protein array analysis. We also tested PDX tumor response to PARP, CHK1, and ATR inhibitors. Fourteen orthotopic HGSOC PDX models with BRCA mutations (BRCAMUT) were established with a 93% success rate. The orthotopic PDX model emulates the natural progression of HGSOC, including development of a primary ovarian tumor and metastasis to abdominal viscera. PDX response to standard chemotherapy correlated to that demonstrated in the patient. Pathogenic mutations and HGSOC markers were preserved after multiple mouse passages, indicating retention of underlying molecular mechanisms of carcinogenesis. A BRCA2MUT PDX with high p-CHK1 demonstrated a similar delay of tumor growth in response to PARP, CHK1, and ATR inhibitors. A poly (ADP-ribose) polymerase (PARP) inhibitor radiotracer correlated with PARP1 activity and showed response to PARP inhibition in the BRCA2MUT PDX model. In summary, the orthotopic HGSOC PDX represents a robust and reliable model to optimize therapeutic strategies for BRCAMUT HGSOC. PMID- 28097237 TI - Oxidized CaMKII promotes asthma through the activation of mast cells. AB - Oxidation of calmodulin-dependent protein kinase II (ox-CaMKII) by ROS has been associated with asthma. However, the contribution of ox-CaMKII to the development of asthma remains to be fully characterized. Here, we tested the effect of ox CaMKII on IgE-mediated mast cell activation in an allergen-induced mouse model of asthma using oxidant-resistant CaMKII MMVVdelta knockin (MMVVdelta) mice. Compared with WT mice, the allergen-challenged MMVVdelta mice displayed less airway hyperresponsiveness (AHR) and inflammation. These MMVVdelta mice exhibited reduced levels of ROS and diminished recruitment of mast cells to the lungs. OVA activated bone marrow-derived mast cells (BMMCs) from MMVVdelta mice showed a significant inhibition of ROS and ox-CaMKII expression. ROS generation was dependent on intracellular Ca2+ concentration in BMMCs. Importantly, OVA activated MMVVdelta BMMCs had suppressed degranulation, histamine release, leukotriene C4, and IL-13 expression. Adoptive transfer of WT, but not MMVVdelta, BMMCs, reversed the alleviated AHR and inflammation in allergen-challenged MMVVdelta mice. The CaMKII inhibitor KN-93 significantly suppressed IgE-mediated mast cell activation and asthma. These studies support a critical but previously unrecognized role of ox-CaMKII in mast cells that promotes asthma and suggest that therapies to reduce ox-CaMKII may be a novel approach for asthma. PMID- 28097238 TI - Quantitative measurement of lymphatic function in mice by noninvasive near infrared imaging of a peripheral vein. AB - Optical imaging methods have been developed to measure lymphatic function in skin; however, the lymphatic system of many organs is not accessible to this technology. Since lymphatic transport of macromolecules from any organ proceeds to the blood circulation, we aimed to develop a method that can measure lymphatic function by monitoring the fluorescence in a superficial vein of an interstitially injected tracer. We selected a 40-kDa PEGylated near-infrared dye conjugate, as it showed lymphatic system-specific uptake and extended circulation in blood. Lymphatic transport to blood from subcutaneous tissue required a transit time before signal enhancement was seen in blood followed by a steady rise in signal over time. Increased lymphatic transport was apparent in awake mice compared with those under continuous anesthesia. The methods were validated in K14-VEGFR-3-Fc and K14-VEGF-C transgenic mice with loss and gain of lymphatic function, respectively. Reduced lymphatic transport to blood was also found in aged mice. The technique was also able to measure lymphatic transport from the peritoneal cavity, a location not suitable for optical imaging. The method is a promising, simple approach for assessment of lymphatic function and for monitoring of therapeutic regimens in mouse models of disease and may have potential for clinical translation. PMID- 28097240 TI - December issue, 2016. PMID- 28097239 TI - Metastasis regulation by PPARD expression in cancer cells. AB - Peroxisome proliferator-activated receptor-delta (PPARD) is upregulated in many major human cancers, but the role that its expression in cancer cells has in metastasis remains poorly understood. Here, we show that specific PPARD downregulation or genetic deletion of PPARD in cancer cells significantly repressed metastasis in various cancer models in vivo. Mechanistically, PPARD promoted angiogenesis via interleukin 8 in vivo and in vitro. Analysis of transcriptome profiling of HCT116 colon cancer cells with or without genetic deletion of PPARD and gene expression patterns in The Cancer Genome Atlas colorectal adenocarcinoma database identified novel pro-metastatic genes (GJA1, VIM, SPARC, STC1, SNCG) as PPARD targets. PPARD expression in cancer cells drastically affected epithelial-mesenchymal transition, migration, and invasion, further underscoring its necessity for metastasis. Clinically, high PPARD expression in various major human cancers (e.g., colorectal, lung, breast) was associated with significantly reduced metastasis-free survival. Our results demonstrate that PPARD, a druggable protein, is an important molecular target in metastatic cancer. PMID- 28097241 TI - Extraforaminal needle tip position reduces risk of intravascular injection in CT fluoroscopic lumbar transforaminal epidural steroid injections. AB - BACKGROUND: Lumbar transforaminal epidural steroid injection is a common and effective tool for managing lumbar radicular pain, although accidental intravascular injection can rarely result in paralysis. The purpose of this study is to determine the safest needle tip position for computed tomography (CT) guided lumbar transforaminal epidural steroid injections as determined by incidence of intravascular injection. METHODS: Three radiologists, in consensus, reviewed procedural imaging for consecutive CT-fluoroscopic lumbar transforaminal epidural steroid injections performed during a 16-month period. Intravascular injections were identified and categorized by needle tip position, vessel type injected, intravascular injection volume and procedural phase containing the intravascular injection. Pearson chi-square and logistic regression testing were used to assess differences between groups, as appropriate. RESULTS: Intravascular injections occurred in 9% (52/606) of injections. The intravascular injection rate was significantly lower (P<0.001) for extraforaminal needle position (0%, 0/109) compared to junctional (8%, 27/319) and foraminal (14%, 25/178) needle tip positions. Of the intravascular injections, 4% (2/52) were likely arterial, 35% (18/52) were likely venous, and 62% (32/52) were indeterminate for vessel type injected. 46% (24/52) of intravascular injections were large volume, 33% (17/52) were small volume, and 21% (11/52) were trace volume. 56% (29/52) of intravascular injections occurred with the contrast trial dose, 29% (15/52) with the steroid/analgesic cocktail, and 15% (8/52) with both. CONCLUSIONS: An extraforaminal needle position for CT-fluoroscopic lumbar transforaminal epidural steroid injections decreases the risk of intravascular injection and therefore may be safer than other needle tip positions. PMID- 28097242 TI - Anterior to psoas (ATP) fusion of the lumbar spine: evolution of a technique facilitated by changes in equipment. AB - BACKGROUND: Lateral interbody cages have been proven useful in spinal fusions. Spanning both lateral cortical rims while sparing the Anterior Longitudinal Ligament, the lateral interbody cages restore and maintain disc height while adding stability prior to supplemental fixation. The standard approach for their insertion is by a 90-degree lateral transpsoas method. This is relatively bloodless compared to other techniques although has its limitations, requiring neuro-monitoring and being, at times, very difficult at L4/5 due to iliac crest obstruction or an anterior plexus position. An oblique approach, with the patient in lateral decubitus, passes anterior to the iliac crest, retroperitoneal, and being anterior to psoas, eliminates the need for neuro-monitoring. METHODS: Twenty-one consecutive patients underwent surgery for a total of 32 levels instrumented with the ATP technique. Mean age at the time of surgery was 62.4+/ 7.4 years. There was a 6 months minimum clinical follow up, with imaging to assess fusion, at 6 and 12 months. Indications included symptomatic degenerative lumbar spondylosis +/- spondylolisthesis, leg and back pain. All patients were assessed with the Oswestry Disability Index (ODI), Visual Analog Scale 100 mm for back pain (VASb) and for leg pain (VASl) preoperatively, at 3, 6 and 12 months. Last follow-up was at 12 months for 9 patients and the rest had 6 months follow up. RESULTS: Statistical analysis showed significance for the results in ODI, VASb and VASl with improvement in all components except for one patient with worsening VASl. Eight patients had complications related to surgery which were still present at last follow-up including moderate weakness of hip flexion and EHL weakness. Lateral cutaneous nerve (LCN) palsy on the side of the approach was also seen as well as sympathectomy effect related to the mobilization of the sympathetic trunk. One patient, who also suffered from multiple sclerosis, experienced psoas abscess 3 months post op that required drainage. CONCLUSIONS: The left sided anterior to psoas approach offers the most natural corridor to the disc space. The novel instruments and method described here allows insertion of large lateral cages between L2 to L5, without the problems associated with the transpsoas approach, particularly at L4/5. PMID- 28097243 TI - Range of motion, sacral screw and rod strain in long posterior spinal constructs: a biomechanical comparison between S2 alar iliac screws with traditional fixation strategies. AB - BACKGROUND: S1 screw failure and L5/S1 non-union are issues with long fusions to S1. Improved construct stiffness and S1 screw offloading can help avoid this. S2AI screws have shown to provide similar stiffness to iliac screws when added to L3-S1 constructs. We sought to examine and compare the biomechanical effects on an L2-S1 pedicle screw construct of adding S2AI screws, AxiaLIF, L5-S1 interbody support via transforaminal lumbar interbody fusion (TLIF), and to examine the effect of the addition of cross connectors to each of these constructs. METHODS: Two S1 screws and one rod with strain gauges (at L5/S1) were used in L2-S1 screw rod constructs in 7 L1-pelvis specimens (two with low BMD). ROM, S1 screw and rod strain were assessed using a pure-moment flexibility testing protocol. Specimens were tested intact, and then in five instrumentation states consisting of: (I) Pedicle screws (PS) L2-S1; (II) PS + S2AI screws; (III) PS + TLIF L5/S1; (IV) PS + AxiaLIF L5/S1; (V) PS + S2AI + AxiaLIF L5/S1. The five instrumentation conditions were also tested with crosslinks at L2/3 and S1/2. Tests were conducted in flexion-extension, lateral bending and axial torsion with no compressive preload. RESULTS: S2A1 produces reduced S1 screw strain for flexion extension, lateral bending and axial torsion, as well as reduced rod strain in lateral bending and axial torsion in comparison to AxiaLIF and interbody instrumentation, at the expense of increased rod flexion-extension strain. Cross connectors may have a role in further reduction of S1 screw and rod strain. CONCLUSIONS: From a biomechanical standpoint, the use of the S2AI technique is at least equivalent to traditional iliac screws, but offers lower prominence and ease of assembly compared to conventional sacroiliac stabilization. PMID- 28097244 TI - Minimising costs in spinal surgery: is group & save testing justified in lumbar decompression surgery? AB - BACKGROUND: Lumbar microdiscectomy and laminectomy are two of the most common neurosurgical procedures performed worldwide. Current practice still sees pre operative group and save testing prior to this surgery. The aim of this study was to determine the need for pre-operative group and save and post-operative blood checks. METHODS: Patient archives were reviewed to identify those undergoing primary elective lumbar decompression surgery at the Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK. Hematology results before and after surgery, whether group and save was carried out, and blood transfusion requirements, if any, were collected. RESULTS: A total of 200 patients in total were included. Ninety-one percent of microdiscectomy patients and 95% of laminectomy patients underwent group and save testing prior to surgery. No patients received a transfusion as a result of their procedure. The mean hemoglobin drop after surgery was 11 g/L for the microdiscectomy group and 17 g/L for the laminectomy group. CONCLUSIONS: Our findings strongly suggest that pre-operative group and save is unnecessary in lumbar microdiscectomy and laminectomy. As such, we support the abandonment of routine pre-operative group and save and post-operative blood checks, with significant cost saving effects. However, O negative blood should always be available in case of major peri operative bleeding. PMID- 28097245 TI - Consideration of proper operative route for interlaminar approach for percutaneous endoscopic lumbar discectomy. AB - BACKGROUND: Percutaneous endoscopic lumbar discectomy (PELD) is one of the less invasive treatments of lumbar disc herniation (LDH), and has three different operative approaches. This study focused on the interlaminar approach (ILA) and investigated the appropriate operative route for this approach. METHODS: ILA was performed in 41 patients with LDH. The width of the interlaminar space, LDH size, and positional relation between LDH and the corresponding nerve root were radiologically evaluated. Thirty-three LDHs were removed via the shoulder of the corresponding nerve root and eight were removed via the axilla of the corresponding nerve root and dural sac. Pre- and postoperative status were evaluated using the modified Japanese Orthopedic Association (mJOA) and numerical rating scale (NRS) scores. RESULTS: The mean age was 41.5 years; there was single level involvement, mostly at L5/S1 (33 cases). The mean recovery rate of mJOA score was 59.8% and mean pre- and postoperative NRS scores were 5.8 and 0.98, respectively. Relatively severe complications developed in three patients treated by ILA via the shoulder. There was persistent numbness in the corresponding nerve area, transient muscular weakness, and transient bladder and rectal disturbance, may be due to excessive compression of the nerve root and/or dural sac by the endoscopic sheath. CONCLUSIONS: ILA can be used to treat LDH revealing an interlaminar space of >=20 mm. The procedure is minimally invasive and effective; however, appropriate selection of an operative route is important to avoid operative complications. Particularly for large LDH, the operative route via the axilla should be considered. PMID- 28097246 TI - Three-year follow-up of a randomized controlled trial comparing preoperative neuroscience education for patients undergoing surgery for lumbar radiculopathy. AB - BACKGROUND: Results from a previous multicenter randomized controlled trial (RCT) on preoperative pain neuroscience education (PNE) for lumbar radiculopathy found no significant difference in patient reported outcomes between groups. However, patients who received PNE viewed their surgical experience more favorably and utilized significantly less healthcare compared to those that did not. The purpose is to determine if the reduction in healthcare costs from 1-year would be continued at 3-year following surgery, and to explore differences (if any) in patient reported outcomes. Study design-analysis of 3-year follow-up data from RCT on preoperative PNE for lumbar radiculopathy. METHODS: Participating patients from the previous RCT were contacted for 3-year follow-up. Of the 67 patients who commenced in the study, there were 61 who completed 1-year follow-up. Data packets were sent to these 61 patients to examine post-operative utilization of healthcare (Utilization of Healthcare Questionnaire); LBP [numeric rating scale (NRS)]; leg pain (NRS); function (Oswestry disability index); and beliefs and experiences related to LS (10 item survey with Likert responses). RESULTS: At 3 year follow-up, 50 patients (29 females) responded, with 22 patients in the experimental group (EG) and 28 in the control group (CG). Cumulative medical expenses were 37% lower for the EG, with those patients spending less on X-rays and visits to their family physician, physical therapist, and massage therapist. There were no differences in patient reported outcomes between groups. Patients who received PNE continued to view their surgical experience more favorably compared to those that did not. CONCLUSIONS: Adding a single PNE session prior to surgery for lumbar radiculopathy results in significant healthcare savings over 3 years. Educating such patients about normal responses to lumbar surgery (LS) in a neuroscience framework may result in lasting behavior changes following surgery. PMID- 28097248 TI - Transpedicular endoscopic surgery for lumbar spinal synovial cyst-report of two cases. AB - BACKGROUND: Lumbar facet cysts are a benign, degenerative, and fairly uncommon cause for lumbar radiculopathy. The standard surgical treatment for lumbar facet cysts often requires a laminectomy and medial facetectomy which can further destabilize a pathological motion segment. The authors present here a novel technique for transpedicular endoscopic access to the pathology that obviates the need to violate the lamina or facet. METHODS: Two patient cases are described where the lumbar 4-5 facet cysts arise medial to the pedicle. Percutaneous access to the cysts was established by drilling through the adjacent pedicle creating a 7-mm corridor to establish access for the endoscopic tubular retractor and the working channel endoscope. Straight and bendable forceps were used to remove the cysts under direct visualization. RESULTS: Following surgery, the patients' symptoms showed immediate regression with complete relief of one patient's foot drop by 6 months. CONCLUSIONS: Transpedicular endoscopic access is described as novel minimally invasive surgical option in the awake patient for lumbar facet cysts adjacent to the Lumbar 4 or 5 pedicle. PMID- 28097247 TI - The management of scoliosis in children with cerebral palsy: a review. AB - Children who suffer with cerebral palsy (CP) have a significant chance of developing scoliosis during their early years and adolescence. The behavior of this scoliosis is closely associated with the severity of the CP disability and unlike idiopathic scoliosis, it continues to progress beyond skeletal maturity. Conservative measures may slow the progression of the curve, however, surgery remains the only definitive management option. Advances in surgical technique over the last 50 years have provided methods to effectively treat the deformity while also reducing complication rates. The increased risk of surgical complications with these complex patients make decisions about treatment challenging, however with careful pre-operative optimization and post-operative care, surgery can offer a significant improvement in quality of life. This review discusses the development of scoliosis in CP patient, evaluates conservative and surgical treatment options and assesses post-operative outcome. PMID- 28097249 TI - Application of a 3D custom printed patient specific spinal implant for C1/2 arthrodesis. AB - The study aims to describe a three-dimensional printed (3DP) posterior fixation implant used for C1/C2 fusion in a 65-year-old female. Spinal fusion remains a common intervention for a range of spinal pathologies including degenerative disc and facet disease when conservative methods are unsuccessful. However, fusion devices are not always entirely efficacious in providing the desired fixation, and surgeons rely on 'off the shelf' implants which may not provide an anatomical fit to address the particular pathology. 3DP refers to a process where three dimensional objects are created through successive layering of material, so called 'additive manufacturing'. Although this technology enables accurate fabrication of patient-specific orthopaedic and spinal implants, literature on its utilization in this regard is rare. A 65-year-old female, with severe facet arthropathy at the C1/C2 level, osteophyte formation and impingement of the exiting C2 nerve root underwent a C1/C2 posterior fusion and rhizolysis of the C2 nerve roots. A custom posterior fixation implant was designed and on-laid over the C2 spinous process and lamina, with screw holes made to a depth and angulation that was pre-calculated based on the preoperative CT based 3D modelling. The patient had an uneventful recovery and reported a significant reduction in occipital neuralgia and sub-occipital pain and 2-month follow-up. We report the first case of a customized 3DP spinal prosthesis for posterior C1/C2 fusion. The implant added significant value reducing the overall time of the procedure, and safety with a reduced risk of neurovascular compromise. PMID- 28097250 TI - Spinal cord compression from Wegener's granulomatosis: an unusual presentation. AB - Wegener's granulomatosis (WG) causing spinal cord compression is very rare with only few cases reported in literature. We present a case report with review of literature. A 55-year-old lady with known WG presented with acute on chronic spinal cord compression. MRI scan revealed spinal cord compression anteriorly and posteriorly at T2-T5 level. Patient underwent urgent surgical decompression with excision of the posterior dural lesion with synthetic duraplasty. Patient made good neurological recovery. Histopathology revealed features consistent with WG. A rare case of spinal cord compression from WG is presented. Urgent surgical decompression with duraplasty resulted in good neurological outcome. PMID- 28097251 TI - Management of progressive late onset scoliosis with magnetic growth rod insertion leading to improvement of neural anomalies-a case report. AB - BACKGROUND: To present the first known reported case of late onset idiopathic scoliosis with concomitant neural anomalies, treated with sequential distraction using magnetic growth rod, had significant improvement in both cranio-cervical and intraspinal anomaly. METHODS: A caucasian, growing female child (at the age of ten) presented with moderately progressive late onset right thoracic scoliosis. She was found to have Chiari type I malformation and a cervicothoracic syrinx on routine pre-operative MRI scanning. We treated this child by inserting magnetic growing rod (MGR) system. After 48 months of follow up with serial distractions, the metalwork (MGR) was removed due to aseptic wound breakdown and granuloma formation. Subsequently due to the progression of deformity, a definitive posterior instrumented spinal fusion was done. A repeat MRI Scan of the Spine was done prior to this definitive procedure to assess for any residual neural anomalies. RESULTS: The Chiari type I malformation appeared to have completely resolved, with no cerebellar tonsillar herniation seen, and a significant improvement in the size of the cervicothoracic syringomyelia effectively downgrading it to a prominent central canal. CONCLUSIONS: This is a unique case of progressive late onset idiopathic scoliosis with associated Chiari malformation and syringomyelia, showing an improvement in these neural anomalies after gradual and protracted distractive lengthening of the spine with MGR. PMID- 28097252 TI - Enterococcus faecalis causing delayed spondylodiscitis in a case with retained intraspinal bullet. AB - Delayed presentations have been reported following gunshot wounds (GSW) with retained intraspinal bullets due to migration of projectile or lead intoxication. We report on the rare occurrence of delayed pyogenic spondylodiscitis and neurological dysfunction following injury from low velocity GSW to the spine with a retained projectile. A 55-year-old male presented 4 months following GSW to the abdomen which resulted in colonic injury and L5 fracture. The patient was treated initially with ileo-transverse anastomosis, antibiotics, without retrieval of the bullet. He developed low back pain, claudication 4 months following GSW and investigations suggested a pyogenic spondylodiscitis at L5-S1. The patient was treated with surgical debridement of infective focus and stabilisation with definitive fusion being performed after an interval of 14 days. The biopsy of the lesion confirmed findings of spondylodiscitis and the culture isolated Enterococcus faecalis species. The patient was treated with antibiotics as per sensitivity and made an uneventful recovery over 4 weeks. The follow-up radiographs showed satisfactory healing at final follow up of 24 months. GSW with colonic perforation have higher incidence of infective complications however majority to these occur in the early postoperative period. This case report demonstrates the possibility of late onset presentation due to spinal infection occurring following colonic perforation with retained intraspinal bullet. PMID- 28097253 TI - Practical implications of the lumbar spine and its function on total hip arthroplasty. AB - Correct component placement is of significant importance to ensure optimal outcomes in total hip arthroplasty (THA). Traditionally, the Lewinnek plane has been referenced as an adequate "safe zone", formed between the anterior superior iliac spines and public tubercles to optimize acetabular orientation. However, recent evidence shows that the positioning of this plane may vary due to the biomechanical relationship between the lumbar spine and hip. Therefore, the plane acquired intraoperatively may not accurately recreate the actual functional plane and acetabular orientation encountered outside of the intraoperative environment. This review summarizes the hip-spine relationship and its implications on THA. PMID- 28097254 TI - Use of OP-1 (rhBMP-7) in posterolateral lumbar arthrodesis. PMID- 28097255 TI - Bio-augmented spinal fusion-the best is yet to come. PMID- 28097256 TI - Trials that fail to show advantages of 3D navigation in spine surgery-is it the technology or the trial? PMID- 28097257 TI - Heterotopic ossification and clinical outcome in nonconstrained cervical arthroplasty. PMID- 28097258 TI - Editorial on "Long-term clinical outcomes of cervical disc arthroplasty: a prospective, randomized, controlled trial" by Sasso et al. PMID- 28097259 TI - Biologic enhancement of spinal fusion with bone morphogenetic proteins: current position based on clinical evidence and future perspective. PMID- 28097260 TI - Arthroplasty in cervical degenerative disc disease: fulfilling its long-term promise? PMID- 28097261 TI - A new dawn in ICUrology. PMID- 28097262 TI - Lessons learned over a decade of pediatric robotic ureteral reimplantation. AB - The da Vinci robotic system has improved surgeon dexterity, ergonomics, and visualization to allow for a minimally invasive option for complex reconstructive procedures in children. Over the past decade, robot-assisted laparoscopic ureteral reimplantation (RALUR) has become a viable minimally invasive surgical option for pediatric vesicoureteral reflux (VUR). However, higher-than-expected complication rates and suboptimal reflux resolution rates at some centers have also been reported. The heterogeneity of surgical outcomes may arise from the inherent and underestimated complexity of the RALUR procedure that may justify its reclassification as a complex reconstructive procedure and especially for robotic surgeons early in their learning curve. Currently, no consensus exists on the role of RALUR for the surgical management of VUR. High success rates and low major complication rates are the expected norm for the current gold standard surgical option of open ureteral reimplantation. Similar to how robot-assisted laparoscopic surgery has gradually replaced open surgery as the most utilized option for prostatectomy in prostate cancer patients, RALUR may become a higher utilized surgical option in children with VUR if the adoption of standardized surgical techniques that have been associated with optimal outcomes can be adopted during the second decade of RALUR. A future standard of RALUR for children with VUR whose parents seek a minimally invasive surgical option can arise if widespread achievement of high success rates and low major complication rates can be obtained, similar to the replacement of open surgery with robot assisted laparoscopic radical prostectomy as the new strandard for men with prostate cancer. PMID- 28097263 TI - Predicting biochemical recurrence in patients with high-risk prostate cancer using the apparent diffusion coefficient of magnetic resonance imaging. AB - PURPOSE: We aimed to investigate whether the apparent diffusion coefficient (ADC) value in diffusion-weighted magnetic resonance imaging predicts the prognoses of patients with high-risk prostate cancer. MATERIALS AND METHODS: A total of 157 patients with high-risk prostate cancer (based on D'Amico's criteria) were included in the analysis. Patients underwent preoperative 3.0 Tesla magnetic resonance imaging within 2 months before radical prostatectomy. Those who received neoadjuvant hormone therapy (33 persons) or radiation therapy (18 persons) were excluded. The ADC of the tumor calculated from 2 b-values (0 and 1,000 s/mm2) was measured. Areas under receiver operating characteristics curves were calculated to maximize the accuracy of the ADC value. Based on the obtained cutoff value, the patients were stratified into 2 groups: Group A consisted of patients with ADC values <746*10-6 mm2/s and group B comprised those with ADC values >=746*10-6 mm2/s. RESULTS: Group A showed higher rate of lymph positive and biochemical recurrence (BCR) rates than group B. Kaplan-Meier analysis showed that the BCR-free survival rate of group A was much lower than that of group B (p<0.001). On Cox proportional regression analyses, ADC group A (hazard ratio [HR], 3.238, p=0.002) and pathologic lymph node positive (HR, 2.242; p=0.009) were independent predictors of BCR. CONCLUSIONS: In patients with high-risk prostate cancer, ADC value is significantly associated with BCR-free survival. Therefore, the ADC value is a useful tool for predicting the prognoses of these high-risk patients. PMID- 28097264 TI - Lymph node density predicts recurrence and death after inguinal lymph node dissection for penile cancer. AB - PURPOSE: To determine the impact of lymph node density (LND) on survival after inguinal lymph node dissection (ILND) for penile cancer. MATERIALS AND METHODS: Our institutional penile cancer database was queried for patients who underwent ILND. Clinicopathologic characteristics including LND and total number of positive lymph nodes (LNs) were analyzed to determine impact on recurrence-free survival (RFS) and overall survival (OS). LND, or the percent of positive LN out of total LN, was calculated as a categorical variable at varying thresholds. RESULTS: Twenty-eight patients with complete follow-up were identified. Indications for ILND were stage >T2 in 20 patients (71.4%), palpable adenopathy in 7 (25%), high grade T1 in 1 (3.6%). Median node yield was 17.5 (interquartile range, 12-22), and positive LNs were found in 14 patients (50%). RFS and OS were significantly lower for patients with >15% LN density (median RFS: 62 months vs. 6.3 months, p=0.0120; median OS: 73.6 months vs. 6.3 months, p<0.001). Controlling for age, medical comorbidities, number of positive LN, T stage, pelvic LN status and indication, LN density >15% was independently associated with worse RFS (hazard ratio [HR], 3.6; p=0.04) and OS (HR, 73.6; p=0.002). The c index for LND was higher than total positive LNs for RFS (0.64 vs. 0.54) and OS (0.79 vs. 0.61). CONCLUSIONS: In this small, retrospective penile cancer cohort, the presence of nodal involvement >15% was associated with decreased RFS and OS, and outperformed total number of positive LN as a prognostic indicator. PMID- 28097266 TI - The effect of posture and repetition on urodynamic parameters: A prospective randomized study. AB - PURPOSE: To evaluate the effect of posture and repetition of filling cystometry on urodynamic parameters. MATERIALS AND METHODS: Seventy-one men with benign prostatic hyperplasia participated in a urodynamic study between September 2015 and August 2016 and were randomly assigned to a supine to supine (group SS, n=16), erect to erect (group EE, n=16), supine to erect (group SE, n=19) or erect to supine (group ES, n=20) group. The patients underwent filling cystometry twice. We evaluated the effect of posture and the effect of repetition on filling cystometric parameters. We also evaluated the correlation between overactive bladder (OAB) and detrusor overactivity (DO) and between maximum voided volume (MVV) and maximum cystometric capacity (MCC) for each posture and filling cystometry time. RESULTS: There was a decrease in bladder sensation and occurrence of DO, and an increase in bladder compliance and MCC in the supine posture group compared to that in the erect posture group. A more significant decrease in bladder sensation and occurrence of DO as well as an increase in MCC was seen during the second filling cystometry than the first one. The supine posture during first filling cystometry showed a better correlation between OAB and DO and between MVV and MCC than erect posture. CONCLUSIONS: There were clear effects of posture and filling cystometry repetition on urodynamic parameters. The supine posture and repeated filling cystometry caused the bladder to be less sensitive and less overactive. The supine posture showed a better correlation to OAB symptoms than erect posture during first filling cystometry. PMID- 28097265 TI - The efficacy of performing shockwave lithotripsy before retrograde intrarenal surgery in the treatment of multiple or large (>=1.5 cm) nephrolithiasis: A propensity score matched analysis. AB - PURPOSE: To investigate the effect of performing shockwave lithotripsy (SWL) before retrograde intrarenal surgery (RIRS) on the treatment outcomes of patients with nephrolithiasis. MATERIALS AND METHODS: The data of 189 patients with renal stones who underwent RIRS from July 2007 to July 2014 was reviewed retrospectively. Patients with stones larger than 1.5 cm were recommended to undergo SWL before RIRS. Patients were divided into 2 groups based on whether the preoperative SWL was performed (group 1, n=68) or not (group 2, n=121). The cohorts of the 2 groups cohorts were matched 1:1 using propensity score analysis. Patient, stone characteristics, operative parameters, and stone-free rates were compared. RESULTS: Patients in groups 1 and 2 were matched with respect to stone size, number, and location, leaving 57 patients in each group. After matching, no differences were identified between the 2 groups regarding age, body mass index, sex, stone composition, density and multiplicity. Compared to group 2 patients, patients in group 1 had fewer number of procedures performed (1.10 vs. 1.26, p=0.045) and higher stone-free rate (89.4% vs.73.6%, p=0.039). In multivariate analysis, Non lower calyceal location (odd ratio [OR], 8.215; 95% confidence interval [CI], 1.782-21.982; p=0.041), stone size (OR, 6.932; 95% CI, 1.022 18.283; p<0.001), and preoperative SWL (OR, 2.210; 95% CI, 1.058-7.157; p=0.019) were independent factors predicting a stone-free state after RIRS. CONCLUSIONS: Performing SWL before RIRS may favor stone eliminations during surgery and increase the stone-free rate in selected patients. PMID- 28097267 TI - Incidence and risk factors of recurrence of overactive bladder symptoms after discontinuation of successful medical treatment. AB - PURPOSE: To identify incidence and risk factors of recurrence after discontinuation of successful antimuscarinic therapy in patients with overactive bladder (OAB). MATERIALS AND METHODS: This was a prospective, multicenter trial. Patients who had antimuscarinic agents for more than 12 weeks and showed successful response were enrolled. Successful response was defined as answering 'benefit' for patient perception of treatment benefit and answer lesser than 3 points in patient's perception of bladder condition (PPBC). The enrolled patients discontinued the antimuscarinics, and we evaluated their recurrence with PPBC and OAB symptom score (OABSS) at 1, 3, 6, and 12 months. Primary purpose was to identify the recurrence rate and secondary purpose was to reveal risk factors. RESULTS: Four hundred forty-one patients enrolled and 371 patients completed 6 month follow-up. The enrolled patients showed 1.6 points in PPBC, 2.9 points in OABSS and 1.4 points in IPSS (quality of life) which represented successful response after using antimuscarinics. The cumulative rates of recurrence were 25.6%, 42.3%, and 52.2% at 1, 3, 6 months, respectively. Among 177 patients who did not show recurrence at 6 months, 41 patients were followed up and 4 patients of the 41 patients (9.7%) showed recurrence at 12 months. On univariate and multivariate analyses of recurrence, OAB wet was the risk factor for recurrence after 6 months of discontinuation. CONCLUSIONS: Discontinuation of antimuscarinic therapy after successful treatment resulted in high recurrence rate with time and OAB wet was the independent risk factor for recurrence. PMID- 28097268 TI - The effect of office based flexible and rigid cystoscopy on pain experience in female patients. AB - PURPOSE: Rigid and flexible cystoscopies are both routinely used in female patients. Literature is conflicting whether flexible cystoscopy is less painful compared to rigid cystoscopy. The aim of this study was therefore to investigate whether using flexible cystoscopy leads to less discomfort and pain compared to rigid cystoscopy in female patients who underwent first time cystoscopy. MATERIALS AND METHODS: One hundred eighty-nine female patients, who never had undergone cystoscopy, were randomized into 2 groups: 92 patients underwent rigid cystoscopy and 97 patients flexible cystoscopy. Directly after the cystoscopy procedure all patients were asked to fill out their pain experience on a 100-mm visual analogue pain scale (VAS). RESULTS: Median VAS score was significantly lower for women undergoing flexible cystoscopy (0 [0-20]) compared to rigid cystoscopy (15 [0-38], p<0.001). In addition, age was inversely associated with VAS score, indicating that younger females experienced more pain (R=-0.30, p=0.001). The use of flexible cystoscopy was associated with a decrease in VAS score and remained significant after adjustment for age, sex of urologist, performing urologist and indication (standardized beta=-0.17, p=0.048). CONCLUSIONS: The use of flexible cystoscopy resulted in a significantly lower pain experience compared to rigid cystoscopy. Based on patient's pain experience during cystoscopy, this study implicates to use flexible cystoscopy in female patients who undergo first time cystoscopy. PMID- 28097269 TI - Recurrence rate of stress urinary incontinence in females with initial cure after transobturator tape procedure at 3-year follow-up. AB - PURPOSE: To assess recurrence rates of urinary incontinence in women with initial cure after transobturator tape (TOT) procedure at 3-year follow-up. MATERIALS AND METHODS: Between June 2006 and May 2013, a total of 402 consecutive patients underwent the TOT procedure for female stress urinary incontinence (SUI) at Dongguk University Ilsan Hospital. Of the 402 patients, 223 had sufficient medical records for analysis. Therefore, they were followed-up for 3 years postoperatively. Patient characteristics, urinary symptoms, physical examination, and urodynamic parameters were evaluated. The primary end point of "cure" was defined as the absence of any complaint of urinary leakage without needing pads for usual activities. RESULTS: Of the 223 patients, 196 patients (87.9%) were initially cured within 6 months postoperatively. Of the 196 patients, 70 (35.7%) had recurrent urinary incontinence at 3 years postoperatively, 51 (26.0%) had SUI, 16 (8.2%) had urgency urinary incontinence, and 3 (1.5%) had mixed urinary incontinence. In univariate analysis, preoperative urinary obstructive symptom was found to significant contributor to the recurrence of urinary incontinence at 3-year postoperatively (p=0.004). CONCLUSIONS: In our study, 35.7% of the women with initial cure after TOT experienced the recurrence of urinary leakage during the 3-year follow-up. The cure rate of TOT was decreased as time went by, although the initial cure rate was high. PMID- 28097272 TI - Erratum: Correction of the references for Figures. Testosterone therapy in men with testosterone deficiency: Are we beyond the point of no return? AB - [This corrects the article on p. 384 in vol. 57.]. PMID- 28097271 TI - Prevalence and management status of urologic diseases in geriatric hospitals in South Korea: A field research. AB - PURPOSE: We aimed to investigate the current management status of urologic diseases in geriatric hospitals in South Korea. MATERIALS AND METHODS: Questionnaire surveys and in-depth person-to-person interviews were conducted at 13 hospitals within the Seoul and Incheon areas. RESULTS: The study was carried out from July to December 2014; 75.6% of patients (1,858/2,458) and 77.5% (779/1,031) of medical personnel responded to our survey. All surveys and interviews were performed by urology specialists, fellows, residents, or nurses. The hospitals included in the study had an average of 215.2 beds (range, 110 367), 189.1 patients (range, 90-345), and 40.2 nurses (range, 10-83). The average number of physicians was 6.2 (range, 3-11), but none of these were certified urologists. Only 4 hospitals provided consultation services for urological disorders. In total, 64% of patients had urological disorders, although only 20.7% of patients were receiving medication. Most patients were being treated using urological interventions; diapers (49.7%), indwelling catheters (19.5%), clean intermittent catheters (12.2%), and external collection urinary drainage (7.9%). However, most interventions were inadequately implemented, and only 17% of the patients had been examined by a certified urologist. Urological complications were found in 20.2% of patients, and secondary complications occurred in 18.8%. Excluding redundant cases, the total prevalence of urological complications was 39.0%. CONCLUSIONS: Urologic diseases are poorly managed, and no certified urologists work in geriatric hospitals. Therefore, more designated urologists are needed in geriatric hospitals. PMID- 28097270 TI - Prospective study analyzing risk factors and characteristics of healthcare associated infections in a Urology ward. AB - PURPOSE: Healthcare-associated infections (HAIs) in urological patients have special features due to specific risk factors. Our objective was to evaluate the characteristics and risk factors for HAIs in patients hospitalized in a Urology ward. MATERIALS AND METHODS: We evaluated prospectively, from 2012 to 2015, the incidence, types and risk factor for HAIs, microbiological and resistance patterns. RESULTS: The incidence of HAIs was 6.3%. The most common types were urinary infections (70.5%) and surgical site infections (22.1%). Univariate analysis showed an increased risk of HAIs among patients with American Society of Anesthesiologists physical status classification system III-IV (odds ratio [OR], 1.39; p<0.001), immunosuppression (OR, 1.80; p=0.013), previous urinary infection (OR, 4.46; p<0,001), and urinary catheter before admission (OR, 1.74; p<0.001). The surgical procedures with the highest incidence of HAIs were radical cystectomy (54.2%) and renal surgery (8.7%). The most frequently isolated microorganisms were Escherichia coli (25.1%), Enterococcus spp. (17.5%), Klebsiella spp. (13.5%) and Pseudomonas aeruginosa (12.3%). Enterococcus sp was the most common microorganism after radical cystectomy and in surgical site infections, E. coli showed resistance rates of 53.5% for fluoroquinolones, 9.3% for amikacin. The percentage of extended-spectrum betalactamase producing E. coli was 24.7%. Klebsiella spp. showed resistance rates of 47.8% for fluoroquinolones, 7.1% for amikacin and 4.3% for carbapenems. Enterococcus spp showed resistance rates of 1.7% for vancomycin and; P. aeruginosa of 33.3% for carbapenems and 26.2% for amikacin. CONCLUSIONS: Comorbidities, previous urinary infections, and urinary catheter are risk factors for HAIs. The microorganisms most commonly isolated were E. coli, Enterococcus and P. aeruginosa. Prospective monitoring may decrease the incidence of infections. PMID- 28097273 TI - Integration of multiple active sites on large-pore mesoporous silica for enantioselective tandem reactions. AB - Facile construction of a multifunctional heterogeneous catalyst through the assembly of Au/carbene and chiral ruthenium/diamine dual complexes in large-pore mesoporous silica was developed. This enables an efficient one-pot hydration asymmetric transfer hydrogenation enantioselective tandem reaction of haloalkynes, affording chiral halohydrins with up to 99% enantioselectivity. Combined multifunctionalities, such as substrate-promoted silanol-functionality, BF4- anion-bonding gold/carbene and covalent-bonding chiral ruthenium/diamine active centers, contributed cooperatively to the catalytic performance. PMID- 28097274 TI - Inverted perovskite solar cells based on lithium-functionalized graphene oxide as an electron-transporting layer. AB - Perovskite solar cells with an inverted p-i-n architecture were constructed under ambient conditions by employing materials of lower cost than standard cells. Thus, graphene oxide was used as a hole transporting material and Li-modified graphene oxide as an electron transporting material, while Al was used as a counter electrode. A maximum solar conversion efficiency of 10.2% was achieved by adding a Ti-based sol on the top of the Li-modified graphene oxide layer. PMID- 28097275 TI - Development of a highly transparent, low-resistance lithium-doped nickel oxide triple-layer film deposited by magnetron sputtering. AB - This research presents a triple-layer transparent conductive oxide thin film, with a lithium-doped nickel oxide/silver/lithium-doped nickel oxide (L-NiO/Ag/L NiO) structure using radio-frequency (RF) magnetron sputtering on glass substrates. The high transmittance L-NiO thin films were deposited using the sputtering method with Ar/H2 as the reaction gases. The triple-layer structure, L NiO/Ag/L-NiO, showed impressive electrical conductivity. The figure of merit (FOM) results indicated that the L-NiO/Ag/L-NiO triple-layer thin films with Ag deposition times of 2 min possessed satisfactory optical and electrical properties for potential applications. PMID- 28097276 TI - Hydrophobicity determines the fate of self-assembled fluorescent nanoparticles in cells. AB - The fate of small molecule nanoparticles (SMNPs) composed of self-assembling intrinsically fluorescent pi-conjugated oligomers was studied in cells as a function of side-chain hydrophobicity. While the hydrophobic SMNPs remained intact upon cellular uptake, the more hydrophilic SMNPs disassembled and dispersed throughout the cytosol. PMID- 28097277 TI - Combining the spin-separated exact two-component relativistic Hamiltonian with the equation-of-motion coupled-cluster method for the treatment of spin-orbit splittings of light and heavy elements. AB - The spin-separated exact two-component (X2C) relativistic Hamiltonian [sf-X2C+so DKHn, J. Chem. Phys., 2012, 137, 154114] is combined with the equation-of-motion coupled-cluster method with singles and doubles (EOM-CCSD) for the treatment of spin-orbit splittings of open-shell molecular systems. Scalar relativistic effects are treated to infinite order from the outset via the spin-free part of the X2C Hamiltonian (sf-X2C), whereas the spin-orbit couplings (SOC) are handled at the CC level via the first-order Douglas-Kroll-Hess (DKH) type of spin-orbit operator (so-DKH1). Since the exponential of single excitations, i.e., exp(T1), introduces sufficient spin orbital relaxations, the inclusion of SOC at the CC level is essentially the same in accuracy as the inclusion of SOC from the outset in terms of the two-component spinors determined variationally by the sf-X2C+so DKH1 Hamiltonian, but is computationally more efficient. Therefore, such an approach (denoted as sf-X2C-EOM-CCSD(SOC)) can achieve uniform accuracy for the spin-orbit splittings of both light and heavy elements. For light elements, the treatment of SOC can even be postponed until the EOM step (denoted as sf-X2C EOM(SOC)-CCSD), so as to further reduce the computational cost. To reveal the efficacy of sf-X2C-EOM-CCSD(SOC) and sf-X2C-EOM(SOC)-CCSD, the spin-orbit splittings of the 2Pi states of monohydrides up to the sixth row of the periodic table are investigated. The results show that sf-X2C-EOM-CCSD(SOC) predicts very accurate results (within 5%) for elements up to the fifth row, whereas sf-X2C EOM(SOC)-CCSD is useful only for light elements (up to the third row but with some exceptions). For comparison, the sf-X2C-S-TD-DFT-SOC approach [spin-adapted open-shell time-dependent density functional theory, Mol. Phys., 2013, 111, 3741] is applied to the same systems. The overall accuracy (1-10%) is satisfactory. PMID- 28097280 TI - Freezing-induced self-assembly of amphiphilic molecules. AB - The self-assembly of amphiphilic molecules usually takes place in a liquid phase, near room temperature. Here, using small angle X-ray scattering (SAXS) experiments performed in real time, we show that freezing of aqueous solutions of copolymer amphiphilic molecules can induce self-assembly below 0 degrees C. PMID- 28097282 TI - Casimir effect between pinned particles in two-dimensional jammed systems. AB - The Casimir effect arises when long-ranged fluctuations are geometrically confined between two surfaces, leading to a macroscopic force. Traditionally, these forces have been observed in quantum systems and near critical points in classical systems. Here we show the existence of Casimir-like forces between two pinned particles immersed in two-dimensional systems near the jamming transition. We observe two components to the total force: a short-ranged, depletion force and a long-ranged, repulsive Casimir-like force. The Casimir-like force dominates as the jamming transition is approached, and when the pinned particles are much larger than the ambient jammed particles. We show that this repulsive force arises due to a clustering of particles with strong contact forces around the perimeter of the pinned particles. As the separation between the pinned particles decreases, a region of high-pressure develops between them, leading to a net repulsive force. PMID- 28097283 TI - Melting upon cooling and freezing upon heating: fluid-solid phase diagram for Svejk-Hasek model of dimerizing hard spheres. AB - A simple model of dimerizing hard spheres with highly nontrivial fluid-solid phase behavior is proposed and studied using the recently proposed resummed thermodynamic perturbation theory for central force (RTPT-CF) associating potentials. The phase diagram has the fluid branch of the fluid-solid coexistence curve located at temperatures lower than those of the solid branch. This unusual behavior is related to the strong dependence of the system excluded volume on the temperature, which for the model at hand decreases with increasing temperature. This effect can be also seen for a wide family of fluid models with an effective interaction that combines short range attraction and repulsion at a larger distance. We expect that for sufficiently high repulsive barrier, such systems may show similar phase behavior. PMID- 28097285 TI - Localization in an idealized heterogeneous elastic sheet. AB - Localized deformation is ubiquitous in many natural and engineering materials as they approach failure, and a significant effort has been made to understand localization processes with simple continuum models. Real materials are much more commonly heterogeneous but it is unclear exactly how heterogeneity affects outcomes. In this work we study the response of an idealized heterogenous elastic sheet on a soft foundation as it is uniaxially compressed. The patterned surface layers are created by selective ultraviolet/ozone treatment of the top surface of a polydimethylsiloxane (PDMS) sample using a TEM grid as a mask. By controlling the exposure time of UV/O3, samples ranging from continuous thin films to sets of isolated small plates were created. We find that patterned regions noticeably localize while bulk regions appear as uniform wrinkles, and that local and global strains depend on the pattern pitch, exposure levels and the treatment protocol. Remarkably, various responses can be modeled using well-understood theory that ignores pattern details aside from the small distance between the adjacent boundaries and the local value of strain. PMID- 28097286 TI - [Pain therapy in small pets]. AB - Although many advances in pain therapy have been made in recent years, pain therapy is more difficult in the small domestic animal than in cats and dogs. However, there is the ethical obligation that these animals also receive adequate pain therapy. An analgesic is rarely authorized for use in small pets, with pharmacological investigations often lacking and dosages frequently only determined empirically. The small size of the animals often requires a higher dose per kilogram bodyweight compared to cats and dogs. The dosage itself is also difficult to apply in small animals, because many analgesics must be diluted before their use. In addition, frequent manipulation of small animals for analgesic administration induces stress in the patient, which can intensify the pain. In the present article, those analgesics suitable for use in the small domestic animal are described and the indications for the use of the various types of analgesics are explained. A specialized section concentrates on pain detection and algesimetry in the small domestic animal. The detection of pain is much more difficult in small domestic animals. In the last few years so-called "grimace scales" have been developed which are used to assess the facial expression of the animals. PMID- 28097287 TI - Using Active Learning to Identify Health Information Technology Related Patient Safety Events. AB - The widespread adoption of health information technology (HIT) has led to new patient safety hazards that are often difficult to identify. Patient safety event reports, which are self-reported descriptions of safety hazards, provide one view of potential HIT-related safety events. However, identifying HIT-related reports can be challenging as they are often categorized under other more predominate clinical categories. This challenge of identifying HIT-related reports is exacerbated by the increasing number and complexity of reports which pose challenges to human annotators that must manually review reports. In this paper, we apply active learning techniques to support classification of patient safety event reports as HIT-related. We evaluated different strategies and demonstrated a 30% increase in average precision of a confirmatory sampling strategy over a baseline no active learning approach after 10 learning iterations. PMID- 28097288 TI - Secondary Analysis of an Electronic Surveillance System Combined with Multi-focal Interventions for Early Detection of Sepsis. AB - : To conduct an independent secondary analysis of a multi-focal intervention for early detection of sepsis that included implementation of change management strategies, electronic surveillance for sepsis, and evidence based point of care alerting using the POC AdvisorTM application. METHODS: Propensity score matching was used to select subsets of the cohorts with balanced covariates. Bootstrapping was performed to build distributions of the measured difference in rates/means. The effect of the sepsis intervention was evaluated for all patients, and High and Low Risk subgroups for illness severity. A separate analysis was performed patients on the intervention and non-intervention units (without the electronic surveillance). Sensitivity, specificity, and the positive predictive values were calculated to evaluate the accuracy of the alerting system for detecting sepsis or severe sepsis/ septic shock. RESULTS: There was positive effect on the intervention units with sepsis electronic surveillance with an adjusted mortality rate of -6.6%. Mortality rates for non-intervention units also improved, but at a lower rate of -2.9%. Additional outcomes improved for patients on both intervention and non-intervention units for home discharge (7.5% vs 1.1%), total length of hospital stay (-0.9% vs -0.3%), and 30 day readmissions (-6.6% vs 1.6%). Patients on the intervention units showed better outcomes compared with non-intervention unit patients, and even more so for High Risk patients. The sensitivity was 95.2%, specificity of 82.0% and PPV of 50.6% for the electronic surveillance alerts. CONCLUSION: There was improvement over time across the hospital for patients on the intervention and non-intervention units with more improvement for sicker patients. Patients on intervention units with electronic surveillance have better outcomes; however, due to differences in exclusion criteria and types of units, further study is needed to draw a direct relationship between the electronic surveillance system and outcomes. PMID- 28097290 TI - The Association of Systemic Medication and Disease With Intraocular Pressure. PMID- 28097289 TI - Binding of CLL subset 4 B-cell receptor immunoglobulins to viable human memory B lymphocytes requires a distinctive IGKV somatic mutation. AB - Amino acid replacement mutations in certain CLL stereotyped B-cell receptor (BCR) immunoglobulins (IGs) at defined positions within antigen-binding sites strongly imply antigen selection. Prime examples of this are CLL subset 4 BCR IGs using IGHV4-34/IGHD5-18/IGHJ6 and IGKV2-30/IGKJ2 rearrangements. Conspicuously and unlike most CLL IGs, subset 4 IGs do not bind apoptotic cells. By testing the (auto)antigenic reactivities of subset 4 IGs toward viable lymphoid-lineage cells and specific autoantigens typically bound by IGHV4-34+ IGs, we found IGs from both subset 4 and non-subset 4 IGHV4-34-expressing CLL cases bind naive B cells. However, only subset 4 IGs react with memory B cells. Furthermore, subset 4 IGs do not bind DNA nor i or I carbohydrate antigens, common targets of IGHV4-34 utilizing antibodies in systemic lupus erythematosus and cold agglutinin disease, respectively. Notably, we found that subset 4 IG binding to memory B lymphocytes depends on an aspartic acid at position 66 of FR3 in the rearranged IGKV2-30 gene; this amino acid residue is acquired by somatic mutation. Our findings illustrate the importance of positive and negative selection criteria for structural elements in CLL IGs and suggest that autoantigens driving normal B cells to become subset 4 CLL cells differ from those driving IGHV4-34+ B cells in other diseases. PMID- 28097291 TI - Evaluation of Segmentation of the Superficial and Deep Vascular Layers of the Retina by Optical Coherence Tomography Angiography Instruments in Normal Eyes. AB - Importance: Correct attribution of vascular features in optical coherence tomography (OCT) angiography depends on accurate segmentation of retinal layers. Objective: To evaluate the segmentation of retinal layers among 3 OCT angiography instruments in the central macula, an area where the superficial and deep vascular plexuses terminate. Design, Setting, and Participants: A retrospective review of a representative OCT angiogram from 1 patient and an evaluation of the vascular pattern in an autopsied eye were conducted at a community retina practice at a university laboratory. A set of 3 * 3-mm scans centered on the fovea using the Cirrus 5000, RTVue XR Avanti, and Triton DRI OCT platforms with default layer segmentations were used to evaluate segmentation accuracy of a normal macula of a white man in his 60s as an emblematic example. A representative histologic section from the central macula of a normal eye was used as an exemplar. Main Outcomes and Measures: Retinal layer segmentation and resultant vascular image compared with vessels as seen in histologic section. Results: The segmentation slab designed to isolate the superficial vascular plexus included the deep vascular plexus in the central macula for all 3 instruments. None of the instruments produced segmented regions that followed the relevant anatomic layers correctly. Conclusions and Relevance: Because of inherent errors in segmentation, studies of the superficial and deep vascular plexuses using manufacturer-recommended default settings are likely to be biased. A proposal for an improved segmentation strategy is presented. PMID- 28097292 TI - Diffuse Retinal Hemorrhages After Uncomplicated Glaucoma Drainage Implantation. PMID- 28097293 TI - Physical Activity on the Weekend: Can It Wait Until Then? PMID- 28097294 TI - A Young Boy With Progressive Dysphonia. PMID- 28097295 TI - Association of Systemic Medication Use With Intraocular Pressure in a Multiethnic Asian Population: The Singapore Epidemiology of Eye Diseases Study. AB - Importance: There is limited understanding of the associations between systemic medication use and intraocular pressure (IOP) in the general population. Objective: To examine the association between systemic medication use and IOP in a multiethnic Asian population. Design, Setting, and Participants: In this post hoc analysis of the Singapore Epidemiology of Eye Diseases study, a population based study of 10 033 participants (78.7% response rate) from 3 racial/ethnic groups (Chinese [recruited from February 9, 2009, through December 19, 2011], Malays [recruited from August 16, 2004, though July 10, 2006], and Indians [recruited from May 21, 2007, through December 29, 2009]), participants with glaucoma, previous ocular surgery, or trauma and an IOP asymmetry greater than 5 mm Hg between eyes were excluded. Intraocular pressure was measured using Goldmann applanation tonometry. An interviewer-administered questionnaire was conducted to collect data on medication and other variables. Data analysis was performed from August 1 through October 31, 2015. Main Outcomes and Measures: Associations between medication and IOP were assessed using linear regression models adjusted for age, sex, body mass index, ethnicity, and the medical condition for which the medication was taken (angiotensin-converting enzyme inhibitors [ACEIs], angiotensin receptor blockers [ARBs], and beta-blockers adjusted for blood pressure, statins adjusted for lipids, and biguanides, sulfonylureas, alpha-glycosidase inhibitors [AGIs], and insulin adjusted for glycosylated hemoglobin). Medications associated with significant IOP differences were incorporated into regression models adjusted for concomitant use of multiple medications. Generalized estimating equation models were used to account for correlation between eyes. Results: Of the 10 033 participants, we analyzed 8063 (mean [SD] age, 57.0 [9.6] years; 4107 female [50.9%]; 2680 Chinese [33.2%], 2757 Malay [34.2%], and 2626 Indian [32.6%] individuals). Systemic beta-blocker use was independently associated with an IOP of 0.45 mm Hg lower (95% CI, -0.65 to 0.25 mm Hg; P < .001). Conversely, higher mean IOP was associated with use of ACEIs (0.33 mm Hg higher; 95% CI, 0.08 to 0.57 mm Hg; P = .008), ARBs (0.40 mm Hg higher; 95% CI, 0.40-0.75 mm Hg; P = .02), statins (0.21 mm Hg higher; 95% CI, 0.02-0.4 mm Hg; P = .03), and sulfonylureas (0.34 mm Hg higher; 95% CI, 0.05-0.63 mm Hg; P = .02). An interaction between medication classes for additive, synergistic, or antagonistic effects on IOP was not identified. Conclusions and Relevance: Although systemic beta-blocker use was associated with lower IOP and systemic ACEI, ARB, statin, and sulfonylurea use was associated with higher IOP in this study, the associations were modest at best. Only the associations with systemic hypoglycemic agents were greater than 1 mm Hg, a threshold that has translated to a 14% greater risk of incident glaucoma across 5 years in other studies. At this point, the effect of systemic medication on IOP in eyes with glaucoma is not well elucidated but important. Our findings indicate that patients with glaucoma may potentially be at risk of higher or lower IOP, depending on medication class, and this would in turn affect management of IOP control. PMID- 28097296 TI - Long-term Postprocedural Outcomes of Palliative Emergency Stenting vs Stoma in Malignant Large-Bowel Obstruction. AB - Importance: Colonic stenting was introduced for palliation of malignant large bowel obstruction (MLBO) more than 20 years ago but remains controversial. Objective: To compare outcomes after palliative stenting vs stoma creation in patients with MLBO requiring emergency management. Design, Setting, and Participants: This observational cohort study assessed 345 patients from New York State with an urgent or emergency admission to the hospital for obstruction secondary to colorectal cancer and who underwent stenting or stoma creation from October 1, 2009, through December 31, 2013. Patients were excluded if they underwent resection within 1 year of the index admission. Exposures: Palliative stenting vs stoma creation. Main Outcomes and Measures: Primary outcomes included subsequent operation and readmission within 90-day and 1-year follow-up. Secondary outcomes were in-hospital death, major medical and surgical complications, length of stay, total charges, and discharge dispositions. Multivariable hierarchical analyses and propensity score matching were used to compare outcomes between the exposure groups. Results: The cohort included 345 patients (mean [SD] age, 69.9 [14.4] years in the stoma group and 70.9 [16.8] years in the stent group; 87 men [50.3%] in the stoma group and 90 [52.3%] in the stent group; and 114 non-Hispanic white patients [65.9%] in the stoma group and 90 [52.3%] in the stent group). Most patients undergoing stenting were treated at high-volume (104 [60.5%]) vs medium-volume (42 [24.4%]) or low-volume (26 [15.1%]) hospitals (P < .001). Patients undergoing stenting were significantly less likely to experience prolonged length of stay (odds ratio [OR], 0.50; 95% CI, 0.26-0.97; P = .04), more likely to be discharged to their usual residence (OR, 0.14; 95% CI, 0.07-0.28; P < .001), and tended to have similar or fewer complications (major events: OR, 0.81; 95% CI, 0.30-2.18; P = .68; procedural complications: OR, 0.57; 95% CI, 0.11-1.22; P = .10). There was no significant difference between the groups in terms of 90-day and 1-year readmission to the hospitals (90 days: OR, 0.93; 95% CI, 0.49-1.78; P = .83; 1 year: OR, 0.72; 95% CI, 0.38-1.37; P = .30). Subsequent operation at 90 days was also not different between the groups (OR, 1.34; 95% CI, 0.26-6.89; P = .72), but there was a higher chance of subsequent operation at 1 year after the stenting procedure (OR, 2.93; 95% CI, 1.12-7.68; P = .03), with most subsequent operations being restenting. Conclusions and Relevance: In patients with MLBO and if resection is not part of the treatment plan, stenting is safe and improves the efficiency of care with obvious quality-of-life benefits. It should be offered at experienced centers, and patients should be counseled regarding increased risk of subsequent stenting within 1 year. PMID- 28097297 TI - Laryngeal Immunoglobulin G4-Related Disease Resulting in Severe Airway Obstruction. PMID- 28097298 TI - Regulatory Action Necessary for Immune Globulin Preparations for Hepatitis A Prophylaxis. PMID- 28097299 TI - Evaluation of Potencies of Immune Globulin Products Against Hepatitis A. PMID- 28097300 TI - Precision Benefit Design-Using "Smarter" Deductibles to Better Engage Consumers and Mitigate Cost-Related Nonadherence. PMID- 28097301 TI - Analysis of the Trend Toward Fuller Lips Among Fashion Models. PMID- 28097302 TI - Association of Extension of Cervical Cord Lesion and Area Postrema Syndrome With Neuromyelitis Optica Spectrum Disorder. PMID- 28097303 TI - Clinicians' Expectations of the Benefits and Harms of Treatments, Screening, and Tests: A Systematic Review. AB - Importance: Inaccurate clinician expectations of the benefits and harms of interventions can profoundly influence decision making and may be contributing to increasing intervention overuse. Objective: To systematically review all studies that have quantitatively assessed clinicians' expectations of the benefits and/or harms of any treatment, test, or screening test. Evidence Review: A comprehensive search strategy of 4 databases (MEDLINE, EMBASE, Cumulative Index of Nursing and Allied Health Literature, and PsycINFO) from the start years to March 17-20, 2015, with no language or study type restriction, was performed. Searches were also conducted on cited references of the included studies, and experts and study authors were contacted. Two researchers independently evaluated methodologic quality and extracted participants' estimates of benefit and harms and authors' contemporaneous estimates. Findings: Of the 8166 records screened, 48 articles (13 011 clinicians) were eligible. Twenty studies focused on treatment, 20 on medical imaging, and 8 on screening. Of the 48 studies, 30 (67%) assessed only harm expectations, 9 (20%) evaluated only benefit expectations, and 6 (13%) assessed both benefit and harm expectations. Among the studies comparing benefit expectations with a correct answer (total of 28 outcomes), most participants provided correct estimation for only 3 outcomes (11%). Of the studies comparing expectations of harm with a correct answer (total of 69 outcomes), a majority of participants correctly estimated harm for 9 outcomes (13%). Where overestimation or underestimation data were provided, most participants overestimated benefit for 7 (32%) and underestimated benefit for 2 (9%) of the 22 outcomes, and underestimated harm for 20 (34%) and overestimated harm for 3 (5%) of the 58 outcomes. Conclusions and Relevance: Clinicians rarely had accurate expectations of benefits or harms, with inaccuracies in both directions. However, clinicians more often underestimated rather than overestimated harms and overestimated rather than underestimated benefits. Inaccurate perceptions about the benefits and harms of interventions are likely to result in suboptimal clinical management choices. PMID- 28097304 TI - Health Insurance Deductibles and Their Associations With Out-of-Pocket Spending and Affordability Barriers Among US Adults With Chronic Conditions. PMID- 28097305 TI - Enhanced Recovery After Surgery: A Review. AB - Importance: Enhanced Recovery After Surgery (ERAS) is a paradigm shift in perioperative care, resulting in substantial improvements in clinical outcomes and cost savings. Observations: Enhanced Recovery After Surgery is a multimodal, multidisciplinary approach to the care of the surgical patient. Enhanced Recovery After Surgery process implementation involves a team consisting of surgeons, anesthetists, an ERAS coordinator (often a nurse or a physician assistant), and staff from units that care for the surgical patient. The care protocol is based on published evidence. The ERAS Society, an international nonprofit professional society that promotes, develops, and implements ERAS programs, publishes updated guidelines for many operations, such as evidence-based modern care changes from overnight fasting to carbohydrate drinks 2 hours before surgery, minimally invasive approaches instead of large incisions, management of fluids to seek balance rather than large volumes of intravenous fluids, avoidance of or early removal of drains and tubes, early mobilization, and serving of drinks and food the day of the operation. Enhanced Recovery After Surgery protocols have resulted in shorter length of hospital stay by 30% to 50% and similar reductions in complications, while readmissions and costs are reduced. The elements of the protocol reduce the stress of the operation to retain anabolic homeostasis. The ERAS Society conducts structured implementation programs that are currently in use in more than 20 countries. Local ERAS teams from hospitals are trained to implement ERAS processes. Audit of process compliance and patient outcomes are important features. Enhanced Recovery After Surgery started mainly with colorectal surgery but has been shown to improve outcomes in almost all major surgical specialties. Conclusions and Relevance: Enhanced Recovery After Surgery is an evidence-based care improvement process for surgical patients. Implementation of ERAS programs results in major improvements in clinical outcomes and cost, making ERAS an important example of value-based care applied to surgery. PMID- 28097306 TI - Universal Trichloroacetic Acid Peel Technique for Light and Dark Skin. AB - Importance: Despite their great potential, medium and deep trichloroacetic acid peels are underused in light-skinned patients and are rarely used in darker skinned patients because of the widespread fear of pigmentary complications and scarring. This concern has led many physicians to opt for the use of lighter types of peels (glycolic acid peel, Jessner peel, etc) and different lasers and intense light technologies. Trichloroacetic acid peels have been described in numerous publications. However, no study to date has described the precise technique and the practical pearls of a successful trichloroacetic acid peel approach in a clear, detailed, and reproducible manner. Objectives: To clarify a practical approach to a universal trichloroacetic acid peel and to offer novice and experienced facial plastic surgeons an organized, easy, and safe technique for medium and deep trichloroacetic acid peels. Design, Setting, and Participants: This study was a case series of universal trichloroacetic acid peels in an academic setting. The study dates were January 1, 1996, to November 1, 2015. Main Outcomes and Methods: This article discusses the preoperative evaluation for a chemical peel, a previously published genetico-racial skin classification, and the trichloroacetic acid peel technique, which aims at standardizing and controlling the application of the acid to improve results and lessen complications. The "strip" technique is described, which increases the physician's control over the peel depth. Results: A total of 923 trichloroacetic acid peels in 803 female patients (87.0%) and 120 male patients (13.0%) were reviewed (mean age, 41.59 years). The follow-up period ranged from 6 months to 13 years (mean, 13 months). This case series revealed a low incidence of complications, including 54 patients (5.9%) with persistent hyperpigmentation, 3 patients (0.3%) with mild telangiectasia, 2 patients (0.2%) with acute herpesvirus infection, 2 patients (0.2%) with bacterial Staphylococcus infection, and 1 patient (0.1%) with hypopigmentation. Conclusions and Relevance: When properly applied, trichloroacetic acid peels are efficient and safe for light and dark skin. The technique can be an easily implementable addition to a physician's cosmetic practice. Level of Evidence: 4. PMID- 28097307 TI - Association of Periodic Discharges With Reduced Brain Tissue Oxygenation: No Longer Straddling the Fence? PMID- 28097308 TI - Mechanical Thrombectomy for Acute Ischemic Stroke: Are We Done? PMID- 28097309 TI - Association of Quality of Life and Location of Lesions in Patients With Vitiligo. PMID- 28097310 TI - Combined Intravenous Thrombolysis and Thrombectomy vs Thrombectomy Alone for Acute Ischemic Stroke: A Pooled Analysis of the SWIFT and STAR Studies. AB - Importance: Mechanical thrombectomy (MT) improves clinical outcomes in patients with acute ischemic stroke (AIS) caused by a large vessel occlusion. However, it is not known whether intravenous thrombolysis (IVT) is of added benefit in patients undergoing MT. Objective: To examine whether treatment with IVT before MT with a stent retriever is beneficial in patients undergoing MT. Design, Setting, and Participants: This post hoc analysis used data from 291 patients treated with MT included in 2 large, multicenter, prospective clinical trials that evaluated MT for AIS (Solitaire With the Intention for Thrombectomy performed from January 1, 2010, through December 31, 2011, and Solitaire Flow Restoration Thrombectomy for Acute Revascularization from January 1, 2010, through December 31, 2012). An independent core laboratory scored the radiologic outcomes in each trial. Interventions: Patients were treated with IVT with tissue plasminogen activator followed by MT (IVT and MT group) with the use of a stent retriever or MT with a stent retriever alone (MT group). Main Outcomes and Measures: Successful reperfusion, functional independence (modified Rankin Scale score of 0-2) and mortality at 90 days, symptomatic intracranial hemorrhage, emboli to new territory, and vasospasm were compared. Results: Of 291 patients included in the analysis, 160 (55.0%) underwent IVT and MT (mean [SD] age, 67 [13] years; 97 female [60.6%]), and 131 (45.0%) underwent MT alone (mean [SD] age, 69 [12] years; 71 [55.7%] female). Median Alberta Stroke Program Early CT Score at baseline was lower in the IVT and MT group (8 vs 9, P = .04). There was no statistically significant difference in the duration from symptom onset to groin puncture (254 minutes for the IVT and MT group vs 262 minutes for the MT group, P = .10). The number of passes, rate of successful reperfusion, functional independence at 90 days, mortality at 90 days, and emboli to new territory were also similar among groups. Symptomatic intracranial hemorrhage (1% vs 4%) and parenchymal hemorrhages type 1 (1% vs 3%) or type 2 (1% vs 2%) did not differ significantly (P = .25). Vasospasm occurred more often in patients who received IVT and MT vs MT alone (27% vs 14%, P = .006). In multivariate analysis, no statistically significant association was observed between IVT and MT vs MT alone for any of the outcomes. Conclusions and Relevance: The results indicate that treatment of patients experiencing AIS due to a large vessel occlusion with IVT before MT does not appear to provide a clinical benefit over MT alone. A randomized clinical trial seems warranted. Trial Registration: clinicaltrials.gov Identifiers: NCT01054560 and NCT01327989. PMID- 28097311 TI - Association of Lymphovascular Space Invasion With Locoregional Failure and Survival in Patients With Node-Negative Oral Tongue Cancers. AB - Importance: The indications for adjuvant therapy in resected oral tongue cancers are based on both clinical and pathological factors, with clear evidence for adjuvant radiation in patients with pathologically positive neck lymph nodes, positive margins, and extracapsular extension, but the data for patients with no nodal disease are sparse. Objective: To investigate determinants of failure and survival in patients with node-negative oral tongue cancer. Design, Setting, and Participants: Medical records for patients with oral tongue cancer treated with definitive surgery from 2003 to 2013 were reviewed. All patients were cN0 negative and classified as pathologically node-negative (pN0) if a neck dissection was performed. Patients received adjuvant radiotherapy (RT) or chemoradiotherapy (CRT) based on standard clinical and pathological determinants. Main Outcomes and Measures: Kaplan-Meier and multivariable (MVA) logistic regression and Cox proportional hazard regression analyses were performed to identify patient, tumor, and treatment characteristics predictive of locoregional control (LRC) and overall survival (OS). Results: A total of 180 patients met entry criteria, with a median follow-up time of 4.9 years (range, 0.9-12.5 years); 102 patients (56.7%) were female and 42 patients (23.3%) were younger than 45 years at diagnosis. One hundred fifty-three patients (85%) had T1/T2 tumors, and 112 patients (62%) had elective neck dissections with confirmed pN0. Lymphovascular space invasion (LVSI) was present in 36 patients (20%). On MVA, LVSI (OR, 0.06; 95% CI, 0.02-0.19; P < .01) was associated with worse LRC. Elective neck dissection (odds ratio [OR], 2.99; 95% CI, 1.16-7.73; P = .02) and receipt of RT (OR, 7.74; 95% CI, 2.27-26.42; P < .01) were associated with improved LRC. Three-year LRC rates were significantly lower for patients with LVSI (38.8%; 95% CI, 22.8%, 54.6%) than those without LVSI (81.9%; 95% CI, 74.4%, 87.4%). On MVA, only LVSI (hazard ratio, 2.20; 95% CI, 1.19-4.06; P = .01) and age greater than 44 years (hazard ratio, 4.38; 95% CI, 1.34-14.27; P = .01) were associated with worse OS. Three-year OS rates were significantly lower in patients with LVSI (71.3%; 95% CI, 53.2%-83.4%) than those without LVSI (90.3%; 95% CI, 83.8%-94.3%). Conclusions and Relevance: Lymphovascular space invasion in patients with node-negative oral tongue cancer treated with upfront definitive surgery is associated with worse LRC and OS. Node-negative oral cavity cancers with LVSI warrant consideration of further adjuvant therapy, which should be further evaluated in a prospective setting. PMID- 28097312 TI - What Van Halen Can Teach Us About the Care of Older Patients. PMID- 28097313 TI - Association of "Weekend Warrior" and Other Leisure Time Physical Activity Patterns With Risks for All-Cause, Cardiovascular Disease, and Cancer Mortality. AB - Importance: More research is required to clarify the association between physical activity and health in "weekend warriors" who perform all their exercise in 1 or 2 sessions per week. Objective: To investigate associations between the weekend warrior and other physical activity patterns and the risks for all-cause, cardiovascular disease (CVD), and cancer mortality. Design, Setting, and Participants: This pooled analysis of household-based surveillance studies included 11 cohorts of respondents to the Health Survey for England and Scottish Health Survey with prospective linkage to mortality records. Respondents 40 years or older were included in the analysis. Data were collected from 1994 to 2012 and analyzed in 2016. Exposures: Self-reported leisure time physical activity, with activity patterns defined as inactive (reporting no moderate- or vigorous intensity activities), insufficiently active (reporting <150 min/wk in moderate intensity and <75 min/wk in vigorous-intensity activities), weekend warrior (reporting >=150 min/wk in moderate-intensity or >=75 min/wk in vigorous intensity activities from 1 or 2 sessions), and regularly active (reporting >=150 min/wk in moderate-intensity or >=75 min/wk in vigorous-intensity activities from >=3 sessions). The insufficiently active participants were also characterized by physical activity frequency. Main Outcomes and Measures: All-cause, CVD, and cancer mortality ascertained from death certificates. Results: Among the 63 591 adult respondents (45.9% male; 44.1% female; mean [SD] age, 58.6 [11.9] years), 8802 deaths from all causes, 2780 deaths from CVD, and 2526 from cancer occurred during 561 159 person-years of follow-up. Compared with the inactive participants, the hazard ratio (HR) for all-cause mortality was 0.66 (95% CI, 0.62-0.72) in insufficiently active participants who reported 1 to 2 sessions per week, 0.70 (95% CI, 0.60-0.82) in weekend warrior participants, and 0.65 (95% CI, 0.58-0.73) in regularly active participants. Compared with the inactive participants, the HR for CVD mortality was 0.60 (95% CI, 0.52-0.69) in insufficiently active participants who reported 1 or 2 sessions per week, 0.60 (95% CI, 0.45-0.82) in weekend warrior participants, and 0.59 (95% CI, 0.48-0.73) in regularly active participants. Compared with the inactive participants, the HR for cancer mortality was 0.83 (95% CI, 0.73-0.94) in insufficiently active participants who reported 1 or 2 sessions per week, 0.82 (95% CI, 0.63-1.06) in weekend warrior participants, and 0.79 (95% CI, 0.66-0.94) in regularly active participants. Conclusions and Relevance: Weekend warrior and other leisure time physical activity patterns characterized by 1 or 2 sessions per week may be sufficient to reduce all-cause, CVD, and cancer mortality risks regardless of adherence to prevailing physical activity guidelines. PMID- 28097315 TI - The Significance of Invasive Breast Cancer Associated With Ductal Carcinoma In Situ (DCIS) Compared With Cancer Without Associated DCIS. PMID- 28097314 TI - Complications of Bilateral Neck Dissection in Thyroid Cancer From a Single High Volume Center. AB - Importance: The morbidity of bilateral lateral neck dissection (BLND) for thyroid cancers has not been described in detail. This study delineates the specific complications arising from BLND for thyroid cancers at a single high-volume center. Objective: To determine the morbidity associated with BLNDs for differentiated thyroid cancers at our institution. Design, Setting, and Participants: This was a retrospective review of medical records performed to identify patients having undergone BLNDs for thyroid cancers by a single surgeon at an academic, tertiary medical center in Toronto, Ontario, Canada, from 1988 to 2015. Patients who underwent BLND for papillary, follicular, or medullary thyroid cancers were identified through operative procedure codes and review of operative and pathology reports. The indication for this procedure was suspicious bilateral lateral compartment on imaging and clinical examination. Sixty-two patients who underwent BLND for thyroid cancers, with or without total thyroidectomy and central compartment dissection, were identified. Main Outcomes and Measures: The main outcome measures for this study were unanticipated medical or surgical complications during the operation or in the postoperative period. Secondary measures were oncologic outcomes, including regional structural or biochemical recurrence. Results: Of the 62 patients, 24 were male (39%), and 38 (61%) were female. Their mean age was 46 years (range, 17-80 years). The overall risk of permanent hypoparathyroidism was 37%. There was 1 case of unanticipated permanent recurrent nerve paralysis and 1 case of temporary nerve paresis. Postoperative chyle fistula occurred in 6 cases (10%). There were 3 readmissions within 30 days of surgery, 1 pulmonary embolism, and 1 perioperative mortality. Fifty percent of patients had pN0 contralateral necks despite preoperative clinical suspicion. Four patients were found to have anaplastic thyroid cancers intraoperatively. Five patients (8%) developed nodal recurrence in the neck. Four patients died of their disease within available follow-up (mean, 3.2 years). Conclusions and Relevance: Bilateral lateral neck dissection for thyroid cancers confers a significant amount of morbidity, including a significant rate of hypoparathyroidism. Knowledge of the complications of this procedure, especially in the setting of questionable survival benefit, may assist in preoperative decision-making and patient counseling. PMID- 28097316 TI - Evaluation of Structural Progression in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. AB - Importance: Considerable research has described the arrhythmic course of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). However, objective data characterizing structural progression, such as ventricular enlargement and cardiac dysfunction, in ARVD/C are relatively scarce. Objectives: To define the extent of structural progression, identify determinants of structural progression, and determine the association between structural progression and electrocardiographic (ECG) changes in patients with ARVD/C. Design, Setting, and Participants: In this cohort study, first- and last available echocardiograms of 85 patients with ARVD/C fulfilling 2010 Task Force diagnostic criteria (TFC) from a transatlantic ARVD/C registry were retrospectively compared to assess structural disease progression. Right ventricular (RV) size and systolic function between baseline and last follow-up were compared. The RV size was determined by RV outflow tract dimension, and RV and left ventricular (LV) systolic function were determined by RV fractional area change (RV-FAC) and LV ejection fraction (LVEF), respectively. Multivariable logistic regression was used to study associations between baseline characteristics and the occurrence of structural progression. Main Outcomes and Measures: The main outcome was the change in variables indicating structural progression. Secondary outcomes were the correlation with electrical progression and identification of the association between baseline characteristics and occurence structural progression. Results: Among the 85 patients with ARVD/C, mean (SD) age at baseline was 42.8 (14.4) years and 47 (55%) were men. After a mean (SD) follow-up of 6.4 (2.5) years, RV outflow tract dimension increased from 35 mm (interquartile range [IQR], 31 to 39) to 37 mm (IQR, 33 to 41) (P < .001), RV-FAC decreased from 39% (IQR, 33% to 44%) to 34% (IQR, 24% to 42%) (P < .001) (rate -3.3% per 5 years; IQR, -8.9% to 1.2%), indicating large interpatient variability. The LVEF decreased from 55% (IQR, 52% to 60%) to 54% (IQR, 49% to 57%) (P = .001) (rate, -0.2% per 5 years; IQR, -6.5% to 1.7%). Forty examinations were reanalyzed to establish the measurement error. Patients exceeding the measurement error by +/-2 SDs were identified with significant progressive disease for RV, with a decrease in RV-FAC greater than 10% (n = 21) and, for LV, a decrease in LVEF greater than 7% (n = 23). Progression of RV disease was associated with depolarization criteria at baseline (odds ratio [OR], 9.0; 95% CI, 1.1-74.2; P = .04), whereas progression of LV disease was associated with phospholamban (PLN) mutation (OR, 8.8; 95% CI, 2.1-37.2; P = .003). There was no association between progressive RV/LV structural disease and newly developed ECG TFC. Conclusions and Relevance: Structural dysfunction in ARVD/C is progressive with substantial interpatient variability. Significant structural RV progression was associated with prior depolarization abnormalities, whereas LV progression is modified by genetic background. Structural progression was not associated with development of new ECG TFC. The results of this study pave the way for designing and launching trials aimed at reducing structural progression in patients with ARVD/C. PMID- 28097317 TI - Surrogate End Points for All-Cause Mortality in Men With Localized Unfavorable Risk Prostate Cancer Treated With Radiation Therapy vs Radiation Therapy Plus Androgen Deprivation Therapy: A Secondary Analysis of a Randomized Clinical Trial. AB - Importance: Several surrogates for prostate cancer-specific mortality satisfying the Prentice criteria exist, but whether these are surrogates for all-cause mortality, and how their performance compares, is unknown. Objective: To ascertain and compare the performance of 4 candidate surrogates (prostate specific antigen [PSA] failure, PSA nadir >0.5 ng/mL, PSA doubling time <9 months, and interval to PSA failure <30 months) for all-cause mortality using the proportion of treatment-effect metric. Design, Setting, and Participants: For this randomized clinical trial, 206 men with unfavorable-risk prostate cancer who were seen at a Harvard-affiliated academic hospital or an associated community hospital between December 1, 1995, to April 15, 2001, were identified, randomized to radiation therapy alone or radiation therapy followed by 6 months of androgen deprivation therapy, and followed for a median 16.62 years. This analysis looks at the subgroup of 157 men with minimal comorbidities or no comorbidity (median follow-up, 16.49 months). Interventions: Patients were previously randomized to receive radiation therapy or radiation and 6 months of androgen deprivation therapy. Main Outcomes and Measures: Risk of all-cause mortality. Results: Overall, a cohort of 157 men (median [interquartile range] age, 72.43 [68.75 75.53]) with unfavorable-risk prostate cancer and minimal or no comorbidities were selected for this study. Three tested metrics met all 4 Prentice criteria for surrogacy for the surrogate covariate in the adjusted model for all-cause mortality: PSA nadir greater than 0.5 ng/mL (adjusted hazard ratio [aHR], 1.72; 95% CI, 1.17-2.52; P = .01), PSA doubling time less than 9 months (aHR, 2.06; 95% CI, 1.29-3.28; P = .003), and interval to PSA failure less than 30 months (aHR, 1.76; 95% CI, 1.06-2.92; P = .03); while PSA failure did not. For the 3 successful surrogates, the proportion of treatment effect values were 103.86%, 43.09%, and 41.26%, respectively. Conclusions and Relevance: A PSA nadir value of greater than 0.5 ng/mL following radiation and androgen deprivation therapy appears to identify men prior to PSA failure who are at high-risk for death. This could be used to select men for entry at the time of PSA nadir onto randomized trials evaluating the impact on survival of salvage androgen deprivation therapy with or without agents shown to prolong survival in men with castrate-resistant metastatic prostate cancer. Trial Registration: clinicaltrials.gov Identifier: NCT00116220. PMID- 28097318 TI - Emerging and Reemerging Infectious Diseases: The Dichotomy Between Acute Outbreaks and Chronic Endemicity. PMID- 28097319 TI - Escalation of Commitment in Treatment Decisions Near the End of Life. PMID- 28097320 TI - Teens, Acne, and Oral Contraceptive Pills: The Need for Greater Clarity on When Teens Can Consent. PMID- 28097321 TI - Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders. AB - Importance: Autosomal recessive inherited neurodevelopmental disorders are highly heterogeneous, and many, possibly most, of the disease genes are still unknown. Objectives: To promote the identification of disease genes through confirmation of previously described genes and presentation of novel candidates and provide an overview of the diagnostic yield of exome sequencing in consanguineous families. Design, Setting, and Participants: Autozygosity mapping in families and exome sequencing of index patients were performed in 152 consanguineous families (the parents descended from a same ancestor) with at least 1 offspring with intellectual disability (ID). The study was conducted from July 1, 2008, to June 30, 2015, and data analysis was conducted from July 1, 2015, to August 31, 2016. Results: Of the 152 consanguineous families enrolled, 1 child (in 45 families [29.6%]) or multiple children (107 families [70.4%]) had ID; additional features were present in 140 of the families (92.1%). The mean (SD) age of the children was 10.3 (9.0) years, and 171 of 297 (57.6%) were male. In 109 families (71.7%), potentially protein-disrupting and clinically relevant variants were identified. Of these, a clear clinical genetic diagnosis was made in 56 families (36.8%) owing to 57 (likely) pathogenic variants in 50 genes already established in neurodevelopmental disorders (46 autosomal recessive, 2 X-linked, and 2 de novo) or in 7 previously proposed recessive candidates. In 5 of these families, potentially treatable disorders were diagnosed (mutations in PAH, CBS, MTHFR, CYP27A1, and HIBCH), and in 1 family, 2 disease-causing homozygous variants in different genes were identified. In another 48 families (31.6%), 52 convincing recessive variants in candidate genes that were not previously reported in regard to neurodevelopmental disorders were identified. Of these, 14 were homozygous and truncating in GRM7, STX1A, CCAR2, EEF1D, GALNT2, SLC44A1, LRRIQ3, AMZ2, CLMN, SEC23IP, INIP, NARG2, FAM234B, and TRAP1. The diagnostic yield was higher in individuals with severe ID (35 of 77 [45.5%]), in multiplex families (42 of 107 [39.3%]), in patients with additional features (30 of 70 [42.9%]), and in those with remotely related parents (15 of 34 [44.1%]). Conclusions and Relevance: Because of the high diagnostic yield of 36.8% and the possibility of identifying treatable diseases or the coexistence of several disease-causing variants, using exome sequencing as a first-line diagnostic approach in consanguineous families with neurodevelopmental disorders is recommended. Furthermore, the literature is enriched with 52 convincing candidate genes that are awaiting confirmation in independent families. PMID- 28097322 TI - Management and Outcomes of ST-Segment Elevation Myocardial Infarction in US Renal Transplant Recipients. AB - Importance: Renal transplantation is associated with reduction in the risk for myocardial infarction (MI) in patients with chronic kidney disease requiring long term dialysis (stage 5D CKD). Whether outcomes of MI differ among renal transplant recipients vs patients with stage 5D CKD or those without CKD has not been well examined. Objectives: To compare in-hospital reperfusion rates and outcomes of ST-segment elevation MI (STEMI) in renal transplant recipients vs the stage 5D CKD group or the non-CKD group. Design, Setting, and Participants: The National Inpatient Sample database was queried to identify patients 18 years or older who were hospitalized with the principal diagnosis of STEMI. All hospitalizations for STEMI in the United States from January 1, 2003, to December 31, 2013, were included. Codes from International Classification of Diseases, Ninth Revision, Clinical Modification, were used to identify patients in the non CKD, stage 5D CKD, or prior renal transplant groups. Data were analyzed from March to May 2016. Main Outcomes and Measures: In-hospital mortality. Results: From 2003 to 2013, 2 319 002 patients in the non-CKD group (34.7% women; 65.3% men; mean [SD] age, 64.2 [14.4] years), 30 072 patients in the stage 5D CKD group (45.0% women; 55.0% men; mean [SD] age, 66.9 [12.5] years), and 2980 patients in the renal transplant group (27.3% women; 72.7% men; mean [SD] age, 57.5 [11.1] years) were identified who were hospitalized with STEMI. Of these, 68.9% of the patients in the non-CKD group, 39.5% in the stage 5D CKD group, and 65.2% in the renal transplant group received in-hospital reperfusion for STEMI. The renal transplant group was more likely to receive reperfusion compared with the stage 5D CKD group (adjusted odds ratio [AOR], 1.83; 95% CI, 1.67-2.01; P < .001) but less likely compared with the non-CKD group (AOR, 0.75; 95% CI, 0.68-0.83; P < .001). Risk-adjusted in-hospital mortality among the renal transplant group with STEMI was markedly lower compared with the stage 5D CKD group (AOR, 0.37; 95% CI, 0.33-0.43; P < .001) but similar compared with the non-CKD group (AOR, 1.14; 95% CI, 0.99-1.31; P = .08). Among renal transplant recipients with STEMI, the use of reperfusion increased from 53.7% in the 2003-2004 interval to 81.4% in the 2011 2013 interval (AOR, 1.33; 95% CI, 1.25-1.43; P < .001 for trend), whereas risk adjusted in-hospital mortality remained unchanged during the study period, from 8.9% in the 2003-2004 interval to 6.1% in the 2011-2013 interval (AOR, 0.94; 95% CI, 0.85-1.05; P = .27 for trend). Conclusions and Relevance: In-hospital mortality rates in renal transplant recipients with STEMI are more favorable compared with those of patients with stage 5D CKD and approach those of the general population with STEMI. PMID- 28097323 TI - Folic Acid for the Prevention of Neural Tube Defects: The US Preventive Services Task Force Statement on Folic Acid Supplementation in the Era of Mandatory Folic Acid Fortification. PMID- 28097325 TI - Imaging Locally Advanced, Recurrent, and Metastatic Prostate Cancer: A Review. AB - Importance: Prostate cancer is the second leading cause of cancer deaths in US men. The course of prostate cancer is highly variable, and timely and accurate detection of clinically significant cancer is critical in positively affecting outcomes. Observations: Molecular imaging methods and magnetic resonance imaging (MRI) are the most promising new developments for prostate tumor visualization. While the benefits of MRI are many, positron emission tomography (PET) radiotracers are still available only as research tools. Conclusions and Relevance: The current research-based evidence on PET imaging has demonstrated encouraging potential in the initial diagnosis and detection of recurrence and metastases of prostate cancer. PMID- 28097324 TI - Molecular-Based Recursive Partitioning Analysis Model for Glioblastoma in the Temozolomide Era: A Correlative Analysis Based on NRG Oncology RTOG 0525. AB - Importance: There is a need for a more refined, molecularly based classification model for glioblastoma (GBM) in the temozolomide era. Objective: To refine the existing clinically based recursive partitioning analysis (RPA) model by incorporating molecular variables. Design, Setting, and Participants: NRG Oncology RTOG 0525 specimens (n = 452) were analyzed for protein biomarkers representing key pathways in GBM by a quantitative molecular microscopy-based approach with semiquantitative immunohistochemical validation. Prognostic significance of each protein was examined by single-marker and multimarker Cox regression analyses. To reclassify the prognostic risk groups, significant protein biomarkers on single-marker analysis were incorporated into an RPA model consisting of the same clinical variables (age, Karnofsky Performance Status, extent of resection, and neurologic function) as the existing RTOG RPA. The new RPA model (NRG-GBM-RPA) was confirmed using traditional immunohistochemistry in an independent data set (n = 176). Main Outcomes and Measures: Overall survival (OS). Results: In 452 specimens, MGMT (hazard ratio [HR], 1.81; 95% CI, 1.37 2.39; P < .001), survivin (HR, 1.36; 95% CI, 1.04-1.76; P = .02), c-Met (HR, 1.53; 95% CI, 1.06-2.23; P = .02), pmTOR (HR, 0.76; 95% CI, 0.60-0.97; P = .03), and Ki-67 (HR, 1.40; 95% CI, 1.10-1.78; P = .007) protein levels were found to be significant on single-marker multivariate analysis of OS. To refine the existing RPA, significant protein biomarkers together with clinical variables (age, Karnofsky Performance Status, extent of resection, and neurological function) were incorporated into a new model. Of 166 patients used for the new NRG-GBM-RPA model, 97 (58.4%) were male (mean [SD] age, 55.7 [12.0] years). Higher MGMT protein level was significantly associated with decreased MGMT promoter methylation and vice versa (1425.1 for methylated vs 1828.0 for unmethylated; P < .001). Furthermore, MGMT protein expression (HR, 1.84; 95% CI, 1.38-2.43; P < .001) had greater prognostic value for OS compared with MGMT promoter methylation (HR, 1.77; 95% CI, 1.28-2.44; P < .001). The refined NRG-GBM-RPA consisting of MGMT protein, c-Met protein, and age revealed greater separation of OS prognostic classes compared with the existing clinically based RPA model and MGMT promoter methylation in NRG Oncology RTOG 0525. The prognostic significance of the NRG-GBM RPA was subsequently confirmed in an independent data set (n = 176). Conclusions and Relevance: This new NRG-GBM-RPA model improves outcome stratification over both the current RTOG RPA model and MGMT promoter methylation, respectively, for patients with GBM treated with radiation and temozolomide and was biologically validated in an independent data set. The revised RPA has the potential to contribute to improving the accurate assessment of prognostic groups in patients with GBM treated with radiation and temozolomide and to influence clinical decision making. Trial Registration: clinicaltrials.gov Identifier: NCT00304031. PMID- 28097326 TI - Population Health Equity: Rate and Burden, Race and Class. PMID- 28097327 TI - Challenges of Assessing Common Problems Presenting in Uncommon High-Risk Patient Populations. PMID- 28097329 TI - Quantifying Disease Progression in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Key to Advancing Therapy. PMID- 28097328 TI - Diabetes Outpatient Care and Acute Complications Before and After High-Deductible Insurance Enrollment: A Natural Experiment for Translation in Diabetes (NEXT-D) Study. AB - Importance: High-deductible health plans (HDHPs) have expanded under the Affordable Care Act and are expected to play a major role in the future of US health policy. The effects of modern HDHPs on chronically ill patients and adverse outcomes are unknown. Objective: To determine the association of HDHP with high-priority diabetes outpatient care and preventable acute complications. Design, Setting, and Participants: Controlled interrupted-time-series study using a large national health insurer database from January 1, 2003, to December 31, 2012. A total of 12 084 HDHP members with diabetes, aged 12 to 64 years, who were enrolled for 1 year in a low-deductible (<=$500) plan followed by 2 years in an HDHP (>=$1000) after an employer-mandated switch were included. Patients transitioning to HDHPs were propensity-score matched with contemporaneous patients whose employers offered only low-deductible coverage. Low-income (n = 4121) and health savings account (HSA)-eligible (n = 1899) patients with diabetes were subgroups of interest. Data analysis was performed from February 23, 2015, to September 11, 2016. Exposures: Employer-mandated HDHP transition. Main Outcomes and Measures: High-priority outpatient visits, disease monitoring tests, and outpatient and emergency department visits for preventable acute diabetes complications. Results: In the 12 084 HDHP members included after the propensity score match, the mean (SD) age was 50.4 (10.0) years; 5410 of the group (44.8%) were women. The overall, low-income, and HSA-eligible diabetes HDHP groups experienced increases in out-of-pocket medical expenditures of 49.4% (95% CI, 40.3% to 58.4%), 51.7% (95% CI, 38.6% to 64.7%), and 67.8% (95% CI, 47.9% to 87.8%), respectively, compared with controls in the year after transitioning to HDHPs. High-priority primary care visits and disease monitoring tests did not change significantly in the overall HDHP cohort; however, high-priority specialist visits declined by 5.5% (95% CI, -9.6% to -1.5%) in follow-up year 1 and 7.1% (95% CI, -11.5% to -2.7%) in follow-up year 2 vs baseline. Outpatient acute diabetes complication visits were delayed in the overall and low-income HDHP cohorts at follow-up (adjusted hazard ratios, 0.94 [95% CI, 0.88 to 0.99] for the overall cohort and 0.89 [95% CI, 0.81 to 0.98] for the low-income cohort). Annual emergency department acute complication visits among HDHP members increased by 8.0% (95% CI, 4.6% to 11.4%) in the overall group, 21.7% (95% CI, 14.5% to 28.9%) in the low-income group, and 15.5% (95% CI, 10.5% to 20.6%) in the HSA-eligible group. Conclusions and Relevance: Patients with diabetes experienced minimal changes in outpatient visits and disease monitoring after an HDHP switch, but low-income and HSA-eligible HDHP members experienced major increases in emergency department visits for preventable acute diabetes complications. PMID- 28097331 TI - Expanding the National Health Service Corps Scholarship Program to General Surgery: A Proposal to Address the National Shortage of General Surgeons in the United States. PMID- 28097330 TI - Electroencephalographic Periodic Discharges and Frequency-Dependent Brain Tissue Hypoxia in Acute Brain Injury. AB - Importance: Periodic discharges (PDs) that do not meet seizure criteria, also termed the ictal interictal continuum, are pervasive on electroencephalographic (EEG) recordings after acute brain injury. However, their association with brain homeostasis and the need for clinical intervention remain unknown. Objective: To determine whether distinct PD patterns can be identified that, similar to electrographic seizures, cause brain tissue hypoxia, a measure of ongoing brain injury. Design, Setting, and Participants: This prospective cohort study included 90 comatose patients with high-grade spontaneous subarachnoid hemorrhage who underwent continuous surface (scalp) EEG (sEEG) recording and multimodality monitoring, including invasive measurements of intracortical (depth) EEG (dEEG), partial pressure of oxygen in interstitial brain tissue (Pbto2), and regional cerebral blood flow (CBF). Patient data were collected from June 1, 2006, to September 1, 2014, at a single tertiary care center. The retrospective analysis was performed from September 1, 2014, to May 1, 2016, with a hypothesis that the effect on brain tissue oxygenation was primarily dependent on the discharge frequency. Main Outcomes and Measures: Electroencephalographic recordings were visually classified based on PD frequency and spatial distribution of discharges. Correlations between mean multimodality monitoring data and change-point analyses were performed to characterize electrophysiological changes by applying bootstrapping. Results: Of the 90 patients included in the study (26 men and 64 women; mean [SD] age, 55 [15] years), 32 (36%) had PDs on sEEG and dEEG recordings and 21 (23%) on dEEG recordings only. Frequencies of PDs ranged from 0.5 to 2.5 Hz. Median Pbto2 was 23 mm Hg without PDs compared with 16 mm Hg at 2.0 Hz and 14 mm Hg at 2.5 Hz (differences were significant for 0 vs 2.5 Hz based on bootstrapping). Change-point analysis confirmed a temporal association of high frequency PD onset (>=2.0 Hz) and Pbto2 reduction (median normalized Pbto2 decreased by 25% 5-10 minutes after onset). Increased regional CBF of 21.0 mL/100 g/min for 0 Hz, 25.9 mL/100 g/min for 1.0 Hz, 27.5 mL/100 g/min for 1.5 Hz, and 34.7 mL/100 g/min for 2.0 Hz and increased global cerebral perfusion pressure of 91 mm Hg for 0 Hz, 100.5 mm Hg for 0.5 Hz, 95.5 mm Hg for 1.0 Hz, 97.0 mm Hg for 2.0 Hz, 98.0 mm Hg for 2.5 Hz, 95.0 mm Hg for 2.5 Hz, and 67.8 mm Hg for 3.0 Hz were seen for higher PD frequencies. Conclusions and Relevance: These data give some support to consider redefining the continuum between seizures and PDs, suggesting that additional damage after acute brain injury may be reflected by frequency changes in electrocerebral recordings. Similar to seizures, cerebral blood flow increases in patients with PDs to compensate for the increased metabolic demand but higher-frequency PDs (>2 per second) may be inadequately compensated without an additional rise in CBF and associated with brain tissue hypoxia, or higher-frequency PDs may reflect inadequacies in brain compensatory mechanisms. PMID- 28097333 TI - Statin Eligibility Under American and European Cholesterol Guidelines-Reply. PMID- 28097332 TI - Effect of Incentive Spirometry on Postoperative Hypoxemia and Pulmonary Complications After Bariatric Surgery: A Randomized Clinical Trial. AB - Importance: The combination of obesity and foregut surgery puts patients undergoing bariatric surgery at high risk for postoperative pulmonary complications. Postoperative incentive spirometry (IS) is a ubiquitous practice; however, little evidence exists on its effectiveness. Objective: To determine the effect of postoperative IS on hypoxemia, arterial oxygen saturation (Sao2) level, and pulmonary complications after bariatric surgery. Design, Setting, and Participants: A randomized noninferiority clinical trial enrolled patients undergoing bariatric surgery from May 1, 2015, to June 30, 2016. Patients were randomized to postoperative IS (control group) or clinical observation (test group) at a single-center tertiary referral teaching hospital. Analysis was based on the evaluable population. Interventions: The controls received the standard of care with IS use 10 times every hour while awake. The test group did not receive an IS device or these orders. Main Outcomes and Measures: The primary outcome was frequency of hypoxemia, defined as an Sao2 level of less than 92% without supplementation at 6, 12, and 24 postoperative hours. Secondary outcomes were Sao2 levels at these times and the rate of 30-day postoperative pulmonary complications. Results: A total of 224 patients (50 men [22.3%] and 174 women [77.7%]; mean [SD] age, 45.6 [11.8] years) were enrolled, and 112 were randomized for each group. Baseline characteristics of the groups were similar. No significant differences in frequency of postoperative hypoxemia between the control and test groups were found at 6 (11.9% vs 10.4%; P = .72), 12 (5.4% vs 8.2%; P = .40), or 24 (3.7% vs 4.6%; P = .73) postoperative hours. No significant differences were observed in mean (SD) Sao2 level between the control and test groups at 6 (94.9% [3.2%] vs 94.9% [2.9%]; P = .99), 12 (95.4% [2.2%] vs 95.1% [2.5%]; P = .40), or 24 (95.7% [2.4%] vs 95.6% [2.4%]; P = .69) postoperative hours. Rates of 30-day postoperative pulmonary complications did not differ between groups (8 patients [7.1%] in the control group vs 4 [3.6%] in the test group; P = .24). Conclusions and Relevance: Postoperative IS did not demonstrate any effect on postoperative hypoxemia, Sao2 level, or postoperative pulmonary complications. Based on these findings, the routine use of IS is not recommended after bariatric surgery in its current implementation. Trial Registration: clinicaltrials.gov Identifier: NCT02431455. PMID- 28097334 TI - The Role of Cardiovascular Implantable Electronic Devices in the Detection and Treatment of Subclinical Atrial Fibrillation: A Review. AB - Importance: Subclinical atrial fibrillation (AF) is associated with an increased risk for stroke. Observations: Subclinical AF is asymptomatic, short in duration, and usually detected with long-term, continuous monitoring. Most prior studies have explored its consequences using cardiovascular implantable electronic devices (CIEDs). Although current prevalence estimates are derived from study populations with prior CIEDs, 3 trials will assess the time to a first AF diagnosis among patients receiving a CIED for purposes of AF detection. Stroke risk estimates are currently limited to patients with a prior CIED and vary widely, ranging from a hazard ratio of 0.87 (95% CI, 0.58-1.31) to 9.40 (95% CI, 1.80-47.00). Stroke risk pathogenesis may include factors that are proximately causal, upstream risk activators, and risk markers. The treatment of subclinical AF may be a useful stroke prevention strategy; however, no direct evidence of benefit from oral anticoagulation exists in this population. Two ongoing trials will assess the risk and benefit of non-vitamin K oral anticoagulants among patients at high risk for stroke with a previously placed implantable CIED, but without a prior diagnosis of clinical AF. If clinical benefit is proven, then the cost-effectiveness of screening for and the treatment of subclinical AF will require additional study. Conclusions and Relevance: At present, no evidence suggests that implanting a CIED to detect AF or initiating oral anticoagulation therapy among those in whom AF is detected is beneficial. Ongoing and future studies will identify people at high risk for developing subclinical AF and will evaluate the efficacy, safety, and economic value of oral anticoagulation therapy in this population. PMID- 28097335 TI - Renaming of Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE) to Acute Multifocal Placoid Choroidopathy (AMP-C). PMID- 28097337 TI - Cancer-Related Depression. PMID- 28097336 TI - Incentive Spirometry After Bariatric Surgery: Yes or No? PMID- 28097339 TI - Concerns About Women's Health. PMID- 28097338 TI - Coping With Uncertainty: Roz, Ray, and the AIDS Epidemic. PMID- 28097340 TI - Bill to Link Rural Physicians With Top Specialists Advances. PMID- 28097341 TI - Augmented Reality Goes Bedside. PMID- 28097342 TI - Second Chances to Improve ESRD Outcomes With a Second-Generation Calcimimetic. PMID- 28097343 TI - Global Burden of Raised Blood Pressure: Coming Into Focus. PMID- 28097344 TI - Strategies for Preventing Folate-Related Neural Tube Defects: Supplements, Fortified Foods, or Both? PMID- 28097345 TI - Patient-Reported Outcomes Following LASIK: Quality of Life in the PROWL Studies. PMID- 28097347 TI - How Would the Next President Ensure Competitiveness in the Health Care Marketplace? PMID- 28097348 TI - Physiologic Aspects of the Working Day Problem. PMID- 28097349 TI - Alternatives in the Evaluation of Suspected Coronary Heart Disease. PMID- 28097350 TI - Alternatives in the Evaluation of Suspected Coronary Heart Disease. PMID- 28097351 TI - Clinical Guidelines for Management of Acne Vulgaris. PMID- 28097352 TI - Alternatives in the Evaluation of Suspected Coronary Heart Disease-Reply. PMID- 28097353 TI - Clinical Guidelines for Management of Acne Vulgaris-Reply. PMID- 28097355 TI - Effect of Etelcalcetide vs Placebo on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: Two Randomized Clinical Trials. AB - Importance: Secondary hyperparathyroidism contributes to extraskeletal complications in chronic kidney disease. Objective: To evaluate the effect of the intravenous calcimimetic etelcalcetide on serum parathyroid hormone (PTH) concentrations in patients receiving hemodialysis. Design, Setting, and Participants: Two parallel, phase 3, randomized, placebo-controlled treatment trials were conducted in 1023 patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism. Trial A was conducted in 508 patients at 111 sites in the United States, Canada, Europe, Israel, Russia, and Australia from March 12, 2013, to June 12, 2014; trial B was conducted in 515 patients at 97 sites in the same countries from March 12, 2013, to May 12, 2014. Interventions: Intravenous administration of etelcalcetide (n = 503) or placebo (n = 513) after each hemodialysis session for 26 weeks. Main Outcomes and Measures: The primary efficacy end point was the proportion of patients achieving greater than 30% reduction from baseline in mean PTH during weeks 20-27. A secondary efficacy end point was the proportion of patients achieving mean PTH of 300 pg/mL or lower. Results: The mean age of the 1023 patients was 58.2 (SD, 14.4) years and 60.4% were men. Mean PTH concentrations at baseline and during weeks 20-27 were 849 and 384 pg/mL vs 820 and 897 pg/mL in the etelcalcetide and placebo groups, respectively, in trial A; corresponding values were 845 and 363 pg/mL vs 852 and 960 pg/mL in trial B. Patients randomized to etelcalcetide were significantly more likely to achieve the primary efficacy end point: in trial A, 188 of 254 (74.0%) vs 21 of 254 (8.3%; P < .001), for a difference in proportions of 65.7% (95% CI, 59.4%-72.1%) and in trial B, 192 of 255 (75.3%) vs 25 of 260 (9.6%; P < .001), for a difference in proportions of 65.7% (95% CI, 59.3%-72.1%). Patients randomized to etelcalcetide were significantly more likely to achieve a PTH level of 300 pg/mL or lower: in trial A, 126 of 254 (49.6%) vs 13 of 254 (5.1%; P < .001), for a difference in proportions of 44.5% (95% CI, 37.8%-51.2%) and in trial B, 136 of 255 (53.3%) vs 12 of 260 (4.6%; P < .001), for a difference in proportions of 48.7% (95% CI, 42.1%-55.4%). In trials A and B, respectively, patients receiving etelcalcetide had more muscle spasms (12.0% and 11.1% vs 7.1% and 6.2% with placebo), nausea (12.4% and 9.1% vs 5.1% and 7.3%), and vomiting (10.4% and 7.5% vs 7.1% and 3.1%). Conclusions and Relevance: Among patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism, use of etelcalcetide compared with placebo resulted in greater reduction in serum PTH over 26 weeks. Further studies are needed to assess clinical outcomes as well as longer-term efficacy and safety. Trial Registration: clinicaltrials.gov Identifiers: NCT01788046. PMID- 28097354 TI - Global Burden of Hypertension and Systolic Blood Pressure of at Least 110 to 115 mm Hg, 1990-2015. AB - Importance: Elevated systolic blood (SBP) pressure is a leading global health risk. Quantifying the levels of SBP is important to guide prevention policies and interventions. Objective: To estimate the association between SBP of at least 110 to 115 mm Hg and SBP of 140 mm Hg or higher and the burden of different causes of death and disability by age and sex for 195 countries and territories, 1990-2015. Design: A comparative risk assessment of health loss related to SBP. Estimated distribution of SBP was based on 844 studies from 154 countries (published 1980 2015) of 8.69 million participants. Spatiotemporal Gaussian process regression was used to generate estimates of mean SBP and adjusted variance for each age, sex, country, and year. Diseases with sufficient evidence for a causal relationship with high SBP (eg, ischemic heart disease, ischemic stroke, and hemorrhagic stroke) were included in the primary analysis. Main Outcomes and Measures: Mean SBP level, cause-specific deaths, and health burden related to SBP (>=110-115 mm Hg and also >=140 mm Hg) by age, sex, country, and year. Results: Between 1990-2015, the rate of SBP of at least 110 to 115 mm Hg increased from 73 119 (95% uncertainty interval [UI], 67 949-78 241) to 81 373 (95% UI, 76 814-85 770) per 100 000, and SBP of 140 mm Hg or higher increased from 17 307 (95% UI, 17 117-17 492) to 20 526 (95% UI, 20 283-20 746) per 100 000. The estimated annual death rate per 100 000 associated with SBP of at least 110 to 115 mm Hg increased from 135.6 (95% UI, 122.4-148.1) to 145.2 (95% UI 130.3-159.9) and the rate for SBP of 140 mm Hg or higher increased from 97.9 (95% UI, 87.5-108.1) to 106.3 (95% UI, 94.6-118.1). For loss of DALYs associated with systolic blood pressure of 140 mm Hg or higher, the loss increased from 95.9 million (95% uncertainty interval [UI], 87.0-104.9 million) to 143.0 million (95% UI, 130.2 157.0 million) [corrected], and for SBP of 140 mm Hg or higher, the loss increased from 5.2 million (95% UI, 4.6-5.7 million) to 7.8 million (95% UI, 7.0 8.7 million). The largest numbers of SBP-related deaths were caused by ischemic heart disease (4.9 million [95% UI, 4.0-5.7 million]; 54.5%), hemorrhagic stroke (2.0 million [95% UI, 1.6-2.3 million]; 58.3%), and ischemic stroke (1.5 million [95% UI, 1.2-1.8 million]; 50.0%). In 2015, China, India, Russia, Indonesia, and the United States accounted for more than half of the global DALYs related to SBP of at least 110 to 115 mm Hg. Conclusions and Relevance: In international surveys, although there is uncertainty in some estimates, the rate of elevated SBP (>=110-115 and >=140 mm Hg) increased substantially between 1990 and 2015, and DALYs and deaths associated with elevated SBP also increased. Projections based on this sample suggest that in 2015, an estimated 3.5 billion adults had SBP of at least 110 to 115 mm Hg and 874 million adults had SBP of 140 mm Hg or higher. PMID- 28097356 TI - Effect of Etelcalcetide vs Cinacalcet on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: A Randomized Clinical Trial. AB - Importance: Secondary hyperparathyroidism contributes to extraskeletal calcification and is associated with all-cause and cardiovascular mortality. Control is suboptimal in the majority of patients receiving hemodialysis. An intravenously (IV) administered calcimimetic could improve adherence and reduce adverse gastrointestinal effects. Objective: To evaluate the relative efficacy and safety of the IV calcimimetic etelcalcetide and the oral calcimimetic cinacalcet. Design, Setting, and Participants: A randomized, double-blind, double dummy active clinical trial was conducted comparing IV etelcalcetide vs oral placebo and oral cinacalcet vs IV placebo in 683 patients receiving hemodialysis with serum parathyroid hormone (PTH) concentrations higher than 500 pg/mL on active therapy at 164 sites in the United States, Canada, Europe, Russia, and New Zealand. Patients were enrolled from August 2013 to May 2014, with end of follow up in January 2015. Interventions: Etelcalcetide intravenously and oral placebo (n = 340) or oral cinacalcet and IV placebo (n = 343) for 26 weeks. The IV study drug was administered 3 times weekly with hemodialysis; the oral study drug was administered daily. Main Outcomes and Measures: The primary efficacy end point was noninferiority of etelcalcetide at achieving more than a 30% reduction from baseline in mean predialysis PTH concentrations during weeks 20-27 (noninferiority margin, 12.0%). Secondary end points included superiority in achieving biochemical end points (>50% and >30% reduction in PTH) and self reported nausea or vomiting. Results: The mean (SD) age of the trial participants was 54.7 (14.1) years and 56.2% were men. Etelcalcetide was noninferior to cinacalcet on the primary end point. The estimated difference in proportions of patients achieving reduction in PTH concentrations of more than 30% between the 198 of 343 patients (57.7%) randomized to receive cinacalcet and the 232 of 340 patients (68.2%) randomized to receive etelcalcetide was -10.5% (95% CI, -17.5% to -3.5%, P for noninferiority, <.001; P for superiority, .004). One hundred seventy-eight patients (52.4%) randomized to etelcalcetide achieved more than 50% reduction in PTH concentrations compared with 138 patients (40.2%) randomized to cinacalcet (P = .001; difference in proportions, 12.2%; 95% CI, 4.7% to 19.5%). The most common adverse effect was decreased blood calcium (68.9% vs 59.8%). Conclusions and Relevance: Among patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism, the use of etelcalcetide was not inferior to cinacalcet in reducing serum PTH concentrations over 26 weeks; it also met superiority criteria. Further studies are needed to assess clinical outcomes as well as longer-term efficacy and safety. Trial Registration: clinicaltrials.gov Identifier: NCT1896232. PMID- 28097357 TI - Folic Acid Supplementation for Prevention of Neural Tube Defects. PMID- 28097359 TI - Aspects of Ending a Lifelong Dream. PMID- 28097361 TI - Folic Acid Supplementation for the Prevention of Neural Tube Defects: An Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. AB - Importance: Neural tube defects are among the most common congenital anomalies in the United States. Periconceptional folic acid supplementation is a primary care relevant preventive intervention. Objective: To review the evidence on folic acid supplementation for preventing neural tube defects to inform the US Preventive Services Task Force for an updated Recommendation Statement. Data Sources: MEDLINE, Cochrane Library, EMBASE, and trial registries through January 28, 2016, with ongoing surveillance through November 11, 2016; references; experts. Study Selection: English-language studies of folic acid supplementation in women. Excluded were poor-quality studies; studies of prepubertal girls, men, women without the potential for childbearing, and neural tube defect recurrence; and studies conducted in developing countries. Data Extraction and Synthesis: Two investigators independently reviewed abstracts, full-text articles, and risk of bias of included studies. One investigator extracted data and a second checked accuracy. Because of heterogeneity, data were not pooled. Main Outcomes and Measures: Neural tube defects, harms of treatment (twinning, respiratory outcomes). Results: A total of 24 studies (N > 58 860) were included. In 1 randomized clinical trial from Hungary initiated in 1984, incidence of neural tube defects for folic acid supplementation compared with trace element supplementation was 0% vs 0.25% (Peto odds ratio [OR], 0.13 [95% CI, 0.03-0.65]; n = 4862). Odds ratios from cohort studies recruiting participants between 1984 and 1996 demonstrated beneficial associations and ranged from 0.11 to 0.27 (n = 19 982). Three of 4 case-control studies with data from 1976 through 1998 reported ORs ranging from 0.6 to 0.7 (n > 7121). Evidence of benefit led to food fortification in the United States beginning in 1998, after which no new prospective studies have been conducted. More recent case-control studies drawing from data collected after 1998 have not demonstrated a protective association consistently with folic acid supplementation, with ORs ranging from 0.93 to 1.4 and confidence intervals spanning the null (n > 13 990). Regarding harms, 1 trial (OR, 1.40 [95% CI, 0.89-2.21]; n = 4767) and 1 cohort study (OR, 1.04 [95% CI, 0.91-1.18]; n = 2620) found no statistically significant increased risk of twinning. Three systematic reviews found no consistent evidence of increased risk of asthma (OR, 1.06 [95% CI, 0.99-1.14]; n = 14 438), wheezing, or allergy. Conclusions and Relevance: In studies conducted before the initiation of food fortification in the United States in 1998, folic acid supplementation provided protection against neural tube defects. Newer postfortification studies have not demonstrated a protective association but have the potential for misclassification and recall bias, which can attenuate the measured association of folic acid supplementation with neural tube defects. PMID- 28097362 TI - Folic Acid Supplementation for the Prevention of Neural Tube Defects: US Preventive Services Task Force Recommendation Statement. AB - Importance: Neural tube defects are among the most common major congenital anomalies in the United States and may lead to a range of disabilities or death. Daily folic acid supplementation in the periconceptional period can prevent neural tube defects. However, most women do not receive the recommended daily intake of folate from diet alone. Objective: To update the 2009 US Preventive Services Task Force (USPSTF) recommendation on folic acid supplementation in women of childbearing age. Evidence Review: In 2009, the USPSTF reviewed the effectiveness of folic acid supplementation in women of childbearing age for the prevention of neural tube defects in infants. The current review assessed new evidence on the benefits and harms of folic acid supplementation. Findings: The USPSTF assessed the balance of the benefits and harms of folic acid supplementation in women of childbearing age and determined that the net benefit is substantial. Evidence is adequate that the harms to the mother or infant from folic acid supplementation taken at the usual doses are no greater than small. Therefore, the USPSTF reaffirms its 2009 recommendation. Conclusions and Recommendation: The USPSTF recommends that all women who are planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400-800 ug) of folic acid. (A recommendation). PMID- 28097363 TI - The Rise of Altmetrics. PMID- 28097365 TI - Drop in Preventable Cancer Deaths. PMID- 28097364 TI - Modest Obesity Reduction In Low-Income Kids. PMID- 28097366 TI - Statin Eligibility Under American and European Cholesterol Guidelines. PMID- 28097367 TI - Impaired Glucose Homeostasis in First-Episode Schizophrenia: A Systematic Review and Meta-analysis. AB - Importance: Schizophrenia is associated with an increased risk of type 2 diabetes. However, it is not clear whether schizophrenia confers an inherent risk for glucose dysregulation in the absence of the effects of chronic illness and long-term treatment. Objective: To conduct a meta-analysis examining whether individuals with first-episode schizophrenia already exhibit alterations in glucose homeostasis compared with controls. Data Sources: The EMBASE, MEDLINE, and PsycINFO databases were systematically searched for studies examining measures of glucose homeostasis in antipsychotic-naive individuals with first episode schizophrenia compared with individuals serving as controls. Study Selection: Case-control studies reporting on fasting plasma glucose levels, plasma glucose levels after an oral glucose tolerance test, fasting plasma insulin levels, insulin resistance, and hemoglobin A1c (HbA1c) levels in first episode antipsychotic-naive individuals with first-episode schizophrenia compared with healthy individuals serving as controls. Two independent investigators selected the studies. Data Extraction: Two independent investigators extracted study-level data for a random-effects meta-analysis. Standardized mean differences in fasting plasma glucose levels, plasma glucose levels after an oral glucose tolerance test, fasting plasma insulin levels, insulin resistance, and HbA1c levels were calculated. Sensitivity analyses examining the effect of body mass index, diet and exercise, race/ethnicity, and minimal (<=2 weeks) antipsychotic exposure were performed. Data Synthesis: Of 3660 citations retrieved, 16 case-control studies comprising 15 samples met inclusion criteria. The overall sample included 731 patients and 614 controls. Fasting plasma glucose levels (Hedges g = 0.20; 95% CI, 0.02 to 0.38; P = .03), plasma glucose levels after an oral glucose tolerance test (Hedges g = 0.61; 95% CI, 0.16 to 1.05; P = .007), fasting plasma insulin levels (Hedges g = 0.41; 95% CI, 0.09 to 0.72; P = .01), and insulin resistance (homeostatic model assessment of insulin resistance) (Hedges g = 0.35; 95% CI, 0.14 to 0.55; P = .001) were all significantly elevated in patients compared with controls. However, HbA1c levels (Hedges g = -0.08; CI, 0.34 to 0.18; P = .55) were not altered in patients compared with controls. Conclusions and Relevance: These findings show that glucose homeostasis is altered from illness onset in schizophrenia, indicating that patients are at increased risk of diabetes as a result. This finding has implications for the monitoring and treatment choice for patients with schizophrenia. PMID- 28097369 TI - Photocatalytic Degradation of Contaminants with Titanium Dioxide: A 40-Year Retrospective on the Paper by John Carey and Colleagues Published in BECT. PMID- 28097370 TI - Osseointegrated prosthesis for patients with an amputation : Multidisciplinary team approach in the Netherlands. AB - This article reviews the development of multidisciplinary osseointegration treatment in the Netherlands since its start in 2009. People experiencing limitations due to their socket prosthesis after a leg amputation present to the Radboud University Nijmegen Medical Centre for an osseointegration implant or "bone-anchored" prosthesis. In this article we share our experience with the first 100 patients regarding referral pattern, selection criteria, available osseointegration systems, preoperative planning, surgical treatment, the rehabilitation protocol, outcome measurement, revision surgery, and future developments. PMID- 28097368 TI - Incidence of and Risk Factors for Skin Cancer in Organ Transplant Recipients in the United States. AB - Importance: Skin cancer is the most common malignancy occurring after organ transplantation. Although previous research has reported an increased risk of skin cancer in solid organ transplant recipients (OTRs), no study has estimated the posttransplant population-based incidence in the United States. Objective: To determine the incidence and evaluate the risk factors for posttransplant skin cancer, including squamous cell carcinoma (SCC), melanoma (MM), and Merkel cell carcinoma (MCC) in a cohort of US OTRs receiving a primary organ transplant in 2003 or 2008. Design, Setting, and Participants: This multicenter retrospective cohort study examined 10 649 adult recipients of a primary transplant performed at 26 centers across the United States in the Transplant Skin Cancer Network during 1 of 2 calendar years (either 2003 or 2008) identified through the Organ Procurement and Transplantation Network (OPTN) database. Recipients of all organs except intestine were included, and the follow-up periods were 5 and 10 years. Main Outcomes and Measures: Incident skin cancer was determined through detailed medical record review. Data on predictors were obtained from the OPTN database. The incidence rates for posttransplant skin cancer overall and for SCC, MM, and MCC were calculated per 100 000 person-years. Potential risk factors for posttransplant skin cancer were tested using multivariate Cox regression analysis to yield adjusted hazard ratios (HR). Results: Overall, 10 649 organ transplant recipients (mean [SD] age, 51 [12] years; 3873 women [36%] and 6776 men [64%]) contributed 59 923 years of follow-up. The incidence rates for posttransplant skin cancer was 1437 per 100 000 person-years. Specific subtype rates for SCC, MM, and MCC were 812, 75, and 2 per 100 000 person-years, respectively. Statistically significant risk factors for posttransplant skin cancer included pretransplant skin cancer (HR, 4.69; 95% CI, 3.26-6.73), male sex (HR, 1.56; 95% CI, 1.34-1.81), white race (HR, 9.04; 95% CI, 6.20-13.18), age at transplant 50 years or older (HR, 2.77; 95% CI, 2.20-3.48), and being transplanted in 2008 vs 2003 (HR, 1.53; 95% CI, 1.22-1.94). Conclusions and Relevance: Posttransplant skin cancer is common, with elevated risk imparted by increased age, white race, male sex, and thoracic organ transplantation. A temporal cohort effect was present. Understanding the risk factors and trends in posttransplant skin cancer is fundamental to targeted screening and prevention in this population. PMID- 28097371 TI - High Resolution Diffusion-Weighted Imaging for Solitary Orbital Tumors : 3D Turbo Field Echo with Diffusion-Sensitized Driven-Equilibrium (DSDE-TFE) Preparation Technique. AB - PURPOSE: To differentiate cystic from solid solitary intraorbital tumors using 3D turbo field echo with diffusion-sensitized driven-equilibrium preparation without contrast material. MATERIALS AND METHODS: This retrospective study was approved by our institutional review boards, and written informed consent was waived. A total of 26 patients with intraorbital tumors were studied. Motion probing gradients were conducted at one direction with b-values of 0 and 500 s/mm2. The voxel size was 1.5 * 1.5 * 1.5 mm3, and acquisition time was 5 min 22 s. Additionally, fat-suppressed T2-weighted imaging (T2WI) and T1WI were obtained. The apparent diffusion coefficients (ADC) of the lesions were measured. Signal intensity on conventional magnetic resonance imaging (MRI) compared to normal appearing white matter was also measured. Statistical analysis was performed with Mann-Whitney U-test, the Steel-Dwass test and the receiver operating characteristic (ROC) analysis. RESULTS: There were 10 cystic (7 dermoids, 2 epidermoids, and 1 cystadenoma) and 16 solid (8 cavernous hemangiomas, 6 pleomorphic adenomas, 1 adenocarcinoma, and 1 sebaceous carcinoma) tumors. The ADC of the cystic tumors (mean +/- SD; 2.21 +/- 0.76 * 10-3 mm2/s) was statistically significantly lower than that of solid tumors (1.43 +/- 0.41 * 10-3 mm2/s; P < 0.05).; however, there were no statistically significant differences on conventional MRI (P > 0.05). There were no statistically significant differences among tumor subtypes in all parameters (P > 0.05). The ROC analysis showed the best diagnostic performance with ADC (Az = 0.77). CONCLUSION: With its insensitivity to field inhomogeneity and high spatial resolution, the 3D DSDE-TFE technique enabled us to discriminate cystic tumors from solid tumors. PMID- 28097373 TI - Vaccination of allogeneic hematopoietic stem cell transplant recipients-what should be considered? PMID- 28097375 TI - Hypoxia-Induced Fibroblast Growth Factor 11 Stimulates Osteoclast-Mediated Resorption of Bone. AB - Over-activation of osteoclasts is directly responsible for pathological bone loss in conditions such as rheumatoid arthritis and cancer metastasis to bone. Hypoxia is a common feature of these conditions, associated with poor prognosis, which also stimulates osteoclast-mediated bone resorption via induction of the hypoxia inducible transcription factor HIF-1alpha. Here, we investigate the effects of fibroblast growth factor 11 (FGF11) on osteoclast function. FGF11 is an intracellular FGF that was induced both by hypoxia (2% O2, p < 0.01) and by inhibition of the HIF-regulating prolyl hydroxylase enzymes (CoCl2, p < 0.001) in osteoclasts. Isoform-specific siRNA demonstrated that the induction of Fgf11 mRNA expression by hypoxia is HIF-1alpha-dependent (p < 0.01). Hypoxic stimulation of bone resorption was inhibited in osteoclasts treated with siRNA targeting FGF11 (p < 0.05). This was at least partially due to reduced secretion of an unidentified pro-resorptive factor downstream of FGF11. FGF11 expression within hypoxic, resorbing osteoclasts co-localised with microtubule-associated alpha tubulin. FGF11 was also abundantly expressed in osteoclasts within the rheumatoid synovium and in giant cell tumour of bone. This study suggests FGF11 as a novel factor driving pathological bone resorption in osteolytic disease and as a potential target for the development of new anti-resorptive therapeutic agents. PMID- 28097372 TI - The role of neuropeptides in adverse myocardial remodeling and heart failure. AB - In addition to traditional neurotransmitters of the sympathetic and parasympathetic nervous systems, the heart also contains numerous neuropeptides. These neuropeptides not only modulate the effects of neurotransmitters, but also have independent effects on cardiac function. While in most cases the physiological actions of these neuropeptides are well defined, their contributions to cardiac pathology are less appreciated. Some neuropeptides are cardioprotective, some promote adverse cardiac remodeling and heart failure, and in the case of others their functions are unclear. Some have both cardioprotective and adverse effects depending on the specific cardiac pathology and progression of that pathology. In this review, we briefly describe the actions of several neuropeptides on normal cardiac physiology, before describing in more detail their role in adverse cardiac remodeling and heart failure. It is our goal to bring more focus toward understanding the contribution of neuropeptides to the pathogenesis of heart failure, and to consider them as potential therapeutic targets. PMID- 28097376 TI - Elemental labelling and mass spectrometry for the specific detection of sulfenic acid groups in model peptides: a proof of concept. AB - Oxidative transformation of cysteine thiol groups into different functional groups is considered a significant posttranslational modification of great importance in pathological and physiological processes. A cysteine sulfenic acid (SA) residue is the transient state for thiol group oxidation and it can react with free thiols to form disulfide bonds or can be further oxidized with reactive oxygen/reactive nitrogen species (ROS/RNS) to form sulfinic and sulfonic acids. The increase in ROS/RNS concentrations is correlated to age-related diseases such as cancer and Alzheimer's disease. Since the formation of SA represents a transient state of oxidation of thiols, its formation can be considered a redox sensitive sensor for the presence of ROS/RNS. Thereby, the detection of the short lived SA will provide greater insight into the redox-mediated events that alter the structure and function of peptides and proteins. The aim of this study is to provide a new strategy for the highly sensitive and specific detection of SA in peptides as a proof of concept. For this aim, SA was firstly generated in model peptides on oxidation with H2O2 and then captured by the linear alkyne beta ketoester (KE) previously linked to a lanthanide (Ln)-containing chelator (Ln DOTA, where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). The linking of the KE to DOTA was performed by click chemistry, resulting in a new reagent (Ln-DOTA-KE) that permits highly sensitive elemental (inductively coupled plasma) and molecular (electrospray) mass spectrometric detection. The new reagent (Ln-DOTA-KE) reacts specifically with SA, offering improved reactivity at physiological pH, facile derivatization and a cell-membrane permeable compound that has promising future applications. Graphical Abstract A new derivatizing reagent for specific detection of sulphenic acid (SA) generated in model peptides by oxidation of cysteine groups is presented in this work. PMID- 28097374 TI - Effects of 5-HT1A, 5-HT2A and 5-HT2C receptor agonists and antagonists on responding for a conditioned reinforcer and its enhancement by methylphenidate. AB - OBJECTIVES: These experiments examined the effects of selective 5-HT1A, 5-HT2A and 5-HT2C receptor ligands on responding for a conditioned reinforcer (CRf). Effects of these ligands were measured under basal conditions and following elevated dopamine (DA) activity produced by the DA reuptake inhibitor methylphenidate. METHODS: Water-restricted rats learned to associate a conditioned stimulus (CS) with water in operant chambers. Subsequently, two response levers were made available; responding on one lever delivered the CS (now a CRf), while responding on the second lever had no consequences. The effects of agonist and antagonists of 5-HT1A (8-hydroxy-2(di-n propylamino)tetralin hydrobromide (8-OH-DPAT) and N-[2-[4-(2-methoxyphenyl)-1 piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY100635)), 5-HT2A (DOI and M100907) and 5-HT2C (Ro60-0175 and SB242084) receptors on responding were examined alone, as well as in the presence of methylphenidate. RESULTS: Responding for a CRf was reduced by the agonists 8-OH-DPAT, DOI and Ro60-0175. 8 OH-DPAT also reduced responding for water and seemed to impair responding in a non-specific fashion. None of the receptor antagonists affected responding. Methylphenidate dose-dependently enhanced responding for a CRf, and this was attenuated by DOI and Ro60-0175. Conversely, the 5-HT2C receptor antagonist SB242084 potentiated the effect of methylphenidate. CONCLUSIONS: No evidence was found for a behaviourally selective effect of 5-HT1A receptor ligands on responding for a CRf. Activation of 5-HT2A receptors selectively inhibits responding for a CRf. 5-HT2C receptor ligands exerted bidirectional modulation of responding for a CRf, especially when DA activity was increased. This indicates that 5-HT2C receptor activity is an important modulator of DA-dependent reward related behaviours. PMID- 28097377 TI - [The Olympic motto of pathology]. PMID- 28097378 TI - [Molecular pathogenesis of Duchenne muscular dystrophy-related fibrosis]. AB - Progressive myofibrosis plays a key role in Duchenne muscular dystrophy. The dystrophic loss of contractile cells triggers a relatively nonspecific restructuring of the surrounding mesenchyme. The increase in connective and fatty tissue leads to muscular weakness and is therefore of critical importance for the cellular pathogenesis of muscular dystrophy. The systematic biochemical analysis of fibrosis using comparative proteomics has identified a number of extracellular matrix proteins that are indirectly involved in muscular dystrophy. An increased concentration was established for collagen I, collagen IV, collagen VI, periostin, dermatopontin, fibronectin, biglycan, asporin, decorin, prolargin, mimecan and lumican. Based on these findings, the identified matrix proteins can now be characterized biochemically and their exact pathophysiological role in Duchenne muscular dystrophy determined. PMID- 28097379 TI - T1 bright appendix sign to exclude acute appendicitis in pregnant women. AB - OBJECTIVE: To evaluate the diagnostic value of the T1 bright appendix sign for the diagnosis of acute appendicitis in pregnant women. MATERIAL AND METHODS: This retrospective study included 125 pregnant women with suspected appendicitis who underwent magnetic resonance (MR) imaging. The T1 bright appendix sign was defined as a high intensity signal filling more than half length of the appendix on T1-weighted imaging. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the T1 bright appendix sign for normal appendix identification were calculated in all patients and in those with borderline-sized appendices (6-7 mm). RESULTS: The T1 bright appendix sign was seen in 51% of patients with normal appendices, but only in 4.5% of patients with acute appendicitis. The overall sensitivity, specificity, PPV, and NPV of the T1 bright appendix sign for normal appendix diagnosis were 44.9%, 95.5%, 97.6%, and 30.0%, respectively. All four patients with borderline sized appendix with appendicitis showed negative T1 bright appendix sign. CONCLUSION: The T1 bright appendix sign is a specific finding for the diagnosis of a normal appendix in pregnant women with suspected acute appendicitis. KEY POINTS: * Magnetic resonance imaging is increasingly used in emergency settings. * Acute appendicitis is the most common cause of acute abdomen. * Magnetic resonance imaging is widely used in pregnant population. * T1 bright appendix sign can be a specific sign representing normal appendix. PMID- 28097380 TI - Successful treatment of pouchitis with Vedolizumab, but not fecal microbiota transfer (FMT), after proctocolectomy in ulcerative colitis. PMID- 28097381 TI - Rotating night shift work, sleep, and colorectal adenoma in women. AB - PURPOSE: This study aims to investigate the associations of rotating night shift work history and sleep duration with risk of colorectal adenoma. METHODS: We evaluated 56,275 cancer-free participants of the Nurses' Health Study II, who had their first colonoscopy or sigmoidoscopy between 1991 and 2011; rotating night shift work and sleep duration were reported by mailed questionnaire. Multivariable-adjusted logistic regression was used to estimate relative risks (RR) of colorectal adenoma, with 95% confidence intervals (CI), across categories of rotating night shift work history (none, 1-4, 5-9, and >=10 years) and sleep duration (<=5, 6, 7, 8, and >=9 h/day). RESULTS: We found no association between duration of rotating night shift work and occurrence of colorectal adenoma (p trend across shift work categories = 0.5). Women with the longest durations of rotating night shift work (>=10 years) had a similar risk of adenoma compared to women without a history of rotating night shift work (multivariable-adjusted RR = 0.96, 95% CI = 0.83-1.11). Similarly, there were no associations of shorter or longer sleep durations with adenoma risk (p-trend = 0.2 across sleep durations of <=5 through 7 h/day and p-trend = 0.5 across sleep durations of 7 through >=9 h/day). Results were similar when we examined associations according to adenoma location and subtype. CONCLUSIONS: Our results do not support an association between rotating night shift work or sleep duration and risk of colorectal adenoma in women. PMID- 28097382 TI - Ventriculoperitoneal shunt malfunction caused by fractures and disconnections over 10 years of follow-up. AB - PURPOSE: We have discussed the diagnosis and treatment approaches in patients with discontinued (disconnected or fractured) ventriculoperitoneal (VP) shunts that caused mechanical dysfunction. METHODS: Between 2006 and 2016, VP shunt surgery was performed on 1357 pediatric patients in our clinic. In follow-up examinations, we retrospectively reviewed patients who underwent revision surgery. Except for diagnosis of discontinued VP shunt, by excluding revision surgery patients, only those patients who underwent surgical treatment owing to discontinued (fracture or disconnection) catheter were included in the study. Age at first surgery, sex, reason for shunt discontinuity, anatomical region of pathology, time to discontinuity diagnosis after first surgery, and presence or absence of symptoms were evaluated. RESULTS: One thousand three hundred fifty seven VP shunt surgeries were performed in total, with 305 (22.4%) patients requiring revision surgery. Of these 305 patients, after accounting for other complications like obstruction, infection, overdrainage, and so on, 25 (8.1%) patients (14 male, 11 female) required re-surgery due to discontinuity. The mean age of these patients was 5.4 +/- 2.1 months during the first VP shunt surgery, and the mean age during revision surgery was 71.7 months. The mean duration until discontinuity was diagnosed was 66.3 +/- 24.1 months (76.1 months for catheter fractures and 45.6 months for disconnections (p 0.021)). CONCLUSION: Disconnection and fracture are two significant mechanical VP shunt dysfunctions and must be adequately researched and understood even during routine follow-ups. A disconnected or fractured shunt may be working and it is not safe to state that the shunt is no longer needed. PMID- 28097384 TI - Stress response physiology of thermophiles. AB - Thermo (or hyperthermo) philic microorganisms are ubiquitous having a wide range of habitats from freshly fallen snow to pasteurized milk to geothermal areas like hot springs. The variations in physicochemical conditions, viz., temperature, pH, nutrient availability and light intensity in the habitats always pose stress conditions for the inhabitants leading to slow growth or cell death. The industrial processes used for harvesting secondary metabolites such as enzymes, toxins and organic acids also create stressed environments for thermophiles. The production of DNA-binding proteins, activation of reactive oxygen species detoxification system, compatible solute accumulation, expression of heat shock proteins and alterations in morphology are a few examples of physiological changes demonstrated by these microscopic lifeforms in stress. These microorganisms exhibit complex genetic and physiological changes to minimize, adapt to and repair damage caused by extreme environmental disturbances. These changes are termed as 'stress responses' which enable them to stabilize their homeostasis. The exploration of important thermophilic factors would pave the way in engineering the microbial strains for various biotechnological applications. This review article presents a picture of physiological responses of thermophiles against various stress conditions as their mechanisms to respond to stress make them model organisms to further explore them for basic and applied biology purposes. PMID- 28097385 TI - Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer. AB - PURPOSE: This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor. METHODS: Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125-16 mg/m2/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Pharmacokinetic (PK) evaluations were performed. Exploratory PK/pharmacodynamic analyses investigated the relationship between litronesib plasma exposure and changes in phosphohistone H3 (pHH3) levels. RESULTS: One hundred and seventeen patients with advanced malignancies were enrolled. Neutropenia was the primary dose-limiting toxicity. Prophylactic pegfilgrastim reduced neutropenia frequency and severity, allowing administration of higher litronesib doses, but increases in the incidences of mucositis and stomatitis were observed. Among 86 response-evaluable patients, 2 patients (2%) achieved partial response, both on the Days 1, 2, 3 regimen (5 and 6 mg/m2/day with pegfilgrastim), and 17 patients (20%) maintained stable disease for >=6 cycles. Dose-dependent increases in litronesib plasma exposure were observed, with minor intra- and inter-cycle accumulation, along with exposure dependent increases in pHH3 expression in tumor and skin biopsies. CONCLUSIONS: On the basis of the results of these studies, two regimens were selected for Phase 2 exploration: 6 mg/m2/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/m2/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle. PMID- 28097386 TI - Biomechanical analysis of clavicle hook plate implantation with different hook angles in the acromioclavicular joint. AB - PURPOSE: A clavicle hook plate is a simple and effective method for treating acromioclavicular dislocation and distal clavicle fractures. However, subacromial osteolysis and peri-implant fractures are complicated for surgeons to manage. This study uses finite element analysis (FEA) to investigate the post implantation biomechanics of clavicle hook plates with different hook angles. METHODS: This FEA study constructed a model with a clavicle, acromion, clavicle hook plate, and screws to simulate the implantation of clavicle hook plates at different hook angles (90 degrees , 95 degrees , 100 degrees , 105 degrees , and 110 degrees ) for treating acromioclavicular joint dislocations. This study investigated the biomechanics of the acromion, clavicle, hook plate, and screws. RESULTS: A smaller hook angle increases the stress on the middle third of the clavicle. A larger hook angle increases the force exerted by the clavicle hook plate on the acromion. The screw at the most medial position on the plate generated the highest stress. The highest stress on the implanted clavicle hook plate was on the turning corner of the hook. CONCLUSIONS: A clavicle hook plate with different hook angles may induce different biomechanical behaviors in the clavicle and acromion. Orthopedic surgeons must select a suitable clavicle hook plate based on the anatomical structure of each patient. PMID- 28097387 TI - All dual mobility cups are not the same. AB - PURPOSE: Although the natural history of dual mobility has been exclusively borne for 20 years by a single company (due to industrial ownership), the concept has undeniably been very widely popularised with nearly 40 cups on the French market which should be regarded as a weight bearing surface, both broadly and in their own right. However, within the same original idea, these implants are not all identical (design, material, fixation ect.).The aim of this work is to propose a classification of different dual mobility cups by distinguishing between thegeneral characteristics of a conventional cup and those particular to this type of implant. METHODS: By comparison with a standard metal-back cup, dual mobility is based on at least one additional interface corresponding to the mobility of the polyethylene insert in the concavity of the acetabular cup called the outersurface. Design, constitutive material, fixation of the cup and characteristics of the retentive insert are analysed through the published results. RESULTS: The complications associated, in particular, the intraprosthetic dislocation and to a lesser extent fixation failures undoubtedly condemned the dissemination of the dual mobility concept, as witnessed by the fact that despite the precedence of this 40-year old concept, the overriding majority of publications (more than 95%) have only appeared in the last ten years. CONCLUSION: The latest generation of dual mobility cups combines: 1) a cast chrome-cobalt alloy cup covered with a bilayer coating of porous titanium and hydroxyapatite for long-term press-fit fixation to 2) an insert designed to eliminate all of the risks of intraprosthetic dislocation, whilst keeping all of the elasticity properties of the polyethylene, which has demonstrated its medium and long term effectiveness on preventing instability by overcoming other complications. PMID- 28097388 TI - Percutaneous omental biopsy: efficacy and complications. AB - PURPOSE: To determine the efficacy and safety of percutaneous omental biopsy. METHODS: Retrospective review was performed of all 181 percutaneous omental biopsies performed at a single institution between 9/18/2002 and 2/12/2016. Mean patient age was 67 (+/-14) years, and 114 (63%) patients were female. Biopsy results were compared to subsequent surgical pathology and paracentesis cytology, when available, and cases were further evaluated based on the imaging appearance of the omental abnormality. Complications were classified using Society of Interventional Radiology (SIR) consensus guidelines. RESULTS: Of the 181 cases, histopathology was positive for malignancy in 166 (92%) patients and showed benign inflammation/fibrosis in 15 (8%) patients. Seventy-three (40%) patients underwent subsequent surgery, and omental malignancy was diagnosed in every case. Percutaneous omental biopsy and surgical pathology results were concordant in all but 1 case (diagnostic accuracy of 99%). In contrast, the accuracy of paracentesis cytology in surgically confirmed malignant cases was only 76% (p = 0.004). Biopsy was positive for malignancy in 95% of patients with omental caking, 92% with omental nodularity, 80% with a single omental nodule, and 20% with omental thickening (p = <0.001). In 118 (65%) patients, a previously unknown (new or additional) malignancy was diagnosed. No clinically significant complications occurred. CONCLUSIONS: Percutaneous biopsy is an effective and safe method to evaluate omental abnormalities. Omental biopsy is more sensitive than paracentesis cytology for determining malignancy. Omental malignancy is more likely as the abnormality advances through the spectrum of imaging appearances from omental thickening to omental caking. PMID- 28097389 TI - Observation time after outpatient non-arterial interventional procedures: standards, safety, and outcomes. AB - PURPOSE: To evaluate the impact of standardized reduced post-procedure observation time on subsequent healthcare encounters such as emergency department (ED) visits, hospital admissions, and clinic visits. METHODS: 800 consecutive patients undergoing outpatient non-arterial interventional radiologic procedures within the vascular interventional department between 1 June 2013 and 21 July 2014 were included in this IRB-approved, HIPAA-compliant single center observational retrospective study. Electronic medical records were reviewed for subsequent healthcare encounters, such as ED visits, hospital admissions, and clinic visits. An attending interventional radiologist and radiology resident reviewed, in consensus, medical records for relevance of the encounter to the index procedure. Procedure-related encounters were analyzed to determine relationship to length of observation time, using Matlab for statistical analysis. RESULTS: 397 and 403 patients were in the pre- and post-standardization groups, respectively. Median observation time decreased overall from 1.67 h [interquartile range (IQR) 1.17-2.17] to 1.42 h (IQR 1.08-1.92), p < 0.001. There was no significant change in either overall or procedure-related ED visits (16.6% [66/397] and 1.0% [4/397] pre-standardization vs. 20.1% [81/403] and 2.2% [9/403] post-standardization, p = 0.24 and 0.26), hospital admissions (27.7% [110/397] and 4.0% [16/397] prestandardization vs. 28.3% [114/403] and 2.7% [11/403] post standardization, p = 0.88 and 0.33), or clinic visits (41.3% [164/397] and 1.0% [4/397] pre-standardization vs. 39.5% [159/403] and 2.2% [9/403] post standardization, p = 0.61 and 0.26). CONCLUSION: Proposed standardized shortened observation times after outpatient interventional radiologic procedures are safe, without change in either total or procedure-related ED visits, hospital admissions, or clinic visits. PMID- 28097391 TI - [Tapering and termination of immunosuppressive therapy : Systemic lupus erythematosus]. AB - Similar to patients with other rheumatic diseases, patients with systemic lupus erythematosus (SLE) nowadays can also have the desire to terminate immunosuppressive and immunomodulatory medications. In order to provide appropriate advice to patients, the two main issues are the risk of severe adverse events under long-term therapy with any drug and the perceived risk of a flare, in particular of severe flares. The risks of long-term therapy vary greatly between drugs, ranging from severe unacceptable risks with cyclophosphamide and higher dose glucocorticoids to low risks usually outweighed by long-term benefits with hydroxychloroquine. The individual risk of flares is often difficult to estimate but clinical remission and at least 3 years of immunosuppression are recommended for lupus nephritis. The duration of remission can also be shorter in cases of milder forms of disease. This review article tries to put the available evidence into a clinical perspective and to derive concrete recommendations. PMID- 28097392 TI - [Tapering and termination of immunosuppressive therapy]. PMID- 28097390 TI - A role of PLC/PKC-dependent pathway in GLP-1-stimulated insulin secretion. AB - Glucagon-like peptide-1 (GLP-1) is an endogenous glucose-lowering hormone and GLP 1 receptor agonists are currently being used as antidiabetic drugs clinically. The canonical signalling pathway (including cAMP, Epac2, protein kinase A (PKA) and KATP channels) is almost universally accepted as the main mechanism of GLP-1 stimulated insulin secretion. This belief is based on in vitro studies that used nanomolar (1-100 nM) concentrations of GLP-1. Recently, it was found that the physiological concentrations (1-10 pM) of GLP-1 also stimulate insulin secretion from isolated islets, induce membrane depolarization and increase of intracellular [Ca2+] in isolated beta cells/pancreatic islets. These responses were unaffected by PKA inhibitors and occurred without detectable increases in intracellular cAMP and PKA activity. These PKA-independent actions of GLP-1 depend on protein kinase C (PKC), involve activation of the standard GLP-1 receptor (GLP1R) and culminate in activation of phospholipase C (PLC), leading to an elevation of diacylglycerol (DAG), increased L-type Ca2+ and TRPM4/TRPM5 channel activities. Here, we review these recent data and contrast them against the effects of nanomolar concentrations of GLP-1. The differential intracellular signalling activated by low and high concentrations of GLP-1 could provide a clue to explain how GLP-1 exerts different function in the central nervous system and peripheral organs. PMID- 28097393 TI - Comparative efficacy and safety of baricitinib 2 mg and 4 mg in patients with active rheumatoid arthritis : A Bayesian network meta-analysis of randomized controlled trials. AB - OBJECTIVE: This study aimed to assess the relative efficacy and safety of once daily baricitinib 2 mg and 4 mg administration in patients with active rheumatoid arthritis (RA). METHODS: In this network meta-analysis, randomized controlled trials (RCTs) examining the efficacy and safety of baricitinib in patients with active RA were included. A Bayesian network meta-analysis was conducted to combine the direct and indirect evidence from the RCTs. RESULTS: Seven RCTs involving 3461 patients met the inclusion criteria. There were ten pairwise comparisons, including seven direct comparisons and five interventions. The ACR20 response rate was significantly higher in the baricitinib 4 mg in combination with disease-modifying antirheumatic drugs (DMARD) group than in the placebo+DMARD group (odds ratio, OR 3.13; 95% credible interval, CrI 2.32-4.33). Compared with the placebo+DMARD group, the baricitinib 4 mg, baricitinib 2 mg + DMARD, and adalimumab 40 mg + methotrexate (MTX) groups showed a significantly higher ACR20 response rate. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that baricitinib 4 mg + DMARD was likely to elicit the best ACR20 response rate (SUCRA = 0.7930), followed by baricitinib 4 mg (SUCRA = 0.7034), baricitinib 2 mg + DMARD (SUCRA = 0.6304), adalimumab 40 mg + MTX (SUCRA = 0.3687), and placebo+DMARD (SUCRA = 0.0045). By contrast, the safety based on the number of treatment-emergent adverse events (TEAEs) did not differ significantly among the five interventions. CONCLUSION: Baricitinib 2 mg and 4 mg administered once daily, in combination with DMARD, were efficacious interventions for active RA that had no significant risk of TEAE development. PMID- 28097394 TI - The morphology and morphometry of the fovea capitis femoris. AB - BACKGROUND: There is little published information on the anatomy of the fovea capitis femoris (FCF), the distal attachment site of the ligament of the head of femur (LHF). This study investigates the morphology of the FCF on dry bones in an attempt to answer some of the debate around the functional significance of the LHF. METHODS: The morphological and morphometric details of the FCF were analysed on 125 dry isolated femora (n = 125) from the Anatomy Museum, University of Otago, New Zealand. RESULTS: All femora had a single distinct FCF. The proximal half of the foveal floor was rough indicating the attachment of the LHF, while the distal half or receptacle zone, was smooth. The long axis of most FCF (63.2%) was directed posteroinferiorly. The FCF measured 1.77 +/- 0.4 cm (SD) in the longitudinal plane and 1.3 +/- 0.32 cm (SD) in the transverse plane and occupied 17% of the surface area of the femoral head. The shape of the FCF was oval in 66%, circular in 28%, and triangular in 6%. In 123 of 125 bones, the FCF was located on the posteroinferior quadrant of the femoral head. Multiple vascular foramina were found in the ligament attachment zone in 76% of the bones and a quarter of the samples showed a shallow perifoveal groove (24%) or a deep perifoveal notch (26%) on the dry bones. DISCUSSION: This study shows that the fovea consistently lies posteroinferior to the true centre of the femoral head and is usually oval in shape. Patent vascular foramina clustered within the LHF attachment site suggest that the ligament conveys some blood supply to the femoral head in adults. PMID- 28097395 TI - ? PMID- 28097396 TI - ? PMID- 28097397 TI - ? PMID- 28097398 TI - Mapping quantitative trait loci for root development under hypoxia conditions in soybean (Glycine max L. Merr.). AB - KEY MESSAGE: Greatest potential, QTLs for hypoxia and waterlogging tolerance in soybean roots were detected using a new phenotypic evaluation method. Waterlogging is a major environmental stress limiting soybean yield in wet parts of the world. Root development is an important indicator of hypoxia tolerance in soybean. However, little is known about the genetic control of root development under hypoxia. This study was conducted to identify quantitative trait loci (QTLs) responsible for root development under hypoxia. Recombinant inbred lines (RILs) developed from a cross between a hypoxia-sensitive cultivar, Tachinagaha, and a tolerant landrace, Iyodaizu, were used. Seedlings were subjected to hypoxia, and root development was evaluated with the value change in root traits between after and before treatments. We found 230 polymorphic markers spanning 2519.2 cM distributed on all 20 chromosomes (Chrs.). Using these, we found 11 QTLs for root length (RL), root length development (RLD), root surface area (RSA), root surface area development (RSAD), root diameter (RD), and change in average root diameter (CARD) on Chrs. 11, 12, 13 and 14, and 7 QTLs for hypoxia tolerance of these root traits. These included QTLs for RLD and RSAD between markers Satt052 and Satt302 on Chr. 12, which are important markers of hypoxia tolerance in soybean; those QTLs were stable between 2 years. To validate the QTLs, we developed a near-isogenic line with the QTL region derived from Iyodaizu. The line performed well under both hypoxia and waterlogging, suggesting that the region contains one or more genes with large effects on root development. These findings may be useful for fine mapping and positional cloning of gene responsible for root development under hypoxia. PMID- 28097400 TI - ? PMID- 28097399 TI - Segregation for fertility and meiotic stability in novel Brassica allohexaploids. AB - KEY MESSAGE: Allohexaploid Brassica populations reveal ongoing segregation for fertility, while genotype influences fertility and meiotic stability. Creation of a new Brassica allohexaploid species is of interest for the development of a crop type with increased heterosis and adaptability. At present, no naturally occurring, meiotically stable Brassica allohexaploid exists, with little data available on chromosome behaviour and meiotic control in allohexaploid germplasm. In this study, 100 plants from the cross B. carinata * B. rapa (A2 allohexaploid population) and 69 plants from the cross (B. napus * B. carinata) * B. juncea (H2 allohexaploid population) were assessed for fertility and meiotic behaviour. Estimated pollen viability, self-pollinated seed set, number of seeds on the main shoot, number of pods on the main shoot, seeds per ten pods and plant height were measured for both the A2 and H2 populations and for a set of reference control cultivars. The H2 population had high segregation for pollen viability and meiotic stability, while the A2 population was characterised by low pollen fertility and a high level of chromosome loss. Both populations were taller, but had lower average fertility trait values than the control cultivar samples. The study also characterises fertility and meiotic chromosome behaviour in genotypes and progeny sets in heterozygous allotetraploid Brassica derived lines, and indicates that genotypes of the parents and H1 hybrids are affecting chromosome pairing and fertility phenotypes in the H2 population. The identification and characterisation of factors influencing stability in novel allohexaploid Brassica populations will assist in the development of this as a new crop species for food and agricultural benefit. PMID- 28097401 TI - ? PMID- 28097402 TI - [Mechanobiology of fracture healing]. PMID- 28097403 TI - ? PMID- 28097404 TI - Complete mitochondrial genome of the endophytic fungus Pestalotiopsis fici: features and evolution. AB - Endophytic fungi (EF) live within plants and have profound impacts on plant communities. They are astonishingly diverse but poorly studied at the genome level. Herein, we assembled the mitochondrial genome (mitogenome) of the EF Pestalotiopsis fici, annotated and compared it with those of other relatives to better understand the evolution of the EF lineage. Except for standard fungal mitochondrial genes, the 69,529-bp circular mitogenome of P. fici harbors 18 introns acquired possibly through lateral transfer from other fungi and nine free standing open reading frames with some scarcely seen in fungal mitogenomes. BLAST analysis detected no obvious duplication events of large fragments between mitochondrial and nuclear genomes of the fungus. Transcription analyses validated the expression of all mitochondrial genes, while most genes showed higher expression on rice than in two other media. The mitogenome of P. fici is highly syntenic with the Xylariales species Annulohypoxylon stygium and the endophyte Epichloe festucae var. lolii, but lacks synteny with another endophyte Penicillium polonicum. This study reports the first mitogenome of Pestalotiopsis and the third published mitogenome from an EF and provides insights into the evolution of the EF lineage. PMID- 28097405 TI - Role of exopolysaccharide in salt stress resistance and cell motility of Mesorhizobium alhagi CCNWXJ12-2T. AB - Mesorhizobium alhagi, a legume-symbiont soil bacterium that forms nodules with the desert plant Alhagi sparsifolia, can produce large amounts of exopolysaccharide (EPS) using mannitol as carbon source. However, the role of EPS in M. alhagi CCNWXJ12-2T, an EPS-producing rhizobium with high salt resistance, remains uncharacterized. Here, we studied the role of EPS in M. alhagi CCNWXJ12 2T using EPS-deficient mutants constructed by transposon mutagenesis. The insertion sites of six EPS-deficient mutants were analyzed using single primer PCR, and two putative gene clusters were found to be involved in EPS synthesis. EPS was extracted and quantified, and EPS production in the EPS-deficient mutants was decreased by approximately 25 times compared with the wild-type strain. Phenotypic analysis revealed reduced salt resistance, antioxidant capacity, and cell motility of the mutants compared with the wild-type strain. In conclusion, our results indicate that EPS can influence cellular Na+ content and antioxidant enzyme activity, as well as play an important role in the stress adaption and cell motility of M. alhagi CCNWXJ12-2T. PMID- 28097406 TI - The UK experience of promoting dementia recognition and management in primary care. AB - BACKGROUND: The early and timely recognition of dementia syndrome is a policy imperative in many countries. In the UK the achievement of earlier and timelier recognition has been pursued through educational interventions, incentivisation of general practitioners and the promotion of a network of memory clinics. OBJECTIVE: The effectiveness of education, incentivisation and memory clinic activity are unknown. This article analyses data from different sources to evaluate the impact of these interventions on the incidence and prevalence of dementia, and the diagnostic performance of memory clinics. MATERIAL AND METHODS: Three data sources were used: 1) aggregated, anonymised data from a network of general practices using the same electronic medical record software, The Health Information Network (THIN), 2) UK Health & Social Care Information Centre data reports and 3) Responses to Freedom of Information Act requests. RESULTS: Educational interventions did not appear to change the recorded incidence of dementia syndrome. There was no apparent effect of education, incentives or memory clinic activity on the reported incidence of dementia syndrome between 1997 and 2011 but there were signs of change in the documentation of consultations with people with dementia. There was no clear impact of incentivisation and memory clinic activity in prevalence data. Memory clinics are seeing more patients but fewer are being diagnosed with dementia. CONCLUSION: It is not clear why there has been no upturn in documented incidence or prevalence of dementia syndrome despite substantial efforts and this requires further investigation to guide policy changes. The performance of memory clinics also needs further study. PMID- 28097407 TI - Scoring Systems are Crucial in Prediction of the Risk of SSI Development After Ventral Hernia Repair. PMID- 28097408 TI - Primary Hyperparathyroidism with Normal Calcium and PTH. PMID- 28097409 TI - Genetic and Epigenetic Intra-tumour Heterogeneity in Colorectal Cancer. AB - INTRODUCTION: Colorectal cancer (CRC) is a highly heterogeneous disease, with pathologically similar cancers having completely different responses to treatment and patient survival. Intra-tumour heterogeneity (defined as distinct morphological and phenotypic differences) has recently been demonstrated to be an important factor in the development and behaviour of cancer cells and can be used to determine response to anticancer therapy. METHOD: Patients with resected CRC had DNA extracted from eight defined tumour areas which were analysed for two genetic mutations (BRAF and KRAS) and one epigenetic trait (CpG island methylator phenotype/CIMP). Normal adjacent tissue was studied as control. RESULTS: Twelve patients with CRC were included. Intra-tumoural heterogeneity for KRAS mutation was seen in 2 patients (17%). There was no statistical evidence of CIMP status heterogeneity (p = 0.85), but 6 of the 12 patients (50%) demonstrated at least one heterogeneous area within the tumour. DISCUSSION: Intra-tumoural heterogeneity for both genetic and epigenetic factors in CRC is more prevalent than previously thought in Stage II and Stage III CRC. This study provides new insight into epigenetic heterogeneity of CRC and supports the development of a more targeted biopsy strategy to support expansion of personalised treatment. PMID- 28097410 TI - Intercostal Trocars Enable Easier Laparoscopic Resection of Liver Tumors in Segments 7 and 8. AB - BACKGROUND: Laparoscopic resection of posterosuperior (PS) tumors of the liver is more difficult than that of anterolateral (AL) tumors, owing to the narrow surgical field in the PS location. In this retrospective cohort study, our aim was to determine if port insertion through the intercostal space would lead to improved outcomes for laparoscopic resection of tumors in PS liver segments 7 and 8. METHOD: Between January 2006 and December 2015, 153 patients underwent laparoscopic resection of solitary liver tumors at Osaka Medical College Hospital. Of these, 107 patients had AL lesions, and 46 had PS lesions. Of the 46 patients with a PS lesion, 23 underwent an abdominal-only approach, and 23 underwent the intercostal trocar approach. Multivariate analyses were performed to investigate outcomes. RESULTS: Conventional abdominal-only laparoscopic resection of PS liver tumors resulted in prolonged surgical time (P = 0.031), increased bleeding (P = 0.012), and a higher open conversion rate (P = 0.022) compared with AL tumors. Among patients with PS tumors, the open conversion rate was significantly higher for those treated with the abdominal-only approach than with the intercostal trocar approach (P = 0.047). Appropriate surgical margins were obtained equally using the intercostal trocar approach (P = 0.648). There was no significant difference in occurrence of complications between the abdominal-only group and the intercostal trocar group. CONCLUSION: Using the intercostal trocar approach for PS liver lesions is a safe and effective method, which significantly reduced the open conversion rate compared with the conventional abdominal-only approach. PMID- 28097411 TI - Identification of Recurrence: Predictive Indicators in Stage I Colorectal Cancer. PMID- 28097412 TI - Acute Pancreatitis After Percutaneous Biliary Drainage: An Obstacle in Liver Surgery for Proximal Biliary Cancer. AB - BACKGROUND: Percutaneous transhepatic biliary drainage (PTBD) has a crucial role in treatment of proximal biliary cancer (PBC). We assessed the incidence, risk factors, and impact of acute pancreatitis (AP) post-PTBD. METHODS: Forty patients with PBC scheduled for PTBD from January 2005 to December 2015 were enrolled. Exclusion criteria were missing clinical data, PTBD performed in other institutions, and palliative PTBD. RESULT: The 40 patients comprised 8 (20%) with gallbladder cancer, 6 (15%) with intrahepatic cholangiocarcinoma, and 26 (65%) with perihilar cholangiocarcinoma. A median of 1 PTBD procedure was performed per patient; 16 (40%) patients underwent PTBD more than once. PTBD was left-sided in 14 (35.0%) patients, right-sided in 21 (52.5%), and bilobar in 5(12.5%). Seventeen (42.5%) patients had one or more drainage-related complications. Five (12.5%) patients developed AP. A significantly higher percentage of patients with than without AP developed sepsis (60.0 vs. 11.4%, respectively) and did not undergo the planned liver resection [2 (40.0%) vs. 0 (0.0%), respectively]. Significantly more patients with than without AP underwent left-sided PTBD [10 (28.6%) vs. 4 (80.0%), respectively]. CONCLUSION: PTBD is frequently complicated by AP. AP plays a key role in the development of sepsis. Nearly half of patients with AP lose the opportunity for surgical treatment. PMID- 28097413 TI - When Surgical Resources are Severely Constrained, Who Receives Care? Determinants of Access to Orthopaedic Trauma Surgery in Uganda. AB - BACKGROUND: In low- and middle-income countries, the volume of traumatic injuries requiring orthopaedic intervention routinely exceeds the capacity of available surgical resources. The objective of this study was to identify predictors of surgical care for lower extremity fracture patients at a high-demand, resource limited public hospital in Uganda. METHODS: Skeletally mature patients admitted with the intention of definitive surgical treatment of an isolated tibia or femur fractures to the national referral hospital in Uganda were recruited to participate in this study. Demographic, socioeconomic, and clinical data were collected through participant interviews at the time of injury and 6 months post injury. Social capital (use of social networks to gain access to surgery), financial leveraging, and ethnicity were also included as variables in this analysis. A probit estimation model was used to identify independent and interactive predictors of surgical treatment. RESULTS: Of the 64 patients included in the final analysis, the majority of participants were male (83%), with a mean age of 40.6, and were injured in a motor vehicle accident (77%). Due to resource constraints, only 58% of participants received surgical care. The use of social capital and femur fractures were identified as significant predictors of receiving surgical treatment, with social capital emerging as the strongest predictor of access to surgery (p < 0.05). CONCLUSION: Limited infrastructure, trained personnel, and surgical supplies rations access to surgical care. In this environment, participants with advantageous social connections were able to self advocate for surgery where demand for these services greatly exceeded available resources. PMID- 28097414 TI - Magnetic Resonance Imaging (MRI): Operative Findings Correlation in 229 Fistula in-Ano Patients. AB - BACKGROUND: To correlate the operative findings of patients with fistula-in-ano with preoperative MRI and quantify the information added with MRI. METHODS: All consecutive fistula-in-ano patients operated between July 2013 and May 2015 were prospectively enrolled. Preoperative MRI was done in every patient. The details of tracts, internal opening and "complex parameters" (additional tract or additional internal opening, horseshoe tract, associated abscess and supralevator extension) found at surgery were compared to the findings determined by MRI. RESULTS: A total of 229 patients (424 tracts) with mean age-49.0 +/- 11.3 years were included. M/F 198/31. James hospital classification: Type I 58, II 20, III 49, IV 86 and V 16. The sensitivity and specificity of MRI in diagnosing fistula tracts were 98.8 and 99.7%, respectively, and in identifying internal opening were 97.7 and 98.6%, respectively. MRI added significant information in 46.7% (107/229) patients which was presence of additional tracts in 71 (66.3%), horseshoe tract in 63 (58.8%), supralevator extension in 16 (14.9%), unsuspected abscess in 11 (10.3%) and multiple internal openings in one patient (1%). The proportion of simple/complex fistula (based on history and clinical examination alone) was 32.8/67.2% which changed to 21.4/78.6% after the MRI scan. MRI added significant information about unsuspecting complex parameters which were missed on history and clinical examination in more than one-third (26/75: 34.6%) of simple fistulae and more than half (81/154: 52.5%) of already known complex fistulae. CONCLUSIONS: MRI is highly accurate in diagnosing fistula-in-ano and added significant information about unsuspected complex parameters in over one third (34.6%) of simple and in half (52.5%) of complex fistula-in-ano. PMID- 28097415 TI - Anesthesia Practices for Interventional Radiology in Europe. AB - PURPOSE: The Cardiovascular and Interventional Radiological Society of Europe (CIRSE) prompted an initiative to frame the current European status of anesthetic practices for interventional radiology, in consideration of the current variability of IR suite settings, staffing and anesthetic practices reported in the literature and of the growing debate on sedation administered by non anesthesiologists, in Europe. METHODS: Anonymous online survey available to all European CIRSE members to assess IR setting, demographics, peri-procedural care, anesthetic management, resources and staffing, pain management, data collection, safety, management of emergencies and personal opinions on the role CIRSE should have in promoting anesthetic care for interventional radiology. RESULTS: Predictable differences between countries and national regulations were confirmed, showing how significantly many "local" factors (type and size of centers, the availability of dedicated inpatient bed, availability of anesthesia staff) can affect the routine practice and the expansion of IR as a subspecialty. In addition, the perception of the need for IR to acquire more sedation-related skills is definitely stronger for those who practice with the lowest availability of anesthesia care. CONCLUSION: Significant country variations and regulations along with a controversial position of the anesthesia community on the issue of sedation administered by non-anesthesiologists substantially represent the biggest drawbacks for the expansion of peri-procedural anesthetic care for IR and for potential initiatives at an European level. PMID- 28097416 TI - [Use of dual mobility cups for revision hip arthroplasty]. AB - The dual mobility cup (DMC) is an increasingly important tool not only in primary but also in revision total hip arthroplasty to prevent dislocation and eventually reduce postoperative complication rates. Various studies have shown survival rates with DMCs of up to 100% with an average dislocation rate of less than 1.5% after primary hip arthroplasty and a follow-up of 10 years. In revision surgery, survival rates of up to 99% were reported with dislocation rates between 0 and 10% after an average of 5 years after implantation. This article is intended to provide an overview of the principle and function of DMCs. Furthermore, indications as well as complications are presented. PMID- 28097417 TI - Bistability induced by generalist natural enemies can reverse pest invasions. AB - Analytical modeling of predator-prey systems has shown that specialist natural enemies can slow, stop and even reverse pest invasions, assuming that the prey population displays a strong Allee effect in its growth. We aimed to formalize the conditions in which spatial biological control can be achieved by generalists, through an analytical approach based on reaction-diffusion equations. Using comparison principles, we obtain sufficient conditions for control and for invasion, based on scalar bistable partial differential equations. The ability of generalist predators to control prey populations with logistic growth lies in the bistable dynamics of the coupled system, rather than in the bistability of prey-only dynamics as observed for specialist predators attacking prey populations displaying Allee effects. As a consequence, prey control is predicted to be possible when space is considered in additional situations other than those identified without considering space. The reverse situation is also possible. None of these considerations apply to spatial predator-prey systems with specialist natural enemies. PMID- 28097418 TI - Heterogeneous network epidemics: real-time growth, variance and extinction of infection. AB - Recent years have seen a large amount of interest in epidemics on networks as a way of representing the complex structure of contacts capable of spreading infections through the modern human population. The configuration model is a popular choice in theoretical studies since it combines the ability to specify the distribution of the number of contacts (degree) with analytical tractability. Here we consider the early real-time behaviour of the Markovian SIR epidemic model on a configuration model network using a multitype branching process. We find closed-form analytic expressions for the mean and variance of the number of infectious individuals as a function of time and the degree of the initially infected individual(s), and write down a system of differential equations for the probability of extinction by time t that are numerically fast compared to Monte Carlo simulation. We show that these quantities are all sensitive to the degree distribution-in particular we confirm that the mean prevalence of infection depends on the first two moments of the degree distribution and the variance in prevalence depends on the first three moments of the degree distribution. In contrast to most existing analytic approaches, the accuracy of these results does not depend on having a large number of infectious individuals, meaning that in the large population limit they would be asymptotically exact even for one initial infectious individual. PMID- 28097420 TI - ? PMID- 28097419 TI - Modelling Wolbachia infection in a sex-structured mosquito population carrying West Nile virus. AB - Wolbachia is possibly the most studied reproductive parasite of arthropod species. It appears to be a promising candidate for biocontrol of some mosquito borne diseases. We begin by developing a sex-structured model for a Wolbachia infected mosquito population. Our model incorporates the key effects of Wolbachia infection including cytoplasmic incompatibility and male killing. We also allow the possibility of reduced reproductive output, incomplete maternal transmission, and different mortality rates for uninfected/infected male/female individuals. We study the existence and local stability of equilibria, including the biologically relevant and interesting boundary equilibria. For some biologically relevant parameter regimes there may be multiple coexistence steady states including, very importantly, a coexistence steady state in which Wolbachia infected individuals dominate. We also extend the model to incorporate West Nile virus (WNv) dynamics, using an SEI modelling approach. Recent evidence suggests that a particular strain of Wolbachia infection significantly reduces WNv replication in Aedes aegypti. We model this via increased time spent in the WNv-exposed compartment for Wolbachia infected female mosquitoes. A basic reproduction number [Formula: see text] is computed for the WNv infection. Our results suggest that, if the mosquito population consists mainly of Wolbachia infected individuals, WNv eradication is likely if WNv replication in Wolbachia infected individuals is sufficiently reduced. PMID- 28097421 TI - ? PMID- 28097422 TI - Novel alignment measurement technique for total knee arthroplasty using patient specific instrumentation. AB - INTRODUCTION: This study was designed to evaluate the true accuracy of patient specific instrumentation (PSI) for total knee arthroplasty (TKA) using a new 3D measurement method. MATERIALS AND METHODS: Consecutive 21 patients (30 knees) who underwent TKA using computed tomography (CT)-based PSI were retrospectively evaluated. Mean patient age was 69.2 years (62 to 77). The postoperative three dimensional (3D) CT image were superimposed onto the preoperative 3D CT plan and measured the absolute difference in the prosthetic alignment using six parameters: coronal, sagittal, and axial alignment of the femoral and tibial prostheses. Cases in which the difference in the prosthetic alignment was greater than 3 degrees were considered outliers. RESULTS: For the femoral prosthesis, mean absolute differences between the preoperative 3D CT plan and postoperative 3D CT image were not significantly different and the rates of outliers were 10.0, 33.3, 23.3% in the coronal, sagittal, and axial planes. For the tibial prosthesis, mean absolute differences were significantly larger in the axial plane than in the coronal and sagittal planes (p < 0.001) and the rates of outliers were 23.3, 36.7, 63.3% in the coronal, sagittal, and axial planes. The rates of outliers for the axial alignment of tibial prosthesis were significantly higher than for the other five planes (p = 0.006). CONCLUSIONS: The rotation of the tibial prosthesis with CT-based PSI was less accurate in the axial plane than in the other five planes. PMID- 28097423 TI - Rehabilitation of Achilles tendon ruptures: is early functional rehabilitation daily routine? AB - INTRODUCTION: Ruptures of the Achilles tendon are the most common tendon injuries of the lower extremities. Besides the initial operative or non-operative treatment, rehabilitation of patients plays a crucial role for tendon healing and long-term outcome. As only limited evidence is available for optimized rehabilitation regimen and guidelines for the initial (e.g., first 6 weeks) rehabilitation are limited, this study investigated the current rehabilitation concepts after Achilles tendon rupture. MATERIALS AND METHODS: We analyzed 213 written rehabilitation protocols that are provided by orthopedic and trauma surgery institutions throughout Germany in terms of recommendations for weight bearing, range of motion (ROM), physiotherapy, and choice of orthosis. All protocols for operatively and non-operatively treated Achilles tendon ruptures were included. Descriptive analysis was carried out and statistical analysis applied where appropriate. RESULTS: Of 213 institutions, 204 offered rehabilitation protocols for Achilles tendon rupture and, therefore, 243 protocols for operative and non-operative treatment could be analyzed. While the majority of protocols allowed increased weight-bearing over time, significant differences were found for durations of fixed plantar flexion between operative (o) and non-operative (n) treatments [fixed 30 degrees (or 20) degrees to 15 degrees (or 10) degrees : 3.6 weeks (+/-0.1; o) vs 4.7 weeks (+/-0.3; n) (p <= 0.0001) and fixed 15 degrees (or 10) degrees to 0 degrees : 5.8 weeks (+/-0.1; o) vs 6.6 weeks (+/-0.2; n) (p <= 0.001)]. The mean time of the recommended start of physiotherapy is at 2.9 weeks (+/-0.2; o) vs 3.3 weeks (+/-0.4; n), respectively. CONCLUSION: Our study shows that a huge variability in rehabilitation after Achilles tendon rupture exists. This study shows different strategies in rehabilitation of Achilles tendon ruptures using a convertible vacuum brace system. To improve patient care, further clinical as well as biomechanical studies need to be conducted. This study might serve as basis for prospective randomized controlled trials to optimize rehabilitation for Achilles tendon ruptures. PMID- 28097424 TI - Analysis of the spleen proteome of chickens infected with reticuloendotheliosis virus. AB - Infection with reticuloendotheliosis virus (REV), a gammaretrovirus in the family Retroviridae, can result in immunosuppression and subsequent increased susceptibility to secondary infections. In the present study, we identified differentially expressed proteins in the spleens of chickens infected with the REV-A HLJ07I strain, using two-dimensional gel electrophoresis on samples from time points coinciding with different phases of the REV life cycle. Differentially expressed proteins were identified using one-dimensional liquid chromatography electrospray ionization tandem mass spectrometry (1D LC ESI MS/MS). Comparative analysis of multiple gels revealed that the majority of changes occurred at early stages of infection. In total, 60 protein spots representing 28 host proteins were detected as either quantitatively (false discovery rate [FDR] <=0.05 and fold change >=2) or qualitatively differentially expressed at least once during different sampling points. The differentially expressed proteins identified in this study included antioxidants, molecular chaperones, cellular metabolism, formation of the cytoskeleton, signal transduction, cell proliferation and cellar aging. The present findings provide a basis for further studies to elucidate the role of these proteins in REV-host interactions. This could lead to a better understanding of REV infection mechanisms that cause immune suppression. PMID- 28097425 TI - A personal perspective on the discovery of dioxygen adducts of copper and iron by Nobumasa Kitajima. AB - Transition metal-dioxygen complexes have fascinated bioinorganic and inorganic chemists for over half a century. The late Nobumasa Kitajima was one of the very successful researchers in this field. Despite his short career (40 years old), he made many important contributions. This Commentary highlights his important accomplishments and how they have impacted subsequent work in this area. PMID- 28097426 TI - Functional diversity increases ecological stability in a grazed grassland. AB - Understanding the factors governing ecological stability in variable environments is a central focus of ecology. Functional diversity can stabilize ecosystem function over time if one group of species compensates for an environmentally driven decline in another. Although intuitively appealing, evidence for this pattern is mixed. We hypothesized that diverse functional responses to rainfall will increase the stability of vegetation cover and biomass across rainfall conditions, but that this effect depends on land-use legacies that maintain functional diversity. We experimentally manipulated grazing in a California grassland to create land-use legacies of low and moderate grazing, across which we implemented rainout shelters and irrigation to create dry and wet conditions over 3 years. We found that the stability of the vegetation cover was greatly elevated and the stability of the biomass was slightly elevated across rainfall conditions in areas with histories of moderate grazing. Initial functional diversity-both in the seed bank and aboveground-was also greater in areas that had been moderately grazed. Rainfall conditions in conjunction with this grazing legacy led to different functional diversity patterns over time. Wet conditions led to rapid declines in functional diversity and a convergence on resource acquisitive traits. In contrast, consecutively dry conditions maintained but did not increase functional diversity over time. As a result, grazing practices and environmental conditions that decrease functional diversity may be associated with lasting effects on the response of ecosystem functions to drought. Our results demonstrate that theorized relationships between diversity and stability are applicable and important in the context of working grazed landscapes. PMID- 28097427 TI - 25th Anniversary of ECAP: the origins of the Journal. PMID- 28097428 TI - Goal formulation and tracking in child mental health settings: when is it more likely and is it associated with satisfaction with care? AB - Goal formulation and tracking may support preference-based care. Little is known about the likelihood of goal formulation and tracking and associations with care satisfaction. Logistic and Poisson stepwise regressions were performed on clinical data for N = 3757 children from 32 services in the UK (M age = 11; SDage = 3.75; most common clinician-reported presenting problem was emotional problems = 55.6%). Regarding the likelihood of goal formulation, it was more likely for pre-schoolers, those with learning difficulties or those with both hyperactivity disorder and conduct disorder. Regarding the association between goal formulation and tracking and satisfaction with care, parents of children with goals information were more likely to report complete satisfaction by scoring at the maximum of the scale. Findings of the present research suggest that goal formulation and tracking may be an important part of patient satisfaction with care. Clinicians should be encouraged to consider goal formulation and tracking when it is clinically meaningful as a means of promoting collaborative practice. PMID- 28097429 TI - Early and noninvasive evaluation using superficial temporal artery duplex ultrasonography after indirect bypass for adult ischemic moyamoya disease. AB - BACKGROUND: The validity of indirect bypass for adult patients with moyamoya disease is still debatable. Some patients are poor responders to indirect bypass, and additive intervention is occasionally required in these cases. Therefore, it is necessary to evaluate the development of collateral circulation as early as possible postoperatively. METHODS: Fifteen adult patients (>17 years old) with moyamoya disease (22 affected sides) who underwent encephalo-duro-arterio synangiosis (EDAS) at Fukuoka University Hospital from April 2008 to August 2014 were included. All patients had ischemic symptoms of at least one hemisphere. Superficial temporal artery duplex ultrasonography (STDU) was performed before and 3, 6, and 12 months postoperatively. Digital subtraction angiography was performed 1 year after the operation to evaluate the development of collateral circulation. Hemispheres exhibiting collateral formation of more than one-third of the MCA distribution were defined as good responders, and those with less than one-third were defined as poor responders. RESULTS: EDAS induced the formation of well-developed collaterals in 17 of 22 affected sides (77.3%) of adult patients with ischemic moyamoya disease. Regardless of the degree of collateral formation, the ischemic event subsided eventually with time in all patients. In good responders, the pulsatility index obtained by STDU showed a drastic decrease 3 months after the operation, while it did not change significantly in poor responders. Absence of this decrease in the pulsatility index along with no change in the flow velocity reliably indicated poor responders. CONCLUSIONS: Neovascularization after EDAS can be evaluated noninvasively in early phase using STDU. PMID- 28097430 TI - How I do it: the mononostril endonasal transethmoidal-paraseptal approach. AB - BACKGROUND: The use of endoscopes in transnasal surgery offers increased visualization. To minimize rhinological morbidity without restriction in manipulation, we introduced the mononostril transethmoidal-paraseptal approach. METHODS: The aim of the transethmoidal-paraseptal approach is to create sufficient space within the nasal cavity, without removal of nasal turbinates and septum. Therefore, as a first step, a partial ethmoidectomy is performed. The middle and superior turbinates are then lateralized into the ethmoidal space, allowing a wide sphenoidotomy with exposure of the central skull base. CONCLUSIONS: This minimally invasive transethmoidal-paraseptal approach is a feasible alternative to traumatic transnasal concepts with middle turbinate and extended septal resection. PMID- 28097431 TI - Placental DAPK1 and autophagy marker LC3B-II are dysregulated by TNF-alpha in a gestational age-dependent manner. AB - Autophagy, a cell-survival process responsible for degradation of protein aggregates and damaged organelles, is increasingly recognized as another mechanism essential for human placentation. A substantial body of experiments suggests inflammation and oxidative stress as the underlying stimuli for altered placental autophagy, giving rise to placenta dysfunction and pregnancy pathologies. Here, the hypothesis is tested whether or not pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha are able to influence the expression profile of autophagy genes in human first-trimester villous placenta. Autophagy-focused qPCR arrays identified substantial downregulation of death-associated protein kinase 1 (DAPK1) in first-trimester placental explants in response to IL-6 and TNF-alpha, respectively. Immunohistochemistry of placental explants detected considerable DAPK1 staining in placental macrophages, villous cytotrophoblasts and less intense in the syncytiotrophoblast. Both immunohistochemistry and Western blot showed decreased DAPK1 protein in TNF-alpha-treated placental explants compared to control. On cellular level, DAPK1 expression decreased in SGHPL-4 trophoblasts in response to TNF-alpha. Observed changes in the expression profile of autophagy-related genes were reflected by significantly decreased lipidation of autophagy marker microtubule-associated protein light chain 3 beta (LC3B-II) in first trimester placental explants in response to TNF-alpha. Analysis of TNF-alpha-treated term placental explants showed decreased DAPK1 protein, whereas in contrast to first trimester LC3B expression and lipidation increased. Immunohistochemistry of placental tissues from early-onset preeclampsia (PE) showed less DAPK1 staining, when compared to controls. Accordingly, DAPK1 mRNA and protein were decreased in primary trophoblasts isolated from early-onset PE, while LC3B-I and -II were increased. Results from this study suggest that DAPK1, a regulator of apoptosis, autophagy and programmed necrosis, decreases in human placenta in response to elevated maternal TNF-alpha, irrespective of gestational age. In contrast, TNF alpha differentially regulates levels of autophagy marker LC3B in human placenta over gestation. PMID- 28097432 TI - Attitudes of palliative home care physicians towards palliative sedation at home in Italy. AB - BACKGROUND: Information about the attitudes towards palliative sedation (PS) at home is limited. AIM: The aim of this survey was to assess the attitudes of palliative care physicians in Italy regarding PS at home. DESIGN: A questionnaire was submitted to a sample of palliative care physicians, asking information about their activity and attitudes towards PS at home. SETTING: This is a survey of home care physicians in Italy who were involved in end-of-life care decisions at home. RESULTS: One hundred and fifty participants responded. A large heterogeneity of home care organizations that generate some problems was found. Indications, intention and monitoring of PS seem to be appropriate, although some cultural and logistic conditions were limiting the use of PS. Specialized home care physicians are almost involved to start PS at home. Midazolam was seldom available at home and opioids were more frequently used. CONCLUSION: These data should prompt health care agencies to make a minimal set of drugs easily available for home care. Further research is necessary to compare attitudes in countries with different sociocultural profiles. PMID- 28097433 TI - Early integration of palliative/supportive cancer care-healthcare professionals' perspectives on the support needs of cancer patients and their caregivers across the cancer treatment trajectory. AB - PURPOSE: Delivering palliative/supportive cancer care (PSCC) early in the course of cancer care can enhance patients' and caregivers' quality of life, reduce anxiety and depression, and prolong patients' lives. However, their support needs are analyzed insufficiently from viewpoints other than their own. The goal of this study was to explore the perspectives of healthcare professionals on desirable standards of support for tumor patients and caregivers across the cancer treatment trajectory. It further aimed at identifying starting points for PSCC to address these needs. METHODS: Nine healthcare professionals of varying disciplines in a large German university hospital each participated in one of two focus groups. The qualitative data was analyzed following the grounded theory methodology. RESULTS: The healthcare professionals described it as desirable standards that tumor patients and caregivers receive support coping with tasks, accepting the situation, generating strength, feeling trust, and gaining clarity, thus increasing their sense of control. These support needs were seen as important throughout the whole cancer treatment trajectory of tumor patients and their caregivers. CONCLUSIONS: Team meetings, supervision, tailored education, and structural improvements may aid healthcare professionals to develop and implement ways to further support patients and caregivers. Also, patients' and caregivers' support needs should be screened regularly, e.g., when treatment phases change. This would complement healthcare professionals' subjective theories of relevant needs during a specific treatment phase. PMID- 28097434 TI - Work-related infections in dentistry: risk perception and preventive measures. AB - OBJECTIVES: Evaluation of (1) the risk perception of work-related infections in dentistry, (2) the vaccination status, (3) knowledge of the blood-borne pathogens and HIV post-exposure prophylaxis (PEP) as well as (4) use of personal protective equipment (PPE) (gloves, goggles, mask) among the staff and students of the Center of Dentistry and Oral Medicine (ZZMK [Carolinum]) of the Goethe University Frankfurt/Main. MATERIAL AND METHODS: All staff (dentists, dental assistants) and students of the ZZMK with direct contact to patients were asked to anonymously complete a questionnaire. The results of this survey were compared with respect to gender, age and occupational group. RESULTS: Of 178 employees working and 234 students studying at the ZZMK with direct contact to patients, 108 (61%) and 167 (71%) participated (1 person did not reveal his/her status). Thirty-three per cent of the participants assessed the risk of transmission of blood-borne diseases in dental practice as high. Whereas 94% of the participants were fully vaccinated against hepatitis B, only 21% knew their anti-HBs titer. Fifty per cent of students, 13% of dentists and 45% of the assistants did not know the standardised procedure of HIV-PEP. Ninety-four per cent of the study participants always wore protective gloves, 87% always wore a surgical mask and 67% always wore protective goggles. CONCLUSIONS: The fear of HIV is still the largest, followed by hepatitis C. The participants assessed the risk of transmission in spite of all protective measures from the patient to the dentist significantly higher than the transmission from the dentist to the patient. The use of protective measures, especially goggles, requires further optimizing. CLINICAL RELEVANCE: In general, the use of protective measures, especially goggles, requires further optimizing. PMID- 28097435 TI - Erratum to: Effects of enamel matrix derivative on non-surgical management of peri-implant mucositis: a double-blind randomized clinical trial. PMID- 28097436 TI - Damaged reward areas in human alcoholics: neuronal proportion decline and astrocyte activation. PMID- 28097437 TI - Two- and three-dimensional topographic analysis of pathologically myopic eyes with dome-shaped macula and inferior staphyloma by spectral domain optical coherence tomography. AB - PURPOSE: To investigate the posterior anatomical structure of pathologically myopic eyes with dome-shaped macula and inferior staphyloma using spectral domain optical coherence tomography (SD-OCT). METHODS: Our database of 260 pathologically myopic eyes was analyzed retrospectively to identify patients with dome-shaped macula and inferior staphyloma. All patients underwent vertical and horizontal SD-OCT scans across the central fovea, with three-dimensional macular map reconstruction. Best-corrected visual acuity, axial length, and choroidal thickness measurements were recorded. The macular bulge height was also analyzed in eyes with dome-shaped macula. In the three-dimensional images, the symmetry and orientation of the main plane of the inward incurvation of the macula were examined. RESULTS: Twenty-eight (10.7%) of the 260 pathologically myopic eyes had dome-shaped macula of one of three different types: a round radially symmetrical dome (eight eyes, 28.5%), a horizontal axially symmetrical oval-shaped dome (15 eyes, 53.5%), or a vertical axially symmetrical oval-shaped dome (five eyes, 17.8%). The macular bulge height was significantly greater in horizontal oval shaped dome eyes (p = 0.01, for each comparison). Inferior posterior staphylomas were observed in ten (3.8%) of the 260 pathologically myopic eyes with asymmetrical macular bends. CONCLUSIONS: Vertical and horizontal OCT sectional scanning in combination with three-dimensional macular map reconstruction provides important information for understanding the posterior anatomical structure of dome-shaped macula and inferior staphyloma in pathologically myopic eyes. PMID- 28097438 TI - Attitudes towards fever amongst UK paediatric intensive care staff. AB - : The role played by fever in the outcome of critical illness in children is unclear. This survey of medical and nursing staff in 35 paediatric intensive care units and transport teams in the United Kingdom and Ireland established attitudes towards the management of children with fever. Four hundred sixty-two medical and nursing staff responded to a web-based survey request. Respondents answered eight questions regarding thresholds for temperature control in usual clinical practice, indications for paracetamol use, and readiness to participate in a clinical trial of permissive temperature control. The median reported threshold for treating fever in clinical practice was 38 degrees C (IQR 38-38.5 degrees C). Paracetamol was reported to be used as an analgesic and antipyretic but also for non-specific comfort indications. There was a widespread support for a clinical trial of a permissive versus a conservative approach to fever in paediatric intensive care units. Within a trial, 58% of the respondents considered a temperature of 39 degrees C acceptable without treatment. CONCLUSIONS: Staff on paediatric intensive care units in the United Kingdom and Ireland tends to treat temperatures within the febrile range. There was a willingness to conduct a randomized controlled trial of treatment of fever. What is known: * The effect of fever on the outcome in paediatric critical illness is unknown. * Paediatricians have traditionally been reluctant to allow fever in sick children. What is new: * Paediatric intensive care staff report a tendency towards treating fever, with a median reported treatment threshold of 38 degrees C. * There is widespread support amongst PICU staff in the UK for a randomized controlled trial of temperature in critically ill children. * Within a trial setting, PICU staff attitudes to fever are more permissive than in clinical practice. PMID- 28097439 TI - Modeling Responses in the Superior Paraolivary Nucleus: Implications for Forward Masking in the Inferior Colliculus. AB - A phenomenological model of the responses of neurons in the superior paraolivary nucleus (SPON) of the rodent is presented in this study. Pure tones at the characteristic frequency (CF) and broadband noise stimuli evoke offset-type responses in these neurons. SPON neurons also phase-lock to the envelope of sinusoidally amplitude-modulated (SAM) stimuli for a range of modulation frequencies. Model SPON neuron received inhibitory input that was relayed by the ipsilateral medial nucleus of the trapezoid body from the contralateral model ventral cochlear nucleus neuron. The SPON model response was simulated by detecting the slope of its inhibitory postsynaptic potential. Responses of the proposed model to pure tones at CF and broadband noise were offset-type independent of the duration of the input stimulus. SPON model responses were also synchronized to the envelope of SAM stimuli with precise timing for a range of modulation frequencies. Modulation transfer functions (MTFs) obtained from the model response to SAM stimuli resemble the physiological MTFs. The output of the proposed SPON model provides an input for models of physiological responses at higher levels of the ascending auditory pathway and can also be utilized to infer possible mechanisms underlying gap detection and duration encoding as well as forward masking at the level of the auditory midbrain. PMID- 28097440 TI - Prevalence of NRAS, PTEN and AKT1 gene mutations in the central nervous system metastases of non-small cell lung cancer. AB - Somatic mutations in NRAS, PTEN and AKT1 genes are rarely (~1%) reported in primary NSCLC, but their role in carcinogenesis have been proven. Therefore, we assessed the frequency of them in 145 FFPE tissue samples from CNS metastases of NSCLC using the real-time PCR technique. We identified four (two NRAS and single AKT1 and PTEN) mutations in CNS metastases of NSCLC. All mutations were observed in current male smokers (4% out of the male group; 4/100 and 4.25% out of smokers; 4/94). Three mutations have been detected in patients with SqCC (10.3% out of SqCC patients; 3/29), and only one mutation in the NRAS gene-in a patient with adenocarcinoma (1.25% out of AC patients; 1/80). The examined genes were mutually exclusive in terms of molecular background in KRAS; EGFR; DDR2; PIK3CA; HER2 and MEK1 genes that were evaluated in our previous studies. The OS of the patients who harbored NRAS, AKT1 and PTEN mutations was 10.1, 12.1, 7.3 and 4 months, respectively (vs 13.5 months of the studied group). Our results suggest that the presence of NRAS, PTEN and AKT1 gene mutations may have an influence on the occurrence of CNS metastases in patients with SqCC. PMID- 28097441 TI - Elevated preoperative neutrophil-to-lymphocytes ratio predicts poor prognosis after esophagectomy in T1 esophageal cancer. AB - BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) has been reported to predict the prognosis of various malignant tumors, including esophageal cancer. However, no previous reports have supported the use of the preoperative NLR as an independent prognostic marker focused on superficial (T1) esophageal cancer. The aim of this study was to elucidate the prognostic impact of the preoperative NLR in T1 esophageal cancer. METHODS: This retrospective study recruited 245 consecutive patients with T1 esophageal cancer who underwent subtotal esophagectomy between 2005 and 2016. The relationship between the preoperative NLR and clinicopathological characteristics was analyzed. RESULTS: The preoperative NLR was significantly higher in male patients (p = 0.029), patients with T1b esophageal cancer (p = 0.0274), and patients with venous vessel invasion (p = 0.0082). In the Kaplan-Meier analysis, the elevated preoperative NLR was significantly associated with a poorer disease-free survival (p < 0.0001) and overall survival (p = 0.0004). In the multivariate Cox model, the elevated preoperative NLR was an independent prognostic marker for both disease-free survival (p = 0.0013) and overall survival (p = 0.0027). CONCLUSION: An elevated preoperative NLR predicts poor prognosis in T1 esophageal cancer, suggesting the utility of the NLR as an easily measurable and generally available independent prognostic marker. PMID- 28097443 TI - Axillary Ultrasound Before Neoadjuvant Chemotherapy for Breast Cancer: Don't Discount the Benefits Yet! PMID- 28097442 TI - LAPTM4B-35 is a novel prognostic factor for glioblastoma. AB - Lysosome-associated protein transmembrane-4 beta (LAPTM4B)-35, a newly identified cancer-associated gene, is overexpressed in a wide variety of malignant tumors. However, studies of its expression and role in glioma have not yet been reported. This study aimed to investigate the expression and the role of LAPTM4B-35 in glioma and to assess its value as a prognostic factor. Seventy-seven glioma cases (Grade II in 18 patients, Grade III in 16 and Grade IV in 43) were immunohistochemically examined for LAPTM4B-35, pAkt, factor VIII and Ki-67 expressions. The LAPTM4B-35 expression score of Grade II gliomas was lower than those of Grade III-IV gliomas (p < 0.05), while the difference between Grade III and IV gliomas was not statistically significant. Of the 43 patients with glioblastoma (GBM), 27 (62.8%) had high LAPTM4B-35 expression, which was associated with high tumor micro-vessel density and pAkt activation. The median progression-free survival (PFS) of GBM patients with high LAPTM4B-35 expression was 5.13 months, significantly shorter than that of those with low LAPTM4B-35 expression (12.0 months, p < 0.0001). The median overall survival (OS) of GBM patients with high LAPTM4B-35 expression was 12.5 months, again significantly shorter than that of those with low LAPTM4B-35 expression (29.6 months, p < 0.0001). Multivariate analysis indicated LAPTM4B-35 to be an independent prognostic factor for PFS and OS of GBM patients. Our findings show LAPTM4B-35 to be strongly associated with tumor proliferation, tumor angiogenesis and poor outcomes of GBM patients, suggesting LAPTM4B-35 to potentially be applicable as a novel prognostic marker and even to possibly play a role in improving GBM treatment. PMID- 28097444 TI - Obstetric outcome of vanishing twins syndrome: a systematic review and meta analysis. AB - PURPOSE: Due to the high number of multiple embryo transfers into the uterus performed in assisted reproductive technology treatment (ART), the incidences of twin pregnancy and of vanishing twin syndrome (VTS) are correspondingly high. A number of studies have described the obstetric outcomes of the remaining fetus produced after the other twin had vanished compared with a singleton at the start following ART, but the results are mixed and contradictory. We performed a systematic review of the existing studies to explore the actual obstetric outcome of VTS to allow physicians to adequately advise their patients. METHODS: A detailed search strategy was used to conduct electronic literature searches (spanning 1978-2015) on Medline, EMBASE, the Cochrane library and Web of Science. As randomized trials are not feasible in this aspect, we included observational (cohort and case-control) studies which compared the obstetric outcomes of the VTS group and singleton at the start control group after ART. The outcomes were evaluated by two aspects, the duration of pregnancy (gestational age, preterm delivery rate, extremely preterm delivery rate) and the birth weight of the fetus [mean birth weight, low birth weight rate, very low birth weight rate and small for gestational age (SGA)]. RESULTS: 1271 publications were identified by the initial search. 499 studies were excluded following duplication checks. 760 were excluded after reviewing the abstracts. Of the remaining 12 articles, 7 were excluded after a detailed full-text review. Two case-control studies and three cohort studies were included in the final analysis. The pooled mean gestational age difference (95% confidence intervals) was -0.27 (-0.60, 0.06) and failed to demonstrate a difference between the two groups. A similar result was found in the preterm delivery rate, with a pooled risk ratio of 1.33 (0.91, 1.94). The prevalence of extremely preterm delivery rate was higher in the VTS group, with a pooled risk ratio of 3.5 (1.72, 7.12). The mean birth weight was lower in the VTS group, with a mean difference of -0.3 (-0.59, -0.01). No difference was found in low birth weight rate, very low birth weight rate and rate of small for gestational age, with risk ratio of 1.85 (0.88, 3.86), 4.86 (0.91, 25.91) and 1.29 (0.52, 3.18), correspondingly. CONCLUSIONS: There is a slight adverse effect of VTS on the remaining fetus for birth weight and extremely preterm delivery rate, but sensitivity analysis shows these effects to be statistically unstable. It is too early to draw conclusions for adverse obstetric outcomes for VTS patients. It could reduce much of the anxiety of couples who experience early embryonic loss of one of their twins. More research with rigorously designed and standardized methodologies are required that include larger, better clinically defined populations. Studies that show no correlation should be published in the future to avoid any possible impact of publication bias. After that, patients can receive the most accurate information. PMID- 28097445 TI - Pregnancy outcomes in HIV-positive women: a retrospective cohort study. AB - PURPOSE: In the United States, an estimated 8500 HIV (human immunodeficiency virus) positive women gave birth in 2014. This rate appears to be increasing annually. Our objective is to examine obstetrical outcomes of pregnancy among HIV positive women. METHODS: A population-based cohort study was conducted using the Nationwide Inpatient Sample database (2003-2011) from the United States. Pregnant HIV-positive women were identified and compared to pregnant women without HIV. Multivariate logistic regression was used to estimate the adjusted effect of HIV status on obstetrical and neonatal outcomes. RESULTS: Among 7,772,999 births over the study period, 1997 were in HIV-positive women (an incidence of 25.7/100,000 births). HIV-infected patients had greater frequency of pre-existing diabetes and chronic hypertension, and use of cigarettes, drugs, and alcohol during pregnancy (p < 0.001). Upon adjustment for baseline characteristics, HIV-infected women had greater likelihood of antenatal complications: preterm premature rupture of membranes (OR 1.35, 95% CI 1.14-1.60) and urinary tract infections (OR 3.02, 95% CI 2.40-3.81). Delivery and postpartum complications were also increased among HIV-infected women: cesarean delivery (OR 3.06, 95% CI 2.79-3.36), postpartum sepsis (OR 8.05, 95% CI 5.44-11.90), venous thromboembolism (OR 2.21, 95% CI 1.46 3.33), blood transfusions (OR 3.67, 95% CI 3.01-4.49), postpartum infection (OR 3.00, 95% CI 2.37-3.80), and maternal mortality (OR 21.52, 95% CI 12.96-35.72). Neonates born to these mothers were at higher risk of prematurity and intrauterine growth restriction. CONCLUSION: Pregnancy in HIV-infected women is associated with adverse maternal and newborn complications. Pregnant HIV-positive women should be followed in high-risk healthcare centers. PMID- 28097446 TI - Temperament Traits and Psychopathology in Young Clinically Referred Children Compared to a General Population Sample. AB - Evidence from general population studies shows the contribution of various temperament traits to the development of child psychopathology. Little is known about which traits are associated with internalizing and externalizing problems in young clinically referred children. The current study assessed temperament and internalizing and externalizing problems in 216 referred children (M = 4.35 years, SD 0.89, 81% boys). A comparison was made with an age and gender matched general population sample. Referred children showed less effortful control than general population children. Less effortful control and more negative affectivity were associated with more internalizing and externalizing problems across groups. Surgency, and specifically temperamental impulsivity, was more strongly associated with externalizing problems in referred children compared to general population. Less soothability, less inhibitory control and more frustration predicted (sub)clinical levels of comborbid internalizing and externalizing problems in referred children. The results can be used in diagnostic and treatment procedures in early childhood. PMID- 28097447 TI - Mannose-binding lectin (MBL) codon 54 (rs1800450) polymorphism predisposes towards medium vessel vasculitis in patients with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multiple etiological factors. Mannose-binding lectin (MBL) plays a key role in innate immunity by activating antibody-independent lectin complement pathway, opsonisation, phagocytosis, and immune complex (IC) clearance. Genetic polymorphisms in the promoter and coding regions of MBL gene affect the circulatory levels and biological activity of MBL. Defects in MBL can lead to defective opsonisation and, hence, hamper clearance of apoptotic debris, the persistence of which can drive autoantibody formation in lupus. The exon1 variants at codon 52, 54, and 57 have been reported to augment the risk of SLE in different ethnic populations. Three hundred South Indian Tamil patients with SLE and 460 age-, sex-, and ethnicity-matched controls were genotyped for three polymorphisms at codon 52, 54, and 57 in exon1 of MBL gene by Taqman real-time PCR. The three polymorphisms in exon1 of MBL were observed not to confer risk of developing SLE. However, MBL codon 54 rs1800450 polymorphism was associated with the development of medium vessel vasculitis and gangrene (OR-2.29, CI 95% 1.08 4.83, p = 0.02), whereas, the ancestral allele G conferred protection (OR-0.44, CI 95% 0.21-0.93, p = 0.02). Genetic variants in the exon1 of MBL gene per se are not risk factors for SLE in South Indian Tamils. However, the association of codon 54 (rs1800450) with medium vessel vasculitis suggests that it may be a genetic modifier of clinical phenotype in SLE. PMID- 28097448 TI - Remission rate is not dependent on the presence of antinuclear antibodies in juvenile idiopathic arthritis. AB - Recently, it has been hypothesized that the subcategories of the ILAR classification of juvenile idiopathic arthritis (JIA) are not homogeneous, and that the presence of antinuclear antibodies (ANA) should lead to a separate entity. Therefore, the aim of this study was to evaluate ANA positivity as a predictor of achieving remission. A retrospective single-center cohort study including all JIA patients diagnosed between January 2000 and May 2014. A minimum follow-up of 1 year was required plus the ANA status. ANA positivity was defined as at least two positive results with a titer >=1:160. Demographic and clinical features were collected. Remission at last follow-up was defined by the Wallace criteria. A total of 625 patients met the inclusion criteria and 230 (37%) were found ANA positive. Analysis showed no difference in remission rate between ANA positive and ANA-negative patients. Additionally, joint count at diagnosis and at last follow-up were comparable in both groups. ANA positivity was correlated to a female predominance and young age at diagnosis (p < 0.001). Remission rates are not different in ANA-positive patients than in ANA-negative patients. This does not support the hypothesis to possibly divide JIA patients based on their ANA status. PMID- 28097449 TI - Open retromuscular large mesh reconstruction of lumbar incisional hernias including the atrophic muscular area. AB - PURPOSE: Lumbar incisional hernias (LIH) are a rare wall defect, whose surgical management is challenging because no recommendation exists. Moreover, LIH are frequently associated with flank bulging which should be taken into account during LIH surgical repair. We aimed to describe a cohort of patients operated on for LIH using a homogeneous surgical technique and to report surgical outcomes. METHODS: The records of all consecutive patients operated on in a specialized surgical center between January 2009 and January 2015 were retrospectively reviewed. The same open technique was performed, i.e., using a mesh into the retroperitoneal space posteriorly, placed with the largest overlap inferiorly and posteriorly, and fixed through the controlateral abdominal wall muscles under strong tension to correct the flank bulging. RESULTS: The cohort included 31 patients, of median age 62, who presented two or more comorbidities in 68% of cases. LIH was recurrent in 45% of patients, and was related to nephrectomy in 61% of patients. The mesh was totally extraperitoneal in 65% of patients. The postoperative mortality rate was null. The rate of specific surgical complications was 32.3%, and the rate of overall postoperative morbidity (Clavien Dindo classification) was 38.7%. After a median follow-up of 27.5 months, the recurrence rate was 6.5% and 9.7% reported chronic pain. CONCLUSION: The open approach for LIH repair was safe and enabled treating flank bulging simultaneously in all patients. Due to the paucity of adequate scientific studies, this reproducible open method could help moving toward a standardization of LIH surgical management. PMID- 28097450 TI - Contemporary thoughts on the management of Spigelian hernia. AB - BACKGROUND: Spigelian hernias are said to be a rare condition of the elderly population, usually arising below the arcuate line. Local experience has led us to challenge these commonly held beliefs. METHODS: Operations for Spigelian hernia from 2006-2016 were identified from the Edinburgh Lothian Surgical Audit computerised database and case notes were reviewed. RESULTS: One hundred and one patients underwent surgery for 107 Spigelian hernias in the 10-year period. The female-to-male ratio was 2:1. Ages ranged from 32 to 88 with a median of 64 years. Sixty-five operations were done open and 42 were laparoscopic. Twelve of the 27 for which the precise anatomic location was recorded were situated above the arcuate line. Twenty-nine hernias had small defects and comprised interstitial fat only with no peritoneal sac. Ages in this group ranged from 32 to 80 (median = 48 years). All presented with intermittent local pain and/or swelling, although in three patients the hernias were impalpable. Those three also underwent ultrasound, CT and/or laparoscopy, but the hernias were only identified after open surgical exploration. The remaining 78 cases had peritoneal sacs of varying size with defects up to 9 cm across, and all were identified on imaging and/or laparoscopy. Ages ranged from 38 to 88 (median = 67 years; p < 0.01). Eighteen patients presented as emergencies and all were in this group. CONCLUSION: Spigelian hernias may be more common than we think and are probably under-diagnosed. They commonly arise above the arcuate line. We describe three clinical stages: Stage 1 hernias are those without peritoneal sacs and tend to arise in younger patients, can be difficult to diagnose and may not seen at laparoscopy. Stages 2 and 3 hernias arise in older patients, do have peritoneal sacs, are visible at laparoscopy and are more likely to present as emergencies. Stage three hernias are too large for laparoscopic repair. The differences between stages likely reflect the natural history of the condition, which begins as extraperitoneal fat protrusion and progresses over many years to develop a peritoneal sac. PMID- 28097451 TI - VRT (verbal reasoning test): a new test for assessment of verbal reasoning. Test realization and Italian normative data from a multicentric study. AB - Verbal reasoning is a complex, multicomponent function, which involves activation of functional processes and neural circuits distributed in both brain hemispheres. Thus, this ability is often impaired after brain injury. The aim of the present study is to describe the construction of a new verbal reasoning test (VRT) for patients with brain injury and to provide normative values in a sample of healthy Italian participants. Three hundred and eighty healthy Italian subjects (193 women and 187 men) of different ages (range 16-75 years) and educational level (primary school to postgraduate degree) underwent the VRT. VRT is composed of seven subtests, investigating seven different domains. Multiple linear regression analysis revealed a significant effect of age and education on the participants' performance in terms of both VRT total score and all seven subtest scores. No gender effect was found. A correction grid for raw scores was built from the linear equation derived from the scores. Inferential cut-off scores were estimated using a non-parametric technique, and equivalent scores were computed. We also provided a grid for the correction of results by z scores. PMID- 28097453 TI - Seven cases of localized invasive sino-orbital aspergillosis. AB - PURPOSE: To describe the clinical manifestations and prognoses in 7 patients with invasive sino-orbital aspergillosis (ISOA). METHODS: This was a retrospective study of consecutive patients who were diagnosed as having ISOA at the Gifu University Hospital and Gifu Municipal Hospital between January 1993 and December 2015. Data were collected on demographics, initial manifestations, examination findings, treatments, clinical course, and outcomes. RESULTS: The median age of the 7 patients with ISOA was 68 years; 5 of them had diabetes. The initial symptoms were reduced blurred vision (57%), unilateral headaches (43%), unilateral abnormal sensations or numbness of the periorbital area (43%), and external ophthalmoplegia (43%). The medical department that the patients first visited was the ophthalmology department in 57% of the cases. The initial CT showed bone destruction in 71% and calcification in 14% of the patients. Six of the 7 cases were misdiagnosed. The definitive diagnosis of ISOA was made by histopathologic examinations of the biopsy specimens, with an average of 2.6 biopsies. All patients received aggressive antifungal treatments after the diagnosis. However, the final visual outcome was no light perception in 86% and death related to the ISOA in 43% of the patients. Patients who were older at the onset had lower survival rates. CONCLUSIONS: The prognosis for patients with ISOA is poor in terms of both vision and life. Ophthalmologists are often the first examiner. ISOA should be considered in the differential diagnosis for patients with a gradually progressive orbital mass, unilateral headaches, numbness of the periorbital area, and a decrease in visual acuity of unknown origin. PMID- 28097452 TI - Toward the optimal strategy for sustained weight loss in overweight cancer survivors: a systematic review of the literature. AB - PURPOSE: To gain more insight into the optimal strategy to achieve weight loss and weight loss maintenance in overweight and obese cancer survivors after completion of initial treatment, this systematic review aimed to provide an overview of the literature on intervention effects on weight, to describe intervention components used in effective interventions, to identify and synthesize behaviour change techniques (BCTs) and to assess the frequency with which these BCTs were used in effective interventions. METHODS: Six databases were searched for original research articles describing weight changes in adult overweight cancer survivors after participation in a lifestyle intervention initiated after completion of initial treatment. Two researchers independently screened the retrieved papers and extracted BCTs using the BCT Taxonomy version 1. RESULTS: Thirty-two papers describing 27 interventions were included. Interventions that were evaluated with a robust study design (n = 8) generally showed <5% weight loss and did not evaluate effects at >=12 months after intervention completion. Effective interventions promoted both diet and physical activity and used the BCTs 'goal setting (behaviour)', 'action planning', 'social support (unspecified)' and 'instruction on how to perform the behaviour'. CONCLUSIONS: The results of this first review on intervention components of effective interventions could be used to inform intervention development and showed a need for future publications to report long-term effects, a detailed intervention description and an extensive process evaluation. IMPLICATIONS FOR CANCER SURVIVORS: This study contributed to increasing knowledge on the optimal strategy to achieve weight loss, which is recommended for overweight cancer survivors to improve health outcomes. PMID- 28097454 TI - In vitro cytogenetic toxicity of bezafibrate in human peripheral blood lymphocytes. AB - Bezafibrate (BF) is a peroxisome proliferator-activated receptor (PPAR) agonist used as a lipid-lowering agent to treat both the familial or acquired combined forms of hyperlipidemia. BF is the only available fibrate drug that acts on all PPAR subtypes of alpha, beta, and delta. Although there are studies that indicate a genotoxic potential associated with the use of fibrates, to our knowledge, the genotoxicity of BF in human peripheral blood lymphocytes has not been studied. In the present study, the genotoxic potential of BF was evaluated using chromosome aberration (CA) and micronucleus (MN) assays in peripheral blood lymphocytes of healthy human subjects. In addition, a high performance liquid chromatography (HPLC) method was used to identify and quantitate the drug passage into the cells. Human peripheral blood lymphocytes were exposed to four different concentrations (100, 175, 250 and 325 MUg/mL) of BF for 24- and 48-h treatment periods. As shown by HPLC, in spite of significant passage of BF into human peripheral blood lymphocytes in 24- and 48-h treatment periods, BF was not found to increase the CA and MN frequency. On the other hand, exposing cells to BF for 24- and 48-h treatment periods caused significant concentration-dependent decreases in the mitotic index (r = -0.995, p < 0.01 for 24-h; r = -0.992, p < 0.01 for 48-h) and nuclear division index (r = -0.990, p < 0.01 for 24-h; r = 0.981, p < 0.01 for 48-h). Our results suggest that BF has cytotoxic effect on cultured human peripheral blood lymphocytes. PMID- 28097455 TI - Leptin, NPY, Melatonin and Zinc Levels in Experimental Hypothyroidism and Hyperthyroidism: The Relation to Zinc. AB - Since zinc mediates the effects of many hormones or is found in the structure of numerous hormone receptors, zinc deficiency leads to various functional impairments in the hormone balance. And also thyroid hormones have important activity on metabolism and feeding. NPY and leptin are affective on food intake and regulation of appetite. The present study is conducted to determine how zinc supplementation and deficiency affect thyroid hormones (free and total T3 and T4), melatonin, leptin, and NPY levels in thyroid dysfunction in rats. The experiment groups in the study were formed as follows: Control (C); Hypothyroidism (PTU); Hypothyroidism+Zinc (PTU+Zn); Hypothyroidism+Zinc deficient; Hyperthyroidism (H); Hyperthyroidism+Zinc (H+Zn); and Hyperthyroidism+Zinc deficient. Thyroid hormone parameters (FT3, FT4, TT3, and TT4) were found to be reduced in hypothyroidism groups and elevated in the hyperthyroidism groups. Melatonin values increased in hyperthyroidism and decreased in hypothyroidism. Leptin and NPY levels both increased in hypo- and hyperthyroidism. Zinc levels, on the other hand, decreased in hypothyroidism and increased in hyperthyroidism. Zinc supplementation, particularly when thyroid function is impaired, has been demonstrated to markedly prevent these changes. PMID- 28097458 TI - Tissue marker clip placement after 11-gauge vacuum-assisted stereotactic breast biopsy: methodological issue on validity and reliability. PMID- 28097459 TI - Are intensive data collection methods in pain research feasible in those with physical disability? A study in persons with chronic pain and spinal cord injury. AB - PURPOSE: Intensive repeated measures data collection procedures, such as ecological momentary assessment (EMA) and end-of-day (EOD) diaries, are becoming more prominent in pain research. Existing data on the feasibility of such methods is encouraging; however, almost nothing is known about feasibility in clinical populations with significant physical disabilities. Research methodology feasibility is crucial to the inclusion of individuals with physical disability in pain research given the high prevalence and impact of pain in these populations. The aim of this study was to examine study compliance, protocol acceptability, and reactivity of intensive data collection methods in adults with chronic pain and spinal cord injury (SCI). METHODS: Secondary analysis of data from a 7-day EMA and EOD diary study in a sample of 131 community dwelling adults with SCI. RESULTS: Results showed rates of missing data ranged from 18.4 to 22.8% across measures. Participant compliance was related to time of day/presence of audible prompts, mobility aid use, race, and baseline levels of pain and pain interference, with more missing data at wake and bedtimes/no prompts, and for those who used hand-held mobility devices, identified as black/African American, and/or reported higher baseline pain and pain interference. Participants rated the study methodology as generally highly acceptable and expressed willingness to participate in similar studies of much longer duration. There was no evidence of reactivity, defined as temporal shifts in pain or pain interference ratings. CONCLUSIONS: Overall, intensive pain data collection is feasible in persons with SCI with no evidence that the methodology impacts pain intensity or pain interference ratings. PMID- 28097460 TI - Synthesis, Spectral Characterization, DNA/ Protein Binding, DNA Cleavage, Cytotoxicity, Antioxidative and Molecular Docking Studies of Cu(II)Complexes Containing Schiff Base-bpy/Phen Ligands. AB - Ternary Cu(II) complexes [Cu(II)(L)(bpy)Cl] 1, [Cu(II)(L)(Phen)Cl] 2 [L = 2,3 dimethyl-1-phenyl-4(2 hydroxy-5-methyl benzylideneamino)-pyrazol-5-one, bpy = 2,2' bipyridine, phen =1,10 phenanthroline) were synthesized and characterized by elemental analyses, UV-Visible, FT-IR, ESR, Mass, thermogravimetric and SEM EDAX techniques. The complexes exhibit octahedral geometry. The interaction of the Cu(II) with cailf thymus DNA (CT-DNA) was explored by using absorption and fluorescence spectroscopic methods. The results revealed that the complexes have an affinity constant for DNA in the order of 104 M-1 and mode of interaction is intercalative mode. The DNA cleavage study showed that the complexes cleaved DNA without any external agent. The interaction of Cu(II) complexes with bovine serum albumin (BSA) was also studied using absorption and fluorescence techniques. The cytotoxic activity of the Cu(II) complexes was probed in HeLa (human breast adenocarcinoma cell line), B16F10 (Murine melanoma cell line) and HEPA1-6 celllines, complex 1 has good cytotoxic activity which is comparable with the doxarubicin drug, with IC50 values ranging from 3 to 12.6 MUM. A further molecular docking technique was employed to understand the binding of the complexes towards the molecular target DNA. Investigation of the antioxidative properties showed that the metal complexes have significant radical scavenging activity potency against DPPH radical. PMID- 28097461 TI - Sonoelectrochemical Synthesis of Nano Zinc(II) Complex with 2-Methyl-8 Hydroxyquinoline Ligand: a Precursor to Produce Pure Phase Nano-Sized Zinc(II) Oxide. AB - A new zinc complex, [Zn(mq)2], (mq = 2-methyl-8-hydroxyquinoline) was prepared via an electrochemical route from the oxidation of zinc metal in the presence of 2-methyl-8-hydroxyquinoline in a fast and facile process. The complex was fully characterized by means of NMR and IR spectra and elemental analysis. The nanostructure of the prepared compound was obtained by sonoelectrochemical process and studied by scanning electron microscopy, X-ray powder diffraction, IR spectroscopy and elemental analysis. Thermal stability of crystalline bulk and nano-size samples of the prepared compound was studied by thermal gravimetric and differential thermal analysis. The photoluminescence properties of the prepared compounds, as crystalline bulk and as nano-structure, have been investigated. The results showed a good correlation between the size and the shape of the complex particle and emission wavelength. The prepared complexes, as bulk and as nano particles, were utilized as a precursor for preparation of ZnO nanoparticles by direct thermal decomposition at 550 degrees C in air. The nano-structures of ZnO were characterized by scanning electron microscopy, X-ray powder diffraction and IR spectroscopy. PMID- 28097463 TI - Neurokinin-1 Receptor-Immunopositive Neurons in the Medullary Dorsal Horn Provide Collateral Axons to both the Thalamus and Parabrachial Nucleus in Rats. AB - It has been suggested that the trigemino-thalamic and trigemino-parabrachial projection neurons in the medullary dorsal horn (MDH) are highly implicated in the sensory-discriminative and emotional/affective aspects of orofacial pain, respectively. In previous studies, some neurons were reported to send projections to both the thalamus and parabrachial nucleus by way of collaterals in the MDH. However, little is known about the chemoarchitecture of this group of neurons. Thus, in the present study, we determined whether the neurokinin-1 (NK-1) receptor, which is crucial for primary orofacial pain signaling, was expressed in MDH neurons co-innervating the thalamus and parabrachial nucleus. Vesicular glutamate transporter 2 (VGLUT2) mRNA, a biomarker for the subgroup of glutamatergic neurons closely related to pain sensation, was assessed in trigemino-parabrachial projection neurons in the MDH. After stereotactic injection of fluorogold (FG) and cholera toxin subunit B (CTB) into the ventral posteromedial thalamic nucleus (VPM) and parabrachial nucleus (PBN), respectively, triple labeling with fluorescence dyes for FG, CTB and NK-1 receptor (NK-1R) revealed that approximately 76 % of the total FG/CTB dually labeled neurons were detected as NK-1R-immunopositive, and more than 94 % of the triple-labeled neurons were distributed in lamina I. In addition, by FG retrograde tract-tracing combined with fluorescence in situ hybridization (FISH) for VGLUT2 mRNA, 54, 48 and 70 % of FG-labeled neurons in laminae I, II and III, respectively, of the MDH co-expressed FG and VGLUT2 mRNA. Thus, most of the MDH neurons co-innervating the thalamus and PBN were glutamatergic. Most MDH neurons providing the collateral axons to both the thalamus and parabrachial nucleus in rats were NK-1R-immunopositive and expressed VGLUT2 mRNA. NK-1R and VGLUT2 in MDH neurons may be involved in both sensory-discriminative and emotional/affective aspects of orofacial pain processing. PMID- 28097462 TI - Thermally Stable Schiff Base and its Metal Complexes: Molecular Docking and Protein Binding Studies. AB - In this paper, interaction of Schiff base and its metal complexes carrying naphthalene ring in the structure with bovine serum albumin (BSA) were investigated using UV-vis absorption, fluorescence spectroscopies and molecular docking methods. The effect on the binding mechanism and properties of these compounds containing metal-free, iron and copper ions were also investigated. The fluorescence spectroscopy results showed that fluorescence intensity of BSA in the presence of different concentration of ligands was decreased through a static quenching mechanism. Binding constants (KSV, Kbin and Ka) and thermodynamic parameters (DeltaG, DeltaH and DeltaS) for the ligand-protein interactions were also determined. DeltaG values of ligand-protein interaction were calculated in the range - 6.3 to -5.5 kcal/mol. These negative values showed that binding process is spontaneous and, hydrogen bonding and van der Waals force were main interaction of the protein and ligands. DeltaH and DeltaS value were also calculated in the range of 1.10 to 1.26 kJ/mol and 0.133 to 0.135 kJ/mol. K, respectively. These positive values indicated that the binding process between ligands and BSA are endothermic and electrostatic interaction, respectively. PMID- 28097464 TI - Cdc42 Promotes Schwann Cell Proliferation and Migration Through Wnt/beta-Catenin and p38 MAPK Signaling Pathway After Sciatic Nerve Injury. AB - Schwann cells (SCs) are unique glial cells in the peripheral nerve and may secrete multiple neurotrophic factors, adhesion molecules, extracellular matrix molecules to form the microenvironment of peripheral nerve regeneration, guiding and supporting nerve proliferation and migration. Cdc42 plays an important regulatory role in dynamic changes of the cytoskeleton. However, there is a little study referred to regulation and mechanism of Cdc42 on glial cells after peripheral nerve injury. The present study investigated the role of Cdc42 in the proliferation and migration of SCs after sciatic nerve injury. Cdc42 expression was tested, showing that the mRNA and protein expression levels of Cdc42 were significantly up-regulated after sciatic nerve injury. Then, we isolated and purified SCs from injuried sciatic nerve at day 7. The purified SCs were transfected with Cdc42 siRNA and pcDNA3.1-Cdc42, and the cell proliferation, cell cycle and migration were assessed. The results implied that Cdc42 siRNA remarkably inhibited Schwann cell proliferation and migration, and resulted in S phase arrest. While pcDNA3.1-Cdc42 showed a contrary effect. Besides, we also observed that Cdc42 siRNA down-regulated the protein expression of beta-catenin, Cyclin D1, c-myc and p-p38, which were up-regulated by pcDNA3.1-Cdc42. Meanwhile, the inhibitor of Wnt/beta-catenin and p38 MAPK signaling pathway IWP-2 and SB203580 significantly inhibited the effect of pcDNA3.1-Cdc42 on cell proliferation and migration. Overall, our data indicate that Cdc42 regulates Schwann cell proliferation and migration through Wnt/beta-catenin and p38 MAPK signaling pathway after sciatic nerve injury, which provides further insights into the therapy of the sciatic nerve injury. PMID- 28097465 TI - Hydroxysafflor Yellow A Improves Motor Dysfunction in the Rotenone-Induced Mice Model of Parkinson's Disease. AB - Dopamine D3 receptor (DRD3) is diminished in patients of Parkinson's disease (PD). Brain-derived neurotrophic factor (BDNF) is responsible for regulating expression of the DRD3 in the brain. Our previous study showed that hydroxysafflor yellow A (HSYA) could increase BDNF content in the striatum of PD mice. This experiment aimed to evaluate whether HSYA can improve the motor dysfunction induced by rotenone through regulating the BDNF/TrkB/DRD3 signaling pathway in mice. Male C57/BL6 mice were intraperitoneally treated with HSYA. Thirty minutes later, they were intragastrically administered with rotenone at a dose of 30 mg/kg. Pole, rotarod and open field tests were investigated at 28 d. Then, tyrosine hydroxylase (TH) in substantia nigra was observed by immunohistochemistry. Dopamine content was detected by high-performance liquid chromatography. The expressions of BDNF, phospho-tropomyosin-related kinase B (p TrkB), tropomyosin-related kinase B (TrkB), phospho-phosphoinositide 3-kinase (p PI3K), phosphoinositide 3-kinase (PI3K), phospho-protein kinase B (p-AKT), protein kinase B (AKT), and DRD3 were assayed by western blotting. Behavioral tests showed that rotenone-challenged mice displayed motor dysfunction. However, treatment with HSYA improved motor dysfunction induced by rotenone. HSYA treatment increased not only the number of TH-containing dopaminergic neurons in substantia nigra, but also the dopamine content in the striatum in PD mice. Moreover, the expressions of BDNF, p-TrkB/TrkB, DRD3, p-PI3K/PI3K, p-AKT/AKT were significantly increased in rotenone plus HSYA group. Our results indicated that HSYA improved motor dysfunction in rotenone-induced PD model and the pharmacological action of HSYA was related to regulating BDNF/TrkB/DRD3 signaling pathway, at least, in part. PMID- 28097466 TI - Trachyspermum ammi Seeds Supplementation Helps Reverse Scopolamine, Alprazolam and Electroshock Induced Amnesia. AB - The present study was designed to explore the beneficial effects of successive 10 days administration of Trachyspermum ammi seed's powder (TASP) along with diet (at the dose of 0.5%, 1.0% and 2.0% w/w) on learning and memory of mice. A total of 306 mice divided in 51 equal groups were employed in the study. Passive avoidance paradigm (PAP) and Object recognition Task (ORT) were employed as exteroceptive models. The brain acetylcholinesterase activity (AChE), serum cholesterol, brain monoaldehyde (MDA), brain reduced glutathione (GSH) and brain nitrite were estimated and Alprazolam, Scopolamine and Electroshock induced amnesia was employed to describe the actions. Treatment of TASP significantly increased step down latency of PAA and significantly increased discrimination index of ORT in groups with or without amnesia when compared to respective control groups. Furthermore, TASP administration resulted in significant fall in brain AChE activity, brain MDA level and brain nitrite level with simultaneous rise in brain GSH level, thereby decreased oxidative damage. A significant decrease in serum cholesterol was also observed. Ajowan supplementation may prove a remedy for the management of cognitive disorders owing to have pro-cholinergic, antioxidant and hypo-lipidemic activities. PMID- 28097467 TI - Strenuous Exercise and Cardiovascular Disease Outcomes. AB - PURPOSE OF REVIEW: This review summarizes several issues at the forefront of recent controversies involving the appropriate exercise dose including epidemiologic data describing mortality trends in those who engage in high levels of physical activity and recent observational data suggesting adverse cardiovascular outcomes among long-term endurance athletes. RECENT FINDINGS: The benefits of habitual and moderate levels of exercise on cardiovascular disease outcomes in the general population have been well established. However, recent data have questioned whether higher doses of physical and athletic activity are associated with adverse cardiovascular outcomes. Specifically in regard to adverse cardiovascular outcomes, the evidence and limitations of the available data associating veteran endurance athletes with an increased risk of atrial fibrillation, exercise-induced arrhythmogenic cardiac remodeling, and accelerated coronary atherosclerosis will be discussed. This review will also provide a conceptual framework in the context of the clinical management of athletic patients and will highlight key areas of future research that may resolve many of these controversial issues. PMID- 28097468 TI - Outcomes of Primary Colorectal Sarcoma: A National Cancer Data Base (NCDB) Review. AB - INTRODUCTION: Primary colorectal sarcomas are a rare entity with anecdotally poor outcomes. We sought to inform surgeons, oncologists, and researchers of the characteristics and outcomes of these understudied and difficult-to-manage tumors. METHODS: The National Cancer Data Base (NCDB) was queried for patients with pathologically confirmed primary sarcoma of the colon or rectum (1998-2012). Gastrointestinal stromal tumors were excluded. Unadjusted overall survival was reported using the Kaplan-Meier method. Patients with colorectal adenocarcinoma were used as a comparison cohort. RESULTS: Four hundred thirty-three patients with primary colorectal sarcoma were identified (57.5% leiomyosarcoma subtype). Median age was 63 [inter-quartile range 52, 75] years with 23.1% between the ages of 18 and 50 and 48.7% female. Majority of sarcomas were located in the colon (70.7%). When compared to 696,902 patients with adenocarcinoma, sarcoma patients were younger, had larger tumors, were more likely node negative and rectal in location, and higher grade (all p < 0.001), while sex, race, and comorbidity score were similar (all p > 0.05). Overall survival was lower at 5 years in patients with sarcoma (43.8%) than adenocarcinoma (52.3%, p < 0.001). CONCLUSION: Primary colorectal sarcomas are rare and present at a younger age and higher grade than adenocarcinoma of the colon and rectum. Survival is significantly worse compared to adenocarcinoma patients. PMID- 28097470 TI - Hepatic Echinococcosis. PMID- 28097469 TI - Laparoscopic-Assisted Percutaneous Endoscopic Cecostomy (LAPEC) in Children and Young Adults. AB - OBJECTIVE: We evaluated the safety and efficacy of the laparoscopic-assisted percutaneous endoscopic cecostomy (LAPEC) procedure both in children and young adults, along with review of their pre-operative motility profiles, antegrade continence enema (ACE) regimen, and postoperative complications. METHODS: This retrospective review investigated 38 patients (32 children and 6 young adults) that underwent the LAPEC procedure. Primary outcomes evaluated were success versus failure of the procedure and post-operative complications. Success was defined as daily stool evacuation with minimal to no fecal incontinence per week. RESULTS: Mean follow up time was 25.8 +/- 22.4 months. Indications for LAPEC included slow transit constipation or colonic neuropathy (n = 22), other types of constipation (n = 5), and a variety of congenital disorders (n = 11). The overall success rate was 95% (36/38 patients) with the two failures in children, both attributed to inability to use the tube due to underlying behavioral disorders or severe anxiety. Five patients above age 18 had leakage compared to 6 in the under age 18 group (83% vs. 19, P = 0.003). There were no other significant complications. CONCLUSION: LAPEC is a safe and effective means of addressing refractory constipation and fecal incontinence in children and young adults who have failed medical management with minimal post-operative complications. PMID- 28097471 TI - Experiences and perceptions regarding clinical breast exam screening by trained laywomen in Malawi. AB - PURPOSE: Despite the increasing burden, breast cancer control in sub-Saharan Africa is insufficient. Late diagnosis and lack of early detection and screening services contribute to high mortality. Clinical breast exam (CBE) screening can be valuable in low-income countries, including use of community health workers and non-health professionals to conduct exams. We assessed experiences of women who underwent CBE screening by trained laywomen in Lilongwe, Malawi, as part of a pilot program. METHODS: The pilot study invited women attending urban health clinics to a breast cancer educational talk followed by CBE screening by trained laywomen. We purposively sampled participants from the pilot study and interviewed them about the screening experience and future cancer education programs and services. RESULTS: Overall participants had positive experiences and were willing to undergo CBE screening by trained laywomen. Participants were motivated by the educational talk, shared newly acquired cancer knowledge with their social networks, and encouraged others to seek screening. Screened women suggested strategies for future interventions including combining breast and cervical cancer screening, using female providers, partnering with community leaders to increase uptake, and expanding services into the community. CONCLUSIONS: Asymptomatic Malawian women accepted CBE screening by trained laywomen and considered breast cancer an important health issue. Women appreciated combined education and screening services and proposed further linkage of breast and cervical cancer screening. Based on our results, training laywomen to educate the public on breast cancer and conduct CBE is a feasible breast cancer control strategy in sub-Saharan Africa. PMID- 28097473 TI - Metabolic syndrome and total cancer mortality in the Third National Health and Nutrition Examination Survey. AB - PURPOSE: Although metabolic syndrome incidence has substantially increased during the last few decades, it largely remains unclear whether this metabolic disorder is associated with total cancer mortality. The present study was carried out to investigate this important question. METHODS: A total of 687 cancer deaths were identified from 14,916 participants in the third National Health and Nutrition Examination Survey by linking them to the National Death Index database through December 31, 2006. Cox proportional hazards regression was performed to calculate hazard ratios (HR) and 95% confidence intervals (CI) for total cancer mortality in relation to metabolic syndrome and its individual components. RESULTS: After adjustment for confounders, a diagnosis of metabolic syndrome was associated with 33% elevated total cancer mortality. Compared with individuals without metabolic syndrome, those with 3, 4 and 5 abnormal components had HRs (95% CIs) of 1.28 (1.03-1.59), 1.24 (0.96-1.60), and 1.87 (1.34-2.63), respectively (p-trend = 0.0003). Systolic blood pressure and serum glucose were associated with an increased risk of death from total cancer [HR (95% CI) for highest vs. lowest quartiles: 1.67 (1.19-2.33), p-trend = 0.002 and 1.34 (1.04-1.74), p-trend = 0.003, respectively]. Overall null results were obtained for lung cancer mortality. The effects of metabolic syndrome and its components on non-lung cancer mortality were generally similar to, but somewhat larger than, those for total cancer mortality. CONCLUSION: Our study is among the first to reveal that metabolic syndrome is associated with increased total cancer mortality. PMID- 28097472 TI - Proceedings of the third international molecular pathological epidemiology (MPE) meeting. AB - Molecular pathological epidemiology (MPE) is a transdisciplinary and relatively new scientific discipline that integrates theory, methods, and resources from epidemiology, pathology, biostatistics, bioinformatics, and computational biology. The underlying objective of MPE research is to better understand the etiology and progression of complex and heterogeneous human diseases with the goal of informing prevention and treatment efforts in population health and clinical medicine. Although MPE research has been commonly applied to investigating breast, lung, and colorectal cancers, its methodology can be used to study most diseases. Recent successes in MPE studies include: (1) the development of new statistical methods to address etiologic heterogeneity; (2) the enhancement of causal inference; (3) the identification of previously unknown exposure-subtype disease associations; and (4) better understanding of the role of lifestyle/behavioral factors on modifying prognosis according to disease subtype. Central challenges to MPE include the relative lack of transdisciplinary experts, educational programs, and forums to discuss issues related to the advancement of the field. To address these challenges, highlight recent successes in the field, and identify new opportunities, a series of MPE meetings have been held at the Dana-Farber Cancer Institute in Boston, MA. Herein, we share the proceedings of the Third International MPE Meeting, held in May 2016 and attended by 150 scientists from 17 countries. Special topics included integration of MPE with immunology and health disparity research. This meeting series will continue to provide an impetus to foster further transdisciplinary integration of divergent scientific fields. PMID- 28097474 TI - IGF-1R Regulates the Extracellular Level of Active MMP-2, Pathological Neovascularization, and Functionality in Retinas of OIR Mouse Model. AB - In ischemic proliferative diseases such as retinopathies, persistent hypoxia leads to the release of numerous neovascular factors that participate in the formation of abnormal vessels and eventually cause blindness. The upregulation and activation of metalloproteinases (MMP-2 and MMP-9) represent a final common pathway in this process. Although many regulators of the neovascular process have been identified, the complete role of the insulin-like growth factor 1 (IGF-1) and its receptor (IGF-1R) appears to be significantly more complex. In this study, we used an oxygen-induced retinopathy (OIR) mouse model as well as an in vitro model of hypoxia to study the role of MMP-2 derived from Muller glial cells (MGCs) and its relation with the IGF-1/IGF-1R system. We demonstrated that MMP-2 protein expression increased in P17 OIR mice, which coincided with the active phase of the neovascular process. Also, glutamine synthetase (GS)-positive cells were also positive for MMP-2, whereas IGF-1R was expressed by GFAP-positive cells, indicating that both proteins were expressed in MGCs. In addition, in the OIR model a single intravitreal injection of the IGF-1R blocking antibody (alphaIR3) administered at P12 effectively prevented pathologic neovascularization, accelerated physiological revascularization, and improved retinal functionality at P17. Finally, in MGC supernatants, the blocking antibody abolished the IGF-1 effect on active MMP-2 under normoxic and hypoxic conditions without affecting the extracellular levels of pro-MMP-2. These results demonstrate, for the first time, that the IGF-1/IGF-1R system regulates active MMP-2 levels in MGCs, thus contributing to MEC remodeling during the retinal neovascular process. PMID- 28097475 TI - SVCT2 Is Expressed by Cerebellar Precursor Cells, Which Differentiate into Neurons in Response to Ascorbic Acid. AB - Ascorbic acid (AA) is a known antioxidant that participates in a wide range of processes, including stem cell differentiation. It enters the cell through the sodium-ascorbate co-transporter SVCT2, which is mainly expressed by neurons in the adult brain. Here, we have characterized SVCT2 expression in the postnatal cerebellum in situ, a model used for studying neurogenesis, and have identified its expression in granular precursor cells and mature neurons. We have also detected SVCT2 expression in the cerebellar cell line C17.2 and in postnatal cerebellum-derived neurospheres in vitro and have identified a tight relationship between SVCT2 expression and that of the stem cell-like marker nestin. AA supplementation potentiates the neuronal phenotype in cerebellar neural stem cells by increasing the expression of the neuronal marker beta III tubulin. Stable over-expression of SVCT2 in C17.2 cells enhances beta III tubulin expression, but it also increases cell death, suggesting that AA transporter levels must be finely tuned during neural stem cell differentiation. PMID- 28097476 TI - Impact of an exercise training program on cardiac neuronal function in heart failure patients on optimal medical therapy : A randomized Iodine-123 metaiodobenzylguanidine scintigraphy study. AB - BACKGROUND: The syndrome of heart failure (HF) is characterized by left ventricular dysfunction and a compensatory chronic over activation of the sympathetic nervous system. We wanted to investigate if the beneficial effects of exercise training (ET) in HF patients on optimal medical therapy (OMT) are associated with alterations in cardiac sympathetic activity. METHODS: Cardiac sympathetic activity was evaluated at baseline and after 12 weeks using metaiodobenzylguanidine scintigraphy in 23 patients with stable HF participating in the SmartEx trial. Patients with HF in New York Heart Association class II or III and left ventricular ejection fraction <35 % were randomized to three different ET groups. RESULTS: We found no statistically significant changes in cardiac sympathetic activity after 12 weeks of ET. Heart to mediastinum (H/M) ratio at 15 minutes (0.00174 +/- 0.0841, P = 0.922), H/M ratio at 4 hours ( 0.00565 +/- 0.1163, P = 0.818) and washout ratio (WR) (-1.2666 +/- 16.5412, P = 0.717). A further group-wise analysis of the three ET groups did not show any difference between the groups. CONCLUSION: A 12-week ET program did not alter the abnormal cardiac sympathetic activity in stable HF patients on modern OMT. PMID- 28097477 TI - SPECT perfusion abnormality associated with arrhythmogenic right ventricular cardiomyopathy. PMID- 28097478 TI - Study of the Influence of Formulation Variables in Bioadhesive Emulgels Using Response Surface Methodology. AB - The aim of the present work was to study the main formulation variables that influence attributes of bioadhesive emulgels based on a combination of polymers, using response surface methodology (RSM). Bioadhesive products continue to gain attention in topical cutaneous administration as they allow long residence times on the application site, which is important when a long dermal action and a reduced product administration frequency are desired. A Box-Behnken design of experiments (DoE) was introduced to study the effect of formulation variables on quality attributes of the emulgels. The effects of concentration of carbomer interpolymer type A (Polym1), xanthan gum (Polym2) and mineral oil (Oil) on detachment force (Fdetch), spreadability (Spread), and phase separation by mechanical stress (PhSep) were investigated. RSM and desirability functions were applied for data analysis. Emulgels were further characterized by viscosity and extrudability measurements. Polym1 showed a positive effect on Fdetch, while the increase in concentrations of Polym2 and Oil decreased this property. Polym1 and Polym2 favored emulgel PhSep. However, their interaction effect decreased it. The combination of 0.4-0.6% of carbomer and 0.2-0.3% of gum was able to produce easy to-spread bioadhesive emulgels with mineral oil as discontinuous phase in the presence of a low surfactant concentration. Based on the DoE results, value ranges for the variables, which could achieve for the experimental domain to get the critical quality attributes of emulgels jointly within the specification limits, were able to be identified using RSM supported by desirability functions. PMID- 28097479 TI - Structural and cooperative length scales in polymer gels. AB - Understanding the relationship between the material structural details, the geometrical confining constraints, the local dynamical events and the global rheological response is at the core of present investigations on complex fluid properties. In the present article, this problem is addressed on a model yield stress fluid made of highly entangled polymer gels of Carbopol which follows at the macroscopic scale the well-known Herschel-Bulkley rheological law. First, performing local rheology measurements up to high shear rates ([Formula: see text] s-1)and under confinement, we evidence unambiguously the breakdown of bulk rheology associated with cooperative processes under flow. Moreover, we show that these behaviors are fully captured with a unique cooperativity length [Formula: see text] over the whole range of experimental conditions. Second, we introduce an original optical microscopy method to access structural properties of the entangled polymer gel in the direct space. Performing image correlation spectroscopy of fluorophore-loaded gels, the characteristic size D of carbopol gels microstructure is determined as a function of preparation protocol. Combining both dynamical and structural information shows that the measured cooperative length [Formula: see text] corresponds to 2-5 times the underlying structural size D, thus providing a strong grounding to the "Shear Transformation Zones" modeling approach. PMID- 28097480 TI - Average flow generation by a pulsating flow near a curved interface. AB - This paper is devoted to the study of curvature influence on the average flow generation near the fluid interface. The time averaging of a non-uniform pulsating flow often results in a nonzero average flow in the bulk. The well known average flow occurs near a solid surface, the so-called Schlichting mechanism of the average flow generation. For flows with a free surface there is the other known mechanism of Longuet-Higgins, according to which the average flow is generated by surface waves traveling on a free surface. We found another mechanism for flow generation near a free surface. This mechanism is associated with the curvature of a free surface and does not depend on its deformations. In the present paper the influence of the curvature is studied for flow generation near the fluid interface. The investigation is carried out on an example of a liquid drop embedded in a viscous liquid. The effective boundary conditions for the tangential stress tensor and tangential velocity jumps are derived. It is shown that for comparable densities of fluids the generation mechanisms are similar to the mechanisms of Dore and Schlichting, which are determined near a flat interface. At a low density (and a low dynamic viscosity) inside the drop all of the above-mentioned mechanisms equally contribute to the average flow generation. PMID- 28097481 TI - Financial development and sectoral CO2 emissions in Malaysia. AB - The paper examines the impacts of financial development on sectoral carbon emissions (CO2) for environmental quality in Malaysia. Since the financial sector is considered as one of the sectors that will contribute to Malaysian economy to become a developed country by 2020, we utilize a cointegration method to investigate how financial development affects sectoral CO2 emissions. The long run results reveal that financial development increases CO2 emissions from the transportation and oil and gas sector and reduces CO2 emissions from manufacturing and construction sectors. However, the elasticity of financial development is not significant in explaining CO2 emissions from the agricultural sector. The results for short-run elasticities were also consistent with the long run results. We conclude that generally, financial development increases CO2 emissions and reduces environmental quality in Malaysia. PMID- 28097482 TI - Heavy metal stabilization in contaminated soil by treatment with calcined cockle shell. AB - In several previous studies, the efficacy of various liming waste materials on the immobilization of heavy metals has been tested and it was found that soils contaminated with heavy metals can be stabilized using this technique. Since lime (CaO) has been identified as the main phase of calcined cockle shell (CCS), it was hypothesized that CCS could be used as a soil amendment to immobilize heavy metals in soil. However, to date, no studies have been conducted using CCS. In this study, the effectiveness of CCS powder on the immobilization of Cd, Pb, and Zn in mine tailing soil was evaluated. After 28 days of incubation, the treated soil samples were exposed to weathering (four cycles of freezing-thawing and four cycles of wetting-drying) for 8 days before being subjected to a leaching test. The results of this study revealed that the soil pH increased from 7.5 to 12.2 with the addition of 5% CCS. A similar soil pH was obtained when the soil was amended with 5% pure CaO. By leaching with 0.1 M HCl, extracted Cd, Pb, and Zn were reduced by up to 85, 85, and 91%, respectively. Therefore, CCS is suggested as a low-cost lime-based soil amendment for stabilizing heavy metals in abandoned mining sites. PMID- 28097483 TI - Phytoremediation of fluoride with garden ornamentals Nerium oleander, Portulaca oleracea, and Pogonatherum crinitum. AB - Nursery grown plants of Nerium oleander, Pogonatherum crinitum, and Portulaca oleracea were observed to remove fluoride up to 92, 80, and 73%, respectively, from NaF solution at the concentration of 10 mg L-1 within 15 days. Concentration range of 10-50 mg L-1 of fluoride revealed a constant decrease of removal from 92 to 51% within 15 days by N. oleander, while the biomass (one to five plants) showed enhancement in removal from 74 to 98% in 10 days. Translocation and bioaccumulation factors calculated after fluoride contents in roots and leaves of N. oleander, P. crinitum, and P. oleracea were 1.85, 1.19, and 1.43, and 9.8, 3.6, and 2.2, respectively. P . oleracea, P. crinitum, and N. oleander showed reductions in chlorophyll contents by 40, 57 and 25 and 8%, carbohydrates by 50, 44, and 16%, and proteins by 38, 53, and 15%, respectively. Activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) in the roots of P. oleracea, P. crinitum, and N. oleander were observed to be induced by 400, 383, and 500%; 80, 105, and 424%; and 153, 77, and 71%, respectively, while the leaves showed induction in SOD, CAT, and GPX activities by 550, 315, and 165%; 196, 227, and 243%; and 280, 242, and 184%, respectively. Results endorsed the superiority of N. oleander for fluoride removal over other plant species. PMID- 28097484 TI - Different physiobiochemical and transcriptomic reactions of rice (Oryza sativa L.) cultivars differing in terms of salt sensitivity under salinity stress. AB - Salinity stress is the most important and common environmental stresses throughout the world, including Iran. The aim of this study was to investigate the expression of several important genes involved in the salinity tolerance of the rice cultivars differing in salt sensitivity. In this research, the expression of four mitochondrial genes, H2O2, malondialdehyde (MDA), proline, sodium, potassium and superoxide dismutase (SOD), was measured in Iranian rice cultivars and two well-known international varieties as checks in response to 100 mM salt stress. The results show that the activity of SOD in the tolerant cultivars is much higher than in the susceptible ones under saline conditions (100 mM NaCl). The study of the gene expression in the tolerant and sensitive cultivars also showed that the expression of the genes increased in the early hours of the stress, with the exception of the OsGR1. Moreover, the amount of the expression in the tolerant cultivars was far more than the susceptible ones. The result of this study showed that the function of a set of antioxidant enzymes can lead to detoxification of the reactive oxygen species, so in order to better understand ROS scavengers, a comprehensive study on the antioxidant system should be conducted. PMID- 28097485 TI - Sorption of organic phosphates and its effects on aggregation of hematite nanoparticles in monovalent and bivalent solutions. AB - Sorption of organic phosphates-myo-inositol hexakisphosphate (IHP) and glycerol phosphate (GP) and its effects on the early stage of hematite aggregation kinetics were investigated at different pH and electrolyte composition. KH2PO4 (KP) was taken as an inorganic P source for comparison. Results indicated that for all types of P, the sorption amounts decreased with increasing solution pH. Sorption amount of IHP was almost two times that of KP, while those of GP and KP were close. Both organic P and inorganic P interacted with hematite via ligand exchange through their phosphate groups, which conveyed negative charges to mineral surface and significantly decreased the zeta potential of hematite. In Na+ solution, critical coagulation concentrations (CCCs) of hematite suspensions increased with increasing P concentration and followed the order of KP < GP < IHP at pH 5.5. Compared with KP, the organic P could more effectively stabilize the hematite suspension not only through increasing the negative charges and electrostatic repulsive force, but also through steric repulsion between P-sorbed hematite nanoparticles. When the pH was increased from 5.5 to 10.0, the CCCs of the hematite suspensions with GP and IHP decreased mainly because of the great reductions in organic P sorption amounts and consequent decreases in electrostatic and steric repulsive forces. However, enhanced aggregation was observed in the presence of IHP at pH 4.5 and above in low Ca2+ solutions. The precipitation of calcium phytate formed net-like structure, which served as bridges to bind hematite nanoparticles and resulted in enhanced aggregation. These results have important implications for assessing the fate and transport of organic P and hematite nanoparticles in soil and aquatic environments. PMID- 28097486 TI - The Therapeutic Effectiveness of Delayed Fetal Spinal Cord Tissue Transplantation on Respiratory Function Following Mid-Cervical Spinal Cord Injury. AB - Respiratory impairment due to damage of the spinal respiratory motoneurons and interruption of the descending drives from brainstem premotor neurons to spinal respiratory motoneurons is the leading cause of morbidity and mortality following cervical spinal cord injury. The present study was designed to evaluate the therapeutic effectiveness of delayed transplantation of fetal spinal cord (FSC) tissue on respiratory function in rats with mid-cervical spinal cord injury. Embryonic day-14 rat FSC tissue was transplanted into a C4 spinal cord hemilesion cavity in adult male rats at 1 week postinjury. The histological results showed that FSC-derived grafts can survive, fill the lesion cavity, and differentiate into neurons and astrocytes at 8 weeks post-transplantation. Some FSC-derived graft neurons exhibited specific neurochemical markers of neurotransmitter (e.g., serotonin, noradrenalin, or acetylcholine). Moreover, a robust expression of glutamatergic and gamma-aminobutyric acid-ergic fibers was observed within FSC derived grafts. Retrograde tracing results indicated that there was a connection between FSC-derived grafts and host phrenic nucleus. Neurophysiological recording of the phrenic nerve demonstrated that phrenic burst amplitude ipsilateral to the lesion was significantly greater in injured animals that received FSC transplantation than in those that received buffer transplantation under high respiratory drives. These results suggest that delayed FSC transplantation may have the potential to repair the injured spinal cord and promote respiratory functional recovery after mid-cervical spinal cord injury. PMID- 28097487 TI - Inter-Individual Responses of Maximal Oxygen Uptake to Exercise Training: A Critical Review. AB - It has recently been reported how to quantify inter-individual differences in the response to an exercise intervention using the standard deviation of the change scores, as well as how to appraise these differences for clinical relevance. In a parallel-group randomised controlled trial, the key trigger for further investigation into inter-individual responses is when the standard deviation of change in the intervention sample is substantially larger than the same standard deviation derived from a suitable comparator sample. 'True' and clinically relevant inter-individual differences in response can then be plausibly expected, and potential moderators and mediators of the inter-individual differences can be explored. We now aim to critically review the research on the inter-individual differences in response to exercise training, focusing on maximal oxygen uptake (VO2max). A literature search through the relevant bibliographic databases resulted in the identification of six relevant studies that were published prior to the influential HEalth, RIsk factors, exercise Training And GEnetics (HERITAGE) Family Study. Only one of these studies was found to include a comparator arm. Re-analysis of the data from this study, accounting for random within-subjects variation, revealed an absence of clinically important inter individual differences in the response of VO2max to exercise training. The standard deviation of change was, in fact, larger (+/-5.6 mL/kg/min) for the comparator than the intervention group (+/-3.7 mL/kg/min). We located over 180 publications that resulted from the HERITAGE Family Study, but we could not find a comparator arm in any of these studies. Some authors did not explain this absence, while others reasoned that only inter-individual differences in exercise response were of interest, thus the intervention sample was investigated solely. We also found this absence of a comparator sample in on-going studies. A perceived high test-retest reliability is offered as a justification for the absence of a comparator arm, but the test-retest reliability analysis for the HERITAGE Family Study was over a much shorter term than the length of the actual training period between baseline and follow-up measurements of VO2max. We also scrutinised the studies in which twins have been investigated, resulting in concerns about how genetic influences on the magnitude of general within-subjects variability has been partitioned out (again in the absence of a comparator no training group), as well as with the intra-class correlation coefficient approach to data analysis. Twin pairs were found to be sometimes heterogeneous for the obviously influential factors of sex, age and fitness, thereby inflating an unadjusted coefficient. We conclude that most studies on inter-individual differences in VO2max response to exercise training have no comparator sample. Therefore, true inter-individual differences in response cannot be quantified, let alone appraised for clinical relevance. For those studies with a comparator sample, we found that the inter-individual differences in training response were not larger than random within-subjects variation in VO2max over the same time period as the training intervention. PMID- 28097488 TI - Polyphenols and Performance: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Polyphenols exert physiological effects that may impact athletic performance. Polyphenols are antioxidants that have been noted to hinder training adaptations, yet conversely they stimulate stress-related cell signalling pathways that trigger mitochondrial biogenesis and influence vascular function. OBJECTIVE: To determine the overall effect of polyphenols on human athletic performance. METHODS: A search strategy was completed using MEDLINE, EMBASE, CINAHL, AMED and SPORTDiscus in April 2016. The studies were screened and independently reviewed by two researchers against predetermined criteria for eligibility. As a result of this screening, 14 studies were included for meta analysis. Of these, the studied populations were predominately-trained males with an average intervention dose of 688 +/- 478 mg.day-1. RESULTS: The pooled results demonstrate polyphenol supplementation for at least 7 days increases performance by 1.90% (95% CI 0.40-3.39). Sub-analysis of seven studies using quercetin identified a performance increase of 2.82% (95% CI 2.05-3.58). There were no adverse effects reported in the studies in relation to the intervention. CONCLUSION: Overall the pooled results show that polyphenols, and of note quercetin, are viable supplements to improve performance in healthy individuals. PMID- 28097489 TI - Enhanced Histone Acetylation in the Infralimbic Prefrontal Cortex is Associated with Fear Extinction. AB - The molecular processes that establish fear memory are complex and involve a combination of genetic and epigenetic influences. Dysregulation of these processes can manifest in humans as a range of fear-related anxiety disorders like post-traumatic stress disorders (PTSD). In the present study, immunohistochemistry for acetyl H3, H4, c-fos, CBP (CREB-binding protein) in the infralimbic prefrontal cortex (IL-PFC) and prelimbic prefrontal cortex (PL-PFC) of mPFC (medial prefrontal cortex) and basal amygdala (BA), lateral amygdala (LA), centrolateral amygdala (CeL), centromedial amygdala (CeM) of the amygdala was performed to link region-specific histone acetylation to fear and extinction learning. It was found that the PL-PFC and IL-PFC along with the sub-regions of the amygdala responded differentially to the fear learning and extinction. Following fear learning, c-fos and CBP expression and acetylation of H3 and H4 increased in the BA, LA, CeM, and CeL and the PL-PFC but not in the IL-PFC as compared to the naive control. Similarly, following extinction learning, c-fos and CBP expression increased in BA, LA, CeL, and IL-PFC but not in PL-PFC and CeM as compared to the naive control and conditioned group. However, the acetylation of H3 increased in both IL and PL as opposed to H4 which increased only in the IL PFC following extinction learning. Overall, region-specific activation in amygdala and PFC following fear and extinction learning as evident by the c-fos activation paralleled the H3/H4 acetylation in these regions. These results suggest that the differential histone acetylation in the PFC and amygdala subnuclei following fear learning and extinction may be associated with the region-specific changes in the neuronal activation pattern resulting in more fear/less fear. PMID- 28097490 TI - Glucose Uptake and Triacylglycerol Synthesis Are Increased in Barth Syndrome Lymphoblasts. AB - Barth syndrome (BTHS) is an X-linked genetic disease resulting in loss of cardiolipin (Ptd2Gro). Patients may be predisposed to hypoglycemia and exhibit increases in whole-body glucose disposal rates and a higher fat mass percentage. We examined the reasons for this in BTHS lymphoblasts. BTHS lymphoblasts exhibited a 60% increase (p < 0.004) in 2-[1,2-3H(N)]deoxy-D-glucose uptake, a 40% increase (p < 0.01) in glucose transporter-3 protein expression, an increase in phosphorylated-adenosine monophosphate kinase (AMPK) and a 58% increase (p < 0.001) in the phosphorylated-AMPK/AMPK ratio compared to controls. In addition, BTHS lymphoblasts exhibited a 90% (p < 0.001) increase in D-[U-14C]glucose incorporated into 1,2,3-triacyl-sn-glycerol (TAG) and a 29% increase (p < 0.025) in 1,2-diacyl-sn-glycerol acyltransferase-2 activity compared to controls. Thus, BTHS lymphoblasts exhibit increased glucose transport and increased glucose utilization for TAG synthesis. These results may, in part, explain why BTHS patients exhibit an increase in whole-body glucose disposal rates, may be predisposed to hypoglycemia and exhibit a higher fat mass percentage. PMID- 28097491 TI - Small Interfering RNA Targeting Dickkopf-1 Contributes to Neuroprotection After Intracerebral Hemorrhage in Rats. AB - Excessive Dickkopf-1 (Dkk-1) plays a vital role in secondary brain injury following ischemic stroke and psychotic disease. However, it is unclear whether an increased expression of Dkk-1 occurred after intracerebral hemorrhage (ICH). The present study examined the potential role of Dkk-1 after ICH. ICH was induced by a single injection of autologous blood into the basal ganglia of rats. Dkk-1 protein levels in brain tissue and serum were detected by enzyme-linked immunosorbent assay after ICH. Rats were treated with small interfering RNA targeting Dkk-1 (siDkk-1) or vehicle following ICH. Behavioral deficits and brain water content were examined. Blood-brain barrier (BBB) integrity was detected by Evans blue extravasation and observed by transmission electron microscopy. Wnt-1 was evaluated by real-time RT-PCR. The tight junction protein zonula occludens-1 (ZO-1) was investigated by immunohistochemistry and Western blot assays. Serum level of Dkk-1 did not differ between the ICH and sham groups. However, the level of Dkk-1 in brain tissue was significantly increased at 24 and 72 h after ICH. BBB disruption and brain edema, as well as neurological deficits, were remarkably ameliorated by administration of siDkk-1. Moreover, siDkk-1 treatment significantly increased the transcription of Wnt-1 mRNA and upregulated the expression of ZO-1. These results provide the first evidence that siDkk-1 treatment is neuroprotective against secondary injury including brain edema and BBB permeability following ICH; the mechanism of neuroprotection may be associated with improvement of BBB integrity. PMID- 28097492 TI - Activation of TRPM2 and TRPV1 Channels in Dorsal Root Ganglion by NADPH Oxidase and Protein Kinase C Molecular Pathways: a Patch Clamp Study. AB - Despite considerable research, the mechanisms of neuropathic pain induced by excessive oxidative stress production and overload calcium ion (Ca2+) entry in dorsal root ganglion (DRG) remain substantially unidentified. The transient receptor potential melastatin 2 (TRPM2) and vanilloid 1 (TRPV1) channels are activated with different stimuli including oxidative stress. TRPM2 and TRPV1 have been shown to be involved in induction of neuropathic pain. However, the activation mechanisms of TRPM2 and TRPV1 via NADPH oxidase and protein kinase C (PKC) pathways are poorly understood. In this study, I investigated the roles of NADPH oxidase and PKC on Ca2+ entry through TRPM2 and TRPV1 channels in in vitro DRG neurons of rats. Rat DRG neurons were used in whole-cell patch clamp experiments. The H2O2-induced TRPM2 current densities were decreased by N-(p amylcinnamoyl)anthranilic acid (ACA), and dose-dependent capsaicin (CAP) and H2O2 induced TRPV1 currents were inhibited by capsazepine (CPZ). The TRPV1 channel is activated in the DRG neurons by 0.01 mM capsaicin but not 0.001 mM or 0.05 mM capsaicin. TRPM2 and TRPV1 currents were increased by the PKC activator, phorbol myristate acetate (PMA), although the currents were decreased by ACA, CPZ, and the PKC inhibitor, bisindolylmaleimide I (BIM). Both channel currents were further increased by PMA + H2O2 as compared to H2O2 only. In the combined presence of PMA + BIM, no TRPM2 or TRPV1 currents were observed. The CAP and H2O2 induced TRPM2 current densities were also decreased by the NADPH oxidase inhibitors apocynin and N-Acetylcysteine. In conclusion, these results demonstrate a protective role for NADPH oxidase and PKC inhibitors on Ca2+ entry through TRPM2 and TRPV1 channels in DRG neurons. Since excessive oxidative stress production and Ca2+ entry are implicated in the pathophysiology of neuropathic pain, the findings may be relevant to the etiology and treatment of neuropathology in DRG neurons. PMID- 28097493 TI - Service Users' Perceptions of an Outreach Wellbeing Service: A Social Enterprise for Promoting Mental Health. AB - Inadequate provision and limited access to mental healthcare has been highlighted with the need to offer more contemporary ways to provide clinically effective interventions. This study aimed to present an insight into service users' perceptions of an outreach Wellbeing Service (WBS), providing psychological therapy in social settings. Descriptive and thematic analysis was undertaken of 50 returned surveys. Comparison of initial and final mental health measures demonstrated a significant improvement in all outcomes with 96% of participants reporting being helped by attending. Participants were assisted to rebuild social connections in a safe and supportive environment and were facilitated to become more self-determining as their resourcefulness to self-manage was cultivated. Situated within different settings within the community, the WBS offers a workable example of a novel approach to supporting and promoting citizens to become more resilient and lead a more fulfilling and independent life in the community. PMID- 28097494 TI - Establishment and characterization of a heart-derived cell line from goldfish (Carassius auratus). AB - The goldfish Carassius auratus, a freshwater fish in the family Cyprinidae, was one of the earliest fish to be domesticated for ornamental purposes. A cell line was established from goldfish heart (GH) tissue to create a biological monitoring tool for viral diseases. The GH cell line was optimally maintained at 25 degrees C in M199 medium supplemented with 10-20% fetal bovine serum. A chromosomal analysis indicated that the cell line remained diploid, with a mean chromosomal count of 100. In viral inoculation assays, significant cytopathic effects (CPEs) were caused by epizootic hematopoietic necrosis virus (EHNV), Andrias davidianus iridovirus (ADIV), and Bohle iridovirus (BIV) infections in the fish cells and the viral titers (average value) of EHNV, ADIV, and BIV in GH cells reached 105.0, 104.5, and 105.0 TCID50/0.1 mL, respectively, within 7 days. However, no CPE was observed in the cells infected with viral hemorrhagic septicemia virus (VHSV), infectious hematopoietic necrosis virus (IHNV), spring viremia of carp virus (SVCV), infectious pancreatic necrosis virus (IPNV), channel catfish virus (CCV), or grass carp reovirus (GCRV). These results suggest that the GH cell line is a valuable tool for studying viral pathogenesis. PMID- 28097495 TI - The expression of hypoxia-inducible factor-1alpha gene is not affected by low oxygen conditions in yellow perch (Perca flavescens) juveniles. AB - Hypoxia can affect various fish populations, including yellow perch Perca flavescens, which is an economically and ecologically important species in Lake Erie, a freshwater system that often experiences hypoxia in the hypolimnetic part of the lake. Fish, similarly to mammals, possess molecular oxygen sensor-hypoxia inducible factor-1 (HIF-1), a transcription factor that can affect expression of many downstream genes related to animal growth and locomotion, protein synthesis, as well as ATP and amino acid metabolism. HIF-1 is a heterodimer, which consists of two subunits: oxygen-sensitive and oxygen-insensitive subunits, alpha and beta, respectively. In this study, we report first on the molecular cloning and sequencing of P. flavescens HIF-1alpha. The full-length complementary DNA (cDNA) was isolated and submitted to the GenBank with accession number KT783483. It consists of 3529 base pairs (bp) carrying a single open-reading frame that encompasses 2250 bp of the coding region, 247 bp of the 5' untranslated region (UTR), and 1032 bp of the 3' UTR. The "de novo" prediction of the 3D structure of HIF-1alpha protein, which consists of 749 amino acids, is presented, too. We then utilized One-Step Taqman(r) real-time RT-PCR technology to monitor changes in HIF 1alpha messenger RNA (mRNA) copies in response to chronic hypoxic stress. An experiment was conducted using 14-day post-swim-up stage yellow perch larvae with uninflated swim bladders. This experiment included three treatment groups: hypoxia, mid-hypoxia, and normoxia, in four replicates (four tanks per treatment) with the following dissolved oxygen levels: 3, 4, and >7 mg O2/L, respectively. At the end (2 weeks) and in the middle (1 week) of the experiment, fish from each tank were sampled for body measurements and molecular biology analysis. The results showed no differences in survival (~90%) between treatment groups. Oxygen concentration was lowered to 3.02 +/- 0.15 (mean +/- SE) mg O2/L with no adverse effect on fish survival. The highest growth rate was observed in the normoxic group. A similar trend was observed with fish body length. The growth rate of fish declined with decreasing water-dissolved oxygen. The number of HIF-1alpha mRNA copies was not significantly different between hypoxic, mid-hypoxic, and normoxic conditions, and this was true for fish obtained in the middle and at the end of the experiment. Graphical abstract. PMID- 28097496 TI - Historical trends of organochlorine pesticides (OCPs) recorded in sediments across the Tibetan Plateau. AB - Sediment cores from four lakes across the Tibetan Plateau were used as natural archives to study the time trends of organochlorine pesticides (OCPs). The total concentrations of dichlorodiphenyltrichloroethane (SigmaDDT) and hexachlorocyclohexane isomers (SigmaHCH) were in the range of 0.04-1.61 and 0.08 1.88 ng/g based on dry weight (dw), while the input fluxes were in the range of 0.3-236 and 0.7-295 pg/cm2/y in the core sediments, respectively. The input fluxes of SigmaDDT and SigmaHCH generally peaked in sediment layers corresponding to the 1970s-1990s and peaked in top sediment layers. The ratio of alpha/gamma HCH decreased in the top layer sediments, implying that the contribution of lindane (pure gamma-HCH) has been increasing in recent years. In addition, the ratio of o,p'-DDT/p,p'-DDT increased significantly over the last 15-20 years, suggesting that dicofol (characterized by high ratio of o,p'-DDT/p,p'-DDT about 7.0) has recently become a relatively more important source of DDT compared to technical DDT itself. The time trends of OCPs recorded in lake sediments examined the impact on such remote alpine regions by human activities. PMID- 28097497 TI - GoPro Hero Cameras for Creation of a Three-Dimensional, Educational, Neurointerventional Video. AB - Neurointerventional education relies on an apprenticeship model, with the trainee observing and participating in procedures with the guidance of a mentor. While educational videos are becoming prevalent in surgical cases, there is a dearth of comparable educational material for trainees in neurointerventional programs. We sought to create a high-quality, three-dimensional video of a routine diagnostic cerebral angiogram for use as an educational tool. A diagnostic cerebral angiogram was recorded using two GoPro HERO 3+ cameras with the Dual HERO System to capture the proceduralist's hands during the case. This video was edited with recordings from the video monitors to create a real-time three-dimensional video of both the actions of the neurointerventionalist and the resulting wire/catheter movements. The final edited video, in either two or three dimensions, can serve as another instructional tool for the training of residents and/or fellows. Additional videos can be created in a similar fashion of more complicated neurointerventional cases. The GoPro HERO 3+ camera and Dual HERO System can be used to create educational videos of neurointerventional procedures. PMID- 28097498 TI - Clinical Applications of a CT Window Blending Algorithm: RADIO (Relative Attenuation-Dependent Image Overlay). AB - A methodology is described using Adobe Photoshop and Adobe Extendscript to process DICOM images with a Relative Attenuation-Dependent Image Overlay (RADIO) algorithm to visualize the full dynamic range of CT in one view, without requiring a change in window and level settings. The potential clinical uses for such an algorithm are described in a pictorial overview, including applications in emergency radiology, oncologic imaging, and nuclear medicine and molecular imaging. PMID- 28097499 TI - Automating Perforator Flap MRA and CTA Reporting. AB - Surgical breast reconstruction after mastectomy requires precise perforator coordinates/dimensions, perforator course, and fat volume in a radiology report. Automatic perforator reporting software was implemented as an OsiriX Digital Imaging and Communications in Medicine (DICOM) viewer plugin. For perforator analysis, the user identifies a reference point (e.g., umbilicus) and marks each perforating artery/vein bundle with multiple region of interest (ROI) points along its course beginning at the muscle-fat interface. Computations using these points and analysis of image data produce content for the report. Post-processing times were compared against conventional/manual methods using de-identified images of 26 patients with surgically confirmed accuracy of perforator locations and caliber. The time from loading source images to completion of report was measured. Significance of differences in mean processing times for this automated approach versus the conventional/manual approach was assessed using a paired t test. The mean conventional reporting time for our radiologists was 76 +/- 27 min (median 65 min) compared with 25 +/- 6 min (median 25 min) using our OsiriX plugin (p < 0.01). The conventional approach had three reports with transcription errors compared to none with the OsiriX plugin. Otherwise, the reports were similar. In conclusion, automated reporting of perforator magnetic resonance angiography (MRA) studies is faster compared with the standard, manual approach, and transcription errors which are eliminated. PMID- 28097500 TI - Update on Aspirin-Exacerbated Respiratory Disease. AB - Aspirin-exacerbated respiratory disease (AERD) is an acquired disease characterized by chronic eosinophilic airway inflammation with underlying dysregulation of arachidonic acid metabolism. The purpose of this paper is to review the latest developments in our understanding of the underlying pathophysiology including the role of eosinophils, mast cells, innate lymphoid cells (ILC2), and platelets. Clinical features such as respiratory reactions induced by alcohol, aggressive nasal polyposis, and anosmia will allow for earlier recognition of these patients in clinical practice. The current state of the art management of AERD will be addressed including the ongoing central role for aspirin desensitization and high-dose aspirin therapy. PMID- 28097501 TI - Efficient production of free fatty acids from ionic liquid-based acid- or enzyme catalyzed bamboo hydrolysate. AB - Two engineered Escherichia coli strains, DQ101 (MG1655 fadD -)/pDQTES and DQ101 (MG1655 fadD -)/pDQTESZ were constructed to investigate the free fatty acid production using ionic liquid-based acid- or enzyme-catalyzed bamboo hydrolysate as carbon source in this study. The plasmid, pDQTES, carrying an acyl-ACP thioesterase 'TesA of E. coli in pTrc99A was constructed firstly, and then (3R) hydroxyacyl-ACP dehydratase was ligated after the TesA to give the plasmid pDQTESZ. These two strains exhibited efficient fatty acid production when glucose was used as the sole carbon source, with a final concentration of 2.45 and 3.32 g/L, respectively. The free fatty acid production of the two strains on xylose is not as efficient as that on glucose, which was 2.32 and 2.96 g/L, respectively. For mixed sugars, DQ101 (MG1655 fadD -)-based strains utilized glucose and pentose sequentially under the carbon catabolite repression (CCR) regulation. The highest total FFAs concentration from the mixed sugar culture reached 2.81 g/L by DQ101 (MG1655 fadD -)/pDQTESZ. Furthermore, when ionic liquid-based enzyme catalyzed bamboo hydrolysate was used as the carbon source, the strain DQ101 (MG1655 fadD -)/pDQTESZ could produce 1.23 g/L FFAs with a yield of 0.13 g/g, and while it just produced 0.65 g/L free fatty acid with the ionic liquid-based acid catalyzed bamboo hydrolysate as the feedstock. The results suggested that enzymatic catalyzed bamboo hydrolysate with ionic liquid pretreatment could serve as an efficient feedstock for free fatty acid production. PMID- 28097503 TI - Blended Chitosan Paste for Infection Prevention: Preliminary and Preclinical Evaluations. AB - BACKGROUND: Local drug delivery devices offer a promising method for delivering vancomycin and amikacin for musculoskeletal wounds. However, current local delivery devices such as beads and sponges do not necessarily allow for full coverage of a wound surface with eluted antibiotics and do not address the need for reducing the antibiotic diffusion distance to help prevent contamination by bacteria or other microorganisms. We blended chitosan/polyethylene glycol (PEG) pastes/sponges to increase biocompatibility and improve antibiotic coverage within the wound. QUESTIONS/PURPOSES: (1) Are blended chitosan/PEG pastes biodegradable? (2) Are the blended pastes biocompatible? (3) How much force does paste require for placement by injection? (4) Will the pastes elute active antibiotics to inhibit bacteria in vitro? (5) Can the pastes prevent infection in a preclinical model with hardware? METHODS: Our blended paste/sponge formulations (0.5% acidic, 1% acidic, and acidic/neutral) along with a control neutral 1% chitosan sponge were tested in vitro for degradability, cytocompatibility, injectability tested by determining the amount of force needed to inject the pastes, elution of antibiotics, and activity tested using zone of inhibition studies. Along with these studies, in vivo models for biocompatibility and infection prevention were tested using a rodent model and an infected mouse model with hardware, respectively. By evaluating these characteristics, an improved local drug delivery device can be determined. RESULTS: All three of the paste formulations evaluated were almost fully degraded and with 6 days of degradation, the percent remaining being was less than that of the control sponge (percent remaining: control 99.251% +/- 1.0%; 0.5% acidic 1.6% +/- 2.1%, p = 0.002; 1% acidic 1.7% +/- 1.6%, p = 0.002; acidic/neutral 2.3% +/- 1.7%, p = 0.010). There was good biocompatibility because cell viability in vitro was high (control 100.0 +/- 14.3; 0.5% acidic formulation at 79.4 +/- 12.6, p < 0.001; 1% acidic formulation at 98.6 +/- 6.1, p = 0.993; acidic/neutral formulation at 106.7 +/- 12.8, p = 0.543), and in vivo inflammation was moderate (control 2.1 +/- 1.2; 0.5% acidic 3.3 +/- 0.2, p = 0.530; 1% acidic 2.5 +/- 0.9, p = 0.657; acidic/neutral 2.9 +/- 1.1, p = 0.784). Force required to inject the 0.5% acidic and 1% acidic pastes was less than the acidic/neutral paste used as a control (control 167.7 +/- 85.6; 0.5% acidic 41.3 +/- 10.7, p = 0.070; 1% acidic 28.0 +/- 7.0, p = 0.940). At 72 hours, all paste formulations exhibited in vitro activity against Staphylococcus aureus (control 2.6 +/- 0.8; 0.5% acidic 98.1 +/- 33.5, p = 0.002; 1% acidic 87.3 +/- 17.2, p = 0.006; acidic/neutral 83.5 +/- 14.3, p = 0.010) and Pseudomonas aeruginosa (control 163.0 +/- 1.7; 0.5% acidic 85.7 +/- 83.6, p = 0.373; 1% acidic 38.0 +/- 45.1, p = 0.896; acidic/neutral 129.7 +/- 78.0, p = 0.896). Also, the paste formulations were able to prevent the infection with 100% clearance on the implanted hardware and surrounding tissue with the control being a 0.5% acidic paste group without antibiotics (control 4 * 104 +/- 4.8 * 104; 0.5% acidic 0.0 +/- 0.0, p value: 0.050; 1% acidic 0.0 +/- 0.0, p = 0.050; acidic/neutral 0.0 +/- 0.0, p = 0.050). CONCLUSIONS: The preliminary studies demonstrated promising results for the blended chitosan/PEG pastes with antibiotics provided degradability, biocompatibility, injectability, and infection prevention for musculoskeletal-type wounds. CLINICAL RELEVANCE: The preliminary studies with the chitosan paste delivered antibiotics to a contaminated musculoskeletal wound with hardware and prevented infection. More studies in a complex musculoskeletal wound and dosage studies are needed for continued development. PMID- 28097504 TI - Estimating the relative weights of visual and auditory tau versus heuristic-based cues for time-to-contact judgments in realistic, familiar scenes by older and younger adults. AB - Estimating time to contact (TTC) involves multiple sensory systems, including vision and audition. Previous findings suggested that the ratio of an object's instantaneous optical size/sound intensity to its instantaneous rate of change in optical size/sound intensity (tau) drives TTC judgments. Other evidence has shown that heuristic-based cues are used, including final optical size or final sound pressure level. Most previous studies have used decontextualized and unfamiliar stimuli (e.g., geometric shapes on a blank background). Here we evaluated TTC estimates by using a traffic scene with an approaching vehicle to evaluate the weights of visual and auditory TTC cues under more realistic conditions. Younger (18-39 years) and older (65+ years) participants made TTC estimates in three sensory conditions: visual-only, auditory-only, and audio-visual. Stimuli were presented within an immersive virtual-reality environment, and cue weights were calculated for both visual cues (e.g., visual tau, final optical size) and auditory cues (e.g., auditory tau, final sound pressure level). The results demonstrated the use of visual tau as well as heuristic cues in the visual-only condition. TTC estimates in the auditory-only condition, however, were primarily based on an auditory heuristic cue (final sound pressure level), rather than on auditory tau. In the audio-visual condition, the visual cues dominated overall, with the highest weight being assigned to visual tau by younger adults, and a more equal weighting of visual tau and heuristic cues in older adults. Overall, better characterizing the effects of combined sensory inputs, stimulus characteristics, and age on the cues used to estimate TTC will provide important insights into how these factors may affect everyday behavior. PMID- 28097502 TI - Should we routinely use DEBTACE for unresectable HCC? cTACE versus DEBTACE: a single-center survival analysis. AB - Conventional trans-arterial chemoembolization (cTACE) for intermediate stage hepatocellular carcinoma (HCC) achieves a partial response in up to 72% of patients and improves median survival. Drug-eluting-beads-TACE (DEBTACE) improves treatment efficacy and tolerance as compared to cTACE. Our aim was to retrospectively evaluate our experience in the treatment of intermediate/advanced HCC with cTACE versus DEBTACE. Overall survival (OS) was the first endpoint. We retrospectively considered our department register data between 2006 and 2012. A total of 82 non-surgical patients, who underwent cTACE or DEBTACE, with a minimum of 12 months follow-up, met the inclusion criteria. Patients received a standard chemotherapy dose (50 mg). Radiological response was evaluated by CT after 30 days and re-treatment was considered. Statistical analysis was performed with SPSS software. 54 patients received cTACE and 28 DEBTACE. In the DEBTACE group the median survival times was 22.7 months (CI 11.6-33.8), while in the cTACE group it was 21.8 months (CI 15.7-27.9). The survival analysis at log-rank (p = 0.708) and Wilcoxon (p = 0.661) tests demonstrated no differences between DEBTACE and cTACE. The probability of death in function of time was significantly associated only to the Child-Pugh score. A Child A score was shown to be protective instead of Child B (OR 0.583; IC 95% = 0.344-0.987). DEBTACE for treating HCC is comparable to cTACE in terms of effectiveness, but seems to be better tolerated. Both treatments can be performed in case of tumor recurrence without substantial increase in procedural complications and risk of liver failure. We do confirm that there are no differences between the two techniques in terms of survival and that it is mainly affected by the reserved liver function proper of each patient. PMID- 28097505 TI - Support for context effects on segmentation and segments depends on the context. AB - Listeners must adapt to differences in speech rate across talkers and situations. Speech rate adaptation effects are strong for adjacent syllables (i.e., proximal syllables). For studies that have assessed adaptation effects on speech rate information more than one syllable removed from a point of ambiguity in speech (i.e., distal syllables), the difference in strength between different types of ambiguity is stark. Studies of word segmentation have shown large shifts in perception as a result of distal rate manipulations, while studies of segmental perception have shown only weak, or even nonexistent, effects. However, no study has standardized methods and materials to study context effects for both types of ambiguity simultaneously. Here, a set of sentences was created that differed as minimally as possible except for whether the sentences were ambiguous to the voicing of a consonant or ambiguous to the location of a word boundary. The sentences were then rate-modified to slow down the distal context speech rate to various extents, dependent on three different definitions of distal context that were adapted from previous experiments, along with a manipulation of proximal context to assess whether proximal effects were comparable across ambiguity types. The results indicate that the definition of distal influenced the extent of distal rate effects strongly for both segments and segmentation. They also establish the presence of distal rate effects on word-final segments for the first time. These results were replicated, with some caveats regarding the perception of individual segments, in an Internet-based sample recruited from Mechanical Turk. PMID- 28097506 TI - Bioequivalence Methodologies for Topical Drug Products: In Vitro and Ex Vivo Studies with a Corticosteroid and an Anti-Fungal Drug. AB - OBJECTIVE: To examine whether in vitro and ex vivo measurements of topical drug product performance correlate with in vivo outcomes, such that more efficient experimental approaches can be reliably and reproducibly used to establish (in)equivalence between formulations for skin application. MATERIALS AND METHODS: In vitro drug release through artificial membranes, and drug penetration into porcine skin ex vivo, were compared with published human in vivo studies. Two betamethasone valerate (BMV) formulations, and three marketed econazole nitrate (EN) creams were assessed. RESULTS: For BMV, the stratum corneum (SC) uptake of drug in 6 h closely matched data observed in vivo in humans, and distinguished between inequivalent formulations. SC uptake of EN from the 3 creams mirrored the in vivo equivalence in man (both clinically and via similar tape-stripping experiments). However, EN clearance from SC ex vivo did not parallel that in vivo, presumably due to the absence of a functioning microcirculation. In vitro release of BMV from the different formulations did not overlap with either ex vivo or in vivo tape-stripping data whereas, for EN, a good correlation was observed. No measurable permeation of either BMV or EN was detected in a 6-h in vitro skin penetration experiment. CONCLUSIONS: In vitro and ex vivo methods for topical bioequivalence determination can show correlation with in vivo outcomes. However, these surrogates have understandable limitations. A "one-size-fits-all" approach for topical bioequivalence evaluation may not always be successful, therefore, and the judicious use of complementary methods may prove a more effective and reliable strategy. PMID- 28097507 TI - In vitro Phase I- and Phase II-Drug Metabolism in The Liver of Juvenile and Adult Gottingen Minipigs. AB - PURPOSE: In view of pediatric drug development, juvenile animal studies are gaining importance. However, data on drug metabolizing capacities of juvenile animals are scarce, especially in non-rodent species. Therefore, we aimed to characterize the in vitro biotransformation of four human CYP450 substrates and one UGT substrate in the livers of developing Gottingen minipigs. METHODS: Liver microsomes from late fetal, Day 1, Day 3, Day 7, Day 28, and adult male and female Gottingen minipigs were incubated with a cocktail of CYP450 substrates, including phenacetin, tolbutamide, dextromethorphan, and midazolam. The latter are probe substrates for human CYP1A2, CYP2C9, CYP2D6, and CYP3A4, respectively. In addition, the UGT multienzyme substrate (from the UGT-GloTM assay), which is glucuronidated by several human UGT1A and UGT2B enzymes, was also incubated with the porcine liver microsomes. RESULTS: For all tested substrates, drug metabolism significantly rose postnatally. At one month of age, 60.5 and 75.4% of adult activities were observed for acetaminophen and dextrorphan formations, respectively, while 35.4 and 43.2% of adult activities were present for 4-OH tolbutamide and 1'-OH-midazolam formations. Biotransformation of phenacetin was significantly higher in 28-day-old and adult females compared with males. CONCLUSIONS: Maturation of metabolizing capacities occurred postnatally, as described in man. PMID- 28097508 TI - Preparation and evaluation of biopolymeric nanoparticles as drug delivery system in effective treatment of rheumatoid arthritis. AB - PURPOSE: The study purposes to evaluate nanocrystalline biopolymeric nanoparticles encapsulating methotrexate and dexamethasone with high biocompatibility, enhanced therapeutic efficacy and reduced toxicity. METHODS: Chitosan nanoparticles were prepared by ionic gelation, and Methotrexate (MTX) and Dexamethasone (DEX) were loaded during the preparation and screened for their in vitro efficacy in HEK and RAW264.7 cells, ex vivo and in vivo efficacy. RESULTS: FTIR confirmed the involvement of phosphoric group of sTPP with amine groups of chitosan and also role of hydrogen bonding involved in the preparation of MTXCHNP and DEXCHNP. Controlled release patterns coupled with diffusion of drug were observed in two different buffers (PBS) at pH 7.4 and pH 5.8. The IC50 for MTXCHNP for HEK was 26.1 MUg/ml and 7.7 MUg/ml for RAW 264.7 cells. In DEXCHNP, the IC50 was 20.12 MUg/ml for HEK and 7.37 MUg/ml for RAW264.7 cells. Enhanced uptake of FITC-CHNP by RAW cells indicated internalization of nanoparticles by phagocytosis. The enhanced release of drug at lower pH justified increased cytotoxicity. Negligible ex-vivo hemolysis indicated the higher biocompatibility of the nanoparticles. 99mTc-CHNP exhibited maximum absorption in blood circulation in 3 h, followed by hepatic metabolism and renal clearance. Higher in-vivo anti-arthritic activity and antioxidant activity was observed post intraperitoneal (i.p.) injections by both MTXCHNP and DEXCHNP when compared to MTX (0.75 mg/Kg by i.p. route) and DEX (0.2 mg/Kg/i.p./daily) per se. CONCLUSION: The nanocrystalline biopolymeric nanoparticles were stable, biocompatible and have potential to be administered through i.p. route with minimal toxicity and high efficacy. PMID- 28097509 TI - Revealing pMDI Spray Initial Conditions: Flashing, Atomisation and the Effect of Ethanol. AB - PURPOSE: Sprays from pressurised metered-dose inhalers are produced by a transient discharge of a multiphase mixture. Small length and short time scales have made the investigation of the governing processes difficult. Consequently, a deep understanding of the physical processes that govern atomisation and drug particle formation has been elusive. METHODS: X-ray phase contrast imaging and quantitative radiography were used to reveal the internal flow structure and measure the time-variant nozzle exit mass density of 50 uL metered sprays of HFA134a, with and without ethanol cosolvent. Internal flow patterns were imaged at a magnification of 194 pixels/mm and 7759 frames per second with 150 ps temporal resolution. Spray projected mass was measured with temporal resolution of 1 ms and spatial resolution 6 um * 5 um. RESULTS: The flow upstream of the nozzle comprised large volumes of vapour at all times throughout the injection. The inclusion of ethanol prevented bubble coalescence, altering the internal flow structure and discharge. Radiography measurements confirmed that the nozzle exit area is dominantly occupied by vapour, with a peak liquid volume fraction of 13%. CONCLUSION: Vapour generation in pMDIs occurs upstream of the sump, and the dominant volume component in the nozzle exit orifice is vapour at all times in the injection. The flow in ethanol-containing pMDIs has a bubbly structure resulting in a comparatively stable discharge, whereas the binary structure of propellant-only flows results in unsteady discharge and the production of unrespirable liquid masses. PMID- 28097510 TI - When Headache Warns of Homeostatic Threat: the Metabolic Headaches. AB - Headache attributable to disorders of homeostasis represents a diverse diagnostic category in which external (i.e., high-altitude) or internal (i.e., fasting) demands exceed homeostatic capacity, resulting in symptomatic headaches. Metabolic headaches, especially fasting headache, have been observed to be common in the general population. In many cases, a history of migraine is a risk factor, consistent with the hypothesis of an adaptive, evolutionary role of headache to warn against environmental and physiological threats. Because many exposures may also be interpreted as migraine triggers, some authors have considered certain disorders in this category to more accurately represent primary headache disorders. Nonetheless, these disorders not only represent important clinical entities, recognition of which may prevent medical morbidity, but also interesting exposure-response models to further our understanding regarding headache pathophysiology. PMID- 28097511 TI - Brain Calcification and Movement Disorders. AB - Brain calcifications may be an incidental finding on neuroimaging in normal, particularly older individuals, but can also indicate numerous hereditary and nonhereditary syndromes, and metabolic, environmental, infectious, autoimmune, mitochondrial, traumatic, or toxic disorders. Bilateral calcifications most commonly affecting the basal ganglia may often be found in idiopathic cases, and a new term, primary familial brain calcification (PFBC), has been proposed that recognizes the genetic causes of the disorder and that calcifications occurred well beyond the basal ganglia. PFBC, usually inherited in an autosomal dominant fashion, is both an intrafamilial and an interfamilial heterogeneous disorder, clinically characterized by an insidious and progressive development of movement disorders, cognitive decline, and psychiatric symptoms, but also cerebellar ataxia, pyramidal signs, and sometimes isolated seizures and headaches/migraines. Heterozygous mutations in four genes (SLC20A2, PDGFRB, PDGFB, XPR1) have recently proved to be the causes of the autosomal dominant forms of PFBC, also suggesting disrupted phosphate homeostasis as "an underlying and converging" pathophysiological mechanism. However, to date, it is not possible to anticipate with acceptable certainty any of known genetic causes of PFBC on the basis of the type, severity, pattern of distribution, or combination of movement disorders (mainly parkinsonism, with or without tremor, but also dystonia, chorea, paroxysmal kinesigenic dyskinesia, orofacial dyskinesia, and gait and speech disorders). PMID- 28097512 TI - Deletion of Nlrp3 protects from inflammation-induced skeletal muscle atrophy. AB - BACKGROUND: Critically ill patients develop atrophic muscle failure, which increases morbidity and mortality. Interleukin-1beta (IL-1beta) is activated early in sepsis. Whether IL-1beta acts directly on muscle cells and whether its inhibition prevents atrophy is unknown. We aimed to investigate if IL-1beta activation via the Nlrp3 inflammasome is involved in inflammation-induced atrophy. METHODS: We performed an experimental study and prospective animal trial. The effect of IL-1beta on differentiated C2C12 muscle cells was investigated by analyzing gene-and-protein expression, and atrophy response. Polymicrobial sepsis was induced by cecum ligation and puncture surgery in Nlrp3 knockout and wild type mice. Skeletal muscle morphology, gene and protein expression, and atrophy markers were used to analyze the atrophy response. Immunostaining and reporter-gene assays showed that IL-1beta signaling is contained and active in myocytes. RESULTS: Immunostaining and reporter gene assays showed that IL-1beta signaling is contained and active in myocytes. IL 1beta increased Il6 and atrogene gene expression resulting in myocyte atrophy. Nlrp3 knockout mice showed reduced IL-1beta serum levels in sepsis. As determined by muscle morphology, organ weights, gene expression, and protein content, muscle atrophy was attenuated in septic Nlrp3 knockout mice, compared to septic wild type mice 96 h after surgery. CONCLUSIONS: IL-1beta directly acts on myocytes to cause atrophy in sepsis. Inhibition of IL-1beta activation by targeting Nlrp3 could be useful to prevent inflammation-induced muscle failure in critically ill patients. PMID- 28097513 TI - Stable Control of Firing Rate Mean and Variance by Dual Homeostatic Mechanisms. AB - Homeostatic processes that provide negative feedback to regulate neuronal firing rates are essential for normal brain function. Indeed, multiple parameters of individual neurons, including the scale of afferent synapse strengths and the densities of specific ion channels, have been observed to change on homeostatic time scales to oppose the effects of chronic changes in synaptic input. This raises the question of whether these processes are controlled by a single slow feedback variable or multiple slow variables. A single homeostatic process providing negative feedback to a neuron's firing rate naturally maintains a stable homeostatic equilibrium with a characteristic mean firing rate; but the conditions under which multiple slow feedbacks produce a stable homeostatic equilibrium have not yet been explored. Here we study a highly general model of homeostatic firing rate control in which two slow variables provide negative feedback to drive a firing rate toward two different target rates. Using dynamical systems techniques, we show that such a control system can be used to stably maintain a neuron's characteristic firing rate mean and variance in the face of perturbations, and we derive conditions under which this happens. We also derive expressions that clarify the relationship between the homeostatic firing rate targets and the resulting stable firing rate mean and variance. We provide specific examples of neuronal systems that can be effectively regulated by dual homeostasis. One of these examples is a recurrent excitatory network, which a dual feedback system can robustly tune to serve as an integrator. PMID- 28097514 TI - Cumulative Risk Exposure and Waist Circumference in Preschool-Aged Children: the Mediating Role of Television and Moderating Role of Sex. AB - BACKGROUND: Children exposed to multiple stressors are more likely to be overweight, but little is known about the mechanisms explaining this association. PURPOSE: This cross-sectional study examined whether children exposed to multiple stressors had higher waist circumference, and whether this association was mediated through children's television time. METHODS: Participants were 319 parent-child dyads. Children were 2-5 years old and had at least one overweight parent (BMI >= 25 kg/m2). Data were collected at baseline of a larger childhood obesity prevention study and included information on psychosocial stressors (e.g., parenting stress), demographic stressors (e.g., low income), children's television time, and children's waist circumference. Two cumulative risk scores were created by summing stressors in each domain (demographic and psychosocial). Mediation and moderated mediation analyses were conducted. RESULTS: Indirect effects of both cumulative risk scores on waist circumference through television time were not significant; however, moderated mediation analyses found significant moderation by gender. The indirect effects of both risk scores on waist circumference through television time were significant and positive for girls, but near-zero for boys. CONCLUSIONS: Reducing television time should be explored as a strategy for buffering against the negative health effects of exposure to multiple stressors among girls. Longitudinal and intervention research is needed to confirm these results and to identify mediating factors between cumulative risk and body weight among boys. PMID- 28097516 TI - Are event-related potentials to dynamic facial expressions of emotion related to individual differences in the accuracy of processing facial expressions and identity? AB - Despite a wealth of knowledge about the neural mechanisms behind emotional facial expression processing, little is known about how they relate to individual differences in social cognition abilities. We studied individual differences in the event-related potentials (ERPs) elicited by dynamic facial expressions. First, we assessed the latent structure of the ERPs, reflecting structural face processing in the N170, and the allocation of processing resources and reflexive attention to emotionally salient stimuli, in the early posterior negativity (EPN) and the late positive complex (LPC). Then we estimated brain-behavior relationships between the ERP factors and behavioral indicators of facial identity and emotion-processing abilities. Structural models revealed that the participants who formed faster structural representations of neutral faces (i.e., shorter N170 latencies) performed better at face perception (r = -.51) and memory (r = -.42). The N170 amplitude was not related to individual differences in face cognition or emotion processing. The latent EPN factor correlated with emotion perception (r = .47) and memory (r = .32), and also with face perception abilities (r = .41). Interestingly, the latent factor representing the difference in EPN amplitudes between the two neutral control conditions (chewing and blinking movements) also correlated with emotion perception (r = .51), highlighting the importance of tracking facial changes in the perception of emotional facial expressions. The LPC factor for negative expressions correlated with the memory for emotional facial expressions. The links revealed between the latency and strength of activations of brain systems and individual differences in processing socio-emotional information provide new insights into the brain mechanisms involved in social communication. PMID- 28097515 TI - Distress is Interdependent in Patients and Caregivers with Newly Diagnosed Incurable Cancers. AB - BACKGROUND: Individuals with advanced, incurable cancer often experience high physical and psychological symptom burden. Family and friend caregivers are at risk for emotional distress. PURPOSE: The aim of the study is to investigate the interrelationship of distress in patient-caregiver dyads at the time of newly diagnosed incurable cancer. METHODS: From May 2011 to July 2015, within 8 weeks of diagnosis of advanced lung or noncolorectal gastrointestinal cancer, 350 patients and 275 family caregivers were enrolled in a randomized controlled trial of early palliative care. Actor-partner interdependence modeling was used to examine relationships between dyad's self-reported anxiety and depressive symptoms on the Hospital Anxiety and Depression Scale at baseline. RESULTS: Comparing patients with caregivers, patients reported more depressive symptoms (M diff = .84; t[274] = 3.17, p = .002, d = .22) and caregivers reported more anxiety symptoms (M diff =1.62, t[274] = 4.91, p < .001, d = .39). Dyads' anxiety symptoms were positively associated, as were depressive symptoms (rs = .21, ps <= .001). Actor-partner interdependence modeling showed that patients' anxiety symptoms were positively associated with their own depressive symptoms, with an equal effect for caregivers (actor effect betas = 0.52, ps < .001). Patients' own anxiety was concurrently positively associated with their caregivers' depressive symptoms, with an equal effect for caregivers to patients (partner effect betas=0.08, ps=.008). CONCLUSIONS: In the context of newly diagnosed incurable cancer, caregivers experience more pronounced anxiety, while patients report greater depressive symptoms. Findings indicate that anxiety and depressive symptoms are interrelated among dyads facing newly diagnosed incurable disease. Results emphasize the importance of addressing distress in both patients and caregivers. Future research should discern when dyadic versus individual psychosocial interventions would be optimal. TRIAL REGISTRATION NUMBER: The trial was registered with the ClinicalTrials.gov database (NCT02349412) https://clinicaltrials.gov/ct2/show/NCT02349412 . PMID- 28097517 TI - In Utero Exposure of Hyperlipidemic Mice to Diesel Exhaust: Lack of Effects on Atherosclerosis in Adult Offspring Fed a Regular Chow Diet. AB - Uterine stress is associated with an increased risk of later life metabolic diseases. In this study, we investigated the effect of diesel exhaust (DE) exposure in utero on adult susceptibility to atherosclerosis in genetically hyperlipidemic mice. Pregnant apolipoprotein E-deficient mice received either DE exposure (~250-300 MUg/m3 PM2.5 for 6 h/day, 5 days/week) or filtered air (FA) throughout gestation. Treatment effects on litter size and gender distribution were recorded. Plasma cholesterol and triglycerides were measured at 8, 12 and 16 weeks of age. Urinary 8-isoprostane and liver 8-hydroxy-deoxyguanosine levels were measured at killing at 16 weeks of age. Expression of the antioxidant genes heme oxygenase-1 and the glutamate-cysteine ligase modifier and catalytic subunits were measured in the lung, liver and aorta. The average area and frequency of atherosclerotic lesions were measured in the aortic sinus and innominate arteries. There were significantly smaller litters and higher postnatal mortality in the DE-exposed mice. There were no significant differences in plasma lipids or lipoprotein profiles, expression of antioxidant genes or markers of oxidative stress between treatment groups. There were also no significant differences in average atherosclerotic lesion area in the aortic sinus or innominate arteries of the DE and FA groups although there was a higher frequency of lesions in the DE-exposed group. Our study indicates that in utero DE exposure does not influence later life lipoprotein metabolism, redox homeostasis or the risk of developing larger atherosclerotic lesions. PMID- 28097518 TI - Beneficial Effects of Ozone Therapy on Oxidative Stress, Cardiac Functions and Clinical Findings in Patients with Heart Failure Reduced Ejection Fraction. AB - The aim of study was to determine the effects of ozone therapy on the oxidative stress, cardiac functions and clinical findings in patients with heart failure reduced ejection fraction (HFrEF). A total of 40 patients with New York Heart Association 2 and 3 HF with left ventricular ejection fraction (LVEF) <35%, and 40 subjects without HF as control group were included in the study. Patients with HFrEF were given additional ozone therapy of major and minor administrations along with conventional HF treatment for 5 weeks. Before and after ozone therapy, left ventricular end-systolic and end-diastolic volumes (LVESV, LVEDV) and the 6 minute walk distance (6MWD) and blood levels of the superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GSHPx), malondialdehyde (MDA), nitric oxide (NO) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured. Ozone therapy significantly reduced the serum levels of NO and MDA (p < 0.001, respectively) and significantly increased the levels of SOD, CAT, GSH and GSHPx (p < 0.001, respectively). LVEDV and LVESV were found to be significantly reduced; however, LVEF was not found to be significantly increased (p = 0.567). As the biochemical improvement marker of HF, NT-proBNP was significantly reduced (p < 0.001). The clinical HF improvement marker of 6 minute walk distance was also modestly increased (p < 0.001). Ozone therapy might be beneficial in terms of activating antioxidant system and merit further therapeutic potential to conventional HF treatment in patients with HFrEF. PMID- 28097519 TI - Guidance of interventions in structural heart disease; three-dimensional techniques are here to stay. PMID- 28097520 TI - Extremity fractures associated with ATVs and dirt bikes: a 10-year national epidemiologic study. AB - BACKGROUND: Morbidity and mortality of all-terrain vehicles and dirt bikes have been studied, as well as the association of helmet use and head injury. HYPOTHESIS/PURPOSE: The purpose of this study is to compare and contrast the patterns of extremity fractures associated with ATVs and dirt bikes. We believe there will be unique and potentially preventable injury patterns associated with dirt bikes and three-wheeled ATVs due to the poor stability of these vehicles. STUDY DESIGN: Descriptive epidemiology study. METHODS: The National Electronic Injury Surveillance System (NEISS) was used to acquire data for extremity fractures related to ATV (three wheels, four wheels, and number of wheels undefined) and dirt bike use from 2007 to 2012. Nationwide estimation of injury incidence was determined using NEISS weight calculations. RESULTS: The database yielded an estimate of 229,362 extremity fractures from 2007 to 2012. The incidence rates of extremity fractures associated with ATV and dirt bike use were 3.87 and 6.85 per 1000 participant-years. The largest proportion of all fractures occurred in the shoulder (27.2%), followed by the wrist and lower leg (13.8 and 12.4%, respectively). There were no differences in the distribution of the location of fractures among four-wheeled or unspecified ATVs. However, three wheeled ATVs and dirt bikes had much larger proportion of lower leg, foot, and ankle fractures compared to the other vehicle types. CONCLUSIONS: While upper extremity fractures were the most commonly observed in this database, three wheeled ATVs and dirt bikes showed increased proportions of lower extremity fractures. Several organizations have previously advocated for better regulation of the sale and use of these specific vehicles due to increased risks. These findings help illustrate some of the specific risks associated with these commonly used vehicles. PMID- 28097521 TI - Alcohol consumption and dementia risk: a dose-response meta-analysis of prospective studies. AB - It is widely believed that light-to-moderate alcohol intake may protect against dementia while excessive drinking may instead increase the risk. Nonetheless, these findings need cautious interpretations due to varying methodologies and lack of standard definition, which hindered our transferring into preventative practice. The objective of this study is to investigate the potential dose response association between alcohol consumption and risk of dementia. A systematic search was conducted in electronic databases to identify relevant studies. Risk estimates were combined using a random-effect model. Eleven studies with 73,330 participants and 4586 cases for all-cause dementia (ACD), five studies with 52,715 participants and 1267 cases for Alzheimer's dementia (AD) and four studies with 49,535 participants and 542 cases for vascular dementia were included. We observed a nonlinear association between alcohol consumption and ACD risk (p nonlinearity < 0.05). The alcohol dose associated with lower risk of dementia was confined to at most 12.5 g/day, with the risk hitting bottom (RR ~ 0.9) at roughly 6 g/day. Of note, the ACD risk seemed to be elevated (~10%) when the dose surpasses certain levels: 23 drinks/week or 38 g/day. For the alcohol type, recommendation for wine is prioritized. The subgroup analysis further indicated that the effect of alcohol may be greater in younger adults (<60 years old) with regard to fighting against dementia. Modest alcohol consumption (<=12.5 g/day) is associated with a reduced risk of dementia with 6 g/day of alcohol conferring a lower risk than other levels while excessive drinking (>=38 g/day) may instead elevate the risk. PMID- 28097522 TI - Severe Aortic Valve Stenosis in Adults is Associated with Increased Levels of Circulating Intermediate Monocytes. AB - Individual monocyte subsets have been associated with atherosclerotic disease, but their distribution has not been evaluated in aortic valve stenosis (AS) so far. In the present study, we have asked whether levels of the circulating intermediate monocyte subset are increased in AS. Classical (CD14++CD16-), intermediate (CD14++CD16+), and non-classical (CD14+CD16++) CD86-positive monocytes and monocyte activation (intensity of CD11b expression) were determined by flow cytometry in peripheral blood of patients with severe AS (n = 100) and matched AS-free controls (n = 75). AS patients exhibited significantly higher levels of circulating intermediate monocytes, while levels of circulating classical and non-classical monocytes or monocyte activation did not differ compared to controls. The difference in levels of intermediate monocytes between groups was independent of age, gender, BMI, LDL-C, NT-proBNP, NYHA functional class, or creatinine levels. The present pilot study provides evidence of an association of severe AS with increased levels of circulating intermediate monocytes. Further studies need to clarify whether this finding is related to the inflammatory status and hemodynamic disturbances associated with severe AS. PMID- 28097524 TI - Pubovisceralis Muscle Fiber Architecture Determination: Comparison Between Biomechanical Modeling and Diffusion Tensor Imaging. AB - Biomechanical analysis of pelvic floor dysfunction requires knowledge of certain biomechanical parameters, such as muscle fiber direction, in order to adequately model function. Magnetic resonance (MR) diffusion tensor imaging (DTI) provides an estimate of overall muscle fiber directionality based on the mathematical description of water diffusivity. This work aimed at evaluating the concurrence between pubovisceralis muscle fiber representations obtained from DTI, and the maximum principal stress lines obtained through the finite element method. Seven datasets from axial T2-weighted images were used to build numerical models, and muscle fiber orientation estimated from the DT images. The in-plane projections of the first eigenvector of both vector fields describing muscle fiber orientation were extracted and compared. The directional consistency was evaluated by calculating the angle between the normalized vectors for the entire muscle and also for the right and left insertions, middle portions, and anorectal area. The values varied between 28 degrees +/- 6 (right middle portion) and 34 degrees +/- 9 (anorectal area), and were higher than the angular precision of the DT estimates, evaluated using wild bootstrapping analysis. Angular dispersion ranged from 17 degrees +/- 4 (left middle portion) to 23 degrees +/- 5 (anorectal area). Further studies are needed to examine acceptability of these differences when integrating the vectors estimated from DTI in the numerical analysis. PMID- 28097523 TI - Intravascular Ultrasound Characterization of a Tissue-Engineered Vascular Graft in an Ovine Model. AB - Patients who undergo implantation of a tissue-engineered vascular graft (TEVG) for congenital cardiac anomalies are monitored with echocardiography, followed by magnetic resonance imaging or angiography when indicated. While these methods provide data regarding the lumen, minimal information regarding neotissue formation is obtained. Intravascular ultrasound (IVUS) has previously been used in a variety of conditions to evaluate the vessel wall. The purpose of this study was to evaluate the utility of IVUS for evaluation of TEVGs in our ovine model. Eight sheep underwent implantation of TEVGs either unseeded or seeded with bone marrow-derived mononuclear cells. Angiography, IVUS, and histology were directly compared. Endothelium, tunica media, and graft were identifiable on IVUS and histology at multiple time points. There was strong agreement between IVUS and angiography for evaluation of luminal diameter. IVUS offers a valuable tool to evaluate the changes within TEVGs, and clinical translation of this application is warranted. PMID- 28097525 TI - Automated Bone Segmentation and Surface Evaluation of a Small Animal Model of Post-Traumatic Osteoarthritis. AB - MicroCT imaging allows for noninvasive microstructural evaluation of mineralized bone tissue, and is essential in studies of small animal models of bone and joint diseases. Automatic segmentation and evaluation of articular surfaces is challenging. Here, we present a novel method to create knee joint surface models, for the evaluation of PTOA-related joint changes in the rat using an atlas-based diffeomorphic registration to automatically isolate bone from surrounding tissues. As validation, two independent raters manually segment datasets and the resulting segmentations were compared to our novel automatic segmentation process. Data were evaluated using label map volumes, overlap metrics, Euclidean distance mapping, and a time trial. Intraclass correlation coefficients were calculated to compare methods, and were greater than 0.90. Total overlap, union overlap, and mean overlap were calculated to compare the automatic and manual methods and ranged from 0.85 to 0.99. A Euclidean distance comparison was also performed and showed no measurable difference between manual and automatic segmentations. Furthermore, our new method was 18 times faster than manual segmentation. Overall, this study describes a reliable, accurate, and automatic segmentation method for mineralized knee structures from microCT images, and will allow for efficient assessment of bony changes in small animal models of PTOA. PMID- 28097526 TI - Improved Measurement of Elastic Properties of Cells by Micropipette Aspiration and Its Application to Lymphocytes. AB - Mechanical deformability of cells is an important property for their function and development, as well as a useful marker of cell state. The classical technique of micropipette aspiration allows single-cell studies and we provide here a method to measure the two basic mechanical parameters, elastic modulus and Poisson's ratio. The proposed method, developed from finite-element analysis of micropipette aspiration experiments, may be implemented in future technologies for the automated measurement of mechanical properties of cells, based on the micropipette aspiration technique or on the cell transit through flow constrictions. We applied this method to measure the elastic parameters of lymphocytes, in which the mechanical properties depend on their activation state. Additionally, we discuss in this work the accuracy of previous models to estimate the elastic modulus of cells, in particular the analytical model by Theret et al., widely used in the field. We show the necessity of using an improved model, taking into account the finite size of the cells, to obtain new insights that may remain hidden otherwise. PMID- 28097527 TI - Breast Cancer Screening and Social Media: a Content Analysis of Evidence Use and Guideline Opinions on Twitter. AB - There is ongoing debate regarding the best mammography screening practices. Twitter has become a powerful tool for disseminating medical news and fostering healthcare conversations; however, little work has been done examining these conversations in the context of how users are sharing evidence and discussing current guidelines for breast cancer screening. To characterize the Twitter conversation on mammography and assess the quality of evidence used as well as opinions regarding current screening guidelines, individual tweets using mammography-related hashtags were prospectively pulled from Twitter from 5 November 2015 to 11 December 2015. Content analysis was performed on the tweets by abstracting data related to user demographics, content, evidence use, and guideline opinions. Standard descriptive statistics were used to summarize the results. Comparisons were made by demographics, tweet type (testable claim, advice, personal experience, etc.), and user type (non-healthcare, physician, cancer specialist, etc.). The primary outcomes were how users are tweeting about breast cancer screening, the quality of evidence they are using, and their opinions regarding guidelines. The most frequent user type of the 1345 tweets was "non-healthcare" with 323 tweets (32.5%). Physicians had 1.87 times higher odds (95% CI, 0.69-5.07) of providing explicit support with a reference and 11.70 times higher odds (95% CI, 3.41-40.13) of posting a tweet likely to be supported by the scientific community compared to non-healthcare users. Only 2.9% of guideline tweets approved of the guidelines while 14.6% claimed to be confused by them. Non-healthcare users comprise a significant proportion of participants in mammography conversations, with tweets often containing claims that are false, not explicitly backed by scientific evidence, and in favor of alternative "natural" breast cancer prevention and treatment. Furthermore, users appear to have low approval and confusion regarding screening guidelines. These findings suggest that more efforts are needed to educate and disseminate accurate information to the general public regarding breast cancer prevention modalities, emphasizing the safety of mammography and the harms of replacing conventional prevention and treatment modalities with unsubstantiated alternatives. PMID- 28097528 TI - Pharmacology and Toxicology of N-Benzylphenethylamine ("NBOMe") Hallucinogens. AB - Serotonergic hallucinogens induce profound changes in perception and cognition. The characteristic effects of hallucinogens are mediated by 5-HT2A receptor activation. One class of hallucinogens are 2,5-dimethoxy-substituted phenethylamines, such as the so-called 2C-X compounds 2,5-dimethoxy-4 bromophenethylamine (2C-B) and 2,5-dimethoxy-4-iodophenethylamine (2C-I). Addition of an N-benzyl group to phenethylamine hallucinogens produces a marked increase in 5-HT2A-binding affinity and hallucinogenic potency. N benzylphenethylamines ("NBOMes") such as N-(2-methoxybenzyl)-2,5-dimethoxy-4 iodophenethylamine (25I-NBOMe) show subnanomolar affinity for the 5-HT2A receptor and are reportedly highly potent in humans. Several NBOMEs have been available from online vendors since 2010, resulting in numerous cases of toxicity and multiple fatalities. This chapter reviews the structure-activity relationships, behavioral pharmacology, metabolism, and toxicity of members of the NBOMe hallucinogen class. Based on a review of 51 cases of NBOMe toxicity reported in the literature, it appears that rhabdomyolysis is a relatively common complication of severe NBOMe toxicity, an effect that may be linked to NBOMe induced seizures, hyperthermia, and vasoconstriction. PMID- 28097529 TI - Sleep Knowledge and Behaviors in Medical Students: Results of a Single Center Survey. AB - OBJECTIVE: There is little known about the demands of medical school on students' sleep behavior. The study's main goal was to examine the interplay between medical students' sleep knowledge, personal attitudes towards sleep, and their sleep habits. METHODS: An anonymous online survey was created and emailed to all students enrolled at a large metropolitan medical school. Data on demographics, sleep perception, and habits in addition to self-reported measures of students' sleep knowledge, beliefs, and sleepiness were collected. RESULTS: There were 261, out of a possible 720, responses to the survey. While 71.5% of respondents believed that they needed >7 h of sleep, only 24.9% of respondents stated they average >7 h of sleep. During the week of an examination, only 15.3% of students stated they averaged >7 h of sleep. A comparison of pre-clinical and clinical students revealed that reported median sleep during a school or rotation night was significantly lower in clinical students as compared to pre-clinical students while mean sleep during examination weeks between the two groups was not statistically different. In regard to sleep knowledge, clinical students were more knowledgeable (65.53% correct) than pre-clinical students (39.83% correct) (t(1) = -8.9, p = .00). However, there was no difference in the assessment of dysfunctional beliefs between the two groups (66.0 for preclinical students, 64.7 for clinical students (t(1) = 0.37, p = .71)) while clinical students had a higher score of sleepiness compared to pre-clinical students (9.12 to 7.83, t(1) = -2.3, p = .023). CONCLUSIONS: A majority of medical students are sleeping an inadequate amount of time during their 4 years, and as they progress from the pre clinical to the clinical years, the amount of time they sleep decreases even though their knowledge about sleep increases. Increased awareness around sleep health is required beyond sleep education, as medical students appear to need help translating knowledge into strategies to improve their own sleep and well being. PMID- 28097531 TI - Living donor liver transplant (LDLT) is the way forward in Asia. AB - Living donor liver transplantation (LDLT) is currently the commonest form of liver transplantation in Asia. Efforts to improve the number of deceased donor liver transplantation have not been uniformly successful. We believe that THE unique combination of demographic, social, economic and political factors that exist in Asia will ensure that LDLT will continue to remain the predominant form of liver transplantation. While efforts to increase deceased donation rates should continue and intensify, progress in LDLT should also be supported and encouraged, as it will be the main workhorse of liver transplantation in Asia in the near and medium-term future. PMID- 28097530 TI - Virus-induced hepatocellular carcinoma with special emphasis on HBV. AB - Hepatocellular carcinoma (HCC) is a common malignant tumor with high lethality, and the hepatitis B virus (HBV) is a chief cause. HBV can accelerate HCC via multiple mechanisms. First, HBV induces immune reactions that lead to repeated hepatic inflammation, fibrosis and a deficient immune microenvironment. Subsequently, HBV can modify host genes near the insertion point through DNA integration to cause host cell genome instability and to generate carcinogenic fusion proteins. Additionally, HBV expresses diverse active proteins, especially HBx and HBs, which have a range of transactivation functions such as regulation of apoptosis, interference with intracellular signaling pathways, and alteration of epigenetics. Currently, primary prevention measures for HBV-induced HCC focus on vaccination and antiviral treatment. Here, we report the epidemiology, the molecular mechanism and the progress in therapeutic strategies for controlling HBV-induced HCC. PMID- 28097532 TI - Medication Overuse in Chronic Pain. AB - PURPOSE OF REVIEW: Chronic pain is usually managed by various pharmacotherapies after exhausting the conservative modalities such as over-the-counter choices. The goal of this review is to investigate current state of opioids and non-opioid medication overuse that includes NSAIDs, skeletal muscle relaxants, antidepressants, membrane stabilization agents, and benzodiazepine. How to minimize medication overuse and achieve better outcome in chronic pain management? RECENT FINDINGS: Although antidepressants and membrane stabilization agents contribute to the crucial components for neuromodulation, opioids were frequently designated as a rescue remedy in chronic pain since adjunct analgesics usually do not provide instantaneous relief. The updated CDC guideline for prescribing opioids has gained widespread attention via media exposure. Both patients and prescribers are alerted to respond to the opioid epidemic and numerous complications. However, there has been overuse of non-opioid adjunct analgesics that caused significant adverse effects in addition to concurrent opioid consumption. It is a common practice to extrapolate the WHO three-step analgesic ladder for cancer pain to apply in non-cancer pain that emphasizes solely on pharmacologic therapy which may result in overuse and escalation of opioids in non-cancer pain. There has been promising progress in non pharmacologic therapies such as biofeedback, complementary, and alternative medicine to facilitate pain control instead of dependency on pharmacologic therapies. This review article presents the current state of medication overuse in chronic pain and proposes precaution to balance the risk and benefit ratio. It may serve as a premier for future study on clinical pathway for comprehensive chronic pain management and reduce medication overuse. PMID- 28097533 TI - Long-Term Use of Ticagrelor in Patients with Coronary Artery Disease. AB - PURPOSE OF REVIEW: This review aims to summarize and discuss safety and effectiveness of the long-term use of ticagrelor in patients with coronary artery disease (CAD). RECENT FINDINGS: Ticagrelor is an orally administered, direct, and reversible inhibitor of the P2Y12-platelet receptor. Long-term use of ticagrelor in patients with previous myocardial infarction (MI) has been investigated in the PEGASUS-TIMI-54 trial. Overall, 21,162 patients with a spontaneous MI 1 to 3 years before randomization were randomly assigned to ticagrelor 90 mg bid, ticagrelor 60 mg bid, or placebo. Compared with placebo, both doses of ticagrelor showed that they were capable of significantly reducing the primary efficacy endpoint, although with a significant increase in TIMI major bleeding. Intracranial hemorrhage or fatal bleeding did not differ across groups. These findings establish clear benefit of DAPT extension with ticagrelor beyond 1 year of treatment, which comes with a tradeoff of clinically meaningful bleeding. Altogether, current evidence suggests that the duration of DAPT remains a patient by-patient decision based on thrombotic and bleeding risk profiles. PMID- 28097534 TI - Successful treatment with low-dose nivolumab in refractory Hodgkin lymphoma after allogeneic stem cell transplantation. AB - Previous studies have reported that an antibody that blocks programmed cell death 1 (PD-1) has therapeutic activity in patients with refractory/relapsed Hodgkin lymphoma (HL). However, the safety and efficacy of these agents in the post allogeneic stem cell transplantation (allo-SCT) setting are not well known. Here, we describe a patient who was diagnosed as classical HL and treated with five regimens of chemotherapies with autologous SCT. Complete remission (CR) was not achieved following this initial treatment, so we performed allo-SCT from an HLA matched sibling donor. Since his disease progressed at day 403 after allo-SCT, we decided to use nivolumab in the treatment of his refractory disease. To prevent the worsening of his chronic graft-versus-host disease (GVHD), we reduced the initial dose and frequency of nivolumab compared with the previous report. After four courses of 0.5 mg/kg of nivolumab every three weeks, FDG-PET imaging showed partial response (PR) to the treatment, a remarkable result. However, since the escalated dose of 2 mg/kg resulted in worsening of dyspnea and skin sclerosis, we initiated systemic administration of prednisolone and reduced nivolumab to 1 mg/kg. At the time of this report, his HL is in stable PR with three weekly administration of nivolumab and steroid controlled mild chronic GVHD. PMID- 28097535 TI - Central retinal artery occlusion after percutaneous nephrolithotomy lithotripsy in the prone position. PMID- 28097537 TI - Optimization of a New Aerodynamic Cylindrical FAIMS Device for Small Molecule Analysis. AB - The implementation of an aerodynamic mechanism to improve ion sampling between nanoelectrospray (n-ESI) and FAIMS was recently reported for proteomic analyses. This investigation explores the new FAIMS interface for small molecule analysis at high liquid flow rates and includes an examination of key differences in ionization between heated-ESI (HESI) and n-ESI. The sheath gas, critical for desolvation with HESI, affects FAIMS operation as higher FAIMS gas flow rates are required to achieve sufficient desolvation. Gas flow rate experiments also uncovered m/z discrimination with the conventional design as larger (slower moving) m/z ions experienced larger signal intensity losses than smaller m/z ions due to the desolvation gas flow having a greater drag effect on slower moving ions. The modified inlet in new FAIMS dampens the gas drag, making the HESI source more amenable as less m/z bias and significantly lower %RSD values were observed. Furthermore, a larger radius inner electrode in new FAIMS enables significantly higher E/N (electric field/number gas density) to be achieved using the existing waveform generator. Thus, new FAIMS signal intensities using only nitrogen improved 1.25- to 2-fold compared with the conventional design and 50% helium. Adding helium to the new FAIMS gave no significant improvements. The larger inner electrode also decreased ion focusing capabilities, and the effect on peak separation and ion intensity was examined in detail. The peak capacity of new FAIMS was approximately double that of conventional FAIMS; separation of seven low m/z ions gave a peak capacity of 37.7 using the gas additive 2 propanol. Graphical Abstract ?. PMID- 28097536 TI - Prevalence and correlates of ADHD in individuals with substance use disorder in Nigeria. AB - Substance use disorder (SUD) is associated with ADHD. ADHD increases the severity of SUD and has negative influence on the prognosis of the disorder. The aim of the study was to determine the prevalence and correlates of ADHD in individuals with SUD. During 2013-2015, a cross-sectional descriptive study of 233 drug treatment-seeking individuals was assessed. Diagnosis of ADHD was done using DSM IV criteria with the Diagnostic Interview for ADHD in Adults (DIVA 2.0), while Semi-structured Assessment for Drug Dependence and Alcoholism (SSADDA 6.1) and Adult ADHD Quality of Life (AAQoL) were used for diagnosis of substance use disorder and assessment of QoL, respectively. Multivariable logistic regression was used to determine factors that were associated with ADHD. The prevalence of ADHD in SUD patients was 21.5%, with the combined subtype being the most prevalent. SUD patient with ADHD had more history of severe dependence on cigarette, depression, suicidal ideation, aggression, dependence on benzodiazepine and heroin, number of relapses, poor QoL and number of hospitalization. After logistic regression, only the number of relapses (p = 0.004), history of aggression (<0.001) and poor QoL differentiated between SUD patients with ADHD from those with no diagnosis of ADHD. The prevalence of ADHD in SUD individuals is high and may be associated with a more severe phenotypic expression of SUD. PMID- 28097538 TI - The role of glutamine synthetase in energy production and glutamine metabolism during oxidative stress. AB - Oxidative stress is known to severely impede aerobic adenosine triphosphate (ATP) synthesis. However, the metabolically-versatile Pseudomonas fluorescens survives this challenge by invoking alternative ATP-generating networks. When grown in a medium with glutamine as the sole organic nutrient in the presence of H2O2, the microbe utilizes glutamine synthetase (GS) to modulate its energy budget. The activity of this enzyme that mediates the release of energy stored in glutamine was sharply increased in the stressed cells compared to the controls. The enhanced activities of such enzymes as acetate kinase, adenylate kinase and nucleotide diphosphate kinase ensured the efficacy of this ATP producing-machine by transferring the high energy phosphate. The elevated amounts of phosphoenol pyruvate carboxylase and pyruvate orthophosphate dikinase recorded in the H2O2 exposed cells provided another route to ATP independent of the reduction of O2. This is the first demonstration of a metabolic pathway involving GS dedicated to ATP synthesis. The phospho-transfer network that is pivotal to the survival of the microorganism under oxidative stress may reveal therapeutic targets against infectious microbes reliant on glutamine for their proliferation. PMID- 28097539 TI - Rhizobium hedysari sp. nov., a novel species isolated from a root nodule of Hedysarum multijugum in China. AB - A strain 5-1-2T was isolated from a root nodule of Hedysarum multijugum collected from Zhangye city, Gansu province, north-west China. Phylogenetic analysis based on the 16S rRNA gene sequence and other housekeeping genes (recA and atpD) indicated that the strain represents a novel species in the genus Rhizobium close to the strain Rhizobium subbaraonis JC85T with similarities of 98.27, 88.92 and 89.62%, respectively. Strain 5-1-2T contained Q-10 as the predominant ubiquinone. Our results showed that the major fatty acids were feature 8 (C18:1 omega7c and/or C18:1 omega6c; 38.90%). In addition, the DNA-DNA hybridizations with the type strains R. subbaraonis JC85T and Rhizobium halophytocola YC6881T were 39.2 +/- 2.1 and 44.3 +/- 1.9, respectively. Therefore, a novel species Rhizobium hedysari sp. nov. is proposed, and 5-1-2T (=CGMCC1.15677T = NBRC112532T) is designated as the type strain. PMID- 28097540 TI - ? PMID- 28097542 TI - ? PMID- 28097541 TI - ? PMID- 28097543 TI - ? PMID- 28097544 TI - ? PMID- 28097545 TI - ? PMID- 28097546 TI - ? PMID- 28097547 TI - ? PMID- 28097548 TI - ? PMID- 28097549 TI - ? PMID- 28097551 TI - ? PMID- 28097550 TI - ? PMID- 28097552 TI - [Cardiovascular safety concerns of glucose-lowering drugs]. PMID- 28097553 TI - [Pumps, sensors and the dream of the artificial pancreas - a clinical update to modern technologies in diabetes]. PMID- 28097555 TI - [Protection against common cold]. PMID- 28097554 TI - [Hanging by a thread - Management of pretibial lacerations]. PMID- 28097556 TI - [Rhinosinusitis - diagnosis and guideline-based therapy]. PMID- 28097557 TI - ? PMID- 28097558 TI - ? PMID- 28097559 TI - ? PMID- 28097560 TI - ? PMID- 28097561 TI - ? PMID- 28097562 TI - ? PMID- 28097563 TI - ? PMID- 28097564 TI - ? PMID- 28097565 TI - ? PMID- 28097566 TI - ? PMID- 28097567 TI - ? PMID- 28097568 TI - ? PMID- 28097569 TI - ? PMID- 28097571 TI - ? PMID- 28097570 TI - ? PMID- 28097572 TI - ? PMID- 28097573 TI - ? PMID- 28097574 TI - ? PMID- 28097575 TI - ? PMID- 28097576 TI - ? PMID- 28097577 TI - ? PMID- 28097578 TI - ? PMID- 28097579 TI - ? PMID- 28097580 TI - ? PMID- 28097581 TI - ? PMID- 28097582 TI - ? PMID- 28097583 TI - ? PMID- 28097584 TI - ? PMID- 28097585 TI - ? PMID- 28097586 TI - ? PMID- 28097588 TI - ? PMID- 28097590 TI - ? PMID- 28097589 TI - ? PMID- 28097591 TI - ? PMID- 28097592 TI - [Mycoses of the skin]. PMID- 28097593 TI - Associations Between Positive Body Image, Sexual Liberalism, and Unconventional Sexual Practices in U.S. Adults. AB - While studies have documented robust relationships between body image and sexual health outcomes, few studies have looked beyond sexual functioning in women. Here, we hypothesized that more positive body image would be associated with greater sexual liberalism and more positive attitudes toward unconventional sexual practices. An online sample of 151 women and 164 men from the U.S. completed measures of sexual liberalism, attitudes toward unconventional sexual practices, and indices of positive body image (i.e., body appreciation, body acceptance by others, body image flexibility, and body pride), and provided their demographic details. Regression analyses indicated that, once the effects of sexual orientation, relationship status, age, and body mass index had been accounted for, higher body appreciation was significantly associated with greater sexual liberalism in women and men. Furthermore, higher body appreciation and body image flexibility were significantly associated with more positive attitudes toward unconventional sexual practices in women and men. These results may have implications for scholars working from a sex-positive perspective, particularly in terms of understanding the role body image plays in sexual attitudes and behaviors. PMID- 28097594 TI - Mechanism of anti-Vibrio activity of marine probiotic strain Bacillus pumilus H2, and characterization of the active substance. AB - Vibriosis is a major epizootic disease that impacts free-living and farmed fish species worldwide. Use of probiotics is a promising approach for prevention of Vibrio infections in aquaculture. A probiotic anti-Vibrio strain, Bacillus pumilus H2, was characterized, and the mechanism of its effect was investigated. All 29 Vibrio strains tested were growth-inhibited by H2. The anti-Vibrio substance present in cell-free supernatant of H2 was purified and characterized by reversed-phase HPLC. Minimum inhibitory concentrations of the purified substance, determined in liquid media for various Vibrio strains, ranged from 0.5 to 64 ug/ml. Addition of the purified substance to Vibrio vulnificus culture inhibited cell growth (estimated by OD600). Confocal microscopy and scanning electron microscopy analyses showed that surface structure of V. vulnificus cells was damaged by the purified substance, as reflected by presence of membrane holes, disappearance of cellular contents, and formation of cell cavities. The major mechanism of this anti-Vibrio activity appeared to involve disruption of cell membranes, and consequent cell lysis. The purified anti-Vibrio substance was shown to be structurally identical to amicoumacin A by MS and NMR analysis. Our findings indicate that B. pumilus H2 has strong potential for prevention or treatment of fish vibriosis in the aquaculture industry. PMID- 28097595 TI - Dependence of Z Parameter for Tensile Strength of Multi-Layered Interphase in Polymer Nanocomposites to Material and Interphase Properties. AB - In this work, the Z interphase parameter which determines the tensile strength of interphase layers in polymer nanocomposites is presented as a function of various material and interphase properties. In this regard, the simple Pukanszky model for tensile strength of polymer nanocomposites is applied and the dependency of Z to different characteristics of constituents and interphase are illustrated by contour plots. The interphase strength (sigma i) and B interfacial parameter in Pukanszky model show direct links with Z parameter. Also, it is found that the volume fractions of nanoparticles and interphase reveal dissimilar effects on Z. A high Z is obtained by a low nanoparticle volume fraction and high content of interphase, but the best values of Z are associated with the level of B parameter. PMID- 28097596 TI - Enhancement of Perovskite Solar Cells Efficiency using N-Doped TiO2 Nanorod Arrays as Electron Transfer Layer. AB - In this paper, N-doped TiO2 (N-TiO2) nanorod arrays were synthesized with hydrothermal method, and perovskite solar cells were fabricated using them as electron transfer layer. The solar cell performance was optimized by changing the N doping contents. The power conversion efficiency of solar cells based on N-TiO2 with the N doping content of 1% (N/Ti, atomic ratio) has been achieved 11.1%, which was 14.7% higher than that of solar cells based on un-doped TiO2. To get an insight into the improvement, some investigations were performed. The structure was examined with X-ray powder diffraction (XRD), and morphology was examined by scanning electron microscopy (SEM). Energy dispersive spectrometer (EDS) and Tauc plot spectra indicated the incorporation of N in TiO2 nanorods. Absorption spectra showed higher absorption of visible light for N-TiO2 than un-doped TiO2. The N doping reduced the energy band gap from 3.03 to 2.74 eV. The photoluminescence (PL) and time-resolved photoluminescence (TRPL) spectra displayed the faster electron transfer from perovskite layer to N-TiO2 than to un doped TiO2. Electrochemical impedance spectroscopy (EIS) showed the smaller resistance of device based on N-TiO2 than that on un-doped TiO2. PMID- 28097597 TI - Self-Powered Active Sensor with Concentric Topography of Piezoelectric Fibers. AB - In this study, we demonstrated a flexible and self-powered sensor based on piezoelectric fibers in the diameter range of nano- and micro-scales. Our work is distinctively different from previous electrospinning research; we fabricated this apparatus precisely via near-field electrospinning which has a spectacular performance to harvest mechanical deformation in arbitrary direction and a novel concentrically circular topography. There are many piezoelectric devices based on electrospinning polymeric fibers. However, the fibers were mostly patterned in parallel lines and they could be actuated in limited direction only. To overcome this predicament, we re-arranged the parallel alignment into concentric circle pattern which made it possible to collect the mechanical energy whenever the deformation is along same axis or not. Despite the change of topography, the output voltage and current could still reach to 5 V and 400 nA, respectively, despite the mechanical deformation was from different direction. This new arbitrarily directional piezoelectric generator with concentrically circular topography (PGCT) allowed the piezoelectric device to harvest more mechanical energy than the one-directional alignment fiber-based devices, and this PGCT could perform even better output which promised more versatile and efficient using as a wearable electronics or sensor. PMID- 28097598 TI - Influence of Doping and Nanostructuration on n-Type Bi2(Te0.8Se0.2)3 Alloys Synthesized by Arc Melting. AB - In competitive thermoelectric devices for energy conversion and generation, high efficiency materials of both n-type and p-type are required. For this, Bi2Te3 based alloys have the best thermoelectric properties in room temperature applications. Partial replacement of tellurium by selenium is expected to introduce new donor states in the band gap, which would alter electrical conductivity and thermopower. We report on the preparation of n-type Bi2(Te1 xSex)3 solid solutions by a straightforward arc-melting technique, yielding nanostructured polycrystalline pellets. X-ray and neutron powder diffraction was used to assess Se inclusion, also indicating that the interactions between quintuple layers constituting this material are weakened upon Se doping, while the covalency of intralayer bonds is augmented. Moreover, scanning electron microscopy shows large surfaces perpendicular to the c crystallographic axis assembled as stacked sheets. Grain boundaries related to this 2D nanostructuration affect the thermal conductivity reducing it below 0.8 Wm-1K-1 at room temperature. Furthermore, Se doping increases the absolute Seebeck coefficient up to -140 MUV K-1 at 400 K, which is also beneficial for improved thermoelectric efficiency. PMID- 28097599 TI - Biosynthesis, Characterization, and Bioactivities Evaluation of Silver and Gold Nanoparticles Mediated by the Roots of Chinese Herbal Angelica pubescens Maxim. AB - A facile synthesis and biological applications of silver (DH-AgNps) and gold nanoparticles (DH-AuNps) mediated by the aqueous extract of Angelicae Pubescentis Radix (Du Huo) are explored. Du Huo is a medicinal root belonging to Angelica pubescens Maxim which possesses anti-inflammatory, analgesic, and antioxidant properties. The absorption spectra of nanoparticles in varying root extract and metal ion concentration, pH, reaction temperatures, and time were recorded by ultraviolet-visible (UV-Vis) spectroscopy. The presence of DH-AgNps and DH-AuNps was confirmed from the surface plasmon resonance intensified at ~414 and ~540 nm, respectively. Field emission transmission electron micrograph (FE-TEM) analysis revealed the formation of quasi-spherical DH-AgNps and spherical icosahedral DH AuNps. These novel DH-AgNps and DH-AuNps maintained an average crystallite size of 12.48 and 7.44 nm, respectively. The biosynthesized DH-AgNps and DH-AuNps exhibited antioxidant activity against 2,2-diphenyl-1-picrylhydrzyl (DPPH) radicals and the former exhibited antimicrobial activity against clinical pathogens including Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Salmonella enterica. The expected presence of flavonoids, sesquiterpenes, and phenols on the nanoparticle surface were conjectured to grant protection against aggregation and free radical scavenging activity. DH-AgNps and DH-AuNps were further investigated for their cytotoxic properties in RAW264.7 macrophages for their potential application as drug carriers to sites of inflammation. In conclusion, this green synthesis is favorable for the advancement of plant mediated nano-carriers in drug delivery systems, cancer diagnostic, and medical imaging. Schematic diagram of biosynthesis of DH-AgNps and DH-AuNps and evaluation of their bioactivities. PMID- 28097600 TI - Network-Forming Nanoclusters in Binary As-S/Se Glasses: From Ab Initio Quantum Chemical Modeling to Experimental Evidences. AB - Network-forming As2(S/Se)m nanoclusters are employed to recognize expected variations in a vicinity of some remarkable compositions in binary As-Se/S glassy systems accepted as signatures of optimally constrained intermediate topological phases in earlier temperature-modulated differential scanning calorimetry experiments. The ab initio quantum chemical calculations performed using the cation-interlinking network cluster approach show similar oscillating character in tendency to local chemical decomposition but obvious step-like behavior in preference to global phase separation on boundary chemical compounds (pure chalcogen and stoichiometric arsenic chalcogenides). The onsets of stability are defined for chalcogen-rich glasses, these being connected with As2Se5 (Z = 2.29) and As2S6 (Z = 2.25) nanoclusters for As-Se and As-S glasses, respectively. The physical aging effects result preferentially from global phase separation in As-S glass system due to high localization of covalent bonding and local demixing on neighboring As2Sem+1 and As2Sem-1 nanoclusters in As-Se system. These nanoclusters well explain the lower limits of reversibility windows in temperature-modulated differential scanning calorimetry, but they cannot be accepted as signatures of topological phase transitions in respect to the rigidity theory. PMID- 28097601 TI - Observation of Anomalous Resistance Behavior in Bilayer Graphene. AB - Our measurement results have shown that bilayer graphene exhibits an unexpected sharp transition of the resistance value in the temperature region 200~250 K. We argue that this behavior originates from the interlayer ripple scattering effect between the top and bottom ripple graphene layer. The inter-scattering can mimic the Coulomb scattering but is strongly dependent on temperature. The observed behavior is consistent with the theoretical prediction that charged impurities are the dominant scatters in bilayer graphene. The resistance increase with increasing perpendicular magnetic field strongly supports the postulate that magnetic field induces an excitonic gap in bilayer graphene. Our results reveal that the relative change of resistance induced by magnetic field in the bilayer graphene shows an anomalous thermally activated property. PMID- 28097602 TI - Dietary Supplementation of Chromium Can Alleviate Negative Impacts of Heat Stress on Performance, Carcass Yield, and Some Blood Hematology and Chemistry Indices of Growing Japanese Quail. AB - The main objective of this work was to investigate the impact of dietary chromium supplementation on growth indices, carcass yield, and some hematological and biochemical blood parameters of growing Japanese quails subjected to heat stress. A total of 360 unsexed 2-week-old Japanese quail chicks were used in a 2 * 3 factorial arrangement that had two ambient temperatures (23 +/- 2 and 33 +/- 2 degrees C) and three dietary chromium (0.00, 500, and 1000 MUg Cr/kg diet as chromium picolinate). For induction of heat stress, the room temperature was set at 33 +/- 2 degrees C from 2 to 6 weeks of age. Results showed that body weight, body weight gain, and feed intake were decreased for birds subjected to heat stress condition during 2 to 4 and 2 to 6 weeks of age. Feed conversion was not significantly (P > 0.05) affected by high ambient temperature throughout the experiment. Carcass, dressing, liver, and heart percentages were not influenced by the ambient temperature or dietary chromium or their combinations. Significant temperature * chromium combinations were observed for hemoglobin value (P = 0.025) and packed cell volume (P = 0.001). Cholesterol and glucose in plasma were increased (P = 0.004 or 0.022) in quails subjected to heat stress condition. Plasma measurements of total proteins, albumin, globulin, lipids, glucose, and A/G ratio of quail chicks were not influenced (P > 0.05) by chromium, while cholesterol was increased with increasing chromium level (P = 0.033). High ambient temperature or dietary chromium levels or their interactions did not (P > 0.05) affect plasma levels of aspartate transaminase (AST), alanine transaminase (ALT), triiodothyronine (T3), thyroxin (T4), or T3/T4 ratio of growing quails. From these observations, it can be concluded that dietary chromium supplementation of growing Japanese quail subjected to heat stress condition could beneficially affect growth performance and carcasses, as well as modulate the hematological and biochemical blood parameters, probably through modulating stress status. PMID- 28097603 TI - Comprehensive preclinical evaluation of a multi-physics model of liver tumor radiofrequency ablation. AB - PURPOSE: We aim at developing a framework for the validation of a subject specific multi-physics model of liver tumor radiofrequency ablation (RFA). METHODS: The RFA computation becomes subject specific after several levels of personalization: geometrical and biophysical (hemodynamics, heat transfer and an extended cellular necrosis model). We present a comprehensive experimental setup combining multimodal, pre- and postoperative anatomical and functional images, as well as the interventional monitoring of intra-operative signals: the temperature and delivered power. RESULTS: To exploit this dataset, an efficient processing pipeline is introduced, which copes with image noise, variable resolution and anisotropy. The validation study includes twelve ablations from five healthy pig livers: a mean point-to-mesh error between predicted and actual ablation extent of 5.3 +/- 3.6 mm is achieved. CONCLUSION: This enables an end-to-end preclinical validation framework that considers the available dataset. PMID- 28097604 TI - Theory-based explanation as intervention. AB - Cogent explanations are an indispensable means of providing new information and an essential component of effective education. Beyond this, we argue that there is tremendous untapped potential in using explanations to motivate behavior change. In this article we focus on health interventions. We review four case studies that used carefully tailored explanations to address gaps and misconceptions in people's intuitive theories, providing participants with a conceptual framework for understanding how and why some recommended behavior is an effective way of achieving a health goal. These case studies targeted a variety of health-promoting behaviors: (1) children washing their hands to prevent viral epidemics; (2) parents vaccinating their children to stem the resurgence of infectious diseases; (3) adults completing the full course of an antibiotic prescription to reduce antibiotic resistance; and (4) children eating a variety of healthy foods to improve unhealthy diets. Simply telling people to engage in these behaviors has been largely ineffective-if anything, concern about these issues is mounting. But in each case, teaching participants coherent explanatory frameworks for understanding health recommendations has shown great promise, with such theory-based explanations outperforming state-of-the-art interventions from national health authorities. We contrast theory-based explanations both with simply listing facts, information, and advice and with providing a full-blown educational curriculum, and argue for providing the minimum amount of information required to understand the causal link between a target behavior and a health outcome. We argue that such theory-based explanations lend people the motivation and confidence to act on their new understanding. PMID- 28097605 TI - Elevated Carbon Dioxide Concentration Reduces Alarm Signaling in Aphids. AB - Insects often rely on olfaction to communicate with conspecifics. While the chemical language of insects has been deciphered in recent decades, few studies have assessed how changes in atmospheric greenhouse gas concentrations might impact pheromonal communication in insects. Here, we hypothesize that changes in the concentration of atmospheric carbon dioxide affect the whole dynamics of alarm signaling in aphids, including: (1) the production of the active compound (E)-beta-farnesene (Ebetaf), (2) emission behavior when under attack, (3) perception by the olfactory apparatus, and (4) the escape response. We reared two strains of the pea aphid, Acyrthosiphon pisum, under ambient and elevated CO2 concentrations over several generations. We found that an increase in CO2 concentration reduced the production (i.e., individual content) and emission (released under predation events) of Ebetaf. While no difference in Ebetaf neuronal perception was observed, we found that an increase in CO2 strongly reduced the escape behavior expressed by an aphid colony following exposure to natural doses of alarm pheromone. In conclusion, our results confirm that changes to greenhouse gases impact chemical communication in the pea aphid, and could potentially have a cascade effect on interactions with higher trophic levels. PMID- 28097607 TI - Capsule Commentary on Steiner, Carrying My Father. PMID- 28097608 TI - Capsule Commentary on Chen et al., A Randomized Trial of Displaying Paid Price Information on Imaging Study and Procedure Ordering Rates. PMID- 28097606 TI - Colorado Medical Students' Attitudes and Beliefs About Marijuana. AB - BACKGROUND: Over the past two decades, state and local governments across the U.S. have been increasingly reforming marijuana laws. Despite growing support for marijuana as a medical treatment, little is known about medical students' perceptions of marijuana use. OBJECTIVE: To assess Colorado medical students' personal and professional opinions on current and future marijuana use in a healthcare setting. DESIGN: A voluntary, anonymous, online cross-sectional survey. PARTICIPANTS: Medical students (n = 624) at the University of Colorado School of Medicine between January and February 2014 were invited to participate. MAIN MEASURES: Numerical responses were quantified using counts and percentages, and Likert scale responses were collapsed for bivariate analysis. Items were gathered thematically and additively scored for each subscale. Internal consistency reliability statistics were calculated for each subscale to ensure that items were assessing similar constructs. Unadjusted t tests and one-way analysis of variance (ANOVA) were used to calculate mean differences in subscale scores between subgroups. KEY RESULTS: We received 236 responses (37%). Students indicated support for marijuana legalization (64%), and few believed that physicians should be penalized for recommending marijuana to patients (6%). Nearly all (97%) believed that further marijuana research should be conducted, and believed marijuana could play a role in the treatment of various medical conditions. Seventy-seven percent reported that they believed marijuana use had the potential for psychological harm, and 68% indicated concern for potential physical harm. Only a minority of students would recommend marijuana to a patient under current law (29%), or if it were legally available (45%). Acceptability of marijuana for treatment of approved conditions was not correlated with age or gender, but was positively correlated with living in Colorado prior to medical school (p < 0.001) and with prior marijuana use (p < 0.001). CONCLUSIONS: Medical students support marijuana legal reform, medicinal uses of marijuana, and increased research, but have concerns regarding risks of marijuana use, and appear hesitant to recommend marijuana to patients. PMID- 28097609 TI - A case of a quadricuspid aortic valve identified preoperatively using transthoracic echocardiography. AB - Quadricuspid aortic valve is an extremely rare congenital heart anomaly that often causes valve incompetence, requiring surgical intervention. Care must be taken to avoid surgical complications in patients with quadricuspid aortic valve; thus, preoperative diagnosis is important. A 76-year-old man presented with exertional dyspnea due to aortic regurgitation. Transthoracic and transesophageal echocardiography revealed severe aortic regurgitation caused by quadricuspid aortic valve. To avoid interference with the cardiac conduction system, we performed aortic valve replacement using an ingenious technique, in which pledgeted sutures on the accessory leaflet were placed from outside the sinus of Valsalva to above the aortic annulus. The patient recovered uneventfully and was discharged from the hospital without any complications. While preoperative diagnosis of quadricuspid aortic valve is considered difficult, we identified it preoperatively using transthoracic echocardiography; we were, thus, able to properly prepare for complete atrioventricular block. PMID- 28097610 TI - On the interdependence of ambulatory and hospital care in the German health system. AB - For some considerable time now the interface between ambulatory and hospital care has been mooted as a cause of inefficiencies in the German health system and there have been calls for a softening of the strict separation between the two sectors. This debate emphasizes the need for detailed empirical information on the interdependence between the two sectors. Using extensive administrative data at the level of the 412 German counties for the years 2007 to 2009 and a simultaneous equation model which allows the numbers of ambulatory and hospital cases to be mutually interdependent, we examine the connection between ambulatory and hospital specialist care separately for ten medical specialties. The results show that the interdependence of ambulatory and hospital services is far from homogeneous. The relationship depends, on the one hand, on the specialty and, on the other, on the direction of the effect observed. This heterogeneity needs to be taken into account for cross-sector needs-based planning. PMID- 28097611 TI - Assessing nitrous oxide effect using electroencephalographically-based depth of anesthesia measures cortical state and cortical input. AB - Existing electroencephalography (EEG) based depth of anesthesia monitors cannot reliably track sedative or anesthetic states during n-methyl-D-aspartate (NMDA) receptor antagonist based anesthesia with ketamine or nitrous oxide (N2O). Here, a physiologically-motivated depth of anesthesia monitoring algorithm based on autoregressive-moving-average (ARMA) modeling and derivative measures of interest, Cortical State (CS) and Cortical Input (CI), is retrospectively applied in an exploratory manner to the NMDA receptor antagonist N2O, an adjuvant anesthetic gas used in clinical practice. Composite Cortical State (CCS) and Composite Cortical State distance (CCSd), two new modifications of CS, along with CS and CI were evaluated on electroencephalographic (EEG) data of healthy control individuals undergoing N2O inhalation up to equilibrated peak gas concentrations of 20, 40 or 60% N2O/O2. In particular, CCSd has been devised to vary consistently for increasing levels of anesthetic concentration independent of the anesthetic's microscopic mode of action for both N2O and propofol. The strongest effects were observed for the 60% peak gas concentration group. For the 50-60% peak gas levels, individuals showed statistically significant reductions in responsiveness compared to rest, and across the group CS and CCS increased by 39 and 42%, respectively, while CCSd was found to decrease by 398%. On the other hand a clear conclusion regarding the changes in CI could not be reached. These results indicate that, contrary to previous depth of anesthesia monitoring measures, the CS, CCS, and especially CCSd measures derived from frontal EEG are potentially useful for differentiating gas concentration and responsiveness levels in people under N2O. On the other hand, determining the utility of CI in this regard will require larger sample sizes and potentially higher gas concentrations. Future work will assess the sensitivity of CS-based and CI measures to other anesthetics and their utility in a clinical environment. PMID- 28097612 TI - WIP1 Phosphatase Plays a Critical Neuroprotective Role in Brain Injury Induced by High-Altitude Hypoxic Inflammation. AB - The hypobaric hypoxic environment in high-altitude areas often aggravates the severity of inflammation and induces brain injury as a consequence. However, the critical genes regulating this process remain largely unknown. The phosphatase wild-type p53-induced phosphatase 1 (WIP1) plays important roles in various physiological and pathological processes, including the regulation of inflammation in normoxia, but its functions in hypoxic inflammation-induced brain injury remain unclear. Here, we established a mouse model of this type of injury and found that WIP1 deficiency augmented the release of inflammatory cytokines in the peripheral circulation and brain tissue, increased the numbers of activated microglia/macrophages in the brain, aggravated cerebral histological lesions, and exacerbated the impairment of motor and cognitive abilities. Collectively, these results provide the first in vivo evidence that WIP1 is a critical neuroprotector against hypoxic inflammation-induced brain injury. PMID- 28097613 TI - Stakeholder contributions to assessment, monitoring, and conservation of threatened species: black skimmer and red knot as case studies. AB - Stakeholder contributions to conservation projects often occur during the problem formulation stage, yet the role of stakeholders throughout the process is seldom considered. We examine the diversity of state and federal agencies, conservation organizations, other non-governmental organizations, environmental justice communities, consultants, industry, and the general public in the conservation of red knot (Calidris canutus rufa) and black skimmer (Rynchops niger) in New Jersey. We suggest that (1) governmental agencies provide the legal, regulatory, and management framework, but it is often the universities, conservation organizations, consultants, and the public that conduct the research and perform activities that lead to increased research and conservation efforts; (2) departments within agencies may have conflicting mandates, making it difficult to resolve differences in actions; (3) there is often conflict among and within state agencies and conservation organizations about roles and priorities; and (4) the role of the public is critical to ongoing research and conservation efforts. Identification of all the relevant stakeholders is necessary to recognizing competing claims, identifying the threats, deciding how to manage the threats, and enhancing population viability. Conflicts occur even within an agency when one department oversees science and protection of populations and another oversees and fosters an industry (aquaculture or fisheries, or permits for off road vehicles). Conflicts also occur between resource agencies, industry, and conservation organizations. Recognizing the different stakeholders and their mandates, and encouraging participation in the process, leads to a better understanding of the threats, risks, and possible solutions when conflicts arise. Tracking stakeholder viewpoints and actions can lead to increased involvement and conflict resolution. PMID- 28097614 TI - Comprehensive and Medically Appropriate Food Support Is Associated with Improved HIV and Diabetes Health. AB - Food insecurity is associated with negative chronic health outcomes, yet few studies have examined how providing medically appropriate food assistance to food insecure individuals may improve health outcomes in resource-rich settings. We evaluated a community-based food support intervention in the San Francisco Bay Area for people living with HIV and/or type 2 diabetes mellitus (T2DM) to determine the feasibility, acceptability, and potential impact of the intervention on nutritional, mental health, disease management, healthcare utilization, and physical health outcomes. The 6-month intervention provided meals and snacks designed to comprise 100% of daily energy requirements and meet nutritional guidelines for a healthy diet. We assessed paired outcomes at baseline and 6 months using validated measures. Paired t tests and McNemar exact tests were used with continuous and dichotomous outcomes, respectively, to compare pre-post changes. Fifty-two participants (out of 72 initiators) had both baseline and follow-up assessments, including 23 with HIV, 24 with T2DM, and 7 with both HIV and T2DM. Median food pick-up adherence was 93%. Comparing baseline to follow-up, very low food security decreased from 59.6% to 11.5% (p < 0.0001). Frequency of consumption of fats (p = 0.003) decreased, while frequency increased for fruits and vegetables (p = 0.011). Among people with diabetes, frequency of sugar consumption decreased (p = 0.006). We also observed decreased depressive symptoms (p = 0.028) and binge drinking (p = 0.008). At follow-up, fewer participants sacrificed food for healthcare (p = 0.007) or prescriptions (p = 0.046), or sacrificed healthcare for food (p = 0.029). Among people with HIV, 95% adherence to antiretroviral therapy increased from 47 to 70% (p = 0.046). Among people with T2DM, diabetes distress (p < 0.001), and perceived diabetes self management (p = 0.007) improved. Comprehensive, medically appropriate food support is feasible and may improve multiple health outcomes for food-insecure individuals living with chronic health conditions. Future studies should formally test the impact of medically appropriate food support interventions for food insecure populations through rigorous, randomized controlled designs. PMID- 28097615 TI - Trends in Injection Risk Behaviors among People Who Inject Drugs and the Impact of Harm Reduction Programs in Ukraine, 2007-2013. AB - The study examined trends in injection risk behaviors among people who inject drugs (PWIDs) and assessed the impact of harm reduction programs in Ukraine during 2007-2013. We performed a secondary analysis of the data collected in serial cross-sectional bio-behavioral surveillance surveys administered with PWIDs in Ukraine in 2007, 2008, 2011, and 2013. Using data from 14 Ukrainian cities, we assessed short-term trends in injection risk behaviors with the Cochran-Armitage test for trend and multivariable logistic regression models, adjusted for age, sex, region, marital status, education level, occupation, age at injection drug use initiation, experience of overdose, and self-reported HIV status. The overall test for trend indicated a statistically significant decrease over time for sharing needle/syringe during the last injection (p < 0.0001), sharing needle/syringe at least once in the last 30 days (p < 0.0001), and using a common container for drug preparation (p < 0.0001). The prevalence of injecting drugs from pre-loaded syringes was high (61.0%) and did not change over the study period. After adjusting for all significant confounders and comparing to 2007, the prevalence of sharing needle/syringe during the last injection was unchanged in 2008 (OR = 1.06, 95% CI = 0.92, 1.21), and declined in 2011 (OR = 0.18, 95% CI = 0.15, 0.22) and 2013 (OR = 0.17, 95% CI = 0.14, 0.21). Sharing needles/syringes in the last 30 days significantly decreased when compared to that in 2007 (2008: OR = 0.81, 95% CI = 0.74, 0.89; 2011: OR = 0.43, 95% CI = 0.38, 0.47; and 2013: OR = 0.31, 95% CI = 0.27, 0.35). The prevalence of using common instruments for drug preparation also decreased compared to that in 2007 (2008: OR = 0.88, 95% CI = 0.85, 0.91; 2011: OR = 0.85, 95% CI = 0.85, 0.90; and 2013: OR = 0.74, 95% CI = 0.71, 0.76). The observed reduction in the prevalence of injection risk behavior over time is encouraging. Our findings suggest that prevention programs in Ukraine have positive impact and provide support for governmental expansion of these programs. PMID- 28097616 TI - Operationalizing the Measurement of Seroadaptive Behaviors: A Comparison of Reported Sexual Behaviors and Purposely-Adopted Behaviors Among Men who have Sex with Men (MSM) in Seattle. AB - Seroadaptive behaviors are traditionally defined by self-reported sexual behavior history, regardless of whether they reflect purposely-adopted risk-mitigation strategies. Among MSM attending an STD clinic in Seattle, Washington 2013-2015 (N = 3751 visits), we used two seroadaptive behavior measures: (1) sexual behavior history reported via clinical computer-assisted self-interview (CASI) (behavioral definition); (2) purposely-adopted risk-reduction behaviors reported via research CASI (purposely-adopted definition). Pure serosorting (i.e. only HIV-concordant partners) was the most common behavior, reported (behavioral and purposely adopted definition) by HIV-negative respondents at 43% and 60% of visits, respectively (kappa = 0.24; fair agreement) and by HIV-positive MSM at 30 and 34% (kappa = 0.25; fair agreement). Agreement of the two definitions was highest for consistent condom use [HIV-negative men (kappa = 0.72), HIV-positive men (kappa = 0.57)]. Overall HIV test positivity was 1.4 but 0.9% for pure serosorters. The two methods of operationalizing behaviors result in different estimates, thus the choice of which to employ should depend on the motivation for ascertaining behavioral information. PMID- 28097617 TI - Rates and Covariates of Recent Sexual and Physical Violence Against HIV-Infected Outpatient Drinkers in Western Kenya. AB - Victimization from physical and sexual violence presents global health challenges. Partner violence is higher in Kenya than Africa. Violence against drinkers and HIV-infected individuals is typically elevated, so dual vulnerabilities may further augment risk. Understanding violence risks can improve interventions. Participants were 614 HIV-infected outpatient drinkers in western Kenya enrolled in a randomized trial to reduce alcohol use. At baseline, past 90-day partner physical and sexual violence were examined descriptively and in gender-stratified regression models. We hypothesized higher reported violence against women than men, and positive violence association with HIV stigma and alcohol use across gender. Women reported significantly more current sexual (26.3 vs. 5.7%) and physical (38.9 vs. 24.8%) victimization than men. Rates were generally higher than Kenyan lifetime national averages. In both regression models, HIV stigma and alcohol-related sexual expectations were significantly associated with violence while alcohol use was not. For women, higher violence risk was also conferred by childhood violence, past-year transactional sex, and younger age. HIV-infected Kenyan drinkers, particularly women, endorse high current violence due to multiple risk factors. Findings have implications for HIV interventions. Longitudinal research is needed to understand development of risk. PMID- 28097618 TI - Sex Behaviors as Social Cues Motivating Social Venue Patronage Among Young Black Men Who Have Sex with Men. AB - HIV prevention programs often focus on the physical social venues where men who have sex with men (MSM) frequent as sites where sex behaviors are assumed to be practiced and risk is conferred. But, how exactly these behaviors influence venue patronage is not well understood. In this study, we present a two-mode network analysis that determines the extent that three types of sex behaviors-condomless sex, sex-drug use, and group sex-influence the patronage of different types of social venues among a population sample of young Black MSM (YBMSM) (N = 623). A network analytic technique called exponential random graph modeling was used in a proof of concept analysis to verify how each sex behavior increases the likelihood of a venue patronage tie when estimated as either: (1) an attribute of an individual only and/or (2) a shared attribute between an individual and his peers. Findings reveal that sex behaviors, when modeled only as attributes possessed by focal individuals, were no more or less likely to affect choices to visit social venues. However, when the sex behaviors of peers were also taken into consideration, we learn that individuals were statistically more likely in all three behavioral conditions to go places that attracted other MSM who practiced the same behaviors. This demonstrates that social venues can function as intermediary contexts in which relationships can form between individuals that have greater risk potential given the venues attraction to people who share the same risk tendencies. As such, structuring interventions around these settings can be an effective way to capture the attention of YBMSM and engage them in HIV prevention. PMID- 28097619 TI - Lipid and Creatinine Adjustment to Evaluate Health Effects of Environmental Exposures. AB - PURPOSE OF REVIEW: Urine- and serum-based biomarkers are useful for assessing individuals' exposure to environmental factors. However, variations in urinary creatinine (a measure of dilution) or serum lipid levels, if not adequately corrected for, can directly impact biomarker concentrations and bias exposure disease association measures. RECENT FINDINGS: Recent methodological literature has considered the complex relationships between creatinine or serum lipid levels, exposure biomarkers, outcomes, and other potentially relevant factors using directed acyclic graphs and simulation studies. The optimal measures of urinary dilution and serum lipids have also been investigated. Existing evidence supports the use of covariate-adjusted standardization plus creatinine adjustment for urinary biomarkers and standardization plus serum lipid adjustment for lipophilic, serum-based biomarkers. It is unclear which urinary dilution measure is best, but all serum lipid measures performed similarly. Future research should assess methods for pooled biomarkers and for studying diseases and exposures that affect creatinine or serum lipids directly. PMID- 28097620 TI - Seminal Tract Amyloidosis: Synchronous Amyloidosis of the Seminal Vesicles, Deferent Ducts and Ejaculatory Ducts. AB - Senile Seminal Vesicle Amyloidosis (SSVA) increases with age. Involvement of the whole seminal tract, i.e. the seminal vesicles, ejaculatory and deferent ducts was first reported by us in the International Symposium on Amyloidosis 1998. Since then we encountered four more cases of SSVA. In all these cases the ejaculatory and deferent ducts were also involved by amyloid. The amyloid was located mostly sub-epithelially, stained positively with Congo red, gave green birefringence under polarized light and was permanganate sensitive, slightly positive for lactoferrin immunostaining and negative for all known amyloid types. In recent years the amyloid was found to be derived from Semenogelin I, a major constituent of the seminal fluid which is present in the epithelial cells of the seminal vesicle and vas deference. This would explain the deposition of amyloid not only in the seminal vesicles but also in the deferent an ejaculatory ducts which transport the seminal fluid. In a review of the literature we found three more articles on SSVA in which the amyloid was not limited to the seminal vesicles alone. We propose to designate this type of amyloid as "Senile seminal Tract Amyloidosis" (SSTA) instead of "Senile Seminal Vesicle Amyloidosis (SSVA)". PMID- 28097621 TI - Practice Patterns of Venous Thromboembolism Prophylaxis in Underweight, Critically Ill Patients with Neurologic Injury. AB - PURPOSE: Venous thromboembolism (VTE) prophylaxis in underweight patients with neurologic injury remains unaddressed by guidelines and primary literature. This study aimed to describe VTE prophylaxis strategies employed in this population and compare the impact of underweight and non-obese patients on thrombotic and bleeding events. METHODS: A retrospective review of adults admitted with a diagnosis of neurologic injury to a neurology/neurosurgery intensive care unit (ICU) over 6 years. Patients admitted >=72 h with an order for VTE prophylaxis during admission, and a body mass index (BMI) <30 kg/m2 were included. Patients were stratified to underweight (BMI <=18.5 kg/m2 or weight <=50.0 kg) or non obese (BMI 18.6-29.9 kg/m2) groups and matched, 2:1, on age, diagnosis, and disease severity. RESULTS: The most common regimen in the underweight (n = 107) and non-obese (n = 214) group was unfractionated heparin (UFH) 5000 units subcutaneously Q12 h (69.1 vs. 83.6%; p = 0.003). Only underweight patients received UFH 2500 units subcutaneously Q12 h (17.8 vs. 0.0%; p < 0.0001). The proportion of overall bleeding and thrombotic events while receiving VTE prophylaxis was not significantly different. The proportion of underweight patients developing intracranial hematoma expansion while receiving prophylaxis versus non-obese patients (45.5 vs. 8.3%; p = 0.017) was significant. Patients receiving >150 units/kg/day of UFH displayed a trend toward increased risk of bleeding (9.7 vs. 4.2%; p = 0.064). CONCLUSIONS: Current practice does not reflect dose reductions for neurologically injured, underweight patients. Caution should be considered when using increased doses of UFH in neurologically injured patients that are underweight and/or may be exposed to >150 units/kg/day of UFH. Continued assessment of VTE prophylaxis is needed to confirm these findings. PMID- 28097622 TI - Selenium rescues orbital fibroblasts from cell death induced by hydrogen peroxide: another molecular basis for the effects of selenium in graves' orbitopathy. PMID- 28097624 TI - Poorly differentiated adenocarcinoma with signet-ring cells in duodenal papilla: a case report. AB - An 82-year-old woman with common bile duct (CBD) dilatation observed during routine ultrasonography was referred to our hospital. Preliminary blood tests revealed elevated levels of hepatobiliary enzymes. Computed tomography (CT) scan showed lower bile duct wall thickening and enhancement. Esophagogastroduodenoscopy revealed mildly swollen papilla of Vater, without ulceration. Endoscopic retrograde cholangiography demonstrated that the CBD was grossly dilated with a constriction in the lower part. The final diagnosis indicated poorly differentiated adenocarcinoma of duodenal papilla with signet ring cells; pT3N0M0, stage IIA (Unio Internationalis Contra Cancrum, 7th edition), for which subtotal stomach-preserving pancreaticoduodenectomy (SSPPD) was performed. This case is quite rare, and the surgery resulted in a desirable outcome. The patient has been disease-free for 5 years since the surgery. PMID- 28097623 TI - Toward a functional definition of ankyloglossia: validating current grading scales for lingual frenulum length and tongue mobility in 1052 subjects. AB - PURPOSE: Alterations of the lingual frenulum may contribute to oromyofacial dysfunction, speech and swallowing impediments, underdevelopment of the maxillofacial skeleton, and even predispose to sleep breathing disorder. This study aims to assess the utility of existing instruments for evaluation of restricted tongue mobility, describe normal and abnormal ranges of tongue mobility, and provide evidence in support of a reliable and efficient measure of tongue mobility. METHODS: A prospective cohort study of 1052 consecutive patients was evaluated during a 3-month period. Age, gender, ethnicity, height, weight, BMI, maximal interincisal mouth opening (MIO), mouth opening with tongue tip to maxillary incisive papillae at roof of mouth (MOTTIP), Kotlow's free-tongue measurement, and presence of severe tongue-tie were recorded. Secondary outcome measures include tongue range of motion deficit (TRMD, difference between MIO and MOTTIP) and tongue range of motion ratio (TRMR, ratio of MOTTIP to MIO). RESULTS: Results indicate that MIO is dependent on age and height; MOTTIP and TRMD are dependent on MIO; Kotlow's free-tongue measurement is an independent measure of free-tongue length and tongue mobility. TRMR is the only independent measurement of tongue mobility that is directly associated with restrictions in tongue function. CONCLUSIONS: We propose the use of tongue range of motion ratio as an initial screening tool to assess for restrictions in tongue mobility. "Functional" ankyloglossia can thus be defined and treatment effects followed objectively by using the proposed grading scale: grade 1: tongue range of motion ratio is >80%, grade 2 50-80%, grade 3 < 50%, grade 4 < 25%. PMID- 28097625 TI - Effects of a web-based intervention on women's breast health behaviors. AB - Helping women make choices to reduce cancer risk and to improve breast health behaviors is important, but the best ways to reach more people with intervention assistance is not known. To test the efficacy of a web-based intervention designed to help women make better breast health choices, we adapted our previously tested, successful breast health intervention package to be delivered on the Internet, and then we tested it in a randomized trial. We recruited women from the general public to be randomized to either an active intervention group or a delayed intervention control group. The intervention consisted of a specialized website providing tailored and personalized risk information to all participants, followed by offers of additional support if needed. Follow-up at one-year post randomization revealed significant improvements in mammography screening in intervention women compared with control women (improvement of 13 percentage points). The intervention effects were more powerful in women who increased breast health knowledge and decreased cancer worry during intervention. These data indicate that increases in mammography can be accomplished in population-based mostly insured samples by implementing this simple, low resource intensive intervention. PMID- 28097626 TI - Peer mentors delivering a physical activity intervention for cancer survivors: effects among mentors. AB - To further inform implementation efforts of a telephone-based physical activity (PA) intervention for breast cancer survivors, we assessed the PA, fatigue, mood, and quality of life of the peer mentors/coaches who delivered the program. The coaches were volunteers with the American Cancer Society's Reach to Recovery program. The coaches (n = 18) delivered the PA intervention to 76 breast cancer survivors in a randomized controlled trial. Coaches completed assessments of PA (self-report), motivational readiness for PA, and standardized measures of psychosocial variables at the start of coaching and at study exit. At study exit, they also responded to an open-ended question on the benefits that they accrued from the study. We used generalized linear models to analyze the PA data and psychosocial variables. Chi-squared analyses were used for motivational readiness. The written responses to the open-ended question were analyzed to identify themes. Coaches' PA exceeded national recommendations at study entry and exit with no significant changes over time. Sixty-one percent were in the maintenance stage of motivational readiness, and 61% remained in the same stage at study exit. Psychosocial functioning also remained stable over time. Qualitative data revealed that the coaches' gains included helping themselves (with four subthemes) and helping others. Intervention delivery had no unintended negative consequences (PA, motivational readiness, and psychosocial functioning) among coaches. They reported gains that were not reflected in standardized psychosocial assessments. These data support further implementation of peer delivered PA programs to enhance the reach of interventions. PMID- 28097628 TI - Erratum to: Optimal Affinity of a Monoclonal Antibody: Guiding Principles Using Mechanistic Modeling. PMID- 28097627 TI - Adherence with physical activity monitoring wearable devices in a community-based population: observations from the Washington, D.C., Cardiovascular Health and Needs Assessment. AB - Wearable mobile health (mHealth) technologies offer approaches for targeting physical activity (PA) in resource-limited, community-based interventions. We sought to explore user characteristics of PA tracking, wearable technology among a community-based population within a health and needs assessment. In 2014-2015, we conducted the Washington, D.C., Cardiovascular Health and Needs Assessment in predominantly African-American churches among communities with higher obesity rates and lower household incomes. Participants received a mHealth PA monitor and wirelessly uploaded PA data weekly to church data collection hubs. Participants (n = 99) were 59 +/- 12 years, 79% female, and 99% African-American, with a mean body mass index of 33 +/- 7 kg/m2. Eighty-one percent of participants uploaded PA data to the hub and were termed "PA device users." Though PA device users were more likely to report lower household incomes, no differences existed between device users and non-users for device ownership or technology fluency. Findings suggest that mHealth systems with a wearable device and data collection hub may feasibly target PA in resource-limited communities. PMID- 28097630 TI - Re-Engagement into Care: The Role of Social Support on Service Use for Recurrent Episodes of Mental Health Distress Among Primary Care Patients. AB - Given high rates of relapse of depression, understanding mechanisms that provide long-term benefits and optimal outcomes for depressed individuals is crucial. The current study examines social support as a relevant component in service use to manage mental health needs for individuals with recurrent depression over a 5 year period. Conducting a secondary data analysis from a randomized clinical trial titled Partners in Care, the study examines direct and moderating effects over two time points of reported 12-month social support on service use for mental health needs at 57-months for an adult sample (n = 991). Direct effects were supported for demographic and need variables. Increased social support at 12 months positively moderated the relationship between health impairment and service use at 57-months. Findings inform and extend the understanding of social support as an important mechanism to care to integrate into the treatment experience, encouraging service use to manage recurrent depressive episodes. PMID- 28097629 TI - Radiomitigation and Tissue Repair Activity of Systemically Administered Therapeutic Peptide TP508 Is Enhanced by PEGylation. AB - TP508 is a synthetically derived tissue repair peptide that has previously demonstrated safety and potential efficacy in phase I/II clinical trials for the treatment of diabetic foot ulcers. Recent studies show that a single injection of TP508 administered 24 h after irradiation significantly increases survival and delays mortality in murine models of acute radiation mortality. Thus, TP508 is being developed as a potential nuclear countermeasure. Because of the short plasma half-life of TP508, we hypothesize that increasing the peptide bioavailability would increase TP508 efficacy or reduce the dosage required for therapeutic effects. We, therefore, evaluated the covalent attachment of various sizes of polyethylene glycol to TP508 at either its N-terminus or at an internal cysteine. A size-dependent increase in TP508 plasma half-life due to PEGylation was observed in blood samples from male CD-1 mice using fluorescently labeled TP508 and PEGylated TP508 derivatives. Biological activity of PEGylated TP508 derivatives was evaluated using a combination of biologically relevant assays for wound closure, angiogenesis, and DNA repair. PEG5k-TP508 enhanced wound closure after irradiation and enhanced angiogenic sprouting in murine aortic ring segments relative to equimolar dosages of TP508 without enhancing circulating half-life. PEG30k-TP508 extended the plasma half-life by approximately 19-fold while also showing enhanced biological activity. Intermediate-sized PEGylated TP508 derivatives had enhanced plasma half-life but were not active in vivo. Thus, increased half-life does not necessarily correlate with increased biological activity. Nevertheless, these results identify two candidates, PEG5k TP508 and PEG30k-TP508, for potential development as second-generation TP508 injectable drugs. PMID- 28097631 TI - Force-dependent calcium signaling and its pathway of human neutrophils on P selectin in flow. AB - P-selectin engagement of P-selectin glycoprotein ligand-1 (PSGL-1) causes circulating leukocytes to roll on and adhere to the vascular surface, and mediates intracellular calcium flux, a key but unclear event for subsequent arresting firmly at and migrating into the infection or injured tissue. Using a parallel plate flow chamber technique and intracellular calcium ion detector (Fluo-4 AM), the intracellular calcium flux of firmly adhered neutrophils on immobilized P-selectin in the absence of chemokines at various wall shear stresses was investigated here in real time by fluorescence microscopy. The results demonstrated that P-selectin engagement of PSGL-1 induced the intracellular calcium flux of firmly adhered neutrophils in flow, increasing P selectin concentration enhanced cellular calcium signaling, and, force triggered, enhanced and quickened the cytoplasmic calcium bursting of neutrophils on immobilized P-selectin. This P-selectin-induced calcium signaling should come from intracellular calcium release rather than extracellular calcium influx, and be along the mechano-chemical signal pathway involving the cytoskeleton, moesin and Spleen tyrosine kinase (Syk). These results provide a novel insight into the mechano-chemical regulation mechanism for P-selectin-induced calcium signaling of neutrophils in flow. PMID- 28097632 TI - Acquisition and adaptation of the airway microbiota in the early life of cystic fibrosis patients. AB - Cystic fibrosis (CF) is a genetic disease in which bacterial infections of the airways play a major role in the long-term clinical outcome. In recent years, a number of next-generation sequencing (NGS)-based studies aimed at deciphering the structure and composition of the airways' microbiota. It was shown that the nasal cavity of CF patients displays dysbiosis early in life indicating a failure in the first establishment of a healthy microbiota. In contrast, within the conducting and lower airways, the establishment occurs normally first, but is sensitive to future dysbiosis including chronic infections with classical pathogens in later life. The objective of this mini-review is to give an update on the current knowledge about the development of the microbiota in the early life of CF patients. Microbial acquisition in the human airways can be described by the island model: Microbes found in the lower airways of CF patients represent "islands" that are at first populated from the upper airways reflecting the "mainland." Colonization can be modeled following the neutral theory in which the most abundant bacteria in the mainland are also frequently found in the lower airways initially. At later times, however, the colonization process of the lower airways segregates by active selection of specific microbes. Future research should focus on those processes of microbial and host interactions to understand how microbial communities are shaped on short- and long-term scales. We point out what therapeutic consequences arise from the microbiome data obtained within ecological framework models. PMID- 28097633 TI - Meropenem Dosing Based on a Population Pharmacokinetic-Pharmacodynamic Model in Elderly Patients with Infection of the Lower Respiratory Tract. AB - BACKGROUND: Meropenem is used for the treatment of severe lower respiratory tract infections (LRTIs) caused by multidrug-resistant Gram-negative bacilli. OBJECTIVE: We evaluated the clinical benefits of a strategy of meropenem dosing based on a population pharmacokinetics/pharmacodynamics (PK/PD) model in elderly patients with an LRTI. METHODS: In this prospective single-center open-label randomized controlled trial, 79 elderly patients with an LRTI caused by Gram negative bacilli were randomized to a study group (SG) or a control group (CG). The latter received meropenem according to a regimen decided by the attending physician. The SG received individualized meropenem therapy with a dosing strategy based on software developed from a meropenem population PK/PD model. The primary endpoint was clinical response to meropenem therapy. Secondary endpoints were the amount of antibiotics used and bacteriologic response. RESULTS: Klebsiella pneumoniae was the most common pathogen (32.9%), followed by Pseudomonas aeruginosa (30.4%) and Escherichia coli (17.7%). A total of 63 (79.7%) patients achieved clinical success. Prevalence of clinical success was significantly higher in the SG than in the CG (89.7 vs. 70.0%; p = 0.029). The daily dose of meropenem was significantly lower in the SG than in the CG (1.5 vs. 2.0 g; p = 0.017). A total of 52 (65.8%) patients experienced bacteriologic success, the median duration of meropenem therapy was 9 days, and the median total dose of meropenem was 18.0 g. There were no significant differences between the groups in these parameters. CONCLUSIONS: A strategy for meropenem dosing based on a population PK/PD model can improve clinical response and avoid overtreatment in elderly patients with an LRTI. ClinicalTrials.gov registration number NCT01944319. PMID- 28097634 TI - Schizophrenia: Impact on Family Dynamics. AB - In many societies, family members are now the primary caregivers of mental health patients, taking on responsibilities traditionally under the purview of hospitals and medical professionals. The impact of this shift on the family is high, having both an emotional and economic toll. The aim of this paper is to review the main changes that occur in family dynamics for patients with schizophrenia. The article addresses three central themes: (i) changes in the family at the onset of the disorder, (ii) consequences for family members because of their caregiver role, and (iii) family interventions aimed at improving the complex dynamics within the family. After analyzing and discussing these themes, it is observed that despite advances in the field, the viability of taking care of a patient with schizophrenia by the family remains a challenge. Improving care will require commitments from the family, the mental health service system, and local and national governments for greater investments to improve the quality of life of society in general and individuals with schizophrenia in particular. PMID- 28097635 TI - Treatment of Functional Impairment in Patients with Bipolar Disorder. AB - Traditionally, functional impairment has received little attention in bipolar disorder, despite the fact that many patients experience significant impairments in daily life. In the last decade, research has changed its focus from clinical remission to functional recovery in bipolar patients as a priority. A literature review of this topic will allow us provide an overview of the relevance of functional impairment as well as the potential factors that can predict or contribute to low functioning in bipolar disorder (BD). Treatment approaches should consider not only euthymia as a goal but also cognitive and functional improvement of patients with such a complex disorder. Functional remediation and psychoeducation among psychological interventions may help to enhance functioning. The combination of cognitive enhancers and cognitive/functional remediation programs may help in improving cognitive and functional impairments. Early interventions are essential to prevent cognitive deficits and disability. PMID- 28097636 TI - Andrographolide: antibacterial activity against common bacteria of human health concern and possible mechanism of action. AB - Increasing bacterial resistance to common drugs is a major public health concern for the treatment of infectious diseases. Certain naturally occurring compounds of plant sources have long been reported to possess potential antimicrobial activity. This study was aimed to investigate the antibacterial activity and possible mechanism of action of andrographolide (Andro), a diterpenoid lactone from a traditional medicinal herb Andrographis paniculata. Extent of antibacterial action was assessed by minimal bactericidal concentration method. Radiolabeled N-acetyl glucosamine, leucine, thymidine, and uridine were used to determine the effect of Andro on the biosyntheses of cell wall, protein, DNA, and RNA, respectively. In addition, anti-biofilm potential of this compound was also tested. Andro showed potential antibacterial activity against most of the tested Gram-positive bacteria. Among those, Staphylococcus aureus was found to be most sensitive with a minimal inhibitory concentration value of 100 MUg/mL. It was found to be bacteriostatic. Specific inhibition of intracellular DNA biosynthesis was observed in a dose-dependent manner in S. aureus. Andro mediated inhibition of biofilm formation by S. aureus was also found. Considering its antimicrobial potency, Andro might be accounted as a promising lead for new antibacterial drug development. PMID- 28097637 TI - Moving from Patient Advocacy to Partnership: A Long and Bumpy Road. AB - Real-life experiences of grassroots patient organizations across a variety of diseases, countries and contexts have been used to develop a four-mode framework of the transition from patient advocacy to partnership, defined by one axis as individual versus collective action and the other axis as activities 'outside' or 'inside' the system. The four quadrants are labeled as advocacy, activism, reform and broker, and engagement is further refined by whether the participation is 'pushed' by the group or 'pulled' by the system. There are many examples of patient advocacy groups transitioning through the four quadrants; however, depending on other factors of culture, opportunity and their own preferences, groups may work primarily through one or two quadrants. PMID- 28097638 TI - Regional Differences in the Prescription of Biologics for Psoriasis in Sweden: A Register-Based Study of 4168 Patients. AB - BACKGROUND: Observational studies suggest an inequitable prescription of biologics in psoriasis care, which may be attributed to geographical differences in treatment access. Sweden regularly ranks high in international comparisons of equitable healthcare, and is, in connection with established national registries, an ideal country to investigate potential inequitable access. OBJECTIVE: The aim was to determine whether the opportunity for patients to receive biologics depends on where they receive care. METHODS: Biologic-naive patients enrolled in the Swedish National Register for Systemic Treatment of Psoriasis (PsoReg) from 2008 to 2015 (n = 4168) were included. The association between the likelihood of initiating a biologic and the region where patients received care was analyzed. The strength of the association was adjusted for patient and clinical characteristics, as well as disease severity using logistic regression analysis. The proportion of patients that switched to a biologic (switch rate) and the probability of switch to a biologic was calculated in 2-year periods. RESULTS: The national switch rate increased marginally over time from 9.7 to 11.0%, though the uptake varied across regions. Adjusted odds ratios for at least one region were significantly different from the reference region in every 2-year period. During the latest period (2014-2015), the average patient in the lowest prescribing region was nearly 2.5 times less likely to switch as a similar patient in the highest prescribing region. CONCLUSIONS: Geographical differences in biologics prescription persist after adjusting for patient characteristics and disease severity. The Swedish example calls for further improvements in delivering equitable psoriasis care. PMID- 28097639 TI - Risk of bleeding and repeated bleeding events in prasugrel-treated patients: a review of data from the Japanese PRASFIT studies. AB - Prasugrel is a third-generation thienopyridine that achieves potent platelet inhibition with less pharmacological variability than other thienopyridines. However, clinical experience suggests that prasugrel may be associated with a higher risk of de novo and recurrent bleeding events compared with clopidogrel in Japanese patients undergoing percutaneous coronary intervention (PCI). In this review, we evaluate the risk of bleeding in Japanese patients treated with prasugrel at the doses (loading/maintenance doses: 20/3.75 mg) adjusted for Japanese patients, evaluate the risk factors for bleeding in Japanese patients, and examine whether patients with a bleeding event are at increased risk of recurrent bleeding. This review covers published data and new analyses of the PRASFIT (PRASugrel compared with clopidogrel For Japanese patIenTs) trials of patients undergoing PCI for acute coronary syndrome or elective reasons. The bleeding risk with prasugrel was similar to that observed with the standard dose of clopidogrel (300/75 mg), including when bleeding events were re-classified using the Bleeding Academic Research Consortium criteria. The pharmacodynamics of prasugrel was not associated with the risk of bleeding events. The main risk factors for bleeding events were female sex, low body weight, advanced age, and presence of diabetes mellitus. Use of a radial puncture site was associated with a lower risk of bleeding during PCI than a femoral puncture site. Finally, the frequency and severity of recurrent bleeding events during continued treatment were similar between prasugrel and clopidogrel. In summary, this review provides important insights into the risk and types of bleeding events in prasugrel treated patients.Trial registration numbers: JapicCTI-101339 and JapicCTI-111550. PMID- 28097640 TI - Priming increases the anti-tumor effect and therapeutic window of 177Lu octreotate in nude mice bearing human small intestine neuroendocrine tumor GOT1. AB - BACKGROUND: 177Lu-[DOTA0, Tyr3]-octreotate (177Lu-octreotate) is used for treatment of patients with somatostatin receptor (SSTR) expressing neuroendocrine tumors. However, complete tumor remission is rarely seen, and optimization of treatment protocols is needed. In vitro studies have shown that irradiation can up-regulate the expression of SSTR1, 2 and 5, and increase 177Lu-octreotate uptake. The aim of the present study was to examine the anti-tumor effect of a 177Lu-octreotate priming dose followed 24 h later by a second injection of 177Lu octreotate compared to a single administration of 177Lu-octreotate, performed on the human small intestine neuroendocrine tumor cell line, GOT1, transplanted to nude mice. RESULTS: Priming resulted in a 1.9 times higher mean absorbed dose to the tumor tissue per administered activity, together with a reduced mean absorbed dose for kidneys. Priming gave the best overall anti-tumor effects. Magnetic resonance imaging showed no statistically significant difference in tumor response between treatment with and without priming. Gene expression analysis demonstrated effects on cell cycle regulation. Biological processes associated with apoptotic cell death were highly affected in the biodistribution and dosimetry study, via differential regulation of, e.g., APOE, BAX, CDKN1A, and GADD45A. CONCLUSIONS: Priming had the best overall anti-tumor effects and also resulted in an increased therapeutic window. Results indicate that potential biomarkers for tumor regrowth may be found in the p53 or JNK signaling pathways. Priming administration is an interesting optimization strategy for 177Lu octreotate therapy of neuroendocrine tumors, and further studies should be performed to determine the mechanisms responsible for the reported effects. PMID- 28097643 TI - Abstracts from the European Hip Society 2002 Domestic Meeting. AB - Abstracts of the European Hip Society 2002 Domestic Meeting Baveno, Italy - 5-8 June 2002. PMID- 28097642 TI - Adrenal cyst with both Mullerian and mesothelial differentiation- a clinicopathological and immunohistochemical study with implications for histogenesis. AB - True epithelial-lined cysts are rare forms of adrenal cystic lesions, the pathogenesis of which is still not fully understood. In this report we present a case of an adrenal cyst diagnosed incidentally on imaging in a 31-year-old, previously healthy, obese woman. Due to non-specific hormonal disorders and enlargement of the lesion, a right-sided laparoscopic adrenalectomy was performed. The cyst was lined predominantly by ciliated cuboidal-to-columnar, Mullerian-type epithelium, and focally by flat-to-cuboidal, mesothelium-like lining. Immunohistochemistry demonstrated a strong positive reaction in the cells of both types of lining for CKAE1+E3, CK19, CK7 and WT1, and both had a negative reaction for CK20, CD34, Melan-A, SF1, TTF1, SMA and CDX2. The cells of the ciliated cuboidal-to-columnar epithelium were strongly positive for PAX8, ER, Ep CAM and EMA, focally positive for PR, and were negative for calretinin, whereas the cells of the flat-to-cuboidal lining were positive for calretinin and podoplanin and showed only a weak positive response in individual cells for PAX8, EMA and Ep-CAM, but were negative for ER and PR. This is the first reported case of an adrenal ciliated epithelial cyst with Mullerian differentiation (confirmed immunohistochemically) in the English literature. The differences in morphology and immunophenotype of the two types of lining (epithelial Mullerian phenotype versus mesothelial phenotype), suggest that some adrenal epithelial cysts probably form due to metaplasia of mesothelium-derived lining. A similar mechanism may also be involved in the pathogenesis of at least some of the so called Mullerian cysts (or inclusions) in other locations. PMID- 28097644 TI - Erratum to: Eur J Ophthalmol. 2002;12(1):1-4 and Eur J Ophthalmol. 2015;25(5):437 442. AB - Erratum To: Eur J Ophthalmol. 2002 Jan-Feb;12(1):1-4. doi: 10.5301/EJO.2008.799. Prevalence of astigmatism among students in northern Greece. A.T. Mandalos, D.K. Peios, T.A. Mavrakanas, V.A. Golias, K.G. Megalou, K.A. Delidou, A.C. Gregoriadou, B.C. Katsougiannopoulos PMID: 11936436 [PubMed - indexed for MEDLINE]We inform our readers that in the author list the full name of one author (T.A. Mavracanas) was published incorrectly. We supply the correct author listing and apologize to the readers. Eur J Ophthalmol. 2015 Sep-Oct;25(5):437-442. doi: 10.5301/ejo.5000594. Choroidal and peripapillary retinal nerve fiber layer thickness in adults with anisometropic amblyopia. Feride Aylin Kantarci, Mehmet Gurkan Tatar, Hasim Uslu, Hatice Nur Colak, Aydin Yildirim, Hasan Goker, Bulent Gurler PMID: 25837640 [PubMed - indexed for MEDLINE] We inform our readers that one author (Emine Esra Karaca) was erroneously included in the author list and should now be removed from this manuscript. We supply the correct author list and apologize to the readers. PMID- 28097646 TI - Visuospatial training improves elementary students' mathematics performance. AB - BACKGROUND: Although spatial ability and mathematics performance are highly correlated, there is scant research on the extent to which spatial ability training can improve mathematics performance. AIMS: This study evaluated the efficacy of a visuospatial intervention programme within classrooms to determine the effect on students' (1) spatial reasoning and (2) mathematics performance as a result of the intervention. SAMPLE: The study involved grade six students (ages 10-12) in eight classes. There were five intervention classes (n = 120) and three non-intervention control classes (n = 66). METHODS: A specifically designed 10 week spatial reasoning programme was developed collaboratively with the participating teachers, with the intervention replacing the standard mathematics curriculum. The five classroom teachers in the intervention programme presented 20 hr of activities aimed at enhancing students' spatial visualization, mental rotation, and spatial orientation skills. RESULTS: The spatial reasoning programme led to improvements in both spatial ability and mathematics performance relative to the control group who received standard mathematics instruction. CONCLUSIONS: Our study is the first to show that a classroom-based spatial reasoning intervention improves elementary school students' mathematics performance. PMID- 28097641 TI - Natural Products Diversity of Marine Ascidians (Tunicates; Ascidiacea) and Successful Drugs in Clinical Development. AB - This present study reviewed the chemical diversity of marine ascidians and their pharmacological applications, challenges and recent developments in marine drug discovery reported during 1994-2014, highlighting the structural activity of compounds produced by these specimens. Till date only 5% of living ascidian species were studied from <3000 species, this study represented from family didemnidae (32%), polyclinidae (22%), styelidae and polycitoridae (11-12%) exhibiting the highest number of promising MNPs. Close to 580 compound structures are here discussed in terms of their occurrence, structural type and reported biological activity. Anti-cancer drugs are the main area of interest in the screening of MNPs from ascidians (64%), followed by anti-malarial (6%) and remaining others. FDA approved ascidian compounds mechanism of action along with other compounds status of clinical trials (phase 1 to phase 3) are discussed here in. This review highlights recent developments in the area of natural products chemistry and biotechnological approaches are emphasized. PMID- 28097645 TI - Bacterial subversion of cAMP signalling inhibits cathelicidin expression, which is required for innate resistance to Mycobacterium tuberculosis. AB - Antimicrobial peptides such as cathelicidins are important components of innate immune defence against inhaled microorganisms, and have shown antimicrobial activity against Mycobacterium tuberculosis in in vitro models. Despite this, little is known about the regulation and expression of cathelicidin during tuberculosis in vivo. We sought to determine whether the cathelicidin-related antimicrobial peptide gene (Cramp), the murine functional homologue of the human cathelicidin gene (CAMP or LL-37), is required for regulation of protective immunity during M. tuberculosis infection in vivo. We used Cramp-/- mice in a validated model of pulmonary tuberculosis, and conducted cell-based assays with macrophages from these mice. We evaluated the in vivo susceptibility of Cramp-/- mice to infection, and also dissected various pro-inflammatory immune responses against M. tuberculosis. We observed increased susceptibility of Cramp-/- mice to M. tuberculosis as compared with wild-type mice. Macrophages from Cramp-/- mice were unable to control M. tuberculosis growth in an in vitro infection model, were deficient in intracellular calcium influx, and were defective in stimulating T cells. Additionally, CD4+ and CD8+ T cells from Cramp-/- mice produced less interferon-beta upon stimulation. Furthermore, bacterial-derived cAMP modulated cathelicidin expression in macrophages. Our results demonstrate that cathelicidin is required for innate resistance to M. tuberculosis in a relevant animal model and is a key mediator in regulation of the levels of pro-inflammatory cytokines by calcium and cyclic nucleotides. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28097647 TI - Microbiota Composition and Pulmonary Surfactant Protein Expression as Markers of Death by Drowning. AB - Pathological diagnosis of drowning remains a challenge for forensic science, because of a lack of pathognomonic findings. We analyzed microbiota and surfactant protein in the lungs for a novel diagnosis of drowning. All rats were divided into drowning, postmortem submersion, and control groups. The water, lungs, closed organs (kidney and liver), and cardiac blood in rats were assayed by targeting 16S ribosomal RNA of Miseq sequencing. Lung samples were analyzed by immunohistochemical staining for surfactant protein A. The closed organs and cardiac blood of drowned group have a lot of aquatic microbes, which have not been detected in postmortem submersion group. Furthermore, intra-alveolar granular staining of surfactant protein A (SP-A) was severely observed in the drowned group than the postmortem submersion and control groups. The findings suggested that the presence of aquatic microbiota in the closed organs and increased expression of SP-A could be markers for a diagnosis of drowning. PMID- 28097648 TI - A systematic review and meta-analysis of prospective transition from major depression to bipolar disorder. AB - OBJECTIVE: Some people with major depressive disorder (MDD) may be at a pre-onset stage for bipolar disorder (BD), where early identification or prevention efforts may be feasible. We aimed to identify rates and characteristics predictive of transition to BD in prospective follow-up studies of people with MDD. METHODS: Using a systematic search strategy, we identified studies with a diagnostic ascertainment of MDD and BD of an adequate standard, and where the minimum length of follow-up was 6 months. We examined the incidence and point prevalence of BD and the pooled odds ratios (OR) for baseline predictors. RESULTS: From 5554 unique publications, 56 were included. Nearly a quarter of adults (22.5%) and adolescents with MDD followed up for a mean length of 12-18 years developed BD, with the greatest risk of transition being in the first 5 years. The meta analysis identified that transition from MDD to BD was predicted by family history of BD (OR = 2.89, 95% CI: 2.01-4.14, N = 7), earlier age of onset of depression (g = -0.33, SE = 0.05, N = 6) and presence of psychotic symptoms (OR = 4.76, 95% CI: 1.79-12.66, N = 5). CONCLUSIONS: Participants with the identified risk factors merit closer observation and may benefit from prevention efforts, especially if outcomes broader than BD are considered. PMID- 28097649 TI - Hospital Variation in Utilization of Life-Sustaining Treatments among Patients with Do Not Resuscitate Orders. AB - OBJECTIVE: To determine between-hospital variation in interventions provided to patients with do not resuscitate (DNR) orders. DATA SOURCES/SETTING: United States Agency of Healthcare Research and Quality, Healthcare Cost and Utilization Project, California State Inpatient Database. STUDY DESIGN: Retrospective cohort study including hospitalized patients aged 40 and older with potential indications for invasive treatments: in-hospital cardiac arrest (indication for CPR), acute respiratory failure (mechanical ventilation), acute renal failure (hemodialysis), septic shock (central venous catheterization), and palliative care. Hierarchical logistic regression to determine associations of hospital "early" DNR rates (DNR order placed within 24 hours of admission) with utilization of invasive interventions. DATA COLLECTION/EXTRACTION METHODS: California State Inpatient Database, year 2011. PRINCIPAL FINDINGS: Patients with DNR orders at high-DNR-rate hospitals were less likely to receive invasive mechanical ventilation for acute respiratory failure or hemodialysis for acute renal failure, but more likely to receive palliative care than DNR patients at low-DNR-rate hospitals. Patients without DNR orders experienced similar rates of invasive interventions regardless of hospital DNR rates. CONCLUSIONS: Hospitals vary widely in the scope of invasive or organ-supporting treatments provided to patients with DNR orders. PMID- 28097650 TI - Scaling of pattern formations and morphogen gradients. AB - The concentration gradient of morphogens provides positional information for an embryo and plays a pivotal role in pattern formation of tissues during the developmental processes. Morphogen-dependent pattern formations show robustness despite various perturbations. Although tissues usually grow and dynamically change their size during histogenesis, proper patterns are formed without the influence of size variations. Furthermore, even when the blastula embryo of Xenopus laevis is bisected into dorsal and ventral halves, the dorsal half of the embryo leads to proportionally patterned half-sized embryos. This robustness of pattern formation despite size variations is termed as scaling. In this review, I focused on the morphogen-dependent dorsal-ventral axis formation in Xenopus and described how morphogens form a proper gradient shape according to the embryo size. PMID- 28097651 TI - The mysterious role of the neuronal anion exchanger-3. PMID- 28097653 TI - Prolongation of somitogenesis in two anguilliform species, the Japanese eel Anguilla japonica and pike eel Muraenesox cinereus, with refined descriptions of their early development. AB - The embryonic development of the Japanese eel Anguilla japonica and pike eel Muraenesox cinereus was morphologically investigated with laboratory-reared specimens to clarify the characteristics of somitogenesis. In A. japonica, somites were first observed at 18 h post fertilization (hpf) when epiboly reached 90%. Somitogenesis progressed at a rate of 1.6 h-1 at mean +/- s.d. 22.6 +/- 0.7 degrees C and completed at 107 hpf (3 days post hatching; dph) when total number of somites (ST) reached 114, which corresponds to the species' number of vertebrae (112-119). In M. cinereus, somites were first observed at 14 hpf when epiboly completed. Somitogenesis progressed at a rate of 1.9 h-1 at mean +/- s.d. 24.4 +/- 0.2 degrees C and completed at 90 hpf (2 dph) with 149 +/- 4 ST, which corresponds to the species' number of vertebrae (142-158). Both species hatched before somitogenesis was completed, at 37 hpf with 47 ST and 42 hpf with 82 +/- 4 ST, respectively. The formation of other organs such as the heart, mouth and pectoral fin bud occurred during somitogenesis. Comparison with the development of zebrafish Danio rerio indicates a prolongation of somitogenesis in A. japonica and M. cinereus. Their somitogenesis rates, however, correspond well with that of D. rerio estimated at the same temperature and their developmental stages at hatching are almost equivalent to other fishes having similar yolk sizes. Therefore, the prolongation of somitogenesis in A. japonica and M. cinereus may be accounted for solely by the increased numbers of somites to be formed, not by a slow somitogenesis rate or an acceleration in organogenesis. PMID- 28097652 TI - MDM4 is a rational target for treating breast cancers with mutant p53. AB - Mutation of the key tumour suppressor p53 defines a transition in the progression towards aggressive and metastatic breast cancer (BC) with the poorest outcome. Specifically, the p53 mutation frequency exceeds 50% in triple-negative BC. Key regulators of mutant p53 that facilitate its oncogenic functions are potential therapeutic targets. We report here that the MDM4 protein is frequently abundant in the context of mutant p53 in basal-like BC samples. Importantly, we show that MDM4 plays a critical role in the proliferation of these BC cells. We demonstrate that conditional knockdown (KD) of MDM4 provokes growth inhibition across a range of BC subtypes with mutant p53, including luminal, Her2+ and triple-negative BCs. In vivo, MDM4 was shown to be crucial for the establishment and progression of tumours. This growth inhibition was mediated, at least in part, by the cell cycle inhibitor p27. Depletion of p27 together with MDM4 KD led to recovery of the proliferative capacity of cells that were growth-inhibited by MDM4 KD alone. Consistently, we identified low levels of p27 expression in basal-like tumours corresponding to high levels of MDM4 and p53. This predicts a signature for a subset of tumours that may be amenable to therapies targeted towards MDM4 and mutant p53. The therapeutic potential of MDM4 as a target in BC with mutant p53 was shown in vitro by use of a small-molecule inhibitor. Overall, our study supports MDM4 as a novel therapeutic target for BC expressing mutant p53. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28097654 TI - Melanopsin-expressing ganglion cells in human retina: Morphology, distribution, and synaptic connections. AB - Melanopsin-expressing retinal ganglion cells are intrinsically photosensitive cells that are involved in non-image forming visual processes such as the pupillary light reflex and circadian entrainment but also contribute to visual perception. Here we used immunohistochemistry to study the morphology, density, distribution, and synaptic connectivity of melanopsin-expressing ganglion cells in four post mortem human donor retinas. Two types of melanopsin-expressing ganglion cells were distinguished based on their dendritic stratification near either the outer or the inner border of the inner plexiform layer. Outer stratifying cells make up on average 60% of the melanopsin-expressing cells. About half of the melanopsin-expressing cells (or 80% of the outer stratifying cells) have their soma displaced to the inner nuclear layer. Inner stratifying cells have their soma exclusively in the ganglion cell layer and include a small proportion of bistratified cells. The dendritic field diameter of melanopsin expressing cells ranges from 250 (near the fovea) to 1,000 um in peripheral retina. The dendritic trees of outer stratifying cells cover the retina independent of soma location. The dendritic fields of both outer and inner stratifying cells show a high degree of overlap with a coverage factor of approximately two. Melanopsin-expressing cells occur at an average peak density of between ~20 and ~40 cells/mm2 at about 2 mm eccentricity, the density drops to below ~10 cells/mm2 at about 8 mm eccentricity. Both the outer and inner stratifying dendrites express postsynaptic density (PSD95) immunoreactive puncta suggesting that they receive synaptic input from bipolar cells. PMID- 28097655 TI - Hermaphroditism in the dash-and-dot goatfish Parupeneus barberinus. AB - Presence of bisexual individuals and a sex-specific bimodal size distribution are suggestive of protogyny in the dash-and-dot goatfish Parupeneus barberinus, but the most parsimonious interpretation of histological analysis is juvenile hermaphroditism. This is the first report of hermaphroditism in the Mullidae. PMID- 28097656 TI - Palliation and breast cancer. AB - Metastatic breast cancer is an incurable disease. With improvement in systemic therapy, survival has improved over the past few years. Removing the primary tumor has shown improved survival in retrospective studies, but this may be due to selection bias. The first reported randomized controlled trial (RCT) from India showed no difference in survival with surgery. However another RCT from Turkey showed that a select group of patient with bone-only metastases have a survival benefit. PMID- 28097657 TI - Public Trust in Health Information Sharing: A Measure of System Trust. AB - OBJECTIVE: To measure public trust in a health information sharing in a broadly defined health system (system trust), inclusive of health care, public health, and research; to identify individual characteristics that predict system trust; and to consider these findings in the context of national health initiatives (e.g., learning health systems and precision medicine) that will expand the scope of data sharing. DATA SOURCES: Survey data (n = 1,011) were collected in February 2014. STUDY DESIGN: We constructed a composite index of four dimensions of system trust-competency, fidelity, integrity, and trustworthiness. The index was used in linear regression evaluating demographic and psychosocial predictors of system trust. DATA COLLECTION: Data were collected by GfK Custom using a nationally representative sample and analyzed in Stata 13.0. PRINCIPAL FINDINGS: Our findings suggest the public's trust may not meet the needs of health systems as they enter an era of expanded data sharing. We found that a majority of the U.S. public does not trust the organizations that have health information and share it (i.e., the health system) in one or more dimensions. Together, demographic and psychosocial factors accounted for ~18 percent of the observed variability in system trust. Future research should consider additional predictors of system trust such as knowledge, attitudes, and beliefs to inform policies and practices for health data sharing. PMID- 28097658 TI - Segmental fibre type composition of the rat iliopsoas muscle. AB - The iliopsoas of the rat is composed of two muscles - the psoas major muscle and the iliacus muscle. The psoas major muscle arises from all the lumbar vertebrae and the iliacus muscle from the fifth and sixth lumbar vertebrae and ilium. Their common insertion point is the lesser trochanter of the femur, and their common action is the lateral rotation of the femur and flexion of the hip joint. Unlike humans, the rat is a quadruped and only occasionally rises up on its hind legs. Therefore, it is expected that the fibre type composition of the rat iliopsoas muscle will be different than that of humans. The iliopsoas muscle of the rat is generally considered to be a fast muscle. However, previous studies of the fibre type composition of the rat psoas muscle showed different results. Moreover, very little is known about the composition of the rat iliacus muscle. The aim of our study was to examine the fibre type composition of the rat iliopsoas muscle in order to better understand the complex function of the listed muscle. The psoas major muscle was examined segmentally at four different levels of its origin. Type I, IIA, IIB and IIX muscle fibres were typed using monoclonal antibodies for myosin heavy chain identification. The percentage of muscle fibre types and muscle fibre cross-sectional areas were calculated. In our study we showed that in the rat iliopsoas muscle both the iliacus and the psoas major muscles had a predominance of fast muscle fibre types, with the highest percentage of the fastest IIB muscle fibres. Also, the IIB muscle fibres showed the largest cross sectional area (CSA) in both muscles. As well, the psoas major muscle showed segmental differences of fibre type composition. Our results showed changes in percentages, as well as the CSAs of muscle fibre types in cranio-caudal direction. The most significant changes were visible in type IIB muscle fibres, where there was a decrease of percentages and the CSAs from the cranial towards the caudal part of the muscle. From our results it is evident that the rat iliopsoas muscle has a heterogeneous composition and is composed of all four muscle fibre types. Primarily, it is a fast, dynamic muscle with a predominance of fast type IIB muscle fibres with the largest CSAs. The composition of the rat psoas major muscles changes in a cranio-caudal direction, thus pointing to a more postural role of the caudal part of the muscle. PMID- 28097659 TI - Substance Use Disorders and Addiction is on the rise: What can we do? PMID- 28097660 TI - In Brief: Myeloid-derived suppressor cells in cancer. AB - The role of myeloid-derived suppressor cells (MDSCs) in cancer development has become clear over recent years, and MDSC targeting is an emerging opportunity for enhancing the effectiveness of current anticancer therapies. As MDSCs are not only able to limit anti-tumour T-cell responses, but also to promote tumour angiogenesis and invasion, their monitoring has prognostic and predictive value. Herein, we review the key features of MDSCs in cancer promotion. (c) 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 28097661 TI - Estimating the Skull-to-Camera Distance from Facial Photographs for Craniofacial Superimposition. AB - The overlay of a skull and a face image for identification purposes requires similar subject-to-camera distances (SCD) to be used at both photographic sessions so that differences in perspective do not compromise the anatomical comparisons. As the facial photograph is the reference standard, it is crucial to determine its SCD first and apply this value to photography of the skull. So far, such a method for estimating the SCD has been elusive (some say impossible), compromising the technical validity of the superimposition procedure. This paper tests the feasibility of using the palpebral fissure length and a well established photographic algorithm to accurately estimate the SCD from the facial photograph. Recordings at known SCD across a 1-10 m range (repeated under two test conditions) demonstrate that the newly formulated method works: a mean SCD estimation error of 7% that translates into <1% perspective distortion error between estimated and actual conditions. PMID- 28097662 TI - Thermal requirements for growth, survival and aerobic performance of weatherfish larvae Misgurnus fossilis. AB - Thermal requirements of larval weatherfish Misgurnus fossilis were investigated in terms of growth, survival and aerobic performance. Growth and survival of M. fossilis larvae acclimated to five temperatures (11, 15, 19, 23 and 27 degrees C) were measured over 25 days. In the upper temperature treatments (19, 23 and 27 degrees C), survival of larvae was stable throughout the entire rearing period (>75%), whereas 11 and 15 degrees C resulted in severe declines in survival (to <10%). Growth of larvae (expressed as dry mass and total length) was highest at 19 and 23 degrees C, but significantly decreased at 27 degrees C. Routine metabolic rate of 3 days post-hatch larvae was estimated as oxygen consumption rate (MO2 ) during acute exposure (30 min to 1 h) to seven temperatures (11, 15, 19, 23, 27, 31 and 35 degrees C). Larval oxygen uptake increased with each consecutive temperature step from 11 to 27 degrees C, until a plateau was reached at temperatures >27 degrees C. All larvae of the 35 degrees C regime, however, died within the MO2 measurement period. M. fossilis larvae show greater than expected tolerance of high temperatures. On the other hand, low temperatures that are within the range of likely habitat conditions are critical because they might lead to high mortality rates when larvae are exposed over periods >10 days. These findings help to improve rearing conditions and to identify suitable waters for stocking and thus support the management of re-introduction activities for endangered M. fossilis. PMID- 28097663 TI - The evolution of male nuptial colour in a sexually dimorphic group of fishes (Percidae: Etheostomatinae). AB - To test hypotheses explaining variation in elaborate male colouration across closely related species groups, ancestral-state reconstructions and tests of phylogenetic signal and correlated evolution were used to examine the evolution of male body and fin colouration in a group of sexually dichromatic stream fishes known as darters (Percidae: Etheostomatinae). The presence or absence of red orange and blue-green male colour traits were scored across six body regions in 99 darter species using a recently estimated amplified fragment length polymorphism (AFLP) phylogeny for comparative analyses. Ancestral-state reconstructions infer the most recent common ancestor of darters to lack red orange colour and possess blue-green colour on different body regions, suggesting variation between species is due to independent gains of red-orange and losses of blue-green. Colour traits exhibit substantial phylogenetic signal and are highly correlated across body regions. Comparative analyses were repeated using an alternative phylogenetic hypothesis based on one mitochondrial and two nuclear genes, yielding similar results to analyses based on the AFLP phylogeny. Red orange colouration in darters appears to be derived; whereas, blue-green appears to be ancestral, which suggests that different selection mechanisms may be acting on these two colour classes in darters. PMID- 28097665 TI - Pharmacokinetics and selected pharmacodynamics of romifidine following low-dose intravenous administration in combination with exercise to quarter horses. AB - Romifidine is an alpha-2 adrenergic agonist used for sedation and analgesia in horses. As it is a prohibited substance, its purported use at low doses in performance horses necessitates further study. The primary goal of the study reported here was to describe the serum concentrations and pharmacokinetics of romifidine following low-dose administration immediately prior to exercise, utilizing a highly sensitive liquid chromatography-tandem mass spectrometry assay that is currently employed in many drug testing laboratories. An additional objective was to describe changes in heart rate and rhythm following intravenous administration of romifidine followed by exercise. Eight adult Quarter Horses received a single intravenous dose of 5 mg (0.01 mg/kg) romifidine followed by 1 h of exercise. Blood samples were collected and drug concentrations measured at time 0 and at various times up to 72 h. Mean +/- SD systemic clearance, steady state volume of distribution and terminal elimination half-life were 34.1 +/- 6.06 mL/min/kg and 4.89 +/- 1.31 L/kg and 3.09 +/- 1.18 h, respectively. Romifidine serum concentrations fell below the LOQ (0.01 ng/mL) and the LOD (0.005 ng/mL) by 24 h postadministration. Heart rate and rhythm appeared unaffected when a low dose of romifidine was administered immediately prior to exercise. PMID- 28097664 TI - Testing mate choice and overdominance at MH in natural families of Atlantic salmon Salmo salar. AB - This study aimed to test mate choice and selection during early life stages on major histocompatibility (MH) genotype in natural families of Atlantic salmon Salmo salar spawners and juveniles, using nine microsatellites to reconstruct families, one microsatellite linked to an MH class I gene and one minisatellite linked to an MH class II gene. MH-based mate choice was only detected for the class I locus on the first year, with lower expected heterozygosity in the offspring of actually mated pairs than predicted under random mating. The genotype frequencies of MH-linked loci observed in the juveniles were compared with frequencies expected from Mendelian inheritance of parental alleles to detect selection during early life stages. No selection was detected on the locus linked to class I gene. For the locus linked to class II gene, observed heterozygosity was higher than expected in the first year and lower in the second year, suggesting overdominance and underdominance, respectively. Within family, juveniles' body size was linked to heterozygosity at the same locus, with longer heterozygotes in the first year and longer homozygotes in the second year. Selection therefore seems to differ from one locus to the other and from year to year. PMID- 28097667 TI - Comparative morphology of the scales of roundscale spearfish Tetrapturus georgii and white marlin Kajikia albida. AB - The comparative morphology of the scales of roundscale spearfish Tetrapturus georgii and white marlin Kajikia albida was investigated. In addition, variation in scale morphology across different body regions within each species was analysed. Although considerable morphological variation was observed among scales from different body regions in both species, scales of K. albida generally have pointed anterior ends, fewer posterior points and are more heavily imbricated than those of T. georgii, which are frequently rounded anteriorly, often have many posterior points and are separated farther within the skin. In all sampled body regions and individuals, scales of T. georgii are significantly broader and have a lower length-to-width aspect ratio than those of K. albida. Superficial to the scales are denticular plates, which are ossified formations occurring on the surface layer of the epidermis; these were observed and described for T. georgii, K. albida and blue marlin Makaira nigricans. Detailed scale descriptions allow for a more accurate characterization of the variation within and differences between these two species and could potentially be a valuable tool for investigating istiophorid systematics. PMID- 28097666 TI - Understanding external cervical resorption patterns in endodontically treated teeth. AB - AIM: To understand the patterns of external cervical resorption (ECR) in endodontically treated teeth. To compare characteristics and mechanisms of ECR in root filled teeth with those established in teeth with vital pulps. METHODOLOGY: Seven cases of endodontically treated permanent teeth displaying ECR were investigated. ECR diagnosis was based on clinical findings and radiographic examination with cone-beam computed tomography. The extracted teeth were further analysed by a nano-focus computed tomographic (nano-CT) system, hard-tissue histology and scanning electron microscopy (SEM). To make a comparison with teeth with vital pulps, representative cases with ECR were also included. RESULTS: All endodontically treated teeth had a similar ECR pattern. This pattern reflected many similarities to that seen in teeth with vital pulps; that is, three stages were observed namely initiation, resorption and repair. In particular, during the initiation stage (1st stage), the resorption started below the gingival epithelial attachment, at the level of cementum. In the resorption stage (2nd stage), ECR spreads towards the treated pulp space and in a coronal-apical direction, creating multiple resorption channels. The pulp and the pericanalar resorption resistant sheet (PRRS) had been removed during root canal treatment and thus offered no retarding or defence mechanism towards ECR. In the reparative stage (3rd stage), reparative hard-tissue formation occurred at a localized scale. CONCLUSIONS: Similar ECR patterns were observed in all examined teeth. These patterns consisted of an initiation, a resorption and a reparative stage. Some differences were noticed between endodontically treated and teeth with vital pulps, mainly in the resorption and reparative stages. The resorption stage in root filled teeth was more intense than the repair stage, as many clastic cells and abundant granulation tissue were observed in all samples. This is possibly due to the absence of the pulp and protective PRRS layer and/or to the altered chemical composition of the root dentine after root canal treatment. Furthermore, at the repair stage, formation of reparative bonelike tissue took place to a lesser extent in root filled teeth. PMID- 28097668 TI - Detection and pharmacokinetics of salmeterol in thoroughbred horses following inhaled administration. AB - Salmeterol is a man-made beta-2-adrenergic receptor agonist used to relieve bronchospasm associated with inflammatory airway disease in horses. Whilst judicious use is appropriate in horses in training, they cannot race with clinically effective concentrations of medications under the British Horseracing Authority's Rules of Racing. Salmeterol must therefore be withdrawn prior to race day and pharmacokinetic (PK) studies used to establish formal detection time advice. Salmeterol xinafoate (Serevent Evohaler(r) ) was administered (0.1 mg twice daily for 4.5 days) via inhalation to six horses. Urine and blood samples were taken up to 103 h postadministration. Hydrolysed samples were extracted using solid phase extraction. A sensitive Ultra high performance tandem mass spectrometry (UPLC-MS/MS) method was developed, with a Lower limit of quantification (LLOQ) for salmeterol of 10 pg/mL in both matrices. The majority of salmeterol plasma concentrations, postlast administration, were below the method LLOQ and so unusable for PK analysis. Urine PK analysis suggested a half life consistent with duration of pharmacological effect. Average estimated urine concentration at steady-state was obtained via PK modelling and used to estimate a urine concentration of 59 +/- 34 pg/mL as a marker of effective lung concentration. From this, potential detection times were calculated using a range of safety factors. PMID- 28097669 TI - Mathematical Modeling of Rotary Blood Pumps in a Pulsatile In Vitro Flow Environment. AB - Nowadays, sacrificing animals to develop medical devices and receive regulatory approval has become more common, which increases ethical concerns. Although in vivo tests are necessary for development and evaluation of new devices, nonetheless, with appropriate in vitro setups and mathematical models, a part of the validation process can be performed using these models to reduce the number of sacrificed animals. The main aim of this study is to present a mathematical model simulating the hydrodynamic function of a rotary blood pump (RBP) in a pulsatile in vitro flow environment. This model relates the pressure head of the RBP to the flow rate, rotational speed, and time derivatives of flow rate and rotational speed. To identify the model parameters, an in vitro setup was constructed consisting of a piston pump, a compliance chamber, a throttle, a buffer reservoir, and the CentriMag RBP. A 40% glycerin-water mixture as a blood analog fluid and deionized water were used in the hydraulic circuit to investigate the effect of viscosity and density of the working fluid on the model parameters. First, model variables were physically measured and digitally acquired. Second, an identification algorithm based on regression analysis was used to derive the model parameters. Third, the completed model was validated with a totally different set of in vitro data. The model is usable for both mathematical simulations of the interaction between the pump and heart and indirect pressure measurement in a clinical context. PMID- 28097670 TI - Acute liver failure in Scotland: changes in aetiology and outcomes over time (the Scottish Look-Back Study). AB - BACKGROUND: Acute liver failure is a rare and devastating clinical condition resulting from sudden loss of hepatic parenchyma and metabolic function. The Scottish Liver Transplant Unit (SLTU) offers specialist management and emergency liver transplantation to patients with acute liver failure from across Scotland. AIM: To describe temporal changes in number of admissions, aetiology of acute liver failure, severity of disease at presentation and outcomes over a 22-year period. METHODS: Retrospective analysis of the SLTU database, including all patients admitted with acute liver injury or acute liver failure between November 1992 and March 2014. RESULTS: There has been no change in the number of patients presenting with acute liver injury or failure secondary to paracetamol overdose, but a reduction in the number of admissions with acute liver injury or failure secondary to non paracetamol causes. Over time, disease severity at presentation has not changed in the paracetamol cohort; those with a non paracetamol aetiology have latterly presented with milder hepatic encephalopathy. Spontaneous survival rates improved significantly over time for those patients with acute liver failure due to paracetamol and non paracetamol aetiologies. The most marked improvement in survival is observed in the sickest patients meeting Kings College Hospital poor prognostic criteria. CONCLUSIONS: The number of admissions to the SLTU with acute liver failure is decreasing, due to reduced numbers of non paracetamol cases. Outcomes in this condition are improving, due to improvements in intensive care management and use of liver transplantation, and the increase in survival is most marked in patients meeting Kings College Hospital poor prognostic criteria. PMID- 28097671 TI - Junctional Ectopic Tachycardia Localization and Procedural Approach using Cryoablation. AB - BACKGROUND: Idiopathic junctional ectopic tachycardia (JET) may still be difficult to control with antiarrhythmic therapy. Transcatheter ablation can be challenging and may be associated with a high risk of unintended atrioventricular block. The objective of this manuscript is to report the procedural technique, the location of the successful ablation, and the procedural characteristics while utilizing 3D mapping for cryoablation of JET. METHODS: A retrospective analysis was performed on all patients who had undergone cryothermal ablation for the treatment of JET at a single center. Patient, arrhythmia, and procedural information and long-term outcomes were evaluated. RESULTS: Thirteen patients with JET were treated by cryothermal ablation. The JET arrhythmia burden varied greatly, generally with inadequate control on medications. Left ventricular dilation was present in three patients, and one patient had dilated cardiomyopathy. The median age at the time of procedure was 13 years, with median weight of 54.1 kg. The ectopic focus was ablated in 11/13 patients within the lower 2/3 of the triangle of Koch (TOK) with cryotherapy. Ablations, which were not successful, low in the TOK were associated with substantially longer procedures, and had a higher risk of recurrence. There was late resolution of the arrhythmia in two of three acutely unsuccessful ablations. There were no complications. CONCLUSION: In the majority of patients JET can be safely ablated with the use of cryotherapy. Foci not identified in the lower 2/3 of the TOK are associated with longer procedures, more lesions, and decreased chance for long term success. PMID- 28097672 TI - Collective resistance despite complicity: High identifiers rise above the legitimization of disadvantage by the in-group. AB - How do individuals deal with group disadvantage when their fellow in-group members conceive it as legitimate? Integrating research on the normative conflict model (Packer, 2008, Pers. Soc. Psychol. Rev., 12, 50) and collective action, we expect high identifiers to reject the in-group norm of legitimacy that justifies the inequality, and to assert that the group is actually able and willing to contest the disadvantage by collective means. In Study 1 and Study 2, we tested this hypothesis in different intergroup contexts. The results confirmed our predictions and also showed one boundary condition for high identifiers, namely that the content of the social identity supports resistance. In Study 3, we found support for our hypothesis using artificial groups and manipulating identification experimentally. These results show that even when a disadvantaged group appears to accept its situation, high identified in-group members will still contest this and, moreover, expect other in-group members to support them in this endeavour. PMID- 28097673 TI - Schoolyard Shade and Sun Exposure: Assessment of Personal Monitoring During Children's Physical Activity. AB - Childhood exposure to ultraviolet radiation (UVR) is a major risk factor for the development of melanoma later in life. However, it is challenging to accurately determine personal outdoor exposure to UVR, specifically erythemally weighted UVR (UVEry ), due to technological constraints, variable time-activity patterns, and the influence of outdoor environmental design. To address this challenge, this study utilized mobile and stationary techniques to examine the UVEry exposures of 14 children in a schoolyard in Lubbock, TX, in spring 2016. The aims of the study were to examine the influence of artificial shade on personal UVEry exposures and to assess full sun exposure ratios (ERs) within the same playground microenvironment. On average, personal wrist dosimeters worn during play in the sun measured 18% of the total onsite UVEry measured by a stationary UV pyranometer. Shade was found to significantly reduce the personal UVEry exposures by 55%, UVB280-315 nm exposures by 91%, and the overall solar radiation by 84%. Substantial benefits can be garnered through focused design of children's recreational space to utilize shade-both natural and artificial-to reduce UVR exposures during play, and to extend safe outdoor stays. Finally, although the wrist is a practical location for a dosimeter, it often underestimates full exposures, particularly during physical activity. PMID- 28097674 TI - Monte Carlo simulations of ceiling scatter in nuclear medicine: 99m Tc, 131 I and 18 F. AB - PURPOSE: In the design of nuclear medicine treatment and examination rooms, an important consideration is the shielding required for ionizing radiation from the radioactive isotopes used. The shielding in the walls is normally limited to a height lower than the actual ceiling height. The direct radiation, possibly with build-up correction, can be calculated relatively easily. However, little data are available to estimate the dose contribution from ionizing radiation traveling over the wall shielding and scattering off the ceiling. We aim to determine the contribution of the ceiling scatter to the radiation dose outside nuclear medicine rooms. METHODS: Monte Carlo simulations were performed using Gate for different heights of lead shielding in the wall, and different ceiling heights. A point source in air of 99m Tc (141 keV), 131 I (365 keV) or 18 F (511 keV) was placed 1.0 m above the floor, 3.0 m from the lead shielding. Simulations of ceiling scatter only and for the total radiation dose were performed for these 3 isotopes, 5 different ceiling heights and 4-8 different wall shielding heights, resulting in a total of 165 simulations. This allowed us to compare the contribution of the radiation passing through the shielding and the ceiling scatter. RESULTS: We find that the shielding required for the primary radiation, measured in half-value layers, is an important factor in determining the relative contribution of ceiling scatter. When more than about 4 half-value layers of shielding are used, ceiling scatter becomes the dominant factor and should be taken into account in the shielding design. In many practical cases for low energy photons (e.g. from 99m Tc; 141 keV; half-value layer of 0.26 mm lead), 2 mm of lead is used and ceiling scatter is a dominating factor contributing >~70% of the dose outside the shielded room. For higher energies (e.g. 18 F; 511 keV; half-value layer of 3.9 mm lead) the ceiling scatter is typically less than about 15% when 8 mm of lead shielding is used. CONCLUSIONS: We have performed simulations that allow an estimation of the contribution of ceiling scatter to the radiation dose outside a room, based on the ceiling height, shielding height, and isotope used. This will allow for improved shielding designs in nuclear medicine departments. PMID- 28097675 TI - The swamplands of reflection: using conversation analysis to reveal the architecture of group reflection sessions. AB - CONTEXT: Many medical schools include group reflection in their curriculum, and many researchers have considered both the concept and the outcomes of reflection. However, no research has been carried out on how 'reflective talk' is structured in the classroom. This paper describes how tutors and residents organise group reflection sessions in situ by describing an example of group reflection in medical education. Our aim is to provide an evidence base that can be used by medical educators to think about the way reflection should be included in their curriculum. METHODS: We video-recorded 47 group reflection sessions of the general practice postgraduate training course at Erasmus University Medical School, Rotterdam. We used conversation analysis to unravel their overall structural organisation: the way participants organise and structure a conversation. Through micro-analysis of the moment-to-moment unfolding of group reflection, we distinguished the main building blocks that form the architecture of these sessions. RESULTS: We found that participants consistently oriented towards the following activity types: significant event, reason for sharing, learning issue and learning uptake. There was variation in the order of the activity types, the amount of time spent on each of them, and how they were accomplished. By studying reflection in its messy social context, we found order, commonalities and patterns that were typical of the architecture of group reflection in this setting, even if no formal structure is prescribed. CONCLUSIONS: In 'Exchange of Experience', the overall structural organisation consisted of activity types through which a case becomes shared, reflectable, learnable and valuable. There are essential discrepancies between cognitive reflection models and the reality of the classroom. Being conscious of this overall structural organisation can be a tool for tutors of these groups to help them navigate from one activity to another or to diagnose what is not working in the group discussion. PMID- 28097676 TI - Morbihan disease complicated by dermatosis neglecta: An unique presentation. AB - Morbihan disease, also referred to as solid facial edema, or rosacea lymphedema, is a rare disorder that involves chronic erythema and solid edema of the cheeks, eyelids, forehead and glabella and may arise as a complication of acne vulgaris or rosacea. Of note, it may be the only initial presenting symptom of these associated diseases. Few cases have been described in the literature, as its first description by Robert Degos in 1957. The condition is characterized by its chronicity, a typical clinical appearance and the lack of specific histopathologic or laboratory findings. The condition may wax and wane but typically does not resolve without treatment. Many cases of this condition tend to be recalcitrant to therapy, with topical and oral antibiotics regimens commonly used for rosacea generally being ineffective. The disease may easily go undiagnosed, as it mimics other more common skin conditions. We present a case of originally undiagnosed Morbihan disease mistaken for an atypical allergic rash, resistant to treatment, and complicated by dermatosis neglecta. PMID- 28097677 TI - Pharmacokinetics of first-line antitubercular drugs in plasma and PBMCs. PMID- 28097678 TI - Aberrant tyrosinase expression in an atypical fibroxanthoma: A case report. AB - Atypical fibroxanthoma (AFX) is a histologic mimicker of a variety of spindle cell neoplasms, and careful microscopic and immunohistochemical evaluation is critical in establishing the correct diagnosis. Here we report the histologic and immunohistochemical work up of a 1 cm nodule involving the left dorsal hand of a 66-year-old patient. Light microscopy revealed fascicles of spindled and pleomorphic cells within the dermis showing increased mitotic activity occurring in the background of sun-damaged skin. There were numerous multinucleated cells with hyperchromatic nuclei and ample finely vacuolated or foamy cytoplasms. There was strong and diffuse CD10 and patchy CD68 expression among the spindled cells and multinucleated cells. The neoplastic cells did not show immunoreactivity against S100, p75-NGFR, HMB-45 or a panel of keratinocytic, vascular and smooth muscle markers. Tyrosinase and Melan-A were not expressed within the spindle cell component of this neoplasm; however, there was tyrosinase expression among numerous multinucleated giant cells. Melan-A expression was also observed among rare multinucleated giant cells. Tyrosinase expression has not previously been reported in AFX. PMID- 28097679 TI - Abnormal levels of seven amino neurotransmitters in depressed rat brain and determination by HPLC-FLD. AB - The determination of amino acids with actions like neurotransmitters or modulators has been increasingly important for diagnosis in many neuropsychiatric diseases. A rapid and simple high-performance liquid chromatography with fluorescence detection method was developed for simultaneous determination of seven amino acids: aspartate (Asp), glutamate (Glu), serine (Ser), glutamine (Gln), glycine (Gly), taurine (Tau) and gamma-aminobutyric' acid (GABA). Homoserine was used as an internal standard. The analysis was performed on a BDS column with methanol and 50 mm sodium acetate solution (pH 6.5) using a simple gradient elution. Several parameters of the developed method were validated including linearity, accuracy, precision, extraction recovery and stability, which were within the acceptable range. The method was successfully applied to determination of real samples: hippocampus and cortex in depressed rats exposed to chronically unpredictable stress in order to study if there existed differences in the seven amino acids levels between depressed rats and control. The results showed that Asp, Gly, Tau and GABA significantly decreased with increasing Gln in the hippocampus of depressed rats, compared with that of the control group, among which obviously lower level of Asp and higher level of Gln in cortex were observed. The analytical method and the results could be useful for clinical diagnosis and further insight into pathophysiological mechanism of depression. PMID- 28097680 TI - Development of a novel algorithm for detecting glucocorticoid-induced diabetes mellitus using a medical information database. AB - WHAT IS KNOWN AND OBJECTIVE: Glucocorticoid-induced diabetes mellitus (GIDM) increases the risk of diabetes mellitus (DM)-related complications but is generally difficult to detect in clinical settings. The criteria for diagnosing GIDM have not been established. Recently, medical information databases (MIDs) have been used in post-marketing surveillance (PMS) studies. We conducted a pharmacoepidemiological study to develop an algorithm for detecting GIDM using MID. METHODS: We selected 1214 inpatients who were newly prescribed with a typical glucocorticoid, prednisolone, during hospitalization from 2008 to 2014 from an MID of Hamamatsu University Hospital in Japan. GIDM was screened based on fasting blood glucose (FBG) and haemoglobin A1c (HbA1c) levels according to the current Japan Diabetes Society (JDS) DM criteria, and its predictability was evaluated by an expert's review of medical records. We investigated further candidate screening factors using receiver operating characteristics analysis. RESULTS: Sixty-three inpatients were identified by the JDS DM criteria. Of these, 33 patients were definitely diagnosed as having GIDM by expert's review (positive predictive value = 52.4%). To develop a highly predictive algorithm, we compared the characteristics of inpatients diagnosed with definite GIDM and those diagnosed as non-GIDM. The maximum levels of HbA1c in patients with GIDM were significantly higher than those of patients with non-GIDM (66.9 mmol/mol vs. 58.7 mmol/mol, P < 0.001). The patients with GIDM had significantly higher relative increase in maximum level of HbA1c (RIM-HbA1c) than those with non-GIDM (0.3 vs. 0.03, P < 0.001). However, we did not observe a significant difference in those of fasting blood glucose (FBG) levels. We applied the RIM-HbA1c as a second screening factor to improve the detection of GIDM. It showed that a 13% increase in RIM-HbA1c separated patients with from patients without GIDM. WHAT IS NEW AND CONCLUSIONS: Patients with GIDM had significantly higher RIM-HbA1c than patients with non-GIDM. There was a 13% increase in RIM-HbA1c in patients with GIDM compared to the others. Our detection algorithm for GIDM using an MID achieved high sensitivity and specificity, and was superior to one based only on the current JDS DM criteria. Our results suggest that monitoring changes in HbA1c levels is important for detecting GIDM and adds to current diagnostic criteria for type 2 DM. PMID- 28097682 TI - Evaluation of perforated demineralized dentin scaffold on bone regeneration in critical-size sheep iliac defects. AB - OBJECTIVES: Regenerating critical-size bone injury is a major problem that continues to inspire the design of new graft materials. Therefore, tissue engineering has become a novel approach for targeting bone regeneration applications. Human teeth are a rich source of stem cells, matrix, trace metal ions, and growth factors. A vital tooth-derived demineralized dentin matrix is acid-insoluble and composed of cross-linked collagen with growth factors. In this study, we recycled human non-functional tooth into a unique geometric dentin scaffold, entitled perforated root-demineralized dentin matrix (PR-DDM). The aim of this study was to evaluate the feasibility of PR-DDM as the scaffold for regenerating bone in critical-size iliac defects. MATERIAL AND METHODS: Artificial macro-pores (1 mm in diameter) were added to human vital wisdom tooth after removing the enamel and pulp portions. The modified tooth was demineralized in 0.34 N HNO3 for 30 min and is referred to as PR-DDM scaffold. Critical-size defect (10 mm * 15 mm * 9 mm O) was created in the iliac crest of six adult sheep. The in vivo bone regeneration by the scaffold was evaluated by micro-CT, 3D micro-CT, and histological examination at 2 and 4 months post-implantation. RESULTS: PR-DDM exhibited better bone ingrowth, especially in the artificial macro-pores. The results of micro-CT and 3D micro-CT revealed good union between scaffold and native bone. New bone formation was observed in almost all portions of PR-DDM. Higher bone volume inside the scaffold was detected at 4 months compared with 2 months. New bone ingrowth was ankylosed with PR-DDM, and both osteoinduction and osteoconduction capability of PR-DDM were confirmed histologically. The ratio of new bone formation was higher at 4 months compared with 2 months by histomorphometric analysis. CONCLUSIONS: Altogether, these results demonstrated that the human tooth-derived graft material with a unique geometric structure, PR-DDM, contributed to active bone ingrowth in critical-size bone defects. This novel scaffold may have great utility in the near-future clinical application. PMID- 28097681 TI - Thromboelastography in Dogs with Chronic Hepatopathies. AB - BACKGROUND: The coagulation status of dogs with liver disease is difficult to predict using conventional coagulation testing. HYPOTHESIS/OBJECTIVES: To evaluate thromboelastography (TEG) results and associations with conventional coagulation results and indicators of disease severity and prognosis in dogs with chronic hepatopathies (CH). ANIMALS: Twenty-one client-owned dogs. METHODS: Dogs with CH were prospectively (10 dogs) and retrospectively (11 dogs) enrolled from 2008 to 2014. Kaolin-activated TEG was performed and compared with reference intervals by t-tests or Mann-Whitney tests. Correlation coefficients for TEG results and conventional coagulation and clinicopathologic results were determined. Significance was set at P < .05. RESULTS: Dogs with CH had significant increases in R (5.30 min vs 4.33 min), K (3.77 min vs 2.11 min), and LY30 (4.77% vs 0.68%) and decreased angles (55.3 degrees vs 62.4 degrees ). G value defined 9 of 21, 7 of 21, and 5 of 21 dogs as normocoagulable, hypercoagulable, and hypocoagulable, respectively. G and MA were correlated with fibrinogen (r = 0.68, 0.83), prothrombin time (PT; r = -0.51, -0.53), and activated partial thromboplastin time (aPTT; r = -0.50, -0.50). K was correlated with PT (r = 0.75) and protein C activity (r = -0.92). Angle was correlated with aPTT (r = -0.63). Clinical score was correlated with PT (r = 0.60), MA (r = 0.53), and R (r = -0.47). Dogs with hyperfibrinolysis (LY30 > 3.04%; 5 of 21) had significantly higher serum transaminase activities. Dogs with portal hypertension had significantly lower G, MA, and angle and prolonged, K, R, and PT. CONCLUSIONS AND CLINICAL RELEVANCE: Dogs with CH have variable TEG results. Negative prognostic indicators in CH correlate with hypocoagulable parameters on TEG. Hyperfibrinolysis in dogs with CH is associated with high disease activity. PMID- 28097683 TI - Echocardiographic Estimates of Left Ventricular Diastolic Dysfunction Do Not Predict the Clinical Course in Elderly Patients Undergoing Transcatheter Atrial Septal Defect Closure: Impact of Early Diastolic Mitral Annular Velocity. AB - OBJECTIVE: This study evaluated the effect of echocardiographic left ventricular (LV) diastolic dysfunction on acute congestive heart failure after transcatheter atrial septal defect (ASD) closure in elderly patients. BACKGROUND: Although there is concern that LV diastolic dysfunction develops acute congestive heart failure after ASD closure, limited information is available regarding the influence, especially in elderly patients with severe LV diastolic dysfunction. METHODS: Two hundred consecutive patients older than 60 years were divided into 3 groups according to echocardiographic LV diastolic dysfunction: severe (early diastolic mitral annular velocity [e'] <5.0 cm/s), mild (5.0<= e' <8.0 cm/s), and normal (e' >= 8.0 cm/s). Changes in plasma B-type natriuretic peptide (BNP) levels were evaluated. RESULTS: No patients with severe LV diastolic dysfunction developed acute congestive heart failure immediately after the procedure. BNP levels unchanged after the procedure in patients with severe LV diastolic dysfunction (126 +/- 181 to 131 +/- 148 pg/ml, P = 0.885), and this increase in BNP levels was not different from that between the diagnosis of ASD and the procedure. The change in BNP levels in patients with severe LV diastolic dysfunction, who were frequently treated with diuretics before the procedure, was equivalent to that in patients with mild LV diastolic dysfunction and normal LV diastolic function (5 +/- 119 vs. 16 +/- 101 vs. 9 +/- 131 pg/ml, P = 0.724). CONCLUSIONS: Our findings suggest that transcatheter ASD closure under volume management is safe and valuable in elderly patients with echocardiographic severe LV diastolic dysfunction. PMID- 28097685 TI - Cartilage oligomeric matrix protein neoepitope in the synovial fluid of horses with acute lameness: A new biomarker for the early stages of osteoarthritis. AB - BACKGROUND: Clinical tools to diagnose the early changes of osteoarthritis (OA) that occur in the articular cartilage are lacking. OBJECTIVES: We sought to identify and quantify a novel cartilage oligomeric matrix protein (COMP) neoepitope in the synovial fluid from the joints of healthy horses and those with different stages of OA. STUDY DESIGN: In vitro quantitative proteomics and assay development with application in synovial fluids samples obtained from biobanks of well-characterised horses. METHODS: Articular cartilage explants were incubated with or without interleukin-1beta for 25 days. Media were analysed via quantitative proteomics. Synovial fluid was obtained from either normal joints (n = 15) or joints causing lameness (n = 17) or with structural OA lesions (n = 7) and analysed for concentrations of the COMP neoepitope using a custom-developed inhibition enzyme-linked immunosorbent assay (ELISA). Explants were immunostained with polyclonal antibodies against COMP and the COMP neoepitopes. RESULTS: Semitryptic COMP peptides were identified and quantified in cell culture media from cartilage explants. A rabbit polyclonal antibody was raised against the neoepitope of the N-terminal portion of one COMP fragment (sequence SGPTHEGVC). An inhibition ELISA was developed to quantify the COMP neoepitope in synovial fluid. The mean concentration of the COMP neoepitope significantly increased in the synovial fluid from the joints responsible for acute lameness compared with normal joints and the joints of chronically lame horses and in joints with chronic structural OA. Immunolabelling for the COMP neoepitope revealed a pericellular staining in the interleukin-1beta-stimulated explants. MAIN LIMITATIONS: The ELISA is based on polyclonal antisera rather than a monoclonal antibody. CONCLUSIONS: The increase in the COMP neoepitope in the synovial fluid from horses with acute lameness suggests that this neoepitope has the potential to be a unique candidate biomarker for the early molecular changes in articular cartilage associated with OA. PMID- 28097686 TI - Context characterization of amino acid homorepeats using evolution, position, and order. AB - Amino acid repeats, or homorepeats, are low complexity protein motifs consisting of tandem repetitions of a single amino acid. Their presence and relative number vary in different proteomes, and some studies have tried to address this variation, proteome by proteome. In this work, we present a full characterization of amino acid homorepeats across evolution. We studied the presence and differential usage of each possible homorepeat in proteomes from various taxonomic groups, using clusters of very similar proteins to eliminate redundancy. The position of each amino acid repeat within proteins, and the order of co-occurring amino acid repeats were also addressed. As a result, we present evidence about the unevenly evolution of homorepeats, as well as the functional implications of their relative position in proteins. We discuss some of these cases in their taxonomic context. Collectively, our results show evolutionary and positional signals that suggest that homorepeats have biological function, likely creating unspecific protein interactions or modulating specific interactions in a context dependent manner. In conclusion, our work supports the functional importance of homorepeats and establishes a basis for the study of other low complexity repeats. Proteins 2017; 85:709-719. (c) 2016 Wiley Periodicals, Inc. PMID- 28097687 TI - Requirements for accurate estimation of anisotropic material parameters by magnetic resonance elastography: A computational study. AB - PURPOSE: To establish the essential requirements for characterization of a transversely isotropic material by magnetic resonance elastography (MRE). THEORY AND METHODS: Three methods for characterizing nearly incompressible, transversely isotropic (ITI) materials were used to analyze data from closed-form expressions for traveling waves, finite-element (FE) simulations of waves in homogeneous ITI material, and FE simulations of waves in heterogeneous material. Key properties are the complex shear modulus MU2 , shear anisotropy phi=MU1/MU2-1, and tensile anisotropy zeta=E1/E2-1. RESULTS: Each method provided good estimates of ITI parameters when both slow and fast shear waves with multiple propagation directions were present. No method gave accurate estimates when the displacement field contained only slow shear waves, only fast shear waves, or waves with only a single propagation direction. Methods based on directional filtering are robust to noise and include explicit checks of propagation and polarization. Curl-based methods led to more accurate estimates in low noise conditions. Parameter estimation in heterogeneous materials is challenging for all methods. CONCLUSIONS: Multiple shear waves, both slow and fast, with different propagation directions, must be present in the displacement field for accurate parameter estimates in ITI materials. Experimental design and data analysis can ensure that these requirements are met. Magn Reson Med 78:2360-2372, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28097688 TI - Initialization-Free Multilevel States Driven by Spin-Orbit Torque Switching. AB - By engineering multidomain formation in Co/Pt multilayers, it is demonstrated how multilevel storage can be achieved by spin-orbit torque switching. It is rather remarkable that, by modulating the writing pulse conditions, the final magnetization states can be controlled, independent of the initial configurations. The initialization-free multilevel memory advances the spin-orbit torque magnetic random access memory to higher storage density for practical applications. PMID- 28097689 TI - Investigating magnetic susceptibility of human knee joint at 7 Tesla. AB - PURPOSE: To evaluate the magnetic susceptibility properties of different anatomical structures within the knee joint using quantitative susceptibility mapping (QSM). METHODS: A collagen tissue model was simulated and ex vivo animal cartilage experiments were conducted at 9.4 Tesla (T) to evaluate the B0 orientation-dependent magnetic susceptibility contrast observed in cartilage. Furthermore, nine volunteers (six healthy subjects without knee pain history and three patients with known knee injury, between 29 and 58 years old) were scanned using gradient-echo acquisitions on a high-field 7T MR scanner. Susceptibility values of different tissues were quantified and diseased cartilage and meniscus were compared against that of healthy volunteers. RESULTS: Simulation and ex vivo animal cartilage experiments demonstrated that collagen fibrils exhibit an anisotropic susceptibility. A gradual change of magnetic susceptibility was observed in the articular cartilage from the superficial zone to the deep zone, forming a multilayer ultrastructure consistent with anisotropy of collagen fibrils. Meniscal tears caused a clear reduction of susceptibility contrast between the injured meniscus and surrounding cartilage illustrated by a loss of the sharp boundaries between the two. Moreover, QSM showed more dramatic contrast in the focal degenerated articular cartilage than R2* mapping. CONCLUSION: The arrangement of the collagen fibrils is significant, and likely the most dominant source of magnetic susceptibility anisotropy. Quantitative susceptibility mapping offers a means to characterize magnetic susceptibility properties of tissues in the knee joint. It is sensitive to collagen damage or degeneration and may be useful for evaluating the status of knee diseases, such as meniscal tears and cartilage disease. Magn Reson Med 78:1933-1943, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28097690 TI - An Overview of Structural Features of Antibacterial Glycoconjugate Vaccines That Influence Their Immunogenicity. AB - Bacterial cell-surface-derived or mimicked carbohydrate moieties that act as protective antigens are used in the development of antibacterial glycoconjugate vaccines. The carbohydrate antigen must have a minimum length or size to maintain the conformational structure of the antigenic epitope(s). The presence or absence of O-acetate, phosphate, glycerol phosphate and pyruvate ketal plays a vital role in defining the immunogenicity of the carbohydrate antigen. The nature of the carrier protein, spacer and conjugation pattern used to develop the glycoconjugate vaccine also defines its overall spatial orientation which in turn affects its avidity and selectivity of interaction with the desired target(s). In addition, the ratio of carbohydrate to protein in glycoconjugate vaccines also makes an important contribution in determining the optimum immunological response. This Review article presents the importance of these variables in the development of antibacterial glycoconjugate vaccines and their effects on immune efficacy. PMID- 28097692 TI - Structural role of a conserved active site cis proline in the Thermotoga maritima acetyl esterase from the carbohydrate esterase family 7. AB - A conserved cis proline residue located in the active site of Thermotoga maritima acetyl esterase (TmAcE) from the carbohydrate esterase family 7 (CE7) has been substituted by alanine. The residue was known to play a crucial role in determining the catalytic properties of the enzyme. To elucidate the structural role of the residue, the crystal structure of the Pro228Ala variant (TmAcEP228A ) was determined at 2.1 A resolution. The replacement does not affect the overall secondary, tertiary, and quaternary structures and moderately decreases the thermal stability. However, the wild type cis conformation of the 227-228 peptide bond adopts a trans conformation in the variant. Other conformational changes in the tertiary structure are restricted to residues 222-226, preceding this peptide bond and are located away from the active site. Overall, the results suggest that the conserved proline residue is responsible for the cis conformation of the peptide and shapes the geometry of the active site. Elimination of the pyrrolidine ring results in the loss of van der Waals and hydrophobic interactions with both the alcohol and acyl moeities of the ester substrate, leading to significant impairment of the activity and perturbation of substrate specificity. Furthermore, a cis-to-trans conformational change arising out of residue changes at this position may be associated with the evolution of divergent activity, specificity, and stability properties of members constituting the CE7 family. Proteins 2017; 85:694-708. (c) 2016 Wiley Periodicals, Inc. PMID- 28097691 TI - Oilseed rape NAC56 transcription factor modulates reactive oxygen species accumulation and hypersensitive response-like cell death. AB - The NAC (NAM, ATAF1/2, CUC2) transcription factor gene family is plant-specific and plays diverse roles in development and responses to abiotic stresses and pathogen challenge. Oilseed rape (Brassica napus) or canola is an important oil crop worldwide, however, the function of NAC genes in it remains largely elusive. In the present study, we identified and characterized the NAC56 gene isolated from oilseed rape. Expression of BnaNAC56 was induced by abscisic acid (ABA), jasmonic acid (JA), methyl viologen (MV) and a necrotrophic fungal pathogen Sclerotinia sclerotiorum, but repressed by cold. BnaNAC56 is a transcription activator and localized to nuclei. Overexpression of BnaNAC56 induced reactive oxygen species (ROS) accumulation and hypersensitive response (HR)-like cell death, with various physiological measurements supporting these. Furthermore, BnaNAC56 expression caused evident nuclear DNA fragmentation. Moreover, quantitative reverse transcription PCR (qRT-PCR) analysis identified that the expression levels of multiple genes regulating ROS homeostasis, cell death and defense response were significantly induced. Using a dual luciferase reporter assay, we further confirmed that BnaNAC56 could activate the expression of a few ROS- and cell death-related genes. In summary, our data demonstrate that BnaNAC56 functions as a stress-responsive transcriptional activator and plays a role in modulating ROS accumulation and cell death. PMID- 28097693 TI - Distinguishing between biochemical and cellular function: Are there peptide signatures for cellular function of proteins? AB - The genome annotation and identification of gene function depends on conserved biochemical activity. However, in the cell, proteins with the same biochemical function can participate in different cellular pathways and cannot complement one another. Similarly, two proteins of very different biochemical functions are put in the same class of cellular function; for example, the classification of a gene as an oncogene or a tumour suppressor gene is not related to its biochemical function, but is related to its cellular function. We have taken an approach to identify peptide signatures for cellular function in proteins with known biochemical function. ATPases as a test case, we classified ATPases (2360 proteins) and kinases (517 proteins) from the human genome into different cellular function categories such as transcriptional, replicative, and chromatin remodelling proteins. Using publicly available tool, MEME, we identify peptide signatures shared among the members of a given category but not between cellular functional categories; for example, no motif sharing is seen between chromatin remodelling and transporter ATPases, similarly between receptor Serine/Threonine Kinase and Receptor Tyrosine Kinase. There are motifs shared within each category with significant E value and high occurrence. This concept of signature for cellular function was applied to developmental regulators, the polycomb and trithorax proteins which led to the prediction of the role of INO80, a chromatin remodelling protein, in development. This has been experimentally validated earlier for its role in homeotic gene regulation and its interaction with regulatory complexes like the Polycomb and Trithorax complex. Proteins 2017; 85:682-693. (c) 2016 Wiley Periodicals, Inc. PMID- 28097694 TI - Serial cytokine alterations and abnormal neuroimaging in newborn infants with encephalopathy. AB - AIM: Inflammatory cytokines may play a role in the final common pathway in the pathogenesis of hypoxic-ischaemic injury in experimental models. We aimed to profile the systemic pro-and anti-inflammatory response over the first week of life in term infants at risk of neonatal encephalopathy. METHOD: In a tertiary referral university neonatal intensive care unit, serial blood samples were analysed from 41 term infants (requiring resuscitation at birth) in this prospective observational pilot study. Serum levels of 10 pro-and anti inflammatory cytokines were evaluated including interleukin(IL)-1alpha, IL-1beta, IL-6, IL-8, IL-10, tumour necrosis factor(TNF)-alpha, interferon (IFN)-gamma, vascular endothelial growth factor (VEGF), granulocyte/colony-stimulating factor (G-CSF) and granulocyte macrophage/colony-stimulating factor (GM-CSF). RESULTS: Infants with neonatal encephalopathy and abnormal neuroimaging (n = 15) had significantly elevated granulocyte macrophage/colony-stimulating factor at 0-24 h and interleukin-8, interleukin-6 and interleukin-10 at 24-48 hour. Tumour necrosis factor-alpha and vascular endothelial growth factor levels were lower at 72-96 hour (p < 0.05). Significantly elevated levels of interleukin-10 were associated with mortality. CONCLUSION: Serum cytokine changes and innate immune dysregulation in the first week of life may be indicators of outcome in neonatal encephalopathy but require validation in larger studies. PMID- 28097696 TI - Postpartum anemia: missed opportunities for prevention and recognition. PMID- 28097697 TI - Erratum. PMID- 28097698 TI - Granulocytes exposed. PMID- 28097699 TI - Maternal red blood cell alloantibodies identified in blood samples obtained from Iranian pregnant women: the first population study in Iran. AB - BACKGROUND: The objective was to determine the frequency of occurrence of alloantibodies among pregnant women in Iran. STUDY DESIGN AND METHODS: This was a prospective cross-sectional study, which was carried out in the immunohematology reference laboratory of the Iranian Blood Transfusion Organization in Tehran, Iran, in 2008 to 2015. Screening and identification of red blood cell (RBC) alloantibodies was done on the sera of 7340 pregnant females using the standard tube method and gel column agglutination technique. RESULTS: Alloantibodies were identified in the serum of 332 of the 7340 (4.5%) pregnant women. A total of 410 antibodies were detected in 332 positive maternal serum samples with no previous history of blood transfusion. Anti-D was the most common antibody accounting for 70.5% of all the antibodies formed in D- women. The incidence of specific alloimmunization other than Rh group was 14.4%. CONCLUSION: We concluded that the alloimmunization rate was high in comparison with wide pattern in previous studies. In Iran, like other developing countries, alloimmunization screening tests are performed only to detect anti-D in pregnant D- women. This high rate of alloimmunization, quite possibly, is due to the fact that the majority of blood samples came from pregnant women known to have previous obstetric problems. However, we suggest that RBC antibody screening tests should be extended to all D+ women. PMID- 28097700 TI - Comparison of hepatitis E virus nucleic acid test screening platforms and RNA prevalence in French blood donors. PMID- 28097702 TI - Credit where credit is due: TRANSFUSION now offers continuing medical education (CME) to reviewers. PMID- 28097701 TI - Epidemiology, performance characteristics, or both? PMID- 28097704 TI - Prophylactic RhCE and Kell antigen matching: impact on alloimmunization in transfusion-dependent patients with myelodysplastic syndromes. AB - BACKGROUND AND OBJECTIVES: Thirty to 80 per cent of patients with myelodysplastic syndromes (MDS) become transfusion-dependent and are at risk for red blood cell (RBC) alloimmunization. This study compared alloimmunization rates in transfusion dependent patients with MDS at an institution with a policy of prophylactic antigen matching for RhCE and K (PAM) with those transfused at institutions without such a policy (non-PAM). MATERIALS AND METHODS: Transfusion records were retrospectively reviewed to determine total number of RBC transfusions received, whether RBC phenotyping was performed, the type and date of first alloantibody development and receipt of prophylactic antigen matching for RhCE and K. RESULTS: In 176 transfusion-dependent patients with MDS, the overall rate of new alloimmunization was 17%; the majority of patients (87%) developed at least one alloantibody to Rh or Kell antigens. The alloimmunization rate at the institution with a PAM policy was 11% compared with 23% at non-PAM institutions (P = 0.06). The rate of Rh/K alloimmunization was 7 vs. 22%, respectively (P = 0.008). No patient who received PAM developed a Rh/K alloantibody. CONCLUSION: The rate of alloimmunization was 11% at an institution with a PAM policy which was non significantly lower than 23% at institutions without a PAM policy. However, rates of Rh/K alloimmunization were significantly lower. Such a policy should be considered in transfusion-dependent patients with MDS, although further studies on cost-effectiveness and careful consideration of resource availability in the local context are required. PMID- 28097707 TI - Covalent-Bond Formation via On-Surface Chemistry. AB - In this Review article pioneering work and recent achievements in the emerging research area of on-surface chemistry is discussed. On-surface chemistry, sometimes also called two-dimensional chemistry, shows great potential for bottom up preparation of defined nanostructures. In contrast to traditional organic synthesis, where reactions are generally conducted in well-defined reaction flasks in solution, on-surface chemistry is performed in the cavity of a scanning probe microscope on a metal crystal under ultrahigh vacuum conditions. The metal first acts as a platform for self-assembly of the organic building blocks and in many cases it also acts as a catalyst for the given chemical transformation. Products and hence success of the reaction are directly analyzed by scanning probe microscopy. This Review provides a general overview of this chemistry highlighting advantages and disadvantages as compared to traditional reaction setups. The second part of the Review then focuses on reactions that have been successfully conducted as on-surface processes. On-surface Ullmann and Glaser couplings are addressed. In addition, cyclodehydrogenation reactions and cycloadditions are discussed and reactions involving the carbonyl functionality are highlighted. Finally, the first examples of sequential on-surface chemistry are considered in which two different functionalities are chemoselectively addressed. The Review gives an overview for experts working in the area but also offers a starting point to non-experts to enter into this exciting new interdisciplinary research field. PMID- 28097705 TI - Non-polar lipids accumulate during storage of transfusion products and do not contribute to the onset of transfusion-related acute lung injury. AB - BACKGROUND AND OBJECTIVES: The accumulation of non-polar lipids arachidonic acid, 5-hydroxyeicosatetraenoic acid (HETE), 12-HETE and 15-HETE during storage of transfusion products may play a role in the onset of transfusion-related acute lung injury (TRALI), a syndrome of respiratory distress after transfusion. MATERIALS AND METHODS: We investigated non-polar lipid accumulation in red blood cells (RBCs) stored for 42 days, plasma stored for 7 days at either 4 or 20 degrees C and platelet (PLT) transfusion products stored for 7 days. Furthermore, we investigated whether transfusion of RBCs with increased levels of non-polar lipids induces TRALI in a 'two-hit' human volunteer model. All products were produced following Dutch Blood Bank protocols and are according to European standards. Non-polar lipids were measured with high-performance liquid chromotography followed by mass spectrometry. RESULTS: All non-polar lipids increased in RBCs after 21 days of storage compared to baseline. The non-polar lipid concentration in plasma increased significantly, and the increase was even more pronounced in products stored at 20 degrees C. In platelets, baseline levels of 5-HETE and 15-HETE were higher than in RBCs or plasma. However, the non-polar lipids did not change significantly during storage of PLT products. Infusion of RBCs with increased levels of non-polar lipids did not induce TRALI in LPS-primed human volunteers. CONCLUSION: We conclude that non-polar lipids accumulate in RBC and plasma transfusion products and that accumulation is temperature dependent. Accumulation of non-polar lipids does not appear to explain the onset of TRALI (Dutch Trial Register - NTR4455). PMID- 28097708 TI - Prenatal testing for neuropsychiatric disorders. PMID- 28097710 TI - Comparative evaluation of label-free quantification methods for shotgun proteomics. AB - RATIONALE: Label-free quantification (LFQ) is a popular strategy for shotgun proteomics. A variety of LFQ algorithms have been developed recently. However, a comprehensive comparison of the most commonly used LFQ methods is still rare, in part due to a lack of clear metrics for their evaluation and an annotated and quantitatively well-characterized data set. METHODS: Five LFQ methods were compared: spectral counting based algorithms SIN , emPAI, and NSAF, and approaches relying on the extracted ion chromatogram (XIC) intensities, MaxLFQ and Quanti. We used three criteria for performance evaluation: coefficient of variation (CV) of protein abundances between replicates; analysis of variance (ANOVA); and the root-mean-square error of logarithmized calculated concentration ratios, referred to as standard quantification error (SQE). Comparison was performed using a quantitatively annotated publicly available data set. RESULTS: The best results in terms of inter-replicate reproducibility were observed for MaxLFQ and NSAF, although they exhibited larger standard quantification errors. Using NSAF, all quantitatively annotated proteins were correctly identified in the Bonferronni-corrected results of the ANOVA test. SIN was found to be the most accurate in terms of SQE. Finally, the current implementations of XIC-based LFQ methods did not outperform the methods based on spectral counting for the data set used in this study. CONCLUSIONS: Surprisingly, the performances of XIC-based approaches measured using three independent metrics were found to be comparable with more straightforward and simple MS/MS-based spectral counting approaches. The study revealed no clear leader among the latter. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28097711 TI - Pharmacists' perceptions of pay for performance versus fee-for-service remuneration for the management of hypertension through pharmacist prescribing. AB - OBJECTIVES: As pharmacists expand their roles as patient care providers, remuneration must be offered for patient care activities apart from dispensing. Most jurisdictions paying for such services utilize the fee-for-service (FFS) model, while little is known about the role of pay for performance (P4P) within the pharmacy profession. This study aimed to elicit the experience of pharmacists practicing under both models within the Alberta Clinical Trial in Optimizing Hypertension (RxACTION) study in Alberta, Canada. METHODS: Pharmacist participants in RxACTION caring for at least one patient under FFS and under P4P were interviewed about their experiences until data saturation was reached. Interviews were conducted in June-July 2015, with responses audio recorded, transcribed and coded to identify key themes. KEY FINDINGS: Eight pharmacists were interviewed, with three key themes identified: a perceived comfort with the existing FFS model particularly due to its ease related to business planning, the transformative effect of the study on their practices and a preference for future models to consider a blend of both service count- and performance-driven metrics. The degree of influence pharmacists feel they can have on outcomes achieved by patients, the perceptions of patients and other healthcare professionals on outcome-based payment, and concerns with the impact of variable remuneration on the pharmacy business model are concerns raised with P4P in pharmacy practice. CONCLUSIONS: This study reveals a hesitation to radically transform payment for pharmacists' patient care services towards a P4P model. Efforts to implement P4P should therefore be gradual and accompanied with a robust evaluation plan. PMID- 28097713 TI - Pharmacist-industry relationships. AB - OBJECTIVES: The purpose of this study was to document, in their own words, beliefs and attitudes that American pharmacists have towards the pharmaceutical industry and pharmacists' interactions with industry. METHODS: An ethnographic style qualitative study was conducted utilizing open-ended interviews with four hospital pharmacists, two independent pharmacists, two retail pharmacists and one administrative pharmacist in the Washington, DC, metropolitan area to elicit descriptions of and attitudes towards pharmacists' relationships with industry. Analysis of the qualitative material followed established ethnographic conventions of narrative thematic analysis. KEY FINDINGS: All pharmacists reported interactions with pharmaceutical company representatives. Most had received free resources or services from industry, including educational courses. Respondents uniformly believed that industry promotional efforts are primarily directed towards physicians. Although respondents felt strongly that drug prices were excessive and that 'me-too' drugs were of limited use, they generally had a neutral-to-positive view of industry-funded adherence/compliance programmes, coupons, vouchers, and copay payment programmes. Interviewees viewed direct-to consumer advertising negatively, but had a generally positive view of industry funded drug information. CONCLUSIONS: Pharmacists may represent a hitherto under identified cohort of health professionals who are targeted for industry influence; expanding roles for pharmacists may make them even more attractive targets for future industry attention. Pharmacy schools should ensure that students learn to rely on unbiased information sources and should teach students about conflicts of interest and the risks of interacting with industry. Further research should be conducted on the extent to which pharmacists' attitudes towards their duties and towards drug assessment and recommendation are influenced by the pharmaceutical industry. PMID- 28097712 TI - Force generation by titin folding. AB - Titin is a giant protein that provides elasticity to muscle. As the sarcomere is stretched, titin extends hierarchically according to the mechanics of its segments. Whether titin's globular domains unfold during this process and how such unfolded domains might contribute to muscle contractility are strongly debated. To explore the force-dependent folding mechanisms, here we manipulated skeletal-muscle titin molecules with high-resolution optical tweezers. In force clamp mode, after quenching the force (<10 pN), extension fluctuated without resolvable discrete events. In position-clamp experiments, the time-dependent force trace contained rapid fluctuations and a gradual increase of average force, indicating that titin can develop force via dynamic transitions between its structural states en route to the native conformation. In 4 M urea, which destabilizes H-bonds hence the consolidated native domain structure, the net force increase disappeared but the fluctuations persisted. Thus, whereas net force generation is caused by the ensemble folding of the elastically-coupled domains, force fluctuations arise due to a dynamic equilibrium between unfolded and molten-globule states. Monte-Carlo simulations incorporating a compact molten globule intermediate in the folding landscape recovered all features of our nanomechanics results. The ensemble molten-globule dynamics delivers significant added contractility that may assist sarcomere mechanics, and it may reduce the dissipative energy loss associated with titin unfolding/refolding during muscle contraction/relaxation cycles. PMID- 28097714 TI - Photoantimicrobial Biohybrids by Supramolecular Immobilization of Cationic Phthalocyanines onto Cellulose Nanocrystals. AB - The development of photoactive and biocompatible nanostructures is a highly desirable goal to address the current threat of antibiotic resistance. Here, we describe a novel supramolecular biohybrid nanostructure based on the non-covalent immobilization of cationic zinc phthalocyanine (ZnPc) derivatives onto unmodified cellulose nanocrystals (CNC), following an easy and straightforward protocol, in which binding is driven by electrostatic interactions. These non-covalent biohybrids show strong photodynamic activity against S. aureus and E. coli, representative examples of Gram-positive and Gram-negative bacteria, respectively, and C. albicans, a representative opportunistic fungal pathogen, outperforming the free ZnPc counterparts and related nanosystems in which the photosensitizer is covalently linked to the CNC surface. PMID- 28097716 TI - Parental knowledge of antibiotic use in children with respiratory infections: a systematic review. AB - OBJECTIVE: Antimicrobial resistance (AMR) is an increasing global problem. AMR threatens the effective prevention and treatment of an ever-increasing range of infections caused by bacteria, parasites, viruses and fungi. The misuse and overuse of antibiotics (AB) is the major contributor to the emergence of resistant bacteria in humans. To present and describe characteristics in parents' knowledge about when and how to use AB for an upper respiratory tract infection (URTI), their attitudes towards doctors and AB use in general, and their behaviour when their child suffers from an URTI. KEY FINDINGS: The database search was conducted in EMBASE and PubMed for articles published in English, French, Spanish and Scandinavian languages from the inception until May 2016. Qualitative and quantitative studies with focus on parent' knowledge, attitude and behaviour concerning treatment with AB for URTIs among children and adolescents were included. Extracted information included date of study, design, focus, location and population, parental knowledge, attitudes and behaviours regarding paediatric AB use and parental socioeconomic and sociodemographic characteristics. Parental knowledge about the causes of URTIs and when to use AB, education and parental and children's age affect attitudes and behaviours. However, good level of knowledge about AB (when and how to use it), often correlated with living in a Western country and belonging to high socioeconomic position, does not always imply judicious use of AB for URTIs among children. Providing parents with a contingency plan and clarifications on why an AB is not needed for common colds improves parental satisfaction with their physicians. SUMMARY: Evidence gathered from 20 countries from studies published in the last 20 years shows that parental knowledge still plays a major role in when and how to use AB for URTIs among children. However, parents are not disappointed if the physician does not prescribe AB, provided that proper explanations and a contingency plan are given. PMID- 28097715 TI - c-di-AMP modulates Listeria monocytogenes central metabolism to regulate growth, antibiotic resistance and osmoregulation. AB - Cyclic diadenosine monophosphate (c-di-AMP) is a conserved nucleotide second messenger critical for bacterial growth and resistance to cell wall-active antibiotics. In Listeria monocytogenes, the sole diadenylate cyclase, DacA, is essential in rich, but not synthetic media and DeltadacA mutants are highly sensitive to the beta-lactam antibiotic cefuroxime. In this study, loss of function mutations in the oligopeptide importer (oppABCDF) and glycine betaine importer (gbuABC) allowed DeltadacA mutants to grow in rich medium. Since oligopeptides were sufficient to inhibit growth of the DeltadacA mutant we hypothesized that oligopeptides act as osmolytes, similar to glycine betaine, to disrupt intracellular osmotic pressure. Supplementation with salt stabilized the DeltadacA mutant in rich medium and restored cefuroxime resistance. Additional suppressor mutations in the acetyl-CoA binding site of pyruvate carboxylase (PycA) rescued cefuroxime resistance and resulted in a 100-fold increase in virulence of the DeltadacA mutant. PycA is inhibited by c-di-AMP and these mutations prompted us to examine the role of TCA cycle enzymes. Inactivation of citrate synthase, but not down-stream enzymes suppressed DeltadacA phenotypes. These data suggested that c-di-AMP modulates central metabolism at the pyruvate node to moderate citrate production and indeed, the DeltadacA mutant accumulated six times the concentration of citrate present in wild-type bacteria. PMID- 28097717 TI - Estimating drug-free period using a graphical method: an alternative way to monitor extended-interval dosing of gentamicin therapy. AB - OBJECTIVES: Published nomograms to monitor extended-interval dosing (EID) gentamicin therapy were based on a fixed dose of 5 or 7 mg/kg. However, the average dose used for EID gentamicin regimen in our setting was about 3 mg/kg per day. We developed a new method of monitoring based on the duration of drug-free period (DFP) in a 24-h dosing interval. METHODS: Hospitalised adult patients on EID gentamicin were selected. We considered a DFP of between 2 and 8 h as appropriate. Data from two blood samples (2 and 6 h postdose) from each patient were used to estimate the duration of DFP (i.e. DFP method 1). DFP was also calculated for the same patient using an empirically estimated elimination rate constant (Ke ) and the same 6 h postdose concentration value (DFP method 2). Correlation between the two methods was made. An alternative graphical method to estimate DFP was attempted. KEY FINDINGS: Correlation between Ke and age was favourable (r = -0.453; P = 0.001). Ke derived from this empirical relationship was used to estimate DFP method 2. DFP method 1 correlated well with DFP method 2 (r = 0.742; P < 0.001). On this basis, two curves representing minimum and maximum DFPs of 2 and 8 h, respectively, were constructed. The final coordinates, which were plotted from an empirically estimated Ke and a 6 h postdose concentration, were used to determine whether the DFP was within the targeted range. CONCLUSIONS: We have proposed using DFP to monitor EID of gentamicin therapy. A graphical method offers a convenient way to estimate this parameter. PMID- 28097718 TI - A prospective study of the use of antibiotics in the Emergency Department of a Chinese University Hospital. AB - BACKGROUND: Antibiotics are one of the most widely misused group of medicines. The aim of this study was to investigate the use of antibiotics in one of the paediatric emergency departments in China. METHODS: We performed a prospective, cross-sectional study of antibiotic use in the paediatric emergency room of West China Second University Hospital. A total of 500 consecutive patients from March 25 to April 3 2013 were included. Clinical details of the patients were also collected in order to analyse antibiotic use. KEY FINDINGS: The median age of patients was 2 years 2 months. The five most common conditions seen in the emergency department were wheezy bronchitis, upper respiratory tract infections, tonsillitis, pneumonia and diarrhoea. A total of 311 children (62%) received antibiotics. The antibiotics prescribed were predominantly cephalosporins and penicillins. More than one antibiotic was used in 51 patients. In total, 75% of the antibiotics prescribed were cephalosporins. More than three-quarters of the young children with wheezy bronchitis received antibiotics. Antibiotic use for children with an upper respiratory tract infections or tonsillitis was greater than the 20% maximum recommended by the European Surveillance of Antimicrobial Consumption. CONCLUSIONS: The majority of children attending the emergency department received antibiotics. For many of the conditions, the use of antibiotics was inappropriate. PMID- 28097719 TI - New antibiotics - old problems. PMID- 28097720 TI - Antibiotic Stewardship: why we must play our part. PMID- 28097721 TI - Short versus regular-course antimicrobial therapy for intraabdominal infections. PMID- 28097722 TI - Antimicrobial utilization in an Iraqi province: a comprehensive evaluation of antibiotic source and cost. AB - PURPOSE: The aims were to calculate total systemic antibiotic consumption and cost in both public and private sectors in all care settings in Al-Najaf province, Iraq, during 2012, recognize the percentage of each pharmacological class for the dispensed antibiotics and identify oral and parenteral antibiotic percentages dispensed and the portions manufactured nationally and imported. METHODS: Cross-sectional study was conducted in Al-Najaf to calculate the total cost and quantities of antibiotics consumed during 2012 using World Health Organization Guidelines for Defined Daily Dose (DDD). KEY FINDINGS: The results showed more than 21 million DDDs were dispensed in Al-Najaf in one year, and more than half (54.2%) were dispensed by governmental healthcare institutions. A thousand inhabitants in the province consumed 45.26 DDDs per day. Extended spectrum (34.49%) and combined penicillins (26.08%) were the most frequently consumed while meropenem was the least frequently consumed (0.02%). Ninety-five per cent of the consumed antibiotics were oral dosage forms, and five per cent were parenteral dosage forms. The total cost of antibiotic consumed was more than nine million U.S dollars. CONCLUSIONS: The antibiotic consumption ratio in this province was comparable to neighbouring countries, but far higher compared to European countries. Penicillins, cephalosporins and quinolones were the most popular antibiotics. Around half of the antibiotics consumed were made by national pharmaceutical companies that mainly produce oral antibiotics. The public sector consumed a higher portion, but spent a lower amount compared to private sectors. This is the first time report of antibiotic consumption in Iraq. More studies evaluating antibiotic consumption can improve utilization. PMID- 28097723 TI - Thoughts for 2017. PMID- 28097724 TI - Unphosphorylated EIIANtr induces ClpAP-mediated degradation of RpoS in Azotobacter vinelandii. AB - The nitrogen-related phosphotransferase system (PTSNtr ) is composed of the EINtr , NPr and EIIANtr proteins that form a phosphorylation cascade from phosphoenolpyruvate. PTSNtr is a global regulatory system present in most Gram negative bacteria that controls some pivotal processes such as potassium and phosphate homeostasis, virulence, nitrogen fixation and ABC transport activation. In the soil bacterium Azotobacter vinelandii, unphosphorylated EIIANtr negatively regulates the expression of genes related to the synthesis of the bioplastic polyester poly-beta-hydroxybutyrate (PHB) and cyst-specific lipids alkylresorcinols (ARs). The mechanism by which EIIANtr controls gene expression in A. vinelandii is not known. Here, we show that, in presence of unphosphorylated EIIANtr , the stability of the stationary phase sigma factor RpoS, which is necessary for transcriptional activation of PHB and ARs synthesis related genes, is reduced, and that the inactivation of genes coding for ClpAP protease complex in strains that carry unphosphorylated EIIANtr , restored the levels and in vivo stability of RpoS, as well as the synthesis of PHB and ARs. Taken together, our results reveal a novel mechanism, by which EIIANtr globally controls gene expression in A. vinelandii, where the unphosphorylated EIIANtr induces the degradation of RpoS by the proteolytic complex ClpAP. PMID- 28097725 TI - Increased cortical porosity in women with hip fracture. AB - BACKGROUND: Hip fractures cause increased mortality and disability and consume enormous healthcare resources. Only 46% of hip fracture patients have osteoporosis at the total hip according to dual-energy X-ray absorptiometry (DXA) measurement. Cortical porosity increases with ageing and is believed to be important for bone strength. OBJECTIVE: To investigate whether older women with hip fracture have higher cortical porosity than controls, and if so whether this difference is independent of clinical risk factors and areal bone mineral density (aBMD). METHODS: From an ongoing population-based study, we identified 46 women with a prevalent X-ray-verified hip fracture and 361 control subjects without any fractures. aBMD was measured with DXA. High-resolution peripheral quantitative computed tomography was used to measure bone microstructure at the standard (ultradistal) site and at 14% (distal) of the tibial length. RESULTS: Women with a previous hip fracture had lower aBMD at the femoral neck (-11.8%) and total hip (-14.6%) as well as higher cortical porosity at the ultradistal (32.1%) and distal (29.3%) tibia compared with controls. In multivariable logistic regression analysis, with adjustment for covariates (age, height, weight, smoking, calcium intake, physical activity, walk time, oral glucocorticoids, parental hip fracture, rheumatoid arthritis, previous fall, current bisphosphonate treatment and femoral neck aBMD), cortical porosity at the ultradistal [odds ratio per standard deviation increase (95% confidence interval) 2.61 (1.77-3.85)] and distal [1.57 (1.12-2.20)] sites was associated with prevalent hip fracture. CONCLUSION: Cortical porosity was associated with prevalent hip fracture in older women independently of femoral neck aBMD and clinical risk factors. PMID- 28097726 TI - Role of the Edge Properties in the Hydrogen Evolution Reaction on MoS2. AB - Molybdenum disulfide, in particular its edges, has attracted considerable attention as possible substitute for platinum catalysts in the hydrogen evolution reaction (HER). The complex nature of the reaction complicates its detailed experimental investigations, which are mostly indirect and sample dependent. Therefore, density functional theory calculations were employed to study how the properties of the MoS2 Mo-edge influence the thermodynamics of hydrogen adsorption onto the edge. The effect of the computational model (one-dimensional nanostripe), border symmetry imposed by its length, sulfur saturation of the edge, and dimensionality of the material are discussed. Hydrogen adsorption was found to depend critically on the coverage of extra sulfur at the Mo edge. The bare Mo-edge and fully sulfur-covered Mo-edge are catalytically inactive. The most favorable hydrogen binding towards HER was found for the Mo-edge covered by sulfur monomers. This edge provides hydrogen adsorption free energies positioned around -0.25 eV at up to 50 % hydrogen coverage, close to the experimental values of overpotential needed for the HER reaction. PMID- 28097728 TI - Dabigatran etexilate in a vitamin-K antagonist non responder patient during Heartware HVAD support. AB - We report a case of a patient supported with a HeartWare left ventricular assist device for idiopathic cardiomyopathy who was resistance to vitamin-K antagonists three months after implantation. The patient initially started low-molecular weight heparin therapy and then, after the onset of an ischemic stroke, switched to dabigatran etexilate (DE). The patient had progressive recovery of cardiac function for which the device was explanted. No thrombotic or bleeding events occurred during DE therapy. PMID- 28097727 TI - Energetics, kinetics, and pathway of SNARE folding and assembly revealed by optical tweezers. AB - Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are universal molecular engines that drive membrane fusion. Particularly, synaptic SNAREs mediate fast calcium-triggered fusion of neurotransmitter containing vesicles with plasma membranes for synaptic transmission, the basis of all thought and action. During membrane fusion, complementary SNAREs located on two apposed membranes (often called t- and v-SNAREs) join together to assemble into a parallel four-helix bundle, releasing the energy to overcome the energy barrier for fusion. A long-standing hypothesis suggests that SNAREs act like a zipper to draw the two membranes into proximity and thereby force them to fuse. However, a quantitative test of this SNARE zippering hypothesis was hindered by difficulties to determine the energetics and kinetics of SNARE assembly and to identify the relevant folding intermediates. Here, we first review different approaches that have been applied to study SNARE assembly and then focus on high resolution optical tweezers. We summarize the folding energies, kinetics, and pathways of both wild-type and mutant SNARE complexes derived from this new approach. These results show that synaptic SNAREs assemble in four distinct stages with different functions: slow N-terminal domain association initiates SNARE assembly; a middle domain suspends and controls SNARE assembly; and rapid sequential zippering of the C-terminal domain and the linker domain directly drive membrane fusion. In addition, the kinetics and pathway of the stagewise assembly are shared by other SNARE complexes. These measurements prove the SNARE zippering hypothesis and suggest new mechanisms for SNARE assembly regulated by other proteins. PMID- 28097730 TI - Exposure to reactive intermediate-inducing drugs during pregnancy and the incident use of psychotropic medications among children. AB - PURPOSE: Our study aimed to investigate the association between prenatal exposure to reactive intermediate (RI)-inducing drugs and the initiation of psychotropic medications among children. METHODS: We designed a cohort study using a pharmacy prescription database. Pregnant women were considered exposed when they received a prescription of RI-inducing drugs. These drugs could be either used alone (RI+/FAA-) or combined with drugs exhibiting folic acid antagonism (FAA, RI+/FAA+). The reference group included pregnant women who did not receive any RI inducing drugs or FAA drugs. RESULTS: We analyzed 4116 exposed and 30 422 reference pregnancies. The hazard ratio (HR) with 95% confidence interval (CI) was 1.27 (95%CI 1.15-1.41) for pregnancies exposed to RI-inducing drugs as a whole. Considering subgroups of RI-inducing drugs, prenatal exposure to both RI+/FAA+ and RI+/FAA- was associated with the children's initiation of psychotropic medications, HRs being 1.35 (95%CI 1.10-1.66) and 1.26 (1.13-1.41), respectively. The HRs were increased with prolonged exposure to RI-inducing drugs, especially in the first and second trimesters. In a detailed examination of the psychotropics, the incidences of receiving antimigraine preparations and psychostimulants were significantly increased for the exposed children, compared with the reference children. The incidences of receiving antipsychotics and hypnotics were also higher for the exposed children; however, the HRs did not reach significance after adjustment. CONCLUSIONS: We found a significantly increased incident use of psychotropic medications among children prenatally exposed to RI-inducing drugs, especially during the first and second trimesters. This suggests a detrimental effect during critical periods of brain development. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28097729 TI - The Role of Orexin Signaling in the Ventral Tegmental Area and Central Amygdala in Modulating Binge-Like Ethanol Drinking Behavior. AB - BACKGROUND: Recent reports have demonstrated that binge-like ethanol (EtOH) drinking leads to an increase in hypothalamic orexin (OX) signaling and that suppressing this signaling via systemic administration of an orexin receptor (OXR) antagonist blocks this behavior; however, the specific OX pathways that modulate this behavior remain unknown. The goal of this study was to further elucidate the role of the OX system in binge-like EtOH drinking using behavioral, molecular, and pharmacological techniques. METHODS: The drinking-in-the-dark (DID) paradigm was used to model binge-like drinking behavior in male C57BL/6J mice. Experiment 1 examined changes in the OX precursor, prepro-orexin, within the hypothalamus following multiple cycle EtOH or sucrose DID using polymerase chain reaction (PCR) analysis. In experiments 2a and 2b, we used site-directed infusion of an OXR antagonist to examine the individual contribution of each OXR subtype within the ventral tegmental area (VTA) and central nucleus of the amygdala (CeA), respectively, in binge-like EtOH or sucrose drinking. RESULTS: Findings from our PCR study revealed that multiple cycles of binge-like EtOH drinking did not lead to changes in prepro-orexin mRNA as a function of binge like EtOH drinking. However, data from site-directed pharmacology studies indicate that the orexin-1 receptor (OX1R) is the predominate receptor subtype within the VTA and CeA that regulates binge-like EtOH drinking. Interestingly, inhibition of OX1Rs did not affect binge-like sucrose intake, which suggests that these OX circuits are specific for EtOH consumption. CONCLUSIONS: As a whole, these data suggest that the VTA and CeA are important regions in which OX regulates binge-like EtOH drinking behavior. Moreover, these findings identify OXR antagonists as a potential treatment option that may be used to ameliorate problematic drinking behavior while leaving responding to natural rewards relatively intact. PMID- 28097731 TI - Efficacy and tolerability of amorolfine 5% nail lacquer in combination with systemic antifungal agents for onychomycosis: A meta-analysis and systematic review. AB - The efficacy and safety of amorolfine 5% nail lacquer in combination with systemic antifungal agents in the treatment of the onychomycosis were evaluated. According to our meta-analysis, combination treatment of amorolfine 5% nail lacquer and systemic antifungals can result in higher percentage of complete clearance of onychomycosis. It showed that the experimental combination group was more effective than monotherapy of the systemic antifungals [OR (odds ratio) = 1.97, 95%CI (95% confidence interval) = 1.44-2.69], and no more adverse events happened with the addition of amorolfine 5% nail lacquer (OR = .96, 95%CI = .56 1.63, p = .95). This effect strengthens the fact that amorolfine 5% nail lacquer in combination with systemic antifungal agents was better than the monotherapy of systemic antifungals like itraconazole and terbinafine. PMID- 28097732 TI - Fundamental mechanisms deliver the Nobel Prize to Ohsumi. PMID- 28097733 TI - Optimized amplitude modulated multiband RF pulse design. AB - PURPOSE: Multiband pulses are characterized by highly temporally modulated waveforms. Rapid phase or frequency modulation can be extremely demanding on the performance of radiofrequency (RF) pulse generation, which can lead to errors that can be avoided if pulses are restricted to amplitude modulation (AM) only. In this work, three existing multiband pulse design techniques are modified to produce AM waveforms. THEORY AND METHODS: Multiband refocusing pulses were designed using phase-optimization, time-shifting, and root-flipping. Each technique was constrained to produce AM pulses by exploiting conjugate symmetry in their respective frequency domain representations. Pulses were designed using the AM and unconstrained techniques for a range of multiband factors (ie, number of simultaneously excited slices), time-bandwidth products, and slice separations. Performance was compared by examining the resulting effective pulse durations. Phantom and in vivo experiments were conducted for validation. RESULTS: Acquired data confirmed that AM pulses can produce precise results when unconstrained designs may produce artifacts. The average duration of AM pulses is longer than the unconstrained versions. Averaged across a range of parameters, the duration cost for AM pulses was 26, 38, and 20% for phase-optimizing, time shifting and root-flipping, respectively. CONCLUSIONS: Amplitude modulation multiband pulses can be produced for a relatively small increase in pulse duration. Magn Reson Med 78:2185-2193, 2017. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 28097734 TI - How lay people understand and make sense of personalized disease risk information. AB - BACKGROUND: Disease risk calculators are increasingly web-based, but previous studies have shown that risk information often poses problems for lay users. OBJECTIVE: To examine how lay people understand the result derived from an online cardiometabolic risk calculator. DESIGN: A qualitative study was performed, using the risk calculator in the Dutch National Prevention Program for cardiometabolic diseases. The study consisted of three parts: (i) attention: completion of the risk calculator while an eye tracker registered eye movements; (ii) recall: completion of a recall task; and (iii) interpretation: participation in a semi structured interview. SETTING AND PARTICIPANTS: We recruited people from the target population through an advertisement in a local newspaper; 16 people participated in the study, which took place in our university laboratory. RESULTS: Eye-tracking data showed that participants looked most extensively at numerical risk information. Percentages were recalled well, whereas natural frequencies and verbal labels were remembered less well. Five qualitative themes were derived from the interview data: (i) numerical information does not really sink in; (ii) the verbal categorical label made no real impact on people; (iii) people relied heavily on existing knowledge and beliefs; (iv) people zoomed in on risk factors, especially family history of diseases; and (v) people often compared their situation to that of their peers. DISCUSSION AND CONCLUSION: Although people paid attention to and recalled the risk information to a certain extent, they seemed to have difficulty in properly using this information for interpreting their risk. PMID- 28097735 TI - Autoimmune enteropathy and hepatitis in pediatric heart transplant recipient. AB - AIE is a rare disorder in children that presents with severe diarrhea and malabsorption, caused by immune-mediated damage to intestinal mucosa. AIE is often associated with various syndromes of immunodeficiency including IPEX syndrome (immune dysregulation, polyendocrinopathy and enteropathy, X-linked). Dysfunctional T regulatory cells are the source of pathology in both IPEX syndrome and AIE as they are essential in maintaining tolerance to self-antigens and eliminating autoreactive B cells. This case report describes a 10-year-old cardiac transplant and total thymectomy patient on chronic immunosuppression with tacrolimus that presented with AIE and extraintestinal manifestations of cyclical hepatitis. Transition from tacrolimus to sirolimus successfully increased T regulatory cells and resolved enteritis and hepatitis symptoms. Data support that thymectomy at <1 year of age increases risk of autoimmune disease due to abnormal immune maturation. Studies suggest that the sirolimus promotes the upregulation of the FoxP3 protein that is classically associated with Tregs. In turn, Tregs prevent the maturation of autoreactive B cells that lead to autoimmune reactions. PMID- 28097736 TI - Restoration and management for plant diversity enhances the rate of belowground ecosystem recovery. AB - The positive relationship between plant diversity and ecosystem functioning has been criticized for its applicability at large scales and in less controlled environments that are relevant to land management. To inform this gap between ecological theory and application, we compared recovery rates of belowground properties using two chronosequences consisting of continuously cultivated and independently restored fields with contrasting diversity management strategies: grasslands restored with high plant richness and managed for diversity with frequent burning (n = 20) and grasslands restored with fewer species that were infrequently burned (n = 15). Restoration and management for plant diversity resulted in 250% higher plant richness. Greater recovery of roots and more predictable recovery of the active microbial biomass across the high diversity management strategy chronosequence corresponded with faster recovery of soil structure. The high diversity grasslands also had greater nutrient conservation indicated by lower available inorganic nitrogen. Thus, mesic grasslands restored with more species and managed for high plant diversity with frequent burning enhances the rate of belowground ecosystem recovery from long-term disturbance at a scale relevant to conservation practices on the landscape. PMID- 28097737 TI - Epidemiological data of type 1 diabetes mellitus in children in Uzbekistan, 1998 2014. AB - AIMS: We aimed to determine the incidence, prevalence and mortality of type 1 diabetes (T1D) in Uzbekistan in children <15 years old. METHODS: In a prospective study from 1998 to 2014 the primary ascertainment of incidence, prevalence and mortality, and cause of death was via data collected by endocrinology dispensaries in Uzbekistan's 14 administrative divisions. A second data collection for 2008-2010 from a national audit in 2011 was used to determine age structure. RESULTS: Over 1998-2014 T1D prevalence roughly doubled (7.8 to 15.3/100,000 population aged <15 years, P = .10), following a doubling of incidence (1.5 to 3.1/100 000 < 15 years), a 5.6% annualized increase, P = .001), with a fall in mortality per 1000 patient years (24.5 to 2.0, P = .001). There was a female preponderance, with a male:female ratio of 0.89 in 2008-2010. In every year, T1D incidence was highest in the 10-14.99 year age-group, although the proportion of diagnoses under 5 years of age increased from 6.0% of total diagnoses in 1998-2002, to 13.4% in 2008-2010. Peak age of onset in 2008-2010 was 13 years. Notable regional variation was evident, with incidence being highest in Tashkent-City (P = .005). The most common cause of death was chronic renal failure-responsible for 31 deaths in children <15 years during the study period. CONCLUSIONS: Our results provide the first long-term epidemiological data for T1D in Uzbekistan and the region. Uzbekistan is country of low but rising T1D incidence and prevalence, and falling mortality. Attention to improving clinical care is warranted, to reduce long-term complications. PMID- 28097738 TI - Enhanced predictive signalling in schizophrenia. AB - Positive symptoms of schizophrenia such as delusions and hallucinations are thought to arise from an alteration in predictive mechanisms of the brain. Here, we empirically tested the hypothesis that schizophrenia is associated with an enhanced signalling of higher-level predictions that shape perception into conformity with acquired beliefs. Twenty-one patients with schizophrenia and twenty-eight healthy controls matched for age and gender took part in a functional magnetic resonance imaging (fMRI) experiment that assessed the effect of an experimental manipulation of cognitive beliefs on the perception of an ambiguous visual motion stimulus. At the behavioural level, there was a generally weaker effect of experimentally induced beliefs on perception in schizophrenia patients compared with controls, but a positive correlation between the effect of beliefs on perception and the severity of positive symptoms. At the neural level, belief-related connectivity between a region encoding beliefs in the orbitofrontal cortex (OFC) and a region encoding visual motion in the visual cortex (V5) was higher in patients compared with controls, indicating a stronger impact of cognitive beliefs on visual processing in schizophrenia. We suggest that schizophrenia might be associated with a generally weaker acquisition of externally generated beliefs and a compensatory increase in the effect of beliefs on sensory processing. Our current results are in line with the notion that enhanced signalling of higher-level predictions that shape perception into conformity with acquired beliefs might underlie positive symptoms in schizophrenia. Hum Brain Mapp 38:1767-1779, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28097739 TI - Cellular plasticity in cardiovascular development and disease. AB - Knowledge on cellular differentiation pathways is critical to understanding organ development, homeostasis, and disease. Studying cell differentiation and cell fate restrictions in these contexts can be done through lineage tracing experiments, which entail permanent labeling of a cell and all its progeny. Recent lineage experiments within the cardiovascular system have uncovered unexpected findings on cellular origins during organogenesis and cell plasticity during disease. For example, there is increasing evidence that multiple progenitor sources exist for a single cell type, and that cells have remarkable expansive capacities under disease settings. Here, we summarize some recent findings in the cardiovascular system and highlight where there is evidence that the underlying concepts are a widespread phenomenon used by other organ systems. Developmental Dynamics 246:328-335, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28097740 TI - In Vivo Dearomatization of the Potent Antituberculosis Agent BTZ043 via Meisenheimer Complex Formation. AB - Nitrobenzothiazinones are among the most potent antituberculosis agents. Herein, we disclose an unprecedented in vivo reduction process that affords Meisenheimer complexes of the clinical candidates BTZ043 and PBTZ169. The reduction is reversible, occurs in all mammalian species investigated, has a profound influence on the in vivo ADME characteristics, and has considerable implications for the design and implementation of clinical studies. The reduction was confirmed by chemical studies that enabled the complete characterization of the Meisenheimer complex and its subsequent chemistry. Combination of the in vivo and chemical studies with LC-MS characterization and assay development also provides a basis for rational lead optimization of this very promising class of antituberculosis agents. PMID- 28097741 TI - "Inherently Chiral" Ionic-Liquid Media: Effective Chiral Electroanalysis on Achiral Electrodes. AB - To achieve enantioselective electroanalysis either chiral electrodes or chiral media are needed. High enantiodiscrimination properties can be granted by the "inherent chirality" strategy of developing molecular materials in which the stereogenic element responsible for chirality coincides with the molecular portion responsible for their specific properties, an approach recently yielding outstanding performances as electrode surfaces. Inherently chiral ionic liquids (ICILs) have now been prepared starting from atropisomeric 3,3'-bicollidine, synthesized from inexpensive reagents, resolved into antipodes without need of chiral HPLC and converted into long-chain dialkyl salts with melting points below room temperature. Both the new ICILs and shorter family terms, solid at room temperature, employed as low-concentration additives in achiral ILs, afford impressive enantioselection for the enantiomers of different probes on achiral electrodes, regularly increasing with additive concentration. PMID- 28097742 TI - Differential dehydration effects on globular proteins and intrinsically disordered proteins during film formation. AB - Globular proteins composed of different secondary structures and fold types were examined by synchrotron radiation circular dichroism spectroscopy to determine the effects of dehydration on their secondary structures. They exhibited only minor changes upon removal of bulk water during film formation, contrary to previously reported studies of proteins dehydrated by lyophilization (where substantial loss of helical structure and gain in sheet structure was detected). This near lack of conformational change observed for globular proteins contrasts with intrinsically disordered proteins (IDPs) dried in the same manner: the IDPs, which have almost completely unordered structures in solution, exhibited increased amounts of regular (mostly helical) secondary structures when dehydrated, suggesting formation of new intra-protein hydrogen bonds replacing solvent-protein hydrogen bonds, in a process which may mimic interactions that occur when IDPs bind to partner molecules. This study has thus shown that the secondary structures of globular and intrinsically disordered proteins behave very differently upon dehydration, and that films are a potentially useful format for examining dehydrated soluble proteins and assessing IDPs structures. PMID- 28097744 TI - In situ electrical monitoring of cancer cells invading vascular endothelial cells with semiconductor-based biosensor. AB - Cellular dynamics is very closely related to ionic behaviors, most of which have been hardly monitored in real time, whereas semiconductor-based biosensors have the unique advantage of direct detection of ionic charges in a real-time and noninvasive manner. In this study, we monitored the invasion process of cancer cells into the vascular endothelial layer in real time by a label-free method using a field-effect transistor (FET) biosensor. Endothelial cells were cultured on the sensing surface of the FET gate, to form a basement membrane between the endothelial cells and the sensing surface. When invasive cancer cells (HeLa cells) approached the endothelial cell-coated gate FET biosensor, a change in the surface potential was clearly detected using the FET biosensor. This is because HeLa cells, which invaded the endothelial cell layer, reduced the molecular charge density in the basement membrane by decomposing it. A platform based on the cell-coated gate FET biosensor is suitable for real-time and noninvasive monitoring of cellular dynamics based on intrinsic ionic charges. PMID- 28097743 TI - Optimizing outcomes in clozapine rechallenge following neutropenia using human leukocyte antigen typing: A case report. PMID- 28097745 TI - Immature Core protein of hepatitis C virus induces an unfolded protein response through inhibition of ERAD-L in a yeast model system. AB - The structural protein Core of hepatitis C virus (HCV), a cytosolic protein, induces endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in hepatocytes, and is responsible for the pathogenesis of persistent HCV infection. Using yeast as a model system, we evaluated mechanisms underlying Core-induced interference of ER homeostasis and UPR, and found that UPR is induced by the immature Core (aa 1-191, Core191) but not by the mature Core (aa 1-177, Core177). Interestingly, Core191 inhibits both ERAD-L, a degradation system responsible for misfolded/unfolded proteins in the ER lumen, and ERAD-M, a degradation system responsible for proteins carrying a misfolded/unfolded region in the ER membrane. In contrast, Core177 inhibits ERAD-M but not ERAD-L. In addition, requirement of an unfolded protein sensor in the ER lumen suggested that inhibition of ERAD-L is probably responsible for Core191-dependent UPR activation. These results implicate inadequate maturation of Core as a trigger for induction of ER stress and UPR. PMID- 28097746 TI - High neutrophil : lymphocyte ratio is associated with refractory Kawasaki disease. AB - BACKGROUND: The clinical significance of the neutrophil : lymphocyte ratio (NLR) has not yet been fully elucidated in Kawasaki disease (KD). The purpose of this study was to investigate the relationship between NLR and response to i.v. immunoglobulin (IVIG), and its effect on coronary abnormalities in KD. METHODS: A total of 196 KD patients treated with IVIG were analyzed. Baseline NLR was evaluated immediately before IVIG therapy and the patients classified into two groups according to NLR. The clinical data, other inflammatory biomarkers, and coronary complications were also assessed. RESULTS: Kawasaki disease patients with NLR >= 5 had a greater incidence of IVIG refractoriness than the NLR < 5 group (31.7% vs 4.3%, P < 0.001), but this was not related to the development of coronary abnormalities. The change in NLR after IVIG (i.e. DeltaNLR) was significantly decreased in the coronary abnormality group (2.65 +/- 1.88 vs 3.81 +/- 2.55, P = 0.042). On multivariate analysis, high NLR and CRP were independent predictors of IVIG refractoriness during the acute phase of KD (P = 0.032 in NLR; P = 0.029 in CRP, respectively). CONCLUSIONS: High NLR was closely associated with resistance to IVIG, but it was not related to the occurrence of coronary abnormalities in KD. Low DeltaNLR after IVIG, however, was significantly associated with coronary artery abnormalities. PMID- 28097747 TI - A literacy-sensitive approach to improving antibiotic understanding in a community-based setting. AB - OBJECTIVE: Antibiotic misuse contributes to antibiotic-resistant bacterial infections. Patient and prescriber knowledge and behaviors influence antibiotic use. Past research has focused on describing and influencing prescriber behavior with less attention to the patient role in antibiotic use. This study seeks to: (1) develop and deploy a program to enhance patient knowledge about antibiotic use; (2) evaluate whether providing patient education is associated with improvements in antibiotic knowledge in a community-based sample; and (3) explore whether health literacy may be associated with knowledge of appropriate antibiotic use. METHOD: This study developed, deployed, and evaluated whether community-based educational seminars enhance patient knowledge about antibiotic use. KEY FINDINGS: Twenty-eight participants from five locations completed the seminar. The antibiotic knowledge index score significantly increased by 2.0 points on the 14 point knowledge index from 10.95 (+/-2.88) to 12.95 (+/-1.72) (P = 0.0011) for the 19 participants completing both the pre and post-test. CONCLUSION: A community-based educational seminar on appropriate antibiotic use can effectively increase patient understanding of their role in antibiotic stewardship and combat the inappropriate use of antibiotics. PMID- 28097748 TI - Schinortriterpenoids: A Case Study in Synthetic Design. AB - Since the pioneering days of total synthesis and retrosynthetic analysis, the community has embraced guiding principles for planning synthetic approaches towards complex natural products. These guideposts have enabled the community to synthesize ever more complex compounds by applying prior knowledge gained in new settings. The recently isolated schinortriterpenoid family of natural products has attracted considerable synthetic attention and provided a rich opportunity to evaluate the lessons learned in the construction of complex, polycyclic scaffolds. In this Minireview, a detailed discussion of the synthetic work within this family is provided, including the six reported total syntheses, as well as a comparative analysis of the approaches utilized in their construction. PMID- 28097750 TI - The Structure of Glycine Dihydrate: Implications for the Crystallization of Glycine from Solution and Its Structure in Outer Space. AB - Glycine, the simplest amino acid, is also the most polymorphous. Herein, we report the structure determination of a long unknown phase of glycine, which was first reported by Pyne and Suryanarayanan in 2001. To date, this phase has only been prepared at 208 K as nanocrystals within ice. Through computational crystal structure prediction and powder X-ray diffraction methods, we identified this elusive phase as glycine dihydrate (GDH), representing the first report on the structure of a hydrated glycine structure. The structure of GDH has important implications for the state of glycine in aqueous solution and the mechanisms of glycine crystallization. GDH may also be the form of glycine that comes to Earth from extraterrestrial sources. PMID- 28097751 TI - Bifunctional Bronsted Base Catalyst Enables Regio-, Diastereo-, and Enantioselective Calpha -Alkylation of beta-Tetralones and Related Aromatic-Ring Fused Cycloalkanones. AB - The catalytic asymmetric synthesis of both alpha-substituted and alpha,alpha disubstituted (quaternary) beta-tetralones through direct alpha-functionalization of the corresponding beta-tetralone precursor remains elusive. A designed Bronsted base-squaramide bifunctional catalyst promotes the conjugate addition of either unsubstituted or alpha-monosubstituted beta-tetralones to nitroalkenes. Under these reaction conditions, not only enolization, and thus functionalization, occurs at the alpha-carbon atom of the beta-tetralone exclusively, but adducts including all-carbon quaternary centers are also formed in highly diastereo- and enantioselective manner. PMID- 28097749 TI - Positive contrast from cells labeled with iron oxide nanoparticles: Quantitation of imaging data. AB - PURPOSE: Conventional T2 -weighted MRI produces a hypointense signal from iron labeled cells, which renders quantification unfeasible. We tested a SWeep Imaging with Fourier Transformation (SWIFT) MRI pulse sequence to generate a quantifiable hyperintense signal from iron-labeled cells. METHODS: Mesenchymal stem cells (MSCs) were labeled with different concentrations of iron oxide particles and examined for cell viability, proliferation, and differentiation. The SWIFT sequence was optimized to detect and quantify the amount of iron in the muscle tissue after injection of iron oxide solution and iron-labeled MSCs. RESULTS: The incubation of MSCs with iron oxide and low concentration of poly-L-lysine mixture resulted in an internalization of up to 22 pg of iron per cell with no adverse effect on MSCs. Phantom experiments showed a dependence of SWIFT signal intensity on the excitation flip angle. The hyperintense signal from iron-labeled cells or solutions was detected, and an amount of the iron oxide in the tissue was quantified with the variable flip angle method. CONCLUSIONS: The SWIFT sequence can produce a quantifiable hyperintense MRI signal from iron-labeled cells. The graft of 18 x 106 cells was detectable for 19 days after injection and the amount of iron was quantifiable. The proposed protocol simplifies the detection and provides a means to quantify cell numbers. Magn Reson Med 78:1900-1910, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28097752 TI - Social Self-Sorting of Colloidal Families in Co-Assembling Microgel Systems. AB - Colloids are valuable model systems to understand the structure and dynamics of matter, explore new self-assembly concepts, and realize advanced materials. Herein, we demonstrate social self-sorting of co-assembled families of colloids by orthogonal host/guest recognition using cyclodextrins. We show that mixtures of four partners self-sort into their respective families without mutual interference. Additionally, the self-assemblies and their interactions are switchable using orthogonal triggers. This study goes beyond previous features of molecular self-sorting, and opens the design space for future self-sorting colloidal systems via rationally designed molecular recognition. PMID- 28097753 TI - Fully Copper-Exchanged High-Silica LTA Zeolites as Unrivaled Hydrothermally Stable NH3 -SCR Catalysts. AB - Diesel engine technology is still the most effective solution to meet tighter CO2 regulations in the mobility and transport sector. In implementation of fuel efficient diesel engines, the poor thermal durability of lean nitrogen oxides (NOx ) aftertreatment systems remains as one major technical hurdle. Divalent copper ions when fully exchanged into high-silica LTA zeolites are demonstrated to exhibit excellent activity maintenance for NOx reduction with NH3 under vehicle simulated conditions even after hydrothermal aging at 900 degrees C, a critical temperature that the current commercial Cu-SSZ-13 catalyst cannot overcome owing to thermal deactivation. Detailed structural characterizations confirm the presence of Cu2+ ions only at the center of single 6-rings that act not only as a catalytically active center, but also as a dealumination suppressor. The overall results render the copper-exchanged LTA zeolite attractive as a viable substitute for Cu-SSZ-13. PMID- 28097754 TI - Synthesis of Bradyrhizose Oligosaccharides Relevant to the Bradyrhizobium O Antigen. AB - The unique alpha-(1->7)-bradyrhizoside linkages are constructed for the first time via judicious choice of the glycosylation partners and conditions, thus tetra- and penta-bradyrhizosides relevant to the peculiar O-antigen of Bradyrhizobium are synthesized, which are shown to adopt the defined right-handed helical conformations and to be unable to induce innate immune responses in plants. PMID- 28097755 TI - A Solution-Processable Liquid-Crystalline Semiconductor for Low-Temperature Annealed Air-Stable N-Channel Field-Effect Transistors. AB - A new solution-processable and air-stable liquid-crystalline n-channel organic semiconductor (2,2'-(2,8-bis(5-(2-octyldodecyl)thiophen-2-yl)indeno[1,2 b]fluorene-6,12-diylidene)dimalononitrile, alpha,omega-2OD-TIFDMT) with donor acceptor-donor (D-A-D) pi conjugation has been designed, synthesized, and fully characterized. The new semiconductor exhibits a low LUMO energy (-4.19 eV) and a narrow optical bandgap (1.35 eV). The typical pseudo-focal-conic fan-shaped texture of a hexagonal columnar liquid-crystalline (LC) phase was observed over a wide temperature range. The spin-coated semiconductor thin films show the formation of large (~0.5-1 MUm) and highly crystalline platelike grains with edge on molecular orientations. Low-temperature-annealed (50 degrees C) top contact/bottom-gate OFETs have provided good electron mobility values as high as 0.11 cm2 (V s)-1 and high Ion /Ioff ratios of 107 to 108 with excellent ambient stability. This indicates an enhancement of two orders of magnitude (100*) when compared with the beta-substituted parent semiconductor, beta-DD-TIFDMT (2,2' (2,8-bis(3-dodecylthiophen-2-yl)indeno[1,2-b]fluorene-6,12 diylidene)dimalononitrile). The current rational alkyl-chain engineering route offers great advantages for D-A-D pi-core coplanarity in addition to maintaining good solubility in organic solvents, and leads to favorable optoelectronic/physicochemical characteristics. These remarkable findings demonstrate that alpha,omega-2OD-TIFDMT is a promising semiconductor material for the development of n-channel OFETs on flexible plastic substrates and LC-state annealing of the columnar liquid crystals can lower the electron mobility for transistor-type charge transport. PMID- 28097756 TI - AAZTA: An Ideal Chelating Agent for the Development of 44 Sc PET Imaging Agents. AB - Unprecedented fast and efficient complexation of ScIII was demonstrated with the chelating agent AAZTA (AAZTA=1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6 methylperhydro-1,4-diazepine) under mild experimental conditions. The robustness of the 44 Sc(AAZTA)- chelate and conjugated biomolecules thereof is further shown by in vivo PET imaging in healthy and tumor mice models. The new results pave the way towards development of efficient Sc-based radiopharmaceuticals using the AAZTA chelator. PMID- 28097757 TI - Palladium-Catalyzed Hydrolytic Cleavage of Aromatic C-O Bonds. AB - Metallic palladium surfaces are highly selective in promoting the reductive hydrolysis of aromatic ethers in aqueous phase at relatively mild temperatures and pressures of H2 . At quantitative conversions, the selectivity to hydrolysis products of PhOR ethers was observed to range from 50 % (R=Ph) to greater than 90 % (R=n-C4 H9 , cyclohexyl, and PhCH2 CH2 ). By analysis of the evolution of products with and without incorporation of H218 O, the pathway was concluded to be initiated by palladium metal catalyzed partial hydrogenation of the phenyl group to an enol ether. Water then rapidly adds to the enol ether to form a hemiacetal, which then undergoes elimination to cyclohexanone and phenol/alkanol products. A remarkable feature of the reaction is that the stronger Ph-O bond is cleaved rather than the weaker aliphatic O-R bond. PMID- 28097758 TI - Alpha blockers in the management of ureteric lithiasis: A meta-analysis. AB - INTRODUCTION: Effective medical expulsion for ureteric stones with alpha-blockers offers numerous advantages over surgical alternatives. However, its effectiveness remains uncertain and with the publication of new trial data, the available evidence requires reappraisal. OBJECTIVE: The aim of this study was to assess the efficacy of alpha-blockers the management of ureteric lithiasis. METHODS: A systematic review of the literature, with predefined search criteria, was conducted using PubMed and Embase. All randomised trials comparing alpha-blocker monotherapy to placebo or standard therapy were included. Stone expulsion rate was the primary outcome measure. Secondary outcome measures were time to stone expulsion, analgesic usage and pain scores. Subgroup analyses assessed individual adrenergic antagonists and variations in standard therapy. Sensitivity analysis was based on stone location, stone size, Cochrane Risk of Bias score and study protocol. Summary effects were calculated using a random-effect model and presented as Relative risks (RR) and mean differences (MD) for dichotomous and continuous outcome measures, respectively. RESULTS: Sixty-seven studies randomising 6654 patients were included in the meta-analysis. Stone expulsion rates improved with alpha-blockers (RR, 1.49; 95% CI 1.38-1.61). Contrast enhanced funnel showed evidence of publication bias. Stone expulsion time was 3.99 days (CI -4.75 to -3.23) shorter with alpha-blockers. Similarly, patients required 106.53 mg [CI -148.20 to -64.86] less diclofenac compared with control/placebo, and had 0.80 [CI -1.07 to -0.54] fewer pain episodes. Visual Analogue Scores were also reduced, -2.43 [CI -3.87 to -0.99]. All formulations of alpha-antagonists all demonstrated beneficial effects over conservative treatment/placebo. Sensitivity analysis demonstrated significant effects of stone location, stone size and study design. CONCLUSIONS AND RELEVANCE: Despite the opposing results of recently published trial, current evidence continues to demonstrate a potential benefit of alpha-blocker treatment particularly for distal stones over 5 mm. PMID- 28097760 TI - Benefits of quitting smoking on work productivity and activity impairment in the United States, the European Union and China. AB - BACKGROUND: Smoking has important health and economic consequences for individuals and society. This study expands the understanding of work-related burden associated with smoking and benefit of smoking cessation across the US, European Union (EU) and China using large-scale, representative survey methodology. METHODS: Data utilised the 2013 National Health and Wellness Survey in United States (US), EU5 (UK, France, Germany, Italy, and Spain) and China. Working-aged respondents 18-64 were used in the analyses (US N=58 500; EU5 N=50 417; China N=17 987) and were categorised into: current smokers, trying to quit, former smokers and never smokers. Generalised linear models controlling for demographics and health characteristics examined the relationship of smoking status with work productivity and activity impairment (WPAI-GH). The WPAI-GH measures were: absenteeism, presenteeism, overall work impairment, and activity impairment. Separately, current smokers were compared with those who quit 0-4, 5 10 and 11 or more years ago on WPAI-GH end-points. RESULTS: Current smokers reported greater absenteeism in the US and China and greater presenteeism, overall work impairment, and activity impairment than former and never smokers across the three regions. Those who quit even 0-4 years ago demonstrated lower absenteeism, presenteeism, and activity impairment in China and lower presenteeism, overall work impairment, and activity impairment in the US and EU5. CONCLUSIONS: Smoking was associated with significant work productivity loss in the US, EU5 and China. The results suggest that quitting benefits extend to work productivity rapidly after cessation, serving to further encourage and promote the implementation of workplace cessation programs. PMID- 28097761 TI - Shortened hospital length of stay and lower costs associated with rivaroxaban in patients with pulmonary embolism managed as observation status. AB - BACKGROUND: Unlike rivaroxaban, treatment of patients with pulmonary embolism (PE) with warfarin requires parenteral bridging and coagulation monitoring that may prolong length-of-stay (LOS) and increase hospital costs. AIMS: The aim of this study was to compare LOS, hospital costs and readmissions in PE patients managed through observation stays treated with rivaroxaban or parenterally bridged warfarin. METHODS: Premier Hospital claims data from November 2012 to March 2015 were used to identify patients with a primary diagnosis code for PE managed through an observation stay and with >=1 claim for a PE-related diagnostic test on day 0-2. Rivaroxaban users, allowing <=2 days of prior parenteral therapy, were 1:1 propensity-score matched to patients receiving parenterally bridged warfarin. LOS, the proportion of encounters lasting >2 midnights, total hospital costs of the index visit and risk of readmission for venous thromboembolism (VTE) or major bleeding during the same month or 2 months subsequent to the index event were compared between matched cohorts using multivariable regression. RESULTS: A total of 312 rivaroxaban users were matched to 312 patients receiving parenterally bridged warfarin. Rivaroxaban was associated with an average of 0.27-day shorter LOS, a 52% decreased odds of an encounter lasting >2 midnights and a $403 mean reduction in costs vs parenterally bridged warfarin (P<=.002 for all). The readmission rate for VTE during the same or subsequent 2 months following the index PE was similar between cohorts (P=.75). No patient in either cohort was readmitted for major bleeding. CONCLUSION: Rivaroxaban was associated with shortened LOS and lowered cost vs parenterally bridged warfarin in PE observation stay patients, without increases in the short-term rate of complications or readmission. PMID- 28097762 TI - Time delays in the diagnosis and treatment of Fabry disease. AB - BACKGROUND: The high variability in clinical manifestations of Fabry disease can lead to delays between symptom onset and correct diagnosis, and between correct diagnosis and initiation of enzyme replacement therapy. We investigated whether these delays have improved in recent years. METHODS: Data were analysed from the Fabry Outcome Survey (FOS; Shire; extracted August 2013) for "index patients", defined as the first patient diagnosed with Fabry disease from a family with several or no additional members registered in FOS. RESULTS: Periods analysed: 2001-2006 vs. 2007-2013, in patients overall and from Europe vs. the rest of the world (ROW). Overall, 598 patients were diagnosed within the study periods. Median age (95% CI) at symptom onset in 2001-2006 and 2007-2013 was 7.0 (5.0 11.0) and 9.0 (6.0-11.0) in children, and 21.0 (15.0-28.0) and 31.0 (26.0-35.0) in adults, respectively. Overall, the delay in diagnosis did not improve, despite showing a trend towards earlier diagnosis in adults (median 14.0 [95% CI 9.0 20.0] vs. 10.5 [8.0-13.0] years) and children (5.0 [1.0-9.0] vs. 4.0 [0.0-8.0] years). In contrast, the delay in treatment onset significantly decreased from 2001-2006 to 2007-2013 in children (4.3 [2.0-7.0] vs. 1.0 [0.8-1.4] year; P<.001) and adults (2.1 [1.3-3.2] vs. 0.9 [0.8-1.1] years; P<.001). Geographically, the delay in treatment onset significantly decreased in the ROW among children (5.3 [4.2-8.0] vs. 1.0 [0.8-1.4] year; P<.001) and adults (5.4 [4.8-6.0] vs. 1.1 [0.9 1.1] years; P<.001), but it did not change in Europe. CONCLUSION: We found that the delay in diagnosis has not improved substantially whereas the delay in treatment onset has improved in recent years. PMID- 28097763 TI - Monitoring thyroid function in patients on levothyroxine: audit findings and suggested change in practice. PMID- 28097764 TI - Novel gene mutation in a patient with Bietti crystalline dystrophy without corneal deposits. PMID- 28097765 TI - A False-Positive Screening Hit in Fragment-Based Lead Discovery: Watch out for the Red Herring. AB - With the rising popularity of fragment-based approaches in drug development, more and more attention has to be devoted to the detection of false-positive screening results. In particular, the small size and low affinity of fragments drives screening techniques to their limit. The pursuit of a false-positive hit can cause significant loss of time and resources. Here, we present an instructive and intriguing investigation into the origin of misleading assay results for a fragment that emerged as the most potent binder for the aspartic protease endothiapepsin (EP) across multiple screening assays. This molecule shows its biological effect mainly after conversion into another entity through a reaction cascade that involves major rearrangements of its heterocyclic scaffold. The formed ligand binds EP through an induced-fit mechanism involving remarkable electrostatic interactions. Structural information in the initial screening proved to be crucial for the identification of this false-positive hit. PMID- 28097766 TI - Water-Enabled Catalytic Asymmetric Michael Reactions of Unreactive Nitroalkenes: One-Pot Synthesis of Chiral GABA-Analogs with All-Carbon Quaternary Stereogenic Centers. AB - Water enables new catalytic reactions for otherwise unreactive substrate systems. Under the "on water" reaction conditions, extremely unreactive beta,beta disubstituted nitroalkenes smoothly underwent enantioselective Michael addition reactions with dithiomalonates using a chiral squaramide catalyst, affording both enantiomers of highly enantioenriched Michael adducts with all-carbon-substituted quaternary centers. The developed "on water" protocol was successfully applied for the scalable one-pot syntheses of chiral GABA analogs with all-carbon quaternary stereogenic centers at the beta-position, which might show highly interesting pharmaceutical properties. PMID- 28097767 TI - Robust Aqua Material: A Pressure-Resistant Self-Assembled Membrane for Water Purification. AB - "Aqua materials" that contain water as their major component and are as robust as conventional plastics are highly desirable. Yet, the ability of such systems to withstand harsh conditions, for example, high pressures typical of industrial applications has not been demonstrated. We show that a hydrogel-like membrane self-assembled from an aromatic amphiphile and colloidal Nafion is capable of purifying water from organic molecules, including pharmaceuticals, and heavy metals in a very wide range of concentrations. Remarkably, the membrane can sustain high pressures, retaining its function. The robustness and functionality of the water-based self-assembled array advances the idea that aqua materials can be very strong and suitable for demanding industrial applications. PMID- 28097768 TI - Biosynthesis of the Carbonylmethylene Structure Found in the Ketomemicin Class of Pseudotripeptides. AB - We recently discovered novel pseudotripeptides, the ketomemicins, which possess a C-terminal pseudodipeptide connected with a carbonylmethylene instead of an amide bond, through heterologous expression of gene clusters identified in actinobacteria. The carbonylmethylene structure is a stable isostere of the amide bond and its biological significance has been shown in several natural and synthetic products. Despite the biological importance of these compounds, little is known about how the carbonylmethylene structure is biosynthesized. In this work, we fully characterized the biosynthetic machinery of the pseudodipeptide. An aldolase, dehydratase, PLP-dependent glycine-C-acetyltransferase, and dehydrogenase were involved in the formation of the pseudodipeptide, with malonyl CoA and phenylpyruvate as starter substrates. PMID- 28097769 TI - High resolution crystal structures of human kynurenine aminotransferase-I bound to PLP cofactor, and in complex with aminooxyacetate. AB - In this study, we report two high-resolution structures of the pyridoxal 5' phosphate (PLP)-dependent enzyme kynurenine aminotransferase-I (KAT-I). One is the native structure with the cofactor in the PLP form bound to Lys247 with the highest resolution yet available for KAT-I at 1.28 A resolution, and the other with the general PLP-dependent aminotransferase inhibitor, aminooxyacetate (AOAA) covalently bound to the cofactor at 1.54 A. Only small conformational differences are observed in the vicinity of the aldimine (oxime) linkage with which the PLP forms the Schiff base with Lys247 in the 1.28 A resolution native structure, in comparison to other native PLP-bound structures. We also report the inhibition of KAT-1 by AOAA and aminooxy-phenylpropionic acid (AOPP), with IC50s of 13.1 and 5.7 MUM, respectively. The crystal structure of the enzyme in complex with the inhibitor AOAA revealed that the cofactor is the PLP form with the external aldimine linkage. The location of this oxime with the PLP, which forms in place of the native internal aldimine linkage of PLP of the native KAT-I, is away from the position of the native internal aldimine, with the free Lys247 substantially retaining the orientation of the native structure. Tyr101, at the active site, was observed in two conformations in both structures. PMID- 28097770 TI - Bond Strength and Reactivity Scales for Lewis Superacid Adducts: A Comparative Study with In(OTf)3 and Al(OTf)3. AB - Metal triflates, often called Lewis superacids, are potent catalysts for organic synthesis. However, the reactivity of a given Lewis superacid toward a given base is difficult to anticipate. A systematic screening of catalysts is often necessary when developing synthetic methodologies. Presented herein is the development of quantitative reactivity and bond strength scales by using mass spectrometry (MS). By applying a collision-induced dissociation (CID) technique to the adducts formed between Lewis superacids Al(OTf)3 or In(OTf)3 with a series of amides bases, including monodentate and bidentate ligands, different dissociation pathways were observed. Quantitative relative energy scales were established by performing energy-resolved mass spectrometry (ERMS) analysis on the adducts. ERMS of the adducts affords a bond strength scale when the fragmentation leads to the loss of a ligand, and reactivity scales when the dissociation leads to the C-F bond activation of one triflate anion or the deprotonation of the ligand. Al(OTf)3 was found to bind stronger to amides than In(OTf)3 and to provide the most reactive adducts. PMID- 28097772 TI - Laser-Irradiation-Induced Melting and Reduction Reaction for the Formation of Pt Based Bimetallic Alloy Particles in Liquids. AB - Laser melting in liquids (LML) is one of the most effective methods to prepare bimetallic alloys; however, despite being an ongoing focus of research, the process involved in the formation of such species remains ambiguous. In this paper, we prepared two types of Pt-based bimetallic alloys by LML, including Pt Au alloys and Pt-iron group metal (iM=Fe/Co/Ni) alloys, and investigated the corresponding mechanisms of alloying process. Detailed component and structural characterizations indicate that laser irradiation induced a quite rapid formation process (not exceeding 10 s) of Pt-Au alloy nanospheres, and the crystalline structures of Pt-Au alloys is determined by the monometallic constituents with higher content. For Pt-iM alloys, we provide direct evidence to support the conclusion that FeOx /CoOx /NiOx colloids can be reduced to elementary Fe/Co/Ni particles by ethanol molecules during laser irradiation, which then react with Pt colloids to form Pt-iM sub-microspheres. These results demonstrate that LML provides an optional route to prepare Pt-based bimetallic alloy particles with tunable size, components, and crystalline phase, which should have promising applications in biological and catalysis studies. PMID- 28097771 TI - Solution Synthesis, Structure, and CO2 Reduction Reactivity of a Scandium(II) Complex, {Sc[N(SiMe3 )2 ]3 }. AB - The first crystallographically characterizable complex of Sc2+ , [Sc(NR2 )3 ]- (R=SiMe3 ), has been obtained by LnA3 /M reactions (Ln=rare earth metal; A=anionic ligand; M=alkali metal) involving reduction of Sc(NR2 )3 with K in the presence of 2.2.2-cryptand (crypt) and 18-crown-6 (18-c-6) and with Cs in the presence of crypt. Dark maroon [K(crypt)]+ , [K(18-c-6)]+ , and [Cs(crypt)]+ salts of the [Sc(NR2 )3 ]- anion are formed, respectively. The formation of this oxidation state of Sc is also indicated by the eight-line EPR spectra arising from the I=7/2 45 Sc nucleus. The Sc(NR2 )3 reduction differs from Ln(NR2 )3 reactions (Ln=Y and lanthanides) in that it occurs under N2 without formation of isolable reduced dinitrogen species. [K(18-c-6)][Sc(NR2 )3 ] reacts with CO2 to produce an oxalate complex, {K2 (18-c-6)3 }{[(R2 N)3 Sc]2 (MU-C2 O4 -kappa1 O:kappa1 O'')}, and a CO2- radical anion complex, [(R2 N)3 Sc(MU-OCO-kappa1 O:kappa1 O')K(18-c-6)]n . PMID- 28097773 TI - Highly Stereoselective Gold-Catalyzed Coupling of Diazo Reagents and Fluorinated Enol Silyl Ethers to Tetrasubstituted Alkenes. AB - We report a highly stereoselective synthesis of all-carbon or fluorinated tetrasubstituted alkenes from diazo reagents and fluorinated enol silyl ethers, using C-F bond as a synthetic handle. Cationic AuI catalysis plays a key role in this reaction. Remarkable fluorine effects on the reactivity and selectivity was also observed. PMID- 28097775 TI - Breaking the Tetra-Coordinated Framework Rule: New Clathrate Ba8 M24 P28+delta (M=Cu/Zn). AB - A new clathrate type has been discovered in the Ba/Cu/Zn/P system. The crystal structure of the Ba8 M24 P28+delta (M=Cu/Zn) clathrate is composed of the pentagonal dodecahedra common to clathrates along with a unique 22-vertex polyhedron with two hexagonal faces capped by additional partially occupied phosphorus sites. This is the first example of a clathrate compound where the framework atoms are not in tetrahedral or trigonal-pyramidal coordination. In Ba8 M24 P28+delta a majority of the framework atoms are five- and six-coordinated, a feature more common to electron-rich intermetallics. The crystal structure of this new clathrate was determined by a combination of X-ray and neutron diffraction and was confirmed with solid-state 31 P NMR spectroscopy. Based on chemical bonding analysis, the driving force for the formation of this new clathrate is the excess of electrons generated by a high concentration of Zn atoms in the framework. The rattling of guest atoms in the large cages results in a very low thermal conductivity, a unique feature of the clathrate family of compounds. PMID- 28097774 TI - Structural and functional insights into thermally stable cytochrome c' from a thermophile. AB - : Thermophilic Hydrogenophilus thermoluteolus cytochrome c' (PHCP) exhibits higher thermal stability than a mesophilic counterpart, Allochromatium vinosum cytochrome c' (AVCP), which has a homo-dimeric structure and ligand-binding ability. To understand the thermal stability mechanism and ligand-binding ability of the thermally stable PHCP protein, the crystal structure of PHCP was first determined. It formed a homo-dimeric structure, the main chain root mean square deviation (rmsd) value between PHCP and AVCP being 0.65 A. In the PHCP structure, six specific residues appeared to strengthen the heme-related and subunit-subunit interactions, which were not conserved in the AVCP structure. PHCP variants having altered subunit-subunit interactions were more severely destabilized than ones having altered heme-related interactions. The PHCP structure further revealed a ligand-binding channel and a penta-coordinated heme, as observed in the AVCP protein. A spectroscopic study clearly showed that some ligands were bound to the PHCP protein. It is concluded that the dimeric PHCP from the thermophile is effectively stabilized through heme-related and subunit-subunit interactions with conservation of the ligand-binding ability. BRIEF SUMMARY: We report the X-ray crystal structure of cytochrome c' (PHCP) from thermophilic Hydrogenophilus thermoluteolus. The high thermal stability of PHCP was attributed to heme-related and subunit-subunit interactions, which were confirmed by a mutagenesis study. The ligand-binding ability of PHCP was examined by spectrophotometry. PHCP acquired the thermal stability with conservation of the ligand-binding ability. This study furthers the understanding of the stability and function of cytochromes c. PMID- 28097776 TI - Molecular mechanisms underlying deoxy-ADP.Pi activation of pre-powerstroke myosin. AB - Myosin activation is a viable approach to treat systolic heart failure. We previously demonstrated that striated muscle myosin is a promiscuous ATPase that can use most nucleoside triphosphates as energy substrates for contraction. When 2-deoxy ATP (dATP) is used, it acts as a myosin activator, enhancing cross-bridge binding and cycling. In vivo, we have demonstrated that elevated dATP levels increase basal cardiac function and rescues function of infarcted rodent and pig hearts. Here we investigate the molecular mechanism underlying this physiological effect. We show with molecular dynamics simulations that the binding of dADP.Pi (dATP hydrolysis products) to myosin alters the structure and dynamics of the nucleotide binding pocket, myosin cleft conformation, and actin binding sites, which collectively yield a myosin conformation that we predict favors weak, electrostatic binding to actin. In vitro motility assays at high ionic strength were conducted to test this prediction and we found that dATP increased motility. These results highlight alterations to myosin that enhance cross-bridge formation and reveal a potential mechanism that may underlie dATP-induced improvements in cardiac function. PMID- 28097777 TI - Activin A in combination with ERK1/2 MAPK pathway inhibition sustains propagation of mouse embryonic stem cells. AB - The Activin/Nodal/TGF-beta signaling pathway plays a major role in maintaining mouse epiblast stem cells (EpiSCs). The EpiSC-maintaining medium, which contains Activin A and bFGF, induces differentiation of mouse embryonic stem cells (ESCs) to EpiSCs. Here, we show that Activin A also has an ability to efficiently propagate ESCs without differentiation to EpiSCs when combined with a MEK inhibitor PD0325901. ESCs cultured in Activin+PD retained high-level expression of naive pluripotency-related transcription factors. Genomewide analysis showed that the gene expression profile of ESCs cultured in Activin+PD resembles that of ESCs cultured in 2i. ESCs cultured in Activin+PD also showed features common to the naive pluripotency of ESCs, including the preferential usage of the Oct4 distal enhancer and the self-renewal response to Wnt pathway activation. Our finding shows a role of Activin/Nodal/TGF-beta signaling in stabilizing self renewal gene regulatory networks in ESCs. PMID- 28097778 TI - Does Smoking History Confer a Higher Risk for Reconstructive Complications in Nipple-Sparing Mastectomy? AB - History of smoking has been implicated as a risk factor for reconstructive complications in nipple-sparing mastectomy (NSM), however there have been no direct analyses of outcomes in smokers and nonsmokers. All patients undergoing NSM at New York University Langone Medical Center from 2006 to 2014 were identified. Outcomes were compared for those with and without a smoking history and stratified by pack-year smoking history and years-to-quitting (YTQ). A total of 543 nipple-sparing mastectomies were performed from 2006 to 2014 with a total of 49 in patients with a history of smoking. Reconstructive outcomes in NSM between those with and without a smoking history were equivalent. Those with a smoking history were not significantly more likely to have mastectomy flap necrosis (p = 0.6251), partial (p = 0.8564), or complete (p = 0.3365) nipple areola complex (NAC) necrosis. Likewise, active smokers alone did not have a higher risk of complications compared to nonsmokers or those with smoking history. Comparing nonsmokers and those with a less or greater than 10 pack-year smoking history, those with a > 10 pack-year history had significantly more complete NAC necrosis (p = 0.0114, <0.0001). Those with <5 YTQ prior to NSM trended toward an increased rate of complete NAC necrosis (p = 0.0752). Outcomes for those with a < 10 pack-year smoking history or >5 YTQ prior to NSM were equivalent to those without a smoking history. We demonstrate that NSM may be safely offered to those with a smoking history although a > 10 pack-year smoking history or <5 YTQ prior to NSM may impart a higher risk of reconstructive complications, including complete NAC necrosis. PMID- 28097779 TI - The McGill Interactive Pediatric OncoGenetic Guidelines: An approach to identifying pediatric oncology patients most likely to benefit from a genetic evaluation. AB - Identifying cancer predisposition syndromes in children with tumors is crucial, yet few clinical guidelines exist to identify children at high risk of having germline mutations. The McGill Interactive Pediatric OncoGenetic Guidelines project aims to create a validated pediatric guideline in the form of a smartphone/tablet application using algorithms to process clinical data and help determine whether to refer a child for genetic assessment. This paper discusses the initial stages of the project, focusing on its overall structure, the methodology underpinning the algorithms, and the upcoming algorithm validation process. PMID- 28097780 TI - A man-made disease: Fetal neonatal alloimmune thrombocytopenia due to incompatibility between oocyte donor and gestational mother. AB - The incompatibility causing fetal and neonatal alloimmune thrombocytopenia (FNAIT) results from a fetus inheriting a paternal human platelet antigen (HPA), which is different from the maternal HPA. We present a unique case of FNAIT in a pregnancy involving an oocyte recipient mother with Turner syndrome. This is the first report of FNAIT in which the suggested mechanism involves antibodies produced by a gestational mother against the incompatible HPA of the oocyte donor. PMID- 28097781 TI - An Analysis of Oncotype DX Recurrence Scores and Clinicopathologic Characteristics in Invasive Lobular Breast Cancer. AB - The Oncotype DX breast cancer assay (Genomic Health, Redwood City, CA) is increasingly being used to guide treatment decisions for patients with early stage, hormone-positive, Her-2-negative breast cancer. The utility of the Oncotype DX in decision making for treatment of invasive lobular carcinoma (ILC) has not been investigated as the results reported by Genomic Health are largely in a population with invasive ductal carcinoma (IDC). The authors hypothesized that the Oncotype DX recurrence score (RS) distribution for ILC is different than that for IDC. We performed a retrospective analysis of early stage breast cancer patients treated at Penn State Cancer Institute from 2001 to 2011 and identified 102 patients with ILC. We also pulled RS data from our institution's prospective registry of consecutive patients with early stage IDC treated during the same time period. Median follow-up was 55 months. We found that the RS distribution for ILC differed significantly from that of IDC (p = 0.024). We also found a statistically significant difference in the RS distribution between the pure ILC and pleomorphic ILC subtypes (p = 0.027). The Oncotype DX RS distribution in ILC is unique, differing significantly from that in ductal carcinoma. Consequently, the clinical usefulness and cost-effectiveness of the Oncotype DX in guiding treatment for ILC should be further investigated. PMID- 28097782 TI - Long-term follow-up of meningeal spread of otherwise stage 4S neuroblastoma without treatment. PMID- 28097783 TI - Type III pleuropulmonary blastoma in a dicer1 germline mutation carrier: The management of residual lung cystic lesions. AB - Pleuropulmonary blastoma (PPB) is a rare malignancy of childhood. It often represents a manifestation of a hereditary tumor predisposition syndrome (DICER1 syndrome). Because of its malignant potential, surgical resection of cystic lung lesions is recommended in germline DICER1 mutation carriers. We present a case of a 3-year-old male child with type III PPB successfully managed with ifosfamide, vincristine, actinomycin-D, and doxorubicin (IVADo) chemotherapy and surgery. A heterozygous germline pR688X mutation of DICER1 gene was demonstrated. Six years after primary diagnosis, several small lung cysts remained stable without further therapy. The management of residual asymptomatic lung cysts represents a clinical challenge in these patients. PMID- 28097784 TI - Reliability of intraoperative frozen section for the diagnosis of renal tumors suspicious for malignancy in children and adolescents. AB - BACKGROUND: The ability of intraoperative frozen section (IFS) to reliably diagnose renal tumors in children and adolescents is largely unknown. The objective of our study is to evaluate the ability of IFS to establish a histologic diagnosis for renal tumors in this population. METHODS: We reviewed our experience with patients who underwent IFS at the time of surgery for a renal tumor suspicious for malignancy from 2005 to 2015. The IFS was compared to the final pathology (FP). Data on concordance and reliability were analyzed. RESULTS: One hundred thirty patients underwent surgical interventions for a renal tumor suspicious for malignancy, and 32 (25%) patients underwent IFS. Median turnaround time for IFS was 20 min (range 13-44). The histologic IFS diagnosis correlated with FP in 26 (81.2%) cases was discrepant in three (9.4%) cases, and IFS was deferred to FP in three (9.4%) cases (kappa 0.71, 95% confidence interval [CI]: 0.52-0.899, P < 0.001). The IFS correctly distinguished between Wilms tumor and non-Wilms tumor in 30 (94%) cases (kappa 0.874, 95% CI: 0.705-1, P < 0.001). A total of 17 of 19 (89.5%) Wilms tumors were correctly diagnosed by IFS, yielding a sensitivity of 0.89 (95% CI: 0.67-0.99) and a specificity of 1 (95% CI: 0.75 1). CONCLUSION: IFS is a reliable tool to establish a histologic diagnosis and to differentiate between Wilms and non-Wilms tumors in children and adolescents with renal tumors. The use of IFS should be encouraged in cases in which obtaining a diagnosis will provide guidance for important "real-time" medical decision making, specifically additional adjunctive surgical procedures. PMID- 28097786 TI - Caribbean Urological Association 18th Annual Conference, Kingston, Jamaica, 4-6 November 2016. PMID- 28097785 TI - Down-regulation of BnDA1, whose gene locus is associated with the seeds weight, improves the seeds weight and organ size in Brassica napus. AB - Brassica napus L. is an important oil crop worldwide and is the main raw material for biofuel. Seed weight and seed size are the main contributors to seed yield. DA1 (DA means big in Chinese) is an ubiquitin receptor and negatively regulates seed size. Down-regulation of AtDA1 in Arabidopsis leads to larger seeds and organs by increasing cell proliferation in integuments. In this study, BnDA1 was down-regulated in B. napus by over expressed of AtDA1R358K , which is a functional deficiency of DA1 with an arginine-to-lysine mutation at the 358th amino acid. The results showed that the biomass and size of the seeds, cotyledons, leaves, flowers and siliques of transgenic plants all increased significantly. In particular, the 1000 seed weight increased 21.23% and the seed yield per plant increased 13.22% in field condition. The transgenic plants had no negative traits related to yield. The candidate gene association analysis demonstrated that the BnDA1 locus was contributed to the seeds weight. Therefore, our study showed that regulation of DA1 in B. napus can increase the seed yield and biomass, and DA1 is a promising target for crop improvement. PMID- 28097787 TI - A Ternary Solvent Method for Large-Sized Two-Dimensional Perovskites. AB - Recent reports demonstrate that a two-dimensional (2D) structural characteristic can endow perovskites with both remarkable photoelectric conversion efficiency and high stability, but the synthesis of ultrathin 2D perovskites with large sizes by facile solution methods is still a challenge. Reported herein is the controlled growth of 2D (C4 H9 NH3 )2 PbBr4 perovskites by a chlorobenzene dimethylformide-acetonitrile ternary solvent method. The critical factors, including solvent volume ratio, crystallization temperature, and solvent polarity on the growth dynamics were systematically studied. Under optimum reaction condition, 2D (C4 H9 NH3 )2 PbBr4 perovskites, with the largest lateral dimension of up to 40 MUm and smallest thickness down to a few nanometers, were fabricated. Furthermore, various iodine doped 2D (C4 H9 NH3 )2 PbBrx I4-x perovskites were accessed to tune the optical properties rationally. PMID- 28097788 TI - Outcome of patients with intracranial relapse enrolled on national Wilms Tumor Study Group clinical trials. AB - BACKGROUND: The occurrence of brain metastases (at diagnosis or at relapse) in patients with Wilms tumor is very rare. METHODS: We retrospectively reviewed the clinical characteristics of patients with Wilms tumor and relapse to the brain enrolled on the National Wilms Tumor Studies (NWTSs) 1-5. RESULTS: Intracranial relapse was documented in 47 patients (0.5%). Of the 45 patients with adequate data, 26 (58%) patients were male. Thirty-eight (84%) patients had favorable histology Wilms tumor. In 30 patients (67%), the appearance of intracranial disease was preceded by relapse at another site. Ten patients did not have any disease-directed therapy. Surgical resection was attempted in 15 patients; gross total resection was achieved in 11 patients. Twenty-nine patients received brain irradiation; the median dose was 3,000 cGy (range 1,080-4,000 cGy). Twenty-seven patients received chemotherapy. The 5-year overall survival from the time of intracranial relapse was 28.7% (95% confidence interval: 14.4-43.1%). Nine patients (all favorable histology Wilms tumor) were alive with a median follow-up from brain relapse of 140 months (range 35-381 months). All nine survivors received radiation therapy, eight received chemotherapy, and four underwent surgery (two gross total resection, two partial resection). The overall survival after brain metastases of the NWTS-5 patients was significantly higher than the overall survival of the NWTS 1-4 patients (P value = 0.029, log-rank test). CONCLUSIONS: Patients with Wilms tumor recurrence involving the brain may have durable survival, particularly those treated in recent years. Multimodality therapy including radiation and chemotherapy should be considered for these patients. PMID- 28097789 TI - Bevacizumab for the treatment of Osler's disease - A note of caution. PMID- 28097790 TI - Visible-Light-Mediated Remote Aliphatic C-H Functionalizations through a 1,5 Hydrogen Transfer Cascade. AB - A redox-neutral, light-mediated functionalization of unactivated C(sp3 )-H bonds via iminyl radicals is presented here. A 1,5-H transfer followed by the functionalization of a C(sp2 )-H bond takes place in aqueous media producing a variety of elaborated fused ketones. Mechanistic investigations have revealed 1,5 H transfer as the reversible, rate-determining step in this transformation. Divergent scaffolds are also accessible via C(sp3 )-N bond formation upon a careful choice of the reaction additives. PMID- 28097791 TI - Alpha-thalassaemia promotes frequent vaso-occlusive crises in children with sickle cell anaemia through haemorheological changes. AB - BACKGROUND: Sickle cell anaemia (SCA) is a severe hereditary haemoglobinopathy characterised by haemorheological abnormalities, which play a role in the occurrence of several acute and chronic clinical complications. While betaS haplotypes and alpha-thalassaemia modulate SCA clinical severity, their effects on blood rheology have been incompletely described. The aim of this study was to test the effects of these genetic modifiers on the haemorheological properties and clinical complication of children with SCA. PROCEDURE: Steady-state haemorheological profile, biological parameters, betaS -haplotypes, alpha-globin status, vaso-occlusive crisis (VOC) and acute chest syndrome frequencies were analysed in 128 children (aged 5 to 18 years) with SCA. RESULTS: Patients with alpha-thalassaemia showed increased red blood cell (RBC) deformability and aggregation compared to those without. Median VOC rate was higher in patients with homozygous alpha-thalassaemia compared to those with a normal alpha genotype. Conversely, the haemorheological profile and clinical complications were not influenced by the betaS -haplotypes in our study. CONCLUSION: Our results demonstrate that alpha-thalassaemia is associated with higher risk for VOC events in children with SCA, which may be due in part to its effects on RBC deformability and aggregation. PMID- 28097792 TI - FISH identifies a KAT6A/CREBBP fusion caused by a cryptic insertional t(8;16) in a case of spontaneously remitting congenital acute myeloid leukemia with a normal karyotype. AB - Cytogenetics can inform risk stratification in pediatric acute myeloid leukemia (AML). We describe the first case of a newborn with leukemia cutis found to have AML harboring a cryptic insertional t(8;16)(p11.2;p13.3) with associated KAT6A/CREBBP fusion identified exclusively by fluorescence in situ hybridization (FISH). Expectant management resulted in spontaneous leukemia resolution. The identification of t(8;16)(p11.2;p13.3) may serve as a biomarker for spontaneous remission in congenital AML. FISH for this translocation is warranted in congenital AML with a normal karyotype, and patients with KAT6A/CREBBP fusion should be conservatively managed. While 50% of spontaneously remitting congenital AML with t(8;16)(p11.2;p13.3) may recur, high salvage rates are attained with standard therapy. PMID- 28097793 TI - Living with cardiac resynchronization therapy: Challenges for people with heart failure. AB - The number of people with heart failure requiring implantation of a cardiac resynchronization device is increasing in Iran. Although this intervention is an effective life-saving treatment, several challenges are associated with patients' lifestyle after insertion. This study identified the challenges and coping mechanisms of Iranians with heart failure living with cardiac resynchronization therapy. A qualitative approach using conventional content analysis was adopted. Seventeen people with heart failure and three nurses were recruited between December 2014 and November 2015 from a teaching hospital and a private clinic in Rasht, Iran. Participants were interviewed using semi-structured interviews lasting 30-60 min. Five themes emerged: (i) fear of implantation, (ii) the panic of receiving a shock from the device, (iii) lack of control over life, (iv) inadequacies of the healthcare system, and (v) psychosocial coping. A heightened understanding of these challenges and coping strategies could prepare healthcare professionals to provide better routine care, education, and support to the recipients of cardiac resynchronization therapy prior to implantation, during the recovery period, and for long-term management. PMID- 28097794 TI - Primary intracranial choriocarcinoma in a very youngest child. PMID- 28097796 TI - Reductive Dehydrogenation of a Stannane via Multiple Sn-H Activation by Frustrated Lewis Pairs. AB - A bulky substituted stannane Ar*SnH3 (Ar*=2,6-(2',4',6' triisopropylphenyl)phenyl) was treated with the well-known frustrated Lewis pair (FLP) PtBu3 /B(C6 F5 )3 in varying stoichiometries. To some degree, hydride abstraction and adduct formation is observed, leading to [Ar*SnH2 (PtBu3 )]+ which is rather unreactive toward further dehydrogenation. In a competing process, the FLP proved to be capable of completely striping-off hydrogen and hydrides to generate the first cationic phosphonio-stannylene [Ar*Sn(PtBu3 )]+ . This behavior provides insight into the activation/abstraction mechanism processes involved in these Group 14 hydride derivatives. PMID- 28097795 TI - Impaired N-linked glycosylation of uptake and efflux transporters in human non alcoholic fatty liver disease. AB - BACKGROUND & AIMS: N-linked glycosylation of proteins is critical for proper protein folding and trafficking to the plasma membrane. Drug transporters are one class of proteins that have reduced function when glycosylation is impaired. N linked glycosylation of plasma proteins has also been investigated as a biomarker for several liver diseases, including non-alcoholic fatty liver disease (NAFLD). The purpose of this study was to assess the transcriptomic expression of genes involved in protein processing and glycosylation, and to determine the glycosylation status of key drug transporters during human NAFLD progression. METHODS: Human liver samples diagnosed as healthy, steatosis, and non-alcoholic steatohepatitis (NASH) were analysed for gene expression of glycosylation-related genes and for protein glycosylation using immunoblot. RESULTS: Genes involved in protein processing in the ER and biosynthesis of N-glycans were significantly enriched for down-regulation in NAFLD progression. Included in the down regulated N-glycan biosynthesis category were genes involved in the oligosaccharyltransferase complex, N-glycan quality control, N-glycan precursor biosynthesis, N-glycan trimming to the core, and N-glycan extension from the core. N-glycan degradation genes were unaltered in the progression to NASH. Immunoblot analysis of the uptake transporters organic anion transporting polypeptide-1B1 (OATP1B1), OATP1B3, OATP2B1, and Sodium/Taurocholate Co transporting Polypeptide (NTCP) and the efflux transporter multidrug resistance associated protein 2 (MRP2) demonstrated a significant loss of glycosylation following the progression to NASH. CONCLUSIONS: These data suggest that the loss of glycosylation of key uptake and efflux transporters in humans NASH may influence transporter function and contribute to altered drug disposition observed in NASH. PMID- 28097797 TI - An Asymmetric Redox Arylation: Chirality Transfer from Sulfur to Carbon through a Sulfonium [3,3]-Sigmatropic Rearrangement. AB - A general, asymmetric redox arylation of ynamides and thioalkynes with chiral sulfoxides is reported. This is the first example of a general 1,4-chirality transfer from sulfur to a carbon stereocenter through a sulfonium [3,3] sigmatropic rearrangement. This reaction delivers alpha-arylated thioesters and amides under mild conditions in an atom-economical manner. The products are formed in high yields with enantiomeric ratios up to 99.5:0.5. Quantum chemical calculations suggest a mechanism for the chirality transfer from sulfur to carbon and explain the experimentally observed correlation of the enantioselectivity with both the catalyst and the substrate. PMID- 28097798 TI - Discovery of Novel Cinchona-Alkaloid-Inspired Oxazatwistane Autophagy Inhibitors. AB - The cinchona alkaloids are a privileged class of natural products and are endowed with diverse bioactivities. However, for compounds with the closely-related oxazatricyclo[4.4.0.0]decane ("oxazatwistane") scaffold, which are accessible from cinchonidine and quinidine by means of ring distortion and modification, biological activity has not been identified. We report the synthesis of an oxazatwistane compound collection through employing state-of-the-art C-H functionalization, and metal-catalyzed cross-coupling reactions as key late diversity-generating steps. Exploration of oxazatwistane bioactivity in phenotypic assays monitoring different cellular processes revealed a novel class of autophagy inhibitors termed oxautins, which, in contrast to the guiding natural products, selectively inhibit autophagy by inhibiting both autophagosome biogenesis and autophagosome maturation. PMID- 28097799 TI - Stereocontrolled Total Synthesis of (-)-Stemaphylline. AB - Homologation of readily available alpha-boryl pyrrolidines with metal carbenoids is especially challenging even when good leaving groups (Cl- ) are employed. By performing a solvent switch from Et2 O to CHCl3 , efficient 1,2-metalate rearrangement of the intermediate boronate occurs with both halide and ester leaving groups. The methodology was used in the total synthesis of the Stemona alkaloid (-)-stemaphylline in just 11 steps (longest linear sequence), with high stereocontrol (>20:1 d.r.) and 11 % overall yield. The synthesis also features a late-stage lithiation-borylation reaction with a tertiary amine containing carbenoid. PMID- 28097800 TI - Inception and utility of a renal replacement registry using administrative health data in North-East Italy. AB - BACKGROUND: Disease registries are useful tools for public health planning, evaluating clinical practice and providing information on cohorts of patients. METHODS: The administrative databases of the regional health information system of Friuli Venezia Giulia, Italy were used to build a regional registry of the resident population in renal replacement therapy (including dialysis and renal transplantation), through an algorithm taking into account hospital discharge and outpatient ambulatory care data. The registry includes an anonymous univocal identifier, the start date for the replacement therapy and changes of status (haemodialysis, peritoneal dialysis, renal transplantation). Data from the registry were used to estimate incidence rate, prevalence and mortality of patients receiving renal replacement therapy in 2014. In addition, we described an example of how the registry can be used to assess the prevalence of selected comorbidities. RESULTS: In Friuli Venezia Giulia in 2014, we estimated an incidence rate of renal replacement therapy of 166 per million inhabitants and a prevalence of 1,400 per million inhabitants. A total of 10% of the patients died in the study year. Hypertension, heart disease and diabetes mellitus were common co-morbidities. CONCLUSION: The registry allows us to estimate the incidence rate and prevalence of renal replacement therapy and also to investigate specific issues regarding these patients through record linkage with other administrative health databases. PMID- 28097801 TI - Odd-Even Alternation in Tautomeric Porous Organic Cages with Exceptional Chemical Stability. AB - Amine-linked (C-NH) porous organic cages (POCs) are preferred over the imine linked (C=N) POCs owing to their enhanced chemical stability. In general, amine linked cages, obtained by the reduction of corresponding imines, are not shape persistent in the crystalline form. Moreover, they require multistep synthesis. Herein, a one-pot synthesis of four new amine-linked organic cages by the reaction of 1,3,5-triformylphloroglucinol (Tp) with different analogues of alkanediamine is reported. The POCs resulting from the odd diamine (having an odd number of -CH2 groups) is conformationally eclipsed, while the POCs constructed from even diamines adopt a gauche conformation. This odd-even alternation in the conformation of POCs has been supported by computational calculations. The synthetic strategy hinges on the concept of Schiff base condensation reaction followed by keto-enol tautomerization. This mechanism is the key for the exceptional chemical stability of cages and facilitates their resistance towards acids and bases. PMID- 28097803 TI - Regulation of mRNA following brain ischemia and reperfusion. AB - There is growing appreciation that mRNA regulation plays important roles in disease and injury. mRNA regulation and ribonomics occur in brain ischemia and reperfusion (I/R) following stroke and cardiac arrest and resuscitation. It was recognized over 40 years ago that translation arrest (TA) accompanies brain I/R and is now recognized as part of the intrinsic stress responses triggered in neurons. However, neuron death correlates to a prolonged TA in cells fated to undergo delayed neuronal death (DND). Dysfunction of mRNA regulatory processes in cells fated to DND prevents them from translating stress-induced mRNAs such as heat shock proteins. The morphological and biochemical studies of mRNA regulation in postischemic neurons are discussed in the context of the large variety of molecular damage induced by ischemic injury. Open issues and areas of future investigation are highlighted. A sober look at the molecular complexity of ischemia-induced neuronal injury suggests that a network framework will assist in making sense of this complexity. The ribonomic network sits between the gene network and the various protein and metabolic networks. Thus, targeting the ribonomic network may prove more effective at neuroprotection than targeting specific molecular pathways, for which all efforts have failed to the present time to stop DND in stroke and after cardiac arrest. WIREs RNA 2017, 8:e1415. doi: 10.1002/wrna.1415 For further resources related to this article, please visit the WIREs website. PMID- 28097802 TI - Genomic analysis and clinical management of adolescent cutaneous melanoma. AB - Melanoma in young children is rare; however, its incidence in adolescents and young adults is rising. We describe the clinical course of a 15-year-old female diagnosed with AJCC stage IB non-ulcerated primary melanoma, who died from metastatic disease 4 years after diagnosis despite three lines of modern systemic therapy. We also present the complete genomic profile of her tumour and compare this to a further series of 13 adolescent melanomas and 275 adult cutaneous melanomas. A somatic BRAFV600E mutation and a high mutational load equivalent to that found in adult melanoma and composed primarily of C>T mutations were observed. A germline genomic analysis alongside a series of 23 children and adolescents with melanoma revealed no mutations in known germline melanoma predisposing genes. Adolescent melanomas appear to have genomes that are as complex as those arising in adulthood and their clinical course can, as with adults, be unpredictable. PMID- 28097804 TI - Adult Living Donor Liver Transplantation for Acute-on-Chronic Liver Failure in High-Model for End-Stage Liver Disease Score Patients. AB - The large volume of adult living donor liver transplantations (ALDLTs) at our center affords a unique opportunity to examine the impact of acute-on-chronic liver failure (ACLF) among high-Model for End-Stage Liver Disease MELD score patients. From February 1998 to March 2010, 1958 cirrhotic recipients were analyzed to study the relationship between MELD scores and ALDLT outcomes. A total of 327 high-MELD score recipients were categorized into ACLF and non-ACLF groups, and their outcomes were compared. The 5-year graft and patient survival in the high-MELD group were 75.2% and 76.4%, respectively, which were significantly worse than the low and intermediate MELD groups. The presence of ACLF associated with higher MELD scores appeared to be the dominant factor responsible for the inferior results of patients with MELD score of 30-34 points. The 5-year graft survivals in the ACLF group was 70.5% and in the non-ACLF group it was 81.0% (p = 0.035). Therefore, ALDLT should be performed as soon as possible in high-MELD score patients prior to ACLF development. Moreover, ACLF patients should be separately categorized when analyzing the outcomes of ALDLT. ALDLT for ACLF patients should not be discouraged because favorable outcomes can be expected through timely ALDLT and comprehensive management. PMID- 28097805 TI - Complement Polymorphisms in Kidney Transplantation: Critical in Graft Rejection? AB - The complement system, as part of the innate immune system, plays an important role in renal transplantation. Complement is involved in the protection against foreign organisms and clearance of apoptotic cells but can also cause injury to the renal allograft, for instance, via antibody binding or in ischemia reperfusion injury. Numerous polymorphisms in complement factors have been identified thus far; some of them result in different functionalities or alter complement levels. In this review, we provide an overview of the literature on the role of complement polymorphisms in renal transplantation. Furthermore, we discuss functional complement polymorphisms that have not yet been investigated in kidney transplantation. By investigating multiple polymorphisms both in donor and recipient at the same time, a complotype can be constructed. Because the combination of multiple polymorphisms is likely to have a greater impact than a single one, this could provide valuable prognostic information. PMID- 28097806 TI - Silicone rubber membrane with specific pore size enhances wound regeneration. AB - A porous structure is critically important for wound dressing or tissue engineering scaffolds. However, the influence of the pore sizes on cell proliferation, tissue regeneration and the underlying mechanism remains unclear. In this study, silicone rubber membranes with different pore sizes were prepared using certain constituents of liquid silicone rubber precursor/liquid paraffin/hexane based on our previous studies. It was found that pore size had a significant impact on cell proliferation and wound healing. The CCK8 analysis revealed that the membrane with a certain pore size (110.47 MUm, middle pore membrane, MPM) was suitable for cell proliferation compared with the membranes with other pore sizes (218.03 MUm, large pore membrane, LPM; 5.27 MUm, small pore membrane, SPM; non-porous membrane, NPM). Further studies demonstrated that the MPM promoted cell proliferation via activating the Wnt/beta-catenin signalling pathway. More importantly, wound healing experiments showed that 7 days post wounding, the rate of wound healing was 89.25% with the MPM, which was significantly higher than with LPM, SPM or NPM. The in vivo data indicated that wound healing was accelerated by treatment with a silicone rubber membrane with a pore size of 110.47 MUm. Our results strongly suggest that different pore structures might affect cell proliferation and wound healing and that a silicone rubber membrane with a specific pore size could potentially be used as a promising wound dressing. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28097807 TI - Parent-adolescent influences on everyday dietary practices: Perceptions of adolescent females with obesity and their mothers. AB - Parents demonstrate an important influence on adolescent obesity and dietary behavior; yet, family-based obesity interventions continue to exhibit limited success among adolescents. To further inform family-based approaches for adolescent obesity treatment, we examined the perceptions of adolescent females with obesity and their mothers of the influences experienced within the parent adolescent relationship that affect everyday dietary practices. We conducted six focus group interviews (three adolescent female and three mother) among 15 adolescent (12-17 years old) females with obesity and 12 of their mothers. Content analysis techniques were used to analyze the transcribed interviews. Adolescent females with obesity discussed a diverse set of parental influences (controlling, supporting and cultivating, overlooking and tempting, acquiescing, providing, attending, and not providing and avoiding) on their daily dietary practices. Among mother focus groups, mothers discussed specific intentional and unintentional types of influences from children that affected the food and drink they consumed, prepared, and acquired. Findings provide a fuller view of the varied social influences on everyday dietary practices within the parent adolescent relationship. They indicate the importance of examining both parent-to child and child-to-parent influences and begin to illuminate the value of attending to the social circumstances surrounding dietary behaviors to strengthen family-based obesity treatment approaches. PMID- 28097808 TI - Identification of NTRK fusions in pediatric mesenchymal tumors. AB - BACKGROUND: NTRK fusions are known oncogenic drivers and have recently been effectively targeted by investigational agents in adults. We sought to assess the frequency of NTRK fusions in a large series of pediatric and adolescent patients with advanced cancers. PROCEDURE: Genomic profiles from 2,031 advanced cancers from patients less than 21 years old who were assayed with comprehensive genomic profiling were reviewed to identify NTRK fusions. RESULTS: Total of nine cases (0.44%) harbored NTRK fusions, including novel partners. Four of these cases were in children less than 2 years old for which infantile fibrosarcoma was considered as a diagnosis, and two harbored the canonical ETV6-NTRK3. The remaining cases carried other diagnoses, at least one that carried the diagnosis of inflammatory myofibroblastic tumor. CONCLUSIONS: NTRK fusions occur in a subset of young patients with mesenchymal or sarcoma-like tumors at a low frequency, and are eminently druggable targets via either investigational agents or approved drugs. PMID- 28097809 TI - Cancer-associated fibroblasts promote M2 polarization of macrophages in pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by remarkable desmoplasia with infiltration of distinct cellular components. Cancer-associated fibroblasts (CAFs) has been shown to be among the most prominent cells and played a significant role in shaping the tumor microenvironment by interacting with other type of cells. Here, we aimed to investigate the effect of CAFs in modulating phenotype of tumor-associated macrophages (TAM). Under treatment of CAFs conditioned medium (CM) or direct co-culture with CAFs, monocytes exhibited enhanced expression of CD206 and CD163 compared with control group (P < 0.01). The induction of M2 polarization was mediated by increased reactive oxygen species (ROS) production in monocytes as ROS elimination abolished the effect of CAFs (P < 0.05). The supernatant analysis showed that pancreatic CAFs produced increased macrophage colony-stimulating factor (M-CSF). Upon treatment of M-CSF neutralizing antibody, the ROS generation and M2 polarization of CAFs CM stimulated monocytes were significantly inhibited (P < 0.05). In addition, the CAFs-induced M2 macrophages significantly enhanced pancreatic tumor cell growth, migration, and invasion. Collectively, our data revealed that pancreatic CAFs were able to induce a tumor-promoting TAM phenotype partly through secreted M-CSF and enhanced ROS production in monocytes, indicating possible treatment strategies by targeting stromal cell interaction within PDAC microenvironment. PMID- 28097810 TI - Physicochemical and biological evaluation of a cinnamamide derivative R,S-(2E)-1 (3-hydroxypiperidin-1-yl)-3-phenylprop-2-en-1-one (KM-608) for nervous system disorders. AB - A cinnamamide scaffold has been successfully incorporated in several compounds possessing desirable pharmacological activities in central and peripheral nervous system such as anticonvulsant, antidepressant, neuroprotective, analgesic, anti inflammatory, muscle relaxant, and sedative/hypnotic properties. R,S-(2E)-1-(3 hydroxypiperidin-1-yl)-3-phenylprop-2-en-1-one (KM-608), a cinnamamide derivative, was synthesized, its chemical structure was confirmed by means of spectroscopy and crystallography, and additionally, thermal analysis showed that it exists in one crystalline form. The compound was evaluated in vivo in rodents as anticonvulsant, antiepileptogenic, analgesic, and neuroprotective agent. The beneficial properties of the compound were found in animal models of seizures evoked electrically (maximal electroshock test, 6-Hz) and chemically (subcutaneous pentylenetetrazole seizure test) as well as in three animal models of epileptogenesis: corneal-kindled mice, hippocampal-kindled rats, and lamotrigine-resistant amygdala-kindled rats. Quantitative pharmacological parameters calculated for the tested compound were comparable to those of currently used antiepileptic drugs. In vivo pharmacological profile of KM-608 corresponds with the activity of valproic acid. PMID- 28097812 TI - Monitoring immune response after allogeneic transplantation of mesenchymal stem cells for osteochondral repair. AB - The aim of this study was to investigate the safety of using allogeneic magnetically labelled mesenchymal stem cells (m-MSCs) to ameliorate osteochondral repair, with immune surveillance using a mixed lymphocyte reaction (MLR) assay. Twenty knees of Japanese white rabbits were randomly divided into two groups: the control (autologous) group, where 2 * 105 autologous m-MSCs were transplanted into the defect site; the experimental (allogeneic) group, where 2 * 105 m-MSCs from Dutch rabbits were transplanted into the defect of Japanese white rabbits. The rabbits were then euthanized after 12 weeks. The repaired tissue was stained with toluidine blue stain in order to produce histological scoring on the Fortier scale. Splenocytes were used to evaluate anti-donor alloreactivity by a MLR assay using the carboxyfluorescein diacetate succimidyl ester (CFSE) labelling technique (CFSE-MLR). In both groups, complete repair of the subchondral bone covered by a layer of chondrogenic tissue was confirmed. Also, there was no histologically significant difference on the Fortier scale. Using the CFSE-MLR assay, CD4+ T-cells showed alloreactivity in each combination, while the stimulation index of CD4+ T-cells was not statistically different between the control and experimental groups. Allogeneic m-MSCs are a safe alternative source to autologous m-MSCs, upholding repair of an osteochondral defect for clinical application using universal donor MSCs through a one-stage surgical procedure. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28097813 TI - Drug addictions: new insight into causes, comorbidity and potential treatments. PMID- 28097811 TI - Fc-Silent Anti-CD154 Domain Antibody Effectively Prevents Nonhuman Primate Renal Allograft Rejection. AB - The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental models is the use of reagents to block the CD40/CD154 pathway. Unfortunately, successful clinical translation of anti-CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti-human CD154 domain antibody (dAb, BMS-986004). The anti-CD154 dAb effectively blocked CD40 CD154 interactions but lacked crystallizable fragment (Fc) binding activity and resultant platelet activation. In a nonhuman primate kidney transplant model, anti-CD154 dAb was safe and efficacious, significantly prolonging allograft survival without evidence of thromboembolism (Median survival time 103 days). The combination of anti-CD154 dAb and conventional immunosuppression synergized to effectively control allograft rejection (Median survival time 397 days). Furthermore, anti-CD154 dAb treatment increased the frequency of CD4+ CD25+ Foxp3+ regulatory T cells. This study demonstrates that the use of a novel anti CD154 dAb that lacks Fc binding activity is safe without evidence of thromboembolism and is equally as potent as previous anti-CD154 agents at prolonging renal allograft survival in a nonhuman primate preclinical model. PMID- 28097814 TI - Detection and Molecular Characterization of Foot and Mouth Disease Viruses from Outbreaks in Some States of Northern Nigeria 2013-2015. AB - Control measures for foot and mouth disease (FMD) in Nigeria have not been implemented due to the absence of locally produced vaccines and risk-based analysis resulting from insufficient data on the circulating FMD virus (FMDV) serotypes/strains. In 2013-2015, blood and epithelial samples were collected from reported FMD outbreaks in four states (Kaduna, Kwara, Plateau and Bauchi) in northern Nigeria. FMDV non-structural protein (NSP) seroprevalence for the outbreaks was estimated at 80% (72 of 90) and 70% (131 of 188) post-outbreak. Antibodies against FMDV serotypes O, A, SAT1, SAT2 and SAT3 were detected across the states using solid-phase competitive ELISA. FMDV genome was detected in 99% (73 of 74) of the samples from FMD-affected animals using rRT-PCR, and cytopathic effect was found in cell culture by 59% (44 of 74) of these samples. Three FMDV serotypes O, A and SAT2 were isolated and characterized. The phylogenetic assessments of the virus isolates showed that two topotypes of FMDV serotype O, East Africa-3 (EA-3) and West Africa (WA) topotypes were circulating, as well as FMDV strains belonging to the Africa genotype (G-IV) of serotype A and FMDV SAT2 topotype VII strains. While the serotype O (EA-3) strains from Nigeria were most closely related to a 1999 virus strain from Sudan, the WA strain in Nigeria shares genetic relationship with three 1988 viruses in Niger. The FMDV serotype A strains were closely related to a known virus from Cameroon, and the SAT2 strains were most closely related to virus subtypes in Libya. This study provides evidence of co-occurrence of FMDV serotypes and topotypes in West, Central, East and North Africa, and this has implication for control. The findings help filling the knowledge gap of FMDV dynamics in Nigeria and West Africa subregion to support local and regional development of vaccination-based control plans and international risk assessment. PMID- 28097815 TI - Urinary bisphenol A concentration and the risk of central obesity in Chinese adults: A prospective study. AB - BACKGROUND: Bisphenol A (BPA) exposure has been associated with diabetes and related metabolic disorders, such as obesity, but studies of the association of urinary BPA concentrations with central obesity risk are limited. The aim of this study was to prospectively investigate the association between urinary BPA and incident central obesity in a Chinese population aged >=40 years. METHODS: The study followed 888 participants from Shanghai, China, who did not have central obesity at baseline (in 2009) for 4 years. Concentrations of BPA were measured in baseline morning spot urine samples. Central obesity was defined as waist circumference >=90 cm in men and >=80 cm in women. RESULTS: During a mean follow up of 4 years, 124 (14.0%) participants developed central obesity. Each 1-unit increase in log [BPA] was positively associated with a 2.30-fold risk of incident central obesity (95% confidence interval [CI] 1.39-3.78; P < 0.001) after adjustment for confounders. Compared with the lowest tertile of urinary BPA concentration, Tertiles 2 and 3 were associated with a higher risk of incident central obesity (odds ratios 1.73 [95% CI 1.04-2.88] and 1.81 [95% CI 1.08-3.05], respectively). Stratified analysis showed significant associations of BPA with incident central obesity in women and individuals <60 years of age, with normal weight, non-smokers, non-drinkers, or non-hypertensives. CONCLUSIONS: The results indicate that higher urinary BPA concentrations may be associated with a greater risk of incident central obesity in Chinese adults. The study emphasizes the effects of BPA exposure on metabolic risk from a public health perspective. PMID- 28097816 TI - Effect of temperature and colonization of Legionella pneumophila and Vermamoeba vermiformis on bacterial community composition of copper drinking water biofilms. AB - It is unclear how the water-based pathogen, Legionella pneumophila (Lp), and associated free-living amoeba (FLA) hosts change or are changed by the microbial composition of drinking water (DW) biofilm communities. Thus, this study characterized the bacterial community structure over a 7-month period within mature (> 600-day-old) copper DW biofilms in reactors simulating premise plumbing and assessed the impact of temperature and introduction of Lp and its FLA host, Vermamoeba vermiformis (Vv), co-cultures (LpVv). Sequence and quantitative PCR (qPCR) analyses indicated a correlation between LpVv introduction and increases in Legionella spp. levels at room temperature (RT), while at 37 degrees C, Lp became the dominant Legionella spp. qPCR analysis suggested Vv presence may not be directly associated with Lp biofilm growth at RT and 37 degrees C, but may contribute to or be associated with non-Lp legionellae persistence at RT. Two-way PERMANOVA and PCoA revealed that temperature was a major driver of microbiome diversity. Biofilm community composition also changed over the seven-month period and could be associated with significant shifts in dissolved oxygen, alkalinity and various metals in the influent DW. Hence, temperature, biofilm age, DW quality and transient intrusions/amplification of pathogens and FLA hosts may significantly impact biofilm microbiomes and modulate pathogen levels over extended periods. PMID- 28097817 TI - Revisiting regulation of potassium homeostasis in Escherichia coli: the connection to phosphate limitation. AB - Two-component signal transduction constitutes the predominant strategy used by bacteria to adapt to fluctuating environments. The KdpD/KdpE system is one of the most widespread, and is crucial for K+ homeostasis. In Escherichia coli, the histidine kinase KdpD senses K+ availability, whereas the response regulator KdpE activates synthesis of the high-affinity K+ uptake system KdpFABC. Here we show that, in the absence of KdpD, kdpFABC expression can be activated via phosphorylation of KdpE by the histidine kinase PhoR. PhoR and its cognate response regulator PhoB comprise a phosphate-responsive two-component system, which senses phosphate limitation indirectly through the phosphate transporter PstCAB and its accessory protein PhoU. In vivo two-hybrid interaction studies based on the bacterial adenylate cyclase reveal pairwise interactions between KdpD, PhoR, and PhoU. Finally, we demonstrate that cross-regulation between the kdpFABC and pstSCAB operons occurs in both directions under simultaneous K+ and phosphate limitation, both in vitro and in vivo. This study for the first time demonstrates direct coupling between intracellular K+ and phosphate homeostasis and provides a mechanism for fine-tuning of the balance between positively and negatively charged ions in the bacterial cell. PMID- 28097818 TI - Staging Evaluation and Response Criteria Harmonization (SEARCH) for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (CAYAHL): Methodology statement. AB - International harmonization of staging evaluation and response criteria is needed for childhood, adolescence, and young adulthood Hodgkin lymphoma. Two Hodgkin lymphoma protocols from cooperative trials in Europe and North America were compared for areas in need of harmonization, and an evidence-based approach is currently underway to harmonize staging and response evaluations with a goal to enhance comparisons, expedite identification of effective therapies, and aid in the approval process for new agents by regulatory agencies. PMID- 28097819 TI - Enantiospecific Trifluoromethyl-Radical-Induced Three-Component Coupling of Boronic Esters with Furans. AB - In the presence of trifluoromethylsulfonium reagents, boronate complexes derived from 2-lithio furan and non-racemic secondary and tertiary alkyl or aryl boronic esters undergo deborylative three-component coupling to give the corresponding 2,5-disubstituted furans with excellent levels of enantiospecificity. The process proceeds via the reaction of boronate complexes with a trifluoromethyl radical, which triggers 1,2-metallate rearrangement upon single-electron oxidation. Alternative electrophiles can also be used in place of trifluoromethylsulfonium reagents to effect similar three-component coupling reactions. PMID- 28097820 TI - Cytograding of mast cell tumours in dogs: destaining or not and staining with what? PMID- 28097821 TI - Development of actinobacterial resources for functional cosmetics. AB - BACKGROUND: Actinobacteria usually produce different functional compounds for various applications. OBJECTIVE: The aim of this research was to develop actinobacterial resources through the isolation and identification of soil bacteria with antibacterial and enzyme inhibitory activities for cosmetics application. METHODS: Soil bacteria were isolated and tested for antibacterial activity against Propionibacterium acnes and Staphylococcus epidermidis using the spotting method. Isolates exhibiting antibacterial activities were assayed for tyrosinase inhibition, elastase inhibition, and free radical scavenging activity. RESULTS: Twelve actinobacterial strains were found to inhibit the growth of P. acnes and S. epidermidis. Among them, ten were from the genus Streptomyces and the other two were from the genera Actinokineospora and Calidifontibacter, and potentially represented novel species. For tyrosinase inhibition activities, when compared with arbutin (IC50 =47.84+/-0.36 MUg mL-1 ), strain T65 had similar activity with an IC50 value of 49.05+/-3.29 MUg mL-1 . For elastase inhibition, strains T65, T811, and R311 had similar activities with IC50 values of 10.78+/ 1.88 MUg mL-1 , 10.19+/-0.82 MUg mL-1 , and 10.19+/-2.1 MUg mL-1 , respectively, which had similar inhibitory activity to the IC50 value of the standard oleanolic acid (8.94+/-1.38 MUg mL-1 ). For DPPH radical scavenging activities, two strains, R311 and T327, with IC50 values of 6.11+/-1.17 MUg mL-1 and 5.25+/-0.93 MUg mL-1 , respectively, had slightly lower activities than ascorbic acid (IC50 =4.08+/-0.03 MUg mL-1 ). CONCLUSION: Among twelve strains of actinobacteria, the most effective strains were selected for the inhibition of both P. acnes and S. epidermidis as well as for enzyme activities. Actinobacterial strains isolated in this study could be used to produce active metabolites for cosmetics applications. PMID- 28097823 TI - Excess Retinoic Acid Induces Fusion of Centra by Degenerating Intervertebral Ligament Cells in Japanese flounder, Paralichthys olivaceus. AB - In marine aquaculture fish, excessive supplement of vitamin A (VA) to zooplanktons for larval culture and experimental exposure of larvae to retinoic acid (RA: active form of VA) have been known to cause vertebral deformity. However, the tissues in the developing vertebral column that are affected by RA and the progression of vertebral deformity remain undetermined. To examine these questions, we histologically traced the progress of vertebral deformity induced by RA in Japanese flounder (Paralichthys olivaceus). Larvae were exposed to RA for 3 days at mid-metamorphosis (G-stage), a critical stage for vertebral deformity. Intervertebral ligament, which is known to form intervertebral joints in cooperation with the notochord, was severely degenerated by RA, leading to fusion of centra. During further development to adult, growth of centra was severely suppressed in an anterior-posterior direction in RA-treated fish and the notochord tissue was lost from fused centra, resulting in complete loss of intervertebral joints and fusion of centra. We conclude that RA initially damages the intervertebral ligaments, and these defects lead to fusion, narrowing of centra, and loss of intervertebral joints in the vertebral column. The cumulative effect of these modifications is a truncated body form. PMID- 28097822 TI - Synthetic lethality: emerging targets and opportunities in melanoma. AB - Great progress has been made in the treatment of melanoma through use of targeted therapies and immunotherapy. One approach that has not been fully explored is synthetic lethality, which exploits somatically acquired changes, usually driver mutations, to specifically kill tumour cells. We outline the various approaches that may be applied to identify synthetic lethal interactions and define how these interactions may drive drug discovery efforts. PMID- 28097824 TI - Mechanisms of metabolic memory and renal hypoxia as a therapeutic target in diabetic kidney disease. AB - Diabetic kidney disease (DKD) is a worldwide public health problem. The definition of DKD is under discussion. Although the term DKD was originally defined as 'kidney disease specific to diabetes,' DKD frequently means chronic kidney disease with diabetes mellitus and includes not only classical diabetic nephropathy, but also kidney dysfunction as a result of nephrosclerosis and other causes. Metabolic memory plays a crucial role in the progression of various complications of diabetes, including DKD. The mechanisms of metabolic memory in DKD are supposed to include advanced glycation end-products, deoxyribonucleic acid methylation, histone modifications and non-coding ribonucleic acid including micro ribonucleic acid. Regardless of the presence of diabetes mellitus, the final common pathway in chronic kidney disease is chronic kidney hypoxia, which influences epigenetic processes, including deoxyribonucleic acid methylation, histone modification, and conformational changes in micro ribonucleic acid and chromatin. Therefore, hypoxia and oxidative stress are appropriate targets of therapies against DKD. Prolyl hydroxylase domain inhibitor enhances the defensive mechanisms against hypoxia. Bardoxolone methyl protects against oxidative stress, and can even reverse impaired renal function; a phase 2 trial with considerable attention to heart complications is currently ongoing in Japan. PMID- 28097827 TI - Anxiety symptoms and functioning in patients with type 2 diabetes. PMID- 28097826 TI - Development Shapes a Consistent Inbreeding Effect in Mouse Crania of Different Line Crosses. AB - Development translates genetic variation into a multivariate pattern of phenotypic variation, distributing it among traits in a nonuniform manner. As developmental processes are largely shared within species, this suggests that heritable phenotypic variation will be patterned similarly, in spite of the different segregating alleles. To investigate developmental effect on the variational pattern in the shape of the mouse skull across genetically differentiated lines, we employed the full set of reciprocal crosses (a.k.a. diallel) between eight inbred mouse strains of the Collaborative Cross Project. We used geometric morphometrics and multivariate analysis to capture cranial size and shape changes in 8 parentals and their 54 F1 crosses. The high heterozygosity generated in the F1 crosses allowed us to compare the multivariate deviations of the F1 phenotypes from the expected midparental phenotypes in different haplotype combinations. In contrast to body weight, we found a high degree of nonadditive deviation in craniofacial shape. Whereas the phenotypic and genetic divergence of parental strains manifested in high dimensionality of additive effects, the nonadditive deviations exhibited lesser dimensionality and in particular a strikingly coherent direction in shape space. We interpret this finding as evidence for a strong structuring effect of a relatively small set of developmental processes on the mapping of genetic to phenotypic variation. PMID- 28097825 TI - Signalling pathways involved in hypoxia-induced renal fibrosis. AB - Renal fibrosis is the common pathological hallmark of progressive chronic kidney disease (CKD) with diverse aetiologies. Recent researches have highlighted the critical role of hypoxia during the development of renal fibrosis as a final common pathway in end-stage kidney disease (ESKD), which joints the scientist's attention recently to exploit the molecular mechanism underlying hypoxia-induced renal fibrogenesis. The scaring formation is a multilayered cellular response and involves the regulation of multiple hypoxia-inducible signalling pathways and complex interactive networks. Therefore, this review will focus on the signalling pathways involved in hypoxia-induced pathogenesis of interstitial fibrosis, including pathways mediated by HIF, TGF-beta, Notch, PKC/ERK, PI3K/Akt, NF kappaB, Ang II/ROS and microRNAs. Roles of molecules such as IL-6, IL-18, KIM-1 and ADO are also reviewed. A comprehensive understanding of the roles that these hypoxia-responsive signalling pathways and molecules play in the context of renal fibrosis will provide a foundation towards revealing the underlying mechanisms of progression of CKD and identifying novel therapeutic targets. In the future, promising new effective therapy against hypoxic effects may be successfully translated into the clinic to alleviate renal fibrosis and inhibit the progression of CKD. PMID- 28097828 TI - Pollen has a microbiome: implications for plant reproduction, insect pollination and human allergies. PMID- 28097829 TI - Barriers to conducting research: A survey of trainees in emergency medicine. AB - OBJECTIVE: Research underpins evidence-based practice, but there are significant barriers to conducting research relevant to each clinical discipline. Understanding these barriers could allow strategies to reduce their impact. The present study was undertaken to understand specific barriers to research for emergency medicine (EM) trainees. METHODS: EM trainees attending research short courses were surveyed. Free-text responses were classified into themes and a list of pre-specified potential barriers was used for ranking purposes. RESULTS: The responders (n = 61/90; 67.8%) were young, mostly male with low confidence in leading a research project and limited previous research experience. There were 155 unique barriers identified from 55 respondents, which fitted into nine categories. The most frequently perceived barrier was time (29%), followed by skills (22.6%) and cultural factors (19.4%). Most trainees (n = 54/56, 96.4%) believed that the barriers could be overcome. Strategies suggested included protection of time, mentoring and education, as well as top-down improved research culture. CONCLUSIONS: Barriers to research in EM are similar to other specialities and were perceived to be manageable. Reorganisation and refocus of the Australasian College for Emergency Medicine training curriculum may be an option to foster an environment to promote research. PMID- 28097830 TI - Plant phosphatidylinositol-specific phospholipase C at the center of plant innate immunity. AB - Understanding plant resistance to pathogenic microbes requires detailed information on the molecular mechanisms controlling the execution of plant innate immune responses. A growing body of evidence places phosphoinositide-specific phospholipase C (PI-PLC) enzymes immediately downstream of activated immune receptors, well upstream of the initiation of early defense responses. An increase of the cytoplasmic levels of free Ca2+ , lowering of the intercellular pH and the oxidative burst are a few examples of such responses and these are regulated by PI-PLCs. Consequently, PI-PLC activation represents an early primary signaling switch between elicitation and response involving the controlled hydrolysis of essential signaling phospholipids, thereby simultaneously generating lipid and non-lipid second messenger molecules required for a swift cellular defense response. Here, we elaborate on the signals generated by PI-PLCs and their respective downstream effects, while providing an inventory of different types of evidence describing the involvement of PI-PLCs in various aspects of plant immunity. We project the discussed information into a model describing the cellular events occurring after the activation of plant immune receptors. With this review we aim to provide new insights supporting future research on plant PI-PLCs and the development of plants with improved resistance. PMID- 28097831 TI - Arthrorheumatism with methotrexate-associated lymphoproliferative disorder in the brain. PMID- 28097832 TI - Registration and timely dissemination of clinical trials and results. PMID- 28097833 TI - Art as an instrument to understand the concept of death. PMID- 28097834 TI - High blood pressure in school children and adolescents in Argentina over the past 25 years: A systematic review of observational studies. AB - INTRODUCTION: Over the past years, hypertension has been recognized as an important health problem in the pediatric population. A systematic review of observational studies published between 1988 and 2014 was conducted to estimate the prevalence of high blood pressure and cardiovascular risk factors among children and adolescents in Argentina. POPULATION AND METHODS: A bibliographic search was done in MEDLINE, SciELO, and LILACS to look for studies on high blood pressure prevalence in school children and adolescents in Argentina. Studies and surveys that had included the measurement of blood pressure in children and adolescents (aged 5-20 years) according to the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents by the American Academy of Pediatrics were included in this study. RESULTS: Fourteen publications were identified. The pooled prevalence in 11 706 subjects (random effects model) was 6.61% (95% confidence interval [CI]: 4.30-9.37). The crude prevalence was 7.35% (95% CI: 6.88-7.83). High blood pressure was more prevalent among adolescents than children <= 10 years old (7.4% versus 4.3%, P = 0.001), and among boys than girls (11.2% versus 6.8%, P = 0.001). The most common risk factors included a sedentary lifestyle (50%), overweight (15.4%), abdominal obesity (13.7%), obesity (11.5%), and smoking (6.5%). CONCLUSIONS: Our data show that the prevalence of high blood pressure and cardiovascular risk factors in school children and adolescents is high, and this accounts for a very important public health problem in Argentina. PMID- 28097835 TI - Cognitive profiles of patients with early detected and treated congenital hypothyroidism. AB - INTRODUCTION: Children with congenital hypothyroidism (CH) detected by newborn screening and adequately treated may have mild cognitive deficits. OBJECTIVES">To assess the intelligence quotient of children with CH and identify the presence of specific cognitive deficits. POPULATION AND METHODS: A group of 60 children with CH detected by newborn screening, who were aged 9-10 years old and received adequate treatment since their first month of life was selected and compared to a control group of 60 children without CH in the same age range. Inclusion criteria: children without concurrent diseases, who were attending school in a single shift, and whose parents had at least completed secondary education. The following tests were administered during individual interviews: the Wechsler Intelligence Scale for Children (third edition), the Rey complex figure test, the Woodcock-Munoz revised test, the Conners Continuous Performance Test II, the Illinois Test of Psycholinguistic Abilities, the verbal fluency test, the Knox Cube Test, the Trail Making Test, the faces test, and the 5 digit test. The statistical analysis was done using Student's t tests (for independent samples) with Bonferroni's correction (p < 0.002). RESULTS: Even within the normal average range, significant differences were observed between both groups in terms of total intelligence quotient and performance intelligence quotient (small and moderate effect sizes, respectively). In terms of performance, children with hypothyroidism had a significantly poorer performance in processing speed, reaction times, attention, cognitive flexibility, visuoconstruction, and long term memory. No significant differences were found between both groups in the verbal area. CONCLUSIONS: Children with congenital hypothyroidism and without mental disability had mild cognitive deficits, which should be taken into account for a comprehensive patient care. PMID- 28097836 TI - Validation of the Argentine Spanish version of Transition Readiness Assessment Questionnaire for adolescents with chronic conditions. AB - INTRODUCTION: The transition of adolescents with chronic conditions to adult follow-up care is an increasingly complex process. Patients need to acquire knowledge and skills that ensure continuity of their care. The goal of this study was to validate the Argentinian Spanish version of the Transition Readiness Assessment Questionnaire (TRAQ) 5.0 tool in adolescents and young adults with chronic conditions. POPULATION AND METHODS: Descriptive, crosssectional, quantitative study. Patients with chronic conditions aged 14 years or older treated at Hospital Garrahan were included. The TRAQ is made up of 20 items divided into 5 subscales (Managing Medication, Appointment Keeping, Tracking Health Issues, Talking with Providers, Managing Daily Activities), and is designed to be self-administered. Patients completed the TRAQ, as well as an opinion survey about its use and a self-perceived autonomy scale; their physicians answered a scale about patients' health impairment due to the condition. Sociodemographic, clinical and TRAQ-related variables were recorded. RESULTS: A total of 191 patients participated. The majority of patients (96.3%) understood the TRAQ 5.0 questionnaire and completed it correctly, in self administered modality, in a short time (median: 5 minutes), with little or no help (81%). Patients who live in poverty or have a lower education level than the one expected for their age needed more help. Internal consistency (Cronbach's alpha) for the overall score was 0.81. Construct validity was demonstrated by testing different hypotheses (all p < 0.05): discrimination by age >= 16 years (3.01 vs. 3.34), sex (women: 3.38 > men: 3.12) and having plans for the future (without plans: 3.01 < with plans: 3.34); correlation with self-perception scale (r= 0.49). CONCLUSION: The TRAQ 5.0 tool is available for use in Argentinian adolescents with chronic conditions. PMID- 28097837 TI - Food and beverage advertising on children's TV channels in Argentina: Frequency, duration, and nutritional quality. AB - : Food and beverage marketing has been identified as one of the determinants of unhealthy food and beverage consumption in the child population. OBJECTIVE: To determine the frequency and duration of food and beverage advertising in children's programming and the nutritional quality of advertised food and beverages. METHODS: Descriptive, cross-sectional study. Children's cable and broadcast channel programming was recorded in two periods: over the week and on the weekend. The type, quantity, and duration of commercials were recorded. The nutritional quality of advertised food and beverages was analyzed. RESULTS: A total of 402.3 hours of children's programming were recorded. In total, 3711 commercials were identified. Among these, 20.9% corresponded to food and beverages, i.e., an average of 1.9 +/- 1.0 commercials per hour or equivalent to 0.68 +/- 0.36 min/hour. Dairy products, candies, and fast-food meals were the most advertised food products. Only a third of advertised food and beverages (35.8%) were categorized as healthy as per the nutrient profiling system. Based on the traffic light labeling system, 50% of advertised food and beverages were high in sugar, 25% were high in saturated fat, and approximately 15% were high in sodium or fat. CONCLUSION: Food and beverage advertising accounted for 20% of television advertising time. The most advertised products were dairy products, followed by candies and sweet snacks, fast-food meals, and beverages. Two-thirds of advertised food and beverages were considered unhealthy. PMID- 28097838 TI - Bullying at school: Agreement between caregivers' and children's perception. AB - INTRODUCTION: Bullying at school is usually kept secret from adults, making them unaware of the situation. OBJECTIVE: To describe caregivers' and children's perception and assess their agreement in terms of bullying situations. METHODS: Cross-sectional study in children aged 8-12 years old attending public schools and their caregivers. The questionnaire on preconceptions of intimidation and bullying among peers (PRECONCIMEI) (child/caregiver version) was used. Studied outcome measures: Scale of bullying, causes of bullying, child involvement in bullying, communication in bullying situations. Univariate and bivariate analyses were done and agreement was estimated using the Kappa index. RESULTS: A total of 529 child/caregiver dyads participated. Among caregivers, 35% stated that bullying occurred in their children's schools. Among children, 133 (25%) admitted to being involved: 70 (13%) were victims of bullying, 40 (8%) were bullies, and 23 (4%) were bullied and perpetrated bullying. Among the 63 caregivers of children who admitted to be bullies, 78% did not consider their children capable of perpetrating bullying. Among children who were bullied or who both suffered bullying and bullied others, 69.9% (65/93) indicated that "if they were the victims of bullying, they would tell their family." However, 89.2% (83/93) of caregivers considered that their children would tell them if they were ever involved in these situations. Agreement was observed in terms of a positive communication (Kappa = -0.04) between 62.6% (57/91) of the child/caregiver dyads school bullying. CONCLUSIONS: Disagreement was observed between children and their caregivers in relation to the frequency and communication of bullying situations. Few caregivers whose children admitted to being involved in these situations believed it was a possibility. PMID- 28097839 TI - Nutritional assessment of a population with a history of childhood craniopharyngioma seen at Hospital "Prof. Dr. Juan P. Garrahan". AB - INTRODUCTION: Craniopharyngiomas are histologically benign malformations located between the pituitary and hypothalamus that may affect key hormone secretion for endocrine regulation and satiety modulation. Although this is a relatively benign disease, the combination of severe hypothalamic obesity and associated comorbidities results in a reduced quality of life. OBJECTIVE: To assess the nutritional status of patients after craniopharyngioma surgery. POPULATION AND METHODS: Patients younger than 21 years old at the time of the study who required craniopharyngioma surgery at Hospital de Pediatr.a Garrahan and who signed an informed consent. Anthropometric characteristics, body composition by impedance analysis, energy expenditure by indirect calorimetry and energy intake were assessed. Insulin resistance and dyslipemia were estimated. RESULTS: A total of 39 patients were included; 41% had a normal weight and 59% were obese. Overall, 68% of patients had a central fat distribution; 40% had insulin resistance; and 32%, dyslipemia. No significant differences were observed in terms of insulin resistance, dyslipemia, energy expenditure at rest, or energy intake between normal weight and obese patients. Among obese patients, 77% had a low energy expenditure, regardless of their percentage of lean body mass (62 A} 2.7% versus 61.2 A} 1.8% of normal versus low energy expenditure at rest; p = 0.8). CONCLUSIONS: A total of 59% of the studied population was obese. No significant differences were observed in terms of metabolic complications between normal weight and obese patients. A lower energy expenditure was observed, regardless of the lean body mass percentage and a similar energy intake. PMID- 28097840 TI - Assessment of lipid profile and some risk factors of atherosclerosis in children whose parents had early onset coronary artery disease. AB - BACKGROUND/AIM: The objective of our study was to analyze the lipid profile and some risk factors of atherosclerosis such as oxidized-low density lipoprotein (ox LDL), small dense LDL (sd LDL) in the offspring of patients with premature coronary heart disease (CHD). POPULATION AND METHODS: Children whose parents had early onset CHD were matched with age and sex pairs. Study and controls were analyzed for lipid levels, apolipoproteins (Apo- A,B,E), ox-LDL, sd LDL and lipoprotein (a) [Lp(a)]. The data were evaluated with SPSS using "Student t and Mann-Whitney U" tests. RESULTS: The study group children (n: 43) had higher LDL, Lp(a) and ox-LDL levels, ratios of TC/HDL, Apo-B/A, LDL/HDL and ox-LDL/HDL (p<0.05) than control group. CONCLUSION: These findings suggest that dyslipidemia and increased LDL, Lp(a) and ox-LDL levels are common in the offspring of patients with early onset CHD and account largely for their familial predisposition for CHD. PMID- 28097841 TI - Oxygen saturation, periodic breathing, and sleep apnea in infants aged 1-4 months old living at 3200 meters above sea level. AB - OBJECTIVES: To describe, in infants aged 1-4 months old living at 3200 meters above sea level (MASL), oxygen saturation (SpO2), sleep apnea indices, and periodic breathing (PB) during sleep. Polysomnographies were done in 18 healthy infants. RESULTS: The median SpO2 was 87%, and the median PB was 7.2% for the total sleep time. The median central sleep apnea index was 30.5/hour, which decreased to 5.4/hour once sleep apneas associated with PB were excluded. The 5th percentile for SpO2 was 76% among awake infants, and 66% among asleep infants. CONCLUSIONS: The SpO2 was lower than that observed at sea level, whereas PB and the central sleep apnea index were higher, once sleep apneas associated with PB were excluded. The latter was similar to that observed at sea level. At 3200 MASL, different cut-off points are required for a normal SpO2, one for infants during the waking state and one for infants during sleep. PMID- 28097842 TI - In-hospital capacity-building in research and management for pediatric professionals. AB - We describe an educational strategy aimed at capacity-building of hospital health care professionals in research and management initiated at a pediatric hospital in 2006, and the results obtained eight years after its implementation. Research and Management in Pediatrics (GIP) is an annual 250-hour course combining meetings and off-site assignments delivered through the Hospital's on-line campus. It provides students with practical tools for research (epidemiology, methodology, bibliographic search, evidencebased medicine, biostatistics) and management (strategic planning, management programs, health services research, quality improvement, health economics). Assessment methods included integrative exercises, a final evaluation, and a group research or management project. Results obtained over the 2006-2013 period were highly satisfactory. An intensive training program on research and management is a useful strategy for in-hospital capacity-building of pediatric health care professionals in basic tools for research activities, critical reading of biomedical literature and rational management of pediatric health services. PMID- 28097843 TI - Colonization and infection in the newborn infant: Does chlorhexidine play a role in infection prevention? AB - Healthcare-associated infections are a major problem in newborn infants, considering their high morbidity, mortality, and long-term sequelae. In preterm infants, it has been shown that skin and gastrointestinal tract colonization undergoes variations compared to healthy term infants, and that preterm infants are more exposed to nosocomial microorganisms given their higher probability of being admitted to the neonatal intensive care unit where they are cared for. This document reviews normal colonization, the changes observed during hospitalization, prematurity, and the potential role of chlorhexidine in the prevention of resistant microorganism transmission, as well as its side effects in newborn infants admitted to the neonatal intensive care unit. PMID- 28097844 TI - [Angel-shaped phalango-epiphyseal dysplasia: case report]. AB - We describe a rare and sporadic condition, characterized by swan neck deformity in hands, hip osteoarthritis in adulthood and malformations of the middle phalanges with an angel shape. The patient is a 4 year old boy who suffered hand trauma and on x-ray examination he was diagnosed with angel-shaped phalango epiphyseal dysplasia. Based on this diagnosis, his mother, who suffered from constant pain in her hips and lower limbs, was diagnosed with this syndrome as well. PMID- 28097845 TI - [Fatal case of rickettsiosis in a toddler from southeastern Mexico]. AB - Rocky Mountain spotted fever is a disease caused by Rickettsia rickettsii, a bacteria transmitted by infected ticks. It is characterized by fever, exanthema, arthralgias and myalgias; but sometimes its clinical presentation is non specific. Due to its similarities with other exanthematic diseases like dengue or chikungunya, Rocky Mountain spotted fever is not a first line diagnosis, even though countries like Mexico show the ecologic and socioeconomic characteristics that favor its transmission, with a 30% mortality rate among pediatric patients. This mortality rate has been associated to a delayed diagnosis and therapy, due to a poor knowledge among physicians regarding this disease; this favors the occurrence of atypical and fulminant cases. The objective of this work is to describe a fulminant case of Rocky Mountain spotted fever, expecting that this disease could be later considered among the differential diagnosis which could directly impact its mortality rate. PMID- 28097846 TI - [Solitary and congenital juvenile xanthogranuloma: case report]. AB - Juvenile xanthogranuloma is a bening pathology and it represents the most common form of non-Langerhans cell histiocytosis. It is characterized by the presence of papules or firm nodules of a pinkish or yellow-brownish nature, which mainly compromise the skin and, exceptionally, other organs. It is a self-limited entity having a spontaneous regression during the first five years of life. We report the case of a one-month-old patient who presented a congenital tumor in the abdomen, whose histopathology showed the presence of multinucleated giant Touton cells, which are typical of this pathology. We emphasize the rare occurrence of this type of lesion and the importance of the multiple differential diagnosis to be taken into account due to the age of the patient and the characteristics of the lesion. PMID- 28097847 TI - [Nicolau syndrome induced by intramuscular injection of a hexavalent vaccine in a 6-month-old girl]. AB - Nicolau syndrome, also known as embolia cutis medicamentosa or livedo-like dermatitis, is a sudden tissue necrosis, a rare complication of intramuscular injection of some drugs. We report a case of a 6-month-old girl who received intramuscularly the third dose of hexavalent vaccine (DTaP- HVB-IPV/HIb), and immediately presented a livedoid lesion around the injection site, progressing to necrosis. We reinforce the importance of early diagnosis to perform a suitable treatment and clinical follow-up to avoid ischemic secondary complications. PMID- 28097848 TI - [Congenital pulmonary capillary hemangiomatosis in a newborn]. AB - Pulmonary capillary hemangiomatosis is a rare entity characterized by the proliferation of capillaries into alveolar walls, interlobular septa, pleura and pulmonary interstitium, without malignant characteristics, with almost constant association with pulmonary hypertension. Until now two cases of congenital presentation have been reported in the literature. This is the third case in a newborn; he has not followed the usual pattern associated with pulmonary hypertension as occurs in most patients with this pathology; the highest incidence is among 20-40 years old. We report a preterm newborn patient of 36 weeks of gestation with progressive respiratory distress requiring mechanical ventilation by constant desaturation during his clinical evolution without clinical, radiological or ultrasonographic signs of pulmonary hypertension. PMID- 28097849 TI - [Case report: intestinal perforation by foreign body]. AB - Accidental ingestion of foreign bodies in childhood is a common event that rarely requires interventional management and presents very few complications involving surgical treatment. We present a clinical case of a 10 month old infant, without abdominal manifestations, in whom it was incidentally found a foreign radiopaque body of 7 cm in length in the abdomen, compatible with a screw. It was not possible to extract it by endoscopy. Therefore, it was necessary to perform surgery and a perforation of the second and third portion of the duodenum was encountered. PMID- 28097850 TI - [A regenerative anemia in infants: 2 cases of Pearson's syndrome]. AB - Anemia is very common in infants. Although its causes are usually not severe and treatable, proper etiologic diagnosis should be established. When anemia is non regenerative, it can be caused by aplastic anemia, myelodysplastic syndrome, bone marrow infiltration or hematopoietic factors deficiencies. Another possible cause is Pearson's syndrome, a rare mitochondrial disease that causes non-regenerative anemia associated with other cytopenias, pancreatic insufficiency, lactic acidosis and great variability in clinical presentation conditioned by heteroplasmy. It is characteristic to find in bone marrow studies variable vacuolization in erythroblastic progenitors and ring sideroblasts. The diagnosis is established by genetic study of mitochondrial deoxyribonucleic acid performed by Southern blot analysis (complete mitochondrial deoxyribonucleic acid amplification by polymerase chain reaction -long), obtaining 70-80% deletion of 4977 bp (NMD 8343-13459). There is no curative therapy and support treatment is the only available nowadays. Death is frequent in early years of life. PMID- 28097851 TI - [Bednar's aphthae in newborn]. AB - The description of the Bednar's ulcer is uncommon in the current literature. It has been associated with the traumatic effect of the bottle's nipple and/or no orthodontic soothers while breastfeeding. We present a newborn of 20 days of life attended at the emergency room for irritability, with the only finding on physical examination of two oral ulcers. We describe the clinical presentation, evolution and treatment. The normality of the diagnostic test, clinical characteristics and evolution lead to the diagnosis of Bednar's ulcer. PMID- 28097852 TI - Laryngotracheal edema due to thermal injury: A complication after thyroidectomy in children. AB - Postoperative respiratory insufficiency is a serious complication of total thyroidectomies which can be multifactorial, especially in children. We report two siblings who had undergone thyroidectomy with subsequent respiratory distress. Electrothermal bipolar and harmonic scalpel were used during thyroid dissections. Both patients had early postoperative respiratory problems. The older one suffered from mild respiratory distress for 24 hours and then he spontaneously recovered. The younger one was extubated but then she had serious stridor accompanied with abdominal and intercostal retractions. She was re intubated and admitted to ICU for mechanical ventilatory support, where she stayed for 14 days due to multiple failed extubation attempts. The symptoms were more severe in the younger child probably due to softer tracheal wall and weaker tracheal cartilages. We should keep in mind the probable postoperative respiratory complications due to thermal injury or inappropriate surgical technique after thyroid surgeries. PMID- 28097853 TI - [Clinical and molecular study in a family with autosomal dominant hypohidrotic ectodermal dysplasia]. AB - Hypohidrotic ectodermal dysplasia (HED) is a rare disease characterized by deficiency in development of structure derived from the ectoderm and is caused by mutations in the genes EDA, EDAR, or EDARADD. Phenotypes caused by mutations in these three may exhibit similar clinical features, explained by a common signaling pathway. Mutations in EDA gene cause X linked HED, which is the most common form. Mutations in EDAR and EDARADD genes cause autosomal dominant and recessive form of HED. The most striking clinical findings in HED are hypodontia, hypotrichosis and hypohidrosis that can lead to episodes of hyperthermia. We report on clinical findings in a child with HED with autosomal dominant inheritance pattern with a heterozygous mutation c.1072C>T (p.Arg358X) in the EDAR gene. A review of the literature with regard to other cases presenting the same mutation has been carried out and discussed. PMID- 28097854 TI - [Citrullinemia type I with recurrent liver failure in a child]. AB - Citrullinemia type I is an autosomal recessive disorder caused by mutation of the gene expressing ASS1 argininosuccinate synthetase, limiting enzyme of the urea cycle. The classic variants are associated with neonatal/infantile forms that cause hyperammonemia leading to death if treatment is not established. Initial symptoms of disorders of the urea cycle include neurological impairment with mild or moderate liver damage. We report a case of recurrent liver failure in an infant diagnosed with type I citrullinemia without severe neurological involvement that was referred to our center for liver transplantation. Acute liver failure can be caused by a wide range of disorders in which inborn errors of metabolism are included. Appropriate treatment of disorders of the urea cycle and in particular citrullinemia I can avoid the need for a transplant. PMID- 28097855 TI - [Prolapsed ureterocele: a diagnosis to be considered for a vulvar mass in an infant: case report]. AB - Ureterocele is a relatively common malformation of the urinary system in children; however, the ureterocele prolapse through the urethra is an extremely rare presentation. Urological nuclear magnetic resonance is the test of choice for definitive diagnosis. Initial treatment of a prolapsed ureterocele involves decompression of the mass. We report the case of a 7-month-old infant with duplication of the collecting system and right ectopic ureterocele appearing as a vulvar mass. PMID- 28097856 TI - [Transition experience of patients with neuromuscular disease]. AB - Neuromuscular diseases are mostly genetic disorders, with chronic and progressive course. Affected people are at high risk of developing physical and emotional disabilities. In the last decades, the advance in technology and science has increased chronic pediatric patients survival rate, thus requiring an ongoing assistance in adult hospitals, making the transition a necessity and a challenge. This article reports the clinical practice designed between Hospital Garrahan and Hospital Ramos Mejia for the transition of 27 adolescents during 2015, setting achievements, findings and challenges resulting from this experience. PMID- 28097857 TI - [Massive poisoning with carbon monoxide: an update from a case]. AB - Carbon monoxide is known as the "silent murderer" because it is a colorless and odorless gas. According to these characteristics, toxicity goes unnoticed which makes the diagnosis difficult. In most cases, the cold periods and group poisoning make suspect its presence because inappropriate heat both in home or public environments. Our goal is to inform about a mass carbon monoxide poisoning in a children's parties room using a combustion source installed, not for the purpose of heating, but as a supply of light (generator), emphasizing that it can occur in any time of the year. PMID- 28097858 TI - [The current status of patient safety in Argentina: Cross sectional study]. AB - BACKGROUND: Patient safety is a priority for healthcare organizations. For the PRONAP's 2013 final exam, the Quality & Patient Safety Subcommittee and the PRONAP managers designed a survey to be answered by pediatrician students nationwide. It was destined to evaluate attitudes, practices and safety conditions in which they worked. AIM: To assess the current state of practices in patient safety. MATERIAL AND METHODS: Setting and sample: PRONAP students (7,438 pediatrician nationwide) who answered 2013 final exam. Instrument: Patient Safety Survey about pediatric inpatient (9 domains) and outpatient (5 domains) practices, and population data. RESULTS: Patient Safety Survey: 6424 answered (86%). Population: age: 42% 30-40 years. Women: 80%. Residence in Pediatrics: 83%. Patient safety training: 30%. geographical origin: all provinces and CABA. Inpatient practices: 15% answered their institution had Patient Safety Committee. 74% of institutions did not have event reporting systems, 70% didn't have a patient's identification system. 32% answered that drug prescription should be done upon vademecum at their institution, and 27% had infection's control programs, 28% performed surgical checklist in operating room and 55% had a standardized patient hand-off. Outpatient practices: 62% said they had washbasins, 56% had soap available, and 63% alcohol gel. 70% answered children with a supposed infectious rash did not wait his turn separately. CONCLUSION: This study shows that most pediatricians in Argentine work without prioritizing patient safety, both in ambulatory and inpatient practice. PMID- 28097859 TI - [Proposal to update the anthropometric evaluation of the newborn]. PMID- 28097860 TI - Emergency Endoscopic Consensus 2016. Executive summary PMID- 28097861 TI - Light-Driven Au-WO3@C Janus Micromotors for Rapid Photodegradation of Dye Pollutants. AB - A novel light-driven Au-WO3@C Janus micromotor based on colloidal carbon WO3 nanoparticle composite spheres (WO3@C) prepared by one-step hydrothermal treatment is described. The Janus micromotors can move in aqueous media at a speed of 16 MUm/s under 40 mW/cm2 UV light due to diffusiophoretic effects. The propulsion of such Au-WO3@C Janus micromotors (diameter ~ 1.0 MUm) can be generated by UV light in pure water without any external chemical fuels and readily modulated by light intensity. After depositing a paramagnetic Ni layer between the Au layer and WO3, the motion direction of the micromotor can be precisely controlled by an external magnetic field. Such magnetic micromotors not only facilitate recycling of motors but also promise more possibility of practical applications in the future. Moreover, the Au-WO3@C Janus micromotors show high sensitivity toward extremely low concentrations of sodium-2,6 dichloroindophenol (DCIP) and Rhodamine B (RhB). The moving speed of motors can be significantly accelerated to 26 and 29 MUm/s in 5 * 10-4 wt % DCIP and 5 * 10 7 wt % RhB aqueous solutions, respectively, due to the enhanced diffusiophoretic effect, which results from the rapid photocatalytic degradation of DCIP and RhB by WO3. This photocatalytic acceleration of the Au-WO3@C Janus micromotors confirms the self-diffusiophoretic mechanism and opens an opportunity to tune the motility of the motors. This work also offers the light-driven micromotors a considerable potential for detection and rapid photodegradation of dye pollutants in water. PMID- 28097862 TI - Dynamic Self-Stiffening and Structural Evolutions of Polyacrylonitrile/Carbon Nanotube Nanocomposites. AB - The self-stiffening under external dynamic strain has been observed for some artificial materials, especially for nanocomposites. However, few systematic studies have been carried out on their structural evolutions, and the effect of the types of nanofillers was unclear. In this study, we used a semicrystalline polymer, polyacrylonitrile (PAN), and various types of carbon nanomaterials including C60, carbon nanotube (CNT), and graphene oxide (GO). An external uniaxial dynamic strain at small amplitude of 0.2% was applied on the prepared nanocomposite films. It was observed that PAN/CNT exhibited significant self stiffening behavior, whereas PAN/GO showed no response. Systematic characterizations were performed to determine the structural evolutions of PAN/CNT film during dynamic strain testing, and it was found that the external dynamic strain not only induced the crystallization of PAN chains but also aligned CNT along the strain direction. PMID- 28097863 TI - Mitochondria Targeted Protein-Ruthenium Photosensitizer for Efficient Photodynamic Applications. AB - Organelle-targeted photosensitization represents a promising approach in photodynamic therapy where the design of the active photosensitizer (PS) is very crucial. In this work, we developed a macromolecular PS with multiple copies of mitochondria-targeting groups and ruthenium complexes that displays highest phototoxicity toward several cancerous cell lines. In particular, enhanced anticancer activity was demonstrated in acute myeloid leukemia cell lines, where significant impairment of proliferation and clonogenicity occurs. Finally, attractive two-photon absorbing properties further underlined the great significance of this PS for mitochondria targeted PDT applications in deep tissue cancer therapy. PMID- 28097864 TI - The Evidence of Giant Surface Flexoelectric Field in (111) Oriented BiFeO3 Thin Film. AB - In this work, the surface structure of a single-domain epitaxial BiFeO3 film with (111) orientation was investigated by in situ grazing incidence X-ray diffraction and X-ray reflectivity. We found that a large strain gradient exists in the surface region (2-3 nm) of the BiFeO3 film. The strain gradient is approximately 107 m-1, which is 2 or 3 orders of magnitude larger than the value inside the film. Moreover, we found that a surface layer with a lower electron density compared with the underlying BiFeO3 layer exists on the surface of BiFeO3 film, and this layer exhibits an irreversible surface structure transition occurs at 500 K, which should be associated with the surface flexoelectric field. We considered that this large strain gradient is originated from the surface depolarization field of ferroelectrics. Our results suggest a coupling between the surface structure and the flexoelectricity and imply that the surface layer and properties would be controlled by the strain gradient in ferroelectric films. PMID- 28097865 TI - Molecular Requirements of High-Fidelity Replication-Competent DNA Backbones for Orthogonal Chemical Ligation. AB - The molecular properties of the phosphodiester backbone that made it the evolutionary choice for the enzymatic replication of genetic information are not well understood. To address this, and to develop new chemical ligation strategies for assembly of biocompatible modified DNA, we have synthesized oligonucleotides containing several structurally and electronically varied artificial linkages. This has yielded a new highly promising ligation method based on amide backbone formation that is chemically orthogonal to CuAAC "click" ligation. A study of kinetics and fidelity of replication through these artificial linkages by primer extension, PCR, and deep sequencing reveals that a subtle interplay between backbone flexibility, steric factors, and ability to hydrogen bond to the polymerase modulates rapid and accurate information decoding. Even minor phosphorothioate modifications can impair the copying process, yet some radical triazole and amide DNA backbones perform surprisingly well, indicating that the phosphate group is not essential. These findings have implications in the field of synthetic biology. PMID- 28097866 TI - Pharmacokinetics and Biodistribution of the Illegal Food Colorant Rhodamine B in Rats. AB - The International Agency for Research on Cancer (IARC) demonstrated rhodamine B as a potential carcinogen in 1978. Nevertheless, rhodamine B has been illegally used as a colorant in food in many countries. Few pharmacokinetic and toxicological investigations have been performed since the first pharmacokinetic study on rhodamine B in 1961. The aims of this study were to develop a simple and sensitive high-performance liquid chromatography method with fluorescence detection for the quantitative detection of rhodamine B in the plasma and organs of rats and to estimate its pharmacokinetics and biodistribution. The results demonstrated that the oral bioavailabilities of rhodamine B were 28.3 and 9.8% for the low-dose and high-dose exposures, respectively. Furthermore, rhodamine B was highly accumulated in the liver and, to a lesser extent, the kidney, but was undetectable in the brain. These results provide useful information for improving the pharmacokinetics and biodistribution of rhodamine B, supporting additional food safety evaluations. PMID- 28097867 TI - Selective Aza Diels-Alder and Domino [4+2]/[2+2] Cycloaddition Reactions of Arynes with N-Sulfonyl Ketimines. AB - Transition-metal-free inverse electron-demand aza Diels-Alder and domino [4+2]/[2+2] cycloaddition reaction of arynes and N-sulfonyl ketimines has been demonstrated. This novel, mild, and efficient protocol allows rapid access to isothiazole dioxide-fused dihydroquinoline or dihydrocyclobutaquinoline derivatives selectively by simply varying the equivalents of aryne precursors. The application of this method has been amply illustrated in the synthesis of 2,4 diarylquinolines. PMID- 28097868 TI - Development of Phenothiazine-Based Theranostic Compounds That Act Both as Inhibitors of beta-Amyloid Aggregation and as Imaging Probes for Amyloid Plaques in Alzheimer's Disease. AB - Early detection of Alzheimer's disease (AD) is imperative in enabling the understanding and clinical treatment of this disorder, as well as in preventing its progression. Imaging agents specifically targeting Abeta plaques in the brain and the retina may lead to the early diagnosis of AD. Among them, near-infrared fluorescent (NIRF) imaging has emerged as an attractive tool to noninvasively identify and monitor diseases during the preclinical and early stages. In the present study, we report the design, synthesis, and evaluation of a series of new near-infrared fluorescent probes. Most of these probes displayed maximum emission in PBS (>650 nm), which falls in the good range for NIRF probes. Among them, 4a1 showed the highest affinity toward Abeta aggregates (Kd = 7.5 nM) and an excellent targeting ability for Abeta plaques in slices of brain and retina tissue from double transgenic mice. These compounds are also found to effectively prevent Abeta fibril formation and disaggregate preformed Abeta fibrils, showing a promising potential as theranostic agents for the diagnosis and therapy of AD. PMID- 28097869 TI - Solvent-Free Processable and Photo-Patternable Hybrid Gate Dielectric for Flexible Top-Gate Organic Field-Effect Transistors. AB - We report a novel solvent-free and direct photopatternable poly[(mercaptopropyl)methyl-siloxane] (PMMS) hybrid dielectric for flexible top gate organic field-effect transistors (OFETs) utilizing a photoactivated thiol ene reaction under UV irradiation of 254 nm to induce cross-linking, even in air and at low temperatures. In particular, a solvent-free PMMS-f dielectric film, for which an optimal cross-linking density is shown by a well-organized molar ratio between thiol and vinyl in the thiol-ene reaction, exhibited a high dielectric constant (5.4 @ 100 Hz) and a low leakage current (<1 nA mm-2 @ 2 MV cm-1). The excellent dielectric characteristics of the solvent-free PMMS-hybrid dielectrics, along with their other unique characteristics of a direct photopatternability for which UV-nanoimprint lithography is used and a high surface energy of 45.6 mJ m-2, allowed the successful application of the dielectrics to flexible solvent-free top-gate OFETs with a high reliability against the radius of curvature (9.5, 7.0, and 5.5 mm) and repetitive bending cycles at the radius of curvature of 5.5 mm. This will eventually enable the proposed dielectric design to be used in a variety of applications such as flexible displays and soft organic sensors including chemical and tactile capability. PMID- 28097870 TI - Bicomponent Supramolecular Architectures at the Vacuum-Solid Interface. AB - This review aims at giving the readers the basic concepts needed to understand two-dimensional bimolecular organizations at the vacuum-solid interface. The first part describes and analyzes molecules-molecules and molecules-substrates interactions. The current limitations and needs in the understanding of these forces are also detailed. Then, a critical analysis of the past and recent advances in the field is presented by discussing most of the key papers describing bicomponents self-assembly on solid surface in an ultrahigh vacuum environment. These sections are organized by considering decreasing molecule molecule interaction strengths (i.e. starting from strong directional multiple H bonds up to weaker nondirectional bonds taking into account the increasing fundamental role played by the surface). Finally, we conclude with some research directions (predicting self-assembly, multi-components systems, and nonmetallic surfaces) and potential applications (porous networks and organic surfaces). PMID- 28097871 TI - Redox-Responsive Self-Assembly Micelles from Poly(N-acryloylmorpholine-block-2 acryloyloxyethyl ferrocenecarboxylate) Amphiphilic Block Copolymers as Drug Release Carriers. AB - Novel well-defined redox-responsive ferrocene-containing amphiphilic block copolymers (PACMO-b-PAEFC) were synthesized by ATRP, with poly(N acryloylmorpholine) (PACMO) as hydrophilic blocks and poly(2-acryloyloxyethyl ferrocenecarboxylate) (PAEFC) as hydrophobic blocks. The copolymers were characterized by FT-IR and 1H NMR spectroscopies and gel permeation chromatography, and the crystalline behavior was determined by X-ray diffraction and small-angle X-ray scattering. The results showed that the size of the lamellar crystals and crystallinity vary with the systematic compositions while the periodic structure of the lamellar stacks has no obvious change. These block copolymers could self-assemble and form globular nanoscaled core-shell micellar aggregates in aqueous solution. The reductive ferrocene groups could be changed into hydrophilic ferrocenium via mild oxidation, whereas the polymer micelles at the oxidation state could reversibly recover from their original states upon reduction by vitamin C. The tunable redox response was investigated and verified by transmission electron microscopy, ultraviolet-visible spectroscopy, cyclic voltammetry, and dynamic light scattering measurements. The copolymer micelles were used to entrap anticancer drug paclitaxel (PTX), with high drug encapsulation efficiency of 61.4%, while the PTX-loaded drug formulation exhibited oxidation-controlled drug release, and the release rate could be mediated by the kinds and concentrations of oxidants. MTT assay was performed to disclose the biocompatibility and security of the copolymer micelles and to assess anticancer efficiency of the PTX-loaded nanomicelles. The developed copolymer nanomicelles with reversible redox response are anticipated to have potential in targeted drug delivery systems for cancer therapy. PMID- 28097872 TI - Dual-Responsive Bola-Type Supra-Amphiphile Constructed from Water-Soluble Pillar[5]arene and Naphthalimide-Containing Amphiphile for Intracellular Drug Delivery. AB - Supramolecular construction of multistimuli platform for drug delivery is a challenging task. In this work, a pH and GSH (glutathione) dual-responsive bola type supramolecular amphiphile was successfully fabricated by the complexation between a water-soluble pillar[5]arene (WP5) and a bolaform naphthalimide guest (G) in water. The resulting bola-type amphiphile further self-assembled into supramolecular binary vesicles, which could be disassembled by low pH, a high-GSH concentration environment, or both. Furthermore, the results of drug loading and releasing tests showed that doxorubicin (DOX), the hydrophobic anticancer drug, could be successfully encapsulated into the Stern region of the obtained supramolecular vesicles and generated the DOX-loaded vesicles with good drug loading efficiency. Moreover, the obtained DOX-loaded vesicles displayed efficient and rapid DOX release at a simulated tumor microenvironment with low-pH or excess-GSH conditions or both. Significantly, cytotoxicity experiments revealed that the DOX-loaded supramolecular vesicles could obviously improve the anticancer efficiency of free DOX for tumor cells while remarkably reducing its side effects for normal cells. In vitro cellular uptake and subcellular localization assays further proved that these smart drug nanovehicles, entering cancer cells mainly via endocytosis, could cause excellent drug accumulation in cancer cells. The present study provides a successful example with which to rational design an effective bola-type stimuli-responsive supramolecular nanocarrier, which might have wide potential applications in the construction of various controlled drug-delivery systems. PMID- 28097873 TI - HPLC-fast scanning fluorimetric detection determination of risk exposure to polycyclic aromatics hydrocarbons biomarkers in human urine. AB - AIM: An HPLC method for the determination of 2-hydroxyfluorene (2-OHF), various hydroxyphenanthrene metabolites (1-, 2-, 3-, 4- and 9-hydroxyphenanthrene, OHPhs), 1-hydroxypyrene (1-OHPy) and 3-hydroxybenzo[a]pyrene (3-OHB[a]Py) in human urine, has been developed using fast scanning fluorimetric detection and gradient elution mode. MATERIALS & METHODS: All reagents were of analytical grade. Standard solutions were prepared separately, by exact weighing or dilution with ultrapure acetonitrile, and were stored at 4 oC in darkness. The standard addition method was used for the analysis of urine samples. RESULTS: In the optimized conditions, 2- and 3-hydroxyphenanthrene, and 1- and 9 hydroxyphenanthrene metabolites eluted at the same retention time; however, all other hydroxy-polycyclic aromatic hydrocarbons were well resolved. Multi-emission detection allows us to monitor each metabolite at its most sensitivity emission wavelength. Detection limits ranged between 0.9 and 4.26 ng ml-1. CONCLUSION: Fortified urine samples of nonexposure and nonsmoker volunteers, previous precipitation step with acetonitrile, were used to test the proposed method. The obtained results confirm the goodness of the method. PMID- 28097875 TI - miRNA profiling for the early detection and clinical monitoring of diabetic kidney disease. PMID- 28097874 TI - Through scaffold modification to 3,5-diaryl-4,5-dihydroisoxazoles: new potent and selective inhibitors of monoamine oxidase B. AB - 3,5-Diaryl-4,5-dihydroisoxazoles were synthesized and evaluated as monoamine oxidase (MAO) enzyme inhibitors and iron chelators. All compounds exhibited selective inhibitory activity towards the B isoform of MAO in the nanomolar concentration range. The best performing compound was preliminarily evaluated for its ability to bind iron II and III cations, indicating that neither iron II nor iron III is coordinated. The best compounds racemic mixtures were separated and single enantiomers inhibitory activity evaluated. Furthermore, none of the synthesised compounds exhibited activity towards MAO A. Overall, these data support our hypothesis that 3,5-diaryl-4,5-dihydroisoxazoles are promising scaffolds for the design of neuroprotective agents. PMID- 28097876 TI - The relationship of perfectionism with psychological symptoms in cancer patients and the contributing role of hyperarousability and coping. AB - OBJECTIVE: Significant levels of anxiety, depression and insomnia symptoms are found in cancer patients. Perfectionism, arousability and coping have been associated with these psychological symptoms in the general population but their role among cancer patients remains to be assessed. This study examined the longitudinal relationships between perfectionism and psychological symptoms (anxiety, depression, insomnia), and the intermediate role of the arousability trait and coping strategies. DESIGN: Participants (N = 853) completed the Multidimensional Perfectionism Scale, the Coping with Health Injuries and Problems questionnaire and the Arousal Predisposition Scale at the perioperative period (T1), and the Hospital Anxiety and Depression Scale and the Insomnia Severity Index two months later (T2). RESULTS: Higher levels of perfectionism (T1) were correlated with greater symptoms of anxiety, depression and insomnia (T2). Moderated mediation models indicated that arousability contributed to the association of perfectionism with all symptoms, with stronger associations found in men than in women. Coping was a significant pathway between perfectionism and anxiety, with associations of a comparable magnitude across sexes. CONCLUSION: If these results are replicated by future longitudinal studies, they would suggest that perfectionist cancer patients are at a higher risk of experiencing psychological symptoms, partly through their hyperarousability and the coping strategies they use. PMID- 28097877 TI - The epigenetics of testicular germ cell tumors: looking for novel disease biomarkers. AB - Testicular germ cell tumors (TGCT) are a group of heterogeneous, biologically diverse and clinically challenging neoplasms. Despite the relatively low incidence and mortality rates, a subgroup of patients with disseminated disease relapse after conventional therapy and have a dismal prognosis. Moreover, TGCT afflict mostly young men and have therapeutic peculiarities, with some patients showing resistance to cisplatin-based treatments and others being troubled by irreversible side effects, such as infertility. Most TGCT share a common tumorigenic pathway and are cytogenetically similar, making room for Epigenetics to explain its heterogeneity at pathological and clinical level. In this review, we summarize the foremost epigenetic alterations among TGCT focusing on their clinical potential as diagnostic, prognostic and predictive biomarkers. PMID- 28097878 TI - Focusing on frequent ASXL1 mutations in myeloid neoplasms, and considering rarer ASXL2 and ASXL3 mutations. PMID- 28097879 TI - Metabolomics biomarkers for tuberculosis diagnostics: current status and future objectives. AB - Numerous studies have contributed to our current understanding of the complex biology of pulmonary tuberculosis and subsequently provided solutions to its control or eradication. Metabolomics, a newcomer to the Omics research domain, has significantly contributed to this understanding by identifying biomarkers originating from the disease-associated metabolome adaptations of both the microbe and host. These biomarkers have shed light on previously unknown disease mechanisms, many of which have been implemented toward the development of improved diagnostic strategies. In this review, we will discuss the role that metabolomics has played in tuberculosis research to date, with a specific focus on new biomarker identification, and how these have contributed to improved disease characterization and diagnostics, and their potential clinical applications. PMID- 28097880 TI - Practical applications of matched series analysis: SAR transfer, binding mode suggestion and data point validation. AB - AIM: The assumption in scaffold hopping is that changing the scaffold does not change the binding mode and the same structure-activity relationships (SARs) are seen for substituents decorating each scaffold. Results/methodology: We present the use of matched series analysis, an extension of matched molecular pair analysis, to automate the analysis of a project's data and detect the presence or absence of comparable SAR between chemical series. CONCLUSION: The presence of SAR transfer can confirm the perceived binding mode overlay of different chemotypes or suggest new arrangements between scaffolds that may have gone unnoticed. The absence of series correlation can highlight the presence of inconsistent data points where assay values should be reconfirmed, or provide challenge to any project dogma. PMID- 28097881 TI - Evaluation of hemoglobin A1c measurement from filter paper using high-performance liquid chromatography and immunoturbidimetric assay. AB - Glycated hemoglobin (HbA1c) measurement from whole blood (WB) samples is inconvenient for epidemic surveillance and self-monitoring of glycemic level. We evaluated HbA1c measurement from WB blotted on filter paper (FP), which can be easily transported to central laboratories, with high-performance liquid chromatography (HPLC) and immunoturbidimetric assay (ITA). WB was applied to Whatman filter paper. By using HPLC and WB samples as reference methods, these FP samples were evaluated on HPLC and ITA. Inter- and intra-assay variation, WB vs. FP agreement and sample stability at 20-25 degrees C and -70 degrees C were assessed by statistical analysis. Results showed that the coefficient of variation (CV, %) of FP samples for HPLC and ITA were 0.44-1.02% and 1.47-2.72%, respectively (intra-assay); 2.13-3.56% and 3.21-4.82%, respectively (inter assay). The correlation of WB HPLC with FP analyzed using HPLC and ITA are both significant (p < 0.001). Sample stability showed that FP method up to 5 days at 20-25 degrees C and 5 weeks at -70 degrees C is accurate and reproducible. In conclusion, FP samples analyzed by HPLC and ITA can both provide an alternative to WB for HbA1c measurement, supporting the use of FP method in epidemic surveillance and healthcare units. PMID- 28097882 TI - Antidiabetic agents and cardiovascular outcomes in patients with heart diseases. AB - INTRODUCTION: This article reviews evidence of the benefits and risk of antidiabetic agents in cardiovascular (CV) outcomes, with a focus on medications approved by the FDA since 2008. STUDY SELECTION: Peer-reviewed articles were identified from MEDLINE and Current Content databases (both 1966 to 1 October 2016) using the search terms insulin, metformin, rosiglitazone, pioglitazone, glyburide, glipizide, glimepiride, acarbose, miglitol, albiglutide, exenatide, liraglutide, lixisenatide, dulaglutide, pramlintide, meglitinide, alogliptin, linagliptin, saxagliptin, sitagliptin, canagliflozin, dapagliflozin, empagliflozin, colesevalam, bromocriptine, mortality, myocardial infarction (MI), heart failure (HF), and stroke. Trials were included if they were randomized clinical trials evaluating adult patients (>=18 years) with type 2 diabetes; had a period of intervention and follow-up of >=12 months; and assessed CV outcomes (CV death, fatal/non-fatal MI or HF) as endpoints. Twenty-three randomized trials were included. Antidiabetic agents: Of agents approved prior to 2008, metformin has not been associated with measurable harm in patients with diabetes in terms of mortality and CV events (and has a trend of benefit). Controversial results existed with the use of sulfonylureas and thiazolidinediones (TZDs) for CV outcomes. Among agents approved after 2008, liraglutide and empagliflozin have been shown to be superior to placebo in improving CV outcomes. CONCLUSIONS: The FDA regulatory mandate to demonstrate CV safety in order to approve new diabetes drugs led to an increase in the number of CV outcome trials. However, these trials have placebo-controlled, non-inferiority designs aiming to show absence of CV toxicity. More studies are needed to address other questions, including comparative effectiveness, and longer-term risk versus benefits. PMID- 28097883 TI - Is angiotensin-(3-4) (Val-Tyr), the shortest angiotensin II-derived peptide, opening new vistas on the renin-angiotensin system? AB - Angiotensin-(3-4) (Ang-(3-4) or Val-Tyr) is the shorter angiotensin (Ang) II derived peptide, formed through successive hydrolysis that culminates with the release of Val-Tyr as a dipeptide. It is formed both in plasma and in kidney from Ang II and Ang III, and can be considered a component of the systemic and organ based renin-angiotensin system. It is potently antihypertensive in humans and rats, and its concerted actions on proximal tubule cells culminate in the inhibition of fluid reabsorption, hyperosmotic urinary excretion of Na+. At the renal cell signaling level, Ang-(3-4) counteracts Ang II-type 1 receptor-mediated responses by acting as an allosteric enhancer in Ang II-type 2 receptor populations that target adenosine triphosphate-dependent Ca2+ and Na+ transporters through a cyclic adenosine monophosphate-activated protein kinase pathway. PMID- 28097884 TI - The pretreatment thrombocytosis may predict prognosis of patients with colorectal cancer: a systematic review and meta-analysis. AB - AIM: Recently, several studies have reported that thrombocytosis may be associated with the poor prognosis of colorectal cancer (CRC). Nevertheless, their conclusions were still controversial. Results & methodology: We searched PubMed, Embase, Cochrane Library and Web of Science up to April 2016. A total of 30 studies including 9129 patients were included in this meta-analysis. Thrombocytosis had a close relationship with the poor overall survival of CRC compared with normal platelet counts, with the pooled hazard ratios being 1.89 (95% CI: 1.45-2.47; p < 0.00001) and 1.83 (95% CI: 1.33-2.53; p = 0.0002), with univariate and multivariate analyses, respectively. DISCUSSION & CONCLUSION: This meta-analysis indicated that thrombocytosis may be a cost-effective and noninvasive indicator for poor prognosis of patients with CRC, especially for overall survival. PMID- 28097885 TI - Transformative biomarkers for drug-induced liver injury: are we there yet? PMID- 28097886 TI - Reagent-free LC-MS/MS-based pharmacokinetic quantification of polyhistidine tagged therapeutic proteins. AB - AIM: Immobilized metal ion affinity chromatography is widely employed for purifying polyhistidine-tagged recombinant proteins from cell lysates. The technique can be applied for quantification of therapeutic proteins in biological matrices by LC-MS/MS. RESULTS: A protein reagent-free workflow was developed for quantifying polyhistidine-tagged proteins by LC-MS/MS. The workflow includes target protein enrichment by immobilized metal ion affinity chromatography, on bead trypsin digestion and quantification of signature peptides by LC-MS/MS. It was applied to quantify a 6*His-tagged protein in a mouse pharmacokinetic study with assay sensitivity of 10.0 ng/ml and linearity up to 10,000 ng/ml. CONCLUSION: The protein reagent-free workflow developed herein can overcome reagent limitation and serve as a viable approach for quantifying polyhistidine tagged therapeutic proteins to support discovery pharmacokinetic and pharmacodynamic studies. PMID- 28097887 TI - Pseudokinases: update on their functions and evaluation as new drug targets. AB - The pseudokinase complement of the human kinase superfamily consists of approximately 60 signaling proteins, which lacks one or more of the amino acids typically required to correctly align ATP and metal ions, and phosphorylate protein substrates. Recent studies in the pseudokinase field have begun to expose the biological relevance of pseudokinases, which are now thought to perform a diverse range of physiological roles and are connected to a multitude of human diseases, including cancer. In this review, we discuss how and why members of the 'pseudokinome' represent important new targets for drug discovery, and describe how knowledge of protein structure and function provides informative clues to help guide the rational chemical design or repurposing of inhibitors to target pseudokinases. PMID- 28097888 TI - Bioprocess enhancement of feather degradation using alkaliphilic microbial mixture. AB - 1. The main aim of this work is to develop a robust method to generate a microbial mixture which can successfully degrade poultry feathers to overcome environmental problems. 2. Four different alkaliphilic microbes were isolated and shown to degrade poultry feathers. 3. Two of the isolates were phylogenetically identified as Lysinibacillus and the others were identified as Nocardiopsis and Micrococcus. 4. The best microbial co-culture for white and black feather degradation was optimised for pH, temperature and relative population of the isolates to achieve almost 96% of degradation compared with a maximum of 31% when applying each isolate individually. 5. The maximum activity of keratinase was estimated to be 1.5 U/ml after 3 d for white feathers and 0.6 U/ml after 4 d for black feathers in a basal medium containing feather as the main carbon source. Additionally, non-denaturing polyacrylamide gel electrophoresis showed 4 and 3 protease activity bands for white and black feather, respectively. 6. This study provides a robust method to develop potential new mixtures of microorganisms that are able to degrade both white and black feathers by applying a Central Composite Design. PMID- 28097891 TI - Incidental Hypercalcemia Caused by Primary Hyperparathyroidism with Rapid Progression to Renal Complications in a Child. PMID- 28097889 TI - Titanium cages versus autogenous iliac crest bone grafts in anterior cervical discectomy and fusion treatment of patients with cervical degenerative diseases: a systematic review and meta-analysis. AB - OBJECTIVE: A systematic review and partial meta-analysis is conducted to compare the efficacy and safety of anterior cervical decompression and fusion procedures employing either rectangular titanium cages or iliac crest autografts in patients suffering from cervical degenerative disc diseases. METHODS: Medline, PubMed, CENTRAL, and Google Scholar databases were searched up to June 2015, using the key words cervical discectomy; bone transplantation; titanium cages; and iliac crest autografts. Outcomes of interbody fusion rates were compared using odds ratios (ORs) with 95% confidence intervals (CIs). Values of the Japanese Orthopaedic Association score, and visual analog scale before and after operation were also compared. RESULTS: The rate of interbody fusion was similar between patients in the iliac crest autograft and titanium cage groups (pooled OR = 0.33, 95% CI = 0.07 to 1.66, P = .178). The overall analysis showed that patients in the two groups did not have significantly different post-surgery Japanese Orthopaedic Association score (pooled difference in means = -0.05, 95% CI = 0.73 to 0.63, P = .876). Improvement in arm and neck pain scores were assessed with a visual analog scale and differed significantly between patients in the iliac crest autograft and titanium cage groups (pooled difference in means = 0.16, 95% CI = -0.44 to 0.76, P = .610; and pooled difference in means = -0.44, 95% CI = 2.23 to 1.36, P = .634, respectively). CONCLUSIONS: Our results suggest that the use of titanium cages constitutes a safe and efficient alternative to iliac crest bone autografts for anterior cervical discectomy with fusion. PMID- 28097890 TI - Novel 1-(2-pyrimidin-2-yl)piperazine derivatives as selective monoamine oxidase (MAO)-A inhibitors. AB - In the present study, a new series of 2-[4-(pyrimidin-2-yl)piperazin-1-yl]-2 oxoethyl 4-substituted piperazine-1-carbodithioate derivatives (2a-n) were synthesized and screened for their monoamine oxidase A and B inhibitory activity. The structures of compounds were elucidated using spectroscopic methods and some physicochemical properties of new compounds were predicted using Molinspiration and MolSoft programs. Compounds 2-[4-(pyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl 4 (4-nitrophenyl)piperazine-1-carbodithioate (2j) and 2-[4-(pyrimidin-2 yl)piperazin-1-yl]-2-oxoethyl 4-benzhydrylpiperazine-1-carbodithioate (2m) exhibited selective MAO-A inhibitory activity with IC50 = 23.10, 24.14 uM, respectively. Some of the biological results were found in accordance with the obtained in silico data based on Lipinski's fule of five. PMID- 28097892 TI - New avenues for targeted therapies and biomarkers in anaplastic large cell lymphoma. PMID- 28097893 TI - Probing the cholinergic system to understand neurodegenerative diseases. PMID- 28097895 TI - Chemotherapy-induced peripheral neuropathy: limitations in current prophylactic strategies and directions for future research. PMID- 28097894 TI - High serum YKL-40 level positively correlates with coronary artery disease. AB - AIM: We investigated the predictive value of chitinase-like protein YKL-40 in coronary artery disease (CAD). PATIENTS: Serum YKL-40 levels in 116 CAD patients and 82 healthy controls were analyzed. Severity of CAD was evaluated using Gensini scores. Spearman's correlation was used to evaluate the correlation between Gensini scores and YKL-40 levels. The predictive value of YKL-40 was determined by receivers operating characteristic curve analysis. RESULTS: Serum YKL-40 levels were significantly elevated in CAD group as compared with control group. A positive correlation was found between the serum YKL-40 level and Gensini score. The optimum cut-off value of YKL-40 concentration was 127.7 ng/ml for distinguishing CAD patients from healthy controls with a 75.9% sensitivity and 57.3% specificity. CONCLUSION: A positive correlation exists between YKL-40 levels and CAD, and YKL-40 might be a useful adjunct in the diagnosis of CAD. PMID- 28097896 TI - A new nitrobenzoxadiazole-based GSTP1-1 inhibitor with a previously unheard of mechanism of action and high stability. AB - CONTEXT: The nitrobezoxadiazole derivative NBDHEX is a potent inhibitor of glutathione transferase P1-1 (GSTP1-1) endowed with outstanding anticancer activity in different tumor models. OBJECTIVE: To characterize by in vitro biochemical and in silico studies the NBDHEX analogues named MC2752 and MC2753. MATERIALS AND METHODS: Synthesis of MC2752 and MC2753, biochemical assays and in silico docking and normal-mode analyses. RESULTS: The presence of a hydrophobic moiety in the side chain of MC2753 confers unique features to this molecule. Unlike its parent drug NBDHEX, MC2753 does not require GSH to trigger the dissociation of the complex between GSTP1-1 and TRAF2, and displays high stability towards the nucleophilic attack of the tripeptide under physiological conditions. DISCUSSION AND CONCLUSION: MC2753 may represent a lead compound for the development of novel GSTP1-1 inhibitors not affected in their anticancer action by fluctuations of cellular GSH levels, and characterized by an increased half-life in vivo. PMID- 28097898 TI - Two approaches to the use of benzo[c][1,2]oxaboroles as active fragments for synthetic transformation of clarithromycin. AB - Clarithromycin (active against Gram positive infections) and 1-hydroxy-1,3 dihydrobenzo[c][1,2]oxaborole derivatives (effective for Gram negative microbes) are the ligands of bacterial RNA. The antimicrobial activities of these benzoxaboroles linked with clarithromycin at 9 or 4" position were compared. Two synthetic pathways for these conjugates were elaborated. First pathway explored the substitution of the C-9 carbonyl group of macrolactone's cycle via oxime linker, the second direction used the modification of the 4"-O-group of cladinose via the formation of carbamates of benzoxaboroles. 4"-O-(3-S-(1-Hydroxy-1,3 dihydro-benzo[c][1,2]oxaborole)-methyl-carbamoyl-clarithromycin showed twofold decrease in MICs for S. epidermidis and S. pneumoniae than clarithromycin. 4"-O Modified clarithromycin demonstrated an efficacy against Gram positive strains only. Compounds with C-9 substitution were more active than 4"-O-substituted antibiotics for susceptible strains E. coli tolC and did not exceed the activity of initial antibiotics. PMID- 28097897 TI - Carbonic anhydrase inhibitory properties of some uracil derivatives. AB - Inhibitors of carbonic anhydrase (CA) have been carried out in many therapeutic applications, especially antiglaucoma activity. In this study, we investigated some uracil derivatives (4-12) to inhibit human CA I (hCA I) and II (hCA II) isoenzymes. The KI values of the compounds 4-12 are in the range of 0.085-428 uM for hCA I and of 0.1715-645 uM against hCA II, respectively. It is concluded from the kinetic investigations, all compounds used in the study act as competitive inhibitors with substrate, 4-NPA. Uracil derivatives are emerging agents for the inhibiton of carbonic anhydrase which could be used in biomedicine. PMID- 28097899 TI - The need for narrative reflection and experiential learning in medical education: A lesson learned through an urban indigenous health elective. AB - In this personal view article, I discuss a formative experience I had during an Urban Indigenous Health elective in which I participated while in my final year of medical school. The elective was developed on the foundation of an experiential learning model, which is central to Indigenous pedagogy and emphasizes learning through experience and narrative reflection. By transforming medical education into a place where such concepts are integrated and valued, I argue that we will create physicians who are self-aware, compassionate and able to provide culturally safe care to all patient populations they will serve in their future practices. PMID- 28097900 TI - Structure-activity relationships of fraxamoside as an unusual xanthine oxidase inhibitor. AB - Fraxamoside, a macrocyclic secoiridoid glucoside featuring a hydroxytyrosol group, was recently identified as a xanthine oxidase inhibitor (XOI) comparable in potency in vitro to the standard antigout drug allopurinol. However, this activity and its considerably higher value than its derivatives oleuropein, oleoside 11-methyl ester, and hydroxytyrosol are not explained by structure activity relationships (SARs) of known XOIs. To exclude allosteric mechanisms, we first determined the inhibition kinetic of fraxamoside. The resulting competitive mechanism prompted a computational SAR characterization, combining molecular docking and dynamics, which fully explained the behavior of fraxamoside and its derivatives, attributed the higher activity of the former to conformational properties of its macrocycle, and showed a substantial contribution of the glycosidic moiety to binding, in striking contrast with glycoside derivatives of most other XOIs. Overall, fraxamoside emerged as a lead compound for a new class of XOIs potentially characterized by reduced interference with purine metabolism. PMID- 28097902 TI - Mistreatment of medical students in the third year may not be the problem. AB - Mistreatment and abuse of medical students has been recognized as a significant problem in medical schools. We believe, however, that the problem of mistreatment has been viewed incorrectly. This misperception of mistreatment exists in two primary ways. First, mistreatment has tended to be viewed as a "diagnosis" of unprofessionalism of the perpetrator when it may be more appropriately viewed as a symptom with a range of possible underlying causes. The second misconception that appears to be prevalent is the belief that the link between mistreatment and student well-being, distress, and falling empathy is clear. It is not. We present (1) evidence that other factors in the clinical learning environment may be having a greater negative impact on student mental health and well-being and (2) recommendations for changes that may produce enhancement to medical student mental health in the clerkship year. PMID- 28097903 TI - Treatment of familial Mediterranean fever with anakinra in patients unresponsive to colchicine. PMID- 28097901 TI - Skin whitening agents: medicinal chemistry perspective of tyrosinase inhibitors. AB - Melanogenesis is a process to synthesize melanin, which is a primary responsible for the pigmentation of human skin, eye and hair. Although numerous enzymatic catalyzed and chemical reactions are involved in melanogenesis process, the enzymes such as tyrosinase and tyrosinase-related protein-1 (TRP-1) and TRP-2 played a major role in melanin synthesis. Specifically, tyrosinase is a key enzyme, which catalyzes a rate-limiting step of the melanin synthesis, and the downregulation of tyrosinase is the most prominent approach for the development of melanogenesis inhibitors. Therefore, numerous inhibitors that target tyrosinase have been developed in recent years. The review focuses on the recent discovery of tyrosinase inhibitors that are directly involved in the inhibition of tyrosinase catalytic activity and functionality from all sources, including laboratory synthetic methods, natural products, virtual screening and structure based molecular docking studies. PMID- 28097904 TI - Estimated burden of cardiovascular disease and value-based price range for evolocumab in a high-risk, secondary-prevention population in the US payer context. AB - AIM: To estimate real-world cardiovascular disease (CVD) burden and value-based price range of evolocumab for a US-context, high-risk, secondary-prevention population. MATERIALS AND METHODS: Burden of CVD was assessed using the UK-based Clinical Practice Research Datalink (CPRD) in order to capture complete CV burden including CV mortality. Patients on standard of care (SOC; high-intensity statins) in CPRD were selected based on eligibility criteria of FOURIER, a phase 3 CV outcomes trial of evolocumab, and categorized into four cohorts: high-risk prevalent atherosclerotic CVD (ASCVD) cohort (n = 1448), acute coronary syndrome (ACS) (n = 602), ischemic stroke (IS) (n = 151), and heart failure (HF) (n = 291) incident cohorts. The value-based price range for evolocumab was assessed using a previously published economic model. The model incorporated CPRD CV event rates and considered CV event reduction rate ratios per 1 mmol/L reduction in low density lipoprotein-cholesterol (LDL-C) from a meta-analysis of statin trials by the Cholesterol Treatment Trialists Collaboration (CTTC), i.e. CTTC relationship. RESULTS: Multiple-event rates of composite CV events (ACS, IS, or coronary revascularization) per 100 patient-years were 12.3 for the high-risk prevalent ASCVD cohort, and 25.7, 13.3, and 23.3, respectively, for incident ACS, IS, and HF cohorts. Approximately one-half (42%) of the high-risk ASCVD patients with a new CV event during follow-up had a subsequent CV event. Combining these real world event rates and the CTTC relationship in the economic model, the value based price range (credible interval) under a willingness-to-pay threshold of $150,000/quality-adjusted life-year gained for evolocumab was $11,990 ($9,341 $14,833) to $16,856 ($12,903-$20,678) in ASCVD patients with baseline LDL-C levels >=70 mg/dL and >=100 mg/dL, respectively. CONCLUSION: Real-world CVD burden is substantial. Using the observed CVD burden in CPRD and the CTTC relationship, the cost-effectiveness analysis showed that, accounting for uncertainties, the expected value-based price for evolocumab is higher than its current annual cost, as long as the payer discount off list price is greater than 20%. PMID- 28097905 TI - Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and IGF-1R. AB - Novel 4-benzylamino benzo-anellated pyrrolo[2,3-b]pyridines have been synthesized with varied substitution patterns both at the molecular scaffold of the benzo anellated ring and at the 4-benzylamino residue. With a structural similarity to substituted thieno[2,3-d]pyrimidines as epidermal growth factor receptor (EGFR) inhibitors, we characterized the inhibition of EGFR for our novel compounds. As receptor heterodimerization gained certain interest as mechanism of cancer cells to become resistant against novel protein kinase inhibitors, we additionally measured the inhibition of insulin-like growth factor receptor IGF-1R which is a prominent receptor for such heterodimerizations with EGFR. Structure-activity relationships are discussed for both kinase inhibitions depending on the varied substitution patterns. We discovered novel dual inhibitors of both receptor tyrosine kinases with interest for further studies to reduce inhibitor resistance developments in cancer treatment. PMID- 28097906 TI - Synthesis of new pyridothienopyrimidinone derivatives as Pim-1 inhibitors. AB - Four series of pyridothienopyrimidin-4-one derivatives were designed and prepared to improve the pim-1 inhibitory activity of the previously reported thieno[2,3 b]pyridines. Significant improvement in the pim-1 inhibition and cytotoxic activity was achieved using structure rigidification strategy via ring closure. Six compounds (6c, 7a, 7c, 7d, 8b and 9) showed highly potent pim-1 inhibitory activity with IC50 of 4.62, 1.18, 1.38, 1.97, 8.83 and 4.18 MUM, respectively. Four other compounds (6b, 6d, 7b and 8a) showed moderate pim-1 inhibition. The most active compounds were tested for their cytotoxic activity on three cell lines [MCF7, HCT116 and PC3]. Compounds 7a [the 2-(2-chlorophenyl)-2,3-dihydro derivative] and 7d [the 2-(2-(trifluoromethyl)-phenyl)-2,3-dihydro derivative] displayed the most potent cytotoxic effect on the three cell lines tested consistent with their highest estimated pim-1 IC50 values. PMID- 28097907 TI - The lignicolous fungus Trametes versicolor (L.) Lloyd (1920): a promising natural source of antiradical and AChE inhibitory agents. AB - This study aimed to determine antiradical (DPPH* and *OH) and acetylcholinesterase (AChE) inhibitory activities along with chemical composition of autochtonous fungal species Trametes versicolor (Serbia). A total of 38 phenolic compounds with notable presence of phenolic acids were identified using HPLC/MS-MS. Its water extract exhibited the highest antiradical activity against *OH (3.21 MUg/mL), among the rest due to the presence of gallic, p-coumaric and caffeic acids. At the concentration of 100 MUg/mL, the same extract displayed a profound AChE inhibitory activity (60.53%) in liquid, compared to donepezil (89.05%), a drug in clinical practice used as positive control. The flavonoids baicalein and quercetin may be responsible compounds for the AChE inhibitory activity observed. These findings have demonstrated considerable potential of T. versicolor water extract as a natural source of antioxidant(s) and/or AChE inhibitor(s) to be eventually used as drug-like compounds or food supplements in the treatment of Alzheimer's disease. PMID- 28097908 TI - Common and specific genes and peripheral biomarkers in children and adults with attention-deficit/hyperactivity disorder. AB - OBJECTIVES: Elucidating the biological mechanisms involved in attention deficit/hyperactivity disorder (ADHD) has been challenging. Relatively unexplored is the fact that these mechanisms can differ with age. METHODS: We present an overview on the major differences between children and adults with ADHD, describing several studies from genomics to metabolomics performed in ADHD children and in adults (cADHD and aADHD, respectively). A systematic search (up until February 2016) was conducted. RESULTS: From a PRISMA flow-chart, a total of 350 and 91 genomics and metabolomics studies were found to be elligible for cADHD and aADHD, respectively. For children, associations were found for genes belonging to dopaminergic (SLC6A3, DRD4 and MAOA) and neurodevelopmental (LPHN3 and DIRAS2) systems and OPRM1 (Yates corrected P = 0.016; OR = 2.27 95%CI: 1.15 4.47). Studies of adults have implicated circadian rhythms genes, HTR2A, MAOB and a more generic neurodevelopmental/neurite outgrowth network (BCHE, SNAP25, BAIAP2, NOS1/NO, KCNIP4 and SPOCK3; Yates corrected P = 0.007; OR = 3.30 95%CI: 1.33-8.29). In common among cADHD and aADHD, the most significant findings are for oxidative stress proteins (MAD, SOD, PON1, ARES, TOS, TAS and OSI), and, in the second level, DISC1, DBH, DDC, microRNA and adiponectin. CONCLUSIONS: Through a convergent functional genomics, this review contributes to clarification of which genetic/biological mechanisms differ with age. The effects of some genes do not change throughout the lifetime, whereas others are linked to age-specific stages. Additional research and further studies are needed to generate firmer conclusions that might someday be useful for predicting the remission and persistence of the disorder. Despite the limitations, some of these genes/proteins could be potential useful biomarkers to discriminate cADHD from aADHD. PMID- 28097909 TI - Administration of ketamine for unipolar and bipolar depression. AB - OBJECTIVE: Clinical trials demonstrated that ketamine exhibits rapid antidepressant efficacy when administered in subanaesthetic dosages. We reviewed currently available literature investigating efficacy, response rates and safety profile. METHODS: Twelve studies investigating unipolar, seven on bipolar depression were included after search in medline, scopus and web of science. RESULTS: Randomized, placebo-controlled or open-label trials reported antidepressant response rates after 24 h on primary outcome measures at 61%. The average reduction of Hamilton Depression Rating Scale (HAM-D) was 10.9 points, Beck Depression Inventory (BDI) 15.7 points and Montgomery-Asberg Depression Rating Scale (MADRS) 20.8 points. Ketamine was always superior to placebo. Most common side effects were dizziness, blurred vision, restlessness, nausea/vomiting and headache, which were all reversible. Relapse rates ranged between 60% and 92%. To provide best practice-based information to patients, a consent-form for application and modification in local language is included. CONCLUSIONS: Ketamine constitutes a novel, rapid and efficacious treatment option for patients suffering from treatment resistant depression and exhibits rapid and significant anti-suicidal effects. New administration routes might serve as alternative to intravenous regimes for potential usage in outpatient settings. However, long term side effects are not known and short duration of antidepressant response need ways to prolong ketamine's efficacy. PMID- 28097910 TI - Purification and biochemical characterization of a novel thermostable serine alkaline protease from Aeribacillus pallidus C10: a potential additive for detergents. AB - An extracellular thermostable alkaline serine protease enzyme from Aeribacillus pallidus C10 (GenBank No: KC333049), was purified 4.85 and 17. 32-fold with a yield of 26.9 and 19.56%, respectively, through DE52 anion exchange and Probond affinity chromatography. The molecular mass of the enzyme was determined through sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), with approximately 38.35 kDa. The enzyme exhibited optimum activity at pH 9 and at temperature 60 degrees C. It was determined that the enzyme had remained stable at the range of pH 7.0-10.0, and that it had preserved more than 80% of its activity at a broad temperature range (20-80 degrees C). The enzyme activity was found to retain more than 70% and 55% in the presence of organic solvents and commercial detergents, respectively. In addition, it was observed that the enzyme activity had increased in the presence of 5% SDS. KM and Vmax values were calculated as 0.197 mg/mL and 7.29 MUmol.mL-1.min-1, respectively. PMID- 28097911 TI - Design, synthesis and docking study of novel coumarin ligands as potential selective acetylcholinesterase inhibitors. AB - New coumaryl-thiazole derivatives with the acetamide moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and in vitro tested as acetylcholinesterase (AChE) inhibitors. 2-(diethylamino)-N-(4-(2-oxo-2H chromen-3-yl)thiazol-2-yl)acetamide (6c, IC50 value of 43 nM) was the best AChE inhibitor with a selectivity index of 4151.16 over BuChE. Kinetic study of AChE inhibition revealed that 6c was a mixed-type inhibitor. Moreover, the result of H4IIE hepatoma cell toxicity assay for 6c showed negligible cell death. Molecular docking studies were also carried out to clarify the inhibition mode of the more active compounds. Best pose of compound 6c is positioned into the active site with the coumarin ring wedged between the residues of the CAS and catalytic triad of AChE. In addition, the coumarin ring is anchored into the gorge of the enzyme by H-bond with Tyr130. PMID- 28097912 TI - Methanethiosulfonate derivatives as ligands of the STAT3-SH2 domain. AB - With the aim to discover new STAT3 direct inhibitors, potentially useful as anticancer agents, a set of methanethiosulfonate drug hybrids were synthesized. The in vitro tests showed that all the thiosulfonic compounds were able to strongly and selectively bind STAT3-SH2 domain, whereas the parent drugs were completely devoid of this ability. In addition, some of them showed a moderate antiproliferative activity on HCT-116 cancer cell line. These results suggest that methanethiosulfonate moiety can be considered a useful scaffold in the preparation of new direct STAT3 inhibitors. Interestingly, an unusual kind of organo-sulfur derivative, endowed with valuable antiproliferative activity, was occasionally isolated. [Formula: see text]. PMID- 28097913 TI - Cost-consequence analysis of different active flowable hemostatic matrices in cardiac surgical procedures. AB - BACKGROUND: A recent retrospective comparative effectiveness study found that use of the FLOSEAL Hemostatic Matrix in cardiac surgery was associated with significantly lower risks of complications, blood transfusions, surgical revisions, and shorter length of surgery than use of SURGIFLO Hemostatic Matrix. These outcome improvements in cardiac surgery procedures may translate to economic savings for hospitals and payers. OBJECTIVE: The objective of this study was to estimate the cost-consequence of two flowable hemostatic matrices (FLOSEAL or SURGIFLO) in cardiac surgeries for US hospitals. METHODS: A cost-consequence model was constructed using clinical outcomes from a previously published retrospective comparative effectiveness study of FLOSEAL vs SURGIFLO in adult cardiac surgeries. The model accounted for the reported differences between these products in length of surgery, rates of major and minor complications, surgical revisions, and blood product transfusions. Costs were derived from Healthcare Cost and Utilization Project's National Inpatient Sample (NIS) 2012 database and converted to 2015 US dollars. Savings were modeled for a hospital performing 245 cardiac surgeries annually, as identified as the average for hospitals in the NIS dataset. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to test model robustness. RESULTS: The results suggest that if FLOSEAL is utilized in a hospital that performs 245 mixed cardiac surgery procedures annually, 11 major complications, 31 minor complications, nine surgical revisions, 79 blood product transfusions, and 260.3 h of cumulative operating time could be avoided. These improved outcomes correspond to a net annualized saving of $1,532,896. Cost savings remained consistent between $1.3m and $1.8m and between $911k and $2.4m, even after accounting for the uncertainty around clinical and cost inputs, in a one-way and probabilistic sensitivity analysis, respectively. CONCLUSIONS: Outcome differences associated with FLOSEAL vs SURGIFLO that were previously reported in a comparative effectiveness study may result in substantial cost savings for US hospitals. PMID- 28097914 TI - Nanostructured lipid carriers (NLC) for the delivery of natural molecules with antimicrobial activity: production, characterisation and in vitro studies. AB - This study describes the preparation, characterisation and in vitro activity of nanostructured lipid carriers (NLCs) encapsulating natural molecules with antimicrobial activity, such as plumbagin, hydroquinon, eugenol, alpha-asarone and alpha-tocopherol. NLCs were prepared by melt and ultrasonication method, characterised by Cryo-TEM for morphology and SdFFF for dimensional distribution and active encapsulation yields. In vitro tests were conducted on bacteria, fungi and human cell cultures. In vitro tests demonstrated that plumbagin is strongly toxic towards F. oxysporum especially when active molecules are loaded on NLC. Plumbagin was completely non toxic on cyanobacterial model strain up to a threshold over which cell viability was completely lost. NLC loaded with active molecules showed a lower toxicity as compared to their free form on human cultured cells. Although further studies need to be performed, these systems can be potentially proposed to control phytopathogenic organisms. PMID- 28097915 TI - The relationship between angiotensin-converting enzyme (ACE) insertion (I) / deletion (D) polymorphism, serum ACE activity and bone mineral density (BMD) in older Chinese. AB - OBJECTIVE: In this study, we set out to investigate the relationship between angiotensin-converting enzyme ( ACE) I/D polymorphism, serum ACE activity and bone mineral density (BMD) in older Chinese. METHODS: A standardized, structured, face-to-face interview was performed to collect demographic information. BMD was measured using dual-energy X-ray absorptiometry (DXA). I/D genotypes of ACE were determined by polymerase chain reaction (PCR) amplification. Serum ACE activity was determined photometrically by a commercially available kinetic kit. Multiple linear regression analysis was used to examine the relationship between ACE I/D polymorphism, serum ACE activity and BMD. RESULTS: A total of 1567 males and 1760 females were selected for analyzing the relationship between ACE I/D polymorphism and BMD. There was no significant difference in spine BMD, total hip BMD and femur neck BMD among different ACE I/D genotypes both in males and females. A total of 1699 males and 1739 females were selected for analyzing the relationship between serum ACE activity and BMD. There was also no significant difference in spine BMD, total hip BMD and femur neck BMD among different serum ACE activity groups both in males and females. CONCLUSION: There was no relationship between ACE I/D polymorphism, serum ACE activity and BMD in older Chinese. PMID- 28097916 TI - Exploring the first Rimonabant analog-opioid peptide hybrid compound, as bivalent ligand for CB1 and opioid receptors. AB - Cannabinoid (CB) and opioid systems are both involved in analgesia, food intake, mood and behavior. Due to the co-localization of u-opioid (MOR) and CB1 receptors in various regions of the central nervous system (CNS) and their ability to form heterodimers, bivalent ligands targeting to both these systems may be good candidates to investigate the existence of possible cross-talking or synergistic effects, also at sub-effective doses. In this work, we selected from a small series of new Rimonabant analogs one CB1R reverse agonist to be conjugated to the opioid fragment Tyr-D-Ala-Gly-Phe-NH2. The bivalent compound (9) has been used for in vitro binding assays, for in vivo antinociception models and in vitro hypothalamic perfusion test, to evaluate the neurotransmitters release. PMID- 28097917 TI - Repeatability of whole-cornea measurements using an anterior segment imaging device based on OCT and Placido-disk. AB - BACKGROUND: Current advances in refractive surgery require high accuracy of corneal measurements. We aim to evaluate the repeatability of topographic measurements using an integrated Placido disk - OCT device. METHODS: Thirty right eyes of thirty healthy and young subjects were included. The topographic parameters of simulated keratometry, asphericity, minimum pachymetry, white-to white distance, spherical aberration and corneal elevation were studied. Three measurements were taken by the same observer using the Visante omni device. The coefficient of repeatability (CoR), coefficient of variation (CoV) and intraclass correlation coefficient (ICC) were calculated to assess the repeatability. The Bland-Altman graphical method was also applied. RESULTS: No significant differences between repeated measurements were found. The mean difference for simulated keratometry was between 0.01 and 0.02 D. For asphericity was -0.01 +/- 0.02, and for minimum pachymetry, spherical aberration and WTW was equal or less than 0.02 mm. The mean differences for corneal elevation, in millimeters and diopters, were between 0.00 and 0.01. Overall, most topographic parameters had a CoV less than 0.4%, a CoR less than 0.3 and an ICC higher than 0.98. CONCLUSIONS: The Visante omni device provides good repeatability for topographical measurements of simulated keratometry, asphericity, pachymetry, spherical aberration and corneal elevation. PMID- 28097918 TI - The hearing benefit of cochlear implantation for individuals with unilateral hearing loss, but no tinnitus. AB - CONCLUSION: Cochlear implants improve the hearing abilities of individuals with unilateral hearing loss and no tinnitus. The benefit is no different from that seen in patients with unilateral hearing loss and incapacitating tinnitus. OBJECTIVE: To evaluate hearing outcomes after cochlear implantation in individuals with unilateral hearing loss and no tinnitus and compare them to those obtained in a similar group who had incapacitating tinnitus. METHODS: Six cases who did not experience tinnitus before operation and 15 subjects with pre operative tinnitus were evaluated with a structured interview, a monosyllabic word test under difficult listening situations, a sound localization test, and an APHAB (abbreviated profile of hearing aid benefit) questionnaire. RESULTS: All subjects used their cochlear implant more than 8 hours a day, 7 days a week. In 'no tinnitus' patients, mean benefit of cochlear implantation was 19% for quiet speech, 15% for speech in noise (with the same signal-to-noise ratio in the implanted and non-implanted ear), and 16% for a more favourable signal-to-noise ratio at the implanted ear. Sound localization error improved by an average of 19 degrees . The global score of APHAB improved by 16%. The benefits across all evaluations did not differ significantly between the 'no tinnitus' and 'tinnitus' groups. PMID- 28097919 TI - Performance of methods for estimating the effect of covariates on group membership probabilities in group-based trajectory models. AB - One purpose of a longitudinal study is to gain insight of how characteristics at earlier points in time can impact on subsequent outcomes. Typically, the outcome variable varies over time and the data for each individual can be used to form a discrete path of measurements, that is a trajectory. Group-based trajectory modelling methods seek to identify subgroups of individuals within a population with trajectories that are more similar to each other than to trajectories in distinct groups. An approach to modelling the influence of covariates measured at earlier time points in the group-based setting is to consider models wherein these covariates affect the group membership probabilities. Models in which prior covariates impact the trajectories directly are also possible but are not considered here. In the present study, we compared six different methods for estimating the effect of covariates on the group membership probabilities, which have different approaches to account for the uncertainty in the group membership assignment. We found that when investigating the effect of one or several covariates on a group-based trajectory model, the full likelihood approach minimized the bias in the estimate of the covariate effect. In this '1-step' approach, the estimation of the effect of covariates and the trajectory model are carried out simultaneously. Of the '3-step' approaches, where the effect of the covariates is assessed subsequent to the estimation of the group-based trajectory model, only Vermunt's improved 3 step resulted in bias estimates similar in size to the full likelihood approach. The remaining methods considered resulted in considerably higher bias in the covariate effect estimates and should not be used. In addition to the bias empirically demonstrated for the probability regression approach, we have shown analytically that it is biased in general. PMID- 28097920 TI - Extending the life-cycle of reverse osmosis membranes: A review. AB - The reverse osmosis (RO) technology for desalination and demineralization serves the global water crisis context, both technically and economically, and its market is growing. However, RO membranes have a limited life-cycle and are often disposed of in landfills. The impacts caused by the disposal of thousands of tonnes per annum of RO membranes have grown dramatically around the world. Waste prevention should have a high priority and take effect before the end-of-life phase of a product is reached. In this review, a summary is presented of the main advances in the performance of the RO technology and the membrane lifespan. Afterwards, this paper reviews the most important relevant literature and summarizes the key findings of the research on reusing and recycling the discarded modules for the purpose of extending the life-cycle of the RO membranes. In addtion, there are some recent researches that indicated recycling RO membranes for use by the microfiltration or ultrafiltration separation processes is a promising solution to the disposal problem. However, there are many gaps and differences in procedures and results. This article also discusses and brings to light key parameters involved and controversies about oxidative treatment of discarded RO membranes. PMID- 28097921 TI - How to care for a patient's eyes in critical care settings. AB - Rationale and key points Eye care is an important aspect of the nursing management of patients who are critically ill. All patients in acute care settings with absent or compromised eye defence mechanisms are at risk of eye complications and ocular surface disease. This article aims to assist nurses to care for the eyes of patients in critical care settings to enable early detection and routine management of ophthalmic issues, thereby avoiding visual compromise on patient discharge from critical care settings. " Corneal exposure is reported to occur in many patients who are critically ill. " Incomplete eyelid closure and lack of lubrication are the main mechanisms that underlie the development of corneal damage in patients who are critically ill. " Unconscious, sedated and/or paralysed patients and those with a reduced Glasgow Coma Scale score depend on healthcare professionals to maintain their ocular surface to prevent complications such as corneal abrasion, infection and ulceration, perforations and blindness. " Meticulous nursing care is required to prevent ophthalmic complications that can result from corneal exposure in this patient group. Regular, evidence-based eye care should be part of routine nursing practice for patients who are critically ill. Reflective activity 'How to' articles can help you update your practice and ensure it remains evidence-based. Apply this article to your practice. Reflect on and write a short account of: 1. How this article might change your practice? 2. How you could use this resource to educate your colleagues in eye care of the unconscious patient? PMID- 28097922 TI - Cascade use indicators for selected biopolymers: Are we aiming for the right solutions in the design for recycling of bio-based polymers? AB - When surveying the trends and criteria for the design for recycling (DfR) of bio based polymers, priorities appear to lie in energy recovery at the end of the product life of durable products, such as bio-based thermosets. Non-durable products made of thermoplastic polymers exhibit good properties for material recycling. The latter commonly enjoy growing material recycling quotas in countries that enforce a landfill ban. Quantitative and qualitative indicators are needed for characterizing progress in the development towards more recycling friendly bio-based polymers. This would enable the deficits in recycling bio based plastics to be tracked and improved. The aim of this paper is to analyse the trends in the DfR of bio-based polymers and the constraints posed by the recycling infrastructure on plastic polymers from a systems perspective. This analysis produces recommendations on how life cycle assessment indicators can be introduced into the dialogue between designers and recyclers in order to promote DfR principles to enhance the cascading use of bio-based polymers within the bioeconomy, and to meet circular economy goals. PMID- 28097923 TI - Co-processing of olive bagasse with crude rapeseed oil via pyrolysis. AB - The co-pyrolysis of olive bagasse with crude rapeseed oil at different blend ratios was investigated at 500oC in a fixed bed reactor. The effect of olive bagasse to crude rapeseed oil ratio on the product distributions and properties of the pyrolysis products were comparatively investigated. The addition of crude rapeseed oil into olive bagasse in the co-pyrolysis led to formation of upgraded biofuels in terms of liquid yields and properties. While the pyrolysis of olive bagasse produced a liquid yield of 52.5 wt %, the highest liquid yield of 73.5 wt % was obtained from the co-pyrolysis of olive bagasse with crude rapeseed oil at a blend ratio of 1:4. The bio-oil derived from olive bagasse contained 5% naphtha, 10% heavy naphtha, 30% gas oil, and 55% heavy gas oil. In the case of bio-oil obtained from the co-pyrolysis of olive bagasse with crude rapeseed oil at a blend ratio of 1:4, the light naphtha, heavy naphtha, and light gas oil content increased. This is an indication of the improved characteristics of the bio-oil obtained from the co-processing. The heating value of bio-oil from the pyrolysis of olive bagasse alone was 34.6 MJ kg-1 and the heating values of bio oils obtained from the co-pyrolysis of olive bagasse with crude rapeseed oil ranged from 37.6 to 41.6 MJ kg-1. It was demonstrated that the co-processing of waste biomass with crude plant oil is a good alternative to improve bio-oil yields and properties. PMID- 28097924 TI - Enhancing the performance of electro-peroxone by incorporation of UV irradiation and BDD anodes. AB - In this work, the treatment of 4-nitrophenol (NP) in water by ozonation, electrolysis, electro-peroxone (EP), and photo-electro-peroxone (PEP) processes was investigated. PEP process is based on the combination of ozonation, UV irradiation, and electrolysis using a carbon felt cathode and a boron-doped diamond (BDD) anode. In this process, H2O2 is electrochemically generated from reduction of O2 in the ozone generator effluent at a carbon felt cathode. The in situ generated H2O2 is simultaneously decomposed by UV-photolysis and by reaction with O3 to form HO* radicals that can rapidly and non-selectively oxidize organic pollutants. The results showed that PEP is the most efficient process for a rapid NP degradation in water than the other individual and combined methods. In addition, PEP process was able to completely remove total organic carbon (TOC) from NP solution after consumption of 4.1 kWh/kg TOC removed. Hydroquinone, 1,2,4 trihydroxybenzene, oxalic and maleic acids were identified as the main intermediates of NP degradation. The addition of iron to NP solution did not significantly affect the efficiency of PEP process. The results demonstrated that the incorporation of BDD anodes and UV light in PEP process can significantly enhance the kinetics and minimize energy requirements. PMID- 28097925 TI - Improving cancer imaging with magnetic nanoparticles: where are we now? PMID- 28097926 TI - A pilot study of a minimally supervised home exercise and walking program for people with Parkinson's disease in Jordan. AB - AIM: This study aimed to evaluate the feasibility and cultural considerations of a minimally supervised, home-based exercise program in Jordan. METHODS: Quantitative and qualitative approaches were used. Thirty participants were randomly allocated to either an 8-week intervention group (n = 16), or a standard care group (n = 14). The intervention incorporated the home use of an exercise DVD, walking program and initial instructional sessions and weekly phone calls provided by a physiotherapist. Interviews were used to explore feasibility. Unified Parkinson's disease rating scale (UPDRS-III); balance and walking speed were assessed. RESULTS: The retention rate was 86.7% and mean adherence rate was 77%. Personal and sociocultural barriers of adherence to the exercise program were identified. UPDRS-III at follow-up was lower in the intervention group. CONCLUSION: A home exercise program was feasible. Sociocultural barriers specific to Arabic culture may affect the uptake of such an intervention in Parkinson's disease in these countries. PMID- 28097927 TI - Assessment and comparison of three high-aluminum fly ash utilization scenarios in Inner Mongolia, China using an eco-efficiency indicator. AB - Utilization of fly ash is of great importance in China in the context of resource and environmental crises. Different fly ash utilization processes are proposed, and some have been practically applied. However, none of these fly ash utilization pathways has been evaluated comprehensively by integrating both environmental and economic perspectives. In this study, three high-aluminum fly ash utilization methods in Mongolia were assessed and compared based on the concept of eco-efficiency. The environmental assessment was conducted in accordance with life-cycle assessment principles, and a monetization-weighting approach was applied to obtain social willingness-to-pay as a reflection of environmental impact. The environmental assessment results revealed that the reuse of fly ash had significant advantage for saving primary resource, while solid waste, depletion of water, and global warming were the three highest environmental impacts from the life cycle perspective. The economic performance assessment showed positive net profits for fly ash utilization, but high value added products were not necessarily indicative of better economic performance due to the relatively high operation cost. Comparison of the eco-efficiency indicators (EEIs) implied that the process of scenario 1#, which produced mullite ceramic and active calcium silicate, was the most recommended out of the three scenarios on the present scale. This judgment was consistent with the evaluation of the resource utilization rate. The present study showed that the EEI could be used to compare different fly ash utilization processes in a comprehensive and objective manner, thus providing definitive and insightful suggestions for decision-making and technical improvement. PMID- 28097928 TI - Validity and reliability of a novel iPhone app for the measurement of barbell velocity and 1RM on the bench-press exercise. AB - The purpose of this study was to analyse the validity and reliability of a novel iPhone app (named: PowerLift) for the measurement of mean velocity on the bench press exercise. Additionally, the accuracy of the estimation of the 1-Repetition maximum (1RM) using the load-velocity relationship was tested. To do this, 10 powerlifters (Mean (SD): age = 26.5 +/- 6.5 years; bench press 1RM . kg-1 = 1.34 +/- 0.25) completed an incremental test on the bench-press exercise with 5 different loads (75-100% 1RM), while the mean velocity of the barbell was registered using a linear transducer (LT) and Powerlift. Results showed a very high correlation between the LT and the app (r = 0.94, SEE = 0.028 m . s-1) for the measurement of mean velocity. Bland-Altman plots (R2 = 0.011) and intraclass correlation coefficient (ICC = 0.965) revealed a very high agreement between both devices. A systematic bias by which the app registered slightly higher values than the LT (P < 0.05; mean difference (SD) between instruments = 0.008 +/- 0.03 m . s-1). Finally, actual and estimated 1RM using the app were highly correlated (r = 0.98, mean difference (SD) = 5.5 +/- 9.6 kg, P < 0.05). The app was found to be highly valid and reliable in comparison with a LT. These findings could have valuable practical applications for strength and conditioning coaches who wish to measure barbell velocity in the bench-press exercise. PMID- 28097929 TI - Improved survival of anchorage-dependent cells in core-shell hydrogel microcapsules via co-encapsulation with cell-friendly microspheres. AB - In this study, we investigated the effect of intracapsular environment on the survival of anchorage-dependent cells (ADCs) encapsulated in alginate microcapsules with three different core structures, i.e. liquid, semi-liquid and microsphere-encapsulating semi-liquid core, using NIH 3T3 fibroblasts as an ADC model. For the latter, we fabricated poly (E-caprolactone) microspheres and co encapsulated them with the cells, to establish cell-substrate interactions in the capsule. The fibroblast cells co-encapsulated with the microspheres exhibited higher survival and growth than those without. This study provides a "proof of concept" for employing microspheres as a cell-friendly surface to establish intracapsular cell-substrate interactions thus prolonging the survival of encapsulated therapeutic ADCs. PMID- 28097930 TI - Encapsulation of Sesbania grandiflora extract in polymeric micelles to enhance its solubility, stability, and antibacterial activity. AB - Clinical applications of Sesbania grandiflora bark extract (SGE) are limited because of its poor water solubility and stability. SGE was loaded in micelles of Pluronics. In vitro and in vivo antibacterial and toxicity tests were investigated using broth dilution and silkworm model. Aqueous solubility of SGE was improved by these micelles. Activity and toxicity of SGE loaded micelles were dependent on type and concentration of Pluronics. The micelles composed of 1:3 SGE to Pluronic F68 (SGE-PF68-13) showed small size (24.95 +/- 0.34 nm), narrow PdI (<0.2), high entrapment efficiency (99.63 +/- 0.19%) and negative zeta potential (-41.53 +/- 0.15 mV). Stability of SGE in SGE-PF68-13 was 10 times higher than the unentrapped SGE. SGE-PF68-13 showed a dose dependent activity and significantly higher therapeutic effect than the unentrapped SGE. It is concluded that encapsulation of SGE in Pluronic micelles can enhance SGE solubility, stability, and antibacterial activity. SGE-PF68-13 is suitable for further study in mammalian animals. PMID- 28097932 TI - Sigrid G. Deeds, MPH, DrPH (1923-2011). PMID- 28097933 TI - Inflammatory myopathy in a patient with collagen VI mutations. PMID- 28097931 TI - Oil encapsulation in core-shell alginate capsules by inverse gelation. I: dripping methodology. AB - The production of capsules by inverse gelation consists of adding dropwise oil containing calcium dispersion into an alginate bath. A dripping technique to produce capsules from oil-in-water (O/W) emulsions was proposed by Abang. However, little is known about the oil encapsulation using water-in-oil (W/O) emulsions. This work aims to develop a new method of W/O emulsions encapsulation by inverse gelation. The success of the W/O emulsion encapsulation is due to three factors: 1) use of an emulsion with moderate stability (50 min); 2) production of an emulsion with at least 90 g/L of CaCl2 and 3) addition of ethanol (20% v/v) into the alginate bath. Both wet and dry capsules were obtained with a spherical shape with diameters of 7 and 3.6 mm, respectively. All volume of oil was encapsulated and the oil loading in the wet and dry capsules was of 23 and 68% v/v, respectively. PMID- 28097934 TI - Automatic and quantitative measurement of laryngeal video stroboscopic images. AB - The laryngeal video stroboscope is an important instrument for physicians to analyze abnormalities and diseases in the glottal area. Stroboscope has been widely used around the world. However, without quantized indices, physicians can only make subjective judgment on glottal images. We designed a new laser projection marking module and applied it onto the laryngeal video stroboscope to provide scale conversion reference parameters for glottal imaging and to convert the physiological parameters of glottis. Image processing technology was used to segment the important image regions of interest. Information of the glottis was quantified, and the vocal fold image segmentation system was completed to assist clinical diagnosis and increase accuracy. Regarding image processing, histogram equalization was used to enhance glottis image contrast. The center weighted median filters image noise while retaining the texture of the glottal image. Statistical threshold determination was used for automatic segmentation of a glottal image. As the glottis image contains saliva and light spots, which are classified as the noise of the image, noise was eliminated by erosion, expansion, disconnection, and closure techniques to highlight the vocal area. We also used image processing to automatically identify an image of vocal fold region in order to quantify information from the glottal image, such as glottal area, vocal fold perimeter, vocal fold length, glottal width, and vocal fold angle. The quantized glottis image database was created to assist physicians in diagnosing glottis diseases more objectively. PMID- 28097935 TI - Finite element simulations of the head-brain responses to the top impacts of a construction helmet: Effects of the neck and body mass. AB - Traumatic brain injuries are among the most common severely disabling injuries in the United States. Construction helmets are considered essential personal protective equipment for reducing traumatic brain injury risks at work sites. In this study, we proposed a practical finite element modeling approach that would be suitable for engineers to optimize construction helmet design. The finite element model includes all essential anatomical structures of a human head (i.e. skin, scalp, skull, cerebrospinal fluid, brain, medulla, spinal cord, cervical vertebrae, and discs) and all major engineering components of a construction helmet (i.e. shell and suspension system). The head finite element model has been calibrated using the experimental data in the literature. It is technically difficult to precisely account for the effects of the neck and body mass on the dynamic responses, because the finite element model does not include the entire human body. An approximation approach has been developed to account for the effects of the neck and body mass on the dynamic responses of the head-brain. Using the proposed model, we have calculated the responses of the head-brain during a top impact when wearing a construction helmet. The proposed modeling approach would provide a tool to improve the helmet design on a biomechanical basis. PMID- 28097936 TI - Experimental study on tissue phantoms to understand the effect of injury and suturing on human skin mechanical properties. AB - Skin injuries are the most common type of injuries occurring in day-to-day life. A skin injury usually manifests itself in the form of a wound or a cut. While a shallow wound may heal by itself within a short time, deep wounds require surgical interventions such as suturing for timely healing. To date, suturing practices are based on a surgeon's experience and may vary widely from one situation to another. Understanding the mechanics of wound closure and suturing of the skin is crucial to improve clinical suturing practices and also to plan automated robotic surgeries. In the literature, phenomenological two-dimensional computational skin models have been developed to study the mechanics of wound closure. Additionally, the effect of skin pre-stress (due to the natural tension of the skin) on wound closure mechanics has been studied. However, in most of these analyses, idealistic two-dimensional skin geometries, materials and loads have been assumed, which are far from reality, and would clearly generate inaccurate quantitative results. In this work, for the first time, a biofidelic human skin tissue phantom was developed using a two-part silicone material. A wound was created on the phantom material and sutures were placed to close the wound. Uniaxial mechanical tests were carried out on the phantom specimens to study the effect of varying wound size, quantity, suture and pre-stress on the mechanical behavior of human skin. Also, the average mechanical behavior of the human skin surrogate was characterized using hyperelastic material models, in the presence of a wound and sutures. To date, such a robust experimental study on the effect of injury and sutures on human skin mechanics has not been attempted. The results of this novel investigation will provide important guidelines for surgical planning and validation of results from computational models in the future. PMID- 28097937 TI - An assembly-type master-slave catheter and guidewire driving system for vascular intervention. AB - Current vascular intervention inevitably exposes a large amount of X-ray to both an operator and a patient during the procedure. The purpose of this study is to propose a new catheter driving system which assists the operator in aspects of less X-ray exposure and convenient user interface. For this, an assembly-type 4 degree-of-freedom master-slave system was designed and tested to verify the efficiency. First, current vascular intervention procedures are analyzed to develop a new robotic procedure that enables us to use conventional vascular intervention devices such as catheter and guidewire which are commercially available in the market. Some parts of the slave robot which contact the devices were designed to be easily assembled and dissembled from the main body of the slave robot for sterilization. A master robot is compactly designed to conduct insertion and rotational motion and is able to switch from the guidewire driving mode to the catheter driving mode or vice versa. A phantom resembling the human arteries was developed, and the master-slave robotic system is tested using the phantom. The contact force of the guidewire tip according to the shape of the arteries is measured and reflected to the user through the master robot during the phantom experiment. This system can drastically reduce radiation exposure by replacing human effort by a robotic system for high radiation exposure procedures. Also, benefits of the proposed robot system are low cost by employing currently available devices and easy human interface. PMID- 28097941 TI - Telemedicine support shortens length of stay after fast-track hip replacement. AB - Background and purpose - Telemedicine could allow patients to be discharged more quickly after surgery and contribute to improve fast-track procedures without compromising quality, patient safety, functionality, anxiety, or other patient perceived parameters. We investigated whether using telemedicine support (TMS) would permit hospital discharge after 1 day without loss of self-assessed quality of life, loss of functionality, increased anxiety, increased rates of re admission, or increased rates of complications after hip replacement. Patients and methods - We performed a randomized controlled trial involving 72 Danish patients in 1 region who were referred for elective fast-track total hip replacement between August 2009 and March 2011 (654 were screened for eligibility). Half of the patients received a telemedicine solution connected to their TV. The patients were followed until 1 year after surgery. Results - Length of stay was reduced from 2.1 days (95% CI: 2.0-2.3) to 1.1 day (CI: 0.9-1.4; p < 0.001) with the TMS intervention. Health-related quality of life increased in both groups, but there were no statistically significant differences between groups. There were also no statistically significant differences between groups regarding timed up-and-go test and Oxford hip score at 3-month follow-up. At 12 month follow-up, the rates of complications and re-admissions were similar between the groups, but the number of postoperative hospital contacts was lower in the TMS group. Interpretation - Length of postoperative stay was shortened in patients with the TMS solution, without compromising patient-perceived or clinical parameters in patients undergoing elective fast-track surgery. These results indicate that telemedicine can be of value in fast-track treatment of patients undergoing total hip replacement. PMID- 28097942 TI - CD25 as an adverse prognostic factor in elderly patients with acute myeloid leukemia. AB - OBJECTIVES: CD25 has been reported to be highly expressed in leukemia stem cells and correlated with adverse outcomes in young patients with acute myeloid leukemia (AML). However, the significance of CD25 expression in elderly patients with AML has not yet been investigated. METHODS: We retrospectively analyzed 154 newly diagnosed AML patients aged 60 years or over by flow cytometry. RESULTS: CD25-positive AML was characterized by high white blood cell counts, secondary AML, rare favorable karyotypes, and positivity for CD34 and CD7 antigens, compared with CD25-negative AML. CD25 positivity was significantly correlated with an inferior complete remission (CR), event-free survival (EFS), and overall survival. Multivariate analysis showed CD25 positivity to be a significant prognostic predictor of CR and EFS. A regimen of low-dose cytarabine and aclarubicin combined with granulocyte-colony-stimulating factor (CAG) led to higher CR rates in the CD25-positive AML patients than intensive chemotherapies. CD25 expression was increased at relapse and in the development of leukemic status from myelodysplastic syndrome or myeloproliferative neoplasm. DISCUSSION: An effective treatment strategy for elderly patients with CD25-positive AML has not been established. Further studies are needed to evaluate the effect of a CAG regimen and allogenic stem cell transplantation in patients. CONCLUSION: CD25 is an independent prognostic factor in elderly AML patients. Alternative therapies for CD25-positive elderly AML patients are needed. PMID- 28097944 TI - 2011 Index of Reviewers. PMID- 28097946 TI - Author Instructions. PMID- 28097947 TI - Evaluating waste printed circuit boards recycling: Opportunities and challenges, a mini review. AB - Rapid generation of waste printed circuit boards has become a very serious issue worldwide. Numerous techniques have been developed in the last decade to resolve the pollution from waste printed circuit boards, and also recover valuable metals from the waste printed circuit boards stream on a large-scale. However, these techniques have their own certain specific drawbacks that need to be rectified properly. In this review article, these recycling technologies are evaluated based on a strength, weaknesses, opportunities and threats analysis. Furthermore, it is warranted that, the substantial research is required to improve the current technologies for waste printed circuit boards recycling in the outlook of large scale applications. PMID- 28097953 TI - Comparison of Emission of Dioxins and Furans from Gasohol- and Ethanol-Powered Vehicles. AB - The exhaust emissions of 17 polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) were investigated in two spark-ignition light-duty vehicles, one gasohol-fueled and a flexible-fuel one fueled with hydrated ethanol. Gasohol is a mixture of gasoline and 22% ethanol. The influence of fuel type and quality, lubricant oil type, and use of fuel additives on the formation of these compounds was tested using standardized U.S. Federal Test Procedure (FTP)-75 cycle tests. The sampling of the PCDD/Fs followed the recommendations of a modified U.S. Environmental Protection Agency (EPA) Method 23 ( http://www.epa.gov/ttn/emc/promgate/m-23.pdf ) and the analysis basically followed the U.S. EPA Method 8290 ( http://www.epa.gov/osw/hazard/testmethods/sw846/pdfs/8290a.pdf ). Results showed that emission factors of PCDD/Fs for the gasohol vehicle varied from undetected to 0.068 pg international toxic equivalency (I-TEQ) km-1 (average of 0.0294 pg I TEQ km-1), whereas in the ethanol vehicle they varied from 0.004 to 0.157 pg (I TEQ) km-1 (average of 0.031 pg I-TEQ km-1). In the gasohol-powered vehicle, the use of fuel additive diminished the emission of Octachlorodibenzo-p-dioxin (OCDD) significantly, whereas in the ethanol vehicle no significant associations were observed between the investigated variables and the emissions. [Box: see text]. PMID- 28097956 TI - Biohydrogen production from used diapers: Evaluation of effect of temperature and substrate conditioning. AB - This research assessed the viability to use disposable diapers as a substrate for the production of biohydrogen, a valuable clean-energy source. The important content of cellulose of disposable diapers indicates that this waste could be an attractive substrate for biofuel production. Two incubation temperatures (35 degrees C and 55 degrees C) and three diaper conditioning methods (whole diapers with faeces, urine, and plastics, WD; diapers without plastic components, with urine and faeces, DWP; diapers with urine but without faeces and plastic, MSD) were tested in batch bioreactors. The bioreactors were operated in the solid substrate anaerobic hydrogenogenic fermentation with intermittent venting mode (SSAHF-IV). The batch reactors were loaded with the substrate at ca. 25% of total solids and 10% w/w inoculum. The average cumulative bioH2 production followed the order WD > MSD > DWP. The bio-H2 production using MSD was unexpectedly higher than DWP; the presence of plastics in the first was expected to be associated to lower degradability and H2 yield. BioH2 production at 55 degrees C was superior to that of 35 degrees C, probably owing to a more rapid microbial metabolism in the thermophilic regime. The results of this work showed low yields in the production of H2 at both temperatures compared with those reported in the literature for municipal and agricultural organic waste. The studied process could improve the ability to dispose of this residue with H2 generation as the value-added product. Research is ongoing to increase the yield of biohydrogen production from waste disposable diapers. PMID- 28097958 TI - Message from the Technical Editor-in-Chief. PMID- 28097957 TI - If medical education was a discipline, she would have five core competencies. AB - To date, many medical schools define medical educators by who they teach rather than the quality of their engagement with learners. In addition, evidence suggests that a traditional terminal degree may not satisfy the developmental needs of educators engaged in competency based medical education. Perhaps, medical educators require additional competencies. This personal view introduces five competencies that enliven the way in which medical educators engage in career paths, recruitment, performance assessment, compensation, and professional development. PMID- 28097959 TI - 2012 Reviewers. PMID- 28097960 TI - Erratum. PMID- 28097961 TI - Corrigendum. PMID- 28097975 TI - UK may face shortfall of 36,000 nurses by 2030. AB - The UK faces a potential shortage of more than 36,000 nurses by 2030, a new study has shown. PMID- 28097974 TI - Abstracts From the 2016 Annual Meeting. PMID- 28097976 TI - Staying enthusiastic after years in nursing. AB - Nursing teams are usually made up of a broad range of knowledge, skills and cultures. Experience only comes with time, and though we are becoming more aware of the need to respect diversity, ongoing misconceptions surrounding ageing can make working as a mature nurse challenging. PMID- 28097977 TI - Police investigate saline tampering. AB - A police investigation is under way at North Cumbria University Hospitals NHS Trust after staff noticed a small number of saline bags appeared to have been tampered with in the Cumberland Infirmary. PMID- 28097979 TI - 'This diagnosis can be extremely scary'. AB - Neurofibromatosis type 2 (NF2) is a rare genetic disorder that occurs in an estimated one in 35,000 people. The condition is often life-limiting and involves tumours growing on the nervous system, typically on the hearing nerves, brain and spine. While the tumours are mainly benign, they can lead to hearing loss, deafness and problems with balance and mobility. Most patients will need surgery or other treatments for NF2-related brain or spinal cord tumours at some point in their lives. PMID- 28097981 TI - Winter crisis increases need to speak up about poor care. AB - Nurses need to raise concerns and speak up now more than ever, the nurse who exposed appalling treatment of patients at Stafford Hospital has urged. PMID- 28097980 TI - Student life - How to ace an exam. AB - As a nursing student, you can expect to sit exams in anything from anatomy and physiology to numeracy and medicine management, and it's important not to let nerves get the better of you. PMID- 28097982 TI - Diversion tactics won't fix a system at breaking point. AB - Winter is always a challenge for the NHS, with the bad weather arriving just as hospitals and community service providers are running out of money at the end of the financial year. PMID- 28097983 TI - TV documentary highlights the reality of working in the NHS. AB - A new TV documentary shows the reality of working for one of the busiest trusts in the NHS. PMID- 28097984 TI - Grow your own career. AB - I recently read an advertisement with the headline 'Goodbye job, hello career'. Although it was for an accountancy course, the same message could easily apply to nursing. PMID- 28097985 TI - Cognitive therapy effective early treatment for children with PTSD. AB - Cognitive therapy can be an effective treatment for children and adolescents with post traumatic stress disorder (PTSD), new study results suggest. PMID- 28097986 TI - Enjoyment of life in older age associated with living longer. AB - Sustained enjoyment of life over several years in older age is associated with lower mortality, and the longer a person reports enjoying life, the lower their risk of death, say researchers from University College London. PMID- 28097988 TI - White managers must tackle discrimination. AB - At the end of last year I received a letter informing me I was to be made a Dame for services to nursing and the Mary Seacole Statue Appeal in the new year's honours list. It came as a great shock to me. PMID- 28097989 TI - About Me (autism passport). AB - This app can improve information sharing for children and young people with a diagnosis of autism, or those undergoing an autism assessment. PMID- 28097987 TI - NHS in crisis: health and care experts call for action. AB - Royal colleges, charities and even the head of NHS England have issued warnings to prime minister Theresa May about the state of the health service. PMID- 28097991 TI - Nursing: An Exquisite Obsession Clark June Nursing: An Exquisite Obsession 220pp L12.99 Quay Books 9781856425094 1856425096 [Formula: see text]. AB - One of the publishing trends of recent years has been nursing memoirs. Heartwarming anecdotes of the nursing care provided for eccentric patients are generally combined with attacks on supposed developments in nurse education after about 1975, and the whole account is bathed in the light of a golden age that has passed. This memoir emphatically rejects such nostalgia. PMID- 28097990 TI - Lowering body temperature improves outcomes in adults with traumatic brain injury. AB - Lowering the body temperature of adults who experience a traumatic brain injury can significantly improve chances of survival, new study results suggest. PMID- 28097992 TI - Blood test could predict risk of heart attack and subsequent death. AB - A high-sensitivity blood test, known as a troponin test, could predict the risk of heart attack and death and patients' response to statins, say researchers from the Universities of Edinburgh and Glasgow. PMID- 28097993 TI - Exploring how mindfulness and self-compassion can enhance compassionate care. AB - Research suggests that the development of mindfulness and self-compassion may help to improve the well-being and resilience of professionals and students in the healthcare setting. This is reflected in the growth of mindfulness training for these individuals. Mindfulness is an important aspect of self-compassion, and healthcare professionals should be aware of the need to care for themselves when caring for others. This article explores the concepts of mindfulness and self compassion and their relationship with, and ability to enhance, compassionate care. PMID- 28097994 TI - Pressure rises in care home sector. AB - There are more beds in nursing and care homes than in NHS hospitals, yet it is only when things go wrong that the importance of the care sector is brought home to us. PMID- 28097995 TI - Gestational Diabetes: Your Survival Guide to Diabetes in Pregnancy Grant Paul Gestational Diabetes: Your Survival Guide to Diabetes in Pregnancy 128pp L9.99 Sheldon Press 9781847094414 1847094414 [Formula: see text]. AB - Gestational diabetes is one of the most common pregnancy complications, and this book is aimed at women who have developed the condition. PMID- 28097996 TI - Additional MRI scan can aid diagnosis of fetal abnormality. AB - Women whose mid-pregnancy ultrasound scans show a potential fetal abnormality should be given an additional MRI scan, say researchers from the University of Sheffield. PMID- 28097998 TI - Fast-track course halves three-year nursing degree. AB - A fast-track nursing degree course in north east England, aimed at addressing the UK's nurse shortage, will take on new students in March. PMID- 28097997 TI - The 4C framework for making reasonable adjustments for people with learning disabilities. AB - Background People with learning disabilities experience significant inequalities in accessing healthcare. Legal frameworks, such as the Equality Act 2010, are intended to reduce such disparities in care, and require organisations to make 'reasonable adjustments' for people with disabilities, including learning disabilities. However, reasonable adjustments are often not clearly defined or adequately implemented in clinical practice. Aim To examine and synthesise the challenges in caring for people with learning disabilities to develop a framework for making reasonable adjustments for people with learning disabilities in hospital. This framework would assist ward staff in identifying and managing the challenges of delivering person-centred, safe and effective healthcare to people with learning disabilities in this setting. Method Fourth-generation evaluation, collaborative thematic analysis, reflection and a secondary analysis were used to develop a framework for making reasonable adjustments in the hospital setting. The authors attended ward manager and matron group meetings to collect their claims, concerns and issues, then conducted a collaborative thematic analysis with the group members to identify the main themes. Findings Four main themes were identified from the ward manager and matron group meetings: communication, choice-making, collaboration and coordination. These were used to develop the 4C framework for making reasonable adjustments for people with learning disabilities in hospital. Discussion The 4C framework has provided a basis for delivering person-centred care for people with learning disabilities. It has been used to inform training needs analyses, develop audit tools to review delivery of care that is adjusted appropriately to the individual patient; and to develop competencies for learning disability champions. The most significant benefit of the 4C framework has been in helping to evaluate and resolve practice-based scenarios. Conclusion Use of the 4C framework may enhance the care of people with learning disabilities in hospital, by enabling reasonable adjustments to be made in these settings. PMID- 28097999 TI - After 54 years in NHS, nursing assistant celebrates her 80th birthday at work. AB - One of the UK's oldest nursing assistants celebrated her 80th birthday with a party at work. PMID- 28098001 TI - Charity enlists nurses to tackle loneliness in older people. AB - An Age UK pilot programme involving nurses is helping to combat loneliness in older people, early findings show. PMID- 28098000 TI - The crisis we all saw coming. AB - The British Red Cross is absolutely right to talk about a humanitarian crisis in the NHS (news online, 6 January; see analysis page 12 ). This strong, emotive terminology is sadly accurate. PMID- 28098002 TI - 'At our lowest points Emma was always there to comfort us'. AB - Our daughter Annabelle was rushed to Evelina Children's Hospital in London. She was seriously ill with acute disseminated encephalomyelitis, a rare disease marked by a sudden, widespread attack of inflammation in the brain and spinal cord. PMID- 28098003 TI - Cervical cancer. AB - Essential facts In the UK in 2013 there were about 3,200 new cases of cervical cancer. It is the 12th most common cancer in UK women, resulting in 890 deaths in 2014. Deaths in England are more common in women living in the most deprived areas. PMID- 28098005 TI - Department of Health backs overhaul of NMC's fitness to practise process. AB - The government has backed proposals to overhaul the Nursing and Midwifery Council's (NMC) 'outdated' legal framework, which could save more than L60 million over the next decade. PMID- 28098006 TI - Emergency departments in crisis. PMID- 28098007 TI - New plan for mental health. AB - The prime minister's announcements about her plans for mental health care are great (news online, 9 January). Or they would be if I hadn't heard it before. PMID- 28098009 TI - Jamaica warns of nurse 'poaching'. AB - Health care in Jamaica is facing 'major and severe' consequences due to nursing staff leaving to work overseas, the country's health minister has warned. PMID- 28098010 TI - Safe staffing is more than a numbers game. AB - Nothing gives a worse impression to the public than a nurse sitting at a desk, tapping away, when he or she should be at the bedside with patients. PMID- 28098011 TI - An evaluation of the Florence Nightingale Foundation scholarships. AB - The Florence Nightingale Foundation (FNF) is a charity that awards scholarships in leadership, travel and research to nurses, midwives and other healthcare professionals to promote excellence in practice. The FNF offers mentoring support to scholars, and provides support with career development and writing articles for publication, in addition to the financial award. The leadership scholarships are bespoke: leadership scholars can access a range of development opportunities that are specially commissioned for them, and select their programme of study and experiences, based on their individual needs. All scholarships provide opportunities to represent the FNF and to meet other scholars at the FNF annual conference. This article provides an overview of the FNF scholarships, based on the findings of two evaluations that demonstrated the value of these scholarships in improving services for patients and carers, as well as enhancing the careers of individual scholars. PMID- 28098012 TI - Emotional intelligence is essential to leadership. AB - Leadership is about influencing others to achieve a common goal. However, this role can be an emotional burden due to the challenges, constant changes and relationships with others. PMID- 28098014 TI - Pressure ulcer prevention. AB - What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The CPD article discussed the importance of preventing pressure ulcers in frail older people. It outlined the risk factors, classification and effects of pressure ulcers, and the methods used to prevent their development. PMID- 28098018 TI - 'Don't be afraid to push at doors'. AB - Alison Twycross started her nursing career in 1981, volunteering at a local hospice while doing her A levels. A registered adult, mental health and children's nurse, she has worked in nurse education for 21 years and is professor and head of children's nursing at London South Bank University. Ms Twycross has edited three books on research related to managing pain in children, and is the editor of the RCNi journal Evidence-Based Nursing. PMID- 28098017 TI - This new year could match 2016 for exciting nursing developments. AB - As this is my first nurse leader column of 2017, I wish everyone a happy new year, although it probably seems a distant memory now. PMID- 28098019 TI - A lesson in the fundamentals. AB - I chose to visit the Philippines for my elective placement at the end of my second year of training. I worked in the department of psychiatry in a small government hospital in a deprived city. PMID- 28098020 TI - Readers' panel - Are there too many routes into nursing? AB - Our experts consider a hot topic of the day. PMID- 28098021 TI - Don't accept bullying, especially due to race. AB - A recent study from Birmingham City University uncovered some alarming examples of students' reactions to negative feedback from their mentors, ranging from manipulative behaviour to making threats and allegations of bullying. PMID- 28098022 TI - System dynamics research of remanufacturing closed-loop supply chain dominated by the third party. AB - With the rapid development of the electronic information industry in recent years, electronic products are being updated faster and faster, and e-waste recycling has become a common problem around the world. Firstly, this article contrasts recycling at home and abroad using the predicament of Midea Corp. Based on a closed-loop supply chain with the system dynamics method, a model is constructed and simulated. In this model, the collection point coverage rate is introduced to adjust the e-waste recycling rate dynamically. Aiming at a recycling mode dominated by the third party of the closed-loop supply chain, the article mainly discusses the impact on the sales rate and market share of the recycling model by third-party enterprises and compares the total revenue of all supply chains. Simulation results show that the model is more effective and optimal than the traditional recycling model. PMID- 28098036 TI - Erratum. PMID- 28098023 TI - Key parameters for behaviour related to source separation of household organic waste: A case study in Hanoi, Vietnam. AB - Proper management of food waste, a major component of municipal solid waste (MSW), is needed, especially in developing Asian countries where most MSW is disposed of in landfill sites without any pretreatment. Source separation can contribute to solving problems derived from the disposal of food waste. An organic waste source separation and collection programme has been operated in model areas in Hanoi, Vietnam, since 2007. This study proposed three key parameters (participation rate, proper separation rate and proper discharge rate) for behaviour related to source separation of household organic waste, and monitored the progress of the programme based on the physical composition of household waste sampled from 558 households in model programme areas of Hanoi. The results showed that 13.8% of 558 households separated organic waste, and 33.0% discharged mixed (unseparated) waste improperly. About 41.5% (by weight) of the waste collected as organic waste was contaminated by inorganic waste, and one third of the waste disposed of as organic waste by separators was inorganic waste. We proposed six hypothetical future household behaviour scenarios to help local officials identify a final or midterm goal for the programme. We also suggested that the city government take further actions to increase the number of people participating in separating organic waste, improve the accuracy of separation and prevent non-separators from discharging mixed waste improperly. PMID- 28098039 TI - Corrigendum. PMID- 28098041 TI - [Prevalence of diabetes mellitus in the Netherlands more than doubled in the period 1999-2014]. AB - OBJECTIVE: To study the trend in the prevalence of diabetes in the Netherlands during the period 1999-2014. DESIGN: Descriptive study of prevalence. METHODS: The prevalence of diabetes during the period 1999-2014 was calculated on the basis of data from the PHARMO Database Network, a network of electronic databases that includes data from public pharmacies for 3.8 million residents of the Netherlands. A person with diabetes was defined as someone with at least two dispensings for a glucose lowering-drug within six months. Prevalence was adjusted for variation in age demographics per sex to investigate the influence of these variations on population demographics. RESULTS: The prevalence of diabetes in the Netherlands increased from 1.8% in 1999 to 4.9% in 2014. The increase was more pronounced among men as age increased. Only half of the increase was explained by changes in age demographics per sex. CONCLUSION: The study showed that the prevalence of diabetes more than doubled during the period 1999-2014. This trend can only be partly explained by changes in age demographics per sex. PMID- 28098040 TI - [Hypocortisolism associated with nephrotic syndrome]. AB - BACKGROUND: With nephrotic syndrome, cortisol levels may be falsely lowered by loss of cortisol-binding globulin (CBG) in the urine. An incorrect diagnosis of adrenal insufficiency could therefore be made. CASE DESCRIPTION: We describe the case of a 52-year-old female with nephrotic syndrome that did not sufficiently respond to medication. Treatment management was complicated by symptomatic hypotension, which was thought to be caused by adrenal insufficiency. The cortisol levels in the blood were low and a clinical cause could not be identified. However, free cortisol in the saliva appeared normal and serum CBG levels were low; this therefore precluded adrenal insufficiency. After complete remission of the nephrotic syndrome, cortisol levels normalised. CONCLUSION: The reduced cortisol level in this patient was caused by the reduced CBG level due to loss associated with nephrotic syndrome. First and foremost it is important to indicate an abnormal laboratory result within an existing disease, before making a new diagnosis of concomitant disease. PMID- 28098042 TI - [Joining forces for quality improvement in tuberculosis control]. AB - The incidence of tuberculosis (TB) in the Netherlands is declining every year. We fear there may be a loss of knowledge and awareness of detecting TB in the new generation of medical specialists. As medical specialists a great challenge lies before us in maintaining the quality of TB control in the Netherlands. Collaboration between pulmonologist, infectious disease specialist, microbiologist and the public health services is a necessity. Here we describe how, in the region of Arnhem, we work closely with these medical specialists based on structural multidisciplinary meetings. We also describe two of the quality indicators - doctor's delay and HIV testing policy - which are included in the national plan for TB control for 2016-2020. We explain how we intend to maintain and improve the quality of TB control by means of our structural meetings and collaboration. PMID- 28098043 TI - [The effects of smoking on health: growth of knowledge reveals even grimmer picture]. AB - - In this article we give a short overview of new insights into the effects of smoking on health, both on smokers themselves and on those who are exposed to other people's tobacco smoke.- The number of diseases and conditions that are known to be caused by active smoking has now risen to over thirty.- The risk of premature death is not, as previously thought, twice as high in smokers as in non smokers, but actually three times as high.- Passive smoking too has been shown to have a whole range of negative effects on health.- Further, the causal mechanisms of, amongst other things, the development of cancer, ischaemic heart disease and nicotine dependence under the influence of smoking have been largely unravelled.- Various issues require further investigation; these include the effect of smoking on psychological health and the effects of 'third-hand' smoke. In the meantime, a concerted campaign against this consumer product with its deleterious effects of the health of the population is overdue. PMID- 28098044 TI - [An acutely dyspnoeic woman after acupuncture]. AB - A 42-year-old woman without a medical history presented herself to the emergency room with sudden onset of dyspnoea and progressive tachypnoea. The X-ray showed a bilateral pneumothorax. Additional anamnesis suggested this was caused by thoracic acupuncture she had received that afternoon because of her chronic low back pain. PMID- 28098045 TI - [On the timing of randomised studies: the sooner initiated, the better?] AB - The study design for randomised double-blind studies is powerful. Randomisation and blinding ensure that the groups that are compared are truly exchangeable. Any differences in health outcomes can be attributed rightfully to the one aspect on which the study groups differ: the treatment. In this commentary, we argue that the use of this powerful study design at the wrong moment can lead to undesirable situations. PMID- 28098046 TI - Monitoring the effects of iodine prophylaxis in the adult population of southern Italy with deficient and sufficient iodine intake levels: a cross-sectional, epidemiological study. AB - I prophylaxis is the most effective strategy to eradicate I deficiency disorders, but it has been shown to affect the thyroid disease pattern. In this study, we assessed the frequency of thyroid disorders in an adult population living in two areas of southern Italy after implementing I prophylaxis. To this aim, a cross sectional, population-based study including 489 subjects from an I-deficient rural and an I-sufficient urban area of southern Italy was conducted. Thyroid ultrasound was performed on all participants, and urine and blood samples were collected from each subject. The levels of thyroid-stimulating hormone (TSH), thyroglobulin (TgAb) and thyroperoxidase antibodies (TPOAb), urinary I excretion (UIE), and thyroid volume and echogenicity were evaluated. We found that the median UIE was higher in the urban than in the rural area (P=0.004), whereas the prevalence of subjects affected by goitre was higher in the rural compared with the urban area (P=0.003). Positive TgAb rather than TPOAb were more frequent in subjects from the urban area compared with the rural area (P=0.009). The hypoechoic pattern at thyroid ultrasound (HT-US) was similar between the two areas, but TgAb were significantly higher (P=0.01) in HT-US subjects from the urban area. The frequency of elevated TSH did not differ between the two screened populations, and no changes were found for TgAb positivity in subjects with high TSH in the urban compared with the rural area. Our findings support that the small risks of I supplementation are far outweighed by the substantial benefits of correcting I deficiency, although continued monitoring of populations is necessary. PMID- 28098047 TI - Vitamin A deficiency suppresses fish immune function with differences in different intestinal segments: the role of transcriptional factor NF-kappaB and p38 mitogen-activated protein kinase signalling pathways. AB - The present study investigated the effects of dietary vitamin A on immune function in the proximal intestine (PI), mid intestine (MI) and distal intestine (DI) of young grass carp (Ctenopharyngodon idella). Fish were fed graded levels of dietary vitamin A for 10 weeks, and then a challenge test using an injection of Aeromonas hydrophila was conducted for 14 d. The results showed that, compared with the optimum vitamin A level, vitamin A deficiency significantly decreased fish growth performance, increased enteritis morbidity, decreased intestinal innate humoral immune response and aggravated intestinal inflammation. However, liver-expressed antimicrobial peptide 2A/B mRNA in the DI and IL-6, IL-17D, IL 10, transforming growth factor (TGF)-beta1 and TGF-beta2 mRNA in the PI were not affected by vitamin A levels. Meanwhile, vitamin A deficiency disturbed inflammatory cytokines in the PI, MI and DI, which might be partly linked to p38 mitogen-activated protein kinase (p38MAPK) signalling and NF-kappaB canonical signalling pathway (IkappaB kinase beta (IKKbeta), IKKgamma, inhibitor of kappaBalpha, NF-kappaB p65 and c-Rel) rather than NF-kappaB non-canonical signalling pathway (NF-kappaB p52 and IKKalpha). However, the signalling molecules NF-kappaB p65 and p38MAPK did not participate in regulating cytokines in the PI. These results suggested that vitamin A deficiency decreased fish growth and impaired intestinal immune function, and that different immune responses in the PI, MI and DI were mediated partly by NF-kappaB canonical signalling and p38MAPK signalling pathways. On the basis of percentage of weight gain, to protect fish against enteritis morbidity and acid phosphatase activity, the optimum dietary vitamin A levels were estimated to be 0.664, 0.707 and 0.722 mg /kg, respectively. PMID- 28098048 TI - Folate and vitamin B12 concentrations are associated with plasma DHA and EPA fatty acids in European adolescents: the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study. AB - This study aimed to examine the association between vitamin B6, folate and vitamin B12 biomarkers and plasma fatty acids in European adolescents. A subsample from the Healthy Lifestyle in Europe by Nutrition in Adolescence study with valid data on B-vitamins and fatty acid blood parameters, and all the other covariates used in the analyses such as BMI, Diet Quality Index, education of the mother and physical activity assessed by a questionnaire, was selected resulting in 674 cases (43 % males). B-vitamin biomarkers were measured by chromatography and immunoassay and fatty acids by enzymatic analyses. Linear mixed models elucidated the association between B-vitamins and fatty acid blood parameters (changes in fatty acid profiles according to change in 10 units of vitamin B biomarkers). DHA, EPA) and n-3 fatty acids showed positive associations with B vitamin biomarkers, mainly with those corresponding to folate and vitamin B12. Contrarily, negative associations were found with n-6:n-3 ratio, trans-fatty acids and oleic:stearic ratio. With total homocysteine (tHcy), all the associations found with these parameters were opposite (for instance, an increase of 10 nmol/l in red blood cell folate or holotranscobalamin in females produces an increase of 15.85 umol/l of EPA (P value <0.01), whereas an increase of 10 nmol/l of tHcy in males produces a decrease of 2.06 umol/l of DHA (P value <0.05). Positive associations between B-vitamins and specific fatty acids might suggest underlying mechanisms between B-vitamins and CVD and it is worth the attention of public health policies. PMID- 28098049 TI - Influence of barley grain particle size and treatment with citric acid on digestibility, ruminal fermentation and microbial protein synthesis in Holstein calves. AB - Chemical and physical treatments of barley grain increase ruminally resistant starch and can improve the rumen fermentation pattern. The objective of the present study was to evaluate the effects of chemical (addition of citric acid, CA) and physical (grinding to two different particle sizes, PS) treatment of barley grain on performance, rumen fermentation, microbial protein yield in the rumen and selected blood metabolites in growing calves. In all, 28 male Holstein calves (172+/-5.1 kg initial BW) were used in a complete randomised design with a factorial arrangement of 2 barley grain particle sizes*2 levels of citric acid. The diets were as follows: (i) small PS (average 1200 um) barley grain soaked in water (no CA addition); (ii) small PS barley grain soaked in a CA solution (adding 20 g CA/kg barley); (iii) large PS (average 2400 um) barley grain soaked in water (no citric acid addition) and (iv) large PS barley grain soaked in a citric acid solution (adding 20 g CA/kg barley). Barley grain was then incorporated at 35% in a total mixed ration and fed to the calves for 11 weeks. Feeding small PS barley decreased feed intake (P=0.02) and average daily weight gain (P=0.01). The addition of CA to barley grain did not affect intake but increased weight gain (P0.05). However, the molar proportion of propionate was increased (P=0.03) when barley was more finely ground, and that of acetate was increased (P=0.04) when CA was added to barley grain. The ruminal concentration of ammonia nitrogen was increased (P<0.01) and microbial nitrogen synthesis in the rumen tended to decrease by adding CA to barley. Treating barley grain with citric acid increased fibre digestibility of total mixed rations, attenuated the decrease in ruminal pH, and improved weight gain and feed efficiency in male Holstein growing calves fed a high-cereal diet (550 g cereal grain/kg diet). PMID- 28098050 TI - Dairy food supplementation may reduce malnutrition risk in institutionalised elderly. AB - Malnutrition in institutionalised elderly increases morbidity and care costs. Meat and dairy foods are high-quality protein sources so adequate intakes may reduce malnutrition risk. We aimed to determine whether inadequate intakes of meat and dairy foods contribute to malnutrition in institutionalised elderly. This cross-sectional study involved 215 elderly residents (70.2 % females, mean age 85.8 years) from twenty-one aged-care facilities in Melbourne, Australia. Dietary intake was assessed using observed plate waste. Food groups and serving sizes were based on the Australian Guide to Healthy Eating. Nutrient content was analysed using a computerised nutrient analysis software (Xyris). Malnutrition risk was assessed using the Mini Nutrition Assessment (MNA) tool; a score between 24 and 30 indicates normal nutritional status. Data were analysed using robust regression. Mean MNA score was 21.6 (sd 2.7). In total, 68 % of residents were malnourished or at risk of malnutrition (MNA score<=23.5). Protein intake was 87 (sd 28) % of the Australian recommended dietary intake (RDI). Consumption averaged 1 serving each of dairy foods and meat daily. Number of dairy and meat servings related to proportion of protein RDI (both P24 points). Provision of meat and dairy foods did not meet recommended levels. On the basis of current dietary intakes in aged-care residents, increasing consumption of dairy foods to the recommended four servings daily ensures protein adequacy and may reduce malnutrition risk in institutionalised elderly, and so reduce risk of comorbidities and costs associated with malnutrition. PMID- 28098051 TI - Chronic Fatigue Syndrome: Cognitive, Behavioural and Emotional Processing Vulnerability Factors. AB - BACKGROUND: Cognitive-behavioural models of chronic fatigue syndrome (CFS) suggest that personality factors such as perfectionism and high moral standards may contribute to the development of CFS. AIMS: To investigate cognitive, behavioural and emotional processing risk factors for CFS. METHOD: CFS patients (n = 67) at a UK specialist clinic completed questionnaires about psychological characteristics both currently and retrospectively (6 months pre-CFS onset). Responses were compared with those of healthy individuals (n = 73) who rated their current characteristics. Forty-four relatives retrospectively rated the pre morbid psychological characteristics of the CFS participants. RESULTS: CFS patients showed similar levels of current perfectionism to controls, though higher pre-morbid perfectionism. CFS patients showed greater self-sacrificial beliefs and more unhelpful beliefs about experiencing and expressing negative emotions, both currently but more markedly prior to onset. In the 6 months pre illness onset, CFS patients showed more disruption to their primary goal and greater general stress than controls. Ratings of pre-morbid psychological characteristics by relatives were consistent with patients' self-reports. The extent of overinvestment in one goal was significantly associated with fatigue. CONCLUSIONS: Perfectionism, self-sacrificial tendencies, unhelpful beliefs about emotions, and perceived stress may be present to a greater extent pre-morbidly in CFS patients compared with healthy individuals. PMID- 28098052 TI - Effect of maternal dietary counselling during the 1st year of life on glucose profile and insulin resistance at the age of 8 years: a randomised field trial. AB - Education interventions that stimulate complementary feeding practices can improve the nutritional status of children and may protect against future chronic diseases. We assessed the long-term effectiveness of dietary intervention during the 1st year of life on insulin resistance levels, and investigated the relationship between insulin resistance and weight changes over time. A randomised field trial was conducted among 500 mothers who gave birth to full term infants between October 2001 and June 2002 in a low-income area in Sao Leopoldo, Brazil. Mother-child pairs were randomly assigned to intervention (n 200) and control groups (n 300), and the mothers in the intervention group received dietary counselling on breast-feeding and complementary feeding of their children during the 1st year of life. Fieldworkers blinded to assignment assessed socio-demographic, dietary and anthropometric data during follow-up at ages 1, 4 and 8 years. Blood tests were performed in 305 children aged 8 years to measure fasting serum glucose and insulin concentrations and the homoeostasis model assessment index of insulin resistance (HOMA-IR). At the age of 8 years, the intervention group showed no changes in glucose and insulin concentrations or HOMA-IR values (change 0.07; 95 % CI -0.06, 0.21 for girls; and change -0.07; 95 % CI -0.19, 0.04 for boys) compared with study controls. Insulin resistance was highly correlated, however, with increases in BMI between birth and 8 years of age. Although this dietary intervention had no impact on glucose profile at age 8 years, our findings suggest that BMI changes in early childhood can serve as an effective marker of insulin resistance. PMID- 28098053 TI - Dairy consumption is associated with a lower incidence of the metabolic syndrome in middle-aged and older Korean adults: the Korean Genome and Epidemiology Study (KoGES). AB - This cohort study examined the association between total and individual dairy products and the risk of developing the metabolic syndrome (MetS) and its components in Korean adults from the Korean Genome and Epidemiology Study. We prospectively analysed 5510 participants aged 40-69 years without the MetS at baseline during a 10-year follow-up period. Dairy consumption was assessed with a semi-quantitative FFQ at baseline and after 4 years. The MetS was defined according to the criteria by the National Cholesterol Education Program Adult Treatment Panel III. The Cox's proportional hazard model was used to examine the association between consumption of total dairy products, milk and yogurt in servings per week and the risk of incident MetS or individual components. A total of 2103 subjects developed the MetS (38.2 %) during an average follow-up of 67.4 months (range 17-104 months). Frequent dairy consumption (>7 servings of total dairy and milk/week, >=4 servings of yogurt/week) was associated with a reduced risk of incident MetS and its components. In the multivariable adjusted model, hazard ratios for the MetS were 0.51 (95 % CI 0.43, 0.61) for total dairy products, 0.50 (95 % CI 0.38, 0.66) for milk and 0.67 (95 % CI 0.57, 0.78) for yogurt in frequent consumers compared with non-consumers. An inverse association between milk/yogurt and low HDL-cholesterol was shown only in women. In conclusion, high consumption of individual dairy products including milk and yogurt as well as total dairy were associated with a reduced risk of incident MetS and individual components in Korean adults. PMID- 28098054 TI - Long-term esophageal motility changes after thyroidectomy: associations with aerodigestive disorders. AB - BACKGROUND: Patients undergoing thyroidectomy often complain aerodigestive disorders. In a previous study we showed the associations between voice impairment and proximal acid reflux, swallowing impairment and Upper Esophageal Sphyncter (UES) incoordination and the decrease in UES pressure in thirty-six patients observed before and soon afterwards uncomplicated thyroidectomy. This study investigated the state of post-thyroidectomy esophageal motility changes and its associations with these disorders after 18-24 months. PATIENTS AND METHODS: The thirty-six patients prospectively recruited according to selection criteria (thyroid volume <=60 ml, benign disease, age 18-65 years, previous neck surgery, thyroiditis, pre- or postoperative vocal cord palsy) underwent voice (VIS) and swallowing (SIS) impairment scores, esophageal manometry and pH monitoring once again. RESULTS: After 18-24 months, both VIS and SIS recovered (respectively: p=0,022; p=0,0001); UES pressure increased (p=0,0001) nearing the preoperative values. The persistence of swallowing complaints were associated with the persistence of esophageal incoordination (p=0,03); the association between voice impairment and proximal acid reflux was confirmed (p<0,001). CONCLUSIONS: Our study confirms that aerodigestive disorders after uncomplicated thyroidectomy, largely transient, are strictly connected with upper esophageal motility changes. In this viewpoint, the innervation of upper aerodigestive anatomical structures (larynx, pharynx, upper esophagus) and its variations should be focused. PMID- 28098055 TI - Nonsurgical treatment of Mason type II radial head fractures in athletes. A retrospective study. AB - OBJECTIVE: The best treatment for moderately displaced radial head fractures (Mason type II) still remains controversial. In cases of isolated fractures, there is no evidence that a fragment displacement of >= 2 mm gives poor results in conservatively treated fractures. PATIENTS AND METHODS: We retrospectively reviewed 52 patients (31M, 21F) affected by an isolated Mason type II fracture, treated with a long arm cast for two weeks between 2008 and 2013. All patients had practiced sports before being injured. They were all either bicyclists, or baseball, boxers, basketball, rugby, tennis or football players. The mean follow up was 36 months. Elbow and forearm range of motion were measured. The Mayo Elbow Performance Score, the Broberg and Morrey rating system and the Disabilities of the Arm, Shoulder and Hand Score (DASH score) were analyzed. Follow-up radiographs were examined for evidence of consolidation, late displacement, early arthritis and non-unions. RESULTS: Flexion was slightly impaired in the injured limb when compared to the uninjured limb (137 degrees +/- 6 degrees versus 139 degrees +/-5 degrees ) as were extension (-3 degrees +/-6 degrees versus 1 degrees +/-4 degrees , p < 0.05), supination (86 degrees +/-6 degrees versus 88 degrees +/-3 degrees ), pronation (87 degrees +/-4 degrees versus 88 degrees +/ 6 degrees ) and valgus deviation (10 degrees +/-4 degrees versus 8 degrees +/-3 degrees , p < 0.05). 40 patients had no elbow complaints; 9 patients experienced occasional pain, 2 a mild instability of the elbow, and 4 a mild loss of grip strength. The DASH score was excellent in 48 patients (92.31%). In only 6 cases (11.53%) degenerative changes were greater in formerly injured elbows than in uninjured elbows. All patients returned to their previous sports activities. CONCLUSIONS: Isolated Mason type II fractures can have a good or excellent mid term functional outcome even when treated conservatively. PMID- 28098056 TI - Follow-up of multicentric HCC according to the mRECIST criteria: role of 320-Row CT with semi-automatic 3D analysis software for evaluating the response to systemic therapy. AB - AIM: To evaluate the role of 320-detector row computed tomography (MDCT) with 3D analysis software in follow up of patients affected by multicentric hepatocellular carcinoma (HCC) treated with systemic therapy by using modified response evaluation criteria in solid tumors (mRECIST). PATIENTS AND METHODS: 38 patients affected by multicentric HCC underwent MDCT. All exams were performed before and after iodinate contrast material intravenous injection by using a 320 detection row CT device. CT images were analyzed by two radiologists using multi planar reconstructions (MPR) in order to assess the response to systemic therapy according to mRECIST criteria: complete response (CR), partial response (PR), progressive disease (PD), stable disease (SD). 30 days later, the same two radiologists evaluated target lesion response to systemic therapy according to mRECIST criteria by using 3D analysis software. The difference between the two systems in assessing HCC response to therapy was assessed by the analysis of the variance (Anova Test). Interobserver agreement between the two radiologists by using MPR images and 3D analysis software was calculated by using Cohen's Kappa test. RESULTS: PR occurred in 10/38 cases (26%), PD in 6/38 (16%), SD in 22/38 (58%). Anova Test showed no statistically significant difference between the two systems for assessing target lesion response to therapy (p >0.05). Inter-observer agreement (k) was respectively of 0.62 for MPR images measurements and 0.86 for 3D analysis ones. CONCLUSIONS: 3D Analysis software provides a semiautomatic system for assessing target lesion response to therapy according to mRECIST criteria in patient affected by multifocal HCC treated with systemic therapy. The reliability of 3D analysis software makes it useful in the clinical practice. PMID- 28098057 TI - Totally implantable catheter migration and its percutaneous retrieval: case report and review of the literature. AB - Totally subcutaneous intravascular portals have been increasingly used to administer long-term chemotherapy and parental nutrition. The reported complications are rare. Accidental endovascular rupture of a fragment of catheter is one of the most formidable complications of the central vein catheterization. The Authors report a case of deployment of a Port-a-Cath catheter and its percutaneous retrieval. The catheter accidentally detached and migrated from the reservoir of the port-a-cath placed in the left subclavian vein to the right heart cavities through the blood stream. A review of the Literature is also given, focusing on the possible factors responsible for this unusual complication. PMID- 28098058 TI - Repair of an inguinoscrotal hernia in a patient with Becker muscular dystrophy. AB - INTRODUCTION: Inguinal hernia repairs are routinely performed as outpatient procedures in most patients, whereas a few require admission due to clinical or social peculiarities. Muscular dystrophies are inherited disorders characterized by progressive muscle wasting and weakness. In case of surgery there is no definite recommendation for either general or regional anesthesia. CASE REPORT: This contribution regards a 48 y. o. male patient diagnosed with Becker Muscular Dystrophy by muscle biopsy 10 years earlier. He had a left-sided sizable inguinoscrotal hernia with repeat episodes of incarceration. An elective mesh repair with suction drainage was accomplished under selective spinal anesthesia. The post-operative course was uneventful. DISCUSSION: A few inguinal hernia repairs require admission due to peculiarities such as extensive scrotal hernias requiring suction drainage. Muscular dystrophies are inherited disorders with no cure and no two dystrophy patients are exactly alike, therefore the health issues will be different for each individual. In case of surgery there is no definite recommendation for either general or regional anesthesia. This contribution regards the successful elective mesh repair with suction drainage of a large left sided inguino-scrotal hernia in a 48 y. o. male patient affected by Becker muscular dystrophy by selective spinal anesthesia obtained by 10 milligrams of hyperbaric bupivacaine. CONCLUSION: Effective mesh repair with suction drainage of large inguinal hernias under spinal anesthesia can be achieved in patients affected by muscular dystrophy. PMID- 28098059 TI - Laparoscopic ileocecal resection in acute and chronic presentations of Crohn's disease. A single center experience. AB - INTRODUCTION: The terminal ileum is the most involved tract in Crohn's disease. The obstruction in this location is the most frequent complication. Acute or chronic presentations can occur. Surgery finds a role in the management of chronic strictures and in acute clinical presentations with complications not improving with conservative therapy. PATIENTS AND METHODS: We investigate the outcome of patients with obstruction of the ileo-cecal bowel tract laparoscopically managed. It was analyzed the average operative time (OT), the conversion rate and the occurrence of re-operation due to surgical complications. RESULTS: 21 patients underwent an ileocecal resection for complicated Crohn's disease between January 2013 and December 2014. The admissions were performed in emergency in 42% of patients. The preintervention hospital stay was 5.8 (Sd 6.23). The mean operative time was 154 min (Sd 41). 28% of the procedures were converted to open surgery. The average hospital stay was 10 days (Sd 5) in uncomplicated patients. The morbidity rate was 28%. In 19% of cases a re intervention was needed due to anastomotic leakage (3pts) and one hemoperitoneum for bleeding from the suture line. DISCUSSION: Laparoscopy seems an affordable technique in the management of obstructive pattern of Crohn's disease. It should be the preferable approach in young patients that probably will be submitted to subsequent surgery for the same disease; in fact, the reduced adhesions formation provided by the less bowel manipulation make easy the subsequent access. Older patients had usually more post-operative morbidity and mortality mostly due to pre-existing conditions; if possible in these patients the treatment should be medical. PMID- 28098060 TI - Gripping forceps "double action" for micro-neurosurgery. AB - Gripping forceps "double action" for microneurosurgery. PMID- 28098062 TI - history, art, humanity in surgery. PMID- 28098061 TI - Prostate cancer immunotherapy, particularly in combination with androgen deprivation or radiation treatment. Customized pharmacogenomic approaches to overcome immunotherapy cancer resistance. AB - Conventional therapeutic approaches for advanced prostate cancer - such as androgen deprivation, chemotherapy, radiation - come up often against lack of effectiveness because of possible arising of correlative cancer cell resistance and/or inadequate anti-tumor immune conditions. Whence the timeliness of resorting to immune-based treatment strategies including either therapeutic vaccination-based active immunotherapy or anti-tumor monoclonal antibody-mediated passive immunotherapy. Particularly attractive, as for research studies and clinical applications, results to be the cytotoxic T-lymphocyte check point blockade by the use of anti-CTLA-4 and PD-1 monoclonal antibodies, particularly when combined with androgen deprivation therapy or radiation. Unlike afore said immune check point inhibitors, both cell-based (by the use of prostate specific antigen carriers autologous dendritic cells or even whole cancer cells) and recombinant viral vector vaccines are able to induce immune-mediated focused killing of specific antigen-presenting prostate cancer cells. Such vaccines, either used alone or concurrently/sequentially combined with above-mentioned conventional therapies, led to generally reach, in the field of various clinical trials, reasonable results particularly as regards the patient's overall survival. Adoptive trasferred T-cells, as adoptive T-cell passive immunotherapy, and monoclonal antibodies against specific antigen-endowed prostate cancer cells can improve immune micro-environmental conditions. On the basis of a preliminary survey about various immunotherapy strategies, are here also outlined their effects when combined with androgen deprivation therapy or radiation. What's more, as regard the immune-based treatment effectiveness, it has to be pointed out that suitable personalized epigenetic/gene profile-achieved pharmacogenomic approaches to target identified gene aberrations, may lead to overcome - as well as for conventional therapies - possible prostate cancer resistance to immunotherapy. PMID- 28098063 TI - The Use of E-Cigarettes. AB - BACKGROUND: Electronic cigarettes (e-cigarettes) are a consumer product whose benefits and risks are currently debated. Advocates of the "tobacco harm reduction" strategy emphasize their potential as an aid to smoking cessation, while advocates of the precautionary principle emphasize their risks instead. There have been only a few studies to date on the prevalence of e-cigarette use in Germany. METHODS: In May 2016, in collaboration with Forsa, an opinion research firm, we carried out a survey among 4002 randomly chosen persons aged 14 and older, asking them about their consumption of e-cigarettes with and without nicotine, reasons for using e-cigarettes, plans for future use, estimation of danger compared to that of tobacco products, smoking behavior, and sociodemographic features. RESULTS: 1.4% of the respondents used e-cigarettes regularly, and a further 2.2% had used them regularly in the past. 11.8% had at least tried them, including 32.7% of smokers and 2.3% of persons who had never smoked. 24.5% of ex-smokers who had quit smoking after 2010 had used e-cigarettes at least once. 20.7% of the respondents considered electronic cigarettes less dangerous than conventional cigarettes, 46.3% equally dangerous, and 16.1% more dangerous. An extrapolation of these data to the general population suggests that about one million persons in Germany use e-cigarettes regularly and another 1.55 million have done so in the past. CONCLUSION: The consumption of electronic cigarettes in Germany is not very widespread, but it is not negligible either. Nearly 1 in 8 Germans has tried e-cigarettes at least once. Regular consumers of e-cigarettes are almost exclusively smokers and ex-smokers. PMID- 28098064 TI - The Association of Hyponatremia, Risk of Confusional State, and Mortality. AB - BACKGROUND: Hyponatremia and delirium are frequent problems in older hospitalized patients. Although confusional states are considered to be a possible complication of hyponatremia, there has been no systematic study to date of the precise prevalence of delirium among patients with hyponatremia and its effect on long-term outcomes. METHODS: In a 13-month period in 2009/2010, all patients with a serum sodium level less than or equal to 130 mmol/L (the hyponatremia group) in a cohort of hospitalized older patients were studied and compared to a normonatremic control group of patients who were matched for age, sex, and diagnosis group. The prevalence of delirium was determined by two-stage examination. Inhospital mortality, mortality six months after initial examination, and functional status were prospectively analyzed. RESULTS: 179 patients were identified whose serum sodium level was less than or equal to 130 mmol/L (7.9% of all treated patients), of whom 141 were included in the hyponatremia group. The mean age of the participants was 83 (range, 63-102), and 84% were women. Patients with hyponatremia suffered more often from delirium (22.7% versus 8.5%; p = 0.002) and had a higher inhospital mortality (10.6% versus 2.1%; p = 0.005). The mortality six months after initial examination was 31.9% versus 22.7% (p = 0.080). 59.7% of patients in the hyponatremia group and 49% in the control group (p = 0.146) needed a higher level of chronic care after discharge than they had needed before the hospitalization. CONCLUSION: Hyponatremia in hospitalized older patients is associated with a higher likelihood of delirium and an elevated in-hospital mortality. PMID- 28098065 TI - The Treatment of Post-Thrombotic Syndrome. AB - BACKGROUND: Post-thrombotic syndrome (PTS) arises in 20-50% of patients who have sustained a deep vein thrombosis and markedly impairs their quality of life. METHODS: This review is based on pertinent publications retrieved by a selective literature search in PubMed and the Cochrane Library, and on the guidelines of the German Societies of Phlebology and Vascular Surgery (Deutsche Gesellschaft fur Phlebologie, Deutsche Gesellschaft fur Gefasschirurgie). RESULTS: The treatment options are conservative treatment with compression and patient exercises, endovascular recanalization with stent angioplasty, and open bypass surgery of the iliac obstructions. The endovascular techniques yield patency rates of 73 to 100%, with thrombotic stent occlusion and hematoma as potential complications. The open operations have only been documented in studies with small case numbers (3 to 85 cases per study, patency rates 58 to 100%). The complications of these invasive procedures can include thrombotic bypass occlusion, hematoma, and wound infection. There have been randomized trials of conservative treatment, but not of surgical treatment. The American Heart Association, in its guidelines, gives the same weak recommendation for all surgical methods (IIb). CONCLUSION: All conservative options should be exhausted as the first line of treatment. If PTS symptoms persist and markedly impair the patient's quality of life, the possible indication for surgery should be considered. As PTS hardly ever leads to death or limb loss, its treatment should be as uninvasive as possible. Endovascular recanalization is an attractive option in this respect. A conclusive evaluation of the role of endovascular procedures in PTS must await randomized trials of this form of treatment and of the optimal stent configuration. PMID- 28098066 TI - Surgical Treatment of Type 2 Diabetes. PMID- 28098067 TI - Renal Function in Type 2 Diabetes Following Gastric Bypass. AB - BACKGROUND: Metabolic surgery for obese patients with type 2 diabetes (T2D) yields short- and long-term remission rates of 60-90%. Its effects on diabetesassociated complications such as neuropathy and nephropathy have not been well studied to date. Hardly any data are available on this subject with respect to moderately obese patients (body mass index [BMI] 25-35 kg/m2) with insulin dependent T2D. Our previous studies suggest that, in such patients, treatment with a Roux-en-Y gastric bypass (RYGB) improves diabetic neuropathy. In this pilot study, we investigate the course of diabetic nephropathy after RYGB surgery. METHODS: 20 insulin-dependent patients whose T2D was inadequately controlled with medication, and whose BMI was in the range 25-35 kg/m2, were prospectively included in a pilot study. All patients underwent a standardized RYGB operation. Blood and urine tests for renal function were performed before surgery and 12 and 24 months afterward. RESULTS: The serum creatinine level fell from 0.82 +/- 0.23 to 0.69 +/- 0.13 mg/dL (p = 0.0025) in the first 12 months after surgery and was unchanged a further 12 months later. The glomerular filtration rate (eGFR) rose in the first 24 months after surgery from 96.4 +/- 28.7 to 111.7 +/- 23.3 mL/min/1.73 m2 (p = 0.0093). The urinary albumin/creatinine and high-molecular-weight adiponectin/creatinine ratios fell markedly in the first 24 months after surgery (2.89 +/- 3.14 versus 1.00 +/- 0.24 mg/mmol [p = 0.0491] and 0.18 +/- 0.06 versus 0.04 +/- 0.01 MUg/g [p = 0.0392]). CONCLUSION: RYGB has positive effects on renal function and may therefore be a good treatment option for moderately obese, insulin-dependent patients whose T2D cannot be adequately controlled with medication. These results still need to be confirmed in randomized, controlled trials with longer periods of followup. PMID- 28098069 TI - Simultaneous Echinococcal Cyst and Hepatocellular Carcinoma Without Underlying Liver Disease. PMID- 28098068 TI - The Differential Diagnosis of Dyspnea. AB - BACKGROUND: Dyspnea is a common symptom affecting as many as 25% of patients seen in the ambulatory setting. It can arise from many different underlying conditions and is sometimes a manifestation of a life-threatening disease. METHODS: This review is based on pertinent articles retrieved by a selective search in PubMed, and on pertinent guidelines. RESULTS: The term dyspnea refers to a wide variety of subjective perceptions, some of which can be influenced by the patient's emotional state. A distinction is drawn between dyspnea of acute onset and chronic dyspnea: the latter, by definition, has been present for more than four weeks. The history, physical examination, and observation of the patient's breathing pattern often lead to the correct diagnosis, yet, in 30-50% of cases, more diagnostic studies are needed, including biomarker measurements and other ancillary tests. The diagnosis can be more difficult to establish when more than one underlying disease is present simultaneously. The causes of dyspnea include cardiac and pulmonary disease (congestive heart failure, acute coronary syndrome; pneumonia, chronic obstructive pulmonary disease) and many other conditions (anemia, mental disorders). CONCLUSION: The many causes of dyspnea make it a diagnostic challenge. Its rapid evaluation and diagnosis are crucial for reducing mortality and the burden of disease. PMID- 28098070 TI - Epidemiology of Cryptosporidium infection in cattle in China: a review. AB - The present review discusses the findings of cryptosporidiosis research conducted in cattle in China and highlights the currently available information on Cryptosporidium epidemiology, genetic diversity, and distribution in China, which is critical to understanding the economic and public health importance of cryptosporidiosis transmission in cattle. To date, 10 Cryptosporidium species have been detected in cattle in China, with an overall infection rate of 11.9%. The highest rate of infection (19.5%) was observed in preweaned calves, followed by that in juveniles (10.69%), postweaned juveniles (9.0%), and adult cattle (4.94%). The dominant species were C. parvum in preweaned calves and C. andersoni in postweaned, juvenile, and adult cattle. Zoonotic Cryptosporidium species (C. parvum and C. hominis) were found in cattle, indicating the possibility of transmission between humans and cattle. Different cattle breeds had significant differences in the prevalence rate and species of Cryptosporidium. This review demonstrates an age-associated, breed-associated, and geographic-related occurrence of Cryptosporidium and provides references for further understanding of the epidemiological characteristics, and for preventing and controlling the disease. PMID- 28098071 TI - Kikuchi's disease: cutaneous involvement and dermoscopic features. PMID- 28098072 TI - Near-infrared image-guided super-selective intra-arterial infusion of high-dose cisplatin for squamous cell carcinoma on the lower lip. PMID- 28098073 TI - Classical density functional study of wetting transitions on nanopatterned surfaces. AB - Even simple fluids on simple substrates can exhibit very rich surface phase behaviour. To illustrate this, we consider fluid adsorption on a planar wall chemically patterned with a deep stripe of a different material. In this system, two phase transitions compete: unbending and pre-wetting. Using microscopic density-functional theory, we show that, for thin stripes, the lines of these two phase transitions may merge, leading to a new two-dimensional-like wetting transition occurring along the walls. The influence of intermolecular forces and interfacial fluctuations on this phase transition and at complete pre-wetting are considered in detail. PMID- 28098074 TI - Comment on 'Electronic structure of Mo(1-x)Re x alloys studied through resonant photoemission spectroscopy'. AB - Further analysis of the resonant photoemission data, found within Sundar et al (2016 J. Phys.: Condens. Matter 28 315502), show the intensities do not follow the elemental composition in the Mo1-x Re x alloy. Similar trends are observed in the published data for Gd1-x Ni x alloy films. The analysis of the resonant photoemission intensities suggests that Mo in the Mo1-x Re x alloy and Gd in the Gd1-x Ni x alloy have nearest neighbor bonds to Re and Ni respectively. This means the A-B bond is favored over the average of the A-A bond and the B-B bond in these binary alloys, so that the short range order favors strong local ordering rather than clustering alloys. PMID- 28098075 TI - Anisotropic superconducting property studies of single crystal PbTaSe2. AB - The anisotropic superconducting properties of PbTaSe2 single crystal is reported. Superconductivity with T c = 3.83 +/- 0.02 K has been characterized fully with electrical resistivity rho(T), magnetic susceptibility chi(T), and specific heat C p (T) measurements using single crystal samples. The superconductivity is type-II with lower critical field H c1 and upper critical field H c2 of 65 and 450 Oe (H? to the ab-plane), 140 and 1500 Oe (H|| to the ab-plane), respectively. These results indicate that the superconductivity of PbTaSe2 is anisotropic. The superconducting anisotropy, electron-phonon coupling lambda ep, superconducting energy gap Delta0, and the specific heat jump DeltaC/gammaT c at T c confirms that PbTaSe2 can be categorized as a bulk superconductor. PMID- 28098076 TI - Melting of large Pt@MgO(1 0 0) icosahedra. AB - On the basis of ab initio calculations, we present a new parametrisation of the Vervisch-Mottet-Goniakowski (VMG) potential (Vervisch et al 2002 Phys. Rev. B 24 245411) for modelling the oxide-metal interaction. Applying this model to mimic the finite temperature behaviour of large platinum icosahedra deposited on the pristine MgO(1 0 0), we find the nanoparticle undergoes two solid-solid transitions. At 650 K the 'squarisation' of the interface layer, while a full reshaping towards a fcc architecture takes place above 950 K. In between, a quite long-lived intermediate state with a (1 0 0) interface but with an icosahedral cap is observed. Our approach reproduces experimental observations, including wetting behaviour and the lack of surface diffusion. PMID- 28098077 TI - Salt Reduction at a Population Level: To do or not to do? PMID- 28098078 TI - Knowledge, attitude and behaviour of the general population towards organ donation: An Indian perspective. AB - BACKGROUND: The rate of organ donation in India is low and research on organ donation among the general population is limited. We assessed the knowledge, attitude and willingness to donate organs among the general population. METHODS: We carried out a cross-sectional descriptive study among 193 randomly selected relatives of patients (not of those seeking organ donation) attending the outpatient department at a tertiary care centre. We used a structured questionnaire to collect data through face-to-face interviews. RESULTS: We found that 52.8% of the participants had adequate knowledge and 67% had a positive attitude towards organ donation. While 181 (93.8%) participants were aware of and 147 (76.2%) supported organ donation, only 120 (62.2%) were willing to donate organs after death. Further, there were significant associations between age, gender, education, economic status and background of the participants with their intention to donate organs. CONCLUSION: Our study advocates for public education programmes to increase awareness among the general population about the legislation related to organ donation. PMID- 28098079 TI - Hyperthermic intraperitoneal chemotherapy for peritoneal surface malignancies: A single institution Indian experience. AB - BACKGROUND: Cytoreductive surgery followed by hyper- thermic intraperitoneal chemotherapy (HIPEC) has shown better oncological outcomes in peritoneal surface malignancies (PSM). We assessed the feasibility and perioperative outcomes of this procedure in Indian patients. METHODS: In this prospective observational study from February 2013 to April 2015, we included 56 patients (41 females, 73.2%) with PSM. They had a good performance status, were either treatment-naive or previously treated by surgery and systemic chemotherapy. They underwent cytoreductive surgery followed by HIPEC using a hyperthermia pump, with the temperature at 42 degrees C for 30-90 minutes. The chemotherapy regimen was based on the primary malignancy. Perioperative outcome data were collected and analysed. We also analysed the short-term oncological outcomes. RESULTS: Our patients included those with peritoneum confined ovarian carcinoma (32, 57.1%), colorectal carcinoma (9, 16.1%), pseudomyxoma peritonei (7, 12.5%), meso- thelioma (2, 3.6%), gastric carcinoma (2, 3.6%) and others (4, 7.1%). The median duration of surgery including HIPEC was 9 hours and the median hospital stay was 12 days. The median time for gastrointestinal recovery was 5 days. One-fifth of patients (11, 19.7%) required an extended stay in the inten- sive care unit. The most common grades 3 and 4 complications were hypocalcaemia 32.1%, hypokalaemia 32.1%, anaemia 21.4% and thrombocytopenia 7.1%. Major morbidity requiring surgical intervention occurred in 8.9% of patients. The 60-day operative mortality was 1.8%. At a median follow-up of 16 months, 7.1% developed peritoneal recurrence, 8.9% had systemic recurrence and 7.1% succumbed to the disease. Patients with platinum-resistant ovarian carcinomas had more peritoneal recurrence (3.6%). CONCLUSION: In patients with PSM, surgical cytoreduction and HIPEC is feasible and potentially beneficial. It can be done with low mortality and acceptable morbidity. It requires a dedicated team of surgeons, anaesthetists and intensivists and proper infrastructure. PMID- 28098080 TI - Access to healthcare among the Empowered Action Group (EAG) states of India: Current status and impeding factors. AB - BACKGROUND: Access to healthcare is crucial for meeting the health needs of Indians. We explored factors impeding access to public sources of healthcare among the Empowered Action Group (EAG) states of India. We also examined the extent to which Indians depend on public and private sources of healthcare in the EAG states. METHODS: Our study is based on the unit-level records of 9988 ailing persons, who were surveyed among the EAG states in the 71st round of the National Sample Survey (NSS), conducted during January-June 2014 on the theme 'Social consumption: Health'. To analyse the socioeconomic factors, we did logistic regression using STATA version 12.0. RESULTS: Despite a vast public health infrastructure in the EAG states, around three-fourths of inpatients are dependent on private sources of healthcare in both rural (70%) and urban (78%) areas. Poor quality and long waiting time in accessing healthcare from public health facilities remain big concerns for inpatients of the EAG states. CONCLUSION: To make public health services more accessible, there is a need to improve the quality of services, enlarge infrastructure to reduce waiting time, and enhance the physical reach to inpatients in the EAG states of India. Public health services will then be able to compete with those in the private sector. PMID- 28098081 TI - Is tobacco use increasing among medical students of Bengaluru city, India? Evidence from two cross-sectional studies. AB - BACKGROUND: Studies investigating secular changes in tobacco use are rare in India. We estimated self-reported prevalence of tobacco use, across a 5-year interval, among medical students in Bengaluru, India. METHODS: We did two cross sectional studies during 2007 and 2013 among third year undergraduate medical students of four medical colleges in Bengaluru. A self-administered questionnaire was used to elicit information on tobacco smoking and chewing. RESULTS: The participation rates were 82% (323/395) in 2007 and 78% (253/324) in 2013 (p=0.2). Among males, there was no statistically significant change in prevalence of current smoking (3.5% [6/172] in 2007 to 8.9% [12/135] in 2013 [p=0.053]); experimental use of tobacco had however increased from 24% (41/172) in 2007 to 42% (56/135) in 2013 (p=0.001). Similarly among females, experimental use was reported by 3.3% (5/151) in 2007 and 11.2% (13/116) in 2013 (p=0.01). Current smoking among female students was <1 % in both the study years. Reported current chewing levels remained unchanged among males, 1.8% (2/171) and 3.7% (5/135) (p=0.2) and fell from 4% (6/146) in 2007 to 0% in 2013 among females (p=0.04). CONCLUSION: There was no increase in current smoking or chewing of tobacco but there was an increase in experimental smoking among male and female medical students in this southern Indian city. Schools and colleges must include tobacco control education in their curriculum. PMID- 28098082 TI - Occupational health profile of workers employed in the manufacturing sector of India. AB - BACKGROUND: The occupational health scenario of workers engaged in the manufacturing sector in India deserves attention for their safety and increasing productivity. We reviewed the status of the manufacturing sector, identified hazards faced by workers, and assessed the existing legislations and healthcare delivery mechanisms. METHODS: From October 2014 to March 2015, we did a literature review by manual search of pre-identified journals, general electronic search, electronic search of dedicated websites/databases and personal communication with experts of occupational health. RESULTS: An estimated 115 million workers are engaged in the manufacturing sector, though the Labour Bureau takes into account only one-tenth of them who work in factories registered with the government. Most reports do not mention the human capital employed neither their quality of life, nor occupational health services available. The incidence of accidents were documented till 2011, and industry-wise break up of data is not available. Occupational hazards reported include hypertension, stress, liver disease, diabetes, tuberculosis, eye/ hearing problems, cancers, etc. We found no studies for manufacturing industries in glass, tobacco, computer and allied products, etc. The incidence of accidents is decreasing but the proportion of fatalities is increasing. Multiple legislations exist which cover occupational health, but most of these are old and have not been amended adequately to reflect the present situation. There is a shortage of manpower and occupational health statistics for dealing with surveillance, prevention and regulation in this sector. CONCLUSION: There is an urgent need of a modern occupational health legislation and an effective machinery to enforce it, preferably through intersectoral coordination between the Employees' State Insurance Corporation, factories and state governments. Occupational health should be integrated with the general health services. PMID- 28098083 TI - Vaccination against malaria: A dream too distant? PMID- 28098084 TI - Genomic classification of acute myeloid leukaemia: An incessantly evolving concept. PMID- 28098085 TI - Experience of a faculty development workshop in mentoring at an Indian medical college. AB - BACKGROUND: Our medical college is running a mentoring programme for undergraduate medical students since 2009. The academic leadership of the college identified the need to change the focus of the programme from mere problem- solving to professional and personal development of mentees. METHODS: A core group of faculty designed and implemented a workshop on mentoring for 28 mentors. The workshop included reflections on the participants' previous experiences about mentoring, discussion on perceptions of mentees about the existing mentoring programme, self-analysis of mentoring skills, overview of the Surrendering, Accepting, Gifting and Extending (SAGE) model and demonstration of effective mentoring skills using role plays and a film. We collected written anonymous feedback from participants at the end of the workshop to elicit their responses regarding various aspects of the programme, change in their views about mentoring and suggestions for future workshops. RESULTS: A majority of the participants (17, 60.7%) said that role plays and reflection on role plays were the most valuable part of workshop as they provided clarity on the concepts about mentoring. The most frequently identified take-home messages were: building trust with the mentee (7, 25%), balance in life and approach towards the mentee (6, 21.4%), and understanding that mentoring is a process geared towards personal and professional development of the mentee (6, 21.4%). CONCLUSION: The participants' reaction to the workshop was positive. The responses of participants suggested that the workshop was successful in changing their views regarding the purpose of the mentoring programme. PMID- 28098086 TI - Movement for Global Mental Health: The crusade and its critique. PMID- 28098087 TI - Specialization and the Indian healthcare scenario: Have we got it right? PMID- 28098088 TI - Building research capacity in resource-poor settings: Triumphs and challenges. PMID- 28098089 TI - Doyle and the Edalji Case. PMID- 28098090 TI - Letter from Mumbai. PMID- 28098091 TI - Letter from Ganiyari. PMID- 28098092 TI - Haemoglobin H disease: All in the family. PMID- 28098093 TI - Hirayama disease. PMID- 28098094 TI - The point system of the Dental Council of India for publications by faculty. PMID- 28098096 TI - The prevalence of pregnancy-related acute renal failure in Asia: A systematic review. AB - Acute renal failure (ARF) is a major complication during pregnancy and is associated with high mortality rate in developing countries. The aim of this study was to report the prevalence of pregnancy-related ARF in Asia. This study is a systematic review Google Scholar, PubMed, and Medline databases were searched for all papers in English on pregnancy related ARF (PR-ARF) in Asian countries that were published between 2010 and 2015 were reviewed. Of all the articles published in that period, 19 were selected - 17 were original articles and two were cases reports. We gathered information on the prevalence of PR-ARF, parity, duration of pregnancy when PR-ARF developed, etiology of PR-ARF, common clinical symptoms, and laboratory findings in PR-ARF. PMID- 28098097 TI - Protective role of Nigella sativa in diabetic nephropathy: A randomized clinical trial. AB - This study aims to evaluate efficacy and safety of Nigella sativa oil supplementation in patients with chronic kidney disease Stage 3 and 4 due to diabetic nephropathy. It was a prospective, comparative, and open-label study. Patients were randomized into two groups. Group 1 (Control) received conservative management of diabetic nephropathy, whereas Group 2 (Test) received N. sativa oil (2.5 mL, once daily and per orally) along with conservative management for 12 weeks. Blood glucose, hemogram, and kidney function test were done at 0, 6, and 12 weeks of treatment. Significance of differences between pre- and post treatment values in each group was assessed using Student's paired t-test and between the groups using unpaired t-test. We found a drop in blood glucose, serum creatinine, blood urea, and 24 h total urinary protein levels and a rise in glomerular filtration rate, 24 h total urinary volume, and hemoglobin level in the treatment group compared to the control group. PMID- 28098098 TI - A study of clinical assessment of frailty in patients on maintenance hemodialysis supported by cashless government scheme. AB - This is a prospective cohort study to assess the prevalence of frailty in patients undergoing maintenance hemodialysis (HD) under the government-funded scheme at our center and to assess the relationship between frailty and falls, hospitalizations, and mortality. This was done at our center which is completely supported by the government, which provides HD to all the patients under poverty line. Epidemiological data, anthropometric measurements, comorbidities assessment, frailty assessment using Fried criteria, subsequent hospitalizations, falls, and mortality were recorded in our prevalent dialysis population at our center between October 2014 and October 2015. Two hundred and twenty-six patients were enrolled during this period. Twenty-one patients were excluded as they did not satisfy the inclusion criteria. Two hundred and five prospective patients were studied for the predictors of frailty. Frailty was present in 82% of the study population. Mean age of our study population was 44.95 +/- 13.27 years. On univariate analysis, diabetes mellitus, hypertension (HTN), cerebrovascular accident (CVA), left ventricular dysfunction (LVD), peripheral vascular disease (PVD), smoking, hepatitis C, inadequate dialysis, intradialytic hypotension (IDH), interdialytic weight gain, low serum creatinine <4 mg/dL, and anemia (Hb <10 g/dL) were found to be statistically significantly different between frail and nonfrail groups On multivariate regression analysis, only HTN, PVD, CVA, anemia, smoking, and IDH were found to be significant. Frailty is highly prevalent among dialysis population. Factors predicting frailty include HTN, smoking, LVD, PVD, CVA, smoking, anemia, and IDH. Frailty is a significant risk factor for falls and hospitalizations. PMID- 28098099 TI - The evaluation of the relationship between serum levels of Interleukin-6 and Interleukin-10 and metabolic acidosis in hemodialysis patients. AB - Chronic kidney disease is defined as progressive kidney dysfunction. The levels of various cytokines increase in hemodialysis (HD) patients. High levels of interleukins (ILs) and presence of metabolic acidosis are described as independent risk factors for morbidity and mortality in these patients. This study was designed to evaluate the relationship between IL-6 and IL-10 and serum bicarbonate and metabolic acidosis in HD patients. In this analytical crosssectional study, patients referred to the HD units of Loghman Hakim and Shahid Ashrafi Esfahani Hospitals were randomly selected. Demographic and laboratory data, such as albumin, creatinine, calcium, phosphorus, parathormone, C-reactive protein, complete blood count, ferritin, ILs-6 and -10, and arterial blood gas analysis, were recorded for each patient. The correlation between IL and serum bicarbonate and other variables were evaluated by SPSS software. The patients were compared for the presence of acidosis and positivity for IL. A total of 84 patients with a mean age of 60.98 years and mean body mass index of 24.86 kg/m[2] were evaluated (53% male and 57% female). The mean dialysis duration was 24.86 +/- 3.98 months. Overall, 41.7% of the patients had diabetes mellitus and 36.9% of them had hypotension. The mean serum levels of IL-6 and IL 10 were 6.036 and 17.46 pg/ml, respectively. There was a significant correlation between IL-6 and IL-10 levels and serum bicarbonate and the incidence of metabolic acidosis (P <0.05). Based on the results, metabolic acidosis and bicarbonate could be considered prognostic factors to differentiate the increased levels of IL-6 and IL-10 and associated morbidity and mortality. PMID- 28098100 TI - Impact of residual renal function on clinical outcome and quality of life in patients on peritoneal dialysis. AB - We studied the impact of residual renal function (RRF) on clinical outcome and quality of life in 61 patients on peritoneal dialysis (PD). They were assigned to two groups, at the time of initiation of PD, based on their estimated glomerular filtration rate (eGFR). The high RRF group had eGFR >=5 mL/min/1.73 m[2] and the low RRF group hade GFR <5 mL/min/1.73 m[2]. All patients were followed up at regular intervals for clinical and biochemical variables. Baselines characteristics including age, sex, body mass index and cause of the kidney disease were similar in both groups. The high RRF group had a higher rate of continuous ambulatory peritoneal dialysis discontinuation. The incidence of peritonitis was higher in the low RRF group. Other infections (cellulitis, gastroenteritis, sepsis) were more common in patients with low RRF, compared to the high RRF group. The quality of life as assessed by depression score, restless leg syndrome, and sleep quality were poor in patients with reduced RRF. We found that a high RRF at the time of initiation of PD, significantly decreased the incidence of infections, depression, better nutrition, and lower levels of alkaline phosphatase; providing indirect evidence of better renal clearance of phosphorous, in those with preserved RRF. PMID- 28098101 TI - Insulin resistance in predialytic, nondiabetic, chronic kidney disease patients: A hospital-based study in Eastern Uttar Pradesh, India. AB - Most investigations have focused on patients with end-stage renal disease (ESRD). More recently, due to increased recognition of the high prevalence of moderate-to severe chronic kidney disease (CKD), attention has been redirected to this patient population to identify risk factors associated with hospitalization, death, and progression to ESRD. The objective of this study was to examine the degree and determinants of insulin resistance (IR) in predialytic, nondiabetic, CKD patients. Our study is a hospital-based cross-sectional study. The participants were aged 18 years and above with CKD due to any cause, were all nondiabetic patients, and the mean serum creatinine was 1.41-5 mg/dL. Anthropometric parameters included body weight, height, and skinfold thickness. Homeostasis model assessment of IR (HOMA-IR) score was 2.5 +/- 1.2 in CKD patients and 1.9 +/- 0.7 in controls. In the unadjusted analysis, there was a significant (P <0.05) correlation between HOMA-IR and body mass index (BMI), waist circumference, cholesterol, and triglyceride (TG) levels. Upon adjusting for age and sex, total body fat (BF), globulin, TG, and C-reactive protein were having positive, significant (P <0.05) correlation with HOMA-IR. In multivariate regression models, BMI and total BF% were significant (P <0.05) predictors of IR in patients with CKD but not in controls. BF% and BMI are indicators of IR in CKD as in non-CKD population. PMID- 28098102 TI - Evaluation of renal lesions and clinicopathologic correlation in rheumatoid arthritis. AB - The most common causes of renal disease in rheumatoid arthritis (RA) are glomerulonephritis (GN), amyloidosis, tubulo-interstitial nephritis, and drug toxicity. Our aim was to evaluate the clinicopathologic correlation of renal lesions and to assess the course and prognosis of renal disease in patients with RA. We conducted a prospective observational study in all adult patients with RA between July 2010 and June 2015. The total number of patients studied was 90, with a female:male ratio of 2.3:1. Mean follow-up duration was 30 +/- 6.5 months. About 54 patients (60%) were asymptomatic. The most common symptom was edema legs (30%), followed by oliguria (10%). About 18 patients (20%) presented with the nephrotic syndrome, 15 patients (16.6%) with nephritic syndrome, and 30 (33%) with asymptomatic urinary abnormalities. Chronic kidney disease (CKD) was seen in 48 of 90 patients (53%).The most common renal pathology noted was mesangioproliferative GN followed by membranous nephropathy (MN). IgM with C3 deposits was the most common immunofluorescence pattern observed. Among the patients who had glomerular diseases, complete remission was seen in nine patients, partial remission in 15, and persistent proteinuria in 14. Duration of RA and a high erythrocyte sedimentation rate correlated significantly with persistent proteinuria. Only one patient in the glomerular disease group progressed to dialysis-dependent renal failure. On followup, 11 out of 48 CKD patients showed a significant decrease in estimated glomerular filtration rate and worsened to the next stage of CKD. Renal disease in RA presents with varied renal pathology. MN was seen frequently and was not associated with gold or penicillamine usage. Relatively high incidence of CKD was noted. Hence, it is important to monitor renal function abnormalities periodically in these patients. PMID- 28098103 TI - Relation of fibroblast growth factor-23 and cardiovascular calcification in end stage kidney disease patients on regular hemodialysis. AB - More than half of deaths in end-stage kidney disease (ESKD) patients are due to cardiovascular disease. Elevated fibroblast growth factor 23 (FGF-23) was found to be associated with mortality in hemodialysis (HD) patients and correlates with peripheral calcification. Aortic calcification is associated with coronary artery calcification. Both aortic and peripheral vascular calcifications were associated with mortality in chronic kidney disease. We aimed to investigate the relation between intact FGF-23 and cardiovascular calcification in patients with ESKD who were maintained on regular HD. Sixty clinically stable ESKD patients on regular HD were enrolled into this cross-sectional study. They were evaluated by basal abdominal X-ray. They were divided into two groups: (Group A, n = 30), patients with abdominal aortic calcification who underwent multislice computerized tomography scan to measure coronary artery calcification score; and (Group B, n = 30), patients without abdominal aortic calcification. All of them were evaluated by lipid profile and dialysis adequacy parameters. Fifty percent of patients had vascular calcification. We found a significant positive correlation between age and intact FGF-23; significant positive correlations between age, body mass index, duration of HD, and abdominal aortic calcification score. FGF-23 of all patients was elevated and had significant positive correlation with aortic and coronary calcifications in addition to lipid profile, left ventricular mass index (LVMI), and inflammatory markers. Plasma intact FGF-23 was elevated in nondiabetic ESKD patients, and vascular calcification was prevalent in such group of patients with many traditional and nontraditional risk factors. Possibly through its disturbing effects on minerals and parathyroid hormone, FGF-23 might indirectly affect vascular calcification. LVMI was higher in patients with vascular calcification and correlated positively with it. PMID- 28098104 TI - Evaluation of arterial stiffness in nondiabetic chronic kidney disease patients. AB - Chronic kidney disease (CKD) is a growing problem worldwide. Clinical and epidemiologic studies have shown that structural and functional changes that occur in major arteries are a major contributing factor to the high mortality in uremic patients. Recent studies have shown a stepwise increase of the carotid femoral pulse wave velocity (cfPWV) from CKD Stage 1 to Stage 5. We evaluated the cfPWV and augmentation index (AIx), as indirect markers of arterial stiffness in patients with nondiabetic CKD and compared the values with normal population; we also evaluated the relationship between various stages of CKD and arterial stiffness markers. This cross-sectional study was carried out in the Department of Nephrology for a duration of two years from January 15, 2012, to January 14, 2014. Fifty patients with nondiabetic CKD were studied along with 50 healthy volunteers who did not have CKD, who served as controls. Assessment of arterial stiffness (blood pressure, PWV, heart rate, aortic augmentation pressure, and AIx) was performed using the PeriScope device. PWV positively correlated with systolic and diastolic blood pressure, mean aortic arterial pressure, serum creatinine, and serum uric acid and negatively correlated with estimated glomerular filtration rate. Arterial stiffness increased as CKD stage increased and was higher in nondiabetic CKD group than in the general population. Arterial stiffness progressed gradually from CKD Stage 2 to 5, and then abruptly, in dialysis patients. Measures to decrease the arterial stiffness and its influence on decreasing cardiovascular events need further evaluation. PMID- 28098105 TI - Fasting in Ramadan is not associated with deterioration of chronic kidney disease: A prospective observational study. AB - Although not mandatory for patients, many Muslims fast in Ramadan. We aimed to investigate the effects of long hours (17.5) fasting on renal functions in patients with chronic kidney disease (CKD). Stage 3-5 CKD patients with stable renal function were recruited to this prospective observational study three months ahead of Ramadan in 2015. All patients were instructed regarding possible deleterious effects of dehydration caused by fasting. Forty-five patients (mean age 66.8 +/- 10.3 years, 68.8% male) chose to fast and 49 (mean, age: 64.1 +/- 12.6 years, 51% male) chose not to fast. Clinical and laboratory data were recorded before and after Ramadan. Baseline clinical and laboratory parameters were similar in the two groups, except for higher serum creatinine and lower estimated glomerular filtration rate (eGFR) in the nonfasting group (2.22 +/- 0.99 vs. 1.64 +/- 0.41 mg/dL, P <0.001 and 3 1.9 +/- 12.4 vs. 42.6 +/- 9.8 mL/min, P <0.001, respectively). More than 30% elevation in serum creatinine after Ramadan occurred in 8.8% and 8.1% of fasting and nonfasting patients, respectively (P = 0.9). More than 25% drop eGFR after Ramadan was noted in seven (15.5%) and six (12.2%) fasting and nonfasting patients, respectively (P = 0.642). Patients with >= 25% drop in eGFR (13 vs. 81) were older (72.3 +/- 8.3 years vs. 64.3 +/- 11.7 years, P = 0.020) and more frequently using diuretics (69.2% vs. 35.8%, P = 0.023). In multiple linear regression analysis, only advanced age was found to be associated with >=25% drop in eGFR after Ramadan in the fasting group. Fasting during Ramadan was not associated with increased risk of declining in renal functions in patients with Stage 3-5 CKD. However, elderly patients may still be under a higher risk. PMID- 28098106 TI - The role of dynamic renal scintigraphy on clinical decision making in hydronephrotic children. AB - Hydronephrosis may be related to an obstructive cause, ureteropelvic/uretero vesical junction obstruction or nonobstructive [vesicoureteral reflux (VUR)]. When an obstructive pathology is considered, dynamic renal scintigraphy may help to predict whether it is a true obstruction or not. In this study, we aimed to determine the contribution of dynamic renal scintigraphy with [99] mTc-MAG-3 to the clinical decision-making for surgery in hydronephrotic children. Files of the patients evaluated by MAG-3 scintigraphy for antenatal (AH)/postnatal (PH) hydronephrosis between 1992 and 2014 were reviewed. Gender, age, hydronephrosis (HN) grade by ultrasound (US), presence of VUR, MAG-3 result (obstructive vs. nonobstructive), ultimate diagnosis, and need for surgery were assessed. Cases with double collecting system and neurogenic bladder were excluded from the study. All of the patients had normal serum creatinine and eGFR. There were a total of 178 patients with 218 hydronephrotic renal units (mean age 34.7 +/- 52.7 months; male/ female = 121/57, AH of 62%). MAG-3 was nonobstructive in 134 and obstructive in 84 hydronephrotic renal units. MAG-3 was obstructive in 47 of 121 (39%) males and 30 of 57 (53%) females (P = 0.058, odds ratio (OR) for obstruction was 1.9 for girls). MAG-3 was obstructive in 47 of 135 (35%) units with AH and 37 of 83 (45%) units with PH (P = 0.137). In 81 units with the society of fetal urology-4 HN by US, MAG-3 was obstructive in 55 (68%), and surgery was required in 52 of 55 (95%). Surgery was required for only two (7%) of the remaining 26 units with nonobstructive dilatation (P <0.001, sensitivity 96%, specificity 89%, OR 208). Antero-posterior diameter >16.5 mm was the best cutoff level for predicting obstruction by MAG-3 (sensitivity 75.2%; specificity 71%; OR 3.8). MAG-3 significantly affects clinical decision for surgery in HN. Hydronephrotic girls have more risk in terms of true obstruction. Combining MAG-3 with US improves the discrimination of true obstruction during follow-up. PMID- 28098107 TI - Knowledge and attitude towards organ donation among adult population in Al-Kharj, Saudi Arabia. AB - Organ transplantation is a lifesaving treatment for patients with end-stage organ failure. Despite the advanced medical science and technology, shortage of organs had led to a growing gap between the demand for organs and the number of donors. With a limited number of studies on the subject and based on those findings, the public knowledge and attitudes must be assessed to understand more clearly that why many people are opposing donating their organs in Saudi Arabia. The objective of our study was to assess the knowledge and attitude of the adult population toward organ donation in Saudi Arabia. This was a hospital-based cross-sectional study where the information was collected using a self-administered questionnaire in Al-Kharj, Saudi Arabia. The questionnaire was distributed in both King Khalid Hospital and Prince Sattam Bin Abdulaziz University Hospital, and data gathered analyzed by Statistical Package for Social Sciences (SPSS version 20.0). There were a total of 403 respondents. Nearly 35.6% did not have the knowledge that organ donation is legal in the KSA. Almost 97% did not know where to go if they want to become donors. All of who were willing to donate, the most common reason was to save someone's life (92.7%). Body distortion (39%) and fear of health complications (35%) were the most common causes people opposed donation. It was suggested that, in order to increase the awareness for organ donation, the important role of health workers and hospital displays should be immediately addressed and public lectures should be held on regular basis. Information regarding organ donation should be incorporated with clear messages in various mass media. PMID- 28098108 TI - The relationship between mean platelet volume and neutrophil/lymphocyte ratio with inflammation and proteinuria in chronic kidney disease. AB - Atherosclerosis, which develops as a result of inflammation, is the most important cause of morbidity and mortality in chronic kidney disease (CKD). In this study, we investigated the relationship of mean platelet volume (MPV) and neutrophil/lymphocyte ratio (NLR) with inflammation and proteinuria in patients with CKD Stage 3-4. Healthy individuals who applied to nephrology clinic for checkup purposes acted as controls. Fifty-three patients and 30 healthy controls were included in the study. Patients with diabetes mellitus, active infection, malignancy, and coronary artery disease were excluded from the study. Biochemistry values and hemograms were recorded for all patients and for control group. NLR was calculated. The relationship between MPV/NLR and protein, fibrinogen, and proteinuria was evaluated. Our study showed a statistically significant difference between CKD group and healthy control (HC) group in uric acid, fibrinogen, C-reactive protein, and NLR values (P <0.01, P <0.01, P = 0.01, P <0.01, respectively). No statistically significant difference was found between CKD and HC groups for MPV (P = 0.307). Correlation analysis revealed a statistically significant relationship between NLR and creatinine (P <0.00, r = 0.571), uric acid (P <0.00, r = 0.436), glomerular filtration rate (P <0.00, r = 0.418), 24 h urine protein (P = 0.004, r = 0.311), and 24 h urine microalbumin (P = 0.001, r = 0.354). A statistically significant relationship was detected between MPV and platelet count (P <0.001, r = -0.422), age (P = 0.004, r = 0.312), uric acid (P = 0.04, r = -0.226), and fibrinogen (P = 0.023, r = -0.249). Whereas, a statistically significant relationship was detected between NLR and microalbuminuria/proteinuria, there was no statistically significant relationship between MPV and microalbuminuria/proteinuria. Our study showed that the NLR is high in CKD group and is correlated with uric acid and proteinuria, which are known to be associated with atherosclerosis, in patients with CKD. NLR may be a determinant of inflammation and atherosclerosis in patients with CKD. PMID- 28098109 TI - Visceral leishmaniasis in adults with nephropathy. AB - The aim of this study is to evaluate the features of visceral leishmaniasis (VL) in adults with nephropathy, who were not infected with the human immunodeficiency virus. This is a retrospective study of 14 adults hospitalized between 2000 and 2014, with VL and renal involvement. Clinical, biological, and therapeutic data were collected from the patients' medical files. Eleven women and three men, most of whom were from the North of the country, with a mean age of 40.5 years were studied. Lupus was present in five cases, the Sicca syndrome in three cases, diabetes in one case, renal failure on dialysis in two cases, and there were three renal transplant recipients. Major clinical symptoms were fever and weakness in all cases. Enlargement of the spleen was present in eight cases and hepatomegaly in six cases. Biologic inflammatory syndrome and anemia were present in all cases, and pancytopenia was present in seven cases. Renal insufficiency was noted in all cases. Diagnosis of VL was confirmed by bone marrow examination or serology. Treatment consisted of antimoniate in 10 cases and amphotericin B in four cases. Seven deaths were recorded. Clinical symptoms of VL are atypical in patients with nephropathy and therefore, the diagnosis should be suspected in such patients because VL is still endemic in our country. PMID- 28098110 TI - Hepatitis C in children with chronic kidney disease: A single-center, Egypt. AB - Prevalence of hepatitis C varies largely according to geographical distribution, and Egypt so far has the highest prevalence worldwide. The aim of this study was to evaluate hepatitis C infection in chronic kidney disease (CKD) children in our center with regard to its incidence and other morbidities. This is a cross sectional study involving 50 children with CKD, not on dialysis. All patients underwent a thorough history taking including disease duration and mean duration of admission, clinical examination including blood pressure measurements, and routine laboratory examination such as hemoglobin level, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, and creatinine. The detection of anti-hepatitis C virus (HCV) antibodies was done in all patients based on the use of third-generation enzyme immunoassay (EIA) that detects antibodies directed against various HCV epitopes. Nine (18%) children were found to be hepatitis C positive and 41 were negative to hepatitis C. Infected cases were of older age group and had a longer duration of CKD, lower estimated glomerular filtration rate (eGFR), lower hemoglobin, higher ALT, higher serum urea, and creatinine. We conclude that 18% of children with CKDs have hepatitis C infection, and those with longer the duration of renal disease is more likely to be positive for HCV. Furthermore, HCV infection may predispose to higher deterioration of eGFR, lower hemoglobin level, and more days of admission. We recommend routine testing of HCV in all children with CKD. PMID- 28098111 TI - Incidence of hepatitis c virus seroconversion among hemodialysis patients in the Nile Delta of Egypt: A single-center study. AB - Egypt has the highest worldwide prevalence of hepatitis C virus (HCV) infection, caused in part by nosocomial transmission. Patients on hemodialysis (HD) are at especially high risk of infection. We aimed to estimate the incidence of seroconversion among HCV-negative patients undergoing regular HD at a unit in a large public hospital in the Nile Delta of Egypt, which implements the Egyptian Ministry of Health guidelines for infection control, and an isolation policy for hepatitis-positive patients. We also assessed the adherence to infection control practices and evaluated nurses and physicians' knowledge and attitude toward infection control procedures. Records of HCV-negative patients undergoing regular HD at the unit from August 2008 to August 2010 were reviewed retrospectively for data on HCV status. Patients were then followed up until September 2011, when polymerase chain reaction was performed for all patients. Infection control practices were evaluated by four checklists applied monthly and analyzed by control charts. Nurses and physicians' knowledge and attitudes toward infection control were assessed by interview questionnaires. Of 60 patients followed up, there was one case of HCV seroconversion giving an incidence rate of 0.676/100 person-years of follow-up (95% confidence interval: 0.017-3.76). There were no cases of hepatitis B virus seroconversion. The mean scores of all the infection control practices' checklists were very high and generally remained above the lower control limit over the 12-month period. Physicians and nurses achieved very high scores on knowledge and attitude on infection control (mean score >95%). This public facility had a low seroconversion rate and high adherence to infection control guidelines. PMID- 28098112 TI - Autosomal dominant polycystic kidney disease: Study of clinical characteristics in an Indian population. AB - Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary form of kidney disease. Clinical data on this multisystem disorder are scarce from developing countries. We conducted a prospective observational study of the clinical profile of ADPKD patients at a single center over a period of six years. A total of 208 patients were studied. Majority were male (60.6%) and the mean age was 45.8 +/- 14.5 years. About 61.5% had early stage (Stages 1-3) of chronic kidney disease (CKD) and 38.5% had advanced CKD (Stages 4 and 5). Clinical features observed included pain abdomen (46.2%), nocturia (65.9%), hematuria (21.6%), nephrolithiasis (38.9%), urinary tract infection (UTI) (38.9%), hypertension (69.5%), and raised serum creatinine (54.3%). The prevalence of nocturia, hypertension, and renal dysfunction showed a significant increase with age (P = 0.001). Extrarenal manifestations were polycystic liver disease in 77 patients (37%), cysts in pancreas in two (1%), and stroke in three (1.5%) (hemorrhage in 2 and infarct in 1). There was significantly higher prevalence of hypertension (P = 0.027) and nephrolithiasis (P = 0.044) in males compared to females. Ninety-two patients (44.2%) had a positive family history for ADPKD. Fifteen (7.2%) had kidney failure at the diagnosis of ADPKD, were hospitalized, and underwent emergency dialysis. A total of 20 patients (9.6%) developed end-stage kidney disease during the study period. The age at diagnosis was higher, and there was a high prevalence of hypertension, nocturia, abdominal pain, nephrolithiasis, UTI, and renal dysfunction in Indian ADPKD patients. PMID- 28098113 TI - Role of renal biopsy in managing pediatric renal diseases: A midterm analysis of a series at bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh. PMID- 28098114 TI - A comparison of health-related quality of life in patients with renal failure under hemodialysis and healthy participants. AB - The objective of this study was to evaluate the health-related quality of life (QoL) of patients under hemodialysis (HD) and to compare this to healthy participants. We compared 154 patients on HD to 308 healthy age- and sex-matched controls recruited from Shahid Beheshti Hospital in Babol, Northern Iran in 2014. The data of health-related QoL in eight subscales were collected with interview using a standard short-form questionnaire of short form-36. The demographic data and dry weight and height were measured. The scores of each subscale were transformed from 0 (the worse state) to 100 (the best state). In univariate analysis, Wilcoxon and Kruskal-Wallis tests were used to compare the distribution of scores between cases and controls according to gender, and multiple linear regression analysis was used to adjust the regression coefficient for possible potential confounding factors. The mean overall score of health-related QoL for men was 44.7 +/- 23.2 and 74.3 +/- 18.1 in patients and controls, respectively, and for women was 37.1 +/- 20.8 and 62.1 +/- 18.7, respectively. In all subscales, the mean score of patients was significantly lower than controls (P = 0.001) in both sexes. In all eight subscales, after adjusting for demographic characteristics, the patients had significantly lower QoL than controls (P = 0.001). In addition, the independent effect of age, gender, and educational level as predictors of QoL was significant across various subscales (P = 0.001). PMID- 28098115 TI - A novel fibrillin-1 mutation in an egyptian marfan family: A proband showing nephrotic syndrome due to focal segmental glomerulosclerosis. AB - Marfan syndrome (MFS), the founding member of connective tissue disorder, is an autosomal dominant disease; it is caused by a deficiency of the microfibrillar protein fibrillin-1 (FBN1) and characterized by involvement of three main systems; skeletal, ocular, and cardiovascular. More than one thousand mutations in FBN1 gene on chromosome 15 were found to cause MFS. Nephrotic syndrome (NS) had been described in very few patients with MFS being attributed to membranoproliferative glomerulonephritis secondary to infective endocarditis. Focal segmental glomerulosclerosis (FSGS) had been reported in NS in conjunction with MFS without confirming the diagnosis by mutational analysis of FBN1. We hereby present an Egyptian family with MFS documented at the molecular level; it showed a male proband with NS secondary to FSGS, unfortunately, we failed to make any causal link between FBN dysfunction and FSGS. In this context, we review the spectrum of renal involvements occurring in MFS patients. PMID- 28098116 TI - Membranous glomerulopathy and massive cervical lymphadenopathy due to immunoglobulin G4-disease. AB - A 32-year-old male presented with acute and severe nephrotic syndrome as well as massive right cervical lymphadenopathy for <2 years. Computed tomography scan of the chest, abdomen, and pelvis did not reveal any lymphadenopathy. Histopathology and immunohistochemical testing of his lymph node biopsy showed infiltrate enriched with immunoglobulin G4 (IgG4)-positive plasma cells. His kidney biopsy showed granular membranous deposits of IgG4 in the basement membrane without interstitial infiltrate. Antiphospholipid 2 receptor antibodies were absent excluding its "idiopathic" nature. Since he was allergic to rituximab, he was treated with corticosteroids for two months and a combination of tacrolimus and mycophenolate. His lymphadenopathy disappeared, and his proteinuria abated. The dose of the latter two medications was reduced to half after four months and will be maintained for a minimum of two years to prevent relapse of his disease. PMID- 28098117 TI - Denosumab for the treatment of bisphosphonate resistant hypercalcemia in a hemodialysis patient. AB - The acronym of malignancy, iatrogenic, intoxication and immobilization, sarcoidosis, hyperparathyroidism and hyperthyroidism, milk-alkali syndrome, and paget is very helpful in diagnosing hypercalcemia. We report on a 94-year-old patient with history of end-stage renal failure secondary to benign nephroangiosclerosis, who was on maintenance hemodialysis during dialysis, his blood chemistry revealed mild hypercalcemia (2.66 mmol/L) with normal level of intact primary hyperparathyroidism (32.37 ng/mL) mandating the discontinuation of Vitamin D[3]. In view of persisting hypercalcemia, denosumab 60 mg/mL was administrated subcutaneously. The serum calcium level showed a decrease and stabilized at near upper limit (2.57 mmol/L). Three weeks later, the serum calcium remained mildly elevated fluctuating between 2.66 and 2.80 mmol/L. PMID- 28098118 TI - Safety of denosumab in dialysis patients on calcium and vitamin D supplements. PMID- 28098119 TI - Acute tubulointerstitial nephritis and uveitis syndrome: A report on four adult cases. AB - Acute tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare disease, generally presenting in children and young women. The interstitial nephritis may precede, follow, or develop concurrent to the uveitis. We report the clinical features and outcomes of four adult patients, aged 41-70 years with the TINU syndrome. PMID- 28098120 TI - An unusual cause of hematuria following coronary intervention. AB - Acute renal infarction is rare. Its true incidence is not known. The paucity of literature and unawareness among the physicians makes it an underdiagnosed entity. Herein, we report a case of renal infarction following coronary intervention. PMID- 28098121 TI - Perspectives on hypertension outcomes after single-stage clearance of a complete staghorn renal calculus. AB - A 55-year-old male presented, in June 2013, with left flank pain. Investigations revealed a complete staghorn stone. He had undergone two sittings of extracorporeal shock wave lithotripsy (ESWL) in 2008 for left renal stone. One year subsequent to this, he was diagnosed with hypertension and diabetes. The management of complete staghorn stones in a single sitting is a difficult proposition. Percutaneous nephrolithotomy (PCNL) is the gold standard to manage such stones. The patient was subjected to PCNL, and complete clearance was achieved in one sitting. On one-year follow-up, there was a significant reduction in blood pressure (BP) and better glycemic control. Although there are several reports where hypertension has been reported after multiple sittings of ESWL, whether ESWL contributed to the genesis of hypertension and diabetes in this patient or it was simply incidental, cannot be stated with certainty. There was a significant reduction in the BP after complete stone removal, but there is uncertainty over the effect of total clearance of renal stones on hypertension, and we need to await the results of more controlled trials studying this phenomenon. A better glycemic control was perhaps achieved secondary to the eradication of recurrent urinary tract infections due to complete stone clearance. PMID- 28098122 TI - A case of abdominal aortic thrombosis associated with the nephrotic syndrome. AB - Thromboembolic disease is an important and frequent complication in patients with the nephrotic syndrome (NS), and the consequences are often severe. Usually, the venous system is affected. Arterial thrombosis has rarely been reported and occurs mainly in children. We report the case of a 27-year-old man with a history of NS due to focal and segmental glomerulosclerosis resistant to steroids and cyclosporine, admitted for bilateral pain in the calves. Aortogram revealed a suspended thrombus in the abdominal aorta just below the origin of the renal arteries with embolism into the left tibioperoneal trunk and the right anterior tibial artery. Endarterectomy was performed followed by systemic heparinization with a good outcome. Arterial thrombosis is rare and must be prevented. PMID- 28098123 TI - Typhoid-associated acute kidney injury masquerading as a relapse of Takayasu arteritis. AB - Renal dysfunction is common in Takayasu arteritis. Uncommonly, renal failure in a case of Takayasu arteritis can be due to an unrelated disease, and if the disease is a rare complication, it is even more difficult to diagnose. We report a 21 year-old male with type IV Takayasu arteritis presenting with fever and renal failure, who was diagnosed to have enteric fever- related glomerulonephritis which was successfully treated. PMID- 28098124 TI - Polymicrobial peritonitis with Leclercia adecarboxylata in a peritoneal dialysis patient. PMID- 28098125 TI - Prevalence of dyslipidemia and macrovascular complications among post kidney transplant patients. PMID- 28098126 TI - Zika virus infection: What should we know as nephrologists? PMID- 28098127 TI - Cultural and religious issues in organ transplantation: Crucial role in multiethnic countries. PMID- 28098128 TI - An atypical presentation of cake kidney. PMID- 28098129 TI - Tophi as the initial manifestation of gout in a normouricemic hemodialysis patient: An unusual case of a common disorder. PMID- 28098130 TI - Acute kidney injury due to multiple wasp stings. PMID- 28098131 TI - End-stage renal disease secondary to pelvic organ prolapse. PMID- 28098132 TI - [Materiality Analysis of Health Plans Based on Stakeholder Engagement and the Issues Included at ISO 26000:2010]. AB - OBJECTIVE: Health plans of the Spanish autonomous communities can incorporate sustainable development criteria in its development. There have been no analysis or proposals about development and indicators. The goal is to add a contribution to help build better health plans aimed at sustainable development and help to manage economic, social and environmental impacts of health systems criteria. METHODS: We used a variation of the RAND/UCLA or modified Delphi technique method. The process consisted of a bibliographical and context matters and issues related to health and social responsibility analysis based on ISO 26000: 2010. A survey by deliberately to a selection of 70 expert members of the identified stakeholders was carried out and a discussion group was held to determine the consensus on the issues addressed in the survey sample. The research was conducted in 2015. RESULTS: From the literature review 33 health issues included in ISO 26000:2010 were obtained. 7 survey proved relevant high consensus, 8 relevance and average consensus and 18 with less relevance and high level of dissent. The expert group excluded 4 of the 18 subjects with less consensus. CONCLUSIONS: 29 issues included 33 at work, divided into 7 subjects contained in the guide ISO 26000 of social responsibility, were relevant stakeholders regarding possible inclusion in health plans. Considering the direct relationship published by ISO (International Organization for Standardization) among the issues ISO 26000 and the economic, social and environmental indicators in GRI (Global Reporting Initiative) in its G4 version, a panel with monitoring indicators related to relevant issues were elaborated. PMID- 28098133 TI - [The Need of a New Integral Approach to the Care of Patient with Severe Mental Disorder Thirty Years after the Psychiatric Reform]. AB - More than thirty years have passed since the beginning of the psychiatric reform, a period of intense and relevant social, scientific and cultural changes which have directly impacted on mental disorders and their management. Improvement in psychopharmacological treatment, a new model of physician-patient relationship, patient's empowerment as a key issue and the fight against social stigma related to mental health disorders, changes in clinical governance and health policy, the assistential burden derived from the treatment of less severe pathology in mental health community centers, improvements in teamwork and coordination with other resources involved... are some of the relevant changes which determine the scene of community-based mental health assistance. We think this is a right time to check the state of the community-based care programmes for severe mental disorders, and the role of mental health center. We propose to have a reflexion about two relevant topics: where we are and where we are heading. PMID- 28098134 TI - [Validity, Reliability and Associated Factors of the International Physical Activity Questionnaire Adapted to Elderly (IPAQ-E)]. AB - OBJECTIVE: Physical activity contributes to improve health and reduce mortality in older people. The objective was to analyze the validity of content and reliability of the short version of IPAQ-E in elderly people who attended to Fernando el Catolico health center between May 2013 and March 2015. METHODS: Validation study of the short version of the international physical activity questionnaire (IPAQ) adapted in Spanish elderly (IPAQ-E). Our sampling was for convenience. The short version of IPAQ in Spanish USA was used and its activities were adapted to Spanish elderly. Two measurements of IPAQ-E with 15 days between them were used to analyze the intraobserver reliability. The intraclass correlation coefficient was used to measure intraobserver reliability, Cronbach's alpha for internal consistency (CI) and Spearman correlation coefficients (CS) to analyze the correlation between IPAQ-E and the Short Physical Performance Battery (SPPB). RESULTS: The sample was 139 people, average age 73,18 years. Intraobserver reliability total was 0.914, besides exceeded 0.9 in the three dimensions of the questionnaire. The CI was 0.518; It exceeded 0.8 in the rest of dimensions of IPAQ-E. The CS between IPAQ-E Total and SPPB was (Rho 0.435), between the total scores SPPB and walking activity was (Rho 0.426), and the score vigorous activity was (Rho 0,248). CONCLUSIONS: The IPAQ-E is a valid and reliable instrument for measuring mobility in Spanish elderly. However, more studies about its validity will be required in the future. PMID- 28098135 TI - [Outbreak of Whooping cough in 2016.Ecija, Seville, Spain]. AB - OBJECTIVE: Whooping cough is a global public health problem, is a highly contagious disease, and despite universal vaccination increased incidence is observed. The aim of this study was to describe the investigation of a population outbreak. METHODS: A descriptive study of a population outbreak of whooping cough between February and June 2016 in Ecija (Seville). Case and outbreak definitions was taken of Whooping Cough Monitoring Protocol. Information was collected from Health History, Epidemiological Monitoring System and Laboratory. For statistical analysis used the free software R, for measuring quantitative variables were presented, median, standard deviation, minimum and maximum values and percentiles for qualitative variables frequency distribution. RESULTS: 91 suspected cases were identified, ruling 33. Of the remaining 58, 42 cases were confirmed and 16 probable cases. The cases have presented an average age of 10,24 years. 62,1% of cases occurred in women. The incidence during the duration of the outbreak was 148,51 cases/100.000 people globally, and 851,06 cases/100.000 people in under 14 years. All children under 18 years were successfully vaccinated in primary vaccination and only 2 children lacked the fifth dose. The average time between onset of symptoms and diagnosis was 24,86 days. CONCLUSIONS: The establishment of monitoring and control measures have managed to limit and resolve the outbreak. It is recommended to enhance the information and coordination between the various levels of care (Primary care/Specialist) and professionals (Clinical/Epidemiology). PMID- 28098137 TI - Origin and evolution of the deep thermochemical structure beneath Eurasia. AB - A unique structure in the Earth's lowermost mantle, the Perm Anomaly, was recently identified beneath Eurasia. It seismologically resembles the large low shear velocity provinces (LLSVPs) under Africa and the Pacific, but is much smaller. This challenges the current understanding of the evolution of the plate mantle system in which plumes rise from the edges of the two LLSVPs, spatially fixed in time. New models of mantle flow over the last 230 million years reproduce the present-day structure of the lower mantle, and show a Perm-like anomaly. The anomaly formed in isolation within a closed subduction network ~22,000 km in circumference prior to 150 million years ago before migrating ~1,500 km westward at an average rate of 1 cm year-1, indicating a greater mobility of deep mantle structures than previously recognized. We hypothesize that the mobile Perm Anomaly could be linked to the Emeishan volcanics, in contrast to the previously proposed Siberian Traps. PMID- 28098136 TI - Exome and genome sequencing of nasopharynx cancer identifies NF-kappaB pathway activating mutations. AB - Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-kappaB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-kappaB signalling, and we observed mutual exclusivity among tumours with somatic NF-kappaB pathway aberrations and LMP1-overexpression, suggesting that NF-kappaB activation is selected for by both somatic and viral events during NPC pathogenesis. PMID- 28098140 TI - Dynamical observations on the crack tip zone and stress corrosion of two dimensional MoS2. AB - Whether and how fracture mechanics needs to be modified for small length scales and in systems of reduced dimensionality remains an open debate. Here, employing in situ transmission electron microscopy, atomic structures and dislocation dynamics in the crack tip zone of a propagating crack in two-dimensional (2D) monolayer MoS2 membrane are observed, and atom-to-atom displacement mapping is obtained. The electron beam is used to initiate the crack; during in situ observation of crack propagation the electron beam effect is minimized. The observed high-frequency emission of dislocations is beyond previous understanding of the fracture of brittle MoS2. Strain analysis reveals dislocation emission to be closely associated with the crack propagation path in nanoscale. The critical crack tip plastic zone size of nearly perfect 2D MoS2 is between 2 and 5 nm, although it can grow to 10 nm under corrosive conditions such as ultraviolet light exposure, showing enhanced dislocation activity via defect generation. PMID- 28098139 TI - Appetite responses to high-fat meals or diets of varying fatty acid composition: a comprehensive review. AB - Dietary fatty acids (FA) act as signaling molecules with diverse effects on physiologic function. The aim of this article is to review and summarize the clinical human studies in the literature on how dietary FA composition in meals and diets affects hunger and satiety signaling in the body. Studies examining FA saturation (monounsaturated (MUFA), saturated or polyunsaturated (PUFA) FAs) or FA chain length from high-fat meals/diets were included. Measures of appetite included visual analog scale (VAS) questionnaires, appetite hormones (Cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), peptide YY (PYY), gastric insulinotropic polypeptide gastric inhibitory peptide (GIP), ghrelin, leptin, insulin) and/or energy intake (EI) data. VAS measures in 9 out of 13 studies were not influenced by FA saturation. PUFAs, followed by MUFAs, tended to induce the greatest stimulatory effect on GLP-1, GIP and PYY, which was found in 6 out of 11 studies measuring appetite-related hormones. Regarding FA chain length, five of six studies show either no difference or less hunger (VAS) and greater satiety hormone levels (two of six studies) for FAs with longer chain lengths. EI does not seem to be affected by the saturation of FAs while EI was inconclusive for studies comparing FA chain length. Possibly due to the inconsistencies in study design, little agreement is observed between the studies on the impact of FA composition on hormonal and subjective measures of appetite as well as EI. Therefore, more research on the long-term impact of dietary FA composition on appetite control may provide clearer outcomes. PMID- 28098141 TI - One million years of glaciation and denudation history in west Greenland. AB - The influence of major Quaternary climatic changes on growth and decay of the Greenland Ice Sheet, and associated erosional impact on the landscapes, is virtually unknown beyond the last deglaciation. Here we quantify exposure and denudation histories in west Greenland by applying a novel Markov-Chain Monte Carlo modelling approach to all available paired cosmogenic 10Be-26Al bedrock data from Greenland. We find that long-term denudation rates in west Greenland range from >50 m Myr-1 in low-lying areas to ~2 m Myr-1 at high elevations, hereby quantifying systematic variations in denudation rate among different glacial landforms caused by variations in ice thickness across the landscape. We furthermore show that the present day ice-free areas only were ice covered ca. 45% of the past 1 million years, and even less at high-elevation sites, implying that the Greenland Ice Sheet for much of the time was of similar size or even smaller than today. PMID- 28098138 TI - SCIMP is a transmembrane non-TIR TLR adaptor that promotes proinflammatory cytokine production from macrophages. AB - Danger signals activate Toll-like receptors (TLRs), thereby initiating inflammatory responses. Canonical TLR signalling, via Toll/Interleukin-1 receptor domain (TIR)-containing adaptors and proinflammatory transcription factors such as NF-kappaB, occurs in many cell types; however, additional mechanisms are required for specificity of inflammatory responses in innate immune cells. Here we show that SCIMP, an immune-restricted, transmembrane adaptor protein (TRAP), promotes selective proinflammatory cytokine responses by direct modulation of TLR4. SCIMP is a non-TIR-containing adaptor, binding directly to the TLR4-TIR domain in response to lipopolysaccharide. In macrophages, SCIMP is constitutively associated with the Lyn tyrosine kinase, is required for tyrosine phosphorylation of TLR4, and facilitates TLR-inducible production of the proinflammatory cytokines IL-6 and IL-12p40. Point mutations in SCIMP abrogating TLR4 binding also prevent SCIMP-mediated cytokine production. SCIMP is, therefore, an immune specific TLR adaptor that shapes host defence and inflammation. PMID- 28098143 TI - Efficient DNA-free genome editing of bread wheat using CRISPR/Cas9 ribonucleoprotein complexes. AB - Substantial efforts are being made to optimize the CRISPR/Cas9 system for precision crop breeding. The avoidance of transgene integration and reduction of off-target mutations are the most important targets for optimization. Here, we describe an efficient genome editing method for bread wheat using CRISPR/Cas9 ribonucleoproteins (RNPs). Starting from RNP preparation, the whole protocol takes only seven to nine weeks, with four to five independent mutants produced from 100 immature wheat embryos. Deep sequencing reveals that the chance of off target mutations in wheat cells is much lower in RNP mediated genome editing than in editing with CRISPR/Cas9 DNA. Consistent with this finding, no off-target mutations are detected in the mutant plants. Because no foreign DNA is used in CRISPR/Cas9 RNP mediated genome editing, the mutants obtained are completely transgene free. This method may be widely applicable for producing genome edited crop plants and has a good prospect of being commercialized. PMID- 28098142 TI - Carbon translocation from a plant to an insect-pathogenic endophytic fungus. AB - Metarhizium robertsii is a common soil fungus that occupies a specialized ecological niche as an endophyte and an insect pathogen. Previously, we showed that the endophytic capability and insect pathogenicity of Metarhizium are coupled to provide an active method of insect-derived nitrogen transfer to a host plant via fungal mycelia. We speculated that in exchange for this insect-derived nitrogen, the plant would provide photosynthate to the fungus. By using 13CO2, we show the incorporation of 13C into photosynthate and the subsequent translocation of 13C into fungal-specific carbohydrates (trehalose and chitin) in the root/endophyte complex. We determined the amount of 13C present in root associated fungal biomass over a 21-day period by extracting fungal carbohydrates and analysing their composition using nuclear magnetic resonance (NMR) spectroscopy. These findings are evidence that the host plant is providing photosynthate to the fungus, likely in exchange for insect-derived nitrogen in a tripartite, and symbiotic, interaction. PMID- 28098144 TI - Oligo-fucoidan prevents renal tubulointerstitial fibrosis by inhibiting the CD44 signal pathway. AB - Tubulointerstitial fibrosis is recognized as a key determinant of progressive chronic kidney disease (CKD). Fucoidan, a sulphated polysaccharide extracted from brown seaweed, exerts beneficial effects in some nephropathy models. The present study evaluated the inhibitory effect of oligo-fucoidan (800 Da) on renal tubulointerstitial fibrosis. We established a mouse CKD model by right nephrectomy with transient ischemic injury to the left kidney. Six weeks after the surgery, we fed the CKD mice oligo-fucoidan at 10, 20, and 100 mg/kg/d for 6 weeks and found that the oligo-fucoidan doses less than 100 mg/kg/d improved renal function and reduced renal tubulointerstitial fibrosis in CKD mice. Oligo fucoidan also inhibited pressure-induced fibrotic responses and the expression of CD44, beta-catenin, and TGF-beta in rat renal tubular cells (NRK-52E). CD44 knockdown downregulated the expression of beta-catenin and TGF-beta in pressure treated cells. Additional ligands for CD44 reduced the anti-fibrotic effect of oligo-fucoidan in NRK-52E cells. These data suggest that oligo-fucoidan at the particular dose prevents renal tubulointerstitial fibrosis in a CKD model. The anti-fibrotic effect of oligo-fucoidan may result from interfering with the interaction between CD44 and its extracellular ligands. PMID- 28098145 TI - Highly thermal-stable ferromagnetism by a natural composite. AB - All ferromagnetic materials show deterioration of magnetism-related properties such as magnetization and magnetostriction with increasing temperature, as the result of gradual loss of magnetic order with approaching Curie temperature TC. However, technologically, it is highly desired to find a magnetic material that can resist such magnetism deterioration and maintain stable magnetism up to its TC, but this seems against the conventional wisdom about ferromagnetism. Here we show that a Fe-Ga alloy exhibits highly thermal-stable magnetization up to the vicinity of its TC, 880 K. Also, the magnetostriction shows nearly no deterioration over a very wide temperature range. Such unusual behaviour stems from dual-magnetic-phase nature of this alloy, in which a gradual structural magnetic transformation occurs between two magnetic phases so that the magnetism deterioration is compensated by the growth of the ferromagnetic phase with larger magnetization. Our finding may help to develop highly thermal-stable ferromagnetic and magnetostrictive materials. PMID- 28098146 TI - Metal/oxide interfacial effects on the selective oxidation of primary alcohols. AB - A main obstacle in the rational development of heterogeneous catalysts is the difficulty in identifying active sites. Here we show metal/oxide interfacial sites are highly active for the oxidation of benzyl alcohol and other industrially important primary alcohols on a range of metals and oxides combinations. Scanning tunnelling microscopy together with density functional theory calculations on FeO/Pt(111) reveals that benzyl alcohol enriches preferentially at the oxygen-terminated FeO/Pt(111) interface and undergoes readily O-H and C-H dissociations with the aid of interfacial oxygen, which is also validated in the model study of Cu2O/Ag(111). We demonstrate that the interfacial effects are independent of metal or oxide sizes and the way by which the interfaces were constructed. It inspires us to inversely support nano-oxides on micro-metals to make the structure more stable against sintering while the number of active sites is not sacrificed. The catalyst lifetime, by taking the inverse design, is thereby significantly prolonged. PMID- 28098147 TI - Nanoparticle-induced unusual melting and solidification behaviours of metals. AB - Effective control of melting and solidification behaviours of materials is significant for numerous applications. It has been a long-standing challenge to increase the melted zone (MZ) depth while shrinking the heat-affected zone (HAZ) size during local melting and solidification of materials. In this paper, nanoparticle-induced unusual melting and solidification behaviours of metals are reported that effectively solve this long-time dilemma. By introduction of Al2O3 nanoparticles, the MZ depth of Ni is increased by 68%, while the corresponding HAZ size is decreased by 67% in laser melting at a pulse energy of 0.18 mJ. The addition of SiC nanoparticles shows similar results. The discovery of the unusual melting and solidification of materials that contain nanoparticles will not only have impacts on existing melting and solidification manufacturing processes, such as laser welding and additive manufacturing, but also on other applications such as pharmaceutical processing and energy storage. PMID- 28098148 TI - Clinical utility gene card for: Non-Syndromic Microphthalmia Including Next Generation Sequencing-Based Approaches. PMID- 28098150 TI - A survey of sub-Saharan gene flow into the Mediterranean at risk loci for coronary artery disease. AB - This study tries to find detectable signals of gene flow of Sub-Saharan origin into the Mediterranean in four genomic regions previously associated with coronary artery disease. A total of 366 single-nucleotide polymorphisms were genotyped in 772 individuals from 10 Mediterranean countries. Population structure analyses were performed, in which a noticeable Sub-Saharan component was found in the studied samples. The overall percentage of this Sub-Saharan component presents differences between the two Mediterranean coasts. D-statistics suggest possible Sub-Saharan introgression into one of the studied genomic regions (10q11). We also found differences in linkage disequilibrium patterns between the two Mediterranean coasts, possibly attributable to differential Sub Saharan admixture. Our results confirm the potentially important role of human demographic history when performing epidemiological studies. PMID- 28098149 TI - Characterising private and shared signatures of positive selection in 37 Asian populations. AB - The Asian Diversity Project (ADP) assembled 37 cosmopolitan and ethnic minority populations in Asia that have been densely genotyped across over half a million markers to study patterns of genetic diversity and positive natural selection. We performed population structure analyses of the ADP populations and divided these populations into four major groups based on their genographic information. By applying a highly sensitive algorithm haploPS to locate genomic signatures of positive selection, 140 distinct genomic regions exhibiting evidence of positive selection in at least one population were identified. We examined the extent of signal sharing for regions that were selected in multiple populations and observed that populations clustered in a similar fashion to that of how the ancestry clades were phylogenetically defined. In particular, populations predominantly located in South Asia underwent considerably different adaptation as compared with populations from the other geographical regions. Signatures of positive selection present in multiple geographical regions were predicted to be older and have emerged prior to the separation of the populations in the different regions. In contrast, selection signals present in a single population group tended to be of lower frequencies and thus can be attributed to recent evolutionary events. PMID- 28098151 TI - Juvenile myelomonocytic leukemia-associated variants are associated with neo natal lethal Noonan syndrome. AB - Gain-of-function variants in some RAS-MAPK pathway genes, including PTPN11 and NRAS, are associated with RASopathies and/or acquired hematological malignancies, most notably juvenile myelomonocytic leukemia (JMML). With rare exceptions, the spectrum of germline variants causing RASopathies does not overlap with the somatic variants identified in isolated JMML. Studies comparing these variants suggest a stronger gain-of-function activity in the JMML variants. As JMML variants have not been identified as germline defects and have a greater impact on protein function, it has been speculated that they would be embryonic lethal. Here we identified three variants, which have previously only been identified in isolated somatic JMML and other sporadic cancers, in four cases with a severe pre or neo-natal lethal presentation of Noonan syndrome. These cases support the hypothesis that these stronger gain-of-function variants are rarely compatible with life. PMID- 28098152 TI - Human farnesyl pyrophosphate synthase is allosterically inhibited by its own product. AB - Farnesyl pyrophosphate synthase (FPPS) is an enzyme of the mevalonate pathway and a well-established therapeutic target. Recent research has focused around a newly identified druggable pocket near the enzyme's active site. Pharmacological exploitation of this pocket is deemed promising; however, its natural biological function, if any, is yet unknown. Here we report that the product of FPPS, farnesyl pyrophosphate (FPP), can bind to this pocket and lock the enzyme in an inactive state. The Kd for this binding is 5-6 MUM, within a catalytically relevant range. These results indicate that FPPS activity is sensitive to the product concentration. Kinetic analysis shows that the enzyme is inhibited through FPP accumulation. Having a specific physiological effector, FPPS is a bona fide allosteric enzyme. This allostery offers an exquisite mechanism for controlling prenyl pyrophosphate levels in vivo and thus contributes an additional layer of regulation to the mevalonate pathway. PMID- 28098153 TI - MECP2 regulates cortical plasticity underlying a learned behaviour in adult female mice. AB - Neurodevelopmental disorders are marked by inappropriate synaptic connectivity early in life, but how disruption of experience-dependent plasticity contributes to cognitive and behavioural decline in adulthood is unclear. Here we show that pup gathering behaviour and associated auditory cortical plasticity are impaired in female Mecp2het mice, a model of Rett syndrome. In response to learned maternal experience, Mecp2het females exhibited transient changes to cortical inhibitory networks typically associated with limited plasticity. Averting these changes in Mecp2het through genetic or pharmacological manipulations targeting the GABAergic network restored gathering behaviour. We propose that pup gathering learning triggers a transient epoch of inhibitory plasticity in auditory cortex that is dysregulated in Mecp2het. In this window of heightened sensitivity to sensory and social cues, Mecp2 mutations suppress adult plasticity independently from their effects on early development. PMID- 28098155 TI - The geometric nature of weights in real complex networks. AB - The topology of many real complex networks has been conjectured to be embedded in hidden metric spaces, where distances between nodes encode their likelihood of being connected. Besides of providing a natural geometrical interpretation of their complex topologies, this hypothesis yields the recipe for sustainable Internet's routing protocols, sheds light on the hierarchical organization of biochemical pathways in cells, and allows for a rich characterization of the evolution of international trade. Here we present empirical evidence that this geometric interpretation also applies to the weighted organization of real complex networks. We introduce a very general and versatile model and use it to quantify the level of coupling between their topology, their weights and an underlying metric space. Our model accurately reproduces both their topology and their weights, and our results suggest that the formation of connections and the assignment of their magnitude are ruled by different processes. PMID- 28098154 TI - Structural basis of ligand interaction with atypical chemokine receptor 3. AB - Chemokines drive cell migration through their interactions with seven transmembrane (7TM) chemokine receptors on cell surfaces. The atypical chemokine receptor 3 (ACKR3) binds chemokines CXCL11 and CXCL12 and signals exclusively through beta-arrestin-mediated pathways, without activating canonical G-protein signalling. This receptor is upregulated in numerous cancers making it a potential drug target. Here we collected over 100 distinct structural probes from radiolytic footprinting, disulfide trapping, and mutagenesis to map the structures of ACKR3:CXCL12 and ACKR3:small-molecule complexes, including dynamic regions that proved unresolvable by X-ray crystallography in homologous receptors. The data are integrated with molecular modelling to produce complete and cohesive experimentally driven models that confirm and expand on the existing knowledge of the architecture of receptor:chemokine and receptor:small-molecule complexes. Additionally, we detected and characterized ligand-induced conformational changes in the transmembrane and intracellular regions of ACKR3 that elucidate fundamental structural elements of agonism in this atypical receptor. PMID- 28098156 TI - Sixfold improved single particle measurement of the magnetic moment of the antiproton. AB - Our current understanding of the Universe comes, among others, from particle physics and cosmology. In particle physics an almost perfect symmetry between matter and antimatter exists. On cosmological scales, however, a striking matter/antimatter imbalance is observed. This contradiction inspires comparisons of the fundamental properties of particles and antiparticles with high precision. Here we report on a measurement of the g-factor of the antiproton with a fractional precision of 0.8 parts per million at 95% confidence level. Our value /2=2.7928465(23) outperforms the previous best measurement by a factor of 6. The result is consistent with our proton g-factor measurement gp/2=2.792847350(9), and therefore agrees with the fundamental charge, parity, time (CPT) invariance of the Standard Model of particle physics. Additionally, our result improves coefficients of the standard model extension which discusses the sensitivity of experiments with respect to CPT violation by up to a factor of 20. PMID- 28098157 TI - Antibody Responses to Trivalent Inactivated Influenza Vaccine in Health Care Personnel Previously Vaccinated and Vaccinated for The First Time. AB - Inactivated influenza vaccination induces a hemagglutinin-specific antibody response to the strain used for immunization. Annual vaccination is strongly recommended for health care personnel. However, it is debatable if repeated vaccination would affect the antibody response to inactivated influenza vaccine through the time. We enrolled health care personnel who had repeated and first trivalent inactivated influenza vaccination in 2005-2008. Serological antibody responses were measured by hemagglutination-inhibition (HI) test. Subjects with repeated vaccination had higher pre-vaccination and lower post-vaccination HI titer than those with first vaccination, although serological responses between groups might vary with different antigen types and while the drifted strain was introduced in the vaccine. Higher fold rise in the HI titer was observed in the group with first than repeated vaccination and the fold increase in the HI titer was inversely correlated with pre-vaccination titer in 2007 and 2008. Nevertheless, no significant difference in the day 28 seroprotection rate was observed between groups with repeated and first vaccination in most circumstances. Further studies are needed to understand the long-term effect of repeated vaccination on the antibody response both at the serological and repertoire levels among health care personnel. PMID- 28098158 TI - Pericytes from Mesenchymal Stem Cells as a model for the blood-brain barrier. AB - Blood brain-barrier (BBB) in vitro models have been widely reported in studies of the BBB phenotype. However, established co-culture systems involve brain endothelial cells, astrocytes, neurons and pericytes, and therefore are often consuming and technically challenging. Here we use mesenchymal system cells (MSC) as a potential substitute for pericytes in a BBB model. Both MSC and pericyte markers in 2D culture environment were evaluated on different extracellular matrix compositions. Further experiments indicated that MSC contributed in a similar manner to pericytes in a co-cultured 3D model on increasing trans endothelial electric resistance (TEER) and decreasing permeability against macromolecules. PMID- 28098159 TI - Fluid shear stress activates YAP1 to promote cancer cell motility. AB - Mechanical stress is pervasive in egress routes of malignancy, yet the intrinsic effects of force on tumour cells remain poorly understood. Here, we demonstrate that frictional force characteristic of flow in the lymphatics stimulates YAP1 to drive cancer cell migration; whereas intensities of fluid wall shear stress (WSS) typical of venous or arterial flow inhibit taxis. YAP1, but not TAZ, is strictly required for WSS-enhanced cell movement, as blockade of YAP1, TEAD1-4 or the YAP1 TEAD interaction reduces cellular velocity to levels observed without flow. Silencing of TEAD phenocopies loss of YAP1, implicating transcriptional transactivation function in mediating force-enhanced cell migration. WSS dictates expression of a network of YAP1 effectors with executive roles in invasion, chemotaxis and adhesion downstream of the ROCK-LIMK-cofilin signalling axis. Altogether, these data implicate YAP1 as a fluid mechanosensor that functions to regulate genes that promote metastasis. PMID- 28098160 TI - A ZIP6-ZIP10 heteromer controls NCAM1 phosphorylation and integration into focal adhesion complexes during epithelial-to-mesenchymal transition. AB - The prion protein (PrP) evolved from the subbranch of ZIP metal ion transporters comprising ZIPs 5, 6 and 10, raising the prospect that the study of these ZIPs may reveal insights relevant for understanding the function of PrP. Building on data which suggested PrP and ZIP6 are critical during epithelial-to-mesenchymal transition (EMT), we investigated ZIP6 in an EMT paradigm using ZIP6 knockout cells, mass spectrometry and bioinformatic methods. Reminiscent of PrP, ZIP6 levels are five-fold upregulated during EMT and the protein forms a complex with NCAM1. ZIP6 also interacts with ZIP10 and the two ZIP transporters exhibit interdependency during their expression. ZIP6 contributes to the integration of NCAM1 in focal adhesion complexes but, unlike cells lacking PrP, ZIP6 deficiency does not abolish polysialylation of NCAM1. Instead, ZIP6 mediates phosphorylation of NCAM1 on a cluster of cytosolic acceptor sites. Substrate consensus motif features and in vitro phosphorylation data point toward GSK3 as the kinase responsible, and interface mapping experiments identified histidine-rich cytoplasmic loops within the ZIP6/ZIP10 heteromer as a novel scaffold for GSK3 binding. Our data suggests that PrP and ZIP6 inherited the ability to interact with NCAM1 from their common ZIP ancestors but have since diverged to control distinct posttranslational modifications of NCAM1. PMID- 28098161 TI - Modelling of occupational exposure to inhalable nickel compounds. AB - The aim of this study was to estimate average occupational exposure to inhalable nickel (Ni) using the German exposure database MEGA. This database contains 8052 personal measurements of Ni collected between 1990 and 2009 in adjunct with information on the measurement and workplace conditions. The median of all Ni concentrations was 9 MUg/m3 and the 95th percentile was 460 MUg/m3. We predicted geometric means (GMs) for welders and other occupations centered to 1999. Exposure to Ni in welders is strongly influenced by the welding process applied and the Ni content of the used welding materials. Welding with consumable electrodes of high Ni content (>30%) was associated with 10-fold higher concentrations compared with those with a low content (<5%). The highest exposure levels (GMs >=20 MUg/m3) were observed in gas metal and shielded metal arc welders using welding materials with high Ni content, in metal sprayers, grinders and forging-press operators, and in the manufacture of batteries and accumulators. The exposure profiles are useful for exposure assessment in epidemiologic studies as well as in industrial hygiene. Therefore, we recommend to collect additional exposure-specific information in addition to the job title in community-based studies when estimating the health risks of Ni exposure. PMID- 28098163 TI - Erratum: Global gain modulation generates time-dependent urgency during perceptual choice in humans. PMID- 28098164 TI - Uncovering the SUMOylation and ubiquitylation crosstalk in human cells using sequential peptide immunopurification. AB - Crosstalk between the SUMO and ubiquitin pathways has recently been reported. However, no approach currently exists to determine the interrelationship between these modifications. Here, we report an optimized immunoaffinity method that permits the study of both protein ubiquitylation and SUMOylation from a single sample. This method enables the unprecedented identification of 10,388 SUMO sites in HEK293 cells. The sequential use of SUMO and ubiquitin remnant immunoaffinity purification facilitates the dynamic profiling of SUMOylated and ubiquitylated proteins in HEK293 cells treated with the proteasome inhibitor MG132. Quantitative proteomic analyses reveals crosstalk between substrates that control protein degradation, and highlights co-regulation of SUMOylation and ubiquitylation levels on deubiquitinase enzymes and the SUMOylation of proteasome subunits. The SUMOylation of the proteasome affects its recruitment to promyelocytic leukemia protein (PML) nuclear bodies, and PML lacking the SUMO interacting motif fails to colocalize with SUMOylated proteasome further demonstrating that this motif is required for PML catabolism. PMID- 28098165 TI - Combination of mometasone furoate and oxymetazoline for the treatment of adenoid hypertrophy concomitant with allergic rhinitis: A randomized controlled trial. AB - In the clinic, approximately 30% of children with adenoid hypertrophy (AH) concomitant with allergic rhinitis (AR) report poor responses to intranasal steroids. To determine whether the combination of mometasone furoate (MF) and oxymetazoline (OXY) is more effective than either agent alone, we performed a two stage, parallel, randomized, double-blind, double-dummy, clinical trial with 240 AH children with concomitant perennial AR. During the first stage, all children were randomly assigned to the MF or control group for six weeks of treatment. During the second stage, the non-responders from stage one were randomly assigned to 4 groups for 8 weeks of treatment that involved receiving the following treatments: MF/OXY, MF/placebo, placebo/OXY, or placebo/placebo. During the first stage of treatment, 39% of the responders treated with MF achieved greater reductions in total and individual symptom scores than did those on placebo. During the second stage of treatment, the nasal congestion scores of the MF/OXY group significantly decreased. The adenoid/choana ratio of the MF/OXY-treated group decreased and the nasal volume increased significantly. Our results suggest that the combination of OXY and MF is effective and safe for the treatment of AH children with concomitant AR and has a rapid onset of action. PMID- 28098166 TI - Inferring Centrality from Network Snapshots. AB - The topology and dynamics of a complex network shape its functionality. However, the topologies of many large-scale networks are either unavailable or incomplete. Without the explicit knowledge of network topology, we show how the data generated from the network dynamics can be utilised to infer the tempo centrality, which is proposed to quantify the influence of nodes in a consensus network. We show that the tempo centrality can be used to construct an accurate estimate of both the propagation rate of influence exerted on consensus networks and the Kirchhoff index of the underlying graph. Moreover, the tempo centrality also encodes the disturbance rejection of nodes in a consensus network. Our findings provide an approach to infer the performance of a consensus network from its temporal data. PMID- 28098167 TI - Electrocatalytic activity of lithium polysulfides adsorbed into porous TiO2 coated MWCNTs hybrid structure for lithium-sulfur batteries. AB - Lithium-sulfur batteries have attracted great attention because of their high energy density, environmental friendliness, natural abundance and intrinsically low cost of sulfur. However, their commercial applications are greatly hindered by rapid capacity decay due to poor conductivity of electrode, fast dissolution of the intermediate polysulfides into the electrolyte, and the volume expansion of sulfur. Herein, we report a novel composite MWCNTs@TiO2-S nanostructure by grafting TiO2 onto the surface of MWCNTs, followed by incorporating sulfur into the composite. The inner MWCNTs improved the mechanical strength and conductivity of the electrode and the outer TiO2 provided the adsorption sites to immobilize polysulfides due to bonding interaction between TiO2 and polysulfides. The MWCNTs@TiO2-S composite with a mass ratio of 50% (MWCNTs in MWCNTs@TiO2) exhibited the highest electrochemistry performance among all compositing ratios of MWCNTs/TiO2. The performance improvement might be attributed to the downward shift of the apparent Fermi level to a more positive potential and electron rich space region at the interface of MWCNTs-TiO2 that facilitates the reduction of lithium polysulfide at a higher potential. Such a novel hybrid structure can be applicable for electrode design in other energy storage applications. PMID- 28098168 TI - The IL-17A rs2275913 single nucleotide polymorphism is associated with protection to tuberculosis but related to higher disease severity in Argentina. AB - Mycobacterium tuberculosis (Mtb) causes nearly 10 millions of new tuberculosis disease cases annually. However, most individuals exposed to Mtb do not develop tuberculosis, suggesting the influence of a human genetic component. Here, we investigated the association of the rs2275913 SNP (G -> A) from IL-17A and tuberculosis in Argentina by a case-control study. Furthermore, we evaluated in vitro the functional relevance of this SNP during the immune response of the host against Mtb and analyzed its impact on clinical parameters of the disease. We found an association between the AA genotype and tuberculosis resistance. Additionally, within the healthy donors population, AA cells stimulated with a Mtb lysate (Mtb-Ag) produced the highest amounts of IL-17A and IFN-gamma, which further support the genetic evidence found. In contrast, within the tuberculosis patients population, AA Mtb-Ag stimulated cells showed the lowest immunological parameters and we evidenced an association between the AA genotype and clinical parameters of disease severity, such as severe radiological lesions and higher bacilli burden in sputum. Overall, our findings demonstrated that the AA genotype from the IL-17A rs2275913 SNP is positively associated with protection to active tuberculosis but related to higher disease severity in the Argentinean population. PMID- 28098169 TI - IFN-gamma regulates human dental pulp stem cells behavior via NF-kappaB and MAPK signaling. AB - During caries, dental pulp expresses a range of pro-inflammatory cytokines in response to the infectious challenge. Interferon gamma (IFN-gamma) is a dimerized soluble cytokine, which is critical for immune responses. Previous study has demonstrated that IFN-gamma at relative high concentration (100 ng/mL) treatment improved the impaired dentinogenic and immunosuppressive regulatory functions of disease-derived dental pulp stem cells (DPSCs). However, little is known about the regulatory effects of IFN-gamma at relative low concentration on healthy DPSC behavior (including proliferation, migration, and multiple-potential differentiation). Here we demonstrate that IFN-gamma at relatively low concentrations (0.5 ng/mL) promoted the proliferation and migration of DPSCs, but abrogated odonto/osteogenic differentiation. Additionally, we identified that NF kappaB and MAPK signaling pathways are both involved in the process of IFN-gamma regulated odonto/osteogenic differentiation of DPSCs. DPSCs treated with IFN gamma and supplemented with pyrrolidine dithiocarbamate (PDTC, an NF-kappaB inhibitor) or SB203580 (a MAPK inhibitor) showed significantly improved potential for odonto/osteogenic differentiation of DPSCs both in vivo and in vitro. These data provide important insight into the regulatory effects of IFN-gamma on the biological behavior of DPSCs and indicate a promising therapeutic strategy for dentin/pulp tissue engineering in future endodontic treatment. PMID- 28098171 TI - Metallurgical investigation on fourth century BCE silver jewellery of two hoards from Samaria. AB - A fourth century BCE silver jewellery collection, which is part of two hoards of Samarian coins (the Samaria and Nablus Hoards), was studied by non-destructive analyses. The collection, which consists of pendants, rings, beads and earrings, had been examined by visual testing, multi-focal microscopy and SEM-EDS analysis. In order to enhance our knowledge of past technologies of silver jewellery production, we developed a metallurgical methodology based on the chemical composition of the joints and bulk. The results show that all artefacts are made of silver containing a small percentage of copper. Higher copper concentrations were measured in the joining regions. Our research indicates that the manufacturing of the jewellery from both hoards involved similar techniques, including casting, cutting, hammering, bending, granulating and joining methods, indicating that the artefacts were made by trained silversmiths. Although the burial date of the Samaria Hoard - 352 BCE - is some 21 years earlier than that of the Nablus Hoard - circa 331 BCE, a noted continuity in the local production technology is apparent in the analysed items. This information provides better understanding of the technological abilities in the late Persian-period province of Samaria and bears implications on the local silver coins produced in the region. PMID- 28098170 TI - Targeting the PI3K/AKT pathway via GLI1 inhibition enhanced the drug sensitivity of acute myeloid leukemia cells. AB - Combination targeted therapy is commonly used to treat acute myeloid leukemia (AML) patients, particularly in refractory/relapse (RR) population. However, concerns have been raised regarding the safety and patient tolerance of combination chemotherapy. It is critical to choose the appropriate treatment for precision therapy. We performed genome-wide RNA profiling using RNA-Seq to compare the RR group and the complete remission (CR) group (a total of 42 adult AML patients). The Hedgehog (Hh) and PI3K/AKT pathways were upregulated in the RR population, which was further confirmed by western blot and/or qPCR. Overexpression of GLI1 in AML cells led to increased AKT phosphorylation and decreased drug sensitivity, which was attenuated by GLI1 inhibition. By contrast, neither the expression of GLI1 nor apoptosis in response to Ara-C treatment of AML cells was significantly affected by PI3K inhibition. Furthermore, co inhibition of GLI1 and PI3K induced apoptosis of hematopoietic stem/progenitor cells (HSPCs), which raised serious concerns about the side effects of this treatment. These results indicated that GLI1 inhibition alone, but not combined inhibition, is sufficient to enhance AML drug sensitivity, which provides a novel therapeutic strategy for AML treatment. PMID- 28098172 TI - Structural diversity of anti-pancreatic cancer capsimycins identified in mangrove derived Streptomyces xiamenensis 318 and post-modification via a novel cytochrome P450 monooxygenase. AB - Polycyclic tetramate macrolactams (PTMs) were identified as distinct secondary metabolites of the mangrove-derived Streptomyces xiamenensis 318. Together with three known compounds-ikarugamycin (1), capsimycin (2) and capsimycin B (3)-two new compounds, capsimycin C (4) with trans-diols and capsimycin D (5) with trans configurations at C-13/C-14, have been identified. The absolute configurations of the tert/tert-diols moiety was determined in 4 by NMR spectroscopic analysis, CD spectral comparisons and semi-synthetic method. The post-modification mechanism of the carbocyclic ring at C-14/C-13 of compound 1 in the biosynthesis of an important intermediate 3 was investigated. A putative cytochrome P450 superfamily gene, SXIM_40690 (ikaD), which was proximally localized to the ikarugamycin biosynthetic pathway, was characterized. In vivo gene inactivation and complementation experiment confirmed that IkaD catalysed the epoxide-ring formation reaction and further hydroxylation of ethyl side chain to form capsimycin G (3'). Binding affinities and kinetic parameters for the interactions between ikarugamycin (1) and capsimycin B (3) with IkaD were measured with Surface Plasmon Resonance. The intermediate compound 3' was isolated and identified as 30-hydroxyl-capsimycin B. The caspimycins 2 and 3, were transferred to methoxyl derivatives, 6 and 7, under acidic and heating conditions. Compounds 1-3 exhibited anti-proliferative activities against pancreatic carcinoma with IC50 values of 1.30-3.37 MUM. PMID- 28098173 TI - Continuous cell supply from Krt7-expressing hematopoietic stem cells during native hematopoiesis revealed by targeted in vivo gene transfer method. AB - The nature of hematopoietic stem cells under normal hematopoiesis remained largely unknown due to the limited assays available to monitor their behavior in situ. Here, we develop a new mouse model to transfer genes specifically into the primitive hematopoietic stem cell compartment through the utilization of a modified Rcas/TVA system. We succeeded in transferring a GFP reporter gene into adult hematopoietic stem cells in vivo, which are predominantly quiescent, by generating pseudotyped-lentivirus. Furthermore, we demonstrate the utility of this system to study neonatal hematopoiesis, a developmental stage that has been difficult to analyze to date. Using the system developed in this study, we observed continuous multi-lineage hematopoietic cell supply in peripheral blood from Krt7-positive hematopoietic stem cells during unperturbed homeostatic condition. This powerful experimental system could provide a new standard tool to analyze hematopoiesis under physiological condition without transplantation. PMID- 28098174 TI - Novel G9 rotavirus strains co-circulate in children and pigs, Taiwan. AB - Molecular epidemiologic studies collecting information of the spatiotemporal distribution of rotavirus VP7 (G) and VP4 (P) genotypes have shown evidence for the increasing global importance of genotype G9 rotaviruses in humans and pigs. Sequence comparison of the VP7 gene of G9 strains identified different lineages to prevail in the respective host species although some of these lineages appear to be shared among heterologous hosts providing evidence of interspecies transmission events. The majority of these events indicates the pig-to-human spillover, although a reverse route of transmission cannot be excluded either. In this study, new variants of G9 rotaviruses were identified in two children with diarrhea and numerous pigs in Taiwan. Whole genome sequence and phylogenetic analyses of selected strains showed close genetic relationship among porcine and human strains suggesting zoonotic origin of Taiwanese human G9 strains detected in 2014-2015. Although the identified human G9P[19] and G9P[13] rotaviruses represented minority strains, the repeated detection of porcine-like rotavirus strains in Taiwanese children over time justifies the continuation of synchronized strain surveillance in humans and domestic animals. PMID- 28098175 TI - Correlated electronic decay in expanding clusters triggered by intense XUV pulses from a Free-Electron-Laser. AB - Irradiation of nanoscale clusters and large molecules with intense laser pulses transforms them into highly-excited non- equilibrium states. The dynamics of intense laser-cluster interaction is encoded in electron kinetic energy spectra, which contain signatures of direct photoelectron emission as well as emission of thermalized nanoplasma electrons. In this work we report on a so far not observed spectrally narrow bound state signature in the electron kinetic energy spectra from mixed Xe core - Ar shell clusters ionized by intense extreme-ultraviolet (XUV) pulses from a free-electron-laser. This signature is attributed to the correlated electronic decay (CED) process, in which an excited atom relaxes and the excess energy is used to ionize the same or another excited atom or a nanoplasma electron. By applying the terahertz field streaking principle we demonstrate that CED-electrons are emitted at least a few picoseconds after the ionizing XUV pulse has ended. Following the recent finding of CED in clusters ionized by intense near-infrared laser pulses, our observation of CED in the XUV range suggests that this process is of general relevance for the relaxation dynamics in laser produced nanoplasmas. PMID- 28098162 TI - Novel genetic loci associated with hippocampal volume. AB - The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness. PMID- 28098176 TI - Comorbid generalized anxiety disorder and its association with quality of life in patients with major depressive disorder. AB - The comorbidity of major depressive disorder (MDD) and generalized anxiety disorder (GAD) is common and often predicts poorer outcomes than either disorder alone. This study aimed to examine the prevalence of comorbid GAD and its association with quality of life (QOL) among MDD patients. A total of 1225 psychiatric outpatients were screened using the Hospital Anxiety and Depression Scale (HADS). Those who scored >=8 on the HADS were interviewed using DSM-IV criteria by two senior psychiatrists. Patients diagnosed with MDD were further assessed using the 9-item Patient Health Questionnaire, Social Support Rating Scale, Pittsburgh Sleep Quality Index, and World Health Organization QOL Scale, brief version (WHOQOL-BREF). Ultimately, 667 patients were diagnosed with MDD, of 71.7% of whom had GAD. Compared to those with MDD alone, comorbid patients had lower scores on the physical (38.64 +/- 10.35 vs.36.54 +/- 12.32, P = 0.026) and psychological (35.54 +/- 12.98 vs. 30.61 +/- 14.66, P < 0.001) domains of the WHOQOL-BREF. The association between comorbid GAD and poor QOL on the two domains remained statistically significant in the multiple linear regression (unstandardized coefficients: -1.97 and -4.65, P < 0.001). In conclusion, the prevalence of comorbid GAD in MDD patients is high, and co-occurring GAD may exacerbate impaired physical and psychological QOL in Chinese MDD patients. PMID- 28098177 TI - An extended N-H bond, driven by a conserved second-order interaction, orients the flavin N5 orbital in cholesterol oxidase. AB - The protein microenvironment surrounding the flavin cofactor in flavoenzymes is key to the efficiency and diversity of reactions catalysed by this class of enzymes. X-ray diffraction structures of oxidoreductase flavoenzymes have revealed recurrent features which facilitate catalysis, such as a hydrogen bond between a main chain nitrogen atom and the flavin redox center (N5). A neutron diffraction study of cholesterol oxidase has revealed an unusual elongated main chain nitrogen to hydrogen bond distance positioning the hydrogen atom towards the flavin N5 reactive center. Investigation of the structural features which could cause such an unusual occurrence revealed a positively charged lysine side chain, conserved in other flavin mediated oxidoreductases, in a second shell away from the FAD cofactor acting to polarize the peptide bond through interaction with the carbonyl oxygen atom. Double-hybrid density functional theory calculations confirm that this electrostatic arrangement affects the N-H bond length in the region of the flavin reactive center. We propose a novel second order partial-charge interaction network which enables the correct orientation of the hydride receiving orbital of N5. The implications of these observations for flavin mediated redox chemistry are discussed. PMID- 28098178 TI - Lithium Accumulates in Neurogenic Brain Regions as Revealed by High Resolution Ion Imaging. AB - Lithium (Li) is a potent mood stabilizer and displays neuroprotective and neurogenic properties. Despite extensive investigations, the mechanisms of action have not been fully elucidated, especially in the juvenile, developing brain. Here we characterized lithium distribution in the juvenile mouse brain during 28 days of continuous treatment that result in clinically relevant serum concentrations. By using Time-of-Flight Secondary Ion Mass Spectrometry- (ToF SIMS) based imaging we were able to delineate temporospatial lithium profile throughout the brain and concurrent distribution of endogenous lipids with high chemical specificity and spatial resolution. We found that Li accumulated in neurogenic regions and investigated the effects on hippocampal neurogenesis. Lithium increased proliferation, as judged by Ki67-immunoreactivity, but did not alter the number of doublecortin-positive neuroblasts at the end of the treatment period. Moreover, ToF-SIMS revealed a steady depletion of sphingomyelin in white matter regions during 28d Li-treatment, particularly in the olfactory bulb. In contrast, cortical levels of cholesterol and choline increased over time in Li treated mice. This is the first study describing ToF-SIMS imaging for probing the brain-wide accumulation of supplemented Li in situ. The findings demonstrate that this technique is a powerful approach for investigating the distribution and effects of neuroprotective agents in the brain. PMID- 28098179 TI - A salivary EF-hand calcium-binding protein of the brown planthopper Nilaparvata lugens functions as an effector for defense responses in rice. AB - The brown planthopper (BPH), Nilaparvata lugens (Stal) (Hemiptera: Delphacidae), a major pest of rice in Asia, is able to successfully puncture sieve tubes in rice with its piercing stylet and then to ingest phloem sap. How BPH manages to continuously feed on rice remains unclear. Here, we cloned the gene NlSEF1, which is highly expressed in the salivary glands of BPH. The NlSEF1 protein has EF-hand Ca2+-binding activity and can be secreted into rice plants when BPH feed. Infestation of rice by BPH nymphs whose NlSEF1 was knocked down elicited higher levels of Ca2+ and H2O2 but not jasmonic acid, jasmonoyl-isoleucine (JA-Ile) and SA in rice than did infestation by control nymphs; Consistently, wounding plus the recombination protein NlSEF1 suppressed the production of H2O2 in rice. Bioassays revealed that NlSEF1-knockdown BPH nymphs had a higher mortality rate and lower feeding capacity on rice than control nymphs. These results indicate that the salivary protein in BPH, NlSEF1, functions as an effector and plays important roles in interactions between BPH and rice by mediating the plant's defense responses. PMID- 28098180 TI - An aposymbiotic primary coral polyp counteracts acidification by active pH regulation. AB - Corals build their skeletons using extracellular calcifying fluid located in the tissue-skeleton interface. However, the mechanism by which corals control the transport of calcium and other ions from seawater and the mechanism of constant alkalization of calcifying fluid are largely unknown. To address these questions, we performed direct pH imaging at calcification sites (subcalicoblastic medium, SCM) to visualize active pH upregulation in live aposymbiotic primary coral polyps treated with HCl-acidified seawater. Active alkalization was observed in all individuals using vital staining method while the movement of HPTS and Alexa Fluor to SCM suggests that certain ions such as H+ could diffuse via a paracellular pathway to SCM. Among them, we discovered acid-induced oscillations in the pH of SCM (pHSCM), observed in 24% of polyps examined. In addition, we discovered acid-induced pH up-regulation waves in 21% of polyps examined, which propagated among SCMs after exposure to acidified seawater. Our results showed that corals can regulate pHSCM more dynamically than was previously believed. These observations will have important implications for determining how corals regulate pHSCM during calcification. We propose that corals can sense ambient seawater pH via their innate pH-sensitive systems and regulate pHSCM using several unknown pH-regulating ion transporters that coordinate with multicellular signaling occurring in coral tissue. PMID- 28098181 TI - Profiling single-guide RNA specificity reveals a mismatch sensitive core sequence. AB - Targeting specificity is an essential issue in the development of CRISPR-Cas technology. Using a luciferase activation assay, off-target cleavage activity of sgRNA was systematically investigated on single nucleotide-mismatched targets. In addition to confirming that PAM-proximal mismatches are less tolerated than PAM distal mismatches, our study further identified a "core" sequence that is highly sensitive to target-mismatch. This sequence is of 4-nucleotide long, located at +4 to +7 position upstream of PAM, and positioned in a steric restriction region when assembled into Cas9 endonuclease. Our study also found that, single or multiple target mismatches at this region abolished off-target cleavage mediated by active sgRNAs, thus proposing a principle for gene-specific sgRNA design. Characterization of a mismatch sensitive "core" sequence not only enhances our understanding of how this elegant system functions, but also facilitates our efforts to improve targeting specificity of a sgRNA. PMID- 28098182 TI - Nephro-toxic effects of intraperitoneally injected EGCG in diabetic mice: involvement of oxidative stress, inflammation and apoptosis. AB - Epigallocatechin gallate (EGCG) has been studied for its beneficial effects. However, some case reports have associated EGCG supplementation with hepato toxicity. In the present study, we investigated the possible nephro-toxic effects of EGCG in diabetic mice. Streptozotocin (150 mg/kg, i.p.) was injected in mice for diabetes induction. EGCG (100 mg/kg/day, i.p.) was then given for 4 days. The administration of EGCG to diabetic mice caused 60% mortality with no death recorded in other groups. Blood samples were collected for estimation of serum cystatin C, neutrophil gelatinase-associated lipocalin and blood urea nitrogen. Animals were then sacrificed and kidneys were rapidly excised for estimation of oxidative stress markers (NADPH oxidase, reduced glutathione, total antioxidant capacity, nuclear factor erythroid 2-related factor 2, heat shock protein 90, hemeoxygenase-1), as well as inflammatory markers (nuclear factor kappa-B and tumor necrosis factor-alpha). Administration of EGCG to diabetic mice showed significant elevation in serum cystatin C and neutrophil gelatinase-associated lipocalin, marked increase in oxidative stress and inflammatory states in addition to marked over expression of active caspase-3. Histopathological examination confirmed EGCG induced renal damage in diabetic mice. In conclusion, despite of its well known favorable effects, EGCG could paradoxically exhibit nephro-toxic effect in the presence of diabetes. PMID- 28098183 TI - Seasonal and regional presence of hymenopteran parasitoids of Drosophila in Switzerland and their ability to parasitize the invasive Drosophila suzukii. AB - Since its introduction into Europe the invasive Drosophila suzukii has established and spread widely, thereby entering habitats populated by native Drosophila species and their natural enemies. The highly prolific D. suzukii will likely interact with these species as a competitor, host or prey. To investigate potential interactions of D. suzukii with parasitoids, a field survey was conducted across several fruit-growing regions in Switzerland in two consecutive years. Eight species of hymenopteran parasitoids were collected using D. melanogaster as sentinel hosts in field-traps. Parasitoid capture was much higher in 2015 than in 2014 and varied among regions, time of the growing season, and habitat type. Laboratory no-choice assays with the field-collected species demonstrated that the larval parasitoids Asobara tabida, Leptopilina boulardi, and L. heterotoma could not use D. suzukii for reproduction, although the latter two reduced the number of emerging D. suzukii. In contrast, the pupal parasitoids Pachycrepoideus vindemmiae, Trichopria drosophilae, Vrestovia fidenas and Spalangia erythromera all developed with D. suzukii as hosts. Regional differences between strains were generally not evident, with the exception of two T. drosophilae strains that differed in parasitization rate. Thus, native parasitoids may interact with D. suzukii and should be regarded when implementing pest control measures. PMID- 28098184 TI - Infrared laser-induced gene expression for tracking development and function of single C. elegans embryonic neurons. AB - Visualizing neural-circuit assembly in vivo requires tracking growth of optically resolvable neurites. The Caenorhabditis elegans embryonic nervous system, comprising 222 neurons and 56 glia, is attractive for comprehensive studies of development; however, embryonic reporters are broadly expressed, making single neurite tracking/manipulation challenging. We present a method, using an infrared laser, for reproducible heat-dependent gene expression in small sublineages (one to four cells) without radiation damage. We go beyond proof-of-principle, and use our system to label and track single neurons during early nervous-system assembly. We uncover a retrograde extension mechanism for axon growth, and reveal the aetiology of axon-guidance defects in sax-3/Robo and vab-1/EphR mutants. We also perform cell-specific rescues, determining DAF-6/patched-related site of action during sensory-organ development. Simultaneous ablation and labelling of cells using our system reveals roles for glia in dendrite extension. Our method can be applied to other optically/IR-transparent organisms, and opens the door to high-resolution systematic analyses of C. elegans morphogenesis. PMID- 28098185 TI - Hydrocarbons in phlogopite from Kasenyi kamafugitic rocks (SW Uganda): cross correlated AFM, confocal microscopy and Raman imaging. AB - This study presents a cross-correlated surface and near surface investigation of two phlogopite polytypes from Kasenyi kamafugitic rocks (SW Uganda) by means of advanced Atomic Force Microscopy (AFM), confocal microscopy and Raman micro spectroscopy. AFM revealed comparable nanomorphology and electrostatic surface potential for the two mica polytypes. A widespread presence of nano-protrusions located on the mica flake surface was also observed, with an aspect ratio (maximum height/maximum width) from 0.01 to 0.09. Confocal microscopy showed these features to range from few nm to several MUm in dimension, and shapes from perfectly circular to ellipsoidic and strongly elongated. Raman spectra collected across the bubbles showed an intense and convolute absorption in the range 3000 2800 cm-1, associated with weaker bands at 1655, 1438 and 1297 cm-1, indicating the presence of fluid inclusions consisting of aliphatic hydrocarbons, alkanes and cycloalkanes, with minor amounts of oxygenated compounds, such as carboxylic acids. High-resolution Raman images provided evidence that these hydrocarbons are confined within the bubbles. This work represents the first direct evidence that phlogopite, a common rock-forming mineral, may be a possible reservoir for hydrocarbons. PMID- 28098186 TI - A novel multi-target regression framework for time-series prediction of drug efficacy. AB - Excavating from small samples is a challenging pharmacokinetic problem, where statistical methods can be applied. Pharmacokinetic data is special due to the small samples of high dimensionality, which makes it difficult to adopt conventional methods to predict the efficacy of traditional Chinese medicine (TCM) prescription. The main purpose of our study is to obtain some knowledge of the correlation in TCM prescription. Here, a novel method named Multi-target Regression Framework to deal with the problem of efficacy prediction is proposed. We employ the correlation between the values of different time sequences and add predictive targets of previous time as features to predict the value of current time. Several experiments are conducted to test the validity of our method and the results of leave-one-out cross-validation clearly manifest the competitiveness of our framework. Compared with linear regression, artificial neural networks, and partial least squares, support vector regression combined with our framework demonstrates the best performance, and appears to be more suitable for this task. PMID- 28098187 TI - Carbon elimination from silicon kerf: Thermogravimetric analysis and mechanistic considerations. AB - 40% of ultrapure silicon is lost as kerf during slicing to produce wafers. Kerf is currently not being recycled due to engineering challenges and costs associated with removing its abundant impurities. Carbon left behind from the lubricant remains as one of the most difficult contaminants to remove in kerf without significant silicon oxidation. The present work enables to better understand the mechanism of carbon elimination in kerf which can aid the design of better processes for kef recycling and low cost photovoltaics. In this paper, we studied the kinetics of carbon elimination from silicon kerf in two atmospheres: air and N2, under a regime of no-diffusion-limitation. We report the apparent activation energy in both atmospheres using three methods: Kissinger, and two isoconversional approaches. In both atmospheres, a bimodal apparent activation energy is observed, suggesting a two stage process. A reaction mechanism is proposed in which (a) C-C and C-O bond cleavage reactions occur in parallel with polymer formation; (b) at higher temperatures, this polymer fully degrades in air but leaves a tarry residue in N2 that accounts for about 12% of the initial total carbon. PMID- 28098188 TI - Insecticide resistance status in the whitefly, Bemisia tabaci genetic groups Asia I, Asia-II-1 and Asia-II-7 on the Indian subcontinent. AB - The present study is a summary of the current level of the insecticide resistance to selected organophosphates, pyrethroids, and neonicotinoids in seven Indian field populations of Bemisia tabaci genetic groups Asia-I, Asia-II-1, and Asia-II 7. Susceptibility of these populations was varied with Asia-II-7 being the most susceptible, while Asia-I and Asia-II-1 populations were showing significant resistance to these insecticides. The variability of the LC50 values was 7x for imidacloprid and thiamethoxam, 5x for monocrotophos and 3x for cypermethrin among the Asia-I, while, they were 7x for cypermethrin, 6x for deltamethrin and 5x for imidacloprid within the Asia-II-1 populations. When compared with the most susceptible, PUSA population (Asia-II-7), a substantial increase in resistant ratios was observed in both the populations of Asia-I and Asia-II-1. Comparative analysis during 2010-13 revealed a decline in susceptibility in Asia-I and Asia II-1 populations of B. tabaci to the tested organophosphate, pyrethroid, and neonicotinoid insecticides. Evidence of potential control failure was detected using probit analysis estimates for cypermethrin, deltamethrin, monocrotophos and imidacloprid. Our results update resistance status of B. tabaci in India. The implications of insecticide resistance management of B. tabaci on Indian subcontinent are discussed. PMID- 28098189 TI - Global identification of microRNAs associated with chlorantraniliprole resistance in diamondback moth Plutella xylostella (L.). AB - The diamondback moth (DBM), Plutella xylostella (L.), is one of the most serious cruciferous pests and has developed high resistance to most insecticides, including chlorantraniliprole. Previous studies have reported several protein coding genes that involved in chlorantraniliprole resistance, but research on resistance mechanisms at the post-transcription level is still limited. In this study, a global screen of microRNAs (miRNAs) associated with chlorantraniliprole resistance in P. xylostella was performed. The small RNA libraries for a susceptible (CHS) and two chlorantraniliprole resistant strains (CHR, ZZ) were constructed and sequenced, and a total of 199 known and 30 novel miRNAs were identified. Among them, 23 miRNAs were differentially expressed between CHR and CHS, and 90 miRNAs were differentially expressed between ZZ and CHS, of which 11 differentially expressed miRNAs were identified in both CHR and ZZ. Using miRanda and RNAhybrid, a total of 1,411 target mRNAs from 102 differentially expressed miRNAs were predicted, including mRNAs in several groups of detoxification enzymes. The expression of several differentially expressed miRNAs and their potential targets was validated by qRT-PCR. The results may provide important clues for further study of the mechanisms of miRNA-mediated chlorantraniliprole resistance in DBM and other target insects. PMID- 28098190 TI - An extraordinary palaeontinid from the Triassic of Korea and its significance. AB - A new, extraordinary palaeontinid Hallakkungis amisanus Nam, Wang &Szwedo, gen. et sp. nov., from the Upper Triassic of the Amisan Formation in Boryeong City, Korea is described. It is the first Palaeontinidae from Korea. The newly described taxon displays a mosaic of characters present in presumed ancestors of this insect family and some highly advanced features. PMID- 28098191 TI - Be12O12 Nano-cage as a Promising Catalyst for CO2 Hydrogenation. AB - An efficient conversion of CO2 into valuable fuels and chemicals has been hotly pursued recently. Here, for the first time, we have explored a series of M12x12 nano-cages (M = B, Al, Be, Mg; X = N, P, O) for catalysis of CO2 to HCOOH. Two steps are identified in the hydrogenation process, namely, H2 activation to 2H*, and then 2H* transfer to CO2 forming HCOOH, where the barriers of two H* transfer are lower than that of the H2 activation reaction. Among the studied cages, Be12O12 is found to have the lowest barrier in the whole reaction process, showing two kinds of reaction mechanisms for 2H* (simultaneous transfer and a step-wise transfer with a quite low barrier). Moreover, the H2 activation energy barrier can be further reduced by introducing Al, Ga, Li, and Na to B12N12 cage. This study would provide some new ideas for the design of efficient cluster catalysts for CO2 reduction. PMID- 28098192 TI - Wearable Atmospheric Pressure Plasma Fabrics Produced by Knitting Flexible Wire Electrodes for the Decontamination of Chemical Warfare Agents. AB - One of the key reasons for the limited use of atmospheric pressure plasma (APP) is its inability to treat non-flat, three-dimensional (3D) surface structures, such as electronic devices and the human body, because of the rigid electrode structure required. In this study, a new APP system design-wearable APP (WAPP) that utilizes a knitting technique to assemble flexible co-axial wire electrodes into a large-area plasma fabric is presented. The WAPP device operates in ambient air with a fully enclosed power electrode and grounded outer electrode. The plasma fabric is flexible and lightweight, and it can be scaled up for larger areas, making it attractive for wearable APP applications. Here, we report the various plasma properties of the WAPP device and successful test results showing the decontamination of toxic chemical warfare agents, namely, mustard (HD), soman (GD), and nerve (VX) agents. PMID- 28098194 TI - New hydrate formation methods in a liquid-gas medium. AB - Conceptually new methods of hydrate formation are proposed. The first one is based on the shock wave impact on a water-bubble medium. It is shown that the hydrate formation rate in this process is typically very high. A gas hydrate of carbon dioxide was produced. The process was experimentally studied using various initial conditions, as well as different external action magnitudes. The obtained experimental data are in good agreement with the proposed model. Other methods are based on the process of boiling liquefied gas in an enclosed volume of water (explosive boiling of a hydrating agent and the organization of cyclic boiling condensation process). The key features of the methods are the high hydrate formation rate combined with a comparatively low power consumption leading to a great expected efficiency of the technologies based on them. The set of experiments was carried out. Gas hydrates of refrigerant R134a, carbon dioxide and propane were produced. The investigation of decomposition of a generated gas hydrate sample was made. The criteria of intensification of the hydrate formation process are formulated. PMID- 28098193 TI - Non-pathogenic tissue-resident CD8+ T cells uniquely accumulate in the brains of lupus-prone mice. AB - Severe lupus often includes psychiatric and neurological sequelae, although the cellular contributors to CNS disease remain poorly defined. Using intravascular staining to discriminate tissue-localized from blood-borne cells, we find substantial accumulation of CD8+ T cells relative to other lymphocytes in brain tissue, which correlates with lupus disease and limited neuropathology. This is in contrast to all other affected organs, where infiltrating CD4+ cells are predominant. Brain-infiltrating CD8+ T cells represent an activated subset of those found in the periphery, having a resident-memory phenotype (CD69+CD122 PD1+CD44+CD62L-) and expressing adhesion molecules (VLA-4+LFA-1+) complementary to activated brain endothelium. Remarkably, infiltrating CD8+ T cells do not cause tissue damage in lupus-prone mice, as genetic ablation of these cells via beta2 m deficiency does not reverse neuropathology, but exacerbates disease both in the brain and globally despite decreased serum IgG levels. Thus, lupus associated inflammation disrupts the blood-brain barrier in a discriminating way biased in favor of non-pathogenic CD8+ T cells relative to other infiltrating leukocytes, perhaps preventing further tissue damage in such a sensitive organ. PMID- 28098195 TI - Global mapping of nonseismic sea level oscillations at tsunami timescales. AB - Present investigations of sea level extremes are based on hourly data measured at coastal tide gauges. The use of hourly data restricts existing global and regional analyses to periods larger than 2 h. However, a number of processes occur at minute timescales, of which the most ruinous are tsunamis. Meteotsunamis, hazardous nonseismic waves that occur at tsunami timescales over limited regions, may also locally dominate sea level extremes. Here, we show that nonseismic sea level oscillations at tsunami timescales (<2 h) may substantially contribute to global sea level extremes, up to 50% in low-tidal basins. The intensity of these oscillations is zonally correlated with mid-tropospheric winds at the 99% significance level, with the variance doubling from the tropics and subtropics to the mid-latitudes. Specific atmospheric patterns are found during strong events at selected locations in the World Ocean, indicating a globally predominant generation mechanism. Our analysis suggests that these oscillations should be considered in sea level hazard assessment studies. Establishing a strong correlation between nonseismic sea level oscillations at tsunami timescales and atmospheric synoptic patterns would allow for forecasting of nonseismic sea level oscillations for operational use, as well as hindcasting and projection of their effects under past, present and future climates. PMID- 28098196 TI - Enhanced removal of As (V) from aqueous solution using modified hydrous ferric oxide nanoparticles. AB - Hydrous ferric oxide (HFO) is most effective with high treatment capacity on arsenate [As(V)] sorption although its transformation and aggregation nature need further improvement. Here, HFO nanoparticles with carboxymethyl cellulose (CMC) or starch as modifier was synthesized for the purpose of stability improvement and As(V) removal from water. Comparatively, CMC might be the optimum stabilizer for HFO nanoparticles because of more effective physical and chemical stability. The large-pore structure, high surface specific area, and the non-aggregated nature of CMC-HFO lead to increased adsorption sites, and thus high adsorption capacities of As(V) without pre-treatment (355 mg.g-1), which is much greater than those reported in previous studies. Second-order equation and dual-mode isotherm model could be successfully used to interpret the sorption kinetics and isotherms of As(V), respectively. FTIR, XPS and XRD analyses suggested that precipitation and surface complexation were primary mechanisms for As(V) removal by CMC modified HFO nanoparticles. A surface complexation model (SCM) was used to simulate As adsorption over pH 2.5-10.4. The predominant adsorbed arsenate species were modeled as bidentate binuclear surface complexes at low pH and as monodentate complexes at high pH. The immobilized arsenic remained stable when aging for 270 d at room temperature. PMID- 28098198 TI - Climate change influences on crop mix shifts in the United States. AB - We examine the impact of current and future climate on crop mixes over space in the US. We find using historical data that temperature and precipitation are among the causal factors for shits in crop production location and mixes, with some crops being more sensitive than others. In particular, we find that when temperature rises, cotton, rice, sorghum and winter wheat are more likely to be chosen. We also find that barley, sorghum, winter wheat, spring wheat and hay are more likely to be chosen as regions become drier, and corn, cotton, rice and soybeans are more likely to be selected in wetter regions. Additionally, we assess how much of the observed crop mix shifts between 1970 and 2010 were contributed to by climate change. There we find climate explains about 7-50% of the shift in latitude, 20-36% in longitude and 4-28% of that in elevation. Finally, we estimate climate change impacts on future crop mix under CMIP5 scenarios. There we find shifts in US production regions for almost all major crops with the movement north and east. The estimates describe how the farmers respond to altering climate and can be used for planning future crop allocations. PMID- 28098197 TI - Dantrolene versus amiodarone for cardiopulmonary resuscitation: a randomized, double-blinded experimental study. AB - Dantrolene was introduced for treatment of malignant hyperthermia. It also has antiarrhythmic properties and may thus be an alternative to amiodarone for the treatment of ventricular fibrillation (VF). Aim of this study was to compare the return of spontaneous circulation (ROSC) with dantrolene and amiodarone in a pig model of cardiac arrest. VF was induced in anesthetized pigs. After 8 min of untreated VF, chest compressions and ventilation were started and one of the drugs (amiodarone 5 mg kg-1, dantrolene 2.5 mg kg-1 or saline) was applied. After 4 min of initial CPR, defibrillation was attempted. ROSC rates, hemodynamics and cerebral perfusion measurements were measured. Initial ROSC rates were 7 of 14 animals in the dantrolene group vs. 5 of 14 for amiodarone, and 3 of 10 for saline). ROSC persisted for the 120 min follow-up in 6 animals in the dantrolene group, 4 after amiodarone and 2 in the saline group (n.s.). Hemodynamics were comparable in both dantrolene group amiodarone group after obtaining ROSC. Dantrolene and amiodarone had similar outcomes in our model of prolonged cardiac arrest, However, hemodynamic stability was not significantly improved using dantrolene. Dantrolene might be an alternative drug for resuscitation and should be further investigated. PMID- 28098199 TI - Optogenetic Modulation of Urinary Bladder Contraction for Lower Urinary Tract Dysfunction. AB - As current clinical approaches for lower urinary tract (LUT) dysfunction such as pharmacological and electrical stimulation treatments lack target specificity, thus resulting in suboptimal outcomes with various side effects, a better treatment modality with spatial and temporal target-specificity is necessary. In this study, we delivered optogenetic membrane proteins, such as channelrhodopsin 2 (ChR2) and halorhodopsin (NpHR), to bladder smooth muscle cells (SMCs) of mice using either the Cre-loxp transgenic system or a viral transfection method. The results showed that depolarizing ChR2-SMCs with blue light induced bladder contraction, whereas hyperpolarizing NpHR-SMCs with yellow light suppressed PGE2 induced overactive contraction. We also confirmed that optogenetic contraction of bladder smooth muscles in this study is not neurogenic, but solely myogenic, and that optogenetic light stimulation can modulate the urination in vivo. This study thus demonstrated the utility of optogenetic modulation of smooth muscle as a means to actively control the urinary bladder contraction with spatial and temporal accuracy. These features would increase the efficacy of bladder control in LUT dysfunctions without the side effects of conventional clinical therapies. PMID- 28098201 TI - Fiber-Laser-Based Ultrasound Sensor for Photoacoustic Imaging. AB - Photoacoustic imaging, especially for intravascular and endoscopic applications, requires ultrasound probes with miniature size and high sensitivity. In this paper, we present a new photoacoustic sensor based on a small-sized fiber laser. Incident ultrasound waves exert pressures on the optical fiber laser and induce harmonic vibrations of the fiber, which is detected by the frequency shift of the beating signal between the two orthogonal polarization modes in the fiber laser. This ultrasound sensor presents a noise-equivalent pressure of 40 Pa over a 50 MHz bandwidth. We demonstrate this new ultrasound sensor on an optical-resolution photoacoustic microscope. The axial and lateral resolutions are 48 MUm and 3.3 MUm. The field of view is up to 1.57 mm2. The sensor exhibits strong resistance to environmental perturbations, such as temperature changes, due to common-mode cancellation between the two orthogonal modes. The present fiber laser ultrasound sensor offers a new tool for all-optical photoacoustic imaging. PMID- 28098200 TI - Cullin 7 mediates proteasomal and lysosomal degradations of rat Eag1 potassium channels. AB - Mammalian Eag1 (Kv10.1) potassium (K+) channels are widely expressed in the brain. Several mutations in the gene encoding human Eag1 K+ channel have been associated with congenital neurodevelopmental anomalies. Currently very little is known about the molecules mediating protein synthesis and degradation of Eag1 channels. Herein we aim to ascertain the protein degradation mechanism of rat Eag1 (rEag1). We identified cullin 7 (Cul7), a member of the cullin-based E3 ubiquitin ligase family, as a novel rEag1 binding partner. Immunoprecipitation analyses confirmed the interaction between Cul7 and rEag1 in heterologous cells and neuronal tissues. Cul7 and rEag1 also exhibited significant co-localization at synaptic regions in neurons. Over-expression of Cul7 led to reduced protein level, enhanced ubiquitination, accelerated protein turn-over, and decreased current density of rEag1 channels. We provided further biochemical and morphological evidence suggesting that Cul7 targeted endoplasmic reticulum (ER)- and plasma membrane-localized rEag1 to the proteasome and the lysosome, respectively, for protein degradation. Cul7 also contributed to protein degradation of a disease-associated rEag1 mutant. Together, these results indicate that Cul7 mediates both proteasomal and lysosomal degradations of rEag1. Our findings provide a novel insight to the mechanisms underlying ER and peripheral protein quality controls of Eag1 channels. PMID- 28098202 TI - Superresolution Imaging of Clinical Formalin Fixed Paraffin Embedded Breast Cancer with Single Molecule Localization Microscopy. AB - Millions of archived formalin-fixed, paraffin-embedded (FFPE) specimens contain valuable molecular insight into healthy and diseased states persevered in their native ultrastructure. To diagnose and treat diseases in tissue on the nanoscopic scale, pathology traditionally employs electron microscopy (EM), but this platform has significant limitations including cost and painstaking sample preparation. The invention of single molecule localization microscopy (SMLM) optically overcame the diffraction limit of light to resolve fluorescently labeled molecules on the nanoscale, leading to many exciting biological discoveries. However, applications of SMLM in preserved tissues has been limited. Through adaptation of the immunofluorescence workflow on FFPE sections milled at histological thickness, cellular architecture can now be visualized on the nanoscale using SMLM including individual mitochondria, undulations in the nuclear lamina, and the HER2 receptor on membrane protrusions in human breast cancer specimens. Using astigmatism imaging, these structures can also be resolved in three dimensions to a depth of ~800 nm. These results demonstrate the utility of SMLM in efficiently uncovering ultrastructural information of archived clinical samples, which may offer molecular insights into the physiopathology of tissues to assist in disease diagnosis and treatment using conventional sample preparation methods. PMID- 28098203 TI - Optical coherence tomography angiography microvascular findings in macular edema due to central and branch retinal vein occlusions. AB - The aim of this study was to evaluate retinal and choriocapillaris vessel density using optical coherence tomography angiography (OCTA) in eyes with central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO) complicated by macular edema (ME). Sixty eyes of 60 patients with CRVO or BRVO and ME and 40 healthy subjects underwent measurements of superficial and deep foveal and parafoveal vessel density (FVD, PFVD) and choricapillary density using OCTA at baseline and 60 days after intravitreal dexamethasone implant (IVDEX). FVD and PFVD of the superficial plexus were not significantly lower in CRVO group compared to the controls while in the BRVO group overall PFVD were significantly lower compared to control group (p < 0.001). Overall PFVD of the deep plexus was significantly lower in CRVO and BRVO groups compared to the control group (p < 0.001). FVD and overall PFVD of choriocapillaris were significantly reduced compared to controls in CRVO group (p < 0.001) and PFVD of choriocapillaris was significantly reduced compared to controls in the affected hemi fields in BRVO groups (p < 0.001). OCTA showed vessel density reduction in BRVO and CRVO with main involvement of the deep retinal plexus compared to the superficial retinal plexus due to ischemia that did not recover after intravitreal dexamethasone implant. PMID- 28098205 TI - Reliable and efficient solution of genome-scale models of Metabolism and macromolecular Expression. AB - Constraint-Based Reconstruction and Analysis (COBRA) is currently the only methodology that permits integrated modeling of Metabolism and macromolecular Expression (ME) at genome-scale. Linear optimization computes steady-state flux solutions to ME models, but flux values are spread over many orders of magnitude. Data values also have greatly varying magnitudes. Standard double-precision solvers may return inaccurate solutions or report that no solution exists. Exact simplex solvers based on rational arithmetic require a near-optimal warm start to be practical on large problems (current ME models have 70,000 constraints and variables and will grow larger). We have developed a quadruple-precision version of our linear and nonlinear optimizer MINOS, and a solution procedure (DQQ) involving Double and Quad MINOS that achieves reliability and efficiency for ME models and other challenging problems tested here. DQQ will enable extensive use of large linear and nonlinear models in systems biology and other applications involving multiscale data. PMID- 28098204 TI - Strain-specific Fibril Propagation by an Abeta Dodecamer. AB - Low molecular weight oligomers of amyloid-beta (Abeta) have emerged as the primary toxic agents in the etiology of Alzheimer disease (AD). Polymorphism observed within the aggregation end products of fibrils are known to arise due to microstructural differences among the oligomers. Diversity in aggregate morphology correlates with the differences in AD, cementing the idea that conformational strains of oligomers could be significant in phenotypic outcomes. Therefore, it is imperative to determine the ability of strains to faithfully propagate their structure. Here we report fibril propagation of an Abeta42 dodecamer called large fatty acid-derived oligomers (LFAOs). The LFAO oligomeric strain selectively induces acute cerebral amyloid angiopathy (CAA) in neonatally injected transgenic CRND8 mice. Propagation in-vitro occurs as a three-step process involving the association of LFAO units. LFAO-seeded fibrils possess distinct morphology made of repeating LFAO units that could be regenerated upon sonication. Overall, these data bring forth an important mechanistic perspective into strain-specific propagation of oligomers that has remained elusive thus far. PMID- 28098207 TI - Using 13C isotopes to explore denitrification-dependent anaerobic methane oxidation in a paddy-peatland. AB - Peatlands are organic-matter-rich but nitrogen-limited natural systems, the carbon/nitrogen (C/N) status of which are subject to increasing exposure from long-term nitrate (NO3-) fertilizer inputs and atmospheric nitrogen (N) deposits. To manage and protect these unique environments, an improved understanding of denitrification-dependent anaerobic oxidation of methane (DAMO) in peatlands is needed. In this study, we used stable isotope measurements and incubation with NO3- additions to facilitate an investigation and comparison of the potential DAMO rates in a paddy-peatland that has been influenced by N fertilizer over 40 years and an undisturbed peatland in northeast China. Monitoring of 13CO2 production confimed DAMO did occur in both the paddy-peatland and the undisturbed peatland, the rates of which increased with NO3- additions, but decreased logarithmically with time. When NO3- was added, there were no significant differences between the CH4 oxidation in the paddy-peatland and peatland samples after 36 hours of incubation (97.08 vs. 143.69 nmol g-1 dry peat) and the potential DAMO rate after incubation for 1 hour (92.53 vs. 69.99 nmol g-1 h-1). These results indicate that the occurrence of DAMO in peatlands might be controlled by the amount of NO3- applied and the depth to which it penetrates into the anoxic layer. PMID- 28098206 TI - Protein kinase C delta signaling is required for dietary prebiotic-induced strengthening of intestinal epithelial barrier function. AB - Prebiotics are non-digestible oligosaccharides that promote the growth of beneficial gut microbes, but it is unclear whether they also have direct effects on the intestinal mucosal barrier. Here we demonstrate two commercial prebiotics, inulin and short-chain fructo-oligosaccharide (scFOS), when applied onto intestinal epithelia in the absence of microbes, directly promote barrier integrity to prevent pathogen-induced barrier disruptions. We further show that these effects involve the induction of select tight junction (TJ) proteins through a protein kinase C (PKC) delta-dependent mechanism. These results suggest that in the absence of microbiota, prebiotics can directly exert barrier protective effects by activating host cell signaling in the intestinal epithelium, which represents a novel alternative mechanism of action of prebiotics. PMID- 28098208 TI - High Efficiency Hydrodynamic DNA Fragmentation in a Bubbling System. AB - DNA fragmentation down to a precise fragment size is important for biomedical applications, disease determination, gene therapy and shotgun sequencing. In this work, a cheap, easy to operate and high efficiency DNA fragmentation method is demonstrated based on hydrodynamic shearing in a bubbling system. We expect that hydrodynamic forces generated during the bubbling process shear the DNA molecules, extending and breaking them at the points where shearing forces are larger than the strength of the phosphate backbone. Factors of applied pressure, bubbling time and temperature have been investigated. Genomic DNA could be fragmented down to controllable 1-10 Kbp fragment lengths with a yield of 75.30 91.60%. We demonstrate that the ends of the genomic DNAs generated from hydrodynamic shearing can be ligated by T4 ligase and the fragmented DNAs can be used as templates for polymerase chain reaction. Therefore, in the bubbling system, DNAs could be hydrodynamically sheared to achieve smaller pieces in dsDNAs available for further processes. It could potentially serve as a DNA sample pretreatment technique in the future. PMID- 28098209 TI - Crystal growth of Dirac semimetal ZrSiS with high magnetoresistance and mobility. AB - High quality single crystal ZrSiS as a theoretically predicted Dirac semimetal has been grown successfully using a vapor phase transport method. The single crystals of tetragonal structure are easy to cleave into perfect square-shaped pieces due to the van der Waals bonding between the sulfur atoms of the quintuple layers. Physical property measurement results including resistivity, Hall coefficient (RH), and specific heat are reported. The transport and thermodynamic properties suggest a Fermi liquid behavior with two Fermi pockets at low temperatures. At T = 3 K and magnetic field of H||c up to 9 Tesla, large magneto resistance up to 8500% and 7200% for I||(100) and I||(110) were found. Shubnikov de Haas (SdH) oscillations were identified from the resistivity data, revealing the existence of two Fermi pockets at the Fermi level via the fast Fourier transform (FFT) analysis. The Hall coefficient (RH) showed hole-dominated carriers with a high mobility of 3.05 * 104 cm2 V-1 s-1 at 3 K. ZrSiS has been confirmed to be a Dirac semimetal by the Dirac cone mapping near the X-point via angle resolved photoemission spectroscopy (ARPES) with a Dirac nodal line near the Fermi level identified using scanning tunneling spectroscopy (STS). PMID- 28098210 TI - Intrinsic Defects and H Doping in WO3. AB - WO3 is widely used as industrial catalyst. Intrinsic and/or extrinsic defects can tune the electronic properties and extend applications to gas sensors and optoelectonics. However, H doping is a challenge to WO3, the relevant mechanisms being hardly understood. In this context, we investigate intrinsic defects and H doping by density functional theory and experiments. Formation energies are calculated to determine the lowest energy defect states. O vacancies turn out to be stable in O-poor environment, in agreement with X-ray photoelectron spectroscopy, and O-H bond formation of H interstitial defects is predicted and confirmed by Fourier transform infrared spectroscopy. PMID- 28098211 TI - Deep-sea crustacean trawling fisheries in Portugal: quantification of effort and assessment of landings per unit effort using a Vessel Monitoring System (VMS). AB - Mapping and quantifying bottom trawling fishing pressure on the seafloor is pivotal to understand its effects on deep-sea benthic habitats. Using data from the Vessel Monitoring System of crustacean trawlers along the Portuguese margin, we have identified the most exploited areas and characterized the most targeted habitats and water depths. We estimated a total trawling effort of 69596, 66766, and 63427 h y-1 for the years 2012, 2013, and 2014 respectively which, considering the total landings estimated for this gear, yield values of 20.76, 21.06, and 19.11 kg of landed fish per trawled hour. The main trawling pressure is exerted in the South and Southwest Portuguese margins, on muddy and muddy-sand bottoms between 200 and 700 m water depths, while in the North and Central-West coasts a minor effort, at shallower waters and across a wider range of habitats, is also applied. The most landed species are crustaceans such as rose shrimp and Norway lobster, although this varies importantly between the different regions of Portugal, being fish and cephalopods the main captures in the Northern ports. We discuss the consequences of trawling for the impacted communities as well as the characteristics of the commercialization of these captures in Portugal. PMID- 28098212 TI - Different Volumetric Measurement Methods for Pituitary Adenomas and Their Crucial Clinical Significance. AB - Confirming the status of residual tumors is crucial. In stationary or spontaneous regression cases, early treatments are inappropriate. The long-used geometric calculation formula is 1/2 (length * width * height). However, it yields only rough estimates and is particularly unreliable for irregularly shaped masses. In our study, we attempted to propose a more accurate method. Between 2004 and 2014, 94 patients with pituitary tumors were enrolled in this retrospective study. All patients underwent transsphenoidal surgery and received magnetic resonance imaging (MRI). The pre- and postoperative volumes calculated using the traditional formula were termed A1 and A2, and those calculated using the proposed method were termed O1 and O2, respectively. Wilcoxon signed rank test revealed no significant difference between the A1 and O1 groups (P = 0.1810) but a significant difference between the A2 and O2 groups (P < 0.0001). Significant differences were present in the extent of resection (P < 0.0001), high-grade cavernous sinus invasion (P = 0.0312), and irregular shape (P = 0.0116). Volume is crucial in evaluating tumor status and determining treatment. Therefore, a more scientific method is especially useful when lesions are irregularly shaped or when treatment is determined exclusively based on the tumor volume. PMID- 28098213 TI - Tunable diffraction-free array in nonlinear photonic crystal. AB - Diffraction-free beams have attracted increasing research interests because of their unique performances and broad applications in various fields. Although many methods have been developed to produce such beams, it is still challenging to realize a tunable non-diffracting beam. Here, we report the generation of a tunable diffraction-free array through second-harmonic generation in a nonlinear photonic crystal, i.e., a 2D periodically-poled LiTaO3 crystal. In such a crystal, the second-harmonic wave is engineered by properly designing the domain structure based on the Huygens-Fresnel principle. The characteristics of the generated diffraction-free array including its period, propagation length, and wavelength can be tuned by simply changing the input wavelength. Our observation not only enriches the diffraction-free optics, but also has potential applications for photolithography and imaging. PMID- 28098214 TI - Clinical Roles of Lung Volumes Detected by Body Plethysmography and Helium Dilution in Asthmatic Patients: A Correlation and Diagnosis Analysis. AB - Roles of lung volumes in asthma remain controversial. We aimed to evaluate the efficacy of lung volumes in differentiating asthma severity levels. Consecutive outpatients with chronic persistent asthma were enrolled, and body plethysmography (BP) and helium dilution (HD) were performed simultaneously to extract RV%pred, TLC%pred, and RV/TLC. Significant negative correlations were found between FEV1%pred and RV%pred (r = -0.557, P < 0.001), TLC%pred (r = 0.387, P < 0.001), and RV/TLC (r = -0.485, P < 0.001) measured by BP, as well as difference in volumes between these two techniques (DeltaRV%pred, DeltaTLC%pred and DeltaRV/TLC). In mild and moderate asthma, AUC of RV%pred detected by BP and DeltaTLC%pred was 0.723 (95%CI 0.571-0.874, P = 0.005) and 0.739 (95%CI 0.607 0.872, P = 0.002) with sensitivity and specificity being 79.41% and 88.24%, and 65.22% and 56.52% at cut-off of 145.40% and 14.23%, respectively. In moderate and severe asthma, AUC of RV%pred detected by BP and DeltaTLC%pred was 0.782 (95%CI 0.671-0.893, P < 0.001) and 0.788 (95%CI 0.681-0.894, P < 0.002) with sensitivity and specificity being 77.78% and 97.22%, and 73.53% and 52.94% at cut-off of 179.85% and 20.22%, respectively. In conclusion, lung volumes are reliable complement of FEV1 in identifying asthma severity levels. PMID- 28098216 TI - Chemical bonding in aqueous hexacyano cobaltate from photon- and electron detection perspectives. AB - The electronic structure of the [Co(CN)6]3- complex dissolved in water is studied using X-ray spectroscopy techniques. By combining electron and photon detection methods from the solutions ionized or excited by soft X-rays we experimentally identify chemical bonding between the metal center and the CN ligand. Non resonant photoelectron spectroscopy provides solute electron binding energies, and nitrogen 1 s and cobalt 2p resonant core-level photoelectron spectroscopy identifies overlap between metal and ligand orbitals. By probing resonances we are able to qualitatively determine the ligand versus metal character of the respective occupied and non-occupied orbitals, purely by experiment. For the same excitations we also detect the emitted X-rays, yielding the complementary resonant inelastic X-ray scattering spectra. For a quantitative interpretation of the spectra, we perform theoretical electronic-structure calculations. The latter provide both orbital energies and orbital character which are found to be in good agreement with experimental energies and with experimentally inferred orbital mixing. We also report calculated X-ray absorption spectra, which in conjunction with our orbital-structure analysis, enables us to quantify various bonding interactions with a particular focus on the water-solvent - ligand interaction and the strength of pi-backbonding between metal and ligand. PMID- 28098215 TI - Epigenetic modifications at DMRs of placental genes are subjected to variations in normal gestation, pathological conditions and folate supplementation. AB - Invasive placentation and cancer development shares many similar molecular and epigenetic pathways. Paternally expressed, growth promoting genes (SNRPN, PEG10 and MEST) which are known to play crucial role in tumorogenesis, are not well studied during placentation. This study reports for the first time of the impact of gestational-age, pathological conditions and folic acid supplementation on dynamic nature of DNA and histone methylation present at their differentially methylated regions (DMRs). Here, we reported the association between low DNA methylation/H3K27me3 and higher expression of SNRPN, PEG10 and MEST in highly proliferating normal early gestational placenta. Molar and preeclamptic placental villi, exhibited aberrant changes in methylation levels at DMRs of these genes, leading to higher and lower expression of these genes, respectively, in reference to their respective control groups. Moreover, folate supplementation could induce gene specific changes in mRNA expression in placental cell lines. Further, MEST and SNRPN DMRs were observed to show the potential to act as novel fetal DNA markers in maternal plasma. Thus, variation in methylation levels at these DMRs regulate normal placentation and placental disorders. Additionally, the methylation at these DMRs might also be susceptible to folic acid supplementation and has the potential to be utilized in clinical diagnosis. PMID- 28098217 TI - Disrupting Hepatocyte Cyp51 from Cholesterol Synthesis Leads to Progressive Liver Injury in the Developing Mouse and Decreases RORC Signalling. AB - Development of mice with hepatocyte knockout of lanosterol 14alpha-demethylase (HCyp51-/-) from cholesterol synthesis is characterized by the progressive onset of liver injury with ductular reaction and fibrosis. These changes begin during puberty and are generally more aggravated in the knockout females. However, a subgroup of (pre)pubertal knockout mice (runts) exhibits a pronounced male prevalent liver dysfunction characterized by downregulated amino acid metabolism and elevated Casp12. RORC transcriptional activity is diminished in livers of all runt mice, in correlation with the depletion of potential RORC ligands subsequent to CYP51 disruption. Further evidence for this comes from the global analysis that identified a crucial overlap between hepatic Cyp51-/- and Rorc-/- expression profiles. Additionally, the reduction in RORA and RORC transcriptional activity was greater in adult HCyp51-/- females than males, which correlates well with their downregulated amino and fatty acid metabolism. Overall, we identify a global and sex-dependent transcriptional de-regulation due to the block in cholesterol synthesis during development of the Cyp51 knockout mice and provide in vivo evidence that sterol intermediates downstream of lanosterol may regulate the hepatic RORC activity. PMID- 28098218 TI - The role of miR-497-5p in myofibroblast differentiation of LR-MSCs and pulmonary fibrogenesis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal fibrotic lung disease characterized by profound changes in stem cell differentiation, epithelial cell phenotypes and fibroblast proliferation. In our study, we found that miR-497-5p was significantly upregulated both during myofibroblast differentiation of lung resident mesenchymal stem cells (LR-MSCs) and in the lung tissues of a pulmonary fibrosis model. In addition, as determined by luciferase assays and Western blot analysis, reversion-inducing cysteine-rich protein with kazal motifs (Reck) was identified to be one of the target genes of miR-497-5p, and Reck could suppress the expression of matrix metalloproteinase-2 (Mmp2) and Mmp9, which could activate latent transforming growth factor-beta1 (TGF-beta1). To test the potential therapeutic significance of this miRNA, we modulated the expression of miR-497-5p in LR-MSCs and relevant animal models. The results demonstrated that upregulation of miR-497-5p could induce LR-MSCs to differentiate into myofibroblasts and promote pulmonary fibrogenesis, while inhibition of its expression could effectively retard these processes. In conclusion, our work supports that controlling pulmonary fibrogenesis via inhibition of miR-497-5p expression may provide a potential therapeutic strategy for IPF. PMID- 28098220 TI - Comparative Transcriptome Analysis of Raccoon Dog Skin to Determine Melanin Content in Hair and Melanin Distribution in Skin. AB - The raccoon dog (Nyctereutes procyonoides) is an important canid fur-bearing animal species worldwide. Chinese raccoon dogs that present a white mutation, especially those with a white coat. Exploring melanin biosynthesis in the hair and skin of raccoon dogs is important for understanding the survival and evolutionary mechanisms of them. In this study, we measured the content of melanin in the hair of two types of raccoon dog and generated stained slices of skin tissue. The results indicated that melanin biosynthesis occurs in the wild type (W) and white-type (B) raccoon dog skin, although less melanin is produced in B skin. We then sequenced the skin transcriptomes of W and B, compared the similarities and differences in expressed genes. A comparison of the gene expression showed 60 up-regulated genes and 127 down-regulated genes in B skin. We analyzed the unigenes and pathways related to the melanogenesis pathway and found that TYR, TYRP1, MC1R, SLC24a5, SLC45a2 and OCA2 were significantly down regulated in B skin and these results were verified via qRT-PCR. We surmised that the phenotypic characteristics of the white mutation might be caused by the reduced expression of these genes and this finding provides new insights for future experiments in raccoon dogs. PMID- 28098219 TI - Combined LRRK2 mutation, aging and chronic low dose oral rotenone as a model of Parkinson's disease. AB - Aging, genetics and environmental toxicity are important etiological factors in Parkinson's disease (PD). However, its pathogenesis remains unclear. A major obstacle is the lack of an appropriate experimental model which incorporates genetic susceptibility, aging and prolonged environmental toxicity. Here, we explored the interplay amongst these factors using mutant LRRK2R1441G (leucine rich-repeat-kinase-2) knockin mice. We found that mutant primary cortical and mesencephalic dopaminergic neurons were more susceptible to rotenone-induced ATP deficiency and cell death. Compared with wild-type controls, striatal synaptosomes isolated from young mutant mice exhibited significantly lower dopamine uptake after rotenone toxicity, due to reduced striatal synaptosomal mitochondria and synaptic vesicular proton pump protein (V-ATPase H) levels. Mutant mice developed greater locomotor deficits in open-field tests than wild type mice following low oral rotenone doses given twice weekly over 50 weeks (half their lifespan). The increased locomotor deficit was associated with specific reduction in striatal mitochondrial Complex-I (NDUFS4) in rotenone treated mutant but not in similarly treated wild-type mice. Our unique experimental model which incorporates genetic effect, natural aging and prolonged oral environmental toxicity administered to mutant knockin LRRK2 mice over half their life span, with observable and measurable phenotype, is invaluable in further studies of the pathogenic process and therapeutics of PD. PMID- 28098221 TI - Remote cooling by a novel thermal lens with anisotropic positive thermal conductivity. AB - A novel thermal lens that can achieve a remote cooling effect is designed by transformation thermodynamics. The effective distance between the separate hot source and cold source is shortened by our shelled thermal lens without any negative thermal conductivity. Numerical simulations verify the performance of our thermal lens. Based on the effective medium theory, we also propose a practical way to realize our lens using two-layered isotropic thermal media that are both found in nature. The proposed thermal lens will have potential applications in remote temperature control and in creating other thermal illusions. PMID- 28098222 TI - Dose-dependency and reversibility of radiation-induced injury in cardiac explant derived cells of mice. AB - We evaluated the dose-dependency and reversibility of radiation-induced injury in cardiac explant-derived cells (CDCs), a mixed cell population grown from heart tissues. Adult C57BL/6 mice were exposed to 0, 10, 50 and 250 mGy gamma-rays for 7 days and atrial tissues were collected for experiments 24 hours after last exposure. The number of CDCs was significantly decreased by daily exposure to over 250 mGy. Interestingly, daily exposure to over 50 mGy significantly decreased the c-kit expression and telomerase activity, increased 53BP1 foci in the nuclei of CDCs. However, CD90 expression and growth factors production in CDCs were not significantly changed even after daily exposure to 250 mGy. We further evaluated the reversibility of radiation-induced injury in CDCs at 1 week and 3 weeks after a single exposure to 3 Gy gamma-rays. The number and growth factors production of CDCs were soon recovered at 1 week. However, the increased expression of CD90 were retained at 1 week, but recovered at 3 weeks. Moreover, the decreased expression of c-kit, impaired telomerase activity, and increased 53BP1 foci were poorly recovered even at 3 weeks. These data may help us to find the most sensitive and reliable bio-parameter(s) for evaluating radiation-induced injury in CDCs. PMID- 28098223 TI - Dispersion of nonresonant third-order nonlinearities in Silicon Carbide. AB - In this paper we present a physical discussion of the indirect two-photon absorption (TPA) occuring in silicon carbide with either cubic or wurtzite structure. Phonon-electron interaction is analyzed by finding the phonon features involved in the process as depending upon the crystal symmetry. Consistent physical assumptions about the phonon-electron scattering mechanisms are proposed in order to give a mathematical formulation to predict the wavelength dispersion of TPA and the Kerr nonlinear refractive index n2. The TPA spectrum is investigated including the effects of band nonparabolicity and the influence of the continuum exciton. Moreover, a parametric analysis is presented in order to fit the experimental measurements. Finally, we have estimated the n2 in a large wavelength range spanning the visible to the mid-IR region. PMID- 28098224 TI - Association of Genome-Wide Association Study (GWAS) Identified SNPs and Risk of Breast Cancer in an Indian Population. AB - To date, no studies have investigated the association of the GWAS-identified SNPs with BC risk in Indian population. We investigated the association of 30 previously reported and replicated BC susceptibility SNPs in 1,204 cases and 1,212 controls from a hospital based case-control study conducted at the Tata Memorial Hospital, Mumbai. As a measure of total susceptibility burden, the polygenic risk score (PRS) for each individual was defined by the weighted sum of genotypes from 21 independent SNPs with weights derived from previously published estimates of association odds-ratios. Logistic regression models were used to assess risk associated with individual SNPs and overall PRS, and stratified by menopausal and receptor status. A total of 11 SNPs from eight genomic regions (FGFR2, 9q31.2, MAP3K, CCND1, ZM1Z1, RAD51L11, ESR1 and UST) showed statistically significant (p-value <= 0.05) evidence of association, either overall or when stratified by menopausal status or hormone receptor status. BC SNPs previously identified in Caucasian population showed evidence of replication in the Indian population mainly with respect to risk of postmenopausal and hormone receptor positive BC. PMID- 28098225 TI - The impacts of air pollution on maternal stress during pregnancy. AB - To investigate the association of air pollution with maternal stress during pregnancy, we enrolled 1,931 women during mid-to-late pregnancy in Shanghai in 2010. The "Life-Event Scale for Pregnant Women" and "Symptom-Checklist-90-Revised Scale" (SCL-90-R) were used to evaluate life event stress and emotional stress, respectively. Air pollution data were collected for each district where pregnant women lived during pregnancy. We associated ambient air pollution with stress scores using multivariable logistic regression models. After adjusting for relevant covariates, an interquartile-range (IQR) increase in sulphur-dioxide (SO2) (OR = 1.30, 95% CI: 1.11-1.52) and particulate-matter with an aerodynamic diameter <10 MUm (PM10) (OR = 1.16, 95% CI: 1.02-1.34) concentrations on the recruitment day, and in the 5-day moving average concentrations of nitrogen dioxide (NO2) (OR = 1.34, 95% CI: 1.05-1.70) were associated with high Global Severity-Indices (P75-P100) of the SCL-90-R. These associations were stronger among women bearing high levels (P25-P100) of air pollutants than among women experiencing low levels (P1-P25) of pollutants. The stronger associations and higher levels of pollutants were observed in the cool season than in the warm season. SO2 increases on the recruitment day were also associated with an increased risk of high depression scores (P75-P100). Our findings supported a dose-dependent association between air pollution and emotional stress during pregnancy. PMID- 28098226 TI - Brother of Regulator of Imprinted Sites (BORIS) suppresses apoptosis in colorectal cancer. AB - Identifying oncogenes that promote cancer cell proliferation or survival is critical for treatment of colorectal cancer. The Brother of Regulator of Imprinted Sites (BORIS) is frequently expressed in most types of cancer, but rarely in normal tissues. Aberrantly expressed BORIS relates to colorectal cancer, but its function in colorectal cancer cells remains unclear. In addition, previous studies indicated the significance of cytoplasm-localized BORIS in cancer cells. However, none of them investigated its function. Herein, we investigated the functions of BORIS in cancer cell proliferation and apoptosis and the role of cytoplasm-localized BORIS in colorectal cancer. BORIS expression correlated with colorectal cancer proliferation. BORIS overexpression promoted colorectal cancer cell growth, whereas BORIS knockdown suppressed cell proliferation. Sensitivity of colorectal cancer cells to 5-fluorouracil (5-FU) was inversely correlated with BORIS expression. These data suggest that BORIS functions as an oncogene in colorectal cancer. BORIS silencing induced reactive oxygen species (ROS) production and apoptosis, whereas BORIS supplementation inhibited apoptosis induced by BORIS short interfering RNA (siRNA), hydrogen peroxide (H2O2) or 5-FU. Introduction of BORIS-ZFdel showed that cytoplasmic localization of BORIS inhibited apoptosis but not ROS production. Our study highlights the anti-apoptotic function of BORIS in colorectal cancer. PMID- 28098227 TI - Adolescents display distinctive tolerance to ambiguity and to uncertainty during risky decision making. AB - Although actuarial data indicate that risk-taking behavior peaks in adolescence, laboratory evidence for this developmental spike remains scarce. One possible explanation for this incongruity is that in the real world adolescents often have only vague information about the potential consequences of their behavior and the likelihoods of those consequences, whereas in the lab these are often clearly stated. How do adolescents behave under such more realistic conditions of ambiguity and uncertainty? We asked 105 participants aged from 8 to 22 years to make three types of choices: (1) choices between options whose possible outcomes and probabilities were fully described (choices under risk); (2) choices between options whose possible outcomes were described but whose probability information was incomplete (choices under ambiguity), and (3) choices between unknown options whose possible outcomes and probabilities could be explored (choices under uncertainty). Relative to children and adults, two adolescent-specific markers emerged. First, adolescents were more accepting of ambiguity; second, they were also more accepting of uncertainty (as indicated by shorter pre-decisional search). Furthermore, this tolerance of the unknown was associated with motivational, but not cognitive, factors. These findings offer novel insights into the psychology of adolescent risk taking. PMID- 28098228 TI - Unique Bacteria Community Composition and Co-occurrence in the Milk of Different Ruminants. AB - Lactation provides the singular source of nourishment to the offspring of mammals. This nutrition source also contains a diverse microbiota affecting the development and health of the newborn. Here, we examined the milk microbiota in water deer (Hydropotes inermis, the most primitive member of the family Cervidae), reindeer (Rangifer tarandus, the oldest semi-domesticated cervid), and the dairy goat (Capra aegagrus, member of the family Bovidae), to determine if common milk microbiota species were present across all three ruminant species. The results showed that water deer had the highest bacterial diversity, followed by reindeer, and then goat. Unifrac distance and correspondence analyses revealed that water deer harbored an increased abundance of Pseudomonas spp. and Acinetobacter spp., while milk from reindeer and goat was dominated by unclassified bacteria from the family Hyphomicrobiaceae and Bacillus spp., respectively. These data indicate significant differences in the composition of milk-based bacterial communities. The presence of Halomonas spp. in three distinct co-occurrence networks of bacterial interactions revealed both common and unique features in milk niches. These results suggest that the milk of water deer and reindeer harbor unique bacterial communities compared with the goat, which might reflect host microbial adaptation caused by evolution. PMID- 28098229 TI - Novel synthesis of ZnO/PMMA nanocomposites for photocatalytic applications. AB - The incorporation of nanostructured photocatalysts in polymers is a strategic way to obtain novel water purification systems. This approach takes the advantages of: (1) the presence of nanostructured photocatalyst; (2) the flexibility of polymer; (3) the immobilization of photocatalyst, that avoids the recovery of the nanoparticles after the water treatment. Here we present ZnO-polymer nanocomposites with high photocatalytic performance and stability. Poly (methyl methacrylate) (PMMA) powders were coated with a thin layer of ZnO (80 nm thick) by atomic layer deposition at low temperature (80 degrees C). Then the method of sonication and solution casting was performed so to obtain the ZnO/PMMA nanocomposites. A complete morphological, structural, and chemical characterization was made by scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) analyses. The remarkable photocatalytic efficiency of the nanocomposites was demonstrated by the degradation of methylene blue (MB) dye and phenol in aqueous solution under UV light irradiation. The composites also resulted reusable and stable, since they maintained an unmodified photo-activity after several MB discoloration runs. Thus, these results demonstrate that the proposed ZnO/PMMA nanocomposite is a promising candidate for photocatalytic applications and, in particular, for novel water treatment. PMID- 28098230 TI - Molecular mechanism of the allosteric regulation of the alphagamma heterodimer of human NAD-dependent isocitrate dehydrogenase. AB - Human NAD-dependent isocitrate dehydrogenase catalyzes the decarboxylation of isocitrate (ICT) into alpha-ketoglutarate in the Krebs cycle. It exists as the alpha2betagamma heterotetramer composed of the alphabeta and alphagamma heterodimers. Previously, we have demonstrated biochemically that the alpha2betagamma heterotetramer and alphagamma heterodimer can be allosterically activated by citrate (CIT) and ADP. In this work, we report the crystal structures of the alphagamma heterodimer with the gamma subunit bound without or with different activators. Structural analyses show that CIT, ADP and Mg2+ bind adjacent to each other at the allosteric site. The CIT binding induces conformational changes at the allosteric site, which are transmitted to the active site through the heterodimer interface, leading to stabilization of the ICT binding at the active site and thus activation of the enzyme. The ADP binding induces no further conformational changes but enhances the CIT binding through Mg2+-mediated interactions, yielding a synergistic activation effect. ICT can also bind to the CIT-binding subsite, which induces similar conformational changes but exhibits a weaker activation effect. The functional roles of the key residues are verified by mutagenesis, kinetic and structural studies. Our structural and functional data together reveal the molecular mechanism of the allosteric regulation of the alphagamma heterodimer. PMID- 28098231 TI - Reduced graphene oxide as a stable and high-capacity cathode material for Na-ion batteries. AB - We report the feasibility of using reduced graphene oxide (RGO) as a cost effective and high performance cathode material for sodium-ion batteries (SIBs). Graphene oxide is synthesized by a modified Hummers' method and reduced using a solid-state microwave irradiation method. The RGO electrode delivers an exceptionally stable discharge capacity of 240 mAh g-1 with a stable long cycling up to 1000 cycles. A discharge capacity of 134 mAh g-1 is obtained at a high current density of 600 mA g-1, and the electrode recovers a capacity of 230 mAh g 1 when the current density is reset to 15 mA g-1 after deep cycling, thus demonstrating the excellent stability of the electrode with sodium de/intercalation. The successful use of the RGO electrode demonstrated in this study is expected to facilitate the emergence of low-cost and sustainable carbon based materials for SIB cathode applications. PMID- 28098232 TI - Crystal structure of Sec10, a subunit of the exocyst complex. AB - The exocyst complex is a heterooctameric protein complex composed of Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70 and Exo84. This complex plays an essential role in trafficking secretory vesicles to the plasma membrane through its interaction with phosphatidylinositol 4,5-bisphosphate and small GTPases. To date, the near full-length structural information of each subunit has been limited to Exo70, although the C-terminal half structures of Sec6, Sec15 and Exo84 and the structures of the small GTPase-binding domains of Sec3, Sec5 and Exo84 have been reported. Here, we report the crystal structure of the near-full-length zebrafish Sec10 (zSec10) at 2.73 A resolution. The structure of zSec10 consists of tandem antiparallel helix bundles that form a straight rod, like helical core regions of other exocyst subunits. This structure provides the first atomic details of Sec10, which may be useful for future functional and structural studies of this subunit and the exocyst complex. PMID- 28098233 TI - MicroRNA-34 directly targets pair-rule genes and cytoskeleton component in the honey bee. AB - MicroRNAs (miRNAs) are key regulators of developmental processes, such as cell fate determination and differentiation. Previous studies showed Dicer knockdown in honeybee embryos disrupt the processing of functional mature miRNAs and impairs embryo patterning. Here we investigated the expression profiles of miRNAs in honeybee embryogenesis and the role of the highly conserved miR-34-5p in the regulation of genes involved in insect segmentation. A total of 221 miRNAs were expressed in honey bee embryogenesis among which 97 mature miRNA sequences have not been observed before. Interestingly, we observed a switch in dominance between the 5-prime and 3-prime arm of some miRNAs in different embryonic stages; however, most miRNAs present one dominant arm across all stages of embryogenesis. Our genome-wide analysis of putative miRNA-target networks and functional pathways indicates miR-34-5p is one of the most conserved and connected miRNAs associated with the regulation of genes involved in embryonic patterning and development. In addition, we experimentally validated that miR-34-5p directly interacts to regulatory elements in the 3'-untranslated regions of pair-rule (even-skipped, hairy, fushi-tarazu transcription factor 1) and cytoskeleton (actin5C) genes. Our study suggests that miR-34-5p may regulate the expression of pair-rule and cytoskeleton genes during early development and control insect segmentation. PMID- 28098234 TI - Maternal cortisol stimulates neurogenesis and affects larval behaviour in zebrafish. AB - Excess glucocorticoid transferred from stressed mother to the embryo affects developing vertebrate offspring, but the underlying programming events are unclear. In this study, we tested the hypothesis that increased zygotic glucocorticoid deposition, mimicking a maternal stress scenario, modifies early brain development and larval behaviour in zebrafish (Danio rerio). Cortisol was microinjected into the yolk at one cell-stage, to mimic maternal transfer, and the larvae [96 hours post-fertilization (hpf)] displayed increased activity in light and a reduction in thigmotaxis, a behavioural model for anxiety, suggesting an increased propensity for boldness. This cortisol-mediated behavioural phenotype corresponded with an increase in primary neurogenesis, as measured by incorporation of EdU at 24 hpf, in a region-specific manner in the preoptic region and the pallium, the teleostean homolog of the hippocampus. Also, cortisol increased the expression of the proneural gene neurod4, a marker of neurogenesis, in a region- and development-specific manner in the embryos. Altogether, excess zygotic cortisol, mimicking maternal stress, affects early brain development and behavioural phenotype in larval zebrafish. We propose a key role for cortisol in altering brain development leading to enhanced boldness, which may be beneficial in preparing the offspring to a stressful environment and enhancing fitness. PMID- 28098236 TI - Wind Wave Behavior in Fetch and Depth Limited Estuaries. AB - Wetland dominated estuaries serve as one of the most productive natural ecosystems through their ecological, economic and cultural services, such as nursery grounds for fisheries, nutrient sequestration, and ecotourism. The ongoing deterioration of wetland ecosystems in many shallow estuaries raises concerns about the contributing erosive processes and their roles in restraining coastal restoration efforts. Given the combination of wetlands and shallow bays as landscape components that determine the function of estuaries, successful restoration strategies require knowledge of wind wave behavior in fetch and depth limited water as a critical design feature. We experimentally evaluate physics of wind wave growth in fetch and depth limited estuaries. We demonstrate that wave growth rate in shallow estuaries is a function of wind fetch to water depth ratio, which helps to develop a new set of parametric wave growth equations. We find that the final stage of wave growth in shallow estuaries can be presented by a product of water depth and wave number, whereby their product approaches 1.363 as either depth or wave energy increases. Suggested wave growth equations and their asymptotic constraints establish the magnitude of wave forces acting on wetland erosion that must be included in ecosystem restoration design. PMID- 28098235 TI - Molecular Characterization of Pediatric Restrictive Cardiomyopathy from Integrative Genomics. AB - Pediatric restrictive cardiomyopathy (RCM) is a genetically heterogeneous heart disease with limited therapeutic options. RCM cases are largely idiopathic; however, even within families with a known genetic cause for cardiomyopathy, there is striking variability in disease severity. Although accumulating evidence implicates both gene expression and alternative splicing in development of dilated cardiomyopathy (DCM), there have been no detailed molecular characterizations of underlying pathways dysregulated in RCM. RNA-Seq on a cohort of pediatric RCM patients compared to other forms of adult cardiomyopathy and controls identified transcriptional differences highly common to the cardiomyopathies, as well as those unique to RCM. Transcripts selectively induced in RCM include many known and novel G-protein coupled receptors linked to calcium handling and contractile regulation. In-depth comparisons of alternative splicing revealed splicing events shared among cardiomyopathy subtypes, as well as those linked solely to RCM. Genes identified with altered alternative splicing implicate RBM20, a DCM splicing factor, as a potential mediator of alternative splicing in RCM. We present the first comprehensive report on molecular pathways dysregulated in pediatric RCM including unique/shared pathways identified compared to other cardiomyopathy subtypes and demonstrate that disruption of alternative splicing patterns in pediatric RCM occurs in the inverse direction as DCM. PMID- 28098237 TI - Controllable Synthesis of TiO2@Fe2O3 Core-Shell Nanotube Arrays with Double-Wall Coating as Superb Lithium-Ion Battery Anodes. AB - Highlighted by the safe operation and stable performances, titanium oxides (TiO2) are deemed as promising candidates for next generation lithium-ion batteries (LIBs). However, the pervasively low capacity is casting shadow on desirable electrochemical behaviors and obscuring their practical applications. In this work, we reported a unique template-assisted and two-step atomic layer deposition (ALD) method to achieve TiO2@Fe2O3 core-shell nanotube arrays with hollow interior and double-wall coating. The as-prepared architecture combines both merits of the high specific capacity of Fe2O3 and structural stability of TiO2 backbone. Owing to the nanotubular structural advantages integrating facile strain relaxation as well as rapid ion and electron transport, the TiO2@Fe2O3 nanotube arrays with a high mass loading of Fe2O3 attained desirable capacity of ~520 mA h g-1, exhibiting both good rate capability under uprated current density of 10 A g-1 and especially enhanced cycle stability (~450 mA h g-1 after 600 cycles), outclassing most reported TiO2@metal oxide composites. The results not only provide a new avenue for hybrid core-shell nanotube formation, but also offer an insight for rational design of advanced electrode materials for LIBs. PMID- 28098238 TI - Expression of the novel maternal centrosome assembly factor Wdr8 is required for vertebrate embryonic mitoses. AB - The assembly of the first centrosome occurs upon fertilisation when male centrioles recruit pericentriolar material (PCM) from the egg cytoplasm. The mechanisms underlying the proper assembly of centrosomes during early embryogenesis remain obscure. We identify Wdr8 as a novel maternally essential protein that is required for centrosome assembly during embryonic mitoses of medaka (Oryzias latipes). By CRISPR-Cas9-mediated knockout, maternal/zygotic Wdr8 null (m/zWdr8-/-) blastomeres exhibit severe defects in centrosome structure that lead to asymmetric division, multipolar mitotic spindles and chromosome alignment errors. Via its WD40 domains, Wdr8 interacts with the centriolar satellite protein SSX2IP. Combining targeted gene knockout and in vivo reconstitution of the maternally essential Wdr8-SSX2IP complex reveals an essential link between maternal centrosome proteins and the stability of the zygotic genome for accurate vertebrate embryogenesis. Our approach provides a way of distinguishing maternal from paternal effects in early embryos and should contribute to understanding molecular defects in human infertility. PMID- 28098240 TI - Metal-Insulator Transition of strained SmNiO3 Thin Films: Structural, Electrical and Optical Properties. AB - Samarium nickelate (SmNiO3) thin films were successfully synthesized on LaAlO3 and SrTiO3 substrates using pulsed-laser deposition. The Mott metal-insulator (MI) transition of the thin films is sensitive to epitaxial strain and strain relaxation. Once the strain changes from compressive to tensile, the transition temperature of the SmNiO3 samples shifts to slightly higher values. The optical conductivity reveals the strong dependence of the Drude spectral weight on the strain relaxation. Actually, compressive strain broadens the bandwidth. In contrast, tensile strain causes the effective number of free carriers to reduce which is consistent with the d-band narrowing. PMID- 28098239 TI - Immunoglobulin light chain (IGL) genes in torafugu: Genomic organization and identification of a third teleost IGL isotype. AB - Here, we report a genome-wide survey of immunoglobulin light chain (IGL) genes of torafugu (Takifugu rubripes) revealing multi-clusters spanning three separate chromosomes (v5 assembly) and 45 scaffolds (v4 assembly). Conventional sequence similarity searches and motif scanning approaches based on recombination signal sequence (RSS) motifs were used. We found that three IGL isotypes (L1, L2, and L3) exist in torafugu and that several loci for each isotype are present. The transcriptional orientations of the variable IGL (VL) segments were found to be either the same (in the L2 isotype) or opposite (in the L1 and L3 isotypes) to the IGL joining (JL) and constant (CL) segments, suggesting they can undergo rearrangement by deletion or inversion when expressed. Alignments of expressed sequence tags (ESTs) to corresponding germline gene segments revealed expression of the three IGL isotypes in torafugu. Taken together, our findings provide a genomic framework for torafugu IGL genes and show that the IG diversity of this species could be attributed to at least three distinct chromosomal regions. PMID- 28098241 TI - Characterization of a P1-like bacteriophage carrying CTX-M-27 in Salmonella spp. resistant to third generation cephalosporins isolated from pork in China. AB - The aim of this study was to elucidate the epidemiology of third generation cephalosporin resistant Samonella isolates from pork of a slaughterhouse in China and the features of transferable elements carrying blaCTX-M genes. One hundred and twenty-six (7.3%) Salmonella isolates were identified; S. Derby and S. Rissen were the most two prevalent serotypes. Among these isolates 20 (15.8%) were resistant to third generation cephalosporins and nine of them carried blaCTX-M 27. S1-PFGE and replicon typing of blaCTX-M-27-carrying plasmids showed that seven were untypeable plasmids of about 104 Kb and two were IncP plasmids of about 300 Kb. Complete sequence analysis of one PBRT-untypeable plasmid showed it was a P1-like bateriophage, named SJ46, which contained a non-phage-associated region with several mobile elements, including Tn1721, ISEcp1B and IS903D. The other six 104 Kb PBRT-untypeable blaCTX-M-27-carrying plasmids also harboured the same phage-insertion region of SJ46 suggesting that they were the same P1-like bacteriophage. PFGE profiles of the parental strains revealed both potential vertical and horizontal spread of this P1-like blaCTX-M-27-containing element. Additionally, the representative gene of the P1 family bacteriophage, repL, was detected in 19.0% (24/126) of the isolates. This study indicated a potential role of P1-family bacteriophage in capture and spread of antimicrobial resistance in pathogens. PMID- 28098242 TI - MerR and ChrR mediate blue light induced photo-oxidative stress response at the transcriptional level in Vibrio cholerae. AB - Blue light (BL) is a major environmental factor that affects the physiology, behavior, and infectivity of bacteria as it contributes to the generation of reactive oxygen species (ROS) while increasing photo-oxidative stress in cells. However, precise photo-oxidative response mechanism in non-phototrophic bacteria is yet to be elucidated. In this study, we investigated the effect of BL in Vibrio cholerae by using genetics and transcriptome profiling. Genome-wide analysis revealed that transcription of 6.3% of V. cholerae genes were regulated by BL. We further showed that BL enhances ROS production, which is generated through the oxidative phosphorylation. To understand signaling mechanisms, we generated several knockouts and analyzed their transcriptome under BL exposure. Studies with a double-knockout confirm an anti-sigma factor (ChrR) and putative metalloregulatory-like protein (MerR) are responsible for the genome-wide regulation to BL response in V. cholerae. Collectively, these results demonstrate that MerR-like proteins, in addition to ChrR, are required for V. cholerae to mount an appropriate response against photo-oxidative stress induced by BL. Outside its natural host, V. cholerae can survive for extended periods in natural aquatic environments. Therefore, the regulation of light response for V. cholerae may be a critical cellular process for its survival in these environments. PMID- 28098244 TI - Stochastic evolution in populations of ideas. AB - It is known that learning of players who interact in a repeated game can be interpreted as an evolutionary process in a population of ideas. These analogies have so far mostly been established in deterministic models, and memory loss in learning has been seen to act similarly to mutation in evolution. We here propose a representation of reinforcement learning as a stochastic process in finite 'populations of ideas'. The resulting birth-death dynamics has absorbing states and allows for the extinction or fixation of ideas, marking a key difference to mutation-selection processes in finite populations. We characterize the outcome of evolution in populations of ideas for several classes of symmetric and asymmetric games. PMID- 28098243 TI - Vanillic acid attenuates Abeta1-42-induced oxidative stress and cognitive impairment in mice. AB - Increasing evidence demonstrates that beta-amyloid (Abeta) elicits oxidative stress, which contributes to the pathogenesis and disease progression of Alzheimer's disease (AD). The aims of the present study were to determine and explore the antioxidant nature and potential mechanism of vanillic acid (VA) in Abeta1-42-induced oxidative stress and neuroinflammation mediated cognitive impairment in mice. An intracerebroventricular (i.c.v.) injection of Abeta1-42 into the mouse brain triggered increased reactive oxygen species (ROS) levels, neuroinflammation, synaptic deficits, memory impairment, and neurodegeneration. In contrast, the i.p. (intraperitoneal) administration of VA (30 mg/kg, for 3 weeks) after Abeta1-42-injection enhanced glutathione levels (GSH) and abrogated ROS generation accompanied by an induction of the endogenous nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) via the activation of Akt and glycogen synthase kinase 3beta (GSK-3beta) in the brain mice. Additionally, VA treatment decreased Abeta1-42-induced neuronal apoptosis and neuroinflammation and improved synaptic and cognitive deficits. Moreover, VA was nontoxic to HT22 cells and increased cell viability after Abeta1-42 exposure. To our knowledge, this study is the first to reveal the neuroprotective effect of VA against Abeta1-42-induced neurotoxicity. Our findings demonstrate that VA could potentially serve as a novel, promising, and accessible neuroprotective agent against progressive neurodegenerative diseases such as AD. PMID- 28098245 TI - Natural cytotoxicity receptor 1 in mouse uNK cell maturation and function. AB - Early and midgestational decidua of mice genetically ablated for expression of the natural killer (NK) cell natural cytotoxicity receptor (NCR; Ncr1Gfp/Gfp mice) shows restricted angiogenesis and atypically small uterine (u)NK cells. We hypothesized that NCR1 inactivation disturbs maturation and angiokine production by uterine natural killer (uNK) cells. Using histological and morphometric approaches, we observed that Ncr1Gfp/Gfp but not control C57BL/6 (B6) implantation sites sustain immature, non-granulated uNK cells into midpregnancy. Mouse uNK cells can be subclassified by their reactivity with Dolichos biflorus agglutinin (DBA) lectin; DBA+ uNK cells with greater Ncr1 expression were investigated. DBA+ uNK cells from Ncr1Gfp/Gfp mice show delayed maturation as indicated by shorter diameters and fewer cytoplasmic granules. Granules in mature Ncr1Gfp/Gfp uNK cells are ultrastructurally abnormal and abundance of granule associated proteins (perforin, granzyme) and of cytoplasmic proteins (vascular endothelial growth factor; placental growth factor) differs from controls. Leukocyte-leukocyte conjugate formation in gestation day 6.5 and 8.5 intact Ncr1Gfp/Gfp decidua was less frequent than in B6; however, this difference involved leukocytes other than DBA+ uNK cells. These studies strongly support roles for NCR1 and its ligands in normal pregnancy promotion. PMID- 28098246 TI - Tryptophan metabolite activation of the aryl hydrocarbon receptor regulates IL-10 receptor expression on intestinal epithelia. AB - IL-10 is a potent anti-inflammatory cytokine that inhibits the production of proinflammatory mediators. Signaling by IL-10 occurs through the IL-10 receptor (IL-10R), which is expressed in numerous cell types, including intestinal epithelial cells (IECs), where it is associated with development and maintenance of barrier function. Guided by an unbiased metabolomics screen, we identified tryptophan (Trp) metabolism as a major modifying pathway in interferon-gamma (IFNgamma)-dominant murine colitis. In parallel, we demonstrated that IFNgamma induction of indoleamine 2,3-dioxygenase 1, an enzyme that catalyzes the conversion of Trp to kynurenine (Kyn), induces IL-10R1 expression. Based on these findings, we hypothesized that IL-10R1 expression on IEC is regulated by Trp metabolites. Analysis of the promoter region of IL-10R1 revealed a functional aryl hydrocarbon response element, which is induced by Kyn in luciferase-based IL 10R1 promoter assays. Additionally, this analysis confirmed that IL-10R1 protein levels were increased in response to Kyn in IEC in vitro. Studies using in vitro wounding assays revealed that Kyn accelerates IL-10-dependent wound closure. Finally, reduction of murine dextran sodium sulfate colitis through Kyn administration correlates with colonic IL-10R1 expression. Taken together, these results provide evidence on the importance of IL-10 signaling in intestinal epithelia and implicate AHR in the regulation of IL-10R1 expression in the colon. PMID- 28098247 TI - c-Jun N-terminal kinase 2 promotes enterocyte survival and goblet cell differentiation in the inflamed intestine. AB - c-Jun N-terminal kinases (JNKs) contribute to immune signaling but their functional role during intestinal mucosal inflammation has remained ill defined. Using genetic mouse models, we characterized the role of JNK1 and JNK2 during homeostasis and acute colitis. Epithelial apoptosis, regeneration, differentiation, and barrier function were analyzed in intestinal epithelium specific (DeltaIEC) or complete JNK1 and bone marrow chimeric or complete JNK2 deficient mice as well as double-knockout animals (JNK1DeltaIECJNK2-/-) during homeostasis and acute dextran sulfate sodium (DSS)-induced colitis. Results were confirmed using human HT-29 cells and wild-type or JNK2-deficient mouse intestinal organoid cultures. We show that nonhematopoietic JNK2 but not JNK1 expression confers protection from DSS-induced intestinal inflammation reducing epithelial barrier dysfunction and enterocyte apoptosis. JNK2 additionally enhanced Atonal homolog 1 expression, goblet cell and enteroendocrine cell differentiation, and mucus production under inflammatory conditions. Our results identify a protective role of epithelial JNK2 signaling to maintain mucosal barrier function, epithelial cell integrity, and mucus layer production in the event of inflammatory tissue damage. PMID- 28098248 TI - Microbial succession in the gastrointestinal tract of dairy cows from 2 weeks to first lactation. AB - Development of the dairy calf gastrointestinal tract (GIT) and its associated microbiota are essential for survival and milk production, as this community is responsible for converting plant-based feeds into accessible nutrients. However, little is known regarding the establishment of microbes in the calf GIT. Here, we measured fecal-associated bacterial, archaeal, and fungal communities of dairy cows from 2 weeks to the middle of first lactation (>2 years) as well as rumen associated communities from weaning (8 weeks) to first lactation. These communities were then correlated to animal growth and health. Although succession of specific operational taxonomic units (OTUs) was unique to each animal, beta diversity decreased while alpha-diversity increased as animals aged. Calves exhibited similar microbial families and genera but different OTUs than adults, with a transition to an adult-like microbiota between weaning and 1 year of age. This suggests that alterations of the microbiota for improving downstream milk production may be most effective during, or immediately following, the weaning transition. PMID- 28098249 TI - Enhancing dielectric permittivity for energy-storage devices through tricritical phenomenon. AB - Although dielectric energy-storing devices are frequently used in high voltage level, the fast growing on the portable and wearable electronics have been increasing the demand on the energy-storing devices at finite electric field strength. This paper proposes an approach on enhancing energy density under low electric field through compositionally inducing tricriticality in Ba(Ti,Sn)O3 ferroelectric material system with enlarged dielectric response. The optimal dielectric permittivity at tricritical point can reach to epsilonr = 5.4 * 104, and the associated energy density goes to around 30 mJ/cm3 at the electric field of 10 kV/cm, which exceeds most of the selected ferroelectric materials at the same field strength. The microstructure nature for such a tricritical behavior shows polarization inhomogeneity in nanometeric scale, which indicates a large polarizability under external electric field. Further phenomenological Landau modeling suggests that large dielectric permittivity and energy density can be ascribed to the vanishing of energy barrier for polarization altering caused by tricriticality. Our results may shed light on developing energy-storing dielectrics with large permittivity and energy density at low electric field. PMID- 28098250 TI - Tailoring femtosecond 1.5-MUm Bessel beams for manufacturing high-aspect-ratio through-silicon vias. AB - Three-dimensional integrated circuits (3D ICs) are an attractive replacement for conventional 2D ICs as high-performance, low-power-consumption, and small footprint microelectronic devices. However, one of the major remaining challenges is the manufacture of high-aspect-ratio through-silicon vias (TSVs), which is a crucial technology for the assembly of 3D Si ICs. Here, we present the fabrication of high-quality TSVs using a femtosecond (fs) 1.5-MUm Bessel beam. To eliminate the severe ablation caused by the sidelobes of a conventional Bessel beam, a fs Bessel beam is tailored using a specially designed binary phase plate. We demonstrate that the tailored fs Bessel beam can be used to fabricate a 2D array of approximately ?10-MUm TSVs on a 100-MUm-thick Si substrate without any sidelobe damage, suggesting potential application in the 3D assembly of 3D Si ICs. PMID- 28098251 TI - Unsaturated lipid bodies as a hallmark of inflammation studied by Raman 2D and 3D microscopy. AB - Endothelial HMEC-1 cells incubated with pro-inflammatory cytokine TNF-alpha for 6 and 24 hours were studied as a model of inflammation using Raman imaging. Striking changes in distribution, composition and concentration of cellular lipids were observed after exposure to TNF-alpha compared to the control. In particular, 3D Raman imaging revealed a significant increase in the amount of lipid entities formed under inflammation. Lipid bodies were randomly distributed in the cytoplasm and two types of droplets were assembled: more saturated one, in spectral characteristics resembling phosphatidylcholine and saturated cholesteryl esters, observed also in the control, and highly unsaturated one, containing also cholesterols, being a hallmark of inflamed cells. The statistical analysis showed that the number of lipid bodies was significantly dependent on the exposure time to TNF-alpha. Overall, observed formation of unsaturated lipid droplets can be directly correlated with the increase in production of prostacyclins - endogenous inflammation mediators. PMID- 28098252 TI - Flexible and Wavelength-Selective MoS2 Phototransistors with Monolithically Integrated Transmission Color Filters. AB - Color-selective or wavelength-tunable capability is a crucial feature for two dimensional (2-D) semiconducting material-based image sensor applications. Here, we report on flexible and wavelength-selective molybdenum disulfide (MoS2) phototransistors using monolithically integrated transmission Fabry-Perot (F-P) cavity filters. The fabricated multilayer MoS2 phototransistors on a polyarylate substrate exhibit decent electrical characteristics (MUFE > 64.4 cm2/Vs, on/off ratio > 106), and the integrated F-P filters, being able to cover whole visible spectrum, successfully modulate the spectral response characteristics of MoS2 phototransistors from ~495 nm (blue) to ~590 nm (amber). Furthermore, power dependence of both responsivity and specific detectivity shows similar trend with other reports, dominated by the photogating effect. When combined with large-area monolayer MoS2 for optical property enhancement and array processing, our results can be further developed into ultra-thin flexible photodetectors for wearables, conformable image sensor, and other optoelectronic applications. PMID- 28098254 TI - Nanoscale measurement of trace element distributions in Spartina alterniflora root tissue during dormancy. AB - This paper reports a nanometer-scale investigation of trace element (As, Ca, Cr, Cu, Fe, Mn, Ni, S and Zn) distributions in the root system Spartina alterniflora during dormancy. The sample was collected on a salt marsh island in Jamaica Bay, New York, in April 2015 and the root was cross-sectioned with 10 MUm resolution. Synchrotron X-ray nanofluorescence was applied to map the trace element distributions in selected areas of the root epidermis and endodermis. The sampling resolution was 60 nm to increase the measurement accuracy and reduce the uncertainty. The results indicate that the elemental concentrations in the epidermis, outer endodermis and inner endodermis are significantly (p < 0.01) different. The root endodermis has relatively higher concentrations of these elements than the root epidermis. Furthermore, this high resolution measurement indicates that the elemental concentrations in the outer endodermis are significantly (p < 0.01) higher than those in the inner endodermis. These results suggest that the Casparian strip may play a role in governing the aplastic transport of these elements. Pearson correlation analysis on the average concentrations of each element in the selected areas shows that most of the elements are significantly (p < 0.05) correlated, which suggests that these elements may share the same transport pathways. PMID- 28098253 TI - The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication. AB - Zika virus (ZIKV) is a member of the Flaviviridae family, along with other agents of clinical significance such as dengue (DENV) and hepatitis C (HCV) viruses. Since ZIKV causes neurological disorders during fetal development and in adulthood, antiviral drugs are necessary. Sofosbuvir is clinically approved for use against HCV and targets the protein that is most conserved among the members of the Flaviviridae family, the viral RNA polymerase. Indeed, we found that sofosbuvir inhibits ZIKV RNA polymerase, targeting conserved amino acid residues. Sofosbuvir inhibited ZIKV replication in different cellular systems, such as hepatoma (Huh-7) cells, neuroblastoma (SH-Sy5y) cells, neural stem cells (NSC) and brain organoids. In addition to the direct inhibition of the viral RNA polymerase, we observed that sofosbuvir also induced an increase in A-to-G mutations in the viral genome. Together, our data highlight a potential secondary use of sofosbuvir, an anti-HCV drug, against ZIKV. PMID- 28098255 TI - Annual time-series analysis of aqueous eDNA reveals ecologically relevant dynamics of lake ecosystem biodiversity. AB - The use of environmental DNA (eDNA) in biodiversity assessments offers a step change in sensitivity, throughput and simultaneous measures of ecosystem diversity and function. There remains, however, a need to examine eDNA persistence in the wild through simultaneous temporal measures of eDNA and biota. Here, we use metabarcoding of two markers of different lengths, derived from an annual time series of aqueous lake eDNA to examine temporal shifts in ecosystem biodiversity and in an ecologically important group of macroinvertebrates (Diptera: Chironomidae). The analyses allow different levels of detection and validation of taxon richness and community composition (beta-diversity) through time, with shorter eDNA fragments dominating the eDNA community. Comparisons between eDNA, community DNA, taxonomy and UK species abundance data further show significant relationships between diversity estimates derived across the disparate methodologies. Our results reveal the temporal dynamics of eDNA and validate the utility of eDNA metabarcoding for tracking seasonal diversity at the ecosystem scale. PMID- 28098256 TI - Dopamine promotes NMDA receptor hypofunction in the retina through D1 receptor mediated Csk activation, Src inhibition and decrease of GluN2B phosphorylation. AB - Dopamine and glutamate are critical neurotransmitters involved in light-induced synaptic activity in the retina. In brain neurons, dopamine D1 receptors (D1Rs) and the cytosolic protein tyrosine kinase Src can, independently, modulate the behavior of NMDA-type glutamate receptors (NMDARs). Here we studied the interplay between D1Rs, Src and NMDARs in retinal neurons. We reveal that dopamine-mediated D1R stimulation provoked NMDAR hypofunction in retinal neurons by attenuating NMDA-gated currents, by preventing NMDA-elicited calcium mobilization and by decreasing the phosphorylation of NMDAR subunit GluN2B. This dopamine effect was dependent on upregulation of the canonical D1R/adenylyl cyclase/cAMP/PKA pathway, of PKA-induced activation of C-terminal Src kinase (Csk) and of Src inhibition. Accordingly, knocking down Csk or overexpressing a Csk phosphoresistant Src mutant abrogated the dopamine-induced NMDAR hypofunction. Overall, the interplay between dopamine and NMDAR hypofunction, through the D1R/Csk/Src/GluN2B pathway, might impact on light-regulated synaptic activity in retinal neurons. PMID- 28098258 TI - Unidirectional invisibility induced by parity-time symmetric circuit. AB - Parity-time (PT) symmetric structures present the unidirectional invisibility at the spontaneous PT-symmetry breaking point. In this paper, we propose a PT symmetric circuit consisting of a resistor and a microwave tunnel diode (TD) which represent the attenuation and amplification, respectively. Based on the scattering matrix method, the circuit can exhibit an ideal unidirectional performance at the spontaneous PT-symmetry breaking point by tuning the transmission lines between the lumped elements. Additionally, the resistance of the reactance component can alter the bandwidth of the unidirectional invisibility flexibly. Furthermore, the electromagnetic simulation for the proposed circuit validates the unidirectional invisibility and the synchronization with the input energy well. Our work not only provides an unidirectional invisible circuit based on PT-symmetry, but also proposes a potential solution for the extremely selective filter or cloaking applications. PMID- 28098257 TI - A comprehensive platform for the analysis of ubiquitin-like protein modifications using in vivo biotinylation. AB - Post-translational modification by ubiquitin and ubiquitin-like proteins (UbLs) is fundamental for maintaining protein homeostasis. Efficient isolation of UbL conjugates is hampered by multiple factors, including cost and specificity of reagents, removal of UbLs by proteases, distinguishing UbL conjugates from interactors, and low quantities of modified substrates. Here we describe bioUbLs, a comprehensive set of tools for studying modifications in Drosophila and mammals, based on multicistronic expression and in vivo biotinylation using the E. coli biotin protein ligase BirA. While the bioUbLs allow rapid validation of UbL conjugation for exogenous or endogenous proteins, the single vector approach can facilitate biotinylation of most proteins of interest. Purification under denaturing conditions inactivates deconjugating enzymes and stringent washes remove UbL interactors and non-specific background. We demonstrate the utility of the method in Drosophila cells and transgenic flies, identifying an extensive set of putative SUMOylated proteins in both cases. For mammalian cells, we show conjugation and localization for many different UbLs, with the identification of novel potential substrates for UFM1. Ease of use and the flexibility to modify existing vectors will make the bioUbL system a powerful complement to existing strategies for studying this important mode of protein regulation. PMID- 28098259 TI - Wafer-scale Thermodynamically Stable GaN Nanorods via Two-Step Self-Limiting Epitaxy for Optoelectronic Applications. AB - We present a method of epitaxially growing thermodynamically stable gallium nitride (GaN) nanorods via metal-organic chemical vapor deposition (MOCVD) by invoking a two-step self-limited growth (TSSLG) mechanism. This allows for growth of nanorods with excellent geometrical uniformity with no visible extended defects over a 100 mm sapphire (Al2O3) wafer. An ex-situ study of the growth morphology as a function of growth time for the two self-limiting steps elucidate the growth dynamics, which show that formation of an Ehrlich-Schwoebel barrier and preferential growth in the c-plane direction governs the growth process. This process allows monolithic formation of dimensionally uniform nanowires on templates with varying filling matrix patterns for a variety of novel electronic and optoelectronic applications. A color tunable phosphor-free white light LED with a coaxial architecture is fabricated as a demonstration of the applicability of these nanorods grown by TSSLG. PMID- 28098260 TI - Hepatitis B virus X protein is capable of down-regulating protein level of host antiviral protein APOBEC3G. AB - The apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) family proteins bind RNA and single-stranded DNA, and create C-to-U base modifications through cytidine deaminase activity. APOBEC3G restricts human immunodeficiency virus 1 (HIV-1) infection by creating hypermutations in proviral DNA, while HIV-1 encoded vif protein antagonizes such restriction by targeting APOBEC3G for degradation. APOBEC3G also inhibits hepatitis B virus (HBV): APOBEC3G co expression inhibits HBV replication and evidences exist indicating APOBEC3G mediated HBV hypermutations in patients. HBV encodes a small non-structural X protein (HBx) with a recognized activating effect on HBV life cycle. In this work, we report the discovery that HBx selectively and dose-dependently decreases the protein level of co-expressed APOBEC3G in transfected Huh-7 cells. The effect was shown to take place post-translationally, but does not rely on protein degradation via proteasome or lysosome. Further work demonstrated that intracellular APOBEC3G is normally exported via exosome secretion and inhibition of exosome biogenesis causes retention of intracellular APOBEC3G. Finally, HBx co expression specifically enhanced externalization of APOBEC3G via exosomes, resulting in decrease of intracellular APOBEC3G protein level. These data suggest the possibility that in addition to other mechanisms, HBx-mediated activation of HBV might also involve antagonizing of intracellular restriction factor APOBEC3G through promotion of its export. PMID- 28098261 TI - Direct Observation of the Layer-by-Layer Growth of ZnO Nanopillar by In situ High Resolution Transmission Electron Microscopy. AB - Catalyst-free methods are important for the fabrication of pure nanowires (NWs). However, the growth mechanism remains elusive due to the lack of crucial information on the growth dynamics at atomic level. Here, the noncatalytic growth process of ZnO NWs is studied through in situ high resolution transmission electron microscopy. We observe the layer-by-layer growth of ZnO nanopillars along the polar [0001] direction under electron beam irradiation, while no growth is observed along the radial directions, indicating an anisotropic growth mechanism. The source atoms are mainly from the electron beam induced damage of the sample and the growth is assisted by subsequent absorption and then diffusion of atoms along the side surface to the top (0002) surface. The different binding energy on different ZnO surface is the main origin for the anisotropic growth. Additionally, the coalescence of ZnO nanocrystals related to the nucleation stage is uncovered to realize through the rotational motions and recrystallization. Our in situ results provide atomic-level detailed information about the dynamic growth and coalescence processes in the noncatalytic synthesis of ZnO NW and are helpful for understanding the vapor-solid mechanism of catalyst-free NW growth. PMID- 28098262 TI - Quantification of the sources and composition of particulate matter by field deployable mass spectrometry: implications for air quality and public health. AB - Airborne particulate matter less than 2.5 MUm in diameter (PM2.5) negatively impacts air quality in cities throughout the world where it has been linked to increased cardiac and respiratory morbidity and mortality. For this reason PM2.5 standards have been established by many countries and the World Health Organization. However, these guidelines are regularly exceeded in North America, Europe and East Asia. While PM2.5 is often reported as a single atmospheric species, it is actually a mixture of organic and inorganic compounds. The organic fraction, termed organic aerosol (OA), contributes approximately 20-70% of the PM2.5 mass globally, and OA itself is a complex mixture of thousands of compounds. Characterizing the chemical properties of OA represents a major analytical challenge that has motivated the development of a range of new instruments. The focus of this perspective is the use of field-deployable mass spectrometers and in particular the Aerodyne Aerosol Mass Spectrometer (AMS) for chemically characterizing submicron particles. Field measurements of the composition of PM2.5 are directly relevant to evaluating its health impact because reductions in life expectancy due to PM2.5 vary according to composition. In addition, AMS measurements are especially useful for characterizing OA. The sources of OA are not well understood as evidenced by the performance of many air quality models, including those run by government agencies, which lack accurate and well constrained parameterizations for simulating secondary OA concentrations in urban regions. Given that OA is an important component of the total PM2.5 mass, this uncertainty makes accurate evaluation of the impact of PM2.5 on public health difficult, especially when evaluating future mitigation strategies. The development of the AMS has been a critical step towards addressing this public health challenge in that it provides quantitative data regarding particulate matter and OA concentration and composition that can be used to constrain uncertainties in air quality models. PMID- 28098263 TI - A lab-on-a-chip for monolith-based preconcentration and electrophoresis separation of phosphopeptides. AB - A microdevice combining online preconcentration and separation of phosphopeptides was developed in a glass microchip. An ethylene glycol methacrylate phosphate (EGMP), acrylamide (AM) and bisacrylamide (BAA) based monolith was synthesized within microchannels through a photo-driven process. Morphological investigations revealed a homogeneous monolithic structure composed of uniform nodules (~0.8 MUm), with a large pore volume (0.62 cm3 g-1) and sufficiently high specific surface area (34.1 m2 g-1). These features make the monolith particularly interesting for preconcentration purposes. Immobilization of Zr4+ ions on the phosphate groups present at the poly(EGMP-co-AM-co-BAA) monolith surface leads to immobilized metal affinity chromatography support. This monolith-Zr4+ showed a great capacity to capture phosphopeptides. Successful preconcentration and separation of a mixture of ERK2 derived peptides differing only by their phosphorylation degree and sites could be achieved with signal enhancement factors between 340 and 910 after only 7 min of preconcentration. This integrated microdevice represents a novel approach for phosphoproteomic applications. PMID- 28098264 TI - Assessment of coulometric array electrochemical detection coupled with HPLC-UV for the absolute quantitation of pharmaceuticals. AB - The use of a coulometric array detector in tandem with HPLC-UV was evaluated for the absolute quantitation of pharmaceutical compounds without standards, an important capability gap in contemporary pharmaceutical research and development. The high-efficiency LC flow-through electrochemical detector system allows for the rapid evaluation of up to 16 different potentials, aiding in the identification and quantitation of electrochemically reactive species. By quantifying the number of electrons added or removed from an analyte during its passage through the detector, the number of moles of the analyte can be established. Herein we demonstrate that molecules containing common electroactive functional groups (e.g. anilines, phenols, parabens and tertiary alkyl amines) can in some cases be reliably quantified in HPLC-EC-UV without the need for authentic standards. Furthermore, the multichannel nature of the CoulArray detector makes it well suited for optimizing the conditions for electrochemical reaction, allowing the impact of changes in potential, flow rate, temperature and pH to be conveniently studied. The electrochemical oxidation of albacivir, zomepirac, diclofenac, rosiglitazone and several other marketed drugs resulted in large linear ranges, predictable recoveries and excellent quantitation using the total moles of electrons and back-calculating using Faraday's law. Importantly, we observed several instances where subtle structural changes within a given class of molecules (e.g. aromatic ring isomers) led to unanticipated changes in electrochemical behavior. Consequently, some care should be taken when applying the technique to the routine quantitation of compound libraries where standards are not available. PMID- 28098265 TI - Depth-selective photothermal IR spectroscopy of skin: potential application for non-invasive glucose measurement. AB - An infrared spectroscopic technique is described that employs a mid-IR broadband (980-1245 cm-1) tunable quantum cascade laser (QCL) to produce a pump beam, and a detection method based on photothermal deflection, enhanced by total internal reflection. The IR spectra thus obtained are depth-dependent by modulating the pump beam with different frequencies between 10 Hz and 500 Hz. A model system consisting of glucose and a polymer film is used to demonstrate the depth selectivity of this technique. We also apply this photothermal depth profiling method to record in vivo IR spectra of the human epidermis at different depths. This information can be used for a non-invasive glucose monitoring on diabetes patients, which is also demonstrated. Beyond biomedical infrared spectroscopy, there are numerous applications for total internal reflection enhanced photothermal deflection spectroscopy (TIR-PTDS). The high penetration depth of mid-IR light compared to the traditional ATR-FTIR technique and the easy sample access make this technique appropriate for in situ measurements, such as in industrial quality control. The depth selectivity of TIR-PTDS may be a convincing argument for its use in the analysis of multilayered samples or for the analysis of artwork, where the layers of interest are covered by a layer of varnish. PMID- 28098266 TI - Self-assembled lipoprotein based gold nanoparticles for detection and photothermal disaggregation of beta-amyloid aggregates. AB - We present a reconstituted lipoprotein-based nanoparticle platform comprising a curcumin fluorescent motif and an NIR responsive gold core. This multifunctional nanosystem is successfully used for aggregation-dependent fluorescence detection and photothermal disassembly of insoluble amyloid aggregates. PMID- 28098267 TI - A tailored multi-frequency EPR approach to accurately determine the magnetic resonance parameters of dynamic nuclear polarization agents: application to AMUPol. AB - To understand the dynamic nuclear polarization (DNP) enhancements of biradical polarizing agents, the magnetic resonance parameters need to be known. We describe a tailored EPR approach to accurately determine electron spin-spin coupling parameters using a combination of standard (9 GHz), high (95 GHz) and ultra-high (275 GHz) frequency EPR. Comparing liquid- and frozen-solution continuous-wave EPR spectra provides accurate anisotropic dipolar interaction D and isotropic exchange interaction J parameters of the DNP biradical AMUPol. We found that D was larger by as much as 30% compared to earlier estimates, and that J is 43 MHz, whereas before it was considered to be negligible. With the refined data, quantum mechanical calculations confirm that an increase in dipolar electron-electron couplings leads to higher cross-effect DNP efficiencies. Moreover, the DNP calculations qualitatively reproduce the difference of TOTAPOL and AMUPol DNP efficiencies found experimentally and suggest that AMUPol is particularly effective in improving the DNP efficiency at magnetic fields higher than 500 MHz. The multi-frequency EPR approach will aid in predicting the optimal structures for future DNP agents. PMID- 28098268 TI - Novel surfactant-directed synthesis of ultra-thin palladium nanosheets as efficient electrocatalysts for glycerol oxidation. AB - Ultra-thin palladium nanosheets (PdNSs) with a diameter of ~0.8 nm and characteristic (110)-oriented flat planes were synthesized by confined growth inside lamellar micelles. The rationally designed pyridinium-type surfactant with a long carbon chain (e.g., C22) is a crucial factor for the construction of PdNSs. The other synthesis parameters, including the reduction rate and concentration of reactants, should be carefully controlled. Owing to the ultra thin feature, PdNSs performed superior electrocatalytic activity towards glycerol oxidation. PMID- 28098269 TI - Electron-transporting polymers based on a double B<-N bridged bipyridine (BNBP) unit. AB - In this communication, we report a series of polymer semiconductors based on a novel electron-deficient building block, double B<-N bridged bipyridine (BNBP). These polymers show ambipolar or unipolar n-channel charge-transporting characteristics with electron mobilities in the range of 0.02-0.32 cm2 V-1 s-1 in organic thin film transistors. PMID- 28098270 TI - Copper(i)/TF-BiphamPhos catalyzed asymmetric nitroso Diels-Alder reaction. AB - A highly efficient enantioselective nitroso Diels-Alder reaction of 6-methyl-2 nitroso pyridine with various 1,3-dienes was successfully developed using a Cu(i)/(S)-TF-BiphamPhos complex as the catalyst. For most of the cyclic dienes, synthetically important heterocyclic 3,6-dihydro-1,2-oxazines were obtained in high yields with excellent regio-, diastereo- and enantioselectivities. Acyclic 2 silyloxy-1,3-diene also worked well in the reaction. PMID- 28098271 TI - A two-channel responsive fluorescent probe with AIE characteristics and its application for selective imaging of superoxide anions in living cells. AB - A two-channel responsive and AIE-active fluorescent probe was developed to selectively detect superoxide anions in living cells, which can be used to track the endogenous superoxide anion level when cells undergo apoptosis and inflammation. PMID- 28098272 TI - A near-infrared light responsive c-di-GMP module-based AND logic gate in Shewanella oneidensis. AB - A novel, biofilm-based AND logic gate was constructed in Shewanella oneidensis through a near-infrared (NIR) light responsive c-di-GMP module. The logic gate was demonstrated in microbial fuel cells with isopropyl beta-d-thiogalactoside (IPTG) and NIR light as the inputs and electrical signals as the output. PMID- 28098273 TI - High definition infrared chemical imaging of colorectal tissue using a Spero QCL microscope. AB - Mid-infrared microscopy has become a key technique in the field of biomedical science and spectroscopy. This label-free, non-destructive technique permits the visualisation of a wide range of intrinsic biochemical markers in tissues, cells and biofluids by detection of the vibrational modes of the constituent molecules. Together, infrared microscopy and chemometrics is a widely accepted method that can distinguish healthy and diseased states with high accuracy. However, despite the exponential growth of the field and its research world-wide, several barriers currently exist for its full translation into the clinical sphere, namely sample throughput and data management. The advent and incorporation of quantum cascade lasers (QCLs) into infrared microscopes could help propel the field over these remaining hurdles. Such systems offer several advantages over their FT-IR counterparts, a simpler instrument architecture, improved photon flux, use of room temperature camera systems, and the flexibility of a tunable illumination source. In this current study we explore the use of a QCL infrared microscope to produce high definition, high throughput chemical images useful for the screening of biopsied colorectal tissue. PMID- 28098274 TI - Janus structured Pt-FeNC nanoparticles as a catalyst for the oxygen reduction reaction. AB - We present a new Janus structured catalyst consisting of Pt nanoparticles on Fe-N C nanoparticles encapsulated by graphene layers for the ORR. The ORR activity of the catalyst increases under potential cycling as the unique Janus nanostructure is further bonded due to a synergetic effect. The present study describes an important advanced approach for the future design of efficient, stable, and low cost Pt-based electrocatalytic systems. PMID- 28098275 TI - The initial stages of melting of graphene between 4000 K and 6000 K. AB - Graphene and its analogues have some of the highest predicted melting points of any materials. Previous work estimated the melting temperature for freestanding graphene to be a remarkable 4510 K. However, this work relied on theoretical methods that do not accurately account for the role of bond breaking or complex bonding configurations in the melting process. Furthermore, experiments to verify these high melting points have been challenging. Practical applications of graphene and carbon nanotubes at high temperatures will require a detailed understanding of the behavior of these materials under these conditions. Therefore, we have used reliable ab initio molecular dynamics calculations to study the initial stages of melting of freestanding graphene monolayers between 4000 and 6000 K. To accommodate large defects, and for improved accuracy, we used a large 10 * 10 periodic unit cell. We find that the system can be heated up to 4500 K for 18 ps without melting, and 3-rings and short lived broken bonds (10 rings) are observed. At 4500 K, the system appears to be in a quasi-2D liquid state. At 5000 K, the system is starting to melt. During the 20 ps simulation, diffusion events are observed, leading to the creation of a 5775 defect. We calculate accurate excitation energies for these configurations, and the pair correlation function is presented. The modified Lindemann criterion was calculated. Graphene and nanotubes together with other proposed high melting point materials would be interesting candidates for experimental tests of melting in the weightless environment of space. PMID- 28098276 TI - Direct white-light-emitting and near-infrared phosphorescence of zeolitic imidazolate framework-8. AB - Zeolitic imidazolate framework-8 directly exhibits unexpected white-light emission and near-infrared (NIR) phosphorescence, due to the host-guest interaction and the alternation of electron-density distribution, as confirmed by both experimental and computational studies. PMID- 28098277 TI - Tuning of intrinsic antiferromagnetic to ferromagnetic ordering in microporous alpha-MnO2 by inducing tensile strain. AB - By employing first principles density functional calculations, we investigated an alpha-MnO2 compound with a tunnel framework, which provides an eminent platform to alter the intrinsic antiferromagnetic (AFM) to ferromagnetic (FM) ordering, through the introduction of chemical or mechanical tensile strain. Our calculations further showed that the strength of FM ordering increases until 10% triaxial tensile strain. Since long range FM ordering is induced, it is realized to be superior as compared to the experimentally observed short-range FM ordering in oxygen-deficient compound. The driving force behind this superior effect is understood from the unusual electron occupancy in Mn atoms as a result of tetrahedral distortion in the MnO6 octahedra and an increase in the sp3 character of the oxygen atoms. Thus, the alpha-MnO2 compound belongs to a class of materials that exhibit good potential for piezomagnetic applications. PMID- 28098278 TI - Understanding the connection between conformational changes of peptides and equilibrium thermal fluctuations. AB - Despite the increasing evidence that conformational transitions in peptides and proteins are driven by specific vibrational energy pathways along the molecule, the current experimental techniques of analysis do as yet not allow to study these biophysical processes in terms of anisotropic energy flows. Computational methods offer a complementary approach to obtain a more detailed understanding of the vibrational and conformational dynamics of these systems. Accordingly, in this work we investigate jointly the vibrational energy distribution and the conformational dynamics of trialanine peptide in water solution at room temperature by applying the Instantaneous Normal Mode analysis to the results derived from equilibrium molecular dynamics simulations. It is shown that conformational changes in trialanine are triggered by the vibrational energy accumulated in the low-frequency modes of the molecule, and that excitation is caused exclusively by thermal fluctuations of the solute-solvent system, thus excluding the possibility of an intramolecular vibrational energy redistribution process. PMID- 28098279 TI - Eu3+-Doped Y3-xNdxAl3O12 garnet: synthesis and structural investigation. AB - Nd3+-Doped yttrium aluminium garnet and Eu3+-Nd3+-co-doped yttrium aluminium garnet were synthesized using an environmentally friendly sol-gel method at low temperatures. The results of X-ray diffraction (XRD) analysis of the powders sintered at 1000 degrees C showed the purity and formation of monophasic compounds. The phase composition and purity confirmation of the samples were also characterized via FTIR spectroscopy. Desirable microstructural features and particle size of phosphorous materials of the polycrystalline samples were studied via scanning electron microscopy (SEM). The local environments of Eu3+ and Nd3+ activator ions of the garnets structure compounds were investigated using nuclear magnetic resonance (NMR) spectroscopy. The local environments of the small number of substituted phosphorous ions (Eu3+ and Nd3+) in YAG were shown to critically influence optical properties. Structural features of garnets were found to correlate with their luminescence properties. The luminescence properties were characterized using the results from a photoluminescence (PL) study. Effective concentration of luminescent ion - Nd in YAG was, observed and the optimum ratio between two phosphorous (Eu3+ and Nd3+) was analysed. The transition among europium and neodymium phosphorus was determined. PMID- 28098280 TI - Single lithium-ion conducting solid polymer electrolytes: advances and perspectives. AB - Electrochemical energy storage is one of the main societal challenges to humankind in this century. The performances of classical Li-ion batteries (LIBs) with non-aqueous liquid electrolytes have made great advances in the past two decades, but the intrinsic instability of liquid electrolytes results in safety issues, and the energy density of the state-of-the-art LIBs cannot satisfy the practical requirement. Therefore, rechargeable lithium metal batteries (LMBs) have been intensively investigated considering the high theoretical capacity of lithium metal and its low negative potential. However, the progress in the field of non-aqueous liquid electrolytes for LMBs has been sluggish, with several seemingly insurmountable barriers, including dendritic Li growth and rapid capacity fading. Solid polymer electrolytes (SPEs) offer a perfect solution to these safety concerns and to the enhancement of energy density. Traditional SPEs are dual-ion conductors, in which both cations and anions are mobile and will cause a concentration polarization thus leading to poor performances of both LIBs and LMBs. Single lithium-ion (Li-ion) conducting solid polymer electrolytes (SLIC SPEs), which have anions covalently bonded to the polymer, inorganic backbone, or immobilized by anion acceptors, are generally accepted to have advantages over conventional dual-ion conducting SPEs for application in LMBs. A high Li-ion transference number (LTN), the absence of the detrimental effect of anion polarization, and the low rate of Li dendrite growth are examples of benefits of SLIC-SPEs. To date, many types of SLIC-SPEs have been reported, including those based on organic polymers, organic-inorganic hybrid polymers and anion acceptors. In this review, a brief overview of synthetic strategies on how to realize SLIC SPEs is given. The fundamental physical and electrochemical properties of SLIC SPEs prepared by different methods are discussed in detail. In particular, special attention is paid to the SLIC-SPEs with high ionic conductivity and high LTN. Finally, perspectives on the main challenges and focus on the future research are also presented. PMID- 28098281 TI - Thermodynamic stability of stoichiometric LaFeO3 and BiFeO3: a hybrid DFT study. AB - BiFeO3 perovskite attracts great attention due to its multiferroic properties and potential use as a parent material for Bi1-xSrxFeO3-delta and Bi1-xSrxFe1-yCoyO3 delta solid solutions in intermediate temperature cathodes of oxide fuel cells. Another iron-based LaFeO3 perovskite is the end member for well-known solid solutions (La1-xSrxFe1-yCoyO3-delta) used for oxide fuel cells and other electrochemical devices. In this study an ab initio hybrid functional approach was used for the study of the thermodynamic stability of both LaFeO3 and BiFeO3 with respect to decompositions to binary oxides and to elements, as a function of temperature and oxygen pressure. The localized (LCAO) basis sets describing the crystalline electron wave functions were carefully re-optimized within the CRYSTAL09 computer code. The results obtained by considering Fe as an all electron atom and within the effective core potential technique are compared in detail. Based on our calculations, the phase diagrams were constructed allowing us to predict the stability region of stoichiometric materials in terms of atomic chemical potentials. This permits determining the environmental conditions for the existence of stable BiFeO3 and LaFeO3. These conditions were presented as contour maps of oxygen atoms' chemical potential as a function of temperature and partial pressure of oxygen gas. A similar analysis was also performed using the experimental Gibbs energies of formation. The obtained phase diagrams and contour maps are compared with the calculated ones. PMID- 28098282 TI - B40 cluster stability, reactivity, and its planar structural precursor. AB - We report a comprehensive first-principles study of the structural and chemical properties of the recently discovered B40 cage. It is found to be highly reactive and can exothermically dimerize, regardless of the orientation, by overcoming a small energy barrier ?0.06 eV. The energy gap of the system varies widely with the aggregation of the increasing number of B40 cages, from 3.14 eV in a single B40, to 1.54 eV in the dimer, to 1.25 eV in the trimer. We also explore a recipe for protecting the B40 cage by sheathing it within a carbon shell and identify carbon nanotubes with a radius of ~6 A as optimal hosts for an isolated cage. It is demonstrated that B40 can be unfolded into a planar 'molecule' that tessellates the plane. The corresponding 2D boron sheet constitutes a structural precursor foldable into this unique boron cage structure of current interest. PMID- 28098283 TI - High precision, localized proton gradients and fluxes generated by a microelectrode device induce differential growth behaviors of pollen tubes. AB - Pollen tubes are tip-growing plant cells that deliver the sperm cells to the ovules for double fertilization of the egg cell and the endosperm. Various directional cues can trigger the reorientation of pollen tube growth direction on their passage through the female tissues. Among the external stimuli, protons serve an important, regulatory role in the control of pollen tube growth. The generation of local guidance cues has been challenging when investigating the mechanisms of perception and processing of such directional triggers in pollen tubes. Here, we developed and characterized a microelectrode device to generate a local proton gradient and proton flux through water electrolysis. We confirmed that the cytoplasmic pH of pollen tubes varied with environmental pH change. Depending on the position of the pollen tube tip relative to the proton gradient, we observed alterations in the growth behavior, such as bursting at the tip, change in growth direction, or complete growth arrest. Bursting and growth arrest support the hypothesis that changes in the extracellular H+ concentration may interfere with cell wall integrity and actin polymerization at the growing tip. A change in growth direction for some pollen tubes implies that they can perceive the local proton gradient and respond to it. We also showed that the growth rate is directly correlated with the extracellular pH in the tip region. Our microelectrode approach provides a simple method to generate protons and investigate their effect on plant cell growth. PMID- 28098284 TI - Oxygen vacancy ordering in SrFe0.25Co0.75O2.63 perovskite material. AB - SrFe0.25Co0.75O2.63 was synthesized by a solid-state reaction. Its structural study at room temperature using conventional X-ray as well as neutron powder diffraction, electron diffraction and high-resolution transmission electron microscopy is presented. An oxygen-vacancy ordering related to the "314" model known for the Sr3Y1Co4O10.5 oxide is proposed despite neither an A-site ordering nor an A-site mismatch. By means of Mossbauer spectroscopy, Mohr salt titration and the difference in the neutron cross sections of Fe and Co, a cation distribution within the crystallographic sites as the following Sr4(Fe0.143+Co0.363+)48h(Fe0.114+Co0.144+Co0.253+)48fO10.52 is suggested, highlighting a natural layered structure with Fe and Co in higher oxidation states in the oxygen replete layers than in the oxygen deficient ones. PMID- 28098285 TI - KB(PO4)F: a novel acentric deep-ultraviolet material. AB - Two challenges to grow KBe2BO3F2 (KBBF), the best known deep-ultraviolet nonlinear optical (NLO) material to date, are the limited crystal sizes and the use of a highly toxic element (Be). Herein we report on the discovery of a novel anhydrous non-centrosymmetric alkali fluorinated borophosphate KB(PO4)F (KBPF) featuring a cut-off wavelength of less than 200 nm and a large second-harmonic generation (SHG) effect similar to KH2PO4 (KDP), hence representing a new promising deep-ultraviolet NLO material. The KBPF crystals consisting of common elements can be grown using green and cost effective processes and do not show any detectable hygroscopicity. The title compound also features a 2-dimensional layer [BPO4F]infinity built from [BO3F]4- and [PO4]3- tetrahedral groups but has much stronger interlayer bonds than KBBF, allowing the growth of large crystals. The title compound has been characterized by PXRD, SEM, TG-DSC, FTIR, UV-Vis-NIR diffuse reflectance and SHG analyses as well as single-crystal X-ray structure refinements. The optical properties of KBPF have also been evaluated by first principles calculations at the density functional theory (DFT) level. PMID- 28098286 TI - Tridentate Lewis-acids based on triphenylsilane. AB - Several derivatives of the propeller-shaped ortho-substituted triphenylsilanes, carrying metal- or silicon-based acceptor groups, are reported. They were synthesized starting from tris(2-bromophenyl)fluorosilane, tris(2 vinylphenyl)fluorosilane and tris(2-ethynylphenyl)fluorosilane to generate a scope of Lewis-acidic molecules with different cavities. An improved synthetic protocol for donor-free tris(2-lithiophenyl)silanes is described. First attempts in host-guest chemistry to probe the binding between a threefold alane functionalised ortho-substituted triphenylsilane and a tridentate Lewis-basic guest molecule are presented. The synthesis and a first molecular structure determination in the crystalline state of a bismasilatriptycene is reported. PMID- 28098287 TI - Second-harmonic phase determination by real-time in situ interferometry. AB - Second Harmonic Generation (SHG) has emerged as a highly sensitive probe of protein conformation. SHG can also be used to determine the tilt angle of an SHG active moiety bound to a surface-adsorbed protein through polarization-dependent measurements. However, due to the coherent nature of SHG, interference occurs between the SHG produced by the SHG-active moieties and background sources at a solid-liquid interface, obscuring the signal of interest. In order to separate the protein-specific signal from the background signal, the phase difference between these two different sources of SHG must be determined. Although the phase difference can be obtained through a conventional interferometric approach involving a phase-modulated SHG source external to the sample, it can be sensitive to drift and other instabilities. We present here a simple, convenient, and crucially, model-independent method to determine the phase difference for any system in which the intensity of SHG-active moieties can be varied. We demonstrate the approach with time-resolved measurements of an SHG-active labeled protein binding to a supported lipid bilayer surface using a total internal reflection (TIR) geometry. This approach requires no additional optics beyond what is required to measure SHG and is highly stable since the interferometry occurs in situ, within the sample over a nanometer length scale, rather than external to it. To validate our measurements and the general approach, we constructed a dual-beam, external SHG interferometer in a TIR geometry. We also validated our approach by applying the in situ method to previously published measurements of the phase difference, obtaining the same values without recourse to a specific adsorption model. PMID- 28098288 TI - Ag-Au bimetallic nanoclusters formed from a homogeneous gas phase: a new thermodynamic expression confirmed by molecular dynamics simulation. AB - In this work, two probabilistic and thermodynamic limits for formation of a bimetallic nanocluster from a homogeneous gas phase were obtained in order to investigate the related phenomena using molecular dynamics simulation. Therefore, by application of some simple assumptions from thermodynamics and statistical mechanics, a new expression for composition of the nanocluster was derived which depends only on the initial conditions of the system and one adjustable parameter. This expression can be easily fitted to the results of molecular dynamics and can be used as a measure of the thermodynamic contribution in the cluster formation process. Then, molecular dynamics simulations were performed for several systems containing the same total number of metallic atoms and different concentrations of Ag and Au atoms. The results of this study exhibited that depending on different initial compositions of Ag and Au types, fcc and icosahedral structures are formed. Moreover, increase of the initial Ag concentration leads to products whose compositions are more controlled by probability limits. However, longer simulation times indicated that creation of more thermodynamically favoured nanoclusters depends on the formation of more probable ones in the early stages of the simulation. PMID- 28098289 TI - Photoactive meso-tetra(4-pyridyl)porphyrin-tetrakis [chloro(2,2'bipyridine)platinum(ii) derivatives recognize and cleave DNA upon irradiation. AB - In this work, we evaluate the interaction of the peripheral Pt(bpy)Cl+ substituted porphyrins, H2PtPor and ZnPtPor with DNA using UV-vis, emission fluorescence, CD spectroscopy, and DNA melting properties altered by the Pt(ii) porphyrinoid compounds. Additionally, we observe the ability of these porphyrin derivatives to generate 1O2 and to efficiently photocleave plasmid DNA upon visible light irradiation based on a mixed (oxidative/hydrolytic) mechanism. PMID- 28098290 TI - In situ ligand exchange-mediated 0D/1D transformation of a polyoxovanadate. AB - The antimonato-polyoxovanadate {NiII(en)3}3[VSbO42(H2O)].ca.15H2O was utilized as a synthon for the solvothermal in situ generation of the new compound {NiII(phen)3}2[{NiII(en)2}VSbO42(H2O)].19H2O, a rearrangement induced by ligand metathesis. While in the precursor structure cations and anions are isolated, the solid-state structure of the product is characterized by 1D chains consisting of alternating [V15Sb6O42(H2O)]6- cluster shells and [Ni(en)2]2+ units covalently linked to neighboring clusters via terminal oxygen atoms. Water clusters composed of sixteen hydrogen-bonded H2O molecules are located in void spaces of the structure. The magnetic properties indicate weak antiferromagnetic interactions of the bridging Ni2+ center and adjacent polyoxovanadate anions, as well as small magnetic anisotropy of the individual Ni2+ centers. PMID- 28098291 TI - Investigation into the bioavailability of milk protein-derived peptides with dipeptidyl-peptidase IV inhibitory activity using Caco-2 cell monolayers. AB - In recent years, peptides derived from a variety of dietary proteins have been reported to exhibit inhibitory activity against the dipeptidyl-peptidase IV (DPP IV) enzyme, a target in the management of type 2 diabetes. While much attention has been given to the production and identification of peptides with DPP-IV inhibitory activity from food proteins, particularly dairy proteins, little is known on the bioavailability of these molecules. In this study, the stability and transport of five previously identified milk-derived peptides (LKPTPEGDL, LPYPY, IPIQY, IPI and WR) and a whey protein isolate (WPI) digest with DPP-IV-inhibitory activity were investigated using Caco-2 cell monolayers as a model system for human intestinal absorption. Even though a small percentage (ranging from 0.05% for LPYPY to 0.47% for WR) of the bioactive peptides added to the apical side was able to cross the monolayer intact, all five peptides investigated were susceptible to peptidase action during the transport study. Conversely, only minor changes to the WPI digest composition were observed. Determination of the DPP-IV inhibitory activity of the peptides and amino acids identified in the apical and basolateral solutions showed that most degradation products were less effective at inhibiting DPP-IV than the peptide they originated from. Findings from this research suggest that the susceptibility of food-derived DPP-IV inhibitory peptides to degradation by intestinal brush border membrane enzymes may alter their biological activity in vivo. Further research should be conducted to enhance the bioavailability of DPP-IV inhibitory peptides. PMID- 28098293 TI - Polyaniline nanofibers: broadening applications for conducting polymers. AB - Polyaniline is a conducting polymer with incredible promise, but it has had limited use due to poor reaction control and processability associated with conventional morphologies. Polyaniline nanofibers, on the other hand, have demonstrated, through manufacturing techniques discovered during the past decade, increased processability, higher surface area, and improved consistency and stability in aqueous dispersions, which are finally allowing for expanded commercial development of this promising polymer. This review explores some intriguing applications of polyaniline nanofibers, as well as the advantages and remaining challenges in developing better products using polyaniline in this new morphology. PMID- 28098292 TI - An andrographolide derivative AGP-26b exhibiting anti-angiogenic activity in HUVECs and zebrafish via blocking the VEGFA/VEGFR2 signaling pathway. AB - The aim of this study is to investigate the anti-angiogenic properties of andrographolide derivatives AGP-26a (12beta-isomer), AGP-26b (12alpha-isomer) and AGP-26 (4 : 1 mixture of AGP-26a and AGP-26b) in vitro and in vivo. Human umbilical vein endothelial cells (HUVECs) and the Tg(fli-1a:EGFP)y1 zebrafish model were used to identify the anti-angiogenic activities of AGP-26, AGP-26a, and AGP-26b. The results showed that AGP-26b exhibits the strongest inhibitory effect on VEGF-induced proliferation, migration, invasion and formation of capillary-like structures in HUVECs. In the zebrafish model, AGP-26b also showed the strongest suppression of ISV development. Further studies showed that the underlying mechanism of the anti-angiogenic effects of AGP-26b was at least partly through the blockage of the VEGF/VEGFR2 signaling pathways. AGP-26b blocked the activation of VEGFR2. Consequently, the phosphorylation of key intracellular proangiogenic kinases such as Src family kinase (Src), focal adhesion kinase (Fak), mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase 1 and 2 (Erk1/2) and Akt induced by VEGF was suppressed by treatment with AGP-26b. Moreover, AGP-26b reduced the protein expression of matrix metalloproteinases (MMP-9 but not MMP-2) in HUVECs. These results provide evidence supporting the notion that AGP-26b may serve as a potential therapeutic anti-angiogenic agent. PMID- 28098294 TI - CO2 as a hydrogen vector - transition metal diamine catalysts for selective HCOOH dehydrogenation. AB - The homogeneous catalytic dehydrogenation of formic acid in aqueous solution provides an efficient in situ method for hydrogen production, under mild conditions, and at an adjustable rate. We synthesized a series of catalysts with the chemical formula [(Cp*)M(N-N')Cl] (M = Ir, Rh; Cp* = pentamethylcyclopentadienyl; N-N = bidentate chelating nitrogen donor ligands), which have been proven to be active in selective formic acid decomposition in aqueous media. The scope of the study was to examine the relationship between stability and activity of catalysts for formic acid dehydrogenation versus electronic and steric properties of selected ligands, following a bottom-up approach by increasing the complexity of the N,N'-ligands progressively. The highest turnover frequency, TOF = 3300 h-1 was observed with a Cp*Ir(iii) complex bearing 1,2-diaminocyclohexane as the N,N'-donor ligand. From the variable temperature studies, the activation energy of formic acid dehydrogenation has been determined, Ea = 77.94 +/- 3.2 kJ mol-1. It was observed that the different steric and electronic properties of the bidentate nitrogen donor ligands alter the catalytic activity and stability of the Ir and Rh compounds profoundly. PMID- 28098296 TI - Naked eye plasmonic indicator with multi-responsive polymer brush as signal transducer and amplifier. AB - For decades, plasmonic nanostructures have been used as important optical sensing platforms, however, the necessity of sensitive optical instruments for detection greatly limits their practical application. Herein, a multi-responsive naked eye plasmonic indicator has been prepared through introduction of a responsive polymer brush (PNIPAm) into the cavity of a Ag nanovolcano array (Ag NVA). According to the phase change of the PNIPAm brush under different external conditions, the as-prepared Ag NVA shows responsive monochromatic colors, which allow the Ag NVA to serve as a plasmonic indicator detected by the naked eye. Importantly, the as-prepared Ag NVA also possesses a rapid response rate as well as excellent repeatability, and is compatible with conventional micro-fabrication methods. All of these excellent features make the as-prepared Ag NVA an attractive candidate for future optical indicating and intelligent color display applications. PMID- 28098295 TI - Spontaneous decoration of silicon surfaces with MoOx nanoparticles for the sunlight-assisted hydrogen evolution reaction. AB - The immersion of oxide-free Si surfaces in MoS42- aqueous solutions induces their spontaneous decoration with isolated MoOx nanoparticles (NPs). The process is versatile and was used on planar Si (100) as well as on antireflective Si (111) micro-pyramid (SimPy) arrays. The NP decoration does not affect the optical properties of the surface in the visible range and improves the performance of the hydrogen evolution reaction (HER) under simulated sunlight. The simplicity and the scalability of the technique make it highly promising for the fabrication of catalytically active photoelectrodes. More specifically, the MoOx-decorated SimPy produced H2 at a rate of 11 MUmol cm-2 min-1 with a faradaic efficiency higher than 90% at -0.35 V vs. RHE. Furthermore, this process can be of great interest for other applications in high-performance electronic devices. PMID- 28098297 TI - Spontaneous assembly of a hybrid crystal-liquid phase in inverse patchy colloid systems. AB - Materials with well-defined architectures are heavily sought after in view of their diverse technological applications. Among the desired target architectures, lamellar phases stand out for their exceptional mechanical and optical features. Here we show that charged colloids, decorated on their poles with two oppositely charged regions possess the unusual ability to spontaneously assemble in different morphologies of (semi-)ordered, layered particle arrangements which maintain their structural stability over a surprisingly large temperature range. This remarkable capacity is related to a characteristic bonding mechanism: stable intra-layer bonds guarantee the formation of planar aggregates, while strong inter-layer bonds favor the stacking of the emerging planar assemblies. These two types of bonds together are responsible for the self-healing processes occurring during the spontaneous assembly. The resulting phases are characterized by parallel, densely packed, particle layers connected by a relatively small number of intra-layer particles. We investigate the properties of the (semi-)ordered phases in terms of static and dynamic correlation functions, focusing in particular on a novel hybrid crystal-liquid phase that prevails at intermediate temperatures where the inter-layer particles form a mobile, fluid phase. PMID- 28098298 TI - Recent progress in mild Csp3-H bond dehydrogenative or (mono-) oxidative functionalization. AB - Over the past few years, the development of oxidative methodologies towards efficient and selective direct Csp3-H bond functionalization processes has attracted tremendous attention from synthetic chemists. However, only a little attention has been given to the key role of the nature of the oxidant. This review aims at providing a brief summary of the recent advances in mild and more benign oxidative Csp3-H bond functionalization reactions, which are classified according to the type of oxidation system employed. PMID- 28098299 TI - Vacancies in functional materials for clean energy storage and harvesting: the perfect imperfection. AB - Vacancies exist throughout nature and determine the physical properties of materials. By manipulating the density and distribution of vacancies, it is possible to influence their physical properties such as band-gap, conductivity, magnetism, etc. This can generate exciting applications in the fields of water treatment, energy storage, and physical devices such as resistance-change memories. In this review, we focus on recent progress in vacancy engineering for the design of materials for energy harvesting applications. A brief discription of the concept of vacancies, the way to create and control them, as well as their fundamental properties, is first provided. Then, emphasis is placed on the strategies used to tailor vacancies for metal-insulator transitions, electronic structures, and introducing magnetism in non-magnetic materials. Finally, we present representative applications of different structures with vacancies as active electrode materials of lithium or sodium ion batteries, catalysts for water splitting, and hydrogen evolution. PMID- 28098300 TI - Exploration of new ferromagnetic, semiconducting and biocompatible Nb3X8 (X = Cl, Br or I) monolayers with considerable visible and infrared light absorption. AB - Ferromagnetic character and biocompatible properties have become key factors for developing next-generation spintronic devices and show potential in biomedical applications. Unfortunately, the Mn-containing monolayer is not biocompatible though it has been extensively studied, and the Cr-containing monolayer is not environmental friendly, although these monolayers are ferromagnetic. Herein, we systematically investigated new types of 2D ferromagnetic monolayers Nb3X8 (X = Cl, Br or I) by means of first principles calculations together with mean field approximation based on the classical Heisenberg model. The small cleavage energy and high in-plane stiffness have been calculated to evaluate the feasibility of exfoliating the monolayers from their layered bulk phase. Spin-polarized calculations together with self-consistently determined Hubbard U were utilized to assess a strong correlation energy, which demonstrated that Nb3X8 (X = Cl, Br or I) monolayers are ferromagnetic. The calculated Curie temperatures for Nb3Cl8, Nb3Br8 and Nb3I8 were 31, 56 and 87 K, respectively, which may be increased by external strain, or electron or hole doping. Moreover, the Nb3X8 (X = Cl, Br or I) monolayers exhibited strong visible and infrared light absorption. The biocompatibility, ferromagnetism and considerable visible and infrared light absorption render the Nb3X8 (X = Cl, Br or I) monolayers with great potential application in next-generation biocompatible spintronic and optoelectronic devices. PMID- 28098302 TI - Carbon/two-dimensional MoTe2 core/shell-structured microspheres as an anode material for Na-ion batteries. AB - Unique-structured composite microspheres of carbon and MoTe2 were prepared by a two-step process. Precursor C-MoOx composite microspheres were prepared by spray pyrolysis, and then the precursor was transformed into C-MoTe2 composite microspheres by a tellurization process. C-MoTe2 composites with a uniform distribution of MoTe2 nanocrystals (C/MoTe2) and core-shell-structured C-MoTe2 composites (C@MoTe2) were synthesized at tellurization temperatures of 450 and 600 degrees C, respectively. At a higher tellurization temperature of 600 degrees C, all of the MoTe2 nanocrystals moved to the surface of the microsphere because of the Ostwald ripening process. The initial discharge capacities of the C/MoTe2, C@MoTe2, and bare MoTe2 (i.e., containing no carbonaceous materials) powders for Na-ion storage at a current density of 1.0 A g-1 were 328, 388, and 341 mA h g-1, respectively. The discharge capacities of the C/MoTe2, C@MoTe2, and bare MoTe2 powders for the 200th cycle were 241, 286, and 104 mA h g-1, respectively, and the corresponding capacity retentions, which were measured from the second cycle were 100%, 99%, and 37%, respectively. The high structural stability and well-developed two-dimensional layer of MoTe2 of the C@MoTe2 microspheres provide superior Na-ion storage properties compared to those of the C/MoTe2 microspheres and bare MoTe2 powder. PMID- 28098301 TI - Optical DNA mapping in nanofluidic devices: principles and applications. AB - Optical DNA mapping has over the last decade emerged as a very powerful tool for obtaining long range sequence information from single DNA molecules. In optical DNA mapping, intact large single DNA molecules are labeled, stretched out, and imaged using a fluorescence microscope. This means that sequence information ranging over hundreds of kilobasepairs (kbp) can be obtained in one single image. Nanochannels offer homogeneous and efficient stretching of DNA that is crucial to maximize the information that can be obtained from optical DNA maps. In this review, we highlight progress in the field of optical DNA mapping in nanochannels. We discuss the different protocols for sequence specific labeling and divide them into two main categories, enzymatic labeling and affinity-based labeling. Examples are highlighted where optical DNA mapping is used to gain information on length scales that would be inaccessible with traditional techniques. Enzymatic labeling has been commercialized and is mainly used in human genetics and assembly of complex genomes, while the affinity-based methods have primarily been applied in bacteriology, for example for rapid analysis of plasmids encoding antibiotic resistance. Next, we highlight how the design of nanofluidic channels can been altered in order to obtain the desired information and discuss how recent advances in the field make it possible to retrieve information beyond DNA sequence. In the outlook section, we discuss future directions of optical DNA mapping, such as fully integrated devices and portable microscopes. PMID- 28098303 TI - Topologically inferring pathway activity for precise survival outcome prediction: breast cancer as a case. AB - Accurately predicting the survival outcome of patients is of great importance in clinical cancer research. In the past decade, building survival prediction models based on gene expression data has received increasing interest. However, the existing methods are mainly based on individual gene signatures, which are known to have limited prediction accuracy on independent datasets and unclear biological relevance. Here, we propose a novel pathway-based survival prediction method called DRWPSurv in order to accurately predict survival outcome. DRWPSurv integrates gene expression profiles and prior gene interaction information to topologically infer survival associated pathway activities, and uses the pathway activities as features to construct Lasso-Cox model. It uses topological importance of genes evaluated by directed random walk to enhance the robustness of pathway activities and thereby improve the predictive performance. We applied DRWPSurv on three independent breast cancer datasets and compared the predictive performance with a traditional gene-based method and four pathway-based methods. Results showed that pathway-based methods obtained comparable or better predictive performance than the gene-based method, whereas DRWPSurv could predict survival outcome with better accuracy and robustness among the pathway-based methods. In addition, the risk pathways identified by DRWPSurv provide biologically informative models for breast cancer prognosis and treatment. PMID- 28098304 TI - Real-time monitoring of plasmon induced dissociative electron transfer to the potential DNA radiosensitizer 8-bromoadenine. AB - The excitation of localized surface plasmons in noble metal nanoparticles (NPs) results in different nanoscale effects such as electric field enhancement, the generation of hot electrons and a temperature increase close to the NP surface. These effects are typically exploited in diverse fields such as surface-enhanced Raman scattering (SERS), NP catalysis and photothermal therapy (PTT). Halogenated nucleobases are applied as radiosensitizers in conventional radiation cancer therapy due to their high reactivity towards secondary electrons. Here, we use SERS to study the transformation of 8-bromoadenine (8BrA) into adenine on the surface of Au and AgNPs upon irradiation with a low-power continuous wave laser at 532, 633 and 785 nm, respectively. The dissociation of 8BrA is ascribed to a hot-electron transfer reaction and the underlying kinetics are carefully explored. The reaction proceeds within seconds or even milliseconds. Similar dissociation reactions might also occur with other electrophilic molecules, which must be considered in the interpretation of respective SERS spectra. Furthermore, we suggest that hot-electron transfer induced dissociation of radiosensitizers such as 8BrA can be applied in the future in PTT to enhance the damage of tumor tissue upon irradiation. PMID- 28098305 TI - Phase behaviour and temperature-responsive properties of a gemini surfactant/Brij 30/water system. AB - The phase behaviour of a ternary system composed of cationic gemini surfactant 2 hydroxypropyl-1,3-bis(myristyldimethylammonium chloride) (14-3(OH)-14(2Cl)), nonionic surfactant polyoxyethylene laurel ether (C12H25(OCH2CH2)10OH, Brij-30) and H2O was studied and its phase diagram was determined. In several different phase regions identified in the phase diagram, the viscoelastic worm-like micellar solution region was investigated. The focus of the investigation was the increase in the viscosity of the micellar solution with the temperature and the Brij-30 content, as suggested by a partial region of the triangular phase diagram. With an increase in the Brij-30 content or temperature, one-dimensional micellar growth occurred, and a maximum appeared in the zero-shear viscosity, eta0, versus Brij-30 content or temperature curves; this was true for mixed solutions containing 14-3(OH)-14(2Cl) and Brij-30 in different mass ratios (WBrij 30/W14-3(OH)-14(2Cl)). After the maximum point, the decrease in viscosity is the result of the micellar shortening in the size with Brij-30 content and of the micellar branching in the network structure with temperature. This rheological analysis was performed to investigate the structural changes in different solutions as well as the effects of various factors on micellar growth. Various techniques were used to study the phase-transition processes occurring in this system, including cryogenic transmission electron microscopy, small-angle X-ray scattering measurements, and differential scanning calorimetry. The transition mechanisms of the aggregates were analysed on the basis of the obtained results. PMID- 28098306 TI - Effective viscosity and dynamics of spreading epithelia: a solvable model. AB - Collective cell migration in spreading epithelia in controlled environments has become a landmark in our current understanding of fundamental biophysical processes in development, regeneration, wound healing or cancer. Epithelial monolayers are treated as thin layers of a viscous fluid that exert active traction forces on the substrate. The model is exactly solvable and shows a broad range of applicabilities for the quantitative analysis and interpretation of force microscopy data of monolayers from a variety of experiments and cell lines. In addition, the proposed model provides physical insights into how the biological regulation of the tissue is encoded in a reduced set of time-dependent physical parameters. In particular the temporal evolution of the effective viscosity entails a mechanosensitive regulation of adhesion. Besides, the observation of an effective elastic tensile modulus can be interpreted as an emergent phenomenon in an active fluid. PMID- 28098307 TI - A ratiometric fluorescence probe for imaging sulfur dioxide derivatives in the mitochondria of living cells. AB - Although sulfur dioxide (SO2) plays an essential role in several physiological processes, monitoring of intracellular SO2 at subcellular levels remains challenging due to the lack of rapid and sensitive methods for its quantification in a 100% aqueous solution. Herein, a new hemicyanine dyes-based fluorescence probe, NBD-Id, was designed and synthesized for the detection of SO2 derivatives in pure aqueous solution and living cells. By virtue of a specific 1,4-addition reaction of SO32-HSO3- and the polymethine chain of hemicyanine, significant changes in the absorption and fluorescence emission spectra were observed in less than 20 seconds. The ratiometric fluorescence (F467/F593) detection of SO2 derivatives was then obtained with high sensitivity (detection limit 3.6 nM). It was noted that NBD-Id has a specific response towards SO2 derivatives without interference from other anions and biomolecules. Intracellular fluorescence imaging indicated that NBD-Id is cell membrane permeable and mainly distributed within the mitochondria. Therefore, ratiometric fluorescence imaging of SO2 derivatives in the mitochondria of MCF-7 cells was successfully demonstrated. PMID- 28098308 TI - A core-multiple shell nanostructure enabling concurrent upconversion and quantum cutting for photon management. AB - Photon management enables the manipulation of the number of input photons by conversion of two or more light quanta into one (upconversion) or vice versa (quantum cutting). Simultaneous realization of both these processes in a single unit provides unique opportunities of efficient utilization of photons throughout a broad spectral range. Yet, concurrent realization of these two parallel optical processes in one single unit remains elusive, limiting its impact on many existing or possible future applications such as for panchromatic photovoltaics. Here, we describe an epitaxial active core/inert shell/active shell/inert shell fluoride nanostructure to implement upconversion and quantum cutting within spatially confined and isolated rare-earth-doped active domains. The core area transforms infrared photons through trivalent erbium (Er3+) ions into three- and two-photon upconverted visible and near infrared luminescence, while the second shell domain splits an excitation photon into two near infrared photons through cooperative quantum cutting from one trivalent terbium ion (Tb3+) to two trivalent ytterbium ions (Yb3+). The inert layer in between the active domains is able to effectively suppress the destructive interference between upconversion and quantum cutting, while the outermost inert shell is able to eliminate surface related quenching. This design enables the colloidal core/multishell nanoparticles to have an upconversion quantum yield of ~1.6%, and to have a luminescence yield of the quantum cutting process as high as ~130%. This work constitutes a solid step for flexible photon management in a single nanostructure, and has an implication for photonic applications beyond photovoltaics. PMID- 28098309 TI - Multi-shelled ceria hollow spheres with a tunable shell number and thickness and their superior catalytic activity. AB - In this work, ceria multi-shelled nanospheres with a tunable shell number and thickness were prepared by a facile coordination polymer (CP) precursor method without the use of any template and surfactant. Interestingly, the number, thickness and structure of the shell can be tuned by varying the reaction time, reaction temperature, ratio of reagent and calcination temperature. The formation process of the multi-shelled hollow spheres was also investigated, which experienced a core contraction and shell separation process. Moreover, the multi shelled CeO2 hollow nanospheres displayed excellent photocatalytic activity in the degradation of RhB. Au and AuPd nanoparticle loaded multi-shelled CeO2 nanocomposites were also prepared. Results show that Au/CeO2 multi-shelled hollow nanospheres showed eximious catalytic activity for the reduction of p-nitrophenol with a reaction rate constant k of 0.416 min. In addition, AuPd/CeO2 exhibited a remarkable catalytic activity for the conversion of CO. Employing this method, heavy rare earth oxide multi-shelled structures and light rare earth oxide solid spheres were obtained. This method may be employed for the preparation of other materials with complex structures. PMID- 28098310 TI - A computational model predicts genetic nodes that allow switching between species specific responses in a conserved signaling network. AB - Cell signaling networks regulate a variety of developmental and physiological processes, and changes in their response to external stimuli are often implicated in disease initiation and progression. To elucidate how different responses can arise from conserved signaling networks, we have developed a mathematical model of the well-characterized Caenorhabditis vulval development network involving EGF, Wnt and Notch signaling that recapitulates biologically observed behaviors. We experimentally block a specific element of the EGF pathway (MEK), and find different behaviors in vulval development in two Caenorhabditis species, C. elegans and C. briggsae. When we separate our parameters into subsets that correspond to these two responses, they yield model behaviors that are consistent with observed experimental results, despite the initial parameter grouping based on perturbation in a single node of the EGF pathway. Finally, our analysis predicts specific parameters that may be critical for the theoretically and experimentally observed differences, suggesting modifications that might allow intentional switching between the two species' responses. Our results indicate that all manipulations within a signal transduction pathway do not yield the same outcome, and provide a framework to identify the specific genetic perturbations within a conserved network that will confer unique behaviors on the network. PMID- 28098311 TI - Transition metal-free direct trifluoromethylthiolation of indoles using trifluoromethanesulfonyl chloride in the presence of triphenylphosphine. AB - A novel triphenylphosphine-mediated direct trifluoromethylthiolation of indole derivatives using trifluoromethanesulfonyl chloride as the SCF3 source was developed. Sodium iodide facilitated this transformation by generating iodine in situ which was found to accelerate this transformation. The use of a transition metal-free protocol, readily available reagents, and mild reaction conditions allowed this protocol to be easily scaled up. PMID- 28098313 TI - The glass transition and interfacial dynamics of single strand fibers of polymers. AB - We investigate the glass transition and interfacial dynamics of single strand fibers of flexible polymers by employing molecular dynamics (MD) simulations along with a coarse grained model. While the polymer fiber has drawn significant attention due to its applicability in tissue engineering and stretchable electronics, its dynamic properties, especially the glass transition temperature (Tg), are yet to be understood at the molecular level. For example, there has been a controversy on the effect of the polymer fiber radius (R) on Tg: Tg decreased with a decrease in R for some polymer fibers, whereas Tg of other polymer fibers was not sensitive to R. In this article, we estimate the bond relaxation time of polymers and evaluate both Tg and fragility (m) as a function of R. We illustrate that Tg of the polymer fiber decreased with a decrease in R monotonically and also that the values of Tg follow faithfully the empirical equation proposed by Keddie et al. as a function of R, which was successfully employed to fit the values of Tg of both polyvinyl alcohol (PVA) fibers and polyethylene (PE) fibers. We also find that the dynamics of polymers at the interface between a polymer fiber and air is faster than that of polymers at the center. By employing Adam-Gibbs theory, we show that the fast interface dynamics of polymer fibers should influence the cooperative motion of monomers, which should be responsible for the decrease in Tg for smaller values of R. Near the interface there are more mobile monomers that participate in the cooperative motions of polymers. Interesting is that due to the curved surface (unlike flat polymer films) the cooperative motion of monomers is anisotropic in polymer fibers. PMID- 28098315 TI - A pH-responsive wormlike micellar system of a noncovalent interaction-based surfactant with a tunable molecular structure. AB - Responsive wormlike micelles are very useful in a number of applications, whereas it is still challenging to create dramatic viscosity changes in wormlike micellar systems. Here we developed a pH-responsive wormlike micellar system based on a noncovalent constructed surfactant, which is formed by the complexation of N erucamidopropyl-N,N-dimethylamine (UC22AMPM) and citric acid at the molar ratio of 3 : 1 (EACA). The phase behavior, aggregate microstructure and viscoelasticity of EACA solutions were investigated by macroscopic appearance observation, rheological and cryo-TEM measurements. It was found that the phase behavior of EACA solutions undergoes transition from transparent viscoelastic fluids to opalescent solutions and then phase separation with white floaters upon increasing the pH. Upon increasing the pH from 2.03 to 6.17, the viscosity of wormlike micelles in the transparent solutions continuously increased and reached ~683 000 mPa s at pH 6.17. As the pH was adjusted to 7.31, the opalescent solution shows a water-like flowing behaviour and the eta0 rapidly declines to ~1 mPa s. Thus, dramatic viscosity changes of about 6 magnitudes can be triggered by varying the pH values without any deterioration of the EACA system. This drastic variation in rheological behavior is attributed to the pH dependent interaction between UC22AMPM and citric acid. Furthermore, the dependence on concentration and temperature of the rheological behavior of EACA solutions was also studied to assist in obtaining the desired pH-responsive viscosity changes. PMID- 28098314 TI - Isoindoline nitroxide-labeled porphyrins as potential fluorescence-suppressed spin probes. AB - A series of isoindoline nitroxide-labeled porphyrins were synthesized by the reaction of 5-phenyldipyrromethane and 5-(4'-carboethoxy methyleneoxyphenyl)dipyrromethane with 5-formyl-1,1,3,3-tetramethylisoindolin-2 yloxyl (FTMIO) using the Lindsey method. The corresponding water-soluble spin labeled porphyrins were also prepared. Subsequently, these compounds were characterized and their in vitro properties were evaluated. The electrochemical assay demonstrated that these isoindoline nitroxide-labeled porphyrins had similar electrochemical and redox properties to 5-carboxy-1,1,3,3 tetramethylisoindolin-2-yloxyl (CTMIO). The electron paramagnetic resonance test showed that these porphyrins exhibited hyperfine splittings and characteristic spectra of CTMIO with typical nitroxide g-values and nitrogen isotropic hyperfine coupling constants. The in vitro cytotoxicity assay indicated that these porphyrins possessed low cytotoxicity to human renal tubular epithelial 293T cells (normal cells) and human hepatoma HepG2 cells (tumor cells). Fluorescence spectroscopy revealed that free base isoindoline nitroxide-labeled porphyrins exhibited fluorescence suppression characteristic of nitroxide-fluorophore systems. In vitro fluorescene imaging demonstrated that the reduced isoindoline nitroxide-labeled porphyrins eliminated fluorescence suppression and displayed strong red fluorescence imaging in HepG2 cells. Thus these isoindoline nitroxide labeled porphyrins may be considered potentially as biological spin probes for fluorescence imaging and EPR spectroscopy. PMID- 28098316 TI - A family of mechanically adaptive supramolecular graphene oxide/poly(ethylenimine) hydrogels from aqueous assembly. AB - Composite hydrogels containing graphene oxide (GO) offer advantageous mechanical properties, but tuning these properties generally requires the synthesis of new hydrogels or if the hydrogel is thermally responsive, utilization of a chemistry determined temperature window. Here, we demonstrate a simple route to generate a family of GO-based hydrogels from aqueous solution based assembly of GO with polycationic poly(ethylenimine), PEI, without any secondary chemical crosslinking. Tuning the ratio of GO : PEI during the assembly produces a family of hydrogels that responds to mechanical compression by irreversibly altering their equilibrium water content and mechanical properties in a controllable manner. Despite the lack of chemical crosslinks, the hydrogels are stable when stored in an excess of water or NaCl solutions (up to 1 M) and exhibit a tunable swelling ratio (mass hydrogel : mass solid) between 44 and 162 based on both composition and compression history. Consequently, the storage modulus from shear rheology can be increased by more than 3 orders of magnitude from this irreversible mechanical compression of the hydrogel. This stiffening of the hydrogels in response to mechanical stimuli enables the prior compression loading of the hydrogel to be determined. We demonstrate that this strategy is generalizable to other anionic 2D materials such as clay (cloisite). This family of mechanically adaptive hydrogels enables facile fabrication and tuning of physical properties that could be advantageous for sensing, energy dissipation, and other applications. PMID- 28098317 TI - A novel withanolide with an unprecedented carbon skeleton from Physalis angulata. AB - A novel withanolide, aromaphysalin A (1), possessing an exceptional C(11)-C(15) bond and an unprecedented 4,9-cyclized aromatic ring (ring A), is isolated from stems and leaves of Physalis angulata L. Its structure was determined by a combination of HRESIMS, 2D NMR spectra, and theoretical calculations. Compound 1 exhibited inhibitory activity on NO production with an IC50 value of 51.64 MUM. A plausible biosynthetic pathway for 1 is also discussed. PMID- 28098318 TI - Correction: On the mechanism of Ni(ii)-promoted Michael-type hydroamination of acrylonitrile and its substituted derivatives. AB - Correction for 'On the mechanism of Ni(ii)-promoted Michael-type hydroamination of acrylonitrile and its substituted derivatives' by S. Lapointe et al., Dalton Trans., 2016, 45, 15800-15810. PMID- 28098319 TI - Copper-catalyzed aromatic C-H alkoxylation with alcohols under aerobic conditions. AB - An efficient protocol for copper-catalyzed aromatic C-H alkoxylation with alcohols has been developed under aerobic conditions. The protocol provides a complementary method to couple arenes and alcohols to furnish aromatic ethers. The advantages of this method are the employment of a cheap Cu(OAc)2 catalyst, oxygen as the terminal oxidant and alcohol as both an alkoxy reagent and a solvent. Notably, the catalytic amount of benzoic acid plays a significant role in this transformation. PMID- 28098320 TI - Versatile tissue lasers based on high-Q Fabry-Perot microcavities. AB - Biolasers are an emerging technology for next generation biochemical detection and clinical applications. Progress has recently been made to achieve lasing from biomolecules and single living cells. Tissues, which consist of cells embedded in an extracellular matrix, mimic more closely the actual complex biological environment in a living body and therefore are of more practical significance. Here, we developed a highly versatile tissue laser platform, in which tissues stained with fluorophores are sandwiched in a high-Q Fabry-Perot microcavity. Distinct lasing emissions from muscle and adipose tissues stained respectively with fluorescein isothiocyanate (FITC) and boron-dipyrromethene (BODIPY), and hybrid muscle/adipose tissue with dual staining were achieved with a threshold of only ~10 MUJ mm-2. Additionally, we investigated how the tissue structure/geometry, tissue thickness, and staining dye concentration affect the tissue laser. Lasing emission from FITC conjugates (FITC-phalloidin) that specifically target F-actin in muscle tissues was also realized. It is further found that, despite the large fluorescence spectral overlap between FITC and BODIPY in tissues, their lasing emissions could be clearly distinguished and controlled due to their narrow lasing bands and different lasing thresholds, thus enabling highly multiplexed detection. Our tissue laser platform can be broadly applicable to various types of tissues/diseases. It provides a new tool for a wide range of biological and biomedical applications, such as diagnostics/screening of tissues and identification/monitoring of biological transformations in tissue engineering. PMID- 28098321 TI - The shortest Th-Th distance from a new type of quadruple bond. AB - Compounds featuring unsupported metal-metal bonds between actinide elements remain highly sought after yet confined experimentally to inert gas matrix studies. Notwithstanding this paucity, actinide-actinide bonding has been the subject of extensive computational research. In this contribution, high level quantum chemical calculations at both the scalar and spin-orbit levels are used to probe the Th-Th bonding in a range of zero valent systems of general formula LThThL. Several of these compounds have very short Th-Th bonds arising from a new type of Th-Th quadruple bond with a previously unreported electronic configuration featuring two unpaired electrons in 6d-based delta bonding orbitals. H3AsThThAsH3 is found to have the shortest Th-Th bond yet reported (2.590 A). The Th2 unit is a highly sensitive probe of ligand electron donor/acceptor ability; we can tune the Th-Th bond from quadruple to triple, double and single by judicious choice of the L group, up to 2.888 A for singly bonded ONThThNO. PMID- 28098322 TI - Flory theory of randomly branched polymers. AB - Randomly branched polymer chains (or trees) are a classical subject of polymer physics with connections to the theory of magnetic systems, percolation and critical phenomena. More recently, the model has been reconsidered for RNA, supercoiled DNA and the crumpling of topologically-constrained polymers. While solvable in the ideal case, little is known exactly about randomly branched polymers with volume interactions. Flory theory provides a simple, unifying description for a wide range of branched systems, including isolated trees in good and theta-solvent, and tree melts. In particular, the approach provides a common framework for the description of randomly branched polymers with quenched connectivity and for randomly branching polymers with annealed connectivity. Here we review the Flory theory for interacting trees in the asymptotic limit of very large polymerization degree for good solvent, theta-solutions and melts, and report its predictions for annealed connectivity in theta-solvents. We compare the predictions of Flory theory for randomly branched polymers to a wide range of available analytical and numerical results and conclude that they are qualitatively excellent and quantitatively good in most cases. PMID- 28098323 TI - Two-dimensional melting of colloids with long-range attractive interactions. AB - The solid-liquid melting transition in a two-dimensional (2-D) attractive colloidal system is visualized using superparamagnetic colloids that interact through a long-range isotropic attractive interaction potential, which is induced using a high-frequency rotating magnetic field. Various experiments, supported by Monte Carlo simulations, are carried out over a range of interaction potentials and densities to determine structure factors, Lindermann parameters, and translational and orientational order parameters. The system shows a first-order solid-liquid melting transition. Simulations and experiments suggest that dislocations and disclinations simultaneously unbind during melting. This is in direct contrast with reports of 2-D melting of paramagnetic particles that interact with a repulsive interaction potential. PMID- 28098324 TI - Ionic screening and dissociation are crucial for understanding chemical self propulsion in polar solvents. AB - Polar solvents like water support the bulk dissociation of themselves and their solutes into ions, and the re-association of these ions into neutral molecules in a dynamic equilibrium, e.g., H2O2 ? H+ + HO2-. Using continuum theory, we study the influence of these association-dissociation reactions on the self-propulsion of colloids driven by surface chemical reactions (chemical swimmers). We find that association-dissociation reactions should have a strong influence on swimmers' behaviour, and therefore should be included in future modelling. In particular, such bulk reactions should permit charged swimmers to propel electrophoretically even if all species involved in the surface reactions are neutral. The bulk reactions also significantly modify the predicted speed of chemical swimmers propelled by ionic currents, by up to an order of magnitude. For swimmers whose surface reactions produce both anions and cations (ionic self diffusiophoresis), the bulk reactions produce an additional reactive screening length, analogous to the Debye length in electrostatics. This in turn leads to an inverse relationship between swimmer radius and swimming speed, which could provide an alternative explanation for recent experimental observations on Pt polystyrene Janus swimmers [S. Ebbens et al., Phys. Rev. E: Stat., Nonlinear, Soft Matter Phys., 2012, 85, 020401]. We also use our continuum theory to investigate the effect of the Debye screening length itself, going beyond the infinitely-thin-screening-length approximation used by previous analytical theories. We identify significant departures from this limiting behaviour for micron-sized swimmers under typical experimental conditions and find that the approximation fails entirely for nanoscale swimmers. PMID- 28098326 TI - Weinreb amide directed cross-coupling reaction between electron-deficient alkenes catalyzed by a rhodium catalyst. AB - A rhodium-catalyzed Weinreb amide directed cross-coupling reaction between electron-deficient alkenes is reported, which provides an efficient route for the synthesis of valuable and versatile Weinreb amide functionalized (Z,E) butadienes. The catalytic system is insensitive to water and oxygen and exhibits broad functional group tolerance. This method also allowed both terminal and internal alkenes as the cross-coupling partners. PMID- 28098332 TI - Revisiting the optimized doping ratio in core/shell nanostructured upconversion particles. AB - The development of rare-earth doped upconversion nanoparticles (RE-UCNPs) in various applications is fuelling the demand for nanoparticles with highly enhanced upconversion luminescence (UCL). Although the core/shell structure is proved to enhance the UCL effectively, there is still plenty of room to further improve the UCL by optimizing the doping ratio of the materials. In this article, a general strategy is demonstrated to achieve highly-enhanced visible UCL in core/shell nanostructured NaREF4 by increasing the doping ratio of Yb3+ in the core region. The energy transfer from RE-UCNPs to surface quenching sites through Yb3+-Yb3+ energy migration is demonstrated to be the main reason for restricting the doping ratio of Yb3+. Notable UCL enhancement (ca. 15 times) of core/shell structured alpha-NaYF4:Yb,Er@CaF2 nanoparticles is observed by increasing the concentration of Yb3+ to 98 mol%. The highly-enhanced visible UCL signal is used to guide the lymphatic vessel resection with the naked eye. PMID- 28098335 TI - Not an exception to the rule: the functional significance of intrinsically disordered protein regions in enzymes. AB - Intrinsically disordered protein regions (IDPRs) are remarkably common and have unique and important biological functions. Enzymes have long been considered an exception to the rule of protein intrinsic disorder due to the structural requirements for catalysis. Although functionally significant IDPRs have been described in several enzymes, there has been no study quantifying the extent of this phenomenon. We have conducted a multilevel computational analysis of missing regions in X-ray crystal structures in the PDB and predicted disorder in 66 representative proteomes. We found that the fraction of predicted disorder was higher in non-enzymes than enzymes, because non-enzymes were more likely to be fully disordered. However, we also found that transferases, hydrolases and enzymes with multiple assigned functional classifications were similar to non enzymes in terms of the length of the longest continuous stretch of predicted disorder. Both eukaryotic enzymes and non-enzymes had a greater disorder content than was seen in bacteria. Disorder at the proteome level appears to emerge in response to organismic and functional complexity, and enzymes are not an exception to this rule. PMID- 28098337 TI - Characterisation of the enzymatic properties of MpAPr1, an aspartic protease secreted by the wine yeast Metschnikowia pulcherrima. AB - BACKGROUND: MpAPr1, encoding an acid protease from the wine yeast Metschnikowia pulcherrima IWBT Y1123, was previously isolated and shown to display potential activity against casein and grape proteins. However, its characterisation remained partial. RESULTS: MpAPr1 was cloned into the pGAPZalphaA vector and transformed into Komagataella pastoris X33 for heterologous expression. After verification of activity, the enzyme properties were characterised. Protease activity within the concentrated supernatant was retained over a pH range of 3.0 to 5.0 and between 10 degrees C and 50 degrees C. Optimal conditions for protease activity were found at 40 degrees C and pH 4.5. Activity was mostly unaffected by the presence of metal ions with the exception of Cu2+ and Ni2+ . Furthermore, proteolytic activity was retained in the presence of sugar and ethanol. pH and temperature conditions for MpAPr1 expression in K. pastoris were optimised. Purification was achieved by means of cation exchange chromatography and kinetic parameters (Km and Vmax ) were determined. MpAPr1 activity against grape proteins was confirmed, but the extent of the degradation was dependent on the nature of these proteins and the environmental conditions. CONCLUSION: Overall, the results suggest that MpAPr1 could be applied in food biotechnology processes such as winemaking. (c) 2017 Society of Chemical Industry. PMID- 28098338 TI - Limitations of a scoring model to predict thrombotic thrombocytopaenic purpura. PMID- 28098336 TI - Preclinical evaluation of intravenous NAX 810-2, a novel GalR2-preferring analog, for anticonvulsant efficacy and pharmacokinetics. AB - OBJECTIVE: Potential clinical utility of galanin or peptidic analogs has been hindered by poor metabolic stability, lack of brain penetration, and hyperglycemia due to galanin receptor subtype 1 (GalR1) activation. NAX 810-2, a galanin receptor subtype 2 (GalR2)-preferring galanin analog, possesses 15-fold greater affinity for GalR2 over GalR1 and protects against seizures in the mouse 6 Hz, corneal kindling, and Frings audiogenic seizure models. The purpose of these studies was to further evaluate the preclinical efficacy and pharmacokinetics of NAX 810-2 in mice. METHODS: NAX 810-2 was administered by intravenous (i.v.; tail vein, bolus) injection to fully kindled (corneal kindling assay) or naive CF-1 mice (6 Hz assay and pharmacokinetic studies). Plasma NAX 810-2 levels were determined from trunk blood samples. NAX 810-2 was also added to human plasma at various concentrations for determination of plasma protein binding. RESULTS: In the mouse corneal kindling model, NAX 810-2 dose-dependently blocked seizures following intravenous administration (median effective dose [ED50 ], 0.5 mg/kg). In the mouse 6 Hz (32 mA) seizure model, it was demonstrated that NAX 810-2 dose-dependently blocked seizures following bolus administration (0.375-1.5 mg/kg, i.v.; ED50 , 0.7 mg/kg), with a time-to-peak effect of 0.5 h posttreatment. Motor impairment was observed at 1.5 mg/kg, i.v., whereas one-half of this dose, 0.75 mg/kg, i.v., was maximally effective in the 6 Hz test. Plasma levels of NAX 810-2 show linear pharmacokinetics following intravenous administration and a half-life of 1.2 h. Functional agonist activity studies demonstrate that NAX 810-2 effectively activates GalR2 at therapeutic concentrations. SIGNIFICANCE: These studies further suggest the potential utility of NAX 810-2 as a novel therapy for epilepsy. PMID- 28098339 TI - The effect of blue light on stomatal oscillations and leaf turgor pressure in banana leaves. AB - Stomatal oscillations are cyclic opening and closing of stomata, presumed to initiate from hydraulic mismatch between leaf water supply and transpiration rate. To test this assumption, mismatches between water supply and transpiration were induced using manipulations of vapour pressure deficit (VPD) and light spectrum in banana (Musa acuminata). Simultaneous measurements of gas exchange with changes in leaf turgor pressure were used to describe the hydraulic mismatches. An increase of VPD above a certain threshold caused stomatal oscillations with variable amplitudes. Oscillations in leaf turgor pressure were synchronized with stomatal oscillations and balanced only when transpiration equaled water supply. Surprisingly, changing the light spectrum from red and blue to red alone at constant VPD also induced stomatal oscillations - while the addition of blue (10%) to red light only ended oscillations. Blue light is known to induce stomatal opening and thus should increase the hydraulic mismatch, reduce the VPD threshold for oscillations and increase the oscillation amplitude. Unexpectedly, blue light reduced oscillation amplitude, increased VPD threshold and reduced turgor pressure loss. These results suggest that additionally, to the known effect of blue light on the hydroactive opening response of stomata, it can also effect stomatal movement by increased xylem-epidermis water supply. PMID- 28098340 TI - Inhibitory effect of blue light emitting diode on migration and invasion of cancer cells. AB - The aim of this study was to determine the effects and molecular mechanism of blue light emitting diode (LED) in tumor cells. A migration and invasion assay for the metastatic behavior of mouse colon cancer CT-26 and human fibrosarcoma HT 1080 cells was performed. Cancer cell migration-related proteins were identified by obtaining a 2-dimensional gel electrophoresis (2-DE) in total cellular protein profile of blue LED-irradiated cancer cells, followed by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) analysis of proteins. Protein levels were examined by immunoblotting. Irradiation with blue LED inhibited CT-26 and HT-1080 cell migration and invasion. The anti-metastatic effects of blue LED irradiation were associated with inhibition of matrix metalloproteinase (MMP)-2 and MMP-9 expression. P38 MAPK phosphorylation was increased in blue LED irradiated CT-26 and HT-1080 cells, but was inhibited after pretreatment with SB203580, a specific inhibitor of p38 MAPK. Inhibition of p38 MAPK phosphorylation by SB203580 treatment increased number of migratory cancer cells in CT-26 and HT-1080 cells, indicating that blue LED irradiation inhibited cancer cell migration via phosphorylation of p38 MAPK. Additionally blue LED irradiation of mice injected with CT-26 cells expressing luciferase decreased early stage lung metastasis compared to untreated control mice. These results indicate that blue LED irradiation inhibits cancer cell migration and invasion in vitro and in vivo. PMID- 28098341 TI - Retrospective cohort study of prophylactic intraoperative uterine artery embolization for abnormally invasive placenta. AB - OBJECTIVE: To evaluate the safety and efficacy of prophylactic intraoperative uterine artery embolization (UAE) during cesarean delivery as conservative treatment for patients with abnormally invasive placenta. METHODS: A retrospective cohort study enrolled patients surgically diagnosed with abnormally invasive placenta who underwent cesarean delivery at the First Affiliated Hospital of Nanjing Medical University, Nanjing, China, between February 1, 2012, and February 28, 2015. Postpartum estimated blood loss, blood transfusions, hysterectomy, and adverse events were compared between patients who underwent cesarean delivery only (control group) and those who underwent concurrent prophylactic intraoperative UAE (UAE group). RESULTS: There were 45 patients included in the study; 26 and 19 in the UAE and control groups, respectively. Among patients who did not undergo hysterectomy owing to placenta accreta, the mean estimated blood loss was lower among patients in the UAE group (P=0.005); however, among patients who did undergo hysterectomy for placenta increta or percreta, no difference in mean estimated blood loss was observed (P=0.973). There were no differences in the hysterectomy rate (P=0.639) or incidence of requiring massive blood transfusion (P=0.050) between the groups. Only one patient in the UAE group experienced uterine necrosis. CONCLUSION: Prophylactic intraoperative UAE was relatively safe and effective for reducing postpartum hemorrhage among patients with placenta accreta. The potential benefits could be lower among patients with placenta increta or percreta. PMID- 28098342 TI - The evolution of regulators of G protein signalling proteins as drug targets - 20 years in the making: IUPHAR Review 21. AB - Regulators of G protein signalling (RGS) proteins are celebrating the 20th anniversary of their discovery. The unveiling of this new family of negative regulators of G protein signalling in the mid-1990s solved a persistent conundrum in the G protein signalling field, in which the rate of deactivation of signalling cascades in vivo could not be replicated in exogenous systems. Since then, there has been tremendous advancement in the knowledge of RGS protein structure, function, regulation and their role as novel drug targets. RGS proteins play an important modulatory role through their GTPase-activating protein (GAP) activity at active, GTP-bound Galpha subunits of heterotrimeric G proteins. They also possess many non-canonical functions not related to G protein signalling. Here, an update on the status of RGS proteins as drug targets is provided, highlighting advances that have led to the inclusion of RGS proteins in the IUPHAR/BPS Guide to PHARMACOLOGY database of drug targets. PMID- 28098343 TI - Mn accumulation in a submerged plant Egeria densa (Hydrocharitaceae) is mediated by epiphytic bacteria. AB - Many aquatic plants act as biosorbents, removing and recovering metals from the environment. To assess the biosorbent activity of Egeria densa, a submerged freshwater macrophyte, plants were collected monthly from a circular drainage area in Lake Biwa basin and the Mn concentrations of the plants were analysed. Mn concentrations in these plants were generally above those of terrestrial hyperaccumulators, and were markedly higher in spring and summer than in autumn. Mn concentrations were much lower in plants incubated in hydroponic medium at various pH levels with and without Mn supplementation than in field-collected plants. The precipitation of Mn oxides on the leaves was determined by variable pressure scanning electron microscopy-energy dispersive X-ray analysis and Leucoberbelin blue staining. Several strains of epiphytic bacteria were isolated from the field-collected E. densa plants, with many of these strains, including those of the genera Acidovorax, Comamonas, Pseudomonas and Rhizobium, found to have Mn-oxidizing activity. High Mn concentrations in E. densa were mediated by the production of biogenic Mn oxide in biofilms on leaf surfaces. These findings provide new insights into plant epidermal bacterial flora that affect metal accumulation in plants and suggest that these aquatic plants may have use in Mn phytomining. PMID- 28098345 TI - Effect of sequential fermentations and grape cultivars on volatile compounds and sensory profiles of Danish wines. AB - BACKGROUND: There has been an increasing interest in the use of selected non Saccharomyces yeasts in co-culture with Saccharomyces cerevisiae. In this work, three non-Saccharomyces yeast strains (Metschnikowia viticola, Metschnikowia fructicola and Hanseniaspora uvarum) indigenously isolated in Denmark were used in sequential fermentations with S. cerevisiae on three cool-climate grape cultivars, Bolero, Rondo and Regent. During the fermentations, the yeast growth was determined as well as key oenological parameters, volatile compounds and sensory properties of finished rose wines. RESULTS: The different non Saccharomyces strains and cool-climate grape cultivars produced wines with a distinctive aromatic profile. A total of 67 volatile compounds were identified, including 43 esters, 14 alcohols, five acids, two ketones, a C13-norisoprenoid, a lactone and a sulfur compound. The use of M. viticola in sequential fermentation with S. cerevisiae resulted in richer berry and fruity flavours in wines. The sensory plot showed a more clear separation among wine samples by grape cultivars compared with yeast strains. CONCLUSION: Knowledge on the influence of indigenous non-Saccharomyces strains and grape cultivars on the flavour generation contributed to producing diverse wines in cool-climate wine regions. (c) 2017 Society of Chemical Industry. PMID- 28098346 TI - Novel founder mutation in French-Canadian families with Naxos disease. PMID- 28098344 TI - Inhibition of oxytocin and vasopressin neuron activity in rat hypothalamic paraventricular nucleus by relaxin-3-RXFP3 signalling. AB - KEY POINTS: Relaxin-3 is a stress-responsive neuropeptide that acts at its cognate receptor, RXFP3, to alter behaviours including feeding. In this study, we have demonstrated a direct, RXFP3-dependent, inhibitory action of relaxin-3 on oxytocin and vasopressin paraventricular nucleus (PVN) neuron electrical activity, a putative cellular mechanism of orexigenic actions of relaxin-3. We observed a Galphai/o -protein-dependent inhibitory influence of selective RXFP3 activation on PVN neuronal activity in vitro and demonstrated a direct action of RXFP3 activation on oxytocin and vasopressin PVN neurons, confirmed by their abundant expression of RXFP3 mRNA. Moreover, we demonstrated that RXFP3 activation induces a cadmium-sensitive outward current, which indicates the involvement of a characteristic magnocellular neuron outward potassium current. Furthermore, we identified an abundance of relaxin-3-immunoreactive axons/fibres originating from the nucleus incertus in close proximity to the PVN, but associated with sparse relaxin-3-containing fibres/terminals within the PVN. ABSTRACT: The paraventricular nucleus of the hypothalamus (PVN) plays an essential role in the control of food intake and energy expenditure by integrating multiple neural and humoral inputs. Recent studies have demonstrated that intracerebroventricular and intra-PVN injections of the neuropeptide relaxin 3 or selective relaxin-3 receptor (RXFP3) agonists produce robust feeding in satiated rats, but the cellular and molecular mechanisms of action associated with these orexigenic effects have not been identified. In the present studies, using rat brain slices, we demonstrated that relaxin-3, acting through its cognate G-protein-coupled receptor, RXFP3, hyperpolarized a majority of putative magnocellular PVN neurons (88%, 22/25), including cells producing the anorexigenic neuropeptides, oxytocin and vasopressin. Importantly, the action of relaxin-3 persisted in the presence of tetrodotoxin and glutamate/GABA receptor antagonists, indicating its direct action on PVN neurons. Similar inhibitory effects on PVN oxytocin and vasopressin neurons were produced by the RXFP3 agonist, RXFP3-A2 (82%, 80/98 cells). In situ hybridization histochemistry revealed a strong colocalization of RXFP3 mRNA with oxytocin and vasopressin immunoreactivity in rat PVN neurons. A smaller percentage of putative parvocellular PVN neurons was sensitive to RXFP3-A2 (40%, 16/40 cells). These data, along with a demonstration of abundant peri-PVN and sparse intra-PVN relaxin-3-immunoreactive nerve fibres, originating from the nucleus incertus, the major source of relaxin-3 neurons, identify a strong inhibitory influence of relaxin-3-RXFP3 signalling on the electrical activity of PVN oxytocin and vasopressin neurons, consistent with the orexigenic effect of RXFP3 activation observed in vivo. PMID- 28098347 TI - Evolutionary origin of phytochrome responses and signaling in land plants. AB - Phytochromes comprise one of the major photoreceptor families in plants, and they regulate many aspects of plant growth and development throughout the plant life cycle. A canonical land plant phytochrome originated in the common ancestor of streptophytes. Phytochromes have diversified in seed plants and some basal land plants because of lineage-specific gene duplications that occurred during the course of land plant evolution. Molecular genetic analyses using Arabidopsis thaliana suggested that there are two types of phytochromes in angiosperms, light labile type I and light-stable type II, which have different signaling mechanisms and which regulate distinct responses. In basal land plants, little is known about molecular mechanisms of phytochrome signaling, although red light/far-red photoreversible physiological responses and the distribution of phytochrome genes are relatively well documented. Recent advances in molecular genetics using the moss Physcomitrella patens and the liverwort Marchantia polymorpha revealed that basal land plants show far-red-induced responses and that the establishment of phytochrome-mediated transcriptional regulation dates back to at least the common ancestor of land plants. In this review, we summarize our knowledge concerning functions of land plant phytochromes, especially in basal land plants, and discuss subfunctionalization/neofunctionalization of phytochrome signaling during the course of land plant evolution. PMID- 28098349 TI - Ectopic expression of two AREB/ABF orthologs increases drought tolerance in cotton (Gossypium hirsutum). AB - Plants have evolved complex molecular, cellular and physiological mechanisms to respond to environmental stressors. Because of the inherent complexity of this response, genetic manipulation to substantially improve water deficit tolerance, particularly in agricultural crops, has been largely unsuccessful, as the improvements are frequently accompanied by slower growth and delayed reproduction. Here, we ectopically express two abiotic stress-responsive bZIP AREB/ABF transcription factor orthologs, Arabidopsis ABF3 and Gossypium hirsutum ABF2D, in G. hirsutum, to compare the effects of exogenous and endogenous AREB/ABF transgene overexpression on dehydration resilience. Our results show that ectopic expression of each of these orthologs increases dehydration resilience, although these increases are accompanied by slower growth. These phenotypic effects are proportional to the ectopic expression level in the GhABF2D transgenic plants, while the phenotypes of all of the AtABF3 transgenic plants are similar, largely independent of ectopic expression level, possibly indicating differential post-transcriptional regulation of these transgenes. Our results indicate that overexpression of exogenous and endogenous ABF homologs in G. hirsutum substantially increases drought resilience, primarily through stomatal regulation, negatively impacting transpiration and photosynthetic productivity. PMID- 28098348 TI - Impact of lysosomal storage disorders on biology of mesenchymal stem cells: Evidences from in vitro silencing of glucocerebrosidase (GBA) and alpha galactosidase A (GLA) enzymes. AB - Lysosomal storage disorders (LDS) comprise a group of rare multisystemic diseases resulting from inherited gene mutations that impair lysosomal homeostasis. The most common LSDs, Gaucher disease (GD), and Fabry disease (FD) are caused by deficiencies in the lysosomal glucocerebrosidase (GBA) and alpha-galactosidase A (GLA) enzymes, respectively. Given the systemic nature of enzyme deficiency, we hypothesized that the stem cell compartment of GD and FD patients might be also affected. Among stem cells, mesenchymal stem cells (MSCs) are a commonly investigated population given their role in hematopoiesis and the homeostatic maintenance of many organs and tissues. Since the impairment of MSC functions could pose profound consequences on body physiology, we evaluated whether GBA and GLA silencing could affect the biology of MSCs isolated from bone marrow and amniotic fluid. Those cell populations were chosen given the former's key role in organ physiology and the latter's intriguing potential as an alternative stem cell model for human genetic disease. Our results revealed that GBA and GLA deficiencies prompted cell cycle arrest along with the impairment of autophagic flux and an increase of apoptotic and senescent cell percentages. Moreover, an increase in ataxia-telangiectasia-mutated staining 1 hr after oxidative stress induction and a return to basal level at 48 hr, along with persistent gamma-H2AX staining, indicated that MSCs properly activated DNA repair signaling, though some damages remained unrepaired. Our data therefore suggest that MSCs with reduced GBA or GLA activity are prone to apoptosis and senescence due to impaired autophagy and DNA repair capacity. PMID- 28098351 TI - The elicitation of steady-state visual evoked potentials during sleep. AB - This study confirmed the hypothesis that it is possible to elicit SSVEPs through closed eyelids during NREM sleep. To test this hypothesis, SSVEP amplitudes were measured in eight subjects across two conditions of stimulation (stimulation on and stimulation off) and three brain states (waking, light sleep, and deep sleep). Results showed a significant interaction between stimulation and brain state. In particular, EEG activity at the frequency of stimulation was higher during both light sleep and deep sleep in the stimulation on condition than in the stimulation off condition. The fact that it is possible to elicit SSVEPs during sleep may provide a new way to study how SSVEPs are generated in the brain one that might help resolve open questions such as identifying the SSVEP activation sequence or deciding if SSVEPs derive from evoked or oscillatory neural processes. PMID- 28098350 TI - Endogenous circadian rhythms in pigment composition induce changes in photochemical efficiency in plant canopies. AB - There is increasing evidence that the circadian clock is a significant driver of photosynthesis that becomes apparent when environmental cues are experimentally held constant. We studied whether the composition of photosynthetic pigments is under circadian regulation, and whether pigment oscillations lead to rhythmic changes in photochemical efficiency. To address these questions, we maintained canopies of bean and cotton, after an entrainment phase, under constant (light or darkness) conditions for 30-48 h. Photosynthesis and quantum yield peaked at subjective noon, and non-photochemical quenching peaked at night. These oscillations were not associated with parallel changes in carbohydrate content or xanthophyll cycle activity. We observed robust oscillations of Chl a/b during constant light in both species, and also under constant darkness in bean, peaking when it would have been night during the entrainment (subjective nights). These oscillations could be attributed to the synthesis and/or degradation of trimeric light-harvesting complex II (reflected by the rhythmic changes in Chl a/b), with the antenna size minimal at night and maximal around subjective noon. Considering together the oscillations of pigments and photochemistry, the observed pattern of changes is counterintuitive if we assume that the plant strategy is to avoid photodamage, but consistent with a strategy where non-stressed plants maximize photosynthesis. PMID- 28098352 TI - DNA repair and erasure of 5-methylcytosine in vertebrates. AB - DNA methylation plays important roles in development and disease. Yet, only recently has the dynamic nature of this epigenetic mark via oxidation and DNA repair-mediated demethylation been recognized. A major conceptual challenge to the model that DNA methylation is reversible is the risk of genomic instability, which may come with widespread DNA repair activity. Here, we focus on recent advances in mechanisms of TET-TDG mediated demethylation and cellular strategies that avoid genomic instability. We highlight the recently discovered involvement of NEIL DNA glycosylases, which cooperate with TDG in oxidative demethylation to accelerate substrate turnover and promote the organized handover of harmful repair intermediates to maintain genome stability. PMID- 28098353 TI - The role of various peroxisome proliferator-activated receptors and their ligands in clinical practice. AB - Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors involved in several physiological processes including modulation of cellular differentiation, development, metabolism of carbohydrates, lipids, proteins, and tumorigenesis. The aim of this review is to examine how different PPAR ligands act, and discuss their use in clinical practice. PPAR ligands have a lot of effects and applications in clinical practice. Some PPAR ligands such as fibrates (PPAR-alpha ligands) are currently used for the treatment of dyslipidemia, while pioglitazone and rosiglitazone (PPAR-gamma ligands) are anti-diabetic and insulin-sensitizing agents. Regarding new generation drugs, acting on both alpha/gamma, beta/delta, or alpha/delta receptors simultaneously, preliminary data on PPAR-alpha/gamma dual agonists revealed a positive effect on lipid profile, blood pressure, atherosclerosis, inflammation, and anti-coagulant effects, while the overexpression of PPAR beta/delta seems to prevent obesity and to decrease lipid storage in cardiac cells. Finally, PPAR-alpha/delta dual agonist induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. PMID- 28098354 TI - Concealed Accessory Pathways with a Single Ventricular and Two Discrete Atrial Insertion Sites. AB - BACKGROUND: Atrioventricular reciprocating tachycardia (AVRT) utilizing a concealed accessory pathway is common. It is well appreciated that some patients may have multiple accessory pathways with separate atrial and ventricular insertion sites. METHODS: We present three cases of AVRT utilizing concealed pathways with evidence that each utilizing a single ventricular insertion and two discrete atrial insertion sites. RESULTS: In case one, two discrete atrial insertion sites were mapped in two separate procedures, and only during the second ablation was the Kent potential identified. Ablation of the Kent potential at this site remote from the two atrial insertion sites resulted in the termination of the retrograde conduction in both pathways. Case two presented with supraventricular tachycardia (SVT) with alternating eccentric atrial activation patterns without alteration in the tachycardia cycle length. The two distinct atrial insertion sites during orthodromic AVRT and ventricular pacing were targeted and each of the two atrial insertion sites were successfully mapped and ablated. In case three, retrograde decremental conduction utilizing both atrial insertion sites was identified prior to ablation. After mapping and ablation of the first discrete atrial insertion site, tachycardia persisted utilizing the second atrial insertion site. Only after ablation of the second atrial insertion site was SVT noninducible, and VA conduction was no longer present. CONCLUSIONS: Concealed retrograde accessory pathways with discrete atrial insertion sites may have a common ventricular insertion site. Identification and ablation of the ventricular insertion site or the separate discrete atrial insertion sites result in successful treatment. PMID- 28098355 TI - A comparative study on composition and antioxidant activities of supercritical carbon dioxide, hexane and ethanol extracts from blackberry (Rubus fruticosus) growing in Poland. AB - BACKGROUND: Large quantities of blackberry seeds are produced as a pomace during the processing of juice and jam production; this by-product is a very interesting raw material both for oil manufacturing and as a source of bioactive compounds. In this work the composition, yield and antioxidant activity of three types of Rubus fructicosus pomace extracts isolated by liquid extraction using solvents of different polarity, as well with supercritical CO2 fluid extraction have been compared. RESULTS: The highest extract yield was reported for Soxhlet extraction using ethanol as a solvent (14.2%). Supercritical carbon dioxide and hexane extracts were characterised by the highest content of phytosterols (1445 and 1583 mg 100 g-1 of extract, respectively) among which beta-sitosterol was the main one, while the concentration of tocopherols, with predominant gamma-isomer, was the highest for both hexane and ethanol extracts, being 2364 and 2334 mg 100 g-1 , respectively. Using a GC-MS method 95 volatiles, in which non-saturated aldehydes were predominant, were identified in the essential oil of seed pomace and in the volatile oil isolated from supercritical extract. The ethanolic extract which is characterised by the highest phenolic content (9443 mg GAE 100 g 1 ) exhibited the highest antioxidant activity (according to the ABTS*+ and DPPH* assays). CONCLUSION: All pomace extracts examined were of high quality, rich in essential omega fatty acids and with a very high content of bioactive compounds, such as phytosterols and tocopherols. The high nutritional value of extracts from berry seed pomace could justify the commercialisation of specific extracts not only as food additives but also as cosmetic components. (c) 2017 Society of Chemical Industry. PMID- 28098357 TI - Partial purification, characterisation and thermal inactivation kinetics of peroxidase and polyphenol oxidase isolated from Kalipatti sapota (Manilkara zapota). AB - BACKGROUND: The extraction, purification, and characterisation of peroxidase (POD) and polyphenol oxidase (PPO) were studied for Kalipatti sapota fruit. The crude enzyme extract was partially purified by ammonium sulfate precipitation followed by BioGel P100 size exclusion and Unosphere Q anion-exchange chromatography. RESULTS: Molecular weights of 20 kDa (POD) and 24 kDa (PPO) were indicated by SDS-PAGE. A single band was observed on SDS-PAGE with a fold purity of 10.38 and 7.42 for POD and PPO, respectively. Michaelis-Menten constants for POD and PPO were 22.3 and 23.0 mmol L-1 using guaiacol and catechol as substrates. Thermal inactivation kinetics was studied in the temperature range of 60-95 degrees C. The crude extract of POD and PPO showed D-values of 2.2-60.2 and 1.0-35.2 min; Z-values of 18.7 +/- 0.4 and 16.0 +/- 0.3 degrees C; and activation energies (Ea ) of 128.6 and 151.0 kJ mol-1 , respectively. CONCLUSION: POD and PPO showed good stability over a wide range of pH and temperature. As reflected by Z and Ea values, the fruit matrix had no significant influence towards enzyme stability. Designing of thermal process should take into consideration D- and Z-values of the enzymes along with D- and Z-values of microorganisms to obtain a product with better shelf life. (c) 2017 Society of Chemical Industry. PMID- 28098356 TI - Mechano-chemo-transduction in cardiac myocytes. AB - The heart has the ability to adjust to changing mechanical loads. The Frank Starling law and the Anrep effect describe exquisite intrinsic mechanisms the heart has for autoregulating the force of contraction to maintain cardiac output under changes of preload and afterload. Although these mechanisms have been known for more than a century, their cellular and molecular underpinnings are still debated. How does the cardiac myocyte sense changes in preload or afterload? How does the myocyte adjust its response to compensate for such changes? In cardiac myocytes Ca2+ is a crucial regulator of contractile force and in this review we compare and contrast recent studies from different labs that address these two important questions. The 'dimensionality' of the mechanical milieu under which experiments are carried out provide important clues to the location of the mechanosensors and the kinds of mechanical forces they can sense and respond to. As a first approximation, sensors inside the myocyte appear to modulate reactive oxygen species while sensors on the cell surface appear to also modulate nitric oxide signalling; both signalling pathways affect Ca2+ handling. Undoubtedly, further studies will add layers to this simplified picture. Clarifying the intimate links from cellular mechanics to reactive oxygen species and nitric oxide signalling and to Ca2+ handling will deepen our understanding of the Frank Starling law and the Anrep effect, and also provide a unified view on how arrhythmias may arise in seemingly disparate diseases that have in common altered myocyte mechanics. PMID- 28098358 TI - Subclinical alteration of the cervical-vaginal microbiome in women with idiopathic infertility. AB - Biomarkers have a wide application in research and clinic, they help to choose the correct treatment for diseases. Recent studies, addressing the vaginal microbiome using next generation sequencing (NGS), reported the involvement of bacterial species in infertility. We compared the vaginal microbiome of idiopathic infertile women with that of healthy, including bacterial vaginosis affected women and non-idiopathic infertile women, to identify bacterial species suitable as biomarkers. Information on microorganisms was obtained from the V3 16S rDNA sequencing of cervical-vaginal fluids of 96 women using the Ion Torrent platform. Data were processed with QIIME and classified against the Vaginal 16S rDNA Reference Database. The analysis revealed a significant beta-diversity variation (p < 0.001) between the four groups included in the study. L. iners, L. crispatus, and L. gasseri distinguished idiopathic infertile women from the other groups. In these women, a microbial profile similar to that observed in bacterial vaginosis women has been detected. Our results suggest that the quantitative assessment and identification of specific microorganisms of the cervical-vaginal microflora could increase the accuracy of available tools for the diagnosis of infertility and improve the adoption of therapeutic protocols. PMID- 28098359 TI - M2-like macrophages induce colon cancer cell invasion via matrix metalloproteinases. AB - The inflammatory milieu plays an important role in colon cancer development and progression. Previously, we have shown that tumor-associated macrophages (TAMs), an important component of the tumor microenvironment, are enriched in tumors compared with normal tissue and confer a poorer prognosis. In the present study, we found that matrix metallopeptidase-9 (MMP-9), which degrades extracellular matrix proteins, was increased in biopsies from colon cancer patients and in mouse xenografts with SW480 cell-derived tumors. SW480 colon cancer cells exposed to M2-like macrophage-conditioned medium (M2-medium) exhibited increased MMP-9 mRNA, protein expression and gelatinase activity. A similar effect was obtained by the addition of tumor necrosis factor-alpha (TNFalpha) and leukotriene D4 (LTD4 ). MMP-9 expression and activity were reduced by a TNFalpha blocking antibody adalimumab and a cysteinyl leukotriene receptor 1 (CysLTR1, the receptor for LTD4 ) antagonist montelukast. M2-medium also induced changes in the epithelial-mesenchymal transition (EMT) markers E-cadherin, beta-catenin, vimentin, and snail in SW480 cells. We also found that both M2-medium and TNFalpha and LTD4 induced stabilization/nuclear translocation of beta-catenin. Furthermore, we also observed an elongated phenotype that may indicate increased invasiveness, as confirmed in a collagen I invasion assay. M2-medium increased the invasive ability, and a similar effect was also obtained by the addition of TNFalpha and LTD4 . The specific MMP inhibitor I or adalimumab and montelukast reduced the number of invasive cells. In conclusion, our findings show that M2 medium enriched in TNFalpha and LTD4 promote colon cancer cell invasion via MMP-9 expression and activation and the induction of EMT. PMID- 28098362 TI - What substances are allergenic and in whom? PMID- 28098363 TI - The itchy scalp. PMID- 28098360 TI - Morroniside, a secoiridoid glycoside from Cornus officinalis, attenuates neuropathic pain by activation of spinal glucagon-like peptide-1 receptors. AB - BACKGROUND AND PURPOSE: Iridoid glycosides containing the double bond scaffold of cyclopentapyran are reversible and orthosteric agonists of glucagon-like peptide 1 (GLP-1) receptors and exert anti-nociceptive and neuroprotective actions. Morroniside, derived from the medicinal herb Cornus officinalis, is an atypical secoiridoid containing a six-membered cyclic inner ether fragment. Here we investigated whether morroniside was an orthosteric GLP-1 receptor agonist and had anti-hypersensitivity activities in a model of neuropathic pain. EXPERIMENTAL APPROACH: We used a model of neuropathic pain, induced by tight ligation of L5/L6 spinal nerves in rats. Hydrogen peroxide-induced oxidative damage was also assayed in N9 microglial cells and human HEK293 cells stably expressing GLP-1 receptors. KEY RESULTS: Morroniside protected against hydrogen peroxide-induced oxidative damage in N9 microglial and HEK293 cells that expressed mouse or human GLP-1 receptors, but not in HEK293T cells without GLP-1 receptors. The GLP-1 receptor orthosteric antagonist exendin(9-39) also concentration-dependently shifted the concentration-protective response curves of morroniside and exenatide to the right without affecting maximal protection, with similar pA2 values. Furthermore, morroniside given by oral gavage or intrathecally in neuropathic rats dose-dependently attenuated mechanical allodynia, with comparable Emax values and ED50 s of 335 mg.kg-1 and 7.1 MUg and completely blocked thermal hyperalgesia. Daily intrathecal injections of morroniside over 7 days did not induce anti-allodynic tolerance. Pretreatment with intrathecal exendin(9-39) completely blocked systemic and intrathecal morroniside-induced mechanical anti allodynia. CONCLUSION AND IMPLICATIONS: Our data demonstrated that morroniside was an orthosteric agonist of GLP-1 receptors and produced antihypersensitivity in a neuropathic pain model by activation of spinal GLP-1 receptors. PMID- 28098364 TI - Mosaicism in the skin: lumping or splitting? PMID- 28098365 TI - Rare diseases and costly treatments: the role of IL-1beta in pustular psoriasis. PMID- 28098366 TI - The evolution of clinical guidelines for dermatologists: GRADE, AGREE and occasionally consensus by experts. PMID- 28098367 TI - PD-1 checkpoint blockade is an emerging treatment for Merkel cell carcinoma. PMID- 28098368 TI - The correlation between clinical and histological clearance of actinic keratoses. PMID- 28098369 TI - Patient-reported outcomes in patients with cutaneous lupus. PMID- 28098370 TI - Effectiveness of phototherapy in chronic urticaria. PMID- 28098371 TI - Assessing the effects of advanced glycation end products in the skin. PMID- 28098372 TI - Missing factors in human skin equivalent models? PMID- 28098374 TI - Editor's Choice January 2017 Alex Anstey. PMID- 28098373 TI - Intercellular IgA dermatosis. PMID- 28098375 TI - Cover Image: Dermoscopy in vivo for the life cycle of Phthirus pubis. PMID- 28098377 TI - Quantitative image analysis for hereditary hair disorders. PMID- 28098376 TI - Why have hospitalization rates for bullous pemphigoid soared? PMID- 28098379 TI - Plain language summaries in Simplified Chinese. PMID- 28098378 TI - Expanding the skin and histopathology manifestations of autoinflammatory diseases. PMID- 28098380 TI - British Association of Dermatologists' guidelines for the care of patients with actinic keratosis 2017. PMID- 28098381 TI - Conflicts of interest and authorship of industry-sponsored publications. PMID- 28098382 TI - The management of acne in primary care. PMID- 28098383 TI - Shortcomings in rosacea diagnosis and classification. PMID- 28098384 TI - Image Gallery: Cutaneous botryomycosis at an unusual site in an immunocompetent patient. PMID- 28098385 TI - Updated guidance for writing a British Association of Dermatologists clinical guideline: the adoption of the GRADE methodology 2016. PMID- 28098386 TI - Plain language summaries. PMID- 28098388 TI - Image Gallery: Relapsing polychondritis associated with monoclonal gammopathy. PMID- 28098389 TI - Rosacea, inflammatory bowel disease and the value of big data and of epidemiological studies. PMID- 28098390 TI - Image Gallery: Systemic sarcoidosis presenting within the black pigment of a cosmetic tattoo. PMID- 28098392 TI - Bayesian nonparametric clustering in phylogenetics: modeling antigenic evolution in influenza. AB - Influenza is responsible for up to 500,000 deaths every year, and antigenic variability represents much of its epidemiological burden. To visualize antigenic differences across many viral strains, antigenic cartography methods use multidimensional scaling on binding assay data to map influenza antigenicity onto a low-dimensional space. Analysis of such assay data ideally leads to natural clustering of influenza strains of similar antigenicity that correlate with sequence evolution. To understand the dynamics of these antigenic groups, we present a framework that jointly models genetic and antigenic evolution by combining multidimensional scaling of binding assay data, Bayesian phylogenetic machinery and nonparametric clustering methods. We propose a phylogenetic Chinese restaurant process that extends the current process to incorporate the phylogenetic dependency structure between strains in the modeling of antigenic clusters. With this method, we are able to use the genetic information to better understand the evolution of antigenicity throughout epidemics, as shown in applications of this model to H1N1 influenza. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28098391 TI - Understanding the formidable nail barrier: A review of the nail microstructure, composition and diseases. AB - The topical treatment of nail fungal infections has been a focal point of nail research in the past few decades as it offers a much safer and focused alternative to conventional oral therapy. Although the current focus remains on exploring the ways of enhancing permeation through the formidable nail barrier, the understanding of the nail microstructure and composition is far from complete. This article reviews our current understanding of the nail microstructure, composition and diseases. A few of the parameters affecting the nail permeability and potential causes of the recurrence of fungal nail infection are also discussed. PMID- 28098393 TI - Clinical and histopathological features of cutaneous nontuberculous mycobacterial infection: a review of 13 cases. AB - BACKGROUND: The incidence of cutaneous nontuberculous mycobacterial (NTM) infection has increased in recent decades because of widespread use of immunosuppressive therapy and better detection methods. The histopathology of cutaneous NTM infection is not pathognomic and the organisms are slow and difficult to culture, making diagnosis challenging. METHODS: We reviewed the clinical and histopathological features of 13 cases of cutaneous NTM infection, and performed panmycobacterial polymerase chain reaction (PCR) on the paraffin blocks. RESULTS: The immunocompetent patients presented with localized lesions on the extremities, whereas the immunocompromised patients presented with disseminated cutaneous lesions. The histopathology in immunocompetent patients was characterized by pseudoepitheliomatous epidermal hyperplasia, intraepithelial abscesses, transepidermal elimination and dermal granulomatous inflammation accompanied by necrosis and suppuration. The immunocompromised patients showed suppurative inflammation with little granuloma formation and numerous acid-fast bacilli. Paraffin block PCR was positive in 4 of 13 cases (31%), whereas culture was positive in 11 of 13 cases (85%). CONCLUSION: The aforementioned histological features should help in diagnosing cutaneous NTM infection when combined with clinical and microbiological correlation. In our study, we did not find paraffin block PCR to be superior to conventional culture in detecting cutaneous NTM infection. PMID- 28098394 TI - Review: Use of Asian samples in genetic research of alcohol use disorders: Genetic variation of alcohol metabolizing enzymes and the effects of acetaldehyde. AB - BACKGROUND AND OBJECTIVES: Epidemiological studies consistently find that Asian populations report lower rates of alcohol use disorders (AUD) compared with other racial groups. These differences result from a variety of biological, genetic, and environmental influences, some of which are related to the metabolism of alcohol. We will review several studies of these metabolic factors, including several alcohol clamping studies conducted in our laboratory, that provide further insight into the role of the alcohol metabolizing genes and drinking behavior among Japanese drinkers. METHODS: This manuscript reviewed studies investigating genetic variations of alcohol metabolizing enzymes among Asians and several mechanisms by which these genes are thought to give rise to differences in rates of alcohol dependence. RESULTS: The inactive aldehyde dehydrogenase 2 (ALDH2) and highly active alcohol dehydrogenase-1B (ADH1B) genes are protective factors for the development of AUD. The inactive ALDH2 provides its protective effect through the accumulation of acetaldehyde after consuming alcohol, resulting in unpleasant effects, and heightened sensitivity to alcohol. However, the suppressive effects of inactive ALDH2 and highly active ADH1B for AUDs are only partial and interact with other factors, such as personality traits, psychiatric comorbidities, and environmental factors. DISCUSSION AND CONCLUSIONS: While Asians are excellent models for the study of certain genetic effects on the development and consequences of AUD, few clinical studies of this population have been conducted. Further exploration of the interactions between various genetic, individual, and environmental factors influencing drinking behavior and, thus affecting the risk of AUD, would enhance our understanding of how alcohol-related problems develop. SCIENTIFIC SIGNIFICANCE: The heterozygous ALDH2*1/*2 genotype has only partial effects on limiting drinking behavior, suggesting the potential interaction with other factors. Therefore AUD patients with inactive ALDH2 may be a useful model to identify and to test a variety of other risk factors of AUD. (Am J Addict 2017;26:469-476). PMID- 28098395 TI - First UHPLC-MS/MS method coupled with automated online SPE for quantification both of tacrolimus and everolimus in peripheral blood mononuclear cells and its application on samples from co-treated pediatric patients. AB - Tacrolimus (TAC, FK-506) and everolimus (EVE, RAD001) are immunosuppressors used to treat pediatric patients undergoing liver transplantation. Their hematic TDM by liquid chromatography became standard practice. However, it does not always reflect concentrations at their active site. Our aim was to develop and validate a new method for the simultaneous TAC and EVE quantification into target cells: peripheral blood mononuclear cells (PBMCs). Peripheral blood mononuclear cells were collected using cell preparation tubes; cells number and mean cell volume were evaluated by an automatic cell counter. TAC and EVE were quantified using UHPLC-MS/MS coupled with an automated online solid-phase extraction platform. Chromatographic run was performed on an Acquity UPLC(r) BEH C18 1.7 MUm (2.1 * 50 mm) column at 45 degrees C, for 6 min at 0.5 ml/min. Mobile phases were water and methanol, both with 2 mm ammonium acetate and 1 ml/l formic acid). XBridge(r) C8 10 MUm (1 * 10 mm) SPE cartridges were used, and the internal standard was ascomycin. Following Food and Drug Administration guidelines, method validation resulted in high sensitivity and specificity. Calibration curves were linear (r2 = 0.998) and intra-day and inter-day imprecision and inaccuracy were <15%. A reproducible matrix effect was observed, with a good recovery for all compounds. Drug amounts in 15 'real' PBMCs samples from five pediatric patients in co treatment resulted within the calibration range (0.039-5 ng). Concentrations from each patient were standardized using their evaluated mean cell volume: intra PBMCs concentration was meanly 19.23 and 218.61 times higher than the hematic one for TAC and EVE, respectively. This method might be useful in clinical routine, giving reliable data on drugs concentration at the active site. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28098396 TI - Effects of chronic cobalt and chromium exposure after metal-on-metal hip resurfacing: An epigenome-wide association pilot study. AB - Metal-on-metal (MOM) hip resurfacing has recently been a popular prosthesis choice for the treatment of symptomatic arthritis, but results in the release of cobalt and chromium ions into the circulation that can be associated with adverse clinical effects. The mechanism underlying these effects remains unclear. While chromosomal aneuploidy and translocations are associated with this exposure, the presence of subtle structural epigenetic modifications in patients with MOM joint replacements remains unexplored. Consequently, we analyzed whole blood DNA methylation in 34 OA patients with MOM hip resurfacing (MOM HR) compared to 34 OA patients with non-MOM total hip replacements (non-MOM THR), using the genome-wide Illumina HumanMethylation 450k BeadChip. No probes showed differential methylation significant at 5% false-discovery rate (FDR). We also tested association of probe methylation levels with blood chromium and cobalt levels directly; there were no significant associations at 5% FDR. Finally, we used the "epigenetic clock" to compare estimated to actual age at sample for all individuals. We found no significant difference between MOM HR and non-MOM THR, and no correlation of age acceleration with blood metal levels. Our results suggest the absence of large methylation differences systemically following metal exposure, however, larger sample sizes will be required to identify potential small effects. Any DNA methylation changes that may occur in the local periprosthetic tissues remain to be elucidated. (c) 2017 The Authors. Orthopaedic Research Society. Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:2323-2328, 2017. PMID- 28098397 TI - Regression analysis of mixed panel count data with dependent terminal events. AB - Event history studies are commonly conducted in many fields, and a great deal of literature has been established for the analysis of the two types of data commonly arising from these studies: recurrent event data and panel count data. The former arises if all study subjects are followed continuously, while the latter means that each study subject is observed only at discrete time points. In reality, a third type of data, a mixture of the two types of the data earlier, may occur and furthermore, as with the first two types of the data, there may exist a dependent terminal event, which may preclude the occurrences of recurrent events of interest. This paper discusses regression analysis of mixed recurrent event and panel count data in the presence of a terminal event and an estimating equation-based approach is proposed for estimation of regression parameters of interest. In addition, the asymptotic properties of the proposed estimator are established, and a simulation study conducted to assess the finite-sample performance of the proposed method suggests that it works well in practical situations. Finally, the methodology is applied to a childhood cancer study that motivated this study. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28098398 TI - Depression and discrimination in the lives of women, transgender and gender liminal people in Ontario, Canada. AB - This article uses an intersectionality lens to explore how experiences of race, gender, sexuality, class and their intersections are associated with depression and unmet need for mental healthcare in a population of 704 women and transgender/gender liminal people from Ontario, Canada. A survey collecting demographic information, information about mental health and use of mental healthcare services, and data for the Everyday Discrimination Scale and the PHQ-9 Questionnaire for Depression was completed by 704 people via Internet or pen-and paper between June 2011 and June 2012. Bivariate and regression analyses were conducted to assess group differences in depression and discrimination experiences, and predictors of depression and unmet need for mental healthcare services. Analyses revealed that race, gender, class and sexuality all corresponded to significant differences in exposure to discrimination, experiences of depression and unmet needs for mental healthcare. Use of interaction terms to model intersecting identities and exclusion contributed to explained variance in both outcome variables. Everyday discrimination was the strongest predictor of both depression and unmet need for mental healthcare. The results suggest lower income and intersections of race with other marginalised identities are associated with more depression and unmet need for mental healthcare; however, discrimination is the factor that contributes the most to those vulnerabilities. Future research can build on intersectionality theory by foregrounding the role of structural inequities and discrimination in promoting poor mental health and barriers to healthcare. PMID- 28098399 TI - MYB, CD117 and SOX-10 expression in cutaneous adnexal tumors. AB - BACKGROUND: Elevated MYB expression has been documented in adenoid cystic carcinoma (ACC), cylindroma, and spiradenoma, but the specificity of this finding is unknown. CD117 and SOX-10 expression also occurs in some cutaneous adnexal tumors. This study assesses MYB, CD117 and SOX-10 expression in cutaneous adnexal tumors. METHODS: Retrospective analysis of 184 benign adnexal tumors (140 eccrine/apocrine, 40 follicular and 10 sebaceous), and 30 malignant adnexal tumors was performed with MYB, SOX-10 and CD117 immunostaining. RESULTS: In the benign adnexal tumors, 16% (23/140) significantly expressed MYB. MYB expression was limited to cylindromas and to a lesser extent, spiradenomas in the benign cohort. Elevated MYB expression was detected in mucinous carcinoma, endocrine mucin-producing sweat gland carcinoma and 1 and 4 cases of extramammary Paget's disease (EMPD) in the malignant cohort. CD117 and SOX-10 had similar overall positivity rates in benign apocrine and eccrine tumors (45% and 68% respectively), and were generally negative in other benign and malignant adnexal tumors. CONCLUSION: Expression of MYB appears limited to a small number of cutaneous adnexal tumors, including cylindromas, spiradenomas, ACCs, mucinous carcinoma, endocrine mucin-producing sweat gland carcinoma and some cases of EMPD. PMID- 28098400 TI - Role of Contrast-Enhanced Sonography in the Evaluation of Axillary Lymph Nodes in Breast Carcinoma: A Monocentric Study. AB - OBJECTIVES: To evaluate the diagnostic performance of contrast-enhanced sonography for characterization of the lymph node status (metastatic or not) in patients with breast carcinomas by comparison with sentinel lymph node biopsy. METHODS: From January to August 2015, 50 female patients with a histologic diagnosis of invasive breast carcinoma were prospectively examined by ipsilateral axillary contrast-enhanced sonography. The test was performed by a single radiologist using an ultrasound system with a broadband 8-12-MHz, 38-mm high resolution linear transducer. For the target lymph node, we chose a node with a sonographic pattern that was suspicious for malignancy: ie, a longitudinal-to transverse diameter ratio of less than 2, absence of a central hyperechogenic hilum, or both. In cases with a lack of sonographic signs of malignancy, we evaluated the node with the maximal transverse diameter. Nodes were considered malignant in cases with total absence of contrast enhancement and in those with enhancement alterations. Within 1 week, all patients underwent sentinel lymph node biopsy, followed by a histologic test. RESULTS: The histologic test showed benignity in 22 of 50 sentinel lymph nodes, whereas 28 were metastatic. Among the 22 patients with negative biopsy results, contrast-enhanced sonography showed 18 concordances and 4 false-positives results; among the 28 with positive biopsy results, contrast-enhanced sonography obtained 100% correct characterizations of the axillary status. The sensitivity, specificity, and accuracy were 100%, 82%, and 92%, respectively. CONCLUSIONS: Contrast-enhanced sonography appears to be a method with high accuracy for characterization of axillary lymph nodes, very close to the reference-standard sentinel lymph node biopsy. This technique seems to have overall high sensitivity. PMID- 28098402 TI - Anion-pi Interactions in Flavoproteins Involve a Substantial Charge-Transfer Component. AB - Anion-pi interactions have been shown to stabilize flavoproteins and to regulate the redox potential of the flavin cofactor. They are commonly attributed to electrostatic forces. Herein we show that anion-flavin interactions can have a substantial charge-transfer component. Our conclusion emanates from a multi approach theoretical analysis and is backed by previously reported observations of absorption bands, originating from charge transfer between oxidized flavin and proximate cysteine thiolate groups. This partial covalency of anion-flavin contacts renders classical simulations of flavoproteins questionable. PMID- 28098401 TI - Antibiotic resistance of Helicobacter pylori in Chinese children: A multicenter retrospective study over 7 years. AB - BACKGROUND: To determine the prevalence of resistance to metronidazole, clarithromycin, levofloxacin, amoxicillin, and furazolidone in Helicobacter pylori isolated from Chinese children. MATERIALS AND METHODS: This multicenter retrospective study was conducted from January 2009 to December 2015. A total of 1746 isolates of H. pylori were collected from nine areas of Zhejiang province in the southeast coastal region of China. H. pylori strains were examined for antibiotics susceptibility by agar dilution method. RESULTS: The resistance rates were 75.20% for metronidazole, 16.38% for clarithromycin, 6.70% for levofloxacin, 0.06% for amoxicillin, and 0.06% for furazolidone. The pattern of H. pylori antibiotic resistance demonstrated no significant changes in the rates of resistance to clarithromycin, amoxicillin, furazolidone, and metronidazole over 7 years. A significant trend of increasing resistance to metronidazole was observed as children aged, but a downward trend in clarithromycin resistance was observed as children aged. No difference in the resistance to other antibiotics was observed among different age groups. Also, there was no significant difference between male and female subjects in rates of resistance to these five types of antibiotics. The predominant dual resistance to metronidazole and clarithromycin was presented in 10.65% of the isolates. CONCLUSIONS: The resistance rates of H. pylori in children from southeast coastal region of China were very high to metronidazole, moderate to clarithromycin and levofloxacin, and low to amoxicillin and furazolidone. It is important to continue monitoring the resistance profiles of H. pylori isolated in this region. PMID- 28098403 TI - MiR-338-5p Promotes Inflammatory Response of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via Targeting SPRY1. AB - Our purpose is to study the roles of microRNA-338-5p (miR-338-5p) on the proliferation, invasion, and inflammatory response of fibroblast-like synoviocytes (SFs) in rheumatoid arthritis patients by regulating SPRY1. The target relationship between miR-338-5p and SPRY1 was validated through luciferase reporter system. The expression of miR-338-5p and SPRY1 in synovial tissues and synovial cells were detected using RT-PCR and western blot. The mimics and inhibitors of miR-338-5p were transfected into SFs. MTT, Transwell, and ELISA assays were used to analyze cell proliferation, invasiveness, and the secreted extracellular pro-inflammatory cytokines (such as IL-1a, IL-6, COX2) levels of SFs. MiR-338-5p was highly expressed in rheumatoid arthritis tissues and cells, and directly down-regulated the expression of SPRY1 in the SFs of rheumatoid arthritis patients. Cell proliferation, invasiveness and the expression level of pro-inflammatory cytokines in synovial cells increased after the transfection of miR-338-5p mimics, while the proliferation, invasion and expression level of pro inflammatory cytokines decreased after the transfection of miR-338-5p inhibitors. In conclusion,miR-338-5p promoted the proliferation, invasion and inflammatory reaction in SFs of rheumatoid arthritis by directly down-regulating SPRY1 expression. J. Cell. Biochem. 118: 2295-2301, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28098404 TI - ESI activity of Br-, BF4- , ClO4- and BPh4- anions in the presence of Li+ and NBu4+ counter-ions. AB - To improve our understanding of the electrospray ionization (ESI) process, we have subjected equimolar mixtures of salts A+ X- (A+ = Li+ , NBu4+ ; X- = Br- , ClO4- , BF4- , BPh4- ) in different solvents (CH3 CN, tetrahydrofuran, CH3 OH, H2 O) to negative-ion mode ESI and analyzed the relative ESI activity of the different anionic model analytes. The ESI activity of the large and hydrophobic BPh4- ion greatly exceeds that of the smaller and more hydrophilic anions Br- , ClO4- and BF4- , which we ascribe to its higher surface activity. Moreover, the ESI activity of the anions is modulated by the action of the counter-ions and their different tendency toward ion pairing. The tendency toward ion pairing can be reduced by the addition of the chelating ligands 12-crown-4 and 2.2.1 cryptand and is, although to a smaller degree, further influenced by the variation of the solvent. Complementary electrical conductivity measurements afford additional information on the interactions of the ionic constituents of the sample solutions. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28098405 TI - Shielding Engineered Islets With Mesenchymal Stem Cells Enhance Survival Under Hypoxia. AB - In the present study we focused on the improvisation of islet survival in hypoxia.The Islet like cell aggregates (ICAs) derived from wharton's jelly mesenchymal stem cells (WJ MSC) were cultured with and without WJ MSC for 48 h in hypoxia and normoxia and tested for their direct trophic effect on beta cell survival. The WJ MSCs themselves secreted insulin upon glucose challenge and expressed the pancreatic markers at both transcription and translational level (C peptide, Insulin, Glucagon, and Glut 2). Direct contact of MSCs with ICAs facilitated highest viability under hypoxia as evidenced by fluorescein diacetate/propidium iodide and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The cytokine analysis of the co-cultured ICAs revealed amplification of anti-inflammatory cytokine like TGFbeta and TNFalpha accompanied by depletion of pro-inflammatory cytokines. The increment in VEGF and PDGFa was also seen showing their ability to vascularize upon transplantation. This was further accompanied by reduction in total reactive oxygen species, nitric oxide, and super oxide ions and down regulation of Caspase3, Caspase8, p53, and up regulation of Bcl2 confirming prevention of apoptosis in ICAs. The western blot analysis confirmed the cytoprotective effect of WJ MSC on ICAs as they enhanced the anti-apoptotic marker BCL2 and reduced the expression of apoptotic markers, Annexin 5 and Caspase 3. There was a significant reduction in the expression of p38 protein in the presence of MSCs making the ICAs responsive to glucose. Taken together our data demonstrate for the first time that the WJ MSC expressed pancreatic markers and their supplementation protected engineered islets against hypoxia and oxidative stress. J. Cell. Biochem. 118: 2672-2683, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28098406 TI - Contemporary migration patterns in the prevalence of Helicobacter pylori infection: A systematic review. AB - BACKGROUND: A rapid growth in the number of international migrants over the past years has occurred with most traveling to more affluent settings. As Helicobacter pylori infects over half of the adult population and its prevalence is higher in developing countries, understanding the prevalence of infection in migrants can provide insight into future trends in the burden and management of infection. We aimed to describe the prevalence of H. pylori among migrants through a systematic literature review. METHODS: We searched PubMed(r) from inception to September 2015 to identify studies reporting the prevalence of H. pylori in international migrants according to country of birth for first-generation, and country of birth and parents' nationality for successive generations. Comparable data from origin and destination populations were obtained from the same studies or, when not present, from a previous systematic review on H. pylori worldwide. RESULTS: A total of 28 eligible studies were identified with data for 29 origin and 12 destination countries. Two studies that evaluated refugees presented prevalences of infection higher than both the origin and destination countries. Otherwise, the prevalences among migrants were generally similar or below that of the origin and higher than the destination. Second- or more generation had lower prevalences compared to first-generation migrants. CONCLUSIONS: Our study findings are consistent with what would be expected based on the prevalence of H. pylori worldwide. The results of this review show that migrants are particularly at risk of infection and help to identify gaps in the knowledge of migrants' prevalence of infection globally. PMID- 28098407 TI - Tumefactive foreign body giant cell reaction following high-pressure paint injection injury: A case report and review of literature. AB - High-pressure paint injection injury is an uncommon but well-described injury. The histologic features of long-term paint injection injury with retained material are less recognized. A 46-year-old male presented clinically as "recurrent giant cell tumor of tendon sheath." The right index finger demonstrated fusiform enlargement by a pigmented mass with diffuse infiltration into the soft tissue of the hand. Histologically the tumor showed multiple giant cells in a fibrotic stroma extending into the dermis. There were multiple types of foreign material including diffuse brown black pigment, weakly optically polarizing foreign material and white inclusions with a "train track" appearance. The cells were positive for CD68 and negative for S100 antigen. Further investigation revealed that the patient had a history of high-pressure paint injection injury to his digit 6 years prior. Foreign material injected under high pressure into tissues may result in a pseudo-neoplastic foreign body granulomatous reaction that can mimic giant cell tumor of tendon sheath. Our case demonstrates that this reaction can be florid and can have slow growth over years. A high index of suspicion, a good clinical history and careful examination can distinguish these 2 entities. PMID- 28098408 TI - Vonoprazan improves the efficacy of Helicobacter pylori eradication therapy with a regimen consisting of clarithromycin and metronidazole in patients allergic to penicillin. AB - BACKGROUND: Although all Helicobacter pylori (H. pylori)-positive patients should receive eradication therapy, the therapy is a challenge for patients allergic to penicillin. There have been a few reports on the efficacy of eradication therapy for such patients. OBJECTIVE: To analyze the efficacy of vonoprazan or proton pump inhibitor (PPI)-based 7-day triple therapy in patients allergic to penicillin. MATERIALS AND METHODS: A total of 88 consecutive patients allergic to penicillin who received H. pylori eradication therapy were retrospectively analyzed. Thirty-one patients had a history of failed eradication therapy. Four 7 day regimens were prescribed during the study period: clarithromycin metronidazole-PPI (13 patients), clarithromycin-metronidazole-vonoprazan (14 patients), metronidazole-sitafloxacin-PPI (44 patients) and metronidazole sitafloxacin-vonoprazan (17 patients). A 13 C-urea breath test was used for confirmation of eradication, and efficacy of eradication was evaluated by "intention-to-treat" analysis and "per-protocol" analysis. RESULTS: Intention-to treat and per-protocol eradication rates were 46.2%/54.6% for patients who received clarithromycin-metronidazole-PPI, 92.9/92.9% for patients who received clarithromycin-metronidazole-vonoprazan, 100/100% for patients who received metronidazole-sitafloxacin-PPI and 88.2/93.8% for patients who received metronidazole-sitafloxacin-vonoprazan. For first eradication, vonoprazan significantly raised the intention-to-treat efficacy of the triple therapy including clarithromycin-metronidazole (vonoprazan: 92.9%, PPI: 46.2%, P=.0128). A 7-day regimen consisting of metronidazole and sitafloxacin was effective for patients allergic to penicillin with or without past failure of eradication. CONCLUSION: For first eradication in patients allergic to penicillin, a 7-day triple therapy consisting of clarithromycin, metronidazole and vonoprazan could be a candidate eradication regimen. PMID- 28098409 TI - TRPV4 Contributes to Resting Membrane Potential in Retinal Muller Cells: Implications in Cell Volume Regulation. AB - Neural activity alters osmotic gradients favoring cell swelling in retinal Muller cells. This swelling is followed by a regulatory volume decrease (RVD), partially mediated by an efflux of KCl and water. The transient receptor potential channel 4 (TRPV4), a nonselective calcium channel, has been proposed as a candidate for mediating intracellular Ca2+ elevation induced by swelling. We previously demonstrated in a human Muller cell line (MIO-M1) that RVD strongly depends on ion channel activation and, consequently, on membrane potential (Vm ). The aim of this study was to investigate if Ca2+ influx via TRPV4 contributes to RVD by modifying intracellular Ca2+ concentration and/or modulating Vm in MIO-M1 cells. Cell volume, intracellular Ca2+ levels, and Vm changes were evaluated using fluorescent probes. Results showed that MIO-M1 cells express functional TRPV4 which determines the resting Vm associated with K+ channels. Swelling-induced increases in Ca2+ levels was due to both Ca2+ release from intracellular stores and Ca2+ influx by a pathway alternative to TRPV4. TRPV4 blockage affected swelling-induced biphasic response (depolarization-repolarization), suggesting its participation in modulating Vm changes during RVD. Agonist stimulation of Ca2+ influx via TRPV4 activated K+ channels hyperpolarizing Vm and accelerating RVD. We propose that TRPV4 forms a signaling complex with Ca2+ and/or voltage dependent K+ channels to define resting Vm and Vm changes during RVD. TRPV4 involvement in RVD depends on the type of stimuli and/or degree of channel activation, leading to a maximum RVD response when Ca2+ influx overcomes a threshold and activates further signaling pathways in cell volume regulation. J. Cell. Biochem. 118: 2302-2313, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28098410 TI - Juror Decision-making in Death Penalty Sentencing when Presented with Defendant's History of Child Abuse or Neglect. AB - Previous studies have found aggravating, mitigating, and null effects of defendant histories of abuse and neglect on punishment preferences in capital sentencing. Perceiving these defendants as more dangerous, jurors may be more likely to favor the death penalty when such evidence is presented. This is counter to the intuition that abuse or neglect reduces culpability, and therefore mitigates the severity of punishment. We investigated the effect of defendant childhood physical abuse, sexual abuse, or neglect on the probability of a prospective juror preferring the death penalty in an between-subject experimental design. Using vignettes and two large samples (students and jurors), defendant histories were found to mitigate the probability that the hypothetical defendant received the death penalty, with sexual abuse having the most salient effect. Further, the effects were conditioned by preference for the death penalty - larger mitigating effects were observed among individuals who favor the death penalty. These findings suggest that initial judgments of abuse and neglect are related to juror leniency, and further research on the interaction of jury instructions and defendant histories is needed. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28098411 TI - An efficient basket trial design. AB - The landscape for early phase cancer clinical trials is changing dramatically because of the advent of targeted therapy. Increasingly, new drugs are designed to work against a target such as the presence of a specific tumor mutation. Because typically only a small proportion of cancer patients will possess the mutational target, but the mutation is present in many different cancers, a new class of basket trials is emerging, whereby the drug is tested simultaneously in different baskets, that is, subgroups of different tumor types. Investigators desire not only to test whether the drug works but also to determine which types of tumors are sensitive to the drug. A natural strategy is to conduct parallel trials, with the drug 's effectiveness being tested separately, using for example, the popular Simon two-stage design independently in each basket. The work presented is motivated by the premise that the efficiency of this strategy can be improved by assessing the homogeneity of the baskets ' response rates at an interim analysis and aggregating the baskets in the second stage if the results suggest the drug might be effective in all or most baskets. Via simulations, we assess the relative efficiencies of the two strategies. Because the operating characteristics depend on how many tumor types are sensitive to the drug, there is no uniformly efficient strategy. However, our investigation demonstrates that substantial efficiencies are possible if the drug works in most or all baskets, at the cost of modest losses of power if the drug works in only a single basket. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28098412 TI - A hierarchical modeling approach to estimate regional acute health effects of particulate matter sources. AB - Exposure to particulate matter (PM) air pollution has been associated with a range of adverse health outcomes, including cardiovascular disease hospitalizations and other clinical parameters. Determining which sources of PM, such as traffic or industry, are most associated with adverse health outcomes could help guide future recommendations aimed at reducing harmful pollution exposure for susceptible individuals. Information obtained from multisite studies, which is generally more precise than information from a single location, is critical to understanding how PM impacts health and to informing local strategies for reducing individual-level PM exposure. However, few methods exist to perform multisite studies of PM sources, which are not generally directly observed, and adverse health outcomes. We developed SHared Across a REgion (SHARE), a hierarchical modeling approach that facilitates reproducible, multisite epidemiologic studies of PM sources. SHARE is a two-stage approach that first summarizes information about PM sources across multiple sites. Then, this information is used to determine how community-level (i.e., county-level or city level) health effects of PM sources should be pooled to estimate regional-level health effects. SHARE is a type of population value decomposition that aims to separate out regional-level features from site-level data. Unlike previous approaches for multisite epidemiologic studies of PM sources, the SHARE approach allows the specific PM sources identified to vary by site. Using data from 2000 to 2010 for 63 northeastern US counties, we estimated regional-level health effects associated with short-term exposure to major types of PM sources. We found that PM from secondary sulfate, traffic, and metals sources was most associated with cardiovascular disease hospitalizations. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28098413 TI - Dermatomal spread following posterior transversus abdominis plane block in pediatric patients: our initial experience. AB - INTRODUCTION: Several techniques for the transversus abdominis plane (TAP) block have been described. The extent of sensory changes using an ultrasound-guided posterior TAP block (pTAP) remains unclear in pediatric patients. The primary aim of this study was to report the extent of sensory changes achieved with pTAP; specifically the highest thoracic dermatome anesthetized. Secondary outcomes were pain scores (PS), opioid consumption, and complications. METHODS: We retrospectively reviewed the medical records of patients less than 21 years of age undergoing abdominal surgery with a unilateral or bilateral pTAP(s) for postoperative analgesia. The local anesthetic was placed posterior to the termination of the transversus abdominis muscle where the thoracolumbar fascia overrides the quadratus lumborum muscle. The extent of sensory changes, pain scores, and opioid consumption were analyzed. RESULTS: A total of 10 patients (15 pTAP blocks) met the inclusion criteria. The mean (sd; range) age and weight were 15 years (5 years; range 7-20 years) and 57 kg (21 kg; 27-97 kg), respectively. The cephalad dermatome levels achieved were: T7 in 6/15 (40%); T8 in 10/15 (67%); and T9 in 14/15 (93%). An inferior dermatome level of T12/L1 and sensory extension from midaxillary line to the midline was documented in 15/15 blocks. The mean intraoperative and postanesthesia care unit (PACU) opioid consumption in morphine equivalents were 0.34 mg.kg-1 (sd = 0.12 mg.kg-1 ) and 0.04 mg.kg-1 (sd = 0.05 mg.kg-1 ), respectively. PACU pain scores were mild (<4) in 60%, moderate (4-7) in 30%, and severe (>7) in 10% of patients. No complications were reported. DISCUSSION: The current uncertainty regarding sensory blockade limits the clinical application of TAP blocks. While the midaxillary approach results in unpredictable sensory changes of the abdomen, we reliably achieved sensory changes up to a T9 level in 93% of the blocks. CONCLUSION: In this small series of patients, we demonstrate a high technical success rate of achieving cutaneous analgesia to the abdominal wall. These results should encourage clinical studies of the efficacy of this block for abdominal surgery in pediatric patients. PMID- 28098414 TI - Integrated photografted molecularly imprinted polymers with a cellulose acetate membrane for the extraction of melamine from dry milk before HPLC analysis. AB - In this study, a new separation technique based on membrane extraction is described for the determination of melamine in dry milk. The water-compatible cellulose acetate membrane, which is photografted by melamine imprinted nanospheres, was prepared by placing the membrane into the polymerization solution containing methacrylic acid as a functional monomer, ethylene glycol dimethacrylate as cross-linker, acetonitrile as porogen, and melamine as the template molecule. The characterization of the polymeric membrane was performed by Fourier transmission infrared spectroscopy and scanning electron microscopy. This integrated composite membrane was used as a solid-phase extraction medium for the extraction of melamine from dry milk samples. Various parameters affecting the extraction efficiency of the membrane were evaluated. The results showed higher binding capacity for melamine imprinted membranes in comparison with the nonimprinted membranes. High-performance liquid chromatography analysis showed that the extraction of melamine from dry milk by the photografted cellulose acetate membrane had a linear calibration curve in the range of 0.02 11.80 MUg/mL with an excellent precision of 2.73%. The limit of detection and quantification of melamine was 0.007 and 0.020 MUg/mL, respectively. The recoveries of melamine were in the range of 88.7-94.8%. PMID- 28098415 TI - Intracranial AAV-IFN-beta gene therapy eliminates invasive xenograft glioblastoma and improves survival in orthotopic syngeneic murine model. AB - The highly invasive property of glioblastoma (GBM) cells and genetic heterogeneity are largely responsible for tumor recurrence after the current standard-of-care treatment and thus a direct cause of death. Previously, we have shown that intracranial interferon-beta (IFN-beta) gene therapy by locally administered adeno-associated viral vectors (AAV) successfully treats noninvasive orthotopic glioblastoma models. Here, we extend these findings by testing this approach in invasive human GBM xenograft and syngeneic mouse models. First, we show that a single intracranial injection of AAV encoding human IFN-beta eliminates invasive human GBM8 tumors and promotes long-term survival. Next, we screened five AAV-IFN-beta vectors with different promoters to drive safe expression of mouse IFN-beta in the brain in the context of syngeneic GL261 tumors. Two AAV-IFN-beta vectors were excluded due to safety concerns, but therapeutic studies with the other three vectors showed extensive tumor cell death, activation of microglia surrounding the tumors, and a 56% increase in median survival of the animals treated with AAV/P2-Int-mIFN-beta vector. We also assessed the therapeutic effect of combining AAV-IFN-beta therapy with temozolomide (TMZ). As TMZ affects DNA replication, an event that is crucial for second-strand DNA synthesis of single-stranded AAV vectors before active transcription, we tested two TMZ treatment regimens. Treatment with TMZ prior to AAV-IFN-beta abrogated any benefit from the latter, while the reverse order of treatment doubled the median survival compared to controls. These studies demonstrate the therapeutic potential of intracranial AAV-IFN-beta therapy in a highly migratory GBM model as well as in a syngeneic mouse model and that combination with TMZ is likely to enhance its antitumor potency. PMID- 28098417 TI - Delivery of anesthesia for children with Mucopolysaccharidosis Type III (Sanfilippo syndrome): a review of 86 anesthetics. AB - BACKGROUND: Sanfilippo syndrome (MPS III) is rare, with 97 cases in the United Kingdom between 1988 and 1998. Mucopolysaccharide infiltration of tissues in mucopolysaccharidosis (MPS) causes multi-systemic pathology including difficult airways and cardiac disease. Published anesthesia case reviews of Sanfilippo syndrome have included limited numbers of patients to date. AIM: To identify the perioperative management and complications of anesthesia in children with mucopolysaccharidosis Type III at Great Ormond Street Hospital. METHODS: A retrospective case note review of all children with MPS III in our institution was undertaken. All medical notes and anesthetic charts were analyzed, and conduct of anesthesia, airway management, perioperative complications, and associated comorbidities were identified. RESULTS: There were 43 patients with MPS III, of which 34 required anesthesia, on 86 occasions for 156 procedures between 1993 and 2015. Dental extraction was the likeliest indication for anesthesia (34%) (general surgery [30%]; ear, nose, and throat [26%]; other [10%]). Thirteen of 34 patients had cardiac pathology (valvular [n = 6], functional [n = 6], electrophysiological [n = 1]). Ten of 34 patients had evidence of clotting abnormality (mild prolonged clotting time [n = 5], low von Willebrand factor [n = 2], thrombocytopenia [n = 3]). The majority of intubations were Cormack-Lehane Grade 1 (n = 47) (Grade 2 [n = 14], Grade 3 [n = 1], Grade 4 [n = 1]). In 86 anesthetics, there were 0 cases of difficulty with mask ventilation. There was 1 case of failed intubation. They were subsequently anesthetized by a different operator uneventfully at a later date. Two perioperative complications occurred: a failed intubation and bleeding during adenoidectomy. CONCLUSION: We demonstrate a difficult airway is unlikely when anesthetizing an MPS III patient although a risk does remain. A significant proportion of MPS III have cardiac involvement although no perioperative complications were described. With associated coagulation issues, bleeding tendency, while uncommon, can occur in this group. PMID- 28098416 TI - Motuporamine Derivatives as Antimicrobial Agents and Antibiotic Enhancers against Resistant Gram-Negative Bacteria. AB - Dihydromotuporamine C and its derivatives were evaluated for their in vitro antimicrobial activities and antibiotic enhancement properties against Gram negative bacteria and clinical isolates. The mechanism of action of one of these derivatives, MOTU-N44, was investigated against Enterobacter aerogenes by using fluorescent dyes to evaluate outer-membrane depolarization and permeabilization. Its efficiency correlated with inhibition of dye transport, thus suggesting that these molecules inhibit drug transporters by de-energization of the efflux pump rather than by direct interaction of the molecule with the pump. This suggests that depowering the efflux pump provides another strategy to address antibiotic resistance. PMID- 28098418 TI - Investigation of the variability of anterior chamber scan protocol with Cirrus high definition optical coherence tomography. AB - IMPORTANCE: The evaluation of anterior chamber scan of Cirrus optical coherence tomography for routine clinical use. BACKGROUND: To assess the variability of anterior chamber angle measurements. DESIGN: This was a cross-sectional study. PARTICIPANTS: Forty subjects aged 40-80 years were included. METHODS: One randomly selected eye from 40 subjects was imaged with Cirrus optical coherence tomography (Carl Zeiss Meditec, Dublin, CA) by two different operators (expert vs. non-expert) with a 15-min interval for inter-observer and intra-observer variability of image acquisition. For image grading, the angle opening distance (AOD750) and the trabecular iris space area (TISA750) of nasal and temporal quadrants were measured with a customized algorithm (ImageJ, NIH, Bethesda, MD) by two different graders in a masked and random fashion. Bland Altman analysis and intraclass correlation coefficient (ICC) were calculated. MAIN OUTCOME MEASURES: ICC and limit of agreements (LOA). RESULTS: There were 15 (37.5%) eyes with closed angles. For inter-observer variability, the mean difference (95% LOA) of AOD750 for image acquisition and grading were -0.0039 mm (-0.0486, 0.0408) and 0.0011 mm (-0.0228, 0.025), respectively. The mean difference (95% LOA) of AOD750 for intra-observer variability for image acquisition and grading were 0.0013 mm ( 0.0362, 0.0389) and -0.0013 mm (-0.0482, 0.0457), respectively. The ICCs were all >=0.9. There was no significant difference in measurement variability between open and closed angles (P > 0.05). CONCLUSIONS AND RELEVANCE: Anterior chamber scan had low inter-observer and intra-observer variability in quantitative evaluation that was not affected by the angle status or the experience of an operator. PMID- 28098419 TI - Determination of a broad spectrum of endocrine-disrupting pesticides in fish samples by UHPLC-MS/MS using the pass-through cleanup approach. AB - We describe a new methodology for the simultaneous determination of the endocrine disrupting herbicides (acetochlor, alachlor, amitrole, and atrazine), fungicides (carbendazim, triadimefon, penconazole, and propiconazole), and insecticides (carbaryl and carbofuran) in fish samples followed by high-performance liquid chromatography with tandem mass spectrometry. Samples were extracted and purified using the pass-through cleanup approach. The recoveries of the pesticides were in the range 71.8-116.5%, with relative standard deviations lower than 15.28%. Limits of quantitation were in the range of 0.03-2.50 MUg/kg. Validation results on linearity, accuracy, and precision, as well as on application to the analysis of the endocrine-disrupting pesticides in 20 fish samples, demonstrated the applicability to screen the presence of pesticides in fish. PMID- 28098420 TI - Deciphering chemical interactions between Glycyrrhizae Radix and Coptidis Rhizoma by liquid chromatography with transformed multiple reaction monitoring mass spectrometry. AB - In this study, we propose an integrated strategy for the efficient identification and quantification of herbal constituents using liquid chromatography with mass spectrometry. First, liquid chromatography with quadrupole time-of-flight mass spectrometry was employed for the chemical profiling of herbs, where a targeted following nontargeted approach was developed to detect trace constituents by using structural correlations and extracted ion chromatograms. Next, ion pairs and parameters of MS2 of quadrupole time-of-flight mass spectrometry were selected to design multiple reaction monitoring transitions for the identified compounds on liquid chromatography with triple quadrupole mass spectrometry. The relative concentration of each constituent was then calculated using a semiquantitative calibration curve. The proposed strategy was applied in a study of chemical interactions between Glycyrrhizae Radix and Coptidis Rhizoma. A total of 140 compounds were identified or tentatively characterized from the herbs, 132 of which were relatively quantified. The visualized quantitative results clearly showed codecoction produced significant constituent concentration variations especially for those with a low polarity. The case study also indicated that the present methodology could provide a reliable, accurate, and labor-saving solution for chemical studies of herbal medicines. PMID- 28098421 TI - Hexagonal Boron Nitride (h-BN) Sheets Decorated with OLi, ONa, and Li2 F Molecules for Enhanced Energy Storage. AB - First-principles electronic structure calculations were carried out on hexagonal boron nitride (h-BN) sheets functionalized with small molecules, such as OLi, ONa, and Li2 F, to study their hydrogen (H2 ) storage properties. We found that OLi and ONa strongly adsorb on h-BN sheets with reasonably large inter-adsorbent separations, which is desirable for H2 storage. Ab initio molecular dynamics (MD) simulations further confirmed the structural stability of OLi-BN and ONa-BN systems at 400 K. On the other hand, Li2 F molecules form clusters over the surface of h-BN at higher temperatures. We performed a Bader charge investigation to explore the nature of binding between the functionalized molecules and h-BN sheets. The density of states (DOS) revealed that functionalized h-BN sheets become metallic with two-sided coverage of each type of molecules. Hydrogenation of OLi-BN and ONa-BN revealed that the functionalized systems adsorb multiple H2 molecules around the Li and Na atoms, with H2 adsorption energies ranging from 0.20 to 0.28 eV, which is desirable for an efficient H2 storage material. PMID- 28098422 TI - Structural Elucidation of a Nonpeptidic Inhibitor Specific for the Human Immunoproteasome. AB - Selective inhibition of the immunoproteasome is a promising approach towards the development of immunomodulatory drugs. Recently, a class of substituted thiazole compounds that combine a nonpeptidic scaffold with the absence of an electrophile was reported in a patent. Here, we investigated the mode of action of the lead compound by using a sophisticated chimeric yeast model of the human immunoproteasome for structural studies. The inhibitor adopts a unique orientation perpendicular to the beta5i substrate-binding channel. Distinct interactions between the inhibitor and the subpockets of the human immunoproteasome account for its isotype selectivity. PMID- 28098424 TI - Application of zein-modified magnetite nanoparticles in dispersive magnetic micro solid-phase extraction of synthetic food dyes in foodstuffs. AB - A simple method for the simultaneous and trace analysis of four synthetic food azo dyes including carmoisine, ponceau 4R, sunset yellow, and allura red from some foodstuff samples was developed by combining dispersive MU-solid-phase extraction and high-performance liquid chromatography with diode array detection. Zein-modified magnetic Fe3 O4 nanoparticles were prepared and used for MU-solid phase extraction of trace amounts of mentioned food dyes. The prepared modified magnetic nanoparticles were characterized by scanning electron microscopy and FTIR spectroscopy. The factors affecting the extraction of the target analytes such as pH, amount of sorbent, extraction time, type and volume of the desorption eluent, and desorption time were investigated. Under the optimized conditions, the method provided good repeatability with relative standard deviations lower than 5.8% (n = 9). Limit of detection values ranged between 0.3 and 0.9 ng/mL with relatively high enrichment factors (224-441). Comparing the obtained results indicated that Fe3 O4 nanoparticles modified by zein biopolymer show better analytical application than bare magnetic nanoparticles. The proposed method was also applied for the determination of target synthetic food dyes in foodstuff samples such as carbonated beverage, snack, and candy samples. PMID- 28098423 TI - Brain-derived neurotrophic factor attenuates doxorubicin-induced cardiac dysfunction through activating Akt signalling in rats. AB - The clinical application of doxorubicin (Dox) is limited by its adverse effect of cardiotoxicity. Previous studies have suggested the cardioprotective effect of brain-derived neurotrophic factor (BDNF). We hypothesize that BDNF could protect against Dox-induced cardiotoxicity. Sprague Dawley rats were injected with Dox (2.5 mg/kg, 3 times/week, i.p.), in the presence or absence of recombinant BDNF (0.4 MUg/kg, i.v.) for 2 weeks. H9c2 cells were treated with Dox (1 MUM) and/or BDNF (400 ng/ml) for 24 hrs. Functional roles of BDNF against Dox-induced cardiac injury were examined both in vivo and in vitro. Protein level of BDNF was reduced in Dox-treated rat ventricles, whereas BDNF and its receptor tropomyosin-related kinase B (TrkB) were markedly up-regulated after BDNF administration. Brain derived neurotrophic factor significantly inhibited Dox-induced cardiomyocyte apoptosis, oxidative stress and cardiac dysfunction in rats. Meanwhile, BDNF increased cell viability, inhibited apoptosis and DNA damage of Dox-treated H9c2 cells. Investigations of the underlying mechanisms revealed that BDNF activated Akt and preserved phosphorylation of mammalian target of rapamycin and Bad without affecting p38 mitogen-activated protein kinase and extracellular regulated protein kinase pathways. Furthermore, the beneficial effect of BDNF was abolished by BDNF scavenger TrkB-Fc or Akt inhibitor. In conclusion, our findings reveal a potent protective role of BDNF against Dox-induced cardiotoxicity by activating Akt signalling, which may facilitate the safe use of Dox in cancer treatment. PMID- 28098425 TI - Cardiovascular effects of glucagon-like peptide-1 receptor agonist therapies in patients with type 1 diabetes. PMID- 28098426 TI - Dapagliflozin in patients with type 1 diabetes: A post hoc analysis of the effect of insulin dose adjustments on 24-hour continuously monitored mean glucose and fasting beta-hydroxybutyrate levels in a phase IIa pilot study. AB - AIMS: To investigate the effects of total daily insulin dose (TDD) reductions on 24-hour continuously monitored mean glucose and fasting beta-hydroxybutyrate (a marker for diabetic ketosis/ketoacidosis [DKA]) levels, using patient-level data from a 14-day, pilot study of dapagliflozin in type 1 diabetes (T1DM). METHODS: A post hoc exploratory correlation analysis was performed to determine the relationship between change in TDD and (1) 24-hour mean glucose, assessed by continuous glucose monitoring, and (2) fasting beta-hydroxybutyrate, in 70 patients with T1DM receiving insulin and dapagliflozin (1, 2.5, 5 or 10 mg) or placebo. The pharmacodynamic effect of dapagliflozin was estimated as a virtual "insulin dose" using 24-hour urinary glucose excretion values and a recognized insulin-to-carbohydrate counting technique. RESULTS: Trends for correlations were observed between change in TDD and 24-hour glucose (day 7: r = -0.264, P = .056) and beta-hydroxybutyrate (day 7: r = -0.187, P = .133; day 14: r = -0.274, P = .047). The pharmacodynamic effect of dapagliflozin 5 or 10 mg was estimated as equivalent to ~20% of baseline TDD. Higher mean and maximum beta-hydroxybutyrate levels were observed on days 7 and 14 in patients with a TDD reduction >20% vs <=20%. CONCLUSIONS: Over 14 days, decreasing the insulin dose diminished the glucose-lowering effect of dapagliflozin-insulin combination therapy and increased levels of beta-hydroxybutyrate. While insulin dose adjustments should always be individualized, these analyses suggest that, as a general rule, TDD reduction in dapagliflozin-treated patients with T1DM should not exceed 20%, to ensure glycaemic control does not deteriorate and to mitigate the potential for an increased risk of DKA. PMID- 28098427 TI - Emergence of mania in two middle-aged patients with a history of unipolar treatment-refractory depression receiving vagus nerve stimulation. AB - OBJECTIVES: We report on two patients who experienced emergence of full manic symptoms while receiving vagal nerve stimulation (VNS). METHODS: Two patients, both with a well-documented and verified history of longstanding unipolar depression, were initiated on VNS for treatment of their severe major depressive episodes. RESULTS: The two patients had emergence of full manic symptoms after 8 and 9 months of VNS, respectively. Manic symptoms were adequately managed with standard treatments (mood stabilizer and electroconvulsive therapy) and VNS was continued in the two subjects for up to 5 years without any further occurrences of manic/hypomanic episodes. CONCLUSIONS: These cases suggest that some patients with treatment-resistant depression may have a previously unrecognized bipolar disorder, triggered only by VNS. This report also provides evidence that VNS induced manic switches, however serious and troubling to patients, can be managed safely, and that VNS maintenance can be continued for an extended period of time without manic relapses. Although the mechanism of action of VNS is not known, emerging evidence supports central nervous system dopaminergic and possibly cholinergic system involvement. PMID- 28098428 TI - The self-sufficient P450 RhF expressed in a whole cell system selectively catalyses the 5-hydroxylation of diclofenac. AB - P450 monooxygenases are able to catalyze the highly regio- and stereoselective oxidations of many organic molecules. However, the scale-up of such bio oxidations remains challenging due to the often-low activity, level of expression and stability of P450 biocatalysts. Despite these challenges they are increasingly desirable as recombinant biocatalysts, particularly for the production of drug metabolites. Diclofenac is a widely used anti-inflammatory drug that is persistent in the environment along with the 4'- and 5-hydroxy metabolites. Here we have used the self-sufficient P450 RhF (CYP116B2) from Rhodococcus sp. in a whole cell system to reproducibly catalyze the highly regioselective oxidation of diclofenac to 5-hydroxydiclofenac. The product is a human metabolite and as such is an important standard for environmental and toxicological analysis. Furthermore, access to significant quantities of 5 hydroxydiclofenac has allowed us to demonstrate further oxidative degradation to the toxic quinoneimine product. Our studies demonstrate the potential for gram scale production of human drug metabolites through recombinant whole cell biocatalysis. PMID- 28098429 TI - Natural history of nonimmune-mediated thrombocytopenia and acute kidney injury in pediatric open-heart surgery. AB - OBJECTIVE: Thrombocytopenia and acute kidney injury (AKI) are common following pediatric cardiac surgery with cardiopulmonary bypass (CPB). However, the relationship between postoperative nadir platelet counts and AKI has not been investigated in the pediatric population. Our objective was to investigate this relationship and examine independent predictors of AKI. DESIGN: After IRB approval, we performed a retrospective review of the institution's medical records and database. SETTING: This study was performed at a single institution over a 5-year period. PATIENTS: We included patients <21 years of age undergoing cardiac surgery with CPB. INTERVENTIONS: Demographics, laboratory, and surgical characteristics were captured, and clinical event rates were recorded. MEASUREMENTS: Descriptive statistics were used to evaluate platelet and creatinine distributions. T-tests and chi-squared tests were used to compare characteristics among Acute Kidney Injury Network groups. Multivariable logistic and ordinal logistic regression models were used to determine the association of our predictor of interest, postoperative nadir platelet count and AKI. RESULTS: Eight hundred and fourteen patients (23% infants and 23% neonates) were included in the analysis. Postoperative platelet counts decreased 48% from baseline reaching a mean nadir value of 150 * 109 .l-1 on postoperative day 3. AKI occurred in 37% of patients including 13%, 17%, and 6% with Acute Kidney Injury Network stages 1, 2, and 3, respectively. The magnitude of nadir platelet counts correlated with the severity of AKI. Independent predictors of severity of AKI include nadir platelet counts, CPB time, Aristotle score, patient weight, intra operative packed red blood cell transfusion, and having a heart transplant procedure. CONCLUSIONS: In pediatric open-heart surgery, thrombocytopenia and AKI occur commonly following CPB. Our findings show a strong association between nadir platelet counts and the severity of AKI. PMID- 28098430 TI - Behavioral and Electrophysiological Alterations for Reinforcement Learning in Manic and Euthymic Patients with Bipolar Disorder. AB - AIMS: Bipolar disorder is characterized by behavioral changes such as risk-taking and increasing goal-directed activities, which may result from altered reward processing. Patients with bipolar disorder show impaired reward learning in situations that require the integration of reinforced feedback over time. In this study, we examined the behavioral and electrophysiological characteristics of reward learning in manic and euthymic patients with bipolar disorder using a probabilistic reward task. METHODS: Twenty-four manic and 20 euthymic patients with bipolar I disorder and 24 healthy control subjects performed the probabilistic reward task. We assessed response bias (RB) as a preference for the stimulus paired with the more frequent reward and feedback-related negativity (FRN) to correct identification of the rich stimulus. RESULTS: Both manic and euthymic patients showed significantly lower RB scores in the early learning stage (block 1) in comparison with the late learning stage (block 2 or block 3) of the task, as well as significantly lower RB scores in the early stage compared to healthy subjects. Relatively more negative FRN amplitude is elicited by no presentation of an expected reward, compared to that elicited by presentation of expected feedback. The FRN became significantly more negative from the early (block 1) to the later stages (blocks 2 and 3) in both manic and euthymic patients, but not in healthy subjects. Changes in RB scores and FRN amplitudes between blocks 2 and 3 and block 1 correlated positively in healthy controls, but correlated negatively in manic and euthymic patients. The severity of manic symptoms correlated positively with reward learning scores and negatively with the FRN. CONCLUSIONS: These findings suggest that patients with bipolar disorder during euthymic or manic states have behavioral and electrophysiological alterations in reward learning compared to healthy subjects. This dysfunctional reward processing may be related to the abnormal decision-making or altered goal directed activities frequently seen in patients with bipolar disorder. PMID- 28098431 TI - Synthesis and Characterisation of Reduced Graphene Oxide/Bismuth Composite for Electrodes in Electrochemical Energy Storage Devices. AB - A reduced graphene oxide/bismuth (rGO/Bi) composite was synthesized for the first time using a polyol process at a low reaction temperature and with a short reaction time (60 degrees C and 3 hours, respectively). The as-prepared sample is structured with 20-50 nm diameter bismuth particles distributed on the rGO sheets. The rGO/Bi composite displays a combination of capacitive and battery like charge storage, achieving a specific capacity value of 773 C g-1 at a current density of 0.2 A g-1 when charged to 1 V. The material not only has good power density but also shows moderate stability in cycling tests with current densities as high as 5 A g-1 . The relatively high abundance and low price of bismuth make this rGO/Bi material a promising candidate for use in electrode materials in future energy storage devices. PMID- 28098432 TI - A Multi-Mitochondrial Anticancer Agent that Selectively Kills Cancer Cells and Overcomes Drug Resistance. AB - Mitochondria are double-membrane-bound organelles involved mainly in supplying cellular energy, but also play roles in signaling, cell differentiation, and cell death. Mitochondria are implicated in carcinogenesis, and therefore dozens of lethal signal transduction pathways converge on these organelles. Accordingly, mitochondria provide an alternative target for cancer management. In this study, F16, a drug that targets mitochondria, and chlorambucil (CBL), which is indicated for the treatment of selected human neoplastic diseases, were covalently linked, resulting in the synthesis of a multi-mitochondrial anticancer agent, FCBL. FCBL can associate with human serum albumin (HSA) to form an HSA-FCBL nanodrug, which selectively recognizes cancer cells, but not normal cells. Systematic investigations show that FCBL partially accumulates in cancer cell mitochondria to depolarize mitochondrial membrane potential (MMP), increase reactive oxygen species (ROS), and attack mitochondrial DNA (mtDNA). With this synergistic effect on multiple mitochondrial components, the nanodrug can effectively kill cancer cells and overcome multiple drug resistance. Furthermore, based on its therapeutic window, HSA-FCBL exhibits clinically significant differential cytotoxicity between normal and malignant cells. Finally, while drug dosage and drug resistance typically limit first-line mono-chemotherapy, HSA-FCBL, with its ability to compromise mitochondrial membrane integrity and damage mtDNA, is expected to overcome those limitations to become an ideal candidate for the treatment of neoplastic disease. PMID- 28098433 TI - Synthesis and Evaluation of Anti-inflammatory N-Substituted 3,5-Bis(2 (trifluoromethyl)benzylidene)piperidin-4-ones. AB - A total of 24 N-substituted 3,5-bis(2-(trifluoromethyl)benzylidene)piperidin-4 one derivatives were synthesized via aldol condensation, and their anti inflammatory activities were evaluated. These compounds were found to have no significant cytotoxicity against mouse bone marrow cells in vitro. However, some compounds, such as c6 (N-(3-methylbenzoyl)-3,5-bis-(2 (trifluoromethyl)benzylidene)piperidin-4-one) and c10 (N-(2-chlorobenzoyl)-3,5 bis-(2-(trifluoromethyl)benzylidene)piperidin-4-one), displayed potent anti inflammatory activity by inhibiting lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF)-alpha, interleukin-6 (IL-6), IL-1beta, prostaglandin E2 (PGE2), and nitric oxide (NO) production in RAW 264.7 cells. Treatment with c6 or c10 at 2.5 or 10 mg kg-1 significantly decreased the paw edema induced by carrageenan in rats, and the anti-inflammatory effects of these compounds were found to be better than those of celecoxib or indomethacin as well as their parent compound C66 (2,6-bis-(2-(trifluoromethyl)benzylidene)cyclohexanone). Pharmacokinetic analysis indicated that c6 has better bioavailability than curcumin. Therefore, these compounds may be valuable leads for the development of new anti-inflammatory drugs. PMID- 28098434 TI - Method for the unique identification of hyperelastic material properties using full-field measures. Application to the passive myocardium material response. AB - Quantitative measurement of the material properties (eg, stiffness) of biological tissues is poised to become a powerful diagnostic tool. There are currently several methods in the literature to estimating material stiffness, and we extend this work by formulating a framework that leads to uniquely identified material properties. We design an approach to work with full-field displacement data-ie, we assume the displacement field due to the applied forces is known both on the boundaries and also within the interior of the body of interest-and seek stiffness parameters that lead to balanced internal and external forces in a model. For in vivo applications, the displacement data can be acquired clinically using magnetic resonance imaging while the forces may be computed from pressure measurements, eg, through catheterization. We outline a set of conditions under which the least-square force error objective function is convex, yielding uniquely identified material properties. An important component of our framework is a new numerical strategy to formulate polyconvex material energy laws that are linear in the material properties and provide one optimal description of the available experimental data. An outcome of our approach is the analysis of the reliability of the identified material properties, even for material laws that do not admit unique property identification. Lastly, we evaluate our approach using passive myocardium experimental data at the material point and show its application to identifying myocardial stiffness with an in silico experiment modeling the passive filling of the left ventricle. PMID- 28098435 TI - Supramolecular Helical Nanofibers Formed by Achiral Monomers and Their Reversible Sol-Gel Transition. AB - Well-defined supramolecular helical nanofibers have been constructed by a rationally designed achiral monomer in aqueous solution based on the 1:2 host guest combination between cucurbit[8]uril and a 4,4'-bipyridin-1-ium chloride (BPY+ ) salt derivative. The formed nanostructures could be adjusted by varying the concentration of monomer from helical nanofibers to a pH-responsive hydrogel. PMID- 28098437 TI - Opiates for Chronic Pain. PMID- 28098436 TI - Bringing 3D tumor models to the clinic - predictive value for personalized medicine. AB - Current decision-guiding algorithms in cancer drug treatment are based on decades of research and numerous clinical trials. For the majority of patients, this data is successfully applied for a systemic disease management. For a number of patients however, treatment stratification according to clinically based risk criteria will not be sufficient. The most effective treatment options are ideally identified prior to the start of clinical drug therapy. This review will discuss the implementation of three-dimensional (3D) cell culture models as a preclinical testing paradigm for the efficacy of clinical cancer treatment. Patient tumor derived cells in 3D cultures duplicate the individual tumor microenvironment with a minimum of confounding factors. Clinical implementation of such personalized tumor models requires a high quality of methodological and clinical validation comparable to other biomarkers. A non-systematic literature search demonstrated the small number of prospective studies that have been conducted in this area of research. This may explain the current reluctance of many physicians and insurance providers in implementing this type of assay into the clinical diagnostic routine despite potential benefit for patients. Achieving valid and reproducible results with a high level of evidence is central in improving the acceptance of preclinical 3D tumor models. PMID- 28098439 TI - Understanding the proteomes using non-proteomics approaches: Expanding the scope of PROTEOMICS. PMID- 28098440 TI - Corrosion Protection of Copper Using Al2O3, TiO2, ZnO, HfO2, and ZrO2 Atomic Layer Deposition. AB - Atomic layer deposition (ALD) is a viable means to add corrosion protection to copper metal. Ultrathin films of Al2O3, TiO2, ZnO, HfO2, and ZrO2 were deposited on copper metal using ALD, and their corrosion protection properties were measured using electrochemical impedance spectroscopy (EIS) and linear sweep voltammetry (LSV). Analysis of ~50 nm thick films of each metal oxide demonstrated low electrochemical porosity and provided enhanced corrosion protection from aqueous NaCl solution. The surface pretreatment and roughness was found to affect the extent of the corrosion protection. Films of Al2O3 or HfO2 provided the highest level of initial corrosion protection, but films of HfO2 exhibited the best coating quality after extended exposure. This is the first reported instance of using ultrathin films of HfO2 or ZrO2 produced with ALD for corrosion protection, and both are promising materials for corrosion protection. PMID- 28098441 TI - Ultrasmooth Perovskite Film via Mixed Anti-Solvent Strategy with Improved Efficiency. AB - Most antisolvents employed in previous research were miscible with perovskite precursor solution. They always led to fast formation of perovskite even if the intermediate stage existed, which was not beneficial to obtain high quality perovskite films and made the formation process less controllable. In this work, a novel ethyl ether/n-hexane mixed antisolvent (MAS) was used to achieve high nucleation density and slow down the formation process of perovskite, producing films with improved orientation of grains and ultrasmooth surfaces. These high quality films exhibited efficient charge transport at the interface of perovskite/hole transport material and perovskite solar cells based on these films showed greatly improved performance with the best power conversion efficiency of 17.08%. This work also proposed a selection principle of MAS and showed that solvent engineering by designing the mixed antisolvent system can lead to the fabrication of high-performance perovskite solar cells. PMID- 28098442 TI - NASICON-Type Mg0.5Ti2(PO4)3 Negative Electrode Material Exhibits Different Electrochemical Energy Storage Mechanisms in Na-Ion and Li-Ion Batteries. AB - A carbon-coated Mg0.5Ti2(PO4)3 polyanion material was prepared by the sol-gel method and then studied as the negative electrode materials for lithium-ion and sodium-ion batteries. The material showed a specific capacity of 268.6 mAh g-1 in the voltage window of 0.01-3.0 V vs Na+/Na0. Due to the fast diffusion of Na+ in the NASICON framework, the material exhibited superior rate capability with a specific capacity of 94.4 mAh g-1 at a current density of 5A g-1. Additionally, 99.1% capacity retention was achieved after 300 cycles, demonstrating excellent cycle stability. By comparison, Mg0.5Ti2(PO4)3 delivered 629.2 mAh g-1 in 0.01 3.0 V vs Li+/Li0, much higher than that of the sodium-ion cells. During the first discharge, the material decomposed to Ti/Mg nanoparticles, which were encapsulated in an amorphous SEI and Li3PO4 matrix. Li+ ions were stored in the Li3PO4 matrix and the SEI film formed/decomposed in subsequent cycles, contributing to the large Li+ capacity of Mg0.5Ti2(PO4)3. However, the lithium ion cells exhibited inferior rate capability and cycle stability compared to the sodium-ion cells due to the sluggish electrochemical kinetics of the electrode. PMID- 28098443 TI - Fe-Cluster Pushing Electrons to N-Doped Graphitic Layers with Fe3C(Fe) Hybrid Nanostructure to Enhance O2 Reduction Catalysis of Zn-Air Batteries. AB - Non-noble metal catalysts with catalytic activity toward oxygen reduction reaction (ORR) comparable or even superior to that of Pt/C are extremely important for the wide application of metal-air batteries and fuel cells. Here, we develop a simple and controllable strategy to synthesize Fe-cluster embedded in Fe3C nanoparticles (designated as Fe3C(Fe)) encased in nitrogen-doped graphitic layers (NDGLs) with graphitic shells as a novel hybrid nanostructure as an effective ORR catalyst by directly pyrolyzing a mixture of Prussian blue (PB) and glucose. The pyrolysis temperature was found to be the key parameter for obtaining a stable Fe3C(Fe)@NDGL core-shell nanostructure with an optimized content of nitrogen. The optimized Fe3C(Fe)@NDGL catalyst showed high catalytic performance of ORR comparable to that of the Pt/C (20 wt %) catalyst and better stability than that of the Pt/C catalyst in alkaline electrolyte. According to the experimental results and first principle calculation, the high activity of the Fe3C(Fe)@NDGL catalyst can be ascribed to the synergistic effect of an adequate content of nitrogen doping in graphitic carbon shells and Fe-cluster pushing electrons to NDGL. A zinc-air battery utilizing the Fe3C(Fe)@NDGL catalyst demonstrated a maximum power density of 186 mW cm-2, which is slightly higher than that of a zinc-air battery utilizing the commercial Pt/C catalyst (167 mW cm-2), mostly because of the large surface area of the N-doped graphitic carbon shells. Theoretical calculation verified that O2 molecules can spontaneously adsorb on both pristine and nitrogen doped graphene surfaces and then quickly diffuse to the catalytically active nitrogen sites. Our catalyst can potentially become a promising replacement for Pt catalysts in metal-air batteries and fuel cells. PMID- 28098444 TI - Heterogeneous Electrocatalyst with Molecular Cobalt Ions Serving as the Center of Active Sites. AB - Molecular Co2+ ions were grafted onto doped graphene in a coordination environment, resulting in the formation of molecularly well-defined, highly active electrocatalytic sites at a heterogeneous interface for the oxygen evolution reaction (OER). The S dopants of graphene are suggested to be one of the binding sites and to be responsible for improving the intrinsic activity of the Co sites. The turnover frequency of such Co sites is greater than that of many Co-based nanostructures and IrO2 catalysts. Through a series of carefully designed experiments, the pathway for the evolution of the Co cation-based molecular catalyst for the OER was further demonstrated on such a single Co-ion site for the first time. The Co2+ ions were successively oxidized to Co3+ and Co4+ states prior to the OER. The sequential oxidation was coupled with the transfer of different numbers of protons/hydroxides and generated an active Co4+?O fragment. A side-on hydroperoxo ligand of the Co4+ site is proposed as a key intermediate for the formation of dioxygen. PMID- 28098445 TI - Circular and Chainlike Copper(II)-Lanthanide(III) Complexes Generated by Assembly Reactions of Racemic and Chiral Copper(II) Cross-Linking Ligand Complexes with LnIII(NO3)3.6H2O (LnIII = GdIII, TbIII, DyIII). AB - The 1:1 assembly reaction of the racemic form of the cross-linking ligand complex Na[CuIILdpen(1R2R/1S2S)] with LnIII(NO3)3.6H2O gave the centrosymmetric circular (CuIILnIII)2 complex [CuIILdpen(1R2R/1S2S)LnIII(NO3)2]2 (1Ln: Ln = Gd, Tb, Dy), while the reaction of the enantiopure form Na[CuIILdpen(1R2R)] with LnIII(NO3)3.6H2O gave the chiral chainlike (CuIILnIII)1infinity complex [CuIILdpen(1R2R)LnIII(NO3)2(CH3CN)]1infinity.CH3CN (2Ln: Ln = Gd, Tb, Dy), where {CuIILdpen(1R2R)}- is (N-((1R,2R)-2-(((E)-3-ethoxy-2-oxybenzylidene)amino)-1,2 diphenylethyl)-2-oxybenzamide)copper(II) and {CuIILdpen(1R2R/1S2S)}- is the racemic mixture of {CuIILdpen(1R2R)}- and {CuIILdpen(1S2S)}-. The copper(II) component functions as a cross-linking ligand complex and bridges two LnIII ions at two phenoxo oxygen atoms and one ethoxy oxygen atom, as well as at an amido oxygen atom. For 1Ln, two binuclear species of [CuIILdpen(1R2R)LnIII(NO3)2] and [CuIILdpen(1S2S)LnIII(NO3)2] with opposite chiralities are linked by two amido oxygen atoms O3 and O3* to form a centrosymmetric circular structure with Gd-Cu = 3.370(1) A and Gd-Cu* = 5.627(1) A. For 2Ln, binuclear species with the same chirality are bridged by Gd-O3* = 2.228(5) A to form a chiral chainlike structure with Gd-Cu = 3.3348(9) A and Gd-Cu* = 6.2326(9) A. The bridged angles through the amido group of Gd-O3*?C7* are 133.9(5) and 177.6(4) degrees for 1Gd and 2Gd, respectively. The magnetic susceptibilities of 1Gd and 2Gd were analyzed by the spin-only Hamiltonian on the basis of the circular tetranuclear (-CuIIGdIII-)2 and linear chainlike (-CuIIGdIII-)1infinity structures, respectively. The CuII GdIII magnetic interactions through two phenoxo bridges and a three-atom N-C?O bridge, J1 and J2, are both ferromagnetic to be J1 = +4.6 cm-1 and J2 = +1.8 cm-1 for 1Gd and J1 = +4.2 cm-1 and J2 = +0.037 cm-1 for 2Gd. The J2 value of 2Gd is much smaller than that of 1Gd. When the temperature was lowered, 1Ln and 2Ln (Ln = Tb, Dy) showed a decrease in the chiMT vs T plot due to crystal field effects on the LnIII ion (Stark splitting) and an increase due to the ferromagnetic CuII LnIII interaction. The magnetization values of 1Ln and 2Ln (Ln = Tb, Dy) without liquid paraffin are considerably larger than the corresponding values with liquid paraffin, indicating the presence of strong magnetic anisotropy. 1Tb and 1Dy showed frequency dependence of ac magnetic susceptibility under zero external dc magnetic field, showing the behavior of single-molecule magnets (SMMs). 2Tb and 2Dy showed no frequency dependence under a zero external magnetic field but showed a meaningful frequency dependence under an external magnetic field. Their energy barriers, Delta/kB, estimated by the Arrhenius plots are 29.4(6) and 20.6(3) K for 1Tb and 2Tb under dc bias fields of 0 and 1000 Oe, respectively, and those of 1Dy and 2Dy are 13.1(9) K and 16.4(2) K under dc bias fields of 0 and 1000 Oe, respectively. PMID- 28098446 TI - Determination of Carbonyl Compounds in Cork Agglomerates by GDME-HPLC-UV: Identification of the Extracted Compounds by HPLC-MS/MS. AB - A new approach is proposed for the extraction and determination of carbonyl compounds in solid samples, such as wood or cork materials. Cork products are used as building materials due to their singular characteristics; however, little is known about its aldehyde emission potential and content. Sample preparation was done by using a gas-diffusion microextraction (GDME) device for the direct extraction of volatile aldehydes and derivatization with 2,4 dinitrophenylhydrazine. Analytical determination of the extracts was done by HPLC UV, with detection at 360 nm. The developed methodology proved to be a reliable tool for aldehyde determination in cork agglomerate samples with suitable method features. Mass spectrometry studies were performed for each sample, which enabled the identification, in the extracts, of the derivatization products of a total of 13 aldehydes (formaldehyde, acetaldehyde, furfural, propanal, 5-methylfurfural, butanal, benzaldehyde, pentanal, hexanal, trans-2-heptenal, heptanal, octanal, and trans-2-nonenal) and 4 ketones (3-hydroxy-2-butanone, acetone, cyclohexanone, and acetophenone). This new analytical methodology simultaneously proved to be consistent for the identification and determination of aldehydes in cork agglomerates and a very simple and straightforward procedure. PMID- 28098448 TI - New Insights into Trihalomethane and Haloacetic Acid Formation Potentials: Correlation with the Molecular Composition of Natural Organic Matter in Source Water. AB - Natural organic matter (NOM) represents the major source of precursors for disinfection byproducts (DBPs), such as trihalomethanes (THMs) and haloacetic acids (HAAs), formed during disinfection of drinking water, but the molecular composition and reactivity of NOM remain not well understood. In this study, electrospray ionization coupled to Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) was used to characterize the molecular composition of NOM of 20 source waters taken across China for the purpose of determining the major precursors of THMs and HAAs at molecular level. It was found that there is a core of NOM compositions that are ubiquitous in different source waters, which is supposed to be more relevant for NOM quality. Formation potentials (FP) of THMs and HAAs were determined for NOM from different source waters during chlorination. Spearman's rank correlation was used to link THMFP and HAAFP with the individual molecular composition of NOM. Significant correlation (P < 0.001) was found between DBPFP and the NOM molecules with a high O/C ratio and low H/C ratio, indicating these molecules could contribute greatly to the formation of THMs and HAAs during chlorination. The link of THMFP and HAAFP with individual NOM molecules may allow us to develop more effective treatment strategies to achieve the drinking water safety objective: effective disinfection of waterborne pathogens while minimizing toxic DBPs. PMID- 28098447 TI - The Stories Tryptophans Tell: Exploring Protein Dynamics of Heptosyltransferase I from Escherichia coli. AB - Heptosyltransferase I (HepI) catalyzes the addition of l-glycero-beta-d-manno heptose to Kdo2-Lipid A, as part of the biosynthesis of the core region of lipopolysaccharide (LPS). Gram-negative bacteria with gene knockouts of HepI have reduced virulence and enhanced susceptibility to hydrophobic antibiotics, making the design of inhibitors of HepI of interest. Because HepI protein dynamics are partially rate-limiting, disruption of protein dynamics might provide a new strategy for inhibiting HepI. Discerning the global mechanism of HepI is anticipated to aid development of inhibitors of LPS biosynthesis. Herein, dynamic protein rearrangements involved in the HepI catalytic cycle were probed by combining mutagenesis with intrinsic tryptophan fluorescence and circular dichroism analyses. Using wild-type and mutant forms of HepI, multiple dynamic regions were identified via changes in Trp fluorescence. Interestingly, Trp residues (Trp199 and Trp217) in the C-terminal domain (which binds ADP-heptose) are in a more hydrophobic environment upon binding of ODLA to the N-terminal domain. These residues are adjacent to the ADP-heptose binding site (with Trp217 in van der Waals contact with the adenine ring of ADP-heptose), suggesting that the two binding sites interact to report on the occupancy state of the enzyme. ODLA binding was also accompanied by a significant stabilization of HepI (heating to 95 degrees C fails to denature the protein when it is in the presence of ODLA). These results suggest that conformational rearrangements, from an induced fit model of substrate binding to HepI, are important for catalysis, and the disruption of these conformational dynamics may serve as a novel mechanism for inhibiting this and other glycosyltransferase enzymes. PMID- 28098449 TI - Targeting Type 2 Diabetes with C-Glucosyl Dihydrochalcones as Selective Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: Synthesis and Biological Evaluation. AB - Inhibiting glucose reabsorption by sodium glucose co-transporter proteins (SGLTs) in the kidneys is a relatively new strategy for treating type 2 diabetes. Selective inhibition of SGLT2 over SGLT1 is critical for minimizing adverse side effects associated with SGLT1 inhibition. A library of C-glucosyl dihydrochalcones and their dihydrochalcone and chalcone precursors was synthesized and tested as SGLT1/SGLT2 inhibitors using a cell-based fluorescence assay of glucose uptake. The most potent inhibitors of SGLT2 (IC50 = 9-23 nM) were considerably weaker inhibitors of SGLT1 (IC50 = 10-19 MUM). They showed no effect on the sodium independent GLUT family of glucose transporters, and the most potent ones were not acutely toxic to cultured cells. The interaction of a C glucosyl dihydrochalcone with a POPC membrane was modeled computationally, providing evidence that it is not a pan-assay interference compound. These results point toward the discovery of structures that are potent and highly selective inhibitors of SGLT2. PMID- 28098450 TI - Serum Amyloid P Component (SAP) Interactome in Human Plasma Containing Physiological Calcium Levels. AB - The pentraxin serum amyloid P component (SAP) is secreted by the liver and found in plasma at a concentration of approximately 30 mg/L. SAP is a 25 kDa homopentamer known to bind both protein and nonprotein ligands, all in a calcium dependent manner. The function of SAP is unclear but likely involves the humoral innate immune system spanning the complement system, inflammation, and coagulation. Also, SAP is known to bind to the generic structure of amyloid deposits and possibly to protect them against proteolysis. In this study, we have characterized the SAP interactome in human plasma containing the physiological Ca2+ concentration using SAP affinity pull-down and co-immunoprecipitation experiments followed by mass spectrometry analyses. The analyses resulted in the identification of 33 proteins, of which 24 were direct or indirect interaction partners not previously reported. The SAP interactome can be divided into categories that include apolipoproteins, the complement system, coagulation, and proteolytic regulation. PMID- 28098451 TI - Effect of Injection Layer Sub-Bandgap States on Electron Injection in Organic Light-Emitting Diodes. AB - It is generally considered that the injection of charges into an active layer of an organic light-emitting diode (OLED) is solely determined by the energetic injection barrier formed at the device interfaces. Here, we demonstrate that the density of surface states of the electron-injecting ZnO layer has a profound effect on both the charge injection and the overall performance of the OLED device. Introducing a dopant into ZnO reduces both the energy depth and density of surface states without altering the position of the energy levels-thus, the magnitude of the injection barrier formed at the organic/ZnO interface remains unchanged. Changes observed in the density of surface states result in an improved electron injection and enhanced luminescence of the device. We implemented a numerical simulation, modeling the effects of energetics and the density of surface states on the electron injection, demonstrating that both contributions should be considered when choosing the appropriate injection layer. PMID- 28098452 TI - A Perspective on Crocus sativus L. (Saffron) Constituent Crocin: A Potent Water Soluble Antioxidant and Potential Therapy for Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most common form of dementia, in which the death of brain cells causes memory loss and cognitive decline. Several factors are thought to play roles in the development and course of AD. Existing medical therapies only modestly alleviate and delay cognitive symptoms. Current research has been focused on developing antibodies to remove the aggregates of amyloid beta (Abeta) and tau protein. This approach has achieved removal of Abeta; however, no cognitive improvement in AD patients has been reported. The biological properties of saffron, the dry stigma of the plant Crocus sativus L., and particularly its main constituent crocin, have been studied extensively for many conditions including dementia and traumatic brain injury. Crocin is a unique antioxidant because it is a water-soluble carotenoid. Crocin has shown potential to improve learning and memory as well as protect brain cells. A search of the studies on saffron and crocin that have been published in recent years for their impact on AD as well as crocin's effects on Abeta and tau protein has been conducted. This review demonstrates that crocin exhibits multifunctional protective activities in the brain and could be a promising agent applied as a supplement or drug for prevention or treatment of AD. PMID- 28098453 TI - Surface-Engineered Multifunctional Eu:Gd2O3 Nanoplates for Targeted and pH Responsive Drug Delivery and Imaging Applications. AB - In this paper, we report the synthesis of surface-engineered multifunctional Eu:Gd2O3 triangular nanoplates with small size and uniform shape via a high temperature solvothermal technique. Surface engineering has been performed by a one-step polyacrylate coating, followed by controlled conjugation chemistry. This creates the desired number of surface functional groups that can be used to attach folic acid as a targeting ligand on the nanoparticle surface. To specifically deliver the drug molecules in the nucleus, the folate density on the nanoparticle surface has been kept low. We have also modified the drug molecules with terminal double bond and ester linkage for the easy conjugation of nanoparticles. The nanoparticle surface was further modified with free thiols to specifically attach the modified drug molecules with a pH-responsive feature. High drug loading has been encountered for both hydrophilic drug daunorubicin (~69% loading) and hydrophobic drug curcumin (~75% loading) with excellent pH responsive drug release. These nanoparticles have also been used as imaging probes in fluorescence imaging. Some preliminary experiments to evaluate their application in magnetic resonance imaging have also been explored. A detailed fluorescence imaging study has confirmed the efficient delivery of drugs to the nuclei of cancer cells with a high cytotoxic effect. Synthesized surface engineered nanomaterials having small hydrodynamic size, excellent colloidal stability, and high drug-loading capacity, along with targeted and pH-responsive delivery of dual drugs to the cancer cells, will be potential nanobiomaterials for various biomedical applications. PMID- 28098454 TI - Highly Sensitive Wearable Textile-Based Humidity Sensor Made of High-Strength, Single-Walled Carbon Nanotube/Poly(vinyl alcohol) Filaments. AB - Textile-based humidity sensors can be an important component of smart wearable electronic-textiles and have potential applications in the management of wounds, bed-wetting, and skin pathologies or for microclimate control in clothing. Here, we report a wearable textile-based humidity sensor for the first time using high strength (~750 MPa) and ultratough (energy-to-break, 4300 J g-1) SWCNT/PVA filaments via a wet-spinning process. The conductive SWCNT networks in the filaments can be modulated by adjusting the intertube distance by swelling the PVA molecular chains via the absorption of water molecules. The diameter of a SWCNT/PVA filament under wet conditions can be as much as 2 times that under dry conditions. The electrical resistance of a fiber sensor stitched onto a hydrophobic textile increases significantly (by more than 220 times) after water sprayed. Textile-based humidity sensors using a 1:5 weight ratio of SWCNT/PVA filaments showed high sensitivity in high relative humidity. The electrical resistance increases by more than 24 times in a short response time of 40 s. We also demonstrated that our sensor can be used to monitor water leakage on a high hydrophobic textile (contact angle of 115.5 degrees ). These smart textiles will pave a new way for the design of novel wearable sensors for monitoring blood leakage, sweat, and underwear wetting. PMID- 28098455 TI - Angular Dependence of Ionization by Circularly Polarized Light Calculated with Time-Dependent Configuration Interaction with an Absorbing Potential. AB - The angular dependence of ionization by linear and circularly polarized light has been examined for N2, NH3, H2O, CO2, CH2O, pyrazine, methyloxirane, and vinyloxirane. Time-dependent configuration interaction with single excitations and a complex absorbing potential was used to simulate ionization by a seven cycle 800 nm cosine squared pulse with intensities ranging from 0.56 * 1014 to 5.05 * 1014 W cm-2. The shapes of the ionization yield for linearly polarized light can be understood primarily in terms of the nodal structure of the highest occupied orbitals. Depending on the orbital energies, ionization from lower-lying orbitals may also make significant contributions to the shapes. The shapes of the ionization yield for circularly polarized light can be readily explained in terms of the shapes for linearly polarized light. Averaging the results for linear polarization over orientations perpendicular to the direction of propagation yields shapes that are in very good agreement with direct calculations of the ionization yield by circularly polarized light. PMID- 28098456 TI - Ultrafast Electronic Relaxation through a Conical Intersection: Nonadiabatic Dynamics Disentangled through an Oscillator Strength-Based Diabatization Framework. AB - We employ surface hopping trajectories to model the short-time dynamics of gas phase and partially solvated 4-(N,N-dimethylamino)benzonitrile (DMABN), a dual fluorescent molecule that is known to undergo a nonadiabatic transition through a conical intersection. To compare theory vs time-resolved fluorescence measurements, we calculate the mixed quantum-classical density matrix and the ensemble averaged transition dipole moment. We introduce a diabatization scheme based on the oscillator strength to convert the TDDFT adiabatic states into diabatic states of La and Lb character. Somewhat surprisingly, we find that the rate of relaxation reported by emission to the ground state is almost 50% slower than the adiabatic population relaxation. Although our calculated adiabatic rates are largely consistent with previous theoretical calculations and no obvious effects of decoherence are seen, the diabatization procedure introduced here enables an explicit picture of dynamics in the branching plane, raising tantalizing questions about geometric phase effects in systems with dozens of atoms. PMID- 28098457 TI - Surface Forces and Rheology of Titanium Dioxide in the Presence of Dicarboxylic Acids: From Molecular Interactions to Yield Stress. AB - The surface forces and yield stress of titanium dioxide were measured in the presence of dicarboxylic acids in order to understand the molecular basis for the observed rheological response. The yield stress was measured using the static vane technique, and the surface forces were characterized using an atomic force microscope. The trans and cis isomers of butenedioic acid (fumaric and maleic acids, respectively) were chosen as the relative orientation of the carboxylic groups differs substantially. This enables us to test the hypothesis that an increase in adhesion leads to an increase in yield stress as a consequence of the dicarboxylic acids participating in highly directed bridging. Unlike fumaric acid, maleic acid caused a yield stress reduction in the titanium dioxide suspensions. Surface force measurements between approaching surfaces found that at low pH, fumaric and maleic acids did not induce any additional attraction between the titanium dioxide surfaces. However, significant differences in adhesion were observed, which can be explained in terms of the configuration of the acids at the surface. The observations are consistent with highly directed bridging in the presence of fumaric acid but not in the presence of maleic acid due to the molecular architecture of the dicarboxylic acids. PMID- 28098458 TI - Sequence of Silicon Monolayer Structures Grown on a Ru Surface: from a Herringbone Structure to Silicene. AB - Silicon-based two-dimensional (2D) materials are uniquely suited for integration in Si-based electronics. Silicene, an analogue of graphene, was recently fabricated on several substrates and was used to make a field-effect transistor. Here, we report that when Ru(0001) is used as a substrate, a range of distinct monolayer silicon structures forms, evolving toward silicene with increasing Si coverage. Low Si coverage produces a herringbone structure, a hitherto undiscovered 2D phase of silicon. With increasing Si coverage, herringbone elbows evolve into silicene-like honeycomb stripes under tension, resulting in a herringbone-honeycomb 2D superlattice. At even higher coverage, the honeycomb stripes widen and merge coherently to form silicene in registry with the substrate. Scanning tunneling microscopy (STM) was used to image the structures. The structural stability and electronic properties of the Si 2D structures, the interaction between the Si 2D structures and the Ru substrate, and the evolution of the distinct monolayer Si structures were elucidated by density functional theory (DFT) calculations. This work paves the way for further investigations of monolayer Si structures, the corresponding growth mechanisms, and possible functionalization by impurities. PMID- 28098459 TI - Two-Dimensional SnO Anodes with a Tunable Number of Atomic Layers for Sodium Ion Batteries. AB - We have systematically changed the number of atomic layers stacked in 2D SnO nanosheet anodes and studied their sodium ion battery (SIB) performance. The results indicate that as the number of atomic SnO layers in a sheet decreases, both the capacity and cycling stability of the Na ion battery improve. The thinnest SnO nanosheet anodes (two to six SnO monolayers) exhibited the best performance. Specifically, an initial discharge and charge capacity of 1072 and 848 mAh g-1 were observed, respectively, at 0.1 A g-1. In addition, an impressive reversible capacity of 665 mAh g-1 after 100 cycles at 0.1 A g-1 and 452 mAh g-1 after 1000 cycles at a high current density of 1.0 A g-1 was observed, with excellent rate performance. As the average number of atomic layers in the anode sheets increased, the battery performance degraded significantly. For example, for the anode sheets with 10-20 atomic layers, only a reversible capacity of 389 mAh g-1 could be obtained after 100 cycles at 0.1 A g-1. Density functional theory calculations coupled with experimental results were used to elucidate the sodiation mechanism of the SnO nanosheets. This systematic study of monolayer dependent physical and electrochemical properties of 2D anodes shows a promising pathway to engineering and mitigating volume changes in 2D anode materials for sodium ion batteries. It also demonstrates that ultrathin SnO nanosheets are promising SIB anode materials with high specific capacity, stable cyclability, and excellent rate performance. PMID- 28098460 TI - Sulfate-Mediated End-to-End Assembly of Gold Nanorods. AB - There is interest in the controlled aggregation of gold nanorods (GNRs) for the production of extended nanoassemblies. Prior studies have relied upon chemical modification of the GNR surface to achieve a desired final aggregate structure. Herein we illustrate that control of electrolyte composition can facilitate end to-end assembly of cetyltrimethylammonium-bromide-coated (CTAB) GNRs. By adjusting either the sulfate anion concentration or the exposure time it is possible to connect GNRs in chain-like assemblies. In contrast, end-to-end assembly was not observed in control experiments using monovalent chloride salts. We attribute the end-to-end assembly to the localized association of sulfate with exposed quaternary ammonium head groups of CTAB at the nanorod tip. To quantify the assembly kinetics, visible-near-infrared extinction spectra were collected over a predetermined time period, and the colloidal behavior of the GNR suspensions was interpreted using plasmon band analysis. Transmission electron microscopy and atomic force microscopy results support the conclusions reached via plasmon band analysis, and the colloidal behavior is consistent with Derjaguin-Landau-Verwey-Overbeek theory. PMID- 28098461 TI - Readily Accessible Unsymmetrical Unsaturated 2,6-Diisopropylphenyl N-Heterocyclic Carbene Ligands. Applications in Enantioselective Catalysis. AB - A new multicomponent procedure was applied to the synthesis of (a)chiral bulky unsymmetrical unsaturated 2,6-diisopropylphenyl N-heterocyclic carbene (NHC) precursors with excellent selectivity (up to 95%) and good yields. This approach offers access to new chiral NHC ligands, which have found successful applications in both copper-catalyzed asymmetric allylic alkylation and copper-catalyzed asymmetric borylation. PMID- 28098462 TI - Total Synthesis of Resolvin D5. AB - Resolvin D5 (RvD5) is a metabolite of docosahexanoic acid with anti-inflammatory activity that has not yet been thoroughly investigated because of its low biological availability. A synthetic route to optically active RvD5 was developed by assembling the C1-C10 aldehyde, C11-C13 phosphonium salt, and C14-C22 aldehyde building blocks. The aldehyde fragments were prepared by Sharpless asymmetric epoxidation of corresponding racemic (E)-1-TMS-1-alken-3-ols followed by reaction of the TBS ethers of the resulting epoxy alcohols with Et2AlCN and DIBAL reduction of the (E)-1-cyano-1-alken-3-ol derivatives. The C14-C22 aldehyde was connected with the C11-C13 fragment, i.e., [TBSO(CH2)3PPh3]+ Br-, by Wittig reaction. The resulting C11-C22 intermediate was converted to the phosphonium salt, which was attached to the C1-C10 aldehyde by Wittig reaction to yield the structure of RvD5. PMID- 28098464 TI - Clustering of Uracil Molecules on Ice Nanoparticles. AB - We generate a molecular beam of ice nanoparticles (H2O)N, N ~ 130-220, which picks up several individual gas phase uracil (U) or 5-bromouracil (BrU) molecules. The mass spectra of the doped nanoparticles prove that the uracil and bromouracil molecules coagulate to clusters on the ice nanoparticles. Calculations of U and BrU monomers and dimers on the ice nanoparticles provide theoretical support for the cluster formation. The (U)mH+ and (BrU)mH+ intensity dependencies on m extracted from the mass spectra suggest a smaller tendency of BrU to coagulate compared to U, which is substantiated by a lower mobility of bromouracil on the ice surface. The hydrated Um.(H2O)nH+ series are also reported and discussed. On the basis of comparison with the previous experiments, we suggest that the observed propensity for aggregation on ice nanoparticles is a more general trend for biomolecules forming strong hydrogen bonds. This, together with their mobility, leads to their coagulation on ice nanoparticles which is an important aspect for astrochemistry. PMID- 28098463 TI - Absolute Configuration of Native Oligomeric Proanthocyanidins with Dentin Biomodification Potency. AB - The structurally complex oligomeric proanthocyanidins (OPACs) are promising biomimetic agents, capable of strengthening the macromolecular backbone of teeth via intermolecular and intermicrofibrillar cross-linking. This study establishes analytical methods capable of determining the absolute configuration of the catechin-type monomeric units of underivatized OPACs. This preserves the capacity of their biological evaluation, aimed at understanding the inevitably stereospecific interactions between the OPACs and dentin collagen. Guided by dental bioassays (modulus of elasticity, long-term stability), two new trimeric and tetrameric A-type OPACs were discovered as dentin biomodifiers from pine (Pinus massoniana) bark: epicatechin-(2beta->O->7,4beta->8)-epicatechin-(2beta->O >7,4beta->8)-catechin (5) and epicatechin-(2beta->O->7,4beta->8)-epicatechin (2beta->O->7,4beta->6)-epicatechin-(2beta->O->7,4beta->8)-catechin (6), respectively. Combining 1D/2D NMR, HRESIMS, ECD, 1H iterative full spin analysis (HiFSA), and gauge-invariant atomic orbital (GIAO) delta calculations, we demonstrate how 13C NMR chemical shifts (diastereomeric building blocks (A-type dimers)) empower the determination of the absolute configuration of monomeric units in the higher oligomers 5 and 6. Collectively, NMR with ECD reference data elevates the level of structural information achievable for these structurally demanding molecules when degradation analysis is to be avoided. Considering their numerous and deceptively subtle, but 3D impactful, structural variations, this advances the probing of OPAC chemical spaces for species that bind selectively to collagenous and potentially other biologically important biomacromolecules. PMID- 28098465 TI - Rejection of Commonly Used Electrolytes in Asymmetric Flow Field Flow Fractionation: Effects of Membrane Molecular Weight Cutoff Size, Fluid Dynamics, and Valence of Electrolytes. AB - Asymmetric flow field flow fractionation (AF4) is an efficient size-based separation technique for the characterization of submicron size particulates. In AF4, membranes having various molecular weight cutoff sizes are used as a barrier to retain particles while allowing the carrier fluid containing electrolytes to permeate. Here, we have hypothesized that electrolyte rejection by the barrier membrane leads to the accumulation of electrolytes in the channel during operation. Electrolyte accumulation can cause various adverse effects that can lead to membrane fouling. An instrument setup containing a conductivity detector was assembled, and the rejection of commonly used carrier electrolytes such as trisodium citrate, ethylenediaminetetraacetic acid, sodium chloride, and ammonium carbonate was evaluated by varying the concentration, cross-flow rate, focusing flow rate, membrane material type, and cutoff sizes. The results showed that electrolyte rejection increased with a decrease in the electrolyte concentration and the molecular weight cutoff size (pore size) or with an increase in the charge state of the anion in the carrier electrolytes. We proposed an electrostatic repulsion-based rejection mechanism and verified it with the measurement of the rejection rate while varying the electrolyte concentration in the running media. PMID- 28098466 TI - Lithography-Free Miniaturization of Resistive Nonvolatile Memory Devices to the 100 nm Scale by Glancing Angle Deposition. AB - The scaling of nonvolatile memory (NVM) devices based on resistive filament switching to below a 100 nm2 footprint area without employing cumbersome lithography is demonstrated. Nanocolumns of the organic semiconductor 4,4-bis[N (1-naphthyl)-N-phenyl-amino]diphenyl (alpha-NPD) were grown by glancing angle deposition on a silver electrode. Individual NVM devices were electrically characterized by conductive atomic force microscopy with the tip of a conductive cantilever serving as second electrode. The resistive switching mechanism is unambiguously attributed to Ag filament formation between the electrodes. This sets the upper limit for the filament diameter to well below 100 nm. Full functionality of these NVM nanodevices is evidenced, revealing a potential memory density of >1 GB/cm2 in appropriate architectures. PMID- 28098467 TI - Modular Two-Step Approach for the Stereodivergent Synthesis of 1,3-Diamines with Three Continuous Stereocenters. AB - A two-step reaction sequence for the highly stereodivergent construction of 1,3 diamines with three continuous stereocenters is reported. This novel method enables the controlled synthesis of any given diastereomer of the 1,3-diamine scaffold from a simple set of starting materials in a highly modular manner. The disclosed approach is based on the reaction of an enamide with an in situ generated N-acylimine followed by a subsequent trapping of the generated intermediate with a suitable nucleophile. By careful choice of starting materials, reagents, and reaction conditions, each stereocenter can be constructed in a highly selective fashion. PMID- 28098468 TI - [How to treat an idiopatic scoliosis]. AB - Scoliosis is a three-dimensional deformity of the spine. In its most common form idiopathic scoliosis (70 to 80 % of cases), the causes are unknown. It is defined as a curve of at least 10 degrees , measured on a standing radiograph using the Cobb technique. A severe form of scoliosis is more commonly found in females. Typically scoliosis does not cause any health problems during growth (except for extreme cases). Patients are generally treated in an attempt to halt the progressive nature of the deformity. We present a treatment of different kind of curves.By the end of growth, the risk of health and social problems in adulthood increases significantly. Problems include reduced quality of life, disability, pain, increased cosmetic deformity, functional limitations, sometimes pulmonary problems, and progression during adulthood. It is necessary to start with the treatment ASAP, because the management of scoliosis includes the prevention of secondary problems associated with the deformity. PMID- 28098469 TI - [Primary malignant bone tumors in children possibilities of limb-saving surgery using allografts]. AB - Therapy of primary malignant bone tumors is always multimodal and requires close cooperation of oncologist, orthopedic surgeon, radiologist and others. In our article, we provide a brief overview of the most common malignant bone tumors in pediatric patients and summarize the commonly used therapeutic procedures. Despite advances in cancer treatment radical surgical resection of the tumor is still necessary. If possible, it should be complete removal of the affected structures, made in terms of the so-called limb-saving (limb-sparing) surgery that preserves the shape and function of the affected limb to the fullest extent possible. In addition the resection must be done at the same time with substitution of the removed bone. Bone grafts, both autografts and allografts, are used in majority of solutions. We also discuss the comparison of different approaches of limb-saving surgery compared to ablative procedures. PMID- 28098470 TI - [Femoroacetabular impingement treatment options]. AB - Femoroacetabular impingement syndrome is a very common hip pathology that is responsible for hip pain in patients under 40 years of age. Anatomic changes in hip joint cause labral tears and cartilage dysfunction, both of these conditions cause severe hip pain and often lead to hip arthritis. This syndrome is very common in the population, but very often misdiagnosed and undertreated.The main treatment option is surgical treatment; conservative treatment alone is not successful. There are many surgical procedures that may be chosen according to the degree of hip pathology. In this article we present treatment options for femoroacetabular impingement syndrome and our results. Recently one of the main treatment options is hip arthroscopy we have very good experience and results with this method. PMID- 28098471 TI - [Limb shortening in the management of leg length discrepancy]. AB - Limb shortening is an option to manage leg length discrepancy. Before skeletal maturity, small length discrepancy between 2 and 5 cm can be corrected by open or closed epiphyseodesis or stapling. All these procedures require exact timing of surgery. In skeletally matured patients is shortening of the femur considered safer than tibial shortening. Length discrepancy more than 10 cm should be corrected either by prolongation or one timed procedures concerning shortening osteotomy of longer limb followed with excised bone segment and its implantation in the contralateral limb. Presented review summarizes advantages and disadvantages of both operational concepts (shortening and lengthening) in leg length discrepancy management. PMID- 28098472 TI - [Avascular necrosis of the femoral head]. AB - Avascular necrosis of the femoral head in adults is not common, but not too rare diseases. In orthopedic practice, it is one of the diseases that are causing implantation of hip replacement at a relatively early age. In the early detection and initiation of therapy can delay the implantation of prosthesis for several years, which is certainly more convenient for the patient and beneficial. This article is intended to acquaint the reader with the basic diagnostic procedures and therapy. PMID- 28098473 TI - [Rehabilitation after total knee and hip arthroplasty]. AB - The main purpose of total hip replacement is to relieve hip pain and recover the lost mobility of the joint. The postoperative functionality of the hip endoprosthesis is closely related to proper physiotherapy. A good range of motion, sufficient pain reduction and minimum disruption to the muscle tissues are conditions allowing the patients to perform individualized muscle strengthening exercises and to exercise the newly gained mobility, following practice sessions during the early postoperative period still in hospital. The authors describe the individual fazes of the physiotherapy and summarize the principles, which lead to a successful rehabilitation of the patient and his early recovery as well as return to normal life activities. PMID- 28098474 TI - [UHMWPE - polyethylene for articulating surfaces of joint replacements]. AB - The introduction of artificial joint replacement constitutes a breakthrough method of treatment for severe joint disease for millions of people worldwide.Annual increase in the number of primary replacement and also increasing demands on the longevity of joint replacements are leading to increased demands on wear resistance of articular surface. Ultra-high molecular weight polyethylene (UHMWPE) is still most commonly used material for the production of articular surface. It was introduced into clinical practice in the 60s of the 20th century. Physical-chemical properties of UHMWPE are subject of many studies. These lead gradually to its improvement in terms of higher wear resistance while maintaining the stability against oxidative degradation.The main objective of this review is to summarize the basic properties of high-molecular weight polyethylene which are important for its use in orthopaedic practice and to explain the possibilities of its modification and sterilization. Knowledge of the latest trends about this material helps to orthopaedic surgeons get oriented in the issues and then to choose for their patients implants with the highest implant longevity. PMID- 28098475 TI - [Artificial bone substitutes]. AB - Bone tissue substitutes are divided into basic classification with its pros and cons described. Arteficial bone grafts are especially pointed out in article, publishing our own experience with two specific synthetic preps. Finally there is a blink in the near future of bone tissue augmentation. PMID- 28098476 TI - [The first experience with dabigatran antidote in the University Hospital Pilsen]. AB - Dabigatran (Pradaxa, Boehringer Ingelheim) is the first direct oral thrombin (FIIa) inhibitor. It is indicated for thromboprophylaxis in patients undergoing elective total replacement hip or knee joint surgery or for the primary or secondary prophylaxis of elderly patients with non-valvular atrial fibrillation or for deep vein thrombosis and pulmonary embolism treatment and prophylaxis. Idarucizumab (Praxbind, Boehringer Ingelheim) is a specific monoclonal antibody fragment indicated in patients treated with dabigatran. It is recommended when reversal of anticoagulant effect of dabigatran is needed especially in cases of life-threatening bleeding, for emergency surgery or urgent procedures purposes. In this article, there is a summary of our clinical and laboratory experience with reversal effect of idarucizumab in our five patients. PMID- 28098477 TI - [Palliative care in Czech Republic in 2016]. AB - In the Czech Republic more than 70,000 patients with chronic incurable diseases need palliative care each year. In 50,000 this need is manageable in the context of general palliative care, 20,000 patients would greatly benefited from specialized palliative care. Most chronically ill patients (> 60 %) died in acute or post acute inpatient health care facilities. Here s the availability and quality of palliative care varies substantially. Inpatient hospices provide end of life palliative care to less than 3000 patients each year. Outpatient and mobile specialized palliative care services are available only to a few hundreds of patients.In the year 2016 palliative care at the appropriate professional level ("state of art") is not a generally available and guaranteed within Czech health care and social system. We perceive an urgent need for the systematic development of general and specialized palliative care at the level of education, healthcare organization and the development of new health and social services. PMID- 28098478 TI - The Work-Family Interface and Sleep Quality. AB - OBJECTIVE: This article investigated whether work-to-family conflict (WFC) and work-to-family enrichment (WFE) were associated with employee sleep quality. WFC and WFE reflect the potential for experiences at work to negatively and positively influence nonworking life respectively, and may have implications for sleep quality. In this article, we examined whether WFC and WFE were linked with sleep quality via hedonic balance (i.e., positive affect relative to negative affect). PARTICIPANTS: The sample included 3,170 employed Australian parents involved in the Household Income and Labour Dynamics in Australia (HILDA) Survey. METHODS: Information on WFC, WFE, hedonic balance, sleep quality, and relevant covariates was collected through a structured interview and self-completion questionnaire. RESULTS: WFC was associated with poorer sleep quality (beta = .27, p < .001), and this relationship was stronger in males than females and in dual parent-single income families. WFC was also found to be indirectly associated with poor sleep quality via a lower hedonic balance (beta = .17, 99% confidence interval [.14, .20]). WFE was not directly associated with sleep quality, but was indirectly associated with better sleep quality via a higher hedonic balance (beta = -.04 [-.07, -.02]). CONCLUSIONS: These results indicate that aspects of the work-family interface are associated with employee sleep quality. Furthermore, affective experiences were found to link WFC and WFE with sleep quality. Workplace interventions that target WFC and WFE may have implications for employee sleep. PMID- 28098479 TI - Screening of visual perceptual disorders following acquired brain injury: A Delphi study. AB - Impairments in visual perception are common after acquired brain injury (ABI) and adequate assessment is crucial for diagnosis and rehabilitation. However, there is no consensus yet on how to assess these disorders after ABI. The aim of the present study was to explore what measures are considered reasonable to be part of a test battery for the screening of a broad range of mid-level and higher order visual perceptual disorders. A Delphi method was used to collect the opinions of 28 international multidisciplinary experts in visual perception in order to achieve consensus on the content of the test battery. Seventeen experts evaluated the test battery proposed in the third and final round of the Delphi process. Consensus was achieved (94%) on a battery of 11 distinctive tests with an expected administration time of 30 minutes. The current study provides an essential step in the development of a standardized and time-efficient test battery for the screening of mid-level and higher-order visual perceptual disorders. The composed battery may improve effectiveness of clinical assessment by providing insight into potential visual deficits in little time, thereby initiating further assessment. Future studies should focus on the validation of the suggested test battery and collect normative data. PMID- 28098483 TI - Academic Performance on First-Year Medical School Exams: How Well Does It Predict Later Performance on Knowledge-Based and Clinical Assessments? AB - Number of appearances in the bottom quartile of 1st-year medical school exams were used to represent the extent to which students were having academic difficulties. Medical educators have long expressed a desire to have indicators of medical student performance that have strong predictive validity. Predictors traditionally used fell into 4 general categories: demographic (e.g., gender), other background factors (e.g., college major), performance/aptitude (e.g., medical college admission test scores), and noncognitive factors (e.g., curiosity). These factors, however, have an inconsistent record of predicting student performance. In comparison to traditional predictive factors, we sought to determine the extent to which academic performance in the 1st-year of medical school, as measured by examination performance in the bottom quartile of the class in 7 required courses, predicted later performance on a variety of assessments, both knowledge based (e.g., United States Medical Licensing Examination Step 1 and Step IICK) and clinical skills based (e.g., clerkship grades and objective structured clinical exam performance). Of all predictors measured, number of appearances in the bottom quartile in Year 1 was the most strongly related to performance in knowledge-based assessments, as well as clinically related outcomes, and, for each outcome, bottom-quartile performance accounted for additional variance beyond that of the traditional predictors. Low academic performance in the 1st year of medical school is a meaningful risk factor with both predictive validity and predictive utility for low performance later in medical school. The question remains as to how we can incorporate this indicator into a system of formative assessment that effectively addresses the challenges of medical students once they have been identified. PMID- 28098484 TI - Romanowsky staining, the Romanowsky effect and thoughts on the question of scientific priority. AB - I give an historical account and analysis of the scientific priority of the discovery of the polychrome staining of microscopic biological preparations provided by mixtures of eosin plus methylene blue and its derivatives, especially azure B. I maintain that both the formal priority for the discovery of the polychrome staining phenomenon and credit for initiating the development of a technique of polychrome staining properly belong to D. L. Romanowsky. His scientific work demonstrated the possibility of using a simple technique to stain hematological preparations selectively to give good contrast, high resolution and the ability to identify malaria parasites. Romanowsky's approach constituted the starting point for the development of a family of polychrome stains for microscopic investigation of hematological preparations by a number of his contemporaries. PMID- 28098485 TI - Effects of umbilical cord blood stem cells on healing factors for diabetic foot injuries. AB - The use of stem or progenitor cells from bone marrow, or peripheral or umbilical cord blood is becoming more common for treatment of diabetic foot problems. These cells promote neovascularization by angiogenic factors and they promote epithelium formation by stimulating cell replication and migration under certain pathological conditions. We investigated the role of CD34 + stem cells from human umbilical cord blood in wound healing using a rat model. Rats were randomly divided into a control group and two groups with diabetes induced by a single dose of 55 mg/kg intraperitoneal streptozocin. Scarred areas 5 mm in diameter were created on the feet of all rats. The diabetic rats constituted the diabetes control group and a diabetes + stem cell group with local injection into the wound site of 0.5 * 106 CD34 + stem cells from human umbilical cord blood. The newly formed skin in the foot wounds following CD34 + stem cell treatment showed significantly improvement by immunohistochemistry and TUNEL staining, and were closer to the wound healing of the control group than the untreated diabetic animals. The increase in FGF expression that accompanied the local injection of CD34 + stem cells indicates that FGF stimulation helped prevent apoptosis. Our findings suggest a promising new treatment approach to diabetic wound healing. PMID- 28098486 TI - Identification and characterization of genes on a single subgenome in the hexaploid wheat (Triticum aestivum L.) genotype 'Chinese Spring'. AB - Gene loss during the formation of hexaploid bread wheat has been repeatedly reported. However, our knowledge on genome-wide analysis of the genes present on a single subgenome (SSG) in bread wheat is still limited. In this study, by analysing the 'Chinese Spring' chromosome arm shotgun sequences together with high-confidence gene models, we detected 433 genes on a SSG. Greater gene loss was observed in A and D subgenomes compared with B subgenome. More than 79% of the orthologs for these SSG genes were detected in diploid and tetraploid relatives of hexaploid wheat. Unexpectedly, no bias in expression breadth or in the distribution patterns of GO (gene ontology) terms for these genes was detected among the high-confidence genes. Further, network and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses indicated that most of these genes were not functionally related to each other. Interestingly, 30.7% of these SSG genes were most highly expressed in root, showing biased distribution given the distribution of the whole high-confidence genes. Collectively, these results facilitate our understanding of the loss of the genes that were retained in a SSG during the formation of hexaploid wheat. PMID- 28098488 TI - Pulse wave velocity and myocardial performance index in premature ovarian insufficiency. AB - OBJECTIVE: Epidemiological studies suggest that women with loss of ovarian function at early ages may be especially burdened by cardiovascular disease (CVD). In this study, we aimed to evaluate pulse wave velocity (PWV) and myocardial performance index (MPI) in patients with premature ovarian insufficiency (POI). DESIGN: We enrolled 51 female patients (mean age 38.9 +/- 6.7 years) with POI and 49 healthy subjects (mean age 36.8 +/- 5.2 years). All participants underwent a detailed echocardiographic examination and PWV measurement, which is basically the velocity of pulse wave travelling from carotid to femoral artery. RESULTS: Both groups were similar with regard to age, body mass index (BMI) and left ventricular ejection fraction. When diastolic functions were assessed, patients with POI had higher mean E/E'ratio (9.3 +/- 1.9 vs. 7.6 +/- 1.6, p < 0.001). POI patients have impaired MPI (0.9 +/- 0.5 vs. 0.5 +/- 0.2, p < 0.001) comparing to healthy controls but PWV measurements did not differ between two groups (5.7 +/- 0.8 vs. 5.6 +/- 0.6 m/s, p = 0.48). CONCLUSIONS: This study showed POI patients might have impaired global left ventricular functions comparing to age matched healthy controls and this might reflect the effects of premature lack of estrogen (E) on women's cardiovascular (CV) system. PMID- 28098491 TI - Particle sizing methods for the detection of protein aggregates in biopharmaceuticals. AB - Protein aggregation is a common biological phenomenon which is responsible for degenerative diseases and is problematic in the pharmaceutical industry. According to the rules provided by regulatory agencies, industry is supposed to assess the product quality regarding the presence of subvisible particles. Also, they should evaluate the technologies that are used to measure these particles. Therefore, US FDA and industry have been looking for methods capable of accurately characterizing the protein products. Four sizing techniques reviewed here are good candidates to be used for characterization of protein and their aggregates: dynamic light scattering, size-exclusion chromatography, electron microscopy and Taylor dispersion analysis. The first three are more established techniques while the last one is a more recent and growing technique. PMID- 28098492 TI - Insomnia Management in the Australian Primary Care Setting. AB - BACKGROUND AND OBJECTIVE: Insomnia is one of the most prevalent and costly sleep disorders presenting in general practice, and when left untreated, has major health consequences. However, studies are limited on how general practitioners respond to this health issue, especially since the reconceptualization of insomnia in DSM 5. Therefore, the aim of this study was to explore how insomnia is diagnosed and treated in Australian general practices. PARTICIPANTS: Twenty four (54% male) general practitioners were recruited throughout the greater Sydney metropolitan area in New South Wales using the professional network of research team members and snowballing technique. METHODS: Participants were interviewed using a semi-structured interview guide. The audio-taped interviews were transcribed verbatim and a framework approach was used for analysis of transcribed data. RESULTS: Participant's responses highlighted that despite being a frequent presentation, insomnia is often trivialized with a low recognition rate in general practices. Lack of support and clear and effective management guidelines for general practitioners are the perceived barriers to early recognition of insomnia in general practices. Treating the underlying causes and initiating the treatment with general practitioners to manage insomnia. Medications including off-label antidepressants are often prescribed based on perceived patient expectation for a prescription. CONCLUSION: Findings of this exploratory study suggest the need for clearly contextualized guidelines that include information about a patient's insomnia experience and treatment expectations. Another significant implication of this study is the need to develop and evaluate a model of collaborative sleep health services in general practice. PMID- 28098495 TI - Psychometric Characteristics of the Insomnia Severity Index in Veterans With History of Traumatic Brain Injury. AB - OBJECTIVE/BACKGROUND: The Insomnia Severity Index (ISI) is a widely used self report measure of insomnia symptoms. However, to date this measure has not been validated or well-characterized in veterans who have experienced traumatic brain injury (TBI). This study assessed the psychometric properties and convergent, divergent, construct, and discriminate validity of the ISI in veterans with a history of TBI. PARTICIPANTS: Eighty-three veterans with history of TBI were seen in the VA San Diego Healthcare System as part of a research protocol. METHODS: Measures included the ISI, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale, Neurobehavioral Symptom Inventory, Beck Depression Inventory II, Beck Anxiety Inventory, and PTSD Checklist-Military Version. RESULTS: The ISI demonstrated moderate to strong or excellent convergent and divergent validity. A principal component analysis indicated a single construct with excellent internal consistency (Cronbach's alpha = 0.92). In exploratory analyses, the ISI discriminated well between those with (73%) and without (27%) sleep disturbance based on the PSQI. CONCLUSIONS: Results from this study indicate validity of the ISI in assessing insomnia in veterans with history of TBI and suggest a cutoff score not dissimilar from non-TBI populations. Findings from this study can help inform clinical applicability of the ISI, as well as future studies of insomnia in TBI. PMID- 28098496 TI - Real-world adherence assessment of lurasidone and other oral atypical antipsychotics among patients with schizophrenia: an administrative claims analysis. AB - OBJECTIVE: To compare adherence with lurasidone to other oral atypical antipsychotics among Medicaid and commercially insured patients with schizophrenia. RESEARCH DESIGN AND METHODS: Administrative claims of patients with schizophrenia treated with atypical antipsychotics (lurasidone, aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone) from October 2010 to September 2011 were identified from MarketScan Commercial and Medicaid Databases, and were classified by the first (index) antipsychotic. Patients were 18-64 years, had insurance coverage 12 months pre- and 6 months post-index, and no pre-index use of the index drug. MAIN OUTCOME MEASURES: Medication possession ratio (MPR), discontinuation rate, and mean time to discontinuation were assessed post-index. Pairwise comparisons (lurasidone versus each drug) were conducted using chi-square tests and Student's t-tests. RESULTS: There were 146 Medicaid (mean age 43.5 years, 47.9% female) and 63 commercial (mean age 40.0 years, 42.9% female) patients treated with lurasidone. In the Medicaid population, the MPR for patients treated with lurasidone was 0.60, versus 0.41-0.48 for patients treated with other antipsychotics (all p < .05). Patients treated with lurasidone exhibited a lower discontinuation rate compared to patients treated with all other antipsychotics (49.3% versus 62.3%-68.3%, all p < .05). The mean time to discontinuation with lurasidone was significantly longer than with ziprasidone (p < .05). In the commercial population, the MPR for patients treated with lurasidone (0.61) was higher compared to patients treated with quetiapine (0.44) and ziprasidone (0.43) (both p < .05). The discontinuation rate (44.4%) was lower for patients treated with lurasidone compared to patients treated with all other antipsychotics except risperidone (p < .05). The mean time to discontinuation was longer for lurasidone than with other antipsychotics. CONCLUSIONS: In Medicaid and commercial populations, patients treated with lurasidone demonstrated greater adherence compared to patients treated with other atypical antipsychotics. Limitations of using administrative claims data include potential errors or inconsistencies in coding, and lack of complete clinical information. PMID- 28098497 TI - Magnetic resonance arthrography results that indicate surgical treatment for partial articular-sided supraspinatus tendon avulsion: a retrospective study in a tertiary center. AB - Background Specific findings on magnetic resonance arthrography (MRA) that indicate the need for surgery in patients with partial articular-sided supraspinatus tendon avulsion (PASTA) are not well understood. Purpose To determine which MRA findings are characteristic of patients who undergo surgery for PASTA. Material and Methods From July 2011 to February 2014, MRA findings for patients treated for PASTA were retrospectively reviewed. The patients were divided into two groups: conservative treatment and surgical repair. MRA findings were compared between the groups. The following MRA results were assessed: length grade, width grade, co-existing superior labrum anterior posterior (SLAP) lesions, degenerative changes in the glenohumeral joint, presence of subacromial subdeltoid bursitis, acromion type, presence of adhesive capsulitis, and tears of the subscapularis or infraspinatus tendon within the rotator cuff. Logistic regression analyses were conducted to identify which MRA findings were significantly associated with surgical treatment. Results Forty-five surgically treated patients and 203 conservatively treated ones were evaluated. The MRA findings showed significant differences between the groups with respect to length grade, width grade, degenerative changes in glenohumeral joint, bursitis, and co existing rotator cuff tears ( P < 0.05). Multivariate logistic regression showed correlations between surgical repair and both grade 3 length tears (odds ratio, 30.8) and co-existing tears of the subscapularis or infraspinatus tendon (odds ratio, 2.9). Conclusion Surgical treatment is commonly performed in PASTA patients whose lesion lengths are grade 3 or who have co-existing tears in the subscapularis or infraspinatus tendon. Radiologists should pay attention to these MRA signs when evaluating PASTA patients. PMID- 28098498 TI - Social health in dementia. Towards a positive dementia discourse. AB - A shift in focus from symptoms and disability towards the capacity and potential of the person with dementia is urgently needed to create a more balanced view of dementia and a more dementia-friendly society, which enables people and their families to adapt to the changes dementia brings in their lives. The new concept of social health suggested by Huber and colleagues seems helpful to make such a shift. In this dedicated special issue, a consensus-based operationalization of the concept of social health in dementia is proposed and several aspects of social health and related dementia care are addressed within the framework of European collaborative projects of the INTERDEM network. PMID- 28098499 TI - Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives. AB - The study presented here aimed at identifying a new class of compounds acting against Leishmania parasites, the causative agent of Leishmaniasis. For this purpose, the thioether derivatives of our in-house library have been evaluated in whole-cell screening assays in order to determine their in vitro activity against Leishmania protozoan. Among them, promising results have been achieved with compound RDS 777 (6-(sec-butoxy)-2-((3-chlorophenyl)thio)pyrimidin-4-amine) (IC50 = 29.43 uM), which is able to impair the mechanism of the parasite defence against the reactive oxygen species by inhibiting the trypanothione reductase (TR) with high efficiency (Ki 0.25 +/- 0.18 uM). The X-ray structure of L. infantum TR in complex with RDS 777 disclosed the mechanism of action of this compound that binds to the catalytic site and engages in hydrogen bonds the residues more involved in the catalysis, namely Glu466', Cys57 and Cys52, thereby inhibiting the trypanothione binding and avoiding its reduction. PMID- 28098500 TI - Exploring Black College Females' Perceptions Regarding HIV Prevention Message Content. AB - Media messages can facilitate the delivery of accurate information related to HIV and sexually transmitted infection. This study's purpose was to examine preexisting media campaigns from the iMPPACS study to assess age-, gender-, and culturally appropriate components identified by African American females who attend historically Black colleges/universities. In 3 separate focus group sessions, 31 Black female college students (M age = 20) viewed 4 vignettes and heard 3 audio-only clips, then ranked and commented on them based on perceived satisfaction with HIV prevention content and appropriateness of delivery. Conventional qualitative analysis using NVivo software was performed until saturation of content was achieved and themes derived. Six major themes emerged and were designated as (a) social media; (b) mirror image; (c) visually dynamic advertisements; (d) the real world; (e) people, place, things; and (f) HIV knowledge. Visually stimulating content (i.e., graphics) was found to be most appealing in marketing HIV prevention, with brief monologue/dialogue from scenarios that resemble daily life. Socially and culturally relevant HIV prevention messages are important to Black college female students. Participants recommended creating short audiovisual messages that encompass familiar contexts like dorm rooms and appealing graphics for HIV health promotion messages, such as emojis. Future audio-only prevention advertisements for this population should use recognizable voices (e.g., celebrities). Finally, messaging should be promoted on open and closed circuit social media platforms. PMID- 28098501 TI - Prevalence of house dust mite allergens in low-income homes with evaporative coolers in a semiarid climate. AB - House dust mites are typically absent in homes in arid and semiarid climates due to low humidity. Evaporative "swamp" cooling significantly increases indoor humidity in dry climates and is suspected of promoting dust mite survival in these regions. We investigated the prevalence and concentration of mite allergens in dust from low-income homes (N = 22) with evaporative coolers in Utah County, Utah. Overall, 15 homes (68.2%) were positive for either Der p 1 or Der f 1 in at least 1 location. Geometric mean allergen levels in mattresses were 0.107 and 0.087 ug/g dust for Der p 1 and Der f 1, respectively. In furniture, levels were 0.143 and 0.165 ug/g dust for Der p1 and Der f 1, respectively. The percentage of positive homes in this study was much higher than previously reported in larger homes with swamp coolers in the same community. These results suggest socioeconomic factors may play a role in dust mite allergen prevalence in homes with evaporative coolers in dry climates. PMID- 28098502 TI - United Kingdom national paediatric bilateral project: Results of professional rating scales and parent questionnaires. AB - OBJECTIVES: This fourteen-centre project used professional rating scales and parent questionnaires to assess longitudinal outcomes in a large non-selected population of children receiving simultaneous and sequential bilateral cochlear implants. METHODS: This was an observational non-randomized service evaluation. Data were collected at four time points: before bilateral cochlear implants or before the sequential implant, one year, two years, and three years after. The measures reported are Categories of Auditory Performance II (CAPII), Speech Intelligibility Rating (SIR), Bilateral Listening Skills Profile (BLSP) and Parent Outcome Profile (POP). RESULTS: Thousand and one children aged from 8 months to almost 18 years were involved, although there were many missing data. In children receiving simultaneous implants after one, two, and three years respectively, median CAP scores were 4, 5, and 6; median SIR were 1, 2, and 3. Three years after receiving simultaneous bilateral cochlear implants, 61% of children were reported to understand conversation without lip-reading and 66% had intelligible speech if the listener concentrated hard. Auditory performance and speech intelligibility were significantly better in female children than males. Parents of children using sequential implants were generally positive about their child's well-being and behaviour since receiving the second device; those who were less positive about well-being changes also generally reported their children less willing to wear the second device. CONCLUSION: Data from 78% of paediatric cochlear implant centres in the United Kingdom provide a real-world picture of outcomes of children with bilateral implants in the UK. This large reference data set can be used to identify children in the lower quartile for targeted intervention. PMID- 28098503 TI - Relationship between perceived competence and performance during real and virtual motor tasks by children with developmental coordination disorder. AB - PURPOSE: (i) To compare children with DCD and typically developing participants via standard motor assessments, two interactive virtual games, measures of physical, social and cognitive self-competence and feedback while playing the virtual games and (ii) To examine the contribution of age and each motor assessment to predict self-competence. METHODS: Participants were 25 boys with DCD and 25 typically developing boys, aged 5-9 years. They completed the M-ABC-2, the Pictorial Scale of Perceived Competence, the 6-Minute Walk Test, and then played the two Kinect games and completed the Short Feedback Questionnaire for Children. RESULTS: Children with DCD showed lower physical competence and lower performance than the typical controls in all standard motor assessments. This performance significantly correlated with the children achievements in part of virtual games and with their self-perceived experience while performing within virtual environments. Among the DCD group, Kinect Running game significantly predicted physical and social competence. CONCLUSIONS: The significant correlations between the virtual games and standard motor assessments support the feasibility of using these games when evaluating children with DCD for the richer profile they provide. Implications for rehabilitation Clinicians should refer to the impacts of DCD on child's self-competence and daily life. Technological rehabilitation and the use of VR games have the potential to improve self competence of children with DCD. By including VR games that simulate real life in the intervention for DCD, clinicians may raise child's enjoyment, self-competence and involvement in therapy. PMID- 28098504 TI - Effects of culturally adaptive walking intervention on cardiovascular disease risks for middle-aged Korean-Chinese female migrant workers. AB - The purpose of this study was to examine the effects of a standard treatment (ST) walking program compared to an ST walking program enhanced (enhanced treatment, ET) on cardiovascular health outcomes among Korean-Chinese female migrant workers in Korea. A quasi-experimental sequential design was used. A total of 132 Korean Chinese women without contraindications to physical activity participated in the study. Both ST and ET groups had monthly goal settings; the ET group received text messages to encourage walking adherence and acculturation. A significant decrease was found in 10-year risk for cardiovascular disease (CVD), blood pressure, fasting glucose, body mass index, and waist-hip ratio at weeks 12 and 24 in both groups, but there were no significant group differences. This indicates that culturally adaptive walking intervention is a promising way to reduce CVD risk factors for underserved Korean-Chinese migrant women. PMID- 28098505 TI - Facilitating and hindering factors for coping with the experience of having a child with cancer: A Lebanese perspective. AB - BACKGROUND: Families with a child with cancer face significant emotional and psychosocial stressors. The frequency of childhood cancer is increasing in Lebanon with more than 282 children diagnosed each year. This condition is reported to evoke a range of challenging emotions for parents, yet no studies have been conducted on the facilitating and hindering factors that affect Lebanese parents coping with a child with cancer. OBJECTIVES: The purpose of the study was to gain an in-depth understanding of factors facilitating and hindering coping methods of Lebanese parents with a child with cancer. METHODS: The study followed purposeful sampling and saturation principles in which 12 parents (mother or father) of a child were interviewed. Data were analyzed following the Utrecht School of phenomenology. RESULTS: Helpful and harmful experiences emerged through the coding process. The enabling factors were social/family support; talking about it; strong religious beliefs; and the communication style of health workers. On the other hand, the deterring factors were the waiting time and the hospital stay; changes in the couple's relationship; and sibling rivalry. CONCLUSION: These results could be used as the basis for additional research aimed at developing a structured approach to care that endorses the coping processes of Lebanese parents with a child with cancer. IMPLICATIONS FOR CLINICAL PRACTICE: Nursing and medical staff need to be conscious of parents' coping strategies and their impact on family dynamics and the relationship between the family and the health care team. PMID- 28098506 TI - Capsicum annuum var. grossum (Bell Pepper) Inhibits beta-Secretase Activity and beta-Amyloid1-40 Aggregation. AB - The deposition of amyloid protein as senile plaques is the major signature of Alzheimer's disease (AD). It is produced by the sequential cleavage of the amyloid precursor protein by secretases. Moreover, peppers are noted for their antiaging and cognitive enhancing properties. Thus, in this study, the effects of polyphenol-rich extracts from bell pepper on amyloid production and aggregation in vitro were investigated. Bell pepper (ripe and unripe) was extracted with methanol-1 N HCl (1:1 v/v). Thereafter, the inhibitory potentials of the extracts on beta-secretase and beta-amyloid1-40 aggregation were determined. Phenolic composition of the pepper fruits was further determined by HPLC-DAD (high performance liquid chromatography-diode array detector). There was a dose dependent inhibition of beta-secretase by the pepper fruits with the ripe fruits (2.17 +/- 0.17 MUg/L) showing a significantly (P < .05) higher inhibitory effect than the unripe (3.44 +/- 0.11 MUg/L). Furthermore, Thioflavin-T and transmission electron microscopy analyses revealed that phenolic extracts from pepper fruits (1 and 10 MUg/L) could counteract the initial aggregation of Abeta1-40, as well as prevent further aggregation preformed fibrils. These inhibitory activities could be attributed to the predominant presence of phenolic constituents in the pepper fruits. It is possible to conclude that bell pepper could be a possible dietary intervention into the management of AD. PMID- 28098507 TI - Development and Evaluation of a Loop-Mediated Isothermal Amplification (Lamp) Assay for the Detection of Haemonchus contortus in Goat Fecal Samples. AB - Haemonchus contortus is one of the most significant strongylid nematodes infecting small ruminants, and it causes great economic losses to the livestock industry worldwide. Accurate diagnosis of H. contortus is crucial to control strategies. Traditional microscopic examinations are the most common methods for the diagnosis of H. contortus , but they are time-consuming and inaccurate. Molecular methods based on PCR are more accurate, but need expensive machines usually only used in the laboratory. Loop-mediated isothermal amplification (LAMP) is a rapid, simple, specific, and sensitive method that has been widely used to detect viruses, bacteria, and parasites. In the present study, a LAMP method targeting ribosomal ITS-2 gene for detection of the H. contortus in goat fecal samples has been established. The established LAMP method was H. contortus specific, and the sensitivity of LAMP was the same as that of the H. contortus species-specific PCR, with the lowest DNA level detected as being 1 pg. Examination of the clinical samples indicated that the positive rate of LAMP was higher than that of PCR, but no statistical difference was observed between LAMP and PCR (chi2 = 17.991, P = 0.053). In conclusion, a LAMP assay with a high specificity and a good sensitivity has been developed to detect H. contortus infection in goats. The established LAMP assay is useful for clinical diagnosis of H. contortus . PMID- 28098508 TI - Evaluation of a Social Norms Approach to a Suicide Prevention Campaign. AB - Suicide is a leading cause of death for college-aged youth, and university counseling centers (UCC) strive to educate students about mental health issues and available campus services. The current research evaluates a college campus social norms campaign that used both peer and celebrity sources to promote help seeking among college students as a suicide prevention strategy. Postcampaign surveys of this quasi-experiment (n = 391) revealed that compared to students in the control neighborhood condition, students exposed to the campaign messages in the experimental neighborhood conditions were more likely to perceive students would refer a friend to the UCC and more likely to visit the UCC for a mental health concern. Students living in the intervention neighborhood with a peer message source reported a greater willingness to refer friends to the UCC compared to those who lived in the celebrity and control neighborhoods. Regardless of condition, students who reported seeing UCC messages reported greater effects than those who reported not viewing the messages (e.g., greater intentions to seek help and to talk to others about the UCC). Results of this study are discussed within a social norms framework and support the need for continued exposure to campaign messages to impact health outcomes. PMID- 28098509 TI - 'Compassionate use' protocol for auditory brainstem implantation in neurofibromatosis type 2: Early House Ear Institute experience. AB - OBJECTIVE: To report the preliminary outcomes of auditory brainstem implantation (ABI) under a compassionate use protocol for two ABI devices that are not approved by the US Food and Drug Administration. METHODS: A retrospective review was performed of neurofibromatosis type 2 (NF2) patients who underwent microsurgery for vestibular schwannoma (VS) and placement of either the Cochlear ABI541 or Med-El Synchrony ABIs. Peri-operative and device- related complications were reviewed. Audiometric performance was also evaluated. RESULTS: Seven patients received either the Cochlear ABI541 (6) or the Med-El Synchrony ABI (1) after the resection of VS. No device or patient-related complications occurred to date. Surgical times and early audiological performance are similar to our previous experience with the Cochlear ABI24 device. CONCLUSIONS: Early experience with the Cochlear ABI541 and Med-El Synchrony ABI devices under a compassionate use protocol suggest that both devices are safe with comparable utility to the Cochlear ABI24 device. PMID- 28098510 TI - DT MRI microstructural cortical lesion damage does not explain cognitive impairment in MS. AB - OBJECTIVE: We combined double inversion recovery (DIR) and diffusion tensor (DT) magnetic resonance imaging (MRI) to quantify the severity of cortical lesion (CL) microstructural tissue abnormalities in a large cohort of relapse-onset multiple sclerosis (MS) patients and its contribution to cognitive dysfunction. METHODS: DIR, DT, dual-echo, and three-dimensional (3D) T1-weighted scans were acquired from 149 MS patients and 40 controls. Cognitively impaired (CI) patients had ?2 abnormal neuropsychological tests. Diffusivity values in CLs, cortex, white matter (WM) lesions, and normal-appearing (NA) WM were assessed. Predictors of cognitive impairment were identified using a random forest analysis. RESULTS: Compared to controls, MS patients had lower normalized brain volume (NBV), gray matter volume (GMV), WM volume, lower fractional anisotropy (FA), and higher mean diffusivity in cortex and normal-appearing white matter (NAWM). A total of 44 (29.5%) patients were CI. Compared to cognitively preserved (CP), CI patients had higher T2 WM lesion volume (LV), lower NBV and GMV, and more severe diffusivity abnormalities in WM lesions, cortex, and NAWM. CL measures did not differ between CI and CP patients. Cortex FA, age, disease duration, T2 WM LV, and GMV best predicted MS-related cognitive impairment (C-statistic = 0.88). CONCLUSION: "Diffuse" GM and NAWM damage and WM lesions, rather than intrinsic CL damage, contribute to cognitive impairment in MS. PMID- 28098511 TI - Hemodynamic effects of HPMA copolymer based doxorubicin conjugate: A randomized controlled and comparative spectral study in conscious rats. AB - Conjugation of Doxorubicin (DOX) to N-(2-hydroxypropyl) methylacrylamide copolymer (HPMA) has significantly reduced the DOX-associated cardiotoxicity. However, the reports on the impact of HPMA-DOX conjugates on the cardiovascular system such as blood pressure (BP) and heart rate (HR) were in restrained animals using tail cuff and/or other methods that lacked the resolution and sensitivity. Herein, we employed radiotelemetric-spectral-echocardiography approach to further understand the in vivo cardiovascular hemodynamics and variability post administration of free DOX and HPMA-DOX. Rats implanted with radio-telemetry device were administered intravenously with DOX (5 mg/kg), HPMA-DOX (5 mg DOX equivalent/kg) and HPMA copolymer and subjected to continuous cardiovascular monitoring and echocardiography for 140 days. We found that DOX-treated rats had ruffled fur, reduced body weight (BW) and a low survival rate. Although BP and HR were normal, spectral analysis indicated that their BP and HR variabilities were reduced. All rats exhibited typical signs of cardiotoxicity at histopathology. In contrast, HPMA-DOX rats gained weight over time and survived. Although BP, HR and related variabilities were unaffected, the left ventricular end diastolic volume (EDV) of these rats, as well as of the HPMA copolymer-treated rats, was found increased at the end of observation period. Additionally, HPMA copolymer caused microscopic injury of the heart tissue. All of these suggest the necessity of caution when employing HPMA as carrier for prolonged drug delivery. The current study also indicates the potential of radiotelemetric-spectral-echocardiography approach for improved preclinical cardiovascular risk assessment of polymer-drug conjugate and other nano-sized-drug constructs. PMID- 28098512 TI - The impact of electric hearing on children's timbre and pitch perception and talker discrimination. PMID- 28098513 TI - Attrition and retention in upper limb prosthetics research: experience of the VA home study of the DEKA arm. AB - PURPOSE: (1) Describe study attrition; (2) identify reasons for attrition, and (3) discuss implications for prosthetic prescription and design of future device studies. Design and methodological procedures used: Completion phase (during in laboratory training, after training, or home use) was identified for 42 participants. Qualitative data were analyzed to identify attrition reasons. Reasons were classified as related to the DEKA arm, or not. RESULTS: Study attrition was 57%, with 43% completing the full study. Attrition during the in laboratory portion was 21%. Reasons for attrition were related to the DEKA arm entirely or in-part for 42%, 25%, respectively. Most common reasons were scheduling/personal (54%); device weight (29%); and dissatisfaction with device (25%). About 21% withdrew because of concerns about compliance with study protocol. CONCLUSIONS: This study had a high attrition rate with evidence of selective attrition due to device characteristics. Strategies to minimize attrition and the importance of tracking reasons for withdrawal are discussed. Given that retention could be an indicator of willingness to adopt the DEKA arm, findings suggest that it would be prudent to provide patients with the opportunity to train with the DEKA arm before a decision is made regarding the appropriateness of the device for the patient. Implications for Rehabilitation This study of a new upper limb prosthesis, the DEKA arm, had a 57% attrition rate with evidence of selective attrition due to characteristics of the DEKA arm. Findings point to the need for strategies to minimize attrition in future studies. Findings also illustrate the importance of tracking reasons for subject withdrawal in longitudinal prosthesis device studies. Because participant retention in longitudinal device studies may be an indicator of future willingness to adopt a device, our findings suggest that it would be prudent to provide patients with the opportunity to train with the DEKA arm before a final decision is made regarding the appropriateness of the device for the patient. PMID- 28098514 TI - Edible and Medicinal Mushrooms: Emerging Brain Food for the Mitigation of Neurodegenerative Diseases. AB - There is an exponential increase in dementia in old age at a global level because of increasing life expectancy. The prevalence of neurodegenerative diseases such as dementia and Alzheimer's disease (AD) will continue to rise steadily, and is expected to reach 42 million cases worldwide in 2020. Despite the advancement of medication, the management of these diseases remains largely ineffective. Therefore, it is vital to explore novel nature-based nutraceuticals to mitigate AD and other age-related neurodegenerative disorders. Mushrooms and their extracts appear to hold many health benefits, including immune-modulating effects. A number of edible mushrooms have been shown to contain rare and exotic compounds that exhibit positive effects on brain cells both in vitro and in vivo. In this review, we summarize the scientific information on edible and culinary mushrooms with regard to their antidementia/AD active compounds and/or pharmacological test results. The bioactive components in these mushrooms and the underlying mechanism of their activities are discussed. In short, these mushrooms may be regarded as functional foods for the mitigation of neurodegenerative diseases. PMID- 28098516 TI - Germacrone Attenuates Hyperlipidemia and Improves Lipid Metabolism in High-Fat Diet-Induced Obese C57BL/6J Mice. AB - We previously showed that Aster spathulifolius Maxim extract (ASE) reduced body weight gain and serum and liver lipid levels and significantly suppressed serum insulin and leptin concentrations in high-fat diet (HFD)-induced obese rats. Germacrone (GM) was identified as a potent bioactive constituent of ASE. In this study, we hypothesized that GM can attenuate hyperlipidemia by alleviating fatty acid (FA) synthesis/uptake and improve lipid metabolism by stimulating FA beta oxidation in HFD-induced obese C57BL/6J mice. To induce obesity, mice were fed an HFD for 6 weeks, while control mice were fed a commercial standard diet. The mice were allocated to six groups and fed either a normal diet, HFD, HFD with GM (5, 10, and 20 mg/kg), or HFD with 200 mg/kg Garcinia cambogia extract for 30 days. In the GM groups, body weight gain, visceral fat pad weight, fasting plasma glucose, serum insulin and leptin, and serum, as well as hepatic lipid, levels were attenuated. Transcriptional factors related to lipid metabolism, such as AMP activated protein kinase alpha, sterol regulatory element-binding protein (SREBP) 1, SREBP 2, acetyl-CoA carboxylase, peroxisome proliferator-activated receptor (PPAR)-alpha, PPAR-gamma, FA synthase, and carnitine palmitoyltransferase 1, showed higher expression in the GM groups. In summary, GM may help attenuate hyperlipidemia by suppressing FA synthesis and uptake by inhibiting SREBP signaling pathway activation and improve lipid metabolism by stimulating FA beta oxidation by activating the AMPKalpha signaling pathway in HFD-induced obesity. PMID- 28098515 TI - A Randomized Open-Label Trial to Assess the Effect of Plant Sterols Associated with Ezetimibe in Low-Density Lipoprotein Levels in Patients with Coronary Artery Disease on Statin Therapy. AB - Consumption of food products enriched with plant sterols and the use of ezetimibe reduce cholesterol absorption in the intestine and effectively reduce low-density lipoprotein (LDL) plasma levels. We evaluated the therapeutic effect of the ezetimibe+plant sterol association in patients with coronary artery disease still not reaching recommended lipid levels despite the use of statins. We performed a prospective open-label study with 41 patients with stable coronary disease and LDL >70 mg/dL. Patients were randomized into four groups for a 6-week treatment: the control (CT) group remained on the same statin therapy, the ezetimibe (EZ) group received 10 mg/day of ezetimibe, the plant sterol (PS) group received spread enriched with 2 g of plant sterols, and the ezetimibe+PS (EZ+PS) group received 10 mg/day EZ +2 g PS. Initial mean LDL level was 97.4 +/- 31.1 mg/dL in control group, 105.1 +/- 23.1 mg/dL in EZ group, 95.4 +/- 27.7 mg/dL in PS group, and 97.0 +/- 8.3 mg/dL in EZ+PS group (P > .05). After 6 weeks of treatment, LDL of patients slightly increased in the control group (+8.9%; P > .05) and dropped in EZ group (-19.1%; P = .06), PS group (-16.6%; P = .01), and EZ+PS group ( 27.3%; P < .01). Mean LDL levels after treatment were 70.5 +/- 17.9 mg/dL in EZ+PS group, lower than the other groups (control was 106.1 +/- 34.9 mg/dL, EZ group was 85.0 +/- 35.6 mg/dL, and PS was 79.6 +/- 29.7 mg/dL) (P = .05 variance analysis factor [ANOVA]). Body weight, body-mass index, and glucose plasma levels did not change significantly after intervention. The combination of PS+ezetimibe was associated with lower LDL levels and suggests beneficial therapeutic effect against major cardiovascular events. PMID- 28098517 TI - Antiobesity Effects of Sansa (Crataegi fructus) on 3T3-L1 Cells and on High-Fat High-Cholesterol Diet-Induced Obese Rats. AB - This study was performed to investigate the effects of Crataegi fructus ethanol extracts (CFEEs) on the differentiation of 3T3-L1 cells, and to evaluate the effects of C. fructus powder (CFP) on lipid metabolism and its antiobesity effect in rats fed a high-fat and high-cholesterol (HFC) diet. Both in vitro and in vivo studies were performed for physiological activity and antiobesity effects on the serum, liver, and adipose tissues in obesity-induced rats. CFEEs showed significant inhibitory action on differentiation and triglyceride (TG) accumulation in 3T3-L1 mature cells in a dose-dependent manner. Subcutaneous, mesenteric, epididymal, and total adipose tissue weights of HFC diet group were heavier than those of normal diet (N) group, whereas those of groups fed CFP were significantly decreased. Levels of serum TGs, total cholesterol (TC), and low density lipoprotein cholesterol were significantly decreased in the CFP groups than in the HFC group, whereas the serum high-density lipoprotein cholesterol level decreased in the HFC group and markedly increased in the CFP groups. TC and TG levels in the liver and adipose tissues were significantly lower in CFP groups than in the HFC groups. In addition, feeding with CFP significantly reduced the occurrence of fatty liver deposits and steatosis, and inhibited an HFC diet induced increase in adipocyte size. These results suggest that C. fructus may improve lipid metabolism in the serum, liver, and adipose tissue, and may potentially reduce lipid storage. PMID- 28098518 TI - A 4-Nitroquinoleneoxide-Induced Pleurotus eryngii Mutant Variety Increases Pin1 Expression in Rat Brain. AB - To develop Pleurotus eryngii varieties with improved medicinal qualities, protoplasts of P. eryngii were mutagenized using 4-nitroquinoleneoxide. The effects of the resulting variant mushrooms on a human cell were evaluated by applying their aqueous extracts to the human hepatoma cell line, HepG2, in vitro and examining any alteration in the proteomes of the treated HepG2. The P. eryngii mutant, NQ2A-12, was selected for its effects on increasing the expression level of Pin1 in HepG2. Pin1 is one of the peptidyl-prolyl cis-trans isomerases known to play an important role in repressing Alzheimer's disease pathogenesis. Validity of NQ2A-12 related to Alzheimer's disease was shown with an enhanced expression of Pin1 in a mouse brain tissue by injecting the NQ2A-12 extract. The mutant mushroom, NQ2A-12, could be developed as a new variety of P. eryngii with potential to protect against Alzheimer's disease. PMID- 28098519 TI - Who Knows? Knowledge Activation, Belief in Certainty of Knowledge, Maximization Tendencies and Need for Cognition in Answerability Judgments. AB - In this study, investigating answerability judgments, 123 participants judged whether each of 46 general knowledge questions could currently be answered by themselves, by someone else, or by no one. There were 26 consensus questions (high expected consensus about their answerability) and 20 non-consensus questions. Before each question, half of the participants rated the extent of their knowledge related to the question. Results showed that answering consensus questions compared with non-consensus led to a lower proportion of "No one knows" answers. Moreover, in the knowledge rating condition compared with the control condition, participants choose "No one knows" proportionally less. Participants' ratings of belief in certainty of knowledge were associated with more "Someone else knows" for the non-consensus questions. Moreover, tendency to maximization led to a higher proportion of "Someone else knows" options for the non-consensus questions. Finally, high need for cognition was associated with fewer choices of "Someone else knows." PMID- 28098520 TI - The Role of the Relationship with Parents with Respect to Work Orientation and Work Ethic. AB - We examined the extent to which individual relationships with mother and father, social support from partner, and quality of the relationship with the partner, are related to work orientation and work ethic. Survey data were obtained from 3841 respondents from the Netherlands Kinship Panel Study (wave 2). The results showed that, overall, people with a more positive relationship with their parents had a more positive work orientation and a stronger work ethic. A positive relationship with the father had a greater influence on these work aspects than a positive relationship with the mother, particularly for men. Partner support and the quality of the partner relationship partially mediated the association between the relationship with one's parents and work orientation only for women. There were no significant relationships between partner support or the quality of the partner relationship, and work ethic. Research on the relationship with parents and work-related variables is discussed. PMID- 28098521 TI - Semantic and Syntactic Associations During Word Search Modulate the Relationship Between Attention and Subsequent Memory. AB - Two experiments were conducted to investigate how linguistic information influences attention allocation in visual search and memory for words. In Experiment 1, participants searched for the synonym of a cue word among five words. The distractors included one antonym and three unrelated words. In Experiment 2, participants were asked to judge whether the five words presented on the screen comprise a valid sentence. The relationships among words were sentential, semantically related or unrelated. A memory recognition task followed. Results in both experiments showed that linguistically related words produced better memory performance. We also found that there were significant interactions between linguistic relation conditions and memorization on eye movement measures, indicating that good memory for words relied on frequent and long fixations during search in the unrelated condition but to a much lesser extent in linguistically related conditions. We conclude that semantic and syntactic associations attenuate the link between overt attention allocation and subsequent memory performance, suggesting that linguistic relatedness can somewhat compensate for a relative lack of attention during word search. PMID- 28098522 TI - McGurk Effect in Gender Identification: Vision Trumps Audition in Voice Judgments. AB - Demonstrations of non-speech McGurk effects are rare, mostly limited to emotion identification, and sometimes not considered true analogues. We presented videos of males and females singing a single syllable on the same pitch and asked participants to indicate the true range of the voice-soprano, alto, tenor, or bass. For one group of participants, the gender shown on the video matched the gender of the voice heard, and for the other group they were mismatched. Soprano or alto responses were interpreted as "female voice" decisions and tenor or bass responses as "male voice" decisions. Identification of the voice gender was 100% correct in the preceding audio-only condition. However, whereas performance was also 100% correct in the matched video/audio condition, it was only 31% correct in the mismatched video/audio condition. Thus, the visual gender information overrode the voice gender identification, showing a robust non-speech McGurk effect. PMID- 28098523 TI - Effects of Psychological Distance and Need for Cognitive Closure on Impression Formation. AB - Based on theoretical and empirical similarities between Construal level theory of psychological distance and the Need for cognitive closure (NFC) theory, it could be hypothesized that psychological distance and NFC represent constructs that overlap to some degree. Since both theories describe judgmental behavior in terms of schematic processing, we hypothesized that primacy effect, a schema-driven phenomenon, is strengthened under the heightened NFC and psychological distance. We tested this hypothesis in an impression formation experiment while manipulating psychological distance and measuring NFC. Low NFC and psychological closeness reflect preference for situationally specific, contextually rich information, and therefore their joint effect resulted in reliance on all available information regardless of their position in a sequence. High NFC and psychological distance produced a preference for clear, schematic, stable knowledge, and therefore weighed first information more, which resulted in the primacy effect. PMID- 28098524 TI - Swine Influenza Virus (H1N2) Characterization and Transmission in Ferrets, Chile. AB - Phylogenetic analysis of the influenza hemagglutinin gene (HA) has suggested that commercial pigs in Chile harbor unique human seasonal H1-like influenza viruses, but further information, including characterization of these viruses, was unavailable. We isolated influenza virus (H1N2) from a swine in a backyard production farm in Central Chile and demonstrated that the HA gene was identical to that in a previous report. Its HA and neuraminidase genes were most similar to human H1 and N2 viruses from the early 1990s and internal segments were similar to influenza A(H1N1)pdm09 virus. The virus replicated efficiently in vitro and in vivo and transmitted in ferrets by respiratory droplet. Antigenically, it was distinct from other swine viruses. Hemagglutination inhibition analysis suggested that antibody titers to the swine Chilean H1N2 virus were decreased in persons born after 1990. Further studies are needed to characterize the potential risk to humans, as well as the ecology of influenza in swine in South America. PMID- 28098525 TI - Genetic Diversity and New Lineages of Dengue Virus Serotypes 3 and 4 in Returning Travelers, Germany, 2006-2015. AB - During 2006-2015, we analyzed 70 dengue virus (DENV) strains isolated from febrile travelers returning to Germany. High genetic diversity, including multiple co-circulating DENV lineages and emerging new lineages of DENV-3 and DENV-4, was demonstrated. Our passive surveillance system based on returning travelers yielded substantial information on DENV diversity. PMID- 28098526 TI - Ancylostoma ceylanicum Hookworm in the Solomon Islands. AB - Although hookworm is highly prevalent in the Solomon Islands, the species involved are unknown. We initiated this study in response to finding Ancylostoma ceylanicum hookworm in a peacekeeper in Australia who had returned from the Solomon Islands. Kato-Katz fecal surveys performed in 2013 and 2014 in 2 village groups in East Malaita, Solomon Islands, identified hookworm-positive samples. These specimens were tested by cytochrome oxidase 1 (cox-1) gene multiplex PCR and sequenced. Of 66 positive specimens, 54 (81.8%) contained only Necator americanus, 11 (16.7%) contained only A. ceylanicum, and 1 (1.5%) contained both species. A. duodenale was not found. Haplotype analysis of cox-1 sequences placed all human isolates (99% bootstrap support) of A. ceylanicum within the zoonotic clade rather than the human-specific clade. This study confirms that A. ceylanicum is endemic in the East Malaita region of this Pacific Island nation. The strain of the A. ceylanicum in this region can be shared among humans, dogs, and cats. PMID- 28098527 TI - Changing Epidemiology of Hepatitis A and Hepatitis E Viruses in China, 1990-2014. AB - We compared the epidemiology of hepatitis A and hepatitis E cases in China from 1990-2014 to better inform policy and prevention efforts. The incidence of hepatitis A cases declined dramatically, while hepatitis E incidence increased. During 2004-2014, hepatitis E mortality rates surpassed those of hepatitis A. PMID- 28098528 TI - Spread and Evolution of Respiratory Syncytial Virus A Genotype ON1, Coastal Kenya, 2010-2015. AB - In February 2012, the novel respiratory syncytial virus (RSV) group A, genotype ON1, was detected in Kilifi County, coastal Kenya. ON1 is characterized by a 72 nt duplication within the highly variable G gene (encoding the immunogenic attachment surface protein). Cases were diagnosed through surveillance of pneumonia in children at the county hospital. Analysis of epidemiologic, clinical, and sequence data of RSV-A viruses detected over 5 RSV seasons (2010/2011 to 2014/2015) indicated the following: 1) replacement of previously circulating genotype GA2 ON1, 2) an abrupt expansion in the number of ON1 variants detected in the 2014/2015 epidemic, 3) recently accumulation of amino acid substitutions within the ON1 duplicated sequence, and 4) no clear evidence of altered pathogenicity relative to GA2. The study demonstrates the public health importance of molecular surveillance in defining the spread, clinical effects, and evolution of novel respiratory virus variants. PMID- 28098529 TI - Multidrug-Resistant Candida haemulonii and C. auris, Tel Aviv, Israel. AB - Candida auris and C. haemulonii are closely related, multidrug-resistant emerging fungal pathogens that are not readily distinguishable with phenotypic assays. We studied C. auris and C. haemulonii clinical isolates from 2 hospitals in central Israel. C. auris was isolated in 5 patients with nosocomial bloodstream infection, and C. haemulonii was found as a colonizer of leg wounds at a peripheral vascular disease clinic. Liberal use of topical miconazole and close contact among patients were implicated in C. haemulonii transmission. C. auris exhibited higher thermotolerance, virulence in a mouse infection model, and ATP dependent drug efflux activity than C. haemulonii. Comparison of ribosomal DNA sequences found that C. auris strains from Israel were phylogenetically distinct from isolates from East Asia, South Africa and Kuwait, whereas C. haemulonii strains from different countries were closely interrelated. Our findings highlight the pathogenicity of C. auris and underscore the need to limit its spread. PMID- 28098530 TI - Fatal Infection with Murray Valley Encephalitis Virus Imported from Australia to Canada, 2011. AB - Murray Valley encephalitis virus (MVEV), a flavivirus belonging to the Japanese encephalitis serogroup, can cause severe clinical manifestations in humans. We report a fatal case of MVEV infection in a young woman who returned from Australia to Canada. The differential diagnosis for travel-associated encephalitis should include MVEV, particularly during outbreak years. PMID- 28098531 TI - Changing Epidemiology of Human Brucellosis, China, 1955-2014. AB - Brucellosis, a zoonotic disease, was made statutorily notifiable in China in 1955. We analyzed the incidence and spatial-temporal distribution of human brucellosis during 1955-2014 in China using notifiable surveillance data: aggregated data for 1955-2003 and individual case data for 2004-2014. A total of 513,034 brucellosis cases were recorded, of which 99.3% were reported in northern China during 1955-2014, and 69.1% (258, 462/374, 141) occurred during February July in 1990-2014. Incidence remained high during 1955-1978 (interquartile range 0.42-1.0 cases/100,000 residents), then decreased dramatically in 1979-1994. However, brucellosis has reemerged since 1995 (interquartile range 0.11-0.23 in 1995-2003 and 1.48-2.89 in 2004-2014); the historical high occurred in 2014, and the affected area expanded from northern pastureland provinces to the adjacent grassland and agricultural areas, then to southern coastal and southwestern areas. Control strategies in China should be adjusted to account for these changes by adopting a One Health approach. PMID- 28098532 TI - Oral Transmission of L-Type Bovine Spongiform Encephalopathy Agent among Cattle. AB - To determine oral transmissibility of the L-type bovine spongiform encephalopathy (BSE) prion, we orally inoculated 16 calves with brain homogenates of the agent. Only 1 animal, given a high dose, showed signs and died at 88 months. These results suggest low risk for oral transmission of the L-BSE agent among cattle. PMID- 28098533 TI - Azithromycin-Nonsusceptible Shigella flexneri 3a in Men Who Have Sex with Men, Taiwan, 2015-2016. AB - We report an outbreak of azithromycin-nonsusceptible Shigella flexneri 3a infection in Taiwan associated with men who have sex with men. The bacterial strains belonged to the sublineage A of a recently reported outbreak lineage associated with men who have sex with men, characterized by reduced azithromycin susceptibility and circulation in shigellosis low-risk regions. PMID- 28098534 TI - Cerebrospinal Fluid Findings in an Adult with Human Metapneumovirus-Associated Encephalitis. PMID- 28098535 TI - Outbreak of Legionnaire's Disease Caused by Legionella pneumophila Serogroups 1 and 13. AB - In Japan, hot springs and public baths are the major sources of legionellosis. In 2015, an outbreak of Legionnaires' disease occurred among 7 patients who had visited a spa house. Laboratory investigation indicated that L. pneumophila serogroup 1 and 13 strains caused the outbreak and that these strains were genetically related. PMID- 28098536 TI - Emergence of blaNDM-7-Producing Enterobacteriaceae in Gabon, 2016. AB - Reports of carbapenemase-producing Enterobacteriaceae in Africa remain rare and assess mostly blaOXA-48-producing isolates from Mediterranean countries and South Africa. We identified blaNDM-7-producing Enterobacteriaceae in Gabon in 2016. The isolates contained blaNDM-7 IncX3 plasmids that were unusual and similar to the one described in a colistin-resistant Klebsiella pneumoniae SZ04 isolate from China. PMID- 28098537 TI - Persistent Infections with Diverse Co-Circulating Astroviruses in Pediatric Oncology Patients, Memphis, Tennessee, USA. AB - Human astroviruses are a major cause of pediatric gastroenteritis, especially in immunocompromised children. We conducted a retrospective study to demonstrate that diverse astrovirus genotypes can co-circulate in pediatric oncology patients. A subset of cases is associated with long-term virus shedding (range 17 183 days). PMID- 28098538 TI - Neisseria meningitidis ST11 Complex Isolates Associated with Nongonococcal Urethritis, Indiana, USA, 2015-2016. AB - At a clinic in Indianapolis, Indiana, USA, we observed an increase in Neisseria gonorrhoeae-negative men with suspected gonococcal urethritis who had urethral cultures positive for N. meningitidis. We describe genomes of 2 of these N. meningitidis sequence type 11 complex urethritis isolates. Clinical evidence suggests these isolates may represent an emerging urethrotropic clade. PMID- 28098539 TI - Incidence of Norovirus-Associated Diarrhea, Shanghai, China, 2012-2013. AB - We conducted sentinel-based surveillance for norovirus in the Pudong area of Shanghai, China, during 2012-2013, by analyzing 5,324 community surveys, 408,024 medical records, and 771 laboratory-confirmed norovirus infections among 3,877 diarrhea cases. Our analysis indicated an outpatient incidence of 1.5/100 person years and a community incidence of 8.9/100 person-years for norovirus-associated diarrhea. PMID- 28098540 TI - Diphyllobothrium nihonkaiense Tapeworm Larvae in Salmon from North America. AB - Diphyllobothriosis is reemerging because of global importation and increased popularity of eating raw fish. We detected Diphyllobothrium nihonkaiense plerocercoids in the musculature of wild pink salmon (Oncorhynchus gorbuscha) from Alaska, USA. Therefore, salmon from the American and Asian Pacific coasts and elsewhere pose potential dangers for persons who eat these fish raw. PMID- 28098541 TI - Cutavirus in Cutaneous Malignant Melanoma. AB - A novel human protoparvovirus related to human bufavirus and preliminarily named cutavirus has been discovered. We detected cutavirus in a sample of cutaneous malignant melanoma by using viral enrichment and high-throughput sequencing. The role of cutaviruses in cutaneous cancers remains to be investigated. PMID- 28098542 TI - Detection of Vaccinia Virus in Urban Domestic Cats, Brazil. AB - We investigated possible vaccinia virus (VACV) in urban house cats in Brazil. Serum samples from 6 cats were positive for VACV by PCR, indicating likely VACV circulation among house cats in urban areas of Brazil. This finding highlights the importance of epidemiologic surveillance to avoid outbreaks among urban human populations. PMID- 28098543 TI - Increasing Antibiotic Resistance in Shigella spp. from Infected New York City Residents, New York, USA. AB - Approximately 20% of Shigella isolates tested in New York City, New York, USA, during 2013-2015 displayed decreased azithromycin susceptibility. Case-patients were older and more frequently male and HIV infected than those with azithromycin susceptible Shigella infection; 90% identified as men who have sex with men. Clinical interpretation guidelines for azithromycin resistance and outcome studies are needed. PMID- 28098544 TI - Fatal Emmonsia sp. Infection and Fungemia after Orthotopic Liver Transplantation. AB - We report a fatal case of disseminated Emmonsia sp. infection in a 55-year-old man who received an orthotopic liver transplant. The patient had pneumonia and fungemia, and multisystem organ failure developed. As human habitats and the number of immunocompromised patients increase, physicians must be aware of this emerging fungal infection. PMID- 28098545 TI - Increase in Urgent Care Center Visits for Sexually Transmitted Infections, United States, 2010-2014. AB - During 2010-2014, urgent care centers saw a ~2-fold increase in the number of visits for chlamydia and gonorrhea testing and a >3-fold increase in visits by persons with diagnosed sexually transmitted infections. As urgent care becomes more popular, vigilance is required to ensure proper management of these diseases. PMID- 28098546 TI - Reoccurrence of Avian Influenza A(H5N2) Virus Clade 2.3.4.4 in Wild Birds, Alaska, USA, 2016. AB - We report reoccurrence of highly pathogenic avian influenza A(H5N2) virus clade 2.3.4.4 in a wild mallard in Alaska, USA, in August 2016. Identification of this virus in a migratory species confirms low-frequency persistence in North America and the potential for re-dissemination of the virus during the 2016 fall migration. PMID- 28098547 TI - mcr-1-Harboring Salmonella enterica Serovar Typhimurium Sequence Type 34 in Pigs, China. AB - We detected the mcr-1 gene in 21 (14.8%) Salmonella isolates from pigs at slaughter; 19 were serovar Typhimurium sequence type 34. The gene was located on IncHI2-like plasmids that also harbored IncF replicons and lacked a conjugative transfer region. These findings highlight the need to prevent further spread of colistin resistance in animals and humans. PMID- 28098549 TI - Diffuse Unilateral Subacute Neuroretinitis Caused by Ancylostoma Hookworm. AB - Diffuse unilateral subacute neuroretinitis is an ocular infectious disease caused by several distinct nematodes. Definite identification of the involved nematodes is rarely achieved. We report on the molecular-based genetic identification of an Ancylostoma ceylanicum hookworm implicated in a case of diffuse unilateral subacute neuroretinitis in a child. PMID- 28098548 TI - Nosocomial Infections with IMP-19-Producing Pseudomonas aeruginosa Linked to Contaminated Sinks, France. AB - We isolated IMP-19-producing Pseudomonas aeruginosa from 7 patients with nosocomial infections linked to contaminated sinks in France. We showed that blaIMP-19 was located on various class 1 integrons among 8 species of gram negative bacilli detected in sinks: P. aeruginosa, Achromobacter xylosoxidans, A. aegrifaciens, P. putida, Stenotrophomonas maltophilia, P. mendocina, Comamonas testosteroni, and Sphingomonas sp. PMID- 28098550 TI - Determination of Elizabethkingia Diversity by MALDI-TOF Mass Spectrometry and Whole-Genome Sequencing. AB - In a hospital-acquired infection with multidrug-resistant Elizabethkingia, matrix assisted laser desorption/ionization time-of-flight mass spectrometry and 16S rRNA gene analysis identified the pathogen as Elizabethkingia miricola. Whole genome sequencing, genus-level core genome analysis, and in silico DNA-DNA hybridization of 35 Elizabethkingia strains indicated that the species taxonomy should be further explored. PMID- 28098551 TI - Seroprevalence and Transmission of Human Influenza A(H5N1) Virus before and after Virus Reassortment, Cambodia, 2006-2014. AB - Thirty-five human influenza A(H5N1) cases were reported in Cambodia during 2013 2014 after emergence of a clade 1.1.2 reassortant virus. We tested 881 villagers and found 2 cases of pauci- or asymptomatic infection. Seroprevalence after emergence of the reassortant strain (0.2%) was lower than the aggregate seroprevalence of 1.3% reported in earlier studies. PMID- 28098552 TI - Hepatitis E Virus Infection in Solid Organ Transplant Recipients, France. AB - The rate of transfusion-transmitted hepatitis E virus (HEV) in transplant recipients is unknown. We identified 60 HEV-positive solid organ transplant patients and retrospectively assessed their blood transfusions for HEV. Seven of 60 patients received transfusions; 3 received HEV-positive blood products. Transfusion is not the major route of infection in this population. PMID- 28098553 TI - Biofilm-Forming Capability of Highly Virulent, Multidrug-Resistant Candida auris. AB - The emerging multidrug-resistant yeast pathogen Candida auris has attracted considerable attention as a source of healthcare-associated infections. We report that this highly virulent yeast has the capacity to form antifungal resistant biofilms sensitive to the disinfectant chlorhexidine in vitro. PMID- 28098554 TI - Risk Factors for Disseminated Coccidioidomycosis, United States. AB - Of 150,000 new coccidioidomycosis infections that occur annually in the United States, ~1% disseminate; one third of those cases are fatal. Immunocompromised hosts have higher rates of dissemination. We identified 8 patients with disseminated coccidioidomycosis who had defects in the interleukin-12/interferon gamma and STAT3 axes, indicating that these are critical host defense pathways. PMID- 28098555 TI - Nematophagous fungus Arthrobotrys oligospora mimics olfactory cues of sex and food to lure its nematode prey. AB - To study the molecular basis for predator-prey coevolution, we investigated how Caenorhabditis elegans responds to the predatory fungus Arthrobotrys oligospora. C. elegans and other nematodes were attracted to volatile compounds produced by A. oligospora. Gas-chromatographic mass-spectral analyses of A. oligospora derived volatile metabolites identified several odors mimicking food cues attractive to nematodes. One compound, methyl 3-methyl-2-butenoate (MMB) additionally triggered strong sex- and stage-specific attraction in several Caenorhabditis species. Furthermore, when MMB is present, it interferes with nematode mating, suggesting that MMB might mimic sex pheromone in Caenorhabditis species. Forward genetic screening suggests that multiple receptors are involved in sensing MMB. Response to fungal odors involves the olfactory neuron AWCs. Single-cell RNA-seq revealed the GPCRs expressed in AWC. We propose that A. oligospora likely evolved the means to use olfactory mimicry to attract its nematode prey through the olfactory neurons in C. elegans and related species. PMID- 28098556 TI - Genetic defects in beta-spectrin and tau sensitize C. elegans axons to movement induced damage via torque-tension coupling. AB - Our bodies are in constant motion and so are the neurons that invade each tissue. Motion-induced neuron deformation and damage are associated with several neurodegenerative conditions. Here, we investigated the question of how the neuronal cytoskeleton protects axons and dendrites from mechanical stress, exploiting mutations in UNC-70 beta-spectrin, PTL-1 tau/MAP2-like and MEC-7 beta tubulin proteins in Caenorhabditis elegans. We found that mechanical stress induces supercoils and plectonemes in the sensory axons of spectrin and tau double mutants. Biophysical measurements, super-resolution, and electron microscopy, as well as numerical simulations of neurons as discrete, elastic rods provide evidence that a balance of torque, tension, and elasticity stabilizes neurons against mechanical deformation. We conclude that the spectrin and microtubule cytoskeletons work in combination to protect axons and dendrites from mechanical stress and propose that defects in beta-spectrin and tau may sensitize neurons to damage. PMID- 28098557 TI - Length-dependent flagellar growth of Vibrio alginolyticus revealed by real time fluorescent imaging. AB - Bacterial flagella are extracellular filaments that drive swimming in bacteria. During motor assembly, flagellins are transported unfolded through the central channel in the flagellum to the growing tip. Here, we applied in vivo fluorescent imaging to monitor in real time the Vibrio alginolyticus polar flagella growth. The flagellar growth rate is found to be highly length-dependent. Initially, the flagellum grows at a constant rate (50 nm/min) when shorter than 1500 nm. The growth rate decays sharply when the flagellum grows longer, which decreases to ~9 nm/min at 7500 nm. We modeled flagellin transport inside the channel as a one dimensional diffusive process with an injection force at its base. When the flagellum is short, its growth rate is determined by the loading speed at the base. Only when the flagellum grows longer does diffusion of flagellin become the rate-limiting step, dramatically reducing the growth rate. Our results shed new light on the dynamic building process of this complex extracellular structure. PMID- 28098559 TI - Lattice Boltzmann simulations of the bead-spring microswimmer with a responsive stroke-from an individual to swarms. AB - Propulsion at low Reynolds numbers is often studied by defining artificial microswimmers which exhibit a particular stroke. The disadvantage of such an approach is that the stroke does not adjust to the environment, in particular the fluid flow, which can diminish the effect of hydrodynamic interactions. To overcome this limitation, we simulate a microswimmer consisting of three beads connected by springs and dampers, using the self-developed waLBerla and [Formula: see text] framework based on the lattice Boltzmann method and the discrete element method. In our approach, the swimming stroke of a swimmer emerges as a balance of the drag, the driving and the elastic internal forces. We validate the simulations by comparing the obtained swimming velocity to the velocity found analytically using a perturbative method where the bead oscillations are taken to be small. Including higher-order terms in the hydrodynamic interactions between the beads improves the agreement to the simulations in parts of the parameter space. Encouraged by the agreement between the theory and the simulations and aided by the massively parallel capabilities of the waLBerla-[Formula: see text] framework, we simulate more than ten thousand such swimmers together, thus presenting the first fully resolved simulations of large swarms with active responsive components. PMID- 28098558 TI - Platelet-derived growth factor (PDGF) signaling directs cardiomyocyte movement toward the midline during heart tube assembly. AB - Communication between neighboring tissues plays a central role in guiding organ morphogenesis. During heart tube assembly, interactions with the adjacent endoderm control the medial movement of cardiomyocytes, a process referred to as cardiac fusion. However, the molecular underpinnings of this endodermal myocardial relationship remain unclear. Here, we show an essential role for platelet-derived growth factor receptor alpha (Pdgfra) in directing cardiac fusion. Mutation of pdgfra disrupts heart tube assembly in both zebrafish and mouse. Timelapse analysis of individual cardiomyocyte trajectories reveals misdirected cells in zebrafish pdgfra mutants, suggesting that PDGF signaling steers cardiomyocytes toward the midline during cardiac fusion. Intriguingly, the ligand pdgfaa is expressed in the endoderm medial to the pdgfra-expressing myocardial precursors. Ectopic expression of pdgfaa interferes with cardiac fusion, consistent with an instructive role for PDGF signaling. Together, these data uncover a novel mechanism through which endodermal-myocardial communication can guide the cell movements that initiate cardiac morphogenesis. PMID- 28098560 TI - Disordered Kitaev chains with long-range pairing. AB - We study the competition of disorder and superconductivity for a generalized Kitaev model in incommensurate potentials. The generalized Kitaev model describes one dimensional spinless fermions with long-range p-wave superconducting pairing, which decays with distance l as a power law ~[Formula: see text]. We focus on the transition from the topological superconducting phase to the topologically trivial Anderson localized phase, and effects of the exponent alpha on this phase transition. In the topological superconducting phase, for a system under open boundary condition the amplitude of zero-mode Majorana fermion has a hybrid exponential-algebraic decay as the distance increases from the edge. In the Anderson localized phase, some single-particle states remain critical for very strong disorders and the number of critical states increases as alpha decreases. In addition, except for critical disorders, the correlation function always has an exponential decay at the short range and an algebraic decay at the long range. Phase transition points are also numerically determined and the topological phase transition happens earlier at a smaller disorder strength for a system with smaller alpha. PMID- 28098561 TI - Decoding of intended saccade direction in an oculomotor brain-computer interface. AB - OBJECTIVE: To date, invasive brain-computer interface (BCI) research has largely focused on replacing lost limb functions using signals from the hand/arm areas of motor cortex. However, the oculomotor system may be better suited to BCI applications involving rapid serial selection from spatial targets, such as choosing from a set of possible words displayed on a computer screen in an augmentative and alternative communication (AAC) application. Here we aimed to demonstrate the feasibility of a BCI utilizing the oculomotor system. APPROACH: We developed a chronic intracortical BCI in monkeys to decode intended saccadic eye movement direction using activity from multiple frontal cortical areas. MAIN RESULTS: Intended saccade direction could be decoded in real time with high accuracy, particularly at contralateral locations. Accurate decoding was evident even at the beginning of the BCI session; no extensive BCI experience was necessary. High-frequency (80-500 Hz) local field potential magnitude provided the best performance, even over spiking activity, thus simplifying future BCI applications. Most of the information came from the frontal and supplementary eye fields, with relatively little contribution from dorsolateral prefrontal cortex. SIGNIFICANCE: Our results support the feasibility of high-accuracy intracortical oculomotor BCIs that require little or no practice to operate and may be ideally suited for 'point and click' computer operation as used in most current AAC systems. PMID- 28098563 TI - Aortic surgery and laparoscopy: still a future in the endovascular surgery era? AB - : Laparoscopic surgery (LS) is the minimally invasive alternative to open surgery and endovascular approach for treating major aortic diseases. Only few reports in the literature describe the long-term outcomes of the laparoscopic approach for major vascular diseases. Furthermore, the widespread use of endovascular techniques has limited the use of LS to wellselected patients. This review evaluated the results of LS for aortic disease and compared the clinical outcomes of laparoscopic technique with those of open and endovascular surgery. A systematic review was performed by using the MEDLINE database, along with a meta analysis of the reported studies on the treatment of abdominal aortic aneurysm (AAA) and/or aorto-iliac occlusive disease (AIOD). Forty-three studies were analyzed (17 for AAA and 26 for AIOD), with a total of 1197 patients with AAA and 1307 patients with AIOD. Laparoscopic surgery, when performed in experienced centers, is a feasible and safe technique for the treatment of AAA and AIOD in patients unfit for open and endovascular repair. Assisted laparoscopic approach has shown better outcomes than totally laparoscopic repair, with a lower rate of mortality and morbidity. Endovascular repair, however, remains the gold standard in the treatment of AAA. KEY WORDS: Abdominal aortic aneurysm, Aorta, Aneurysm, Aorto-iliac occlusive disease, Endovascular aneurysm repair, EVAR, Laparoscopy, Endovascular, Repair, Laparoscopic Assisted, Laparoscopy Vascular, Laparoscopic surgery, Totally. PMID- 28098564 TI - Male breast cancer originating in an ectopic breast tissue in the umbilicus A Case Report. AB - INTRODUCTION: Accessory breast tissue is a rare finding in the general population with an incidence of 1-2%. Carcinomas of accessory breast tissue account for ~0.3% of breast cancers, 5% of which are arising within a supernumerary breast. They are usually diagnosed at a later stage compared with breast cancer, due to their rarity and low clinical suspicion. CASE PRESENTATION: We present the case of a 58 years old male who was admitted to our hospital for an umbilical hernia, surgical repair. During surgery a small skin biopsy was excised and sent for pathological examination as routine procedure. The histological report revealed the presence of a poorly differentiated carcinoma. Immunochemical analysis confirmed adenocarcinoma of breast origin. CONCLUSION: Carcinomas of accessory breast tissue are rare and therefore they are usually of advanced stage in time of diagnosis. Few cases have been reported in literature of accessory breast tissue carcinomas in men. To the best of our knowledge, this is the only case in the literature, of ectopic breast tissue cancer in the umbilicus. KEY WORDS: Ectopic breast, Male breast cancer, Umbilicus. PMID- 28098565 TI - Bio-Engineering tissue and V.A.C. therapy: A new method for the treatment of extensive necrotizing infection in the diabetic foot. AB - AIM: The aim of the study is to compare the standard care for progressive necrotizing infection in diabetic foot with a treatment protocol based on the association between autologous fibroblast grafts and vacuum-assisted closure therapy (V.A.C.). MATERIAL OF STUDY: A retrospective matched Case-Control study was carried out on 20 patients with diabetic foot infection, 10 treated with the standard care and 10 with our new protocol. Inclusion criteria were: acute diabetic foot necrosis (Wagner III and IV), ulcer size (30 to 80 cm2), tendon and bone exposure. Success in the treatment was evaluated as: percentage of healing at the 20th week, time of healing, deambulation, recurrence and major amputation rate. RESULTS: A 90% healing rate was observed after 20 weeks in the study group, compared to a 28.6% in the control group. The recurrence rate in the treated areas was 20% in the study group and 100% in the control group. None of the patients in either group required major amputations. DISCUSSION: We achieved very promising results by associating autologous fibroblasts grafts and V.A.C. therapy, in comparison with standard care. V.A.C. therapy seems to improve the growth rate of the fibroblasts, probably by sealing the wound and providing a moist environment following the fibroblast graft. The improved neoangiogenesis of the neo-dermis could explain the reduced recurrence rate of the study group. CONCLUSIONS: Despite the low number of patients involved and the retrospective nature of the analysis, this study showed a reliable, safe and cost-effective method of treating extensive infection in the diabetic foot. KEY WORDS: Bio Engineered Tissue, Diabetic foot, Fibroblast graft, V.A.C. THERAPY: PMID- 28098566 TI - Comprehensive surgical. Orthodontic treatment of class III malocclusion in cleft patient involving minimally invasive surgery Case report and literature review. AB - AIM: Surgical and orthodontic treatment of a teenage cleft patient. CASE REPORT: Authors describe the case of a 13 year old female cleft patient presented with class III malocclusion RESULT: The patient underwent comprehensive surgical secondary bone grafting and orthodontic treatment. Stable skeletal and occlusal class I relationship was achived and maintained in the post treatment observation period till the age of 16. DISCUSSION: Although several authors suggests primary gingivoperiosteoplasty, other advocates that such early intervention can cause later restrictions in maxillary growth. For alveolar reconstruction, maxillary growth and dental age were the main considerations in determining the timing of surgical intervention. CONCLUSION: This case showed that borderline cases of complex dentoalveolar and skeletal anomaly in cleft patients could be successfully treated with comprehensive secondary bone grafting and orthodontic treatment thus avoiding the need for orthognatic surgery. KEY WORDS: Alveolar bone grafting, Cleft, Malocclusion. PMID- 28098567 TI - Multiple enlarged lymph nodes in axilla A case report of Merkel Cell Carcinoma. AB - : We present the case of a 59-year-old man with a growing mass in his left axillary area. A biopsy and immunostainings demonstrated neuroendocrine carcinoma, which is Merkel cell carcinoma (MCC). The disease is characterised by neurosecretory granules in tumor cells. MCC is a rare entity. The disease is predominantly seen in the inguinal region or the axilla and typically found incidentally. It presents clinically as multiple lymph nodes enlargement. Yet controversy exists regarding treatment modality of MCC. We report the first case of MCC in (Left) Axilla where there were two cases reported previously in (Right) Axilla. KEY WORDS: Lymph nodes enlargement, Merkel cell carcinoma, Radiotherapy. PMID- 28098568 TI - Giant retroperitoneal dedifferentiated liposarcoma. AB - INTRODUCTION: Liposarcoma is the most frequent type of retroperitoneal sarcomas. Dedifferentiated liposarcoma is the least common subtype and is an extremely rare tumor. CASE REPORT: We present the case of a 53-year-old male who was referred with a giant retroperitoneal mass. The patients' mass was deemed unresectable by the previous institution and received chemotherapy with no benefit. We macroscopically removed the 38x32 cm mass with right nefrectomy. Pathological examination revealed dedifferentiated liposarcoma. CONCLUSION: Surgery is the gold standart in the treatment of retroperitoneal sarcomas. Giant masses present a challenge for the surgeon with possible major vascular injuries and multiorgan resections. Therefore it is important for these patients to be referred for surgery without delay. KEY WORDS: Dedifferentiated liposarcoma, Liposarcoma, Retroperitoneal sarcoma. PMID- 28098569 TI - Human Papillomavirus Genotyping of Incidental Malignant and Premalignant Lesions on Hemorrhoidectomy Specimens. AB - Routine histopathologic examination of hemorrhoidectomy specimens is controversial having been described as not useful and expensive with few of these common cases demonstrating incidental lesions. However, unexpected premalignant and malignant lesions have been detected on excised hemorrhoids. The high-risk human papillomavirus (HR-HPV) types associated with these incidentally identified high-grade lesions are presently unknown. We aimed to identify cases of incidental high-grade anal intraepithelial neoplasia (HG-AIN) and anal squamous cell carcinoma incidentally discovered on hemorrhoidectomy specimens, genotype HR HPVs from these lesions, and assess p53 and p16 expression by immunohistochemistry to identify risk factors for their development. With institutional approval, cases with associated demographics from 1995 to 2015 were reviewed to identify and confirm incidental HG-AIN or squamous cell carcinoma in hemorrhoidectomy specimens. Genotyping for HR-HPV types and immunohistochemical staining for p53 and p16 was performed. Statistical analysis comparing HPV genotypes, p53 and p16 staining, and potential risk factors by the Fisher exact test was performed. In the largest series of incidental high-grade lesions on hemorrhoidectomy, HPV 16 was the most common HR-HPV detected though multiple-type infections were common including some HPV 16/18-negative cases. By genotyping, HPV 39 was significantly associated with IV-drug abuse history (P=0.0015) and HIV positive status (P=0.037), whereas HPV 58 detection correlated with chemotherapy induced immunosuppression (P=0.029). There was frequent overlap between p53 staining and HPV positivity, particularly when HPV 31 was detected. We also identified several mimickers of HG-AIN that may present diagnostic challenges in these specimens. Our data support continued routine examination of hemorrhoidectomy specimens and suggest that adjunctive studies such as immunohistochemistry for challenging cases may be useful. PMID- 28098570 TI - Preferential Localization of MET Expression at the Invasion Front and in Spreading Cells Through Air Spaces in Non-Small Cell Lung Carcinomas. AB - The involvement of the HGF/MET pathway in acquisition of an invasive phenotype in non-small cell lung carcinomas (NSCLCs) suggests that MET inhibitors might prove effective against these cancers, but clinical trials have yielded conflicting results. The aim of our study was to evaluate how intratumoral heterogeneity (ITH) of MET staining affects the determination of MET status for therapeutic purposes. We analyzed 64 NSCLC samples, including 33 adenocarcinomas (ADCs) and 31 squamous cell carcinomas (SCCs). We used immunohistochemistry to detect MET and phospho-MET on whole slides and determined the MET SP44 immunoscore and the H score. A high METMab score (2+/3+) was observed in 34% of NSCLCs and was more prevalent in ADCs (52%) than in SCCs (16%). We found ITH in 73% of ADCs and 77% of SCCs, with higher levels of MET and phospho-MET at the invasion front (in 52% of ADCs and 22% of SCCs) and in tumor cells spreading through air spaces in ADCs. Within-sample ITH was high in 40% of the ADCs and 29% of the SCCs. When different samples from the same tumor were compared, discordant assessments (high MET vs. low MET) were made for 12% of the ADCs and 10% of the SCCs. C-MET and phospho-MET overexpression occurred preferentially in ADCs and in areas involved in tumor progression, in support of the view that MET activation plays a role in the development of an invasive phenotype in NSCLC. To use MET status adequately as a biomarker, one must take the resulting high level of ITH into account. PMID- 28098571 TI - Operating Room Anesthesia Subspecialization Is Not Associated With Significantly Greater Quality of Supervision of Anesthesia Residents and Nurse Anesthetists. AB - BACKGROUND: Supervision of anesthesia residents and nurse anesthetists is a major responsibility of faculty anesthesiologists. The quality of their supervision can be assessed quantitatively by the anesthesia residents and nurse anesthetists. Supervision scores are an independent measure of the contribution of the anesthesiologist to patient care. We evaluated the association between quality of supervision and level of specialization of anesthesiologists. METHODS: We used two 6-month periods, one with no feedback to anesthesiologists of the residents' and nurse anesthetists' evaluations, and the other with feedback. Supervision scores provided by residents and nurse anesthetists were considered separately. Sample sizes among the 4 combinations ranged from n = 51 to n = 62 University of Iowa faculty. For each supervising anesthesiologist and 6-month period, we calculated the proportion of anesthetic cases attributable to each anesthesia Current Procedural Terminology code. The sum of the square of the proportions, a measurement of diversity, is known as the Herfindahl index. The inverse of this index represents the effective number of common procedures. The diversity (degree of specialization) of each faculty anesthesiologist was measured attributing each case to: (1) the anesthesiologist who supervised for the longest total period of time, (2) the anesthesiologist who started the case, or (3) the anesthesiologist who started the case, limited to cases started during "regular hours" (defined as nonholiday Monday to Friday, 07:00 AM to 02:59 PM). Inferential analysis was performed using bivariate-weighted least-squares regression. RESULTS: The point estimates of all 12 slopes were in the direction of greater specialization of practice of the evaluated faculty anesthesiologist being associated with significantly lower supervision scores. Among supervision scores provided by nurse anesthetists, the association was statistically significant for the third of the 6-month periods under the first and second ways of attributing the cases (uncorrected P < .0001). However, the slopes of the relationships were all small (eg, 0.109 +/- 0.025 [SE] units on the 4-point supervision scale for a change of 10 common procedures). Among supervision scores provided by anesthesia residents, the association was statistically significant during the first period for all 3 ways of attributing the case (uncorrected P < .0001). However, again, the slopes were small (eg, 0.127 +/- 0.027 units for a change of 10 common procedures). CONCLUSIONS: Greater clinical specialization of faculty anesthesiologists was not associated with meaningful improvements in quality of clinical supervision. PMID- 28098572 TI - Metastatic Organotropism: An Intrinsic Property of Breast Cancer Molecular Subtypes. AB - It has long been known that some cancers have the propensity to metastasize to certain organs thus creating a nonrandom distribution of sites for distant relapse, a phenomenon known as "metastatic organotropism." Some of these examples include ovary primary to abdominal cavity, prostate primary to bone, and pancreas primary to liver. In contrast, other tumor types, such as mammary and renal cell carcinoma, can relapse in multiple organs although approximately half of advanced breast cancers metastasize to bone. On the other hand gene expression profiling studies have identified various breast cancer classes with prognostic significance. Recent studies have revealed that breast cancer subtypes differ not only in primary tumor characteristics but also in their metastatic behavior. In particular, the luminal tumors are remarkable for their significant bone-seeking phenotype; the HER2 subtype demonstrates a significant liver-homing characteristic; whereas so-called triple-negative breast cancers predispose to lung metastases. These findings suggest that this knowledge could potentially be utilized in the development of effective disease surveillance strategies in the pursuit of precision medicine, thus necessitating further investigation. PMID- 28098573 TI - Managing Maternal Sepsis: Early Warning Criteria to ECMO. AB - Maternal sepsis is now a leading cause of direct maternal death during pregnancy. This review addresses the latest advances in the identification and management of critically ill parturients. Specifically, this review will focus on the vulnerability of pregnant women to sepsis, the utility of early warning criteria in the identification of the septic parturient, emphasize the immediate antibiotic management of suspected sepsis, and elaborate upon the latest understanding in the ventilatory management of parturients with sepsis. PMID- 28098574 TI - New Developments in Robotics and Single-site Gynecologic Surgery. AB - Within the last 10 years there have been significant advances in minimal-access surgery. Although no emerging technology has demonstrated improved outcomes or fewer complications than standard laparoscopy, the introduction of the robotic surgical platform has significantly lowered abdominal hysterectomy rates. While operative time and cost were higher in robotic-assisted procedures when the technology was first introduced, newer studies demonstrate equivalent or improved robotic surgical efficiency with increased experience. Single-port hysterectomy has not improved postoperative pain or subjective cosmetic results. Emerging platforms with flexible, articulating instruments may increase the uptake of single-port procedures including natural orifice transluminal endoscopic cases. PMID- 28098575 TI - Obstetric Anesthesia Liability Concerns. AB - Obstetric practice carries a high risk of medical liability and involves both obstetricians and anesthesiologists. Analysis of data from the Anesthesia Closed Claims Project database shows an increase in the proportion of anesthesia claims for maternal death and brain damage between the 1990s and 2000 and later, primarily due to hemorrhage. The proportion of claims for newborn brain damage remained unchanged while those for maternal nerve injury and minor injuries decreased. Use of massive transfusion protocols and clinical drills have been shown to improve outcomes from hemorrhage. Good communication and teamwork are critical for reducing obstetric liability. PMID- 28098576 TI - Grafting and Dental Implantation in Patients With Jawbone Cavitation: Case Series and 3-Year Follow-Up. AB - PURPOSE: Jawbone cavitation (BC) is not uncommon and is considered to be related to some cases of unexpected implant displacement into deep jawbone space. Here, a series of cases with BC is described, in which the lesions were accidentally found and successfully treated by bone grafting and dental implantation. METHODS: Thirty-four partially edentulous patients who were found to have BC during dental implant surgeries were included in this study. Alloplast bone substitute (beta tricalcium phosphate) grafting with immediate or staged locking-taper implant placement was performed. Bone filling and implants on BC were followed up to 36 months, and they were evaluated clinically and radiographically to verify treatment outcome. RESULTS: A total of 41 BCs were found at premolar and molar regions, which involved one or more teeth breadth. Nearly most of the lesions occurred in the mandible (95.1%, 39/41). Histologically, they were compatible with focal osteoporotic marrow defects. Fifty-two locking-taper implants and final restorations were delivered on 38 BCs. One implant failed due to loss of integration. The overall cumulative 3-year implant survival rate was 98.1%. CONCLUSION: By carefully examining and managing the surgical bed, the current treatment modality was shown to yield a satisfactory outcome for restoration of edentulous ridge with underneath BC. PMID- 28098578 TI - Helicobacter pylori and Risk of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. AB - BACKGROUND/OBJECTIVES: Helicobacter pylori (H. pylori) is the most common chronic bacterial infection. Patients with H. pylori infection may be at an increased risk of nonalcoholic fatty liver disease (NAFLD) because of chronic inflammation and insulin resistance. Several epidemiologic studies attempting to determine this risk have yielded inconsistent results. This meta-analysis was conducted with the aims to summarize all available evidence and estimate the risk of NAFLD in patients with H. pylori infection. METHODS: A literature search was performed using MEDLINE and EMBASE database from inception to June 2016. Studies that reported relative risks, odd ratios, or hazard ratios comparing the risk of NAFLD among patients with H. pylori infection versus without H. pylori infection were included. Pooled odds ratios and 95% confidence intervals were calculated using a random-effect, generic inverse variance method. RESULTS: Six studies met our eligibility criteria and were included in this analysis. We found a statistically significant increased risk of NAFLD among patients with H. pylori infection with the pooled odds ratios of 1.21 (95% confidence interval, 1.07-1.37). The statistical heterogeneity was low with an I of 49%. CONCLUSIONS: A significantly increased risk of NAFLD among patients with H. pylori infection was demonstrated in this meta-analysis. Further studies are required to clarify how this risk should be addressed in clinical practice. PMID- 28098579 TI - XEN Gel Stent Internal Ostium Occlusion: Ab-Interno Revision. AB - Minimally invasive glaucoma surgery aims to provide a safer and less-invasive means of reducing IOP compared with traditional surgery, with the goal of reducing the need for topical medications. The XEN gel stent is an ab-interno minimally invasive glaucoma surgery device that approaches intraocular pressure reduction by creating a subconjunctival drainage pathway. As with any new device there is lack of experience and knowledge about its long-term results in terms of efficacy, technique, and complications. We report a clinical case of a XEN blood clot internal ostium obstruction and how it was managed. The ab-interno approach with microforceps seems a minimally invasive, safe, and effective procedure. PMID- 28098580 TI - An Investigation of Treatment Engagement Among Returning Veterans With Problematic Anger. AB - Anger is a commonly reported problem among returning veterans, yet little attention has been devoted to studying treatment engagement among veterans who report anger problems but do not have posttraumatic stress disorder (PTSD). This study compares Iraq-Afghanistan veterans with anger/no PTSD (n = 159) to others reporting significant PTSD symptoms (n = 285) and those reporting neither anger nor PTSD (n = 716) on rates of treatment utilization, perceived barriers to treatment, and preferences for care. Relative to the PTSD group, the anger/no PTSD group was significantly less likely to have received mental health treatment in the last year, despite endorsing barriers to treatment at a lower rate. Furthermore, the anger/no-PTSD group endorsed fewer preferences than the PTSD group. Results suggest that the anger/no-PTSD group is a unique subgroup that may be less likely to identify a need for treatment. Implications are discussed. PMID- 28098577 TI - Mitochondria Initiate and Regulate Sarcopenia. AB - We present the hypothesis that an accumulation of dysfunctional mitochondria initiates a signaling cascade leading to motor neuron and muscle fiber death and culminating in sarcopenia. Interactions between neural and muscle cells that contain dysfunctional mitochondria exacerbate sarcopenia. Preventing sarcopenia will require identifying mitochondrial sources of dysfunction that are reversible. PMID- 28098581 TI - Timing of Pavlik Harness Initiation: Can We Wait? AB - BACKGROUND: Developmental dysplasia of the hip is effectively treated with a Pavlik harness (PH) within the first 6 months of life. Over 80% of unstable hips in the newborn period will naturally stabilize by 2 months of age. If there is no difference in the effectiveness of initiating PH treatment at 1 week compared with 4 weeks of age, waiting may allow the hips to naturally stabilize and avoid treatment. The purpose of this study is to evaluate whether the timing of PH implementation influences its effectiveness in the treatment of developmental dysplasia of the hip. METHODS: A retrospective review was conducted between 2004 and 2010. Patients were included if PH therapy was prescribed for hip instability or dislocation at or before 6 months of age. PH failure was defined as requiring any operative procedure for definitive management. Groups were divided based on the age at which the PH was initiated-group1=<30 days, group 2=30 to 60 days, group 3=>60 days. RESULTS: A total of 176 children were included with 38 (21.6%) failing PH treatment. The mean age at PH initiation was 1.3 months (SD=1.3) in the successfully treated children and 1.4 months (SD=1.2) in the failures (P=0.77). There was no difference in the failure rates by age with group 1=19.1% (18/94), group 2=22.5% (9/40), and group 3=26.2% (11/42) (P=0.87). There was no statistical difference with respect to sex or breech positioning in the success or failure groups; however, there was a higher percentage of bilateral involvement in the failure group (P=0.04). CONCLUSIONS: Patients who had PH initiation before 30 days of age were no more or less likely to fail than when PH was initiated after 30 days of age. Parents can be counseled that waiting until after 30 days of age is appropriate before PH implementation. By avoiding swaddling during this period, the hips may stabilize without treatment and allow for more parental-infant bonding before implementation of PH. LEVEL OF EVIDENCE: Level III-therapeutic, case control study. PMID- 28098583 TI - Dyschromatopsia in Multiple Sclerosis Patients: A Marker of Subclinical Involvement?: Response. PMID- 28098582 TI - Dyschromatopsia in Multiple Sclerosis Patients: A Marker of Subclinical Involvement?: Comment. PMID- 28098584 TI - Interrater Agreement of Manual Palpation for Identification of Myofascial Trigger Points: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To achieve a statistical estimate of the agreement of manual palpation for identification of myofascial trigger points (MTrPs) and secondarily to investigate potential factors impacting the agreement of this technique. METHODS: We searched MEDLINE(R) and Embase for studies examining the reproducibility of manual palpation for the identification of MTrPs from the year 2007 to present. In addition, we utilized studies identified by 2 comprehensive systematic reviews that covered the period before 2007. The included studies were original peer reviewed research articles and included Cohen kappa measures or data with which to calculate Cohen kappa. Studies were excluded if they lacked a measure of variability or information required to calculate variability. Studies that examined palpation through body cavities were also excluded. Of the 18 potentially relevant articles only 6 met inclusion criteria including 363 patients. Modified QUADAS tool was used to assess study validity. Subgroup comparisons were made utilizing Q and Z tests. RESULTS: An estimate of kappa=0.452 (95% confidence interval, 0.364-0.540) was obtained for interrater agreement of manual palpation of MTrPs. Localized tenderness (kappa=0.676) and pain recognition (kappa=0.575) were the most reliable criteria. Only 1 study met inclusion criteria for intrarater agreement and therefore no meta-analysis was performed. DISCUSSION: Use of manual palpation for identification of MTrPs is unreliable, and future investigation should focus on integration with more reliable techniques. PMID- 28098585 TI - The Missing Record of Mental Status in Written Sign-outs. AB - OBJECTIVE: The aim of the study was to determine how frequently mental status and mental status changes are documented in the written patient summary ("sign-out") provided to covering physicians. PATIENTS AND METHODS: This was a retrospective cohort study of general medical patients hospitalized between March 16, 2009, and March 15, 2010, conducted at 2 teaching hospitals. Participants included patients with mental status change adverse events (MSAEs) and their providers. Chart review was performed to identify patients with MSAEs and details about these events. Sign-outs were reviewed for documentation of mental status. Main outcome measures were (1) proportion of patients with MSAEs who had mental status ever recorded in sign-out entries and (2) the proportion of patients with MSAEs whose change in mental status was recorded in the sign-out. RESULTS: Sixty-eight patients had MSAEs and were included in the sample. Fifty percent of MSAEs were attributed to medications; 75% of these events were first detected by nurses. Only 25% of patients with MSAEs had their change in mental status recorded in sign-outs. CONCLUSIONS: Recording mental status in written sign-outs is uncommon. Particularly concerning is that patients with MSAEs identified by chart review seldom had sign-outs that reflected those events. Interventions should be designed to increase the recording of this information in sign-outs. PMID- 28098586 TI - Comparing the Outcomes of Reporting and Trigger Tool Methods to Capture Adverse Events in the Emergency Department. AB - BACKGROUND: Little is known about which methods are best for detecting adverse events in the emergency department (ED). OBJECTIVES: This study compared the ability of trigger tool and reporting methods to capture adverse events in the ED and investigated the characteristics of the adverse events identified by each. METHODS: This 1-year prospective observational cohort study evaluated a monitoring system that combined 2 reporting methods and 5 trigger tool methods to capture adverse events in the ED of an academic medical center. Measurement outcomes included the number, type, and physical impact of the captured adverse events. RESULTS: Among 69,327 adult nontrauma ED visits, 285 adverse events were identified. Of these adverse events, 77.2% were identified using reporting methods, 26% using trigger tool methods, and 3.2% using both methods. Most patients (81.7%) incurred temporary, minor physical impacts. Of the adverse events that occurred, 86.7% were related to clinical performance. Compared with reporting methods, trigger tool methods had a lower positive predictive rate to identify adverse events (odds ratio [OR], 0.1; 95% confidence interval [CI], 0.09 0.16), a greater proportion of adverse events occurring during the preinterventation and postintervention phases (OR, 17.0; 95% CI, 8.48-34.16), and more cases of severe physical impact or death (OR, 5.4; 95% CI, 2.62-11.10). CONCLUSIONS: The reporting methods more effectively captured greater numbers of adverse events, whereas the adverse events captured by the trigger tool methods were more likely to be severe physical impacts. The combined use of the different methods had synergistic benefits for monitoring adverse events in the ED.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 28098587 TI - Reducing the Shock of Acute Respiratory Distress Syndrome: Is Veno-Venous ECMO a Viable Therapy in the Hemodynamically Unstable Patient? PMID- 28098588 TI - Choice of Anesthesia for Cesarean Delivery: An Analysis of the National Anesthesia Clinical Outcomes Registry. AB - Neuraxial anesthesia use in cesarean deliveries (CDs) has been rising since the 1980s, whereas general anesthesia (GA) use has been declining. In this brief report we analyzed recent obstetric anesthesia practice patterns using National Anesthesiology Clinical Outcomes Registry data. Approximately 218,285 CD cases were identified between 2010 and 2015. GA was used in 5.8% of all CDs and 14.6% of emergent CDs. Higher rates of GA use were observed in CDs performed in university hospitals, after hours and on weekends, and on patients who were American Society of Anesthesiologists class III or higher and 18 years of age or younger. PMID- 28098589 TI - Can Mandibular Condylar Mobility Sonography Measurements Predict Difficult Laryngoscopy? AB - BACKGROUND: Limited mandibular condylar mobility plays an important role in difficult laryngoscopy. Indirect assessment methods, such as mouth opening, have been proven to be useful predictors of difficult laryngoscopy. Sonography is a new direct assessment method for the limited mandibular condylar mobility. However, whether this method could be used in predicting difficult laryngoscopy still remains unknown. This study aimed to observe its ability to predict difficult laryngoscopy. METHODS: Adult patients who were administered tracheal intubations for elective surgery under general anesthesia were enrolled in the study. Mandibular condylar mobility was assessed by sonography through condylar translation measurements. Beside mouth opening, other indirect variables that correlated with temporomandibular joint mobility, such as mandibular protrusion distance, upper lip bite test, and whether the condyle-tragus distance was <1 finger breadth, were also evaluated before anesthesia. The primary outcome was difficult laryngoscopy defined as the Cormack-Lehane level 3 or 4. RESULTS: A total of 484 patients were prospectively included, and difficult laryngoscopy was reported in 41 patients. The condylar translation prediction criterion for difficult laryngoscopy was <=10 mm. The condylar translation was correlated with Cormack-Lehane level (Spearman correlation coefficient, -0.46; 99% confidence interval [CI], -0.55 to -0.36) and owned the highest area under the receiver operating characteristic curve (0.93; 99% CI, 0.90 to 0.96, compared with that of the other predictors, P < .001) with difficult laryngoscopy. The condylar translation <=10 mm was with a considerable kappa value (kappa = 0.52; 99% CI, 0.37 to 0.67) to difficult laryngoscopy and proved to be an independent predictor by a multivariate logistic regression. CONCLUSIONS: Compared with indirect assessments, such as mouth opening and other parameters, mandibular condylar mobility, as assessed directly using sonography, was correlated with difficult laryngoscopy and demonstrated an independent and notably predictive property. PMID- 28098590 TI - Analgesia and Sedation Requirements in Mechanically Ventilated Trauma Patients With Acute, Preinjury Use of Cocaine and/or Amphetamines. AB - BACKGROUND: The purpose of this study was to determine whether mechanically ventilated trauma patients with a positive urine drug screen (UDS) for cocaine and/or amphetamines have different opioid analgesic and sedative requirements compared with similar patients with a negative drug screen for these stimulants. METHODS: This retrospective, single-center cohort study at a tertiary care, academic medical and level 1 trauma center in the United States included patients >=16 years of age who were admitted to an adult intensive care unit with a diagnosis of trauma between 2009 and 2013 with a UDS documented within 24 hours of admission, and were mechanically ventilated for >24 hours. The primary end point was the daily dose of opioid received during mechanical ventilation, expressed as morphine equivalents, for patients presenting with a positive UDS for cocaine and/or amphetamines compared with patients with a negative UDS for these stimulants. Secondary end points included the daily benzodiazepine dose and median infusion rates of propofol and dexmedetomidine received during mechanical ventilation, duration of mechanical ventilation, intensive care unit and hospital length of stay, and in-hospital mortality. Analgesic and sedative goals were similar for the duration of the study period, and both intermittent and continuous infusions of opioids and sedatives were administered to achieve these targets, although a standardized approach was not used. A multivariate logistic regression analysis and a propensity-adjusted model evaluated patient characteristics predictive of a higher median opioid requirement. RESULTS: A total of 150 patients were included in the final analysis. In a univariate analysis, opioid and sedative requirements were similar for patients presenting with a positive UDS for cocaine and/or amphetamines compared with patients with a negative UDS for these stimulants. In the multivariate regression analysis, increasing age and Abbreviated Injury Scale (head and neck) were associated with decreased daily opioid requirements (odds ratio [OR], .95, 95% confidence interval [CI], .93-.97 and OR, .71, 95% CI, .65-.77, respectively), whereas preinjury stimulant use was not predictive of opioid requirements (OR, .88, 95% CI, .40-1.90). In a propensity score--adjusted model, preinjury stimulant use was similarly not predictive of opioid requirements during mechanical ventilation (OR, .97, 95% CI, .44-2.11). CONCLUSIONS: For trauma patients presenting with acute, preinjury use of cocaine and/or amphetamines, analgesic and sedative requirements are variables and may not be greater than those patients presenting with a stimulant-negative UDS to achieve desirable pain control and depth of sedation, although this observation should be interpreted cautiously in light of the wide CI observed in the propensity score--adjusted model. Although unexpected, these findings indicate that empirically increasing analgesic and sedative doses based on positive UDS results for these stimulants may not be necessary. PMID- 28098592 TI - Protocolized Early Sepsis Care Is Not Only Helpful for Patients: It Prevents Medical Errors. PMID- 28098591 TI - Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. AB - OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012." DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality. PMID- 28098593 TI - Familial dysbetalipoproteinemia: an underdiagnosed lipid disorder. AB - PURPOSE OF REVIEW: To review pathophysiological, epidemiological and clinical aspects of familial dysbetalipoproteinemia; a model disease for remnant metabolism and remnant-associated cardiovascular risk. RECENT FINDINGS: Familial dysbetalipoproteinemia is characterized by remnant accumulation caused by impaired remnant clearance, and premature cardiovascular disease. Most familial dysbetalipoproteinemia patients are homozygous for apolipoprotein epsilon2, which is associated with decreased binding of apolipoprotein E to the LDL receptor. Although familial dysbetalipoproteinemia is an autosomal recessive disease in most cases, 10% is caused by autosomal dominant mutations. Of people with an epsilon2epsilon2 genotype 15% develops familial dysbetalipoproteinemia, which is associated with secondary risk factors, such as obesity and insulin resistance, that inhibit remnant clearance by degradation of the heparan sulfate proteoglycan receptor. The prevalence of familial dysbetalipoproteinemia ranges from 0.12 to 0.40% depending on the definition used. Clinical characteristics of familial dysbetalipoproteinemia are xanthomas and mixed hyperlipidemia (high total cholesterol and triglycerides); the primary lipid treatment goal in familial dysbetalipoproteinemia is non-HDL-cholesterol; and treatment consists of dietary therapy and treatment with statin and fibrate combination. SUMMARY: Familial dysbetalipoproteinemia is a relatively common, though often not diagnosed, lipid disorder characterized by mixed hyperlipidemia, remnant accumulation and premature cardiovascular disease, which should be treated with dietary therapy and statin and fibrate combination. PMID- 28098595 TI - Editorial. PMID- 28098594 TI - Mediators of diabetic neuropathy: is hyperglycemia the only culprit? AB - PURPOSE OF REVIEW: Diabetic peripheral neuropathy (DPN) is a disabling, highly prevalent complication of both type 1 and type 2 diabetes mellitus (T1DM and T2DM). Large clinical studies support the concept that, in addition to hyperglycemia, components of the metabolic syndrome (MetS) may underlie the pathogenesis of DPN, especially in T2DM. This review will present the evidence supporting the MetS and its individual components as potential causal factors for the development of neuropathy. RECENT FINDINGS: In addition to poor glycemic control and duration of diabetes, components of MetS such as dyslipidemia, obesity, and hypertension may have an important impact on the prevalence of DPN. Obesity and prediabetes have the most data to support their role in neuropathy, whereas hypertension and dyslipidemia have more mixed results. Nonmetabolic factors, such as genetic susceptibility, age, height, sex, smoking, and alcohol, have also been highlighted as potential risk factors in peripheral neuropathy, although the exact contribution of these factors to DPN remains unknown. SUMMARY: DPN is a chronic and disabling disease, and the accurate identification and modification of DPN risk factors is important for clinical management. Recent data support a role for components of the MetS and other risk factors in the development of DPN, offering novel targets beyond hyperglycemia for therapeutic development. PMID- 28098596 TI - Erythema Nodosum Leprosum-Like Lesions Are a Histopathologic Pattern in Whipple's Disease and a Sign of the Immune Reconstitution Inflammatory Syndrome: A Case Series and Review of the Literature. AB - Inflammatory and subcutaneous nodules can arise in treated and untreated cases of Whipple disease (WD). The inflammatory immune reconstitution syndrome describes paradoxical clinical inflammatory worsening of a preexisting condition because of a return of immune function. Clinicopathologic examination of 4 patients with WD who presented with erythema nodosum leprosum (ENL)-like lesions and the findings of a systematic review of this phenomenon revealed that ENL-like lesions occurred in predominantly middle-aged male patients who suffered from WD, mostly on the legs. Patients showed a nonvasculitic, mostly septal panniculits with neutrophils, macrophages, and lymphocytes. Numerous bacteria-laden periodic acid Schiff + macrophages and free bacilli were detected in the dermis, as well as subcutaneous septae and adipose lobules. These lesions occurred in both untreated and treated patients as part of inflammatory immune reconstitution syndrome. In conclusion, ENL-like lesions represent a characteristic histopathologic pattern associated with WD, which can occur in different contexts whenever there is a change in the immunological status of the patient. This change can be triggered by antimicrobial treatment, immunomodulatory and immunosuppressant therapy, or occur spontaneously, rarely. PMID- 28098597 TI - Sporadic Trichoblastomas and Those Occurring in the Setting of Multiple Familial Trichoepithelioma/Brooke-Spiegler Syndrome Show No BAP1 Loss. PMID- 28098598 TI - Science of intracrinology in postmenopausal women. AB - OBJECTIVE: To illustrate the marked differences between classical endocrinology that distributes hormones to all tissues of the body through the bloodstream and the science of intracrinology, whereby each cell of each peripheral tissue makes a small and appropriate amount of estrogens and androgens from the inactive precursor dehydroepiandrosterone (DHEA), DHEA being mainly of adrenal origin. Because only the inactivated sex steroids are released in the blood, influence in the other tissues is avoided. METHODS: Molecular biology has been used for the identification/characterization of the steroid-forming and steroid-inactivating enzymes, whereas steroids have been measured by mass spectrometry-based assays validated according to the US Food and Drug Administration guidelines. RESULTS: Evolution over 500 million years has engineered the expression of about 30 steroid-forming enzymes specific for each peripheral tissue. These tissue specific enzymes transform DHEA into the appropriate small amounts of estrogens and androgens for a strictly intracellular and local action. Humans, contrary to species below primates, also possess intracellular steroid-inactivating enzymes, especially glucuronyl transferases and sulfotransferases, which inactivate the estrogens and androgens at their local site of formation, thus preventing the release of a biologically significant amount of estradiol (E2) and testosterone in the circulation. Since DHEA becomes the unique source of sex steroids after menopause, serum E2 and testosterone are thus maintained at low biologically inactive concentrations with no activity outside the cells of origin. DHEA secretion, unfortunately, starts decreasing at about the age of 30 at various rates in different women. Moreover, there is no feedback mechanism to increase DHEA secretion when the concentration of serum DHEA decreases. Considering this mechanism is unique to the human, it seems logical to replace DHEA locally in women suffering from vulvovaginal atrophy (genitourinary syndrome of menopause). The clinical data obtained using a small dose of intravaginal DHEA (prasterone) confirm the mechanisms of intracrinology mentioned above which avoid biologically significant changes in serum E2 and testosterone. CONCLUSIONS: The symptoms and signs of vulvovaginal atrophy (genitourinary syndrome of menopause) can be successfully treated by the intravaginal administration of DHEA without safety concerns. This strategy exclusively replaces in the vagina the missing cell specific intracellular estrogens and androgens. This approach avoids systemic exposure and the potential risks of estrogen exposure for the tissues other than the vagina. PMID- 28098599 TI - Is there a SERM in your menopause toolkit? AB - Over the past 3 decades, compounds called selective estrogen receptor modulators (SERMs) have been developed that block the estrogen receptor in some tissues (estrogen receptor antagonists) or stimulate the estrogen receptor in other tissues (estrogen receptor agonists). This Practice Pearl focuses on SERMs that clinicians can use for menopausal patients. PMID- 28098610 TI - Images in Anesthesiology: Laryngeal Cleft. PMID- 28098612 TI - Cutaneous Mitochondrial Po2: A Beginning of a New Era? PMID- 28098613 TI - In Reply. PMID- 28098614 TI - Flumazenil Modulation of the gamma-Aminobutyric Acid Type A Receptor: Competitive versus Noncompetitive Antagonism at the Agonist-binding Site. PMID- 28098615 TI - A Rising Tide Lifts All Boats: Increased Ventilation May Be Involved in Accelerated Recovery from Isoflurane Anesthesia after Flumazenil Administration. PMID- 28098616 TI - In Reply. PMID- 28098617 TI - Nobel Prize for Anesthesia Pioneer. PMID- 28098618 TI - In Reply. PMID- 28098619 TI - As the Pendulum Swings from the Needle to the Scalpel, the Evolution of Emergency Airway Management Will Continue. PMID- 28098620 TI - In Reply. PMID- 28098621 TI - LONG-TERM FOLLOW-UP OF RETINAL PIGMENT EPITHELIUM RESTORATION AFTER A TRIPLE TEAR. AB - PURPOSE: To demonstrate longitudinal multimodal imaging findings in a case of neovascular age-related macular degeneration presenting with multiple retinal pigment epithelium (RPE) tears showing progressive RPE restoration. METHODS: Observational clinical case report. RESULTS: A 79-year-old woman diagnosed with neovascular age-related macular degeneration developed 3 consecutive RPE tears in her right eye during the course of treatment with intravitreal anti-vascular endothelial growth factor therapy. The RPE tears initially appeared hypoautofluorescent on fundus autofluorescence. Spectral domain optical coherence tomography showed contractile folds of the RPE with adjacent subretinal fluid and overlying ellipsoid zone disruption. Over an 8-year follow-up period, the RPE defects progressively resolved with a return of patchy fundus autofluorescence. Eye-tracked spectral domain optical coherence tomography showed gradual restoration of the RPE band defects over an enlarging Type 1 neovascular lesion. CONCLUSION: Some RPE tears may show observable remodeling and restoration over time. These changes may be followed longitudinally with multimodal imaging, including eye-tracked spectral domain optical coherence tomography and fundus autofluorescence. PMID- 28098622 TI - Physician-Assisted Suicide and Euthanasia in the ICU: A Dialogue on Core Ethical Issues. AB - OBJECTIVE: Many patients are admitted to the ICU at or near the end of their lives. Consequently, the increasingly common debate regarding physician-assisted suicide and euthanasia holds implications for the practice of critical care medicine. The objective of this article is to explore core ethical issues related to physician-assisted suicide and euthanasia from the perspective of healthcare professionals and ethicists on both sides of the debate. SYNTHESIS: We identified four issues highlighting the key areas of ethical tension central to evaluating physician-assisted suicide and euthanasia in medical practice: 1) the benefit or harm of death itself, 2) the relationship between physician-assisted suicide and euthanasia and withholding or withdrawing life support, 3) the morality of a physician deliberately causing death, and 4) the management of conscientious objection related to physician-assisted suicide and euthanasia in the critical care setting. We present areas of common ground and important unresolved differences. CONCLUSIONS: We reached differing positions on the first three core ethical questions and achieved unanimity on how critical care clinicians should manage conscientious objections related to physician-assisted suicide and euthanasia. The alternative positions presented in this article may serve to promote open and informed dialogue within the critical care community. PMID- 28098623 TI - Greater Protein and Energy Intake May Be Associated With Improved Mortality in Higher Risk Critically Ill Patients: A Multicenter, Multinational Observational Study. AB - OBJECTIVES: Controversy exists about the value of greater nutritional intake in critically ill patients, possibly due to varied patient nutritional risk. The objective of this study was to investigate whether clinical outcomes vary by protein or energy intake in patients with risk evaluated by the NUTrition Risk in the Critically Ill score. DESIGN: Prospective observational cohort. SETTING: A total of 202 ICUs. PATIENTS: A total of 2,853 mechanically ventilated patients in ICU greater than or equal to 4 days and a subset of 1,605 patients in ICU greater than or equal to 12 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In low-risk (NUTrition Risk in the Critically Ill, < 5) and high-risk (NUTrition Risk in the Critically Ill, >= 5) patients, mortality and time to discharge alive up to day 60 were assessed relative to nutritional intake over the first 12 days using logistic regression and Cox proportional hazard regression, respectively. In high-risk but not low-risk patients, mortality was lower with greater protein (4-d sample: odds ratio, 0.93; 95% CI, 0.89-0.98; p = 0.003 and 12-d sample: odds ratio, 0.90; 95% CI, 0.84-0.96; p = 0.003) and energy (4-d sample: odds ratio, 0.93; 95% CI, 0.89-0.97; p < 0.001 and 12-d sample: odds ratio, 0.88; 95% CI, 0.83-0.94; p < 0.001) intake. In the 12-day sample, there was significant interaction among NUTrition Risk in the Critically Ill category, mortality, and protein and energy intake, whereas in the 4-day sample, the test for interaction was not significant. In high-risk but not low-risk patients, time to discharge alive was shorter with greater protein (4-d sample: hazard ratio, 1.05; 95% CI, 1.01-1.09; p = 0.01 and 12-d sample: hazard ratio, 1.09; 95% CI, 1.03-1.16; p = 0.002) and energy intake (4-d sample: hazard ratio, 1.05; 95% CI, 1.01-1.09; p = 0.02 and 12-d sample: hazard ratio, 1.09; 95% CI, 1.03-1.16; p = 0.002). In the 12-day sample, there was significant interaction among NUTrition Risk in the Critically Ill category, time to discharge alive, and protein and energy intake, whereas in the 4-day sample, the test for interaction was not significant. CONCLUSIONS: Greater nutritional intake is associated with lower mortality and faster time to discharge alive in high-risk, longer stay patients but not significantly so in nutritionally low-risk patients. PMID- 28098624 TI - Long-Term Survival in Adults Treated With Extracorporeal Membrane Oxygenation for Respiratory Failure and Sepsis. AB - OBJECTIVE: The use of extracorporeal membrane oxygenation in adults with respiratory failure and sepsis is steadily increasing, but the knowledge on long term survival in this group is scarce. The aim of the present study was to investigate the 5-year survival rates and causes of late death in this group of patients. DESIGN: Single-center retrospective cohort study. SETTING: Karolinska University Hospital, Stockholm, Sweden. PATIENTS: Adult patients treated with extracorporeal membrane oxygenation for respiratory failure and sepsis between the service being established for adults in 1995 and December 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Survival status was attained from a national Causes of Death registry. Minimal patient background data, along with data on survival and causes of death were collected. Survival rates were calculated using the Kaplan-Meier method. Of 255 subjects, 64% survived to discharge. The median follow-up time in survivors was 4.4 years. There was a high mortality rate within the first months after discharge. In the group of patients who survived the first 90 days after treatment, the 5-year survival rate was 87% and was particularly beneficial in patients treated for infectious diseases (88 100%). Late deaths were seen in most diagnostic groups, but the Kaplan-Meier curves flattened out over time. CONCLUSIONS: Extracorporeal membrane oxygenation treatment in adult patients with respiratory failure and sepsis can be lifesaving in appropriately selected patients. For patients who survive the first months after extracorporeal membrane oxygenation treatment, long-term survival seems good, especially in patients treated for infections. PMID- 28098625 TI - Innovative Interdisciplinary Strategies to Address the Intensivist Shortage. PMID- 28098627 TI - Global Collaboration in Acute Care Clinical Research: Opportunities, Challenges, and Needs. AB - The most impactful research in critical care comes from trials groups led by clinician-investigators who study questions arising through the day-to-day care of critically ill patients. The success of this model reflects both "necessity" the paucity of new therapies introduced through industry-led research-and "clinical reality"-nuanced modulation of standard practice can have substantial impact on clinically important outcomes. Success in a few countries has fueled efforts to build similar models around the world and to collaborate on an unprecedented scale in large international trials. International collaboration brings opportunity-the more rapid completion of clinical trials, enhanced generalizability of the results of these trials, and a focus on questions that have evoked international curiosity. It has changed practice, improved outcomes, and enabled an international response to pandemic threats. It also brings challenges. Investigators may feel threatened by the loss of autonomy inherent in collaboration, and appropriate models of academic credit are yet to be developed. Differences in culture, practice, ethical frameworks, research experience, and resource availability create additional imbalances. Patient and family engagement in research is variable and typically inadequate. Funders are poorly equipped to evaluate and fund international collaborative efforts. Yet despite or perhaps because of these challenges, the discipline of critical care is leading the world in crafting new models of clinical research collaboration that hold the promise of not only improving the care of the most vulnerable patients in the healthcare system but also transforming the way that we conduct clinical research. PMID- 28098626 TI - The Brain and Hypothermia-From Aristotle to Targeted Temperature Management. PMID- 28098628 TI - The ABCDEF Bundle: Science and Philosophy of How ICU Liberation Serves Patients and Families. AB - Over the past 20 years, critical care has matured in a myriad of ways resulting in dramatically higher survival rates for our sickest patients. For millions of new survivors comes de novo suffering and disability called "the postintensive care syndrome." Patients with postintensive care syndrome are robbed of their normal cognitive, emotional, and physical capacity and cannot resume their previous life. The ICU Liberation Collaborative is a real-world quality improvement initiative being implemented across 76 ICUs designed to engage strategically the ABCDEF bundle through team- and evidence-based care. This article explains the science and philosophy of liberating ICU patients and families from harm that is both inherent to critical illness and iatrogenic. ICU liberation is an extensive program designed to facilitate the implementation of the pain, agitation, and delirium guidelines using the evidence-based ABCDEF bundle. Participating ICU teams adapt data from hundreds of peer-reviewed studies to operationalize a systematic and reliable methodology that shifts ICU culture from the harmful inertia of sedation and restraints to an animated ICU filled with patients who are awake, cognitively engaged, and mobile with family members engaged as partners with the ICU team at the bedside. In doing so, patients are "liberated" from iatrogenic aspects of care that threaten his or her sense of self-worth and human dignity. The goal of this 2017 plenary lecture at the 47th Society of Critical Care Medicine Congress is to provide clinical ICU teams a synthesis of the literature that led to the creation of ICU liberation philosophy and to explain how this patient- and family-centered, quality improvement program is novel, generalizable, and practice changing. PMID- 28098629 TI - Right Dose, Right Now: Customized Drug Dosing in the Critically Ill. AB - Drugs are key weapons that clinicians have to battle against the profound pathologies encountered in critically ill patients. Antibiotics in particular are commonly used and can improve patient outcomes dramatically. Despite this, there are strong opportunities for further reducing the persisting poor outcomes for infected critically ill patients. However, taking these next steps for improving patient care requires a new approach to antibiotic therapy. Giving the right dose is highly likely to increase the probability of clinical cure from infection and suppress the emergence of resistant pathogens. Furthermore, in some patients with higher levels of sickness severity, reduced mortality from an optimized approach to antibiotic use could also occur. To enable optimized dosing, the use of customized dosing regimens through either evidence-based dosing nomograms or preferably through the use of dosing software supplemented by therapeutic drug monitoring data should be embedded into daily practice. These customized dosing regimens should also be given as soon as practicable as reduced time to initiation of therapy has been shown to improve patient survival, particularly in the presence of septic shock. However, robust data supporting these logical approaches to therapy, which may deliver the next step change improvement for treatment of infections in critically ill patients, are lacking. Large prospective studies of patient survival and health system costs are now required to determine the value of customized antibiotic dosing, that is, giving the right dose at the right time. PMID- 28098631 TI - After the Fall: The Tapestry of Disturbance and Recovery. AB - On July 3, 2015, Nalini Nadkarni, a world-renowned ecologist who had been studying the biologic processes of ecosystem disturbance and recovery, sustained a catastrophic 50-foot free-fall from the top of the rainforest canopy to the forest floor at her remote field research site. She lost consciousness in shock and sustained life-threatening injuries. Her accompanying students hiked out, radio-called 911, and the Harborview Medical Center (Seattle) Medivac team arrived 4 hours later to rescue her. Her prognosis was extremely grim; her family gathered in anticipation of her death as she underwent four operations during her 10 days in the ICU. As she emerged from coma, she spent weeks of hospital recovery and months of progressive mobility and physical therapy during medical leave from work. She experienced ICU psychosis and postintensive care syndrome, but slowly recovered nearly totally, to the point where she can solo hike up to 18 miles in a day, and has fully resumed her professional responsibilities as professor of biology, including climbing tall trees for her canopy research. She attributes her survival and remarkable recovery to both exquisite medical critical care and support she received, and also to incorporating lessons learned from her interdisciplinary study of how diverse natural systems commonly experience and recover from catastrophic disturbances (e.g., forest fires, traffic jams, orphaned children, and refugee survivors of war). Insights from her own encounter with critical illness and study of disturbance and recovery led her to reflect on the tapestry of disturbance and recovery that permeate all ecosystems, and with relevance to the evolving Society of Critical Care Medicine, postintensive care syndrome, and THRIVE initiatives. PMID- 28098632 TI - Palliative Care in the ICU and the Role for Physician-Assisted Dying-Or Lack Thereof. PMID- 28098630 TI - Collapse of the Microbiome, Emergence of the Pathobiome, and the Immunopathology of Sepsis. AB - The definition of sepsis has been recently modified to accommodate emerging knowledge in the field, while at the same time being recognized as challenging, if not impossible, to define. Here, we seek to clarify the current understanding of sepsis as one that has been typically framed as a disorder of inflammation to one in which the competing interests of the microbiota, pathobiota, and host immune cells lead to loss of resilience and nonresolving organ dysfunction. Here, we challenge the existence of the idea of noninfectious sepsis given that critically ill humans never exist in a germ-free state. Finally, we propose a new vision of the pathophysiology of sepsis that includes the invariable loss of the host's microbiome with the emergence of a pathobiome consisting of both "healthcare-acquired and healthcare-adapted pathobiota." Under this framework, the critically ill patient is viewed as a host colonized by pathobiota dynamically expressing emergent properties which drive, and are driven by, a pathoadaptive immune response. PMID- 28098633 TI - More Food for Thought: Nutrition, the Nutrition Risk in the Critically Ill Score, and the Dilemma of "Goal" Feeding. PMID- 28098634 TI - Long-Term Survival After Extracorporeal Membrane Oxygenation Therapy: The Attention It Deserves! PMID- 28098635 TI - Bringing the ABCDEF Bundle to Life and Saving Lives Through the Process. PMID- 28098636 TI - ICU Rounds: "What We've Got Here Is Failure to Communicate". PMID- 28098637 TI - Oxygen: Breath of Life or Kiss of Death. PMID- 28098638 TI - Triangulating Weakness, Morbidity, and Mortality Among Acute Respiratory Distress Syndrome Survivors: A Story Emerges. PMID- 28098639 TI - Why So Few Randomized Trials Are Useful. PMID- 28098640 TI - Sepsis Quality Improvement Initiatives: Prepare for the Marathon, Not the Sprint. PMID- 28098641 TI - Vitamin D Deficiency in Sepsis: "Body Humors" Imbalance or Sepsis "Epiphenomenon"? PMID- 28098642 TI - Readmissions: Accepting Those That Cannot Be Prevented, Courage to Prevent Those That Can Be, and the Wisdom to Know the Difference. PMID- 28098643 TI - Are ICU Length of Stay Predictions Worthwhile? PMID- 28098644 TI - Using Noninvasive Ventilation in Ordinary Wards to Treat Acute Respiratory Failure: But Where, When, and Whom to Treat? PMID- 28098645 TI - The authors reply. PMID- 28098646 TI - Outcome Prediction for Acute Respiratory Distress Syndrome: Are the Current Three Variables Really Optimal? PMID- 28098647 TI - The authors reply. PMID- 28098648 TI - Does Lactate Ringer Matter or Sodium-Free Solution Matter? PMID- 28098649 TI - The authors reply. PMID- 28098650 TI - Was the Intraaortic Balloon Pumping Under Venoarterial Extracorporeal Membrane Oxygenation Really Effective in Reducing the Mortality of Cardiogenic Patients? PMID- 28098651 TI - The authors reply. PMID- 28098652 TI - Call for Subcategory of Severe Acute Pancreatitis: "Fulminant Acute Pancreatitis". PMID- 28098653 TI - The author replies. PMID- 28098654 TI - Meta-Analysis of Time to Antimicrobial Therapy in Sepsis: Confounding as Well as Bias. PMID- 28098655 TI - The authors reply. PMID- 28098656 TI - High-Flow Nasal Cannula Meta-Analysis: Do Not Mix Apples and Oranges! PMID- 28098657 TI - The authors reply. PMID- 28098658 TI - Critical Illness Needs Better Science, Not Clinical "Precision". PMID- 28098659 TI - Reply. PMID- 28098660 TI - To the Editor. PMID- 28098661 TI - Posterior Reversible Encephalopathy Syndrome Triggered by Vertebral Artery Angiogram. PMID- 28098662 TI - Management of a Patient With Antiphospholipid Syndrome Undergoing Aortic Valve Replacement Using the Hepcon Hemostasis Management System Plus and Rotational Thromboelastometry: A Case Report. AB - A 72-year-old woman with antiphospholipid syndrome underwent aortic valve replacement. Her preoperative activated partial thromboplastin time was 61.7 seconds and activated clotting time was 219 seconds. During cardiopulmonary bypass, the Hepcon Hemostasis Management System (HMS) Plus determined the heparin dose needed to maintain whole-body heparin at 3 U/mL. After cardiopulmonary bypass, 100 mg of protamine was administered based on heparin-protamine neutralization, and the activated clotting time decreased. We applied rotational thromboelastometry (ROTEM) to diagnose residual heparin using the INTEM/HEPTEM clotting time ratio. The HMS and ROTEM are useful for heparin-protamine control in antiphospholipid syndrome. PMID- 28098663 TI - Adenosquamous Carcinoma of the Pancreas Demonstrated on 18F-FDG PET/CT Imaging. AB - A 69-year-old woman had gradually worsening abdominal discomfort over a year. A pancreatic mass was revealed by abdominal CT. The patient underwent FDG PET/CT for staging, which demonstrated the hypermetabolic pancreatic mass with multiple liver metastases. The lesion was pathologically confirmed as pancreatic adenosquamous carcinoma after biopsy. PMID- 28098664 TI - Pancreatic Cancer Complicated by Pancreatitis Demonstrated on FDG PET/CT. AB - A 73-year-old man was referred for F-FDG PET/CT study for staging of biopsy proven pancreatic adenocarcinoma. The scan demonstrated focal intense FDG uptake in the pancreatic head, localizing the primary tumor. Additional moderate diffuse uptake was seen throughout the pancreas, suggestive of acute pancreatitis. Concurrent diagnostic CT showed diffuse pancreatic hypoenhancement consistent with edema. Serum lipase level was elevated, confirming a diagnosis of acute pancreatitis. PMID- 28098665 TI - Source of Ectopic ACTH Secretion Easily Identified by 68 Ga DOTANOC PET/CT. AB - Malignant tumors account for most sources of ectopic ACTH Cushing syndrome (EA CS). Early localization of the source and complete removal can be curative and also prevent metastasis. Diagnostic CT is known to perform better than PET/CT (low dose) in characterizing lung pathologies. However, bronchial carcinoids, a common source of EA-CS, may be difficult to detect on chest CT scan especially when it is small and located close to the hilar region. We present a case of EA CS due to bronchial carcinoid, which was easily seen on Ga DOTANOC PET/CT after a diagnostic chest CT was reported as normal. PMID- 28098666 TI - Estimated Internal and External Radiation Exposure of Caregivers of Patients With Pediatric Neuroblastoma Undergoing 131I Metaiodobenzylguanidine Therapy: A Prospective Pilot Study. AB - PURPOSE: Current recommendations suggest that family members should participate in the care of children receiving in-hospital I metaiodobenzylguanidine (MIBG) therapy for neuroblastoma. The present study aimed to measure the external radiation exposure and estimate the internal radiation exposure of caregivers during the hospital stay for I MIBG therapy. MATERIALS AND METHODS: Caregivers received radiation safety instructions and a potassium iodide solution for thyroid blockade before patient admission. External radiation exposure was determined using a personal pocket dosimeter. Serial 24-hour urine samples were collected from caregivers during the hospital stay. Estimated internal radiation exposure was calculated based on the urine activity. RESULTS: Twelve cases (mean age, 6.2 +/- 3.5 years; range, 2-13 years) were enrolled. The mean administered activity was 233.3 +/- 74.9 (range, 150.0-350.0) mCi. The mean external radiation dose was 5.8 +/- 7.2 (range, 0.8-19.9) mSv. Caregivers of children older than 4 years had significantly less external radiation exposure than those of children younger than 4 years (1.9 +/- 1.0 vs 16.4 +/- 5.0 mSv; P = 0.012). The mean estimated internal radiation dose was 11.3 +/- 10.2 (range, 1.0-29.8) MUSv. CONCLUSIONS: Caregivers receive both external and internal radiation exposure while providing in-hospital care to children receiving I MIBG therapy for neuroblastoma. However, the internal radiation exposure was negligible compared with the external radiation exposure. PMID- 28098667 TI - 18F-NaF PET-CT in Symptomatic Fabella Syndrome. AB - Fabella is a sesamoid bone, located within the tendon of the lateral head of the gastrocnemius muscle. It may be associated with posterolateral knee pain because of repetitive friction over the posterolateral femoral condyle. We report a case of a 64-year-old woman presenting with right posterolateral knee pain. F-NaF PET CT demonstrated increased uptake posterior to the right knee joint localizing to a fabella. Standard examination and radiographic imaging excluded other causes for posterolateral knee pain, and the increased activity was considered to be secondary to fabella syndrome. NaF PET-CT can provide useful information in the evaluation of posterolateral knee pain. PMID- 28098669 TI - Eye problems in a woman with Churg-Strauss syndrome. AB - Churg-Strauss syndrome is a rare, systemic vasculitis of unknown cause. Ocular involvement is a rare but established complication and can lead to vision damage or blindness if not treated promptly. Treatment of ocular manifestations corresponds with systemic treatment of the disease and consists primarily of corticosteroids. PMID- 28098670 TI - Understanding therapeutic hypothermia. AB - Therapeutic hypothermia is a relatively new protocol that can improve patients' chances of favorable neurologic outcomes after cardiac arrest. However, implementation rates remain low nationwide. This article describes recommendations for and benefits of therapeutic hypothermia in postresuscitation care. PMID- 28098671 TI - The effects of effleurage hand massage on anxiety and pain in patients undergoing chemotherapy. AB - OBJECTIVE: To determine the effectiveness of effleurage hand massage performed by trained volunteers on reducing anxiety and pain in patients receiving treatment at a chemotherapy center in Fort Wayne, Ind., as measured by heart rate, respiratory rate, BP, visual analogue scale for anxiety (VAS-A), and visual analogue scale for pain (VAS-P). METHODS: Volunteers trained in effleurage massage gave 10-minute hand massages to 24 patients at the beginning of their chemotherapy session. Baseline and post-treatment vital signs were collected. Patients completed VAS-A and VAS-P scales before massage and after the chemotherapy session. Analysis of premassage and post-treatment data was performed using one-tailed Wilcoxon signed rank test. RESULTS: Significant reductions were noted in systolic BP (z=-1.66, P<0.05), heart rate (z=-3.902, P<0.001), VAS-A (z=-3.91, P<0.001), and VAS-P (z=-3.49, P<0.001); no significant difference was found for diastolic BP (P=0.47) or respiratory rate (P=0.06). CONCLUSION: In patients receiving chemotherapy, effleurage hand massages performed by trained volunteers effectively reduced anxiety and pain similar to previously reported results with massages administered by massage therapists. These findings could have important future implications, allowing for training of family members and caregivers in the technique of effleurage massage. PMID- 28098672 TI - A chronicle of PA journals. AB - At its semicentennial mark, the PA profession appears to be flourishing. Over the past 50 years, a number of journals have emerged to highlight the development of the profession and offer observations on it. The Physician Associate Journal, launched in 1970, was the first foray into PA reporting. Following this small effort, a dozen journals or newspapers came into print, lasted for a while, and then were replaced or died. Of journals that survived to the present, four are in English and one in Dutch. Three of the five journals are association-based, and four produce clinical articles; publication is monthly, quarterly, or semiannually. Two journals produce original health services research or studies on the PA education process and have citable track records. Readership of all journals is growing, and collectively these periodicals produce a body of scholarly work that clarifies the PA as a healthcare professional growing on a world stage. This article describes the journalistic history of one aspect of PA development. PMID- 28098673 TI - Pelvic inflammatory disease. PMID- 28098674 TI - Diethylstilbestrol: Potential health risks for women exposed in utero and their offspring. AB - Diethylstilbestrol (DES) is a synthetic estrogen given to pregnant women to prevent miscarriages and preterm labor; the drug was used between 1941 and 1971 in the United States and into the 1980s in other countries. DES exposure is associated with significant long-term health effects, including increased risk for breast cancer, cervical and vaginal clear cell adenocarcinoma, reproductive tract abnormalities, infertility, poor pregnancy outcomes, and early menopause. This article reviews the potential health risks associated with DES exposure, how to assess which patients are at risk, and management recommendations for patients exposed to DES. PMID- 28098676 TI - What is causing this man's facial flushing? PMID- 28098678 TI - An intangible gift. PMID- 28098677 TI - A poetic tongue in cheek. PMID- 28098679 TI - A patient with a curious case of cyclical vomiting. AB - Cannabis-related ED visits are on the rise due to wider legalization and availability of marijuana, and habitual daily use is increasingly common. Cannabis abuse has long been associated with various short-term and long-term adverse reactions. One such reaction is cannabinoid hyperemesis syndrome: cyclical vomiting, nausea, and abdominal pain that only resolves with a warm bath or shower. Healthcare providers must understand the signs and symptoms of cannabinoid hyperemesis syndrome so the problem can be recognized early and patients avoid unnecessary testing. PMID- 28098680 TI - Insight into scabies. AB - Scabies, an infectious disease caused by the scabies mite, manifests as an intensely pruritic skin rash. Children, the underprivileged, and patients with immunocompromise are at a higher risk of acquiring this contagious disease. Infectivity occurs worldwide in patients of all races, ages, and sex. The classical appearance of papular burrows between the webbed spaces of digits or along the wrists can help distinguish scabies from other dermatologic diseases. Practitioners need to be familiar with how scabies may present so that patients can be treated and taught how to prevent spread of the disease. PMID- 28098681 TI - Remembering the USPHS. PMID- 28098682 TI - A Hole Lot Better: The Dural Puncture Epidural Technique. PMID- 28098683 TI - Threading the Needle With Peripheral Nerve Blocks: Achieving Analgesia, Avoiding Neurological Injury. PMID- 28098684 TI - Closed-Loop Anesthesia: Ready for Prime Time? PMID- 28098685 TI - Pain, Pain Relief, Satisfaction and Excellence in Obstetric Anesthesia: A Surprisingly Complex Relationship. PMID- 28098686 TI - We Should Train for Strain. PMID- 28098687 TI - Is There Anything New About Preoxygenation? Duh, Yeah! PMID- 28098688 TI - The 2017 Virginia Apgar Collection Part I: Analgesic Innovations. PMID- 28098689 TI - Inconsistency Between Different Methods to Indicate Statistical Significance. PMID- 28098690 TI - In Response. PMID- 28098691 TI - Comparative Effectiveness of Lower Leg Compression Devices Versus Sequential Compression Devices to Prevent Postspinal Hypotension During Cesarean Delivery. PMID- 28098692 TI - Postoperative Cognitive Dysfunction and Low Regional Cerebral Oxygen Saturation: Is This Relationship Fragile or Fractured Altogether? PMID- 28098693 TI - In Response. PMID- 28098694 TI - If the Goal Is Balance, Why Not Fresh Frozen Plasma? PMID- 28098695 TI - In Response. PMID- 28098696 TI - Global Health for the Global North? PMID- 28098697 TI - In Response. PMID- 28098698 TI - Clinical and Practical Aspects of Restoring Thrombin Generation in Acute Coagulopathic Bleeding. PMID- 28098699 TI - In Response. PMID- 28098700 TI - High Risk of Aspiration in Patients With ReShape Intragastric Balloon Weight Loss System. PMID- 28098701 TI - Chloroform Anesthesia, Antarctica, 1908. PMID- 28098702 TI - Laparoscopic Surgery: Are Vital Signs Important? PMID- 28098703 TI - Can We Continue to Deny Neuraxial Anesthesia to Otherwise-Healthy Parturients With Thrombocytopenia? PMID- 28098704 TI - In Response. PMID- 28098705 TI - Heterotopic Ossification in Acetabular Fracture Surgery. AB - Heterotopic ossification (HO) is a common complication of the surgical treatment of acetabular fractures. HO is the formation of trabecular bone in soft tissues where bone does not usually occur. Over the last decade, many risk factors have been identified for HO after surgical fixation of acetabular fractures; however, prophylaxis and treatment of this condition are controversial. Potential preventive measures range from NSAIDs to external beam irradiation, but recent studies have questioned the utility of these measures. The Brooker classification system, which has been correlated with patient function and outcomes, is most commonly used to describe HO severity. Advances will assist in the diagnosis, prevention, and management of HO as well as the assessment of risk factors that could affect outcomes. PMID- 28098706 TI - Current Trends in Ulnar Collateral Ligament Reconstruction Surgery Among Newly Trained Orthopaedic Surgeons. AB - INTRODUCTION: Ulnar collateral ligament (UCL) reconstructions are being performed with an increasing annual incidence. The purpose of this study was to evaluate trends in UCL surgery among recently trained orthopaedic surgeons. METHODS: The American Board of Orthopaedic Surgeons (ABOS) database was used to identify all UCL reconstructions from 2004 to 2013. Procedures were identified by Current Procedural Terminology (CPT) codes and verified by International Classification of Disease, Ninth Revision (ICD-9) codes. Data on surgeon fellowship, practice location, concomitant surgical procedures, and complications were collected. RESULTS: One hundred sixty-four UCL reconstructions were performed by 133 ABOS Part II candidates. The annual incidence increased from 1.52 to 3.46 cases per 10,000 (P = 0.042). Reconstructions were most commonly performed by surgeons with fellowship training in sports medicine (65.9%), hand and upper extremity (18.9%), and shoulder and elbow (9.1%). Most reconstructions were performed in isolation (57.3%), or with ulnar nerve transposition (32.9%) or elbow arthroscopy (9.8%). Concomitant elbow arthroscopy rates decreased significantly (P = 0.022). Complications occurred in 9.8% of cases, although the rates did not significantly change (P = 0.466). CONCLUSIONS: UCL reconstructions are being performed with increasing frequency. Concomitant procedure rates remained the same, although arthroscopy was less commonly performed. Complication rates did not change considerably over the observed period. Further study of the surgical trends and associated long-term outcomes is warranted. LEVEL OF EVIDENCE: Level IV. PMID- 28098707 TI - Descriptive Epidemiology of Acetabular Dysplasia: The Academic Network of Conservational Hip Outcomes Research (ANCHOR) Periacetabular Osteotomy. AB - BACKGROUND: Periacetabular osteotomy (PAO) is an established treatment for symptomatic acetabular dysplasia, which is a well-recognized cause of hip pain, functional limitations, and secondary osteoarthritis. The purpose of this study was to describe the demographics of patients undergoing PAO, the baseline patient reported outcome measures for this population, and the types of adjunctive procedures performed at the time of PAO surgery. METHODS: Demographics, disease characteristics, and patient-reported functional measures were prospectively collected from all patients who underwent PAO performed by 12 surgeons from 2008 to 2013. RESULTS: We enrolled 950 consecutive patients (982 hips) in the study; 83% were female and 17% were male, with an average age of 25.3 years and an average body mass index (BMI) of 24.6 kg/m. Most patients were Caucasian (87%), and 15% had undergone previous hip surgery. Before PAO was performed, most patients had had symptoms for 1 to 3 years. Baseline modified Harris Hip and University of California Los Angeles activity scores (61.8 and 6.6, respectively) indicated that patients had considerable functional limitations. DISCUSSION: Patients undergoing PAO for symptomatic dysplasia were predominantly young, female, and Caucasian with a normal BMI. Many patients had undergone prior hip surgery, and most had had symptoms for several years before treatment. Baseline patient-reported functional scores demonstrated marked functional limitations. Adjunctive procedures for intra-articular pathology, especially femoral osteochondroplasty and hip arthroscopy, are commonly performed at the time of PAO. PMID- 28098708 TI - Intramedullary Fixation of Clavicle Fractures: Anatomy, Indications, Advantages, and Disadvantages. PMID- 28098709 TI - MULTIMODAL IMAGING DURING THE EVOLUTION OF BLOOD-BRAIN BARRIER DISRUPTION MACULOPATHY. AB - PURPOSE: To highlight the course of blood-brain barrier disruption maculopathy in a patient with successfully managed relapsed central nervous system lymphoma. METHODS: Case report with fundus autofluorescence and optical coherence tomography imaging, and literature review. RESULTS: A 57-year-old patient diagnosed with central nervous system large B-cell lymphoma had a normal ophthalmic evaluation on his first visit. Subsequently, when his malignancy recurred locally, he was started on blood-brain barrier disruption therapy and intraarterial methotrexate. During the course of the therapy, he developed bilateral retinal pigment epithelial abnormalities located in the foveal and perifoveal zones. The changes were first mildly progressive and then marginally regressive in nature with minimal eventual loss of visual acuity to 20/32 and 20/25 in his right and left eye, respectively. CONCLUSION: Maculopathy is a known complication in patients with central nervous system malignancies undergoing blood-brain barrier disruption. A detailed clinical evaluation using fundus autofluorescence and high-definition optical coherence tomography are informative in managing such patients. PMID- 28098710 TI - STELLATE NONHEREDITARY IDIOPATHIC FOVEOMACULAR RETINOSCHISIS ACCOMPANIED BY CONTRALATERAL PERIPHERAL RETINOSCHISIS. AB - PURPOSE: To present a patient with stellate nonhereditary idiopathic foveomacular retinoschisis on one eye and peripheral retinoschisis without foveal affection on the other eye. METHODS: A case report with complete workup of family history and clinical examination, including multimodal imaging with optical coherence tomography and angiography, fluorescein angiography, and infrared fundus imaging. Genetic testing for gene mutation XRLS1 was performed. RESULTS: A white woman with unremarkable medical history presented with stellate foveal splitting of the outer plexiform layer on the right eye and peripheral splitting of the outer plexiform layer on both eyes. All known allegeable trigger factors for the existence of a hereditary or acquired foveomacular retinoschisis were ruled out either by clinical presentation or genetic testing. This led to the diagnosis of stellate nonhereditary idiopathic foveomacular retinoschisis with central involvement only present on one eye. CONCLUSION: Although peripheral schisis of the outer plexiform layer is often concomitant with central splitting in X-linked juvenile retinoschisis, this is the first known report of nonhereditary cleavage of the outer plexiform layer of the peripheral retina without central affection in a patient with documented stellate nonhereditary idiopathic foveomacular retinoschisis on the other eye. These findings suggest an accurate bilateral examination of the peripheral retina while confirming the diagnose of stellate nonhereditary idiopathic foveomacular retinoschisis. PMID- 28098711 TI - Primary Septal Cartilage Graft for the Unilateral Cleft Rhinoplasty. AB - BACKGROUND: Since 2006, the authors have explored the option of using septal cartilage as an alar rim graft on the cleft side during primary rhinoplasty to improve nasal symmetry. The aim of this study was to compare the nasal shape with or without rim graft. METHODS: A total of 98 patients with unilateral complete cleft lip and palate were included; 39 patients had septal cartilage as the rim graft, and 59 patients did not. Measurements of the nostril height, nostril width, one-fourth medial part of nostril height, nostril area, nasal dome height, and nostril axis were obtained on the cleft and noncleft sides. Ratios of these measurements were calculated. These ratios were then compared between the graft and nongraft groups. The levels of asymmetry were categorized into four levels less than 5 percent, 5 to 10 percent, 10 to 15 percent, and greater than 15 percent-based on the percentages deviated from perfect symmetry (100 percent). Panel assessment was also performed. Nasolabial angle and tip projection ratio were measured for the comparison of nasal growth. RESULTS: The nostril height, height-to-width ratio, and nasal dome height were higher in the graft group (p = 0.003, p < 0.001, and p < 0.001, respectively). The graft group showed more consistency regarding the nostril shape and axis, and the differences were statistically significant (p < 0.05). The nasolabial angle and tip projection ratio showed no significant difference between the two groups. CONCLUSION: This preliminary study suggests that the use of a primary septal cartilage graft may offer better support at the alar rim and improve the long-term outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28098712 TI - Business Education for Plastic Surgeons: A Systematic Review, Development, and Implementation of a Business Principles Curriculum in a Residency Program. AB - BACKGROUND: Rising health care costs, decreasing reimbursement rates, and changes in American health care are forcing physicians to become increasingly business minded. Both academic and private plastic surgeons can benefit from being educated in business principles. The authors conducted a systematic review to identify existing business curricula and integrated a business principles curriculum into residency training. METHODS: The authors anonymously surveyed their department regarding perceived importance of business principles and performed a systematic literature review from 1993 to 2013 using PubMed and Embase to identify residency training programs that had designed/implemented business curricula. Subsequently, the authors implemented a formal, quarterly business curriculum. RESULTS: Thirty-two of 36 physicians (88.9 percent; 76.6 percent response rate) stated business principles are either "pretty important" or "very important" to being a doctor. Only 36 percent of faculty and 41 percent of trainees had previous business instruction. The authors identified 434 articles in the systematic review: 29 documented formal business curricula. Twelve topics were addressed, with practice management/administration (n = 22) and systems-based practice (n = 6) being the most common. Four articles were from surgical specialties: otolaryngology (n = 1), general surgery (n = 2), and combined general surgery/plastic surgery (n = 1). Teaching formats included lectures and self-directed learning modules; outcomes and participant satisfaction were reported inconsistently. From August of 2013 to June of 2015, the authors held eight business principles sessions. Postsession surveys demonstrated moderately to extremely satisfied responses in 75 percent or more of resident/fellow respondents (n = 13; response rate, 48.1 percent) and faculty (n = 9; response rate, 45.0 percent). CONCLUSIONS: Business principles can be integrated into residency training programs. Having speakers familiar with the physician audience and a session coordinator is vital to program success. PMID- 28098713 TI - Regional Oxygen Saturation Index: A Novel Criterion for Free Flap Assessment Using Tissue Oximetry. PMID- 28098714 TI - Reply: Regional Oxygen Saturation Index: A Novel Criterion for Free Flap Assessment Using Tissue Oximetry. PMID- 28098715 TI - One versus Two Venous Anastomoses in Anterolateral Thigh Flap Reconstruction after Oral Cancer Ablation. PMID- 28098716 TI - Reply: One versus Two Venous Anastomoses in Anterolateral Thigh Flap Reconstruction after Oral Cancer Ablation. PMID- 28098717 TI - Effectiveness of Autologous Fat Grafting in Adherent Scars: Results Obtained by a Comprehensive Scar Evaluation Protocol. PMID- 28098718 TI - Double Exposure to Adverse Psychosocial Work Factors and High Family Responsibilities as Related to Ambulatory Blood Pressure at Work: A 5-Year Prospective Study in Women With White-Collar Jobs. AB - OBJECTIVE: Accumulating evidence shows that psychosocial work factors of the demand-control and effort-reward imbalance models may contribute to increase blood pressure (BP). Women are more likely to be exposed to these psychosocial factors than men. Moreover, women spend twice as much time per week performing family responsibilities than men. This study aimed to evaluate the longitudinal association of the double exposure to psychosocial work factors and high family responsibilities in women with BP for a 5-year follow-up. METHODS: At baseline, the study sample was composed of 1215 working women. Psychosocial work factors were measured using validated scales. Family responsibilities were measured using items related to "the number of children and their age" and "housework and children care." Ambulatory BP measures were taken every 15 minutes during a working day. Associations between psychosocial measures and BP were examined using analyses of covariance. RESULTS: Women with a double exposure to effort reward imbalance and high family responsibilities had significantly higher BP means than women not exposed to these factors at baseline (diastolic: +2.75 mm Hg), at 3-year follow-up (systolic: +2.22 mm Hg and diastolic: +2.55 mm Hg), and at 5-year follow-up (systolic: +2.94 mm Hg and diastolic: + 3.10 mm Hg). No adverse effect on BP was observed for the double exposure to the psychosocial work factors of the demand-control model and high family responsibilities. CONCLUSIONS: A double exposure to effort-reward imbalance at work and high family responsibilities might contribute to elevated ambulatory BP at work among women. BP elevations related to this double exposure may persist for several years. PMID- 28098721 TI - The Endocannabinoid System and Its Role in Eczematous Dermatoses. AB - The skin serves as the foremost barrier between the internal body and the external world, providing crucial protection against pathogens and chemical, mechanical, and ultraviolet damages. The skin is a central player in the intricate network of immune, neurologic, and endocrine systems. The endocannabinoid system (ECS) includes an extensive network of bioactive lipid mediators and their receptors, functions to modulate appetite, pain, mood, and memory, and has recently been implicated in skin homeostasis. Disruption of ECS homeostasis is implicated in the pathogenesis of several prevalent skin conditions. In this review, we highlight the role of endocannabinoids in maintaining skin health and homeostasis and discuss evidence on the role of ECS in several eczematous dermatoses including atopic dermatitis, asteatotic eczema, irritant contact dermatitis, allergic contact dermatitis, and chronic pruritus. The compilation of evidence may spark directions for future investigations on how the ECS may be a therapeutic target for dermatologic conditions. PMID- 28098719 TI - Regional Gray Matter Volumes as Related to Psychomotor Slowing in Adults with Type 1 Diabetes. AB - OBJECTIVE: Psychomotor slowing is a common cognitive complication in type 1 diabetes (T1D), but its neuroanatomical correlates and risk factors are unclear. In nondiabetic adults, smaller gray matter volume (GMV) and presence of white matter hyperintensities are associated with psychomotor slowing. We hypothesize that smaller GMV in prefronto-parietal regions explains T1D-related psychomotor slowing. We also inspect the contribution of microvascular disease and hyperglycemia. METHODS: GMV, white matter hyperintensities (WMH), and glucose levels were measured concurrently with a test of psychomotor speed (Digit Symbol Substitution Test [DSST]) in 95 adults with childhood-onset T1D (mean age/duration = 49/41 years) and 135 similarly aged non-T1D adults. Linear regression models tested associations between DSST and regional GMV, controlling for T1D, sex, and education; a bootstrapping method tested whether regional GMV explained between-group differences in DSST. For the T1D cohort, voxel-based and a priori regions-of-interest methods further tested associations between GMV and DSST, adjusting for WMH, hyperglycemia, and age. RESULTS: Bilateral putamen, but no other regions examined, significantly attenuated DSST differences between the cohorts (bootstrapped unstandardized indirect effects: -3.49, -3.26; 95% confidence interval = -5.49 to -1.80, -5.29 to -1.44, left and right putamen, respectively). Among T1D, DSST was positively associated with GMV of bilateral putamen and left thalamus. Neither WMH, hyperglycemia, age, nor other factors substantially modified these relationships. CONCLUSIONS: For middle-aged adults with T1D and cerebral microvascular disease, GMV of basal ganglia may play a critical role in regulating psychomotor speed, as measured via DSST. Studies to quantify the impact of basal ganglia atrophy concurrent with WMH progression on psychomotor slowing are warranted. PMID- 28098722 TI - Prevalence of Preservatives Across All Product Types in the Contact Allergen Management Program. AB - BACKGROUND: Preservatives are known causes of allergic contact dermatitis. OBJECTIVE: The aim of this study was to determine the prevalence of preservatives in each product category in the Contact Allergen Management Program and compare prevalence with reported rates of allergic contact dermatitis. METHODS: Contact Allergen Management Program product information was queried based on the 53 approved preservatives for cosmetic products by the European Union and Association of Southeast Asian Nations plus 5 additional preservatives used in US products. RESULTS: Phenoxyethanol and parabens were the most common preservatives with 23.9% of products containing phenoxyethanol and 20.75% of products containing parabens. Methylisothiazolinone (MI) was found in 12.9% of products, most commonly in hair care and household products. Preservatives like MI and methylchloroisothiazolinone (MCI) that are both common in products and have a high incidence of allergic contact dermatitis are of greatest concern as contact allergy hazards. Phenoxyethanol and parabens are common and have weak sensitizing power, making them preferred preservatives. CONCLUSIONS: Evaluating the prevalence of preservatives provides important information on allergen exposures. Using current positive reaction rates, the risk of sensitization to a given preservative can be more accurately estimated and may affect the use of certain preservatives by industry in the future. PMID- 28098723 TI - ASSESSMENT OF THE INTERNAL LIMITING MEMBRANE STATUS WHEN A MACULAR EPIRETINAL MEMBRANE IS REMOVED IN A PROSPECTIVE STUDY. AB - PURPOSE: To describe the presence and integrity of the internal limiting membrane (ILM) after removal of the macular epiretinal membrane (ERM) and to investigate the accuracy of tissue identification using surgical dyes when compared to histopathology results. METHODS: Patients with idiopathic ERM were enrolled in a prospective study and randomized to one of two surgical techniques. In one (Group M), only the ERM was deliberately removed and in the other (Group L) the ILM was also removed. Pars plana vitrectomy and extraction of the ERM with trypan blue dye were performed in all patients. The ILM status was assessed with brilliant blue G dye, and in Group L patients, the ILM was then removed. Histopathology was performed on all samples. RESULTS: Twenty-six patients underwent the study procedure: 11 in the Group M and 15 in the Group L. The patients' median age was 70.65 years (53-81), and the average follow-up was 15.35 months (4.86-25.10). The ILM extraction patterns were as follows: In Group M in block in 8 of 11 patients and partial in 3 of 11 patients; In Group L in block in 9 of 15 patients, partial in 5 of 15 patients and sequential in 1 of 15 patients. In only 3.8% of patients was the ILM intact after ERM removal. Thirty-two surgical samples were analyzed, containing both ERM and ILM, ERM only, or ILM only. In 84.37% of samples, the tissue identification using surgical dyes was consistent with identification according to pathological examination. This consistency was higher still at 96.7% when focused on ILM identification. CONCLUSION: It is technically difficult to extract the ERM in isolation from the ILM. There is good consistency between the content of removed tissue as identified using surgical dyes and the histopathological results of the samples. This is higher in ILM than in ERM. PMID- 28098724 TI - CENTRAL MACULAR THICKNESS IN 6.5-YEAR-OLD CHILDREN BORN EXTREMELY PRETERM IS STRONGLY ASSOCIATED WITH GESTATIONAL AGE EVEN WHEN ADJUSTED FOR RISK FACTORS. AB - PURPOSE: To assess the macular thickness in 6.5-year-old children born extremely preterm (EPT) in comparison with children born at term and to investigate risk factors associated with the macular thickness in the preterm group. METHODS: A population-based study of 6.5-year-old children born before the gestational age of 27 weeks and age-matched control subjects. Macular assessments with optical coherence tomography were performed, and the results were compared with neonatal risk factors and sex. RESULTS: Adequate optical coherence tomography measurements were obtained from 134 children born EPT (mean gestational age of 25 weeks [range 23-26]) and 145 control subjects. The mean (range) of central macula thickness was significantly increased (P < 0.001) in the EPT group (right eyes: 282 MUm [238-356], left eyes: 283 MUm [229-351]), compared with the control group (right eyes: 249 MUm [208-293], left eyes: 248 MUm [207-290]). A multiple linear mixed model analysis of the EPT group revealed gestational age, retinopathy of prematurity, and male gender as important risk factors for an increased macular thickness. The macular thickness decreased by 3.9 MUm per gestational week, when adjusted for retinopathy of prematurity and sex. CONCLUSION: Extremely preterm birth constitutes a substantial risk factor for a thick central macula, even when adjusted for retinopathy of prematurity and male gender. PMID- 28098725 TI - HOW VITREOMACULAR INTERFACE MODIFIES THE EFFICACY OF ANTI-VEGF THERAPY FOR MYOPIC CHOROIDAL NEOVASCULARIZATION. AB - PURPOSE: To evaluate the efficacy of intravitreal ranibizumab in the treatment of myopic choroidal neovascularization (mCNV) complicated by vitreoretinal interface alterations. METHODS: Thirty-two patients affected by mCNV and concurrent vitreoretinal interface disorders, including macular epiretinal membrane (18 patients), lamellar macular hole (4 patients), full-thickness macular hole (1 patient), broad/focal vitreomacular traction (3 patients), broad/focal vitreomacular adhesion (4 patients), and myopic foveoschisis (2 patients), were enrolled in a prospective study. After a comprehensive ophthalmologic examination, including best-corrected visual acuity (BCVA), fluorescein angiography, and spectral-domain optical coherence tomography, each patient received a first intravitreal ranibizumab. Further re-treatments were performed in the presence of choroidal neovascularization activity (new hemorrhages, leakage on fluorescein angiography, intraretinal/subretinal fluid on spectral domain optical coherence tomography, visual acuity loss of five letters). Main outcome measure was the change in the BCVA and in the central foveal thickness. Data were compared with the historical control group with uncomplicated mCNV. RESULTS: The median BCVA in the epiretinal membrane-myopic choroidal neovascularization subgroup showed a stabilization from the baseline value of 0.30 logarithm of minimal angle resolution (20/40) to 0.40 (20/50, P: 0.49) at the last visit (30 +/- 13 months). Median BCVA significantly improved from 0.30 (20/40) to 0.10 (20/25, P: 0.0005) in the mCNV group and was better than the epiretinal membrane-myopic choroidal neovascularization subgroup (0.008). Central foveal thickness reduced significantly within both groups, with no difference between the groups at the final examination. Considering the vitreoretinal alterations with lower prevalence, BCVA stabilization was registered after a follow-up of 28.9 +/- 13 months, with a median BCVA of 0.3 logarithm of minimal angle resolution (20/40) at the baseline and at the final examination. A nonstatistically significant reduction in the median central foveal thickness was registered at the final examination (P: 0.12). CONCLUSION: The data show that ranibizumab is effective in controlling mCNV activity when associated with vitreoretinal interface alterations. However, a visual recovery was observed only in patients with uncomplicated mCNV. PMID- 28098727 TI - PERSISTENT OVERPRODUCTION OF INTRAOCULAR VASCULAR ENDOTHELIAL GROWTH FACTOR AS A CAUSE OF LATE VITREOUS HEMORRHAGE AFTER VITRECTOMY FOR PROLIFERATIVE DIABETIC RETINOPATHY. AB - PURPOSE: The purpose of this study was to investigate whether vitreous levels of vascular endothelial growth factor (VEGF) predict late vitreous hemorrhage (VH) after vitrectomy for proliferative diabetic retinopathy, and how VEGF level changes in patients with postoperative late VH. METHODS: Eighty-five eyes of 68 patients with proliferative diabetic retinopathy who underwent vitrectomy were analyzed retrospectively. Vitreous samples were collected from eyes undergoing primary vitrectomy and from eyes with late VH undergoing second vitrectomy. Vitreous VEGF levels were measured using enzyme-linked immunosorbent assay. The relationship between VEGF level and late VH (>4 weeks) occurring during follow-up as well as clinical findings, and changes in VEGF level in eyes with late VH undergoing second vitrectomy were analyzed. RESULTS: Late VH occurred in 20 (24%) of 85 eyes, and 9 eyes required second vitrectomy. Vitreous levels of VEGF were significantly higher (median: 1,945 pg/mL; P < 0.0001) in eyes with late VH than in those without. Preexisting iris neovascularization (P < 0.0001), hypertension (P = 0.002), and proteinuria (P = 0.040) were also significant risk factors of late VH. Multivariate logistic regression analysis showed that a higher vitreous VEGF level was independently associated with a risk of postoperative late VH in patients with proliferative diabetic retinopathy (odds ratio: 20.8, 95% confidence interval: 2.72-159.47; P = 0.003). Vitreous VEGF level at second vitrectomy in patients with late VH was significantly lower compared with that at primary vitrectomy, but remained elevated (median: 1,610 pg/mL; P = 0.023). CONCLUSION: In patients with proliferative diabetic retinopathy, high intraocular VEGF level at primary vitrectomy was identified as an independent risk factor of postoperative late VH. Persistent overproduction of intraocular VEGF may be associated with postoperative late VH. PMID- 28098726 TI - ASSESSMENT OF RETINAL BLOOD FLOW IN DIABETIC RETINOPATHY USING DOPPLER FOURIER DOMAIN OPTICAL COHERENCE TOMOGRAPHY. AB - PURPOSE: To evaluate retinal blood flow measurements in normal eyes and eyes with varying levels of diabetic retinopathy (DR) using Doppler Fourier-domain optical coherence tomography (FD-OCT). METHODS: Twenty-two eyes of 19 subjects, 10 with severe nonproliferative DR (NPDR) and 12 with proliferative DR (PDR), were compared with 44 eyes of 40 healthy control subjects. All eyes were scanned by RTvue FD-OCT. Color disk photographs and cube/volume scans of the optic nerve head were obtained. Doppler OCT scans and accessory imaging data were imported into Doppler OCT of Retinal Circulation grading software to calculate TRBF and vascular parameters (e.g., venous and arterial cross-sectional area). Measurements were compared between cases and controls using independent t-tests. RESULTS: Mean TRBF was 44.98 +/- 9.80 (range: 30.18-64.58) uL/minute for normal eyes, 35.80 +/- 10.48 (range: 20.69-49.56) uL/minute for eyes with severe NPDR, and 34.79 +/- 10.61 (range: 16.77-48.9) uL/minute for eyes with PDR. Mean TRBF was significantly lower in eyes with severe NPDR (P = 0.01) and PDR (P = 0.003) than in normal eyes. CONCLUSION: Total retinal blood flow was significantly lower in eyes with severe NPDR and PDR compared with normal eyes. Retinal blood flow determined by Doppler OCT may be a useful parameter for evaluating patients with DR. PMID- 28098728 TI - PERIPAPILLARY RETINAL NERVE FIBER THICKNESS CHANGES AFTER VITRECTOMY FOR EPIRETINAL MEMBRANE IN EYES WITH AND WITHOUT VITREOUS DETACHMENT. AB - PURPOSE: To compare the changes in postoperative peripapillary retinal nerve fiber layer (p-RNFL) thickness after vitrectomy for epiretinal membrane in eyes with preexisting posterior vitreous detachment (PVD) and eyes with surgically induced PVD. METHODS: This study included consecutive patients who underwent 25 gauge vitrectomy for epiretinal membrane. Eyes were divided, according to intraoperative PVD status, into a preexisting PVD group and surgically induced PVD group. Best-corrected visual acuity, p-RNFL thickness, and central retinal thickness were performed before and at 1, 3, and 6 months after surgery. RESULTS: One hundred and twenty eyes of 120 patients were enrolled: 64 eyes in the preexisting PVD group and 56 eyes in the surgically induced PVD group. In the preexisting PVD group at 6 months, the mean global p-RNFL thickness did not change, whereas it was reduced in the temporal sector (P = 0.034). In the surgically induced PVD group at 6 months, significant decreases were observed in global p-RNFL thickness (P = 0.027), temporal (P = 0.021), temporal inferior (P = 0.030), and nasal inferior sectors (P = 0.010). At 6 months, the two groups differed significantly in temporal (P < 0.001) and temporal inferior sectors (P = 0.004). The preoperative mean best-corrected visual acuity improved significantly at 6 months in both groups. CONCLUSION: Postoperative p-RNFL thickness after vitrectomy for epiretinal membrane tended to decrease in the temporal sector in all eyes and in the temporal inferior and nasal inferior sectors in eyes with surgically induced PVD. PMID- 28098729 TI - VITRECTOMY FOR PERSISTENT MACULAR HOLES FOLLOWING OCRIPLASMIN INJECTION: A Comparative Multicenter Study. AB - PURPOSE: To determine functional and anatomical outcomes of pars plana vitrectomy for persistent full-thickness macular hole (MH) after intravitreal injection of ocriplasmin. METHODS: This is a multicenter retrospective interventional study of 37 eyes of 37 patients who underwent pars plana vitrectomy with internal limiting membrane peeling for persistent MH after ocriplasmin treatment between December 2013 and December 2015 and comparison with 35 eyes of 35 patients who were offered ocriplasmin injection but underwent pars plana vitrectomy alone without pharmacologic vitreolysis before surgery. In addition, 24 matched pairs (MH diameter at baseline +/-5 um) were analyzed. Clinical data such as visual acuity, intraoperative characteristics, and spectral domain optical coherence tomography images were reviewed. Main outcome measures were visual acuity and MH closure rate. RESULTS: After a mean follow-up period of 9 months, postoperative mean visual acuity showed no significant differences between ocriplasmin-treated eyes (logarithm of minimum angle of resolution 0.37 +/- 0.26, Snellen 20/47) and eyes without ocriplasmin treatment (logarithm of minimum angle of resolution 0.39 +/- 0.25; Snellen 20/49) (P > 0.9). After ocriplasmin injection, mean MH diameter enlarged from 217 +/- 102 um to 384 +/- 239 um (P < 0.001). Matched-pair analysis revealed no difference in gain of visual acuity between the first visit and the last follow-up (P = 0.29). Macular hole closure was observed in similar proportion in ocriplasmin-treated eyes (97%) and vitrectomy-only eyes (94%) (P > 0.5). CONLCUSION: Eyes with persistent MH after ocriplasmin injection showed significant visual improvement after pars plana vitrectomy. Matched-pair analysis revealed no statistical differences in functional and anatomical postoperative results comparing with eyes of similar MH diameter that proceeded directly to surgery without ocriplasmin pretreatment. PMID- 28098730 TI - NOVEL CLASSIFICATION SYSTEM FOR COMBINED HAMARTOMA OF THE RETINA AND RETINAL PIGMENT EPITHELIUM. AB - PURPOSE: To develop an anatomical classification scheme for combined hamartoma of the retina and retinal pigment epithelium (RPE) and specify recommendations for follow-up interval. METHODS: Retrospective review of patients with combined hamartoma of the retina and RPE examined during a 7-year period (2008-2015). The clinical presentation, fundus examination, and optical coherence tomography were analyzed. RESULTS: Lesions were classified based on location, fundus features, and optical coherence tomography findings. Lesion location: macular/peripapillary Zone 1; mid-periphery-Zone 2; and far periphery-Zone 3. Associated fundus findings: no retinal traction-Stage 1; retinal traction and/or retinoschisis Stage 2; and retinal detachment-Stage 3. Optical coherence tomography findings: epiretinal component only-A; partial retinal involvement-B; and complete retinal and RPE involvement-C. Complete ophthalmologic evaluation is recommended at least every 6 months for patients younger than 12 years, with more frequent follow-up in patients with: lesions in the macula/peripapillary (Zone 1) or with retinal traction, retinoschisis, or retinal detachment (Stage 2 and 3). Surgical intervention is recommended in patients with vision loss secondary to macular traction or retinal detachment. CONCLUSION: A new clinical classification system is proposed for evaluating and managing patients with combined hamartoma of the retina and RPE. The zone and stage of combined hamartoma of the retina and RPE lesion will assist in determining follow-up interval and surgical intervention. Application of a uniform classification scheme will facilitate assessment and comparison of findings across different studies. PMID- 28098731 TI - CHOROIDAL STRUCTURE ALTERED BY DEGENERATION OF RETINA IN EYES WITH RETINITIS PIGMENTOSA. AB - PURPOSE: To compare the structural characteristics of the choroid in the areas with greater retinal degeneration to the areas with less retinal degeneration in eyes with retinitis pigmentosa (RP). METHODS: Patients with RP who had a hyperautofluorescent ring were studied. The choroidal images obtained by enhanced depth imaging optical coherence tomography located 7,500 MUm from the optic disk in the horizontal plane were analyzed. The cross-sectional areas of the total, luminal, and stromal choroid were measured. The area within the hyperautofluorescent ring was defined as the "central choroid" with less retinal degeneration. RESULTS: Thirty-seven eyes of 24 patients with RP were studied. The cross-sectional area of the total choroid was significantly smaller in the RP eyes than that in the control eyes (P < 0.01). The stromal areas of the choroid were not significantly different from the stromal areas of the controls. However, the luminal areas of the nasal and temporal choroid in the RP eyes were significantly smaller than that of the corresponding areas of the controls. The ratio of the luminal area to the total choroidal area in the central choroid was 68.0 +/- 3.3% which was significantly larger than that of the nasal or the temporal choroid (P < 0.01). CONCLUSION: The choroidal structure is differentially altered in eyes with RP. The changes in the choroid were dependent on whether they were located within the hyperautofluorescent or outside the hyperautofluorescent ring. PMID- 28098732 TI - SIGNIFICANT REDUCTION OF PERIPAPILLARY CHOROIDAL THICKNESS IN PATIENTS WITH UNILATERAL BRANCH RETINAL VEIN OCCLUSION. AB - PURPOSE: To evaluate changes in peripapillary choroidal thickness in patients with branch retinal vein occlusion (BRVO) over 12 months, using spectral-domain optical coherence tomography with enhanced depth imaging. METHODS: This retrospective, interventional case series included 20 treatment-naive patients with unilateral BRVO with at least 12 months follow-up. The peripapillary choroidal thickness was measured over 12 months. RESULTS: In BRVO-affected eyes, the mean peripapillary choroidal thickness was 213.5 +/- 51.7 MUm (126.1[FIGURE DASH]326.9 MUm) at baseline and 129.6 +/- 39.3 MUm (65.9[FIGURE DASH]197.1 MUm) at 12 months. In nonaffected contralateral eyes, the mean peripapillary choroidal thickness was 194.1 +/- 39.8 MUm (158.5[FIGURE DASH]238.3 MUm) at baseline and 156.6 +/- 56.2 MUm (125.9[FIGURE DASH]213.9 MUm) at 12 months. The mean peripapillary choroidal thickness decreased significantly over 12 months in both BRVO-affected and nonaffected eyes (P < 0.001, both eyes). Although the mean peripapillary choroidal thickness was not significantly different between groups at baseline (P = 0.472), it was significantly lower in BRVO-affected eyes than in nonaffected eyes at 12 months (P = 0.036). CONCLUSION: Peripapillary choroidal thickness decreased significantly over 12 months in BRVO-affected eyes and nonaffected eyes in patients with unilateral BRVO. PMID- 28098733 TI - PREVENTING PUPILLARY CAPTURE AFTER VITRECTOMY AND TRANSSCLERAL FIXATION OF AN INTRAOCULAR LENS: Iridotomy Using a Vitrectomy Probe. AB - PURPOSE: To investigate the effects of concurrent iridotomy using a vitreous cutter probe on the prevention of pupillary capture in patients undergoing transscleral fixation of intraocular lens implantation. METHODS: A total of 79 eyes from 79 patients, who underwent transscleral fixation of intraocular lens without preexisting vitreoretinal disorders and who were followed up for 6 months were included. Subjects were divided into a noniridotomy group (51 eyes) and an iridotomy group (28 eyes). After conventional 23-gauge vitrectomy and transscleral fixation of intraocular lens implantation in all patients, 28 patients underwent concurrent iridotomy intraoperatively. The patients were followed up to evaluate the incidence of surgery-related complications, including pupillary capture. RESULTS: There were no statistically significant differences in the preoperative demographic findings between the two groups (all P > 0.05). There was a significant difference in pupillary capture in 15 eyes (29.4%) of the noniridotomy group, compared with 1 eye (3.6%) of the iridotomy group (P = 0.007). There were no differences in postoperative best-corrected visual acuity between the two groups, and no iridotomy-related complications were observed. CONCLUSION: Concurrent iridotomy using a vitreous cutter probe is an easy, rapid, and effective procedure to prevent possible pupillary capture after combined vitrectomy and transscleral fixation of intraocular lens implantation. PMID- 28098734 TI - MULTIMODAL FUNDUS IMAGING OF OUTER RETINAL TUBULATIONS IN CHOROIDAL OSTEOMA PATIENTS. AB - PURPOSE: To evaluate the morphological findings of outer retinal tubulations (ORTs) shown on multimodal imaging modalities in patients with choroidal osteoma. METHODS: Nineteen eyes of 17 patients with choroidal osteoma underwent full clinical and imaging assessments. Color fundus photography, spectral-domain optical coherence tomography (OCT), and en face OCT were used to identify and detect the characteristics of ORT structures, including the shape, configuration, location, and distribution in the fundus. Optical coherence tomography angiography was implemented as an assist to differentiate tumor's feeder vessels from choroidal neovascularization. The correlations between age, gender, tumor features, best-corrected visual acuity at baseline, OCT characteristics, and the presence of ORTs were analyzed. RESULTS: Outer retinal tubulations were identified in five eyes (26.3%). All were located at the decalcified region of the tumor where the choroidal vessels, retinal pigment epithelium, and overlying outer retinal structures were considerably disrupted to varying degrees. With spectral-domain OCT, the ORTs appeared as one or multiple, round or ovoid, hyporeflective lumens with hyperreflective borders confined to the outer nuclear layer, sometimes with hyperreflective luminal content (four eyes, 80%). In one eye, ORTs were found at the focal choroidal excavation. On en face OCT, these tubulations exhibited different shapes, including a dendritic pattern in two eyes, a tube-like pattern in one eye, a circular pattern in one eye, and a hairpin pattern in one eye. Simultaneous OCT angiography imaging demonstrated that the area of choroidal neovascularization was underneath ORT in one eye and very close to ORT in two eyes. The ORTs of three eyes were above or adjacent to tumor's rich feeder vessels. Statistically, age (P = 0.007), greatest tumor linear dimension (P = 0.003), total tumor area (P = 0.002), decalcification area (P = 0.000), and the presence of intraretinal fluid (P = 0.01) and retinal pigment epithelium alterations (P = 0.038) within the foveola and central 1-mm region of patients with ORT were significantly different from those of patients without ORTs. CONCLUSION: The results of this study suggest that age, the greatest tumor linear dimension, total tumor area, decalcification area, and the presence of intraretinal fluid and retinal pigment epithelium alterations within the foveola and central 1-mm region might be risk factors for ORT formation. Spectral-domain OCT combined with en face OCT provides comprehensive imaging information for ORTs in choroidal osteoma. PMID- 28098735 TI - OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF THE FOVEA IN CHILDREN BORN PRETERM. AB - PURPOSE: To compare the foveal avascular zone (FAZ) area measured by optical coherence tomography angiography in children who had been born preterm with age matched controls. METHODS: In this cross-sectional observational comparative case series, 43 eyes of 26 children (28 eyes of 15 former preterm infants and 15 eyes of 11 former term infants) between the ages of 4 and 12 years old were included. Optical coherence tomography angiography with a scan size of 3 * 3 was performed for all eyes. Foveal avascular zone area was measured using the Optovue RTVue AVANTI instrument (Optovue Inc, Fremont, CA) software. Inner and outer retinal thicknesses were measured with the instrument caliper. RESULTS: A distinct FAZ was absent in 12 eyes (42.8%) of children with a history of preterm birth, however, it was present in all (100%) control eyes. The FAZ area was significantly correlated with gestational age (r = 0.82, P < 0.001) and birth weight (r = 0.80, P < 0.001). The gestational age was less than 29 weeks and birth weight was less than 1,480 grams in eyes with no distinct FAZ. Mean central foveal vessel density in the superficial capillary plexus was 41.8 +/- 4.4% in the preterm group and 32.8 +/- 5.8% in the control group (P < 0.001). In all eyes, a significant negative correlation was found between the central foveal vessel density and gestational age (r = -0.63, P = 0.001) and birth weight (r = 0.59, P = 0.002). On spectral domain optical coherence tomography examination, the foveal depression was absent and the inner retinal layers were preserved in all eyes with absent FAZ. In all eyes, a significant negative correlation was found between the inner retinal thickness and gestational age (r = -0.68, P < 0.001) and birth weight (r = -0.61, P = 0.001). Ten eyes of 6 preterm children had a history of laser therapy for retinopathy of prematurity. A distinct FAZ was absent in six eyes (60%) with retinopathy of prematurity with history of laser therapy, and six eyes (33.3%) with preterm birth without laser therapy. Eyes with history of laser therapy had a statistically significantly higher inner retinal thickness and central foveal vessel density and smaller FAZ compared with the eyes with preterm birth without laser therapy (P < 0.001, P = 0.04 and P = 0.03, respectively). CONCLUSION: Optical coherence tomography angiography is a novel modality for noninvasive visualization of the retinal vasculature in pediatric patients and expands our knowledge of foveal abnormalities in retinopathy of prematurity. A small or absent FAZ seems to be a distinct sign of prematurity. PMID- 28098736 TI - FOVEAL EXUDATE AND CHOROIDAL NEOVASCULARIZATION IN ATYPICAL CASES OF MULTIPLE EVANESCENT WHITE DOT SYNDROME. AB - PURPOSE: To describe atypical cases of multiple evanescent white dot syndrome (MEWDS) associated with foveal exudation, increased choroidal thickness, and secondary Type 2 (subretinal) neovascularization. METHODS: Four cases of atypical MEWDS were studied at a retina referral center. Patients underwent evaluation with multimodal retinal imaging, including fluorescein angiography, indocyanine green angiography, spectral-domain and enhanced depth imaging optical coherence tomography (OCT). Two patients were imaged with OCT angiography. RESULTS: Four patients (3 female, 1 male) with a median age of 23.5 years presented with acute onset, painless, decreased central vision. All cases demonstrated fundus findings consistent with MEWDS on color photography, indocyanine green angiography, fluorescein angiography, fundus autofluorescence, and structural OCT imaging. On structural OCT, all 4 patients were noted to have hyperreflective subretinal material and increased subfoveal choroidal thickness ranging from 307 MUm to 515 MUm. Type 2 neovascularization was diagnosed in all four patients using fluorescein angiography, indocyanine green angiography, and/or OCT angiography. Two patients had poor visual acuity at the last follow-up despite resolution of characteristic clinical findings of MEWDS. CONCLUSION: A subset of patients with atypical MEWDS may develop persistent poor vision due to subfoveal exudation and secondary Type 2 neovascularization. Patients showing increased choroidal thickness at presentation may be more susceptible to this unusual presentation. PMID- 28098737 TI - INCREASED INTRAOCULAR PRESSURE IS A RISK FACTOR FOR UNEXPLAINED VISUAL LOSS DURING SILICONE OIL ENDOTAMPONADE. AB - PURPOSE: To identify the incidence rate and risk factors for unexplained visual loss associated with silicone oil endotamponade used during primary repair of macula-sparing rhegmatogenous retinal detachments. METHODS: This retrospective cohort study included patients undergoing pars plana vitrectomy for primary surgical repair of macula-sparing rhegmatogenous retinal detachments in whom silicone oil endotamponade was used. The primary outcome measure was the incidence rate of unexplained visual loss and identification of risk factors associated with vision loss. RESULTS: Of 1,218 eyes undergoing pars plana vitrectomy for primary retinal detachment repair, 44 eyes were included for analysis. In 9 eyes (20%), an unexplained vision loss occurred. Logistic regression identified increased intraocular pressure (IOP) (prospectively defined as IOP readings during silicone oil endotamponade >=21 mmHg on two consecutive visits or >=25 mmHg at any time during this period) as significant predictor (odds ratio = 4.9; P = 0.04) and a classification tree ranked IOP as the most important variable for vision loss. Incidence rate of vision loss in eyes experiencing IOP increase was 4.5 vision loss events per 1,000 days at risk compared with 1 event per 1,000 days in eyes without IOP increase, yielding an incidence rate ratio of 4.5 (95% confidence interval: 1.1-17.9; P = 0.02). CONCLUSION: Sufficient control of IOP during silicone oil endotamponade for primary retinal detachment repair is warranted to reduce the probability of vision loss. PMID- 28098738 TI - SUBRETINAL CELL-BASED THERAPY: An Analysis of Surgical Variables to Increase Cell Survival. AB - PURPOSE: To develop a novel surgical approach to provide consistent delivery of cell suspension into the subretinal space without cell leakage into the vitreous. METHODS: Cell viability was assessed following mock injections to determine the optimal size cannula for delivery of the cells. A pars plana without vitrectomy approach was used to create a subretinal bleb with balanced salt solution using a 41-gauge cannula. GFP-labeled retinal pigment epithelium cells were injected through transretinal (n = 8) and transscleral (n = 16) injection approaches. Optical coherence tomography, fundus photography and autofluorescence, and histological analysis were used to evaluate surgical success. RESULTS: The 30 gauge cannula yielded the highest recovery of cells with highest viability. The transretinal approach consistently resulted in transplanted cells in the vitreous, with some cells coming to rest on the inner limiting membrane. Conversely, the transscleral approach resulted in transplantation of cells into the subretinal space in 100% of cases. Histological analysis confirmed these results. CONCLUSION: We have developed a novel surgical approach that resulted in encapsulation of transplanted cells into the subretinal space with a 100% success rate. This approach will provide a useful tool for further cell transplantation study and may provide an approach for clinical application of delivering cells to the subretinal space. PMID- 28098739 TI - Three-Dimensional Head-Mounted Display System for Ophthalmic Surgical Procedures. PMID- 28098740 TI - Adult Scoliosis Deformity Surgery: Comparison of Outcomes Between One Versus Two Attending Surgeons. AB - STUDY DESIGN: Retrospective review of prospectively collected data. OBJECTIVE: Assess outcomes of adult spinal deformity (ASD) surgery performed by one versus two attending surgeons. SUMMARY OF BACKGROUND DATA: ASD centers have developed two attending teams to improve efficiency; their effects on complications and outcomes have not been reported. METHODS: Patients with ASD with five or more levels fused and more than 2-year follow-up were included. Estimated blood loss (EBL), length of stay (LOS), operating room (OR) time, complications, quality of life (Health Related Quality of Life), and x-rays were analyzed. Outcomes were compared between one-surgeon (1S) and two-surgeon (2S) centers. A deformity matched cohort was analyzed. RESULTS: A total of 188 patients in 1S and 77 in 2S group were included. 2S group patients were older and had worse deformity based on the Scoliosis Research Society-Schwab classification (P < 0.05). There were no significant differences in levels fused (P = 0.57), LOS (8.7 vs 8.9 days), OR time (445.9 vs 453.2 min), or EBL (2008 vs 1898 cm; P > 0.05). 2S patients had more three-column osteotomies (3CO; P < 0.001) and used less bone morphogenetic protein 2 (BMP-2; 79.9% vs 15.6%; P < 0.001). The 2S group had fewer intraoperative complications (1.3% vs 11.1%; P = 0.006). Postoperative (6 wk to 2 yr) complications were more frequent in the 2S group (4.8% vs 15.6%; P < 0.002). After matching for deformity, there were no differences in (9.1 vs 10.1 days), OR time (467.8 vs 508.4 min), or EBL (3045 vs 2247 cm; P = 0.217). 2S group used less BMP-2 (20.6% vs 84.8%; P < 0.001), had fewer intraoperative complications (P = 0.015) but postoperative complications due to instrumentation failure/pseudarthrosis were more frequent (P < 0.01). CONCLUSION: No significant differences were found in LOS, OR time, or EBL between the 1S and 2S groups, even when matching for severity of deformity. 2S group had less BMP-2 use, fewer intraoperative complications but more postoperative complications. LEVEL OF EVIDENCE: 2. PMID- 28098741 TI - Does Familial Aggregation of Chronic Low Back Pain Affect Recovery?: A Population Based Twin Study. AB - STUDY DESIGN: Longitudinal twin-cohort study. OBJECTIVE: To investigate the effect familial aggregation of chronic low back pain (LBP) has on the recovery from chronic LBP. SUMMARY OF BACKGROUND DATA: LBP is a worldwide problem, with pain and disability often becoming chronic. Genetics and familial behaviors could significantly affect the recovery from chronic LBP but have not been extensively investigated. METHODS: A total of 624 Spanish twins from the Murcia Twin Registry reported experiencing chronic LBP within the past 2 years during the 2009/11 data collection wave and were followed up in 2013. Familial aggregation of chronic LBP was determined by the co-twin experiencing chronic LBP within the past 2 years at baseline. Twins reporting LBP "within the past 4 weeks" at follow-up were considered to have not recovered. RESULTS: There were 455 twins with available data on LBP at follow-up and available data on LBP from their co-twin at baseline. Twins with an affected co-twin at baseline were significantly more likely to have not recovered from chronic LBP at follow-up (odds ratio [OR] = 1.6, 95% confidence interval [CI]: 1.0-2.4, P = 0.046). This relationship was stronger for monozygotic twins (OR = 2.5, 95% CI: 1.3-4.8, P = 0.006) (n = 172) but disappeared when considering only dizygotic twins (OR = 1.1, 95% CI: 0.6-2.0, P = 0.668) (n = 283). Sibling-relative recurrence risk (lambda s) was 1.2 for the total sample, 1.5 for monozygotic twins, and 1.1 for dizygotic twins. CONCLUSION: Having a sibling with chronic LBP at baseline increased the likelihood of LBP at follow-up by 20%, with this likelihood increasing to 50% if the sibling was an identical twin. These results are novel and highlight the important influence genetics have on people's recovery from chronic LBP. Information regarding the presence of chronic LBP within a family is easy to obtain and has the potential to inform clinicians on which patients are less likely to recover when treatment implementation is not considered. LEVEL OF EVIDENCE: 3. PMID- 28098742 TI - Does Transection of the C2 Nerve Roots During C1 Lateral Mass Screw Placement for Atlantoaxial Fixation Result in a Superior Outcome?: A Systematic Review of the Literature and Meta-analysis. AB - STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: To evaluate the clinical and functional outcomes of transection of the C2 roots during C1 lateral mass screw placement for atlantoaxial fixation. SUMMARY OF BACKGROUND DATA: Transection of the C2 nerve roots has been recommended during atlantoaxial fixation to facilitate C1 lateral mass screw placement and possibly reduce postoperative occipital neuralgia, although this practice remains controversial. METHODS: We searched MEDLINE, EMBASE, Web of Science, and the Cochrane Library for studies evaluating the outcomes of C1-2 fixation involving sacrifice of the C2 roots. We calculated transformed proportions with 95% confidence intervals (CI) for the outcomes of occipital neuralgia, numbness, bony fusion, and procedural morbidity. For studies comparing C2 transection with nerve sparing surgery, we performed meta-analyses for the outcomes of occipital neuralgia, occipital numbness, blood loss, and operative time. RESULTS: Eight observational studies (N = 393) met eligibility criteria. The rate of postoperative occipital neuralgia among included studies was 0% to 25%; occipital numbness, 6.7% to100%; bony fusion, 96.7% to 100%; and procedural morbidity, 0% to 14.3%. Among comparative studies, C2 transection was associated with a higher rate of occipital numbness [odds ratio (OR) 178.6 (95% CI 26.6 to 1198.4)], lower blood loss [mean difference (MD) -195.3 mL (95% CI -317.7 to -72.8 mL)] and shorter operative times [MD -57.5 mins (95% CI -76.9 to -38.2 mins)] than when the C2 roots were spared. We found no difference in rates of occipital neuralgia [OR 1.44 (95% CI 0.45 to 4.68)]. CONCLUSION: Transection of the C2 nerve roots appears to be a viable, safe option when undertaking placement of C1 lateral mass screws. The procedure is associated with reduced operative duration and blood loss, increased rate of occipital numbness, and no change in the rate of occipital neuralgia. However, given the relatively low quality of evidence, prospective, controlled studies to evaluate this strategy are recommended. LEVEL OF EVIDENCE: N /A. PMID- 28098743 TI - Analysis of Incident and Accident Reports and Risk Management in Spine Surgery. AB - STUDY DESIGN: A review of accident and incident reports. OBJECTIVE: To analyze prevalence, characteristics, and details of perioperative incidents and accidents in patients receiving spine surgery. SUMMARY OF BACKGROUND DATA: In our institution, a clinical error that potentially results in an adverse event is usually submitted as an incident or accident report through a web database, to ensure anonymous and blame-free reporting. All reports are analyzed by a medical safety management group. These reports contain valuable data for management of medical safety, but there have been no studies evaluating such data for spine surgery. METHODS: A total of 320 incidents and accidents that occurred perioperatively in 172 of 415 spine surgeries were included in the study. Incidents were defined as events that were "problematic, but with no damage to the patient," and accidents as events "with damage to the patient." The details of these events were analyzed. RESULTS: There were 278 incidents in 137 surgeries and 42 accidents in 35 surgeries, giving prevalence of 33% (137/415) and 8% (35/415), respectively. The proportion of accidents among all events was significantly higher for doctors than non-doctors [68.0% (17/25) vs. 8.5% (25/295), P < 0.01] and in the operating room compared with outside the operating room [40.5% (15/37) vs. 9.5% (27/283), P < 0.01]. There was no significant difference in years of experience among personnel involved in all events. The major types of events were medication-related, line and tube problems, and falls and slips. Accidents also occurred because of a long-term prone position, with complications such as laryngeal edema, ulnar nerve palsy, and tooth damage. CONCLUSION: Surgery and procedures in the operating room always have a risk of complications. Therefore, a particular effort is needed to establish safe management of this environment and to provide advice on risk to the doctor and medical care team. LEVEL OF EVIDENCE: 4. PMID- 28098744 TI - Trabecular Microstructure and Damage Affect Cement Leakage From the Basivertebral Foramen During Vertebral Augmentation. AB - STUDY DESIGN: A prospective study on cadaver specimens. OBJECTIVE: To explore why cement leakage from basivertebral foramen (BF) easily occurs during vertebral augmentation procedures. SUMMARY OF BACKGROUND DATA: Type B (through BF, basivertebral foramen) cement leakage is the most common type after vertebral augmentation, but the mechanism of this is still controversial. The contribution of vertebral trabecular bone orientation and trabecular damage during compression fracture to cement leakage is still unknown. METHODS: In this study, 12 fresh frozen human lumbar spines (T12-L5) were collected and divided into 24 three segment units. Mechanical testing was performed to simulate a compression fracture. MicroCT were performed on all segments before and after mechanical testing, and trabecular microstructure of the superior, middle (containing BF), and inferior 1/3 of each vertebral body was analyzed. The diameter variation of intertrabecular space before and after compression fracture was used to quantify trabecular injury. After mechanical testing, vertebral augmentation, and imaging based diagnosis were used to evaluate cement leakage. RESULTS: Trabecular bone microstructural parameters in middle region (containing BF) were lower than those of the superior or inferior regions (P < 0.01). After compressive failure, 3D reconstruction of the vertebral body by MicroCT demonstrated that intertrabecular distance in the middle region was markedly increased. Type B cement leakage was the most common type after vertebral augmentation, as found previously in Wang et al. (Spine J 2014;14: 1551-1558). CONCLUSION: The presence of the BF and the relative sparsity of trabecular bone make the middle region of the vertebral body the mechanically weakest region. Trabecular bone in middle region suffered the most severe damage during compressive failure of the vertebral body, which resulted in the greatest intervertebral spacing, and subsequently the highest percentage of type B cement leakage. These data suggest specific mechanisms by which cement may leak from the BF, and the contribution of trabecular microstructure and trabecular injury. LEVEL OF EVIDENCE: 4. PMID- 28098745 TI - Effect of Freeze-Dried Allograft Bone With Human Basic Fibroblast Growth Factor Containing a Collagen-Binding Domain From Clostridium histolyticum Collagenase on Bone Formation After Lumbar Posterolateral Fusion Surgery in Rats. AB - STUDY DESIGN: An experimental study. OBJECTIVE: To evaluate the effectiveness of freeze-dried bone allograft (FDBA) with basic fibroblast growth factor (bFGF) fused with the polycystic kidney disease domain (PKD) and the collagen-binding domain (CBD) of Clostridium histolyticum collagenase, for the acceleration of lumbar posterolateral fusion in rats. SUMMARY OF BACKGROUND DATA: Reports indicate bFGF is an effective growth factor with osteogenic potential for promoting bone regeneration, although its efficiency decreases rapidly following its diffusion in body fluid from the host site. We developed a bFGF fusion protein containing the PKD and the CBD of C histolyticum collagenase (bFGF-PKD CBD), which markedly enhanced bone formation at a relatively low concentration when applied to the surface of rat femurs in a previous study. The potential of this novel protein to accelerate bone fusion in a rat model of lumbar posterolateral fusion has yet to be investigated. METHODS: Bilateral L4-L5 posterolateral fusions were performed, using 150 mg of FDBA powder per side. A total of 20 male Sprague-Dawley rats weighing 200 to 250 g/each were divided into two groups of 10 rats: FDBA was incubated with either phosphate-buffered saline (control group) or 0.58 nmol bFGF-PKD-CBD (bFGF-PKD-CBD group) before fusion surgery. The effect of bFGF-PKD-CBD was estimated using radiographs, microcomputed tomography, and histology (hematoxylin-eosin and von Kossa staining). RESULTS: Both grafted bone volume in the posterolateral lesion and the volume of new bone formation on the surface of laminae and spinal processes were significantly higher in the bFGF-PKD-CBD group than in the control group. Histologically, new bone formation and surrounding chondrocytes and fibroblasts were prominent in the bFGF-PKD-CBD group. CONCLUSION: FDBA infused with bFGF-PKD CBD may be a promising material for accelerating spinal fusion, and the FDBA based delivery system for localizing bFGF-PKD-CBD may offer novel therapeutic approaches to augment spinal fusion. LEVEL OF EVIDENCE: N/A. PMID- 28098746 TI - Marine Antibody-Drug Conjugates: Design Strategies and Research Progress. AB - Antibody-drug conjugates (ADCs), constructed with monoclonal antibodies (mAbs), linkers, and natural cytotoxins, are innovative drugs developed for oncotherapy. Owing to the distinctive advantages of both chemotherapy drugs and antibody drugs, ADCs have obtained enormous success during the past several years. The development of highly specific antibodies, novel marine toxins' applications, and innovative linker technologies all accelerate the rapid R&D of ADCs. Meanwhile, some challenges remain to be solved for future ADCs. For instance, varieties of site-specific conjugation have been proposed for solving the inhomogeneity of DARs (Drug Antibody Ratios). In this review, the usages of various natural toxins, especially marine cytotoxins, and the development strategies for ADCs in the past decade are summarized. Representative ADCs with marine cytotoxins in the pipeline are introduced and characterized with their new features, while perspective comments for future ADCs are proposed. PMID- 28098748 TI - Propagation Modeling and Defending of a Mobile Sensor Worm in Wireless Sensor and Actuator Networks. AB - WSANs (Wireless Sensor and Actuator Networks) are derived from traditional wireless sensor networks by introducing mobile actuator elements. Previous studies indicated that mobile actuators can improve network performance in terms of data collection, energy supplementation, etc. However, according to our experimental simulations, the actuator's mobility also causes the sensor worm to spread faster if an attacker launches worm attacks on an actuator and compromises it successfully. Traditional worm propagation models and defense strategies did not consider the diffusion with a mobile worm carrier. To address this new problem, we first propose a microscopic mathematical model to describe the propagation dynamics of the sensor worm. Then, a two-step local defending strategy (LDS) with a mobile patcher (a mobile element which can distribute patches) is designed to recover the network. In LDS, all recovering operations are only taken in a restricted region to minimize the cost. Extensive experimental results demonstrate that our model estimations are rather accurate and consistent with the actual spreading scenario of the mobile sensor worm. Moreover, on average, the LDS outperforms other algorithms by approximately 50% in terms of the cost. PMID- 28098747 TI - Integrated Treatment of PTSD and Substance Use Disorders: The Mediating Role of PTSD Improvement in the Reduction of Depression. AB - Posttraumatic stress disorder (PTSD) represents one of the most common mental health disorders, particularly among veterans, and is associated with significant distress and impairment. This highly debilitating disorder is further complicated by common comorbid psychiatric disorders, such as substance use disorders (SUD). Individuals with PTSD and co-occurring SUD also commonly present with secondary symptoms, such as elevated depression. Little is known, however, about how these secondary symptoms are related to treatment outcome. The aim of the present study, therefore, was to examine (1) the effects of treatment of comorbid PTSD/SUD on depressive symptoms; and (2) whether this effect was mediated by changes in PTSD severity or changes in SUD severity. Participants were 81 U.S. military veterans (90.1% male) with PTSD and SUD enrolled in a randomized controlled trial examining the efficacy of an integrated, exposure-based treatment (Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure; n = 54) versus relapse prevention (n = 27). Results revealed significantly lower depressive symptoms at post-treatment in the COPE group, as compared to the relapse prevention group. Examination of the mechanisms associated with change in depression revealed that reduction in PTSD severity, but not substance use severity, mediated the association between the treatment group and post-treatment depression. The findings underscore the importance of treating PTSD symptoms in order to help reduce co-occurring symptoms of depression in individuals with PTSD/SUD. Clinical implications and avenues for future research are discussed. PMID- 28098749 TI - A Semipersistent Plant Virus Differentially Manipulates Feeding Behaviors of Different Sexes and Biotypes of Its Whitefly Vector. AB - It is known that plant viruses can change the performance of their vectors. However, there have been no reports on whether or how a semipersistent plant virus manipulates the feeding behaviors of its whitefly vectors. Cucurbit chlorotic yellows virus (CCYV) (genus Crinivirus, family Closteroviridae) is an emergent plant virus in many Asian countries and is transmitted specifically by B and Q biotypes of tobacco whitefly, Bemisia tabaci (Gennadius), in a semipersistent manner. In the present study, we used electrical penetration graph (EPG) technique to investigate the effect of CCYV on the feeding behaviors of B. tabaci. The results showed that CCYV altered feeding behaviors of both biotypes and sexes of B. tabaci with different degrees. CCYV had stronger effects on feeding behaviors of Q biotype than those of B biotype, by increasing duration of phloem salivation and sap ingestion, and could differentially manipulate feeding behaviors of males and females in both biotype whiteflies, with more phloem ingestion in Q biotype males and more non-phloem probing in B biotype males than their respective females. With regard to feeding behaviors related to virus transmission, these results indicated that, when carrying CCYV, B. tabaci Q biotype plays more roles than B biotype, and males make greater contribution than females. PMID- 28098750 TI - Cluster-Based Maximum Consensus Time Synchronization for Industrial Wireless Sensor Networks. AB - Time synchronization is one of the key technologies in Industrial Wireless Sensor Networks (IWSNs), and clustering is widely used in WSNs for data fusion and information collection to reduce redundant data and communication overhead. Considering IWSNs' demand for low energy consumption, fast convergence, and robustness, this paper presents a novel Cluster-based Maximum consensus Time Synchronization (CMTS) method. It consists of two parts: intra-cluster time synchronization and inter-cluster time synchronization. Based on the theory of distributed consensus, the proposed method utilizes the maximum consensus approach to realize the intra-cluster time synchronization, and adjacent clusters exchange the time messages via overlapping nodes to synchronize with each other. A Revised-CMTS is further proposed to counteract the impact of bounded communication delays between two connected nodes, because the traditional stochastic models of the communication delays would distort in a dynamic environment. The simulation results show that our method reduces the communication overhead and improves the convergence rate in comparison to existing works, as well as adapting to the uncertain bounded communication delays. PMID- 28098752 TI - Microbiological Load of Edible Insects Found in Belgium. AB - Edible insects are gaining more and more attention as a sustainable source of animal protein for food and feed in the future. In Belgium, some insect products can be found on the market, and consumers are sourcing fresh insects from fishing stores or towards traditional markets to find exotic insects that are illegal and not sanitarily controlled. From this perspective, this study aims to characterize the microbial load of edible insects found in Belgium (i.e., fresh mealworms and house crickets from European farms and smoked termites and caterpillars from a traditional Congolese market) and to evaluate the efficiency of different processing methods (blanching for all species and freeze-drying and sterilization for European species) in reducing microorganism counts. All untreated insect samples had a total aerobic count higher than the limit for fresh minced meat (6.7 log cfu/g). Nevertheless, a species-dependent blanching step has led to a reduction of the total aerobic count under this limit, except for one caterpillar species. Freeze-drying and sterilization treatments on European species were also effective in reducing the total aerobic count. Yeast and mold counts for untreated insects were above the Good Manufacturing Practice limits for raw meat, but all treatments attained a reduction of these microorganisms under this limit. These results confirmed that fresh insects, but also smoked insects from non European trades, need a cooking step (at least composed of a first blanching step) before consumption. Therefore, blanching timing for each studied insect species is proposed and discussed. PMID- 28098753 TI - Reagent-Less and Robust Biosensor for Direct Determination of Lactate in Food Samples. AB - Lactic acid is a relevant analyte in the food industry, since it affects the flavor, freshness, and storage quality of several products, such as milk and dairy products, juices, or wines. It is the product of lactose or malo-lactic fermentation. In this work, we developed a lactate biosensor based on the immobilization of lactate oxidase (LOx) onto N,N'-Bis(3,4-dihydroxybenzylidene) 1,2-diaminobenzene Schiff base tetradentate ligand-modified gold nanoparticles (3,4DHS-AuNPs) deposited onto screen-printed carbon electrodes, which exhibit a potent electrocatalytic effect towards hydrogen peroxide oxidation/reduction. 3,4DHS-AuNPs were synthesized within a unique reaction step, in which 3,4DHS acts as reducing/capping/modifier agent for the generation of stable colloidal suspensions of Schiff base ligand-AuNPs assemblies of controlled size. The ligand in addition to its reduction action-provides a robust coating to gold nanoparticles and a catalytic function. Lactate oxidase (LOx) catalyzes the conversion of l-lactate to pyruvate in the presence of oxygen, producing hydrogen peroxide, which is catalytically oxidized at 3,4DHS-AuNPs modified screen-printed carbon electrodes at +0.2 V. The measured electrocatalytic current is directly proportional to the concentration of peroxide, which is related to the amount of lactate present in the sample. The developed biosensor shows a detection limit of 2.6 MUM lactate and a sensitivity of 5.1 +/- 0.1 MUA.mM-1. The utility of the device has been demonstrated by the determination of the lactate content in different matrixes (white wine, beer, and yogurt). The obtained results compare well to those obtained using a standard enzymatic-spectrophotometric assay kit. PMID- 28098755 TI - Exopolysaccharides Isolated from Milk Fermented with Lactic Acid Bacteria Prevent Ultraviolet-Induced Skin Damage in Hairless Mice. AB - BACKGROUND: We studied the mechanism by which fermented milk ameliorates UV-B induced skin damage and determined the active components in milk fermented with lactic acid bacteria by evaluating erythema formation, dryness, epidermal proliferation, DNA damage and cytokine mRNA levels in hairless mice exposed to acute UV-B irradiation. METHODS: Nine week-old hairless mice were given fermented milk (1.3 g/kg BW/day) or exopolysaccharide (EPS) concentrate (70 mg/kg BW/day) orally for ten days. Seven days after fermented milk or EPS administration began, the dorsal skin of the mice was exposed to a single dose of UV-B (20 mJ/cm2). RESULTS: Ingestion of either fermented milk or EPS significantly attenuated UV-B induced erythema formation, dryness and epidermal proliferation in mouse skin. Both fermented milk and EPS were associated with a significant decrease in cyclobutane pyrimidine dimers and upregulated mRNA levels of xeroderma pigmentosum complementation group A (XPA), which is involved in DNA repair. Furthermore, administration of either fermented milk or EPS significantly suppressed increases in the ratio of interleukin (IL)-10/IL-12a and IL 10/interferon-gamma mRNA levels. CONCLUSION: Together, these results indicate that EPS isolated from milk fermented with lactic acid bacteria enhanced DNA repair mechanisms and modulated skin immunity to protect skin against UV damage. PMID- 28098754 TI - Drp1-Dependent Mitochondrial Fission Plays Critical Roles in Physiological and Pathological Progresses in Mammals. AB - Current research has demonstrated that mitochondrial morphology, distribution, and function are maintained by the balanced regulation of mitochondrial fission and fusion, and perturbation of the homeostasis between these processes has been related to cell or organ dysfunction and abnormal mitochondrial redistribution. Abnormal mitochondrial fusion induces the fragmentation of mitochondria from a tubular morphology into pieces; in contrast, perturbed mitochondrial fission results in the fusion of adjacent mitochondria. A member of the dynamin family of large GTPases, dynamin-related protein 1 (Drp1), effectively influences cell survival and apoptosis by mediating the mitochondrial fission process in mammals. Drp1-dependent mitochondrial fission is an intricate process regulating both cellular and organ dynamics, including development, apoptosis, acute organ injury, and various diseases. Only after clarification of the regulative mechanisms of this critical protein in vivo and in vitro will it set a milestone for preventing mitochondrial fission related pathological processes and refractory diseases. PMID- 28098756 TI - Detection of the Vascular Endothelial Growth Factor with a Novel Bioluminescence Resonance Energy Transfer Pair Using a Two-Component System. AB - In this paper we describe a two-component BRET (bioluminescence resonance energy transfer)-based method to detect vascular endothelial growth factor (VEGF) molecules in unknown samples as the basis for subsequent in vivo use. A luminescent VEGF binding molecule, which binds in the receptor binding motif of VEGF, is used as the energy donor, transferred to a fluorophore-coupled VEGF binding molecule (acceptor), which binds to the neuropilin binding motif of VEGF, thus enabling energy transfer from the donor to the acceptor molecule. This leads to the emission of light at a longer wavelength and thus the generation of an increased BRET signal only when VEGF is bound to both the donor and acceptor molecules. We further describe a novel BRET pair that uses the Renilla reniformis mutant luciferase RLuc8 and the chemically engineered fluorophore PerCP-Cy5.5(r), which exhibits superior peak separation of approximately 300 nm. The implantation of capsules consisting of the two BRET components in solution, permeable for VEGF for its in vivo detection, would provide a new and improved method for monitoring VEGF-induced pathologies and thus an adjustment of therapy to patient needs. PMID- 28098757 TI - Role of miR-34a-5p in Hematopoietic Progenitor Cells Proliferation and Fate Decision: Novel Insights into the Pathogenesis of Primary Myelofibrosis. AB - Primary Myelofibrosis (PMF) is a chronic Philadelphia-negative myeloproliferative neoplasm characterized by a skewed megakaryopoiesis and an overproduction of proinflammatory and profibrotic mediators that lead to the development of bone marrow (BM) fibrosis. Since we recently uncovered the upregulation of miR-34a-5p in PMF CD34+ hematopoietic progenitor cells (HPCs), in order to elucidate its role in PMF pathogenesis here we unravelled the effects of miR-34a-5p overexpression in HPCs. We showed that enforced expression of miR-34a-5p partially constrains proliferation and favours the megakaryocyte and monocyte/macrophage commitment of HPCs. Interestingly, we identified lymphoid enhancer-binding factor 1 (LEF1) and nuclear receptor subfamily 4, group A, member 2 (NR4A2) transcripts as miR-34a-5p-targets downregulated after miR-34a-5p overexpression in HPCs as well as in PMF CD34+ cells. Remarkably, the knockdown of NR4A2 in HPCs mimicked the antiproliferative effects of miR-34a-5p overexpression, while the silencing of LEF1 phenocopied the effects of miR-34a-5p overexpression on HPCs lineage choice, by favouring the megakaryocyte and monocyte/macrophage commitment. Collectively our data unravel the role of miR-34a 5p in HPCs fate decision and suggest that the increased expression of miR-34a-5p in PMF HPCs could be important for the skewing of megakaryopoiesis and the production of monocytes, that are key players in BM fibrosis in PMF patients. PMID- 28098758 TI - Neurotrophin Promotes Neurite Outgrowth by Inhibiting Rif GTPase Activation Downstream of MAPKs and PI3K Signaling. AB - Members of the well-known semaphorin family of proteins can induce both repulsive and attractive signaling in neural network formation and their cytoskeletal effects are mediated in part by small guanosine 5'-triphosphatase (GTPases). The aim of this study was to investigate the cellular role of Rif GTPase in the neurotrophin-induced neurite outgrowth. By using PC12 cells which are known to cease dividing and begin to show neurite outgrowth responding to nerve growth factor (NGF), we found that semaphorin 6A was as effective as nerve growth factor at stimulating neurite outgrowth in PC12 cells, and that its neurotrophic effect was transmitted through signaling by mitogen-activated protein kinases (MAPKs) and phosphatidylinositol-3-kinase (PI3K). We further found that neurotrophin induced neurite formation in PC12 cells could be partially mediated by inhibition of Rif GTPase activity downstream of MAPKs and PI3K signaling. In conclusion, we newly identified Rif as a regulator of the cytoskeletal rearrangement mediated by semaphorins. PMID- 28098759 TI - Reactive Oxygen Species Generated by NADPH Oxidases Promote Radicle Protrusion and Root Elongation during Rice Seed Germination. AB - Seed germination is a complicated biological process that requires regulation through various enzymatic and non-enzymatic mechanisms. Although it has been recognized that reactive oxygen species (ROS) regulate radicle emergence and root elongation in a non-enzymatic manner during dicot seed germination, the role of ROS in monocot seed germination remains unknown. NADPH oxidases (NOXs) are the major ROS producers in plants; however, whether and how NOXs regulate rice seed germination through ROS generation remains unclear. Here, we report that diphenyleneiodinium (DPI), a specific NOX inhibitor, potently inhibited embryo and seedling growth-especially that of the radicle and of root elongation-in a dose-dependent manner. Notably, the DPI-mediated inhibition of radicle and root growth could be eliminated by transferring seedlings from DPI to water. Furthermore, ROS production/accumulation during rice seed germination was quantified via histochemistry. Superoxide radicals (O2-), hydrogen peroxide (H2O2) and hydroxyl radicals (*OH) accumulated steadily in the coleorhiza, radicle and seedling root of germinating rice seeds. Expression profiles of the nine typical NOX genes were also investigated. According to quantitative PCR, OsNOX5, 7 and 9 were expressed relatively higher. When seeds were incubated in water, OsNOX5 expression progressively increased in the embryo from 12 to 48 h, whereas OsNOX7 and 9 expressions increased from 12 to 24 h and decreased thereafter. As expected, DPI inhibits the expression at predetermined time points for each of these genes. Taken together, these results suggest that ROS produced by NOXs are involved in radicle and root elongation during rice seed germination, and OsNOX5, 7 and 9 could play crucial roles in rice seed germination. These findings will facilitate further studies of the roles of ROS generated by NOXs during seed germination and seedling establishment and also provide valuable information for the regulation of NOX family gene expression in germinating seeds of monocot cereals. PMID- 28098761 TI - Pancreatic Neuroendocrine Neoplasms: Basic Biology, Current Treatment Strategies and Prospects for the Future. AB - Pancreatic neuroendocrine neoplasms (pNENs) are rare tumors accounting for only 1%-2% of all pancreatic tumors. pNENs are pathologically heterogeneous and are categorized into three groups (neuroendocrine tumor: NET G1, NET G2; and neuroendocrine carcinoma: NEC) on the basis of the Ki-67 proliferation index and the mitotic count according to the 2010 World Health Organization (WHO) classification of gastroenteropancreatic NENs. NEC in this classification includes both histologically well-differentiated and poorly differentiated subtypes, and modification of the WHO 2010 classification is under discussion based on genetic and clinical data. Genomic analysis has revealed NETs G1/G2 have genetic alterations in chromatin remodeling genes such as MEN1, DAXX and ATRX, whereas NECs have an inactivation of TP53 and RB1, and these data suggest that different treatment approaches would be required for NET G1/G2 and NEC. While there are promising molecular targeted drugs, such as everolimus or sunitinib, for advanced NET G1/G2, treatment stratification based on appropriate predictive and prognostic biomarkers is becoming an important issue. The clinical outcome of NEC is still dismal, and a more detailed understanding of the genetic background together with preclinical studies to develop new agents, including those already under investigation for small cell lung cancer (SCLC), will be needed to improve the prognosis. PMID- 28098763 TI - New Abietane and Kaurane Type Diterpenoids from the Stems of Tripterygium regelii. AB - Eleven new abietane type (1-11), and one new kaurane (12), diterpenes, together with eleven known compounds (13-23), were isolated and identified from the stems of Tripterygium regelii, which has been used as a traditional folk Chinese medicine for the treatment of rheumatoid arthritis in China. The structures of new compounds were characterized by means of the interpretation of high resolution electrospray ionization mass spectrometry (HRESIMS), extensive nuclear magnetic resonance (NMR) spectroscopic data and comparisons of their experimental CD spectra with calculated electronic circular dichroism (ECD) spectra. Compound 1 is the first abietane type diterpene with an 18->1 lactone ring. Compound 19 was isolated from the plants of the Tripterygium genus for the first time, and compounds 14-17 were isolated from T. regelii for the first time. Triregelin I (9) showed significant cytotoxicity against A2780 and HepG2 with IC50 values of 5.88 and 11.74 uM, respectively. It was found that this compound was inactive against MCF-7 cells. The discovery of these twelve new diterpenes not only provided information on chemical substances of T. regelii, but also contributed to the chemical diversity of natural terpenoids. PMID- 28098760 TI - Autocrine and Paracrine Mechanisms Promoting Chemoresistance in Cholangiocarcinoma. AB - Resistance to conventional chemotherapeutic agents, a typical feature of cholangiocarcinoma, prevents the efficacy of the therapeutic arsenal usually used to combat malignancy in humans. Mechanisms of chemoresistance by neoplastic cholangiocytes include evasion of drug-induced apoptosis mediated by autocrine and paracrine cues released in the tumor microenvironment. Here, recent evidence regarding molecular mechanisms of chemoresistance is reviewed, as well as associations between well-developed chemoresistance and activation of the cancer stem cell compartment. It is concluded that improved understanding of the complex interplay between apoptosis signaling and the promotion of cell survival represent potentially productive areas for active investigation, with the ultimate aim of encouraging future studies to unveil new, effective strategies able to overcome current limitations on treatment. PMID- 28098764 TI - IQGAP1 in Podosomes/Invadosomes Is Involved in the Progression of Glioblastoma Multiforme Depending on the Tumor Status. AB - Glioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumor. GBM is formed by a very heterogeneous astrocyte population, neurons, neovascularization and infiltrating myeloid cells (microglia and monocyte derived macrophages). The IQGAP1 scaffold protein interacts with components of the cytoskeleton, cell adhesion molecules, and several signaling molecules to regulate cell morphology and motility, cell cycle and other cellular functions. IQGAP1 overexpression and delocalization has been observed in several tumors, suggesting a role for this protein in cell proliferation, transformation and invasion. IQGAP1 has been identified as a marker of amplifying cancer cells in GBMs. To determine the involvement of IQGAP1 in the onco-biology of GBM, we performed immunohistochemical confocal microscopic analysis of the IQGAP1 protein in human GBM tissue samples using cell type-specific markers. IQGAP1 immunostaining and subcellular localization was heterogeneous; the protein was located in the plasma membrane and, at variable levels, in nucleus and/or cytosol. Moreover, IQGAP1 positive staining was found in podosome/invadopodia like structures. IQGAP1+ staining was observed in neurons (Map2+ cells), in cancer stem cells (CSC; nestin+) and in several macrophages (CD31+ or Iba1+). Our results indicate that the IQGAP1 protein is involved in normal cell physiology as well as oncologic processes. PMID- 28098765 TI - Validation of an Online Food Frequency Questionnaire against Doubly Labelled Water and 24 h Dietary Recalls in Pre-School Children. AB - The development of easy-to-use and accurate methods to assess the intake of energy, foods and nutrients in pre-school children is needed. KidMeal-Q is an online food frequency questionnaire developed for the LifeGene prospective cohort study in Sweden. The aims of this study were to compare: (i) energy intake (EI) obtained using KidMeal-Q to total energy expenditure (TEE) measured via doubly labelled water and (ii) the intake of certain foods measured using KidMeal-Q to intakes acquired by means of 24 h dietary recalls in 38 children aged 5.5 years. The mean EI calculated using KidMeal-Q was statistically different (p < 0.001) from TEE (4670 +/- 1430 kJ/24 h and 6070 +/- 690 kJ/24 h, respectively). Significant correlations were observed for vegetables, fruit juice and candy between KidMeal-Q and 24 h dietary recalls. Only sweetened beverage consumption was significantly different in mean intake (p < 0.001), as measured by KidMeal-Q and 24 h dietary recalls. In conclusion, KidMeal-Q had a relatively short answering time and comparative validity to other food frequency questionnaires. However, its accuracy needs to be improved before it can be used in studies in pre-school children. PMID- 28098766 TI - Single Electrode Deep Brain Stimulation with Dual Targeting at Dual Frequency for the Treatment of Chronic Pain: A Case Series and Review of the Literature. AB - Deep Brain Stimulation (DBS) has been used to target many deep brain structures for the treatment of chronic pain. The periaqueductal grey and periventricular grey (PAG/PVG) is an effective target but results are variable, sometimes short lived or subject to tolerance. The centromedian intra-laminar parafascicular complex (CMPf) modulates medial pain pathways and CMPf DBS may address the affective aspects of pain perception. Stimulation of multiple deep brain targets may offer a strategy to optimize management of patients with complex pain symptomatology. However, previous attempts to stimulate multiple targets requires multiple trajectories and considerable expense. Using a single electrode to stimulate multiple targets would help overcome these challenges. A pre-requisite of such a technique is the ability to use different stimulation parameters at different contacts simultaneously on the same electrode. We describe a novel technique in 3 patients with chronic pain syndromes for whom conventional medical and/or neuromodulation therapy had failed using a single electrode technique to stimulate PVG/PAG and CMPf at dual frequencies. PMID- 28098767 TI - Cheese Consumption and Risk of All-Cause Mortality: A Meta-Analysis of Prospective Studies. AB - The association between cheese consumption and risk for major health endpoints has been investigated in many epidemiologic studies, but findings are inconsistent. As all-cause mortality can be viewed as the final net health effect of dietary intakes, we conducted a meta-analysis to examine the long-term association of cheese consumption with all-cause mortality. Relevant studies were identified by a search of the PubMed database through May 2016. Reference lists from retrieved articles were also reviewed. Summary relative risks (RR) and 95% confidence intervals (CI) were calculated using a random-effects model. Pre specified stratified and dose-response analyses were also performed. The final analysis included nine prospective cohort studies involving 21,365 deaths. The summary RR of all-cause mortality for the highest compared with the lowest cheese consumption was 1.02 (95% CI: 0.97, 1.06), and little evidence of heterogeneity was observed. The association between cheese consumption and risk of all-cause mortality did not significantly differ by study location, sex, age, number of events, study quality score or baseline diseases excluded. There was no dose response relationship between cheese consumption and risk of all-cause mortality (RR per 43 g/day = 1.03, 95% CI: 0.99-1.07). No significant publication bias was observed. Our findings suggest that long-term cheese consumption was not associated with an increased risk of all-cause mortality. PMID- 28098768 TI - Preventive Effects of Drinking Hydrogen-Rich Water on Gingival Oxidative Stress and Alveolar Bone Resorption in Rats Fed a High-Fat Diet. AB - Obesity induces gingival oxidative stress, which is involved in the progression of alveolar bone resorption. The antioxidant effect of hydrogen-rich water may attenuate gingival oxidative stress and prevent alveolar bone resorption in cases of obesity. We examined whether hydrogen-rich water could suppress gingival oxidative stress and alveolar bone resorption in obese rats fed a high-fat diet. Male Fischer 344 rats (n = 18) were divided into three groups of six rats each: a control group (fed a regular diet and drinking distilled water) and two experimental groups (fed a high-fat diet and drinking distilled water or hydrogen rich water). The level of 8-hydroxydeoxyguanosine was determined to evaluate oxidative stress. The bone mineral density of the alveolar bone was analyzed by micro-computerized tomography. Obese rats, induced by a high-fat diet, showed a higher gingival level of 8-hydroxydeoxyguanosine and a lower level of alveolar bone density compared to the control group. Drinking hydrogen-rich water suppressed body weight gain, lowered gingival level of 8-hydroxydeoxyguanosine, and reduced alveolar bone resorption in rats on a high-fat diet. The results indicate that hydrogen-rich water could suppress gingival oxidative stress and alveolar bone resorption by limiting obesity. PMID- 28098769 TI - Sensory Acceptability of Infant Cereals with Whole Grain in Infants and Young Children. AB - In many countries, infant cereals are one of the first foods introduced during the complementary feeding stage. These cereals are usually made with refined cereal flours, even though several health benefits have been linked to the intake of whole grain cereals. Prior evidence suggests that food preferences are developed at early stages of life, and may persist in later childhood and adulthood. Our aim was to test whether an infant cereal with 30% of whole grain was similarly accepted both by parents and infants in comparison to a similar cereal made from refined flour. A total of 81 infants between 4 and 24 months old were included in the study. Parent-infant pairs participated in an 8-day experimental study. Acceptance was rated on hedonic scales (4-points for infants and 7-points for parents). Other attributes like color, smell, and taste were evaluated by the parents. Acceptability for infant cereals with whole grain and refined cereals was very similar both for infants (2.30 +/- 0.12 and 2.32 +/- 0.11, p = 0.606) and parents (6.1 +/- 0.8 and 6.0 +/- 0.9, p = 0.494). Therefore, our findings show that there is an opportunity to introduce whole grain cereals to infants, including those who are already used to consuming refined infant cereals, thereby accelerating the exposure of whole grain in early life. PMID- 28098770 TI - Can Malaysian Young Adults Report Dietary Intake Using a Food Diary Mobile Application? A Pilot Study on Acceptability and Compliance. AB - Mobile applications may improve dietary reporting among young adults due to their high accessibility and embedded camera function. This pilot study aimed to (i) evaluate users' acceptability and compliance in reporting dietary intake using a newly developed food diary mobile application (food app); and (ii) identify issues and recommendations for improving dietary assessment using this food app via quantitative and qualitative protocols. Twenty-eight university students each used a food app for seven consecutive days and attended one of five focus group interviews. A 42% decrement in reporting compliance was observed throughout the seven-day recording period. An average of 5.9 recording days were reported and 4.8 occasions of meal data were uploaded each day. Based on questionnaires, high levels of agreement were reported in terms of perceived usefulness (69.3%), perceived ease of use (77.1%), attitude (73.6%), perceived enjoyment (62.6%), and smartphone experience (91.1%), but such agreement was not reported for intention to use (38.1%) and social influence (33.4%). Four major themes emerged from the focus group interviews, namely, (i) features; (ii) potential use; (iii) utility issues of the food app; and (iv) suggestions for improvements. While the food app was well-accepted by most of the young adults, the current prototype would benefit from incorporation of a barcode scanning function, customizable reminders, in-app tutorial, an entertainment component, and enhancement in overall appearance. PMID- 28098772 TI - A Non-Intrusive Cyber Physical Social Sensing Solution to People Behavior Tracking: Mechanism, Prototype, and Field Experiments. AB - Tracking people's behaviors is a main category of cyber physical social sensing (CPSS)-related people-centric applications. Most tracking methods utilize camera networks or sensors built into mobile devices such as global positioning system (GPS) and Bluetooth. In this article, we propose a non-intrusive wireless fidelity (Wi-Fi)-based tracking method. To show the feasibility, we target tracking people's access behaviors in Wi-Fi networks, which has drawn a lot of interest from the academy and industry recently. Existing methods used for acquiring access traces either provide very limited visibility into media access control (MAC)-level transmission dynamics or sometimes are inflexible and costly. In this article, we present a passive CPSS system operating in a non-intrusive, flexible, and simplified manner to overcome above limitations. We have implemented the prototype on the off-the-shelf personal computer, and performed real-world deployment experiments. The experimental results show that the method is feasible, and people's access behaviors can be correctly tracked within a one second delay. PMID- 28098773 TI - Continuous Space Estimation: Increasing WiFi-Based Indoor Localization Resolution without Increasing the Site-Survey Effort. AB - Although much research has taken place in WiFi indoor localization systems, their accuracy can still be improved. When designing this kind of system, fingerprint based methods are a common choice. The problem with fingerprint-based methods comes with the need of site surveying the environment, which is effort consuming. In this work, we propose an approach, based on support vector regression, to estimate the received signal strength at non-site-surveyed positions of the environment. Experiments, performed in a real environment, show that the proposed method could be used to improve the resolution of fingerprint-based indoor WiFi localization systems without increasing the site survey effort. PMID- 28098771 TI - Breast Cancer Brain Metastases: Clonal Evolution in Clinical Context. AB - Brain metastases are highly-evolved manifestations of breast cancer arising in a unique microenvironment, giving them exceptional adaptability in the face of new extrinsic pressures. The incidence is rising in line with population ageing, and use of newer therapies that stabilise metastatic disease burden with variable efficacy throughout the body. Historically, there has been a widely-held view that brain metastases do not respond to circulating therapeutics because the blood-brain-barrier (BBB) restricts their uptake. However, emerging data are beginning to paint a more complex picture where the brain acts as a sanctuary for dormant, subclinical proliferations that are initially protected by the BBB, but then exposed to dynamic selection pressures as tumours mature and vascular permeability increases. Here, we review key experimental approaches and landmark studies that have charted the genomic landscape of breast cancer brain metastases. These findings are contextualised with the factors impacting on clonal outgrowth in the brain: intrinsic breast tumour cell capabilities required for brain metastatic fitness, and the neural niche, which is initially hostile to invading cells but then engineered into a tumour-support vehicle by the successful minority. We also discuss how late detection, abnormal vascular perfusion and interstitial fluid dynamics underpin the recalcitrant clinical behaviour of brain metastases, and outline active clinical trials in the context of precision management. PMID- 28098774 TI - Learning to Diagnose Cirrhosis with Liver Capsule Guided Ultrasound Image Classification. AB - This paper proposes a computer-aided cirrhosis diagnosis system to diagnose cirrhosis based on ultrasound images. We first propose a method to extract a liver capsule on an ultrasound image, then, based on the extracted liver capsule, we fine-tune a deep convolutional neural network (CNN) model to extract features from the image patches cropped around the liver capsules. Finally, a trained support vector machine (SVM) classifier is applied to classify the sample into normal or abnormal cases. Experimental results show that the proposed method can effectively extract the liver capsules and accurately classify the ultrasound images. PMID- 28098776 TI - Distinguishing Benign from Malignant Pancreatic and Periampullary Lesions Using Combined Use of 1H-NMR Spectroscopy and Gas Chromatography-Mass Spectrometry. AB - Previous work demonstrated that serum metabolomics can distinguish pancreatic cancer from benign disease. However, in the clinic, non-pancreatic periampullary cancers are difficult to distinguish from pancreatic cancer. Therefore, to test the clinical utility of this technology, we determined whether any pancreatic and periampullary adenocarcinoma could be distinguished from benign masses and biliary strictures. Sera from 157 patients with malignant and benign pancreatic and periampullary lesions were analyzed using proton nuclear magnetic resonance (1H-NMR) spectroscopy and gas chromatography-mass spectrometry (GC-MS). Multivariate projection modeling using SIMCA-P+ software in training datasets (n = 80) was used to generate the best models to differentiate disease states. Models were validated in test datasets (n = 77). The final 1H-NMR spectroscopy and GC-MS metabolomic profiles consisted of 14 and 18 compounds, with AUROC values of 0.74 (SE 0.06) and 0.62 (SE 0.08), respectively. The combination of 1H NMR spectroscopy and GC-MS metabolites did not substantially improve this performance (AUROC 0.66, SE 0.08). In patients with adenocarcinoma, glutamate levels were consistently higher, while glutamine and alanine levels were consistently lower. Pancreatic and periampullary adenocarcinomas can be distinguished from benign lesions. To further enhance the discriminatory power of metabolomics in this setting, it will be important to identify the metabolomic changes that characterize each of the subclasses of this heterogeneous group of cancers. PMID- 28098775 TI - Mammary Gland Involution Provides a Unique Model to Study the TGF-beta Cancer Paradox. AB - Transforming Growth Factor-beta (TGF-beta) signaling in cancer has been termed the "TGF-beta paradox", acting as both a tumor suppresser and promoter. The complexity of TGF-beta signaling within the tumor is context dependent, and greatly impacted by cellular crosstalk between TGF-beta responsive cells in the microenvironment including adjacent epithelial, endothelial, mesenchymal, and hematopoietic cells. Here we utilize normal, weaning-induced mammary gland involution as a tissue microenvironment model to study the complexity of TGF-beta function. This article reviews facets of mammary gland involution that are TGF beta regulated, namely mammary epithelial cell death, immune activation, and extracellular matrix remodeling. We outline how distinct cellular responses and crosstalk between cell types during physiologically normal mammary gland involution contribute to simultaneous tumor suppressive and promotional microenvironments. We also highlight alternatives to direct TGF-beta blocking anti-cancer therapies with an emphasis on eliciting concerted microenvironmental mediated tumor suppression. PMID- 28098777 TI - New Irradiation Method with Indocyanine Green-Loaded Nanospheres for Inactivating Periodontal Pathogens. AB - Antimicrobial photodynamic therapy (aPDT) has been proposed as an adjunctive strategy for periodontitis treatments. However, use of aPDT for periodontal treatment is complicated by the difficulty in accessing morphologically complex lesions such as furcation involvement, which the irradiation beam (which is targeted parallel to the tooth axis into the periodontal pocket) cannot access directly. The aim of this study was to validate a modified aPDT method that photosensitizes indocyanine green-loaded nanospheres through the gingivae from outside the pocket using a diode laser. To establish this trans-gingival irradiation method, we built an in vitro aPDT model using a substitution for gingivae. Irradiation conditions and the cooling method were optimized before the bactericidal effects on Porphyromonas gingivalis were investigated. The permeable energy through the gingival model at irradiation conditions of 2 W output power in a 50% duty cycle was comparable with the transmitted energy of conventional irradiation. Intermittent irradiation with air cooling limited the temperature increase in the gingival model to 2.75 degrees C. The aPDT group showed significant bactericidal effects, with reductions in colony-forming units of 99.99% after 5 min of irradiation. This effect of aPDT against a periodontal pathogen demonstrates the validity of trans-gingival irradiation for periodontal treatment. PMID- 28098778 TI - Bone Niches, Hematopoietic Stem Cells, and Vessel Formation. AB - Bone marrow (BM) is a source of hematopoietic stem cells (HSCs). HSCs are localized in both the endosteum, in the so-called endosteal niche, and close to thin-walled and fenestrated sinusoidal vessel in the center of BM, in the so called vascular niche. HSCs give rise to all types of mature blood cells through a process finely controlled by numerous signals emerging from the bone marrow niches where HSCs reside. This review will focus on the description of the role of BM niches in the control of the fate of HSCs and will also highlight the role of the BM niches in the regulation of vasculogenesis and angiogenesis. Moreover, alterations of the signals in niche microenvironment are involved in many aspects of tumor progression and vascularization and further knowledge could provide the basis for the development of new therapeutic strategies. PMID- 28098779 TI - Unravelling the Diversity of the Cyclopiazonic Acid Family of Mycotoxins in Aspergillus flavus by UHPLC Triple-TOF HRMS. AB - Cyclopiazonic acid (alpha-cyclopiazonic acid, alpha-CPA) is an indole-hydrindane tetramic acid neurotoxin produced by various fungal species, including the notorious food and feed contaminant Aspergillus flavus. Despite its discovery in A. flavus cultures approximately 40 years ago, its contribution to the A. flavus mycotoxin burden is consistently minimized by our focus on the more potent carcinogenic aflatoxins also produced by this fungus. Here, we report the screening and identification of several CPA-type alkaloids not previously found in A. flavus cultures. Our identifications of these CPA-type alkaloids are based on a dereplication strategy involving accurate mass high resolution mass spectrometry data and a careful study of the alpha-CPA fragmentation pattern. In total, 22 CPA-type alkaloids were identified in extracts from the A. flavus strains examined. Of these metabolites, 13 have been previously reported in other fungi, though this is the first report of their existence in A. flavus. Two of our metabolite discoveries, 11,12-dehydro alpha-CPA and 3-hydroxy-2-oxo CPA, have never been reported for any organism. The conspicuous presence of CPA and its numerous derivatives in A. flavus cultures raises concerns about the long-term and cumulative toxicological effects of these fungal secondary metabolites and their contributions to the entire A. flavus mycotoxin problem. PMID- 28098780 TI - Adding Salt to Meals as a Risk Factor of Type 2 Diabetes Mellitus: A Case-Control Study. AB - OBJECTIVE: Type 2 diabetes mellitus (T2DM) is thought to arise from the complex interplay between genetic and environmental factors. It is important to identify modifiable risk factors that may help to reduce the risk of diabetes. Data on salt intake and the risk of type 2 diabetes are limited. The aim of this study was to assess the relationship between adding salt to prepared meals and the risk of type 2 diabetes. METHODS: In a case-control study, we included 234 cases, all of whom were patients aged 35-86 years with a newly confirmed diagnosis of T2DM, and 468 controls that were free of the disease. Cases and controls (ratio 1:2) were matched by gender and age (+/-5 years). A questionnaire was used to collect information on possible risk factors for diabetes. Adding salt to prepared meals was assessed according to: Never, when there was not enough, or almost every time without tasting. The odds ratios (OR), and 95% confidence intervals (CI) for type 2 diabetes was calculated using a conditional logistic regression. RESULTS: The cases had a higher body mass index and a significantly lower education level compared to the controls. Variables such as waist circumference, body mass index, eating speed, smoking, family history of diabetes, arterial hypertension, plasma triglycerides, educational level, occupational status, morning exercise, marital status, daily urine sodium excretion, and daily energy intake were retained in the models as confounders. After adjusting for possible confounders, an approximately two-fold increased risk of type 2 diabetes was determined in subjects who add salt to prepared meals when "it is not enough" or "almost every time without tasting" (1.82; 95% CI 1.19-2.78; p = 0.006) compared with never adding salt. CONCLUSION: Presented data suggest the possible relationship between additional adding of salt to prepared meals and an increased risk of type 2 diabetes. PMID- 28098781 TI - Distinct Neurotoxicity Profile of Listeriolysin O from Listeria monocytogenes. AB - Cholesterol-dependent cytolysins (CDCs) are protein toxins that originate from Gram-positive bacteria and contribute substantially to their pathogenicity. CDCs bind membrane cholesterol and build prepores and lytic pores. Some effects of the toxins are observed in non-lytic concentrations. Two pathogens, Streptococcus pneumoniae and Listeria monocytogenes, cause fatal bacterial meningitis, and both produce toxins of the CDC family-pneumolysin and listeriolysin O, respectively. It has been demonstrated that pneumolysin produces dendritic varicosities (dendrite swellings) and dendritic spine collapse in the mouse neocortex, followed by synaptic loss and astrocyte cell shape remodeling without elevated cell death. We utilized primary glial cultures and acute mouse brain slices to examine the neuropathological effects of listeriolysin O and to compare it to pneumolysin with identical hemolytic activity. In cultures, listeriolysin O permeabilized cells slower than pneumolysin did but still initiated non-lytic astrocytic cell shape changes, just as pneumolysin did. In an acute brain slice culture system, listeriolysin O produced dendritic varicosities in an NMDA dependent manner but failed to cause dendritic spine collapse and cortical astrocyte reorganization. Thus, listeriolysin O demonstrated slower cell permeabilization and milder glial cell remodeling ability than did pneumolysin and lacked dendritic spine collapse capacity but exhibited equivalent dendritic pathology. PMID- 28098782 TI - Auranofin Inhibits the Enzyme Activity of Pasteurella multocida Toxin PMT in Human Cells and Protects Cells from Intoxication. AB - The AB-type protein toxin from Pasteurella multocida (PMT) contains a functionally important disulfide bond within its catalytic domain, which must be cleaved in the host cell cytosol to render the catalytic domain of PMT into its active conformation. Here, we found that the reductive potential of the cytosol of target cells, and more specifically, the activity of the thioredoxin reductase (TrxR) is crucial for this process. This was demonstrated by the strong inhibitory effect of the pharmacological TrxR inhibitor auranofin, which inhibited the intoxication of target cells with PMT, as determined by analyzing the PMT-catalyzed deamidation of GTP-binding proteins (G-proteins) in the cytosol of cells. The amount of endogenous substrate levels modified by PMT in cells pretreated with auranofin was reduced compared to cells treated with PMT alone. Auranofin had no inhibitory effect on the activity of the catalytic domain of constitutively active PMT in vitro, demonstrating that auranofin did not directly inhibit PMT activity, but interferes with the mode of action of PMT in cells. In conclusion, the results show that TrxR is crucial for the mode of action of PMT in mammalian cells, and that the drug auranofin can serve as an efficient inhibitor, which might be a starting point for novel therapeutic options against toxin-associated diseases. PMID- 28098783 TI - The Influence of the Toxin/Antitoxin mazEF on Growth and Survival of Listeria monocytogenes under Stress. AB - A major factor in the resilience of Listeria monocytogenes is the alternative sigma factor B (sigmaB). Type II Toxin/Antitoxin (TA) systems are also known to have a role in the bacterial stress response upon activation via the ClpP or Lon proteases. Directly upstream of the sigmaB operon in L. monocytogenes is the TA system mazEF, which can cleave mRNA at UACMU sites. In this study, we showed that the mazEF TA locus does not affect the level of persister formation during treatment with antibiotics in lethal doses, but exerts different effects according to the sub-inhibitory stress added. Growth of a DeltamazEF mutant was enhanced relative to the wildtype in the presence of sub-inhibitory norfloxacin and at 42 degrees C, but was decreased when challenged with ampicillin and gentamicin. In contrast to studies in Staphylococcus aureus, we found that the mazEF locus did not affect transcription of genes within the sigmaB operon, but MazEF effected the expression of the sigmaB-dependent genes opuCA and lmo0880, with a 0.22 and 0.05 fold change, respectively, compared to the wildtype under sub-inhibitory norfloxacin conditions. How exactly this system operates remains an open question, however, our data indicates it is not analogous to the system of S. aureus, suggesting a novel mode of action for MazEF in L. monocytogenes. PMID- 28098784 TI - Fused-Ring Oxazolopyrrolopyridopyrimidine Systems with Gram-Negative Activity. AB - Fused polyheterocyclic derivatives are available by annulation of a tetramate scaffold, and been shown to have antibacterial activity against a Gram-negative, but not a Gram-positive, bacterial strain. While the activity is not potent, these systems are structurally novel showing, in particular, a high level of polarity, and offer potential for the optimization of antibacterial activity. PMID- 28098785 TI - Neighborhood Design, Physical Activity, and Wellbeing: Applying the Walkability Model. AB - Neighborhood design affects lifestyle physical activity, and ultimately human wellbeing. There are, however, a limited number of studies that examine neighborhood design types. In this research, we examine four types of neighborhood designs: traditional development, suburban development, enclosed community, and cluster housing development, and assess their level of walkability and their effects on physical activity and wellbeing. We examine significant associations through a questionnaire (n = 486) distributed in Tucson, Arizona using the Walkability Model. Among the tested neighborhood design types, traditional development showed significant associations and the highest value for walkability, as well as for each of the two types of walking (recreation and transportation) representing physical activity. Suburban development showed significant associations and the highest mean values for mental health and wellbeing. Cluster housing showed significant associations and the highest mean value for social interactions with neighbors and for perceived safety from crime. Enclosed community did not obtain the highest means for any wellbeing benefit. The Walkability Model proved useful in identifying the walkability categories associated with physical activity and perceived crime. For example, the experience category was strongly and inversely associated with perceived crime. This study provides empirical evidence of the importance of including vegetation, particularly trees, throughout neighborhoods in order to increase physical activity and wellbeing. Likewise, the results suggest that regular maintenance is an important strategy to improve mental health and overall wellbeing in cities. PMID- 28098786 TI - Retinoic Acid and Its Role in Modulating Intestinal Innate Immunity. AB - Vitamin A (VA) is amongst the most well characterized food-derived nutrients with diverse immune modulatory roles. Deficiency in dietary VA has not only been associated with immune dysfunctions in the gut, but also with several systemic immune disorders. In particular, VA metabolite all-trans retinoic acid (atRA) has been shown to be crucial in inducing gut tropism in lymphocytes and modulating T helper differentiation. In addition to the widely recognized role in adaptive immunity, increasing evidence identifies atRA as an important modulator of innate immune cells, such as tolerogenic dendritic cells (DCs) and innate lymphoid cells (ILCs). Here, we focus on the role of retinoic acid in differentiation, trafficking and the functions of innate immune cells in health and inflammation associated disorders. Lastly, we discuss the potential involvement of atRA during the plausible crosstalk between DCs and ILCs. PMID- 28098787 TI - Pathological Impairment, Cell Cycle Arrest and Apoptosis of Thymus and Bursa of Fabricius Induced by Aflatoxin-Contaminated Corn in Broilers. AB - This study aimed to evaluate the comparative effects of aflatoxin-contaminated corn on the thymus and bursa of Fabricius (BF) in chickens by detecting histopathological lesions, cell cycle phase distribution and apoptosis. A total of 900 COBB500 male broilers were randomly allocated into five groups. The experiment lasted for six weeks and the five dietary treatments consisted of uncontaminated corn (control), 25% contaminated corn, 50% contaminated corn, 75% contaminated corn and 100% contaminated corn groups. The gross changes showed the decreased size of the thymus and BF, as well as the pale color of the BF in the broilers after aflatoxin contaminated diet exposure. There were more nuclear debris in the thymus and BF of birds in the 50%, 75%, and 100% contaminated corn groups, but the pathological impairments of the BF were more obvious than those of the thymus, which showed as more obvious lymphocyte depletion and the proliferation of reticulocytes and fibroblasts. At 21 days of age, the percentage of thymocytes and BF cells in the G2M phase was increased in a dose-dependent manner in the four AFB-contaminated corn groups. However, at 42 days of age, dietary AFB1 induced cell cycle perturbation at the G0G1 phase in thymocytes, but at the G2M phase in BF cells. The increased percentage of apoptotic cells in the thymus and BF were similarly observed in the AFB groups. According to these results, the severity of histopathological lesions may be correlated with the different sensitivity of the two central immune organs when exposed to AFB; different arrested cell cycle phases suggest that different mechanisms may be involved in the lesions of the thymus and BF, which need to be further researched. PMID- 28098788 TI - Evaluation of Potential Average Daily Doses (ADDs) of PM2.5 for Homemakers Conducting Pan-Frying Inside Ordinary Homes under Four Ventilation Conditions. AB - Several studies reported that commercial barbecue restaurants likely contribute to the indoor emission of particulate matters with a diameter of 2.5 micrometers or less (PM2.5) while pan-frying meat. However, there is inadequate knowledge of exposure level to indoor PM2.5 in homes and the contribution of a typical indoor pan-frying event. We measured the indoor PM2.5 concentration and, using Monte Carlo simulation, estimated potential average daily dose (ADD) of PM2.5 for homemakers pan-frying a piece of pork inside ordinary homes. Convenience-based sampling at 13 homes was conducted over four consecutive days in June 2013 (n = 52). Although we pan-fried 100 g pork for only 9 min, the median (interquartile range, IQR) value was 4.5 (2.2-5.6) mg/m3 for no ventilation and 0.5 (0.1-1.3) mg/m3 with an active stove hood ventilation system over a 2 h sampling interval. The probabilities that the ADDs from inhalation of indoor PM2.5 would be higher than the ADD from inhalation of PM2.5 on an outdoor roadside (4.6 MUg/kg.day) were 99.44%, 97.51%, 93.64%, and 67.23%, depending on the ventilation conditions: (1) no window open; (2) one window open in the kitchen; (3) two windows open, one each in the kitchen and living room; and (4) operating a forced-air stove hood, respectively. PMID- 28098789 TI - Implications of Changing Temperatures on the Growth, Fecundity and Survival of Intermediate Host Snails of Schistosomiasis: A Systematic Review. AB - Climate change has been predicted to increase the global mean temperature and to alter the ecological interactions among organisms. These changes may play critical roles in influencing the life history traits of the intermediate hosts (IHs). This review focused on studies and disease models that evaluate the potential effect of temperature rise on the ecology of IH snails and the development of parasites within them. The main focus was on IH snails of schistosome parasites that cause schistosomiasis in humans. A literature search was conducted on Google Scholar, EBSCOhost and PubMed databases using predefined medical subject heading terms, Boolean operators and truncation symbols in combinations with direct key words. The final synthesis included nineteen published articles. The studies reviewed indicated that temperature rise may alter the distribution, optimal conditions for breeding, growth and survival of IH snails which may eventually increase the spread and/or transmission of schistosomiasis. The literature also confirmed that the life history traits of IH snails and their interaction with the schistosome parasites are affected by temperature and hence a change in climate may have profound outcomes on the population size of snails, parasite density and disease epidemiology. We concluded that understanding the impact of temperature on the growth, fecundity and survival of IH snails may broaden the knowledge on the possible effects of climate change and hence inform schistosomiasis control programmes. PMID- 28098790 TI - Synthesis, Structure and Antimicrobial Properties of Novel Benzalkonium Chloride Analogues with Pyridine Rings. AB - Quaternary ammonium compounds (QACs) are a group of compounds of great economic significance. They are widely used as emulsifiers, detergents, solubilizers and corrosion inhibitors in household and industrial products. Due to their excellent antimicrobial activity QACs have also gained a special meaning as antimicrobials in hospitals, agriculture and the food industry. The main representatives of the microbiocidal QACs are the benzalkonium chlorides (BACs), which exhibit biocidal activity against most bacteria, fungi, algae and some viruses. However, the misuses of QACs, mainly at sublethal concentrations, can lead to an increasing resistance of microorganisms. One of the ways to avoid this serious problem is the introduction and use of new biocides with modified structures instead of the biocides applied so far. Therefore new BAC analogues P13-P18 with pyridine rings were synthesized. The new compounds were characterized by NMR, FT-IR and ESI-MS methods. PM3 semiempirical calculations of molecular structures and the heats of formation of compounds P13-P18 were also performed. Critical micellization concentrations (CMCs) were determined to characterize the aggregation behavior of the new BAC analogues. The antimicrobial properties of novel QACs were examined by determining their minimal inhibitory concentration (MIC) values against the fungi Aspergillus niger, Candida albicans, Penicillium chrysogenum and bacteria Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa. The MIC values of N,N-dimethyl-N-(4-methylpyridyl)-N-alkylammonium chlorides for fungi range from 0.1 to 12 mM and for bacteria, they range from 0.02 to 6 mM. PMID- 28098791 TI - Development of High-Throughput Method for Measurement of Vascular Nitric Oxide Generation in Microplate Reader. AB - BACKGROUND: Despite the importance of nitric oxide (NO) in vascular physiology and pathology, a high-throughput method for the quantification of its vascular generation is lacking. OBJECTIVE: By using the fluorescent probe 4-amino-5 methylamino-2',7'-difluorofluorescein (DAF-FM), we have optimized a simple method for the determination of the generation of endothelial nitric oxide in a microplate format. METHODS: A nitric oxide donor was used (3 morpholinosydnonimine hydrochloride, SIN-1). Different factors affecting the method were studied, such as the effects of dye concentration, different buffers, time of reaction, gain, and number of flashes. RESULTS: Beer's law was linear over a nanomolar range (1-10 nM) of SIN-1 with wavelengths of maximum excitation and emission at 495 and 525 nm; the limit of detection reached 0.897 nM. Under the optimized conditions, the generation of rat aortic endothelial NO was measured by incubating DAF-FM with serial concentrations (10-1000 uM) of acetylcholine (ACh) for 3 min. To confirm specificity, Nomega-Nitro-l-arginine methyl ester (l-NAME)-the standard inhibitor of endothelial NO synthase-was found to inhibit the ACh-stimulated generation of NO. In addition, vessels pre-exposed for 1 h to 400 uM of the endothelial damaging agent methyl glyoxal showed inhibited NO generation when compared to the control stimulated by ACh. CONCLUSIONS: The capability of the method to measure micro-volume samples makes it convenient for the simultaneous handling of a very large number of samples. Additionally, it allows samples to be run simultaneously with their replicates to ensure identical experimental conditions, thus minimizing the effect of biological variability. PMID- 28098793 TI - Osteocyte Alterations Induce Osteoclastogenesis in an In Vitro Model of Gaucher Disease. AB - Gaucher disease (GD) is caused by mutations in the glucosylceramidase beta (GBA 1) gene that confer a deficient level of activity of glucocerebrosidase (GCase). This deficiency leads to the accumulation of the glycolipid glucocerebroside in the lysosomes of cells, mainly in the monocyte/macrophage lineage. Its mildest form is Type I GD, characterized by non-neuronopathic involvement. Bone compromise is the most disabling aspect of the Gaucher disease. However, the pathophysiological aspects of skeletal alterations are not yet fully understood. The bone tissue homeostasis is maintained by a balance between resorption of old bone by osteoclasts and new bone formation by osteoblasts. A central player in this balance is the osteocyte as it controls both processes. We studied the involvement of osteocytes in an in vitro chemical model of Gaucher disease. The osteocyte cell line MLO-Y4 was exposed to conduritol-beta-epoxide (CBE), an inhibitor of GCase, for a period of 7, 14 and 21 days. Conditioned media from CBE treated osteocytes was found to induce osteoclast differentiation. GCase inhibition caused alterations in Cx43 expression and distribution pattern and an increase in osteocyte apoptosis. Osteoclast differentiation involved osteocyte apoptotic bodies, receptor activator of nuclear factor kappa-B ligand (RANKL) and soluble factors. Thus, our results indicate that osteocytes may have a role to play in the bone pathophysiology of GD. PMID- 28098794 TI - Ftr82 Is Critical for Vascular Patterning during Zebrafish Development. AB - Cellular components and signaling pathways are required for the proper growth of blood vessels. Here, we report for the first time that a teleost-specific gene ftr82 (finTRIM family, member 82) plays a critical role in vasculature during zebrafish development. To date, there has been no description of tripartite motif proteins (TRIM) in vascular development, and the role of ftr82 is unknown. In this study, we found that ftr82 mRNA is expressed during the development of vessels, and loss of ftr82 by morpholino (MO) knockdown impairs the growth of intersegmental vessels (ISV) and caudal vein plexus (CVP), suggesting that ftr82 plays a critical role in promoting ISV and CVP growth. We showed the specificity of ftr82 MO by analyzing ftr82 expression products and expressing ftr82 mRNA to rescue ftr82 morphants. We further showed that the knockdown of ftr82 reduced ISV cell numbers, suggesting that the growth impairment of vessels is likely due to a decrease of cell proliferation and migration, but not cell death. In addition, loss of ftr82 affects the expression of vascular markers, which is consistent with the defect of vascular growth. Finally, we showed that ftr82 likely interacts with vascular endothelial growth factor (VEGF) and Notch signaling. Together, we identify teleost-specific ftr82 as a vascular gene that plays an important role for vascular development in zebrafish. PMID- 28098795 TI - Broad-Spectrum Inhibition of the CC-Chemokine Class Improves Wound Healing and Wound Angiogenesis. AB - Angiogenesis is involved in the inflammation and proliferation stages of wound healing, to bring inflammatory cells to the wound and provide a microvascular network to maintain new tissue formation. An excess of inflammation, however, leads to prolonged wound healing and scar formation, often resulting in unfavourable outcomes such as amputation. CC-chemokines play key roles in the promotion of inflammation and inflammatory-driven angiogenesis. Therefore, inhibition of the CC-chemokine class may improve wound healing. We aimed to determine if the broad-spectrum CC-chemokine inhibitor "35K" could accelerate wound healing in vivo in mice. In a murine wound healing model, 35K protein or phosphate buffered saline (PBS, control) were added topically daily to wounds. Cohorts of mice were assessed in the early stages (four days post-wounding) and in the later stages of wound repair (10 and 21 days post-wounding). Topical application of the 35K protein inhibited CC-chemokine expression (CCL5, CCL2) in wounds and caused enhanced blood flow recovery and wound closure in early-mid stage wounds. In addition, 35K promoted neovascularisation in the early stages of wound repair. Furthermore, 35K treated wounds had significantly lower expression of the p65 subunit of NF-kappaB, a key inflammatory transcription factor, and augmented wound expression of the pro-angiogenic and pro-repair cytokine TGF beta. These findings show that broad-spectrum CC-chemokine inhibition may be beneficial for the promotion of wound healing. PMID- 28098796 TI - Comparative Metabolite Profiling of Triterpenoid Saponins and Flavonoids in Flower Color Mutations of Primula veris L. AB - Primula veris L. is an important medicinal plant with documented use for the treatment of gout, headache and migraine reaching back to the Middle Ages. Triterpenoid saponins from roots and flowers are used in up-to-date phytotherapeutic treatment of bronchitis and colds due to their expectorant and secretolytic effects. In addition to the wild type plants with yellow petals, a red variant and an intermediate orange form of Primula veris L. have recently been found in a natural habitat. The secondary metabolite profiles of roots, leaves and flowers of these rare variants were investigated and compared with the wild type metabolome. Two flavonoids, six flavonoid glycosides, four novel methylated flavonoid glycosides, five anthocyanins and three triterpenoid saponins were identified in alcoholic extracts from the petals, leaves and roots of the three variants by high performance liquid chromatography (HPLC)-diode array detection (DAD)/mass spectrometry (MSn) analyses. Anthocyanins were detected in the petals of the red and orange variety, but not in the wild type. No other effects on the metabolite profiles of the three varieties have been observed. The possibility is discussed that a regulatory step of the anthocyanin biosynthetic pathway may have been affected by mutation thus triggering color polymorphism in the petals. PMID- 28098797 TI - Nonlinear Fusion of Multispectral Citrus Fruit Image Data with Information Contents. AB - The main issue of vison-based automatic harvesting manipulators is the difficulty in the correct fruit identification in the images under natural lighting conditions. Mostly, the solution has been based on a linear combination of color components in the multispectral images. However, the results have not reached a satisfactory level. To overcome this issue, this paper proposes a robust nonlinear fusion method to augment the original color image with the synchronized near infrared image. The two images are fused with Daubechies wavelet transform (DWT) in a multiscale decomposition approach. With DWT, the background noises are reduced and the necessary image features are enhanced by fusing the color contrast of the color components and the homogeneity of the near infrared (NIR) component. The resulting fused color image is classified with a C-means algorithm for reconstruction. The performance of the proposed approach is evaluated with the statistical F measure in comparison to some existing methods using linear combinations of color components. The results show that the fusion of information in different spectral components has the advantage of enhancing the image quality, therefore improving the classification accuracy in citrus fruit identification in natural lighting conditions. PMID- 28098798 TI - Free Radical Scavenging Activity of Drops and Spray Containing Propolis-An EPR Examination. AB - The influence of heating at a temperature of 50 degrees C and UV-irradiation of propolis drops and spray on their free radical scavenging activity was determined. The kinetics of interactions of the propolis samples with DPPH free radicals was analyzed. Interactions of propolis drops and propolis spray with free radicals were examined by electron paramagnetic resonance spectroscopy. A spectrometer generating microwaves of 9.3 GHz frequency was used. The EPR spectra of the model DPPH free radicals were compared with the EPR spectra of DPPH in contact with the tested propolis samples. The antioxidative activity of propolis drops and propolis spray decreased after heating at the temperature of 50 degrees C. A UV-irradiated sample of propolis drops more weakly scavenged free radicals than an untreated sample. The antioxidative activity of propolis spray increased after UV-irradiation. The sample of propolis drops heated at the temperature of 50 degrees C quenched free radicals faster than the unheated sample. UV-irradiation weakly changed the kinetics of propolis drops or spray interactions with free radicals. EPR analysis indicated that propolis drops and spray should not be stored at a temperature of 50 degrees C. Propolis drops should not be exposed to UV-irradiation. PMID- 28098799 TI - Occurrence of Emerging Micropollutants in Water Systems in Gauteng, Mpumalanga, and North West Provinces, South Africa. AB - The ubiquitous occurrence of emerging micropollutants (EMPs) in water is an issue of growing environmental-health concern worldwide. However, there remains a paucity of data regarding their levels and occurrence in water. This study determined the occurrence of EMPs namely: carbamazepine (CBZ), galaxolide (HHCB), caffeine (CAF), tonalide (AHTN), 4-nonylphenol (NP), and bisphenol A (BPA) in water from Gauteng, Mpumalanga, and North West provinces, South Africa using comprehensive two-dimensional gas chromatography coupled to high resolution time of-flight mass spectrometry (GCxGC-HRTOFMS). Kruskal-Wallis test and ANOVA were performed to determine temporal variations in occurrence of the EMPs. Principal component analysis (PCA) and Surfer Golden Graphics software for surface mapping were used to determine spatial variations in levels and occurrence of the EMPs. The mean levels ranged from 11.22 +/- 18.8 ng/L for CAF to 158.49 +/- 662 ng/L for HHCB. There was no evidence of statistically significant temporal variations in occurrence of EMPs in water. Nevertheless, their levels and occurrence vary spatially and are a function of two principal components (PCs, PC1 and PC2) which controlled 89.99% of the variance. BPA was the most widely distributed EMP, which was present in 62% of the water samples. The detected EMPs pose ecotoxicological risks in water samples, especially those from Mpumalanga province. PMID- 28098800 TI - Characterization of the Transcriptome and Gene Expression of Brain Tissue in Sevenband Grouper (Hyporthodus septemfasciatus) in Response to NNV Infection. AB - Grouper is one of the favorite sea food resources in Southeast Asia. However, the outbreaks of the viral nervous necrosis (VNN) disease due to nervous necrosis virus (NNV) infection have caused mass mortality of grouper larvae. Many aqua farms have suffered substantial financial loss due to the occurrence of VNN. To better understand the infection mechanism of NNV, we performed the transcriptome analysis of sevenband grouper brain tissue, the main target of NNV infection. After artificial NNV challenge, transcriptome of brain tissues of sevenband grouper was subjected to next generation sequencing (NGS) using an Illumina Hi seq 2500 system. Both mRNAs from pooled samples of mock and NNV-infected sevenband grouper brains were sequenced. Clean reads of mock and NNV-infected samples were de novo assembled and obtained 104,348 unigenes. In addition, 628 differentially expressed genes (DEGs) in response to NNV infection were identified. This result could provide critical information not only for the identification of genes involved in NNV infection, but for the understanding of the response of sevenband groupers to NNV infection. PMID- 28098801 TI - A Novel Antihypertensive Derived from Adlay (Coix larchryma-jobi L. var. ma-yuen Stapf) Glutelin. AB - Our previous studies have shown that Coix glutelin pepsin hydrolysate can effectively inhibit angiotensin converting enzyme (ACE) activity in vitro. The main purpose of this study was to obtain potent anti-hypertensive peptides from Coix glutelin. The Coix glutelin hydrolysates (CGH) were prepared by pepsin catalysis and further separated by an ultrafitration (UF) system, gel filtration chromatography (GFC) and reversed-phase high performance liquid chromatography (RP-HPLC). As a result, the sub-fraction F5-3 had the highest ACE-inhibitory activity. Six ACE inhibitory peptides were identifiedusing nano-liquid chromatography coupled to tandem mass spectrometry. The most potent peptide GAAGGAF (IC50 = 14.19 MUmol.L-1) was finally obtained by further molecular simulation screening and a series of division and optimization. Single oral administration of synthesized GAAGGAF at 15 mg/kg body weight (BW) in spontaneously hypertensively rats (SHR) could reduce the systolic blood pressure (SBP) around 27.50 mmHg and blood pressure-lowering effect lasted for at least 8 h. The study demonstrated for the first time that the ACE inhibitory peptide GAAGGAF from Coix glutelin has a significant antihypertensive effect, and it could be a good natural ingredient for pharmaceuticals against hypertension and the related diseases. PMID- 28098802 TI - Penduliflaworosin, a Diterpenoid from Croton crassifolius, Exerts Anti-Angiogenic Effect via VEGF Receptor-2 Signaling Pathway. AB - Anti-angiogenesis targeting vascular endothelial growth factor receptor-2 (VEGFR 2) has been considered as an important strategy for cancer therapy. Penduliflaworosin is a diterpenoid isolated from the plant Croton crassifolius. Our previous study showed that this diterpenoid possesses strong anti-angiogenic activity by inhibiting vessel formation in zebrafish. This study was conducted to further investigate the anti-angiogenic activity and mechanism of penduliflaworosin. Results revealed that penduliflaworosin significantly inhibited VEGF-induced angiogenesis processes including proliferation, invasion, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). Moreover, it notably inhibited VEGF-induced sprout formation of aortic rings and blocked VEGF-induced vessel formation in mice. Western blotting studies showed that penduliflaworosin inhibited phosphorylation of the VEGF receptor-2 and its downstream signaling mediators in HUVECs, suggesting that the anti-angiogenic activity was due to an interference with the VEGF/VEGF receptor-2 pathway. In addition, molecular docking simulation indicated that penduliflaworosin could form hydrogen bonds within the ATP-binding region of the VEGF receptor-2 kinase unit. Finally, cytotoxicity assay showed that penduliflaworosin possessed little toxicity toward both cancer and normal cells. Taken together, our findings demonstrate that penduliflaworosin exerts its anti-angiogenic effect via the VEGF receptor-2 signaling pathway. The anti-angiogenic property and low cytotoxicity of penduliflaworosin suggest that it may be useful in cancer treatments. PMID- 28098803 TI - Optimization of the Production of 1-Phenylethanol Using Enzymes from Flowers of Tea (Camellia sinensis) Plants. AB - 1-Phenylethanol (1PE) can be used as a fragrance in food flavoring and cosmetic industries and as an intermediate in the pharmaceutical industry. 1PE can be synthesized from acetophenone, and the cost of 1PE is higher than the cost of acetophenone. Therefore, it is important to establish an effective and low-cost approach for producing 1PE. Our previous studies found that tea (Camellia sinensis) flowers, which are an abundant and waste resource, contained enzymes that could transform acetophenone to 1PE. In the present study, we extracted crude enzymes from tea flowers and optimized the production conditions of 1PE using response surface methodology. The optimized conditions were an extraction pH of 7.0, a reaction pH of 5.3, a reaction temperature of 55 degrees C, a reaction time of 100 min, a coenzyme NADPH concentration of 3.75 MUmol/mL in the reaction assay, and a substrate acetophenone concentration of 1.25 MUmol/mL in the reaction assay. The results provide essential information for future industrial 1PE production using plant-derived enzymes. PMID- 28098804 TI - GADD45a Regulates Olaquindox-Induced DNA Damage and S-Phase Arrest in Human Hepatoma G2 Cells via JNK/p38 Pathways. AB - Olaquindox, a quinoxaline 1,4-dioxide derivative, is widely used as a feed additive in many countries. The potential genotoxicity of olaquindox, hence, is of concern. However, the proper mechanism of toxicity was unclear. The aim of the present study was to investigate the effect of growth arrest and DNA damage 45 alpha (GADD45a) on olaquindox-induced DNA damage and cell cycle arrest in HepG2 cells. The results showed that olaquindox could induce reactive oxygen species (ROS)-mediated DNA damage and S-phase arrest, where increases of GADD45a, cyclin A, Cdk 2, p21 and p53 protein expression, decrease of cyclin D1 and the activation of phosphorylation-c-Jun N-terminal kinases (p-JNK), phosphorylation p38 (p-p38) and phosphorylation-extracellular signal-regulated kinases (p-ERK) were involved. However, GADD45a knockdown cells treated with olaquindox could significantly decrease cell viability, exacerbate DNA damage and increase S-phase arrest, associated with the marked activation of p-JNK, p-p38, but not p-ERK. Furthermore, SP600125 and SB203580 aggravated olaquindox-induced DNA damage and S phase arrest, suppressed the expression of GADD45a. Taken together, these findings revealed that GADD45a played a protective role in olaquindox treatment and JNK/p38 pathways may partly contribute to GADD45a regulated olaquindox induced DNA damage and S-phase arrest. Our findings increase the understanding on the molecular mechanisms of olaquindox. PMID- 28098806 TI - Antibacterial Activities and Possible Modes of Action of Acacia nilotica (L.) Del. against Multidrug-Resistant Escherichia coli and Salmonella. AB - Medicinal plants are frequently used for the treatment of various infectious diseases. The objective of this study was to evaluate the antibacterial activity and mode of action of Acacia nilotica and the antibiogram patterns of foodborne and clinical strains of Escherichia coli and Salmonella. The mechanism of action of acacia extracts against E. coli and Salmonella was elucidated by observing morphological damages including cell integrity and cell membrane permeability, as well as changes in cell structures and growth patterns in kill-time experiments. The clinical isolates of E. coli and Salmonella were found resistant to more of the tested antibiotics, compared to food isolates. Minimum inhibitory concentration and minimum bactericidal concentration of acacia leaf extracts were in the ranges of 1.56-3.12 mg/mL and 3.12-6.25 mg/mL, respectively, whereas pods and bark extracts showed somewhat higher values of 3.12-6.25 mg/mL and 6.25-12.5 mg/mL, respectively, against all tested pathogens. The release of electrolytes and essential cellular constituents (proteins and nucleic acids) indicated that acacia extracts damaged the cellular membrane of the pathogens. These changes corresponded to simultaneous reduction in the growth of viable bacteria. This study indicates that A. nilotica can be a potential source of new antimicrobials, effective against antibiotic-resistant strains of pathogens. PMID- 28098807 TI - Throughput Measurement of a Dual-Band MIMO Rectangular Dielectric Resonator Antenna for LTE Applications. AB - An L-shaped dual-band multiple-input multiple-output (MIMO) rectangular dielectric resonator antenna (RDRA) for long term evolution (LTE) applications is proposed. The presented antenna can transmit and receive information independently using fundamental TE111 and higher order TE121 modes of the DRA. TE111 degenerate mode covers LTE band 2 (1.85-1.99 GHz), 3 (1.71-1.88 GHz), and 9 (1.7499-1.7849 GHz) at fr = 1.8 GHz whereas TE121 covers LTE band 7 (2.5-2.69 GHz) at fr = 2.6 GHz, respectively. An efficient design method has been used to reduce mutual coupling between ports by changing the effective permittivity values of DRA by introducing a cylindrical air-gap at an optimal position in the dielectric resonator. This air-gap along with matching strips at the corners of the dielectric resonator keeps the isolation at a value more than 17 dB at both the bands. The diversity performance has also been evaluated by calculating the envelope correlation coefficient, diversity gain, and mean effective gain of the proposed design. MIMO performance has been evaluated by measuring the throughput of the proposed MIMO antenna. Experimental results successfully validate the presented design methodology in this work. PMID- 28098805 TI - Chemical Constituents from the Roots and Rhizomes of Asarum heterotropoides var. mandshuricum and the In Vitro Anti-Inflammatory Activity. AB - Anti-inflammatory compounds were investigated from the ethanol extract of the roots and rhizomes of Asarum heterotropoides var. mandshuricum, a traditional Chinese medicine called Xixin and used for pain and inflammatory. Nine new compounds were isolated, including six new lignans, neoasarinin A-C (1-3), neoasarininoside A and B (4 and 5), and asarinin B (7), and one new monoterpene, asarincin A (8), two new amides, asaramid II and III (10 and 11), and one new natural monoterpene, asaricin B (9), along with 37 known compounds (6, 12-47). Their structures and absolute configurations were elucidated on the basis of spectroscopic methods and chemical analyses. This is the first report of the absolute configuration of asarinin A (6). The 8-O-4' neolignans (1-5) were reported in the genus Asarum for the first time. The 15 compounds 17, 19, 22-25, 28, 31, 36, 40, 42, 43, 45-47 were isolated from the genus Asarum, and compounds 16, 32, 33, 37 and 39 were isolated from A. heterotropoides var. mandshuricum for the first time. Thirty-seven of the isolates were evaluated for anti-inflammatory activity against the release of beta-glucuronidase in polymorphonuclear leukocytes (PMNs) induced by the platelet-activating factor (PAF), and compounds 1, 4, 7, 8, 14, 17-19, 22, 24, 25, 29, 30, 32, 33, 40-43, 45, and 46 showed potent anti-inflammatory activities in vitro, with 27.9%-72.6% inhibitions at 10 5 mol/L. The results of anti-inflammatory assay suggested that lignans obtained from the CHCl3 extract might be the main active components of Xixin. PMID- 28098808 TI - Infectious Bursal Disease Virus-Host Interactions: Multifunctional Viral Proteins that Perform Multiple and Differing Jobs. AB - Infectious bursal disease (IBD) is an acute, highly contagious and immunosuppressive poultry disease caused by IBD virus (IBDV). The consequent immunosuppression increases susceptibility to other infectious diseases and the risk of subsequent vaccination failure as well. Since the genome of IBDV is relatively small, it has a limited number of proteins inhibiting the cellular antiviral responses and acting as destroyers to the host defense system. Thus, these virulence factors must be multifunctional in order to complete the viral replication cycle in a host cell. Insights into the roles of these viral proteins along with their multiple cellular targets in different pathways will give rise to a rational design for safer and effective vaccines. Here we summarize the recent findings that focus on the virus-cell interactions during IBDV infection at the protein level. PMID- 28098810 TI - State-of-the-Art: DTM Generation Using Airborne LIDAR Data. AB - Digital terrain model (DTM) generation is the fundamental application of airborne Lidar data. In past decades, a large body of studies has been conducted to present and experiment a variety of DTM generation methods. Although great progress has been made, DTM generation, especially DTM generation in specific terrain situations, remains challenging. This research introduces the general principles of DTM generation and reviews diverse mainstream DTM generation methods. In accordance with the filtering strategy, these methods are classified into six categories: surface-based adjustment; morphology-based filtering, triangulated irregular network (TIN)-based refinement, segmentation and classification, statistical analysis and multi-scale comparison. Typical methods for each category are briefly introduced and the merits and limitations of each category are discussed accordingly. Despite different categories of filtering strategies, these DTM generation methods present similar difficulties when implemented in sharply changing terrain, areas with dense non-ground features and complicated landscapes. This paper suggests that the fusion of multi-sources and integration of different methods can be effective ways for improving the performance of DTM generation. PMID- 28098809 TI - The Clinical Benefits and Accuracy of Continuous Glucose Monitoring Systems in Critically Ill Patients-A Systematic Scoping Review. AB - Continuous Glucose Monitoring (CGM) systems could improve glycemic control in critically ill patients. We aimed to identify the evidence on the clinical benefits and accuracy of CGM systems in these patients. For this, we performed a systematic search in Ovid MEDLINE, from inception to 26 July 2016. Outcomes were efficacy, accuracy, safety, workload and costs. Our search retrieved 356 articles, of which 37 were included. Randomized controlled trials on efficacy were scarce (n = 5) and show methodological limitations. CGM with automated insulin infusion improved time in target and mean glucose in one trial and two trials showed a decrease in hypoglycemic episodes and time in hypoglycemia. Thirty-two articles assessed accuracy, which was overall moderate to good, the latter mainly with intravascular devices. Accuracy in critically ill children seemed lower than in adults. Adverse events were rare. One study investigated the effect on workload and cost, and showed a significant reduction in both. In conclusion, studies on the efficacy and accuracy were heterogeneous and difficult to compare. There was no consistent clinical benefit in the small number of studies available. Overall accuracy was moderate to good with some intravascular devices. CGM systems seemed however safe, and might positively affect workload and costs. PMID- 28098811 TI - Aspalathin Protects the Heart against Hyperglycemia-Induced Oxidative Damage by Up-Regulating Nrf2 Expression. AB - Aspalathin (ASP) can protect H9c2 cardiomyocytes against high glucose (HG) induced shifts in myocardial substrate preference, oxidative stress, and apoptosis. The protective mechanism of ASP remains unknown. However, as one of possible, it is well known that phytochemical flavonoids reduce oxidative stress via nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation resulting in up regulation of antioxidant genes and enzymes. Therefore, we hypothesized that ASP protects the myocardium against HG- and hyperglycemia-induced oxidative damage by up-regulating Nrf2 expression in H9c2 cardiomyocytes and diabetic (db/db) mice, respectively. Using an oxidative stress RT2 Profiler PCR array, ASP at a dose of 1 uM was demonstrated to protect H9c2 cardiomyocytes against HG-induced oxidative stress, but silencing of Nrf2 abolished this protective response of ASP and exacerbated cardiomyocyte apoptosis. Db/db mice and their non-diabetic (db/+) littermate controls were subsequently treated daily for six weeks with either a low (13 mg/kg) or high (130 mg/kg) ASP dose. Compared to nondiabetic mice the db/db mice presented increased cardiac remodeling and enlarged left ventricular wall that occurred concomitant to enhanced oxidative stress. Daily treatment of mice with ASP at a dose of 130 mg/kg for six weeks was more effective at reversing complications than both a low dose ASP or metformin, eliciting enhanced expression of Nrf2 and its downstream antioxidant genes. These results indicate that ASP maintains cellular homeostasis and protects the myocardium against hyperglycemia-induced oxidative stress through activation of Nrf2 and its downstream target genes. PMID- 28098812 TI - Novel Aflatoxin-Degrading Enzyme from Bacillus shackletonii L7. AB - Food and feed contamination by aflatoxin (AF)B1 has adverse economic and health consequences. AFB1 degradation by microorganisms or microbial enzymes provides a promising preventive measure. To this end, the present study tested 43 bacterial isolates collected from maize, rice, and soil samples for AFB1-reducing activity. The higher activity was detected in isolate L7, which was identified as Bacillus shackletonii. L7 reduced AFB1, AFB2, and AFM1 levels by 92.1%, 84.1%, and 90.4%, respectively, after 72 h at 37 degrees C. The L7 culture supernatant degraded more AFB1 than viable cells and cell extracts; and the degradation activity was reduced from 77.9% to 15.3% in the presence of proteinase K and sodium dodecyl sulphate. A thermostable enzyme purified from the boiled supernatant was designated as Bacillus aflatoxin-degrading enzyme (BADE). An overall 9.55-fold purification of BADE with a recovery of 39.92% and an activity of 3.85 * 103 U.mg 1 was obtained using chromatography on DEAE-Sepharose. BADE had an estimated molecular mass of 22 kDa and exhibited the highest activity at 70 degrees C and pH 8.0, which was enhanced by Cu2+ and inhibited by Zn2+, Mn2+, Mg2+, and Li+. BADE is the major protein involved in AFB1 detoxification. This is the first report of a BADE isolated from B. shackletonii, which has potential applications in the detoxification of aflatoxins during food and feed processing. PMID- 28098813 TI - Reverse Vaccinology: An Approach for Identifying Leptospiral Vaccine Candidates. AB - Leptospirosis is a major public health problem with an incidence of over one million human cases each year. It is a globally distributed, zoonotic disease and is associated with significant economic losses in farm animals. Leptospirosis is caused by pathogenic Leptospira spp. that can infect a wide range of domestic and wild animals. Given the inability to control the cycle of transmission among animals and humans, there is an urgent demand for a new vaccine. Inactivated whole-cell vaccines (bacterins) are routinely used in livestock and domestic animals, however, protection is serovar-restricted and short-term only. To overcome these limitations, efforts have focused on the development of recombinant vaccines, with partial success. Reverse vaccinology (RV) has been successfully applied to many infectious diseases. A growing number of leptospiral genome sequences are now available in public databases, providing an opportunity to search for prospective vaccine antigens using RV. Several promising leptospiral antigens were identified using this approach, although only a few have been characterized and evaluated in animal models. In this review, we summarize the use of RV for leptospirosis and discuss the need for potential improvements for the successful development of a new vaccine towards reducing the burden of human and animal leptospirosis. PMID- 28098814 TI - Thioridazine: A Non-Antibiotic Drug Highly Effective, in Combination with First Line Anti-Tuberculosis Drugs, against Any Form of Antibiotic Resistance of Mycobacterium tuberculosis Due to Its Multi-Mechanisms of Action. AB - This review presents the evidence that supports the use of thioridazine (TZ) for the therapy of a pulmonary tuberculosis infection regardless of its antibiotic resistance status. The evidence consists of in vitro and ex vivo assays that demonstrate the activity of TZ against all encountered Mycobacterium tuberculosis (Mtb) regardless of its antibiotic resistance phenotype, as well as in vivo as a therapy for mice infected with multi-drug resistant strains of Mtb, or for human subjects infected with extensively drug resistant (XDR) Mtb. The mechanisms of action by which TZ brings about successful therapeutic outcomes are presented in detail. PMID- 28098816 TI - Estrogen Enhances the Expression of the Multidrug Transporter Gene ABCG2 Increasing Drug Resistance of Breast Cancer Cells through Estrogen Receptors. AB - BACKGROUND: Multidrug resistance is a major obstacle in the successful therapy of breast cancer. Studies have proved that this kind of drug resistance happens in both human cancers and cultured cancer cell lines. Understanding the molecular mechanisms of drug resistance is important for the reasonable design and use of new treatment strategies to effectively confront cancers. RESULTS: In our study, ATP-binding cassette sub-family G member 2 (ABCG2), adenosine triphosphate (ATP) synthase and cytochrome c oxidase subunit VIc (COX6C) were over-expressed more in the MCF-7/MX cell line than in the normal MCF7 cell line. Therefore, we believe that these three genes increase the tolerance of MCF7 to mitoxantrone (MX). The data showed that the high expression of COX6C made MCF-7/MX have more stable on mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) expression than normal MCF7 cells under hypoxic conditions. The accumulation of MX was greater in the ATP-depleted treatment MCF7/MX cells than in normal MCF7/MX cells. Furthermore, E2 increased the tolerance of MCF7 cells to MX through inducing the expression of ABCG2. However, E2 could not increase the expression of ABCG2 after the inhibition of estrogen receptor alpha (ERalpha) in MCF7 cells. According to the above data, under the E2 treatment, MDA-MB231, which lacks ER, had a higher sensitivity to MX than MCF7 cells. CONCLUSIONS: E2 induced the expression of ABCG2 through ERalpha and the over-expressed ABCG2 made MCF7 more tolerant to MX. Moreover, the over-expressed ATP synthase and COX6c affected mitochondrial genes and function causing the over-expressed ABCG2 cells pumped out MX in a concentration gradient from the cell matrix. Finally lead to chemoresistance. PMID- 28098815 TI - Replication Fork Protection Factors Controlling R-Loop Bypass and Suppression. AB - Replication-transcription conflicts have been a well-studied source of genome instability for many years and have frequently been linked to defects in RNA processing. However, recent characterization of replication fork-associated proteins has revealed that defects in fork protection can directly or indirectly stabilize R-loop structures in the genome and promote transcription-replication conflicts that lead to genome instability. Defects in essential DNA replication associated activities like topoisomerase, or the minichromosome maintenance (MCM) helicase complex, as well as fork-associated protection factors like the Fanconi anemia pathway, both appear to mitigate transcription-replication conflicts. Here, we will highlight recent advances that support the concept that normal and robust replisome function itself is a key component of mitigating R-loop coupled genome instability. PMID- 28098817 TI - Spatial Analysis of Human Health Risk Due to Arsenic Exposure through Drinking Groundwater in Taiwan's Pingtung Plain. AB - Chronic arsenic (As) exposure continues to be a public health problem of major concern worldwide, affecting hundreds of millions of people. A long-term groundwater quality survey has revealed that 20% of the groundwater in southern Taiwan's Pingtung Plain is clearly contaminated with a measured As concentration in excess of the maximum level of 10 ug/L recommended by the World Health Organization. The situation is further complicated by the fact that more than half of the inhabitants in this area continue to use groundwater for drinking. Efforts to assess the health risk associated with the ingestion of As from the contaminated drinking water are required in order to determine the priorities for health risk management. The conventional approach to conducting a human health risk assessment may be insufficient for this purpose, so this study adopts a geostatistical Kriging method to perform a spatial analysis of the health risk associated with ingesting As through drinking groundwater in the Pingtung Plain. The health risk is assessed based on the hazard quotient (HQ) and target cancer risk (TR) established by the U.S. Environmental Protection Agency. The results show that most areas where the HQ exceeds 1 are in the southwestern part of the study area. In addition, the high-population density townships of Daliao, Linyuan, Donggang, Linbian, Jiadong, and Fangliao presently have exceedingly high TR values that are two orders of magnitude higher than the acceptable standard. Thus, the use of groundwater for drinking in these townships should be strictly avoided. A map that delineates areas with high TR values and high population densities is provided. The findings broaden the scope of the spatial analysis of human health risk and provide a basis for improving the decision-making process. PMID- 28098818 TI - A Study on Coexistence Capability Evaluations of the Enhanced Channel Hopping Mechanism in WBANs. AB - As an important coexistence technology, channel hopping can reduce the interference among Wireless Body Area Networks (WBANs). However, it simultaneously brings some issues, such as energy waste, long latency and communication interruptions, etc. In this paper, we propose an enhanced channel hopping mechanism that allows multiple WBANs coexisted in the same channel. In order to evaluate the coexistence performance, some critical metrics are designed to reflect the possibility of channel conflict. Furthermore, by taking the queuing and non-queuing behaviors into consideration, we present a set of analysis approaches to evaluate the coexistence capability. On the one hand, we present both service-dependent and service-independent analysis models to estimate the number of coexisting WBANs. On the other hand, based on the uniform distribution assumption and the additive property of Possion-stream, we put forward two approximate methods to compute the number of occupied channels. Extensive simulation results demonstrate that our estimation approaches can provide an effective solution for coexistence capability estimation. Moreover, the enhanced channel hopping mechanism can significantly improve the coexistence capability and support a larger arrival rate of WBANs. PMID- 28098819 TI - Low Cost and Flexible UAV Deployment of Sensors. AB - This paper presents a platform for airborne sensor applications using low-cost, open-source components carried by an easy-to-fly unmanned aircraft vehicle (UAV). The system, available in open-source , is designed for researchers, students and makers for a broad range of exploration and data-collection needs. The main contribution is the extensible architecture for modularized airborne sensor deployment and real-time data visualisation. Our open-source Android application provides data collection, flight path definition and map tools. Total cost of the system is below 800 dollars. The flexibility of the system is illustrated by mapping the location of Bluetooth beacons (iBeacons) on a ground field and by measuring water temperature in a lake. PMID- 28098820 TI - Applying Human ADAR1p110 and ADAR1p150 for Site-Directed RNA Editing-G/C Substitution Stabilizes GuideRNAs against Editing. AB - Site-directed RNA editing is an approach to reprogram genetic information at the RNA level. We recently introduced a novel guideRNA that allows for the recruitment of human ADAR2 to manipulate genetic information. Here, we show that the current guideRNA design is already able to recruit another human deaminase, ADAR1, in both isoforms, p110 and p150. However, further optimization seems necessary as the current design is less efficient for ADAR1 isoforms. Furthermore, we describe hotspots at which the guideRNA itself is edited and show a way to circumvent this auto-editing without losing editing efficiency at the target. Both findings are important for the advancement of site-directed RNA editing as a tool in basic biology or as a platform for therapeutic editing. PMID- 28098822 TI - Application of Fault Tree Analysis and Fuzzy Neural Networks to Fault Diagnosis in the Internet of Things (IoT) for Aquaculture. AB - In the Internet of Things (IoT) equipment used for aquaculture is often deployed in outdoor ponds located in remote areas. Faults occur frequently in these tough environments and the staff generally lack professional knowledge and pay a low degree of attention in these areas. Once faults happen, expert personnel must carry out maintenance outdoors. Therefore, this study presents an intelligent method for fault diagnosis based on fault tree analysis and a fuzzy neural network. In the proposed method, first, the fault tree presents a logic structure of fault symptoms and faults. Second, rules extracted from the fault trees avoid duplicate and redundancy. Third, the fuzzy neural network is applied to train the relationship mapping between fault symptoms and faults. In the aquaculture IoT, one fault can cause various fault symptoms, and one symptom can be caused by a variety of faults. Four fault relationships are obtained. Results show that one symptom-to-one fault, two symptoms-to-two faults, and two symptoms-to-one fault relationships can be rapidly diagnosed with high precision, while one symptom-to two faults patterns perform not so well, but are still worth researching. This model implements diagnosis for most kinds of faults in the aquaculture IoT. PMID- 28098823 TI - Integrative miRNA-Gene Expression Analysis Enables Refinement of Associated Biology and Prediction of Response to Cetuximab in Head and Neck Squamous Cell Cancer. AB - This paper documents the process by which we, through gene and miRNA expression profiling of the same samples of head and neck squamous cell carcinomas (HNSCC) and an integrative miRNA-mRNA expression analysis, were able to identify candidate biomarkers of progression-free survival (PFS) in patients treated with cetuximab-based approaches. Through sparse partial least square-discriminant analysis (sPLS-DA) and supervised analysis, 36 miRNAs were identified in two components that clearly separated long- and short-PFS patients. Gene set enrichment analysis identified a significant correlation between the miRNA first component and EGFR signaling, keratinocyte differentiation, and p53. Another significant correlation was identified between the second component and RAS, NOTCH, immune/inflammatory response, epithelial-mesenchymal transition (EMT), and angiogenesis pathways. Regularized canonical correlation analysis of sPLS-DA miRNA and gene data combined with the MAGIA2 web-tool highlighted 16 miRNAs and 84 genes that were interconnected in a total of 245 interactions. After feature selection by a smoothed t-statistic support vector machine, we identified three miRNAs and five genes in the miRNA-gene network whose expression result was the most relevant in predicting PFS (Area Under the Curve, AUC = 0.992). Overall, using a well-defined clinical setting and up-to-date bioinformatics tools, we are able to give the proof of principle that an integrative miRNA-mRNA expression could greatly contribute to the refinement of the biology behind a predictive model. PMID- 28098821 TI - Tumor Microenvironment Modulation via Gold Nanoparticles Targeting Malicious Exosomes: Implications for Cancer Diagnostics and Therapy. AB - Exosomes are nanovesicles formed in the endosomal pathway with an important role in paracrine and autocrine cell communication. Exosomes secreted by cancer cells, malicious exosomes, have important roles in tumor microenvironment maturation and cancer progression. The knowledge of the role of exosomes in tumorigenesis prompted a new era in cancer diagnostics and therapy, taking advantage of the use of circulating exosomes as tumor biomarkers due to their stability in body fluids and targeting malignant exosomes' release and/or uptake to inhibit or delay tumor development. In recent years, nanotechnology has paved the way for the development of a plethora of new diagnostic and therapeutic platforms, fostering theranostics. The unique physical and chemical properties of gold nanoparticles (AuNPs) make them suitable vehicles to pursuit this goal. AuNPs' properties such as ease of synthesis with the desired shape and size, high surface:volume ratio, and the possibility of engineering their surface as desired, potentiate AuNPs' role in nanotheranostics, allowing the use of the same formulation for exosome detection and restraining the effect of malicious exosomes in cancer progression. PMID- 28098824 TI - Fabrication of a Miniature Multi-Parameter Sensor Chip for Water Quality Assessment. AB - Water contamination is a main inducement of human diseases. It is an important step to monitor the water quality in the water distribution system. Due to the features of large size, high cost, and complicated structure of traditional water determination sensors and devices, it is difficult to realize real-time water monitoring on a large scale. In this paper, we present a multi-parameter sensor chip, which is miniature, low-cost, and robust, to detect the pH, conductivity, and temperature of water simultaneously. The sensor chip was fabricated using micro-electro-mechanical system (MEMS) techniques. Iridium oxide film was electrodeposited as the pH-sensing material. The atomic ratio of Ir(III) to Ir(IV) is about 1.38 according to the X-ray photoelectron spectroscopy (XPS) analysis. The pH sensing electrode showed super-Nernstian response (-67.60 mV/pH) and good linearity (R2 = 0.9997), in the range of pH 2.22 to pH 11.81. KCl-agar and epoxy were used as the electrolyte layer and liquid junction for the solid state reference electrode, respectively, and its potential stability in deionized water was 56 h. The conductivity cell exhibited a linear determination range from 21.43 MU S / cm to 1.99 mS / cm , and the electrode constant was 1.566 cm-1. Sensitivity of the temperature sensor was 5.46 Omega / degrees C . The results indicate that the developed sensor chip has potential application in water quality measurements. PMID- 28098825 TI - Optical Fibre Sensors Using Graphene-Based Materials: A Review. AB - Graphene and its derivatives have become the most explored materials since Novoselov and Geim (Nobel Prize winners for Physics in 2010) achieved its isolation in 2004. The exceptional properties of graphene have attracted the attention of the scientific community from different research fields, generating high impact not only in scientific journals, but also in general-interest newspapers. Optical fibre sensing is one of the many fields that can benefit from the use of these new materials, combining the amazing morphological, chemical, optical and electrical features of graphene with the advantages that optical fibre offers over other sensing strategies. In this document, a review of the current state of the art for optical fibre sensors based on graphene materials is presented. PMID- 28098827 TI - Shared Sulfur Mobilization Routes for tRNA Thiolation and Molybdenum Cofactor Biosynthesis in Prokaryotes and Eukaryotes. AB - Modifications of transfer RNA (tRNA) have been shown to play critical roles in the biogenesis, metabolism, structural stability and function of RNA molecules, and the specific modifications of nucleobases with sulfur atoms in tRNA are present in pro- and eukaryotes. Here, especially the thiomodifications xm5s2U at the wobble position 34 in tRNAs for Lys, Gln and Glu, were suggested to have an important role during the translation process by ensuring accurate deciphering of the genetic code and by stabilization of the tRNA structure. The trafficking and delivery of sulfur nucleosides is a complex process carried out by sulfur relay systems involving numerous proteins, which not only deliver sulfur to the specific tRNAs but also to other sulfur-containing molecules including iron sulfur clusters, thiamin, biotin, lipoic acid and molybdopterin (MPT). Among the biosynthesis of these sulfur-containing molecules, the biosynthesis of the molybdenum cofactor (Moco) and the synthesis of thio-modified tRNAs in particular show a surprising link by sharing protein components for sulfur mobilization in pro- and eukaryotes. PMID- 28098826 TI - Hair Growth Promoting and Anticancer Effects of p21-activated kinase 1 (PAK1) Inhibitors Isolated from Different Parts of Alpinia zerumbet. AB - PAK1 (p21-activated kinase 1) is an emerging target for the treatment of hair loss (alopecia) and cancer; therefore, the search for PAK1 blockers to treat these PAK1-dependent disorders has received much attention. In this study, we evaluated the anti-alopecia and anticancer effects of PAK1 inhibitors isolated from Alpinia zerumbet (alpinia) in cell culture. The bioactive compounds isolated from alpinia were found to markedly promote hair cell growth. Kaempferol-3-O-beta d-glucuronide (KOG) and labdadiene, two of the isolated compounds, increased the proliferation of human follicle dermal papilla cells by approximately 117%-180% and 132%-226%, respectively, at 10-100 MUM. MTD (2,5-bis(1E,3E,5E)-6-methoxyhexa 1,3,5-trien-1-yl)-2,5-dihydrofuran) and TMOQ ((E)-2,2,3,3-tetramethyl-8-methylene 7-(oct-6-en-1-yl)octahydro-1H-quinolizine) showed growth-promoting activity around 164% and 139% at 10 MUM, respectively. The hair cell proliferation induced by these compounds was significantly higher than that of minoxidil, a commercially available treatment for hair loss. Furthermore, the isolated compounds from alpinia exhibited anticancer activity against A549 lung cancer cells with IC50 in the range of 67-99 MUM. Regarding the mechanism underlying their action, we hypothesized that the anti-alopecia and anticancer activities of these compounds could be attributed to the inhibition of the oncogenic/aging kinase PAK1. PMID- 28098828 TI - Development of a Topical Resveratrol Formulation for Commercial Applications Using Dendrimer Nanotechnology. AB - Resveratrol (RSV) is well known for its anti-oxidant and anti-aging properties. However, resveratrol is insoluble in water and has stability issues. Recently, efforts were placed to prepare a resveratrol-based advanced anti-aging topical product but it contains harsh organic solvents and oils that could be harmful to the human body and the environment. Hence, we propose the use of a multifunctional dendrimer to solve the solubility and stability issues of resveratrol. A dendrimer-resveratrol complex was prepared, optimized and tested for solubility enhancement, stability in solution and cream dosage forms. We have also developed a high performance liquid chromatography method to measure the resveratrol within the final product. PAMAM dendrimers increased the solubility and stability of resveratrol in water and semisolid dosage forms. Therefore, this product would be water based 'green' formulation devoid of harsh organic solvents and oils and can be safely applied to the skin. Additionally, we have shown that the dendrimer helped to increase overall RSV loading and skin penetration of resveratrol. The dendrimer-RSV formulation was successfully scaled up towards commercialization. Dendrimer with RSV has led to an innovation in anti-aging cream and solutions that could be commercially marketed. Dendrimer-RSV complex could also be added to other product forms for additional purposes and applications. PMID- 28098829 TI - Rapid Transfer Alignment of MEMS SINS Based on Adaptive Incremental Kalman Filter. AB - In airborne MEMS SINS transfer alignment, the error of MEMS IMU is highly environment-dependent and the parameters of the system model are also uncertain, which may lead to large error and bad convergence of the Kalman filter. In order to solve this problem, an improved adaptive incremental Kalman filter (AIKF) algorithm is proposed. First, the model of SINS transfer alignment is defined based on the "Velocity and Attitude" matching method. Then the detailed algorithm progress of AIKF and its recurrence formulas are presented. The performance and calculation amount of AKF and AIKF are also compared. Finally, a simulation test is designed to verify the accuracy and the rapidity of the AIKF algorithm by comparing it with KF and AKF. The results show that the AIKF algorithm has better estimation accuracy and shorter convergence time, especially for the bias of the gyroscope and the accelerometer, which can meet the accuracy and rapidity requirement of transfer alignment. PMID- 28098830 TI - Bulk Data Dissemination in Low Power Sensor Networks: Present and Future Directions. AB - Wireless sensor network-based (WSN-based) applications need an efficient and reliable data dissemination service to facilitate maintenance, management and data distribution tasks. As WSNs nowadays are becoming pervasive and data intensive, bulk data dissemination protocols have been extensively studied recently. This paper provides a comprehensive survey of the state-of-the-art bulk data dissemination protocols. The large number of papers available in the literature propose various techniques to optimize the dissemination protocols. Different from the existing survey works which separately explores the building blocks of dissemination, our work categorizes the literature according to the optimization purposes: Reliability, Scalability and Transmission/Energy efficiency. By summarizing and reviewing the key insights and techniques, we further discuss on the future directions for each category. Our survey helps unveil three key findings for future direction: (1) The recent advances in wireless communications (e.g., study on cross-technology interference, error estimating codes, constructive interference, capture effect) can be potentially exploited to support further optimization on the reliability and energy efficiency of dissemination protocols; (2) Dissemination in multi-channel, multi task and opportunistic networks requires more efforts to fully exploit the spatial-temporal network resources to enhance the data propagation; (3) Since many designs incur changes on MAC layer protocols, the co-existence of dissemination with other network protocols is another problem left to be addressed. PMID- 28098831 TI - A Fast Multimodal Ectopic Beat Detection Method Applied for Blood Pressure Estimation Based on Pulse Wave Velocity Measurements in Wearable Sensors. AB - Automatic detection of ectopic beats has become a thoroughly researched topic, with literature providing manifold proposals typically incorporating morphological analysis of the electrocardiogram (ECG). Although being well understood, its utilization is often neglected, especially in practical monitoring situations like online evaluation of signals acquired in wearable sensors. Continuous blood pressure estimation based on pulse wave velocity considerations is a prominent example, which depends on careful fiducial point extraction and is therefore seriously affected during periods of increased occurring extrasystoles. In the scope of this work, a novel ectopic beat discriminator with low computational complexity has been developed, which takes advantage of multimodal features derived from ECG and pulse wave relating measurements, thereby providing additional information on the underlying cardiac activity. Moreover, the blood pressure estimations' vulnerability towards ectopic beats is closely examined on records drawn from the Physionet database as well as signals recorded in a small field study conducted in a geriatric facility for the elderly. It turns out that a reliable extrasystole identification is essential to unsupervised blood pressure estimation, having a significant impact on the overall accuracy. The proposed method further convinces by its applicability to battery driven hardware systems with limited processing power and is a favorable choice when access to multimodal signal features is given anyway. PMID- 28098833 TI - Role of Electron-Driven Proton-Transfer Processes in the Ultrafast Deactivation of Photoexcited Anionic 8-oxoGuanine-Adenine and 8-oxoGuanine-Cytosine Base Pairs. AB - It has been reported that 8-oxo-7,8-dihydro-guanosine (8-oxo-G), which is the main product of oxidative damage of DNA, can repair cyclobutane pyrimidine dimer (CPD) lesions when incorporated into DNA or RNA strands in proximity to such lesions. It has therefore been suggested that the 8-oxo-G nucleoside may have been a primordial precursor of present-day flavins in DNA or RNA repair. Because the electron transfer leading to the splitting of a thymine-thymine pair in a CPD lesion occurs in the photoexcited state, a reasonably long excited-state lifetime of 8-oxo-G is required. The neutral (protonated) form of 8-oxo-G exhibits a very short (sub-picosecond) intrinsic excited-state lifetime which is unfavorable for repair. It has therefore been argued that the anionic (deprotonated) form of 8 oxo-G, which exhibits a much longer excited-state lifetime, is more likely to be a suitable cofactor for DNA repair. Herein, we have investigated the exited-state quenching mechanisms in the hydrogen-bonded complexes of deprotonated 8-oxo-G- with adenine (A) and cytosine (C) using ab initio wave-function-based electronic structure calculations. The calculated reaction paths and potential-energy profiles reveal the existence of barrierless electron-driven inter-base proton transfer reactions which lead to low-lying S1/S0 conical intersections. The latter can promote ultrafast excited-state deactivation of the anionic base pairs. While the isolated deprotonated 8-oxo-G- nucleoside may have been an efficient primordial repair cofactor, the excited states of the 8-oxo-G--A and 8 oxo-G--C base pairs are likely too short-lived to be efficient electron-transfer repair agents. PMID- 28098834 TI - Volatile Compound Profiling by HS-SPME/GC-MS-FID of a Core Olive Cultivar Collection as a Tool for Aroma Improvement of Virgin Olive Oil. AB - Virgin olive oil (VOO) is the only food product requiring official sensory analysis to be classified in commercial categories, in which the evaluation of the aroma plays a very important role. The selection of parents, with the aim of obtaining new cultivars with improved oil aroma, is of paramount importance in olive breeding programs. We have assessed the volatile fraction by headspace solid-phase microextraction/gas chromatography-mass spectrometry-flame ionization detection (HS-SPME/GC-MS-FID) and the deduced aroma properties of VOO from a core set of olive cultivars (Core-36) which possesses most of the genetic diversity found in the World Olive Germplasm Collection (IFAPA Alameda del Obispo) located in Cordoba, Spain. The VOO volatile fractions of Core-36 cultivars display a high level of variability. It is mostly made of compounds produced from polyunsaturated fatty acids through the lipoxygenase pathway, which confirms to be a general characteristic of the olive species (Olea europaea L.). The main group of volatile compounds in the oils was six straight-chain carbon compounds derived from linolenic acid, some of them being the main contributors to the aroma of the olive oils according to their odor activity values (OAV). The high level of variability found for the volatile fraction of the oils from Core-36 and, therefore, for the aroma odor notes, suggest that this core set may be a very useful tool for the choice of optimal parents in olive breeding programs in order to raise new cultivars with improved VOO aroma. PMID- 28098832 TI - Therapeutic Potential of Targeting the Th17/Treg Axis in Autoimmune Disorders. AB - A disruption of the crucial balance between regulatory T-cells (Tregs) and Th17 cells was recently implicated in various autoimmune disorders. Tregs are responsible for the maintenance of self-tolerance, thus inhibiting autoimmunity, whereas pro-inflammatory Th17-cells contribute to the induction and propagation of inflammation. Distortion of the Th17/Treg balance favoring the pro inflammatory Th17 side is hence suspected to contribute to exacerbation of autoimmune disorders. This review aims to summarize recent data and advances in targeted therapeutic modification of the Th17/Treg-balance, as well as information on the efficacy of candidate therapeutics with respect to the treatment of autoimmune diseases. PMID- 28098835 TI - An Electrostatic-Barrier-Forming Window that Captures Airborne Pollen Grains to Prevent Pollinosis. AB - An electrostatic-barrier-forming window (EBW) was devised to capture airborne pollen, which can cause allergic pollinosis. The EBW consisted of three layers of insulated conductor wires (ICWs) and two voltage generators that supplied negative charges to the two outer ICW layers and a positive charge to the middle ICW layer. The ICWs generated an attractive force that captured pollen of the Japanese cedar, Cryptomeria japonica, from air blown through the EBW. The attractive force was directly proportional to the applied voltage. At >=3.5 kV, the EBW exerted sufficient force to capture all pollen carried at an air flow of 3 m/s, and pollen-free air passed through the EBW. The findings demonstrated that the electrostatic barrier that formed inside the EBW was very effective at capturing airborne pollen; thus, it could allow a home to remain pollen-free and healthy despite continuous pollen exposure. PMID- 28098836 TI - Association of School Environment and After-School Physical Activity with Health Related Physical Fitness among Junior High School Students in Taiwan. AB - The relationship between students' school environment and exercise habits is complex, and is affected by numerous factors. However, the few studies that have been conducted on this relationship have reported inconsistent results, especially regarding Taiwanese students. We conducted this cross-sectional study to investigate the association of school environment and after-school physical activity with health-related physical fitness in Taiwanese adolescents. Data were drawn from a national survey conducted by the Ministry of Education in Taiwan in 2008 of health-related physical fitness measurements among junior high school students (649,442 total) in grades seven to nine.School environment (level of urbanization, school size, presence of sports field or gymnasium) and after school physical activity were assessed for their association with adolescents' physical fitness measurements (body mass index (BMI), bent-leg sit-ups, 800-/1600 m run, sit-and-reach, standing long jump). Urban boys and girls perform significantly better in muscle strength and endurance, cardiorespiratory endurance, flexibility, and explosive power; girls from rural areas exhibited significantly worse scores in body composition. Boys from large-size schools performed the worst in cardiorespiratory endurance, flexibility, and explosive power; whereas girls from large-size schools performed the worst in muscle strength, muscle endurance, and explosive power, but had the best score for body composition. However, the differences in body composition of boys from large-, medium-, and small- size schools did not reach a statistically significant level. Adolescents of both genders in schools with a sports field or gymnasium exhibited significantly better in muscle strength and endurance, cardiorespiratory endurance, and explosive power. Boys in schools with a sports field or gymnasium had significantly better body composition; girls in schools with sports field or gymnasium differed significantly in flexibility. Adolescents of both genders who participated in physical activity after school had significantly better body composition, cardiorespiratory endurance, and flexibility. Boys who participated in physical activity after school significantly differed in explosive power, whereas girls who participated in physical activity after school exhibited significantly better flexibility. Thus, the current study demonstrated that some factors, including urbanization (school location in rural or urban areas), school size, school facility provision (school with or without sports fields or gymnasiums), and after-school physical activity participation are more important than others in shaping adolescents' physical fitness in Taiwan; meanwhile, these association patterns differed by gender. PMID- 28098837 TI - Casein Glycomacropeptide Hydrolysates Exert Cytoprotective Effect against Cellular Oxidative Stress by Up-Regulating HO-1 Expression in HepG2 Cells. AB - Oxidative stress is considered as an important mediator in the progression of metabolic disorders. The objective of this study was to investigate the potential hepatoprotective effects and mechanisms of bovine casein glycomacropeptide hydrolysates (GHP) on hydrogen peroxide (H2O2)-induced oxidative damage in HepG2 cells. Results showed that GHP significantly blocked H2O2-induced intracellular reactive oxygen species (ROS) generation and cell viability reduction in a dose dependent manner. Further, GHP concentration-dependently induced heme oxygenase-1 (HO-1) expression and increased nuclear factor-erythroid 2-related factor 2 (Nrf2) nuclear translocation. Moreover, pretreatment of GHP increased the activation of p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated protein kinase 1/2 (ERK1/2), which were shown to contribute to Nrf2-mediated HO-1 expression. Taken together, GHP protected HepG2 cells from oxidative stress by activation of Nrf2 and HO-1 via p38 MAPK and ERK1/2 signaling pathways. Our findings indicate that bovine casein glycomacropeptide hydrolysates might be a potential ingredient in the treatment of oxidative stress-related disorders and further studies are needed to investigate the protective effects in vivo. PMID- 28098838 TI - Role of UDP-Glucuronosyltransferase 1A1 in the Metabolism and Pharmacokinetics of Silymarin Flavonolignans in Patients with HCV and NAFLD. AB - Silymarin is the most commonly used herbal medicine by patients with chronic liver disease. Silymarin flavonolignans undergo rapid first-pass metabolism primarily by glucuronidation. The aims of this investigation were: (1) to determine the association of UGT1A1*28 polymorphism with the area under the plasma concentration-time curves (AUCs) for silybin A (SA) and silybin B (SB); (2) to evaluate the effect of UGT1A1*28 polymorphism on the profile of flavonolignan glucuronide conjugates found in the plasma; and (3) to investigate the role of UGT1A1 enzyme kinetics on the pharmacokinetics of SA and SB. AUCs and metabolic ratios for thirty-three patients with chronic liver disease administered oral doses of silymarin were compared between different UGT1A1*28 genotypes. The AUCs, metabolic ratios, and the profiles of major SA and SB glucuronides did not differ significantly among the three UGT1A1 genotypes. In contrast, an increase in the proportion of sulfated flavonolignan conjugates in plasma was observed in subjects with UGT1A1*28/*28 genotype compared to subjects carrying wild type alleles. Differences in SA and SB in vitro intrinsic clearance estimates for UGTIA1 correlated inversely with SA and SB exposures observed in vivo indicating a major role for UGT1A1 in silymarin metabolism. In addition, a significant difference in the metabolic ratio observed between patients with NAFLD and HCV suggests that any effect of UGT1A1 polymorphism may be obscured by a greater effect of liver disease on the pharmacokinetics of silymarin. Taken together, these results suggest the presence of the UGT1A1*28 allele does not contribute significantly to a large inter-subject variability in the pharmacokinetics of silybin A and silybin B which may obscure the ability to detect beneficial effects of silymarin in patients with liver disease. PMID- 28098839 TI - Continuous Glucose Monitoring Enables the Detection of Losses in Infusion Set Actuation (LISAs). AB - Reliable continuous glucose monitoring (CGM) enables a variety of advanced technology for the treatment of type 1 diabetes. In addition to artificial pancreas algorithms that use CGM to automate continuous subcutaneous insulin infusion (CSII), CGM can also inform fault detection algorithms that alert patients to problems in CGM or CSII. Losses in infusion set actuation (LISAs) can adversely affect clinical outcomes, resulting in hyperglycemia due to impaired insulin delivery. Prolonged hyperglycemia may lead to diabetic ketoacidosis-a serious metabolic complication in type 1 diabetes. Therefore, an algorithm for the detection of LISAs based on CGM and CSII signals was developed to improve patient safety. The LISA detection algorithm is trained retrospectively on data from 62 infusion set insertions from 20 patients. The algorithm collects glucose and insulin data, and computes relevant fault metrics over two different sliding windows; an alarm sounds when these fault metrics are exceeded. With the chosen algorithm parameters, the LISA detection strategy achieved a sensitivity of 71.8% and issued 0.28 false positives per day on the training data. Validation on two independent data sets confirmed that similar performance is seen on data that was not used for training. The developed algorithm is able to effectively alert patients to possible infusion set failures in open-loop scenarios, with limited evidence of its extension to closed-loop scenarios. PMID- 28098840 TI - Comparative Solid-State Stability of Perindopril Active Substance vs. Pharmaceutical Formulation. AB - This paper presents the results obtained after studying the thermal stability and decomposition kinetics of perindopril erbumine as a pure active pharmaceutical ingredient as well as a solid pharmaceutical formulation containing the same active pharmaceutical ingredient (API). Since no data were found in the literature regarding the spectroscopic description, thermal behavior, or decomposition kinetics of perindopril, our goal was the evaluation of the compatibility of this antihypertensive agent with the excipients in the tablet under ambient conditions and to study the effect of thermal treatment on the stability of perindopril erbumine. ATR-FTIR (Attenuated Total Reflectance Fourier Transform Infrared) spectroscopy, thermal analysis (thermogravimetric mass curve (TG-thermogravimetry), derivative thermogravimetric mass curve (DTG), and heat flow (HF)) and model-free kinetics were chosen as investigational tools. Since thermal behavior is a simplistic approach in evaluating the thermal stability of pharmaceuticals, in-depth kinetic studies were carried out by classical kinetic methods (Kissinger and ASTM E698) and later with the isoconversional methods of Friedman, Kissinger-Akahira-Sunose and Flynn-Wall-Ozawa. It was shown that the main thermal degradation step of perindopril erbumine is characterized by activation energy between 59 and 69 kJ/mol (depending on the method used), while for the tablet, the values were around 170 kJ/mol. The used excipients (anhydrous colloidal silica, microcrystalline cellulose, lactose, and magnesium stearate) should be used in newly-developed generic solid pharmaceutical formulations, since they contribute to an increased thermal stability of perindopril erbumine. PMID- 28098841 TI - Compressed Sensing Techniques Applied to Ultrasonic Imaging of Cargo Containers. AB - One of the key issues in the fight against the smuggling of goods has been the development of scanners for cargo inspection. X-ray-based radiographic system scanners are the most developed sensing modality. However, they are costly and use bulky sources that emit hazardous, ionizing radiation. Aiming to improve the probability of threat detection, an ultrasonic-based technique, capable of detecting the footprint of metallic containers or compartments concealed within the metallic structure of the inspected cargo, has been proposed. The system consists of an array of acoustic transceivers that is attached to the metallic structure-under-inspection, creating a guided acoustic Lamb wave. Reflections due to discontinuities are detected in the images, provided by an imaging algorithm. Taking into consideration that the majority of those images are sparse, this contribution analyzes the application of Compressed Sensing (CS) techniques in order to reduce the amount of measurements needed, thus achieving faster scanning, without compromising the detection capabilities of the system. A parametric study of the image quality, as a function of the samples needed in spatial and frequency domains, is presented, as well as the dependence on the sampling pattern. For this purpose, realistic cargo inspection scenarios have been simulated. PMID- 28098842 TI - Modulation Index Adjustment for Recovery of Pure Wavelength Modulation Spectroscopy Second Harmonic Signal Waveforms. AB - A new technique of modulation index adjustment for pure wavelength modulation spectroscopy second harmonic signal waveforms recovery is presented. As the modulation index is a key parameter in determining the exact form of the signals generated by the technique of wavelength modulation spectroscopy, the method of modulation index adjustment is applied to recover the second harmonic signal with wavelength modulation spectroscopy. By comparing the measured profile with the theoretical profile by calculation, the relationship between the modulation index and average quantities of the scanning wavelength can be obtained. Furthermore, when the relationship is applied in the experimental setup by point-by-point modulation index modification for gas detection, the results show good agreement with the theoretical profile and signal waveform distortion (such as the amplitude modulation effect caused by diode laser) can be suppressed. Besides, the method of modulation index adjustment can be used in many other aspects which involve profile improvement. In practical applications, when the amplitude modulation effect can be neglected and the stability of the detection system is limited by the sampling rate of analog-to-digital, modulation index adjustment can be used to improve detection into softer inflection points and solve the insufficient sampling problem. As a result, measurement stability is improved by 40%. PMID- 28098844 TI - Modeling and Calibration of a Novel One-Mirror Galvanometric Laser Scanner. AB - A laser stripe sensor has limited application when a point cloud of geometric samples on the surface of the object needs to be collected, so a galvanometric laser scanner is designed by using a one-mirror galvanometer element as its mechanical device to drive the laser stripe to sweep along the object. A novel mathematical model is derived for the proposed galvanometer laser scanner without any position assumptions and then a model-driven calibration procedure is proposed. Compared with available model-driven approaches, the influence of machining and assembly errors is considered in the proposed model. Meanwhile, a plane-constraint-based approach is proposed to extract a large number of calibration points effectively and accurately to calibrate the galvanometric laser scanner. Repeatability and accuracy of the galvanometric laser scanner are evaluated on the automobile production line to verify the efficiency and accuracy of the proposed calibration method. Experimental results show that the proposed calibration approach yields similar measurement performance compared with a look up table calibration method. PMID- 28098843 TI - PERM Hypothesis: The Fundamental Machinery Able to Elucidate the Role of Xenobiotics and Hormesis in Cell Survival and Homeostasis. AB - In this article the Proteasome, Endoplasmic Reticulum and Mitochondria (PERM) hypothesis is discussed. The complex machinery made by three homeostatic mechanisms involving the proteasome (P), endoplasmic reticulum (ER) and mitochondria (M) is addressed in order to elucidate the beneficial role of many xenobiotics, either trace metals or phytochemicals, which are spread in the human environment and in dietary habits, exerting their actions on the mechanisms underlying cell survival (apoptosis, cell cycle regulation, DNA repair and turnover, autophagy) and stress response. The "PERM hypothesis" suggests that xenobiotics can modulate this central signaling and the regulatory engine made fundamentally by the ER, mitochondria and proteasome, together with other ancillary components such as peroxisomes, by acting on the energetic balance, redox system and macromolecule turnover. In this context, reactive species and stressors are fundamentally signalling molecules that could act as negative modulating signals if PERM-mediated control is offline, impaired or dysregulated, as occurs in metabolic syndrome, degenerative disorders, chronic inflammation and cancer. Calcium is an important oscillatory input of this regulation and, in this hypothesis, it might play a role in maintaining the correct rhythm of this PERM modulation, probably chaotic in its nature, and guiding cells to a more drastic decision, such as apoptosis. The commonest effort sustained by cells is to maintain their survival balance and the proterome has the fundamental task of supporting this mechanism. Mild stress is probably the main stimulus in this sense. Hormesis is therefore re-interpreted in the light of this hypothetical model and that experimental evidence arising from flavonoid and hormesis reasearch. PMID- 28098846 TI - Localization-Free Detection of Replica Node Attacks in Wireless Sensor Networks Using Similarity Estimation with Group Deployment Knowledge. AB - Due to the unattended nature and poor security guarantee of the wireless sensor networks (WSNs), adversaries can easily make replicas of compromised nodes, and place them throughout the network to launch various types of attacks. Such an attack is dangerous because it enables the adversaries to control large numbers of nodes and extend the damage of attacks to most of the network with quite limited cost. To stop the node replica attack, we propose a location similarity based detection scheme using deployment knowledge. Compared with prior solutions, our scheme provides extra functionalities that prevent replicas from generating false location claims without deploying resource-consuming localization techniques on the resource-constraint sensor nodes. We evaluate the security performance of our proposal under different attack strategies through heuristic analysis, and show that our scheme achieves secure and robust replica detection by increasing the cost of node replication. Additionally, we evaluate the impact of network environment on the proposed scheme through theoretic analysis and simulation experiments, and indicate that our scheme achieves effectiveness and efficiency with substantially lower communication, computational, and storage overhead than prior works under different situations and attack strategies. PMID- 28098845 TI - Optical Tip Clearance Measurements as a Tool for Rotating Disk Characterization. AB - An experimental investigation on the vibrational behavior of a rotating disk by means of three optical fiber sensors is presented. The disk, which is a scale model of the real disk of an aircraft engine, was assembled in a wind tunnel in order to simulate real operation conditions. The pressure difference between the upstream and downstream sides of the disk causes an airflow that might force the disk to vibrate. To characterize this vibration, a set of parameters was determined by measuring the tip clearance of the disk: the amplitude, the frequency and the number of nodal diameters in the disk. All this information allowed the design of an upgraded prototype of the disk, whose performance was also characterized by the same method. An optical system was employed for the measurements, in combination with a strain gauge mounted on the disk surface, which served to confirm the results obtained. The data of the strain gauge coincided closely with those provided by the optical fiber sensors, thus demonstrating the suitability of this innovative technique to evaluate the vibrational behavior of rotating disks. PMID- 28098847 TI - Polish Yellow Sweet Clover (Melilotus officinalis L.) Honey, Chromatographic Fingerprints, and Chemical Markers. AB - A case study of Polish Melilotus officinalis honey was presented for the first time. Gas chromatography-mass spectrometry (GC-MS) (after steam distillation, Soxhlet extraction, ultrasonic solvent extraction, and solid phase extraction (SPE)) and targeted high performance liquid chromatography with a photodiode array detector (HPLC-PAD) were applied to determine the characteristic components of honey. While ubiquitous in most honeys, carbohydrates, terpene derivatives, and phenylacetic acid dominated in the Soxhlet extracts (25.54%) and in the application of SPE (13.04%). In addition, lumichrome (1.85%) was found, and may be considered as a marker of this honey. Due to the presence of these compounds, Polish yellow sweet clover honey is similar to French lavender honeys. The major compounds determined in the methanolic extract were (+)-catechine (39.7%) and gallic acid (up to 30%), which can be regarded as specific chemical markers of the botanical origin of melilot honey. With respect to total phenolic and flavonoid contents, 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays were determined spectrophotometrically. The honey exhibited a moderate antioxidant activity, typical for light honeys, which correlates well with its phenolic and flavonoid composition. PMID- 28098849 TI - No evidence for MHC class II-based non-random mating at the gametic haplotype in Atlantic salmon. AB - Genes of the major histocompatibility complex (MHC) are a likely target of mate choice because of their role in inbreeding avoidance and potential benefits for offspring immunocompetence. Evidence for female choice for complementary MHC alleles among competing males exists both for the pre- and the postmating stages. However, it remains unclear whether the latter may involve non-random fusion of gametes depending on gametic haplotypes resulting in transmission ratio distortion or non-random sequence divergence among fused gametes. We tested whether non-random gametic fusion of MHC-II haplotypes occurs in Atlantic salmon Salmo salar. We performed in vitro fertilizations that excluded interindividual sperm competition using a split family design with large clutch sample sizes to test for a possible role of the gametic haplotype in mate choice. We sequenced two MHC-II loci in 50 embryos per clutch to assess allelic frequencies and sequence divergence. We found no evidence for transmission ratio distortion at two linked MHC-II loci, nor for non-random gamete fusion with respect to MHC-II alleles. Our findings suggest that the gametic MHC-II haplotypes play no role in gamete association in Atlantic salmon and that earlier findings of MHC-based mate choice most likely reflect choice among diploid genotypes. We discuss possible explanations for these findings and how they differ from findings in mammals. PMID- 28098848 TI - Identification of Phenolic Compounds from Hancornia speciosa (Apocynaceae) Leaves by UHPLC Orbitrap-HRMS. AB - Apocynaceae is a botanical family distributed mainly in tropical and subtropical regions of the world. In Brazil, they comprise about 90 genera and 850 species, inhabiting various types of vegetation. Within this large botanical family, the genus Hancornia is considered monotypic, with its only species Hancornia speciosa Gomes. Antihypertensive, antidiabetic, and antiviral activities are described for this species. Despite having been the target of some studies, knowledge of its chemical composition is still limited. In this study, the phenolics of H. speciosa leaves were analyzed using ultra-high performance liquid chromatography (UHPLC) coupled to Orbitrap high-resolution mass spectrometry (HRMS). As a result, 14 compounds were identified viz. protocatechuic acid, catechin, and quercetin, and another 14 were putatively identified viz. B- and C-type procyanidins, while just one compound remained unknown. From the identified compounds, 17 are reported for the first time viz. coumaroylquinic acid isomers and eriodyctiol. The results show that Hancornia speciosa can serve as source of valuable phenolics. PMID- 28098851 TI - Solving Large-Scale Inverse Magnetostatic Problems using the Adjoint Method. AB - An efficient algorithm for the reconstruction of the magnetization state within magnetic components is presented. The occurring inverse magnetostatic problem is solved by means of an adjoint approach, based on the Fredkin-Koehler method for the solution of the forward problem. Due to the use of hybrid FEM-BEM coupling combined with matrix compression techniques the resulting algorithm is well suited for large-scale problems. Furthermore the reconstruction of the magnetization state within a permanent magnet as well as an optimal design application are demonstrated. PMID- 28098852 TI - Adaptive processes explain variations in human thermal sensation. PMID- 28098850 TI - A rare exception to Haldane's rule: Are X chromosomes key to hybrid incompatibilities? AB - The prevalence of Haldane's rule suggests that sex chromosomes commonly have a key role in reproductive barriers and speciation. However, the majority of research on Haldane's rule has been conducted in species with conventional sex determination systems (XY and ZW) and exceptions to the rule have been understudied. Here we test the role of X-linked incompatibilities in a rare exception to Haldane's rule for female sterility in field cricket sister species (Teleogryllus oceanicus and T. commodus). Both have an XO sex determination system. Using three generations of crosses, we introgressed X chromosomes from each species onto different, mixed genomic backgrounds to test predictions about the fertility and viability of each cross type. We predicted that females with two different species X chromosomes would suffer reduced fertility and viability compared with females with two parental X chromosomes. However, we found no strong support for such X-linked incompatibilities. Our results preclude X-X incompatibilities and instead support an interchromosomal epistatic basis to hybrid female sterility. We discuss the broader implications of these findings, principally whether deviations from Haldane's rule might be more prevalent in species without dimorphic sex chromosomes. PMID- 28098853 TI - Does human resource primacy moderate the impact of psychological distress on subsequent risk for disability retirement? AB - Objective Human resource primacy (HRP) refers to employees' perceptions of how the organization shows interests in its employees' welfare, happiness, and health. The aims of this study were to determine whether (i) perceptions of HRP are related to the risk for disability retirement and (ii) HRP moderates the impact of psychological distress on later risk for disability retirement. Methods The study relied on a combination of self-report survey questionnaire data on HRP and psychological distress supplemented with official register data on disability benefits from the Norwegian Labor and Welfare Administration. The sample comprised 14 501 Norwegian employees from various occupations and industries. Results HRP was significantly associated with reduced risk of disability retirement [hazard ratio (HR) in bivariate analysis 0.84, 95% confidence interval (95% CI) 0.77-0.93] and after adjusting for gender and educational level. However, HRP (HR 0.97, 95% CI 0.87-1.07) was not associated with later risk for disability retirement after adjusting for psychological distress and did not moderate the association between psychological distress and disability retirement. Conclusions A positive impression of HRP may reduce the risk of disability retirement in general but not in cases following psychological distress. Upcoming research should identify other factors that may be more beneficial with regard to reducing the risk for disability retirement following distress. PMID- 28098854 TI - LSD1 sustains estrogen-driven endometrial carcinoma cell proliferation through the PI3K/AKT pathway via di-demethylating H3K9 of cyclin D1. AB - A recent study reported that histone lysine specific demethylase 1 (LSD1, KDM1A) is overexpressed in endometrioid endometrial carcinoma (EEC) and associated with tumor progression as well as poor prognosis. However, the physiological function and mechanism of LSD1 in endometrial cancer (EC) remains largely unknown. In this study, we demonstrate that beta-estradiol (E2) treatment increased LSD1 expression via the GPR30/PI3K/AKT pathway in endometrial cancer cells. Both siGPR30 and the PI3K inhibitor LY294002 block this effect. RNAi-mediated silencing of LSD1 abolished estrogen-driven endometrial cancer cell (ECC) proliferation, and induced G1 cell arrest and apoptosis. Mechanistically, we find that LSD1 silencing results in PI3K/AKT signal inactivation, but without the elevation of PTEN expression as expected. This is because the inhibition of LSD1 induces dimethylation of lysine 9 on histone H3 (H3K9m2) accumulation at the promoter region of cyclin D1. Interfering with cyclin D1 leads to PI3K/AKT signal suppression. Re-overexpression of cyclin D1 in LSD1-knockdown ECCs reverses the LSD1 inhibitory action. Our finding connects estrogen signaling with epigenetic regulation in EEC and provides novel experimental support for LSD1 as a potential target for endometrial cancer therapeutics. PMID- 28098855 TI - Regulation of EMT by STAT3 in gastrointestinal cancer (Review). AB - Gastrointestinal (GI) cancer is characterized by its aggressiveness and tendency to metastasize at early stage. Epithelial-mesenchymal transition (EMT), commonly known as the preparing step of metastasis, may account for the aggressive phenotype of GI cancer cells. The process of EMT is finely orchestrated by multiple layers of regulators. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor constitutively activated in diverse malignancies. Recent studies have suggested an involvement of STAT3 in GI cancer EMT. In this review, we first take an insight into the oncogenic functions of STAT3 in GI cancer, and then summarize the possible mechanisms by which STAT3 regulates the EMT process. Through the extensive interactions with EMT-inducing transcription factors and non-coding RNAs, and crosstalk with other signaling pathways, STAT3 has been demonstrated to promote the mesenchymal and invasive phenotype of GI cancer, which provides rationales for specifically targeting STAT3 to prevent and reverse the progression of GI cancer. PMID- 28098856 TI - Anti-wrinkle effect of fermented black ginseng on human fibroblasts. AB - Fermented black ginseng (FBG) is processed by the repeated steaming and drying of fresh ginseng followed by fermentation with Saccharomyces cerevisiae. It is known to possess anti-oxidative effects. Skin wrinkle formation is associated with oxidative stress and inflammatory reactions. The aim of this study was to determine whether FBG possesses anti-wrinkle activity using human fibroblasts (HS68). According to the Korea Ministry of Food and Drug Safety (MFDS) guidelines for the evaluation of the efficacy of functional anti-wrinkle cosmetics, we attempted to elucidate the effects of FBG on type I procollagen, matrix metalloproteinase (MMP)-1, MMP-2, MMP-9 and tissue inhibitor of metalloproteinase 2 (TIMP-2). In addition, the eye irritation potential of FBG was examined using the EpiOcular-EIT kit. Our results revealed that FBG was not cytotoxic at concentrations <10 ug/ml. It was considered as safe for the eyes at concentrations of up to 100 ug/ml. Treatment with FBG at concentrations from 0.3 to 10 ug/ml significantly (P<0.05) increased the type I procollagen expression levels from 117.61+/-1.51 to 129.95+/-4.47% in the human fibroblasts. By contrast, FBG significantly (P<0.05) decreased the MMP-1 expression level from 18.41+/-4.95 to 27.41+/-3.96%. FBG at 3 ug/ml also increased the expression of TIMP-2 up to 154.55%. However, FBG at 10 ug/ml decreased the expression levels of MMP-2 and MMP-9 to 45.15 and 66.65%, respectively. These results suggest that FBG has potential anti-wrinkle effects as a potential ingredient in cosmetics. PMID- 28098857 TI - Anticancer effects of ginsenoside Rg3 (Review). AB - Cancer is a life-threatening disease with an alarmingly increased annual mortality rate globally. Although various therapies are employed for cancer, the final effect is not satisfactory. Chemotherapy is currently the most commonly used treatment option. However, the unsatisfactory efficacy, severe side-effects and drug resistance hinder the therapeutic efficacy of chemotherapeutic drugs. There is increasing evidence indicating that ginsenoside Rg3, a naturally occurring phytochemical, plays an important role in the prevention and treatment of cancer. The suggested mechanisms mainly include the induction of apoptosis, and the inhibition of proliferation, metastasis and angiogenesis, as well as the promotion of immunity. In addition, ginsenoside Rg3 can be used as an adjuvant to conventional cancer therapies, improving the efficacy and/or reducing adverse effects via synergistic activities. Ginsenoside Rg3 may be a widely applied natural medicine against cancer. To date however, there is no systematic summary available of the anticancer effects of ginsenoside Rg3. Therefore, in this review, all available literature over the past 10 years was reviewed and discussed in order to facilitate further research of ginsenoside Rg3. PMID- 28098858 TI - miR-345 inhibits tumor metastasis and EMT by targeting IRF1-mediated mTOR/STAT3/AKT pathway in hepatocellular carcinoma. AB - MicroRNAs (miRNAs) have been reported to play critical roles in tumor progression including hepatocellular carcinoma (HCC). Thus, the underlying mechanisms need further investigation. Previous study reported that loss of miR-345 expression indicated a poor prognosis of HCC patients. This study evaluated whether loss of miR-345 could promote the tumor metastasis and epithelial-mesenchymal-transition (EMT) of HCC by targeting interferon regulatory factor 1 (IRF1)-mediated mTOR/STAT3/AKT signaling. Underexpression of miR-345 was identified in 65 cases of human HCC compared to matched tumor-adjacent tissues by qRT-PCR. Moreover, we found that reduced expression of mi-345 was observed in HCC cell lines. The restoration of miR-345 inhibited cell migration and invasion in HCCLM3 cells, while its loss facilitated the cell mobility of HepG2 cells. Furthermore, miR-345 over-expression reduced lung metastases of HCC cells in nude mice. Notably, miR 345 overexpression prohibited, while its knockdown enhanced the EMT process of HCC cell lines in vitro. Bioinformatics software predicted that IRF1 was a direct target of miR-345. We then observed the negative regulation of miR-345 on IRF1 protein expression and the direct binding between them was further verified by dual-luciferase assays in HCC cells. In addition, over-expression of IRF1 mRNA was inversely correlated with the level of miR-345 in HCC specimens. Restoration of IRF1 resulted in promoted EMT and cell mobility in miR-345 overexpressing HCCLM3 cells. It was found that mTOR/STAT3/AKT pathway and its downstream targets including Slug, Snail and Twist may be involved in IRF1 mediated EMT process. In conclusion, miR-345 acts as an inhibitor of EMT process in HCC cells by targeting IRF1 and this study highlights the potential effects of miR-345 on prognosis and treatment of HCC. PMID- 28098860 TI - Chondroitin sulfate proteoglycan protein is stimulated by interleukin 11 and promotes endometrial epithelial cancer cell proliferation and migration. AB - Endometrial cancer is the most common gynecological cancer. We identified interleukin 11 (IL11) as a critical mediator of endometrial tumourigenesis and demonstrated that IL11 regulates chondroitin sulfate proteoglycan (CSPG4) in human placental trophoblasts. CSPG4 is a cell membrane protein overexpressed in numerous human cancers, although its role in endometrial cancer has not been investigated. We examined CSPG4 expression and localization in primary human type I endometrioid grade (G) 1-3 tumours by qPCR and immunohistochemistry and determined whether IL11 stimulated CSPG4. IL11 upregulated CSPG4 mRNA in HEC1A (G2-derived endometrial epithelial cancer cell line) cells. IL11 administration to BALB/c nude mice enhanced HEC1A xenograft tumour growth and increased CSPG4 protein in tumours. CSPG4 mRNA was unchanged between human G1-3 endometrial cancer and control tissues. CSPG4 protein levels were elevated in the epithelium of G2 and G3 endometrial cancer and in the tumour-associated stroma of G3 tumour tissues compared to proliferative phase or post-menopausal endometrium. CSPG4 knockdown by siRNA reduced HEC1A proliferation and migration in vitro and reduced gene expression of the key epithelial-to-mesenchymal transition (EMT) regulator SNAIL. Our data suggest that CSPG4 inhibition may impair endometrial cancer progression by reducing cancer cell proliferation, migration and potentially EMT. PMID- 28098859 TI - DNA damage response defect in Williams-Beuren syndrome. AB - Williams-Beuren syndrome (WBS, no. OMIM 194050) is a rare multisystem genetic disorder caused by a microdeletion on chromosome 7q11.23 and characterized by cardiovascular malformations, mental retardation, and a specific facial dysmorphism. Recently, we reported that a series of non-Hodgkin's lymphoma occurs in children with WBS and thus hypothesized that a predisposition to cancer may be associated with this genetic disorder. The aim of the present study was to ascertain the role played by three genes hemizygously deleted in WBS (RFC2, GTF2I and BAZ1B) in DNA damage response pathways. Cell proliferation, cell cycle analysis, gamma-H2A.X induction, and expression of DNA damage response proteins were investigated upon exposure to genotoxic treatments in WBS patient-derived primary fibroblasts and in the 293T cell line treated with specific siRNAs targeting RFC2, GTF2I and BAZ1B. An impaired hydroxyurea-induced phosphorylation of CHK1 was observed in the WBS cells. However, this defective DNA damage response was not associated with an increased sensitivity to genotoxic agents. In addition, depletion of RFC2, GTF2I and BAZ1B using specific siRNAs did not have a significant impact on the DNA damage response in 293T cells. Our results highlight that the ATR-dependent DNA damage response is impaired in WBS patient cells but is also dispensable for viability when these cells undergo a genotoxic stress. The mechanism by which the ATR pathway is impaired in WBS warrants elucidation through further investigation. PMID- 28098861 TI - Triptolide inhibits viability and induces apoptosis in liver cancer cells through activation of the tumor suppressor gene p53. AB - The present study investigated the effect of triptolide on viability and apoptosis along with underlying mechanism in liver cancer cells. CCK-8 assay showed that triptolide treatment for 48 h significantly reduced the viability of HepG2 and QSG7701 cells at 50 uM concentration. Annexin V-FITC and propidium iodide staining showed that triptolide treatment of HepG2 cells at 50 uM concentrations induced apoptosis in 56.45% cells compared to only 2.36% cells in the control cultures. Western blot assay showed that treatment of HepG2 cells with 50 uM concentration of triptolide significantly induced phosphorylation of p53 in a 2 h-treatment. Phosphorylation of histone H2A.X indicator of DNA damage was induced by triptolide treatment after 12 h in HepG2 cells. The level of nuclear p53 in a 6 h-treatment with 0, 10, 20, 30, 40 and 50 uM concentration of triptolide was found to be 15.3, 19.6, 28.5, 43.7, 63.8 and 91.5%, respectively. Treatment of HepG2 cells with triptolide at 50 uM concentration caused a significant increase in the binding potential of p53 to DNA. Triptolide treatment of HepG2 cells caused a significant increase in the expression of p21, Bax and DR5 genes in HepG2 cells. It also increased the expression of miR-34b and miR-34c in HepG2 cells markedly. Treatment of HepG2 cells with p53 inhibitor, pifithrin alpha prior to incubation with triptolide significantly prevented induction of cell apoptosis. Suppression of p53 expression by siRNA inhibited the expression of p53 as well as its target genes along with the prevention of apoptosis induction. In conclusion, triptolide inhibits viability and induces apoptosis in liver cancer cells through activation of the tumor suppressor gene p53. Thus, triptolide can be used for the treatment of liver cancer. PMID- 28098862 TI - Rhein suppresses matrix metalloproteinase production by regulating the Rac1/ROS/MAPK/AP-1 pathway in human ovarian carcinoma cells. AB - Matrix metalloproteinases (MMPs) are a family of calcium-dependent zinc containing endopeptidases, which play an integral role in migration and invasion of ovarian cancer. Rac1 proteins might mostly influence cell migration and invasion by generating endogenous reactive oxygen species. Therefore, inhibiting MMPs and regulating the Rac1/ROS/MAPK/AP-1 pathway may be a new therapeutic strategy for ovarian cancer. In this study, we found that rhein could suppress the invasion and migration of SKOV3-PM4 cells with characteristics of directional highly lymphatic metastasis. Phorbol 12-myristate 13-acetate (PMA), which is a Rac1 activator, significantly enhanced the expression levels of MMP-2, -3, -9 and -19 proteins, whereas the results of rhein and Rac1 inhibitor NSC23766 were just the opposite. The inhibitory effects of rhein were associated with the upregulation of tissue inhibitors of metalloproteinase (TIMP)-1, TIMP-2 and NM23 H1. Subsequent mechanism studies revealed that rhein reduce the production of reactive oxygen species (ROS) and lower NADPH oxidase activity. Furthermore, rhein significantly inhibited JNK, AP-1 phosphorylation in the cells treated with PMA. The results obtained from the cells treated with NSC23766 alone or NSC23766 combined with rhein, were consistent with rhein treatment alone. Taken together, these results indicate that rhein may be a potential inhibitor of Rac1 and can inhibit the migration and invasion of SKOV3-PM4 cells through modulating matrix metalloproteinases and RAC1/ROS/MAPK/AP-1 signaling pathway-associated proteins. PMID- 28098863 TI - Effect and mechanism of resveratrol on drug resistance in human bladder cancer cells. AB - Multidrug resistance (MDR) is a significant barrier to the effective treatment of bladder cancer. In order to improve the management of bladder cancer, it is crucial to identify strategies that may reverse MDR. The effects of three herbal medicines, ginsenoside Rh2, (-)-epigallocatechin gallate (EGCG) and resveratrol (RES) on bladder cancer were determined. The effect of these three herbal medicines against the drug resistance in adriamycin (ADM)-resistant pumc-91 cells (pumc-91/ADM) was assessed using the Cell Counting Kit-8 cell proliferation assay system. Cell cycle distribution analysis was performed using flow cytometry following treatment with RES. The mRNA and protein expression levels of multidrug resistance protein 1 (MRP1), lung resistance protein (LRP), glutathione S transferase (GST), B cell leukemia/lymphoma-2 (BCL-2) and topoisomerase-II (Topo II) were evaluated using reverse transcription-quantitative polymerase chain reaction and immunofluorescence, respectively. RES enhanced the cytotoxicity of anticancer agents on pumc-91/ADM cells; however, Rh2 and EGCG were unable to induce a similar effect. Additionally, RES treatment led to S phase cell cycle arrest accompanied by a decrease in the number of cells in the G1 phase. A significant decrease of MRP1, LRP, GST, BCL-2 levels and an increase of Topo-II levels were observed in RES groups compared with the control group. RES effectively reversed ADM resistance in pumc-91/ADM cells and the underlying molecular mechanism may be associated with the alteration of MRP1, LRP, GST, BCL 2 and Topo-II expression levels. Therefore, RES may be a potential candidate for reversing drug resistance in bladder cancer chemotherapy. PMID- 28098864 TI - VICTOR: Vinflunine in advanced metastatic transitional cell carcinoma of the urothelium: A retrospective analysis of the use of vinflunine in multi-centre real life setting as second line chemotherapy through Free of Charge Programme for patients in the UK and Ireland. AB - There is no standard of care in the UK or Ireland for second-line chemotherapy for patients with advanced transitional cell carcinoma (TCCU). Vinflunine is approved for TCCU patients who have failed a platinum-based regimen, and is standard of care in Europe but is not routinely available in the UK. Data were collected retrospectively on patients who received vinfluine as a second-line treatment. The aims were to document the toxicity and efficacy in a real life setting. Data were collected on 49 patients from 9 sites across the UK and Ireland [median age, 64 (IQR, 57-70) years, 33 males]. All patients had advanced metastatic TCCU. Thirteen patients had bone or liver metastases, 4 patients had PS 2 and 11 patients had HB <10. Median vinflunine administration was 3.5 cycles (range 1-18). Most common grade 3-4 toxicities were constipation (4 patients) and fatigue (3 patients). Partial response rate was 29% (14 PR, 11 SD, 19 PD, 4 NE, 1 not available). Median OS was 9.1 (6.0, 12.7) months. Results are consistent with real life data from Europe. Toxicity is further reduced with prophylactic laxative and oral antibiotics. Vinflunine is an efficient and tolerable second line treatment in advanced TCCU. PMID- 28098865 TI - Endophytic fungi from mangrove inhibit lung cancer cell growth and angiogenesis in vitro. AB - The secondary metabolites of mangrove-derived endophytic fungi contain multiple substances with novel structures and biological activities. In the present study, three types of mangrove plants, namely Kandelia candel, Rhizophora stylosa and Rhizophoraceae from Zhanjiang region including the leaves, roots and stems were collected, and endophytic fungi were isolated, purified and identified from these mangrove plants. MTT assay was used to observe the effects of the isolated endophytic fungi on the growth of A549 and NCI-H460 lung cancer cells. The effect of the endophytic fungi on lung cancer angiogenesis in vitro induced by the HPV 16 E7 oncoprotein was observed. Our results showed that 28 strains of endophytic fungi were isolated, purified and identified from the three types of mangrove plants. Ten strains of endophytic fungi significantly suppressed the growth of A549 and NCI-H460 cells. The average inhibitory rates in the A549 cells were 64.4, 59.5, 81.9, 43.9, 58.3, 56.2, 48.3, 42.4, 93.0 and 49.7%, respectively. The average inhibitory rates in the NCI-H460 cells were 41.2, 49.3, 82.7, 40.7, 53.9, 52.6, 56.8, 64.3, 91.0 and 45.6%, respectively. Particularly, three strains of endophytic fungi markedly inhibited HPV-16 E7 oncoprotein-induced lung cancer angiogenesis in vitro. These findings contribute to the further screening of potential chemotherapeutic agents from mangrove-derived endophytic fungi. PMID- 28098867 TI - [Retracted] Nuclear import of prototype foamy virus transactivator Bel1 is mediated by KPNA1, KPNA6 and KPNA7. AB - We would like to retract the article entitled "Nuclear import of prototype foamy virus transactivator Bel1 is mediated by KPNA1, KPNA6 and KPNA7" published in International Journal of Molecular Medicine 38: 339-406, 2016. The results presented in Fig. 6 have been demonstrated to be unreproducible, and we cannot provide an explanation for this. Furthermore, we have recently identified that the cell cultures used in our experiments were partly contaminated with Mycoplasma, which could have contributed to the irreproducibility of the results. In addition, we are currently in dispute with a colleague who has contributed towards this study, but does not wish to be included as a named author on the paper. We are therefore going to retract this article. All the authors unanimously agree to the retraction of this paper, and we deeply apologize to readers and editors for any inconvenience caused by this retraction. [the original article was published in the International Journal of Molecular Medicine 38: 399-406, 2016; DOI: 10.3892/ijmm.2016.2635]. PMID- 28098866 TI - In vitro long-term treatment with MAPK inhibitors induces melanoma cells with resistance plasticity to inhibitors while retaining sensitivity to CD8 T cells. AB - The development of BRAF V600 and MEK inhibitors constitutes a breakthrough in the treatment of patients with BRAF-mutated metastatic melanoma. However, although there is an increase in overall survival, these patients generally confront recurrence, and several resistance mechanisms have already been described. In the present study we describe a different resistance mechanism. After several weeks of long-term in vitro treatment of two different V600E BRAF-mutated melanoma cell lines with MARK inhibitors, PLX4032 and/or GDC-0973, the majority of the cells died whereas some remained viable and quiescent (SUR). Markedly, discontinuing treatment of SUR cells with MAPK inhibitors allowed the population to regrow and these cells retained drug sensitivity equal to that of the parental cells. SUR cells had increased expression levels of CD271 and ABCB5 and presented senescence associated characteristics. Notably, SUR cells were efficiently lysed by cytotoxic T lymphocytes recognizing MART-1 and gp100 melanoma differentiation antigens. We propose quiescent plasticity as a mechanism of resistance to BRAF and MEK inhibitors while retaining sensitivity to immune effectors. PMID- 28098868 TI - MicroRNA-187 promotes growth and metastasis of gastric cancer by inhibiting FOXA2. AB - MicroRNAs (miRNAs) play an active role in the pathogenesis of gastric cancer. The expression and biological function for miR-187 in gastric cancer remains unknow. In the present study, we demonstrated that miR-187 expression was increased in gastric cancer (GC) tissues and cells. Increased expression level of miR-187 was associated with adverse clinical features including tumor size, lymph metastasis and TNM stage, and decreased overall survival and disease-free survival of GC patients. Functionally, overexpression miR-187 could promote while inhibition of miR-187 could suppress, the proliferation, migration and invasion of GC cells in vitro. In vivo experiments showed that overexpression of miR-187 promoted the growth and lung metastasis of SGC-7901 cells in nude mice. Mechanically, we confirmed that FOXA2 was the downstream target of miR-187 in GC cells using luciferase assay, qRT-PCR and western blot analysis. Moreover, overexpression of FOXA2 abrogated the promoting effects of miR-187 overexpression on SGC-7901 cell proliferation, migration and invasion, while inhibition of FOXA2 reversed the inhibitory effects of miR-187 downregulation on these biological functions of AGS cells, suggesting that FOXA2 was a functional mediator of miR-187 in GC. Therefore, this study indicates that miR-187 is potentially a biomarker and treatment target for GC patients. PMID- 28098869 TI - Core-shell lipid polymer nanoparticles for combined chemo and gene therapy of childhood head and neck cancers. AB - Pediatric head and neck cancers account for overall 12% of all pediatric cancers. Despite recent advances in therapeutic modalities, children with tumor metastasis have poor prognosis. Therefore, there is an unmet need for new and effective treatment modalities for pediatric head and neck cancers. The present study describes a simple and efficient method for fabrication of cationic lipid-polymer hybrid nanoparticles (CLPNs) for co-delivery of cisplatin (CDDP) and DNA (CDDP/DNA CLPNs) for the therapy of childhood head and neck cancers. CDDP/DNA CLPNs were prepared by the modified double emulsion solvent evaporation method with self-assembly. CDDP-loaded CLPNs (CDDP CLPNs), CDDP-loaded polymeric nanoparticles (PNPs) (CDDP PNPs), and DNA-loaded Lipofectamine(r) 2000 (DNA LIPO) were also prepared for comparison. The results illustrated that the concentration of the cationic lipid has influence on the characteristics of CLPNs. In vitro anticancer effect, in vitro transfection efficiency, in vivo antitumor and gene delivery efficacy of CDDP/DNA CLPNs have advantages over other formulations tested. In conclusion, outstanding delivery ability of CLPNs for both CDDP and DNA could combine the therapeutic efficiency of both drug and gene for the treatment of pediatric rhabdomyosarcoma (RMS). PMID- 28098870 TI - miR-148a increases the sensitivity to cisplatin by targeting Rab14 in renal cancer cells. AB - MicroRNA (miR) can exert various biological functions by targeting oncogenes or tumor suppressor genes in numerous human malignancies. Recent evidence has shown that miR-148a increases the drug sensitivity of various cancer cells. Herein, we show that ectopic expression of miR-148a induces apoptosis, reduces clonogenicity, and increases the sensitivity to TRAIL and cisplatin in renal cancer cells. The luciferase reporter assay showed that miR-148a negatively regulated ras-related protein 14 (Rab14) expression by binding to the miR-148a binding site in the 3' untranslated region (3'UTR) of Rab14. Rab14-specific siRNA induced downregulation of Rab14 increases the sensitivity to cisplatin, while forced expression of Rab14 lacking 3'-UTR abrogated the pro-apoptotic function of miR-148a in renal cancer cells. These findings suggest that miR-148a acts as a tumor suppressor and holds great potential for renal cancer therapy by directly targeting Rab14. PMID- 28098871 TI - Lectin PCL inhibits the Warburg effect of PC3 cells by combining with EGFR and inhibiting HK2. AB - Prostatic carcinoma is the most aggressive tumor in adult men. Warburg effect is an important characteristic of tumor cell metabolism including prostate cancer cells, in which hexokinase 2 (HK2), a major rate-limiting enzyme involved in Warburg effect, is selectively upregulated. The lectin PCL is a mannose binding lectin which induces tumor cell apoptosis and autophagy. In the present study, we report that PCL could lower glucose consumption and lactate production, shift the Warburg effect by inhibiting the expression of HK2 in PC3 cells and the suppression of HK2 by siRNA reversed the effect of PCL on glucose consumption and lactate production. The expression of HK2 is closely related to epidermal growth factor receptor (EGFR) and downstream signaling pathway activation, therefore, we investigated the interaction of PCL with EGFR by western blot analysis and found that PCL could suppress the binding of epidermal growth factor (EGF) with EGFR and HK2 expression. Also, we explored the binding mechanism between the PCL and EGFR through molecular docking and molecular dynamics simulations and found that PCL bocked the active site of EGFR which is also the binding site of the nature ligand EGF, the resulting conformation has higher stability than EGF in complex with EGFR. The results indicated that PCL could competitively bind to EGFR binding pocket and then prevent EGF from binding to EGFR, blocking the autophosphorylation of the EGFR tyrosine kinase, after that the EGFR activation is inhibited. Collectively, our studies concluded that PCL inhibits tumor cell glycolysis by combining with EGFR and reducing HK2 expression. PMID- 28098872 TI - TRIM29 promotes progression of thyroid carcinoma via activating P13K/AKT signaling pathway. AB - Thyroid cancer (TC) is a common malignancy of the endocrine system. Abnormal expression of tripartite motif-containing 29 (TRIM29) has been reported to promote tumorigenesis and predict poor prognosis in several human malignancies. The aim of this study was to assess the involvement of TRIM29 in the significance and prognosis of TC. Fifty-six tumor samples and their clinicopathological para meters were obtained from TC patients; the expression level of TRIM29 was detected by RT-qPCR and western blotting. TRIM29 expression was knocked down by small interfering RNA (siRNA) among TT, TPC-1, and K1 cells to investigate the biological role of TRIM29 in TC cells. The results showed that TRIM29 expression was significantly increased in TC tissue samples and cells compared to normal tissues and cells (P<0.01, respectively). Overexpression of TRIM29 was associated with TNM stage (P<0.01), extrathyroidal extension (P<0.01), lymph node metastasis (P<0.05), and distant metastasis (P<0.05). Furthermore, the overall survival and disease-free rates of patients with high TRIM29 expression were decreased significantly compared with those with low TRIM29 expression (P<0.01, respectively). Knockdown of TRIM29 obviously suppressed cell proliferation; enhanced chemosensitivity to cisplatin; inhibited cell invasion and migration; caused cell cycle arrest at G0/G1 phase by decreasing cyclin B1, cyclin D1 and CDK2, while increasing p21 and p27; and induced cell apoptosis by enhancing the activities of caspase-3, caspase-9, and Bax, while decreased Bcl-2. Notably, decreased TRIM29 expression significantly inhibited the activation of P13K/AKT signaling pathway as well. Taken together, our findings suggested that TRIM29 played a crucial role in the progression and malignancy of TC, and silencing of TRIM29 exerted its antitumor effect by blocking P13K/AKT signaling pathway. Thus, TRIM29 might be a potential therapeutic target for the treatment of TC. PMID- 28098873 TI - TRIM37 promotes epithelial-mesenchymal transition in colorectal cancer. AB - There is substantial research on the oncogenic role of tripartite motif containing 37 (TRIM37); however, its importance in colorectal cancer (CRC) remains to be elucidated. The present study used reverse transcription quantitative polymerase chain reaction, immunohistochemistry and western blotting to detect the expression level of TRIM37 in CRC. The importance of TRIM37 in cell proliferation, invasion and metastasis of CRC were investigated through overexpressing or knocking-down of TRIM37 in CRC cell lines, to observe its function. The present study revealed that TRIM37 was overexpressed in human CRC tissues. High TRIM37 expression resulted in increased CRC proliferation, migration and invasion. Mechanistically, it was confirmed that TRIM37 enhanced invasion and metastasis of CRC via the epithelial-mesenchymal transition pathway. In conclusion, the present study suggested that TRIM3 may contribute to CRC and act as a potential therapeutic target for CRC treatment. PMID- 28098874 TI - MICA/IL-12: A novel bifunctional protein for killer cell activation. AB - Natural killer (NK) cells have the potential to be effective killers of tumor cells. They are governed by inhibitory and activating receptors such as NKG2D, whose ligands are normally upregulated in cells that are stressed, like cancer cells. Advanced cancer cells, however, have ways to reduce the expression of these ligands, leaving them less detectable by NK cells. Along with these receptors, NK cells also require activating cytokines, such as IL-12. A previous study in our laboratory showed that a fusion protein of the extracellular domain of mouse UL-16 binding protein-like transcript 1 (MULT1E) and mouse interleukin 12 (IL-12) can effectively activate mouse NK cells by in vitro assays and in vivo in animal tumor models. The aim of the present study was to expand the concept of developing a novel bifunctional fusion protein for enhanced NK cell activation to human killer cells. The proposed protein combines the extracellular domain of a human NKG2D ligand, MHC class I polypeptide-related sequence A (MICA) and IL-12. It is hypothesized that when expressed by tumor cells, the protein will activate human NK and other killer cells using the NKG2D receptor, and deliver IL-12 to the NK cells where it can interact with the IL-12R and enhance cytotoxicity. The fusion protein, when expressed by engineered tumor cells, indeed activated NK92 cells as measured by an increase in interferon-gamma (IFN-gamma) production and an increase in cytotoxicity of tumor cells. The fusion protein was also able to increase the proliferation of human peripheral blood mononuclear cells (PBMCs) and augment their production of IFN-gamma. This study along with the data from the previous mouse studies suggest that the MICA/IL-12 bifunctional fusion protein represents an effective activator of killer cells for cancer treatment. PMID- 28098875 TI - Exposure to TNF-alpha combined with TGF-beta induces carcinogenesis in vitro via NF-kappaB/Twist axis. AB - Persistent human papilloma virus (HPV) infection induces chronic inflammation resulting in human cervical cancer. However, the mechanisms underlying carcinogenesis via chronic inflammation remain largely unclear. We investigated the role of pro-inflammatory factors in epithelial-mesenchymal transition (EMT) and cancer stem cell-like (CSCL) characteristics of HeLa cells exposed to TNF alpha with or without TGF-beta. We then determined the role of NF-kappaB/Twist signal axis in the pathogenesis of cervical cancer. We found that HeLa cells exposed to TNF-alpha following chronic treatment with TGF-beta exhibited EMT, self-renewal and high mobility. Knockdown of NF-kappaBp65 inhibited NF-kappaB and Twist1 expression, and EMT and CSCL properties of HeLa cells following co treatment with TNF-alpha and TGF-beta. Conversely, overexpression of NF-kappaBp65 potentiated the above effects. However, knockdown or overexpression of Twist1 had no effect on NF-kappaBp65 expression, but inhibited or promoted EMT and CSCL features. Notably, overexpression of Twist1 rescued NF-kappaBp65 knockdown. Our results demonstrate the role of NF-kappaB/Twist signaling axis in which HeLa cells treated with TNF-alpha following chronic exposure to TGF-beta induce EMT and CSCL properties. The NF-kappaB/Twist signal axis may represent an effective therapeutic target in cervical cancer. PMID- 28098876 TI - BDNF regulates the expression and secretion of VEGF from osteoblasts via the TrkB/ERK1/2 signaling pathway during fracture healing. AB - Brain-derived neurotrophic factor (BDNF), a member of the neurotropic family, is expressed in osteoblast-like cells of a fracture callus, however, its role in fracture healing remains to be fully elucidated. Osteoblasts isolated from Sprague Dawley rats were stimulated by BDNF in a dose- and time-dependent manner. Immunoblotting and immunofluorescence was used to detect the expression and distribution of targeted proteins. The concentration of vascular endothelial growth factor (VEGF) released in medium was determined using an ELISA. PD98059 and K252a were used to investigate the signaling pathways that may be involved. The present study demonstrated that BDNF was involved in fracture repair by controlling the expression and secretion of VEGF from osteoblasts, which predominantly drives angiogenesis during fracture healing. Tropomyosin-related kinase B (TrkB), the specific receptor of BDNF, was shown to be expressed at high levels in the osteoblasts. Following BDNF stimulation, TrkB and extracellular signal-regulated kinase 1/2 (ERK1/2) were rapidly activated. The inhibition of TrkB by K252a decreased the expression and secretion of VEGF, and suppressed the phosphorylation level of ERK1/2. PD98059, an antagonist of ERK1/2, elicited the same effects on VEGF from the BDNF-stimulated osteoblasts, however, it did not affect the phosphorylation of TrkB. In conclusion, during fracture healing, BDNF was found to stimulate the expression and secretion of VEGF from osteoblasts via the TrkB/ERK1/2 signaling pathway. PMID- 28098877 TI - Differentiation of osteoblast-like cells and ectopic bone formation induced by bone marrow stem cells transfected with chitosan nanoparticles containing plasmid BMP2 sequences. AB - The present study investigated the efficiency of the use of chitosan nanoparticles containing plasmid-bone morphogenetic protein 2 (pBMP2) sequences (CNPBs) to induce the differentiation of bone marrow stem cells (BMSCs) into osteoblast-like cells that may be able to promote ectopic bone formation. pBMP2s were constructed, and chitosan nanoparticles were incubated with 50, 100 or 200 ug/ml pBMP2. BMSCs were collected from the tibiae and femurs of 6-week old rats, cultured and treated with the CNPBs or 200 ug/ml pBMP2 as a positive control. Transfection efficiency was confirmed using the green fluorescent protein assay. Histological staining methods, including alkaline phosphatase, Wright's and von Kasso staining, were used to identify features of osteoblast-like cells differentiated from BMSCs. Expression levels of the markers of osteoblasts, such as alkaline phosphatase, osteoprotegerin, osteocalcin and osteopontin, were determined to verify the differentiation of BMSCs into osteoblast-like cells. Ectopic bone formation was observed following the integration of polyglycolic acid (PGA) scaffolds with CNPBs and BMSCs, which were implanted into the dorsal muscles of Sprague-Dawley rats. Exposure to CNPBs led to the transfection of BMSCs with BMP2. The transfected BMSCs possessed the characteristic phenotypes of osteoblasts. The expression levels of alkaline phosphatase, osteoprotegerin, osteocalcin and osteopontin were significantly higher in the transfected cells compared with the control group, particularly the CBP200 group. PGA scaffolds integrated with BMSCs and CNPBs induced ectopic bone formation, as changes in the morphology of cells were observed using histological staining. Therefore, CNPBs may be a promising method of promoting the formation of novel bone tissue. PMID- 28098878 TI - Early growth response 3 inhibits growth of hepatocellular carcinoma cells via upregulation of Fas ligand. AB - Hepatocellular carcinoma (HCC) is a prevalent malignancy with aggressive biological behavior and poor prognosis. Early growth response 3 (EGR3) is a zinc finger transcription factor, and has been studied primarily in the context of neurodevelopment, autoimmunity, inflammation and angiogenesis. Accumulating evidence indicates that EGR3 is a novel suppressor gene of tumor initiation and progression in certain cancer events, but little work has been carried out in exploring the relationship between EGR3 and HCC growth. The purpose of this study was to investigate the possible effects of EGR3 on cell proliferation and apoptosis in HCC, and determine the underlying mechanisms. Here, we observed that EGR3 expression was frequently downregulated in HCC tissues and cell lines. Ectopic expression of EGR3 contributed to cell proliferation inhibition and apoptosis induction in HCC cells in vitro. Furthermore, the expression of Fas ligand (FasL) was significantly enhanced following upregulation of EGR3 in HCC cells, accompanied by an obvious increase of pro-apoptotic Bak and cell cycle inhibitor p21 expression. Based on nude mouse models, we demonstrated that ectopic expression of EGR3 markedly restricted tumor growth, and the expression of FasL was significantly increased in the xenograft tumor tissues which exhibited high EGR3 expression. We further established a co-transfection in HCC cells with EGR3 overexpression plasmid and FasL siRNA. We found that silencing of FasL gene impeded the anti-proliferative and pro-apoptotic effects, as well as the increase of Bak and p21 expression, suggesting an essential role of FasL in EGR3-mediated growth suppression in HCC cells. Collectively, in conclusion, EGR3 contributes to cell growth inhibition via upregulation of FasL in HCC. PMID- 28098879 TI - Cytokines, inducers and inhibitors modulate MMP-2 and MMP-9 secretion by human Fanconi anemia immortalized fibroblasts. AB - Acute myeloid leukemia and head and neck squamous cell carcinomas are the major causes of mortality and morbidity in Fanconi anemia (FA) patients. Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, have been implicated in tumor invasion and metastasis. Various cytokines, mitogens, growth factors, inducers and inhibitors control MMP activities. We investigated the roles of these in the regulation of MMP-2 and MMP-9 in human immortalized fibroblasts from FA. Human FA immortalized fibroblast cell lines FA-A:PD220 and FA-D2:PD20 were grown in minimum essential medium (MEM) supplemented with 15% fetal bovine serum (FBS) and antibiotics in 24-well tissue culture plates. At near confluence, the cells were washed with phosphate-buffered saline (PBS) and incubated in serum free media with the following: phorbol 12-myristate 13-acetate (PMA) at 10-100 ng/ml; tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) at 0.1-25 ng/ml; lipopolysaccharide (LPS) at 10-100 ug/ml; epigallocatechin gallate (EGCG) and doxycycline (Dox) at 10-100 uM without and with PMA; a nutrient mixture (NM) without and with PMA at 10-1,000 ug/ml; actinomycin-D and cyclohexamide at 2 and 4 uM; retinoic acid and dexamethasone at 50 uM. After 24 h, media were removed and analyzed for MMP-2 and MMP-9 by zymography. Both FA cell lines expressed only MMP-2 and responded similarly to cytokines, mitogens, inducers and inhibitors. PMA potently stimulated MMP-9 and had a moderate effect on MMP-2. TNF-alpha showed variable effects on MMP-2 and significantly enhanced MMP-9. IL-1beta enhanced MMP-2 slightly and MMP-9 significantly. LPS had a moderate stimulatory effect on MMP-2 and no effect on MMP-9. EGCG, Dox and NM, without and with PMA, downregulated MMP-2 and MMP-9 expression. Actinomycin-D, retinoic acid and dexamethasone also had inhibitory effects on MMP-2. Our results showed that cytokines, mitogens and inhibitors modulated FA fibroblast MMP-2 and MMP-9 expression, suggesting the clinical use of MMP inhibitors, particularly such potent and non-toxic ones as the NM and its component EGCG in the management of FA cancers. PMID- 28098881 TI - Overexpression of GRP75 inhibits inflammation in a rat model of intracerebral hemorrhage. AB - Glucose-regulated protein 75 (GRP75) is a member of the heat shock protein 70 family and previous studies have demonstrated that GRP75 is involved in diseases of the central nervous system. However, the biological function of GRP75 in intracerebral hemorrhage (ICH) remains to be clarified. Thus, the aim of the present study was to evaluate the effects of GRP75 in a rat model of ICH. Western blotting was used to detect the protein expression of GRP75, active caspase-3, Bax, Bcl-2, p-Akt and Akt in brain tissues following ICH. The levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1beta were evaluated using ELISA assay. Expression of GRP75 mRNA and protein was demonstrated to be reduced in the brain tissues of rats with ICH compared with sham-operated rats. In addition, overexpression of GRP75 in brain tissues with ICH significantly inhibited the production of the inflammatory cytokines TNF-alpha and IL-1beta and increased Bcl-2/decreased Bax levels compared with ICH alone. Furthermore, overexpression of GRP75 in brain tissues with ICH resulted in significantly increased phosphorylation of Akt compared with ICH alone. Therefore, the present study demonstrated, for the first time to the best of our knowledge, significantly reduced GRP75 expression in brain tissues following ICH, and that overexpression of GRP75 inhibits inflammation and potentially inhibits neuronal apoptosis in a rat model of ICH. GRP75 may, therefore, represent a promising target in the treatment of ICH. PMID- 28098880 TI - The role of gap junctions in inflammatory and neoplastic disorders (Review). AB - Gap junctions are intercellular channels made of connexin proteins, mediating both electrical and biochemical signals between cells. The ability of gap junction proteins to regulate immune responses, cell proliferation, migration, apoptosis and carcinogenesis makes them attractive therapeutic targets for treating inflammatory and neoplastic disorders in different organ systems. Alterations in gap junction profile and expression levels are observed in hyperproliferative skin disorders, lymphatic vessel diseases, inflammatory lung diseases, liver injury and neoplastic disorders. It is now recognized that the therapeutic effects mediated by traditional pharmacological agents are dependent upon gap junction communication and may even act by influencing gap junction expression or function. Novel strategies for modulating the function or expression of connexins, such as the use of synthetic mimetic peptides and siRNA technology are considered. PMID- 28098882 TI - Downregulation of microRNA-34b is responsible for the elevation of blood pressure in spontaneously hypertensive rats. AB - The present study aimed to identify the microRNA (miRNA) responsible for the development of primary hypertension, and examine the downstream signaling pathway, which mediates the effect of the miRNA. Reverse transcription quantitative polymerase chain reaction analysis was performed to identify which miRNA may be involved in the pathogenesis of hypertension. In silico analysis and a luciferase assay were used to validate the target of the selected miRNA, and miRNA mimics and small interfering (si)RNA of the target were transfected into smooth muscle cells to examine its effect on the biological activity of the cells. miR-34b was found to be upregulated in spontaneously hypertensive rats (SHRs), compared with Wistar Kyoto (WKY) rats. Therefore, the present study used online miRNA target prediction tools to predict the candidate target genes of miR 34b in the database, and consequently identified cyclin G1 (CCNG1) and cyclin dependent kinase 6 (CDK6) as its possible target genes. CDK6 subsequently identified to be the direct target gene of miR-34b using a luciferase reporter assay in vascular smooth muscle cells (VSMCs). The present study also established the possible negative regulatory association between miR-34b and CDK6 via investigating the mRNA and protein expression levels of CDK6 and CCNG1 in VSMCs collected from the SHRs and WKY rats, respectively. To investigate the signaling pathways between miR-34b and CDK6, the mRNA and protein expression levels of CDK6, and the proliferation rates were compared in VSMCs transfected with CDK6 siRNA or miR-34b mimics, the results of which indicated that the miR-34b mimics exerted the same effects on the expression of CDK6 and cell proliferation as CDK6 siRNA. The negative regulatory association between miR-34b and its target, CDK6, was confirmed, which may offer potential as a novel therapeutic target in the treatment of hypertension. PMID- 28098883 TI - Developmental expression of Toll-like receptors in the guinea pig lung. AB - The guinea pig is a useful model for investigating infectious and non-infectious lung diseases due to the sensitivity of its respiratory system and susceptibility to infectious agents. Toll-like receptors (TLRs) are important components of the innate immune response and are critical for lung immune function. In the present study, the differentiation of epithelial cells in the guinea pig lung was examined during gestation by studying anatomic morphology and the major epithelial cell types using cell type-specific markers. The developmental expression of all 9 TLRs and the TLR signaling adaptors myeloid differentiation factor 88 (MyD88) and tumor necrosis factor receptor associated factor 6 (TRAF-6) were investigated by reverse transcription-quantitative polymerase chain reaction and western blotting analysis. The formation of lung lobes in guinea pigs was observed at 45 days of gestation (dGA), along with the expression of the basal cell marker keratin 14 and the alveolar type II cell marker pro-surfactant protein. However, the cube cell marker secretoglobin family1A member 1 and ciliated cell marker b-tubulin IV were only detected in the lungs from 52 dGA onward. The expression levels of all TLRs, MyD88 and TRAF-6 were determined in lung tissues harvested from embryos, newborn, postnatal and adult animals. The expression levels of all TLR signaling components displayed similar dynamic expression patterns with gestation age and postnatal maturation time, except for TLR-4 and TLR-7. mRNA expression levels of TLR components were significantly increased in the lungs at 45 and 52 dGA, compared with later developmental stages. These results suggest that TLR expression in the guinea pig lung is developmentally regulated, enhancing the understanding of lung biology in guinea pig models. PMID- 28098885 TI - Carboxamide analog ITR-284 evokes apoptosis and inhibits migration ability in human lung adenocarcinoma A549 cells. AB - Lung adenocarcinoma is the most common type of lung cancer and found in both smokers and non-smokers, but the treatment of lung cancer is limited. ITR-284 has been shown to be a potent carboxamide-derived anticancer agent and to induce apoptosis in leukemia and colon cancer cells. However, little is known whether ITR-284 has anticancer activity in human lung adenocarcinoma cells through induction of apoptosis and suppression of migration in vitro. We showed that ITR 284 inhibited human lung cancer A549 cells using the thiazolyl blue tetrazolium bromide (MTT) assay and evoked apoptosis via the cell cycle distribution at S phase arrest. After treatment with 20 nM ITR-284 for 24 h, apoptotic cells were induced and detected by Annexin V-FITC/PI staining. The production of reactive oxygen species (ROS) was dose-dependently increased in A549 cells caused by ITR 284. The results from immunoblotting analysis showed an elevation of protein levels of p53 and phosphorylation of p53 in A549 cells prior to ITR-284 exposure. Additionally, apoptosis-associated proteins such as Bax, cleaved caspase-3 and cleaved PARP were upregulated after ITR-284 treatment. By wound healing assay, low concentrations (1-5 nM) of ITR-284 exerted a greater effect on inhibition of A549 cell migration. The protein levels of E-cadherin and vimentin, which are the epithelial-mesenchymal transition (EMT) markers, were modulated in ITR-284 treated cells assessed by western blot analysis. Taken together, our data suggest that ITR-284 may be an effective anticancer agent for treating lung adenocarcinoma. PMID- 28098884 TI - Renin-angiotensin system activation accelerates atherosclerosis in experimental renal failure by promoting endoplasmic reticulum stress-related inflammation. AB - In this study, we investigated the association between the renin-angiotensin system (RAS), endoplasmic reticulum (ER) stress and atherosclerosis (AS) in uremic apolipoprotein E knockout (apoE-/-) mice. Mild uremia was induced by a 5/6 nephrectomy (5/6 Nx) in 10-week-old apoE-/- mice. Four weeks after nephrectomy, the mice received losartan or no treatment for 16 weeks. Sham-operated mice served as the controls. We found that uremia accelerated AS at the aortic root. The activation of ER stress and the significant upregulation of pro-inflammatory cytokines and chemokines were observed in the uremic mice. Phosphorylated inositol-requiring 1alpha (p-IRE1alpha), an ER stress marker protein, was mainly expressed in macrophages in the atherosclerotic lesions. Treatment with losartan significantly attenuated aortic AS, inhibited ER stress and reduced aortic inflammation. In in vitro experiments, angiotensin II (Ang II) increased the levels of the common ER stress maker, glucose-regulated protein 78 (GRP78) and the phosphorylation of IRE1alpha in RAW264.7 macrophages. Treatment with losartan inhibited the activation of ER stress and the upregulation of GRP78, and enhanced the expression of nuclear factor-kappaB (NF-kappaB) inhibitor (IkappaB) in Ang II stimulated RAW264.7 macrophages. IRE1alpha-siRNA suppressed inflammation and downregulated IkappaB expression and IkappaB kinase (IKK) phosphorylation, which inhibited IkappaB degradation and NF-kappaB p65 nuclear translocation in Ang II treated RAW264.7 macrophages. These findings suggest that RAS activation accelerates AS by promoting ER stress-related inflammation in uremic mice. PMID- 28098886 TI - Novel zinc phthalocyanine as a promising photosensitizer for photodynamic treatment of esophageal cancer. AB - Photodynamic therapy (PDT) has gathered much attention in the field of cancer treatment and is increasingly used as an alternative solution for esophageal cancer therapy. However, there is a constant need for improving the effectiveness and tolerability of the applied photosensitizers (PS). Here, we propose tetra triethyleneoxysulfonyl substituted zinc phthalocyanine (ZnPc) as a promising PS for photodynamic treatment of esophageal cancer. ZnPc-induced phototoxicity was studied in two human esophageal cancer cell lines: OE-33 (adenocarcinoma) and Kyse-140 (squamous cell carcinoma). In vitro studies focused on the uptake and intracellular distribution of the novel ZnPc as well as on its growth inhibitory potential, reactive oxygen species (ROS) formation and the induction of apoptosis. The chicken chorioallantoic membrane assay (CAM assay) and studies on native Wistar rats were employed to determine the antineoplastic and antiangiogenic activity of ZnPc-PDT as well as the tolerability and safety of non photoactivated ZnPc in vivo. ZnPc was taken up by cancer cells in a dose- and time-dependent manner and showed a homogeneous cytoplasmic distribution. Photoactivation of ZnPc-loaded (1-10 uM) cells led to a dose-dependent growth inhibition of esophageal adenocarcinoma and squamous cell carcinoma cells of >90%. The antiproliferative effect was based on ROS-induced cytotoxicity and the induction of mitochondria-driven apoptosis. In vivo studies on esophageal tumor plaques grown on the CAM revealed pronounced antiangiogenic and antineoplastic effects. ZnPc-PDT caused long-lasting changes in the vascular architecture and a marked reduction of tumor feeding blood vessels. Animal studies confirmed the good tolerability and systemic safety of ZnPc, as no changes in immunological, behavioral and organic parameters could be detected upon treatment with the non photoactivated ZnPc. Our findings show the extraordinary photoactive potential of the novel ZnPc as a photosensitizer for PDT of esophageal cancer. PMID- 28098887 TI - miRNA-375 regulates the cell survival and apoptosis of human non-small cell carcinoma by targeting HER2. AB - micro (mi)-RNAs are a class of small non-coding RNAs that regulate gene expression by binding to the 3'-untranslated region of mRNA, which may lead to mRNA degradation or transcription regulation. Previous studies indicated that miRNAs are important for the pathogenesis of human cancer. miR-375 has been implicated in various tumor types; however, the biological activity in human non small cell lung carcinoma (NSCLC) cells remains to be fully elucidated. The purpose of the present study was to investigate the biological importance of miR 375 in human NSCLC cells. The expression of miRNAs and mRNA was determined using reverse transcription-quantitative polymerase chain reaction. Cell proliferation was analyzed using a Cell Counting kit-8 assay. Cell apoptosis was analyzed using a fluorescence-activated cell sorting assay. The migration and invasion abilities of cells were evaluated using an in vivo mouse model. Dual-luciferase assay and western blotting were used to determine the potential target of miR-375. The results indicated that the expression of miR-375 in human NSCLC cells was significantly downregulated and induction of miR-375 may inhibit the proliferation of human NSCLC cells by inducing apoptosis. An animal model was used to determine that the upregulation of miR-375 inhibited the migration and invasion of A549 human NSCLC cells in vivo. It was also determined that human epidermal growth factor receptor 2 (HER-2) was a direct target gene of miR-375 and induction of miR-375 may reduce the expression of HER-2 in human NSCLC cells. These findings suggested that miR-375 may act as a potential therapeutic target for human NSCLC cancer in the future. PMID- 28098888 TI - hCLOCK induction by hypoxia promotes inflammatory responses by activating the NF kappaB pathway. AB - The expression and secretion of infla-mmation-associated cytokines are induced by hypoxia. Circadian locomotor output cycles protein kaput (CLOCK) has previously been shown to activate the nuclear factor-kappaB (NF-kappaB) pathway, which is a key transcription factor during hypoxia. The present study evaluated the role of the NF-kappaB pathway in the CLOCK-induced inflammatory response. Under hypoxic conditions, the expression levels of NF-kappaB and proinflammatory cytokines, including interleukin (IL)-1, IL-1beta, IL-6, intercellular adhesion molecule 1, cyclooxygenase 2 and tumor necrosis factor alpha, were significantly increased compared with under control conditions. Conversely, human umbilical vein endothelial cells (HUVECs) that were transfected with small hairpin RNA against human CLOCK exhibited reversed effects. Furthermore, inhibition of NF-kappaB with pyrrolidine dithiocarbamate (PDTC) reduced the expression of proinflammatory cytokines in HUVECs treated under hypoxic conditions. In addition, the CLOCK induced inflammatory response was abolished with PDTC treatment. These findings suggest that the mechanism by which CLOCK induces inflammation mainly involves activation of the NF-kappaB signaling pathway. PMID- 28098889 TI - IsomiR expression patterns in canonical and Dicer-independent microRNAs. AB - Multiple microRNA (miRNA) variants, known as isomiRs, are extensively distributed in miRNA loci and predominantly derive from the alternative cleavage of Drosha/Dicer and 3'addition events. The present study aimed to investigate the expression patterns of multiple isomiRs in typical miRNA and Dicer-independent miRNA loci by conducting evolutionary and expression analysis using public datasets. Although different miRNA maturation processes exist, multiple isomiRs can be detected by similar expression distributions. However, isomiR expression in Dicer-independent miRNA loci tends to be at a moderate level, particularly for random distribution in the ends that are split by Dicer in the typical miRNA loci. Compared with the mature miRNA locus (dominant miRNA locus), the non dominant miRNA locus indicates an expression distribution similar to that of the Dicer-independent miRNA locus. These results increase the understanding of multiple isomiRs in the progression of diseases. PMID- 28098890 TI - Characterization of the microRNA profile in early-stage cervical squamous cell carcinoma by next-generation sequencing. AB - Squamous cell carcinoma (SCC) is histologically the most prominent type of cervical cancer. There is accumulating evidence suggesting that microRNAs (miRNAs) play important regulatory roles in the biological processes of cervical squamous cell carcinoma (CSCC). Deciphering the miRNA regulatory network in CSCC could deepen our understanding at the molecular level of CSCC initiation and progression. In the present study, we performed next-generation sequencing (NGS) to profile miRNA expression in 3 pairs of early-stage CSCC samples. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to verify primary findings in another 20 pairs of CSCC samples. We identified 37 known miRNAs that exhibited significant alterations in expression (2-fold change or greater), among which 8 miRNAs were upregulated and 29 miRNAs were downregulated. Nine of these miRNAs were selected for further qRT-PCR validation. A novel miRNA candidate was also reported for the first time in the present study to be upregulated. The Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that its target genes were involved in MAPK, calcium and adherent junction signaling pathways. The present study systematically characterized the miRNA expression variation in early-stage CSCC and provides novel biomarkers for diagnosis and treatment as well as an opportunity for further investigation of the molecular mechanisms underlying the pathogenesis and development of CSCC. PMID- 28098891 TI - NHE1 is upregulated in gastric cancer and regulates gastric cancer cell proliferation, migration and invasion. AB - Na+/H+ exchanger isoform 1 (NHE1) is known to play a key role in regulating intracellular pH and osmotic homeostasis and is involved in the development and progression of several types of cancer. However, the function and specific mechanism of NHE1 in gastric cancer (GC) are not clearly understood. In the present study, we report that NHE1 is overexpressed in tissues and cell lines from GC patients, and knockdown or inhibition of NHE1 suppressed GC cell proliferation via regulation of G1/S and G2/M cell cycle phase transitions, concomitant with a marked decrease in positive cell cycle regulators, including cyclin D1 and cyclin B1. Likewise, NHE1 was required for GC cell migration and invasion through the regulation of epithelial-mesenchymal transition (EMT) proteins, and NHE1 inhibition resulted in an acidic intracellular environment, providing possible mechanisms underlying NHE1-mediated GC progression both in vitro and in vivo. These data highlight the important role of NHE1 in GC progression and suggest that NHE1 may be a useful target for GC therapy. PMID- 28098892 TI - Metabolomics study on primary dysmenorrhea patients during the luteal regression stage based on ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. AB - Primary dysmenorrhea (PD) is a common gynecological disorder which, while not life-threatening, severely affects the quality of life of women. Most patients with PD suffer ovarian hormone imbalances caused by uterine contraction, which results in dysmenorrhea. PD patients may also suffer from increases in estrogen levels caused by increased levels of prostaglandin synthesis and release during luteal regression and early menstruation. Although PD pathogenesis has been previously reported on, these studies only examined the menstrual period and neglected the importance of the luteal regression stage. Therefore, the present study used urine metabolomics to examine changes in endogenous substances and detect urine biomarkers for PD during luteal regression. Ultra performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry was used to create metabolomic profiles for 36 patients with PD and 27 healthy controls. Principal component analysis and partial least squares discriminate analysis were used to investigate the metabolic alterations associated with PD. Ten biomarkers for PD were identified, including ornithine, dihydrocortisol, histidine, citrulline, sphinganine, phytosphingosine, progesterone, 17-hydroxyprogesterone, androstenedione, and 15-keto-prostaglandin F2alpha. The specificity and sensitivity of these biomarkers was assessed based on the area under the curve of receiver operator characteristic curves, which can be used to distinguish patients with PD from healthy controls. These results provide novel targets for the treatment of PD. PMID- 28098894 TI - 17beta-Estradiol treatment drives Sp1 to upregulate MALAT-1 expression and epigenetically affects physiological processes in U2OS cells. AB - Osteosarcoma is the most common primary bone tumor characterized by high risk of metastasis, thus presents with an overall survival rate of 60%, despite the use of chemotherapy and surgery. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) has been reported to upregulated and epigenetically regulate the metastasis in osteosarcoma; however, the regulatory mechanisms of MALAT-1 expression remain unclear. In the current study, significant upregulation of MALAT-1 was observed subsequent to exposure to low concentrations of 17beta estradiol (E2) in U2OS cells. Using chromatin immunoprecipitation assays, E2 activated estrogen receptor alpha (ERalpha) was identified to promote the binding of specificity protein 1 (Sp1) to the MALAT-1 promoter. Electrophoretic mobility shift assay and immunoprecipitation results demonstrate that ERalpha binds indirectly to the MALAT-1 promoter by binding directly to Sp1 protein. Notably, without E2 stimulation, overexpressed ERalpha results in no significant promotion of the Sp1/MALAT-1 promoter, indicating that the translocation of ERalpha to nuclei stimulated by E2 is necessary. The immunofluorescence assay confirmed that E2 stimulation promotes the translocation of Sp1 to the nuclei in an ERalpha dependent manner. Subsequently, the effects of E2 on osteosarcoma physiological processes were further analyzed. Consistently, E2 treatment was observed to promote proliferation, colony formation, migration and invasion in U2OS cells. Taken together, the results indicate a role for E2 in regulating the physiological processes of osteosarcoma cells by regulating MALAT-1 expression levels. PMID- 28098893 TI - Systematic analysis of microarray datasets to identify Parkinson's disease associated pathways and genes. AB - In order to investigate commonly disturbed genes and pathways in various brain regions of patients with Parkinson's disease (PD), microarray datasets from previous studies were collected and systematically analyzed. Different normalization methods were applied to microarray datasets from different platforms. A strategy combining gene co-expression networks and clinical information was adopted, using weighted gene co-expression network analysis (WGCNA) to screen for commonly disturbed genes in different brain regions of patients with PD. Functional enrichment analysis of commonly disturbed genes was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Co-pathway relationships were identified with Pearson's correlation coefficient tests and a hypergeometric distribution-based test. Common genes in pathway pairs were selected out and regarded as risk genes. A total of 17 microarray datasets from 7 platforms were retained for further analysis. Five gene coexpression modules were identified, containing 9,745, 736, 233, 101 and 93 genes, respectively. One module was significantly correlated with PD samples and thus the 736 genes it contained were considered to be candidate PD associated genes. Functional enrichment analysis demonstrated that these genes were implicated in oxidative phosphorylation and PD. A total of 44 pathway pairs and 52 risk genes were revealed, and a risk gene pathway relationship network was constructed. Eight modules were identified and were revealed to be associated with PD, cancers and metabolism. A number of disturbed pathways and risk genes were unveiled in PD, and these findings may help advance understanding of PD pathogenesis. PMID- 28098895 TI - MicroRNA-133b is regulated by TAp63 while no gene mutation is present in colorectal cancer. AB - Downregulation of miR-133b has been reported in multiple types of malignancies including colorectal cancer (CRC). We previously confirmed that TAp63 actively translates microRNA-133b (miR-133b) transcripts. While the presence of miRNA mutations have frequently been described in CRC, most CRCs do not show any variation in the miR-133b coding sequence. Therefore, it is important to elucidate the relationship between TAp63 and miR-133b, and identify other mediators of miR-133b downregulation in CRC. The expression of TAp63 was detected by RT-qPCR, western blotting, immunohistochemistry (IHC) and densitometric analysis using Image-Pro Plus 6.0 software in 38 CRC and corresponding non cancerous tissues (NCTs). The expression of mature miR-133b was determined by RT qPCR, in situ hybridization (ISH) and densitometric analysis using Image-Pro Plus 6.0 software. The DNA from 38 CRC tissues and NCTs were screened for miR-133b mutations through sequence analysis. Compared with the NCTs, TAp63 mRNA expression was significantly lower in 21 (55.27%) tumor tissues. Compared with the NCTs, the miR-133b expression level was significantly lower in 31 (81.58%) tumor tissues. The expression of miR-133b was found to be positively correlated with TAp63. Loss of TAp63 and miR-133b was associated with an increased likelihood of metastatic events. The area under the ROC curve (AUC) of TAp63 for CRC was 0.623 [95% confidence interval (CI), 0.497-0.748; P=0.046], with 73.7% sensitivity and 50% specificity, respectively. The AUC of miR-133b for CRC was 0.857 (95% CI, 0.774-0.940; P<0.0001), with 78.9% sensitivity and 81.6% specificity, respectively. The combined AUC of TAp63 and miR-133b for CRC was 0.881 (95% CI, 0.805-0.956; P<0.0001), with 89.5% sensitivity and 71.1% specificity, respectively. Point mutations within the seed region of miR-133b were found in 1 patient, but the point mutation did not impact the secondary structure of the pre-miR-133b. Therefore, downregulation of TAp63 may be one reason for the dysregulation of miR-133b in CRC. The expression analysis of TAp63 and miR-133b revealed that they may be used as valuable prognostic biomarkers for CRC. PMID- 28098896 TI - MicroRNA-194 represses glioma cell epithelial-to-mesenchymal transition by targeting Bmi1. AB - MicroRNA-194 (miR-194) is frequently dysregulated in many types of cancer. However, the function of miR-194 in glioma remains unknown. In the present study, we aimed to investigate the biological functions of miR-194 in glioma and the potential molecular mechanism of miR-194 involved in glioma progression. We found that miR-194 expression was significantly reduced in glioma specimens and cell lines, as detected by real-time quantitative polymerase chain reaction (RT-qPCR) analysis. The overexpression of miR-194 inhibited while the suppression of miR 194 promoted cell migration, invasion and epithelial mesenchymal transition (EMT) in glioma cells. Bioinformatics analysis showed that the B cell-specific moloney murine leukemia virus insertion site 1 (Bmi1) was a direct target of miR-194, which was validated by dual-luciferase reporter assay, RT-qPCR and western blot analysis. The restoration of Bmi1 expression significantly abrogated the suppressive effect of miR-194 on glioma cell EMT. Taken together, the present study suggests that miR-194 inhibits glioma cell EMT by targeting Bmi1 providing novel insights into understanding the pathogenesis of glioma. The restoration of miR-194 may be a potential therapeutic strategy for glioma treatment. PMID- 28098897 TI - Overexpression of ARF1 is associated with cell proliferation and migration through PI3K signal pathway in ovarian cancer. AB - ADP-ribosylation factor 1 (ARF1) is a small G protein that regulates many cellular processes such as reorganization of the actin cytoskeleton and is highly expressed in various tumor cells and tissues. However, the role of ARF1 in ovarian cancer progression remains unknown. In the present study, we explored the expression patterns of ARF1 in clinical ovarian cancer samples and adjacent noncancerous tissues. The results revealed that ARF1 overexpressed in EOC tissues and cell lines, compared with the adjacent non-tumorous tissues and normal ovarian cells. In addition, the immunoreactivity of ARF1 was positively correlated with EOC grade and Ki-67 expression. Knockdown of ARF1 expression notably inhibited cell proliferation and migration rate of EOC cells by the auxiliary of PI3K. Taken together, our findings provide new insights into the functional role of ARF1 on EOC cell growth and migration and it may serve as a diagnostic and therapeutic target. PMID- 28098898 TI - A hepatic stem cell vaccine is superior to an embryonic stem cell vaccine in the prophylaxis and treatment of murine hepatocarcinoma. AB - Stem cells and cancer cells express a common subset of antigens called oncofetal antigens. Theoretically, vaccination with stem cells is effective at boosting the preexisting anticancer immune response. Herein we describe the efficacy of two stem cell-based vaccines in the prophylaxis and treatment of subcutaneous hepatic tumors transplanted into mice. C57BL/6j mice were vaccinated weekly with either hepatic stem cells (HSCs) or embryonic stem cells (ESCs) for three weeks, followed by a subcutaneous challenge with Hepa 1-6 cells at one week (group 1) or four weeks (group 2) after vaccination. No tumor formation was observed in HSC vaccinated mice when challenged within one week after vaccination (group 1), but tumors formed in 10% of mice in the ESC-vaccinated group and in 60% of mice in the unvaccinated group. When the long-term memory response was examined (group 2), only 10% of HSC-vaccinated mice and 20% of ESC-vaccinated mice developed macroscopic hepatocarcinomas compared to 60% of the unvaccinated mice. Besides their function as prophylactic vaccines, administration of either HSC or ESC could be a potential treatment for cancer. In mice with subcutaneous hepatocarcinomas, complete clearance of tumor burden was observed in 80% of mice receiving HSC vaccination, but 40% of ESC-vaccinated mice presented with tumors that did not increase in size over time. These data support that HSC is a superior vaccine candidate for durable antitumor protection in this hepatocarcinoma model. PMID- 28098899 TI - Analysis of gene expression profiles of non-small cell lung cancer at different stages reveals significantly altered biological functions and candidate genes. AB - We attempt to dissect the pathology of non-small cell lung cancer (NSCLC) patients at different stages and discover the novel candidate genes. Microarray data (GSE21933) were retrieved from the Gene Expression Omnibus database. The differential expression profiles of lung tumor tissues during different stages were analyzed. The significantly altered functions and pathways were assessed and the key nodes in a protein-protein interaction (PPI) network were screened out. Then, the coexpression gene pairs and tumor-related genes were assessed. RT-PCR analysis was performed to validate the candidate gene, natural killer-tumor recognition sequence (NKTR). The number of differentially expressed genes (DEGs) for stage IB, IIB, IIIA and IV tumors were 499, 602, 592 and 457, respectively. Most of the DEGs were NSCLC-related genes identified through literature research. A few genes were commonly downregulated in all the 4 stages of tumors, such as CNTN6 and LBX2. The DEGs in early-stage tumors were closely related with the negative regulation of signal transduction, the apoptosis pathway and the p53 signaling pathway. DEGs in late-stage tumors were significantly enriched in transcription, response to organic substances and synapse regulation-related biological processes. A total of 16 genes (including NKTR) made up the significant coexpression network. NKTR was a key node in the PPI network and was significantly upregulated in lung cancer cells. The mechanism of NSCLC progression in different tumor stages may be different. NKTR may be the target candidate for NSCLC prevention and treatment. PMID- 28098900 TI - Endothelial microparticles activate endothelial cells to facilitate the inflammatory response. AB - Endothelial microparticles (EMPs) and endothelial cells (ECs) are involved in the pathophysiological mechanisms of sepsis and septic shock. EMPs are small vesicles released by ECs and are considered biomarkers for endothelial cell function and mediators for intercellular information exchange. However, the effect of EMPs on their parental ECs remains unknown. The present study collected tumor necrosis factor-alpha-derived EMPs and detected the proinflammatory cytokines released from unstimulated and EMP-stimulated ECs by proteome profiler array. This revealed that EMPs induce an inflammatory response in ECs. Within this response, interferon gamma-induced protein 10 was revealed by ELISA to be associated with the activity of EMPs in a time- and dose-dependent manner. It was hypothesized that the possible mechanism underlying this phenomenon was nuclear factor-kappaB. This was demonstrated to be crucial for the expression of IP-10 in EMP-stimulated ECs and the function of EMPs by immunofluorescence and western blot analysis. The present study enhances understanding of the involvement of EMPs and ECs in sepsis and will assist with the early diagnosis and treatment of sepsis. PMID- 28098901 TI - Effect of evodiamine and berberine on the interaction between DNMTs and target microRNAs during malignant transformation of the colon by TGF-beta1. AB - The tissue microenvironment functions as a crucial player in carcinogenesis, and transforming growth factor-beta1 (TGF-beta1) within the microenvironment stimulates the formation of neoplasms. Using an in vitro model of malignancy induced by TGF-beta1, we assessed the effect of evodiamine and berberine on the interaction between DNA methyltransferases (DNMTs) and target microRNAs (miRNAs) in the model. Colon tissues from neonatal rats 7 days of age were cultured and malignancy was induced by TGF-beta1 in vitro for 48 h, and then the tissues were respectively treated with evodiamine and berberine for 24 h. Morphological alteration of tissues was observed by an inverted microscope, histological structures were observed using hematoxylin and eosin staining, and the expression levels of DNMTs and targeted miRNAs screened by bioinformatics software combined with Gene chip analysis in our previous study were detected by immunohistochemistry and quantified by real-time PCR. Twenty-four hours after treatment with TGF-beta1, expression levels of DNMT1, DNMT3A, DNMT3B and miR-152 (target DNMT1), miR-429 (target DNMT3A) and miR-29a (target DNMT3A/3B) were markedly decreased; however, after 48 h, the expression levels of DNMT1 and DNMT3A were significantly increased, but their target miRNAs were still decreased. After treatment with a DNMT inhibitor (5-Aza-dC), expression levels of the miRNAs were increased to a larger extent, but did not reach normal levels. After treatment with berberine and evodiamine for 24 h, respectively, increased expression of DNMT1, DNMT3A, DNMT3B and miR-152, miR-429, miR-29a was noted. In conclusion, the results of the present study suggest that miRNAs can also be post transcriptionally regulated by their corresponding DNMTs and that berberine and evodiamine regulate the expression of these genes, which provides early epigenetic evidence for the prevention and therapy of colorectal cancer. PMID- 28098902 TI - Downregulation of leucine-rich-alpha-2-glycoprotein 1 expression is associated with the tumorigenesis of head and neck squamous cell carcinoma. AB - Leucine-rich-alpha-2-glycoprotein 1 (LRG1) is considered as a potential biomarker as it is aberrantly expressed in various malignancies. However, there is limited information regarding its role in head and neck squamous cell carcinoma (HNSCC). In the present study, we aimed to explore the expression pattern of LRG1 in HNSCC and its clinicopathological significance. We first analyzed LRG1 gene expression in HNSCC by investigating data obtained from the Gene Expression Omnibus (GEO) database. The results showed that LRG1 was downregulated in HNSCC tissues and its expression level was negatively related to tumor T and N stages and degree of malignancy. Then, we further tested a tissue microassay and clinical samples, respectively, by immunohistochemical staining and western blotting. Consistently, the results revealed that LRG1 expression was decreased in tumor tissues regardless of the grade of the tumor. Moreover, the protein level of LRG1 showed slight differences among four T stages or three N stages. In addition, there were no significant associations between LRG1 protein expression and other clinicopathological parameters such as gender, age, tumor location and clinical staging. These findings imply that downregulation of the expression of LRG1 is correlated with tumorigenesis but not with the development of HNSCC, indicating the potential clinical value of LRG1 in the early diagnosis of HNSCC. PMID- 28098903 TI - Vitexin alleviates lipopolysaccharide-induced islet cell injury by inhibiting HMGB1 release. AB - Diabetes mellitus (DM) is a chronic metabolic disease, where the predominant pathogenesis is pancreatic beta-cells dysfunction or injury. It has been well established that inflammation leads to a gradual exhaustion of pancreatic beta cell function with decreased beta-cell mass likely resulting from pancreatic beta cells apoptosis or death. Vitexin, a major bioactive flavonoid compound in plants has numerous pharmacological properties, including antioxidant, anti-inflammatory and antimyeloperoxidase. Whether vitexin can protect pancreatic beta-cells against lipopolysaccharide (LPS)-induced pro-inflammatory cytokine production and apoptosis has received little attention. The present study investigated the potential effects of vitexin on LPS-induced pancreatic beta-cell injury and apoptosis. It was revealed that apoptosis and damage induced by LPS in islet tissue of rats and INS-1 cells was significantly decreased in response to vitexin treatment. In addition, pretreatment with vitexin decreased the levels of the pro inflammatory cytokines tumor necrosis factor-alpha and high mobility group box 1 (HMGB1) in LPS-induced rats. Further experiments demonstrated that vitexin pretreatment suppressed the activation of P38 mitogen-activated protein kinase signaling pathways in LPS-induced INS-1 cells. In conclusion, the results indicated that vitexin prevented LPS-induced islet tissue damage in rats, and INS 1 cells injury and apoptosis by inhibiting HMGB1 release. Therefore, the present study provided clear evidence indicating that vitexin may be a viable therapeutic strategy for the treatment of DM. PMID- 28098904 TI - Identification of biomarkers of intrahepatic cholangiocarcinoma via integrated analysis of mRNA and miRNA microarray data. AB - The present study aimed to identify potential therapeutic targets of intrahepatic cholangiocarcinoma (ICC) via integrated analysis of gene (transcript version) and microRNA (miRNA/miR) expression. The miRNA microarray dataset GSE32957 contained miRNA expression data from 16 ICC, 7 mixed type of combined hepatocellular cholangiocarcinoma (CHC), 2 hepatic adenoma, 3 focal nodular hyperplasia (FNH) and 5 healthy liver tissue samples, and 2 cholangiocarcinoma cell lines. In addition, the mRNA microarray dataset GSE32879 contained mRNA expression data from 16 ICC, 7 CHC, 2 hepatic adenoma, 5 FNH and 7 healthy liver tissue samples. The datasets were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and miRNAs (DEMs) in ICC samples compared with healthy liver tissues were identified via the limma package, following data preprocessing. Genes that exhibited alternative splicing (AS) in ICC samples were identified via AltAnalyze software. Functional enrichment analysis of DEGs was performed using the Database for Annotation, Visualization and Integrated Analysis. Target genes of DEMs were identified using the TargetScan database. The regulatory association between DEMs and any overlaps among DEGs, alternative splicing genes (ASGs) and target genes of DEMs were retrieved, and a network was visualized using the Cytoscape software. A total of 2,327 DEGs, 70 DEMs and 623 ASGs were obtained. Functional enrichment analysis indicated that DEGs were primarily enriched in biological processes and pathways associated with cell activity or the immune system. A total of 63 overlaps were obtained among DEGs, ASGs and target genes of DEMs, and a regulation network that contained 243 miRNA gene regulation pairs was constructed between these overlaps and DEMs. The overlapped genes, including sprouty-related EVH1 domain containing 1, protein phosphate 1 regulatory subunit 12A, chromosome 20 open reading frame 194, and DEMs, including hsa-miR-96, hsa-miR-1 and hsa-miR-25, may be potential therapeutic targets for the future treatment of ICC. PMID- 28098905 TI - Cripto-1 promotes epithelial-mesenchymal transition in prostate cancer via Wnt/beta-catenin signaling. AB - The Cripto-1 (CR-1) derived EGF-CFC family was overexpressed in tumor development enhancing proliferation, epithelial-mesenchymal transition (EMT) and migration of tumor cells. However, correlation between CR-1 and prostate cancer (PCa) remains still unclear. In the present study, we proved that CR-1 was expressed in PCa and its function was in the progression of PCa. Compared with benign prostatic hyperplasia (BPH) tissues, we confirmed that PCa tissues had high expression of CR-1 by immunohistochemistry and statistical data showed that CR-1 promoted properties of EMT in PCa tissues, including the downregulation of the cell adhesion molecules beta-catenin (membrane) and E-cadherin while upregulating transcription factors beta-catenin. Overexpression of CR-1 had close relationship with PSA, Gleason, clinical staging and lymph node metastasis in PCa patients. Then, we found that PC-3 cells transfected with CR-1-shRNA inhibited EMT using RT PCR, RT-qPCR, western blotting and immunofluorescence. Also, we evaluated cell invasive ability in vitro by transwell and wound-healing assay. Our data showed that transfected CR-1-shRNA altered EMT including beta-catenin, E-cadherin, c myc, GSK-3, p-GSK and Wnt/beta-catenin pathway in PC-3. It also suppressed PC-3 cell migration. Additionally, our results displayed that Licl had antitumor activity against PC-3 through the inhibition of Wnt/beta-catenin pathway. Inhibition of cell viability was dose-time dependent. The present study proved that CR-1 regulates EMT of PCa by Wnt/beta-catenin pathway. Hence, CR-1 may provide a new biological marker, and possibly contributes to clinical treatment against PCa. PMID- 28098906 TI - miR-15a-5p acts as an oncogene in renal cell carcinoma. AB - miRNAs have been reported to be involved in multiple cellular processes and the tumorigenesis of various cancers. miR-15a-5p (also termed miR-15a) has previously been determined to be upregulated in renal cell carcinoma (RCC) by microarray profile. However, the expression and function of miR-15a-5p in RCC remain to be validated. In the present study, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to detect the expression levels of miR-15a 5p in RCC tissues and cells. The expression level of miR-15a-5p was upregulated or downregulated by transfecting synthesized miR-15a-5p mimics or inhibitors. The MTT assay, CCK-8 assay, Transwell assay, wound healing assay, Hoechest 33342 staining and flow cytometry were conducted to investigate the role of miR-15a-5p in RCC. The results of the RT-qPCR demonstrated that miR-15a-5p was upregulated in RCC tissues and ACHN, 786-O and 769P RCC cells compared with paired normal tissues and HEK-293T cells. miR-15a-5p was observed to be associated with RCC cell proliferation, migration, invasion and apoptosis. The results demonstrated that miR-15a-5p may be important as a tumor promoter in RCC. To the best of our knowledge, the present study is the first to describe miR-15a-5p as a tumor promoter in RCC. Further research will be performed to investigate the underlying signaling pathway of miR-15a-5p and the potential role of miR-15a-5p as a biomarker for early detection, prognosis prediction and a therapeutic target of RCC. PMID- 28098907 TI - Synergistic combination of YS-1 and adriamycin inhibits human renal cancer through ERK1/2 signaling pathway in vitro and in vivo. AB - Adriamycin (ADM) is a principal drug for the treatment of renal cell cancer (RCC). Due to its limited response and high renal and cardiac toxicity, synergistic effects of ADM in combination with other drugs have been widely researched. In this study, we found the combination between YS-1 and ADM, performed higher anticancer activity on 786-O human RCC cells in vitro and in vivo, than that reported on its anti-angiogenesis effect compared with monotherapy of ADM. Our data showed that when combined with ADM, YS-1 promoted the sensitivity of 786-O cells to ADM. The combination of YS-1 and ADM also inhibited cell proliferation, but without affecting cell apoptosis. We found that ADM monotherapy treatment notably upregulated the activity of extracellular signal-regulated kinase ERK1 and ERK2 (ERK1/2), but when combined with YS-1, the p-ERK1/2 level was reduced; then inhibited the Ras/Raf/MEK pathway. Additionally, the synergistic effects on cell cycle arrest inhibition were eliminated when ERK1/2 was silenced using siRNA. Our combination therapy of YS-1 with ADM showed the strongest antitumor effects in vivo (inhibition ratio: 5 mg/kg YS-1 combined with 1 mg/kg ADM, 68.19%) in comparison with individual effects (inhibition ratio: 5 mg/kg YS-1, 30.07%; 1 mg/kg ADM, 50.42%). Collectively, these findings indicated that YS-1 did not only enhance the ability of ADM to inhibit tumor proliferation, but also reduce the renal toxicity to protect the normal renal tissues. PMID- 28098908 TI - Protective effects of ethyl pyruvate on lipopolysaccharide-induced acute lung injury through inhibition of autophagy in neutrophils. AB - Among a number of clinical factors, bacterial infection is one of the most common causes of acute lung injury (ALI), a serious complication that carries a high risk of mortality (~40%). During the process of ALI, intense local and systemic inflammation is elicited, which exacerbates the injury. Neutrophil infiltration into airspace is observed in early stage of ALI, and is required for the full development of ALI through an array of mechanisms, including the release of granule contents and the production of pro-inflammatory cytokines, due to the overactivation of complement and cytokines. The present study noted that ethyl pyruvate alleviated ALI in lipopolysaccharide (LPS)-induced ALI mice. Increased autophagy in neutrophils from ALI mice was observed, while ethyl pyruvate diminished autophagy in neutrophils and constrained granule release, and therefore myeloperoxidase (MPO) in bronchoalveolar lavage fluid and the production of proinflammatory cytokines. Using neutrophil cells, it was identified that autophagy was required for neutrophil activation and granule release, and that ethyl pyruvate caused neutrophil autophagy, leading to the restriction of granule release, and thus contributing to the mitigation of ALI. If autophagy was obviated through knockdown of key regulator of autophagy Atg5, the effects of ethyl pyruvate on granule release by neutrophils disappeared. Taken together, the results demonstrated that ethyl pyruvate alleviates ALI through inhibition of autophagy-induced granule release by neutrophils, and this mechanism suggested a novel potential therapeutic target in autophagy regulation for ALI. PMID- 28098909 TI - Biology and function of glypican-3 as a candidate for early cancerous transformation of hepatocytes in hepatocellular carcinoma (Review). AB - Glypican-3 (GPC-3), a transmembrane heparan sulfate proteoglycan (HSPG), has recently been investigated as a player in tissue-dependent cellular signaling, specifically as a regulator of growth. Noteworthy, the regulatory protein has been implicated in both stimulatory and inhibitory pathways involving cell growth. Initially, GPC-3 was thought to act as a cell cycle regulator, as a loss of-function mutation in the gene caused a hyper-proliferative state known as Simpson-Golabi-Behmel (SGB) overgrowth syndrome. Additionally, certain cancer types have displayed a downregulation of GPC-3 expression. More recently, the protein has been evaluated as a useful marker for hepatocellular carcinoma (HCC) due to its increased expression in the liver during times of growth. In contrast, the GPC-3 marker is not detectable in normal adult liver. Immunotherapy that targets GPC-3 and its affiliated proteins is under investigation as these new biomarkers may hold potential for the detection and treatment of HCC and other diseases in which GPC-3 may be overexpressed. Studies have reported that an overexpression of GPC-3 in HCC predicts a poorer prognosis. This prognostic value further pushes the question regarding GPC-3's role in the regulation and progression of HCC. This review will summarize the current knowledge regarding the clinical aspects of GPC-3, while also synthesizing the current literature with the aim to better understand this molecule's biological interactions at a molecular level, not only in the liver, but in the rest of the body as well. Due to the existing gap in the literature surrounding GPC-3, we believe further investigation of function, structure and domains, cellular localization, and other subfields is warranted to evaluate the protein as a whole, as well as its part in the study of HCC. PMID- 28098910 TI - Hydrogen-rich saline improves non-alcoholic fatty liver disease by alleviating oxidative stress and activating hepatic PPARalpha and PPARgamma. AB - Non-alcoholic fatty liver disease (NAFLD) comprises a range of liver diseases, between steatosis and non-alcoholic steatohepatitis and liver cirrhosis, which are closely associated with diabetes mellitus. Previous studies have indicated that oxidative stress is a key factor in the development of NAFLD. Molecular hydrogen (H2) may ameliorate oxidative stress injuries by selectively neutralizing peroxynitrite and hydroxyl radicals. The present study evaluated the effects of H2 on NAFLD in rats and concluded that H2-rich saline had significant therapeutic effects on NAFLD induced by hyperglycemia and hyperlipidemia, as demonstrated by hematoxylin and eosin and terminal deoxynucleotidyl-transferase mediated dUTP nick end labeling staining. H2-rich saline improved fasting blood glucose, fasting insulin, insulin sensitivity and glucose tolerance, and lowered the expression levels of tumor necrosis factor alpha, interleukin-1 beta, 3 nitrotyrosine and 8-hydroxy-2'-deoxyguanosine in the liver. In addition, the present study revealed that H2-rich saline could significantly increase peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma expression in hepatocytes. In conclusion, H2-rich saline may significantly improve NAFLD, possibly by reducing oxidative stress and activating hepatic PPARalpha and PPARgamma expression. PMID- 28098911 TI - Diagnosis for choroideremia in a large Chinese pedigree by next-generation sequencing (NGS) and non-invasive prenatal testing (NIPT). AB - To develop an effective strategy to isolate and use cell-free fetal DNA (cffDNA) for the combined use of next-generation sequencing (NGS) for diagnosing choroideremia and non-invasive prenatal testing (NIPT) for Y chromosome determination, a large Chinese family with an X-linked recessive disease, choroideremia, was recruited. Cell-free DNA was extracted from maternal plasma, and SRY polymerase chain reaction amplification was performed using NIPT. Sanger sequencing was subsequently used for fetal amniotic fluid DNA verification. A nonsense mutation (c.C799T:p.R267X) of the CHM gene on the X chromosome of the proband (IV:7) and another 5 males with choroideremia were detected, while 3 female carriers with no symptoms were also identified. The fetus (VI:7) was identified as female from the cffDNA, and the same heterozygous nonsense mutation present in her mother was also confirmed. At one and a half years of age, the female baby did not present with any associated symptoms of choroideremia. Therefore, cffDNA was successfully used for the combined use of NGS for diagnosing choroideremia in a large Chinese pedigree, and NIPT for Y chromosome determination. This approach should result in a markedly increased use of prenatal diagnosis and improvement, and more sophisticated clinical management of diseases in China and other developing countries. The establishment of a highly accurate method for prenatal gene diagnosis will allow for more reliable gene diagnosis, improved genetic counseling, and personalized clinical management of our patients. PMID- 28098913 TI - Diets link metabolic syndrome and colorectal cancer development (Review). AB - Diets have been believed to be an important factor in the development of metabolic syndrome and colorectal cancer (CRC). In recent years, many studies have shown an intimate relationship between mucosal immunity, metabolism and diets, which has led to a greater understanding of the pathophysiology of metabolic syndrome and CRC development. Although the precise effects of diets on oncogenesis have not been compl-etely elucidated, microbiota changes and inflammation are believed to be important factors that influence the development of CRC. Moreover, increased release of pro-inflammatory cytokines and alteration of adipokine levels have been observed in patients with colorectal adenoma and/or CRC, and these all have been considered as the important mechanisms that link diets to the development of metabolic syndrome and CRC. Importantly, a high-fat, low-fiber diet is associated with dysbiosis, and as the gut signature becomes more important in metabolic syndrome and CRC, an increased understanding of diets on bacterial activity in the pathogenesis of metabolic syndrome and CRC will lead to new preventive and therapeutic strategies. PMID- 28098912 TI - MicroRNA-9 limits hepatic fibrosis by suppressing the activation and proliferation of hepatic stellate cells by directly targeting MRP1/ABCC1. AB - Liver fibrosis is a chronic liver disease characterized by the proliferation and activation of hepatic stellate cells (HSCs) and excessive deposition of extracellular matrix (ECM). Research suggests that microRNAs (miRNAs) are a new type of regulator of liver fibrosis. In the present study, we investigated the role of microRNA-9 (miR-9) in the process of liver fibrosis, as well as the underlying mechanism of action. Downregulated levels of miR-9 were found in fibrotic liver tissues and activated HSCs as detected by qRT-PCR; whereas, expression of multidrug resistance-associated protein 1 (MRP1/ABCC1) was upregulated in the fibrotic liver tissues and activated HSCs. CCK-8 and BrdU assays revealed that miR-9 reduced the proliferative ability of the HSCs. In addition, expression levels of ECM-related genes (alpha-SMA, Col-1 and Timp-1), which are markers of HSC activation, were downregulated by miR-9. Conversely, an miR-9 inhibitor promoted cell proliferation and HSC activation. In addition, a luciferase reporter assay indicated that miR-9 targets the 3'-untranslated region (3'-UTR) of MRP1 and causes a significant decrease in MRP1. miR-9 inhibited the activation of the Hedgehog (Hh) pathway and the expression of MRP1, while this suppression was rescued by the overexpression of MRP1. Finally, a CCl4-induced mouse model of liver fibrosis was used to investigate the effects of miR-9 on liver fibrosis in vivo. The results showed that miR-9 abrogated hepatic fibrosis by suppressing the expression of MRP1 in CCl4-induced liver fibrotic mice. In conclusion, the present study demonstrated that miR-9 suppresses the proliferation and activation of HSCs through the Hh pathway by targeting MRP1, which suggests that miR-9 has therapeutic potential for liver fibrosis. PMID- 28098915 TI - Somatic mutational spectrum analysis in a prospective series of 104 gastrointestinal stromal tumors. AB - Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors distinguished by driver mutations in proto-oncogenes KIT or PDGFRA in 85-90% of cases. These mutations have been linked to the response to imatinib, a multikinase inhibitor, and have independent prognostic impact. Here, we describe the prospective study of the molecular characteristics of 104 GISTs from French adult patients analyzed routinely through the National Hospital Program of Molecular Cancer Diagnosis. All patients with GISTs diagnosed at the University Hospital of Besancon between August 2005 and October 2014 were prospectively included in the present study. KIT, PDGFRA and KRAS-codons 12 and 13 as well as BRAF codon 600 mutations were analyzed by Sanger sequencing or SNaPshot. KIT and PDGFRA mutations were detected in 71.2 and 19.2% of the cases, respectively. A total of 43 different mutations were detected of which 13 had never been described. As expected, KIT exon 9 and PDGFRA exon 18 mutations were associated with small bowel and gastric localizations respectively. No mutation was found in KRAS and BRAF. Molecular studies are critical to improve the management of GISTs. Our study enhances the current knowledge by describing 13 new mutations in KIT. A common molecular pattern in all KIT exon 11 substitutions is also described for the first time in this study but its significance remains unknown since genetic and environmental risk factors favoring the development of GISTs such as DNA repair defects and exposure to carcinogens are not currently known. PMID- 28098914 TI - Role of miR-647 in human gastric cancer suppression. AB - MicroRNAs (miRNAs) regulate various oncogenes concomitantly, resulting in tumor suppression. They regulate proliferation and migration pathways in tumor development, suggesting a potential therapeutic role. In the present study, we found that miR-647 was markedly downregulated in gastric cancer (GC), and was significantly correlated with reduced tumor size and metastasis. In addition, miR 647 was also reduced in GC cell lines. Furthermore, overexpression of miR-647 in the GC cell lines inhibited cell proliferation, promoted cell cycle arrest at the G0/G1 phase and induced cell apoptosis. miR-647 also significantly inhibited tumor growth in vivo. Notably, we found that miR-647 overexpression suppressed the migration and invasion of the cancer cells, particularly liver metastasis in nude mice. miR-647 also reduced the expression levels of genes associated with proliferation and metastasis in tumors, including ANK2, FAK, MMP2, MMP12, CD44 and SNAIL1. Overall, our findings demonstrated that miR-647 exerts powerful antitumorigenic effects in vitro and in vivo, and may represent a promising therapeutic agent against GC. PMID- 28098916 TI - Depression and suicidal ideation among Canadians aged 15 to 24. AB - BACKGROUND: Among Canadians aged 15 to 24, the rate of depression is higher than at any other age, and suicide is the second leading cause of death. The current study provides detailed information about depression and suicidal ideation among young Canadians, including their use of mental health support. DATA AND METHODS: Data from the 2012 Canadian Community Health Survey-Mental Health (CCHS-MH) were used to describe rates and experiences of depression and suicidal ideation among Canadians aged 15 to 24, including psychosocial characteristics of those who had depression or reported suicidal thoughts. Characteristics associated with seeking professional support were also examined. RESULTS: About 11% of Canadians aged 15 to 24 had experienced depression in their lifetime; 7%, in the past year. Approximately 14% reported having had suicidal thoughts in their lifetime; 6%, in the past year. Lifetime depression and suicidal thoughts were moderately correlated (r = .34, p ? .001). Individuals with lifetime depression had more than four times the odds of seeking professional support in the previous year, compared with those who did not have lifetime depression; those with lifetime suicidal thoughts had more than three times the odds of seeking professional support, compared with those who did not have lifetime suicidal thoughts. Psychosocial factors such as negative social interactions and lower perceived ability to deal with stress were associated with depression and suicidal thoughts, although these associations differed for males and females. INTERPRETATION: The findings suggest that many young Canadians have depression and/or suicidal thoughts. Their odds of seeking professional support are significantly high. PMID- 28098917 TI - Tanning equipment use: 2014 Canadian Community Health Survey. AB - BACKGROUND: Tanning equipment use is related to the early onset of cancer, with the risk increasing as the duration and repetition of exposure increase. In 2009, the International Agency for Research on Cancer classified tanning equipment use as carcinogenic to humans, and according to the World Health Organization, the risk of skin melanoma increases significantly when use begins before age 35. DATA AND METHODS: The rapid response component of the 2014 Canadian Community Health Survey collected data on the use of tanning equipment in the previous 12 months, including reasons for use, frequency/duration of use, precautions taken, and adverse reactions or injuries. This analysis examines the prevalence of self reported indoor tanning in a nationally representative sample of Canadians aged 12 or older in the 10 provinces. RESULTS: In 2014, 4.5% of Canadians (an estimated 1.35 million) reported that they had used tanning equipment in the past year; 70.3% of them were female, and just over half of female users were aged 18 to 34. The prevalence of indoor tanning was highest among people with some postsecondary education and among those in higher income households (trend p value ? 0.0001). Most users reported fewer than 10 sessions in the past year. The most common reason (62.0%) was to develop a "protective" base tan. INTERPRETATION: Females made up the majority of tanning equipment users, particularly at ages 18 to 34. Efforts to increase awareness of the risks may be beneficial, given the high percentage of users who believed that indoor tanning offers some level of skin protection from future sun exposure. PMID- 28098919 TI - [The Journal in 2016]. PMID- 28098918 TI - [The new standard for quality of care]. PMID- 28098920 TI - [(Too) long in tbs? A study on patients receiving forensic psychiatric tbs treatment for 15 years or longer]. AB - BACKGROUND: In 2013 in the Netherlands about 100 forensic psychiatric patients were treated in tbs-hospitals for 15 years or more.
AIM: To investigate the variables that characterise patients who have been receiving forensic psychiatric treatment (tbs) for 15 years or more, and to obtain insight in which actions might be helpful to facilitate discharge or transfer of such patients to other (mental health care) facilities, according to their caregivers and experts.
METHOD: The group of long-term tbs-patients (n = 97) was compared with regard to diagnostic characteristics, 'basic historical risks' (as assessed by risk assessment instruments), and behaviour to three other groups of forensic patients: a. a group who had received treatment for 5 to 10 years, b. a group of patients who had been recently discharged, and c. a group of long-stay tbs patients.
RESULTS: Long-term tbs-patients relatively often had been sex offenders (50% compared to about 20% of recently discharged tbs-patients), and had been admitted in a tbs-hospital at a relatively young age (on average they had been five years younger on admission). The professional clinicians of the long-term tbs-patients considered that the psychopathology of the long term tbs patients was more severe than the psychopathology of the average tbs-patient. The clinicians also indicated that the long-term tbs-patients all need long-term supervision; however, they considered that only a minority of these patients (17%) required a maximum level of security and very restricted possibilities for temporary leave.
CONCLUSION: Patient related factors and organisational factors within the tbs-hospital and the general mental health care system seem to play a role in the lengthy period of tbs-treatment of the long-term tbs-patients. According to tbs-clinicians, these patients require prolonged and intensive supervision which the general mental health care system is often not equipped to deliver. PMID- 28098921 TI - [Does less seclusion create a safer environment? An attempt to map the concept of 'feeling safe']. AB - BACKGROUND: The degree of restraint imposed by a psychiatrist seems to be influenced by the safety of the team. So far, there have been few attempts to map the concept of 'feeling safe'.
AIM: To analyse, define and quantify the concept of 'feeling safe'.
METHOD: Concept mapping involves combining, in a structured way, qualitative (item collection) and quantitative methods (multi dimensional scaling and hierarchical clusteranalysis) with the knowledge of professionals from psychiatric practice (N=24), first on an individual basis and then as a group (N=8).
RESULTS: The participants generated and prioritised a total of 97 different items. These were then divided into six clusters: organisational structure, professionalism of team members, increased expertise, marginal conditions, internal and external features of the hospital building, views on mental health care and policy. Group members gave almost equal priority to the clusters, but they assigned different degrees of importance to separate items (ranging from 4.63 to 2.38 on a five-point scale).
CONCLUSION: Concept mapping is an adequate method of defining the concept of 'feeling safe'. Professionalism of the team and qualities such as openness and ability to communicate, expertise and trusting one's colleagues and having an adequate alarm system available are all important factors that help to make employees 'feel safe' in their respective departments. PMID- 28098922 TI - [Depression and anxiety in Turkish and Moroccan minorities in the Netherlands: prevalence, symptoms, risk factors and protective factors A systematic review]. AB -

. PMID- 28098923 TI - [SSRIs and depressive symptoms in schizophrenia: a systematic review]. AB - BACKGROUND: Patients with schizophrenia frequently have depressive symptoms. Current guidelines do not provide specific recommendations regarding the treatment of these symptoms, nor do they mention the role that selective serotonin reuptake inhibitors (ssris) can play in the treatment.
AIM: To investigate whether ssris are more effective than placebo in treating depressive symptoms in patients with schizophrenia.
METHOD: We searched the literature systematically using PubMed, embase, Cochrane Library and Psycinfo. We selected articles on the basis of inclusion and exclusion criteria and the methodologies used and compared the severity of patients symptoms before and after treatment.
RESULTS: We found only four published studies of randomised, double blind, placebo-controlled trials. These showed that an ssri was significantly more effective than a placebo (the difference being 0.4 - 6.7 points on the Hamilton Depression Rating Scale and 0.2 - 2.6 on the Calgary Depression Scale for Schizophrenia).
CONCLUSION: There are indications that ssris are effective for the treatment of depressive symptoms in patients with schizophrenia. However, the total sample size was limited and individual studies had several methodological limitations. PMID- 28098925 TI - [Personality disorders: life span perspective makes sense]. PMID- 28098924 TI - [Hypernatremia caused by treatment with GHB obtained via a doctor's prescription]. AB - In the last few years, gamma hydroxybutyric acid (GHB) has been used increasingly as a party drug; this has led to a marked increase in the number of requests for professional help with the treatment of GHB addiction. Pharmaceutical GHB (sodium oxybate, the sodium-salt of GHB), registered for cataplexia in narcolepsy patients, is used off-label to treat the withdrawal symptoms associated with GHB addiction. Pharmaceutical GHB has a high sodium load. In this report we present the cases of two patients who developed symptomatic hypernatremia following treatment with pharmaceutical GHB and who thereafter needed intensive care for the severe withdrawal symptoms that they experienced. PMID- 28098926 TI - Relevance of osteoclast-specific enzyme activities in cell-based in vitro resorption assays. AB - Cell-based in vitro resorption assays are an important tool to simulate the in vivo biodegradation of resorbable bone graft materials and to predict their clinical performance. The present study analyses the activity of osteoclast specific enzymes as potential surrogate measures for classical pit assay, which is not applicable on irregular structured materials. Osteoclasts derived from human peripheral blood mononuclear cells were cultivated on different surfaces: calcium phosphate bone cements (CPC), dentin discs, osteoblast-derived extracellular matrix (ECM) and tissue culture polystyrene as control. Pit formation on the resorbable materials was investigated and correlated with the activity of tartrate resistant acid phosphatase (TRAP), carbonic anhydrase II (CAII) and cathepsin K (CTSK). Furthermore, the relation between intra- and extracellular enzyme activities was examined for TRAP and CTSK during resorption of the different materials. Resorbed area of CPC correlated with intracellular TRAP activity and intracellular CAII activity. Highest resorption was detected at around pH 7.2. Resorbed area on dentin correlated with the extracellular CTSK activity and extracellular TRAP activity and was maximal at around pH 6.8. Osteoclasts cultivated on cell-derived mineralised ECM showed a good correlation between both extracellular TRAP and CTSK activity and the release of calcium ions. Based on these data a different regulation of TRAP and CTSK secretion is hypothesised for the resorption of inorganic calcium phosphate compared to the resorption of collagenous mineralised matrix. PMID- 28098927 TI - The role of HE4 and CA125 in differentiation between malignant and non-malignant endometrial pathologies. AB - OBJECTIVES: The aim of the study was to assess the role of HE4 and CA125 in differentiation between malignant and non-malignant endometrial pathologies. MATERIAL AND METHODS: A retrospective study of 87 patients with endometrial pathologies was conducted. Tumor markers were assessed two weeks before surgical intervention in each subject. The final diagnosis was established on the basis of the histopathological examination of the endometrium. RESULTS: Serum HE4 levels were significantly higher in patients with endometrial cancer (EC) as compared to non-malignant endometrial pathologies (p < 0.001), patients with stage I EC as compared to non-malignant endometrial pathologies (p < 0.001), and patients with stage Ia EC as compared to non-malignant endometrial pathologies (p = 0.003). Serum CA125 levels were not significantly different as far as these groups of patients were concerned. Both tumor markers were significantly higher in patients with stage II-III as compared to stage I EC and non-malignant endometrial pathologies (p < 0.001 for both markers). Sensitivity and specificity of HE4 at the cut-off level of 70 pmol/L for detecting endometrial malignancies were 73.08% and 85.71%, respectively. Sensitivity and specificity of CA125 at the cut-off level of 35 U/mL were 29.41% and 94.29%, respectively. The area under the curve (AUC) for HE4 was 0.875, suggesting that this marker reliably differentiates malignant from non-malignant endometrial pathologies (p < 0.001). AUC for CA125 was 0.552, suggesting that this marker does not reliably differentiate between malignant and non-malignant endometrial pathologies (p = 0.414). CONCLUSION: HE4, in contrast to CA125, might be a useful tool for detecting malignant endometrial pathologies. PMID- 28098928 TI - 2D/3D ultrasonography for endometrial evaluation in a cohort of 118 postmenopausal women with abnormal uterine bleedings. AB - OBJECTIVES: 2D/3D transvaginal ultrasonography in evaluation of endometrium in postmenopausal women with abnormal uterine bleedings (AUB). MATERIAL AND METHODS: 2D/3D transvaginal ultrasonography (TVU) was performed in 118 menopausal women with AUB. Endometrial volume and thickness, uterine volume and endometrial vascularity were evaluated. Complete histologic evaluation of the endometrium was obtained through dilatation & curettage (D&C) and/or hysteroscopy. Accordingly, patients were divided into 3 groups: controls (no endometrial pathology, n = 49), GI (benign endometrial pathology, n = 37), GII (endometrial carcinoma, n = 32). RESULTS: GII had greater thickness and volume of the endometrium, compared to GI and controls. The presence of arterial vascular flow was identified only in GI and GII (51.35% and 93.75%, respectively). Endometrial volume merged together with uterine volume measurements (TVU-3D) showed a strong, statistical significance between GI and GII, allowing differentiation of begin and malignant endometrial pathologies in postmenopausal women. CONCLUSIONS: In TVU diagnostics of postmenopausal women with AUB the following play the most significant role: 1) endometrial thickness (TVU-2D); 2) endometrial volume (TVU-3D); 3) uterine plus endometrial volume (TVU-3D); 4) vascularization within the endometrium, allowing to differentiate between pathological and normal endometrium (TVU-2/3D). Evaluation of the endometrial vascularity, both in TVU-2D and TVU-3D technique, does not allow for reliable differentiation between benign lesions and endometrial cancer. PMID- 28098929 TI - The organization and financing of cervical cancer prevention carried out by midwives in primary health care. AB - OBJECTIVE: The main objective of the project was the evaluation of the organizational and financial aspects of midwives in primary health care (PHC), functioning under The Population Program for the Early Detection of Cervical Cancer two years after the implementation of new law regulations, which enable this occupational group to collect cytological material for screening. MATERIAL AND METHODS: Under this project, the data of the Program's Coordinating Centre, affecting midwives' postgraduate education in the field of pap smear tests, was taken into analysis. Furthermore, The National Health Fund (NFZ) reports on contracts entered in the field of the discussed topics, taking into consideration the value of health services performed within the Program in respect of ambulatory care and primary care units. RESULTS: NFZ concluded contracts for the provision of PHC service with 6124 service providers in 2016, including the contracts in the field of providing health services under the cervical cancer prevention program by PHC midwifes, which were entered into by 358 institutions (5.85%). The value of the basic services under the Program, carried out under NFZ contracts in 2014, amounted to approx. PLN 12.3 million, while the value of services performed by PHC midwives represented only 0.38% of this sum. CONCLUSIONS: The introduction of legislative changes, allowing PHC midwives to collect cytological material for screening, did not cause, in the period of the observation on a national scale, the expected growth of availability of basic stage services within the cervical cancer prevention program. PMID- 28098930 TI - Can neonates born at 34 weeks be classified as late preterm? AB - OBJECTIVES: In recent years, much attention has been given to infants born prematurely, at 34 0/7 to 36 6/7 weeks of gestation (WG), which have been classified as 'late preterm'. Neonates from that subgroup are less physiologically and metabolically mature than term infants. The aim of the study was to determine whether infants born at 34WG can be classified as 'late preterm' or 'preterm' newborns. MATERIAL AND METHODS: A total of 141 newborns were included in the study: 25 born <= 33WG, 53 late-preterm newborns, and 63 term infants. Cord-blood neutrophil gelatinase-associated lipocalin (NGAL) and creatinine concentrations were measured in all newborns. Also, the incidence of clinical complications in the early adaptive period during hospitalization was evaluated. RESULTS: Higher NGAL concentration was noted among preterm newborns as compared to late-preterm neonates (p < 0.05), and term newborns (p < 0.05), especially in children born at 34WG as compared to 35WG (p < 0.001). However, no differences in NGAL concentration were found between neonates born at 35WG and 36WG, as well as children born at 36WG and term infants. A relationship between umbilical NGAL levels and gestational age was observed. Additionally, a statistically significant difference was found in the incidence of respiratory distress syndrome (p < 0.05) and infections (p < 0.05) among neonates born at 34WG as compared to 35WG. CONCLUSIONS: Late preterm neonates should be defined as 'preterm' between 35 0/7 and 36 6/7 WG. Infants born at 34WG should be included in the preterm group. PMID- 28098931 TI - Diagnostic value of CA 19-9 in pregnancies complicated by spinal neural tube defects: a preliminary study. AB - OBJECTIVES: Various physiological and pathological conditions can induce significant variations in plasma concentrations of tumor markers, such as CA 19 9, which is present in the serum and amniotic fluid of pregnant women. Herein, we aimed to determine the clinical importance of maternal serum CA 19-9 levels in the diagnosis of neural tube defects (NTDs). MATERIAL AND METHODS: A total of 100 women were included in this controlled cross-sectional study. Thirty-three patients whose pregnancies were complicated by isolated meningocele or meningomyelocele constituted the study group, whereas 33 normal, healthy pregnant women constituted the control group, and 34 age- and body mass index (BMI) matched non-pregnant women were chosen for the validation group. RESULTS: The mean maternal serum CA 19-9 levels were 17.2 +/- 17.0 IU/mL, 7.1 +/- 5.9 IU/mL, and 4.7 +/- 3.6 IU/mL in the study, control, and validation groups, respectively (p < 0.001). ROC analyses showed that elevated CA 19-9 values may predict NTDs (p < 0.001). The cut-off value for CA 19-9 was found to be 9.6 IU/mL at 70% (51% 84%, 95% CI) sensitivity and 84% (74%-92%, 95% CI) specificity. CONCLUSIONS: CA 19-9 may be a promising noninvasive marker for NTDs. Further studies are needed to reveal the clinical applicability and diagnostic potential of maternal serum CA 19-9 levels in the identification of NTDs. PMID- 28098932 TI - Personality type, social support and other correlates of risk for affective disorders in early puerperium. AB - OBJECTIVES: The purpose of this study was to assess the prevalence of risk for postpartum mood disorders in mothers during the early postnatal period and to search for coexisting conditions. MATERIAL AND METHODS: We studied 546 women in the first week after delivery. The subjects filled out a questionnaire concerning their health, social and demographic status, the Edinburgh Postnatal Depression Scale, the Patient Health Questionnaire, the NEO-FFI Personality Inventory and the Berlin Social Support Scales. RESULTS: Probable mood disorders affected 15.85% of these patients. The risk increased with a current cesarean section (ORa = 2.54), a higher level of neuroticism (ORa = 1.65), greater fear of childbirth (ORa = 1.18), a lower level of extraversion (ORa = 0.77) and greater need for social support (ORa = 2.68). CONCLUSIONS: High level of neuroticism and introversion, as well as higher fear of delivery and the need of social support are among factors increasing the probability of mood disturbances in early postpartum period. A cesarean section might elevate the risk similarly. The mental health of such patients should be carefully examined. PMID- 28098933 TI - Assisted reproductive technology in reproductive medicine - possibilities and limitations. AB - Infertility has become an increasingly common health problem and has been estimated to affect approximately 10% of women in the reproductive age. Due to its high prevalence, it has been deemed a social disease by the World Health Organization (WHO). The causes of infertility are numerous and vary from person to person. As for treatment, the three main therapeutic strategies include pharmacological therapy, surgical therapy - mostly endoscopy, and assisted reproductive technology (ART). Recent decades have witnessed great progress in ART, resulting in successful treatment of the previously untreatable cases, particularly in the field of fertility preservation, preimplantation screening for aneuploidy, uterine transplantations and mitochondrial replacement techniques as prevention against a number of severe diseases. Regardless, ART treatment does not guarantee pregnancy and live birth. The success rate is much smaller as compared to the failure rate, it being among its most important limitations. Embryo implantation is an extremely complex process and represents the most critical step of the reproduction process in humans. Attempts to evaluate endometrial receptivity and strategies for its correction have been discussed. The search for new effective predictors of an individual prognosis remains a crucial challenge for the contemporary reproductive medicine. PMID- 28098934 TI - Clinical, ultrasound parameters and tumor marker-based mathematical models and scoring systems in pre-surgical diagnosis of adnexal tumors. AB - The choice of management for patients with adnexal tumors requires careful pre surgical assessment. In case of adnexal masses, the diagnostic difficulties arise from the heterogenic nature of the adnexal diseases, presence of multiple functional changes, and lack of early symptoms of malignancy. A reliable pre surgical differentiation cannot be performed using clinical features, ultrasound examination, or tumor markers alone. New diagnostic techniques and novel markers are under investigations, however no single test can be used to conclusively differentiate between malignant and non-malignant adnexal masses. Mathematical models and scoring systems based on different clinical, ultrasonographic and laboratory parameters alone or together may facilitate the diagnosis. Selected mathematical models and scoring systems are presented in this article. Models using only ultrasound features include simple rules, regression models, Gynecologic Imaging Report and Data System, and various morphologic scores. Some logistic regression models are based on multiple clinical and ultrasound data. The OVA1 test is based on five tumor markers without using other data. The Risk of Malignancy Algorithm uses two tumor markers with one clinical parameter. i.e. the menopausal status. Some models used clinical, ultrasound and tumor marker data together. This group of models includes risk of malignancy indices, artificial neural networks, and the ADNEX model. Although some of these models have been compared in the literature, more prospective studies are needed to select the most effective model, to develop the existing models, or to create new more effective models of oncological assessment of the adnexal tumors. PMID- 28098935 TI - Diaphragmatic hernia as an early ultrasound manifestation of Apert syndrome. AB - n/a. PMID- 28098936 TI - Evaluation of the effectiveness of selected natural fertility symptoms used for contraception: estimation of the Pearl index of Lady-Comp, Pearly and Daysy cycle computers based on 10 years of observation in the Polish market. AB - OBJECTIVES: Cycle computers are medical devices which use sophisticated statistical methods in addition to a comprehensive on-board database. Their main function is to precisely indicate the fertile and infertile phases of the menstrual cycle, based on daily basal body temperature measurements. A recent medical research program aimed at evaluating the EFFECTIVENESS of cycle computers for contraceptive purposes was conducted. MATERIAL AND METHODS: This study was conducted between May and June 2016 on 3,450 Polish women. The Polish distributor sent an anonymous questionnaire to the participants. To date, 361 women, representing 17,322 cycles have returned accurately completed questionnaires. RESULTS: In the resultant group only 4 unintended pregnancies were observed, resulting in a Pearl index of 0.4989. This suggests that fewer than 5 in 1000 women, who use a cycle computer correctly over a period of one year, may become pregnant unintentionally. This result is slightly better than the results from 2010, when the Pearl index was 0.64. CONCLUSIONS: The results obtained from the study indicate that the effectiveness of cycle computers for contraceptive purposes is comparable with other methods, such as hormonal contraception, and therefore cycle computers can be recommended for women who either cannot use or do not wish to use traditional contraception. These results confirm the effectiveness of using natural fertility symptoms, such as basal body temperature changes in the context of cycle computer technology for the purposes of contraception. PMID- 28098937 TI - Sodium selenate treatment improves symptoms and seizure susceptibility in a malin deficient mouse model of Lafora disease. AB - OBJECTIVE: To search for new therapies aimed at ameliorating the neurologic symptoms and epilepsy developing in patients with Lafora disease. METHODS: Lafora disease is caused by loss-of-function mutations in either the EPM2A or EPM2B genes. Epm2a-/- and Epm2b-/- mice display neurologic and behavioral abnormalities similar to those found in patients. Selenium is a potent antioxidant and its deficiency has been related to the development of certain diseases, including epilepsy. In this study, we investigated whether sodium selenate treatment improved the neurologic alterations and the hyperexcitability present in the Epm2b-/- mouse model. RESULTS: Sodium selenate ameliorates some of the motor and memory deficits and the sensitivity observed with pentylenetetrazol (PTZ) treatments in Epm2b-/- mice. Neuronal degeneration and gliosis were also diminished after sodium selenate treatment. SIGNIFICANCE: Sodium selenate could be beneficial for ameliorating some symptoms that present in patients with Lafora disease. PMID- 28098938 TI - Towards prognostic biomarkers from BOLD fluctuations to differentiate a first epileptic seizure from new-onset epilepsy. AB - OBJECTIVE: The diagnosis of epilepsy cannot be reliably made prior to a patient's second seizure in most cases. Therefore, adequate diagnostic tools are needed to differentiate subjects with a first seizure from those with a seizure preceding the onset of epilepsy. The objective was to explore spontaneous blood oxygen level-dependent (BOLD) fluctuations in subjects with a first-ever seizure and patients with new-onset epilepsy (NOE), and to find characteristic biomarkers for seizure recurrence after the first seizure. METHODS: We examined 17 first-seizure subjects, 19 patients with new-onset epilepsy (NOE), and 18 healthy controls. All subjects underwent clinical investigation and received electroencephalography and resting-state functional magnetic resonance imaging (MRI). The BOLD time series were analyzed in terms of regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuations (fALFFs). RESULTS: We found significantly stronger amplitudes (higher fALFFs) in patients with NOE relative to first-seizure subjects and healthy controls. The frequency range of 73-198 mHz (slow-3 subband) appeared most useful for discriminating patients with NOE from first-seizure subjects. The ReHo measure did not show any significant differences. SIGNIFICANCE: The fALFF appears to be a noninvasive measure that characterizes spontaneous BOLD fluctuations and shows stronger amplitudes in the slow-3 subband of patients with NOE relative first-seizure subjects and healthy controls. A larger study population with follow-up is required to determine whether fALFF holds promise as a potential biomarker for identifying subjects at increased risk to develop epilepsy. PMID- 28098939 TI - A systematic review of economic evaluations of treatments for patients with epilepsy. AB - The increasing number of treatment options and the high costs associated with epilepsy have fostered the development of economic evaluations in epilepsy. It is important to examine the availability and quality of these economic evaluations and to identify potential research gaps. As well as looking at both pharmacologic (antiepileptic drugs [AEDs]) and nonpharmacologic (e.g., epilepsy surgery, ketogenic diet, vagus nerve stimulation) therapies, this review examines the methodologic quality of the full economic evaluations included. Literature search was performed in MEDLINE, EMBASE, NHS Economic Evaluation Database (NHS EED), Econlit, Web of Science, and CEA Registry. In addition, Cochrane Reviews, Cochrane DARE and Cochrane Health Technology Assessment Databases were used. To identify relevant studies, predefined clinical search strategies were combined with a search filter designed to identify health economic studies. Specific search strategies were devised for the following topics: (1) AEDs, (2) patients with cognitive deficits, (3) elderly patients, (4) epilepsy surgery, (5) ketogenic diet, (6) vagus nerve stimulation, and (7) treatment of (non)convulsive status epilepticus. A total of 40 publications were included in this review, 29 (73%) of which were articles about pharmacologic interventions. Mean quality score of all articles on the Consensus Health Economic Criteria (CHEC)-extended was 81.8%, the lowest quality score being 21.05%, whereas five studies had a score of 100%. Looking at the Consolidated Health Economic Evaluation Reporting Standards (CHEERS), the average quality score was 77.0%, the lowest being 22.7%, and four studies rated as 100%. There was a substantial difference in methodology in all included articles, which hampered the attempt to combine information meaningfully. Overall, the methodologic quality was acceptable; however, some studies performed significantly worse than others. The heterogeneity between the studies stresses the need to define a reference case (e.g., how should an economic evaluation within epilepsy be performed) and to derive consensus on what constitutes "standard optimal care." PMID- 28098940 TI - Characterization of Date (Deglet Nour) Seed Free and Bound Polyphenols by High Performance Liquid Chromatography-Mass Spectrometry. AB - Date (Pheonix dactylifera L.) seeds are a valuable and abundant by-product with various potential food applications. Free polyphenols (FPPs) and bound polyphenols (BPPs) of date seeds from Deglet Nour variety grown in Australia were investigated using high-performance liquid chromatography-mass spectrometry. The FPP fraction contained the following main phenolic compounds per gram of date seed powder; procyanidin B1 (499.8 +/- 7.8 MUg), procyanidin B2 (288.6 +/- 6.1 MUg), catechin (167.6 +/- 2.1 MUg), epicatechin (39.44 +/- 0.39 MUg), and protocatechuic acid (1.77 +/- 0.22 MUg). Additionally, one of the 2 A-type dimers was confirmed as procyanidin A2 (24.05 +/- 0.12 MUg/g). A-type dimers have not been reported before in date seeds. The BPP fraction contained epicatechin (52.59 +/- 0.76 MUg/g) and procyanidin B2 (294.2 +/- 3.7 MUg/g), while several peaks exhibiting ESI- m/z of 153 indicated dihydroxybenzoic acid isomers including protocatechuic acid (2.138 +/- 0.025 MUg/g). These findings contributed to our knowledge of date seed phytochemicals and understanding of their contribution to the reported bioactivities. PMID- 28098941 TI - Posterior cortex epilepsy surgery in childhood and adolescence: Predictors of long-term seizure outcome. AB - OBJECTIVE: We aimed to investigate the long-term seizure outcome of children and adolescents who were undergoing epilepsy surgery in the parietooccipital cortex and determine their predictive factors. METHODS: We retrospectively analyzed the data of 50 consecutive patients aged 11.1 (mean) +/- 5.1 (standard deviation) years at surgery. All patients but one had a magnetic resonance imaging (MRI) visible lesion. Resections were parietal in 40%, occipital in 32%, and parietooccipital in 28% cases; 24% patients additionally underwent a resection of the posterior border of the temporal lobe. Etiology included focal cortical dysplasia in 44%, benign tumors (dysembryoplastic neuroepithelial tumor, ganglioglioma, angiocentric glioma, and pilocystic astrocytoma) in 32%, peri- or postnatal ischemic lesions in 16%, and tuberous sclerosis in 8% cases. RESULTS: At last follow-up (mean 8 years, range 1.5-18 years), 60% patients remained seizure-free (Engel class I): 30% had discontinued and 20% had reduced antiepileptic drugs. Most seizure recurrences (71%) occurred within the first 6 months, and only three patients presented with seizures >=2 years after surgery. Independent predictors of seizure recurrence included left-sided as well as parietal epileptogenic zones and resections. Longer epilepsy duration to surgery was identified as the only modifiable independent predictor of seizure recurrence. SIGNIFICANCE: Our study demonstrates that posterior cortex epilepsy surgery is highly effective in terms of lasting seizure control and antiepileptic drug cessation in selected pediatric candidates. Most importantly, our data supports the early consideration of surgical intervention in children and adolescents with refractory posterior cortex epilepsy. PMID- 28098942 TI - Biomarkers for the Detection of Prenatal Alcohol Exposure: A Review. AB - Alcohol exposure during pregnancy can cause adverse effects to the fetus, because it interferes with fetal development, leading to later physical and mental impairment. The most common clinical tool to determine fetal alcohol exposure is maternal self-reporting. However, a more objective and useful method is based on the use of biomarkers in biological specimens alone or in combination with maternal self-reporting. This review reports on clinically relevant biomarkers for detection of prenatal alcohol exposure (PAE). A systematic search was performed to ensure a proper overview in existing literature. Studies were selected to give an overview on clinically relevant neonatal and maternal biomarkers. The direct biomarkers fatty acid ethyl esters (FAEEs), ethyl glucuronide (EtG), ethyl sulfate, and phosphatidylethanol (PEth) were found to be the most appropriate biomarkers in relation to detection of PAE. To review each biomarker in a clinical context, we have compared the advantages and disadvantages of each biomarker, in relation to its window of detectability, ease of collection, and the ease and cost of analysis of each biomarker. The biomarkers PEth, FAEEs, and EtG were found to be applicable for detection of even low levels of alcohol exposure. Meconium is an accessible matrix for determination of FAEEs and EtG, and blood an accessible matrix for determination of PEth. PMID- 28098943 TI - A Survey of the Peptide Profile in Prato Cheese as Measured by MALDI-MS and Capillary Electrophoresis. AB - In this study, we describe the characterization of the peptide profile in commercial Prato cheese by matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) and capillary electrophoresis (CE). Ten commercial Prato cheese brands were characterized via their physicochemical composition and subjected to fractionation according to solubility at pH 4.6. The pH 4.6 insoluble fraction was evaluated by CE, whereas MALDI-MS was applied to the fraction soluble at pH 4.6 and in 70% ethanol. CE revealed a characteristic pattern of hydrolysis, with formation of para-kappa-casein, hydrolysis of alphas1 -casein at the Phe23 - Phe24 bond, and hydrolysis of beta-casein. For the MALDI MS data, a complex peptide profile was observed, with the identification of 44 peptides previously reported (24 peptides from alphas1 -casein, 14 from beta casein, 3 from kappa-casein, and 3 from alphas2 -casein). It was also observed that cheeses with salt-in-moisture content greater than 5% showed an accumulation of a bitter-tasting peptide (m/z 1536, alphas1 -CN f1-13), suggesting a relationship between the higher salt concentration and the abundance of this peptide. In conclusion, the results showed that even commercial cheeses produced with different raw material and processing conditions showed very similar peptide profiles when assessed at the molecular level, and only 9 peptides were responsible for discrimination of cheeses. PMID- 28098944 TI - Validation of a smartphone-based point-of-care hemoglobin assay for use in dogs. AB - OBJECTIVE: To validate a smartphone-based spectrophotometric assay for point-of care (POC) measurement of hemoglobin (Hgb) concentration against the standard measurement method in dogs without increases in serum lipemia, hemolysis, or bilirubin. DESIGN: Prospective observational study. SETTING: University teaching hospital. ANIMALS: One hundred thirty-nine dogs that had a CBC and corresponding biochemical profile submitted to the clinical pathology laboratory. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Blood tubes submitted for CBC were collected for hemoglobin (Hgb) measurements performed on a POC smartphone device. Each whole blood sample was run on the smartphone in duplicate using 2 strips, for a total of 4 POC Hgb readings per dog. Data collected for each dog included CBC Hgb value, 4 POC Hgb values, and select biochemistry values (bilirubin, lipemia, hemolysis, icterus). A calibration equation was estimated using a weighted linear regression: estimated CBC = (avgPOC-0.4871)/1.0015. For each dog, the percent error was computed between estimated and actual Hgb values; 95% of the percent errors ranged from -13.2% to 20.1%. The standard deviation of percent errors was 7.9% overall. When samples were further divided according to CBC Hgb concentration (low, normal or high), the standard deviation of percent error was 6.7% when Hgb<13 g/dL [130 g/L], 8.9% when Hgb 13-20 g/dL [130-200 g/L], and 6.5% when Hgb>20 g/dL [200 g/L]. The coefficient of variability among the 4 individual POC readings was 3.4%. CONCLUSIONS: A smartphone-based photometric method for measuring Hgb represents a clinically useful POC alternative to a standard laboratory Hgb measurement. There was excellent intrasample reproducibility, and the standard deviation of percent errors was relatively constant across CBC ranges. Additional sampling of patients with a greater range of diseases and biochemical abnormalities that may influence spectrophotometric assays (ie, abnormal bilirubin, icterus, lipemia, hemolysis) is warranted to extend the findings of this study. PMID- 28098945 TI - Frequency of CNKSR2 mutation in the X-linked epilepsy-aphasia spectrum. AB - Synaptic proteins are critical to neuronal function in the brain, and their deficiency can lead to seizures and cognitive impairments. CNKSR2 (connector enhancer of KSR2) is a synaptic protein involved in Ras signaling-mediated neuronal proliferation, migration and differentiation. Mutations in the X-linked gene CNKSR2 have been described in patients with seizures and neurodevelopmental deficits, especially those affecting language. In this study, we sequenced 112 patients with phenotypes within the epilepsy-aphasia spectrum (EAS) to determine the frequency of CNKSR2 mutation within this complex set of disorders. We detected a novel nonsense mutation (c.2314 C>T; p.Arg712*) in one Ashkenazi Jewish family, the male proband of which had a severe epileptic encephalopathy with continuous spike-waves in sleep (ECSWS). His affected brother also had ECSWS with better outcome, whereas the sister had childhood epilepsy with centrotemporal spikes. This mutation segregated in the three affected siblings in an X-linked manner, inherited from their mother who had febrile seizures. Although the frequency of point mutation is low, CNKSR2 sequencing should be considered in families with suspected X-linked EAS because of the specific genetic counseling implications. PMID- 28098946 TI - Negative Association Between MR-Spectroscopic Glutamate Markers and Gray Matter Volume After Alcohol Withdrawal in the Hippocampus: A Translational Study in Humans and Rats. AB - BACKGROUND: Both chronic alcohol consumption and alcohol withdrawal lead to neural tissue damage which partly recovers during abstinence. This study investigated withdrawal-associated changes in glutamatergic compounds, markers of neuronal integrity, and gray matter volumes during acute alcohol withdrawal in the hippocampus, a key region in development and maintenance of alcohol dependence in humans and rats. METHODS: Alcohol-dependent patients (N = 39) underwent magnetic resonance imaging (MRI) and MR spectroscopy (MRS) measurements within 24 hours after the last drink and after 2 weeks of abstinence. MRI and MRS data of healthy controls (N = 34) were acquired once. Our thorough quality criteria resulted in N = 15 available spectra from the first and of N = 21 from the second measurement in patients, and of N = 19 from healthy controls. In a translational approach, chronic intermittent ethanol-exposed rats and respective controls (8/group) underwent 5 MRS measurements covering baseline, intoxication, 12 and 60 hours of withdrawal, and 3 weeks of abstinence. RESULTS: In both species, higher levels of markers of glutamatergic metabolism were associated with lower gray matter volumes in the hippocampus in early abstinence. Trends of reduced N-acetylaspartate levels during intoxication persisted in patients with severe alcohol withdrawal symptoms over 2 weeks of abstinence. We observed a higher ratio of glutamate to glutamine during alcohol withdrawal in our animal model. CONCLUSIONS: Due to limited statistical power, we regard the results as preliminary and discuss them in the framework of the hypothesis of withdrawal induced hyperglutamatergic neurotoxicity, alcohol-induced neural changes, and training-associated effects of abstinence on hippocampal tissue integrity. PMID- 28098947 TI - Conservation vs divergence in LEAFY and APETALA1 functions between Arabidopsis thaliana and Cardamine hirsuta. AB - A conserved genetic toolkit underlies the development of diverse floral forms among angiosperms. However, the degree of conservation vs divergence in the configuration of these gene regulatory networks is less clear. We addressed this question in a parallel genetic study between the closely related species Arabidopsis thaliana and Cardamine hirsuta. We identified leafy (lfy) and apetala1 (ap1) alleles in a mutant screen for floral regulators in C. hirsuta. C. hirsuta lfy mutants showed a complete homeotic conversion of flowers to leafy shoots, mimicking lfy ap1 double mutants in A. thaliana. Through genetic and molecular experiments, we showed that AP1 activation is fully dependent on LFY in C. hirsuta, by contrast to A. thaliana. Additionally, we found that LFY influences heteroblasty in C. hirsuta, such that loss or gain of LFY function affects its progression. Overexpression of UNUSUAL FLORAL ORGANS also alters C. hirsuta leaf shape in an LFY-dependent manner. We found that LFY and AP1 are conserved floral regulators that act nonredundantly in C. hirsuta, such that LFY has more obvious roles in floral and leaf development in C. hirsuta than in A. thaliana. PMID- 28098948 TI - Phosphorus acquisition efficiency in arbuscular mycorrhizal maize is correlated with the abundance of root-external hyphae and the accumulation of transcripts encoding PHT1 phosphate transporters. AB - Plant interactions with arbuscular mycorrhizal fungi have long attracted interest for their potential to promote more efficient use of mineral resources in agriculture. Their use, however, remains limited by a lack of understanding of the processes that determine the outcome of the symbiosis. In this study, the impact of host genotype on growth response to mycorrhizal inoculation was investigated in a panel of diverse maize lines. A panel of 30 maize lines was evaluated with and without inoculation with arbuscular mycorrhizal fungi. The line Oh43 was identified to show superior response and, along with five other reference lines, was characterized in greater detail in a split-compartment system, using 33 P to quantify mycorrhizal phosphorus uptake. Changes in relative growth indicated variation in host capacity to profit from the symbiosis. Shoot phosphate content, abundance of root-internal and -external fungal structures, mycorrhizal phosphorus uptake, and accumulation of transcripts encoding plant PHT1 family phosphate transporters varied among lines. Superior response in Oh43 is correlated with extensive development of root-external hyphae, accumulation of specific Pht1 transcripts and high phosphorus uptake by mycorrhizal plants. The data indicate that host genetic factors influence fungal growth strategy with an impact on plant performance. PMID- 28098950 TI - Diagnosis of childhood obesity using BMI: potential ethicolegal implications and downstream effects. PMID- 28098949 TI - Identification of cellular targets involved in cardiac failure caused by PKI in oncology: an approach combining pharmacovigilance and pharmacodynamics. AB - AIMS: The aims of the present study were to evaluate the risk of cardiac failure (CF) associated with 15 anticancer protein kinase inhibitors (PKIs) through a case/noncase analysis and to identify which PK(s) and pathways are involved in PKI-induced CF. METHODS: In order to evaluate the risk of CF, adjusted reporting odds ratios (aRORs) were calculated for the 15 anticancer PKIs in the World Health Organization safety report database (VigiBase(r)). We realised a literature review to identify 21 protein kinases (PKs) that were possibly involved in CF caused by PKIs. Pearson correlation coefficients (r) between aRORs and affinity data of the 15 PKIs for the 21 PKs were calculated to identify the cellular target most likely to be involved in PKI-induced CF. RESULTS: A total of 141 601 individual case safety reports (ICSRs) were extracted from VigiBase(r) for the following PKIs: afatinib, axitinib, bosutinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, ruxolitinib, sorafenib, sunitinib and vandetanib. Among them, 2594 ICSRs concerned CF. The disproportionality analysis revealed that, for dasatinib, imatinib, bosutinib, sunitinib and nilotinib, disproportionality for CF was significantly higher than for other PKIs, with aRORs of 2.52 [95% CI 2.26, 2.82], 1.79 (95% CI 1.57, 2.03), 1.73 (95% CI 1.18, 2.54), 1.67 (95% CI 1.51, 1.84) and 1.38 (95% CI 1.18, 1.61), respectively. Significant values for correlation coefficients between the product of dissociation constant (pKd) and aROR were observed for two non-receptor protein kinases: ABL1 (non-phosphorylated and phosphorylated forms) and ABL2 protein kinases, with values of r = 0.83 (P = 0.0001), r = 0.75 (P = 0.0014) and r = 0.78 (P = 0.0006), respectively. CONCLUSION: We observed a higher disproportionality for CF with dasatinib, imatinib, bosutinib, sunitinib and nilotinib than with other PKIs. In addition, the study highlighted the role of ABL tyrosine kinases in CF caused by anticancer PKIs. PMID- 28098951 TI - Lessons Learned From a Practice-Based, Multisite Intervention Study With Nurse Participants. AB - PURPOSE: To identify challenges and solutions to the efficient conduct of a multisite, practice-based randomized controlled trial to improve nurses' adherence to personal protective equipment use in ambulatory oncology settings. DESIGN: The Drug Exposure Feedback and Education for Nurses' Safety (DEFENS) study is a clustered, randomized, controlled trial. Participating sites are randomized to Web-based feedback on hazardous drug exposures in the sites plus tailored messages to address barriers versus a control intervention of a Web based continuing education video. APPROACH: The study principal investigator, the study coordinator, and two site leaders identified challenges to study implementation and potential solutions, plus potential methods to prevent logistical challenges in future studies. FINDINGS: Noteworthy challenges included variation in human subjects' protection policies, grants and contracts budgeting, infrastructure for nursing-led research, and information technology variation. Successful strategies included scheduled Web conferences, site-based study champions, site visits by the principal investigator, and centrally based document preparation. Strategies to improve efficiency in future studies include early and continued engagement with contract personnel in sites, and proposed changes to the common rule concerning human subjects. The DEFENS study successfully recruited 393 nurses across 12 sites. To date, 369 have completed surveys and 174 nurses have viewed educational materials. CONCLUSIONS: Multisite studies of nursing personnel are rare and challenging to the existing infrastructure. These barriers can be overcome with strong engagement and planning. CLINICAL RELEVANCE: Leadership engagement, onsite staff support, and continuous communication can facilitate successful recruitment to a workplace based randomized, controlled behavioral trial. PMID- 28098952 TI - Solving the Puzzle of One-Carbon Loss in Ripostatin Biosynthesis. AB - Ripostatin is a promising antibiotic that inhibits RNA polymerase by binding to a novel binding site. In this study, the characterization of the biosynthetic gene cluster of ripostatin, which is a peculiar polyketide synthase (PKS) hybrid cluster encoding cis- and trans-acyltransferase PKS genes, is reported. Moreover, an unprecedented mechanism for phenyl acetic acid formation and loading as a starter unit was discovered. This phenyl-C2 unit is derived from phenylpyruvate (phenyl-C3) and the mechanism described herein explains the mysterious loss of one carbon atom in ripostatin biosynthesis from the phenyl-C3 precursor. Through in vitro reconstitution of the whole loading process, a pyruvate dehydrogenase like protein complex was revealed that performs thiamine pyrophosphate dependent decarboxylation of phenylpyruvate to form a phenylacetyl-S-acyl carrier protein species, which is supplied to the subsequent biosynthetic assembly line for chain extension to finally yield ripostatin. PMID- 28098953 TI - Mesoporous Germanium Anode Materials for Lithium-Ion Battery with Exceptional Cycling Stability in Wide Temperature Range. AB - Porous structured materials have unique architectures and are promising for lithium-ion batteries to enhance performances. In particular, mesoporous materials have many advantages including a high surface area and large void spaces which can increase reactivity and accessibility of lithium ions. This study reports a synthesis of newly developed mesoporous germanium (Ge) particles prepared by a zincothermic reduction at a mild temperature for high performance lithium-ion batteries which can operate in a wide temperature range. The optimized Ge battery anodes with the mesoporous structure exhibit outstanding electrochemical properties in a wide temperature ranging from -20 to 60 degrees C. Ge anodes exhibit a stable cycling retention at various temperatures (capacity retention of 99% after 100 cycles at 25 degrees C, 84% after 300 cycles at 60 degrees C, and 50% after 50 cycles at -20 degrees C). Furthermore, full cells consisting of the mesoporous Ge anode and an LiFePO4 cathode show an excellent cyclability at -20 and 25 degrees C. Mesoporous Ge materials synthesized by the zincothermic reduction can be potentially applied as high performance anode materials for practical lithium-ion batteries. PMID- 28098954 TI - Use of Play Therapy in Nursing Process: A Prospective Randomized Controlled Study. AB - PURPOSE: Play therapy is a nursing intervention employed in multidisciplinary approaches to develop the social, emotional, and behavioral skills of children. In this study, we aim to determine the effects of play therapy on the social, emotional, and behavioral skills of pre-school children through the nursing process. DESIGN: A single-blind, prospective, randomized controlled study was undertaken. The design, conduct, and reporting of this study adhere to the Consolidated Standards of Reporting Trials (CONSORT) guidelines. METHODS: The participants included 4- to 5-year-old kindergarten children with no oral or aural disabilities and parents who agreed to participate in the study. The Pre school Child and Family Identification Form and Social Competence and the Behavior Evaluation Scale were used to gather data. Games in the play therapy literature about nursing diagnoses (fear, social disturbance, impaired social interactions, ineffective coping, anxiety), which were determined after the preliminary test, constituted the application of the study. FINDINGS: There was no difference in the average scores of the children in the experimental and control groups in their Anger-Aggression (AA), Social Competence (SC), and Anxiety-Withdrawal (AW) scores beforehand (t = 0.015, p = .988; t = 0.084, p = .933; t = 0.214, p = .831, respectively). The difference between the average AA and SC scores in the post-test (t = 2.041, p = .045; t = 2.692, p = .009, respectively), and the retests were statistically significant in AA and SC average scores in the experimental and control groups (t = 4.538, p = .000; t = 4.693; p = .000, respectively). In AW average scores, no statistical difference was found in the post-test (t = 0.700, p = .486), whereas in the retest, a significant difference was identified (t = 5.839, p = .000). CONCLUSIONS: Play therapy helped pre-school children to improve their social, emotional, and behavioral skills. It also provided benefits for the children to decrease their fear and anxiety levels, to improve their communication and coping skills, and to increase their self-esteem. CLINICAL RELEVANCE: The study concluded that play therapy helps develop the social, emotional, and behavioral skills of pre-school children. It has also helped children lower their fear and anxiety levels, improve their communication and coping skills, and promote their self-esteem. Pediatric nurses are recommended to include play therapy in their profession and in the nursing process. PMID- 28098955 TI - The impact of childhood cancer: Perceptions of adult survivors. AB - BACKGROUND: The objective of this study was to describe perceptions and associated risk factors of the impact of cancer on functional outcomes, including social relationships, exercise, finances, and religion, among adult survivors of childhood cancer. METHODS: Evaluable participants included 3001 adult survivors (mean age, 32.5 years; range, 18.3-63.8 years; 24.1 years from diagnosis; 50.8% male; 84.9% Caucasian) who were enrolled in the St. Jude Lifetime Cohort study. Perceptions of the impact of cancer were assessed using the Brief Cancer Impact Assessment (BCIA). Regression models were used to evaluate risk factors for functional outcomes. RESULTS: The median response on the BCIA was a perception that cancer had minimal impact on the domains assessed. Approximately 33.1% to 46.6% of survivors indicated this response across the 4 subscales, although responses ranged from very positive to very negative impact. Other than diagnosis (with survivors of brain tumors generally indicating a more negative impact of cancer, with subscale estimates of -1.25 for caregiving and finance and -1.01 for social and emotional and an odds ratio of 1.83 for exercise and diet), most variability was because of demographic factors, including sex, age, race, education, and employment. CONCLUSIONS: The current findings highlight that many long-term adult survivors perceive minimal impact of childhood cancer on functional aspects of adulthood, including caregiving, finances, exercise, social emotional relationships, and religion. This suggests that survivors may not be focusing on the influence of likely physical and psychological late effects of their disease in their day-to-day lives. For those who do perceive a negative impact, variability in responses suggests that there are of survivors who may benefit from interventions focused on the achievement of functional goals. Cancer 2017;123:1625-1634. (c) 2017 American Cancer Society. PMID- 28098956 TI - The Effect of Reference Group Classification and Change in Alcohol Consumption on the Association Between Alcohol Consumption and Cardiovascular Disease. AB - BACKGROUND: Many studies suggest that mild alcohol consumption can help avert cardiovascular disease (CVD). This study investigated the association between alcohol consumption and CVD incidence, and assessed whether this differed by reference group classification. As alcohol consumption amounts may change over time, the results of simple and time-dependent analyses were compared. METHODS: Data were from a community-based cohort study on 40- to 69-year-old Koreans recruited in 2001 to 2002. A total of 8,330 participants were followed up for 10 years and classed as nondrinkers (0 g/d), drinker group 1 (<15 g/d), and drinker group 2 (>=15 g/d). The risk of CVD, including myocardial infarction and coronary artery disease, was compared among groups using simple and time-dependent Cox analysis. Occasional drinkers (<2.5 g/d), nondrinkers, and lifetime abstainers were used as comparison reference groups. RESULTS: Simple Cox analysis indicated that drinker group 1 exhibited a significantly lower risk of myocardial infarction (hazard ratio [HR]: 0.44, 95% confidence interval [CI]: 0.21, 0.92) and coronary artery disease (HR: 0.61, 95% CI: 0.4, 0.94) than nondrinkers. Time dependent analysis based on alcohol consumption change showed that the beneficial effects of drinker group 1 were significant only for myocardial infarction, not for coronary artery disease. The benefits did not change significantly when either nondrinkers or lifetime abstainers were the reference group. However, when occasional drinkers were included in the reference group, the benefits of drinker group 1 were not significant for myocardial infarction (HR: 0.65, 95% CI: 0.29, 1.45) or coronary artery disease (HR: 0.71, 95% CI: 0.42, 1.19). Occasional drinkers and drinkers had more similar sociodemographic characteristics than did nondrinkers and drinkers. CONCLUSIONS: Further studies on alcohol consumption and its effects on health must use repeated measurement to define drinking status, as simple and time-dependent analyses can show different alcohol consumption risks. These findings do not indicate a beneficial effect of drinking <15 g/d when occasional drinkers and nondrinkers are included in the reference group. PMID- 28098958 TI - Perilesional Hyperintensity on T1-Weighted Images in Intra-Axial Brain Masses other than Cavernous Malformations. AB - BACKGROUND AND PURPOSE: Hyperintensity on T1-weighted imaging in perilesional vasogenic edema has been reported as a useful sign for differentiating cavernous malformation from other hemorrhagic intra-axial masses. In this study, we investigated the frequency of perilesional hyperintensity on T1-weighted imaging in patients with intra-axial hemorrhagic and nonhemorrhagic brain masses. METHODS: The study was performed with the approval of the institutional review board. Magnetic resonance images of 218 patients with 282 intra-axial brain masses (129 metastases, 46 gliomas, 18 primary central nervous system lymphomas [PCNSLs], 25 intracerebral hemorrhages, 50 cavernous malformations, and 14 patients with brain abscesses) were evaluated. The signal intensity in perilesional area was qualitatively evaluated on T1-weighted sequences. In addition, signal intensity in perilesional area was quantitatively measured on T1 weighted sequences and normalized to the contralateral white matter. RESULTS: Hyperintensity on T1-weighted imaging in perilesional vasogenic edema was found in 12 (9%) of 129 metastases, 8 (16%) of 50 cavernous malformations, 1 (4%) in 25 nonneoplastic intracerebral hemorrhages, and none of the patients with high-grade glioma, PCNSL, or abscess. All of the lesions with perilesional hyperintensity showed either acute or subacute hemorrhage. Pairwise comparison of qualitative hyperintensity on T1-weighted imaging demonstrated no significant difference between the groups. Perilesional hyperintensity on T1-weighted imaging showed high specificity in both metastasis and cavernous malformation groups (94%). CONCLUSION: Perilesional hyperintensity on T1-weighted imaging is not limited to cavernous malformations and frequently evident with melanoma and other hemorrhagic metastasis to the brain. In our experience, it was not seen in high grade glioma, PCNSL, and brain abscess. PMID- 28098959 TI - Influence of electronic and molecular structure on the fragmentation dynamic of even-electron carbocationic triangulenes and helicenes in the gas phase. AB - Stable, long-lived organic cations are directly transferred by electrospray ionization (ESI) from solution into the gas phase where their collision-induced dissociations (CID) are studied by tandem mass spectrometry. Three related types of triphenyl carbenium ions are investigated, in which the meta positions are either substituted by methoxy groups or tertiary nitrogen bridges, including tetramethoxyphenylacridinium (TMPA+ ), dimethoxyquinacridinium (DMQA+ ), and triazatriangulenium (TATA+ ) cations. These ions are triangular in shape with increasing degrees of planarity. Fragmentation occurs at the periphery of the triangular molecule, involving the methoxy groups and the substituent of the nitrogen bridge. Each initial precursor cation is an even electron (EE) system and shows competing dissociations into both even (EE) and odd electron (OE) fragment ions. The latter reaction is a breach of the classic 'even-electron rule' in mass spectrometry. While the EE fragment dissociates similar to the precursor, the OE fragment ion shows a rich radical-induced fragmentation pattern. Two driving forces direct the fragmentation of the EE precursor ion toward OE fragment ions, including the release of stabilized radicals and the extension of the pi-system by increasing planarization of the triangulene core. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28098957 TI - The risk factors for postpartum depression: A population-based study. AB - BACKGROUND: Postpartum depression (PPD) can result in negative personal and child developmental outcomes. Only a few large population-based studies of PPD have used clinical diagnoses of depression and no study has examined how a maternal depression history interacts with known risk factors. The objective of this study was to examine the impact of a depression history on PPD and pre- and perinatal risk factors. METHODS: A nationwide prospective cohort study of all women with live singleton births in Sweden from 1997 through 2008 was conducted. Relative risk (RR) of clinical depression within the first year postpartum and two-sided 95% confidence intervals were estimated. RESULTS: The RR of PPD in women with a history of depression was estimated at 21.03 (confidence interval: 19.72-22.42), compared to those without. Among all women, PPD risk increased with advanced age (1.25 (1.13-1.37)) and gestational diabetes (1.70 (1.36-2.13)). Among women with a history of depression, pregestational diabetes (1.49 (1.01-2.21)) and mild preterm delivery also increased risk (1.20 (1.06-1.36)). Among women with no depression history, young age (2.14 (1.79-2.57)), undergoing instrument-assisted (1.23 (1.09-1.38)) or cesarean (1.64(1.07-2.50)) delivery, and moderate preterm delivery increased risk (1.36 (1.05-1.75)). Rates of PPD decreased considerably after the first postpartum month (RR = 0.27). CONCLUSION: In the largest population-based study to date, the risk of PPD was more than 20 times higher for women with a depression history, compared to women without. Gestational diabetes was independently associated with a modestly increased PPD risk. Maternal depression history also had a modifying effect on pre- and perinatal PPD risk factors. PMID- 28098960 TI - A Hollow Spherical Carbon Derived from the Spray Drying of Corncob Lignin for High-Rate-Performance Supercapacitors. AB - Controlling the microstructure of biomass-derived carbon is of essential importance for directing its use. Herein, a hollow spherical carbon (HSC) was prepared from corncob lignin through spray drying and subsequent heat treatment. The HSC, which is characterized by its hierarchically porous structure, delivers high rate capability when it is directly used as electrode material for supercapacitors. This strategy that uses lignin as the precursor avoids the intrinsic difficulty in tuning the microstructure of the biomass-derived carbons and is suitable for mass production for practical use. PMID- 28098962 TI - Gold-Catalyzed Suzuki Coupling of ortho-Substituted Hindered Aryl Substrates. AB - A method that allows hindered ortho-substituted aryl iodides to be efficiently coupled to phenylboronic acid using a gold-catalyzed C-C bond formation is presented. The use of a molecularly-defined dinuclear gold chloride catalytic precursor that is stabilized by a new tetradentate (N,N')-diamino-(P,P') diphosphino ferrocene hybrid ligand in a Suzuki-type reaction is described for the first time. Electron-rich isopropyl groups on phosphorus were found essential for a superior activity, while the performances of a set of analogous gold dinuclear complexes that were fully characterized by multinuclear NMR spectroscopy and XRD analysis, were investigated. Therefore, arylation of para and ortho-substituted iodoarenes bearing electron-rich, electron-poor functional groups, and even hindered polycyclic aromatic compounds is described. PMID- 28098961 TI - Angiogenic and osteogenic regeneration in rats via calcium phosphate scaffold and endothelial cell co-culture with human bone marrow mesenchymal stem cells (MSCs), human umbilical cord MSCs, human induced pluripotent stem cell-derived MSCs and human embryonic stem cell-derived MSCs. AB - Angiogenesis is a limiting factor in regenerating large bone defects. The objective of this study was to investigate angiogenic and osteogenic effects of co-culture on calcium phosphate cement (CPC) scaffold using human umbilical vein endothelial cells (hUVECs) and mesenchymal stem cells (MSCs) from different origins for the first time. hUVECs were co-cultured with four types of cell: human umbilical cord MSCs (hUCMSCs), human bone marrow MSCs (hBMSCs) and MSCs from induced pluripotent stem cells (hiPSC-MSCs) and embryonic stem cells (hESC MSCs). Constructs were implanted in 8 mm cranial defects of rats for 12 weeks. CPC without cells served as control 1. CPC with hBMSCs served as control 2. Microcapillary-like structures were successfully formed on CPC in vitro in all four co-cultured groups. Microcapillary lengths increased with time (p < 0.05). Osteogenic and angiogenic gene expressions were highly elevated and mineralization by co-cultured cells increased with time (p < 0.05). New bone amount and blood vessel density of co-cultured groups were much greater than controls (p < 0.05) in an animal study. hUVECs co-cultured with hUCMSCs, hiPSC MSCs and hESC-MSCs achieved new bone and vessel density similar to hUVECs co cultured with hBMSCs (p > 0.1). Therefore, hUCMSCs, hiPSC-MSCs and hESC-MSCs could serve as alternative cell sources to hBMSCs, which require an invasive procedure to harvest. In conclusion, this study showed for the first time that co cultures of hUVECs with hUCMSCs, hiPSC-MSCs, hESC-MSCs and hBMSCs delivered via CPC scaffold achieved excellent osteogenic and angiogenic capabilities in vivo. The novel co-culture constructs are promising for bone reconstruction with improved angiogenesis for craniofacial/orthopaedic applications. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28098963 TI - Scaffolding of Enzymes on Virus Nanoarrays: Effects of Confinement and Virus Organization on Biocatalysis. AB - Organizing active enzyme molecules on nanometer-sized scaffolds is a promising strategy for designing highly efficient supported catalytic systems for biosynthetic and sensing applications. This is achieved by designing model nanoscale enzymatic platforms followed by thorough analysis of the catalytic activity. Herein, the virus fd bacteriophage is considered as an enzyme nanocarrier to study the scaffolding effects on enzymatic activity. Nanoarrays of randomly oriented, or directionally patterned, fd bacteriophage virus are functionalized with the enzyme glucose oxidase (GOx), using an immunological assembly strategy, directly on a gold electrode support. The scaffolding process on the virus capsid is monitored in situ by AFM (atomic force microscopy) imaging, while cyclic voltammetry is used to interrogate the catalytic activity of the resulting functional GOx-fd nanoarrays. Kinetic analysis reveals the ability to modulate the activity of GOx via nanocarrier patterning. The results evidence, for the first time, enhancement of the enzymatic activity due to scaffolding on a filamentous viral particle. PMID- 28098964 TI - 2017 - One Decade of Journal of Biophotonics. PMID- 28098965 TI - Continuous Tuning of Phase Transition Temperature in VO2 Thin Films on c-Cut Sapphire Substrates via Strain Variation. AB - Vanadium dioxide (VO2) thin films with controlled thicknesses are deposited on c cut sapphire substrates with Al-doped ZnO (AZO) buffer layers by pulsed laser deposition. The surface roughness of AZO buffer layers is varied by controlling oxygen pressure during growth. The strain in the VO2 lattice is found to be dependent on the VO2 thickness and the VO2/AZO interface roughness. The semiconductor-to-metal transition (SMT) properties of VO2 thin films are characterized and the transition temperature (Tc) is successfully tuned by the VO2 thickness as well as the VO2/AZO interface roughness. It shows that the Tc of VO2 decreases with the decrease of film thickness or VO2/AZO interface roughness. Other SMT properties of the VO2 films are maintained during the Tc tuning. The results suggest that the strain tuning induced by AZO buffer provides an effective approach for tuning Tc of VO2 continuously. PMID- 28098966 TI - Surface Optical Rectification from Layered MoS2 Crystal by THz Time-Domain Surface Emission Spectroscopy. AB - Surface optical rectification was observed from the layered semiconductor molybdenum disulfide (MoS2) crystal via terahertz (THz) time-domain surface emission spectroscopy under linearly polarized femtosecond laser excitation. The radiated THz amplitude of MoS2 has a linear dependence on ever-increasing pump fluence and thus quadratic with the pump electric field, which discriminates from the surface Dember field induced THz radiation in InAs and the transient photocurrent-induced THz generation in graphite. Theoretical analysis based on space symmetry of MoS2 crystal suggests that the underlying mechanism of THz radiation is surface optical rectification under the reflection configuration. This is consistent with the experimental results according to the radiated THz amplitude dependences on azimuthal and incident polarization angles. We also demonstrated the damage threshold of MoS2 due to microscopic bond breaking under the femtosecond laser irradiation, which can be monitored via THz time-domain emission spectroscopy and Raman spectroscopy. PMID- 28098967 TI - Synthesis of Fluorinated Graphene/CoAl-Layered Double Hydroxide Composites as Electrode Materials for Supercapacitors. AB - CoAl-layered double hydroxide/fluorinated graphene (CoAl-LDH/FGN) composites were fabricated via a two-step hydrothermal method. The synthesized CoAl-LDH/FGN composites have been characterized by powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), field-emission scanning electron microscopy (FESEM), energy dispersive X-ray spectroscopy (EDS), and electrochemical measurements. The results indicated that the fluorinated carbon with various configuration forms were grafted onto the framework of graphene, and the C-F bond configuration and fluorine content could be tuned by the fluorination time. Most of semi-ionic C-F bonds were formed at an appropriate fluorination time and, then, converted into fluorine rich surface groups (such as CF2, CF3, etc.) which were electrochemically inactive as the fluorination time prolonged. Moreover, the CoAl-LDH/FGN composites prepared at the optimal fluorination time exhibited the highest specific capacitance (1222 F/g at 1 A/g), the best rate capability, and the most stable capacitance retention, which offered great promise as electrode materials for supercapacitors. PMID- 28098968 TI - Functional Microcapsules via Thiol-Ene Photopolymerization in Droplet-Based Microfluidics. AB - Thiol-ene chemistry was exploited in droplet-based microfluidics to fabricate advanced microcapsules with tunable encapsulation, degradation, and thermal properties. In addition, by utilizing the thiol-ene photopolymerization with tunable cross-link density, we demonstrate the importance of monomer conversion on the retention of omniphilic cargo in double emulsion templated microcapsules. Furthermore, we highlight the rapid cure kinetics afforded by thiol-ene chemistry in a continuous flow photopatterning device for hemispherical microparticle production. PMID- 28098969 TI - Exciplex-Forming Co-Host-Based Red Phosphorescent Organic Light-Emitting Diodes with Long Operational Stability and High Efficiency. AB - The use of exciplex forming cohosts and phosphors incredibly boosts the efficiency of organic light-emitting diodes (OLEDs) by providing a barrier-free charge injection into an emitting layer and a broad recombination zone. However, most of the efficient OLEDs based on the exciplex forming cohosts has suffered from the short operational lifetime. Here, we demonstrated phosphorescent OLEDs (PhOLEDs) having both high efficiency and long lifetime by using a new exciplex forming cohost composed of N,N'-diphenyl-N,N'-bis(1,1'-biphenyl)-4,4'-diamine (NPB) and (1,3,5-triazine-2,4,6-triyl)tris(benzene-3,1 diyl))tris(diphenylphosphine oxide) (PO-T2T). The red-emitting PhOLEDs using the exciplex forming cohost achieved a maximum external quantum efficiency (EQE) of 34.1% and power efficiency of 62.2 lm W1- with low operating voltages and low efficiency roll-offs. More importantly, the device demonstrated a long lifetime around 2249 h from 1000 cd m-2 to 900 cd m-2 (LT90) under a continuous flow of constant current. The efficiencies of the devices are the highest for red OLEDs with an LT90 > 1000 h. PMID- 28098970 TI - Strong Enhancement of Photoelectric Conversion Efficiency of Co-hybridized Polymer Solar Cell by Silver Nanoplates and Core-Shell Nanoparticles. AB - A new way was meticulously designed to utilize the localized surface plasmon resonance (LSPR) effect and the light scattering effect of silver nanoplate (Ag nPl) and core-shell Ag@SiO2 nanoparticles (Ag@SiO2-NPs) to enhance the photovoltaic performances of polymer solar cells (PSCs). To prevent direct contact between silver nanoparticles (Ag-NPs) and photoactive materials which will cause electrons quenching, bare Ag-nPl were spin-coated on indium tin oxide and silica capsulated Ag-NPs were incorporated to a PBDTTT-C-T:PC71BM active layer. As a result, the devices incorporated with Ag-nPl and Ag@SiO2-NPs showed great enhancements. With the dual effects of Ag-nPl and Ag@SiO2-NPs in devices, all wavelength sensitization in the visible range was realized; therefore, the power conversion efficiency (PCE) of PSCs showed a great enhancement of 14.0% to 8.46%, with an increased short-circuit current density of 17.23 mA.cm-2. The improved photovoltaic performances of the devices were ascribed to the LSPR effect and the light scattering effect of metallic nanoparticles. Apart from optical effects, the charge collection efficiency of PSCs was improved after the incorporation of Ag-nPl. PMID- 28098971 TI - Photodiode Response in a CH3NH3PbI3/CH3NH3SnI3 Heterojunction. AB - Here we report another surprising feature of the methylammonium metal halide material family, the phototunability of the diode response of a heterojunction made of CH3NH3PbI3 and its close relative, CH3NH3SnI3. In the dark state the device behaves as a diode, with the Sn homologue acting as the "p" side. The junction is extremely sensitive to illumination. A complete reversal of the diode polarity, the first observation of its kind, is seen when the junction is exposed to red laser light of 25 mW/cm2 or larger power density. This finding opens up the possibility for a novel class of optoelectronic devices. PMID- 28098973 TI - Electrochemiluminescence Detection of Escherichia coli O157:H7 Based on a Novel Polydopamine Surface Imprinted Polymer Biosensor. AB - In this paper, a facilely prepared electrochemiluminescence (ECL) biosensor was developed for Escherichia coli O157:H7 quantitative detection based on a polydopamine (PDA) surface imprinted polymer (SIP) and nitrogen-doped graphene quantum dots (N-GQDs). N-GQDs with a high quantum yield of 43.2% were synthesized. The uniform PDA SIP film for E. coli O157:H7 was established successfully with a facile route. The dopamine and target bacteria were electropolymerized directly on the electrode. After removal of the E. coli O157:H7 template, the established PDA SIP can selectively recognize E. coli O157:H7. Accordingly, E. coli O157:H7 polyclonal antibody (pAb) was labeled with N-GQDs. The bioconjugation of SIP-E. coli O157:H7/pAb-N-GQDs can generate intensive ECL irradiation with K2S2O8. As a result, E. coli O157:H7 was detected with the ECL sensing system. Under optimal conditions, the linear relationships between the ECL intensity and E. coli O157:H7 concentration were obtained from 101 colony-forming units (CFU) mL-1 to 107 CFU mL-1 with a limit of detection of 8 CFU mL-1. The biosensor based on this SIP film was applied in water sample detection successfully. The N-GQD-based ECL analytical method for E. coli O157:H7 was reported for the first time. The sensing system had high selectivity to the target analyte, provided new opportunities for use, and increased the rate of disease diagnosis and treatment and the prevention of pathogens. PMID- 28098972 TI - Hepta-Mutant Staphylococcus aureus Sortase A (SrtA7m) as a Tool for in Vivo Protein Labeling in Caenorhabditis elegans. AB - In vivo protein ligation is of emerging interest as a means of endowing proteins with new properties in a controlled fashion. Tools to site-specifically and covalently modify proteins with small molecules, peptides, or other proteins in living cells are few and far between. Here, we describe the development of a Staphylococcus aureus sortase (SrtA)-based protein ligation approach for site specific conjugation of fluorescent dyes and ubiquitin (Ub) to modify proteins in Caenorhabditis elegans. Hepta-mutant SrtA (SrtA7m) expressed in C. elegans is functional and supports in vitro sortase reactions in a low-Ca2+ environment. Feeding SrtA7m-expressing C. elegans with small peptide-based probes such as (Gly)3- biotin or (Gly)3-fluorophores enables in vivo target protein modification. SrtA7m also catalyzes the circularization of suitably modified linear target proteins in vivo and allows the installation of F-box domains on targets to induce their degradation in a ubiquitin-dependent manner. This is a noninvasive method to achieve in vivo protein labeling, protein circularization, and targeted degradation in C. elegans. This technique should improve our ability to monitor and alter the function of intracellular proteins in vivo. PMID- 28098974 TI - Surfactant-Free Preparation of Au@Resveratrol Hollow Nanoparticles with Photothermal Performance and Antioxidant Activity. AB - Nanocomposites based on hollow Au nanostructures have gained considerable attention in theranostics applications because of their unique plasmonic structures and attractive physicochemical properties. The exploration of feasible and facile methods for constructing multifunctional nanocomposites combined with bioactive molecules is greatly needed for the development of multifunctional theranostics platforms. In this work, resveratrol, a natural polyphenol with antioxidant activity and cancer-chemopreventive propertyies is employed as the reducing agent cum coating agent for the surfactant-free preparation of Au@resveratrol hollow NPs (Au@Res HNPs). The as-prepared Au@Res HNPs were found to present good photothermal performance and chemical inhibition for cancer therapy. In vitro experiments indicated that the Au@Res HNPs can block cell cycles to inhibit cell division and lead to cell apoptosis after 808-nm laser irradiation. Because no toxic surfactants are introduced, the current protocol avoids the tedious surfactant separation and surface modification processes that are necessary for most theranostics materials. PMID- 28098975 TI - Development of Spiro[cyclopenta[1,2-b:5,4-b']dithiophene-4,9'-fluorene]-Based A pi-D-pi-A Small Molecules with Different Acceptor Units for Efficient Organic Solar Cells. AB - Three acceptor-pi-donor-pi-acceptor (A-pi-D-pi-A) small molecules (STFYT, STFRDN, and STFRCN) with spiro[cyclopenta[1,2-b:5,4-b']dithiophene-4,9'-fluorene] (STF) as the central donor unit, terthiophene as the pi-conjugated bridge, indenedione, 3-ethylrhodanine, or 2-(1,1-dicyanomethylene)rhodanine as the acceptor unit are designed, synthesized, and characterized as electron donor materials in solution processing organic solar cells (OSCs). The effects of the spiro STF-based central core and different acceptors on the molecular configuration, absorption properties, electronic energy levels, carrier transport properties, the morphology of active layers, and photovoltaic properties are investigated in detail. The three molecules exhibit desirable physicochemical features: wide absorption bands (300-850 nm) and high molar absorption coefficients (4.82 * 104 to 7.56 * 104 M-1 cm-1) and relatively low HOMO levels (-5.15 to -5.38 eV). Density functional theory calculations reveal that the spiro STF central core benefits to reduce the steric hindrance effect between the central donor block and terthiophene bridge and suppress excessive intermolecular aggregations. The optimized OSCs based on these molecules deliver power conversion efficiencies (PCEs) of 6.68%, 3.30%, and 4.33% for STFYT, STFRDN, and STFRCN, respectively. The higher PCE of STFYT-based OSCs should be ascribed to its better absorption ability, higher and balanced hole and electron mobilities, and superior active layer morphology as compared to the other two compounds. So far, this is the first example of developing the A-pi-D-pi-A type small molecules with a spiro central donor core for high-performance OSC applications. Meanwhile, these results demonstrate that using spiro central block to construct A-pi-D-pi-A molecule is an alternative and effective strategy for achieving high-performance small molecule donor materials. PMID- 28098976 TI - Adsorption Neutralization Model and Floc Growth Kinetics Properties of Aluminum Coagulants Based on Sips and Boltzmann Equations. AB - Single-molecule aluminum salt AlCl3, medium polymerized polyaluminum chloride (PAC), and high polymerized polyaluminum chloride (HPAC) were prepared in a laboratory. The characteristics and coagulation properties of these prepared aluminum salts were investigated. The Langmuir, Freundlich, and Sips adsorption isotherms were first used to describe the adsorption neutralization process in coagulation, and the Boltzmann equation was used to fit the reaction kinetics of floc growth in flocculation. It was novel to find that the experimental data fitted well with the Sips and Boltzmann equation, and the significance of parameters in the equations was discussed simultaneously. Through the Sips equation, the adsorption neutralization reaction was proved to be spontaneous and the adsorption neutralization capacity was HPAC > PAC > AlCl3. Sips equation also indicated that the zeta potential of water samples would reach a limit with the increase of coagulant dosage, and the equilibrium zeta potential values were 30.25, 30.23, and 27.25 mV for AlCl3, PAC, and HPAC, respectively. The lower equilibrium zeta potential value of HPAC might be the reason why the water sample was not easy to achieve restabilization at a high coagulant dosage. Through the Boltzmann equation modeling, the maximum average floc size formed by AlCl3, PAC, and HPAC were 196.0, 188.0, and 203.6 MUm, respectively, and the halfway time of reactions were 31.23, 17.08, and 9.55 min, respectively. The HPAC showed the strongest floc formation ability and the fastest floc growth rate in the flocculation process, which might be caused by the stronger adsorption and bridging functions of Alb and Alc contained in HPAC. PMID- 28098978 TI - Reliable and Low-Power Multilevel Resistive Switching in TiO2 Nanorod Arrays Structured with a TiOx Seed Layer. AB - The electrical performance of TiO2 nanorod array (NRA)-based resistive switching memory devices is examined in this paper. The formation of a seed layer on the fluorine-doped tin oxide (FTO) glass substrate after treatment in TiCl4 solution, before the growth of TiO2 NRAs on the FTO substrate via a hydrothermal process, is shown to significantly improve the resistive switching performance of the resulting TiO2 NRA-based device. As fabricated, the Al/TiO2 NRA/TiOx layer/FTO device displayed electroforming-free bipolar resistive switching behavior while maintaining a stable ON/OFF ratio for more than 500 direct sweeping cycles over a retention period of 3 * 104 s. Meanwhile, the programming current as low as ~10-8 A and 10-10 A for low resistance state and high resistance state respectively makes the fabricated devices suitable for low-power memristor applications. The TiOx precursor seed layer not only promotes the uniform and preferred growth of TiO2 nanorods on the FTO substrate but also functions as an additional source layer of trap centers due to its oxygen-deficient composition. Our data suggest that the primary conduction mechanism in these devices arises from trap-mediated space-charge-limited current (SCLC). Multilevel memory performance in this new device is achieved by varying the SET voltage. The origin of this effect is also discussed. PMID- 28098977 TI - Lamellar Metal Organic Framework-Derived Fe-N-C Non-Noble Electrocatalysts with Bimodal Porosity for Efficient Oxygen Reduction. AB - Developing highly efficient and stable non-Pt electrocatalysts for the oxygen reduction reaction (ORR) to replace the state-of-the-art noble metal is essential for commercialization of fuel cells. Fe-N-C-based electrocatalysts are considered as a promising alternative to commercial Pt/C. An efficient electrocatalyst commonly requires large density of active site, high surface area, and desirable porosity, especially multimodal porosity with both large pores for efficient mass transfer and small pores for exposing as many active sites as possible. Herein, a lamellar metal organic framework (MOF) was developed as a precursor to directly achieve such a highly active Fe-N-C electrocatalyst with high surface area and desirable bimodal porosity. The mesopores arising from the special lamellar morphology of MOF benefits efficient mass transfer, and the nanopores resulting from pyrolysis of the MOF makes the majority of active sites accessible to electrolyte and thus effective for ORR. Uniform distribution of active elements N, C, and Fe at the molecular level in MOF precursor ensures abundant well dispersed highly active sites in the catalyst. As a result, the catalyst exhibited superior ORR electrocatalytic activity and stability to commercial Pt/C. This strategy, using rarely reported lamellar MOF to prepare ORR catalysts with the merits mentioned, could inspire the exploration of a wide range of electrocatalysts from lamellar MOF precursors for various applications. PMID- 28098979 TI - Electroactive Self-Assembled Monolayers Detect Micelle Formation. AB - The interfacial electrochemistry of self-assembled monolayers (SAMs) of ferrocenyldodecanethiolate on gold (FcC12SAu) electrodes is applied to detect the micellization of some common anionic surfactants, sodium n-alkyl sulfates, sodium n-alkyl sulfonates, sodium diamyl sulfosuccinate, and sodium dodecanoate, in aqueous solution by cyclic voltammetry. The apparent formal redox potential (E degrees 'SAM) of the FcC12SAu SAM is used to track changes in the concentration of the unaggregated surfactant anions and determine the critical micelle concentration (cmc). The effect of added salt (NaF) on the sodium alkyl sulfate concentration dependence of E degrees 'SAM is also investigated. Weakly hydrated anions, such as ClO4-, pair with the electrogenerated SAM-bound ferroceniums to neutralize the excess positive charge created at the SAM/electrolyte solution interface and stabilize the oxidized cations. E degrees 'SAM exhibits a Nernstian type dependence on the anion activity in solution. Aggregation of the surfactant anions into micelles above the cmc causes the free surfactant anion activity to deviate from the molar concentration of added surfactant, resulting in a break in the plot of E degrees 'SAM versus the logarithm of the concentration of anionic surfactant. The concentration at which this deviation occurs is in good agreement with literature or experimentally determined values of the cmc. The effects of Ohmic potential drop, liquid junction potential, and surfactant adsorption behavior on E degrees 'SAM are addressed. Ultimately, the E degrees 'SAM response as a function of the anionic surfactant concentration exhibits the same features reported using potentiometry and surfactant ion-selective electrodes, which provide a direct measure of the free surfactant anion activity, thus making FcC12SAu SAM electrodes useful for the detection of surfactant aggregation and micelle formation. PMID- 28098980 TI - Ruthenium(II) Complex-Based Luminescent Bifunctional Probe for Ag+ and Phosphate Ions: Ag+-Assisted Detection and Imaging of rRNA. AB - A new bis-heteroleptic Ru(II) complex (1) of benzimidazole-substituted 1,2,3 triazole pyridine ligand has been designed and constructed for the photoluminescent detection of cationic and anionic analytes, Ag+ and phosphate ions. Compound, 1[PF6]2 was fully characterized by various spectroscopic techniques and the solid-state structure was determined via single-crystal X-ray diffraction. The cation and anion sensing properties in 50% aqueous buffer (pH 9.2) and pure acetonitrile were carefully examined in photoluminescence (PL) spectroscopy. The 1[PF6]2 was found to be highly selective to pyrophosphate; PPi/HP2O73- and H2PO4- ions in CH3CN. It showed ~10-fold PL intensity enhancement at 583 nm in the presence of only 1 and 2 equiv of PPi and H2PO4- ions, respectively. The PL titrations of 1[PF6]2 with PPi and H2PO4- in CH3CN furnished the association constant (Ka = 3.3 * 103 M-1 and 6.8 * 103 M-1) and the detection limit was as low as 5.73 and 5.19 ppb, respectively. The 1[PF6]2 also selectively detected Ag+ over other competitive cations through the luminescence light up in 50% aqueous buffer (pH 9.2) media. The PL titration of 1[PF6]2 with Ag+ showed ~8 fold luminescence enhancement at 591 nm and yielded association constant, Ka = 3.5 * 104 M-1 and the detection limit was determined to be 5.05 ppb. A new cation sensing mechanism has been established where the Ag+ ion is detected in photoluminescence spectroscopy through the unique cyclometalated Ag+-triazolide complex formation. The high selectivity of 1[PF6]2 for phosphates and Ag+ was established by PL in the presence of various competing ions. Finally, for biological application, the cytotoxicity study was performed. The probe showed low cytotoxicity and was suitable for intracellular Ag+ imaging. The cell imaging and in vitro photoluminescence study revealed that the probe stained the cell nucleoli and specifically bind with ribosomal RNA (rRNA) and, therefore, it can also serve as a luminescent probe for rRNA in the presence of Ag+. PMID- 28098981 TI - Comparing Ion Exchange Adsorbents for Nitrogen Recovery from Source-Separated Urine. AB - Separate collection of urine, which is only 1% of wastewater volume but contains the majority of nitrogen humans excrete, can potentially reduce the costs and energy input of wastewater treatment and facilitate recovery of nitrogen for beneficial use. Ion exchange was investigated for recovery of nitrogen as ammonium from urine for use as a fertilizer or disinfectant. Cation adsorption curves for four adsorbents (clinoptilolite, biochar, Dowex 50, and Dowex Mac 3) were compared in pure salt solutions, synthetic urine, and real stored urine. Competition from sodium and potassium present in synthetic and real urine did not significantly decrease ammonium adsorption for any of the adsorbents. Dowex 50 and Dowex Mac 3 showed nearly 100% regeneration efficiencies. Estimated ion exchange reactor volumes to capture the nitrogen for 1 week from a four-person household were lowest for Dowex Mac 3 (5 L) and highest for biochar (19 L). Although Dowex Mac 3 had the highest adsorption capacity, material costs ($/g N removed) were lower for clinoptilolite and biochar because of their substantially lower unit cost. PMID- 28098982 TI - Glycine Substitutions in Collagen Heterotrimers Alter Triple Helical Assembly. AB - Osteogenesis imperfecta typically results from missense mutations in the collagen genome where the required glycine residues are replaced with another amino acid. Many models have attempted to replicate the structure of mutated collagen on the triple helix level. However, composition and register control of the triple helix is complicated and requires extreme precision, especially when these destabilizing mutations are present. Here we present mutations to a composition- and register-controlled AAB helix where one of the requisite glycines in the A chain of the triple helix is changed to serine or alanine. We see a loss of compositional control when the A chain is mutated, resulting in an A'BB composition that minimizes the number of mutations included in the triple helix. However, when both A and B chains are mutated and no nonmutated peptide chains are available, the designed A'A'B' composition is reestablished. Our work shows the ability of the mutations to influence and alter the composition and register of the collagen triple helix. PMID- 28098983 TI - Redox-Initiated Reactivity of Dinuclear beta-Diketiminatoniobium Imido Complexes. AB - High-valent dichloride and dimethylniobium complexes 1 and 2 bearing tert butylimido and N,N'-bis(2,4,6-trimethylphenyl)-beta-diketiminate (BDIAr) ligands were prepared. The dimethyl complex reacted with dihydrogen to release methane and generate the hydride-bridged diniobium(IV) complex 3 in high yield. One electron oxidation of 3 with silver salts resulted in the release of dihydrogen and conversion to a mixed-valent NbIII-NbIV complex, 4, that displayed a frozen solution X-band electron paramagnetic resonance signal consistent with a slight dissymmetry between the two Nb centers. Spectroscopic and computational analysis supported the presence of Nb-Nb sigma-bonding interactions in both 3 and 4. Finally, one-electron reduction of 4 resulted in conversion to the highly dissymmetric NbV-NbV dimer 5 that formed from the reductive C-N bond cleavage of one of the BDIAr supporting ligands. PMID- 28098984 TI - Red-Emitting Ruthenium(II) and Iridium(III) Complexes as Phosphorescent Probes for Methylglyoxal in Vitro and in Vivo. AB - Transition-metal complexes, ruthenium(II) and iridium(III) complexes in particular, with fascinating triplet emissions are rapidly emerging as important phosphorescent dyes for application in the sensing and imaging of biological makers in live cells and organisms. In this contribution, two red-emitting transition-metal complexes, [Ru(bpy)2(DA-phen)](PF6)2 and [Ir(ppy)2(DA phen)](PF6) (bpy = 2,2'-bipyridine, DA-phen = 4,5-diamino-1,10-phenanthroline, and ppy = 2-phenylpyridine), were designed and synthesized as phosphorescent probes for the highly sensitive and selective detection of methylglyoxal (MGO), an essential biomarker in the etiopathogenesis of several diseases. Both probes showed weak emissions in aqueous media because of the existence of an effective photoinduced-electron-transfer process, while their emissions could be remarkably enhanced upon the addition of MGO. The photophysical and electrochemical properties, as well as phosphorescent responses of the probes toward MGO, were examined. The ground- and excited-state properties of the probes and their reaction products with MGO, [Ru(bpy)2(MP-phen)](PF6)2 and [Ir(ppy)2(MP phen)](PF6) (MP-phen = 2-methylpyrazino-1,10-phenanthroline), the sensing mechanism, and several important experimental facts were investigated and validated using density functional theory (DFT)/time-dependent DFT computations. The results indicated that the phosphorescence switch-ON is due to the elimination of electron transfer and followed the reestablishment of emissive triplet excited states. To evaluate the feasibility of [Ru(bpy)2(DA-phen)](PF6)2 and [Ir(ppy)2(DA-phen)](PF6) as bioprobes, their cytotoxicity was examined, and their applicability for visualizing intracellular and in vivo MGO was demonstrated. PMID- 28098986 TI - Investigation of the Energy-Transfer Mechanism in Ho3+- and Yb3+-Codoped Lu2O3 Phosphor with Efficient Near-Infrared Downconversion. AB - A high-temperature solid-state method was used to synthesize the Ho3+- and Yb3+ codoped cubic Lu2O3 powders. The crystal structures of the as-prepared powders were characterized by X-ray diffraction. The energy-transfer (ET) phenomenon between Ho3+ ions and Yb3+ ions was verified by the steady-state spectra including visible and near-infrared (NIR) regions. Beyond that, the decay curves were also measured to certify the existence of the ET process. The downconversion phenomena appeared when the samples were excited by 446 nm wavelength corresponding to the transition of Ho3+: 5I8->5G6/5F1. On the basis of the analysis of the relationship between the initial transfer rate of Ho3+: 5F3 level and the Yb3+ doping concentration, it indicates that the ET from 5F3 state of Ho3+ ions to 2F5/2 state of Yb3+ ions is mainly through a two-step ET process, not the long-accepted cooperative ET process. In addition, a 62% ET efficiency can be achieved in Lu2O3: 1% Ho3+/30% Yb3+. Unlike the common situations in which the NIR photons are all emitted by the acceptors Yb3+, the sensitizers Ho3+ also make contributions to the NIR emission upon 446 nm wavelength excitation. Meanwhile, the 5I5->5I8 transition and 5F4/5S2->5I6 transition of Ho3+ as well as the 2F5/2->2F7/2 transition of Yb3+ match well with the optimal spectral response of crystalline silicon solar cells. The current research indicates that Lu2O3: Ho3+/Yb3+ is a promising material to improve conversion efficiency of crystalline silicon solar cell. PMID- 28098985 TI - HMGB1 Stimulates Activity of Polymerase beta on Nucleosome Substrates. AB - The process of base excision repair (BER) recognizes and repairs small lesions or inappropriate bases on DNA through either a short-patch or long-patch pathway. The enzymes involved in BER have been well-characterized on DNA substrates, and, somewhat surprisingly, many of these enzymes, including several DNA glycosylases, AP endonuclease (APE), FEN1 endonuclease, and DNA ligases, have been shown to have activity on DNA substrates within nucleosomes. DNA polymerase beta (Pol beta), however, exhibits drastically reduced or no activity on nucleosomal DNA. Interestingly, acetylation of Pol beta, by the acetyltransferase p300, inhibits its 5' dRP-lyase activity and presumably pushes repair of DNA substrates through the long-patch base excision repair (LP-BER) pathway. In addition to the major enzymes involved in BER, a chromatin architectural factor, HMGB1, was found to directly interact with and enhance the activity of APE1 and FEN1, and thus may aid in altering the structure of the nucleosome to be more accessible to BER factors. In this work, we investigated whether acetylation of Pol beta, either alone or in conjunction with HMGB1, facilitates its activity on nucleosome substrates. We find acetylated Pol beta exhibits enhanced strand displacement synthesis activity on DNA substrates, but, similar to the unmodified enzyme, has little or no activity on nucleosomes. Preincubation of DNA templates with HMGB1 has little or no stimulatory effect on Pol beta and even is inhibitory at higher concentrations. In contrast, preincubation of nucleosomes with HMGB1 rescues Pol beta gap-filling activity in nucleosomes, suggesting that this factor may help overcome the repressive effects of chromatin. PMID- 28098987 TI - Predicting Copper Speciation in Estuarine Waters-Is Dissolved Organic Carbon a Good Proxy for the Presence of Organic Ligands? AB - A new generation of speciation-based aquatic environmental quality standards (EQS) for metals have been developed using models to predict the free metal ion concentration, the most ecologically relevant form, to set site-specific values. Some countries such as the U.K. have moved toward this approach by setting a new estuarine and marine water EQS for copper, based on an empirical relationship between copper toxicity to mussels (Mytilus sp.) and ambient dissolved organic carbon (DOC) concentrations. This assumes an inverse relationship between DOC and free copper ion concentration owing to complexation by predominantly organic ligands. At low DOC concentrations, the new EQS is more stringent, but above 162 MUM DOC it is higher than the previous value. However, the relationship between DOC and copper speciation is poorly defined in estuarine waters. This research discusses the influence of DOC from different sources on copper speciation in estuaries and concludes that DOC is not necessarily an accurate predictor of copper speciation. Nevertheless, the determination of ligand strength and concentrations by Competitive Ligand Exchange Adsorptive Cathodic Stripping Voltammetry enabled the prediction of the free metal ion concentration within an order of magnitude for estuarine waters by using a readily available metal speciation model (Visual MINTEQ). PMID- 28098988 TI - C-F Bond Cleavage Enabled Redox-Neutral [4+1] Annulation via C-H Bond Activation. AB - Using alpha,alpha-difluoromethylene alkyne as a nontraditional one-carbon reaction partner, a synthetically novel method for the construction of isoindolin 1-one derivatives via Rh(III)-catalyzed [4+1] annulation reaction is reported. The 2-fold C-F bond cleavage not only enables the generation of desired product under an overall oxidant-free condition but also results in a net migration of carbon-carbon triple bond. In addition, the present reaction protocol exhibits a tolerance of a wide spectrum of functional groups due to the mild reaction conditions employed. PMID- 28098990 TI - Chemo- and Regioselective Distal Heteroaryl ipso-Migration: A General Protocol for Heteroarylation of Unactivated Alkenes. AB - Herein we report a novel, general protocol for distal heteroaryl ipso-migration and its application to the elusive heteroarylation of unactivated alkenes. A set of nitrogen-containing heteroaryl groups showcase the migratory aptitude. This reaction provides a variety of fluoroalkyl functionalized heteroarenes under mild reaction conditions. This is the first report of a difunctionalization of unactivated alkenes with distal heteroaryl migration. PMID- 28098989 TI - Discovery of 40 Classes of Per- and Polyfluoroalkyl Substances in Historical Aqueous Film-Forming Foams (AFFFs) and AFFF-Impacted Groundwater. AB - Aqueous film-forming foams (AFFFs), containing per- and polyfluoroalkyl substances (PFASs), are released into the environment during response to fire related emergencies. Repeated historical applications of AFFF at military sites were a result of fire-fighter training exercises and equipment testing. Recent data on AFFF-impacted groundwater indicates that ~25% of the PFASs remain unidentified. In an attempt to close the mass balance, a systematic evaluation of 3M and fluorotelomer-based AFFFs, commercial products, and AFFF-impacted groundwaters from 15 U.S. military bases was conducted to identify the remaining PFASs. Liquid chromatography quadrupole time-of-flight mass spectrometry was used for compound discovery. Nontarget analysis utilized Kendrick mass defect plots and a "nontarget" R script. Suspect screening compared masses with those of previously reported PFASs. Forty classes of novel anionic, zwitterionic, and cationic PFASs were discovered, and an additional 17 previously reported classes were observed for the first time in AFFF and/or AFFF-impacted groundwater. All 57 classes received an acronym and IUPAC-like name derived from collective author knowledge. Thirty-four of the 40 newly identified PFAS classes derive from electrochemical fluorination (ECF) processes, most of which have the same base structure. Of the newly discovered PFASs found only in AFFF-impacted groundwater, 11 of the 13 classes are ECF-derived, and the remaining two classes are fluorotelomer-derived, which suggests that both ECF- and fluorotelomer-based PFASs are persistent in the environment. PMID- 28098991 TI - Evidence of Absence: Estrogenicity Assessment of a New Food-Contact Coating and the Bisphenol Used in Its Synthesis. AB - Consumer concerns about exposure to substances found in food contact materials with estrogenic activity (EA) have created substantial demand for alternatives. We assessed the potential EA of both a new bisphenol monomer used to synthesize polymeric coatings for metal food-contact applications and the nonintentionally added substances (NIAS) that may migrate into food. We evaluated tetramethyl bisphenol F (TMBPF) using in vitro and in vivo assays. We extracted the polymeric coating using food simulants ethanol (50% v/v) and acetic acid (3% w/v) and measured migration using tandem liquid chromatography (LC)/mass spectrometry (MS) and LC time-of-flight MS for TMBPF and NIAS, respectively. We also tested migrants for EA using the E-SCREEN assay. TMBPF did not show estrogenic activity in the uterotrophic assay and did not alter puberty in male and female rats or mammary gland development in female rats. Neither TMBPF nor the migrants from the final polymeric coating increased proliferation of estrogen-sensitive MCF7 cells. TMBPF did not show estrogen-agonist or antagonist activity in the estrogen receptor-transactivation assay. TMBPF migration was below the 0.2 parts per billion detection limit. Our findings provide compelling evidence for the absence of EA by TMBPF and the polymeric coating derived from it and that human exposure to TMBPF would be negligible. PMID- 28098992 TI - Mechanistic Insights into Tunable Metal-Mediated Hydrolysis of Amyloid-beta Peptides. AB - An amyloidogenic peptide, amyloid-beta (Abeta), has been implicated as a contributor to the neurotoxicity of Alzheimer's disease (AD) that continues to present a major socioeconomic burden for our society. Recently, the use of metal complexes capable of cleaving peptides has arisen as an efficient tactic for amyloid management; unfortunately, little has been reported to pursue this strategy. Herein, we report a novel approach to validate the hydrolytic cleavage of divalent metal complexes toward two major isoforms of Abeta (Abeta40 and Abeta42) and tune their proteolytic activity based on the choice of metal centers (M = Co, Ni, Cu, and Zn) which could be correlated to their anti-amyloidogenic properties. Such metal-dependent tunability was facilitated employing a tetra-N methylated cyclam (TMC) ligand that imparts unique geometric and stereochemical control, which has not been available in previous systems. Co(II)(TMC) was identified to noticeably cleave Abeta peptides and control their aggregation, reporting the first Co(II) complex for such reactivities to the best of our knowledge. Through detailed mechanistic investigations by biochemical, spectroscopic, mass spectrometric, and computational studies, the critical importance of the coordination environment and acidity of the aqua-bound complexes in promoting amide hydrolysis was verified. The biological applicability of Co(II)(TMC) was also illustrated via its potential blood-brain barrier permeability, relatively low cytotoxicity, regulatory capability against toxicity induced by both Abeta40 and Abeta42 in living cells, proteolytic activity with Abeta peptides under biologically relevant conditions, and inertness toward cleavage of structured proteins. Overall, our approaches and findings on reactivities of divalent metal complexes toward Abeta, along with the mechanistic insights, demonstrate the feasibility of utilizing such metal complexes for amyloid control. PMID- 28098993 TI - In Situ Hydrogenation of the Zintl Phase SrGe. AB - Hydrides (deuterides) of the CrB-type Zintl phases AeTt (Ae = alkaline earth; Tt = tetrel) show interesting bonding properties with novel polyanions. In SrGeD4/3 x (gamma phase), three zigzag chains of Ge atoms are condensed and terminated by covalently bound D atoms. A combination of in situ techniques (thermal analysis and synchrotron and neutron powder diffraction) revealed the existence of two further hydride (deuteride) phases with lower H (D) content (called alpha and beta phases). Both are structurally related to the parent Zintl phase SrGe and to the ZrNiH structure type containing variable amounts of H (D) in Sr4 tetrahedra. For alpha-SrGeDy, the highest D content y = 0.29 was found at 575(2) K under 5.0(1) MPa of D2 pressure, and beta-SrGeDy shows a homogeneity range of 0.47 < y < 0.63. Upon decomposition of SrGeD4/3-x (gamma-SrGeDy), tetrahedral Sr4 voids stay filled, while the Ge-bound D4 site loses D. When reaching the lower D content limit, SrGeD4/3-x (gamma phase) with 0.10 < x < 0.17, decomposes to the beta phase. All three hydrides (deuterides) of SrGe show variable H (D) content. PMID- 28098994 TI - Hydrides of Alkaline Earth-Tetrel (AeTt) Zintl Phases: Covalent Tt-H Bonds from Silicon to Tin. AB - Zintl phases form hydrides either by incorporating hydride anions (interstitial hydrides) or by covalent bonding of H to the polyanion (polyanionic hydrides), which yields a variety of different compositions and bonding situations. Hydrides (deuterides) of SrGe, BaSi, and BaSn were prepared by hydrogenation (deuteration) of the CrB-type Zintl phases AeTt and characterized by laboratory X-ray, synchrotron, and neutron diffraction, NMR spectroscopy, and quantum-chemical calculations. SrGeD4/3-x and BaSnD4/3-x show condensed boatlike six-membered rings of Tt atoms, formed by joining three of the zigzag chains contained in the Zintl phase. These new polyanionic motifs are terminated by covalently bound H atoms with d(Ge-D) = 1.521(9) A and d(Sn-D) = 1.858(8) A. Additional hydride anions are located in Ae4 tetrahedra; thus, the features of both interstitial hydrides and polyanionic hydrides are represented. BaSiD2-x retains the zigzag Si chain as in the parent Zintl phase, but in the hydride (deuteride), it is terminated by H (D) atoms, thus forming a linear (SiD) chain with d(Si-D) = 1.641(5) A. PMID- 28098995 TI - A Chemometrics Approach to the Investigation of the Intraspecific Variability of the Volatile Oil of Eupatorium tremulum from Southern Brazil. AB - Eupatorium tremulum is a South American shrub reported to cause cattle digestive intoxication, of which the volatile oil, mainly composed by bisabolane- and amorphane-type sesquiterpenoids, exhibits high quantitative variability. This report describes the application of chemometric tools for the identification of volatile compounds that characterize phenophasical changes in the plant. Preblooming, blooming, and postblooming specimens were paired-sampled and submitted to hydrodistillation and GC-MS analysis. Differential results were analyzed by orthogonal projection to latent structures-discriminant analysis (OPLS-DA), and the substances with different distribution in each phase were highlighted. Mean results between phases were submitted to factor analysis (FA), and correlations between the variables were demonstrated. Preblooming to blooming phase change was characterized by decreased levels of amorpha-4-en-7-ol (13) and epi-alpha-bisabolol (19) and increased amounts of amorpha-4,7(11)-diene (1). Blooming to postblooming change was characterized by decreases in 1, germacrene D (2), and beta-bisabolene (4) and increases in 13 and 19. Finally, enhanced levels of 1, 4, and 2 reflected the change from the postblooming to the preblooming phase. FA revealed a strong correlation in the variability between the bisabolane hydrocarbons, possibly related to its common enzymatic origin. Another strong source of negative correlation showed bisabolane- and amorphane-type alcohols, on one side, and amorphane-type furans, on the other side, to occur in two alternative oxidation routes. Finally, 1 was strongly negatively correlated to its oxidized furan and ketofuran derivatives [verboccidentafuran (16) and 3-oxo verboccidentafuran (23)] and additionally to a third compound, putatively identified as a biosynthetic intermediate between this hydrocarbon and the furans, amorpha-4,7(11)-dien-8-one (20). PMID- 28098996 TI - Ulapualides C-E Isolated from a Hawaiian Hexabranchus sanguineus Egg Mass. AB - Three new ulapualides (3-5) were isolated from egg masses of the nudibranch Hexabranchus sanguineus. The structures of 3-5 were deduced by analyses of physical and spectroscopic data in comparisons with ulapualides A (1) and B (2). Ulapualide C demonstrated submicromolar cytotoxicity against select NCI cell lines (768-0, DU-145, MDA-MB-231, and A549) with the most potent activity against MDA-MB-231 cells (IC50 0.58 MUM). Ulapualides A (1) and B (2) were 2- to 4-fold more potent than 3. PMID- 28098997 TI - Two-Step Design of a Single-Doped White Phosphor with High Color Rendering. AB - A strategy to design step by step an inorganic single-doped white phosphor is demonstrated. The method consists in tuning different contributions of the emission by successively controlling the chemical compositions of the solid solution or nanosegregated host matrix and the oxidation states of the single dopant. We use this approach to design a white phosphor Na4CaMgSc4Si10O30:Eu with excellent color rendering (CRI > 90) that is similar to common mixed-phosphor light sources but for a single-phase. We show that this methodology can also be extended to other phosphors for use in diverse applications such as biomedicine or telecommunications. PMID- 28098998 TI - Chemical and Antioxidant Properties of Betalains. AB - Betalains are vacuolar pigments composed of a nitrogenous core structure, betalamic acid. Betalamic acid condenses with imino compounds (cyclo-DOPA/its glucosyl derivates) or amino acids/derivates to form violet betacyanins and yellow betaxanthins. These pigments have gained the curiosity of scientific researchers in recent decades. Their importance was increased not only by market orientation toward natural colorants and antioxidants but also by their safety and health promoting properties. To date, about 78 betalains have been identified from plants of about 17 families. In this review, all of the identified pigments are presented, followed by a comprehensive discussion of their structure-activity relationship. PMID- 28098999 TI - DNA Deformation-Coupled Recognition of 8-Oxoguanine: Conformational Kinetic Gating in Human DNA Glycosylase. AB - 8-Oxoguanine (8-oxoG), a mutagenic DNA lesion generated under oxidative stress, differs from its precursor guanine by only two substitutions (O8 and H7). Human 8 oxoguanine glycosylase 1 (OGG1) can locate and remove 8-oxoG through extrusion and excision. To date, it remains unclear how OGG1 efficiently distinguishes 8 oxoG from a large excess of undamaged DNA bases. We recently showed that formamidopyrimidine-DNA glycosylase (Fpg), a bacterial functional analog of OGG1, can selectively facilitate eversion of oxoG by stabilizing several intermediate states, and it is intriguing whether OGG1 also employs a similar mechanism in lesion recognition. Here, we use molecular dynamics simulations to explore the mechanism by which OGG1 discriminates between 8-oxoG and guanine along the base eversion pathway. The MD results suggest an important role for kinking of the DNA by the glycosylase, which positions DNA phosphates in a way that assists lesion recognition during base eversion. The computational predictions were validated through experimental enzyme assays on phosphorothioate substrate analogs. Our simulations suggest that OGG1 distinguishes between 8-oxoG and G using their chemical dissimilarities not only at the active site but also at earlier stages during base eversion, and this mechanism is at least partially conserved in Fpg despite a lack of structural homology. The similarity also suggests that lesion recognition through multiple gating steps may be a common theme in DNA repair. Our results provide new insight into how enzymes can exploit kinetics and DNA conformational changes to probe the chemical modifications present in DNA lesions. PMID- 28099000 TI - Application of Nano FeIII-Tannic Acid Complexes in Modifying Aqueous Acrylic Latex for Controlled-Release Coated Urea. AB - Acrylic latexes are valuable waterborne materials used in controlled-release fertilizers. Controlled-release urea coated with these latexes releases a large amount of nutrients, making it difficult to meet the requirement of plants. Herein, FeIII-tannic acid (TA) complexes were blended with acrylic latex and subsequently reassembled on a surface of polyacrylate particles. These complexes remarkably retarded the release of urea (the preliminary solubility was decreased from 22.3 to 0.8%) via decreasing the coating tackiness (Tg was increased from 4.17 to 6.42 degrees C), increasing the coating strength (tensile stress was improved from 3.88 to 4.45 MPa), and promoting the formation of denser structures (surface tension was decreased from 37.37 to 35.94 mN/m). Overall, our findings showed that a simple blending of FeIII-TA complexes with acrylic latex produces excellent coatings that delay the release of urea, which demonstrates great potential for use in controlled-release fertilizers coated with waterborne polymers. PMID- 28099002 TI - Theory and Applications of Generalized Pipek-Mezey Wannier Functions. AB - The theory for the generation of Wannier functions within the generalized Pipek Mezey approach (Lehtola, S.; Jonsson, H. J. Chem. Theory Comput. 2014, 10, 642) is presented and an implementation thereof is described. Results are shown for systems with periodicity in one, two, and three dimensions as well as isolated molecules. The generalized Pipek-Mezey Wannier functions (PMWF) are highly localized orbitals consistent with chemical intuition where a distinction is maintained between sigma- and pi-orbitals. The PMWF method is compared with the so-called maximally localized Wannier functions (MLWFs) that are frequently used for the analysis of condensed matter calculations. Whereas PMWFs maximize the localization criterion of Pipek and Mezey, MLWFs maximize that of Foster and Boys and have the disadvantage of mixing sigma- and pi-orbitals in many cases. The PMWF orbitals turn out to be as localized as the MLWF orbitals as evidenced by cross-comparison of the values of the PMWF and MLWF objective functions for the two types of orbitals. Our implementation in the atomic simulation environment (ASE) is compatible with various representations of the wave function, including real-space grids, plane waves, and linear combinations of atomic orbitals. The projector-augmented wave formalism for the representation of atomic core electrons is also supported. Results of calculations with the GPAW software are described here, but our implementation can also use output from other electronic structure software such as ABINIT, NWChem, and VASP. PMID- 28099001 TI - Conformational Dynamics in Penicillin-Binding Protein 2a of Methicillin-Resistant Staphylococcus aureus, Allosteric Communication Network and Enablement of Catalysis. AB - The mechanism of the beta-lactam antibacterials is the functionally irreversible acylation of the enzymes that catalyze the cross-linking steps in the biosynthesis of their peptidoglycan cell wall. The Gram-positive pathogen Staphylococcus aureus uses one primary resistance mechanism. An enzyme, called penicillin-binding protein 2a (PBP2a), is brought into this biosynthetic pathway to complete the cross-linking. PBP2a effectively discriminates against the beta lactam antibiotics as potential inhibitors, and in favor of the peptidoglycan substrate. The basis for this discrimination is an allosteric site, distal from the active site, that when properly occupied concomitantly opens the gatekeeper residues within the active site and realigns the conformation of key residues to permit catalysis. We address the molecular basis of this regulation using crystallographic studies augmented by computational analyses. The crystal structures of three beta-lactams (oxacillin, cefepime, ceftazidime) complexes with PBP2a-each with the beta-lactam in the allosteric site-defined (with preceding PBP2a structures) as the "open" or "partially open" PBP2a states. A particular loop motion adjacent to the active site is identified as the driving force for the active-site conformational change that accompanies active-site opening. Correlation of this loop motion to effector binding at the allosteric site, in order to identify the signaling pathway, was accomplished computationally in reference to the known "closed" apo-PBP2a X-ray crystal structure state. This correlation enabled the computational simulation of the structures coinciding with initial peptidoglycan substrate binding to PBP2a, acyl enzyme formation, and acyl transfer to a second peptidoglycan substrate to attain cross-linking. These studies offer important insights into the structural bases for allosteric site-to-active site communication and for beta-lactam mimicry of the peptidoglycan substrates, as foundational to the mechanistic understanding of emerging PBP2a resistance mutations. PMID- 28099004 TI - Nickel-Mediated Decarbonylation of Simple Unstrained Ketones through the Cleavage of Carbon-Carbon Bonds. AB - Despite advances in methods for the decarbonylation of aldehydes, the decarbonylation of ketones has been met with limited success because this process requires the activation of two inert carbon-carbon bonds. All of the decarbonylation reactions of simple unstrained ketones reported to date require the addition of a stoichiometric rhodium complex. We report herein the nickel/N heterocyclic carbene-mediated decarbonylation of simple diaryl ketones. This reaction shows unique acceleration effects based on the presence of both electron donating and electron-withdrawing groups. PMID- 28099003 TI - (-)-Neocaryachine, an Antiproliferative Pavine Alkaloid from Cryptocarya laevigata, Induces DNA Double-Strand Breaks. AB - Twelve benzylisoquinoline alkaloids, including pavine and phenanthroindolizidine types, were isolated from a MeOH/CH2Cl2 extract of Cryptocarya laevigata (stem bark) through bioactivity-guided fractionation for antitumor effects. Selected compounds were evaluated for antiproliferative activity against five human tumor cell lines, including a multidrug-resistant subline. Since more common 2,3,8,9 tetrasubstituted pavine alkaloids, such as crychine (3), exhibit very mild or no cytotoxicity, this compound type has not been well investigated for antitumor activity. Thus, this report is the first discovery of a 7-hydroxylated pavine alkaloid, (-)-neocaryachine (1), to demonstrate strong antiproliferative activity, with IC50 values of 0.06 to 0.41 MUM against five tested tumor cell lines, including an MDR subline. Further mechanism of action studies revealed that 1 impacts the cellular S-phase by inducing DNA double-strand breaks. PMID- 28099005 TI - Complementarity of DFT Calculations, NMR Anisotropy, and ECD for the Configurational Analysis of Brevipolides K-O from Hyptis brevipes. AB - Brevipolides K-O (1-5), five new cytotoxic 6-(6'-cinnamoyloxy-2',5'-epoxy-1' hydroxyheptyl)-5,6-dihydro-2H-pyran-2-ones (IC50 values against six cancer cell lines, 1.7-10 MUM), were purified by recycling HPLC from Hyptis brevipes. The structures, containing a distinctive tetrahydrofuran ring, were established by comprehensive quantum mechanical calculations and experimental spectroscopic analysis of their NMR and ECD data. Detailed analysis of the experimental NMR 1H 1H vicinal coupling constants in comparison with the corresponding DFT-calculated values at the B3LYP/DGDZVP level confirmed the absolute configuration of 3 and revealed its conformational preferences, which were further strengthened by NOESY correlations. NMR anisotropy experiments by the application of Mosher's ester methodology and chemical correlations were also used to conclude that this novel brevipolide series (1-5) share the same absolute configuration corresponding to C 6(R), C-1'(S), C-2'(R), C-5'(S), and C-6'(S). PMID- 28099006 TI - Constituents of the Rhizomes of Boesenbergia pandurata and Their Antiausterity Activities against the PANC-1 Human Pancreatic Cancer Line. AB - Human pancreatic cancer cell lines have a remarkable tolerance to nutrition starvation, which enables them to survive under a tumor microenvironment. The search for agents that preferentially inhibit the survival of cancer cells under low nutrient conditions represents a novel antiausterity strategy in anticancer drug discovery. In this investigation, a methanol extract of the rhizomes of Boesenbergia pandurata showed potent preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrient-deprived conditions, with a PC50 value of 6.6 MUg/mL. Phytochemical investigation of this extract led to the isolation of 15 compounds, including eight new cyclohexene chalcones (1-8). The structures of the new compounds were elucidated by NMR spectroscopic data analysis. Among the isolated compounds obtained, isopanduratin A1 (14) and nicolaioidesin C (15) exhibited potent preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrition-deprived conditions, with PC50 values of 1.0 and 0.84 MUM, respectively. PMID- 28099007 TI - Pyridinium Boranephosphonate Modified DNA Oligonucleotides. AB - The synthesis of previously unknown derivatives of boranephosphonate that contain amine substitutions at boron and the incorporation of these derivatives into the backbone of DNA oligonucleotides is described. These derivatives result from iodine-mediated replacement of one BH3 hydride of a boranephosphonate linkage by pyridine, various substituted pyridines, other aromatic amines, and certain unsaturated amines. Oligonucleotides containing these backbone modifications show enhanced uptake, relative to unmodified DNA, in mammalian cells. The redox behavior of the boranephosphonate and pyridinium boranephosphonate conjugated linkages has also been studied. PMID- 28099008 TI - Critical Analysis of Rate Constants and Turnover Frequency in Nucleic Acid Templated Reactions: Reaching Terminal Velocity. AB - Nucleic acid-templated reactions have attracted significant attention for nucleic acid sensing and imaging. The level of signal amplification obtained from templated reactions is a function of the template turnover, wherein the template acts as the catalyst. Herein, we report the application of a pyridinium linker that immolates upon photocatalytic reduction with a ruthenium complex to yield the fastest nucleic acid templated reaction reported to date. We show that the templated reaction turnover is limited by the duplex dissociation kinetics beyond probes longer than a 6-mer and proceeded fastest for a 5-mer PNA probe. Using a beacon architecture that masks the catalytic template, we show that this methodology can be used for nucleic acid sensing extending the analyte recognition beyond a 5-mer. The system proceeds with a catalytic efficiency of 105 M-1 s-1 and achieves turnover frequency of >100 h-1. PMID- 28099009 TI - Thickness-Controlled Quasi-Two-Dimensional Colloidal PbSe Nanoplatelets. AB - We demonstrate controlled synthesis of discrete two-dimensional (2D) PbSe nanoplatelets (NPLs), with measurable photoluminescence, via oriented attachment directed by quantum dot (QD) surface chemistry. Halide passivation is critical to the growth of these (100) face-dominated NPLs, as corroborated by density functional theory studies. PbCl2 moieties attached to the (111) and (110) of small nanocrystals form interparticle bridges, aligning the QDs and leading to attachment. We find that a 2D bridging network is energetically favored over a 3D network, driving the formation of NPLs. Although PbI2 does not support bridging, its presence destabilizes the large (100) faces of NPLs, providing means for tuning NPL thickness. Spectroscopic analysis confirms the predicted role of thickness-dependent quantum confinement on the NPL band gap. PMID- 28099010 TI - Functional-Group-Tolerant, Silver-Catalyzed N-N Bond Formation by Nitrene Transfer to Amines. AB - Silver(I) promotes the highly chemoselective N-amidation of tertiary amines under catalytic conditions to form aminimides by nitrene transfer from PhI?NTs. Remarkably, this transformation proceeds in a selective manner in the presence of olefins and other functional groups without formation of the commonly observed aziridines or C-H insertion products. The methodology can be applied not only to rather simple tertiary amines but also to complex natural molecules such as brucine or quinine, where the products derived from N-N bond formation were exclusively formed. Theoretical mechanistic studies have shown that this selective N-amidation reaction proceeds through triplet silver nitrenes. PMID- 28099011 TI - Montagnuphilones A-G, Azaphilones from Montagnulaceae sp. DM0194, a Fungal Endophyte of Submerged Roots of Persicaria amphibia. AB - Seven azaphilones, montagnuphilones A-G (1-7), together with previously known azaphilones 8-11, were encountered in Montagnulaceae sp. DM0194, an endophytic fungus isolated from submerged roots of Persicaria amphibia. The structures of 1 7 were elucidated on the basis of their MS and NMR spectroscopic analysis. Compounds 1-8 were evaluated for their cytotoxicity and ability to inhibit nitric oxide (NO) production in lipopolysaccharide-activated RAW264.7 macrophage cells. Among these, none were found to be cytotoxic to RAW264.7 cells up to 100.0 MUM, but 8, 5, and 2 showed NO inhibitory activity with IC50 values of 9.2 +/- 0.9, 25.5 +/- 1.1, and 39.6 +/- 1.8 MUM, respectively. PMID- 28099012 TI - Aqueous Photochemistry of Secondary Organic Aerosol of alpha-Pinene and alpha Humulene Oxidized with Ozone, Hydroxyl Radical, and Nitrate Radical. AB - Formation of secondary organic aerosols (SOA) from biogenic volatile organic compounds (BVOC) occurs via O3- and OH-initiated reactions during the day and reactions with NO3 during the night. We explored the effect of these three oxidation conditions on the molecular composition and aqueous photochemistry of model SOA prepared from two common BVOC. A common monoterpene, alpha-pinene, and sesquiterpene, alpha-humulene, were used to form SOA in a smog chamber via BVOC + O3, BVOC + NO3, and BVOC + OH + NOx oxidation. Samples of SOA were collected on filters, water-soluble compounds from SOA were extracted in water, and the resulting aqueous solutions were photolyzed to simulate the photochemical aqueous processing of SOA. The extent of change in the molecular level composition of SOA over 4 h of photolysis (approximately equivalent to 64 h of photolysis under ambient conditions) was assessed with high-resolution electrospray ionization mass spectrometry. The analysis revealed significant differences in the molecular composition between SOA formed by the different oxidation pathways. The composition further evolved during photolysis with the most notable change corresponding to the nearly complete removal of nitrogen-containing organic compounds. Hydrolysis of SOA compounds also occurred in parallel with photolysis. The preferential loss of larger SOA compounds during photolysis and hydrolysis made the SOA compounds more volatile on average. This study suggests that aqueous processes may under certain conditions lead to a reduction in the SOA loading as opposed to an increase in SOA loading commonly assumed in the literature. PMID- 28099014 TI - Magneto-Structural Analysis of Iron(III) Keggin Polyoxometalates. AB - A computational study and magnetic susceptibility measurements of three homonuclear Fe(III) Keggin structures are herein presented: the [FeO4@Fe12F24(MU OCH3)12]5- anion (1), the [Bi6{FeO4@Fe12O12(OH)12}(MU-O2CCCl3)12]+ cation (2) and its polymorph [Bi6{FeO4@Fe12O12(OH)10(H2O)2}(MU-O2CCF3)10]3+ (3). These results are contrasted with the exchange interactions present in the previously characterized [Fe6(OH)3Ge2W18O68(OH)6]11- and [H12As4Fe8W30O120(H2O)2]4- anions. The computational analysis shows that the most significant antiferromagnetic spin coupling takes place at the junction between each of the {Fe3O6(OH)3}/{Fe3F6(OCH3)3} framework motifs, a possibility that had been previously discarded in the literature on the basis of the Fe-Fe distances. For all the examined iron(III) Keggin structures, it is found that the magnitude of the magnetic couplings within each structural subunit follows the same trend. PMID- 28099013 TI - Dynamic Nuclear Polarization Signal Enhancement with High-Affinity Biradical Tags. AB - Dynamic nuclear polarization is an emerging technique for sensitizing solid-state NMR experiments by transferring polarization from electrons to nuclei. Stable biradicals, the polarization source for the cross effect mechanism, are typically codissolved at millimolar concentrations with proteins of interest. Here we describe the high-affinity biradical tag TMP-T, created by covalently linking trimethoprim, a nanomolar affinity ligand of dihydrofolate reductase (DHFR), to the biradical polarizing agent TOTAPOL. With TMP-T bound to DHFR, large enhancements of the protein spectrum are observed, comparable to when TOTAPOL is codissolved with the protein. In contrast to TOTAPOL, the tight binding TMP-T can be added stoichiometrically at radical concentrations orders of magnitude lower than in previously described preparations. Benefits of the reduced radical concentration include reduced spectral bleaching, reduced chemical perturbation of the sample, and the ability to selectively enhance signals for the protein of interest. PMID- 28099015 TI - Intersystem Crossing Rates of Isolated Fullerenes: Theoretical Calculations. AB - Although the triplet states of fullerenes have prosperous applications, it remains unclear how the structural parameters of singlet and triplet states control the intersystem crossing (ISC) rates. Here, electronic structure calculations (reorganization energy, driving force, and spin-orbit coupling) and a rate theory (Marcus formula) are employed to quantitatively predict the ISC rates of isolated fullerenes Cn (n = 60-110). The results demonstrate that the driving force is not the only factor to predict the ISC rates. For instance, although C80, C82, and C110 have the favorable driving force, the ISC rates are close to zero because of small spin obit couplings, whereas small ISC rates of C96 and C100 result from quite small reorganization energies. Meanwhile, in addition to well-known C60 and C70, C92 possesses good ISC property with obviously large ISC rate. C92 also has a higher triplet-state energy than singlet state oxygen energy; it may thus have a good photoactive property. PMID- 28099016 TI - Influence of Energetic Disorder on Exciton Lifetime and Photoluminescence Efficiency in Conjugated Polymers. AB - Using time-resolved photoluminescence (TRPL) spectroscopy the exciton lifetime in a range of conjugated polymers is investigated. For poly(p-phenylenevinylene) (PPV)-based derivatives and a polyspirobifluorene copolymer (PSBF) we find that the exciton lifetime is correlated with the energetic disorder. Better ordered polymers exhibit a single exponential PL decay with exciton lifetimes of a few hundred picoseconds, whereas polymers with a larger degree of disorder show multiexponential PL decays with exciton lifetimes in the nanosecond regime. These observations are consistent with diffusion-limited exciton quenching at nonradiative recombination centers. The measured PL decay time reflects the time that excitons need to diffuse toward these quenching sites. Conjugated polymers with large energetic disorder and thus longer exciton lifetime also exhibit a higher photoluminescence quantum yield due to the slower exciton diffusion toward nonradiative quenching sites. PMID- 28099017 TI - Absence of Intramolecular Charge Transfer with 4-Fluoro-N,N-dimethylaniline (DMA4F), Contrary to an Experimental Report Supported by Computations. AB - With 4-fluoro-N,N-dimethylaniline (DMA4F), only a single fluorescence from a locally excited (LE) state is observed, irrespective of solvent polarity, temperature, and excitation wavelength. The relatively small excited state dipole moment MUe = 7.3 D confirms the identification as LE. The single exponential fluorescence decays in the nonpolar n-hexane (2.04 ns) and in the strongly polar acetonitrile (5.73 ns) are a further support. Similar results are obtained with 4 chloro-N,N-dimethylaniline (DMA4Cl), having a chlorobenzene subgroup, a somewhat better electron acceptor than the fluorobenzene moiety in DMA4F. The absence of intramolecular charge transfer (ICT) with DMA4F is in accord with its large energy gap DeltaE(S1,S2) of 8300 cm-1 in n-hexane between the two lowest singlet excited states, which is even larger than that (6300 cm-1) of N,N-dimethylaniline (DMA), for which an LE -> ICT reaction likewise does not occur. The results with DMA4F are in contradiction with a publication by Fujiwara et al. ( Chem. Phys. Lett. 2013 , 586 , 70 ), in which the appearance of dual LE + ICT emission is reported for DMA4F in n-hexane and MeCN at room temperature. The ICT/LE fluorescence quantum yield ratio Phi'(ICT)/Phi(LE) reached a maximum value of ~2, in n-hexane and surprisingly also in MeCN, as the excitation wavelength approaches the red-edge of the absorption spectrum. These, in our opinion, erroneous observations were supported by time-dependent density functional theory (TDDFT) calculations, which compute a perpendicularly twisted lowest ICT state (TICT) state. This is a further example of the general tendency of computations to find a TICT conformation for the lowest excited singlet state of electron donor/acceptor molecules such as p-substituted anilines. PMID- 28099018 TI - Reactive Ni/Al Nanocomposites: Structural Characteristics and Activation Energy. AB - Stochastically structured Ni/Al reactive nanocomposites (RNCs) were prepared using short-term high-energy ball milling. Several milling times were utilized to prepare RNCs with differing internal nanostructures. These internal structures were quantitatively and statistically analyzed by use of serial focused ion beam sectioning coupled with 3D reconstruction techniques. The reaction kinetics were analyzed using the electrothermal explosion technique for each milling condition. It is shown that the effective activation energy (Eef) ranges from 79 to 137 kJ/mol and is directly related to the surface area contact between the reactants. Essentially, the reaction kinetics can be accurately controlled through mechanical processing techniques. Finally, the nature of the reaction is considered; the mechanistic effect of the reactive and three diffusive activation energies on the effective activation energy is examined. PMID- 28099019 TI - Combined Molecular Dynamics, Atoms in Molecules, and IR Studies of the Bulk Monofluoroethanol and Bulk Ethanol To Understand the Role of Organic Fluorine in the Hydrogen Bond Network. AB - The presence of the fluorocarbon group in fluorinated alcohols makes them an important class of molecules that have diverse applications in the field of separation techniques, synthetic chemistry, polymer industry, and biology. In this paper, we have performed the density function theory calculation along with atom in molecule analysis, molecular dynamics simulation, and IR measurements of bulk monofluoroethanol (MFE) and compared them with the data for bulk ethanol (ETH) to understand the effect of the fluorocarbon group in the structure and the hydrogen bond network of bulk MFE. It has been found that the intramolecular O H...F hydrogen bond is almost absent in bulk MFE. Molecular dynamics simulation and density function theory calculation along with atom in molecule analysis clearly depict that in the case of bulk MFE, a significant amount of intermolecular O-H...F and C-H...F hydrogen bonds are present along with the intermolecular O-H...O hydrogen bond. The presence of intermolecular O-H...F and C-H...F hydrogen bonds causes the difference in the IR spectrum of bulk MFE as compared to bulk ETH. This study clearly depicts that the organic fluorine (fluorocarbon) of MFE acts as a hydrogen bond acceptor and plays a significant role in the structure and hydrogen bond network of bulk MFE through the formation of weak O-H...F as well C-H...F hydrogen bonds, which may be one of the important reasons behind the unique behavior of the fluoroethanols. PMID- 28099020 TI - Two-Dimensional Electronic Stark Spectroscopy. AB - Characterizing ultrafast energy and charge transfer is important for understanding a wide range of systems, from natural photosynthetic complexes to organic photovoltaics. Distinguishing the kinetic processes of energy transfer and charge separation in such systems is challenging due to the lack of clear spectral signatures of charge transfer states, which are typically nonradiative. Stark spectroscopy has proven to be a valuable method for uncovering charge transfer states. Here we extend the dimensionality of Stark spectroscopy to perform two-dimensional electronic Stark spectroscopy. We demonstrate the method on TIPS-pentacene in 3-methylpentane at 77 K. The additional frequency dimension of two-dimensional Stark spectroscopy promises to enable the identification of charge transfer states, their coupling to other charge transfer and exciton states, and their involvement in charge separation processes. PMID- 28099021 TI - Location of Methanol on the S2 State Mn Cluster in Photosystem II Studied by Proton Matrix Electron Nuclear Double Resonance. AB - Proton matrix electron nuclear double resonance (ENDOR) spectroscopy was performed to specify the location of the methanol molecule near the manganese cluster in photosystem II. Comparison of the ENDOR spectra in the presence of CH3OH and CD3OH revealed two pairs of hyperfine couplings, 1.2 MHz for A? and 2.5 MHz for A//, arising from the methyl group in methanol. On the basis of the crystal structure, the possible location of methanol close to the manganese cluster was discussed. PMID- 28099022 TI - Molecular Weight Dependence of Interdiffusion and Adhesion of Polymers at Short Contact Times. AB - The autohesion and subsequent debonding of thin layers of three linear and monodisperse random copolymers of styrene-butadiene (SBR) with molecular weights varying between 30 and 75 times the average molecular weight between entanglements Me were investigated using a carefully controlled tack adhesion testing device in conjunction with a fast camera setup over a range of contact times tc (10 ms to 10 s) much shorter in comparison to the terminal relaxation times of the polymers. The evolution of the stress-strain curves and debonding mechanisms with increasing contact time was examined, and the work required to debond the layers was found to be strongly dependent on molecular weight at long contact times, but not at short contact times. We propose a cutoff contact time of 300 ms, corresponding to 104 times the entanglement time taue after which molecular weight becomes important in controlling the interdiffusion process and the debonding mechanisms of the tack test. For contact times over 300 ms, the debonding energy plotted as a function of tc normalized by the reptation time taurep, collapses onto a master curve. Below this threshold tc, by comparing the adhesion of SBR on itself with the adhesion of SBR on glass, we also show that interdiffusion plays a part in adhesion of two identical polymer layers even at the shortest contact times, where the interdiffusion is controlled by the number of entanglements formed which scales with 1/?N. PMID- 28099024 TI - Surface Interactions and Confinement of Methane: A High Pressure Magic Angle Spinning NMR and Computational Chemistry Study. AB - Characterization and modeling of the molecular-level behavior of simple hydrocarbon gases, such as methane, in the presence of both nonporous and nanoporous mineral matrices allows for predictive understanding of important processes in engineered and natural systems. In this study, changes in local electromagnetic environments of the carbon atoms in methane under conditions of high pressure (up to 130 bar) and moderate temperature (up to 346 K) were observed with 13C magic-angle spinning (MAS) NMR spectroscopy while the methane gas was mixed with two model solid substrates: a fumed nonporous, 12 nm particle size silica and a mesoporous silica with 200 nm particle size and 4 nm average pore diameter. Examination of the interactions between methane and the silica systems over temperatures and pressures that include the supercritical regime was allowed by a novel high pressure MAS sample containment system, which provided high resolution spectra collected under in situ conditions. For pure methane, no significant thermal effects were found for the observed 13C chemical shifts at all pressures studied here (28.2, 32.6, 56.4, 65.1, 112.7, and 130.3 bar). However, the 13C chemical shifts of resonances arising from confined methane changed slightly with changes in temperature in mixtures with mesoporous silica. The chemical shift values of 13C nuclides in methane change measurably as a function of pressure both in the pure state and in mixtures with both silica matrices, with a more pronounced shift when meso-porous silica is present. Molecular-level simulations utilizing GCMC, MD, and DFT confirm qualitatively that the experimentally measured changes are attributed to interactions of methane with the hydroxylated silica surfaces as well as densification of methane within nanopores and on pore surfaces. PMID- 28099023 TI - Computational Models of the Gastrointestinal Environment. 1. The Effect of Digestion on the Phase Behavior of Intestinal Fluids. AB - Improved models of the gastrointestinal environment have great potential to assist the complex process of drug formulation. Molecular dynamics (MD) is a powerful method for investigating phase behavior at a molecular level. In this study we use multiple MD simulations to calculate phase diagrams for bile before and after digestion. In these computational models, undigested bile is represented by mixtures of palmitoyl-oleoylphosphatidylcholine (POPC), sodium glycodeoxycholate (GDX), and water. Digested bile is modeled using a 1:1 mixture of oleic acid and palmitoylphosphatidylcholine (lysophosphatidylcholine, LPC), GDX, and water. The computational phase diagrams of undigested and digested bile are compared, and we describe the typical intermolecular interactions that occur between phospholipids and bile salts. The diffusion coefficients measured from MD simulation are compared to experimental diffusion data measured by DOSY-NMR, where we observe good qualitative agreement. In an additional set of simulations, the effect of different ionization states of oleic acid on micelle formation is investigated. PMID- 28099025 TI - Optical Line Width Broadening Mechanisms at the 10 kHz Level in Eu3+:Y2O3 Nanoparticles. AB - We identify the physical mechanisms responsible for the optical homogeneous broadening in Eu3+:Y2O3 nanoparticles to determine whether rare-earth crystals can be miniaturized to volumes less than lambda3 while preserving their appeal for quantum technology hardware. By studying how the homogeneous line width depends on temperature, applied magnetic field, and measurement time scale, the dominant broadening interactions for various temperature ranges above 3 K were characterized. Below 3 K the homogeneous line width is dominated by an interaction not observed in bulk crystal studies. These measurements demonstrate that broadening due to size-dependent phonon interactions is not a significant contributor to the homogeneous line width, which contrasts previous studies in rare-earth ion nanocrystals. Importantly, the results provide strong evidence that for the 400 nm diameter nanoparticles under study the minimum line width achieved (45 +/- 1 kHz at 1.3 K) is not fundamentally limited. In addition, we highlight that the expected broadening caused by electric field fluctuations arising from surface charges is comparable to the observed broadening. Under the assumption that such Stark broadening is a significant contribution to the homogeneous line width, several strategies for reducing this line width to below 10 kHz are discussed. Furthermore, it is demonstrated that the Eu3+ hyperfine state lifetime is sufficiently long to preserve spectral features for time scales up to 1 s. These results allow integrated rare-earth ion quantum optics to be pursued at a submicron scale and, hence, open up directions for greater scaling of rare-earth quantum technology. PMID- 28099026 TI - Unimer-Assisted Exfoliation for Highly Concentrated Aqueous Dispersion Solutions of Single- and Few-Layered van der Waals Materials. AB - We suggest a unimer-assisted exfoliation method for the exfoliation of van der Waals two-dimensional (2D) materials such as graphene, MoS2, and h-BN and show that the micellar size is a critical parameter for enhancing the exfoliation efficiency. To explain the effectiveness of the unimers in the exfoliation, the influence of the micellar size of a biocompatible block copolymer, Pluronic F-68, is evaluated in view of the yield and thickness of exfoliated 2D flakes. By the addition of water-soluble alcohols, the surfactants exist in the form of a unimer, which facilitates the intercalation into the layered materials and their exfoliation. The results showed that the high exfoliation efficiency could be achieved by controlling the micellar size mostly to be unimers; the average yield rate of MoS2 exfoliation was 4.51% per hour, and the very high concentration of 1.45 mg/mL was obtained by sonication for 3 h. We also suggested the dielectrophoresis technique as a method for forming a film composed of 2D flakes for diverse applications requiring electrical signals. The unimer-assisted exfoliation method will be substantially utilized to achieve highly concentrated aqueous dispersion solutions of 2D materials. PMID- 28099027 TI - Inactivation of Soybean Trypsin Inhibitor by Epigallocatechin Gallate: Stopped Flow/Fluorescence, Thermodynamics, and Docking Studies. AB - Tea is one of the most widely daily consumed beverages all over the world, and it is usually consumed with milk and/or soy milk. However, very few researches have studied the interactions between tea polyphenols (TPs) and soy milk proteins as compared with milk proteins. Here, we reported that epigallocatechin gallate (EGCG), a major component of TPs, can effectively inhibit the inhibitory activity of Kunitz trypsin inhibitor (KTI, a major antinutrient in soy milk). The mechanism of inactivation of KTI by EGCG was investigated by stopped flow/fluorescence, thermodynamics, and docking studies. The results indicated that EGCG binds KTI via both hydrophobic and hydrophilic interactions with an association constant of 6.62 * 105 M-1 to form a 1:1 complex. Molecular docking showed the participation of amino acids includes three amino acid residues (Asn13, Pro72, and Trp117) near the reactive site of KTI, which may prevent KTI from contacting trypsin and hence inactivate KTI. PMID- 28099028 TI - Chemical Insights into the Design and Development of Face-Centered Cubic Ruthenium Catalysts for Fischer-Tropsch Synthesis. AB - Ruthenium is a promising low-temperature catalyst for Fischer-Tropsch synthesis (FTS). However, its scarcity and modest specific activity limit its widespread industrialization. We demonstrate here a strategy for tuning the crystal phase of catalysts to expose denser and active sites for a higher mass-specific activity. Density functional theory calculations show that upon CO dissociation there are a number of open facets with modest barrier available on the face-centered cubic (fcc) Ru but only a few step edges with a lower barrier on conventional hexagonal closest packed (hcp) Ru. Guided by theoretical calculations, water-dispersible fcc Ru catalysts containing abundant open facets were synthesized and showed an unprecedented mass-specific activity in the aqueous-phase FTS, 37.8 molCO.molRu 1.h-1 at 433 K. The mass-specific activity of the fcc Ru catalysts with an average size of 6.8 nm is about three times larger than the previous best hcp catalyst with a smaller size of 1.9 nm and a higher specific surface area. The origin of the higher mass-specific activity of the fcc Ru catalysts is identified experimentally from the 2 orders of magnitude higher density of the active sites, despite its slightly higher apparent barrier. Experimental results are in excellent agreement with prediction of theory. The great influence of the crystal phases on site distribution and their intrinsic activities revealed here provides a rationale design of catalysts for higher mass-specific activity without decrease of the particle size. PMID- 28099029 TI - Energy Transfer Between Coherently Delocalized States in Thin Films of the Explosive Pentaerythritol Tetranitrate (PETN) Revealed by Two-Dimensional Infrared Spectroscopy. AB - Pentaerythritol tetranitrate (PETN) is a common secondary explosive and has been used extensively to study shock initiation and energy propagation in energetic materials. We report 2D IR measurements of PETN thin films that resolve vibrational energy transfer and relaxation mechanisms. Ultrafast anisotropy measurements reveal a sub-500 fs reorientation of transition dipoles in thin films of vapor-deposited PETN that is absent in solution measurements, consistent with intermolecular energy transfer. The anisotropy is frequency dependent, suggesting spectrally heterogeneous vibrational relaxation. Cross peaks are observed in 2D IR spectra that resolve a specific energy transfer pathway with a 2 ps time scale. Transition dipole coupling calculations of the nitrate ester groups in the crystal lattice predict that the intermolecular couplings are as large or larger than the intramolecular couplings. The calculations match well with the experimental frequencies and the anisotropy, leading us to conclude that the observed cross peak is measuring energy transfer between two eigenstates that are extended over multiple PETN molecules. Measurements of the transition dipole strength indicate that these vibrational modes are coherently delocalized over at least 15-30 molecules. We discuss the implications of vibrational relaxation between coherently delocalized eigenstates for mechanisms relevant to explosives. PMID- 28099030 TI - Ultrafast Broadband Photodetectors Based on Three-Dimensional Dirac Semimetal Cd3As2. AB - Photodetection with extreme performances in terms of ultrafast response time, broad detection wavelength range, and high sensitivity has a wide range of optoelectronic and photonic applications, such as optical communications, interconnects, imaging, and remote sensing. Graphene, a typical two-dimensional Dirac semimetal, has shown excellent potential toward a high-performance photodetector with high operation speed, broadband response, and efficient carrier multiplications benefiting from its linear dispersion band structure with a high carrier mobility and zero bandgap. As the three-dimensional analogues of graphene, Dirac semimetal Cd3As2 processes all advantages of graphene as a photosensitive material but potentially has stronger interaction with light as a bulk material and thus enhanced responsivity. In this work, we report the realization of an ultrafast broadband photodetector based on Cd3As2. The prototype metal-Cd3As2-metal photodetector exhibits a responsivity of 5.9 mA/W with a response time of about 6.9 ps without any special device optimization. Broadband responses from 532 nm to 10.6 MUm are achieved with a potential detection range extendable to far-infrared and terahertz. Systematical studies indicate that the photothermoelectric effect plays an important role in photocurrent generation. Our results suggest this emerging class of exotic quantum materials can be harnessed for photodetection with a high sensitivity and high speed (~145 GHz) over a broad wavelength range. PMID- 28099031 TI - Stereospecific Intramolecular Arylation of 2- and 3-Pyridyl Substituted Alkylamines via Configurationally Stable alpha-Pyridyl Organolithiums. AB - Treatment of N'-aryl urea derivatives of enantiomerically enriched alpha-(2 pyridyl) and alpha-(3-pyridyl)alkylamines with a base leads to the migration of the N'-aryl substituent from N to C in a 'nonclassical' intramolecular nucleophilic aromatic substitution reaction. Both electron-rich and -poor rings migrate successfully. A new quaternary stereogenic center is formed adjacent to the pyridine ring with high stereospecificity, even when the intermediate anion is a presumably planar 2-picolyllithium. Base hydrolysis of the urea gives enantiomerically enriched alpha-pyridylalkylamines. PMID- 28099032 TI - Pathogenicity Genes in Ustilaginoidea virens Revealed by a Predicted Protein Protein Interaction Network. AB - Rice false smut, caused by Ustilaginoidea virens, produces significant losses in rice yield and grain quality and has recently emerged as one of the most important rice diseases worldwide. Despite its importance in rice production, relatively few studies have been conducted to illustrate the complex interactome and the pathogenicity gene interactions. Here a protein-protein interaction network of U. virens was built through two well-recognized approaches, interolog- and domain-domain interaction-based methods. A total of 20 217 interactions associated with 3305 proteins were predicted after strict filtering. The reliability of the network was assessed computationally and experimentally. The topology of the interactome network revealed highly connected proteins. A pathogenicity-related subnetwork involving up-regulated genes during early U. virens infection was also constructed, and many novel pathogenicity proteins were predicted in the subnetwork. In addition, we built an interspecies PPI network between U. virens and Oryza sativa, providing new insights for molecular interactions of this host-pathogen pathosystem. A web-based publicly available interactive database based on these interaction networks has also been released. In summary, a proteome-scale map of the PPI network was described for U. virens, which will provide new perspectives for finely dissecting interactions of genes related to its pathogenicity. PMID- 28099033 TI - Hemobilia due to intracholecystic papillary neoplasm. AB - We report the case of a 39-year-old patient who presented an episode of upper gastrointestinal bleeding due to hemobilia. The imaging tests showed the gallbladder occupied by solid tissue, with a diagnosis of intracholecystic papillary neoplasm after the cholecystectomy. The intracholecystic papillary neoplasm of the gallbladder is a newly established entity and it is considered a subtype of intraductal papillary neoplasm of the bile duct. Its presentation in the form of hemobilia has barely been described in the literature. PMID- 28099034 TI - Re: "Evidence That Dry Needling Is the Intent to Bypass Regulation to Practice Acupuncture in the United States" by Fan et al. (J Altern Complement Med 2016;22:591-593). PMID- 28099035 TI - "Let the Algorithm Do the Work": Reduction of Hypoglycemia Using Sensor-Augmented Pump Therapy with Predictive Insulin Suspension (SmartGuard) in Pediatric Type 1 Diabetes Patients. AB - BACKGROUND: A sensor-augmented insulin pump (SAP) using the MiniMed(r) 640G system with SmartGuardTM technology allows an automatic stop of insulin delivery based on prediction of low glucose levels. Since pediatric patients are particularly prone to hypoglycemia, this device may offer additional protection beyond conventional sensor-augmented therapy. METHODS: This prospective, pediatric multicenter user evaluation assessed 6 weeks of SAP with SmartGuard (threshold setting for hypoglycemia: 70 mg/dL) compared to a preceding period of 2 weeks with SAP only. The primary outcome was the potential reduction in the frequency of hypoglycemic episodes and hypoglycemic intensity (area under the curve [AUC] and time <70 mg/dL). RESULTS: The study included 24 patients with at least 3 months of insulin pump use (average age: 11.6 +/- 5.1 years, 15 female, average type 1 diabetes duration: 7.5 +/- 4.2 years, mean +/- SD) who had on average 3.2 +/- 1.0 predictive suspensions/patient/day. The mean sensor glucose minimum during suspension was 78 +/- 6 mg/dL and the average suspension time was 155 +/- 47 min/day. Use of SmartGuard in patients treated as per the protocol (n = 18) reduced the number of instances in which the glucose level was <70 mg/dL (1.02 +/- 0.52 to 0.72 +/- 0.36; P = 0.027), as well as AUC <70 mg/dL (0.76 +/- 0.73 to 0.38 +/- 0.24; P = 0.027) and the time/day the level fell below 70 mg/dL (73 +/- 56 to 31 +/- 22 min). The reduction of hypoglycemia was not associated with a significant change in mean glucose concentration (171 +/- 26 to 180 +/- 19 mg/dL, P = 0.111) and HbA1c (7.5% +/- 0.5% to 7.6% +/- 0.7%, (P = 0.329). Manual resumption of insulin delivery followed by carbohydrate intake resulted in significantly higher glucose levels 1 h after suspension compared to SmartGuard suspensions with automatic resume (190.8 +/- 26.5 vs. 138.7 +/- 10.3 mg/dL; P < 0.001). CONCLUSIONS: SmartGuard technology significantly reduced the risk for hypoglycemia in pediatric type 1 diabetes patients without increasing HbA1c. Patients must be educated that when using combining predictive low-glucose insulin suspension technology, extra carbohydrate intake in response to an alarm combined with manual resumption is likely to cause rebound hyperglycemia. The best results were achieved when the user did not interfere with pump operation. PMID- 28099036 TI - Another Generation of Stigma? Assessing Healthcare Student Perceptions of HIV Positive Patients in Mwanza, Tanzania. AB - HIV-related stigma remains a persistent global health concern among people living with HIV/AIDS (PLWA) in developing nations. The literature is lacking in studies about healthcare students' perceptions of PLWA. This study is the first effort to understand stigmatizing attitudes toward HIV-positive patients by healthcare students in Mwanza, Tanzania, not just those who will be directly treating patients but also those who will be indirectly involved through nonclinical roles, such as handling patient specimens and private health information. A total of 208 students were drawn from Clinical Medicine, Laboratory Sciences, Health Records and Information Management, and Community Health classes at the Tandabui Institute of Health Sciences and Technology for a voluntary survey that assessed stigmatizing beliefs toward PLWA. Students generally obtained high scores on the overall survey instrument, pointing to low stigmatizing beliefs toward PLWA and an overall willingness to treat PLWA with the same standard of care as other patients. However, there are gaps in knowledge that exist among students, such as a comprehensive understanding of all routes of HIV infection. The study also suggests that students who interact with patients as part of their training are less likely to exhibit stigmatizing beliefs toward PLWA. A comprehensive course in HIV infection, one that includes classroom sessions focused on the epidemiology and routes of transmission as well as clinical opportunities to directly interact with PLWA-perhaps through teaching sessions led by PLWA-may allow for significant reductions in stigma toward such patients and improve clinical outcomes for PLWA around the world. PMID- 28099037 TI - Letter to the Editor. PMID- 28099039 TI - Gilles de la Tourette Syndrome, Depression, Depressive Illness, and Correlates in a Child and Adolescent Population. AB - OBJECTIVE: Gilles de la Tourette syndrome (GTS) and depression are both common disorders. It has been suggested that depression occurs in 13%-76% GTS patients. Despite this, there are few studies into the specific relationships and correlates between the two disorders. There is only some consensus as to the precise relationship between the two disorders. MATERIALS AND METHODS: We undertook the study to investigate the relationship between depressive symptomatology and the core clinical features of GTS in a well-characterized clinical population of youth with this disorder. Our aim was to verify the association between depression and comorbid obsessive-compulsive disorder and explore further other potential associations highlighted in some, but not all, of the studies focused on this topic. RESULTS: Our results demonstrated that (1) the GTS patients were significantly older than the controls, (2) the GTS patients were significantly more depressed than controls, (3) depression was associated with tic severity, (4) the Diagnostic Confidence Index scores were higher in GTS patients without depression, (5) anxiety, attention-deficit/hyperactivity disorder (ADHD), conduct disorder (CD), and behavioral problems were significantly associated with depression, and (6) finally, patients with GTS and depression have a positive family history of depression. However, obsessionality (CY-BOCS) did not differentiate between depressed and not depressed GTS patients. CONCLUSIONS: Depression is common in patients with GTS and occurs significantly more in GTS than in controls. Depression is significantly associated with GTS factors such as tic severity, comorbidity with ADHD, and the presence of coexistent anxiety, CDs, and behavior problems. Depression is importantly significantly associated with a positive family history of depression. Intriguingly, depression in our sample was not related to obsessionality. PMID- 28099038 TI - An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis. AB - RATIONALE: Idiopathic pulmonary fibrosis (IPF) is an increasingly recognized, often fatal lung disease of unknown etiology. OBJECTIVES: The aim of this study was to use whole-exome sequencing to improve understanding of the genetic architecture of pulmonary fibrosis. METHODS: We performed a case-control exome wide collapsing analysis including 262 unrelated individuals with pulmonary fibrosis clinically classified as IPF according to American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines (81.3%), usual interstitial pneumonia secondary to autoimmune conditions (11.5%), or fibrosing nonspecific interstitial pneumonia (7.2%). The majority (87%) of case subjects reported no family history of pulmonary fibrosis. MEASUREMENTS AND MAIN RESULTS: We searched 18,668 protein coding genes for an excess of rare deleterious genetic variation using whole exome sequence data from 262 case subjects with pulmonary fibrosis and 4,141 control subjects drawn from among a set of individuals of European ancestry. Comparing genetic variation across 18,668 protein-coding genes, we found a study wide significant (P < 4.5 * 10-7) case enrichment of qualifying variants in TERT, RTEL1, and PARN. A model qualifying ultrarare, deleterious, nonsynonymous variants implicated TERT and RTEL1, and a model specifically qualifying loss-of function variants implicated RTEL1 and PARN. A subanalysis of 186 case subjects with sporadic IPF confirmed TERT, RTEL1, and PARN as study-wide significant contributors to sporadic IPF. Collectively, 11.3% of case subjects with sporadic IPF carried a qualifying variant in one of these three genes compared with the 0.3% carrier rate observed among control subjects (odds ratio, 47.7; 95% confidence interval, 21.5-111.6; P = 5.5 * 10-22). CONCLUSIONS: We identified TERT, RTEL1, and PARN-three telomere-related genes previously implicated in familial pulmonary fibrosis-as significant contributors to sporadic IPF. These results support the idea that telomere dysfunction is involved in IPF pathogenesis. PMID- 28099040 TI - Effect of Bacoside A on growth and biofilm formation by Staphylococcus aureus and Pseudomonas aeruginosa. AB - The goal of this study was to evaluate the antibiofilm and antimicrobial activities of Bacoside A, a formulation of phytochemicals from Bacopa monnieri, against Staphylococcus aureus and Pseudomonas aeruginosa, which are known to form biofilms as one of their virulence traits. The antimicrobial effects of Bacoside A were tested using the minimum inhibitory concentration and minimum bactericidal concentration assays. A cell membrane disruption assay was performed to find its possible target site. MTT assay, crystal violet assay, and microscopic studies were performed to assess the antibiofilm activity. Bacoside A showed antimicrobial activity against both test organisms in their planktonic and biofilm states. At a subminimum inhibitory concentration of 200 MUg.mL-1, Bacoside A significantly removed ~88%-93% of bacterial biofilm developed on microtiter plates. Biochemical and microscopic studies suggested that the eradication of biofilm might be due to the loss of extracellular polymeric substances and to a change in cell membrane integrity of the selected bacterial strains treated with Bacoside A. These results indicate that Bacoside A might be considered as an antimicrobial having the ability to disrupt biofilms. Thus, either alone or in combination with other therapeutics, Bacoside A could be useful to treat biofilm-related infections caused by opportunistic bacterial pathogens. PMID- 28099041 TI - Eyes on New Product Development. PMID- 28099042 TI - Sex differences in associations between insulin resistance, heart rate variability, and arterial stiffness in healthy women and men: a physiology study. AB - Diabetes confers greater cardiovascular risk to women than to men. Whether insulin-resistance-mediated risk extends to the healthy population is unknown. Measures of insulin resistance (fasting insulin, homeostatic model assessment, hemoglobin A1c, quantitative insulin sensitivity check index, glucose) were determined in 48 (56% female) healthy subjects. Heart rate variability (HRV) was calculated by spectral power analysis and arterial stiffness was determined using noninvasive applanation tonometry. Both were measured at baseline and in response to angiotensin II infusion. In women, there was a non-statistically significant trend towards increasing insulin resistance being associated with an overall unfavourable HRV response and increased arterial stiffness to the stressor, while men demonstrated the opposite response. Significant differences in the associations between insulin resistance and cardiovascular physiological profile exist between healthy women and men. Further studies investigating the sex differences in the pathophysiology of insulin resistance in cardiovascular disease are warranted. PMID- 28099043 TI - Validation of the Arabic Version of the Infant Feeding Intentions Scale Among Lebanese Women. AB - BACKGROUND: The Infant Feeding Intentions (IFI) scale was shown to reliably measure maternal intentions to initiate breastfeeding and continue exclusive breastfeeding until 1, 3, or 6 months in English and Spanish but not in Arab contexts. Research aim: This study aimed to validate an Arabic version of the IFI scale (IFI-A) and examine its ability to predict exclusive breastfeeding at 1, 3, or 6 months in pregnant Lebanese women. METHODS: The internal consistency reliability and construct validity of the IFI-A scale were tested on 50 pregnant women (Group 1), whereas its predictive ability was tested on 196 pregnant women (Group 2), who were surveyed monthly about their infants' nutrition method until 6 months. RESULTS: The IFI-A scale's Cronbach's alpha internal consistency reliability is .82. Its corrected item-total correlations ranged from .26 for Item 2 ("at least give breastfeeding a try") to .86 for Item 4 ("will be exclusively breastfeeding at 3 months"). Exploratory factor analysis revealed that it is unidimensional. IFI-A scores correlated significantly with exclusive breastfeeding duration in Group 1 ( r = .624; p = .001) and with participants' breastfeeding attitude ( r = .390; p < .001) and previous breastfeeding duration ( r = .237; p = .011) in Group 2, thus confirming its external construct validity. In adjusted analysis, the IFI-A scale predicted exclusive breastfeeding at 3 months, albeit weakly (odds ratio = 1.16; 95% confidence interval [0.99, 1.36]), but not at 1 or 6 months. CONCLUSION: The IFI-A scale is a reliable and valid tool to assess maternal feeding intentions and predict exclusive breastfeeding at 3 months in the Arab context. Further studies are needed in other Arab contexts to confirm our findings. PMID- 28099044 TI - Affect of Early Skin-to-Skin Mother-Infant Contact in the Maintenance of Exclusive Breastfeeding: Experience in a Health Department in Spain. AB - BACKGROUND: Breastfeeding has been shown to result in extensive physical and psychological benefits for both the mother and the newborn. However, the rate and duration of exclusive breastfeeding (EBF) remains low worldwide. Mother-infant skin-to-skin contact (SSC) immediately after birth has demonstrated results that support the argument for breastfeeding continuation. Research aim: This study aimed to investigate the prevalence of EBF 3 months postpartum and the effect of early SSC in maintaining optimal EBF practices for mothers and their healthy newborns. METHODS: We conducted an observational, retrospective study in Spain from 2013 to 2015. Pregnant women were interviewed immediately postpartum and again at 3 months postpartum regarding variables associated with breastfeeding initiation and continuation. RESULTS: There were 1,071 women recruited. Early SSC was performed in 92% of vaginal births but only 57% of urgent cesarean births. Of women breastfeeding at discharge, 69.5% performed SSC with their newborn. We found that 68.6% of women were exclusively breastfeeding by discharge and 46.7% by 3 months postpartum. Type of feeding at discharge, country of origin, and parity were found to be associated with each other ( p = .003, p = .001, respectively). Early SSC was also significantly associated with type of feeding at discharge, 1 month, 2 months, and 3 months postpartum ( p < .001). Hypogalactia (19.8%) was the most frequently reported factor for breastfeeding discontinuation. CONCLUSION: Breastfeeding promotion interventions are likely to improve breastfeeding rates at 3 months postpartum. Social and economic factors should be taken into account when such programs are planned to be implemented. PMID- 28099045 TI - Factors Associated With Extended Breastfeeding in India. AB - BACKGROUND: Extended breastfeeding duration is common in India. Extended breastfeeding protects the infant from infectious disease and promotes child spacing. In the 1990s, the median breastfeeding duration in India was 24 months. Research aim: This study aimed to investigate the median duration of breastfeeding in India and to identify the factors associated with extended breastfeeding to 24 months as recommended by the World Health Organization. METHODS: This cross-sectional data analysis used nationally representative data from the 2011-2012 Indian Human Development Survey II. The outcome in this study was extended breastfeeding defined as breastfeeding to 24 months or more. Multivariate logistic regression was used to identify the factors associated with extended breastfeeding. RESULTS: The median duration of breastfeeding was 12 months; approximately 25% of women breastfed 24 months or more. Women were at greater odds of breastfeeding 24 months or more if the infant was a boy compared with a girl, if the women lived in a rural area compared with an urban area, if the women were married at a young age (< 17 vs. 20 years or older at marriage), and if the delivery was assisted by a friend or relative compared with a doctor. CONCLUSION: The median duration of breastfeeding has decreased by 50% from 1992 1993 to 2011-2012. The women who continue to breastfeed 24 months or more tend to be more traditional (i.e., living in rural areas, marrying young, and having family/friends as birth attendants). Further research to study the health effect of decreased breastfeeding duration is warranted. PMID- 28099046 TI - Death Notification: Someone Needs To Call the Family. AB - BACKGROUND: The death notification process can affect family grief and bereavement. It can also affect the well-being of involved physicians. There is no standardized process for making death notification phone calls. We assumed that residents are likely to be unprepared before and troubled after. OBJECTIVE: We investigated current death notification practices to develop an evidence-based template for standardizing this process. DESIGN: We used results of a literature review and open-ended interviews with faculty, residents, and widows to develop a survey regarding resident training and experience in death notification by phone. SETTING/SUBJECTS: We invited all internal medicine (IM) residents at our institution to complete the survey. MEASUREMENTS: Sixty-seven of 93 IM residents (72%) responded to the survey. Eighty-seven percent of responders reported involvement in a death that required notification by phone. RESULTS: Eighty percent of residents felt inadequately trained for this task. Over 25% reported that calls went poorly. Attendings were involved in 17% of cases. Primary care physicians were not involved. Nurses and chaplains were not involved. Respondents never delayed notification of death until family arrived at the hospital. There was no consistent approach to rehearsing or making the call, advising families about safe travel to the hospital, greeting families upon arrival, or following up with expressions of condolence. CONCLUSIONS: Poor communication skills during death notification may contribute to complicated grief for surviving relatives and stress among physicians. This study is the first to describe current practices of death notification by IM residents. More training is needed and could be combined with training in disclosure of medical error. PMID- 28099047 TI - Factors Influencing the Breastfeeding Practices of Young Mothers Living in a Maternity Shelter: A Qualitative Study. AB - BACKGROUND: Young mothers have the lowest breastfeeding rates in Canada. Young mothers and their infants who access maternity shelters are especially at risk for poor outcomes, some of which breastfeeding may help to mitigate, yet little is known of the breastfeeding practices of this population. Research aim: The purpose of this study was to answer the research question, "What factors influence the breastfeeding practices of young mothers who live or have lived in a maternity shelter?" METHODS: The study was conducted using interpretive description methodology and inductive content analysis. Data were collected by means of one-on-one interviews, with the participants recruited from a maternity shelter in Ontario, Canada. RESULTS: Nine young mothers ages 17 to 24 years, who had initiated breastfeeding and resided at a maternity shelter, were interviewed. The five themes that emerged from the data were as follows: (a) choice, (b) special, (c) importance of early postpartum support, (d) being part of the "in crowd," and (e) importance of ongoing supports. The participants in this study took ownership of their choice to breastfeed. Hospital postpartum nurses and lactation consultants had a critical role in the establishment of early breastfeeding, and ongoing, accessible, and nonjudgmental peer, family, and community support were important to breastfeeding duration. CONCLUSION: A combination of emotional and practical supports from multiple trusted sources, including professional and peer supports on an ongoing basis, enabled young mothers to reach their breastfeeding goals. PMID- 28099048 TI - Effects of Enhancing School-Based Body Mass Index Screening Reports with Parent Education on Report Utility and Parental Intent To Modify Obesity Risk Factors. AB - BACKGROUND: School-based body mass index screenings (SBMIS) have been controversial. We aimed to determine if parents would indicate improved utility with SBMIS when the report included parent education and whether parental intent to modify obesity risk factors would vary with report type or child weight. METHODS: A cluster-controlled trial was conducted with 31 elementary schools randomized to distribute a standard SBMIS report or the standard report plus education (SBMIS+). A random subsample of parents completed a mailed survey (731 SBMIS, 738 SBMIS+). Using a two-stage cluster sampling design, logistic regression models with school-level random effect were used to assess differences between conditions and by weight category. RESULTS: Parents in the SBMIS+ condition vs. the standard condition were more likely to indicate that the report provided useful information (not significant) and an intent to help their child get enough sleep (p < 0.001). Parents of children who were overweight or obese were less likely than parents of children who were not to indicate that the report provided useful information about their child's weight status (p < 0.001) or access to resources (p < 0.05). However, these parents were more likely to plan a visit to healthcare provider (p < 0.001) and to intend to limit sugar sweetened beverages (p < 0.05). CONCLUSIONS: Parental education can enhance the utility of the SBMIS report and parental intention to modify at least one obesity risk factor. SBMIS reports prompted parents of children with overweight and obesity to seek clinical care and limit sugar-sweetened drinks. PMID- 28099049 TI - Effects of Hydrogen Sulfide-Releasing Compounds on Aqueous Humor Outflow Facility in Porcine Ocular Anterior Segments, Ex Vivo. AB - PURPOSE: To investigate the pharmacological actions of hydrogen sulfide (H2S) releasing compounds l-cysteine and sodium hydrosulfide (NaHS) on aqueous humor (AH) outflow facility in porcine ocular anterior segment. METHODS: Porcine ocular anterior segments were perfused with Dulbecco's modified Eagle's medium at a constant pressure of 7.35 mmHg. After stable outflow baseline, explants were exposed to NaHS or l-cysteine. The increase in outflow generated by the H2S releasing compounds was measured in the absence and presence of inhibitor of H2S biosynthesis (aminooxyacetic acid; AOAA), blocker of KATP channels (glibenclamide), and inhibitor of adenylyl cyclase (SQ 22536). Hematoxylin and eosin (H&E) staining was used to assess trabecular meshwork (TM) morphology. RESULTS: l-cysteine elicited a concentration-dependent increase in AH outflow facility, reaching maximal effect at 100 nM (150.6% +/- 17.2% of basal level). This increase in outflow induced by l-cysteine was significantly (P < 0.001) antagonized by AOAA (30 MUM) and glibenclamide (100 MUM). AOAA and glibenclamide had no significant action on baseline outflow, whereas SQ 22536 (100 MUM) increased outflow for only an hour. In addition, NaHS produced a concentration dependent increase in AH outflow, with a maximal effect at 10 MUM (151.4% +/- 22.9% of basal level). Likewise, the increase in outflow caused by NaHS was significantly (P < 0.04) blocked by glibenclamide and SQ 22536. H&E staining revealed that l-cysteine or NaHS did not alter TM conformation. CONCLUSION: H2S releasing compounds can increase outflow facility in porcine ocular anterior segment. The stimulatory action of these compounds on outflow is mediated, in part by endogenously produced H2S, KATP channels, and adenylyl cyclase. PMID- 28099050 TI - Lipohypertrophy in China: Prevalence, Risk Factors, Insulin Consumption, and Clinical Impact. AB - BACKGROUND: Lipohypertrophy (LH) is a complication of insulin therapy. We assessed LH prevalence, risk factors, insulin usage, and clinical and health economic effects in China. METHODS: In four cities, 401 adult patients injecting insulin >=1 year were surveyed for diabetes/insulin injection history and practices, pen needle reimbursement (PNR), and health resource utilization, followed by structured examination and HbA1c testing. Differences between those with and without LH were evaluated by Student's t-test or the Wilcoxon rank sum test. Insulin costs were calculated. RESULTS: Patients were 59.6 +/- 11.5 years old; 50% male; 93.5% type 2 diabetes. LH prevalence was 53.1%. Compared to those without LH, patients with LH had higher body mass index (BMI; 26 vs. 24.8 kg/m2) and HbA1c (8.2% vs. 7.7% [66 vs. 61 mmol/mol]), took 11 IU (0.13 IU/kg or 31.7%) more insulin costing $1.4 versus $1.0 (RMB 9.5 vs. 6.8) daily, reused PNs more times, and had less PNR (all P <= 0.003). LH patients correctly rotated injection sites less often (67.6% vs. 92.3%, P < 0.0001). By stepwise logistic regression, BMI, needle reuse frequency, and PNR remained modestly associated with LH prevalence (odds ratios [OR] <1.9; P <= 0.03); weight-adjusted insulin dose and incorrect site rotation showed ORs of nearly 7 and 8.4, respectively (P <= 0.001). Extrapolated to 9 million insulin-injecting patients in China and adjusted for therapy adherence, LH-related excess annual insulin consumption cost is estimated at nearly $297 million (RMB 2 billion). CONCLUSIONS: LH is common in China and associated with worse glycemic control, despite nearly one-third greater insulin consumption, with large cost implications. Proper injection technique education may reduce LH prevalence. PMID- 28099051 TI - Mobile Health (mHealth) for Diabetes Care: Opportunities and Challenges. PMID- 28099052 TI - mHealth Intervention Elements and User Characteristics Determine Utility: A Mixed Methods Analysis. AB - BACKGROUND: Mobile health (mHealth) interventions are improving the medication adherence of adults with type 2 diabetes mellitus (T2DM), but few studies examine how users experience these interventions. Therefore, we used a mixed-methods approach to understand how T2DM users experience a text messaging and interactive voice response (IVR)-delivered medication adherence intervention called MEssaging for Diabetes (MED). METHODS: Adults with T2DM used MED as part of a 3-month pilot study. MED sends daily tailored text messages addressing adherence barriers, daily assessment text messages asking about adherence, and weekly tailored IVR calls providing adherence feedback, encouragement, and questions to facilitate problem solving. Sixty participants completed feedback interviews. We used a mixed-methods approach to understand their experience, examining associations between participants' characteristics and their feedback. RESULTS: Participants who completed feedback interviews were on average 50.0 +/- 10.1 years old; 65% female, 62% non-white; 15% had less than a high school education, 70% had annual incomes less than $20K; and average hemoglobin A1c was 8.0% +/- 1.9%. Participants rated each intervention element favorably; common reasons for MED's helpfulness included receiving novel information about diabetes medications, emotional support, and reminders to take medication. People who were younger and more recently diagnosed with T2DM had more favorable experiences using MED. In general, users valued text messages more than IVR calls. CONCLUSIONS: Consideration of the user experience is critical for developing engaging mHealth interventions. User feedback reveals what mHealth elements have the most value and why, which users to target, and how to optimize an intervention's utility and appeal. PMID- 28099053 TI - Palliative Care Involvement Is Associated with Less Intensive End-of-Life Care in Adolescent and Young Adult Oncology Patients. AB - BACKGROUND: Adolescent and young adult oncology (AYAO) patients often receive intensive medical care and experience significant symptoms at the end of life (EOL). OBJECTIVE: This study aimed to describe the characteristics of AYAO patients aged 15-26 years who died as inpatients in a hospital and to compare the illness and EOL experiences of AYAO patients who did and did not receive palliative care (PC). DESIGN AND SETTING: A standardized data extraction tool was used to collect information about demographics, treatment, terminal characteristics, and symptoms during the last month of life (LMOL) for 69 AYAO patients who died while hospitalized between 2008 and 2014. MEASUREMENTS AND RESULTS: AYAO patients who died in the hospital required considerable medical and psychosocial care and experienced numerous symptoms during the LMOL. Compared to those patients who received no formal PC services, patients followed by the PC team were less likely to die in the intensive care unit (ICU) (38% vs. 68%, p = 0.024) and less likely to have been on a ventilator (34% vs. 63%, p = 0.028) during the LMOL. They also received fewer invasive medical procedures during the LMOL (median, 1 vs. 3 procedures, p = 0.009) and had a do not resuscitate order in place for a longer time before death (median, 6 vs. two days, p = 0.008). CONCLUSIONS: Involvement of the PC team was associated with the receipt of less intensive treatments and fewer deaths in the ICU. PMID- 28099054 TI - Association between Do Not Resuscitate/Do Not Intubate Status and Resident Physician Decision-making. A National Survey. AB - RATIONALE: Compared with their Full Code counterparts, patients with do not resuscitate/do not intubate (DNR/DNI) status receive fewer interventions and have higher mortality than predicted by clinical characteristics. OBJECTIVES: To assess whether internal medicine residents, the front-line providers for many hospitalized patients, would manage hypothetical patients differently based on code status. We hypothesized respondents would be less likely to provide a variety of interventions to DNR/DNI patients than to Full Code patients. METHODS: Cross-sectional, randomized survey of U.S. internal medicine residents. We created two versions of an internet survey, each containing four clinical vignettes followed by questions regarding possible interventions; the versions were identical except for varying code status of the vignettes. Residency programs were randomly allocated between the two versions. RESULTS: Five hundred thirty-three residents responded to the survey. As determined by Chi-squared and Fisher's exact test, decisions to intubate or perform cardiopulmonary resuscitation were largely dictated by patient code status (>94% if Full Code, <5% if DNR/DNI; P < 0.0001 for all scenarios). Resident proclivity to deliver noninvasive interventions (e.g., blood cultures, medications, imaging) was uniformly high (>90%) and unaffected by code status. However, decisions to pursue other aggressive or invasive options (e.g., dialysis, bronchoscopy, surgical consultation, transfer to intensive care unit) differed significantly based on code status in most vignettes. CONCLUSIONS: Residents appear to assume that patients who would refuse cardiopulmonary resuscitation would prefer not to receive other interventions. Without explicit clarification of the patient's goals of care, potentially beneficial care may be withheld against the patient's wishes. PMID- 28099055 TI - Mastering Robotic Surgery: Where Does the Learning Curve Lead Us? AB - The robotic surgical technology introduced over the last decade and a half has revolutionized many aspects of performing complex procedures. It combines technological and clinical innovations to improve surgical quality and patient outcomes. Yet, to date, there is still a lack of standardization in training and certification of robotic surgeons. The criteria for proficiency and credentialing in robotic surgery vary widely among institutions. The aim of this review is to discuss the key points of training and surgeon assessment in robotic surgery, as well as the challenges that still need to be overcome. PMID- 28099056 TI - Multidisciplinary Approach to Esophageal Achalasia: A Single Center Experience. AB - BACKGROUND: The treatment of achalasia is palliative. Pneumatic dilatation (PD) or laparoscopic Heller myotomy (LHM) just eliminates the outflow obstruction allowing easier emptying of the esophagus. The aim of this study was to evaluate the results of a multidisciplinary approach to esophageal achalasia. MATERIALS AND METHODS: A consecutive series of patients with achalasia treated by a multidisciplinary esophageal team consisting of radiologists, gastroenterologists, and surgeons in a quaternary care center between May 2008 and April 2015 were analyzed. RESULTS: A total of 147 patients with achalasia underwent LHM and partial fundoplication. Sixty-two patients (42%) had been treated preoperatively with PD and/or botulinum toxin (BT). The preoperative Eckardt score (ES) was 6.4 +/- 2. At a median follow-up of 22 months, 128 patients (87%) did well and required no further treatment (ES 0.1). The remaining 19 patients (13%) had recurrence of symptoms and required further treatment: 12 were treated with PD and improved (ES 0.7); 4 were treated with PD and BT and improved (ES 1.3); 3 failed PD. These 3 patients had been treated with multiple sessions of PD and BT before the myotomy. Overall, 144 patients (98%) did well with laparoscopic (87%) or laparoscopic and endoscopic treatment (11%). CONCLUSIONS: The results of this study show that (a) LHM is an effective treatment modality, (b) PD improved symptoms in the majority of patients with recurrent dysphagia after myotomy and (c) multiple preoperative endoscopic treatments seem to affect outcomes of LHM. Patients with achalasia should be treated in a quaternary care center by a multidisciplinary team. PMID- 28099057 TI - A Provisional Experience with Robot-Assisted Soave Procedure for Older Children with Hirschsprung Disease: Back to the Future? AB - Hirschsprung disease is a congenital disease characterized by intestinal aganglionosis of various extents. Most patients are younger than 1 year of age. Though, a minority of cases can be older or even adult. Older the patient the more difficult and prolonged is the endorectal dissection required for the pull through procedure. Longer surgery leads to longer anal dilatation and trauma with subsequent higher likelihood of continence impairment. The article aims at describing the first case series of robot-assisted Soave procedure, which was adopted as an alternative minimally invasive approach to older patients with Hirschsprung disease. The technical principles are represented by intraoperative seromuscolar leveling biopsies, intracorporeal endorectal cranial dissection, and endorectal pull-through with colo-anal anastomosis. The authors report three procedures that were carried on without complication with a limited requirement for anal dilatation and trauma, given the reduced need for endorectal caudal dissection. The results demonstrate the feasibility of the proposed approach. The robotic approach should be considered as an alternative minimally invasive approach for older children or adults with Hirschsprung disease. PMID- 28099058 TI - Two-Site Appendectomy in Children: Description of Technique and Outcomes. AB - PURPOSE: Laparoscopic appendectomy is one of the most common operations. Single site appendectomy has been gaining popularity; however, it has certain disadvantages. The purpose of this study was to review the results of an essentially scarless laparoscopic appendectomy technique. METHODS: A retrospective review of all patients who underwent two-site appendectomy for appendicitis between January 2015 and February 2016 was performed. For all cases, a 4 mm trocar and a 5 mm trocar were placed through an infraumbilical incision and a 3 mm trocar was placed in the suprapubic region. RESULTS: Fifty patients underwent appendectomy using this technique. The average age was 9.7 years (5-16 years) and average weight was 40 kg (15.7-73.3 kg). The classifications of appendicitis consisted of 32 simple, 5 suppurative, 4 gangrenous, and 8 perforated. The average operative time was 29 minutes (6-53 minutes) and average length of stay was 1.9 days (1-6 days). There were three minor complications, and all cases were completed with this technique, including in obese patients and for perforated appendicitis. All patients reported satisfaction with their postoperative cosmetic outcome. CONCLUSIONS: This technique allows for the main incision to be hidden at the umbilicus, creating an essentially scarless cosmetic result. The addition of a 3 mm suprapubic port leads to increased maneuverability of the instruments and better retraction of the appendix. It is also feasible in obese children and cases of perforated appendicitis. PMID- 28099059 TI - Family Physician Readiness for Value-Based Payments: Does Ownership Status Matter? AB - Value-based payments are rapidly replacing fee-for-service arrangements, necessitating advancements in physician practice capabilities and functions. The objective of this study was to examine potential differences among family physicians who are owners versus employed with respect to their readiness for value-based payment models. The authors surveyed more than 550 family physicians from the American Academy of Family Physician's membership; nearly 75% had made changes to participate in value-based payments. However, owners were significantly more likely to report that their practices had made no changes in value-based payment capabilities than employed physicians (owners 35.2% vs. employed 18.1%, P < 0.05). This study identified 3 key areas in which physician owners' value-based practice capabilities were not as advanced as the employed physician group: (1) quality improvement strategies, (2) human capital investment, and (3) identification of high-risk patients. Specifically, the employed physician group reported more quality improvement strategies, including quality measures, Plan-Do-Study-Act, root cause analysis, and Lean Six Sigma (P < 0.05 for all). More employed physicians reported that their practices had full time care management staff (19.8% owners vs. 30.8% employed, P < 0.05), while owners were more likely to report that they had no resources/capacity to hire care managers or care coordinators (31.4% owners vs. 19.4% employed, P < 0.05). Owners were significantly more likely to respond that they do not have the resources/capacity to identify high-risk patients (23.1% owners vs. 19.3% employed, P < 0.05). As public and private payers transition to value-based payments, consideration of different population health management needs according to ownership status has the potential to support the adoption of value-based care delivery for family physicians. PMID- 28099060 TI - Understanding Medicaid Managed Care Investments in Members' Social Determinants of Health. AB - Despite widespread interest in addressing social determinants of health (SDH) as a means to improve health and to reduce health care spending, little information is available about how to develop, sustain, and scale nonmedical interventions in diverse payer environments, including Medicaid Managed Care. This study aimed to explore how Medicaid Managed Care Organization (MMCO) leaders interpret their roles and responsibilities around SDH, how they garner resources to develop and sustain interventions to address SDH, and how they perceive the influences of external organizations on related activities. Semistructured qualitative key informant interviews were conducted with a purposive sample of 26 Medicaid Managed Care corporate executives. Data were analyzed with an iterative coding, thematic development and interpretation process. MMCO leaders' interests and activities around interventions to address SDH are described, as well as their perceptions of existing and potential incentives and barriers to expanding these interventions. Despite significant experimentation and programmatic diversity of interventions addressing social determinants, MMCO leaders struggle with clinical integration, financing, and evaluation efforts that could promote sustainability. Though their efforts are nascent, MMCO leaders are investing in tackling social determinants to improve health and to decrease health care spending in managed care settings that serve low-income populations. Results highlight both opportunities and concerns about sustaining and scaling clinical interventions addressing SDH. PMID- 28099061 TI - Iodometric and Molecular Detection of ESBL Production Among Clinical Isolates of E. coli Fingerprinted by ERIC-PCR: The First Egyptian Report Declares the Emergence of E. coli O25b-ST131clone Harboring blaGES. AB - The extensive use of beta-lactam antibiotics has led to emergence and spread of extended-spectrum beta-lactamases (ESBLs). This study was conducted to investigate the prevalence of 7 different ESBL genes (blaTEM, blaSHV, blaCTX-M, blaVEB, blaPER, blaGES, and blaOXA-10) and O25b-ST131 high-risk clone among 61 clinical isolates of Escherichia coli. Also, one broad-spectrum beta-lactamase (blaOXA-1) was investigated. This study was also constructed to evaluate iodometric overlay method in detection of ESBL production. Phenotypic identification of E. coli isolates using API 20E revealed 18 distinct biotypes. DNA fingerprinting using enterobacterial repetitive intergenic consensus polymerase chain reaction (ERIC-PCR) differentiated all isolates into 2 main phylogenetic groups with 60 distinct genetic profiles. Elevated values of minimal inhibitory concentration (MIC)50 and MIC90 for third- and fourth-generation cephalosporins were observed. Phenotypic tests revealed that 85.24% of isolates were ESBL producers. The incidence rates of blaTEM, blaSHV, blaCTX-M, blaGES, blaOXA-1, and blaOXA-10 among E. coli ESBL producer phenotype were 69.23%, 25%, 96.15%, 3.85%, 11.54%, and 48%, respectively. On the other hand, blaVEB and blaPER were not detected. Sequencing of blaTEM and blaSHV revealed that blaTEM 214 and blaSHV-11 were the most prevalent variants. Group characterization of blaCTX-M revealed that blaCTX-M-1 was the most prevalent group of blaCTX-M family. It was found that 30.77% of E. coli ESBL producers belonged to O25b-ST131 clone harboring blaCTX-M-15. This study concluded that iodometric overlay method was 100% sensitive in detection of ESBL production. To our knowledge, this is the first Egyptian study that declares the emergence of E. coli O25b-ST131 harboring blaGES. PMID- 28099062 TI - Rectal Carriage of Extended-Spectrum Beta-Lactamase and Carbapenemase Producing Gram-Negative Bacilli in Intensive Care Units in Tunisia. AB - This study was conducted to evaluate the rate of fecal carriage of Gram-negative bacilli (GNB) resistant to third-generation cephalosporins (third GC) in patients hospitalized in the intensive care unit (ICU) of Charles Nicolle Hospital of Tunis and to identify the enzymatic mechanisms involved. From February to April 2014, rectal swabs were collected from all patients (n = 38) at admission and once weekly thereafter to identify acquisition. They were cultured on desoxycholate-lactose-agar plates supplemented with cefotaxime (2 mg/L). The rate of fecal carriage of GNB resistant to third GC was 0% (0/38) at admission and the acquisition rate was 45.16% (14/31). Nineteen GNB resistant to C3G were collected from 14 patients. The major species collected were Acinetobacter baumannii (n = 5), Klebsiella pneumoniae (n = 5), and Enterobacter cloacae (n = 5). Thirteen extended-spectrum beta-lactamase (ESBL) producing GNB were found; CTX-M-15 (n = 10) and CTX-M-14 (n = 1) among Enterobacteriacae and GES-12 (n = 2) among A. baumannii. Ten strains were carbapenem resistant. OXA-48 (n = 4) and NDM-1 (n = 1) were detected among Enterobacteriacae and OXA-23 (n = 5), and GES-11 (n = 1) were detected in A. baumannii. Gene encoding the ACT-16 AmpC-type-beta-lactamase was detected in two isolates. All Escherichia coli isolates were assigned to group B2. Among virulence genes, prevalence of fimH, fuyA, ompT, pai, and usp were highest observed in all E. coli isolates. Among K. pneumoniae mrkD and entB were the most frequent (n = 5) followed by ybtS (n = 4) and kfu (n = 2). This study revealed a high prevalence of fecal carriage of multidrug-resistant GNB, including ESBLs, carbapenemases, and cephalosporinases producing bacteria in patients hospitalized in ICU. PMID- 28099063 TI - Improve Quality, Control Spending, Maintain Access - Can the Merit-Based Incentive Payment System Deliver? PMID- 28099064 TI - Surgical Intervention for Primary Spontaneous Pneumothorax in Pediatric Population: When and Why? AB - INTRODUCTION: Spontaneous pneumothorax in pediatric patients is relatively uncommon. The management strategy varies in different centers due to dearth of evidence-based pediatric guidelines. In this study, we reviewed our experience of thoracoscopic management of primary spontaneous pneumothorax (PSP) in children and identified risk factors associated with postoperative air leakage and recurrence. MATERIALS AND METHODS: We performed a retrospective analysis of pediatric patients who had PSP and underwent surgical management in our institution between April 2008 and March 2015. Demographic data, radiological findings, interventions, and surgical outcomes were analyzed. RESULTS: A total of 92 patients with 110 thoracoscopic surgery for PSP were identified. The indications for surgery were failed nonoperative management with persistent air leakage in 32.7%, recurrent ipsilateral pneumothorax in 36.4%, first contralateral pneumothorax in 14.5%, bilateral pneumothorax in 10%, and significant hemopneumothorax in 5.5%. Bulla was identified in 101 thoracoscopy (91.8%) with stapled bullectomy performed. 14.5% patients had persistent postoperative air leakage and treated with reinsertion of thoracostomy tube and chemical pleurodesis. 17.3% patients had postoperative recurrence occurred at mean time of 11 months. Operation within 7 days of symptoms onset was associated with less postoperative air leakage (P = .04). Bilateral pneumothorax and those with abnormal radiographic features had significantly more postoperative air leakage (P = .002, P < .01 respectively) and recurrence (P < .01, P = .007). CONCLUSION: Early thoracoscopic mechanical pleurodesis and stapled bullectomy after thoracostomy tube insertion could be offered as a primary option for management of large PSP in pediatric population, since most of these patients had bulla identified as the culprit of the disease. PMID- 28099065 TI - Exploring Variation in Transformation of Primary Care Practices to Patient Centered Medical Homes: A Mixed Methods Approach. AB - The objective was to quantify the activities required for patient-centered medical home (PCMH) transformation in a sample of small to medium-sized National Committee for Quality Assurance (NCQA) recognized practices, and explore barriers and facilitators to transformation. Eleven small to medium-sized PCMH practices in Southeastern Pennsylvania completed a survey, which was adapted from the 2011 NCQA standards. Semistructured follow-up interviews were conducted, descriptive statistics were computed for the quantitative analysis, and a process of thematic coding was deployed for the qualitative analysis. Practices had considerable quantitative variation in their workforce composition and the PCMH-related activities they implemented. Most practices improved access and continuity through staff training and team-based care as well as expanded data collection for population management. The barriers to PCMH recognition were least burdensome for the largest practices. The heterogeneity of the small PCMH practices within the study sample underscore the need to understand the key transformation issues as efforts to disseminate the PCMH model continue. PMID- 28099066 TI - New Vaccines against Epidemic Infectious Diseases. PMID- 28099067 TI - Implementation of a Comprehensive Population Health Management Model. PMID- 28099069 TI - Essential Values for Population Health Improvement. PMID- 28099068 TI - Same Story, Different Story. AB - Differences in people's beliefs can substantially impact their interpretation of a series of events. In this functional MRI study, we manipulated subjects' beliefs, leading two groups of subjects to interpret the same narrative in different ways. We found that responses in higher-order brain areas-including the default-mode network, language areas, and subsets of the mirror neuron system tended to be similar among people who shared the same interpretation, but different from those of people with an opposing interpretation. Furthermore, the difference in neural responses between the two groups at each moment was correlated with the magnitude of the difference in the interpretation of the narrative. This study demonstrates that brain responses to the same event tend to cluster together among people who share the same views. PMID- 28099070 TI - Laparoscopic Rectal Dissection Assisted by Transanal Endoluminal Videoendoscopy Through a Blunt Tip Trocar. AB - BACKGROUND AND AIMS: Laparoscopic resection is a well-established approach for colorectal cancer surgery. In patients with rectal cancer treated by neoadjuvant chemoradiotherapy, it may be difficult to identify a clear safety margin for endostapling and subsequent anastomosis. We designed an innovative technical approach to assist colorectal anastomosis in these patients. TECHNIQUE: A four trocar laparoscopic approach is used. After exploration of the abdominal cavity, the left colic flexure is completely mobilized. Using a medial to lateral approach, the inferior mesenteric artery and vein are divided between clips, and the left colon proximal to the tumor is transected with a linear stapler. A total mesorectal excision is performed. At this point, if the free margin distal to the tumor site cannot be clearly identified, a blunt tip trocar (BTT, 10 mm; Medtronic, Minneapolis, MN) is inserted into the anus and the proximal foam sponge is secured to the anal verge to avoid displacement and gas leakage. Under low flow rate gas insufflation, a 0 degrees scope inserted into the trocar allows a clear observation of the distal margin of the lesion and guides the low rectal laparoscopic dissection and the precise placement of the stapler. The BTT is then removed to perform the transanal colorectal anastomosis; at the end of the procedure, the BTT can be reinserted to check the anastomosis for bleeding and leakage. RESULTS: We used this novel technique on 3 patients who underwent neoadjuvant therapy for T3 rectal cancer. In all of them, identification of the distal tumor margin was difficult at laparoscopy. All surgical procedures were safely completed and resulted in R0 resection. The average length of stay was 6 days. All patients were free from recurrences at 1 year follow-up. CONCLUSION: Endoluminal videoendoscopy through a transanal BTT is a useful ancillary technique to achieve a safe free margin during low rectal resection. PMID- 28099071 TI - An Observational Study of Provider Perspectives on Alternative Payment Models. AB - Over the past decade, reimbursement in the US health care system has undergone rapid transformation. The Affordable Care Act and the Medicare Access and CHIP Reauthorization Act are some of the many changes challenging traditional modes of practice and raising concerns about practitioners' ability to adapt. Recently, physician satisfaction was proposed as an addition to the Triple Aim in acknowledgment of how the physician's attitude can affect outcomes. To understand how physicians perceive alternative payment models (APMs) and how those perceptions may vary by their organizational role, non-leader physicians (N = 31), physician leaders (N = 67), and health system leaders (N = 49) were surveyed using a mixed-methods approach. Respondents to the electronic survey, who were identified from a Jefferson College of Population Health program participant database, rated their organizations' responses to APMs and provided commentary. Analysis of the Likert scale quantitative data indicates a significant difference in ratings between the 3 groups, particularly between health system leaders and non-leader physicians. The aggregated Attitudes Toward APMs Scale indicates that health system leaders were statistically significantly more likely to rate themselves and their organizations as better prepared for APMs compared to non leader physicians and physician leaders. Qualitative analysis of comments indicates that non-leader physicians are more negative of APMs, often expressing frustration at added administrative burdens, barriers to implementation, and inconsistent or unclear measurement requirements. These findings indicate that the negative feelings non-leader physicians and physician leaders, in particular, expressed could contribute to physician burnout and decreased professional satisfaction, and impede the effective implementation of APMs. PMID- 28099072 TI - Re: "Cigarette Smoking and Breast Cancer Risk in Hispanic and Non-Hispanic White Women: The Breast Cancer Health Disparities Study" by Conner et al. (J Womens Health (Larchmt) 2016;25:299-310). PMID- 28099073 TI - CDC's DELTA FOCUS Program: Identifying Promising Primary Prevention Strategies for Intimate Partner Violence. AB - According to 2011 data, nearly one in four women and one in seven men in the United States experience severe physical violence by an intimate partner, creating a public health burden requiring population-level solutions. To prevent intimate partner violence (IPV) before it occurs, the CDC developed Domestic Violence Prevention Enhancements and Leadership Through Alliances, Focusing on Outcomes for Communities United with States to identify promising community- and societal-level prevention strategies to prevent IPV. The program funds 10 state domestic violence coalitions for 5 years to implement and evaluate programs and policies to prevent IPV by influencing the environments and conditions in which people live, work, and play. The program evaluation goals are to promote IPV prevention by identifying promising prevention strategies and describing those strategies using case studies, thereby creating a foundation for building practice-based evidence with a health equity approach. PMID- 28099074 TI - New Developments in Breast Cancer Screening and Treatment. AB - The clinical update serves as a brief review of recently published, high-impact, and potentially practice-changing journal articles summarized for our readers. In this clinical update, we selected top recent articles regarding breast health that may change the clinical practice of women's health providers. We identified articles by reviewing high-impact medical and women's health journals as well as national practice guidelines. Three of our articles are dedicated to the rapid changes in breast cancer screening. With regard to breast cancer treatment, we focused on two articles that impact who we treat with traditional aggressive regimens. PMID- 28099075 TI - OCCURRENCE AND RELEVANCE OF MYCOPLASMA STURNI IN FREE-RANGING CORVIDS IN GERMANY. AB - Several Mycoplasma spp. are well-known pathogens in poultry. In birds of prey, White Storks ( Ciconia ciconia ), and some waterfowl (Anatidae, Pelecanidae) species, mycoplasmas occur commonly and seem to be apathogenic or commensal and most likely belong to the physiologic microbial flora of the respiratory tract. In other bird species, such as Common Nightingales ( Luscinia megarhynchos ) and tits (Paridae), Mycoplasma spp. are absent in healthy birds. In corvids, the prevalence and role of Mycoplasma spp. in disease remains unclear. In previous studies, Mycoplasma sturni was detected in diseased corvids; however, those studies included only a limited sample size or preselected individuals. We collected tracheal swabs of 97 free-ranging Corvidae, including 68 randomly selected individuals from hunting bags and 29 birds that had been admitted to a veterinary clinic. Tracheal swabs were examined for Mycoplasma spp. using culture and genus-specific PCR. If Mycoplasma spp. were detected, the species were identified by sequencing the 16S ribosomal (r) RNA gene and 16-23S rRNA intergenic transcribed spacer region. Five of 68 (7%) of the hunted birds and nine of 29 (31%) of the birds admitted to the veterinary clinic were PCR positive. In 13 of 14 PCR-positive samples, mycoplasmas were cultured and M. sturni was the only mycoplasmal species identified. None of the positive corvids from the hunting bags had clinical signs, whereas five of nine birds admitted to the veterinary clinic showed apathy, lameness, injuries, or fractures, which may not be associated with mycoplasmal infections. These data support the notion that M. sturni is the Mycoplasma sp. most frequently found in corvids, though its prevalence and ability to cause disease may involve interaction with other aspects of bird health. PMID- 28099076 TI - Extension of the Avian Host Range of Collyriclosis in Europe. AB - We describe cases of collyriclosis in apodiform and passeriform birds in Portugal, Switzerland, and Germany. We extend the host range of Collyriculm faba to include apodiform birds ( Apus apus , Apus melba , and Apus pallidus ) and the passerine Sitta europaea (Eurasian Nuthatch). Infections varied in severity from an incidental finding to severe debilitation and death. The infection route remains unclear with the apparent absence from Germany, Portugal, and Switzerland of the first intermediate host of C. faba, the aquatic gastropod Bythinella austriaca, implying that other organisms might be involved in the parasite's life cycle. Furthermore, the detection of C. faba cysts in very young passerine birds may indicate an infection during the nestling stage and a rapid development of parasite-containing subcutaneous cysts. This series of cases highlights an increased geographic range into Portugal and the potential debilitating nature of a parasite of migratory birds in Europe. However, given the rarity of cases, collyriclosis does not seem to present an important threat to migratory species preservation. PMID- 28099077 TI - DISEASE COMPLEXITY IN A DECLINING ALASKAN MUSKOX (OVIBOS MOSCHATUS) POPULATION. AB - The muskox ( Ovibos moschatus ) population inhabiting the eastern North Slope (ENS) of Alaska, US declined dramatically during 1999-2006, whereas populations in western Alaska (WA) were stable or increasing. To understand morbidity and mortality factors contributing to the decline, Alaska Department of Fish and Game conducted pathologic investigations of carcasses from 2005 until 2008. Additionally, archived sera from both ENS and WA muskoxen collected during 1984 92, before the documented beginning of the ENS decline; sera collected during 2000, near the beginning of the decline; and contemporary sera (from live capture release, adult females) collected during 2006, 2007, and 2008 were analyzed to determine whether prevalence of antibody to potential pathogens differed in the two areas or changed over time. The pathogens investigated were those that were believed could cause lameness or poor reproduction or adversely affect general health. Furthermore, trace mineral levels, hemograms, and gastrointestinal parasites were evaluated in live adult females captured 2006-08. Pathologic investigations identified several comorbid conditions, including predation, polyarthritis caused by or consistent with Chlamydophila spp. infection, hoof lesions, copper deficiency, contagious ecthyma, verminous pneumonia, hepatic lipidosis suggestive of negative energy balance, and bacterial bronchopneumonia due to Trueperella pyogenes and Bibersteinia trehalosi . Pathogens suspected to be newly introduced in the ENS muskox population on the basis of serologic detection include bovine viral diarrhea, respiratory syncytial virus, Chlamydophila spp., Brucella spp., Coxiella burnetii , and Leptospira spp., whereas parainfluenza virus-3 antibody prevalence has increased in the WA population. Although multiple disease syndromes were identified that contributed to mortality and, in combination, likely limited the ENS muskox population, further holistic investigations of disease agents, trace mineral status, and nutritional factors in conjunction with intensive demographic and environmental analyses would provide a better understanding of factors that influence Alaskan muskox populations. PMID- 28099078 TI - PREVALENCE OF TERRAPENE HERPESVIRUS 1 IN FREE-RANGING EASTERN BOX TURTLES (TERRAPENE CAROLINA CAROLINA) IN TENNESSEE AND ILLINOIS, USA. AB - Diseases affecting the upper respiratory tract, such as herpesviruses, are well described in captive chelonians worldwide, but their importance in free-ranging populations is less well known. To characterize the disease epidemiology of terrapene herpesvirus 1 (TerHV1), 409 free-ranging eastern box turtles ( Terrapene carolina carolina) in Tennessee and Illinois, US were tested for TerHV1 in 2013 and 2014 using TaqMan quantitative PCR. Whole blood and swabs of the oral mucosa were collected from 365 adults (154 females, 195 males, 16 unknown sex) and 44 juveniles. The prevalence of detection was 31.3% (n=128). Turtles were more likely to be positive for TerHV1 in July (50%; n=67) compared to September (38%; n=44) and May (11%; n=17). Turtles sampled in 2014 had a significantly higher prevalence (50%; n=98) than in 2013 (14%; n=30). In a multivariate model, only season, year, and the interaction between season and year were maintained; turtles were most likely to be positive in July (odds ratio: 30.5) and September (odds ratio: 41.8) 2014 compared to May 2013. The prevalence was not statistically different by state of collection, sex, or age class. Packed cell volume (25.5%) and total solids (4.8 mg/dL) in positive turtles were significantly higher than in negative turtles (23.0%; 4.3 mg/dL). Positive turtles had increased eosinophil concentrations, fewer lymphocytes, and fewer monocytes. No clinical sign was associated with detection of herpesvirus. Widespread DNA evidence of TerHV1 infection was detected in eastern box turtles, and knowledge of the epidemiology of this virus may aid in management of free ranging and captive individuals. PMID- 28099080 TI - Catastrophic Antiphospholipid Syndrome: Candidate Therapies for a Potentially Lethal Disease. AB - Catastrophic antiphospholipid syndrome (CAPS) is a potentially lethal disease that presents with rapidly progressive multiple organ thromboses. Anticoagulation, corticosteroids, intravenous immunoglobulin, and plasma exchange are the most commonly used treatments for CAPS patients. However, the high mortality despite these medications necessitates new treatment strategies. Following a brief review of current diagnostic and management strategies, we discuss the candidate therapies, i.e., hydroxychloroquine, rituximab, eculizumab, sirolimus, and defibrotide, that can be considered in CAPS patients refractory to traditional treatment. PMID- 28099079 TI - Lymphangioleiomyomatosis: A Monogenic Model of Malignancy. AB - Lymphangioleiomyomatosis (LAM) is a rare, low-grade, metastasizing neoplasm that arises from an unknown source, spreads via the lymphatics, and targets the lungs. All pulmonary structures become infiltrated with benign-appearing spindle and epithelioid cells (LAM cells) that express smooth-muscle and melanocyte-lineage markers, harbor mTOR-activating mutations in tuberous sclerosis complex (TSC) genes, and recruit abundant stromal cells. Elaboration of lymphangiogenic growth factors and matrix remodeling enzymes by LAM cells enables their access to lymphatic channels and likely drives the cystic lung remodeling that often culminates in respiratory failure. Dysregulated cellular signaling results in a shift from oxidative phosphorylation to glycolysis as the preferred mode of energy generation, to allow for the accumulation of biomass required for cell growth and tolerance of nutrient-poor, anaerobic environments. Symptomatic LAM occurs almost exclusively in females after menarche, highlighting the central but as yet poorly understood role for sex-restricted anatomical structures and/or hormones in disease pathogenesis. LAM is an elegant model of malignancy because biallelic mutations at a single genetic locus confer all features that define cancer upon the LAM cell-metabolic reprogramming and proliferative signals that drive uncontrolled growth and inappropriate migration and invasion, the capacity to exploit the lymphatic circulation as a vehicle for metastasis and access to the lungs, and destruction of remote tissues. The direct benefit of the study of this rare disease has been the rapid identification of an effective FDA-approved therapy, and the collateral benefits have included elucidation of the pivotal roles of mTOR signaling in the regulation of cellular metabolism and the pathogenesis of cancer. PMID- 28099081 TI - Controversies in the Treatment of Ductal Carcinoma in Situ. AB - Ductal carcinoma in situ (DCIS) accounts for 20% of all newly diagnosed breast cancers. Mastectomy was once the gold standard for the treatment of DCIS; however, breast-conserving surgery (BCS) has been adopted as the treatment of choice for patients with small, screen-detected lesions. Both adjuvant radiation and hormonal therapy following BCS have been demonstrated in randomized trials to reduce the risk of both invasive and DCIS recurrence, but neither affects survival. With the variety of surgical and adjuvant treatment options available, there has been great interest in tailoring the treatment to the individual, with the goal of optimizing the balance of risks and benefits according to the values and priorities of the woman herself. Prospective studies of women with "low-risk" DCIS treated with BCS alone have successfully identified women at lower than average risk but have not achieved the goal of identifying a subset of women with DCIS at minimal risk of recurrence after surgical excision alone. No studies have evaluated the safety of medical management alone. PMID- 28099083 TI - Update on Alzheimer's Disease Therapy and Prevention Strategies. AB - Alzheimer's disease (AD) is the primary cause of age-related dementia. Effective strategies to prevent and treat AD remain elusive despite major efforts to understand its basic biology and clinical pathophysiology. Significant investments in therapeutic drug discovery programs over the past two decades have yielded some important insights but no blockbuster drugs to alter the course of disease. Because significant memory loss and cognitive decline are associated with neuron death and loss of gray matter, especially in the frontal cortex and hippocampus, some focus in drug development has shifted to early prevention of cellular pathology. Although clinical trial design is challenging, due in part to a lack of robust biomarkers with predictive value, some optimism has come from the identification and study of inherited forms of early-onset AD and genetic risk factors that provide insights about molecular pathophysiology and potential drug targets. In addition, better understanding of the Abeta amyloid pathway and the tau pathway-leading to amyloid plaques and neurofibrillary tangles, respectively, which are histopathological hallmarks of AD-continues to drive significant drug research and development programs. The main focus of this review is to summarize the most recent basic biology, biochemistry, and pharmacology that serve as a foundation for more than 50 active advanced-phase clinical trials for AD prevention and therapy. PMID- 28099084 TI - Mechanisms and New Strategies for Primary Sjogren's Syndrome. AB - Primary Sjogren's syndrome (SS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands, mainly salivary and lacrimal, resulting in oral and ocular dryness, although virtually any organ system can be affected. SS-related systemic manifestations are classified as either related to the presence of periepithelial infiltrates in exocrine and parenchymal organs or resulting from immunocomplex deposition due to B cell hyperactivity with increased risk for B cell lymphoma development. Activation of both innate and adaptive immune pathways contributes to disease pathogenesis, with prominent interferon (IFN) signatures identified in both peripheral blood and affected salivary gland tissues. Recently, LINE-1 genomic repeat elements have been proposed as potential triggers of type I IFN pathway activation in SS through activation of Toll-like receptor-dependent and -independent pathways. In view of the increasingly appreciated variability of SS, elucidation of distinct operating pathways in relation to diverse clinical phenotypes and selection of the optimal therapeutic intervention remain major challenges. Inhibition of cathepsin S molecules, blockade of costimulation through administration of abatacept and inhibitors of B7-related molecules and CD40, blockade of B cell function and B cell survival factors, and disruption of the formation of ectopic germinal centers are considered the main therapeutic targets. Well-controlled multicenter clinical trials are ongoing and data are awaited. PMID- 28099085 TI - Lysosomal Proteins as a Therapeutic Target in Neurodegeneration. AB - Several proteins that are mutated in lysosomal storage diseases are linked to neurodegenerative disease. This review focuses on some of these lysosomal enzymes and transporters, as well as current therapies that have emerged from the lysosomal storage disease field. Given the deeper genetic understanding of lysosomal defects in neurodegeneration, we explore why some of these orphan disease drug candidates are also attractive targets in subpopulations of individuals with neurodegenerative disease. PMID- 28099082 TI - Therapeutics Targeting Drivers of Thoracic Aortic Aneurysms and Acute Aortic Dissections: Insights from Predisposing Genes and Mouse Models. AB - Thoracic aortic diseases, including aneurysms and dissections of the thoracic aorta, are a major cause of morbidity and mortality. Risk factors for thoracic aortic disease include increased hemodynamic forces on the ascending aorta, typically due to poorly controlled hypertension, and heritable genetic variants. The altered genes predisposing to thoracic aortic disease either disrupt smooth muscle cell (SMC) contraction or adherence to an impaired extracellular matrix, or decrease canonical transforming growth factor beta (TGF-beta) signaling. Paradoxically, TGF-beta hyperactivity has been postulated to be the primary driver for the disease. More recently, it has been proposed that the response of aortic SMCs to the hemodynamic load on a structurally defective aorta is the primary driver of thoracic aortic disease, and that TGF-beta overactivity in diseased aortas is a secondary, unproductive response to restore tissue function. The engineering of mouse models of inherited aortopathies has identified potential therapeutic agents to prevent thoracic aortic disease. PMID- 28099086 TI - Maximal heart rate declines linearly with age independent of cardiorespiratory fitness levels. AB - There have been many conflicting observations between the linear or curvilinear decline in maximal heart rate (HRmax) with age. The aim of this study was to determine if linear or curvilinear equations would better describe the decline in HRmax with age in individuals of differing cardiorespiratory fitness (CRF) levels. Treadmill cardiopulmonary exercise test (CPX) results from participants (1510 men and 1134 women; 18-76 years) free of overt cardiovascular disease were retrospectively examined using cross-sectional and longitudinal study designs. Participants completing >=2 CPX with >=1 year between test dates were included in the longitudinal analysis (325 men and 150 women). Linear and quadratic regressions were applied to age and HRmax for the whole cohort and respective CRF groups (high, moderate, and low, relative to age and gender normative values). To test for differences among linear, quadratic, and polynomial equations, the change in R2 (cross-sectional analysis) and Bayesian information criterion (BIC) (longitudinal analysis) from the linear to the more complex models were calculated. The quadratic or polynomial regression in the cross-sectional analysis, marginally improved the variance in HRmax explained by age compared to the linear regression for the whole cohort (0.2%), moderate fit group (0.3%), and low fit group (0.8%). With no improvements in the high fit group. BIC did not improve for any CRF category in the longitudinal analysis. In conclusion, the minimal differences among linear, quadratic, and polynomial equations in the respective CRF groups, emphasizes the use of linear prediction equations to estimate HRmax. PMID- 28099087 TI - Effects of biochar on the emissions, soil distribution, and nematode control of 1,3-dichloropropene. AB - Emissions of volatile soil fumigant 1,3-dichloropropene (1,3-D) from soil to air are a significant concern in relation to air quality, and cost-effective strategies to reduce such emissions are urgently required by growers to help them comply with increasingly stringent regulations. In this work, application of a rice husk-derived biochar to the surface of a sandy loam soil chamber reduced soil-air emissions of 1,3-D from 42% in a control (no biochar) to 8% due to adsorption onto the biochar. This adsorbed 1,3-D showed a potential for re volatilization into air and solubilization into the soil-liquid phase. Biochar at the soil surface also reduced soil-gas concentrations in the upper soil; based on the determination of concentration-time values, this may limit 1,3-D-induced nematode control in the upper soil. In batch studies, the mixing of biochar into the soil severely limited nematode control; 1,3-D application rates around four times greater than the maximum permissible limit would be required to give nematode control under such conditions. Therefore, the use of biochar as a surface amendment, while showing an emission reduction benefit, may limit pest control during subsequent fumigations if, as seems probable, it is plowed into the soil. PMID- 28099088 TI - Mother gestational exposure to organophosphorus pesticide induces neuron and glia loss in daughter adult brain. AB - Chlorpyrifos (CPF) is a widely used organophosphorus pesticide with developmental neurotoxicity such as morphogenesis toxicity. In the present study, we assessed the effects of prenatal CPF exposure on systemic parameters and cytoarchitecture of medial prefrontal cortex (mPFC) in adulthood. Gestational dams were exposed to 5mg/kg/d of CPF during gestational days 13-17, while body weight, organ coefficient, and neuron and glia counts of offspring were determined on postnatal day 60. Our results showed that CPF treatment induced little or no effects on body weight and organ coefficients. There were also no significant pathological changes in mPFC. However, neuron and glia count analysis showed that CPF treatment reduced neuron and glia counts in anterior cingulate, prelimbic, and infralimbic areas of mPFC. The CPF react pattern was similar in both sexes, and there was no statistical difference in most of the sub-regions. Thus, our results revealed an embryonic origin brain deficit induced by gestational mother pesticide exposure. PMID- 28099089 TI - Genotypic characterization of quinolone resistant-Escherichia coli isolates from retail food in Morocco. AB - This study was conducted to assess the retail food as a possible vehicle for antimicrobial resistant, particularly quinolones resistant and pathogenic Escherichia coli. We determined the prevalence and characteristics of nalidixic acid (Nal) resistant E. coli isolates from diverse retail food samples. In all, 70 (28%) of 250 E. coli isolates studied were Nal-resistant E. coli and 91% of these were multi-drug resistant. Plasmid mediated quinolone resistance genes were identified in 32 isolates, including aac(6')-Ib-cr (n = 16), qnrS1 (n = 11) and qnrB19 (n = 7). Mutations in gyr A and par C genes were detected among 80% of the isolates, and the isolates showed substitution Ser83-Leu and Asp87-Asn in gyrA and Ser80-Ile in parC. In addition, three different gene cassettes were identified (aadA1, aadA7, aac(3)-Id) in 18%. Virulence-associated genes stx1, eae, sfa, hlyA and stx2 were found in six (8%), three (4%), two (3%), three (4%) and three (4%) isolates, respectively. E. coli isolates of phylogenetic group A were dominant (64%, 45/70). Pulsed field gel electrophoresis revealed none epidemiological relationship between these isolates. The results of this work report the higher frequency of Nal-resistant E. coli isolates from Moroccan retail food samples including MDR and pathogenic isolates. PMID- 28099090 TI - Nutritional evaluation, bioaccumulation and toxicological assessment of heavy metals in edible fruits of FicussurForssk (Moraceae). AB - Ficussur (Moraceae) is an indigenous medicinal plant with a wide distribution in Africa. In this study, the nutritional potential fruit of this indigenous plant to meet domestic food demands and reduce food insecurity in KwaZulu-Natal. South Africa, was investigated. The proximate composition and concentrations of metals in the edible fruits collected from eight different sites in KwaZulu-Natal were determined to assess for nutritional value and the concentrations of metals in the growth soil was determined to evaluate the impact of soil quality on elemental uptake. The fruits contained high levels of moisture (88.8%) and carbohydrates (65.6%). The concentrations of elements in the fruits were found to be in decreasing order of Ca>Mg >Fe >Zn>Cu >Mn> Se with low levels of toxic metals (As, Cd, Co and Pb). This study shows that the consumption of the fruits of F. sur can contribute positively to the nutritional needs of rural communities in South Africa for most essential nutrients without posing the risk of adverse health effects. PMID- 28099091 TI - Acute toxicity of chlorpyrifos to embryo and larvae of banded gourami Trichogaster fasciata. AB - This study elucidated the acute toxicity of chlorpyrifos on the early life stages of banded gourami (Trichogaster fasciata). To determine the acute effects of chlorpyrifos on their survival and development, we exposedthe embryos and two-day old larvae to six concentrations (0, 0.01, 0.10, 1.0, 10 and 100 ug L-1) of chlorpyrifos in plastic bowls. Log-logistic regression was used to calculate LC10 and LC50 values. Results showed that embryo mortality significantly increased with increasing chlorpyrifos concentrations. The 24-h LC10 and LC50 values (with 95% confidence limits) of chlorpyrifos for embryos were 0.89 (0.50-1.58) and 11.8 (9.12-15.4) ug L-1, respectively. Hatching success decreased and mortality of larvae significantly increased with increasing concentrations of chlorpyrifos. The 24-h LC10 and LC50 values (with 95% confidence limits) of chlorpyrifos for larvae were 0.53 (0.27-1.06) and 21.7 (15.9-29.4) ug L-1, respectively; the 48-h LC10 and LC50 for larvae were 0.04 (0.02-0.09) and 5.47 (3.77-7.94) ug L-1, respectively. The results of this study suggest that 1 ug L-1 of chlorpyrifos in the aquatic environment may adversely affect the development and the reproduction of banded gourami. Our study also suggests that banded gourami fish can serve as an ideal model species for evaluating developmental toxicity of environmental contaminants. PMID- 28099092 TI - Training and development of Canadian wheelchair basketball players. AB - Considering the growth in research, examining the development of mainstream sport athletes over the past two decades, studies examining development of athletes with disabilities have been surprisingly limited. While similarities in developmental trajectories between the two cohorts may exist regarding factors such as the value of practice, which tend to be universal regardless of context, disability-related issues (e.g. whether the disability was congenital or acquired) may influence the course of development, affecting variables such as starting age, training and developmental milestones. Fifty-two male and female athletes training with the Wheelchair Basketball Canada National Academy provided detailed training histories. Athletes illustrated similar developmental patterns (e.g. milestones, training adjustments) as they progressed through their sporting career. However, athletes with congenital disabilities started participation in wheelchair basketball and unorganised practice at significantly younger ages (t49 = -4.35, p < .001, d = 1.32; t49 = -3.49, p < .001, d = 1.03, respectively). While athletes with congenital disabilities continued to reach a majority of the sporting milestones at younger ages, athletes with acquired disabilities were able to reach late career milestones (e.g. national debuts) at similar ages. Athletes' disability severity did not influence their progress through the developmental milestones and time devoted to training throughout their sporting career. Future work may consider examining developmental trajectories and training histories of athletes in various parasports to extend our understanding of their development and skill acquisition. PMID- 28099093 TI - Patients with Infectious Endocarditis and Drug Dependence Have Worse Clinical Outcomes after Valvular Surgery. AB - BACKGROUND: Patients with infective endocarditis (IE) are at high risk for post operative morbidity and death, which might be associated with drug abuse. The purpose of this study is to evaluate the impact of drug dependence on outcomes in patients who have IE and undergo valvular surgery (VS). PATIENTS AND METHODS: The Nationwide/National Inpatient Sample 2001-2012 was queried to select patients with IE who had elective VS using International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis and procedure codes. Among them, patients with drug dependence (PDD) were identified, and their health status and post-operative outcomes were compared with those in patients without drug dependence (control group). Chi-square and Wilcoxon rank sum tests as well as multi-variable regression analysis were used for statistics. RESULTS: A total of 809 (12.9%) PDD of the 6,264 patients who underwent VS were evaluated. They were younger compared with those in the control group (39.0 +/- 10.8 y vs. 54.4 +/- 14.8 y; p < 0.0001), had less age-related co-morbidities such as hypertension, diabetes mellitus, congestive heart failure, renal failure, obesity, but greater rates of alcohol abuse, liver disease, and psychoses. Despite the younger age and fewer co-morbidities, PDD compared with control patients were more likely to have post-operative complications develop overall (odds ratio [OR] = 1.6; 95% confidence interval [CI] 1.34-2.01), including infectious complications (OR = 1.5; 95% CI 1.27-1.78), specifically pneumonia (OR = 1.4; 95% CI 1.14-1.74) and sepsis (OR = 1.4; 95% CI 1.16-1.63), renal complications (OR = 1.5; 95% CI 1.23 1.77), and pulmonary embolism (OR = 1.9; 95% CI 1.44-2.52). Further, PDD had 11% longer hospital length of stay than those in the control groups (p < 0.0001). We did not find significant difference in hospital deaths, however, between these groups. CONCLUSION: Drug dependence is associated with worse post-operative outcomes in patients with infective endocarditis who underwent valvular surgery and lengthens their hospital stay. PMID- 28099094 TI - Case 242. PMID- 28099095 TI - When Imaging Becomes Clinically Relevant: Multikinase Inhibitor-related Pancreatic Insufficiency and Pancreatic Atrophy. PMID- 28099096 TI - Two Decades of Progress Measured by Big Steps and Driven by Persistence. PMID- 28099097 TI - Blood-Brain Barrier Leakage in Patients with Early Alzheimer Disease. PMID- 28099098 TI - Evaluation of Peripheral Arterial Disease with Nonenhanced Quiescent-Interval Single-Shot MR Angiography. PMID- 28099099 TI - Quantitative Assessment of Rectal Cancer Response to Neoadjuvant Combined Chemotherapy and Radiation Therapy. PMID- 28099100 TI - Lung Shunting: An Indicator of Survival, But Not Necessarily a Tool for Selecting Patients for Radioembolization. PMID- 28099101 TI - Myeloperoxidase Nuclear Imaging for Epileptogenesis. PMID- 28099102 TI - Interaction of Vascular Damage and Alzheimer Dementia: Focal Damage and Disconnection. PMID- 28099103 TI - Impact of Data-driven Respiratory Gating in Clinical PET. PMID- 28099104 TI - Morton A. Bosniak, MD. PMID- 28099105 TI - Quantitative Assessment of Rectal Cancer Response to Neoadjuvant Combined Chemotherapy and Radiation Therapy: Comparison of Three Methods of Positioning Region of Interest for ADC Measurements at Diffusion-weighted MR Imaging. PMID- 28099106 TI - Costing in Radiology and Health Care: Rationale, Relativity, Rudiments, and Realities. AB - Costs direct decisions that influence the effectiveness of radiology in the care of patients on a daily basis. Yet many radiologists struggle to harness the power of cost measurement and cost management as a critical path toward establishing their value in patient care. When radiologists cannot articulate their value, they risk losing control over how imaging is delivered and supported. In the United States, recent payment trends directing value-based payments for bundles of care advance the imperative for radiology providers to articulate their value. This begins with the development of an understanding of the providers' own costs, as well as the complex interrelationships and imaging-associated costs of other participants across the imaging value chain. Controlling the costs of imaging necessitates understanding them at a procedural level and quantifying the costs of delivering specific imaging services. Effective product-level costing is dependent on a bottom-up approach, which is supported through recent innovations in time-dependent activity-based costing. Once the costs are understood, they can be managed. Within the high fixed cost and high overhead cost environment of health care provider organizations, stakeholders must understand the implications of misaligned top-down cost management approaches that can both paradoxically shift effort from low-cost workers to much costlier professionals and allocate overhead costs counterproductively. Radiology's engagement across a broad spectrum of care provides an excellent opportunity for radiology providers to take a leading role within the health care organizations to enhance value and margin through principled and effective cost management. Following a discussion of the rationale for measuring costs, this review contextualizes costs from the perspectives of a variety of stakeholders (relativity), discusses core concepts in how costs are classified (rudiments), presents common and improved methods for measuring costs in health care, and discusses how cost management strategies can either improve or hinder high-value health care (realities). (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28099107 TI - Case 238: Spontaneous Pneumothorax Secondary to Intrapulmonary Necrobiotic Rheumatoid Nodule. AB - History A 54-year-old white woman with a history of rheumatoid arthritis who was taking glucocorticoids and methotrexate presented to the emergency department in December with worsening shortness of breath and chest heaviness for 1 week. She reported additional symptoms of weakness, headache, and arthralgia primarily involving her bilateral hands, wrist, ankles, and feet. She denied experiencing fevers, syncope or presyncope, focal neurologic deficits, chest pain, nausea, vomiting, unintentional weight loss, or recent trauma. Additional medical history included hypertension, asthma, degenerative disk disease, and migraine, all of which were reportedly controlled with medications. This patient had a smoking history of 80 pack-years, but she had quit smoking 2 months prior to presentation. She denied abuse of alcohol or recreational drugs and reported she was up-to-date on her immunizations, including those for pneumonia and flu. Family history was pertinent for breast cancer in her mother, sister, and maternal aunt. The patient reported normal findings at screening mammography and colonoscopy. A physical examination was remarkable for slightly asymmetric breath sounds, which appeared to be diminished on the right side. This patient had multiple joint deformities, most notably in the bilateral metacarpophalangeal joints. Initial electrocardiography findings and cardiac biomarkers were negative. Her complete blood count and basic metabolic profile were unremarkable. Posteroanterior and lateral chest radiographs were obtained in the emergency department. Subsequently, computed tomography (CT) of the chest was performed. PMID- 28099108 TI - Integration of Contrast-enhanced US into a Multimodality Approach to Imaging of Nodules in a Cirrhotic Liver: How I Do It. AB - Accurate characterization of cirrhotic nodules and early diagnosis of hepatocellular carcinoma (HCC) are of vital importance. Currently, computed tomography (CT) and magnetic resonance (MR) imaging are standard modalities for the investigation of new nodules found at surveillance ultrasonography (US). This article describes the successful integration of contrast material-enhanced US into a multimodality approach for diagnosis of HCC and its benefits in this population. The application of contrast-enhanced US immediately following surveillance US allows for prompt dynamic contrast-enhanced evaluation, removing the need for further imaging of benign lesions. Contrast-enhanced US also provides dynamic real-time assessment of tumor vascularity so that contrast enhancement can be identified regardless of its timing or duration, allowing for detection of arterial hypervascularity and portal venous washout. The purely intravascular nature of US contrast agents is valuable as the rapid washout of nonhepatocyte malignancies is highly contributory to their differentiation from HCC. The authors believe contrast-enhanced US provides complementary information to CT and MR imaging in the characterization of nodules in high-risk patients. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28099109 TI - Arterial Spin Labeling to Predict Brain Tumor Grading: Limits of Cutoff Cerebral Blood Flow Values. PMID- 28099110 TI - Management Matters. PMID- 28099112 TI - Science to Practice: Multiparametric Molecular and Functional US Imaging Goes Three-dimensional. AB - Although microbubbles can boost the diagnostic value of ultrasonography (US), they are not routinely applied in clinical tumor diagnosis. This can be explained by the limited reproducibility of US examinations and the fact that single or few recorded image sections may not be representative of the entire tumor. Three dimensional (3D) US may help to overcome these limitations. Therefore, Wang and coworkers applied a 3D matrix transducer to monitor response of colon cancer xenografts to antiangiogenic therapy with functional and molecular US imaging. It was shown that tumor response to therapy can be assessed early, precisely, and in high agreement with histologic findings. PMID- 28099113 TI - RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma. AB - Asthma is a chronic inflammatory disease. Although many patients with asthma develop type-2 dominated eosinophilic inflammation, a number of individuals develop paucigranulocytic asthma, which occurs in the absence of eosinophilia or neutrophilia. The aetiology of paucigranulocytic asthma is unknown. However, both respiratory syncytial virus (RSV) infection and mutations in the receptor for advanced glycation endproducts (RAGE) are risk factors for asthma development. Here, we show that RAGE deficiency impairs anti-viral immunity during an early life infection with pneumonia virus of mice (PVM; a murine analogue of RSV). The elevated viral load was associated with the release of high mobility group box-1 (HMGB1) which triggered airway smooth muscle remodelling in early-life. Re infection with PVM in later-life induced many of the cardinal features of asthma in the absence of eosinophilic or neutrophilic inflammation. Anti-HMGB1 mitigated both early-life viral disease and asthma-like features, highlighting HMGB1 as a possible novel therapeutic target. PMID- 28099114 TI - Mitochondrial respiratory gene expression is suppressed in many cancers. AB - The fundamental metabolic decision of a cell, the balance between respiration and fermentation, rests in part on expression of the mitochondrial genome (mtDNA) and coordination with expression of the nuclear genome (nuDNA). Previously we described mtDNA copy number depletion across many solid tumor types (Reznik et al., 2016). Here, we use orthogonal RNA-sequencing data to quantify mtDNA expression (mtRNA), and report analogously lower expression of mtRNA in tumors (relative to normal tissue) across a majority of cancer types. Several cancers exhibit a trio of mutually consistent evidence suggesting a drop in respiratory activity: depletion of mtDNA copy number, decreases in mtRNA levels, and decreases in expression of nuDNA-encoded respiratory proteins. Intriguingly, a minority of cancer types exhibit a drop in mtDNA expression but an increase in nuDNA expression of respiratory proteins, with unknown implications for respiratory activity. Our results indicate suppression of respiratory gene expression across many cancer types. PMID- 28099115 TI - Examination of the reliability of an inertial sensor-based gait analysis system. AB - Gait analysis is an important and useful part of the daily therapeutic routine. InvestiGAIT, an inertial sensor-based system, was developed for using in different research projects with a changing number and position of sensors and because commercial systems do not capture the motion of the upper body. The current study is designed to evaluate the reliability of InvestiGAIT consisting of four off-the-shelf inertial sensors and in-house capturing and analysis software. Besides the determination of standard gait parameters, the motion of the upper body (pelvis and spine) can be investigated. Kinematic data of 25 healthy individuals (age: 25.6+/-3.3 years) were collected using a test-retest design with 1 week between measurement sessions. We calculated different parameters for absolute [e.g. limits of agreement (LoA)] and relative reliability [intraclass correlation coefficients (ICC)]. Our results show excellent ICC values for most of the gait parameters. Midswing height (MH), height difference (HD) of initial contact (IC) and terminal contact (TC) and stride length (SL) are the gait parameters, which did not exhibit acceptable values representing absolute reliability. Moreover, the parameters derived from the motion of the upper body (pelvis and spine) show excellent ICC values or high correlations. Our results indicate that InvestiGAIT is suitable for reliable measurement of almost all the considered gait parameters. PMID- 28099116 TI - Determination of glucose-6-phosphate dehydrogenase cut-off values in a Tunisian population. AB - BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest enzymopathy worldwide. The incidence depends essentially on the methods used for the assessment. In this respect, we attempted in this study to set cut-off values of G6PD activity to discriminate among normal, heterozygous, and deficient individuals using the World Health Organization (WHO) classification and the receiver operating characteristics (ROC) curve analysis. METHODS: Blood samples from 250 female and 302 male subjects were enrolled in this study. The G6PD activity was determined using a quantitative assay. The common G6PD mutations in Tunisia were determined using the amplification refractory mutation system (ARMS PCR) method. The ROC curve was used to choice the best cut-off. RESULTS: Normal G6PD values were 7.69+/-2.37, 7.86+/-2.39, and 7.51+/-2.35 U/g Hb for the entire, male, and female groups, respectively. Cut-off values for the total, male, and female were determined using the WHO classification and ROC curves analysis. In the male population, both cut-offs established using ROC curve analysis (4.00 U/g Hb) and the 60% level (3.82 U/g Hb), respectively are sensitive and specific resulting in a good efficiency of discrimination between deficient and normal males. For the female group the ROC cut-off (5.84 U/g Hb) seems better than the 60% level cut-off (3.88 U/g Hb) to discriminate between normal and heterozygote or homozygote women with higher Youden Index. CONCLUSIONS: The establishment of the normal values for a population is important for a better evaluation of the assay result. The ROC curve analysis is an alternative method to determine the status of patients since it correlates DNA analysis and G6PD activity. PMID- 28099117 TI - CASZ1 loss-of-function mutation contributes to familial dilated cardiomyopathy. AB - BACKGROUND: The zinc finger transcription factor CASZ1 plays a key role in cardiac development and postnatal adaptation, and in mice, deletion of the CASZ1 gene leads to dilated cardiomyopathy (DCM). However, in humans whether genetically defective CASZ1 contributes to DCM remains unclear. METHODS: The coding exons and splicing junction sites of the CASZ1 gene were sequenced in 138 unrelated patients with idiopathic DCM. The available family members of the index patient harboring an identified CASZ1 mutation and 200 unrelated, ethnically matched healthy individuals used as controls were genotyped for CASZ1. The functional characteristics of the mutant CASZ1 were analyzed in contrast to its wild-type counterpart using a luciferase reporter assay system. RESULTS: A novel heterozygous CASZ1 mutation, p.K351X, was identified in an index patient with DCM. Genetic analysis of the mutation carrier's family showed that the mutation co-segregated with DCM, which was transmitted in an autosomal dominant pattern with complete penetrance. The nonsense mutation, which was absent in 400 referential chromosomes, altered the amino acid that was highly conserved evolutionarily. Biological investigations revealed that the mutant CASZ1 had no transcriptional activity. CONCLUSIONS: The current study reveals CASZ1 as a new gene responsible for human DCM, which provides novel mechanistic insight and potential therapeutic target for CASZ1-associated DCM, implying potential implications in improved prophylactic and therapeutic strategies for DCM, the most common type of primary myocardial disease. PMID- 28099118 TI - Assessment of autoantibodies to interferon-omega in patients with autoimmune polyendocrine syndrome type 1: using a new immunoprecipitation assay. AB - BACKGROUND: Measurements of autoantibodies to interferon-omega (IFN-omega) in patients with autoimmune polyglandular syndrome type 1 (APS-1) were performed using a new immunoprecipitation assay (IPA) based on 125I-labeled IFN-omega. METHODS: We have developed and validated a new IPA based on 125I-labeled IFN omega. Sera from 78 patients (aged 3-78 years) with clinically diagnosed APS-1, 35 first degree relatives, 323 patients with other adrenal or non-adrenal autoimmune diseases and 84 healthy blood donors were used in the study. In addition, clinical features and autoimmune regulator (AIRE) genotype for the APS 1 patients were analyzed. RESULTS: Sixty-six (84.6%) of 78 APS-1 patients were positive for IFN-omega Ab using 125I-labeled IFN-omega IPA. IFN-omega Ab was the most prevalent of the six different autoantibodies tested in this group of APS-1 patients. All 66 IFN-omega Ab-positive APS-1 patients had AIRE mutations and 7 IFN-omega Ab-negative patients had no detectable AIRE mutations, whereas 3 (3.8%) patients were discrepant for IFN-omega Ab positivity and AIRE mutation results. Out of autoimmune controls studied, two patients were positive for IFN-omega Ab. Positivity and levels of IFN-omega Ab in the APS-1 patients studied were similar irrespective of patient's clinical phenotype and AIRE genotype. Furthermore, IFN omega Ab levels did not change over time (up to 36 years of disease duration) in 8 APS-1 patients studied. CONCLUSIONS: We have developed a novel, highly sensitive and specific assay for measurement of IFN-omega Ab. It provides a simple and convenient method for the assessment of patients with APS-1 and selecting patients suspected of having APS-1 for AIRE gene analysis. PMID- 28099119 TI - Interference in Na+ measurements on the Siemens RAPIDPoint(r) 500 after nortriptyline intoxication: a case report. PMID- 28099120 TI - The clinical significance of platelet microparticle-associated microRNAs. AB - Circulating blood platelets play a central role in the maintenance of hemostasis. They adhere to subendothelial extracellular matrix proteins that become exposed upon vessel wall damage, which is followed by platelet activation, further platelet recruitment, platelet aggregation and formation of an occlusive, or non occlusive, platelet thrombus. Platelets host a surprisingly diverse transcriptome, which is comprised of ~9500 messenger RNAs (mRNAs) and different classes of non-coding RNAs, including microRNAs, as well as a significant repertoire of proteins that contribute to their primary (adhesion, aggregation, granule secretion) and alternative (RNA transfer, mRNA translation, immune regulation) functions. Platelets have the propensity to release microparticles (MPs; 0.1-1 MUm in diameter) upon activation, which may mediate inflammatory responses and contribute to exacerbate inflammatory diseases and conditions. Carrying components of the platelets' cytoplasm, platelet MPs may exert their effects on recipient cells by transferring their content in platelet-derived bioactive lipid mediators, cytokines, mRNAs and microRNAs. Platelet MP-associated microRNAs may thus function also outside of platelets and play an important role in intercellular signaling and gene expression programming across the entire circulatory system. The role and importance of platelet MP-associated microRNAs in various aspects of biology and pathophysiology are increasingly recognized, and now provide the scientific basis and rationale to support further translational research and clinical studies. The clinical significance, pathophysiological role as well as the diagnostic and therapeutic potential of platelet MP-associated microRNAs in cardiovascular diseases, platelet transfusion and cancer will be discussed. PMID- 28099121 TI - Early mixed hematopoietic chimerism detection by digital droplet PCR in patients undergoing gender-mismatched hematopoietic stem cell transplantation. AB - BACKGROUND: Clinical decision making after allogeneic stem cell transplantation (HSCT) is partially based on hematopoietic chimerism analysis. Polymerase chain reaction amplification of polymorphic short tandem repeats (STR-PCR) is currently considered the gold standard for chimerism surveillance after transplantation. Nevertheless, this method has shown several limitations. Emerging technologies such as digital PCR (dPCR) has been applied to detect hematopoietic chimerism. Despite previous reports, the clinical usefulness of dPCR is unclear because the studies were performed in limited patient populations with short follow-ups. METHODS: In order to compare hematopoietic chimerism detection time and rate, we analyzed 591 samples from 155 patients undergoing gender-mismatched HSCT using STR-PCR and dPCR. We also established the correlation between both methods in artificial DNA mixtures prepared in known proportions and in clinical samples. RESULTS: Depending on the artificial DNA mixture analyzed the correlation coefficient between both methods was 0.9946 and 0.9732. The limit of detection for dPCR was 0.01%. Of 157 samples with donor and recipient DNA, mixed chimerism (MC) was detected solely by dPCR in 66 samples. Within the group of patients relapsing after HSCT (n=32) MC was detected earlier in 15 of these patients with dPCR in comparison with STR-PCR. The mean time from MC detection to relapse was 155 days (range: 13-385 days) and 65 days (range: 0-203 days) for dPCR and STR PCR, respectively. CONCLUSIONS: dPCR is a sensitive and accurate method for the quantification of hematopoietic chimerism allowing earlier MC detection compared to STR-PCR. PMID- 28099122 TI - Parathormone stability in hemodialyzed patients and healthy subjects: comparison on non-centrifuged EDTA and serum samples with second- and third-generation assays. AB - BACKGROUND: Parathyroid hormone (PTH) stability is important. Many studies have shown divergent results between EDTA and serum, which are mainly linked to differences in protocols or cut-offs used to determine whether or not PTH remained stable. No studies have yet compared PTH stability as measured by second and third-generation assays on the same samples in hemodialyzed patients and healthy subjects. METHODS: Five pairs of samples (EDTA and gel tubes) were obtained in 10 hemodialyzed patients before a dialysis session and in 10 healthy subjects. One pair was centrifuged and run directly to define the "T0". Two pairs were kept at +4 degrees C and two pairs were kept at +25 degrees C. They were centrifuged after 4 and 18 h. Supernatant was kept at -80 degrees C for 1 week. All samples were measured in a single batch, on Roche Cobas and DiaSorin XL second- and third-generation PTH assays. We used three different approaches to evaluate PTH stability: Wilcoxon test, an Acceptable Change Limit (ACL) according to ISO Guide 5725-6 and a Total Change Limit (TCL) derived from the sum of biological and technical variability according to WHO. RESULTS: PTH decreased in all samples. Stability of PTH was mainly dependent on the way it was evaluated. Percentages of decrease were systematically lower in EDTA vs. serum. Wilcoxon and ACL showed that PTH was no more stable after 4 h at +4 degrees C in EDTA or serum gel tubes. None of the subjects presented a PTH decrease higher than the TCL with EDTA plasma. In serum gel tubes, PTH was unstable only when kept at 25 degrees C for 18 h. CONCLUSIONS: PTH seems more stable in EDTA than in serum gel tubes but only when samples have to stay unprocessed for a long period (18 h) at room temperature (25 degrees C), which can happen when samples are delivered from external care centers. For all the other conditions, using serum gel tubes is recommended since calcium measurement, which is necessary for a good PTH results interpretation, can be achieved on the same tube. PMID- 28099123 TI - Hyperandrogenemia in women with polycystic ovary syndrome: prevalence, characteristics and association with body mass index. AB - BACKGROUND: Hyperandrogenemia is one of the major diagnostic features for the diagnosis of polycystic ovary syndrome (PCOS). The aim of this study was to estimate the prevalence and the characteristics of hyperandrogenemia in women with PCOS and to investigate the association of clinical and biochemical characteristics with body mass index (BMI) according to the presence of hyperandrogenemia. MATERIALS AND METHODS: We studied 266 women diagnosed with PCOS. Hyperandrogenemia was defined by testosterone (T) and/or free testosterone (FT) and/or ?4 androstenedione (Delta4-A) higher than 75% of the upper limits of each hormone. Patients were stratified in two groups according to a BMI threshold of 25 kg/m2. RESULTS: Hyperandrogenemia was present in 78.2% of the patients. Elevated levels of T were found in 58.4%, while elevated levels of FT and Delta4 A were found in 42.5% and 34.1% of patients. In normal weight women (BMI<=25 kg/m2) with hyperandrogenemia lower values of hip circumference and HOMA-IR and increased levels of T, FT, Delta4-A, 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone sulfate (DHEAS), white blood cells (WBC) and neutrophils were observed compared to women without hyperandrogenemia. Also, in overweight women higher levels of T, FT, Delta4-A, 17-OHP, DHEAS and cortisol were measured, while lower thyroid-stimulating hormone (TSH) levels were comparable to women without hyperandrogenemia. CONCLUSION: This study showed high prevalence of hyperandrogenemia in PCOS women. Women with BMI<=25 kg/m2 have significant differences in androgens, WBC, neutrophils and HOMA-IR and women with BMI>=25 kg/m2 in androgens, TSH and cortisol according to the presence or not of hyperandrogenemia. PMID- 28099124 TI - Browning of white adipose tissue: lessons from experimental models. AB - Beige or brite (brown-in-white) adipocytes are present in white adipose tissue (WAT) and have a white fat-like phenotype that when stimulated acquires a brown fat-like phenotype, leading to increased thermogenesis. This phenomenon is known as browning and is more likely to occur in subcutaneous fat depots. Browning involves the expression of many transcription factors, such as PR domain containing 16 (PRDM16) and peroxisome proliferator-activated receptor (PPAR) gamma, and of uncoupling protein (UCP)-1, which is the hallmark of thermogenesis. Recent papers pointed that browning can occur in the WAT of humans, with beneficial metabolic effects. This fact indicates that these cells can be targeted to treat a range of diseases, with both pharmacological and nutritional activators. Pharmacological approaches to induce browning include the use of PPAR alpha agonist, adrenergic receptor stimulation, thyroid hormone administration, irisin and FGF21 induction. Most of them act through the induction of PPAR-gamma coactivator (PGC) 1-alpha and the consequent mitochondrial biogenesis and UCP1 induction. About the nutritional inducers, several compounds have been described with multiple mechanisms of action. Some of these activators include specific amino acids restriction, capsaicin, bile acids, Resveratrol, and retinoic acid. Besides that, some classes of lipids, as well as many plant extracts, have also been implicated in the browning of WAT. In conclusion, the discovery of browning in human WAT opens the possibility to target the adipose tissue to fight a range of diseases. Studies have arisen showing promising results and bringing new opportunities in thermogenesis and obesity control. PMID- 28099125 TI - Meningococcal ACWY vaccine uptake and awareness among student freshers enrolled at Northern Ireland universities. AB - A new MenACWY conjugate meningococcal vaccination programme was introduced in Northern Ireland (NI) in August 2015, for 13-18 year olds, as well as for first time university entrants up to 25 years. This reflected the response made by Public Health England, due to the recent rapid increase of meningococcal group W (MenW) disease and on advice of the UK Joint Committee on Vaccination and Immunisation (JCVI). The aims of this study were to evaluate (i) the uptake of the MenACWY vaccine among first-time university students, (ii) vaccine and meningitis awareness, (iii) optimal communication modalities via a multidisciplinary team (MDT) model and (iv) current international vaccination policies relating to non-UK students. A survey was completed by 1210 students, 868 first-time freshers and 342 non-freshers, from healthcare-related, non healthcare-related and engineering/computing faculties. The survey included an anonymous questionnaire and consented students were aged 17-50 years with a 2:3 ratio of male:female. Vaccine uptake amongst 18-year-old students was 90.7% and 87.3% in female and male cohorts, respectively, falling to 72.1% and 67.7% (19 year cohort) and 32.7% and 39.6% (20- to 25-year cohort) in males and females, respectively. Students reported that posters, clinics and talks were the preferred methods of communication and not social media. There was general lack of awareness of the signs/symptoms of meningitis and approximately 30% of students falsely believed that administration of the MenACWY vaccine excluded the risk of contracting meningitis. Overall, there was a successful vaccination campaign; however, there was a lack of meningitis awareness. Due to differing international meningococcal vaccination schedules, international students enrolling at UK universities need to be informed about current UK policies. For the successful introduction of any vaccination programme amongst university students, it is fundamental that a MDT is established to inform and deliver such a programme in an efficient and timely manner. PMID- 28099126 TI - Aminoguanidine pretreatment prevents methotrexate-induced small intestinal injury in the rat by attenuating nitrosative stress and restoring the activities of vital mitochondrial enzymes. AB - BACKGROUND: One of the major toxic side effects of methotrexate (MTX) is enterocolitis, for which there is no efficient standard treatment. Nitric oxide overproduction has been reported to play an important role in MTX-induced mucositis. This study was designed to investigate whether pretreatment with aminoguanidine (AG) - a selective iNOS inhibitor - prevents MTX-induced mucositis in rats. METHODS: Rats were pretreated with AG (30 and 50 mg/kg body weight) i.p. daily 1 h before MTX (7 mg/kg body weight) administration for 3 consecutive days. After the final dose of MTX, the rats were killed, and the small intestines were used for analysis. RESULTS: The small intestines of MTX-treated rats showed moderate to severe injury. Pretreatment with AG had a dose-dependent protective effect on MTX-induced mucositis. AG pretreatment reduced iNOS protein levels, mucosal nitric oxide levels, and protein tyrosine nitration. AG pretreatment also restored the activities of electron transport chain (ETC) complexes, vital tricarboxylic acid (TCA cycle) enzymes, and mitochondrial antioxidant enzymes. CONCLUSIONS: These findings suggest that AG is beneficial in ameliorating MTX induced enteritis in rats. PMID- 28099127 TI - Prevalence, risk factors and consequences of overweight and obesity among schoolchildren: a cross-sectional study in Kashmir, India. AB - BACKGROUND: Obesity among children and adolescents is a growing public health problem. The objective of this study was to evaluate the prevalence, risk factors and metabolic consequences of obesity among schoolchildren from Kashmir, India. METHODS: The study subjects (n=2024) included 870 boys and 1154 girls, aged between 6 and 18 years. Data were collected by interviewer-administered questionnaires. Information was obtained about different lifestyles, anthropometric parameters and dietary habits. Obesity was defined as body mass index (BMI) percentile as per the guidelines of Centers for Disease Control, 2000. For the evaluation of different clinical parameters, blood samples were collected from the subjects in the fasting state at 8 to 9 am after an overnight (10-12 h) fast. RESULTS: The highest representation of subjects was from fee paying private schools. Out of the total subjects, 6.69% were overweight and 4.64% were obese. The hip circumference, abdominal circumference, BMI, blood pressure (BP), use of ready-made foods as well as the clinical parameters like glucose, phosphorous, cholesterol and triglycerides were found significantly higher among girls than boys (p<0.05). Boys were taller and were physically more active than girls (p<0.01). Compared to the boys (3.33%), the girls were found to be more obese (5.63%). Rural dwelling subjects (4.22%) exhibited a lower percentage of obesity than urban population (5.00%). The difference in obesity among the different age groups was found statistically significant (p<0.05). Additionally, children with active lives in the form of vigorous (10.59%) or moderate (10.34%) exercise decreased their chances of gaining weight substantially. CONCLUSIONS: Results from the present study have shown that prevalence of obesity among children was high in our population. PMID- 28099128 TI - Bone health assessment of food allergic children on restrictive diets: a practical guide. AB - BACKGROUND: Food allergy in childhood is on the rise globally and is managed with avoidance diets; recent case reports of food allergic children with nutritional rickets in the literature highlight the importance of close monitoring of bone health in this population. METHODS: There is no consensus as yet with regard to bone health evaluation in food allergic children; therefore, extensive literature search was performed and the existing evidence is presented, along with a relevant algorithm. RESULTS: Children allergic to cow's milk protein or presenting with allergy in more than three food items, as well as patients with severe allergic phenotypes or comorbidities known to affect the skeleton, seem to be at risk of metabolic bone disorders. As a practical guide, suspicious cases can be investigated with basic bone profile, whereas more severe cases (persistent bone pain and fractures) may undergo advanced bone health assessment, with bone mineral density (BMD) and metabolic bone markers' evaluation. Of note, these diagnostic steps call for further studies in the field of food allergy, as they are not performed as a routine. Evidence is accumulating with regard to vitamin D deficiency, osteopenia and imbalanced bone metabolism in those food allergic children who show poor dietary compliance or have inadequate medical supervision. CONCLUSIONS: Ensuring optimal bone accrual in a food allergic child is an important task for the clinician and requires close monitoring of the restrictive diet and prompt therapeutic intervention, in an effort to avoid rickets or osteopenia. PMID- 28099129 TI - The association between obesity, hypertension and left ventricular mass in adolescents. AB - BACKGROUND: Obesity and hypertension (HT) are well known cardiac risk factors. Our goal was to show that even if arterial blood pressure (BP) measurements of obese adolescents are normal during clinical examination, ambulatory blood pressure monitoring (ABPM) can be high, may include cardiac involvement and can also detect left ventricular mass indices (LVMI) value for obese adolescents to diagnose left ventricular hypertrophy (LVH). METHODS: This study included 130 children (57 obese hypertensive, 36 obese normotensive, 14 normal weight hypertensive and 23 normal weight normotensive). Adolescents whose BP was measured during clinical examination, after 24-h BP was detected using ABPM, were examined with echocardiography for calculation of LVMI to determine cardiac risk factors for LVH. RESULTS: There was a significant difference between the LVMI of obese-normotensive and obese-hypertensive adolescents, which showed the effect of obesity on LVMI independent of HT. Twenty (35.7%) of 56 obese adolescents with HT detected with ABPM had normal BP measurements during clinical examination. Dipper and nondipper features of obese adolescents were significantly higher in ABPM than those with normal body mass index. When the cutoff LVMI value for LVH was set at >=38 g/m2.7, 38.9% of obese-normotensive and 50.9% of obese-hypertensive subjects had LVH; however, when the cutoff value was set at >=51 g/m2.7, the rates were 2.8% and 19.3%, respectively. CONCLUSIONS: Obesity is a risk factor for LVH independent of HT. To identify masked HT, 24-h ABPM and cardiac examination should be routinely performed in obese adolescents. Using a limit of LVMI >=38 g/m2.7 in evaluating LVH secondary to HT in obese individuals may lead to an overestimated diagnosis rate of LVH. PMID- 28099130 TI - Epidermal growth factor receptor (EGFR) involvement in successful growth hormone (GH) signaling in GH transduction defect. AB - BACKGROUND: Growth hormone (GH) transduction defect (GHTD) is a growth disorder with impaired signal transducer and activator of transcription 3 (STAT3) phosphorylation mediated by overexpression of cytokine-inducible SH2-containing protein (CIS), which causes increased growth hormone receptor (GHR) degradation. This study investigated the role of epidermal growth factor (EGF) in the restoration of normal GH signaling in GHTD. METHODS: Protein expression, cellular localization and physical contact of proteins of the GH and EGF signaling pathways were studied by Western immunoblotting, immunofluorescence and co immunoprecipitation, respectively. These were performed in fibroblasts of one GHTD patient (P) and one control child (C) at the basal state and after induction with human GH (hGH) 200 MUg/L (GH200), either with or without silencing of CIS mRNA, and after induction with hGH 1000 MUg/L (GH1000) or 50 ng/mL EGF. RESULTS: The membrane availability of the EGF receptor (EGFR) and the activated EGFR (pEGFR) was increased in P only after simultaneous GH200 and silencing of CIS mRNA or with GH1000, whereas this occurred in C after GH200 alone. After EGF induction, the membrane localization of GHR, STAT3 and that of EGFR were increased in P more than in C. CONCLUSIONS: In conclusion, in GHTD, the EGFR seems to participate in successful GH signaling, but induction of GHTD fibroblasts with a higher dose of hGH is needed. The EGF/EGFR pathway, in contrast to the GH/GHR pathway, seems to function normally in P and is more primed compared to C. The involvement of the EGFR in successful GH signaling may explain the catch-up growth seen in the Ps when exogenous hGH is administered. PMID- 28099131 TI - Turner syndrome and pituitary adenomas: a case report and review of literature. AB - BACKGROUND: Turner syndrome (TS) is the most common sex chromosome abnormality in females, typically associated with primary amenorrhea and premature ovarian failure due to gonadal dysgenesis. The association of TS with hypopituitarism is an uncommon finding. The objective of the study was to describe an adolescent with TS with hypergonadotropic hypogonadism and subsequent hypogonadotropic hypogonadism. CASE PRESENTATION: A 16-year-old female with primary amenorrhea was diagnosed with TS based on karyotype 45,XO. Other laboratory values included FSH 45.52 IU/L, LH 17.4 IU/L, undetectable estradiol, and prolactin 1.08 nmol/L. Two months later and before treatment, she presented with severe headache and a new left cranial nerve VI palsy. Brain MRI showed a 2.7-cm hemorrhagic pituitary macroadenoma expanding the sella. Laboratory evaluation showed FSH 5.9 IU/L, LH 0.9 IU/L, prolactin 0.09 nmol/L, and GH 1.03 ng/mL. She underwent transphenoidal hypophysectomy, and pathology revealed pituitary adenoma with immunohistochemical staining positive for growth hormone and prolactin. She subsequently developed multiple pituitary hormone deficiencies. Review of the literature identified eight case reports of women with TS who developed pituitary adenomas. CONCLUSIONS: This case illustrates an uncommon co-occurrence of TS and pituitary macroadenoma. Sequential gonadotropin measurements demonstrate the evolution of hypergonadotropic hypogonadism into hypogonadotropic hypogonadism due to hemorrhagic pituitary macroadenoma. PMID- 28099132 TI - Efficacy of long-term growth hormone therapy in short non-growth hormone deficient children. AB - BACKGROUND: In recent years, several studies have been published showing different responses to growth hormone (GH) treatment in idiopathic short stature children. The aim of the present study was to investigate whether non-growth hormone-deficient (non-GHD) short children could benefit from long-term GH treatment as GHD patients. METHODS: We enrolled 22 prepubertal children and 22 age- and sex-matched GHD patients, with comparable height, body mass index (BMI), bone age, and insulin-like growth factor 1 (IGF-I) circulating levels. The patients were treated with recombinant human GH (rhGH) and followed until they reach adult height. RESULTS: During GH treatment, the two groups grew in parallel, reaching the same final height-standard deviation score (SDS) and the same height gain. On the contrary, we found significantly lower IGF-I serum concentrations in non-GHD patients than in GHD ones, at the end of therapy (p=0.0055). CONCLUSIONS: In our study, the response to GH treatment in short non GHD patients proved to be similar to that in GHD ones. However, a careful selection of short non-GHD children to be treated with GH would better justify the cost of long-term GH therapy. PMID- 28099133 TI - Association between screen time and snack consumption in children and adolescents: The CASPIAN-IV study. AB - BACKGROUND: The relationship between screen time (ST) and the frequency of snack consumption in a national sample of Iranian children and adolescents was assessed. The present nationwide survey was conducted on 14,880 school students living in urban and rural areas of 30 provinces in Iran. Trained healthcare providers conducted the physical examination and completed the questionnaire of the World Health Organization - Global School-Based Student Health Survey (WHO GSHS). METHODS: The association between ST (total time spent watching TV and using a computer in leisure time) and the frequency of snack consumption was determined using ordinal logistic regression analysis. The subjects were 13,486 students out of the 14,880 invited including 50.8% boys. The mean (SD) age of participants was 12.47 (3.36) years. RESULTS: In multivariate models, for students who had prolonged ST (more than 4 h/day), the odds of daily consumption of sweets (odds ratio, OR 1.25; 95% CI 1.14-1.4), salty snacks (OR 1.6; 95% CI 1.5-1.76), soft drinks (OR 1.52; 95% CI 1.4-1.7), canned fruit juice (OR 1.3; 95% CI 1.2-1.4), and fast food (OR 1.53; 95% CI 1.4-1.7) were higher compared to those with low ST. Furthermore, the odds of daily consumption of milk in students who had prolonged ST (more than 4 h/day) were lower compared to those with low ST (OR 0.9; 95% CI 0.8-0.99). CONCLUSIONS: Prolonged time spent watching TV and using a computer during leisure time might be associated with unhealthy dietary habits. Moreover, inactivity induced by prolonged ST may also lead to unhealthy dietary habits and in turn excess weight in children and adolescents. PMID- 28099134 TI - Carboxyhemoglobin - the forgotten parameter of neonatal hyperbilirubinemia. AB - BACKGROUND: Neonatal hyperbilirubinemia is influenced by a wide variety of factors, one of which is hemolysis. Serious hyperbilirubinemia may lead to a kernicterus with detrimental neurologic sequelae. Patients suffering from hemolytic disease have a higher risk of developing kernicterus. Carbon monoxide (CO), a byproduct of hemolysis or heme degradation, was described by Sjostrand in the 1960s. It is transported as carboxyhemoglobin (COHb) and exhaled through the lungs. We were interested in a potential correlation between COHb and total serum bilirubin (TSB) and the time course of both parameters. MATERIALS AND METHODS: We used a point of care (POC) blood gas analyzer and did a retrospective analysis of bilirubin and COHb data collected over a 60-day period. RESULTS: An arbitrary cut off point set at 2% COHb identified four patients with hemolytic disease of different origins who required phototherapy. In one patient with atypical hemolytic uremic syndrome (aHUS), COHb preceded the rise in bilirubin by about 2 days. Despite this displacement, there was a moderately good correlation of COHb with TSB levels <15 mg/dL (257 MUmol/L) (r2: 0.80) and direct bilirubin (r2: 0.78) in the first patient. For all the four patients and all time points the correlation was slightly lower (r2: 0.59). CONCLUSIONS: COHb might be useful as a marker for high hemoglobin turnover to allow an earlier identification of newborns at risk to a rapid rise in bilirubin. PMID- 28099135 TI - Mycoplasma/Ureaplasma infection in pregnancy: to screen or not to screen. AB - Mycoplasmata have been linked to pregnancy complications and neonatal risk. While formerly a limited number of species could be discovered by cultures, molecular biology nowadays discovers both lower quantities and more diverse species, making us realize that mycoplasmata are ubiquitous in the vaginal milieu and do not always pose a danger for pregnant women. As the meaning of mycoplasmata in pregnancy is not clear to many clinicians, we summarized the current knowledge about the meaning of different kinds of mycoplasmata in pregnancy and discuss the potential benefits and disadvantages of treatment. Currently, there is no general rule to screen and treat for mycoplasmata in pregnancy. New techniques seem to indicate that Ureaplasma parvum (Up), which now can be distinguished from U. urealyticum (Uu), may pose an increased risk for preterm birth and bronchopulmonary disease in the preterm neonate. Mycoplasma hominis (Mh) is related to early miscarriages and midtrimester abortions, especially in the presence of abnormal vaginal flora. Mycoplasma genitalium (Mg) is now recognized as a sexually transmitted infection (STI) that is involved in the causation of cervicitis, pelvic inflammatory disease (PID) in non-pregnant, and preterm birth and miscarriages in pregnant women, irrespective of the presence of concurrent other STIs, like Chlamydia or gonorrhoea. Proper studies to test for efficacy and improved pregnancy outcome are scarce and inconclusive. Azythromycin is the standard treatment now, although, for Mg, this may not be sufficient. The role of clarithromycin in clinical practice still has to be established. There is a stringent need for new studies based on molecular diagnostic techniques and randomized treatment protocols with promising and safe antimicrobials. PMID- 28099136 TI - Alexithymia and automatic processing of emotional stimuli: a systematic review. AB - Alexithymia is a personality trait characterized by difficulties in recognizing and verbalizing emotions and the utilization of a cognitive style that is oriented toward external events, rather than intrapsychic experiences. Alexithymia is considered a vulnerability factor influencing onset and course of many psychiatric disorders. Even though emotions are, in general, elicited involuntarily and emerge without conscious effort, it is surprising that little attention in etiological considerations concerning alexithymia has been given to deficits in automatic emotion processing and their neurobiological bases. In this article, results from studies using behavioral or neurobiological research methods were systematically reviewed in which automatic processing of external emotional information was investigated as a function of alexithymia in healthy individuals. Twenty-two studies were identified through a literature search of Psycinfo, PubMed, and Web of Science databases from 1990 to 2016. The review reveals deficits in the automatic processing of emotional stimuli in alexithymia at a behavioral and neurobiological level. The vast majority of the reviewed studies examined visual processing. The alexithymia facets externally oriented thinking and difficulties identifying feelings were found to be related to impairments in the automatic processing of threat-related facial expressions. Alexithymic individuals manifest low reactivity to barely visible negative emotional stimuli in brain regions responsible for appraisal, encoding, and affective response, e.g. amygdala, occipitotemporal areas, and insula. Against this background, it appears plausible to assume that deficits in automatic emotion processing could be factors contributing to alexithymic personality characteristics. Directions for future research on alexithymia and automatic emotion perception are suggested. PMID- 28099137 TI - Epilepsy-associated alterations in hippocampal excitability. AB - The hippocampus exhibits a wide range of epilepsy-related abnormalities and is situated in the mesial temporal lobe, where limbic seizures begin. These abnormalities could affect membrane excitability and lead to overstimulation of neurons. Multiple overlapping processes refer to neural homeostatic responses develop in neurons that work together to restore neuronal firing rates to control levels. Nevertheless, homeostatic mechanisms are unable to restore normal neuronal excitability, and the epileptic hippocampus becomes hyperexcitable or hypoexcitable. Studies show that there is hyperexcitability even before starting recurrent spontaneous seizures, suggesting although hippocampal hyperexcitability may contribute to epileptogenesis, it alone is insufficient to produce epileptic seizures. This supports the concept that the hippocampus is not the only substrate for limbic seizure onset, and a broader hyperexcitable limbic structure may contribute to temporal lobe epilepsy (TLE) seizures. Nevertheless, seizures also occur in conditions where the hippocampus shows a hypoexcitable phenotype. Since TLE seizures most often originate in the hippocampus, it could therefore be assumed that both hippocampal hypoexcitability and hyperexcitability are undesirable states that make the epileptic hippocampal network less stable and may, under certain conditions, trigger seizures. PMID- 28099138 TI - Role of glial cell line-derived neurotrophic factor in the pathogenesis and treatment of mood disorders. AB - Glial cell line-derived neurotrophic factor (GDNF) is widely recognized as a survival factor for dopaminergic neurons, but GDNF has also been shown to promote development, differentiation, and protection of other central nervous system neurons and was thought to play an important role in various neuropsychiatric disorders. Severe mood disorders, such as primarily major depressive disorder and bipolar affective disorder, attract particular attention. These psychopathologies are characterized by structural alterations accompanied by the dysregulation of neuroprotective and neurotrophic signaling mechanisms required for the maturation, growth, and survival of neurons and glia. The main objective of this review is to summarize the recent findings and evaluate the potential role of GDNF in the pathogenesis and treatment of mood disorders. Specifically, it describes (1) the implication of GDNF in the mechanism of depression and in the effect of antidepressant drugs and mood stabilizers and (2) the interrelation between GDNF and brain neurotransmitters, playing a key role in the pathogenesis of depression. This review provides converging lines of evidence that (1) brain GDNF contributes to the mechanism underlying depressive disorders and the effect of antidepressants and mood stabilizers and (2) there is a cross-talk between GDNF and neurotransmitters representing a feedback system: GDNF-neurotransmitters and neurotransmitters-GDNF. PMID- 28099139 TI - Quantitative EEG in obstructive sleep apnea syndrome: a review of the literature. AB - Obstructive sleep apnea syndrome (OSAS) is characterized by the recurrent cessation (apnea) or reduction (hypopnea) of airflow due to the partial or complete upper airway collapse during sleep. Respiratory disturbances causing sleep fragmentation and repetitive nocturnal hypoxia are responsible for a variety of nocturnal and daytime complaints of sleep apnea patients, such as snoring, daytime sleepiness, fatigue, or impaired cognitive functions. Different techniques, such as magnetic resonance imaging, magnetic resonance spectroscopy, and positron emission tomography, are used to evaluate the structural and functional changes in OSAS patients. With quantitative electroencephalographic (qEEG) analysis, the possible existence of alterations in the brain electrical activity of OSAS patients can be investigated. We review the articles on qEEG results of sleep apnea patients and summarize the possible explanations of these qEEG measures. Finally, we review the impact of continuous positive airway pressure (CPAP) treatment on these alterations to assess whether CPAP use can eliminate alterations in the brain activity of OSAS patients. PMID- 28099140 TI - Telomerase antagonist imetelstat increases radiation sensitivity in esophageal squamous cell carcinoma. AB - The morbidity and mortality of esophageal cancer is one of the highest around the world and the principal therapeutic method is radiation. Thus, searching for sensitizers with lower toxicity and higher efficiency to improve the efficacy of radiation therapy is critical essential. Our research group has previously reported that imetelstat, the thio-phosphoramidate oligonucleotide inhibitor of telomerase, can decrease cell proliferation and colony formation ability as well as increase DNA breaks induced by radiation in esophageal cancer cells. Further study in this project showed that imetelstat significantly sensitized esophageal cancer cells to radiation in vitro. Later study showed that imetelstat leads to increased cell apoptosis. We also measured the expression level of several DNA repair and apoptosis signaling proteins. pS345 CHK1, gamma-H2AX, p53 and caspase3 expression were up-regulated in imetelstat treated cells, identifying these factors as molecular markers. Mouse in vivo model using imetelstat at clinically achievable concentrations and fractionated irradiation scheme yielded results demonstrating radiosensitization effect. Finally, TUNEL assay, caspase 3 and Ki67 staining in tumor tissue proved that imetelstat sensitized esophageal cancer to radiation in vivo through promoting cell apoptosis and inhibiting cell proliferation. Our study supported imetelstat increase radiation sensitivity of esophageal squamous cell carcinoma through inducing cell apoptosis and the specific inhibitor of telomerase might serve as a potential novel therapeutic tool for esophageal squamous cell carcinoma therapy. PMID- 28099141 TI - Antitumor activity of a Trans-thiosemicarbazone schiff base palladium (II) complex on human gastric adenocarcinoma cells. AB - The development of transition-metal-based antitumor drug candidates increases the metallopharmaceuticals study dramatically. Two trans-thiosemicarbazone-based, Schiff base palladium (Pd) (II) complexes, DMABTSPd (TSPd) and DMABPTSPd (PTSPd), were prepared and characterized as described in our previous study. Here, we investigated whether the two complexes have antitumor effect on human gastric adenocarcinoma cell lines, BGC-823 and SGC-7901, compared with normal human gastric mucosal epithelial cell line, Ges-1. The results show that the Pd complex with the bare amino group (DMABTSPd(TSPd)) can inhibit cell viabilities and induce apoptosis in human gastric carcinoma cells, rather than the Pd complex without the bare amino group (DMABPTSPd (PTSPd)). This occurs via a mitochondrial related pathway by down-regulating the level of Bcl-2 expression and up regulating the level of Bid expression. Meanwhile, DMABTSPd (TSPd) suppressed tumor growth via a mitochondrial-related pathway in a nude mouse tumor xenograft model derived from BGC-823 cells. These findings demonstrate that DMABTSPd (TSPd) is worthy of further structural optimization and representing a promising Pd complex for the development of a new antitumor therapeutic agent. PMID- 28099142 TI - The pentapeptide Gly-Thr-Gly-Lys-Thr confers sensitivity to anti-cancer drugs by inhibition of CAGE binding to GSK3beta and decreasing the expression of cyclinD1. AB - We previously reported the role of cancer/testis antigen CAGE in the response to anti-cancer drugs. CAGE increased the expression of cyclinD1, and pGSK3betaSer9, an inactive GSK3beta, while decreasing the expression of phospho-cyclinD1Thr286. CAGE showed binding to GSK3beta and the domain of CAGE (amino acids 231-300) necessary for binding to GSK3beta and for the expression regulation of cyclinD1 was determined. 269GTGKT273 peptide, corresponding to the DEAD box helicase domain of CAGE, decreased the expression of cyclinD1 and pGSK3betaSer9 while increasing the expression of phospho-cyclinD1Thr286. GTGKT peptide showed the binding to CAGE and prevented CAGE from binding to GSK3beta. GTGKT peptide changed the localization of CAGE and inhibited the binding of CAGE to the promoter sequences of cyclin D1. GTGKT peptide enhanced the apoptotic effects of anti-cancer drugs and decreased the migration, invasion, angiogenic, tumorigenic and metastatic potential of anti-cancer drug-resistant cancer cells. We found that Lys272 of GTGKT peptide was necessary for conferring anti-cancer activity. Peptides corresponding to the DEAD box helicase domain of CAGE, such as AQTGTGKT, QTGTGKT and TGTGKT, also showed anti-cancer activity by preventing CAGE from binding to GSK3beta. GTGKT peptide showed ex vivo tumor homing potential. Thus, peptides corresponding to the DEAD box helicase domain of CAGE can be developed as anti-cancer drugs in cancer patients expressing CAGE. PMID- 28099143 TI - Desirable cytolytic immune effector cell recruitment by interleukin-15 dendritic cells. AB - Success of dendritic cell (DC) therapy in treating malignancies is depending on the DC capacity to attract immune effector cells, considering their reciprocal crosstalk is partially regulated by cell-contact-dependent mechanisms. Although critical for therapeutic efficacy, immune cell recruitment is a largely overlooked aspect regarding optimization of DC vaccination. In this paper we have made a head-to-head comparison of interleukin (IL)-15-cultured DCs and conventional IL-4-cultured DCs with regard to their proficiency in the recruitment of (innate) immune effector cells. Here, we demonstrate that IL-4 DCs are suboptimal in attracting effector lymphocytes, while IL15 DCs provide a favorable chemokine milieu for recruiting CD8+ T cells, natural killer (NK) cells and gamma delta (gammadelta) T cells. Gene expression analysis revealed that IL 15 DCs exhibit a high expression of chemokines involved in antitumor immune effector cell attraction, while IL-4 DCs display a more immunoregulatory profile characterized by the expression of Th2 and regulatory T cell-attracting chemokines. This is confirmed by functional data indicating an enhanced recruitment of granzyme B+ effector lymphocytes by IL-15 DCs, as compared to IL-4 DCs, and subsequent superior killing of tumor cells by the migrated lymphocytes. Elevated CCL4 gene expression in IL-15 DCs and lowered CCR5 expression on both migrated gammadelta T cells and NK cells, led to validation of increased CCL4 secretion by IL15 DCs. Moreover, neutralization of CCR5 prior to migration resulted in an important inhibition of gammadelta T cell and NK cell recruitment by IL-15 DCs. These findings further underscore the strong immunotherapeutic potential of IL-15 DCs. PMID- 28099144 TI - MiR-199a-5p and let-7c cooperatively inhibit migration and invasion by targeting MAP4K3 in hepatocellular carcinoma. AB - : Hepatocellular carcinoma (HCC) has a high recurrence rate, and patients exhibit poor survival mainly because intrahepatic metastasis is common. We previously reported that let-7c down-regulation is significantly associated with poor differentiation level in HCC. In the present study, we demonstrate that miR-199a 5p and let-7c are frequently down-regulated in HCC cells and tissues, and low expression of miR-199a-5p is correlated with tumor size, liver envelope invasion. Furthermore, miR-199a-5p and let-7c cooperatively inhibit HCC cell migration and invasion in vitro. MAP4K3 is identified as the direct target of miR-199a-5p and let-7c and this regulation is further confirmed by luciferase reporter assays and Western blotting. In addition, MAP4K3 functions as a metastasis promoter since the results demonstrate that MAP4K3 could promote HCC cell migration and invasion. We also find that miR-199a-5p and let-7c increase the sensitivity of HCC cells to sorafenib. CONCLUSIONS: We report that miR-199a-5p and let-7c cooperatively and efficiently inhibit HCC cell migration and invasion by targeting the metastasis promoter MAP4K3 and MAP4K3-mediated drug sensitization, suggesting that the use of miRNAs and sorafenib in combination therapy may be a powerful approach to the treatment of HCC. PMID- 28099145 TI - Down-regulation of toll-like receptor 4 alleviates intestinal ischemia reperfusion injury and acute lung injury in mice. AB - Intestinal ischemia reperfusion (IR) injury is a critical problem, which can cause intestinal injury locally and acute lung injury (ALI) distally by inflammatory responses and oxidative stress. Toll-like receptor 4 (TLR4) is involved in innate immune and inflammatory responses. This study was to determine whether TLR4 mutant can attenuate intestinal and lung injuries after intestinal IR. Wild type (WT) and TLR4 mutant mice were submitted to intestinal IR by occluding the superior mesenteric artery. Histological assessment of the intestine and the lung were conducted by HE staining. The levels of proinflammatory cytokines, oxidative stress markers, apoptotic index and other mediators were measured. In addition, a 24-hour survival study was performed. Histological assessment showed that intestinal IR caused serious injuries in the intestine and the lung, corroborated by increased proinflammatory cytokines in the circulation. TLR4 mutant suppressed the histological injuries as demonstrated by significantly decreased pathological scores. Consistent with the morphological results, the TLR4 mutant mice exhibited remarkably lowered cytokine expressions in the intestine (TNF-alpha, IL-6, IL-1beta, and NF-kappaB) and the lung (NO, iNOS, MCP-1, MIP-2, NF-kappaB, and Caspase-3). ALT and creatinine were also significantly dampened in the liver and kidney, respectively. Furthermore, the survival rate over the course of 24 hours was significantly improved. Collectively, the findings reveal that TLR4 mutant significantly abated the intestinal IR injury and ALI at least in part by alleviating the inflammatory response and oxidative stress. PMID- 28099146 TI - Long non-coding RNA growth arrest specific transcript 5 acts as a tumour suppressor in colorectal cancer by inhibiting interleukin-10 and vascular endothelial growth factor expression. AB - Long non-coding RNAs (lncRNAs) are highly involved in diverse biological processes of human malignancies. The expression profile and underlying mechanism of lncRNA growth arrest specific transcript 5 (GAS5) in colorectal cancer (CRC) is poorly understood. In this study, we found that GAS5 was commonly downregulated in CRC tissues, serum of CRC patients and CRC cell lines. Knockdown of GAS5 promoted CRC cell proliferation and colony formation, whereas overexpression of GAS5 produced the opposite result. We further demonstrated that knockdown of GAS5 increased the expression and secretion of interleukin-10 (IL 10) and vascular endothelial growth factor (VEGF-A) via NF-kappaB and Erk1/2 pathways. Neutralization of IL-10 and VEGF-A reduced tumour proliferation caused by GAS5 knockdown. Moreover, GAS5 expression showed a statistically significant correlation with the mRNA levels of IL-10 and VEGF-A in CRC tissues. We further illustrated that GAS5 was markedly downregulated and negatively correlated with the cytokine expression in a mouse model of colitis-associated cancer (CAC). These results delineate a novel mechanism of lncRNA GAS5 in suppressing colorectal carcinogenesis. The cytokines IL-10 and VEGF-A inhibited by GAS5 may provide targets for lncRNA-based therapies for CRC. PMID- 28099147 TI - CTLA-4 positive breast cancer cells suppress dendritic cells maturation and function. AB - Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a potent immunoregulatory molecule, can down-regulate T-cell activation and inhibit anti-tumor immune response. This study showed that LPS-stimulated human dendritic cells (DCs) decreased the expression of HLA-DR, CD83 and costimulatory molecules (CD40, CD80 and CD86) following coculturing with CTLA-4+ breast cancer cells. Moreover, the suppressed DCs further inhibited proliferation of allogeneic CD4+/CD8+ T-cells, differentiation of Th1 and function of cytotoxic lymphocytes (CTLs). However, CTLA-4 blockade in breast cancer cells could recover DC maturation and cytokine production, elevate antigen-presenting function of DCs, reverse Th1/CTLs response and cytokine secretion. Subsequent study demonstrated that the activation of extracellular-signal regulated kinase and signal transducer and activator of transcription 3 of DCs caused by CTLA-4+ breast cancer cells were the predominant mechanism of DC suppression. In addition, CTLA-4 blockade treatment also directly inhibited proliferation and induced apoptosis of CTLA-4+ breast cancer cells. Collectively, CTLA-4 was expressed and functional on human breast cancer cells through influencing maturation and function of DCs in vitro, and CTLA-4 blockage not only recovered the antigen-presenting function of DCs and T-cells activation but also suppressed the biological activity of breast cancer cells themselves. This study highlights the clinical application of CTLA-4 blockade therapy in breast cancer. PMID- 28099148 TI - Suberoylanilide hydroxamic acid increases anti-cancer effect of tumor necrosis factor-alpha through up-regulation of TNF receptor 1 in lung cancer cells. AB - Suberoylanilide hydroxamic acid (SAHA) as a histone deacetylase (HDAC) inhibitor has anti-cancer effect. Here, we evaluated the effect of SAHA on HDAC activity and cell growth in many normal lung and cancer cells. We observed that the HDAC activities of lung cancer cells were higher than that of normal lung cells. SAHA inhibited the growth of lung cancer cells regardless of the inhibitory effect on HDAC. This agent induced a G2/M phase arrest and apoptosis, which was accompanied by mitochondrial membrane potential (MMP: DeltaPsim) loss in lung cancer cells. However, SAHA did not induce cell death in normal lung cells. All tested caspase inhibitors prevented apoptotic cell death in SAHA-treated A549 and Calu-6 lung cancer cells. Treatment with tumor necrosis factor-alpha (TNF-alpha) enhanced apoptosis in SAHA-treated lung cancer cells through caspase-8 and caspase-9 activations. Especially, SAHA increased the expression level of TNF-alpha receptor 1 (TNFR1), especially acetylation of the region of TNFR1 promoter -223/ 29 in lung cancer cells. The down-regulation of TNFR1 suppressed apoptosis in TNF alpha and SAHA-treated lung cancer cells. In conclusion, SAHA inhibited the growth of lung cancer cells via a G2/M phase arrest and caspase-dependent apoptosis. SAHA also enhanced apoptotic effect of TNF-alpha in human lung cancer cells through up-regulation of TNFR1. TNF-alpha may be a key to improve anti cancer effect of HDAC inhibitors. PMID- 28099149 TI - Clinically relevant HIF-1alpha-dependent metabolic reprogramming in oropharyngeal squamous cell carcinomas includes coordinated activation of CAIX and the miR 210/ISCU signaling axis, but not MCT1 and MCT4 upregulation. AB - Metabolic reprogramming is a very heterogeneous phenomenon in cancer. It mostly consists on increased glycolysis, lactic acid formation and extracellular acidification. These events have been associated to increased activity of the hypoxia inducible factor, HIF-1alpha. This study aimed at defining the metabolic program activated by HIF-1alpha in oropharyngeal squamous cell carcinomas (SCC) and assessing its clinical impact. Global gene/miRNA expression was analyzed in SCC-derived cells exposed to hypoxia. Expression of HIF-1alpha, the carbonic anhydrase CAIX, and the lactate/H+ transporters MCT1 and MCT4 were analyzed by immunohistochemistry in 246 SCCs. Cell-based analysis revealed that HIF-1alpha driven metabolic program includes over-expression of glycolytic enzymes and the microRNA miR-210 coupled to down-regulation of its target, the iron-sulfur cluster assembly protein, ISCU. pH-regulator program entailed over-expression of CAIX, but not MCT1 or MCT4. Accordingly, significant overlapping exists between over-expression of HIF-1alpha and CAIX, but not HIF-1alpha and MCT1 or MCT4, in tumor cells. Increased miR-210 and concomitant decreased ISCU RNA levels were found in ~40% of tumors and this was significantly associated with HIF-1alpha and CAIX, but not MCT1 or MCT4, over-expression. HIF-1alpha and/or CAIX over expression was associated with high recurrence rate and low overall survival of surgically treated patients. By contrast, clinically significant correlations were not found in tumors with MCT1 or MCT4 over-expression. This is the first study that provides in vivo evidences of coordinated activation of HIF-1alpha, CAIX, miR-210 and ISCU in carcinoma and association with poor prognosis, a finding with important implications for the development of metabolic-targeting therapies against hypoxia. PMID- 28099150 TI - Elimination of quiescent slow-cycling cells via reducing quiescence depth by natural compounds purified from Ganoderma lucidum. AB - The medical mushroom Ganoderma lucidum has long been used in traditional Chinese medicine and shown effective in the treatment of many diseases including cancer. Here we studied the cytotoxic effects of two natural compounds purified from Ganoderma lucidum, ergosterol peroxide and ganodermanondiol. We found that these two compounds exhibited cytotoxicity not only against fast proliferating cells, but on quiescent, slow-cycling cells. Using a fibroblast cell-quiescence model, we found that the cytotoxicity on quiescent cells was due to induced apoptosis, and was associated with a shallower quiescent state in compound-treated cells, resultant from the increased basal activity of an Rb-E2F bistable switch that controls quiescence exit. Accordingly, we showed that quiescent breast cancer cells (MCF7), compared to its non-transformed counterpart (MCF10A), were preferentially killed by ergosterol peroxide and ganodermanondiol treatment presumably due to their already less stable quiescent state. The cytotoxic effect of natural Ganoderma lucidum compounds against quiescent cells, preferentially on quiescent cancer cells vs. non-cancer cells, may help future antitumor development against the slow-cycling cancer cell subpopulations including cancer stem and progenitor cells. PMID- 28099151 TI - Clinical impact of serum survivin positivity and tissue expression of EBV-encoded RNA in diffuse large B-cell lymphoma patients treated with rituximab-CHOP. AB - Survivin is an inhibitor of apoptosis and is upregulated by Epstein-Barr virus (EBV) latent genes. Given the frequent association of EBV with lymphoid malignancies, survivin is expected to have prognostic value in diffuse large B cell lymphoma (DLBCL). Thus, we measured the pretreatment serum level of survivin in DLBCL patients and analyzed its association with survival outcome and EBV status, as represented by EBV-encoded RNA (EBER) in DLBCL. Pretreatment serum survivin level was measured in patients registered in a prospective cohort study (n = 210), and serum survivin-positivity was defined as any detectable level of survivin. EBV status was determined using EBER in situ hybridization, and EBER positivity was defined as 20% of examined cells showing nuclear positivity. Mean serum survivin level was higher in patients with relapsed or refractory disease than with responsive disease (59.89 pg/mL versus 17.34 pg/mL, P = 0.041). Serum survivin-positive patients had worse overall and progression-free survival (P = 0.023 and 0.022, respectively). Serum survivin positivity was associated with unfavorable characteristics including stage. In patients with non-germinal center B-cell type DLBCL, serum survivin-positive patients also had significantly worse survival than serum survivin-negative patients (P < 0.001). EBER-positivity was found in 6.7% (14/210) of patients, and EBER-positive patients had worse survival (P < 0.05). Patients having concomitant positivity for serum survivin and EBER expression (2.8%, 6/210) showed extremely poor prognosis. In the present era of rituximab in DLBCL, DLBCL with serum survivin positivity showed adverse clinical features and followed worse clinical course, especially in non-GCB subtype DLBCL. EBER-positivity was still associated with worse outcomes in DLBCL. PMID- 28099152 TI - The EMSY threonine 207 phospho-site is required for EMSYdriven suppression of DNA damage repair. AB - BRCA1 and BRCA2 are essential for the repair of double-strand DNA breaks, and alterations in these genes are a hallmark of breast and ovarian carcinomas. Other functionally related genes may also play important roles in carcinogenesis. Amplification of EMSY, a putative BRCAness gene, has been suggested to impair DNA damage repair by suppressing BRCA2 function. We employed direct repeat GFP (DR GFP) and RAD51 foci formation assays to show that EMSY overexpression impairs the repair of damaged DNA, suggesting that EMSY belongs to the family of BRCAness proteins. We also identified a novel phospho-site at threonine 207 (T207) and demonstrated its role in EMSY-driven suppression of DNA damage repair. In vitro kinase assays established that protein kinase A (PKA) directly phosphorylates the T207 phospho-site. Immunoprecipitation experiments suggest that EMSY-driven suppression of DNA damage repair is a BRCA2-independent process. The data also suggest that EMSY amplification is a BRCAness feature, and may help to expand the population of patients who could benefit from targeted therapies that are also effective in BRCA1/2-mutant cancers. PMID- 28099154 TI - Vitamin K epoxide reductase regulation of androgen receptor activity. AB - Long-term use of warfarin has been shown to be associated with a reduced risk of prostate cancer. Warfarin belongs to the vitamin K antagonist class of anticoagulants, which inhibit vitamin K epoxide reductase (VKOR). The vitamin K cycle is primarily known for its role in gamma-carboxylation, a rare post translational modification important in blood coagulation. Here we show that warfarin inhibits the transcriptional activity of the androgen receptor (AR), an important driver of prostate cancer development and progression. Warfarin treatment or knockdown of its target VKOR inhibits the activity of AR both in cell lines and in mouse prostate tissue. We demonstrate that AR can be gamma carboxylated, and mapped the gamma-carboxylation to glutamate residue 2 (E2) using mass spectrometry. However, mutation of E2 and other glutamates on AR failed to suppress the effects of warfarin on AR suggesting that inhibition of AR is gamma-carboxylation independent. To identify pathways upstream of AR signaling that are affected by warfarin, we performed RNA-seq on prostates of warfarin treated mice. We found that warfarin inhibited peroxisome proliferator-activated receptor gamma (PPARgamma) signaling, which in turn, inhibited AR signaling. Although warfarin is unfit for use as a chemopreventative due to its anticoagulatory effects, our data suggest that its ability to reduce prostate cancer risk is independent of its anticoagulation properties. Furthermore, our data show that warfarin inhibits PPARgamma and AR signaling, which suggests that inhibition of these pathways could be used to reduce the risk of developing prostate cancer. PMID- 28099153 TI - Building personalized treatment plans for early-stage colorectal cancer patients. AB - We developed a series of models to predict the likelihood of recurrence and the response to chemotherapy for the personalized treatment of stage I and II colorectal cancer patients. A recurrence prediction model was developed from 235 stage I/II patients. The model successfully distinguished between high-risk and low-risk groups, with a hazard ratio of recurrence of 4.66 (p < 0.0001). More importantly, the model was accurate for both stage I (hazard ratio = 5.87, p = 0.0006) and stage II (hazard ratio = 4.30, p < 0.0001) disease. This model performed much better than the Oncotype and ColoPrint commercial services in identifying patients at high risk for stage II recurrence. And unlike the commercial services, the robust model included recurrence prediction for stage I patients. As stage I/II CRC patients usually do not receive chemotherapy, we generated chemotherapy efficacy prediction models with data from 358 stage III patients. The predictions were highly accurate: the hazard ratio of recurrence for responders vs. non-responders was 4.13 for those treated with FOLFOX (p < 0.0001), and 3.16 (p = 0.0012) for those treated with fluorouracil. We have thus created a prognostic model that accurately identifies patients at high risk for recurrence, and the first accurate chemotherapy efficacy prediction model for individual patients. In the future, complete personalized treatment plans for stage I/II patients may be developed if the drug prediction models generated from stage III patients are verified to be effective for stage I and II patients in prospective studies. PMID- 28099156 TI - Quasi-monochromatic imaging in x-ray CT via spectral deconvolution using photon counting detectors. AB - Photon-counting detectors can obtain the spectral information from an incident x ray spectrum, although the detected counts may differ from the incident counts due to the detector response. If uncorrected or uncompensated, the response will lead to distortion in CT reconstruction. With the intention of reducing the distortion and exploring the potential of photon-counting detectors, a novel reconstruction strategy with spectral deconvolution, which attempts to set itself apart from traditional material decomposition frameworks, is proposed in this paper. It applies deconvolution to the energy window counts using a calibrated detector response and then uses the post-deconvolution photon counts to reconstruct images in multi-energy windows. The output has a quantitative meaning as a quasi-monochromatic attenuation coefficient, because a relatively narrow energy window width is selected. The deconvolution settings and results are carefully discussed in the numerical simulation. An experimental study is then carried out to verify the effectiveness and robustness. The results show that the reconstructed attenuation coefficients after deconvolution fit the standard reference data very well in most of the energy windows, which implies the feasibility of this quasi-monochromatic imaging method. PMID- 28099155 TI - Metformin promotes apoptosis in hepatocellular carcinoma through the CEBPD induced autophagy pathway. AB - Metformin, as an AMP-activated protein kinase (AMPK) activator, can activate autophagy. A study showed that metformin decreased the risk of hepatocellular carcinoma (HCC) in diabetic patients. However, the detailed mechanism in the metformin-mediated anticancer effect remains an open question. Transcription factor CCAAT/enhancer-binding protein delta (CEBPD) has been suggested to serve as a tumor suppressor and is responsive to multiple anticancer drugs in HCC. In this study, we found that CEBPD and autophagy are involved in metformin-induced cell apoptosis in Huh7 cells. The underlying mechanisms in this process included a reduction in Src-mediated CEBPD protein degradation and an increase in CEBPD regulated LC3B and ATG3 gene transcription under metformin treatment. We also found that AMPK is involved in metformin-induced CEBPD expression. Combined treatment with metformin and rapamycin can enhance autophagic cell death through the AMPK-dependent and AMPK-independent pathway, respectively. Taken together, we provide a new insight and therapeutic approach by targeting autophagy in the treatment of HCC. PMID- 28099157 TI - High quality epitaxial graphene by hydrogen-etching of 3C-SiC(111) thin-film on Si(111). AB - Etching with atomic hydrogen, as a preparation step before the high-temperature growth process of graphene onto a thin 3C-SiC film grown on Si(111), greatly improves the structural quality of topmost graphene layers. Pit formation and island coalescence, which are typical of graphene growth by SiC graphitization, are quenched and accompanied by widening of the graphene domain sizes to hundreds of nanometers, and by a significant reduction in surface roughness down to a single substrate bilayer. The surface reconstructions expected for graphene and the underlying layer are shown with atomic resolution by scanning tunnelling microscopy. Spectroscopic features typical of graphene are measured by core-level photoemission and Raman spectroscopy. PMID- 28099158 TI - Single transmission-line readout method for silicon photomultiplier based time-of flight and depth-of-interaction PET. AB - We propose a novel single transmission-line readout method for whole-body time-of flight positron emission tomography applications, without compromising on performance. The basic idea of the proposed multiplexing method is the addition of a specially prepared tag signal ahead of the scintillation pulse. The tag signal is a square pulse that encodes photon arrival time and channel information. The 2D position of a silicon photomultiplier (SiPM) array is encoded by the specific width and height of the tag signal. A summing amplifier merges the tag and scintillation signals of each channel, and the final output signal can be acquired with a one-channel digitizer. The feasibility and performance of the proposed method were evaluated using a 1:1 coupled detector consisting of 4 * 4 array of LGSO crystals and 16 channel SiPM. The sixteen 3 mm LGSO crystals were clearly separated in the crystal-positioning map with high reliability. The average energy resolution and coincidence resolving time were 11.31 +/- 0.55% and 264.7 +/- 10.7 ps, respectively. We also proved that the proposed method does not degrade timing performance with increasing multiplexing ratio. The two types of LGSO crystals (L0.95GSO and L0.20GSO) in phoswich detector were also clearly identified with the high-reliability using pulse shape discrimination, thanks to the well-preserved pulse shape information. In conclusion, the proposed multiplexing method allows decoding of the 3D interaction position of gamma rays in the scintillation detector with single-line readout. PMID- 28099159 TI - Reducing false arrhythmia alarm rates using robust heart rate estimation and cost sensitive support vector machines. AB - To lessen the rate of false critical arrhythmia alarms, we used robust heart rate estimation and cost-sensitive support vector machines. The PhysioNet MIMIC II database and the 2015 PhysioNet/CinC Challenge public database were used as the training dataset; the 2015 Challenge hidden dataset was for testing. Each record had an alarm labeled with asystole, extreme bradycardia, extreme tachycardia, ventricular tachycardia or ventricular flutter/fibrillation. Before alarm onsets, 300 s multimodal data was provided, including electrocardiogram, arterial blood pressure and/or photoplethysmogram. A signal quality modified Kalman filter achieved robust heart rate estimation. Based on this, we extracted heart rate variability features and statistical ECG features. Next, we applied a genetic algorithm (GA) to select the optimal feature combination. Finally, considering the high cost of classifying a true arrhythmia as false, we selected cost sensitive support vector machines (CSSVMs) to classify alarms. Evaluation on the test dataset showed the overall true positive rate was 95%, and the true negative rate was 85%. PMID- 28099160 TI - Phase shift between respiratory oscillations in cerebral blood flow velocity and arterial blood pressure. AB - We aim to investigate whether phase shift between respiratory oscillations in cerebral blood flow velocity (CBFV) and arterial blood pressure (ABP) is associated with changes in cerebral autoregulation (CA) or reflects the mechano elastic properties of the cerebrovascular bed. The relationships between respiratory phase shift and slow wave phase shift versus cerebrovascular time constant (the product of cerebrovascular resistance and compliance) and the index of CA (Mx) were analyzed during breathing at 6, 10, and 15 breaths min-1 in 39 volunteers. With increasing respiratory rate the time constant, Mx, and respiratory phase shift decreased, whereas slow wave phase shift increased. The time constant correlated moderately strongly with the respiratory phase shift (R = 0.49, p [Formula: see text] 0.001) and did not correlate with the slow wave phase shift. The slow wave phase shift was significantly associated with Mx (R = -0.46, p [Formula: see text] 0.001). The respiratory phase shift more accurately reflects the mechano-elastic properties of the cerebrovascular bed, whereas CA is better described by the slow wave phase shift. PMID- 28099161 TI - Menstrual cycle and the temporal discrimination threshold. AB - The temporal discrimination threshold (TDT) is a proposed pre-clinical biomarker (endophenotype) for adult onset isolated focal dystonia (AOIFD). Age- and sex related effects on temporal discrimination demonstrate that women, before the age of 40 years, have faster temporal discrimination than men but their TDTs worsen with age at almost three times the rate of men. Thus after 40 years the TDT in women is progressively worse than in men. AOIFD is an increasingly female predominant disorder after the age of 40; it is not clear whether this age related sexually-dimorphic difference observed for both the TDT and sex ratio at disease onset in AOIFD is a hormonal or chromosomal effect. The aim of this study was to examine temporal discrimination at weekly intervals during two consecutive menstrual cycles in 14 healthy female volunteers to determine whether physiological hormonal changes affected temporal discrimination. We observed no significant differences in weekly temporal discrimination threshold values during the menstrual cycles and no significant correlation with the menstrual cycle stage. This observed stability of temporal discrimination during cyclical hormonal change raises interesting questions concerning the age-related sexually dimorphic decline observed in temporal discrimination. Our findings pave the way for future studies exploring potential pathomechanisms for this age-related deterioration. PMID- 28099162 TI - Thermography-based blood flow imaging in human skin of the hands and feet: a spectral filtering approach. AB - The determination of the relationship between skin blood flow and skin temperature dynamics is the main problem in thermography-based blood flow imaging. Oscillations in skin blood flow are the source of thermal waves propagating from micro-vessels toward the skin's surface, as assumed in this study. This hypothesis allows us to use equations for the attenuation and dispersion of thermal waves for converting the temperature signal into the blood flow signal, and vice versa. We developed a spectral filtering approach (SFA), which is a new technique for thermography-based blood flow imaging. In contrast to other processing techniques, the SFA implies calculations in the spectral domain rather than in the time domain. Therefore, it eliminates the need to solve differential equations. The developed technique was verified within 0.005-0.1 Hz, including the endothelial, neurogenic and myogenic frequency bands of blood flow oscillations. The algorithm for an inverse conversion of the blood flow signal into the skin temperature signal is addressed. The examples of blood flow imaging of hands during cuff occlusion and feet during heating of the back are illustrated. The processing of infrared (IR) thermograms using the SFA allowed us to restore the blood flow signals and achieve correlations of about 0.8 with a waveform of a photoplethysmographic signal. The prospective applications of the thermography-based blood flow imaging technique include non-contact monitoring of the blood supply during engraftment of skin flaps and burns healing, as well the use of contact temperature sensors to monitor low-frequency oscillations of peripheral blood flow. PMID- 28099163 TI - Adapting smartphone-based photoplethysmograpy to suboptimal scenarios. AB - Photoplethysmography (PPG) is an optical technique used to measure the heart rate (HR) and other cardiovascular variables by analyzing volume changes in the microvascular bed of tissue. At the moment, smartphone users can already measure their HR using PPG applications that use the smartphone's built-in camera. However, available applications are unreliable when artifacts are present, such as those caused by movement, finger pressure, or ambient light changes. This contribution aims to analyze the limitations of a smartphone-based PPG algorithm capable of measuring N-N intervals when such artifacts are present by comparing it to a 2-lead electrocardiography (ECG). By using a Bandpass filter and a zero crossing detection algorithm on a PPG signal captured at 800 * 600 pixels and 30 Hz, we have designed an approach capable of assessing N-N intervals when movement artifacts are present. An evaluation performed on n = 31 users shows our algorithm is capable of measuring N-N intervals with an average relative error of 9.23 ms, when compared to a 2-lead ECG. Our approach proves the reliability of smartphone-based photoplethysmography to measure N-N intervals, even under the presence of movement artifacts, and opens the door for its future use in remote diagnosis scenarios. PMID- 28099164 TI - Investigation of time-resolved proton radiography using x-ray flat-panel imaging system. AB - Proton beam therapy benefits from the Bragg peak and delivers highly conformal dose distributions. However, the location of the end-of-range is subject to uncertainties related to the accuracy of the relative proton stopping power estimates and thereby the water-equivalent path length (WEPL) along the beam. To remedy the range uncertainty, an in vivo measurement of the WEPL through the patient, i.e. a proton-range radiograph, is highly desirable. Towards that goal, we have explored a novel method of proton radiography based on the time-resolved dose measured by a flat panel imager (FPI). A 226 MeV pencil beam and a custom designed range modulator wheel (MW) were used to create a time-varying broad beam. The proton imaging technique used exploits this time dependency by looking at the dose rate at the imager as a function of time. This dose rate function (DRF) has a unique time-varying dose pattern at each depth of penetration. A relatively slow rotation of the MW (0.2 revolutions per second) and a fast image acquisition (30 frames per second, ~33 ms sampling) provided a sufficient temporal resolution for each DRF. Along with the high output of the CsI:Tl scintillator, imaging with pixel binning (2 * 2) generated high signal-to-noise data at a very low radiation dose (~0.1 cGy). Proton radiographs of a head phantom and a Gammex CT calibration phantom were taken with various configurations. The results of the phantom measurements show that the FPI can generate low noise and high spatial resolution proton radiographs. The WEPL values of the CT tissue surrogate inserts show that the measured relative stopping powers are accurate to ~2%. The panel did not show any noticeable radiation damage after the accumulative dose of approximately 3831 cGy. In summary, we have successfully demonstrated a highly practical method of generating proton radiography using an x-ray flat panel imager. PMID- 28099165 TI - The spectral properties of DNA and RNA macromolecules at low temperatures: fundamental and applied aspects. AB - This paper summarizes the results of studies of the spectral properties-optical absorption, fluorescence and phosphorescence-of DNA and RNA macromolecules and synthetic poly-, oligo- and mono-nucleotides, which have been carried out in our laboratory. The system of first excited singlet and triplet energy levels for DNA and RNA is evaluated using low-temperature (4.2 K-77 K) luminescent measurements. The traps of the singlet and triplet electronic excitations in these compounds are identified. An important self-protection mechanism against photo-damage of DNA and RNA by UV photons or penetrative radiation based on the capture of triplet electronic-energy excitations by the most photostable centers-in DNA, the complex formed by neighboring adenosine (A) and thymidine (T) links; in RNA, the adenosine links-is described. It is confirmed that despite similarities in the chemical and partly energy structures DNA is more stable than RNA. The spectral manifestation of the telomeres (the important functional system) in DNA macromolecules is examined. The results obtained on telomere fragments provide the possibility of finding the configuration peculiarities of the triplet excitations traps in DNA macromolecules. The resulting spreading length of the migrating singlet (l s) and triplet (l t) excitations for DNA and RNA macromolecules are evaluated. PMID- 28099166 TI - Despiking SEEG signals reveals dynamics of gamma band preictal activity. AB - Interictal epileptiform discharges, or 'interictal spikes', are the hallmark of epilepsy. Still, there is growing evidence that oscillatory activity-whether in the gamma band (30-120 Hz) or at higher frequencies is another important marker of hyperexcitable tissues. A major difficulty arises from the fact that interictal spikes and oscillations overlap in the frequency domain. This hampers the correct delineation of the cortex producing pathological oscillations by simple filtering. Here, we propose a nonlinear technique for fitting the spike waveform in order to remove it, resulting in a 'despiked' signal. This strategy was first applied to simulated data inspired from real stereo electroencephalographic (SEEG) signals, then to real data. We show that despiking leads to a better space-time-frequency analysis of the oscillatory part of the signal. Thus, in the real SEEG signals, the spatio-temporal maps show a buildup of gamma oscillations during the preictal period in the despiked signals, whereas in the original signals this activity is masked by spikes. Despiking is thus a promising venue for a better characterization of oscillatory activity in electrophysiology of epilepsy. PMID- 28099167 TI - Non-invasive measurement of volume-time curves in patients with mitral regurgitation and in healthy volunteers, using a new operator-independent screening tool. AB - Left ventricular volume-time curves (VTCs) provide hemodynamic data, and may help clinical decision making. The generation of VTCs using echocardiography, however, is time-consuming and prone to inter-operator variability. In this study, we used a new non-invasive, operator-independent technique, the hemodynamic cardiac profiler (HCP), to generate VTCs. The HCP, which uses a low-intensity, patient safe, high-frequency applied AC current, and 12 standard ECG electrodes attached on the thorax in a pre-defined pattern, was applied to five young healthy volunteers, five older healthy volunteers, and five patients with severe mitral regurgitation. From the VTCs generated by the HCP, the presence or absence of an isovolumetric contraction phase (ICP) was assessed, as well as the left ventricular ejection time (LVET), time of the pre-ejection period (tPEP), and ratio of the volumes of the early (E) and late (A) diastolic filling (E V/A V ratio), and compared to 2D transthoracic echocardiography (2D TTE) at rest. The reproducibility by two different operators showed good results (RMS = 5.2%). For intra-patient measurement RMS was 2.8%. Both LVET and the E V/A V ratio showed a strong significant correlation between HCP and 2D TTE derived parameters (p < 0.05). For tPEP, the correlation was still weak (p = 0.32). In all five patients with mitral regurgitation, the ICP was absent in the VTC from the HCP, whereas it was present in the 10 healthy volunteers, which is in accordance with pathophysiology. We conclude that the HCP seems to be a method for reproducible VTC generation, and may become a useful early screening tool for cardiac dysfunction in the future. PMID- 28099168 TI - A non-invasive approach to investigation of ventricular blood pressure using cardiac sound features. AB - Heart sounds (HSs) are produced by the interaction of the heart valves, great vessels, and heart wall with blood flow. Previous researchers have demonstrated that blood pressure can be predicted by exploring the features of cardiac sounds. These features include the amplitude of the HSs, the ratio of the amplitude, the systolic time interval, and the spectrum of the HSs. A single feature or combinations of several features have been used for prediction of blood pressure with moderate accuracy. Experiments were conducted with three beagles under various levels of blood pressure induced by different doses of epinephrine. The HSs, blood pressure in the left ventricle and electrocardiograph signals were simultaneously recorded. A total of 31 records (18 262 cardiac beats) were collected. In this paper, 91 features in various domains are extracted and their linear correlations with the measured blood pressures are examined. These features are divided into four groups and applied individually at the input of a neural network to predict the left ventricular blood pressure (LVBP). The analysis shows that non-spectral features can track changes of the LVBP with lower standard deviation. Consequently, the non-spectral feature set gives the best prediction accuracy. The average correlation coefficient between the measured and the predicted blood pressure is 0.92 and the mean absolute error is 6.86 mmHg, even when the systolic blood pressure varies in the large range from 90 mmHg to 282 mmHg. Hence, systolic blood pressure can be accurately predicted even when using fewer HS features. This technique can be used as an alternative to real-time blood pressure monitoring and it has promising applications in home health care environments. PMID- 28099169 TI - A comparison of stimulus presentation methods in temporal discrimination testing. AB - The temporal discrimination threshold (TDT) is the shortest time interval at which an individual detects two stimuli to be asynchronous (normal = 30-50 ms). It has been shown to be abnormal in patients with disorders affecting the basal ganglia including adult onset idiopathic focal dystonia (AOIFD). Up to 97% of patients have an abnormal TDT with age- and sex-related penetrance in unaffected relatives, demonstrating an autosomal dominant inheritance pattern. These findings support the use of the TDT as a pre-clinical biomarker for AOIFD. The usual stimulus presentation method involves the presentation of progressively asynchronous stimuli; when three sequential stimuli are reported asynchronous is taken as a participant's TDT. To investigate the robustness of the 'staircase' method of presentation, we introduced a method of randomised presentation order to explore any potential 'learning effect' that may be associated with this existing method. The aim of this study was to investigate differences in temporal discrimination using two methods of stimulus presentation. Thirty healthy volunteers were recruited to the study (mean age 33.73 +/- 3.4 years). Visual and tactile TDT testing using a staircase and randomised method of presentation order was carried out in a single session. There was a strong relationship between the staircase and random method for TDT values. This observed consistency between testing methods suggests that the existing experimental approach is a robust method of recording an individual's TDT. In addition, our newly devised randomised paradigm is a reproducible and more efficient method for data acquisition in the clinic setting. However, the two presentation methods yield different absolute TDT results and either of the two methods should be used uniformly in all participants in any one particular study. PMID- 28099170 TI - Exploring the ability of the nalidixate to sensitize visible and near-infrared emitting lanthanide(III) cations. AB - Recently, a strong interest has been directed towards near-infrared (NIR) emitting lanthanide(III) compounds as they do possess complementary advantages in respect to organic molecules and semi-conductor nanocrystals, especially in the fields of biological analysis and imaging. To benefit from their emission, a key requirement to fulfill is the sensitization of lanthanide(III) cations with an appropriate chromophore. This condition is especially challenging to address for the lanthanide(III) cations emitting in the NIR. The quest for new chromophores well adapted to the NIR-emitting lanthanide(III) ions is an important direction of research in order to broaden the rationalization of the parameters that control the sensitization process. In this work, we have investigated the ability of a readily available chromophoric ligand, the nalidixic acid, to sensitize lanthanide(III) cations with a specific interest for those emitting in the NIR. We have therefore performed an extensive study of the luminescence properties of lanthanide(III) complexes emitting in the visible and in the NIR ranges formed in situ upon mixing the corresponding Ln(III) nitrates (Ln(III) = Pr, Nd, Sm, Eu, Tb, Dy, Ho, Tm, Yb) with nalidixic acid (HNA) in a 1:3 molar ratio in the presence of a base. Luminescence spectra, quantum yields and luminescence lifetimes have been measured and discussed. The red emission of Eu with a quantum yield value of 5.90(3)%, red and NIR of Pr (7(1) . 10-4 and 5.6(1) . 10-4%) and Ho (9.3(2) . 10-4 and 2.8(1) . 10-4%), green of Tb (5.21(5)%), yellow and NIR of Dy (0.51(2) and 0.065(4)%), orange and NIR of Sm (0.147(5) and 0.037(2)%), as well as NIR of Nd (0.0321(2)%) and Yb (0.021(1)%) were observed. These results and analysis show that the nalidixate is a versatile chromophoric ligand that is suitable for the sensitization of nine different lanthanide(III) cations, five of them emitting in the NIR. PMID- 28099171 TI - An approach to estimate spatial distribution of analyte within cells using spectrally-resolved fluorescence microscopy. AB - While fluorescence microscopy has become an essential tool amongst chemists and biologists for the detection of various analyte within cellular environments, non uniform spatial distribution of sensors within cells often restricts extraction of reliable information on relative abundance of analytes in different subcellular regions. As an alternative to existing sensing methodologies such as ratiometric or FRET imaging, where relative proportion of analyte with respect to the sensor can be obtained within cells, we propose a methodology using spectrally-resolved fluorescence microscopy, via which both the relative abundance of sensor as well as their relative proportion with respect to the analyte can be simultaneously extracted for local subcellular regions. This method is exemplified using a BODIPY sensor, capable of detecting mercury ions within cellular environments, characterized by spectral blue-shift and concurrent enhancement of emission intensity. Spectral emission envelopes collected from sub microscopic regions allowed us to compare the shift in transition energies as well as integrated emission intensities within various intracellular regions. Construction of a 2D scatter plot using spectral shifts and emission intensities, which depend on the relative amount of analyte with respect to sensor and the approximate local amounts of the probe, respectively, enabled qualitative extraction of relative abundance of analyte in various local regions within a single cell as well as amongst different cells. Although the comparisons remain semi-quantitative, this approach involving analysis of multiple spectral parameters opens up an alternative way to extract spatial distribution of analyte in heterogeneous systems. The proposed method would be especially relevant for fluorescent probes that undergo relatively nominal shift in transition energies compared to their emission bandwidths, which often restricts their usage for quantitative ratiometric imaging in cellular media due to strong cross-talk between energetically separated detection channels. PMID- 28099172 TI - Decrease of muscle fiber conduction velocity correlates with strength loss after an endurance run. AB - Monitoring surface electromyographic (EMG) signals can provide useful insights for characterizing muscle fatigue, which is defined as an exercise-induced strength loss. This experiment investigated the muscle fiber conduction velocity (CV) changes induced by an endurance run. The day before and immediately after a half-marathon run (21.097 km) 11 amateur runners performed maximum voluntary contractions (MVCs) of knee extensor muscles. During the MVC, multichannel EMG was recorded from the vastus lateralis and EMG amplitude and CV were calculated. After the run, knee extensors showed a decreased strength (-13 +/- 9%, p = 0.001) together with a reduction in EMG amplitude (-13 +/- 10%, p = 0.003) and in CV (-6 +/- 8%, p = 0.032). Knee extensor strength loss positively correlated with vastus lateralis CV differences (r = 0.76, p = 0.006). Thus, the exercises-induced muscle fatigue was associated not only with a decrease in EMG amplitude, but also with a reduction in CV. This finding suggests that muscle fibers with higher CV (i.e. those with greater fiber size) were the most impaired during strength production after an endurance run. PMID- 28099173 TI - Surgical approach for ulcerated locally advanced breast cancer. A single Center experience: a retrospective study. AB - AIM: The aim of our retrospective study is to analyze surgical possibilities for the extended LABC in those cases not suitable for a neoadjuvant chemotherapy step and to consider various reconstruction techniques. MATERIAL OF STUDY: Between 2009 and 2015 we enrolled 11 patients, admitted to the Emergency Department, presenting ulcerated LABC that needed palliative surgical demolitive procedures because of bleeding and anemia and in which was necessary to use natural tissues transposition or synthetic substitutes for the reconstruction of the skin flaps. RESULTS: The mean follow up was 12 months. Mortality rate was 82% (9 patients); in 2 cases there was local relapse after 6 months; 9 months was the longest disease free survival. DISCUSSION: Thanks to multidisciplinary strategies LABC's surgical treatment improved results with a five-year survival rate between 30-40% and better quality of survival. Despite extended demolitive approach, there is still a 50% of death because of metastases. CONCLUSIONS: Our results confirm that musculocutaneous flap, skin anterior thigh grafts, bilayer matrix wound dressing are excellent reconstructive strategies in locally advanced ulcerated breast cancer after aggressive extended surgery even if palliative to improve patients' further survival. Our data also showed that those patients presenting medium level of malignancy as "luminal b" subtype (7 patients) if treated earlier with a radical surgical procedure would have better prognosis. KEY WORDS: Oncoplastic techniques, Ulcerated breast cancer. PMID- 28099174 TI - Discordance Rate in Estrogen Receptor, Progesterone Receptor, HER2 Status, and Ki67 Index Between Primary Unifocal and Multiple Homogenous Breast Carcinomas and Synchronous Axillary Lymph Node Metastases Have an Impact on Therapeutic Decision. AB - BACKGROUND: We aimed to demonstrate that in breast carcinomas the tumor profile is not stable during the metastatic process, with impact on therapeutic decisions. MATERIALS AND METHODS: We analyzed the estrogen receptor (ER), progesterone receptor (PR), and HER2 status and Ki67 index in 41 primary unifocal (PU) and 37 primary multiple (PM) breast carcinomas with identical immunohistochemical profiles among multiple tumor foci and the matched axillary lymph node metastases. We defined as concordant cases in which the primary tumor (PU or PM) and lymph node metastases displayed identical positivity or negativity for ER, PR, HER2, Ki67 and as discordant cases in which there was a mismatch in at least 1 biological parameter among PU and PM tumor and lymph node metastases. Moreover, we defined as concordant cases in which the molecular profile (based on the immunohistochemical evaluation of ER, PR, HER2, and Ki67) was concordant among PU and PM tumors and lymph node metastases and mismatch cases as those in which the molecular profile of the primary tumor differs from one of the lymph node metastases in at least 1 lymph node. RESULTS: The positivity for the biological markers is not stable during the metastatic process. In this study the total rate of discordant cases was 92.7% in PU tumors and 75.7% in PM homogenous tumors (P=0.058, odds ratio=0.245, 95% confidence interval, 0.06-0.991). The total rate of shifted cases was 64.9% in PM tumors and 82.9% in PU tumors. The highest rate of shifting was encountered from Luminal B-like to Luminal A-like. In 11 out of 37 (29.7%) PM and in 17 out of 41 (41.5%) PU cases the subtype shifted to a poorer one with respect to prognosis. CONCLUSIONS: The patients in whom the primary tumor is hormone receptor and/or HER2 negative but is positive for these markers in the axillary lymph nodes could become eligible for hormonal treatment and/or trastuzumab treatment, which may significantly improve the patient's outcome. PMID- 28099175 TI - Two for One: A Case Report of Intravenous Lipid Emulsion to Treat Local Anesthetic Systemic Toxicity in Term Pregnancy. AB - Combined spinal-epidural (CSE) analgesia is a frequently used method of labor analgesia. Although it is considered safe and effective, CSE can be complicated by local anesthetic systemic toxicity (LAST), a potentially life-threatening condition. We present a case of LAST that developed in a primigravida 50 minutes after uneventful placement of a CSE. Her symptoms resolved within 10 minutes of administering intralipid emulsion. She subsequently underwent cesarean delivery under spinal anesthesia for failure to progress without sequelae in the mother or infant. LAST in pregnancy can occur at traditionally subthreshold dosing; anesthesiologists must be vigilant to ensure prompt and effective treatment. PMID- 28099176 TI - Teaching Population Health: Community-Oriented Primary Care Revisited. PMID- 28099177 TI - Medical Students' Perspectives on Implementing Curriculum Change at One Institution. AB - Training physicians to be effective practitioners throughout their careers begins in undergraduate medical education with particular focus on self-directed inquiry, professional and interprofessional development, and competency-based assessment. A select number of medical schools are restructuring their curricula by placing the student at the center of content delivery to enhance the learning experience. While this restructuring may benefit the adult learner, administrators often make assumptions about how students will perceive and respond to such innovative and unfamiliar educational concepts. This can create a disconnect between students and their curriculum. Administrative mindfulness of student experiences is needed to ensure successful implementation of curricular change, facilitate the transition from old to new modalities, and train competent physician graduates.Vanderbilt University School of Medicine (VUSM) recently completed a curriculum update, and student representatives have been essential participants in the transition, from the earliest stages in preplanning to rapid cycle feedback as the curriculum runs. Two of the authors are members of VUSM's Student Curriculum Committee, which facilitates gathering and relaying student feedback to the administration. Drawing from their experiences, five specific considerations to address and manage when implementing student-centered curricular change are presented: (1) Communicate the rationale, (2) acknowledge anxiety, (3) adjust extracurricular leadership roles, (4) manage "The Bulge" of learners in the clinical environment, and (5) foster ongoing collaboration of students and administrators. For each consideration, examples and proposed solutions are provided. PMID- 28099178 TI - Clinical Performance Evaluations of Third-Year Medical Students and Association With Student and Evaluator Gender. AB - PURPOSE: Clinical performance evaluations are major components of medical school clerkship grades. But are they sufficiently objective? This study aimed to determine whether student and evaluator gender is associated with assessment of overall clinical performance. METHOD: This was a retrospective analysis of 4,272 core clerkship clinical performance evaluations by 829 evaluators of 155 third year students, within the Alpert Medical School grading database for the 2013 2014 academic year. Overall clinical performance, assessed on a three-point scale (meets expectations, above expectations, exceptional), was extracted from each evaluation, as well as evaluator gender, age, training level, department, student gender and age, and length of observation time. Hierarchical ordinal regression modeling was conducted to account for clustering of evaluations. RESULTS: Female students were more likely to receive a better grade than males (adjusted odds ratio [AOR] 1.30, 95% confidence interval [CI] 1.13-1.50), and female evaluators awarded lower grades than males (AOR 0.72, 95% CI 0.55-0.93), adjusting for department, observation time, and student and evaluator age. The interaction between student and evaluator gender was significant (P = .03), with female evaluators assigning higher grades to female students, while male evaluators' grading did not differ by student gender. Students who spent a short time with evaluators were also more likely to get a lower grade. CONCLUSIONS: A one-year examination of all third-year clerkship clinical performance evaluations at a single institution revealed that male and female evaluators rated male and female students differently, even when accounting for other measured variables. PMID- 28099179 TI - Traditional Sternotomy Versus Minimally Invasive Aortic Valve Replacement in Patients Stratified by Ejection Fraction. AB - OBJECTIVE: Low ejection fraction (EF < 40%) portends adverse outcomes in patients undergoing valvular heart surgery. The role of traditional median sternotomy aortic valve replacement (SAVR) compared with minimally invasive aortic valve replacement (MIAVR) in this cohort remains incompletely understood. METHODS: A multi-institutional retrospective review of 1503 patients who underwent SAVR (n = 815) and MIAVR via right anterior thoracotomy (n = 688) from 2011 to 2014 was performed. Patients were stratified into two groups: EF of less than 40% and EF of 40% or more. In each EF group, SAVR and MIAVR patients were propensity matched by age, sex, body mass index, race, diabetes, hypertension, dyslipidemia, dialysis, cerebrovascular disease, cardiovascular disease, cerebrovascular accident, peripheral vascular disease, last creatinine level, EF, previous MI and cardiogenic shock, and the Society for Thoracic Surgeons (STS) score. RESULTS: Among patients with an EF of 40% or more (377 pairs), patients who underwent MIAVR compared with SAVR had decreased intensive care unit hours (56.8% vs 84.6%, P < 0.001), postoperative length of stay (7.1 vs 7.9 days, P = 0.04), incidence of atrial fibrillation (18.8% vs 38.7%, P < 0.001), bleeding (0.8% vs 3.2%, P = 0.04), and a trend toward decreased 30-day mortality (0.3% vs 1.3%, P = 0.22). The STS scores were largely equivalent in patients undergoing MIAVR compared with SAVR (2.4% vs 2.6%, P = 0.09). In patients with an EF of less than 40% (35 pairs), there was no difference in intensive care unit hours (69% vs 72.6%, P = 0.80), postoperative length of stay (10.3 vs 7.2 days, P = 0.13), 30-day mortality (3.8% vs 0.8%, P = 0.50), or the STS score (3.3% vs 3.2%, P = 0.68). CONCLUSIONS: Minimally invasive aortic valve replacement in patients with preserved EF was associated with improved short-term outcomes compared with SAVR. In patients with left ventricular dysfunction, short-term outcomes between MIAVR and SAVR are largely equivalent. PMID- 28099180 TI - KBG syndrome: 16q24.3 microdeletion in an Indian patient. PMID- 28099181 TI - Adverse events and risk factors during emergency intubation in a tertiary paediatric emergency department. AB - BACKGROUND: Rapid sequence intubation and emergency intubation in the emergency department (ED) can be life-saving procedures, but require the appropriate skills, experience and preparation to avoid complications ranging from simple trauma to life-threatening desaturation. Only scarce data exist in the published literature on complications following emergency intubation in children and most guidelines are extrapolated from the adult population. PATIENTS AND METHODS: We reviewed all emergency intubations of patients in our tertiary paediatric ED within a 2-year period to estimate the incidence of complications and to analyse the risk factors associated with this procedure. RESULTS: Seventy-two children were intubated; complications occurred in one in four and repeated attempts at intubation in 17/23 children. The median age of the children was 2 years (range: 0 days-6 years). The most common reason for intubation was altered level of consciousness and the most frequent diagnosis at the time of intubation was seizure/status epilepticus. Complications were related to desaturation (n=7), equipment failure (n=3), intravenous access (n=2) and hypotension (n=2), erroneous or insufficient drug preparation (n=1) and other reasons (n=3). There was no significant association of complications with the child's age or weight, time of arrival to ED, preintubation hypotension or combination of drugs used. CONCLUSION: Complications of rapid sequence intubation, a relatively low frequency procedure in the paediatric ED, occurred in one of four children and repeat attempts at intubation were made in another 24%. We suggest that the use of an intubation checklist including the preparation of equipment and recommendations for drug use would minimize the occurrence of adverse events of intubation in children. PMID- 28099182 TI - Reliability of the revised Swiss Emergency Triage Scale: a computer simulation study. AB - BACKGROUND: The Swiss Emergency Triage Scale (SETS) is a four-level emergency scale that previously showed moderate reliability and high rates of undertriage due to a lack of standardization. It was revised to better standardize the measurement and interpretation of vital signs during the triage process. OBJECTIVE: The aim of this study was to explore the inter-rater and test-retest reliability, and the rate of correct triage of the revised SETS. PATIENTS AND METHODS: Thirty clinical scenarios were evaluated twice at a 3-month interval using an interactive computerized triage simulator by 58 triage nurses at an urban teaching emergency department admitting 60 000 patients a year. Inter-rater and test-retest reliabilities were determined using kappa statistics. Triage decisions were compared with a gold standard attributed by an expert panel. Rates of correct triage, undertriage, and overtriage were computed. A logistic regression model was used to identify the predictors of correct triage. RESULTS: A total of 3387 triage situations were analyzed. Inter-rater reliability showed substantial agreement [mean kappa: 0.68; 95% confidence interval (CI): 0.60-0.78] and test-retest almost perfect agreement (mean kappa: 0.86; 95% CI: 0.84-0.88). The rate of correct triage was 84.1%, and rates of undertriage and overtriage were 7.2 and 8.7%, respectively. Vital sign measurement was an independent predictor of correct triage (odds ratios for correct triage: 1.29 for each additional vital sign measured, 95% CI: 1.20-1.39). CONCLUSION: The revised SETS incorporating standardized vital sign measurement and interpretation during the triage process resulted in high reliability and low rates of mistriage. PMID- 28099184 TI - Efficacy of Vitamin B6 in Lithium-Associated Tremor: A Case Series. PMID- 28099183 TI - Memantine as an Adjuvant Treatment for Obsessive Compulsive Symptoms in Manic Phase of Bipolar Disorder: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. AB - PURPOSE/BACKGROUND: The aim of this study is to examine the effects of memantine as an adjuvant treatment for obsessive compulsive (OC) symptoms in patients with bipolar disorder (BD) type I, manic phase. METHODS/PROCEDURES: In this 16-week double-blind placebo-controlled randomized clinical trial, 58 patients in the manic phase of BD who had OC symptoms were randomly allocated to receive memantine or placebo plus their routine medications (lithium + olanzapine + clonazepam). The Yale Brown Obsessive Compulsive Behavior Scale was used to assess the outcomes. Adverse effects were also recorded. FINDINGS/RESULTS: Thirty eight patients (19 in the memantine group and 19 in the placebo group) completed the trial. Throughout the trial, the mean score decreased from 20.26 +/- 5.91 to 9.73 +/- 5.44 in the memantine group (P < 0.000) and from 22.89 +/- 5.70 to 16.63 +/- 4.00 in the placebo group (P < 0.000). At the end of the study, 15 (78.94%) patients in the memantine group and 7 (36.84%) patients in the placebo group demonstrated more than 34% decline in the Yale Brown Obsessive Compulsive Behavior Scale score (P < 0.01). No serious adverse effects were reported. IMPLICATIONS/CONCLUSIONS: Our double-blind controlled clinical trial showed that memantine is an effective adjuvant agent for reducing OC symptoms in patients with BD. However, it needs to be noted that our study is preliminary, and larger double-blind controlled studies are needed to confirm the results. PMID- 28099185 TI - Ketamine and Suicidal Ideation: Direct Effect or Epiphenomenon? PMID- 28099186 TI - Poststroke depression: risk factors and potential effects on functional recovery. AB - The factors that may cause poststroke depression were investigated in the literature focusing on lesion localization, age, stroke severity, and impairments in physical and cognitive function. The aim of this study was to examine the risk factors influencing the development of poststroke depression and to determine the effect of depression on the patients' functional improvement after rehabilitation. Patients in the first 6-month period after stroke who were hospitalized in the Physical Medicine and Rehabilitation Clinic were included in this study. Patients who were admitted to the hospital within 0-30 and 30-120 days from the date of stroke were considered early and late rehabilitation entrants, respectively. The sample of this study included 93 patients. Patients' demographic and clinical characteristics, complications, and medical history were recorded. Upper extremity motor function, ambulation, and mood were evaluated according to the Frenchay Arm Test, the Functional Ambulation Scale, and the Beck Depression Inventory, respectively. The Functional Independence Measure (FIM) was applied to patients at admission to the hospital, at discharge, and 1 month after discharge (follow-up). The mean age of the patients was 58 years and the mean disease duration was 53 days. Depression was diagnosed in 49 (53%) patients. Except for age and disease duration, none of the factors of sex, hemiplegic side, stroke severity, stroke etiology, neglect, spasticity, sedentary lifestyle, poststroke immobility, and early-onset or late-onset to rehabilitation was found to induce statistically significant differences in the development of depression. Statistically significant changes occurred in total FIM levels between the groups with and without depression between admission and discharge, admission and follow up, and discharge and follow-up. The levels were significantly higher in patients without depression than in patients with depression. Depression was found in a high frequency in stroke patients. Younger age and long disease duration were found to be factors affecting the development of depression. FIM scores were observed to be lower in stroke patients with depression. PMID- 28099187 TI - A Comparative Study of Anterior Decompression With Fusion and Posterior Decompression With Laminoplasty for the Treatment of Cervical Spondylotic Myelopathy Patients With Large Anterior Compression of the Spinal Cord. AB - STUDY DESIGN: This is a retrospective observational single-center study. OBJECTIVES: To compare anterior decompression and fusion (ADF) and laminoplasty (LAMP) for the treatment of cervical spondylotic myelopathy (CSM) patients with large anterior compression in terms of clinical and radiologic outcomes. SUMMARY OF BACKGROUND DATA: We have reported that insufficient posterior decompression could be often seen after laminoplasty for CSM patients with preoperative anterior clearance of the spinal cord, defined as an interval <4 mm between the preoperative the modified K-line and anterior structure of the spinal canal at most compressive segment on sagittal T1-weighted magnetic resonance imaging. Here we conduct a study comparing ADF and LAMP for the treatment of CSM patients with such a risk factor. MATERIALS AND METHODS: Of the 221 consecutive CSM patients treated with either ADF or LAMP between 2008 and 2012 at our hospital, 79 patients in whom the interval was <4 mm with age ranged from 50 to 79 years were enrolled. Patients with myelopathy caused by single-level disk herniation, tumor or ossification of posterior longitudinal ligament, or patients with a history of cervical spine injury were excluded. The Japanese Orthopedic Association (JOA) scoring system for cervical myelopathy, recovery rate of the JOA score at the time of 2 years after surgery were investigated as clinical outcomes to compare these 2 groups. RESULTS: Demographics were almost similar between ADF and LAMP groups. The mean preoperative and postoperative JOA scores were 10.9 and 13.8 points for ADF group and 10.1 and 12.4 points for LAMP group, indicating that the recovery rate of JOA score was significantly greater in ADF group (49.6%) than that in LAMP group (38.2%; P=0.047). In LAMP group, spinal cord deformity was a significant predictive factor for unsatisfactory clinical outcome. CONCLUSION: ADF provided better surgical treatment for the patients with absence of preoperative anterior clearance of the spinal cord. PMID- 28099188 TI - Hepatitis B incidence and prevention with antiretroviral therapy among HIV positive individuals in Uganda. AB - OBJECTIVE: Antiretroviral therapy (ART) may interfere with replication of hepatitis B virus (HBV), raising the hypothesis that HBV infection might be prevented by ART. We investigated the incidence and risk factors associated with HBV among HIV-infected adults in Rakai, Uganda. METHODS: We screened stored sera from 944 HIV-infected adults enrolled in the Rakai Community Cohort Study between September 2003 and March 2015 for evidence of HBV exposure. Serum from participants who tested anti-hepatitis B core-negative (497) at baseline were tested over 3-7 consecutive survey rounds for incident HBV. Poisson incidence methods were used to estimate incidence of HBV with 95% confidence intervals (CIs), whereas Cox proportional regression methods were used to estimate hazard ratios (HRs). RESULTS: Thirty-nine HBV infections occurred over 3342 person years, incidence 1.17/100 person-years. HBV incidence was significantly lower with ART use: 0.49/100 person-years with ART and 2.3/100 person-years without ART [adjusted HR (aHR) 0.25, 95% CI 0.1-0.5, P < 0.001], and with lamivudine (3TC) use: 0.58/100 person-years) with 3TC and 2.25/100 person-years without 3TC (aHR 0.32, 95% CI 0.1-0.7, P = < 0.007). No new HBV infections occurred among those on tenofovir-based ART. HBV incidence also decreased with HIV RNA suppression: 0.6/100 person-years with 400 copies/ml or less and 4.0/100 person-years with more than 400 copies/ml (aHR, 6.4, 95% CI 2.2-19.0, P < 0.001); and with age: 15 29 years versus 40-50 years (aHR 3.2, 95% CI 1.2-9.0); 30-39 years versus 40-50 years (aHR 2.1, 95% CI 0.9-5.3). CONCLUSION: HBV continues to be acquired in adulthood among HIV-positive Ugandans and HBV incidence is dramatically reduced with HBV-active ART. In addition to widespread vaccination, initiation of ART may prevent HBV acquisition among HIV-positive adults in sub-Saharan Africa. PMID- 28099189 TI - Productive infection of human neural progenitor cells by R5 tropic HIV-1: opiate co-exposure heightens infectivity and functional vulnerability. AB - OBJECTIVE: HIV type-1 (HIV-1) causes a spectrum of central nervous system (CNS) complications; many are worsened by opiate co-exposure. Human neural progenitor cells (hNPCs) give rise to all CNS neurons and macroglia. We tested the hypothesis that hNPC maturation and fate are altered by HIV and opiates, contributing to HIV-1-related neuropathology. Reports of hNPC infection remain controversial. We rigorously examined this question, testing whether hNPCs propogated infection, and whether HIV affected hNPCs absent their infection. DESIGN AND METHODS: Primary hNPCs were characterized over multiple passages. Following R5 HIV-1BaL exposure, p24, Nef, and tat assays monitored infection; a serial dilution approach tested infection transfer to naive hNPCs. Bromodeoxyuridine uptake, population doubling time, and immunostaining assessed proliferation and differentiation. Morphine co-exposure assessed opiate interactions. Supernatant from HIV-1BaL-infected PBMCs (HIVsup), HIV-1BaL, and ultraviolet light-inactivated HIVsup were compared to test effects of inflammatory milieu versus virus or infection per se. RESULTS: The hNPCs (CD4/CD8/Iba/CXC3CL1/CD11b) were infectable and could transfer infection to naive hNPCs. Infection was partly blocked by maraviroc, implicating CCR5. HIVsup reduced hNPC proliferation and caused premature differentiation into neurons/astroglia. Effects on proliferation were due to soluble factors/viral proteins, not infection per se. Morphine co-exposure exacerbated certain functional consequences of HIVsup, and sustained the infection of hNPCs. CONCLUSION: hNPCs can be infected and propagate virus in vitro. hNPCs or their progeny may represent an underappreciated viral reservoir. Factors from infected cells alter hNPC proliferation and neural cell maturation, which likely compromises CNS structure and function. Morphine-HIV interactions may worsen dysfunction and sustain infection. PMID- 28099190 TI - Coagulation imbalance and neurocognitive functioning in older HIV-positive adults on suppressive antiretroviral therapy. AB - OBJECTIVES: The aim of this study was to compare plasma biomarkers of coagulation between HIV-infected individuals and HIV-uninfected controls and to assess the impact of disturbances in coagulation on neurocognitive functioning in HIV. DESIGN: A cross-sectional study of 66 antiretroviral therapy treated, virally suppressed, HIV-infected and 34 HIV-uninfected older (>=50 years of age) adults. METHODS: Participants completed standardized neurobehavioral and neuromedical assessments. Neurocognitive functioning was evaluated using a well validated comprehensive neuropsychological battery. Plasma biomarkers associated with procoagulation (fibrinogen, p-selectin, tissue factor and von Willebrand factor), anticoagulation (antithrombin, protein C and thrombomodulin), fibrinolysis (d dimer, plasminogen activator inhibitor-1 and plasminogen) were collected. Multivariable linear regression was used to test the interaction of HIV and coagulation on neurocognitive functioning. RESULTS: Most participants were male (78.0%) and non-Hispanic white (73.0%) with a mean age of 57.8 years. Among HIV infected participants, mean estimated duration of HIV infection was 19.4 years and median current CD4 cell count was 654 cells/MUl. Levels of soluble biomarkers of procoagulation, anticoagulation and fibrinolysis were comparable between the HIV serostatus groups. Coagulation and HIV had an interacting effect on neurocognitive functioning, such that greater coagulation imbalance was associated with poorer neurocognitive functioning among the HIV-infected participants. The moderating effect of coagulation on neurocognition was driven by procoagulant but not anticoagulant or fibrinolytic biomarkers. CONCLUSIONS: Elevated levels of procoagulants may exert a particularly detrimental effect on neurocognitive functioning among older HIV-infected persons. A better understanding of the specific role of coagulation in the cause of HIV-associated neurocognitive disorders may lead to treatments aimed at reducing coagulopathy, thereby improving neurocognitive outcomes. PMID- 28099191 TI - Long-acting combination anti-HIV drug suspension enhances and sustains higher drug levels in lymph node cells than in blood cells and plasma. AB - OBJECTIVE: The aim of the present study was to determine whether a combination of anti-HIV drugs - tenofovir (TFV), lopinavir (LPV) and ritonavir (RTV) - in a lipid-stabilized nanosuspension (called TLC-ART101) could enhance and sustain intracellular drug levels and exposures in lymph node and blood cells above those in plasma. DESIGN: Four macaques were given a single dose of TLC-ART101 subcutaneously. Drug concentrations in plasma and mononuclear cells of the blood (PBMCs) and lymph nodes (LNMCs) were analysed using a validated combination LC MS/MS assay. RESULTS: For the two active drugs (TFV, LPV), plasma and PBMC intracellular drug levels persisted for over 2 weeks; PBMC drug exposures were three- to four-fold higher than those in plasma. Apparent terminal half-lives (t1/2) of TFV and LPV were 65.3 and 476.9 h in plasma, and 169.1 and 151.2 h in PBMCs. At 24 and 192 h, TFV and LPV drug levels in LNMCs were up to 79-fold higher than those in PBMCs. Analysis of PBMC intracellular TFV and its active metabolite TFV-diphosphate (TFV-DP) indicated that intracellular exposures of total TFV and TFV-DP were markedly higher and persisted longer than in humans and macaques dosed with oral TFV prodrugs, tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). CONCLUSIONS: A simple, scalable three-drug combination, lipid-stabilized nanosuspension exhibited persistent drug levels in cells of lymph nodes and the blood (HIV host cells) and in plasma. With appropriate dose adjustment, TLC-ART101 may be a useful HIV treatment with a potential to impact residual virus in lymph nodes. PMID- 28099192 TI - Aerobic Exercise Training in Very Severe Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To evaluate the effectiveness of exercise training in patients with very severe chronic obstructive pulmonary disease (COPD). DESIGN: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature databases using the following as search terms: COPD, Chronic Obstructive Pulmonary Disease, Exercise, and Pulmonary Rehabilitation. We included randomized controlled trials (RCTs) of subjects with forced expiratory volume in the first second of less than 35% of the predicted normal value enrolled in in-patient, outpatient, or home- or community-based training programs lasting at least 4 weeks with respect to usual care. We included RCTs with outcome measures including the 6-minute walking test and/or health-related quality of life assessed by the St. George's Respiratory Questionnaire (SGRQ). RESULTS: Of 580 articles screened, 10 were included. The programs' duration ranged from 4 to 52 weeks with 1 to 5 sessions per week lasting 15 to 40 minutes each. The intervention group improved in 6-minute walking test [weighted mean difference, 67.1 (95% confidence interval [CI], 37.897-98.927); standardized mean difference, 3.86 (95% CI, 2.04-5.67)], and St. George's Respiratory Questionnaire [weighted mean difference, -8.041 (95% CI, 15.273 to -0.809); standardized mean difference, -1.23 (95% CI, -2.14 to -0.31)]. CONCLUSIONS: Exercise training improves exercise tolerance and health-related quality of life in patients with very severe COPD. However, because few studies on severely affected patients are available and the training programs are Highly heterogeneous, larger RCTs are needed. PMID- 28099193 TI - The Effect of Peripheral Nerve Stimulation on Shoulder Biomechanics: A Randomized Controlled Trial in Comparison to Physical Therapy. AB - OBJECTIVE: To establish the effects on shoulder biomechanics from a peripheral nerve stimulation (PNS) treatment compared to physical therapy (PT) in stroke survivors with chronic hemiplegic shoulder pain. DESIGN: Single-site, pilot, randomized controlled trial for adults with chronic shoulder pain after stroke. Participants were randomized to receive a 3-week treatment of single-lead PNS or physical therapy (PT). The outcomes included isometric shoulder abduction strength, pain-free shoulder external rotation range of motion (ROM), delay in initiation and termination of shoulder abduction electromyogram (EMG) activity, and the Fugl-Meyer Motor Assessment (upper extremity section). Outcomes were measured at baseline, and at weeks 1, 4, 12, and 16. RESULTS: Twenty-five participants were recruited, 13 to PNS and 12 to PT. There were significant improvements for both PNS and PT in maximum isometric shoulder abduction strength, pain-free external rotation ROM, and Fugl-Meyer Motor Assessment. There were no significant changes in delay of initiation or termination of deltoid EMG with either treatment. CONCLUSIONS: Both PNS and PT are capable of improving shoulder biomechanics in those with HSP, though changes in biomechanics alone do not account for the greater pain relief associated with PNS than PT. PMID- 28099194 TI - Chronic Resistance Training Does Not Ameliorate Unloading-Induced Decrements in Neuromuscular Function. AB - OBJECTIVE: The aim of this study was to assess the efficacy of long-term resistance training in preventing the detrimental effects of muscle unloading on neuromuscular function. DESIGN: Eleven untrained men and 11 men with extensive backgrounds in resistance training were tested for several parameters of neuromuscular function at various isokinetic contractile velocities before and after 7 days of muscle unloading. Measurements included muscle mass, strength, power, total work, electromyography, and neuromuscular transmission efficiency using superimposed electrical stimulation of maximally contracting muscles. RESULTS: Muscle performance was superior in resistance-trained subjects before and after unloading. In both groups of participants, unloading resulted in significantly (P < 0.05) diminished muscle performance, but only at isometric or slower isokinetic contractile velocities. Electromyography activity was significantly higher in trained than in untrained subjects before and after unloading. Thigh muscle mass was greater among trained subjects before and after unloading. Neither electromyography activity, thigh muscle mass, nor neuromuscular transmission efficiency was significantly altered by unloading in trained or untrained participants. CONCLUSIONS: Chronic resistance training was found to be ineffective in neutralizing the deleterious effects of unloading on neuromuscular function. It appears that positive adaptations associated with long term resistance training provide no prophylactic effect when neuromuscular systems are subjected to unloading. PMID- 28099195 TI - Systolic peak foot-to-apex time interval, a novel oscillometric technique for systolic blood pressure measurement. AB - BACKGROUND: Noninvasive blood pressure (BP) measurement is essential for the study of human physiology but automatic oscillometric devices only estimate SBP and DBP using various, undisclosed algorithms, precluding standardization and interchangeability. We propose a novel approach by tracking, during pneumatic cuff deflation, the time interval from the foot to the apex of the systolic peak of the oscillometric signal, which reaches a maximum concomitant with the first Korotkoff sound. METHOD: In 145 study participants and patients (group 1), we measured the systolic brachial artery blood pressure by Korotkoff sound recording, conventional oscillometry, and our fully automated systolic peak foot to-apex time interval (SFATI) technique. In 35 other patients (group 2), we compared SFATI with intra-arterial measurement. RESULTS: In group 1, the concordance correlation coefficient was 0.989 and 0.984 between SFATI and Korotkoff sounds, 0.884 and 0.917 between oscillometry and Korotkoff sounds, and 0.882 and 0.919 between SFATI and oscillometry, respectively, on the left and right arm. In group 2, it was 0.72 between SFATI and intra-arterial measurement, 0.67 between oscillometry and intra-arterial measurement, and 0.92 between SFATI and Korotkoff sounds. In 40 study participants, the reproducibility study yielded a concordance coefficient of 0.95 for SFATI and 0.94 for Korotkoff sounds. CONCLUSION: SFATI BP measurement shows an excellent concordance with the auscultatory technique, offering a major improvement over current oscillometric techniques and allowing standardization. PMID- 28099196 TI - Use of Engineered Exosomes Expressing HLA and Costimulatory Molecules to Generate Antigen-specific CD8+ T Cells for Adoptive Cell Therapy. AB - Dendritic cell-derived exosomes (DEX) comprise an efficient stimulator of T cells. However, the production of sufficient DEX remains a barrier to their broad applicability in immunotherapeutic approaches. In previous studies, genetically engineered K562 have been used to generate artificial antigen presenting cells (AAPC). Here, we isolated exosomes from K562 cells (referred to as CoEX-A2s) engineered to express human leukocyte antigen (HLA)-A2 and costimulatory molecules such as CD80, CD83, and 41BBL. CoEX-A2s were capable of stimulating antigen-specific CD8 T cells both directly and indirectly via CoEX-A2 cross dressed cells. Notably, CoEX-A2s also generated similar levels of HCMV pp65 specific and MART1-specific CD8 T cells as DEX in vitro. The results suggest that these novel exosomes may provide a crucial reagent for generating antigen specific CD8 T cells for adoptive cell therapies against viral infection and tumors. PMID- 28099197 TI - Relative Frequencies of Arteritic and Nonarteritic Anterior Ischemic Optic Neuropathy in an Arab Population. AB - BACKGROUND: To evaluate the relative frequencies of arteritic and nonarteritic anterior ischemic optic neuropathy (AION) in an Arab population and to compare and contrast these findings with known epidemiological data from Caucasian populations. METHODS: A retrospective review of the medical records of all patients diagnosed with AION at the King Khaled Eye Specialist Hospital (KKESH) in Riyadh, Saudi Arabia, between 1997 and 2012. RESULTS: Of 171 patients with AION, 4 had biopsy-proven giant-cell arteritis (GCA). The relative frequencies of arteritic anterior ischemic optic neuropathy (AAION) and nonarteritic anterior ischemic optic neuropathy (NAION) in this Arab cohort were 2.3% and 97.7%, respectively. CONCLUSIONS: The relative frequencies of arteritic anterior ischemic optic neuropathy and nonarteritic anterior ischemic optic neuropathy differ between Arab and North American clinic-based populations, with giant-cell arteritis-related ischemia being much less frequent in Saudi Arabia. PMID- 28099198 TI - Osteomyelitis of the accessory and body of the navicular bone: a case report. AB - A 16-year-old boy developed left foot pain of unknown cause that was unresponsive to conservative treatment, associated with fever and difficulty walking. He was admitted to our hospital with osteomyelitis of the accessory and body of the navicular bone. Surgery could not be performed because the patient had been diagnosed with Wiskott-Aldrich syndrome. After antibiotic therapy, laboratory abnormalities and pain had resolved. One year after treatment, the patient had returned to his original level of sports activity. Both an accessory navicular and the body of the navicular bone may develop osteomyelitis in immunocompromised patients; early diagnosis is important for prescribing effective conservative treatment. PMID- 28099199 TI - Chronic lateral epiphyseal separation of the proximal tibia causes late-onset tibia vara. AB - An adolescent obese boy showed late-onset unilateral tibia vara associated with physeal separation (slipped epiphysis) of the lateral proximal tibia and physeal widening of the lateral distal femur. These affected physes showed normal signal intensities by MRI. He was treated with lateral hemiepiphysiodesis of the left proximal tibia and the distal femur using two parallel eight-Plates, and varus deformity rapidly improved postoperatively without recurrence. This is the first case of late-onset tibia vara caused by lateral physeal separation of the proximal tibia. Normal growth of the medial physes around the knee would contribute toward significant correction after surgery. PMID- 28099200 TI - Perception and Acceptability of Medical Photography in Chinese Dermatologic Patients: A Questionnaire Survey. AB - BACKGROUND: Medical photography is increasingly used by physicians, but studies assessing the perception and acceptability of medical photography by Chinese dermatologic patients are scarce. OBJECTIVE: To assess the perception and acceptability of medical photography in Chinese dermatologic patients. MATERIALS AND METHODS: From July to December 2014, adult patients visiting the Dermatology Clinic of The First Affiliated Hospital of Third Military Medical University were included in this study. They were required to fill an anonymous questionnaire regarding perception and acceptability of medical photography. RESULTS: A total of 509 consecutive patients completed the questionnaire, with 35 and 474 declining and undergoing medical photography, respectively. Meanwhile, 81.0% of the patients preferred to be photographed by attending physicians; 63.3% favored clinic-owned cameras, and 81.0% would rather have their photographs stored in the department's database. Besides, most patients allowed their photographs to be used in case studies (92.8%) or medical record keeping (90.3%). CONCLUSION: Most Chinese dermatologic patients accept medical photography. However, the principles of privacy protection and informed consent should be strictly enforced in clinical practice, and appropriate photographic devices and storage methods should be used, for better acceptance. PMID- 28099201 TI - Medial Canthal Reconstruction With Malar Advancement Flap Combined With Cutaneous Island Flap Created Using "Conventionally Discarded" Tissue. PMID- 28099202 TI - Early Changes in Facial Profile Following Structured Filler Rhinoplasty: An Anthropometric Analysis Using a 3-Dimensional Imaging System. AB - BACKGROUND: Quantitative measurements are important for objective evaluation of postprocedural outcomes. Three-dimensional (3D) imaging is known as an objective, accurate, and reliable system for quantifying the soft tissue dimensions of the face. OBJECTIVE: To compare the preprocedural and acute postprocedural nasofrontal, nasofacial, nasolabial, and nasomental angles, early changes in the height and length of the nose, and nasal volume using a 3D surface imaging with a light-emitting diode. METHODS: The 3D imaging analysis of 40 Korean women who underwent structured nonsurgical rhinoplasty was conducted. The 3D assessment was performed before, immediately after, 1 day, and 2 weeks after filler rhinoplasty with a Morpheus 3D scanner (Morpheus Co., Seoul, Korea). RESULTS: There were significant early changes in facial profile following nonsurgical rhinoplasty with a hyaluronic acid filler. An average increase of 6.03 degrees in the nasofrontal angle, an increase of 3.79 degrees in the nasolabial angle, increase of 0.88 degrees in the nasomental angle, and a reduction of 0.83 degrees in the nasofacial angle was observed at 2 weeks of follow-up. Increment in nasal volume and nose height was also found after 2 weeks. Side effects, such as hematoma, nodules, and skin necrosis, were not observed. CONCLUSION: The 3D surface imaging quantitatively demonstrated the early changes in facial profile after structured filler rhinoplasty. The study results describe significant acute spatial changes in nose shape following treatment. PMID- 28099203 TI - Evaluation of Gene Expression Patterns in Micrografts Demonstrate Induction of Catagen-Like Processes During Storage. AB - BACKGROUND: Alterations of gene expression patterns may contribute to the commonly observed transient reduction of hair shaft elongation in hair restoration surgery. OBJECTIVE: To elucidate the molecular causes, we evaluated changes in gene expression patterns in hair follicle micrografts during storage. MATERIALS AND METHODS: Micrografts with different amounts of adjacent connective tissue (regular, skinny, and chubby) were stored for different periods, and the expression of key genes was determined: dermal papilla (DP): FGF7, alkaline phosphatase (ALP), versican; outer root sheath: Krt15; inner root sheath: Krt 25; cuticula: Krt85; Henle layer: filaggrin; genes related to apoptosis and growth/differentiation: Caspase 3, Ovol1, and Foxo1. RESULTS: A significant decrease in FGF7 (4 * 10 fold) was observed after 4 hours, with further decrease after 48 hours. A significant decrease of versican (0.35 fold) and ALP (0.004 fold) was observed after 24 hours of storage. No differences relating to adjacent connective tissue were observed. No changes of different keratins genes or genes related to growth/differentiation and apoptosis were observed. CONCLUSION: These data clearly demonstrate a reduction in the specific function of cells in the DP, which seem to be the causative for the induction of hair follicle cycling during micrograft preparation and storage. PMID- 28099205 TI - The HDL cholesterol/apolipoprotein A-I ratio: an indicator of cardiovascular disease. AB - PURPOSE OF REVIEW: In multiple studies, the HDL cholesterol (HDL-C) concentration has been shown to be inversely associated with cardiovascular disease (CVD) and CVD risk. Based on this observation, increasing the plasma HDL-C concentration is thought to be a desirable strategy, in the 21st century, for decreasing the burden of CVD. RECENT FINDINGS: Recent studies have shown that powerful HDL-C concentration-increasing drugs are ineffective for decreasing CVD. Increasing evidence now shows that HDL is an unstable and heterogeneous particle, and that 'HDL particle functionality' is far more important in atheroprotection than is the HDL-C level, alone. Apolipoprotein A-I (apoA-I) is the major protein component of HDL, and increasing evidence suggests that the ratio of HDL-C to apoA-I may give additional insight as a risk marker not just for CVD but also for all-cause and cancer mortality. SUMMARY: In this review, we discuss the importance of HDL composition, apoA-I levels, and the HDL-C/apoA-I ratio for predicting CVD and mortality outcomes. PMID- 28099204 TI - Narrowing in on the anti-beta cell-specific T cells: looking 'where the action is'. AB - PURPOSE OF REVIEW: By necessity, the vast majority of information we have on autoreactive T cells in human type 1 diabetes (T1D) has come from the study of peripheral blood of donors with T1D. It is not clear how representative the peripheral autoreactive T-cell repertoire is of the autoreactive T cells infiltrating the islets in T1D. We will summarize and discuss what is known of the immunohistopathology of insulitis, the T-cell receptor repertoire expressed by islet-infiltrating T cells, and the autoreactivity and function of islet infiltrating T cells in T1D. RECENT FINDINGS: Recovery and analysis of live, islet-infiltrating T cells from the islets of cadaveric donors with T1D revealed a broad repertoire and proinflammatory phenotype of CD4 T-cell autoreactivity to peptide targets from islet proteins, including proinsulin, as well as CD4 T-cell reactivity to a number of post-translationally modified peptides, including peptides with citrullinations and hybrid insulin peptide fusions. Islet infiltrating CD8 T cells were also derived and required further isolation and characterization. SUMMARY: The recovery of live, islet-infiltrating T cells from donors with T1D, reactive with a broad range of known targets and post translationally modified peptides, allows for the specific functional analysis of islet-infiltrating T cells for the development of antigen-specific immunotherapies. PMID- 28099206 TI - Is a beta cell a beta cell? AB - PURPOSE OF REVIEW: This report examines recent publications identifying phenotypic and functional heterogeneity among pancreatic beta cells and investigating their potential roles in normal and abnormal islet function. The development of new methods and tools for the study of individual islet cells has produced a surge of interest in this topic. RECENT FINDINGS: Studies of beta cell maturation and pregnancy-induced proliferation have identified changes in serotonin and transcription factors SIX2/3 expression as markers of temporal heterogeneity. Structural and functional heterogeneity in the form of functionally distinct 'hub' and 'follower' beta cells was found in mouse islets. Heterogeneous expression of Fltp (in mouse beta cells) and ST8SIA1 and CD9 (in human beta cells) were associated with distinct functional potential. Several impressive reports describing the transcriptomes of individual beta cells were also published in recent months. Some of these reveal previously unknown beta cell subpopulations. SUMMARY: A wealth of information on functional and phenotypic heterogeneity has been collected recently, including the transcriptomes of individual beta cells and the identities of functionally distinct beta cell subpopulations. Several studies suggest the existence of two broad categories: a more proliferative but less functional and a less proliferative but more functional beta cell type. The identification of functionally distinct subpopulations and their association with type 2 diabetes underlines the potential clinical importance of these investigations. PMID- 28099207 TI - Could high-density lipoprotein cholesterol predict increased cardiovascular risk? AB - PURPOSE OF REVIEW: Serum high-density lipoprotein (HDL) is considered to be protective against cardiovascular disease. However, there is emerging evidence that under certain conditions the HDL molecule can become dysfunctional and proinflammatory, paradoxically leading to increased risk of cardiovascular disease. This review will provide a brief outline of the potential mechanisms by which HDL can become atherogenic and summarize some of the clinical evidence on this topic. RECENT FINDINGS: HDL metabolism, structure, and function in addition to its level can be profoundly altered under conditions of marked oxidative stress and chronic inflammation. These abnormalities, in turn, lead to impaired reverse cholesterol transport, increased systemic oxidative stress/inflammation, and endothelial dysfunction that subsequently may contribute to atherogenesis and progression of cardiovascular disease. SUMMARY: Association of serum HDL cholesterol level with outcomes is not only dependent on its serum concentration but also on the qualities/properties of this lipoprotein at a given point in time. Hence, it is essential that future studies examining association of HDL with risk of cardiovascular disease take into account the complexities of HDL metabolism and function and address the impact of the HDL particle as a whole (quantity as well as various properties) on atherosclerosis and cardiovascular outcomes. PMID- 28099208 TI - The upside down world of diabetes care medical economics and what we might do to improve it. AB - PURPOSE OF REVIEW: Increasingly over the past generation, the American healthcare delivery system has received consistently poor marks with regard to public health outcomes and costs. This review by two seasoned diabetes care providers is intended to shed light on the fundamental flaws we believe to underlie that poor performance, and suggest options for better outcomes and cost efficiencies. RECENT FINDINGS: Despite major advances in diabetes management medications and tools, overall public health with regard to diabetes outcomes remains poor. Efforts focused on controlling costs appear to be exacerbating the problem. SUMMARY: For chronic diseases like diabetes, fee-for-service care models are fundamentally flawed and predictably fail. We suggest that a major overhaul of the medical economics underlying diabetes care can improve patient outcomes and decrease costs. PMID- 28099209 TI - Functional neuroimaging in obesity. AB - PURPOSE OF REVIEW: The review examines recent advances in the use of functional neuroimaging to study human obesity, a field that is rapidly expanding and continues to be of paramount importance for a better understanding of the pathogenesis of this condition. With rising levels of obesity worldwide and limited therapeutic options, there is a great need for the development of new solutions that can benefit patients. RECENT FINDINGS: Studies that utilize functional neuroimaging are beginning to shed light on the nature of behavioral and neurocognitive dysfunctions previously identified in individuals with obesity. Significant progress has occurred in the study of reward-related processes, cognition-reward interactions, mechanisms of weight loss, genetic influences, and the case of obesity in children and adolescents. Research findings confirm that obesity and its related overeating behaviors are strongly associated with the brain, both at a regional level and a large-scale network level. SUMMARY: Functional neuroimaging studies bring unprecedented levels of detail to examine the brain basis of obesity, and show promise for the development of future brain-based biomarkers and interventions in this condition. PMID- 28099210 TI - Pazopanib, a promising option for the treatment of aggressive fibromatosis. AB - Desmoid tumour/aggressive fibromatosis (DT/AF) is a rare soft-tissue neoplasm that is locally aggressive but does not metastasize. There is no standard systemic treatment for symptomatic patients, although a number of agents are used. Tyrosine kinase inhibitors have recently been reported to show useful activity. We reviewed our bi-institutional (Royal Marsden Hospital, Cambridge University Hospitals) experience with the tyrosine kinase inhibitor pazopanib in the treatment of progressing DT/AF. Eight patients with DT/AF were treated with pazopanib at Royal Marsden Hospital and Cambridge University Hospitals between June 2012 and June 2016. The median age of the patients was 37.5 (range: 27-60) years. The median duration of pazopanib treatment was 12 (range: 5-22) months and for three patients the treatment is ongoing. Three patients discontinued treatment early (patient preference, intolerable toxicity and logistical reasons, respectively). None of the patients showed radiological progression while on treatment, best responses according to Response Evaluation Criteria In Solid Tumors 1.1 were partial response in 3/8 and stable disease in 5/8 cases. Six patients derived clinical benefit from treatment in terms of improved function and/or pain reduction. Median progression-free survival was 13.5 (5-36) months. Only one patient experienced intolerable toxicity (grade 3 hypertension) leading to early treatment discontinuation. In our series of patients with DT/AF, pazopanib demonstrated important activity both in terms of symptom control (75%) and absence of radiological progression (100%). Results of ongoing confirmatory trials are eagerly awaited. PMID- 28099213 TI - Hydroxychloroquine-Induced Erythema Multiforme. PMID- 28099214 TI - Rheumatoid Arthritis: Selecting Monotherapy Versus Combination Therapy. AB - The overall goal of therapy for patients with rheumatoid arthritis (RA) is to achieve low disease activity or remission and to prevent or control joint damage, prevent loss of function, and decrease pain. However, many patients with RA do not have the disease adequately controlled, and only a minority attain consistent remission. To successfully treat to target, rheumatologists need practical guidance to select monotherapy and combination therapy regimens based on available data. Differences in study design, dosing regimens, and data from defined and specific patient populations pose challenges to clinicians who treat patients with diverse characteristics and needs. Because clinical trial results are not always translated into real-life clinical practice, this article synthesizes evidence from all sources, including meta-analyses of clinical trial data, data from patient registries in RA, and results of pragmatic trial designs. Practical guidance with these strategies is demonstrated using application in patient case scenarios, which will enable rheumatology health care professionals to more easily compare the effectiveness and safety of RA treatment strategies as experienced in real-life practice settings. Combination therapy is important for most patients with RA; however, there remain no clear guidelines for selecting the most appropriate combination strategy. PMID- 28099215 TI - Prevalence and Severity of Depression and Anxiety in Patients With Systemic Sclerosis: An Epidemiologic Survey and Investigation of Clinical Correlates. AB - BACKGROUND: Systemic sclerosis (SSc) is a chronic multisystem connective tissue disorder with detrimental impact on quality of life. Patients with SSc face emotional distress and frequently meet criteria for a psychiatric disorder. However, the pattern of psychiatric manifestations may vary according to socioethnic background. OBJECTIVES: We investigated the prevalence of depressive and anxiety symptoms and examined their association with sociodemographic and clinical factors in Iranian SSc patients. METHODS: Depressive and anxiety symptoms were evaluated by Beck Depression Inventory and Cattell questionnaire in 114 SSc patients. The associations between sociodemographic and clinical factors and depressive/anxiety symptoms were examined via multivariate analysis. RESULTS: The prevalence of depressive symptoms was 68.4%. There was a significant association between depressive symptoms and pulmonary and gastrointestinal manifestations. Also, diffuse SSc patients were more prone to depressive symptoms. Mean Rodnan scores were significantly higher in patients with depressive symptoms in comparison with subjects with no depressive symptoms. The prevalence of anxiety symptoms was 23.6%. Anxiety symptoms were not associated with demographic characteristics, SSc subtype, disease duration, Rodnan score, other clinical features, and previous history of depression in the patients or their family. The coincidence of anxiety and depression was 82.8%. CONCLUSIONS: Depressive and anxiety symptoms are prevalent among Iranian SSc population. The depressive symptoms showed correlation with pulmonary and gastrointestinal involvement, as well as diffuse SSc subtype. PMID- 28099216 TI - A Rare Case of Amyopathic Juvenile Dermatomyositis Associated With Psoriasis Successfully Treated With Ustekinumab. PMID- 28099217 TI - Indirect Carotid-Cavernous Fistula Mimicking Scleritis. PMID- 28099218 TI - Perceptions in Rheumatoid Arthritis: Comparative Study Between Patients and Their Close Families. AB - OBJECTIVE: To compare perceptions of patients with rheumatoid arthritis (RA) to those of their families regarding pain and subjective experience of the disease. METHODS: It was a monocentric study, including 120 RA patients (according to the American College of Rheumatology criteria). The questionnaires were developed during meetings of RA patients, rheumatologists, and methodologists while referring to the literature. The patient questionnaire comprised 22 items organized in 4 sections: pain, perceived experience of the disease, activity restrictions, and help received. Concordance among patients, family, and friends replies was evaluated using the kappa coefficient. RESULTS: The mean age was 42 +/- 12 years with female predominance 110 (91.7%). The family member was usually the spouse (46.3%). Joint pain was described by patients as spontaneous (98.3%), unpredictable (95.9%), and variable (95.1%). RA had negatively affected work related activities (100%), recreational activities (98.4%), family life (87.6%), relationships with friends (77.7%), sexual activities (50.4%), plans for having children (47.1%), and intimate relationships (46.3%). Concordance between patients and family perceptions was mediocre for pain severity (kappa: 0.3) and main joint-pain characteristics, excellent for majority items of experience of the disease (kappa > 0.80). Family tended to underestimate pain severity and to overestimate negative effects of RA on patient's life. CONCLUSION: We found a good agreement between patients' and family members' perceptions. It is essential that any family support be in accordance with patients' needs. Our qualitative analysis objectified, in addition to a major physical impact of the disease, a negative psychosocial effect. PMID- 28099212 TI - Dysfunctional tear syndrome: dry eye disease and associated tear film disorders - new strategies for diagnosis and treatment. AB - Dysfunctional tear syndrome (DTS) is a common and complex condition affecting the ocular surface. The health and normal functioning of the ocular surface is dependent on a stable and sufficient tear film. Clinician awareness of conditions affecting the ocular surface has increased in recent years because of expanded research and the publication of diagnosis and treatment guidelines pertaining to disorders resulting in DTS, including the Delphi panel treatment recommendations for DTS (2006), the International Dry Eye Workshop (DEWS) (2007), the Meibomian Gland Dysfunction (MGD) Workshop (2011), and the updated Preferred Practice Pattern guidelines from the American Academy of Ophthalmology pertaining to dry eye and blepharitis (2013). Since the publication of the existing guidelines, new diagnostic techniques and treatment options that provide an opportunity for better management of patients have become available. Clinicians are now able to access a wealth of information that can help them obtain a differential diagnosis and treatment approach for patients presenting with DTS. This review provides a practical and directed approach to the diagnosis and treatment of patients with DTS, emphasizing treatment that is tailored to the specific disease subtype as well as the severity of the condition. PMID- 28099219 TI - A Review of the Clinical Utility of Intravascular Ultrasound and Optical Coherence Tomography in the Assessment and Treatment of Coronary Artery Disease. AB - Coronary artery disease remains one of the leading causes of morbidity and mortality in the United States. As a medical society, we continue to search for ways to better treat coronary artery disease and prevent acute coronary syndrome (ACS). As it stands, only statins and antiplatelet agents have been proven to significantly reduce the occurrence of ACS. A histopathological understanding of the pathogenesis of ACS has provided insight into the importance of plaque morphology. Therefore, it has been proposed that increasing the ability to detect true vulnerable, "at-risk" lesions, would foster the use of percutaneous coronary intervention as a means for the prevention of ACS. There are now several different imaging modalities to help cardiologists stratify plaque stability. These include, but are not limited to, angioscopy, magnetic resonance angiography, intravascular ultrasound (IVUS), optical coherence tomography (OCT), and near-infrared fluorescence. To date, the most studied and frequently used in clinical trials are IVUS and OCT. Following a brief background discussion of IVUS and OCT, we will objectively evaluate each modality's ability to detect specific morphological characteristics. This article will also discuss IVUS and OCT's clinical utility with regard to proper stent placement and follow-up after percutaneous coronary interventions. PMID- 28099220 TI - Evacetrapib: Another CETP Inhibitor for Dyslipidemia With No Clinical Benefit. AB - Evacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that has been recently studied as a cholesterol modifying agent to reduce cardiovascular risk and mortality in high risk cardiovascular disease patients. Evacetrapib acts to decrease lipid exchange through CETP inhibition. CETP acts to transfer cholesteryl esters from high-density lipoprotein-cholesterol (HDL-C) to low density lipoprotein cholesterol (LDL-C) and very-low-density lipoprotein (VLDL C). HDL-C is involved in reverse cholesterol transport and its blood levels have been shown to be inversely correlated with cardiovascular risk. Thus, a pharmacologic agent that can elevate HDL-C has been seen as an exciting area of research. In recent studies, evacetrapib was shown to be safe and efficacious. It produced an increase in HDL-C up to 128% and a 35% decrease in LDL-C, in comparison to placebo. In addition, evacetrapib was also shown to be more potent than previous CETP inhibitors. HDL-C particles treated with evacetrapib remained functional and had improved cholesterol efflux. A previously studied CETP inhibitor, torcetrapib, exhibited side effects of hyperaldosteronism, manifesting in electrolyte disturbances, and hypertension. These detrimental effects were not seen with evacetrapib. Recently, the results of evacetrapib's phase III ACCELERATE trial showed no significant reduction in major adverse cardiovascular events or mortality, and the drug will not be marketed. Although beneficial cholesterol effects were seen with this drug, more needs to be known to understand what role, if any, evacetrapib has in the reduction of cardiovascular risk. PMID- 28099221 TI - Practice Guidelines as Implementation Science: The Journal Editors' Perspective. PMID- 28099222 TI - A Users' Guide to the 2016 Surviving Sepsis Guidelines. PMID- 28099223 TI - Median Lingual Lymph Nodes: Prevalence on Imaging and Potential Implications for Oral Cavity Cancer Staging. AB - OBJECTIVE: This study sought to estimate the prevalence of median lingual lymph node (MLLN) metastases from oral cavity squamous cell carcinoma (OCSCC) and determine the frequency with which MLLNs can be identified with magnetic resonance imaging (MRI) in control subjects. METHODS: Pathology reports were used to identify patients with surgically treated OCSCC who underwent preoperative positron emission tomography-computed tomography to define the prevalence of MLLN metastases. As a control group, 500 consecutive face-neck MRIs from noncancer patients were reviewed for structures consistent with MLLNs. RESULTS: In the study group, 1 (0.95%) of 105 OCSCC cases demonstrated a single MLLN metastasis from a lateral tongue tumor (T4aN2c). The MLLN exceeded 1 cm in all planes and was abnormal in morphology. The frequency of suspected MLLNs in controls was 1.0%, with a maximum measurement of 0.9 cm. CONCLUSIONS: Median lingual lymph nodes are infrequently identified with MRI in controls, concordant with the low prevalence of metastases from OCSCC to this inconstant nodal group. PMID- 28099224 TI - Comparison of Model-Based Iterative Reconstruction, Adaptive Statistical Iterative Reconstruction, and Filtered Back Projection for Detecting Hepatic Metastases on Submillisievert Low-Dose Computed Tomography. AB - OBJECTIVE: The aim of the study was to compare the diagnostic performance of model-based iterative reconstruction (MBIR), adaptive statistical iterative reconstruction (ASIR), and filtered back projection (FBP) on submillisievert low dose computed tomography (LDCT) for detecting hepatic metastases. METHODS: Thirty eight patients having hepatic metastases underwent abdomen CT. Computed tomography protocol consisted of routine standard-dose portal venous phase scan (120 kVp) and 90-second delayed low-dose scan (80 kVp). The LDCT images were reconstructed with FBP, ASIR, and MBIR, respectively. Two readers recorded the number of hepatic metastases on each image set. RESULTS: A total of 105 metastatic lesions were analyzed. For reader 1, sensitivity for detecting metastases was stationary between FBP (49%) and ASIR (52%, P = 0.0697); however, sensitivity increased in MBIR (66%, P = 0.0035). For reader 2, it was stationary for all the following sets: FBP (65%), ASIR (68%), and MBIR (67%, P > 0.05). CONCLUSIONS: The MBIR and ASIR showed a limited sensitivity for detecting hepatic metastases in submillisievert LDCT. PMID- 28099225 TI - The Performance of Noncontrast Magnetic Resonance Angiography in Detecting Renal Artery Stenosis as Compared With Contrast Enhanced Magnetic Resonance Angiography Using Conventional Angiography as a Reference. AB - OBJECTIVE: The aims of this study were to evaluate the performance of noncontrast magnetic resonance angiography (NC MRA) for detecting renal artery stenosis (RAS) as compared with contrast-enhanced magnetic resonance angiography (CE MRA) and to evaluate the clinical feasibility, technical success rate, and performance of NC MRA for detecting RAS as compared with CE MRA. METHODS: Thirty-six subjects who underwent NC MRA and/or CE MRA were enrolled. Feasibility, technical success rate, and image quality scores were compared. Diagnostic ability was calculated using conventional angiography as a reference. RESULTS: Noncontrast MRA had higher feasibility and technical success rates than CE MRA did (100% and 97.2% vs 83.3% and 90%, respectively). Noncontrast MRA yielded significantly better image quality in motion artifact (P = 0.016). The diagnostic ability for detecting RAS is without significant difference between NC MRA and CE MRA. CONCLUSION: Although NC MRA and CE MRA demonstrated comparable ability in diagnosing RAS, NC MRA achieved better technical success rates, feasibility, and image quality in motion artifacts than CE MRA did. PMID- 28099226 TI - Computed Tomography in Cystic Fibrosis: Combining Low-Dose Techniques and Iterative Reconstruction. AB - OBJECTIVE: The aim of the study was to evaluate the impact of iterative reconstruction (IR) and low-kilovolt technique on dose reduction and image quality of chest computed tomography scans obtained in patients with cystic fibrosis (CF). METHODS: A total of 124 CF patients were examined; group A (n = 63) was examined with a dose reduction protocol using IR and group B (n = 61) with a standard protocol using filtered back projection. Further subgroups with tube voltage modulations were established. Quantitative and qualitative image quality was assessed. RESULTS: The radiation dose in groups with comparable image quality was approximately 40% lower using IR compared with filtered back projection. The IR protocol combined with 80-kV tube voltage showed adequate image quality with a mean effective dose of only 0.47 mSv. CONCLUSIONS: Iterative reconstruction helps extensively reduce radiation dose by improving image quality. It permits the use of low-kilovolt protocols without significantly degrading image reading ability in the monitoring of the predominantly young patients with CF. PMID- 28099228 TI - Transitioning to Second-line Antiretroviral Therapy Among Adolescents in Copperbelt Province, Zambia: Predictors of Treatment Switching and Adherence to Second-line Regimens. AB - BACKGROUND: Adolescents living with HIV (ALHIV) experience less favorable antiretroviral therapy (ART) outcomes than other age groups. First-line treatment failure complicates ART management as second-line regimens can be costlier and have greater pill burdens. Understanding predictors of switching ART regimens and adherence among adolescents on second-line ART may help to prevent poor treatment outcomes. METHODS: A quantitative survey was administered to 309 ALHIV attending 3 ART clinics in the Copperbelt Province, Zambia. Medical chart data, including pharmacy refill data, were abstracted. Associations between being on second-line ART and sociodemographic, psychosocial and ART adherence characteristics were tested. Cox proportional hazards models were used to estimate the effect of baseline ART variables on time to switching. RESULTS: Ten percent of participants were on second-line regimens. Compared with ALHIV on first-line ART, adolescents on second-line regimens were older (P = 0.02), out of school due to completion of secondary studies (P = 0.04) and on ART longer (P = 0.03). Adolescents on second line regimens were more likely to report missing >=48 consecutive hours of drugs in the last 3 months (P = 0.01). Multivariable analysis showed that adolescents who initiated ART with efavirenz-based regimens were more likely to switch to second-line than those put on nevirapine-based regimens (hazard ratio = 2.6; 95% confidence interval: 1.1-6.4). CONCLUSIONS: Greater support is needed for ALHIV who are on second-line regimens. Interventions for older adolescents that bridge the gap between school years and young adulthood would be helpful. More research is needed on why ALHIV who start on efavirenz-based regimens are more likely to switch within this population. PMID- 28099229 TI - Twenty-four-hour ambulatory blood pressure monitoring for clinical evaluation of hypertensive patients in primary care: which groups would most benefit? AB - BACKGROUND: Arterial hypertension is an important risk factor for cardiovascular outcomes. Blood pressure (BP) control levels remain largely out of target among primary healthcare (PHC) patients. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) may contribute toward the identification of cardiovascular risk groups. OBJECTIVE: To assess concordance between conventional office BP measurements and 24-h ABPM of hypertension control in cardiovascular risk groups of PHC hypertensive patients. PATIENTS AND METHODS: A cross-sectional study with 569 hypertensive patients was carried out. The evaluation of BP was performed by a PHC doctor, and the 24-h ABPM was performed by a different and blinded provider. The therapeutic targets for BP followed the guidance of The Eighth Joint National Committee, the Brazilian guideline, and the 2013 European Society of Hypertension. Considering the hypertension control therapeutic targets, the guidelines were not similar and were used to evaluate differences in BP value concordances compared with BP standard measurements. RESULTS: After a multivariate logistic regression analysis, a conventional BP was used in comparison with ABPM in different cardiovascular risk groups of hypertensive patients. According to the ABPM by European Society of Hypertension guideline, the subgroup of inactive patients (P=0.006), with altered glycemia (P=0.015) and over 30 mg/dl albuminuria (P=0.001), presented discordance among methods. When a conventional BP measurement in comparison with the ABPM results according to the Brazilian ABPM guideline was used, the discordance occurred significantly in inactive (P=0.001) and microalbuminuria more than 30 mg/dl (P=0.022) subgroups. However, in this comparison, a concordance between high-density lipoprotein more than 60 mg/dl (P=0.015) and obesity (P=0.035) subgroups occurred. CONCLUSION: Uncontrolled glucose levels, a sedentary lifestyle, and the presence of microalbuminuria correspond to some cardiovascular risk groups that would particularly benefit from 24-h ABPM as a tool for the control of BP with the PHC hypertensive patients of this study. PMID- 28099230 TI - Primary Orbital Chondromyxoid Fibroma: A Rare Case. AB - A 56-year-old male with history of chronic sinusitis was found to have a 3 cm left orbital lesion on CT. Subsequent MRI demonstrated a multilobulated enhancing soft tissue lesion at the superotemporal region of the left orbit. Initial biopsy was reported as a low-grade sarcoma. On further evaluation, a consensus was made that the lesion was likely a benign mixed mesenchymal type tumor but should nonetheless be surgically removed. Left lateral orbitotomy was performed which revealed a tumor originating in the lateral orbital bone with segments eroding through the wall of the orbit. Intraoperative frozen sections revealed myoepitheliod tissue with locally aggressive features and the tumor was completely removed. The final histopathologic analysis of the tissue was consistent with a chondromyxoid fibroma. Chondomyxoid fibroma is a rare entity in the orbital bones and is more commonly seen in long bones. PMID- 28099231 TI - Vemurafenib (BRAF Inhibitor) Therapy for Orbital Erdheim-Chester Disease. AB - Erdheim-Chester disease is a rare xanthogranulomatous systemic disease, which involves the orbit in some cases. Through this case report, the authors review the treatment modalities used in orbital Erdheim-Chester disease and explore a newer modality of treatment. Cases of orbital Erdheim-Chester disease were identified in the literature utilizing a PubMed search and all the treatment modalities were reviewed. The response to treatment of orbital Erdheim-Chester disease has been poor with the various medical and surgical treatment modalities used in the past. The authors report the use of BRAF inhibitor with a remarkable response in our case. PMID- 28099232 TI - Keratocystic Odontogenic Tumor Involving the Orbital Apex. PMID- 28099233 TI - Primary Outcome Measures in Pediatric Septic Shock Trials: A Systematic Review. AB - OBJECTIVE: To evaluate all published pediatric randomized controlled trials of patients with septic shock from any cause to examine the outcome measures used, the strengths and limitations of these measurements and whether the trial outcomes met feasibility criteria. DATA SOURCES: We used a previously published database of pediatric critical care randomized controlled trials (PICUtrials.net) derived from searches of MEDLINE, EMBASE, LILACS, and CENTRAL. STUDY SELECTION: We included randomized controlled trials of interventions to children admitted to a PICU with septic or dengue hemorrhagic shock which were published in English. DATA EXTRACTION: Study characteristics and outcomes were retrieved by two independent reviewers with disagreement being resolved by a third reviewer. We defined feasibility as 1) recruitment of at least 90% of the targeted sample size and agreement of the observed outcome rate in the control group with the rate used for the sample size calculation to within 10% or 2) finding of a statistically significant difference in an interim or final analysis. DATA SYNTHESIS: Nineteen of 321 identified articles were selected for review. Fourteen of 19 studies (74%) provided an a priori definition of their primary outcome measure in their "Methods section." Mortality rate was the most commonly reported primary outcome (8/14; 57%), followed by duration of shock (4/14; 29%) followed by organ failure (1/14; 7%). Only three of 19 included trials met feasibility criteria. CONCLUSIONS: Our review found that use of mortality alone as a primary outcome in pediatric septic shock trials was associated with significant limitations and that long-term patient-centered outcomes were not used in this setting. Composite outcomes incorporating mortality and long-term outcomes should be explored for use in future pediatric septic shock trials. PMID- 28099235 TI - Serum Levels of Cardiotroponin I in Burn Patients and Its Relation to Outcome of the Disease. PMID- 28099234 TI - Electrographic Seizures in Children and Neonates Undergoing Extracorporeal Membrane Oxygenation. AB - OBJECTIVE: We aimed to determine the prevalence and risk factors for electrographic seizures in neonates and children requiring extracorporeal membrane oxygenation support. DESIGN: Prospective quality improvement project. SETTING: Quaternary care pediatric institution. PATIENTS: Consistent with American Clinical Neurophysiology Society electroencephalographic monitoring recommendations, neonates and children requiring extracorporeal membrane oxygenation support underwent clinically indicated electroencephalographic monitoring. INTERVENTIONS: We performed a 2-year quality improvement study from July 2013 to June 2015 evaluating electrographic seizure prevalence and risk factors. MAIN RESULTS: Ninety-nine of 112 patients (88%) requiring extracorporeal membrane oxygenation support underwent electroencephalographic monitoring. Electrographic seizures occurred in 18 patients (18%), of whom 11 patients (61%) had electrographic status epilepticus and 15 patients (83%) had exclusively electrographic-only seizures. Electrographic seizures were more common in patients with low cardiac output syndrome (p = 0.03). Patients with electrographic seizures were more likely to die prior to discharge (72% vs 30%; p = 0.01) and have unfavorable outcomes (54% vs 17%; p = 0.004) than those without electrographic seizures. CONCLUSIONS: Electrographic seizures occurred in 18% of neonates and children requiring extracorporeal membrane oxygenation support, often constituted electrographic status epilepticus, and were often electrographic-only thereby requiring electroencephalographic monitoring for identification. Low cardiac output syndrome was associated with an increased risk for electrographic seizures. Electrographic seizures were associated with higher mortality and unfavorable outcomes. Further investigation is needed to determine whether electrographic seizures identification and management improves outcomes. PMID- 28099236 TI - Intratracheal Instillation of Perfluorohexane Modulates the Pulmonary Immune Microenvironment by Attenuating Early Inflammatory Factors in Patients With Smoke Inhalation Injury: A Randomized Controlled Clinical Trial. AB - Smoke inhalation injury (SII) is associated with significant morbidity and mortality in burn patients, and effective treatments are lacking. Perfluorocarbons (PFCs) have a protective effect against acute lung injury. We aimed to assess the therapeutic effects of perfluorohexane on burn patients with SII. Patients with burns complicated by moderately severe SII were randomly divided into control (n = 11) and PFC groups (n = 12). The control group received conventional treatment (anti-infection, nutritional support, antishock measures, and supportive treatment). The PFC group received endotracheal perfluorohexane instillation in addition to conventional treatment. On admission and 3 days later, therapeutic effects were evaluated and inflammatory mediators in bronchoalveolar lavage fluid and plasma were analyzed. There was no significant difference between the control and PFC group on admission. After 3 days, perfluorohexane treatment significantly (P < .05) increased lung dynamic compliance, and reduced alveolar-arterial oxygen gradient, Acute Physiology and Chronic Health Evaluation II score, percentage of neutrophils, and levels of interleukin-6, interleukin-8, and tumor necrosis factor alpha in bronchoalveolar lavage fluid; there was no significant change in the control group before and after treatment. Intratracheal instillation of perfluorohexane modulates the pulmonary immune microenvironment and supplements current conventional treatments for burn patients with SII. PMID- 28099237 TI - Lower-Limb Muscular Strength, Balance, and Mobility Levels in Adults Following Severe Thermal Burn Injuries. AB - Severe burn injuries are associated with hypermetabolic response and increased catabolism. These lead to a vast loss of muscle mass and reduced muscle strength and function. Therefore, the aim of this study is to determine the impact of severe burn injuries on lower-limb muscular strength, balance, and mobility level in adults. Forty burned adults with burned TBSA (burned TBSA) >=40% participated in this study. The peak torque and total work of quadriceps and knee flexors were calculated at 150 degrees /sec using Biodex isokinetic dynamometer. Balance and mobility were tested via the Biodex balance device and the high mobility assessment tool, respectively. Twenty-three matched nonburned healthy adults were evaluated and served as a control group. Severely burned adults exhibited significantly lower peak torque and total work in their quadriceps (27.50 and 22.58%, P < .05) and knee flexors (23.72, and 21.65%, P < .05) relative to the nonburned adults. Burned adults had a significant decrease in stability index and balance including the dynamic limits of stability (P < .05). The high mobility assessment tool scores were significantly lower (42 +/- 7.64, P < .05) when compared with control subjects (51 +/- 1.62). Patients who had severe burns (burned TBSA >= 40%) showed muscular weakness, limited balance, and mobility levels between 16 and 24 weeks after discharge from the hospital compared with matched nonburned control subjects. These results can guide therapists in creating rehabilitation programs that focus on the specific difficulties faced by burned patients. PMID- 28099238 TI - Evaluation of the New North Carolina Burn Registry. AB - High-quality burn registries can facilitate best practices in burn treatment, patient education, and research. A new burn registry was designed and implemented at the North Carolina Jaycee Burn Center in June 2013. The primary goals for the design of the new North Carolina (NC) burn registry were to improve reporting to the American Burn Association's National Burn Repository while maintaining current functionality and preserving previously collected data. The objective of this evaluation was to review the literature for best practices in designing a disease registry, benchmark the design of the NC burn registry with the best practices identified in the literature, and compare data quality before and after implementation of the new NC burn registry. The NC burn registry was evaluated using six measurable elements identified from essential indicators of the Agency for Healthcare Research and Quality user's guide for design, implementation, analysis, interpretation, and quality evaluation of registries. These elements were achieving objectives, using literature to inform the choice of data elements, improving completeness of information, employing consistency checks, providing clear, operational definitions of outcomes and other data elements, and minimizing active data collection. Five of the six chosen essential elements were found to have been met during the evaluation of the new NC burn registry. One essential element, improving completeness of information, had mixed results. The new NC burn registry improved reporting to the National Burn Repository while maintaining current functionality and preserving previously collected data. PMID- 28099239 TI - Jewelry Ring-Associated Electrothermal Burn Injuries: A Nine-Patient Case Series. AB - Ring-associated burns are infrequent, comprising only a small fraction of burn consults and admissions. However, because of the location of these burns and the propensity for circumferential wounds, small burn size may belie the severity of resultant injuries. Herein, the authors present their experience with this potentially severe type of burn. Records from a regional burn center were retrospectively analyzed during a 36-month period. All patients who sustained ring burns were included. Data points included demographics, burn location, need for surgical intervention, grafted area, hospital days (length of stay), percent graft take, complications, and time to re-epithelialization. Nine patients sustained ring-associated burns during the study period, accounting for 1.4% of all patients with burns seen during the same period. Average age was 41 years (range: 29-52 years). Seven (77%) ring-associated burns involved contact with a battery. All injuries were circumferential. Average burn TBSA was 0.07%. Two patients (22%) had third-degree injuries, both of which received split-thickness skin grafts. Grafted area was 4 and 5 cm, respectively. Average length of stay was 2.8 days. Mean graft take was 99.5 +/- 1.5%. Average time to complete re epithelialization was 12 days. One patient suffered temporary disability. No patients suffered from compartment syndrome. Ring-associated burns are an uncommon source of injury in the burn population. Despite small burn TBSA, these patients are more likely to require split-thickness skin grafts and suffer dysfunction compared with similarly-sized burns in other body regions. Expedient treatment and coordination with occupational therapy should be undertaken to achieve optimal outcomes. PMID- 28099240 TI - Inter-relationship of Soft Contact Lens Diameter, Base Curve Radius, and Fit. AB - PURPOSE: To evaluate the inter-relationship of soft contact lens base curve radius (BC), diameter, and lens fit using a mathematical model. METHODS: A spreadsheet mathematical model was used to evaluate theoretical fitting characteristics for various combinations of soft lens BC and diameter. The designs were evaluated using ocular topography data collected from 163 UK subjects. The model evaluated lens tightness (edge strain) and on-eye diameter (horizontal corneal overlap) and assumed that acceptable values fell within the range 0 to 6% and 0.2 to 1.2 mm, respectively. Analyses were undertaken of various trends relating to soft lens fit, including (1) the effect of BC and diameter on fitting success; (2) the effect of lens asphericity, BC, and sag on lens diameter on the eye; and (3) the effect of lens diameter on lens tightness. RESULTS: The highest overall success rate (90.2%) was achieved with an 8.60/14.2 mm (BC/diameter) design. Using this design on the sample population, the median edge strain value was 3.2% (IQR: 2.1%) whereas median corneal overlap was 0.62 mm (IQR: 0.35). There was a positive correlation (r = 0.37, P < .0001) between edge strain and corneal overlap. Edge strain showed significant correlations with each of the ocular topography variables, most notably corneal asphericity (-0.62, P < .0001). Corneal overlap showed significant correlations with corneal asphericity (r = -0.42, P < .0001) and corneal diameter (r = 0.92, P < .0001). For a 0.4 mm change in BC, it is necessary to change diameter by 0.2 mm to maintain similar on eye diameter (arclength). When changing lens diameter, a change in BC of 0.2 mm is required to maintain similar tightness of fit. CONCLUSIONS: Mathematical modeling is a useful technique for large-scale evaluation of the interactions of soft contact lens design and fit. The study has given useful insights into the general performance of soft lens designs. PMID- 28099241 TI - fMRI with Central Vision Loss: Effects of Fixation Locus and Stimulus Type. AB - PURPOSE: In patients with central visual field scotomata, a large part of visual cortex is not adequately stimulated. Patients often use a new eccentric fixation area on intact peripheral retina ("preferred retinal locus"-PRL) that functions as a pseudo-fovea. We used functional magnetic resonance imaging (fMRI) to examine whether stimulating this pseudo-fovea leads to increased activation or altered activation patterns in visual cortex in comparison to stimulating a comparable peripheral area in the opposite hemifield (OppPRL). METHODS: Nineteen patients with binocular central scotomata caused by hereditary retinal dystrophies and an age-matched control group were tested. The center of the visual field, PRL, and OppPRL were stimulated with flickering checkerboard stimuli and object pictures during fMRI measurement. RESULTS: Results show that stimulation with pictures of everyday objects led to overall larger BOLD (blood oxygen level dependent) responses in visual cortex compared to that evoked by stimulation with flickering checkerboards. Patients showed this enhancement as early as in V1. When the PRL was directly stimulated with object pictures, the central representation area in early visual cortex was coactivated in the patients but not in the controls. In higher visual areas beyond retinotopic cortex, BOLD responses to stimulation of the PRL with object pictures were significantly enhanced in comparison to stimulation of the OppPRL area. Highly stable eccentric fixation with the PRL was associated with a higher BOLD signal in visual cortex in patients, and this effect was most pronounced in the conditions with object picture stimulation. CONCLUSIONS: The observed results suggest that naturalistic images are more likely to trigger top-down processes that regulate activation in early visual cortex in patients with central vision loss. PMID- 28099242 TI - Acquired Bronchoesophageal Fistula and Gastroesophageal Junction Mass. PMID- 28099243 TI - Supraclavicular Brachial Plexus Block in the Presence of a Cervical Rib. PMID- 28099244 TI - Presepsin (sCD14-ST) Is a Novel Marker for Risk Stratification in Cardiac Surgery Patients. AB - BACKGROUND: Presepsin (soluble cluster-of-differentiation 14 subtype [sCD14-ST]) is a humoral risk stratification marker for systemic inflammatory response syndrome and sepsis. It remains unknown whether presepsin can be used to stratify risk in elective cardiac surgery. The authors therefore determined the usefulness of presepsin for risk stratification in patients having elective cardiac surgery. METHODS: Eight hundred fifty-six cardiac surgical patients were prospectively studied. Preoperative plasma concentrations of presepsin, procalcitonin, N terminal pro-hormone natriuretic peptide, cystatin C, and the additive European System of Cardiac Operative Risk Evaluation 2 were compared to mortality at 30 days (primary outcome), 6 months, and 2 yr. Discrimination was assessed with C statistic. Logistic regression analysis was used to calculate univariable and multivariable odds ratios. RESULTS: Thirty-day mortality was 3.2%, 6-month mortality was 6.1%, and 2-yr mortality was 10.4% across the population. Median preoperative presepsin concentrations were significantly greater in 30-day nonsurvivors than in survivors: 842 pg/ml (interquartile range, 306 to 1,246) versus 160 pg/ml (interquartile range, 122 to 234); difference, 167 pg/ml (interquartile range, 92 to 301; P < 0.001). The results were similar for 6-month and 2-yr mortality. Compared to the European System of Cardiac Operative Risk Evaluation 2, presepsin concentration provided better discrimination for postoperative mortality at all follow-up periods, including 30 days (C statistic 0.88 vs. 0.74), 6 months (0.87 vs. 0.76), and 2 yr (0.81 vs. 0.74). Presepsin also provided better discrimination than cystatin C, N-terminal pro-hormone natriuretic peptide, or procalcitonin. Elevated presepsin remained an independent risk predictor after adjustment for potential confounding factors. CONCLUSIONS: Elevated preoperative plasma presepsin concentration is an independent predictor of postoperative mortality in elective cardiac surgery patients and is a stronger predictor than several other commonly used assessments. PMID- 28099245 TI - Ketamine: A Drug at War with Itself. PMID- 28099246 TI - Paradoxical Emergence: Administration of Subanesthetic Ketamine during Isoflurane Anesthesia Induces Burst Suppression but Accelerates Recovery. AB - BACKGROUND: Promoting arousal by manipulating certain brain regions and/or neurotransmitters has been a recent research focus, with the goal of trying to improve recovery from general anesthesia. The current study tested the hypothesis that a single subanesthetic dose of ketamine during isoflurane anesthesia would increase cholinergic tone in the prefrontal cortex and accelerate recovery. METHODS: Adult male rats were implanted with electroencephalography electrodes (frontal, parietal, and occipital cortex) and a microdialysis guide cannula targeted for the prefrontal cortex. After establishing general anesthesia with isoflurane, animals were randomly assigned to receive a saline control or ketamine injection. When isoflurane was discontinued nearly 90 min after drug or saline administration, recovery from anesthesia was measured by experimenters and blinded observers. During the entire experiment, electrophysiologic signals were recorded and acetylcholine was quantified by high-performance liquid chromatography with electrochemical detection. RESULTS: A single dose of subanesthetic ketamine caused an initial 125% increase in burst suppression ratio (last isoflurane sample: 37.48 +/- 24.11% vs. isoflurane after ketamine injection: 84.36 +/- 8.95%; P < 0.0001), but also a significant 44% reduction in emergence time (saline: 877 +/- 335 s vs. ketamine: 494 +/- 108 s; P = 0.0005; n = 10 per treatment). Furthermore, ketamine caused a significant 317% increase in cortical acetylcholine release (mean after ketamine injection: 0.18 +/- 0.16 pmol vs. ketamine recovery: 0.75 +/- 0.41 pmol; P = 0.0002) after isoflurane anesthesia was discontinued. CONCLUSIONS: Administration of subanesthetic doses of ketamine during isoflurane anesthesia increases anesthetic depth but paradoxically-accelerates the recovery of consciousness, possibly through cholinergic mechanisms. PMID- 28099247 TI - Images in Anesthesiology: Hypercoagulability during Resternotomy for Prosthetic Valve Endocarditis. PMID- 28099248 TI - Overexpression of YKL-40 Predicts Poor Prognosis in Patients Undergoing Curative Resection of Pancreatic Cancer. AB - OBJECTIVES: The aim of this study was to determine the prognostic value of YKL-40 expression in patients undergoing curative resection of pancreatic cancer. METHODS: This cohort study included 234 consecutive patients with pancreatic ductal adenocarcinoma who underwent curative resection. Surgical specimens were immunohistochemically assessed for YKL-40 expression. Kaplan-Meier method and Cox regression were used to evaluate the prognostic impact of YKL-40 expression. A multivariate logistic regression model was performed to examine the correlation between YKL-40 expression and tumor stage. RESULTS: Of the 234 patients, YKL-40 overexpression was detected in 149 (63.7%) patients. Survival curves showed that patients with YKL-40 overexpression had significantly shorter survival time than those with low YKL-40 expression (P < 0.001). Cox regression analysis indicated that YKL-40 expression was an independent prognostic factor for both overall survival (hazard ratio, 3.82; 95% confidence interval [CI], 2.38-6.13) and progression-free survival (hazard ratio, 3.73; 95% CI, 2.33-5.99). Multivariate logistic regression analysis demonstrated that YKL-40 overexpression was an independent predictor for advanced tumor stage (odds ratio 4.15; 95% CI, 1.35 12.71). CONCLUSIONS: YKL-40 overexpression predicts poor prognosis and advanced tumor stage in patients undergoing curative resection of pancreatic cancer. Application of adjuvant treatment targeting the YKL-40 pathway may improve prognosis. PMID- 28099249 TI - Immunohistochemical Antibody Panel for the Differential Diagnosis of Pancreatic Ductal Carcinoma From Gastrointestinal Contamination and Benign Pancreatic Duct Epithelium in Endoscopic Ultrasound-Guided Fine-Needle Aspiration. AB - OBJECTIVES: The diagnosis of pancreatic ductal adenocarcinoma (PDAC) by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) can be challenging to distinguish tumor cells from benign epithelium (BE). The aim of the present study was to set a minimal antibody panel to differentiate PDAC from contaminated BE in EUS-FNA specimens. METHODS: Immunohistochemistry using claudin 4, EZH2, Ki 67, maspin, p53, and S100P was performed on tissue microarray sections containing 53 PDACs and 33 BE as well as cell blocks of EUS-FNA including 53 PDACs and 22 BE. The positive rate was scored as 0 to 4+. The receiver operating characteristic curve was applied to determine a cutoff point, and the Classification And Regression Trees method was used to obtain a classification tree of the best panel. RESULTS: The cutoff point was 1+ for claudin 4, EZH2, Ki 67, p53, and S100P and 2+ for maspin. All BE scored 0 for p53. The classification tree revealed using p53, S100P, and claudin 4 was the most powerful. The sensitivity and specificity of the tree were 96.2% and 100% in tissue microarrays and 100% and 95.5% in EUS-FNA, respectively. CONCLUSIONS: The classification tree using p53, S100P, and claudin 4 seems to successfully distinguish PDAC from the accompanying BE. PMID- 28099250 TI - Interleukin-36alpha Induces Inflammatory Mediators From Human Pancreatic Myofibroblasts Via a MyD88 Dependent Pathway. AB - OBJECTIVES: Interleukin-36 (IL-36) is a recently described proinflammatory cytokine, characterized by the induction of inflammatory mediators. In the present study, we investigated the biological activity and the signal transduction of IL-36alpha in human pancreatic myofibroblasts. METHODS: The mRNA and protein expression of inflammatory mediators was evaluated using real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The expression of IL-36alpha and its receptor in the pancreatic tissue was evaluated using immunohistochemical technique. Intracellular signaling pathways were evaluated using immunoblotting and specific small interference RNA transfected cells. RESULTS: Interleukin-36alpha and its receptor complex IL 36R/IL-1RAcP were detected in fibrotic tissue of chronic pancreatitis. Interleukin-36alpha dose- and time-dependently induced the mRNA expression and protein secretion of CXCL1, CXCL8, MMP-1, and MMP-3 from human pancreatic myofibroblasts. Interleukin-36alpha assembled MyD88 adaptor proteins (MyD88, TRAF6, IRAK1, and TAK1) into a complex. Furthermore, IL-36alpha induced the phosphorylation of mitogen-activated protein kinases and the activation of nuclear factor kappaB and activator protein 1. Mitogen-activated protein kinase inhibitors and small interference RNAs specific for nuclear factor kappaB and activator protein 1 significantly suppressed the protein secretion of inflammatory mediators induced by IL-36alpha stimulation. CONCLUSIONS: It was suggested that IL-36alpha plays an important role in the pathophysiology of inflammation and fibrosis in the pancreas via an autocrine function. PMID- 28099251 TI - Utility of Assessing the Number of Mutated KRAS, CDKN2A, TP53, and SMAD4 Genes Using a Targeted Deep Sequencing Assay as a Prognostic Biomarker for Pancreatic Cancer. AB - OBJECTIVES: KRAS, CDKN2A, TP53, and SMAD4 have been recognized as major driver genes in pancreatic carcinogenesis. We examined somatic mutations in 50 cancer related genes, including the four above-mentioned driver genes, to identify genomic biomarkers for predicting the outcome of patients with pancreatic cancer. METHODS: Genomic DNA was extracted from fresh-frozen specimens obtained from 100 patients with pancreatic cancer who had undergone a pancreatectomy with curative intent. The mutation profile was obtained using a single targeted deep sequencing assay performed with a next-generation sequencer, and the associations with clinicopathological factors were analyzed. RESULTS: Mutations in the KRAS, CDKN2A, TP53, and SMAD4 genes were detected in 96% (96/100), 42% (42/100), 13% (13/100), and 7% (7/100) of all patients, respectively. Among the 71 patients who underwent a radical operation followed by adjuvant chemotherapy, patients with fewer mutations among the four driver genes tended to have a better outcome. A multivariate analysis using the Cox proportional hazard model showed that the presence of 0 to 2 mutated driver genes was an independent predictor of a better overall survival (hazard ratio for death, 0.20; P = 0.0040). CONCLUSIONS: The number of mutated driver genes assessed using a targeted deep sequencing assay was a promising prognostic biomarker for pancreatic cancer. PMID- 28099252 TI - The Role of Pancreatic Enzyme Replacement Therapy in Unresectable Pancreatic Cancer: A Prospective Cohort Study. AB - OBJECTIVES: Although patients with pancreatic cancer (PC) are prone to exocrine pancreatic insufficiency, there are little evidence about pancreatic enzyme replacement therapy (PERT) in patients with PC, especially those receiving chemotherapy. METHODS: This is a prospective consecutive observational study of PERT in patients with unresectable PC. We prospectively enrolled patients receiving chemotherapy for unresectable PC from April 2012 to February 2014 and prescribed oral pancrelipase of 48,000 lipase units per meal (pancrelipase group). N-benzoyl-tryrosyl para-aminobenzoic acid test was performed at baseline. Patients receiving chemotherapy before April 2012 were retrospectively studied as a historical cohort. Data on the nutritional markers at baseline and 16 weeks were extracted, and serial changes, defined as the ratio of markers at 16 weeks/baseline, were compared between 2 groups. RESULTS: A total of 91 patients (46 in the pancrelipase group and 45 in the historical cohort) were analyzed. N benzoyl-tryrosyl para-aminobenzoic acid test was low in 94% of the pancrelipase group. Serial change in the pancrelipase group versus historical cohort was 1.01 versus 0.95 in body mass index (P < 0.001) and 1.03 versus 0.97 in serum albumin (P = 0.131). CONCLUSIONS: The rate of exocrine pancreatic insufficiency in unresectable PC was high, and PERT can potentially improve the nutritional status during chemotherapy. PMID- 28099253 TI - Smoking Status and the Incidence of Pancreatic Cancer Concomitant With Intraductal Papillary Mucinous Neoplasm. AB - OBJECTIVES: The effect of smoking status on the incidence of pancreatic ductal adenocarcinoma (PDAC) concomitant with intraductal papillary mucinous neoplasm (IPMN) has not been clarified. This study investigated the association of smoking status with PDAC concomitant with IPMN. METHODS: The subjects were 124 consecutive patients undergoing resection of IPMNs (intraductal papillary mucinous adenoma (IPMA): N = 77, invasive IPMN: N = 31, and PDAC with IPMN: N = 16) between April 2008 and October 2015. The associations between smoking status (never/former/current smoker) or cumulative pack-years (0-19/20-39/>=40) and the incidence of PDAC concomitant with IPMN or invasive IPMN were evaluated. RESULTS: Current smoking, not former smoking, was associated with the incidence of PDAC concomitant with IPMN (PDAC with IPMN vs IPMN alone; P = 0.004, PDAC with IPMN vs IPMA; P = 0.004, PDAC with IPMN vs invasive IPMN; P = 0.04, respectively), but not that of invasive IPMN (invasive IPMN vs IPMA; P = 0.85). Cumulative pack years were higher in patients who had PDAC concomitant with IPMN than in patients with invasive IPMN (P = 0.04). Cumulative pack-years were not associated with smoking status (current vs former). CONCLUSIONS: Current smoking, not former smoking, was associated with the incidence of PDAC concomitant with IPMN. Cessation of smoking may be recommended for patients with IPMN. PMID- 28099254 TI - Everolimus in Pancreatic Neuroendocrine Carcinomas G3. AB - OBJECTIVE: The aim of this study was to investigate everolimus efficacy in well moderately differentiated pancreatic NEC (pNEC) G3. METHODS: This was a retrospective analysis of patients with pNEC G3 and Ki67 20% to 55% treated with everolimus. RESULTS: Fifteen patients with median Ki67 30% and Eastern Cooperative Oncology Group performance status 0 to 1 were evaluated. Of these, 4 patients received everolimus as first-line treatment, whereas 11 had been pretreated with chemotherapy or peptide receptor radionuclide therapy. Median progression-free survival was 6 months, and median overall survival was 28 months. Eleven patients achieved disease stabilization (DS) at 3 month follow-up. Six patients (40%) maintained DS for at least 12 months. Three of 4 patients who received everolimus as first-line therapy had sustained DS (progression-free survival, 12, 17, and 22 months). The safety profile was consistent with that previously reported, with adverse events occurring in 9 patients (66.7%). CONCLUSIONS: This study suggests that everolimus is active in pNEC G3 with well moderately differentiated morphology and Ki67 less than 55%, in which more toxic systemic chemotherapy is, to date, the only available treatment. PMID- 28099255 TI - Effect of Combinatory Treatment With Resveratrol and Guggulsterone on Mild Acute Pancreatitis in Mice. AB - OBJECTIVES: This study was conducted to assess the preventive/therapeutic effects of combined administration of resveratrol and guggulsterone on cerulein-induced acute pancreatitis in mice. METHODS: Acute pancreatitis was induced by intraperitoneal injection of cerulein in mice. Serum amylase assay and histology were performed to measure the severity of pancreatitis. Western blotting and multiplex cytokine/chemokine analysis were conducted to understand the action mechanisms of the reagents. RESULTS: Serum amylase assay and histology revealed that the severity of acute pancreatitis was reduced by the combinatory treatment with resveratrol and guggulsterone, but the ratio of the band intensity implied that reduced nuclear factor-kappaB activation is primarily responsible for the effect. The reduced amounts of keratinocyte chemoattractant (chemokine [C-X-C motif] ligand 1), interferon gamma-induced protein 10 (C-X-C motif chemokine 10) and interleukin 6 expression in the sera could be involved in attenuated immune cell migration and reduced inflammation by these reagents. CONCLUSIONS: Combinatory treatment with resveratrol and guggulsterone marginally reduced cerulein-induced mild acute pancreatitis in mice. PMID- 28099256 TI - Diagnosis of Chronic Pancreatitis Incorporating Endosonographic Features, Demographics, and Behavioral Risk. AB - OBJECTIVES: Diagnosing chronic pancreatitis remains challenging. Endoscopic ultrasound (EUS) is utilized to evaluate pancreatic disease. Abnormal pancreas function test is considered the "nonhistologic" criterion standard for chronic pancreatitis. We derived a prediction model for abnormal endoscopic pancreatic function test (ePFT) by enriching EUS findings with patient demographic and pancreatitis behavioral risk characteristics. METHODS: Demographics, behavioral risk characteristics, EUS findings, and peak bicarbonate results were collected from patients evaluated for pancreatic disease. Abnormal ePFT was defined as peak bicarbonate of less than 75 mEq/L. We fit a logistic regression model and converted it to a risk score system. The risk score was validated using 1000 bootstrap simulations. RESULTS: A total of 176 patients were included; 61% were female with median age of 48 years (interquartile range, 38-57 years). Abnormal ePFT rate was 39.2% (69/176). Four variables formulated the risk score: alcohol or smoking status, number of parenchymal abnormalities, number of ductal abnormalities, and calcifications. Abnormal ePFT occurred in 10.7% with scores 4 or less versus 92.0% scoring 20 or greater. The model C-statistic was 0.78 (95% confidence interval, 0.71-0.85). CONCLUSIONS: Number of EUS pancreatic duct and parenchymal abnormalities, presence of calcification, and smoking/alcohol status were predictive of abnormal ePFT. This simple model has good discrimination for ePFT results. PMID- 28099258 TI - Patient Preferences for Management of Cystic Neoplasms of the Pancreas: A Cross Sectional Survey Study. AB - OBJECTIVE: The aim of this study was to determine how patient anxiety, knowledge, and cancer worry influence preferences for management of pancreatic cysts. METHODS: We performed a prospective, cross-sectional study using a disease specific survey instrument. We included patients older than 18 years who were diagnosed with a pancreatic cyst. A telephone survey instrument was developed to assess baseline anxiety using the Hospital Anxiety and Depression Scale (HADS), knowledge regarding pancreatic cysts, cancer worry, and patient preferences using a standard gamble. RESULTS: Of the 100 studied participants (median age, 65 years; 72% women), median Hospital Anxiety and Depression Scale score was 4 (normal range). In terms of knowledge, 96% of the patients were not aware of their specific cyst type, and 58% were unaware of the possibility of any cyst related malignancy. Overall, 8% of respondents had some degree of cancer worry. Respondents were more willing to undergo magnetic resonance imaging surveillance compared with endoscopic ultrasound or surgery. Knowledge of cyst type was a significant predictor of willingness to undergo invasive testing. CONCLUSIONS: There is a significant gap in patient knowledge with respect to pancreatic cysts. Greater emphasis on patient education can help patients make informed decisions regarding cyst management. PMID- 28099257 TI - Antifibrotic Effect of Saturated Fatty Acids via Endoplasmic Reticulum Stress Response in Rat Pancreatic Stellate Cells. AB - OBJECTIVES: We investigated the effect of saturated fatty acids on chronic pancreatitis pathogenesis by elucidating the endoplasmic reticulum (ER) stress response in pancreatic stellate cells (PSCs), which are major effector cells in pancreatic fibrosis. METHODS: Wistar Bonn/Kobori rats were fed either control diet or high-fat diet (HFD) for 4 weeks. Meanwhile, cultured rat PSCs were stimulated with thapsigargin, an ER stress inducer, or palmitic acid (PA). Pancreatic fibrosis, expressions of fibrosis-related and ER stress-related proteins and mRNA, cell viability, and apoptosis were examined. RESULTS: The HFD reduced fibrosis and alpha-smooth muscle actin expression (ie, activated PSCs) but upregulated ER stress-related mRNA expression in the pancreas of young HFD fed Wistar Bonn/Kobori rats. Induction of ER stress response in PSCs with thapsigargin or PA induced apoptosis, activated the protein kinase-like ER kinase (PERK) pathway, inhibited cell viability, and downregulated fibrosis-related protein and mRNA expression. The PERK inhibitor negated PA-induced ER stress response. CONCLUSIONS: Saturated fatty acids can inhibit but may not promote the fibrogenesis of chronic pancreatitis, at least in the early stage, via an ER stress response (ie, the PERK pathway) in PSCs. Moreover, induction of an apoptotic ER stress response in PSCs might be a novel therapeutic strategy for pancreatic fibrosis. PMID- 28099259 TI - Smad2/3 Linker Phosphorylation Is a Possible Marker of Pancreatic Stem/Progenitor Cells in the Regenerative Phase of Acute Pancreatitis. AB - OBJECTIVES: The aims of this study are to characterize cell proliferation and differentiation during regeneration after pancreatitis and pancreatic buds during development to evaluate the role of Smad2/3, phosphorylated at the specific linker threonine residues (pSmad2/3L-Thr) in positive cells. METHODS: Male C57BL/6 mice received hourly intraperitoneal injections of cerulein and were analyzed after induced pancreatitis. Pancreatitis-affected tissue sections and pancreatic buds were immunostained for pSmad2/3L-Thr, with other markers thought to be stem/progenitor markers of the pancreas. RESULTS: pSmad2/3L-Thr immunostaining-positive cells increased as the pancreatitis progressed. The expression of pSmad2/3L-Thr was seen in acinar cells and ductlike tubular complexes. These results suggest that pSmad2/3L-Thr is expressed during acinar ductal metaplasia. Immunohistochemical colocalization of pSmad2/3L-Thr with Ki67 was never observed. pSmad2/3L-Thr-positive cells may remain in an undifferentiated state. During the pancreatic development process, pSmad2/3L-Thr was expressed as other markers. pSmad2/3L-Thr develops in duct structure of the undifferentiated cell population in the last part of viviparity that acinar structure is formed clearly. CONCLUSIONS: pSmad2/3L-Thr expression occurs during acinar-ductal metaplasia after pancreatitis and may represent the contribution of stem cells and/or progenitor cells to the differentiation of the pancreas. PMID- 28099260 TI - Differentiation of Pancreatic Masses via Endoscopic Ultrasound Strain Ratio Elastography Using Adjacent Pancreatic Tissue as the Reference. AB - OBJECTIVES: The aims of this study were to evaluate diagnostic value of endoscopic ultrasound strain ratio elastography in patients with focal pancreatic masses and to determine the cutoff value between the pancreatic malignancies and inflammatory pancreatic masses using reference areas different than those used by other investigators. METHODS: In a prospective single-center study, strain ratio was measured in patients with pancreatic masses. After the diagnosis was established, statistical analysis was used to compare the group with pancreatic malignancies to the one with inflammatory masses. RESULTS: Strain ratio cutoff of 7.59 provided 100% sensitivity, 95% specificity, and 97% overall accuracy for differentiation of patients with pancreatic malignancies from those with inflammatory masses. CONCLUSIONS: Our data show high sensitivity and specificity for the calculated strain ratio. Adjacent normal pancreatic tissue is adequate as a reference area based on the inclusion criteria. Diverse cutoff values and standardization of methods in the studies published so far require further investigations, before the implementation of the method in a routine clinical practice becomes possible. PMID- 28099261 TI - Health Care Utilization and Costs Associated With Acute Pancreatitis. AB - OBJECTIVE: Acute pancreatitis is a common inpatient diagnosis among gastrointestinal disorders. The aim of this study was to evaluate the incidence of inpatient admissions, costs, and mortality rates associated with acute pancreatitis in the United States. METHODS: We analyzed the National Inpatient Sample for all patients in which acute pancreatitis (International Classification of Diseases, Ninth Revision code: 577.0) was the principal discharge diagnosis during the period 1997-2012. The statistical significance of the difference in the hospital discharges, length of stay, and costs over the study period was determined by utilization of regression analysis. RESULTS: In 1997, there were 164,776 admissions with a principal discharge diagnosis of acute pancreatitis as compared with 275,170 in 2012 (P < 0.001). The mean length of stay for acute pancreatitis decreased from 6.4 days in 1997 to 4.7 days in 2012 (P < 0.001). However, during this period, the mean hospital charges increased by 118.6% from $15,433 in 1997 to $33,744 in 2012 (P < 0.001). The in-hospital mortality rate decreased significantly from 1.9% in 1997 to 0.78% in 2012 (P < 0.001). CONCLUSIONS: Inpatient admissions for acute pancreatitis and associated costs have increased markedly over the last 16 years in the United States. However, the lengths of stay and mortality rates have decreased significantly. PMID- 28099262 TI - Angiotensin II Type 2 Receptor Activation With Compound 21 Augments Islet Function and Regeneration in Streptozotocin-Induced Neonatal Rats and Human Pancreatic Progenitor Cells. AB - OBJECTIVES: We investigated the effects of compound 21 (C21), a nonpeptide angiotensin II type 2 receptor agonist, on islet cell function and survival in streptozotocin (STZ)-treated neonatal rats and human pancreatic progenitor cells. METHODS: Neonatal rats were randomized into 5 groups, including a control, an STZ (100 mg/kg, intraperitoneally), and 3 STZ + C21 (0.25, 0.5, and 1 mg/kg per day for 7 days, intraperitoneally) groups. Body weight and blood glucose were monitored daily. On the last experimental day, serum insulin levels and glucose tolerance were assessed, and the rat pups' pancreata were extracted for examination of islet cell function/mass and involvement of signaling pathways. RESULTS: The C21-treated STZ rats, particularly in the 0.5- and 1 mg/kg-dosage groups, had significantly decreased blood glucose, increased serum insulin concentrations, higher glucose-stimulated insulin secretion activity, and greater islet-cell mass and up-regulated expression of insulin and Ngn3 in the pancreas than did the control groups; these rats also demonstrated increased beta-cell proliferation, lower superoxide levels and enhanced SOD1 expression, and up regulated phospho-AKT expression; consistently, similar results were also observed in human pancreatic progenitor cells. CONCLUSIONS: These data suggest that C21 has a beneficial effect on islet cell function and regeneration, probably via proliferative and antioxidative pathways. PMID- 28099263 TI - International Intraductal Papillary Mucinous Neoplasms Registry: Long-Term Results Based on the New Guidelines. AB - OBJECTIVE: The aim of this study was to analyze the outcomes of a long-term intraductal papillary mucinous neoplasm (IPMN) registry and evaluate new guidelines. METHODS: A prospectively maintained IPMN registry involving 6 centers in Europe and the United States was used to collect the data. Patients with more than 1-year follow-up and no malignancy diagnosed within the first 3 months of surveillance were included. RESULTS: From 1999 to 2014, 620 patients were included. The median follow-up time was 3 years. Thirty-seven (6%) patients developed malignancy with a median time from IPMN diagnosis to malignancy of 10.3 months. The 1-, 5-, and 10-year actuarial rates of disease-free survival were 97%, 93%, and 92% respectively. Four hundred thirty-one patients met criteria for low-risk branch duct IPMN consisting of cyst size less than 3 cm, with no solid component or main duct dilation. Eight malignancies were diagnosed in this subgroup, all of them within the first 5 years. From this subcohort, 112 patients had a follow-up time of more than 5 years, and no malignancy was diagnosed. CONCLUSIONS: In IPMN lesions with low-risk features at baseline, the risk of progression to malignancy after the first 5 years of follow-up was minimal. Furthermore, the main cyst characteristics remained unchanged during their surveillance. PMID- 28099264 TI - Post-treatment 18F-FDG-PET/CT versus contrast-enhanced CT in patients with oropharyngeal squamous cell carcinoma: comparative effectiveness study. AB - OBJECTIVE: To compare the accuracy of same-day therapy-assessment PET/computed tomography (PET/CT) and conventional contrast-enhanced computed tomography (CECT) in patients with oropharyngeal squamous cell carcinoma (OPSCC). METHODS: A total of 110 (95 men and 15 women; mean age 59 years) patients with biopsy-proven OPSCC were evaluated with same-day PET/CT and CECT pair scans as part of follow-up therapy assessment. Scans were performed within 6 months after the completion of primary treatment (median time: 3.1 months; range: 0.5-6 months). PET/CT and CECT scans were reviewed retrospectively for residual primary site disease, and right and left cervical lymph node involvement. Histopathology or 6 month clinical/imaging follow-up were used as the gold standard. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated for the primary site and cervical nodal disease. RESULTS: Of 110 OPSCC patients, 90.9% were human papilloma virus positive, 80.8% were stage 4, and 76.4% received chemoradiation as the primary treatment. The sensitivity, specificity, PPV, NPV, and accuracy of PET/CT and CECT were similar in the evaluation of the primary cancer site (PET/CT: 75.0, 91.5, 25.0, 99.0, and 90.9, respectively, versus CECT: 75.0, 90.6, 23.1, 99.0, and 90.0, respectively). In evaluating cervical lymph node involvement, PET/CT appeared to have higher accuracy (96.8 vs. 81.7%), specificity (97.7 vs. 81.7%), and PPV (45.8 vs. 16.5%), comparable NPV (99.4% for both), and lower sensitivity (65 vs. 75%) compared with same-day CECT. CONCLUSION: Same-day PET/CT and CECT scans had comparable accuracy in the evaluation of primary tumor sites after completion of therapy in patients with OPSCC. PET/CT showed higher accuracy in the evaluation of cervical lymph node involvement. PMID- 28099265 TI - Observer agreement of treatment responses on planar bone scintigraphy in prostate cancer patients: importance of the lesion assessment method. AB - PURPOSE: The aim of this study was to assess observer agreement on the evaluation of treatment responses of bone metastases by bone scintigraphy (BS) using different scoring methods in prostate cancer patients. PATIENTS AND METHODS: Sixty-three paired BS from 55 patients were included. BS was performed before and after more than 12 weeks of anticancer treatment. A panel of experienced nuclear medicine physicians from several institutions evaluated treatment response using three different methods: (a) standard clinical assessment, (b) MD Anderson criteria, and (c) Prostate Cancer Working Group 2 (PCWG-2) criteria. All methods were based on the evaluation of paired before-after bone scans. RESULTS: Readers were able to classify the presence of bone metastases at baseline with a high level of agreement [Cohen's kappa=0.94, 95% confidence interval (CI) 0.82-1.00]. Observer agreement on bone response by PCWG-2 criteria showed considerable agreement (Cohen's kappa=0.84, 95% CI: 0.69-0.99). Evaluation using standard clinical assessment and MD Anderson criteria showed moderate agreement (0.52, 95% CI: 0.36-0.69 and 0.64, 95% CI: 0.48-0.79, respectively). There was considerable variation among readers for regional lesion count on individual scans, with limits of agreement of -10 to 10 lesions or more for the majority of anatomical regions, including the thorax, spine, and pelvis. CONCLUSION: Observer agreement on treatment response by BS varied notably across methods. Optimal agreement was achieved by the PCWG-2 criteria. Variation in the classification of treatment response of bone metastases may have a significant impact on clinical decision making, emphasizing the need for a uniform approach, including during clinical practice. Response assessment by lesion counting on repeated BS without access to previous scans cannot be recommended. PMID- 28099266 TI - Posttraumatic Stress Disorder and Gastrointestinal Disorders in the Danish Population. AB - BACKGROUND: Evidence for the association between posttraumatic stress disorder (PTSD) and gastrointestinal (GI) disorders is mixed, owing in part to methodologic differences across studies. Furthermore, studies which have combined GI disorders or symptoms for examination as one overall category may potentially obscure associations between PTSD and individual GI diagnoses. METHODS: This nationwide cohort study examined the incidence of all major nonmalignant GI disorders in patients with a prior PTSD diagnosis (n = 4,076), compared with the general population incidence from 1995 to 2013, using Danish medical registry data. We examined differences by sex, age, marital status, psychiatric and somatic comorbidity, and follow-up time. Risks, standardized incidence rates (SIRs), and confidence intervals (95% CIs) were calculated. RESULTS: Risk of any GI disorder among PTSD patients was 25% (95% CI: 21%, 29%); the SIR for any GI disorder was 1.8 (95% CI: 1.7, 2.0). Risk and SIRs varied by disorder (e.g., no association with diverticula of the intestines [SIR: 1.1, 95% CI: 0.83, 1.5]; stronger association with peptic ulcer, site unspecified [SIR: 3.3, 95% CI: 1.8, 5.5]). Stratified analyses revealed that some associations were stronger for persons ages 16-39 or unmarried at PTSD diagnosis, persons with comorbid psychiatric diagnoses, and in the year following PTSD diagnosis. CONCLUSIONS: This study documents associations between clinician-diagnosed PTSD and all major nonmalignant GI disorders in an unselected nationwide cohort with long follow-up. Differences in associations across GI disorders and important modifiers may account for previous conflicting research findings. PMID- 28099267 TI - Measurement Error Correction for Predicted Spatiotemporal Air Pollution Exposures. AB - BACKGROUND: Air pollution cohort studies are frequently analyzed in two stages, first modeling exposure then using predicted exposures to estimate health effects in a second regression model. The difference between predicted and unobserved true exposures introduces a form of measurement error in the second stage health model. Recent methods for spatial data correct for measurement error with a bootstrap and by requiring the study design ensure spatial compatibility, that is, monitor and subject locations are drawn from the same spatial distribution. These methods have not previously been applied to spatiotemporal exposure data. METHODS: We analyzed the association between fine particulate matter (PM2.5) and birth weight in the US state of Georgia using records with estimated date of conception during 2002-2005 (n = 403,881). We predicted trimester-specific PM2.5 exposure using a complex spatiotemporal exposure model. To improve spatial compatibility, we restricted to mothers residing in counties with a PM2.5 monitor (n = 180,440). We accounted for additional measurement error via a nonparametric bootstrap. RESULTS: Third trimester PM2.5 exposure was associated with lower birth weight in the uncorrected (-2.4 g per 1 MUg/m difference in exposure; 95% confidence interval [CI]: -3.9, -0.8) and bootstrap-corrected (-2.5 g, 95% CI: 4.2, -0.8) analyses. Results for the unrestricted analysis were attenuated (-0.66 g, 95% CI: -1.7, 0.35). CONCLUSIONS: This study presents a novel application of measurement error correction for spatiotemporal air pollution exposures. Our results demonstrate the importance of spatial compatibility between monitor and subject locations and provide evidence of the association between air pollution exposure and birth weight. PMID- 28099268 TI - Vascular Nature and Existence of Anastomoses of Extrinsic Postauricular Fascia: Application for Staged Auricular Reconstruction. AB - A staged auricular reconstruction in microtia patients was developed by using superficial mastoid fascia (as part of extrinsic postauricular fascia) to cover the cartilagenous framework due to its highly vascularized nature. Three branches of external carotid artery (superficial temporal artery, posterior auricular artery and occipital artery) were found to supply this fascia, this study was therefore aimed to investigate the dimension of blood supply from each vessel and also to demonstrate the existence of anastomoses among these arteries. Thirty eight pinnas and postauricular fascias from Thai fresh adult cadavers were included to document the anastomoses by showing both perfused dye connection (10 dissections) and visible anastomotic branches (8 dissections) among them. Distribution of each vessel trunk and its branches were demonstrated using superimposed illustration in the other 20 dissections with dye injection into each artery to designate 3 zones of anastomotic area between each arterial pair. Maximal size of viable postauricular fascial flap for staged reconstruction according to this vascular study was thus estimated to be at least 5 cm above and 3 cm below the Frankfurt horizontal plane and about 6 cm posterior to external acoustic meatus owing to the course of posterior auricular artery and its anastomoses. In addition, greater size of flap with dual blood supply from both superficial temporal and posterior auricular arteries can be raised by harvesting beyond 5 cm above external acoustic meatus. PMID- 28099269 TI - Bilateral Leg Replantation in a 3-Month-Old Baby After a Knee Level Crush Amputation-A 2-Year Follow-up. AB - We present a case of a successful bilateral leg replantation in a 3-month-old baby after a knee-level crush amputation with the loss of both knee joints. The legs were replanted after 4 hours of warm and an additional 2.5 and 3.5 hours of cold ischemia time. Both legs show motor and sensory reinnervation, without additional procedures performed on the right leg, and after a nerve reconstruction with cadaveric allografts on the left leg. Both replanted legs exhibit excellent bony and soft tissue growth. Two years after the injury, the patient is progressing well with rehabilitation, with favourable odds of having knee reconstructions performed at a later age. This is the youngest patient reported to have had successful replantation of both legs. PMID- 28099270 TI - A Prospective Assessment of Surgical Risk Factors in 114 Gluteal Fold Flap Reconstructions After Oncological Vulvoperineal Resection. AB - BACKGROUND AND AIM: To date, clinically relevant selection criteria have not been established for the use of the gluteal fold flap after oncological vulvoperineal resection. We prospectively assessed the surgical risk factors of this reconstructive technique in a large series. METHODOLOGY: From April of 2000 through December of 2015, 114 gluteal fold flaps were used for vulvoperineal reconstruction after excision of (pre)malignant skin disorders in 75 women. The possible influence of 10 patient-related and 6 procedure-related risk factors on flap-related postoperative complications was statistically analyzed. RESULTS: We observed a major complication in 13 flaps (11%) and a minor complication in 19 flaps (17%). Previous radiotherapy (P = 0.01) was associated with significantly more complications, and a rotation flap design rather than VY advancement (P = 0.02) was associated with major complications. Recurrent disease, multifocal tumor localization, incomplete removal of tumor, and bilateral flap procedure were found to be clinically relevant risk factors, but not significantly so. The same applied to recurrence of disease during postoperative follow-up. CONCLUSIONS: We identified surgical risk factors for gluteal fold flap use after oncological vulvoperineal resection. These observations may potentially allow for more favorable future surgical outcomes by adaption of selection of patients or procedure. PMID- 28099271 TI - Innovative strategies for adverse karyotype acute myeloid leukemia. AB - PURPOSE OF REVIEW: Adverse karyotype acute myeloid leukemia is a disease particularly of older patients, but also observed in younger patients. Despite all efforts, standard chemotherapy is still generally applied in fit patients, as already for decades, and for nearly all different subtypes of acute myeloid leukemia. Lack of more specifically targeted therapy and the often older age of the patients are complicating treatment, and in the subgroup of patients achieving a complete remission, the strikingly high frequency of relapse is a characteristic of this disease. This review aims to give an overview of current treatment approaches as well as emerging therapies. RECENT FINDINGS: Currently, the approach of a targeted therapy specific to the genetic and/or epigenetic aberrations detected in the individual patient is still not possible, and a 'one treatment fits all' course of action is still used, with allografting as curative consolidation. However, first immunotherapeutic approaches are emerging as treatment options and first phase 1 and 2 studies are described. SUMMARY: Treatment of acute myeloid leukemia with adverse karyotype is still not individualized, most treatment options currently not being curative. This can change in the near future, but recent findings will have to be implemented into larger phase 3 studies before being standard of care. PMID- 28099272 TI - Mixed-phenotype acute leukemia: current challenges in diagnosis and therapy. AB - PURPOSE OF REVIEW: Mixed-phenotype acute leukemia (MPAL) is a rare disease that poses many diagnostic and therapeutic challenges. Patients with MPAL are considered to have poor outcomes. The difficulties in classifying this leukemia, the lack of prospectively collected data concerning therapeutic outcomes, and rare incidence result in much uncertainty as to the best approach for patients with MPAL. RECENT FINDINGS: Recent studies demonstrated that most MPALs are associated with cytogenetic abnormalities; genetic sequencing studies disclose a high frequency of somatic mutations in genes encoding epigenetic regulators, tumor suppressors, and transcription factors. The limited available data suggest that higher remission rates are achieved with acute lymphoblastic leukemia-like induction regimens compared with acute myeloid leukemia-type approaches. Allogeneic transplantation in first remission may be associated with improved survival compared with consolidation chemotherapy. SUMMARY: Advances in understanding the genetic landscape of MPAL may allow a more biologically driven classification of this heterogeneous group of leukemias in the future that will lead to optimized therapies for individual patients. Most data that inform therapy are based on retrospective, uncontrolled studies; prospective trials that incorporate targeted approaches based on genetics and immunophenotype are needed. PMID- 28099273 TI - Making the most of hypomethylating agents in myelodysplastic syndrome. AB - PURPOSE OF REVIEW: Hypomethylating agents (HMA) are the preferred therapy for patients with higher risk myelodysplastic syndromes (MDS) and an alternative therapeutic strategy for older patients with acute myeloid leukemia. These agents have improved both survival and quality of life, but results overall remain poor. The purpose of this review is to highlight recent developments in clinical research with HMA in MDS/acute myeloid leukemia over the last year. RECENT FINDINGS: Combination of HMA with B-cell lymphoma-2 inhibitors, hedgehog inhibitors, and a variety of other agents are underway, as are further studies with reformulated HMA that have more favorable pharmacokinetics (including oral bioavailability). HMA may also be promising in maintenance therapy after allogeneic transplantation. Generally speaking, testing new agents in randomized studies after 'HMA failure,' however, may be suboptimal for assessing efficacy. SUMMARY: No clear 'winner' as a combination partner with HMA or novel formulation of HMA has yet emerged. We concur with growing trends to test novel agents early in the drug development timeline, including the frontline treatment setting in combination with HMA, to bring new agents to Food and Drug Administration approval more quickly. HMA are standard in name only, clinical research should be the standard of care. PMID- 28099274 TI - Can any patients with chronic myeloid leukemia outside of a clinical trial have their tyrosine kinase inhibitor discontinued? AB - PURPOSE OF REVIEW: This article critically appraises the state of treatment-free remission as a strategy for patients with chronic myeloid leukemia (CML) in deep remission after therapy with tyrosine kinase inhibitors (TKIs). RECENT FINDINGS: Approximately half of patients with CML defined fairly narrowly by trial criteria - TKI sensitive, in deep molecular remission for a defined period - can successfully maintain protective levels of response after TKI cessation. Those who cannot appear at very low risk of disease control loss and can promptly regain remission with TKI resumption. Increasing numbers of patients followed longer term in trials have proven as well as a lack of additional late relapse in either group and that 'functional cure' of CML is feasible. Both the definition of remission sufficient to attempt treatment-free remission and the trigger to resume treatment have been relaxed somewhat while outcomes have remained the same. Based on repeated confirmatory data, economic pressures, and pragmatism, the question of feasibility and safety of TKI cessation outside of clinical trials is at hand. SUMMARY: TKI cessation outside of clinical trials, if performed under strict guidelines, utilizing optimal monitoring techniques, with counsel available from experts in the field, and after full disclosure of the risks and benefits with the patient, may be safe (see video, supplemental digital content 1, which summarizes the abstract and offers the author's perspective,http://links.lww.com/COH/A15). PMID- 28099275 TI - Characterization, regulation, and targeting of erythroid progenitors in normal and disordered human erythropoiesis. AB - PURPOSE OF REVIEW: The erythroid progenitors burst-forming unit-erythroid and colony-forming unit-erythroid have a critical role in erythropoiesis. These cells represent a heterogeneous and poorly characterized population with modifiable self-renewal, proliferation and differentiation capabilities. This review focuses on the current state of erythroid progenitor biology with regard to immunophenotypic identification and regulatory programs. In addition, we will discuss the therapeutic implications of using these erythroid progenitors as pharmacologic targets. RECENT FINDINGS: Erythroid progenitors are classically characterized by the appearance of morphologically defined colonies in semisolid cultures. However, these prior systems preclude a more thorough understanding of the composite nature of progenitor populations. Recent studies employing novel flow cytometric and cell-based assays have helped to redefine hematopoiesis, and suggest that erythroid progenitors may arise from different levels of the hematopoietic tree. Moreover, the identification of cell surface marker patterns in human burst-forming unit-erythroid and colony-forming unit-erythroid enhance our ability to perform downstream functional and molecular analyses at the population and single cell level. Advances in these techniques have already revealed novel subpopulations with increased self-renewing capacity, roles for erythroid progenitors in globin gene expression, and insights into pharmacologic mechanisms of glucocorticoids and pomalidomide. SUMMARY: Immunophenotypic and molecular characterization resolves the diversity of erythroid progenitors, and may ultimately lead to the ability to target these progenitors to ameliorate diseases of dyserythropoiesis. PMID- 28099276 TI - Factors in the Efficacy, Safety, and Impact on Quality of Life for Treatment of Drooling with Botulinum Toxin Type A in Patients with Cerebral Palsy. AB - OBJECTIVE: To assess the efficacy and safety of botulinum toxin A (BoNT-A) injected in both submandibular and parotid versus only in parotid glands as a treatment for drooling in patients with spastic and dyskinetic cerebral palsy (CP), including an assessment of impact on quality of life (QoL) based on items from the International Classification of Functioning, Disability, and Health (ICF) core set. DESIGN: Forty patients with CP 18 years or older (mean, 21.8 years) participated in a prospective, single-center, randomized controlled interventional study. All participants were classified as Gross Motor Function Classification System level III or higher and all had significant drooling as defined in prior studies. One group (group A) was treated with 100 U of BoNT-A, and another group (group B) served as control. In the treatment group, all patients first received combined parotid and submandibular injections, and then parotid injections only. The main outcome variables were a postinjection decrease in the drooling quotient (DQ) of 50% or more, total flow of 30% or more, and QoL as assessed by a set of 10 items related to drooling from the ICF. RESULTS: The proportion of patients who achieved at least 50% reduction in DQ was 45% in group A versus 0.0% in group B; 0.0% (P = 0.0012); and of those who achieved at least 30% reduction in total flow was 90% in group A versus 10% in group B (P < 0.0001). Within group A, 42.1% of the dyskinetic patients versus 58.0% of the spastic ones showed 50% or better response in DQ, which is not a statistically significant difference (P = 0.8045). With regard to ICF questions, group A showed statistically significant improvements in several related items. There did not seem to be a significant difference in overall response for providing parotid only injections. Additional correlations and uncommon adverse effect experiences are also reviewed. CONCLUSION: Botulinum toxin A injection of the salivary glands is frequently effective and generally safe for the treatment of drooling in patients with either spastic or dyskinetic CP, both in objective measurement of saliva production and subjective symptoms related to the condition. There does not seem to be a significant advantage of injecting both submandibular and parotid glands over injecting parotid glands alone. PMID- 28099277 TI - Benefits of Comprehensive Rehabilitation Therapy in Thymectomy for Myasthenia Gravis: A Propensity Score Matching Analysis. AB - OBJECTIVE: To demonstrate the effectiveness of a comprehensive program of rehabilitation therapy in patients undergoing thymectomy for myasthenia gravis (MG). DESIGN: From 2005 to 2010, 46 consecutive patients affected by MG underwent a rehabilitation program both before and after thymectomy. We matched each patient with a "control patient" who underwent thymectomy within the period 1999 to 2004 with no preoperative rehabilitation, who had the closest propensity score matching. RESULTS: All patients but 2 were able to complete the intended program. Eighteen patients (41%) experienced mild fatigue (>25 at MG quantitative score). Propensity score selected a group of 17 patients for the matching process. The group of patients who underwent the rehabilitation program showed significant preoperative improvement associated with a reduced operative risk, a decreased early postoperative morbidity, a lower rate of postoperative intensive care unit needed (12% vs 35%; P = 0.01) and a shorter hospital stay (3 vs 5 days; P = 0.04). After the expected perioperative decline, all major myasthenic outcomes demonstrated a significant faster recovery at 3 months. Complete stable remission did not reveal significant differences. CONCLUSIONS: Exercise is not necessarily a contraindication in MG, and rehabilitation can be safely performed before and after thymectomy, reducing operative risks and decreasing recovery time. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCMECME OBJECTIVES: Upon completion of this article, the reader should be able to do the following: (1) appreciate the benefits of physical therapy in individuals with myasthenia gravis; (2) describe the benefits of physical therapy on postoperative morbidity in myasthenia gravis patients who undergo thymectomy; and (3) incorporate appropriate rehabilitation into the treatment plan of patient with myasthenia gravis. LEVEL: AdvancedACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this activity for a maximum of 1.5 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. PMID- 28099278 TI - Recurrent Median Nerve Injury in a Weight Lifter. AB - Recurrent median neuropathy is an uncommon injury that can be commonly mistaken for other pathological causes. It is important to be aware of the potential causes and symptoms of injury as delay in diagnosis can lead to permanent decrease in hand function and disability. This case is a description of a 33-year old male patient who previously presented with radicular symptoms and had complete resolution of his pain after a C7 selective nerve root block. Several months after presentation, he developed significant thenar atrophy, localized pain, and weakness associated with weight lifting activities. He was originally diagnosed with a recurrence of his C7 symptoms and a wrist sprain and was treated with a prednisone taper and wrist splint. After no improvement, he was referred to a physiatrist at an outpatient orthopedic clinic where he was examined and found to have a recurrent median neuropathy on electrodiagnostic studies. A left hand MRI was ordered which demonstrated no anatomical evidence of a compressive nerve lesion, and it was concluded that his injury was secondary to direct compression from high intensity weight lifting. PMID- 28099279 TI - New Survival Target for Duchenne Muscular Dystrophy. AB - We report a patient with a typical phenotype and clinical history of Duchenne muscular dystrophy who is currently 53 years old. Because of improvements in cardiopulmonary care, there has been a great improvement in survival and preservation of quality of life for many of these patients. Whereas it is no longer rare to find patients with Duchenne muscular dystrophy living into their fifth decade, this is the first report of a patient in his sixth decade of life. We believe that besides use of continuous noninvasive respiratory support, the fortuitous absence of dilated cardiomyopathy associated with the particular point mutation of his dystrophin gene has permitted prolonged survival. PMID- 28099280 TI - A Novel Approach for Ultrasound-Guided Botulinum Toxin Injections: Botulis-MUS Projects. PMID- 28099281 TI - Vision-Related Quality of Life Before and After Deep Anterior Lamellar Keratoplasty. AB - OBJECTIVES: To determine changes in the vision-related quality of life in patients undergoing deep anterior lamellar keratoplasty (DALK) by using the 25 item National Eye Institute Visual Function Questionnaire (NEI VFQ-25). METHODS: Thirty-five patients who were scheduled for DALK between March 1, 2013, and March 1, 2014 were asked to complete the NEI VFQ-25. NEI VFQ-25 was administered again at 6 months and at 1 year postoperatively. Data on patients' age, sex, preoperative diagnosis, preoperative and postoperative best-corrected visual acuity, and postoperative astigmatism were recorded. RESULTS: Successful DALK with the Anwar big bubble technique was achieved in 23 of 35 (65.7%) patients. The indications for surgery were keratoconus in 15 patients (62.2%), stromal corneal dystrophies in 4 (17%), and corneal scar in 4 (17%). The mean preoperative NEI VFQ-25 composite score (55.2+/-19.7) improved significantly (76.9+/-11.6) at 6 months after DALK and continued to improve (84.3+/-6.6) at 1 year postoperatively (Friedman test, P=0.001). All NEI VFQ-25 subscale item scores increased significantly after surgery. The patients' age was significantly correlated with the NEI VFQ-25 subscale score of mental health at 6 month and at 1 year postoperatively (r=0.92, P=0.008 and r=0.94, P=0.005, respectively). There was a negative relationship between postoperative astigmatism at 1 year and NEI VFQ-25 ocular pain, social functioning, peripheral vision, and mental health subscale scores (r=-0.76, P=-0.07; r=-0.53, P=0.2; r=-0.53, P=0.27; r=-0.80, P=0.05). CONCLUSION: Vision-related quality of life improved significantly after DALK and continued to improve after suture removal. PMID- 28099282 TI - Risk Factors for Acanthamoeba Keratitis-A Multistate Case-Control Study, 2008 2011. AB - OBJECTIVE: To identify modifiable risk factors contributing to Acanthamoeba keratitis (AK) infection. METHODS: A case-control investigation was conducted. Case patients were soft contact lens wearers with laboratory-confirmed AK. Control were soft contact lens wearers >=12 years of age, with no history of AK. Case patients were recruited from 14 ophthalmology referral centers and a clinical laboratory. Control were matched on state of residence and type of primary eye care provider (ophthalmologist or optometrist). Participants were interviewed using a standardized questionnaire. Univariable and multivariable conditional logistic regression analyses were conducted. Matched odds ratios (mORs) were calculated. RESULTS: Participants included 88 case patients and 151 matched control. Case patients were more likely to be aged <25 years (unadjusted mOR 2.7, 95% confidence interval 1.3-5.5) or aged >53 years (mOR 2.5, 1.1-5.7), and more likely to be men (mOR 2.6, 1.4-4.8). Unadjusted analyses identified multiple risk factors: rinsing (mOR 6.3, 1.3-29.9) and storing lenses in tap water (mOR 3.9, 1.2-12.3), topping off solution in the lens case (mOR 4.0, 2.0 8.0), having worn lenses <=5 years (mOR 2.4, 1.3-4.4), rinsing the case with tap water before storing lenses (mOR 2.1, 1.1-4.1), and using hydrogen peroxide (mOR 3.6, 1.1-11.7) versus multipurpose solution. Significant risk factors in multivariable modeling included age >53 years, male sex, topping off, and using saline solution. CONCLUSIONS: Numerous modifiable risk factors for AK were identified, mostly involving hygiene practices. To reduce the risk of AK, lens wearers should observe recommended lens care practices. PMID- 28099283 TI - The Characteristics of Excimer Laser Refractive Surgery Candidates. AB - PURPOSE: To determine the demographic and refractive characteristics of excimer laser refractive surgery candidates in Iran. METHODS: This was a cross-sectional study between 2010 and 2014. All information was collected from 28 centers randomly selected from 12 provinces. Then, for each season of the year, one week was chosen through simple random selection, and within each week, 3 days were again chosen randomly. All excimer laser surgical procedures performed during these 3 days were identified by training staff, and data were extracted from patient charts. RESULTS: A total of 14,569 charts were reviewed; 67.5% of the subjects were female and the rest were male. Of the total surgeries, 18.6% had been done in 2010 which reached to 19.1% in 2014. The mean age of people receiving refractive surgery showed an upward trend (P<0.001) and female patients were significantly younger than male patients (P<0.001). The 25 to 39 years age group received the highest number of surgeries (31.9% of the total) and there was a significant association with gender (P<0.001). The most common refractive error was compound myopic astigmatism with a prevalence of 79.3%. In 2010, 33.3% of the performed surgeries were covered by insurance policies, and this decreased to 30.2% in 2014 (P<0.001). CONCLUSION: Women with compound myopic astigmatism in the age range of 25 and 35 years are the most frequent users of excimer laser refractive surgery. Less than one-third of laser refractive surgeries are covered by insurance policies. Therefore, proper planning for improving services to this group must be given priority. PMID- 28099284 TI - The Presence of Conjunctivochalasis in Obstructive Sleep Apnea Patients. AB - OBJECTIVES: The aim of our study was to detect the presence of conjunctivochalasis (CCh) in obstructive sleep apnea (OSA) patients. METHODS: We included 54 subjects (41 OSA patients and 14 control subjects) in the study. All the patients were assessed regarding the presence and stage of CCh. RESULTS: The patients were grouped according to their apnea-hypopnea index as determined during nocturnal polysomnography in our laboratory as mild (12 patients), moderate (16 patients), and severe (13 patients) OSA. The CCh rate was 87.8% in the OSA group and 57.1% in the control group (P=0.022). Mean CCh stage was 1.58+/ 1.24, 2.38+/-0.88, and 2.15+/-0.98 in the mild, moderate, and severe OSA groups, respectively, and 0.71+/-0.72 in the control group (P=0.0001). CONCLUSIONS: The moderate and severe OSA groups were associated with higher rates and more advanced stages of CCh. We believe that detailed conjunctival assessment is necessary for patients with complaints such as burning, stinging, and foreign body sensation, which we frequently confront in daily practice. In particular, young patients diagnosed with CCh must be carefully assessed regarding sleep apnea. In light of the above findings, we suggest that patients with ocular surface symptoms that are not relieved by topical medical treatment should be assessed for CCh and OSA. Longitudinal studies monitoring the response of CCh to OSA treatment are needed to clarify the relationship between CCh and OSA. PMID- 28099285 TI - Comparison of Silicone Hydrogel and Hydrogel Daily Disposable Contact Lenses. AB - OBJECTIVE: To compare subjective, objective and safety performance of silicone hydrogel (SiHy) daily disposable (DD) with hydrogel (Hy) DD contact lenses. METHOD: Retrospective analysis on approximately 40 participants (Px) each in 5 trials. Lenses grouped into SiHy (delefilcon A, somofilcon A, narafilcon A) and Hy (omafilcon A, nelfilcon A). Participants attended follow-up visits at baseline, 2 weeks, 1 and 3 months. Subjective ratings (1-10 scale), adverse events (percentage of Px), physiological variables (0-4 scale), and wearing time were collected at each visit and compared between groups. RESULT: Trials enrolled 201 Px totally. No differences in age, sex, and lens wear experience were found between SiHy and Hy groups (P>=0.09). There was greater increase in limbal redness from baseline in Hy group (0.18+/-0.38 vs. 0.02+/-0.47, P<0.001), whereas conjunctival staining and indentation were less in Hy group (P<0.001). No differences in comfortable wearing time were found between groups (P=0.41), and comfort at insertion, during day, and end of day was also no different (P>=0.71). Incidence of corneal infiltrative events (SiHy vs. Hy: 6.7% vs. 2.5%; P=0.32) and mechanical adverse events (SiHy vs. Hy: 0.0% vs. 0.0%; P=1.00) were no different. CONCLUSION: Though some statistical significance was found between the groups, these differences were within measurement error. Neither material types showed superiority in comfort, and adverse event rates were low with both material types. These findings suggest that choice of material is a patient and practitioner preference; however, for patients at risk of hypoxia-related complications, SiHy materials should be considered. PMID- 28099286 TI - Multicenter Study Validating Accuracy of a Continuous Respiratory Rate Measurement Derived From Pulse Oximetry: A Comparison With Capnography. AB - BACKGROUND: Intermittent measurement of respiratory rate via observation is routine in many patient care settings. This approach has several inherent limitations that diminish the clinical utility of these measurements because it is intermittent, susceptible to human error, and requires clinical resources. As an alternative, a software application that derives continuous respiratory rate measurement from a standard pulse oximeter has been developed. We sought to determine the performance characteristics of this new technology by comparison with clinician-reviewed capnography waveforms in both healthy subjects and hospitalized patients in a low-acuity care setting. METHODS: Two independent observational studies were conducted to validate the performance of the Medtronic Nellcor Respiration Rate Software application. One study enrolled 26 healthy volunteer subjects in a clinical laboratory, and a second multicenter study enrolled 53 hospitalized patients. During a 30-minute study period taking place while participants were breathing spontaneously, pulse oximeter and nasal/oral capnography waveforms were collected. Pulse oximeter waveforms were processed to determine respiratory rate via the Medtronic Nellcor Respiration Rate Software. Capnography waveforms reviewed by a clinician were used to determine the reference respiratory rate. RESULTS: A total of 23,243 paired observations between the pulse oximeter-derived respiratory rate and the capnography reference method were collected and examined. The mean reference-based respiratory rate was 15.3 +/- 4.3 breaths per minute with a range of 4 to 34 breaths per minute. The Pearson correlation coefficient between the Medtronic Nellcor Respiration Rate Software values and the capnography reference respiratory rate is reported as a linear correlation, R, as 0.92 +/- 0.02 (P < .001), whereas Lin's concordance correlation coefficient indicates an overall agreement of 0.85 +/- 0.04 (95% confidence interval [CI] +0.76; +0.93) (healthy volunteers: 0.94 +/- 0.02 [95% CI +0.91; +0.97]; hospitalized patients: 0.80 +/- 0.06 [95% CI +0.68; +0.92]). The mean bias of the Medtronic Nellcor Respiration Rate Software was 0.18 breaths per minute with a precision (SD) of 1.65 breaths per minute (healthy volunteers: 0.37 +/- 0.78 [95% limits of agreement: -1.16; +1.90] breaths per minute; hospitalized patients: 0.07 +/- 1.99 [95% limits of agreement: -3.84; +3.97] breaths per minute). The root mean square deviation was 1.35 breaths per minute (healthy volunteers: 0.81; hospitalized patients: 1.60). CONCLUSIONS: These data demonstrate the performance of the Medtronic Nellcor Respiration Rate Software in healthy subjects and patients hospitalized in a low-acuity care setting when compared with clinician-reviewed capnography. The observed performance of this technology suggests that it may be a useful adjunct to continuous pulse oximetry monitoring by providing continuous respiratory rate measurements. The potential patient safety benefit of using combined continuous pulse oximetry and respiratory rate monitoring warrants assessment. PMID- 28099287 TI - Anesthetic Outcomes of Children With Arthrogryposis Syndromes: No Evidence of Hyperthermia. AB - BACKGROUND: Arthrogryposis syndromes are a heterogeneous group of disorders characterized by congenital joint contractures often requiring multiple surgeries during childhood to address skeletal and visceral abnormalities. Previous reports suggest that these children have increased perioperative risk, including hypermetabolic events discrete from malignant hyperthermia, difficult airway management, isolated hyperthermia, and difficult IV line placement. We sought to compare children with arthrogryposis multiplex congenita (AMC) versus the less severe, distal arthrogryposis syndromes (DAS) and to evaluate possible intraoperative hyperthermia of patients with AMC. We hypothesized that children with AMC had a greater incidence of intraoperative hyperthermia and more difficulty with airway management and IV access. METHODS: Children aged 0 to 25 years with arthrogryposis syndromes who underwent anesthesia from 1972 to 2013 were identified. The medical records were reviewed for demographics, arthrogryposis type, and anesthetic complications. AMC subjects were compared with DAS subjects. To evaluate the probability of hyperthermia and hypermetabolic responses of patients with AMC, we performed a post hoc case-control analysis. Patients with AMC were matched in a 1:2 ratio to patients without arthrogryposis to evaluate the primary outcome of maximum intraoperative temperature. RESULTS: Forty-five patients with AMC and 16 patients with DAS underwent 264 and 105 unique anesthetics, respectively. There was no significant difference in intraoperative hyperthermia or hypermetabolic events (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.36-2.47; P = .90). Children with AMC were more likely to have difficult IV access (OR, 7.1; 95% CI, 1.81-27.90; P = .005). Additional evidence suggested that difficult airway management (OR, 4.06; 95% CI, 1.01 16.39; P = .049) and hemodynamic instability (OR, 4.22; 95% CI, 1.03-17.26; P = .045) were more likely in children with AMC. From post hoc case-control analysis, there was no significant difference in the mean maximum intraoperative temperature (estimated difference +0.04 degrees C; 95% CI, -0.14 to +0.22; P = .64) or odds of intraoperative hyperthermia (OR, 1.49; 95% CI, 0.78-2.82; P = .223) for patients with AMC compared with control subjects. CONCLUSIONS: Children with arthrogryposis syndromes present challenges to the anesthesia and surgical teams, including greater neuromuscular disease burden and challenging peripheral IV placement, with additional evidence suggesting difficult airway management and intraoperative hemodynamic instability. Although more definitive studies are warranted, we did not find evidence of increased odds of intraoperative hyperthermia or hypermetabolic responses. PMID- 28099288 TI - Assessing the Agreement Between Radiologic and Clinical Measurements of Lumbar and Cervical Epidural Depths in Patients Undergoing Prone Interlaminar Epidural Steroid Injection. AB - BACKGROUND: Fluoroscopy-guided epidural steroid injection (ESI) commonly is performed to treat radicular pain yet can lead to adverse events if the needle is not advanced with precision. Accurate preoperative assessment of the distance from the skin to the epidural space holds the potential for reducing the risks of adverse effects from ESI. It was hypothesized that the distance from the skin to the epidural space as measured on preoperative magnetic resonance imaging (MRI) would agree with the distance traveled by a Tuohy needle to reach the epidural space during midline, interlaminar ESI. This study compared the final needle depth measurement at the point of loss of resistance (LOR) from cervical or lumbar ESI to the distance from the skin to the anterior and posterior borders of the epidural space on the associated cervical and lumbar preoperative MRI. METHODS: This retrospective chart review analyzed the procedure notes, MRI, and demographic data of patients who received a prone, interlaminar ESI at an outpatient chronic pain clinic between June 1, 2013, and June 1, 2015. The following data were collected: body mass index (BMI), age, sex, intervertebral level of the ESI, and LOR depth. We then measured the distance from the skin surface to the anterior border of the ligamentum flavum (ligamentum flavum depth [LFD]) and dura (dura depth [DD]) on MRI. A total of 335 patients were categorized into the following patient subgroups: age >=65 years, age <65 years, BMI >=30 kg/m (obese), BMI <30 kg/m (nonobese), male, and female. Secondary analyses were then performed to compare the agreement between LOR depth and DD with that between LOR depth and LFD within each patient subgroup. Intraclass correlation coefficient (ICC) and Bland-Altman plot were used to assess the agreement between DD or LFD and LOR depth. RESULTS: Data from 335 ESIs were analyzed, including 147 cervical ESIs and 188 lumbar ESIs. Estimated ICC values for the agreement between LOR depth and LFD for all lumbar and cervical measurements were 0.88 (95% confidence interval [CI], 0.85-0.91) and 0.72 (95% CI, 0.64-0.79), respectively. Estimated ICC values for the agreement between LOR depth and DD for all lumbar and cervical measurements were 0.86 (95% CI, 0.82 0.89) and 0.69 (95% CI, 0.60-0.77), respectively. CONCLUSIONS: This study assessed the agreement between MRI-derived measurements of epidural depth and those determined clinically. MRI-derived measurements from the skin to the anterior border of the ligamentum flavum, which represents the most posterior aspect of the epidural space, revealed stronger agreement with LOR depths than did measurements to the dura or the most anterior aspect of the epidural space. These results require further analysis and refinement before supporting clinical application. PMID- 28099289 TI - Orthogonal Views of Coronary Vessels: A Method for Imaging the Delivery of Blood Cardioplegia Using Transesophageal Echocardiography. AB - Coronary blood flow can be disrupted during cardiac interventions such as mitral valve surgeries, left atrial appendage ligation, transcatheter aortic valve implantation, and aortic procedures involving reimplantation of coronary buttons. Although difficult to accomplish, coronary imaging using transesophageal echocardiography can be performed by the use of orthogonal imaging with the ability for real-time tilt for angle adjustment. The technique described herein allows imaging of the right coronary artery, left main coronary artery bifurcation, left anterior descending, and circumflex coronary arteries. The imaging is facilitated by acquisition during the delivery of blood cardioplegia. Coronary sinus and great cardiac vein imaging also can be obtained during the delivery of retrograde cardioplegia. Although further studies are needed, this imaging technique may prove useful in procedures where coronary flow disruption is suspected or as an additional parameter to confirm delivery of cardioplegia. PMID- 28099290 TI - Increased Perinatal Morbidity and Mortality Among Asian American and Pacific Islander Women in the United States. AB - BACKGROUND: Asian American/Pacific Islanders (AAPIs) are the fastest-growing racial group in the United States. Despite a higher socioeconomic status, AAPI women experience higher rates of maternal morbidity and mortality. METHODS: Using the National Inpatient Sample, we performed a retrospective cohort analysis of women who were hospitalized for delivery from 2002 to 2013. The primary outcome variable was inpatient mortality rate, and the presence of severe maternal morbidities was estimated using the Bateman Comorbidity Index, a validated tool for predicting obstetric morbidity. RESULTS: AAPI women presenting for delivery between 2003 and 2012 were older, more likely to reside in a zip code in the top quartile of annual income, be privately insured than Caucasian women, and less likely to have a higher Bateman Comorbidity Index. However, AAPI women had a higher likelihood of postpartum hemorrhage (3.4% vs 2.7%, P < .001), uterine atony, severe perineal lacerations, and severe maternal morbidities. Procedures such as transfusion, hysterectomy, and mechanical ventilation were also more common in AAPI women. Furthermore, AAPI women had a higher mortality rate that persisted despite adjustment for an apparently higher income and comorbidities (odds ratio 1.72, 95% confidence interval: 1.14-2.59, P = .01). CONCLUSIONS: Despite having a higher socioeconomic status, AAPI women had higher rates of maternal mortality during hospitalization for delivery. This increase persisted even after adjustment for factors known to affect peripartum outcomes. Further investigation is needed to better clarify the causes of racial differences in maternal morbidity and mortality. PMID- 28099291 TI - Transcutaneous Carbon Dioxide Measurements in Women Receiving Intrathecal Morphine for Cesarean Delivery: A Prospective Observational Study. AB - BACKGROUND: Neuraxial morphine is the most commonly used analgesic technique after cesarean delivery. The incidence of respiratory depression is reported to be very low (0%-1.2%) in this patient population as measured by pulse oximetry and respiratory rates. However, hypercapnia may be a more sensitive measure of respiratory depression. In the current study, the incidence of hypercapnia events (transcutaneous CO2 [TcCO2] >50 mm Hg) for >=2-minute duration was evaluated using the Topological Oscillation Search with Kinematical Analysis monitor in women who received intrathecal morphine for postcesarean delivery analgesia. METHODS: Healthy women (>37 weeks of gestation) scheduled for a cesarean delivery with spinal anesthesia with intrathecal morphine were recruited. Baseline STOP BANG sleep apnea questionnaire and TcCO2 readings were obtained. Spinal anesthesia was initiated with 12 mg hyperbaric bupivacaine, 15 ug fentanyl, and 150 ug morphine. The Topological Oscillation Search with Kinematical Analysis monitor was reapplied in the postanesthesia care unit and TcCO2 measurements obtained for up to 24 hours. Supplemental opioid administration and adverse respiratory events were recorded. The primary outcome was the incidence of hypercapnia events, defined as a TcCO2 reading >50 mm Hg for >=2 minutes in the first 24 hours after delivery. RESULTS: Of the 120 women who were recruited, 108 completed the study. Thirty-five women (32%; 99.15% confidence interval, 21%-45%) reached the primary outcome of a sustained hypercapnia event. The median time (interquartile range [IQR]) from intrathecal morphine administration to the hypercapnia event was 300 (124-691) minutes. The median (IQR) number of events was 3 (1-6) and longest duration of an event was 25.6 (8.4-98.7) minutes. Baseline median (IQR) TcCO2 measurements were 35 (30-0) mm Hg and postoperatively, median (IQR) TcCO2 measurements were 40 (36-43) mm Hg, a difference of 5 mm Hg (99.15% confidence interval of the difference 2-8 mm Hg, P < .001). The incidence of hypercapnia events was 5.4% in women with a baseline TcCO2 value <=31 mm Hg, 22.5% with a baseline TcCO2 between 32 and 38 mm Hg, and 77.4% with a baseline TcCO2 >38 mm Hg (P < .001). CONCLUSIONS: Hypercapnia events (>50 mm Hg for >=2-minute duration) occurred frequently in women receiving 150 MUg intrathecal morphine for postcesarean analgesia. Higher baseline TcCO2 readings were observed in women who had hypercapnia events. PMID- 28099292 TI - Evaluating the Necessity of Antibiotics in the Treatment of Acute Epididymitis in Pediatric Patients: A Literature Review of Retrospective Studies and Data Analysis. AB - OBJECTIVES: This literature review and data analysis aims to evaluate the percentage of pediatric patients with acute epididymitis found to have bacterial etiology and the percentage of patients in these studies that were treated with antibiotic therapy versus conservative therapy. METHODS: A search of EBSCO through January 13, 2016, using the key words epididymitis or epididymo-orchitis and child, children, or pediatric, identified 542 potential studies.Twenty-seven retrospective studies met the inclusion criteria, containing patients aged 21 years or younger with acute epididymitis or epididymo-orchitis. The number and age of patients, urine cultures and urinalysis results, number of patients treated with antibiotics, and incidence were extracted. RESULTS: A total of 1496 patients with acute epididymitis were identified. A urinalysis was obtained for 1124 patients, and 190 (16.9%) were positive. A urine culture was obtained for 670 patients, and 100 (14.9%) were positive. Fourteen studies addressed antibiotic administration wherein 652 patients were with acute epididymitis and 554 (85%) received antibiotics.Of 502 patients with urinalysis results, urine culture results, and antibiotic treatment rates, 54 (10.8%) were positive for a bacterial source. Antibiotics were administered to 410 (81.7%) of these 502 patients. CONCLUSIONS: Practitioners should consider only prescribing antibiotics to patients with acute epididymitis if there is an abnormal urinalysis or urine culture. PMID- 28099293 TI - Validating a Clinical Prediction Rule for Ventricular Shunt Malfunction. AB - OBJECTIVE: This study aims to validate a published ventricular shunt clinical prediction rule for the identification of children at low risk for ventricular shunt malfunction based on the absence of 3 high-risk clinical predictors (irritability, nausea or vomiting, and headache). METHODS: We identified children aged 21 years and younger with a ventricular shunt who presented between 2010 and 2013 to a single pediatric emergency department (ED) for evaluation of potential shunt malfunction. We defined a ventricular shunt malfunction as obstruction to cerebrospinal fluid flow requiring operative neurosurgical intervention within 72 hours of initial ED evaluation. We applied this ventricular shunt clinical prediction rule to the study population and report the test characteristics. RESULTS: We identified 755 ED visits for 294 children with potential ventricular shunt malfunction. Of these encounters, 146 (19%; 95% confidence interval [CI], 17%-22%) had a ventricular shunt malfunction. The ventricular shunt clinical prediction rule had a sensitivity of 99% (95% CI, 94%-100%), specificity of 7% (95% CI, 5%-9%), and negative predictive value of 95% (95% CI, 82%-99%). Two children with a ventricular shunt malfunction were misclassified as low risk by this clinical prediction rule. CONCLUSIONS: Ventricular shunt malfunctions were common. Although children classified as low risk by the ventricular shunt clinical prediction rule were less likely to have a shunt malfunction, routine neuroimaging may still be required because exclusion of ventricular shunt malfunction may be difficult on clinical grounds alone. PMID- 28099294 TI - Examination of Pediatric Radiation Dose Delivered After Cervical Spine Trauma. AB - OBJECTIVES: Pediatric cervical spine injuries (CSIs) are rare but potentially fatal injuries. Plain radiographs (x-rays) and computed tomography (CT) are used to diagnose CSIs. Given concerns related to radiation exposure, the utility of x rays in diagnosing CSIs compared with other forms of imaging must be examined. METHODS: Patients younger than 19 years presenting with possible CSI to an urban tertiary care hospital who received imaging for possible CSI between January 1, 2011, and December 31, 2013, were included. The dose-length product was abstracted from the PACS system. Test performance for x-ray, CT, and MRI were calculated and effective radiation dose by age group was analyzed using the Kruskal-Wallis Test. RESULTS: A total of 671 patient charts were reviewed, 574 children were included in the study cohort. Median age of enrolled children was 9.70 (interquartile range, 4.78-13.83) years; 42.5% were female. Test performance of x-ray, CT, and MRI to detect CSI were calculated. Cervical x-rays performed only slightly inferior to CT. Sensitivity was 83% (95% confidence interval [CI], 36-99%), and specificity was 97% (95% CI, 96%-99%) versus 100% (95% CI, 96%-100%) for CT. Median effective dose of radiation for cervical CTs was 4.51 mSv (interquartile range, 3.84-5.59 mSv). Median dose significantly increased with age (2.94-5.10 mSv, P < 0.001). CONCLUSIONS: Plain radiographs were largely sufficient to screen for CSIs, indicating their utility as a screening tool for CSIs. The incidence of CSIs in our sample was similar to prior reports. The effective radiation dose delivered during pediatric head and cervical CTs were lower than previously published estimates. PMID- 28099295 TI - Comparison of Resource Utilization and Length of Hospitalization Between Overweight and Healthy-Weight Pediatric Trauma Patients Presenting to a Pediatric Emergency Department With Moderate to Severe Injury: A Prospective Study. AB - OBJECTIVES: Our study aimed to compare overweight and healthy-weight pediatric trauma patient outcomes, specifically with respect to hospital length of stay and resource utilization. We hypothesized that overweight pediatric trauma patients would have increased hospital length of stay and radiographic study use compared with their healthy-weight counterparts. METHODS: This was a prospective, observational, cohort study of pediatric trauma patients aged 2 to 19 years presenting to an urban pediatric emergency department over a period of 1 year. Using measured height and weight values, body mass index (BMI) for age was calculated and plotted on the Centers for Disease Control and Prevention BMI-for age growth charts. Patients were followed up throughout their hospitalization, and the following items were recorded: trauma alert level, mechanism of injury, age, sex, race, Glasgow Coma Scale score, total number of days in hospital, total number of intensive care unit days, total number of radiographs obtained, total number of computed tomography scans obtained, and mechanism of injury. RESULTS: Our study population included 109 subjects. The mean age of the subjects was 9.7 years. The number of patients meeting the definition of obese (BMI for age >=95%) was 15, or 14% of the total study population. There was no significant difference between the overweight cohort and the healthy-weight cohort found among any of the variables recorded and analyzed. CONCLUSIONS: Although there are many chronic conditions in children associated with obesity, in the case of trauma, it does not seem to be a strong concern. A continued focus on preventing and reversing childhood obesity for other physical and mental health outcomes may be more important. PMID- 28099296 TI - A Reexamination of the Accuracy of the Broselow Tape as an Instrument for Weight Estimation. AB - BACKGROUND: Accurate weight estimation is important for calculating appropriate medication dosages, determining rates of fluid replacement, and selecting correct equipment sizes in critically ill children requiring resuscitation. The actual measurement of the weight of a critically ill or injured child is often not possible. The Broselow Pediatric Emergency Tape (BT) is an important tool for predicting a child's weight based on his/her height. Although BT has previously been validated, given the increasing prevalence of obesity in today's society, it behooves clinicians relying on this resuscitation aid to revisit the issue. OBJECTIVE: The aim of this study was to evaluate the accuracy of the color-coded BT in weight estimation and the influence of obesity on its accuracy. METHODS: This is a retrospective study conducted in a pediatric clinic of urban hospital. This study reviewed the medical records of children up to 96 months of age, who presented during 2008-2010. We recorded the child's age (in months), actual (measured) weight (in kilograms), and height (in centimeters). Based on the height, weight estimation was obtained using the color-coded BT. The actual weight was compared with the predicted weight obtained by the height-based BT. Patients presenting with any medical condition that would substantially affect growth of the child were excluded. A univariate logistic regression model was utilized to predict any underestimation based on age, sex, and body mass index (BMI) percentile. RESULTS: The medical records of 538 children were reviewed. There was a discrepancy in 226 children (42%). Broselow Pediatric Emergency Tape underestimated weight (measured weight was higher than predicted weight) in 158 children (29.4%) and overestimated (measured weight was lower than predicted weight) in 68 children (12.6%). Of the 158 underestimated children, 138 were off by 1 color zone, 16 by 2 color zones, and 4 by more than 2 color zones. When characterized by BMI, 46 children (13.6%) had normal BMI, 27 (45.8%) were overweight, and 84 (80.8%) were obese, whereas one child (2.8%) was underweight. CONCLUSIONS: In our population, BT was inaccurate in predicting weight in 42% of children (underestimation in 158 children [29.4%] and overestimation weight in 68 children [12.6%]). However, the majority of discrepancies involved only 1 BT color zone. Emergency physicians should be aware of this discrepancy until more accurate methods become available. PMID- 28099297 TI - Sedentary Behavior, Cadence, and Physical Activity Outcomes after Knee Arthroplasty. AB - PURPOSE: This study comprehensively examined sedentary behavior and physical activity patterns in people with severe knee osteoarthritis awaiting total knee arthroplasty (TKA) and in individuals after TKA. METHODS: Preoperative (n = 32, mean +/- SD = 69.9 +/- 5.3 yr) and 1-yr postoperative participants with TKA (n = 38, 67.9 +/- 7.3 yr) wore ActiGraph GT3X+ activity monitors for 6.8 +/- 0.6 d. Total sedentary time, time in long sedentary bouts (>=30 min), and physical activity outcomes (steps, time in moderate-to-vigorous physical activity [MVPA], cadence) were examined. RESULTS: There were no differences between pre- and postoperative groups for total sedentary time (9.3 +/- 1.4 vs 9.2 +/- 1.4 h.d, P = 0.62) and number of long sedentary bouts per day (median [interquartile range] = 3.4 [1.9] vs 3.1 [2.0], P = 0.37). Daily steps, peak 30-min cadence, and peak 1 min cadence values were greater in people after TKA compared with those awaiting surgery (5935 [3316] vs 3724 [2338], 55.6 [31.0] vs 35.9 [19.3], and 91.5 +/- 20.6 vs 70.0 +/- 23.7, respectively, all P < 0.01). There were no differences in lifestyle MVPA between groups. The number of bouts of Freedson MVPA was greater in postoperative participants, but the differences were not substantial (one bout per week). CONCLUSION: Patients report less knee pain and improved function after TKA; however, sedentary behavior does not differ and physical activity is only marginally increased compared with those awaiting surgery. After TKA, daily walking at slow, moderate, and brisk paces and engagement in MVPA do not match levels seen in healthy older adults, which, when combined with high levels of sedentary behavior, leaves patients at increased risk for physical disability and cardiovascular disease. PMID- 28099298 TI - Low-Dose Aspirin Is Effective Chemoprophylaxis Against Clinically Important Venous Thromboembolism Following Total Joint Arthroplasty: A Preliminary Analysis. AB - BACKGROUND: Aspirin is a safe and effective prophylaxis for the prevention of venous thromboembolism following total joint arthroplasty. The optimal dose of aspirin prophylaxis is unknown. Our hypothesis was that lower-dose aspirin is as effective as higher-dose aspirin for the prevention of venous thromboembolism and is associated with fewer gastrointestinal side effects. METHODS: In a prospective, crossover study, we analyzed 4,651 primary total joint arthroplasty cases performed from July 2013 to June 2015. For 4 weeks, 3,192 patients received enteric-coated 325-mg aspirin twice daily (the 325-mg aspirin group) and 1,459 patients received 81-mg aspirin twice daily (the 81-mg aspirin group). There were no significant differences (p > 0.05) in sex, body mass index, or Charlson Comorbidity Index between the two patient populations. Recorded complications occurring within 90 days postoperatively included symptomatic venous thromboembolism (deep venous thrombosis and pulmonary embolism), gastrointestinal complications, acute periprosthetic joint infection, and death. RESULTS: The incidence of venous thromboembolism of 0.1% (95% confidence interval [CI], 0% to 0.3%) in the 81-mg aspirin group (1 with deep venous thrombosis and 1 with pulmonary embolism) was not significantly different (p = 0.345) from 0.3% (95% CI, 0.1% to 0.6%) in the 325-mg aspirin group (7 with deep venous thrombosis and 5 with pulmonary embolism). The incidence of gastrointestinal bleeding or ulceration of 0.3% (95% CI, 0% to 0.5%) in the 81-mg aspirin group was slightly, but not significantly (p = 0.66), lower than the 0.4% (95% CI, 0.2% to 0.6%) in the 325-mg aspirin group. The incidence of acute periprosthetic joint infection was 0.2% (95% CI, 0% to 0.4%) in the 81-mg aspirin group compared with 0.5% (95% CI, 0.2% to 0.7%) in the 325-mg aspirin group (p = 0.28). The 90-day mortality rate was similar in both groups at 0.1% (95% CI, 0% to 0.2%) in the 81-mg aspirin group and 0.1% (95% CI, 0% to 0.2%) in the 325-mg aspirin group (p = 0.78). CONCLUSIONS: Our study demonstrates that low-dose aspirin is not inferior to high dose aspirin for venous thromboembolism prophylaxis following total joint arthroplasty. This is not unexpected, as the available literature demonstrates that low-dose aspirin is as effective as higher-dose aspirin in the prevention of acute coronary syndrome and cerebrovascular events. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 28099299 TI - Direct Anterior Approach: Risk Factor for Early Femoral Failure of Cementless Total Hip Arthroplasty: A Multicenter Study. AB - BACKGROUND: The direct anterior approach for total hip arthroplasty (THA) is marketed with claims of superiority over other approaches. Femoral exposure can be technically challenging and potentially lead to early failure. We examined whether surgical approach is associated with early THA failure. METHODS: A retrospective review of 478 consecutive early revision THAs performed within 5 years after the primary THAs at 3 academic centers from 2011 through 2014 was carried out. Exclusion criteria resulted in a final analysis sample of 342 early failure THAs. The surgical approach of the primary operation that was revised, the time to the revision, and the etiology of the failure leading to the revision were documented. RESULTS: Analysis of the revisions due to early femoral failure showed them to be more common in patients who had undergone the direct anterior approach (57/112; 50.9%) than in those treated with the direct lateral (39/112; 34.8%) or the posterior (16/112; 14.3%) approach (p = 0.001). In multivariate regression analysis controlling for age, sex, laterality, Dorr bone type, body mass index (BMI) at revision, bilateral procedure (yes/no), and femoral stem type, the direct anterior approach remained a significant predictor of early femoral failure (p = 0.007). The majority of early revisions due to instability were associated with the posterior (19/40; 47.5%) or direct anterior (15/40; 37.5%) approach (p = 0.001 for the comparison with the direct lateral approach [6/40; 15.0%]). CONCLUSIONS: Despite claims of earlier recovery and improved outcomes with the direct anterior approach for THA, our findings indicate that that approach may confer a greater risk of early femoral failure and, along with the posterior approach, confer a greater risk of early instability compared with the direct lateral approach. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28099300 TI - Plate Fixation Compared with Nonoperative Treatment for Displaced Midshaft Clavicular Fractures: A Multicenter Randomized Controlled Trial. AB - BACKGROUND: The use of operative treatment for clavicular fractures is increasing, despite varying results in previous studies. The aim of this study was to compare plate fixation and nonoperative treatment for displaced midshaft clavicular fractures with respect to nonunion, adverse events, and shoulder function. METHODS: In this multicenter, prospective, randomized controlled trial, patients between 18 and 60 years old with a displaced midshaft clavicular fracture were randomized between nonoperative treatment and open reduction with internal plate fixation. The primary outcome was evidence of nonunion at 1 year. Other outcomes were secondary operations, arm function as measured with the Constant shoulder score and Disabilities of the Arm, Shoulder and Hand (DASH) score, pain, cosmetic results, and general health status. Outcomes were recorded at 6 weeks, 3 months, and 1 year following trauma. RESULTS: One hundred and sixty patients were randomized. The rate of nonunion was significantly higher in the nonoperatively treated group than in the operatively treated group (23.1% compared with 2.4%; p < 0.0001), as was the rate of nonunion for which secondary plate fixation was performed (12.9% compared with 1.2%; p = 0.006). The rate of secondary operations was 27.4% in the operatively treated group (16.7% for elective plate removal) and 17.1% in the nonoperatively treated group (p = 0.18). Nineteen percent of the patients in the operatively treated group had persistent loss of sensation around the scar. No difference was found between the groups with respect to the Constant and DASH scores at all time points. CONCLUSIONS: For patients with a diaphyseal fracture of the clavicle displaced at least 1 shaft width, plate fixation improves the chances that the bone will heal; however, the rate of patients who need a second operation is considerable. In addition, the procedure does not improve shoulder function or general symptoms, and it does not decrease limitations compared with nonoperative treatment in a sling. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 28099301 TI - Unicompartmental Knee Arthroplasty Provides Higher Activity and Durability Than Valgus-Producing Proximal Tibial Osteotomy at 5 to 7 Years. AB - BACKGROUND: The cases of patients with medial compartment osteoarthritis who were <=55 years old and had a proximal tibial osteotomy (PTO) or medial unicompartmental knee arthroplasty (UKA) were compared. Outcomes included postoperative activity level, function, and survivorship free of revision to total knee arthroplasty. METHODS: Between 1998 and 2013, data were available for 240 patients between 18 and 55 years old with medial compartment arthritis and varus malalignment who were treated either with PTO (57 patients) or with UKA (183 patients). The mean age was 42.7 years for the 57 patients (41 men and 16 women) in the PTO group versus 49.2 years for the 183 patients (82 men and 101 women) in the UKA group. The Tegner activity level and Lysholm knee scores were evaluated at 3 months and at 1, 2, and 5 years postoperatively as well as at the time of the final follow-up. The end point for survival was defined as revision to total knee arthroplasty. A Wilcoxon rank-sum test was used to evaluate the difference between the groups with respect to the Tegner and Lysholm scores at the respective follow-up intervals. Multivariate regression was used to assess potential confounders. RESULTS: Preoperatively, the PTO and UKA groups had similar Tegner (3.0 +/- 1.3 and 2.6 +/- 0.09, respectively) and Lysholm scores (69.5 +/- 7.3 and 71.6 +/- 5.4). Postoperatively, the UKA group had significantly superior mean Tegner scores compared with the PTO group at 3 months (3.82 and 2.02, respectively), at 2 years (4.33 and 3.75), and at the time of the final follow-up (4.48 and 3.08), while the Lysholm scores were higher at 3 months (88.0 and 76.3) and at the final follow-up (90.0 and 80.2) (p < 0.01 for all). Multivariate analysis showed UKA to be an independent predictor of activity level at 3 months, 1 year, and 2 years, as well as at the final follow-up. The survivorship was 77% in the PTO group at an average of 7.2 years and 94% in the UKA group at an average of 5.8 years (p < 0.01). The average time to failure was 98 months (range, 38 to 169 months) in the PTO group and 42 months (range, 2 to 123 months) in the UKA group (p < 0.01). CONCLUSIONS: In this comparative cohort study of young patients with isolated unicompartmental arthritis, those treated with UKA reached a higher level of activity early after surgery and it persisted at mid-term follow-up. The UKA group had earlier, but less frequent, revision to total knee arthroplasty. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28099302 TI - Comparison of Ultrasound and MRI for the Diagnosis of Glenohumeral Dysplasia in Brachial Plexus Birth Palsy. AB - BACKGROUND: In this study, we investigated the agreement between measurements made on ultrasound and those made on magnetic resonance imaging (MRI) in the assessment of glenohumeral dysplasia resulting from brachial plexus birth palsy. METHODS: Thirty-nine patients (14 male and 25 female) with brachial plexus birth palsy were evaluated at 2 tertiary care centers. All patients underwent ultrasonography and MRI for suspected glenohumeral dysplasia. Studies were obtained at an average of 2 months apart (range, 0 to 6 months). The average patient age at the time of the initial imaging study was 20 months (range, 4 to 54 months). Four blinded independent evaluators measured the alpha angle, the posterior humeral head displacement (PHHD), and glenoid version on both the ultrasound and MRI study for each patient. The percentage of the humeral head anterior to the scapular axis (PHHA) was determined on MRI only. Measurements were obtained on OsiriX software (Pixmeo). Intraclass correlation coefficients (ICCs) were used to assess the intrarater and interrater reliability, and Bland Altman plots were used to compare MRI and ultrasound measurement agreement. RESULTS: We found excellent interrater reliability for measurements of the alpha angle on MRI, glenoid version on MRI, and the alpha angle on ultrasound (ICC: 0.83, 0.75, and 0.78, respectively). The interrater reliability for the PHHD on both MRI and ultrasound was good (ICC: 0.70 and 0.68, respectively), and the interrater reliability for the PHHA on MRI was fair (ICC: 0.57). However, the interrater reliability for glenoid version on ultrasound was poor (ICC: 0.30). Relative to MRI measurements, ultrasound measurements were found to underestimate the alpha angle and glenoid version by an average of 13 degrees +/- 23 degrees and 6 degrees +/- 17 degrees , respectively, and overestimate the PHHD by an average of 4% +/- 20%. Increasing patient age corresponded with a significant increase in the MRI-ultrasound measurement difference for the alpha angle (p < 0.01) and a marginally significant increase in the difference for the PHHD (p < 0.06). CONCLUSIONS: Measurements on MRI and ultrasound were reliable, with measured bias. The poor agreement between measurements on MRI and ultrasound calls into question the validity of using ultrasonography as a stand-alone modality in the evaluation of glenohumeral dysplasia. MRI remains the gold standard for fully evaluating the glenohumeral joint. The clinical role of ultrasonography may be that of a screening tool or a way of evaluating joint reduction in real time. LEVEL OF EVIDENCE: Diagnostic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 28099303 TI - Quality of Life in Bilateral Vs. Unilateral End-Stage Ankle Arthritis and Outcomes of Bilateral Vs. Unilateral Total Ankle Replacement. AB - BACKGROUND: We performed a retrospective cohort study to compare preoperative health-related quality of life (HRQoL) between patients with bilateral and those with unilateral end-stage ankle arthritis. We also compared midterm outcomes in a subgroup of patients who had undergone staged bilateral total ankle replacement (TAR) with the outcomes in the group treated with unilateral TAR. METHODS: The HRQoL before surgical treatment was compared between 53 patients with bilateral end-stage ankle arthritis identified from the Canadian Orthopaedic Foot and Ankle Society Prospective Ankle Reconstruction Database and 106 patients with unilateral arthritis selected from the same database. Short Form-36 (SF-36) and American Academy of Orthopaedic Surgeons Foot and Ankle Module (AAOS-FAM) scores were used to assess preoperative HRQoL. Midterm outcomes (implant survival, HRQoL, and reoperation and revision rates) were compared between 37 patients who had undergone staged bilateral TAR and 106 patients treated with unilateral TAR; all patients were followed for at least 2 years. RESULTS: Preoperatively, patients with unilateral disease had a higher prevalence of posttraumatic arthritis, whereas patients with bilateral disease had a higher prevalence of primary and secondary arthritis (p < 0.001). The mean preoperative SF-36 physical component summary (PCS) score in the unilateral group was higher than that in the bilateral group (p < 0.002). The mean postoperative follow-up (and standard deviation) was 5.0 +/- 2.0 years in the bilateral TAR group and 4.0 +/- 1.8 years in the unilateral TAR group. The patients who underwent either unilateral or staged bilateral TAR demonstrated improved SF-36 PCS scores between the preoperative and postoperative evaluations (p < 0.001). The postoperative SF-36 PCS scores were similar between the patients with unilateral TAR and those with bilateral TAR (p = 0.70). Six ankles (6%) in the unilateral cohort and 6 ankles (8%) in the bilateral cohort required revision of the metal component (p = 0.52). The mean implant survival time was 10.9 years (95% confidence interval [CI] = 10.1 to 11.7 years) in the bilateral cohort and 9.2 years (95% CI = 8.5 to 9.8 years) in the unilateral cohort (p = 0.60). CONCLUSIONS: Preoperative SF-36 scores demonstrated that bilateral end-stage ankle arthritis is a more debilitating condition than unilateral arthritis. Patients who underwent staged bilateral TAR benefited as much as patients who underwent unilateral TAR, despite having a worse preoperative health status. Metal component revision rates and implant survival were similar between the 2 groups. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28099304 TI - Three-Dimensional Analysis of Acute Scaphoid Fracture Displacement: Proximal Extension Deformity of the Scaphoid. AB - BACKGROUND: Our goal was to analyze the movement of acute scaphoid waist fracture fragments and adjacent bones in a common coordinate system. Our hypothesis was that the distal scaphoid fragment flexes and pronates and the proximal fragment extends. METHODS: Computed tomography (CT) scans of patients diagnosed with an acute scaphoid waist fracture were evaluated using a 3-dimensional (3D) model. The scans of 57 nondisplaced and 23 displaced fractures were compared with a control group of 27 scans showing no pathological involvement of the wrist. Three anatomical landmarks were labeled on the distal and proximal fragments of the scaphoid, the lunate, and the trapezium. Each set of labels formed a triangle representing the bone or fragment. Four landmarks were labeled on the distal radial articular surface and used to create a common coordinate system. The position of each bone or fragment was calculated in reference to these coordinates. RESULTS: The displaced fracture group showed significant extension, supination, and volar translation of the proximal scaphoid fragment when compared with the other groups. The lunate tended toward a supinated position, which was not statistically significant. The distal scaphoid fragment and the trapezium showed no movement. CONCLUSIONS: In acute displaced scaphoid fractures, it is the proximal fragment that displaces and should be reduced. CLINICAL RELEVANCE: The typical "humpback" deformity is actually a "proximal extension" deformity, the consequence of displacement of the proximal fragment of the scaphoid (with the lunate). Manipulating only the proximal fragment (with the lunate) may be technically easier and more effective than manipulating both fragments. PMID- 28099305 TI - Characterizing the Propionibacterium Load in Revision Shoulder Arthroplasty: A Study of 137 Culture-Positive Cases. AB - BACKGROUND: Propionibacterium is commonly recovered from explants or surrounding tissues in revision shoulder arthroplasty. Rather than attempting to differentiate a true infection from a false-positive result on the basis of the number of positive cultures, we characterized the amount of these bacteria in each specimen and shoulder. METHODS: The study included 137 revision shoulder arthroplasties from which a minimum of 4 specimens had been submitted for culture and at least 1 was positive for Propionibacterium. Standard microbiology procedures were used to assign a semiquantitative value (0.1, 1, 2, 3, or 4), called the Specimen Propi Value, to the amount of growth in each specimen. The sum of the Specimen Propi Values for each shoulder was defined as the Shoulder Propi Score, which was then divided by the total number of specimens to calculate the Average Shoulder Propi Score. RESULTS: The number and percentage of positive specimen-specific cultures (of material obtained from the stem explant, head explant, glenoid explant, humeral membrane, collar membrane, other soft tissue, fluid, or other) per shoulder ranged from 1 to 6 and 14% to 100%. A high percentage of specimens (mean, 43%; median, 50%) from the culture-positive shoulders showed no growth. Only 32.6% of the fluid cultures were positive in comparison with 66.5% of the soft-tissue cultures and 55.6% of the cultures of explant specimens. The average Specimen Propi Value (and standard deviation) for fluid specimens (0.35 +/- 0.89) was significantly lower than those for the soft tissue (0.92 +/- 1.50) and explant (0.66 +/- 0.90) specimens (p < 0.001). The Shoulder Propi Score was significantly higher in men (3.56 +/- 3.74) than in women (1.22 +/- 3.11) (p < 0.001). Similarly, men had a significantly higher Average Shoulder Propi Score (0.53 +/- 0.51) than women (0.19 +/- 0.43) (p < 0.001). CONCLUSIONS: This investigation suggests that Propionibacterium is unevenly distributed within culture-positive revised shoulders. As a result, the specimen number and source (explant, soft tissue, or fluid) have major influences on the culture results for a revised shoulder arthroplasty. We found no evidence that suggested useful threshold values for defining a true infection. LEVEL OF EVIDENCE: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28099306 TI - Nonoperatively Corrected Clubfoot at Age 2 Years: Radiographs Are Not Helpful in Predicting Future Relapse. AB - BACKGROUND: Nonoperative treatment of idiopathic clubfoot is standard. The purpose of this study was to determine if measurements made on standing lateral radiographs of successfully treated clubfeet made at 18 to 24 months of age were predictive of late recurrence. METHODS: Inclusion criteria were idiopathic clubfoot with an age at presentation of <=3 months, nonoperative treatment resulting in a clinically plantigrade foot at 2 years of age, standing lateral radiograph of the involved foot made at 18 to 24 months of age, and a minimum age of 4 years at the time of follow-up. The radiographs were assessed for the talocalcaneal angle and the tibiocalcaneal angle, with measurements made by 2 trained practitioners. The average values of the 2 raters were used. The interobserver reliability was calculated using intraclass correlation coefficients (ICCs). A total of 211 patients with 312 clubfeet were evaluated. The average age at the time of follow-up was 8.0 years (range, 4.0 to 13.3 years). Results at the time of follow-up were rated as good (maintained plantigrade foot), fair (required limited surgery to maintain, or return to, a plantigrade position), or poor (required posteromedial release). RESULTS: Over time, 75% of the feet had a good result, 19% had a fair result, and 6% had a poor result. With regard to radiographic assessment, the ICCs were 0.97 (talocalcaneal angle) and 0.98 (tibiocalcaneal angle), demonstrating excellent agreement between the raters. The mean talocalcaneal angle differed significantly between the feet with a good clinical outcome and those with a fair outcome (28 degrees versus 24 degrees ; p < 0.02), but did not differ significantly between those with a good versus poor outcome (28 degrees versus 26 degrees ), or a fair versus poor outcome (24 degrees versus 26 degrees ). There were no significant differences in the mean tibiocalcaneal angle among the groups (86 degrees , 90 degrees , and 84 degrees , respectively) (p = 0.17). CONCLUSIONS: Most clubfeet that were clinically plantigrade at 2 years of age remained so, while one-fourth subsequently required some surgery for late recurrence, primarily limited procedures. The tibiocalcaneal angle and talocalcaneal angle from standing lateral radiographs made at 18 to 24 months of age were not helpful in predicting future relapse. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28099307 TI - The American Academy of Orthopaedic Surgeons Appropriate Use Criteria for the Management of Patients with Orthopaedic Implants Undergoing Dental Procedures. PMID- 28099308 TI - What's New in Adult Reconstructive Knee Surgery. PMID- 28099309 TI - The Core Competencies for General Orthopaedic Surgeons. AB - BACKGROUND: With the changing delivery of orthopaedic surgical care, there is a need to define the knowledge and competencies that are expected of an orthopaedist providing general and/or acute orthopaedic care. This article provides a proposal for the knowledge and competencies needed for an orthopaedist to practice general and/or acute care orthopaedic surgery. METHODS: Using the modified Delphi method, the General Orthopaedic Competency Task Force consisting of stakeholders associated with general orthopaedic practice has proposed the core knowledge and competencies that should be maintained by orthopaedists who practice emergency and general orthopaedic surgery. RESULTS: For relevancy to clinical practice, 2 basic sets of competencies were established. The assessment competencies pertain to the general knowledge needed to evaluate, investigate, and determine an overall management plan. The management competencies are generally procedural in nature and are divided into 2 groups. For the Management 1 group, the orthopaedist should be competent to provide definitive care including assessment, investigation, initial or emergency care, operative or nonoperative care, and follow-up. For the Management 2 group, the orthopaedist should be competent to assess, investigate, and commence timely non-emergency or emergency care and then either transfer the patient to the appropriate subspecialist's care or provide definitive care based on the urgency of care, exceptional practice circumstance, or individual's higher training. This may include some higher-level procedures usually performed by a subspecialist, but are consistent with one's practice based on experience, practice environment, and/or specialty interest. CONCLUSIONS: These competencies are the first step in defining the practice of general orthopaedic surgery including acute orthopaedic care. Further validation and discussion among educators, general orthopaedic surgeons, and subspecialists will ensure that these are relevant to clinical practice. CLINICAL RELEVANCE: These competencies provide many stakeholders, including orthopaedic educators and orthopaedists, with what may be the minimum knowledge and competencies necessary to deliver acute and general orthopaedic care. This document is the first step in defining a practice-based standard for training programs and certification groups. PMID- 28099310 TI - National Institutes of Health Funding to Departments of Orthopaedic Surgery at U.S. Medical Schools. AB - BACKGROUND: The National Institutes of Health (NIH) is the largest supporter of biomedical research in the U.S., yet its contribution to orthopaedic research is poorly understood. In this study, we analyzed the portfolio of NIH funding to departments of orthopaedic surgery at U.S. medical schools. METHODS: The NIH RePORT (Research Portfolio Online Reporting Tools) database was queried for NIH grants awarded to departments of orthopaedic surgery in 2014. Funding totals were determined for award mechanisms and NIH institutes. Trends in NIH funding were determined for 2005 to 2014 and compared with total NIH extramural research funding. Funding awarded to orthopaedic surgery departments was compared with that awarded to departments of other surgical specialties in 2014. Characteristics of NIH-funded principal investigators were obtained from department web sites. RESULTS: In 2014, 183 grants were awarded to 132 investigators at 44 departments of orthopaedic surgery. From 2005 to 2014, NIH funding increased 24.3%, to $54,608,264 (p = 0.030), but the rates of increase seen did not differ significantly from those of NIH extramural research funding as a whole (p = 0.141). Most (72.6%) of the NIH funding was awarded through the R01 mechanism, with a median annual award of $343,980 (interquartile range [IQR], $38,372). The majority (51.1%) of the total funds supported basic science research, followed by translational (33.0%), clinical (10.0%), and educational (5.9%) research. NIH-funded orthopaedic principal investigators were predominately scientists whose degree was a PhD (71.1%) and who were male (79.5%). Eleven NIH institutes were represented, with the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) providing the preponderance (74.2%) of the funding. In 2014, orthopaedic surgery ranked below the surgical departments of general surgery, ophthalmology, obstetrics and gynecology, otolaryngology, and urology in terms of NIH funding received. CONCLUSIONS: The percentage increase of NIH funding to departments of orthopaedic surgery from 2005 to 2014 was not significantly greater than that of total NIH extramural research funding. Funding levels to orthopaedic surgery departments lag behind funding to departments of other surgical disciplines. Funding levels may not match the academic potential of orthopaedic faculty, and interventions may be needed to increase NIH grant procurement. PMID- 28099311 TI - Aspirin, the Unsung Champion of Deep Venous Thrombosis Chemoprophylaxis: A Historical Perspective: Commentary on an article by Javad Parvizi, MD, FRCS, et al.: "Low-Dose Aspirin Is Effective Chemoprophylaxis Against Clinically Important Venous Thromboembolism Following Total Joint Arthroplasty. A Preliminary Analysis". PMID- 28099312 TI - The Emperor May Truly Have New Clothes: Commentary on an article by Zahab S. Ahsan, MD, et al.: "Characterizing the Propionibacterium Load in Revision Shoulder Arthroplasty. A Study of 137 Culture-Positive Cases." PMID- 28099313 TI - What Makes a Competent Orthopaedist?: Commentary on an article by James F. Kellam, MD, on behalf of the General Orthopaedic Competency Task Force: "The Core Competencies for General Orthopaedic Surgeons". PMID- 28099314 TI - FUNDUS AUTOFLUORESCENCE LIFETIMES AND CENTRAL SEROUS CHORIORETINOPATHY. AB - PURPOSE: To quantify retinal fluorescence lifetimes in patients with central serous chorioretinopathy (CSC) and to identify disease specific lifetime characteristics over the course of disease. METHODS: Forty-seven participants were included in this study. Patients with central serous chorioretinopathy were imaged with fundus photography, fundus autofluorescence, optical coherence tomography, and fluorescence lifetime imaging ophthalmoscopy (FLIO) and compared with age-matched controls. Retinal autofluorescence was excited using a 473-nm blue laser light and emitted fluorescence light was detected in 2 distinct wavelengths channels (498-560 nm and 560-720 nm). Clinical features, mean retinal autofluorescence lifetimes, autofluorescence intensity, and corresponding optical coherence tomography (OCT) images were further analyzed. RESULTS: Thirty-five central serous chorioretinopathy patients with a mean visual acuity of 78 ETDRS letters (range, 50-90; mean Snellen equivalent: 20/32) and 12 age-matched controls were included. In the acute stage of central serous chorioretinopathy, retinal fluorescence lifetimes were shortened by 15% and 17% in the respective wavelength channels. Multiple linear regression analysis showed that fluorescence lifetimes were significantly influenced by the disease duration (P < 0.001) and accumulation of photoreceptor outer segments (P = 0.03) but independent of the presence or absence of subretinal fluid. Prolonged central macular autofluorescence lifetimes, particularly in eyes with retinal pigment epithelial atrophy, were associated with poor visual acuity. CONCLUSION: This study establishes that autofluorescence lifetime changes occurring in central serous chorioretinopathy exhibit explicit patterns which can be used to estimate perturbations of the outer retinal layers with a high degree of statistical significance. PMID- 28099315 TI - FACTORS ASSOCIATED WITH VISUAL OUTCOME AFTER MACULA-OFF RHEGMATOGENOUS RETINAL DETACHMENT SURGERY. AB - PURPOSE: To evaluate preoperative factors influencing the visual outcome and postoperative factors associated with the changes in visual acuity, after reattachment surgery to treat macula-off rhegmatogenous retinal detachment. METHODS: A total of 180 eyes of 180 patients who underwent reattachment surgery to treat macula-off rhegmatogenous retinal detachment, and who were followed up for more than 12 months, were reviewed retrospectively. Preoperative and postoperative characteristics, including optical coherence tomography findings, were comprehensively analyzed using univariate and multivariate models to evaluate preoperative factors influencing best-corrected visual acuity 12 months after macula-off rhegmatogenous retinal detachment surgery and postoperative factors associated with changes in best-corrected visual acuity after surgery. RESULTS: Preoperatively, the extent of detachment (P = 0.037), macula-off duration (P < 0.001), and integrity of the external limiting membrane (beta = 0.163; P = 0.002) were significantly associated with postoperative visual prognosis. Six factors were associated with changes in visual acuity after surgery: disruption of ellipsoid zone integrity (beta = 0.167; P < 0.001), the Henle's fiber layer and the outer nuclear layer (HFL + ONL)/photoreceptor layer ratio (beta = 0.199; P < 0.001), the photoreceptor outer segment length (beta = 0.020; P < 0.001), the photoreceptor inner segment length/photoreceptor outer segment length ratio (beta = 0.047; P = 0.005), the ratio of photoreceptor layer thickness between the RD eye and fellow eye (beta = -0.126; P = 0.018), and the photoreceptor outer segment length ratio between the RD eye and fellow eye (beta = -0.425; P < 0.001). CONCLUSION: Preoperative factors associated with the visual outcome after macula-off rhegmatogenous retinal detachment surgery were the extent of detachment, macula-off duration, and external limiting membrane integrity. Postoperatively, predictive factors were the outer retinal microstructures, particularly the photoreceptor outer segment layer. PMID- 28099316 TI - PNEUMATIC VITREOLYSIS FOR RELIEF OF VITREOMACULAR TRACTION. AB - PURPOSE: To evaluate the outcome of perfluoropropane (C3F8) gas injection for symptomatic vitreomacular traction (VMT) with or without Stage 2 macular hole (MH). METHODS: A retrospective review of eyes with VMT treated with 0.3 mL of C3F8 gas was performed. Patients avoided the supine position until gas resolution. Patients with small MH maintained partial face-down positioning. RESULTS: Forty-nine consecutive patients (50 eyes) with symptomatic VMT underwent pneumatic vitreolysis between 2010 and 2016. A posterior vitreous detachment developed in 43 eyes (86.0%) after a single gas injection, at a median of 3.0 weeks. Twenty-eight of 35 eyes (80.0%) with VMT only and all 15 eyes (100%) with a small Stage 2 MH developed a posterior vitreous detachment, with MH closure in 10 of 15 eyes (66.7%). Median baseline and last best spectacle-corrected visual acuities were 20/50 and 20/40, respectively (P < 0.001). Mean follow-up time was 11.1 +/- 9.9 months. Rate of posterior vitreous detachment was reduced with presence of diabetes mellitus (25%) and with thick cellophane membrane (50%). Univariate analysis showed increased VMT release for eyes with VMT extent within 1 disk area (chi = 13.1, P = 0.002), eyes with absence of diabetes mellitus (chi = 8.8, P = 0.007), and eyes with Stage 2 MH (chi = 5.47, P = 0.019); there was a trend between success and lack of thick cellophane membrane (chi = 3.32, P = 0.068). Results using logistic regression also showed younger age (P = 0.012), followed by better baseline best spectacle-corrected visual acuity (P = 0.044), lack of diabetes mellitus (P = 0.077), and female gender (P = 0.045) to be predictors of increased VMT release. One VMT-only eye formed a MH and another VMT only eye developed a retinal detachment. Both eyes responded to vitrectomy. CONCLUSION: Pneumatic vitreolysis with limited face-down position is a viable option for treating VMT with few adverse events. More studies are needed to elucidate its indications, benefits, and risks. PMID- 28099317 TI - STARGARDT DISEASE: Beyond Flecks and Atrophy. AB - PURPOSE: To identify changes in the outer retina in areas without atrophy or flecks of Stargardt disease (STGD) using spectral-domain optical coherence tomography. METHODS: Twenty-three STGD patients and 26 control subjects were assessed for outer retina (from the outer border of Bruch membrane [BrM] to the inner border of the inner segment ellipsoid zone [EZ]), BrM-retinal pigment epithelium apex, the EZ thickness, and apical process interdigitation zone. RESULTS: Patients with STGD had increased BrM-EZ thickness in areas without apparent disease versus control subjects at 1,000, 1,500, 2,000, and 2,500 MUm superior and 1,500 MUm, 2,000 MUm, and 2,500 MUm inferior to the fovea (P < 0.05 to P < 0.001), greatest difference (3.4 MUm) at 2,500 MUm superiorly. The BrM retinal pigment epithelium segment showed larger fractional contribution of 0.48 to 0.51 to the overall BrM-EZ thickness compared with 0.35 to 0.42 in control subjects. The thickness of EZ and the interspace between the retinal pigment epithelium apex and EZ were smaller in the STGD patients (P < 0.05 to P < 0.001). Patients with STGD displayed an interrupted interdigitation zone in 16 (84.2%) of 19 eyes versus 6 (23.1%) of 26 eyes of the control subjects (P < 0.001). The BrM EZ segment of the outer retina of STGD patients lacked the typical normal trilaminar pattern. CONCLUSION: Subtle changes are present within the BrM-EZ segment of the outer retina of STGD patients in areas that are devoid of atrophy and flecks. These findings suggest that pathologic changes in STGD are more widespread than that seen by clinical examination. PMID- 28099318 TI - LOW ENDOPHTHALMITIS RATES AFTER INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR INJECTIONS IN AN OPERATION ROOM: A Retrospective Multicenter Study. AB - PURPOSE: To evaluate the rate of presumed endophthalmitis (EO) after intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections in three European hospitals performed in an operation room (OR) under sterile conditions. METHODS: A retrospective multicenter study between 2003 and 2016 at three European sites, City Hospital Triemli Zurich, Switzerland (CHT), Zealand University Hospital Roskilde, Denmark (ZUH) and University Clinic Bern, Switzerland (UCB). Intravitreal injection (IVI) database of each department was reviewed. All anti vascular endothelial growth factor injections were performed using a standardized sterile technique in an operation room. Injection protocols were similar between the three sites. No preinjection antibiotics were given. Postoperative antibiotics varied among sites. RESULTS: A total of 134,701 intravitreal injections were performed at the 3 sites between 2003 and 2016. Ten cases of presumed endophthalmitis were documented: 4 in 50,721 at CHT (95% CI: 0.0071 0.0087%), 2 in 44,666 at ZUH (95% CI: 0.0039-0.0051%), and 4 in 39,314 at UCB (95% CI: 0.0092-0.011%). This results in one case in 13,470 intravitreal injections and a combined incidence of 0.0074% per injection (95% CI: 0.0070 0.0078%). Positive cultures were found in 4 out of 10 presumed endophthalmitis cases. CONCLUSION: The standardized sterile technique in an operation room with laminar airflow showed very low rates of endophthalmitis at three European sites. PMID- 28099319 TI - Reply. PMID- 28099320 TI - Closed-Loop Delivery Systems Versus Manually Controlled Administration of Total IV Anesthesia: A Meta-analysis of Randomized Clinical Trials. AB - Bispectral Index Scale (BIS)-guided closed-loop delivery of anesthetics has been extensively studied. We performed a meta-analysis of all the randomized clinical trials comparing efficacy and performance between BIS-guided closed-loop delivery and manually controlled administration of total IV anesthesia. Scopus, PubMed, EMBASE, and the Cochrane Central Register of clinical trials were searched for pertinent studies. Inclusion criteria were random allocation to treatment and closed-loop delivery systems versus manually controlled administration of total IV anesthesia in any surgical setting. Exclusion criteria were duplicate publications and nonadult studies. Twelve studies were included, randomly allocating 1284 patients. Use of closed-loop anesthetic delivery systems was associated with a significant reduction in the dose of propofol administered for induction of anesthesia (mean difference [MD] = 0.37 [0.17-0.57], P for effect <0.00001, P for heterogeneity = 0.001, I = 74%) and a significant reduction in recovery time (MD = 1.62 [0.60-2.64], P for effect <0.0001, P for heterogeneity = 0.06, I = 47%). The target depth of anesthesia was preserved more frequently with closed-loop anesthetic delivery than with manual control (MD = -15.17 [-23.11 to 7.24], P for effect <0.00001, P for heterogeneity <0.00001, I = 83%). There were no differences in the time required to induce anesthesia and the total propofol dose. Closed-loop anesthetic delivery performed better than manual-control delivery. Both median absolute performance error and wobble index were significantly lower in closed-loop anesthetic delivery systems group (MD = 5.82 [3.17-8.46], P for effect <0.00001, P for heterogeneity <0.00001, I = 90% and MD = 0.92 [0.13-1.72], P for effect = 0.003, P for heterogeneity = 0.07, I = 45%). When compared with manual control, BIS-guided anesthetic delivery of total IV anesthesia reduces propofol requirements during induction, better maintains a target depth of anesthesia, and reduces recovery time. PMID- 28099321 TI - Preoxygenation: Physiologic Basis, Benefits, and Potential Risks. AB - Preoxygenation before anesthetic induction and tracheal intubation is a widely accepted maneuver, designed to increase the body oxygen stores and thereby delay the onset of arterial hemoglobin desaturation during apnea. Because difficulties with ventilation and intubation are unpredictable, the need for preoxygenation is desirable in all patients. During emergence from anesthesia, residual effects of anesthetics and inadequate reversal of neuromuscular blockade can lead to hypoventilation, hypoxemia, and loss of airway patency. In accordance, routine preoxygenation before the tracheal extubation has also been recommended. The objective of this article is to discuss the physiologic basis, clinical benefits, and potential concerns about the use of preoxygenation. The effectiveness of preoxygenation is assessed by its efficacy and efficiency. Indices of efficacy include increases in the fraction of alveolar oxygen, increases in arterial oxygen tension, and decreases in the fraction of alveolar nitrogen. End points of maximal preoxygenation (efficacy) are an end-tidal oxygen concentration of 90% or an end-tidal nitrogen concentration of 5%. Efficiency of preoxygenation is reflected in the rate of decline in oxyhemoglobin desaturation during apnea. All investigations have demonstrated that maximal preoxygenation markedly delays arterial hemoglobin desaturation during apnea. This advantage may be blunted in high-risk patients. Various maneuvers have been introduced to extend the effect of preoxygenation. These include elevation of the head, apneic diffusion oxygenation, continuous positive airway pressure (CPAP) and/or positive end expiratory pressure (PEEP), bilevel positive airway pressure, and transnasal humidified rapid insufflation ventilatory exchange. The benefit of apneic diffusion oxygenation is dependent on achieving maximal preoxygenation, maintaining airway patency, and the existence of a high functional residual capacity to body weight ratio. Potential risks of preoxygenation include delayed detection of esophageal intubation, absorption atelectasis, production of reactive oxygen species, and undesirable hemodynamic effects. Because the duration of preoxygenation is short, the hemodynamic effects and the accumulation of reactive oxygen species are insufficient to negate its benefits. Absorption atelectasis is a consequence of preoxygenation. Two approaches have been proposed to reduce the absorption atelectasis during preoxygenation: a modest decrease in the fraction of inspired oxygen to 0.8, and the use of recruitment maneuvers, such as CPAP, PEEP, and/or a vital capacity maneuver (all of which are commonly performed during the administration of anesthesia). Although a slight decrease in the fraction of inspired oxygen reduces atelectasis, it does so at the expense of a reduction in the protection afforded during apnea. PMID- 28099322 TI - Mitochondrial DNA and TLR9 Signaling Is Not Involved in Mechanical Ventilation Induced Inflammation. AB - Exogenous administration of mitochondrial DNA (mtDNA) causes inflammatory lung injury in a toll-like receptor (TLR) 9-dependent manner. We investigated whether mechanical ventilation results in endogenous release of mtDNA and whether TLR9 plays a role in the pulmonary inflammatory response induced by mechanical ventilation.Wild-type and TLR9/ C57bl/6 mice were ventilated with low (8 mL/kg) and high (32 mL/kg) tidal volumes for 4 hours. Levels of nuclear DNA and mtDNA in bronchoalveolar lavage fluid, as well as pulmonary concentrations of keratinocyte derived chemokine, interleukin-1beta, and interleukin-6, were determined.Cytokine and nuclear DNA, but not mtDNA, levels were increased after mechanical ventilation with both tidal volumes. Cytokine concentrations were similar between wild-type and TLR9/ mice. Mechanical ventilation does not result in the release of mtDNA, and TLR9 is not involved in mechanical ventilation-induced inflammation. PMID- 28099323 TI - Anesthesia and Databases: Pediatric Cardiac Disease as a Role Model. AB - Large data sets have now become ubiquitous in clinical medicine; they are particularly useful in high-acuity, low-volume conditions such as congenital heart disease where data must be collected from many centers. These data fall into 2 categories: administrative data arising from hospital admissions and charges and clinical data relating to specific diseases or procedures. In congenital cardiac diseases, there are now over a dozen of these data sets or registries focusing on various elements of patient care. Using probabilistic statistic matching, it is possible to marry administrative and clinical data post hoc using common elements to determine valuable information about care patterns, outcomes, and costs. These data sets can also be used in a collaborative fashion between institutions to drive quality improvement (QI). Because these data may include protected health information (PHI), care must be taken to adhere to federal guidelines on their use. A fundamental principle of large data management is the use of a common language and definition (nomenclature) to be effective. In addition, research derived from these information sources must be appropriately balanced to ensure that risk adjustments for preoperative and surgical factors are taken into consideration during the analysis. Care of patients with cardiac disease both in the United States and abroad consistently shows wide variability in mortality, morbidity, and costs, and there has been a tremendous amount of discussion about the benefits of regionalization of care based on center volume and outcome measurements. In the absence of regionalization, collaborative learning techniques have consistently been shown to minimize this variability and improve care at all centers, but before changes can be made it is necessary to accurately measure accurately current patient outcomes. Outcomes measurement generally falls under hospital-based QI initiatives, but more detailed analysis and research require Institutional Review Board and administrative oversight. Cardiac anesthesia providers for these patients have partnered with the Society of Thoracic Surgeons Congenital Heart surgeons to include anesthesia elements to help in this process. PMID- 28099325 TI - Intraoperative Clinical Decision Support for Anesthesia: A Narrative Review of Available Systems. AB - With increasing adoption of anesthesia information management systems (AIMS), there is growing interest in utilizing AIMS data for intraoperative clinical decision support (CDS). CDS for anesthesia has the potential for improving quality of care, patient safety, billing, and compliance. Intraoperative CDS can range from passive and post hoc systems to active real-time systems that can detect ongoing clinical issues and deviations from best practice care. Real-time CDS holds the most promise because real-time alerts and guidance can drive provider behavior toward evidence-based standardized care during the ongoing case. In this review, we describe the different types of intraoperative CDS systems with specific emphasis on real-time systems. The technical considerations in developing and implementing real-time CDS are systematically covered. This includes the functional modules of a CDS system, development and execution of decision rules, and modalities to alert anesthesia providers concerning clinical issues. We also describe the regulatory aspects that affect development, implementation, and use of intraoperative CDS. Methods and measures to assess the effectiveness of intraoperative CDS are discussed. Last, we outline areas of future development of intraoperative CDS, particularly the possibility of providing predictive and prescriptive decision support. PMID- 28099324 TI - Interaction of Isoflurane, Tumor Necrosis Factor-alpha and beta-Amyloid on Long term Potentiation in Rat Hippocampal Slices. AB - BACKGROUND: The relationship between inhalational anesthetics such as isoflurane and cognitive impairment in the elderly is controversial. Both beta-amyloid peptide (Abeta), associated with Alzheimer disease, and tumor necrosis factor alpha (TNF-alpha), a proinflammatory stress-related peptide, impair the synaptic function. We hypothesized that transient exposure to isoflurane and these peptides would impair synaptic function, manifest as a depression of long-term potentiation (LTP) and paired pulse facilitation (PPF), in the rat hippocampus. METHODS: Hippocampal slices were prepared from 3- to 4-week-old male Wistar rats. Preliminary experiments identified minimal concentrations of Abeta1-42 peptide and TNF-alpha that produced statistically detectable suppressing effects on LTP (600 nM Abeta1-42 and 5 ng/mL TNF-alpha). These concentrations of peptides were applied to slices alone, with 1.5% isoflurane, or in combination for 1 hour and then washed out. Measurements of LTP (field excitatory postsynaptic potentials [fEPSPs]) from neurons in the CA1 area by stimulation of the Schaffer-Collateral pathway were made after high-frequency stimulation (100 Hz, 1 second). Analysis of variance with correction for multiple comparisons was used to compare LTP under steady-state conditions and averaged for the 40- to 60-minute period after LTP induction. RESULTS: EPSP amplitude after LTP induction was 155% +/- 9% of baseline and was not affected by isoflurane exposure and washout (150% +/- 4% of baseline, P = .47). Both Abeta1-42 and TNF-alpha reduced LTP by approximately 15% compared with control (129% +/- 7% and 131% +/- 11% of baseline respectively, means +/- SD, both P < .001). When Abeta1-42 was combined with isoflurane, LTP was not impaired (151% +/- 9% of control, P = .85), but isoflurane had no effect on LTP depression caused by TNF-alpha or a combination of Abeta and TNF-alpha. CONCLUSIONS: Brief exposure to isoflurane prevents rather than impairs the decrease in LTP caused by Abeta1-42 in rat hippocampus. In contrast, isoflurane had no effect on synaptic impairment caused by TNF-alpha or a combination of TNF alpha and Abeta. Although this is an in vitro study and translation to clinical medicine requires additional work, the interactions of isoflurane, Abeta, and TNF alpha revealed here could have implications for patients with Alzheimer disease or perioperative neuroinflammation. PMID- 28099326 TI - Implementation of a Needs-Based, Online Feedback Tool for Anesthesia Residents With Subsequent Mapping of the Feedback to the ACGME Milestones. AB - BACKGROUND: Optimizing feedback that residents receive from faculty is important for learning. The goals of this study were to (1) conduct focus groups of anesthesia residents to define what constitutes optimal feedback; (2) develop, test, and implement a web-based feedback tool; and (3) then map the contents of the written comments collected on the feedback tool to the Accreditation Council for Graduate Medical Education (ACGME) anesthesiology milestones. METHODS: All 72 anesthesia residents in the program were invited to participate in 1 of 5 focus groups scheduled over a 2-month period. Thirty-seven (51%) participated in the focus groups and completed a written survey on previous feedback experiences. On the basis of the focus group input, an initial online feedback tool was pilot tested with 20 residents and 62 feedback sessions, and then a final feedback tool was deployed to the entire residency to facilitate the feedback process. The completed feedback written entries were mapped onto the 25 ACGME anesthesiology milestones. RESULTS: Focus groups revealed 3 major barriers to good feedback: (1) too late such as, for example, at the end of month-long clinical rotations, which was not useful because the feedback was delayed; (2) too general and not specific enough to immediately remedy behavior; and (3) too many in that the large number of evaluations that existed that were unhelpful such as those with unclear behavioral anchors compromised the overall feedback culture. Thirty residents (42% of 72 residents in the program) used the final online feedback tool with 121 feedback sessions with 61 attendings on 15 rotations at 3 hospital sites. The number of feedback tool uses per resident averaged 4.03 (standard deviation 5.08, median 2, range 1-21, 25th-75th % quartile 1-4). Feedback tool uses per faculty averaged 1.98 (standard deviation 3.2, median 1, range 1-25, 25th-75th % quartile 1-2). For the feedback question item "specific learning objective demonstrated well by the resident," this yielded 296 milestone-specific responses. The majority (71.3%) were related to the patient care competency, most commonly the anesthetic plan and conduct (35.8%) and airway management (11.1%) milestones; 10.5% were related to the interpersonal and communication skills competency, most commonly the milestones communication with other professionals (4.4%) or with patients and families (4.4%); and 8.4% were related to the practice-based learning and improvement competency, most commonly self-directed learning (6.1%). For the feedback tool item "specific learning objective that resident may improve," 67.0% were related to patient care, most commonly anesthetic plan and conduct (33.5%) followed by use/interpretation of monitoring and equipment (8.5%) and airway management (8.5%); 10.2% were related to practice-based learning and improvement, most commonly self-directed learning (6.8%); and 9.7% were related to the systems-based practice competency. CONCLUSIONS: Resident focus groups recommended that feedback be timely and specific and be structured around a tool. A customized online feedback tool was developed and implemented. Mapping of the free-text feedback comments may assist in assessing milestones. Use of the feedback tool was lower than expected, which may indicate that it is just 1 of many implementation steps required for behavioral and culture change to support a learning environment with frequent and useful feedback. PMID- 28099327 TI - A meta-analysis and systematic review: Success of endoscopic ultrasound guided biliary stenting in patients with inoperable malignant biliary strictures and a failed ERCP. AB - BACKGROUND: In patients with inoperable malignant biliary strictures, endoscopic retrograde cholangiopancreatography (ERCP) guided biliary stenting fails in 5% to 10% patients due to difficult anatomy/inability to cannulate the papilla. Recently, endoscopic ultrasound guided biliary drainage (EUS-BD) has been described.Primary outcomes were to evaluate the biliary drainage success rates with EUS and compare it to percutaneous transhepatic biliary drainage (PTBD). Secondary outcomes were to evaluate overall procedure related complications. METHODS: STUDY SELECTION CRITERIA:: Studies evaluating the efficacy of EUS-BD and comparing EUS-BD versus PTBD in inoperable malignant biliary stricture patients with a failed ERCP were included in this analysis. DATA COLLECTION AND EXTRACTION: Articles were searched in Medline, PubMed, and Ovid journals. Two authors independently searched and extracted data. The study design was written in accordance to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Subgroup analyses of prospective studies and EUS-BD versus PTBD were performed. STATISTICAL METHOD: Pooled proportions were calculated using fixed and random effects model. I statistic was used to assess heterogeneity among studies. RESULTS: Initial search identified 846 reference articles, of which 124 were selected and reviewed. Sixteen studies (N = 528) that met the inclusion criteria were included in this analysis. In the pooled patient population, the percentage of patients that had a successful biliary drainage with EUS was 90.91% (95% CI = 88.10-93.38). The proportion of patients that had overall procedure related complications with EUS-PD was 16.46% (95% CI = 13.20 20.01). The pooled odds ratio for successful biliary drainage in EUS-PD versus PTBD group was 3.06 (95% CI = 1.11-8.43). The risk difference for overall procedure related complications in EUS-PD versus PTBD group was -0.21 (95% CI = 0.35 to -0.06). Relative risk for infectious complications and bile leak in EUS BD versus PTBD was 0.25 (95% CI = 0.07-0.94) and 0.33 (95% CI = 0.12-0.87), respectively. CONCLUSIONS: In patients with inoperable malignant biliary strictures who failed an ERCP guided biliary stenting, EUS-BD seems to be an excellent management option and superior to PTBD with higher successful biliary drainage rates and relatively fewer complications. PMID- 28099328 TI - Clinical and prognostic significance of Merkel cell polyomavirus in nonsmall cell lung cancer. AB - Recently, an association between Merkel cell polyomavirus (MCPyV) and epidermal growth factor receptor (EGFR) mutations in nonsmall cell lung cancer (NSCLC) was reported. However, the underlying carcinogenic effects and the prognosis related to MCPyV are still unclear. The aim of this study was to clarify the incidence and prognosis related to MCPyV infections in NSCLC.Tissue samples from 167 NSCLC patients (92 with squamous cell carcinomas [SCCs] and 75 with adenocarcinomas) were analyzed for the presence of MCPyV and EGFR mutations. Clinicopathological characteristics, disease-free survival rate, and overall survival rate were assessed with respect to MCPyV.MCPyV DNA was detected in 30 patients (18.0%) out of 167 patients, and EGFR mutations were found in 31 out of 127 patients (24.4%). EGFR mutations were more frequently detected in MCPyV-positive patients than in MCPyV-negative patients; however, this did not reach statistical significance (P = 0.075). There was no difference in overall survival between patients with and without MCPyV infections. The disease-free survival rate of patients with pN0 stage, SCC, or EGFR mutations was lower for patients with MCPyV than without MCPyV (P = 0.036, 0.042, and 0.050, respectively).Although the prevalence of MCPyV infection was relatively low, the presence of MCPyV DNA was significantly correlated with cancer prognosis in subgroups of NSCLC patients. These results suggest that MCPyV may be partly associated with pathogenesis and prognosis in some cases of NSCLC. PMID- 28099329 TI - Evaluation of efficacy of transcatheter arterial chemoembolization combined with computed tomography-guided radiofrequency ablation for hepatocellular carcinoma using magnetic resonance diffusion weighted imaging and computed tomography perfusion imaging: A prospective study. AB - BACKGROUND: The purpose of this study is to evaluate the efficacy of transcatheter arterial chemoembolization (TACE) combined with computed tomography guided radiofrequency ablation (CT-RFA) in the treatment of hepatocellular carcinoma (HCC) using magnetic resonance diffusion weighted imaging (MR-DWI) and CT perfusion imaging (CT-PI). METHODS: From January 2008 to January 2014, a total of 522 HCC patients receiving TACE combined with CT-RFA were included in this study. All patients underwent TACE followed by CT-RFA, and 1 day before treatment and 1 month after treatment they received MR-DWI and CT-PI. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the concentration of alpha fetoprotein (AFP). Tumor response was evaluated using the revised RECIST criteria. One-year follow-up was conducted on all patients. Receiver-operating characteristic (ROC) curve was drawn to evaluate the efficacy of TACE combined with CT-RFA for HCC using MR-DWI and CT-PI. RESULTS: Total effective rate (complete remission [CR] + partial remission [PR]) of TACE combined with CT-RFA for HCC was 82.95%. HCC patients of CR + PR had lower hepatic blood flow (HBF), hepatic blood volume (HBV), permeability surface (PS), hepatic arterial perfusion (HAP), and hepatic perfusion index (HPI) levels than those of SD + PD, but HCC patients of CR + PR had higher mean transit time (MTT) level than those of SD + PD. The patients of PR + CR had higher apparent diffusion coefficient (ADC) values than those of SD + PD. The patients of PR + CR showed lower AFP concentration than those of SD + PD. ROC curve analysis indicated that the area under the curve (AUC) of AFP, HBV, PS, HAP, HPI, and ADC was more than 0.7, but the AUC of HBF, MTT, and PVP were less than 0.7. After treatment, the AFP, HBF, HBV, PS, HAP, and HPI in the HCC patients with recurrence were higher than those in the HCC patients without, but MTT and ADC in the HCC patients with recurrence were lower than those in the HCC patients without. CONCLUSION: These findings indicate that MR-DWI and CT-PI can effectively evaluate the efficacy of TACE combined with CT-RFA and postoperative recurrence of HCC. PMID- 28099330 TI - Clarifying the debate on population-based screening for breast cancer with mammography: A systematic review of randomized controlled trials on mammography with Bayesian meta-analysis and causal model. AB - BACKGROUND: The recent controversy about using mammography to screen for breast cancer based on randomized controlled trials over 3 decades in Western countries has not only eclipsed the paradigm of evidence-based medicine, but also puts health decision-makers in countries where breast cancer screening is still being considered in a dilemma to adopt or abandon such a well-established screening modality. METHODS: We reanalyzed the empirical data from the Health Insurance Plan trial in 1963 to the UK age trial in 1991 and their follow-up data published until 2015. We first performed Bayesian conjugated meta-analyses on the heterogeneity of attendance rate, sensitivity, and over-detection and their impacts on advanced stage breast cancer and death from breast cancer across trials using Bayesian Poisson fixed- and random-effect regression model. Bayesian meta-analysis of causal model was then developed to assess a cascade of causal relationships regarding the impact of both attendance and sensitivity on 2 main outcomes. RESULTS: The causes of heterogeneity responsible for the disparities across the trials were clearly manifested in 3 components. The attendance rate ranged from 61.3% to 90.4%. The sensitivity estimates show substantial variation from 57.26% to 87.97% but improved with time from 64% in 1963 to 82% in 1980 when Bayesian conjugated meta-analysis was conducted in chronological order. The percentage of over-detection shows a wide range from 0% to 28%, adjusting for long lead-time. The impacts of the attendance rate and sensitivity on the 2 main outcomes were statistically significant. Causal inference made by linking these causal relationships with emphasis on the heterogeneity of the attendance rate and sensitivity accounted for the variation in the reduction of advanced breast cancer (none-30%) and of mortality (none-31%). We estimated a 33% (95% CI: 24 42%) and 13% (95% CI: 6-20%) breast cancer mortality reduction for the best scenario (90% attendance rate and 95% sensitivity) and the poor scenario (30% attendance rate and 55% sensitivity), respectively. CONCLUSION: Elucidating the scenarios from high to low performance and learning from the experiences of these trials helps screening policy-makers contemplate on how to avoid errors made in ineffective studies and emulate the effective studies to save women lives. PMID- 28099331 TI - Atorvastatin-induced necrotizing autoimmune myositis: An emerging dominant entity in patients with autoimmune myositis presenting with a pure polymyositis phenotype. AB - The general aim of this study was to evaluate the disease spectrum in patients presenting with a pure polymyositis (pPM) phenotype. Specific objectives were to characterize clinical features, autoantibodies (aAbs), and membrane attack complex (MAC) in muscle biopsies of patients with treatment-responsive, statin exposed necrotizing autoimmune myositis (NAM). Patients from the Centre hospitalier de l'Universite de Montreal autoimmune myositis (AIM) Cohort with a pPM phenotype, response to immunosuppression, and follow-up >=3 years were included. Of 17 consecutive patients with pPM, 14 patients had a NAM, of whom 12 were previously exposed to atorvastatin (mean 38.8 months). These 12 patients were therefore suspected of atorvastatin-induced AIM (atorAIM) and selected for study. All had aAbs to 3-hydroxy-3-methylglutaryl coenzyme A reductase, and none had overlap aAbs, aAbs to signal recognition particle, or cancer. Three stages of myopathy were recognized: stage 1 (isolated serum creatine kinase [CK] elevation), stage 2 (CK elevation, normal strength, and abnormal electromyogram [EMG]), and stage 3 (CK elevation, proximal weakness, and abnormal EMG). At diagnosis, 10/12 (83%) patients had stage 3 myopathy (mean CK elevation: 7247 U/L). The presenting mode was stage 1 in 6 patients (50%) (mean CK elevation: 1540 U/L), all of whom progressed to stage 3 (mean delay: 37 months) despite atorvastatin discontinuation. MAC deposition was observed in all muscle biopsies (isolated sarcolemmal deposition on non-necrotic fibers, isolated granular deposition on endomysial capillaries, or mixed pattern). Oral corticosteroids alone failed to normalize CKs and induce remission. Ten patients (83%) received intravenous immune globulin (IVIG) as part of an induction regimen. Of 10 patients with >=1 year remission on stable maintenance therapy, IVIG was needed in 50%, either with methotrexate (MTX) monotherapy or combination immunosuppression. In the remaining patients, MTX monotherapy or combination therapy maintained remission without IVIG. AtorAIM emerged as the dominant entity in patients with a pPM phenotype and treatment-responsive myopathy. Isolated CK elevation was the mode of presentation of atorAIM. The new onset of isolated CK elevation on atorvastatin and persistent CK elevation on statin discontinuation should raise early suspicion for atorAIM. Statin-induced AIM should be included in the differential diagnosis of asymptomatic hyperCKemia. Three patterns of MAC deposition, while nonpathognomonic, were pathological clues to atorAIM. AtorAIM was uniformly corticosteroid resistant but responsive to IVIG as induction and maintenance therapy. PMID- 28099332 TI - Lung ultrasound for the diagnosis of pneumonia in adults: A meta-analysis. AB - BACKGROUND: Pneumonia is a common and serious infectious disease that can cause high mortality. The role of lung ultrasound (LUS) in the diagnosis of pneumonia is becoming more and more important. METHODS: In the present study, we collected existing evidence regarding the use of LUS to diagnose pneumonia in adults and conducted a systematic review to summarize the technique's diagnostic accuracy. We specifically searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and Embase databases and retrieved outcome data to evaluate the efficacy of LUS for the diagnosis of pneumonia compared with chest radiography or chest computed tomography. The pooled sensitivity (SEN) and specificity (SPE) were determined using the Mantel-Haenszel method, and the pooled diagnostic odds ratio (DOR) was determined using the DerSimonian-Laird method. We also assessed heterogeneity of sensitivity, specificity, and diagnostic odds ratio using the Q and I statistics. RESULTS: Twelve studies containing 1515 subjects were included in our meta-analysis. The SEN and SPE were 0.88 (95% CI: 0.86-0.90) and 0.86 (95% CI: 0.83-0.88), respectively. The pooled negative likelihood ratio (LR) was 0.13 (95% CI: 0.08-0.23), the positive LR was 5.37 (95% CI: 2.76-10.43), and the DOR was 65.46 (95% CI: 29.24-146.56). The summary receiver operating characteristic curve indicated a relationship between sensitivity and specificity. The area under the curve for LUS was 0.95. CONCLUSION: LUS can help to diagnose adult pneumonia with high accuracy. PMID- 28099333 TI - Sarcomatoid carcinoma of the common bile duct: A case report. AB - RATIONALE: Sarcomatoid carcinoma is an extremely rare lesion in the common bile duct (CBD). PATIENT CONCERNS: We present a case of sarcomatoid carcinoma of the distal CBD in a 51-year-old woman who presented with jaundice and abdominal pain. Whipple's operation was performed successfully. Microscopically, the tumor was a poorly differentiated carcinoma containing a component of sarcoma-like differentiation. The tumor cells displayed spindle-shaped nuclei with occasional mitotic figures. Cytokeratin (CK) 7, CK19, CK18, and pan-CK (AE1/AE3) staining was positive on immunohistochemistry. Vimentin and carcinoembryonic antigen (CEA) staining were also positive. DIAGNOSES: Sarcomatoid carcinoma of the distal CBD. INTERVENTIONS: The patient received three cycles of chemotherapy after surgery. OUTCOMES: The patient has experienced no adverse events in the 3 years post surgery. LESSONS: We present here a case report of sarcomatoid carcinoma of the distal CBD. The patient received chemotherapy after surgery, and was event-free for 3 years post-surgery, suggesting a relatively better prognosis, despite the infiltrative pattern of the tumor. PMID- 28099334 TI - Laparoscopic Toupet fundoplication with duodenojejunostomy for the management of superior mesenteric artery syndrome with reflux symptoms. AB - RATIONALE: The patient had symptoms of GERD and the reflux even caused the symptom of cough. Gaining weight is a risk factor for the treatment of reflux as it could exacerbated symptoms of reflux and the drug treatment is not effective. Surgical intervention becomes necessary when there is failure following conservative medical therapy or the patient. PATIENT CONCERNS: The patient was not satisfied with the drug treatment. DIAGNOSES: Superior mesenteric artery syndrome, gastroesophageal reflux disease. INTERVENTIONS: Laparoscopic Toupet fundoplication with duodenojejunostomy. OUTCOMES: The patient discharged from hospital 10 days after surgery without any postoperative complication. The patient achieved complete relief of symptoms and discontinuation of drug. LESSONS SUBSECTIONS: Superior mesenteric artery (SMA) syndrome may manifest the symptoms of GERD such as heartburn, acid reflux and cough. It is necessary to complete examination to exclude superior mesenteric artery syndrome for these patients. Laparoscopic fundoplication with duodenojejunostomy provided an effective treatment for patients who failed drug treatment. PMID- 28099335 TI - Micronodular pattern of organizing pneumonia: Case report and systematic literature review. AB - RATIONALE: Organizing pneumonia (OP) is a clinicopathological entity characterized by granulation tissue plugs in the lumen of small airways, alveolar ducts, and alveoli. OP can be cryptogenic (primary) (COP) or secondary to various lung injuries. PATIENT CONCERNS: We report the case of a 38-year-old male smoker with COP presenting in the form of diffuse micronodules on computed tomography (CT) scan and describe the clinical, radiological, and functional characteristics of micronodular pattern of organizing pneumonia (MNOP) based on a review of the literature including 14 cases.Patients were younger (36.3 +/- 15.5 years) than those with the classical form of OP. The clinical presentation was subacute in all cases with a mean duration of symptoms before admission of 14.5 +/- 13.2 days. The radiological pattern was characterized by centrilobular nodules and "bud-in-tree" sign in 86.7% of patients. The diagnosis was based on histological examination of transbronchial (28.6%) or surgical biopsies (71.4%). DIAGNOSIS: An associated condition was identified in 65% of cases and included illicit substance abuse (44.5%), myeloproliferative disease (33.5%), and infections (22%). OUTCOMES: Steroid therapy was effective in all patients with improvement of symptoms and documented radiologic resolution. No relapse was recorded. LESSONS: MNOP should be recognized and distinguished from other diagnoses, mainly infectious bronchiolitis and disseminated tumor, as it requires early specific steroid therapy. PMID- 28099336 TI - Prognostic significance of nonprotein respiratory quotient in patients with liver cirrhosis. AB - The aim of this study was to examine the effect of nonprotein respiratory quotient (npRQ), as assessed using indirect calorimetry, on clinical outcomes in patients with liver cirrhosis (LC). A total of 244 LC patients were evaluated in this study. For the univariate analysis, for each continuous variable, the optimal cutoff value that maximized the sum of sensitivity and specificity was selected using receiver operating curve (ROC) analysis for survival. There were 137 men and 107 women with the median (range) age of 67 (25-90) years. Indirect calorimetry indicated that 54 patients (22.1%) had hepatocellular carcinoma (HCC) on radiological findings and 59 patients (24.2%) had protein energy malnutrition, as defined by npRQ <0.85 and serum albumin level <3.5 g/dL. In ROC analysis of npRQ for survival, the optimal cutoff point of npRQ was 0.849 for all cases (area under the ROC = 0.61272; sensitivity, 66.22%; and specificity, 57.06%). The median follow-up periods after indirect calorimetry were 4.35 years (range, 1.01 9.66 years) in patients with npRQ >=0.85 (n = 122) and 3.71 years (range, 0.19 9.51 years) in patients with npRQ <0.85 (n = 122). The 1-, 3-, and 5-year cumulative OS rates in patients with npRQ >=0.85 were 100%, 87.79%, and 77.24%, respectively, whereas those in patients with npRQ <0.85 were 94.26%, 73.65% and 57.78%, respectively (P = 0.0004). In the multivariate analysis, presence of HCC (P = 0.0045), body mass index (P < 0.0001), serum albumin (P = 0.0441), prothrombin time (P = 0.0463), npRQ (P = 0.0024), estimated glomerular filtration rate (P = 0.0086), and des-gamma-carboxy prothrombin (P = 0.0268) were found to be significant predictors associated with OS. For all cases, risk stratification for survival was well performed using these significant variables. In conclusion, npRQ value, as assessed by indirect calorimetry, can be helpful for predicting clinical outcomes for LC patients. PMID- 28099337 TI - Phototoxic maculopathy induced by quartz infrared heat lamp: A clinical case report. AB - RATIONALE: A large proportion of the output of quartz infrared heat lamps is emitted as infrared radiation (IR). Retinal damage induced by IR-A and visible light on arc welders has been reported. However, case reports of retinal damage caused by quartz infrared heat lamps are rare. To the best of our knowledge, this is the first reported case of phototoxic maculopathy induced by quartz infrared heat lamps. PATIENT CONCERNS: We report a female with a 1-month history of progressive blurred vision and dysmorphopsia in her right eye after improper staring at the tubes of a quartz infrared heater. Her best corrected visual acuity of the right eye was 20/32. Optical coherence tomography revealed a defect from the ellipsoid zone to retinal pigment epithelium (RPE)/Bruch's complex layer with a diameter of 360mmat its widest. P1 amplitudes in the two central concentric rings were reduced as assessed by multifocal electroretinography. DIAGNOSES: The patient was diagnosed with phototoxic maculopathy. INTERVENTIONS: The patient was advised to cease all exposure to the infrared heater and was treated with peribulbar injections of methylprednisolone, oral Pancreatic Kininogenase, and oral Mecobalamin. OUTCOMES: Ten months later, her BCVA improved to 20/20. All examination results returned to normal except for a small residual defect in the interdigitation zone and RPE/Bruch's complex layer in her optical coherence tomography. LESSONS: Light emitted by quartz infrared heat lamps may cause damage to the retina through photothermal and photochemical means. The public is insufficiently aware of the hazard potential of infrared heat lamps and other IR-A sources on human retina. PMID- 28099338 TI - Liver steatosis in children with chronic hepatitis B and C: Prevalence, predictors, and impact on disease progression. AB - Only scarce data on liver steatosis in children with chronic hepatitis B and C (CHB and CHC) are available. The objective of this study was to evaluate the prevalence, predictors, and impact of hepatic steatosis on children with CHB and CHC. A total of 78 patients aged 11.5 +/- 3.4 years were included: 30 (38%) had CHB, and 48 (62%) had CHC. Steatosis was scored on a 5-point scale, as follows: absent; minimal (<=5% hepatocytes affected), mild (6-33%), moderate (34-66%), and severe (>66%). Stepwise logistic regression was used to determine the factors associated with steatosis and moderate-to-severe steatosis. Steatosis was observed in 4/30 (13%) patients with CHB and 13/48 (27%) patients with CHC (P = 0.17). Moderate-to-severe steatosis was observed in 6/78 (8%) patients: 1/30 (3%) had CHB and 5/48 (10%) had CHC (P = 0.40). The body mass index (BMI) z-score was positively associated with the presence of steatosis in children with CHB (odds ratio [OR] = 3.3, 95% confidence interval [CI]: 1.02-10.64). In CHC, steatosis occurred more frequently in patients with hepatitis C virus genotype 3 compared with other genotypes (P = 0.002). In patients with non-3 genotype hepatitis C virus, steatosis was associated with the stage of fibrosis (OR = 3.35, 95% CI: 1.01-11.07) and inversely associated with the duration of infection (OR = 0.74, 95% CI: 0.55-0.97). Moderate-to-severe steatosis was positively associated with the BMI z-score (OR = 3.62, 95% CI: 1.22-10.75) and stage of fibrosis (OR = 3.89, 95% CI: 1.05-14.47). Steatosis is a common finding in children with chronic viral hepatitis. It is associated with metabolic factors in CHB, whereas in patients with CHC, metabolic and viral factors may have a combined effect, leading to more advanced grades of steatosis in children with higher BMI z-scores. Moderate-to severe steatosis is a predictor of advanced fibrosis in children with CHC. PMID- 28099339 TI - Pedicle screw placement accuracy of bone-mounted miniature robot system. AB - This article describes factors affecting the accuracy of transpedicle screw placements performed with the Renaissance robot-guided system and reviews the relevant literature. Between January 2013 and January 2015, Renaissance robot guided spinal surgery was performed in 125 patients at Kaohsiung Medical University Hospital in Kaohsiung, Taiwan. The surgeries included 662 transpedicle screw implants and 49 Kirschner wire (K-wire) reimplants performed by intraoperative repositioning. The lead author evaluated the accuracy of all K wire insertions and classified their accuracy into 3 categories relative to the preoperative plan for transpedicle screw placement. For cases in which screws required repositioning after the registration step, factors affecting pedicle screw placement were determined according to the consensus of 3 experienced spinal surgeons. According to the scheme developed by Kuo et al (PLoS One 2016;11:e0153235), the K-wire placement accuracies before and after repositioning were respectively classified as follows: 76.1% and 77.6% in type I; 12.2% and 17.7% in type IIa; 4.3% and 4.5% in type IIb; 6.4% and 0% in type IIIa; and 1% and 1% in type IIIb. The percentage of screws requiring repositioning due to drilling error was 85.7% (42/49). Comparisons of preoperative and postoperative function showed significantly improved accuracy. This study showed that inaccurate pedicle screw placement mainly results from errors in preoperative planning, mounting, registration, drilling, and robot assembly. Pedicle screw placement using a bone-mounted miniature robot system requires meticulous preoperative planning to minimize these errors. PMID- 28099340 TI - Clinical effectiveness of acupuncture on Parkinson disease: A PRISMA-compliant systematic review and meta-analysis. AB - BACKGROUND: Parkinson's disease (PD) is the second-most-common chronic and progressive neurodegenerative disease. The long-term use of levodopa leads to a loss of efficacy and to complications. Therefore, many patients with PD have turned to complementary therapies to help relieve their symptoms. Acupuncture is most commonly used as a complementary therapy in patients with PD. This paper presents a systematic review and meta-analysis of the effects of acupuncture for patients with PD. This study was performed to summarize and evaluate evidence regarding the effectiveness of acupuncture in the relief of PD symptoms. METHODS: Seven databases, namely, MEDLINE, EMBASE, the Cochrane Library, the China National Knowledge Infrastructure [CNKI], and three Korean medical databases, were searched from their inception through August 2015 without language restrictions. Randomized controlled trials (RCTs) were included if they contained reports of acupuncture compared with no treatment and conventional treatment alone or acupuncture plus conventional treatment compared with conventional treatment alone for PD symptoms. Assessments were performed with the unified PD rating scales (UPDRS) I, II, III, and IV and the total score, the Webster scale, and effectiveness rating. Methodological quality was assessed using the Physiotherapy Evidence Database (PEDro) scale and the Cochrane risk of bias (ROB). RESULTS: In all, 982 potentially relevant articles were identified; 25 RCTs met our inclusion criterion, 19 of 25 RCTs were high-quality studies (i.e., a score of 6 or higher). The included RCTs showed favorable results for acupuncture plus conventional treatment compared with conventional treatment alone in the UPDRS II, III, and IV and the total score. Acupuncture was effective in relieving PD symptoms compared with no treatment and conventional treatment alone, and acupuncture plus conventional treatment had a more significant effect than conventional treatment alone. CONCLUSIONS: We performed a systematic review and meta-analysis to evaluate the use of acupuncture for relief of PD symptoms and found that acupuncture has significant positive effects. Acupuncture can be considered as a combination treatment with conventional treatment for patients with PD. Further studies on this topic should be carried out according to rigorous methodological designs in both the East and the West. PMID- 28099341 TI - Laparoscopic distal splenoadrenal shunt for the treatment of portal hypertension in children with congenital hepatic fibrosis: A case report. AB - BACKGROUND: The distal splenorenal shunt is an effective procedure for the treatment of portal hypertension in children. However, there has been no report about laparoscopic distal splenorenal shunt in the treatment of portal hypertension in children. METHODS: From December 2015 to August 2016, 4 children with upper gastrointestinal bleeding underwent laparoscopic distal splenoadrenal shunt. Portal hypertension and splenomegaly were demonstrated on the preoperative computed tomography (CT) and sonography. The distal splenic vein was mobilized and anastomosed to the left adrenal vein laparoscopically. All patients were followed-up postoperatively. RESULTS: The laparoscopic distal splenoadrenal shunt was successfully performed in all patients. The liver fibrosis was diagnosed by postoperative liver pathology. The operative time ranged from 180 to 360 minutes. The blood loss was minimal. The length of hospital stay was 6 to 13 days. The duration of following-up was 1 to 9 months (median: 3 months). The portal pressure and splenic size were decreased postoperatively. The complete blood count normalized and the biochemistry tests were within normal range after surgery. Postoperative ultrasound and CT confirmed shunt patency and satisfactory flow in the splenoadrenal shunt in all patients. No patient developed recurrence of variceal bleeding. CONCLUSIONS: The laparoscopic splenoadrenal shunt is a feasible treatment of portal hypertension in children. PMID- 28099342 TI - Successful surgical treatment for squamous cell carcinoma arising from hidradenitis suppurativa: A case report and literature review. AB - RATIONALE: Hidradenitis suppurativa (HS) is a disabling inflammatory disease mainly affecting apocrine glands. Marjolin ulcer (MU) is a term used to describe a rare type of squamous cell carcinoma (SCC) arising within sites of chronic wounds or preexisting scars. Chronic HS may result in a rare type of SCC, MU, which has a poor prognosis due to its high metastatic rate. CONCERNS OF THE PATIENT: Here we reported a 60-year-old male who developed SCC on the right buttock after suffering from HS for 15 years. INTERVENTIONS: Radical resection with clear margin was performed, after which topical negative pressure (TNP) was applied followed by split-thickness skin grafting. OUTCOMES: In a 1-year follow up, there was no recurrence of malignancy. LESSONS: Cases reported in English literature since 1991 were reviewed to get a general grasp of status quo. The authors conclude that chronic HS lesion especially in the gluteal region should be cautiously observed. Once tumor arisen from HS lesion, immediate radical excision should be performed. With assured clear margin, TNP could be chosen to offer a favorable environment for the survival of skin grafting. PMID- 28099343 TI - Efficacy and safety of bisphosphonates in management of low bone density in inflammatory bowel disease: A meta-analysis. AB - This study aims to determine whether bisphosphonates are safe, as well as effective against bone mineral loss in inflammatory bowel disease (IBD). A computerized search of electronic databases from 1966 to 2016 was performed. Randomized controlled trials (RCTs) were included in this review to evaluate the role of bisphosphonates in the management of osteoporosis in IBD patients. A revised 7-point Jadad scale was used to evaluate the quality of each study. Overall, 13 RCTs and 923 patients met the inclusion criteria of this meta analysis. The result showed that bisphosphonates decreased bone mass density (BMD) loss at the lumbar spine (P = 0.0002), reduced the risk of new fractures (P = 0.01), and retained the similar adverse events (P = 0.86). Bisphosphonates may provide protection and safety against bone mineral loss in IBD patients. PMID- 28099344 TI - Laparoscopic total pancreatectomy: Case report and literature review. AB - RATIONALE: Laparoscopic total pancreatectomy is a complicated surgical procedure and rarely been reported. This study was conducted to investigate the safety and feasibility of laparoscopic total pancreatectomy. PATIENTS AND METHODS: Three patients underwent laparoscopic total pancreatectomy between May 2014 and August 2015. We reviewed their general demographic data, perioperative details, and short-term outcomes. General morbidity was assessed using Clavien-Dindo classification and delayed gastric emptying (DGE) was evaluated by International Study Group of Pancreatic Surgery (ISGPS) definition. DIAGNOSIS AND OUTCOMES: The indications for laparoscopic total pancreatectomy were intraductal papillary mucinous neoplasm (IPMN) (n = 2) and pancreatic neuroendocrine tumor (PNET) (n = 1). All patients underwent laparoscopic pylorus and spleen-preserving total pancreatectomy, the mean operative time was 490 minutes (range 450-540 minutes), the mean estimated blood loss was 266 mL (range 100-400 minutes); 2 patients suffered from postoperative complication. All the patients recovered uneventfully with conservative treatment and discharged with a mean hospital stay 18 days (range 8-24 days). The short-term (from 108 to 600 days) follow up demonstrated 3 patients had normal and consistent glycated hemoglobin (HbA1c) level with acceptable quality of life. LESSONS: Laparoscopic total pancreatectomy is feasible and safe in selected patients and pylorus and spleen preserving technique should be considered. Further prospective randomized studies are needed to obtain a comprehensive understanding the role of laparoscopic technique in total pancreatectomy. PMID- 28099345 TI - Trigeminal somatosensory-evoked potential: A neurophysiological tool to monitor the extent of lesion of ganglion radiofrequency thermocoagulation in idiopathic trigeminal neuralgia: A case-control study. AB - To reflect the extent of thermolesion of ganglion by testing the change of trigeminal somatosensory-evoked potential (TSEP) before and after ganglion radiofrequency thermocoagulation surgery (GRT), and evaluate long-term clinic effect by follow-up visiting of 1 year.Patients with idiopathic trigeminal neuralgia (TN) in the second division were enrolled between October 2014 and October 2015. They were treated with computed tomography-guided GRT and a follow up visiting of 1 year. Bilateral TSEP measurements were performed 1 day before and 2 days after the GRT surgery. The latency and peak-to-peak amplitude of W2 and W3 were recorded.Immediate postprocedure pain relief (grades I-III) was 100% and 92.5% 1 year later. Facial numbness rate of grades III and IV was 70%, 40%, and 12.5%, respectively, at immediate, 2 days, and 1 year after GRT. No sever complications happened. The latency of W2 and W3 of patients who had no pain no numbness after 1 year of GRT was 1.74 +/- 0.24 and 3.84 +/- 0.66 ms, respectively, of TN side, and 1.71 +/- 0.39 and 3.63 +/- 0.85 ms of the healthy side before GRT. The amplitude of W2 and W3 was 1.13 +/- 0.50 and 1.99 +/- 1.09 uv, respectively, of TN side and 1.24 +/- 0.40 and 1.89 +/- 0.81 uv of the healthy side before GRT. There was no statistical difference of the latency and amplitude between 2 sides of W2 and W3 before surgery (P > 0.05). The latency of W2 and W3 delayed and the amplitude reduced especially in TN side after surgery comparing before (P < 0.001). And, comparisons of the latency and amplitude of W2 and W3 between TN side and the healthy side after surgery showed the latency of W2 and W3 delayed (W2: P = 0.02; W3: P = 0.01) and the amplitude of W2 reduced (P = 0.003), but the amplitude of W3 had no statistical difference (P = 0.22). The mean delayed latency and 95% confident interval of W2 and W3 were 0.22 +/- 0.35 (0.1-0.34) ms and 0.35 +/- 0.64 (0.14-0.57) ms, respectively. The mean decreased amplitude and 95% confident interval of W2 and W3 were 22 +/- 24 (14-30)% and 23 +/- 32 (12-34)%, respectively.GRT can make the latency delay and the amplitude decrease of TSEP. And the latency and amplitude of W2 and W3 can be considered reliable and safe reference for monitoring the extent of thermolesion. PMID- 28099346 TI - Liuwei Dihuang pill treats diabetic nephropathy in rats by inhibiting of TGF beta/SMADS, MAPK, and NF-kB and upregulating expression of cytoglobin in renal tissues. AB - Liuwei Dihuang pill (LDP) was assessed for its effects on renal deficiency.90 STZ induced DN rats were divided into groups (n = 22) without treatment (STZ) and LDP treated (STZ-L) (n = 23), Zhenwu decoction treated (STZ-Z) (n = 22), and valsartan treated (STZ-V) (n = 23) groups, with 16 normal control rats. Total urine protein (TP), blood urea nitrogen (BUN), and serum creatinine (Cr) were measured. Superoxide dismutase (SOD), nitric oxide synthase (NOS), and malondialdehyde (MDA) concentrations as well as expression/phosphorylation of SMAD3, SMAD2, and alpha-SMA, TGF-beta, RI /II, P38, ERK, and NF-kB in renal tissues were determined. In vitro experiments analyzed the effect of enhanced TGF beta containing rat serums of the STZ groups on mesangial cells with and without transient transfection with a cytoglobin-containing plasmid.LDP treatment reduced the kidney coefficient, serum creatinine, blood urea nitrogen, and urine protein and prevented pathological changes. Expression of SOD and NOS in kidney tissue was increased but MDA expression reduced. LDP modulated multiple pathways, and its administration inhibited the phosphorylation of SMADS, ERK, p38, and the expression of NF-kB, alpha-SMA, and TGF-beta RI/II, and upregulated the expression of cytoglobin. In vitro studies revealed that overexpression of cytoglobin suppressed phosphorylation of Smad2, ERK, and p38 induced by TGF-beta and expression of NF-kB, alpha-SMA, and TGF-beta RI.LDP prevented renal fibrosis and protected glomerular mesangial cells by upregulation of cytoglobin and suppression of multiple pathways involving TGF-beta/SMADS, MAPK, NF-kB signaling. PMID- 28099347 TI - Prediction of risk of diabetic retinopathy for all-cause mortality, stroke and heart failure: Evidence from epidemiological observational studies. AB - To examine and quantify the potential relation between diabetic retinopathy (DR) and risk of all-cause mortality, stroke and heart failure (HF).The resources of meta-analysis of epidemiological observational studies were from Pub-med, EMBASE, CINAHL, Cochrane Library, conference, and proceedings.Random/fixed effects models were used to calculate pooled subgroup analysis stratified by different grades of DR was performed to explore the potential source of heterogeneity. Statistical manipulations were undertaken using program STATA.Of the included 25 studies, comprising 142,625 participants, 19 studies were concluded to find the relation of DR to all-cause mortality, 5 for stroke, and 3 for HF. Risk ratio (RR) for all cause mortality with the presence of DR was 2.33 (95% CI 1.92-2.81) compared with diabetic individuals without DR. Evidences showed a higher risk of all-cause mortality associated with DR in patients with T2D or T1D (RR 2.25, 95% CI 1.91 2.65. RR 2.68, 95% CI 1.34-5.36). According to different grades of DR in patients with T2D, RR for all-cause mortality varied, the risk of nonproliferative diabetic retinopathy (NPDR) was 1.38 (1.11-1.70), while the risk of proliferative diabetic retinopathy (PDR) was 2.32 (1.75-3.06). There was no evidence of significant heterogeneity (Cochran Q test P = 0.29 vs 0.26, I = 19.6% vs 22.6%, respectively). Data from 5 studies in relation to DR and the risk of stroke showed that DR was significantly associated with increased risk of stroke (RR = 1.74, 95%CI: 1.35-2.24), compared with patients without DR. Furthermore, DR (as compared with individuals without DR) was associated with a marginal increased risk of HF in patients with diabetes mellitus (DM) (n = 3 studies; RR 2.24, 95% CI 0.98-5.14, P = 0.056).Our results showed that DR increased the risk of all cause mortality, regardless of the different stages, compared with the diabetic individuals without DR. DR predicted increased risk of stroke and HF. Although only 3 studies about HF were available, the association between DR and HF should be careful. PMID- 28099348 TI - Prognostic value of inflammation-based markers in patients with recurrent malignant obstructive jaundice treated by reimplantation of biliary metal stents: A retrospective observational study. AB - We aimed to assess the therapeutic effect of reimplantation of biliary metal stents by percutaneous transhepatic cholangial drainage (PTCD) in patients with recurrent malignant obstructive jaundice (MOJ). Furthermore, we explored the prognostic value of inflammation-based markers in these patients.We reviewed 33 cases of recurrent MOJ after implantation of biliary metal stents by PTCD, all of which underwent reimplantation of stents under digital subtraction angiography guidance. Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin were compared between before and after reimplantation (1 week, 1 month, and 3 months postoperatively). Preoperative clinical data were collected to calculate the inflammation-based markers, including systemic immune inflammation index (SII, neutrophil * platelets/ lymphocyte), platelets-to lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and monocyte-to lymphocyte ratio (MLR). The primary outcome was overall survival (OS), which was estimated by the Kaplan-Meier method and Cox regression analysis.The levels of ALT, AST, total bilirubin, and direct bilirubin significantly reduced after the reimplantation operation. During a median follow-up time of 10 months, 18 (54.5%) patients died. Gender, albumin, SII, PLR, NLR, and MLR were found to be associated with OS by the log-rank test and univariate analysis. Multivariate Cox analysis identified elevated levels of SII and PLR as significant factors for predicting poor OS.Reimplantation is clinically feasible in patients with recurrent MOJ after implantation of biliary metal stents. SII and PLR are independent, useful inflammation-based prognostic models for predicting outcomes in these patients. PMID- 28099349 TI - Development of diabetes mellitus associated with quetiapine: A case series. AB - We aimed to describe the characteristics and clinical course of patients who developed diabetes associated with the use of quetiapine.This study included patients who received quetiapine for over a month between April 2008 and November 2013, and were diagnosed as having new-onset diabetes after initiation of quetiapine. We excluded patients who developed diabetes more than 1 year after discontinuation of quetiapine. We identified new-onset diabetes by hemoglobin A1c or prescriptions of antidiabetic drugs.Among 1688 patients who received quetiapine, hemoglobin A1c had been measured in 595 (35.2%) patients at least once during the observation period, and 33 (2.0%) patients had received hypoglycemic drugs. Eighteen (1.1%) patients were considered to have developed new-onset diabetes associated with quetiapine after a median of 1.6 years following initiation of quetiapine. Median (interquartile range) age was 54.5 (29.8) years, 8 patients were male, and median (interquartile range) duration of mental illness was 15.3 (13.8) years. Median hemoglobin A1c and body mass index (BMI) were 7.1 (1.4) % and 28.4 (7.0) kg/m, respectively. Seventeen patients had dyslipidemia when diabetes was discovered. All of these discontinued quetiapine within 3 months after the diagnosis of diabetes, and the diabetes in 4 patients had ameliorated without hypoglycemic drugs. Of 13 patients who had received either oral hypoglycemic drugs or insulin, 2 patients achieved well-controlled hemoglobin A1c without hypoglycemic drugs, and 10 patients had hemoglobin A1c 5.0% to 7.7% with the continued use of hypoglycemic drugs.We demonstrated that almost all patients who developed quetiapine-associated diabetes had dyslipidemia and increased BMI. There was no life-threatening hyperglycemia and diabetes was ameliorated just by discontinuation of quetiapine in several patients. The monitoring of metabolic parameters during antipsychotic treatment is important to diagnose and treat diabetes earlier. PMID- 28099350 TI - Retrospective observational study comparing the international hip dysplasia institute classification with the Tonnis classification of developmental dysplasia of the hip. AB - The Tonnis radiographic classification of developmental dysplasia of the hip (DDH) has been widely used. The International Hip Dysplasia Institute (IHDI) classification, a new classification system recently developed by the IHDI, is beginning to be applied to evaluate DDH with the absence of an ossification center. This study aimed to validate its reliability in evaluating DDH with an ossification center and compared the 2 classifications in evaluating all DDH hips. In addition, the prediction values of the 2 classifications on clinical management selection were compared.In total, the pelvic radiographs of 212 DDH patients (318 hips) between the ages of 6 and 48 months admitted to Shanghai Children's Medical Center between 2007 and 2014 were assessed by 3 observers retrospectively using the 2 classifications. Intraobserver and interobserver agreements were evaluated using the kappa method. We also assessed the correlation of the 2 radiographic classifications in terms of treatment selection.In total, 216 hips received closed reduction, 61 hips received open reduction, and 41 hips received pelvic osteotomy. Both classifications showed excellent intraobserver and interobserver reliability. However, the IHDI demonstrated more interobserver reliability, especially for evaluating DDH without an ossification center. Both classifications were found to be relevant in detecting the DDH treatment type (P < 0.01). The Tonnis classification was also relevant, especially for evaluating DDH with an ossification center.The IHDI classification exhibited good practicability in classifying the radiographic severity of DDH compared to the Tonnis classification, particularly in hips without an ossification center. Like the Tonnis classification, the IHDI classification can predict treatment plans. Therefore, the IHDI classification seems to be the upgraded version of the Tonnis classification. PMID- 28099351 TI - Effectiveness of a radiation reduction campaign targeting children with gastrointestinal symptoms in a pediatric emergency department. AB - Children feature more active cellular division and a smaller body area, which leads to a greater radiation dosage accumulation. We tried to reduce radiation hazards by reducing unnecessary radiological studies in a pediatric emergency department (PED) through the radiation reduction campaign.Our campaign involved a reduction from 2 (erect and supine) to 1 ordered abdominal plain radiograph (erect). This quasi-experimental, uncontrolled before-and-after study aimed to evaluate the campaign effect. We compared simple radiograph orders, length of stay (LOS) in PED, and return visit (RV) to PED between the before period (June 1, 2011-May 30, 2014) and the after period (June 1, 2014-May 30, 2015). Piecewise regression was used to assess rate differences between the periods.A total of 10,729 and 3515 patients were included before and after the campaign, respectively. During study periods, 9647 (90%) and 2710 (77%) total abdominal radiographs were ordered, respectively (rate difference = 13%; P < 0.001), and the slopes of rate changes were 0.03 and -0.71, respectively (P = 0.056). The total abdominal erect and supine film rate slope decreased from -0.19 to -2.86 (P = 0.004). The RV rate did not change (220 [2%] vs 56 [2%], respectively; P = 0.104). The slope of total RV rate changed from -0.01 to -0.05 (P = 0.132), and the slope of LOS changed from 0.001 to -0.352 (P = 0.243).The campaign to reduce abdominal radiograph orders in pediatric patients successfully reduced the abdominal plain film X-ray rate without on the RV rate and the LOS. PMID- 28099352 TI - Acute pancreatitis in patients with pancreatic cancer: Timing of surgery and survival duration. AB - Acute pancreatitis (AP) is a rare manifestation of pancreatic cancer (PC). The relationship between AP and PC remains less distinct.From January 2009 to November 2015, 47consecutive patients with PC who presented with AP were reviewed for this study. Clinical features, clinicopathologic variables, postoperative complications, and follow-up evaluations of patients were documented in detail from our database. In order to identify cutoff threshold time for surgery, receiver operating curve (ROC) was built according to patients with or without postoperative complications. Cumulative rate of survival was calculated by using the Kaplan-Meier method. The study was conducted in accordance with the principles of the Declaration of Helsinki and the guidelines of West China Hospital.This study included 35 men (74.5%) and 12 women (25.5%) (mean age: 52 years), with a median follow-up of 40 months. AP was clinically mild in 45 (95.7%) and severe in 2 (4.3%). The diagnosis of PC was delayed by 2 to 660 days (median 101 days). Thirty-nine (83.0%) cases underwent surgery. Eight (17.0%) cases performed biopsies only. Of 39 patients, radical surgery was performed in 32 (82.1%) cases and palliative in 7 (19.9%) cases. Two (8.0%) patients were needed for vascular resection and reconstruction. Postoperative complications occurred in 12 (30.8%) patients. About 24.5 days was the best cutoff point, with an area under curve (AUC) of 0.727 (P = 0.025, 95% confidence interval: 0.555 0.8999). The survival rate of patients at 1 year was 23.4%. The median survival in patients with vascular resection and reconstruction was 18 months, compared with 10 months in patients without vascular resection (P = 0.042). For the primary stage (T), Tix was identified in 3 patients, the survival of whom were 5, 28, 50 months, respectively. And 2 of them were still alive at the follow-up period.The severity of AP was mainly mild. Surgical intervention after 24.5 days may benefit for reducing postoperative complications. Patients with vascular resection and reconstruction, thus achieving tumor-free margins, had a long-time survival. PMID- 28099353 TI - A predictive model to estimate the pretest probability of metastasis in patients with osteosarcoma. AB - Osteosarcomas (OSs) represent a huge challenge to improve the overall survival, especially in metastatic patients. Increasing evidence indicates that both tumor associated elements but also on host-associated elements are under a remarkable effect on the prognosis of cancer patients, especially systemic inflammatory response. By analyzing a series prognosis of factors, including age, gender, primary tumor size, tumor location, tumor grade, and histological classification, monocyte ratio, and NLR ratio, a clinical predictive model was established by using stepwise logistic regression involved circulating leukocyte to compute the estimated probabilities of metastases for OS patients. The clinical predictive model was described by the following equations: probability of developing metastases = ex/(1 + ex), x = -2.150 + (1.680 * monocyte ratio) + (1.533 * NLR ratio), where is the base of the natural logarithm, the assignment to each of the 2 variables is 1 if the ratio >1 (otherwise 0). The calculated AUC of the receiver-operating characteristic curve as 0.793 revealed well accuracy of this model (95% CI, 0.740-0.845). The predicted probabilities that we generated with the cross-validation procedure had a similar AUC (0.743; 95% CI, 0.684-0.803). The present model could be used to improve the outcomes of the metastases by developing a predictive model considering circulating leukocyte influence to estimate the pretest probability of developing metastases in patients with OS. PMID- 28099354 TI - Apparent diffusion coefficient normalization of normal liver: Will it improve the reproducibility of diffusion-weighted imaging at different MR scanners as a new biomarker? AB - Apparent diffusion coefficient (ADC) measurement in diffusion-weighted imaging (DWI) has been reported to be a helpful biomarker for detection and characterization of lesion. In view of the importance of ADC measurement reproducibility, the aim of this study was to probe the variability of the healthy hepatic ADC values measured at 3 MR scanners from different vendors and with different field strengths, and to investigate the reproducibility of normalized ADC (nADC) value with the spleen as the reference organ. Thirty enrolled healthy volunteers received DWI with GE 1.5T, Siemens 1.5T, and Philips 3.0T magnetic resonance (MR) systems on liver and spleen (session 1) and were imaged again after 10 to 14 days using only GE 1.5T MR and Philips 3.0T MR systems (session 2). Interscan agreement and reproducibility of ADC measurements of liver and the calculated nADC values (ADCliver/ADCspleen) were statistically evaluated between 2 sessions. In session 1, ADC and nADC values of liver were evaluated for the scanner-related variability by 2-way analysis of variance and intraclass correlation coefficients (ICCs). Coefficients of variation (CVs) of ADCs and nADCs of liver were calculated for both 1.5 and 3.0-T MR system. Interscan agreement and reproducibility of ADC measurements of liver and related nADCs between 2 sessions were found to be satisfactory with ICC values of 0.773 to 0.905. In session 1, the liver nADCs obtained from different scanners were consistent (P = 0.112) without any significant difference in multiple comparison (P = 0.117 to >0.99) by using 2-way analysis of variance with post-hoc analysis of Bonferroni method, although the liver ADCs varied significantly (P < 0.001). nADCs measured by 3 scanners were in good interscanner agreements with ICCs of 0.685 to 0.776. The mean CV of nADCs of both 1.5T MR scanners (9.6%) was similar to that of 3.0T MR scanner (8.9%). ADCs measured at 3 MR scanners with different field strengths and vendors could not be compared directly. Normalization of ADCs, however, may provide better reproducibility by overcoming these potential issues. PMID- 28099355 TI - Hereditary spastic paraplegia due to a novel mutation of the REEP1 gene: Case report and literature review. AB - RATIONALE: Hereditary spastic paraplegia (HSP) is a heterogeneous group of diseases little known in clinical practice due to its low prevalence, slow progression, and difficult diagnosis. This results in an underestimation of HSP leading to belated diagnosis and management. In depth diagnosis is based on clinical presentation and identification of genomic mutations. We describe the clinical presentation and pathogeny of HSP through a report of a case due to a novel mutation of the REEP1 gene (SPG31). PATIENT CONCERNS: A 64-year-old woman presented gait disturbances due to spasticity of the lower limbs progressing since her third decade. Previous investigations failed to find any cause. INTERVENTIONS: DNA analysis was performed to search for HSP causing mutations. DIAGNOSES: A novel heterozygote mutation (c.595 + 1G>A) of the REEP1 gene, within the splice site of intron 6, was discovered. This nucleotide change causes exon 6 skipping leading to frame shift and a truncated transcript identified by complementary DNA sequencing of reverse transcription polymerase chain reaction products. OUTCOMES: REEP1 is a known protein predominantly located in the upper motor neurons. Mutation of REEP1 primary affects the longest axons explaining predominance of pyramidal syndrome on lower limbs. LESSONS: Slow progressive pyramidal syndrome of the lower limbs should elicit a diagnosis of HSP. We describe a novel mutation of the REEP1 gene causing HSP. Pathogeny is based on resulting abnormal REEP1 protein which is involved in the development of longest axons constituting the corticospinal tracts. PMID- 28099356 TI - Increased risk of Parkinson disease with diabetes mellitus in a population-based study. AB - This nationwide population-based study investigated the risk of Parkinson disease (PD) in relation to diabetes mellitus (DM) through the National Health Insurance Research Database in Taiwan.A retrospective study was conducted, consisting of 36,294 patients who were newly diagnosed with DM between January 1, 2000 and December 31, 2006 and 108,882 individuals without DM as healthy controls from insurance claims data from Taiwan's National Health Research Institutes Dataset. The subjects were followed up until December 31, 2011 or until the first manifestation of PD. The hazard ratio (HR) of DM for PD incidence was estimated by Cox proportional hazard regression model.Compared with the non-DM cohort, the incidence density rate of PD was 1.36-fold higher in the DM cohort (1.53 vs 2.08 per 1000 person-years) with an adjusted HR of 1.19 (95% confidence interval = 1.08-1.32) after adjusting for age, sex, comorbidities, and medication use. The adjusted HR of PD for DM with a larger magnitude was observed in females (1.29, 1.12-1.49); individuals age 65 years and older (1.20, 1.06-1.35); those without schizophrenia (1.20, 1.08-1.33), bipolar disorder (1.20, 1.08-1.33), hypertension (1.18, 1.06-1.32), hyperlipidemia (1.21, 1.09-1.34), chronic obstructive pulmonary disease (1.19, 1.06-1.32), coronary artery disease (1.22, 1.09-1.36), stroke (1.23, 1.10-1.37), asthma (1.20, 1.08-1.34), flunarizine use (1.21, 1.08 1.35), zolpidem use (1.16, 1.04-1.30), Charlson comorbidity index score of 0 (1.23, 1.08-1.40), and those using metoclopramide (1.35, 1.14-1.60) and zolpidem (1.46, 1.12-1.90).DM increased the risk of PD during a mean follow-up of 7.3 years. Further mechanistic research on the effect of DM on PD is needed. PMID- 28099357 TI - Bilayered negative-pressure wound therapy preventing leg incision morbidity in coronary artery bypass graft patients: A randomized controlled trial. AB - BACKGROUNDS: The harvesting of great saphenous veins for coronary artery bypass graft (CABG) patients may result in significant complications, including lymphorrhagia, lymphoedema, incision infection, wound dehiscence, and skin flap necrosis. We investigated the function of a self-designed bilayered negative pressure wound therapy (b-NPWT) for reducing the above-mentioned complications using a clinical randomized controlled trial. METHODS: A single-center, pilot randomized controlled trial was conducted. From December 2013 to March 2014, a total of 72 coronary heart disease patients (48 men and 24 women) received CABG therapy, with great saphenous veins were selected as grafts. Patients were equally randomized into a treatment and a control group. After the harvesting of the great saphenous veins and direct closure of the wound with sutures, b-NPWT was used for the thigh incision in the treatment group for 5 days (treatment thigh). Traditional surgical pads were applied to both the shank incisions of the treatment group patients (treatment shank) and the entire incisions of the control group (control thigh, control shank). Postoperative complications were recorded and statistically analyzed based on outcomes of thigh treatment, shank treatment, thigh control, and shank control groups. RESULTS: The incidence rates of early complications, such as lymphorrhagia, lymphoedema, infection, wound dehiscence, and skin flap necrosis, of the vascular donor site in the thigh treatment group was significantly lower than those in the 3 other groups. CONCLUSIONS: The self-designed b-NPWT can effectively reduce postoperative complications, such as lymphedema, incision infection, wound dehiscence, and skin flap necrosis, in CABG patients who underwent great saphenous veins harvesting. TRIAL REGISTRATION: ClinicalTrials.gov. The unique registration number is NCT02010996. PMID- 28099358 TI - The gender-specific association of rs334558 in GSK3beta with major depressive disorder. AB - Major depressive disorder (MDD) is one of the most prevalent psychiatric illnesses with a heritability ranging from 40% to 50%. The single nucleotide polymorphism (SNP) rs334558 on the glycogen synthase kinase-3beta (GSK3beta) gene has been identified as a genetic risk loci associated with schizophrenia and bipolar disorder. However, results from replication studies examining the association between rs334558 and MDD remain inconsistent.In the present study, first, we conducted a meta-analysis of the association between rs334558 and MDD by combining 5 available case-control samples totaling 2311 cases and 2535 controls. Second, genotyping data from patients with MDD at our institution, after further stratification by gender, were analyzed to determine the association between rs334558 and MDD.All studies retrieved and included in the meta-analysis were from Korea and China. The meta-analysis suggested that the functional polymorphism rs334558 within the GSK3beta promoter region was associated with MDD risk (P < 0.05). The associations were observed both in the allelic and genetic models. Analysis of the genotyping data extracted from our hospital database revealed that rs334558 exhibited exclusive association with MDD in female patients (P=0.015).Our findings suggest that GSK3beta rs334558 polymorphisms might be a potential risk for MDD, and females with GSK3beta rs334558 polymorphisms might have higher penetrance of MDD. If validated in larger scale samples and in different ethnic populations, these findings might be of value as diagnostic references for MDD. PMID- 28099359 TI - Evaluation of pulmonary function using single-breath-hold dual-energy computed tomography with xenon: Results of a preliminary study. AB - Xenon-enhanced dual-energy computed tomography (xenon-enhanced CT) can provide lung ventilation maps that may be useful for assessing structural and functional abnormalities of the lung. Xenon-enhanced CT has been performed using a multiple breath-hold technique during xenon washout. We recently developed xenon-enhanced CT using a single-breath-hold technique to assess ventilation. We sought to evaluate whether xenon-enhanced CT using a single-breath-hold technique correlates with pulmonary function testing (PFT) results.Twenty-six patients, including 11 chronic obstructive pulmonary disease (COPD) patients, underwent xenon-enhanced CT and PFT. Three of the COPD patients underwent xenon-enhanced CT before and after bronchodilator treatment. Images from xenon-CT were obtained by dual-source CT during a breath-hold after a single vital-capacity inspiration of a xenon-oxygen gas mixture. Image postprocessing by 3-material decomposition generated conventional CT and xenon-enhanced images.Low-attenuation areas on xenon images matched low-attenuation areas on conventional CT in 21 cases but matched normal-attenuation areas in 5 cases. Volumes of Hounsfield unit (HU) histograms of xenon images correlated moderately and highly with vital capacity (VC) and total lung capacity (TLC), respectively (r = 0.68 and 0.85). Means and modes of histograms weakly correlated with VC (r = 0.39 and 0.38), moderately with forced expiratory volume in 1 second (FEV1) (r = 0.59 and 0.56), weakly with the ratio of FEV1 to FVC (r = 0.46 and 0.42), and moderately with the ratio of FEV1 to its predicted value (r = 0.64 and 0.60). Mode and volume of histograms increased in 2 COPD patients after the improvement of FEV1 with bronchodilators. Inhalation of xenon gas caused no adverse effects.Xenon-enhanced CT using a single-breath-hold technique depicted functional abnormalities not detectable on thin-slice CT. Mode, mean, and volume of HU histograms of xenon images reflected pulmonary function. Xenon images obtained with xenon-enhanced CT using a single breath-hold technique can qualitatively depict pulmonary ventilation. A larger study comprising only COPD patients should be conducted, as xenon-enhanced CT is expected to be a promising technique for the management of COPD. PMID- 28099360 TI - Aggressive intramuscular hemangiomas in the upper extremity: A case report. AB - INTRODUCTION: Intramuscular hemangioma (IMH) is a rare congenital soft tissue tumor. Here, we report a case of IMH patient who had undergone several surgeries and other treatments that were all ineffective before he visited us. CLINICAL FINDINGS: This IMH patient was a 16-yearold male who was born with a tumor of unknown size in his right hand and forearm. On physical examination, the tumor and skin flap complex was seen with a size of 14 cm_12 cm in his right hand, and the multiple postoperative scars were shown on his right hand and forearm. The patient was not able to raise his right shoulder, and the ranges of motion of his right elbow, wrist, and finger were almost zero degrees. INTERVENTIONS: Considering that the tumor had been surgically excised for several times and the multiple recurrences had affected adversely his daily life, an amputation of his right hand, forearm, and the part of his right arm was performed. DIAGNOSES: The pathological examination confirmed the diagnosis of IMH. OUTCOMES: After the amputation surgery, the patient gained a functional recovery and the tumor did not recur during the 2 years after the surgery. CONCLUSION: A treatment of choice should be personalized according to an IMH patient's overall situation. For an IMH patient like our case with a history of multiple tumor recurrences, we suggest that an amputation surgery should be performed as early as possible to avoid the repeated, but ineffective surgical excisions and the unnecessary sufferings. PMID- 28099361 TI - The cardiotoxicity of cetuximab as single therapy in Chinese chemotherapy refractory metastatic colorectal cancer patients. AB - The cardiac safety of cetuximab, particularly as single approach, has not been investigated extensively. This trial was designed to evaluate the cardiac safety of cetuximab as salvage monotherapy in Chinese chemotherapy-refractory metastatic colorectal cancer (mCRC) patients.Cetuximab was administrated at an initial dose of 400 mg/mon day 1 (week 1), followed by a maintenance dose of 250 mg/m on day 1 of each 7-day cycle. Electrocardiograph (ECG), routine laboratory tests, and troponin I (TNI) Ultra were performed at baseline, during, and after the cetuximab therapy. The incidence of abnormal ECGs, elevated TNI Ultra, cardiac events, and noncardiac events were recorded and analyzed.TNI Ultra+ was found in 20 patients (32.3%) during the cetuximab therapy.TNI Ultra+ occurred more frequently in patients with more than 3 organs affected and accepted fourth or above lines of chemotherapy. The most frequent abnormal ECG was ST depression in 24 (38.7%) patients. The elevated TNI Ultra and abnormal ECGs could recover after the cetuximab therapy. The most of cardiac adverse events were mild and transient and the noncardiac adverse events were also consistent with the known safety profile for cetuximab.Cetuximab showed its cardiac safety as a single agent for chemotherapy-refractory mCRC patients. And TNI Ultra and ECG could be sensitive and convenient approaches for the surveillance of adverse events. PMID- 28099362 TI - Laparoscopic pancreaticoduodenectomy in A-92-older Chinese patient for cancer of head of the pancreas: A Case report. AB - INTRODUCTION: Laparoscopic pancreaticoduodenectomy (LPD) is one of the most complex gastrointestinal procedures performed in laparoscopic abdominal surgery. However, the concern for elderly undergoing LPD remains. To the best of our knowledge, there are no reports describing LPD for A-92-older patient. This study aimed to share the experience of a tertiary pancreatic center and confirm the safety, feasibility of LPD for the elderly. METHOD: The patient had complained of 6-months history of abdominal discomfort and progressive jaundice. Abdominal computed tomography CT/MR imaging revealed a 3 * 3 cm solid hypovascular mass in the head of the pancreas. LPD was successfully performed after multidisciplinary team (MDT). Operation time was 450 minutes, and blood loss was 120 mL. Histological examination of the resected specimen confirmed the diagnosis of pancreatic ductal adenocarcinoma (PDAC). OUTCOMES: The patient was discharged on POD13 following an uneventful postoperative period. She was followed up 4 months without any sign of recurrence. CONCLUSION: LPD can be performed safely in patients of any age who are fit for surgery in specialist centers. PMID- 28099363 TI - Different RET gene mutation-induced multiple endocrine neoplasia type 2A in 3 Chinese families. AB - BACKGROUD: Multiple endocrine neoplasia type 2A (MEN2A) is a condition with inherited autosomal dominant mutations in RET (rearranged during transfection) gene that predisposes the carrier to extremely high risk of medullary thyroid cancer (MTC) and other MEN2A-associated tumors such as parathyroid cancer and/or pheochromocytoma. Little is reported about MEN2A syndrome in the Chinese population. METHODS: All members of the 3 families along with specific probands of MEN2A were analyzed for their clinical, laboratory, and genetic characteristics. Exome sequencing was performed on the 3 probands, and specific mutation in RET was further screened on each of the family members. RESULTS: Different mutations in the RET gene were identified: C634S in Family 1, C611Y in Family 2, and C634Y in Family 3. Proband 1 mainly showed pheochromocytoma with MTC, both medullary thyroid carcinoma and pheochromocytoma were seen in proband 2, and proband 3 showed medullary thyroid carcinoma. CONCLUSION: The genetic evaluation is strongly recommended for patients with a positive family history, early onset of age, or multiple sites of masses. If the results verified the mutations of RET gene, thyroidectomy should be undertaken as the guide for better prognosis. PMID- 28099364 TI - Endoscopic retrieval of gastric trichophytobezoar: Case report of a 12-year-old girl with trichophagia. AB - RATIONALE: Trichophytobezoars, which are composed of hair and plant fibers, are usually located in the stomach. They are often associated with trichophagia and trichotillomania. The most commonly reported methods of trichophytobezoar treatment are open surgery and laparoscopic retrieval; there are few reports of endoscopic removal of trichophytobezoars. PATIENT CONCERNS AND DIAGNOSES: Twelve year-old girl presented with a 3-day history of increasing upper abdominal pain, anorexia, and postprandial emesis. She had a 3-year history of pulling out and eating her own hair. Endoscopic examination showed a large intragastric trichophytobezoar measuring 10.5 cm * 3.5 cm in size, with extension of a few hairs through the pylorus. INTERVENTIONS AND OUTCOMES: The trichophytobezoar was packed with hair fibers and contained a hard core of mixed hair and vegetable fibers. After the core was cut, the trichophytobezoar was fragmented into pieces with the alternating use of a polypectomy snare and argon plasma coagulation. A small amount of hair and nondigestible food fibers was removed with grasping forceps during the initial procedure. The remaining hairball was loosened with biopsy forceps and was injected with sodium bicarbonate solution. The trichophytobezoar was removed completely at repeat endoscopy 5 days later. After 6 months of psychological intervention, the patient had no recurrence of trichophagia or trichophytobezoar. LESSONS: Endoscopy with sodium bicarbonate injection is an effective and minimally invasive method of retrieving a gastric trichophytobezoar. PMID- 28099365 TI - Melanoma during pregnancy: a report of 60 pregnancies complicated by melanoma. AB - The management of melanoma during pregnancy is challenging as maternal benefits and fetal risks need to be balanced. Here, we present an overview of the incidence, the demographic and clinical characteristics and the treatment modalities used. After analysis of obstetric, fetal and maternal outcome, recommendations for clinical practice are provided. From the 'International Network on Cancer, Infertility and Pregnancy' database, pregnant patients with melanoma were identified and analysed. Sixty pregnancies were eligible for analysis. Fifty percent of the patients presented with advanced melanoma during pregnancy (14 stage III and 16 stage IV), and 27% were diagnosed with recurrent melanoma. Surgery was the main therapeutic strategy during pregnancy. Only four patients with advanced melanoma were treated during pregnancy with systemic therapy (n=1) or radiotherapy (n=3). Premature delivery was observed in 18% of the ongoing pregnancies, all which were induced and 78% of which involved patients with advanced melanoma. Thirty-nine percent of the patients died within 5 years; all had been diagnosed with stage III or IV disease during pregnancy. Melanoma can present in a more advanced stage during pregnancy. New systemic therapies may be beneficial for patients with metastatic melanoma but may not be pregnancy compatible. In these patients, preterm induction of labour need to be discussed, despite the short-term and long-term negative effects on the child. PMID- 28099366 TI - Does the distribution pattern of brain metastases during BRAF inhibitor therapy reflect phenotype switching? AB - Brain metastases (brain mets) are frequent in metastatic melanoma patients. The aim of this study was to investigate the morphology and progression pattern of brain mets in melanoma patients treated with BRAF inhibitors (BRAFi) compared with patients who did not receive targeted therapy (BRAFi group and control group). The number and size of brain mets were compared between a baseline and a comparative MRI at progression. The number of brain mets was grouped into seven number classes (N=1-4, N=5-10, N=11-20, N=21-30, N=31-40, N=41-50, and N>50) and its difference was reported as the change of class that occurred. The mean size of the newly developed lesions was determined by representative measurements and the evolution of three persisting target lesions was assessed on the basis of modified RECIST criteria. Of 96 patients studied, 42 were in the BRAFi group and 54 were in the control group. Patients under BRAFi treatment had a significantly greater increase in the number of brain mets, where the median change of class for the BRAFi compared with the control group was 2 versus 0 (P<0.01). The mean size of the new lesions was smaller in the BRAFi group. Pre-existing target lesions did not show any prominent or different patterns of how they evolved in either group. Brain mets in patients treated with BRAFi showed a progression pattern characterized by a high propensity to disseminate, which might reflect an in-vivo manifestation of phenotype switching in response to targeted therapy, with a predominance of the invasive/migratory tumor cell phenotype. Drivers of invasiveness may present promising targets for therapeutic interventions. PMID- 28099367 TI - Antiphospholipid syndrome associated with combined immune checkpoint inhibitor therapy. PMID- 28099368 TI - Recurrence behavior in early-stage cutaneous melanoma: pattern, timing, survival, and influencing factors. AB - Nearly one-third of all melanoma patients will experience disease recurrence and the majority of the relapses eventually develop metastatic disease as a consequence of disease progression in the early-stage melanoma patients. As very few number of studies have investigated the natural recurrence history of early stage cutaneous melanoma at the first relapse, we analyzed the time until recurrence along with the patterns and outcomes of the relapses in this retrospective study. A total of 332 patients who were initially diagnosed with nonmetastatic melanoma and developed recurrence during the disease course and/or follow-up were included in the analysis. Locoregional relapse alone defined regional lymph node metastases, distant skin, subcutaneous, and satellite/in transit metastases. Nearly half of the primary recurrences were locoregional metastasis alone (50.6%), followed by mixed locoregional and distant metastases (25.9%), and distant metastases alone (23.5%). In terms of distant metastasis, the lung was the most frequently affected site (30.7%), followed by bone (15.7%), liver (13.9%), and brain (10.8%). The time intervals for each of the recurrence patterns and distant metastasis sites were identical and nearly 16 months. Nearly two-thirds of the relapses occurred within the first 2 years of diagnosis. A significant survival advantage was observed in locoregional relapse alone compared with other relapse patterns (P<0.0001). In conclusion, about half of the melanoma patients developed locoregional relapse alone and it was found to be associated with a favorable prognosis for outcome. Because nearly two-thirds of the relapses occurred within the first 2 years of diagnosis, we suggest that all early-stage melanoma patients should be kept under a strict, thorough, and close follow-up program for at least 2 years following the diagnosis. PMID- 28099369 TI - The cessation of anti-PD-1 antibodies of complete responders in metastatic melanoma. AB - The optimal duration of PD-1 antibodies for metastatic melanoma is unknown. In previous trials, there has been the potential to cease therapy if the patient achieves a complete response (CR). We aimed to assess the outcomes of patients who had ceased anti-PD-1 antibodies in this setting. A retrospective review was carried out of CR to PD-1-based therapy across two institutions. Patients were from the Pembrolizumab Named Patient Program (PEM NPP), Nivolumab monotherapy (NIVO), and reimbursed Pembrolizumab (r PEM). Patients had to have experienced a CR to PD-1-based therapy and ceased therapy because of this. Disease recurrence was the primary outcome measured. Twenty-nine patients (PEM NPP, N=20; Nivo, N=3; r PEM, N=6) ceased anti-PD-1 therapy after CR for observation. The median age was 64 (27-83) years. All patients had treatment discontinued for observation. The median time to CR was 10.5 months in the PEM NPP, 7.5 months on r PEM groups, and 17 months in the NIVO group. The median time off therapy in PEM NPP was 10 months, NIVO was 9 months, and r PEM was 4.5 months. To date, three patients have shown a relapse at a median follow-up off treatment of 8 months. This is the first report of patients who have intentionally ceased PD-1-based therapy because of CR. With a follow-up of 8 months off treatment, the risk of relapse was low. Data such as these are clinically relevant as we need to be able to discuss cessation of therapy and relevant from a pharmacoeconomic perspective, given the cost of PD-1 antibodies to society. PMID- 28099370 TI - A Course-Based Approach to the Doctor of Nursing Practice Project: Supporting Student Growth From Concept to Completion. AB - We describe a course-based approach to the doctor of nursing practice project in which students work in groups of 8 to 12 with a faculty member to complete individual final projects that require a minimum of 360 practicum hours in 3 semester-long courses. Project teams include agency or community-based mentors. Project findings are disseminated through written and oral reports. This approach preserves faculty resources and provides students with mentoring, opportunities for reflection, and time for project development. PMID- 28099371 TI - Examining the Relationships Between Clinical Judgment, Simulation Performance, and Clinical Performance. AB - Simulation-based learning experiences are designed to prepare the student for clinical practice; however, there is little documentation of a relationship between simulation performance and performance in the clinical setting. When essential aspects of a clinical situation are replicated in simulation, students should readily understand and manage similar situations in clinical practice. This study examined the relationships between clinical nursing judgment development, simulation performance, and clinical performance. PMID- 28099372 TI - Effect of Sequence of Simulated and Clinical Practicum Learning Experiences on Clinical Competency of Nursing Students. AB - Two different sequences of blocks of simulated and clinical practicum learning experiences compared the clinical competency development of nursing students using a randomized crossover design. Competency was measured 3 times: after each block of simulated and clinical experiences and after a final simulated experience. No significant differences in competency scores between the 2 groups across the 3 time points were found. Using alternative models of clinical and simulation learning may help address barriers to the delivery of clinical education faced by schools of nursing. PMID- 28099373 TI - Deconstructing Clinical Workflow: Identifying Teaching-Learning Principles for Barcode Electronic Medication Administration With Nursing Students. AB - The purpose of this quality improvement project was to better understand how to teach medication administration underpinned by an electronic medication administration record (eMAR) system used in simulated, prelicensure nursing education. Methods included a workflow and integration analysis and a detailed process mapping of both an oral and a sublingual medication administration. Procedural and curriculum development considerations related to medication administration using eMAR technology are presented for nurse educators. PMID- 28099374 TI - The origins and current applications of classic eponymous terms for pelvic and acetabular fractures: A historic review. AB - We present the historical background of 5 eponymous terms in pelvic and acetabular injury treatment. The eponymous terms Duverney fracture, Malgaigne fracture, Judet-Letournel classification, Kocher-Langenbeck approach and Stoppa approach are discussed. After presenting the original description by the coining author, a short biography of the author is given. For each eponymous term the current clinical implication is given and discussed afterwards. PMID- 28099375 TI - Routine neurosurgical consultation is not necessary in mild blunt traumatic brain injury. AB - BACKGROUND: The Brain Trauma Foundation guidelines provide indications for neurosurgical intervention in traumatic brain injury (TBI) with moderate or severe intracranial hemorrhage (ICH). In TBI patients with less severe ICH, the utility of neurosurgical consultation remains unclear. We sought to determine if routine neurosurgical consultation is necessary for mild blunt TBI patients with ICH. METHODS: A retrospective cohort study was conducted on 500 consecutive blunt TBI patients aged 15 years or older with Glasgow Coma Scale score of >=13 and ICH on initial head computed tomography admitted to a Level I trauma center over 28 months. Outcomes were neurosurgical intervention (craniotomy, craniectomy, ventriculostomy, or intracranial pressure monitor placement) and in-hospital mortality. Statistical significance was assessed at a p < 0.05. RESULTS: Of 500 patients, 49 (9.8%) underwent neurosurgical intervention. Neurosurgical intervention was more frequent in male patients (75.5% vs. 61.2%, p = 0.049), patients with higher head Abbreviated Injury Scale score (4.7 vs. 3.8, p < 0.0001), patients with an abnormal initial neurological examination (30.6% vs. 12.6%, p = 0.001), or patients with skull fracture (28.6% vs. 16.0%, p = 0.026) and was associated with higher mortality (8.2% vs. 2.0%, p = 0.010). Neurosurgical intervention was not associated with intoxication, preinjury antiplatelet/anticoagulation agents, or progression of ICH on second head computed tomography. Neurosurgical consultation was documented in 466 patients (93.2%). For patients without neurosurgical intervention, consultation did not change management. CONCLUSION: Routine neurosurgical consultation for blunt TBI with ICH seems unnecessary, regardless of intoxication or preinjury antiplatelet or anticoagulation therapy. A more selective approach is warranted to decrease hospital charges and optimize use of neurosurgical consultation. LEVEL OF EVIDENCE: Care management study, level IV. PMID- 28099376 TI - ECMO in trauma: What are the outcomes? PMID- 28099377 TI - What is the current role of laparoscopic lavage in perforated diverticulitis? PMID- 28099378 TI - American College of Surgeons Level I trauma centers outcomes do not correlate with patients' perception of hospital experience. AB - BACKGROUND: The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey is a data collection methodology for measuring a patient's perception of his/her hospital experience, and it has been selected by the Centers of Medicare and Medicaid Services as the validated and transparent national survey tool with publicly available results. Since 2012, hospital reimbursements rates have been linked to HCAHPS data based on patient satisfaction scores. The aim of this study was, therefore, to assess whether HCAHPS scores of Level I trauma centers correlate with actual hospital performance. METHODS: Retrospective analysis of the latest publicly available HCAHPS data (2014-2015) was performed. American College of Surgeons (ACS) verified Level I trauma centers for each state were identified from the ACS registry and then the following data points were collected for each hospital: HCAHPS linear mean scores regarding cleanliness of the hospital, doctor and nurse communication with the patient, staff responsiveness, pain management, overall hospital rating, and patient willingness to recommend the hospital. Our outcome measure were serious complication scores, failure-to-rescue (FTR) scores and readmission-after-discharge scores. Spearman correlation analysis was performed. RESULTS: A total of 119 ACS verified Level I trauma centers across 46 states were included. The median [IQR] overall hospital rating score for Level I trauma centers was 89 (87-90). The mean +/- SD score for serious complication was 0.96 +/- 0.266, FTR was 123.06 +/- 22.5, and readmission after discharge was 15.71 +/- 1.07. The Spearman correlation analysis showed that overall HCAHP-based hospital rating scores did not correlate with serious complications (correlation coefficient = 0.14 p = 0.125), FTR (correlation coefficient = -0.15 p = 0.073), or readmission after discharge (correlation coefficient = -0.18 p = 0.053). CONCLUSION: The findings of our study suggest that no correlation exists between HCAHPS patient satisfaction scores and hospital performance for Level I trauma centers. Consequently, the Centers of Medicare and Medicaid Services should reconsider hospital reimbursement decisions based on HCAHP patient satisfaction scores. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III; therapeutic study, level IV. PMID- 28099379 TI - Systemic intraoperative anticoagulation during arterial injury repair: Implications for patency and bleeding. AB - BACKGROUND: The role of systemic intraoperative anticoagulation (SIAC) during surgical repair of major arterial injuries is controversial. Any potential improvement in arterial patency must be weighed against the risk of hemorrhage in these critically injured patients. We hypothesized that SIAC would increase arterial patency without increasing bleeding complications. METHODS: We conducted a multi-institution, retrospective cohort study of trauma patients with major vascular injury from 2005 to 2013 in three Level I centers. Arterial injuries of the neck, torso, and proximal extremities requiring operative management were included. Our primary endpoint was maintenance of arterial patency during index hospitalization. Complications related to bleeding were assessed. The association between SIAC and arterial patency was evaluated using chi-square, t test, and multiple logistic regression modeling. RESULTS: Of 323 study patients, most were male (88%) and injured by gunshot wounds (69%). Patients repaired with SIAC (n = 154) were compared to those repaired without SIAC (n = 169). No difference in age, gender, mechanism, admission heart rate, or concomitant injury was detected between the groups (all p > 0.05). SIAC use was associated with greater arterial patency rates (93% vs. 85%, p = 0.02) without increasing return to OR for bleeding (4% vs. 6%, p = 0.29). After controlling for gender, admission hemodynamics, ISS, injury location, and postoperative anticoagulation, multivariable regression determined that SIAC patients were 2.6 times more likely (OR 2.6, 95% CI 1.1-6.2, p = 0.03) to maintain patency. Patients who maintained arterial patency were then less likely to return to the OR (9% vs. 78%, p < 0.001) with shorter intensive care unit (median 3 vs. 9 days, p < 0.01) and hospital length of stay (median 13 vs. 21 days, p < 0.01). CONCLUSION: Patients who underwent operative repair of arterial injuries utilizing SIAC experienced better arterial patency without additional bleeding complications as compared to those repaired without SIAC. Our data suggest that SIAC may improve arterial patency rates after repair and the attributable bleeding risk of SIAC may be overstated. LEVEL OF EVIDENCE: Therapeutic/care management, level IV. PMID- 28099380 TI - Predicting appendiceal tumors among patients with appendicitis. AB - BACKGROUND: As nonoperative management of appendicitis gains popularity, vigilance for appendiceal tumors becomes increasingly important. We hypothesized that, among patients presenting with acute appendicitis, those with advanced age, multiple comorbidities, atypical presentation, and complicated appendicitis would be more likely to have underlying appendiceal tumors. METHODS: We performed a 4 year retrospective cohort analysis of 677 consecutive adult patients who underwent appendectomy for appendicitis at our tertiary care center. Patients with an appendiceal tumor on their final pathology report were compared to patients with no tumor. Conditions present on admission were used to create a multivariate logistic regression model to predict appendiceal tumor. Risk factors were reported as odds ratio (OR) [95% CI]. Model strength was assessed by area under the receiver operating characteristic curve. RESULTS: Seventeen patients (2.5%) had an appendiceal tumor. Within this group. 14 underwent immediate appendectomy, two initially had nonoperative management but failed to improve on antibiotics and underwent appendectomy during the initial admission, and one had successful nonoperative management and elective appendectomy 19 days after discharge. Four variables contributed to the multivariate model to predict the presence appendiceal tumor: age >= 50 (OR 3.6 [1.1-11.4]), outpatient steroid/immunosuppressant use (OR 12.1 [2.0-72.5]), the absence of migratory right lower quadrant pain (OR 4.7 [1.2-18.1]), and the appearance of a phlegmon on CT scan (OR 7.0 [1.6-30.2]); model area under the receiver operating characteristic curve: 0.860 [0.705-0.969]. CONCLUSION: For patients presenting with acute appendicitis, conditions present on admission may predict underlying appendiceal tumor. Patients with advanced age, multiple comorbidities, atypical presentation, and complicated appendicitis should be considered for appendectomy during the index admission or at earliest convenience if nonoperative management is necessary. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 28099382 TI - Failure of nonoperative management of pediatric blunt liver and spleen injuries: A prospective Arizona-Texas-Oklahoma-Memphis-Arkansas Consortium study. AB - BACKGROUND: Nonoperative management (NOM) is standard of care for most pediatric blunt liver and spleen injuries (BLSI); only 5% of patients fail NOM in retrospective reports. No prospective studies examine failure of NOM of BLSI in children. The aim of this study was to determine the frequency and clinical characteristics of failure of NOM in pediatric BLSI patients. METHODS: A prospective observational study was conducted on patients 18 years or younger presenting to any of 10 Level I pediatric trauma centers April 2013 and January 2016 with BLSI on computed tomography. Management of BLSI was based on the Arizona-Texas-Oklahoma-Memphis-Arkansas Consortium pediatric guideline. Failure of NOM was defined as needing laparoscopy or laparotomy. RESULTS: A total of 1008 patients met inclusion; 499 (50%) had liver injury, 410 (41%) spleen injury, and 99 (10%) had both. Most patients were male (n = 624; 62%) with a median age of 10.3 years (interquartile range, 5.9, 14.2). A total of 69 (7%) underwent laparotomy or laparoscopy, but only 34 (3%) underwent surgery for spleen or liver bleeding. Other (nonexclusive) operations were for 21 intestinal injuries; 15 hematoma evacuations, washouts, or drain placements; 9 pancreatic injuries; 5 mesenteric injuries; 3 diaphragm injuries; and 2 bladder injuries. Patients who failed were more likely to receive blood (52 of 69 vs. 162 of 939; p < 0.001) and median time from injury to first blood transfusion was 2.3 hours for those who failed versus 5.9 hours for those who did not (p = 0.002). Overall mortality rate was 24% (8 of 34) in those who failed NOM due to bleeding. CONCLUSION: NOM fails in 7% of children with BLSI, but only 3% of patients failed for bleeding due to liver or spleen injury. For children failing NOM due to bleeding, the mortality was 24%. LEVEL OF EVIDENCE: Therapeutic study, level II. PMID- 28099381 TI - Daily propranolol administration reduces persistent injury-associated anemia after severe trauma and chronic stress. AB - BACKGROUND: After severe trauma, patients develop a norepinephrine-mediated persistent, injury-associated anemia. This anemia is associated with suppression of bone marrow (BM) erythroid colony growth, along with decreased iron levels, and elevated erythropoietin (EPO) levels, which are insufficient to promote effective erythropoiesis. The impact of norepinephrine on iron regulators, such as ferroportin, transferrin, and transferrin receptor-1 (TFR-1), is unknown. Using a clinically relevant rodent model of lung contusion (LC), hemorrhagic shock (HS), and chronic stress (CS), we hypothesize that daily propranolol (BB), a nonselective beta blocker, restores BM function and improves iron homeostasis. METHODS: Male Sprague-Dawley rats were subjected to LCHS +/- BB and LCHS/CS +/- BB. BB was achieved with propranolol (10 mg/kg) daily until the day of sacrifice. Hemoglobin, plasma EPO, plasma hepcidin, BM cellularity and BM erythroid colony growth were assessed. RNA was isolated to measure transferrin, TFR-1 and ferroportin expression. Data are presented as mean +/- SD; *p < 0.05 versus untreated counterpart by t test. RESULTS: The addition of CS to LCHS leads to persistent anemia on posttrauma day 7, while the addition of BB improved hemoglobin levels (LCHS/CS: 10.6 +/- 0.8 vs. LCHS/CS + BB: 13.9 +/- 0.4* g/dL). Daily BB use after LCHS/CS improved BM cellularity, colony-forming units granulocyte, erythrocyte, monocyte megakaryocyte, burst-forming unit erythroid and colony-forming unit erythroid cell colony growth. LCHS/CS + BB significantly reduced plasma EPO levels and increased plasma hepcidin levels on day 7. The addition of CS to LCHS resulted in decreased liver ferroportin expression as well as decreased BM transferrin and TFR-1 expression, thus, blocking iron supply to erythroid cells. However, daily BB after LCHS/CS improved expression of all iron regulators. CONCLUSION: Daily propranolol administration after LCHS/CS restored BM function and improved anemia after severe trauma. In addition, iron regulators are significantly reduced after LCHS/CS, which may contribute to iron restriction after injury. However, daily propranolol administration after LCHS/CS improved iron homeostasis. PMID- 28099383 TI - A case of a gunshot wound to the fetus in utero. PMID- 28099384 TI - Towards a broader view of police prehospital transport. PMID- 28099385 TI - Re: ECMO in trauma: What are the outcomes? PMID- 28099386 TI - Re: Towards a broader view of police prehospital transport. PMID- 28099387 TI - Use of an evidence-based algorithm for patients with traumatic hemothorax reduces need for additional interventions. AB - BACKGROUND: Concerted management of the traumatic hemothorax is ill-defined. Surgical management of specific hemothoraces may be beneficial. A comprehensive strategy to delineate appropriate patients for additional procedures does not exist. We developed an evidence-based algorithm for hemothorax management. We hypothesize that the use of this algorithm will decrease additional interventions. METHODS: A pre-/post-study was performed on all patients admitted to our trauma service with traumatic hemothorax from August 2010 to September 2013. An evidence-based management algorithm was initiated for the management of retained hemothoraces. Patients with length of stay (LOS) less than 24 hours or admitted during an implementation phase were excluded. Study data included age, Injury Severity Score, Abbreviated Injury Scale chest, mechanism of injury, ventilator days, intensive care unit (ICU) LOS, total hospital LOS, and interventions required. Our primary outcome was number of patients requiring more than 1 intervention. Secondary outcomes were empyema rate, number of patients requiring specific additional interventions, 28-day ventilator-free days, 28-day ICU-free days, hospital LOS, all-cause 6-month readmission rate. Standard statistical analysis was performed for all data. RESULTS: Six hundred forty-two patients (326 pre and 316 post) met the study criteria. There were no demographic differences in either group. The number of patients requiring more than 1 intervention was significantly reduced (49 pre vs. 28 post, p = 0.02). Number of patients requiring VATS decreased (27 pre vs. 10 post, p < 0.01). Number of catheters placed by interventional radiology increased (2 pre vs. 10 post, p = 0.02). Intrapleural thrombolytic use, open thoracotomy, empyema, and 6-month readmission rates were unchanged. The "post" group more ventilator-free days (median, 23.9 vs. 22.5, p = 0.04), but ICU and hospital LOS were unchanged. CONCLUSION: Using an evidence-based hemothorax algorithm reduced the number of patients requiring additional interventions without increasing complication rates. Defined criteria for surgical intervention allows for more appropriate utilization of resources. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 28099389 TI - Monitoring of vascular endothelial growth factor and its soluble receptor levels in early trauma. AB - BACKGROUND: This clinical observation study aimed to investigate the relationship between the serum levels of vascular endothelial growth factor (VEGF) and its soluble receptors with the severity and the occurrence of late acute respiratory distress syndrome (ARDS) in early trauma. METHODS: Sixty patients with multiple injuries were divided into three groups according to the Injury Severity Score (ISS) and the serum levels of VEGF, soluble VEGF receptor 1 (sVEGFR1), and sVEGFR2, were measured. Ten healthy people were recruited as controls. The incidence of late ARDS was also monitored, and its relationship to the above measures analyzed. RESULTS: VEGF was not associated with ISS (p > 0.05); sVEGFR1 was positively associated with ISS (r = 0.459, p < 0.0001); however, sVEGFR2 was negatively associated with ISS (r = 0.510, p < 0.0001). The serum VEGF levels between the ARDS group and the non-ARDS group showed no significant difference (p > 0.05). sVEGFR1 in the ARDS group was significantly higher than that in the non ARDS group (p < 0.0001), and sVEGFR2 in the ARDS group was significantly lower than that in the non-ARDS group (p < 0.0001). CONCLUSION: In conclusion, the increasing of sVEGFR1 and the decreasing of sVEGFR2 in early trauma might be closely related to the occurrence of late ARDS. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 28099388 TI - Valproic acid mitigates the inflammatory response and prevents acute respiratory distress syndrome in a murine model of Escherichia coli pneumonia at the expense of bacterial clearance. AB - BACKGROUND: Histone deacetylase inhibitors (HDACI) are members of a family of epigenetic modifying agents with broad anti-inflammatory properties. These anti inflammatory properties may have important therapeutic implications in acute respiratory distress syndrome (ARDS). However, administration of HDACI may create an immunosuppressive environment conducive to bacterial growth. Accordingly, the aim of the current study is to investigate the effect of HDACI valproic acid (VPA) on host inflammatory response and bacterial burden in a murine model of Escherichia coli pneumonia-induced ARDS. METHODS: ARDS was induced in male C57BL6 mice (n = 24) by endotracheal instillation of 3 * 10 E. coli. VPA (250 mg/kg) was administered 30 minutes after E. coli instillation in the intervention group. Blood samples were collected at 3 and 6 hours, and animals were sacrificed at 6 hours. Bronchoalveolar lavage (BAL) was performed, and tissue specimens were harvested. Cytokine levels were measured in blood and BAL, and so was transalveolar protein transit. Cell counts and colony forming units were quantified in BAL fluid. RESULTS: VPA reduced neutrophil influx into the lungs and local tissue destruction through decreased myeloperoxidase activity. It also ameliorated the pulmonary and systemic inflammatory response. This led to greater bacterial proliferation in the pulmonary parenchyma. CONCLUSION: Administration of VPA in a clinically relevant bacterial model of murine ARDS mitigates the host inflammatory response, essentially preventing ARDS, but creates an immunosuppressive environment that favors bacterial overgrowth. PMID- 28099390 TI - To nearly come full circle: Nonoperative management of high-grade IV-V blunt splenic trauma is safe using a protocol with routine angioembolization. AB - INTRODUCTION: Nonoperative management (NOM) of hemodynamically stable high-grade (IV-V) blunt splenic trauma remains controversial given the high failure rates (19%) that persist despite angioembolization (AE) protocols. The NOM protocol was modified in 2011 to include mandatory AE of all grade (IV-V) injuries without contrast blush (CB) along with selective AE of grade (I-V) with CB. The purpose of this study was to determine if this new AE (NAE) protocol significantly lowered the failure rates for grade (IV-V) injuries allowing for safe observation without surgery and if the exclusion of grade III injuries allowed for the prevention of unnecessary angiograms without affecting the overall failure rates. METHODS: The records of patients with blunt splenic trauma from January 2000 to October 2014 at a Level I trauma center were retrospectively reviewed. Patients were divided into two groups and failure of NOM (FNOM) rates compared: NAE protocol (2011-2014) with mandatory AE for all grade (IV-V) injuries without CB and selective AE for grade (I-V) with CB versus old AE (OAE) protocol (2000-2010) with selective AE for grade (I-V) with CB. RESULTS: Seven hundred twelve patients underwent NOM with 522 (73%) in the OAE group and 190 (27%) in the NAE group. Evolving from the OAE to the NAE strategy resulted in a significantly lower FNOM rate for the overall group (grade I-V) (OAE vs. NAE, 4% to 1%, p = 0.04) and the grade (IV-V) group (OAE vs. NAE, 19% vs. 3%, p = 0.01). Angiograms were avoided in 113 grade (I-III) injuries with no CB; these patients had NOM with observation alone and none failed. CONCLUSIONS: A protocol using mandatory AE of all high grade (IV-V) injuries without CB and selective AE of grade (I-V) with CB may provide for optimum salvage with safe NOM of the high-grade injuries (IV-V) and limited unnecessary angiograms. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 28099392 TI - Re: The role of timely emergency care for hypotensive trauma patients-the three Rs. PMID- 28099391 TI - The role of timely emergency care for hypotensive trauma patients. PMID- 28099393 TI - The need for a National Trauma Institute within the National Institutes of Health. PMID- 28099394 TI - Comparison of open and closed chest compressions after traumatic arrest. PMID- 28099395 TI - Re: Comparison of open and closed chest compressions after traumatic arrest. PMID- 28099396 TI - Successful Treatment of Refractory Langerhans Cell Histiocytosis of the Choroid Plexus in a Child With Pulse Dexamethasone and Lenalidomide. AB - Refractory/relapsed Langerhans cell histiocytosis (LCH) has a difficult course with a guarded prognosis. Salvage treatments available are both expensive and highly toxic. On the basis of the pathophysiology of LCH, we used a novel protocol including pulse dexamethasone and lenalidomide in a child with refractory LCH involving the choroid plexus, which resulted in durable remission with minimal toxicity. The protocol was extrapolated from the FIRST trial for patients with multiple myeloma. We present the clinical course, treatment protocol, and outcome in this child, who is at present disease free and in remission 18 months posttreatment. PMID- 28099397 TI - The Effects of Attention Problems on Psychosocial Functioning in Childhood Brain Tumor Survivors: A 2-Year Postcraniospinal Irradiation Follow-up. AB - OBJECTIVE: To examine the psychosocial outcomes and impact of attention problems in survivors of pediatric brain tumor. STUDY DESIGN: The survivors' cognitive functioning was measured using the Wechsler Intelligence Scale for Children. The Child Behavior Checklist-Attention Problems scale was used to screen for attention problems, and participants were classified as having attention problems (n=15) or normal attention (n=36). Psychosocial functioning was examined with the Korean Personality Rating scale for Children (K-PRC) at precraniospinal radiation and at 2-year follow-up. RESULTS: The attention problem group showed significantly higher depression and externalizing symptoms (delinquency, hyperactivity) and more significant impairment in family relationships than did the normal attention group at baseline. At follow-up, the attention problem group demonstrated significantly more delinquency and impaired family and social relationships. With the K-PRC scores, except for the somatization, social relationship subscale, there were significant differences between groups, but not in terms of treatment by time interaction or within time. At follow-up, multiple linear regressions showed that age at diagnosis significantly predicted K-PRC somatization (B=-1.7, P=0.004) and social relationships (B=-1.7, P=0.004), baseline full-scale intelligence quotient predicted K-PRC depression (B=-0.4, P=0.032) and somatization (B=-0.3, P=0.015), and attention problems at baseline predicted K-PRC depression (B=-15.2, P=0.036) and social relationships (B=-11.6, P=0.016). CONCLUSION: Pediatric brain tumor survivors, in particular, patients with attention problems, had worse psychosocial functioning at baseline and follow-up. Attention problems at baseline need to be carefully evaluated in assessing psychosocial functioning of pediatric brain tumor survivors. PMID- 28099398 TI - Utilizing a Novel Mobile Health "Selfie" Application to Improve Compliance to Iron Chelation in Pediatric Patients Receiving Chronic Transfusions. AB - Iron chelation therapy can prevent iron overload for pediatric patients with sickle cell disease and beta-thalassemia major; however, adherence is suboptimal. Therefore, we developed an intensive training program (ITP), to improve medication management and disease knowledge. The objectives were to determine feasibility of the ITP and its preliminary impact on adherence, disease knowledge, and health outcomes. Pediatric patients were recruited to participate in the ITP over a 90-day period and were followed for 6 months. The ITP consisted of 3 components: (1) provider-led education modules; (2) patient recording daily videos of at-home medication administration; and (3) provider feedback through video messages through the ITP app. Eleven patients participated (mean=12.4 y). Initially, patients endorsed high satisfaction and ease of use and tracked their medication usage 81% (24 out of 30) of days. At 90 days, adherence rates remained consistent (80%) and disease knowledge retention was high (96%). At 6 months, participants exhibited a clinically relevant decrease in serum ferritin, which trended toward statistical significance (P=0.068). Medication possession ratio did not significantly increase (0.65 to 0.72; not significant). The mobile ITP was feasibly implemented in a clinical setting; in addition, high levels of compliance, disease knowledge retention, and acceptance encourage larger studies evaluating mobile health technology to improve child health parameters. PMID- 28099399 TI - The Association of Serum 25-Hydroxyvitamin D With Biomarkers of Hemolysis in Pediatric Patients With Sickle Cell Disease. AB - Although vitamin D deficiency (VDD) has been linked to anemia among sickle cell disease (SCD), its relationship with hemolysis is unclear. Serum 25 hydroxyvitamin D and biomarkers of hemolysis (hemoglobin [Hb]/hematocrit, reticulocyte percentage, absolute reticulocyte, and lactate dehydrogenase [LDH] levels) in 36 hydroxyurea-naive SCD children were quantified. Correlations were significantly positive with Hb/hematocrit (r=0.40, P=0.017; r=0.45, P=0.006, respectively); inverse with reticulocyte percentage, absolute reticulocyte, and LDH (r=-0.44, P=0.008; r=-0.47, P=0.007; r=-0.45, P=0.007, respectively). In VDD groups, Hb was lower (P=0.014), reticulocyte counts and LDH were higher (P=0.047 and 0.003, respectively). Serum 25-hydroxyvitamin D correlated with biomarkers of hemolysis in SCD and VDD may play a role in SCD pathogenesis. PMID- 28099400 TI - CNS-directed Prophylactic Approach to Langerhans Cell Histiocytosis. PMID- 28099401 TI - Vocal Cord Palsy in Children With Cancer: A 10-Year Analysis of UK Pediatric Intensive Care Admissions. AB - Vocal cord palsy (VCP) is a rare but potentially life-threatening complication in children with cancer. This study reviews UK Intensive Care admissions for children with cancer and VCP using data obtained from the Pediatric Intensive Care Audit Network (PICANet) database. 26 children with cancer and VCP were admitted to intensive care from 2002 to 2012. The majority of admissions (23/26) required respiratory intervention (17 invasive ventilation, 8 noninvasive ventilation, and 5 tracheostomy). VCP should be considered early in children with cancer who present with signs of upper airway obstruction, especially in those receiving vinca-alkaloids as VCP is likely to be reversible. PMID- 28099402 TI - Transplant Center Volume and the Risk of Pancreas Allograft Failure. AB - BACKGROUND: Successful pancreas transplantation requires surgical expertise and multidisciplinary medical management. The impact of transplant center volume on pancreas allograft survival remains unclear. METHODS: We examined Organ Procurement and Transplantation Network data on 11 568 simultaneous pancreas kidney (SPK) and 4308 solitary pancreas (pancreas transplant alone and pancreas after kidney) transplants between 2000 and 2013. RESULTS: Average annual transplant center volume was categorized by tertiles into low, medium, and high volume, respectively, as follows: 1 to 6 (n = 3861), 7 to 13 (n = 3891), and 14 to 34 (n = 3888) for SPK, and 1 to 3 (n = 1417), 4 to 10 (n = 1518), and 11 to 33 (n = 1377) for solitary pancreas transplants. Favorable donor characteristics were seen in low-volume centers. For SPK transplantation, low (adjusted hazard ration [aHR], 1.55, 95% confidence interval [CI], 1.34-1.8) and medium (aHR, 1.24; 95% CI, 1.07-1.44) center volumes were associated with a higher risk of early pancreas graft failure at 3 months. The increased risk associated with low center volume extended to 1, 5, and 10 years. For solitary pancreas transplants, low, but not medium, center volume was associated with a higher risk of early pancreas graft failure at 3 months (aHR, 1.56; 95% CI, 1.232-1.976), and this risk persisted over 10 years. Patients transplanted at high-volume centers had better pancreas survival rates across all categories of the Pancreas Donor Risk Index. CONCLUSION: On average, low center volume were associated with higher risk for pancreas failure. Future studies should seek to identify care processes that support optimal outcomes after pancreas transplantation irrespective of center volume. PMID- 28099403 TI - Outcome of Liver Transplant Recipients With Revascularized Coronary Artery Disease: A Comparative Analysis With and Without Cardiovascular Risk Factors. AB - BACKGROUND: Coronary artery disease (CAD) is a significant problem during evaluation for liver transplantation (LT). We aim to assess survival in LT recipients based on presence, severity, extent of CAD, and cardiac events within 90 days of LT. METHODS: Eighty-seven LT recipients with history of pre-LT angiogram (December 2005 to December 2012) were compared with 2 control groups without prior angiogram, 72 LT recipients matched for cardiovascular risk factors (control group I), and 119 consecutive LT recipients without any CV risk factors (control group II). CAD was assessed by (1) vessel score (>=50% reduction in luminal diameter), and (2) Extent score (Reardon scoring system). RESULTS: Of the 87 LT recipients (study group), 58 (66.7%) had none or less than 50% stenosis, 29 (33.3%) had obstructive CAD (>=50% stenosis), 7 (8%) with single-vessel disease, and 22 (25.3%) with multivessel disease. In the study group, irrespective of prerevascularization severity of CAD (P = 0.357), number of segments involved (0, 1-2, > 2 segments, P = 0.304) and extent of CAD based on Reardon score (0, 1-9, >10, P = 0.224), comparable posttransplant survival was noted. Overall, patient survival in the revascularized CAD group was comparable to angiogram group without obstructive CAD, and both control group I and control group II (P = 0.184, Log Rank). Postoperative cardiac events within 90 days of LT predicted poor survival in study group as well as control groups. CONCLUSIONS: Severity or extent of CAD does not impact post-LT survival, if appropriately revascularized. Early postoperative cardiac events are associated with inferior survival in LT recipients, irrespective of underlying CAD. PMID- 28099404 TI - Risk of Aggressive Skin Cancers After Kidney Retransplantation in Patients With Previous Posttransplant Cutaneous Squamous Cell Carcinomas: A Retrospective Study of 53 Cases. AB - BACKGROUND: The course of skin cancer after retransplantation in organ-transplant recipients who have already developed posttransplant skin cancer has not been assessed. METHODS: This retrospective multicentric study included 53 patients with a history of cutaneous squamous cell carcinoma (SCC) after a first kidney transplantation who received a second kidney transplantation. The primary endpoint was the occurrence of aggressive cutaneous SCC after the second transplantation. Secondary endpoints included the course of skin cancers over 3 periods (first transplantation, return to dialysis, second transplantation), the time to occurrence, and risk factors for aggressive SCC after retransplantation. RESULTS: The first SCC developed in 47 patients with a functional graft and in 6 after return to dialysis. After the first transplantation, 17 (33.3%) patients developed SCC in dialysis and 39 (73.6%) after the second transplantation, respectively. Twenty aggressive SCC developed over the study period. They occurred in 14 (26.4%) patients after retransplantation vs 5 (9.4%) after the first transplantation with a median delay of 50 months and were responsible for 5 deaths. Fair skin type, multiple tumors before retransplantation, treatment with azathioprine, T cell-depleting antibodies, and delayed revision of immunosuppression were associated with an increased risk of aggressive cutaneous SCC after retransplantation. CONCLUSIONS: Candidates to retransplantation with a history of posttransplant SCC have a high risk of aggressive SCC. Our data suggest that the risk could be reduced by a tailored immunosuppression. A wait period may be required depending on the clinicopathological characteristics of the previous SCC and discussed on an individual patient basis. PMID- 28099405 TI - Insights in Transplanting Complex Pediatric Renal Recipients With Vascular Anomalies. AB - BACKGROUND: Children with end-stage kidney disease may have coexisting iatrogenic or congenital vascular anomalies making transplantation difficult. We describe our approach in 5 recipients with vascular anomalies and significant comorbidities, including one case of blood group incompatibility. METHODS: Five children aged 3 to 17 years (median, 7 years), weighing 14 to 34 kg (median, 18 kg) kg of whom 4 had occluded inferior vena cava or iliac veins and 2 had previous complex vascular reconstructions before transplantation for midaortic syndrome and multiple aortic aneurysms, respectively underwent renal transplantation. To establish implant feasibility surgery was commenced in 2 recipients before the donor surgery. RESULTS: There was 4 (80%) of 5 patient survival after 1 death from sepsis (with a functioning graft) and 2 cases of delayed graft function. At the latest median follow-up of 19 months, there was 100% (death-censored) renal allograft survival with estimated glomerular filtration rates (mL/min per 1.73 m) of 43 to 72 (median, 55). CONCLUSIONS: We conclude that major vascular anomalies do not necessarily preclude transplantation in complex pediatric patients and that surgical exploration of the recipient before commencing the donor surgery is valuable where feasibility and safety are uncertain. In addition, we have developed a novel classification system of congenital vascular abnormalities and propose its use in complex pediatric transplantation. PMID- 28099406 TI - Reducing the Threshold for Clinical Renal Xenotransplantation. PMID- 28099407 TI - Effects of functional CYP2C8,CYP2C9,CYP3A5,and ABCB1 genetic variants on the pharmacokinetics of insulin sensitizer pioglitazone in Chinese Han individuals. AB - BACKGROUND AND OBJECTIVES: Pioglitazone is a thiazolidinedione antihyperglycemic drug with insulin-sensitizing properties. We investigated whether the variant genotypes of cytochrome P450 2C8 (CYP2C8), CYP2C9, CYP3A5 and transporter ABCB1 influence the pharmacokinetic phenotype of the substrate pioglitazone in Chinese individuals. PARTICIPANTS AND METHODS: Single-nucleotide polymorphisms were determined by the PCR-restriction fragment length polymorphism method in 244 (CYP2C8 and CYP2C9) healthy Chinese Han individuals. After a single oral dose of 30 mg pioglitazone, the plasma concentrations of the parent drug and of two major active metabolites M-III and M-IV were measured using a validated LC-MS/MS in 21 (genotyping CYP3A5 and ABCB1) of these 244 volunteers. RESULTS: The results confirmed that the unique frequencies of CYP2C8*2 (0.0%), CYP2C8*3 (0.0%), and CYP2C9*2 (0.0%) alleles were significantly different from those reported in Whites and Africans, and there were only 10 variant CYP2C9*1/*3 heterozygous (CYP2C9*3 carriers) among 244 Chinese individuals. These results were similar to those reported in Asian ethnic populations, including the Chinese. Unexpectedly, the pioglitazone AUC0-48 in CYP2C9*3 carriers was lower (50.8%), whereas the AUC0 48 ratios of metabolites M-III/pioglitazone and M-IV/pioglitazone increased to 134.3 and 155.8%, respectively, compared with the wild-type CYP2C9*1/*1 homozygous. Moreover, this phenomenon was not observed in individuals with genetic variants of CYP3A5*3 and ABCB1 (C1236T). CONCLUSION: The present research suggests that the CYP2C8, CYP3A5, and ABCB1 genes play no significant role in the interindividual variation of pioglitazone pharmacokinetics, whereas CYP2C9*3 carriers are likely to accelerate the metabolism of this antidiabetic drug in the Chinese Han ethnic population. PMID- 28099409 TI - Up-Regulated Expression of SPRY4-IT1 Predicts Poor Prognosis in Colorectal Cancer. AB - BACKGROUND Long non-coding RNA SPRY4 intronic transcript 1 (lncRNA SPRY4-IT1) has been reported to be associated with the progression of several cancers, but its expression level in colorectal cancer (CRC) has rarely been reported. The purpose of this study was to estimate the clinical significance of SPRY4-IT1 in CRC. MATERIAL AND METHODS The relative expression levels of SPRY4-IT1 were detected by quantitative real-time polymerase chain reaction (qRT-PCR) in diseased tissues and the adjacent normal tissues of 106 CRC patients. Chi-square method was used to evaluate the association between SPRY4-IT1 expression and the clinical features. Additionally, we assessed the overall survival at different expression levels of SPRY4-IT1 using Kaplan-Meier method. The prognostic significance of SPRY4-IT1 was estimated by Cox regression analysis. RESULTS Up-regulated level of SPRY4-IT1 was detected in pathologic tissues of CRC patients compared with adjacent normal tissues (P=0.000). The relative expression of SPRY4-IT1 was associated with the tumor size, the depth of invasion, lymph node invasion, distant invasion, and tumor stage (P<0.05). Patients with high expression of SPRY4-IT1 had poor overall survival compared with those with high level (39.3 vs. 49.3 months, log-rank test, P=0.016). Cox regression analysis showed that SPRY4 IT1 could act as an independent prognostic factor in CRC (HR=2.341, 95% CI=1.136 4.826, P=0.021). CONCLUSIONS SPRY4-IT1 might be associated with tumorigenesis and progression of CRC, and it may be a promising biomarker for prognosis in patients with CRC. PMID- 28099410 TI - Cancer: Double trouble for tumours. PMID- 28099408 TI - Multiphenotype association study of patients randomized to initiate antiretroviral regimens in AIDS Clinical Trials Group protocol A5202. AB - BACKGROUND: High-throughput approaches are increasingly being used to identify genetic associations across multiple phenotypes simultaneously. Here, we describe a pilot analysis that considered multiple on-treatment laboratory phenotypes from antiretroviral therapy-naive patients who were randomized to initiate antiretroviral regimens in a prospective clinical trial, AIDS Clinical Trials Group protocol A5202. PARTICIPANTS AND METHODS: From among 5 9545 294 polymorphisms imputed genome-wide, we analyzed 2544, including 2124 annotated in the PharmGKB, and 420 previously associated with traits in the GWAS Catalog. We derived 774 phenotypes on the basis of context from six variables: plasma atazanavir (ATV) pharmacokinetics, plasma efavirenz (EFV) pharmacokinetics, change in the CD4+ T-cell count, HIV-1 RNA suppression, fasting low-density lipoprotein-cholesterol, and fasting triglycerides. Permutation testing assessed the likelihood of associations being by chance alone. Pleiotropy was assessed for polymorphisms with the lowest P-values. RESULTS: This analysis included 1181 patients. At P less than 1.5*10, most associations were not by chance alone. Polymorphisms with the lowest P-values for EFV pharmacokinetics (CYPB26 rs3745274), low-density lipoprotein -cholesterol (APOE rs7412), and triglyceride (APOA5 rs651821) phenotypes had been associated previously with those traits in previous studies. The association between triglycerides and rs651821 was present with ATV-containing regimens, but not with EFV-containing regimens. Polymorphisms with the lowest P-values for ATV pharmacokinetics, CD4 T-cell count, and HIV-1 RNA phenotypes had not been reported previously to be associated with that trait. CONCLUSION: Using data from a prospective HIV clinical trial, we identified expected genetic associations, potentially novel associations, and at least one context-dependent association. This study supports high-throughput strategies that simultaneously explore multiple phenotypes from clinical trials' datasets for genetic associations. PMID- 28099411 TI - Corrigendum: Structural basis of N6-adenosine methylation by the METTL3-METTL14 complex. PMID- 28099412 TI - Ultrafast nonthermal photo-magnetic recording in a transparent medium. AB - Discovering ways to control the magnetic state of media with the lowest possible production of heat and at the fastest possible speeds is important in the study of fundamental magnetism, with clear practical potential. In metals, it is possible to switch the magnetization between two stable states (and thus to record magnetic bits) using femtosecond circularly polarized laser pulses. However, the switching mechanisms in these materials are directly related to laser-induced heating close to the Curie temperature. Although several possible routes for achieving all-optical switching in magnetic dielectrics have been discussed, no recording has hitherto been demonstrated. Here we describe ultrafast all-optical photo-magnetic recording in transparent films of the dielectric cobalt-substituted garnet. A single linearly polarized femtosecond laser pulse resonantly pumps specific d-d transitions in the cobalt ions, breaking the degeneracy between metastable magnetic states. By changing the polarization of the laser pulse, we deterministically steer the net magnetization in the garnet, thus writing '0' and '1' magnetic bits at will. This mechanism outperforms existing alternatives in terms of the speed of the write-read magnetic recording event (less than 20 picoseconds) and the unprecedentedly low heat load (less than 6 joules per cubic centimetre). PMID- 28099413 TI - Communication between viruses guides lysis-lysogeny decisions. AB - Temperate viruses can become dormant in their host cells, a process called lysogeny. In every infection, such viruses decide between the lytic and the lysogenic cycles, that is, whether to replicate and lyse their host or to lysogenize and keep the host viable. Here we show that viruses (phages) of the SPbeta group use a small-molecule communication system to coordinate lysis lysogeny decisions. During infection of its Bacillus host cell, the phage produces a six amino-acids-long communication peptide that is released into the medium. In subsequent infections, progeny phages measure the concentration of this peptide and lysogenize if the concentration is sufficiently high. We found that different phages encode different versions of the communication peptide, demonstrating a phage-specific peptide communication code for lysogeny decisions. We term this communication system the 'arbitrium' system, and further show that it is encoded by three phage genes: aimP, which produces the peptide; aimR, the intracellular peptide receptor; and aimX, a negative regulator of lysogeny. The arbitrium system enables a descendant phage to 'communicate' with its predecessors, that is, to estimate the amount of recent previous infections and hence decide whether to employ the lytic or lysogenic cycle. PMID- 28099414 TI - Neurotoxic reactive astrocytes are induced by activated microglia. AB - Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease, but their role is poorly understood. Here we show that a subtype of reactive astrocytes, which we termed A1, is induced by classically activated neuroinflammatory microglia. We show that activated microglia induce A1 astrocytes by secreting Il-1alpha, TNF and C1q, and that these cytokines together are necessary and sufficient to induce A1 astrocytes. A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when the formation of A1 astrocytes is blocked. Finally, we show that A1 astrocytes are abundant in various human neurodegenerative diseases including Alzheimer's, Huntington's and Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. Taken together these findings help to explain why CNS neurons die after axotomy, strongly suggest that A1 astrocytes contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders, and provide opportunities for the development of new treatments for these diseases. PMID- 28099416 TI - Materials science: Versatile gel assembly on a chip. PMID- 28099415 TI - Structure of a eukaryotic cyclic-nucleotide-gated channel. AB - Cyclic-nucleotide-gated channels are essential for vision and olfaction. They belong to the voltage-gated ion channel superfamily but their activities are controlled by intracellular cyclic nucleotides instead of transmembrane voltage. Here we report a 3.5-A-resolution single-particle electron cryo-microscopy structure of a cyclic-nucleotide-gated channel from Caenorhabditis elegans in the cyclic guanosine monophosphate (cGMP)-bound open state. The channel has an unusual voltage-sensor-like domain, accounting for its deficient voltage dependence. A carboxy-terminal linker connecting S6 and the cyclic-nucleotide binding domain interacts directly with both the voltage-sensor-like domain and the pore domain, forming a gating ring that couples conformational changes triggered by cyclic nucleotide binding to the gate. The selectivity filter is lined by the carboxylate side chains of a functionally important glutamate and three rings of backbone carbonyls. This structure provides a new framework for understanding mechanisms of ion permeation, gating and channelopathy of cyclic nucleotide-gated channels and cyclic nucleotide modulation of related channels. PMID- 28099417 TI - Virology: Phages make a group decision. PMID- 28099418 TI - IL-17 is a neuromodulator of Caenorhabditis elegans sensory responses. AB - Interleukin-17 (IL-17) is a major pro-inflammatory cytokine: it mediates responses to pathogens or tissue damage, and drives autoimmune diseases. Little is known about its role in the nervous system. Here we show that IL-17 has neuromodulator-like properties in Caenorhabditis elegans. IL-17 can act directly on neurons to alter their response properties and contribution to behaviour. Using unbiased genetic screens, we delineate an IL-17 signalling pathway and show that it acts in the RMG hub interneurons. Disrupting IL-17 signalling reduces RMG responsiveness to input from oxygen sensors, and renders sustained escape from 21% oxygen transient and contingent on additional stimuli. Over-activating IL-17 receptors abnormally heightens responses to 21% oxygen in RMG neurons and whole animals. IL-17 deficiency can be bypassed by optogenetic stimulation of RMG. Inducing IL-17 expression in adults can rescue mutant defects within 6 h. These findings reveal a non-immunological role of IL-17 modulating circuit function and behaviour. PMID- 28099420 TI - Addendum: The rewards of restraint in the collective regulation of foraging by harvester ant colonies. PMID- 28099419 TI - Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer. AB - The genome of pancreatic ductal adenocarcinoma (PDAC) frequently contains deletions of tumour suppressor gene loci, most notably SMAD4, which is homozygously deleted in nearly one-third of cases. As loss of neighbouring housekeeping genes can confer collateral lethality, we sought to determine whether loss of the metabolic gene malic enzyme 2 (ME2) in the SMAD4 locus would create cancer-specific metabolic vulnerability upon targeting of its paralogous isoform ME3. The mitochondrial malic enzymes (ME2 and ME3) are oxidative decarboxylases that catalyse the conversion of malate to pyruvate and are essential for NADPH regeneration and reactive oxygen species homeostasis. Here we show that ME3 depletion selectively kills ME2-null PDAC cells in a manner consistent with an essential function for ME3 in ME2-null cancer cells. Mechanistically, integrated metabolomic and molecular investigation of cells deficient in mitochondrial malic enzymes revealed diminished NADPH production and consequent high levels of reactive oxygen species. These changes activate AMP activated protein kinase (AMPK), which in turn directly suppresses sterol regulatory element-binding protein 1 (SREBP1)-directed transcription of its direct targets including the BCAT2 branched-chain amino acid transaminase 2) gene. BCAT2 catalyses the transfer of the amino group from branched-chain amino acids to alpha-ketoglutarate (alpha-KG) thereby regenerating glutamate, which functions in part to support de novo nucleotide synthesis. Thus, mitochondrial malic enzyme deficiency, which results in impaired NADPH production, provides a prime 'collateral lethality' therapeutic strategy for the treatment of a substantial fraction of patients diagnosed with this intractable disease. PMID- 28099421 TI - Estimation of adult and neonatal RBC lifespans in anemic neonates using RBCs labeled at several discrete biotin densities. AB - BACKGROUND: Prior conclusions that autologous neonatal red blood cells (RBC) have substantially shorter lifespans than allogeneic adult RBCs were not based on direct comparison of autologous neonatal vs. allogeneic adult RBCs performed concurrently in the same infant. Biotin labeling of autologous neonatal RBCs and allogeneic adult donor RBCs permits concurrent direct comparison of autologous vs. allogeneic RBC lifespan. METHODS: RBCs from 15 allogeneic adult donors and from 15 very-low-birth-weight (VLBW) neonates were labeled at separate biotin densities and transfused simultaneously into the 15 neonates. Two mathematical models that account for the RBC differences were employed to estimate lifespans for the two RBC populations. RESULTS: Mean +/- SD lifespan for adult allogeneic RBC was 70.1 +/- 19.1 d, which is substantially shorter than the 120 d lifespan of both autologous and adult allogeneic RBC in healthy adults. Mean +/- SD lifespan for neonatal RBC was 54.2 +/- 11.3 d, which is only about 30% shorter than that of the adult allogeneic RBCs. CONCLUSION: This study provides evidence that extrinsic environmental factors primarily determine RBC survival (e.g., small bore of the capillaries of neonates, rate of oxygenation/deoxygenation cycles) rather than factors intrinsic to RBC. PMID- 28099422 TI - Relationship between perfusion index and patent ductus arteriosus in preterm infants. AB - BACKGROUND: Perfusion index (PI) is a noninvasive measure of perfusion. DeltaPI (difference between pre- and postductal PI) may identify hemodynamically significant PDA. However, studies are limited to brief and intermittent DeltaPI sampling. Our objective is to assess the value of continuous high resolution DeltaPI monitoring in the diagnosis of PDA. METHODS: Continuous DeltaPI monitoring in preterm infants was prospectively performed using two high resolution pulse oximeters. Perfusion Index measures (DeltaPI mean and variability, pre- and postductal PI) were analyzed over a 4-h period prior to echocardiography. A cardiologist blinded to the results evaluated for PDA on echocardiography. Linear mixed regression models were utilized for analyses. RESULTS: We obtained 31 echocardiography observations. Mean DeltaPI (-0.23 vs. 0.16; P < 0.05), mean pre-PI (0.86 vs. 1.26; P < 0.05), and DeltaPI variability (0.39 vs. 0.61; P = 0.05) were lower in infants with PDA compared to infants without PDA at the time of echocardiography. CONCLUSION: Mean DeltaPI, DeltaPI variability, and mean pre-PI measured 4 h prior to echocardiography detect PDA in preterm infants. PI is dynamic and should be assessed continuously. Perfusion index is a promising bedside measurement to identify PDA in preterm infants. PMID- 28099423 TI - High-dose erythropoietin population pharmacokinetics in neonates with hypoxic ischemic encephalopathy receiving hypothermia. AB - BACKGROUND: High-dose erythropoietin (Epo) is a promising neuroprotective treatment in neonates with hypoxic-ischemic encephalopathy (HIE) receiving hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of high-dose Epo in this population to inform future dosing strategies. METHODS: We performed a population pharmacokinetic analysis of 47 neonates with HIE treated with hypothermia who received up to six doses of Epo in two previous clinical trials. We compared the ability of different dosing regimens to achieve the target neuroprotective Epo exposure levels determined from animal models of hypoxic-ischemia (i.e., area under the curve during the first 48 h of treatment (AUC48 h) 140,000 mU*h/ml). RESULTS: Birth weight scaled via allometry was a significant predictor of Epo clearance and volume of distribution (P < 0.001). After accounting for birth weight, variation in Epo pharmacokinetics between neonates was low (CV% 20%). All 23 neonates who received 1,000 U/kg every 24 h for the first 2 d of therapy achieved the target AUC48 h 140,000 mU*h/ml. No neonate who received a lower dosing regimen achieved this target. CONCLUSION: In neonates with HIE receiving hypothermia, Epo 1,000 U/kg every 24 h for the first 2 d of therapy resulted in consistent achievement of target exposures associated with neuroprotection in animal models. PMID- 28099424 TI - The establishment of cow's milk protein allergy in infants is related with a deficit of regulatory T cells (Treg) and vitamin D. AB - BACKGROUND: Cow's milk protein allergy (CMPA) is the most common food allergy in infants. However, little is known about which specific immune mechanisms are related with the CMPA onset. The objective was to investigate which immune alterations constitute differential factors between allergy and tolerance, and hence could be implicated in the CMPA establishment in infants. METHODS: An extensive analysis of immune subsets, including Treg and cytokine-secreting cells was performed in blood samples from 28 infants younger than 9 mo obtained 1-4 d after the first adverse reaction to milk. RESULTS: Less than 4 d after first allergic reaction, infants who developed CMPA had decreased Treg counts and increased frequency of IL4-secreting CD4 T cells compared to controls. The deficit of Tregs was correlated with decreased serum levels of vitamin D. Values of Tregs, IL4-secreting cells and vitamin D were good predictors of CMPA diagnosis. Basal vitamin D levels in CMPA infants also predicted those CMPA patients developing spontaneous tolerance in the first year. CONCLUSION: Establishment of CMPA in infants was related with lower Treg and vitamin D levels. These immune alterations would be crucial factors behind the CMPA establishment and they could constitute a therapeutic target for treatment of CMPA. PMID- 28099425 TI - Genetic ablation of Bach1 gene enhances recovery from hyperoxic lung injury in newborn mice via transient upregulation of inflammatory genes. AB - BACKGROUND: BTB and CNC homology 1 (Bach1) is a transcriptional repressor of heme oxygenase (HO)-1. The effects of Bach1 disruption on hyperoxic lung injury in newborn mice have not been determined. We aimed to investigate the role of Bach1 in the newborns exposed to hyperoxia. METHODS: Bach1-/- and WT newborn mice were exposed to 21% or 95% oxygen for 4 d and were then allowed to recover in room air. Lung histology was assessed and lung Bach1, HO-1, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1 mRNA levels were evaluated using RT-PCR. Lung inflammatory cytokine levels were determined using cytometric bead arrays. RESULTS: After 10 d recovery from neonatal hyperoxia, Bach1-/- mice showed improved lung alveolarization compared with WT. HO-1, IL-6, and MCP-1 mRNA levels and IL-6 and MCP-1 protein levels were significantly increased in the Bach1-/- lungs exposed to neonatal hyperoxia. Although an increase in apoptosis was observed in the Bach1-/- and WT lungs after neonatal hyperoxia, there were no differences in apoptosis between these groups. CONCLUSION: Bach1-/- newborn mice were well-recovered from hyperoxia-induced lung injury. This effect is likely achieved by the antioxidant/anti-inflammatory activity of HO-1 or by the transient overexpression of proinflammatory cytokines. PMID- 28099426 TI - Fetal origins of adult cardiac disease: a novel approach to prevent fetal growth restriction induced cardiac dysfunction using insulin like growth factor. AB - BACKGROUND: Fetal growth restriction (FGR) is a risk factor for adult cardiovascular disease. Intraplacental gene transfer of human insulin-like growth factor-1 (IGF-1) corrects birth weight in our mouse model of FGR. This study addresses long term effects of FGR on cardiac function and the potential preventive effect of IGF-1. STUDY DESIGN: Laparotomy was performed on pregnant C57BL/6J mice at embryonic day 18 and pups were divided into three groups: Sham operated; FGR (induced by mesenteric uterine artery ligation); treatment (intraplacental injection of IGF-1 after uterine artery ligation). Pups were followed until 32 wk of life. Transthoracic echocardiography was performed starting at 12 wk. RESULTS: Systolic cardiac function was significantly impaired in the FGR group with reduced fractional shortening compared with sham and treatment group starting at week 12 of life (20 +/- 4 vs. 31 +/- 5 vs. 32 +/- 5, respectively, n = 12 for each group; P < 0.001) with no difference between the sham and treatment groups. CONCLUSION: Intraplacental gene transfer of IGF-1 prevents FGR induced cardiac dysfunction. This suggests that in utero therapy may positively impact cardiac remodeling and prevent adult cardiovascular disease. PMID- 28099428 TI - Biomarkers of adiposity are elevated in preterm very-low-birth-weight infants at 1, 2, and 3 y of age. AB - BACKGROUND: Preterm, very-low-birth-weight (PT-VLBW) neonates are at-risk for metabolic syndrome later in life. At 1-3 y, they exhibit excessive weight-for length z-scores (Wt-LZ) and elevated systolic blood pressures (SBP). Serum adipokines are biomarkers of adiposity, but expression in PT-VLBW infants is unclear. We examined the correlation between serum adipokine levels, anthropometric measures and SBP in PT-VLBW neonates at follow-up. METHODS: This was a cross-sectional cohort study of PT-VLBW infants at 1, 2, and 3 y of age (40/cohort). We measured SBP, abdominal circumference (AC) and anthropometrics; calculated age/gender-specific z-scores for Wt, L, Wt-L and subscapular skin fold (SSZ), and measured serum adipokines. RESULTS: Serum leptin was unaffected by chronologic age and gender, but was positively correlated with weight, Wt-LZ, AC, and SSZ at 1 and 3 y (P < 0.01). Female infants at 1 and 3 y had a more significant relationship than males between serum leptin and SSZ (P < 0.001, R = 0.75 and P < 0.001, R = 0.70, respectively). Adiponectin levels were 16-20% lower at 3 vs. 1-2 y (P = 0.02, ANOVA) and negatively correlated with SBP. CONCLUSION: Although serum leptin was unrelated to advancing age, gender, and SBP in PT-VLBW infants, levels correlated with measures of adiposity at 1 and 3 y, females > males, suggesting leptin resistance may occur in early infancy. PMID- 28099427 TI - Exposure to bisphenols and phthalates and association with oxidant stress, insulin resistance, and endothelial dysfunction in children. AB - BACKGROUND: The health effects of bisphenol A (BPA) and di-(2-ethylhexyl) phthalate (DEHP) have been studied extensively in children. The impact of other chemicals in these two classes has not been investigated as fully. METHODS: We conducted a cross-sectional pilot study of 10-13 y old healthy children. We assessed descriptive, univariable, and multivariable associations of urinary metabolites of bisphenols and phthalates with oxidant stress, insulin resistance, body mass, and endothelial dysfunction. Possible associations with brachial artery distensibility, pulse wave velocity (markers of vascular stiffness), and serum endothelial cell-derived microparticle levels were also assessed. RESULTS: We enrolled 41 participants, 12.1 +/- 1.0 y, most of whom were Mexican Americans (42%) or other Hispanics (34%). Increased BPA levels were associated with increased levels of F2-isoprostane (ng/ml) (P = 0.02), with a similar trend for DEHP metabolites. Each log unit increase of high molecular weight (HMW) phthalate metabolites was associated with a 0.550 increase in Homeostatic Model Assessment of insulin resistance (HOMA-IR) units (P = 0.019) and altered circulating levels of activated endothelial cell-derived microparticles (% per ml) (P = 0.026). Bisphenol S (BPS), a replacement for BPA, was associated with increased albumin (mg):creatinine (g) ratio (P = 0.04). Metabolites of HMW phthalates were also associated with decreased brachial artery distensibility (P = 0.047). CONCLUSION: Exposure to bisphenols and phthalates, including a BPA replacement, is associated with increased oxidant stress, insulin resistance, albuminuria, as well as disturbances in vascular function in healthy children. PMID- 28099429 TI - Vitamin D insufficiency in neonatal hypoxic-ischemic encephalopathy. AB - BACKGROUND: Vitamin D has neuroprotective and immunomodulatory properties, and deficiency is associated with worse stroke outcomes. Little is known about effects of hypoxia-ischemia or hypothermia treatment on vitamin D status in neonates with hypoxic-ischemic encephalopathy (HIE). We hypothesized vitamin D metabolism would be dysregulated in neonatal HIE altering specific cytokines involved in Th17 activation, which might be mitigated by hypothermia. METHODS: We analyzed short-term relationships between 25(OH) and 1,25(OH)2 vitamin D, vitamin D binding protein, and cytokines related to Th17 function in serum samples from a multicenter randomized controlled trial of hypothermia 33 degrees C for 48 h after HIE birth vs. normothermia in 50 infants with moderate to severe HIE. RESULTS: Insufficiency of 25(OH) vitamin D was observed after birth in 70% of infants, with further decline over the first 72 h, regardless of treatment. 25(OH) vitamin D positively correlated with anti-inflammatory cytokine IL-17E in all HIE infants. However, Th17 cytokine suppressor IL-27 was significantly increased by hypothermia, negating the IL-27 correlation with vitamin D observed in normothermic HIE infants. CONCLUSION: Serum 25(OH) vitamin D insufficiency is present in the majority of term HIE neonates and is related to lower circulating anti-inflammatory IL-17E. Hypothermia does not mitigate vitamin D deficiency in HIE. PMID- 28099430 TI - Pooled CRISPR screening with single-cell transcriptome readout. AB - CRISPR-based genetic screens are accelerating biological discovery, but current methods have inherent limitations. Widely used pooled screens are restricted to simple readouts including cell proliferation and sortable marker proteins. Arrayed screens allow for comprehensive molecular readouts such as transcriptome profiling, but at much lower throughput. Here we combine pooled CRISPR screening with single-cell RNA sequencing into a broadly applicable workflow, directly linking guide RNA expression to transcriptome responses in thousands of individual cells. Our method for CRISPR droplet sequencing (CROP-seq) enables pooled CRISPR screens with single-cell transcriptome resolution, which will facilitate high-throughput functional dissection of complex regulatory mechanisms and heterogeneous cell populations. PMID- 28099431 TI - Exacerbated Leishmaniasis Caused by a Viral Endosymbiont can be Prevented by Immunization with Its Viral Capsid. AB - Recent studies have shown that a cytoplasmic virus called Leishmaniavirus (LRV) is present in some Leishmania species and acts as a potent innate immunogen, aggravating lesional inflammation and development in mice. In humans, the presence of LRV in Leishmania guyanensis and in L. braziliensis was significantly correlated with poor treatment response and symptomatic relapse. So far, no clinical effort has used LRV for prophylactic purposes. In this context, we designed an original vaccine strategy that targeted LRV nested in Leishmania parasites to prevent virus-related complications. To this end, C57BL/6 mice were immunized with a recombinant LRV1 Leishmania guyanensis viral capsid polypeptide formulated with a T helper 1-polarizing adjuvant. LRV1-vaccinated mice had significant reduction in lesion size and parasite load when subsequently challenged with LRV1+ Leishmania guyanensis parasites. The protection conferred by this immunization could be reproduced in naive mice via T-cell transfer from vaccinated mice but not by serum transfer. The induction of LRV1 specific T cells secreting IFN-gamma was confirmed in vaccinated mice and provided strong evidence that LRV1-specific protection arose via a cell mediated immune response against the LRV1 capsid. Our studies suggest that immunization with LRV1 capsid could be of a preventive benefit in mitigating the elevated pathology associated with LRV1 bearing Leishmania infections and possibly avoiding symptomatic relapses after an initial treatment. This novel anti-endosymbiotic vaccine strategy could be exploited to control other infectious diseases, as similar viral infections are largely prevalent across pathogenic pathogens and could consequently open new vaccine opportunities. PMID- 28099432 TI - An Analysis of the Last Clinical Encounter before Outpatient Mortality among Children with HIV Infection and Exposure in Lilongwe, Malawi. AB - BACKGROUND: Human immunodeficiency virus (HIV) contributes to nearly 20% of all deaths in children under five years of age in Malawi. Expanded coverage of antiretroviral therapy has allowed children to access treatment on an outpatient basis. Little is known about characteristics of the final outpatient encounter prior to mortality in the outpatient setting. METHODS: This retrospective cohort study assessed clinical factors associated with mortality among HIV-exposed infants and HIV-infected children less than 18 years of age at the Baylor College of Medicine Abbott Fund Children's Center of Excellence in Lilongwe, Malawi. We compared clinical indicators documented from the final outpatient encounter for patients who died in the outpatient setting versus those who were alive after their penultimate clinical encounter. RESULTS: Of the 8,546 patients who were attended to over a 10-year period at the Baylor Center of Excellence, 851 had died (10%). Of children who died, 392 (46%) were directly admitted to the hospital after their last clinical encounter and died as inpatients. Of the remaining 459 who died as outpatients after their last visit, 53.5% had a World Health Organization (WHO) stage IV condition at their last visit, and 25% had a WHO stage III condition. Multivariate regression analysis demonstrated that poor nutritional status, female gender, shorter time as a patient, more clinical encounters in the prior month, if last visit was an unscheduled sick visit, and if the patient had lost weight since their prior visit independently predicted increased mortality in the outpatient setting after the final clinical encounter. CONCLUSION: Clinical indicators may assist in identifying children with HIV who have increased risk of mortality in the outpatient setting. Recognizing these indicators may aid in identifying HIV-infected children who require a higher level of care or closer follow-up. PMID- 28099433 TI - Defining Seropositivity Thresholds for Use in Trachoma Elimination Studies. AB - BACKGROUND: Efforts are underway to eliminate trachoma as a public health problem by 2020. Programmatic guidelines are based on clinical signs that correlate poorly with Chlamydia trachomatis (Ct) infection in post-treatment and low endemicity settings. Age-specific seroprevalence of anti Ct Pgp3 antibodies has been proposed as an alternative indicator of the need for intervention. To standardise the use of these tools, it is necessary to develop an analytical approach that performs reproducibly both within and between studies. METHODOLOGY: Dried blood spots were collected in 2014 from children aged 1-9 years in Laos (n = 952) and Uganda (n = 2700) and from people aged 1-90 years in The Gambia (n = 1868). Anti-Pgp3 antibodies were detected by ELISA. A number of visual and statistical analytical approaches for defining serological status were compared. PRINCIPAL FINDINGS: Seroprevalence was estimated at 11.3% (Laos), 13.4% (Uganda) and 29.3% (The Gambia) by visual inspection of the inflection point. The expectation-maximisation algorithm estimated seroprevalence at 10.4% (Laos), 24.3% (Uganda) and 29.3% (The Gambia). Finite mixture model estimates were 15.6% (Laos), 17.1% (Uganda) and 26.2% (The Gambia). Receiver operating characteristic (ROC) curve analysis using a threshold calibrated against external reference specimens estimated the seroprevalence at 6.7% (Laos), 6.8% (Uganda) and 20.9% (The Gambia) when the threshold was set to optimise Youden's J index. The ROC curve analysis was found to estimate seroprevalence at lower levels than estimates based on thresholds established using internal reference data. Thresholds defined using internal reference threshold methods did not vary substantially between population samples. CONCLUSIONS: Internally calibrated approaches to threshold specification are reproducible and consistent and thus have advantages over methods that require external calibrators. We propose that future serological analyses in trachoma use a finite mixture model or expectation maximisation algorithm as a means of setting the threshold for ELISA data. This will facilitate standardisation and harmonisation between studies and eliminate the need to establish and maintain a global calibration standard. PMID- 28099435 TI - Insensitivity of Tree-Ring Growth to Temperature and Precipitation Sharpens the Puzzle of Enhanced Pre-Eruption NDVI on Mt. Etna (Italy). AB - On Mt. Etna (Italy), an enhanced Normalized Difference in Vegetation Index (NDVI) signature was detected in the summers of 2001 and 2002 along a distinct line where, in November 2002, a flank eruption subsequently occurred. These observations suggest that pre-eruptive volcanic activity may have enhanced photosynthesis along the future eruptive fissure. If a direct relation between NDVI and future volcanic eruptions could be established, it would provide a straightforward and low-cost method for early detection of upcoming eruptions. However, it is unclear if, or to what extent, the observed enhancement of NDVI can be attributed to volcanic activity prior to the subsequent eruption. We consequently aimed at determining whether an increase in ambient temperature or additional water availability owing to the rise of magma and degassing of water vapour prior to the eruption could have increased photosynthesis of Mt. Etna's trees. Using dendro-climatic analyses we quantified the sensitivity of tree ring widths to temperature and precipitation at high elevation stands on Mt. Etna. Our findings suggest that tree growth at high elevation on Mt. Etna is weakly influenced by climate, and that neither an increase in water availability nor an increase in temperature induced by pre-eruptive activity is a plausible mechanism for enhanced photosynthesis before the 2002/2003 flank eruption. Our findings thus imply that other, yet unknown, factors must be sought as causes of the pre eruption enhancement of NDVI on Mt. Etna. PMID- 28099434 TI - MLST-Based Population Genetic Analysis in a Global Context Reveals Clonality amongst Cryptococcus neoformans var. grubii VNI Isolates from HIV Patients in Southeastern Brazil. AB - Cryptococcosis is an important fungal infection in immunocompromised individuals, especially those infected with HIV. In Brazil, despite the free availability of antiretroviral therapy (ART) in the public health system, the mortality rate due to Cryptococcus neoformans meningitis is still high. To obtain a more detailed picture of the population genetic structure of this species in southeast Brazil, we studied 108 clinical isolates from 101 patients and 35 environmental isolates. Among the patients, 59% had a fatal outcome mainly in HIV-positive male patients. All the isolates were found to be C. neoformans var. grubii major molecular type VNI and mating type locus alpha. Twelve were identified as diploid by flow cytometry, being homozygous (AalphaAalpha) for the mating type and by PCR screening of the STE20, GPA1, and PAK1 genes. Using the ISHAM consensus multilocus sequence typing (MLST) scheme, 13 sequence types (ST) were identified, with one being newly described. ST93 was identified from 81 (75%) of the clinical isolates, while ST77 and ST93 were identified from 19 (54%) and 10 (29%) environmental isolates, respectively. The southeastern Brazilian isolates had an overwhelming clonal population structure. When compared with populations from different continents based on data extracted from the ISHAM-MLST database (mlst.mycologylab.org) they showed less genetic variability. Two main clusters within C. neoformans var. grubii VNI were identified that diverged from VNB around 0.58 to 4.8 million years ago. PMID- 28099436 TI - A New Approach to Model Pitch Perception Using Sparse Coding. AB - Our acoustical environment abounds with repetitive sounds, some of which are related to pitch perception. It is still unknown how the auditory system, in processing these sounds, relates a physical stimulus and its percept. Since, in mammals, all auditory stimuli are conveyed into the nervous system through the auditory nerve (AN) fibers, a model should explain the perception of pitch as a function of this particular input. However, pitch perception is invariant to certain features of the physical stimulus. For example, a missing fundamental stimulus with resolved or unresolved harmonics, or a low and high-level amplitude stimulus with the same spectral content-these all give rise to the same percept of pitch. In contrast, the AN representations for these different stimuli are not invariant to these effects. In fact, due to saturation and non-linearity of both cochlear and inner hair cells responses, these differences are enhanced by the AN fibers. Thus there is a difficulty in explaining how pitch percept arises from the activity of the AN fibers. We introduce a novel approach for extracting pitch cues from the AN population activity for a given arbitrary stimulus. The method is based on a technique known as sparse coding (SC). It is the representation of pitch cues by a few spatiotemporal atoms (templates) from among a large set of possible ones (a dictionary). The amount of activity of each atom is represented by a non-zero coefficient, analogous to an active neuron. Such a technique has been successfully applied to other modalities, particularly vision. The model is composed of a cochlear model, an SC processing unit, and a harmonic sieve. We show that the model copes with different pitch phenomena: extracting resolved and non-resolved harmonics, missing fundamental pitches, stimuli with both high and low amplitudes, iterated rippled noises, and recorded musical instruments. PMID- 28099437 TI - Overexpression of Rad51 Predicts Poor Prognosis in Colorectal Cancer: Our Experience with 54 Patients. AB - BACKGROUND: Aberrant Rad51 expression is implicated in the progression of human malignancies. However, the role of Rad51 in colorectal cancer (CRC) remains undefined. This study aimed to establish a relationship between Rad51 and clinicopathologic features of CRC. METHODS: We retrospectively examined the paraffin-embedded tissue samples obtained from 54 patients with CRC who had received surgical therapies at our institution during 2006-2008. Rad51 expression in adenocarcinoma, paracancerous tissue, and normal colonic tissue was determined by immunohistochemistry. The correlation between Rad51 immunoreactivity and clinicopathologic features of these patients was evaluated. RESULTS: Rad51 immunoreactivity was detected in 67% of adenocarcinoma, 48% of paracancerous tissue, and 27% of normal colonic mucosa. Rad51 expression in adenocarcinoma was significantly higher than normal colonic tissue (p < 0.05). Rad51 was also overexpressed in poorly differentiated tumors and tumor samples from patients with lymph node metastasis (p < 0.05). Patients with Rad51 overexpression had a 69% two-year survival, 49% three-year survival, and 16% five-year survival, considerably worse than patients with negative Rad51 expression (p < 0.05). CONCLUSION: Our data suggest that Rad51 overexpression is correlated with malignant phenotypes of CRC and may predict poor prognosis for these patients. PMID- 28099438 TI - Age Related Patterns of Disease and Mortality in Hospitalised Adults in Malawi. AB - BACKGROUND: The epidemic of non-communicable diseases (NCDs) in low and middle income countries (LMICs) is widely recognised as the next major challenge to global health. However, in many LMICs, infectious diseases are still prevalent resulting in a "double burden" of disease. With increased life expectancy and longevity with HIV, older adults may particularly be at risk of this double burden. Here we describe the relative contributions of infections and NCDs to hospital admissions and mortality, according to age, in Malawi's largest hospital. METHODS: Primary diagnosis on discharge/death, mortality rates, and HIV status were recorded prospectively on consecutive adult medical in-patients over 2 years using an electronic medical records system. Diagnoses were classified as infections or NCDs and analysed according to age and gender. FINDINGS: 10,191 records were analysed. Overall, infectious diseases, particularly those associated with HIV, were the leading cause of admission. However, in adults >=55 years, NCDs were the commonest diagnoses. In adults <55 years 71% of deaths were due to infections whereas in adults >=55 years 56% of deaths were due to NCDs. INTERPRETATION: Infectious diseases are still the leading cause of adult admission to a central hospital in Malawi but in adults aged >=55 years NCDs are the most frequent diagnoses. HIV was an underlying factor in the majority of adults with infections and was also present in 53% of those with NCDs. These findings highlight the need for further health sector shifts to address the double burden of infectious and NCDs, particularly in the ageing population. PMID- 28099439 TI - Single versus Serial Measurements of Neuron-Specific Enolase and Prediction of Poor Neurological Outcome in Persistently Unconscious Patients after Out-Of Hospital Cardiac Arrest - A TTM-Trial Substudy. AB - BACKGROUND: Prediction of neurological outcome is a crucial part of post cardiac arrest care and prediction in patients remaining unconscious and/or sedated after rewarming from targeted temperature management (TTM) remains difficult. Current guidelines suggest the use of serial measurements of the biomarker neuron specific enolase (NSE) in combination with other predictors of outcome in patients admitted after out-of-hospital cardiac arrest (OHCA). This study sought to investigate the ability of NSE to predict poor outcome in patients remaining unconscious at day three after OHCA. In addition, this study sought to investigate if serial NSE measurements add incremental prognostic information compared to a single NSE measurement at 48 hours in this population. METHODS: This study is a post-hoc sub-study of the TTM trial, randomizing OHCA patients to a course of TTM at either 33 degrees C or 36 degrees C. Patients were included from sites participating in the TTM-trial biobank sub study. NSE was measured at 24, 48 and 72 hours after ROSC and follow-up was concluded after 180 days. The primary end point was poor neurological function or death defined by a cerebral performance category score (CPC-score) of 3 to 5. RESULTS: A total of 685 (73%) patients participated in the study. At day three after OHCA 63 (9%) patients had died and 473 (69%) patients were not awake. In these patients, a single NSE measurement at 48 hours predicted poor outcome with an area under the receiver operating characteristics curve (AUC) of 0.83. A combination of all three NSE measurements yielded the highest discovered AUC (0.88, p = .0002). Easily applicable combinations of serial NSE measurements did not significantly improve prediction over a single measurement at 48 hours (AUC 0.58-0.84 versus 0.83). CONCLUSION: NSE is a strong predictor of poor outcome after OHCA in persistently unconscious patients undergoing TTM, and NSE is a promising surrogate marker of outcome in clinical trials. While combinations of serial NSE measurements may provide an increase in overall prognostic information, it is unclear whether actual clinical prognostication with low false-positive rates is improved by application of serial measurements in persistently unconscious patients. The findings of this study should be confirmed in another prospective cohort. TRIAL REGISTRATION: NCT01020916. PMID- 28099440 TI - Engagement of Components of DNA-Break Repair Complex and NFkappaB in Hsp70A1A Transcription Upregulation by Heat Shock. AB - An involvement of components of DNA-break repair (DBR) complex including DNA dependent protein kinase (DNA-PK) and poly-ADP-ribose polymerase 1 (PARP-1) in transcription regulation in response to distinct cellular signalling has been revealed by different laboratories. Here, we explored the involvement of DNA-PK and PARP-1 in the heat shock induced transcription of Hsp70A1A. We find that inhibition of both the catalytic subunit of DNA-PK (DNA-PKc), and Ku70, a regulatory subunit of DNA-PK holo-enzyme compromises transcription of Hsp70A1A under heat shock treatment. In immunoprecipitation based experiments we find that Ku70 or DNA-PK holoenzyme associates with NFkappaB. This NFkappaB associated complex also carries PARP-1. Downregulation of both NFkappaB and PARP-1 compromises Hsp70A1A transcription induced by heat shock treatment. Alteration of three bases by site directed mutagenesis within the consensus kappaB sequence motif identified on the promoter affected inducibility of Hsp70A1A transcription by heat shock treatment. These results suggest that NFkappaB engaged with the kappaB motif on the promoter cooperates in Hsp70A1A activation under heat shock in human cells as part of a DBR complex including DNA-PK and PARP-1. PMID- 28099441 TI - PUMA and NF-kB Are Cell Signaling Predictors of Reovirus Oncolysis of Breast Cancer. AB - BACKGROUND AND PURPOSE: Reovirus is a ubiquitous RNA virus that exploits aberrant signaling pathways for its replication. The oncolytic potential of reovirus against numerous cancers under pre-clinical/clinical conditions has been documented by us and others. Despite its proven clinical activity, the underlying mechanisms of reovirus oncolysis is still not well elucidated. If reovirus therapy is to be optimized for cancer, including breast cancer patients, it is imperative to understand the mechanisms of reovirus oncolysis, especially in treatment of resistant tumour. EXPERIMENTAL APPROACH AND RESULTS: In the present study global gene expression profiling was utilized as a preliminary roadmap to tease-out pivotal molecules involved in reovirus induced apoptosis in breast cancer. Reovirus treated HTB133 and MCF7 breast cancer cells revealed transcriptional alteration of a defined subset of apoptotic genes and members of the nuclear factor-kappa B (NF-kB) family and p53 upregulated modulator of apoptosis (PUMA) were prominent. Since NF-kB can paradoxically suppress or promote apoptosis in cancer, the significance of NF-kB in reovirus oncolysis of breast cancer was investigated. Real time PCR analysis indicated a 2.9-4.3 fold increase in NF-kB p65 message levels following reovirus infection of MCF7 and HTB133, respectively. Nuclear translocation of NF-kB p65 protein was also dramatically augmented post reovirus treatment and correlated with enhanced DNA binding. Pharmacologic inhibition of NF-kB lead to oncolytic protection and significant down regulation of PUMA message levels. PUMA down regulation using siRNA suppressed reovirus oncolysis via significantly repressed apoptosis in p53 mutant HTB133 cells. CONCLUSIONS: This study demonstrates for the first time that a prominent pathway of reovirus oncolysis of breast cancer is mediated through NF kB and that PUMA upregulation is dependent on NF-kB activation. These findings represent potential therapeutic indicators of reovirus treatment in future clinical trials. PMID- 28099442 TI - A Whole Genome DArTseq and SNP Analysis for Genetic Diversity Assessment in Durum Wheat from Central Fertile Crescent. AB - Until now, little attention has been paid to the geographic distribution and evaluation of genetic diversity of durum wheat from the Central Fertile Crescent (modern-day Turkey and Syria). Turkey and Syria are considered as primary centers of wheat diversity, and thousands of locally adapted wheat landraces are still present in the farmers' small fields. We planned this study to evaluate the genetic diversity of durum wheat landraces from the Central Fertile Crescent by genotyping based on DArTseq and SNP analysis. A total of 39,568 DArTseq and 20,661 SNP markers were used to characterize the genetic characteristic of 91 durum wheat land races. Clustering based on Neighbor joining analysis, principal coordinate as well as Bayesian model implemented in structure, clearly showed that the grouping pattern is not associated with the geographical distribution of the durum wheat due to the mixing of the Turkish and Syrian landraces. Significant correlation between DArTseq and SNP markers was observed in the Mantel test. However, we detected a non-significant relationship between geographical coordinates and DArTseq (r = -0.085) and SNP (r = -0.039) loci. These results showed that unconscious farmer selection and lack of the commercial varieties might have resulted in the exchange of genetic material and this was apparent in the genetic structure of durum wheat in Turkey and Syria. The genomic characterization presented here is an essential step towards a future exploitation of the available durum wheat genetic resources in genomic and breeding programs. The results of this study have also depicted a clear insight about the genetic diversity of wheat accessions from the Central Fertile Crescent. PMID- 28099444 TI - The Functional Significance of Affect Recognition, Neurocognition, and Clinical Symptoms in Schizophrenia. AB - OBJECTIVES: The complex relationship and exact extent of the contribution of plausible indictors to social functional outcome in schizophrenia remain unclear. The present study aimed to explore the functional significance of clinical symptoms, neurocognition, and affect recognition simultaneously in schizophrenia. METHODS: The clinical symptoms, basic neurocognition, facial emotion recognition, and social functioning of 154 subjects, including 74 with schizophrenia and 80 nonclinical comparisons, were assessed. RESULTS: We observed that various subdomains of social functioning were extensively related to general intelligence, basic neurocognition, facial emotion recognition, and clinical symptoms, with different association patterns. Multivariate regression analyses revealed that years of education, age, sustained attention, working memory, and facial emotion recognition were significantly associated with global social functioning in schizophrenia. CONCLUSION: Our findings suggest that affect recognition combined with nonsocial neurocognition demonstrated a crucial role in predicting global social function in schizophrenia. PMID- 28099443 TI - Inhibition of Human Drug Transporter Activities by the Pyrethroid Pesticides Allethrin and Tetramethrin. AB - Pyrethroids are widely-used chemical insecticides, to which humans are commonly exposed, and known to alter functional expression of drug metabolizing enzymes. Limited data have additionally suggested that drug transporters, that constitute key-actors of the drug detoxification system, may also be targeted by pyrethroids. The present study was therefore designed to analyze the potential regulatory effects of these pesticides towards activities of main ATP-binding cassette (ABC) and solute carrier (SLC) drug transporters, using transporter overexpressing cells. The pyrethroids allethrin and tetramethrin were found to inhibit various ABC and SLC drug transporters, including multidrug resistance associated protein (MRP) 2, breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, organic anion transporter (OAT) 3, multidrug and toxin extrusion transporter (MATE) 1, organic cation transporter (OCT) 1 and OCT2, with IC50 values however ranging from 2.6 MUM (OCT1 inhibition by allethrin) to 77.6 MUM (OAT3 inhibition by tetramethrin) and thus much higher than pyrethroid concentrations (in the nM range) reached in environmentally pyrethroid-exposed humans. By contrast, allethrin and tetramethrin cis-stimulated OATP2B1 activity and failed to alter activities of OATP1B3, OAT1 and MATE2-K, whereas P-glycoprotein activity was additionally moderately inhibited. Twelve other pyrethoids used at 100 MUM did not block activities of the various investigated transporters, or only moderately inhibited some of them (inhibition by less than 50%). In silico analysis of structure-activity relationships next revealed that molecular parameters, including molecular weight and lipophilicity, are associated with transporter inhibition by allethrin/tetramethrin and successfully predicted transporter inhibition by the pyrethroids imiprothrin and prallethrin. Taken together, these data fully demonstrated that two pyrethoids, i.e., allethrin and tetramethrin, can act as regulators of the activity of various ABC and SLC drug transporters, but only when used at high and non relevant concentrations, making unlikely any contribution of these transporter activity alterations to pyrethroid toxicity in environmentally exposed humans. PMID- 28099445 TI - Prevalence of Diabetes among Migrant Women and Duration of Residence in the United Arab Emirates: A Cross Sectional Study. AB - BACKGROUND: The prevalence rate of type 2 diabetes mellitus (T2DM) is one of the highest in United Arab Emirates (UAE), however data for the expatriate population is limited. This study aimed to identify the prevalence of T2DM amongst migrant women and test the hypothesis that acculturation (measured by years of residency) is associated with an increased risk of T2DM. METHODS: This was a cross-sectional study and we recruited a representative sample (n = 599, 75% participation rate) of migrant women aged 18 years and over in Al Ain, UAE. The American Diabetes Association criteria were used to diagnose T2DM. An adapted WHO STEPS questionnaire was used to collect socio-demographic, lifestyle and clinical data. Logistic regression analysis was performed to identify correlates of T2DM including length of UAE residence. RESULTS: The mean age of participants was 34.1 (+/- 9.5) years. Of the study participants, based on HbA1C levels, 18.6% (95% CI: 13.9-24.4) had prediabetes and 10.7% (95% CI: 7.2-15.6) had T2DM. Prevalence of prediabetes was 8.5% for Filipinos, 16.7% for Arabs and 30.3% for South Asians. Similarly the prevalence of T2DM was 1.7% for Filipinos, 12.2% for Arabs and 16.7% for South Asians. Significant correlates of overall T2DM (measured and known diabetes) included length of UAE residence for more than 10 years (Adjusted Odds Ratio [AOR] 2.74, 95% CI: 1.21-6.20), age >=40 years (AOR = 3.48, 95% CI: 1.53-7.87) and South Asian nationality (AOR 2.10, 95% CI: 0.94-4.70). CONCLUSION: Diabetes is a significant public health problem among migrant women in the UAE, particularly for South Asians. Longer length of residence in the UAE is associated with a higher prevalence of diabetes. PMID- 28099446 TI - Reconstruction of the Cortical Maps of the Tasmanian Tiger and Comparison to the Tasmanian Devil. AB - The last known Tasmanian tiger (Thylacinus cynocephalus)-aka the thylacine-died in 1936. Because its natural behavior was never scientifically documented, we are left to infer aspects of its behavior from museum specimens and historical recollections of bushmen. Recent advances in brain imaging have made it possible to scan postmortem specimens of a wide range of animals, even more than a decade old. Any thylacine brain, however, would be more than 100 years old. Here, we show that it is possible to reconstruct white matter tracts in two thylacine brains. For functional interpretation, we compare to the white matter reconstructions of the brains of two Tasmanian devils (Sarcophilus harrisii). We reconstructed the cortical projection zones of the basal ganglia and major thalamic nuclei. The basal ganglia reconstruction showed a more modularized pattern in the cortex of the thylacine, while the devil cortex was dominated by the putamen. Similarly, the thalamic projections had a more orderly topography in the thylacine than the devil. These results are consistent with theories of brain evolution suggesting that larger brains are more modularized. Functionally, the thylacine's brain may have had relatively more cortex devoted to planning and decision-making, which would be consistent with a predatory ecological niche versus the scavenging niche of the devil. PMID- 28099447 TI - Genome-Wide Immune Modulation of TLR3-Mediated Inflammation in Intestinal Epithelial Cells Differs between Single and Multi-Strain Probiotic Combination. AB - Genome-wide transcriptional analysis in intestinal epithelial cells (IEC) can aid in elucidating the impact of single versus multi-strain probiotic combinations on immunological and cellular mechanisms of action. In this study we used human expression microarray chips in an in vitro intestinal epithelial cell model to investigate the impact of three probiotic bacteria, Lactobacillus helveticus R0052 (Lh-R0052), Bifidobacterium longum subsp. infantis R0033 (Bl-R0033) and Bifidobacterium bifidum R0071 (Bb-R0071) individually and in combination, and of a surface-layer protein (SLP) purified from Lh-R0052, on HT-29 cells' transcriptional profile to poly(I:C)-induced inflammation. Hierarchical heat map clustering, Set Distiller and String analyses revealed that the effects of Lh R0052 and Bb-R0071 diverged from those of Bl-R0033 and Lh-R0052-SLP. It was evident from the global analyses with respect to the immune, cellular and homeostasis related pathways that the co-challenge with probiotic combination (PC) vastly differed in its effect from the single strains and Lh-R0052-SLP treatments. The multi-strain PC resulted in a greater reduction of modulated genes, found through functional connections between immune and cellular pathways. Cytokine and chemokine analyses based on specific outcomes from the TNF-alpha and NF-kappaB signaling pathways revealed single, multi-strain and Lh-R0052-SLP specific attenuation of the majority of proteins measured (TNF-alpha, IL-8, CXCL1, CXCL2 and CXCL10), indicating potentially different mechanisms. These findings indicate a synergistic effect of the bacterial combinations relative to the single strain and Lh-R0052-SLP treatments in resolving toll-like receptor 3 (TLR3)-induced inflammation in IEC and maintaining cellular homeostasis, reinforcing the rationale for using multi-strain formulations as a probiotic. PMID- 28099448 TI - The Effects of Low-Power Laser Irradiation on Inflammation and Apoptosis in Submandibular Glands of Diabetes-Induced Rats. AB - Diabetes can lead to dysfunction of the secretory capacity in salivary glands. Activation of the receptor for advanced glycation end products (RAGE) and its ligands has been suggested to participate in chronic disorders such as diabetes and its complications. In this study, the expression of RAGE, high mobility group box 1 (HMGB1) and advanced glycation end products (AGE), as well as the effects of low-power laser irradiation (LPLI) in salivary glands of diabetic rats were evaluated, and the mechanisms involved were characterized. The expression of RAGE and HMGB1 at the protein and mRNA levels was observed in submandibular glands (SMGs) of streptozotocin-induced diabetic rats. A diode laser was applied at 660 nm, 70 mW, 20 J/cm2, 0.56 J/point, with a spot area of 0.028 cm2 and its in vivo effects and the pathways involved were evaluated. Immunohistochemistry and western blotting analysis were performed for inflammatory and apoptosis markers. Diabetes up-regulates HMGB1/AGE/RAGE axis gene expression in SMGs that is associated with activation of the nuclear factor kappa B (NF-kappaB) pathway. Interestingly, LPLI suppresses NF-kappaB activation induced by inflammation. LPLI also reduces diabetes-induced apoptosis. That effect was accompanied by decreased levels of Bax, and cleaved caspase 3, which were up-regulated in diabetes. Taken together, our data suggest that LPLI reduces diabetes-induced inflammation by reducing the induction of HMGB1, ultimately leading to inhibition of apoptosis in submandibular glands of diabetic rats. PMID- 28099449 TI - The Use of Functional Data Analysis to Evaluate Activity in a Spontaneous Model of Degenerative Joint Disease Associated Pain in Cats. AB - INTRODUCTION AND OBJECTIVES: Accelerometry is used as an objective measure of physical activity in humans and veterinary species. In cats, one important use of accelerometry is in the study of therapeutics designed to treat degenerative joint disease (DJD) associated pain, where it serves as the most widely applied objective outcome measure. These analyses have commonly used summary measures, calculating the mean activity per-minute over days and comparing between treatment periods. While this technique has been effective, information about the pattern of activity in cats is lost. In this study, functional data analysis was applied to activity data from client-owned cats with (n = 83) and without (n = 15) DJD. Functional data analysis retains information about the pattern of activity over the 24-hour day, providing insight into activity over time. We hypothesized that 1) cats without DJD would have higher activity counts and intensity of activity than cats with DJD; 2) that activity counts and intensity of activity in cats with DJD would be inversely correlated with total radiographic DJD burden and total orthopedic pain score; and 3) that activity counts and intensity would have a different pattern on weekends versus weekdays. RESULTS AND CONCLUSIONS: Results showed marked inter-cat variability in activity. Cats exhibited a bimodal pattern of activity with a sharp peak in the morning and broader peak in the evening. Results further showed that this pattern was different on weekends than weekdays, with the morning peak being shifted to the right (later). Cats with DJD showed different patterns of activity from cats without DJD, though activity and intensity were not always lower; instead both the peaks and troughs of activity were less extreme than those of the cats without DJD. Functional data analysis provides insight into the pattern of activity in cats, and an alternative method for analyzing accelerometry data that incorporates fluctuations in activity across the day. PMID- 28099450 TI - Advanced Neonatal Medicine in China: A National Baseline Database. AB - Previous surveys of neonatal medicine in China have not collected comprehensive information on workforce, investment, health care practice, and disease expenditure. The goal of the present study was to develop a national database of neonatal care units and compare present outcomes data in conjunction with health care practices and costs. We summarized the above components by extracting data from the databases of the national key clinical subspecialty proposals issued by national health authority in China, as well as publicly accessible databases. Sixty-one newborn clinical units from provincial or ministerial hospitals at the highest level within local areas in mainland China, were included for the study. Data were gathered for three consecutive years (2008-2010) in 28 of 31 provincial districts in mainland China. Of the 61 newborn units in 2010, there were 4,948 beds (median = 62 [IQR 43-110]), 1,369 physicians (median = 22 [IQR 15-29]), 3,443 nurses (median = 52 [IQR 33-81]), and 170,159 inpatient discharges (median = 2,612 [IQR 1,436-3,804]). During 2008-2010, the median yearly investment for a single newborn unit was US$344,700 (IQR 166,100-585,800), median length of hospital stay for overall inpatient newborns 9.5 (IQR 8.2-10.8) days, median inpatient antimicrobial drug use rate 68.7% (IQR 49.8-87.0), and median nosocomial infection rate 3.2% (IQR1.7-5.4). For the common newborn diseases of pneumonia, sepsis, respiratory distress syndrome, and very low birth weight (<1,500 grams) infants, their lengths of hospital stay, daily costs, hospital costs, ratios of hospital cost to per-capita disposable income, and ratios of hospital cost to per-capita health expenditure, were all significantly different across regions (North China, Northeast China, East China, South Central China, Southwest China, and Northwest China). The survival rate of extremely low birth weight (ELBW) infants (Birth weight <1,000 grams) was 76.0% during 2008-2010 in the five hospitals where each unit had more than 20 admissions of ELBW infants in 2010; and the median hospital cost for a single hospital stay in ELBW infants was US$8,613 (IQR 8,153-9,216), which was 3.0 times (IQR 2.0-3.2) the average per capita disposable income, or 63 times (IQR 40.3-72.1) the average per-capita health expenditure of local urban residents in 2011. Our national database provides baseline data on the status of advanced neonatal medicine in China, gathering valuable information for quality improvement, decision making, longitudinal studies and horizontal comparisons. PMID- 28099451 TI - Drawbacks of Dialysis Procedures for Removal of EDTA. AB - Ethylenediaminetetraacetic acid (EDTA) is a chelating agent commonly used in protein purification, both to eliminate contaminating divalent cations and to inhibit protease activity. For a number of subsequent applications EDTA needs to be exhaustively removed. Most purification methods rely in extensive dialysis and/or gel filtration in order to exchange or remove protein buffer components, including metal chelators. We report here that dialysis protocols, even as extensive as those typically employed for protein refolding, may not effectively remove EDTA, which is reduced only by approximately two-fold and it also persists after spin-column gel filtration, as determined by NMR and by colorimetric methods. Remarkably, the most efficient removal was achieved by ultrafiltration, after which EDTA became virtually undetectable. These results highlight a potentially widespread source of experimental variability affecting free divalent cation concentrations in protein applications. PMID- 28099452 TI - How Does the Concentration of Determinants Affect Industrial Innovation Performance? - An Empirical Analysis of 23 Chinese Industrial Sectors. AB - The agglomeration of innovation determinants has a significant influence on the innovation performance of industries and enterprises. Such an effect has received less attention in empirical research studies. This study involves a survey of the agglomeration effect of two important innovation determinants, R&D investment and R&D personnel, and its influence on innovation performance from the perspective of the industrial level. We analysed the agglomeration features based on the panel data of 23 Chinese industrial sectors from 2001~2013. An interpretation model is proposed to examine the agglomeration effect on innovation performance for 4 industrial groups: state-owned enterprises, individual enterprises, foreign owned enterprises and enterprises as a whole. We found two main results. First, the agglomeration of determinants has a clear positive effect on the innovation performance of all 4 groups but affects individual enterprises more significantly, followed by state-owned and foreign-owned enterprises. Second, the state-owned enterprises show a much higher concentration of R&D investment and R&D personnel than other groups. However, the induced innovation efficiency in the state-owned enterprises is worse than in the individual enterprises. The advantage of resources and capital does not translate into corresponding innovation output. The privately owned small and medium-sized enterprises (SMEs) show a high capability of technological innovation and mercerization but have limited innovation resources. PMID- 28099453 TI - Elimination of Porcine Epidemic Diarrhea Virus in an Animal Feed Manufacturing Facility. AB - Porcine Epidemic Diarrhea Virus (PEDV) was the first virus of wide scale concern to be linked to possible transmission by livestock feed or ingredients. Measures to exclude pathogens, prevent cross-contamination, and actively reduce the pathogenic load of feed and ingredients are being developed. However, research thus far has focused on the role of chemicals or thermal treatment to reduce the RNA in the actual feedstuffs, and has not addressed potential residual contamination within the manufacturing facility that may lead to continuous contamination of finished feeds. The purpose of this experiment was to evaluate the use of a standardized protocol to sanitize an animal feed manufacturing facility contaminated with PEDV. Environmental swabs were collected throughout the facility during the manufacturing of a swine diet inoculated with PEDV. To monitor facility contamination of the virus, swabs were collected at: 1) baseline prior to inoculation, 2) after production of the inoculated feed, 3) after application of a quaternary ammonium-glutaraldehyde blend cleaner, 4) after application of a sodium hypochlorite sanitizing solution, and 5) after facility heat-up to 60 degrees C for 48 hours. Decontamination step, surface, type, zone and their interactions were all found to impact the quantity of detectable PEDV RNA (P < 0.05). As expected, all samples collected from equipment surfaces contained PEDV RNA after production of the contaminated feed. Additionally, the majority of samples collected from non-direct feed contact surfaces were also positive for PEDV RNA after the production of the contaminated feed, emphasizing the potential role dust plays in cross-contamination of pathogen throughout a manufacturing facility. Application of the cleaner, sanitizer, and heat were effective at reducing PEDV genomic material (P < 0.05), but did not completely eliminate it. PMID- 28099454 TI - High Cable Forces Deteriorate Pinch Force Control in Voluntary-Closing Body Powered Prostheses. AB - BACKGROUND: It is generally asserted that reliable and intuitive control of upper limb prostheses requires adequate feedback of prosthetic finger positions and pinch forces applied to objects. Body-powered prostheses (BPPs) provide the user with direct proprioceptive feedback. Currently available BPPs often require high cable operation forces, which complicates control of the forces at the terminal device. The aim of this study is to quantify the influence of high cable forces on object manipulation with voluntary-closing prostheses. METHOD: Able-bodied male subjects were fitted with a bypass-prosthesis with low and high cable force settings for the prehensor. Subjects were requested to grasp and transfer a collapsible object as fast as they could without dropping or breaking it. The object had a low and a high breaking force setting. RESULTS: Subjects conducted significantly more successful manipulations with the low cable force setting, both for the low (33% more) and high (50%) object's breaking force. The time to complete the task was not different between settings during successful manipulation trials. CONCLUSION: High cable forces lead to reduced pinch force control during object manipulation. This implies that low cable operation forces should be a key design requirement for voluntary-closing BPPs. PMID- 28099455 TI - Evaluating the Impact of DNA Extraction Method on the Representation of Human Oral Bacterial and Fungal Communities. AB - The application of high-throughput, next-generation sequencing technologies has greatly improved our understanding of the human oral microbiome. While deciphering this diverse microbial community using such approaches is more accurate than traditional culture-based methods, experimental bias introduced during critical steps such as DNA extraction may compromise the results obtained. Here, we systematically evaluate four commonly used microbial DNA extraction methods (MoBio PowerSoil(r) DNA Isolation Kit, QIAamp(r) DNA Mini Kit, Zymo Bacterial/Fungal DNA Mini PrepTM, phenol:chloroform-based DNA isolation) based on the following criteria: DNA quality and yield, and microbial community structure based on Illumina amplicon sequencing of the V3-V4 region of the 16S rRNA gene of bacteria and the internal transcribed spacer (ITS) 1 region of fungi. Our results indicate that DNA quality and yield varied significantly with DNA extraction method. Representation of bacterial genera in plaque and saliva samples did not significantly differ across DNA extraction methods and DNA extraction method showed no effect on the recovery of fungal genera from plaque. By contrast, fungal diversity from saliva was affected by DNA extraction method, suggesting that not all protocols are suitable to study the salivary mycobiome. PMID- 28099456 TI - Burden of Idiopathic Pulmonary Fibrosis Progression: A 5-Year Longitudinal Follow Up Study. AB - Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with an unpredictable course. An observational study was set up using the French hospital discharge database to describe the reasons, outcomes and costs of hospitalisations related to this disease. Patients newly hospitalised for idiopathic pulmonary fibrosis (ICD-10 code: J84.1) in 2008 were identified and followed for 5 years. As J84.1 includes other fibrotic pulmonary diseases, an algorithm excluding age<50 years and presence of a differential diagnosis in the following year was defined. Overall, 6,476 patients were identified; of whom 30% were admitted through the emergency unit and 12% died during their first hospitalisation. Most of patients were hospitalised at least once for one or several acute events (n = 5,635; 87.0% of patients), of whom 36.5% of patients with an acute respiratory worsening (in hospital mortality of 17.0% and median cost of ?3,224; interquartile range (IQR ?889-6,092)), 43.7% of patients with a respiratory infection (in-hospital mortality of 29.5% and median cost of ?5,432 (IQR, ?3,620-9,115)) and 51.7% of patients with a cardiac event (in-hospital mortality of 35.7% and median cost of ?4,584 (IQR, ?2,803-6,399)); 30.2% of these events occurred during the first hospitalisation. Finally, the 3-year in-hospital mortality crude rate was 36.8%. This study is the first providing extensive data on hospitalisations in patients with pulmonary fibrosis, mostly idiopathic, in France, demonstrating high burden and hospital cost. PMID- 28099457 TI - Comparing and Evaluating Metagenome Assembly Tools from a Microbiologist's Perspective - Not Only Size Matters! AB - With the constant improvement in cost-efficiency and quality of Next Generation Sequencing technologies, shotgun-sequencing approaches -such as metagenomics- have nowadays become the methods of choice for studying and classifying microorganisms from various habitats. The production of data has dramatically increased over the past years and processing and analysis steps are becoming more and more of a bottleneck. Limiting factors are partly the availability of computational resources, but mainly the bioinformatics expertise in establishing and applying appropriate processing and analysis pipelines. Fortunately, a large diversity of specialized software tools is nowadays available. Nevertheless, choosing the most appropriate methods for answering specific biological questions can be rather challenging, especially for non-bioinformaticians. In order to provide a comprehensive overview and guide for the microbiological scientific community, we assessed the most common and freely available metagenome assembly tools with respect to their output statistics, their sensitivity for low abundant community members and variability in resulting community profiles as well as their ease-of-use. In contrast to the highly anticipated "Critical Assessment of Metagenomic Interpretation" (CAMI) challenge, which uses general mock community based assembler comparison we here tested assemblers on real Illumina metagenome sequencing data from natural communities of varying complexity sampled from forest soil and algal biofilms. Our observations clearly demonstrate that different assembly tools can prove optimal, depending on the sample type, available computational resources and, most importantly, the specific research goal. In addition, we present detailed descriptions of the underlying principles and pitfalls of publically available assembly tools from a microbiologist's perspective, and provide guidance regarding the user-friendliness, sensitivity and reliability of the resulting phylogenetic profiles. PMID- 28099458 TI - Gender Differences in Factors Related to HIV Risk Behaviors among People Who Inject Drugs in North-East India. AB - People who inject drugs (PWID) in India are at high risk for HIV, with women being at elevated risk. Using a socio-ecological framework, this study assessed whether factors associated with HIV transmission risk behaviors differed across men and women PWID. Data for this cross-sectional study were collected from 6449 PWID in 7 cities in Northeast India. Men (n = 5653) and women (n = 796) PWID were recruited using respondent-driven sampling (RDS). We assessed sex differences in two recent HIV transmission risk behaviors: multiple sex partners and needle/syringe sharing. We used multi-level logistic regression models, which incorporated sampling weights and random intercepts for city, to assess factors associated with these HIV risks, separately among men and women. The prevalence of HIV was significantly higher among women than men (53% vs 18.4%, p<0.01). Nearly 13% of men and 8% of women (p = .30) had multiple partners. Employment in men and relationship status and stigma in women were significantly associated with multiple partners. Approximately 25% of men and 19% of women engaged in needle sharing (p = .16). Younger age in women and depression symptoms in men were significantly associated with increased risk for sharing needles. We found that sexual and drug related risk behaviors were common among PWID in Northeast India, and there were differences between men and women in the socio-ecologic correlates of these behaviors. Contextually-integrated and gender-specific HIV prevention and intervention efforts are needed that consider factors at individual, interpersonal- and community-levels that uniquely impact HIV risks among PWID. PMID- 28099459 TI - Correction: The Burden of Leprosy in Cameroon: Fifteen Years into the Post elimination Era. AB - [This corrects the article DOI: 10.1371/journal.pntd.0005012.]. PMID- 28099460 TI - Impact of Radiofrequency Ablation-Induced Glisson's Capsule-Associated Complications in Patients with Hepatocellular Carcinoma. AB - BACKGROUND: Radiofrequency ablation (RFA) is commonly used to locally treat hepatocellular carcinoma (HCC). However, when tumors are close to the Glisson's capsule, RFA may induce injury in this region, complicating therapeutic efforts. We investigated the impact of RFA-induced Glisson's capsule-associated complications on liver function and prognosis of HCC patients. METHODS: We retrospectively reviewed our patient database and found 170 early-stage HCC patients treated via RFA from April 2004 to December 2012. We defined RFA-induced Glisson's capsule-associated complication as lasting hepatic arterioportal (AP) fistula, major intrahepatic bile-duct dilatation (affecting two or more subsegments), or hepatic infarction. We also defined liver failure as initial occurrence of either total bilirubin increase (>3.0 mg/dL), uncontrolled ascites, or encephalopathy. RESULTS: In our cohort, 15 patients had RFA-induced Glisson's capsule-associated complications (incidence of related complications, with some overlap: lasting AP fistula, n = 9; major intrahepatic bile-duct dilatation, n = 7; and hepatic infarction, n = 2). The cumulative incidence of liver failure before stage progression was significantly higher and the median overall survival (OS) was significantly lower (52.3 months) in HCC patients with Glisson's capsule associated complications than in those without Glisson's capsule-associated complications (95.0 months). In addition, multivariate analysis demonstrated that Glisson's capsule-associated complication was a significant independent factor associated with OS. CONCLUSIONS: In this study, we have shown that early-stage HCC patients with RFA-induced Glisson's capsule-associated complications may have higher risks in poor prognosis. PMID- 28099461 TI - Whole Exome Sequencing of Growing and Non-Growing Cutaneous Neurofibromas from a Single Patient with Neurofibromatosis Type 1. AB - The growth behaviors of cutaneous neurofibromas in patients with Neurofibromatosis type 1 are highly variable. The role of the germline NF1 mutation, somatic NF1 mutation and mutations at modifying loci, are poorly understood. We performed whole exome sequencing of three growing and three non growing neurofibromas from a single individual to assess the role of acquired somatic mutations in neurofibroma growth behavior. 1-11 mutations were identified in each sample, including two deleterious NF1 mutations. No trends were present between the types of somatic mutations identified and growth behavior. Mutations in the HIPPO signaling pathway appeared to be overrepresented. PMID- 28099462 TI - Acute and Chronic Sustained Hypoxia Do Not Substantially Regulate Amyloid-beta Peptide Generation In Vivo. AB - BACKGROUND: Recent epidemiological evidence has linked hypoxia with the development of Alzheimer disease (AD). A number of in vitro and in vivo studies have reported that hypoxia can induce amyloid-beta peptide accumulation through various molecular mechanisms including the up-regulation of the amyloid-beta precursor protein, the beta-secretase Bace1, or the gammagamma-secretase complex components, as well as the down-regulation of Abeta-degrading enzymes. OBJECTIVES: To investigate the effects of acute and chronic sustained hypoxia in Abeta generation in vivo. METHODS: 2-3 month-old C57/Bl6J wild-type mice were exposed to either normoxia (21% O2) or hypoxia (9% O2) for either 4 to 72 h (acute) or 21-30 days (chronic sustained) in a hermetic chamber. Brain mRNA levels of Abeta-related genes were measured by quantitative real-time PCR, whereas levels of Bace1 protein, full length AbetaPP, and its C-terminal fragments (C99/C88 ratio) were measured by Western blot. In addition, 8 and 14 month-old APP/PS1 transgenic mice were subjected to 9% O2 for 21 days and levels of Abeta40, Abeta42, full length AbetaPP, and soluble AbetaPPalpha (sAbetaPPalpha) were measured by ELISA or WB. RESULTS: Hypoxia (either acute or chronic sustained) did not impact the transcription of any of the Abeta-related genes in young wild-type mice. A significant reduction of Bace1 protein level was noted with acute hypoxia for 16 h but did not correlate with an increased level of full length AbetaPP or a decreased C99/C83 ratio. Chronic sustained hypoxia did not significantly alter the levels of Bace1, full length AbetaPP or the C99/C83 ratio. Last, chronic sustained hypoxia did not significantly change the levels of Abeta40, Abeta42, full length AbetaPP, or sAbetaPPalpha in either young or aged APP/PS1 mice. DISCUSSION: Our results argue against a hypoxia-induced shift of AbetaPP proteolysis from the non-amyloidogenic to the amyloidogenic pathways. We discuss the possible methodological caveats of previous in vivo studies. PMID- 28099463 TI - The Differential Effects of Anesthetics on Bacterial Behaviors. AB - Volatile anesthetics have been in clinical use for a long period of time and are considered to be promiscuous by presumably interacting with several ion channels in the central nervous system to produce anesthesia. Because ion channels and their existing evolutionary analogues, ion transporters, are very important in various organisms, it is possible that volatile anesthetics may affect some bacteria. In this study, we hypothesized that volatile anesthetics could affect bacterial behaviors. We evaluated the impact of anesthetics on bacterial growth, motility (swimming and gliding) and biofilm formation of four common bacterial pathogens in vitro. We found that commonly used volatile anesthetics isoflurane and sevoflurane affected bacterial motility and biofilm formation without any effect on growth of the common bacterial pathogens studied here. Using available Escherichia coli gene deletion mutants of ion transporters and in silico molecular docking, we suggested that these altered behaviors might be at least partly via the interaction of volatile anesthetics with ion transporters. PMID- 28099464 TI - Laparoscopically Assisted Anorectal Pull-Through versus Posterior Sagittal Anorectoplasty for High and Intermediate Anorectal Malformations: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: Anorectal malformations (ARMs) are one of the commonest anomalies in neonates. Both laparoscopically assisted anorectal pull-through (LAARP) and posterior sagittal anorectoplasty (PSARP) can be used for the treatment of ARMs. The aim of this systematic review and meta-analysis is to compare these two approaches in terms of intraoperative and postoperative outcomes. METHODS: MEDLINE, Embase, Web of Science and the Cochrane Library were searched from 2000 to August 2016. Both randomized and non-randomized studies, assessing LAARP and PSARP in pediatric patients with high/intermediate ARMs, were included. The primary outcome measures were operative time, length of hospital stay and total postoperative complications. The second outcome measures were rectal prolapse, anal stenosis, wound infection/dehiscence, anorectal manometry, Kelly's clinical score, and Krickenbeck classification. The quality of the randomized and non randomized studies was assessed using the Cochrane Collaboration's Risk of Bias tool and Newcastle-Ottawa scale (NOS) respectively. The quality of evidence was assessed by GRADEpro. RESULTS: From 332 retrieved articles, 1, 1, and 8 of randomized control, prospective and retrospective studies, respectively, met the inclusion criteria. The randomized clinical trial was judged to be of low risk of bias, and the nine cohort studies were of moderate to high quality. 191 and 169 pediatric participants had undergone LAARP and PSARP, respectively. Shorter hospital stays, less wound infection/dehiscence, higher anal canal resting pressure, and a lower incidence of grade 2 or 3 constipation were obtained after LAARP compared with PSARP group values. Besides, the LAARP group had marginally less total postoperative complications. However, the result of operative time was inconclusive; meanwhile, there was no significant difference in rectal prolapse, anal stenosis, anorectal manometry, Kelly's clinical score and Krickenbeck classification. CONCLUSION: For pediatric patients with high/intermediate anorectal malformations, LAARP is a better option compared with PSARP. However, the quality of evidence was very low to moderate. PMID- 28099465 TI - Impact of a Multi-Strategy Community Intervention to Reduce Maternal and Child Health Inequalities in India: A Qualitative Study in Haryana. AB - A multi-strategy community intervention, known as National Rural Health Mission (NRHM), was implemented in India from 2005 to 2012. By improving the availability of and access to better-quality healthcare, the aim was to reduce maternal and child health (MCH) inequalities. This study was planned to explore the perceptions and beliefs of stakeholders about extent of implementation and effectiveness of NRHM's health sector plans in improving MCH status and reducing inequalities. A total of 33 in-depth interviews (n = 33) with program managers, community representatives, mothers and 8 focus group discussions (n = 42) with health service providers were conducted from September to December 2013, in Haryana, post NRHM. Using NVivo software (version 9), an inductive applied thematic analysis was done based upon grounded theory, program theory of change and a framework approach. Almost all the participants reported that there was an improvement in overall health infrastructure through an increased availability of accredited social health activists, free ambulance services, and free treatment facilities in rural areas. This had increased the demand and utilization of MCH services, especially for those related to institutional delivery, even by the poor families. Service providers felt that acute shortage of human resources was a major health system level barrier. District-specific individual, community, and socio-political level barriers were also observed. Overall program managers, service providers and community representatives believed that NRHM had a role in improving MCH outcomes and in reduction of geographical and socioeconomic inequalities, through improvement in accessibility, availability and affordability of the MCH services in the rural areas and for the poor. Any reduction in gender-based inequalities, however, was linked to the adoption of small family sizes and an increase in educational levels. PMID- 28099466 TI - Biogeography in Cellana (Patellogastropoda, Nacellidae) with Special Emphasis on the Relationships of Southern Hemisphere Oceanic Island Species. AB - Oceanic islands lacking connections to other land are extremely isolated from sources of potential colonists and have acquired their biota mainly through dispersal from geographically distant areas. Hence, isolated island biota constitutes interesting models to infer biogeographical mechanisms of dispersal, colonization, differentiation, and speciation. Limpets of the genus Cellana (Nacellidae: Patellogastropoda) show limited dispersal capacity but are broadly distributed across the Indo-Pacific including many endemic species in isolated oceanic islands. Here, we examined main distributional patterns and geographic boundaries among Cellana lineages with special emphasis in the relationships of Southern Hemisphere oceanic islands species. Phylogenetic reconstructions based on mtDNA (COI) recognized three main clades in Cellana including taxa from different provinces of the Indo-Pacific. Clear genetic discontinuities characterize the biogeography of Cellana and several lineages are associated to particular areas of the Indo-Pacific supporting the low dispersal capacity of the genus across recognized biogeographical barriers in the region. However, evolutionary relationships within Cellana suggest that long-distance dispersal processes have been common in the history of the genus and probably associated to the origin of the species in Hawaii and Juan Fernandez Archipelago. Therefore, the presence of Cellana species in geographically distant Southern Hemisphere oceanic islands, such as the Juan Fernandez Archipelago, suggests that long distance dispersal mediated by rafting may have played an important role in the biogeography of the genus. PMID- 28099467 TI - Senescent Atrophic Epidermis Retains Lrig1+ Stem Cells and Loses Wnt Signaling, a Phenotype Shared with CD44KO Mice. AB - Lrig1 is known to repress the epidermal growth through its inhibitory activity on EGFR, while CD44 promotes it. We analyzed the expression of these molecules in senescent atrophic human epidermis and in the epidermis of CD44KO mice. In normal human epidermis, Lrig1+ cells form clusters located in the basal layer in which CD44 expression is downregulated and Lef1 expression reflects an active Wnt signaling. In senescent atrophic human epidermis, we found retention of Lrig1high+ cells all along the basal layer, forming no clusters, with decrease of CD44 and lef1 expression. In vitro silencing of CD44 indicated that CD44 may be required for Wnt signaling. However, if looking at the ear epidermis of CD44KO mice, we only found a limited interfollicular epidermal atrophy and unchanged Lrig1high+ cells in the hair follicle. Cell lineage tracing further revealed that interfollicular epidermis did lost its self-renewing capacity but that its homeostasis relied on Lrig1-derived keratinocytes migrating from the hair follicle. Therefore, we conclude that CD44 downregulation is part of the phenotype of senescent atrophic human epidermis, and contributes to reduce Wnt signaling and to alter Lrig1high+ stem cell distribution. PMID- 28099468 TI - miR 1296-5p Inhibits the Migration and Invasion of Gastric Cancer Cells by Repressing ERBB2 Expression. AB - The metastasis of gastric cancer, one of the most common tumors, has a molecular mechanism that is still largely unclear. Here we investigated the role of possible tumor-suppressor miR-1296-5p in the cell migration and invasion of ERBB2 positive gastric cancer. It found that miR-1296-5p was significantly down regulated in gastric cancer tissues. Moreover, it was down-regulated in lymph node metastatic gastric cancer tissues compared with non-metastatic gastric cancer tissues. The luciferase activity of ERBB2 3'-untranslated region-based reporters constructed in SNU-216 and NUGC-4 gastric cancer cells suggested that ERBB2 was the target gene of miR-1296-5p. Overexpressed miR-1296-5p reduced its target protein level and Rac1 activation, and inhibited the migration and invasion of SNU-216 and NUGC-4 gastric cancer cells. MiR-1296-5p was down regulated in ERBB2-positive gastric cancer tissues compared with ERBB2-negative gastric cancer tissues. In ERBB2-positive gastric cancers, the miR-1296-5p expression was suppressed in a majority of metastatic lymph node tissues compared to non-metastatic gastric cancer samples. The migration and invasion of gastric cancer cells was inhibited by miR-1296-5p overexpression or herceptin treatment, and rescued by the overexpression of constitutively active Rac1-Q61L or ERBB2. Taken together, our findings first suggest that miR-1296-5p might be involved in the regulation on the migration and invasion of human gastric cancer cells at least in part via targeting ERBB2/Rac1 signaling pathway. PMID- 28099469 TI - The Prevalence of Nonalcoholic Fatty Liver Disease and Related Metabolic Comorbidities Was Associated with Age at Onset of Moderate to Severe Plaque Psoriasis: A Cross-Sectional Study. AB - Nonalcoholic fatty liver disease (NAFLD) has been found to be highly prevalent in psoriatic patients. Adult onset psoriasis could be divided into either early or late onset psoriasis. The associations between NAFLD and related metabolic comorbidities and age at onset of psoriasis have not yet been investigated. Our study was to evaluate the associations between prevalence of NAFLD and related metabolic conditions and early, late, and childhood onset psoriasis. A cross sectional observational study was conducted on patients with moderate to severe plaque psoriasis. Data on clinical characteristics of NAFLD and related metabolic diseases (diabetes, hypertriglyceridemia, hyperuricemia, and metabolic syndrome) were collected. The prevalence of NAFLD in 439 patients (mean: 51+/-14 years, range: 18-85 years) was 55.8%. NAFLD was frequently identified in early onset patients (74.2%), and this diagnosis was particularly common in patients currently younger than 40 (85.3%). Diabetes was the least prevalent component of metabolic syndrome in early onset patients with metabolic syndrome but the most often found component in late onset ones. Patients with childhood onset psoriasis had the lowest frequencies of all metabolic comorbidities except hyperuricemia among the three groups. In the multivariate analyses, early onset was independently and positively associated with NAFLD, hypertriglyceridemia and hyperuricemia and independently and negatively associated with diabetes among early and late onset patients. The results suggested prevalence of NAFLD and related metabolic comorbidities was associated with age at onset of moderate to severe plaque psoriasis. Early onset of psoriasis was independently associated with greater odds of NAFLD, hypertriglyceridemia, hyperuricemia and smaller odds of diabetes compared to late onset. Early onset patients have metabolic syndrome mainly related to lipid disorders and abnormal glucose metabolism was not often involved. PMID- 28099470 TI - A Gene-Oriented Haplotype Comparison Reveals Recently Selected Genomic Regions in Temperate and Tropical Maize Germplasm. AB - The extensive genetic variation present in maize (Zea mays) germplasm makes it possible to detect signatures of positive artificial selection that occurred during temperate and tropical maize improvement. Here we report an analysis of 532,815 polymorphisms from a maize association panel consisting of 368 diverse temperate and tropical inbred lines. We developed a gene-oriented approach adapting exonic polymorphisms to identify recently selected alleles by comparing haplotypes across the maize genome. This analysis revealed evidence of selection for more than 1100 genomic regions during recent improvement, and included regulatory genes and key genes with visible mutant phenotypes. We find that selected candidate target genes in temperate maize are enriched in biosynthetic processes, and further examination of these candidates highlights two cases, sucrose flux and oil storage, in which multiple genes in a common pathway can be cooperatively selected. Finally, based on available parallel gene expression data, we hypothesize that some genes were selected for regulatory variations, resulting in altered gene expression. PMID- 28099471 TI - Molybdate in Rhizobial Seed-Coat Formulations Improves the Production and Nodulation of Alfalfa. AB - Rhizobia-legume symbiosis is the most well researched biological nitrogen fixation system. Coating legume seeds with rhizobia is now a recognized practical measure for improving the production of legume corp. However, the efficacy of some commercial rhizobia inoculants cannot be guaranteed in China due to the low rate of live rhizobia in these products. A greenhouse experiment was conducted to assess the effects of different rhizobial inoculant formulations on alfalfa productivity and nitrogen fixation. Two rhizobia strains, (ACCC17631 and ACCC17676), that are effective partners with alfalfa variety Zhongmu No. 1 were assessed with different concentrations of ammonium molybdate in seed-coat formulations with two different coating adhesives. Our study showed that the growth, nodulation, and nitrogen fixation ability of the plants inoculated with the ACCC17631 rhizobial strain were greatest when the ammonium molybdate application was0.2% of the formulation. An ammonium molybdate concentration of 0.1% was most beneficial to the growth of the plants inoculated with the ACCC17676 rhizobial strain. The sodium carboxymethyl cellulose and sodium alginate, used as coating adhesives, did not have a significant effect on alfalfa biomass and nitrogen fixation. However, the addition of skimmed milk to the adhesive improved nitrogenase activity. These results demonstrate that a new rhizobial seed-coat formulation benefitted alfalfa nodulation and yield. PMID- 28099472 TI - Elastic Tape Improved Shoulder Joint Position Sense in Chronic Hemiparetic Subjects: A Randomized Sham-Controlled Crossover Study. AB - BACKGROUND: Elastic tape has been widely used in clinical practice in order to improve upper limb (UL) sensibility. However, there is little evidence that supports this type of intervention in stroke patients. OBJECTIVE: To verify the effect of elastic tape, applied to the paretic shoulder, on joint position sense (JPS) during abduction and flexion in subjects with chronic hemiparesis compared to sham tape (non-elastic tape). Furthermore, to verify if this potential effect is correlated to shoulder subluxation measurements and sensorimotor impairment. METHODS: A crossover and sham-controlled study was conducted with post-stroke patients who were randomly allocated into two groups: 1) those who received Sham Tape (ST) first and after one month they received Elastic Tape (ET); 2) those who received Elastic Tape (ET) first and after one month they received Sham Tape (ST). The JPS was evaluated using a dynamometer. The absolute error for shoulder abduction and flexion at 30 degrees and 60 degrees was calculated. Sensorimotor impairment was determined by Fugl-Meyer, and shoulder subluxation was measured using a caliper. RESULTS: Thirteen hemiparetic subjects (average time since stroke 75.23 months) participated in the study. At baseline (before interventions), the groups were not different for abduction at 30 degrees (p = 0.805; p = 0.951), and 60 degrees (p = 0.509; p = 0.799), or flexion at 30 degrees (p = 0.872; p = 0.897) and 60 degrees (p = 0.853; p = 0.970). For the ET group, differences between pre and post-elastic tape for abduction at 30 degrees (p<0.010) and 60 degrees (p<0.010), and flexion at 30 degrees p<0.010) and 60 degrees (p<0.010) were observed. For the ST group, differences were also observed between pre and post-elastic tape for abduction at 30 degrees (p<0.010) and 60 degrees (p<0.010), and flexion at 30 degrees (p<0.010,) and 60 degrees (p<0.010). Potential effects were only correlated with shoulder subluxation during abduction at 30 degrees (p = 0.001, r = -0.92) and 60 degrees (p = 0.020, r = -0.75). CONCLUSION: Elastic tape improved shoulder JPS of subjects with chronic hemiparesis regardless of the level of UL sensorimotor impairment. However, this improvement was influenced by the subluxation degree at abduction. PMID- 28099473 TI - The Staphylococcus aureus SrrAB Regulatory System Modulates Hydrogen Peroxide Resistance Factors, Which Imparts Protection to Aconitase during Aerobic Growth. AB - The SrrAB two-component regulatory system (TCRS) positively influences the transcription of genes involved in aerobic respiration in response to changes in respiratory flux. Hydrogen peroxide (H2O2) can arise as a byproduct of spontaneous interactions between dioxygen and components of respiratory pathways. H2O2 damages cellular factors including protein associated iron-sulfur cluster prosthetic groups. We found that a Staphylococcus aureus strain lacking the SrrAB two-component regulatory system (TCRS) is sensitive to H2O2 intoxication. We tested the hypothesis that SrrAB manages the mutually inclusive expression of genes required for aerobic respiration and H2O2 resistance. Consistent with our hypothesis, a DeltasrrAB strain had decreased transcription of genes encoding for H2O2 resistance factors (kat, ahpC, dps). SrrAB was not required for the inducing the transcription of these genes in cells challenged with H2O2. Purified SrrA bound to the promoter region for dps suggesting that SrrA directly influences dps transcription. The H2O2 sensitivity of the DeltasrrAB strain was alleviated by iron chelation or deletion of the gene encoding for the peroxide regulon repressor (PerR). The positive influence of SrrAB upon H2O2 metabolism bestowed protection upon the solvent accessible iron-sulfur (FeS) cluster of aconitase from H2O2 poisoning. SrrAB also positively influenced transcription of scdA (ytfE), which encodes for a FeS cluster repair protein. Finally, we found that SrrAB positively influences H2O2 resistance only during periods of high dioxygen dependent respiratory activity. SrrAB did not influence H2O2 resistance when cellular respiration was diminished as a result of decreased dioxygen availability, and negatively influenced it in the absence of respiration (fermentative growth). We propose a model whereby SrrAB-dependent regulatory patterns facilitate the adaptation of cells to changes in dioxygen concentrations, and thereby aids in the prevention of H2O2 intoxication during respiratory growth upon dixoygen. PMID- 28099474 TI - DNA Double-Strand Breaks Induce the Nuclear Actin Filaments Formation in Cumulus Enclosed Oocytes but Not in Denuded Oocytes. AB - As a gamete, oocyte needs to maintain its genomic integrity and passes this haploid genome to the next generation. However, fully-grown mouse oocyte cannot respond to DNA double-strand breaks (DSBs) effectively and it is also unable to repair them before the meiosis resumption. To compensate for this disadvantage and control the DNA repair events, oocyte needs the cooperation with its surrounding cumulus cells. Recently, evidences have shown that nuclear actin filament formation plays roles in cellular DNA DSB repair. To explore whether these nuclear actin filaments are formed in the DNA-damaged oocytes, here, we labeled the filament actins in denuded oocytes (DOs) and cumulus-enclosed oocytes (CEOs). We observed that the nuclear actin filaments were formed only in the DNA damaged CEOs, but not in DOs. Formation of actin filaments in the nucleus was an event downstream to the DNA damage response. Our data also showed that the removal of cumulus cells led to a reduction in the nuclear actin filaments in oocytes. Knocking down of the Adcy1 gene in cumulus cells did not affect the formation of nuclear actin filaments in oocytes. Notably, we also observed that the nuclear actin filaments in CEOs could be induced by inhibition of gap junctions. From our results, it was confirmed that DNA DSBs induce the nuclear actin filament formation in oocyte and which is controlled by the cumulus cells. PMID- 28099475 TI - Development of a Patient-Centred, Psychosocial Support Intervention for Multi Drug-Resistant Tuberculosis (MDR-TB) Care in Nepal. AB - Multi-drug-resistant tuberculosis (MDR-TB) poses a major threat to public health worldwide, particularly in low-income countries. The current long (20 month) and arduous treatment regime uses powerful drugs with side-effects that include mental ill-health. It has a high loss-to-follow-up (25%) and higher case fatality and lower cure-rates than those with drug sensitive tuberculosis (TB). While some national TB programmes provide small financial allowances to patients, other aspects of psychosocial ill-health, including iatrogenic ones, are not routinely assessed or addressed. We aimed to develop an intervention to improve psycho social well-being for MDR-TB patients in Nepal. To do this we conducted qualitative work with MDR-TB patients, health professionals and the National TB programme (NTP) in Nepal. We conducted semi-structured interviews (SSIs) with 15 patients (10 men and 5 women, aged 21 to 68), four family members and three frontline health workers. In addition, three focus groups were held with MDR-TB patients and three with their family members. We conducted a series of meetings and workshops with key stakeholders to design the intervention, working closely with the NTP to enable government ownership. Our findings highlight the negative impacts of MDR-TB treatment on mental health, with greater impacts felt among those with limited social and financial support, predominantly married women. Michie et al's (2011) framework for behaviour change proved helpful in identifying corresponding practice- and policy-level changes. The findings from this study emphasise the need for tailored psycho-social support. Recent work on simple psychological support packages for the general population can usefully be adapted for use with people with MDR-TB. PMID- 28099476 TI - Whole-Body Counter Evaluation of Internal Radioactive Cesium in Dogs and Cats Exposed to the Fukushima Nuclear Disaster. AB - As a result of the 2011 nuclear incident that occurred at the Fukushima Nuclear Power Plant, a large number of abandoned dogs and cats were left within the disaster zone. A small number of these animals were rescued and cared for at shelters. Prior to the dispersal of these animals to their owners or fosterers, we evaluated the degree of internal radiocesium contamination using a specially designed whole-body counter. We conducted 863 non-invasive measurements of gamma rays due to internal radioactive cesium for 68 dogs and 120 cats at one shelter. After plotting graphs of 137Cs density we generated exponential functions of decay from seven dogs and six cats. From the regression formulae, we were able to determine the biological half-lives as 38.2 days for dogs and 30.8 days for cats. We found that in dogs there was a correlation between the biological half-life of radioactive cesium and age. Using our data, we estimated whole-body densities for each cat and dog at the time when they were rescued. We found that there were deviations in the data distributions among the different species, likely due to the timing of rescue, or living habits prior to rescue. A significant correlation was found when extracted feline reproductive organs were analyzed; the coefficients for the estimation of whole-body densities were approximately 7-fold higher than those based on the extracted feline reproductive organs. This may be due to the fact that majority of the radioactive cesium accumulates within muscular tissue with less distribution in other organs. It is possible to plan the appropriate management period in an animal shelter based on the use of the biological half-life of radioactive cesium calculated in this study. We believe that the correlations we uncovered in this work would be of great use for the management of companion animals in the event of a future nuclear accident. PMID- 28099478 TI - Small Is Big: Interactive Trumps Passive Information in Breaking Information Barriers and Impacting Behavioral Antecedents. AB - The wealth of information available on seemingly every topic creates a considerable challenge both for information providers trying to rise above the noise and discerning individuals trying to find relevant, trustworthy information. We approach this information problem by investigating how passive versus interactive information interventions can impact the antecedents of behavior change using the context of solar energy adoption, where persistent information gaps are known to reduce market potential. We use two experiments to investigate the impact of both passive and interactive approaches to information delivery on the antecedents (attitudes, subjective norms, and perceived behavioral control in the Theory of Planned Behavior) of intentions and behavior, as well as their effect on intentions and behavior directly. The passive information randomized control trial delivered via Amazon Mechanical Turk tests the effectiveness of delivering the same content in a single message versus multiple shorter messages. The interactive information delivery uses an online (mobile and PC) trivia-style gamification platform. Both experiments use the same content and are carried out over a two-week time period. Our findings suggest that interactive, gamified information has greater impact than passive information, and that shorter multiple messages of passive information are more effective than a single passive message. PMID- 28099477 TI - Chronic Maternal Low-Protein Diet in Mice Affects Anxiety, Night-Time Energy Expenditure and Sleep Patterns, but Not Circadian Rhythm in Male Offspring. AB - Offspring of murine dams chronically fed a protein-restricted diet have an increased risk for metabolic and neurobehavioral disorders. Previously we showed that adult offspring, developmentally exposed to a chronic maternal low-protein (MLP) diet, had lower body and hind-leg muscle weights and decreased liver enzyme serum levels. We conducted energy expenditure, neurobehavioral and circadian rhythm assays in male offspring to examine mechanisms for the body-weight phenotype and assess neurodevelopmental implications of MLP exposure. C57BL/6J dams were fed a protein restricted (8%protein, MLP) or a control protein (20% protein, C) diet from four weeks before mating until weaning of offspring. Male offspring were weaned to standard rodent diet (20% protein) and single-housed until 8-12 weeks of age. We examined body composition, food intake, energy expenditure, spontaneous rearing activity and sleep patterns and performed behavioral assays for anxiety (open field activity, elevated plus maze [EPM], light/dark exploration), depression (tail suspension and forced swim test), sociability (three-chamber), repetitive (marble burying), learning and memory (fear conditioning), and circadian behavior (wheel-running activity during light dark and constant dark cycles). We also measured circadian gene expression in hypothalamus and liver at different Zeitgeber times (ZT). Male offspring from separate MLP exposed dams had significantly greater body fat (P = 0.03), less energy expenditure (P = 0.004), less rearing activity (P = 0.04) and a greater number of night-time rest/sleep bouts (P = 0.03) compared to control. MLP offspring displayed greater anxiety-like behavior in the EPM (P<0.01) but had no learning and memory deficit in fear-conditioning assay (P = 0.02). There was an effect of time on Per1, Per 2 and Clock circadian gene expression in the hypothalamus but not on circadian behavior. Thus, transplacental and early developmental exposure of dams to chronic MLP reduces food intake and energy expenditure, increases anxiety like behavior and disturbs sleep patterns but not circadian rhythm in adult male offspring. PMID- 28099479 TI - Social Contact Structures and Time Use Patterns in the Manicaland Province of Zimbabwe. AB - BACKGROUND: Patterns of person-to-person contacts relevant for infectious diseases transmission are still poorly quantified in Sub-Saharan Africa (SSA), where socio-demographic structures and behavioral attitudes are expected to be different from those of more developed countries. METHODS AND FINDINGS: We conducted a diary-based survey on daily contacts and time-use of individuals of different ages in one rural and one peri-urban site of Manicaland, Zimbabwe. A total of 2,490 diaries were collected and used to derive age-structured contact matrices, to analyze time spent by individuals in different settings, and to identify the key determinants of individuals' mixing patterns. Overall 10.8 contacts per person/day were reported, with a significant difference between the peri-urban and the rural site (11.6 versus 10.2). A strong age-assortativeness characterized contacts of school-aged children, whereas the high proportion of extended families and the young population age-structure led to a significant intergenerational mixing at older ages. Individuals spent on average 67% of daytime at home, 2% at work, and 9% at school. Active participation in school and work resulted the key drivers of the number of contacts and, similarly, household size, class size, and time spent at work influenced the number of home, school, and work contacts, respectively. We found that the heterogeneous nature of home contacts is critical for an epidemic transmission chain. In particular, our results suggest that, during the initial phase of an epidemic, about 50% of infections are expected to occur among individuals younger than 12 years and less than 20% among individuals older than 35 years. CONCLUSIONS: With the current work, we have gathered data and information on the ways through which individuals in SSA interact, and on the factors that mostly facilitate this interaction. Monitoring these processes is critical to realistically predict the effects of interventions on infectious diseases dynamics. PMID- 28099480 TI - Controlled Aggregation and Increased Stability of beta-Glucuronidase by Cellulose Binding Domain Fusion. AB - Cellulose-binding domains (CBDs) are protein domains with cellulose-binding activity, and some act as leaders in the localization of cellulosomal scaffoldin proteins to the hydrophobic surface of crystalline cellulose. In this study, we found that a CBD fusion enhanced and improved soluble beta-glucuronidase (GusA) enzyme properties through the formation of an artificially oligomeric state. First, a soluble CBD fused to the C-terminus of GusA (GusA-CBD) was obtained and characterized. Interestingly, the soluble GusA-CBD showed maximum activity at higher temperatures (65 degrees C) and more acidic pH values (pH 6.0) than free GusA did (60 degrees C and pH 7.5). Moreover, the GusA-CBD enzyme showed higher thermal and pH stabilities than the free GusA enzyme did. Additionally, GusA-CBD showed higher enzymatic activity in the presence of methanol than free GusA did. Evaluation of the protease accessibility of both enzymes revealed that GusA-CBD retained 100% of its activity after 1 h incubation in 0.5 mg/ml protease K, while free GusA completely lost its activity. Simple fusion of CBD as a single domain may be useful for tunable enzyme states to improve enzyme stability in industrial applications. PMID- 28099481 TI - Correction: Comparing Maternal Services Utilization and Expense Reimbursement Before and After the Adjustment of the New Rural Cooperative Medical Scheme Policy in Rural China. AB - [This corrects the article DOI: 10.1371/journal.pone.0158473.]. PMID- 28099482 TI - A New Statistical Approach to Characterize Chemical-Elicited Behavioral Effects in High-Throughput Studies Using Zebrafish. AB - Zebrafish have become an important alternative model for characterizing chemical bioactivity, partly due to the efficiency at which systematic, high-dimensional data can be generated. However, these new data present analytical challenges associated with scale and diversity. We developed a novel, robust statistical approach to characterize chemical-elicited effects in behavioral data from high throughput screening (HTS) of all 1,060 Toxicity Forecaster (ToxCastTM) chemicals across 5 concentrations at 120 hours post-fertilization (hpf). Taking advantage of the immense scale of data for a global view, we show that this new approach reduces bias introduced by extreme values yet allows for diverse response patterns that confound the application of traditional statistics. We have also shown that, as a summary measure of response for local tests of chemical associated behavioral effects, it achieves a significant reduction in coefficient of variation compared to many traditional statistical modeling methods. This effective increase in signal-to-noise ratio augments statistical power and is observed across experimental periods (light/dark conditions) that display varied distributional response patterns. Finally, we integrated results with data from concomitant developmental endpoint measurements to show that appropriate statistical handling of HTS behavioral data can add important biological context that informs mechanistic hypotheses. PMID- 28099483 TI - Reading the Leaves' Palm: Leaf Traits and Herbivory along the Microclimatic Gradient of Forest Layers. AB - Microclimate in different positions on a host plant has strong direct effects on herbivores. But little is known about indirect effects due to changes of leaf traits. We hypothesized that herbivory increases from upper canopy to lower canopy and understory due to a combination of direct and indirect pathways. Furthermore, we hypothesized that herbivory in the understory differs between tree species in accordance with their leaf traits. We investigated herbivory by leaf chewing insects along the vertical gradient of mixed deciduous forest stands on the broad-leaved tree species Fagus sylvatica L. (European beech) with study sites located along a 140 km long transect. Additionally, we studied juvenile Acer pseudoplatanus L. (sycamore maple) and Carpinus betulus L. (hornbeam) individuals within the understory as a reference of leaf traits in the same microclimate. Lowest levels of herbivory were observed in upper canopies, where temperatures were highest. Temperature was the best predictor for insect herbivory across forest layers in our study. However, the direction was opposite to the generally known positive relationship. Herbivory also varied between the three tree species with lowest levels for F. sylvatica. Leaf carbon content was highest for F. sylvatica and probably indicates higher amounts of phenolic defense compounds. We conclude that the effect of temperature must have been indirect, whereby the expected higher herbivory was suppressed due to unfavorable leaf traits (lower nitrogen content, higher toughness and carbon content) of upper canopy leaves compared to the understory. PMID- 28099484 TI - Increased Anterior Pelvic Angle Characterizes the Gait of Children with Attention Deficit/Hyperactivity Disorder (ADHD). AB - BACKGROUND: Children with attention deficit/hyperactivity disorder (ADHD) frequently have motor problems. Previous studies have reported that the characteristic gait in children with ADHD is immature and that subjects demonstrate higher levels of variability in gait characteristics for the lower extremities than healthy controls. However, little is known about body movement during gait in children with ADHD. The purpose of this study was to identify the characteristic body movements associated with ADHD symptoms in children with ADHD. METHODS: Using a three-dimensional motion analysis system, we compared gait variables in boys with ADHD (n = 19; mean age, 9.58 years) and boys with typical development (TD) (n = 21; mean age, 10.71 years) to determine the specific gait characteristics related to ADHD symptoms. We assessed spatiotemporal gait variables (i.e. speed, stride length, and cadence), and kinematic gait variables (i.e. angle of pelvis, hip, knee, and ankle) to measure body movement when walking at a self-selected pace. RESULTS: In comparison with the TD group, the ADHD group demonstrated significantly higher values in cadence (t = 3.33, p = 0.002) and anterior pelvic angle (t = 3.08, p = 0.004). In multiple regression analysis, anterior pelvic angle was associated with the ADHD rating scale hyperactive/impulsive scores (beta = 0.62, t = 2.58, p = 0.025), but not other psychiatric symptoms in the ADHD group. CONCLUSIONS: Our results suggest that anterior pelvic angle represents a specific gait variable related to ADHD symptoms. Our kinematic findings could have potential implications for evaluating the body movement in boys with ADHD. PMID- 28099486 TI - Do Thai Physicians Recommend Seasonal Influenza Vaccines to Pregnant Women? A Cross-Sectional Survey of Physicians' Perspectives and Practices in Thailand. AB - BACKGROUND: Physicians play a major role in influencing acceptance and uptake of vaccines. However, little is known about physicians' perspectives on influenza vaccination of pregnant women in Thailand, for whom vaccine coverage is estimated at <1%. METHOD: In 2013, a self-administered questionnaire on physicians' perceptions, attitudes and practices related to influenza vaccination for pregnant women was distributed to 1,134 hospitals with an antenatal care clinic (ANC) in Thailand. At each hospital, one physician working at the ANC completed the survey. Predictors of routine recommendation of influenza vaccine were analyzed utilizing log-binomial regression. RESULTS: A total of 580 (51%) complete responses were received from physicians practicing at ANCs. A favorable attitude towards vaccination was expressed by 436 (75%) physicians, however only 142 (25%) reported routinely recommending influenza vaccine to pregnant women in their current practice. Physicians were more likely to recommend influenza vaccine routinely when they had more than three years of practice (prevalence ratio [PR] 1.9, 95% CI 1.2-2.3), had treated pregnant women for influenza (PR 1.8, 95% CI 1.3-2.7), perceived the influenza vaccine to be effective (moderate level: PR 1.6, 95% CI 1.1-2.4; high level: PR 1.9, 95% CI 1.3-2.9) and were aware of the Ministry of Public Health's (MOPH) recommendation of influenza vaccination in pregnancy (PR 1.3, 95% CI 1.1-1.7). Vaccine not being available, perception that policy was ambiguous and lack of awareness of MOPH recommendations were the most commonly cited barriers to routine recommendation of influenza vaccine. CONCLUSION: Despite a national policy to vaccinate pregnant women for influenza, only 25% of Thai physicians working in ANCs routinely recommend vaccination. Strategies are needed to increase vaccine availability and free vaccine services, address clinician concerns over vaccine effectiveness and expand healthcare provider awareness of MOPH recommendations. PMID- 28099485 TI - Cell-Based Systems Biology Analysis of Human AS03-Adjuvanted H5N1 Avian Influenza Vaccine Responses: A Phase I Randomized Controlled Trial. AB - BACKGROUND: Vaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood. OBJECTIVE AND METHODS: We compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18-49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination. RESULTS: Both vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling related genes was also found to predict seroprotection 56 days after first vaccination. CONCLUSIONS: Using this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed. TRIAL REGISTRATION: ClinicalTrials.gov NCT01573312. PMID- 28099487 TI - Metabolic Imaging of Head and Neck Cancer Organoids. AB - Head and neck cancer patients suffer from toxicities, morbidities, and mortalities, and these ailments could be minimized through improved therapies. Drug discovery is a long, expensive, and complex process, so optimized assays can improve the success rate of drug candidates. This study applies optical imaging of cell metabolism to three-dimensional in vitro cultures of head and neck cancer grown from primary tumor tissue (organoids). This technique is advantageous because it measures cell metabolism using intrinsic fluorescence from NAD(P)H and FAD on a single cell level for a three-dimensional in vitro model. Head and neck cancer organoids are characterized alone and after treatment with standard therapies, including an antibody therapy, a chemotherapy, and combination therapy. Additionally, organoid cellular heterogeneity is analyzed quantitatively and qualitatively. Gold standard measures of treatment response, including cell proliferation, cell death, and in vivo tumor volume, validate therapeutic efficacy for each treatment group in a parallel study. Results indicate that optical metabolic imaging is sensitive to therapeutic response in organoids after 1 day of treatment (p<0.05) and resolves cell subpopulations with distinct metabolic phenotypes. Ultimately, this platform could provide a sensitive high throughput assay to streamline the drug discovery process for head and neck cancer. PMID- 28099488 TI - "I Cannot Be Worried": Living with Chagas Disease in Tropical Bolivia. AB - BACKGROUND: Chagas disease (CD) profoundly affects the social and emotional dimensions of patients' lives, and disproportionately impacts poor, marginalized populations in Latin America. Biomedical treatment for CD fails to reach up to 99% of the people affected, and in any case seldom addresses the emotional health or socioeconomic conditions of patients. This study examines patient strategies for coping with CD in the department of Santa Cruz, Bolivia. METHODOLOGY: In this ethnographic study, semistructured interviews took place from March-June 2013 with 63 patients who had previously tested positive for CD. During the fieldwork period, participant observation was conducted and patient family members, providers, community members, and public health officials were consulted. PRINCIPAL FINDINGS: Patients often experienced emotional distress when diagnosed with CD, yet were generally unable to find biomedical treatment. Respondents stressed the need to avoid powerful emotions which would worsen the impact of CD symptoms. To manage CD, patients embraced a calm state of mind, described in Spanish as tranquilidad, which partially empowered them to return to a normal existence. CONCLUSIONS: In the perceived absence of biomedical treatment options, patients seek their own means of coping with CD diagnosis. Rather than fatalism or resignation, patients' emphasis on maintaining calm and not worrying about CD represents a pragmatic strategy for restoring a sense of normalcy and control to their lives. Programs focused on treatment of CD should remain mindful of the emotional and social impact of the disease on patients. PMID- 28099490 TI - Correction: Rapid Classification and Identification of Microcystis aeruginosa Strains Using MALDI-TOF MS and Polygenetic Analysis. AB - [This corrects the article DOI: 10.1371/journal.pone.0156275.]. PMID- 28099489 TI - Acute Inactivation of Primary Auditory Cortex Causes a Sound Localisation Deficit in Ferrets. AB - The objective of this study was to demonstrate the efficacy of acute inactivation of brain areas by cooling in the behaving ferret and to demonstrate that cooling auditory cortex produced a localisation deficit that was specific to auditory stimuli. The effect of cooling on neural activity was measured in anesthetized ferret cortex. The behavioural effect of cooling was determined in a benchmark sound localisation task in which inactivation of primary auditory cortex (A1) is known to impair performance. Cooling strongly suppressed the spontaneous and stimulus-evoked firing rates of cortical neurons when the cooling loop was held at temperatures below 10 degrees C, and this suppression was reversed when the cortical temperature recovered. Cooling of ferret auditory cortex during behavioural testing impaired sound localisation performance, with unilateral cooling producing selective deficits in the hemifield contralateral to cooling, and bilateral cooling producing deficits on both sides of space. The deficit in sound localisation induced by inactivation of A1 was not caused by motivational or locomotor changes since inactivation of A1 did not affect localisation of visual stimuli in the same context. PMID- 28099491 TI - Death of Monocytes through Oxidative Burst of Macrophages and Neutrophils: Killing in Trans. AB - Monocytes and their descendants, macrophages, play a key role in the defence against pathogens. They also contribute to the pathogenesis of inflammatory diseases. Therefore, a mechanism maintaining a balance in the monocyte/macrophage population must be postulated. Our previous studies have shown that monocytes are impaired in DNA repair, rendering them vulnerable to genotoxic stress while monocyte-derived macrophages are DNA repair competent and genotoxic stress resistant. Based on these findings, we hypothesized that monocytes can be selectively killed by reactive oxygen species (ROS) produced by activated macrophages. We also wished to know whether monocytes and macrophages are protected against their own ROS produced following activation. To this end, we studied the effect of the ROS burst on DNA integrity, cell death and differentiation potential of monocytes. We show that monocytes, but not macrophages, stimulated for ROS production by phorbol-12-myristate-13-acetate (PMA) undergo apoptosis, despite similar levels of initial DNA damage. Following co-cultivation with ROS producing macrophages, monocytes displayed oxidative DNA damage, accumulating DNA single-strand breaks and a high incidence of apoptosis, reducing their ability to give rise to new macrophages. Killing of monocytes by activated macrophages, termed killing in trans, was abolished by ROS scavenging and was also observed in monocytes co-cultivated with ROS producing activated granulocytes. The data revealed that monocytes, which are impaired in the repair of oxidised DNA lesions, are vulnerable to their own ROS and ROS produced by macrophages and granulocytes and support the hypothesis that this is a mechanism regulating the amount of monocytes and macrophages in a ROS-enriched inflammatory environment. PMID- 28099492 TI - Priming Cross-Protective Bovine Viral Diarrhea Virus-Specific Immunity Using Live Vectored Mosaic Antigens. AB - Bovine viral diarrhea virus (BVDV) plays a key role in bovine respiratory disease complex, which can lead to pneumonia, diarrhea and death of calves. Current vaccines are not very effective due, in part, to immunosuppressive traits and failure to induce broad protection. There are diverse BVDV strains and thus, current vaccines contain representative genotype 1 and 2 viruses (BVDV-1 & 2) to broaden coverage. BVDV modified live virus (MLV) vaccines are superior to killed virus vaccines, but they are susceptible to neutralization and complement mediated destruction triggered by passively acquired antibodies, thus limiting their efficacy. We generated three novel mosaic polypeptide chimeras, designated NproE2123; NS231; and NS232, which incorporate protective determinants that are highly conserved among BVDV-1a, 1b, and BVDV-2 genotypes. In addition, strain specific protective antigens from disparate BVDV strains were included to broaden coverage. We confirmed that adenovirus constructs expressing these antigens were strongly recognized by monoclonal antibodies, polyclonal sera, and IFN-gamma secreting T cells generated against diverse BVDV strains. In a proof-of-concept efficacy study, the multi-antigen proto-type vaccine induced higher, but not significantly different, IFN-gamma spot forming cells and T-cell proliferation compared to a commercial MLV vaccine. In regards to the humoral response, the prototype vaccine induced higher BVDV-1 specific neutralizing antibody titers, whereas the MLV vaccine induced higher BVDV-2 specific neutralizing antibody titers. Following BVDV type 2a (1373) challenge, calves immunized with the proto type or the MLV vaccine had lower clinical scores compared to naive controls. These results support the hypothesis that a broadly protective subunit vaccine can be generated using mosaic polypeptides that incorporate rationally selected and validated protective determinants from diverse BVDV strains. Furthermore, regarding biosafety of using a live vector in cattle, we showed that recombinant human adenovirus-5 was cleared within one week following intradermal inoculation. PMID- 28099493 TI - Different Phenotypes of the Two Chinese Probands with the Same c.889G>A (p.C162Y) Mutation in COCH Gene Verify Different Mechanisms Underlying Autosomal Dominant Nonsyndromic Deafness 9. AB - OBJECTIVES: By analyzing the different phenotypes of two Chinese DFNA9 families with the same mutation located in the intervening region between the LCCL and vWFA domains of cochlin and testing the functional changes in the mutant cochlin, we investigated the different pathogeneses for mutations in LCCL and vWFA domains. METHODS: Targeted next-generation sequencing for deafness-related genes was used to identify the mutation in the proband in family #208. The probands of family #208 and family #32 with the same p.C162Y mutation were followed for more than 3 years to evaluate the progression of hearing loss and vestibular dysfunction using pure-tone audiometry, caloric testing, electrocochleogram, vestibular-evoked myogenic potential, and video head-impulse test. The disruption of normal cleavage to produce secreted LCCL domain fragments and the tendency to form aggregations of mutant cochlins were tested by in vitro cell experiments. RESULTS: The two families showed different clinical symptoms. Family #32 was identified as having early-onset, progressive sensorineural hearing loss, similar to the symptoms in DFNA9 patients with cochlin mutations in the vWFA domain. The proband of family #208 endured late-onset recurrent paroxysmal vertigo attacks and progressively deteriorating hearing, similar to symptoms in those with cochlin mutations in the LCCL domain. We therefore suggest that the disrupted cleavage of the LCCL domain fragment is likely to cause vestibular dysfunction, and aggregation of mutant cochlin caused by mutations in the vWFA domain is responsible for early-onset hearing loss. The p.C162Y mutation causes either disruption of LCCL domain fragment cleavage or aggregation of mutant cochlin, resulting in the different phenotypes in the two families. CONCLUSION: This study demonstrates that DFNA9 families with the same genotype may have significantly different phenotypes. The mutation site in cochlin is related to the pathological mechanism underlying the different phenotypes. PMID- 28099494 TI - A 3D Printed Toolbox for Opto-Mechanical Components. AB - In this article we present the development of a set of opto-mechanical components (a kinematic mount, a translation stage and an integrating sphere) that can be easily built using a 3D printer based on Fused Filament Fabrication (FFF) and parts that can be found in any hardware store. Here we provide a brief description of the 3D models used and some details on the fabrication process. Moreover, with the help of three simple experimental setups, we evaluate the performance of the opto-mechanical components developed by doing a quantitative comparison with its commercial counterparts. Our results indicate that the components fabricated are highly customizable, low-cost, require a short time to be fabricated and surprisingly, offer a performance that compares favorably with respect to low-end commercial alternatives. PMID- 28099495 TI - Intestinal Bacteria Composition and Translocation of Bacteria in Inflammatory Bowel Disease. AB - BACKGROUND: Live commensal intestinal bacteria are present in the peripheral blood where they can induce inflammation. OBJECTIVE: To evaluate the intestinal bacteria composition and translocation of bacteria in IBD. METHODS: Both blood and tissue biopsy samples were collected from adult patients with active/inactive Crohn's disease (CD), active/inactive ulcerative colitis (UC) and healthy individuals. Most of the patients were newly diagnosed and none of them received antibiotics. Using a reverse transcription-quantitative real-time PCR (RT-qPCR) method, we determined the composition of microbiota. NOD2/CARD15 genotyping was also studied. RESULTS: Total bacterial DNA concentration was increased in tissue and blood samples of IBD patients compared to healthy controls. Furthermore, the active IBD cases had higher total bacterial DNA concentration levels compared to the inactive cases. Three species characterized dysbiosis in IBD, namely an increase of Bacteroides spp in active and inactive IBD samples, and a decrease in Clostridium leptum group (IV), and Faecalibacterium prausnitzi in both active and inactive IBD patients. No significant association between bacterial translocation and NOD2/CARD15 mutations was found. CONCLUSIONS: The composition of the microbiota in IBD patients differs from that of healthy controls. The high rate of bacterial DNA in the blood samples indicates translocation in inflammatory bowel disease. PMID- 28099496 TI - Plasticity of Daily Behavioral Rhythms in Foragers and Nurses of the Ant Camponotus rufipes: Influence of Social Context and Feeding Times. AB - Daily activities within an ant colony need precise temporal organization, and an endogenous clock appears to be essential for such timing processes. A clock drives locomotor rhythms in isolated workers in a number of ant species, but its involvement in activities displayed in the social context is unknown. We compared locomotor rhythms in isolated individuals and behavioral rhythms in the social context of workers of the ant Camponotus rufipes. Both forager and nurse workers exhibited circadian rhythms in locomotor activity under constant conditions, indicating the involvement of an endogenous clock. Activity was mostly nocturnal and synchronized with the 12:12h light-dark-cycle. To evaluate whether rhythmicity was maintained in the social context and could be synchronized with non-photic zeitgebers such as feeding times, daily behavioral activities of single workers inside and outside the nest were quantified continuously over 24 hours in 1656 hours of video recordings. Food availability was limited to a short time window either at day or at night, thus mimicking natural conditions of temporally restricted food access. Most foragers showed circadian foraging behavior synchronized with food availability, either at day or nighttime. When isolated thereafter in single locomotor activity monitors, foragers mainly displayed arrhythmicity. Here, high mortality suggested potential stressful effects of the former restriction of food availability. In contrast, nurse workers showed high overall activity levels in the social context and performed their tasks all around the clock with no circadian pattern, likely to meet the needs of the brood. In isolation, the same individuals exhibited in turn strong rhythmic activity and nocturnality. Thus, endogenous activity rhythms were inhibited in the social context, and timing of daily behaviors was flexibly adapted to cope with task demands. As a similar socially-mediated plasticity in circadian rhythms was already shown in honey bees, the temporal organization in C. rufipes and honey bees appear to share similar basic features. PMID- 28099497 TI - Assessing the Mental Health Impact of the 2011 Great Japan Earthquake, Tsunami, and Radiation Disaster on Elementary and Middle School Children in the Fukushima Prefecture of Japan. AB - BACKGROUND: On March 11, 2011, a magnitude 9.0 earthquake occurred off of Japan's Pacific coast, which was followed by huge tsunamis that destroyed many coastal cities in the area. Due to the earthquake and subsequent tsunami, malfunctions occurred at the Fukushima Daiichi (Fukushima I) nuclear power plant, resulting in the release of radioactive material in the region. While recent studies have investigated the effects of these events on the mental health of adults in the region, no studies have yet been performed investigating similar effects among children. METHODS AND FINDINGS: This study aims to fill that gap by: 1) assessing the mental health of elementary and middle school children living within the Fukushima prefecture of Japan, and 2) identifying risk and protective factors that are associated with the children's mental health scores. These factors were quantified using an original demographics survey, the Strengths and Difficulties Questionnaire (SDQ), and the Impact of Event Scale-Revised (IES-R), the latter two of which have been previously validated in a Japanese setting. The surveys were distributed to approximately 3,650 elementary and middle school students during the months of February and March, 2012. The data suggests that those children who had been relocated to the city of Koriyama had significantly higher SDQ scores than those children who were native to Koriyama (p < .05) as well as a control group that lived outside of the Fukushima prefecture (p < .01). Using a multivariate regression, we also found that younger age and parental trauma were significantly correlated with higher SDQ scores (p < .001), while gender, displacement from one's home, and exposure to violence were not. CONCLUSIONS: These results suggest that, among children affected by natural disasters, younger children and those with parents suffering from trauma-related distress are particularly vulnerable to the onset of pediatric mental disturbances. PMID- 28099498 TI - Oral Tolerance Induced by OVA Intake Ameliorates TNBS-Induced Colitis in Mice. AB - INTRODUCTION: Literature data have shown that the consumption of dietary proteins may cause modulatory effects on the host immune system, process denominated oral tolerance by bystander suppression. It has been shown that the bystander suppression induced by dietary proteins can improve inflammatory diseases such as experimental arthritis. Here, we evaluated the effects of oral tolerance induced by ingestion of ovalbumin (OVA) on TNBS-induced colitis in mice, an experimental model for human Crohn's disease. METHODS AND RESULTS: Colitis was induced in BALB/c mice by instilling a single dose of TNBS (100 mg/kg) in ethanol into the colon. Tolerized mice received OVA (4mg/mL) dissolved in the drinking water for seven consecutive days, prior to or concomitantly with the intrarectal instillation. Control groups received protein-free water and ethanol by intrarectal route. We observed that either the prior or concomitant induction of oral tolerance were able to reduce the severity of colitis as noted by recovery of body weight gain, improvement of clinical signs and reduction of histological abnormalities. The in vitro proliferation of spleen cells from tolerant colitic mice was lower than that of control mice, the same as the frequencies of CD4+ T cells secreting IL-17 and IFN-gamma. The frequencies of regulatory T cells and T cells secreting IL-10 have increased significantly in mice orally treated with OVA. The levels of inflammatory cytokines (IL-17A, TNF-alpha, IL-6 and IFN-gamma) were lower in supernatants of cells from tolerant colitic mice, whereas IL-10 levels were higher. CONCLUSION: Our data show that the modulation of immune response induced by oral tolerance reduces the severity of experimental colitis. Such modulation may be partially attributed to the increase of Treg cells and reduction of pro-inflammatory cytokines in peripheral lymphoid organs of tolerant mice by bystander suppression. PMID- 28099499 TI - Oral Microbiota in Infants Fed a Formula Supplemented with Bovine Milk Fat Globule Membranes - A Randomized Controlled Trial. AB - BACKGROUND: In a recent study, supplementation of infant formula with milk fat globule membranes (MFGM) decreased the incidence of otitis media in infants <6 months of age. OBJECTIVES: The aim of the present study was to characterize the oral microbiota in infants fed MFGM-supplemented formula and compare it to that of infants fed standard formula or breast milk. METHODS: In a prospective double blinded randomized controlled trial, exclusively formula-fed infants <2 months of age were randomized to be fed experimental formula (EF, n = 80) with reduced energy and protein and supplemented with a bovine MFGM concentrate, or standard formula (SF, n = 80) until 6 months of age. A breast-fed reference (BFR, n = 80) group was also recruited. The oral microbiota was analyzed at 4 (n = 124) and 12 (n = 166) months of age using Illumina MiSeq multiplex sequencing and taxonomic resolution against the HOMD 16S rDNA database of oral bacteria. RESULTS: Species richness in the oral samples did not differ between the EF and SF groups, but partial least square modeling identified a few taxa that were significantly associated with being in either group, e.g. lower level of Moraxella catarrhalis in the EF group. Infants in the BFR group had significantly lower species richness at 4 months of age and their microbiota pattern differed markedly from the formula-fed groups. CONCLUSIONS: Supplementation of infant formula with MFGM yielded moderate effects on the oral microbiome. Moraxella catarrhalis was less prevalent in infants fed EF than in those fed SF and may be associated with the decrease in otitis media seen in the same group. PMID- 28099500 TI - Genetic Analysis of Vibrio parahaemolyticus O3:K6 Strains That Have Been Isolated in Mexico Since 1998. AB - Vibrio parahaemolyticus is an important human pathogen that has been isolated worldwide from clinical cases, most of which have been associated with seafood consumption. Environmental and clinical toxigenic strains of V. parahaemolyticus that were isolated in Mexico from 1998 to 2012, including those from the only outbreak that has been reported in this country, were characterized genetically to assess the presence of the O3:K6 pandemic clone, and their genetic relationship to strains that are related to the pandemic clonal complex (CC3). Pathogenic tdh+ and tdh+/trh+ strains were analyzed by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Also, the entire genome of a Mexican O3:K6 strain was sequenced. Most of the strains were tdh/ORF8 positive and corresponded to the O3:K6 serotype. By PFGE and MLST, there was very close genetic relationship between ORF8/O3:K6 strains, and very high genetic diversities from non-pandemic strains. The genetic relationship is very close among O3:K6 strains that were isolated in Mexico and sequences that were available for strains in the CC3, based on the PubMLST database. The whole-genome sequence of CICESE-170 strain had high similarity with that of the reference RIMD 2210633 strain, and harbored 7 pathogenicity islands, including the 4 that denote O3:K6 pandemic strains. These results indicate that pandemic strains that have been isolated in Mexico show very close genetic relationship among them and with those isolated worldwide. PMID- 28099501 TI - Environmental Persistence Influences Infection Dynamics for a Butterfly Pathogen. AB - Many pathogens, including those infecting insects, are transmitted via dormant stages shed into the environment, where they must persist until encountering a susceptible host. Understanding how abiotic conditions influence environmental persistence and how these factors influence pathogen spread are crucial for predicting patterns of infection risk. Here, we explored the consequences of environmental transmission for infection dynamics of a debilitating protozoan parasite (Ophryocystis elektroscirrha) that infects monarch butterflies (Danaus plexippus). We first conducted an experiment to observe the persistence of protozoan spores exposed to natural conditions. Experimental results showed that, contrary to our expectations, pathogen doses maintained high infectivity even after 16 days in the environment, although pathogens did yield infections with lower parasite loads after environmental exposure. Because pathogen longevity exceeded the time span of our experiment, we developed a mechanistic model to better explore environmental persistence for this host-pathogen system. Model analysis showed that, in general, longer spore persistence led to higher infection prevalence and slightly smaller monarch population sizes. The model indicated that typical parasite doses shed onto milkweed plants must remain viable for a minimum of 3 weeks for prevalence to increase during the summer breeding season, and for 11 weeks or longer to match levels of infection commonly reported from the wild, assuming moderate values for parasite shedding rate. Our findings showed that transmission stages of this butterfly pathogen are long lived and indicated that this is a necessary condition for the protozoan to persist in local monarch populations. This study provides a modeling framework for future work examining the dynamics of an ecologically important pathogen in an iconic insect. PMID- 28099502 TI - Clinical and Immune Effects of Lenalidomide in Combination with Gemcitabine in Patients with Advanced Pancreatic Cancer. AB - PURPOSE: To assess the immunomodulatory and clinical effects of lenalidomide with standard treatment of gemcitabine in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Patients with advanced pancreatic cancer were treated in first line with lenalidomide orally for 21 days of a 28 days cycle and the standard regimen for gemcitabine. In Part I, which we previously have reported, the dose of lenalidomide was defined (n = 12). In Part II, every other consecutive patient was treated with either lenalidomide (Group A, n = 11) or gemcitabine (Group B, n = 10) during cycle 1. From cycle 2 on, all Part II patients received the combination. RESULTS: A significant decrease in the proliferative response of peripheral blood mononuclear cells and the frequency of DCs were noted in patients at baseline compared to healthy control donors while the frequencies of CD4+ and CD8+ T cells, NK-cells and MDSCs were significantly higher in patients compared to controls. In Group A, a significant increase in the absolute numbers of activated (HLA-DR+) CD4 and CD8 T cells and CD8 effector memory T cells (p<0.01) was noted during treatment. A statistical increment in the absolute numbers of Tregs were seen after cycle 1 (p<0.05). The addition of gemcitabine, reduced most lymphocyte subsets (p<0.05). In Group B, the proportion of lymphocytes remained unchanged during the study period. There was no difference in overall survival, progression free survival and survival rate at one year comparing the two groups. DISCUSSION: Patients with advanced pancreatic carcinoma had impaired immune functions. Lenalidomide augmented T cell reactivities, which were abrogated by gemcitabine. However, addition of lenalidomide to gemcitabine seemed to have no therapeutic impact compared to gemcitabine alone in this non-randomized study. TRIAL REGISTRATION: ClinicalTrials.gov NCT01547260. PMID- 28099503 TI - 3D Functional Corneal Stromal Tissue Equivalent Based on Corneal Stromal Stem Cells and Multi-Layered Silk Film Architecture. AB - The worldwide need for human cornea equivalents continues to grow. Few clinical options are limited to allogenic and synthetic material replacements. We hypothesized that tissue engineered human cornea systems based on mechanically robust, patterned, porous, thin, optically clear silk protein films, in combination with human corneal stromal stem cells (hCSSCs), would generate 3D functional corneal stroma tissue equivalents, in comparison to previously developed 2D approaches. Silk film contact guidance was used to control the alignment and distribution of hCSSCs on RGD-treated single porous silk films, which were then stacked in an orthogonally, multi-layered architecture and cultured for 9 weeks. These systems were compared similar systems generated with human corneal fibroblasts (hCFs). Both cell types were viable and preferentially aligned along the biomaterial patterns for up to 9 weeks in culture. H&E histological sections showed that the systems seeded with the hCSSCs displayed ECM production throughout the entire thickness of the constructs. In addition, the ECM proteins tested positive for keratocyte-specific tissue markers, including keratan sulfate, lumican, and keratocan. The quantification of hCSSC gene expression of keratocyte-tissue markers, including keratocan, lumican, human aldehyde dehydrogenase 3A1 (ALDH3A1), prostaglandin D2 synthase (PTDGS), and pyruvate dehydrogenase kinase, isozyme 4 (PDK4), within the 3D tissue systems demonstrated upregulation when compared to 2D single silk films and to the systems generated with the hCFs. Furthermore, the production of ECM from the hCSSC seeded systems and subsequent remodeling of the initial matrix significantly improved cohesiveness and mechanical performance of the constructs, while maintaining transparency after 9 weeks. PMID- 28099504 TI - Direction-Specific Impairments in Cervical Range of Motion in Women with Chronic Neck Pain: Influence of Head Posture and Gravitationally Induced Torque. AB - BACKGROUND: Cervical range of motion (ROM) is commonly assessed in clinical practice and research. In a previous study we decomposed active cervical sagittal ROM into contributions from lower and upper levels of the cervical spine and found level- and direction-specific impairments in women with chronic non specific neck pain. The present study aimed to validate these results and investigate if the specific impairments can be explained by the neutral posture (defining zero flexion/extension) or a movement strategy to avoid large gravitationally induced torques on the cervical spine. METHODS: Kinematics of the head and thorax was assessed in sitting during maximal sagittal cervical flexion/extension (high torque condition) and maximal protraction (low torque condition) in 120 women with chronic non-specific neck pain and 40 controls. We derived the lower and upper cervical angles, and the head centre of mass (HCM), from a 3-segment kinematic model. Neutral head posture was assessed using a standardized procedure. FINDINGS: Previous findings of level- and direction specific impairments in neck pain were confirmed. Neutral head posture was equal between groups and did not explain the direction-specific impairments. The relative magnitude of group difference in HCM migration did not differ between high and low torques conditions, lending no support for our hypothesis that impairments in sagittal ROM are due to torque avoidance behaviour. INTERPRETATION: The direction- and level-specific impairments in cervical sagittal ROM can be generalised to the population of women with non-specific neck pain. Further research is necessary to clarify if torque avoidance behaviour can explain the impairments. PMID- 28099505 TI - Evaluation of 6 and 10 Year-Old Child Human Body Models in Emergency Events. AB - Emergency events can influence a child's kinematics prior to a car-crash, and thus its interaction with the restraint system. Numerical Human Body Models (HBMs) can help understand the behaviour of children in emergency events. The kinematic responses of two child HBMs-MADYMO 6 and 10 year-old models-were evaluated and compared with child volunteers' data during emergency events braking and steering-with a focus on the forehead and sternum displacements. The response of the 6 year-old HBM was similar to the response of the 10 year-old HBM, however both models had a different response compared with the volunteers. The forward and lateral displacements were within the range of volunteer data up to approximately 0.3 s; but then, the HBMs head and sternum moved significantly downwards, while the volunteers experienced smaller displacement and tended to come back to their initial posture. Therefore, these HBMs, originally intended for crash simulations, are not too stiff and could be able to reproduce properly emergency events thanks, for instance, to postural control. PMID- 28099506 TI - Spatial and Host-Related Variation in Prevalence and Population Density of Wheat Curl Mite (Aceria tosichella) Cryptic Genotypes in Agricultural Landscapes. AB - The wheat curl mite (WCM), Aceria tosichella Keifer, is a major pest of cereals worldwide that also comprises a complex of at least 16 genetic lineages with divergent physiological traits, including host associations and specificity. The goal of this study was to test the extent to which host-plant species and landscape spatial variation influence WCM presence and population density across the entire area of Poland (>311,000 km2). Three important findings arose from the results of the study. (1) The majority of WCM lineages analyzed exhibited variation in patterns of prevalence and/or population density on both spatial and host-associated scales. (2) Areas of occurrence and local abundance were delineated for specific WCM lineages and it was determined that the most pestiferous lineages are much less widespread than was expected, suggesting relatively recent introductions into Poland and the potential for further spread. (3) The 16 WCM lineages under study assorted within four discrete host assemblages, within which similar host preferences and host infestation patterns were detected. Of these four groups, one consists of lineages associated with cereals. In addition to improving basic ecological knowledge of a widespread arthropod herbivore, the results of this research identify high-risk areas for the presence of the most pestiferous WCM lineages in the study area (viz. the entirety of Poland). They also provide insight into the evolution of pest species of domesticated crops and facilitate testing of fundamental hypotheses about the ecological factors that shape this pest community. PMID- 28099508 TI - Effects of Soil Salinity on the Expression of Bt Toxin (Cry1Ac) and the Control Efficiency of Helicoverpa armigera in Field-Grown Transgenic Bt Cotton. AB - An increasing area of transgenic Bacillus thuringiensis (Bt) cotton is being planted in saline-alkaline soil in China. The Bt protein level in transgenic cotton plants and its control efficiency can be affected by abiotic stress, including high temperature, water deficiency and other factors. However, how soil salinity affects the expression of Bt protein, thus influencing the control efficiency of Bt cotton against the cotton bollworm (CBW) Helicoverpa armigera (Hubner) in the field, is poorly understood. Our objective in the present study was to investigate the effects of soil salinity on the expression of Bt toxin (Cry1Ac) and the control efficiency of Helicoverpa armigera in field-grown transgenic Bt cotton using three natural saline levels (1.15 dS m-1 [low soil salinity], 6.00 dS m-1 [medium soil-salinity] and 11.46 dS m-1 [high soil salinity]). We found that the Bt protein content in the transgenic Bt cotton leaves and the insecticidal activity of Bt cotton against CBW decreased with the increasing soil salinity in laboratory experiments during the growing season. The Bt protein content of Bt cotton leaves in the laboratory were negatively correlated with the salinity level. The CBW populations were highest on the Bt cotton grown in medium-salinity soil instead of the high-salinity soil in field conditions. A possible mechanism may be that the relatively high-salinity soil changed the plant nutritional quality or other plant defensive traits. The results from this study may help to identify more appropriate practices to control CBW in Bt cotton fields with different soil salinity levels. PMID- 28099507 TI - Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the HdhQ150/Q150 Mouse Model of Huntington's Disease. AB - A variety of mouse models have been developed that express mutant huntingtin (mHTT) leading to aggregates and inclusions that model the molecular pathology observed in Huntington's disease. Here we show that although homozygous HdhQ150 knock-in mice developed motor impairments (rotarod, locomotor activity, grip strength) by 36 weeks of age, cognitive dysfunction (swimming T maze, fear conditioning, odor discrimination, social interaction) was not evident by 94 weeks. Concomitant to behavioral assessments, T2-weighted MRI volume measurements indicated a slower striatal growth with a significant difference between wild type (WT) and HdhQ150 mice being present even at 15 weeks. Indeed, MRI indicated significant volumetric changes prior to the emergence of the "clinical horizon" of motor impairments at 36 weeks of age. A striatal decrease of 27% was observed over 94 weeks with cortex (12%) and hippocampus (21%) also indicating significant atrophy. A hypothesis-free analysis using tensor-based morphometry highlighted further regions undergoing atrophy by contrasting brain growth and regional neurodegeneration. Histology revealed the widespread presence of mHTT aggregates and cellular inclusions. However, there was little evidence of correlations between these outcome measures, potentially indicating that other factors are important in the causal cascade linking the molecular pathology to the emergence of behavioral impairments. In conclusion, the HdhQ150 mouse model replicates many aspects of the human condition, including an extended pre-manifest period prior to the emergence of motor impairments. PMID- 28099510 TI - Regulation of NUB1 Activity through Non-Proteolytic Mdm2-Mediated Ubiquitination. AB - NUB1 (Nedd8 ultimate buster 1) is an adaptor protein which negatively regulates the ubiquitin-like protein Nedd8 as well as neddylated proteins levels through proteasomal degradation. However, molecular mechanisms underlying this function are not completely understood. Here, we report that the oncogenic E3 ubiquitin ligase Mdm2 is a new NUB1 interacting protein which induces its ubiquitination. Interestingly, we found that Mdm2-mediated ubiquitination of NUB1 is not a proteolytic signal. Instead of promoting the conjugation of polyubiquitin chains and the subsequent proteasomal degradation of NUB1, Mdm2 rather induces its di ubiquitination on lysine 159. Importantly, mutation of lysine 159 into arginine inhibits NUB1 activity by impairing its negative regulation of Nedd8 and of neddylated proteins. We conclude that Mdm2 acts as a positive regulator of NUB1 function, by modulating NUB1 ubiquitination on lysine 159. PMID- 28099509 TI - A Comparative Study on Antioxidant System in Fish Hepatopancreas and Intestine Affected by Choline Deficiency: Different Change Patterns of Varied Antioxidant Enzyme Genes and Nrf2 Signaling Factors. AB - The liver and intestine are susceptible to the oxidative damage which could result in several diseases. Choline deficiency induced oxidative damage in rat liver cells. Thus, this study aimed to investigate the potential molecular mechanisms responsible for choline deficiency-induced oxidative damage. Juvenile Jian carp were fed diets differing in choline content [165 (deficient group), 310, 607, 896, 1167 and 1820 mg/kg diet] respectively for 65 days. Oxidative damage, antioxidant enzyme activities and related gene expressions in the hepatopancreas and intestine were measured. Choline deficiency decreased choline and phosphatidylcholine contents, and induced oxidative damage in both organs, as evidenced by increased levels of oxidative-stress markers (malondialdehyde, protein carbonyl and 8-hydroxydeoxyguanosine), coupled with decreased activities of antioxidant enzymes [Copper-zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD), glutathione peroxidase (GPx) and glutathione-S transferase (GST)]. However, choline deficiency increased glutathione contents in the hepatopancreas and intestine. Furthermore, dietary choline deficiency downregulated mRNA levels of MnSOD, GPx1b, GST-rho, mGST3 and Kelch-like ECH associating protein 1 (Keap1b) in the hepatopancreas, MnSOD, GPx1b, GPx4a, GPx4b, GST-rho, GST-theta, GST-mu, GST-alpha, GST-pi and GST-kappa in the intestine, as well as intestinal Nrf2 protein levels. In contrast, choline deficiency upregulated the mRNA levels of GPx4a, GPx4b, mGST1, mGST2, GST-theta, GST-mu, Keap1a and PKC in the hepatopancreas, mGST3, nuclear factor erythoid 2-related factor 2 (Nrf2) and Keap1a in the intestine, as well as hepatopancreatic Nrf2 protein levels. This study provides new evidence that choline deficiency-induced oxidative damage is associated with changes in the transcription of antioxidant enzyme and Nrf2/Keap1 signaling molecules in the hepatopancreas and intestine. Additionally, this study firstly indicated that choline deficiency induced varied change patterns of different GPx and GST isoforms. Meanwhile, the changes of some GPx and GST isoforms caused by choline deficiency in the intestine were contrary to those in the hepatopancreas. PMID- 28099511 TI - Extracellular Fluid/Intracellular Fluid Volume Ratio as a Novel Risk Indicator for All-Cause Mortality and Cardiovascular Disease in Hemodialysis Patients. AB - BACKGROUND: In hemodialysis patients, fluid overload and malnutrition are accompanied by extracellular fluid (ECF) expansion and intracellular fluid (ICF) depletion, respectively. We investigated the relationship between ECF/ICF ratio (as an integrated marker reflecting both fluid overload and malnutrition) and survival and cardiovascular disease (CVD) in the context of malnutrition inflammation-arteriosclerosis (MIA) complex. METHODS: Seventy-seven patients from a single hemodialysis unit were prospectively enrolled. The ECF/ICF volume was measured by segmental multi-frequency bioimpedance analysis. MIA and volume status were measured by serum albumin, C-reactive protein (CRP), pulse wave velocity (PWV) and plasma B-type natriuretic peptide (BNP), respectively. RESULTS: The mean ECF/ICF ratio was 0.56+/-0.06 and the cut-off value for maximum discrimination of survival was 0.57. Compared with the low ECF/ICF group, the high ECF/ICF group (ratio>=0.57, 42%) had higher all-cause mortality, CVD, CRP, PWV, and BNP, but lower serum albumin. During the 5-year follow-up, 24 all-cause mortality and 38 CVD occurred (18 and 24, respectively, in the high ECF/ICF group versus 6 and 14 respectively in the low ECF/ICF group, P<0.001). In the adjusted Cox analysis, the ECF/ICF ratio nullifies the effects of the MIA and volume status on survival and CVD and was an independent predictor of all-cause mortality and CVD: hazard ratio (95% confidence interval); 1.12 (1.01-1.25) and 1.09 (1.01-1.18) for a 0.01 increase in the ECF/ICF ratio. The degree of malnutrition (albumin), inflammation (CRP), arteriosclerosis (PWV), and fluid overload (BNP) were correlated well with the ECF/ICF ratio. CONCLUSIONS: Hemodialysis patients with high ECF/ICF ratio are not only fluid overloaded, but malnourished and have stiff artery with more inflammation. The ECF/ICF ratio is highly related to the MIA complex, and is a major risk indicator for all-cause mortality and CVD. PMID- 28099512 TI - Age-Dependent Oxidative DNA Damage Does Not Correlate with Reduced Proliferation of Cardiomyocytes in Humans. AB - BACKGROUND: Postnatal human cardiomyocyte proliferation declines rapidly with age, which has been suggested to be correlated with increases in oxidative DNA damage in mice and plays an important role in regulating cardiomyocyte proliferation. However, the relationship between oxidative DNA damage and age in humans is unclear. METHODS: Sixty right ventricular outflow myocardial tissue specimens were obtained from ventricular septal defect infant patients during routine congenital cardiac surgery. These specimens were divided into three groups based on age: group A (age 0-6 months), group B (age, 7-12 months), and group C (>12 months). Each tissue specimen was subjected to DNA extraction, RNA extraction, and immunofluorescence. RESULTS: Immunofluorescence and qRT-PCR analysis revealed that DNA damage markers-mitochondrial DNA copy number, oxoguanine 8, and phosphorylated ataxia telangiectasia mutated-were highest in Group B. However immunofluorescence and qRT-PCR demonstrated that two cell proliferation markers, Ki67 and cyclin D2, were decreased with age. In addition, wheat germ agglutinin-staining indicated that the average size of cardiomyocytes increased with age. CONCLUSIONS: Oxidative DNA damage of cardiomyocytes was not correlated positively with age in human beings. Oxidative DNA damage is unable to fully explain the reduced proliferation of human cardiomyocytes. PMID- 28099513 TI - The Tetraspanin-Associated Uroplakins Family (UPK2/3) Is Evolutionarily Related to PTPRQ, a Phosphotyrosine Phosphatase Receptor. AB - Uroplakins are a widespread group of vertebrate integral membrane proteins that belong to two different families: UPK1a and UPK1b belong to the large tetraspanin (TSPAN) gene family, and UPK3a, UPK3b, UPK3c, UPK3d, UPK2a and UPK2b form a family of their own, the UPK2/3 tetraspanin-associated family. In a previous study, we reported that uroplakins first appeared in vertebrates, and that uroplakin tetraspanins (UPK1a and UPK1b) should have originated by duplication of an ancestor tetraspanin gene. However, the evolutionary origin of the UPK2/3 family remains unclear. In this study, we provide evidence that the UPK2/3 family originated by gene duplication and domain loss from a protoPTPRQ-like basal deuterostome gene. PTPRQs are members of the subtype R3 tyrosine phosphatase receptor (R3 PTPR) family, which are characterized by having a unique modular composition of extracellular fibronectin (FN3) repeats, a transmembrane helix, and a single intra-cytoplasmic phosphotyrosine phophatase (PTP) domain. Our assumption of a deuterostome protoPTPRQ-like gene as an ancestor of the UPK2/3 family by gene duplication and loss of its PTP and fibronectin (FN3) domains, excluding the one closest to the transmembrane helix, is based on the following: (i) phylogenetic analyses, (ii) the existence of an identical intron/exon gene pattern between UPK2/3 and the corresponding genetic region in R3 PTPRs, (iii) the conservation of cysteine patterns and protein motifs between UPK2/3 and PTPRQ proteins and, (iv) the existence in tunicates, the closest organisms to vertebrates, of two sequences related to PTPRQ; one with the full subtype R3 modular characteristic and another without the PTP domain but with a short cytoplasmic tail with some sequence similarity to that of UPK3a. This finding will facilitate further studies on the structure and function of these important proteins with implications in human diseases. PMID- 28099514 TI - PET/CT Scanner and Bone Marrow Biopsy in Detection of Bone Marrow Involvement in Diffuse Large B-Cell Lymphoma. AB - Evaluation of bone marrow involvement (BMI) is paramount in diffuse large B-cell lymphoma (DLBCL) for prognostic and therapeutic reasons. PET/CT scanner (PET) is now a routine examination for the staging of DLBCL with prognostic and therapeutic implications. This study evaluates the role of PET for detecting marrow involvement compared to bone marrow biopsy (BMB). This monocentric study included 54 patients diagnosed with DLBCL between 2009 and 2013 and who had FDG PET/CT in a pre-treatment setting. A correlation analysis of the detection of BMI by PET and BMB was performed. A prognostic evaluation of BMI by BMB and/or PET/CT and correlation with an overall 2-year survival were analyzed. PET was more sensitive for the detection of BMI than BMB (92.3% vs. 38.5%). It can be considered a discriminatory Pre-BMB test with a negative predictive value of 97.6%. In addition, BMI by PET had a prognostic value with strong correlation with progression-free survival (PFS) (HR = 3.81; p = 0.013) and overall survival (OS) (HR = 4.12; p = 0.03) while the BMB had not. PET shows superior performance to the BMB for the detection of marrow involvement in DLBCL. It may be considered as the first line examination of bone marrow instead of the biopsy. PMID- 28099515 TI - Polymorphisms and Mutational Covariation Associated with Death in a Prospective Cohort of HIV/AIDS Patients Receiving Long-Term ART in China. AB - BACKGROUND: HIV drug resistance is associated with faster clinical progression of AIDS. However, the effect of significant polymorphisms and mutational covariation on mortality among HIV/AIDS patients receiving long-term antiretroviral therapy (ART), have rarely been studied. METHODS: In this prospective cohort study from December 2003 to December 2014, we present a new computational modelling approach based on bioinformatics-based models and several statistical methods to elucidate the molecular mechanisms involved in the acquisition of polymorphisms and mutations on death in HIV/AIDS patients receiving long-term ART in China. RESULTS: This study involved 654 ART-treated patients, who had been followed for 5473.4 person-years, a median of 9.8 years, and 178 died (25.2%, 3.3/100 person years). The first regimens included AZT/d4T + NVP+ ddI (78.9%) or AZT/d4T + NVP+ 3TC (20.0%). We calculated an individual Ka/Ks value for each specific amino acid mutation. Result showed that 20 polymorphisms (E6D, Q18H, E35D, S37N, T39A, K43E, S68N, L74I, I93L, K103N, V106A, E169D, Y181C, G190A, Q197K, T200V, T200E, T215I, E224D and P225H) were strongly associated with AIDS related deaths. Among them, 7 polymorphisms (L74I, K103N, V106A, Y181C, G190A, T215I and P225H) were known to be drug resistance mutations, 7 polymorphisms (E6D, E35D, S37N, I93L, E169D, T200V and T200E were considered to be potential drug resistance mutations, and 6 polymorphisms (T39A, K43E, S68N, Q197K, T200V and E224D) were newly found to have an association with drug resistance mutations, which formed a complex network of relationships. CONCLUSIONS: Some polymorphisms and mutational covariation may be the important influencing factors in the failure of treatment. Understanding these mechanisms is essential for the development of new therapies, designing optimal drug combinations, and determining effective clinical management of individual patients. PMID- 28099516 TI - Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. AB - Clinical practice guidelines (CPGs) for rare diseases (RDs) are scarce, may be difficult to identify through Internet searches and may vary in quality depending on the source and methodology used. In order to contribute to the improvement of the diagnosis, treatment and care of patients, Orphanet (www.orpha.net) has set up a procedure for the selection, quality evaluation and dissemination of CPGs, with the aim to provide easy access to relevant, accurate and specific recommendations for the management of RDs. This article provides an analysis of selected CPGs by medical domain coverage, prevalence of diseases, languages and type of producer, and addresses the variability in CPG quality and availability. CPGs are identified via bibliographic databases, websites of research networks, expert centres or medical societies. They are assessed according to quality criteria derived from the Appraisal of Guidelines, REsearch and Evaluation (AGREE II) Instrument. Only open access CPGs and documents for which permission from the copyright holders has been obtained are disseminated on the Orphanet website. From January 2012 to July 2015, 277 CPGs were disseminated, representing coverage of 1,122 groups of diseases, diseases or subtypes in the Orphanet database. No language restriction is applied, and so far 10 languages are represented, with a predominance of CPGs in English, French and German (92% of all CPGs). A large proportion of diseases with identified CPGs belong to rare oncologic, neurologic, hematologic diseases or developmental anomalies. The Orphanet project on CPG collection, evaluation and dissemination is a continuous process, with regular addition of new guidelines, and updates. CPGs meeting the quality criteria are integrated to the Orphanet database of rare diseases, together with other types of textual information and the appropriate services for patients, researchers and healthcare professionals in 40 countries. PMID- 28099517 TI - Walking on a Vertically Oscillating Treadmill: Phase Synchronization and Gait Kinematics. AB - Sensory motor synchronization can be used to alter gait behavior. This type of therapy may be useful in a rehabilitative setting, though several questions remain regarding the most effective way to promote and sustain synchronization. The purpose of this study was to describe a new technique for using synchronization to influence a person's gait and to compare walking behavior under this paradigm with that of side by side walking. Thirty one subjects walked on a motorized treadmill that was placed on a platform that oscillated vertically at various frequencies and amplitudes. Synchronization with the platform and stride kinematics were recorded during these walking trials and compared with previously reported data from side by side walking. The results indicated that vertical oscillation of the treadmill surface at frequencies that matched subjects preferred stride or step frequency resulted in greater unintentional synchronization when compared with side by side walking data (up to 78.6+/-8.3% of the trial vs 59.2+/-17.4%). While intermittent phase locking was observed in all cases, periods of synchronization occurred more frequently and lasted longer while walking on the oscillating treadmill (mean length of periods of phase locking 11.85 steps vs 5.18 steps). Further, stride length, height and duration were altered by changing the frequency of treadmill oscillation. These results suggest that synchronization to a haptic signal may hold implications for use in a clinical setting. PMID- 28099518 TI - Evaluation of Methods for the Concentration and Extraction of Viruses from Sewage in the Context of Metagenomic Sequencing. AB - Viral sewage metagenomics is a novel field of study used for surveillance, epidemiological studies, and evaluation of waste water treatment efficiency. In raw sewage human waste is mixed with household, industrial and drainage water, and virus particles are, therefore, only found in low concentrations. This necessitates a step of sample concentration to allow for sensitive virus detection. Additionally, viruses harbor a large diversity of both surface and genome structures, which makes universal viral genomic extraction difficult. Current studies have tackled these challenges in many different ways employing a wide range of viral concentration and extraction procedures. However, there is limited knowledge of the efficacy and inherent biases associated with these methods in respect to viral sewage metagenomics, hampering the development of this field. By the use of next generation sequencing this study aimed to evaluate the efficiency of four commonly applied viral concentrations techniques (precipitation with polyethylene glycol, organic flocculation with skim milk, monolithic adsorption filtration and glass wool filtration) and extraction methods (Nucleospin RNA XS, QIAamp Viral RNA Mini Kit, NucliSENS(r) miniMAG(r), or PowerViral(r) Environmental RNA/DNA Isolation Kit) to determine the viriome in a sewage sample. We found a significant influence of concentration and extraction protocols on the detected viriome. The viral richness was largest in samples extracted with QIAamp Viral RNA Mini Kit or PowerViral(r) Environmental RNA/DNA Isolation Kit. Highest viral specificity were found in samples concentrated by precipitation with polyethylene glycol or extracted with Nucleospin RNA XS. Detection of viral pathogens depended on the method used. These results contribute to the understanding of method associated biases, within the field of viral sewage metagenomics, making evaluation of the current literature easier and helping with the design of future studies. PMID- 28099519 TI - CRISPR-Cas9 Mediated NOX4 Knockout Inhibits Cell Proliferation and Invasion in HeLa Cells. AB - Increased expression of NOX4 protein is associated with cancer progression and metastasis but the role of NOX4 in cell proliferation and invasion is not fully understood. We generated NOX4 knockout HeLa cell lines using the CRISPR-Cas9 gene editing system to explore the cellular functions of NOX4. After transfection of CRISPR-Cas9 construct, we performed T7 endonuclease 1 assays and DNA sequencing to generate and identify insertion and deletion of the NOX4 locus. We confirmed the knockout of NOX4 by Western blotting. NOX4 knockout cell lines showed reduced cell proliferation with an increase of sub-G1 cell population and the decrease of S/G2/M population. Moreover, NOX4 deficiency resulted in a dramatic decrease in invadopodium formation and the invasive activity. In addition, NOX4 deficiency also caused a decrease in focal adhesions and cell migration in HeLa cells. These results suggest that NOX4 is required for both efficient proliferation and invasion of HeLa cells. PMID- 28099520 TI - Oral Medications Enhance Adherence to Surveillance for Hepatocellular Carcinoma and Survival in Chronic Hepatitis B Patients. AB - BACKGROUND/AIMS: Regular surveillance for hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients is essential to detect HCC earlier and to improve prognosis. This study investigated whether prescription of oral medication contributes to adherence to surveillance, early tumor detection, and overall survival (OS). METHODS: A total of 401 CHB patients who were newly diagnosed with HCC were included: 134 patients received no medication (group 1), 151 received hepatoprotective agents such as ursodeoxycholic acid and silymarin (group 2), and 116 received antiviral agents (group 3) at two years before HCC diagnosis. The primary endpoint was OS, and secondary endpoints were compliance to regular surveillance and HCC status at diagnosis. RESULTS: Compared to group 1, both group 2 and 3 had higher rates of good compliance to regular surveillance (defined as participation in >80% of imaging intervals being <=6 months) (58.2%, 90.1%, and 97.4%, respectively; P<0.001), more HCC diagnosed at a very early stage (20.9%, 32.5%, and 36.2%; P = 0.019) and smaller tumor size (2.8+/-2.4cm, 1.9+/-1.1cm, and 1.8+/-0.9cm; P<0.001). Finally, compared to group 1, both group 2 (hazard ratio, 0.63; 95% confidence interval, 0.41-0.97; P = 0.035) and group 3 (hazard ratio, 0.40; 95% confidence interval, 0.22-0.71; P = 0.002) had significantly longer OS. In mediation analysis, prolonged OS is resulted considerably from indirect effect mediated by shorter imaging interval (>100% in group 2 and 14.5% in group 3) rather than direct effect of medication itself. CONCLUSIONS: Prescription of oral medication improves compliance to surveillance and enables early detection of HCC, which is associated with enhanced survival. PMID- 28099521 TI - Nuclear Localization and Cleavage of STAT6 Is Induced by Kaposi's Sarcoma Associated Herpesvirus for Viral Latency. AB - Emerging evidence implies that STAT6 plays an important role in both the adaptive and innate immune responses to virus infection. Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic gamma-herpesvirus agent associated with several human malignancies, including Kaposi's sarcoma (KS) and primary effusion lymphomas (PELs). Previously, we demonstrated that KSHV blocks IL-4-induced STAT6 phosphorylation and retains a basal IL-13/STAT6 constitutive activation for cell survival and proliferation. However, the mechanism by which KSHV regulates STAT6 remains largely unknown. Here, we found that KSHV-encoded LANA interacts with STAT6 and promotes nuclear localization of STAT6 independent of the tyrosine 641 phosphorylation state. Moreover, nuclear localization of STAT6 is also dramatically increased in KS tissue. The latent antigen LANA induces serine protease-mediated cleavage of STAT6 in the nucleus, where the cleaved STAT6 lacking transactivation domain functions as a dominant-negative regulator to repress transcription of Replication and Transcription Activator (RTA) and in turn shut off viral lytic replication. Blockade of STAT6 by small interference RNA dramatically enhances expression of RTA, and in turn reduces KSHV-infected endothelial cell growth and colony formation. Taken together, these results suggest that nuclear localization and cleavage of STAT6 is important for modulating the viral latency and pathogenesis of KSHV. PMID- 28099522 TI - Anodal Transcranial Direct Current Stimulation Shows Minimal, Measure-Specific Effects on Dynamic Postural Control in Young and Older Adults: A Double Blind, Sham-Controlled Study. AB - We investigated whether stimulating the cerebellum and primary motor cortex (M1) using transcranial direct current stimulation (tDCS) could affect postural control in young and older adults. tDCS was employed using a double-blind, sham controlled design, in which young (aged 18-35) and older adults (aged 65+) were assessed over three sessions, one for each stimulatory condition-M1, cerebellar and sham. The effect of tDCS on postural control was assessed using a sway referencing paradigm, which induced platform rotations in proportion to the participant's body sway, thus assessing sensory reweighting processes. Task difficulty was manipulated so that young adults experienced a support surface that was twice as compliant as that of older adults, in order to minimise baseline age differences in postural sway. Effects of tDCS on postural control were assessed during, immediately after and 30 minutes after tDCS. Additionally, the effect of tDCS on corticospinal excitability was measured by evaluating motor evoked potentials using transcranial magnetic stimulation immediately after and 30 minutes after tDCS. Minimal effects of tDCS on postural control were found in the eyes open condition only, and this was dependent on the measure assessed and age group. For young adults, stimulation had only offline effects, as cerebellar stimulation showed higher mean power frequency (MPF) of sway 30 minutes after stimulation. For older adults, both stimulation conditions delayed the increase in sway amplitude witnessed between blocks one and two until stimulation was no longer active. In conclusion, despite tDCS' growing popularity, we would caution researchers to consider carefully the type of measures assessed and the groups targeted in tDCS studies of postural control. PMID- 28099523 TI - The Role of Liquid Based Cytology and Ancillary Techniques in the Peritoneal Washing Analysis: Our Institutional Experience. AB - BACKGROUND: The cytological analysis of peritoneal effusions serves as a diagnostic and prognostic aid for either primary or metastatic diseases. Among the different cytological preparations, liquid based cytology (LBC) represents a feasible and reliable method ensuring also the application of ancillary techniques (i.e immunocytochemistry-ICC and molecular testing). METHODS: We recorded 10348 LBC peritoneal effusions between January 2000 and December 2014. They were classified as non-diagnostic (ND), negative for malignancy-NM, atypical suspicious for malignancy-SM and positive for malignancy-PM. RESULTS: The cytological diagnosis included 218 ND, 9.035 NM, 213 SM and 882 PM. A total of 8048 (7228 NM, 115SM, 705 PM) cases with histological follow-up were included. Our NM included 21 malignant and 7207 benign histological diagnoses. Our 820 SMs+PMs were diagnosed as 107 unknown malignancies (30SM and 77PM), 691 metastatic lesions (81SM and 610PM), 9 lymphomas (2SM and 7PM), 9 mesotheliomas (1SM and 8SM), 4 sarcomas (1SM and 3PM). Primary gynecological cancers contributed with 64% of the cases. We documented 97.4% sensitivity, 99.9% specificity, 98% diagnostic accuracy, 99.7% negative predictive value (NPV) and 99.7% positive predictive value (PPV). Furthermore, the morphological diagnoses were supported by either 173 conclusive ICC results or 50 molecular analyses. Specifically the molecular testing was performed for the EGFR and KRAS mutational analysis based on the previous or contemporary diagnoses of Non Small Cell Lung Cancer (NSCLC) and colon carcinomas. We identified 10 EGFR in NSCCL and 7 KRAS mutations on LBC stored material. CONCLUSIONS: Peritoneal cytology is an adjunctive tool in the surgical management of tumors mostly gynecological cancers. LBC maximizes the application of ancillary techniques such as ICC and molecular analysis with feasible diagnostic and predictive yields also in controversial cases. PMID- 28099524 TI - Role of Myo/Nog Cells in Neuroprotection: Evidence from the Light Damaged Retina. AB - PURPOSE: To identify Myo/Nog cells in the adult retina and test their role in protecting retinal photoreceptors from light damage. METHODS: Light damage was induced by exposing albino rats raised in dim cyclic light to 1000 lux light for 24 hours. In one group of rats, Myo/Nog cells were purified from rat brain tissue by magnetic cell sorting following binding of the G8 monoclonal antibody (mAb). These cells were injected into the vitreous humour of the eye within 2 hours following bright light exposure. Retinal function was assessed using full-field, flash electroretinogram (ERG) before and after treatment. The numbers of Myo/Nog cells, apoptotic photoreceptors, and the expression of glial fibrillary acidic protein (GFAP) in Muller cells were assessed by immunohistochemistry. RESULTS: Myo/Nog cells were present in the undamaged retina in low numbers. Light induced damage increased their numbers, particularly in the choroid, ganglion cell layer and outer plexiform layer. Intravitreal injection of G8-positive (G8+) cells harvested from brain mitigated all the effects of light damage examined, i.e. loss of retinal function (ERG), death of photoreceptors and the stress-induced expression of GFAP in Muller cells. Some of the transplanted G8+ cells were integrated into the retina from the vitreous. CONCLUSIONS: Myo/Nog cells are a subpopulation of cells that are present in the adult retina. They increase in number in response to light induced stress. Intravitreal injection of Myo/Nog cells was protective to the retina, in part, by reducing retinal stress as measured by the Muller cell response. These results suggest that Myo/Nog cells, or the factors they produce, are neuroprotective and may be therapeutic in neurodegenerative retinal diseases. PMID- 28099525 TI - Polyethylene Glycol Camouflaged Earthworm Hemoglobin. AB - Nearly 21 million components of blood and whole blood and transfused annually in the United States, while on average only 13.6 million units of blood are donated. As the demand for Red Blood Cells (RBCs) continues to increase due to the aging population, this deficit will be more significant. Despite decades of research to develop hemoglobin (Hb) based oxygen (O2) carriers (HBOCs) as RBC substitutes, there are no products approved for clinical use. Lumbricus terrestris erythrocruorin (LtEc) is the large acellular O2 carrying protein complex found in the earthworm Lumbricus terrestris. LtEc is an extremely stable protein complex, resistant to autoxidation, and capable of transporting O2 to tissue when transfused into mammals. These characteristics render LtEc a promising candidate for the development of the next generation HBOCs. LtEc has a short half-life in circulation, limiting its application as a bridge over days, until blood became available. Conjugation with polyethylene glycol (PEG-LtEc) can extend LtEc circulation time. This study explores PEG-LtEc pharmacokinetics and pharmacodynamics. To study PEG-LtEc pharmacokinetics, hamsters instrumented with the dorsal window chamber were subjected to a 40% exchange transfusion with 10 g/dL PEG-LtEc or LtEc and followed for 48 hours. To study the vascular response of PEG-LtEc, hamsters instrumented with the dorsal window chamber received multiple infusions of 10 g/dL PEG-LtEc or LtEc solution to increase plasma LtEc concentration to 0.5, then 1.0, and 1.5 g/dL, while monitoring the animals' systemic and microcirculatory parameters. Results confirm that PEGylation of LtEc increases its circulation time, extending the half-life to 70 hours, 4 times longer than that of unPEGylated LtEc. However, PEGylation increased the rate of LtEc oxidation in vivo. Vascular analysis verified that PEG-LtEc showed the absence of microvascular vasoconstriction or systemic hypertension. The molecular size of PEG-LtEc did not change the colloid osmotic pressure or blood volume expansion capacity compared to LtEc, due to LtEc's already large molecular size. Taken together, these results further encourage the development of PEG-LtEc as an O2 carrying therapeutic. PMID- 28099526 TI - Executive Functioning in Men with Schizophrenia and Substance Use Disorders. Influence of Lifetime Suicide Attempts. AB - BACKGROUND: Lifetime suicide attempts in patients with comorbidity between psychotic disorders and Substance Use Disorder (SUD), known as dual diagnosis, was associated with a worse clinical and cognitive state, poor prognosis and premature death. However, to date no previous study has examined the cognitive performance of these patients considering as independent the presence or absence of lifetime suicide attempts. METHODS: We explore executive functioning differences between suicide attempters and non-attempters in dual schizophrenia (DS) patients and the possible related factors for both executive performance and current suicide risk. Fifty DS male patients in remission of SUD and clinically stables, 24 with and 26 without lifetime suicide attempts, were evaluated. We considered Z scores for all neuropsychological tests and a composite summary score for both premorbid IQ and executive functioning. RESULTS: DS patients showed low performance in set-shifting, planning and problem solving tasks. Those with suicide attempts presented lower composite summary scores, together with worse problem solving skills and decision-making, compared with non-attempters. However, after controlling for alcohol dependence, only differences in decision making remained. Executive functioning was related to the premorbid intelligence quotient, and several clinical variables (duration, severity, months of abstinence and relapses of SUD, global functioning and negative symptoms). A relationship between current suicide risk, and first-degree relatives with SUD, insight and positive symptoms was also found. CONCLUSIONS: Our results suggest that problem solving and, especially, decision-making tasks might be sensitive to cognitive impairment of DS patients related to presence of lifetime suicide attempts. The assessment of these executive functions and cognitive remediation therapy when necessary could be beneficial for the effectiveness of treatment in patients with DS. However, further research is needed to expand our findings and overcome some limitations of this study. PMID- 28099527 TI - The Association between Osteoarthritis and Occupational Clusters in the Korean Population: A Nationwide Study. AB - Osteoarthritis (OA) is a considerable health problem worldwide. It is known to be associated with certain occupational risk factors. We examined the prevalence rate of OA by occupational cluster. Data were collected from the Korea National Health and Nutrition Examination Surveys (2010-2013). The total number of unweighted sample size was 9,905 participants: 4,460 men and 5,445 women, and OA prevalence was 5.3% and 18.4% respectively. OA patients were defined as participants with knee/hip joint pain and radiographic change of knee/hip joint. Occupational type was classified as either white, pink, blue, or green collar based on the occupational characteristics following physical demand: white for manager and professionals; pink for clerks and service/sales workers; blue for craft/trade workers, machine operators and assemblers, and elementary manual workers; and green for agricultural/fishery workers. We calculated the odds ratios (ORs) and 95% confidence intervals (95% CI) for the odds of a participant's having OA according to the occupational cluster, with gender stratification. The multiple logistic regression model showed that, compared to the white collar group, the ORs of the pink, blue, and green collar workers were 1.23 (95% CI 0.64-2.36), 1.85 (95% CI 1.18-2.88), and 2.91 (95% CI 1.86-4.54), respectively, in males, and 2.53 (95% CI 1.71-3.73), 2.86 (95% CI 1.94-4.21), and 3.90 (95% CI 2.60-5.83), respectively in females. The prevalence rate of OA was associated with the occupational cluster, in order from highest to lowest: green, blue, pink, and white collar. PMID- 28099528 TI - iNOS as a Driver of Inflammation and Apoptosis in Mouse Skeletal Muscle after Burn Injury: Possible Involvement of Sirt1 S-Nitrosylation-Mediated Acetylation of p65 NF-kappaB and p53. AB - Inflammation and apoptosis develop in skeletal muscle after major trauma, including burn injury, and play a pivotal role in insulin resistance and muscle wasting. We and others have shown that inducible nitric oxide synthase (iNOS), a major mediator of inflammation, plays an important role in stress (e.g., burn) induced insulin resistance. However, it remains to be determined how iNOS induces insulin resistance. Moreover, the interrelation between inflammatory response and apoptosis is poorly understood, although they often develop simultaneously. Nuclear factor (NF)-kappaB and p53 are key regulators of inflammation and apoptosis, respectively. Sirt1 inhibits p65 NF-kappaB and p53 by deacetylating these transcription factors. Recently, we have shown that iNOS induces S nitrosylation of Sirt1, which inactivates Sirt1 and thereby increases acetylation and activity of p65 NF-kappaB and p53 in various cell types, including skeletal muscle cells. Here, we show that iNOS enhances burn-induced inflammatory response and apoptotic change in mouse skeletal muscle along with S-nitrosylation of Sirt1. Burn injury induced robust expression of iNOS in skeletal muscle and gene disruption of iNOS significantly inhibited burn-induced increases in inflammatory gene expression and apoptotic change. In parallel, burn increased Sirt1 S nitrosylation and acetylation and DNA-binding capacity of p65 NF-kappaB and p53, all of which were reversed or ameliorated by iNOS deficiency. These results indicate that iNOS functions not only as a downstream effector but also as an upstream enhancer of burn-induced inflammatory response, at least in part, by Sirt1 S-nitrosylation-dependent activation (acetylation) of p65 NF-kappaB. Our data suggest that Sirt1 S-nitrosylation may play a role in iNOS-mediated enhanced inflammatory response and apoptotic change, which, in turn, contribute to muscle wasting and supposedly to insulin resistance after burn injury. PMID- 28099530 TI - Nationwide Seropositivity of Hepatitis A in Republic of Korea from 2005 to 2014, before and after the Outbreak Peak in 2009. AB - BACKGROUND/AIMS: The epidemiologic shift of hepatitis A virus (HAV) infection in the South Korean population resulted in a peak outbreak of hepatitis in 2009. The aim of this study was to clarify the seropositivity of anti-HAV antibody (anti HAV) and its demographic characteristics before and after the peak outbreak from 2005 to 2014. METHODS: This retrospective study analyzed the anti-HAV data of all individuals from 1,795 medical institutions referred to a major central laboratory from January 2005 through December 2014, as a sentineal tool for monitoring annual variation of anti-HAV positivity. The prevalence of anti-HAV was adjusted for age and area with the standard population based on the 2010 Census data. RESULTS: A total of 424,245 individuals were included in this study. The overall age-adjusted anti-HAV prevalence decreased from 65.6% in 2005 to 62.2% in 2014. During the 10-year period, the seroprevalence continuously decreased in persons aged 30 to 39 years (69.6% to 32.4%) and those aged 40 to 49 years (97.9% to 79.3%) due to the cohort effect. In contrast, it increased in persons aged 10 to 19 years (15.4% to 35.2%), while it was the lowest (8.7%) in 2010 before rebounding to 20.2% in 2014 in persons aged 20 to 29 years due to a vaccination effect. CONCLUSION: Although the HAV vaccination rate increased, the anti-HAV seropositivity in South Korea decreased from 65.6% to 62.2% in this study population. In particular, the immunity of young adults was still low, and an outbreak of HAV is possible in the near future. Therefore, continuous monitoring and optimal preventive measures to prevent future outbreaks should be considered. PMID- 28099532 TI - Vitiligo patients experience barriers in accessing care. AB - Vitiligo is a loss of pigment occurring in approximately 0.4% to 2% of the worldwide population. The aim of this study was to determine and characterize barriers to access of care in US patients with vitiligo. An Internet-based, deidentified survey consisting of 82 questions about topics including demographics, recommendations for care, and/or barriers to receiving recommended care was designed and distributed to member participants in an online vitiligo support community consisting of patients (and parents/guardians of adolescents). Results indicated that treatment cost, relationships, work schedule, school schedule, number of sites affected, and female sex may be barriers to receiving prescribed care in some patients with vitiligo. Exploration of mechanisms by which these barriers can be reduced in the medical care of vitiligo may allow more patients to successfully receive treatment. PMID- 28099533 TI - Tinea capitis caused by Trichophyton rubrum mimicking favus. AB - Favus is an uncommon form of tinea capitis (TC) currently seen in geographic areas with poor sanitation and limited access to health care such as emerging nations. Several variants of this condition have been described including one exhibiting a plaque composed of parchmentlike material. The makeup of this plaque has not been described. Tinea capitis is rare in adults, particularly when the infectious agent is Trichophyton rubrum, and affected patients often exhibit comorbidities associated with diminished immune surveillance. This case report describes an elderly woman with TC due to T rubrum mimicking a rare form of favus. PMID- 28099531 TI - Sarcoidosis and squamous cell carcinoma: a connection documented in a case series of 3 patients. AB - Sarcoidosis is a chronic multisystem disease characterized by the formation of noncaseating granulomas in multiple organs, including the skin. An association between multisystem sarcoidosis and an increased risk for malignancy has been established. Dermatologists should be aware of the increased risk for nonmelanoma skin cancers in patients with sarcoidosis. We report a series of 3 patients with primarily cutaneous sarcoidosis who presented with new-onset cutaneous squamous cell carcinoma (SCC). Two patients were black women and 1 patient presented with lesions of cutaneous sarcoidosis arising concurrently with SCCs in the same location, distinguishable only by biopsy. These cases highlight the association between sarcoidosis and an increased risk for SCC. Because dermatologists may be the primary clinicians caring for these patients, it is important that they remain aware of the increased risk for cutaneous malignancies and that they have a low threshold for biopsy of new and unusual skin lesions. Furthermore, 2 patients were black women, a population not commonly affected by skin cancer, which further exemplifies the need for comprehensive skin examinations in black patients. Although the precise mechanism for an increased risk for malignancy in these patients requires further investigation, chronic inflammation and immune dysregulation may play a role. PMID- 28099534 TI - A noninvasive mechanical treatment to reduce the visible appearance of cellulite. AB - Cellulite is a cosmetic condition of subcutaneous fat herniation through fibrous connective tissue that results in a dimpled appearance of the skin. Occurring in approximately 85% to 90% of all women worldwide, cellulite has been well studied. The result has been the development of a plethora of treatment protocols yielding little to no success. We describe a noninvasive mechanical treatment for women with cellulite, evaluating the safety and effectiveness of a technique that utilizes a unique patented device for the reduction of the visible appearance of cellulite. PMID- 28099529 TI - A Possible Role of the Full-Length Nascent Protein in Post-Translational Ribosome Recycling. AB - Each cycle of translation initiation in bacterial cell requires free 50S and 30S ribosomal subunits originating from the post-translational dissociation of 70S ribosome from the previous cycle. Literature shows stable dissociation of 70S from model post-termination complexes by the concerted action of Ribosome Recycling Factor (RRF) and Elongation Factor G (EF-G) that interact with the rRNA bridge B2a/B2b joining 50S to 30S. In such experimental models, the role of full length nascent protein was never considered seriously. We observed relatively slow release of full-length nascent protein from 50Sof post translation ribosome, and in that process, its toe prints on the rRNA in vivo and in in vitro translation with E.coli S30 extract. We reported earlier that a number of chemically unfolded proteins like bovine carbonic anhydrase (BCA), lactate dehydrogenase (LDH), malate dehydrogenase (MDH), lysozyme, ovalbumin etc., when added to free 70Sin lieu of the full length nascent proteins, also interact with identical RNA regions of the 23S rRNA. Interestingly the rRNA nucleotides that slow down release of the C-terminus of full-length unfolded protein were found in close proximity to the B2a/B2b bridge. It indicated a potentially important chemical reaction conserved throughout the evolution. Here we set out to probe that conserved role of unfolded protein conformation in splitting the free or post-termination 70S. How both the RRF-EFG dependent and the plausible nascent protein-EFG dependent ribosome recycling pathways might be relevant in bacteria is discussed here. PMID- 28099536 TI - A potpourri of things to do correctly. PMID- 28099535 TI - Physicians must encourage HPV vaccine. PMID- 28099537 TI - Flesh-colored papular eruption. PMID- 28099538 TI - Psoriasis treatment considerations in military patients: unique patients, unique drugs. AB - Psoriasis is a common dermatologic problem with a chronic and sometimes debilitating course. Psoriasis can impair a service member's ability to perform job-related activities and should certainly be treated; however, use of immunosuppressive treatments can prevent deployment to strategic locations around the world for numerous reasons, such as the need for laboratory monitoring, minimal access to climate-controlled storage, and potential increased risk of exposure to virulent pathogens while on these medications. Similar obstacles can exist for nonmilitary patients who are placed in austere conditions or participate in worldwide travel. Although treatment efficacy, cost, and side effect profiles are always paramount considerations in deciding on treatment regimens with patients, herein we focus our discussion on a consideration that might be easily overlooked when treating patients in modern society, that being the "logistics" of treatment. PMID- 28099539 TI - Firm pink nodule on the scalp. PMID- 28099540 TI - Using the blanch sign to differentiate weathering nodules from auricular tophaceous gout. PMID- 28099541 TI - Purple curvilinear papules on the back. PMID- 28099542 TI - Pruritic and painful nodules on the tongue. PMID- 28099544 TI - Oral fixed drug eruption due to tinidazole. PMID- 28099543 TI - A rare association in Down syndrome: milialike idiopathic calcinosis cutis and palpebral syringoma. PMID- 28099545 TI - Cutaneous adnexal carcinoma with apocrine differentiation. AB - Primary cutaneous apocrine carcinomas are uncommon malignant neoplasms that can be difficult, if not impossible, to distinguish histologically from metastatic breast carcinomas. We present the case of a 71-year-old man with a 5-year history of extensive ulcerated plaques on the posterior neck and posterior scalp. Biopsy revealed a poorly differentiated infiltrating adenocarcinoma consistent with either primary cutaneous apocrine carcinoma or occult metastatic breast carcinoma. Immunohistochemical analysis demonstrated positive staining for cytokeratin (CK) 7, estrogen receptor, and progesterone receptor, and negative staining for p63, podoplanin, CK20, and thyroid transcription factor 1. Extensive radiologic imaging studies showed no evidence of occult breast or other internal malignancies. Based on the indolent clinical course, lack of evidence for an internal primary site, and immunohistochemical staining, the lesion was determined to be consistent with a cutaneous neoplasm with features of apocrine differentiation. This case highlights the distinction between apocrine carcinoma and other primary adnexal carcinomas for which p63 and D2-40 have been reported to be sensitive and specific markers but are negative in apocrine carcinomas. PMID- 28099546 TI - Multiple keratoacanthomas occurring in surgical margins and de novo treated with intralesional methotrexate. AB - Keratoacanthomas (KAs) are common skin lesions known for their rapid growth and spontaneous regression. Keratoacanthomas also can occur in sites of prior trauma, such as surgical scars. We report a case of multiple KAs occurring in the site of trauma from a prior surgery and de novo as well as the response to treatment with intralesional methotrexate (MTX). PMID- 28099547 TI - Primary cutaneous Mycobacterium avium complex infection following squamous cell carcinoma excision. AB - Primary cutaneous Mycobacterium avium complex (MAC) infection is rare, particularly among immunocompetent patients. We present the case of a purportedly healthy patient with primary cutaneous MAC infection arising within the excision margins of multiple infiltrating squamous cell carcinomas. PMID- 28099548 TI - Teledermatology in Tijuana, Mexico. AB - The Health Frontiers in Tijuana (HFiT) clinic is a binational partnership between the University of California, San Diego School of Medicine (San Diego, California); the Universidad Autonoma de Baja California School of Medicine (Tijuana, Mexico); and Desayunador Salesiano Padre Chava, a community grassroots organization in Tijuana, Mexico. Health Frontiers in Tijuana provides accessible quality health care for the underserved in Tijuana's Zona Norte. This article is a narrative meant to share my clinical experience as a dermatology resident who worked with HFiT to establish teledermatology services at this clinic. PMID- 28099549 TI - Warming up for mechanosynthesis - temperature development in ball mills during synthesis. AB - We present a first direct measurement of the temperature during milling combined with in situ Raman spectroscopy monitoring. The data reveal a low temperature increase due to the mechanical impact and clear temperature increases as a consequence of the reaction heat. Based on the data, temperature rises as postulated in the magma plasma and hot spot theory can be excluded for soft matter milling syntheses. PMID- 28099550 TI - Factors associated with the contraindicated use of oral contraceptives in Brazil. AB - OBJECTIVE: To estimate the prevalence of the contraindicated use of oral contraceptives and the associated factors in Brazilian women. METHODS: 20,454 women who answered the VIGITEL survey in 2008 also participated in this study, of which 3,985 reported using oral contraceptives. We defined the following conditions for the contraindicated use of contraceptives: hypertension; cardiovascular diseases such as heart attack, stroke/cerebrovascular accident; diabetes mellitus; being smoker and 35 years old or older. We estimated the prevalence and 95% confidence intervals of contraindicated use in users of oral contraceptives and the factors associated with contraindication by prevalence ratio and 95% confidence intervals. RESULTS: In the total population, 21% (95%CI 19.7-21.9) of women showed some contraindication to the use of oral contraceptives, of which 11.7% (95%CI 10.6-13.7) belonged to the group of users of oral contraceptives. The most frequent contraindication in users of oral contraceptives was hypertension (9.1%). The largest proportion of women with at least one contraindication was aged between 45 and 49 years (45.8%) and with education level between zero and eight years (23.8%). The prevalence of contraindication to oral contraceptives was higher in women less educated (zero to eight years of study) (PR = 2.46; 95%CI 1.57-3.86; p < 0.05) and with age between 35-44 years (PR = 4.00; 95%CI 2.34-6.83) and 45-49 years (PR = 5.59; 95%CI 2.90-10.75). CONCLUSIONS: Age greater than or equal to 35 and low education level were demographic and iniquity factors, respectively, in the contraindicated use of oral contraceptives. OBJETIVO: Estimar a prevalencia de contraindicacao ao uso de anticoncepcionais orais e os fatores associados em mulheres brasileiras. METODOS: Participaram 20.454 mulheres que responderam ao inquerito Vigitel em 2008, das quais 3.985 reportaram uso de contraceptivos orais. Definiu-se como uso contraindicado de anticoncepcionais quando presente pelo menos uma condicao: hipertensao; doencas cardiovasculares como infarto, derrame/acidente vascular encefalico; diabetes mellitus; ser tabagista e ter idade igual ou maior de 35 anos. Foram estimadas as prevalencias e intervalos de 95% de confianca de uso contraindicado em usuarias de anticoncepcionais orais e fatores associados a contraindicacao por meio de razoes de prevalencia e intervalos de 95% de confianca. RESULTADOS: Na populacao total, 21,0% (IC95% 19,7-21,9) das mulheres apresentaram alguma contraindicacao ao uso de anticoncepcionais orais, das quais 11,7% (IC95% 10,6-13,7) pertenciam ao grupo de usuarias de anticoncepcionais orais. A contraindicacao mais frequente entre as usuarias de anticoncepcionais orais foi hipertensao (9,1%). A maior proporcao de mulheres com pelo menos uma contraindicacao tinha entre 45 a 49 anos (45,8%) e escolaridade entre zero e oito (23,8%). A prevalencia de contraindicacao de anticoncepcionais orais foi maior nas mulheres menos escolarizadas (zero a oito anos de estudos) (RP = 2,46; IC95% 1,57-3,86; p < 0,05) e idade entre 35-44 anos (RP = 4,00; IC95% 2,34-6,83) e 45 49 anos (RP = 5,59; IC95% 2,90-10,75). CONCLUSOES: Idade maior ou igual a 35 e escolaridade baixa foram fatores demograficos e de iniquidade, respectivamente, no uso contraindicado de contraceptivos orais. PMID- 28099551 TI - Cholesterol and prevention of atherosclerotic events: limits of a new frontier. AB - Control of atherosclerotic cardiovascular disease - a highly prevalent condition and one of the main causes of mortality in Brazil and worldwide - is a recurrent subject of great interest for public health. Recently, three new guidelines on dyslipidemia and atherosclerosis prevention have been published. The close release of these important publications is a good opportunity for comparison: the Brazilian model has greater sensitivity, the English model does not work with risk stratification, and the American model may be overestimating the risk. This will allow reflection on current progress and identification of controversial aspects which still require further research and debate. It is also an opportunity to discuss issues related to early diagnosis and its efficiency as a preventive strategy for atherosclerotic disease: the transformation of risk into disease, the gradual reduction of cut-off points, the limitations of the screening strategy, and the problem of overdiagnosis. RESUMO O controle da doenca cardiovascular aterosclerotica - morbidade de alta prevalencia e uma das principais causas de mortalidade no Brasil e no mundo - continua sendo tema de grande interesse para a Saude Publica. Recentemente, tres novas diretrizes sobre dislipidemia e prevencao da aterosclerose foram divulgadas. A convergencia no tempo dessas importantes publicacoes constitui boa oportunidade para sua comparacao: o modelo brasileiro tem maior sensibilidade, o ingles nao trabalha com risco estratificado e o norte-americano parece estar superestimando o risco.Isso permitira reflexoes acerca dos avancos que ja foram alcancados e identificacao de aspectos ainda controversos, que seguem exigindo novas pesquisas e debates. E tambem uma oportunidade para discutir questoes relacionadas ao diagnostico precoce e sua eficiencia como estrategia preventiva da doenca aterosclerotica: as transformacoes do risco em doenca, a diminuicao progressiva de pontos de corte, as insuficiencias da estrategia de rastreamento e o problema do sobrediagnostico. PMID- 28099552 TI - Association between the concentration of fine particles in the atmosphere and acute respiratory diseases in children. AB - OBJECTIVE: To analyze the association between fine particulate matter concentration in the atmosphere and hospital care by acute respiratory diseases in children. METHODS: Ecological study, carried out in the region of Grande Vitoria, Espirito Santo, in the winter (June 21 to September 21, 2013) and summer (December 21, 2013 to March 19, 2014). We assessed data of daily count for outpatient care and hospitalization by respiratory diseases (ICD-10) in children from zero to 12 years in three hospitals in the Region of Grande Vitoria. For collecting fine particulate matter, we used portable samplers of particles installed in six locations in the studied region. The Generalized Additive Model with Poisson distribution, fitted for the effects of predictor covariates, was used to evaluate the relationship between respiratory outcomes and concentration of fine particulate matter. RESULTS: The increase of 4.2 ug/m3 (interquartile range) in the concentration of fine particulate matter increased in 3.8% and 5.6% the risk of medical care or hospitalization, respectively, on the same day and with six-day lag from the exposure. CONCLUSIONS: We identified positive association between outpatient care and hospitalizations of children under 12 years due to acute respiratory diseases and the concentration of fine particulate matter in the atmosphere. OBJETIVO: Analisar a associacao entre a concentracao de material particulado fino na atmosfera e atendimento hospitalar por doencas respiratorias agudas em criancas. METODOS: Estudo ecologico, realizado na Regiao da Grande Vitoria, ES, no inverno (21 de junho a 21 de setembro de 2013) e no verao (21 de dezembro de 2013 a 19 de marco de 2014). Foram avaliados dados de contagem diaria de atendimentos ambulatoriais e hospitalizacoes por doencas respiratorias (CID-10) em criancas de zero a 12 anos em tres hospitais da Regiao da Grande Vitoria. Para a coleta de material particulado fino foram utilizados amostradores portateis de particulas instalados em seis locais na regiao estudada. O Modelo Aditivo Generalizado com distribuicao de Poisson, ajustado para efeitos das covariaveis preditoras, foi utilizado para avaliar a relacao entre os desfechos respiratorios e a concentracao de material particulado fino. RESULTADOS: O incremento de 4,2 ug/m3 (intervalo interquartilico) na concentracao de material particulado fino aumentou em 3,8% e 5,6% o risco de atendimento ou internacao, respectivamente, no mesmo dia e com seis dias de defasagem da exposicao. CONCLUSOES: Foi identificada associacao positiva entre atendimentos ambulatoriais e hospitalizacoes de criancas com ate 12 anos devido a doencas respiratorias agudas e a concentracao de material particulado fino na atmosfera. PMID- 28099553 TI - The new era and paradigms for patient consent. PMID- 28099554 TI - No correlation was observed between vitamin D levels and disability of patients with multiple sclerosis between latitudes 18 degrees and 30 degrees South. AB - Objective: Vitamin D has taken center stage in research and treatment of multiple sclerosis (MS). The objective of the present study was to assess the serum vitamin D levels of a large population of patients with MS and controls living in a restricted tropical area. Methods: Data from 535 patients with MS and 350 control subjects were obtained from 14 cities around the Tropic of Capricorn. Results: The mean serum 25-OH vitamin D level was 26.07 +/- 10.27 ng/mL for the control subjects, and 28.03 +/- 12.19 ng/mL for patients with MS. No correlation was observed between vitamin D levels and the disability of patients over the disease duration. Conclusion: At least for the region around the Tropic of Capricorn, serum levels of vitamin D typically are within the range of 20 to 30 ng/mL for controls and patients with MS. PMID- 28099555 TI - Modulation of the ultradian human nasal cycle by sleep stage and body position. AB - Objective:: The nasal cycle, which is present in a significant number of people, is an ultradian side-to-side rhythm of nasal engorgement associated with cyclic autonomic activity. We studied the nasal cycle during REM/non-REM sleep stages and examined the potentially confounding influence of body position on lateralized nasal airflow. Methods:: Left- and right-side nasal airflow was measured in six subjects during an eight-hour sleep period using nasal thermistors. Polysomnography was performed. Simultaneously, body positions were monitored using a video camera in conjunction with infrared lighting. Results:: Significantly greater airflow occurred through the right nasal chamber (relative to the left) during periods of REM sleep than during periods of non-REM sleep (p<0.001). Both body position (p < 0.001) and sleep stage (p < 0.001) influenced nasal airflow lateralization. Conclusions:: This study demonstrates that the lateralization of nasal airflow and sleep stage are related. Some types of asymmetrical somatosensory stimulation can alter this relationship. PMID- 28099556 TI - Erratum. AB - [This corrects the article doi: 10.1590/0004-282X20160065]. PMID- 28099557 TI - Patients with sickle cell disease are frequently excluded from the benefits of transcranial doppler screening for the risk of stroke despite extensive and compelling evidence. AB - Methods:: Transcranial doppler was performed in accordance with the Stroke Prevention Trial in Sickle Cell Anemia Protocol. Results:: Of the 396 patients, 69.5% had homozygous SS hemoglobin. The TCD result was abnormal in 4.8%, conditional in 12.6%, inadequate in 4.3% and abnormally low in 1% of patients. The highest mean flow velocities were 121+/-23.83cm/s and 124+/-27.21cm/s in the left and right middle cerebral artery respectively. A total of 28.8% patients (mean age 9.19+/-5.92 years) were evaluated with TCD for the first time. Conclusions:: The SCD patients were evaluated with TCD at an older age, representing an important missed opportunity for stroke prevention. Since TCD screening in patients with SCD is important to detect those at high risk for stroke, it is recommended that this screening should be made more readily available. PMID- 28099558 TI - The mortality rate after hospital discharge in patients with myelomeningocele decreased after implementation of mandatory flour fortification with folic acid. AB - Objective:: To evaluate the mandatory folic acid fortification of flour on mortality rates after the hospital discharge of children born with myelomeningocele, the most affected age group and the most frequent cause of death. Methods:: A retrospective study of 383 children born with myelomeningocele from January 1990 to December 2013 in a high-fetal-risk reference hospital. Results:: A total of 39 patients died (10.1%),of which 23 (6%) died after discharge. Most children who died were younger than 12 months of age. The most frequent cause of death was infection of the central nervous system, followed by urinary tract sepsis and infections of the respiratory system. Symptomatic Chiari II malformation was the most frequent comorbidity factor. Conclusion:: Although there was no significant difference in infant mortality before and after folic acid fortification, there was a significant reduction in deaths after hospital discharge in babies born after implementation of mandatory folic acid fortification. PMID- 28099559 TI - Pain-induced depression is related to overestimation of sleep quality in a very elderly population with pain. AB - Objective:: To study the quality of sleep in very elderly people with chronic pain. Methods:: We investigated 51 very elderly people without dementia and with chronic pain according to the Geriatric Pain Measure. Katz and Lawton questionnaires were used to evaluate functionality. The Geriatric Depression Scale and Geriatric Psychosocial Assessment of Pain-induced Depression were also used. Self-perceptions of sleep and quality of sleep were checked using the Pittsburgh Sleep Quality Index. Results:: Moderate pain was seen in 64.7% participants. The tracking of depression was positive for 41.2%. Poor quality of sleep was noted in 49% of them, but 82.3% perceived that they had a very good, or a good, sleep. The main factors associated with poor sleep quality were measurement of pain, self-perception of sleep, and pain-induced depression. Conclusion:: Very elderly people with chronic pain, and without dementia, had a higher prevalence of poor sleep; however, they overestimated their sleep quality. Poor quality of sleep was associated with a poor self-perception of sleep and pain-induced depression. PMID- 28099560 TI - Expression of NMDA receptor and microRNA-219 in rats submitted to cerebral ischemia associated with alcoholism. AB - Objective:: To evaluate the microRNA-219 and NMDA expression in brain tissue and blood of animals subjected to cerebral ischemia associated with alcoholism. Methods:: Fifty Wistar rats were divided into groups: control, sham, ischemic, alcoholic, and ischemic plus alcoholic. The expression of microRNA-219 and NMDA were analyzed by real-time PCR. Results:: When compared to the control group, the microRNA-219 in brain tissue was less expressed in the ischemic, alcoholic, and ischemic plus alcoholic groups. In the blood, this microRNA had lower expression in alcoholic and ischemic plus alcoholic groups. In the brain tissue the NMDA gene expression was greater in the ischemic, alcoholic, and ischemic plus alcoholic groups. Conclusion:: A possible modulation of NMDA by microRNA-219 was observed with an inverse correlation between them. PMID- 28099561 TI - MacArthur Competence Assessment Tool for Treatment in Alzheimer disease: cross cultural adaptation. AB - Objective:: We adapted the MacArthur Competence Assessment Tool for Treatment (MacCAT-T) to Brazilian Portuguese, pilot testing it on mild and moderate patients with Alzheimer's disease (AD). Methods:: The cross-cultural process required six steps. Sixty-six patients with AD were assessed for competence to consent to treatment, global cognition, working memory, awareness of disease, functionality, depressive symptoms and dementia severity. Results:: The items had semantic, idiomatic, conceptual and experiential equivalence. We found no difference between mild and moderate patients with AD on the MacCAT-T domains. The linear regressions showed that reasoning (p = 0.000) and functional status (p = 0.003) were related to understanding. Understanding (p = 0.000) was related to appreciation and reasoning. Awareness of disease (p = 0.001) was related to expressing a choice. Conclusions:: The MacCAT-T adaptation was well-understood and the constructs of the original version were maintained. The results of the pilot study demonstrated an available Brazilian tool focused on decision-making capacity in AD. PMID- 28099562 TI - Development and validation of the Bush-Francis Catatonia Rating Scale - Brazilian version. AB - Objective:: This article aims to describe the adaptation and translation process of the Bush-Francis Catatonia Rating Scale (BFCRS) and its reduced version, the Bush-Francis Catatonia Screening Instrument (BFCSI) for Brazilian Portuguese, as well as its validation. Methods:: Semantic equivalence processes included four steps: translation, back translation, evaluation of semantic equivalence and a pilot-study. Validation consisted of simultaneous applications of the instrument in Portuguese by two examiners in 30 catatonic and 30 non-catatonic patients. Results:: Total scores averaged 20.07 for the complete scale and 7.80 for its reduced version among catatonic patients, compared with 0.47 and 0.20 among non catatonic patients, respectively. Overall values of inter-rater reliability of the instruments were 0.97 for the BFCSI and 0.96 for the BFCRS. Conclusion:: The scale's version in Portuguese proved to be valid and was able to distinguish between catatonic and non-catatonic patients. It was also reliable, with inter evaluator reliability indexes as high as those of the original instrument. PMID- 28099563 TI - Brazilian guidelines for endovascular treatment of patients with acute ischemic stroke. AB - These guidelines are the result of a joint effort from writing groups of the Brazilian Stroke Society, the Scientific Department of Cerebrovascular Diseases of the Brazilian Academy of Neurology, the Brazilian Stroke Network and the Brazilian Society of Diagnostic and Therapeutic Neuroradiology. Members from these groups participated in web-based discussion forums with predefined themes, followed by videoconference meetings in which controversies and position statements were discussed, leading to a consensus. This guidelines focuses on the implications of the recent clinical trials on endovascular therapy for acute ischemic stroke due to proximal arterial occlusions, and the final text aims to guide health care providers, health care managers and public health authorities in managing patients with this condition in Brazil. PMID- 28099565 TI - Scott Fitzgerald: famous writer, alcoholism and probable epilepsy. AB - Scott Fitzgerald, a world-renowned American writer, suffered from various health problems, particularly alcohol dependence, and died suddenly at the age of 44. According to descriptions in A Moveable Feast, by Ernest Hemingway, Fitzgerald had episodes resembling complex partial seizures, raising the possibility of temporal lobe epilepsy. PMID- 28099564 TI - Guideline for multiple sclerosis treatment in Brazil: Consensus from the Neuroimmunology Scientific Department of the Brazilian Academy of Neurology. AB - Multiple sclerosis has become an ever-increasing challenge to neurologists. With the release of the latest medications on the market, Brazilian neurologists feel divided between following their patients' evolution in accordance with the strict rules established by the Brazilian Ministry of Health regarding drug distribution, or following disease progression and worsening in accordance with the evidence in the literature. Therefore, a systematic review of the main published treatment guidelines was conducted and an escalating therapy proposed for guiding multiple sclerosis patient treatment in Brazil. PMID- 28099566 TI - Wilson's disease: the 60th anniversary of Walshe's article on treatment with penicillamine. AB - This historical review describes Professor Walshe's seminal contribution to the treatment of Wilson's disease on the 60th anniversary of his pioneering article on penicillamine, the first effective treatment for the condition. PMID- 28099567 TI - Muscle biopsy with dystrophic pattern and rimmed vacuoles: GNE myopathy in a Brazilian patient. PMID- 28099568 TI - Progressive hearing loss and cerebellar ataxia in anti-Ma2-associated autoimmune encephalitis. PMID- 28099569 TI - Sudden back pain as clinical presentation of spontaneous spinal epidural hematoma. PMID- 28099570 TI - Variation of the interphase heterochromatin in Artemia (Crustacea, Anostraca) of the Americas is related to changes in nuclear size and ionic composition of hipersaline habitats. AB - The populations of Artemia (or brine shrimp) from the Americas exhibit a wide variation in the amount of interphase heterochromatin. There is interest in understanding how this variation affects different parameters, from the cellular to the organismal levels. This should help to clarify the ability of this organism to tolerate brine habitats regularly subject to strong abiotic changes. In this study, we assessed the amount of interphase heterochromatin per nucleus based on chromocenter number (N-CHR) and relative area of chromocenter (R-CHR) in two species of Artemia, A. franciscana (Kellog, 1906) (n=9 populations) and A. persimilis (Piccinelli and Prosdocimi, 1968) (n=3 populations), to investigate the effect on nuclear size (S-NUC). The relationship of the R-CHR parameter with the ionic composition (IC) of brine habitats was also analysed. Our results indicate a significant variation in the amount of heterochromatin both within and between species (ANOVA, p<0.001). The heterochromatin varied from 0.81 +/- 1.17 to 12.58 +/- 3.78 and from 0.19 +/- 0.34% to 11.78 +/- 3.71% across all populations, for N-CHR and R-CHR parameters, respectively. N-CHR showed less variation than R-CHR (variation index 15.5-fold vs. 62-fold). At least five populations showed a significant association (p<0.05) between R-CHR and S-NUC, either with negative (four populations, r= from -0.643 to -0.443), or positive (one population, r= 0.367) values.Within each species, there were no significant associations between both parameters (p>0.05). The R-CHR and IC parameters were associated significantly for the magnesium ion (r= 0.496, p<0.05) and also for the chloride, sodium and calcium ions (r = from -0.705 to -0.478, p<0.05). At species level, a significant association between both parameters was also found in A. franciscana populations, for the sulphate and calcium ions, in contrast to A. persimilis. These findings suggest that the amount of interphase heterochromatin modifies the nuclear size in Artemia. Our data also indicate that change in the amount of interphase heterochromatin is in line with the ionic composition of brines. This would be a species-specific phenomenon, whose occurrence may be involved in the ability of this organism to survive in these environments. PMID- 28099571 TI - First report of the parasitoid Pachycrepoideus vindemmiae (Rondani, 1875) (Hymenoptera: Pteromalidae) parasitizing Synthesiomyia nudiseta (Van der Wulp, 1883) (Diptera: Muscidae). PMID- 28099572 TI - Occurrence of ants (Hymenoptera: Formicidae) in Banisteriopsis laevifolia (A.Juss.) B.Gates (Malpighiaceae) in Sao Paulo State, Brazil. PMID- 28099573 TI - Hematological and morphometric differences of blood cells from rheas, Rhea americana (Struthioniformes: Rheidae) on two conservation farms. AB - Today, blood tests are an indispensable tool in avian medicine. This study aimed to describe and compare hematological and morphometric data of erythrocytes, leukocytes and thrombocytes of rhea, Rhea americana. To do so, 58 rheas of both sexes on two farms, one in Cachoeiro do Itapemirim, Espirito Santo (ES), and the other in Sao Carlos, Sao Paulo (SP), were selected. Blood samples were taken and their RBC counts, PCV and Hb levels were determined and used in hematimetric index calculations. The total and differentiated leukocyte counts and the TPP and fibrinogen serum levels were also obtained. The results from the two farms analyzed were compared by means of the t test. There were differences in the parameters of the erythrocyte series between the two flocks because of a process of hypochromic macrocytic anemia observed among the rheas in ES. The values for the erythrocyte series and indexes were: RBC, 2.81 +/- 0.15 x106/MUl; PCV, 44.20 +/- 2.86%; Hb, 12.12 +/- 0.74 g/dL; MCV, 15.75 +/- 0.89 fL; MCH, 43.18 +/- 1.82 pg; and MCHC, 27.44 +/- 0.80 g/dL. The values for the leukocyte series were: WBC, 12,072 +/- 4116 /MUL; heterophils, 64.10 +/- 9.90%; eosinophils, 2.05 +/- 2.06%; monocytes, 6.40 +/- 2.99%; lymphocytes, 26.93 +/- 9.62%; and basophils, 0.52 +/- 1.27%. These can all be suggested as references for rheas reared in Brazil. Statistical differences were observed in erythrocyte length measurements, which were higher in the rheas in SP than in those in ES. Regarding width, the heterophils, lymphocytes and monocytes of the birds in ES were statistically greater than those of the birds in SP. It was concluded that rheas may exhibit morphometric alterations to blood cells and differences in blood elements according to the type of management to which they are subjected. PMID- 28099574 TI - Anatomy and micromorphometric analysis of leaf Catasetum x apolloi Benelli & Grade with addition of potassium silicate under different light sources. AB - The aim of this study was to compare vitroplants Catasetum x apolloi grown under natural light and artificial light and different concentrations of potassium silicate, providing data on the anatomical differentiation that aids the acclimatization process of this species. Plants from in vitro seeding were used; 5 protocorms of approximately 0.5 cm were inoculated into vials with a capacity of 500 mL containing 100 mL of alternative culture medium plus potassium silicate (0.0, 0.5; 1.0 mL L-1), pH adjusted to 5.5 +/- 0.5 and gelated with 4GL-1 agar before the autoclaving process. Cultures were maintained under natural light (TNE) and artificial light (TAE) for 90 days, and micromorphometric analysis was performed for polar and equatorial diameter, density and stomatal index, blade thickness in the central rib, and secondary veins. Applications in K2SiO4 alternative medium provided the following: elongation of the hypodermis, thicker mesophyll, and more prominent midrib; elipptical guard cells; formation of epistomatal chamber; and lower stomatal density and stomatal with lower equatorial and polar diameters. The conditions that favored the acclimatization were lower light intensities and lower potassium silicate doses. PMID- 28099575 TI - Evaluation of sperm quality of Erythrolamprus poecilogyrus sublineatus (Cope, 1860) (Serpentes, Dipsadidae). AB - Erythrolamprus poecilogyrus sublineatus (Cope, 1860), is a species widely distributed in the Pampa Domain, occurring in Rio Grande do Sul, Argentina and Uruguay, mainlyin the pampa region. In the coastal region of southern Brazil this is serpent is considered one of the most abundant. The purpose of the present study is to describe the techniques of sperm evaluation in vitro for E. poecilogyrus sublineatus in the coastal plain of Rio Grande do Sul, Brazil. After laparatomy the efferent vases were collected and the semen was diluted in 1ml Beltsville Thawing Solution. The characteristics of motility, membrane integrity, mitochondria, acrosome, DNA, cell viability and cellular functionality were evaluated. Fluorescent probes were used for the evaluation of sperm structure in epifluorescence microscope. With the techniques described, it was possible to identify intact and injured cells, enabling the determination of cell characteristics for the spring season (October and November). It was observed in the analyses that 80% of sperm cells were mobile and that 84.1 +/- 8.0% of sperm membranes were intact. The standards found were of 48 +/- 13.8% of intact acrosome, 73.6 +/- 6.0 of perfect DNA and of 91.8 +/- 4.0 of functional mitochondria. Thus, these values from the sperm analysis can be used as standards for the species Erythrolamprus poecilogyrus sublineatus. PMID- 28099576 TI - BPI-fold (BPIF) containing/plunc protein expression in human fetal major and minor salivary glands. AB - The aim of this study was to determine expression, not previously described, of PLUNC (palate, lung, and nasal epithelium clone) (BPI-fold containing) proteins in major and minor salivary glands from very early fetal tissue to the end of the second trimester and thus gain further insight into the function of these proteins. Early fetal heads, and major and minor salivary glands were collected retrospectively and glands were classified according to morphodifferentiation stage. Expression of BPI-fold containing proteins was localized through immunohistochemistry. BPIFA2, the major BPI-fold containing protein in adult salivary glands, was detected only in the laryngeal pharynx; the lack of staining in salivary glands suggested salivary expression is either very late in development or is only in adult tissues. Early expression of BPIFA1 was seen in the trachea and nasal cavity with salivary gland expression only seen in late morphodifferentiation stages. BPIFB1 was seen in early neural tissue and at later stages in submandibular and sublingual glands. BPIFA1 is significantly expressed in early fetal oral tissue but BPIFB1 has extremely limited expression and the major salivary BPIF protein (BPIFA2) is not produced in fetal development. Further studies, with more sensitive techniques, will confirm the expression pattern and enable a better understanding of embryonic BPIF protein function. PMID- 28099577 TI - Effects of periodontal treatment on primary sjogren's syndrome symptoms. AB - The aim of this longitudinal prospective study was to evaluate the effects of periodontal treatment on the clinical, microbiological and immunological periodontal parameters, and on the systemic activity (ESSDAI) and subjective (ESSPRI) indexes in patients with primary Sjogren's Syndrome (pSS). Twenty-eight female patients were divided into four groups: pSS patients with or without chronic periodontitis (SCP, SC, respectively), and systemically healthy patients with or without chronic periodontitis (CP, C, respectively). Periodontal clinical examination and immunological and microbiological sample collection were performed at baseline, 30 and 90 days after nonsurgical periodontal treatment (NSPT). Levels of interleukin IL-1beta, IL-8 and IL-10 in saliva and gingival crevicular fluid (GCF) were evaluated by ELISA, as well as the expression of Porphyromonas gingivalis (Pg), Aggregatibacter actinomycetemcomitans, (Aa) Tannerella forsythia (Tf), and Treponema denticola (Td), by qPCR. Systemic activity and pSS symptoms were evaluated by ESSDAI and ESSPRI. NSPT resulted in improved periodontal clinical parameters in both SCP and CP groups (p>0.05). Pg, Aa, and Tf levels decreased after NSPT only in CP patients (p<0.05). Significantly greater levels of IL-10 in GCF were verified in both SCP and CP groups (p<0.05). SCP patients showed increased salivary flow rates and decreased ESSPRI scores after NSPT. In conclusion, NSPT in pSS patients resulted in improved clinical and immunological parameters, with no significant effects on microbiological status. pSS patients also showed increased salivary flow and lower ESSPRI scores after therapy. Therefore, it can be suggested that NSPT may improve the quality of life of pSS patients. PMID- 28099578 TI - IL-6 and IL-10 gene polymorphisms in patients with aggressive periodontitis: effects on GCF, serum and clinic parameters. AB - Genetic variations observed in cytokines affect periodontitis susceptibility. The aim of this study was to investigate interleukin(IL)-6(-174) and IL-10(-597) gene polymorphisms in generalized aggressive periodontitis (GAgP) patients. Also, we aimed to evaluate the effects of IL-6 and IL-10 gene polymorphisms on the clinical outcomes of non-surgical periodontal therapy and cytokine levels in gingival crevicular fluid(GCF) and serum. Fifty-three patients with GAgP and 50 periodontally healthy individuals were included in this study. Clinical parameters, GCF and blood samples were collected at baseline and at 6-week. Non surgical periodontal therapy was performed in patients with GAgP. Gene analysis were determined by PCR-RFLP(polymerase chain reaction-restriction fragment length polymorphism) and cytokine levels were determined by enzyme-linked immunosorbent assay(ELISA).GAgP patients showed significant improvement on clinical parameters after periodontal therapy(p<0.05). In the GAgP group, IL-6 GG genotype and G allele frequency were higher than in the control group. GCF IL-6 level was also significantly lower at 6-week in the GAgP group. Higher GCF IL-10 levelswere observed in patients carrying the IL-6 GG genotype than in those carrying the GC+CC genotype at baseline. In conclusion, IL-6(-174) and IL-10(-597) gene polymorphisms were found to be associated with GAgP and genotype distribution did not affect the outcome of non-surgical periodontal therapy, while patients with IL-6(-174) GG genotype had higher levels of GCF IL-10 levels. PMID- 28099579 TI - Factors for determining dental anxiety in preschool children with severe dental caries. AB - The aim of this study was to assess the clinical and socioeconomic indicators associated with dental anxiety in preschool children with severe dental caries. A total of 100 children between 3 and 5 years of age were selected during a dental screening procedure. The selection criteria were having at least one tooth with dental caries and a visible pulpal involvement, ulceration, fistula, and abscess (PUFA) index of >=1 in primary teeth. Before the clinical examination or any treatment procedure was performed, we evaluated the children's dental anxiety using the Facial Image Scale (FIS). Parents completed a questionnaire on socioeconomic conditions, which included the family structure, number of siblings, parental level of education, and family income. A dentist blinded to FIS and socioeconomic data performed the clinical examination. Poisson regressions associate clinical and socioeconomic conditions with the outcome. Most of the children (53%) experienced extensive dental caries (dmf-t >= 6), and all children had severe caries lesions, with a PUFA index of >=1 in 41% and that of >=2 in 59%. The multivariate adjusted model showed that older children (4-5 year old) experienced lower dental anxiety levels compared with younger children (3-year old) (RR = 0.35; 95%CI: 0.17-0.72 and RR = 0.18; 95%CI: 0.04-0.76, respectively), and children with three or more siblings were associated with higher levels of dental anxiety (RR = 2.27; 95%CI: 1.06-4.87). Older age is associated with low dental anxiety, and more number of siblings is associated with high dental anxiety in preschool children, whereas the severity or extent of dental caries is not associated with dental anxiety. PMID- 28099580 TI - Risk factors, hyposalivation and impact of xerostomia on oral health-related quality of life. AB - To determine xerostomia-related frequency, factors, salivary flow rates and Oral Health-Related Quality of Life (OHRQoL) of patients attending the Universidad Andres Bello Dental School Clinic, in the city of Vina del Mar, Chile. The study involved 566 patients assessed with xerostomia, based on a single standardized questionnaire. The severity and impact of xerostomia on OHRQoL was assessed using a visual analogue scale (VAS) and the short version of the Oral Health Impact Profile Questionnaire (OHIP-14sp), respectively. Stimulated and non-stimulated salivary flow rates were obtained from a sample of patients. Xerostomia was reported in 61 patients (10.8%), comprising 50 women (83.3%) and 11 men (16.7%) (p < 0.013). The prevalence was 13% among the women and 6.1% among the men. Gender, age and medication were found to be independent risk factors for the development of xerostomia. Hyposalivation was found in 10 of the 35 patients with xerostomia (28.6%) and in 2 patients without it (p < 0.011). Patients with xerostomia had a reduced OHRQoL, compared with patients without xerostomia, as shown by the total OHIP-14sp score (p < 0.001). Xerostomia was a common, potentially debilitating condition with a major impact on the OHRQoL of a patient population attending a university-based dental clinic. Hyposalivation was present in almost 30% of the patients who complained of xerostomia. It is important that general dentists be aware of this condition, so that they can provide patients with a good diagnosis, treatment and follow-up. PMID- 28099581 TI - Minimal residual disease detection in Tunisian B-acute lymphoblastic leukemia based on immunoglobulin gene rearrangements. AB - IGH gene rearrangement and IGK-Kde gene deletion can be used as molecular markers for the assessment of B lineage acute lymphoblastic leukemia (B-ALL). Minimal residual disease detected based on those markers is currently the most reliable prognosis factor in B-ALL. The aim of this study was to use clonal IGH/IGK-Kde gene rearrangements to confirm B-ALL diagnosis and to evaluate the treatment outcome of Tunisian leukemic patients by monitoring the minimal residual disease (MRD) after induction chemotherapy. Seventeen consecutive newly diagnosed B-ALL patients were investigated by multiplex PCR assay and real time quantitative PCR according to BIOMED 2 conditions. The vast majority of clonal VH-JH rearrangements included VH3 gene. For IGK deletion, clonal VK1f/6-Kde recombinations were mainly identified. These rearrangements were quantified to follow-up seven B-ALL after induction using patient-specific ASO. Four patients had an undetectable level of MRD with a sensitivity of up to 10-5. This molecular approach allowed identification of prognosis risk group and adequate therapeutic decision. The IGK-Kde and IGH gene rearrangements might be used for diagnosis and MRD monitoring of B-ALL, introduced for the first time in Tunisian laboratories. PMID- 28099582 TI - A simple and efficient method for poly-3-hydroxybutyrate quantification in diazotrophic bacteria within 5 minutes using flow cytometry. AB - The conventional method for quantification of polyhydroxyalkanoates based on whole-cell methanolysis and gas chromatography (GC) is laborious and time consuming. In this work, a method based on flow cytometry of Nile red stained bacterial cells was established to quantify poly-3-hydroxybutyrate (PHB) production by the diazotrophic and plant-associated bacteria, Herbaspirillum seropedicae and Azospirillum brasilense. The method consists of three steps: i) cell permeabilization, ii) Nile red staining, and iii) analysis by flow cytometry. The method was optimized step-by-step and can be carried out in less than 5 min. The final results indicated a high correlation coefficient (R2=0.99) compared to a standard method based on methanolysis and GC. This method was successfully applied to the quantification of PHB in epiphytic bacteria isolated from rice roots. PMID- 28099584 TI - Iodine-131 treatment of thyroid cancer cells leads to suppression of cell proliferation followed by induction of cell apoptosis and cell cycle arrest by regulation of B-cell translocation gene 2-mediated JNK/NF-kappaB pathways. AB - Iodine-131 (131I) is widely used for the treatment of thyroid-related diseases. This study aimed to investigate the expression of p53 and BTG2 genes following 131I therapy in thyroid cancer cell line SW579 and the possible underlying mechanism. SW579 human thyroid squamous carcinoma cells were cultured and treated with 131I. They were then assessed for 131I uptake, cell viability, apoptosis, cell cycle arrest, p53 expression, and BTG2 gene expression. SW579 cells were transfected with BTG2 siRNA, p53 siRNA and siNC and were then examined for the same aforementioned parameters. When treated with a JNK inhibitor of SP600125 and 131I or with a NF-kappaB inhibitor of BMS-345541 and 131I, non-transfected SW579 cells were assessed in JNK/NFkappaB pathways. It was observed that 131I significantly inhibited cell proliferation, promoted cell apoptosis and cell cycle arrest. Both BTG2 and p53 expression were enhanced in a dose-dependent manner. An increase in cell viability by up-regulation in Bcl2 gene, a decrease in apoptosis by enhanced CDK2 gene expression and a decrease in cell cycle arrest at G0/G1 phase were also observed in SW579 cell lines transfected with silenced BTG2 gene. When treated with SP600125 and 131I, the non-transfected SW579 cell lines significantly inhibited JNK pathway, NF-kappaB pathway and the expression of BTG2. However, when treated with BMS-345541 and 131I, only the NF-kappaB pathway was suppressed. 131I suppressed cell proliferation, induced cell apoptosis, and promoted cell cycle arrest of thyroid cancer cells by up regulating B-cell translocation gene 2-mediated activation of JNK/NF-kappaB pathways. PMID- 28099583 TI - Swimming training prevents coronary endothelial dysfunction in ovariectomized spontaneously hypertensive rats. AB - Estrogen deficiency and hypertension are considered major risk factors for the development of coronary heart disease. On the other hand, exercise training is considered an effective form to prevent and treat cardiovascular diseases. However, the effects of swimming training (SW) on coronary vascular reactivity in female ovariectomized hypertensive rats are not known. We aimed to evaluate the effects of SW on endothelium-dependent coronary vasodilation in ovariectomized hypertensive rats. Three-month old spontaneously hypertensive rats (SHR, n=50) were divided into four groups: sham (SH), sham plus swimming training (SSW), ovariectomized (OVX), and ovariectomized plus swimming training (OSW). The SW protocol (5 times/week, 60 min/day) was conducted for 8 weeks. The vasodilatory response was measured in isolated hearts in the absence and presence of a nitric oxide synthase inhibitor (L-NAME, 100 uM). Cardiac oxidative stress was evaluated in situ by dihydroethidium fluorescence, while the expression of antioxidant enzymes (SOD-2 and catalase) and their activities were assessed by western blotting and spectrophotometry, respectively. Vasodilation in SHR was significantly reduced by OVX, even in the presence of L-NAME, in conjunction with an increased oxidative stress. These effects were prevented by SW, and were associated with a decrease in oxidative stress. Superoxide dismutase 2 (SOD-2) and catalase expression increased only in the OSW group. However, no significant difference was found in the activity of these enzymes. In conclusion, SW prevented the endothelial dysfunction in the coronary bed of ovariectomized SHR associated with an increase in the expression of antioxidant enzymes, and therefore may prevent coronary heart disease in hypertensive postmenopausal women. PMID- 28099585 TI - Impact of Different Normality Thresholds for 24-hour ABPM at the Primary Health Care Level. AB - Background:: Hypertension is an important risk factor for cardiovascular outcomes. Primary health care (PHC) physicians should be prepared to act appropriately in the prevention of cardiovascular risk factors. However, the rates of patients with control of blood pressure (BP) remain low. The impact of the reclassification of high BP by 24-hour ambulatory BP monitoring (ABPM) can lead to different medical decisions in PHC. Objective:: To evaluate the agreement between the BP measured by a conventional method by PHC physicians and by 24-hour ABPM, considering different BP normal thresholds for the 24-hour ABPM according to the V Brazilian ABPM Guidelines and the European Society of Hypertension Guidelines. Methods:: A cross-sectional study including 569 hypertensive patients. The BP was initially measured by the PHC physicians and, later, by 24 hour ABPM. The BP measurements were obtained independently between the two methods. The therapeutic targets for the conventional BP followed the guidelines by the Eighth Joint National Committee (JNC 8), the V ABPM Brazilian Guidelines, and the 2013 European Hypertension Guidelines. Results:: There was an accuracy of 54.8% (95% confidence interval [95%CI] 0.51 - 0.58%) for the BP measured with the conventional method when compared with the 24-hour ABPM, with a sensitivity of 85% (95%CI 80.8 - 88.6%), specificity of 31.9% (95%CI 28.7 - 34.7%), and kappa value of 0.155, when considering the European Hypertension Guidelines. When using more stringent thresholds to characterize the BP as "normal" by ABPM, the accuracy was 45% (95%CI 0.41 - 0.47%) for conventional measurement when compared with 24-hour ABPM, with a sensitivity of 86.7% (95%CI 0.81 - 0.91%), specificity of 29% (95%CI 0.26 - 0.30%), and kappa value of 0.103. Conclusion:: The BP measurements obtained by PHC physicians showed low accuracy when compared with those obtained by 24-hour ABPM, regardless of the threshold set by the different guidelines. Fundamentos:: A hipertensao arterial sistemica e um fator de risco importante para desfechos cardiovasculares. Medicos da atencao primaria a saude (APS) devem estar preparados para atuar adequadamente na prevencao de fatores de risco cardiovascular. No entanto, as taxas de pacientes com pressao arterial (PA) controlada continuam baixas. O impacto da reclassificacao do diagnostico de hipertensao pela utilizacao da monitorizacao ambulatorial da PA (MAPA) de 24 horas pode levar a diferentes decisoes medicas na APS. Objetivo:: Avaliar a concordancia entre as PAs medidas por metodo convencional por medicos da APS e por MAPA de 24 horas, considerando diferentes limiares de normalidade para a MAPA de 24 horas de acordo com as recomendacoes da V Diretriz Brasileira de MAPA e da Diretriz da Sociedade Europeia de Hipertensao. Metodos:: Estudo transversal com 569 pacientes hipertensos. A PA foi medida inicialmente por medicos da APS e, posteriormente, pela MAPA de 24 horas. As medidas foram obtidas de forma independente entre os dois metodos. Os alvos terapeuticos para a PA convencional seguiram as orientacoes do Eighth Joint National Committee (JNC 8), das V Diretrizes Brasileiras de MAPA e das Diretrizes Europeias de Hipertensao de 2013. Resultados:: Foi observada uma acuracia de 54,8% (intervalo de confianca de 95% [IC95%] 0,51 - 0,58%) para a PA aferida de forma convencional quando comparada a obtida com a MAPA de 24 horas, alem de uma sensibilidade de 85% (IC95% 80,8 - 88,6%), especificidade de 31,9% (IC95% 28,7 - 34,7%) e kappa de 0,155, quando consideradas as Diretrizes Europeias de Hipertensao. Quando utilizados limiares mais rigidos para caracterizar a PA como "normal" pela MAPA, foi identificada uma acuracia de 45% (IC95% 0,41 - 0,47%) pela medida convencional quando comparada a obtida pela MAPA de 24 horas, alem de uma sensibilidade de 86,7% (IC95% 0,81 - 0,91%), especificidade de 29% (IC95% 0,26 - 0,30%) e kappa de 0,103. Conclusao:: As medidas de PA avaliadas pelos medicos da APS apresentaram baixa acuracia quando comparadas as medidas pela MAPA de 24 horas, independente do limiar utilizado pelas diferentes diretrizes. PMID- 28099586 TI - Serotoninergic Modulation of Basal Cardiovascular Responses and Responses Induced by Isotonic Extracellular Volume Expansion in Rats. AB - Background:: Isotonic blood volume expansion (BVE) induced alterations of sympathetic and parasympathetic activity in the heart and blood vessels, which can be modulated by serotonergic pathways. Objective:: To evaluate the effect of saline or serotonergic agonist (DOI) administration in the hypothalamic paraventricular nucleus (PVN) on cardiovascular responses after BVE. Methods:: We recorded pulsatile blood pressure through the femoral artery to obtain the mean arterial pressure (MAP), systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR) and the sympathetic-vagal ratio (LF/HF) of Wistar rats before and after they received bilateral microinjections of saline or DOI into the PVN, followed by BVE. Results:: No significant differences were observed in the values of the studied variables in the different treatments from the control group. However, when animals are treated with DOI followed by BVE there is a significant increase in relation to the BE control group in all the studied variables: MBP (114.42+/ 7.85 vs 101.34+/-9.17); SBP (147.23+/-14.31 vs 129.39+/-10.70); DBP (98.01 +/ 4.91 vs 87.31+/-8.61); HR (421.02+/-43.32 vs 356.35+/-41.99); and LF/HF ratio (2.32+/-0.80 vs 0.27+/-0.32). Discussion:: The present study showed that the induction of isotonic BVE did not promote alterations in MAP, HR and LF/HF ratio. On the other hand, the injection of DOI into PVN of the hypothalamus followed by isotonic BVE resulted in a significant increase of all variables. Conclusion:: These results suggest that serotonin induced a neuromodulation in the PVN level, which promotes an inhibition of the baroreflex response to BVE. Therefore, the present study suggests the involvement of the serotonergic system in the modulation of vagal reflex response at PVN in the normotensive rats. Fundamento:: Expansao de volume extracelular (EVEC) promove alteracoes da atividade simpatica e parassimpatica no coracao e vasos sanguineos, os quais podem ser moduladas por vias serotoninergicas. Objetivo:: Avaliar o efeito da administracao de salina ou agonista serotoninergico (DOI) nos nucleos paraventriculares hipotalamico (NPV) sobre respostas cardiovasculares apos EVEC. Metodos:: Foram obtidos registros da pressao arterial pulsatil, por meio da arteria femoral, para obtencao dos valores da pressao arterial media (PAM), sistolica (PAS), diastolica (PAD), frequencia cardiaca (FC) e razao simpatico-vagal (LF/HF) de ratos Wistar antes e apos receberem microinjecoes bilaterais no NPV de salina ou DOI seguida de EVEC. Resultados:: Nao foram observadas diferencas significativas dos valores das variaveis estudadas nos diferentes tratamentos do grupo controle. Entretanto, quando os animais sao tratados com DOI seguida de EVEC ocorre aumento significativo em relacao ao grupo controle com EVEC em todas as variaveis estudadas: PAM (114,42+/-7,85 vs 101,34+/-9,17), PAS (147,23+/-14,31 vs 129,39+/ 10,70), PAD (98,01 +/-4,91 vs 87,31+/-8,61), FC (421,02+/-43,32 vs 356,35+/ 41,99) e LF/HF (2,32+/-0,80 vs 0,27+/-0,32). Discussao:: O presente estudo mostrou que a inducao de EVEC isotonica nao promoveu alteracoes na PAM, PAD, PAS, FC e LF/HF. Por outro lado, os animais que receberam microinjecao de DOI no NPV seguida de EVEC apresentaram aumento significativo de todas as variaveis. Conclusao:: Esses resultados sugerem que a serotonina exerce uma neuromodulacao em nivel do NPV, e essa promove uma inibicao da resposta barorreflexa frente a EVEC. Assim, o presente trabalho sugere o envolvimento serotoninergico na neuromodulacao no nivel do NPV na resposta reflexa vagal em ratos normotensos. PMID- 28099587 TI - Non-Invasive Ventilation in Patients with Heart Failure: A Systematic Review and Meta-Analysis. AB - Non-invasive ventilation (NIV) may perfect respiratory and cardiac performance in patients with heart failure (HF). The objective of the study to establish, through systematic review and meta-analysis, NIV influence on functional capacity of HF patients. A systematic review with meta-analysis of randomized studies was carried out through research of databases of Cochrane Library, SciELO, Pubmed and PEDro, using the key-words: heart failure, non-invasive ventilation, exercise tolerance; and the free terms: bi-level positive airway pressure (BIPAP), continuous positive airway pressure (CPAP), and functional capacity (terms were searched for in English and Portuguese) using the Boolean operators AND and OR. Methodological quality was ensured through PEDro scale. Weighted averages and a 95% confidence interval (CI) were calculated. The meta-analysis was done thorugh the software Review Manager, version 5.3 (Cochrane Collaboration). Four randomized clinical trials were included. Individual studies suggest NIV improved functional capacity. NIV resulted in improvement in the distance of the six minute walk test (6MWT) (68.7m 95%CI: 52.6 to 84.9) in comparison to the control group. We conclude that the NIV is an intervention that promotes important effects in the improvement of functional capacity of HF patients. However, there is a gap in literature on which are the most adequate parameters for the application of this technique. Resumo A ventilacao nao invasiva (VNI) pode aperfeicoar o desempenho cardiaco e respiratorio dos pacientes com insuficiencia cardiaca (IC). O objetivo do estudo e estabelecer, por meio de revisao sistematica e meta-analise, a influencia da VNI na capacidade funcional (CF) de individuos com IC. Foi realizada uma revisao sistematica com meta-analise de estudos randomizados atraves da pesquisa nas bases de dados Biblioteca Cochrane, SciELO, Pubmed e PEDro, utilizando-se as palavras-chave: insuficiencia cardiaca, ventilacao nao invasiva, tolerancia ao exercicio; e os termos livres: pressao positiva em dois niveis nas vias aereas (BIPAP), pressao positiva continua em vias aereas (CPAP), CF e seus correlatos na lingua inglesa, com a combinacao dos operadores booleanos (AND e OR). A avaliacao da qualidade metodologica se deu via escala de PEDro. Foram calculadas as medias ponderadas e o intervalo de confianca (IC) de 95%. Meta-analise foi realizada com software Review Manager versao 5.3 (Colaboracao Cochrane). Foram incluidos quatro ensaios clinicos randomizados. Estudos individuais sugerem que a VNI contribuiu para melhora da CF. VNI resultou em melhora na distancia do teste de caminhada de seis minutos (TC6) (68,7m 95% IC: 52,6 a 84,9) comparado ao grupo controle. Concluimos que a VNI e uma intervencao que promove efeitos importantes na melhora da CF de pacientes com IC. No entanto, ha uma lacuna na literatura de quais sao os parametros mais adequados para aplicacao dessa tecnica. PMID- 28099588 TI - Dobutamine Stress Echocardiography Safety in Chagas Disease Patients. AB - Background:: A few decades ago, patients with Chagas disease were predominantly rural workers, with a low risk profile for obstructive coronary artery disease (CAD). As urbanization has increased, they became exposed to the same risk factors for CAD of uninfected individuals. Dobutamine stress echocardiography (DSE) has proven to be an important tool in CAD diagnosis. Despite being a potentially arrhythmogenic method, it is safe for coronary patients without Chagas disease. For Chagas disease patients, however, the indication of DSE in clinical practice is uncertain, because of the arrhythmogenic potential of that heart disease. Objectives:: To assess DSE safety in Chagas disease patients with clinical suspicion of CAD, as well as the incidence of arrhythmias and adverse events during the exam. Methods:: Retrospective analysis of a database of patients referred for DSE from May/2012 to February/2015. This study assessed 205 consecutive patients with Chagas disease suspected of having CAD. All of them had their serology for Chagas disease confirmed. Results:: Their mean age was 64+/-10 years and most patients were females (65.4%). No patient had significant adverse events, such as acute myocardial infarction, ventricular fibrillation, asystole, stroke, cardiac rupture and death. Regarding arrhythmias, ventricular extrasystoles occurred in 48% of patients, and non-sustained ventricular tachycardia in 7.3%. Conclusion:: DSE proved to be safe in this population of Chagas disease patients, in which no potentially life-threatening outcome was found. Fundamento:: Ate poucas decadas atras, os pacientes chagasicos eram predominantemente trabalhadores rurais, com baixo perfil de risco para doenca obstrutiva coronaria. Com a crescente urbanizacao, passaram a ter os mesmos fatores de risco para doenca aterosclerotica que individuos nao infectados. O ecocardiograma sob estresse com dobutamina (EED) e uma importante ferramenta no diagnostico de coronariopatia. E referido, porem, como um metodo potencialmente arritmogenico, mas seguro, em pacientes coronarianos nao chagasicos. Entretanto, ha inseguranca na pratica clinica de indica-lo no paciente chagasico, devido ao potencial arritmogenico ja intrinseco nesta cardiopatia. Objetivos:: Analisar a seguranca do EED em uma populacao de chagasicos com suspeita clinica de coronariopatia. Metodos:: Analise retrospectiva de um banco de dados de pacientes encaminhados para a realizacao do EED entre maio/2012 e fevereiro/2015. Avaliou se pacientes consecutivos portadores de doenca de Chagas e com suspeita de coronariopatia. Confirmou-se a sorologia para doenca de Chagas em todos os pacientes. Resultados:: A media etaria dos 205 pacientes analisados foi de 64 +/- 10 anos, sendo a maioria do sexo feminino (65,4%). Nenhum paciente apresentou eventos adversos significativos, como infarto agudo do miocardio, fibrilacao ventricular, assistolia, acidente vascular encefalico, ruptura cardiaca ou morte. Quanto as arritmias, extrassistoles ventriculares frequentes ocorreram em 48% dos pacientes, taquicardia ventricular nao sustentada em 7,3%, bigeminismo em 4,4%, taquicardia supraventricular e taquicardia ventricular sustentada em 1% e fibrilacao atrial em 0,5%. Conclusao:: O EED mostrou ser um exame seguro nessa populacao de pacientes chagasicos, onde nenhum desfecho grave foi encontrado. PMID- 28099589 TI - Which Coronary Lesions Are More Prone to Cause Acute Myocardial Infarction? AB - Background:: According to common belief, most myocardial infarctions (MIs) are due to the rupture of nonsevere, vulnerable plaques with < 70% obstruction. Data from recent trials challenge this belief, suggesting that the risk of coronary occlusion is, in fact, much higher after severe stenosis. The aim of this study was to investigate whether or not acute ST-elevation MIs result from high-grade stenoses by evaluating the presence of coronary collateral circulation (CCC). Methods:: We retrospectively included 207 consecutive patients who had undergone primary percutaneous coronary intervention for acute ST-elevation MI. Collateral blood flow distal to the culprit lesion was assessed by two investigators using the Rentrop scoring system. Results:: Out of the 207 patients included in the study, 153 (73.9%) had coronary collateral vessels (Rentrop 1-3). The Rentrop scores were 0, 1, 2, and 3 in 54 (26.1%), 50 (24.2%), 51 (24.6%), and 52 (25.1%) patients, respectively. Triglycerides, mean platelet volume (MPV), white cell (WBC) count, and neutrophil count were significantly lower in the group with good collateral vessels (p = 0.013, p = 0.002, p = 0.003, and p = 0.021, respectively). Conclusion:: More than 70% of the patients with acute MI had CCC with Rentrop scores of 1-3 during primary coronary angiography. This shows that most cases of acute MI in our study originated from underlying high-grade stenoses, challenging the common believe. Higher serum triglycerides levels, greater MPV, and increased WBC and neutrophil counts were independently associated with impaired development of collateral vessels. Fundamento:: Ha uma crenca geral de que a maioria dos infartos agudos do miocardio (IAM) ocorrem devido a ruptura de placas vulneraveis, nao graves, com obstrucao < 70%. Dados de ensaios recentes desafiam esta crenca, sugerindo que o risco de oclusao coronariana e, na realidade, muito maior apos estenose grave. O objetivo deste estudo foi investigar se a presenca ou nao de IAM com supradesnivel do segmento ST resulta de estenoses de alto grau atraves da avaliacao da presenca de circulacao colateral coronariana (CCC). Metodos:: Nos incluimos retrospectivamente 207 pacientes consecutivos submetidos a intervencao coronariana percutanea primaria devido a ocorrencia de IAM com supradesnivel do segmento ST. O fluxo sanguineo colateral distal a lesao culpada foi avaliado por dois investigadores com utilizacao do sistema de escores de Rentrop. Resultados:: Dos 207 pacientes incluidos no estudo, 153 (73,9%) apresentavam vasos coronarianos colaterais (Rentrop 1-3). Os escores Rentrop foram de 0, 1, 2 e 3 em 54 (26,1%), 50 (24,2%), 51 (24,6%) e 52 (25,1%) pacientes, respectivamente. Triglicerides, volume plaquetario medio (VPM), contagem de celulas brancas (CCB) e contagem de neutrofilos estiveram significativamente mais baixos no grupo com bons vasos colaterais (p = 0,013, p = 0,002, p = 0,003 e p = 0,021, respectivamente). Conclusao:: Mais de 70% dos pacientes com IAM apresentaram CCC com escores de Rentrop de 1-3 durante angiografia coronariana primaria. Isto demonstra que a maioria dos casos de IAM em nosso estudo originou a partir de estenoses subjacentes de alto grau, contrariamente a sabedoria comum. Niveis sericos mais elevados de triglicerides, maior VPM e elevacao na CCB e na contagem de neutrofilos estiveram independentemente associados com comprometimento no desenvolvimento de vasos colaterais. PMID- 28099590 TI - Palmar hyperhidrosis: clinical, pathophysiological, diagnostic and therapeutic aspects. AB - Palmar hyperhidrosis affects up to 3% of the population and inflict significant impact on quality of life. It is characterized by chronic excessive sweating, not related to the necessity of heat loss. It evolves from a localized hyperactivity of the sympathetic autonomic system and can be triggered by stressful events. In this study, the authors discuss clinical findings, pathophysiological, diagnostic and therapeutic issues (clinical and surgical) related to palmar hyperhidrosis. PMID- 28099591 TI - Analysis of effectiveness of a surgical treatment algorithm for basal cell carcinoma. AB - BACKGROUND:: Surgical excision is the treatment of choice for basal cell carcinoma and micrographic surgery considered the gold standard, however not yet used routinely worldwide available, as in Brazil. Considering this, a previously developed treatment guideline, which the majority of tumors were treated by conventional technique (not micrographic) was tested. OBJECTIVE:: To establish the recurrence rate of basal cell carcinomas treated according to this guideline. METHOD:: Between May 2001 and July 2012, 919 basal cell carcinoma lesions in 410 patients were treated according to the proposed guideline. Patients were followed up and reviewed between September 2013 and February 2014 for clinical, dermatoscopic and histopathologic detection of possible recurrences. RESULTS:: After application of exclusion criteria, 520 lesions were studied, with 88.3% primary and 11.7% recurrent tumors. Histological pattern was indolent in 85.5%, 48.6% were located in high risk areas and 70% small tumors. Only 7.3% were treated by Mohs micrographic surgery. The recurrence rate, in an average follow up period of 4.37 years, was 1.3% for primary and 1.63% for recurrent tumors. Study limitations: unicenter study, with all patients operated on by the same surgeon. CONCLUSION:: The treatment guideline utilized seems a helpful guide for surgical treatment of basal cell carcinoma, especially if micrographic surgery is not available. PMID- 28099592 TI - Epidemiological analysis of occupational dermatitis notified in Brazil in the period 2007 to 2012. AB - BACKGROUND:: Occupational dermatitis affects the quality of life and productivity of workers. Studies on the subject are scarce in Brazil. It is estimated that the disease is underreported and that many affected patients do not seek health care. OBJECTIVES:: To conduct an epidemiological analysis of occupational dermatitis notified via SINAN in Brazil from January 2007 to December 2012; evaluate the profile of patients assisted; and check the main etiological agents involved. METHODS:: We analyzed the compulsory notification forms of cases of occupational dermatitis filled nationwide during January 2007 to December 2012. RESULTS:: During the study period 3027 cases of occupational dermatitis were notified in Brazil. In 61.4% of cases patients were men aged between 35-49 years (39.6%). The most described etiological agent was chromium (13.9%). The location of the body most affected was the hands, with 28.4% of cases. The construction sector is implicated in 28.7% of cases and domestic services by 18%. Allergic contact dermatitis is the most prevalent occupational dermatitis (20.6%) and the region with the highest number of notifications was the Midwest, with 376.4 cases per million inhabitants. CONCLUSIONS:: The profile of patients most affected by occupational dermatitis in Brazil during the study period was: men with elementary school, aged between 20 and 49 years old and working in the construction industry. The most common occupational dermatitis were allergic contact dermatitis caused by chromium after years of exposure, being the hands and head the parts of the body most affected. PMID- 28099593 TI - Angiosarcoma in HIV-negative patients is not associated with HHV-8. AB - BACKGROUND:: Angiosarcoma is an aggressive, malignant neoplasm of vascular or lymphatic origin. Herpes virus 8 (HHV-8) is a member of the herpes family with a tropism for endothelial cells and it has been proven to induce vascular neoplasms, such as Kaposi's sarcoma. The role of HHV-8 in the pathogenesis of angiosarcoma has not been well defined. OBJECTIVE:: To investigate the relationship between the presence of HHV-8 and angiosarcoma. METHODS:: In this study, the team investigated the relationship between the presence of HHV-8, as determined by polymerase chain reaction, and angiosarcoma, using samples from patients with epidemic Kaposi's sarcoma as controls. RESULTS:: While all control cases with epidemic Kaposi's sarcoma were positive for HHV-8, none of the angiosarcoma cases was. CONCLUSION:: These findings support most previous studies that found no association between HHV-8 and angiosarcoma. PMID- 28099594 TI - Diagnosis and underdiagnosis of comorbidities in psoriasis patients - need for a multidisciplinary approach. AB - BACKGROUND:: Psoriasis is an immune-mediated disease that manifests predominantly in the skin, although systemic involvement may also occur. Although associated comorbidities have long been recognized and despite several studies indicating psoriasis as an independent risk factor for cardiovascular events, little has been done in general medical practice regardind screening. In the United States, less than 50% of clinicians are aware of these recommendations. OBJECTIVE:: To identify the prevalence of these comorbidities in 296 patients followed up at a university dermatology clinic. METHODS:: Systematically investigated comorbidity frequencies were compared with general practitioners' registry frequencies. Clinical features correlated with comorbidities were also investigated. RESULTS:: High prevalences of systematically investigated comorbidities such as hypertension (30%) and dyslipidemia (26.5%) were documented. Conversely, data from general practitioners' records showed that 33% of dyslipidemia cases were undiagnosed and indicated possible underdiagnosis of some comorbidities. Furthermore, an association was found between: the number of comorbidities and psoriasis duration, age and high body mass index an association was found between the number of comorbidities and psoriasis duration, age, high body mass index, waist circumference or waist-to-hip ratio. (p<0.05). CONCLUSION:: Disease duration, age and high body mass index, waist circumference or waist-to-hip ratio are possible criteria for choosing which patients should be screened for comorbidities. Underdiagnosis of comorbidities by general practitioners highlights the need for a multidisciplinary approach in psoriasis management. PMID- 28099595 TI - Exome sequence analysis of Kaposiform hemangioendothelioma: identification of putative driver mutations. AB - BACKGROUND:: Kaposiform hemangioendothelioma is a rare, intermediate, malignant tumor. The tumor's etiology remains unknown and there are no specific treatments. OBJECTIVE:: In this study, we performed exome sequencing using DNA from a Kaposiform hemangioendothelioma patient, and found putative candidates for the responsible mutations. METHOD:: The genomic DNA for exome sequencing was obtained from the tumor tissue and matched normal tissue from the same individual. Exome sequencing was performed on HiSeq2000 sequencer platform. RESULTS:: Among oncogenes, germline missense single nucleotide variants were observed in the TP53 and APC genes in both the tumor and normal tissue. As tumor-specific somatic mutations, we identified 81 candidate genes, including 4 nonsense changes, 68 missense changes and 9 insertions/deletions. The mutations in ITGB2, IL-32 and DIDO1 were included in them. CONCLUSION:: This is a pilot study, and future analysis with more patients is needed to clarify: the detailed pathogenesis of this tumor, the novel diagnostic methods by detecting specific mutations, and the new therapeutic strategies targeting the mutation. PMID- 28099596 TI - Impact of chronic urticaria on the quality of life of patients followed up at a university hospital. AB - BACKGROUND:: Chronic urticaria is a debilitating disease that considerably affects health-related quality of life, and the Chronic Urticaria Quality of Life Questionnaire is the only questionnaire specifically designed for its evaluation. OBJECTIVE:: To evaluate the quality of life of patients with chronic urticaria, using the Brazilian Portuguese version of the Chronic Urticaria Quality of Life Questionnaire. METHODS:: The Chronic Urticaria Quality of Life Questionnaire was self-administered in 112 chronic urticaria patients and disease activity was assessed through the Urticaria Activity Score. Clinical and socio-demographic characteristics of patients were studied, such as: age, sex, etiologic diagnosis of chronic urticaria, duration of disease and Urticaria Activity Score. RESULTS:: The population studied was composed 85.72% of women with a mean age of 46 years (18-90), while the median disease duration period was 10 years (3 months-60 years). Regarding the etiologic diagnosis, 48.22% had chronic spontaneous urticaria; 22.32% associated with inducible urticaria, 28.57% with chronic autoimmune urticaria, and 23.21% had physical urticaria alone. Disease activity evaluated using the Urticaria Activity Score was 1.04 +/- 1.61 (0-6). The total score for the Chronic Urticaria Quality of Life Questionnaire was 36 (0-100) and dimension I (sleep/mental status/eating) had a greater impact on quality of life. The items with the highest mean scores were nervousness and shame over lesions, while the items with the lowest scores were lip swelling and limitations on sporting activities. CONCLUSIONS:: Chronic urticaria compromises patients' quality of life, mainly those with more severe disease or who are diagnosed with chronic autoimmune urticaria. PMID- 28099597 TI - Correlation between the histopathology of chronic urticaria and its clinical picture. AB - BACKGROUND:: Chronic urticaria is characterized by transient, pruritic lesions of varying sizes, with central pallor and well-defined edges, with disease duration longer than six weeks. Its cellular infiltrate consists of neutrophils, lymphocytes and eosinophils. There is a subgroup of patients with eosinophilic or neutrophilic urticaria, resistant to the treatment with antihistamines, but that respond to a combination of antihistamine with other drugs. OBJECTIVE:: To evaluate the present infiltration in chronic urticaria biopsies and correlate it with the clinical disease activity and response to treatment. METHODS:: Forty-one patients with chronic urticaria were classified according to the score of severity of the disease, response to treatment and type of perivascular infiltrate. Inflammatory infiltrates were divided in eosinophilic (46.30%), neutrophilic and mixed. RESULTS:: An association was found between the eosinophilic infiltrate and clinical scores of greater severity (p = 0.002). CONCLUSION:: This association shows that the eosinophilic inflammatory infiltrates denote high clinical activity, which means more severe and exuberant clinical pictures of the disease. PMID- 28099598 TI - Dermatoscopy-guided therapy of pigmented basal cell carcinoma with imiquimod. AB - BACKGROUND:: Dermatoscopy is a non-invasive diagnostic tool used to examine skin lesions with an optical magnification. It has been suggested as a useful tool for monitoring therapeutic response in lentigo maligna patients treated with imiquimod. OBJECTIVE:: To examine the accuracy of dermatoscopy as a tool to monitor the therapeutic response of pigmented basal cell carcinoma treated with imiquimod. METHOD:: The authors designed a prospective study. Patients with pigmented basal cell carcinoma were included and data regarding the dermatoscopy features were collected following the Menzies criteria, prior to initiating the imiquimod treatment. Subsequent dermatoscopic evaluations were performed at weeks 4 and 8, following imiquimod discontinuation. RESULTS:: Twenty lesions were included. The most common pigmented dermatoscopy features were large blue-grey ovoid nests (80%), followed by blue-grey globules (50%) and leaf-like areas (30%). No spoke wheel areas were observed. In 17 out of 20 patients, a response was noted during the first evaluation at 4 weeks, while the clearance was noted at the second check-up after 8 weeks. In two patients, the clearance was found at the initial evaluation at 4 weeks, while in one patient, the response remained unchanged. Blue-grey globules were the fastest to exhibit clearance (50% at week 4), followed by leaf-like areas (15%) and large blue-grey ovoid nests (6.25%). CONCLUSION:: According to our results, dermatoscopic evaluation enhances the accuracy in the assessment of the clinical response to imiquimod in pigmented basal cell carcinoma. PMID- 28099599 TI - Knowledge, beliefs, and perceptions of Turkish vitiligo patients regarding their condition. AB - BACKGROUND:: Vitiligo is an acquired pigmentary skin disorder that affects 0.5% to 2.0% of the population. OBJECTIVE:: Patients' knowledge, opinions, and attitudes about vitiligo were evaluated. METHODS:: The team conducted a cross sectional, descriptive, prospective study between June 2014 and May 2015. The study included 100 patients aged over 12 years who were diagnosed with vitiligo. A questionnaire including items on knowledge, opinions, and beliefs about vitiligo and the Illness Perception Questionnaire (IPQ) were filled out by the patients, and the results were analyzed. RESULTS:: In total, 100 (58 female, 42 male) patients were included in the study. Of them, 74% knew the name of their disease, 90% thought that vitiligo was not contagious, 48% reported that they obtained information on the disease from a doctor, and 69% believed they had adequate information on vitiligo. Eighty percent reported no negative effects from vitiligo on relationships with friends or family. It was believed that stress, excessive sun exposure, and heredity were causes of vitiligo, according to 84%, 37%, and 22% of the patients, respectively. Thirty-six patients (36%) believed that their illness was a serious disease and 35% deemed that it did not have a major impact on their lives. CONCLUSIONS:: Our results show that vitiligo patients were generally highly aware of their condition. The disease did not negatively affect patient opinions or attitudes about vitiligo. The authors believe that improving patient-physician communication will impact positively on the course of the disease. PMID- 28099600 TI - DHEA and frontal fibrosing alopecia: molecular and physiopathological mechanisms. AB - The transforming growth factor-beta 1 (TGFbeta1) promotes fibrosis, differentiating epithelial cells and quiescent fibroblasts into myofibroblasts and increasing expression of extracellular matrix. Recent investigations have shown that PPAR (peroxisome proliferator-activated receptor*) is a negative regulator of fibrotic events induced by TGFbeta1. Dehydroepiandrosterone (DHEA) is an immunomodulatory hormone essential for PPAR functions, and is reduced in some processes characterized by fibrosis. Although scarring alopecia characteristically develops in the female biological period in which occurs decreased production of DHEA, there are no data in the literature relating its reduction to fibrogenic process of this condition. This article aims to review the fibrogenic activity of TGFbeta1, its control by PPAR and its relation with DHEA in the frontal fibrosing alopecia. PMID- 28099602 TI - Psychotropics in different causes of itch: systematic review with controlled studies. AB - Among the wide range of symptoms neglected or resistant to conventional treatments in clinical practice, itch is emerging gradually as a theme to be studied. Itch complaints and the negative effects in the quality of life are observed in several medical fields. Although the partially obscure pathophysiology, some researchers decided to check and test the use of psychotropic drugs in resistant itch to conventional topical treatments and antihistamines. The objective of this study was to evaluate scientific evidence in psychotropic use in the treatment of itch of various causes. This is a systematic review of scientific literature. The following databases were used: PubMed, Web of Science, Scopus and Scielo. Randomized controlled trials that should focus on treatment with psychotropic drugs of pruritus of various causes were the inclusion criteria. All articles were analyzed by the authors, and the consensus was reached in cases of disagreement. Fifteen articles were included after analysis and selection in databases, with the majority of clinical trials focusing on psychopharmacological treatment of itch on account of chronic kidney disease. Clinical trials with psychotropic drugs mostly indicated significant improvement in the itching. In most trials of chronic kidney disease as basal disease for itch, greater effectiveness was observed with the use of psychotropic drugs compared with placebo or other antipruritic. However, the small amount of controlled trials conducted precludes the generalization that psychiatric drugs are effective for itch of various causes. PMID- 28099603 TI - Squamoid eccrine ductal carcinoma. AB - Squamoid eccrine ductal carcinoma is an eccrine carcinoma subtype, and only twelve cases have been reported until now. It is a rare tumor and its histopathological diagnosis is difficult. Almost half of patients are misdiagnosed as squamous cell carcinoma by the incisional biopsy. We report the thirteenth case of squamoid eccrine ductal carcinoma. Female patient, 72 years old, in the last 6 months presenting erythematous, keratotic and ulcerated papules on the nose. The incisional biopsy diagnosed squamoid eccrine ductal carcinoma. After excision, histopathology revealed positive margins. A wideningmargins surgery and grafting were performed, which again resulted in positive margins. The patient was then referred for radiotherapy. After 25 sessions, the injury reappeared. After another surgery, although the intraoperative biopsy showed free surgical margins, the product of resection revealed persistent lesion. Distinction between squamoid eccrine ductal carcinoma and squamous cell carcinoma is important because of the more aggressive nature of the first, which requires wider margins surgery to avoid recurrence. PMID- 28099601 TI - Psoriasis comorbidities: complications and benefits of immunobiological treatment. AB - During the last decade, different studies have converged to evidence the high prevalence of comorbidities in subjects with psoriasis. Although a causal relation has not been fully elucidated, genetic relation, inflammatory pathways and/or common environmental factors appear to be underlying the development of psoriasis and the metabolic comorbidities. The concept of psoriasis as a systemic disease directed the attention of the scientific community in order to investigate the extent to which therapeutic interventions influence the onset and evolution of the most prevalent comorbidities in patients with psoriasis. This study presents scientific evidence of the influence of immunobiological treatments for psoriasis available in Brazil (infliximab, adalimumab, etanercept and ustekinumab) on the main comorbidities related to psoriasis. It highlights the importance of the inflammatory burden on the clinical outcome of patients, not only on disease activity, but also on the comorbidities. In this sense, systemic treatments, whether immunobiologicals or classic, can play a critical role to effectively control the inflammatory burden in psoriatic patients. PMID- 28099604 TI - Granuloma faciale: clinical, morphological and immunohistochemical aspects in a series of 10 patients. AB - Granuloma faciale is a chronic, benign, cutaneous vasculitis with well established clinical and morphological patterns, but with an unknown etiology. This study describes clinical and pathologic aspects of patients diagnosed with granuloma faciale. The authors analyzed demographic, clinical, morphological and immunohistochemical data from patients with a final diagnosis of granuloma faciale, confirmed between 1998 and 2012. There was a proportional and mixed inflammatory infiltrate, Grenz zones were present in almost all the samples. Immunophenotyping confirmed a higher intensity of T lymphocytes than B lymphocytes in thirteen samples, with a predominance of T CD8 lymphocytes in 64% of cases, in contrast to the literature, which indicates that the major component is T CD4 lymphocytes. All cases were positive for IgG4 but the majority (12/14) had less than 25% of stained cells. The pathogenesis of granuloma faciale remains poorly understood, making studies of morphological and immunohistochemical characterization important to better understand it. PMID- 28099605 TI - Acute localized exanthematous pustulosis caused by cefoperazone and sodium sulbactam. AB - Acute localized exanthematous pustulosis is a localized variant of acute generalized exanthematous pustulosis, which is characterized by the eruption of multiple scattered pustules following drug administration. A 72-year-old woman presented with multiple erythematous pustules on her face, which had appeared two days after using cefoperazone and sodium sulbactam. Histopathological findings showed subcorneal pustules and mixed inflammatory cell infiltration in the dermis. The pustules resolved within about two weeks after the patient discontinued the antibiotics. This report discusses the case of a woman with a cutaneous drug reaction consistent with acute localized exanthematous pustulosis that occurred after cefoperazone and sodium sulbactam were administered. PMID- 28099606 TI - Bacillary angiomatosis with bone invasion. AB - Bacillary angiomatosis is an infection determined by Bartonella henselae and B. quintana, rare and prevalent in patients with acquired immunodeficiency syndrome. We describe a case of a patient with AIDS and TCD4+ cells equal to 9/mm3, showing reddish-violet papular and nodular lesions, disseminated over the skin, most on the back of the right hand and third finger, with osteolysis of the distal phalanx observed by radiography. The findings of vascular proliferation with presence of bacilli, on the histopathological examination of the skin and bone lesions, led to the diagnosis of bacillary angiomatosis. Corroborating the literature, in the present case the infection affected a young man (29 years old) with advanced immunosuppression and clinical and histological lesions compatible with the diagnosis. PMID- 28099607 TI - A single black ulcer in a child with acute lymphocytic leukemia. AB - Ecthyma gangrenosum is an uncommon dermatological manifestation characterized by round, indurated ulcers with a central necrotic black eschar and surrounding erythema. This report describes the case of a 5-year-old girl, affected by acute lymphocytic leukemia, presenting with a black eschar on her right thigh. Such lesions should always be correctly identified to avoid potentially fatal bacteraemia. Furthermore, because of its similar clinical presentation, cutaneous anthrax must be ruled out. PMID- 28099608 TI - Subungual squamous cell carcinoma. AB - Although subungual squamous cell carcinoma is rare, it is the most common primary malignant neoplasms in this location. The higher incidence occurs in the fingernails, but involvement of the toenails is also possible. Subungual squamous cell carcinoma often looks like other more common benign lesions, such as fungal infection, onychomycosis, or viral wart. These factors, together with a general lack of awareness of this disease among physicians, often result in delayed diagnosis. Therefore, it is underdiagnosed, with few reports in the literature. The authors present a case of a man with a diagnosis of subungual squamous cell carcinoma in the hallux, without bone involvement, which was submitted to the appropriate surgical treatment. PMID- 28099609 TI - Premature ventricular contractions associated with isotretinoin use. AB - Isotretinoin has been considered a unique drug for acne treatment. However, it is associated with numerous adverse effects. Isotretinoin can trigger premature ventricular contractions. This report describes a 33-year-old-woman who presented with palpitations for 1 week while undergoing 1-month isotretinoin treatment for mild-moderate facial acne. An electrocardiogram and Holter monitoring showed premature ventricular contractions during isotretinoin (Roaccutane, Roche) treatment. Isotretinoin-related premature ventricular contractions were strongly suggested in this case due to the existence of documented premature ventricular contractions on electrocardiograms and the disappearance of these premature ventricular contractions two weeks after termination of the treatment To the authors' knowledge, there has been 1 reported case of premature ventricular contractions linked to isotretinoin use; this report describes a second such case. PMID- 28099610 TI - Dermatophytosis caused by Microsporum gypseum in infants: report of four cases and review of the literature. AB - Dermatophytosis caused by Microsporum gypseum is rare, especially in infants, with few published cases. Diagnosis in this age group is frequently delayed. We review the literature and report 4 new cases of tinea of glabrous skin caused by M. gypseum mimicking eczema in infants. Considering new and previously reported cases, half of patients were exposed to sand, emphasizing the importance of this transmission vehicle in this age group. In conclusion, although rare, dermatophytosis by M. gypseum should be part of the differential diagnosis of inflammatory dermatosis in infants. A clinical suspicion and the availability of culture are keys to the diagnosis. PMID- 28099611 TI - Norwegian scabies - rare case of atypical manifestation. AB - Human scabies affects all social classes and different races around the world. It is highly contagious, but the exact figures on its prevalence are unknown. A 19 year-old male patient was admitted to the emergency room reporting fever (38 degrees C) and multiple lesions throughout the body, except face, soles, and palms. Lesions were non-pruritic, which hampered the initial diagnostic suspicion. Skin biopsy was performed, and the final diagnosis was crusted scabies (Norwegian). It was concluded that human scabies is a significant epidemic disease, due to its different clinical manifestations, and because it is extremely contagious. PMID- 28099612 TI - Tinea faciei on the right eyebrow caused by Trichophyton interdigitale. AB - Tinea faciei is a relatively uncommon dermatophyte infection entailing atypical clinical symptoms, usually misdiagnosed and treated with corticosteroids. The authors describe a case of tinea faciei on the right eyebrow caused by Trichophyton interdigitale. The patient was an 18-year-old girl, who had an inflammatory plaque with a scaly, pustular surface on the right eyebrow and upper eyelid, which had persisted for over 1 month. She was once misdiagnosed as having eczema and was treated using corticosteroid cream. A diagnosis of tinea faciei was made based on direct microscopy and culture. The sequencing of the nuclear ribosomal ITS region and beta-tubulin gene of the isolate established its T. interdigitale lineage. The patient was cured by treatment with systemic terbinafine in combination with topical application of 1% naftifine-0.25% ketaconazole cream for 2 weeks. PMID- 28099613 TI - Disseminated cryptococcosis with cutaneous involvement in an immunocompetent patient. AB - Cryptococcosis is a fungal infection of opportunistic behavior that is unusual in immunocompetent patients. We report a rare case of disseminated cryptococcosis with cutaneous involvement in an immunocompetent individual. During hospitalization, Cryptococcus gattii was isolated from skin lesions, lung and spinal fluid. The diagnosis of disseminated cryptococcosis was confirmed and treatment was established. The patient showed improvement. Due to the probable clinical severity of the disease and the possibility that skin lesions may be the first manifestation of this illness, prompt diagnosis must be established and treatment provided. PMID- 28099614 TI - Dermoscopy: a useful tool for assisting the diagnosis of Pseudomonas folliculitis. AB - This report describes the usefulness of dermoscopy as a supportive diagnostic tool in a pseudomonas folliculitis case. PMID- 28099615 TI - Do you know this syndrome? Dyspigmentation along the Blaschko lines caused by trisomy 7 mosaicism. AB - Dyspigmentation along the Blaschko lines is strongly suggestive of a mosaic skin disorder. We report a 9-year-old male patient who presented with swirls and streaks of both hypo and hyperpigmentation involving the entire body. Additionally, he had hypertrichosis, musculoskeletal and minor neurodevelopment abnormalities but no intellectual disability. Cultured fibroblast displayed trisomy 7 mosaicism, which can explain this pigmentary phenotype. Widespread dyspigmentation associated with involvement of other organs should prompt systemic examination to detect additional anomalies and genetic evaluation should be considered, even with normal fetal karyotype. PMID- 28099617 TI - Case for diagnosis. Lichen myxedematosus. AB - Scleromyxedema or lichen myxedematosus is a rare papular mucinosis of chronic and progressive course and unknown etiology. It is commonly associated with monoclonal gammopathy and may show extracutaneous manifestations, affecting the heart, lung, kidney, and nerves. The diagnosis is based on four criteria: generalized papular and sclerodermoid lesions; mucin deposition, fibroblast proliferation, and fibrosis in the histopathology; monoclonal gammopathy; and no thyroid disorders. This article reports the case of a scleromyxedema patient with a recent history of acute myocardial infarction and monoclonal gammopathy. PMID- 28099616 TI - Do you know this syndrome? Type 2 benign symmetric lipomatosis (Launois Bensaude). AB - A 57-year-old female showed bulky, loose tumors, which progressively spread to her arms, anterior chest, and back. She reported dysphagia and dyspnea after mild exertion. She denied alcohol consumption. CT scan of her chest showed no internal lesions. Benign symmetric lipomatosis is a rare syndrome, clinically described as multiple nonencapsulated lipomas of various sizes and symmetrical distribution. This syndrome has three known phenotypes; in type 2 (Launois-Bensaude syndrome), lesions occur primarily on the shoulders, upper arms, and chest, and is unrelated to alcoholism. It causes aesthetic deformities and might block the upper airways. Mediastinal invasion might occur as well. PMID- 28099618 TI - Late-onset alopecia areata: descriptive analysis of 30 cases. AB - Alopecia areata is an autoimmune disease characterized by non-scaring hair loss. The onset in over 50-year-old patients is rare and has barely been studied. Cases of this disease have been retrospectively analyzed - according to clinical forms, extension, and associated diseases - to assess alopecia areata characteristics in a group of patients whose disease onset was after the age of 50. 30 patients were studied; a few of them presented with autoimmune-related diseases or family history. The disease onset after the age of 50 seems to have different characteristics from those found in young people. PMID- 28099619 TI - Conservative surgical management of in situ subungual melanoma: long-term follow up. AB - Subungual melanoma represents 20% of all melanomas in Hispanic population. Here, we report the outcome of 15 patients with in situ subungual melanoma treated with resection of the nail unit with a 5-mm margin without amputation, followed up for 55.93 +/- 43.08 months. The most common complications included inclusion cysts and nail spicules. We found no evidence of local or distant recurrences at the last visit of our follow up. Functional outcome was good, with only one patient reporting persistent mild pain. These results support functional, non-amputative surgical management of in situ subungual melanomas. PMID- 28099620 TI - Oral mucosal diseases in children - casuistics from the Department of Dermatology - University of Sao Paulo - Brazil. AB - There are no studies about pediatric oral mucosal diseases performed by dermatologists in Brazil. This study presents the casuistics of oral mucosal diseases in children examined at the Oral Diseases Clinic at the Department of Dermatology - University of Sao Paulo - Brazil. Cases were retrospectively studied from the hospital records from 2003 to 2015. A hundredsix children have been examined. Commoner lesions examined included mucoceles and aphthae. Rare and difficult cases were also seen and have been published; this clinic is based in a tertiary hospital center that deals mostly with complex cases. PMID- 28099621 TI - Scientific production of Brazilian dermatology: analysis of abstracts submitted at the Annual Meeting of the American Academy of Dermatology (2005 to 2013) and those eventually published. AB - In the last decade the presence of Brazilian physicians in International Meetings of Dermatology has been expressive. In parallel it has also been expressive the submission of poster abstracts in those Meetings. Considering the meetings from 2005 to 2013, 379 posters were presented in meetings of the American Academy of Dermatology. Brazilian universities were the origin of 59.9%. The Brazilian Society of Dermatology's recognized residency programs were the origin of 69.9% of the presented posters. Considering the period from 2005 to 2010 (n = 165 posters) the papers effectively published were 19 (11.5%). PMID- 28099622 TI - Finger pad tophi in gout: a rare presentation. PMID- 28099623 TI - Heparin induced bullous hemorrhagic dermatosis at a site distant from the injection. A report of five cases. PMID- 28099624 TI - Hyperpigmentation and chikungunya fever. PMID- 28099625 TI - Changes in melanocytic nevi after treatment with intense pulsed light observed in total body mapping. PMID- 28099626 TI - Vitiligo-specific instrument on quality of life - Brazilian Portuguese version. PMID- 28099627 TI - Iatrogenic Kaposi's sarcoma caused by corticosteroids. PMID- 28099628 TI - Elevated plasma concentrations of S100 calcium-binding protein B and tumor necrosis factor alpha in children with autism spectrum disorders. AB - Objective:: To investigate plasma concentrations of S100B (a calcium-binding protein derived primarily from the glia) and inflammatory cytokines in children with autism and the relationship between S100B and cytokine concentrations. Methods:: Plasma levels of S100B, tumor necrosis factor alpha (TNF-alpha), interferon gamma, interleukin (IL)-1beta, IL-4, IL-6, IL-10, and IL-17A were measured in 40 unmedicated children with autism and 35 normally developing healthy children. The severity of autism was assessed using the Childhood Autism Rating Scale (CARS). Results:: Concentrations of both S100B and TNF-alpha were higher in children with autism before and after adjusting for a priori-selected confounders (age, sex, and body mass index). S100B concentrations were higher in children with severe autism compared to children with mild-moderate autism. However, this association remained as a trend after adjusting for confounders. S100B concentrations correlated positively with TNF-alpha concentrations. Conclusion:: Our findings showing an increase in peripheral concentrations of S100B and TNF-alpha provide limited support to the hypothesis about the roles of altered immune function and S100B in autism spectrum disorder (ASD). Studies of larger numbers of well-characterized individuals with ASD are needed to clarify the potential role of the immune system in the pathophysiology of this disorder. PMID- 28099629 TI - The role of the CNR1 gene in schizophrenia: a systematic review including unpublished data. AB - Objective:: Schizophrenia is a multifactorial disorder. It is known that a combination of extensive multiple common alleles may be involved in its etiology, each contributing with a small to moderate effect, and, possibly, some rare alleles with a much larger effect size. We aimed to perform a systematic review of association studies between schizophrenia (and its subphenotypes) and polymorphisms in the CNR1 gene, which encodes cannabinoid receptors classically implicated in schizophrenia pathophysiology, as well as to present unpublished results of an association study in a Brazilian population. Methods:: Two reviewers independently searched for eligible studies and extracted outcome data using a structured form. Papers were retrieved from PubMed and ISI Web of Knowledge using the search term schizophrenia in combination with CNR1 or CB1 or cannabinoid receptor. Twenty-four articles met our inclusion criteria. We additionally present data from a study of our own comparing 182 patients with schizophrenia and 244 healthy controls. Results:: No consistent evidence is demonstrated. Conclusion:: Some seemingly positive association studies stress the need for further investigations of the possible role of endocannabinoid genetics in schizophrenia. PMID- 28099630 TI - The brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism affects memory performance in older adults. AB - Objective:: Memory impairment is an important contributor to the reduction in quality of life experienced by older adults, and genetic risk factors seem to contribute to variance in age-related cognitive decline. Brain-derived neurotrophic factor (BDNF) is an important nerve growth factor linked with development and neural plasticity. The Val66Met polymorphism in the BDNF gene has been associated with impaired episodic memory in adults, but whether this functional variant plays a role in cognitive aging remains unclear. The purpose of this study was to investigate the effects of the BDNF Val66Met polymorphism on memory performance in a sample of elderly adults. Methods:: Eighty-seven subjects aged > 55 years were recruited using a community-based convenience sampling strategy in Porto Alegre, Brazil. The logical memory subset of the Wechsler Memory Scale-Revised was used to assess immediate verbal recall (IVR), delayed verbal recall (DVR), and memory retention rate. Results:: BDNF Met allele carriers had lower DVR scores (p = 0.004) and a decline in memory retention (p = 0.017) when compared to Val/Val homozygotes. However, we found no significant differences in IVR between the two groups (p = 0.088). Conclusion:: These results support the hypothesis of the BDNF Val66Met polymorphism as a risk factor associated with cognitive impairment, corroborating previous findings in young and older adults. PMID- 28099631 TI - Associations of cerebrovascular metabolism genotypes with neuropsychiatric symptoms and age at onset of Alzheimer's disease dementia. AB - Objective:: To study associations of cerebrovascular metabolism genotypes and haplotypes with age at Alzheimer's disease dementia (AD) onset and with neuropsychiatric symptoms according to each dementia stage. Methods:: Consecutive outpatients with late-onset AD were assessed for age at dementia onset and Neuropsychiatric Inventory scores according to Clinical Dementia Rating scores, apolipoprotein E gene (APOE) haplotypes, angiotensin-converting enzyme gene (ACE) variants rs1800764 and rs4291, low-density lipoprotein cholesterol receptor gene (LDLR) variants rs11669576 and rs5930, cholesteryl ester transfer protein gene (CETP) variants I422V and TaqIB, and liver X receptor beta gene (NR1H2) polymorphism rs2695121. Results:: Considering 201 patients, only APOE-E4 carriers had earlier dementia onset in multiple correlations, as well as less apathy, more delusions, and more aberrant motor behavior. Both ACE polymorphisms were associated with less intense frontally mediated behaviors. Regarding LDLR variants, carriers of the A allele of rs11669576 had less anxiety and more aberrant motor behavior, whereas carriers of the A allele of rs5930 had less delusions, less anxiety, more apathy, and more irritability. CETP variants that included G alleles of I422V and TaqIB were mostly associated with less intense frontally mediated behaviors, while severely impaired carriers of the T allele of rs2695121 had more anxiety and more aberrant motor behavior. Conclusion:: Though only APOE haplotypes affected AD onset, cerebrovascular metabolism genotypes were associated with differences in several neuropsychiatric manifestations of AD. PMID- 28099632 TI - Getting a consensus: advantages and disadvantages of Sepsis 3 in the context of middle-income settings. PMID- 28099633 TI - The implications of intensive care unit capacity strain for the care of critically ill patients. PMID- 28099634 TI - How could we make nutrition in the intensive care unit simple? PMID- 28099635 TI - Currently used dosage regimens of vancomycin fail to achieve therapeutic levels in approximately 40% of intensive care unit patients. AB - Objective:: This study aimed to assess whether currently used dosages of vancomycin for treatment of serious gram-positive bacterial infections in intensive care unit patients provided initial therapeutic vancomycin trough levels and to examine possible factors associated with the presence of adequate initial vancomycin trough levels in these patients. Methods:: A prospective descriptive study with convenience sampling was performed. Nursing note and medical record data were collected from September 2013 to July 2014 for patients who met inclusion criteria. Eighty-three patients were included. Initial vancomycin trough levels were obtained immediately before vancomycin fourth dose. Acute kidney injury was defined as an increase of at least 0.3mg/dL in serum creatinine within 48 hours. Results:: Considering vancomycin trough levels recommended for serious gram-positive infection treatment (15 - 20ug/mL), patients were categorized as presenting with low, adequate, and high vancomycin trough levels (35 [42.2%], 18 [21.7%], and 30 [36.1%] patients, respectively). Acute kidney injury patients had significantly greater vancomycin trough levels (p = 0.0055, with significance for a trend, p = 0.0023). Conclusion:: Surprisingly, more than 40% of the patients did not reach an effective initial vancomycin trough level. Studies on pharmacokinetic and dosage regimens of vancomycin in intensive care unit patients are necessary to circumvent this high proportion of failures to obtain adequate initial vancomycin trough levels. Vancomycin use without trough serum level monitoring in critically ill patients should be discouraged. PMID- 28099636 TI - Use of reactive hyperemia - peripheral arterial tonometry and circulating biological markers to predict outcomes in sepsis. AB - Objective:: To evaluate the usefulness and prognostic value of reactive hyperemia - peripheral arterial tonometry in patients with sepsis. Moreover, we investigated the association of reactive hyperemia - peripheral arterial tonometry results with serum levels of certain inflammatory molecules. Methods:: Prospective study, conducted in an 18-bed mixed intensive care unit for adults. The exclusion criteria included severe immunosuppression or antibiotic therapy initiated more than 48 hours before assessment. We measured the reactive hyperemia - peripheral arterial tonometry on inclusion (day 1) and on day 3. Interleukin-6, interleukin-10, high-mobility group box 1 protein and soluble ST2 levels were measured in the blood obtained upon inclusion. Results:: Seventeen of the 79 patients (21.6%) enrolled were determined to have reactive hyperemia - peripheral arterial tonometry signals considered technically unreliable and were excluded from the study. Thus, 62 patients were included in the final analysis, and they underwent a total of 95 reactive hyperemia - peripheral arterial tonometry exams within the first 48 hours after inclusion. The mean age was 51.5 (SD: 18.9), and 49 (62%) of the patients were male. Reactive hyperemia indexes from days 1 and 3 were not associated with vasopressor need, Sequential Organ Failure Assessment score, Acute Physiology and Chronic Health Evaluation II score, or 28-day mortality. Among the patients who died, compared with survivors, there was a significant increase in the day 3 reactive hyperemia index compared with day 1 (p = 0.045). There was a weak negative correlation between the day 1 reactive hyperemia - peripheral arterial tonometry index and the levels of high mobility group box 1 protein (r = -0.287). Conclusion:: Technical difficulties and the lack of clear associations between the exam results and clinical severity or outcomes strongly limits the utility of reactive hyperemia - peripheral arterial tonometry in septic patients admitted to the intensive care unit. PMID- 28099637 TI - Factors associated with maternal death in an intensive care unit. AB - Objective:: To identify factors associated with maternal death in patients admitted to an intensive care unit. Methods:: A cross-sectional study was conducted in a maternal intensive care unit. All medical records of patients admitted from January 2012 to December 2014 were reviewed. Pregnant and puerperal women were included; those with diagnoses of hydatidiform mole, ectopic pregnancy, or anembryonic pregnancy were excluded, as were patients admitted for non-obstetrical reasons. Death and hospital discharge were the outcomes subjected to comparative analysis. Results:: A total of 373 patients aged 13 to 45 years were included. The causes for admission to the intensive care unit were hypertensive disorders of pregnancy, followed by heart disease, respiratory failure, and sepsis; complications included acute kidney injury (24.1%), hypotension (15.5%), bleeding (10.2%), and sepsis (6.7%). A total of 28 patients died (7.5%). Causes of death were hemorrhagic shock, multiple organ failure, respiratory failure, and sepsis. The independent risk factors associated with death were acute kidney injury (odds ratio [OR] = 6.77), hypotension (OR = 15.08), and respiratory failure (OR = 3.65). Conclusion:: The frequency of deaths was low. Acute kidney injury, hypotension, and respiratory insufficiency were independent risk factors for maternal death. PMID- 28099638 TI - Risk factors for agitation in critically ill patients. AB - Objective:: To evaluate the incidence of agitation in the first 7 days after intensive care unit admission, its risk factors and its associations with clinical outcomes. Methods:: This single-center prospective cohort study included all patients older than 18 years with a predicted stay > 48 hours within the first 24 hours of intensive care unit admission. Agitation was defined as a Richmond Agitation Sedation Scale score >= +2, an episode of agitation or the use of a specific medication recorded in patient charts. Results:: Agitation occurred in 31.8% of the 113 patients. Multivariate analysis showed that delirium [OR = 24.14; CI95% 5.15 - 113.14; p < 0.001], moderate or severe pain [OR = 5.74; CI95% 1.73 - 19.10; p = 0.004], mechanical ventilation [OR = 10.14; CI95% 2.93 - 35.10; p < 0.001], and smoking habits [OR = 4.49; CI95% 1.33 - 15.17; p = 0.015] were independent factors for agitation, while hyperlactatemia was associated with a lower risk [OR = 0.169; CI95% 0.04 - 0.77; p = 0.021]. Agitated patients had fewer mechanical ventilation-free days at day 7 (p = 0.003). Conclusion:: The incidence of agitation in the first 7 days after admission to the intensive care unit was high. Delirium, moderate/severe pain, mechanical ventilation, and smoking habits were independent risk factors. Agitated patients had fewer ventilator-free days in the first 7 days. PMID- 28099639 TI - Failure to activate the in-hospital emergency team: causes and outcomes. AB - Objective:: To determine the incidence of afferent limb failure of the in hospital Medical Emergency Team, characterizing it and comparing the mortality between the population experiencing afferent limb failure and the population not experiencing afferent limb failure. Methods:: A total of 478 activations of the Medical Emergency Team of Hospital Pedro Hispano occurred from January 2013 to July 2015. A sample of 285 activations was obtained after excluding incomplete records and activations for patients with less than 6 hours of hospitalization. The sample was divided into two groups: the group experiencing afferent limb failure and the group not experiencing afferent limb failure of the Medical Emergency Team. Both populations were characterized and compared. Statistical significance was set at p <= 0.05. Result:: Afferent limb failure was observed in 22.1% of activations. The causal analysis revealed significant differences in Medical Emergency Team activation criteria (p = 0.003) in the group experiencing afferent limb failure, with higher rates of Medical Emergency Team activation for cardiac arrest and cardiovascular dysfunction. Regarding patient outcomes, the group experiencing afferent limb failure had higher immediate mortality rates and higher mortality rates at hospital discharge, with no significant differences. No significant differences were found for the other parameters. Conclusion:: The incidence of cardiac arrest and the mortality rate were higher in patients experiencing failure of the afferent limb of the Medical Emergency Team. This study highlights the need for health units to invest in the training of all healthcare professionals regarding the Medical Emergency Team activation criteria and emergency medical response system operations. PMID- 28099640 TI - Cardiopulmonary resuscitation of adults with in-hospital cardiac arrest using the Utstein style. AB - Objective:: The objective of this study was to analyze the clinical profile of patients with in-hospital cardiac arrest using the Utstein style. Methods:: This study is an observational, prospective, longitudinal study of patients with cardiac arrest treated in intensive care units over a period of 1 year. Results:: The study included 89 patients who underwent cardiopulmonary resuscitation maneuvers. The cohort was 51.6% male with a mean age 59.0 years. The episodes occurred during the daytime in 64.6% of cases. Asystole/bradyarrhythmia was the most frequent initial rhythm (42.7%). Most patients who exhibited a spontaneous return of circulation experienced recurrent cardiac arrest, especially within the first 24 hours (61.4%). The mean time elapsed between hospital admission and the occurrence of cardiac arrest was 10.3 days, the mean time between cardiac arrest and cardiopulmonary resuscitation was 0.68 min, the mean time between cardiac arrest and defibrillation was 7.1 min, and the mean duration of cardiopulmonary resuscitation was 16.3 min. Associations between gender and the duration of cardiopulmonary resuscitation (19.2 min in women versus 13.5 min in men, p = 0.02), the duration of cardiopulmonary resuscitation and the return of spontaneous circulation (10.8 min versus 30.7 min, p < 0.001) and heart disease and age (60.6 years versus 53.6, p < 0.001) were identified. The immediate survival rates after cardiac arrest, until hospital discharge and 6 months after discharge were 71%, 9% and 6%, respectively. Conclusions:: The main initial rhythm detected was asystole/bradyarrhythmia; the interval between cardiac arrest and cardiopulmonary resuscitation was short, but defibrillation was delayed. Women received cardiopulmonary resuscitation for longer periods than men. The in hospital survival rate was low. PMID- 28099641 TI - Sepsis-related acute respiratory distress syndrome in children with cancer: the respiratory dynamics of a devastating condition. AB - Objective:: To evaluate the clinical course and respiratory parameters of mechanically ventilated children with cancer suffering from sepsis-related acute respiratory distress syndrome. Methods:: This 2-year prospective, longitudinal, observational cohort study enrolled 29 children and adolescents. Clinical data, measurements of blood gases and ventilation parameters were collected at four different time points. Fluctuations between measurements as well as differences in estimated means were analyzed by linear mixed models in which death within 28 days from the onset of acute respiratory distress syndrome was the primary endpoint. Results:: There were 17 deaths within 28 days of acute respiratory distress syndrome onset and another 7 between 29 - 60 days. Only 5 patients survived for more than 60 days. Nine (31%) patients died as a direct consequence of refractory hypoxemia, and the others died of multiple organ failure and catecholamine-refractory shock. In 66% of the measurements, the tidal volume required to obtain oxygen saturation equal to or above 90% was greater than 7mL/kg. The estimated means of dynamic compliance were low and were similar for survivors and non-survivors but with a negative slope between the first and final measurements, accompanied by a negative slope of the tidal volume for non survivors. Non-survivors were significantly more hypoxemic, with PaO2/FiO2 ratios showing lower estimated means and a negative slope along the four measurements. Peak, expiratory and mean airway pressures showed positive slopes in the non survivors, who also had more metabolic acidosis. Conclusions:: In most of our children with cancer, sepsis and acute respiratory distress syndrome progressed with deteriorating ventilation indexes and escalating organic dysfunction, making this triad nearly fatal in children. PMID- 28099642 TI - Sedation protocols versus daily sedation interruption: a systematic review and meta-analysis. AB - Objective:: The aim of this study was to systematically review studies that compared a mild target sedation protocol with daily sedation interruption and to perform a meta-analysis with the data presented in these studies. Methods:: We searched Medline, Scopus and Web of Science databases to identify randomized clinical trials comparing sedation protocols with daily sedation interruption in critically ill patients requiring mechanical ventilation. The primary outcome was mortality in the intensive care unit. Results:: Seven studies were included, with a total of 892 patients. Mortality in the intensive care unit did not differ between the sedation protocol and daily sedation interruption groups (odds ratio [OR] = 0.81; 95% confidence interval [CI] 0.60 - 1.10; I2 = 0%). Hospital mortality, duration of mechanical ventilation, intensive care unit and hospital length of stay did not differ between the groups either. Sedation protocols were associated with an increase in the number of days free of mechanical ventilation (mean difference = 6.70 days; 95%CI 1.09 - 12.31 days; I2 = 87.2%) and a shorter duration of hospital length of stay (mean difference = -5.05 days, 95%CI -9.98 - 0.11 days; I2 = 69%). There were no differences in regard to accidental extubation, extubation failure and the occurrence of delirium. Conclusion:: Sedation protocols and daily sedation interruption do not appear to differ in regard to the majority of analyzed outcomes. The only differences found were small and had a high degree of heterogeneity. PMID- 28099643 TI - Balanced crystalloids for septic shock resuscitation. AB - Timely fluid administration is crucial to maintain tissue perfusion in septic shock patients. However, the question concerning which fluid should be used for septic shock resuscitation remains a matter of debate. A growing body of evidence suggests that the type, amount and timing of fluid administration during the course of sepsis may affect patient outcomes. Crystalloids have been recommended as the first-line fluids for septic shock resuscitation. Nevertheless, given the inconclusive nature of the available literature, no definitive recommendations about the most appropriate crystalloid solution can be made. Resuscitation of septic and non-septic critically ill patients with unbalanced crystalloids, mainly 0.9% saline, has been associated with a higher incidence of acid-base balance and electrolyte disorders and might be associated with a higher incidence of acute kidney injury. This can result in greater demand for renal replacement therapy and increased mortality. Balanced crystalloids have been proposed as an alternative to unbalanced solutions in order to mitigate their detrimental effects. Nevertheless, the safety and effectiveness of balanced crystalloids for septic shock resuscitation need to be further addressed in a well-designed, multicenter, pragmatic, randomized controlled trial. PMID- 28099645 TI - Mechanical ventilation in Coffin-Lowry syndrome: a case report. AB - We describe a 27-year-old patient with Coffin-Lowry syndrome with severe community pneumonia, septic shock and respiratory failure. We summarize both the mechanical ventilatory assistance and the hospitalization period in the intensive care unit. PMID- 28099644 TI - Use of biomarkers in pediatric sepsis: literature review. AB - Despite advances in recent years, sepsis is still a leading cause of hospitalization and mortality in infants and children. The presence of biomarkers during the response to an infectious insult makes it possible to use such biomarkers in screening, diagnosis, prognosis (risk stratification), monitoring of therapeutic response, and rational use of antibiotics (for example, the determination of adequate treatment length). Studies of biomarkers in sepsis in children are still relatively scarce. This review addresses the use of biomarkers in sepsis in pediatric patients with emphasis on C-reactive protein, procalcitonin, interleukins 6, 8, and 18, human neutrophil gelatinase, and proadrenomedullin. Assessment of these biomarkers may be useful in the management of pediatric sepsis. PMID- 28099646 TI - To: Ralstonia pickettii bacteremia in hemodialysis patients: a report of two cases. PMID- 28099647 TI - Reply to: Ralstonia pickettii bacteremia in hemodialysis patients: a report of two cases. PMID- 28099648 TI - ERRATUM: ERICA: prevalence of metabolic syndrome in Brazilian adolescents. AB - [This corrects the article doi: 10.1590/S01518-8787.2016050006701]. PMID- 28099650 TI - Sexual aggression in the Sao Paulo nightlife scenarios: a public health concern. PMID- 28099649 TI - Revista de Saude Publica: 50 years disseminating the knowledge in nutrition. AB - This work describes and comments on articles in the area of Public Health Nutrition published in Revista de Saude Publica (RSP - Public Health Journal) from 1967 to 2016. We searched in the PubMed database restricted to the periodical "Revista de Saude Publica" and using terms related to key topics in the area of Public Health Nutrition. We retrieved 742 articles and, after exclusion of duplicates and articles unrelated to the subject, we analyzed 441 articles, grouped according to subject: dental caries, anemia, hypovitaminosis A, macro/micronutrients, malnutrition, nutritional assessment, overweight/obesity, food consumption, low birthweight, and breastfeeding. We observed significant increase in the number of articles published and diversification of subjects addressed over the 50 years, representing the consistent development of the scientific field of Nutrition in Brazil. Since its inception, RSP has played an important role in the dissemination of knowledge about the main nutritional issues in Brazil. RESUMO Este trabalho descreve e comenta os artigos na area de Nutricao em Saude Publica, publicados na Revista de Saude Publica (RSP) de 1967 a 2016. Foi realizada busca na base de dados PubMed restrita ao periodico "Revista de Saude Publica" e utilizando termos relacionados com tematicas chaves da area de Nutricao em Saude Publica. Foram recuperados 742 artigos e, apos as exclusoes dos artigos repetidos e daqueles nao relacionados com a tematica, foram analisados 441 artigos, agrupados segundo o tema: carie dental, anemia, hipovitaminose A, macro/micronutrientes, desnutricao, avaliacao do estado nutricional, sobrepeso/obesidade, consumo de alimentos, baixo peso ao nascer, e aleitamento materno. Observou-se incremento significativo no numero de artigos publicados e a diversificacao dos temas tratados ao longo destes 50 anos, retratando o consistente desenvolvimento do campo cientifico da Nutricao no Brasil. Desde seu inicio, a RSP desempenhou importante papel na divulgacao do conhecimento sobre os principais agravos nutricionais no Brasil. PMID- 28099651 TI - Contribution of Oswaldo Paulo Forattini to public health: analysis of scientific production. AB - OBJECTIVE: To analyze the main characteristics of the scientific production of Oswaldo Paulo Forattini, researcher and, for 40 years, editor of Revista de Saude Publica. METHODS: Descriptive study with bibliometric approach conducted in three steps. (1) identification of bibliographic records using the following search strategy: "Oswaldo Paulo Forattini" OR "Forattini OP" OR "Forattini" up information sources Google Scholar, Web of Science, and PubMed, in July 2016, which retrieved 867 records. (2) composition of research corpus, in which we included 351 bibliographic records of articles, books, book chapters, editorials, book reviews, informative notes and annual reports of the RSP and excluded 516 duplicates and acknowledgement notes, obituary notes, and nonretrievable citations. (3) data organization and analysis, in which we built databases for descriptive analysis and development of the MeSH coauthors and terms networks in VOSviewer software. For analysis of editorials, three reviewers read the full text of each editorial and categorized them according to subject, historical context and perspectives, relating them with historical milestones. RESULTS: Forattini's scientific production occurred from 1946 to 2009, most consisting of articles (n = 218; 62.1%), editorials (n = 43; 12.3%), and books (n = 13; 3.7%). The main subjects were Culicidae (36.8%), Triatominae (12.5%), and Epidemiology (10.0%). The coauthors of articles were his professors, colleagues of his generation, and graduate students. His editorials addressed critical reflections on the production of knowledge, research priorities, and factors that contributed to or hindered progress. The scope of subjects is broad, referring to socioeconomic and scientific development, public health issues in developed countries, or global health. CONCLUSIONS: The analysis shows Forattini's commitment with public health, research with vectors, training of researchers, and scientific communication. OBJETIVO: Analisar as principais caracteristicas da producao cientifica de Oswaldo Paulo Forattini, pesquisador e, por 40 anos, editor da Revista de Saude Publica. METODOS: Estudo descritivo com abordagem bibliometrica realizado em tres etapas. (1) Identificacao dos registros bibliograficos, utilizando a seguinte estrategia de busca: "Oswaldo Paulo Forattini" OR "Forattini OP" OR "Forattini O" nas fontes de informacao Google Scholar, Web of Science e PubMed, em julho de 2016, o que recuperou 867 registros. (2) Composicao do corpus da pesquisa, na qual foram incluidos 351 registros bibliograficos de artigos, livros, capitulos de livros, editoriais, resenhas de livros, notas informativas e relatorios anuais da RSP e excluidos 516 duplicatas e notas de agradecimento, notas de obituarios e citacoes nao recuperaveis. (3) Organizacao e analise dos dados, na qual foram construidos bancos de dados para analise descritiva e elaboracao das redes de coautores e de termos do MeSH no software VOSviewer. Para analise dos editoriais, tres revisores leram o texto completo de cada editorial e os categorizaram segundo assunto, contexto historico e perspectivas, relacionando-o com marcos historicos. RESULTADOS: A producao cientifica de Forattini ocorreu de 1946 a 2009, a maioria composta por artigos (n = 218; 62,1%), editoriais (n = 43; 12,3%) e livros (n = 13; 3,7%). Os principais assuntos foram Culicidae (36,8%), Triatominae (12,5%) e Epidemiologia (10,0%). Os coautores dos artigos foram seus mestres, colegas de sua geracao e alunos de pos-graduacao. Seus editoriais abordaram reflexoes criticas sobre a producao de conhecimento, prioridades em pesquisa e fatores que contribuiam ou desfavoreciam o progresso. O escopo dos assuntos e amplo, remetendo ao desenvolvimento cientifico e socioeconomico, questoes de saude publica em paises desenvolvidos ou saude global. CONCLUSOES: A analise mostra o comprometimento de Forattini com a saude publica, na pesquisa com vetores, na formacao de pesquisadores e na comunicacao cientifica. PMID- 28099653 TI - ERRATUM: The genesis of the AIDS policy and AIDS Space in Brazil (1981-1989). AB - [This corrects the article doi: 10.1590/S1518-8787.2016050005801]. PMID- 28099654 TI - Meanings and vulnerability to HIV/AIDS among long-distance truck drivers in Brazil. AB - OBJECTIVE: To understand the meanings assigned by long-distance truck drivers to HIV/AIDS and its transmission and prevention, bearing in mind different contexts of vulnerability. METHODS: Qualitative research with 22 truck drivers. Semi structured interviews and participant observation were conducted in highways of the state of Bahia in 2013. We selected male truck drivers, with one year or more of work experience in long-distance routes. We carried out the thematic analysis of the interviews, to identify different contexts of vulnerability. RESULTS: The results showed that the insertion of truck drivers in contexts of high social vulnerability (poor working conditions, violence on the roads, and use of alcohol and other drugs) along with the advances in access and effectiveness of treatment for AIDS promote a reduced perception of the risk and severity of this disease. In addition, the notion of "risk group" and the symbolic division between "home space" (protected) and "street space" (unprotected) intensified a restricted and specific use of condoms, guided by the opposition between "woman of the street" (unknown women, prostitutes, among others) and "woman of the house" (wives, girlfriends). CONCLUSIONS: The meanings assigned by truckers to AIDS incorporated elements of recent transformations of the expanded social context, such as the development of health technologies (especially anti-retroviral drugs) and the guarantee of free access to treatment in the Brazilian public health system; but also incorporated old elements of social vulnerability context - such as the poor working conditions on Brazilian highways. OBJETIVO: Compreender os significados atribuidos pelos caminhoneiros de rota longa ao HIV/aids e a sua transmissao e prevencao, tendo em vista diferentes contextos de vulnerabilidade. METODOS: Pesquisa qualitativa com 22 caminhoneiros. Foram realizadas entrevistas semi estruturadas e observacao participante em rodovias do estado da Bahia em 2013. Foram selecionados caminhoneiros do sexo masculino, com um ano ou mais de experiencia de trabalho em rotas de longa distancia. Realizou-se analise tematica das entrevistas, orientada para identificacao de diferentes contextos de vulnerabilidade. RESULTADOS: Os resultados mostraram que a insercao dos caminhoneiros em contextos de alta vulnerabilidade social (mas condicoes de trabalho, violencia nas estradas e uso de alcool e outras drogas) e os avancos no acesso e efetividade do tratamento para aids favorecem a minimizacao da percepcao de risco e gravidade dessa doenca. Alem disso, a nocao de "grupo de risco" e a divisao simbolica entre "espaco da casa" (protegido) e "espaco da rua" (desprotegido) intensificaram um uso restrito e especifico do preservativo, orientado pela oposicao entre "mulher do mundo" (desconhecidas, prostitutas, entre outros) e "mulher de casa" (esposas, namoradas). CONCLUSOES: Os significados atribuidos pelos caminhoneiros a aids incorporaram elementos de transformacoes recentes do contexto social ampliado, como o desenvolvimento de tecnologias em saude (com destaque para os antirretrovirais) e a garantia de acesso gratuito ao tratamento no sistema publico de saude no Brasil; mas tambem incorporaram antigos elementos do contexto de vulnerabilidade social - a exemplo das mas condicoes de trabalho nas estradas brasileiras. PMID- 28099652 TI - Path of infectious diseases in Brazil in the last 50 years: an ongoing challenge. AB - In this article, we comment on the main features of infectious diseases in Brazil in the last 50 years, highlighting how much of this path Revista de Saude Publica could portray. From 1967 to 2016, 1,335 articles focusing on infectious diseases were published in Revista de Saude Publica. Although the proportion of articles on the topic have decreased from about 50.0% to 15.0%, its notability remained and reflected the growing complexity of the research required for its control. It is noteworthy that studies design and analysis strategies progressively became more sophisticated, following the great development of epidemiology in Brazil in the recent decades. Thus, the journal has followed the success of public health interventions that permitted to control or eliminate numerous infectious diseases - which were responsible, in the past, for high rates of morbidity and mortality , and also followed the reemergence of diseases already controlled and the emergence of until then unknown diseases, with a strong impact on the Brazilian population, establishing a little predictable and very challenging path. RESUMO Neste artigo, comentamos as principais caracteristicas das doencas infecciosas no Brasil, nos ultimos 50 anos, destacando o quanto a Revista de Saude Publica conseguiu capturar essa trajetoria. De 1967 a 2016, foram publicados 1.335 artigos na Revista de Saude Publica com foco em doencas infecciosas. Ainda que a proporcao de artigos sobre esse tema tenha declinado de cerca de 50,0% para 15,0%, seu destaque se manteve e refletiu a crescente complexidade das pesquisas necessarias para o seu controle. Nota-se que os desenhos dos estudos e as estrategias de analise ganharam progressivamente maior sofisticacao, acompanhando o grande desenvolvimento da epidemiologia no Brasil, nas ultimas decadas. Assim, foi registrado nao apenas o sucesso de intervencoes de saude publica que permitiram o controle ou a eliminacao de inumeras doencas infecciosas responsaveis, no passado, por elevadas taxas de morbimortalidade, como tambem a reemergencia de males ja controlados e o surgimento de doencas ate entao desconhecidas, com forte impacto na populacao brasileira, desenhando uma trajetoria pouco previsivel e muito desafiadora. PMID- 28099655 TI - Assessment on the ownership and use of mosquito nets in Mozambique. AB - OBJECTIVE: To assess the ownership and use of mosquito nets in 2014, in Mozambique. METHODS: This observational and cross-sectional study assessed, in February and March 2015, 69 districts (nine of 11 provinces of Mozambique) that have benefited from the mass distribution of mosquito nets. The Lot Quality Assurance Sampling methodology was used. Each locality was denominated supervision area. The Lot Quality Assurance Sampling opts for a minimum of 19 households (in this case, we decided for a minimum of 100 households per district) from each supervision area to assess an indicator (in this case, two indicators were assessed: ownership and use of mosquito nets). Two questions guided the research: a) received a mosquito net; b) used a mosquito net the night before. RESULTS: A total of 6,725 households were assessed. Eighty three percent of them had received mosquito nets in the campaign. Of the 6,232 respondents, 82.0% said they used mosquito nets the night before. The districts of the provinces with low coverage of ownership and use were Tete (69.5% and 60.0%, respectively), Zambezia (79.0% and 60.0%, respectively), and Gaza (81.6% and 70.7%, respectively). The largest coverage of ownership and use were observed in the districts of Nampula (96.7% and 93.8%, respectively) and Niassa (86.0% and 85.4% respectively). CONCLUSIONS: In the districts assessed, the progression of ownership and use of mosquito nets is satisfactory. Nampula and Niassa are the only provinces where ownership and use are at desired levels. OBJECTIVO: Avaliar a posse e o uso das redes mosquiteiras no ano de 2014 em Mocambique. METODOS: Este estudo observacional transversal avaliou, em fevereiro e marco de 2015, 68 distritos (nove das 11 provincias de Mocambique) que se beneficiaram da distribuicao de redes em massa. Usou-se a metodologia Lot Quality Assurance Sampling. Cada localidade foi designada de area de supervisao. O Lot Quality Assurance Sampling opta por um minimo de 19 agregados familiares (neste caso decidiu-se um minimo de 100 agregados familiares por distrito) de cada area de supervisao, a fim de avaliar um indicador (neste caso dois indicadores foram avaliados: posse e uso de redes mosquiteiras). Duas perguntas nortearam a pesquisa: a) recebeu rede; b) usou rede na noite anterior. RESULTADOS: Foram avaliados 6.725 agregados familiares . Desses, 83,0% tinham recebido redes na campanha. Dos 6.232 inqueridos, 82,0% disseram que usaram na noite anterior. As provincias com distritos com menores coberturas de posse e uso foram Tete (69,5% e 60,0%, respectivamente), Zambezia (79,0% e 60,0%, respectivamente) e Gaza (81,6% e 70,7%, respectivamente). As maiores coberturas de posse e uso foram observadas nos distritos de Nampula (96,7% e 93,8%, respectivamente) e Niassa (86,0% e 85,4%, respectivamente). CONCLUSOES: Nos distritos avaliados, a progressao para a posse e uso de redes mosquiteiras e satisfatoria. Nampula e Niassa sao as unicas provincias onde a posse e o uso estao em niveis desejados. PMID- 28099656 TI - Association between diabetes and tuberculosis: case-control study. AB - OBJECTIVE: To test the association between diabetes and tuberculosis. METHODS: It is a case-control study, matched by age and sex. We included 323 new cases of tuberculosis with positive results for bacilloscopy. The controls were 323 respiratory symptomatic patients with negative bacilloscopy, from the same health services, such as: ambulatory cases from three referral hospitals and six basic health units responsible for the notifications of new cases of tuberculosis in Salvador, Bahia. Data collection occurred between 2008 and 2010. The instruments used were structured interview, including clinical data, capillary blood glucose (during fasting or postprandial), and the CAGE questionnaire for screening of abusive consumption of alcohol. Descriptive, exploratory, and multivariate analysis was performed using conditional logistic regression. RESULTS: The average age of the cases was 38.5 (SD = 14.2) years and of the controls, 38.5 (SD = 14.3) years. Among cases and controls, most subjects (61%) were male. In univariate analysis we found association between the occurrence of diabetes and tuberculosis (OR = 2.37; 95%CI 1.04-5.42), which remained statistically significant after adjustment for potential confounders (OR = 3.12; 95%CI 1.12 7.94). CONCLUSIONS: The association between diabetes and tuberculosis can hinder the control of tuberculosis, contributing to the maintainance of the disease burden. The situation demands increasing early detection of diabetes among people with tuberculosis, in an attempt to improve disease control strategies. OBJETIVO: Testar a associacao entre diabetes e tuberculose. METODOS: Trata-se de estudo caso-controle, pareado por idade e sexo. Foram incluidos 323 casos novos de tuberculose com resultados positivos a baciloscopia. Os controles foram 323 sintomaticos respiratorios com baciloscopia negativa, oriundos dos mesmos servicos de saude dos casos: ambulatorios de tres hospitais de referencia e seis unidades basicas de saude responsaveis pelas notificacoes dos casos novos de tuberculose em Salvador, Bahia. A coleta de dados ocorreu entre 2008 e 2010. Os instrumentos utilizados foram entrevista estruturada, incluindo dados clinicos, glicemia capilar (em jejum ou pos-prandial) e o questionario CAGE para triagem de consumo abusivo de alcool. Foi realizada analise descritiva, exploratoria e multivariada utilizando-se de regressao logistica condicional. RESULTADOS: A media de idade dos casos foi 38,5 (DP = 14,2) anos e dos controles, 38,5 (DP = 14,3) anos. Tanto entre os casos quanto entre os controles, a maioria (61%) dos individuos era do sexo masculino. Na analise univariada, houve associacao entre ocorrencia de diabetes e de tuberculose (OR = 2,37; IC95% 1,04-5,42), que permaneceu estatisticamente significante apos ajuste pelos potenciais confundidores (OR = 3,12; IC95% 1,12-7,94). CONCLUSOES: A associacao entre diabetes e tuberculose pode dificultar o controle da tuberculose, contribuindo para manutencao da elevada carga da doenca. A situacao demanda intensificacao da deteccao precoce de diabetes entre pessoas com tuberculose, na tentativa de maior efetividade das estrategias de controle da doenca. PMID- 28099657 TI - Quality of life and treatment adherence in hypertensive patients: systematic review with meta-analysis. AB - OBJECTIVE: To verify the effects of antihypertensive treatment (pharmacological and non-pharmacological) on the health-related quality of life of individuals with hypertension. METHODS: We conducted a systematic review with meta-analysis using the following databases: IBECS, LILACS, SciELO, Medline, Cochrane, Science Direct, Scopus and the Brazilian Capes Theses and Dissertations Database. The statistical analysis was performed using Review Manager, version 5.2. The average difference was used for the summarization of meta-analytic effect by the fixed effect model. Twenty studies were included. RESULTS: The summarization of the effect showed an average increase of 2.45 points (95%CI 1.02-3.87; p < 0.0008) in the quality of life of individuals adhering to non-pharmacological treatment for arterial hypertension. Adherence to pharmacological treatment indicated an average increase of 9.24 points (95%CI 8.16-10.33; p < 0.00001) in the quality of life of individuals with arterial hypertension. CONCLUSIONS: Non-pharmacological treatment improves the overall quality of life and physical domain of people with arterial hypertension. Adherence to pharmacological treatment has a positive impact on the mental and physical domains of patients, as it did on the overall quality of life score. OBJETIVO: Verificar os efeitos do tratamento anti hipertensivo (farmacologico e nao-farmacologico) na qualidade de vida relacionada a saude de pessoas com hipertensao arterial. METODOS: Foi conduzida revisao sistematica com metanalise utilizando as bases de dados IBECS, Lilacs, SciELO, Medline, Cochrane, Science Direct, Scopus e o banco de teses da Capes. A analise estatistica foi realizada pelo Review Manager versao 5.2. Foi utilizada a diferenca da media na sumarizacao do efeito metanalitico pelo modelo de efeito fixo. Vinte estudos foram incluidos. RESULTADOS: A sumarizacao do efeito mostrou incremento de 2,45 pontos na media (IC95% 1,02-3,87; p < 0,0008) da qualidade de vida em pessoas com adesao ao tratamento nao farmacologico para hipertensao arterial. A adesao ao tratamento farmacologico indicou aumento de 9,24 pontos na media (IC95% 8,16-10,33; p < 0,00001) da qualidade de vida em pessoas com hipertensao arterial. CONCLUSOES: O tratamento nao-farmacologico melhora a qualidade de vida global e o dominio fisico de pessoas com hipertensao arterial. A adesao ao tratamento farmacologico impacta positivamente nos dominios mental, fisico e escore total da qualidade de vida. PMID- 28099658 TI - Background noise analysis in urban airport surroundings of Brazilian cities, Congonhas Airport, Sao Paulo. AB - OBJECTIVE: To perform a quantitative analysis of the background noise at Congonhas Airport surroundings based on large sampling and measurements with no interruption. METHODS: Measuring sites were chosen from 62 and 72 DNL (day-night level) noise contours, in urban sites compatible with residential use. Fifteen sites were monitored for at least 168 hours without interruption or seven consecutive days. Data compilation was based on cross-reference between noise measurements and air traffic control records, and results were validated by airport meteorological reports. Preliminary diagnoses were established using the standard NBR-13368. Background noise values were calculated based on the Sound Exposure Level (SEL). Statistic parameters were calculated in one-hour intervals. RESULTS: Only four of the fifteen sites assessed presented aircraft operations as a clear cause for the noise annoyance. Even so, it is possible to detect background noise levels above regulation limits during periods of low airport activity or when it closes at night. CONCLUSIONS: All the sites monitored showed background noise levels above regulation limits between 7:00 and 21:00. In the intervals between 6:00-6:59 and 21:00-22:59 the noise data, when analyzed with the current airport operational characteristics, still allow the development of additional mitigating measures. OBJETIVO: Avaliar quantitativamente o ruido de fundo no entorno do aeroporto de Congonhas, com base em ampla amostragem e medicoes sem interrupcao. METODOS: Locais de medicao escolhidos a partir de curvas de ruido de 62 e 72 LDN (day-night level), em equipamentos urbanos de uso compativel com o residencial. Quinze locais foram avaliados por mais de 168 horas consecutivas cada um (sete dias). A compilacao baseou-se em cruzamentos de dados do controle de trafego aereo e os resultados foram validados por meio de relatorios meteorologicos do aeroporto. Diagnosticos preliminares foram estabelecidos utilizando a NBR-13368. O ruido de fundo foi calculado com base no Sound Exposure Level (SEL). Os parametros estatisticos foram calculados em intervalos de uma hora. RESULTADOS: Apenas quatro dos 15 locais avaliados apresentaram clara contribuicao da operacao de aeronaves no incomodo. Mesmo assim, e possivel identificar ruido de fundo acima do regulamentar durante os periodos de baixa atividade ou de fechamento do aeroporto durante a noite. CONCLUSOES: Todos os locais avaliados apresentaram ruido de fundo acima do regulamentar entre 7:00h e 21:00h. Nos intervalos entre 6:00h-6:59h e 21:00h 22:59h, os dados de monitoramento, quando analisados em conjunto com as atuais caracteristicas operacionais do aeroporto, ainda possibilitam a elaboracao de medidas mitigadoras adicionais. PMID- 28099659 TI - Factors associated with the use of antihypertensives among seniors. AB - OBJECTIVE: Analyze the use of antihypertensives among seniors and the association with socioeconomic and behavioral characteristics. METHODS: In this seriate cross sectional study, we used data from the Saude, Bem Estar e Envelhecimento study (SABE - Health, Well-being, and Aging), conducted in 2000, 2006, and 2010 in the city of Sao Paulo. Association between the use of antihypertensives and the demographic, behavioral, and socioeconomic characteristics and risk factors was analyzed by using multilevel logistic regression models. RESULTS: We observed increased proportion of use of antihypertensive, from 48.7% in 2000 to 61.3% in 2006, reaching 65.7% in 2010. Among the seniors who made use of this type of medicine, we also observed increased adoption of combined therapy in the period, from 69.9% to 82.6% from 2000 to 2006 and reaching 91.6% in 2010. Multilevel analysis indicated statistically significant increase in use of antihypertensives, even after control by socioeconomic and behavioral characteristics, both in 2006 and in 2010 (OR = 1.90; 95%CI 1.60-2.24 and OR = 1.94; 95%CI 1.62-2.33, respectively). Use of antihypertensives showed positive association with females, higher age group, black skin color, overweight, and smoking history. CONCLUSIONS: High use of antihypertensives and its association with sociodemographic and behavioral characteristics can help guide the discussion of strategies to improve the epidemiological situation, the quality of life, and the distribution of medicines to the elderly population. OBJETIVO: Analisar o uso de medicamentos anti-hipertensivos em idosos e a associacao com caracteristicas socioeconomicas e comportamentais. METODOS: Neste estudo transversal seriado, foram utilizados dados do estudo SABE (Saude, Bem Estar e Envelhecimento), realizado em 2000, 2006 e 2010 no municipio de Sao Paulo. A associacao entre o uso de medicamentos anti-hipertensivos e as caracteristicas demograficas, socioeconomicas comportamentais e fatores de risco foi analisada por meio de modelos de regressao logisticos multinivel. RESULTADOS: Foi observado aumento da proporcao do uso de anti-hipertensivo, de 48,7% em 2000 para 61,3% em 2006, chegando a 65,7% em 2010. Entre os idosos que faziam uso desse tipo de medicamento, tambem foi observado aumento da adocao da terapia combinada no periodo, passando de 69,9% para 82,6% de 2000 a 2006 e alcancando 91,6% em 2010. A analise multinivel indicou aumento estatisticamente significativo do uso de anti-hipertensivos, mesmo apos controle pelas caracteristicas socioeconomicas e comportamentais, tanto em 2006 como em 2010 (OR = 1,90; IC95% 1,60-2,24 e OR = 1,94; IC95% 1,62-2,33, respectivamente). O uso de anti-hipertensivos apresentou associacao positiva com sexo feminino, maior faixa etaria, cor da pele preta, sobrepeso e historico de tabagismo. CONCLUSOES: O uso elevado de anti hipertensivos e sua associacao com as caracteristicas sociodemograficas e comportamentais podem ajudar a orientar a discussao de estrategias para a melhoria do quadro epidemiologico, da qualidade de vida, e da distribuicao de medicamentos para a populacao idosa. PMID- 28099660 TI - Socioeconomic, hygienic, and sanitation factors in reducing diarrhea in the Amazon. AB - OBJECTIVE: To analyze the contributions of the socioeconomic, hygienic, and sanitation improvements in reducing the prevalence of diarrhea in a city of the Amazon. METHODS: In this population-based cross-sectional study, we analyzed data from surveys conducted in the city of Jordao, Acre. In 2005 and 2012, these surveys evaluated, respectively, 466 and 826 children under five years old. Questionnaires were applied on the socioeconomic conditions, construction of houses, food and hygienic habits, and environmental sanitation. We applied Pearson's Chi-squared test and Poisson regression to verify the relationship between origin of water, construction of homes, age of introduction of cow's milk in the diet, place of birth and the prevalence of diarrhea. RESULTS: The prevalence of diarrhea was reduced from 45.1% to 35.4%. We identified higher probability of diarrhea in children who did not use water from the public network, in those receiving cow's milk in the first month after birth, and in those living in houses made of paxiuba. Children born at home presented lower risk of diarrhea when compared to those who were born in hospital, with this difference reversing for the 2012 survey. CONCLUSIONS: Sanitation conditions improved with the increase of bathrooms with toilets, implementation of the Programa de Saude da Familia (PSF - Family Health Program), and water treatment in the city. The multivariate regression model identified a statistically significant association between use of water from the public network, construction of houses, late introduction of cow's milk, and access to health service with occurrence of diarrhea. OBJETIVO: Analisar as contribuicoes das melhorias socioeconomicas, higienicas e de saneamento na reducao da prevalencia de diarreia em uma cidade na Amazonia. METODOS: Neste estudo transversal de base populacional, foram analisados dados dos inqueritos realizados no municipio de Jordao, Acre. Em 2005 e 2012, foram avaliadas, respectivamente, 466 e 826 criancas menores de cinco anos. Foram aplicados questionarios sobre as condicoes socioeconomicas, construcao dos domicilios, habitos higienicos e alimentares e saneamento ambiental. Foi aplicado o teste Qui-quadrado de Pearson e a Regressao de Poisson para verificar a relacao existente entre procedencia da agua, tipo de construcao do domicilio, idade de introducao de leite de vaca na dieta e local de nascimento e a prevalencia de diarreia. RESULTADOS: A prevalencia de diarreia foi reduzida de 45,1% para 35,4%. Foi identificada maior probabilidade de desenvolvimento de diarreia em criancas que nao utilizaram agua da rede publica, as que receberam leite de vaca no primeiro mes apos o nascimento e as residentes em domicilios de paxiuba. As criancas que nasceram no domicilio apresentaram menor risco de diarreia quando comparadas as que nasceram em hospital, com essa diferenca se invertendo para o inquerito de 2012. CONCLUSOES: Ocorreu melhora nas condicoes de saneamento com aumento no numero de banheiro com vasos sanitarios, implantacao do Programa de Saude da Familia e tratamento de agua na sede do municipio. O modelo de regressao multivariada identificou associacao estatisticamente significativa entre utilizacao de agua da rede publica, construcao da moradia, introducao tardia de leite de vaca e acesso a servico de saude com ocorrencia de diarreia. PMID- 28099661 TI - Pharmaceutical lobbying in Brazil: a missing topic in the public health research agenda. AB - In the US, where registration of lobbyists is mandatory, the pharmaceutical industry and private health-care providers spend huge amounts of money seeking to influence health policies and government decisions. In Brazil, where lobbying lacks transparency, there is virtually no data on drug industry expenditure to persuade legislators and government officials of their viewpoints and to influence decision-making according to commercial interests. Since 1990, however, the Associacao da Industria Farmaceutica de Pesquisa (Interfarma - Pharmaceutical Research Industry Association), Brazilian counterpart of the Pharmaceutical Research and Manufacturers of America (PhRMA), main lobbying organization of the US pharmaceutical industry, has played a major role in the advocacy of interests of major drug companies. The main goals of Interfarma lobbying activities are: shortening the average time taken by the Brazilian regulatory agency (ANVISA) to approve marketing authorization for a new drug; making the criteria for incorporation of new drugs into SUS (Brazilian Unified Health System) more flexible and speeding up technology incorporation; changing the Country's ethical clearance system and the ethical requirements for clinical trials to meet the need of the innovative drug industry, and establishing a National Policy for Rare Diseases that allows a prompt incorporation of orphan drugs into SUS. Although lobbying affects community health and well-being, this topic is not in the public health research agenda. The impacts of pharmaceutical lobbying on health policies and health-care costs are of great importance for SUS and deserve to be investigated. PMID- 28099662 TI - Effects of neighborhood socioeconomic status on blood pressure in older adults. AB - OBJECTIVE: To test if the neighborhood socioeconomic status is associated with systolic blood pressure and hypertension in older adults. METHODS: A cross sectional population-based study with a sample of 1,705 older adults from Florianopolis, SC, Southern Brazil. The contextual variable used was the average years of schooling of the head of the household in census tracts. Participants were considered hypertensive when the systolic blood pressure was >= 140 mmHg, diastolic >= 90 mmHg, or both. Additionally, the use of antihypertensive medication was also considered. Data were analyzed by using multilevel models of logistic and linear regression. RESULTS: The average age of the sample was 70.7 years and the average of systolic and diastolic blood pressure was 133.5 mmHg (SD = 20.5 mmHg) and 81.9 mmHg (SD = 12.5 mmHg), respectively. The systolic blood pressure was 4.46 mmHg (95%CI 1.00-7.92) higher and the chance of hypertension was 1.80 (95%CI 1.26-2.57) among those who lived in census tracts with lower level of schooling. When the use of antihypertensive medication was combined with blood pressure levels, none association was found between the outcome and the level of schooling of the census tract. CONCLUSIONS: Analytical models more robust (such as multilevel analysis) in Brazil are still little used, with a small number of articles published. Neighborhood socioeconomic status is associated with systolic blood pressure and the chance of hypertension, regardless of individual characteristics. PMID- 28099663 TI - Primary Health Care: care coordinator in regionalized networks? AB - OBJECTIVE: To analyze the breadth of care coordination by Primary Health Care in three health regions. METHODS: This is a quantitative and qualitative case study. Thirty-one semi-structured interviews with municipal, regional and state managers were carried out, besides a cross-sectional survey with the administration of questionnaires to physicians (74), nurses (127), and a representative sample of users (1,590) of Estrategia Saude da Familia (Family Health Strategy) in three municipal centers of health regions in the state of Bahia. RESULTS: Primary Health Care as first contact of preference faced strong competition from hospital outpatient and emergency services outside the network. Issues related to access to and provision of specialized care were aggravated by dependence on the private sector in the regions, despite progress observed in institutionalizing flows starting out from Primary Health Care. The counter-referral system was deficient and interprofessional communication was scarce, especially concerning services provided by the contracted network. CONCLUSIONS: Coordination capacity is affected both by the fragmentation of the regional network and intrinsic problems in Primary Health Care, which poorly supported in its essential attributes. Although the health regions have common problems, Primary Health Care remains a subject confined to municipal boundaries. OBJETIVO: Analisar o alcance da coordenacao do cuidado pela Atencao Primaria a Saude em tres regioes de saude. METODOS: Trata-se de estudo de caso, com abordagem quantitativa e qualitativa. Foram realizadas 31 entrevistas semiestruturadas com gestores municipais, regionais e estaduais e estudo transversal com aplicacao de questionarios para medicos (74), enfermeiros (127) e amostra representativa de usuarios (1.590) da Estrategia Saude da Familia em tres municipios-sede de regioes de saude do estado da Bahia. RESULTADOS: A funcao de porta de entrada preferencial pela Atencao Primaria a Saude deparava-se com forte concorrencia de servicos ambulatoriais hospitalares e de pronto-atendimento, desarticulados da rede. Problemas de acesso e oferta de atencao especializada eram agravados pela dependencia do setor privado nas regioes, ainda que tenham sido observados avancos na institucionalizacao de fluxos desde a Atencao Primaria a Saude. A contrarreferencia era deficiente e a comunicacao interprofissional escassa, principalmente quando o usuario era atendido na rede contratada ou conveniada. CONCLUSOES: A capacidade de coordenacao mostra-se afetada tanto pela fragmentacao da rede regional, quanto por problemas intrinsecos a Atencao Primaria a Saude, pouco fortalecida em seus atributos essenciais. Apesar de as regioes de saude apresentarem problemas em comum, a Atencao Primaria a Saude continua sendo um tema circunscrito aos limites municipais. PMID- 28099664 TI - Costs of Public Pharmaceutical Services in Rio de Janeiro Compared to Farmacia Popular Program. AB - OBJECTIVE: To analyze the costs of public pharmaceutical services compared to Farmacia Popular Program (Popular Pharmacy Program). METHODS: Comparison between prices paid by Aqui Tem Farmacia Popular Program (Farmacia Popular is available here) with the full costs of medicine provision by the Municipal Health Department of Rio de Janeiro. The comparison comprised 25 medicines supplied by both the municipal pharmaceutical service and Aqui Tem Farmacia Popular Program. Calculating the cost per pharmaceutical unit of each medicine included expenditure by Municipal Health Department of Rio de Janeiro with procurement (price), logistics, and local dispensation. The reference price of medicines paid by Aqui Tem Farmacia Popular was taken from the Brazilian Ministry of Health standard in force in 2012. Comparisons included full reference price; reference price minus 10.0% copayment by users; and maximum reference paid by the Ministry of Health (minus copayment and taxes). Simulations were carried out of the differences between the costs of Municipal Health Department of Rio de Janeiro with the common medicines and those potentially incurred based on the reference price of Aqui Tem Farmacia Popular. RESULTS: The Municipal Health Department of Rio de Janeiro spent R$28,526,526.57 with 25 medicines of the common list in 2012; 58.7% accounted for direct procurement costs. The estimated costs of the Health Department were generally lower than the reference prices of the Aqui Tem Farmacia Popular Program for 20 medicines, regardless of reference prices. The potential costs incurred by Health Department if expenditure of its consumption pattern were based on the reference prices of Aqui Tem Farmacia Popular would be R$124,170,777.76, considering the best scenario of payment by the Brazilian Ministry of Health (90.0% of the reference price, minus taxes). CONCLUSIONS: The difference in costs between public provision by Municipal Health Department of Rio de Janeiro and Farmacia Popular Program indicates that some reference prices could be reviewed aiming at their reduction. OBJETIVO: Analisar custos da assistencia farmaceutica publica frente ao Programa Farmacia Popular. METODOS: Comparacao entre os valores pagos pelo Programa Aqui Tem Farmacia Popular com os custos integrais relativos a provisao de medicamentos pela Secretaria Municipal de Saude do Rio de Janeiro. A comparacao compreendeu 25 medicamentos, comuns tanto a provisao pela assistencia farmaceutica publica municipal quanto pelo Programa Aqui Tem Farmacia Popular. O calculo do custo unitario por unidade farmacotecnica de cada medicamento envolveu os gastos da Secretaria Municipal de Saude com custos de aquisicao (preco), logisticos e com a dispensacao em nivel local. O valor de referencia dos medicamentos pago pelo Aqui Tem Farmacia Popular foi extraido da norma ministerial em vigor em 2012. As comparacoes envolveram o valor de referencia pleno; valor de referencia com desconto dos 10,0% pagos de contrapartida pelos usuarios; e valor de referencia maximo pago pelo Ministerio da Saude (descontados contrapartida e sem impostos).Foram realizadas simulacoes das diferencas entre os gastos da Secretaria Municipal de Saude do Rio de Janeiro com os medicamentos do elenco comum e os que seriam incorridos se esses tivessem sido executados com base no valor de referencia do Aqui Tem Farmacia Popular. RESULTADOS: A Secretaria Municipal de Saude do Rio de Janeiro gastou R$28.526.526,57 com 25 medicamentos do rol comum em 2012; 58,7% corresponderam a custos diretos com a aquisicao dos produtos. Os custos estimados da Secretaria Municipal de Saude do Rio de Janeiro foram, em geral, menores que os valores de referencia do Programa Aqui Tem Farmacia Popular em 20 medicamentos, independentemente dos valores de referencia. Os custos que seriam incorridos pela Secretaria Municipal de Saude do Rio de Janeiro, caso seu padrao de consumo tivesse como valor de pagamento os valores de referencia do Aqui Tem Farmacia Popular seriam de R$124.170.777,76 considerando a melhor situacao de pagamento pelo Ministerio da Saude (90,0% do valor de referencia, com impostos descontados). CONCLUSOES: A diferenca de custos entre a provisao publica pela Secretaria Municipal de Saude do Rio de Janeiro e o Programa Aqui Tem Farmacia Popular sinaliza que alguns valores de referencia poderiam ser objetos de exame para sua reducao. PMID- 28099665 TI - Adherence to dietary recommendations for preschoolers: clinical trial with teenage mothers. AB - OBJECTIVE: To assess the effect of educational dietary intervention offered in the child's first year of life, as well as teenage mothers and grandmothers in carrying out the dietary recommendations at four to seven years. METHODS: Randomized clinical trial initiated in 2006, in Porto Alegre, RS, involving 323 teenage mothers and grandmothers who cohabited. The intervention consisted of six counseling sessions on breastfeeding and healthy complementary feeding. The first session occurred in the maternity ward and the other ones in the households of mothers at seven, 15, 30, 60, and 120 days of the child's life. The information about the child's diet were obtained on a monthly basis in the first six months, every two months in the second half-year, and at four to seven years, using a food frequency questionnaire. To assess the adequacy of food consumption to the recommendations from the Ministry of Health, we elaborated a score system that would reflect the compliance with the Ten Steps for Healthy Toddlers from 2 to 10 Years. The average scores of intervention and control groups were compared using the t-test. RESULTS: Low adherence to recommendations on child nutrition was found in the study population, with no difference in implementation the steps between the groups. The score on the compliance with the steps was similar in both groups (9.6 [SD = 1.63] and 9.3 [SD = 1.60] in the intervention and control groups, respectively) and no influence of the cohabitation with the grandmother was found. CONCLUSIONS: Educational dietary intervention in the first four months of the child's life for teenage mothers and grandmothers had no effect on the compliance with the recommendations at four to seven years of the child's life. OBJETIVO: Avaliar o efeito de intervencao alimentar educativa oferecida, no primeiro ano de vida da crianca, a maes adolescentes e avos maternas, no cumprimento das recomendacoes alimentares aos quatro a sete anos. METODOS: Ensaio clinico randomizado iniciado em 2006, em Porto Alegre, RS, envolvendo 323 maes adolescentes e avos maternas, quando em coabitacao. A intervencao consistiu em seis sessoes de aconselhamento sobre aleitamento materno e alimentacao complementar saudavel. A primeira sessao ocorreu na maternidade e as demais, nos domicilios das maes aos sete, 15, 30, 60 e 120 dias de vida da crianca. As informacoes sobre alimentacao da crianca foram obtidas mensalmente nos primeiros seis meses de vida, a cada dois meses no segundo semestre, e aos quatro a sete anos, por meio de questionario de frequencia alimentar. Para avaliar a adequacao do consumo alimentar as recomendacoes do Ministerio da Saude, elaborou-se um sistema de escore que refletisse o cumprimento dos Dez Passos Para Uma Alimentacao Saudavel Para Criancas de 2 a 10 Anos. As medias dos escores dos grupos intervencao e controle foram comparadas por meio do teste t. RESULTADOS: Houve baixa adesao as recomendacoes sobre alimentacao infantil na populacao estudada, sem diferenca no cumprimento dos passos entre os grupos. O escore relativo ao cumprimento dos passos foi semelhante nos dois grupos (9,6 [DP = 1,63] e 9,3 [DP = 1,60] nos grupos intervencao e controle, respectivamente) e nao houve influencia da coabitacao com a avo materna. CONCLUSOES: Intervencao alimentar educativa nos primeiros quatro meses de vida da crianca para maes adolescentes e avos maternas nao teve efeito no cumprimento das recomendacoes alimentares aos quatro a sete anos de vida. PMID- 28099666 TI - Access to medicines in Brazil based on monetary and non-monetary acquisition data obtained from the 2008/2009 Household Budget Survey. AB - OBJECTIVE: To investigate the access to medicines by Brazilian families by monetary and non-monetary acquisition data. METHODS: This is a cross-sectional study based on data obtained from the 2008/2009 Brazilian Household Budget Survey. The units of assessment were households that participated in the survey and the data on the acquisition of medicines over the 30 days prior to the interviews. The medicines were classified according to the Anatomical Therapeutic Chemical classification system. RESULTS: Acquisition of medicines was reported by 82.9% of Brazilian households, with 2.38 medicines/household, and 0.72 medicine/individual. In the South and Southeast regions, the average acquisition was slightly greater than the national average (2.53 and 2.49, respectively). In 22.3% of Brazilian households, it was reported that a medicine was not acquired due to lack of financial resources, mainly in the North and Northeastern regions, and in rural areas. Approximately 15.0% of medicines were obtained with no costs, 90.1% of them by the Brazilian Unified Health System. The medicines most acquired were those acting on the nervous system (28.8% of Brazilian households), on the cardiovascular system (15.7%), on the digestive tract and metabolism (14.3%), and on the respiratory system (12.1%). Overall, the quantity of medicines acquired was greater in higher socioeconomic classes of the population, with the exception of antiparasitic products, most likely because of the precarious sanitary conditions faced by less privileged social classes. CONCLUSIONS: The acquisition of medicines is a common practice in Brazil, being reported by over 80.0% of the Brazilian households in 2008/2009. Although the data obtained from the Brazilian Household Budget Survey have some limitations, the information obtained in this study can help health authorities to design national and regional policies to guarantee access to these products while promoting their rational use. PMID- 28099667 TI - Clinical-Functional Vulnerability Index-20 (IVCF-20): rapid recognition of frail older adults. AB - OBJECTIVE: To evaluate the adequacy of the Clinical-Functional Vulnerability Index-20, a rapid triage instrument to test vulnerability in Brazilian older adults, for the use in primary health care. METHODS: The study included convenience sample of 397 patients aged older than or equal to 60 years attended at Centro de Referencia para o Idoso (Reference Center for Older Adults) and of 52 older adults the same age attended at the community. The results of the questionnaire, consisting of 20 questions, were compared with those of the Comprehensive Geriatric Assessment, considered a reference for identifying frail older adults. Spearman's correlation was evaluated in the Clinical-Functional Vulnerability Index-20 with the Comprehensive Geriatric Assessment; the validity was verified by the area under the ROC curve; reliability was estimated by the percentage of agreement among evaluators and by the kappa coefficient, both with quadratic weighted. The cut-off point was obtained based on the higher accuracy criterion. Cronbach's alpha, a measure of internal consistency, was estimated. RESULTS: The Spearman's correlation coefficient was high and positive for both groups (0.792 for older adults attended at the Reference Center and 0.305 for older adults from the community [p < 0.001]). The area under the ROC curve for older adults attended at the Reference Center was substantial (0.903). The cut off point obtained was six, and older adults with scores in Clinical-Functional Vulnerability Index-20 above that value had strong possibility of being frail. For older adults from the community, the quadratic weighted agreement among evaluators was 99.5%, and the global quadratic weighted kappa coefficient was 0.94. Cronbach's alpha was high for older adults attended at the Reference Center (0.861) and those attended at the community (0.740). CONCLUSIONS: The Clinical Functional Vulnerability Index-20 questionnaire, in the sample examined, turned out to be positively correlated with the Comprehensive Geriatric Assessment, in addition to the results indicating a high degree of validity and reliability. Thus, the Clinical-Functional Vulnerability Index-20 proves to be viable as a triage instrument in the primary health care that identifies frail older adults (older adults at risk of weakening and frail older adults). OBJETIVO: Avaliar a adequacao do Indice de Vulnerabilidade Clinico-Funcional-20 , instrumento de triagem rapida de vulnerabilidade em idosos brasileiros, para utilizacao pela atencao basica. O estudo incluiu amostra de conveniencia de 397 pacientes com idade maior ou igual a 60 anos atendidos em um Centro de Referencia para o Idoso e de 52 idosos da mesma idade atendidos na comunidade. Os resultados do questionario, constituido por 20 perguntas, foram comparados com aqueles da Avaliacao Geriatrica Ampla, considerada referencia para identificacao do idoso fragil. Foi avaliada a correlacao de Spearman do Indice de Vulnerabilidade Clinico-Funcional-20 com a Avaliacao Geriatrica Ampla; a validade foi verificada pela area sob a curva ROC; a confiabilidade foi estimada pelo percentual de concordancia entre avaliadores e coeficiente kappa, ambos com ponderacao quadratica. Obteve-se ponto de corte com base no criterio de maior acuracia. O alfa de Cronbach, medida de consistencia interna, foi calculado. O coeficiente de correlacao de Spearman foi elevado e positivo em ambos os grupos (0,792 para idosos atendidos no Centro de Referencia para o Idoso e 0,305 para idosos da comunidade [p < 0,001]). A area sob a curva ROC para idosos atendidos no Centro de Referencia para o Idoso foi substancial (0,903). O ponto de corte obtido foi seis e idosos com pontuacao no Indice de Vulnerabilidade Clinico-Funcional-20 acima desse valor tinham forte possibilidade de serem frageis. Para idosos da comunidade, a concordancia ponderada quadratica entre avaliadores foi 99,5% e o coeficiente kappa ponderado quadratico global, 0,94. O alfa de Cronbach foi elevado para idosos atendidos no Centro de Referencia para o Idoso (0,861) e da comunidade (0,740). CONCLUSOES: O questionario do Indice de Vulnerabilidade Clinico-Funcional-20, na amostra analisada, mostrou ser positivamente correlacionado com a Avaliacao Geriatrica Ampla, alem de os resultados indicarem alto grau de validade e confiabilidade. Assim, o Indice de Vulnerabilidade Clinico-Funcional-20 se mostra viavel como instrumento de rastreio na atencao basica que identifica o idoso com fragilidade (idoso em risco de fragilizacao e idoso fragil). PMID- 28099668 TI - Developing Better Pneumococcal Vaccines for Adults. PMID- 28099669 TI - Predatory Publication: The Conference Version. PMID- 28099670 TI - The Updated Nursing Professional Development Scope and Standards of Practice. AB - The third edition of Nursing Professional Development: Scope and Standards of Practice was released in July 2016. This article summarizes the changes to the foundational document that describes the nursing professional development specialty. J Contin Educ Nurs. 2017;48(1):5-7. PMID- 28099671 TI - Critical Thinking as a Leadership Attribute. AB - Leaders are tasked with making decisions that have substantial impact on an organization's well-being. Decision making requires critical thinking and requisite action taking. The nature of critical thinking and how professional development educators can strengthen this attribute are presented. J Contin Educ Nurs. 2017;48(1):9-11. PMID- 28099672 TI - If You Give a Nurse a Cookie: Sharing Teaching Strategies for Nurse Educator Development. AB - Nurse educators often do not have time or a space to discuss ideas about effective teaching. To address this issue, an instructor at one school of nursing initiated Cookie Swap, a bimonthly, school-wide e-mail featuring stories about teaching strategies and tools used in face-to-face, online, and clinical courses. J Contin Educ Nurs. 2017;48(1):12-13. PMID- 28099673 TI - Accelerated Second-Degree Bachelor of Science in Nursing Graduates' Transition to Professional Practice. AB - BACKGROUND: Few studies have investigated accelerated second baccalaureate degree nursing program (ASBSN) graduates' transition to practice. METHOD: ASBSN graduates (N = 7) were interviewed within 12 to 15 months of graduation about their transition to practice. Using interpretive description, data were analyzed to identify common themes. RESULTS: Eleven themes emerged, including (a) Intense Situations Evoked Strong Emotions, (b) Patient Safety Was Paramount as I Built Confidence, (c) Being on My Own Was Frightening, and (d) The ASBSN Program Mirrored the Intensity of Real-Life Nursing and Helped Me Transition to Practice. CONCLUSION: ASBSN graduates' transition shared similarities with traditional baccalaureate nursing program graduates. They experienced stress, needed support, and contributed to the health care team as they gained confidence. The intensity of the interviewees' ASBSN program prepared them for real-life nursing practice. Graduates' accounts of their transition should persuade staff development professionals to plan postorientation development that considers previous education, work experience, and potential for organizational leadership. J Contin Educ Nurs. 2017;48(1):14-19. PMID- 28099675 TI - A Newly Licensed Nurse Orientation Program Evaluation: Focus on Outcomes. AB - The aim of this project was to evaluate the effectiveness and outcomes of a redesigned newly licensed nurse orientation program. A unique aspect of this program was an end-of-orientation simulated four-patient assignment that was designed to assess five categories of critical thinking: prioritization and delegation, problem recognition, clinical decision making, clinical implementation, and reflection. Newly licensed nurses' critical thinking was measured by the Advisory Board's Critical Thinking Diagnostic tool at 10 weeks, 6 months, and 12 months. Findings showed that in all five categories of critical thinking, a significant increase was found between the 10-week and 6-month evaluation. Two of the categories-prioritization and delegation, and problem recognition-were found to have a significant increase from the 6-month evaluation to the 12-month evaluation. In addition, newly licensed nurses reported improvement in their confidence and in their preparation to work independently. J Contin Educ Nurs. 2017;48(1):22-28. PMID- 28099676 TI - Development of Nurses' Professional Competence Early in Their Career: A Longitudinal Study. AB - BACKGROUND: Research on newly graduated nurses' competence development and associated factors is relatively scarce. METHOD: Data for this longitudinal, descriptive, correlation study were collected during 2012-2014 from 318 Finnish nurses to explore their competence development during the first 3 years after graduation and to estimate the extent to which given work-related factors predicted change in competence. Data were analyzed using NCSS 10 statistical software. RESULTS: Nurses' initially fairly high level of competence showed an increase in the third year, as measured by the Nurse Competence Scale. Empowerment increased minimally, whereas perceptions of practice environment, ethical climate, and occupational commitment decreased. Willingness to leave the profession and dissatisfaction with current job and nursing profession increased. Empowerment, satisfaction with current job and quality of care, time from graduation, and work experience explained 25.6% of the change in competence. CONCLUSION: Competence development was modest but increasing. Willingness to leave the profession was concerning. Factors enhancing or preventing competence development need further studying and developing proactive interventions. J Contin Educ Nurs. 2017;48(1):29-39. PMID- 28099677 TI - Enhancement of Professional Development of Front-Line Nurse Preceptors in a Dedicated Education Unit. AB - BACKGROUND: Dedicated education units (DEUs) have been well established throughout the country as a means of developing clinical skills in nursing students. In a DEU, maintaining an adequate number of well-prepared clinical nurse preceptors is essential for unit sustainability and effective student perception. METHOD: This study was a quasi-experimental design using self reported survey data. A comparison analysis was conducted using the initial results of the Revised Professional Practice Environment (RPPE) survey (i.e., pre participation and no orientation) after completion of an orientation program and participation as preceptor in a DEU. RESULTS: Front-line nurses who participated as preceptors for one semester in a DEU demonstrated statistically significant improvement in two of the eight components of professional practice measured by the RPPE. CONCLUSION: This study lends support to the notion that preceptors do experience improvement in professional practice as a result of participation in a DEU. J Contin Educ Nurs. 2017;48(1):40-46. PMID- 28099678 TI - Using the Teach-Back Method in Patient Education to Improve Patient Satisfaction. AB - BACKGROUND: This quasi-experimental research study used two similar nursing units to test the effects of teach back on Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores. METHOD: A pretest-posttest design tested 24 nurses' knowledge, attitudes, and beliefs about teach back. Education specialists provided a 1-hour teaching session on teach back to all nurses in the intervention unit. RESULTS: A significant improvement in knowledge scores in the pretest-posttest was found using paired t tests (p = .002). Qualitative analysis of nurses' comments demonstrated strong support for teach back in the post-test. The HCAHPS scores were not significantly improved in the intervention unit when compared with the control unit. CONCLUSION: More research needs to be conducted to determine the effectiveness of teach back on HCAHPS scores. J Contin Educ Nurs. 2017;48(1):47-52. PMID- 28099679 TI - Clinical outcomes for couples containing a reciprocal chromosome translocation carrier without preimplantation genetic diagnosis. AB - OBJECTIVE: To evaluate the pregnancy outcomes of couples containing a carrier of a reciprocal chromosome translocation (RCT) after assisted reproductive technology without preimplantation genetic diagnosis. METHODS: A retrospective study was performed using data for couples with an RCT carrier and control couples with a normal karyotype (1:4 ratio) who underwent assisted reproductive technology cycles at a Chinese fertility center in 2010-2011. The embryos were fertilized via in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Only the first pick-up cycles were used for analysis. Clinical variables were compared. RESULTS: Compared with the control group (n=164), the RCT group (n=41) had a marginally lower clinical pregnancy rate (46.3% [19/41] vs 54.3% [89/164]), implantation rate (21.7% [23/106] vs 26.9% [118/438]), multiple gestation pregnancy rate (21.1% [4/19] vs 32.6% [29/89]), and delivery rate (36.6% [15/41] vs 47.6% [78/164]), whereas the spontaneous abortion rate was slightly higher (21.1% [4/19] vs 12.4% [11/89]). However, none of these differences were significant. CONCLUSION: The clinical outcomes for RCT carriers were acceptable after IVF/ICSI without performing preimplantation genetic diagnosis, indicating that this approach might comprise a feasible alternative fertility treatment for RCT carriers. PMID- 28099681 TI - Uptake of cervical cancer screening among the migrant population of Prato Province, Italy. AB - OBJECTIVE: To determine the level of participation in cervical cancer screening among the migrant population of Prato Province, Italy. METHODS: A retrospective cross-sectional study was conducted using data for women aged 25-64 years who were resident in one of the municipalities of Prato Province and had received at least one invitation to undergo a cervical cancer screening test. Data were extracted from both the Local Health Unit Serviceable Registry and cervical cancer screening archives for the period July 1, 2004, to June 30, 2007. RESULTS: Of the 69 459 residents eligible for cervical cancer screening, 7339 (10.6%) did not have Italian citizenship. Adherence with cervical cancer screening among the migrant population was lower than that of the Italian resident population: uptake increased from 52.4% in 2004 to 57.3% in 2007 among the Italian resident population, but decreased from 31.4% to 28.2% among migrants. CONCLUSION: The migrant population of Prato Province has decreased adherence with cervical cancer screening. PMID- 28099680 TI - Novel putative pharmacological therapies to protect the right ventricle in pulmonary hypertension: a review of current literature. AB - Pulmonary hypertension (PH) is defined by elevated mean pulmonary artery pressure following the pathological remodelling of small pulmonary arteries. An increase in right ventricular (RV) afterload results in RV hypertrophy and RV failure. The pathophysiology of PH, and RV remodelling in particular, is not well understood, thus explaining, at least in part, why current PH therapies have a limited effect. Existing therapies mostly target the pulmonary circulation. Because the remodelled RV fails to support normal cardiac function, patients eventually succumb from RV failure. Developing novel therapies that directly target the function of the RV may therefore benefit patients with PH. In the past decade, several promising studies have investigated novel cardioprotective strategies in experimental models of PH. This review aims to comprehensively discuss and highlight these novel experimental approaches to confer, in the long-term, greater health benefit in patients with PH. PMID- 28099682 TI - Feasibility of using pessaries for treatment of pelvic organ prolapse in rural Nepal. AB - OBJECTIVE: To evaluate the acceptability, feasibility, and outcomes of pessary fitting in rural Nepali communities. METHODS: A 1-year prospective cohort study was conducted in the Ramechhap district of Nepal in January 2013-January 2014 among women attending a free gynecology health camp. All women with symptomatic pelvic organ prolapse (POP) were offered ring pessaries. Demographic information was collected and questionnaires on POP were completed. A urogynecologic examination was performed. At the 1-year follow-up, women were questioned on pessary use and underwent an examination. Logistic regression was used to identify associations. RESULTS: In total, 411 women attended the health camps, of whom 142 presented with symptomatic POP. Initial fitting was accomplished for 134 (94.4%) of the women. At the 1-year follow-up, 130 (97.0%) women in the cohort were evaluated, and 72 (55.4%) were still using the pessary. The primary reason for discontinuation was the pessary falling out (35/58, 60.3%). The most common complication was vaginal erosion (18/130, 13.8%), observed exclusively among postmenopausal women. Postmenopausal status was a predictor of continued use (odds ratio 3.12, 95% confidence interval 1.45-6.72; P=0.004). CONCLUSION: Pessaries were found to be an acceptable and feasible option with minimal complications for treating POP in rural Nepal. PMID- 28099683 TI - Angiogenesis mediators in women with idiopathic heavy menstrual bleeding. AB - OBJECTIVE: To assess the relationship between stromal cell-derived factor 1 (SDF 1) and mature endothelial cells in patients with heavy menstrual bleeding (HMB). METHODS: In a prospective observational study, women with idiopathic HMB and control individuals attending Menoufia University Hospital, Egypt, between August 2015 and January 2016 were enrolled. The inclusion criteria were a regular menstrual cycle, a normal coagulation study, and no anomalous ultrasonographic or hysteroscopic findings. Blood samples were collected during different phases of the menstrual cycle (day 5, ovulation, day 24) for measurement of the SDF-1 plasma level (by enzyme-linked immunosorbent assay) and for quantification of mature endothelial cells (by flow cytometry). RESULTS: Overall, 20 women with HMB and 10 control individuals were enrolled. The SDF-1 level was significantly lower in the HMB group than in the control group during all phases of the menstrual cycle (P<=0.05 for all). The percentage of mature endothelial cells was significantly higher in the HMB group than among controls (P<0.001 for all). The SDF-1 level and the percentage of endothelial cells were negatively correlated throughout the cycle (P<0.001 for all). CONCLUSION: Some mediators of angiogenesis, such as SDF-1 and endothelial cells, are disturbed in women with idiopathic HMB. PMID- 28099684 TI - A multistate population-based analysis of linked maternal and neonatal discharge records to identify risk factors for neonatal brachial plexus injury. AB - OBJECTIVE: To evaluate the interaction and contribution of maternal and fetal risk factors associated with neonatal brachial plexus injury (BPI). METHODS: In a case-control study, matched maternal and neonatal discharge records were accessed from US State Inpatient Databases for New Jersey (2010-2012), Michigan (2010 2011), and Hawaii (2010-2011). Univariate and multivariate logistic regressions were used to evaluate associations between risk factors and BPI. Area under the receiver operating characteristic curve was used to build predictive models, including two stratified models evaluating deliveries among obese and diabetic cohorts. RESULTS: Among 376 325 deliveries, BPI was diagnosed in 274 (0.1%). Significant BPI risk factors included maternal obesity (odds ratio [OR] 2.7, 95% confidence interval [CI] 1.7-4.4), maternal diabetes (OR 4.6, 95% CI 3.0-7.0), use of forceps (OR 4.6, 95% CI 2.3-9.0), and vacuum assistance (OR 2.3, 95% CI 1.7-3.3). After adjusting for shoulder dystocia and other predictive factors, cesarean reduced the risk of BPI by 88% (OR 0.1, 95% CI 0.07-0.2). When stratified by obesity and diabetes, the ORs for BPI increased significantly for macrosomia, forceps, and vacuum assistance. CONCLUSION: The analysis confirms and quantifies more precisely the impact of risk factors for neonatal BPI, and provides a reliable basis for evidence-based clinical decision-making models. PMID- 28099685 TI - Meta-analysis comparing the safety of laparoscopic and open surgical approaches for suspected adnexal mass during the second trimester. AB - BACKGROUND: The safety of laparoscopic surgery during the second trimester of pregnancy remains a controversial subject. OBJECTIVES: To compare the safety of laparoscopic surgery and laparotomy for suspected adnexal mass during the second trimester. SEARCH STRATEGY: Articles published in any language prior to April 31, 2016, were retrieved from PubMed, Scopus, EMBSCO, and the Cochrane Library using keywords including pregnant, adnexal mass, laparoscopy, laparotomy, pregnancy outcomes, and surgical outcomes. SELECTION CRITERIA: Randomized and non randomized controlled trials reporting at least one obstetric or surgical outcome were included if they compared laparoscopic surgery and laparotomy for adnexal masses during the second trimester. DATA COLLECTION AND ANALYSIS: Data were independently extracted by two reviewers. Homogeneous data were pooled using a fixed effects model and heterogeneous data were qualitatively analyzed. MAIN RESULTS: Four comparative effectiveness studies including a total of 240 patients were identified. Laparoscopic surgery was associated with a reduced risk of post operative adverse events (relative risk 0.20, 95% confidence interval 0.06-0.72); no difference was recorded in the risk of post-operative spontaneous abortion (P=0.26) or threatened spontaneous abortion (P=0.13). CONCLUSIONS: Laparoscopic surgery could be preferable to laparotomy for suspected adnexal mass during the second trimester of pregnancy. PMID- 28099686 TI - The clinical implementation of primary HPV screening. AB - OBJECTIVE: To evaluate, from a gynecology perspective, the transition from cytology-based HPV screening to primary HPV screening. METHODS: Studies examining switching from cytology-based screening to primary HPV-DNA testing with triaging of patients with positive test results were retrieved and reviewed, with a particular focus on screening in an Italian setting. RESULTS: The increased complexity of patient-management decisions when implementing HPV-based screening was a critical issue discussed in the literature. The change in strategy represents a paradigm shift in moving from a medical perspective of identifying the disease in individual patients, to a public-healthcare perspective of excluding HPV from the healthy population and identifying a small sub-group of individuals at increased risk of HPV. CONCLUSION: With knowledge about HPV screening evolving rapidly, new programs and related algorithms need to be sufficiently flexible to be adjusted according to ongoing research and the validation of new assays. The establishment of a national working group (including epidemiologists, gynecologists, pathologists, and healthcare providers) will be necessary to properly implement and govern this important technical and cultural transition. PMID- 28099687 TI - Comparison of the effect of sperm collection by condom or masturbation on the outcome of in vitro fertilization. PMID- 28099688 TI - Discerning the survival advantage among patients with prostate cancer who undergo radical prostatectomy or radiotherapy: The limitations of cancer registry data. AB - BACKGROUND: The objective of this study was to compare the overall survival of patients who undergo radical prostatectomy or radiotherapy versus noncancer controls to discern whether there is a survival advantage according to prostate cancer treatment and the impact of selection bias on these results. METHODS: A matched cohort study was performed using the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database. In total, 34,473 patients ages 66 to 75 years were identified who were without significant comorbidity, were diagnosed with localized prostate cancer, and received treatment treated with surgery or radiotherapy between 2004 and 2011. These patients were matched to a noncancer control cohort. The rates of all-cause mortality that occurred within the study period were compared. Cox proportional hazards regression analysis was used to identify determinants associated with overall survival. RESULTS: Of 34,473 patients who were included in the analysis, 21,740 (63%) received radiation therapy, and 12,733 (37%) underwent surgery. There was improved survival in patients who underwent surgery (hazard ratio, 0.35; 95% confidence interval, 0.32 0.38) and in those who received radiotherapy (hazard ratio, 0.72; 95% confidence interval, 0.68-0.75) compared with noncancer controls. Overall survival improved significantly in both treatment groups, with the greatest benefit observed among patients who underwent surgery (log rank P < .001). CONCLUSIONS: Population-based data indicated that patients with prostate cancer who received treatment with either surgery or radiotherapy had improved overall survival compared with a cohort of matched noncancer controls. Surgery produce longer survival compared with radiation therapy. These results suggest an inherent selection-bias because of unmeasured confounding variables. Cancer 2017;123:1617-1624. (c) 2017 American Cancer Society. PMID- 28099689 TI - Effectiveness and safety of procalcitonin evaluation for reducing mortality in adults with sepsis, severe sepsis or septic shock. AB - BACKGROUND: Serum procalcitonin (PCT) evaluation has been proposed for early diagnosis and accurate staging and to guide decisions regarding patients with sepsis, severe sepsis and septic shock, with possible reduction in mortality. OBJECTIVES: To assess the effectiveness and safety of serum PCT evaluation for reducing mortality and duration of antimicrobial therapy in adults with sepsis, severe sepsis or septic shock. SEARCH METHODS: We searched the Central Register of Controlled Trials (CENTRAL; 2015, Issue 7); MEDLINE (1950 to July 2015); Embase (Ovid SP, 1980 to July 2015); Latin American Caribbean Health Sciences Literature (LILACS via BIREME, 1982 to July 2015); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; EBSCO host, 1982 to July 2015), and trial registers (ISRCTN registry, ClinicalTrials.gov and CenterWatch, to July 2015). We reran the search in October 2016. We added three studies of interest to a list of 'Studies awaiting classification' and will incorporate these into formal review findings during the review update. SELECTION CRITERIA: We included only randomized controlled trials (RCTs) testing PCT-guided decisions in at least one of the comparison arms for adults (>= 18 years old) with sepsis, severe sepsis or septic shock, according to international definitions and irrespective of the setting. DATA COLLECTION AND ANALYSIS: Two review authors extracted study data and assessed the methodological quality of included studies. We conducted meta-analysis with random-effects models for the following primary outcomes: mortality and time spent receiving antimicrobial therapy in hospital and in the intensive care unit (ICU), as well as time spent on mechanical ventilation and change in antimicrobial regimen from a broad to a narrower spectrum. MAIN RESULTS: We included 10 trials with 1215 participants. Low-quality evidence showed no significant differences in mortality at longest follow-up (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.65 to 1.01; I2 = 10%; 10 trials; N = 1156), at 28 days (RR 0.89, 95% CI 0.61 to 1.31; I2 = 0%; four trials; N = 316), at ICU discharge (RR 1.03, 95% CI 0.50 to 2.11; I2 = 49%; three trials; N = 506) and at hospital discharge (RR 0.98, 95% CI 0.75 to 1.27; I2 = 0%; seven trials; N = 805; moderate-quality evidence). However, mean time receiving antimicrobial therapy in the intervention groups was -1.28 days (95% CI to -1.95 to -0.61; I2 = 86%; four trials; N = 313; very low-quality evidence). No primary study has analysed the change in antimicrobial regimen from a broad to a narrower spectrum. AUTHORS' CONCLUSIONS: Up-to-date evidence of very low to moderate quality, with insufficient sample power per outcome, does not clearly support the use of procalcitonin-guided antimicrobial therapy to minimize mortality, mechanical ventilation, clinical severity, reinfection or duration of antimicrobial therapy of patients with septic conditions. PMID- 28099690 TI - Intimate partner violence and constraints to reproductive autonomy and reproductive health among women seeking abortion services in Bangladesh. AB - OBJECTIVE: To understand intersections between intimate partner violence (IPV) and other constraints to women's reproductive autonomy, and the influence of IPV on reproductive health. METHODS: A secondary analysis examined cross-sectional data from a facility-based sample of women seeking abortion care (for spontaneous or induced abortion) between March 1 and October 31, 2013. Women aged 18-49 years, who received abortion services and selected a short-acting contraceptive method or no contraception completed an interviewer-administered survey after treatment. Adjusted prevalence ratios (aPRs) were calculated for associations between IPV experience and potential constraints to reproductive autonomy and health outcomes. RESULTS: There were 457 participants included in the present analysis and 118 (25.8%) had experienced IPV in the preceding year. IPV was associated with discordance in fertility intentions with husbands/partners and in laws, with in-law opposition to contraception, with perceived religious prohibition of contraception, and with presenting unaccompanied (all P<0.05). IPV was also associated with receiving post-abortion care after an induced abortion compared with accessing legal menstrual regulation, and with the use of medication abortion compared with manual vacuum aspiration (both P<0.05). CONCLUSION: Intimate partner violence was associated with additional constraints on reproductive autonomy from husbands/partners, in-laws, and religious communities. Seeking induced abortion unaccompanied and using medication abortion could be strategies to access abortion covertly among women experiencing IPV. Ensuring women's reproductive freedom requires addressing IPV and related constraints. PMID- 28099691 TI - Prospective observational study comparing traditional laparoscopy and three dimensional laparoscopy in gynecologic surgery. AB - OBJECTIVE: To compare perioperative details among patients who underwent gynecologic surgery between traditional laparoscopy and three-dimensional laparoscopy. METHODS: The present prospective non-randomized study enrolled all consecutive patients diagnosed with gynecologic pathology who underwent laparoscopic surgery at Reina Sofia Hospital, Cordoba, Spain between January 1 and April 30, 2014. Perioperative data, adverse events, and patient satisfaction were compared between patients who underwent treatment with two-dimensional and three-dimensional laparoscopic surgery techniques. RESULTS: The study enrolled 60 consecutive patients; 31 (52%) patients who underwent three-dimensional surgery and 29 (48%) who underwent traditional two-dimensional surgery. No significant differences were observed in the adverse-event rate, operating time, or perioperative parameters. A higher use of sealing devices was recorded among patients who underwent three-dimensional laparoscopy (P=0.021). No difference was recorded in patient satisfaction between the two patient groups. CONCLUSION: Although there was no impact on surgical outcomes, three-dimensional surgery could give a more accurate view of the surgical field. Performing three dimensional surgery could be beneficial for more complex procedures although further comparative studies are required to investigate this hypothesis. PMID- 28099692 TI - A hospital-based study of intimate partner violence during pregnancy. AB - OBJECTIVE: To determine the prevalence and types of intimate partner violence (IPV) during pregnancy, factors linked with IPV, and effects of IPV on maternal fetal outcomes. METHODS: In a prospective observational study at a tertiary care hospital in Delhi, India, 400 women at 20-28 weeks of pregnancy were screened for IPV between December 2013 and April 2015. The women completed a detailed questionnaire and were followed up until delivery. RESULTS: Overall, 49 (12.3%) women experienced IPV during pregnancy. The most prevalent type of IPV was emotional (43/400 [10.7%]), followed by physical (40/400 [10.0%]) and sexual (7/400 [1.8%]). The most prevalent factor triggering IPV was intimate partner's desire for a son (17/49 [34.7%]). Women and their intimate partners were older in the IPV group than in the control group, and duration of marriage was longer (P<0.05 for all). Multigravidity, lower socioeconomic status, low education level of intimate partner, and partners' addiction were more common in the IPV group (P<0.05 for all). Obstetric outcomes were similar in both groups. Depression was diagnosed in 19 (46.3%) women affected by IPV. CONCLUSION: IPV was documented in approximately 12% of participants. Population-based surveys need to be done to investigate further. PMID- 28099693 TI - Factors associated with maternal mortality among patients meeting criteria of severe maternal morbidity and near miss. AB - OBJECTIVE: To evaluate factors associated with maternal death among women experiencing life-threatening conditions during pregnancy, childbirth, or within 42 days of termination of pregnancy. METHODS: A secondary analysis of data prospectively collected in a Brazilian multicenter cross-sectional study between July 2009 and June 2010 was conducted. Women were identified who delivered at a hospital in Ceara and who had potentially life-threatening conditions. Stepwise logistic regression was used to identify factors associated with maternal death. RESULTS: Overall, 941 women were identified and 11 died. Among criteria for severe maternal morbidity, eclampsia (adjusted odds ratio [aOR] 203.70, 95% CI 5.03 to 8254.20; P=0.005) and intensive care unit (ICU) admission (aOR 69.30, 95% CI 6.63-724.26; P<0.001) were risk factors for progression to death, whereas use of magnesium sulfate (aOR 0.002, 95% CI <0.01-0.11; P=0.002) was a protective factor. Meeting near-miss criteria other than survival (aOR 5.96, 95% CI 1.69 20.98; P=0.005) was associated with maternal death. Of criteria for near miss, management criteria were most strongly associated with maternal death: all 11 women who died met some management criteria. CONCLUSION: Among WHO's criteria for severe maternal morbidity and near miss, eclampsia, low oxygen saturation, ICU admission, intubation, mechanical ventilation, and cardiopulmonary resuscitation were most associated with maternal death. Use of magnesium sulfate was a protective factor. PMID- 28099694 TI - Evaluation of sonographic endometrial patterns and endometrial thickness as predictors of ectopic pregnancy. AB - OBJECTIVE: To evaluate whether endometrial patterns and thickness could be used for the prediction of ectopic pregnancy (EP). METHODS: A prospective study was conducted in a center in India between October 2007 and December 2008. It included 100 women with an early pregnancy confirmed by urine pregnancy testing but for whom an intrauterine gestational sac was not visualized on transvaginal ultrasonography (TVS). The women were divided into an EP group and an intrauterine pregnancy (IUP) group depending on the final diagnosis. The endometrial pattern and endometrial thickness were determined by TVS. Sensitivity and receiver operating characteristic curve analyses were performed to determine the predictive value. RESULTS: A heterogenous hyperechoic or trilaminar endometrial pattern was noted in 53 (77%) of 69 women in the EP group and 12 (39%) of 31 in the IUP group, and a homogenous hyperechoic pattern in 3 (4%) women in the EP group and 13 (42%) in the IUP group. An endometrial thickness of less than 9.8 mm was predictive of EP (P<0.001), and an endometrial pattern other than homogenous hyperechoic had a sensitivity and a negative predictive value of 81.3% for the diagnosis of EP. CONCLUSION: Evaluation of endometrial thickness and pattern by TVS helps to identify women with a pregnancy of unknown location for close supervision. PMID- 28099695 TI - Low maternal pregnancy-associated plasma protein A during the first trimester of pregnancy and pregnancy outcomes. AB - OBJECTIVE: To assess the association between pregnancy-associated placental protein A (PAPP-A) levels in the first trimester of pregnancy and adverse pregnancy outcomes. METHOD: A retrospective study included data from a group of patients in the first trimester of pregnancy with PAPP-A levels below 0.3 multiples of median who attended the Helsinki University Hospital, Finland, between January 1, 2009 and December 31, 2012; an age-matched control group of patients with PAPP-A levels 0.9-1.1 multiples of median was also enrolled. The incidences of adverse pregnancy outcomes in the two groups were compared. RESULTS: There were 961 patients included in each of the groups. Significantly increased risks of aneuploidies (odds ratio [OR] 116.0; 95% confidence interval [CI] 16.2-836.6) and spontaneous abortion (OR 7.7; 95% CI 2.7-22.0) were observed among patients with low PAPP-A (both P<0.001). Preterm delivery (OR 2.5, 95% CI 1.8-3.5), pre-eclampsia (OR 10.9, 95% CI 4.3-27.6), and small for gestational age neonates (OR 4.9, 95% CI 3.2-7.5) were also observed more frequently among patients with low PAPP-A (all P<0.001). There were 9 (0.9%) stillbirths recorded among patients with low PAPP-A and none recorded in the control group. CONCLUSION: Low PAPP-A was associated with adverse pregnancy outcomes and aneuploidy. These risks should be considered when planning follow-up for patients with low PAPP-A pregnancies. PMID- 28099696 TI - Reaching vulnerable women through maternity waiting homes in Malawi. AB - OBJECTIVE: To determine whether two maternity waiting homes (MWHs) supported by the Safe Motherhood Initiative are reaching vulnerable women during the early phase of their implementation. METHODS: A cross-sectional interview-based study was conducted among women who attended two centers in Malawi with attached MWHs (Area 25 Health Centre, Lilongwe; and Kasungu District Hospital, Kasungu). Between April and June 2015, exit interviews were conducted among MWH users and non-users. RESULTS: Compared with non-users, MWH users at Area 25 were significantly more likely to report a prior spontaneous abortion (10/46 [21.7%] vs 5/95 [5.3%]; P=0.006) and to be in the lowest wealth quintile (4/87 [4.6%] vs 0/150; P=0.029). Although not significant, a greater percentage of MWH users at Kasungu District Hospital than non-users had a prior stillbirth (6/84 [7.1%] vs 0/77) or spontaneous abortion (3/84 [3.6%] vs 2/77 [2.6%]), and were in the lowest wealth quintile (15/175 [8.6%] vs 5/141 [3.5%]). MWH users at Kasungu lived further from the hospital than did non-MWH users, although the difference was not significant (mean 6.81+/-9.1 km vs 4.05+/-7.42 km; P=0.067). CONCLUSION: MWHs offer a promising strategy to reduce maternal mortality in Malawi and other low-income countries. PMID- 28099697 TI - Applicability of the modified ACOG/SGO referral criteria for adnexal mass within a limited-resource setting. AB - OBJECTIVE: To evaluate the performance of the modified American Congress of Obstetricians and Gynecologists (ACOG)/Society of Gynecologic Oncology (SGO) referral guidelines in a high-risk limited-resource setting. METHODS: In a retrospective study, data were assessed for all women who underwent surgery for an adnexal mass at John H. Stroger Jr Hospital, Chicago, IL, USA, between July 2006 and July 2011. Sensitivity, specificity, and positive and negative predictive values were calculated both for actual practice referral patterns and for the modified ACOG/SGO guidelines. RESULTS: Among 542 study women, 176 (32.5%) were diagnosed with ovarian malignancy. The ACOG/SGO guidelines showed 81.3% sensitivity and 71.9% specificity for the prediction of malignancy at time of surgery, with positive and negative predictive values of 58.1% and 88.9%, respectively. Actual practice patterns demonstrated lower sensitivity (68.2%; P<0.001) but higher specificity (84.2%; P<0.001). CONCLUSION: As compared with practice patterns, the modified ACOG/SGO guidelines lacked sufficient specificity for referral and might not be applicable in high-risk, low-resource settings. For this population, screening should be based on stratifying patients into low-, intermediate-, and high-risk categories to allow limited resources to be focused on women at highest risk. PMID- 28099698 TI - Safety of vaginal delivery among dichorionic diamniotic twins over 10 years in a UK teaching hospital. AB - OBJECTIVE: To determine whether vaginal delivery among dichorionic diamniotic twins remains a safe option following full implementation of the European Working Time Directive in the UK. METHODS: A retrospective study was conducted using data for women with dichorionic diamniotic twin pregnancies who attended a teaching hospital in London, UK, for delivery between January 4, 2000, and December 23, 2010. RESULTS: Among 892 women, 474 (53.1%) attempted vaginal delivery, 220 (46.4%) of whom achieved spontaneous vaginal delivery of both twins. Instrumental vaginal delivery was performed among 89 women (18.8%), and 165 (34.8%) women underwent emergency cesarean delivery. Delivery of the second twin by emergency cesarean (n=31) was predominantly for fetal distress (13 [41.9%]) or abnormal lie (10 [32.3%]). A 5-minute Apgar score of 9 or 10 was recorded for 384 (83.7%) of 459 first twins and 369 (82.9%) of 445 second twins, irrespective of the mode of delivery. CONCLUSION: Vaginal delivery among dichorionic diamniotic twins had a good success rate and a low intrapartum emergency cesarean delivery rate. Training in cardiotocography and intrapartum procedures might further reduce the need for emergency cesarean delivery. PMID- 28099700 TI - A systematic review and meta-analysis of randomized controlled trials comparing hysteroscopic morcellation with resectoscopy for patients with endometrial lesions. AB - BACKGROUND: Results on the efficacy of hysteroscopic morcellation for patients with endometrial lesions remain conflicting. OBJECTIVES: To compare hysteroscopic morcellation with conventional resectoscopy for removal of endometrial lesions. SEARCH STRATEGY: Electronic databases were searched for reports published up to February 1, 2016, using terms such as "morcellator," "morcellators," "morcellate," "morcellation," "morcellated," "hysteroscopy," "hysteroscopy," "uteroscope," and "transcervical." SELECTION CRITERIA: Randomized controlled trials were included if they assessed success rate, procedure speed, complications, tolerability, and/or learning curve. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent reviewers and a meta-analysis was performed. MAIN RESULTS: Four trials including 392 patients were analyzed. Successful removal of all endometrial lesions was more frequent with hysteroscopic morcellation than conventional resectoscopy (odds ratio 4.49, 95% confidence interval [CI] 1.94-10.41; P<0.001). Total operative time was also shorter with hysteroscopic morcellation (mean difference -4.94 minutes, 95% CI 7.20 to -2.68; P<0.001). No significant differences in complications were found. Meta-analyses were not possible for tolerability and learning curve. In one study, hysteroscopic morcellation was acceptable to more patients (P=0.009). CONCLUSIONS: Hysteroscopic morcellation is associated with a higher operative success rate and a shorter operative time among patients with endometrial lesions than is resectoscopy. More high-quality trials are required to validate these results. PMID- 28099699 TI - Randomized controlled trial comparing operative times between standard and robot assisted laparoscopic hysterectomy. AB - OBJECTIVE: To compare the operative time between robot-assisted laparoscopic hysterectomies and standard laparoscopic hysterectomies. METHODS: A prospective, randomized controlled trial enrolled women aged 18-80 years attending Penn State Hershey Medical Center between April 23 and October 20, 2014 to undergo hysterectomy. Participants were randomized using a random number generator to undergo either robot-assisted or standard laparoscopic hysterectomy. The primary outcome was the total operative time (surgeon incision to surgeon stop, including robot docking time, if applicable). Intention-to-treat analyses were performed and the operative time was compared between the two treatments for non inferiority, defined as a difference in operative time of no longer than 15 minutes. RESULTS: There were 72 patients randomized to each treatment arm. The mean operative time was 73.9 minutes (median 67.0 minutes; interquartile range 59.0-83.0 minutes) in the robot-assisted hysterectomy group and 74.9 minutes (median 65.5 minutes; interquartile range 57.0-90.5 minutes) in the standard laparoscopic hysterectomy group. The upper bound of the 95% confidence interval of the difference in operative time was 6.6 minutes, below the 15-minute measure of non-inferiority. CONCLUSION: When performed by a surgeon experienced in both techniques, the operative time for robot-assisted laparoscopic hysterectomy was non-inferior to that achieved with standard laparoscopic hysterectomy. CLINICALTRIALS.GOV: NCT02118974. PMID- 28099701 TI - A systematic review of implementation strategies to deliver guidelines on obstetric care practice in low- and middle-income countries. AB - BACKGROUND: Healthcare measures to prevent maternal deaths are well known. However, effective implementation of this knowledge to change practice remains a challenge. OBJECTIVES: To assess whether strategies to promote the use of guidelines can improve obstetric practices in low- and middle-income countries (LMICs). SEARCH STRATEGY: Electronic databases were searched up to February 7, 2014, using relevant terms for implementation strategies (e.g. "audit," "education," "reminder"), and maternal mortality. SELECTION CRITERIA: Randomized and non-randomized studies of implementation strategies targeting healthcare professionals within the formal health services in LMICs were included. DATA COLLECTION AND ANALYSIS: Cochrane methodological guidance was followed. Because of heterogeneity in the interventions, a narrative synthesis was completed. MAIN RESULTS: Nine studies met the inclusion criteria. Moderate-to-low-quality evidence was found to show improvement in the areas of doctor-patient communication (one study), analgesic provision (one study), the management of emergencies (two studies) and maternal and late neonatal mortality (one study each). Intervention effects were not consistent across studies. CONCLUSIONS: Implementation strategies targeting health professionals could lead to improvement in obstetric care in LMICs. Future research should explore what feature of an intervention is effective in one context and how this could be translated into another context. PROSPERO: CRD42014010310. PMID- 28099702 TI - Organizing an international-standard obstetric ultrasonography training program in a low-resource setting. PMID- 28099704 TI - High-risk human papillomavirus infection clearance following conization among patients with cervical intraepithelial neoplasm grade 3 aged at least 45 years. AB - OBJECTIVE: To investigate high-risk human papillomavirus (HPV) infection clearance rates following successful cold knife conization and factors predictive of HPV clearance among patients with cervical intraepithelial neoplasm grade 3. METHOD: The present retrospective study analyzed clinical data from patients aged at least 45 years with cervical intraepithelial neoplasm grade 3 who had undergone successful cold knife conization and attended regular follow-up at Peking Union Medical College Hospital, China, between January 1, 2002 and December 31, 2012. HPV clearance rates and potential indicators for HPV clearance were analyzed. RESULTS: Data from 156 patients were included; persistent high risk HPV infection was recorded in 78 (50.0%), 45 (28.8%), 35 (22.4%), 24 (15.4%), and 21 (13.5%) patients at 4, 8, 12, 18, and 24 months after conization, respectively. Clearance rates were significantly lower among patients aged at least 55 years compared with younger patients, with increased odds of persistent HPV infection at 8 months (odds ratio [OR] 4.038; 95% confidence interval [CI] 1.766-10.839), 12 months (OR 5.923; 95% CI 2.450-16.604), 18 months (OR 5.957; 95% CI 2.031-17.469), and 24 months (OR 5.327; 95% CI 1.909-17.971) compared with patients aged 45-49 years. CONCLUSION: Age was a prognostic factor for post operative high-risk HPV infection clearance. Lower clearance rates were observed among patients aged at least 55 years. PMID- 28099703 TI - Prevalence and 3-year persistence of human papillomavirus serotypes in asymptomatic patients in Northern Mexico. AB - OBJECTIVE: To investigate clinical outcomes and 3-year persistence of human papillomavirus (HPV) infections among women in Mexico. METHODS: A prospective study enrolled sexually active women attending primary healthcare clinics in metropolitan Monterrey, Mexico, between June 3 and August 30, 2002. Baseline data were collected and participants underwent HPV screening. Patients with HPV infections were asked to attend a repeat screening appointment after 3 years, when the same screening data were gathered. Descriptive analyses were performed and the prevalence of cervical lesions and viral infections were examined. RESULTS: In total, 1188 patients who underwent initial HPV screening were included. Cervical lesions were detected in 5 (0.4%) patients and 239 (20.1%) patients had HPV infections; 129 (54.0%) of these patients attended 3-year follow up. Among the 357 HPV serotypes identified, the most prevalent serotypes were HPV 59, HPV-52, HPV-16, and HPV-56, detected 62 (17.4%), 38 (10.6%), 27 (7.6%), and 18 (5.0%) times, respectively. Of the 129 patients attending 3-year follow-up, 104 (80.6%) were clear from HPV infections, 13 (10.1%) patients had persistent HPV infections, and 12 (9.3%) had HPV infections with different HPV types. CONCLUSIONS: The HPV prevalence was 20.1% in the present study; the most prevalent infections were HPV-59, HPV-52, HPV-16, and HPV-56. At 3-year follow up, 25 (19.4%) patients had HPV infections. PMID- 28099705 TI - Prevalence of induced abortions and contraceptive use among married women in an urban slum of Delhi, India. AB - OBJECTIVE: To document abortion practices and contraceptive use among women of reproductive age in an urban slum of Delhi. METHODS: Data were collected as part of a cross-sectional study conducted in an urban resettlement colony in the North East District of Delhi between November 2010 and December 2011. Systematic random sampling was used to enroll 200 married women aged 15-49 years from each of the four blocks of the colony. Participants were interviewed and data were entered into a pretested semi-structured questionnaire. RESULTS: Among 802 participants, 284 (35.4%) reported at least one spontaneous or induced abortion, and 196 (24.4%) reported induced abortions. Unsupervised medical termination was reported by 78 (27.5%) of the 284 women. Overall, only 207 (25.8%) women practiced any type of contraception. The predominant decision maker regarding contraception was the husband for 95 (45.9%) women and the mother-in-law for 78 (37.7%). CONCLUSION: There is a need for focused community-based education to address specific issues, particularly regarding the dangers of unsafe abortion and choosing a method of contraception in consultation with a healthcare practitioner. PMID- 28099706 TI - Factors influencing HPV vaccine delivery by healthcare professionals at public health posts in Sao Paulo, Brazil. AB - OBJECTIVE: To assess the association between Brazilian healthcare providers' characteristics and their knowledge, perceptions, and practices regarding the HPV vaccine. METHODS: An observational cross-sectional study was conducted at five public health posts in Sao Paulo between July 28 and August 8, 2014. Healthcare professionals directly involved in patient care were asked to complete a written survey. Factors associated with routine verification of HPV vaccination status were evaluated using Poisson regression. RESULTS: Among 200 participants included, 74 (38.5%) reported never and 70 (36.5%) reported always asking about HPV immunization status. Doctors were significantly less likely to report always asking than were community health agents (5/39 [12.8%] vs 32/60 [53.3%]; adjusted prevalence ratio [aPR] 0.25 [95% confidence interval (CI) 0.07-0.91]). Knowledge about the correct dosing schedule was associated with always rather than never verifying vaccination status (aPR 2.46 [95% CI 1.06-5.70]). CONCLUSION: Knowledge and attitude played secondary roles in influencing HPV vaccine verification. Community health agents were crucial for vaccine promotion; continued education and support of this group is essential for the sustained success of HPV immunization efforts in Brazil. PMID- 28099707 TI - IJGO serving you better in 2017. PMID- 28099709 TI - Preliminary study of the effects of furosemide on blood pressure during late onset pre-eclampsia in patients with high cardiac output. AB - OBJECTIVE: To examine the effect of furosemide on hypertension and edema in patients with pre-eclampsia experiencing high cardiac output. METHODS: The present cohort study enrolled patients with pre-eclampsia who were admitted to the pregnancy pathology unit of the Department of Obstetrics and Gynecology, University of Pecs, Hungary, between January 1 and December 31, 2015. Eligible patients had singleton pregnancies with no fetal anomalies, high blood volume, visible edema, and a hematocrit concentration below 37 L/L. Blood pressure was measured and impedance cardiography was used to determine cardiac output for all patients before they received a 40-mg dose of furosemide; after 60 minutes blood pressure and cardiac output were measured again. RESULTS: The study enrolled 14 patients. Lower cardiac output (P=0.002), systolic blood pressure (P=0.002), and diastolic blood pressure (P=0.002) were recorded after furosemide administration, with patient heart rates remaining stable. CONCLUSION: The heart-rate stability suggests that the change of cardiac output was due to a decrease in blood volume. These data suggest that diuretics could be useful in the management of late-onset pre-eclampsia, indicating that an increase in water retention could play a role in the development of late-onset pre-eclampsia. PMID- 28099708 TI - Association between previous spontaneous abortion and pre-eclampsia during a subsequent pregnancy. AB - OBJECTIVE: To determine the impact of a history of spontaneous abortion on pre eclampsia during a subsequent pregnancy. METHODS: A cross-sectional study enrolled pregnant women admitted to obstetrics and gynecology wards at 103 hospitals in Tehran, Iran for delivery between July 6 and July 21, 2015. Consenting participants were interviewed by midwives; data were collected using a five-part questionnaire and patients' medical records were retrieved. Patient data were analyzed by multiple logistic regression to identify variables associated with increased odds of pre-eclampsia. RESULTS: In total, 5170 patients were interviewed and 252 had experienced pre-eclampsia. The number of previous spontaneous abortions was found to be associated with pre-eclampsia, and a higher number of previous spontaneous abortions was associated with increased odds of patients having experienced pre-eclampsia (adjusted odds ratio 1.28, 95% confidence interval 1.03-1.59; P=0.025). CONCLUSION: A history of spontaneous abortion was associated with increased odds of pre-eclampsia during a subsequent pregnancy. PMID- 28099710 TI - Predictive value of serum HE4 and CA125 concentrations for lymphatic metastasis of endometrial cancer. AB - OBJECTIVE: To evaluate the predictive value of serum HE4 and CA125 concentrations in the preoperative prediction of risk of lymph node metastasis in endometrial cancer. METHODS: A retrospective study was undertaken of data for patients with endometrial carcinoma treated surgically at a university hospital in China between August 2011 and December 2015. The preoperative serum levels of HE4 and CA125 were measured and analyzed by clinicopathologic characteristics. RESULTS: Overall, 258 patients were included. The HE4 and CA125 concentrations were significantly elevated in patients with large lesions (>=2 cm), deep myometrial invasion (>=50%), an advanced disease stage, or lymph node metastasis (P<0.05 for all). HE4 concentrations also rose with age and histologic grade (P<0.01 for both). For lymph node metastasis, HE4 had higher sensitivity and negative predictive value than did CA125. The diagnostic performance of HE4 and CA125 in combination was superior to that of either marker alone. CONCLUSION: The combined evaluation of serum HE4 and CA125 could provide gynecologic oncologists with improved information to guide the decision of whether to perform lymphadenectomy. PMID- 28099711 TI - Introducing the World Health Organization Postpartum Family Planning Compendium. AB - The postpartum period offers multiple opportunities for healthcare providers to assist with family planning decision making. However, there are also many changing factors during the first year after delivery that can affect family planning choices. Given that several different documents have addressed WHO guidance on postpartum family planning, the electronic WHO Postpartum Family Planning Compendium (http://srhr.org/postpartumfp) has been introduced. This resource integrates essential guidance on postpartum family planning for clinicians, program managers, and policy makers. The development of the Compendium included consultations with family planning experts, key international stakeholders, and web developers. Once the website had been created, user testing by family planning experts allowed for improvements to be made before the official launch. Future directions are adaptation of the website into a mobile application that can be more easily integrated to low-resource settings, and translation of the content into French and Spanish. PMID- 28099712 TI - Comparison of selective and non-selective internal iliac artery embolization for abnormal placentation with major postpartum hemorrhage. PMID- 28099713 TI - Systematic review of obstetric care from a women-centered perspective in Nigeria since 2000. AB - BACKGROUND: A women-centered approach can improve the quality of patient care. OBJECTIVE: To review issues in the provision of obstetric care from a patient centered care perspective in Nigeria. SEARCH STRATEGY: Using terms related to maternal and perinatal mortality, in combination with "Nigeria", MEDLINE, Embase, CINAHL, Web of Knowledge, and African Journal Online were searched, between December 1, 2013 and January 31, 2014, for articles in any language. SELECTION CRITERIA: Articles published in a Nigerian setting after 2000 that investigated causes of and circumstance surrounding maternal deaths and complications, or clinical practice related to maternal care were included. DATA COLLECTION AND ANALYSIS: Data were extracted by two reviewers using a standardized abstraction form and were analyzed from a patient-centered perspective. MAIN RESULTS: The analysis included 57 studies. Clandestine induced abortions, lack of prenatal care, delays in seeking care, and the use of spiritual churches for delivery were found to contribute to adverse pregnancy outcomes. CONCLUSIONS: Healthcare systems respond inadequately to patients' needs in terms of abortion care, information sharing, transitioning between prenatal and obstetric care, and patients' non-medical needs. Data from clinician-led maternal death audits provided insights into how women-centered care can be provided; nonetheless, more focused studies from a primarily patient-centered perspective are warranted. PMID- 28099714 TI - Zika virus infection in Brazil and human rights obligations. AB - The February 2016 WHO declaration that congenital Zika virus syndrome constitutes a Public Health Emergency of International Concern reacted to the outbreak of the syndrome in Brazil. Public health emergencies can justify a spectrum of human rights responses, but in Brazil, the emergency exposed prevailing inequities in the national healthcare system. The government's urging to contain the syndrome, which is associated with microcephaly among newborns, is confounded by lack of reproductive health services. Women with low incomes in particular have little access to such health services. The emergency also illuminates the harm of restrictive abortion legislation, and the potential violation of human rights regarding women's health and under the UN Conventions on the Rights of the Child and on the Rights of Persons with Disabilities. Suggestions have been proposed by which the government can remedy the widespread healthcare inequities among the national population that are instructive for other countries where congenital Zika virus syndrome is prevalent. PMID- 28099715 TI - Assessment of the body composition of patients with polycystic ovary syndrome using dual-energy X-ray absorptiometry. AB - OBJECTIVE: To compare the body composition among patients with polycystic ovary syndrome (PCOS) and patients without PCOS. METHODS: A cross-sectional study enrolled patients aged 12-39 years, with body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) at least 18.5 but below 25, who attended the Endocrine Gynecology Clinic of Santa Casa de Sao Paulo School of Medical Sciences, Brazil, between January 1, 2014, and July 31, 2015. Anthropometric measurements, metabolic and androgenic profiles, and dual-energy X ray absorptiometry measurements were compared between patients with PCOS and those without PCOS. RESULTS: In total, 102 eligible patients attended the study clinical during the study period; 43 were excluded owing to not meeting the inclusion criteria or declining to undergo complete study testing, and 15 withdrew from the study. Of the 44 participants, 28 had PCOS and 16 were included in the control group. Serum 17-hydroxyprogesterone concentration (P=0.046), leg fat (P=0.031), and truncal-fat (P=0.001) were all higher among patients with PCOS. CONCLUSION: The present study demonstrated increased truncal and leg fat among women with PCOS. The study did not detect any difference in insulin parameters but larger studies could be more suitably powered to investigate this. CLINICALTRIALS.GOV: NCT02467751. PMID- 28099716 TI - Long hospitalization for severe ovarian hyperstimulation syndrome with persistent right hydrothorax and two occurrences of pneumonia. PMID- 28099717 TI - Maternal serum amyloid A level as a novel marker of primary unexplained recurrent early pregnancy loss. AB - OBJECTIVE: To assess maternal serum amyloid A (SAA) levels among women with primary unexplained recurrent early pregnancy loss (REPL). METHODS: A prospective study was conducted among women with missed spontaneous abortion in the first trimester at Ain Shams University Maternity Hospital, Cairo, Egypt, between January 21 and December 25, 2014. Women with at least two consecutive primary unexplained REPLs and no previous live births were enrolled. A control group was formed of women with no history of REPL who had at least one previous uneventful pregnancy with no adverse outcomes. Serum samples were collected to measure SAA levels. The main outcome was the association between SAA and primary unexplained REPL. RESULTS: Each group contained 96 participants. Median SAA level was significantly higher among women with REPL (50.0 MUg/mL, interquartile range 26.0 69.0) than among women in the control group (11.6 MUg/mL, interquartile range 6.2 15.5; P<0.001). The SAA level was an independent indicator of primary unexplained REPL, after adjusting for maternal age and gestational age (odds ratio 1.12, 95% confidence interval 1.06-1.19; P<0.001). CONCLUSION: Elevated SAA levels found among women with primary unexplained REPL could represent a novel biomarker for this complication of pregnancy. PMID- 28099718 TI - Vaginal delivery with prior cesarean delivery following appendix rupture and diffuse purulent peritonitis in a patient with complete wound dehiscence. PMID- 28099719 TI - Evaluating vaginal-delivery rates after previous cesarean delivery using the Robson 10-group classification system at a tertiary center in Brazil. PMID- 28099720 TI - Birth characteristics of Syrian refugees and Turkish citizens in Turkey in 2015. AB - OBJECTIVE: To compare the birth characteristics of Syrian refugees with those of Turkish citizens. METHODS: In a retrospective study, data were obtained for singleton live births that occurred at a hospital in Bursa, Turkey, between June 1 and December 31, 2015. All Syrian refugees were eligible for inclusion; one Turkish citizen was included for each refugee. RESULTS: Overall, 545 Syrian refugees and 545 Turkish citizens were included. Cesarean delivery was undertaken for 176 (32.3%) Syrians and 235 (43.1%) Turks (P<0.001). Median neonatal birth weight was higher among Turkish citizens (3300 g, range 970-4720) than among Syrian refugees (3110 g, range 540-4790; P<0.001). Gestational diabetes was recorded for 42 (7.7%) Turkish citizens and 9 (1.7%) Syrian refugees (P<0.001). Pre-eclampsia affected 21 (3.9%) Turkish citizens and 8 (1.5%) Syrians (P=0.014). CONCLUSION: Cesarean delivery is more common among pregnant Turkish citizens than among Syrian refugees. Other notable differences between the groups were recorded. PMID- 28099721 TI - The impact of thermal stability of oxytocin on access, and the importance of setting proper product specifications. PMID- 28099722 TI - Risk of cesarean delivery among pregnant women with class III obesity. AB - OBJECTIVE: To identify factors associated with cesarean delivery among women with class III obesity attempting vaginal delivery. METHODS: In a retrospective study, medical charts were reviewed for women aged 18 years or older with a singleton pregnancy of at least 37 weeks and a body mass index (calculated as weight in kilograms divided by the square of height in meters) of 40 or higher who were eligible to attempt vaginal delivery at a maternity hospital in Lille, France, between 1999 and 2012. RESULTS: Among 345 eligible women, 301 (87.2%) attempted vaginal delivery; 211 (70.1%) were successful and 90 (29.9%) delivered by cesarean. The frequency of nulliparity was higher among those undergoing cesarean after a trial of labor (64 [71.1%]) than among those who delivered vaginally (57 [27.0%]; P<0.001). Induction of labor was also more frequent among those who ultimately delivered by cesarean (61 [67.8%] vs 96 [45.5%]; P<0.001). In multivariate analysis, induction of labor was an independent predictor of cesarean among women attempting vaginal delivery (odds ratio [OR] 2.30, 95% confidence interval [CI] 1.25-4.22), whereas history of vaginal delivery was protective (OR 0.08, 95% CI 0.04-0.17). CONCLUSION: Nulliparous women with class III obesity attempting a vaginal delivery should be warned of the high risk of cesarean delivery, especially if they require induction. PMID- 28099723 TI - Rape-myth acceptance among students at the University of Cape Coast, Ghana. PMID- 28099724 TI - Costs of integrating cervical cancer screening at an HIV clinic in Kenya. AB - OBJECTIVE: To estimate the societal-level costs of integrating cervical cancer screening into HIV clinics in Nairobi, Kenya. METHODS: A cross-sectional micro costing study was performed at Coptic Hope Center for Infectious Diseases and Kenyatta National Hospital, Kenya, between July 1 and October 31, 2014. To estimate direct medical, non-medical, and indirect costs associated with screening, a time-and-motion study was performed, and semi-structured interviews were conducted with women aged at least 18 years attending the clinic for screening during the study period and with clinic staff who had experience relevant to cervical cancer screening. RESULTS: There were 148 patients and 23 clinic staff who participated in interviews. Visual inspection with acetic acid was associated with the lowest estimated marginal per-screening costs ($3.30), followed by careHPV ($18.28), Papanicolaou ($24.59), and Hybrid Capture 2 screening ($31.15). Laboratory expenses were the main cost drivers for Papanicolaou and Hybrid Capture 2 testing ($11.61 and $16.41, respectively). Overhead and patient transportation affected the costs of all methods. Indirect costs were cheaper for single-visit screening methods ($0.43 per screening) than two-visit screening methods ($2.88 per screening). CONCLUSIONS: Integrating cervical cancer screening into HIV clinics would be cost-saving from a societal perspective compared with non-integrated screening. These findings could be used in cost-effectiveness analyses to assess incremental costs per clinical outcome in an integrated setting. PMID- 28099725 TI - Maternal and newborn outcomes at a tertiary care hospital in Lusaka, Zambia, 2008 2012. AB - OBJECTIVE: To measure key obstetric and neonatal outcomes recorded at a tertiary hospital in Zambia over a 5-year period. METHODS: A retrospective analysis was conducted among women who had delivered at the University Teaching Hospital in Lusaka, between January 1, 2008, and December 31, 2012. Data were extracted from electronic medical records. The main outcomes were maternal mortality, cesarean delivery, prenatal or intrapartum hemorrhage, stillbirth, a 5-minute Apgar score of less than 7, and admission to the neonatal intensive care unit. RESULTS: A total of 62 470 deliveries were recorded. Rates of maternal mortality, cesarean delivery, and hemorrhage during pregnancy all declined over time. Decreased admissions to the neonatal intensive care unit were observed; however, the rate spiked temporarily in late 2011 and early 2012 before returning to previous levels. The proportion of stillbirths remained stable over time but reports of a 5-minute Apgar score of less than 7 rose. CONCLUSION: Routinely collected obstetric and neonatal data could aid ongoing program monitoring and should be used to guide quality improvement activities. PMID- 28099727 TI - Association of biochemical markers with the severity of pre-eclampsia. AB - OBJECTIVE: To assess the association between pre-eclampsia severity and biochemical and ultrasonography markers. METHODS: A retrospective study was undertaken of women with severe pre-eclampsia (group 1, n=90), mild pre-eclampsia (group 2, n=90), or a normal pregnancy (group 3, n=90) who attended a hospital in Egypt in October 2013-April 2015. Associations between pre-eclampsia and biochemical, cardiotocography, and ultrasonography markers were investigated. RESULTS: There were significant differences between the groups in C-reactive protein (331.44+/-112.38, 251.43+/-59.05, and 23.81+/-16.19 nmol/L; P<=0.05 for all), platelet count (113.40+/-36.72, 172.93+/-57.60, and 212.68+/-70.00*109 /L; P<=0.05 for group 1 comparisons), alanine transaminase (52.24+/-14.83, 38.34+/ 13.12, and 23.11+/-6.92 U/L; P<=0.05 for group 1 comparisons), and serum uric acid (600.80+/-117.19, 481.83+/-118.97, and 243.89+/-53.54 MUmol/L; P=0.050 for group 3 comparisons). Cardiotocography score was worse among women with severe pre-eclampsia than among those in the other two groups (P=0.039 for both comparisons). Biophysical profile score and umbilical artery resistance index differed by group (P<=0.05 for all). Middle cerebral artery resistance index was lower among women with severe pre-eclampsia (P<=0.05). CONCLUSION: The levels of C-reactive protein, blood urea nitrogen, serum uric acid, and alanine transaminase, and the platelet count were linked with the presence and severity of pre-eclampsia. PMID- 28099726 TI - A systematic review and meta-analysis of the effect of prophylactic tranexamic acid treatment in major benign uterine surgery. AB - BACKGROUND: The value of tranexamic acid (TA) treatment as bleeding prophylaxis in major uterine surgery is unclear. OBJECTIVES: To evaluate the antihemorrhagic effect of prophylactic TA treatment in major benign uterine surgery. SEARCH STRATEGY: PubMed, Embase, Cochrane Library, and Web of Science were searched from 1980 to 2015 without language restriction using search terms related to major uterine surgery combined with TA. SELECTION CRITERIA: Randomized controlled trials comparing prophylactic TA with placebo or no intervention in women undergoing elective major benign uterine surgery. DATA COLLECTION AND ANALYSIS: Basic information and outcomes were collected and meta-analyses performed. MAIN RESULTS: Sixteen trials were included, with five trials considered to have an overall low risk of bias. In cesarean delivery, TA significantly reduced intraoperative bleeding (mean -136 mL, 95% confidence interval [CI] -189 to -83), blood loss of more than 1000 mL (relative risk 0.38, 95% CI 0.18-0.81), and blood transfusion (relative risk 0.32, 95% CI 0.17-0.59). In abdominal myomectomy, TA also significantly reduced intraoperative bleeding (mean -251 mL, 95% CI -391 to 110). CONCLUSIONS: Prophylactic TA treatment significantly reduced operative bleeding in women undergoing elective cesarean delivery or abdominal myomectomy. Additional randomized trials with low risk of bias are needed. PMID- 28099728 TI - Effects of an intervention initiated by a national society to improve postabortion care in rural facilities in Burkina Faso. AB - OBJECTIVE: To evaluate the results of an intervention by the Societe de Gynecologues et Obstetriciens du Burkina (SOGOB) to improve postabortion care (PAC) in rural areas of Burkina Faso. METHODS: From June 1, 2012, to May 31, 2013, SOGOB increased capacity for PAC by providing training in health care and equipment to 45 rural health facilities. Performance in PAC in the year before intervention (June 1, 2011, to May 31, 2012) was compared with that in the year following intervention (June 1, 2013, to May 31, 2014). RESULTS: The number of cases of incomplete abortion managed within a year increased from 1812 before the intervention to 2738 afterwards. Before capacity building, none of the health facilities was using misoprostol for management of incomplete abortion. After capacity building, misoprostol was used in 805 (29.4%) cases. The use of inappropriate methods to empty the uterus decreased (27.5% [498/1812] vs 1.4% [38/2738]; P<0.001). The frequencies of uterine perforation and pelvic infection also decreased (P<=0.01 for both). In the year after implementation, 2035 (78.3%) of 2600 women had taken up a family planning method before leaving the facility. CONCLUSION: SOGOB's intervention has improved the quality of PAC in rural health facilities in Burkina Faso. PMID- 28099729 TI - Maternal c-reactive protein and oxidative stress markers as predictors of delivery latency in patients experiencing preterm premature rupture of membranes. AB - OBJECTIVE: To evaluate the usefulness of maternal serum c-reactive protein (CRP), lipid peroxide, and oxygen radical absorbance capacity (ORAC), to predict the interval between membrane rupture and delivery in patients with preterm premature rupture of membranes (PPROM). METHODS: The present prospective study included patients with singleton pregnancies experiencing PPROM at earlier than 34 weeks of pregnancy who underwent spontaneous vaginal delivery between August 1, 2010 and July 31, 2013 at Chonnam National University Hospital, Republic of Korea. Patients were categorized based on whether delivery occurred within 3 days of PPROM or after. CRP levels, lipid peroxide (using malondialdehyde levels), ORAC, protein carbonyl, and other potential risk factors were compared between the groups. RESULTS: There were 72 patients included. Maternal serum CRP levels, malondialdehyde levels, and Bishop Score were higher in patients who underwent delivery within 3 days (all P<0.05); ORAC levels were lower among these patients (P=0.002). A receiver operating characteristic curve analysis showed that CRP, malondialdehyde, and ORAC levels were predictive of delivery within 3 days after PPROM. CONCLUSION: Maternal serum CRP, malondialdehyde, and ORAC levels at admission were useful in predicting the latent period in patients with PPROM. PMID- 28099730 TI - Development, updates, and future directions of the World Health Organization Selected Practice Recommendations for Contraceptive Use. PMID- 28099731 TI - Provision of harm-reduction services to limit unsafe abortion in Tanzania. AB - OBJECTIVE: To investigate the feasibility of providing harm-reduction services to reduce unsafe abortion in Tanzania. METHODS: A cross-sectional study was conducted among 110 women who received harm-reduction counseling at a public health center in Dar es Salaam between February 10 and October 10, 2014. Background and clinical information was collected for all women; a subgroup (n=50) undertook a semi-structured survey that measured the type of services women received, women's perception of the services, and pregnancy outcome. The main study outcomes were attendance at the follow-up visit, type and quality of information women received on both visits, and misoprostol use for pregnancy termination. RESULTS: Overall, 55 (50.0%) women attended follow-up services. Misoprostol was used for induced abortion among 54 (98.2%); 38 (70.4%) of these women had obtained contraception at the follow-up visit. Likelihood of attendance for follow-up was increased among women who were older than 34 years (odds ratio [OR] 2.2, 95% confidence interval [CI] 0.1-35.8), were married (OR 2.1, 95% CI 0.8-5.7), and had a post-primary education level (OR 2.0, 95% CI 0.8-5.3). On average, 44 (87.0%) women received all required information at the initial counseling session and none reported major complications that required hospitalization. CONCLUSION: Harm-reduction services for unsafe abortion are feasible and acceptable, and could provide an excellent opportunity to fight abortion-related morbidity and mortality in Tanzania. PMID- 28099732 TI - The impact of laparoscopic cystectomy on ovarian reserve in patients with unilateral and bilateral endometrioma. AB - OBJECTIVE: To evaluate the effects of laparoscopic cystectomy on serum anti Mullerian hormone (AMH) level as a marker of ovarian reserve in patients with endometrioma. METHODS: A prospective observational study enrolled patients aged younger than 40 years who were referred to a tertiary center in Tehran, Iran, between January 1, 2013 and December 31, 2014 to undergo laparoscopic cystectomy for ovarian endometriomas at least 30 mm in diameter, or regardless of size for patients with infertility, dysmenorrhea, dyspareunia, or dyschezia. Baseline and 6-month post-operative AMH levels were compared. RESULTS: Data from 70 patients were included in the analyses. Among patients with unilateral endometriomas, lower pre-operative AMH levels were observed in patients with endometriomas at least 50 mm in diameter (P=0.027), whereas cyst size was not associated with differences in pre-operative AMH level in patients with bilateral endometriomas (P=0.227). Across the entire study population, post-operative AMH levels were lower than the baseline (P=0.008). Greater post-operative decreases in AMH were associated with bilateral cysts compared with unilateral cysts (P=0.046), cysts being at least 50 mm in diameter among patients with unilateral cysts (P=0.028), and both cysts being at least 50 mm in diameter among patients with bilateral cysts (P=0.025). CONCLUSION: Laparoscopic cystectomy was associated with post operative decreases in serum AMH, particularly with bilateral involvement and endometriomas at least 50 mm in diameter. PMID- 28099733 TI - Implementation of a modified obstetric early warning system to improve the quality of obstetric care in Zimbabwe. AB - OBJECTIVE: To implement a modified obstetric early warning system (MOEWS) to promote identification and stabilization of unwell women. METHODS: A before-and after study of MOEWS implementation took place between April 2013 and January 2014 in a government referral hospital in Bulawayo, Zimbabwe. After piloting MOEWS, cesarean case files were retrospectively assessed to compare preoperative stabilization. A longitudinal "spot-check" study measured use of MOEWS and action taken on abnormal results. A quality indicator was introduced to assess ongoing implementation. RESULTS: Analysis of women undergoing cesarean before (n=79) and after (n=85) MOEWS implementation showed that preoperative stabilization improved significantly post-intervention (odds ratio 2.78, 95% confidence interval 1.39 5.54). The longitudinal analysis of women at baseline (n=43) and after (n=85) MOEWS implementation also showed a significant improvement in action taken (1/24 [4%] vs 28/45 [62%]; P=0.001). The 6-month aggregated quality indicator revealed that 78 (62%) of 125 patients had a completed MOEWS chart, with appropriate stabilization of 65 (93%) of 70 women. CONCLUSION: Implementation of MOEWS improved women's care through action being taken on abnormal observations. Before whole-scale adoption of MOEWS in low-resource settings, the study should be scaled up and repeated to ensure replicable findings. PMID- 28099734 TI - Tertiary-level study of the implementation of a technique checklist for cesarean deliveries at a university hospital in Uruguay. AB - OBJECTIVE: To assess the adherence of healthcare providers to cesarean-delivery techniques before and after the introduction of a technique checklist at a university hospital. METHODS: A retrospective cross-sectional cohort study included data from all cesarean deliveries at Gynecology Clinic B of the University of the Republic, Montevideo, Uruguay, between January 1 and December 31, 2011. The data were grouped based on whether delivery occurred before or after the implementation of the checklist and were compared across a range of cesarean-delivery techniques. RESULTS: Data from 296 cesarean deliveries were included; 130 from before implementation and 166 from after. After the implementation of the checklist, complete adherence to all techniques was observed in 28 (16.9%) deliveries. Following the introduction of the checklist, the odds of prophylactic cefazolin (OR 8.35, 95% CI 3.74-20.9), chlorhexidine (OR 8.98, 95% CI 3.72-23.7), cord traction for the third stage of labor (OR 2.26, 95% CI 1.33-3.85), and double-layer hysterorrhaphy (OR 3.65, 95% CI 2.09-6.55) being properly applied increased compared with before the implementation of the checklist. CONCLUSIONS: Overall adherence to the prescribed techniques was low. The implementation of this checklist improved the odds of several techniques being applied by between two- and eight-fold. PMID- 28099735 TI - Negative HPV testing among patients with biopsy-proven cervical intraepithelial neoplasia grade 2/3 or cervical cancer. AB - OBJECTIVE: To determine the proportion of patients diagnosed with cervical cancer or cervical intraepithelial neoplasia grade 2 or 3 (CIN 2/3) despite testing negative for HPV. METHODS: A prospective study was conducted at a university hospital in Barcelona, Spain, between March 2003 and January 2015 among women with abnormal cytology results according to the Bethesda classification system. All participants underwent HPV testing, cytology, and colposcopy. RESULTS: Among 1376 participants, 609 (44.3%) were diagnosed with CIN 2/3. Of these women, 74 (12.2%) tested negative for HPV. Among 479 women with colposcopy-guided biopsy sampling showing CIN 2/3, cone biopsy results that were negative for CIN 2/3 were more frequent among patients with negative HPV testing (13/61 [21.3%]) than among those with positive HPV tests (58/418 [13.9%]; P=0.03). Additionally, among 59 patients diagnosed with cervical cancer, 9 (15.3%) tested negative for HPV. CONCLUSION: The HPV test was negative for 12% and 15% of patients diagnosed with biopsy-proven CIN 2/3 and cervical cancer, respectively. PMID- 28099736 TI - Systematic review of same-day discharge after minimally invasive hysterectomy. AB - BACKGROUND: Same-day discharge has been suggested to safe and acceptable following minimally invasive hysterectomy. OBJECTIVES: To evaluate the feasibility of same-day discharge following minimally invasive hysterectomy and to identify associated factors. SEARCH STRATEGY: Medline, Embase and the Cochrane Central Register of Controlled Trials were systematically searched using the terms "same day discharge", "minimally invasive surgery", and "hysterectomy" between October 1 and October 31, 2015. No language or publication date restrictions were included. SELECTION CRITERIA: Randomized controlled trials and observational studies evaluating same-day discharge before midnight on the day of minimally invasive hysterectomy were included. DATA COLLECTION AND ANALYSIS: Study characteristics, pre-operative selection criteria, and predictive factors for same-day discharge were analyzed. MAIN RESULTS: There were 15 observational studies with 11 992 patients included. Significant heterogeneity was observed in the studies, and publication and selection bias could have potentially affected the results. All the studies concluded that same-day discharge was feasible. However, some factors were associated with a decreased possibility of same-day discharge; these were older age, beginning surgery later than 1:00 pm and completing surgery later than 6:00 pm, longer duration of operation, and high estimated blood loss. CONCLUSIONS: Same-day discharge appears feasible for a majority of patients who undergo minimally invasive hysterectomies if adequate emphasis is placed on pre-surgical planning and careful patient selection. PMID- 28099738 TI - Professionalism in obstetric and gynecologic practice. PMID- 28099737 TI - Decreased rates of shoulder dystocia and brachial plexus injury via an evidence based practice bundle. AB - OBJECTIVE: To evaluate whether a standardized approach to identify pregnant women at risk for shoulder dystocia (SD) is associated with reduced incidence of SD and brachial plexus injury (BPI). METHODS: Between 2011 and 2015, prospective data were collected from 29 community-based hospitals in the USA during implementation of an evidence-based practice bundle, including an admission risk assessment, required "timeout" before operative vaginal delivery (OVD), and low-fidelity SD drills. All women with singleton vertex pregnancies admitted for vaginal delivery were included. Rates of SD, BPI, OVD, and cesarean delivery were compared between a baseline period (January 2011-September 2013) and an intervention period (October 2013-June 2015), during which there was a system-wide average bundle compliance of 90%. RESULTS: There was a significant reduction in the incidence of SD (17.6%; P=0.028), BPI (28.6%; P=0.018), and OVD (18.0%; P<0.001) after implementation of the evidence-based practice bundle. There was a nonsignificant reduction in primary (P=0.823) and total (P=0.396) cesarean rates, but no association between SD drills and incidence of BPI. CONCLUSION: Implementation of a standard evidence-based practice bundle was found to be associated with a significant reduction in the incidence of SD and BPI. Utilization of low-fidelity drills was not associated with a reduction in BPI. PMID- 28099739 TI - Associations between HIV, highly active anti-retroviral therapy, and hypertensive disorders of pregnancy among maternal deaths in South Africa 2011-2013. AB - OBJECTIVE: To explore potential relationships between HIV and highly active anti retroviral therapy (HAART), and hypertensive disorders of pregnancy (HDP). METHODS: A retrospective secondary analysis of maternal-deaths data from the 2011 2013 Saving Mothers Report from South Africa. The incidence of HIV infection amongst individuals who died owing to HDP was determined and comparisons were made based on HIV status and the use of HAART. RESULTS: Among 4452 maternal deaths recorded in the Saving Mothers report, a lower risk of a maternal deaths being due to HDP was observed among women who had HIV infections compared with women who did not have HIV (relative risk [RR] 0.57, 95% confidence interval [CI] 0.51-0.64). Further, reduced odds of death being due to HDP were recorded among women with AIDS not undergoing HAART compared with women with HIV who did not require treatment (RR 0.42, 95% CI 0.3-0.58). Notably, among all women with AIDS, a greater risk of death due to HDP was demonstrated among those who received HAART compared with those who did not (RR 1.15, 95% CI 1.02-1.29). CONCLUSION: HIV and AIDS were associated with a decreased risk of HDP being the primary cause of death; the use of HAART increased this risk. PMID- 28099740 TI - Association of previous severe low birth weight with adverse perinatal outcomes in a subsequent pregnancy among HIV-prevalent urban African women. AB - OBJECTIVE: To evaluate the association between severity of prior low birth weight (LBW) delivery and adverse perinatal outcomes in the subsequent delivery among an HIV-prevalent urban African population. METHODS: A retrospective cohort study was conducted among 41 109 women who had undergone two deliveries in Lusaka, Zambia, between February 1, 2006, and May 31, 2013. The relationship between prior LBW delivery (<2500 g) and a composite measure of adverse perinatal outcome in the second pregnancy was assessed using multivariate logistic regression. RESULTS: Women with prior LBW delivery (n=4259) had an increased risk of LBW in the second delivery versus those without prior LBW delivery (n=37 642). Such risk correlated with the severity of first delivery LBW. The adjusted odds ratio (AOR) was 2.89 (95% confidence interval [CI] 2.05-4.09) for a birth weight of 1000-1499 g, 3.05 (95% CI 2.42-3.86) for a birth weight of 1500-1999 g, and 2.02 (95% CI 1.81-2.27) for a birth weight of 2000-2499 g. Previous LBW delivery also increased the risk of adverse perinatal outcome, with an AOR of 1.4 (95% CI 1.2-1.7). CONCLUSION: Severe prior LBW delivery conferred substantial risk for adverse perinatal outcomes in a subsequent pregnancy. PMID- 28099741 TI - Abortion choices among women in Cambodia after introduction of a socially marketed medicated abortion product. AB - OBJECTIVE: To assess whether a social marketing initiative focusing on medicated abortion via a mifepristone/misoprostol "combipack" has contributed to reducing unsafe abortion in Cambodia. METHODS: In a questionnaire-based cross-sectional study, annual household surveys were conducted across 13 Cambodian provinces in 2010, 2011, and 2012. One married woman of reproductive age who was not pregnant and did not wish to be within the next 2 years in each randomly selected household was approached for inclusion. Participants were interviewed using a structured questionnaire. RESULTS: The questionnaire was completed by 1843 women in 2010, 2068 in 2011, and 2059 in 2012. Manual vacuum aspiration was reported by 61 (72.6%) of 84 women surveyed in 2010 who reported an abortion in the previous 12 months, compared with only 28 (52.8%) of 53 in 2012 (P=0.001). The numbers of women undergoing medicated abortion increased from 22 (26.2%) of 84 in 2010 to 27 (49.1%) of 53 in 2012 (P=0.003), whereas the numbers undergoing unsafe abortion decreased from 4 (4.8%) in 2010 to 0 in 2012 (P=0.051). CONCLUSION: Social marketing of medication abortion coupled with provider training in clinical and behavioral change could have contributed to a reduction in the prevalence of unsafe abortion and shifted the types of abortion performed in Cambodia, while not increasing the overall number of abortions. PMID- 28099742 TI - Does breech delivery in an upright position instead of on the back improve outcomes and avoid cesareans? AB - OBJECTIVE: To compare breech outcomes when mothers delivering vaginally are upright, on their back, or planning cesareans. METHODS: A retrospective cohort study was undertaken of all women who presented for singleton breech delivery at a center in Frankfurt, Germany, between January 2004 and June 2011. RESULTS: Of 750 women with term breech delivery, 315 (42.0%) planned and received a cesarean. Of 269 successful vaginal deliveries of neonates, 229 in the upright position were compared with 40 in the dorsal position. Upright deliveries were associated with significantly fewer delivery maneuvers (OR 0.45, 95% CI 0.31-0.68) and neonatal birth injuries (OR 0.08, 95% CI 0.01-0.58), second stages that were 42% shorter on average (1.02 vs 1.77 hours), and nonsignificantly decreased serious perineal lacerations (OR 0.34, 95% CI 0.05-3.99). When upright position was used almost exclusively, the cesarean rate decreased. Serious fetal and neonatal morbidity potentially related to birth mode was low, and similar for upright vaginal deliveries compared with planned cesareans (OR 1.37, 95% CI 0.10-19.11). Three neonates died; all had lethal birth defects. Forceps were never required. CONCLUSION: Upright vaginal breech delivery was associated with reductions in duration of the second stage of labor, maneuvers required, maternal/neonatal injuries, and cesarean rate when compared with vaginal delivery in the dorsal position. PMID- 28099743 TI - Professionally responsible advocacy for professional liability law. PMID- 28099744 TI - A retrospective cohort study of hemostatic agent use during hysterectomy and risk of post-operative complications. AB - OBJECTIVE: To determine if the use of intraoperative hemostatic agents was a risk factor for post-operative adverse events within 30 days of patients undergoing hysterectomy. METHOD: A population-based retrospective cohort study included data from patients undergoing hysterectomy for any indication between January 1, 2013, and December 31, 2014, at 52 hospitals in Michigan, USA. Any individuals with missing covariate data were excluded, and multivariable logistic regression and propensity score-matching were used to estimate the rate of post-operative adverse events associated with intra-operative hemostatic agents independent of demographic and surgical factors. RESULTS: There were 17 960 surgical procedures included in the analysis, with 4659 (25.9%) that included the use of hemostatic agents. Hemostatic agent use was associated with an increase in predicted hospital re-admissions (P=0.007). Among all hysterectomy approaches, and after adjusting for demographic and surgical factors, hemostatic agent use during robotic-assisted laparoscopic hysterectomy was associated with an increased predicted rate of blood transfusions (P=0.019), an increased predicted rate of pelvic abscess diagnoses (P=0.001), an increased predicted rate of hospital re admission (P=0.001), and an increased predicted rate of re-operation (P=0.021). CONCLUSION: Hemostatic agents should be used carefully owing to associations with increased post-operative re-admissions and re-operations when used during hysterectomy. PMID- 28099745 TI - Cross-sectional study of the ultrasonographic and hormonal characteristics of obstetric fistula patients with and without secondary amenorrhea. PMID- 28099746 TI - Contemporary Issues in Women's Health. PMID- 28099748 TI - Medium-term outcomes of laparoscopic sacrocolpopexy or sacrohysteropexy versus vaginal sacrospinous ligament fixation for middle compartment prolapse. AB - OBJECTIVE: To compare laparoscopic sacrocolpopexy (LSC) or sacrohysteropexy (LSH) with vaginal sacrospinous ligament fixation (VSSLF) for middle compartment pelvic organ prolapse (POP). METHODS: Data were retrospectively reviewed from patients with POP (stage 3 or worse) who underwent LSC, LSH, or VSSLF at a center in Shanghai between January 2009 and March 2014. POP quantification (POP-Q) and Pelvic Floor Distress Inventory scores were compared at the 2-year follow-up. RESULTS: Data were available for the 2-year follow-up for 102 LSC, 11 LSH, and 94 VSSLF procedures. Compared with patients who had undergone VSSLF, those who had undergone LSC/LSH had better POP-Q C values (P<0.001), longer total vaginal length (TVL) (P<0.001), and lower Aa and Ba scores (P=0.003 and P=0.002, respectively). Apical compartment and overall success rates of LSC/LSH and VSSLF did not differ significantly. Quality of life was improved in both groups (P<0.001). Both groups achieved symptomatic relief, although bowel and urinary functions were significantly improved only in the VSSLF group (P<0.001 for both). More patients in the LSC/LSH group were sexually active at 2 years (P<0.001); improvement in sex life was similar between the groups. CONCLUSION: Although LSC/LSH achieved longer TVL, both groups achieved the same success rate and improvement in quality of life. Specifically, VSSLF yielded a significant improvement in bowel and urinary function. PMID- 28099747 TI - Observational study comparing the performance of first-trimester screening protocols for detecting trisomy 21 in a North Indian population. AB - OBJECTIVE: To evaluate first-trimester screening protocols for detecting trisomy 21 in an Indian population. METHODS: The present prospective study collected data from women with singleton pregnancies and a crown-to-rump length of 45-84 mm who presented at the fetal medicine unit of a tertiary care center in North India between June 1, 2006, and December 31, 2015, for combined first-trimester screening. Maternal age, nuchal translucency, nasal bone, and maternal serum levels of free beta human chorionic gonadotropin and pregnancy-associated plasma protein A were assessed for calculating the risk of trisomy 21. Tricuspid regurgitation and qualitative analysis of ductus venosus data were available from June 2010, and were included where available. Trisomy-21 detection rates were calculated for various screening protocols and were compared. RESULTS: There were 4523 women screened and 24 records of trisomy 21. Combined screening with maternal age, nuchal translucency, nasal bone, tricuspid regurgitation, and ductus venosus demonstrated optimal detection and false-positive rates of 93.8% and 1.9%, respectively. Screening using only maternal age yielded a detection rate of 37.5%; using fixed nuchal translucency cut-off values of 2.5 and 3 mm resulted in detection rates of 66.7% and 37.5%, respectively. CONCLUSION: Combined first-trimester screening performed well in an Indian population; combining maternal age, nuchal translucency, nasal bone, ductus venosus, and tricuspid regurgitation yielded the most accurate screening. PMID- 28099749 TI - A systematic review of maternal near miss and mortality due to postpartum hemorrhage. AB - BACKGROUND: Postpartum hemorrhage (PPH) is the principal direct cause of maternal mortality worldwide. Analysis of maternal near miss could increase understanding of survival among women with life-threatening PPH. OBJECTIVES: To determine the near-miss ratio and maternal mortality index for PPH globally. SEARCH STRATEGY: A prevalence systematic review was conducted of English-language articles published from 1995 to 2014. Suitable articles were identified from the Scopus, PubMed, Embase, and Grey Literature databases. The main search terms used were "maternal near-miss" and "severe acute maternal morbidity." SELECTION CRITERIA: Near-miss studies and audits describing the severe maternal outcome rate for PPH were included. DATA COLLECTION AND ANALYSIS: Data were extracted from eligible publications. Quantitative analysis and narrative synthesis were used. MAIN RESULTS: For 26 included studies, the median near-miss ratio for PPH was 3 per 1000 live births. The mortality index for PPH was 6.6% (range 0.0%-40.7%). The mortality index was highest in low-income countries and lower middle-income countries. Overall, PPH was the most frequent contributor to obstetric hemorrhage, with atonic uterus identified as the main cause. CONCLUSIONS: Women in low-income countries and lower middle-income countries have an increased likelihood of severe PPH and of dying from PPH-related consequences. PMID- 28099750 TI - Intrapartum fetal head circumference and estimated fetal weight as predictors of operative delivery. AB - OBJECTIVE: To assess intrapartum sonographic measurements of fetal head circumference (HC) and estimated fetal weight (EFW) to predict operative delivery. METHODS: In a prospective study, 200 spontaneously parturient primiparous women aged 20-30 years were enrolled at a teaching hospital in Cairo, Egypt, between October 2, 2015, and January 28, 2016. HC and EFW were measured by transabdominal ultrasonography. After delivery, the association between type of delivery and ultrasonography findings was assessed. RESULTS: Intrapartum HC and EFW were significantly higher among women with operative delivery (n=76) than among those with normal vaginal delivery (n=124; P<0.001 for both). Intrapartum HC of 36.8 cm or more was associated with an increased risk of operative delivery (relative risk [RR] 2.87, 95% CI 1.87-4.41), as was EFW of 3920 g or more (RR 3.69, 95% CI 2.13-6.40). The area under the receiver operating characteristic curve was 0.807 and 0.748 for HC and EFW, respectively (P<0.001 for both). At 36.8-cm cutoff, HC had 44.7% sensitivity, 91.9% specificity, 77.3% positive predictive value (PPV), and 73.1% negative predictive value (NPV). At 3920-g cutoff, EFW had 68.4% sensitivity, 82.3% specificity, 70.3% PPV, and 81.0% NPV. Intrapartum HC and EFW were directly correlated with second-stage duration (P=0.005 and 0.002, respectively). CONCLUSION: Intrapartum HC and EFW seem to be good predictors of operative delivery. PMID- 28099751 TI - Postoperative anatomic and quality-of-life outcomes after vaginal sacrocolporectopexy for vaginal vault prolapse. AB - OBJECTIVE: To assess anatomic outcome and quality of life (QOL) after vaginal sacrocolporectopexy among patients with pelvic organ prolapse. METHODS: A noncomparative observational study was conducted at Hanover Medical School, Germany, among patients who underwent vaginal sacrocolporectopexy for uterine or vaginal vault prolapse between May 1, 2006, and October 31, 2012. A validated German version of the Prolapse QOL (P-QOL) questionnaire was sent to eligible patients; respondents were invited for follow-up examination. RESULTS: Overall, 128 patients were enrolled. Concomitant hysterectomy was performed among 82 (64.1%) patients, anterior colporrhaphy among 105 (82.0%), and posterior colporrhaphy among 58 (45.3%). After a mean interval of 26.5 months (range 1.0 81.3 months), seven patients exhibited recurrent vaginal vault prolapse of at least stage 2, giving a success rate of 92.3% (95% confidence interval 85.9% 96.5%). The P-QOL scores were either low (<40) or very low (<20), indicating high QOL. Regarding symptoms related to pelvic organ prolapse, patients reported little or no impact on QOL after vaginal sacrocolporectopexy. CONCLUSION: Vaginal sacrocolporectopexy seemed safe and feasible, leading to anatomically correct fixation of the vaginal apex, high anatomic success rates, and good QOL. This procedure might be considered as an alternative to laparoscopic or abdominal sacrocolpopexy. PMID- 28099752 TI - Association between timing of elective cesarean delivery and adverse outcomes among women with at least two previous cesareans. AB - OBJECTIVE: To assess the impact of delivery at 37 weeks of pregnancy versus 38 weeks or later on maternal and neonatal outcomes among women with multiple previous cesareans. METHODS: In a retrospective study, data were assessed from women with at least two previous cesareans who delivered by cesarean at 37 weeks of pregnancy or later at a tertiary referral hospital in Jordan between January 2013 and November 2015. RESULTS: Among 886 eligible women, 505 (57.0%) delivered at 37 weeks (group 1) and 381 (43.0%) delivered at 38 weeks or later (group 2). There was no difference in intraoperative or postoperative complications between the two groups. In multivariate analysis, women in group 2 had lower odds of delivering neonates with respiratory distress syndrome than did those in group 1 (adjusted odds ratio 0.3, 95% confidence interval 0.2-0.5; P=0.046). However, neonatal jaundice was more common in group 2 (adjusted odds ratio 2.1, 95% confidence interval 1.7-2.7; P=0.035). CONCLUSION: Among women with multiple cesareans, delivery at 37 weeks was associated with increased risk of neonatal respiratory morbidity and decreased risk of neonatal jaundice, but not with a reduction in maternal complications, as compared with delivery at 38 weeks or later. PMID- 28099753 TI - Correlation between rapid HIV testing and fourth-generation ELISA results for HIV detection among pregnant patients in the delivery room. AB - OBJECTIVE: To analyze the usefulness of rapid HIV testing in pregnant patients in the delivery room. METHODS: This prospective study compared a rapid test and a fourth-generation enzyme-linked immunoassay (ELISA) for HIV screening among pregnant patients admitted in labor with an unknown HIV status at a university hospital in Mexico between July 2015 and February 2016. Pearson correlation analysis was performed, and the diagnostic accuracy of the two tests was assessed with HIV RNA polymerase chain reaction (PCR) as the reference method. RESULTS: Overall, 534 patients were included. With a signal-to-cutoff (S/CO) value of 1.0 or more as a diagnostic criterion, 6 (1.1%) patients had a positive ELISA result. Three had a negative rapid test and three had a positive test (r=0.705). With an S/CO value of 2.0 or more as cutoff, 4 (0.7%) patients had a positive ELISA result. Three had a positive rapid test and one had a negative test (r=0.865). Only three of six patients with an S/CO of 1.0 or more were confirmed to have HIV by RNA PCR. CONCLUSION: The rapid test showed a strong correlation with the fourth-generation ELISA. Therefore, rapid testing is a useful tool in the delivery room for patients with unknown HIV status. PMID- 28099754 TI - Addressing the Crisis in the Treatment of Osteoporosis: A Path Forward. AB - Considerable data and media attention have highlighted a potential "crisis" in the treatment of osteoporosis. Specifically, despite the availability of several effective drugs to prevent fractures, many patients who need pharmacological therapy are either not being prescribed these medications or if prescribed a medication, are simply not taking it. Although there are many reasons for this "gap" in the treatment of osteoporosis, a major factor is physician and patient concerns over the risk of side effects, especially atypical femur fractures (AFFs) related to bisphosphonate (and perhaps other antiresorptive) drug therapy. In this perspective, we review the current state of undertreatment of patients at increased fracture risk and suggest possible short-, intermediate-, and long-term approaches to address patient concerns, specifically those related to AFF risk. We suggest improved patient and physician education on prodromal symptoms, extended femur scans using dual-energy X-ray absorptiometry (DXA) to monitor patients on antiresorptive treatment, better identification of high-risk patients perhaps using geometrical parameters from DXA and other risk factors, and more research on pharmacogenomics to identify risk markers. Although not the only impediment to appropriate treatment of osteoporosis, concern over AFFs remains a major issue and one that needs to be resolved for effective dissemination of existing treatments to reduce fracture risk. (c) 2017 American Society for Bone and Mineral Research. PMID- 28099755 TI - Comparing effects of insulin analogues and human insulin on nocturnal glycaemia in hypoglycaemia-prone people with Type 1 diabetes. AB - AIMS: To assess the difference between analogue and human insulin with regard to nocturnal glucose profiles and risk of hypoglycaemia in people with recurrent severe hypoglycaemia. METHODS: A total of 72 people [46 men, mean +/- sd age 54 +/- 12 years, mean +/- sd HbA1c 65 +/- 12 mmol/mol (8.1 +/- 1.1%), mean +/- sd duration of diabetes 30 +/- 14 years], who participated in a 2-year randomized, crossover trial of basal-bolus therapy with insulin detemir/insulin aspart or human NPH insulin/human regular insulin (the HypoAna trial) were studied for 2 nights during each treatment. Venous blood was drawn hourly during sleep. Primary endpoints were nocturnal glucose profiles and occurrence of hypoglycaemia (blood glucose <= 3.9 mmol/l). RESULTS: During insulin analogue treatment, the mean nocturnal plasma glucose level was significantly higher than during treatment with human insulin (10.6 vs 8.1 mmol/l). The fasting plasma glucose level was similar between the treatments. Nocturnal hypoglycaemia was registered during 41/101 nights (41%) in the human insulin arm and 19/117 nights (16%) in the insulin analogue arm, corresponding to a hazard ratio of 0.26 (95% CI 0.14 to 0.45; P < 0.0001) with insulin analogue. CONCLUSIONS: Treatment with insulin analogue reduces the occurrence of nocturnal hypoglycaemia assessed by nocturnal glucose profiles in people with Type 1 diabetes prone to severe hypoglycaemia. Nocturnal glucose profiles provide a more comprehensive assessment of clinical benefit of insulin regimens as compared to conventional recording of hypoglycaemia. PMID- 28099756 TI - Levofloxacin effect on erlotinib absorption. Evaluation of the interaction in undernutrition situations through population pharmacokinetic analysis in rats. AB - The main objective of this study was to develop a pharmacokinetic model in order to describe the intestinal absorption of erlotinib in rat and to quantify the interaction of levofloxacin on this process in well- and under-nourished rats. Absorption studies were performed in male Wistar rats. Concentration-time profiles in proximal and distal intestine were analysed through non-linear mixed effect modelling using the NONMEM software version 7.3. Simulations were performed in order to explore the influence of covariates on the apparent absorption rate constant. A passive absorption and an active secretion process best-described erlotinib absorption from lumen to enterocyte. The developed model indicates that levofloxacin exerts an inhibition on erlotinib efflux transporters of the gut epithelium. Undernourishment proved to significantly decrease the maximum capacity of the secretion process. Simulations evidenced that erlotinib absorption only takes place at high enough drug concentrations to overcome the effect of efflux transporters. On the other hand, when levofloxacin is present in the intestinal lumen of undernourished rats, erlotinib drug absorption takes place even at low erlotinib concentrations. In the clinical setting, this interaction may result in increased exposure to erlotinib, especially in undernourished cancer patients. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28099757 TI - Quality of Memories in Women Abused by Their Intimate Partner: Analysis of Traumatic and Nontraumatic Narratives. AB - Traditional models of posttraumatic stress disorder (PTSD) claim that the high emotional intensity of traumatic events leads to deficits in the voluntary access of traumatic memories. This may result in disorganized narratives, with a high sense of emotional and sensory reliving. Alternatively, the basic mechanisms view suggests that high arousal leads to more available involuntary and voluntary memories. Traumatic narratives would not be impaired; indeed, they would be immersive and rich in detail. To test this perspective, this study compared the trauma narratives of 50 battered women (trauma-exposed group) with narratives about positive experiences and narratives of 50 nonexposed women (controls), and analyzed the relationship between trauma narrative aspects and the severity of PTSD. Results showed that trauma narratives were detailed, oriented, and coherent. Affective process words and emotional tone were related to trauma centrality and anxiety during disclosure, and predicted the severity of PTSD (R2 = .26). These variables, together with the use of present tense verbs, accounted for a significant variance in intrusions (R2 = .34). As hypothesized, narrative aspects related to a sense of reliving and narrative immersion were better predictors of PTSD than aspects reflecting impaired access to voluntary traumatic memories. PMID- 28099758 TI - Melatonin alleviates cadmium-induced liver injury by inhibiting the TXNIP-NLRP3 inflammasome. AB - Cadmium (Cd) is a persistent environmental and occupational contaminant that accumulates in the liver and induces oxidative stress and inflammation. Melatonin possesses potent hepatoprotective properties against the development and progression of acute and chronic liver injury. Nevertheless, the molecular mechanism underlying the protective effects of melatonin against Cd-induced hepatotoxicity remains obscure. In this study, we aimed to investigate the effects of melatonin on Cd-induced liver inflammation and hepatocyte death. Male C57BL/6 mice were intraperitoneally injected with melatonin (10 mg/kg) once a day for 3 days before exposure to CdCl2 (2.0 mg/kg). We found that Cd induced hepatocellular damage and inflammatory infiltration as well as increased serum ALT/AST enzymes. In addition, we showed that Cd triggered an inflammatory cell death, which is mediated by the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome. Moreover, melatonin treatment significantly alleviated Cd induced liver injury by decreasing serum ALT/AST levels, suppressing pro inflammatory cytokine production, inhibiting NLRP3 inflammasome activation, ameliorating oxidative stress, and attenuating hepatocyte death. Most importantly, melatonin markedly abrogated Cd-induced TXNIP overexpression and decreased the interaction between TXNIP and NLRP3 in vivo and in vitro. However, treatment with siRNA targeting TXNIP blocked the protective effects of melatonin in Cd-treated primary hepatocytes. Collectively, our results suggest that melatonin confers protection against Cd-induced liver inflammation and hepatocyte death via inhibition of the TXNIP-NLRP3 inflammasome pathway. PMID- 28099759 TI - Usefulness of the WHO C-Model to optimize the cesarean delivery rate in a tertiary hospital setting. AB - OBJECTIVE: To assess use of the C-Model in a tertiary hospital setting in terms of its validity and utility for optimizing the cesarean delivery (CD) rate. METHODS: A prospective observational study included women admitted for delivery at a university teaching hospital in Assiut, Egypt, in 2015. The women were asked about the demographic and obstetric information needed to calculate the probability of CD using the WHO C-Model. A receiver operating characteristic (ROC) curve comparing the predicted and observed CD rates was constructed. In addition, the mean predicted CD rates were compared with the mean observed CD rates in the 10 groups of the Robson classification. RESULTS: In total, 1000 women were recruited; 38.6% had a previous CD and 13.5% had complications during the current pregnancy. The final mode of delivery was vaginal delivery in 38.7% and CD in 61.3%; the predicted CD rate for this cohort was 45.0%. The area under the ROC curve was 0.928 (95% confidence interval 0.912-0.945). Comparison of the predicted and observed CD rates in the 10 Robson groups showed an overuse of CD ranging from 2% to 50%. CONCLUSION: The WHO C-Model is valid and can be used in hospital settings to optimize CD rates. PMID- 28099760 TI - Clinical, behavioural and social indicators for poor glycaemic control around the time of transfer to adult care: a longitudinal study of 126 young people with diabetes. AB - AIMS: To describe and compare changes in glycaemic control in young people with Type 1 diabetes over time between the last 2 years in paediatric care and the first 2 years in adult care and to identify risk factors for poor glycaemic control. METHODS: Our retrospective cohort study followed participants aged 14-22 years from 2 years before to 2 years after transfer from paediatric to adult care. Changes in glycaemic control were calculated using repeated measurements. We adjusted for gender, age at diabetes onset, age at transfer, duration of diabetes at transfer, gap (amount of time) between last paediatric and first adult visit, comorbidity, learning disability and/or mental health conditions and family structure. We examined associations between acute hospital admissions, low visit attendance rate, loss to follow-up and baseline HbA1c level. RESULTS: Among 126 participants, the mean HbA1c level was 80 mmol/mol (9.4%) pre-transfer but decreased by an average of 3 mmol/mol (0.3%) each year post-transfer (P = 0.005). Young people with a learning disability and/or a mental health condition had worse glycaemic control (P = 0.041) and the mean HbA1c of those with divorced parents was 14 mmol/mol (1.2%) higher (P = 0.014). Almost one-third of participants were admitted to the hospital for acute diabetes care. Low visit attendance rate, high baseline HbA1c level, learning disability and/or mental health conditions and divorced parents predicted acute hospital admissions. CONCLUSIONS: Glycaemic control improved significantly after transfer to adult care, but the mean HbA1c level remained high. Future interventions should focus on young people with divorced parents, those with a learning disability and/or mental health condition and those who do not attend clinical visits to improve HbA1c levels and thereby reduce hospitalization rates. PMID- 28099761 TI - Size structuring and allometric scaling relationships in coral reef fishes. AB - Temperate marine fish communities are often size-structured, with predators consuming increasingly larger prey and feeding at higher trophic levels as they grow. Gape limitation and ontogenetic diet shifts are key mechanisms by which size structuring arises in these communities. Little is known, however, about size structuring in coral reef fishes. Here, we aimed to advance understanding of size structuring in coral reef food webs by examining the evidence for these mechanisms in two groups of reef predators. Given the diversity of feeding modes amongst coral reef fishes, we also compared gape size-body size allometric relationships across functional groups to determine whether they are reliable indicators of size structuring. We used gut content analysis and quantile regressions of predator size-prey size relationships to test for evidence of gape limitation and ontogenetic niche shifts in reef piscivores (n = 13 species) and benthic invertivores (n = 3 species). We then estimated gape size-body size allometric scaling coefficients for 21 different species from four functional groups, including herbivores/detritivores, which are not expected to be gape limited. We found evidence of both mechanisms for size structuring in coral reef piscivores, with maximum prey size scaling positively with predator body size, and ontogenetic diet shifts including prey type and expansion of prey size. There was, however, little evidence of size structuring in benthic invertivores. Across species and functional groups, absolute and relative gape sizes were largest in piscivores as expected, but gape size-body size scaling relationships were not indicative of size structuring. Instead, relative gape sizes and mouth morphologies may be better indicators. Our results provide evidence that coral reef piscivores are size-structured and that gape limitation and ontogenetic niche shifts are the mechanisms from which this structure arises. Although gape allometry was not indicative of size structuring, it may have implications for ecosystem function: positively allometric gape size-body size scaling relationships in herbivores/detritivores suggests that loss of large-bodied individuals of these species will have a disproportionately negative impact on reef grazing pressure. PMID- 28099762 TI - Human transporters, PEPT1/2, facilitate melatonin transportation into mitochondria of cancer cells: An implication of the therapeutic potential. AB - Melatonin is present in virtually all organisms from bacteria to mammals, and it exhibits a broad spectrum of biological functions, including synchronization of circadian rhythms and oncostatic activity. Several functions of melatonin are mediated by its membrane receptors, but others are receptor-independent. For the latter, melatonin is required to penetrate membrane and enters intracellular compartments. However, the mechanism by which melatonin enters cells remains debatable. In this study, it was identified that melatonin and its sulfation metabolites were the substrates of oligopeptide transporter (PEPT) 1/2 and organic anion transporter (OAT) 3, respectively. The docking analysis showed that the binding of melatonin to PEPT1/2 was attributed to their low binding energy and suitable binding conformation in which melatonin was embedded in the active site of PEPT1/2 and fitted well with the cavity in three-dimensional space. PEPT1/2 transporters play a pivotal role in melatonin uptake in cells. Melatonin's membrane transportation via PEPT1/2 renders its oncostatic effect in malignant cells. For the first time, PEPT1/2 were identified to localize in the mitochondrial membrane of human cancer cell lines of PC3 and U118. PEPT1/2 facilitated the transportation of melatonin into mitochondria. Melatonin accumulation in mitochondria induced apoptosis of PC3 and U118 cells. Thus, PEPT1/2 can potentially be used as a cancer cell-targeted melatonin delivery system to improve the therapeutic effects of melatonin in cancer treatment. PMID- 28099763 TI - The effectiveness of a multidisciplinary, team-based approach to cesarean hysterectomy in modern obstetric practice. AB - OBJECTIVE: To examine the effectiveness of a multidisciplinary, team-based approach to management of cesarean hysterectomy. METHODS: In a retrospective chart review, data were analyzed from a quality assurance database of hysterectomies performed after cesarean delivery at one institution in the USA. Patients were identified through billing codes for cesarean delivery, cross referenced to codes for hysterectomy. Demographic, reproductive, and outcome data were compared before (2000-2005) and after (2011-2013) implementation of a multidisciplinary team-based protocol. RESULTS: Across the two study periods, 107 cesarean hysterectomies were identified (69 pre-implementation, 38 post implementation). In univariate analysis, the post-implementation group had fewer days in surgical intensive care than did the pre-implementation group (0.21 +/- 0.41 vs 1.04 +/- 2.44 days; P=0.011), and a lower frequency of febrile morbidity (4 [11%] vs 22 [32%]; P=0.033]. In multivariate analysis with adjustment for potential confounders, the likelihood of postoperative febrile morbidity was higher during the pre-implementation than the post-implementation period (adjusted odds ratio 3.5, 95% confidence interval 1.09-13.65; P=0.048). CONCLUSION: Outcomes were improved after the multidisciplinary team-based approach to cesarean hysterectomy was implemented. Team-based approaches to care of women undergoing cesarean hysterectomy are important to improve outcomes. PMID- 28099764 TI - The Posttraumatic Growth Inventory: A Revision Integrating Existential and Spiritual Change. AB - Spiritual Change (SC) is one of 5 domains of posttraumatic growth (PTG). The current Posttraumatic Growth Inventory (PTGI) assesses this area of growth with only 2 items, one focusing on religiosity and the other focusing on spiritual understanding. The addition of 4 newly developed spiritual-existential change (SEC) items, creating an expanded PTGI (Posttraumatic Growth Inventory-X), reflects a diversity of perspectives on spiritual-existential experiences that are represented in different cultures. Samples were obtained from 3 countries: the United States (n = 250), Turkey (n = 502), and Japan (n = 314). Analyses indicated that the newly added items capture additional experiences of growth outside traditional religious concepts, yet still are correlated with the original SC items, especially in the U.S. and Turkish samples. Relationships of the PTGI-X to established predictors of PTG, event-related rumination, and core beliefs, were as predicted in all 3 countries. The new 6-item SEC factor demonstrated high internal reliability, and the 5-factor structure of the expanded scale was supported by confirmatory factor analysis. The resulting 25 item PTGI-X can be used as a validated instrument in a wide range of samples in which traditional religious beliefs are less dominant. PMID- 28099765 TI - When and why does sex chromosome dosage compensation evolve? AB - In many species, sex is determined by sex chromosomes, and the sex-specific chromosome (Y or W) stops recombining until it degenerates and carries fewer genes than its recombining counterpart (X or Z). This creates an imbalance in the dosage of most sex-linked genes between males and females. Early work in model organisms demonstrated that X chromosomes in multiple groups independently evolved regulatory mechanisms maintaining balanced expression of X-linked genes. However, recent studies have shown that these dosage compensation mechanisms are far from universal. It remains unclear why dosage compensation mechanisms evolved in some groups of organisms and not others. Two factors have led to confusion in this area: first, different authors sometimes define dosage compensation in different ways; second, dosage compensation is sometimes viewed as an all-or nothing phenomenon, even though it may vary across cell types, developmental stages, and different classes of genes. Here, I discuss current approaches to testing for sex chromosome dosage compensation and highlight patterns in the phylogenetic distribution of dosage compensation mechanisms and possible explanations for those patterns. I conclude by outlining how the presence of dosage compensation can be tested in nearly any nonmodel organism and provide some recommendations for future studies. PMID- 28099766 TI - High Salinity Relaying to Reduce Vibrio parahaemolyticus and Vibrio vulnificus in Chesapeake Bay Oysters (Crassostrea virginica). AB - Cases of Vibrio infections in the United States have tripled from 1996 to 2009 and these infections are most often associated with the consumption of seafood, particularly oysters (Crassostrea virginica). Information is needed on how to reduce numbers of Vibrio parahaemolyticus and Vibrio vulnificus in bi-valve molluscan shellfish (for example, oysters). The purpose of this study was to evaluate the effectiveness of high salinity relaying or treatment in recirculating aquaculture systems (RASs) as methods to reduce the abundance of V. parahaemolyticus and V. vulnificus in oysters. For relaying field trials, oysters were collected from approved harvest waters, temperature abused outside under a tarp for 4 h, and then transferred to high (29 to 33 ppt.) and moderate (12 to 19 ppt.) salinities. For RAS treatment trial, oysters were transferred to 32 to 34 ppt. salinity at 15 degrees C. After 7, 14, 21, and in some instances 28 d, oysters were collected and analyzed for V. parahaemolyticus and V. vulnificus levels using multiplex real-time PCR. Initial levels of V. parahaemolyticus and V. vulnificus ranged from 3.70 to 5.64 log10 MPN/g, and were reduced by 2 to 5 logs after 21 to 28 d in high salinity water (29 to 34 ppt.). Oyster mortalities averaged 4% or less, and did not exceed 7%. Relaying of oysters to high salinity field sites or transfer to high salinity RAS tanks was more effective in reducing V. vulnificus compared with V. parahaemolyticus. These results suggest that high salinity relaying of oysters is more effective in reducing V. vulnificus than V. parahaemolyticus in the oyster species used in this study. PMID- 28099767 TI - A Comparative Study of Phenolic Antioxidant Activity and Flavonoid Biosynthesis Related Gene Expression Between Summer and Winter Strawberry Cultivars. AB - Strawberry (Fragaria ananassa Duch.) possesses good antioxidant properties. Phenolic compounds in strawberries, such as anthocyanins and ellagic acid, mainly act as antioxidants. This study aimed to compare the phenolic content and expression patterns of genes involved in flavonoid biosynthesis between summer and winter strawberry cultivars affected by seasonal variation, degree of ripeness, and genotype. Antioxidant activity and the total content of phenols and flavonoids decreased with fruit ripening. Most notably, summer strawberry cultivars showed higher antioxidant activity than winter cultivars. The expression patterns of flavonoid biosynthetic genes tested were cultivar dependent and were also affected by ripening. These results help us understand the nutritional and physiological characteristics of selected cultivars and provide a range of information for strawberry consumption. PMID- 28099768 TI - Effects of Metmyoglobin Reducing Activity and Thermal Stability of NADH-Dependent Reductase and Lactate Dehydrogenase on Premature Browning in Ground Beef. AB - Premature browning is a condition wherein ground beef exhibits a well-done appearance before reaching the USDA recommended internal cooked meat temperature of 71.1 degrees C; however, the mechanism is unclear. The objectives of this study were: (1) to determine the effects of packaging and temperature on metmyoglobin reducing activity (MRA) of cooked ground beef patties and (2) to assess the effects of temperature and pH on thermal stability of NADH-dependent reductase, lactate dehydrogenase (LDH), and oxymyoglobin (OxyMb) in-vitro. Beef patties (lean: fat = 85:15) were packaged in high-oxygen modified atmosphere (HiOX-MAP) or vacuum (VP) and cooked to either 65 or 71 degrees C. Internal meat color and MRA of both raw and cooked patties were determined. Purified NADH dependent reductase and LDH were used to determine the effects of pH and temperature on enzyme activity. MRA of cooked patties was temperature and packaging dependent (P < 0.05). Vacuum packaged patties cooked to 71 degrees C had greater (P < 0.05) MRA than HiOX-MAP counterparts. Thermal stability of OxyMb, NADH-dependent reductase, and LDH were different and pH-dependent. LDH was able to generate NADH at 84 degrees C; whereas NADH-dependent reductase was least stable to heat. The results suggest that patties have MRA at cooking temperatures, which can influence cooked meat color. PMID- 28099769 TI - Persistent Serious Mental Illness Among Former Applicants for VA PTSD Disability Benefits and Long-Term Outcomes: Symptoms, Functioning, and Employment. AB - : Millions of U.S. veterans have returned from military service with posttraumatic stress disorder (PTSD), for which a substantial number receive U.S. Department of Veterans Affairs (VA) disability benefits. Although PTSD is treatable, comorbid serious mental illness (defined here as schizophrenia, schizoaffective disorder, and bipolar spectrum disorders) could complicate these veterans' recovery. Using VA administrative data, we examined the burden of persistent serious mental illness in a nationally representative cohort of 1,067 men and 1,513 women who applied for VA PTSD disability benefits between 1994 and 1998 and served during or after the Vietnam conflict. Self-reported outcomes were restricted to the 713 men and 1,015 women who returned surveys at each of 3 collection points. More than 10.0% of men and 20.0% of women had persistent serious mental illness; of these, more than 80.0% also had persistent PTSD. On repeated measures modeling, those with persistent serious mental illness consistently reported more severe PTSD symptoms and poorer functioning in comparison to other participants (ps < .001); their employment rate did not exceed 21.0%. Interactions between persistent serious mental illness and PTSD were significant only for employment (p = .002). Persistent serious mental illness in this population was almost 2 to 19 times higher than in the general U.S. POPULATION: The implications of these findings are discussed. PMID- 28099770 TI - Cryptic lineages of a common alpine mayfly show strong life-history divergence. AB - Understanding ecological divergence of morphologically similar but genetically distinct species - previously considered as a single morphospecies - is of key importance in evolutionary ecology and conservation biology. Despite their morphological similarity, cryptic species may have evolved distinct adaptations. If such ecological divergence is unaccounted for, any predictions about their responses to environmental change and biodiversity loss may be biased. We used spatio-temporally replicated field surveys of larval cohort structure and population genetic analyses (using nuclear microsatellite markers) to test for life-history divergence between two cryptic lineages of the alpine mayfly Baetis alpinus in the Swiss Alps. We found that the more widespread and abundant cryptic lineage represents a 'generalist' with at least two cohorts per year, whereas the less abundant lineage is restricted to higher elevations and represents a 'specialist' with a single cohort per year. Importantly, our results indicate partial temporal segregation in reproductive periods between these lineages, potentially facilitating local coexistence and reproductive isolation. Taken together, our findings emphasize the need for a taxonomic revision: widespread and apparently generalist morphospecies can hide cryptic lineages with much narrower ecological niches and distribution ranges. PMID- 28099771 TI - Purging putative siblings from population genetic data sets: a cautionary view. AB - : Interest has surged recently in removing siblings from population genetic data sets before conducting downstream analyses. However, even if the pedigree is inferred correctly, this has the potential to do more harm than good. We used computer simulations and empirical samples of coho salmon to evaluate strategies for adjusting samples to account for family structure. We compared performance in full samples and sibling-reduced samples of estimators of allele frequency (P^), population differentiation (F^ST) and effective population size (N^e). RESULTS: (i) unless simulated samples included large family groups together with a component of unrelated individuals, removing siblings generally reduced precision of P^ and F^ST; (ii) N^e based on the linkage disequilibrium method was largely unbiased using full random samples but became increasingly upwardly biased under aggressive purging of siblings. Under nonrandom sampling (some families over represented), N^e using full samples was downwardly biased; removing just the right 'Goldilocks' fraction of siblings could produce an unbiased estimate, but this sweet spot varied widely among scenarios; (iii) weighting individuals based on the inferred pedigree (to produce a best linear unbiased estimator, BLUE) maximized precision of P^ when the inferred pedigree was correct but performed poorly when the pedigree was wrong; (iv) a variant of sibling removal that leaves intact small sibling groups appears to be more robust to errors in inferences about family structure. Our results illustrate the complex challenges posed by presence of family structure, suggest that no single optimal solution exists and argue for caution in adjusting population genetic data sets for the presence of putative siblings without fully understanding the consequences. PMID- 28099772 TI - Exploring the symbiont diversity of ancient western redcedars: arbuscular mycorrhizal fungi of long-lived hosts. AB - Arbuscular mycorrhizal fungi (AMF) are globally distributed, monophyletic root symbionts with ancient origins. Their contribution to carbon cycling and nutrient dynamics is ecologically important, given their obligate association with over 70% of vascular plant species. Current understanding of AMF species richness and community structure is based primarily on studies of grasses, herbs and agricultural crops, typically in disturbed environments. Few studies have considered AMF interactions with long-lived woody perennial species in undisturbed ecosystems. Here we examined AMF communities associated with roots and soils of young, mature and old western redcedar (Thuja plicata) at two sites in the old-growth temperate rainforests of British Columbia. Due to the unique biology of AMF, community richness and structure were assessed using a conservative, clade-based approach. We found 91 AMF OTUs across all samples, with significantly greater AMF richness in the southern site, but no differences in richness along the host chronosequence at either site. All host age classes harboured AMF communities that were overdispersed (more different to each other than expected by chance), with young tree communities most resembling old tree communities. A comparison with similar clade richness data obtained from the literature indicates that western redcedar AMF communities are as rich as those of grasses, tropical trees and palms. Our examination of undisturbed temperate old-growth rainforests suggests that priority effects, rather than succession, are an important aspect of AMF community assembly in this ecosystem. PMID- 28099773 TI - Comparison of green and albino individuals of the partially mycoheterotrophic orchid Epipactis helleborine on molecular identities of mycorrhizal fungi, nutritional modes and gene expression in mycorrhizal roots. AB - Some green orchids obtain carbon from their mycorrhizal fungi, as well as from photosynthesis. These partially mycoheterotrophic orchids sometimes produce fully achlorophyllous, leaf-bearing (albino) variants. Comparing green and albino individuals of these orchids will help to uncover the molecular mechanisms associated with mycoheterotrophy. We compared green and albino Epipactis helleborine by molecular barcoding of mycorrhizal fungi, nutrient sources based on 15 N and 13 C abundances and gene expression in their mycorrhizae by RNA-seq and cDNA de novo assembly. Molecular identification of mycorrhizal fungi showed that green and albino E. helleborine harboured similar mycobionts, mainly Wilcoxina. Stable isotope analyses indicated that albino E. helleborine plants were fully mycoheterotrophic, whereas green individuals were partially mycoheterotrophic. Gene expression analyses showed that genes involved in antioxidant metabolism were upregulated in the albino variants, which indicates that these plants experience greater oxidative stress than the green variants, possibly due to a more frequent lysis of intracellular pelotons. It was also found that some genes involved in the transport of some metabolites, including carbon sources from plant to fungus, are higher in albino than in green variants. This result may indicate a bidirectional carbon flow even in the mycoheterotrophic symbiosis. The genes related to mycorrhizal symbiosis in autotrophic orchids and arbuscular mycorrhizal plants were also upregulated in the albino variants, indicating the existence of common molecular mechanisms among the different mycorrhizal types. PMID- 28099774 TI - Drivers of soil and tree carbon dynamics in urban residential lawns: a modeling approach. AB - Soils constitute the largest sink of terrestrial carbon (C), and urban soils have the potential to provide significant soil C storage. Soils in urbanized landscapes experience a multitude of human alterations, such as compaction and management subsidies, that impact soil C dynamics. While field studies may provide data on urban soil C storage, modeling soil C dynamics under various human impact scenarios will provide a basis for identifying drivers of urban soil C dynamics and for predicting the potential for these highly altered soils to store C over time intervals not typically amenable to empirical validation. The goal of this study was to model soil C dynamics in residential lawns using CENTURY, a dynamic mechanistic model, to determine whether drivers of soil C dynamics in natural systems (e.g., soil texture) were equally useful for estimating soil C content of highly modified soils in urban residential areas. Without incorporating human impacts, we found no relationship between initial CENTURY model simulations and observed soil C (P > 0.05). Factors that best explained soil C accumulation for the observed soil C (bulk density, r2 = 0.30; home age, r2 = 0.37; P < 0.01) differed from those found important for the CENTURY model simulations (percent sand, r2 = 0.72, P < 0.001). Therefore, we conducted a modeling exercise to test whether simulating potential construction disturbance and lawn management practices would improve modeled soil and tree C. We found that incorporating these factors did improve CENTURY's ability to model soil and tree C (P < 0.001). The results from this analysis suggest that incorporating various human disturbances and management practices that occur in urban landscapes into CENTURY model runs will improve its ability to predict urban soil C dynamics, at least within a 100-yr time frame. Thus, enhancing our ability to provide recommendations for management and development practices that result in increasing urban soil C storage. PMID- 28099775 TI - The population genomic signature of environmental association and gene flow in an ecologically divergent tree species Metrosideros polymorpha (Myrtaceae). AB - Genomewide markers enable us to study genetic differentiation within a species and the factors underlying it at a much higher resolution than before, which advances our understanding of adaptation in organisms. We investigated genomic divergence in Metrosideros polymorpha, a woody species that occupies a wide range of ecological habitats across the Hawaiian Islands and shows remarkable phenotypic variation. Using 1659 single nucleotide polymorphism (SNP) markers annotated with the genome assembly, we examined the population genetic structure and demographic history of nine populations across five elevations and two ages of substrates on Mauna Loa, the island of Hawaii. The nine populations were differentiated into two genetic clusters distributed on the lower and higher elevations and were largely admixed on the middle elevation. Demographic modelling revealed that the two genetic clusters have been maintained in the face of gene flow, and the effective population size of the high-altitude cluster was much smaller. A FST -based outlier search among the 1659 SNPs revealed that 34 SNPs (2.05%) were likely to be under divergent selection and the allele frequencies of 21 of them were associated with environmental changes along elevations, such as temperature and precipitation. This study shows a genomic mosaic of M. polymorpha, in which contrasting divergence patterns were found. While most genomic polymorphisms were shared among populations, a small fraction of the genome was significantly differentiated between populations in diverse environments and could be responsible for the dramatic adaptation to a wide range of environments. PMID- 28099776 TI - Understanding the Connection Between Posttraumatic Stress Symptoms and Respiratory Problems: Contributions of Anxiety Sensitivity. AB - Respiratory problems and posttraumatic stress disorder (PTSD) are the signature health consequences associated with the September 11, 2001 (9/11), World Trade Center disaster and frequently co-occur. The reasons for this comorbidity, however, remain unknown. Anxiety sensitivity is a transdiagnostic trait that is associated with both PTSD and respiratory symptoms. The present study explored whether anxiety sensitivity could explain the experience of respiratory symptoms in trauma-exposed smokers with PTSD symptoms. Participants (N = 135; Mage = 49.18 years, SD = 10.01) were 9/11-exposed daily smokers. Cross-sectional self-report measures were used to assess PTSD symptoms, anxiety sensitivity, and respiratory symptoms. After controlling for covariates and PTSD symptoms, anxiety sensitivity accounted for significant additional variance in respiratory symptoms (DeltaR2 = .04 to .08). This effect was specific to the somatic concerns dimension (beta = .29, p = .020); somatic concerns contributed significantly to accounting for the overlap between PTSD and respiratory symptoms, b = 0.03, 95% CI [0.01, 0.07]. These findings suggest that the somatic dimension of anxiety sensitivity is important in understanding respiratory symptoms in individuals with PTSD symptoms. These findings also suggest that it may be critical to address anxiety sensitivity when treating patients with comorbid respiratory problems and PTSD. PMID- 28099777 TI - Positive selection on sperm ion channels in a brooding brittle star: consequence of life-history traits evolution. AB - Closely related species are key models to investigate mechanisms leading to reproductive isolation and early stages of diversification, also at the genomic level. The brittle star cryptic species complex Ophioderma longicauda encompasses the sympatric broadcast-spawning species C3 and the internal brooding species C5. Here, we used de novo transcriptome sequencing and assembly in two closely related species displaying contrasting reproductive modes to compare their genetic diversity and to investigate the role of natural selection in reproductive isolation. We reconstructed 20 146 and 22 123 genes for C3 and C5, respectively, and characterized a set of 12 229 orthologs. Genetic diversity was 1.5-2 times higher in C3 compared to C5, confirming that species with low parental investment display higher levels of genetic diversity. Forty-eight genes were the targets of positive diversifying selection during the evolution of the two species. Notably, two genes (NHE and TetraKCNG) are sperm-specific ion channels involved in sperm motility. Ancestral sequence reconstructions show that natural selection targeted the two genes in the brooding species. This may result from an adaptation to the novel environmental conditions surrounding sperm in the brooding species, either directly affecting sperm or via an increase in male/female conflict. This phenomenon could have promoted prezygotic reproductive isolation between C3 and C5. Finally, the sperm receptors to egg chemoattractants differed between C3 and C5 in the ligand-binding region. We propose that mechanisms of species-specific gamete recognition in brittle stars occur during sperm chemotaxis (sperm attraction towards the eggs), contrary to other marine invertebrates where prezygotic barriers to interspecific hybridization typically occur before sperm-egg fusion. PMID- 28099779 TI - Trapped within the city: integrating demography, time since isolation and population-specific traits to assess the genetic effects of urbanization. AB - Urbanization is a severe form of habitat fragmentation that can cause many species to be locally extirpated and many others to become trapped and isolated within an urban matrix. The role of drift in reducing genetic diversity and increasing genetic differentiation is well recognized in urban populations. However, explicit incorporation and analysis of the demographic and temporal factors promoting drift in urban environments are poorly studied. Here, we genotyped 15 microsatellites in 320 fire salamanders from the historical city of Oviedo (Est. 8th century) to assess the effects of time since isolation, demographic history (historical effective population size; Ne ) and patch size on genetic diversity, population structure and contemporary Ne . Our results indicate that urban populations of fire salamanders are highly differentiated, most likely due to the recent Ne declines, as calculated in coalescence analyses, concomitant with the urban development of Oviedo. However, urbanization only caused a small loss of genetic diversity. Regression modelling showed that patch size was positively associated with contemporary Ne , while we found only moderate support for the effects of demographic history when excluding populations with unresolved history. This highlights the interplay between different factors in determining current genetic diversity and structure. Overall, the results of our study on urban populations of fire salamanders provide some of the very first insights into the mechanisms affecting changes in genetic diversity and population differentiation via drift in urban environments, a crucial subject in a world where increasing urbanization is forecasted. PMID- 28099778 TI - Pseudozyma and other non-Candida opportunistic yeast bloodstream infections in a large stem cell transplant center. AB - Non-Candida opportunistic yeasts are emerging causes of bloodstream infection (BSI) in immunocompromised hosts. However, their clinical presentation, management, and outcomes in stem cell transplant (SCT) recipients are not well described. We report the first case to our knowledge of Pseudozyma BSI in a SCT recipient. He had evidence of cutaneous involvement, which has not been previously described in the literature. He became infected while neutropenic and receiving empiric micafungin, which is notable because Pseudozyma is reported to be resistant to echinocandins. He was successfully treated with the sequential use of liposomal amphotericin B and voriconazole. A review of the literature revealed nine reported instances of Pseudozyma fungemia. We performed a retrospective review of 3557 SCT recipients at our institution from January 2000 to June 2015 and identified four additional cases of non-Candida yeast BSIs. These include two with Cryptococcus, one with Trichosporon, and one with Saccharomyces. Pseudozyma and other non-Candida yeasts are emerging pathogens that can cause severe and disseminated infections in SCT recipients and other immunocompromised hosts. Clinicians should have a high degree of suspicion for echinocandin-resistant yeasts, if patients develop breakthrough yeast BSIs while receiving echinocandin therapy. PMID- 28099780 TI - The genetic architecture of defence as resistance to and tolerance of bacterial infection in Drosophila melanogaster. AB - Defence against pathogenic infection can take two forms: resistance and tolerance. Resistance is the ability of the host to limit a pathogen burden, whereas tolerance is the ability to limit the negative consequences of infection at a given level of infection intensity. Evolutionarily, a tolerance strategy that is independent of resistance could allow the host to avoid mounting a costly immune response and, theoretically, to avoid a co-evolutionary arms race between pathogen virulence and host resistance. Biomedically, understanding the mechanisms of tolerance and how they relate to resistance could potentially yield treatment strategies that focus on health improvement instead of pathogen elimination. To understand the impact of tolerance on host defence and identify genetic variants that determine host tolerance, we defined genetic variation in tolerance as the residual deviation from a binomial regression of fitness under infection against infection intensity. We then performed a genomewide association study to map the genetic basis of variation in resistance to and tolerance of infection by the bacterium Providencia rettgeri. We found a positive genetic correlation between resistance and tolerance, and we demonstrated that the level of resistance is highly predictive of tolerance. We identified 30 loci that predict tolerance, many of which are in genes involved in the regulation of immunity and metabolism. We used RNAi to confirm that a subset of mapped genes have a role in defence, including putative wound repair genes grainy head and debris buster. Our results indicate that tolerance is not an independent strategy from resistance, but that defence arises from a collection of physiological processes intertwined with canonical immunity and resistance. PMID- 28099781 TI - Old Drug Scaffold, New Activity: Thalidomide-Correlated Compounds Exert Different Effects on Breast Cancer Cell Growth and Progression. AB - Thalidomide was first used for relief of morning sickness in pregnant women and then withdrawn from the market because of its dramatic effects on normal fetal development. Over the last decades, it has been used successfully for the treatment of several pathologies, including cancer. Many analogues with improved activity have been synthesized and tested. Herein we report some effects on the growth and progression of MCF-7 and MDA-MB-231 breast cancer cells by a small series of thalidomide-correlated compounds, which are very effective at inducing cancer cell death by triggering TNFalpha-mediated apoptosis. The most active compounds are able to drastically reduce the migration of breast cancer cells by regulation of the two major proteins involved in epithelial-mesenchymal transition (EMT): vimentin and E-cadherin. Moreover, these compounds diminish the intracellular biosynthesis of vascular endothelial growth factor (VEGF), which is primarily involved in the promotion of angiogenesis, sustaining tumor progression. The multiple features of these compounds that act on various key points of the tumorigenesis process make them good candidates for preclinical studies. PMID- 28099782 TI - Back to basics: using colour polymorphisms to study evolutionary processes. AB - Here, I suggest that colour polymorphic study systems have been underutilized to answer general questions about evolutionary processes, such as morph frequency dynamics between generations and population divergence in morph frequencies. Colour polymorphisms can be used to study fundamental evolutionary processes like frequency-dependent selection, gene flow, recombination and correlational selection for adaptive character combinations. However, many previous studies of colour polymorphism often suffer from weak connections to population genetic theory. I argue that too much focus has been directed towards noticeable visual traits (colour) at the expense of understanding the evolutionary processes shaping genetic variation and covariation associated with polymorphisms in general. There is thus no need for a specific evolutionary theory for colour polymorphisms beyond the general theory of the maintenance of polymorphisms in spatially or temporally variable environments or through positive or negative frequency-dependent selection. I outline an integrative research programme incorporating these processes and suggest some fruitful avenues in future investigations of colour polymorphisms. PMID- 28099783 TI - Ketosis and diabetic ketoacidosis in response to SGLT2 inhibitors: Basic mechanisms and therapeutic perspectives. AB - Inhibitors of the sodium-glucose cotransporter SGLT2 are a new class of antihyperglycemic drugs that have been approved for the treatment of type 2 diabetes mellitus (T2DM). These drugs inhibit glucose reabsorption in the proximal tubules of the kidney thereby enhancing glucosuria and lowering blood glucose levels. Additional consequences and benefits include a reduction in body weight, uric acid levels, and blood pressure. Moreover, SGLT2 inhibition can have protective effects on the kidney and cardiovascular system in patients with T2DM and high cardiovascular risk. However, a potential side effect that has been reported with SGLT2 inhibitors in patients with T2DM and particularly during off label use in patients with type 1 diabetes is diabetic ketoacidosis. The US Food and Drug Administration recently warned that SGLT2 inhibitors may result in euglycemic ketoacidosis. Here, we review the basic metabolism of ketone bodies, the triggers of diabetic ketoacidosis, and potential mechanisms by which SGLT2 inhibitors may facilitate the development of ketosis or ketoacidosis. This provides the rationale for measures to lower the risk. We discuss the role of the kidney and potential links to renal gluconeogenesis and uric acid handling. Moreover, we outline potential beneficial effects of modestly elevated ketone body levels on organ function that may have therapeutic relevance for the observed beneficial effects of SGLT2 inhibitors on the kidney and cardiovascular system. PMID- 28099784 TI - Investigating the extent of parallelism in morphological and genomic divergence among lake trout ecotypes in Lake Superior. AB - Understanding the emergence of species through the process of ecological speciation is a central question in evolutionary biology which also has implications for conservation and management. Lake trout (Salvelinus namaycush) is renowned for the occurrence of different ecotypes linked to resource and habitat use throughout North America. We aimed to unravel the fine genetic structure of the four lake trout ecotypes in Lake Superior. A total of 486 individuals from four sites were genotyped at 6822 filtered SNPs using RADseq technology. Our results revealed different extent of morphological and genetic differentiation within the different sites. Overall, genetic differentiation was weak but significant and was on average three times higher between sites (mean FST = 0.016) than between ecotypes within sites (mean FST = 0.005) indicating higher level of gene flow or a more recent shared ancestor between ecotypes within each site than between populations of the same ecotype. Evidence of divergent selection was also found between ecotypes and/or in association with morphological variation. Outlier loci found in genes related to lipid metabolism and visual acuity were of particular interest in this context of ecotypic divergence. However, we did not find clear indication of parallelism at the genomic level, despite the presence of phenotypic parallelism among some ecotypes from different sampling sites. Overall, the occurrence of different levels of both genomic and phenotypic differentiation between ecotypes within each site with several differentiated loci linked to relevant biological functions supports the presence of a continuum of divergence in lake trout. PMID- 28099785 TI - A Dual Topoisomerase Inhibitor of Intense Pro-Apoptotic and Antileukemic Nature for Cancer Treatment. AB - Classic cytotoxic drugs remain indispensable instruments in antitumor therapy due to their effectiveness and a more prevalent insensitivity toward tumor resistance mechanisms. Herein we describe the favorable properties of 6-(N,N-dimethyl-2 aminoethoxy)-11-(3,4,5-trimethoxyphenyl)pyrido[3,4-c][1,9]phenanthroline (P8-D6), a powerful inducer of apoptosis caused by an equipotent inhibition of human topoisomerase I and II activities. A broad-spectrum effect against human tumor cell lines at nanomolar concentrations, as well as strong antileukemic effects, were shown to be superior to those of marketed topoisomerase-targeting drugs and dual topoisomerase inhibitors in clinical trials. The facile four-step synthesis, advantageous drugability properties, and initial in vivo data encourage the application of P8-D6 in appropriate animal tumor models and further drug development. PMID- 28099786 TI - Labor Intervention and Outcomes in Women Who Are Nulliparous and Obese: Comparison of Nurse-Midwife to Obstetrician Intrapartum Care. AB - BACKGROUND: Women who are obese have slower labors than women of normal weight, and show reduced response to interventions designed to speed labor progress like oxytocin augmentation and artificial rupture of membranes. The optimal labor management for these women has not been described. METHODS: This retrospective cohort study compared 2 propensity score-matched groups of women (N = 360) who were healthy, nulliparous, spontaneously laboring, and obese (body mass index >= 30 kg/m2 ). Labors were managed by either a certified nurse-midwife (CNM) or an obstetrician at one hospital from 2005 through 2012. Comparisons were made on a range of labor processes and outcomes. RESULTS: Women who were obese and cared for in labor by CNMs were 87.0% less likely to have operative vaginal birth (adjusted odds ratio [aOR], 0.15; 95% confidence interval [CI], 0.06-0.41) and 76.3% less likely to have third- or fourth-degree perineal lacerations (aOR, 0.31; 95% CI, 0.13-0.79) compared to a matched group of women who were obese and had similarly sized neonates but who were cared for by obstetricians. The rates of unplanned cesarean birth, postpartum hemorrhage, maternal intrapartum fever, and neonatal intensive care unit admission were similar between groups. CNM patients were significantly less likely than patients of obstetricians to have labor anesthesia, synthetic oxytocin augmentation, or intrauterine pressure catheters. By contrast, CNM patients were significantly more likely than patients of obstetricians to use physiologic labor interventions, including intermittent fetal monitoring, ambulation, and hydrotherapy. DISCUSSION: In women with spontaneous labor onset who were healthy, obese, and nulliparous, watchful waiting and use of physiologic labor interventions, characterizing CNM intrapartum care, were associated with outcomes that were similar to, or better than, those of women who were obese and exposed to more high-technology interventions characterizing intrapartum care by obstetricians. In women who were obese, physiologic labor interventions were safe for both mothers and neonates. PMID- 28099787 TI - Cultural Sensitivity Among Clinical Nurses: A Descriptive Study. AB - PURPOSE: The purpose of this study was to investigate the cultural sensitivity of nurses working in rural and urban hospitals in Turkey. DESIGN AND METHODS: The sampling of this descriptive and correlational study was composed of only 516 clinical nurses working in inpatient clinics. The data collection tools were the Socio-Demographic Questionnaire and the Intercultural Sensitivity Scale. FINDINGS: A majority of the participating nurses experienced culture-related problems. Intercultural Sensitivity Scale results were partially high. The nurses had more problems in areas related to language barriers, patients' education level, and health perception about disease and religious beliefs when providing health care. Participants who were female, had an undergraduate or graduate education, had received in-service education on cultural care, or had taken transcultural nursing coursework obtained higher scores on the Intercultural Sensitivity Scale and its Interaction Engagement subscale. The cultural sensitivity level was 84.01 +/- 9.1 (range = 43-107). The proportion of nurses who had received no in-service education was very high. They wanted to participate in an education program to gain better understanding of the culture of the society in which they lived. CONCLUSIONS: The results of the present study demonstrated that nurses should be prepared in cultural sensitivity and cultural competence. CLINICAL RELEVANCE: Continuing education and formal courses on cultural sensitivity for nursing professionals are essential for optimal health outcomes. Thus, inequalities in health could be prevented and the quality of health care could be improved. PMID- 28099788 TI - Deploying and measuring a risk and patient safety program. AB - Health care continues to evolve at a rapid rate. Over just the past decade, the industry has seen the introduction and widespread implementation of an electronic health record, increase in presence of nurse practitioners and physician assistants to help manage the shortage of physicians, and the introduction of accountable care organizations. It is with these changes that new challenges and opportunities emerge. One such challenge is the increase in the severity of medical malpractice claims throughout the nation. Another emerging challenge is the introduction of outcome-based reimbursements, with providers potentially losing a portion of their payment should the patient experience result in a preventable adverse event. These trends are resulting in providers continuously seeking innovative approaches to reducing risk and improving patient safety. PMID- 28099789 TI - EHR-related medication errors in two ICUs. AB - The objective of this study was to describe the frequency, potential harm, and nature of electronic health record (EHR)-related medication errors in intensive care units (ICUs). Using a secondary data analysis of a large database of medication safety events collected in a study on EHR technology in ICUs, we assessed the EHR relatedness of a total of 1622 potential preventable adverse drug events (ADEs) identified in a sample of 624 patients in 2 ICUs of a medical center. Thirty-four percent of the medication events were found to be EHR related. The EHR-related medication events had greater potential for more serious patient harm and occurred more frequently at the ordering stage as compared to non-EHR-related events. Examples of EHR-related events included orders with omitted information and duplicate orders. The list of EHR-related medication errors can be used by health care delivery organizations to monitor implementation and use of the technology and its impact on patient safety. Health information technology (IT) vendors can use the list to examine whether their technology can mitigate or reduce EHR-related medication errors. PMID- 28099790 TI - Case law update. PMID- 28099791 TI - Mitigating the prescription drug abuse epidemic. AB - Focused attention on the prescription drug abuse epidemic needs to include evidence-based training for clinicians who manage patients with pain to facilitate accurate screening with consideration of comorbid conditions, diagnosis, selection of the appropriate treatment regimen, and focused monitoring of adherence to the established course of therapy. DEA licensure requirements need to be amended to mandate targeted training focused on pain medication upon initial application and renewal of license. A nationwide mandated real-time dispenser database that requires verification every time a clinician prescribes opioids and other key controlled substances should be a top priority. PMID- 28099792 TI - Implementing an error disclosure coaching model: A multicenter case study. AB - National guidelines call for health care organizations to provide around-the clock coaching for medical error disclosure. However, frontline clinicians may not always seek risk managers for coaching. As part of a demonstration project designed to improve patient safety and reduce malpractice liability, we trained multidisciplinary disclosure coaches at 8 health care organizations in Washington State. The training was highly rated by participants, although not all emerged confident in their coaching skill. This multisite intervention can serve as a model for other organizations looking to enhance existing disclosure capabilities. Success likely requires cultural change and repeated practice opportunities for coaches. PMID- 28099793 TI - Risks without walls. PMID- 28099794 TI - The formula for being a successful risk manager. PMID- 28099795 TI - Failures of foreseeability: Risk management considerations in reducing allegations of sexual violence in psychiatric units. AB - This article begins with a brief discussion of findings on causal factors leading to allegations of sexual violence in health care facilities and then offers the author's account of 4 such cases that he reviewed, 3 of which occurred in psychiatric units. These cases show remarkably similar variables, especially involving decisions to allow male and female patients to commingle, the inadequate physical layout of the units, poor or absent video surveillance, and staff unacquainted with institutional policies on patient safety or refusing to enforce relevant rules. These variables arguably amount to "failures of foreseeability" that reasonably cautious health care personnel should recognize as facilitating or enabling sexual violence. As such, the proactive message of this article for health care risk management urges critical and robust attention paid to a unit's environmental/physical design as well as to performance factors among personnel so as to prevent sexual attacks and diminish the probability of malpractice actions. PMID- 28099796 TI - A Fixed-Dose Combination of Bisoprolol and Amlodipine for Hypertension: A Potential Benefit to Selected Patients. PMID- 28099797 TI - Epitaxy-Induced Assembly and Enantiomeric Switching of an On-Surface Formed Dinuclear Organocobalt Complex. AB - We report on the surface-guided synthesis of a dinuclear organocobalt complex, its self-assembly into a complex nanoarchitecture, and a single-molecule level investigation of its switching behavior. Initially, an organic layer is prepared by depositing hexakis((trimethylsilyl)ethynyl)-benzene under ultrahigh-vacuum conditions onto Ag(111). After Co dosage at 200 K, low-temperature scanning tunneling microscopy (STM) reveals an epitaxy-mediated organization mechanism of molecules and on-surface formed organometallic complexes. The dinuclear complexes contain two bis(eta2-alkynyl) pi-tweezer motifs, each stabilizing a single Co atom and express two enantiomers due to a conformation twist. The chirality is transferred to the two-dimensional architecture, whereby its Co adatoms are located at the corners of a 3.4.6.4 rhombitrihexagonal tessellation due to the systematic arrangement and anchoring of the complexes. Extensive density functional theory simulations support our interpretation of an epitaxy-guided surface tessellation and its chiral character. Additionally, STM tip-assisted manipulation experiments on isolated dinuclear complexes reveal controlled and reversible switching between the enantiomeric states via inelastic electron processes. After activation by bias pulses, structurally modified complexes display a distinctive Kondo feature attributed to metastable Co configurations. PMID- 28099798 TI - Development of a QuEChERS-Based Method for the Simultaneous Determination of Acidic Pesticides, Their Esters, and Conjugates Following Alkaline Hydrolysis. AB - An analytical procedure was developed allowing the simultaneous determination of acidic pesticides and their conjugates by addition of an alkaline hydrolysis step into the European Union (EU) version of the QuEChERS method. The procedure resulted additionally in hydrolysis of most esters of phenoxy acids. On the basis of information from metabolism studies and the hydrolytic conditions employed in supervised field trials as well as results on the influence of physical and chemical parameters (temperature, time, type of solvent, type of matrix), alkaline hydrolysis for 30 min at 40 degrees C was deemed a good compromise for the determination of residues of 2,4-D, dichlorprop, fluazifop, haloxyfop, MCPA, and MCPB. The applicability of the proposed method was tested by analyzing food samples with incurred residues in six German laboratories not involved in method development. Up to 6 times higher residues are measured by using the QuEChERS extraction procedure with the newly developed alkaline hydrolysis step. PMID- 28099799 TI - Hierarchically Porous Electrocatalyst with Vertically Aligned Defect-Rich CoMoS Nanosheets for the Hydrogen Evolution Reaction in an Alkaline Medium. AB - Effective electrocatalysts for the hydrogen evolution reaction (HER) in alkaline electrolytes can be developed via a simple solvothermal process. In this work, first, the prepared CoMoS nanomaterials through solvothermal treatment have a porous, defect-rich, and vertically aligned nanostructure, which is beneficial for the HER in an alkaline medium. Second, electron transfer from cobalt to MoS2 that reduces the unoccupied d orbitals of molybdenum can also enhance the HER kinetics in an alkaline medium. This has been demonstrated via a comparison of the catalytic performances of CoMoS, CoS, and MoS2. Third, the solvothermal treatment time evidently impacts the electrocatalytic activity. As a result, after 24 h of solvothermal treatment, the prepared CoMoS nanomaterials exhibit the lowest onset potential (42 mV) and overpotential (98 mV) for delivering a current density of 10 mA cm-2 in a 1 M KOH solution. Thus, this study provides a simple method to prepare efficient electrocatalysts for the HER in an alkaline medium. PMID- 28099800 TI - Interfacial Structures of Trihexyltetradecylphosphonium-bis(mandelato)borate Ionic Liquid Confined between Gold Electrodes. AB - Atomistic molecular dynamics simulations have been performed to study microscopic the interfacial ionic structures, molecular arrangements, and orientational preferences of trihexyltetradecylphosphonium-bis(mandelato)borate ([P6,6,6,14][BMB]) ionic liquid confined between neutral and charged gold electrodes. It was found that both [P6,6,6,14] cations and [BMB] anions are coabsorbed onto neutral electrodes at different temperatures. The hexyl and tetradecyl chains in [P6,6,6,14] cations lie preferentially flat on neutral electrodes. The oxalato and phenyl rings in [BMB] anions are characterized by alternative parallel-perpendicular orientations in the mixed innermost ionic layer adjacent to neutral electrodes. An increase in temperature has a marginal effect on the interfacial ionic structures and molecular orientations of [P6,6,6,14][BMB] ionic species in a confined environment. Electrifying gold electrodes leads to peculiar changes in the interfacial ionic structures and molecular orientational arrangements of [P6,6,6,14] cations and [BMB] anions in negatively and positively charged gold electrodes, respectively. As surface charge density increases (but lower than 20 MUC/cm2), the layer thickness of the mixed innermost interfacial layer gradually increases due to a consecutive accumulation of [P6,6,6,14] cations and [BMB] anions at negatively and positively charged electrodes, respectively, before the formation of distinct cationic and anionic innermost layers. Meanwhile, the molecular orientations of two oxalato rings in the same [BMB] anions change gradually from a parallel-perpendicular feature to being partially characterized by a tilted arrangement at an angle of 45 degrees from the electrodes and finally to a dominant parallel coordination pattern along positively charged electrodes. Distinctive interfacial distribution patterns are also observed accordingly for phenyl rings that are directly connected to neighboring oxalato rings in [BMB] anions. PMID- 28099801 TI - Highly Specific and Sensitive Fluorescent Nanoprobes for Image-Guided Resection of Sub-Millimeter Peritoneal Tumors. AB - A current challenge in the treatment of peritoneal carcinomatosis is the inability to detect, visualize, and resect small or microscopic tumors of pancreatic, ovarian, or mesothelial origin. In these diseases, the completeness of primary tumor resection is directly correlated with patient survival, and hence, identifying small sub-millimeter tumors (i.e., disseminated disease) is critical. Thus, new imaging techniques and probes are needed to improve cytoreductive surgery and patient outcomes. Highly fluorescent rhodamine-labeled expansile nanoparticles (HFR-eNPs) are described for use as a visual aid during cytoreductive surgery of pancreatic carcinomatosis. The covalent incorporation of rhodamine into ~30 nm eNPs increases the fluorescent signal compared to free rhodamine, thereby affording a brighter and more effective probe than would be achieved by a single rhodamine molecule. Using the intraperitoneal route of administration, HFR-eNPs localize to regions of large (~1 cm), sub-centimeter, and sub-millimeter intraperitoneal tumor in three different animal models, including pancreatic, mesothelioma, and ovarian carcinoma. Tumoral localization of the HFR-eNPs depends on both the material property (i.e., eNP polymer) as well as the surface chemistry (anionic surfactant vs PEGylated noncharged surfactant). In a rat model of pancreatic carcinomatosis, HFR-eNP identification of tumor is validated against gold-standard histopathological analysis to reveal that HFR eNPs possess high specificity (99%) and sensitivity (92%) for tumors, in particular, sub-centimeter and microscopic sub-millimeter tumors, with an overall accuracy of 95%. Finally, as a proof-of-concept, HFR-eNPs are used to guide the resection of pancreatic tumors in a rat model of peritoneal carcinomatosis. PMID- 28099802 TI - Stabilization of Giant Fullerenes C2(41)-C90, D3(85)-C92, C1(132)-C94, C2(157) C96, and C1(175)-C98 by Encapsulation of a Large La2C2 Cluster: The Importance of Cluster-Cage Matching. AB - Successful isolation and unambiguous crystallographic assignment of a series of higher carbide cluster metallofullerenes present new insights into the molecular structures and cluster-cage interactions of endohedral metallofullerenes. These new species are identified as La2C2@C2(41)-C90, La2C2@D3(85)-C92, La2C2@C1(132) C94, La2C2@C2(157)-C96, and La2C2@C1(175)-C98. This is the first report for these new cage structures except for D3(85)-C92. Our experimental and theoretical results demonstrate that La2C92-106 are more inclined to exist stably in the carbide form La2C2@C90-104 rather than as the dimetallofullerenes La2@C92-106, which are rationalized by considering a synergistic effect of inserting a C2 unit into the cage, which ensures strong metal-cage interactions by partially neutralizing the charges from the metal ions and by fulfilling the coordination requirement of the La3+ ions as much as possible. PMID- 28099804 TI - Diastereoselective Borocyclopropanation of Allylic Ethers Using a Boromethylzinc Carbenoid. AB - A borocyclopropanation of (E)- and (Z)-allylic ethers and styrene derivatives via the Simmons-Smith reaction using a novel boromethylzinc carbenoid is described. The carbenoid precursor is prepared via a 3-step sequence from inexpensive and commercially available starting materials. This methodology allows for the preparation of 1,2,3-substituted borocyclopropanes in high yields and diastereoselectivities. Several postfunctionalization reactions were also performed to illustrate the versatility of these building blocks. PMID- 28099805 TI - The Importance of Cannizzaro-Type Reactions during Electrocatalytic Reduction of Carbon Dioxide. AB - A seemingly catalytically inactive electrode, boron-doped diamond (BDD), is found to be active for CO2 and CO reduction to formaldehyde and even methane. At very cathodic potentials, formic acid and methanol are formed as well. However, these products are the result of base-catalyzed Cannizzaro-type disproportionation reactions. A local alkaline environment near the electrode surface, caused by the hydrogen evolution reaction, initiates aldehyde disproportionation promoted by hydroxide ions, which leads to the formation of the corresponding carboxylic acid and alcohol. This phenomenon is strongly influenced by the electrolyte pH and buffer capacity and not limited to BDD or formaldehyde, but can be generalized to different electrode materials and to C2 and C3 aldehydes as well. The importance of these reactions is emphasized as the formation of acids and alcohols is often ascribed to direct CO2 reduction products. The results obtained here may explain the concomitant formation of acids and alcohols often observed during CO2 reduction. PMID- 28099803 TI - Deep Learning to Predict the Formation of Quinone Species in Drug Metabolism. AB - Many adverse drug reactions are thought to be caused by electrophilically reactive drug metabolites that conjugate to nucleophilic sites within DNA and proteins, causing cancer or toxic immune responses. Quinone species, including quinone-imines, quinone-methides, and imine-methides, are electrophilic Michael acceptors that are often highly reactive and comprise over 40% of all known reactive metabolites. Quinone metabolites are created by cytochromes P450 and peroxidases. For example, cytochromes P450 oxidize acetaminophen to N-acetyl-p benzoquinone imine, which is electrophilically reactive and covalently binds to nucleophilic sites within proteins. This reactive quinone metabolite elicits a toxic immune response when acetaminophen exceeds a safe dose. Using a deep learning approach, this study reports the first published method for predicting quinone formation: the formation of a quinone species by metabolic oxidation. We model both one- and two-step quinone formation, enabling accurate quinone formation predictions in nonobvious cases. We predict atom pairs that form quinones with an AUC accuracy of 97.6%, and we identify molecules that form quinones with 88.2% AUC. By modeling the formation of quinones, one of the most common types of reactive metabolites, our method provides a rapid screening tool for a key drug toxicity risk. The XenoSite quinone formation model is available at http://swami.wustl.edu/xenosite/p/quinone . PMID- 28099806 TI - Melting Behavior of Zipper-Structured Lipopeptides in Lipid Bilayer. AB - A zipper-structured lipopeptide is expected to play a role of "intelligent valve" in the lipid bilayer. In this paper, a series of zipper-structured lipopeptides have been designed for preparing thermocontrollable hybrid liposomes. Their conformational transition as a function of temperature in lipid bilayer has been investigated for understanding the influences of molecular structure and bilayer property on biofunction. The melting temperatures Tm of the lipopeptides have been found to depend on their molecular structures. When the lipopeptides have been doped in bilayer, an increase of size of alkyl chain increases the stability of the alpha-helix resulting in a decrease in fluidity of lipid bilayer. However, an increase of amino groups at N-terminal is found to decrease the stability of the spatial structure. The thermocontrollability of the "valve" in lipid bilayer is confirmed by drug release experiments under different temperatures. Meanwhile, effects of bilayer properties on the thermosensitivity of lipopeptides have also been investigated. Results show the Tm of lipopeptide doped in bilayer decreases with the increase of membrane fluidity. Furthermore, the reversibility of the thermocontrolled "valve" is also proven by release drug under intermittent temperatures. It could be concluded that the molecular structure of the lipopeptide, as well as the property of bilayer, give great influence on the biofunction of the hybrid liposomes. PMID- 28099807 TI - Investigation of Donor-Acceptor Stenhouse Adducts as New Visible Wavelength Responsive Switching Elements for Lipid-Based Liquid Crystalline Systems. AB - The ability of donor-acceptor Stenhouse adducts (DASAs) to function as a green light responsive switch for lipid-based liquid crystalline drug delivery systems was investigated. The host matrix comprising phytantriol cubic phase was selected due to its high sensitivity toward changes in lipid packing. Small-angle X-ray scattering demonstrated that the matrix undergoes rapid and fully reversible order-order phase transitions upon irradiation with 532 nm light, converting between the bicontinuous cubic phase and reversed hexagonal phases. This approach shows promise for use as an actuator for the development of visible wavelength light-activated, "on-demand" drug delivery systems. PMID- 28099808 TI - Dynamics in a Room-Temperature Ionic Liquid from the Cation Perspective: 2D IR Vibrational Echo Spectroscopy. AB - The dynamics of the room-temperature ionic liquid (RTIL) 1-butyl-3 methylimidazolium bis(trifluoromethylsulfonyl)imide (BmimNTf2) were investigated with two-dimensional infrared (2D IR) vibrational echo spectroscopy and polarization selective pump-probe (PSPP) experiments. The CN stretch frequency of a modified Bmim+ cation (2-SeCN-Bmim+), in which a SeCN moiety was substituted onto the C-2 position of the imidazolium ring, was used as a vibrational probe. A major result of the 2D IR experiments is the observation of a long time scale structural spectral diffusion component of 600 ps in addition to short and intermediate time scales similar to those measured for selenocyanate anion (SeCN ) dissolved in BmimNTf2. In contrast to 2-SeCN-Bmim+, SeCN- samples its inhomogeneous line width nearly an order of magnitude faster than the complete structural randomization time of neat BmimNTf2 liquid (870 +/- 20 ps) measured with optical heterodyne-detected optical Kerr effect (OHD-OKE) experiments. The orientational correlation function obtained from PSPP experiments on 2-SeCN-Bmim+ exhibits two periods of restricted angular diffusion (wobbling-in-a-cone) followed by complete orientational randomization on a time scale of 900 +/- 20 ps, significantly slower than observed for SeCN- but identical within experimental error to the complete structural randomization time of BmimNTf2. The experiments indicate that 2-SeCN-Bmim+ is sensitive to local motions of the ionic region that influence the spectral diffusion and reorientation of small, anionic, and neutral molecules as well as significantly slower, longer-range fluctuations that are responsible for complete randomization of the liquid structure. PMID- 28099809 TI - Gemcitabine Based Peptide Conjugate with Improved Metabolic Properties and Dual Mode of Efficacy. AB - Gemcitabine is a clinically established anticancer agent potent in various solid tumors but limited by its rapid metabolic inactivation and off-target toxicity. We have previously generated a metabolically superior to gemcitabine molecule (GSG) by conjugating gemcitabine to a gonadotropin releasing hormone receptor (GnRH-R) ligand peptide and showed that GSG was efficacious in a castration resistant prostate cancer (CRPC) animal model. The current article provides an in depth metabolic and mechanistic study of GSG, coupled with toxicity assays that strengthen the potential role of GSG in the clinic. LC-MS/MS based approaches were employed to delineate the metabolism of GSG, its mechanistic cellular uptake, and release of gemcitabine and to quantitate the intracellular levels of gemcitabine and its metabolites (active dFdCTP and inactive dFdU) resulting from GSG. The GnRH-R agonistic potential of GSG was investigated by quantifying the testosterone levels in animals dosed daily with GSG, while an in vitro colony forming assay together with in vivo whole blood measurements were performed to elucidate the hematotoxicity profile of GSG. Stability showed that the major metabolite of GSG is a more stable nonapeptide that could prolong gemcitabine's bioavailability. GSG acted as a prodrug and offered a metabolic advantage compared to gemcitabine by generating higher and steadier levels of dFdCTP/dFdU ratio, while intracellular release of gemcitabine from GSG in DU145 CRPC cells depended on nucleoside transporters. Daily administrations in mice showed that GSG is a potent GnRH-R agonist that can also cause testosterone ablation without any observed hematotoxicity. In summary, GSG could offer a powerful and unique pharmacological approach to prostate cancer treatment: a single nontoxic molecule that can be used to reach the tumor site selectively with superior to gemcitabine metabolism, biodistribution, and safety while also agonistically ablating testosterone levels. PMID- 28099810 TI - Anisotropic Self-Assembly of Supramolecular Polymers and Plasmonic Nanoparticles at the Liquid-Liquid Interface. AB - The study of supramolecular polymers in the bulk, in diluted solution, and at the solid-liquid interface has recently become a major topic of interest, going from fundamental aspects to applications in materials science. However, examples of supramolecular polymers at the liquid-liquid interface are mostly unexplored. Here, we describe the supramolecular polymerization of triarylamine molecules and their light-triggered organization at a chloroform-water interface. The resulting interfacial nematic layer of these 1D supramolecular polymers is further used as a template for the precise alignment of spherical gold nanoparticles coming from the water phase. These hybrid thin films are spontaneously formed in a single process, without chemical prefunctionalization of the metallic nanoparticles, and their ordering is improved by centrifugation. The resulting polymer chains and strings of nanoparticles can be co-aligned with high anisotropy over very large distances. By using a combination of experimental and theoretical investigations, we decipher the full sequence of this oriented self-assembly process. In such a highly anisotropic configuration, electron energy loss spectroscopy reveals that the self-assembled nanoparticles behave as plasmonic waveguides. PMID- 28099812 TI - Method for Determining the Polymer Content in Nonsoluble Polydiacetylene Films: Application to Pentacosadiynoic Acid. AB - The absorptivities of polydiacetylenes (PDAs) used in Langmuir films or vesicles for the development of PDA sensor films or other applications such as nonlinear optics and field-effect transistors are not known, so the polymer contents cannot be deduced from experimental spectra. Here we introduce a novel method, using nuclear reaction analysis (NRA), that allows a quantitative determination of the polymer content X proportion of monomers that have been incorporated into PDA chains. We apply it to pentacosadiynoic acid (PCDA) evaporated microcrystalline films. A calibration curve giving X as a function of the area under an absorption spectrum normalized to the monomer areal density is obtained for blue and red PCDA. The method is applicable to all kinds of films and to other PDAs, provided films with known molecular areal density are available. An example of the application to a PCDA Langmuir film is given. PMID- 28099813 TI - Photoactive Donor-Acceptor Composite Nanoparticles Dispersed in Water. AB - A major issue that inhibits the large-scale fabrication of organic solar modules is the use of chlorinated solvents considered to be toxic and hazardous. In this work, composite particles of poly[N-9'-heptadecanyl-2,7-carbazole-alt-5,5-(4,7-di 2-thienyl-2',1',3'-benzothiadiazole] (PCDTBT) and [6,6]-phenyl C71 butyric acid methyl ester (PC71BM) were obtained in water from a versatile and a ready-to market methodology based on postpolymerization miniemulsification. Depending on the experimental conditions, size-controlled particles comprising both the electron donor and the electron acceptor were obtained and characterized using transmission electron microscopy (TEM), atomic force microscopy (AFM), small angle neutron scattering (SANS), UV-visible absorption, and fluorescence spectroscopy. Intimate mixing of the two components was definitely asserted through PCDTBT fluorescence quenching in the composite nanoparticles. The water based inks were used for the preparation of photovoltaic active layers that were subsequently integrated into organic solar cells. PMID- 28099811 TI - Nanomolar-Potency Aminophenyl-1,3,5-triazine Activators of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Chloride Channel for Prosecretory Therapy of Dry Eye Diseases. AB - Dry eye disorders are a significant health problem for which limited therapeutic options are available. CFTR is a major prosecretory chloride channel at the ocular surface. We previously identified, by high-throughput screening, aminophenyl-1,3,5-triazine CFTRact-K089 (1) that activated CFTR with EC50 ~ 250 nM, which when delivered topically increased tear fluid secretion in mice and showed efficacy in an experimental dry eye model. Here, functional analysis of aminophenyl-1,3,5-triazine analogs elucidated structure-activity relationships for CFTR activation and identified substantially more potent analogs than 1. The most potent compound, 12, fully activated CFTR chloride conductance with EC50 ~ 30 nM, without causing cAMP or calcium elevation. 12 was rapidly metabolized by hepatic microsomes, which supports its topical use. Single topical administration of 25 pmol of 12 increased tear volume in wild-type mice with sustained action for 8 h and was without effect in CFTR-deficient mice. Topically delivered 12 may be efficacious in human dry eye diseases. PMID- 28099814 TI - Geometric and Electronic Structures of Dibenzo-15-Crown-5 Complexes with Alkali Metal Ions Studied by UV Photodissociation and UV-UV Hole-Burning Spectroscopy. AB - We measure UV photodissociation (UVPD) and UV-UV hole-burning (HB) spectra of dibenzo-15-crown-5 (DB15C5) complexes with alkali metal ions, M+.DB15C5 (M = Li, Na, K, Rb, and Cs), under cold (~10 K) conditions in the gas phase. The UV-UV HB spectra of the M+.DB15C5 (M = K, Rb, and Cs) complexes indicate that there is one dominant conformation for each complex except the Na+.DB15C5 complex, which has two conformers with a comparable abundance ratio. It was previously reported that the M+.(benzo-15-crown-5) (M+.B15C5, M = K, Rb, and Cs) complexes each have three conformers. Thus, the attachment of one additional benzene ring to the crown cavity of benzo-15-crown-5 reduces conformational flexibility, giving one dominant conformation for the M+.DB15C5 (M = K, Rb, and Cs) complexes. In the UVPD spectra of the K+.DB15C5, Rb+.DB15C5, and Cs+.DB15C5 complexes, the S1-S0 and S2-S0 transitions are observed independently at different positions with different vibronic structures. The spectral features are substantially different from those of the K+.(dibenzo-18-crown-6) (K+.DB18C6) complex, which belongs to the C2v point group and exhibits exciton splitting with an interval of 2.7 cm-1. The experimental and theoretical results suggest that in the M+.DB15C5 complexes the two benzene rings are not symmetrically equivalent with each other and the S1 S0 and S2-S0 electronic excitations are almost localized in one of the benzene rings. The electronic interaction energy between the two benzene chromophores is compared between the K+.DB15C5 and K+.DB18C6 complexes by quantum chemical calculations. The interaction energy of the K+.DB15C5 complex is estimated to be less than half of that of the K+.DB18C6 complex (~30 cm-1) due to less suitable relative angles between the transition dipole moments of the two benzene chromophores in K+.DB15C5. PMID- 28099815 TI - Stocks, Flows, and Distribution of Critical Metals in Embedded Electronics in Passenger Vehicles. AB - One of the major applications of critical metals (CMs) is in electrical and electronic equipment (EEE), which is increasingly embedded in other products, notably passenger vehicles. However, recycling strategies for future CM quantities in end-of-life vehicles (ELVs) are poorly understood, mainly due to a limited understating of the complexity of automotive embedded EEE. We introduce a harmonization of the network structure of automotive electronics that enables a comprehensive quantification of CMs in all embedded EEE in a vehicle. This network is combined with a material flow analysis along the vehicle lifecycle in Switzerland to quantify the stocks and flows of Ag, Au, Pd, Ru, Dy, La, Nd, and Co in automotive embedded EEE. In vehicles in use, we calculated 5-2+3 t precious metals in controllers embedded in all vehicle types and 220-60+90 t rare earth elements (REE); found mainly in five electric motors: alternator, starter, radiator-fan and electronic power steering motor embedded in conventional passenger vehicles and drive motor/generator embedded in hybrid and electric vehicles. Dismantling these devices before ELV shredding, as well as postshredder treatment of automobile shredder residue may increase the recovery of CMs from ELVs. Environmental and economic implications of such recycling strategies must be considered. PMID- 28099816 TI - New treatment options and emerging drugs for axial spondyloarthritis: biological and targeted synthetic agents. AB - INTRODUCTION: Ankylosing spondylitis (AS) and axial spondyloarthritis (ax SpA) are chronic inflammatory diseases mainly involving the axial skeleton. Pharmacological treatments for AS and ax SpA usually include local glucocorticoid injections, NSAIDs and anti-TNFalpha agents. Since around 30% to 40% of patients are non responders or intolerant to anti-TNFalpha agents, we need new therapeutic options for AS and ax SpA. Areas covered: This review describes the new biological agents that can be used or are in development for AS or ax SpA as well as emerging synthetic targeted drugs. Expert opinion: Based on the rationale of the involvement of the IL-23/Th17 axis in AS, novel biological agents have been developed and include secukinumab, an anti-IL-17A agent and ustekinumab, an anti IL-23 antibody. New compounds in the class of synthetic drugs are apremilast, a PDE4 inhibitor, and inhibitors of kinase pathways. Secukinumab gave positive results in the treatment of AS. Ustekinumab yielded promising results in AS in an open labeled study. Apremilast is not effective in AS while results with kinase inhibitors are preliminary. Future studies will clarify the place of secukinumab in the therapeutic management of AS, its influence on radiographic progression and its effects on the non radiographic form of the disease. PMID- 28099817 TI - Applying proteomics to tick vaccine development: where are we? AB - INTRODUCTION: Ticks are second to mosquitoes as a vector of human diseases and are the first vector of animal diseases with a great impact on livestock farming. Tick vaccines represent a sustainable and effective alternative to chemical acaricides for the control of tick infestations and transmitted pathogens. The application of proteomics to tick vaccine development is a fairly recent area, which has resulted in the characterization of some tick-host-pathogen interactions and the identification of candidate protective antigens. Areas covered: In this article, we review the application and possibilities of various proteomic approaches for the discovery of tick and pathogen derived protective antigens, and the design of effective vaccines for the control of tick infestations and pathogen infection and transmission. Expert commentary: In the near future, the application of reverse proteomics, immunoproteomics, structural proteomics, and interactomics among other proteomics approaches will likely contribute to improve vaccine design to control multiple tick species with the ultimate goal of controlling tick-borne diseases. PMID- 28099818 TI - Intraperitoneal chemotherapy and cytoreductive surgery for peritoneal metastases coupled with curative treatment of colorectal liver metastases: an updated systematic review. AB - INTRODUCTION: We aimed to assess the efficacy and safety of delivering intraperitoneal chemotherapy and cytoreductive surgery for peritoneal metastases coupled with curative treatment of colorectal liver metastases. Areas covered: A comprehensive literature search using PubMed was conducted to screen for eligible records. Studies evaluating colorectal surgery and intraperitoneal chemotherapy combined with curative treatment of liver metastases were included. We excluded duplicate publications. Sixty-seven full-text papers were assessed and six papers were finally included. The overall survival in the included studies ranged from 6 49 months. Five-year survival ranged from 18%-28%, three-year survival ranged from 22%-42% and two-year survival ranged from 34%-78%. Survival was lower in patients with liver metastases and peritoneal carcinomatosis (PC) than those with PC alone in the majority of studies. Expert commentary: This review poses questions rather than presenting answers. The heterogeneity of survival data suggests the possible benefit of this aggressive treatment approach in selected patients. Standardization of the technique used for intraperitoneal chemotherapy instillation, agent used as well as the systemic chemotherapy and targeted therapy type and duration through prospective controlled trials is required to provide an evidence of a higher strength to support or prohibit this treatment strategy. PMID- 28099819 TI - Powerful Ideas for Global Access to Medicines. PMID- 28099820 TI - New and developing non-adrenoreceptor small molecule drugs for the treatment of asthma. AB - INTRODUCTION: Inhaled corticosteroids (ICS) alone or in combination with an inhaled long-acting beta2-agonist (LABA) are the preferred long-term treatment for adults and adolescents with symptomatic asthma. Additional drugs include leukotriene-receptor antagonists, slow-release theophylline and the long-acting muscarinic antagonist (LAMA) tiotropium (approved in 2015). There is a need for more effective therapies, as many patients continue to have poorly controlled asthma. Areas covered: New and developing long-acting non-adrenoreceptor synthetic drugs for the treatment of symptomatic chronic asthma despite treatment with an ICS alone or combined with a LABA. Data was reviewed from studies published up until November 2016. Expert opinion: Tiotropium improves lung function and has a modest effect in reducing exacerbations when added to ICS alone or ICS and LABA. The LAMAs umeclidinium and glycopyrronium are under development in fixed dose combination with ICS and LABA. Novel small molecule drugs, such as CRTH2 receptor antagonists, PDE4 inhibitors, protein kinase inhibitors and nonsteroidal glucocorticoid receptor agonists and 'off-label' use of licensed drugs, such as macrolides and statins are under investigation for asthma, although their effectiveness in clinical practice is not established. To better achieve the goal of developing effective novel small molecule drugs for asthma will require greater understanding of mechanisms of disease and the different phenotypes and endotypes of asthma. PMID- 28099822 TI - Psychocatalytic Benefits of the Unexpected. PMID- 28099821 TI - Medication non-adherence in adult patients affected by inflammatory bowel disease: a critical review and update of the determining factors, consequences and possible interventions. AB - INTRODUCTION: Achieving adherence to medications can be a serious challenge for patients affected by inflammatory bowel disease (IBD). Medical treatment is fundamental for inducing and maintaining remission, preventing flares and reducing the risk of colorectal cancer. Non-adherence may affect patients' quality of life resulting in unfavourable treatment outcomes, more hospitalizations and higher healthcare-related costs. Recognising and improving adherence is therefore a primary aim for the treatment of IBD. Areas covered: We critically discuss the current knowledge on medication non-adherence in adult patients affected by IBD, also mentioning a few issues concerning the paediatric and adolescent populations. In particular, we reviewed the literature focusing on the definition and detection of non-adherence, on its extent and on the possible non-modifiable and modifiable factors involved (patient-centred, therapy-related, disease-related and physician-related). Furthermore, we analysed the interventional studies performed so far. The literature review was conducted through PubMed addressing medication non-adherence in IBD, using the keywords 'adherence' and related terms and 'IBD, ulcerative colitis or Crohn's disease'. Expert commentary: Adherence to therapy for IBD is a complex yet fundamental issue that cannot be solved by addressing a single aspect only. Future studies should focus on patient-tailored and multidimensional interventions. PMID- 28099823 TI - Transparency and Trust - Online Patient Reviews of Physicians. PMID- 28099824 TI - Mechanisms, Pathophysiology, and Management of Obesity. PMID- 28099826 TI - Serrated Marine Nose. PMID- 28099825 TI - Transmission of Extensively Drug-Resistant Tuberculosis in South Africa. AB - BACKGROUND: Drug-resistant tuberculosis threatens recent gains in the treatment of tuberculosis and human immunodeficiency virus (HIV) infection worldwide. A widespread epidemic of extensively drug-resistant (XDR) tuberculosis is occurring in South Africa, where cases have increased substantially since 2002. The factors driving this rapid increase have not been fully elucidated, but such knowledge is needed to guide public health interventions. METHODS: We conducted a prospective study involving 404 participants in KwaZulu-Natal Province, South Africa, with a diagnosis of XDR tuberculosis between 2011 and 2014. Interviews and medical record reviews were used to elicit information on the participants' history of tuberculosis and HIV infection, hospitalizations, and social networks. Mycobacterium tuberculosis isolates underwent insertion sequence (IS)6110 restriction-fragment-length polymorphism analysis, targeted gene sequencing, and whole-genome sequencing. We used clinical and genotypic case definitions to calculate the proportion of cases of XDR tuberculosis that were due to inadequate treatment of multidrug-resistant (MDR) tuberculosis (i.e., acquired resistance) versus those that were due to transmission (i.e., transmitted resistance). We used social-network analysis to identify community and hospital locations of transmission. RESULTS: Of the 404 participants, 311 (77%) had HIV infection; the median CD4+ count was 340 cells per cubic millimeter (interquartile range, 117 to 431). A total of 280 participants (69%) had never received treatment for MDR tuberculosis. Genotypic analysis in 386 participants revealed that 323 (84%) belonged to 1 of 31 clusters. Clusters ranged from 2 to 14 participants, except for 1 large cluster of 212 participants (55%) with a LAM4/KZN strain. Person-to person or hospital-based epidemiologic links were identified in 123 of 404 participants (30%). CONCLUSIONS: The majority of cases of XDR tuberculosis in KwaZulu-Natal, South Africa, an area with a high tuberculosis burden, were probably due to transmission rather than to inadequate treatment of MDR tuberculosis. These data suggest that control of the epidemic of drug-resistant tuberculosis requires an increased focus on interrupting transmission. (Funded by the National Institute of Allergy and Infectious Diseases and others.). PMID- 28099827 TI - Variant Creutzfeldt-Jakob Disease in a Patient with Heterozygosity at PRNP Codon 129. PMID- 28099828 TI - Swirl Sign - Intestinal Volvulus after Roux-en-Y Gastric Bypass. PMID- 28099829 TI - Case 2-2017. An 18-Year-Old Woman with Acute Liver Failure. PMID- 28099830 TI - Ribociclib for HR-Positive, Advanced Breast Cancer. PMID- 28099831 TI - Clinical Trials Involving Hypertension. PMID- 28099832 TI - Myocarditis with Immune Checkpoint Blockade. PMID- 28099833 TI - Myocarditis with Immune Checkpoint Blockade. PMID- 28099834 TI - Long-Term Oxygen for COPD. PMID- 28099835 TI - Long-Term Oxygen for COPD. PMID- 28099836 TI - Antibodies to Mycobacterium tuberculosis. PMID- 28099837 TI - Cost-Effectiveness Analysis 2.0. PMID- 28099838 TI - Osteoarthritis Year in Review 2016: biomarkers (biochemical markers). AB - PURPOSE: The aim of this "Year in Review" article is to summarize and discuss the implications of biochemical marker related articles published between the Osteoarthritis Research Society International (OARSI) 2015 Congress in Seattle and the OARSI 2016 Congress in Amsterdam. METHODS: The PubMed/MEDLINE bibliographic database was searched using the combined keywords: 'biomarker' and 'osteoarthritis'. The PubMed/MEDLINE literature search was conducted using the Advanced Search Builder function (http://www.ncbi.nlm.nih.gov/pubmed/advanced). RESULTS: Over two hundred new biomarker-related papers were published during the literature search period. Some papers identified new biomarkers whereas others explored the biological properties and clinical utility of existing markers. There were specific references to several adipocytokines including leptin and adiponectin. ADAM Metallopeptidase with Thrombospondin Type 1 motif 4 (ADAMTS-4) and aggrecan ARGS neo-epitope fragment (ARGS) in synovial fluid (SF) and plasma chemokine (CeC motif) ligand 3 (CCL3) were reported as potential new knee biomarkers. New and refined proteomic technologies and novel assays including a fluoro-microbead guiding chip (FMGC) for measuring C-telopeptide of type II collagen (CTX-II) in serum and urine and a novel magnetic nanoparticle-based technology (termed magnetic capture) for collecting and concentrating CTX-II, were described this past year. CONCLUSION: There has been steady progress in osteoarthritis (OA) biomarker research in 2016. Several novel biomarkers were identified and new technologies have been developed for measuring existing biomarkers. However, there has been no "quantum leap" this past year and identification of novel early OA biomarkers remains challenging. During the past year, OARSI published a set of recommendations for the use of soluble biomarkers in clinical trials, which is a major step forward in the clinical use of OA biomarkers and bodes well for future OA biomarker development. PMID- 28099839 TI - TrpC5 Mediates Acute Leptin and Serotonin Effects via Pomc Neurons. AB - The molecular mechanisms underlying acute leptin and serotonin 2C receptor induced hypophagia remain unclear. Here, we show that neuronal and pro opiomelanocortin (Pomc)-specific loss of transient receptor potential cation 5 (TrpC5) subunits is sufficient to decrease energy expenditure and increase food intake resulting in elevated body weight. Deficiency of Trpc5 subunits in Pomc neurons is also sufficient to block the anorexigenic effects of leptin and serotonin 2C receptor (Ht2Cr) agonists. The loss of acute anorexigenic effects of these receptors is concomitant with a blunted electrophysiological response to both leptin and Ht2Cr agonists in arcuate Pomc neurons. We also demonstrate that the Ht2Cr agonist lorcaserin-induced improvements in glucose and insulin tolerance are blocked by TrpC5 deficiency in Pomc neurons. Together, our results link TrpC5 subunits in the brain with leptin- and serotonin 2C receptor-dependent changes in neuronal activity, as well as energy balance, feeding behavior, and glucose metabolism. PMID- 28099840 TI - Testis-Specific Histone Variant H3t Gene Is Essential for Entry into Spermatogenesis. AB - Cellular differentiation is associated with dynamic chromatin remodeling in establishing a cell-type-specific epigenomic landscape. Here, we find that mouse testis-specific and replication-dependent histone H3 variant H3t is essential for very early stages of spermatogenesis. H3t gene deficiency leads to azoospermia because of the loss of haploid germ cells. When differentiating spermatogonia emerge in normal spermatogenesis, H3t appears and replaces the canonical H3 proteins. Structural and biochemical analyses reveal that H3t-containing nucleosomes are more flexible than the canonical nucleosomes. Thus, by incorporating H3t into the genome during spermatogonial differentiation, male germ cells are able to enter meiosis and beyond. PMID- 28099841 TI - Targeted Inhibition of EGFR and Glutaminase Induces Metabolic Crisis in EGFR Mutant Lung Cancer. AB - Cancer cells exhibit increased use of nutrients, including glucose and glutamine, to support the bioenergetic and biosynthetic demands of proliferation. We tested the small-molecule inhibitor of glutaminase CB-839 in combination with erlotinib on epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) as a therapeutic strategy to simultaneously impair cancer glucose and glutamine utilization and thereby suppress tumor growth. Here, we show that CB 839 cooperates with erlotinib to drive energetic stress and activate the AMP activated protein kinase (AMPK) pathway in EGFR (del19) lung tumors. Tumor cells undergo metabolic crisis and cell death, resulting in rapid tumor regression in vivo in mouse NSCLC xenografts. Consistently, positron emission tomography (PET) imaging with 18F-fluoro-2-deoxyglucose (18F-FDG) and 11C-glutamine (11C-Gln) of xenografts indicated reduced glucose and glutamine uptake in tumors following treatment with CB-839 + erlotinib. Therefore, PET imaging with 18F-FDG and 11C Gln tracers can be used to non-invasively measure metabolic response to CB-839 and erlotinib combination therapy. PMID- 28099842 TI - Brown Adipogenic Reprogramming Induced by a Small Molecule. AB - Brown adipose tissue (BAT) has attracted considerable research interest because of its therapeutic potential to treat obesity and associated metabolic diseases. Augmentation of brown fat mass and/or its function may represent an attractive strategy to enhance energy expenditure. Using high-throughput phenotypic screening to induce brown adipocyte reprogramming in committed myoblasts, we identified a retinoid X receptor (RXR) agonist, bexarotene (Bex), that efficiently converted myoblasts into brown adipocyte-like cells. Bex-treated mice exhibited enlarged BAT mass, enhanced BAT function, and a modest browning effect in subcutaneous white adipose tissue (WAT). Expression analysis showed that Bex initiated several "browning" pathways at an early stage during brown adipocyte reprogramming. Our findings suggest RXRs as new master regulators that control brown and beige fat development and activation, unlike the common adipogenic regulator PPARgamma. Moreover, we demonstrated that selective RXR activation may potentially offer a therapeutic approach to manipulate brown/beige fat function in vivo. PMID- 28099844 TI - Acetate Recapturing by Nuclear Acetyl-CoA Synthetase 2 Prevents Loss of Histone Acetylation during Oxygen and Serum Limitation. AB - Acetyl-CoA is a key metabolic intermediate with an important role in transcriptional regulation. The nuclear-cytosolic acetyl-CoA synthetase 2 (ACSS2) was found to sustain the growth of hypoxic tumor cells. It generates acetyl-CoA from acetate, but exactly which pathways it supports is not fully understood. Here, quantitative analysis of acetate metabolism reveals that ACSS2 fulfills distinct functions depending on its cellular location. Exogenous acetate uptake is controlled by expression of both ACSS2 and the mitochondrial ACSS1, and ACSS2 supports lipogenesis. The mitochondrial and lipogenic demand for two-carbon acetyl units considerably exceeds the uptake of exogenous acetate, leaving it to only sparingly contribute to histone acetylation. Surprisingly, oxygen and serum limitation increase nuclear localization of ACSS2. We find that nuclear ACSS2 recaptures acetate released from histone deacetylation for recycling by histone acetyltransferases. Our work provides evidence for limited equilibration between nuclear and cytosolic acetyl-CoA and demonstrates that ACSS2 retains acetate to maintain histone acetylation. PMID- 28099843 TI - Human Carboxylesterase 2 Reverses Obesity-Induced Diacylglycerol Accumulation and Glucose Intolerance. AB - Serine hydrolases are a large family of multifunctional enzymes known to influence obesity. Here, we performed activity-based protein profiling to assess the functional level of serine hydrolases in liver biopsies from lean and obese humans in order to gain mechanistic insight into the pathophysiology of metabolic disease. We identified reduced hepatic activity of carboxylesterase 2 (CES2) and arylacetamide deacetylase (AADAC) in human obesity. In primary human hepatocytes, CES2 knockdown impaired glucose storage and lipid oxidation. In mice, obesity reduced CES2, whereas adenoviral delivery of human CES2 reversed hepatic steatosis, improved glucose tolerance, and decreased inflammation. Lipidomic analysis identified a network of CES2-regulated lipids altered in human and mouse obesity. CES2 possesses triglyceride and diacylglycerol lipase activities and displayed an inverse correlation with HOMA-IR and hepatic diacylglycerol concentrations in humans. Thus, decreased CES2 is a conserved feature of obesity and plays a causative role in the pathogenesis of obesity-related metabolic disturbances. PMID- 28099846 TI - Cell of Origin Links Histotype Spectrum to Immune Microenvironment Diversity in Non-small-Cell Lung Cancer Driven by Mutant Kras and Loss of Lkb1. AB - Lung cancers exhibit pronounced functional heterogeneity, confounding precision medicine. We studied how the cell of origin contributes to phenotypic heterogeneity following conditional expression of KrasG12D and loss of Lkb1 (Kras;Lkb1). Using progenitor cell-type-restricted adenoviral Cre to target cells expressing surfactant protein C (SPC) or club cell antigen 10 (CC10), we show that Ad5-CC10-Cre-infected mice exhibit a shorter latency compared with Ad5-SPC Cre cohorts. We further demonstrate that CC10+ cells are the predominant progenitors of adenosquamous carcinoma (ASC) tumors and give rise to a wider spectrum of histotypes that includes mucinous and acinar adenocarcinomas. Transcriptome analysis shows ASC histotype-specific upregulation of pro inflammatory and immunomodulatory genes. This is accompanied by an ASC-specific immunosuppressive environment, consisting of downregulated MHC genes, recruitment of CD11b+ Gr-1+ tumor-associated neutrophils (TANs), and decreased T cell numbers. We conclude that progenitor cell-specific etiology influences the Kras;Lkb1-driven tumor histopathology spectrum and histotype-specific immune microenvironment. PMID- 28099845 TI - Absence of Neurofibromin Induces an Oncogenic Metabolic Switch via Mitochondrial ERK-Mediated Phosphorylation of the Chaperone TRAP1. AB - Mutations in neurofibromin, a Ras GTPase-activating protein, lead to the tumor predisposition syndrome neurofibromatosis type 1. Here, we report that cells lacking neurofibromin exhibit enhanced glycolysis and decreased respiration in a Ras/ERK-dependent way. In the mitochondrial matrix of neurofibromin-deficient cells, a fraction of active ERK1/2 associates with succinate dehydrogenase (SDH) and TRAP1, a chaperone that promotes the accumulation of the oncometabolite succinate by inhibiting SDH. ERK1/2 enhances both formation of this multimeric complex and SDH inhibition. ERK1/2 kinase activity is favored by the interaction with TRAP1, and TRAP1 is, in turn, phosphorylated in an ERK1/2-dependent way. TRAP1 silencing or mutagenesis at the serine residues targeted by ERK1/2 abrogates tumorigenicity, a phenotype that is reverted by addition of a cell permeable succinate analog. Our findings reveal that Ras/ERK signaling controls the metabolic changes orchestrated by TRAP1 that have a key role in tumor growth and are a promising target for anti-neoplastic strategies. PMID- 28099847 TI - Leukocytes Breach Endothelial Barriers by Insertion of Nuclear Lobes and Disassembly of Endothelial Actin Filaments. AB - The endothelial cytoskeleton is a barrier for leukocyte transendothelial migration (TEM). Mononuclear and polymorphonuclear leukocytes generate gaps of similar micron-scale size when squeezing through inflamed endothelial barriers in vitro and in vivo. To elucidate how leukocytes squeeze through these barriers, we co-tracked the endothelial actin filaments and leukocyte nuclei in real time. Nuclear squeezing involved either preexistent or de novo-generated lobes inserted into the leukocyte lamellipodia. Leukocyte nuclei reversibly bent the endothelial actin stress fibers. Surprisingly, formation of both paracellular gaps and transcellular pores by squeezing leukocytes did not require Rho kinase or myosin II-mediated endothelial contractility. Electron-microscopic analysis suggested that nuclear squeezing displaced without condensing the endothelial actin filaments. Blocking endothelial actin turnover abolished leukocyte nuclear squeezing, whereas increasing actin filament density did not. We propose that leukocyte nuclei must disassemble the thin endothelial actin filaments interlaced between endothelial stress fibers in order to complete TEM. PMID- 28099848 TI - Biophysical Attributes of CpG Presentation Control TLR9 Signaling to Differentially Polarize Systemic Immune Responses. AB - It is currently unknown whether and how mammalian pathogen recognition receptors (PRRs) respond to biophysical patterns of pathogen-associated molecular danger signals. Using synthetic pathogen-like particles (PLPs) that mimic physical properties of bacteria or large viruses, we have discovered that the quality and quantity of Toll-like receptor 9 (TLR9) signaling by CpG in mouse dendritic cells (mDCs) are uniquely dependent on biophysical attributes; specifically, the surface density of CpG and size of the presenting PLP. These physical patterns control DC programming by regulating the kinetics and magnitude of MyD88-IRAK4 signaling, NF-kappaB-driven responses, and STAT3 phosphorylation, which, in turn, controls differential T cell responses and in vivo immune polarization, especially T helper 1 (Th1) versus T helper 2 (Th2) antibody responses. Our findings suggest that innate immune cells can sense and respond not only to molecular but also pathogen-associated physical patterns (PAPPs), broadening the tools for modulating immunity and helping to better understand innate response mechanisms to pathogens and develop improved vaccines. PMID- 28099849 TI - Cyclic AMP Recruits a Discrete Intracellular Ca2+ Store by Unmasking Hypersensitive IP3 Receptors. AB - Inositol 1,4,5-trisphosphate (IP3) stimulates Ca2+ release from the endoplasmic reticulum (ER), and the response is potentiated by 3',5'-cyclic AMP (cAMP). We investigated this interaction in HEK293 cells using carbachol and parathyroid hormone (PTH) to stimulate formation of IP3 and cAMP, respectively. PTH alone had no effect on the cytosolic Ca2+ concentration, but it potentiated the Ca2+ signals evoked by carbachol. Surprisingly, however, the intracellular Ca2+ stores that respond to carbachol alone could be both emptied and refilled without affecting the subsequent response to PTH. We provide evidence that PTH unmasks high-affinity IP3 receptors within a discrete Ca2+ store. We conclude that Ca2+ stores within the ER that dynamically exchange Ca2+ with the cytosol maintain a functional independence that allows one store to be released by carbachol and another to be released by carbachol with PTH. Compartmentalization of ER Ca2+ stores adds versatility to IP3-evoked Ca2+ signals. PMID- 28099850 TI - Synaptotagmin 2 Is the Fast Ca2+ Sensor at a Central Inhibitory Synapse. AB - GABAergic synapses in brain circuits generate inhibitory output signals with submillisecond latency and temporal precision. Whether the molecular identity of the release sensor contributes to these signaling properties remains unclear. Here, we examined the Ca2+ sensor of exocytosis at GABAergic basket cell (BC) to Purkinje cell (PC) synapses in cerebellum. Immunolabeling suggested that BC terminals selectively expressed synaptotagmin 2 (Syt2), whereas synaptotagmin 1 (Syt1) was enriched in excitatory terminals. Genetic elimination of Syt2 reduced action potential-evoked release to ~10%, identifying Syt2 as the major Ca2+ sensor at BC-PC synapses. Differential adenovirus-mediated rescue revealed that Syt2 triggered release with shorter latency and higher temporal precision and mediated faster vesicle pool replenishment than Syt1. Furthermore, deletion of Syt2 severely reduced and delayed disynaptic inhibition following parallel fiber stimulation. Thus, the selective use of Syt2 as release sensor at BC-PC synapses ensures fast and efficient feedforward inhibition in cerebellar microcircuits. PMID- 28099851 TI - A Molecular and Cellular Context-Dependent Role for Ir76b in Detection of Amino Acid Taste. AB - Amino acid taste is expected to be a universal property among animals. Although sweet, bitter, salt, and water tastes have been well characterized in insects, the mechanisms underlying amino acid taste remain elusive. From a Drosophila RNAi screen, we identify an ionotropic receptor, Ir76b, as necessary for yeast preference. Using calcium imaging, we identify Ir76b+ amino acid taste neurons in legs, overlapping partially with sweet neurons but not those that sense other tastants. Ir76b mutants have reduced responses to amino acids, which are rescued by transgenic expression of Ir76b and a mosquito ortholog AgIr76b. Co-expression of Ir20a with Ir76b is sufficient for conferring amino acid responses in sweet taste neurons. Notably, Ir20a also serves to block salt response of Ir76b. Our study establishes the role of a highly conserved receptor in amino acid taste and suggests a mechanism for mutually exclusive roles of Ir76b in salt- and amino acid-sensing neurons. PMID- 28099852 TI - Yeast Short-Lived Actin-Associated Protein Forms a Metastable Prion in Response to Thermal Stress. AB - Self-perpetuating ordered protein aggregates (amyloids and prions) are associated with a variety of neurodegenerative disorders. Although environmental agents have been linked to certain amyloid diseases, the molecular basis of their action remains unclear. We have employed endogenous yeast prions as a model system to study environmental control of amyloid formation. A short-lived actin-associated yeast protein Lsb2 can trigger prion formation by other proteins in a mode regulated by the cytoskeleton and ubiquitin-dependent processes. Here, we show that such a heterologous prion induction is due to the ability of Lsb2 to form a transient prion state, generated in response to thermal stress. Evolutionary acquisition of prion-inducing activity by Lsb2 is traced to a single amino acid change, coinciding with the acquisition of thermotolerance in the Saccharomyces yeast lineage. This raises the intriguing possibility that the transient prion formation could aid in functioning of Lsb2 at higher temperatures. PMID- 28099854 TI - Single-Cell Transcriptomic Analysis Defines Heterogeneity and Transcriptional Dynamics in the Adult Neural Stem Cell Lineage. AB - Neural stem cells (NSCs) in the adult mammalian brain serve as a reservoir for the generation of new neurons, oligodendrocytes, and astrocytes. Here, we use single-cell RNA sequencing to characterize adult NSC populations and examine the molecular identities and heterogeneity of in vivo NSC populations. We find that cells in the NSC lineage exist on a continuum through the processes of activation and differentiation. Interestingly, rare intermediate states with distinct molecular profiles can be identified and experimentally validated, and our analysis identifies putative surface markers and key intracellular regulators for these subpopulations of NSCs. Finally, using the power of single-cell profiling, we conduct a meta-analysis to compare in vivo NSCs and in vitro cultures, distinct fluorescence-activated cell sorting strategies, and different neurogenic niches. These data provide a resource for the field and contribute to an integrative understanding of the adult NSC lineage. PMID- 28099853 TI - A Tissue-Mapped Axolotl De Novo Transcriptome Enables Identification of Limb Regeneration Factors. AB - Mammals have extremely limited regenerative capabilities; however, axolotls are profoundly regenerative and can replace entire limbs. The mechanisms underlying limb regeneration remain poorly understood, partly because the enormous and incompletely sequenced genomes of axolotls have hindered the study of genes facilitating regeneration. We assembled and annotated a de novo transcriptome using RNA-sequencing profiles for a broad spectrum of tissues that is estimated to have near-complete sequence information for 88% of axolotl genes. We devised expression analyses that identified the axolotl orthologs of cirbp and kazald1 as highly expressed and enriched in blastemas. Using morpholino anti-sense oligonucleotides, we find evidence that cirbp plays a cytoprotective role during limb regeneration whereas manipulation of kazald1 expression disrupts regeneration. Our transcriptome and annotation resources greatly complement previous transcriptomic studies and will be a valuable resource for future research in regenerative biology. PMID- 28099855 TI - Primary Cell Culture of Live Neurosurgically Resected Aged Adult Human Brain Cells and Single Cell Transcriptomics. AB - Investigation of human CNS disease and drug effects has been hampered by the lack of a system that enables single-cell analysis of live adult patient brain cells. We developed a culturing system, based on a papain-aided procedure, for resected adult human brain tissue removed during neurosurgery. We performed single-cell transcriptomics on over 300 cells, permitting identification of oligodendrocytes, microglia, neurons, endothelial cells, and astrocytes after 3 weeks in culture. Using deep sequencing, we detected over 12,000 expressed genes, including hundreds of cell-type-enriched mRNAs, lncRNAs and pri-miRNAs. We describe cell type- and patient-specific transcriptional hierarchies. Single-cell transcriptomics on cultured live adult patient derived cells is a prime example of the promise of personalized precision medicine. Because these cells derive from subjects ranging in age into their sixties, this system permits human aging studies previously possible only in rodent systems. PMID- 28099856 TI - Screening Bioactives Reveals Nanchangmycin as a Broad Spectrum Antiviral Active against Zika Virus. AB - Zika virus is an emerging arthropod-borne flavivirus for which there are no vaccines or specific therapeutics. We screened a library of 2,000 bioactive compounds for their ability to block Zika virus infection in three distinct cell types with two different strains of Zika virus. Using a microscopy-based assay, we validated 38 drugs that inhibited Zika virus infection, including FDA-approved nucleoside analogs. Cells expressing high levels of the attachment factor AXL can be protected from infection with receptor tyrosine kinase inhibitors, while placental-derived cells that lack AXL expression are insensitive to this inhibition. Importantly, we identified nanchangmycin as a potent inhibitor of Zika virus entry across all cell types tested, including physiologically relevant primary cells. Nanchangmycin also was active against other medically relevant viruses, including West Nile, dengue, and chikungunya viruses that use a similar route of entry. This study provides a resource of small molecules to study Zika virus pathogenesis. PMID- 28099858 TI - Mucosal Microbes Mitigate Maladies. AB - Understanding the factors that promote or prevent HIV transmission remains a critical component of the global battle against HIV/AIDS. Gosmann et al. (2017) reveal a putative role for the vaginal microbiome in modulating heterosexual transmission of HIV, uncovering a potential strategy for protecting women from acquisition of the virus. PMID- 28099857 TI - A Systems Approach Reveals MAVS Signaling in Myeloid Cells as Critical for Resistance to Ebola Virus in Murine Models of Infection. AB - The unprecedented 2013-2016 outbreak of Ebola virus (EBOV) resulted in over 11,300 human deaths. Host resistance to RNA viruses requires RIG-I-like receptor (RLR) signaling through the adaptor protein, mitochondrial antiviral signaling protein (MAVS), but the role of RLR-MAVS in orchestrating anti-EBOV responses in vivo is not known. Here we apply a systems approach to MAVS-/- mice infected with either wild-type or mouse-adapted EBOV. MAVS controlled EBOV replication through the expression of IFNalpha, regulation of inflammatory responses in the spleen, and prevention of cell death in the liver, with macrophages implicated as a major cell type influencing host resistance. A dominant role for RLR signaling in macrophages was confirmed following conditional MAVS deletion in LysM+ myeloid cells. These findings reveal tissue-specific MAVS-dependent transcriptional pathways associated with resistance to EBOV, and they demonstrate that EBOV adaptation to cause disease in mice involves changes in two distinct events, RLR MAVS antagonism and suppression of RLR-independent IFN-I responses. PMID- 28099859 TI - How Many Subsets of Innate Lymphoid Cells Do We Need? AB - Innate lymphoid cells (ILCs) are composed of three main subsets. In this issue of Immunity, Simoni et al. (2017) show using mass-cytometry that human ILCs are highly heterogeneous between individuals and tissues and lack a previously proposed helper-type ILC1 population. PMID- 28099860 TI - Follicular Dendritic Cell Activation by TLR Ligands Promotes Autoreactive B Cell Responses. AB - A hallmark of autoimmunity in murine models of lupus is the formation of germinal centers (GCs) in lymphoid tissues where self-reactive B cells expand and differentiate. In the host response to foreign antigens, follicular dendritic cells (FDCs) maintain GCs through the uptake and cycling of complement-opsonized immune complexes. Here, we examined whether FDCs retain self-antigens and the impact of this process in autoantibody secretion in lupus. We found that FDCs took up and retained self-immune complexes composed of ribonucleotide proteins, autoantibody, and complement. This uptake, mediated through CD21, triggered endosomal TLR7 and led to the secretion of interferon (IFN) alpha via an IRF5 dependent pathway. Blocking of FDC secretion of IFN-alpha restored B cell tolerance and reduced the amount of GCs and pathogenic autoantibody. Thus, FDCs are a critical source of the IFN-alpha driving autoimmunity in this lupus model. This pathway is conserved in humans, suggesting that it may be a viable therapeutic target in systemic lupus erythematosus. PMID- 28099861 TI - T Cells Take on Zika Virus. AB - Although CD8+ T cells provide protection against many viral infections, their role in Zika virus (ZIKV) immunity has not been extensively examined. In a recent issue of Cell Host & Microbe, Elong Ngono et al. (2017) define antigenic epitopes determining CD8+ T cell immunity in murine models of ZIKV infection. PMID- 28099862 TI - Neutrophils in Homeostasis, Immunity, and Cancer. AB - Neutrophils were among the first leukocytes described and visualized by early immunologists. Prominent effector functions during infection and sterile inflammation classically placed them low in the immune tree as rapid, mindless aggressors with poor regulatory functions. This view is currently under reassessment as we uncover new aspects of their life cycle and identify transcriptional and phenotypic diversity that endows them with regulatory properties that extend beyond their lifetime in the circulation. These properties are revealing unanticipated roles for neutrophils in supporting homeostasis, as well as complex disease states such as cancer. We focus this review on these emerging functions in order to define the true roles of neutrophils in homeostasis, immunity, and disease. PMID- 28099863 TI - Satb1: Restraining PD1 and T Cell Exhaustion. AB - Mechanisms that govern PD1 expression and exhaustion in T cells are not fully understood. In this issue of Immunity, Stephen et al. (2017) uncover a key role for the genome organizer Satb1 in restraining PD1 expression and promoting tumor immunity. PMID- 28099865 TI - Fugue G Minor: Getting the Lymph Node Ensemble Together with Circadian Rhythm. AB - A fugue is characterized by the systematic repetition of a principal theme in simultaneous melodic lines. In this issue of Immunity, Druzd et al. (2017) show that a similar phenomenon occurs in lymph nodes (LNs), in which lymphocyte entry and exit is governed by repetitive circadian rhythms. PMID- 28099864 TI - SATB1 Expression Governs Epigenetic Repression of PD-1 in Tumor-Reactive T Cells. AB - Despite the importance of programmed cell death-1 (PD-1) in inhibiting T cell effector activity, the mechanisms regulating its expression remain poorly defined. We found that the chromatin organizer special AT-rich sequence-binding protein-1 (Satb1) restrains PD-1 expression induced upon T cell activation by recruiting a nucleosome remodeling deacetylase (NuRD) complex to Pdcd1 regulatory regions. Satb1 deficienct T cells exhibited a 40-fold increase in PD-1 expression. Tumor-derived transforming growth factor beta (Tgf-beta) decreased Satb1 expression through binding of Smad proteins to the Satb1 promoter. Smad proteins also competed with the Satb1-NuRD complex for binding to Pdcd1 enhancers, releasing Pdcd1 expression from Satb1-mediated repression, Satb1 deficient tumor-reactive T cells lost effector activity more rapidly than wild type lymphocytes at tumor beds expressing PD-1 ligand (CD274), and these differences were abrogated by sustained CD274 blockade. Our findings suggest that Satb1 functions to prevent premature T cell exhaustion by regulating Pdcd1 expression upon T cell activation. Dysregulation of this pathway in tumor infiltrating T cells results in diminished anti-tumor immunity. PMID- 28099866 TI - Effector Regulatory T Cell Differentiation and Immune Homeostasis Depend on the Transcription Factor Myb. AB - FoxP3-expressing regulatory T (Treg) cells are essential for maintaining immune homeostasis. Activated Treg cells undergo further differentiation into an effector state that highly expresses genes critical for Treg cell function, although how this process is coordinated on a transcriptional level is poorly understood. Here, we demonstrate that mice lacking the transcription factor Myb in Treg cells succumbed to a multi-organ inflammatory disease. Myb was specifically expressed in, and required for the differentiation of, thymus derived effector Treg cells. The combination of transcriptome and genomic footprint analyses revealed that Myb directly regulated a large proportion of the gene expression specific to effector Treg cells, identifying Myb as a critical component of the gene regulatory network controlling effector Treg cell differentiation and function. PMID- 28099867 TI - Th17 Cells Require You to Chew before You Swallow. AB - How immunity is regulated at distinct epithelial tissues that vary in microbial occupancy and environmental and tissue specific cues isn't clear. Dutzan et al. (2017) report that mechanical-derived signals, not those from micro-organisms, are key to maintaining interleukin-17-expressing T helper (Th17) cells at the oral epithelia. PMID- 28099868 TI - PDC-SGB: Prediction of effective drug combinations using a stochastic gradient boosting algorithm. AB - Combinatorial therapy is a promising strategy for combating complex diseases by improving the efficacy and reducing the side effects. To facilitate the identification of drug combinations in pharmacology, we proposed a new computational model, termed PDC-SGB, to predict effective drug combinations by integrating biological, chemical and pharmacological information based on a stochastic gradient boosting algorithm. To begin with, a set of 352 golden positive samples were collected from the public drug combination database. Then, a set of 732 dimensional feature vector involving biological, chemical and pharmaceutical information was constructed for each drug combination to describe its properties. To avoid overfitting, the maximum relevance & minimum redundancy (mRMR) method was performed to extract useful ones by removing redundant subsets. Based on the selected features, the three different type of classification algorithms were employed to build the drug combination prediction models. Our results demonstrated that the model based on the stochastic gradient boosting algorithm yield out the best performance. Furthermore, it is indicated that the feature patterns of therapy had powerful ability to discriminate effective drug combinations from non-effective ones. By analyzing various features, it is shown that the enriched features occurred frequently in golden positive samples can help predict novel drug combinations. PMID- 28099869 TI - Amitriptyline down-regulates coenzyme Q10 biosynthesis in lung cancer cells. AB - Amitriptyline, a tricyclic antidepressant, has been proposed as an antitumoral drug in oxidative therapy. Its pro-apoptotic effects, mediated by high reactive oxygen species generation, have been already described. In this study we analysed the effect of amitriptyline on the biosynthesis of coenzyme Q10 (CoQ), an essential component for electron transport and a potent membrane antioxidant involved in redox signaling. We treated H460 cells, a non-small-cell lung cancer cell line, with amitriptyline and we analysed CoQ levels by HPLC and CoQ biosynthesis rate, as well as the enzymes involved in CoQ biosynthesis by real time PCR and Western blot. Amitriptyline treatment induced a dose-dependent decrease in CoQ levels in tumor cells. CoQ decreased levels were associated with down-regulation of the expression of COQ4 gene, as well as decreased Coq4 and Coq6 protein levels. Our findings suggest that the effect of amitriptyline on CoQ biosynthesis highlights the potential of this drug for antitumoral oxidative therapy. PMID- 28099870 TI - Single embryo-resolution quantitative analysis of reporters permits multiplex spatial cis-regulatory analysis. AB - Cis-regulatory modules (CRMs) control spatiotemporal gene expression patterns in embryos. While measurement of quantitative CRM activities has become efficient, measurement of spatial CRM activities still relies on slow, one-by-one methods. To overcome this bottleneck, we have developed a high-throughput method that can simultaneously measure quantitative and spatial CRM activities. The new method builds profiles of quantitative CRM activities measured at single-embryo resolution in many mosaic embryos and uses these profiles as a 'fingerprint' of spatial patterns. We show in sea urchin embryos that the new method, Multiplex and Mosaic Observation of Spatial Information encoded in Cis-regulatory modules (MMOSAIC), can efficiently predict spatial activities of new CRMs and can detect spatial responses of CRMs to gene perturbations. We anticipate that MMOSAIC will facilitate systems-wide functional analyses of CRMs in embryos. PMID- 28099871 TI - Fluoride and arsenic exposure affects spatial memory and activates the ERK/CREB signaling pathway in offspring rats. AB - Fluoride and arsenic are inorganic contaminants that occur in the natural environment. Chronic fluoride and/or arsenic exposure can induce developmental neurotoxicity and negatively influence intelligence in children, although the underlying molecular mechanisms are poorly understood. This study explored the effects of fluoride and arsenic exposure in drinking water on spatial learning, memory and key protein expression in the ERK/CREB signaling pathway in hippocampal and cerebral cortex tissue in rat offspring. Pregnant rats were divided into four groups. Control rats drank tap water, while rats in the three exposure groups drank water with sodium fluoride (100mg/L), sodium arsenite (75mg/L), and a sodium fluoride (100mg/L) and sodium arsenite (75mg/L) combination during gestation and lactation. After weaning, rat pups drank the same solution as their mothers. Spatial learning and memory ability of pups at postnatal day 21 (PND21) and postnatal day 42 (PND42) were measured using a Morris water maze. ERK, phospho-ERK (p-ERK), CREB and phospho-CREB (p-CREB) protein expression in the hippocampus and cerebral cortex was detected using Western blot. Compared with the control pups, escape latencies increased in PND42 pups exposed to arsenic and co-exposed to fluoride and arsenic, and the short term and long-term spatial memory ability declined in pups exposed to fluoride and arsenic, both alone and in combination. Compared with controls, ERK and p-ERK levels decreased in the hippocampus and cerebral cortex in pups exposed to combined fluoride and arsenic. CREB protein expression in the cerebral cortex decreased in pups exposed to fluoride, arsenic, and the fluoride and arsenic combination. p-CREB protein expression in both the hippocampus and cerebral cortex was decreased in pups exposed to fluoride and arsenic in combination compared to the control group. There were negative correlation between the proteins expression and escape latency periods in pups. These data indicate that exposure to fluoride and arsenic in early life stage changes ERK, p-ERK, CREB and p-CREB protein expression in the hippocampus and cerebral cortex of rat offspring at PND21 and PND 42, which may contribute to impaired neurodevelopment following exposure. PMID- 28099872 TI - Assessment of gait and sensorimotor deficits in the D1CT-7 mouse model of Tourette syndrome. AB - Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple motor and phonic tics. While TS patients have been also shown to exhibit subtle abnormalities of sensorimotor integration and gait, animal models of this disorder are seldom tested for these functions. To fill this gap, we assessed gait and sensorimotor integration in the D1CT-7 mouse, one of the best-validated animal models of TS. D1CT-7 mice exhibit spontaneous tic-like manifestations, which, in line with the clinical phenomenology of TS, are markedly exacerbated by environmental stress. Thus, to verify whether stress may affect sensorimotor integration and gait functions in D1CT-7 mice, we subjected these animals to a 20 min session of spatial confinement, an environmental stressor that was recently shown to worsen tic-like manifestations. Immediately following this manipulation (or no confinement, for controls), animals were subjected to either the sticky tape task, to test for sensorimotor integration; or a 60-min session in an open field (42*42cm) force-plate actometer for gait analysis. Gait analyses included spatial, temporal, and dynamic (force) parameters. D1CT-7 mice displayed a longer latency to remove a sticky tape, indicating marked impairments in sensorimotor integration; furthermore, these mutants exhibited shortened stride length, increased stride rate, nearly equal early-phase velocity, and higher late-phase velocity. D1CT-7 mice also ran with greater force amplitude than wild-type (WT) littermates. None of these phenotypes was worsened by spatial confinement. These results highlight the potential importance of testing sensorimotor integration and gait functions as a phenotypic correlate of cortical connectivity deficits in animal models of TS. PMID- 28099873 TI - Antimicrobial photodynamic therapy as an adjunct for treatment of deep carious lesions-A systematic review. AB - For deep carious lesions, a more conservative treatment modality ("selective caries removal") has been proposed, where only the heavily contaminated dentine is removed. In this regard, effective adjuncts for cavity disinfection such as the antimicrobial photodynamic therapy (aPDT) can be valuable clinically prior to definitive restoration. Therefore, the aim of this study was to systematically assess clinical studies on the effectiveness of aPDT as a supplementary tool in the treatment of deep caries lesions. Searches were performed in four databases (PubMed, EMBASE, ISI Web of Science, ClinicalTrials.gov) from 1st January, 2011 until 21st June, 2016 for search terms relevant to the observed parameters, pathological condition, intervention and anatomic entity. The pooled information was evaluated according to PRISMA guidelines. At first, 1651 articles were recovered, of which 1249 full-text articles were evaluated, 270 articles thereof were reviewed for eligibility and finally 6 articles met all inclusion criteria. The aPDT protocols involved Methylene Blue, Toluidine Blue and aluminium-chloride phthalocyanine as photosensitizers and diode lasers, light-emitting diodes and halogen light-sources. The data from five reports, utilizing both culture dependent and -independent methods, disclosed significant reduction of cariogenic bacterial load after mechanical caries removal with adjunct aPDT. As these studies exhibit some methodological limitations, e.g. lack of positive controls, this systematic review can support the application of aPDT to a limited extent only in terms of reducing the microbial load in deep carious lesions before restorative treatment. PMID- 28099874 TI - IgM, lgG and IL-6 profiles in the Trypanosoma brucei brucei monkey model of human African trypanosomiasis. AB - Human African trypanosomiasis (HAT) patients manifest immunological profiles, whose variations over time can be used to indicate disease progression. However, monitoring of these biomarkers in human patients is beset by several limitations which can be offset by using chronic animal models. A recent improved monkey model of HAT using a Trypanosoma brucei brucei isolate has been developed but the immunological profile has not been elucidated. The objectives of the current study was to determine the IgM, IgG and IL-6 profiles in blood and cerebrospinal fluid (CSF) in vervet monkeys infected with T. b. brucei. Three vervet monkeys were infected intravenously with 105T. b. brucei, monitored for disease development and subsequently treated 28days post infection (dpi) sub-curatively using diminazene aceturate (DA) to induce late stage disease and curatively treated with melarsoprol (Mel B) at 119 dpi, respectively. Matched serum and cerebrospinal fluid (CSF) samples were obtained at regular intervals and immunospecific IgM, immunoglobulin G (IgG) were quantified by ELISA while IL-6 was assayed using a cytometric bead array (CBA) kit. Results showed that following infection, CSF IgM, IgG, IL-6 and serum IL-6 were significantly (p<0.05) elevated with peak levels coinciding with relapse parasitaemia. The IgG levels increased to reach OD peak levels of 0.442+/-0.5 at 126 dpi. After curative treatment with MelB, the serum IgM and Ig G levels fell rapidly to attain pre-infection levels within 35 and 49days, respectively. This shows that the profile of these immunoglobulins can be used as an indicator of curative treatment. CSF IL-6 concentrations of infected vervet monkeys showed no significant change (P>0.05) between infection and 35 dpi but levels increased significantly (P<0.05) with the highest level of 55.53pg/ml recorded at112 dpi. IL-6 elevation from 35 dpi may be indicative of parasite neuroinvasion hence can be used as possible candidate marker for late stage disease in the monkey model. Further, the marker can also be used in conjunction with IgG and IgM as markers for development of test of cure for HAT. PMID- 28099875 TI - Sustained attention and heart rate variability in children and adolescents with ADHD. AB - The autonomic nervous system (ANS) plays an important role in attention and self regulation by modulating physiological arousal to meet environmental demands. Core symptoms of ADHD such as inattention and behavioral disinhibition may be related to dysregulation of the ANS, however previous findings have been equivocal. We examined autonomic activity and reactivity by assessing heart rate variability (HRV) in a large sample of un-medicated children and adolescents (6 19 years) with ADHD (n=229) compared to typically-developing controls (n=244) during rest and sustained attention. Four heart rate variability measures were extracted: Root mean square of successive differences between inter-beat intervals (rMSSD), absolute high frequency (HFA) power, absolute low frequency (LFA) power and ratio of low frequency power to high frequency power (LF/HF). There were no group differences in HFA or rMSSD, even when assessing across child and adolescent groups separately, by gender or ADHD subtype. LF/HF however was higher in ADHD during both rest and sustained attention conditions, particularly in male children. Sustained attention was impaired in ADHD relative to controls, and a higher LF/HF ratio during sustained attention was associated with poorer performance in both groups. Lower rMSSD and HFA were associated with higher anxiety, oppositional behaviors and social problems, supporting prevailing theories that these measures index emotion regulation and adaptive social behavior. Different measures of heart rate variability provide important insights into the sustained attention and emotional and behavioral regulation impairments observed in ADHD and may aid in delineating ADHD pathophysiology. PMID- 28099876 TI - Antitumoral activity of sesquiterpene lactone diacethylpiptocarphol in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sesquiterpene lactones are organic compounds derived from plants that exhibit anti-inflammatory and antitumor activities being one of the locking mechanisms of action of NF-kB pathway and synthesis of cytokines such as IL-1 and TNF- alpha. AIM OF THE STUDY: The overall objective of the present study was to evaluate the antitumor activity of the sesquiterpene lactone diacethylpiptocarphol (DPC) from Vernonia scorpioides (Lam.) Pers. in animal models Ehrlich tumors that has shown antitumor activity. MATERIALS AND METHODS: The antitumor effects of Intraperitonial administration of DPC (5mg/kg/day) were evaluated in Balb/c mice on Ehrlich tumors, and further the body weight, the ascitic cells volume measurement, solid tumor measured and TNF alpha level was determinate. RESULTS: Balb/c mice bearing Ehrlich tumors were treated daily with 5mg/kg/day of the DPC for one week and showed no tumor in the peritoneum after treatment, besides presenting a reduction of TNF-alpha cytokine. Also the solid tumor reduced size after one week of treatment with DPC. CONCLUSIONS: Sesquiterpene lactone DPC, isolated from Vernonia scorpioides showed antitumor activity because it decreased the size of the solid tumor and abolished the ascitic tumor development, and also did not affect the mice body weight, however the treatment reduced the TNF-alpha level in mice. PMID- 28099877 TI - Use of the channel fill level in defining a design space for twin screw wet granulation. AB - Twin screw wet granulation is a key process in the continuous manufacture of oral solid dosage forms. Previous research has qualitatively suggested that the channel fill level influences the granules produced. In this paper a quantitative measure of the total volumetric fraction of the conveying element channels of the screw filled with powder (phi) was used. Experimental results are shown which demonstrate that very similar particle size distributions can be obtained at the same phi with the same material and screw configuration but radically different solids feed rates and screw speeds. Morphology of the granules also correlates with phi. This is consistent with previous observations in the literature correlating granule attributes with powder feed rate and screw speed but also considers the two parameters in combination. A process design space approach based on phi is proposed. This can be determined empirically, and potentially has value in setting process control strategies, assuring process robustness and allowing process flexibility during the product lifecycle. PMID- 28099879 TI - High-dose BAFF receptor specific mAb-siRNA conjugate generates Fas-expressing B cells in lymph nodes and high-affinity serum autoantibody in a myasthenia mouse model. AB - We investigated potential therapeutic effects of a conjugate of BAFF receptor specific-monoclonal antibody and short interference RNA in a mouse model of myasthenia gravis (EAMG). Whereas high-dose siRNA conjugate resulted in significant accumulation of Fas expressing CD19+/B220+ cells and concurrent expression of type 1 interferon in lymph nodes, low-dose conjugate did not induce FAS expression but caused marked BAFF receptor deficiency in lymph nodes that was further associated with improved MG symptoms. Unexpectedly, despite inhibiting BAFF receptor significantly in PBMCs and secondary lymphoid organs, conjugate treatment did not reduce the levels of autoantibody. Rather, at high dose, it caused robust increase in high affinity anti-AChR antibody and increased levels of serum IL10 and IL-4 cytokines. Our findings reveal a previously undocumented, dose dependent, immunomodulatory distant effect resulting from BAFF receptor specific mAb-siRNA conjugate treatment in an in vivo model of autoimmune disease. PMID- 28099878 TI - Screening, verification, and analysis of biomarkers for drug-induced cardiac toxicity in vitro based on RTCA coupled with PCR Array technology. AB - Cardiotoxicity is one of the most serious side effects of new drugs. Early detection of the drug induced cardiotoxicity based on the biomarkers provides an important preventative strategy for detecting potential cardiotoxicity of candidate drugs. In this study, we aim to identify the predictive genomics biomarkers for drug-induced cardiac toxicity based on the RTCA coupled with PCR Array technology in primary cells. Three prototypical cardiotoxic compounds (doxorubicin, isoproterenol, ouabain) with different mechanisms were firstly real time monitored to diagnose the cytotoxicity by using the RTCA, while the functional alterations of cardiomyocytes were also monitored by analyzing the beating frequency of cardiomyocytes. Then cardiac specific toxicity gene expression changes were studied by using the technology of PCR Array, which can detect the changes of 84 cardiac functions related genes. Rps6kb1 was identified to be the common cardiac biomarkers by using multivariate statistical and integration analyses. The biomarker was further verified by selecting other drugs with or without cardiotoxicity, and the results showed that the gene exhibited specific changes in cardiac toxicity. Moreover, IPA was applied to combine relevant pathways of Rps6kb1, and identify the main types of cardiac toxicity. These results would further enrich the evaluating strategy of drug-induced cardiotoxicity in vitro, and Rps6kb1 could be used as the specific biomarker of cardiotoxcity during safety assessment of the novel drug candidates. PMID- 28099880 TI - Modifications of inhibitory transmission onto pyramidal neurons by postnatal exposure to MK-801: Effects of enriched environment. AB - Early enriched environment (EE) prevents several deficits associated with postnatal MK-801 [N-Methyl-d-Aspartate (NMDA) receptor antagonist] treatment such as cognitive and locomotor deficits. We sought physiological correlates to such changes by looking at inhibitory synaptic inputs onto pyramidal cells in a prefrontal cortex slice preparation. Pharmacologically isolated gamma-amino butyric acid A (GABAA) receptor-mediated currents were measured using whole-cell patch clamp recordings. Wistar rats were raised in standard or EE from birth up to the time of experiments and were injected with saline or MK-801 (1mg/kg) on postnatal days (P) 6-10. We recorded miniature inhibitory post-synaptic currents (mIPSCs) of pyramidal cells in layer II/III of prefrontal cortex and measured their frequency, amplitude and kinetics. In control animals, the amplitude and frequency of mIPSCs increased strikingly during development from P21 to P28. MK 801 accelerated the development of mIPSCs frequency but caused a significant decrease in the amplitude of mIPSCs on P28 suggesting a significant reduction of inhibition onto pyramidal cells. EE per se led to a significant increase in both frequency and amplitude of mIPSCs, but its application to MK-801-treated rats resulted in moderate rescue of GABAergic transmission on P28. We conclude that postnatal MK-801 leads to reduced inhibitory transmission onto pyramidal cells of prefrontal cortex at adolescence which may underlie behavioural and morphological differences detected in vivo in rats. EE presentation from birth rather prevents GABAergic alterations associated with postnatal MK-801 treatment at adolescence. PMID- 28099881 TI - Mesencephalic astrocyte-derived neurotrophic factor alleviated 6-OHDA-induced cell damage via ROS-AMPK/mTOR mediated autophagic inhibition. AB - Autophagy and apoptosis are commonly involved in the dopaminergic neuron damage in the pathogenesis of Parkinson's disease. Recently, the autophagy pathway is thought to be critical to the process of PD. Therefore, the regulation of autophagy may be a potential strategy for PD treatment. Mesencephalic astrocyte derived neurotrophic factor (MANF) has been reported to have neuroprotective effects through anti-apoptosis, anti-oxidative, and anti-inflammatory mechanisms in PD. In this study, we investigated the role of autophagy system in MANF mediated neuroprotection against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. Our results showed that MANF protected SH-SY5Y cells against 6 OHDA-induced cell viability decrease and apoptosis by inhibiting autophagy. Mitochondrion damage and energetic dysfunction triggered by reactive oxidative stress (ROS) accumulation were also alleviated by MANF treatment. Furthermore, MANF downregulated phosphorylation of AMP-activated protein kinase (AMPK), a cellular energy sensor and regulator, but upregulated phosphorylation of Mammalian target of rapamycin (mTOR) under energy depletion conditions, indicating AMPK/mTOR signaling pathway is involved in the autophagic inhibition of MANF. These results suggest that autophagic inhibition provides protective mechanism of MANF in 6-OHDA-induced SH-SY5Y cell death and this inhibition is associated with AMPK/mTOR pathway. PMID- 28099882 TI - The 35-year odyssey of beta blockers in cirrhosis: any gender difference in sight? AB - Cirrhosis is the end-stage of chronic liver disease and leads to the development of portal hypertension and its complications such as esophagogastric varices. Non selective beta blockers (NSBB) are the keystone for the treatment of portal hypertension since the 1980s and, over the decades, several studies have confirmed their beneficial effect on the prevention of variceal (re)bleeding. Pharmacological studies showed effects of gender, sex hormones, oral contraceptives, and pregnancy on cytochrome P450 (CYPs) enzymes that metabolise NSBB, suggesting that gender differences might exist in the effect of NSBB. In this review, we focused on the 35-year knowledge about the use of beta blockers in cirrhosis and potential gender differences. We specifically examined the role of NSBB in pre-primary, primary and secondary prophylaxis of variceal bleeding, compared two commonly used NSBB (i.e., Propranolol and Carvedilol), and present the current controversies about the window of treatment in advanced cirrhosis with a specific focus on gender differences in NSBB effects. NSBB are not currently recommended in pre-primary prophylaxis of varices mainly because of lack of proven efficacy. On the other hand, NSBB are strongly recommended in patient with cirrhosis as primary (as alternative to endoscopic band ligation, EBL) and secondary prophylaxis (in addition to EBL) of variceal bleeding. To date, no studies have focused specifically on the effect of gender on NSBB treatment. Data extrapolated from clinical studies show that gender was neither a risk factor for the development of varices nor associated with a different response to treatment in primary or secondary prophylaxis. According to the available guidelines, no different, gender-based treatment for portal hypertension is recommended. PMID- 28099883 TI - Beta2-adrenergic signaling affects the phenotype of human cardiac progenitor cells through EMT modulation. AB - Human cardiac progenitor cells (CPCs) offer great promises to cardiac cell therapy for heart failure. Many in vivo studies have shown their therapeutic benefits, paving the way for clinical translation. The 3D model of cardiospheres (CSs) represents a unique niche-like in vitro microenvironment, which includes CPCs and supporting cells. CSs have been shown to form through a process mediated by epithelial-to-mesenchymal transition (EMT). beta2-Adrenergic signaling significantly affects stem/progenitor cells activation and mobilization in multiple tissues, and crosstalk between beta2-adrenergic signaling and EMT processes has been reported. In the present study, we aimed at investigating the biological response of CSs to beta2-adrenergic stimuli, focusing on EMT modulation in the 3D culture system of CSs. We treated human CSs and CS-derived cells (CDCs) with the beta2-blocker butoxamine (BUT), using either untreated or beta2 agonist (clenbuterol) treated CDCs as control. BUT-treated CS-forming cells displayed increased migration capacity and a significant increase in their CS forming ability, consistently associated with increased expression of EMT-related genes, such as Snai1. Moreover, long-term BUT-treated CDCs contained a lower percentage of CD90+ cells, and this feature has been previously correlated with higher cardiogenic and therapeutic potential of the CDCs population. In addition, long-term BUT-treated CDCs had an increased ratio of collagen-III/collagen-I gene expression levels, and showed decreased release of inflammatory cytokines, overall supporting a less fibrosis-prone phenotype. In conclusion, beta2 adrenergic receptor block positively affected the stemness vs commitment balance within CSs through the modulation of type1-EMT (so called "developmental"). These results further highlight type-1 EMT to be a key process affecting the features of resident cardiac progenitor cells, and mediating their response to the microenvironment. PMID- 28099884 TI - Characterization of human and Staphylococcus aureus proteins in respiratory mucosa by in vivo- and immunoproteomics. AB - : Staphylococcus aureus is a Gram-positive opportunistic bacterium which can be found as a commensal in the nares of about 50% of the human population. Besides asymptomatic carriage, S. aureus has also been found to colonize nasal polyps, a subform of chronic rhinosinusitis, in 60 to 100% of cases, and even reside intracellularly in nasal polyp tissue. The aim of this study was to shed light on the behavior of S. aureus in the human airways by analyzing S. aureus-specific proteins in nasal polyp tissue from patients with chronic rhinosinusitis and to characterize the immunogenic potential of the identified (mainly secreted) proteins. As a result, in total >600 S. aureus proteins were identified by high resolution mass spectrometry or multiple reaction monitoring. Of those roughly 180 are typically localized in the membrane, surface exposed or secreted. For 115 S. aureus proteins, partially also detected in vivo by mass spectrometry, IgA- and IgG-specific antibody signals were profiled. Strong antibody signals were predominantly found for surface expose or secreted proteins. SIGNIFICANCE: In this study, we used high resolution mass spectrometry to identify S. aureus proteins directly in infected nasal polyp tissue. We discovered bacterial proteins involved in invasion of tissue, virulence, bacterial signal transduction or acquisition of nutrients. Some of the detected superantigens and Spls are known to provoke secretion of a broad spectrum of cytokines. Therefore, our manuscript contains new information about the invasion of S. aureus in nasal polyp tissue and its protein-specific immunogenicity. PMID- 28099885 TI - Oestrus synchronisation and superovulation alter the cervicovaginal mucus proteome of the ewe. AB - : Although essential for artificial insemination (AI) and MOET (multiple ovulation and embryo transfer), oestrus synchronisation and superovulation are associated with increased female reproductive tract mucus production and altered sperm transport. The effects of such breeding practices on the ovine cervicovaginal (CV) mucus proteome have not been detailed. The aim of this study was to qualitatively and quantitatively investigate the Merino CV mucus proteome in naturally cycling (NAT) ewes at oestrus and mid-luteal phase, and quantitatively compare CV oestrus mucus proteomes of NAT, progesterone synchronised (P4) and superovulated (SOV) ewes. Quantitative analysis revealed 60 proteins were more abundant during oestrus and 127 were more abundant during the luteal phase, with 27 oestrus specific and 40 luteal specific proteins identified. The oestrus proteins most disparate in abundance compared to mid luteal phase were ceruloplasmin (CP), chitinase-3-like protein 1 (CHI3L1), clusterin (CLU), alkaline phosphatase (ALPL) and mucin-16 (MUC16). Exogenous hormones greatly altered the proteome with 51 and 32 proteins more abundant and 98 and 53 proteins less abundant, in P4 and SOV mucus, respectively when compared to NAT mucus. Investigation of the impact of these proteomic changes on sperm motility and longevity within mucus may help improve sperm transport and fertility following cervical AI. SIGNIFICANCE: This manuscript is the first to detail the proteome of ovine cervicovaginal mucus using qualitative and quantitative proteomic methods over the oestrous cycle in naturally cycling ewes, and also after application of common oestrus synchronisation and superovulation practices. The investigation of the mucus proteome throughout both the follicular and luteal periods of the oestrous cycle, and also after oestrous synchronisation and superovulation provides information about the endocrine control and the effects that exogenous hormones have on protein expression in the female reproductive tract. This information contributes to the field by providing important information on the changes that occur to the cervicovaginal mucus proteome after use of exogenous hormones in controlled breeding programs, which are commonly used on farm and also in a research setting. PMID- 28099886 TI - iTRAQ-based quantitative proteome revealed metabolic changes of Flammulina velutipes mycelia in response to cold stress. AB - : Temperature is one of the pivotal factors influencing mycelium growth and fruit body formation of Flammulina velutipes. To gain insights into hyphae growth and fruit-body formation events and facilitate the identification of potential stage specific biomarker candidates, we investigated the proteome response of F. velutipes mycelia to cold stresses using iTRAQ-coupled two-dimensional liquid chromatography tandem mass spectrometry (2D LC-MS/MS) technique. Among 1198 proteins identified with high confidence, a total of 63 displayed altered expression level after cold stress treatments. In-depth data analysis reveals that differentially expressed proteins were involved in a variety of cellular processes, particularly metabolic processes. Among the 31 up-regulated proteins, 24 (77.42%) were associated with 22 specific KEGG pathways. These up-regulated proteins could possibly serve as potential biomarkers to study the molecular mechanisms of F. velutipes mycelia response to cold stresses. These data of the proteins might provide valuable evidences to better understand the molecular mechanisms of mycelium resistance to cold stress and fruit-body formation in fungi. BIOLOGICAL SIGNIFICANCE: Low-temperature is one of the pivotal factors in some Flammulina velutipes industrial processes influencing mycelium growth, inducing primordia and controlling fruit-body development. Preliminary study has indicated that effectively regulating cultivation could augment the yield by controlling optimal cold stress level on mycelia. However, we are still far from understanding the molecular and physiological mechanisms of adaptation of these fungi at cold stress. In the present study, the experiments reported above were undertaken to investigate chronological changes of protein expression during F. velutipes mycelia in response to cold stress by using iTRAQ-coupled 2D LC-MS/MS technique. This result would provide new insights to the underlying mycelium growth and fruit-body formation mechanisms of basidiomycetes under cold stress. PMID- 28099888 TI - The non-canonical NOTCH1 ligand Delta-like 1 homolog (DLK1) self interacts in mammals. AB - Delta-like 1 homolog (DLK1) is an imprinted gene, which is widely expressed during mammalian development and plays a pivotal role in differentiation of various tissue types. Most recently, we have shown that DLK1 interacts with NOTCH1, yet several Notch independent mechanisms have previously been suggested as well, but only poorly confirmed in a mammalian context. In the present study, we employed the mammalian two-hybrid (MTH) system, a genetic in vivo protein protein interaction system, to show robust DLK1-DLK1, DLK1-FnI (Fibronectin) and DLK1-CFR (cysteine-rich FGF receptor) interactions, whereas the proposed DLK1 IGFBP1 interaction was not supported by MTH. Very little has previously been described on the DLK1 self-interaction. Herein, we showed by immunoprecipitation as well as Sulfo-SBED label transfer that the DLK1-DLK1 interaction likely is part of Dlk1's function in preadipocytes. Furthermore our data suggest that DLK1 interacts with itself through EGF domain 4 and 5, which is distinct from the recently described NOTCH1-DLK1 interaction, which occurs between EGF domain 5 and 6. This opens up the possibility that Notch independent mechanisms like the DLK1 DLK1 interaction may modulate the non-canonical NOTCH1-DLK1 interaction further complexing this system. PMID- 28099887 TI - Comparative proteomics of paired vocal fold and oral mucosa fibroblasts. AB - : Injuries of the vocal folds frequently heal with scar formation, which can have lifelong detrimental impact on voice quality. Current treatments to prevent or resolve scars of the vocal fold mucosa are highly unsatisfactory. In contrast, the adjacent oral mucosa is mostly resistant to scarring. These differences in healing tendency might relate to distinct properties of the fibroblasts populating oral and vocal fold mucosae. We thus established the in vitro cultivation of paired, near-primary vocal fold fibroblasts (VFF) and oral mucosa fibroblasts (OMF) to perform a basic cellular characterization and comparative cellular proteomics. VFF were significantly larger than OMF, proliferated more slowly, and exhibited a sustained TGF-beta1-induced elevation of pro-fibrotic interleukin 6. Cluster analysis of the proteomic data revealed distinct protein repertoires specific for VFF and OMF. Further, VFF displayed a broader protein spectrum, particularly a more sophisticated array of factors constituting and modifying the extracellular matrix. Conversely, subsets of OMF-enriched proteins were linked to cellular proliferation, nuclear events, and protection against oxidative stress. Altogether, this study supports the notion that fibroblasts sensitively adapt to the functional peculiarities of their respective anatomical location and presents several molecular targets for further investigation in the context of vocal fold wound healing. BIOLOGICAL SIGNIFICANCE: Mammalian vocal folds are a unique but delicate tissue. A considerable fraction of people is affected by voice problems, yet many of the underlying vocal fold pathologies are sparsely understood at the molecular level. One such pathology is vocal fold scarring - the tendency of vocal fold injuries to heal with scar formation -, which represents a clinical problem with highly suboptimal treatment modalities. This study employed proteomics to obtain comprehensive insight into the protein repertoire of vocal fold fibroblasts, which are the cells that predominantly synthesize the extracellular matrix in both physiological and pathophysiological conditions. Protein profiles were compared to paired fibroblasts from the oral mucosa, a neighboring tissue that is remarkably resistant to scarring. Bioinformatic analyses of the data revealed a number of pathways as well as single proteins (e.g. ECM-remodeling factors, transcription factors, enzymes) that were significantly different between the two fibroblast types. Thereby, this study has revealed novel interesting molecular targets which can be analyzed in the future for their impact on vocal fold wound healing. PMID- 28099889 TI - Evaluation of organosolv pretreatment on the structural characteristics of lignin polymers and follow-up enzymatic hydrolysis of the substrates from Eucalyptus wood. AB - In the present study, Eucalyptus was subjected to organosolv pretreatment processes with aqueous 2-propanol at 200-220 degrees C to obtain lignin with benign characters for its valorization and digestible substrates for bioethanol production. Results showed that different delignification ratios (64.00%-81.26%) and molecular weights (Mw=610-2680g/mol) of lignin fractions were dissociated from various pretreatment conditions, and the glucose yields of all the pretreated substrates significantly increased to 54.65-88.59% as compared to that of raw material (9.20%). Additionally, the amounts of beta-O-4, beta-beta, and beta-5 substructures were regularly decreased with the increased temperature and time. By contrast, the structural characteristics of the lignin fractions obtained with 70% 2-PrOH/water were less-altered than those with 50% 2-PrOH/water pretreatment. Remarkably, lignin with the lowest molecular weight (Mw=610g/mol) and less-altered chemical structure was achieved at 200 degrees C for 120min, which is beneficial to subsequent catalytic degradation of lignin. PMID- 28099890 TI - An investigation on biosorption of nitrate from water by chitosan based organic inorganic hybrid biocomposites. AB - In this study, three types of crosslinked organic-inorganic hybrid biocomposites, such as chitosan/bentonite, chitosan/titanium oxide, and chitosan/alumina (ChBT, ChTi, and ChAl respectively) were prepared and utilized for the removal of nitrate from water by batch biosorption experiments. Effects of crosslinker dose, initial nitrate concentration, contact time, initial pH of the nitrate solution, biosorbent dose, temperature, and the presence of competitive ions on adsorption capacities were investigated. Actual adsorption capacities of ChBT, ChTi, and ChAl at a crosslinker to chitosan solution ratio of 1:40 were 35.68 and 43.62, and 45.38mg/g as nitrate respectively. The actual adsorption capacities decreased with increase in crosslinker dose. Adsorption equilibrium isotherm models data were well fitted to the linear Freundlich isotherm model. Thermodynamic parameters indicate that adsorption process was spontaneous and endothermic. The adsorption process was better described by a pseudo-second-order equation. The results show that chitosan based organic-inorganic biocomposites were effective, low cost, and reusable for the removal of nitrate from water. PMID- 28099891 TI - Dihedral angle preferences of DNA and RNA binding amino acid residues in proteins. AB - A protein can interact with DNA or RNA molecules to perform various cellular processes. Identifying or analyzing DNA/RNA binding site amino acid residues is important to understand molecular recognition process. It is quite possible to accurately model DNA/RNA binding amino acid residues in experimental protein DNA/RNA complex by using the electron density map whereas, locating/modeling the binding site amino acid residues in the predicted three dimensional structures of DNA/RNA binding proteins is still a difficult task. Considering the above facts, in the present work, we have carried out a comprehensive analysis of dihedral angle preferences of DNA and RNA binding site amino acid residues by using a classical Ramachandran map. We have computed backbone dihedral angles of non DNA/RNA binding residues and used as control dataset to make a comparative study. The dihedral angle preference of DNA and RNA binding site residues of twenty amino acid type is presented. Our analysis clearly revealed that the dihedral angles (phi, psi) of DNA/RNA binding amino acid residues prefer to occupy (-89 degrees to -60 degrees , -59 degrees to -30 degrees ) bins. The results presented in this paper will help to model/locate DNA/RNA binding amino acid residues with better accuracy. PMID- 28099892 TI - A novel starch-based stimuli-responsive nanosystem for theranostic applications. AB - The aim of this study was to synthesis and characterization of a novel stimuli responsive polymeric nanosystem for theranostic applications. For this purpose, starch was modified by itaconic anhydride to afford an itaconat-functionalized starch macromonomer (starch-IA). This macromonomer with carboxylic functional groups was subsequently adsorbed onto the surface of iron oxide nanoparticles (Fe3O4 NPs), and then copolymerized with N-isopropylacrylamide (NIPAAm) monomer via a 'free' radical initiated polymerization technique to produce a temperature responsive magnetic nanohydrogel (MNHG). The chemical structures of all samples as representatives were characterized by means of Fourier transform infrared (FTIR) spectroscopy. The lower critical solution temperature (LCST), thermal responsibility, morphology, elemental composition, thermal stability, and magnetic properties of the synthesized MNHG were investigated. In addition, the methotrexate (MTX)-loading capacity (~74%) and stimuli-responsive drug release ability of the synthesized MNHG were also evaluated. As results, we envision that the synthesized starch-g-PNIPAAm/Fe3O4 MNHG may be find theranostic applications, in part due to its smart physicochemical properties. PMID- 28099893 TI - Lead-binding capacity of calcium pectates with different molecular weight. AB - Nowadays, heavy metal contamination of environment is considered as a serious threat to public health because of toxicity of these pollutants and the lack of effective materials with metal-binding properties. Some biopolymers such as pectins were proposed for removal of metal ions from industrial water disposals. Chemical structure of pectins is quite variable and substantially affects their metal binding properties. In this work, relationship between molecular weight and Pb(II)-binding capacity of calcium pectates was investigated in a batch sorption system. The results showed that all pectate samples are able to form complexes with Pb(II) ions. The effects of contact time, pH of the media and equilibrium metal concentration on metal-binding process were tested in experiments. The equilibrium time min required for uptake of Pb(II) by pectate compounds was found to be 60min. Langmuir and Freundlich models were applied for description of interactions between pectates and metal ions. Binding capacity of low molecular pectate was highest among all the samples tested. Langmuir model was figured out to be the best fit within the whole range of pH values. These results demonstrate that calcium pectate with low molecular weight is more promising agent for elimination of Pb(II) ions from contaminated wastewaters. PMID- 28099894 TI - Handheld new technology Raman and portable FT-IR spectrometers as complementary tools for the in situ identification of organic materials in modern art. AB - A non-invasive approach has been carried out to characterize painting materials used in modern artworks conserved in the art collection of Carandente's museum at Palazzo Collicola in Spoleto (Italy). This work is focused on the cross validation of the handheld BRAVO Raman spectrometer, that uses a sequentially Shifted Excitation (SSE) to mitigate fluorescence, for the characterization specifically of organic materials. The analytical procedure, combining XRF, Raman and reflection infrared spectroscopy, allowed a complete characterization of the artists' palettes; particularly eight different synthetic dyes belonging to the class of pigment red (PR) and pigment yellow (PY.), synthetic and traditional binders, such as alkyd resin and lipids have been easily identified. PMID- 28099895 TI - Imaging of MSC transplantation in neuroscience. PMID- 28099896 TI - Hypothalamic microRNAs flip the switch for fertility. PMID- 28099897 TI - Oxidative stress in neurodegenerative disease: causation or association? PMID- 28099898 TI - The best strategy for HCC patients at each BCLC stage: a network meta-analysis of observational studies. AB - BACKGROUND AND AIMS: Currently, the Barcelona Clinic Liver Cancer staging system remains huge controversies in the management of hepatocellular carcinoma. To determine the best therapeutic strategy for patients at each stage, we conducted a network meta-analysis and aimed to provide a new treatment concept. MATERIALS AND METHODS: PubMed, Embase and Cochrane Library database were searched for observational studies up to August 31, 2016. We extracted data on overall survival rate from studies that compared various strategies for use with patients at different stages. Network meta-analysis was conducted by evaluating the different overall survival rate of each stage. Cumulative probability value was utilized to rank the strategies under examination. A node-splitting model was employed to assess consistency and inconsistency. RESULTS: A total of 198 observational studies were included in the network meta-analysis with a focus on Stages 0-D. By comparing the overall survival rate of each stage, the results revealed that liver transplantation and liver transplantation plus transcatheter arterial chemoembolization were the best options for patients with Stages 0 and A. The applications of surgical resection plus transcatheter arterial chemoembolization and surgical resection plus sorafenib were the best strategies for Stages B and C. For Stage D, whole net connection could not be established, but intra-arterial infusion chemotherapy and liver transplantation could be potential primary options. CONCLUSIONS: The existing therapeutic flowchart needs to be updated. Potential best strategies relating to all stages were identified and should be used as references for clinical treatments. PMID- 28099899 TI - Concurrent neoadjuvant chemoradiotherapy could improve survival outcomes for patients with esophageal cancer: a meta-analysis based on random clinical trials. AB - BACKGROUND: The long-term survival benefit of concurrent neoadjuvant chemoradiotherapy in patients with resectable esophageal cancer remains controversial. In the present study, we conducted a meta-analysis to assess these effectiveness. METHODS: We searched for most relevant studies published up to the end of August 2016, using Pubmed and web of knowledge. And additional articles were identified from previous meta-analysis. The hazard ratio (HR, for overall survival and progression free survival) or risk ratio (RR, for R0 resection) with its corresponding 95 % confidence interval (CI) were used to assess the pooled effect. RESULTS: Twelve articles including 1756 patients were included in the meta-analysis. Concurrent neoadjuvant chemoradiotherapy followed by surgery was associated with significantly improved overall survival (HR=0.76 , 95% CI= 0.68 0.86), progression survival (HR =0.69, 95% CI= 0.59-0.81), and R0 resection rate(RR =1.17, 95% CI= 1.03-1.33). Subgroup analysis suggested that concurrent neoadjuvant chemoradiotherapy could improve overall survival outcome for squamous cell carcinoma (HR=0.73, 95%CI=0.61-0.88) but not those for adenocarcinoma (HR=0.72, 95%CI=0.48-1.04). CONCLUSION: Our findings suggested that concurrent neoadjuvant chemoradiotherapy was associated with a significant survival benefit in patients with esophageal cancer. PMID- 28099901 TI - Efficacy of sequential therapies with sorafenib-sunitinib versus sunitinib sorafenib in metastatic renal cell carcinoma: A systematic review and meta analysis. AB - The most efficient sequence of targeted agents for metastatic renal cell carcinoma patients has yet to be identified. Whether the sequence of sorafenib and sunitinib really matters is controversial and not answered clearly until now. This meta-analysis aims to estimate the efficacy of receptor tyrosine kinase inhibitors sorafenib-sunitinib and sunitinib-sorafenib for metastatic renal cell carcinoma, on the outcome of first-line progression-free survival, second-line progression-free survival, total progression-free survival and overall survival.We searched PubMed, Embase, Cochrane Library and ClinicalTrails.gov for eligible studies. Data were analyzed using random or fixed effects model depending on the heterogeneity of the eligible studies. Heterogeneity across studies were analyzed using Q and I2 statistics.Of 902 identified studies, ten were qualified in our analysis (N = 1732 patients). Sorafenib-sunitinib yielded no statistically significant benefit in first-line progression-free survival (fixed effects; HR = 0.95; 95%CI 0.75-1.21; p = 0.702), total progression-free survival (random effects; HR = 0.92; 95%CI 0.71-1.19; p = 0.531) and overall survival (fixed effects; HR = 0.89; 95%CI 0.72-1.09; p = 0.257), compared with sunitinib-sorafenib. Second-line progression-free survival was longer for sorafenib-sunitinib than sunitinib-sorafenib (fixed effects; HR = 0.55; 95%CI 0.44-0.68; p = 0.000).Sequential therapies with sorafenib and sunitinib is well tolerated and efficient in mRCC. However, there are no evidence supported that sorafenib-sunitinib has the superiority to sunitinib-sorafenib in sequence. The ideal sequence of targeted agents requires further elucidation. PMID- 28099900 TI - Skeletal muscle aging: influence of oxidative stress and physical exercise. AB - Skeletal muscle abnormalities are responsible for significant disability in the elderly. Sarcopenia is the main alteration occurring during senescence and a key public health issue as it predicts frailty, poor quality of life, and mortality. Several factors such as reduced physical activity, hormonal changes, insulin resistance, genetic susceptibility, appetite loss, and nutritional deficiencies are involved in the physiopathology of muscle changes. Sarcopenia is characterized by structural, biochemical, molecular and functional muscle changes. An imbalance between anabolic and catabolic intracellular signaling pathways and an increase in oxidative stress both play important roles in muscle abnormalities. Currently, despite the discovery of new targets and development of new drugs, nonpharmacological therapies such as physical exercise and nutritional support are considered the basis for prevention and treatment of age-associated muscle abnormalities. There has been an increase in information on signaling pathways beneficially modulated by exercise; nonetheless, studies are needed to establish the best type, intensity, and frequency of exercise to prevent or treat age-induced skeletal muscle alterations. PMID- 28099903 TI - Talin-1 interaction network promotes hepatocellular carcinoma progression. AB - Talin-1 is a known oncogene-associated protein. In this study, we set out to determine its role and mechanisms in hepatocellular carcinoma (HCC) progression. We found Talin-1 to be highly expressed in HCC cells relative to non-cancer liver epithelial cells and to promote tumor growth and metastasis. We used Whole Human Genome Oligo Microarray analysis with HCC cells and HCC cells in which Talin-1 was knocked down using shRNA to identify transcripts regulated by Talin-1. Of the 40,000 tested genes, 3099 were differentially expressed after Talin-1 knockdown; expression of 1924 genes was increased, while expression of 2175 was decreased. Gene ontology (GO) profiling indicated that Talin-1 promotes many HCC progression related activities, including ion transport and membrane depolarization, cell growth, and cell adhesion. We also characterized the network of gene transcripts regulated by Talin-1 and their role in promoting HCC progression. Our findings confirm the role of Talin-1 in carcinogenesis and provided a set of novel therapeutic targets for the treatment of HCC. PMID- 28099902 TI - Anthelmintic mebendazole enhances cisplatin's effect on suppressing cell proliferation and promotes differentiation of head and neck squamous cell carcinoma (HNSCC). AB - Head and neck squamous cell carcinoma (HNSCC) is one of the most common and aggressive types of human cancers worldwide. Nearly a half of HNSCC patients experience recurrence within five years of treatment and develop resistance to chemotherapy. Thus, there is an urgent clinical need to develop safe and novel anticancer therapies for HNSCC. Here, we investigate the possibility of repurposing the anthelmintic drug mebendazole (MBZ) as an anti-HNSCC agent. Using the two commonly-used human HNSCC lines CAL27 and SCC15, we demonstrate MBZ exerts more potent anti-proliferation activity than cisplatin in human HNSCC cells. MBZ effectively inhibits cell proliferation, cell cycle progression and cell migration, and induces apoptosis of HNSCC cells. Mechanistically, MBZ can modulate the cancer-associated pathways including ELK1/SRF, AP1, STAT1/2, MYC/MAX, although the regulatory outcomes are context-dependent. MBZ also synergizes with cisplatin in suppressing cell proliferation and inducing apoptosis of human HNSCC cells. Furthermore, MBZ is shown to promote the terminal differentiation of CAL27 cells and keratinization of CAL27-derived xenograft tumors. Our results are the first to demonstrate that MBZ may exert its anticancer activity by inhibiting proliferation while promoting differentiation of certain HNSCC cancer cells. It's conceivable the anthelmintic drug MBZ can be repurposed as a safe and effective agent used in combination with other frontline chemotherapy drugs such as cisplatin in HNSCC treatment. PMID- 28099904 TI - Tianfoshen oral liquid: a CFDA approved clinical traditional Chinese medicine, normalizes major cellular pathways disordered during colorectal carcinogenesis. AB - Colorectal cancer remains the third leading cause of cancer death worldwide, suggesting exploration of novel therapeutic avenues may be useful. In this study, therefore, we determined whether Tianfoshen oral liquid, a Chinese traditional medicine that has been used to treat non-small cell lung cancer, would be therapeutically beneficial for colorectal cancer patients. Our data show that Tianfoshen oral liquid effectively inhibits growth of colorectal cancer cells both in vitro and in vivo. We further employed a comprehensive strategy that included chemoinformatics, bioinformatics and network biology methods to unravel novel insights into the active compounds of Tianfoshen oral liquid and to identify the common therapeutic targets and processes for colorectal cancer treatment. We identified 276 major candidate targets for Tianfoshen oral liquid that are central to colorectal cancer progression. Gene enrichment analysis showed that these targets were associated with cell cycle, apoptosis, cancer related angiogenesis, and chronic inflammation and related signaling pathways. We also validated experimentally the inhibitory effects of Tianfoshen oral liquid on these pathological processes, both in vitro and in vivo. In addition, we demonstrated that Tianfoshen oral liquid suppressed multiple relevant key players that sustain and promote colorectal cancer, which is suggests the potential therapeutic efficacy of Tianfoshen oral liquid in future colorectal cancer treatments. PMID- 28099905 TI - Prolyl hydroxylase domain protein 3 and asparaginyl hydroxylase factor inhibiting HIF-1 levels are predictive of tumoral behavior and prognosis in hepatocellular carcinoma. AB - Hypoxia-inducible factors (HIFs) are key regulators in oxygen homeostasis. Their stabilization and activity are regulated by prolyl hydroxylase domain (PHD)-1, 2, -3 and factor inhibiting HIF (FIH). This study investigated the relation between these oxygen sensors and the clinical behaviors and prognosis of hepatocellular carcinoma (HCC). Tissue microarray and RT-PCR analysis of tumor tissues and adjacent non-tumor liver tissues revealed that mRNA and protein levels of both PHD3 and FIH were lower within tumors. The lower expression of PHD3 in tumor was associated with larger tumor size, incomplete tumor encapsulation, vascular invasion and higher Ki-67 LI (p < 0.05). The lower expression of FIH in tumor was associated with incomplete tumor encapsulation, vascular invasion, as well as higher TNM stage, BCLC stage, microvascular density and Ki-67 LI (p < 0.05). Patients with reduced expression of PHD3 or FIH had markedly shorter disease-free survival (DFS), lower overall survival (OS), or higher recurrence (p < 0.05), especially early recurrence. Patients with simultaneously reduced expression of PHD3 and FIH exhibited the least chance of forming tumor encapsulation, highest TNM stage (p < 0.0083), lowest OS and highest recurrence rate (p < 0.05). Multivariate analysis indicated that a lower expression of FIH independently predicted a poor prognosis in HCC. These findings indicate that downregulation of PHD3 and FIH in HCC is associated with more aggressive tumor behavior and a poor prognosis. PHD3 and FIH may be potential therapeutic targets for HCC treatment. PMID- 28099906 TI - Genomic characteristics of pancreatic squamous cell carcinoma, an investigation by using high throughput sequencing after in-solution hybrid capture. AB - Squamous cell carcinoma (SCC) of pancreas is a rare histotype of pancreatic ductal carcinoma which is distinct from pancreatic adenocarcinoma (AC). Although there are standard treatments for pancreatic AC, no precise therapies exist for pancreatic SCC. Here, we screened 1033 cases of pancreatic cancer and identified 2 cases of pure SCC, which were pathologically diagnosed on the basis of finding definite intercellular bridges and/or focal keratin peal formation in the tumor cells. Immunohistochemistry assay confirmed the positive expression of CK5/6 and p63 in pancreatic SCC. To verify the genomic characteristics of pancreatic SCC, we employed in-solution hybrid capture targeting 137 cancer-related genes accompanied by high throughput sequencing (HTS) to compare the different genetic variants in SCC and AC of pancreas. We compared the genetic alterations of known biomarkers of pancreatic adenocarcinoma in different pancreatic cancer tissues, and identified nine mutated genes in SCC of pancreas: C7orf70, DNHD1, KPRP, MDM4, MUC6, OR51Q1, PTPRD, TCF4, TET2, and nine genes (ABCB1, CSF1R, CYP2C18, FBXW7, ITPA, KIAA0748, SOD2, SULT1A2, ZNF142) that are mutated in pancreatic AC. This study may have taken one step forward on the discovery of potential biomarkers for the targeted treatment of SCC of the pancreas. PMID- 28099907 TI - Increased incidence of ectopic pregnancy after in vitro fertilization in women with decreased ovarian reserve. AB - The incidence of ectopic pregnancy after assisted reproductive technology is increased approximately 2.5-5-fold compared with natural conceptions.Strategies were used to decrease the incidence of ectopic pregnancy, but ectopic pregnancy still occurs. In the present study, women were selected with decreased ovarian reserve (defined as FSH > 10 IU/L) aged 20 to 38 years who underwent IVF-ET between 2009 and 2014. These 2,061 women were age-matched with an equal number of women with normal ovarian reserve (defined as FSH <= 10 IU/L). During cycles following fresh embryo transfer, 93 patients were diagnosed with ectopic pregnancy. The incidence of ectopic pregnancy in clinical pregnancies was significantly higher in the decreased ovarian reserve than in the normal ovarian reserve group (5.51% vs. 2.99%). After adjusting for confounding factors, the incidence of ectopic pregnancy was significantly associated with decreased ovarian reserve. Our results showed that decreased ovarian reserve is an independent risk factor for ectopic pregnancy after in vitro fertilization-embryo transfer. PMID- 28099908 TI - The association of two polymorphisms in adiponectin-encoding gene with hypertension risk and the changes of circulating adiponectin and blood pressure: A meta-analysis. AB - OBJECTIVES: This meta-analysis was prepared to synthesize published data on the association of two polymorphisms (T45G and G276T) in adiponectin-encoding gene (ADIPOQ) with hypertension risk and the changes of circulating adiponectin and blood pressure. Methodology and Major Findings: Data were collected and corrected by two authors, and were managed with Stata software. In total, 12 articles were synthesized, including 12 studies (3358 cases and 5121 controls) for the association of two study polymorphisms with hypertension risk and 11 studies (3053 subjects) for the between-genotype changes of adiponectin and/or blood pressure. Based on all qualified studies, the risk prediction for hypertension was nonsignificant for both polymorphisms, with significant heterogeneity for G276T polymorphism (I2 = 53.8%). Overall changes in adiponectin and blood pressure were also nonsignificant for T45G, while contrastingly 276GT genotype was associated with significantly higher levels of adiponectin (weighted mean difference [WMD] = 0.72 MUg/mL, 95% confidence interval [CI]: 0.04 to 1.41, P = 0.038), systolic (WMD = 5.15 mm Hg, 95% CI: 0.98 to 9.32, P = 0.016) and diastolic (WMD = 3.45 mm Hg, 95% CI: 0.37 to 6.53, P = 0.028) blood pressure with evident heterogeneity (I2 = 72.0%, 78.3% and 80.0%, respectively), and these associations were more obvious in hypertensive patients. Publication bias was a low probability event for overall comparisons. CONCLUSIONS: Our findings suggested that in spite of the nonsignificant association between ADIPOQ T45G or G276T polymorphism and hypertension, the heterozygous mutation of G276T was observed to account for increased levels of circulating adiponectin and blood pressure, especially in hypertensive patients. PMID- 28099909 TI - Pathway of peritoneal carcinomatosis maybe hematogenous metastasis rather than peritoneal seeding. AB - GOALS: This study aimed to summarize the clinicopathological data of the cases of gastric cancer or colon cancer with regular metastasis in the mesentery of small intestine and explore the pathway of peritoneal carcinomatosis. MATERIALS AND METHODS: We retrospectively analyzed 5 cases of gastric cancer and 3 cases of colon cancer with regular metastasis in the mesentery of the small intestine from January 2014 to June 2016, including clinical information, gross manifestations during operation, treatment, and pathology. RESULTS: The clinical characteristics of all 8 cases were fully collected. The symptoms were various without specificity. All patients were found to present with metastasis in peritoneum during operation and the metastatic lesions arranged along the blood vessels orderly. The metastatic lesions of all studied patients were proved to be malignant carcinoma histopathologically, the same as the original tumor. Tumor emboli were seen in the vessel and invasive neoplastic foci was also seen in the vascular wall. CONCLUSIONS: The traditional view that peritoneal carcinomatosis is due to seeding has no sufficient basis. Hematogenous metastasis maybe the real way of peritoneal carcinomatosis combined with clinical presentation. PMID- 28099910 TI - Multiple biological functions of Twist1 in various cancers. AB - Twist1 is a well-known regulator of transcription during embryonic organogenesis in many species. In humans, Twist1 malfunction was first linked to Saethre Chotzen syndrome and later identified to play an essential role in tumor initiation, stemness, angiogenesis, invasion, metastasis, and chemo-resistance in a variety of carcinomas, sarcomas, and hematological malignances. In this review, we will first focus on systematically elaborating the diverse pathological functions of Twist1 in various cancers, then delineating the intricate underlying network of molecular mechanisms, based on which we will summarize current therapeutic strategies in cancer treatment that target and modulate Twist1 involved signaling pathways. Most importantly, we will put special emphasis on revealing the independence and interdependency of these multiple biological functions of Twist1, piecing together the whole delicate picture of Twist1's diversified pathological roles in different cancers and providing new perspectives to guide future research. PMID- 28099911 TI - Bradykinin regulates cell growth and migration in cultured human cardiac c-Kit+ progenitor cells. AB - Bradykinin is a well-known endogenous vasoactive peptide. The present study investigated the bradykinin receptor expression in human cardiac c-Kit+ progenitor cells and the potential role of bradykinin in regulating cell cycling progression and mobility. It was found that mRNA and protein of bradykinin type 2 receptors, but not bradykinin type 1 receptors, were abundant in cultured human cardiac c-Kit+ progenitor cells. Bradykinin (1-10 nM) stimulated cell growth and migration in a concentration-dependent manner. The increase of cell proliferation was related to promoting G0/G1 transition into G2/M and S phase. Western blots revealed that bradykinin significantly increased pAkt and pERK1/2 as well as cyclin D1, which were countered by HOE140 (an antagonist of bradykinin type 2 receptors) or by silencing bradykinin type 2 receptors. The increase of pAkt, pERK1/2 and cyclin D1 by bradykinin was prevented by the PI3K inhibitor Ly294002, the PLC inhibitors U73122 and neomycin, and/or the PKC inhibitor chelerythrine and the MAPK inhibitor PD98059. Our results demonstrate the novel information that bradykinin promotes cell cycling progression and migration in human cardiac c-Kit+ progenitor cells via activating PI3K, PLC, PKC, cyclin D1, pERK1/2, and pAkt. PMID- 28099913 TI - ZiBuPiYin recipe improves cognitive decline by regulating gut microbiota in Zucker diabetic fatty rats. AB - Numerous researches supported that microbiota can influence behavior and modulate cognitive function through "microbiota-gut-brain" axis. Our previous study has demonstrated that ZiBuPiYin recipe (ZBPYR) possesses excellent pharmacological effects against diabetes-associated cognitive decline. To elucidate the role of ZBPYR in regulating the balance of gut microbiota to improve psychological-stress induced diabetes-associated cognitive decline (PSDACD), we compared blood glucose, behavioral and cognitive functions and diversity of the bacterial community among experimental groups. The Zucker diabetic fatty (ZDF) rats with PSDACD exhibited behavioral and cognitive anomalies showing as increased anxiety- and depression-like behaviors and decreased learning and memory abilities. High throughput sequencing of the bacterial 16S rRNA gene revealed that Roseburia and Coprococcus were decreased in ZDF rats with PSDACD compared with control group. Notably, these changes were reversed by ZBPYR treatment. Our findings indicate that ZBPYR might prevent PSDACD by maintaining the compositions of gut microbiota, which could be developed as a new therapy for T2D with PSDACD. PMID- 28099912 TI - Bone marrow micro-environment is a crucial player for myelomagenesis and disease progression. AB - Despite the advent of many therapeutic agents, such as bortezomib and lenalidomide that have significantly improved the overall survival, multiple myeloma remains an incurable disease. Failure to cure is multifactorial and can be attributed to the underlying genetic heterogeneity of the cancer and to the surrounding micro-environment. Understanding the mutual interaction between myeloma cells and micro-environment may lead to the development of novel treatment strategies able to eradicate this disease. In this review we discuss the principal molecules involved in the micro-environment network in multiple myeloma and the currently available therapies targeting them. PMID- 28099914 TI - Advances in epigenetic glioblastoma therapy. AB - Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults despite contemporary gold-standard first-line treatment strategies. This type of tumor recurs in virtually all patients and no commonly accepted standard treatment exists for the recurrent disease. Therefore, advances in all scientific and clinical aspects of GBM are urgently needed. Epigenetic mechanisms are one of the major factors contributing to the pathogenesis of cancers, including glioblastoma. Epigenetic modulators that regulate gene expression by altering the epigenome and non-histone proteins are being exploited as therapeutic drug targets. Over the last decade, numerous preclinical and clinical studies on histone deacetylase (HDAC) inhibitors have shown promising results in various cancers. This article provides an overview of the anticancer mechanisms of HDAC inhibitors and the role of HDAC isoforms in GBM. We also summarize current knowledge on HDAC inhibitors on the basis of preclinical studies and emerging clinical data. PMID- 28099915 TI - Liquid biopsy genotyping in lung cancer: ready for clinical utility? AB - Liquid biopsy is a blood test that detects evidence of cancer cells or tumor DNA in the circulation. Despite complicated collection methods and the requirement for technique-dependent platforms, it has generated substantial interest due, in part, to its potential to detect driver oncogenes such as epidermal growth factor receptor (EGFR) mutants in lung cancer. This technology is advancing rapidly and is being incorporated into numerous EGFR tyrosine kinase inhibitor (EGFR-TKI) development programs. It appears ready for integration into clinical care. Recent studies have demonstrated that biological fluids such as saliva and urine can also be used for detecting EGFR mutant DNA through application other user friendly techniques. This review focuses on the clinical application of liquid biopsies to lung cancer genotyping, including EGFR and other targets of genotype directed therapy and compares multiple platforms used for liquid biopsy. PMID- 28099916 TI - Involvement of NF-kappaBIZ and related cytokines in age-associated renal fibrosis. AB - Chronic inflammation is a major contributor to age-related nephropathic changes, including renal fibrosis. In this study, various experimental paradigms were designed to delineate the role played by NF-kappaBIZ (also known as IkappaBzeta) in age-associated renal fibrosis. Analyses based on RNA-sequencing findings obtained by next generation sequencing (NGS) revealed the upregulations of NF kappaBIZ and of IL-6 and MCP-1 (both known to be regulated by NF-kappaBIZ) during aging. The up-regulation of NF-kappaBIZ in aged rat kidneys coincided with increased macrophage infiltration. In LPS-treated macrophages, oxidative stress was found to play a pivotal role in NF-kappaBIZ expression, suggesting age related oxidative stress is associated with NF-kappaBIZ activation. Furthermore, these in vitro findings were confirmed in LPS-treated old rats, which showed higher levels of oxidative stress and NF-kappaBIZ in kidneys than LPS-treated young rats. Additional in vitro experiments using macrophages and kidney fibroblasts demonstrated NF-kappaBIZ and related cytokines participate in fibrosis. In particular, increased levels of NF-kappaBIZ-associated cytokines in macrophages significantly up-regulated TGF-beta induced kidney fibroblast activation. Moreover, experiments with NF-kappaBIZ knocked down macrophages showed reduced TGF-beta-induced kidney fibroblast activation. The findings of the present study provide evidence regarding an involvement of NF-kappaBIZ in age associated progressive renal fibrosis and provides potential targets for its prevention. PMID- 28099918 TI - Association of T-cadherin levels with the response to neoadjuvant chemotherapy in locally advanced breast cancer. AB - PURPOSE: To examine the association of T-cadherin with pathologic complete response (pCR) after neoadjuvant chemotherapy for locally advanced breast cancer. RESULTS: T-cadherin expression before and after neoadjuvant chemotherapy was similar (P = 0.162). The multivariable analysis indicated that negative T cadherin expression was independently associated with pCR after neoadjuvant TAC chemotherapy (P = 0.001). MATERIALS AND METHODS: A total of 136 patients with locally advanced breast cancer received four cycles of neoadjuvant TAC chemotherapy (docetaxel + epirubicin + cyclophosphamide), followed by surgery. T cadherin, estrogen receptor (ER), progesterone receptor (PR), HER-2, and Ki-67 were analyzed by immunohistochemistry. The association between T-cadherin expression and pCR after neoadjuvant chemotherapy was analyzed using multivariable logistic analysis. CONCLUSIONS: Negative T-cadherin expression before and after neoadjuvant chemotherapy for locally advanced breast cancer was similar. T-cadherin could be considered an independent factor associated with the efficacy of such therapy. PMID- 28099917 TI - Cleavage of Fibulin-2 by the aggrecanases ADAMTS-4 and ADAMTS-5 contributes to the tumorigenic potential of breast cancer cells. AB - Fibulin-2 participates in the assembly of extracellular matrix components through interactions with multiple ligands and promotes contacts between cells and their surrounding environment. Consequently, identification of processes that could lead to an altered Fibulin-2 could have a major impact not only in the maintenance of tissue architecture and morphogenesis but also in pathological situations including cancer. Herein, we have investigated the ability of the secreted metalloproteases ADAMTS-4 and ADAMTS-5 to digest Fibulin-2. Using in vitro approaches and cultured breast cancer cell lines we demonstrate that Fibulin-2 is a better substrate for ADAMTS-5 than it is for ADAMTS-4. Moreover, Fibulin-2 degradation is associated to an enhancement of the invasive potential of T47D, MCF-7 and SK-BR-3 cells. We have also found that conditioned medium from MCF-7 cells that simultaneously overexpress Fibulin-2 and ADAMTS-5 significantly induced the migratory and invasive ability of normal breast fibroblasts using 3D collagen matrices. Immunohistochemical analysis highlights the close proximity or partial overlap of both Fibulin-2 and ADAMTS-5 in breast tumor samples. Additionally, proteolytic products derived from a potential degradation of Fibulin-2 by ADAMTS-5 were also identified in these samples. Finally, we also show that the cleavage of Fibulin-2 by ADAMTS-5 is counteracted by ADAMTS-12, a metalloprotease that interacts with Fibulin-2. Overall, our results provide direct evidence indicating that Fibulin-2 is a novel substrate of ADAMTS-5 and that this proteolysis could alter the cellular microenvironment affecting the balance between protumor and antitumor effects associated to both Fibulin-2 and the ADAMTSs metalloproteases. PMID- 28099919 TI - Autophagy-related gene LRRK2 is likely a susceptibility gene for systemic lupus erythematosus in northern Han Chinese. AB - Autophagy is associated with various immune diseases, including systemic lupus erythematosus (SLE). Seven variants within autophagy-related genes previously reported to show top association signals by genome-wide association studies in immune diseases were selected for analysis. Initially, 510 SLE patients (631 controls) were enrolled in the study. An additional independent cohort of 511 SLE patients (687 controls) was included for replication. Polymorphism rs2638272 in LRRK2 gene showed significant association with susceptibility to SLE (P = 1.14 * 10-2) within the initial patient population. This was independently replicated (second patient cohort), and was reinforced with combination (P = 2.82 * 10-3). By combining multiple layers of regulatory effects, rs1491941 in high linkage disequilibrium with rs2638272 (r2 = 0.99) was regarded to have the strongest function in LRRK2. The rs1491941 protective A-allele exhibited an increase of nuclear protein binding, and an increase in LRRK2 transcription compared with G allele. Furthermore, we observed increased transcription levels of LRRK2 in peripheral blood mononuclear cells from SLE patients compared with controls. In conclusion, we have identified a novel genetic association between the autophagy related LRRK2 gene and susceptibility to SLE. By integrating layers of functional data, we derived the beneficial effect of autophagy on the pathogenesis of SLE. PMID- 28099920 TI - Prognostic implications of intratumoral CD103+ tumor-infiltrating lymphocytes in pulmonary squamous cell carcinoma. AB - CD103 is the alphaE subunit of alphaEbeta7 integrin that is expressed in tissue resident memory T cells, where it promotes cytotoxic T cell responses against tumors. However, little is known about its expression or clinicopathological implications in non-small cell lung cancer (NSCLC). This study investigated the prognostic implications of CD103+ tumor-infiltrating lymphocytes (TILs) in NSCLC. We established two cohorts: patients with resected NSCLC (n = 132) and patients with pulmonary squamous cell carcinoma (pSCC), a subset of NSCLC (n = 378), to estimate the prognostic significance of CD103+ TILs. The numbers of CD103+ TILs in the intratumoral (i.e., intraepithelial) and stromal regions of NSCLC were estimated using immunohistochemistry and automated image analysis. In the NSCLC cohort, high numbers of intratumoral CD103+ TILs were significantly associated with prolonged disease-free survival (DFS) and overall survival (OS) in patients with pSCC but not in those with pulmonary adenocarcinoma. In the pSCC cohort, a positive correlation was observed between the numbers of intratumoral CD103+ and CD8+ TILs (correlation coefficient = 0.736, P < 0.001). The ratio of intratumoral/stromal CD103+ TILs was higher in pSCC with high compared to low E cadherin expression (P = 0.021). According to Kaplan-Meier analysis, high intratumoral but not stromal CD103+ TILs were associated with prolonged DFS and OS in patients with resected pSCC (P = 0.021 and 0.002, respectively). Multivariate analysis revealed that a high number of intratumoral CD103+ TILs is an independent predictor of a more favorable DFS (P = 0.021). Thus, a high number of intratumoral CD103+ TILs is a favorable prognostic indicator in patients with pSCC. PMID- 28099922 TI - PAFR selectively mediates radioresistance and irradiation-induced autophagy suppression in prostate cancer cells. AB - Platelet-activating factor receptor (PAFR) promotes tumorigenesis, angiogenesis and metastasis. Here, we defined the PAFR as a yielding new inhibiting target to selectively enhance the sensitivity of prostate cancer (PCa) cells to radiation. The selective responding to PAFR inhibiter may be caused by the differential expression pattern of PAFR in PCa cells. In this study, we also determined PAFR as a molecular basis by which the radiation induces autophagy suppression independent of activating mTOR pathway. PAFR can bind to the autophagy indispensable protein Beclin 1, leading to the disability in its serine phosphorylation. The PAFR antagonist Ginkgolide B (GB) can sensitize radiotherapy by disrupting the formation of PAFR/Beclin 1 complex in PC3 and LNCaP cells, which have elevated PAFR expression after radiation exposure. Most importantly, GB efficiently radiosensitized PC3 and LNCaP tumor xenografts in vivo, and significantly reduced tumor burden. Overall, our results elucidated a significant role of GB in selectively improving the outcomes of PCa receiving radiation therapy. PMID- 28099921 TI - Stiehopus japonieus acidic mucopolysaccharide inhibits the proliferation of pancreatic cancer SW1990 cells through Hippo-YAP pathway. AB - Previous studies have indicated that stiehopus japonieus acidic mucopolysaccharide (SJAMP) could inhibit the proliferation of pancreatic cancer cell SW1990. However, the mechanism remains unclear. In our study, YAP expression was identified by immunohistochemistry and quantitative Real-time PCR from 45 pairs of human pancreatic ductal adenocarcinoma (PDAC) tissues and their adjacent non-tumor samples. We found that the YAP expression was associated with the histological differentiation degree, and negatively correlated with pancreatic cancer patients' survival. More YAP localization in nuclear and enhanced expression of YAP mRNA in pancreatic cancer tissue was found in comparison with in the normal tissue. These results identify YAP acts as an amazing regulator in the pathogenesis of pancreatic cancer. After affected by SJAMP, YAP and TEAD1 were down regulated, while MST1 and pYAP were upregulated gradually with the prolong of effect time. SJAMP also improved YAP phosphorylation, nuclear-to cytoplasmic translocation and inactivation. After successfully knocked-down by YAP siRNA, the inhibition of proliferation of SJAMP to cancer cells was attenuated. Interestingly, we indicated a down-regulation of that TEAD with SJAMP 4 mg/ml, 8 mg/ml for 24 h and with 8 mg/ml SJAMP for 24 h, 48 h even after YAP silencing. That might mean that the SJAMP has other targets, not only YAP, to downregulate TEAD. We proposed a hypothesis that Hippo-YAP pathway involved in carcinogenesis of pancreatic cancer and in the inhibition effect of SJAMP to the proliferation of pancreatic cancer cell, although maybe not the sole signaling pathway. PMID- 28099923 TI - Significant association between Let-7-KRAS rs712 G > T polymorphism and cancer risk in the Chinese population: a meta-analysis. AB - Association between let-7-KRAS rs712 polymorphism and cancer risk was inconsistent. We therefore conducted this meta-analysis to clarify the association between let-7-KRAS rs712 polymorphism and cancer risk with STATA 14.0 software. A systemic literature search in online databases (PubMed, Embase, CNKI and Wanfang database) was preformed to obtain relevant articles. A total of 13 case-control studies involving 3,453 patients and 4,470 controls were identified up to May 16, 2015. The pooled results indicated that significantly increased risk were observed in Chinese population in T vs. G (OR = 1.21, 95% CI = 1.03 1.42) and TT vs. GG + GT genetic models (OR = 1.69, 95% CI = 1.17-2.42). Sensitivity analysis was conducted and the result without heterogeneity showed significant associations in all five genetic models. Subgroup analyses of cancer type indicated a similar result in digestive cancer (for T vs. G: OR = 1.41, 95% CI = 1.26-1.57; GT vs. GG: OR = 1.24, 95% CI = 1.07-1.43; TT vs. GG: OR = 2.53, 95% CI = 1.86-3.44; GT + TT vs. GG: OR = 1.36, 95% CI = 1.19-1.56; TT vs. GG + GT: OR = 2.35, 95% CI = 1.73-3.19). In summary, these evidences demonstrate that let-7-KRAS rs712 G > T polymorphism might be associated with digestive system cancer risk in the Chinese population. PMID- 28099925 TI - Role of VEGF-A in chronic pain. PMID- 28099924 TI - MicroRNA-140 mediates RB tumor suppressor function to control stem cell-like activity through interleukin-6. AB - We established an in vitro cell culture system to determine novel activities of the retinoblastoma (Rb) protein during tumor progression. Rb depletion in p53 null mouse-derived soft tissue sarcoma cells induced a spherogenic phenotype. Cells retrieved from Rb-depleted spheres exhibited slower proliferation and less efficient BrdU incorporation, however, much higher spherogenic activity and aggressive behavior. We discovered six miRNAs, including mmu-miR-18a, -25, -29b, 140, -337, and -1839, whose expression levels correlated tightly with the Rb status and spherogenic activity. Among these, mmu-miR-140 appeared to be positively controlled by Rb and to antagonize the effect of Rb depletion on spherogenesis and tumorigenesis. Furthermore, among genes potentially targeted by mmu-miR-140, Il-6 was upregulated by Rb depletion and downregulated by mmu-mir 140 overexpression. Altogether, we demonstrate the possibility that mmu-mir-140 mediates the Rb function to downregulate Il-6 by targeting its 3'-untranslated region. Finally, we detected the same relationship among RB, hsa-miR-140 and IL-6 in a human breast cancer cell line MCF-7. Because IL-6 is a critical modulator of malignant features of cancer cells and the RB pathway is impaired in the majority of cancers, hsa-miR-140 might be a promising therapeutic tool that disrupts linkage between tumor suppressor inactivation and pro-inflammatory cytokine response. PMID- 28099926 TI - Functional sites for anesthetics in GABAA receptors. PMID- 28099927 TI - Approaching Alzheimer's disease from a network level. PMID- 28099928 TI - The SDF-1/CXCR4 axis promotes recovery after spinal cord injury by mediating bone marrow-derived from mesenchymal stem cells. AB - This study aims to explore the role of the SDF-1/CXCR4 axis in mediating BMSCs and SCI recovery. BMSCs were collected and SCI rat models were established. Wistar rats were assigned into the blank control, sham, SCI, SCI + BMSCs, SCI + BMSCs + SDF-1, SCI + BMSCs + AMD3100 (an inhibitor of SDF-1/CXCR4 axis) and SCI + BMSCs + SDF-1 + AMD3100 groups. Hind limb motor function was measured 7, 14, 21 and 28 days after operation. qRT-PCR, western blotting and ELISA was performed to determine the expressions of SDF-1, CXCR4, NGF, BDNF, GFAP and GAP-43, TNF-alpha, IL-1beta, L-6 and IFN-gamma. Hind limb motor function scores 7 days after the operation were reduced in the SCI rats of the blank control and sham groups. Hind limb function was found to be better in the SCI + BMSCs and SCI + BMSCs + SDF-1 groups than in the SCI, SCI + BMSCs + AMD3100 and SCI + BMSCs + SDF-1 + AMD3100 groups 14, 21 and 28 days after operation. Furthermore, the SCI group had lower SDF-1, CXCR4, NGF, BDNF and GAP-43 expressions but higher GFAP, TNF-alpha, IL 1beta, IL-6 and IFN-gamma than the blank control and sham groups 28 days after operation. While, the SCI + BMSCs, SCI + BMSCs + SDF-1 and SCI + BMSCs + SDF-1 + AMD3100 groups displayed opposite trends to the SCI and SCI + BMSCs + AMD3100 groups. In conclusion, SDF-1/CXCR4 axis promotes recovery after SCI by mediating BMSCs. PMID- 28099929 TI - Modeling the phenotype of spinal muscular atrophy by the direct conversion of human fibroblasts to motor neurons. AB - Spinal muscular atrophy (SMA) is a lethal autosomal recessive neurological disease characterized by selective degeneration of motor neurons in the spinal cord. In recent years, the development of cellular reprogramming technology has provided an alternative and effective method for obtaining patient-specific neurons in vitro. In the present study, we applied this technology to the field of SMA to acquire patient-specific induced motor neurons that were directly converted from fibroblasts via the forced expression of 8 defined transcription factors. The infected fibroblasts began to grow in a dipolar manner, and the nuclei gradually enlarged. Typical Tuj1-positive neurons were generated at day 23. After day 35, induced neurons with multiple neurites were observed, and these neurons also expressed the hallmarks of Tuj1, HB9, ISL1 and CHAT. The conversion efficiencies were approximately 5.8% and 5.5% in the SMA and control groups, respectively. Additionally, the SMA-induced neurons exhibited a significantly reduced neurite outgrowth rate compared with the control neurons. After day 60, the SMA-induced neurons also exhibited a liability of neuronal degeneration and remarkable fracturing of the neurites was observed. By directly reprogramming fibroblasts, we established a feeder-free conversion system to acquire SMA patient-specific induced motor neurons that partially modeled the phenotype of SMA in vitro. PMID- 28099930 TI - Efficacy of transcatheter arterial chemoembolization for liver metastases arising from pancreatic cancer. AB - PURPOSE: The aim of the study was to evaluate the efficacy of transcatheter arterial chemoembolization (TACE) in treating patients with liver metastases from pancreatic cancer, and explore the prognostic risk factors. RESULTS: Three of the 27 patients were totally recovered, and 12 were partially alleviated. The total efficacy rate was 55.6% (15/27). The median survival time was 13.6 months, and the 0.5-, 1-, 2-, 3-, and 5-year survival rates were 70.4% (19/27), 48.1% (13/27), 22.2% (6/27), 14.8 (4/27), 11.1% (3/27), respectively. None of the groups showed any severe complications. Univariate analysis showed that pathological type, concomitant therapies for liver metastasis, vascular supply, CA199 levels and extrahepatic metastasis were related to prognosis (P < 0.05). Multivariate analysis indicated that pancreatic cancer pathology and extrahepatic metastasis were independent risk factors influencing patients' prognosis (chi2 = 13.182, 17.989, P < 0.05). METHODS: The clinical records of 27 patients with lliver metastases from pancreatic cancer diagnosed at the First Affiliated Hospital of Zhejiang University between May 2009 and May 2015 were retrospectively analyzed. The short-term and long-term efficacy and toxic side effects of TACE were observed. The prognostic risk factors were analyzed using Cox (proportional hazards) regression model. CONCLUSION: TACE is an effective therapy for treating liver metastases from pancreatic malignancy. Pathological type and extrahepatic metastasis of pancreatic tumor are independent risk factors for patients' prognosis. The prognosis of patients with liver metastasis from pancreatic neuroendocrine neoplasm is superior to that of extrahepatic metastasis. PMID- 28099932 TI - Allelic imbalance in human breast cancer. PMID- 28099931 TI - A new semisynthetic cardenolide analog 3beta-[2-(1-amantadine)- 1-on-ethylamine] digitoxigenin (AMANTADIG) affects G2/M cell cycle arrest and miRNA expression profiles and enhances proapoptotic survivin-2B expression in renal cell carcinoma cell lines. AB - Cardiac glycosides are well known in the treatment of cardiovascular diseases; however, their application as treatment option for cancer patients is under discussion. We showed that the cardiac glycoside digitoxin and its analog AMANTADIG can inhibit the growth of renal cell carcinoma (RCC) cell lines and increase G2/M cell cycle arrest. To identify the signaling pathways and molecular basis of this G2/M arrest, microRNAs were profiled using microRNA arrays. Cardiac glycoside treatment significantly deregulated two microRNAs, miR-2278 and miR-670 5p. Pathway enrichment analysis showed that all cardiac glycoside treatments affected the MAPK and the axon guidance pathway. Within these pathways, three genes, MAPK1, NRAS and RAC2, were identified as in silico targets of the deregulated miRNAs. MAPK1 and NRAS are known regulators of G2/M cell cycle arrest. AMANTADIG treatment enhanced the expression of phosphorylated MAPK1 in 786-O cells. Secondly, we studied the expression of survivin known to be affected by cardiac glycosides and to regulate the G2/M cell phase. AMANTADIG treatment upregulated the expression of the pro-apoptotic survivin-2B variant in Caki-1 and 786-O cells. Moreover, treatment with AMANTADIG resulted in significantly lower survivin protein expression compared to 786-O control cells. Summarizing, treatment with all cardiac glycosides induced G2/M cell cycle arrest and downregulated the miR-2278 and miR-670-5p in microarray analysis. All cardiac glycosides affected the MAPK-pathway and survivin expression, both associated with the G2/M phase. Because cells in the G2/M phase are radio- and chemotherapy sensitive, cardiac glycosides like AMANTADIG could potentially improve the efficacy of radio- and/or chemotherapy in RCCs. PMID- 28099933 TI - Loss of maternal chromosome 11 is a signature event in SDHAF2, SDHD, and VHL related paragangliomas, but less significant in SDHB-related paragangliomas. AB - Germline mutations in the succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD, SDHAF2) or Von Hippel-Lindau (VHL) genes cause hereditary paraganglioma/pheochromocytoma. While SDHB (1p36) and VHL (3p25) are associated with autosomal dominant disease, SDHD (11q23) and SDHAF2 (11q13) show a remarkable parent-of-origin effect whereby tumor formation is almost completely dependent on paternal transmission of the mutant allele. Loss of the entire maternal copy of chromosome 11 occurs frequently in SDHD-linked tumors, and has been suggested to be the basis for this typical inheritance pattern.Using fluorescent in situ hybridization, microsatellite marker and SNP array analysis, we demonstrate that loss of the entire copy of chromosome 11 is also frequent in SDHAF2-related PGLs, occurring in 89% of tumors. Analysis of two imprinted differentially methylated regions (DMR) in 11p15, H19-DMR and KvDMR, showed that this loss always affected the maternal copy of chromosome 11. Likewise, loss of maternal chromosome 11p15 was demonstrated in 85% of SDHD and 75% of VHL-related PGLs/PCCs. By contrast, both copies of chromosome 11 were found to be retained in 62% of SDHB-mutated PGLs/PCCs, while only 31% showed loss of maternal chromosome 11p15. Genome-wide copy number analysis revealed frequent loss of 1p in SDHB mutant tumors and show greater genomic instability compared to SDHD and SDHAF2.These results show that loss of the entire copy of maternal chromosome 11 is a highly specific and statistically significant event in SDHAF2, SDHD and VHL related PGLs/PCCs, but is less significant in SDHB-mutated tumors, suggesting that these tumors have a distinct genetic etiology. PMID- 28099934 TI - Tolfenamic acid-induced alterations in genes and pathways in pancreatic cancer cells. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are being tested extensively for their role in the treatment and prevention of several cancers. Typically NSAIDs exhibit anti-tumor activities via modulation of cyclooxygenase (COX)-dependent mechanisms, however, an anti-cancer NSAID tolfenamic acid (TA) is believed to work through COX-independent pathways. Results from our laboratory and others have demonstrated the anti-cancer activity of TA in various cancer models including pancreatic cancer. TA has been shown to modulate certain cellular processes including, apoptosis, reactive oxygen species and signaling. In this study, molecular profiling was performed to precisely understand the mode of action of TA. Three pancreatic cancer cell lines, L3.6pl, MIA PaCa-2, and Panc1 were treated with TA (50 MUM for 48 h) and the changes in gene expression was evaluated using the Affymetrix GeneChip Human Gene ST Array platform. Microarray results were further validated using quantitative PCR for seven genes altered by TA treatment in all three cell lines. Functional analysis of differentially expressed genes (2 fold increase or decrease, p < 0.05) using Ingenuity Pathway Analysis software, revealed that TA treatment predominantly affected the genes involved in cell cycle, cell growth and proliferation, and cell death and survival. Promoter analysis of the differentially expressed genes revealed that they are enriched for Sp1 binding sites, suggesting that Sp1 could be a major contributor in mediating the effect of TA. The gene expression studies identified new targets involved in TA's mode of action, while supporting the hypothesis about the association of Sp1 in TA mediated effects in pancreatic cancer. PMID- 28099935 TI - Frequent amplification of receptor tyrosine kinase genes in welldifferentiated/ dedifferentiated liposarcoma. AB - Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are closely related tumors commonly characterized by MDM2/CDK4 gene amplification, and lack clinically effective treatment options when inoperable. To identify novel therapeutic targets, we performed targeted genomic sequencing analysis of 19 WDLPS and 37 DDLPS tumor samples using a panel of 104 cancer related genes (NCC oncopanel v3) developed specifically for genomic testing to select suitable molecular targeted therapies. The results of this analysis indicated that these sarcomas had very few gene mutations and a high frequency of amplifications of not only MDM2 and CDK4 but also other genes. Potential driver mutations were found in only six (11%) samples; however, gene amplification events (other than MDM2 and CDK4 amplification) were identified in 30 (54%) samples. Receptor tyrosine kinase (RTK) genes in particular were amplified in 18 (32%) samples. In addition, growth of a WDLPS cell line with IGF1R amplification was suppressed by simultaneous inhibition of CDK4 and IGF1R, using palbociclib and NVP-AEW541, respectively. Combination therapy with CDK4 and RTK inhibitors may be an effective therapeutic option for WDLPS/DDLPS patients with RTK gene amplification. PMID- 28099936 TI - Transcription factor HBP1 is a direct anti-cancer target of transcription factor FOXO1 in invasive oral cancer. AB - Either FOXO1 or HBP1 transcription factor is a downstream effector of the PI3K/Akt pathway and associated with tumorigenesis. However, the relationship between FOXO1 and HBP1 in oral cancer remains unclear. Analysis of 30 oral tumor specimens revealed that mean mRNA levels of both FOXO1 and HBP1 in non-invasive and invasive oral tumors were found to be significantly lower than that of the control tissues, and the status of low FOXO1 and HBP1 (< 0.3 fold of the control) was associated with invasiveness of oral tumors. To investigate if HBP1 is a direct transcription target of FOXO1, we searched potential FOXO1 binding sites in the HBP1 promoter using the MAPPER Search Engine, and two putative FOXO1 binding sites located in the HBP1 promoter -132 to -125 bp and -343 to -336 bp were predicted. These binding sites were then confirmed by both reporter gene assays and the in cellulo ChIP assay. In addition, Akt activity manipulated by PI3K inhibitor LY294002 or Akt mutants was shown to negatively affect FOXO1 mediated HBP1 promoter activation and gene expression. Last, the biological significance of the FOXO1-HBP1 axis in oral cancer malignancy was evaluated in cell growth, colony formation, and invasiveness. The results indicated that HBP1 knockdown potently promoted malignant phenotypes of oral cancer and the suppressive effect of FOXO1 on cell growth, colony formation, and invasion was alleviated upon HBP1 knockdown in invasive oral cancer cells. Taken together, our data provide evidence for HBP1 as a direct downstream target of FOXO1 in oral cancer malignancy. PMID- 28099937 TI - Inactivation of CK1alpha in multiple myeloma empowers drug cytotoxicity by affecting AKT and beta-catenin survival signaling pathways. AB - Recent evidence indicates that protein kinase CK1alpha may support the growth of multiple myeloma (MM) plasma cells. Here, by analyzing a large cohort of MM cases, we found that high CK1alpha mRNA levels are virtually associated with all MM patients. Moreover, we provided functional evidence that CK1alpha activity is essential for malignant plasma cell survival even in the protective niche generated by co-cultures with bone marrow stromal cells. We demonstrated that CK1alpha inactivation, while toxic for myeloma cells, is dispensable for the survival of healthy B lymphocytes and stromal cells. Disruption of CK1alpha function in myeloma cells resulted in decreased Mdm2, increased p53 and p21 and reduced expression of beta-catenin and AKT. These effects were mediated partially by p53 and caspase activity. Finally, we discovered that CK1alpha inactivation enhanced the cytotoxic effect of both bortezomib and lenalidomide. Overall, our study supports a role for CK1alpha as a potential therapeutic target in MM in combination with proteasome inhibitors and/or immunomodulatory drugs. PMID- 28099938 TI - BI-RADS 3-5 microcalcifications can preoperatively predict breast cancer HER2 and Luminal a molecular subtype. AB - PURPOSE: To investigate associations between breast cancer molecular subtype and the patterns of mammographically detected calcifications. RESULTS: Identified were 93 (19.1%) Luminal A, 242 (49.9%) Luminal B, 108 (22.2%) HER2 and 42 (8.7%) basal subtypes. In univariate analysis, the clinicopathological parameters and BI RADS 3-5 microcalcifications, which consisted 9 selected features was significantly associated with breast cancer molecular subtype (all P < 0.05). Among subtypes, multivariate analysis showed that calcification >2 cm in range (OR: 1.878, 95% CI: 1.150 to 3.067) and calcification > 0.5 mm in diameter (OR:2.206, 95% CI: 1.235 to 3.323) was independently predictive of HER2 subtype. The model showed good discrimination for predicting HER2 subtype, with a C-index of 0.704. In addition, multivariate analysis showed that calcification morphology (amorphour or coarse heterogenous calcifications OR: 2.847, 95% CI: 1.526 to 5.312) was independently predictive of Luminal A subtype. The model showed good discrimination for predicting Luminal A subtype, with a C-index of 0.74. And we demonstrated that amorphour or coarse heterogenous calcifications were associated with a higher incidence of Luminal A subtype than pleomorphic or fine linear or branching calcifications. There was no significant difference between breast cancer subtypes (Luminal B vs. other; Basal vs. other) and the patterns of mammographically detected calcifications. MATERIALS AND METHODS: Mammographic images of 485 female patients were included. The correlation between mammographic imaging features and breast cancer subtype was analyzed using Chi-square test, univariate and binary logistic regression analysis. CONCLUSIONS: This study shows that BI-RADS 3-5 microcalcifications can be conveniently used to facilitate the preoperative prediction of HER2 and Luminal A molecular subtype in patients with infiltrating ductal carcinoma. PMID- 28099939 TI - Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome. AB - Expression of type 5 phosphodiesterase (PDE5), a cGMP-specific hydrolytic enzyme, is frequently altered in human cancer, but its specific role in tumorigenesis remains controversial. Herein, by analyzing a cohort of 69 patients affected by glioblastoma multiforme (GBM) who underwent chemo- and radiotherapy after surgical resection of the tumor, we found that PDE5 was strongly expressed in cancer cells in about 50% of the patients. Retrospective analysis indicated that high PDE5 expression in GBM cells significantly correlated with longer overall survival of patients. Furthermore, silencing of endogenous PDE5 by short hairpin lentiviral transduction (sh-PDE5) in the T98G GBM cell line induced activation of an invasive phenotype. Similarly, pharmacological inhibition of PDE5 activity strongly enhanced cell motility and invasiveness in T98G cells. This invasive phenotype was accompanied by increased secretion of metallo-proteinase 2 (MMP-2) and activation of protein kinase G (PKG). Moreover, PDE5 silencing markedly enhanced DNA damage repair and cell survival following irradiation. The enhanced radio-resistance of sh-PDE5 GBM cells was mediated by an increase of poly(ADP ribosyl)ation (PARylation) of cellular proteins and could be counteracted by poly(ADP-ribose) polymerase (PARP) inhibitors. Conversely, PDE5 overexpression in PDE5-negative U87G cells significantly reduced MMP-2 secretion, inhibited their invasive potential and interfered with DNA damage repair and cell survival following irradiation. These studies identify PDE5 as a favorable prognostic marker for GBM, which negatively affects cell invasiveness and survival to ionizing radiation. Moreover, our work highlights the therapeutic potential of targeting PKG and/or PARP activity in this currently incurable subset of brain cancers. PMID- 28099940 TI - Characteristics of Chinese herbal medicine usage in ischemic heart disease patients among type 2 diabetes and their protection against hydrogen peroxide mediated apoptosis in H9C2 cardiomyoblasts. AB - Evidence for long-term use of Chinese herbal medicine (CHM) as an adjuvant treatment in patients with type 2 diabetes (T2D) remains limited. This study aimed to assess the frequency of use, utilization patterns, and therapeutic effects of adjuvant CHM for ischemic heart disease (IHD) in patients with T2D in Taiwan. We identified 4620 IHD patients with T2D. After matching for age, gender, and insulin use, 988 subjects each were allocated to a CHM group and a non-CHM group. There were no differences in baseline characteristics except for comorbidities. The CHM group contained more cases with chronic obstructive pulmonary disease, hepatitis, ulcer disease, and hyperlipidemia. The cumulative survival probability was higher in CHM users than in matched non-CHM users aged 60 years or older (P < .0001, log rank test) regardless of gender (P = .0046 for men, P = .0010 for women, log rank test). Among the top 12 CHM combinations, Shu Jing-Huo-Xue-Tang and Shao-Yao-Gan-Cao-Tang (13.6%) were the most common. This dual combination improved antiapoptotic activity in H2O2-exposed H9C2 cells by enhancing phosphorylation of glycogen synthase kinase-3beta and p38 mitogen activated protein kinase and could increase the survival of myocardial cells. Our study suggests that adjuvant CHM therapy may increase the survival probability and provides a comprehensive list for future investigations of the safety and efficacy of CHM for IHD patients with T2D. PMID- 28099941 TI - The roles of RRP15 in nucleolar formation, ribosome biogenesis and checkpoint control in human cells. AB - The nucleolus controls ribosome biogenesis and its perturbation induces nucleolar stress that inhibits cell cycle progression and activates checkpoint responses. Here, we investigate the roles of ribosomal RNA processing protein, RRP15, in nucleolar formation, ribosome biogenesis, cell cycle progression and checkpoint control in human cells. RRP15 is localized in the nucleolus and required for nucleolar formation. In contrast to the budding yeast Rrp15p that was reported as a component of pre-60S subunits, RRP15 is found in both pre-40S and pre-60S subunits and involved in regulating rRNA transcription and ribosome biogenesis. Perturbation of RRP15 induces nucleolar stress that activates RPL5/RPL11/5S rRNA (RP)-Mdm2-p53 axis checkpoint response and arrests cells at G1-G1/S in p53 proficient non-transformed RPE1 cells but not in p53-deficient HeLa and MCF7 tumor cells. Instead, p53-deficient HeLa and MCF7 cells with RRP15-dependent nucleolar stress enter S-phase with S-phase perturbation that activates ATR-Chk1- gammaH2AX axis DNA replication/damage checkpoint response, delaying S-G2/M progression and, ultimately, causing cell death. The selective checkpoint response, cell cycle inhibition and/or cytotoxicity induced by RRP15-dependent nucleolar stress in p53-proficient non-transformed cells and p53-deficient tumor cells suggest that RRP15 might be a potential target for cancer therapy. PMID- 28099942 TI - Bigh3 silencing increases retinoblastoma tumor growth in the murine SV40-TAg-Rb model. AB - BIGH3, a secreted protein of the extracellular matrix interacts with collagen and integrins on the cell surface. BIGH3 can have opposing functions in cancer, acting either as tumor suppressor or promoter by enhancing tumor progression and angiogenesis. In the eye, BIGH3 is expressed in the cornea and the retinal pigment epithelium and could impact on the development of retinoblastoma, the most common paediatric intraocular neoplasm. Retinoblastoma initiation requires the inactivation of both alleles of the RB1 tumor suppressor gene in the developing retina and tumor progression involves additional genomic changes. To determine whether BIGH3 affects retinoblastoma development, we generated a retinoblastoma mouse model with disruption of the Bigh3 genomic locus. Bigh3 silencing in these mice resulted in enhanced tumor development in the retina. A decrease in apoptosis is involved in the initial events of tumorigenesis, followed by an increased activity of the pro-survival ERK pathway as well as an upregulation of cyclin-dependent kinases (CDKs). Taken together, these data suggest that BIGH3 acts as a tumor suppressor in the retina. PMID- 28099943 TI - A nomogram to predict lymph node metastasis in patients with early gastric cancer. AB - BACKGROUND: Lymph node status is crucial to determining treatment for early gastric cancer (EGC). We aim to establish a nomogram to predict the possibility of lymph node metastasis (LNM) in EGC patients. METHODS: Medical records of 952 EGC patients with curative resection, from 2002 to 2014, were retrospectively retrieved. Univariate and multivariate analysis were performed to examine risk factors associated with LNM. A nomogram for predicting LNM was established and internally validated. RESULTS: Five variables significantly associated with LNM were included in our model, these are sex (Odd ratio [OR] = 1.961, 95% confidence index [CI], 1.334 to 2.883; P = 0.001), depth of tumor (OR = 2.875, 95% CI, 1.872 to 4.414; P = 0.000), tumor size (OR = 1.986, 95% CI, 1.265 to 3.118; P = 0.003), histology type (OR = 2.926, 95% CI, 1.854 to 4.617; P = 0.000) and lymphovascular invasion (OR = 4.967, 95% CI, 2.996 to 8.235; P = 0.000). The discrimination of the prediction model was 0.786. CONCLUSIONS: A nomogram for predicting lymph node metastasis in patients with early gastric cancer was successfully established, which was superior to the absolute endoscopic submucosal dissection (ESD) indication in terms of the clinical performance. PMID- 28099944 TI - Cordycepin induces apoptosis by caveolin-1-mediated JNK regulation of Foxo3a in human lung adenocarcinoma. AB - Forkhead transcription factor (Foxo3a) is a downstream effector of JNK-induced tumor suppression. However, it is not clear whether the caveolin-1 (CAV1) mediated JNK/Foxo3a pathway is involved in cancer cell apoptosis. We found that cordycepin upregulates CAV1 expression, which was accompanied by JNK phosphorylation (p-JNK) and subsequent Foxo3a translocation into the nucleus, resulting in the upregulation of Bax protein expression. Furthermore, we found that CAV1 overexpression upregulated p-JNK, whereas CAV1 siRNA downregulated p JNK. Additionally, SP600125, a specific JNK inhibitor, significantly increased Foxo3a phosphorylation, which downregulated Foxo3a translocation into the nucleus, indicating that CAV1 mediates JNK regulation of Foxo3a. Foxo3a siRNA downregulated Bax protein and attenuated A549 apoptosis, indicating that the CAV1 mediated JNK/Foxo3a pathway induces the apoptosis of A549 lung cancer cells. Cordycepin significantly decreased tumor volume in nude mice. Taken together, these results indicate that cordycepin promotes CAV1 upregulation to enhance JNK/Foxo3a signaling pathway activation, inducing apoptosis in lung cancer cells, and support its potential as a therapeutic agent for lung cancer. PMID- 28099945 TI - In vivo and in vitro effects of microRNA-27a on proliferation, migration and invasion of breast cancer cells through targeting of SFRP1 gene via Wnt/beta catenin signaling pathway. AB - This study aims to explore the effects of microRNA-27a (miR-27a) targeting of SFRP1 on the proliferation, migration and invasion of breast cancer (BC) cells through the regulation of Wnt/beta-catenin signaling pathway. BC and normal breast tissues were obtained from 396 female BC patients and 308 female patients with benign breast lesions respectively. Human normal mammary epithelial (MCF 10A) and BC cell lines (BT-20, MCF-7, T-47D and MDA-MB-231) were cultured. After cell transfection, BC cells were assigned to six groups: control, miR-27a mimics, miR-27a inhibitors, negative control (NC), si-SFRP1 and si-SFRP1 + miR-27a inhibitors groups. qRT-PCR assay and Western blot were employed to detect the expressions of miR-27a, SFRP1, Wnt, beta-catenin and GSK3beta. MTT assay, wound healing test and Transwell assay were used to test cell proliferation, migration and invasion. BC tissues were found to have higher miR-27a expression and lower SFRP1 mRNA and protein expressions than MCF-10A cells and normal breast tissues. Compared with the control and NC groups, the miR-27a mimics and si-SFRP1 groups exhibited down-regulation of SFRP1, up-regulation of Wnt, beta-catenin and GSK3beta, and promotion of cell proliferation, migration and invasion. The miR 27a inhibitor group showed up-regulation of SFRP1 and inhibition of cell proliferation, migration and invasion in comparison to the miR-27a mimic group. The si-SFRP1 + miR-27a inhibitors group also exhibited up-regulation of SFRP1 and inhibition of cell proliferation, migration and invasion in comparison to the si SFRP1 group. miR-27a may activate the Wnt/beta-catenin signaling pathway by negatively regulating SFRP1 to promote the proliferation, migration and invasion of BC cells. PMID- 28099946 TI - Long non-coding RNA ZFAS1 interacts with miR-150-5p to regulate Sp1 expression and ovarian cancer cell malignancy. AB - We reported that long non-coding RNA ZFAS1 was upregulated in epithelial ovarian cancer tissues, and was negatively correlated to the overall survival rate of patients with epithelial ovarian cancer in this study. While depletion of ZFAS1 inhibited proliferation, migration, and development of chemoresistance, overexpression of ZFAS1 exhibited an even higher proliferation rate, migration activity, and chemoresistance in epithelial ovarian cancer cell lines. We further found miR-150-5p was a potential target of ZFAS1, which was downregulated in epithelial ovarian cancer tissue. MiR-150-5p subsequently inhibited expression of transcription factor Sp1, as evidence by luciferase assays. Inhibition of miR-150 5p rescued the suppressed proliferation and migration induced by depletion of ZFAS1 in epithelial ovarian cancer cells, at least in part. Taken together, our findings revealed a critical role of ZFAS1/miR-150-5p/Sp1 axis in promoting proliferation rate, migration activity, and development of chemoresistance in epithelial ovarian cancer. And ZFAS1/miR-150-5p may serve as novel markers and therapeutic targets of epithelial ovarian cancer. PMID- 28099947 TI - Short-term efficacy of different chemotherapy regimens in the treatment of advanced gastric cancer: a network meta-analysis. AB - OBJECTIVE: A network meta-analysis was performed to compare the short-term efficacy of different chemotherapy regimens in the treatment of advanced gastric cancer. METHODS: Randomized controlled trials of different chemotherapy regimens for advanced gastric cancer were included in this study. Network meta-analysis combined direct evidence and indirect evidence to evaluate the odds ratio and draw surface under the cumulative ranking curves of different chemotherapy regimens in advanced gastric cancer. RESULTS: The results of surface under the cumulative ranking curves showed that S-1 and capecitabine regimens were better than fluorouracil. As for multi-drug combination regimens, the disease control rate of cisplatin + capecitabine, docetaxel + cisplatin + fluorouracil and etoposide + cisplatin + capecitabine regimens were relatively better, while fluorouracil + adriamycin + mitomycin regimen was relatively poorer when compared with cisplatin + fluorouracil regimen. Additionally, the overall response ratio of cisplatin + capecitabine, paclitaxel + fluorouracil, docetaxel + cisplatin + fluorouracil and etoposide + cisplatin + fluorouracil regimens were relatively better, while the disease control rate of fluorouracil + adriamycin + mitomycin regimen was relatively poorer when compared with cisplatin + fluorouracil regimen. Furthermore, the results of cluster analysis demonstrated that cisplatin + capecitabine, etoposide + cisplatin + capecitabine, S-1 + paclitaxel and S-1 + irinotecan chemotherapy regimens had better disease control rate and overall response ratio for advanced gastric cancer patients. CONCLUSION: This network meta-analysis clearly showed that multi-drug combination chemotherapy regimens based on capecitabine and S-1 might be the best chemotherapy regimen for advanced gastric cancer. PMID- 28099949 TI - Synthetic microneurotrophins in therapeutics of neurodegeneration. PMID- 28099948 TI - MDM4 genetic variants and risk of gastric cancer in an Eastern Chinese population. AB - MDM4 is a p53-interacting protein and plays an important role in carcinogenesis. In this study of 1,077 gastric cancer (GCa) cases and 1,173 matched cancer-free controls, we investigated associations between three tagging single nucleotide polymorphisms (SNPs) (rs11801299 G>A, rs1380576 C>G and rs10900598 G>T) in MDM4 and gastric cancer risk in an Eastern Chinese Population. In logistic regression analysis, a significantly decreased GCa risk was associated with the rs1380576 GG variant genotype (adjusted odds ratio [OR] =0.74, 95% confidence interval [CI] =0.56-0.98) under a recessive model, which remained significant after correction by the false-positive reporting probability. This risk was more evident in subgroups of older subjects, males, never smokers, never drinkers and cancers of non-cardia. We then performed SNP-mRNA expression correlation analysis and found that the GG variant genotype was associated with significantly decreased expression of MDM4 mRNA in normal cell lines for 44 Chinese (P=0.032 for GG vs. CC) as well as for 269 multi-ethnic subjects (P<0.0001 for GG vs. CC). Our results suggest that the MDM4 rs1380576 G variant may be markers for GCa susceptibility. Larger, independent studies are warranted to validate our findings. PMID- 28099950 TI - Nano-particle assembled porous core-shell ZnMn2O4 microspheres with superb performance for lithium batteries. AB - Porous ZnMn2O4 microspheres were prepared via a facile co-precipitation method followed by calcination at various temperatures and evaluated as anode materials for lithium ion batteries. The sample prepared at 600 degrees C outperformed the other samples in terms of electrochemical performance with high reversible capacity, high-rate capability, and excellent cycling performance. The capacity of the sample remained as high as 999 mAh g-1 at a current rate of 100 mA g-1 after 50 cycles-one of the best ever reported for ZnMn2O4-based materials. A high reversible capacity of 400 mAh g-1 was retainable at a current density of 2000 mA g-1 after 2500 cycles. A novel electrochemical reaction mechanism of ZnMn2O4 anodes was established and investigated at length. The Mn3O4 observed during the charge process was largely responsible for the enhanced performance, as confirmed by x-ray photoelectron spectroscopy, scanning electron microscopy, and transmission electron microscopy. The relatively large surface area, abundant porosity, large ion exchange space, and strong mechanical stability of the porous connected 3D framework were responsible for the unique oxidation/reduction Mn2+ < > Mn3+ process we observed. PMID- 28099951 TI - Complex X-Chromosomal Rearrangements in Two Women with Ovarian Dysfunction: Implications of Chromothripsis/Chromoanasynthesis-Dependent and -Independent Origins of Complex Genomic Alterations. AB - Our current understanding of the phenotypic consequences and the molecular basis of germline complex chromosomal rearrangements remains fragmentary. Here, we report the clinical and molecular characteristics of 2 women with germline complex X-chromosomal rearrangements. Patient 1 presented with nonsyndromic ovarian dysfunction and hyperthyroidism; patient 2 exhibited various Turner syndrome- associated symptoms including ovarian dysfunction, short stature, and autoimmune hypothyroidism. The genomic abnormalities of the patients were characterized by array-based comparative genomic hybridization, high-resolution karyotyping, microsatellite genotyping, X-inactivation analysis, and bisulfite sequencing. Patient 1 carried a rearrangement of unknown parental origin with a 46,X,der(X)(pter-> p22.1::p11.23->q24::q21.3->q24::p11.4->pter) karyotype, indicative of a catastrophic chromosomal reconstruction due to chromothripsis/chromoanasynthesis. Patient 2 had a paternally derived isochromosome with a 46,X,der(X)(pter-> p22.31::q22.1->q10::q10->q22.1::p22.31 >pter) karyotype, which likely resulted from 2 independent, sequential events. Both patients showed completely skewed X inactivation. CpG sites at Xp22.3 were hypermethylated in patient 2. The results indicate that germline complex X chromosomal rearrangements underlie nonsyndromic ovarian dysfunction and Turner syndrome. Disease-causative mechanisms of these rearrangements likely include aberrant DNA methylation, in addition to X-chromosomal mispairing and haploinsufficiency of genes escaping X inactivation. Notably, our data imply that germline complex X-chromosomal rearrangements are created through both chromothripsis/chromoanasynthesis-dependent and -independent processes. PMID- 28099953 TI - Social Networks among the Older Chinese Population in the USA: Findings from the PINE Study. AB - BACKGROUND: Social network research has become central to studies of health and aging. Its results may yield public health insights that are actionable and improve the quality of life of older adults. However, little is known about the social networks of older immigrant adults, whose social relationships often develop in the context of migration, compounded by cultural and linguistic barriers. OBJECTIVES: This report aims to describe the structure, composition, and emotional components of social networks in the Chinese aging population of the USA, and to explore ways in which their social networks may be critical to their health decision-making. METHODS: Our data come from the PINE study, a population-based epidemiological study of community-dwelling older Chinese American adults, aged 60 years and above, in the greater Chicago area. We conducted individual interviews in participants' homes from 2011 until 2013. Based on sociodemographic and socioeconomic characteristics, this study computed descriptive statistics and trend tests for the social network measures adapted from the National Social Life, Health, and Aging Project study. RESULTS: The findings show that older Chinese adults have a relatively small social network in comparison with their counterparts from other ethnic and racial backgrounds. Only 29.6% of the participants could name 5 close network members, and 2.2% could name 0 members. Their network composition was more heavily kin oriented (95.0%). Relationships with network members differed according to the older adults' sociodemographic and socioeconomic characteristics. Subgroup variations included the likelihood of discussing health-related issues with network members. CONCLUSION: This study highlights the dynamic nature of social networks in later life Chinese immigrants. For healthcare practitioners, developing cost-effective strategies that can mobilize social network support remains a critical undertaking in health intervention. Longitudinal studies are needed to examine the causal impact of social networks on various domains of health. PMID- 28099952 TI - Zebrin II Is Expressed in Sagittal Stripes in the Cerebellum of Dragon Lizards (Ctenophorus sp.). AB - Aldolase C, also known as zebrin II (ZII), is a glycolytic enzyme that is expressed in cerebellar Purkinje cells of the vertebrate cerebellum. In both mammals and birds, ZII is expressed heterogeneously, such that there are sagittal stripes of Purkinje cells with high ZII expression (ZII+) alternating with stripes of Purkinje cells with little or no expression (ZII-). In contrast, in snakes and turtles, ZII is not expressed heterogeneously; rather all Purkinje cells are ZII+. Here, we examined the expression of ZII in the cerebellum of lizards to elucidate the evolutionary origins of ZII stripes in Sauropsida. We focused on the central netted dragon (Ctenophorus nuchalis) but also examined cerebellar ZII expression in 5 other dragon species (Ctenophorus spp.). In contrast to what has been observed in snakes and turtles, we found that in these lizards, ZII is heterogeneously expressed. In the posterior part of the cerebellum, on each side of the midline, there were 3 sagittal stripes consisting of Purkinje cells with high ZII expression (ZII+) alternating with 2 sagittal stripes with weaker ZII expression (ZIIw). More anteriorly, most of the Purkinje cells were ZII+, except laterally, where the Purkinje cells did not express ZII (ZII-). Finally, all Purkinje cells in the auricle (flocculus) were ZII-. Overall, the parasagittal heterogeneous expression of ZII in the cerebellum of lizards is similar to that in mammals and birds, and contrasts with the homogenous ZII+ expression seen in snakes and turtles. We suggest that a sagittal heterogeneous expression of ZII represents the ancestral condition in stem reptiles which was lost in snakes and turtles. PMID- 28099954 TI - An Evolution of Management in Hypertrophic Cardiomyopathy: Myectomy, Alcohol Septal Ablation, Mitral Valve Replacement, MitraClip. PMID- 28099955 TI - Dermoscopy of Granuloma Annulare: A Clinical and Histological Correlation Study. AB - BACKGROUND: Dermoscopy of granuloma annulare has been investigated by several studies, but none of them took into account the variability of dermoscopic findings according to clinical characteristics and/or histological subtype. OBJECTIVE: To describe the dermoscopic features of classic granuloma annulare and seek possible dermoscopic clues related to specific clinical findings/histological subpatterns. METHODS: A representative dermoscopic image of a target lesion (the most active lesion underwent histological examination) was retrospectively assessed for the presence of specific morphological findings, correlating them with clinical variables, i.e. disease duration and extension (localized or generalized) and clinical aspect (annular or non-annular) and localization (trunk or extremities) of the biopsied lesion, and with histological subtype. RESULTS: A total of 25 lesions from 25 subjects were analysed; an "interstitial" histological variant was detected in 11 cases, while a "palisading granuloma" histological pattern was found in 14 instances. The most common dermoscopic findings included blurry vessels having variable appearance (dotted, linear-irregular, and branching) over a more or less evident pinkish-reddish background, followed by whitish and/or yellowish-orange areas. Additional findings were rosettes, crystalline structures, and whitish scaling. No difference (p > 0.05) in the frequency of dermoscopic features according to clinical findings was found, while we observed a strict association (p < 0.001) between the presence of yellowish-orange structureless areas on dermoscopy and "palisading granuloma" histology. CONCLUSION: The dermoscopic aspect of granuloma annulare is independent from clinical features but varies according to histological subtype, with the detection of yellowish-orange colour being indicative of the "palisading granuloma" variant. PMID- 28099957 TI - Results of Surgical Salvage Treatment for Anal Canal Cancer: A Retrospective Analysis with Overview of the Literature. AB - BACKGROUND AND AIM: Chemoradiotherapy (CRT) is the gold standard treatment for anal cancer, which permits the maintenance of the anal function. However, about 30-40% of patients develop local disease progression, for which surgery represents a good salvage therapy. The aim of this study is to evaluate survival and morbidity rate in patients who undergo salvage surgery in our single institution, with an overview of the literature. METHODS: A retrospective study was carried out on patients who underwent surgical treatment of anal canal cancer after failure of CRT. We evaluated overall survival at 1, 3, and 5 years and postoperative morbidity rate. RESULTS: Twenty patients who underwent radical surgery with abdominoperineal resection were included in the study. The survival rates at 1, 3, and 5 years were 75, 60, and 37.4%; with a disease-free survival of 67, 53, and 35%, respectively. There was no postoperative mortality. The morbidity rate was 35%. CONCLUSION: Surgery represents the recommended therapy for persistent or recurrent anal canal cancer after CRT, with a good survival rate and an acceptable morbidity. PMID- 28099956 TI - High Body Mass Index Worsens Survival in Patients with Esophageal Squamous Cell Carcinoma after Esophagectomy. AB - AIMS: To investigate the prognostic significance of body mass index (BMI) on the survival of patients with esophageal squamous cell carcinoma (ESCC) after esophagectomy. METHODS: Between 2005 and 2008, 291 patients with ESCC who met the inclusion criteria were included in the study. The BMI cut-off values were as follows: 18.5-23 kg/m2 for normal weight; 23-27.5 kg/m2 for overweight; and >=27.5 kg/m2 for those with obesity. Univariate and multivariate analyses were performed to identify prognostic factors for long-term survival. RESULTS: Patients were divided into 3 groups: normal weight (n = 138), overweight (n = 103), and obese (n = 50). The median survival time was 56 months. The 5-year overall survival (OS) rates were 40.8, 44.7, and 20.8% for normal weight, overweight, and obese patients respectively (p < 0.05). Multivariate analysis identified BMI as an independent prognostic factor for OS (p < 0.05). For 179 patients without lymph node metastasis, the 5-year OS rates were 46.5, 50.7, and 27.0% for normal weight, overweight, and obese patients respectively (p < 0.05). CONCLUSIONS: A BMI >=27.5 kg/m2 has a distinctly adverse impact on the long-term survival of ESCC patients after esophagectomy. High BMI is a potential predictor of worse prognosis in ESCC patients, particularly in patients without lymph node metastasis. PMID- 28099958 TI - Distance from Left Renal Vein to Inferior Pancreaticoduodenal Artery: A Landmark for Identifying Inferior Pancreaticoduodenal Artery in Pancreatoduodenectomy. AB - BACKGROUND/AIM: During pancreatoduodenectomy, early ligation of major afferent arteries to pancreatic head prior to dissection of the corresponding veins may reduce intraoperative bleeding. Inferior pancreaticoduodenal artery (IPDA), one of the major afferent arteries, is difficult to identify. We measured the distance from left renal vein to IPDA based on preoperative multi-detector row computed tomography (MDCT) images for use as a new landmark for IPDA. METHODS: The distance between left renal vein and IPDA was measured in 417 patients using MDCT images. RESULTS: IPDA was identified on MDCT images in 415 out of the 417 patients (99.5%). The root of IPDA was located on cranial side of the root of left renal vein in 88 among the 415 patients (21.2%), and the distance was expressed as negative in these cases. The distance was 6.09 +/- 7.46 mm. The distance when IPDA formed a common vessel with first jejunal artery (8.03 +/- 6.74 mm; 323 cases, 77.8%) was significantly longer than when IPDA branched directly from superior mesenteric artery (SMA; -0.81 +/- 5.74 mm; 62 cases, 15.0%) or posterior and anterior IPDAs branched separately from SMA (-2.04 +/- 5.36 mm; 30 cases, 7.2%). CONCLUSIONS: The distance between left renal vein and IPDA can serve as a landmark for IPDA identification. PMID- 28099959 TI - Fecal Volume after Laparoscopic Low Anterior Resection Predicts Anastomotic Leakage. AB - BACKGROUND/AIM: Anastomotic leakage (AL) is a major complication after laparoscopic low anterior resection (Lap-LAR). Many surgeons encounter AL following severe postoperative diarrhea. However, little is known about the relationship between postoperative fecal volume and AL. This study determined whether postoperative fecal volume can predict AL. METHODS: A retrospective assessment was performed with data from 176 patients with rectal cancers who underwent Lap-LAR between April 2011 and August 2015. A transanal tube was routinely placed in all cases. The fecal volume from the transanal tube was measured daily. The total fecal volume for 3 days after surgery was compared between the AL and non-AL groups. RESULTS: AL occurred in 11 patients. There were 3 patients with a fecal volume >=1,000 mL for 3 days after surgery. AL occurred in these 3 patients. In patients with a fecal volume <1,000 mL, the total fecal volume was significantly greater in the AL group than that in the non-AL group (p = 0.0003). The cut-off value of the total fecal volume in AL was 118 mL. CONCLUSIONS: The volume of fecal discharge for 3 days after surgery is associated with the incidence of AL, and a fecal volume >=118 mL may be a reliable predictor for AL. PMID- 28099960 TI - Prognostic Factors after Curative Resection for Single-Lesion Hepatocellular Carcinoma in Patients with Normal Liver Function: A Historical Cohort Study. AB - BACKGROUND: Hepatic resection for hepatocellular carcinoma (HCC) is now established as the treatment most likely to yield the best outcome. We aimed to clarify the risk factors for HCC recurrence after curative resection of single HCC in patients with normal liver function (NLF). METHODS: The clinical records of 105 patients with NFL and a single HCC less than 5 cm in diameter who had undergone curative liver resection between April 2000 and January 2013 were investigated. We analyzed risk factors for recurrence of HCC. RESULTS: Forty of the 105 patients suffered recurrence of HCC, and median recurrence-free survival (RFS) was 22.0 (5.1-148.5) months after surgery, and the liver was the most frequent site of recurrence. Univariate analysis showed that limited resection (LR; p = 0.002), the indocyanine green retention rate at 15 min (p = 0.023), C reactive protein value (p = 0.001), bilirubin value (p = 0.042), neutrophil to lymphocyte ratio (p = 0.042), operation time (p = 0.018), and amount of bleeding (p = 0.011) were associated with RFS. Multivariate analysis showed that LR (p = 0.007) was a significant risk factor associated with RFS. CONCLUSION: LR is a risk factor for HCC recurrence in patients with single-lesion HCC and NLF. PMID- 28099961 TI - Perineural Invasion Is Associated with Poor Survival after Preoperative Chemoradiation Therapy for Advanced Lower Rectal Cancer. AB - BACKGROUND: Preoperative chemoradiation therapy (pCRT) is a standard procedure for patients with advanced lower rectal cancer. It has been reported that pCRT cannot prolong the survival of patients with advanced lower rectal cancer. The aim of this study is to address the controllable and uncontrollable pathological factors of pCRT in predicting local and distant recurrences. METHODS: One hundred two patients with stages 2 and 3 cancer were consecutively enrolled to the study. The first 51 patients (October 2008-August 2010) underwent curative resection without pCRT. The latter 51 patients (September 2010-May 2015) underwent curative resection after pCRT. Pathological factors of patients were evaluated to assess the association between local and distant recurrences. RESULTS: Multivariate analyses for local and distant recurrences of patients without pCRT revealed that the independent risk factors were tumor deposit and perineural invasion respectively. pCRT was able to diminish circumferential resection margin, tumor deposit, venous invasion, and lymphatic permeation but not neural invasion and lymph node involvement. Kaplan-Meier curve of local and distant recurrence-free survival of patients with pCRT illustrated that tumor deposit is controllable, whereas perineural invasion is uncontrollable by pCRT. CONCLUSION: pCRT uncontrollable perineural invasion may be a factor for distant recurrence of advanced rectal cancer patients, leading to poor survival. PMID- 28099962 TI - Quality of Life after Intestinal Resection in Patients with Crohn Disease: A Systematic Review. AB - BACKGROUND/AIMS: Most patients with Crohn disease (CD) require surgery within 10 years of diagnosis. Intestinal resection is the most commonly performed operation although the effects on health-related quality of life (HRQOL), particularly long term, are contentious. METHODS: We conducted a systematic review evaluating the impact of intestinal resection on the HRQOL of CD patients, predictors of postoperative HRQOL, and patient satisfaction with surgery. RESULTS: Nine studies including 1,108 CD patients undergoing intestinal resection were identified as eligible for inclusion. The median age at surgery was 29-41 years with varying follow-up period (range 30 days-5 years). Ileocolic resection was the most commonly performed operation on an elective basis (range 95-100%). HRQOL improved as early as 2 weeks postoperatively and lasted up to 5 years across both generic and gastrointestinal domains. Gender, smoking, and disease recurrence were potential predictors of postoperative HRQOL. Patient satisfaction is high with regard to surgery, with preference for a laparoscopic approach. CONCLUSION: Intestinal resection in CD patients improved HRQOL in the short- and long-term and patients describe high satisfaction about their surgery. Further studies are needed to validate potential predictors of postoperative HRQOL in this cohort. PMID- 28099963 TI - Low-Molecular-Weight Hydrophilic and Lipophilic Antioxidants in Nonmelanoma Skin Carcinomas and Adjacent Normal-Looking Skin. AB - Low-molecular-weight antioxidants are some of the most efficient agents of the skin defense mechanism against environmental factors, such as cosmic rays, smoke, and pollutants. The total skin concentrations of hydrophilic ascorbic and uric acids, as well as lipophilic alpha-tocopherol, beta-carotene, and ubiquinol-10 antioxidants were determined by an HPLC-EC detector from 18 biopsies of human nonmelanoma skin carcinomas and 18 biopsies from skin areas adjacent to carcinomas. No significant differences in the concentrations of lipophilic antioxidants in both carcinomas and normal-looking skin areas adjacent to carcinomas were observed. On the contrary, ascorbic and uric acid concentrations were found to be 18 and 36% lower in carcinomas than in normal-looking skin areas, respectively. No statistical significance was observed between antioxidant concentrations and age, sex, phototype, profession, site of tumor, frequency, and time of UV light exposure either. Accordingly the antioxidant concentrations in both cancerous skin and adjacent normal-looking areas were found to be much higher than in normal skin, in contrast to literature data. PMID- 28099965 TI - Pilot Test of a New Personal Health System Integrating Environmental and Wearable Sensors for Telemonitoring and Care of Elderly People at Home (SMARTA Project). AB - BACKGROUND: The increase in life expectancy is accompanied by a growing number of elderly subjects affected by chronic comorbidities, a health issue which also implies important socioeconomic consequences. Shifting from hospital or community dwelling care towards a home personalized healthcare paradigm would promote active aging with a better quality of life, along with a reduction in healthcare related costs. OBJECTIVE: The aim of the SMARTA project was to develop and test an innovative personal health system integrating standard sensors as well as innovative wearable and environmental sensors to allow home telemonitoring of vital parameters and detection of anomalies in daily activities, thus supporting active aging through remote healthcare. METHODS: A first phase of the project consisted in the definition of the health and environmental parameters to be monitored (electrocardiography and actigraphy, blood pressure and oxygen saturation, weight, ear temperature, glycemia, home interaction monitoring - water tap, refrigerator, and dishwasher), the feedbacks for the clinicians, and the reminders for the patients. It was followed by a technical feasibility analysis leading to an iterative process of prototype development, sensor integration, and testing. Once the prototype had reached an advanced stage of development, a group of 32 volunteers - including 15 healthy adult subjects, 13 elderly people with cardiac diseases, and 4 clinical operators - was recruited to test the system in a real home setting, in order to evaluate both technical reliability and user perception of the system in terms of effectiveness, usability, acceptance, and attractiveness. RESULTS: The testing in a real home setting showed a good perception of the SMARTA system and its functionalities both by the patients and by the clinicians, who appreciated the user interface and the clinical governance system. The moderate system reliability of 65-70% evidenced some technical issues, mainly related to sensor integration, while the patient's user interface showed excellent reliability (100%). CONCLUSIONS: Both elderly people and clinical operators considered the SMARTA system a promising and attractive tool for improving patients' healthcare while reducing related costs and preserving quality of life. However, the moderate reliability of the system should prompt further technical developments in terms of sensor integration and usability of the clinical operator's user interface. PMID- 28099964 TI - Advancing Age Decreases Pressure-Sensitive Modulation of Calcium Signaling in the Endothelium of Intact and Pressurized Arteries. AB - Aging is the summation of many subtle changes which result in altered cardiovascular function. Impaired endothelial function underlies several of these changes and precipitates plaque development in larger arteries. The endothelium transduces chemical and mechanical signals into changes in the cytoplasmic calcium concentration to control vascular function. However, studying endothelial calcium signaling in larger arteries in a physiological configuration is challenging because of the requirement to focus through the artery wall. Here, pressure- and agonist-sensitive endothelial calcium signaling was studied in pressurized carotid arteries from young (3-month-old) and aged (18-month-old) rats by imaging from within the artery using gradient index fluorescence microendoscopy. Endothelial sensitivity to acetylcholine increased with age. The number of cells exhibiting oscillatory calcium signals and the frequency of oscillations were unchanged with age. However, the latency of calcium responses was significantly increased with age. Acetylcholine-evoked endothelial calcium signals were suppressed by increased intraluminal pressure. However, pressure dependent inhibition of calcium signaling was substantially reduced with age. While each of these changes will increase endothelial calcium signaling with increasing age, decreases in endothelial pressure sensitivity may manifest as a loss of functionality and responsiveness in aging. PMID- 28099966 TI - Involvement of XBP1s in Blue Light-Induced A2E-Containing Retinal Pigment Epithelium Cell Death. AB - PURPOSE: Retinal pigment epithelium (RPE) cell dysfunction is essential to the development of retinal degenerative disease. This study was designed to investigate how spliced X-box-binding protein 1 (XBP1s) regulates different modes of RPE cell death in vitro. METHODS: Human ARPE19 cells were incubated with 25 MUM N-retinylidene-N-retinylethanolamine (A2E) and irradiated with blue light. Expressions of glucose-regulated protein 78 (GRP78) and XBP1s were detected by real-time quantitative PCR and Western blot. STF-083010 was used to suppress XBP1s expression. ARPE19 cell apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling and flow cytometry. Receptor-interacting protein kinase-3 (RIP3) was detected by Western blot. Changes in the morphology of ARPE19 cells were identified by transmission electron microscopy. RESULTS: Blue light-induced A2E-containing ARPE19 cell damage caused a transient elevation of GRP78 and XBP1s, while RIP3 rose in the late stage. STF-083010 effectively inhibited XBP1s expression and brought about the aggravation of apoptosis together with an alleviation of RIP3 expression. Most of the dying cells exhibited apoptotic morphology. CONCLUSION: A2E, along with blue light, brought about apoptosis and necroptosis of ARPE19 cells, and XBP1s was transiently elevated. The suppression of XBP1s induced ARPE19 cell death by promoting apoptosis rather than necroptosis. XBP1s might play a role in the pathogenesis of retinal degenerative diseases. PMID- 28099967 TI - Somatosensory Tinnitus: Correlation between Cranio-Cervico-Mandibular Disorder History and Somatic Modulation. AB - In a subpopulation of patients, tinnitus can be modulated by movements of the jaw or head and neck due to complex somatosensory-auditory interactions. In some of these subjects, tinnitus could be related to an underlying temporomandibular (TMJ) or craniocervical (NECK) dysfunction that, if correctly identified, could streamline treatment and increase chances of tinnitus improvement. However, it is still unclear whether somatic modulation of tinnitus could be used as a screening tool for identifying such patients. In this study, we included 310 tinnitus patients with normal hearing, no psychiatric comorbidities, and a positive history of TMJ and/or NECK dysfunction and/or a positive modulation of tinnitus to evaluate the characteristics of somatic modulation, investigate the relationship between positive history and positive modulation, and identify factors most strongly associated with somatic modulation. Tinnitus modulation was present in 79.67% of the patients. We found a significant association within the same subjects between a positive history and a positive tinnitus modulation for the same region, mainly for TMJ in unilateral tinnitus patients and for TMJ + NECK in bilateral tinnitus patients. A strong correlation between history and modulation in the same somatic region within the same subgroups of subjects was also identified. Most TMJ maneuvers resulted in an increased loudness, while NECK maneuvers showed an increase in tinnitus loudness in about 59% of cases. High pitched tinnitus and male gender were associated with a higher prevalence of modulation; no differences were found for tinnitus onset, Tinnitus Handicap Inventory score, and age. In this paper, we report a strong association between history and modulation for the same regions within the same patients; such an association should always be investigated to improve chances of a correct diagnosis of somatosensory tinnitus. PMID- 28099968 TI - Musculoskeletal ultrasound and ESPER. PMID- 28099969 TI - Digital Ischemia as a paraneoplastic phenomenon. AB - Digital ischemia is a rare paraneoplastic phenomenon associated with several malignant tumours, particularly adenocarcinomas. The underlying pathogenic mechanisms remain unknown and it can be the first manifestation, occur after the diagnosis or during treatment. We report a case of a 50 year old woman presenting with digital ischemia, whose diagnostic workup led to an invasive breast cancer, with significant improvement of digital ischemia after a successful treatment of the neoplasm. PMID- 28099970 TI - Keeping the Name of Acute Posterior Multifocal Placoid Pigment Epitheliopathy. PMID- 28099971 TI - Warfarin-Associated Nonuremic Calciphylaxis. AB - Importance: Classic calciphylaxis associated with renal failure is a life threatening disease. Warfarin-associated calciphylaxis without renal injury has been described, but whether it is a subset of classic calciphylaxis or a different entity remains unknown. We describe 1 case of warfarin-associated calciphylaxis, present data from 2 others from our institution, and review all cases of warfarin-associated calciphylaxis available in the literature. Our review indicates that warfarin-associated calciphylaxis is clinically and pathophysiologically distinct from classic calciphylaxis. Objective: To review warfarin-associated calciphylaxis and determine its relationship to classic calciphylaxis. Design, Setting, and Participants: We searched MEDLINE and Ovid without language or date restrictions for case reports of calciphylaxis from the inpatient setting using the terms "calciphylaxis and warfarin," "non-uremic calciphylaxis," and "nonuremic calciphylaxis." We defined nonuremic calciphylaxis as a histopathologic diagnosis of calciphylaxis without severe kidney disease (serum creatinine level >3 mg/dL; glomerular filtration rate <15 mL/min; acute kidney injury requiring dialysis; and renal transplantation). Exposures: Each patient had been exposed to warfarin before the onset of calciphylaxis. Main Outcomes and Measures: Patient data were abstracted from published reports. Original patient medical records were requested and reviewed when possible. Results: We identified 18 patients with nonuremic calciphylaxis, 15 from the literature, and 3 from our institution. Patients were predominantly female (15 of 18 [83%]) with ages ranging from 19 to 86 years. Duration of warfarin therapy prior to calciphylaxis onset averaged 32 months. Lesions were usually located below the knees (in 12 of 18 [67%]). No cases reported elevated calcium-phosphate products (0 of 17 [0%]). Calcifications were most often noted in the tunica media (n = 8 [44%]) or in the vessel lumen and tunica intima (n = 7 [39%]). The most common treatments included substitution of heparin or low-molecular weight heparin for warfarin (n = 13 [72%]), intravenous sodium thiosulfate (n = 9 [50%]), and hyperbaric oxygen (n = 3 [17%]). The survival rate on hospital discharge was remarkably high, with 15 cases (83%) reporting full recovery and 3 cases ending in death. Conclusions and Relevance: Warfarin-associated calciphylaxis is distinct from classic calciphylaxis in pathogenesis, course, and, particularly, outcome. This finding should influence clinical management of the disease and informs targeted treatment of the disease. PMID- 28099972 TI - Prurigo Pigmentosa in White Monozygotic Twins. PMID- 28099973 TI - Effect Size Estimation in Neuroimaging. PMID- 28099974 TI - Temporary Vacuum-Assisted Closure of the Open Abdomen in Neonates. AB - Introduction The need for open abdomen in the treatment of severely ill neonates will increase in time as more complex abdominal procedures are undertaken. However, the experience of temporary closure of an open abdomen using vacuum assisted closure (VAC) system is still relatively limited in premature and term neonates. The aim of this study is to describe and review our experience in the use of temporary VAC of the open abdomen for neonates with varying pathological processes. Materials and Methods A retrospective folder review of all neonates treated with VAC for open abdomen over the study period of 2010 to 2014 at our institution was performed. Results A total of 15 neonates were included in this study. Mean gestational age and postbirth age at VAC application were 33.6 +/- 4.1 (28-40) weeks and 14 +/- 10.2 (2-30) days, respectively. Mean weight at VAC application was 1,797.7 +/- 730.8 (960-3,200) g. Initial diagnoses were necrotizing enterocolitis (seven), intestinal perforation (three), gastroschisis (two), congenital diaphragmatic hernia (two), and primary abdominal compartment syndrome (ACS) (one). Reasons for VAC application included confirmed ACS (2) and application to prevent ACS (13). Duration of VAC use was 4 +/- 3.4 (0-13) days during which 2 +/- 1.2 (1-5) applications were performed. Overall survival rate was 80% (12 of 15 patients). One patient with primary ACS died from sepsis with an open abdomen. The only potential VAC-related complication was an enterocutaneous fistula. Conclusion Temporary VAC of the open abdomen is a safe method of temporary abdominal closure to prevent ACS in high-risk postoperative conditions in neonates of any gestational age and birth weight. PMID- 28099975 TI - Functional Outcome of CAD/CAM-Assisted versus Conventional Microvascular, Fibular Free Flap Reconstruction of the Mandible: A Retrospective Study of 30 Cases. AB - Background Different advantages of virtually planned and guided mandibular reconstructions have been described. Functional analyses and comparisons with conventionally reconstructed patients. Methods We retrospectively analyzed 30 cases of mandibular reconstructions that involved virtually planned or conventional microvascular, fibular free flaps that occurred between April 2011 and December 2014 at a single center. The results were also compared with a healthy cohort of 30 participants. Axiographic measurements were performed postoperatively, and uni- and multivariate regressions analyses were performed to determine the association between possible predictor variables on functional outcome. Results Operation time, hospital stay, number of osteotomies, incidence of postoperative temporomandibular joint pain, noise, and tension did not differ significantly between the conventional and computer-aided design/computer-aided manufacturing (CAD/CAM) groups (each p > 0.05). Mouth opening and protrusion and laterotrusion also did not differ significantly (each p > 0.05) but were significantly reduced compared with the healthy group. Univariate analysis showed a significant influence of postoperative irradiation on mouth opening and laterotrusion in the conventional group (p = 0.047 and p = 0.028). In addition, multivariate analysis showed a significant influence of indication and number of osteotomies on laterotrusion (p = 0.005 and p = 0.043). Uni and multivariate analyses revealed a significant influence of indication, preoperative irradiation, and number of osteotomies on protrusion and mouth opening in the CAD/CAM group (p = 0.016, p = 0.044, and p = 0.028). Conclusion CAD/CAM-assisted reconstructions of the mandible give comparable functional results with those of the conventional technique, but no functional superiority has been established. Nevertheless, the integration of virtual planning and guided surgery is definitely of significant value but should be indicated individually case by case. PMID- 28099976 TI - Vasculature Characterization of a Multiterritory Perforator Flap: An Experimental Study. AB - Background Tip necrosis in the perforator flap is a significant problem in clinical practice. This study aimed to characterize the vasculature of a multiterritory perforator flap using a rat model and to investigate the impact of the vasculature on flap survival. Methods In total, 105 Sprague Dawley rats were divided into seven groups, including the control, 3 hours postoperative (PO), 12 hours PO, 1 day PO, 3 days PO, 5 days PO, and 7 days PO. A perforator flap with three territories based on the deep iliac circumflex artery was performed. Flaps with only skin incisions and vessel exposure were performed in the control group. The first choke zone (FCZ) was located between the anatomical and dynamic territories, and the second choke zone (SCZ) was located between the dynamic and potential territories. Sodium fluorescein and lead oxide-gelatin angiography and histological examination were performed in each group. Results Sodium fluorescein angiography revealed delayed staining in the perforator flap PO, particularly in the FCZ and SCZ. The delay phenomenon disappeared after 12 hours PO in the FCZ and after 1 day PO in the SCZ. Nonfluorescein-stained areas were found distal to the potential territory. In the FCZ PO, the choke vessels were dilated, while the number of microvessels was increased in the SCZ without choke vessel dilation. Conclusions The remodeling of choke vessels and increase in microvessel number represent arteriogenesis and angiogenesis, respectively. This neovascularization was responsible for flap survival in the entire dynamic territory and part of the potential territory. PMID- 28099977 TI - A Step-by-Step Clinical Approach for the Management of Neuroendocrine Tumours. AB - Neuroendocrine tumours (NET) are rare neoplasms, but the incidence is permanently increasing. Most of the NETs are slow proliferating and clinically silent, and for that reason, they are often diagnosed at a stage with advanced disease. The complexity and diversity of the NET-biology require the treatment of patients in specialised centres to guarantee a qualified, multidisciplinary treatment planning. At our institution, we developed an interdisciplinary model for the assessment and treatment of NET. The aim was to adapt the guidelines to the clinical practice, exchange of current knowledge, and a tailored approach to the individual patient. In our team are included medical professionals from pathology, radiology, oncology, gastroenterology, oncological surgery, and nuclear medicine. In this paper, we describe step-by-step a procedural algorithm for the management of patients with neuroendocrine tumours, focusing on midgut NETs in terms of therapy. PMID- 28099978 TI - Association of Perinatal Risk Factors with Autism Spectrum Disorder. AB - Objective To examine the association between exposures to perinatal factors and autism spectrum disorders (ASD). Study Design A retrospective cohort study of ASD among children born in Kaiser Permanente Southern California hospitals between 1991 and 2009 (n = 594,638). Medical records were used to determine exposure to perinatal (antepartum and intrapartum) complications. ASD was diagnosed using DSM IV criteria. Multivariable Cox regression was used to estimate hazard ratios (HRs). Result Children with ASD were more likely to be exposed to perinatal complications (HR = 1.15, 95% confidence interval [CI]: 1.09-1.21) than neurotypical children. Children exposed to antepartum (HR = 1.22, 95% CI: 1.10 1.36) and intrapartum (HR = 1.10, 95% CI: 1.04-1.17) complications were at increased risk of ASD. The risk was even greater when both antepartum and intrapartum conditions were present (HR = 1.44, 95% CI: 1.26-1.63). Conclusion Exposure to antepartum or intrapartum complications increases the risk of ASD in the offspring. Therefore, pregnancy complications may help identify children who could benefit from early screening and intervention for this common neurodevelopmental condition. PMID- 28099979 TI - Milrinone Pharmacokinetics and Pharmacodynamics in Neonates with Persistent Pulmonary Hypertension of the Newborn. AB - Objective To describe the pharmacokinetics and pharmacodynamics of milrinone in infants with persistent pulmonary hypertension of the newborn (PPHN) and to explore the impact of age on milrinone disposition. Design Randomized, open label pilot study. Setting Multicenter; level 3 and level 4 neonatal intensive care units. Patients Six infants >=34 weeks' gestational age and <10 days of life with persistent hypoxemia receiving inhaled nitric oxide. Intervention Intravenous milrinone lactate in one of two dosing regimens: (1) low dose, 20 mcg/kg bolus followed by 0.2 mcg/kg/minute, and (2) standard dose, 50 mcg/kg bolus followed by 0.5 mcg/kg/minute. Measurements and Main Results The final structural model was a two-compartment disposition model with interindividual variability estimated on clearance (CL). The estimated value of CL is 7.65 mL/minute/3.4 kg (3.05 mL/minute/kg). The addition of age improved the precision of the CL estimate, and CL increased with chronological age in days. The oxygenation index was highly variable within each participant and improved with time. There were no observed safety concerns in either dosing group. Conclusion The CL of milrinone in newborns with PPHN is reduced and increases with age. In this pilot study, we did not see significant pharmacodynamic or safety effects associated with drug exposure. PMID- 28099980 TI - Challenges Faced in Translating the Benefits of Surfactant Replacement Therapy to a Resource-Limited Setting. AB - Aim To determine the challenges, if any, in translating the benefits of surfactant replacement therapy (SRT) to a resource-limited setting. Method This was a retrospective descriptive study comparing the outcome of 75 cases who received surfactant and 69 controls who did not at the University Hospital of the West Indies during the period 2001 to 2011. Descriptive analyses were performed. Statistical significance was taken at the level p < 0.05. Results Only 13% of neonates with respiratory distress syndrome received surfactant therapy. The median time of surfactant administration was 16.5 hours (interquartile range: 6 37 hours). The mean +/- standard deviation time between repeat doses was 19.1 +/- 14 hours. There was no difference in mortality between cases (67%) and controls (59%) (p = 0.32). However, the cases who survived were less mature (28.3 +/- 2 weeks) and less clinically stable (CRIB II [Clinical Risk Index for Babies] score: 8.2 +/- 3) than their controls who survived (30.0 +/- 2 weeks; CRIB II score: 6.0 +/- 3) (p = 0.01). There was no difference in mean gestational age or CRIB II scores between nonsurviving cases and controls. A high incidence of sepsis, pneumothoraces, and pulmonary hemorrhage was noted in both cases and controls. Conclusion SRT did not improve the overall outcome in preterm neonates treated with RDS. Challenges encountered in optimizing SRT included affordability and accessibility of surfactant, supportive equipment, and supportive therapies, as well as a high incidence of complications related to prematurity. PMID- 28099981 TI - Use of Esophageal Hemoximetry to Assess the Effect of Packed Red Blood Cell Transfusion on Gastrointestinal Oxygenation in Newborn Infants. AB - Objectives There are no widely accepted methods of continuously monitoring gut oxygenation in the newborn during packed red blood cell transfusion. We investigated the use of an orally inserted light spectroscopy probe to measure lower esophageal oxyhemoglobin saturations (eStO2) before, during, and after transfusion and made comparisons with abdominal near-infrared spectroscopy (NIRS) and superior mesenteric artery (SMA) flow. Study Design Thirteen neonates with corrected gestational ages ranging from 22 weeks, 0 day to 37 weeks, 5 days were enrolled. eStO2 and NIRS measurements were recorded continuously for a 25-hour period starting 1 hour prior to starting the 4-hour transfusion. Transabdominal ultrasound was used to measure SMA flow prior to, upon completion, and 20 hours after the transfusion. Results Twelve infants completed the study. eStO2 was well tolerated and was weakly (r = 0.06) correlated (p < 0.001) with NIRS. Compared with NIRS, eStO2 demonstrated a markedly greater variation in oxyhemoglobin values. NIRS and SMA flow measurements did not change, while eStO2 increased from 48 +/- 5% and 45 +/- 5% in the pre- and intratransfusion periods to 57 +/- 4% in the posttransfusion period (p = 0.03). Conclusion Measurement of eStO2 is feasible in neonates and may provide a continuous and sensitive index of rapid changes in mesenteric oxygenation in this patient population. PMID- 28099982 TI - [E-learning in ENT: Usage in University Medical Centers in Germany]. AB - E-learning is an essential part of innovative medical teaching concepts. The challenging anatomy and physiology in ENT is considered particularly suitable for self-assessed and adaptive e-learning. Usage and data on daily experience with e learning in German ENT-university hospitals are currently unavailable and the degree of implementation of blended learning including feed-back from medical students are currently not known. We investigated the current need and usage of e learning in academic ENT medical centers in Germany. We surveyed students and chairs for Otorhinolaryngology electronically and paperbased during the summer semester 2015. Our investigation revealed an overall heterogenous picture on quality and quantity of offered e-learning applications. While the overall amount of e-learning in academic ENT in Germany is rather low, at least half of the ENT hospitals in medical faculties reported that e-learning had improved their own teaching activities. More collaboration among medical faculties and academic ENT centers may help to explore new potentials, overcome technical difficulties and help to realize more ambitious projects. PMID- 28099983 TI - [The Relevance of Abducent Nerve Palsy in ENT]. AB - Patients suffering from abducent nerve palsy are usually primary seen by a conservative medical Specialist. In most cases the ENT specialist is secondary involved for treatment. In the majority of cases abducent nerve palsy is a temporary symptom associated with neurologic or vascular diseases. Rarely inflammation, neoplasm or fracture of the skull base cause this symptom and lead to an intervention done by the ENT surgeon. This case series describes retrospectively the abducent palsy seen through the eyes of an ENT surgeon. From 2008 to 2011 15 patients suffering from abducent nerve palsy. One patient suffering from a temporal bone fracture has been treated conservatively while 14 patients needed surgery. 6 patients had a complicated inflammation of the skull base. In 7 patients skull base neoplasms were found in endoscopic surgery. In one case the underlying pathology remained unclear. 2 third of the patients that suffered from complications of inflammatory diseases completely recovered after a combined operative and conservative therapy. The patients who suffered from neoplasms of the skull base partially recovered in only one third, none, achieved full recovery. The patient with the temporal bone fracture achieved a partial recovery after 3 months. If the leading symptom of abducent palsy is caused by a severe extracranial inflammation, neoplasm or trauma an experienced skull base surgeon is mandatory. The recovery rate of abducent palsy in our case series was 60 %. The prognosis of abducent palsy in skull base inflammation is much better compared to patients with skull base neoplasm. PMID- 28099984 TI - [Longterm Results of a Screening Procedure for Adult Cochlear Implant Candidates]. AB - This study gives an estimation of the long term outcome of a screening procedure for cochlear implant candidacy in hearing aid users.In a recent retrospective study, hearing aid performance and audiometric measures in 185 subjects (318 ears) were analyzed. In the context of 2 years follow-up, the outcome of the ipsilateral screening procedure was analyzed. For patients who did receive a cochlear implant, their audiometric outcome measures were viewed into relation to their preoperative results.From the 96 ears identified as cochlear implant candidates, 34 were provided with a cochlear implant. 222 ears were identified as hearing aid users. Only 4 of these 222 ears were provided with a cochlear implant. Cochlear implant recipients with a preoperative speech recognition score with hearing aids above zero showed a mean improvement of 65% points in Freiburg monosyllabics.The audiometry-based screening procedure enables an effective management of the referral process of cochlear implant candidates. PMID- 28099986 TI - Editorial. PMID- 28099985 TI - [Prospective Evaluation of the Quality of the Results of Thyroid Surgery in an ENT-Department]. AB - Although the thyroid gland is located in the neck it is not a matter of fact that it is a clinical issue for the otorhinolaryngologist in Germany. Probably due to historic reasons general surgeons usually perform operations on the thyroid. As at our department this kind of treatment is an established procedure we prospectively evaluated our thyroid cases in order to present our results.The prospective study started in the year of 2014. So far 231 patients were enrolled with an average age of 53,5 years (16-89). The sex ratio showed a preponderance of the female patients with 187 and 64 males. In 155 cases we didn't insert a Redon-drainage. The mean operation time was 133 min. The preoperative concentration of calcium was 2.44 mg/ml with a postoperative decrease to 2.21 mg/ml. In cases of malignancies revealed in histology a second procedure with complete thyroidectomy and neck dissection took place immediately afterwards.Many symptoms of disorders of the thyroid become manifest in a genuine region of our speciality. Therefore we cannot detect any convincing reason why head and neck surgeons should not perform thyroidectomies. Skills like the specific clinical examination, the preoperative diagnostic work flow including sonography, the precise surgical management of soft tissue and neural structures and the postoperative care are typical features of our discipline. However, besides the surgeon's expertise a close collaboration with the colleagues of nuclear medicine and the general practitioner respectively the endocrinologist is mandatory in order to achieve a high quality of treatment. PMID- 28099988 TI - Exercise-based rehabilitation programmes for pulmonary hypertension. AB - BACKGROUND: Individuals with pulmonary hypertension (PH) have reduced exercise capacity and quality of life. Despite initial concerns that exercise training may worsen symptoms in this group, several studies have reported improvements in functional capacity and well-being following exercise-based rehabilitation in PH. OBJECTIVES: To assess the efficacy and safety of exercise-based rehabilitation for people with PH. Primary outcomes were exercise capacity, adverse events during the intervention period and health-related quality of life (HRQoL). Secondary outcomes included cardiopulmonary haemodynamics, functional class, clinical worsening during follow-up, mortality and changes in B-type natriuretic peptide. SEARCH METHODS: We searched the Cochrane Airways Specialised Register of Trials up to August 2016, which is based on regular searches of CINAHL, AMED, Embase, PubMed, MEDLINE, PsycINFO and registries of clinical trials. In addition we searched CENTRAL and the PEDro database up to August 2016 and handsearched relevant journals. SELECTION CRITERIA: All randomised controlled trials (RCTs) focusing on exercise-based rehabilitation programmes for PH. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data independently. For binary outcomes, we calculated odds ratios and their 95% confidence interval (CI), on an intention-to treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a random-effects model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. MAIN RESULTS: We included six RCTs and were able to extract data from five studies. The majority of participants were Group I pulmonary artery hypertension (PAH). Study duration ranged from three to 15 weeks. Exercise programmes included both inpatient- and outpatient-based rehabilitation that incorporated both upper and lower limb exercise. The mean six-minute walk distance following exercise training was 60.12 metres higher than control (30.17 to 90.07 metres, n = 165, 5 RCTs, low-quality evidence; minimal important difference was 30 metres), the mean peak oxygen uptake was 2.4 ml/kg/minute higher (1.4 to 3.4 ml/kg/min, n = 145, 4 RCTs, low-quality evidence) and the mean peak power in the intervention groups was 16.4 W higher (10.9 to 22.0 higher, n = 145, 4 RCTs, low-quality evidence). The mean change in HRQoL for the SF-36 physical component score was 4.63 points higher (0.80 to 8.47 points, n = 33, 2 RCTs, low-quality evidence) and for the SF-36 mental component score was 4.17 points higher (0.01 to 8.34 points; n = 33; 2 RCTs, low-quality evidence). One study reported a single adverse event, where a participant stopped exercise training due to lightheadedness. AUTHORS' CONCLUSIONS: In people with PH, exercise-based rehabilitation results in clinically relevant improvements in exercise capacity. Exercise training was not associated with any serious adverse events. Whilst most studies reported improvements in HRQoL, these may not be clinically important. Overall, we assessed the quality of the evidence to be low. The small number of studies and lack of information on participant selection makes it difficult to generalise these results across the spectrum of people with PH. PMID- 28099989 TI - Effects of a dietary ketone ester on hippocampal glycolytic and tricarboxylic acid cycle intermediates and amino acids in a 3xTgAD mouse model of Alzheimer's disease. AB - In patients with Alzheimer's disease (AD) and in a triple transgenic (3xTgAD) mouse model of AD low glucose metabolism in the brain precedes loss of memory and cognitive decline. The metabolism of ketones in the brain by-passes glycolysis and therefore may correct several deficiencies that are associated with glucose hypometabolism. A dietary supplement composed of an ester of D-beta hydroxybutyrate and R-1,3 butane diol referred to as ketone ester (KE) was incorporated into a rodent diet and fed to 3xTgAD mice for 8 months. At 16.5 months of age animals were killed and brains dissected. Analyses were carried out on the hippocampus and frontal cortex for glycolytic and TCA (Tricarboxylic Acid) cycle intermediates, amino acids, oxidized lipids and proteins, and enzymes. There were higher concentrations of d-beta-hydroxybutyrate in the hippocampus of KE-fed mice where there were also higher concentrations of TCA cycle and glycolytic intermediates and the energy-linked biomarker, N-acetyl aspartate compared to controls. In the hippocampi of control-fed animals the free mitochondrial [NAD+ ]/[NADH] ratio were highly oxidized, whereas, in KE-fed animals the mitochondria were reduced. Also, the levels of oxidized protein and lipids were lower and the energy of ATP hydrolysis was greater compared to controls. 3xTgAD mice maintained on a KE-supplemented diet had higher concentrations of glycolytic and TCA cycle metabolites, a more reduced mitochondrial redox potential, and lower amounts of oxidized lipids and proteins in their hippocampi compared to controls. The KE offers a potential therapy to counter fundamental metabolic deficits common to patients and transgenic models. Read the Editorial Highlight for this article on page 162. PMID- 28099990 TI - Statistical significance for hierarchical clustering. AB - Cluster analysis has proved to be an invaluable tool for the exploratory and unsupervised analysis of high-dimensional datasets. Among methods for clustering, hierarchical approaches have enjoyed substantial popularity in genomics and other fields for their ability to simultaneously uncover multiple layers of clustering structure. A critical and challenging question in cluster analysis is whether the identified clusters represent important underlying structure or are artifacts of natural sampling variation. Few approaches have been proposed for addressing this problem in the context of hierarchical clustering, for which the problem is further complicated by the natural tree structure of the partition, and the multiplicity of tests required to parse the layers of nested clusters. In this article, we propose a Monte Carlo based approach for testing statistical significance in hierarchical clustering which addresses these issues. The approach is implemented as a sequential testing procedure guaranteeing control of the family-wise error rate. Theoretical justification is provided for our approach, and its power to detect true clustering structure is illustrated through several simulation studies and applications to two cancer gene expression datasets. PMID- 28099991 TI - BayesCAT: Bayesian co-estimation of alignment and tree. AB - Traditionally, phylogeny and sequence alignment are estimated separately: first estimate a multiple sequence alignment and then infer a phylogeny based on the sequence alignment estimated in the previous step. However, uncertainty in the alignment is ignored, resulting, possibly, in overstated certainty in phylogeny estimates. We develop a joint model for co-estimating phylogeny and sequence alignment which improves estimates from the traditional approach by accounting for uncertainty in the alignment in phylogenetic inferences. Our insertion and deletion (indel) model allows arbitrary-length overlapping indel events and a general distribution for indel fragment size. We employ a Bayesian approach using MCMC to estimate the joint posterior distribution of a phylogenetic tree and a multiple sequence alignment. Our approach has a tree and a complete history of indel events mapped onto the tree as the state space of the Markov Chain while alternative previous approaches have a tree and an alignment. A large state space containing a complete history of indel events makes our MCMC approach more challenging, but it enables us to infer more information about the indel process. The performances of this joint method and traditional sequential methods are compared using simulated data as well as real data. Software named BayesCAT (Bayesian Co-estimation of Alignment and Tree) is available at https://github.com/heejungshim/BayesCAT. PMID- 28099992 TI - On estimation of time-dependent attributable fraction from population-based case control studies. AB - Population attributable fraction (PAF) is widely used to quantify the disease burden associated with a modifiable exposure in a population. It has been extended to a time-varying measure that provides additional information on when and how the exposure's impact varies over time for cohort studies. However, there is no estimation procedure for PAF using data that are collected from population based case-control studies, which, because of time and cost efficiency, are commonly used for studying genetic and environmental risk factors of disease incidences. In this article, we show that time-varying PAF is identifiable from a case-control study and develop a novel estimator of PAF. Our estimator combines odds ratio estimates from logistic regression models and density estimates of the risk factor distribution conditional on failure times in cases from a kernel smoother. The proposed estimator is shown to be consistent and asymptotically normal with asymptotic variance that can be estimated empirically from the data. Simulation studies demonstrate that the proposed estimator performs well in finite sample sizes. Finally, the method is illustrated by a population-based case-control study of colorectal cancer. PMID- 28099993 TI - Conditional estimation in two-stage adaptive designs. AB - We consider conditional estimation in two-stage sample size adjustable designs and the consequent bias. More specifically, we consider a design which permits raising the sample size when interim results look rather promising, and which retains the originally planned sample size when results look very promising. The estimation procedures reported comprise the unconditional maximum likelihood, the conditionally unbiased Rao-Blackwell estimator, the conditional median unbiased estimator, and the conditional maximum likelihood with and without bias correction. We compare these estimators based on analytical results and a simulation study. We show how they can be applied in a real clinical trial setting. PMID- 28099994 TI - The impact of primer sets on detection of the gene encoding biofilm-associated protein (Bap) in Acinetobacter baumannii: in silico and in vitro analysis. AB - : The Acinetobacter baumannii virulence protein Bap is encoded by a large gene and contains both variable sequence and repetitive modules. To date, four primer sets targeting different regions of bap have been designed, but no study has evaluated all these primers simultaneously for detection of bap. Here, we assessed the effect of primer sets Bap I-IV, on detection of bap both in silico and in vitro. Using the primer set Bap II, all 143 tested strains yielded an amplicon corresponding to the bap gene. This primer set showed the highest sensitivity (100, 95% CI: 97.9-100%) compared to the other primer sets. This study demonstrates that primer set Bap II performs with optimal efficiency for detection of the bap gene among different strains. SIGNIFICANCE AND IMPACT OF THE STUDY: This study investigated the effect of nucleotide variation on PCR detection of the bap gene in various Acinetobacter baumannii strains. Since bap is the target gene for many detection assays, this variation can affect the detection efficiency. Here we present a primer set Bap II with optimal detection efficiency amongst 143 different strains, as shown by in silico and in vitro evidence. PMID- 28099995 TI - Technical Note: Fast respiratory motion estimation using sorted singles without unlist processing: A feasibility study. AB - PURPOSE: The study aims to demonstrate the feasibility of fast respiratory motion estimation using singles data available as a sorted format in list-mode files acquired in an integrated positron emission tomography/magnetic resonance imaging (PET/MRI) system for a proof-of-concept. METHODS: The derivation of singles driven respiratory motion (SDRM) is enabled by singles recorded and binned by second for each detector crystal in PET list-mode data acquired in a SIGNA PET/MR. The proposed method is to derive a SDRM trace by summing up all singles from all detectors through the PET data acquisition. To assess the feasibility of SDRM for data-driven gating (DDG), SDRM traces were derived from the list-mode data acquired in five liver-focused 68 Ga-DOTA-TOC PET/MRI scans, and compared with the traces derived from bellows (pressure belt). Pearson's correlation coefficients and trigger time differences at peak-inhalation phases between SDRM and bellows traces were measured for quantitative evaluation. RESULTS: The method presented the average processing time of 4.2 +/- 0.42 s (range: 3.9 ~ 4.7 s) for the derivation of SDRM traces. The majority of the time was spent for reading singles data from a list-mode file (3.1 +/- 0.40 s, range: 2.7 ~ 3.7s). On average, the correlation coefficient of SDRM and bellows traces was 0.69 +/- 0.16 (range: 0.41 ~ 0.80) and the time offset of SDRM-driven triggers from bellows driven triggers was 0.25 +/- 0.39 s (range: -0.85 ~ 2.69 s later than bellows triggers), demonstrating the similar patterns and phases of SDRM and bellows traces. CONCLUSIONS: We introduced PET singles-driven respiratory motion (SDRM) estimation as a proof-of-principle, using sorted singles ready for immediate processing in list-mode data. The results demonstrated the feasibility of SDRM and its potential use for gated PET with fast processing time. PMID- 28099996 TI - Estimation and testing problems in auditory neuroscience via clustering. AB - The processing of auditory information in neurons is an important area in neuroscience. We consider statistical analysis for an electrophysiological experiment related to this area. The recorded synaptic current responses from the experiment are observed as clusters, where the number of clusters is related to an important characteristic of the auditory system. This number is difficult to estimate visually because the clusters are blurred by biological variability. Using singular value decomposition and a Gaussian mixture model, we develop an estimator for the number of clusters. Additionally, we provide a method for hypothesis testing and sample size determination in the two-sample problem. We illustrate our approach with both simulated and experimental data. PMID- 28099997 TI - On joint estimation of Gaussian graphical models for spatial and temporal data. AB - In this article, we first propose a Bayesian neighborhood selection method to estimate Gaussian Graphical Models (GGMs). We show the graph selection consistency of this method in the sense that the posterior probability of the true model converges to one. When there are multiple groups of data available, instead of estimating the networks independently for each group, joint estimation of the networks may utilize the shared information among groups and lead to improved estimation for each individual network. Our method is extended to jointly estimate GGMs in multiple groups of data with complex structures, including spatial data, temporal data, and data with both spatial and temporal structures. Markov random field (MRF) models are used to efficiently incorporate the complex data structures. We develop and implement an efficient algorithm for statistical inference that enables parallel computing. Simulation studies suggest that our approach achieves better accuracy in network estimation compared with methods not incorporating spatial and temporal dependencies when there are shared structures among the networks, and that it performs comparably well otherwise. Finally, we illustrate our method using the human brain gene expression microarray dataset, where the expression levels of genes are measured in different brain regions across multiple time periods. PMID- 28099998 TI - A generalized Levene's scale test for variance heterogeneity in the presence of sample correlation and group uncertainty. AB - We generalize Levene's test for variance (scale) heterogeneity between k groups for more complex data, when there are sample correlation and group membership uncertainty. Following a two-stage regression framework, we show that least absolute deviation regression must be used in the stage 1 analysis to ensure a correct asymptotic chik-12/(k-1) distribution of the generalized scale (gS) test statistic. We then show that the proposed gS test is independent of the generalized location test, under the joint null hypothesis of no mean and no variance heterogeneity. Consequently, we generalize the recently proposed joint location-scale (gJLS) test, valuable in settings where there is an interaction effect but one interacting variable is not available. We evaluate the proposed method via an extensive simulation study and two genetic association application studies. PMID- 28100000 TI - Interdisciplinary management of an adult patient with significant restorative treatment needs and a complex malocclusion. AB - Transverse maxillary deficiency may be associated with dental crowding, compromised aesthetics and impaired function. Non-surgical correction of maxillary transverse deficiency through rapid maxillary expansion is routinely performed for young patients; however, surgical intervention is generally required for adults. An interdisciplinary treatment approach is necessary to achieve the desired treatment objectives for challenging cases. This case report demonstrates a pleasing treatment outcome for a patient with a severe maxillary transverse deficiency, significant crowding and extensive active caries. PMID- 28099999 TI - High-level intrathymic thyrotrophin receptor expression in thyroiditis-prone mice protects against the spontaneous generation of pathogenic thyrotrophin receptor autoantibodies. AB - The thyrotrophin receptor (TSHR) A-subunit is the autoantigen targeted by pathogenic autoantibodies that cause Graves' hyperthyroidism, a common autoimmune disease in humans. Previously, we reported that pathogenic TSHR antibodies develop spontaneously in thyroiditis-susceptible non-obese diabetic (NOD).H2h4 mice bearing a human TSHR A-subunit transgene, which is expressed at low levels in both the thyroid and thymus (Lo-expressor transgene). The present study tested recent evidence that high intrathymic TSHR expression protects against the development of pathogenic TSHR antibodies in humans. By successive back-crossing, we transferred to the NOD.H2h4 background a human TSHR A-subunit transgene expressed at high levels in the thyroid and thymus (Hi-expressor transgene). In the sixth back-cross generation (> 98% NOD.H2h4 genome), only transgenic offspring produced spontaneously immunoglobulin (Ig)G class non-pathogenic human TSHR A-subunit antibodies. In contrast, both transgenic and non-transgenic offspring developed antibodies to thyroglobulin and thyroid peroxidase. However, non-pathogenic human TSHR antibody levels in Hi-expressor offspring were lower than in Lo-expressor transgenic mice. Moreover, pathogenic TSHR antibodies, detected by inhibition of TSH binding to the TSHR, only developed in back-cross offspring bearing the Lo-expressor, but not the Hi-expressor, transgene. High versus low expression human TSHR A-subunit in the NOD.H2h4 thymus was not explained by the transgene locations, namely chromosome 2 (127-147 Mb; Hi expressor) and chromosome 1 (22.9-39.3 Mb; low expressor). Nevertheless, using thyroiditis-prone NOD.H2h4 mice and two transgenic lines, our data support the association from human studies that low intrathymic TSHR expression is associated with susceptibility to developing pathogenic TSHR antibodies, while high intrathymic TSHR expression is protective. PMID- 28100002 TI - Targeting IkappaBNS in allergic asthma: where it resides, matters. PMID- 28100001 TI - Transplantation tolerance: don't forget about the B cells. AB - Establishing a state of transplantation tolerance that leads to indefinite graft survival without the need for lifelong immunosuppression has been achieved successfully in limited numbers of transplant recipients in the clinic. These successes led to studies aimed at identifying potential biomarkers that diagnose allograft tolerance and identify the patients most amenable to drug minimization, and implicated an enriched B cell signature of tolerance. The emergence of a specialized subset of regulatory B cell (Bregs ), that possess immune-modulatory function in inflammation and autoimmune disease, raised the possibility that Bregs play critical roles in the promotion of transplantation tolerance and that Bregs are the underlying explanation for the B cell signature of tolerance. However, B cells are best known to play a key role in humoral immunity, and excessive production of donor specific antibodies has clear deleterious effects in transplantation. Thus, for tolerance to be persistent, alloantibody responses must also be curtailed, either through the suppression of T cell help or the induction of B cell-intrinsic dysfunction. Recent findings indicate a unique subset of follicular regulatory T cells (Tfr) that can suppress B cell function and induce epigenetic modifications that result in sustained defects in B cell differentiation and function. In this review, we summarize studies in animals and humans that suggest roles for Bregs and dysfunctional B cells in transplantation tolerance, and discuss how these insights may provide a roadmap for new approaches to diagnose, and new therapies to induce allograft tolerance. PMID- 28100003 TI - Neonatal morbidity after spontaneous labor onset prior to intended cesarean delivery at term: a cohort study. AB - INTRODUCTION: We aimed to investigate if labor onset before planned cesarean delivery (CD) affects the risk of neonatal admission, respiratory distress, or neonatal infectious morbidity. MATERIAL AND METHODS: Our cohort included singleton term pregnant women with intended CD who delivered at Aarhus University Hospital from 1990 to 2012. Two groups of women were identified: women with intended CD performed before labor (nonlabor CD) and women with intended CD performed after spontaneous labor onset (labor-onset CD); in both groups there was no other maternal or fetal medical indication for an immediate CD or for early-term CD scheduling. Data were stratified in early-term (37-38 weeks) and full-term (39-40 weeks) deliveries. The main outcome measures were neonatal admission, respiratory distress and neonatal infectious morbidity. RESULTS: Among 103 919 live births, 5071 deliveries were nonlabor CDs and 731 were labor-onset CDs. Compared to nonlabor CD, labor-onset CD was associated with similar risks of neonatal admission and respiratory distress, both at early and full term, but with a two- to three-fold increased risk of newborn septicemia or antibiotic treatment at early term. Labor onset at early term was associated with a lower risk of maternal blood loss of more than 500 mL, but with a higher risk of postoperative antibiotic treatment and endometritis. CONCLUSIONS: Labor onset before planned CD was not associated with a decrease in neonatal respiratory morbidity, but may be associated with increased risks of neonatal infection. PMID- 28100004 TI - Technical Note: Measurement of common carotid artery lumen dynamics using black blood MR cine imaging. AB - PURPOSE: To demonstrate the feasibility of measuring the common carotid artery (CCA) lumen dynamics using a black-blood cine (BB-cine) imaging method. METHODS: Motion-sensitized driven-equilibrium (MSDE) prepared spoiled gradient sequence was used for the BB-cine imaging. CCAs of eleven healthy volunteers were studied using this method. Lumen dynamics, including lumen area evolution waveforms and distension values, were measured and evaluated by comparing this method with bright-blood cine (BrB-cine) imaging. RESULTS: Compared with the BrB-cine images, flow artifacts were effectively suppressed in the BB-cine images. BrB-cine images generally show larger lumen areas than BB-cine images. The lumen area waveforms and distension measurements from BB-cine imaging showed smaller variances among different subjects than BrB-cine imaging. CONCLUSIONS: The proposed BB-cine imaging technique can suppress the flow artifacts effectively and reduce the partial volume effects from the vessel wall. This might allow more accurate lumen dynamics measurements than traditional BrB-cine imaging, which may further be valuable for investigating biomechanical and functional properties of the cardiovascular system. PMID- 28100005 TI - Reply. PMID- 28100007 TI - Race or genetic makeup for hepatitis C virus treatment decisions? PMID- 28100009 TI - What is the benefit of early follow-up after hospitalization for patients with cirrhosis? PMID- 28100006 TI - The fingerprint of antimitochondrial antibodies and the etiology of primary biliary cholangitis. AB - : The identification of environmental factors that lead to loss of tolerance has been coined the holy grail of autoimmunity. Our work has focused on the reactivity of antimitochondrial autoantibodies (AMA) to chemical xenobiotics and has hypothesized that a modified peptide within PDC-E2, the major mitochondrial autoantigen, will have been immunologically recognized at the time of loss of tolerance. Herein, we successfully applied intein technology to construct a PDC E2 protein fragment containing amino acid residues 177-314 of PDC-E2 by joining a recombinant peptide spanning residues 177-252 (PDC-228) with a 62-residue synthetic peptide from 253 to 314 (PP), which encompasses PDC-E2 inner lipoyl domain (ILD). We named this intein-constructed fragment PPL. Importantly, PPL, as well as lipoic acid conjugated PPL (LA-PPL) and xenobiotic 2-octynoic acid conjugated PPL (2OA-PPL), are recognized by AMA. Of great importance, AMA has specificity for the 2OA-modified PDC-E2 ILD peptide backbone distinct from antibodies that react with native lipoylated PDC-E2 peptide. Interestingly, this unique AMA subfraction is of the immunoglobulin M isotype and more dominant in early-stage primary biliary cholangitis (PBC), suggesting that exposure to 2OA PPL-like compounds occurs early in the generation of AMA. To understand the structural basis of this differential recognition, we analyzed PPL, LA-PPL, and 2OA-PPL using electron paramagnetic resonance spectroscopy, with confirmations by enzyme-linked immunosorbent assay, immunoblotting, and affinity antibody analysis. We demonstrate that the conformation of PDC-E2 ILD is altered when conjugated with 2OA, compared to conjugation with lipoic acid. CONCLUSION: A molecular understanding of the conformation of xenobiotic-modified PDC-E2 is critical for understanding xenobiotic modification and loss of tolerance in PBC with widespread implications for a role of environmental chemicals in the induction of autoimmunity. (Hepatology 2017;65:1670-1682). PMID- 28100010 TI - Fine-scale genetic structure analyses reveal dispersal patterns in a critically endangered primate, Trachypithecus leucocephalus. AB - Dispersal is a critically important life history trait of social organisms that has a major impact on the population genetic structure and social relationships within groups. Primates exhibit highly diversified dispersal and philopatry patterns, but knowledge of these patterns is difficult to obtain and usually limited to observations of a small number of focal social groups or individuals. Here, we investigated the dispersal pattern of a critically endangered colobine monkey, the white-headed langur (Trachypithecus leucocephalus), using molecular approaches, and sex-specific population genetic structure analyses at fine geographical scales. We non-invasively collected 403 fecal samples from 41 social groups across 90% of the langur's range in Fusui (FS) and Chongzuo (CZ) in southwestern Guangxi Province, China. We identified 214 unique individuals from the samples by genotyping 15 polymorphic autosomal microsatellite loci, a sex specific marker, and sequencing the mitochondrial DNA (mtDNA) hypervariable region I (HVRI). We found higher intragroup than intergroup genetic relatedness in males and females in both populations. A significant positive correlation between genetic distance and geographical distance, that is a pattern of isolation-by-distance, was detected in females from the FS population, but not in males. Spatial autocorrelation analyses revealed high within-group relatedness in both sexes and populations, as well as an additional positive correlation at the 0.5-km distance class in females from the FS population. Furthermore, we inferred first-generation migrants using genetic assignment tests. Our results suggest that male T. leucocephalus disperse at random distances within habitat areas, whereas dispersal of females may mainly occur among adjacent groups near their home site. Our study provides the first genetic evidence for sex-biased dispersal in T. leucocephalus, which has important management and conservation implications for the species. PMID- 28100008 TI - Is moderate alcohol use in nonalcoholic fatty liver disease good or bad? A critical review. AB - Moderate alcohol consumption in patients with nonalcoholic fatty liver disease (NAFLD) is common, yet the effects on cardiovascular and liver health are unclear. Moderate alcohol use is associated with improved insulin sensitivity and decreased cardiovascular mortality in the general population, but whether similar benefits would be observed in persons with NAFLD remains largely unstudied. There is significant overlap in the pathogenesis of alcoholic liver disease (ALD) and NAFLD, although studies of ALD have focused on pathological alcohol intake and few mechanistic studies of moderate alcohol use in NAFLD exist. We undertook a critical review of the effect of moderate alcohol use on cardiovascular and liver disease in patients with NAFLD. A total of seven observational studies met the criteria for inclusion (one for cardiovascular endpoints and six for liver endpoints). Insufficient studies have assessed the association of moderate alcohol use with cardiovascular outcomes. There was a positive association between moderate alcohol use and decreased NASH and fibrosis; however, heavy episodic drinking may accelerate fibrosis progression and moderate alcohol use may increase the risk of hepatocellular carcinoma in patients with advanced fibrosis. Significant methodological limitations were present, including incomplete adjustment for confounding factors and failure to measure lifetime use or the pattern of alcohol intake. Thus, a strong recommendation of benefit of moderate alcohol use in NAFLD cannot be made. There remains a need for additional high-quality longitudinal studies that evaluate both cardiovascular and liver outcomes among NAFLD patients with moderate or lesser degrees of alcohol use. (Hepatology 2017;65:2090-2099). PMID- 28100011 TI - Association mapping of morphological traits in wild and captive zebra finches: reliable within, but not between populations. AB - Identifying causal genetic variants underlying heritable phenotypic variation is a long-standing goal in evolutionary genetics. We previously identified several quantitative trait loci (QTL) for five morphological traits in a captive population of zebra finches (Taeniopygia guttata) by whole-genome linkage mapping. We here follow up on these studies with the aim to narrow down on the quantitative trait variants (QTN) in one wild and three captive populations. First, we performed an association study using 672 single nucleotide polymorphisms (SNPs) within candidate genes located in the previously identified QTL regions in a sample of 939 wild-caught zebra finches. Then, we validated the most promising SNP-phenotype associations (n = 25 SNPs) in 5228 birds from four populations. Genotype-phenotype associations were generally weak in the wild population, where linkage disequilibrium (LD) spans only short genomic distances. In contrast, in captive populations, where LD blocks are large, apparent SNP effects on morphological traits (i.e. associations) were highly repeatable with independent data from the same population. Most of those SNPs also showed significant associations with the same trait in other captive populations, but the direction and magnitude of these effects varied among populations. This suggests that the tested SNPs are not the causal QTN but rather physically linked to them, and that LD between SNPs and causal variants differs between populations due to founder effects. While the identification of QTN remains challenging in nonmodel organisms, we illustrate that it is indeed possible to confirm the location and magnitude of QTL in a population with stable linkage between markers and causal variants. PMID- 28100012 TI - Characterization and Management of Patients with Heroin versus Nonheroin Opioid Overdoses: Experience at an Academic Medical Center. AB - STUDY OBJECTIVES: To characterize the differences between patients who had heroin and nonheroin opioid overdoses and to determine whether there were any significant differences in their management with regard to the naloxone use. DESIGN: Retrospective cohort study. SETTING: Large academic medical center. PATIENTS: A total of 923 patients admitted to the medical center who were identified for overdose by heroin or other opiate-related narcotics between January 2010 and September 2015; 480 patients experienced a nonheroin opioid overdose event, and 443 patients experienced a heroin overdose event. MEASUREMENTS AND MAIN RESULTS: Patients presenting with heroin overdose tended to be younger and male, with higher rates of hepatitis C virus (HCV) infection compared with those presenting with nonheroin opioid overdose (p<0.05). Patients in the heroin group were also more likely to have a previous overdose event, history of injection drug use, and history of prescription opioid abuse compared with the nonheroin group (p<0.05). Those presenting with heroin overdose were more likely to receive naloxone in the prehospital setting (p<0.05) but were less likely to receive naloxone once admitted (p<0.05). Patients with nonheroin opioid overdoses required more continuous infusions of naloxone (p<0.05) and admission to the intensive care unit (p<0.05). Of all 923 patients, 178 (19.3%) had a repeat admission for any reason, and 70 (7.6%) were readmitted over the course of the study period for another overdose event with the same drug. The proportion of patients presenting with a heroin overdose steadily increased from 2010-2015; the number of patients presenting to the emergency department with nonheroin opioid overdoses steadily decreased. As rates of heroin overdose increased each year, the incidence of HCV infection increased dramatically. CONCLUSION: This study indicates that the incidence of heroin overdoses has significantly increased over the last several years, and the rates of HCV infection 4-fold since the start of the study period. Patients admitted for nonheroin opioid overdose were more likely to be admitted to the hospital and intensive care unit compared with those admitted for heroin overdose. The rise in overdose events only further illustrates a gap in our understanding of the cycle of addiction, drug abuse, and overdose events. PMID- 28100015 TI - The (R)Evolution is here! PMID- 28100014 TI - Mg2+ improves the thermotolerance of probiotic Lactobacillus rhamnosus GG, Lactobacillus casei Zhang and Lactobacillus plantarum P-8. AB - : Food-related carbohydrates and proteins are often used as thermoprotectants for probiotic lactobacilli during industrial production and processing. However, the effect of inorganic salts is rarely reported. Magnesium is the second-most abundant cation in bacteria, and commonly found in various foods. Mg2+ homeostasis is important in Salmonella and has been reported to play a critical role in their thermotolerance. However, the role of Mg2+ in thermotolerance of other bacteria, in particular probiotic bacteria, still remains a hypothesis. In this study, the effect of Mg2+ on thermotolerance of probiotic lactobacilli was investigated in three well-documented probiotic strains, Lactobacillus rhamnosus GG, Lactobacillus casei Zhang and Lactobacillus plantarum P-8, in comparison with Zn2+ and Na+ . Concentrations of Mg2+ between 10 and 50 mmol l-1 were found to increase the bacterial survival upon heat challenge. Remarkably, Mg2+ addition at 20 mmol l-1 led to a 100-fold higher survival of L. rhamnosus GG upon heat challenge. This preliminary study also showed that Mg2+ shortened the heat induced extended lag time of bacteria, which indicated the improvement in bacterial recovery from thermal injury. SIGNIFICANCE AND IMPACT OF THE STUDY: In order to improve the productivity and stability of live probiotics, extensive investigations have been carried out to improve thermotolerance of probiotics. However, most of these studies focused on the effects of carbohydrates, proteins or amino acids. The roles of inorganic salts in various food materials, which have rarely been reported, should be considered when incorporating probiotics into these foods. In this study, Mg2+ was found to play a significant role in the thermotolerance of probiotic lactobacilli. A novel strategy may be available in the near future by employing magnesium salts as protective agents of probiotics during manufacturing process. PMID- 28100013 TI - Cushing's syndrome mutant PKAL205R exhibits altered substrate specificity. AB - The PKAL205R hotspot mutation has been implicated in Cushing's syndrome through hyperactive gain-of-function PKA signaling; however, its influence on substrate specificity has not been investigated. Here, we employ the Proteomic Peptide Library (ProPeL) approach to create high-resolution models for PKAWT and PKAL205R substrate specificity. We reveal that the L205R mutation reduces canonical hydrophobic preference at the substrate P + 1 position, and increases acidic preference in downstream positions. Using these models, we designed peptide substrates that exhibit altered selectivity for specific PKA variants, and demonstrate the feasibility of selective PKAL205R loss-of-function signaling. Through these results, we suggest that substrate rewiring may contribute to Cushing's syndrome disease etiology, and introduce a powerful new paradigm for investigating mutation-induced kinase substrate rewiring in human disease. PMID- 28100016 TI - Validation of an enzyme immunoassay and comparison of fecal cortisol metabolite levels in black and gold howler monkeys (Alouatta caraya) inhabiting fragmented and continuous areas of the humid Chaco region, Argentina. AB - : In the last years, the study of how environmental stimuli influence the physiology and specifically the endocrinology of an organism became increasingly important, relying mainly on the quantification of glucocorticoids to monitor animal welfare. Most studies investigating cortisol levels in primates were focused on the impact of social stressors; however, a major concern for the conservation of howler monkeys is the increased habitat fragmentation led by the advancement of the agricultural frontier. We compared fecal cortisol metabolite levels (FGCM) in howler monkeys (Alouatta caraya) living in fragmented and continuous forests of the Argentine humid Chaco region, throughout the warm season (spring-summer). Fecal samples (n = 114) were collected from adult individuals, and steroid extracts analyzed with an enzyme immunoassay also validated in this work. Parallel displacement curves were obtained between dilutions of pooled fecal extracts and the cortisol standard curve (r2 = 0.99; P = 0.23). Efficiency of the fecal extraction procedure was 79.4% +/- 38%; recovery of exogenous hormone added to fecal extracts indicated a low interference of components in the feces with antibody binding. The exogenous administration of ACTH in captive-bred animals demonstrated a "cause-and-effect" relationship between the adrenal gland activation and increased FGCM levels. Contrary to our initial prediction, we were not able to demonstrate a significant difference in FGCM levels of caraya monkeys inhabiting the continuous versus fragmented habitats in our study site (83.2 +/- 4.9 ng/g [n = 10 individuals] vs. 71.5 +/- 4.9 ng/g [n = 7 individuals]; P = 0.29); this could be the result of low levels of disturbance imposed by a moderate and selective logging, which has proved to be beneficial for this species with high resilience by adjusting their diet to cope with feeding in degraded habitats but with new leaves and buds. Regardless of the habitat, cortisol metabolites were significantly higher in females than in males (86.4 +/- 4.2 ng/g [n = 12 individuals] vs. 60.7 +/- 5.0 ng/g [n = 5 individuals] respectively; P = 0.007). RESEARCH HIGHLIGHTS: Validation of an enzyme immunoassay and comparison of fecal cortisol metabolite levels in black and gold howler monkeys (Alouatta caraya) inhabiting fragmented and continuous areas of the humid Chaco region, Argentina. Contrary to our initial prediction, no significant differences in Alouatta caraya fecal cortisol metabolite levels were detected; cortisol metabolites were significantly higher in females. Probably, animals adjusted their diet to cope with feeding in degraded habitats, but with new leaves and buds. PMID- 28100017 TI - Subspecies delineation amid phenotypic, geographic and genetic discordance in a songbird. AB - Understanding the processes that drive divergence within and among species is a long-standing goal in evolutionary biology. Traditional approaches to assessing differentiation rely on phenotypes to identify intra- and interspecific variation, but many species express subtle morphological gradients in which boundaries among forms are unclear. This intraspecific variation may be driven by differential adaptation to local conditions and may thereby reflect the evolutionary potential within a species. Here, we combine genetic and morphological data to evaluate intraspecific variation within the Nelson's (Ammodramus nelsoni) and salt marsh (Ammodramus caudacutus) sparrow complex, a group with populations that span considerable geographic distributions and a habitat gradient. We evaluated genetic structure among and within five putative subspecies of A. nelsoni and A. caudacutus using a reduced-representation sequencing approach to generate a panel of 1929 SNPs among 69 individuals. Although we detected morphological differences among some groups, individuals sorted along a continuous phenotypic gradient. In contrast, the genetic data identified three distinct clusters corresponding to populations that inhabit coastal salt marsh, interior freshwater marsh and coastal brackish-water marsh habitats. These patterns support the current species-level recognition but do not match the subspecies-level taxonomy within each species-a finding which may have important conservation implications. We identified loci exhibiting patterns of elevated divergence among and within these species, indicating a role for local selective pressures in driving patterns of differentiation across the complex. We conclude that this evidence for adaptive variation among subspecies warrants the consideration of evolutionary potential and genetic novelty when identifying conservation units for this group. PMID- 28100018 TI - Conversion of Amazon rainforest to agriculture alters community traits of methane cycling organisms. AB - Land use change is one of the greatest environmental impacts worldwide, especially to tropical forests. The Amazon rainforest has been subject to particularly high rates of land use change, primarily to cattle pasture. A commonly observed response to cattle pasture establishment in the Amazon is the conversion of soil from a methane sink in rainforest, to a methane source in pasture. However, it is not known how the microorganisms that mediate methane flux are altered by land use change. Here, we use the deepest metagenomic sequencing of Amazonian soil to date to investigate differences in methane cycling microorganisms and their traits across rainforest and cattle pasture soils. We found that methane-cycling microorganisms responded to land use change, with the strongest responses exhibited by methane-consuming, rather than methane producing, microorganisms. These responses included a reduction in the relative abundance of methanotrophs and a significant decrease in the abundance of genes encoding particulate methane monooxygenase. We also observed compositional changes to methanotroph and methanogen communities as well as changes to methanotroph life history strategies. Our observations suggest that methane cycling microorganisms are vulnerable to land use change, and this vulnerability may underlie the response of methane flux to land use change in Amazon soils. PMID- 28100020 TI - Independent evolution of sexual dimorphism and female-limited mimicry in swallowtail butterflies (Papilio dardanus and Papilio phorcas). AB - Several species of swallowtail butterflies (genus Papilio) are Batesian mimics that express multiple mimetic female forms, while the males are monomorphic and nonmimetic. The evolution of such sex-limited mimicry may involve sexual dimorphism arising first and mimicry subsequently. Such a stepwise scenario through a nonmimetic, sexually dimorphic stage has been proposed for two closely related sexually dimorphic species: Papilio phorcas, a nonmimetic species with two female forms, and Papilio dardanus, a female-limited polymorphic mimetic species. Their close relationship indicates that female-limited polymorphism could be a shared derived character of the two species. Here, we present a phylogenomic analysis of the dardanus group using 3964 nuclear loci and whole mitochondrial genomes, showing that they are not sister species and thus that the sexually dimorphic state has arisen independently in the two species. Nonhomology of the female polymorphism in both species is supported by population genetic analysis of engrailed, the presumed mimicry switch locus in P. dardanus. McDonald Kreitman tests performed on SNPs in engrailed showed the signature of balancing selection in a polymorphic population of P. dardanus, but not in monomorphic populations, nor in the nonmimetic P. phorcas. Hence, the wing polymorphism does not balance polymorphisms in engrailed in P. phorcas. Equally, unlike in P. dardanus, none of the SNPs in P. phorcas engrailed were associated with either female morph. We conclude that sexual dimorphism due to female polymorphism evolved independently in both species from monomorphic, nonmimetic states. While sexual selection may drive male-female dimorphism in nonmimetic species, in mimetic Papilios, natural selection for protection from predators in females is an alternative route to sexual dimorphism. PMID- 28100021 TI - Identifying the Biphasic Role of Calcineurin/NFAT Signaling Enables Replacement of Sox2 in Somatic Cell Reprogramming. AB - Induction of pluripotency with defined factors (octamer-binding transcription factor 4 [Oct4], SRY (sex determining region Y)-box 2 [Sox2], Kruppel-like factor 4 [Klf4], c-Myc) raises hopes for successful clinical trials. Despite considerable efforts, the molecular mechanism of reprogramming remains poorly understood. The aim of the present study was to identify the role of calcineurin/nuclear factor of activated T cells (NFAT) in reprogramming. Our results demonstrated a biphasic role for calcineurin/NFAT signaling during reprogramming. In the early phase of reprogramming, calcineurin activity is required to maintain proper cell cycle division and for mesenchymal-epithelial transition. In the late phase, calcineurin exerts a negative effect that is mediated by NFATc2. NFATc2 interacts with Hdac3, Ezh2, and Suv39h1 to increase H3K9me3 and H3K27me3 over the Sox2 enhancer and Klf2 promoter, respectively, resulting in the downregulation of their expression. Moreover, Galphaq was identified as a positive upstream regulator for calcineurin. The Galphaq/calcineurin/NFATc2 axis negatively regulates the late step of reprogramming. By inhibiting NFATc2 or calcineurin, induced pluripotent stem cells could be established without exogenous Sox2. Thus, the present study revealed another regulatory level of reprogramming, and proposes a biological axis that could be useful for cancer therapy. Stem Cells 2017;35:1162-1175. PMID- 28100019 TI - A randomized trial to assess whether portal pressure guided therapy to prevent variceal rebleeding improves survival in cirrhosis. AB - : Monitoring the hemodynamic response of portal pressure (PP) to drug therapy accurately stratifies the risk of variceal rebleeding (VRB). We assessed whether guiding therapy with hepatic venous pressure gradient (HVPG) monitoring may improve survival by preventing VRB. Patients with cirrhosis with controlled variceal bleeding were randomized to an HVPG-guided therapy group (N = 84) or to a control group (N = 86). In both groups, HVPG and acute beta-blocker response were evaluated at baseline and HVPG measurements were repeated at 2-4 weeks to determine chronic response. In the HVPG-guided group, acute responders were treated with nadolol and acute nonresponders with nadolol+nitrates. Chronic nonresponders received nadolol+prazosin and had a third HVPG study. Ligation sessions were repeated until response was achieved. The control group was treated with nadolol+nitrates+ligation. Between-group baseline characteristics were similar. During long-term follow-up (median of 24 months), mortality was lower in the HVPG-guided therapy group than in the control group (29% vs. 43%; hazard ratio [HR] = 0.59; 95% confidence interval [CI] = 0.35-0.99). Rebleeding occurred in 19% versus 31% of patients, respectively (HR = 0.53; 95% CI = 0.29-0.98), and further decompensation of cirrhosis occurred in 52% versus 72% (HR = 0.68; 95% CI = 0.46-0.99). The survival probability was higher with HVPG-guided therapy than in controls, both in acute (HR = 0.59; 95% CI = 0.32-1.08) and chronic nonresponders (HR = 0.48; 95% CI = 0.23-0.99). HVPG-guided patients had a greater reduction of HVPG and a lower final value than controls (P < 0.05). CONCLUSION: HVPG monitoring, by stratifying risk and targeting therapy, improves the survival achieved with currently recommended treatment to prevent VRB using beta-blockers and ligation. HVPG-guided therapy achieved a greater reduction in PP, which may have contributed to reduce the risk of rebleeding and of further decompensation of cirrhosis, thus contributing to a better survival. (Hepatology 2017;65:1693 1707). PMID- 28100022 TI - Mycorrhizal specificity does not limit the distribution of an endangered orchid species. AB - What factors determine the distribution of a species is a central question in ecology and conservation biology. In general, the distribution of plant species is assumed to be controlled by dispersal or environmentally controlled recruitment. For plant species which are critically dependent on mycorrhizal symbionts for germination and seedling establishment, specificity in mycorrhizal associations and availability of suitable mycorrhizal fungi can be expected to have a major impact on successful colonization and establishment and thus ultimately on a species distribution. We combined seed germination experiments with soil analyses and fungal assessments using 454 amplicon pyrosequencing to test the relative importance of dispersal limitation, mycorrhizal availability and local growth conditions on the distribution of the orchid species Liparis loeselii, which, despite being widely distributed, is rare and endangered in Europe. We compared local soil conditions, seed germination and mycorrhizal availability in the soil between locations in northern Belgium and France where L. loeselii occurs naturally and locations where conditions appear suitable, but where adults of the species are absent. Our results indicated that mycorrhizal communities associating with L. loeselii varied among sites and plant life cycle stages, but the observed variations did not affect seed germination, which occurred regardless of current L. loeselii presence and was significantly affected by soil moisture content. These results indicate that L. loeselii is a mycorrhizal generalist capable of opportunistically associating with a variety of fungal partners to induce seed germination. They also indicate that availability of fungal associates is not necessarily the determining factor driving the distribution of mycorrhizal plant species. PMID- 28100023 TI - Frontotemporal lobar degeneration: Pathogenesis, pathology and pathways to phenotype. AB - Frontotemporal Lobar Degeneration (FTLD) is a clinically, pathologically and genetically heterogeneous group of disorders that affect principally the frontal and temporal lobes of the brain. There are three major associated clinical syndromes, behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD) and progressive non-fluent aphasia (PNFA); three principal histologies, involving tau, TDP-43 and FUS proteins; and mutations in three major genes, MAPT, GRN and C9orf72, along with several other less common gene mutations. All three clinical syndromes can exist separately or in combination with Amyotrophic Lateral Sclerosis (ALS). SD is exclusively a TDP-43 proteinopathy, and PNFA may be so, with both showing tight clinical, histological and genetic inter relationships. bvFTD is more of a challenge with overlapping histological and genetic features, involvement of any of the three aggregating proteins, and changes in any of the three major genes. However, when ALS is present, all cases show a clear histological phenotype with TDP-43 aggregated proteins, and familial forms are associated with expansions in C9orf72. TDP-43 and FUS are nuclear carrier proteins involved in the regulation of RNA metabolism, whereas tau protein - the product of MAPT - is responsible for the assembly/disassembly of microtubules, which are vital for intracellular transport. Mutations in TDP-43 and FUS genes are linked to clinical ALS rather than FTLD (with or without ALS), suggesting that clinical ALS may be a disorder of RNA metabolism. Conversely, the protein products of GRN and C9orf72, along with those of the other minor genes, appear to form part of the cellular protein degradation machinery. It is possible therefore that FTLD is a reflection of dysfunction within lysosomal/proteasomal systems resulting in failure to remove potentially neurotoxic (TDP-43 and tau) aggregates, which ultimately overwhelm capacity to function. Spread of aggregates along distinct pathways may account for the different clinical phenotypes, and patterns of progression of disease. PMID- 28100024 TI - Evaluation of Cast Re-Orientation on a Dental Surveyor Using Three Tripod Techniques: A Survey and In Vitro Study. AB - PURPOSE: To survey different educational levels (i.e., students, interns, technicians, and prosthodontic faculty) with regard to their opinions, attitudes, and adoption of three selected tripod techniques. The study will also investigate the accuracy of these techniques to reposition casts on the dental surveyor in anterio-posterior (AP) and lateral directions at both technique and educational levels. MATERIALS AND METHODS: Tripod points, scored lines, and cemented post tripod techniques were used in this study. Three Kennedy class II modification I stone casts, duplicated from a standard cast, were assigned to each of the tripod techniques. The tilt angles of all casts were set on the dental surveyor to 10 degrees (control angle) in AP and lateral directions using a digital angle gauge with an accuracy of 0.2 degrees . The casts were tripoded accordingly. A total of 243 participants were involved in this study. Participants were first asked to remount the three casts on three different dental surveyors using the tripod technique noted on each cast. Questionnaires were then given to each participant in an individual interview setting; this assured a 100% response rate. The angle differences were calculated. All data were coded and entered into an Excel Spreadsheet file. Statistical analyses were performed using a paired Chi-square, Wilcoxon Matched-pairs, ANOVA, and Tukey post hoc tests at 5% level of significance. RESULTS: No significant difference was found between the educational levels relative to the responses to technique demands, sensitivity, and time required for reorientation (p = 0.08202, 0.8108, 0.6874, respectively); however, the majority of respondents reported low technique demands, low sensitivity, and time saving for technique C in comparison to techniques A and B. Significant differences were noted among the educational levels in response to preference and adoption questions (p = 0.0035 and 0.0015, respectively). The highest percentage of faculty chose technique A for inclusion into the academic curriculum. Wilcoxon Matched-pairs test revealed that technique C was the least difficult and most practical (p = 0.0001, 0.0427, respectively). One-way ANOVA revealed significance in angle differences from the set position for technique A in lateral tilt and techniques A and B in AP tilt (p = 0.0466, 0.0194, 0.0424, respectively). A comparison of positivity (overtilt) and negativity (undertilt) between the three techniques in lateral and AP tilts using Chi-square test resulted in significant differences in both directions of tilt (p < 0.0001). Technique C resulted in remounting the casts at the control position in 15.64% in both directions; this was a higher percentage than the other two techniques (A and B). Wilcoxon Matched-pairs test was used to compare between the techniques relative to angle differences from the standard position. No differences were found between technique A and B in lateral tilt position (p = 0.9271), while significance was detected in AP tilt (p < 0.0001). Significant differences were detected between technique C in comparison to A (p < 0.0001, p = 0.0303) and B (p < 0.0001) in lateral and AP tilt directions. CONCLUSIONS: Within the limitations of this study, it can be concluded that technique C (cemented post technique) was more favored among the respondents across all educational levels. This technique presented high potential in accurately reorienting casts on the dental surveyor in comparison to the tripod points and scoring techniques (p < 0.0001). PMID- 28100025 TI - Sex-biased transcriptome divergence along a latitudinal gradient. AB - Sex-dependent gene expression is likely an important genomic mechanism that allows sex-specific adaptation to environmental changes. Among Drosophila species, sex-biased genes display remarkably consistent evolutionary patterns; male-biased genes evolve faster than unbiased genes in both coding sequence and expression level, suggesting sex differences in selection through time. However, comparatively little is known of the evolutionary process shaping sex-biased expression within species. Latitudinal clines offer an opportunity to examine how changes in key ecological parameters also influence sex-specific selection and the evolution of sex-biased gene expression. We assayed male and female gene expression in Drosophila serrata along a latitudinal gradient in eastern Australia spanning most of its endemic distribution. Analysis of 11 631 genes across eight populations revealed strong sex differences in the frequency, mode and strength of divergence. Divergence was far stronger in males than females and while latitudinal clines were evident in both sexes, male divergence was often population specific, suggesting responses to localized selection pressures that do not covary predictably with latitude. While divergence was enriched for male biased genes, there was no overrepresentation of X-linked genes in males. By contrast, X-linked divergence was elevated in females, especially for female biased genes. Many genes that diverged in D. serrata have homologs also showing latitudinal divergence in Drosophila simulans and Drosophila melanogaster on other continents, likely indicating parallel adaptation in these distantly related species. Our results suggest that sex differences in selection play an important role in shaping the evolution of gene expression over macro- and micro ecological spatial scales. PMID- 28100027 TI - Moving beyond presence and absence when examining changes in species distributions. AB - Species distributions are often simplified to binary representations of the ranges where they are present and absent. It is then common to look for changes in these ranges as indicators of the effects of climate change, the expansion or control of invasive species or the impact of human land-use changes. We argue that there are inherent problems with this approach, and more emphasis should be placed on species relative abundance rather than just presence. The sampling effort required to be confident of absence is often impractical to achieve, and estimates of species range changes based on survey data are therefore inherently sensitive to sampling intensity. Species niches estimated using presence-absence or presence-only models are broader than those for abundance and may exaggerate the viability of small marginal sink populations. We demonstrate that it is possible to transform models of predicted probability of presence to expected abundance if the sampling intensity is known. Using case studies of Antarctic mosses and temperate rain forest trees, we demonstrate additional insights into biotic change that can be gained using this method. While species becoming locally extinct or colonising new areas are extreme and obviously important impacts of global environmental change, changes in abundance could still signal important changes in biological systems and be an early warning indicator of larger future changes. PMID- 28100026 TI - miR-203 inhibits augmented proliferation and metastasis of hepatocellular carcinoma residual in the promoted regenerating liver. AB - Liver resection is still the most commonly used therapeutic treatment for hepatocellular carcinoma (HCC), and liver regeneration promotes HCC growth in the regenerating liver. The high recurrence/metastasis of HCC is the main cause of death for HCC patients after liver resection. However, how the augmented growth and metastasis of residual HCC induced by the promoted liver regeneration following liver resection can be abolished remains unclear. In this study, a rat model with liver cirrhosis and diffused HCC was established by administration of diethylnitrosamine. Recombinant miR-203 adenovirus was administered to induce hepatic miR-203 overexpression and 30% partial hepatectomy (PH) followed. The effect of miR-203 on the proliferation, invasion and metastasis of the residual HCC in the remnant cirrhotic liver with promoted regeneration was investigated. We found that the basic spontaneous regeneration of the non-tumorous liver by 30% PH promoted proliferation, invasion and lung metastasis of the hepatic residual HCC. miR-203 overexpression further promoted the regeneration of the non-tumorous liver by upregulating Ki67 expression and enhancing IL-6/SOCS3/STAT3 pro proliferative signals. Importantly, miR-203 overexpression markedly inhibited the proliferation, invasion and metastasis of hepatic residual HCC through suppressing expression of Ki67, CAPNS1 and lung metastasis. Moreover, it was found that miR-203 overexpression reversed the epithelial-mesenchymal transition induced by hepatectomy through targeting IL-1beta, Snail1 and Twist1. In conclusion, our results suggested that miR-203 overexpression inhibited the augmented proliferation and lung metastasis of the residual HCC induced by the promoted liver regeneration following PH partly by regulating epithelial mesenchymal transition. PMID- 28100028 TI - Perirhinal cortex involvement in allocentric spatial learning in the rat: Evidence from doubly marked tasks. AB - It has recently been suggested that the different cortices of the medial temporal lobe support a mixture of object and spatial processing functions, challenging the anterior model that emphasized a strict functional differentiation between regions. However, for some structures, the perirhinal cortex (Prh) for example, a number of studies using lesion methods have shown a profound deficit exclusively in tasks involving object learning but not allocentric spatial learning. It may be that the learning paradigms used in previous studies have not been sensitive enough to detect a possible allocentric deficit in Prh-lesioned animals. To examine whether Prh lesions critically affect allocentric spatial learning, experimental and control rats were trained in two doubly marked navigation tasks. In experiment 1, the use of either one of two different memory systems, allocentric versus egocentric, made it possible to locate the goal arm in a four arm radial maze. In experiment 2, rats had to choose between an allocentric versus a S-R/habit strategy, both of which predicted the location of the goal arm. Results showed that both experimental and control animals learned both navigation tasks well, reaching the same level of performance at the end of training. However, a probe test performed 1 day after the learning ended revealed that Prh-damaged animals learned both tasks predominantly using a non-allocentric strategy. Specifically, in lesioned subjects the percentage of egocentric correct responses (experiment 1) and the percentage of habit-based correct responses (experiment 2) was significantly higher than in the control rats. On the other hand, in both experiments, control rats in the probe test presented a significantly higher number of allocentric correct responses than the lesioned subjects. These results clearly suggest that Prh is normally needed for using allocentric strategies in order to solve a navigation problem. (c) 2017 Wiley Periodicals, Inc. PMID- 28100029 TI - Isolation with asymmetric gene flow during the nonsynchronous divergence of dry forest birds. AB - Dry forest bird communities in South America are often fragmented by intervening mountains and rainforests, generating high local endemism. The historical assembly of dry forest communities likely results from dynamic processes linked to numerous population histories among codistributed species. Nevertheless, species may diversify in the same way through time if landscape and environmental features, or species ecologies, similarly structure populations. Here we tested whether six co-distributed taxon pairs that occur in the dry forests of the Tumbes and Maranon Valley of northwestern South America show concordant patterns and modes of diversification. We employed a genome reduction technique, double digest restriction site-associated DNA sequencing, and obtained 4407-7186 genomewide SNPs. We estimated demographic history in each taxon pair and inferred that all pairs had the same best-fit demographic model: isolation with asymmetric gene flow from the Tumbes into the Maranon Valley, suggesting a common diversification mode. Overall, we also observed congruence in effective population size (Ne ) patterns where ancestral Ne were 2.9-11.0* larger than present-day Maranon Valley populations and 0.3-2.0* larger than Tumbesian populations. Present-day Maranon Valley Ne was smaller than Tumbes. In contrast, we found simultaneous population isolation due to a single event to be unlikely as taxon pairs diverged over an extended period of time (0.1-2.9 Ma) with multiple nonoverlapping divergence periods. Our results show that even when populations of codistributed species asynchronously diverge, the mode of their differentiation can remain conserved over millions of years. Divergence by allopatric isolation due to barrier formation does not explain the mode of differentiation between these two bird assemblages; rather, migration of individuals occurred before and after geographic isolation. PMID- 28100031 TI - Impact of melatonin receptor-signaling on Zeitgeber time-dependent changes in cell proliferation and apoptosis in the adult murine hippocampus. AB - The hippocampus is subjected to diurnal/circadian rhythms on both the morphological and molecular levels. Certain aspects of cell proliferation in the adult hippocampus are regulated by melatonin and accompanied by apoptosis to ensure proper tissue maintenance and function. The present study investigated Zeitgeber time (ZT)-dependent changes in cell proliferation and apoptosis in the adult murine hippocampus and their regulation by melatonin receptor type1 and type2 (MT1/2)-mediated signaling. Adult melatonin-proficient C3H/HeN mice and melatonin-proficient (C3H/HeN) mice with targeted deletion of MT1/2 were adapted to a 12-h light, 12-h dark photoperiod and were sacrificed at ZT00, ZT06, ZT12, and ZT18. Immunohistochemistry for Ki67 and activated caspase-3 in combination with different markers for the diverse cell types residing in the hippocampus served to identify and quantify proliferating and apoptotic cells in the hippocampal subregions. ZT-dependent changes in cell proliferation and apoptosis were found exclusively in the subgranular zone (SGZ) and granule cell layer (GCL) of melatonin-proficient mice with functional MT1/2. Cell proliferation in the SGZ showed ZT-dependent changes indicated by an increase of proliferating immature neurons during the dark phase of the 24-h light-dark cycle. Apoptosis showed ZT dependent changes in the SGZ and GCL indicated by an increase of apoptotic immature neurons at ZT06 (SGZ) and a decrease of immature and mature neurons at ZT18 (GCL). Our results indicate that ZT-dependent changes in proliferation of immature neurons in the SGZ are counterbalanced by ZT-dependent changes in apoptosis of immature and mature neurons in the SGZ and GCL exclusively in mice with functional MT1/2. Therefore, MT1/2-mediated signaling appears to be crucial for generation and timing of ZT-dependent changes in cell proliferation and apoptosis and for differentiation of proliferating cells into neurons in the SGZ. (c) 2017 Wiley Periodicals, Inc. PMID- 28100030 TI - Epigenetics in normal and malignant hematopoiesis: An overview and update 2017. AB - Epigenetic regulation in hematopoiesis has been a field of rapid expansion. Genome-wide analyses have revealed, and will continue to identify genetic alterations in epigenetic genes that are present in various types of hematopoietic neoplasms. Development of new mouse models for individual epigenetic modifiers has revealed their novel, sometimes unexpected, functions. In this review, we provide an overview of genetic alterations within epigenetic genes in various types of hematopoietic neoplasms. We then summarize the physiologic roles of these epigenetic modifiers during hematopoiesis, and describe therapeutic approaches targeting the epigenetic modifications. Interestingly, the mutational spectrum of epigenetic genes indicates that myeloid neoplasms are similar to T-cell neoplasms, whereas B-cell lymphomas have distinct features. Furthermore, it appears that the epigenetic mutations related to active transcription are more associated with myeloid/T-cell neoplasms, whereas those that repress transcription are associated with B-cell lymphomas. These observations may imply that the global low-level or high-level transcriptional activity underlies the development of myeloid/T-cell tumors or B-cell tumors, respectively. PMID- 28100032 TI - Sequential learning during contextual fear conditioning guides the rate of systems consolidation: Implications for consolidation of multiple memory traces. AB - Systems consolidation has been described as a time-dependent reorganization process involving the neocortical and hippocampal networks underlying memory storage and retrieval. Previous studies of our lab were able to demonstrate that systems consolidation is a dynamic process, rather than a merely passive, time dependent phenomenon. Here, we studied the influence of sequential learning in contextual fear conditioning (CFC) with different training intensities in the time-course of hippocampal dependency and contextual specificity. We found that sequential learning with high-intensity shocks during CFC induces generalization of the first learning (context A) and maintains contextual specificity of the second learning (context B) 15 days after acquisition. Moreover, subsequent experiences reorganize brain structures involved in retrieval, accelerating the involvement of cortical structures and diminishing the hippocampal participation. Exposure to original context before novelty seems to only induce context specificity in hippocampal-dependent memories. We propose that systems consolidation could be considered a potential biological mechanism for reducing possible interferences between similar memory traces. (c) 2017 Wiley Periodicals, Inc. PMID- 28100033 TI - Relaxin-3 inputs target hippocampal interneurons and deletion of hilar relaxin-3 receptors in "floxed-RXFP3" mice impairs spatial memory. AB - Hippocampus is innervated by gamma-aminobutyric acid (GABA) "projection" neurons of the nucleus incertus (NI), including a population expressing the neuropeptide, relaxin-3 (RLN3). In studies aimed at gaining an understanding of the role of RLN3 signaling in hippocampus via its Gi/o -protein-coupled receptor, RXFP3, we examined the distribution of RLN3-immunoreactive nerve fibres and RXFP3 mRNA positive neurons in relation to hippocampal GABA neuron populations. RLN3 positive elements were detected in close-apposition with a substantial population of somatostatin (SST)- and GABA-immunoreactive neurons, and a smaller population of parvalbumin- and calretinin-immunoreactive neurons in different hippocampal areas, consistent with the relative distribution patterns of RXFP3 mRNA and these marker transcripts. In light of the functional importance of the dentate gyrus (DG) hilus in learning and memory, and our anatomical data, we examined the possible influence of RLN3/RXFP3 signaling in this region on spatial memory. Using viral-based Cre/LoxP recombination methods and adult mice with a floxed Rxfp3 gene, we deleted Rxfp3 from DG hilar neurons and assessed spatial memory performance and affective behaviors. Following infusions of an AAV(1/2) -Cre-IRES eGFP vector, Cre expression was observed in DG hilar neurons, including SST positive cells, and in situ hybridization histochemistry for RXFP3 mRNA confirmed receptor depletion relative to levels in floxed-RXFP3 mice infused with an AAV(1/2) -eGFP (control) vector. RXFP3 depletion within the DG hilus impaired spatial reference memory in an appetitive T-maze task reflected by a reduced percentage of correct choices and increased time to meet criteria, relative to control. In a continuous spontaneous alternation Y-maze task, RXFP3-depleted mice made fewer alternations in the first minute, suggesting impairment of spatial working memory. However, RXFP3-depleted and control mice displayed similar locomotor activity, anxiety-like behavior in light/dark box and elevated-plus maze tests, and learning and long-term memory retention in the Morris water maze. These data indicate endogenous RLN3/RXFP3 signaling can modulate hippocampal dependent spatial reference and working memory via effects on SST interneurons, and further our knowledge of hippocampal cognitive processing. (c) 2017 Wiley Periodicals, Inc. PMID- 28100034 TI - Murine Rankl-/- Mesenchymal Stromal Cells Display an Osteogenic Differentiation Defect Improved by a RANKL-Expressing Lentiviral Vector. AB - Autosomal recessive osteopetrosis (ARO) is a severe bone disease characterized by increased bone density due to impairment in osteoclast resorptive function or differentiation. Hematopoietic stem cell transplantation is the only available treatment; however, this therapy is not effective in RANKL-dependent ARO, since in bone this gene is mainly expressed by cells of mesenchymal origin. Of note, whether lack of RANKL production might cause a defect also in the bone marrow (BM) stromal compartment, possibly contributing to the pathology, is unknown. To verify this possibility, we generated and characterized BM mesenchymal stromal cell (BM-MSC) lines from wild type and Rankl-/- mice, and found that Rankl-/- BM MSCs displayed reduced clonogenicity and osteogenic capacity. The differentiation defect was significantly improved by lentiviral transduction of Rankl-/- BM-MSCs with a vector stably expressing human soluble RANKL (hsRANKL). Expression of Rankl receptor, Rank, on the cytoplasmic membrane of BM-MSCs pointed to the existence of an autocrine loop possibly activated by the secreted cytokine. Based on the close resemblance of RANKL-defective osteopetrosis in humans and mice, we expect that our results are also relevant for RANKL-dependent ARO patients. Data obtained in vitro after transduction with a lentiviral vector expressing hsRANKL would suggest that restoration of RANKL production might not only rescue the defective osteoclastogenesis of this ARO form, but also improve a less obvious defect in the osteoblast lineage, thus possibly achieving higher benefit for the patients, when the approach is translated to clinics. Stem Cells 2017;35:1365 1377. PMID- 28100035 TI - Stromal Cells Act as Guardians for Endothelial Progenitors by Reducing Their Immunogenicity After Co-Transplantation. AB - Regeneration of injured tissues requires effective therapeutic strategies supporting vasculogenesis. The lack of instantly available autologous cell sources and immunogenicity of allogeneic endothelial (progenitor) cells limits clinical progress. Based on the immunosuppressive potency of mesenchymal stem/progenitor cells (MSCs), we investigated whether crosstalk between endothelial colony-forming progenitor cells (ECFCs) and MSCs during vasculogenesis could lower allogeneic T cell responses against ECFCs allowing long-term engraftment in vivo. Immunodeficient mice received subcutaneous grafts containing human ECFCs alone, or pairs of human ECFCs/MSCs from the same umbilical cord (UC) to study vasculogenesis in the presence of human leukocyte antigen (HLA)-mismatched human peripheral blood mononuclear cells (PBMCs). In vitro, cell surface marker changes due to interferon gamma (IFNgamma) stimulation during ECFC/MSC coculture were determined and further effects on allostimulated T cell proliferation and cytotoxic lysis were measured. IFNgamma-induced HLA-DR expression on ECFCs and MSCs, but both cell types had significantly less HLA-DR in cocultures. ECFC-induced T cell proliferation was abolished after MSC coculture as a result of HLA-DR downregulation and indolamin-2,3-dioxygenase activation. Additionally, allospecific CD8+ T cell-mediated lysis of ECFCs was reduced in cocultures. ECFC/MSC coapplication in immunodeficient mice not only promoted the generation of improved blood vessel architecture after 6 weeks, but also reduced intragraft immune cell infiltration and endothelial HLA-DR expression following PBMC reconstitution. Crosstalk between UC-derived ECFCs and MSCs after combined transplantation can lower the risk of ECFC rejection, thus enabling their coapplication for therapeutic vasculogenesis. Stem Cells 2017;35:1233-1245. PMID- 28100036 TI - HPV type 45-positive condyloma acuminata of the bladder in a renal transplant recipient. AB - Condyloma acuminata (CA) are warty lesions caused by human papilloma virus (HPV) that generally affect the external genitalia and mucocutaneous junctions. Involvement of the urinary tract is rare, and involvement of the urinary bladder is thought to be due to immunosuppression. A 30-year-old woman was diagnosed with urethral CA 12 months after renal transplantation. She underwent transurethral resection (TUR) of the urethral lesions. During the operation, multiple sessile warty lesions were found incidentally inside the bladder and were also removed by TUR. The patient's postoperative course was uneventful. Pathological examination confirmed that the lesions were CA. Multiplex real-time polymerase chain reaction was performed to confirm the HPV genotype and revealed type 45 HPV DNA. CA of the urethra are uncommon, and bladder involvement is extremely rare. This case is the first reported, to our knowledge, to involve HPV type 45 in bladder condyloma. TUR may be the preferred option for the management of CA in the urinary bladder. PMID- 28100037 TI - Donor-derived infections in solid organ transplant recipients: Challenging the 30 day paradigm. PMID- 28100039 TI - Low Dose Radiation Causes Skin Cancer in Mice and Has a Differential Effect on Distinct Epidermal Stem Cells. AB - The carcinogenic effect of ionizing radiation has been evaluated based on limited populations accidently exposed to high dose radiation. In contrast, insufficient data are available on the effect of low dose radiation (LDR), such as radiation deriving from medical investigations and interventions, as well as occupational exposure that concern a large fraction of western populations. Using mouse skin epidermis as a model, we showed that LDR results in DNA damage in sebaceous gland (SG) and bulge epidermal stem cells (SCs). While the first commit apoptosis upon low dose irradiation, the latter survive. Bulge SC survival coincides with higher HIF-1alpha expression and a metabolic switch upon LDR. Knocking down HIF-1alpha sensitizes bulge SCs to LDR-induced apoptosis, while upregulation of HIF-1alpha in the epidermis, including SG SCs, rescues cell death. Most importantly, we show that LDR results in cancer formation with full penetrance in the radiation sensitive Patched1 heterozygous mice. Overall, our results demonstrate for the first time that LDR can be a potent carcinogen in individuals predisposed to cancer. Stem Cells 2017;35:1355-1364. PMID- 28100038 TI - TRIM8 regulates stemness in glioblastoma through PIAS3-STAT3. AB - Glioblastoma (GBM) is the most malignant form of primary brain tumor, and GBM stem-like cells (GSCs) contribute to the rapid growth, therapeutic resistance, and clinical recurrence of these fatal tumors. STAT3 signaling supports the maintenance and proliferation of GSCs, yet regulatory mechanisms are not completely understood. Here, we report that tri-partite motif-containing protein 8 (TRIM8) activates STAT3 signaling to maintain stemness and self-renewing capabilities of GSCs. TRIM8 (also known as 'glioblastoma-expressed ring finger protein') is expressed equally in GBM and normal brain tissues, despite its hemizygous deletion in the large majority of GBMs, and its expression is highly correlated with stem cell markers. Experimental knockdown of TRIM8 reduced GSC self-renewal and expression of SOX2, NESTIN, and p-STAT3, and promoted glial differentiation. Overexpression of TRIM8 led to higher expression of p-STAT3, c MYC, SOX2, NESTIN, and CD133, and enhanced GSC self-renewal. We found that TRIM8 activates STAT3 by suppressing the expression of PIAS3, an inhibitor of STAT3, most likely through E3-mediated ubiquitination and proteasomal degradation. Interestingly, we also found that STAT3 activation upregulates TRIM8, providing a mechanism for normalized TRIM8 expression in the setting of hemizygous gene deletion. These data demonstrate that bidirectional TRIM8-STAT3 signaling regulates stemness in GSC. PMID- 28100041 TI - Contrasting growth forecasts across the geographical range of Scots pine due to altitudinal and latitudinal differences in climatic sensitivity. AB - Ongoing changes in global climate are altering ecological conditions for many species. The consequences of such changes are typically most evident at the edge of a species' geographical distribution, where differences in growth or population dynamics may result in range expansions or contractions. Understanding population responses to different climatic drivers along wide latitudinal and altitudinal gradients is necessary in order to gain a better understanding of plant responses to ongoing increases in global temperature and drought severity. We selected Scots pine (Pinus sylvestris L.) as a model species to explore growth responses to climatic variability (seasonal temperature and precipitation) over the last century through dendrochronological methods. We developed linear models based on age, climate and previous growth to forecast growth trends up to year 2100 using climatic predictions. Populations were located at the treeline across a latitudinal gradient covering the northern, central and southernmost populations and across an altitudinal gradient at the southern edge of the distribution (treeline, medium and lower elevations). Radial growth was maximal at medium altitude and treeline of the southernmost populations. Temperature was the main factor controlling growth variability along the gradients, although the timing and strength of climatic variables affecting growth shifted with latitude and altitude. Predictive models forecast a general increase in Scots pine growth at treeline across the latitudinal distribution, with southern populations increasing growth up to year 2050, when it stabilizes. The highest responsiveness appeared at central latitude, and moderate growth increase is projected at the northern limit. Contrastingly, the model forecasted growth declines at lowland southern populations, suggesting an upslope range displacement over the coming decades. Our results give insight into the geographical responses of tree species to climate change and demonstrate the importance of incorporating biogeographical variability into predictive models for an accurate prediction of species dynamics as climate changes. PMID- 28100042 TI - Diagnostic open brain biopsy following initial negative results of cerebrospinal fluid assessment for Toxoplasma. PMID- 28100043 TI - Communication skills training in other languages. PMID- 28100040 TI - Concise Review: Induced Pluripotent Stem Cell Research in the Era of Precision Medicine. AB - Recent advances in DNA sequencing technologies are revealing how human genetic variations associate with differential health risks, disease susceptibilities, and drug responses. Such information is now expected to help evaluate individual health risks, design personalized health plans and treat patients with precision. It is still challenging, however, to understand how such genetic variations cause the phenotypic alterations in pathobiologies and treatment response. Human induced pluripotent stem cell (iPSC) technologies are emerging as a promising strategy to fill the knowledge gaps between genetic association studies and underlying molecular mechanisms. Breakthroughs in genome editing technologies and continuous improvement in iPSC differentiation techniques are particularly making this research direction more realistic and practical. Pioneering studies have shown that iPSCs derived from a variety of monogenic diseases can faithfully recapitulate disease phenotypes in vitro when differentiated into disease relevant cell types. It has been shown possible to partially recapitulate disease phenotypes, even with late onset and polygenic diseases. More recently, iPSCs have been shown to validate effects of disease and treatment-related single nucleotide polymorphisms identified through genome wide association analysis. In this review, we will discuss how iPSC research will further contribute to human health in the coming era of precision medicine. Stem Cells 2017;35:545-550. PMID- 28100044 TI - Conceptions of teaching: an illustrated review. AB - BACKGROUND: Asking teachers what the term 'teaching' means to them can be a useful first activity in a faculty development session, as it typically leads to an engaging and enlightening discussion for participants and facilitators. Mapping their responses to 'conceptions of teaching' (sets of assumptions, knowledge and beliefs about teaching) in the literature seems particularly helpful in illuminating the inconsistencies, gaps and additional ways of thinking about teaching that participants may wish to consider. LITERATURE REVIEW: At least 25 conceptions of teaching can be identified in the literature. Each of these are briefly described and illustrated in this article, along with detailed examples and suggestions of how conceptions of teaching can be explored in faculty development. There is evidence that a teacher's conceptions of teaching affect the way that they approach their teaching, which in turn can affect learner learning. There is also some evidence that helping teachers examine and develop their conceptions of teaching may be more effective and have more impact on learner learning than other forms of faculty development. TAKE-HOME MESSAGES: Different conceptions of teaching seem to be more or less appropriate in different teaching situations and contexts. It is likely that the more ways in which teachers can conceptualise and reflect on what they are doing, and why, the more adaptable, responsive and effective their teaching will be. Teachers have much to gain from learning more about themselves, their values and assumptions, and how these can influence their practice. This article offers a practical approach aimed at helping them to achieve this. A teacher's conceptions of teaching affect the way that they approach their teaching. PMID- 28100046 TI - Using drawing in clinical teaching. PMID- 28100045 TI - iPads in clinical rotations: a student perspective. PMID- 28100047 TI - Being centred in education and health care. PMID- 28100048 TI - Unanticipated Stickiness of alpha-Pinene. AB - The adsorption of alpha-pinene to solid surfaces is an important primary step during the chemical conversion of this common terpene over mesoporous materials, as well as during the formation of atmospheric aerosols. We provide evidence of tight and loose physisorbed states of alpha-pinene bound on amorphous SiO2 as determined by their adsorption entropy, enthalpy, and binding free energies characterized by computational modeling and vibrational sum frequency generation (SFG) spectroscopy. We find that adsorption is partially (40-60%) irreversible over days at 294-342 K and 1 ATM total pressure of helium, which is supported by molecular dynamics (MD) simulations. The distribution of alpha-pinene orientation remains invariant with temperature and partial pressure of alpha-pinene. Using the Redlich-Peterson adsorption model in conjunction with a van't Hoff analysis of adsorption isotherms recorded for up to 2.6 Torr alpha-pinene in 1 ATM total pressure of helium, we obtain DeltaS degrees ads, DeltaH degrees ads, and DeltaG degrees ads values of -57 (+/-7) J mol-1 K-1, -39 (+/-2) kJ mol-1, and -22 (+/-5) kJ mol-1, respectively, associated with the reversibly bound population of alpha pinene. These values are in good agreement with density functional theory (DFT) corrected force field calculations based on configurational sampling from MD simulations. Our findings are expected to have direct implications on the conversion of terpenes by silica-based catalysts and for the synthesis of secondary organic aerosol (SOA) in atmospheric chambers and flow tubes. PMID- 28100049 TI - Cell-Free Translation Is More Variable than Transcription. AB - Although RNA synthesis can be reliably controlled with different T7 transcriptional promoters during cell-free gene expression with the PURE system, protein synthesis remains largely unaffected. To better control protein levels, we investigated a series of ribosome binding sites (RBSs). Although RBS strength did strongly affect protein synthesis, the RBS sequence could explain less than half of the variability of the data. Protein expression was found to depend on other factors besides the strength of the RBS, including the GC content of the coding sequence. The complexity of protein synthesis in comparison to RNA synthesis was observed by the higher degree of variability associated with protein expression. This variability was also observed in an E. coli cell extract based system. However, the coefficient of variation was larger with E. coli RNA polymerase than with T7 RNA polymerase, consistent with the increased complexity of E. coli RNA polymerase. PMID- 28100050 TI - Charge Carrier Hopping Dynamics in Homogeneously Broadened PbS Quantum Dot Solids. AB - Energetic disorder in quantum dot solids adversely impacts charge carrier transport in quantum dot solar cells and electronic devices. Here, we use ultrafast transient absorption spectroscopy to show that homogeneously broadened PbS quantum dot arrays (sigmahom2:sigmainh2 > 19:1, sigmainh/kBT < 0.4) can be realized if quantum dot batches are sufficiently monodisperse (delta ? 3.3%). The homogeneous line width is found to be an inverse function of quantum dot size, monotonically increasing from ~25 meV for the largest quantum dots (5.8 nm diameter/0.92 eV energy) to ~55 meV for the smallest (4.1 nm/1.3 eV energy). Furthermore, we show that intrinsic charge carrier hopping rates are faster for smaller quantum dots. This finding is the opposite of the mobility trend commonly observed in device measurements but is consistent with theoretical predictions. Fitting our data to a kinetic Monte Carlo model, we extract charge carrier hopping times ranging from 80 ps for the smallest quantum dots to over 1 ns for the largest, with the same ethanethiol ligand treatment. Additionally, we make the surprising observation that, in slightly polydisperse (delta ? 4%) quantum dot solids, structural disorder has a greater impact than energetic disorder in inhibiting charge carrier transport. These findings emphasize how small improvements in batch size dispersity can have a dramatic impact on intrinsic charge carrier hopping behavior and will stimulate further improvements in quantum dot device performance. PMID- 28100051 TI - Basement Membrane Mimics of Biofunctionalized Nanofibers for a Bipolar-Cultured Human Primary Alveolar-Capillary Barrier Model. AB - In vitro reconstruction of an alveolar barrier for modeling normal lung functions and pathological events serve as reproducible, high-throughput pharmaceutical platforms for drug discovery, diagnosis, and regenerative medicine. Despite much effort, the reconstruction of organ-level alveolar barrier functions has failed due to the lack of structural similarity to the natural basement membrane, functionalization with specific ligands for alveolar cell function, the use of primary cells and biodegradability. Here we report a bipolar cultured alveolar capillary barrier model of human primary cells supported by a basement membrane mimics of fully synthetic bifunctional nanofibers. One-step electrospinning process using a bioresorbable polyester and multifunctional star-shaped polyethylene glycols (sPEG) enables the fabrication of an ultrathin nanofiber mesh with interconnected pores. The nanofiber mesh possessed mechanical stability against cyclic expansion as seen in the lung in vivo. The sPEGs as an additive provide biofunctionality to fibers through the conjugation of peptide to the nanofibers and hydrophilization to prevent unspecific protein adsorption. Biofunctionalized nanofiber meshes facilitated bipolar cultivation of endothelial and epithelial cells with fundamental alveolar functionality and showed higher permeability for molecules compared to microporous films. This nanofiber mesh for a bipolar cultured barrier have the potential to promote growth of an organ-level barrier model for modeling pathological conditions and evaluating drug efficacy, environmental pollutants, and nanotoxicology. PMID- 28100052 TI - Spotlights: Volume 8, Issue 2. PMID- 28100053 TI - The Grateful Infrared: Sequential Protein Structural Changes Resolved by Infrared Difference Spectroscopy. AB - The catalytic activity of proteins is a function of structural changes. Very often these are as minute as protonation changes, hydrogen bonding changes, and amino acid side chain reorientations. To resolve these, a methodology is afforded that not only provides the molecular sensitivity but allows for tracing the sequence of these hierarchical reactions at the same time. This feature article showcases results from time-resolved IR spectroscopy on channelrhodopsin (ChR), light-oxygen-voltage (LOV) domain protein, and cryptochrome (CRY). All three proteins are activated by blue light, but their biological role is drastically different. Channelrhodopsin is a transmembrane retinylidene protein which represents the first light-activated ion channel of its kind and which is involved in primitive vision (phototaxis) of algae. LOV and CRY are flavin binding proteins acting as photoreceptors in a variety of signal transduction mechanisms in all kingdoms of life. Beyond their biological relevance, these proteins are employed in exciting optogenetic applications. We show here how IR difference absorption resolves crucial structural changes of the protein after photonic activation of the chromophore. Time-resolved techniques are introduced that cover the time range from nanoseconds to minutes along with some technical considerations. Finally, we provide an outlook toward novel experimental approaches that are currently developed in our laboratories or are just in our minds ("Gedankenexperimente"). We believe that some of them have the potential to provide new science. PMID- 28100054 TI - Efficacy of silver/hydrophilic poly(p-xylylene) on preventing bacterial growth and biofilm formation in urinary catheters. AB - Catheter associated urinary tract infections (CAUTI), caused by several strains of bacteria, are a common complication for catheterized patients. This may eventually lead to a blockage of the catheter due to the formation of a crystalline or amorphous biofilm. Inhibiting bacteria should result in a longer application time free of complaints. This issue has been investigated using an innovative type of silver-coated catheter with a semipermeable cap layer to prevent CAUTI. In this work, two different types of silver catheters were investigated, both of which were capped with poly(p-xylylene) (PPX-N) and exhibited different surface properties that completely changed their wetting conduct with water. The contact angle of conventionally deposited PPX-N is approximately 80 degrees . After O2 plasma treatment, the contact angle drops to approximately 30 degrees . These two systems, Ag/PPX-N and Ag/PPX-N-O2, were tested in synthetic urine at a body temperature of 37 degrees C. First, the optical density and the inhibition zones of both bacteria strains (Escherichia coli and Staphylococcus cohnii) were examined to confirm the antibacterial effect of these silver-coated catheters. Afterward, the efficacy of silver catheters with different treatments of biofilm formed by E. coli and S. cohnii were tested with crystal violet staining assays. To estimate the life cycles of silver/PPX catheters, the eluted amount of silver was assessed at several time intervals by anodic stripping voltammetry. The silver catheter with hydrophilic PPX-N coating limited bacterial growth in synthetic urine and prevented biofilm formation. The authors attribute the enhanced bacteriostatic effect to increased silver ion release detected under these conditions. With this extensive preparatory analytic work, the authors studied the ability of the two different cap layers (without silver), PPX-N and oxygen plasma treated PPX-N, to control the growth of a crystalline biofilm by measuring the concentrations of the Ca2+ and Mg2+ ions after exposure of the catheters to saturated urine for 24 h. The higher concentrations of Ca2+ and Mg2+ in the precipitates on the PPX-N catheters indicates that the hydrophilic PPX-N coating is superior to the simple PPX-N coating, with regard to the formation of a crystalline biofilm. Moreover, hydrophilic PPX-N as a cap layer may promote wettability and increase silver ion release rate and thus reduce the adhesion of suspended crystals to the catheter. Reduced bacterial growth and reduced adhesion may help to prevent CAUTI. PMID- 28100055 TI - Superior mesenteric artery syndrome: an uncommon cause of intestinal obstruction. AB - Superior mesenteric artery syndrome, also Wilkie's syndrome, is an uncommon cause of upper intestinal obstruction. It includes compression of the third duodenal portion by the aorta and the overlying superior mesenteric artery when the angle formed by these two structures becomes smaller. It may result from significant weight loss or abdominal trauma, or may have a congenital origin. Treatment for most cases is conservative. PMID- 28100056 TI - Pneumatosis cystoides intestinalis. AB - A 54-year-old woman underwent colonoscopy for colon cancer screening. Colonoscopy showed multiple cysts in the sigmoid colon, with the largest being 4 cm in diameter. One of the cysts was biopsied. Cyst walls were observed; during biopsy, the gas was released and the cyst collapsed. Computed tomography of the abdomen confirmed a diagnosis of pneumatosis cystoides intestinalis. Pneumatosis cystoides intestinalis is a rare disease characterized by the presence in the intestinal submucosa or subserosa of multiple cysts filled with gas (nitrogen, oxygen, carbon dioxide and hydrogen). This condition occurs more often in males than in females, with cysts most frequently located in the colon. Causes may include elevated intraluminal pressure, pulmonary diseases, bacterial gas production, malnutrition, chemotherapy, connective tissue diseases, among others. Symptoms of pneumatosis cystoides intestinalis include abdominal pain, diarrhea, bloating and gastrointestinal bleeding. This condition is diagnosed by endoscopy or computed tomography of the abdomen. Conservative treatment is successful in 93% of patients. However, 3% of patients develop complications such as intestinal obstruction or perforation. PMID- 28100058 TI - Endoscopic retrieval of toothbrushes in a schizophrenic patient. AB - Foreign bodies are a common problem in the daily endoscopic practice. Nevertheless, long objects as toothbrushes, sometimes pose a special problem when trying to remove them from the stomach, due to the difficulty of passing through the hiatus. Endoscopic retrieval of toothbrushes has seldom be reported. PMID- 28100057 TI - Wilkie's syndrome. AB - We report the case of a 14 year-old woman, who presents epigastric abdominal pain, abundant vomits and an important abdominal distension. Previously, she presented similar episodes. She has not any significant prior medical history. CT is performed and the imaging findings are consistent with Wilkie's syndrome. Wilkie's syndrome is a rare condition, that results from a intestinal obstruction caused by third portion duodenal compression between the abdominal aorta and the superior mesenteric artery. When the angle between both structures diminishes and the distance between the SMA and the aorta decreases (the most diagnostic value), duodenal obstruction occurs. Initially conservative management is adopted, but in some cases surgical treatment is necessary. Multislice CT has demonstrated an excellent diagnostic value when this entity is suspected. It provides multiplanar reconstructions, which are useful to measure the distance and the aortomesenteric angle and to rule out other possible etiologies. PMID- 28100059 TI - All that glitters is not gold. A different cause for an "ulcerative colitis". AB - The authors present the case of a 32-year-old Caucasian male, engineer, who was submitted to a colonoscopy after a presumptive diagnosis of ulcerative colitis. The patient referred an acute bloody and mucous diarrhea, lasting for three weeks, with no fever or rectal tenesmus. Stool studies were negative. During the procedure, colonic segments with continuous hyperemic and exudative mucosa, with small papules with apical ulcers and erosions, were observed. PMID- 28100060 TI - Boerhaave's syndrome: diagnostic gastroscopy. AB - A 47-year-old man was attended at the emergency room for severe chest pain after eating sausage with subsequent vomiting and mild upper gastrointestinal bleeding. In the chest radiography we could not see abnormalities. He referred previous episodes of choking without consulting. The urgent gastroscopy detected tertiary contractile activity (nutcracker esophagus) and a foreign body in the lower third of the esophagus. After removing the food bolus, we observed a 4 cm longitudinal tear compatible with esophageal rupture or Boerhaave's syndrome in the right posterior wall of the lower esophagus, proximal to the gastroesophageal junction. Thoracic-abdominal computed tomography (TC) confirmed a perforation of the lower esophagus, with pneumothorax and cervical and chest emphysema. Surgical treatment was indicated: esophageal suture, myotomy and gastric fundoplication. The patient presented good evolution. Boerhaave's syndrome is a rare syndrome, but with high mortality (35%). Mackler triad is very characteristic: vomiting, retrosternal pain and cervical subcutaneous emphysema; but it occurs rarely. Chest radiography is useful, showing abnormalities in up to 90% of patients. The differential diagnosis includes cardiorespiratory disorders: acute myocardial infarction, spontaneous pneumothorax, pericarditis or pneumonia. The role of endoscopy is small, mainly limited to prosthesis placement in high-risk surgical patients. In our case the chest radiograph was initially normal, probably related to bolus impaction and, in presence of upper gastrointestinal bleeding, gastroscopy was performed which allowed us to early diagnosis and treatment. PMID- 28100062 TI - Prevalence and correlates of psychological distress of middle-aged and older women living with HIV. AB - The aims of this study were to examine the prevalence and correlates of psychological distress among older women living with HIV in comparison to their male counterparts and younger women and to identify the sociodemographic and disease-related factors associated with psychological distress. The sample consisted of 508 HIV-infected patients (65 older women, 323 women aged below 50 years, and 120 older men) recruited from 10 Portuguese hospitals. Data regarding psychological distress were collected using the Brief Symptom Inventory (BSI). Seven older women (10.8%), eight older men (6.7%), and 61 younger women (18.9%) reported a T-score >= 63 for global severity index (GSI), indicative of a need for further psychological evaluation. Overall, younger women reported significantly higher psychological distress than older men. The odds of having clinically significant psychological distress score were significantly lower for older women reporting sexual transmission, while for younger women, having other co-infections was a significant correlate of higher psychological distress. Younger women were 2.67 (95% CI: 1.22-5.84) times more likely to report psychological distress than were older men. The odds were not significantly different from older women. This study shows that older women do not differ substantially from younger women and older men in terms of psychological distress. The results reinforce, however, that mental health interventions should be tailored to reflect individuals' circumstances as well as developmental contexts. Moreover, they draw attention to the importance of examining resilience characteristics in older adults to understand the mechanisms behind 'successful ageing' while living with HIV. PMID- 28100063 TI - Evaluation of a Potential Interaction Between New Regimens to Treat Hepatitis C and Warfarin: Twelve-Week Post-treatment Follow-up. PMID- 28100061 TI - Outpatient Palliative Care and Aggressiveness of End-of-Life Care in Patients with Metastatic Colorectal Cancer. AB - BACKGROUND: Palliative care in outpatient setting has been shown to promote better symptom management and transition to hospice care among patients with advanced cancer. Nevertheless, specialized palliative care is rarely provided at cancer centers in Korea. Herein, we aimed to assess aggressiveness of end-of-life care for patients with metastatic colorectal cancer according to the use of outpatient palliative care (OPC) at a single cancer center in Korea. METHODS: We performed a retrospective medical record review for 132 patients with metastatic colorectal cancer who died between 2011 and 2014. Fifty patients used OPC (OPC group), while 82 patients did not (non-OPC group). Indicators of aggressiveness of end-of-life care including chemotherapy use, emergency department visits, hospitalization, and utilization of hospice care were analyzed according to the use of OPC. RESULTS: More patients in the OPC group were admitted to hospice than those in the non-OPC group (32% vs 17%, P = .047). The mean of inpatient days within 30 days of death was shorter for the OPC group than the non-OPC group (4.02 days vs 7.77 days, respectively, P = .032). There were no differences in the proportions of patients who received chemotherapy and visited the emergency department within 30 days from death. CONCLUSION: Among patients with metastatic colorectal cancer, OPC was associated with shorter inpatient days near death and greater hospice utilization. Further prospective studies are needed to evaluate the impact of OPC on end-of-life care in Korea. PMID- 28100064 TI - A risk stratifying tool to facilitate safe late-stage percutaneous endoscopic gastrostomy in ALS. AB - BACKGROUND: The safety of percutaneous endoscopic gastrostomy (PEG) insertion in amyotrophic lateral sclerosis (ALS) patients with significant respiratory compromise has been questioned. OBJECTIVES: To review the characteristics of an ALS clinic patient cohort undergoing PEG, and the introduction of a risk stratification tool with procedural adaptations for higher-risk individuals. METHODS: Patients undergoing PEG insertion were analysed (n = 107). Cases stratified as higher-risk underwent insertion in a semi-recumbent position, minimising sedation, with the option of nasal non-invasive ventilation. RESULTS: All underwent successful PEG. One-third had pre-procedure FVC <=50% (mean, 64 +/- 22%). Of those who underwent PEG insertion after introduction of risk stratification (n = 58), 39 (67%) met criteria for being higher risk, 16 (41%) of whom had FVC <=50% (p = 0.005). High-risk patients received lower sedative doses vs. the low-risk group (midazolam 2.1 +/- 1.1 vs.2.8 +/- 0.95mg, p = 0.021; fentanyl 42 +/- 16 vs. 60 +/- 21MUg, p = 0.015). Four deaths occurred within one month of insertion (attributable to the natural disease course). CONCLUSIONS: Risk stratification identified a greater number of patients with evidence of respiratory compromise than using the sole criterion of FVC <=50%. A modified PEG procedure enabled safe insertion despite respiratory compromise, in those who might not have tolerated attempted insertion by alternative means such as radiologically-inserted gastrostomy. PMID- 28100065 TI - Evaluation of sulphur amino acid requirement of male Korean native ducklings from hatch to 21 day of age. AB - 1. A dose-response experiment was conducted with male Korean native ducklings (KND) to evaluate the total sulphur amino acid (TSAA) requirement from hatch to 21 d of age. 2. A completely randomised design with 7 dietary TSAA concentrations (0.62%, 0.65%, 0.68%, 0.71%, 0.74%, 0.77% and 0.80%) were used with 6 replications per treatment. 3. Body weight (BW) and feed intake were measured weekly to calculate average daily gain (ADG), average daily feed intake (ADFI) and feed conversion ratio (FCR). One duckling per pen (n = 6) was killed by cervical dislocation to weigh empty body and drumsticks at the conclusion of experiment. 4. BW was improved significantly with increasing TSAA content, in a non-linear manner. A significant decrease of FCR was shown with increasing TSAA contents. TSAA requirement was determined by taking a mean value after fitting the data to both a linear-plateau and a quadratic-plateau model. Estimated TSAA requirements were 0.70%, 0.70%, 0.66% and 0.70% for the maximum BW, ADG and ADFI and for the minimum FCR, respectively. Increasing TSAA content improved quantity of full body weight (FBW), empty body weight (EBW) and drumstick weight (DSW), but there was no effect on proportion of DSW in relation to EBW and proportion of EBW to FBW. 5. In conclusion, the growth of male KND during 1 to 21 d of age was improved with increasing TSAA content, suggesting optimal TSAA requirements estimated by two analysis models. PMID- 28100066 TI - Identification of eggs from different production systems based on hyperspectra and CS-SVM. AB - 1. To identify the origin of table eggs more accurately, a method based on hyperspectral imaging technology was studied. 2. The hyperspectral data of 200 samples of intensive and extensive eggs were collected. Standard normalised variables combined with a Savitzky-Golay were used to eliminate noise, then stepwise regression (SWR) was used for feature selection. Grid search algorithm (GS), genetic search algorithm (GA), particle swarm optimisation algorithm (PSO) and cuckoo search algorithm (CS) were applied by support vector machine (SVM) methods to establish an SVM identification model with the optimal parameters. The full spectrum data and the data after feature selection were the input of the model, while egg category was the output. 3. The SWR-CS-SVM model performed better than the other models, including SWR-GS-SVM, SWR-GA-SVM, SWR-PSO-SVM and others based on full spectral data. The training and test classification accuracy of the SWR-CS-SVM model were respectively 99.3% and 96%. 4. SWR-CS-SVM proved effective for identifying egg varieties and could also be useful for the non destructive identification of other types of egg. PMID- 28100067 TI - Race-based experiences of ethnic minority health professionals: Arab physicians and nurses in Israeli public healthcare organizations. AB - : Increasing workforce diversity was found to contribute to the narrowing of disparities in health. However, racism toward ethnic minority health professionals has not been adequately researched. In Israel, public healthcare organizations that serve a mixed Jewish-Arab population employ Arab minority healthcare professionals. Instances of prejudice and manifestations of racism toward them, which frequently surface in public discussion and the media, have unfortunately gained little scholarly attention. We used the intergroup contact approach and the theory of the social process of everyday racism as a theoretical framework. The objective of the research was to study race-based experiences of Israeli Arab healthcare professionals. METHODOLOGY: We used a qualitative research method that allows respondents to describe their views, experiences, beliefs and behavior in the way they think about them. During 2013 and 2014 we conducted in-depth interviews with a snowball sample of 10 Arab physicians and 13 Arab nurses who work in Israeli public hospitals. The study protocol was ethically approved. FINDINGS: Interviewees noted institutional efforts to maintain egalitarianism and equality. However, at the micro-level, interviewees, mostly nurses, reported instances that ranged from refusal to accept treatment from an Arab nurse, through verbal abuse, to the use of physical violence against them. At the meso-level, interviewees, mostly physicians, reported experiences of institutional discrimination. At the macro-level, one physician reported policy related discrimination in the context of the immigration of Russian Jewish physicians to Israel. CONCLUSIONS: We recommend combining the intergroup contact approach with the social process theory of racism to examine minorities' subjective perceptions, especially in conflictual and violent contexts; conducting broad-based quantitative research in Israeli healthcare organizations, which may have important implications for the specific strategies to be used; and emphasizing the importance of institutional support. By reconstructing race-based experiences of ethnic minority health professionals, health organizations can better manage racial situations and reduce their frequency. PMID- 28100068 TI - Prevalence, patterns, and correlates of HIV disclosure among TB-HIV patients initiating antiretroviral therapy in Lesotho. AB - Disclosure of HIV-positive status has important implications for patient outcomes and preventing HIV transmission, but has been understudied in TB-HIV patients. We assessed disclosure patterns and correlates of non-disclosure among adult TB-HIV patients initiating ART enrolled in the START Study, a mixed-methods cluster randomized trial conducted in Lesotho, which evaluated a combination intervention package (CIP) versus standard of care. Interviewer-administered questionnaire data were analyzed to describe patterns of disclosure. Patient-related factors were assessed for association with non-disclosure to anyone other than a health care provider and primary partners using generalized linear mixed models. Among 371 participants, 95% had disclosed their HIV diagnosis to someone other than a health-care provider, most commonly a spouse/primary partner (76%). Age, TB knowledge, not planning to disclose TB status, greater perceived TB stigma, and CIP were associated with non-disclosure in unadjusted models (p < .1). In adjusted models, all point estimates were similar and greater TB knowledge (adjusted odds ratio [aOR] 0.59, 95% confidence interval [CI] 0.39-0.90) and CIP (aOR 0.20, 95% CI 0.05-0.79) remained statistically significant. Among 220 participants with a primary partner, 76% had disclosed to that partner. Significant correlates of partner non-disclosure (p < .1) in unadjusted analyses included being female, married/cohabitating, electricity at home, not knowing if partner was HIV-positive, and TB knowledge. Adjusted point estimates were largely similar, and being married/cohabitating (aOR 0.03, 95% CI 0.01-0.12), having electricity at home (aOR 0.38, 95% CI 0.17-0.85) and greater TB knowledge (aOR 0.76, 95% CI 0.59-0.98) remained significant. In conclusion, although nearly all participants reported disclosing their HIV status to someone other than a health care provider at ART initiation, nearly a quarter of participants with a primary partner had not disclosed to their partner. Additional efforts to support HIV disclosure (e.g., counseling) may be needed for TB-HIV patients, particularly for women and those unaware of their partners' status. PMID- 28100069 TI - The effect of N-acetylcysteine supplementation on serum homocysteine levels and hepatic and renal oxidative stress in homocysteine thiolactone-treated rats. AB - The effect of N-acetylcysteine (NAC) (1 g/kg body weight/day) on serum homocysteine (Hcy) levels, insulin resistance (IR), and hepatic and renal prooxidant-antioxidant balance was evaluated in rats treated with homocysteine thiolactone (HcyT) (500 mg/kg body weight/day for 6 weeks). Reactive oxygen species (ROS), malondialdehyde (MDA), glutathione, ferric reducing antioxidant power, and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were determined in the liver and kidney. HcyT elevated serum Hcy levels and caused IR, but liver and kidney function tests remained unchanged. HcyT increased ROS and MDA without any change in hepatic antioxidants, but it elevated renal SOD and GSH-Px activities. NAC decreased serum Hcy, hepatic and renal ROS and MDA levels, and renal SOD and GSH-Px activities in rats with high Hcy levels. However, it did not ameliorate IR. Our results indicate that NAC supplementation may be effective in decreasing Hcy levels and Hcy-induced hepatic and renal oxidative stress. PMID- 28100070 TI - Exploring relationships among social integration, social isolation, self-rated health, and demographics among Latino day laborers. AB - OBJECTIVES: Research indicates social integration and social isolation are related to health, and Latino day laborers (LDLs) tend to be socially isolated and, thus, at high risk for adverse health consequences. relationships among social isolation, social integration, self-rated health (SRH), and demographics were examined in a sample of LDLs to contribute to the literature on social networks and health in this and other migrant populations. DESIGN: We analyzed data from 324 LDLs who participated in Proyecto SHILOS (Salud del Hombre Inmigrante Latino), a Houston-based survey of Latino immigrant men's health. Based on the literature, we hypothesized SRH would be (1) positively associated with social integration and (2) negatively associated with social isolation. All proposed measures were first entered into a correlation matrix to identify significant bivariate relationships (p <= .05, two-tailed). Associations between variables that were directly correlated with SRH and variables that were, in turn, proximally associated with these variables were then used to develop a structural equation path model of SRH. Individual paths in the model were measured for significance, and goodness of fit was assessed by the model chi square, the Comparative Fit Index, and the Root Mean Square Error of Approximation. RESULTS: Inconsistent with the first hypothesis, SRH was negatively associated with social integration, as measured by the number of trusted friends. Consistent with the second hypothesis, SRH was negatively associated with social isolation, as measured by needing someone to talk to. More frequent contact with family was also negatively associated with social isolation. DISCUSSION: Our findings suggest social integration may not always protect and promote health. Therefore, assessing the quality of LDLs' different relationships, not just the quantity, is vital. Future studies should further analyze the effects that social resources have on perceptions of social isolation and health in LDLs and other migrant populations. PMID- 28100071 TI - Neck-Tongue syndrome: A systematic review. AB - Objective Neck-Tongue syndrome (NTS) is characterized by brief attacks of neck or occipital pain, or both, brought out by abrupt head turning and accompanied by ipsilateral tongue symptoms. As the disorder is rare, we undertook a systematic review of the literature to identify all reported cases in order to phenotype clinically the disorder and subsequently inform clinical diagnostic criteria. Methods Two electronic databases were searched using the search term "neck tongue syndrome". All English language references were reviewed in full. Cases were abstracted using a standardized abstraction form and the references of the retrieved articles were reviewed by hand to identify additional references and cases. Conference proceedings from recent headache meetings were searched. We also report six new cases from our centers. Results There were 39 primary cases, 56% of which were female. Mean age (SD) at onset was 16 (12) years. Twenty (53%) experienced neck pain, seven (18%) occipital pain, and 11 (29%) both. Pain was most often sharp or stabbing and severe, lasting several seconds to several minutes. Eleven experienced numbness and/or tingling in the neck/occiput following the pain. Thirty-six had an accompanying tongue sensory disturbance and three a motor/posture disturbance; five had both. Thirteen had other headaches, and four a family history of Neck-Tongue syndrome. Conclusions Neck-Tongue syndrome typically has pediatric or adolescent onset, suggesting that ligamentous laxity during growth and development may facilitate transient subluxation of the lateral atlantoaxial joint with sudden head turning. Familial cases suggest a genetic predisposition in some individuals. Neck-Tongue syndrome should be re instated in the International Classification of Headache Disorders. PMID- 28100072 TI - Trial Vocal Fold Injection Predicts Thyroplasty Outcomes in Nonparalytic Glottic Incompetence. AB - OBJECTIVES: Trial vocal fold injection (TVFI) may be used prior to permanent medialization when voice outcome is uncertain. We aimed to determine whether voice outcomes of TVFI are predictive of, or correlate with outcomes after type I Gore-Tex medialization thyroplasty (GMT) in patients with nonparalytic glottic incompetence (GI). METHODS: Thirty-five patients with nonparalytic GI who underwent TVFI followed by GMT were retrospectively reviewed. Change in voice related quality of life (VRQOL) after TVFI was compared to change in VRQOL 3 to 9 months after GMT. Similar comparisons were made for change in glottal function index (GFI) and change in grade, roughness, breathiness, asthenia, and strain (GRBAS). Sample correlation coefficients were calculated. RESULTS: Change in VRQOL after TVFI showed good correlation with change in VRQOL after GMT, r = 0.55. Change in GFI after TVFI showed strong correlation with change in GFI after GMT, r = 0.74. Change in GRBAS after TVFI showed excellent correlation with change in GRBAS after GMT, r = 0.90. CONCLUSION: The TVFI is a useful tool in nonparalytic GI when outcomes from glottic closure procedures are not clear. Voice outcome measures after TVFI strongly correlate with outcomes from GMT. These data may be used to more confidently counsel patients regarding their predicted outcomes of permanent medialization. PMID- 28100073 TI - Depression in HIV and HCV co-infected patients: a systematic review and meta analysis. AB - The aim of this study was to carry out a systematic review and meta-analysis of the differences in the prevalence of depression and presence of depressive symptoms between HIV/HCV co-infection, HIV mono-infection, and hepatitis C virus (HCV) mono-infection. A systematic electronic search of bibliographic databases was performed to locate articles published from the earliest available online until December 2014. Outcomes of depression were based on clinical interviews and validated self-reported measures of depression/depressive symptoms. Of the 188 records initially screened, 29 articles were included in the descriptive systematic review and six were included in the meta-analysis. The meta-analytic results indicated that, as measured by self-reported measures of depression, HIV/HCV co-infected patients were significantly more likely to report depressive symptoms than either HIV (SMD = .24, 95% CI: .03-.46, p = .02) or HCV mono infected (SMD = .55, 95% CI: .17-.94, p = .005) patients. The variability of the results of the reviewed studies, largely dependent on the samples' characteristics and the methods of assessment of depression, suggests that a clear interpretation of how depression outcomes are affected by the presence of HIV/HCV co-infection is still needed. Failing to diagnose depression or to early screen depressive symptoms may have a significant impact on patients' overall functioning and compromise treatments' outcomes. PMID- 28100074 TI - Antioxidant capacity and identification of the constituents of ethyl acetate fraction from Rhus verniciflua Stokes by HPLC-MS. AB - Ethyl acetate fraction (EAF) from Rhus verniciflua Stokes is an important source of bioactive compounds. The aim of this study was the tentative identification and quantification of phenolic compounds, comparison of the phenolic structure antioxidant activity relationships. Twelve compounds of EAF belonging to polyphenol types were detected by high performance liquid chromatography and analysed on line with negative ion electrospray ionisation tandem mass spectrometry, which were ethoxy 3-hydroxy benzoic acid, gallic acid (GA), 3,4 dihydroxy amygdalic acid, gallic acid cetyl ester, protocatechuic acid (PA), fustin, ethyl gallate (EG), garbanzol, fisetin, sulfuretin, butin and 3,7 dihydroxyflavanone-4'-rhamnoside. The antioxidant activity were evaluated based on the different types of radical scavenging capacities, i.e. DPPH., ABTS.+ and OH. The antioxidant capacity of EAF mainly depended on the GA, EG, PA, fisetin, sulfuretin and butin. The phenolics exhibited a dose-dependent behaviour and high antioxidant ability. PMID- 28100076 TI - Precuneus Structure Changes in Amnestic Mild Cognitive Impairment. AB - Patients with amnestic mild cognitive impairment (aMCI) are at risk for developing Alzheimer's disease. Due to their prominent memory impairment, structural magnetic resonance imaging (MRI) often focuses on the hippocampal region. However, recent positron-emission tomography data suggest that within a network of frontal and temporal changes, patients with aMCI show metabolic alterations in the precuneus, a key region for higher cognitive functions. Using high-resolution MRI and whole-brain cortical thickness analyses in 28 patients with aMCI and 25 healthy individuals, we wanted to investigate whether structural changes in the precuneus would be associated with cortical thickness reductions in frontal and temporal brain regions in patients with aMCI. In contrast to healthy people, patients with aMCI showed an association of cortical thinning in the precuneus with predominantly left-hemispheric thickness reductions in medial temporal and frontal cortices. Our data highlight structural neuronal network characteristics among patients with aMCI. PMID- 28100077 TI - Effects of M2000 (D-Mannuronic Acid) on Learning, Memory Retrieval, and Associated Determinants in a Rat Model of Alzheimer's Disease. AB - The d-mannuronic acid (M2000) is a novel nonsteroidal anti-inflammatory drug that has immunosuppressive effects together with antioxidant property. M2000 has shown a notable efficacy in experimental models of multiple sclerosis, rheumatoid arthritis, and nephrotic syndrome. In this work, the effect of M2000 on the treatment of Alzheimer's disease (AD) was performed by Morris water maze experiment, and the immunological assessments were carried out by Western blot, apoptosis (procaspase-3, Bax/Bcl2, P53), enzymatic (superoxide dismutase [SOD]), and nonenzymatic oxidative stress (malondialdehyde [MDA]) tests. We found that pretreatment of AD in the rat model by M2000 had a potent efficacy on rat behavior and also it led to a significant inhibition of amyloid plaque production. Moreover, our data showed that M2000 can reduce the amount of Bax/Bcl2, P53, MDA, and SOD, as well as it normalized the level of procaspase-3. Our results suggest M2000 is a potential therapeutic agent for the treatment of AD. PMID- 28100075 TI - Urinary Incontinence in Alzheimer's Disease. AB - OBJECTIVES: Urinary incontinence (UI) is more prevalent in the elderly populations with dementia than without dementia, and Alzheimer's disease (AD) is the most common cause of dementia. Urinary incontinence may complicate AD morbidity and mortality. Therefore, this study aimed to evaluate the prevalence and annual incidence and determine the risk possibility of UI, which is the main type of incontinence in patients with AD in Taiwan. METHODS: A total of 933 patients with AD were included in the study cohort, and a total of 2799 patients without AD by 1:3 proportion compared to the study cohort were used as a matched cohort. All participants were selected from the National Health Insurance Research Database in 2000 sample population. We utilize Cox proportional hazard regression to evaluate the risk of UI and cumulative incidence ratio curve to analyze the cumulative incidence function. Prevalence and annual incidence rate are calculated in individual medication including rivastigmine, donepezil, galantamine, and memantine only being initiated in patients with AD. RESULTS: The risk of UI is higher in AD cohort (hazard ratio: 1.54, 95% confidence interval: 1.13-2.09). The cumulative incidence ratio of UI event between AD cohort and matched cohort presents statistical significance ( P < .001). Annual incidence and prevalence of UI in patients with AD are 6.2% and 4.2%, respectively. CONCLUSION: The present results suggest that the risk of UI is higher in patients with AD than in the general population. PMID- 28100078 TI - Percutaneous microwave ablation (MWA) increased the serum levels of VEGF and MMP 9 in Stage I non-small cell lung cancer (NSCLC). AB - BACKGROUND: Lung cancer is the leading cause of cancer death around the world. Percutaneous microwave ablation (MWA) is an emerging treatment strategy for medically inoperable early-stage non-small cell lung cancer (NSCLC). In this study, we investigated the association of MWA and serum angiogensis promoters VEGF and MMP-9 in these patients subgroup. METHODS: We enrolled 52 patients with Stage I NSCLC patients in this study. For each patient, blood samples were drawn by venous puncture, one immediately prior to MWA and the others on Post-Procedure Days (PPD) 1, 3, 5, 7, 10 and 14. Serum samples were analysed for VEGF and MMP-9 levels with use of commercially available enzyme-linked immunosorbent assay. Also, blood samples of 28 healthy volunteers were set as the healthy controls. RESULTS: We did not observe a significant difference of serum VEGF and MMP-9 between NSCLC patients and healthy controls. The VEGF levels increased on the first day (256.0 +/- 6.16 pg/ml, p < 0.05) after MWA and peaked on the PPD3 (418.0 +/- 14.54 pg/ml, p < 0.05). Although it gradually reduced afterwards, its levels on PPD14 (141.2 +/- 4.41 pg/ml, p < 0.05) was still higher than pre procedure level. The serum MMP-9 level was significantly elevated from PPD1 (231.3 +/- 7.93 ng/ml, p < 0.05) until PPD10 (155.3 +/- 5.62 ng/ml, p < 0.05), while it normalised to pre-procedure level on PPD14 (90.78 +/- 3.36 ng/ml, p > 0.05). The highest MMP-9 level was observed on PPD5 (399.7 +/- 17.70 ng/ml, p < 0.05). CONCLUSION: Our preliminary results indicated that percutaneous MWA resulted in increased serum levels of VEGF and MMP-9 in Stage I NSCLC patients. Antiangiogenesis approaches may be helpful for patients defending against metastases during the immediate post-ablation time window. PMID- 28100079 TI - A novel proton transfer salt of 2-amino-6-sulfamoylbenzothiazole and its metal complexes: the evaluation of their inhibition effects on human cytosolic carbonic anhydrases. AB - A novel proton transfer compound (SMHABT)+(HDPC)- (1) obtained from 2-amino-6 sulfamoylbenzothiazole (SMABT) and 2,6-pyridinedicarboxylic acid (H2DPC) and its Fe(III), Co(II), Ni(II) complexes (2-4), and Fe(II) complex of SMABT (5) have been prepared and characterized by spectroscopic techniques. Additionally, single crystal X-ray diffraction techniques were applied to complexes (2-4). All complexes (2-4) have distorted octahedral conformations and the structure of 5 might be proposed as octahedral according to spectral and analytical results. All compounds, including acetazolamide (AAZ) as the control compound, were also evaluated for their in vitro inhibition effects on human hCA I and hCA II for their hydratase and esterase activities. The synthesized compounds have remarkable inhibitory activities on hCA I and hCA II. Especially, the inhibition potentials of the salt and the metal complexes (1-5) are comparable with AAZ. Inhibition data have been analyzed by using a one-way analysis of variance for multiple comparisons (p < .0001). PMID- 28100080 TI - The commercialization of genome-editing technologies. AB - The emergence of new gene-editing technologies is profoundly transforming human therapeutics, agriculture, and industrial biotechnology. Advances in clustered regularly interspaced short palindromic repeats (CRISPR) have created a fertile environment for mass-scale manufacturing of cost-effective products ranging from basic research to translational medicine. In our analyses, we evaluated the patent landscape of gene-editing technologies and found that in comparison to earlier gene-editing techniques, CRISPR has gained significant traction and this has established dominance. Although most of the gene-editing technologies originated from the industry, CRISPR has been pioneered by academic research institutions. The spinout of CRISPR biotechnology companies from academic institutions demonstrates a shift in entrepreneurship strategies that were previously led by the industry. These academic institutions, and their subsequent companies, are competing to generate comprehensive intellectual property portfolios to rapidly commercialize CRISPR products. Our analysis shows that the emergence of CRISPR has resulted in a fivefold increase in genome-editing bioenterprise investment over the last year. This entrepreneurial movement has spurred a global biotechnology revolution in the realization of novel gene editing technologies. This global shift in bioenterprise will continue to grow as the demand for personalized medicine, genetically modified crops and environmentally sustainable biofuels increases. However, the monopolization of intellectual property, negative public perception of genetic engineering and ambiguous regulatory policies may limit the growth of these market segments. PMID- 28100081 TI - Brexit and rare diseases: big risk, bigger opportunity? AB - The UK's planned exit from the EU will leave its national health sector in a very dangerous position. It will also have profound consequences for domestic UK law. The impact may be particularly drastic for patients for whom EU law protects the right to treatment. At a particular risk are patients with rare, 'orphan', diseases whose treatments are uniquely enabled at the EU level. We examine the potential effects of Brexit on the orphan sector and identify an opportunity to solve long-standing and intensifying difficulties, especially the pricing of orphan drugs. PMID- 28100084 TI - Obituary. PMID- 28100082 TI - Synthesis and bioactivity of several new hetaryl sulfonamides. AB - 1-(4-Methylsulfonyl)-2-thione-4-aryl-5-Z-6-methyl and oxyalkyl-imidazoles were synthesized from different tetrahydropyrimidinethiones and aryl sulfonyl chloride. These compunds were tested for metal chelating effects and to determine the phrase in which inhibition occured between two physiologically pertinent compunds and carbonic anhydrase (CA) isozymes I and II (hCA I and II), butyrylcholinesterase (BChE) and acetylcholinesterase (AChE). AChE was detected in high concentrations in the brain and red blood cells. BChE is another enzymes that is abundant available in the liver and released into the blood in a soluble form. Newly synthesized hetaryl sulfonamides exhibited impressive inhibition profiles with Ki values in the range of 1.42-6.58 nM against hCA I, 1.72-7.41 nM against hCA II, 0.20-1.14 nM against AChE and 1.55-5.92 nM against BChE. Moreover, acetazolamide showed Ki values of 43.69 +/- 6.44 nM against hCA I and 31.67 +/- 8.39 nM against hCA II. Additionally, tacrine showed Ki values of 25.75 +/- 3.39 nM and 37.82 +/- 2.08 against AChE and BChE, respectively. PMID- 28100083 TI - alpha-Glucosidase inhibitory activity and cytotoxic effects of some cyclic urea and carbamate derivatives. AB - The inhibitory activities of selected cyclic urea and carbamate derivatives (1 13) toward alpha-glucosidase (alpha-Gls) in in vitro assay were examined in this study. All examined compounds showed higher inhibitory activity (IC50) against alpha-Gls compared to standard antidiabetic drug acarbose. The most potent was benzyl (3,4,5-trimethoxyphenyl)carbamate (12) with IC50 = 49.85 +/- 0.10 uM. In vitro cytotoxicity of the investigated compounds was tested on three human cancer cell lines HeLa, A549 and MDA-MB-453 using MTT assay. The best antitumour activity was achieved with compound 2 (trans-5-phenethyl-1-phenylhexahydro-1H imidazo[4,5-c]pyridin-2(3H)-one) against MDA-MB-453 human breast cancer cell line (IC50 = 83.41 +/- 1.60 uM). Cyclic ureas and carbamates showed promising anti alpha-glucosidase activity and should be further tested as potential antidiabetic drugs. The PLS model of preliminary QSAR study indicated that, in planing the future synthesis of more potent compounds, the newly designed should have the substituents capable of polar interactions with receptor sites in various positions, while avoiding the increase of their lipophilicity. PMID- 28100086 TI - Tracking down a solution: exploring the acceptability and value of wearable GPS devices for older persons, individuals with a disability and their support persons. AB - PURPOSE: To explore the acceptability and value of three wearable GPS devices for older persons and individuals with a disability and safety concerns when accessing the community. METHODS: This pilot study explored six wearers' and their support persons' experience of using three different wearable GPS devices (a pendant, watch, and mini GPS phone), each for a two-week period. RESULTS: Participants identified safety as the main value of using a wearable GPS device. The acceptability and value of these devices was strongly influenced by device features, ease of use, cost, appearance, the reliability of the GPS coordinates, the wearer's health condition and the users familiarity with technology. Overall, participants indicated that they preferred the pendant. CONCLUSIONS: Wearable GPS devices are potentially useful in providing individuals who have safety concerns with reassurance and access to assistance as required. To ensure successful utilization, future device design and device selection should consider the user's familiarity with technology and their health condition. This study also revealed that not all wearable GPS devices provide continuous location tracking. It is therefore critical to ensure that the device's location tracking functions address the wearer's requirements and reason for using the device. Implications for Rehabilitation The acceptability and usability of wearable GPS devices is strongly influenced by the device features, ease of use, cost, appearance, the reliability of the device to provide accurate and timely GPS coordinates, as well as the health condition of the wearer and their familiarity with technology. Wearable GPS devices need to be simple to use and support and training is essential to ensure they are successfully utilized. Not all wearable GPS devices provide continuous location tracking and accuracy of location is impacted by line of sight to satellites. Therefore, care needs to be taken when choosing a suitable device, to ensure that the device's location tracking features are based on the wearer's requirements and value behind using the device. PMID- 28100085 TI - Heterogeneity of macrophages in canine histiocytic ulcerative colitis. AB - Histiocytic ulcerative colitis (HUC) is a chronic enteropathy which most notably occurs in Boxer dogs and French bulldogs. The inflamed mucosa is hallmarked by large, foamy, periodic acid-Schiff (PAS)-positive macrophages infiltrating the colonic mucosa. As little is known about their origin and phenotype, an immunohistochemical study was performed using different macrophage markers. Generally, canine colonic macrophages showed high expression of ionised calcium binding adaptor molecule 1 and MHC class II. In canine HUC, macrophages revealed up-regulation of lysozyme and L1 Ag but decreased CD163 expression compared with controls, suggesting them to be pro-inflammatory cells, whereas the healthy colonic mucosa was characterised by an anti-inflammatory macrophage phenotype. In addition, PAS reaction was used to discriminate macrophage subpopulations. PAS- macrophages displayed higher expression of L1 Ag and CD64, whereas PAS+ cells, which were only present in HUC patients, were characterised by increased expression of lysozyme, inducible nitric oxide synthase and CD204. This indicates PAS+ cells to be mature macrophages contributing to the inflammatory process, which are most likely maintained by differentiation of immature PAS- macrophages continuously recruited from blood monocytes. In summary, macrophage heterogeneity in canine HUC probably illustrates their different maturation states and functions compared with the healthy animals. PMID- 28100087 TI - A UHF RFID positioning system for use in warehouse navigation by employees with cognitive disability. AB - Unemployment among the almost 5 million working-age adults with cognitive disabilities in the USA is a costly problem in both tax dollars and quality of life. Job coaching is an effective tool to overcome this, but the cost of job coaching services sums with every new employee or change of employment roles. There is a need for a cost-effective, automated alternative to job coaching that incurs a one-time cost and can be reused for multiple employees or roles. An effective automated job coach must be aware of its location and the location of destinations within the job site. This project presents a design and prototype of a cart-mounted indoor positioning and navigation system with necessary original software using Ultra High Frequency Radio Frequency Identification (UHF RFID). The system presented in this project for use within a warehouse setting is one component of an automated job coach to assist in the job of order filler. The system demonstrated accuracy to within 0.3 m under the correct conditions with strong potential to serve as the basis for an effective indoor navigation system to assist warehouse workers with disabilities. Implications for rehabilitation An automated job coach could improve employability of and job retention for people with cognitive disabilities. An indoor navigation system using ultra high frequency radio frequency identification was proposed with an average positioning accuracy of 0.3 m. The proposed system, in combination with a non-linear context aware prompting system, could be used as an automated job coach for warehouse order fillers with cognitive disabilities. PMID- 28100088 TI - Comparability of a short food frequency questionnaire to assess diet quality: the DISCOVER study. AB - This study aims to assess comparability of a short food frequency questionnaire (SFFQ) used in the Determinants of Suicide: Conventional and Emergent Risk Study (DISCOVER Study) with a validated comprehensive FFQ (CFFQ). A total of 127 individuals completed SFFQ and CFFQ. Healthy eating was measured using Healthy Eating Score (HES). Estimated food intake and healthy eating assessed by SFFQ was compared with the CFFQ. For most food groups and HES, the highest Spearman's rank correlation coefficients between the two FFQs were r > .60. For macro-nutrients, the correlations exceeded 0.4. Cross-classification of quantile analysis showed that participants were classified between 46% and 81% into the exact same quantiles, while 10% or less were misclassified into opposite quantiles. The Bland-Altman plots showed an acceptable level of agreement between the two dietary measurement methods. The SFFQ can be used for Canadian with psychiatric disorders to rank them based on their dietary intake. PMID- 28100089 TI - Assistive technology outcomes in post-secondary students with disabilities: the influence of diagnosis, gender, and class-level. AB - This study investigated how outcomes of assistive technology (AT) services for college students with disabilities are influenced by diagnosis, gender and class level (e.g., Freshman). Students' pre- and post-intervention ratings of their performance and satisfaction of common academic tasks (using the Canadian Occupational Performance Measure, COPM) were analyzed, as well as students' responses on a survey about AT service provision, use, and preferences. Data from 455 students revealed "learning disability" to be the most prevalent diagnosis (38%), similar numbers of females and males served, and Freshmen (23.1%) as the largest class-level seeking AT services. For COPM data, each two-way analysis of variance (ANOVA) (grouping variable = diagnosis) revealed that pre-post change scores significantly improved for the entire sample, and that students with a mood disorder experienced the greatest changes compared to other diagnoses. COPM scores significantly and similarly improved for females and males, and across class levels. AT Survey ratings about timeliness of services and independent AT use were significantly lower for students with mobility deficits/pain and neurological damage, respectively. Gender and class-level variables did not significantly impact AT Survey ratings. The study results reveal that features of a college student's diagnosis may influence AT service outcomes, and student perceptions of AT services ability to use AT. Implications for Rehabilitation College students who are Freshman and/or who have a learning disability are the most prevalent students referred for campus-based assistive technology services. While student ratings of academic task performance significantly increase across diagnostic groupings, these improvements were greatest for those with a mood disorder compared to other diagnostic groups. Service-providers should consider that features of certain diagnoses or disabilities may influence the student?s perception of AT service provision and their ability to use AT. A student's gender and class-level (e.g., Freshman) do not appear to influence the outcomes of AT services for college students with disabilities. PMID- 28100090 TI - Patterns of use of systemic therapies among patients with metastatic melanoma: a retrospective claims database analysis in the United States. AB - OBJECTIVES: This retrospective analysis of the IMS PharMetrics Plus claims database aimed to describe the current real-world treatment patterns for metastatic melanoma in the USA. METHODS: Included patients (aged >=18 years) had >=1 prescription for ipilimumab, vemurafenib, temozolomide or dacarbazine between 1 January 2011 and 31 August 2013; diagnosis of melanoma and metastasis before first use (index date); no index drug use prior to the index date; continuous health plan enrollment for >=6 months before and >=3 months after index date. Proportion of days covered (PDC) was defined as days exposed to index therapy divided by continuously enrolled days between index date and last prescription date. RESULTS: Overall, 1043 patients were included (median age 57 years, 63% male), of whom 39% received the index drug ipilimumab, 35% vemurafenib, 19% temozolomide and 7% dacarbazine. Mean treatment duration (days) was 174 (vemurafenib), 100 (temozolomide) and 64 (dacarbazine). Mean PDC was 81% (vemurafenib), 67% (temozolomide) and 51% (dacarbazine). For patients receiving ipilimumab, 58% had the full 4 doses, 20% 3 doses, 14% 2 doses and 9% 1 dose only for the first induction course; 4% received re-induction, and none had a second re-induction. CONCLUSIONS: This study provides insights into the treatment patterns for metastatic melanoma, including newer agents, in real-world clinical practice. PMID- 28100091 TI - The effects of polyethylenimine/DNA nanoparticle on transcript levels of apoptosis-related genes. AB - CONTEXT: Polyethylenimine (PEI) is a cationic polymer commonly used in gene transfer. Although numerous investigations have indicated that PEI can induce apoptosis/necrosis but the mechanism of its cytotoxicity is still poorly understood. OBJECTIVE: The purpose of this study was to investigate the effects of PEI/DNA complexes on the expression of apoptotic genes in human colon adenocarcinoma cells (HT29). METHODS: HT29 cells were exposed to PEI/DNA complex (C/P = 0.8) for 24 h. Then, qRT PCR was used to assess the expression of 26 apoptotic-related genes. RESULT: Analysis of the transcript level of genes revealed that while the expression of anti-apoptotic genes such as Bclx, Bcl2, NFkB, and AIF was not significantly reduced but the expression of pro-apoptotic genes such as Fasl, Bax, TNFR1, DR4, Casp8, and cytochrome C was considerably increased in transfected HT29 cell lines. CONCLUSIONS: Our results showed that PEI could increase the level of pro-apoptotic genes and decrease antiapoptotic genes as a possible mechanism involved in PEI cytotoxicity. PMID- 28100092 TI - Sample size requirements for one-year treatment effects using deep gray matter volume from 3T MRI in progressive forms of multiple sclerosis. AB - OBJECTIVE: The subcortical deep gray matter (DGM) develops selective, progressive, and clinically relevant atrophy in progressive forms of multiple sclerosis (PMS). This patient population is the target of active neurotherapeutic development, requiring the availability of outcome measures. We tested a fully automated MRI analysis pipeline to assess DGM atrophy in PMS. DESIGN/METHODS: Consistent 3D T1-weighted high-resolution 3T brain MRI was obtained over one year in 19 consecutive patients with PMS [15 secondary progressive, 4 primary progressive, 53% women, age (mean+/-SD) 50.8+/-8.0 years, Expanded Disability Status Scale (median, range) 5.0, 2.0-6.5)]. DGM segmentation applied the fully automated FSL-FIRST pipeline ( http://fsl.fmrib.ox.ac.uk ). Total DGM volume was the sum of the caudate, putamen, globus pallidus, and thalamus. On-study change was calculated using a random-effects linear regression model. RESULTS: We detected one-year decreases in raw [mean (95% confidence interval): -0.749 ml ( 1.455, -0.043), p = 0.039] and annualized [-0.754 ml/year (-1.492, -0.016), p = 0.046] total DGM volumes. A treatment trial for an intervention that would show a 50% reduction in DGM brain atrophy would require a sample size of 123 patients for a single-arm study (one-year run-in followed by one-year on-treatment). For a two-arm placebo-controlled one-year study, 242 patients would be required per arm. The use of DGM fraction required more patients. The thalamus, putamen, and globus pallidus, showed smaller effect sizes in their on-study changes than the total DGM; however, for the caudate, the effect sizes were somewhat larger. CONCLUSIONS: DGM atrophy may prove efficient as a short-term outcome for proof-of concept neurotherapeutic trials in PMS. PMID- 28100093 TI - p19-targeted ABD-derived protein variants inhibit IL-23 binding and exert suppressive control over IL-23-stimulated expansion of primary human IL-17+ T cells. AB - Interleukin-23 (IL-23), a heterodimeric cytokine of covalently bound p19 and p40 proteins, has recently been closely associated with development of several chronic autoimmune diseases such as psoriasis, psoriatic arthritis or inflammatory bowel disease. Released by activated dendritic cells, IL-23 interacts with IL-23 receptor (IL-23R) on Th17 cells, thus promoting intracellular signaling, a pivotal step in Th17-driven pro-inflammatory axis. Here, we aimed to block the binding of IL-23 cytokine to its cell-surface receptor by novel inhibitory protein binders targeted to the p19 subunit of human IL-23. To this goal, we used a combinatorial library derived from a scaffold of albumin-binding domain (ABD) of streptococcal protein G, and ribosome display selection, to yield a collection of ABD-derived p19-targeted variants, called ILP binders. From 214 clones analyzed by ELISA, Western blot and DNA sequencing, 53 provided 35 different sequence variants that were further characterized. Using in silico docking in combination with cell-surface competition binding assay, we identified a group of inhibitory candidates that substantially diminished binding of recombinant p19 to the IL-23R on human monocytic THP-1 cells. Of these best p19-blockers, ILP030, ILP317 and ILP323 inhibited IL-23-driven expansion of IL-17 producing primary human CD4+ T-cells. Thus, these novel binders represent unique IL-23-targeted probes useful for IL-23/IL-23R epitope mapping studies and could be used for designing novel p19/IL-23-targeted anti-inflammatory biologics. PMID- 28100094 TI - Preliminary reliability and internal consistency of the Wheelchair Components Questionnaire for Condition. AB - Wheelchair durability and maintenance condition are key factors of wheelchair function. Durability studies done with double drum and drop testers, although valuable, do not perfectly imitate conditions of use. Durability may be harvested from clinical records; however, these may be inconsistent because protocols for recording information differ from place to place. Wheelchair professionals with several years of experience often develop a good eye for wheelchair maintenance condition. The Wheelchair Components Questionnaire for Condition (WCQc) was developed as a professional report questionnaire to provide data specifically on the maintenance condition of a wheelchair. The goal of this study was to obtain preliminary test-retest reliability and internal consistency for the WCQc. Participants were a convenience sample of wheelchair professionals who self reported more than two years' of wheelchair experience, and completed the WCQc on the same wheelchair twice. Results indicated preliminary reliability and internal consistency for domain related questions and the entire questionnaire. Implications for rehabilitation The WCQc, if administered routinely at regular intervals, can be used to monitor wheelchair condition and alert users and health professionals about the need for repair or replacement. The WCQc is not difficult to use, making early monitoring for wear or damage more feasible. The earlier a tool can detect need for maintenance, the higher likelihood that appropriate measures may be employed in a timely fashion to maximize the overall durability of wheelchairs and minimize clinical complications. Keeping wheelchairs appropriately maintained allows users to minimize effort expended when using them, and maximize their function. It also lowers the risk of injury due to component failure. When assessing groups of similar wheelchairs, organizations involved in funding wheelchairs can use data from the WCQc to make purchase decisions based on durability, and manufacturers can use WCQc data for responsive design change. PMID- 28100096 TI - Targeting therapy-resistant cancer stem cells by hyperthermia. AB - Eradication of all malignant cells is the ultimate but challenging goal of anti cancer treatment; most traditional clinically-available approaches fail because there are cells in a tumour that either escape therapy or become therapy resistant. A subpopulation of cancer cells, the cancer stem cells (CSCs), is considered to be of particular significance for tumour initiation, progression and metastasis. CSCs are considered in particular to be therapy-resistant and may drive disease recurrence, which positions CSCs in the focus of anti-cancer research, but successful CSC-targeting therapies are limited. Here, we argue that hyperthermia - a therapeutic approach based on local heating of a tumour - is potentially beneficial for targeting CSCs in solid tumours. First, hyperthermia has been described to target cells in hypoxic and nutrient-deprived tumour areas where CSCs reside and ionising radiation and chemotherapy are least effective. Second, hyperthermia can modify factors that are essential for tumour survival and growth, such as the microenvironment, immune responses, vascularisation and oxygen supply. Third, hyperthermia targets multiple DNA repair pathways, which are generally upregulated in CSCs and protect them from DNA-damaging agents. Addition of hyperthermia to the therapeutic armamentarium of oncologists may thus be a promising strategy to eliminate therapy-escaping and -resistant CSCs. PMID- 28100095 TI - Shoulder kinetics during start-up and propulsion with a manual wheelchair within the initial phase of uninstructed training. AB - PURPOSE: Wheelchair locomotion is constraining for the upper limbs and involves a set of motor tasks that need to be learnt by a novice user. To understand this integration process, we investigated the evolution of shoulder kinetics during start-up and propulsion within the initial phase of low-intensity uninstructed training. MATERIALS AND METHODS: Seventeen novice able-bodied subjects performed a 120-min uninstructed practice distributed over 4 weeks. During the initial and final sessions, upper limbs kinematics and hand-rim kinetics were continuously collected. Inverse kinematics and dynamics coupled to a three-dimensional linked segment model were used to compute shoulder net moments. RESULTS: Participants increased the speed of the wheelchair with practice. In average, an increase of shoulder net moments and mechanical work during the push phase was observed. Conversely, during the recovery phase, participants slightly increased shoulder power but maintained a similar level of shoulder loading. However, individual evolutions allowed the definition of two groups defined as: "increasers", who increased shoulder loading and mechanical work versus "decreasers", who managed to limit shoulder loading while improving the wheelchair speed. CONCLUSION: These findings underline that individual adaptation strategies are essential to take into account when designing a rehabilitation protocol for wheelchair users. Implications for Rehabilitation The learning process of manual wheelchair locomotion is essential for the assimilation of motor tasks leading individuals to select their propulsion technique. Novice users display different learning strategies: some people increase shoulder loading very early but others spontaneously manage to increase the wheelchair speed while maintaining a constant level of shoulder loading. Wheelchair rehabilitation programs should be individualized to take into account the subject-specific learning strategy. PMID- 28100097 TI - Spina bifida and lower limb amputation in Northern Ireland: A retrospective study of demographics and outcome. AB - BACKGROUND: Spina bifida is an uncommon cause for lower limb amputation. The causes and level of amputation and mobility outcome for these patients have not been reported previously. CASE DESCRIPTION: To identify the causes and level of amputation and the mobility outcome for amputee patients with spina bifida. STUDY DESIGN: Retrospective case series. METHODS: Chart review of patients identified by computer as having an amputation secondary to neurological or congenital cause. Additional patients identified from the Regional Spina Bifida Medical Clinic. Demographics, cause and level of mobility pre- and post-amputation recorded from the prosthetic notes. FINDINGS: In total, 16 patients were identified who had a diagnosis of spina bifida and a lower limb amputation. Mean age at the time of amputation was 28.5 years. In total, 15 patients had a transtibial amputation. In total, 14 patients post-amputation were able to maintain their mobility, wheelchair or walking, without any change in type of aid needed. CONCLUSION: Patients with spina bifida appear to require lower limb amputation at a younger age than patients with peripheral vascular disease. Almost all patients had prior chronic skin infection/osteomyelitis as precursors for amputation. The most common level for amputation was transtibial. Mobility was maintained for all patients, albeit for two in a more supported way. Clinical relevance Spina bifida is an uncommon reason for amputation. Patients, are often younger and medically complicated. Chronic skin ulceration, was the most common indication for amputation. Wheelchair or walking ambulance was maintained at the same level for most patients. PMID- 28100098 TI - Analyzing Further Predictors of Correctional Officer Professional Orientations: The Role of Turnover Intentions. AB - Four professional orientations to which correctional officers can ascribe have been identified in extant literature, and they include the counseling roles, concern for corruption of authority, social distance, and punitive ideologies. Studies have generally found officer demographics and correctional working conditions to be significant predictors of these orientations. No study to date, however, has examined the predictive influence of officer voluntary resignation intentions. Linear regression equations using questionnaire data from a statewide population of maximum security correctional officers ( N = 649) were therefore estimated to explore whether officer desires to terminate their employment accounted for variance in their self-reported orientations. Stronger turnover intentions shared statistically significant associations with three orientations, including negatively predicting the counseling roles and positively predicting the punitive ideology. Implications for correctional policy are addressed. PMID- 28100099 TI - A user-centered qualitative study on experiences with ankle-foot orthoses and suggestions for improved design. AB - BACKGROUND: Improving ankle-foot orthosis design can best be done by implementing a user-centered approach. OBJECTIVE: To provide insight into the ideas of ankle foot orthosis users with flaccid ankle muscle paresis on the importance of activities and suggestions for an improved ankle-foot orthosis design. STUDY DESIGN: A focus-group discussion with eight ankle-foot orthosis users (57 +/- 5 years, 50% female). METHODS: Main inclusion criteria were as follows: ?18 years, unable to stand on tip-toe and unable to lift toes. Main exclusion criterion was spasticity of lower extremity muscles. Transcribed data were coded according to the International Classification of Functioning, Disability and Health. Thematic analysis with inductive approach was chosen to order and interpret codes. RESULTS: Ankle-foot orthosis users ranked walking the most important activity followed by sitting down/standing up from a chair. Their opinion was that ankle foot orthoses facilitate walking and standing. Ankle-foot orthosis users suggested that an improved ankle-foot orthosis design should balance between stability and flexibility. CONCLUSION: Current ankle-foot orthoses facilitate walking which was the most important activity according to ankle-foot orthosis users. An improved ankle-foot orthosis design should enable walking and should optimize between stability and flexibility dependent on the activity and the paresis severity. Clinical relevance Experienced users of ankle-foot orthosis agreed that matching ankle-foot orthosis functions to daily-life activities is a trade-off between stability and flexibility. An improved ankle-foot orthosis design should at least enable level walking. PMID- 28100101 TI - Espresso coffee foam delays cooling of the liquid phase. AB - Espresso coffee foam, called crema, is known to be a marker of the quality of espresso coffee extraction. However, the role of foam in coffee temperature has not been quantitatively clarified. In this study, we used an automatic machine for espresso coffee extraction. We evaluated whether the foam prepared using the machine was suitable for foam analysis. After extraction, the percentage and consistency of the foam were measured using various techniques, and changes in the foam volume were tracked over time. Our extraction method, therefore, allowed consistent preparation of high-quality foam. We also quantitatively determined that the foam phase slowed cooling of the liquid phase after extraction. High quality foam plays an important role in delaying the cooling of espresso coffee. PMID- 28100100 TI - A new update for radiocontrast-induced nephropathy aggravated with glycerol in rats: the protective potential of epigallocatechin-3-gallate. AB - Contrast media (CM) is known to have nephrotoxic adverse effects. Epigallocatechin-3-gallate (EGCG) is the most abundant and active catechin in green tea, and has strong antioxidant and anti-inflammatory properties. This study investigated whether EGCG can reduce contrast-induced nephrotoxicity (CIN), alone or with glycerol (GLY)-induced renal damage, and to understand its mechanisms of protection against toxicity, using models of GLY and CIN in rats. The rats were separated into eight groups (n = 6 in each), as follows: Healthy, GLY, CM, GLY + CM, CM + EGCG 50 mg/kg (po), GLY + CM + EGCG 50 mg/kg (po), CM + EGCG 100 mg/kg (po), and GLY + CM + EGCG 100 mg/kg (po). Both doses of EGCG protected against CM-induced renal dysfunction, as measured by serum creatinine and blood urea nitrogen (BUN). In addition, EGCG treatment markedly improved CIN induced oxidative stress, and resulted in a significant down-regulatory effect on tumor necrosis factor (TNF)-alpha and nuclear factor (NF)-kappaB mRNA expression. Moreover, histopathological analysis showed that EGCG also attenuated CM-induced kidney damage. Considering the potential clinical use of CM and the numerous health benefits of EGCG, this study showed the protective role of multi-dose EGCG treatment on CIN and GLY-aggravated CIN through different mechanisms. PMID- 28100102 TI - Pharmacokinetics and tissue distribution of crotonoside. AB - 1. Crotonoside is a bioactive ingredient from Croton Herba with a strong antitumour activity. This study aimed to develop a highly sensitive and selective high-performance liquid chromatography (HPLC) method to quantify crotonoside in biological samples for pharmacokinetics and distribution studies. 2. Protein precipitation by perchloric acid was used to separate crotonoside from the biological samples, and the recovery rates for crotonoside and the internal standard (luteoloside) were >80%. All calibration curves examining the crotonoside levels in plasma and tissues were linear (all correlation coefficients > 0.99). 3. The response to crotonoside appeared to be dose disproportional to the maximum plasma concentration and the area under the time concentration curve in plasma over the range of 12.5-50.0 mg/kg, and crotonoside was highly distributed in tissues after intravenous administration. The highest crotonoside level was detected in the liver (28.79 +/- 14.96 MUg/g), whereas crotonoside was undetected in the brain. PMID- 28100103 TI - Systematic Review of Genetic Risk Factors for Sustaining a Mild Traumatic Brain Injury. AB - This systematic review examined the association between genetics and risk for sustaining a traumatic brain injury. We retrieved articles published in English from 1980 to July 2016 obtained from the online databases PubMed, PsycINFO(r), MEDLINE(r), Embase, and Web of Science. In total 5903 articles were identified, 77 underwent full-text screening, and 6 were included in this review. Five studies examined the risk of concussion associated with apolipoprotein E alleles (APOE-E2, E3,E4), and polymorphisms of the APOE promoter (rs405509), brain derived neurotrophic factor (BDNF, rs6265), and dopamine receptor D2 (DRD2, rs1800497) were each considered in two studies. Microtubule associated protein tau (TAU exon 6 polymorphisms His47Tyr [rs2258689] and Ser53Pro [rs10445337]), and neurofilament heavy (NEHF, rs165602) genotypic variants, were the focus of single studies. No study showed an increased risk associated solely with the presence of the APOE-E4 allele, nor were there any significant findings for the NEFH, TAU, or DRD2 genotypic variants. Two studies examined the APOE promoter 219G/T polymorphism in athletes, and both found an association with concussion. Both BDNF studies also found a significant association with concussion incidence; United States soldiers with the Met/Met genotype were more likely to report a history of concussion prior to deployment and to sustain a concussion during deployment. We conclude that the APOE promoter -219G/T polymorphism and the BDNF Met/Met genotype might confer risk for sustaining a TBI. Based on research to date, the APOE-E4 allele does not appear to influence risk. More research is needed to determine if these findings replicate. PMID- 28100104 TI - Theoretical predication of temperature effects on accommodative processes in simulated amyotrophic lateral sclerosis during hypothermia and hyperthermia. AB - Electrotonic potentials allow the accommodative processes to long-lasting subthreshold polarizing stimuli to be assessed. The present study investigates such potentials in previously simulated cases of amyotrophic lateral sclerosis, termed as ALS1, ALS2 and ALS3, respectively, when the temperature is changed during hypothermia ([Formula: see text]C) and hyperthermia ([Formula: see text]C). The ALS cases are modeled as three progressively severe uniform axonal dysfunctions along the human motor nerve fiber which is simulated by our temperature-dependent multi-layered numerical model. The results show that the polarizing electrotonic potentials in the ALS1 case are quite similar to those in the normal case during hypothermia. Their defining currents are caused by the activation of potassium fast (K[Formula: see text]) and slow (K[Formula: see text]) channels in the nodal and internodal axolemma beneath the myelin sheath. Except in the ALS3 case at 20[Formula: see text]C, where the accommodative processes are blocked by depolarizing stimuli, in the ALS2 and ALS3 cases during hypothermia these stimuli activate the classical "transient" Na[Formula: see text] channels in the nodal and internodal axolemma beneath the myelin sheath. And this leads to action potential generations during the early parts of electrotonic responses in all compartments along the fiber length. Only in the ALS3 case after the termination of long-lasting subthreshold hyperpolarizing stimuli, action potential generations are obtained in the late parts of electrotonic potentials along the fiber length. In comparison to the normal case, in the gradually severe ALS cases, the depolarizing electrotonic potentials gradually increase, while the hyperpolarizing electrotonic potentials gradually decrease during hyperthermia. However, the repetitive firings are not obtained in these polarizing electrotonic potentials. The results show that the accommodative processes to depolarizing stimuli in the ALS3 case are more likely to be blocked during hypothermia than hyperthermia. The results also show that the polarizing electrotonic potentials in the three simulated ALS cases are specific indicators for the motor nerve disease ALS during hypothermia and hyperthermia. PMID- 28100105 TI - Inventing a co-axial atomic resolution patch clamp to study a single resonating protein complex and ultra-low power communication deep inside a living neuron cell. AB - To read the signals of single molecules in vitro on a surface, or inside a living cell or organ, we introduce a coaxial atom tip (coat) and a coaxial atomic patch clamp (COAPAP). The metal-insulator-metal cavity of these probes extends to the atomic scale (0.1[Formula: see text]nm), it eliminates the cellular or environmental noise with a S/N ratio 105. Five ac signals are simultaneously applied during a measurement by COAT and COAPAP to shield a true signal under environmental noise in five unique ways. The electromagnetic drive in the triaxial atomic tips is specifically designed to sense anharmonic vibrational and transmission signals for any system between 0.1[Formula: see text]nm and 50[Formula: see text]nm where the smallest nanopatch clamp cannot reach. COAT and COAPAP reliably pick up the atomic scale vibrations under the extreme noise of a living cell. Each protein's distinct electromagnetic, mechanical, electrical and ionic vibrational signature studied in vitro in a protected environment is found to match with the ones studied inside a live neuron. Thus, we could confirm that by using our probe blindly we could hold on to a single molecule or its complex in the invisible domain of a living cell. Our decade long investigations on perfecting the tools to measure bio-resonance of all forms and simultaneously in all frequency domains are summarized. It shows that the ratio of emission to absorption resonance frequencies of a biomaterial is around [Formula: see text], only a few in the entire em spectrum are active that regulates all other resonances, like mechanical, ionic, etc. PMID- 28100107 TI - Corrigendum. PMID- 28100106 TI - Systemic lupus erythematosus in the light of the regulatory effects of galectin-1 on T-cell function. AB - Galectin-1 is an endogenous immunoregulatory lectin-type protein. Its most important effects are the inhibition of the differentiation and cytokine production of Th1 and Th17 cells, and the induction of apoptosis of activated T cells. Galectin-1 has been identified as a key molecule in antitumor immune surveillance, and data are accumulating about the pathogenic role of its deficiency, and the beneficial effects of its administration in various autoimmune disease models. Initial animal and human studies strongly suggest deficiencies in both galectin-1 production and responsiveness in systemic lupus erythematosus (SLE) T-cells. Since lupus features widespread abnormalities in T cell activation, differentiation and viability, in this review the authors wished to highlight potential points in T-cell signalling processes that may be influenced by galectin-1. These points include GM-1 ganglioside-mediated lipid raft aggregation, early activation signalling steps involving p56Lck, the exchange of the CD3 zeta-ZAP-70 to the FcRgamma-Syk pathway, defective mitogen activated protein kinase pathway activation, impaired regulatory T-cell function, the failure to suppress the activity of interleukin 17 (IL-17) producing T-cells, and decreased suppression of the PI3K-mTOR pathway by phosphatase and tensin homolog (PTEN). These findings place galectin-1 into the group of potential pathogenic molecules in SLE. PMID- 28100108 TI - The common-sense model of self-regulation and its role in predicting and facilitating health outcomes. PMID- 28100110 TI - Mortality in Patients With Septic Shock by Multidrug Resistant Bacteria. AB - BACKGROUND: Patients with septic shock by multidrug resistant (MDR) microorganism maybe considered a specific population of critical patients at very high risk of death in whom the effects of standard sepsis treatment has never been assessed. The objective of this retrospective analysis was to evaluate the risk factors for 30-day mortality and the impact of sepsis management in patients with septic shock caused by MDR bacteria. METHODS: Patients with septic shock by MDR bacteria admitted to the mixed intensive care unit (ICU) of Modena University Hospital during a 6-year period were studied. The clinical and microbiological characteristics and sepsis treatments provided were analyzed and compared between survivors (S) and nonsurvivors (NS) at 30 days after septic shock appearance. RESULTS: Ninety-four patients were studied. All therapeutic interventions applied to patients during their ICU stay did not show statistical significance between S and NS groups, except for administration of immunoglobulin M (IgM) preparation which were provided more frequently in S group ( P < .05). At the multivariate adjusted analysis, preexisting cancer (odds ratio [OR] = 2.965) and Acinetobacter baumannii infections (OR = 3.197) were independently correlated with an increased risk of 30-day mortality, whereas treatment with IgM preparation was protective (OR = 0.283). CONCLUSIONS: This retrospective study showed that in patients with septic shock caused by MDR bacteria, history of cancer and infection sustained by A baumannii increase the risk of mortality and that standard sepsis treatments do not seem to provide any protective effect. Adjunctive therapy with IgM preparation seems to be beneficial, but further appropriate studies are needed to confirm the results observed. PMID- 28100109 TI - Stem Cell Trafficking During Endometriosis: May Epigenetics Play a Pivotal Role? PMID- 28100111 TI - Noteworthy Literature Published in 2016 for Abdominal Organ Transplantation Anesthesiologists. AB - More than 3000 peer-reviewed publications on the topic of liver transplantation were published in 2016. The goal of this article is to provide a concise review of pertinent literature for anesthesiologists who participate in liver transplantation. The authors selected and presented 33 articles published in 2016 on the topics of MELD policy; cardiovascular, pulmonary, and renal issues; coagulation and transfusion; anesthetic agents; hemodynamic monitors; acute liver failure; and donor issues. PMID- 28100112 TI - Abortion attitudes among South Africans: findings from the 2013 social attitudes survey. AB - Abortion is legal in South Africa, but over half of abortions remain unsafe there. Evidence suggests women who are (Black) African, of lower socioeconomic status, living with HIV, or residents of Gauteng, KwaZulu-Natal, or Limpopo provinces are disproportionately vulnerable to morbidity or mortality from unsafe abortion. Negative attitudes toward abortion have been documented in purposively sampled studies, yet it remains unclear what attitudes exist nationally or whether they differ across sociodemographic groups, with implications for inequities in service accessibility and health. In the current study, we analysed nationally representative data from 2013 to estimate the prevalence of negative abortion attitudes in South Africa and to identify racial, socioeconomic and geographic differences. More respondents felt abortion was 'always wrong' in the case of family poverty (75.4%) as compared to foetal anomaly (55%), and over half of respondents felt abortion was 'always wrong' in both cases (52.5%). Using binary logistic regression models, we found significantly higher odds of negative abortion attitudes among non-Xhosa African and Coloured respondents (compared to Xhosa respondents), those with primary education or less, and residents of Gauteng and Limpopo (compared to Western Cape). We contextualise and discuss these findings using a human rights-based approach to health. PMID- 28100113 TI - Characterization and production of multifunctional cationic peptides derived from rice proteins. AB - Food proteins have been identified as a source of bioactive peptides. These peptides are inactive within the sequence of the parent protein and must be released during gastrointestinal digestion, fermentation, or food processing. Of bioactive peptides, multifunctional cationic peptides are more useful than other peptides that have specific activity in promotion of health and/or the treatment of diseases. We have identified and characterized cationic peptides from rice enzymes and proteins that possess multiple functions, including antimicrobial, endotoxin-neutralizing, arginine gingipain-inhibitory, and/or angiogenic activities. In particular, we have elucidated the contribution of cationic amino acids (arginine and lysine) in the peptides to their bioactivities. Further, we have discussed the critical parameters, particularly proteinase preparations and fractionation or purification, in the enzymatic hydrolysis process for producing bioactive peptides from food proteins. Using an ampholyte-free isoelectric focusing (autofocusing) technique as a tool for fractionation, we successfully prepared fractions containing cationic peptides with multiple functions. PMID- 28100114 TI - Borderline personality disorder and the ethics of risk management: The action/consequence model. AB - Patients with borderline personality disorder are frequent users of inpatient mental health units, with inpatient crisis intervention often used based on the risk of suicide. However, this can present an ethical dilemma for nursing and medical staff, with these clinician responses shifting between the moral principles of beneficence and non-maleficence, dependent on the outcomes of the actions of containing or tolerating risk. This article examines the use of crisis intervention through moral duties, intentions and consequences, culminating in an action/consequence model of risk management, used to explore potential outcomes. This model may be useful in measuring adherence and violation of the principles of beneficence and non-maleficence and therefore an aid to clinical decision making. PMID- 28100115 TI - Paternal Age Is Not Associated With Pregnancy Outcomes After Single Thawed Euploid Blastocyst Transfer. AB - Although controversial, increasing paternal age has been shown to negatively affect assisted reproductive technology (ART) outcomes and success rates. Most studies investigating the effect of paternal age on ART outcomes use a donor oocyte model to minimize maternal aneuploidy contribution. This study sought to determine whether increasing paternal age is associated with adverse in vitro fertilization (IVF) outcomes when aneuploidy is minimized using preimplantation genetic screening. There were 573 single thawed euploid embryo transfers from 473 patients undergoing oocyte donor and autologous IVF cycles. Cycles were categorized according to paternal age at oocyte retrieval, and an age adjustment was performed for maternal age in order to evaluate for an isolated paternal age effect. Fertilization rate was found to decrease significantly with increasing paternal age ( P = .04). After controlling for oocyte age, there was no significant difference in pregnancy outcomes across all paternal age categories after euploid embryo transfer, including implantation rate ( P = .23), clinical pregnancy rate ( P = .51), and spontaneous abortion rate ( P = .55). Therefore, if a couple is able to produce and transfer a single thawed euploid embryo, no difference in IVF pregnancy outcomes is identified with increasing paternal age. PMID- 28100116 TI - Physician opinions concerning legal abortion in Bogota, Colombia. AB - Since the decriminalisation of abortion in 2006, women in Colombia have continued to seek clandestine abortions, endangering their health and contributing to maternal mortality and morbidity. The goal of this study was to explore physicians' opinions towards and knowledge about legal abortion in Bogota, Colombia, and key barriers to the legal abortion access. We conducted 13 key informant interviews followed by a survey with a probability sample of 49 doctors working in public hospitals in Bogota. Interview and survey data showed lack of technical experience in the provision of abortion and nuanced opinions towards its practice. Key informants described ignorance and lack of abortion training in medical schools as key barriers to provision. In the survey, 16/49 respondents had performed an abortion, 24/49 had referred a woman for an abortion and only 33/49 showed correct knowledge of the law. PMID- 28100117 TI - Evaluating the usability of a commercial cooling vest in the Hong Kong industries. AB - OBJECTIVE: The provision of appropriate personal cooling vests is recognized as an effective measure to combat heat stress. However, personal cooling vests are not widely implemented in the Hong Kong industries. The current study aims to evaluate the usability of a hybrid cooling vest that is associated with the success of its application in industrial settings. METHODS: A self-administrated questionnaire focusing on 10 subjective attributes of cooling effect, ergonomic design and usability of a hybrid cooling vest was administered with 232 occupational workers in the construction, horticultural and cleaning, airport apron services and kitchen and catering industries. RESULTS: A structural equation model estimated by analysis of moment structures was constructed to evaluate the usability of the cooling vest, as influenced by cooling effect and ergonomic design. Results showed that cooling effect (path coefficient = 0.69, p < 0.001) and ergonomic design (path coefficient = 0.55, p < 0.001) significantly affect the usability of the cooling vest. CONCLUSIONS: The structural equation model is feasible to examine the complex nature of the structural relationships among the subjective perceptions of personal cooling vests. The empirical findings furnish sound evidence for further optimization of the hybrid cooling vest in terms of cooling effect and ergonomic design for occupational workers. PMID- 28100118 TI - Assessing Sexual Interest in Children Using the Go/No-Go Association Test. AB - The present study investigated whether a latency-based Go/No-Go Association Task (GNAT) could be used as an indirect measure of sexual interest in children. A sample of 29 individuals with a history of exclusive extrafamilial offenses against a child and 15 individuals with either a history of exclusive intrafamilial or mixed offenses (i.e., against both adults and children) were recruited from a treatment center in the United States. Also, a sample of 26 nonoffenders was recruited from a university in the United Kingdom. All participants completed the Sexual Fantasy-GNAT, a Control-GNAT, and two self report measures of sexual fantasy. It was hypothesized that, relative to the two comparison groups, the extrafamilial group would respond faster on the block that paired "sexual fantasy" and "children." Also, GNAT scores were expected to correlate with child-related sexual fantasies. Support was found for both hypotheses. Response-latency indices were also found to effectively distinguish the extrafamilial group, as well as those who self-reported using child-related sexual fantasies. The implications of these findings, along with the study's limitations and suggestions for future research, are discussed. PMID- 28100119 TI - Distribution of saccharides and salts on amphoteric ion-exchange resin. AB - An amphoteric ion-exchange resin hardly shrank in 550 and 300 g/L glucose and sodium chloride solutions, respectively; however, the bed packed with a cation exchange resin shrank considerably. From the distribution coefficients of some saccharides, the swelling pressure of the amphoteric ion-exchange resin was estimated to be 2.0 MPa at 25 degrees C. The distribution coefficients of glucose, galactose, fructose, and mannose were independent of their concentration and were about 0.621. On the other hand, the apparent distribution coefficients of NaF, NaCl, NaBr, NaI, LiCl, KCl, and CsCl largely depended on concentration. A model for the distribution of salts on the amphoteric resin was proposed, assuming an interaction between the anion of the salt and the positively charged fixed ions with binding constant B. The B values of the chloride salts were nearly the same (1.69-2.94 L/mol), while the values of the sodium salts were largely different depending on the anion. PMID- 28100120 TI - Hybrid Stage I Procedure as Initial Palliation for Neonate With Hypoplastic Left Heart Syndrome and Right Congenital Diaphragmatic Hernia. AB - During the past decade, a hybrid procedure has emerged and dramatically evolved as an alternative stage I palliation to the conventional Norwood procedure in neonates with hypoplastic left heart syndrome (HLHS). The hybrid approach avoids the need for cardiopulmonary bypass (CPB) utilizing stenting of the arterial duct and bilateral pulmonary artery banding. Cerebral and coronary perfusion pressure is maintained, and the pulmonary vasculature is protected from higher systemic pressure. Elimination of risks associated with CPB gains vital time to stabilize the patient and correct coexisting noncardiac anomalies and allows growth in preparation for the later stages of the Fontan pathway. The association of HLHS with right congenital diaphragmatic hernia (CDH) is rare. We report performing a successful hybrid stage I palliation on a neonate with HLHS and severe right CDH. PMID- 28100121 TI - Effects of bovine pregnancy on the fatty acid composition of milk: the significance for humans needs. AB - Milk from 40 Holstein dairy cows was collected from two different farms in Galicia (Spain). The differences in the fatty acid composition of two groups of cows, 20 pregnant and 20 non-pregnant, was studied to determine whether pregnancy status is a determinant factor that can alter the fatty acid profile of milk. Gas chromatography (GC) coupled to flame ionisation detection (FID) was used for the determination of the fatty acids. Differences in the milk fatty acids between pregnant and non-pregnant cows were pronounced showing statistically significant differences for some fatty acids and the total saturated and monounsaturated fatty acids. Milk from non-pregnant cows was lower in saturated fatty acids and higher in monounsaturated fatty acids (unlike milk from pregnant cows). The effects of the consumption of bovine milk, particularly milk fat, on human health have been studied in depth and sometimes are associated with negative effects, but milk has also several beneficial characteristics linked to some fatty acids. PMID- 28100122 TI - Using the self-determination theory to understand Chinese adolescent leisure-time physical activity. AB - PURPOSES: This study applies the self-determination theory (SDT) to test the hypothesized relationships among perceived autonomy support from parents, physical education (PE) teachers, and peers, the fulfilment of psychological needs (i.e., autonomy, competence, and relatedness), autonomous motivation, and leisure-time physical activity of Chinese adolescents. METHOD: There are 255 grade six to eight student participants from four middle schools around Shanghai, China included in this study. An accelerometer was used to measure the moderate to-vigorous physical activity (MVPA). The participants completed the questionnaires regarding SDT variables. The structural equation modelling was applied to examine the hypothesized relationships among the study variables. RESULTS: The model of hypothesized relationships demonstrated a good fit with the data [X2 = 20.84, df = 9, P = .01; CFI = 0.98; IFI = 0.98; SRMR = 0.04; RMSEA = 0.05]. The findings revealed that autonomy support from parents, PE teachers, and peers foster social conditions in which the three basic psychological needs can be met. In turn, autonomy, competence, and relatedness are positively associated with autonomous motivation for MVPA. The autonomous motivation positively relates to the MVPA time of adolescents. The three psychological needs partially mediate the influence of autonomy support from parents (beta = 0.18, P < .01; Bootstrap 95% CI = 0.06-0.33) and teachers (beta = 0.17, P < .01; Bootstrap 95% CI = 0.03 0.26) in the autonomous motivation. CONCLUSION: In conclusion, these findings support the applicability of SDT in understanding and promoting physical activity of Chinese adolescents. PMID- 28100123 TI - Relay exchanges in elite short track speed skating. AB - In short track speed skating, the relay exchange provides an additional strategic component to races by allowing a team to change the skater involved in the pack race. Typically executed every 11/2 laps, it is the belief of skaters and coaches that during this period of the race, time can be gained or lost due to the execution of the relay exchange. As such, the aim of this study was to examine the influence of the relay exchange on a team's progression through a 5000 m relay race. Using data collected from three World Cup relay events during the 2012-2013 season, the time taken to complete the straight for the scenarios with and without the relay exchange were compared at different skating speeds for the corner exit prior to the straight. Overall, the influence of the relay exchange was found to be dependent on this corner exit speed. At slower corner exit speeds (12.01-13.5 m/s), relay exchange straight times were significantly faster than the free skating scenario (P < 0.01). While at faster corner exit speeds (14.01 15 m/s), straight times were significantly slower (P < 0.001). The findings of this study suggest that the current norm of executing relay exchanges every 11/2 laps may not be optimal. Instead, varying the frequency of relay exchange execution throughout the race could allow: (1) time to be gained relative to other teams; and (2) facilitate other race strategies by providing an improved opportunity to overtake. PMID- 28100124 TI - Compelling overuse injury incidence in youth multisport athletes. AB - The present investigation was carried out to examine the incidence and pattern of injuries in adolescent multisport athletes from youth sports academy. Injury data were prospectively collected from 166 athletes during the seasons from 2009 to 2014. A total of 643 injuries were identified, 559 (87.0%) were time-loss injuries. The overall injury incidence was 5.5 (95% confidence interval CI: 5.1 6.0), the incidence of time-loss injuries was 4.8 (95% CI: 4.4-5.2), the incidence of growth conditions was 1.2 (95% CI: 1.0-1.4) and incidence of serious injuries was 0.6 (95% CI: 0.5-0.8) per 1000 h of exposure. The prevalence of overuse injuries was 50.3%. Growth conditions represented 20.0%. Most of the injuries (67.0%) involved the lower extremities, and both foot and ankle were the most predominant injured body parts (22.0%). Knee injuries were mostly from overuse (50 vs. 23, p = .02), whereas foot and ankle injuries resulted from an acute mechanism (94 vs. 31, p < .0001). Minor and moderate injuries accounted for 87.0%. Muscle, tendon and osteochondrosis injuries accounted for 52.0% of all injuries. Comparing groups, squash sport was having the highest injury incidence (8.5 injuries per athlete). Higher exposure was associated with greater overuse relative risk (RR = 1.03, 95% CI: 1.01-1.014, p < .001). In conclusion, the results of this study identified a high incidence of injuries in this youth sports population. Striking was the prevalence of overuse injuries of 50%, which suggests the need for injury prevention protocols for adolescent highly trained athletes. PMID- 28100125 TI - Sulphur dioxide in meat products: 3-year control results of an accredited Italian laboratory. AB - Sulphiting agents are well-known food preservatives. The European legislation does not allow their addition in fresh meat preparations. Therefore this type of food products has often been verified. To high sulphite levels in food is a health safety risk, due to toxic effects that these compounds may exercise on humans. In this study the control activity as performed by an Italian accredited laboratory from 2013 to 2015, relating to determination of sulphites in meat products, is described. Six hundred and sixty-nine meat product samples were analysed. Both applied techniques, a screening method (malachite green test) and a confirmatory method (ion chromatography), were accredited. Forty-three samples resulted positive at screening test and nineteen of these samples showed high sulphite concentrations, in the range 67.6-1437 mg kg-1. The non-negligible percentage of positives (6.4%) and the high concentrations verified confirmed that the control of sulphuring treatment of fresh meat preparations is an important task for organisations in charge of food inspections and control. PMID- 28100126 TI - Everolimus-Eluting Stent for Patients With Critical Limb Ischemia and Infrapopliteal Arterial Occlusive Disease. AB - BACKGROUND: Critical limb ischemia (CLI), despite revascularization, may result in minor or major amputations with devastating psychological effects and a negative impact on patient survival. Randomized clinical trials demonstrated that drug-eluting stents improve 1-year primary patency and decrease target lesion revascularization, compared to standard angioplasty and bare-metal stents, in patients with short occlusive below-the-knee lesions. OBJECTIVES: This prospective clinical study was designed to evaluate if one straight-line flow revascularization to the foot, using Xience-Prime Everolimus-Eluting Stent (EES), is an effective treatment of patients in Rutherford-Becker category 4 to 5 with distal popliteal and proximal tibial arteries long occlusive lesions up to 10 cm. METHODS: All patients with angiographic documented segment P3 of popliteal artery and proximal tibial arteries stenosis >70%, and lesion length between 20 mm and 100 mm, meeting the inclusion criteria, were included in the Etna Registry. The end points assessed were 1- and 3-year primary patency, major amputation-free survival, target lesion revascularization, and wound healing rates. RESULTS: Between June 2011 and April 2014, 122 patients were included in the study, with mean lesion length of 52.7 mm (range: 20-100 mm). The 1- and 3-year primary patency rates were 88.9% and 80.1%, respectively. The survival, major amputation free survival, and target lesion revascularization rates were 88.1%, 93%, and 91.5% at 1-year and 70.4%, 89.3%, and 85.1% at 3-year follow-up, respectively. Primary patency influenced major amputation rate, which was 60% in patients with no target artery patency versus 5.4% in patients with patency ( P = .022). At 1 year follow-up, 78 (88.6%) of 88 patients improved 1 or more of their Rutherford Becker category, and 48 (80%) of 69 patients had wound healing. CONCLUSIONS: The results of our study suggest that a conservative approach, with EES, seems feasible in selected patients with CLI and infrapopliteal artery occlusive disease. PMID- 28100127 TI - Response to "Management of Acute Mesenteric Ischemia: A Critical Review and Treatment Algorithm". PMID- 28100128 TI - Multidisciplinary sleep clinic: A patient-centered approach. PMID- 28100129 TI - Red spots. PMID- 28100130 TI - Influence of cold-water immersion on limb blood flow after resistance exercise. AB - This study determined the influence of cold (8 degrees C) and cool (22 degrees C) water immersion on lower limb and cutaneous blood flow following resistance exercise. Twelve males completed 4 sets of 10-repetition maximum squat exercise and were then immersed, semi-reclined, into 8 degrees C or 22 degrees C water for 10-min, or rested in a seated position (control) in a randomized order on different days. Rectal and thigh skin temperature, muscle temperature, thigh and calf skin blood flow and superficial femoral artery blood flow were measured before and after immersion. Indices of vascular conductance were calculated (flux and blood flow/mean arterial pressure). The colder water reduced thigh skin temperature and deep muscle temperature to the greatest extent (P < .001). Reductions in rectal temperature were similar (0.2-0.4 degrees C) in all three trials (P = .69). Femoral artery conductance was similar after immersion in both cooling conditions, with both conditions significantly lower (55%) than the control post-immersion (P < .01). Similarly, there was greater thigh and calf cutaneous vasoconstriction (40-50%) after immersion in both cooling conditions, relative to the control (P < .01), with no difference between cooling conditions. These findings suggest that cold and cool water similarly reduce femoral artery and cutaneous blood flow responses but not muscle temperature following resistance exercise. PMID- 28100131 TI - Influence of activated sewage sludge amendment on PAH removal efficiency from a naturally contaminated soil: application of the landfarming treatment. AB - The removal of polycyclic aromatic hydrocarbons (PAHs) from a naturally co contaminated soil by PAHs and heavy metals with an initial concentration of 620 mg of total PAHs kg-1 dry soil was investigated. The efficiency of landfarming in removing phenanthrene, pyrene, benzo(a)pyrene and the group of total 16 US EPA PAHs was evaluated. The process was biostimulated by adding centrifuged activated sewage sludge (SS) as an organic amendment. The tested ratios of contaminated soil to SS were 1:2, 1:1, 1:0.5 and 1:0 as wet weight basis. The process performance was monitored through chemical, microbiological and ecotoxicological analyses during 105 days of incubation. The results of analyses demonstrated that the treatment without centrifuged SS achieved a significantly higher total 16 US EPA PAH removal efficiency (i.e. 32%) compared to treatments with amendment. In the same treatment, the removal efficiency of the PAH bioavailable fraction was 100% for phenanthrene, benzo(a)pyrene and the group of total 16 US EPA PAHs, whereas 76% for pyrene. Ecotoxicity test performed with bioluminescent bacteria Vibrio fischeri confirmed the effectiveness of landfarming. Finally, the results showed that indigenous microorganisms under certain and controlled operating conditions have greater potential for PAH biodegradation compared to allochthonous microorganisms. PMID- 28100132 TI - The Dogma of occlusal paradigms: What do we really have figured out? PMID- 28100133 TI - Development of the clinically adaptive multidimensional outcome survey. AB - OBJECTIVE: Routine outcome monitoring (ROM) has been strongly endorsed by psychotherapy researchers, but has yet to achieve widespread implementation in clinical settings. This article describes the development of the Clinically Adaptive Multidimensional Outcome Survey (CAMOS), an innovative ROM system that allows for local adaptation while providing high quality data. METHOD: Three hundred and four clients at a university counseling center and 211 female patients at an eating disorder treatment facility were administered the CAMOS at intake, and 118 took the CAMOS at both intake and discharge. Two models were developed and compared. Both models were developed using exploratory and confirmatory factor analysis. RESULTS: A five-factor model was found to have the best model fit, internal consistency, convergent validity, and discriminant validity. CONCLUSIONS: The CAMOS has evidence to support its reliability and validity as a measure of various dimensions of distress. Distinctive tailoring features of the CAMOS compared to other ROM measures are described. PMID- 28100134 TI - AVA/SVG Meeting Peebles, Scotland 8-10 April 2016. PMID- 28100135 TI - Whitman Richards (1932-2016). PMID- 28100136 TI - Barriers to access and uptake of antiretroviral therapy among HIV-positive men who have sex with men in Hanoi, Vietnam: from HIV testing to treatment. AB - Little is known about the experiences of Vietnamese men who have sex with men in accessing HIV testing and treatment. We aimed to explore barriers to access and uptake of antiretroviral therapy (ART) among HIV-positive men who have sex with men in Hanoi. During 2015, we conducted qualitative interviews with 35 participants recruited using snowball sampling based on previous research and social networks. Key individual impediments to ART uptake included inadequate preparation for a positive diagnosis and the dual stigmatisation of homosexuality and HIV and its consequences, leading to fear of disclosure of HIV status. Health system barriers included lack of clarity and consistency about how to register for and access ART, failure to protect patient confidentiality and a reticence by providers to discuss sexual identity and same-sex issues. Results suggest fundamental problems in the way HIV testing is currently delivered in Hanoi, including a lack of client-centred counselling, peer support and clear referral pathways. Overcoming these barriers will require educating men who have sex with men about the benefits of routine testing, improving access to quality diagnostic services and building a safe, confidential treatment environment for HIV-positive men to access, receive and remain in care. PMID- 28100137 TI - Corrigendum. PMID- 28100138 TI - Perceptions of Interdisciplinary Communication Among Correctional Health Care Providers. AB - Collaborative practice is a health care standard that improves patient outcomes through maximizing the use of resources and mutual work of all health care providers. Since collaborative practice depends on interdisciplinary communication, effective communication training for health care participants is imperative for success. This article presents the results of research that studied perceptions of interdisciplinary communication and collaborative practice among 24 health care personnel in three correctional facilities in Orange County, California. The research explored different approaches in terms of team structure, mutual support, situation monitoring, leadership, and communication practices. The study used questionnaires to examine the perceptions of teamwork and interdisciplinary communication and how they can be impacted by one educational session. The study results are discussed in terms of modern approaches to health care, including evidence-based practice, along with nationwide initiatives for improving the health of inmates with psychiatric issues. PMID- 28100139 TI - The Collision of Inmate and Patient. AB - Every year in France 100 inmates die in prison from illness, but their experiences with end of life (EOL) have not been investigated to date. The purpose of this article is to highlight the realities regarding inmates at the end of life, putting into perspective the viewpoints of the sick prisoners with those of the health and correctional professionals accompanying them. Based on qualitative research, the challenge is to identify potential barriers to palliative care for inmates in order to consider possible improvements. The study results reveal that EOL inmates were not fully considered as patients and did not benefit from a comprehensive palliative care approach. For most dying inmates, and according to many health professionals, compassionate release on medical grounds remains the best approach to deal with EOL issues. PMID- 28100140 TI - Human Rights and Dignity Behind Bars. AB - Death and dying in prisons constitute a topic of growing importance across the globe. Based on the contributions made in this special issue, we reflect on current debates and outline recommendations for dialogue and practice. Scientific dialogue across the Atlantic, and across the globe, provides insights into different national carceral systems and their ways of dealing with end of life behind bars. At the same time, the comparison also helps to identify basic needs and practices that can work in various settings. We identify several issues where further efforts need to be taken to deepen the dialogue. A common ground for all advancement of legislation and practice constitute the minimal level of rights to which every human being is entitled. PMID- 28100141 TI - Caring to Learn and Learning to Care. AB - The increasing numbers of aging and chronically ill prisoners incarcerated in Western nations is well-documented, as is the growing need for prison-based palliative and end-of-life care. Less often discussed is specifically how end-of life care can and should be provided, by whom, and with what resources. One strategy incorporates prisoner volunteers into end-of-life services within a peer care program. This article reports on one such program based on focused ethnographic study including in-depth interviews with inmate hospice volunteers, nursing staff, and corrections officers working in the hospice program. We describe how inmate volunteers learn hospice care through formal education and training, supervised practice, guidance from more experienced inmates, and support from correctional staff. We discuss how emergent values of mentorship and stewardship are seen by volunteers and staff as integral to prison hospice sustainability and discuss implications of this volunteer-centric model for response-ability for the end-of-life care of prisoners. PMID- 28100142 TI - Reduction in Jail Emergency Department Visits and Closure After Implementation of On-Site Urgent Care. AB - This descriptive study evaluates the impact of implementation of full service on site urgent care services at the Los Angeles County Jail (LACJ) by examining the number of patients seen at the referral hospital, Los Angeles County + University of Southern California Medical Center (LAC+USC), and the number of hours that the referral hospital was closed to transfers in the periods before and after the development of the LACJ Urgent Care. The appropriate utilization of public resources is a critical priority for an overburdened county medical health care system. Implementing on-site urgent care staffed by emergency physicians led to reductions in the average number of patients transferred to LAC+USC, the average number of monthly closure hours, and the average days per month when closure to transfer occurred, and a cost savings of some $2 million, primarily in personnel costs. PMID- 28100144 TI - Journal of Correctional Health Care. PMID- 28100143 TI - End of Life in High-Security Prisons in Switzerland. AB - Similar to other institutions, the Swiss prison system faces a growing number of elderly prisoners, trends toward securitization, and, in consequence, more prisoners who will spend the end-of-life (EOL) period of time in prison. By law, prisoners should have the same access to care as the rest of the population. However, custody makes meeting the demands of medical and palliative care difficult. This article focuses on the organizational challenges related to EOL care. Based on ethnographic and documentary research, it examines the institutional logic of the prison and the competing "new" logic emerging with EOL care. It illustrates the ambivalences within these logics and the blurred distinction between "care" and "custody" and evaluates how prison staff interpret this overlap and the effects in shaping everyday practices. PMID- 28100145 TI - Chronic Health Conditions Among Incoming Canadian Federally Sentenced Women. AB - Over a 13-month period, health data on all consecutive incoming Canadian federally sentenced women offenders were collected and analyzed ( N = 280). The most common health conditions cited were back pain, head injury, hepatitis C virus (HCV), and asthma. Rates of chronic health problems were generally similar to those of their male offender counterparts, with the notable exception of HCV, which was higher for women. Aboriginal women offenders had particularly high rates of HCV. The study provides valuable information on the self-reported physical health status of federally sentenced women offenders that can be used as a benchmark to examine health trends over time. PMID- 28100146 TI - Examining the Relationship Between Childhood Victimization, High-Risk Behaviors, and Health Among Criminal Justice-Involved Women. AB - The purpose of this study was to develop and test a conceptual model of the pathways through which childhood victimization influences adult health outcomes. Specifically, measures of high-risk behaviors, tobacco use, alcohol use, illegal substance use, and HIV risk behaviors were hypothesized to mediate the relationship between childhood victimization and adult physical health. The sample consisted of 406 women on probation and parole with a history of childhood victimization in Jefferson County, Kentucky. Structural equation modeling was used to examine the relationship between childhood victimization, high-risk behaviors, and physical health outcomes. The findings indicate partial mediation, with health risk behaviors accounting for 12.5% of the variance in the relationship between childhood victimization and health outcomes. Implications for policy and treatment practice in the health and criminal justice arena are discussed. PMID- 28100147 TI - Editor's Letter. PMID- 28100148 TI - Palliative Care in UK Prisons. AB - Despite falling crime rates in England and Wales over the past 20 years, the number of prisoners has doubled. People over the age of 50 constitute the fastest growing section of the prison population, and increasing numbers of older prisoners are dying in custody. This article discusses some of the issues raised by these changing demographics and draws on preliminary findings from a study underway in North West England. It describes the context behind the rise in the numbers of older prisoners; explores the particular needs of this growing population; and discusses some of the practical and emotional challenges for prison officers, health care staff, and fellow prisoners who are involved in caring for dying prisoners in a custodial environment. PMID- 28100149 TI - The Meaning of Ending Life in Prison. AB - There are many ways that life can end in prison. This article takes suicides, murder, and the whole life sentence as three forms of unnatural death that illustrate important features of the prison experience and that take on a special meaning in this environment. These forms of death in custody challenge the "legitimate penological purposes of imprisonment." Reflections on the importance of hope and dignity in prison are informed by this account. PMID- 28100150 TI - Polycyclic aromatic hydrocarbon levels and risk assessment for food from service facilities in Korea. AB - In this study, levels of benzo[a]anthracene, chrysene, benzo[b]fluoranthene, benzo[k]fluoranthene, benzo[a]pyrene (BaP), dibenzo[a,h]anthracene, benzo[g,h,i]perylene and indeno[1,2,3-c,d]pyrene in 412 food items collected from food service facilities in Korea were analysed. The concentrations of the eight polycyclic aromatic hydrocarbons (PAHs) ranged 0.13-0.48 MUg/kg. The concentrations of benzo[a]pyrene in all food samples were <1 MUg/kg, which is the lowest maximum limit in foods regulated by European Union legislation. PAH contents were employed to conduct exposure and risk assessment. The chronic daily intake of PAHs from 412 food samples was 5.48 * 10-6-4.70 *x 10-4 ug TEQBaP/kg/day with margins of exposure of 1.04 * 109-1.16 * 1011. PMID- 28100151 TI - Renin inhibition by soyasaponin I: a potent native anti-hypertensive compound. AB - One way to control hypertension is inactivation of the Renin- Angiotensin- Aldosterone System (RAAS). Inhibition of renin as a rate-limiting step of this system is an effective way to stop up RAAS. It has been proved that soyasaponin I, an herbal compound obtained from soybeans, has anti-hypertensive effect via renin inhibition, so it has the potential of being an anti-hypertensive drug. Herein, some theoretical approaches such as Docking Simulation, Molecular Dynamics (MD) Simulation and MMPBSA analysis have been used to study how soyasaponin I inhibits renin at the structural level. The results of docking simulation and hydrogen bond pattern show that this ligand is able to bind to the active site of renin and a region near the active site. Results of MD simulation for renin - soyasaponin I complexes confirm that soyasaponin I binds to the active site of renin and has inhibition effect on it via competing with the substrate. Besides, according to MMPBSA analysis, the binding free energy for renin - soyasaponin I complex is -42.61 kcal/mol when it binds to the active site. Comparing to the peptide obtained from angiotensinogen, DeltaG = -74.96 kcal/mol, it may inferred that although binding of soyasaponin I to the active site of renin does not have a complete competition with the substrate, it might attenuate the formation of renin - angiotensinogen complex and have partial non competitive effect. The results of this survey might be helpful to design partial non - competitive renin inhibitors with pharmaceutical capability. PMID- 28100152 TI - Rare Iatrogenic Cardiovascular Embolization Following Dialysis. AB - Intracardiac or intrapulmonary dislodgement of dialysis catheter or guidewire coating is extremely rare. When present, it can be potentially lethal as it may get complicated by arrhythmias, myocardial or pulmonary artery rupture, valvular perforation, pulmonary thromboembolism, infarction, and infective endocarditis. Percutaneous removal should be attempted as an initial measure and is usually effective in most of the cases. We report 2 such cases, where in first patient it was the hemodialysis catheter which broke, with a large part migrating into the heart, while in second patient, it was the hydrophilic coating of the guidewire that migrated into the pulmonary arteries. Percutaneous retrieval of these foreign bodies was done successfully in both the cases. PMID- 28100153 TI - Long-Term Survival After Coverage With Prevertebral Fascia for Abdominal Aortic Stump Closure. AB - Abdominal aortic graft-enteric fistula is an uncommon but grave complication. Acceptable early results of its management have been reported in recent years, but aortic stump disruption remains a dreaded problem in the remote period. This report describes a case of a 71-year-old male with graft-enteric fistula following after a distant abdominal aortic aneurysm repair. The patient underwent 1-stage operation with extra-anatomic bypass preceding the complete removal of the infected aortic graft and intestinal repair. For coverage of the aortic stump closure, the prevertebral fascia was harvested as a flap and was successfully used to buttress the closure. Additionally, omental wrap was secured around the stump and around the area after complete graft removal. Postoperative intravenous antibiotic with meropenem was administered for 8 weeks, followed by suppression with ongoing oral antibiotic with trimethoprim-sulfamethoxazole for 6 months. Although sigmoidectomy and the left ureteral reconstruction were required, the patient is doing well without recurrent infection and without stump disruption after 8 years of follow-up. PMID- 28100154 TI - One-Year Follow-Up After Hybrid Thoracoabdominal Aortic Repair. AB - BACKGROUND: Compared to open thoracoabdominal aortic aneurysm (TAAA) repair, hybrid repair is thought to be less invasive with better perioperative outcomes. Due to the extent of the operation and long recovery period, studying perioperative results may not be sufficient for evaluation of the true treatment effect. The aim of this study is to evaluate 1-year mortality and morbidity in patients with TAAA undergoing hybrid repair. METHODS: In a retrospective cohort study, all medical records of patients undergoing hybrid repair for TAAA at the Erasmus University Medical Center between January 2007 and January 2015 were studied. Primary outcome measures were 30-day and 1-year mortality. Secondary outcome measures included major in-hospital postoperative complications. RESULTS: A total of 15 patients were included. All-cause mortality was 33% (5 of the 15) at 30 days and 60% (9 of the 15) at 1 year. Aneurysm-related mortality was 33% (5 of the 15) and 53% (8 of the 15) at 30-day and 1-year follow-up, respectively, with colon ischemia being the most common cause of death. Major complication rate was high: myocardial infarction in 2 (13%) cases, acute kidney failure in 5 (33%) cases, bowel ischemia in 3 (20%) cases, and spinal cord ischemia in 1 (7%) case. CONCLUSION: The presumed less invasive nature of hybrid TAAA repair does not seem to result in lower complication rates. The high mortality rate at 30 days continues to rise dramatically thereafter, suggesting that 1-year mortality is a more useful clinical parameter to use in preoperative decision-making for this kind of repair. PMID- 28100155 TI - Management of Type II Endoleak From Internal Iliac Artery Immediately After Endovascular Aneurysm Repair. AB - Inadvertent coverage of origin of internal iliac artery (IIA) during endovascular aneurysm repair may lead to type II endoleak. Except for open surgery, the endovascular solution is limited. We report a case with such complication that was successfully treated with coil embolization using retrograde extrastent approach. This is a new technique that has not been reported before, and as such, had been useful in the treatment of type II endoleak from IIA as an alternative to open ligation of IIA origin. PMID- 28100156 TI - Transcatheter Embolization of Type I Endoleaks Associated With Endovascular Abdominal Aortic Aneurysm Repair Using Ethylene Vinyl Alcohol Copolymer. AB - PURPOSE: To evaluate the feasibility, safety, and outcome of transcatheter embolization using ethylene vinyl alcohol copolymer (EVOH) of type I endoleaks associated with endovascular abdominal aortic aneurysm repair. PATIENT POPULATION AND METHODS: Retrospective chart review was performed to identify 8 consecutive patients who had undergone EVOH embolization for type I endoleaks between 2012 and 2015. The primary approach used to access the endoleak was the perigraft technique, where the endoleak itself is catheterized at the anastomotic site. RESULTS: Six type Ia and 2 type Ib endoleaks were treated. In 2 patients, a direct transabdominal approach was used to access the endoleak because it was inaccessible via the perigraft approach. Coils were used in addition to EVOH in 5 cases. Residual endoleak was noted in 1 case, whereas 2 patients developed a recurrent type I endoleak during follow-up. No EVOH complications were observed. The 5 remaining patients demonstrated freedom from endoleak and reintervention at a mean follow-up of 6.9 months. CONCLUSION: Type I endoleaks can be safely and effectively treated by embolotherapy with EVOH. Larger endoleaks resulting from grossly undersized endografts appear to be unsuitable for EVOH embolization. PMID- 28100157 TI - Characterization of Planned and Unplanned 30-Day Readmissions Following Vascular Surgical Procedures. AB - OBJECTIVE: Thirty-day readmission is increasingly used as a quality of care indicator. Patients undergoing vascular surgery have historically been at high risk for readmission. We analyzed hospital readmission details to identify patients at high risk for readmission in order to better understand these readmissions and improve resource utilization in this patient population. METHODS: A retrospective review and analysis of our medical center's admission and discharge data were conducted from October 2012 to March 2015. All patients who were discharged from the vascular surgery service and subsequently readmitted as an inpatient within 30 days were included. RESULTS: We identified 649 vascular surgery discharges with 135 (21%) readmissions. Common comorbidities were diabetes (56%), coronary artery disease (40%), congestive heart failure (CHF; 24%), and chronic obstructive pulmonary disease (19%). Index vascular operations included open lower extremity procedures (39%), diagnostic angiograms (35%), endovascular lower extremity procedures (16%), dialysis access procedures (7%), carotid/cerebrovascular procedures (7%), amputations (6%), and abdominal aortic procedures (5%). Average index length of stay (LOS) was 7.48 days (+/-6.73 days). Reasons for readmissions were for medical causes (43%), surgical complications (35.5%), and planned procedures (21.5%). Reasons for medical readmissions most commonly included malaise or failure to thrive (28%), unrelated infection (24%), and hypoxia/CHF complications (21%). Common surgical causes for readmission were surgical site infections (69%), graft failure (19%), and bleeding complications (8%). Of the planned readmissions, procedures were at the same site (79%), a different site (14%), and planned podiatry procedures (7%). Readmission LOS was on average 7.43 days (+/-7.22 days). CONCLUSION: Causes for readmission of vascular surgery patients are multifactorial. Infections, both related and unrelated to the surgical site, remain common reasons for readmission and represent an opportunity for improvement strategies. Improved understanding of readmissions following vascular surgery could help adjust policy benchmarks for targeted readmission rates and help reduce resource utilization. PMID- 28100158 TI - Double Inferior Vena Cava (IVC) With Intrahepatic Interruption, Hemiazygos Vein Continuation, and Intrahepatic Venous Shunt. AB - The duplication of the inferior vena cava (IVC) is a rare congenital anomaly, which also has some variations regarding the complex embryological development of the IVC. In the typical form, infrarenal IVC segments are duplicated and the left IVC joins the left renal vein, which crosses anterior to the aorta in the normal fashion to join the right IVC. In variant forms, the interruption of the intrahepatic segment of the IVC, azygos or hemiazygos continuation, or retroaortic course of the renal vein may be seen. An intrahepatic venous shunt accompanying a double IVC variant is an extremely rare anomaly. We report a case of 40-year-old female patient with double IVC, hemiazygos continuation, intrahepatic IVC interruption, and a transhepatic venous shunt. PMID- 28100159 TI - Interventional Therapy for Transplant Renal Artery Stenosis Is Safe and Effective in Preserving Allograft Function and Improving Hypertension. AB - PURPOSE: To evaluate the outcomes of percutaneous intervention (PI) for transplant renal artery stenosis (TRAS). MATERIALS AND METHODS: Doppler ultrasonography was used as the screening tool, and angiography was the diagnostic method for TRAS. The indications for PI were (1) a reduction in lumen diameter of >50% or (2) a mean pressure gradient of >15 mm Hg. Technical success was assessed immediately after the procedure. The short-term results of stenosis were evaluated by serum creatinine (Scr) levels and blood pressure (BP). The long term results were assessed by graft survival and renal function. RESULTS: From October 2009 to July 2015, a total of 660 patients had kidney transplantation and 22 cases underwent PI. The technical success was 100%. The mean Scr level preintervention was 321.6 +/- 167.2 (range, 171.3-862.0) MUmol/L, and it decreased to 145.3 +/- 44.7 (range, 74.3-260.8) MUmol/L 1 month postintervention ( P < .001). Blood pressure was also improved at 1 month postintervention, as assessed by systolic (157.0 +/- 13.0 vs 131.0 +/- 11.0 mm Hg, P < .001), diastolic (95.0 +/- 5.0 vs 77.0 +/- 9.0 mm Hg, P < .001), and mean arterial pressure (116.0 +/- 7.0 vs 95.0 +/- 9.0 mm Hg, P < .001). The patency rate was 100%, 91.7%, and 85.7% at 1, 3, and 12 months, respectively. The secondary patency rate was 100%. Graft survival was 100% during follow-up. There was no significant deterioration in graft function or BP ( P > .05) postintervention when compared to posttransplantation. CONCLUSIONS: Percutaneous intervention for TRAS is safe and results in significant improvement both in allograft function and in BP. PMID- 28100161 TI - Retraction Notice - 3. PMID- 28100160 TI - Determining the potential benefits of yoga in chronic stroke care: a systematic review and meta-analysis. AB - BACKGROUND: Survivors of stroke have long-term physical and psychological consequences that impact their quality of life. Few interventions are available in the community to address these problems. Yoga, a type of mindfulness-based intervention, is shown to be effective in people with other chronic illnesses and may have the potential to address many of the problems reported by survivors of stroke. OBJECTIVES: To date only narrative reviews have been published. We sought to perform, the first systematic review with meta-analyses of randomized controlled trials (RCTs) that investigated yoga for its potential benefit for chronic survivors of stroke. METHODS: Ovid Medline, CINHAL plus, AMED, PubMed, PsychINFO, PeDro, Cochrane database, Sport Discuss, and Google Scholar were searched for papers published between January 1950 and August 2016. Reference lists of included papers, review articles and OpenGrey for Grey literature were also searched. We used a modified Cochrane tool to evaluate risk of bias. The methodological quality of RCTs was assessed using the GRADE approach, results were collated, and random effects meta-analyses performed where appropriate. RESULTS: The search yielded five eligible papers from four RCTs with small sample sizes (n = 17-47). Quality of RCTs was rated as low to moderate. Yoga is beneficial in reducing state anxiety symptoms and depression in the intervention group compared to the control group (mean differences for state anxiety 6.05, 95% CI:-0.02 to 12.12; p = 0.05 and standardized mean differences for depression: 0.50, 95% CI:-0.01 to 1.02; p = 0.05). Consistent but nonsignificant improvements were demonstrated for balance, trait anxiety, and overall quality of life. CONCLUSIONS: Yoga may be effective for ameliorating some of the long-term consequences of stroke. Large well-designed RCTs are needed to confirm these findings. PMID- 28100162 TI - Retraction Notice - 2. PMID- 28100163 TI - A Vector-Based Short Hairpin RNA Targeting Aurora B Suppresses Human Prostatic Carcinoma Growth. AB - Aurora kinase B, playing a vital, important role in mitosis, is frequently detected to be overexpressed in many cancer cell lines and various tumor tissues, including prostatic carcinoma. Given the essential function of Aurora kinase B in mitosis and its association with tumorigenesis, it might be a drug target for prostatic carcinoma treatment. In our study, short hairpin RNA targeting Aurora kinase B was cloned into a pGPU6 plasmid vector and then transfected into human prostatic carcinoma cells. The expression level of Aurora kinase B was verified by reverse transcription-polymerase chain reaction and Western blot. At the same time, cell apoptosis was detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide, fluorescent staining, and flow cytometric analysis. Furthermore, prostate carcinoma cells were injected into mice to establish a tumor xenograft model. Previous studies have shown the effect of pGPU6-shAURKB plasmid on tumor growth in a prostate carcinoma xenogenic implantation model. From the study, we knew that the Aurora kinase B was significantly downregulated in prostate carcinoma cells, and cell apoptosis was also detected higher in treated groups than that in control groups. Moreover, in the prostate carcinoma xenogenic implantation model, compared with the control groups, the tumor growth was inhibited about 78.7% in the pGPU6-shAURKB plasmid-treated group, and cell apoptosis in the experimental group was notably higher than that in control groups. The average duration of tumor-bearing mice was prolonged to about 35 days. The results of experiment indicated that specific knockdown of Aurora kinase B led to prostate carcinoma cells apoptosis and inhibited tumor growth. Our data clearly confirmed that specific knockdown of Aurora kinase B expression by vector-based short hairpin RNA/liposome may be a potential new approach to treat human prostatic carcinoma. PMID- 28100164 TI - Relation between arterial stiffness and aerobic capacity: Importance of proximal aortic stiffness. AB - Brachial-ankle pulse wave velocity (baPWV) has become a popular modality of arterial stiffness measurement. However, its projected arterial segment does not include the proximal aorta which plays important roles for attenuating cardiac pulsation and reducing afterload. We hypothesised that aerobic capacity would be more strongly associated with PWV including the proximal aorta than that omitting the proximal aorta. To test our hypothesis, we compared the association between aerobic capacity and arterial stiffness parameters omitting vs. including the proximal aorta (i.e. baPWV vs. heart-ankle PWV [haPWV]) in 82 apparently healthy men (18-64 years). Estimated VO2max significantly correlated with baPWV (r = 0.394, P < .001), and more strongly with haPWV (r = -0.546, P < .001). The forward stepwise multi-regression analysis revealed that haPWV (beta = -0.335), as well as age, heart rate, and body mass index (beta = -0.280 to -0.297), was a significant independent determinant explaining variance of estimated VO2max. These results suggest that aerobic capacity is influenced more strongly by the proximal aortic stiffness than distal aortic stiffness. PMID- 28100165 TI - Genomic predictions for economically important traits in Brazilian Braford and Hereford beef cattle using true and imputed genotypes. AB - BACKGROUND: Genomic selection (GS) has played an important role in cattle breeding programs. However, genotyping prices are still a challenge for implementation of GS in beef cattle and there is still a lack of information about the use of low-density Single Nucleotide Polymorphisms (SNP) chip panels for genomic predictions in breeds such as Brazilian Braford and Hereford. Therefore, this study investigated the effect of using imputed genotypes in the accuracy of genomic predictions for twenty economically important traits in Brazilian Braford and Hereford beef cattle. Various scenarios composed by different percentages of animals with imputed genotypes and different sizes of the training population were compared. De-regressed EBVs (estimated breeding values) were used as pseudo-phenotypes in a Genomic Best Linear Unbiased Prediction (GBLUP) model using two different mimicked panels derived from the 50 K (8 K and 15 K SNP panels), which were subsequently imputed to the 50 K panel. In addition, genomic prediction accuracies generated from a 777 K SNP (imputed from the 50 K SNP) were presented as another alternate scenario. RESULTS: The accuracy of genomic breeding values averaged over the twenty traits ranged from 0.38 to 0.40 across the different scenarios. The average losses in expected genomic estimated breeding values (GEBV) accuracy (accuracy obtained from the inverse of the mixed model equations) relative to the true 50 K genotypes ranged from -0.0007 to -0.0012 and from -0.0002 to -0.0005 when using the 50 K imputed from the 8 K or 15 K, respectively. When using the imputed 777 K panel the average losses in expected GEBV accuracy was -0.0021. The average gain in expected EBVs accuracy by including genomic information when compared to simple BLUP was between 0.02 and 0.03 across scenarios and traits. CONCLUSIONS: The percentage of animals with imputed genotypes in the training population did not significantly influence the validation accuracy. However, the size of the training population played a major role in the accuracies of genomic predictions in this population. The losses in the expected accuracies of GEBV due to imputation of genotypes were lower when using the 50 K SNP chip panel imputed from the 15 K compared to the one imputed from the 8 K SNP chip panel. PMID- 28100166 TI - SMITE: an R/Bioconductor package that identifies network modules by integrating genomic and epigenomic information. AB - BACKGROUND: The molecular assays that test gene expression, transcriptional, and epigenetic regulation are increasingly diverse and numerous. The information generated by each type of assay individually gives an insight into the state of the cells tested. What should be possible is to add the information derived from separate, complementary assays to gain higher-confidence insights into cellular states. At present, the analysis of multi-dimensional, massive genome-wide data requires an initial pruning step to create manageable subsets of observations that are then used for integration, which decreases the sizes of the intersecting data sets and the potential for biological insights. Our Significance-based Modules Integrating the Transcriptome and Epigenome (SMITE) approach was developed to integrate transcriptional and epigenetic regulatory data without a loss of resolution. RESULTS: SMITE combines p-values by accounting for the correlation between non-independent values within data sets, allowing genes and gene modules in an interaction network to be assigned significance values. The contribution of each type of genomic data can be weighted, permitting integration of individually under-powered data sets, increasing the overall ability to detect effects within modules of genes. We apply SMITE to a complex genomic data set including the epigenomic and transcriptomic effects of Toxoplasma gondii infection on human host cells and demonstrate that SMITE is able to identify novel subnetworks of dysregulated genes. Additionally, we show that SMITE outperforms Functional Epigenetic Modules (FEM), the current paradigm of using the spin-glass algorithm to integrate gene expression and epigenetic data. CONCLUSIONS: SMITE represents a flexible, scalable tool that allows integration of transcriptional and epigenetic regulatory data from genome-wide assays to boost confidence in finding gene modules reflecting altered cellular states. PMID- 28100167 TI - Conserved gene expression in sperm reservoirs between birds and mammals in response to mating. AB - BACKGROUND: Spermatozoa are stored in the oviductal functional sperm reservoir in animals with internal fertilization, including zoologically distant classes such as pigs or poultry. They are held fertile in the reservoir for times ranging from a couple of days (in pigs), to several weeks (in chickens), before they are gradually released to fertilize the newly ovulated eggs. It is currently unknown whether females from these species share conserved mechanisms to tolerate such a lengthy presence of immunologically-foreign spermatozoa. Therefore, global gene expression was assessed using cDNA microarrays on tissue collected from the avian utero-vaginal junction (UVJ), and the porcine utero-tubal junction (UTJ) to determine expression changes after mating (entire semen deposition) or in vivo cloacal/cervical infusion of sperm-free seminal fluid (SF)/seminal plasma (SP). RESULTS: In chickens, mating changed the expression of 303 genes and SF-infusion changed the expression of 931 genes, as compared to controls, with 68 genes being common to both treatments. In pigs, mating or SP-infusion changed the expressions of 1,722 and 1,148 genes, respectively, as compared to controls, while 592 genes were common to both treatments. The differentially expressed genes were significantly enriched for GO categories related to immune system functions (35.72-fold enrichment). The top 200 differentially expressed genes of each treatment in each animal class were analysed for gene ontology. In both pig and chicken, an excess of genes affecting local immune defence were activated, though frequently these were down-regulated. Similar genes were found in both the chicken and pig, either involved in pH-regulation (SLC16A2, SLC4A9, SLC13A1, SLC35F1, ATP8B3, ATP13A3) or immune-modulation (IFIT5, IFI16, MMP27, ADAMTS3, MMP3, MMP12). CONCLUSION: Despite being phylogenetically distant, chicken and pig appear to share some gene functions for the preservation of viable spermatozoa in the female reservoirs. PMID- 28100168 TI - Effects of Pleistocene sea-level fluctuations on mangrove population dynamics: a lesson from Sonneratia alba. AB - BACKGROUND: A large-scale systematical investigation of the influence of Pleistocene climate oscillation on mangrove population dynamics could enrich our knowledge about the evolutionary history during times of historical climate change, which in turn may provide important information for their conservation. RESULTS: In this study, phylogeography of a mangrove tree Sonneratia alba was studied by sequencing three chloroplast fragments and seven nuclear genes. A low level of genetic diversity at the population level was detected across its range, especially at the range margins, which was mainly attributed to the steep sea level drop and associated climate fluctuations during the Pleistocene glacial periods. Extremely small effective population size (Ne) was inferred in populations from both eastern and western Malay Peninsula (44 and 396, respectively), mirroring the fragility of mangrove plants and their paucity of robustness against future climate perturbations and human activity. Two major genetic lineages of high divergence were identified in the two mangrove biodiversity centres: the Indo-Malesia and Australasia regions. The estimated splitting time between these two lineages was 3.153 million year ago (MYA), suggesting a role for pre-Pleistocene events in shaping the major diversity patterns of mangrove species. Within the Indo-Malesia region, a subdivision was implicated between the South China Sea (SCS) and the remaining area with a divergence time of 1.874 MYA, corresponding to glacial vicariance when the emerged Sunda Shelf halted genetic exchange between the western and eastern coasts of the Malay Peninsula during Pleistocene sea-level drops. Notably, genetic admixture was observed in populations at the boundary regions, especially in the two populations near the Malacca Strait, indicating secondary contact between divergent lineages during interglacial periods. These interregional genetic exchanges provided ample opportunity for the re-use of standing genetic variation, which could facilitate mangrove establishment and adaptation in new habitats, especially in the context of global climate changes. CONCLUSION: Phylogeogrpahic analysis in this study reveal that Pleistocene sea-level fluctuations had profound influence on population differentiation of the mangrove tree S. alba. Our study highlights the fragility of mangrove plants and offers a guide for the conservation of coastal mangrove communities experiencing ongoing changes in sea-level. PMID- 28100169 TI - Medium throughput bisulfite sequencing for accurate detection of 5-methylcytosine and 5-hydroxymethylcytosine. AB - BACKGROUND: Epigenetic modifications of DNA, such as 5-methylcytosine and 5 hydroxymethycytosine, play important roles in development and disease. Here, we present a cost-effective and versatile methodology for the analysis of DNA methylation in targeted genomic regions, which comprises multiplexed, PCR-based preparation of bisulfite DNA libraries followed by customized MiSeq sequencing. RESULTS: Using bisulfite and oxidative bisulfite conversion of DNA, we have performed multiplexed targeted sequencing to analyse several kilobases of genomic DNA in up to 478 samples, and achieved high coverage data of 5-methylcytosine and 5-hydroxymethycytosine at single-base resolution. Our results demonstrate the ability of this methodology to detect all levels of cytosine modifications at greater than 100* coverage in large sample sets at low cost compared to other targeted methods. CONCLUSIONS: This approach can be applied to multiple settings, from candidate gene to clinical studies, and is especially useful for validation of differentially methylated or hydroxymethylated regions following whole-genome analyses. PMID- 28100170 TI - Interaction between acyl-ghrelin and BMI predicts clinical outcomes in hemodialysis patients. AB - BACKGROUND: Ghrelin, a gastric orexigenic peptide, and body mass index (BMI) are known as inversely associated to each other and are both linked to cardiovascular (CV) risk and mortality in maintenance hemodialysis (MHD) patients. However, it is unclear whether the interaction between ghrelin and BMI is associated with a risk of all-cause and CV death in this population. METHODS: A prospective observational study was performed on 261 MHD outpatients (39% women, mean age 68.6 +/- 13.6 years) recruited from October 2010 through April 2012, and were followed until November 2014 (median follow-up-28 months, interquartile range-19 34 months). We measured acyl-ghrelin (AG) levels, appetite, nutritional and inflammatory markers, prospective all-cause and cardiovascular (CV) mortality. RESULTS: During follow-up, 109 patients died, 51 due to CV causes. A significant interaction effect of high BMI and high AG (defined as levels higher than median) on all-cause mortality was found. Crude Cox HR for the product termed BMI x AG was 0.52, with a 95% confidence interval (CI): 0.29 to 0.95 (P = 0.03). Evaluating the interaction on an additive scale revealed that the combined predictive value of BMI and AG is larger than the sum of their individual predictive values (synergy index was 1.1). Across the four BMI-AG categories, the group with high BMI and high AG exhibited better all-cause and cardiovascular mortality irrespective of appetite and nutritional status (multivariable adjusted hazard ratios were 0.31, 95% CI 0.16 to 0.62, P = 0.001, and 0.35, 95% CI 0.13 to 0.91, P = 0.03, respectively). Data analyses made by dividing patients according to fat mass-AG, but not to lean body mass-AG categories, provided similar results. CONCLUSIONS: Higher AG levels enhance the favourable association between high BMI and survival in MHD patients irrespective of appetite, nutritional status and inflammation. PMID- 28100171 TI - Genome-wide standing variation facilitates long-term response to bidirectional selection for antibody response in chickens. AB - BACKGROUND: Long-term selection experiments provide a powerful approach to gain empirical insights into adaptation, allowing researchers to uncover the targets of selection and infer their contributions to the mode and tempo of adaptation. Here we implement a pooled genome re-sequencing approach to investigate the consequences of 39 generations of bidirectional selection in White Leghorn chickens on a humoral immune trait: antibody response to sheep red blood cells. RESULTS: We observed wide genome involvement in response to this selection regime. Many genomic regions were highly differentiated resulting from this experimental selection regime, an involvement of up to 20% of the chicken genome (208.8 Mb). While genetic drift has certainly contributed to this, we implement gene ontology, association analysis and population simulations to increase our confidence in candidate selective sweeps. Three strong candidate genes, MHC, SEMA5A and TGFBR2, are also presented. CONCLUSIONS: The extensive genomic changes highlight the polygenic genetic architecture of antibody response in these chicken populations, which are derived from a common founder population, demonstrating the extent of standing immunogenetic variation available at the onset of selection. PMID- 28100172 TI - Integrated genomics-based mapping reveals the genetics underlying maize flavonoid biosynthesis. AB - BACKGROUND: Flavonoids constitute a diverse class of secondary metabolites which exhibit potent bioactivities for human health and have been indicated to play an important role in plant development and defense. However, accumulation and variation of flavonoid content in diverse maize lines and the genes responsible for their biosynthesis in this important crop remain largely unknown. In this study, we combine genetic mapping, metabolite profiling and gene regulatory network analysis to further enhance understanding of the maize flavonoid pathway. RESULTS: We repeatedly detected 25 QTL corresponding to 23 distinct flavonoids across different environments or populations. In addition, a total of 39 genes were revealed both by an expression based network analysis and genetic mapping. Finally, the function of three candidate genes, including two UDP glycosyltransferases (UGT) and an oxygenase which belongs to the flavone synthase super family, was revealed via preliminary molecular functional characterization. CONCLUSION: We explored the genetic influences on the flavonoid biosynthesis based on integrating the genomic, transcriptomic and metabolomic information which provided a rich source of potential candidate genes. The integrated genomics based genetic mapping strategy is highly efficient for defining the complexity of functional genetic variants and their respective regulatory networks as well as in helping to select candidate genes and allelic variance before embarking on laborious transgenic validations. PMID- 28100173 TI - Whole genome-wide transcript profiling to identify differentially expressed genes associated with seed field emergence in two soybean low phytate mutants. AB - BACKGROUND: Seed germination is important to soybean (Glycine max) growth and development, ultimately affecting soybean yield. A lower seed field emergence has been the main hindrance for breeding soybeans low in phytate. Although this reduction could be overcome by additional breeding and selection, the mechanisms of seed germination in different low phytate mutants remain unknown. In this study, we performed a comparative transcript analysis of two low phytate soybean mutants (TW-1 and TW-1-M), which have the same mutation, a 2 bp deletion in GmMIPS1, but show a significant difference in seed field emergence, TW-1-M was higher than that of TW-1 . RESULTS: Numerous genes analyzed by RNA-Seq showed markedly different expression levels between TW-1-M and TW-1 mutants. Approximately 30,000-35,000 read-mapped genes and ~21000-25000 expressed genes were identified for each library. There were ~3900-9200 differentially expressed genes (DEGs) in each contrast library, the number of up-regulated genes was similar with down-regulated genes in the mutant TW-1and TW-1-M. Gene ontology functional categories of DEGs indicated that the ethylene-mediated signaling pathway, the abscisic acid-mediated signaling pathway, response to hormone, ethylene biosynthetic process, ethylene metabolic process, regulation of hormone levels, and oxidation-reduction process, regulation of flavonoid biosynthetic process and regulation of abscisic acid-activated signaling pathway had high correlations with seed germination. In total, 2457 DEGs involved in the above functional categories were identified. Twenty-two genes with 20 biological functions were the most highly up/down- regulated (absolute value Log2FC >5) in the high field emergence mutant TW-1-M and were related to metabolic or signaling pathways. Fifty-seven genes with 36 biological functions had the greatest expression abundance (FRPM >100) in germination-related pathways. CONCLUSIONS: Seed germination in the soybean low phytate mutants is a very complex process, which involves a series of physiological, morphological and transcriptional changes. Compared with TW-1, TW-1-M had a very different gene expression profile, which included genes related to plant hormones, antioxidation, anti-stress and energy metabolism processes. Our research provides a molecular basis for understanding germination mechanisms, and is also an important resource for the genetic analysis of germination in low phytate crops. Plant hormone- and antioxidation-related genes might strongly contribute to the high germination rate in the TW-1-M mutant. PMID- 28100175 TI - Do experiences with pregnancy, birth and postnatal care in Norway vary by the women's geographic origin? a comparison of cross-sectional survey results. AB - BACKGROUND: A national survey was conducted to measure and benchmark women's experiences with pregnancy, birth and postnatal care in Norway. The purpose of this secondary analysis is to explore potential variation in these experiences with regard to the survey respondents' geographic origin. METHODS: Data were collected in a national observational cross-sectional study, by a self administered questionnaire and from registries. The questionnaire collects patient reported experience measures (PREMS) of mainly nontechnical aspects of the health-care services. While taking the clustered characteristics of the respondents into consideration, we compared the mean scores on 16 indexes between women of four different geographic origins using linear regression models. RESULTS: The origin of the 4904 respondents were classified as Norway (n = 4028, 82%), Western Europe, North-America, Oceania (n = 233, 5%), Eastern Europe (n = 290, 6%), and Asia, Turkey, Africa, and South-America) (n = 353, 7%). The observed differences were moderate, and no consistency was present in the results in respect of direction or magnitude of the differences between the groups. CONCLUSIONS: With some important cautions, we conclude that this study did not detect systematic differences between groups of different geographic origin, in their experiences with pregnancy and maternity care in Norway. PMID- 28100176 TI - Effect of training and structured medication review on medication appropriateness in nursing home residents and on cooperation between health care professionals: the InTherAKT study protocol. AB - BACKGROUND: Pharmacotherapy in residents of nursing homes is critical due to the special vulnerability of this population. Medical care and interprofessional communication in nursing homes are often uncoordinated. As a consequence, polypharmacy and inappropriate medication use are common and may lead to hospitalizations and health hazards. The aim of this study is to optimize communication between the involved professional groups by specific training and by establishing a structured medication review process, and to improve medication appropriateness and patient-relevant health outcomes for residents of nursing homes. METHODS/DESIGN: The trial is designed as single-arm study. It involves 300 nursing home residents aged >= 65 years and the members of the different professional groups practising in nursing home care (15-20 general practitioners, nurses, pharmacists). The intervention consists of interprofessional education on safe medication use in geriatric patients, and a systematic interprofessional therapy check (recording, reviewing and adapting the medication of the participating residents by means of a specific online platform). The intervention period is divided into two phases; total project period is 3 years. Primary outcome measure is the change in medication appropriateness according to the Medication Appropriateness Index. Secondary outcomes are cognitive performance, occurrence of delirium, agitation, tendency of falls, total number of drugs, number of potentially dangerous drug-drug interactions and appropriateness of recorded analgesic therapy regimens according to the Medication Appropriateness Index. Data are collected at t0 (before the start of the intervention), t1 (after the first intervention period) and t2 (after the second intervention period). Cooperation and communication between the professional groups are investigated twice by qualitative interviews. DISCUSSION: The project aims to establish a structured system for monitoring of drug therapy in nursing home residents. The newly developed online platform is designed to systematize and to improve the communication between the professional groups and, thus, to enhance quality and safety of drug therapy. Limitations of the study are the lack of a control group and the non-randomly recruited study sample. TRIAL REGISTRATION: DRKS Data Management, DRKS-ID: DRKS00007900. PMID- 28100174 TI - Prediction of ineffective elective cardioversion of atrial fibrillation: a retrospective multi-center patient cohort study. AB - BACKGROUND: Elective cardioversion (ECV) of atrial fibrillation (AF) is a standard procedure to restore sinus rhythm. However, predictors for ineffective ECV (failure of ECV or recurrence of AF within 30 days) are unknown. METHODS: We investigated 1998 ECVs performed for AF lasting >48 h in 1,342 patients in a retrospective multi-center study. Follow-up data were collected from 30 days after ECV. RESULTS: Median number of cardioversions was one per patient with a range of 1-10. Altogether 303/1998 (15.2%) ECVs failed. Long (>5 years) AF history and over 30 days duration of the index AF episode were independent predictors for ECV failure and low (<60/min) ventricular rate of AF predicted success of ECV. In patients with successful ECVs an early recurrence of AF was detected in 549 (32.4%) cases. Female gender, high (>60/min) ventricular rate, renal failure and antiarrhythmic agents at discharge were the independent predictors for recurrence. In total ECV was ineffective in 852 (42.6%) cases. Female gender (OR 1.44, CI95% 1.15-1.80, p < 0.01), young (<65 years) age (OR 1.31, CI95% 1.07-1.62, p = 0.01), ventricular rate >60/min (OR 1.92, CI95% 1.08 3.41, p = 0.03), antiarrhythmic medication at discharge (OR 1.48, CI95% 1.14 1.93, p < 0.01) and low (<60/ml/min) estimated glomerular filtration rate (OR 1.59, CI95% 1.08-2.33, p = 0.02) were predictors of ineffective ECV. CONCLUSIONS: Female gender, use of antiarrhythmic drug therapy and renal failure predicted both recurrence of AF and the composite end point. For the first time in a large real-life study several clinical predictors for clinically ineffective ECV were identified. PMID- 28100177 TI - Effect of desflurane-remifentanil vs. Propofol-remifentanil anesthesia on arterial oxygenation during one-lung ventilation for thoracoscopic surgery: a prospective randomized trial. AB - BACKGROUND: One-lung ventilation during thoracic surgery frequently disturbs normal systemic oxygenation. However, the effect of anesthetics on arterial oxygenation during one-lung ventilation has not been well established in human study. In this clinical trial, we investigated whether a difference between desflurane-remifentanil and propofol-remifentanil anesthesia can be observed with regard to oxygenation during one-lung ventilation for thoracoscopic surgery. METHODS: Adult patients with lung cancer, scheduled for video-assisted thoracoscopic lobectomy without preoperative oxygen support, were screened and randomized to receive desflurane or propofol, with remifentanil continuous infusion in both groups. Mechanical ventilation was performed with tidal volume of 8 ml/kg and FIO2 0.5 during two-lung ventilation, and 6 ml/kg and 1.0 during one-lung ventilation, both with positive end-expiratory pressure of 5 cmH2O. Arterial blood gas analysis was performed preoperatively, during two-lung ventilation, and after 15, 30, 45, and 60 min of one-lung ventilation. The primary endpoint was PaO2 at 30 min after initiating one-lung ventilation. Statistical analyses included the independent t-test for the primary endpoint and a mixed model with a post-hoc analysis to evaluate the serial changes in values. RESULTS: Patients were recruited between July 9 and December 2, 2014. In total, 103 patients were analyzed (n = 52 in desflurane group and n = 51 in propofol group). The primary endpoint, PaO2 at 30 min of one-lung ventilation was lower in the desflurane group than the propofol group (170 +/- 72 vs. 202 +/- 82 mmHg; p = 0.039). Serial changes in PaO2 during one-lung ventilation showed lower levels during desflurane anesthesia compared with propofol anesthesia (mean difference, 45 mmHg; 95% confidence interval, 16-75 mmHg; p = 0.003). CONCLUSIONS: In conclusion, desflurane-remifentanil anesthesia resulted in decreased arterial oxygenation compared with that of propofol-remifentanil anesthesia during one lung ventilation for thoracoscopic surgery in patients with lung cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02191371 , registered on July 7, 2014. PMID- 28100179 TI - Exploring surface cleaning strategies in hospital to prevent contact transmission of methicillin-resistant Staphylococcus aureus. AB - BACKGROUND: Cleaning of environmental surfaces in hospitals is important for the control of methicillin-resistant Staphylococcus aureus (MRSA) and other hospital acquired infections transmitted by the contact route. Guidance regarding the best approaches for cleaning, however, is limited. METHODS: In this study, a mathematical model based on ordinary differential equations was constructed to study MRSA concentration dynamics on high-touch and low-touch surfaces, and on the hands and noses of two patients (in two hospitals rooms) and a health care worker in a hypothetical hospital environment. Two cleaning interventions - whole room cleaning and wipe cleaning of touched surfaces - were considered. The performance of the cleaning interventions was indicated by a reduction in MRSA on the nose of a susceptible patient, relative to no intervention. RESULTS: Whole room cleaning just before first patient care activities of the day was more effective than whole room cleaning at other times, but even with 100% efficiency, whole room cleaning only reduced the number of MRSA transmitted to the susceptible patient by 54%. Frequent wipe cleaning of touched surfaces was shown to be more effective that whole room cleaning because surfaces are rapidly re contaminated with MRSA after cleaning. Wipe cleaning high-touch surfaces was more effective than wipe cleaning low-touch surfaces for the same frequency of cleaning. For low wipe cleaning frequency (<=3 times per hour), high-touch surfaces should be targeted, but for high wipe cleaning frequency (>3 times per hour), cleaning should target high- and low-touch surfaces in proportion to the surface touch frequency. This study reproduces the observations from a field study of room cleaning, which provides support for the validity of our findings. CONCLUSIONS: Daily whole room cleaning, even with 100% cleaning efficiency, provides limited reduction in the number of MRSA transmitted to susceptible patients via the contact route; and should be supplemented with frequent targeted cleaning of high-touch surfaces, such as by a wipe or cloth containing disinfectant. PMID- 28100178 TI - A retinopathy in young patient with co-inheritance of heterozygous alpha + thalassemia and sickle trait: a case report. AB - BACKGROUND: The retinopathy is an uncommon complication in individuals with sickle cell trait except for the cases of sickle cell trait associated with systemic arterial hypertension, diabetes mellitus, syphilis, tuberculosis and sarcoidosis. CASE PRESENTATION: A retinopathy in a 16 year-old child with no history of consanguinity in the parents revealed a sickle S trait associated to heterozygous alpha thalassemia. His mother has Sickle cell anaemia (Hb SS) and his father is a carrier of heterozygous alpha-thalassemia status that it was unknown before. CONCLUSION: This case report describes a proliferative retinopathy in a 16 year-old patient with co-inheritance of heterozygous alpha + thalassemia and sickle trait. PMID- 28100180 TI - Extensive bilateral corneal edema 6 weeks after cataract surgery: Keratopathy due to Asclepias physocarpa: a case report. AB - BACKGROUND: Surgeons may be unaware of the ability of plant toxins to cause corneal damage. Therefore, corneal damage following intraocular surgery due to plant toxins may be misdiagnosed as postoperative infection. CASE PRESENTATION: A 74-year-old man presented with hyperemia and reduced visual acuity in both eyes 6 weeks after uneventful cataract surgery. We observed extensive hyperemia and corneal stromal edema with Descemet's folds in both eyes. After obtaining a detailed patient history, we diagnosed plant toxin-induced corneal edema due to Asclepias physocarpa, which can induce corneal edema by inhibiting the Na+/K+ ATPase activity of the corneal endothelium. Antimicrobial and steroid eye drops and an oral steroid were prescribed accordingly. Symptons began to improve on day 3 and had almost completely resolved by day 6. At 1 month, the patient had fully recovered without any sequelae. CONCLUSION: The correct diagnosis was possible in the present case as symptoms were bilateral and the patient was able to report his potential exposure to plant toxins. However, if the symptoms had been unilateral and the patient had been unaware of these toxins, he may have undergone unnecessary surgical interventions to treat non-existent postoperative endophthalmitis. PMID- 28100181 TI - Gestational diabetes mellitus and retinal microvasculature. AB - BACKGROUND: Small-vessel dysfunction may be an important consequence of chronic hyperglycemia. We examined the association between gestational diabetes mellitus (GDM), a state of transient hyperglycemia during pregnancy, and retinal microvascular changes in pregnant women at 26-28 weeks of pregnancy. METHODS: A total of 1136 pregnant women with singleton pregnancies were recruited during their first trimester at two major Singapore maternity hospitals in an on-going birth cohort study. Participants underwent an oral glucose tolerance test and retinal imaging at 26-28 weeks gestation (n = 542). We used the 1999 World Health Organization (WHO) criteria to define GDM: >=7.0 mmol/L for fasting glucose and/or >=7.8 mmol/L for 2-h post-glucose. Retinal microvasculature was measured using computer software (Singapore I Vessel Analyzer, SIVA version 3.0, Singapore Eye Research Institute, Singapore) from the retinal photographs. RESULTS: In a multiple linear regression model adjusting for age, ethnicity and maternal education, mothers with GDM had narrower arteriolar caliber (-1.6 MUm; 95% Confidence Interval [CI]: -3.1 MUm, -0.2 MUm), reduced arteriolar fractal dimension (-0.01 Df; 95% CI: -0.02 Df, -0.001 Df;), and larger arteriolar branching angle (1.8 degrees ; 95% CI: 0.3 degrees , 3.3 degrees ) than mothers without GDM. After further adjusting for traditional risks of GDM, arteriolar branching angle remained significantly larger in mothers with GDM than those without GDM (2.0 degrees ; 95% CI: 0.5 degrees , 3.6 degrees ). CONCLUSIONS: GDM was associated with a series of retinal arteriolar abnormalities, including narrower caliber, reduced fractal dimension and larger branching angle, suggesting that transient hyperglycemia during pregnancy may cause small-vessel dysfunction. PMID- 28100182 TI - Electrocardiographic assessments and cardiac events after fingolimod first dose - a comprehensive monitoring study. AB - BACKGROUND: First dose observation for cardiac effects is required for fingolimod, but recommendations on the extent vary. This study aims to assess cardiac safety of fingolimod first dose. Individual bradyarrhythmic episodes were evaluated to assess the relevance of continuous electrocardiogram (ECG) monitoring. METHODS: START is an ongoing open-label, multi-center study. At the time of analysis 3951 patients were enrolled. The primary endpoints are the incidence of bradycardia (heart rate < 45 bpm) and second-/third-degree AV blocks during treatment initiation. The relevance of Holter was assessed by matching ECG findings with the occurrence of clinical symptoms as well as by rigorous analysis of AV blocks with regard to the duration of pauses and the minimal heart rate recorded during AV block. RESULTS: Thirty-one patients (0.8%) developed bradycardia (<45 bpm), 62 patients (1.6%) had second-degree Mobitz I and/or 2:1 AV blocks with a lowest reading (i.e. mean of ten consecutive beats) of 35 bpm and the longest pause lasting for 2.6 s. No Mobitz II or third-degree AV blocks were observed. Only one patient complained about mild chest discomfort and fatigue. After 1 week, there was no second-/third-degree AV block. CONCLUSIONS: Continuous Holter ECG monitoring in this large real-life cohort revealed that bradycardia and AV conduction abnormalities were rare, transient and benign. No further unexpected abnormalities were detected. The data presented here give an indication that continuous Holter ECG monitoring does not add clinically relevant value to patients' safety. TRIAL REGISTRATION: NCT01585298 ; registered April 23, 2012. PMID- 28100183 TI - Short-term blood pressure variability - variation between arm side, body position and successive measurements: a population-based cohort study. AB - BACKGROUND: Precise blood pressure (BP) measurements are central for the diagnosis of hypertension in clinical and epidemiological studies. The purpose of this study was to quantify the variability in BP associated with arm side, body position, and successive measurements in the setting of a population-based observational study. Additionally, we aimed to evaluate the influence of different measurement conditions on prevalence of hypertension. METHODS: The sample included 967 men and 812 women aged 45 to 83 years at baseline. BP was measured according to a standardized protocol with oscillometric devices including three sitting measurements at left arm, one simultaneous supine measurement at both arms, and four supine measurements at the arm with the higher BP. Hypertension was defined as systolic BP (SBP) >=140 mmHg and/or diastolic BP (DBP) >=90 mmHg. Variability in SBP and DBP were analysed with sex-stratified linear covariance pattern models. RESULTS: We found that overall, no mean BP differences were measured according to arm-side, but substantial higher DBP and for men also higher SBP was observed in sitting than in supine position and there was a clear BP decline by consecutive measurement. Accordingly, the prevalence of hypertension depends strongly on the number and scheme of BP measurements taken to calculate the index values. CONCLUSIONS: Thus, BP measurements should only be compared between studies applying equal measurement conditions and index calculation. Moreover, the first BP measurement should not be used to define hypertension since it overestimates BP. The mean of second and third measurement offers the advantage of better reproducibility over single measurements. PMID- 28100184 TI - CNVs into the wild: screening the genomes of conifer trees (Picea spp.) reveals fewer gene copy number variations in hybrids and links to adaptation. AB - BACKGROUND: Copy number variations (CNVs) have been linked to different phenotypes in human, including many diseases. A genome-scale understanding of CNVs is available in a few plants but none are wild species, leaving a knowledge gap regarding their genome biology and evolutionary role. We developed a reliable CNV detection method for species lacking contiguous reference genome. We selected multiple probes within 14,078 gene sequences and developed comparative genome hybridization on arrays. Gene CNVs were assessed in three full-sib families from species with 20 Gb genomes, i.e., white and black spruce, and interior spruce - a natural hybrid. RESULTS: We discovered hundreds of gene CNVs in each species, 3612 in total, which were enriched in functions related to stress and defense responses and narrow expression profiles, indicating a potential role in adaptation. The number of shared CNVs was in accordance with the degree of relatedness between individuals and species. The genetically mapped subset of these genes showed a wide distribution across the genome, implying numerous structural variations. The hybrid family presented significantly fewer CNVs, suggesting that the admixture of two species within one genome reduces the occurrence of CNVs. CONCLUSIONS: The approach we developed is of particular interest in non-model species lacking a reference genome. Our findings point to a role for CNVs in adaptation. Their reduced abundance in the hybrid may limit genetic variability and evolvability of hybrids. We propose that CNVs make a qualitatively distinct contribution to adaptation which could be important for short term change. PMID- 28100186 TI - Influenza epidemic surveillance and prediction based on electronic health record data from an out-of-hours general practitioner cooperative: model development and validation on 2003-2015 data. AB - BACKGROUND: Annual influenza epidemics significantly burden health care. Anticipating them allows for timely preparation. The Scientific Institute of Public Health in Belgium (WIV-ISP) monitors the incidence of influenza and influenza-like illnesses (ILIs) and reports on a weekly basis. General practitioners working in out-of-hour cooperatives (OOH GPCs) register diagnoses of ILIs in an instantly accessible electronic health record (EHR) system. This article has two objectives: to explore the possibility of modelling seasonal influenza epidemics using EHR ILI data from the OOH GPC Deurne-Borgerhout, Belgium, and to attempt to develop a model accurately predicting new epidemics to complement the national influenza surveillance by WIV-ISP. METHOD: Validity of the OOH GPC data was assessed by comparing OOH GPC ILI data with WIV-ISP ILI data for the period 2003-2012 and using Pearson's correlation. The best fitting prediction model based on OOH GPC data was developed on 2003-2012 data and validated on 2012-2015 data. A comparison of this model with other well established surveillance methods was performed. A 1-week and one-season ahead prediction was formulated. RESULTS: In the OOH GPC, 72,792 contacts were recorded from 2003 to 2012 and 31,844 from 2012 to 2015. The mean ILI diagnosis/week was 4.77 (IQR 3.00) and 3.44 (IQR 3.00) for the two periods respectively. Correlation between OOHs and WIV-ISP ILI incidence is high ranging from 0.83 up to 0.97. Adding a secular trend (5 year cycle) and using a first-order autoregressive modelling for the epidemic component together with the use of Poisson likelihood produced the best prediction results. The selected model had the best 1-week ahead prediction performance compared to existing surveillance methods. The prediction of the starting week was less accurate (+/-3 weeks) than the predicted duration of the next season. CONCLUSION: OOH GPC data can be used to predict influenza epidemics both accurately and fast 1-week and one-season ahead. It can also be used to complement the national influenza surveillance to anticipate optimal preparation. PMID- 28100185 TI - An improved genome assembly uncovers prolific tandem repeats in Atlantic cod. AB - BACKGROUND: The first Atlantic cod (Gadus morhua) genome assembly published in 2011 was one of the early genome assemblies exclusively based on high-throughput 454 pyrosequencing. Since then, rapid advances in sequencing technologies have led to a multitude of assemblies generated for complex genomes, although many of these are of a fragmented nature with a significant fraction of bases in gaps. The development of long-read sequencing and improved software now enable the generation of more contiguous genome assemblies. RESULTS: By combining data from Illumina, 454 and the longer PacBio sequencing technologies, as well as integrating the results of multiple assembly programs, we have created a substantially improved version of the Atlantic cod genome assembly. The sequence contiguity of this assembly is increased fifty-fold and the proportion of gap bases has been reduced fifteen-fold. Compared to other vertebrates, the assembly contains an unusual high density of tandem repeats (TRs). Indeed, retrospective analyses reveal that gaps in the first genome assembly were largely associated with these TRs. We show that 21% of the TRs across the assembly, 19% in the promoter regions and 12% in the coding sequences are heterozygous in the sequenced individual. CONCLUSIONS: The inclusion of PacBio reads combined with the use of multiple assembly programs drastically improved the Atlantic cod genome assembly by successfully resolving long TRs. The high frequency of heterozygous TRs within or in the vicinity of genes in the genome indicate a considerable standing genomic variation in Atlantic cod populations, which is likely of evolutionary importance. PMID- 28100188 TI - High expression of micro RNA-135A in hepatocellular carcinoma is associated with recurrence within 12 months after resection. AB - BACKGROUND: Hepatocellular carcinoma has a dismal prognosis due to recurrence rates of up to 70% after curative resection. Early recurrence is driven by synchronous microscopic intrahepatic metastases. The predictive value of histological parameters is discussed controversially and adjuvant therapy is not established. The aim of this study was to identify patients at high risk for early intrahepatic recurrence by expression profiling of selected micro RNAs. METHODS: In 52 patients undergoing HCC resection between 2011 and 2014, liver and tumor tissue was collected during surgery. Twelve patients with incomplete data regarding HCC recurrence, secondary liver transplantation, or perioperative death were excluded, leaving 40 patients with early recurrence <12 months (R+) or without recurrence for >24 months (R-) to compare grading, T, L, V, and R status. If tissue quality permitted, micro RNAs were measured in HCC and liver tissue. RESULTS: Ten women and 30 men (64.0 +/- 10.2 years) were analyzed. R+ occurred in 29 patients 6.2 +/- 4.5 months after resection. Surveillance of R- was 26.2 +/- 5.2 months. High intratumoral expression of miR-135a was associated with high risk of recurrence (HR = 4.2, p = 0.024, time to recurrence 8.8 +/- 2.0 vs. 24.8 +/- 4.4 months in patients with low miR-135a expression). As expected, T3 status was correlated with early recurrence, while other histological parameters and expression of miR-21, miR-122, and miR-125a did not. CONCLUSIONS: We show a significant association between high expression of miR-135a and early HCC recurrence. Therefore, high intratumoral miR-135a expression might serve as a novel biomarker to identify patients urgently requiring adjuvant therapy post resection. PMID- 28100187 TI - Prevalence of HIV and syphilis co-infection and associated factors among non commercial men who have sex with men attending a sexually transmitted disease clinic in Shenzhen, China. AB - BACKGROUND: Although HIV and syphilis co-infection has been frequently observed in men who have sex with men (MSM), only few studies have focused on it. Different subgroups of MSM might exhibit heterogeneous HIV and syphilis risk profiles, indicating that interventions for HIV and HIV-related co-infections may vary with different subgroups of MSM. However, no previous study has investigated HIV and syphilis co-infection among non-commercial MSM (ncMSM) attending a sexually transmitted disease (STD) clinic. Therefore, this study aimed to explore the prevalence of HIV and syphilis co-infection and associated factors among ncMSM attending an STD clinic in Shenzhen, China. METHODS: NcMSM attending the STD clinic of Shenzhen Center for Chronic Disease Control were recruited in this cross-sectional study every Monday between March 2013 and August 2015 using a site based convenience sampling method. An anonymous questionnaire was used to collect data regarding socio-demographic characteristics, risky sexual behaviors and HIV-related knowledge. Blood samples were collected to perform HIV and syphilis tests. RESULTS: Totally 533 participants were enrolled in this study and the prevalence of HIV and syphilis co-infection among them was 13.13%. Multivariable analyses indicated that having lived in Shenzhen for less than one year (aOR = 2.80, 95% CI = 1.30-6.05), having first anal sexual intercourse before the age of 18 (aOR = 2.78, 95% CI = 1.29-5.89), having 3 to 5 anal sexual partners in the past six months (aOR = 2.54, 95% CI = 1.19-5.40), playing exclusively receptive (aOR = 6.87, 95% CI = 3.02-15.61) or both insertive and receptive (aOR = 3.65, 95% CI = 1.64-8.09) roles in anal sexual intercourse and not always using condom in anal sexual intercourse (aOR = 2.13, 95% CI = 1.08 4.19) were associated risk factors for HIV and syphilis co-infection, relative to the non-infected ncMSM. Compared with the mono-infected ncMSM, associated risk factors for the co-infection were being unmarried (aOR = 2.47, 95% CI = 1.03 5.89) and playing exclusively receptive role (aOR = 2.44, 95% CI = 1.04-5.73) in anal sexual intercourse. CONCLUSIONS: HIV and syphilis co-infection is quite prevalent among the study participants in Shenzhen. Integrated and intensified intervention strategies, specifically targeting at the non-infected and mono infected ncMSM attending the STD clinic, are needed to reduce HIV and syphilis co infection. Most importantly, non-infected and mono-infected ncMSM attending the STD clinic with the aforementioned associated risk factors should be given special concern. PMID- 28100190 TI - Translation of a tailored nutrition and resistance exercise intervention for elderly people to a real-life setting: adaptation process and pilot study. AB - BACKGROUND: Combining increased dietary protein intake and resistance exercise training for elderly people is a promising strategy to prevent or counteract the loss of muscle mass and decrease the risk of disabilities. Using findings from controlled interventions in a real-life setting requires adaptations to the intervention and working procedures of healthcare professionals (HCPs). The aim of this study is to adapt an efficacious intervention for elderly people to a real-life setting (phase one) and test the feasibility and potential impact of this prototype intervention in practice in a pilot study (phase two). METHODS: The Intervention Mapping approach was used to guide the adaptation in phase one. Qualitative data were collected from the original researchers, target group, and HCPs, and information was used to decide whether and how specified intervention elements needed to be adapted. In phase two, a one-group pre-test post-test pilot study was conducted (n = 25 community-dwelling elderly), to elicit further improvements to the prototype intervention. The evaluation included participant questionnaires and measurements at baseline (T0) and follow-up (T1), registration forms, interviews, and focus group discussions (T1). Qualitative data for both phases were analysed using an inductive approach. Outcome measures included physical functioning, strength, body composition, and dietary intake. Change in outcomes was assessed using Wilcoxon signed-rank tests. RESULTS: The most important adaptations to the original intervention were the design of HCP training and extending the original protein supplementation with a broader nutrition programme aimed at increasing protein intake, facilitated by a dietician. Although the prototype intervention was appreciated by participants and professionals, and perceived applicable for implementation, the pilot study process evaluation resulted in further adaptations, mostly concerning recruitment, training session guidance, and the nutrition programme. Pilot study outcome measures showed significant improvements in muscle strength and functioning, but no change in lean body mass. CONCLUSION: The combined nutrition and exercise intervention was successfully adapted to the real-life setting and seems to have included the most important effective intervention elements. After adaptation of the intervention using insights from the pilot study, a larger, controlled trial should be conducted to assess cost-effectiveness. TRIAL REGISTRATION: Trial registration number: ClinicalTrials.gov NL51834.081.14 (April 22, 2015). PMID- 28100189 TI - An SNP-based saturated genetic map and QTL analysis of fruit-related traits in Zucchini using Genotyping-by-sequencing. AB - BACKGROUND: Cucurbita pepo is a cucurbit with growing economic importance worldwide. Zucchini morphotype is the most important within this highly variable species. Recently, transcriptome and Simple Sequence Repeat (SSR)- and Single Nucleotide Polymorphism (SNP)-based medium density maps have been reported, however further genomic tools are needed for efficient molecular breeding in the species. Our objective is to combine currently available complete transcriptomes and the Zucchini genome sequence with high throughput genotyping methods, mapping population development and extensive phenotyping to facilitate the advance of genomic research in this species. RESULTS: We report the Genotyping-by-sequencing analysis of a RIL population developed from the inter subspecific cross Zucchini x Scallop (ssp. pepo x ssp. ovifera). Several thousands of SNP markers were identified and genotyped, followed by the construction of a high-density linkage map based on 7,718 SNPs (average of 386 markers/linkage group) covering 2,817.6 cM of the whole genome, which is a great improvement with respect to previous maps. A QTL analysis was performed using phenotypic data obtained from the RIL population from three environments. In total, 48 consistent QTLs for vine, flowering and fruit quality traits were detected on the basis of a multiple environment analysis, distributed in 33 independent positions in 15 LGs, and each QTL explained 1.5-62.9% of the phenotypic variance. Eight major QTLs, which could explain greater than 20% of the phenotypic variation were detected and the underlying candidate genes identified. CONCLUSIONS: Here we report the first SNP saturated map in the species, anchored to the physical map. Additionally, several consistent QTLs related to early flowering, fruit shape and length, and rind and flesh color are reported as well as candidate genes for them. This information will enhance molecular breeding in C. pepo and will assist the gene cloning underlying the studied QTLs, helping to reveal the genetic basis of the studied processes in squash. PMID- 28100191 TI - Diagnostic dilemma of pulmonary tuberculosis among adults with severe mental illness in Beijing, China. AB - BACKGROUND: Although the prevalence of tuberculosis has decreased significantly over the past decades, the certain populations with mental illness are at increased risk for tuberculosis infection and transmission. However, no studies have examined the performance of different laboratory examination methods among people with severe mental illness in China. METHODS: In this study, we firstly performed a retrospective study to evaluate the feasibility of three routine laboratory methods, including sputum microscopy, solid culture and GeneXpert, to diagnose tuberculosis patients with mental illness. RESULTS: During August 2010 and March 2013, a total of 251 TB patients based on clinical and radiographic criteria with severe mental illness were enrolled in this study. The majority of patients was homeless (97/251, 38.6%), and the other 62 (24.7%) and 92 (36.7%) were from urban and rural region, respectively. The most frequently diagnosed mental illness was schizophrenia, accounting for 84.1% (211/251) of patients available for analysis. In addition, the laboratory received 753 sputum samples collected from these 251 TB patients, of which 76.0% (572/753) of samples were classified as salivary sputum, which were unqualified for microscopy and culture. When the test results were analyzed by patients, the positive numbers of TB patients detected by sputum microscopy, solid culture and GeneXpert were 3 (1.2%), 5 (2.0%) and 5 (2.0%), respectively. CONCLUSIONS: In conclusion, our findings reveal that the current laboratory examinations based on sputum samples seem not to be suitable for the diagnosis of active TB in the persons with severe mental illness. The products using a non-invasive specimen such as urine deserve further evaluation, which may generate benefit for the early diagnosis of TB in this special population. PMID- 28100192 TI - Design and rationale of a large, international, prospective cohort study to evaluate the occurrence of malformations and perinatal/neonatal death using insulin detemir in pregnant women with diabetes in comparison with other long acting insulins. AB - BACKGROUND: There are a lack of data regarding the effect of basal insulin analogues on rates of events like congenital malformation and perinatal mortality in diabetic pregnancy. METHODS: The present study is a prospective, non interventional, multicentre cohort study conducted in seven countries, designed to assess the safety of insulin detemir during pregnancy, and to monitor the health status of resulting infants (exposed in utero) up to 1 year of age. The study population includes women with type 1 or type 2 diabetes, who are pregnant and being treated with insulin. Data will be collected in the context of routine practice. The primary endpoint is the proportion of pregnancies in women treated with insulin detemir, compared with other basal insulin regimens, which do not result in any of the following events: major congenital malformations, perinatal death or neonatal death. A sample size of 3075 pregnancies was calculated to provide an 80% power to detect a difference of 3.5% between groups in the primary endpoint at a 5% level. DISCUSSION: The study will also examine other important maternal endpoints (e.g., incidences of severe hypoglycaemia and pre-eclampsia) and perinatal outcomes such as overweight neonates, as well as infant outcomes at 1 year of age. It has a fixed recruitment period from 2013 to 2018, enrolling all eligible patients, and is expected to inform future prescribing with basal insulins in diabetic pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01892319 (date registered: 27.06.2013). PMID- 28100193 TI - Long-time sickness absence among parents of pre-school children with cerebral palsy, spina bifida and down syndrome: a longitudinal study. AB - BACKGROUND: Taking care of a child with special needs can be draining and difficult and require a lot of parental time and resources. The present study investigated the long-term sickness absence of parents who have children with spina bifida, cerebral palsy and Down syndrome compared to that of parents without a child with special needs. METHODS: The sample consisted of primiparae women who gave birth between 2001 and 2005 and the fathers of the children (N = 202,593). Data were obtained from the Medical Birth Registry of Norway (MBRN), which is linked to the Central Population Register, education and income registries and Historical Event Database (FD-Trygd) of Statistics Norway (SSB). The linkage data provide longitudinal data, together with annual updates on children and their parents. Statistical analyses were performed using difference in-difference (DD) study design. RESULTS: Caring for a child with special needs affected maternal sickness absence, particularly in the first year after the birth. The level of sickness absence of mothers caring for a child with spina bifida and cerebral palsy was greater than that of mothers caring for a child with Down syndrome. In contrast, the sickness absence of fathers caring for a child with special needs was, on average, comparable to that of fathers without a special-needs child in the post-birth period. CONCLUSIONS: Caring for a child with special needs affected the long-term sickness absence of mothers but not fathers. The findings indicate that the burden of care in the case of children with special needs falls especially on the mother. PMID- 28100194 TI - Interspecies transfer of vancomycin, erythromycin and tetracycline resistance among Enterococcus species recovered from agrarian sources. AB - BACKGROUND: Enterococci are now well recognised for their ability to transfer antibiotic resistance and for their association with nosocomial infections, but less is known regarding their relevance in the wider environment. Enterococcus faecalis and Enterococcus faecium were isolated from a range of agrarian associated sources (low-flow water, septic tank, poultry litter, high flow water, slurry/soil) and were assessed for latent ability to transfer antimicrobial resistance. RESULTS: The isolates were tested for phenotypic clumping in the presence of cell-free supernatant from other isolates. Some isolates were identified which demonstrated clumping, indicating that they possessed peptide sex pheromone conjugal machinery. All isolates were also tested for antibiotic resistance phenotypes using both disc diffusion and minimum inhibitory concentration (MIC) assays. These tests revealed that the enterococci demonstrated both phenotypic clumping and antibiotic resistance phenotypes. Based on these selection criteria, the isolates were identified as having the potential for horizontal gene transfer and were used to investigate the transfer of multiple antibiotic resistance phenotypes. Conjugal transfer of antibiotic resistance phenotypes was determined using a solid agar mating method followed by a standard antibiotic selection test resulting in different transfer patterns. An interspecies conjugal transfer of vancomycin resistance from E. faecalis to E. faecium was identified while the remaining reactions were within the same species. Transfer efficiencies ranging from 2 * 10-1 to 2.3 * 10-5 were determined based on the reactions of three donor isolates (MF06036, MF0410 and MF06035) and two recipient isolates (MW01105Rif and ST01109Rif), with the transfer of vancomycin, erythromycin and tetracycline resistance genes. CONCLUSIONS: The conjugation reactions and selection conditions used in this study resulted in a variety of co-transferred resistance phenotypes suggesting the presence of different mobile elements in the set of natural isolates. This study highlights the potential for extensive horizontal gene transfer in a previously neglected reservoir for enterococci. PMID- 28100195 TI - Assessment of the length of sick leave in patients with ischemic heart disease. AB - BACKGROUND: The prevalence of ischemic heart disease is high. Few recent studies have investigated the periods of sick leave of these patients. Our aim is to determine the length of sick leave after an acute coronary syndrome, its costs, associated factors and to assess the use of antidepressants and/or anxiolytics. METHODS: An observational study of a retrospective cohort of patients on sick leave due to ischemic heart disease in a health region between 2008-2011, with follow-up until the first return to work, death, or end of the study (31/12/2012). MEASUREMENTS: length of sick leave, sociodemographic variables and medical prescriptions. RESULTS: Four hundred and ninety-seven patients (mean age 53 years, 90.7% male), diagnosed with acute myocardial infarction (60%), angina pectoris (20.7%) or chronic form of ischemic heart disease (19.1%). Thirty-seven per cent of patients took anxiolytics the year after diagnosis and 15% took antidepressants. The average duration of sick leave was 177 days (95% CI: 163-191 days). Patients diagnosed with acute myocardial infarction returned to work after a mean of 192 days, compared to 128 days in cases with angina pectoris. Patients who took antidepressants during the year after diagnosis returned to work after a mean of 240 days. The mean work productivity loss was estimated to be 9,673 euros/person. CONCLUSIONS: The mean duration of sick leave due to ischemic heart disease was almost six months. Consumption of psychotropic medication doubled after the event. Older age, suffering an acute myocardial infarction and taking antidepressants were associated with a longer sick leave period. PMID- 28100196 TI - Exposure to hepatitis C virus in homeless men in Central Brazil: a cross sectional study. AB - BACKGROUND: Homeless men are highly vulnerable to acquisition of the hepatitis C virus (HCV) compared to the general population. In Brazil, a country of continental dimensions, the extent of HCV infection in this population remains unknown. The objective of this study is to investigate the epidemiological profile of exposure to HCV in homeless men in Central Brazil. METHODS: A Cross sectional study was conducted in 481 men aged over 18 years attending therapeutic communities specialized in the recovery and reintegration of homeless people. Participants were tested for anti-HCV markers using rapid tests. Poisson regression analysis was used to verify the risk factors associated with exposure to HCV. RESULTS: The prevalence of HCV exposure was 2.5% (95.0% CI: 1.4 to 4.3%) and was associated with age, absence of family life, injection drug use, number of sexual partners, and history of sexually transmitted infections (STI). Participants reported multiple risk behaviors, such as alcohol (78.9%), cocaine (37.1%) and/or crack use (53.1%), and inconsistent condom use (82.6%). Injection drug use was reported by 8.7% of participants. CONCLUSIONS: The prevalence of HCV infection among homeless men was relatively high. Several risk behaviors were commonly reported, which shows the high vulnerability of this population. These findings emphasize the need for the development of specific strategies to reduce the risk of HCV among homeless men. PMID- 28100198 TI - MR imaging for detection of trampoline injuries in children. AB - BACKGROUND: The recreational use of trampolines is an increasingly popular activity among children and adolescents. Several studies reported about radiological findings in trampoline related injuries in children. The following publication presents our experience with MRI for detection of trampoline injuries in children. METHODS: 20 children (mean 9.2 years, range: 4-15 years) who had undergone an MRI study for detection of suspected trampoline injuries within one year were included. 9/20 (45%) children had a radiograph as the first imaging modality in conjunction with primary care. In 11/20 (55%) children MR imaging was performed as the first modality. MR imaging was performed on two 1.5 T scanners with 60 and 70 cm bore design respectively without sedation. In 9/20 (45%) children the injury mechanism was a collision with another child. 7/20 (35%) children experienced leg pain several hours to one day after using the trampoline without acute accident and 4/20 (20%) children described a fall from the trampoline to the ground. RESULTS: All plain radiographs were performed in facilities outside the study centre and all were classified as having no pathological findings. In contrast, MR imaging detected injuries in 15/20 (75%) children. Lower extremity injuries were the most common findings, observed in 12/15 (80%) children. Amongst these, injuries of the ankle and foot were diagnosed in 7/15 (47%) patients. Fractures of the proximal tibial metaphysis were observed in 3/15 children. One child had developed a thoracic vertebral fracture. The two remaining children experienced injuries to the sacrum and a soft tissue injury of the thumb respectively. Seven children described clinical symptoms without an overt accident. Here, fractures of the proximal tibia were observed in 2 children, a hip joint effusion in another 2, and an injury of the ankle and foot in 1 child. There were no associated spinal cord injuries, no fracture dislocations, no vascular injuries and no head and neck injuries. CONCLUSIONS: In the majority of children referred for MR imaging with pain after trampoline MR imaging detects injuries. These injuries are often not visible on plain radiographs. Therefore we recommend a generous use of MR imaging in these children after initial negative plain radiography. PMID- 28100197 TI - A two-phase approach for the identification of refugees with priority need for mental health care in Lebanon: a validation study. AB - BACKGROUND: Time and resource efficient mental disorder screening mechanisms are not available to identify the growing number of refugees and other forcibly displaced persons in priority need for mental health care. The aim of this study was to identify efficient screening instruments and mechanisms for the detection of moderate and severe mental disorders in a refugee setting. METHODS: Lay interviewers applied a screening algorithm to detect individuals with severe distress or mental disorders in randomly selected households in a Palestinian refugee camp in Beirut, Lebanon. The method included household informant and individual level interviews using a Vignettes of Local Terms and Concepts for mental disorders (VOLTAC), individual and household informant portions of the field-test version of the WHO-UNHCR Assessment Schedule of Serious Symptoms in Humanitarian Settings (WASSS) and the WHO Self Reporting Questionnaire (SRQ-20). A subset of participants were then reappraised utilizing the Mini International Neuropsychiatric Interview (MINI), WHO Disability Assessment Schedule II, and the Global Assessment of Functioning. The study constitutes a secondary analysis of interview data from 283 randomly selected households (n = 748 adult residents) who participated in a mental health disorders prevalence study in 2010. RESULTS: The 5-item household informant portion of WASSS was the most efficient instrument among those tested. It detected adults with severe mental disorders with 95% sensitivity and 71% specificity (Area Under Curve (AUC) = 0.85) and adults with moderate or severe mental disorder with 85.1% sensitivity and 74.8% specificity (AUC = 0.82). The complete screening algorithm demonstrated 100% sensitivity and 58% specificity. CONCLUSIONS: Our results suggest that a two phase, screen confirm approach is likely a useful strategy to detect incapacitating mental disorders in humanitarian contexts where mental health specialists are scarce, and that in the context of a multi-step screen confirm mechanism, the household informant portion of field-test version of the WASSS may be an efficient screening tool to identify adults in greatest need for mental health care in humanitarian settings. PMID- 28100199 TI - Antioxidant and hepatoprotective potential of Lawsonia inermis L. leaves against 2-acetylaminofluorene induced hepatic damage in male Wistar rats. AB - BACKGROUND: Lawsonia inermis (Lythraceae) is an ethnomedicinal plant, traditionally known for curing several ailments such as skin diseases, bacterial infections, jaundice, renal lithiases and inflammation etc. The present work deals with assessment of in vitro antioxidant and in vivo hepatoprotective potential of butanolic fraction (But-LI) of Lawsonia inermis L. leaves. METHODS: Antioxidant activity was evaluated using deoxyribose degradation, lipid peroxidation inhibition and ferric reducing antioxidant power (FRAP) assay. In vivo protective potential of But-LI was assessed at 3 doses [100, 200 & 400 mg/kg body weight (bw)] against 2-acetylaminofluorene (2-AAF) induced hepatic damage in male Wistar rats. RESULTS: But-LI effectively scavenged hydroxyl radicals in deoxyribose degradation assay (IC50 149.12 MUg/ml). Fraction also inhibited lipid peroxidation and demonstrated appreciable reducing potential in FRAP assay. Treatment of animals with 2-AAF resulted in increased hepatic parameters such as SGOT (2.22 fold), SGPT (1.72 fold), ALP (5.68 fold) and lipid peroxidation (2.94 fold). Different concentration of But-LI demonstrated pronounced protective effects via decreasing levels of SGOT, SGPT, ALP and lipid peroxidation altered by 2-AAF treatment. But-LI administration also restored the normal liver architecture as evident from histopathological studies. CONCLUSIONS: The present experimental findings revealed that phytoconstituents of Lawsonia inermis L. possess potential to effectively protect rats from the 2-AAF induced hepatic damage in vivo possibly by inhibition of reactive oxygen species and lipid peroxidation. PMID- 28100200 TI - Prevalence and factors associated with anaemia among children aged 6 to 59 months in Namutumba district, Uganda: a cross- sectional study. AB - BACKGROUND: Anaemia is one of the major causes of death among children under five years in Africa, with a prevalence of 64.6% among pre-school children. In 2014, we conducted a cross-sectional study in Namutumba district in East-central Uganda to determine the prevalence and factors associated with anaemia among children aged 6 to 59 months. METHODS: We conducted a household survey in 376 randomly selected households. One child aged 6 to 59 months was randomly sampled from each selected household. A structured questionnaire administered to an adult caregiver was used to collect household data. Blood was collected by finger or heel prick to estimate the haemoglobin level using a portable haemocue analyser. Anthropometric data including age, weight and height was collected for each child. A modified poisson regression model was used to determine the correlates of anaemia, prevalence ratios and their 95% confidence intervals (CI). RESULTS: The prevalence of anaemia was high (58.8%) and was highest among children aged 12 to 23 months (68.5%) and males (61.3%). About 27.7% children were stunted. Children aged 6-11 and 12-23 months were more likely to be anaemic (APR = 1.12; 95% CI: 1.05-1.19 and APR = 1.12; 95% CI: 1.00-1.24 respectively), Resident of Magada and Namutumba (urban areas) were less likely to be anaemic (APR = 0.89; 95% CI: 0.87-0.91and APR = 0.86; 95% CI: 0. 85-0.88 respectively). Children of caretakers of a big family size (seven or more children) and with any formal education were less likely to be anaemic (APR = 0.94; 95% CI: 0.89-0.99 and APR = 0.93; 95% CI: 0.87-0.99). Stunting (HAZ scores) was a predictor of anaemia (APR = 1.07; 95% CI: 1.02-1.12). CONCLUSION: Anaemia is highly prevalent among children and there is need to invest in measures to prevent anaemia, especially among children in the rural areas. PMID- 28100201 TI - Developing a practice guideline for the occupational health services by using a community of practice approach: a process evaluation of the development process. AB - BACKGROUND: One way to facilitate the translation of research into the occupational health service practice is through clinical practice guidelines. To increase the implementability of guidelines it is important to include the end users in the development, for example by a community of practice approach. This paper describes the development of an occupational health practice guideline aimed at the management of non-specific low back pain (LBP) by using a community of practice approach. The paper also includes a process evaluation of the development providing insight into the feasibility of the process. METHODS: A multidisciplinary community of practice group (n = 16) consisting of occupational nurses, occupational physicians, ergonomists/physical therapists, health and safety engineers, health educators, psychologists and researchers from different types of occupational health services and geographical regions within Sweden met eleven times (June 2012-December 2013) to develop the practice guideline following recommendations of guideline development handbooks. Process-outcomes recruitment, reach, context, satisfaction, feasibility and fidelity were assessed by questionnaire, observations and administrative data. RESULTS: Group members attended on average 7.5 out of 11 meetings. Half experienced support from their workplace for their involvement. Feasibility was rated as good, except for time scheduling. Most group members were satisfied with the structure of the process (e.g. presentations, multidisciplinary group). Fidelity was rated as fairly high. CONCLUSIONS: The described development process is a feasible process for guideline development. For future guideline development expectations of the work involved should be more clearly communicated, as well as the purpose and tasks of the CoP-group. Moreover, possibilities to improve support from managers and colleagues should be explored. This paper has important implications for future guideline development; it provides valuable information on how practitioners can be included in the development process, with the aim of increasing the implementability of the developed guidelines. PMID- 28100202 TI - A novel reflex cough testing device. AB - BACKGROUND: The reflex cough test is useful for detecting silent aspiration, a risk factor for aspiration pneumonia. However, assessing the risk of aspiration pneumonia requires measuring not only the cough reflex but also cough strength. Currently, no reflex cough testing device is available that can directly measure reflex cough strength. We therefore developed a new testing device that can easily and simultaneously measure cough strength and the time until the cough reflex, and verified whether screening with this new instrument is feasible for evaluating the risk of aspiration pneumonia. METHODS: This device consists of a special pipe with a double lumen, a nebulizer, and an electronic spirometer. We used a solution of prescription-grade L-tartaric acid to initiate the cough reflex. The solution was inhaled through a mouthpiece as a microaerosol produced by an ultrasonic nebulizer. The peak cough flow (PCF) of the induced cough was measured with the spirometer. The 70 patients who participated in this study comprised 49 patients without a history of pneumonia (group A), 21 patients with a history of pneumonia (group B), and 10 healthy volunteers (control group). RESULTS: With the novel device, PCF and time until cough reflex could be measured without adverse effects. The PCF values were 118.3 +/- 64.0 L/min, 47.7 +/- 38.5 L/min, and 254.9 +/- 83.8 L/min in group A, group B, and the control group, respectively. The PCF of group B was significantly lower than that of group A and the control group (p < 0.0001), while that of group B was significantly lower than that of the control group (p < 0.0001). The time until the cough reflex was 4.2 +/- 5.9 s, 7.0 +/- 7.0 s, and 1 s in group A, group B, and the control group, respectively. This duration was significantly longer for groups A and B than for the control group (A: p < 0.001, B: p < 0.001), but there was no significant difference between groups A and B (p = 0.0907). CONCLUSION: Our newly developed device can easily and simultaneously measure the time until the cough reflex and the strength of involuntary coughs for assessment of patients at risk of aspiration pneumonia. PMID- 28100203 TI - Diaphragmatic breathing during virtual reality exposure therapy for aviophobia: functional coping strategy or avoidance behavior? a pilot study. AB - BACKGROUND: Although there is solid evidence for the efficacy of in vivo and virtual reality (VR) exposure therapy for a specific phobia, there is a significant debate over whether techniques promoting distraction or relaxation have impairing or enhancing effects on treatment outcome. In the present pilot study, we investigated the effect of diaphragmatic breathing (DB) as a relaxation technique during VR exposure treatment. METHOD: Twenty-nine patients with aviophobia were randomly assigned to VR exposure treatment either with or without diaphragmatic breathing (six cycles per minute). Subjective fear ratings, heart rate and skin conductance were assessed as indicators of fear during both the exposure and the test session one week later. RESULTS: The group that experienced VR exposure combined with diaphragmatic breathing showed a higher tendency to effectively overcome the fear of flying. Psychophysiological measures of fear decreased and self-efficacy increased in both groups with no significant difference between the groups. CONCLUSIONS: Our findings indicate that diaphragmatic breathing during VR exposure does not interfere with the treatment outcome and may even enhance treatment effects of VR exposure therapy for aviophobic patients. TRIAL REGISTRATION: Retrospectively registered. ClinicalTrials.gov NCT02990208 . Registered 07 December 2016. PMID- 28100204 TI - Acceptance and attitudes of healthcare staff towards the introduction of clinical pharmacy service: a descriptive cross-sectional study from a tertiary care hospital in Sri Lanka. AB - BACKGROUND: Multidisciplinary patient management including a clinical pharmacist shows an improvement in patient quality use of medicine. Implementation of a clinical pharmacy service represents a significant novel change in practice in Sri Lanka. Although attitudes of doctors and nurses are an important determinant of successful implementation, there is no Sri Lankan data about staff attitudes to such changes in clinical practice. This study determines the level of acceptance and attitudes of doctors and nurses towards the introduction of a ward based clinical pharmacy service in Sri Lanka. METHODS: This is a descriptive cross-sectional sub-study which determines the acceptance and attitudes of healthcare staff about the introduction of a clinical pharmacy service to a tertiary care hospital in Sri Lanka. The level of acceptance of pharmacist's recommendations regarding drug-related problems (DRPs) was measured. Data regarding attitudes were collected through a pre-tested self-administered questionnaires distributed to doctors (baseline, N =13, post-intervention period, N = 12) and nurses (12) worked in professorial medical unit at baseline and post intervention period. RESULTS: A total of 274 (272 to doctors and 2 to nurses) recommendations regarding DRPs were made. Eighty three percent (225/272) and 100% (2/2) of the recommendations were accepted by doctors and nurses, respectively. The rate of implementation of pharmacist's recommendations by doctors was 73.5% (200/272) (95% CI 67.9 - 78.7%; P < 0.001). The response rate of doctors was higher at the post-intervention period (92.3%; 12/13) compared to the baseline (66.7%; 8/12). At the post-intervention survey 91.6% of doctors were happy to work with competent clinical pharmacists and accepted the necessity of this service to improve standards of care. The nurses' rate of response at baseline and post-intervention surveys were 80.0 and 0.0% respectively. Their perceptions on the role of clinical pharmacist were negative at baseline survey. CONCLUSIONS: There was high acceptance and implementation of clinical pharmacist's recommendations regarding DRPs by the healthcare team. The doctors' views and attitudes were positive regarding the inclusion of a ward-based pharmacist to the healthcare team. However there is a need to improve liaison between clinical pharmacist and nursing staff. TRIAL REGISTRATION: Sri Lanka Clinical Trials Registry SLCTR/2013/029 Date: 13 September 2013; retrospectively registered. PMID- 28100207 TI - Rate and associated factors of non-retention of mother-baby pairs in HIV care in the elimination of mother-to-child transmission programme, Gulu-Uganda: a cohort study. AB - BACKGROUND: Poor retention in HIV care of mother-baby pairs remains a public health challenge in the elimination of mother-to-child transmission (eMTCT) of HIV. We determined the rate of non-retention and time to non-retention of mother baby pairs and associated factors in Gulu district, Northern Uganda. METHODS: Mother-baby pairs enrolled into the eMTCT programme at Gulu Regional Referral Hospital (GRRH) and Lacor Hospital (LH) were retrospectively followed for 18 months. The primary outcomes were the rate of non-retention and time to non retention of mother-baby pairs in HIV care. Data were abstracted from the antiretroviral treatment and early infant diagnosis (EID) registers, and mother/baby appointment books at the health facilities. Additional data on possible reasons for non-retention were obtained from cross-sectional interviews of mothers. Time to non-retention was calculated as the duration between enrolment of mother-baby pair into care and the date when the mother and/or baby missed a scheduled visit and did not return within 30 days. Factors associated with time to non-retention were assessed using Cox proportional hazards regression analysis. The measures of association were expressed as hazards ratio (HR) with 95% confidence intervals. Alpha was set at 0.05. The adjusted analysis includes variables with p <0.2 in the bivariable analysis or considered potential confounders. The Analysis used Stata version 12. RESULTS: A total of 410 mother baby pairs were enrolled in this study. Overall, non-retention by 18 month was 30.5%; higher at GRRH (34.7%) than LH (25.8%), p = 0.049. Non-retention was higher among pairs where the infant had no EID, adjusted (adj) HR = 5.81; 95% CI (2.55, 13.24), non-disclosure of mother's HIV status, adj.HR = 1.86; 95% CI (1.22, 2.85), and lack of privacy during counselling session, adj.HR = 1.86; 95% CI (1.26, 2.85). Non-retention was about 60% lower [adj.HR = 0.43; 95% CI (0.20, 0.92)] among pairs where the mothers understood and appreciated the importance of adhering to all clinic appointments together with the baby. CONCLUSION: Nearly a third of mother-baby pairs are not retained in HIV care. Lack of EID services, poor quality service, non-disclosure of mother's HIV status, and understanding the importance of adhering to all appointments together with the baby, were associated with time to non-retention. PMID- 28100205 TI - A fast and effective determination of the biodistribution and subcellular localization of fluorescent immunoliposomes in freshly excised animal organs. AB - BACKGROUND: Preclinical research implementing fluorescence-based approaches is inevitable for drug discovery and technology. For example, a variety of contrast agents developed for biomedical imaging are usually evaluated in cell systems and animal models based on their conjugation to fluorescent dyes. Biodistribution studies of excised organs are often performed by macroscopic imaging, whereas the subcellular localization though vital, is often neglected or further validated by histological procedures. Available systems used to define the subcellular biodistribution of contrast agents such as intravital microscopes or ex vivo histological analysis are expensive and not affordable by the majority of researchers, or encompass tedious and time consuming steps that may modify the contrast agents and falsify the results. Thus, affordable and more reliable approaches to study the biodistribution of contrast agents are required. We developed fluorescent immunoliposomes specific for human fibroblast activation protein and murine endoglin, and used macroscopic fluorescence imaging and confocal microscopy to determine their biodistribution and subcellular localization in freshly excised mice organs at different time points post intravenous injection. RESULTS: Near infrared fluorescence macroscopic imaging revealed key differences in the biodistribution of the respective immunoliposomes at different time points post injection, which correlated to the first-pass effect as well as the binding of the probes to molecular targets within the mice organs. Thus, a higher accumulation and longer retention of the murine endoglin immunoliposomes was seen in the lungs, liver and kidneys than the FAP specific immunoliposomes. Confocal microscopy showed that tissue autofluorescence enables detection of organ morphology and cellular components within freshly excised, non processed organs, and that fluorescent probes with absorption and emission maxima beyond the tissue autofluorescence range can be easily distinguished. Hence, the endoglin targeting immunoliposomes retained in some organs could be detected in the vascular endothelia cells of the organs. CONCLUSIONS: The underlying work represents a quick, effective and more reliable setup to validate the macroscopic and subcellular biodistribution of contrast agents in freshly excised animal organs. The approach will be highly beneficial to many researchers involved in nanodrug design or in fluorescence-based studies on disease pathogenesis. PMID- 28100206 TI - Hypoglycemic effects of Trichosanthes kirilowii and its protein constituent in diabetic mice: the involvement of insulin receptor pathway. AB - BACKGROUND: Diabetes is a serious chronic metabolic disorder. Trichosanthes kirilowii Maxim. (TK) is traditionally used for the treatment of diabetes in traditional Chinese medicine (TCM). However, the clinical application of TK on diabetic patients and the hypoglycemic efficacies of TK are still unclear. METHODS: A retrospective cohort study was conducted to analyze the usage of Chinese herbs in patients with type 2 diabetes in Taiwan. Glucose tolerance test was performed to analyze the hypoglycemic effect of TK. Proteomic approach was performed to identify the protein constituents of TK. Insulin receptor (IR) kinase activity assay and glucose tolerance tests in diabetic mice were further used to elucidate the hypoglycemic mechanisms and efficacies of TK. RESULTS: By a retrospective cohort study, we found that TK was the most frequently used Chinese medicinal herb in type 2 diabetic patients in Taiwan. Oral administration of aqueous extract of TK displayed hypoglycemic effects in a dose-dependent manner in mice. An abundant novel TK protein (TKP) was further identified by proteomic approach. TKP interacted with IR by docking analysis and activated the kinase activity of IR. In addition, TKP enhanced the clearance of glucose in diabetic mice in a dose-dependent manner. CONCLUSIONS: In conclusion, this study applied a bed-to-bench approach to elucidate the hypoglycemic efficacies and mechanisms of TK on clinical usage. In addition, we newly identified a hypoglycemic protein TKP from TK. Our findings might provide a reasonable explanation of TK on the treatment of diabetes in TCM. PMID- 28100208 TI - Access to primary health care for acute vascular events in rural low income settings: a mixed methods study. AB - BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of global mortality. Among the CVDs, acute vascular events (AVE) mainly ischemic heart diseases and stroke are the largest contributors. To achieve 25% reduction in preventable deaths from CVDs by 2025, health systems need to be equipped with extended service coverage in order to provide person-centered care. The overall goal of this proposed study is to assess access to health care in-terms of service availability, care seeking patterns and barriers to access care after AVE in rural Bangladesh. We will consider myocardial infarction (MI) and stroke as acute vascular events. METHODS/DESIGN: We will conduct a mixed methods study in rural Matlab, Bangladesh. This study will comprise of a) health facility survey, b) structured questionnaire interview and c) qualitative study. We will assess service availabilities by creating an inventory of public and private health facilities. Readiness of the facilities to deliver services for AVE will be assessed through a health facility survey using 'service availability and readiness assessment' (SARA) tools of the World Health Organization (WHO). We will interview survivors of AVE and caregivers (present and accompanied the person during the event) of person who died from AVE for exploring patterns of care seeking during an AVE. For exploring barriers to access care for AVE, we will conduct in-depth interview with survivors of AVE and caregivers of the person who died from AVE. We will also conduct key informant interviews with the service providers at primary health care (PHC) facilities and government high level officials at central health administration of Bangladesh. DISCUSSION: This study will provide a comprehensive picture of access to primary health care services during acute cardiovascular events as stroke & MI in rural context of Bangladesh. It will explore available service facilities in rural area for management, utilization of services and barriers to access care during an acute emergency. This study will help to generate hypothesis, develop programs and policies for better access to care for AVE in similar rural settings considering barriers of access and improving utilization. PMID- 28100210 TI - PREVALENCE of psychiatric morbidity in a community sample in Western Kenya. AB - BACKGROUND: About 25% of the worldwide population suffers from mental, neurological and substance use disorders but unfortunately, up to 75% of affected persons do not have access to the treatment they need. Data on the magnitude of the mental health problem in Kenya is scarce. The objectives of this study were to establish the prevalence and the socio-demographic factors associated with mental and substance use disorders in Kosirai division, Nandi County, Western Kenya. METHODS: This was a cross sectional descriptive study in which participants were selected by simple random sampling. The sampling frame was obtained from a data base of the population in the study area developed during door-to-door testing and counseling exercises for HIV/AIDS. Four hundred and twenty consenting adults were interviewed by psychologists using the Mini International Neuropsychiatric Interview Version 7 for Diagnostic and Statistical Manual 5th Edition and a researcher-designed social demographic questionnaire. RESULTS: One hundred and ninety one (45%) of the participants had a lifetime diagnosis of at least one of the mental disorders. Of these, 66 (15.7%) had anxiety disorder, 53 (12.3%) had major depressive disorder; 49 (11.7%) had alcohol and substance use disorder. 32 (7.6%) had experienced a psychotic episode and 69 (16.4%) had a life-time suicidal attempt. Only 7 (1.7%) had ever been diagnosed with a mental illness. Having a mental condition was associated with age less than 60 years and having a medical condition. CONCLUSION: A large proportion of the community has had a mental disorder in their lifetime and most of these conditions are undiagnosed and therefore not treated. These findings indicate a need for strategies that will promote diagnosis and treatment of community members with psychiatric disorders. In order to screen more people for mental illness, we recommend further research to evaluate a strategy similar to the home based counseling and testing for HIV and the use of simple screening tools. PMID- 28100209 TI - Lifelong vegetarianism and breast cancer risk: a large multicentre case control study in India. AB - BACKGROUND: The lower incidence of breast cancer in Asian populations where the intake of animal products is lower than that of Western populations has led some to suggest that a vegetarian diet might reduce breast cancer risk. METHODS: Between 2011 and 2014 we conducted a multicentre hospital based case-control study in eight cancer centres in India. Eligible cases were women aged 30-70 years, with newly diagnosed invasive breast cancer (ICD10 C50). Controls were frequency matched to the cases by age and region of residence and chosen from the accompanying attendants of the patients with cancer or those patients in the general hospital without cancer. Information about dietary, lifestyle, reproductive and socio-demographic factors were collected using an interviewer administered structured questionnaire. Multivariate logistic regression models were used to estimate the odds ratio (OR) and 95% confidence intervals for the risk of breast cancer in relation to lifelong vegetarianism, adjusting for known risk factors for the disease. RESULTS: The study included 2101 cases and 2255 controls. The mean age at recruitment was similar in cases (49.7 years (SE 9.7)) and controls (49.8 years (SE 9.1)). About a quarter of the population were lifelong vegetarians and the rates varied significantly by region. On multivariate analysis, with adjustment for known risk factors for the disease, the risk of breast cancer was not decreased in lifelong vegetarians (OR 1.09 (95% CI 0.93-1.29)). CONCLUSIONS: Lifelong exposure to a vegetarian diet appears to have little, if any effect on the risk of breast cancer. PMID- 28100211 TI - Waist circumference and waist-to-height ratio are associated with periodontal pocketing-results of the Health 2000 Survey. AB - BACKGROUND: Body mass index (BMI) has been found to associate with different parameters of chronic periodontal disease in previous studies. It is reasonable to expect that central adiposity measures, such as waist circumference and waist to-height ratio, which indirectly takes into account visceral fat, are more accurate measures of obesity-related oral health risks than BMI. The aim of this study was to examine whether central obesity is associated with periodontal pocketing, an indication of infectious chronic periodontal disease. METHODS: The study was based on a subpopulation from the national Health 2000 Survey in Finland. It included dentate, non-diabetic, never-smoking subjects aged 30-49 (n = 1287). The outcome variable was the number of teeth with deepened periodontal pockets (4 mm or more) and the number of teeth with deep periodontal pockets (6 mm or more). Central obesity was measured by means of waist circumference (WC) and waist-to-height ratio (WHtR). Poisson regression models were used to estimate prevalence rate ratios (PRR) and their 95% confidence intervals. RESULTS: Our main finding was that both WC and WHtR were associated with the number of teeth with deeper (4 mm or more) periodontal pockets; the PRR for the fifth quintile in WC was 1.5, CI: 1.2-1.9 and in WHtR 1.4, CI: 1.1-1.7, when compared to the lowest quintile. Corresponding figures for deep (6 mm or more) periodontal pockets were 2.3, CI: 0.9-6.1 for WC and 1.9, CI: 0.8-4.4 for WHtR. There were no essential differences in the strengths of the associations between WC and WHtR and the number of teeth with deepened periodontal pockets. CONCLUSION: Both central adipose measures-WC and WHtR-seem to be associated with periodontal pocketing in non-diabetic, never-smoking subjects aged 30-49 years old. PMID- 28100212 TI - The effects of breakfast on short-term cognitive function among Chinese white collar workers: protocol for a three-phase crossover study. AB - BACKGROUND: As the first meal of the day, breakfast plays an important role in supplying energy and nutrients, which are critical to working and learning activities. A three-phase crossover study was designed to investigate the effects of breakfast on cognitive function among Chinese white-collar workers. The planned study protocol is presented. METHODS: A total of 264 participants aged 25 45 years will be recruited from Shenyang and Chongqing. Self-administered questionnaires will be used to collect information on age, gender, marital status, education level, occupation, smoking habits, drinking habits, and breakfast behaviours. The participants will be randomly assigned to 3 equal-sized groups (Groups A, B, and C) and will be provided with a nutrition-adequate breakfast, a nutrition-inadequate breakfast, or no breakfast, respectively. Each participant will receive the breakfast treatment on the basis of assignment to one of three sequences (ABC/BCA/CAB). Each participant will complete a battery of cognitive tests assessing short-term memory, attention, and working memory 120 minutes after breakfast. Mood will be measured through a self-administered questionnaire assessing the dimensions of positive and negative frames of mind. Additionally, fasting blood glucose and postprandial 2-hour blood glucose levels will be tested with a blood-glucose meter (Roche ACCU-CHEK(r)-Performa). All the participants will take all the tests in three successive weeks, and the order of presentation will be counter-balanced across groups. DISCUSSION: The present study will be the first investigation of the effect of breakfast food type and quality on cognitive function amongst white-collar workers in China. We predict that a nutrition-adequate breakfast, compared with a nutrition-inadequate breakfast and no breakfast, will significantly improve short-term cognitive function. The results of this study should provide scientific evidence of the effect of breakfast quality on cognitive function and provide scientific data to inform nutrition education strategies and promote a healthy lifestyle. TRIAL REGISTRATION: Chinese clinical trial registry (Primary registry in the WHO registry network) Registration number: ChiCTR-IPR-15007114 . Date of registration: August 25, 2015. PMID- 28100213 TI - Transcriptomic response of wolf spider, Pardosa pseudoannulata, to transgenic rice expressing Bacillus thuringiensis Cry1Ab protein. AB - BACKGROUND: Bacillum thuringiensis (Bt) toxin produced in Cry1-expressing genetically modified rice (Bt rice) is highly effective to control lepidopteran pests, which reduces the needs for synthetic insecticides. Non-target organisms can be exposed to Bt toxins through direct feeding or trophic interactions in the field. The wolf spider Pardosa pseudoannulata, one of the dominant predators in South China, plays a crucial role in the rice agroecosystem. In this study, we investigated transcriptome responses of the 5th instar spiders fed on preys maintained on Bt- and non-Bt rice. RESULTS: Comparative transcriptome analysis resulted in 136 differentially expressed genes (DEGs) between spiderlings preying upon N. lugens fed on Bt- and non-Bt rice (Bt- and non-Bt spiderlings). Functional analysis indicated a potential impact of Bt toxin on the formation of new cuticles during molting. GO and KEGG enrichment analyses suggested that GO terms associated with chitin or cuticle, including "chitin binding", "chitin metabolic process", "chitin synthase activity", "cuticle chitin biosynthetic process", "cuticle hydrocarbon biosynthetic process", and "structural constituent of cuticle", and an array of amino acid metabolic pathways, including "alanine, asparatate and glutamate metabolism", "glycine, serine and theronine metabolism", "cysteine and methionine metabolism", "tyrosine metabolism", "phenylalanine metabolism and phenylalanine", and "tyrosine and tryptophan biosynthesis" were significantly influenced in response to Cry1Ab. CONCLUSIONS: The Cry1Ab may have a negative impact on the formation of new cuticles during molting, which is contributed to the delayed development of spiderlings. To validate these transcriptomic responses, further examination at the translational level will be warranted. PMID- 28100215 TI - A discrete event simulation model to evaluate the use of community services in the treatment of patients with Parkinson's disease in the United Kingdom. AB - BACKGROUND: The number of people affected by Parkinson's disease (PD) is increasing in the United Kingdom driven by population ageing. The treatment of the disease is complex, resource intensive and currently there is no known cure to PD. The National Health Service (NHS), the public organisation delivering healthcare in the UK, is under financial pressures. There is a need to find innovative ways to improve the operational and financial performance of treating PD patients. The use of community services is a new and promising way of providing treatment and care to PD patients at reduced cost than hospital care. The aim of this study is to evaluate the potential operational and financial benefits, which could be achieved through increased integration of community services in the delivery of treatment and care to PD patients in the UK without compromising care quality. METHODS: A Discrete Event Simulation model was developed to represent the PD care structure including patients' pathways, treatment modes, and the mix of resources required to treat PD patients. The model was parametrised with data from a large NHS Trust in the UK and validated using information from the same trust. Four possible scenarios involving increased use of community services were simulated on the model. RESULTS: Shifting more patients with PD from hospital treatment to community services will reduce the number of visits of PD patients to hospitals by about 25% and the number of PD doctors and nurses required to treat these patients by around 32%. Hospital based treatment costs overall should decrease by 26% leading to overall savings of 10% in the total cost of treating PD patients. CONCLUSIONS: The simulation model was useful in predicting the effects of increased use of community services on the performance of PD care delivery. Treatment policies need to reflect upon and formalise the use of community services and integrate these better in PD care. The advantages of community services need to be effectively shared with PD patients and carers to help inform management choices and care plans. PMID- 28100214 TI - Preoperative lipiodol marking and its role on survival and complication rates of CT-guided cryoablation for small renal masses. AB - BACKGROUND: Partial nephrectomy for small renal masses (SRM) may be useful for preserving renal function, but is technically more difficult than radical nephrectomy. Cryoablation may be performed under local anesthesia. The objective of the present study is to assess the safety and therapeutic efficacy of cryoablation with lipiodol marking for SRM. METHODS: Cryoablation therapy was performed on 42 patients under local anesthesia. Their median age was 74 years (31-91). The median tumor diameter was 21 mm (10-42). Responses to the treatment were evaluated using modified Response Evaluation Criteria in Solid Tumors (mRECIST) by contrast-enhanced CT. In six patients (14.3%) for whom it was not possible to use contrast medium, plain CT findings were assessed according to Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Twenty-nine (69%) and five (12%) patients achieved complete responses (CR) and partial responses (PR), respectively, while four (10%) and four (10%) patients each had stable disease (SD) and progressive disease (PD) after the first course of therapy. A second course of cryoablation therapy with lipiodol marking was performed on three out of four patients with PD after the first course of therapy, and resulted in a total of 32 patients achieving CR (76%). Four (36.4%) out of 11 patients for whom lipiodol marking was not conducted had PD, whereas none of the 31 patients for whom lipiodol marking was conducted had PD. All grade complications were reported in 11 (24.4%) patients while grade 3 in two (4.4%) patients. 11 (24.4%) A significant difference was observed in postoperative hemorrhagic events in all grades (18% in patients undergoing cryoablation without lipiodol marking vs. 0% in patients undergoing cryoablation without lipiodol marking). CONCLUSIONS: Although further studies involving more patients are needed in order to evaluate long-term results, cryoablation therapy appears to be a useful treatment option for SRM. Preoperative marking with lipiodol was helpful for improving complication and survival rates with cryoablation. PMID- 28100216 TI - Antispasmodic, bronchodilator, vasorelaxant and cardiosuppressant effects of Buxus papillosa. AB - BACKGROUND: The present research was carried out to investigate pharmacological properties of Buxus papillosa C.K. Schneid. (Buxaceae). METHODS: Buxus papillosa extracts of leaves (BpL), stem (BpS), roots (BpR) and BpL fractions: hexane (BpL H), aqueous (BpL-A) also plant constituent, cyclomicrobuxine effect were studied in jejunum, atria, aorta and tracheal preparations from rabbit and guine-peg. RESULTS: Ca++ antagonistic effect of BpS, BpR, BpL-H, BpL-A and cyclomicrobuxine were conclusively suggested, when spontaneous contractions of rabbit jejunal preparation was relaxed along with subsequent relaxation of potassium chloride (80 mM) induced contractions. Ca++ antagonistic effect was further confirmed, when a prominent right shift like that of verapamil was observed in Ca++ concentration-response curves, drawn in a tissue pretreated with BpL (0.3-1.0 mg/mL). In rabbit tracheal tissues BpL, BpS, BpR, BpL-H and BpL-A produced a prominent relaxation in contractions induced by potassium chloride (80 mM) and carbachol (1 MUm). When tested in rabbit aortic rings, BpL, BpS, BpR, BpL-H and BpL-A showed concentration-dependent (0.1-3.0 mg/mL) vasorelaxant effect against phenylephrine (1 MUM) and high K+-induced contractions. In isolated guinea-pig right atria, BpL, BpS, BpR, BpL-H and BpL-A suppressed atrial force of spontaneous contractions, with BpL-A being most potent. CONCLUSIONS: Our results reveal that Buxus papillosa possesses gut, airways and cardiovascular inhibitory actions. PMID- 28100217 TI - Variation in branchial expression among insulin-like growth-factor binding proteins (igfbps) during Atlantic salmon smoltification and seawater exposure. AB - BACKGROUND: In preparation for migration from freshwater to marine habitats, Atlantic salmon (Salmo salar L.) undergo smoltification, a transformation that includes the acquisition of hyposmoregulatory capacity. The growth hormone (Gh)/insulin-like growth-factor (Igf) axis promotes the development of branchial ionoregulatory functions that underlie ion secretion. Igfs interact with a suite of Igf binding proteins (Igfbps) that modulate hormone activity. In Atlantic salmon smolts, igfbp4,-5a,-5b1,-5b2,-6b1 and-6b2 transcripts are highly expressed in gill. We measured mRNA levels of branchial and hepatic igfbps during smoltification (March, April, and May), desmoltification (July) and following seawater (SW) exposure in March and May. We also characterized parallel changes in a broad suite of osmoregulatory (branchial Na+/K+-ATPase (Nka) activity, Na + /K + /2Cl - cotransporter 1 (nkcc1) and cystic fibrosis transmembrane regulator 1 (cftr1) transcription) and endocrine (plasma Gh and Igf1) parameters. RESULTS: Indicative of smoltification, we observed increased branchial Nka activity, nkcc1 and cftr1 transcription in May. Branchial igfbp6b1 and -6b2 expression increased coincidentally with smoltification. Following a SW challenge in March, igfbp6b1 showed increased expression while igfbp6b2 exhibited diminished expression. igfbp5a,-5b1 and-5b2 mRNA levels did not change during smolting, but each had lower levels following a SW exposure in March. CONCLUSIONS: Salmonids express an especially large suite of igfbps. Our data suggest that dynamic expression of particular igfbps accompanies smoltification and SW challenges; thus, transcriptional control of igfbps may provide a mechanism for the local modulation of Igf activity in salmon gill. PMID- 28100218 TI - Antiviral effect of compounds derived from the seeds of Mammea americana and Tabernaemontana cymosa on Dengue and Chikungunya virus infections. AB - BACKGROUND: The transmission of Dengue virus (DENV) and Chikungunya virus (CHIKV) has increased worldwide, due in part to the lack of a specific antiviral treatment. For this reason, the search for compounds with antiviral potential, either as licensed drugs or in natural products, is a research priority. The objective of this study was to identify some of the compounds that are present in Mammea americana (M. americana) and Tabernaemontana cymosa (T. cymosa) plants and, subsequently, to evaluate their cytotoxicity in VERO cells and their potential antiviral effects on DENV and CHIKV infections in those same cells. METHODS: Dry ethanolic extracts of M. americana and T. cymosa seeds were subjected to open column chromatographic fractionation, leading to the identification of four compounds: two coumarins, derived from M. americana; and lupeol acetate and voacangine derived from T. cymosa.. The cytotoxicity of each compound was subsequently assessed by the MTT method (at concentrations from 400 to 6.25 MUg/mL). Pre- and post-treatment antiviral assays were performed at non toxic concentrations; the resulting DENV inhibition was evaluated by Real-Time PCR, and the CHIKV inhibition was tested by the plating method. The results were analyzed by means of statistical analysis. RESULTS: The compounds showed low toxicity at concentrations <= 200 MUg/mL. The compounds coumarin A and coumarin B, which are derived from the M. americana plant, significantly inhibited infection with both viruses during the implementation of the two experimental strategies employed here (post-treatment with inhibition percentages greater than 50%, p < 0.01; and pre-treatment with percentages of inhibition greater than 40%, p < 0.01). However, the lupeol acetate and voacangine compounds, which were derived from the T. cymosa plant, only significantly inhibited the DENV infection during the post-treatment strategy (at inhibition percentages greater than 70%, p < 0.01). CONCLUSION: In vitro, the coumarins are capable of inhibiting infection by DENV and CHIKV (with inhibition percentages above 50% in different experimental strategies), which could indicate that these two compounds are potential antivirals for treating Dengue and Chikungunya fever. Additionally, lupeol acetate and voacangine efficiently inhibit infection with DENV, also turning them into promising antivirals for Dengue fever. PMID- 28100219 TI - Increased amygdala reactivity following early life stress: a potential resilience enhancer role. AB - BACKGROUND: Amygdala hyper-reactivity is sometimes assumed to be a vulnerability factor that predates depression; however, in healthy people, who experience early life stress but do not become depressed, it may represent a resilience mechanism. We aimed to test these hypothesis examining whether increased amygdala activity in association with a history of early life stress (ELS) was negatively or positively associated with depressive symptoms and impact of negative life event stress in never-depressed adults. METHODS: Twenty-four healthy participants completed an individually tailored negative mood induction task during functional magnetic resonance imaging (fMRI) assessment along with evaluation of ELS. RESULTS: Mood change and amygdala reactivity were increased in never-depressed participants who reported ELS compared to participants who reported no ELS. Yet, increased amygdala reactivity lowered effects of ELS on depressive symptoms and negative life events stress. Amygdala reactivity also had positive functional connectivity with the bilateral DLPFC, motor cortex and striatum in people with ELS during sad memory recall. CONCLUSIONS: Increased amygdala activity in those with ELS was associated with decreased symptoms and increased neural features, consistent with emotion regulation, suggesting that preservation of robust amygdala reactions may reflect a stress buffering or resilience enhancing factor against depression and negative stressful events. PMID- 28100220 TI - Effect of patient's age on the profitability of inpatient cardiac catheterization: a contribution margin analysis of frequently performed procedures over a 5-year period. AB - BACKGROUND: Due to a continuing age shift in the German society hospital providers are concerned about the additional costs associated with the treatment of elderly patients. It is not clear if cardiac catheterization in aged patients leads to higher resource utilization and if DRG-revenues do compensate for this factor. METHODS: Procedure-related and administrative data of all patients who underwent cardiac catheterization at a tertiary heart center between 2007 and 2011 were collected and analyzed. Then a profitability analysis was performed by comparing the case related variable costs with the Diagnosis-related group (DRG) per case revenues. A particular emphasis was placed on a comparative analysis of identical clusters of procedures. RESULTS: The most frequently performed catheterization procedure (n = 1800) was associated with significantly higher material expenditure in very old patients (178 +/- 48 ?) than in old (171 +/- 28; p = 0.001) and young patients (172 +/- 39; p = 0.046). Furthermore, radiation time and the length of hospital stay were increased in very old patients (3.5 +/- 3.8 min and 6.2 +/- 4.8 days) compared to old (2.7 +/- 2.8 min and 4.6 +/- 3.8 days; p < 0.001) and young patients (2.5 +/- 2.5 min and 4.5 +/- 3.9 days; p < 0.001). Due to higher DRG revenues very old patients achieved higher absolute contribution margins (2065 +/- 1033 ?) than old (1804 +/- 1902 ?; p < 0.001) and young patients (1771 +/- 902 ?; p < 0.001). However, the contribution margins per day were significantly smaller (440 +/- 226 ?) than those in old (488 +/- 234 ?; p = 0.001) and young patients (484 +/- 206 ?; p = 0.001). CONCLUSIONS: Catheterization of very old patients is related to lower contribution margins per day despite higher material and time expenditures. Since efforts to reduce the length of hospital stay of these patients are limited, this may result in a competitive disadvantage of hospitals which are more affected by the demographic change. PMID- 28100221 TI - Psychosocial work factors and social inequalities in psychological distress: a population-based study. AB - BACKGROUND: Mental health problems (MHP) are the leading cause of disability worldwide. The inverse association between socioeconomic position (SEP) and MHP has been well documented. There is prospective evidence that factors from the work environment, including adverse psychosocial work factors, could contribute to the development of MHP including psychological distress. However, the contribution of psychosocial work factors to social inequalities in MHP remains unclear. This study evaluates the contribution of psychosocial work factors from two highly supported models, the Demand-Control-Support (DCS) and the Effort Reward Imbalance (ERI) models to SEP inequalities of psychological distress in men and women from a population-based sample of Quebec workers. METHODS: Data were collected during a survey on working conditions, health and safety at work. SEP was evaluated using education, occupation and household income. Psychosocial work factors and psychological distress were assessed using validated instruments. Mean differences (MD) in the score of psychological distress were estimated separately for men and women. RESULTS: Low education level and low household income were associated with psychological distress among men (MD, 0.56 (95% CI 0.06; 1.05) and 1.26 (95% CI 0.79; 1.73) respectively). In men, the contribution of psychosocial work factors from the DCS and the ERI models to the association between household income and psychological distress ranged from 9% to 24%. No clear inequalities were observed among women. CONCLUSIONS: These results suggest that psychosocial work factors from the DCS and the ERI models contribute to explain a part of social inequalities in psychological distress among men. Psychosocial factors at work are frequent and modifiable. The present study supports the relevance of targeting these factors for the primary prevention of MHP and for health policies aiming to reduce social inequalities in mental health. PMID- 28100222 TI - Gestational age and 1-year hospital admission or mortality: a nation-wide population-based study. AB - BACKGROUND: Describe the 1-year hospitalization and in-hospital mortality rates, in infants born after 31 weeks of gestational age (GA). METHODS: This nation-wide population-based study used the French medico-administrative database to assess the following outcomes in singleton live-born infants (32-43 weeks) without congenital anomalies (year 2011): neonatal hospitalization (day of life 1 - 28), post-neonatal hospitalization (day of life 29 - 365), and 1-year in-hospital mortality rates. Marginal models and negative binomial regressions were used. RESULTS: The study included 696,698 live-born babies. The neonatal hospitalization rate was 9.8%. Up to 40 weeks, the lower the GA, the higher the hospitalization rate and the greater the likelihood of requiring the highest level of neonatal care (both p < 0.001). The relative risk adjusted for sex and pregnancy-related diseases (aRR) reached 21.1 (95% confidence interval [CI]: 19.2 23.3) at 32 weeks. The post-neonatal hospitalization rate was 12.1%. The raw rates for post-neonatal hospitalization fell significantly from 32 - 40 and increased at 43 weeks and this persisted after adjustment (aRR = 3.6 [95% CI: 3.3 3.9] at 32 and 1.5 [95% CI: 1.1-1.9] at 43 compared to 40 weeks). The main causes of post-neonatal hospitalization were bronchiolitis (17.2%), gastroenteritis (10.4%) ENT diseases (5.4%) and accidents (6.2%). The in-hospital mortality rate was 0.850/00, with a significant decrease (p < 0.001) according to GA at birth (aRR = 3.8 [95% CI: 2.4-5.8] at 32 and 6.6 [95% CI: 2.1-20.9] at 43, compared to 40 weeks. CONCLUSION: There's a continuous change in outcome in hospitalized infants born above 31 weeks. Birth at 40 weeks gestation is associated with the lowest 1-year morbidity and mortality. PMID- 28100223 TI - Surface attachment, promoted by the actomyosin system of Toxoplasma gondii is important for efficient gliding motility and invasion. AB - BACKGROUND: Apicomplexan parasites employ a unique form of movement, termed gliding motility, in order to invade the host cell. This movement depends on the parasite's actomyosin system, which is thought to generate the force during gliding. However, recent evidence questions the exact molecular role of this system, since mutants for core components of the gliding machinery, such as parasite actin or subunits of the MyoA-motor complex (the glideosome), remain motile and invasive, albeit at significantly reduced efficiencies. While compensatory mechanisms and unusual polymerisation kinetics of parasite actin have been evoked to explain these findings, the actomyosin system could also play a role distinct from force production during parasite movement. RESULTS: In this study, we compared the phenotypes of different mutants for core components of the actomyosin system in Toxoplasma gondii to decipher their exact role during gliding motility and invasion. We found that, while some phenotypes (apicoplast segregation, host cell egress, dense granule motility) appeared early after induction of the act1 knockout and went to completion, a small percentage of the parasites remained capable of motility and invasion well past the point at which actin levels were undetectable. Those act1 conditional knockout (cKO) and mlc1 cKO that continue to move in 3D do so at speeds similar to wildtype parasites. However, these mutants are virtually unable to attach to a collagen-coated substrate under flow conditions, indicating an important role for the actomyosin system of T. gondii in the formation of attachment sites. CONCLUSION: We demonstrate that parasite actin is essential during the lytic cycle and cannot be compensated by other molecules. Our data suggest a conventional polymerisation mechanism in vivo that depends on a critical concentration of G-actin. Importantly, we demonstrate that the actomyosin system of the parasite functions in attachment to the surface substrate, and not necessarily as force generator. PMID- 28100224 TI - Radical Scavenging Activities of Lagerstroemia speciosa (L.) Pers. Petal Extracts and its hepato-protection in CCl4-intoxicated mice. AB - BACKGROUND: Lagerstroemia speciosa (L.) Pers. has medicinal importance. Bioactive phytochemicals isolated from different parts of L. speciosa, have revealed hypoglycemic, antibacterial, anti-inflammatory, antioxidant and hepato protective properties. Despite one report from Philippines detailing the use of L. speciosa as curative for fever and as well as diuretic, there is no experimental evidence about the hepatoprotective activity of the flower extracts. METHODS: Several spectroscopic methods, including GC-MS, were used to characterize phytochemicals present in the petal extract of L. speciosa. Ethanol extract of petals was evaluated for anti-oxidant and free radical scavenging properties by using methods related to hydrogen atom transfer, single electron transfer, reducing power, and metal chelation. This study has also revealed the in vitro antioxidant and in vivo hepatoprotective properties of petal extract against carbon tetra chloride (CCl4)-induced liver toxicity in Swiss albino mice. Hepatoprotection in CCl4 -intoxicated mice was studied with the aid of histology and different enzymatic and non-enzymatic markers of liver damage. Cytotoxicity tests were done using murein spleenocytes and cancareous cell lines, MCF7 and HepG2. RESULT: GCMS of the extract has revealed the presence of several potential antioxidant compounds, of them gamma-Sitosterol and 1,2,3-Benzenetriol (Pyrogallol) were the predominant ones. The antioxidants activities of the flower-extract were significantly higher than curcumin (in terms of Nitric oxide scavenging activity; p = 0.0028) or ascorbic acid (in terms of 2,2-Diphenyl-1-Picrylhydrazyl (DPPH) assay; p = 0.0022). The damage control by the flower extract can be attributed to the reduction in lipid peroxidation and restoration of catalase activity. In vitro cytotoxicity tests have shown that the flower extract did not affect growth and survivability of the cell lines. It left beyond doubt that a flower of L. speciosa is a reservoir of antioxidant and hepatoprotective agents capable of reversing the damage inflicted by CCl4-intoxication. CONCLUSION: Results from the present study may be used in developing a potential hepato-protective health drink enriched with antioxidants from Lagerstroemia speciosa (L.) Pers. PMID- 28100225 TI - Percutaneous nephrolithotomy versus retrograde intrarenal surgery for the treatment of kidney stones up to 2 cm in patients with solitary kidney: a single centre experience. AB - BACKGROUND: To compare the treatment outcomes between percutaneous nephrolithotomy (PCNL) and retrograde intrarenal surgery (RIRS) for the management of stones larger than 2 cm in patients with solitary kidney. METHODS: One hundred sixteen patients with a solitary kidney who underwent RIRS (n = 56) or PCNL (n = 60) for large renal stones (>2 cm) between Jan 2010 and Nov 2015 have been considered. The patients' characteristics, stone characteristics, operative time, incidence of complications, hospital stay, and stone-free rates (SFR) have been evaluated. RESULTS: SFRs after one session were 19.6% and 35.7% for RIRS and PCNL respectively (p = 0.047), but the SFR at 3 months follow-up comparable in both groups (82.1% vs. 88.3%, p = 0.346). The calculated mean operative time for RIRS was longer (p < 0.001), but the mean postoperatively hospital stay was statistically significantly shorter (p < 0.001) and average drop in hemoglobin level was less (p = 0.040). PCNL showed a higher complication rate, although this difference was not statistically significant. CONCLUSIONS: Satisfactory stone clearance can be achieved with multi-session RIRS in the treatment of renal stones larger than 2 cm in patients with solitary kidney. RIRS can be considered as an alternative to PCNL in selected cases. PMID- 28100226 TI - Multidimensional poverty and catastrophic health spending in the mountainous regions of Myanmar, Nepal and India. AB - BACKGROUND: Economic burden to households due to out-of-pocket expenditure (OOPE) is large in many Asian countries. Though studies suggest increasing household poverty due to high OOPE in developing countries, studies on association of multidimensional poverty and household health spending is limited. This paper tests the hypothesis that the multidimensionally poor are more likely to incur catastrophic health spending cutting across countries. DATA AND METHODS: Data from the Poverty and Vulnerability Assessment (PVA) Survey carried out by the International Center for Integrated Mountain Development (ICIMOD) has been used in the analyses. The PVA survey was a comprehensive household survey that covered the mountainous regions of India, Nepal and Myanmar. A total of 2647 households from India, 2310 households in Nepal and 4290 households in Myanmar covered under the PVA survey. Poverty is measured in a multidimensional framework by including the dimensions of education, income and energy, water and sanitation using the Alkire and Foster method. Health shock is measured using the frequency of illness, family sickness and death of any family member in a reference period of one year. Catastrophic health expenditure is defined as 40% above the household's capacity to pay. RESULTS: Results suggest that about three-fifths of the population in Myanmar, two-fifths of the population in Nepal and one-third of the population in India are multidimensionally poor. About 47% of the multidimensionally poor in India had incurred catastrophic health spending compared to 35% of the multidimensionally non-poor and the pattern was similar in both Nepal and Myanmar. The odds of incurring catastrophic health spending was 56% more among the multidimensionally poor than among the multidimensionally non poor [95% CI: 1.35-1.76]. While health shocks to households are consistently significant predictors of catastrophic health spending cutting across country of residence, the educational attainment of the head of the household is not significant. CONCLUSION: The multidimensionally poor in the poorer regions are more likely to face health shocks and are less likely to afford professional health services. Increasing government spending on health and increasing households' access to health insurance can reduce catastrophic health spending and multidimensional poverty. PMID- 28100227 TI - Prenatal and postnatal mothering by diesel exhaust PM2.5-exposed dams differentially program mouse energy metabolism. AB - BACKGROUND: Obesity is one of the leading threats to global public health. It is consequent to abnormal energy metabolism. Currently, it has been well established that maternal exposure to environmental stressors that cause inappropriate fetal development may have long-term adverse effects on offspring energy metabolism in an exposure timing-dependent manner, known as developmental programming of health and diseases paradigm. Rapidly increasing evidence has indicated that maternal exposure to ambient fine particles (PM2.5) correlates to abnormal fetal development. In the present study, we therefore assessed whether maternal exposure to diesel exhaust PM2.5 (DEP), the major component of ambient PM2.5 in urban areas, programs offspring energy metabolism, and further examined how the timing of exposure impacts this programming. RESULTS: The growth trajectory of offspring shows that although prenatal maternal exposure to DEP did not impact the birth weight of offspring, it significantly decreased offspring body weight from postnatal week 2 until the end of observation. This weight loss effect of prenatal maternal exposure to DEP coincided with decreased food intake but not alteration in brown adipose tissue (BAT) morphology. The hypophagic effect of prenatal maternal exposure to DEP was in concord with decreased hypothalamic expression of an orexigenic peptide NPY, suggesting that the prenatal maternal exposure to DEP impacts offspring energy balance primarily through programming of food intake. Paradoxically, the reduced body weight resulted from prenatal maternal exposure to DEP was accompanied by increased mass of epididymal adipose tissue, which was due to hyperplasia as morphological analysis did not observe any hypertrophy. In direct contrast, the postnatal mothering by DEP-exposed dams increased offspring body weight during lactation and adulthood, paralleled by markedly increased fat accumulation and decreased UCP1 expression in BAT but not alteration in food intake. The weight gain induced by postnatal mothering by DEP exposed dams was also expressed as an increased adiposity. But it concurred with a marked hypertrophy of adipocytes. CONCLUSION: Prenatal and postnatal mothering by DEP-exposed dams differentially program offspring energy metabolism, underscoring consideration of the exposure timing when examining the adverse effects of maternal exposure to ambient PM2.5. PMID- 28100228 TI - Association of stem cell factor gene expression with severity and atopic state in patients with bronchial asthma. AB - BACKGROUND: Bronchial asthma is a chronic inflammatory and remodeling disorder of the airways, in which many cells, cellular elements, and cytokines play important roles. Stem cell factor (SCF) may contribute to the inflammatory changes occurring in asthma. We aimed to show the expression of SCF gene in patients with asthma as a means of diagnosis and its association with severity and atopic state in these patients. METHODS: This study was carried out on 80 subjects, 50 asthmatic patients and 30 age and gender matched healthy control persons. They were subjected to full history taking, general and local chest examination, spirometric measurements (pre and post broncodilators) using a spirometer, serum IgE, and real time PCR for assessment of SCF mRNA expression. RESULTS: This study showed significant difference between the studied groups regarding pulmonary function tests (P < 0.001). Asthmatic patients had significant higher SCF expression compared to control (P < 0.001), also atopic patients vs non atopic (P = 0.03) and severe asthmatic patients vs mild ones (P < 0.001). SCF expression at cut off point (0.528) is sufficient to discriminate asthmatic patients from control while at cut off point (1.84) for discrimination of atopic patients from non-atopic patients and at cut off point (1.395) for discrimination of severe asthmatic patients from mild ones. A significant negative correlation between SCF expression and inhaled steroid while significant positive correlation with serum IgE was found. CONCLUSION: Measuring SCF mRNA expression can be used as an efficient marker for evaluation of atopy and detection of severity of bronchial asthma. PMID- 28100229 TI - Surveillance of life-long antibiotics: a review of antibiotic prescribing practices in an Australian Healthcare Network. AB - BACKGROUND: The rise of antimicrobial use in the twentieth century has significantly reduced morbidity due to infection, however it has also brought with it the rise of increasing resistance. Some patients are on prolonged, if not "life-long" course of antibiotics. The reasons for this are varied, and include non-infectious indications. We aimed to study the characteristics of this potential source of antibiotic resistance, by exploring the antibiotic dispensing practices and describing the population of patients on long-term antibiotic therapy. METHODS: A retrospective cross-sectional study of antibiotic dispensing records was performed at a large university hospital-based healthcare network in Melbourne, Australia. Outpatient prescriptions were extracted from the hospital pharmacy database over a 6 month period in 2014. Medical records of these patients were reviewed to determine the indication for prescription, including microbiology, the intended duration, and the prescribing unit. A descriptive analysis was performed on this data. RESULTS: 66,127 dispensing episodes were reviewed. 202 patients were found to have been prescribed 1 or more antibiotics with an intended duration of 1 year or longer. 69/202 (34%) of these patients were prescribed prolonged antibiotics for primary prophylaxis in the setting of immunosuppression. 43/202 (21%) patients were prescribed long-term suppressive antibiotics for infections of thought incurable (e.g. vascular graft infections), and 34/43 (79%) were prescribed by Infectious Diseases doctors. 66/202 (33%) patients with cystic fibrosis were prescribed prolonged courses of macrolides or fluoroquinolones, by respiratory physicians. There was great heterogeneity noted in indications for prolonged antibiotic courses, as well as antibiotic agents utilised. CONCLUSION: Our study found that that continuous antibiotic therapy represented only a small proportion of overall antibiotic prescribing at our health network. Prolonged courses of antibiotics were used mainly to suppress infections thought incurable, but also as primary and secondary prophylaxis and as anti-inflammatory agents. More research is needed to understand the impact of long-term antibiotic consumption on both patients and microbial ecology. PMID- 28100230 TI - Seroprevalence of Toxoplasma gondii infection in feral cats in Qatar. AB - BACKGROUND: Cats are essential in the life cycle of Toxoplasma gondii as they can shed the environmentally resistant oocysts after acquiring infection. Human populations living in cities with high densities of feral cats are therefore likely to be at risk of infection. The current study is the first to estimate the seroprevalence of T. gondii in the feral cat population in Qatar. We investigated the seroprevalence of T. gondii among 495 adult cats from urban and suburban districts in Qatar. Using results from the Modified Agglutination Test, we fitted statistical models with host sex, area and season as explanatory factors and seropositivity as the outcome. RESULTS: The analysis revealed an overall seroprevalence of 82%. Seroprevalence was significantly higher in the summer season (P = 0.006). No significant difference was detected (P > 0.05) between seroprevalence in female and male cats and in cats from urban and suburban districts of Qatar. CONCLUSIONS: Despite the seasonal difference, the observed seroprevalence of T. gondii suggests high environmental contamination throughout the year, with some female cats generating more intense responses compared to males. Both findings merit further investigations. PMID- 28100231 TI - Can screening instruments accurately determine poor outcome risk in adults with recent onset low back pain? A systematic review and meta-analysis. AB - BACKGROUND: Delivering efficient and effective healthcare is crucial for a condition as burdensome as low back pain (LBP). Stratified care strategies may be worthwhile, but rely on early and accurate patient screening using a valid and reliable instrument. The purpose of this study was to evaluate the performance of LBP screening instruments for determining risk of poor outcome in adults with LBP of less than 3 months duration. METHODS: Medline, Embase, CINAHL, PsycINFO, PEDro, Web of Science, SciVerse SCOPUS, and Cochrane Central Register of Controlled Trials were searched from June 2014 to March 2016. Prospective cohort studies involving patients with acute and subacute LBP were included. Studies administered a prognostic screening instrument at inception and reported outcomes at least 12 weeks after screening. Two independent reviewers extracted relevant data using a standardised spreadsheet. We defined poor outcome for pain to be >= 3 on an 11-point numeric rating scale and poor outcome for disability to be scores of >= 30% disabled (on the study authors' chosen disability outcome measure). RESULTS: We identified 18 eligible studies investigating seven instruments. Five studies investigated the STarT Back Tool: performance for discriminating pain outcomes at follow-up was 'non-informative' (pooled AUC = 0.59 (0.55-0.63), n = 1153) and 'acceptable' for discriminating disability outcomes (pooled AUC = 0.74 (0.66-0.82), n = 821). Seven studies investigated the Orebro Musculoskeletal Pain Screening Questionnaire: performance was 'poor' for discriminating pain outcomes (pooled AUC = 0.69 (0.62-0.76), n = 360), 'acceptable' for disability outcomes (pooled AUC = 0.75 (0.69-0.82), n = 512), and 'excellent' for absenteeism outcomes (pooled AUC = 0.83 (0.75-0.90), n = 243). Two studies investigated the Vermont Disability Prediction Questionnaire and four further instruments were investigated in single studies only. CONCLUSIONS: LBP screening instruments administered in primary care perform poorly at assigning higher risk scores to individuals who develop chronic pain than to those who do not. Risks of a poor disability outcome and prolonged absenteeism are likely to be estimated with greater accuracy. It is important that clinicians who use screening tools to obtain prognostic information consider the potential for misclassification of patient risk and its consequences for care decisions based on screening. However, it needs to be acknowledged that the outcomes on which we evaluated these screening instruments in some cases had a different threshold, outcome, and time period than those they were designed to predict. SYSTEMATIC REVIEW REGISTRATION: PROSPERO international prospective register of systematic reviews registration number CRD42015015778 . PMID- 28100232 TI - Equitable health services for the young? A decomposition of income-related inequalities in young adults' utilization of health care in Northern Sweden. AB - BACKGROUND: Despite the goal of the Swedish health system to offer health care according to the principle of horizontal equity, little is known about the equality in access to health care use among young people. To explore this issue, the present study aimed i) to assess horizontal inequity in health care utilization among young people in Northern Sweden; and ii) to explore the contribution of different factors to explain the observed inequalities. METHODS: Participants (N = 3016 youths aged 16-25 years) came from the "Health on Equal terms" survey conducted in 2014 in the four northernmost counties in Sweden. Concentration indices (C) and horizontal inequity indices (HI) were calculated to measure inequalities in the utilization of two health care services (general practitioners (GP) and youth clinics). The HI was calculated based on health care utilization and variables representing socioeconomic status (household income), health care needs factors and non-need factors affecting health care use. A decomposition analysis was carried out to explain the income-related inequalities. RESULTS: Results showed a significant positive income-related inequality for youth clinic utilization in women (C = 0.166) and total sample (C = 0.097), indicating that services were concentrated among the better-off. In contrast, general practitioner visits showed inequality pointing toward a higher utilization among less affluent individuals; significant in women (C = -0.079), men (C = -0.101) and pooled sample (C = -0.097). After taking health care needs into consideration, the utilization of youth clinics remained significantly pro rich in women (HI = 0.121) and total sample (HI = 0.099); and consistently pro poor for the GP visits in the pooled sample (HI = -0.058). The decomposition analyses suggest that socioeconomic inequalities explain a considerable portion of the pro-rich utilization of youth clinics services among young women. The corresponding analyses for GP visits showed that need factors and socioeconomic conditions accounted for the pro-poor concentration of GP visits. CONCLUSION: The distribution of GP visits among young people in Northern Sweden slightly favored the low-income group, and thus seems to meet the premises of horizontal equity. In contrast, the findings suggest substantial pro-rich horizontal inequity in the utilization of youth clinics among young women, which are largely rooted in socioeconomic inequalities. PMID- 28100234 TI - Arthroscopic reduction and fixation of coronoid fractures with an exchange rod-a new technique. AB - BACKGROUND: The ulnar coronoid process plays a central role in maintaining elbow stability. Some of its fractures were often combined with injury of bone and ligament. Arthroscopy enables perfect visualization to allow anatomical repair. METHODS: From January 2012 to December 2013, six patients (four males, two females) with a mean age of 26.6 years were treated. The left and right ulnas were involved in two and four patients, respectively. All patients suffered from ipsilateral subluxation of the elbow without associated radial fracture. According to the Regan and Morrey fracture classification and O'Driscoll's classification, two and four patients were classified as type I and type II and as having tip fracture (O'Driscoll type I) and anteromedial fracture (O'Driscoll type II), respectively. Exchange rod technology via the elbow front center approach was used for reduction and fixation of fractures of the coronoid process of the ulna. RESULTS: Intra- and postoperative X-ray examination showed that the fractures were satisfactorily fixed and that the screw and fracture line were vertical to each other. Follow-ups showed that the fractures had healed well, and the average elbow extension was -2 degrees while the average flexion was 140 degrees . No problems related to pronation or supination, elbow instability, or complications of blood vessels or nerves were reported. The elbows showed excellent results according to the Mayo Elbow Performance Score. CONCLUSIONS: Arthroscopy using an exchange rod can provide excellent visual exposure of the fractured joints, without the need for a large incision during the anatomical repair. Moreover, it protects the surrounding soft tissue, shows good stability of the components, and allows early rehabilitation exercises. PMID- 28100233 TI - The role of the endothelium in asthma and chronic obstructive pulmonary disease (COPD). AB - COPD and asthma are important chronic inflammatory disorders with a high associated morbidity. Much research has concentrated on the role of inflammatory cells, such as the neutrophil, in these diseases, but relatively little focus has been given to the endothelial tissue, through which inflammatory cells must transmigrate to reach the lung parenchyma and cause damage. There is evidence that there is an abnormal amount of endothelial tissue in COPD and asthma and that this tissue and its' progenitor cells behave in a dysfunctional manner. This article reviews the evidence of the involvement of pulmonary endothelium in COPD and asthma and potential treatment options for this. PMID- 28100235 TI - Solitary fibrous tumour of the liver-report on metastasis and local recurrence of a malignant case and review of literature. AB - BACKGROUND: Solitary fibrous tumours (SFT) are neoplasms of mesenchymal origin that predominantly arise from the pleura. SFT of the liver (SFTL) are a rare occurrence with little number of cases reported in English literature. Malignant cases of hepatic SFT are an even rarer occurrence. For this reason, the prognostic evaluation of SFTLs is unknown and difficult to measure. METHODS: A search on English literature on "Solitary Fibrous Tumour of the Liver" was conducted on common search engines (PubMed, Google). All published articles, case reports and literature reviews and their reference lists were reviewed. CASE REPORT: This paper presents a 61-year-old male who was referred to a tertiary hospital in April 2010 with marked hepatomegaly. USS, CT and MRI scans were suggestive of a neoplasm, and the patient underwent a subsegmental IVb resection in June 2010. The specimen demonstrated histological and immunohistochemical features of malignant SFTL with clear resection margins. The patient was followed up regularly for 3 years with imaging and no suggestion of recurrence. Six years after the initial surgery, the patient represented with worsening right upper quadrant pain and dyspnoea secondary to extensive tumour recurrence adjacent to the resection site and metastatic deposits in the pleura. The patient was managed symptomatically and discharged for community follow-up after palliative involvement. CONCLUSIONS: SFTL are rare with only 84 cases reported in the English Literature including the present case. The average age of patients is 57.1 and occurs in females more than males (1.4:1). Most SFTLs follow a benign course, however, 17.9% of cases displayed malignant histological features. Only three cases including the current case are reported to have both local recurrence and metastasis. Surgical resection remains the mainstay of treatment and appears to be curative of most cases. The rarity of this tumour makes it difficult to evaluate its prognosis and natural course. PMID- 28100236 TI - Human beta-defensin-2 production from S. cerevisiae using the repressible MET17 promoter. AB - BACKGROUND: Baker's yeast Saccharomyces cerevisiae is a proven host for the commercial production of recombinant biopharmaceutical proteins. For the manufacture of heterologous proteins with activities deleterious to the host it can be desirable to minimise production during the growth phase and induce production late in the exponential phase. Protein expression by regulated promoter systems offers the possibility of improving productivity in this way by separating the recombinant protein production phase from the yeast growth phase. Commonly used inducible promoters do not always offer convenient solutions for industrial scale biopharmaceutical production with engineered yeast systems. RESULTS: Here we show improved secretion of the antimicrobial protein, human beta defensin-2, (hBD2), using the S. cerevisiae MET17 promoter by repressing expression during the growth phase. In shake flask culture, a higher final concentration of human beta-defensin-2 was obtained using the repressible MET17 promoter system than when using the strong constitutive promoter from proteinase B (PRB1) in a yeast strain developed for high-level commercial production of recombinant proteins. Furthermore, this was achieved in under half the time using the MET17 promoter compared to the PRB1 promoter. Cell density, plasmid copy number, transcript level and protein concentration in the culture supernatant were used to study the effects of different initial methionine concentrations in the culture media for the production of human beta-defensin-2 secreted from S. cerevisiae. CONCLUSIONS: The repressible S. cerevisiae MET17 promoter was more efficient than a strong constitutive promoter for the production of human beta defensin-2 from S. cerevisiae in small-scale culture and offers advantages for the commercial production of this and other heterologous proteins which are deleterious to the host organism. Furthermore, the MET17 promoter activity can be modulated by methionine alone, which has a safety profile applicable to biopharmaceutical manufacturing. PMID- 28100237 TI - Surveillance and response for high-risk populations: what can malaria elimination programmes learn from the experience of HIV? AB - To eliminate malaria, malaria programmes need to develop new strategies for surveillance and response appropriate for the changing epidemiology that accompanies transmission decline, in which transmission is increasingly driven by population subgroups whose behaviours place them at increased exposure. Conventional tools of malaria surveillance and response are likely not sufficient in many elimination settings for accessing high-risk population subgroups, such as mobile and migrant populations (MMPs), given their greater likelihood of asymptomatic infections, illegal risk behaviours, limited access to public health facilities, and high mobility including extended periods travelling away from home. More adaptive, targeted strategies are needed to monitor transmission and intervention coverage effectively in these groups. Much can be learned from HIV programmes' experience with "second generation surveillance", including how to rapidly adapt surveillance and response strategies to changing transmission patterns, biological and behavioural surveys that utilize targeted sampling methods for specific behavioural subgroups, and methods for population size estimation. This paper reviews the strategies employed effectively for HIV programmes and offers considerations and recommendations for adapting them to the malaria elimination context. PMID- 28100239 TI - Elective breast radiotherapy including level I and II lymph nodes: A planning study with the humeral head as planning risk volume. AB - BACKGROUND: The aim of this study was to assess the dose to the humeral head planning risk volume with the currently used high tangential fields (HTF) and compare different planning techniques for breast radiotherapy including axillary level I and II lymph nodes (PTVn) while sparing the humeral head. METHODS: Ten patients with left-sided breast cancer were enrolled in a planning study with 16 fractions of 2.66 Gy. Four planning techniques were compared: HTF, HTF with sparing of the humeral head, 6-field IMRT with sparing of the humeral head and VMAT with sparing of the humeral head. The humeral head + 10 mm was spared by restricting V40Gy < 1 cc. RESULTS: The dose to the humeral head was too high with HTF (V40Gy on average 20.7 cc). When sparing the humeral head in HTF, PTVn V90% decreased significantly from 97.9% to 89.4%. 6-field IMRT and VMAT had a PTVn V90% of 98.2% and 99.5% respectively. However, dose to the lungs, heart and especially the contralateral breast increased with VMAT. CONCLUSIONS: The humeral head is rarely spared when using HTF. When sparing the humeral head, the 6-field IMRT technique leads to adequate PTV coverage while not increasing the dose to the OARs. PMID- 28100238 TI - Chronic physical conditions, multimorbidity and physical activity across 46 low- and middle-income countries. AB - BACKGROUND: There are no nationally representative population-based studies investigating the relationship between physical activity, chronic conditions and multimorbidity (i.e., two or more chronic conditions) in low- and middle-income countries (LMICs), and studies on a multi-national level are lacking. This is an important research gap, given the rapid increase in the prevalence of chronic diseases associated with lifestyle changes in these countries. This cross sectional study aimed to assess the association between chronic conditions, multimorbidity and low physical activity (PA) among community-dwelling adults in 46 LMICs, and explore the mediators of these relationships. METHODS: World Health Survey data included 228,024 adults aged >=18 years from 46 LMICs. PA was assessed by the International Physical Activity Questionnaire (IPAQ). Nine chronic physical conditions (chronic back pain, angina, arthritis, asthma, diabetes, hearing problems, tuberculosis, visual impairment and edentulism) were assessed. Multivariable logistic regression and mediation analyses were used to assess the association between chronic conditions or multimorbidity and low PA. RESULTS: Overall, in the multivariable analysis, arthritis (OR = 1.12), asthma (1.19), diabetes (OR = 1.33), edentulism (OR = 1.46), hearing problems (OR = 1.90), tuberculosis (OR = 1.24), visual impairment (OR = 2.29), multimorbidity (OR = 1.31; 95% CI = 1.21-1.42) were significantly associated with low PA. More significant associations were observed in individuals aged >=50 years. In older adults, depression mediated between 5.1% (visual impairment) to 23.5% (angina) of the association between a chronic condition and low PA. Mobility difficulties explained more than 25% of the association for seven of the eight chronic conditions. Pain was a strong mediator for angina (65.9%) and arthritis (64.9%), while sleep problems mediated up to 43.7% (angina) of the association. CONCLUSIONS: In LMICs, those with chronic conditions and multimorbidity are significantly less physically active (especially older adults). Research on the efficacy and effectiveness of PA in the management of chronic diseases in LMICs is urgently needed. Targeted promotion of physical activity to populations in LMICs experiencing chronic conditions may ameliorate associated depression, mobility difficulties and pain that are themselves important barriers for initiating or adopting an active lifestyle. PMID- 28100241 TI - Personalized life expectancy and treatment benefit index of antiretroviral therapy. AB - BACKGROUND: The progression of Human Immunodeficiency Virus (HIV) within host includes typical stages and the Antiretroviral Therapy (ART) is shown to be effective in slowing down this progression. There are great challenges in describing the entire HIV disease progression and evaluating comprehensive effects of ART on life expectancy for HIV infected individuals on ART. METHODS: We develop a novel summative treatment benefit index (TBI), based on an HIV viral dynamics model and linking the infection and viral production rates to the Weibull function. This index summarizes the integrated effect of ART on the life expectancy (LE) of a patient, and more importantly, can be reconstructed from the individual clinic data. RESULTS: The proposed model, faithfully mimicking the entire HIV disease progression, enables us to predict life expectancy and trace back the timing of infection. We fit the model to the longitudinal data in a cohort study in China to reconstruct the treatment benefit index, and we describe the dependence of individual life expectancy on key ART treatment specifics including the timing of ART initiation, timing of emergence of drug resistant virus variants and ART adherence. CONCLUSIONS: We show that combining model predictions with monitored CD4 counts and viral loads can provide critical information about the disease progression, to assist the design of ART regimen for maximizing the treatment benefits. PMID- 28100242 TI - Intraoperative radiotherapy in gynaecological and genito-urinary malignancies: focus on endometrial, cervical, renal, bladder and prostate cancers. AB - Intraoperative radiotherapy (IORT) refers to the delivery of a single radiation dose to a limited volume of tissue during a surgical procedure. A literature review was performed to analyze the role of IORT in gynaecological and genito urinary cancer including endometrial, cervical, renal, bladder and prostate cancers.Literature search was performed by Pubmed and Scopus, using the words "intraoperative radiotherapy/IORT", "gynaecological cancer", "uterine/endometrial cancer", "cervical/cervix cancer", "renal/kidney cancer", "bladder cancer" and "prostate cancer". Forty-seven articles were selected from the search databases, analyzed and briefly described.Literature data show that IORT has been used to optimize local control rate in genito-urinary tumours mainly in retrospective studies. The results suggest that IORT could be advantageous in the setting of locally advanced and recurrent disease although further prospective trials are needed to confirm this findings. PMID- 28100243 TI - Combating substance misuse: competences and preparation of special education department students. AB - BACKGROUND: This study examines Jordanian special education department students' competences and preparation relating to combating substance misuse (SM). METHOD: Thematic analysis was performed on data from interviews with 150 students. RESULTS: Some participants denied the possibility of addiction among students with disabilities, and presented negative attitudes toward their role in combating SM. In general, the participants displayed low levels of professionalism relating to combating SM, and the results revealed that they felt that their preparation programme had been inadequate and they desired more courses that related to combating SM. CONCLUSIONS: These results suggest that Jordanian Universities should emphasise the role of teachers in a preventive approach to SM. PMID- 28100240 TI - Reactivation of dormant anti-tumor immunity - a clinical perspective of therapeutic immune checkpoint modulation. AB - In favor of their outgrowth, cancer cells must resist immune surveillance and edit the immune response. Cancer immunoediting is characterized by fundamental changes in the cellular composition and the inflammatory cytokine profiles in the microenvironment of the primary tumor and metastatic niches, with an ever increasing complexity of interactions between tumor cells and the immune system. Recent data suggest that genetic instability and immunoediting are not necessarily disparate processes. Increasing mutational load may be associated with multiple neoepitopes expressed by the tumor cells and thus increased chances for the immune system to recognize and combat these cells. At the same time the immune system is more and more suppressed and exhausted by this process. Consequently, immune checkpoint modulation may have the potential to be most successful in genetically highly altered and usually extremely unfavorable types of cancer. Moreover, the fact that epitopes recognized by the immune system are preferentially encoded by passenger gene mutations opens windows of synergy in targeting cancer-specific signaling pathways by small molecules simultaneously with antibodies modifying T-cell activation or exhaustion.This review covers some aspects of the current understanding of the immunological basis necessary to understand the rapidly developing therapeutic endeavours in cancer treatment, the clinical achievements made, and raises some burning questions for translational research in this field. PMID- 28100244 TI - Is aclidinium alone or combined with a LABA a rational choice for symptomatic COPD patients? AB - BACKGROUND: As emphasized by international recommendations and largely confirmed by clinical experience, long-acting bronchodilators play a central role in the maintenance treatment of chronic obstructive pulmonary disease (COPD) due to their proven efficacy in reducing airflow obstruction and improving symptoms. MAIN BODY: There are some important aspects to define with regard to inhalation therapy for COPD, particularly those concerning the selection criteria and the optimal use of long-acting bronchodilators. First of all, it needs to be determined in which patients and clinical situations monotherapy with one bronchodilator, such as a long-acting muscarinic antagonist (LAMA), should be considered adequate, and in which cases the use of combination therapies, such as the "double bronchodilation" with a LAMA and a long-acting beta2-agonist (LABA), should be preferred. Another critical issue concerns the effect of the frequency of daily administration of inhaled agents on the control of symptoms during the 24 h. COPD symptoms are known to exhibit considerable circadian variability with worsening in the early morning, and a significant proportion of patients have disease-related sleep disorders which can adversely affect their quality of life. The worsening of symptoms in the early morning may be due, at least in part, to a reduction in airway caliber caused by an increased "cholinergic tone" at night. As such, the coverage of nighttime and early morning symptoms is a reasonable therapeutic goal, which can be achieved by many patients using LAMAs such as aclidinium bromide twice daily (BID). Therapeutic adherence is known to be a multifactorial phenomenon that is frequently affected by other aspects than dosing frequency, including the technical features and ease of use of the inhalers. To this end, it should be mentioned that certain new-generation inhalers such as Genuair(r) have been associated in clinical trials with higher patient preference. CONCLUSION: In this work, in addition to presenting an overview of the main evidence on the efficacy of COPD treatment with the LAMA aclidinium bromide BID, we suggest some selection criteria for the monotherapy with one long-acting bronchodilator or the combination therapy with LAMA and LABA in COPD patients, with particular reference to specific clinical scenarios. PMID- 28100245 TI - Meeting report: the 5th International expert symposium in Fukushima on radiation and health. AB - BACKGROUND: The symposium entitled "Chernobyl +30, Fukushima +5: Lessons and Solutions for Fukushima's Thyroid Question" was held in September, 2016 in Fukushima. The aim of the Symposium was to revisit and recapitulate evidence from the studies in Chernobyl in order to share multidisciplinary opinions and views on the likely reason for the high rate of thyroid cancer detected by the Thyroid Ultrasound Examination program in Fukushima Prefecture. PARTICIPANTS AND MATTERS DISCUSSED: The high prevalence of thyroid cancer in young individuals causes concerns among Fukushima residents and the general public that it might be due to putative radiation exposure from the Fukushima Daiichi Nuclear Power Plant accident. Twenty-six experts from Japan and abroad, including participants affiliated with international organizations, reviewed the results of radiation epidemiology investigations in Chernobyl, presented clinical experience of diagnosis, treatment and follow-up of patients with radiation-related thyroid cancer, and scrutinized the findings on thyroid cancer in Fukushima. CONCLUSION: Conclusions drawn at the symposium included understanding that in contrast to Chernobyl, doses to the public from the accident in Fukushima were too low to give rise to a discernible excess risk for thyroid cancer. The high detection rate of thyroid cancer and benign abnormalities resulted from the use of highly sensitive ultrasound equipment and sophisticated protocol of examination used in the Thyroid Ultrasound Examination, and therefore not attributable to radiation. Coordinated efforts will be necessary to avoid overdiagnosis and overtreatment, which may carry its own health disbenefits. Clear communication to the screening participants and their families is recommended in regard to why the examination is being conducted and to explain the likely outcomes and risks, including the means and options for treatment if a thyroid disorder is detected. PMID- 28100247 TI - The evolution of the medical workforce in Cape Verde since independence in 1975. AB - BACKGROUND: Cape Verdean doctors have always graduated abroad. The first experience of pre-graduate medical education in Cape Verde begun in October 2015. Counting how many doctors Cape Verde has, knowing who they are, and knowing how they are distributed are very important to help fine-tune the medical training. The aim of this study is to analyze the evolution of the medical workforce in Cape Verde to support medical education implementation. METHODS: Secondary data on doctors, from July 1975 until December 2014, collected from the Ministry of Health, were entered into an SPSS 20 database and studied by a simple descriptive statistical analysis. RESULTS: The database included data on 401 medical doctors. There was a predominance of females (n = 218; 54.4%). The overwhelming majority (n = 378; 94.3%) graduated from 5 of the 17 countries that contributed to the training of Cape Verdean doctors. All the islands of this archipelago country contributed to the 324 (80.8%) doctors born in the country. Of the 272 doctors still active in December 2014, 119 (43.6%) were general practitioners and 153 (56.4%) had specialized in one of the 31 specialties. The national ratio of doctors per 10 000 inhabitants was 5.25, but the reality varied significantly among islands. About one third of the doctors (n = 86; 32%) were at the primary care level, 38 (14%) at the secondary care level, and 144 (52%) in central hospitals. In 2053, all active physicians in 2014 will already be retired. CONCLUSIONS: This is a unique study of the evolution of the medical workforce of a country over 40 years, from the first day of independence. The study illustrates the importance of international collaborations, particularly of Cuba, in sustaining the medical workforce in Cape Verde. It is an example of how this collaboration was used to equip the country with doctors in an increasingly more equitable distribution across all islands. The study further illustrates the progressive feminization of the medical workforce. The study clarifies the effort required from the emerging medical faculty to supply the national health system with the needed number of doctors. PMID- 28100248 TI - Mediastinal lymph node dissection and distal esophagectomy is not essential in early esophagogastric junction adenocarcinoma. AB - BACKGROUND: Optimal extent of surgery remains controversial in types 2 and 3 adenocarcinoma of esophagogastric junction (AEG). We aimed to determine whether the extended procedure including mediastinal lymphadenectomy is essential in all patients with AEG by comparing prognosis and recurrence of proximal gastric adenocarcinoma based on total gastrectomy with intra-abdominal lymphadenectomy. METHODS: The clinicopathologic characteristics of 672 patients (type 2: 90, type 3: 211, upper third of the stomach: 371 cases) who underwent curative total gastrectomy with lymphadenectomy between 2003 and 2009 were reviewed. RESULTS: Recurrence was observed in 36.7, 16.1, and 16.1% of cases of type 2 AEG, type 3 AEG, and cancer of the upper third of the stomach, respectively. The 5-year disease-free survival rates were 62.6, 82.5, and 84.6%, respectively. Subgroup analysis revealed that in early cancers, there was no difference in survival between the groups (93.2 vs. 96.7 vs. 98.7%) but in advanced cancers, there was a difference (47.9 vs. 75.4 vs. 71.8%, P < 0.001). There was no survival difference in stage 1 (97.5 vs. 98.7 vs. 98.3%), but, in stage 2, type 2 AEG had a worse prognosis (41.9 vs. 92.1 vs. 83.0%). Types 2 and 3 advanced AEG had higher rates of locoregional recurrence, especially in the vicinity of the esophagojejunostomy and mediastinal lymph nodes compared to proximal gastric cancer. CONCLUSIONS: Total gastrectomy without mediastinal lymphadenectomy might produce favorable outcomes in early AEG and acquisition of a greater length of proximal margin, and removal of mediastinal lymph nodes might be helpful in advanced cancers. PMID- 28100246 TI - Genetic effect of interleukin-1 beta (C-511T) polymorphism on the structural covariance network and white matter integrity in Alzheimer's disease. AB - BACKGROUND: Inflammatory processes play a pivotal role in the degenerative process of Alzheimer's disease. In humans, a biallelic (C/T) polymorphism in the promoter region (position-511) (rs16944) of the interleukin-1 beta gene has been significantly associated with differences in the secretory capacity of interleukin-1 beta. In this study, we investigated whether this functional polymorphism mediates the brain networks in patients with Alzheimer's disease. METHODS: We enrolled a total of 135 patients with Alzheimer's disease (65 males, 70 females), and investigated their gray matter structural covariance networks using 3D T1 magnetic resonance imaging and their white matter macro-structural integrities using fractional anisotropy. The patients were classified into two genotype groups: C-carriers (n = 108) and TT-carriers (n = 27), and the structural covariance networks were constructed using seed-based analysis focusing on the default mode network medial temporal or dorsal medial subsystem, salience network and executive control network. Neurobehavioral scores were used as the major outcome factors for clinical correlations. RESULTS: There were no differences between the two genotype groups in the cognitive test scores, seed, or peak cluster volumes and white matter fractional anisotropy. The covariance strength showing C-carriers > TT-carriers was the entorhinal-cingulum axis. There were two peak clusters (Brodmann 6 and 10) in the salience network and four peak clusters (superior prefrontal, precentral, fusiform, and temporal) in the executive control network that showed C-carriers < TT-carriers in covariance strength. The salience network and executive control network peak clusters in the TT group and the default mode network peak clusters in the C-carriers strongly predicted the cognitive test scores. CONCLUSIONS: Interleukin-1 beta C-511 T polymorphism modulates the structural covariance strength on the anterior brain network and entorhinal-interconnected network which were independent of the white matter tract integrity. Depending on the specific C-511 T genotype, different network clusters could predict the cognitive tests. PMID- 28100249 TI - Intraoperative radiation therapy (IORT) in soft-tissue sarcoma. AB - Soft-tissue sarcoma (STS) represent a rare tumor entity, accounting for less than 1% of adult malignancies. The cornerstone of curative intent treatment is surgery with free margins, although the extent of the surgical approach has been subject to change in the last decades. Multimodal approaches usually including radiation therapy have replaced extensive surgical procedures in order to preserve functionality while maintaining adequate local control. However, the possibility to apply adequate radiation doses by external beam radiation therapy (EBRT) can be limited in some situation especially in case of directly adjacent organs at risk with low radiation tolerance. Application of at least a part of the total dose via intraoperative radiation therapy (IORT) with a single fraction during the surgical procedure may overcome those limitations, because radiosensitive structures can be moved out of the radiation field resulting in reduced toxicity while the enhanced biological effectivity of the high single dose improves local control. The current review summarizes rationale, techniques, oncological and functional outcomes including possible pitfalls and associated toxicities based on the published literature for IORT focusing on extremity and retroperitoneal STS. In extremity STS, combination of limb-sparing surgery, IORT and pre- or postoperative EBRT with moderate doses consistently achieved excellent local control rates at least comparable to approaches using EBRT alone but usually including patient cohorts with higher proportions of unfavourable prognostic factors. Further on, IORT containing approaches resulted in very high limb preservation rates and good functional outcome, probably related to the smaller high dose volume. In retroperitoneal STS, the combination of preoperative EBRT, surgery and IORT consistently achieved high local control rates which seem superior to surgery alone or surgery with EBRT at least with regard to local control and in some reports even to overall survival. Further on, preoperative EBRT in combination with IORT seems to be superior to the opposite combination with regard to local control and toxicity. No major differences in wound healing disturbances or postoperative complication rates can be observed with IORT compared to non-IORT containing approaches. Neuropathy of major nerves remains a dose limiting toxicity requiring dose restrictions or exclusion from target volume. Gastrointestinal structures and ureters should be excluded from the IORT area whenever possible and the IORT volume should be restricted to the available minimum. Nevertheless, IORT represents an ideal boosting method if combined with EBRT and properly executed by experiences users which should be further evaluated preferably in prospective randomized trials. PMID- 28100250 TI - 5'UTR point substitutions and N-terminal truncating mutations of ANKRD26 in acute myeloid leukemia. AB - Thrombocytopenia 2 (THC2) is an inherited disorder caused by monoallelic single nucleotide substitutions in the 5'UTR of the ANKRD26 gene. Patients have thrombocytopenia and increased risk of myeloid malignancies, in particular, acute myeloid leukemia (AML). Given the association of variants in the ANKRD26 5'UTR with myeloid neoplasms, we investigated whether, and to what extent, mutations in this region contribute to apparently sporadic AML. To this end, we studied 250 consecutive, non-familial, adult AML patients and screened the first exon of ANKRD26 including the 5'UTR. We found variants in four patients. One patient had the c.-125T>G substitution in the 5'UTR, while three patients carried two different variants in the 5' end of the ANKRD26 coding region (c.3G>A or c.105C>G). Review of medical history showed that the patient carrying the c. 125T>G was actually affected by typical but unrecognized THC2, highlighting that some apparently sporadic AML cases represent the evolution of a well characterized familial predisposition disorder. As regards the c.3G>A and the c.105C>G, we found that both variants result in the synthesis of N-terminal truncated ANKRD26 isoforms, which are stable and functional in cells, in particular, have a strong ability to activate the MAPK/ERK signaling pathway. Moreover, investigation of one patient with the c.3G>A showed that mutation was associated with strong ANKRD26 overexpression in vivo, which is the proposed mechanism for predisposition to AML in THC2 patients. These data provide evidence that N-terminal ANKRD26 truncating mutations play a potential pathogenetic role in AML. Recognition of AML patients with germline ANKRD26 pathogenetic variants is mandatory for selection of donors for bone marrow transplantation. PMID- 28100252 TI - A cognitive electrophysiological signature differentiates amnestic mild cognitive impairment from normal aging. AB - BACKGROUND: Noninvasive and effective biomarkers for early detection of amnestic mild cognitive impairment (aMCI) before measurable changes in behavioral performance remain scarce. Cognitive event-related potentials (ERPs) measure synchronized synaptic neural activity associated with a cognitive event. Loss of synapses is a hallmark of the neuropathology of early Alzheimer's disease (AD). In the present study, we tested the hypothesis that ERP responses during working memory retrieval discriminate aMCI from cognitively normal controls (NC) matched in age and education. METHODS: Eighteen NC, 17 subjects with aMCI, and 13 subjects with AD performed a delayed match-to-sample task specially designed not only to be easy enough for impaired participants to complete but also to generate comparable performance between subjects with NC and those with aMCI. Scalp electroencephalography, memory accuracy, and reaction times were measured. RESULTS: Whereas memory performance separated the AD group from the others, the performance of NC and subjects with aMCI was similar. In contrast, left frontal cognitive ERP patterns differentiated subjects with aMCI from NC. Enhanced P3 responses at left frontal sites were associated with nonmatching relative to matching stimuli during working memory tasks in patients with aMCI and AD, but not in NC. The accuracy of discriminating aMCI from NC was 85% by using left frontal match/nonmatch effect combined with nonmatch reaction time. CONCLUSIONS: The left frontal cognitive ERP indicator holds promise as a sensitive, simple, affordable, and noninvasive biomarker for detection of early cognitive impairment. PMID- 28100251 TI - Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. AB - Aromatic L-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurometabolic disorder that leads to a severe combined deficiency of serotonin, dopamine, norepinephrine and epinephrine. Onset is early in life, and key clinical symptoms are hypotonia, movement disorders (oculogyric crisis, dystonia, and hypokinesia), developmental delay, and autonomic symptoms.In this consensus guideline, representatives of the International Working Group on Neurotransmitter Related Disorders (iNTD) and patient representatives evaluated all available evidence for diagnosis and treatment of AADCD and made recommendations using SIGN and GRADE methodology. In the face of limited definitive evidence, we constructed practical recommendations on clinical diagnosis, laboratory diagnosis, imaging and electroencephalograpy, medical treatments and non-medical treatments. Furthermore, we identified topics for further research. We believe this guideline will improve the care for AADCD patients around the world whilst promoting general awareness of this rare disease. PMID- 28100253 TI - Minimally invasive percutaneous osteosynthesis versus ORIF for Sanders type II and III calcaneal fractures: a prospective, randomized intervention trial. AB - BACKGROUND: This randomized controlled trial compared the clinical outcomes and complications of a novel minimally invasive percutaneous osteosynthesis (MIPO) with those of conventional treatment via an extended L-shaped lateral approach for calcaneal fractures. METHODS: Sixty-four patients with displaced intraarticular calcaneal fractures were enrolled. The patients were randomly allocated to receive either MIPO (29 patients) or open reduction and internal fixation via an extended L-shaped lateral approach (35 patients). The same calcaneal plate (AO Synthes, Oberdorf, Switzerland) was used in both groups. The primary clinical outcomes included operative time, VAS postoperatively, and wound healing complications. Secondary clinical outcomes included time to operation, length of incision, postoperative drainage, length of hospital stay, medical expense, AOFAS score, and SF-36 score. Preoperative and postoperative calcaneal height, width, and length, Bohler's angle, and Gissane's angle were compared. RESULTS: The operative time in the MIPO group was 52.5 +/- 11.1 min, which was significantly shorter than 82.8 +/- 16.2 min in the conventional treatment group (P < 0.001). One week postoperatively, the VAS value was 3.2 +/- 1.4 in the MIPO group, which was lower than that in the conventional treatment group, 3.9 +/- 1.3 (P = 0.038). In the conventional treatment group, 13 of 35 fractures (37.1%) had wound healing problems, whereas this issue occurred in only 2 of 29 fractures (6.7%) in the MIPO group (P = 0.004). In the MIPO group, deep and superficial infections occurred in none of the cases and 1 of 29 (3.4%) patients, respectively. Length of incision in the MIPO group was shorter than that in the conventional treatment group (4.2 +/- 0.6 vs. 10.9 +/- 1.5 cm; P < 0.001). Hospital stay was 9.7 +/- 2.8 days in the MIPO group and 11.7 +/- 2.6 days in the conventional treatment group (P = 0.004). At the last follow-up, the SF-36 scores and AOFAS scores in the two groups were comparable (P > 0.05). The postoperative radiographic data, the Bohler's angle, Gissane's angle, and calcaneal height, width, and length in the two groups were comparable (P > 0.05). CONCLUSIONS: Compared with conventional ORIF, the advantages of MIPO are a considerably shortened operating time and hospital stay, decreased postoperative pain, and reduced risk of wound healing complications. PMID- 28100254 TI - Challenges in orphan drug development and regulatory policy in China. AB - While regulatory policy is well defined for orphan drug development in the United States and Europe, rare disease policy in China is still evolving. Many Chinese patients currently pay out of pocket for international treatments that are not yet approved in China. The lack of a clear definition and therefore regulatory approval process for rare diseases has, until now, de-incentivized pharmaceutical companies to pursue rare disease drug development in China. In turn, many grassroots movements have begun to support rare disease patients and facilitate drug discovery through research. Recently, the Chinese FDA set new regulatory guidelines for drugs being developed in China, including an expedited review process for life-saving treatments. In this review, we discuss the effects of these new policy changes on and suggest potential solutions to innovate orphan drug development in China. PMID- 28100255 TI - Early-life exposure to air pollution and greater use of academic support services in childhood: a population-based cohort study of urban children. AB - BACKGROUND: There is a growing literature showing associations between prenatal and early-life exposure to air pollution and children's neurodevelopment. However, it is unclear if decrements in neurodevelopment observed in epidemiologic research translate into observable functional outcomes in the broader pediatric population. The objective of this study was to examine the association between early-life exposures to common urban air toxics and the use of academic support services, such as early intervention and special education within a population-based cohort of urban children. METHODS: Data for 201,559 children born between 1994 and 1998 in New York City were obtained through administrative data linkages between birth, early intervention and educational records. Use of academic support services was ascertained from birth through attendance in 3rd grade. Census tract at birth was used to assign estimates of annual average ambient concentrations of benzene, toluene, ethylbenzene and xylenes (BTEX) using the 1996 National Air Toxics Assessment. Discrete-time hazard models were fit to the data and adjusted for confounders including maternal, childhood and neighborhood factors. RESULTS: Children with higher exposures to BTEX compounds were more likely to receive academic support services later in childhood. For example, the adjusted hazard ratio comparing children exposed to the highest decile of benzene to those with lower exposure was 1.09 (95% confidence interval 1.05, 1.13). Results were consistent across individual BTEX compounds, for exposure metrics which summarized exposure to all four BTEX pollutants and for multiple sensitivity analyses. CONCLUSIONS: These findings suggest urban air pollution may affect children's neurodevelopment and educational trajectories. They also demonstrate the use of public health data systems to advance children's environmental health research. PMID- 28100256 TI - Transcriptomic signatures differentiate survival from fatal outcomes in humans infected with Ebola virus. AB - BACKGROUND: In 2014, Western Africa experienced an unanticipated explosion of Ebola virus infections. What distinguishes fatal from non-fatal outcomes remains largely unknown, yet is key to optimising personalised treatment strategies. We used transcriptome data for peripheral blood taken from infected and convalescent recovering patients to identify early stage host factors that are associated with acute illness and those that differentiate patient survival from fatality. RESULTS: The data demonstrate that individuals who succumbed to the disease show stronger upregulation of interferon signalling and acute phase responses compared to survivors during the acute phase of infection. Particularly notable is the strong upregulation of albumin and fibrinogen genes, which suggest significant liver pathology. Cell subtype prediction using messenger RNA expression patterns indicated that NK-cell populations increase in patients who survive infection. By selecting genes whose expression properties discriminated between fatal cases and survivors, we identify a small panel of responding genes that act as strong predictors of patient outcome, independent of viral load. CONCLUSIONS: Transcriptomic analysis of the host response to pathogen infection using blood samples taken during an outbreak situation can provide multiple levels of information on both disease state and mechanisms of pathogenesis. Host biomarkers were identified that provide high predictive value under conditions where other predictors, such as viral load, are poor prognostic indicators. The data suggested that rapid analysis of the host response to infection in an outbreak situation can provide valuable information to guide an understanding of disease outcome and mechanisms of disease. PMID- 28100257 TI - Food-specific sublingual immunotherapy is well tolerated and safe in healthy dogs: a blind, randomized, placebo-controlled study. AB - BACKGROUND: Food allergies are increasing in prevalence but no treatment strategies are currently available to cure dogs with food allergy. Over the past decade, experimental food allergen-specific sublingual immunotherapy (FA-SLIT) has emerged as a potential treatment for food allergies in human medicine. However, FA-SLIT has not been investigated in dogs. Therefore, the objective of this study was to prospectively evaluate the safety, tolerability and dispenser sterility of FA-SLIT in healthy dogs before testing it in food allergic dogs. Eight experimental healthy beagle dogs, never orally exposed to peanut, were randomized in two groups to receive SLIT with peanut or placebo for 4 months. Subjects were monitored daily for local and systemic adverse effects. Blood samples for complete blood count and serum biochemistry, and urine for urinalysis were collected and the dogs' body weight was recorded at day 0, 35 and 119 of the SLIT treatment. Sera for the determination of peanut-specific IgG and IgE were collected at day 0, 35, 49, 70, 91, 105 and 119. Intradermal tests were performed before (day 0) and after (day 119) the experiment. The content of each dispenser used to administer treatment or placebo was tested for sterility after usage. In order to assess the presence or absence of sensitization, dogs were challenged 6 months after the end of the study with 2000 MUg of peanut extract daily for 7 to 14 days. RESULTS: All dogs completed the study. The treatment did not provoke either local or systemic side-effects. Peanut-specific IgG significantly increased in treatment group. Even though a significant increase in peanut specific IgE was also seen, intradermal tests were negative in all dogs before and after the experiment, and the challenge test did not trigger any adverse reactions in the treated dogs, which shows the protocol did not cause sensitization to peanut, but nevertheless primed the immune system as indicated by the humoral immune response. All dispenser solutions were sterile. CONCLUSIONS: Our results demonstrate that the used peanut-SLIT protocol is well tolerated and safe in healthy dogs. Further studies should evaluate tolerability, safety and efficacy in dogs with food allergy. PMID- 28100258 TI - Association between work time loss and quality of life in patients with Herpes Zoster: a pooled analysis of the MASTER studies. AB - BACKGROUND: Herpes zoster (HZ) has a significant negative effect on the productive work life of individuals, and has been shown to be responsible for cases of absenteeism, presenteeism and decreased work effectiveness. The aim of this study was to evaluate health utility scores and associated predictors in an actively employed population of Herpes Zoster (HZ) patients with and without work time loss (WTL). METHODS: This was a pooled analysis of the prospective, observational MASTER cohort studies, conducted in 8 countries across North America, Latin America and Asia. A total of 428 HZ patients engaged in full or part time work were included. WTL, defined as missing >= 1 partial or full work day, and work effectiveness, reported on a scale of 0-100%, were evaluated with the Work and Productivity Questionnaire (WPQ). The Pearson product-moment correlation was used to assess the correlation between work effectiveness and HRQoL. Mixed models with repeated measures assessed the relationship between HZ related WTL over a 6-month follow-up period, and HRQoL, as evaluated by the EQ 5D. Additional predictors of HRQoL were also identified. RESULTS: Overall, 57.7% of respondents reported WTL. Mean (SD) percent work effectiveness of patients in the WTL group was significantly lower compared to non-WTL (NWTL) patients at baseline [50.3 (31.6) vs. 71.4 (27.8); p < 0.001]. Patients in the WTL group also reported lower health utility scores at baseline and overall than their NWTL counterparts, with WTL identified as an independent negative predictor of both the EQ-5D summary scores and the EQ-5D VAS (p < 0.001). Decrease in work effectiveness was negatively associated with HRQoL overall (p < 0.001). Predictors of lower HRQoL were worst Zoster Brief Pain Inventory (ZBPI) pain score, the presence of HZ complications and country income (predictor of EQ-5D VAS only). CONCLUSIONS: HZ adversely impacts the work and productive life of actively employed individuals. In turn, HZ-related reductions in work effectiveness and work time are associated with a negative effect on HRQoL. PMID- 28100259 TI - Antitumor activity of miR-34a in peritoneal mesothelioma relies on c-MET and AXL inhibition: persistent activation of ERK and AKT signaling as a possible cytoprotective mechanism. AB - BACKGROUND: The value of microRNAs (miRNAs) as novel targets for cancer therapy is now widely recognized. However, no information is currently available on the expression/functional role of miRNAs in diffuse malignant peritoneal mesothelioma (DMPM), a rapidly lethal disease, poorly responsive to conventional treatments, for which the development of new therapeutic strategies is urgently needed. Here, we evaluated the expression and biological effects of miR-34a-one of the most widely deregulated miRNAs in cancer and for which a lipid-formulated mimic is already clinically available-in a large cohort of DMPM clinical samples and a unique collection of in house-developed preclinical models, with the aim to assess the potential of a miR-34a-based approach for disease treatment. METHODS: miR-34a expression was determined by qRT-PCR in 45 DMPM and 7 normal peritoneum specimens as well as in 5 DMPM cell lines. Following transfection with miR-34a mimic, the effects on DMPM cell phenotype, in terms of proliferative potential, apoptotic rate, invasion ability, and cell cycle distribution, were assessed. In addition, three subcutaneous and orthotopic DMPM xenograft models were used to examine the effect of miR-34a on tumorigenicity. The expression of miRNA targets and the activation status of relevant pathways were investigated by western blot. RESULTS: miR-34a was found to be down-regulated in DMPM clinical specimens and cell lines compared to normal peritoneal samples. miR-34a reconstitution in DMPM cells significantly inhibited proliferation and tumorigenicity, induced an apoptotic response, and declined invasion ability, mainly through the down regulation of c-MET and AXL and the interference with the activation of downstream signaling. Interestingly, a persistent activation of ERK1/2 and AKT in miR-34a-reconstituted cells was found to counteract the antiproliferative and proapoptotic effects of miRNA, yet not affecting its anti-invasive activity. CONCLUSIONS: Our preclinical data showing impressive inhibitory effects induced by miR-34a on DMPM cell proliferation, invasion, and growth in immunodeficient mice strongly suggest the potential clinical utility of a miR-34a-replacement therapy for the treatment of such a still incurable disease. On the other hand, we provide the first evidence of a potential cytoprotective/resistance mechanism that may arise towards miRNA-based therapies through the persistent activation of RTK downstream signaling. PMID- 28100261 TI - Serotypes of Streptococcus suis isolated from healthy pigs in Phayao Province, Thailand. AB - BACKGROUND: Streptococcus suis (S. suis) is an important swine and human pathogen. There are 33 serotypes that have been described. Zoonotic cases are very common the Northern part of Thailand, especially in Phayao Province. However, the prevalence of S. suis and, more particularly the different serotypes, in pigs in this region is poorly known and needed to be addressed. THE CONTEXT AND PURPOSE OF THE STUDY: Distribution of S. suis serotypes varies depending on the geographical area. Knowledge of the serotype distribution is important for epidemiological studies. Consequently, 180 tonsil samples from slaughterhouse pigs in Phayao Province had been collected for surveillance, from which 196 S. suis isolates were recovered. Each isolate was subcultured and its serotype identified using multiplex PCR. Slide agglutination combined with precipitation tests were used following multiplex PCR to differentiate the isolates showing similar sizes of amplified products specific to either serotype 1 or 14 and 2 or 1/2. Non-typable isolates by multiplex PCR were serotyped by the coagglutination test. RESULTS: Of the 196 isolates, 123 (62.8%) were typable and 73 (37.2%) were non-typable. This study revealed the presence of serotypes 1, 1/2, 2, 3, 4, 5, 7, 9, 11, 12, 13, 14, 21, 22, 23, 24, 25, 29, and 30. Serotype 23 was the most prevalent (20/196, 10.2%), followed by serotype 9 (16/196, 8.2%), serotype 7 (16/196, 8.2%), and serotype 2 (11/196, 5.6%). The latter is the serotype responsible for most human cases. CONCLUSION: Almost all serotypes previously described are present in Northern Thailand. Therefore, this report provides useful data for future bacteriological studies. PMID- 28100260 TI - iRegNet3D: three-dimensional integrated regulatory network for the genomic analysis of coding and non-coding disease mutations. AB - The mechanistic details of most disease-causing mutations remain poorly explored within the context of regulatory networks. We present a high-resolution three dimensional integrated regulatory network (iRegNet3D) in the form of a web tool, where we resolve the interfaces of all known transcription factor (TF)-TF, TF-DNA and chromatin-chromatin interactions for the analysis of both coding and non coding disease-associated mutations to obtain mechanistic insights into their functional impact. Using iRegNet3D, we find that disease-associated mutations may perturb the regulatory network through diverse mechanisms including chromatin looping. iRegNet3D promises to be an indispensable tool in large-scale sequencing and disease association studies. PMID- 28100262 TI - Dental caries status of patients with schizophrenia in Seville, Spain: a case control study. AB - BACKGROUND: The aim of this study was to assess the dental status (DMFT) in patients with schizophrenia compared with a control group. MATERIAL: In this case control study, 50 patients with schizophrenia attended in the Psychiatric Unit at the Virgen Macarena University Hospital of Seville were compared with 50 people (without systemic diseases and not taking psychotropic drugs) in a control group attended in the School of Dentistry of Seville. Decayed, missing and filled teeth (DMFT) were assessed according to the World Health Organization WHO criteria. RESULTS: Patients with schizophrenia showed a decayed teeth (DT) score of 7.26 +/ 5.69 compared with 6.50 +/- 4.37 for patients the control group. These differences were significant and suggest that dental caries are most prevalent in patients with schizophrenia. People who smoked showed significantly higher DT scores in both groups. Among patients with schizophrenia, smokers scored 9.34 +/- 5.42 compared with 4.38 +/- 4.82 for non-smokers. Among the healthy controls, smokers scored 6.88 +/- 4.85 compared with 6.12 +/- 3.85 for non-smokers (p < 0.05). Patients with schizophrenia showed a missing teeth (MT) score of 9.10 +/- 8.56 compared with 5.38 +/- 5.14 in control patients. MT scores increased significantly with age and with smoking in both groups of patients (p < 0.05). Patients with schizophrenia showed a filled teeth (FT) score of 1.38 +/- 2.70 compared with 2.34 +/- 3.48 in control patients. FT differences in gender and smoking habits between patients with schizophrenia and healthy control subjects were statistically significant (p < 0.05). This data, along with the DT scores, suggests that patients with schizophrenia have extensive untreated dental disease. CONCLUSIONS: Patients with schizophrenia constitute a high risk population for dental health. This group showed a greater prevalence of decayed and missing teeth and more extensive treatment needs. PMID- 28100263 TI - Benzene poisoning, clinical and blood abnormalities in two Brazilian female gas station attendants: two case reports. AB - BACKGROUND: Brazilian gas station workers are chronically exposed to benzene, toluene, xylene (BTX) during their working time. Describe below two cases of latin female gas station workers with benzene poisoning symptoms and miscarriage history. CASE PRESENTATION: In both cases were identified complex chromosomal rearrangements (CCR) with fluorescence in situ hybridization, applied to whole chromosome paints by chromosomes 1, 2 and 4. The lower natural killer cell (NK) cells have also been observed in cases correspondents, especially the rare type of NK (NKbright) in their peripheral blood cells. CONCLUSIONS: It is known that acquired chromosomal aberrations are positively correlated with cancer and reproductive risk. In concordance, lower NK cytotoxicity increases the risk for cancer, as well. Thus, this is the first study providing hints on a possible causative relation of lower NK cytotoxicity and increase rates of chromosomal rearrangements including CCRs. PMID- 28100264 TI - Cross-sectional examination of musculoskeletal conditions and multimorbidity: influence of different thresholds and definitions on prevalence and association estimates. AB - BACKGROUND: Multimorbidity and musculoskeletal conditions create substantial burden for people and health systems. Quantifying the extent of co-occurring conditions is hampered by conceptual heterogeneity, imprecision and/or indecision about how multimorbidity is defined. The purpose of this study is to examine the influence of different ways of operationalising multimorbidity on multimorbidity prevalence rates with a focus on working-age adults with musculoskeletal conditions. Weighted population prevalence rates of multimorbidity among working age Australians were estimated using data from the National Health Survey. Two nominal thresholds (2+ or 3+ co-occurring conditions) and three operational definitions of multimorbidity (survey-, policy- and research-based) were examined. Using logistic regression, we estimated the association between the prevalence of multimorbidity among persons with musculoskeletal conditions compared to persons with non-musculoskeletal conditions for each definition and threshold combination. RESULTS: As few as 7.9% of working-age Australians have 2+ conditions using the research-based definition (95% CI 7.4-8.5%), compared to estimates of 15.3% (95% CI 14.3-16.2%) and 61.5% (95% CI 60.3-62.7%). with the policy- and survey-based definitions, respectively. Depending on definition, with the 3+ threshold multimorbidity prevalence ranged from 2.1% (research) to 41.9% (survey). Among the sub-sample with musculoskeletal conditions, multimorbidity with the 2+ threshold ranged from 20.2 to 92.2%; and with 3+ threshold from 5.9 to 75.4%, again lowest with the research-definition and highest with the survey definition. When compared to any other condition (i.e. non-musculoskeletal conditions), all musculoskeletal conditions were positively associated with multimorbidity, regardless of definition or threshold. CONCLUSIONS: Depending on definition and threshold, multimorbidity is either rare or endemic in working-age Australians. Irrespective of definition, musculoskeletal conditions are a near ubiquitous feature of multimorbidity. PMID- 28100266 TI - Arranging blood for elective thyroid surgeries: dilemma continues in the developing world. AB - BACKGROUND: Cross matched blood is frequently ordered based on a subjective anticipation of blood loss for a procedure. Excessive blood arrangement and wastage overburdens the blood bank in terms of work load and storage of blood, increases cost of medical care and results in injudicious use of a limited resource. The aim of this short report is to assess the current practice for arranging cross matched blood in elective thyroid surgeries by comparing cross match to blood transfused ratio. FINDINGS: Medical records for all patients from January 2009 to December 2014 undergoing thyroid surgery were retrieved and reviewed through electronic health information management system (HIMS). A total of 91 patients were included in the study, out of which 18 (19.7%) were male and 73 (80.2%) were female. A total of 107 units of blood were arranged and only 9 were transfused. 47 patients underwent a total thyroidectomy, while 44 underwent a hemithyroidectomy. The cross match to transfusion ratio came out to be 11.88. CONCLUSIONS: Routine arrangement of cross matched blood is not required in elective thyroid surgeries. All institutions should have a maximum blood ordering schedule planned for elective procedures, and blood products should be arranged accordingly to avoid unnecessary cross matching. PMID- 28100265 TI - Allogeneic stem cell transplantation in adult patients with acute myeloid leukaemia and 17p abnormalities in first complete remission: a study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT). AB - BACKGROUND: Acute myeloid leukaemia (AML) with 17p abnormalities (abn(17p)) carries a very poor prognosis due to high refractoriness to conventional chemotherapy, and allogeneic stem cell transplantation (allo-SCT) appears as the only potential curative option. METHODS: To address outcomes after allo-SCT in patients with abn(17p), we retrospectively analysed de novo or secondary AML undergoing SCT between 2000 and 2013 from the EBMT registry. RESULTS: One hundred thirty-nine patients with confirmed abn(17p) have been selected. At the time of transplant, one hundred twenty-five were in first remission (CR1). Median age was 54 years old. Abn(17p) was associated with a monosomal karyotype in 83% of patients, complex karyotype in 91%, monosomy 5 or 5q deletion (-5/5q-) in 55%, monosomy 7 (-7) in 39% and both -5/5q and -7 in 27%. Seventy-three patients (59%) had a reduced-intensity conditioning regimen. The 2-year overall survival (OS) and leukaemia-free survival (LFS) were 28 and 24%, respectively. The 2-year non relapse mortality (NRM) was 15%, and 2-year relapse incidence (RI) was 61%. The cumulative incidence of grade II to IV acute graft-versus-host disease (GvHD) was 24% and that of chronic GvHD was 21%. In multivariate analysis, the presence of a -5/5q- in addition to abn(17p) was significantly and independently associated with worse OS, LFS and higher RI. Age and donor types did not correlate with outcome. Conditioning intensity was not statistically associated with OS, LFS and NRM when adjusted for patients' age. CONCLUSIONS: In contrast to the dismal prognosis reported for AML patients harbouring abn(17p) undergoing conventional chemotherapy, allogeneic SCT provides responses in about 25% of those patients transplanted in CR1. PMID- 28100267 TI - A bibliometric analysis of two decades of aromatherapy research. AB - BACKGROUND: Quantitative data are lacking on the profile of published research in aromatherapy. The objective of the study was to investigate the profile of original and review articles under the topic aromatherapy using bibliometric analysis. METHODS: Articles on aromatherapy, published between 1995 and 2014, were retrieved from the Science Citation Index-Expanded database from the Web of Science. The records extracted were analyzed for citation characteristics, including the distribution of publication years, languages, countries or regions, journals, articles, and authors using HistCite 12.03.17. VOSviewer v.1.61 was used to construct bibliometric diagrams. RESULTS: A total of 549 original and review articles, published in 287 different peer-reviewed journals by 1888 authors, were identified. There was a steady increase in the number of published articles from 1995 to 2014. The majority of the articles was written in English (95.8%) and the United States was the leading country in the total number of published articles (n = 107, 19.5%) Journal of Alternative and Complementary Medicine published the greatest number of articles on the topic (n = 31, 5.6%). The article that received the greatest number of citations was published in Complementary Therapies in Medicine. Visualization analysis based on co occurrences of words in the title and abstract revealed three clusters of research topics, including essential oil, intervention, and complementary medicine. CONCLUSIONS: This study provided a systematic overview of productivity and visibility of research work in aromatherapy and the findings could be used for organizing and prioritizing future research efforts in aromatherapy research. PMID- 28100268 TI - Upper lip metastasis of sarcomatoid carcinoma of the lung - an unusual site of disease: a case report. AB - BACKGROUND: Lip metastases are rare clinical events that are frequently mistaken for other diagnoses. For sarcomatoid lung carcinoma, a rare histologic variant of non-small cell lung cancer, the incidence and pattern of cutaneous spread is poorly understood. CASE PRESENTATION: We present a case of a 79-year-old African American man with a rapidly progressive upper lip cutaneous lesion that provided the first evidence of distant metastatic spread of sarcomatoid lung carcinoma. CONCLUSIONS: This is the first reported case of lip metastasis in sarcomatoid lung carcinoma. It highlights the importance of maintaining a high level of suspicion for metastatic disease in the presence of new cutaneous findings as they may be the first evidence of advanced disease. PMID- 28100269 TI - A spleen tyrosine kinase inhibitor attenuates the proliferation and migration of vascular smooth muscle cells. AB - BACKGROUND: Pathologic vascular smooth muscle cell (VSMC) proliferation and migration after vascular injury promotes the development of occlusive vascular disease. Therefore, an effective chemical agent to suppress aberrant proliferation and migration of VSMCs can be a potential therapeutic modality for occlusive vascular disease such as atherosclerosis and restenosis. To find an anti-proliferative chemical agent for VSMCs, we screened an in-house small molecule library, and the selected small molecule was further validated for its anti-proliferative effect on VSMCs using multiple approaches, such as cell proliferation assays, wound healing assays, transwell migration assays, and ex vivo aortic ring assay. RESULTS: Among 43 initially screened small molecule inhibitors of kinases that have no known anti-proliferative effect on VSMCs, a spleen tyrosine kinase (Syk) inhibitor (BAY61-3606) showed significant anti proliferative effect on VSMCs. Further experiments indicated that BAY61 attenuated the VSMC proliferation in both concentration- and time-dependent manner, and it also significantly suppressed the migration of VSMCs as assessed by both wound healing assays and transwell assays. Additionally, BAY61 suppressed the sprouting of VSMCs from endothelium-removed aortic rings. CONCLUSION: The present study identified a Syk kinase inhibitor as a potent VSMC proliferation and migration inhibitor and warrants further studies to elucidate its underlying molecular mechanisms, such as its primary target, and to validate its in vivo efficacy as a therapeutic agent for restenosis and atherosclerosis. PMID- 28100270 TI - Pro-inflammation NF-kappaB signaling triggers a positive feedback via enhancing cholesterol accumulation in liver cancer cells. AB - BACKGROUND: Hepatocellular carcinoma (HCC) develops in a complex microenvironment characterized by chronic inflammation. In recent years, cholesterol metabolic abnormalities have been implicated the importance in cancer cell physiology. This study was designed to investigate the relationship between inflammation and cholesterol accumulation in HCC cells. METHODS: Human HCC cells HepG2 and Huh7 were cultured and stimulated with lipopolysaccharide (LPS) for 24 h. The changes of HCC cells related to cholesterol metabolism including intracellular cholesterol concentrations, cholesterol uptake, and the expression of cholesterol related genes 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), LDL receptor (LDLR), sterol regulatory element-binding transcription factor 2 (SREBF2), and proprotein convertase subtilisin/kexin 9 (PCSK9) were comparatively analyzed. Simultaneously, the effects of nuclear factor-kappa B (NF-kappaB) signaling pathway on cholesterol metabolism were clarified by knocking-down of nuclear factor kappa-B kinase subunit alpha (IKKalpha) and TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 (TAB3) via RNAi and microRNA (miR)-195. Subsequently, the roles of cholesterol accumulation in LPS induced pro inflammatory effects were further investigated. RESULTS: Pro-inflammatory factor LPS significantly increased intracellular cholesterol accumulation by upregulating the expression of HMGCR, LDLR, and SREBF2, while downregulating the expression of PCSK9. These effects were revealed to depend on NF-kappaB signaling pathway by knocking-down and overexpression of IKKalpha and TAB3. Additionally, miR-195, a regulator directly targeting IKKalpha and TAB3, blocked the effects of cholesterol accumulation, further supporting the critical role of pro inflammation NF-kappaB signaling in regulating cholesterol accumulation. Intriguingly, the accumulation of cholesterol conversely exerted an augmented pro inflammation effects by further activating NF-kappaB signaling pathway. CONCLUSIONS: These results indicated that pro-inflammation effects of NF-kappaB signaling could be augmented by a positive feedback via enhancing the cholesterol accumulation in liver cancer cells. PMID- 28100271 TI - Evaluation of three sample preparation methods for the direct identification of bacteria in positive blood cultures by MALDI-TOF. AB - BACKGROUND: Patient mortality is significantly reduced by rapid identification of bacteria from sterile sites. MALDI-TOF can identify bacteria directly from positive blood cultures and multiple sample preparation methods are available. We evaluated three sample preparation methods and two MALDI-TOF score cut-off values. Positive blood culture bottles with organisms present in Gram stains were prospectively analysed by MALDI-TOF. Three lysis reagents (Saponin, SDS, and SepsiTyper lysis bufer) were applied to each positive culture followed by centrifugation, washing and protein extraction steps. Methods were compared using the McNemar test and 16S rDNA sequencing was used to assess discordant results. RESULTS: In 144 monomicrobial cultures, using >=2.000 as the cut-off value, species level identifications were obtained from 69/144 (48%) samples using Saponin, 86/144 (60%) using SDS, and 91/144 (63%) using SepsiTyper. The difference between SDS and SepsiTyper was not statistically significant (P = 0.228). Differences between Saponin and the other two reagents were significant (P < 0.01). Using >=1.700 plus top three results matching as the cut-off value, species level identifications were obtained from 100/144 (69%) samples using Saponin, 103/144 (72%) using SDS, and 106/144 (74%) using SepsiTyper and there was no statistical difference between the methods. No true discordances between culture and direct MALDI-TOF identification were observed in monomicrobial cultures. In 32 polymicrobial cultures, MALDI-TOF identified one organism in 34 75% of samples depending on the method. CONCLUSIONS: This study demonstrates two inexpensive in-house detergent lysis methods are non-inferior to a commercial kit for analysis of positive blood cultures by direct MALDI-TOF in a clinical diagnostic microbiology laboratory. PMID- 28100273 TI - Erratum to: Quartz-Seq: a highly reproducible and sensitive single-cell RNA sequencing method, reveals non-genetic gene-expression heterogeneity. PMID- 28100272 TI - Bibliometric analysis of literature on toxic epidermal necrolysis and Stevens Johnson syndrome: 1940 - 2015. AB - BACKGROUND: Stevens Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but fatal adverse skin reactions that affect all age groups. In order to better understand literature on this topic, we conducted a bibliometric study using Scopus database to shed light on number and growth of publications, most active countries, institutions, journals and authors involved in publishing articles in this field, citation analysis, top cited articles, international collaboration, role of medications and genetic association. Bibliometric analysis will enrich the literature on these rare conditions and will provide baseline data for future comparison. RESULTS: Three thousand eight hundred fifty-six journal articles were retrieved. The h-index of retrieved documents was 95. Growth rates of publications were highest from 1966 to 1975 and from 2006 to 2015. The United States of America (n = 640; 16.57%) was the leading country in number of publications. However, French and Japanese researchers and institutions were most active in publishing articles on SJS and TEN. International collaboration among active countries was relatively low and ranges from 32.5% for Swiss researchers and 1.47% for Spanish researchers. The most frequently mentioned medication in retrieved articles was carbamazepine (n = 146) followed by phenytoin (n = 114) and allopurinol (n = 112). Mycoplasma infection was mentioned in 111 articles. Most documents on SJS and TEN were published in dermatology journals, specifically Archives of Dermatology. However, in the last decade, top cited articles appeared in dermatology and pharmacogenetic journals. Carbamazepine was frequently encountered with Han Chinese and HLA-B 1502 terms while allopurinol was frequently encountered with HLA-B 5801 and Japanese terms. CONCLUSION: Bibliometric analysis reveals that research publications on SJS and TEN have been increasing since the l940s, with relatively low international collaboration. Documents are being published, not only in dermatology journals, but also in genetic, public health and general medicine journals. Research on SJS and TEN can be helpful to clinicians and researchers not only to document complications and fatal outcomes, but also to identify potential causative agents and potential ethnic variations to note gaps in research. PMID- 28100275 TI - Cell-in-cell structures are more potent predictors of outcome than senescence or apoptosis in head and neck squamous cell carcinomas. AB - BACKGROUND: This study sheds light on cell inactivating processes with focus on the phenomenon of cell-in-cell (CIC). Cell-in-cell describes a cell process where one cell is being engulfed by another non-professional phagocyte. We determined frequency and prognostic impact of CIC structures (CICs) as well as of senescent and apoptotic cells in head and neck squamous cell carcinomas (HNSCC). METHODS: These different forms of cell inactivation as well as the proportion of proliferating and tumor cells were assessed in 169 pre-radiochemotherapy biopsies and 32 post-therapy tumor resections by immunohistochemistry of tissue microarrays. Four consecutive cancer sections were stained with antibodies specific for E-cadherin for CIC detection, cleaved caspase-3 for apoptosis, H3K9Me for senescence and Ki67 as a proliferation marker. Positive events were quantified in corresponding tumor areas. RESULTS: CICs were found in 55.5%, senescent cells in 67.1% and apoptotic cells in 93.3% of samples. While no prognostic impact of apoptotic and senescent cells was observed, CICs turned out to significantly influence overall-survival (p = 0.016) with a lack of CICs being prognostically beneficial. There was no correlation between CICs and apoptosis and 98.9% of CICs were negative for cleaved caspase-3. CONCLUSION: CIC formation is a frequent event in HNSCC and a superior predictive marker compared to senescence and apoptosis. Independence of CIC and apoptosis and the adverse prognosis associated with numerous CICs lead to the assumption that CICs might take up necrotic rather than apoptotic cells preventing an adequate antitumoral immune response that would otherwise be initiated by necrotic cells through damage-associated molecular pattern molecules. PMID- 28100274 TI - Using medical specialty and selection criteria clusters to study specialty selection by Israeli medical students. AB - BACKGROUND: During their final year of medical school, Israeli students must consider which specialty to choose for residency. Based on the vocational counseling literature we presumed that choices are made by selecting from a cluster of related specialties while considering professional and socio-economic issues. METHODS: Questionnaires distributed to final-year medical students at two Israeli medical schools ascertained inclinations toward various medical specialties and the importance of various selection criteria. Analysis focused on seven specialties where >20% of students reported they had positive inclinations. For each such specialty, the specialty and selection criteria query were compared using unpaired two-tailed Student's t-tests to determine differences between students with positive inclinations toward the specialty with those not so inclined. These data were placed in tables, with the significant differences highlighted to facilitate visual recognition of cluster patterns. RESULTS: Completed questionnaires were obtained from 317 of 455 students. Students often had positive inclinations toward more than one specialty (specialty clusters) associated with a group of selection criteria (selection criteria clusters). For example, interest in internal medicine was clustered with interest in internal medicine subspecialties, cardiology and research. Furthermore, there was a "reciprocal" aspect to some specialty cluster patterns. For example, those interested in internal medicine had little interest in surgical specialties. Selection criteria clusters revealed occupational interests and socio environmental factors associated with the specialty clusters. For example, family medicine, which clustered with pediatrics and psychiatry, had a sub-cluster of: Bedside specialty with family orientation affording long-term patient care. Another sub-cluster was time for childrearing and family, only daytime work and outpatient care. Clusters also revealed students' perceptions that differed from expected: Cardiology is changing from a cognitive to a procedure-oriented subspecialty, clustering not only with internal medicine and its subspecialties but also with emergency medicine, surgical subspecialties and anesthesiology. CONCLUSIONS: The concept that career choice involves selecting from a cluster of related specialties provides information about the specialties students might be considering. Moreover, students are not only looking for individual aspects of a specialty, but for a package including clusters of socio-economic and occupational features. Practically, examining clusters can help in career counseling of medical students and assist residency program directors in marketing their specialties. PMID- 28100276 TI - Realising stratified psychiatry using multidimensional signatures and trajectories. AB - BACKGROUND: Stratified or personalised medicine targets treatments for groups of individuals with a disorder based on individual heterogeneity and shared factors that influence the likelihood of response. Psychiatry has traditionally defined diagnoses by constellations of co-occurring signs and symptoms that are assigned a categorical label (e.g. schizophrenia). Trial methodology in psychiatry has evaluated interventions targeted at these categorical entities, with diagnoses being equated to disorders. Recent insights into both the nosology and neurobiology of psychiatric disorder reveal that traditional categorical diagnoses cannot be equated with disorders. We argue that current quantitative methodology (1) inherits these categorical assumptions, (2) allows only for the discovery of average treatment response, (3) relies on composite outcome measures and (4) sacrifices valuable predictive information for stratified and personalised treatment in psychiatry. METHODS AND FINDINGS: To achieve a truly 'stratified psychiatry' we propose and then operationalise two necessary steps: first, a formal multi-dimensional representation of disorder definition and clinical state, and second, the similar redefinition of outcomes as multidimensional constructs that can expose within- and between-patient differences in response. We use the categorical diagnosis of schizophrenia conceptualised as a label for heterogeneous disorders-as a means of introducing operational definitions of stratified psychiatry using principles from multivariate analysis. We demonstrate this framework by application to the Clinical Antipsychotic Trials of Intervention Effectiveness dataset, showing heterogeneity in both patient clinical states and their trajectories after treatment that are lost in the traditional categorical approach with composite outcomes. We then systematically review a decade of registered clinical trials for cognitive deficits in schizophrenia highlighting existing assumptions of categorical diagnoses and aggregate outcomes while identifying a small number of trials that could be reanalysed using our proposal. CONCLUSION: We describe quantitative methods for the development of a multi-dimensional model of clinical state, disorders and trajectories which practically realises stratified psychiatry. We highlight the potential for recovering existing trial data, the implications for stratified psychiatry in trial design and clinical treatment and finally, describe different kinds of probabilistic reasoning tools necessary to implement stratification. PMID- 28100279 TI - Severe community-acquired adenovirus pneumonia treated with oral ribavirin: a case report. AB - BACKGROUND: Adenovirus is a common pathogen of acute upper respiratory infection in children and is generally self-limiting. Severe adenovirus infections have been reported in immunocompromised hosts especially bone marrow transplantation recipients due to hematologic malignancy. Severe adenovirus pneumonia in immunocompetent hosts has rarely been reported and optimal treatment has not been established. We report a case of community-acquired severe adenovirus pneumonia which was successfully treated with early administration of oral ribavirin. CASE PRESENTATION: A 39 year-old, previously healthy Korean male was admitted with symptoms of cough, myalgia, febrile sensation. Laboratory findings revealed that he had hypoxemia, thrombocytopenia and elevated transaminase. Chest imaging showed a consolidation with pleural effusion, which was rapidly progressed. All microbiological tests were negative except multiplex real-time reverse transcriptase polymerase chain reaction using respiratory specimen, which was positive for human adenovirus. Under the diagnosis of severe adenovirus pneumonia, we started oral ribavirin, which results in complete recovery without any complications. CONCLUSIONS: This case demonstrates that oral ribavirin, instead of other expensive antiviral treatment, could be a good therapeutic option for the severe adenovirus pneumonia at least occurred in immunocompetent hosts. PMID- 28100277 TI - Stress echo 2020: the international stress echo study in ischemic and non ischemic heart disease. AB - BACKGROUND: Stress echocardiography (SE) has an established role in evidence based guidelines, but recently its breadth and variety of applications have extended well beyond coronary artery disease (CAD). We lack a prospective research study of SE applications, in and beyond CAD, also considering a variety of signs in addition to regional wall motion abnormalities. METHODS: In a prospective, multicenter, international, observational study design, > 100 certified high-volume SE labs (initially from Italy, Brazil, Hungary, and Serbia) will be networked with an organized system of clinical, laboratory and imaging data collection at the time of physical or pharmacological SE, with structured follow-up information. The study is endorsed by the Italian Society of Cardiovascular Echography and organized in 10 subprojects focusing on: contractile reserve for prediction of cardiac resynchronization or medical therapy response; stress B-lines in heart failure; hypertrophic cardiomyopathy; heart failure with preserved ejection fraction; mitral regurgitation after either transcatheter or surgical aortic valve replacement; outdoor SE in extreme physiology; right ventricular contractile reserve in repaired Tetralogy of Fallot; suspected or initial pulmonary arterial hypertension; coronary flow velocity, left ventricular elastance reserve and B-lines in known or suspected CAD; identification of subclinical familial disease in genotype-positive, phenotype- negative healthy relatives of inherited disease (such as hypertrophic cardiomyopathy). RESULTS: We expect to recruit about 10,000 patients over a 5 year period (2016-2020), with sample sizes ranging from 5,000 for coronary flow velocity/ left ventricular elastance/ B-lines in CAD to around 250 for hypertrophic cardiomyopathy or repaired Tetralogy of Fallot. This data-base will allow to investigate technical questions such as feasibility and reproducibility of various SE parameters and to assess their prognostic value in different clinical scenarios. CONCLUSIONS: The study will create the cultural, informatic and scientific infrastructure connecting high-volume, accredited SE labs, sharing common criteria of indication, execution, reporting and image storage of SE to obtain original safety, feasibility, and outcome data in evidence-poor diagnostic fields, also outside the established core application of SE in CAD based on regional wall motion abnormalities. The study will standardize procedures, validate emerging signs, and integrate the new information with established knowledge, helping to build a next-generation SE lab without inner walls. PMID- 28100278 TI - Prevalence and risk factors of undernutrition among schoolchildren in the Plateau Central and Centre-Ouest regions of Burkina Faso. AB - BACKGROUND: Multiple factors determine children's nutritional status, including energy and nutrient intake, recurrent infectious diseases, access (or lack thereof) to clean water and improved sanitation, and hygiene practices, among others. The "Vegetables go to School: improving nutrition through agricultural diversification" (VgtS) project implements an integrated school garden programme in five countries, including Burkina Faso. The aim of this study was to determine the prevalence of undernutrition and its risk factors among schoolchildren in Burkina Faso before the start of the project. METHODS: In February 2015, a cross sectional survey was carried out among 455 randomly selected children, aged 8-14 years, in eight schools in the Plateau Central and Centre-Ouest regions of Burkina Faso. Nutritional status was determined by anthropometric assessment. Helminth and intestinal protozoa infections were assessed using the Kato-Katz and a formalin-ether concentration method. A urine filtration technique was used to identify Schistosoma haematobium eggs. Prevalence of anaemia was determined by measuring haemoglobin levels in finger-prick blood samples. Questionnaires were administered to children to determine their knowledge of nutrition and health and their related attitudes and practices (KAP). Questionnaires were also administered to the children's caregivers to identify basic household socio demographic and economic characteristics, and water, sanitation and hygiene (WASH) conditions. To determine the factors associated with schoolchildren's nutritional status, mixed logistic regression models were used. Differences and associations were considered statistically significant if P-values were below 0.05. RESULTS: Complete datasets were available for 385 children. The prevalence of undernutrition, stunting and thinness were 35.1%, 29.4% and 11.2%, respectively. The multivariable analysis revealed that undernutrition was associated with older age (i.e. 12-14 years compared to <12 years; adjusted odds ratio (aOR) = 3.45, 95% confidence interval (CI) 2.12-5.62, P < 0.001), multiple pathogenic parasitic infections (aOR = 1.87, 95% CI 1.02-3.43, P = 0.044) and with moderate and severe anaemia in children (aOR = 2.52, 95% CI 1.25-5.08, P = 0.010). CONCLUSIONS: We found high prevalence of undernutrition among the children surveyed in the two study regions of Burkina Faso. We further observed that undernutrition, anaemia and parasitic infections were strongly associated. In view of these findings, concerted efforts are needed to address undernutrition and associated risk factors among school-aged children. As part of the VgtS project, WASH, health education and nutritional interventions will be implemented with the goal to improve children's health. TRIAL REGISTRATION: ISRCTN17968589 (date assigned: 17 July 2015). PMID- 28100281 TI - Erratum to: Diet and exercise in uterine cancer survivors (DEUS pilot) - piloting a healthy eating and physical activity program: study protocol for a randomized controlled trial. PMID- 28100280 TI - Erratum to: The whole genome sequence of the Mediterranean fruit fly, Ceratitis capitata (Wiedemann), reveals insights into the biology and adaptive evolution of a highly invasive pest species. PMID- 28100284 TI - Role of flavonoids and nitrates in cardiovascular health. AB - CVD remain the leading cause of death globally. Effective dietary strategies for their reduction are of high priority. Increasing evidence suggests that phytochemicals, particularly dietary flavonoids and nitrates, are key modulators of CVD risk reduction through impact on multiple risk factors. The aim of this review is to explore the evidence for the impact of flavonoid- and nitrate-rich foods and supplements on CVD risk, with specific reference to their importance as mediators of vascular health and platelet function. There is accumulating evidence to support benefits of dietary flavonoids on cardiovascular health. Dose dependent recovery of endothelial function and lowering of blood pressure have been reported for the flavanol (-)-epicatechin, found in cocoa, apples and tea, through production and availability of endothelial nitric oxide (NO). Furthermore, flavonoids, including quercetin and its metabolites, reduce in vitro and ex vivo platelet function via inhibition of phosphorylation-dependent cellular signalling pathways, although further in vivo studies are required to substantiate these mechanistic effects. Hypotensive effects of dietary nitrates have been consistently reported in healthy subjects in acute and chronic settings, although there is less evidence for these effects in patient groups. Proposed mechanisms of actions include endothelial-independent NO availability, which is dependent on the entro-salivary circulation and microbial conversion of dietary nitrate to nitrite in the mouth. In conclusion, flavonoid- and nitrate rich foods show promising effects on vascular function, yet further randomly controlled studies are required to confirm these findings and to determine effective doses. PMID- 28100283 TI - Genetic influences on hormonal markers of chronic hypothalamic-pituitary-adrenal function in human hair. AB - BACKGROUND: Cortisol is the primary output of the hypothalamic-pituitary-adrenal (HPA) axis and is central to the biological stress response, with wide-ranging effects on psychiatric health. Despite well-studied biological pathways of glucocorticoid function, little attention has been paid to the role of genetic variation. Conventional salivary, urinary and serum measures are strongly influenced by diurnal variation and transient reactivity. Recently developed technology can be used to measure cortisol accumulation over several months in hair, thus indexing chronic HPA function. METHOD: In a socio-economically diverse sample of 1070 twins/multiples (ages 7.80-19.47 years) from the Texas Twin Project, we estimated effects of sex, age and socio-economic status (SES) on hair concentrations of cortisol and its inactive metabolite, cortisone, along with their interactions with genetic and environmental factors. This is the first genetic study of hair neuroendocrine concentrations and the largest twin study of neuroendocrine concentrations in any tissue type. RESULTS: Glucocorticoid concentrations increased with age for females, but not males. Genetic factors accounted for approximately half of the variation in cortisol and cortisone. Shared environmental effects dissipated over adolescence. Higher SES was related to shallower increases in cortisol with age. SES was unrelated to cortisone, and did not significantly moderate genetic effects on either cortisol or cortisone. CONCLUSIONS: Genetic factors account for sizable proportions of glucocorticoid variation across the entire age range examined, whereas shared environmental influences are modest, and only apparent at earlier ages. Chronic glucocorticoid output appears to be more consistently related to biological sex, age and genotype than to experiential factors that cluster within nuclear families. PMID- 28100285 TI - Characterization of the complete mitochondrial genome of Setaria digitata (Nematoda: Setariidae) from China. AB - Setaria digitata is a filarial parasite that causes fatal cerebrospinal nematodiasis in goats, horses and sheep, resulting in substantial economic losses to livestock farmers. In the present study, the complete mitochondrial (mt) genome of S. digitata from China was determined, characterized and compared with that of S. digitata from Sri Lanka. The identity of the mt genomes was 98.3% between S. digitata from China and Sri Lanka, and the complete mt genome sequence of S. digitata from China was slightly shorter (25 bp) than that from Sri Lanka. For the 12 protein genes, this comparison revealed sequence differences at both the nucleotide (1.4%) and amino acid (2.2%) levels. The present study determined the complete mt genome sequence of S. digitata from China, providing novel genetic markers for the study of the population genetics and molecular epidemiology of S. digitata in animals. PMID- 28100282 TI - Optimal regimens of sulfamethoxazole-trimethoprim for chemoprophylaxis of Pneumocystis pneumonia in patients with systemic rheumatic diseases: results from a non-blinded, randomized controlled trial. AB - BACKGROUND: Sulfamethoxazole-trimethoprim (SMX/TMP) is a standard drug for the prophylaxis of Pneumocystis pneumonia (PJP) in immunosuppressed patients with systemic rheumatic diseases, but is sometimes discontinued due to adverse events (AEs). The objective of this non-blinded, randomized, 52-week non-inferiority trial was to quest an effective chemoprophylaxis regimen for PJP with a low drug discontinuation rate. Results at week 24 were reported. METHODS: Adult patients with systemic rheumatic diseases who started prednisolone >=0.6 mg/kg/day were randomized into three dosage groups: a single-strength group (SS, SMX/TMP of 400/80 mg daily), half-strength group (HS, 200/40 mg daily), and escalation group (ES, started with 40/8 mg daily, increasing incrementally to 200/40 mg daily). The primary endpoint was non-incidence rates (non-IR) of PJP at week 24. RESULTS: Of 183 patients randomly allocated at a 1:1:1 ratio into the three groups, 58 patients in SS, 59 in HS, and 55 in ES started SMX/TMP. A total of 172 patients were included in the analysis. No cases of PJP were reported up to week 24. Estimated non-IR of PJP in patients who received daily SMX/TMP of 200/40 mg, either starting at this dose or increasing incrementally, was 96.8-100% using the exact confidence interval as a post-hoc analysis. The overall discontinuation rate was significantly lower with HS compared to SS (p = 0.007). The discontinuation rates due to AEs were significantly lower with HS (p = 0.006) and ES (p = 0.004) compared to SS. The IR of AEs requiring reduction in the dose of SMX/TMP (p = 0.009) and AEs of special interest (p = 0.003) were different among the three groups with significantly higher IR in SS compared to HS and ES. CONCLUSIONS: Although there were no PJP cases, the combined group of HS and ES had an excellent estimated non-IR of PJP and both were superior in safety to SS. From the perspective of feasibility and drug discontinuation rates, the daily half-strength regimen was suggested to be optimal for prophylaxis of PJP in patients with systemic rheumatic diseases. TRIAL REGISTRATION: The University Hospital Medical Information Network Clinical Trials Registry number is UMIN000007727 , registered 10 April 2012. PMID- 28100287 TI - Characterisation of fatty acid metabolism in different insulin-resistant phenotypes by means of stable isotopes. AB - The obese insulin resistant and/or prediabetic state is characterised by systemic lipid overflow, mainly driven by an impaired lipid buffering capacity of adipose tissue, and an impaired capacity of skeletal muscle to increase fat oxidation upon increased supply. This leads to the accumulation of bioactive lipid metabolites in skeletal muscle interfering with insulin sensitivity via various mechanisms. In this review, the contribution of dietary v. endogenous fatty acids to lipid overflow, their extraction or uptake by skeletal muscle as well as the fractional synthetic rate, content and composition of the muscle lipid pools is discussed in relation to the development or presence of insulin resistance and/or an impaired glucose metabolism. These parameters are studied in vivo in man by combining a dual stable isotope methodology with [2H2]- and [U-13C]-palmitate tracers with the arterio-venous balance technique across forearm muscle and biochemical analyses in muscle biopsies. The insulin-resistant state is characterised by an elevated muscle TAG extraction, despite similar supply, and a reduced skeletal muscle lipid turnover, in particular after intake of a high fat, SFA fat meal, but not after a high fat, PUFA meal. Data are placed in the context of current literature, and underlying mechanisms and implications for long-term nutritional interventions are discussed. PMID- 28100286 TI - Disease burden of hepatitis E in a rural population in China: a community-based survey. AB - This study aimed to estimate the disease burden of hepatitis E in a rural region in China. A total of 489 hepatitis E cases were reported according to a community based survey in an active hepatitis surveillance system between 2008 and 2015, the questionnaire and record-review methods were constructed to evaluate the economic and health burden of hepatitis E virus infections from societal perspectives. All costs were converted to US$ in 2015. The age-standardized cumulative incidence rate was 107.9/100 000, and the median age-standardized annual incidence rate was 16.5/100 000. The median direct, indirect, and intangible cost were $1046.0, $49.1, and $77.3/patient, respectively, and the median economic burden per patient was $1836.5, which accounted for 51.2% of per capita disposable income. Moreover, the median quality-adjusted life year and visual analogue scale score were 0.7 and 70.0/case, respectively. Both economic burden and health burden of inpatients was more serious than that of outpatients (P < 0.001). Disease burden of hepatitis E is heavy on patients, their families, and society. More studies on the disease burden of hepatitis E are necessary to increase social awareness of the disease and confirm reasonable disease-control measures. PMID- 28100288 TI - Childhood maltreatment and eating disorder pathology: a systematic review and dose-response meta-analysis. AB - BACKGROUND: Meta-analyses have established a high prevalence of childhood maltreatment (CM) in patients with eating disorders (EDs) relative to the general population. Whether the prevalence of CM in EDs is also high relative to that in other mental disorders has not yet been established through meta-analyses nor to what extent CM affects defining features of EDs, such as number of binge/purge episodes or age at onset. Our aim is to provide meta-analyses on the associations between exposure to CM (i.e. emotional, physical and sexual abuse) on the occurrence of all types of EDs and its defining features. METHOD: Systematic review and meta-analyses. Databases were searched until 4 June 2016. RESULTS: CM prevalence was high in each type of ED (total N = 13 059, prevalence rates 21 59%) relative to healthy (N = 15 092, prevalence rates 1-35%) and psychiatric (N = 7736, prevalence rates 5-46%) control groups. ED patients reporting CM were more likely to be diagnosed with a co-morbid psychiatric disorder [odds ratios (ORs) range 1.41-2.46, p < 0.05] and to be suicidal (OR 2.07, p < 0.001) relative to ED subjects who were not exposed to CM. ED subjects exposed to CM also reported an earlier age at ED onset [effect size (Hedges' g) = -0.32, p < 0.05], to suffer a more severe form of the illness (g = 0.29, p < 0.05), and to binge purge (g = 0.31, p < 0.001) more often compared to ED patients who did not report any CM. CONCLUSION: CM, regardless of type, is associated with the presence of all types of ED and with severity parameters that characterize these illnesses in a dose dependent manner. PMID- 28100289 TI - Hepatitis B virus in drug users in France: prevalence and vaccination history, ANRS-Coquelicot Survey 2011-2013. AB - People who use drugs (PWUD) are a key population for hepatitis B virus (HBV) vaccination and screening. We aimed to estimate the seroprevalence of HBs antigen (HBsAg) and self-reported HBV vaccination history in French PWUD attending harm reduction centres using data from the ANRS-Coquelicot multicentre survey conducted in 2011-2013 in 1718 PWUD. Self-fingerprick blood samples were collected on dried blood spots to detect the presence of HBsAg. HBsAg seroprevalence was estimated at 1.4% [95% confidence interval (CI) 0.8-2.5]. It varied between PWUD born in high (7.6%, 95% CI 2.7-19.1), moderate (2.2%, 95% CI 0.8-5.7) and low (0.7%, 95% CI 0.3-1.5) endemic zones. Factors independently associated with HBsAg carriage were being born in a moderate or high endemic zone or reporting precarious housing. Self-reported HBV vaccination history varied from 47.4% in high endemic zones, to 59.3% and 62.6% for moderate and low endemic zones, respectively. Our results suggest that drug use plays a small and substantial role, respectively, in HBsAg carriage in PWUD born in high/moderate and low endemic zones. PMID- 28100290 TI - Familial confounding of the association between maternal smoking during pregnancy and internalizing disorders in offspring. AB - BACKGROUND: Maternal smoking has consistently been associated with multiple adverse childhood outcomes including externalizing disorders. In contrast the association between maternal smoking during pregnancy (MSDP) and internalizing (anxiety and depressive) disorders in offspring has received less investigation. METHOD: We conducted a nationwide cohort study including 957635 individuals born in Denmark between 1991 and 2007. Data on MSDP and diagnoses of depression or anxiety disorders were derived from national registers and patients were followed up from the age of 5 years to the end of 2012. Hazard rate ratios (HRRs) were estimated using stratified Cox regression models. Sibling data were used to disentangle individual- and familial-level effects of MSDP and to control for unmeasured familial confounding. RESULTS: At the population level, offspring exposed to MSDP were at increased risk for both severe depression [HRR 1.29, 95% confidence interval (CI) 1.22-1.36] and severe anxiety disorders (HRR 1.26, 95% CI 1.20-1.32) even when controlling for maternal and paternal traits. However, there was no association between MSDP and internalizing disorders when controlling for the mother's propensity for MSDP (depression: HRR 1.11, 95% CI 0.94-1.30; anxiety disorders: HRR 0.94, 95% CI 0.80-1.11) or comparing differentially exposed siblings (depression: HRR 1.18, 95% CI 0.75-1.89; anxiety disorders: HRR 0.87, 95% CI 0.55-1.36). CONCLUSIONS: The results suggest that familial background factors account for the association between MSDP and severe internalizing disorders not the specific exposure to MSDP. PMID- 28100291 TI - Systematic Review of Neuropsychological Rehabilitation for Prospective Memory Deficits as a Consequence of Acquired Brain Injury. AB - OBJECTIVES: Prospective memory (PM) impairments are common following acquired brain injury (ABI). PM is the ability to keep a goal in mind for future action and interventions have the potential to increase independence. This review aimed to evaluate studies examining PM rehabilitation approaches in adults and children with ABI. METHODS: Relevant literature was identified using PsycARTICLES (1894 to present), PsycINFO (1880 to present), the Cochrane Library (1972 to present), MEDLINE PubMed, reference lists from relevant journal articles, and searches of key journals. Literature searches were conducted using variants of the terms brain injury, stroke, encephalitis, meningitis, and tumor, combined with variants of the terms rehabilitation and prospective memory. RESULTS: Of the 435 papers identified, 11 were included in the review. Findings demonstrated a variety of interventions to alleviate PM deficits, including compensatory strategies (e.g., external memory aids) that provide either content-specific or content-free cueing, and remediation strategies (e.g., meta-cognitive training programs) aimed at improving the self-monitoring of personal goals. Risk of bias for individual studies was considered and the strengths and limitations of each of the included studies and the review itself were discussed. CONCLUSIONS: Interventions used with adults can be effective; PM abilities can be improved by using simple reminder systems and performance can be generalized to facilitate everyday PM functioning. There is, however, a lack of research of PM interventions conducted with children with ABI, and pediatric interventions need to consider on-going cognitive maturation. (JINS, 2017, 22, 1-12). PMID- 28100292 TI - Evidence, knowledge, implementation: glossary of terminology. PMID- 28100293 TI - Psychiatric rehabilitation in Europe. AB - To describe the core elements of modern psychiatric rehabilitation. Based on selected examples we describe the discussion about values in mental health care with focus on Europe. We present outcome data from studies, which have tried to implement care structures based on this value discussion. In the second half of the 20th century, mental health care in all European and other high-income countries changed conceptually and structurally. Deinstitutionalisation reduced the number of psychiatric beds and transferred priority to outpatient care and community-based services, but community mental health programs developed differently across and within these countries. High-income countries in Europe continued to invest in costly traditional services that were neither evidence based nor person-centered by emphasising inpatient services, sheltered group homes and sheltered workshops. We argue that evidence-based, person-centred, recovery-oriented psychiatric rehabilitation offers a parsimonious solution to developing a consensus plan for community-based care in Europe. The challenges to scaling up effective psychiatric rehabilitation services in high-income countries are not primarily a lack of resources, but rather a lack of political will and inefficient use and dysfunctional allocation of resources. PMID- 28100296 TI - Rouxiella badensis sp. nov. and Rouxiella silvae sp. nov. isolated from peat bog soil and emendation description of the genus Rouxiella. AB - Four bacterial strains isolated from peat bog soil or swampy meadow in Baden Wurttemberg (Germany) and found to have rrs sequences close to that of Rouxiella chamberiensis were compared to this species by using multi-locus sequence analysis and phenotypic tests. The four strains constituted two discrete groups (referred to as the Baden and the Silva groups) belonging to the genus Rouxiella. These groups differed in their ability to grow at 37 degrees C, reduce nitrate into nitrite, and to produce acid from several carbohydrates. Two novel species are, therefore, proposed: Rouxiella badensis sp. nov. for the Baden group (type strain, 323T=CIP 111153T=DSM 100043T) and Rouxiella silvae for the Silva group (type strain, 213T=CIP 111154T=DSM 103735T). The definition of the genus Rouxiellahas also been emended in order to take these two novel species into account. PMID- 28100295 TI - Physical state and copy numbers of HPV16 in oral asymptomatic infections that persisted or cleared during the 6-year follow-up. AB - Persistent human papillomavirus (HPV) infection is a key event in HPV-induced carcinogenesis. As part of the prospective Finnish Family HPV Study, we analysed the physical state and viral copy numbers of HPV16 in asymptomatic oral infections that either persisted or cleared during the 6-year follow-up. The persister group comprised 14 women and 7 men with 51 and 21 HPV16-positive brush samples. The clearance group included 41 women and 13 men, with 64 and 24 samples, respectively. Physical state and viral DNA load were assessed by using quantitative PCR for HPV16 E2 and E6 genes. E2/E6 ratio was calculated and HPV16 was classified as episomal, mixed or integrated with values of 0.93-1.08, <0.93 and 0, respectively. In both genders, the physical state of HPV16 was significantly different between the cases and controls (P<0.001). HPV16 was episomal in all men and 66 % (27/41) of women who cleared their infection. HPV16 was mixed and/or integrated in71 % and 57 %of the women and men persisters, respectively. The mean HPV16 copy number per 50 ng genomic DNA was nearly 5.5 fold higher in the women than in the men clearance group (P=0.011). Only in men, HPV16 copy numbers were higher in persisters than in the clearance group (P=0.039). To conclude, in both genders, persistent oral HPV16 infections were associated with the mixed or integrated form of HPV16, while in the clearance groups, episomal HPV16 predominated. This indicates that HPV16 integration is a common event even in asymptomatic oral infections, which might predispose the infected subjects to progressive disease. PMID- 28100297 TI - Transcriptional analysis of mating and pre-infection stages of the anther smut, Microbotryum lychnidis-dioicae. AB - Microbotryum lychnidis-dioicae is an obligate biotrophic parasite of the wildflower species, Silene latifolia. This dikaryotic fungus, commonly known as an anther smut, requires that haploid, yeast-like sporidia of opposite mating types fuse and differentiate into dikaryotic hyphae that penetrate host tissue as part of the fungal lifecycle. Mating occurs under conditions of cool temperatures and limited nutrients. Further development requires host cues or chemical mimics, including a variety of lipids, e.g., phytols. To identify global changes in transcription associated with developmental shifts, RNA-Seq was conducted at several in vitro stages of fungal propagation, i.e., haploid cells grown independently on rich and nutrient-limited media, mated cells on nutrient-limited media, as well as a time-course of such mated cells exposed to phytol. Comparison of haploid cells grown under rich and nutrient-limited conditions identified classes of genes likely associated with general nutrient availability, including components of the RNAi machinery. Some gene enrichment patterns comparing the nutrient-limited and mated transcriptomes suggested gene expression changes associated with the mating program (e.g., homeodomain binding proteins, secreted proteins, proteins unique to M. lychnidis-dioicae multicopper oxidases, and RhoGEFs). Analysis for phytol treatment compared with mated cells alone allowed identification of genes likely involved in the dikaryotic switch (e.g., oligopeptide transporters). Gene categories of particular note in all three conditions included those in the major facilitator superfamily, proteins containing PFAM domains of the secretory lipase family, as well as proteins predicted to be secreted, many of which have the hallmarks of fungal effectors with potential roles in pathogenicity. PMID- 28100294 TI - Why do we remember? The communicative function of episodic memory. AB - Episodic memory has been analyzed in a number of different ways in both philosophy and psychology, and most controversy has centered on its self referential, 'autonoetic' character. Here, we offer a comprehensive characterization of episodic memory in representational terms, and propose a novel functional account on this basis. We argue that episodic memory should be understood as a distinctive epistemic attitude taken towards an event simulation. On this view, episodic memory has a metarepresentational format and should not be equated with beliefs about the past. Instead, empirical findings suggest that the contents of human episodic memory are often constructed in the service of the explicit justification of such beliefs. Existing accounts of episodic memory function that have focused on explaining its constructive character through its role in 'future-oriented mental time travel' neither do justice to its capacity to ground veridical beliefs about the past nor to its representational format. We provide an account of the metarepresentational structure of episodic memory in terms of its role in communicative interaction. The generative nature of recollection allows us to represent and communicate the reasons for why we hold certain beliefs about the past. In this process, autonoesis corresponds to the capacity to determine when and how to assert epistemic authority in making claims about the past. A domain where such claims are indispensable are human social engagements. Such engagements commonly require the justification of entitlements and obligations, which is often possible only by explicit reference to specific past events. PMID- 28100299 TI - Pathogenicity of modified bat influenza virus with different M genes and its reassortment potential with swine influenza A virus. AB - In our previous studies, the reassortant virus containing only the PR8 H1N1 matrix (M) gene in the background of the modified bat influenza Bat09 : mH1mN1 virus could be generated. However, whether M genes from other origins can be rescued in the background of the Bat09 : mH1mN1 virus and whether the resulting novel reassortant virus is virulent remain unknown. Herein, two reassortant viruses were generated in the background of the Bat09 : mH1mN1 virus containing either a North American or a Eurasian swine influenza virus M gene. These two reassortant viruses and the reassortant virus with PR8 M as well as the control Bat09 : mH1mN1 virus replicated efficiently in cultured cells, while the reassortant virus with PR8 M grew to a higher titre than the other three viruses in tested cells. Mouse studies showed that reassortant viruses with either North American or Eurasian swine influenza virus M gene did not enhance virulence, whereas the reassortant virus with PR8 M gene displayed higher pathogenicity when compared to the Bat09 : mH1mN1 virus. This is most likely due to the fact that the PR8 H1N1 virus is a mouse-adapted virus. Furthermore, reassortment potential between the Bat09 : mH1mN1 virus and an H3N2 swine influenza virus (A/swine/Texas/4199-2/1998) was investigated using co-infection of Madin-Darby canine kidney cells, but no reassortant viruses were detected. Taken together, our results indicate that the modified bat influenza virus is most likely incapable of reassortment with influenza A viruses with in vitro co-infection experiments, although reassortant viruses with different M genes can be generated by reverse genetics. PMID- 28100300 TI - Molecular analysis and species diversity of Nocardia in the hospital environment in a developing country, a potential health hazard. AB - PURPOSE: Despite hundreds of reports on the isolation of Nocardia from clinical samples, the presence and diversity of Nocardia species that are capable of survival in a harsh and adverse condition, such as a hospital environment, have not been comprehensively studied. The aim of this study was to assess Nocardia species diversity in a hospital environment to provide a better insight into their potential threat as a reservoir for the development of nosocomial infections. METHODOLOGY: A total of 90 samples of hospital water, dust and soil, collected from 30 hospitals, were analysed for the presence of Nocardia using standard protocols for isolation and characterization of the isolates. Conventional tests were used for preliminary identification, and PCR amplification of the 596 bp amplicon of the 16S rRNA and sequence analysis of 16S rRNA were performed for genus and species identification. RESULTS: A total of 25 Nocardia isolates (27.7 %) from 10 species were recovered from 90 samples. The three most prevalent species were N. cyriacigeorgica, 24 %, N. asteroides, 16 % and N. kroppenstedtii, 12 %, followed by N. salmonicida-like, 8 % and single isolates of N.otitidiscaviarum, N. flavorozea-like, N. neocaledoniensis-like and N. sungurluensis-like. Thirteen out of twenty five isolates showed characteristics of six novel species. CONCLUSION: Our study showed that the hospital environment is a potential reservoir of a diverse range of Nocardia species, due to the remarkable survival capability of these bacteria in an adverse hospital environment, which carries a threat to the health of patients. PMID- 28100298 TI - Description of two novel members of the family Erysipelotrichaceae: Ileibacterium valens gen. nov., sp. nov. and Dubosiella newyorkensis, gen. nov., sp. nov., from the murine intestine, and emendation to the description of Faecalibaculum rodentium. AB - To better characterize murine intestinal microbiota, a large number (187) of Gram positive-staining, rod- and coccoid-shaped, and facultatively or strictly anaerobic bacteria were isolated from small and large intestinal contents from mice. Based on 16S rRNA gene sequencing, a total 115 isolates formed three phylogenetically distinct clusters located within the family Erysipelotrichaceae. Group 1, as represented by strain NYU-BL-A3T, was most closely related to Allobaculum stercoricanis, with 16S rRNA gene sequence similarity values of 87.7 %. A second group, represented by NYU-BL-A4T, was most closely related to Faecalibaculum rodentium, with 86.6 % 16S rRNA gene sequence similarity. A third group had a nearly identical 16S rRNA gene sequence (99.9 %) compared with the recently described Faecalibaculum rodentium, also recovered from a laboratory mouse; however, this strain had a few differences in biochemical characteristics, which are detailed in an emended description. The predominant (>10 %) cellular fatty acids of strain NYU-BL-A3T were C16 : 0 and C18 : 0, and those of strain NYU-BL-A4T were C10 : 0, C16 : 0, C18 : 0 and C18 : 1omega9c. The two groups could also be distinguished by multiple biochemical reactions, with the group represented by NYU-BL-A4T being considerably more active. Based on phylogenetic, biochemical and chemotaxonomic criteria, two novel genera are proposed, Ileibacterium valens gen. nov., sp. nov. with NYU-BL-A3T (=ATCC TSD-63T=DSM 103668T) as the type strain and Dubosiella newyorkensis gen. nov., sp. nov. with NYU-BL-A4T (=ATCC TSD-64T=DSM 103457T) as the type strain. PMID- 28100301 TI - High-throughput screening of a GlaxoSmithKline protein kinase inhibitor set identifies an inhibitor of human cytomegalovirus replication that prevents CREB and histone H3 post-translational modification. AB - To identify new compounds with anti-human cytomegalovirus (HCMV) activity and new anti-HCMV targets, we developed a high-throughput strategy to screen a GlaxoSmithKline Published Kinase Inhibitor Set. This collection contains a range of extensively characterized compounds grouped into chemical families (chemotypes). From our screen, we identified compounds within chemotypes that impede HCMV protein production and identified kinase proteins associated with inhibition of HCMV protein production that are potential novel anti-HCMV targets. We focused our study on a top 'hit' in our screen, SB-734117, which we found inhibits productive replication of several HCMV strains. Kinase selectivity data indicated that SB-734117 exhibited polypharmacology and was an inhibitor of several proteins from the AGC and CMCG kinase groups. Using Western blotting, we found that SB-734711 inhibited accumulation of HCMV immediate-early proteins, phosphorylation of cellular proteins involved in immediate-early protein production (cAMP response element-binding protein and histone H3) and histone H3 lysine 36 trimethylation (H3K36me3). Therefore, we identified SB-734117 as a novel anti-HCMV compound and found that inhibition of AGC and CMCG kinase proteins during productive HCMV replication was associated with inhibition of viral protein production and prevented post-translational modification of cellular factors associated with viral protein production. PMID- 28100302 TI - Faecal virome of healthy chickens reveals a large diversity of the eukaryote viral community, including novel circular ssDNA viruses. AB - This study is focused on the identification of the faecal virome of healthy chickens raised in high-density, export-driven poultry farms in Brazil. Following high-throughput sequencing, a total of 7743 de novo-assembled contigs were constructed and compared with known nucleotide/amino acid sequences from the GenBank database. Analyses with blastx revealed that 279 contigs (4 %) were related to sequences of eukaryotic viruses. Viral genome sequences (total or partial) indicative of members of recognized viral families, including Adenoviridae, Caliciviridae, Circoviridae, Parvoviridae, Picobirnaviridae, Picornaviridae and Reoviridae, were identified, some of those representing novel genotypes. In addition, a range of circular replication-associated protein encoding DNA viruses were also identified. The characterization of the faecal virome of healthy chickens described here not only provides a description of the viruses encountered in such niche but should also represent a baseline for future studies comparing viral populations in healthy and diseased chicken flocks. Moreover, it may also be relevant for human health, since chickens represent a significant proportion of the animal protein consumed worldwide. PMID- 28100303 TI - Ethanol, glycogen and glucosylglycerol represent competing carbon pools in ethanol-producing cells of Synechocystis sp. PCC 6803 under high-salt conditions. AB - Cyanobacteria are photoautotrophic micro-organisms, which are increasingly being used as microbial cell factories to produce, for example, ethanol directly from solar energy and CO2. Here, we analysed the effects of different salt concentrations on an ethanol-producing strain of Synechocystis sp. PCC 6803 that overexpresses the pyruvate decarboxylase (pdc) from Zymomonas mobilis and the native alcohol dehydrogenase (adhA). Moderate salinities of 2 % NaCl had no negative impact on ethanol production, whereas the addition of 4 % NaCl resulted in significantly decreased ethanol yields compared to low-salt conditions. Proteomic analysis identified a defined set of proteins with increased abundances in ethanol-producing cells. Among them, we found strong up-regulation of alpha 1,4 glucan phosphorylase (GlgP, Slr1367) in the producer strain, which consistently resulted in a massive depletion of glycogen pools in these cells regardless of the salinity. The salt-induced accumulation of the compatible solute glucosylglycerol was not affected by the ethanol production. Glycogen and probably compatible solutes could present competing pools with respect to organic carbon, explaining the decreased ethanol production at the highest salinity. PMID- 28100304 TI - Iron responsive-like elements in the parasite Entamoeba histolytica. AB - In Entamoeba histolytica, iron modulates virulence and gene expression via unknown regulatory mechanisms. The existence of a posttranscriptional iron regulatory system parallel with the iron-responsive element (IRE)/iron regulatory protein (IRP) system in the protozoan Trichomonas vaginalis has recently been reported. Due to their evolutionary closeness and the importance of iron for growth and virulence in these protozoa, we hypothesized the existence of an IRE/IRP-like mechanism in E. histolytica. To determine the presence of IRE-like elements in some mRNAs from this parasite, we performed in silico analyses of the 5'- and 3'-UTRs of mRNAs encoding virulence factors and cytoskeleton, ribosomal and metabolism proteins. The Zuker mfold software predicted IRE-like secondary structures in 52 of the 135 mRNAs analysed. However, only nine structures shared sequence similarity with the apical loop sequence (CAGUGN) of the previously reported human IRE-ferritin, whereas the GUU/UUG protozoan-specific motif was detected in 23 stem-loop structures. A new motif, AUU/AUUU, was also observed in 23 structures, suggesting the possible existence of an amoeba-specific motif. Additionally, cross-linking and RNA electrophoretic mobility shift assays showed specific RNA-protein interactions, using as a model two amoebic IRE-like elements from iron-regulated mRNAs and HeLa, T. vaginalis and E. histolytica cytoplasmic proteins. Our data suggest the presence of a posttranscriptional iron regulatory IRE/IRP-like mechanism in E. histolytica. PMID- 28100306 TI - Diverse novel astroviruses identified in wild Himalayan marmots. AB - With advances in viral surveillance and next-generation sequencing, highly diverse novel astroviruses (AstVs) and different animal hosts had been discovered in recent years. However, the existence of AstVs in marmots had yet to be shown. Here, we identified two highly divergent strains of AstVs (tentatively named Qinghai Himalayanmarmot AstVs, HHMAstV1 and HHMAstV2), by viral metagenomic analysis in liver tissues isolated from wild Marmota himalayana in China. Overall, 12 of 99 (12.1 %) M. himalayana faecal samples were positive for the presence of genetically diverse AstVs, while only HHMAstV1 and HHMAstV2 were identified in 300 liver samples. The complete genomic sequences of HHMAstV1 and HHMAstV2 were 6681 and 6610 nt in length, respectively, with the typical genomic organization of AstVs. Analysis of the complete ORF 2 sequence showed that these novel AstVs are most closely related to the rabbit AstV, mamastrovirus 23 (with 31.0 and 48.0 % shared amino acid identity, respectively). Phylogenetic analysis of the amino acid sequences of ORF1a, ORF1b and ORF2 indicated that HHMAstV1 and HHMAstV2 form two distinct clusters among the mamastroviruses, and may share a common ancestor with the rabbit-specific mamastrovirus 23. These results suggest that HHMAstV1 and HHMAstV2 are two novel species of the genus Mamastrovirus in the Astroviridae. The remarkable diversity of these novel AstVs will contribute to a greater understanding of the evolution and ecology of AstVs, although additional studies will be needed to understand the clinical significance of these novel AstVs in marmots, as well as in humans. PMID- 28100308 TI - Williamsia spongiae sp. nov., an actinomycete isolated from the marine sponge Amphimedon viridis. AB - A novel actinobacterium, designated isolate B138T, was isolated from the marine sponge, Amphimedon viridis, which was collected from Praia Guaeca (Sao Paulo, Brazil), and its taxonomic position was established using data from a polyphasic study. The organism showed a combination of chemotaxonomic and morphological characteristics consistent with its classification in the genus Williamsia and it formed a distinct phyletic line in the Williamsia 16S rRNA gene tree. It was most closely related to Williamsia serinedens DSM 45037T and Williamsia deligens DSM 44902T (99.0 % 16S rRNA gene sequence similarity) and Williamsia maris DSM 44693T (97.5 % 16S rRNA gene sequence similarity), but was distinguished readily from these strains by the low DNA-DNA relatedness values (62.3-64.4 %) and by the discriminatory phenotypic properties. Based on the data obtained, the isolate B138T (=CBMAI 1094T=DSM 46676T) should be classified as the type strain of a novel species of the genus Williamsia, for which the name Williamsia spongiae sp. nov. is proposed. PMID- 28100309 TI - Nioella sediminis sp. nov., isolated from surface sediment and emended description of the genus Nioella. AB - A bacterial strain, designated JS7-11T, was isolated from the surface sediment of the Jiulong River and characterized using a polyphasic taxonomic approach. Cells of JS7-11T were Gram-staining-negative, non-motile and short-rod-shaped. Growth was observed at 10-40 degrees C (optimum 25-30 degrees C), at pH 6-8 (optimum 7) and in 1-12 % NaCl (optimum 3-4 %, w/v). The results of phylogenetic analysis based on 16S rRNA gene sequences indicated that JS7-11T and Nioella nitratireducens SSW136T formed an independent cluster, sharing 97.9 % similarity between the two strains, and less than 96.0 % similarities with other type strains of members of the family Rhodobacteraceae. The major fatty acids were summed feature 8 and C16 : 0. The quinone was identified as Q-10. The polar lipids comprised phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol and two unidentified phospholipids. The DNA G+C content was 63.4 mol%. The digital DNA-DNA hybridization and average nucleotide identity values between JS7-11T and N. nitratireducens SSW136T were 22.1 and 79.4 %, respectively. The results of phenotypic, phylogenetic and chemotaxonomic analyses clearly indicated that JS7-11T represents a novel species within the genus Nioella, for which the name Nioellasediminis sp. nov. is proposed. The type strain of the novel species is JS7-11T (=MCCC 1A00710T=KCTC 42144T). PMID- 28100305 TI - Environment-directed activation of the Escherichia coliflhDC operon by transposons. AB - The flagellar system in Escherichia coli K12 is expressed under the control of the flhDC-encoded master regulator FlhDC. Transposition of insertion sequence (IS) elements to the upstream flhDC promoter region up-regulates transcription of this operon, resulting in a more rapid motility. Wang and Wood (ISME J 2011;5:1517-1525) provided evidence that insertion of IS5 into upstream activating sites occurs at higher rates in semi-solid agar media in which swarming behaviour is allowed as compared with liquid or solid media where swarming cannot occur. We confirm this conclusion and show that three IS elements, IS1, IS3 and IS5, transpose to multiple upstream sites within a 370 bp region of the flhDC operon control region. Hot spots for IS insertion correlate with positions of stress-induced DNA duplex destabilization (SIDD). We show that IS insertion occurs at maximal rates in 0.24 % agar, with rates decreasing dramatically with increasing or decreasing agar concentrations. In mixed cultures, we show that these mutations preferentially arise from the wild-type parent at frequencies of up to 3*10-3 cell-1 day-1 when the inoculated parental and co-existing IS-activated mutant cells are entering the stationary growth phase. We rigorously show that the apparent increased mutation frequencies cannot be accounted for by increased swimming or by increased growth under the selective conditions used. Thus, our data are consistent with the possibility that appropriate environmental conditions, namely those that permit but hinder flagellar rotation, result in the activation of a mutational pathway that involves IS element insertion upstream of the flhDC operon. PMID- 28100310 TI - Growth inhibition of fungus Phycomyces blakesleeanus by anion channel inhibitors anthracene-9-carboxylic and niflumic acid attained through decrease in cellular respiration and energy metabolites. AB - Increasing resistance of fungal strains to known fungicides has prompted identification of new candidates for fungicides among substances previously used for other purposes. We have tested the effects of known anion channel inhibitors anthracene-9-carboxylic acid (A9C) and niflumic acid (NFA) on growth, energy metabolism and anionic current of mycelium of fungus Phycomyces blakesleeanus. Both inhibitors significantly decreased growth and respiration of mycelium, but complete inhibition was only achieved by 100 and 500 uM NFA for growth and respiration, respectively. A9C had no effect on respiration of human NCI-H460 cell line and very little effect on cucumber root sprout clippings, which nominates this inhibitor for further investigation as a potential new fungicide. Effects of A9C and NFA on respiration of isolated mitochondria of P. blakesleeanus were significantly smaller, which indicates that their inhibitory effect on respiration of mycelium is indirect. NMR spectroscopy showed that both A9C and NFA decrease the levels of ATP and polyphosphates in the mycelium of P. blakesleeanus, but only A9C caused intracellular acidification. Outwardly rectifying, fast inactivating instantaneous anionic current (ORIC) was also reduced to 33+/-5 and 21+/-3 % of its pre-treatment size by A9C and NFA, respectively, but only in the absence of ATP. It can be assumed from our results that the regulation of ORIC is tightly linked to cellular energy metabolism in P. blakesleeanus, and the decrease in ATP and polyphosphate levels could be a direct cause of growth inhibition. PMID- 28100311 TI - Evaluation of three different bottles in BACTEC 9240 automated blood culture system and direct identification of Candida species to shorten the turnaround time of blood culture. AB - PURPOSE: Candida spp. are the most common causes of fungemia. Rapid and accurate diagnostic methods are very important for appropriate management of candidemia. At present, blood culture is the essential diagnostic test despite having a long detection time and low sensitivity rate. We aimed to investigate the ways to shorten the turnaround time from blood culture collection to final identification in candidemia. METHODOLOGY: Sixty clinical bloodstream isolates of Candida were included, and Plus Aerobic/F, Peds Plus/F and Mycosis IC/Fbottles were used with a BACTEC 9240 blood culture instrument. Germ tube production, carbohydrate assimilation (API 20C AUX) and peptide nucleic acid fluorescent in situ hybridization yeast traffic light tests were performed directly from positive signalled bottles. RESULTS: Time to positivity of blood cultures was affected by species of Candida, fungal load and bottle type. Candidatropicalis had the shortest and Candidaglabrata had the longest time to positivity. Mycosis IC/F culture bottle had a significant superiority in the isolation of yeasts, especially for C. glabrata and if there was a low fungal load in the bottle. Direct germ tube test had 90 % sensitivity and 97.6 % specificity for Candidaalbicans in two hours after signalling. The compliance between direct and classical assimilation tests was 98.3 %. Sensitivity and specificity of peptide nucleic acid fluorescent in situ hybridization were 100 %. CONCLUSION: We think that it is possible to shorten the turnaround time for the identification of Candida in blood culture even with currently available methods. PMID- 28100313 TI - Rectinema cohabitans gen. nov., sp. nov., a rod-shaped spirochaete isolated from an anaerobic naphthalene-degrading enrichment culture. AB - The anaerobic, non-motile strain HMT was isolated from the naphthalene-degrading, sulfate-reducing enrichment culture N47. For 20 years, strain HMT has been a stable member of culture N47 although it is neither able to degrade naphthalene nor able to reduce sulfate in pure culture. The highest similarity of the 16S rRNA gene sequence of strain HMT (89 %) is with a cultivated member of the family Spirochaetaceae, Treponema caldariumstrain H1T (=DSM 7334T), an obligately anaerobic, thermophilic spirochaete isolated from cyanobacterial mat samples collected at a freshwater hot spring in Oregon, USA. In contrast to this strain and the majority of spirochaete species described, strain HMT showed a rod-shaped morphology. Growth occurred at temperatures between 12 and 50 degrees C (optimum 37 degrees C) but the isolate was not able to grow at 60 degrees C. The strain fermented various sugars including d-glucose, d-fructose, lactose and sucrose. Addition of 0.1 % (w/v) yeast extract or 0.1 % (w/v) tryptone to the culture medium was essential for growth and could not be replaced by either the vitamin solutions tested or by 0.1 % (w/v) peptone or 0.1 % (w/v) casamino acids. The DNA G+C content of the isolate was 51.5 mol%. The major fatty acids were C14 : 0, C18 : 1omega13c, C16 : 1omega9t, C16 : 1omega11c and C16 : 1omega9c. Based on the unique morphology and the phylogenetic distance from the closest cultivated relative, a novel genus and species, Rectinema cohabitans gen. nov., sp. nov., is proposed. The type strain is strain HMT (=DSM 100378T=JCM 30982T). PMID- 28100312 TI - Frankia coriariae sp. nov., an infective and effective microsymbiont isolated from Coriaria japonica. AB - The taxonomic description of a nitrogen-fixing actinobacterium, strain BMG5.1T, as a novel species within the genus Frankia was based on a polyphasic approach. The strain was isolated from the root nodules of Coriaria japonica, and it fulfilled Koch's postulates by inducing effective nodules on Coriaria spp. and Datisca spp. Based on phenotypic and chemotaxonomic features, strain BMG5.1T is distinguishable from all other species of the genus Frankia. It is characterized by the presence of phosphatidylinositol, diphosphatidylglycerol, phosphatidylglycerol and glycophospholipids in its polar lipids; galactose, glucose, mannose and a trace of ribose as cellular sugars; meso-diaminopimelic acid as cell-wall peptidoglycan; C18 : 1omega9c as major fatty acid (>30 %); and MK-9(H6) (44.7 %) as predominant isoprenolog (>30 %). The 16S rRNA gene sequence similarities and the digital DNA-DNA hybridization values between the described novel strain and strains of the other species of the genus Frankia correspond to a range of 97-98.4 % and 22.1-24 %, respectively. The DNA G+C content is 70.2 mol%. On the basis of these results, strain BMG5.1T (=CECT 9032T=DSM 100624T) is proposed as the type strain of a novel species of the genus Frankia, named Frankia coriariae sp. nov. PMID- 28100314 TI - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for rapid identification of fungal rhinosinusitis pathogens. AB - PURPOSE: Filamentous fungi are among the most important pathogens, causing fungal rhinosinusitis (FRS). Current laboratory diagnosis of FRS pathogens mainly relies on phenotypic identification by culture and microscopic examination, which is time consuming and expertise dependent. Although matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS has been employed to identify various fungi, its efficacy in the identification of FRS fungi is less clear. METHODOLOGY: A total of 153 FRS isolates obtained from patients were analysed at the Clinical Laboratory at the Beijing Tongren Hospital affiliated to the Capital Medical University, between January 2014 and December 2015. They were identified by traditional phenotypic methods and Bruker MALDI-TOF MS (Bruker, Biotyper version 3.1), respectively. Discrepancies between the two methods were further validated by sequencing. RESULTS: Among the 153 isolates, 151 had correct species identification using MALDI-TOF MS (Bruker, Biot 3.1, score >=2.0 or 2.3). MALDI TOF MS enabled identification of some very closely related species that were indistinguishable by conventional phenotypic methods, including 1/10 Aspergillus versicolor, 3/20 Aspergillus flavus, 2/30 Aspergillus fumigatus and 1/20 Aspergillus terreus, which were misidentified by conventional phenotypic methods as Aspergillus nidulans, Aspergillus oryzae, Aspergillus japonicus and Aspergillus nidulans, respectively. In addition, 2/2 Rhizopus oryzae and 1/1 Rhizopus stolonifer that were identified only to the genus level by the phenotypic method were correctly identified by MALDI-TOF MS. CONCLUSION: MALDI TOF MS is a rapid and accurate technique, and could replace the conventional phenotypic method for routine identification of FRS fungi in clinical microbiology laboratories. PMID- 28100315 TI - Flavobacterium arcticum sp. nov., isolated from Arctic seawater. AB - A Gram-reaction-negative, aerobic, non-flagellated, rod-shaped and yellow pigmented bacterium, designated strain SM1502T, was isolated from Arctic seawater. The isolate grew at 10-40 degrees C and with 0-8.0 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the isolate was affiliated with the genus Flavobacterium, with the highest sequence similarity (96.0 %) found with Flavobacterium suzhouense XIN-1T. The major fatty acids of strain SM1502T were iso-C15 : 0, iso-C17 : 1omega9c, iso-C15 : 1 G, C15 : 0, iso-C17 : 0 3-OH and unknown ECL 13.565. The major respiratory quinone of strain SM1502T was menaquinone-6 (MK-6). Polar lipids of strain SM1502T included phosphatidylethanolamine and one unidentified aminolipid and lipid. The genomic DNA G+C content of strain SM1502T was 37.0 mol%. Based on the polyphasic data obtained in this study, strain SM1502T is considered to represent a novel species of the genus Flavobacterium, for which the name Flavobacterium arcticum sp. nov. is proposed. The type strain is SM1502T (=KCTC 42668T=CCTCC AB 2015346T). PMID- 28100316 TI - Optimizing nutrition of the preterm infant. AB - The goal of nutrition of the preterm infant is to meet the growth rate of the healthy fetus of the same gestational age and to produce the same body composition of the healthy fetus in terms of organ growth, tissue components, and cell number and structure. Nutritional quantity and quality are fundamental for normal growth and development of preterm infants, including neurodevelopmental outcomes. Failure to provide the necessary amounts of all of the essential nutrients has produced not only growth failure, but also increased morbidity and less than optimal neurodevelopment. Growth velocities during the NICU hospitalization period for preterm infants exert a significant effect on neurodevelopmental and anthropometric outcomes. Despite the obvious need for optimal nutrition, growth failure is almost universal among preterm infants. There is every reason, therefore, to optimize nutrition of the preterm infant, in terms of total energy and protein, but also in terms of individual components such as amino acids, specific carbohydrates and lipids, and even oxygen. This review presents scientific rationale for nutrient requirements and practical guidelines and approaches to intravenous and enteral feeding for preterm infants. Intravenous feeding, including amino acids, should be started right after birth at rates that are appropriate for the gestational age of the infant. Enteral feeding should be started as soon as possible after birth, using mother's colostrum and milk as first choices. Enteral feeding should begin with trophic amounts and advanced as rapidly as tolerated, decreasing IV nutrition accordingly, while maintaining nutrient intakes at recommended rates. Feeding protocols are valuable for improving nutrition and related outcomes. Further research is needed to determine the optimal nutrition and rate of growth in preterm infants that will achieve optimal neurocognitive benefits while minimizing the longer-term risk of chronic diseases. PMID- 28100317 TI - [Suggestions for diagnosis of primary immunodifficiency disease in infants less than 3 months of age]. PMID- 28100318 TI - [Clinical characteristics of clonal evolution after immunosuppressive therapy in children with severe/very severe aplastic anemia]. AB - OBJECTIVE: To evaluate the clinical characteristics and risk factors of clonal evolution after immunosuppressive therapy (IST) in children with severe/very severe aplastic anemia (SAA/VSAA). METHODS: The clinical data of 231 children with newly-diagnosed SAA/VSAA who received IST were retrospectively studied. The incidence and risk factors of clonal evolution after IST were analyzed. RESULTS: The 5-year overall survival rate of the 231 patients was 82.7%. Except for 18 cases of early deaths, 213 patients were evaluated for IST efficacy. Among the 231 patients, cytogenetic abnormalities for at least two chromosome metaphase were detectable in 14 (7.4%) patients, and PNH clones were detectable in either peripheral red blood cells or neutrophils for 95 patients. Among the 213 patients evaluated for IST efficacy, 15 patients experienced clonal evolution after IST. Five patients had PNH and trisomy 8 which were defined as favorable progressions, and ten patients experienced monosomy 7 and MDS/AML as unfavorable progressions. The 5-year accumulative incidence of favorable and unfavorable progression were (2.2+/-2.2)% and (4.8+/-3.3)%, respectively. Until the last follow-up, 100% (5/5) of patients with favorable progressions and 50% (5/10) of patients with unfavorable progressions survived. WBC>3.5*109/L, CD3+T cell percentage>80%, dosage of antithymocyte globulin >3.0 mg/(kg.d) and no response to IST were related to unfavorable progressions by univariate analysis. Cox multivariate analysis revealed that an increased CD3+T cell percentage (>80%) and no response to IST were independent risk factors for unfavorable progressions. CONCLUSIONS: The children with SAA/VSAA who have an increased CD3+T cell percentage at diagnosis or have no response to IST are in high risks of unfavorable progressions. PMID- 28100319 TI - [Epidemiological analysis of 440 cases of respiratory adenovirus infections in children from the Suzhou area between 2006 and 2015]. AB - OBJECTIVE: To study the epidemiological characteristics of respiratory adenovirus (ADV) infections in children from the Suzhou area, China. METHODS: The clinical data of ADV-positive children out of 35 529 children with respiratory tract infections who were hospitalized in the Children's Hospital of Soochow University between January 2006 and December 2015 were retrospectively studied. RESULTS: Of the 35 529 children with respiratory tract infections, 440 (1.24%) were ADV positive. There was no significant difference in the rate of ADV infections between boys and girls (1.18% vs 1.34%). The ADV infection rates of children at the age of <1 year old, 1-3 years old, 3-7 years old and 7-14 years old were 0.39% (71/18 002), 1.12% (103/9 191), 3.14% (201/6 398), and 3.35%( 65/1 938) respectively and the rate increased with age (P<0.01). The ADV infection rates in spring [1.85%(60/8 658)] and summer [2.20%(189/8 606)] were significantly higher than in autumn [0.30%(27/8 952)] and winter [0.69%(64/9 313)] (P<0.01). CONCLUSIONS: The ADV infection rate is increased with age in the children from the Suzhou area, but it is not associated with gender. ADV infections are more common in spring and summer. PMID- 28100320 TI - [Association of TLR3-1377C/T gene polymorphisms and expression with susceptibility to enterovirus 71 encephalitis in children]. AB - OBJECTIVE: To investigate the association of gene polymorphisms of Toll-like receptor 3 (TLR3)-1377C/T and expression of TLR3 with the susceptibility to enterovirus 71 (EV71) encephalitis in children. METHODS: A total of 187 children with EV71 infection (59 children in the encephalitis group and 128 in the non encephalitis group) and 232 children who underwent physical examination were enrolled in the case-control study. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the TLR3-1377C/T gene polymorphisms. ELISA was used to measure the serum level of TLR3. RESULTS: There were no significant differences in the genotype and allele frequencies of TLR3 1377C/T between the non-encephalitis group and the encephalitis group. Compared with the control group, the encephalitis group and the non-encephalitis group had significant increases in the serum level of TLR3 (P<0.05), and the non encephalitis group had the highest level (P<0.05). The encephalitis group had a significantly higher EV71 viral load than the non-encephalitis group (P<0.01). The children aged <1 year or >=1 year in the encephalitis group and the non encephalitis group had significant increases in the serum level of TLR3 compared with their counterparts in the control group (P<0.05), and the children aged <1 year or >=1 year in the non-encephalitis group had a significantly higher serum level of TLR3 than those in the encephalitis group (P<0.05). In the encephalitis group, the children aged >=1 year had a significantly higher TLR3 concentration than those aged <1 year (P<0.05), and there were no significant differences in the TLR3 concentration between the children aged >=1 year and <1 year in the non encephalitis group and the control group. In the encephalitis group, the proportion of children aged <1 year was significantly higher than those aged >=1 year (P<0.05). CONCLUSIONS: The TLR3-1377C/T gene polymorphisms are not significantly associated with the development of EV71 encephalitis. Low expression of TLR3 might weaken the inhibitory effect on virus replication and promote the development of EV71 encephalitis. The deficiency in the expression of TLR3 in serum after EV71 infection might be an important factor for the development of encephalitis in infants. PMID- 28100321 TI - [Application of esmolol in severe hand, foot, and mouth disease]. AB - OBJECTIVE: To study the clinical effect and mechanism of action of esmolol in the treatment of severe hand, foot, and mouth disease (HFMD). METHODS: A prospective randomized controlled trial was performed. A total of 102 children with severe HFMD were enrolled in the study and were randomly divided into conventional treatment and esmolol treatment groups (n=51 each). The children in the conventional treatment group were given conventional treatment according to the guidelines for the diagnosis and treatment of HFMD. Those in the esmolol treatment group were given esmolol in addition to the conventional treatment. The heart rate (HR), systolic blood pressure (SBP), and respiratory rate (RR) were continuously monitored for all children. Blood samples were collected from all children before treatment and 1, 3, and 5 days after treatment to measure the levels of norepinephrine (NE), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and nuclear factor-kappa B (NF-kappaB) p65 in mononuclear cells. Serum levels of myocardial enzymes and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured before treatment and after 5 days of treatment. RESULTS: There were no significant differences in HR, SBP, RR, NE, TNF-alpha, IL 6, NF-kappaB p65, serum myocardial enzymes, and NT-proBNP before treatment between the conventional treatment and esmolol treatment groups. Both groups had significant reductions in these parameters at each time point (P<0.05). Compared with the conventional treatment group, the esmolol treatment group had significant improvements in the above parameters after 1 and 3 days of treatment (P<0.05). After 5 days of treatment, the esmolol treatment group had significant improvements in serum levels of myocardial enzymes and NT-proBNP compared with the conventional treatment group (P<0.05). CONCLUSIONS: Early application of esmolol can effectively stabilize the vital signs of the children with severe HFMD. Its mechanism of action may be related to reducing serum catecholamine concentration, alleviating myocardial damage, improving cardiac function, and reducing inflammatory response. PMID- 28100322 TI - [Association between risk factors during maternal pregnancy and the neonatal period and childhood bronchial asthma]. AB - OBJECTIVE: To study the association of the risk factors during maternal pregnancy and the neonatal period with childhood bronchial asthma. METHODS: A total of 306 children with asthma (asthma group) and 250 healthy children (control group) were enrolled. Their clinical data during the neonatal period and the maternal data during pregnancy were retrospectively studied. RESULTS: The univariate analysis showed that there were significant differences in the rates of maternal use of antibiotics during pregnancy, use of antibiotics and probiotics during the neonatal period, preterm birth, cesarean section, low birth weight, and breast feeding (>6 months) between the asthma and control groups (P<0.05). The multivariate logistic regression analysis showed that use of antibiotics during pregnancy (OR=3.908, 95%CI: 1.277-11.962), use of antibiotics during neonatal period (OR=24.154, 95%CI: 7.864-74.183), preterm birth (OR=8.535, 95%CI: 2.733 26.652), and cesarean section (OR=4.588, 95%CI: 2.887-7.291) were independent risk factors for childhood asthma. The use of probiotics during the neonatal period (OR=0.014, 95%CI: 0.004-0.046) and breast feeding (>6 months) (OR=0.161, 95%CI: 0.103-0.253) were protective factors for childhood asthma. CONCLUSIONS: The early prevention of childhood asthma can be improved by reducing the use of antibiotics during pregnancy, reducing cesarean section, avoiding abuse of antibiotics during the neonatal period, trying breast feeding and taking probiotics in early stage. PMID- 28100323 TI - [High-risk factors and clinical characteristics of massive pulmonary hemorrhage in infants with extremely low birth weight]. AB - OBJECTIVE: To explore the high-risk factors and analyze the clinical characteristics of massive pulmonary hemorrhage (MPH) in infants with extremely low birth weight (ELBW). METHODS: Two hundred and eleven ELBW infants were included in this study. Thirty-five ELBW infants who were diagnosed with MPH were labelled as the MPH group, and 176 ELBW infants without pulmonary hemorrhage were labelled as the control group. The differences in clinical characteristics, mortality rate, and incidence of complications between the two groups were analysed. The high-risk factors for MPH were identified by multiple logistic regression analysis. RESULTS: The MPH group had significantly lower gestational age, birth weight, and 5-minute Apgar score than the control group (P<0.05). The MPH group had significantly higher rates of neonatal respiratory distress syndrome, patent ductus arteriosus (PDA), early-onset sepsis (EOS), intracranial hemorrhage, pulmonary surfactant utilization, and death compared with the control group (P<0.01). The multiple logistic regression analysis showed that 5-minute Apgar score was a protective factor for MPH (OR=0.666, P<0.05), and that PDA and EOS were risk factors for MPH (OR=3.717, 3.276 respectively; P<0.01). In the infants who were discharged normally, the MPH group had a longer duration of auxiliary ventilation and a higher incidence rate of ventilator-associated pneumonia (VAP) compared with the control group (P<0.05). CONCLUSIONS: A higher 5 minute Apgar score is associated a decreased risk for MPH, and the prensence of PDA or EOS is associated an increased risk for MPH in ELBW infants. ELBW infants with MPH have a prolonged mechanical ventilation, a higher mortality, and higher incidence rates of VAP and intracranial hemorrhage compared with those without pulmonary hemorrhage. PMID- 28100324 TI - [Characteristics of DUOXA2 gene mutation in children with congenital hypothyroidism]. AB - OBJECTIVE: To investigate the characteristics of DUOXA2 gene mutation and the genotype-phenotype relationship in children with congenital hypothyroidism (CH) in Guangzhou, China. METHODS: A total of 20 CH patients with suspected thyroid dyshormonogenesis who had no DUOX2 gene mutation were enrolled. These patients who were born between 2011 and 2012 were screened and diagnosed with CH in the Guangzhou Newborn Screening Center. PCR and direct sequencing were used to analyze DUOXA2 gene mutation. RESULTS: Among the 20 patients, 2 had p.Y246X/p.Y246X homozygous mutation; 4 had monoallelic heterozygous mutation, among whom 2 carried the known pathogenic mutation c.413-414insA, 1 carried p.Y246X, and 1 carried a novel mutation, p.G79R. Reevaluation was performed at the age of 2-3 years, and the results showed that the two patients with p.Y246X/p.Y246X homozygous mutation were manifested as transient and mild permanent CH, respectively. Among the four patients with monoallelic heterozygous mutation, the one who carried p.Y246X mutation was manifested as typical permanent CH, and the other three were manifested as transient CH. CONCLUSIONS: DUOXA2 gene mutation is a common molecular pathogenic basis for CH children with suspected thyroid dyshormonogenesis in Guangzhou, and most of them are manifested as transient CH. There is no association between DUOXA2 genotypes and phenotypes. The novel mutation p.G79R is probably a pathogenic mutation. PMID- 28100325 TI - [An investigation of dietary nutrition in kindergartens of Chongqing, China]. AB - OBJECTIVE: To investigate the status of dietary nutrition in kindergartens of Chongqing, China. METHODS: A total of 295 kindergartens (47 first-class ones, 88 second-class ones, and 160 third-class ones) from the 11 districts or counties of Chongqing by stratified cluster random sampling were investigated. The dietary nutrition in each kindergarten was evaluated by weighing. The dietary qualification rates were compared between the three classes of kindergartens. RESULTS: The qualification rates of energy, proteins, most vitamins, minerals, and quality proteins supply were over 60% in all three classes of kindergartens, while the qualification rates of vitamin A, ascorbic acid, calcium, and zinc supply were less than 60%. The energy supply rates at breakfast, lunch, supper and snack met the standards in less than 40% in all kindergartens. There were significant differences in the qualification rates of some nutrient parameters between different classes of kindergartens, highest in the first-class kindergartens. CONCLUSIONS: The dietary nutrition is good in the first-, second-, and third-class kindergartens of Chongqing, but there is still nutrient imbalance. It is necessary to strengthen the dietary guidance in kindergartens, especially second-, and third-class kindergartens. PMID- 28100326 TI - [Feeding difficulty and developmental delay for 8 months and nystagmus for 4 months in an infant]. AB - Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive hereditary disease and is a congenital metabolic disorder of neurotransmitter biosynthesis. It is mainly manifested as hypotonia, oculogyric crisis, autonomic dysfunction, and developmental delay. This article reports a boy manifested as delayed motor development, hypotonia, and oculogyric crisis. Gene screening for metabolic disorders revealed new compound heterozygous mutations, c.1063dupA (p.I355fs) and c.250A>C (p.S84R), in the exon of DDC gene. The boy had a significant increase in 3-O-methyldopa as measured by dried blood spot. Therefore, he was diagnosed with AADC deficiency. After treatment with the dopamine receptor agonist pramipexole dihydrochloride, the catechol-O methyltransferase inhibitor entacapone, and vitamin B6, the boy showed mild improvements in hypotonia, blepharoptosis, and oculogyric crisis. Clinical physicians should enhance their ability for identifying AADC deficiency, so as to facilitate early diagnosis and treatment of this disorder. Genetic counseling for birth health and prenatal diagnosis should be performed for parents in need. PMID- 28100327 TI - [Intermittent convulsions for 1.5 years and psychomotor retardation in a girl]. AB - The study reports a girl with pyridoxine-dependent epilepsy. The girl was admitted at the age of 2 years because of intermittent convulsions for 1.5 years and psychomotor retardation. She had a history of "hypoxia" in the neonatal period. At the age of 5 months recurrent epileptic seizures occurred. The child was resistant to antiepileptic drugs, and had many more seizures when she got cold or fever. She also had a lot of convulsive status epilepticus. No discharges were found during several video-EEG monitorings. Cerebral MRI examinations showed normal results. So Dravet syndrome was clinically suspected. ALDH7N1 gene mutation analysis revealed two heterozygote mutations, and pyridoxine-dependent epilepsy was thus confirmed. Seizures were generally controlled after pyridoxine supplementation. PMID- 28100328 TI - [Repeated yellowing of the skin and sclera for 2 years]. AB - A two-year-old girl was admitted due to repeated yellowing of the skin and sclera for 2 years and had no other specific symptoms or signs. The use of phenobarbital could relieve the symptoms of jaundice. Multiple examinations showed increased indirect bilirubin levels, and the results of aminotransferases and liver imaging were normal. There was no evidence of hemolysis. The analysis of UGT1A1 gene in her family found that this child had double homozygous mutation of c.211G>A(G71R) and c.1456T>G(Y486D), which had been reported as the pathogenic mutation for Gilbert syndrome. Her parents carried double heterozygous mutation of G71R and Y486D and had no symptom of jaundice. The child was diagnosed as having Gilbert syndrome. It is concluded that as for patients with unconjugated hyperbilirubinemia which cannot be explained by liver damage and hemolysis, their family history should be investigated in detail and gene analysis should be performed as early as possible, in order to identify congenital bilirubin metabolic disorders. PMID- 28100329 TI - [Protective effect of histone acetylation against cortical injury in neonatal rats]. AB - OBJECTIVE: To investigate the protective effect of histone acetylation against hypoxic-ischemic cortical injury in neonatal rats. METHODS: A total of 90 neonatal rats aged 3 days were divided into three groups: sham-operation, cortical injury model, and sodium butyrate (a histone deacetylase inhibitor) treatment. The rats in the model and the sodium butyrate treatment groups were intraperitoneally injected with lipopolysaccharide (0.05 mg/kg), and then right common carotid artery ligation was performed 2 hours later and the rats were put in a hypoxic chamber (oxygen concentration 6.5%) for 90 minutes. The rats in the sham-operation group were intraperitoneally injected with normal saline and the right common carotid artery was only separated and exposed without ligation or hypoxic treatment. The rats in the sodium butyrate treatment group were intraperitoneally injected with sodium butyrate (300 mg/kg) immediately after establishment of the cortical injury model once a day for 7 days. Those in the sham-operation and the model groups were injected with the same volume of normal saline. At 7 days after establishment of the model, Western blot was used to measure the protein expression of histone H3 (HH3), acetylated histone H3 (AH3), B-cell lymphoma/leukemia-2 (Bcl-2), Bcl-2-associated X protein (BAX), cleaved caspase-3 (CC3), and brain-derived neurotrophic factor (BDNF). Immunofluorescence assay was used to measure the expression of 5-bromo-2'-deoxyuridine (BrdU) as the cortex cell proliferation index. RESULTS: The sodium butyrate treatment group had a significantly lower HH3/AH3 ratio than the model group (P<0.05), which suggested that the sodium butyrate treatment group had increased acetylation of HH3. Compared with the model group, the sodium butyrate treatment group had a significant increase in Bcl-2/Bax ratio, a significant reduction in CC3 expression, and a significant increase in BDNF expression (P<0.05). The sodium butyrate treatment group had a significant increase in the number of BrdU positive cells in the cortex compared with the model group (P<0.05), and BrdU was mainly expressed in the neurons. CONCLUSIONS: Increased histone acetylation may protect neonatal rats against cortical injury by reducing apoptosis and promoting regeneration of neurons. The mechanism may be associated with increased expression of BDNF. PMID- 28100330 TI - [Protective effects of heat shock protein 70 against hypoxic pulmonary hypertension in neonatal rats]. AB - OBJECTIVE: To investigate the protective effect of heat shock protein 70 (HSP70) against hypoxic pulmonary hypertension (HPH) in neonatal rats. METHODS: A total of 128 neonatal rats were randomly divided into blank control group, HPH model group, empty virus group, and HSP70 group, with 32 rats in each group. Before the establishment of an HPH model, the rats in the blank control group and HPH model group were given caudal vein injection of 5 MUL sterile saline, those in the empty virus group were given caudal vein injection of 5 MUL Ad-GFP (1 010 PFU/mL), and those in the HSP70 group were given caudal vein injection of 5 MUL Ad-HSP70 (1 010 PFU/mL). HPH model was prepared in the HPH model, empty virus, and HSP70 groups after transfection. At 3, 7, 10, and 14 days after model establishment, a multi-channel physiological recorder was used to record mean pulmonary arterial pressure (mPAP), optical and electron microscopes were used to observe the structure and remodeling parameters of pulmonary vessels, and Western blot was used to measure the protein expression of HSP70, hypoxia-inducible factor-1alpha (HIF-1alpha), endothelin-1 (ET-1), and inducible nitric oxide synthase (iNOS) in lung tissues. RESULTS: At 3, 7, 10, and 14 days after model establishment, the HPH model group and the empty virus group had a significantly higher mPAP than the blank control group (P<0.05). On days 7 and 10 of hypoxia, the blank control group and the HSP70 group had significantly lower MA% and MT% than the HPH model group and the empty virus group (P<0.01); on day 14 of hypoxia, the HPH model group, empty virus group, and HSP70 group had similar MA% and MT% (P>0.05), but had significantly higher MA% and MT% than the blank control group (P<0.01). On days 3, 7 and 10 of hypoxia, the HSP70 group had significantly higher protein expression of HSP70 than the HPH model group, empty virus group, and blank control group (P<0.01); the HSP70 group had significantly lower expression of HIF-1alpha, ET-1, and iNOS than the HPH model group and the empty virus group (P<0.05) and similar expression of HIF-1alpha, ET-1, and iNOS as the blank control group (P>0.05). CONCLUSIONS: In neonatal rats with HPH, HSP70 transfection can increase the expression of HSP70 in lung tissues, downregulate the expression of HIF-1alpha, ET-1, and iNOS, alleviate pulmonary vascular remodeling, and reduce pulmonary artery pressure; therefore, it may become a new strategy for the treatment of HPH in neonates. PMID- 28100331 TI - [HMGB1/TLR4/NF-kappaB signaling pathway and role of vitamin D in asthmatic mice]. AB - OBJECTIVE: To investigate the changes in the mRNA and protein expression of high mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4), and nuclear factor kappa B (NF-kappaB) in lung tissues of asthmatic mice and the interventional effect of vitamin D. METHODS: A total of 48 BALB/c mice were randomly divided into control group, asthma group, and 1,25-(OH)2D3 intervention group, with 16 mice in each group. An animal model of asthma was established, and lung tissue samples were taken in each group at weeks 1 and 2 of ovalbumin challenging. Conventional hematoxylin-eosin staining was used to measure airway wall thickness. Immunohistochemical staining was used to observe the expression of HMGB1, TLR4, and NF-kappaB in lung tissues. Quantitative real-time PCR and Western blot were used to investigate the changes in the mRNA and protein expression of HMGB1, TLR4, and NF-kappaB. RESULTS: At weeks 1 and 2 of ovalbumin challenging, compared with the control group, the asthma group had a significant increase in airway wall thickness and the intervention group had a significant reduction compared with the asthma group (P<0.05). The asthma group had significantly higher mRNA expression of HMGB1, TLR4, and NF-kappaB in lung tissues than the control group, and the intervention group had significantly lower mRNA expression of TLR4 and NF-kappaB than the asthma group (P<0.05). At week 1 of ovalbumin challenging, there was no significant difference in the mRNA expression of HMGB1 between the intervention group and the asthma group (P>0.05). At week 2, the intervention group had a significant reduction in the mRNA expression of HMGB1 compared with the asthma group (P<0.05). At weeks 1 and 2 of ovalbumin challenging, the asthma group had significantly higher protein expression of HMGB1, TLR4, and NF-kappaB in lung tissues than the control group, and the intervention group had significantly lower expression than the asthma group (P<0.05). Airway wall thickness was positively correlated with the mRNA expression of HMGB1, TLR4, and NF-kappaB in lung tissues (r=0.804, 0.895, and 0.834; P<0.05). CONCLUSIONS: The HMGB1/TLR4/NF-kappaB signaling pathway plays an important role in the pathogenesis of asthma, and an appropriate amount of 1,25 (OH)2D3 has a regulatory effect on this pathway and may prevent the progression of asthma. Therefore, 1,25-(OH)2D3 is expected to become a new choice for the treatment of asthma. PMID- 28100332 TI - [Expression and significance of mTOR/4EBP1/HIF-1alpha/VEGF signaling pathway in lung tissues of asthmatic mice]. AB - OBJECTIVE: To study the expression and significance of the mammalian target of rapamycin (mTOR)/eukaryote initiating factor 4E binding protein 1(4EBP1)/hypoxia inducible factor-1alpha (HIF-1alpha)/vascular endothelial growth factor (VEGF) signaling pathway in asthmatic mice. METHODS: Forty SPF level 6-8 week-old female Balb/C mice were randomly divided into control, asthma, budesonide and mTOR inhibitor (rapamycin) intervention groups (n=10 each). The asthmatic mouse model was prepared via OVA induction and challenge test. The intervention groups were administered with rapamycin at the dosage of 3 mg/kg by an intraperitoneal injection or budesonide suspension at the dosage of l mg by aerosol inhalation respectively 30 minutes before the OVA challenge. The control and asthma groups were treated with normal saline instead. The concentrations of HIF-1alpha and VEGF in bronchoalveolar lavage fluid (BALF) were examined using ELISA 24 hours after the last challenge. The pathological changes of lung tissue were observed by hematoxylin-eosin (HE) staining. The p-mTOR and p-4EBP1 from the lung tissues were detected by immunohistochemistry and Western blot. Pearson analysis was used to study the correlation between p-mTOR, p-4EBP1, HIF-1alpha, and VEGF expression. RESULTS: Compared with the control group, inflammatory cell infiltration and secretions in the trachea increased in the asthma group. The levels of HIF-1alpha and VEGF in BALF and p-mTOR and p-4EBP1 expression in lung tissues also increased (P<0.01). Compared with the asthma group, inflammatory cell infiltration and secretions in the trachea were reduced in the two intervention groups, and the levels of HIF-1alpha and VEGF in BALF and p-mTOR and p-4EBP1 expression in lung tissues were also reduced (P<0.01). There were no significant differences in the above changes between the two intervention groups and control group (P>0.05). In the asthma group, there was a pairwise positive correlation between lung p-mTOR and p-4EBP1 expression and HIF-1alpha and VEGF levels in BALF (P<0.05). However, there were no correlations in the above indexes in the intervention groups and control group. CONCLUSIONS: p-mTOR, p-4EBP1, HIF 1alpha and VEGF together are involved in the pathogenesis of asthma. Rapamycin treatment can block this signaling pathway, suggesting that this pathway can be used as a novel target for asthma treatment. PMID- 28100333 TI - [Streptococcus pneumoniae induces SPLUNC1 and the regulatory effects of resveratrol]. AB - OBJECTIVE: To investigate the host-defense role of short palate, lung, and nasal epithelium clone 1 (SPLUNC1) in Streptococcus pneumoniae (SP) infection and the effect of resveratrol (Res) on SPLUNC1 expression, and to provide new thoughts for the treatment of diseases caused by SP infection. METHODS: According to the multiplicity of infection (MOI), BEAS-2B cells with SP infection were divided into control group, MOI20 SP group, and MOI50 SP group. According to the different concentrations of Res, the BEAS-2B cells with MOI20 SP infection pretreated by Res were divided into 12.5Res+SP group, 25Res+SP group, and 50Res+SP group (the final concentrations of Res were 12.5, 25, and 50 MUmol/L, respectively). Cell Counting Kit-8 was used to measure cell activity and determine the optimal concentration and action time of SP and Res. In the formal experiment, the cells were divided into control group, Res group, SP group, and Res+SP group. Real-time PCR and ELISA were used to measure the mRNA and protein expression of SPLUNC1. RESULTS: Over the time of SP infection, cell activity tended to decrease. Compared with the control group and the MOI20 SP group, the MOI50 SP group had a reduction in cell activity. Compared with the MOI20 SP group, the 25Res+SP group had increased cell activity and the 50Res+SP group had reduced cell activity (P<0.05). MOI20 SP bacterial suspension and 25 MUmol/L Res were used for the formal experiment. Over the time of SP infection, the mRNA expression of SPLUNC1 in BEAS-2B cells firstly increased and then decreased in the SP group and the Res+SP group (P<0.05). Compared with the SP group, the Res+SP group had significant increases in the mRNA and protein expression of SPLUNC1 at all time points (P<0.05). Compared with the control group, the Res group had no significant changes in the mRNA and protein expression of SPLUNC1 (P>0.05). CONCLUSIONS: SP infection can induce SPLUNC1 expression and the host defense role of SPLUNC1. Res can upregulate SPLUNC1 expression during the development of infection and enhance cell protection in a concentration- and time dependent manner. PMID- 28100334 TI - [A case report of childhood primary hemophagocytic syndrome]. PMID- 28100335 TI - [Methods for establishing animal model of bronchopulmonary dysplasia and their evaluation]. AB - With the development of treatment, the survival rate of premature infants has significantly increased, especially extremely premature infants and very low birth weight infants. This has led to an increase in incidence of bronchopulmonary dysplasia (BPD) year by year. BPD has been one of the most common respiratory system diseases in premature infants, especially the small premature infants. Arrested alveolar development is an important cause of BPD. Therefore, the mechanism of arrested alveolar development and the intervention measures for promoting alveolar development are the focuses of research on BPD. Selecting the appropriate animal model of BPD is the key to obtaining meaningful results in the basic research on BPD. Based on above, several common methods for establishing an animal model of BPD and the corresponding changes in pathophysiology are summarized and evaluated in order to provide a reference for selecting the appropriate animal model in studies on the pathogenesis, pathophysiology, and prevention and control strategies of BPD. PMID- 28100336 TI - [Research advances in circadian rhythm of epileptic seizures]. AB - The time phase of epileptic seizures has attracted more and more attention. Epileptic seizures have their own circadian rhythm. The same type of epilepsy has different seizure frequencies in different time periods and states (such as sleeping/awakening state and natural day/night cycle). The circadian rhythm of epileptic seizures has complex molecular and endocrine mechanisms, and currently there are several hypotheses. Clarification of the circadian rhythm of epileptic seizures and prevention and administration according to such circadian rhythm can effectively control seizures and reduce the adverse effects of drugs. The research on the circadian rhythm of epileptic seizures provides a new idea for the treatment of epilepsy. PMID- 28100337 TI - [The new long march on the healthy Chinese dream]. PMID- 28100338 TI - [Clinical considerations of statin therapy for hypertensive patients]. PMID- 28100339 TI - [Expert recommendation on the clinical application of optical coherence tomography in percutaneous coronary intervention for patients with coronary artery disease]. PMID- 28100340 TI - [Outcome comparison of different therapy procedures in surgical high-risk elderly patients with severe aortic stenosis]. AB - Objective: To compare the outcome of surgical high-risk elderly patients with severe aortic stenosis(SAS) treated by different therapy procedures, including transcatheter aortic valve implantation(TAVI), surgical aortic valve replacement(SAVR), and drug therapy. Methods: We retrospectively analyzed the clinical data of 242 surgical high-risk elderly (age >=65 years old) SAS patients hospitalized in Fuwai Hospital between September 2012 and June 2015. According to the treatment method, patients were divided into TAVI group (81 cases), SAVR group (59 cases) and drug therapy group (102 cases). The primary end point was all-cause mortality at 1 year post procedure, and secondary end point included cardiac function class(NYHA), vascular complication, valvular function, non-fatal myocardial infarction, new atrial fibrillation, stroke, bleeding, pacemaker implantation, acute renal failure, and readmission. We used the Kaplan-Meier method to estimate survival function based on follow up data and survival was compared between groups with the use of the log-rank test. Results: (1) In the baseline data, there were statistically significant difference among 3 groups for the age, left ventricular ejection fraction, cardiac function class III and IV, rates of combined diabetes, chronic renal failure, mild and moderate mitral regurgitation (P<0.01 or 0.05). The risk score of the Society of Thoracic Surgeons(STS) was 7.28+/-4.98 in the TAVI group, and 5.67+/-3.49 in the SAVR group(P=0.036). (2) The perioperative rates of pacemaker implantation(11.3%(9/81) vs. 0, P=0.025) and mild paravalvular regurgitation(29.6%(24/81) vs.1.7%(1/59), P<0.001) were significantly higher in TAVI group than in SAVR group.(3)The rate of rehospitalization was significantly lower in TAVI group than in SAVR group(3.0%(2/67) vs. 22.7%(10/44) P=0.005) and the rate of pacemaker implantation was significantly higher in TAVI group than in SAVR group(17.5 (12/67) vs. 0, P=0.008) after 1 year. The rates of death from any cause in the TAVI (5.8%(4/67)) and SAVR group (11.4%(5/44)) were significantly lower than that in the drug therapy group (54.9%(50/91), both P<0.05) after 1 year and was similar between TAVI group and SAVR group(P=0.622). (4) The rates of cardiac function classIandII increased and III and IV decreased in TAVI and SAVR group after 1 year when compared with base line(P<0.001). The rates of cardiac function class II, and III increased , class I and IV decreased in drug therapy group after 1 year compared with base line (P=0.020). (5)The survival rates after 1 year were significantly higher in the TAVI group and SAVR group than in the drug therapy group(log-rank test, P<0.001), and the difference was similar between TAVI group and SAVR group (log-rank test, P=0.062). Conclusion: In surgical high-risk elderly patients with SAS, the prognosis of drug therapy was poor, and TAVI and SAVR were associated with similarly improved rates of survival after 1 year, although there were significant differences in periprocedural complications between TAVI and SAVR groups. PMID- 28100342 TI - [The effect on myocardial perfusion and clinical outcome of intracoronary nicorandil injection prior to percutaneous coronary intervention in ST-segment elevation myocardial infarction]. AB - Objective: To investigate the effect of intracoronary administration of nicorandil prior to primary percutaneous coronary intervention (PPCI) on myocardial perfusion and short-term clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI). Methods: A total of 158 patients with STEMI undergoing PPCI from January 2014 to December 2015 in Fuzhou General Hospital were enrolled consecutively in this prospective controlled randomized trial. Patients were assigned into three groups with random number table: the nicorandil group (patients received intracoronary administration of 6 mg nicorandil after guide wire or balloon successfully crossed the target lesion, n=53), the nitroglycerin group (patients received intracoronary administration of 300 MUg nitroglycerin after after guide wire or balloon successfully crossed the target lesion, n=52) and the control group(patients received routine treatment, n=53). The primary outcomes were myocardial perfusion, including the levels of corrected TIMI frame count (cTFC), and the incidence of no reflow or slow flow after PPCI. The secondary outcomes included the incidence of major adverse cardiovascular events (MACE) during hospitalization (all-cause death, reperfusion arrhythmia within 2 hours after PPCI, angina within 24 hours after PPCI, new heart failure or worsening cardiac function, and repeat revascularization) and within 3 months of follow-up (all-cause death, nonfatal myocardial infarction, repeat revascularization, post-infarction angina, and re-hospitalization for congestive heart failure). Results: The age of enrolled patients was (62.9+/ 11.3) years old, and 130 cases (82.3%) of them were male. The median time of symptom-onset to balloon was 4.50 (3.20, 6.43) hours. There were significantly difference in cTFC immediately after PPCI((21.68+/-7.43)frames, (24.74+/ 8.66)frames, and(27.06+/-10.40)frames), incidence of no reflow or slow flow after PPCI(5.7%(3/53), 13.5%(7/52), and 22.6%(12/53)), ST-segment resolution at 2 hours after procedure(90.6%(48/53), 84.6%(44/52), and 74.5%(38/53)), and reperfusion arrhythmia at 2 hours after procedure(15.1%(8/53), 36.6%(19/52), and 34.0%(18/53)) among the 3 groups(P<0.01 or 0.05). In the multivariate logistic regression models, intracoronary administration of nicorandil could lower the cTFC level (OR=0.17, 95%CI 0.10-0.41, P=0.001), acted as a protecting factor on lowering the incidence of no reflow or slow flow (OR=0.13, 95%CI 0.02-0.96, P=0.045) and reperfusion arrhythmia (OR=0.26, 95%CI 0.09-0.74, P=0.012), as well as facilitating the ST-segment resolution at 2 hours after procedure (OR=4.62, 95%CI 1.14-18.82, P=0.033). However, observed parameters were similar between intracoronary administration of nitroglycerin group compared with control group (all P>0.05). MACE within 3 months of follow-up were similar among the 3 groups(all P>0.05). Conclusion: Intracoronary administration of nicorandil prior to balloon dilation can significantly improve the myocardial perfusion and reduce the occurrence of reperfusion arrhythmia during PPCI for STEMI, but does not affect the short-term prognosis in STEMI patients. PMID- 28100341 TI - [Comparison on the long-term outcomes post percutaneous coronary intervention or coronary artery bypass grafting for bifurcation lesions in unprotected left main coronary artery]. AB - Objective: To compare the long-term clinical outcomes of consecutive patients treated with coronary artery bypass grafting (CABG) or percutaneous coronary intervention(PCI) with drug-eluting stents (DES) for bifurcation lesions in unprotected left main coronary artery (ULMCA). Methods: A total of 663 consecutively patients with unprotected left main bifurcation disease (defined as stenosis>=50%) who received either drug-eluting stents (DES) implantation (n=316) or underwent CABG (n=347) between January 2003 and July 2009 in Beijing Anzhen Hospital were enrolled retrospectively in this study.The endpoints of the study were death, repeat revascularization, myocardial infarction (MI), stroke, the composite of cardiac death, MI or stroke and MACCE (major adverse cardiac and cerebrovascular events, the composite of cardiac death, MI, stroke or repeat revascularization). To reduce the bias between two compared groups , our study applid propensity score matching by logistic regression.Cumulative survival rate was calculated by Kaplan-Meier method.Multiple regression analyses, hazard ratio(HR) and 95%CI were tested by Cox proportional hazard models with the CABG group as the reference category. Results: The median follow-up was 7.2 years (interquartile range 5.1 to 8.3 years) in the overall patients.Unadjusted analysis showed that MACCE rate (PCI 44.5% vs. CABG 45.7%, P=0.036), the rate of repeat revascularization (PCI 33.7% vs. CABG 19.5%, P<0.001), the composite rate of serious outcomes (cardiac death, MI or stroke) (PCI 20.4% vs. CABG 34.3%, P=0.032), stroke rate (PCI 3.7% vs. CABG 23.5%, P<0.001) were significantly different for patients undergoing PCI or CABG. Death rate (PCI 13.0% vs. CABG 18.9%, P=0.12) and MI rate (PCI 11.3% vs. CABG 6.1%, P=0.108) were similar between PCI and CABG group.After adjusting covariates with multivariate Cox hazard regression model, there was no significant difference in rates of death (P=0.286), MI(P=0.165) and the composite rate of serious outcomes (cardiac death, MI or stroke) (P=0.305) between the two groups. Patients in PCI group suffered significant higher rates of MACCE(P=0.011), mainly driven by the significant higher rates of repeat revascularization(HR=2.46, 95%CI 1.662-3.642, P<0.001). However, stroke rate was still significantly higher in CABG group than in PCI group(P=0.001)after multivariate adjusting. After propensity score matching (PSM), there was no more significant difference for all covariates in the matched cohorts (202 pairs). Further PSM analysis showed that overall findings were consistent with multivariate Cox hazard regression model except for MI (PCI 12.7% vs. CABG 3.8%, P=0.039). Conclusions: During a follow-up up to 8.3 years, the survival rate is similar between the PCI and the CABG group in patients with unprotected left main bifurcation disease.The rate of repeat revascularization is significantly higher whereas stroke rate is significantly lower in the PCI group compared to CABG group.After propensity score matching, PCI group not only had a significant higher rate of repeat revascularization, but also had significantly higher risk of MI in the matched cohorts; while they did not seem to translate into any disparity of mortality in ULMCA bifurcation disease patients.Accordingly, PCI for ULMCA disease can be used as a reasonable treatment option alternative to CABG. PMID- 28100343 TI - [Effect of stenting for the proximal atherosclerotic extracranial vertebral artery stenosis]. AB - Objective: To evaluate the effect of stenting for proximal atherosclerotic extracranial vertebral artery stenosis. Methods: A total of 204 proximal atherosclerotic extracranial vertebral artery stenosis patients underwent stent implantation at Fuwai Hospital were enrolled consecutively between August 2007 and June 2014 prospectively. Medical records were collected and the clinical results were obtained through outpatient and telephone follow up. Results: (1) The patients were (64.1+/-7.9) years old, and 179 were male (87.7%). (2) Stent implantation was performed on 210 proximal atherosclerotic extracranial vertebral artery stenosis lesions with 210 stents (156 on the left, 54 on the right), and 6 patients received both sides stent implantations. Technical success rate was 100%(210/210). The stenosis of the lesions was decreased from (85.1+/-6.4) % to (6.5+/-3.2) % after the stent implantation (P<0.01). (3) Three (1.5%) patients experienced transient ischemic attack during the procedure, and two (1.0%) patients suffered from minor posterior circulation ischemic strokes on the 2nd and 10th day after the procedure, respectively. (4)The median follow-up was 1.5 (0.8-2.5) years. Three(1.5%) patients died (two non-vacular deaths, and the other one due to sudden cardiac death). Three (1.5%) patients developed stroke (one case ipsilateral posterior circulation stroke, and two cases unrelated area stroke). Four (2.0%) patients experienced transient ischemic attack. One patient suffered nonfatal myocardial infraction. In-stent restenosis occurred in thirty nine (19.4%) patients, of which fourteen (35.9%) patients were totally occluded and four (10.3%) patients with symptomatic restenosis. Kaplan-Meier survival curve showed that the primary patency rate of the vertebral artery were 85.6%, 78.6%, 72.2% and 64.4% at 1, 2, 3 and 5 years, respectively. Conclusions: Stenting for proximal atherosclerotic extracranial vertebral artery stenosis is safe and feasible, with a good middle to long-term patency rate. However, further trials are required to validate the effective results found in this patients cohort. PMID- 28100344 TI - [Recurrent syncope related to catecholaminergic polymorphic ventricular tachycardia due to de novo RyR2-R2401H mutation]. AB - Objective: To explore the clinical and molecular genetic features of a Chinese patient with catecholaminergic polymorphic ventricular tachycardia (CPVT). Methods: Clinical data including resting electrocardiography, echocardiography and treadmill exercise testing of a patient with CPVT admitted to our department in March 2013 were analyzed, and the peripheral venous blood samples of the patient and his family members and 400 ethnicity-matched healthy controls were obtained. All exons and exon-intron boundaries of the six CPVT-related genes including RYR2, CASQ2, TRDN, CALM1, KCNJ2 and ANKB were sequenced to detect the variants related to CPVT. The relationship between the genotypes and phenotypes was analyzed to direct the target therapy. Results: Recurrent syncope induced either by exercise or extreme frightened fear was observed in this patient. There was no positive family history of syncope or sudden death. The resting electrocardiography and echocardiography of the patient were normal, while the exercise testing revealed bidirectional and polymorphic ventricular tachycardia. A cardiac ryanodine receptor gene mutation (R2401H) was identified in this patient, while this mutation was absent in his parents and sister and 400 controls. No variant was detected in the remaining five candidate genes. Treatment with high dose of metoprolol succinate (118.75 mg/d) was effective and patient was free of syncopal attack during the 2 years follow-up. Conclusion: This is the first report on RyR2-R2401H mutation in Chinese patient with CPVT, and high dose of metoptolol is the effective therapy option for CPVT related to RyR2 mutation. PMID- 28100345 TI - [Anti-beta(2)GPIantibodies accelerate the formation of atherosclerosis in high fat diet fed ApoE deficient mice]. AB - Objective: To investigate the effects of anti-beta(2) glycoprotein I(beta(2)GPI) antibody on atherosclerosis in ApoE deficient mice. Methods: A total of 24 male ApoE deficient mice of specific pathogen free level(six to eight-week old)were divided into normal control group, high fat diet group, high fat diet with anti beta(2)GPI group, high fat diet with homologous control antibody group (n=6 each group). During the feeding period, mice were weighed every 2 weeks and were intraperitoneally injected with anti-beta(2)GPIIgG (100 MUg/per) and homologous control IgG (100 MUg/per) according to grouping once a week. At the 16th week, the carotid arterial lipid deposition was observed by small animal magnetic resonance imaging, and blood samples were collected from internal vein of eyeball and the concentrations of TC, TG, HDL-C and LDL-C in plasma were measured after EDTA anticoagulant treatment. AI was calculated. The mice were then sacrificed and carotid arteries were removed, hematoxylin-eosin staining was used to observe the atherosclerotic lesions near the bifurcation of carotid artery and to calculate lesion size. Results: (1) The body weight of mice was significantly higher in the high fat diet group compared to other 3 groups(all P<0.05), which was similar among high fat diet+ anti-beta(2)GPIantibody group, high fat diet+ homologous control IgG group and normal diet control group (P>0.05). (2) After 16 weeks, plasma concentrations of TC and LDL-C in high fat diet group, high fat diet+ anti-beta(2)GPIantibody group and high fat diet+ homologous control IgG group were significantly higher than in normal diet group (all P<0.05), there was no significant difference among high fat diet groups. The level of HDL-C was significantly higher in high fat diet control group than in normal diet control group. The concentration of TG was similar among groups. However, the value of AI in high fat+ anti-beta(2)GPI antibody group was significantly higher than in other groups (all P<0.05). (3) After 16 weeks, magnetic resonance imaging revealed that mice in high fat diet+ anti-beta(2)GPI antibody group had more obviously lipid deposition in the carotid arteries, it was significantly higher than that in the other groups, and the cross sections of carotid arteries stained with HE also demonstrated obviously carotid lumen stenosis and the percentage of carotid plaque area to carotid artery was (37.545+/-1.351)% in the high fat diet+ anti-beta(2)GPI antibody group, it was significantly higher than normal diet group ((1.235+/-0.460)%), high fat diet control group((11.635+/-2.751)%) and high fat diet+ homologous control IgG group ((11.815+/-2.623)%), all P<0.01. In high fat diet+ anti-beta(2)GPI antibody group, the area of carotid plaque was (3.121+/ 0.124)*10(4) MUm(2,) it was also significantly higher than normal diet group ((0.094+/-0.015)*10(4) MUm(2)), high fat diet control group ((1.309+/ 0.147)*10(4) MUm(2)) and high fat diet+ homologous control IgG group ((1.027+/ 0.228)*10(4)MUm(2)), all P<0.01. Conclusion: Anti-beta(2)GPI antibody can promote atherosclerotic plaque formation in high fat diet fed ApoE deficient mice. PMID- 28100346 TI - [Impact of CD137-CD137L signaling mediated exocytosis of autophagosome within vascular smooth muscle cells on the formation of atherosclerotic calcification]. AB - Objective: To explore whether CD137-CD137L signaling mediated exocytosis of autophagosome within vascular smooth muscle cells (VSMCs) could influence the formation of atherosclerotic calcification. Methods: Fifteen 8-week-old male ApoE(-/-)(C57BL/6J-KO) mice fed with high fat diet for 5 weeks were randomly divided into three groups by using stochastic indicator method as follows: control group, n=5; agonist-CD137 group: agonist-CD137 antibody 200 MUg/2 weeks for 4 weeks, ip, n=5; anti-CD137 group: 200 MUg anti-CD137 antibody+ 200 MUg agonist-CD137 antibody/2 weeks for 4 weeks, ip, n=5. Von Kossa staining was applied to observe the calcification of the thoracic aortic atherosclerotic plaque in each group. Immunohistochemistry was used to detect the expression of LC3 and Beclin1 which were the autophage markers of early-to-mid stage; Western blot was adopted to quantify protein level of microtubule-associated proteins 1 light chain 3B(LC3B) and mammalian ortholog of the yeast autophagy-related gene 6 (Beclin1). Transmission electron microscope (TME) was used to observe the formation of autophagosome in plaque. C57BL/6J mouse VSMCs were cultured by using tissue piece inoculation method. Groups of in vitro studies were the same as in vivo study: control group, agonist-CD137 group, anti-CD137 group, the agonist CD137 groups was treated with agonist-CD137 antibody (10 MUg/ml) and anti-CD137 group was treated with anti-CD137 antibody (10 MUg/ml) for 30 minutes, followed by agonist-CD137 antibody (10 MUg/ml). Von Kossa staining and osteogenesis phenotypic alkaline phosphatase (ALP) activity detection were adopted to observe calcification in VSMCs. Autophagosomes were separated from the supernatant of the agonist-CD137 group with density gradient centrifugation method. VSMCs were divided into two groups: positive group (containing complete medium with above autophagosomes to a final concentration 15 MUg/ml) and negative group (only complete medium) after being pretreated with mixed inflammatory cytokines (IL 1beta,IFN-gamma and TNF-alpha, final concentration was 25 ng/ml respectively) for 24 hours and calcium deposition and osteogenesis phenotypic marker bone morphogenetic protein 2(BMP2) were then detected. Results: (1) Compared with the control group, activation of the CD137-CD137L signal significantly increased the formation of calcification area in thoracic aortic atherosclerotic plaque of ApoE(-/-) mice((1.82+/-0.15)*10(4) MUm(2) vs. (0.34+/-0.08)*10(4) MUm(2,) P<0.01), this effect was significantly attenuated by inhibiting this signal ((0.83+/-0.30)*10(4) MUm(2) vs. (1.82+/-0.15)*10(4) MUm(2,) P<0.05); positive autophagy makers LC3B and Beclin1 were detected in both agonist-CD137 group and anti-CD137 groups and the expression of LC3B and Beclin1 was substantially higher in anti-CD137 group. Western blot analysis indicated that the expression of LC3B and Beclin1 in agonist-CD137 group was significantly upregulated compared with the control group (0.17+/-0.01 vs. 0.03+/-0.08, P<0.05, and 0.12+/-0.02 vs. 0.06+/-0.02, P<0.05), which could be significantly downregulated in anti-CD137 group (0.28+/-0.09 vs. 0.17+/-0.01, P<0.05 and 0.17+/-0.02 vs. 0.12+/-0.02, P<0.05). TME showed that the number (QTY /HP) of autophagosome of agonist-CD137 group and anti-CD137 group in plaque were both increased (14.67+/-2.52 vs. 3.67+/ 1.53, P<0.01, and 15.33+/-2.08 vs. 3.67+/-1.53, P<0.01), while in the agonist CD137 group, the number of extracellular autophagosome within thoracic aortic atherosclerotic plaque of ApoE(-/-) mice increased more substantially (5.33+/ 1.53 vs. 1.33+/-0.58, P<0.01). (2) In vitro study showed that activating CD137 CD137L signal could promote calcium deposition in extracellular matrix and the activity of osteogenesis phenotypic ALP((6.73+/-0.02) MUmol/mg protein vs. (1.07+/-0.03) MUmol/mg protein, P<0.05), and ((563.20+/-0.72) U/mg protein vs. (117.50+/-0.64) U/mg protein, P<0.05), while these effects were significantly blunted in anti-CD137 group ((1.94+/-0.05) MUmol/mg protein vs. (6.73+/-0.02) MUmol/mg protein, P<0.05, and (236.10+/-0.14) U/mg protein vs. (563.20+/-0.72) U/mg protein, P<0.05). TME showed that the number of intracellular autophagosome in agonist-CD137 group and anti-CD137 group was both significantly higher than in control group ((21.65+/-1.34) MUg/ml vs. (8.32+/-1.58) MUg/ml, P<0.01, and (15.42+/-1.65) MUg/ml vs. (8.32+/-1.58) MUg/ml, P<0.05). After the density gradient centrifugation, exocytotic autophagosome in the medium of agonist-CD137 group was markedly higher than in control group ((14.67+/-1.53) MUg/ml vs. (2.33+/-1.15) MUg/ml, P<0.01). (3) Compared with the control group, autophagosomes isolated from culture supernatant (final concentration: 15 MUg/ml) could significantly stimulate calcium deposition((2.30+/-0.10) MUmol/mg protein vs. (0.15+/-0.40) MUmol/mg protein, P<0.05) and enhance the expression of bone morphogenetic protein 2 (2.10+/-0.04 vs. 0.30+/-0.01, P<0.05). Conclusion: CD137 CD137L signaling could mediate exocytosis of autophagosome within VSMCs, thus influence the formation of atherosclerotic calcification. PMID- 28100348 TI - [Right coronary artery spasm induced acute inferior wall myocardial infarction complicating electrical storm: a case report]. PMID- 28100347 TI - [Salvianolate protects H9c2 cells from hypoxia/reoxygenation injury-induced apoptosis by attenuating mitochondrial DNA oxidative damage]. AB - Objective: To investigate the possible mechanism related to the protective effects of salvianolate in H9c2 cells underwent hypoxia/reoxygenation (H/R) injury. Methods: H9c2 cells were divided into four groups: control group, salvianolate group (S group), H/R group, and salvianolate+ H/R group(S+ H/R group), in which the H9c2 cells were pretreated with salvianolate before H/R treatment.Apoptotic cells were detected by Tunel assays and AnnexinV-FITC apoptosis detection kit.The intracellular ATP level, the change of mitochondrial membrane potential and the mitochondrial DNA oxidative damage were also determined in these groups. Results: (1) The apoptosis rate of H/R group(26.36+/ 5.14)% was significantly higher compared to control group(2.71+/-1.66)%(P=0.000 4), which could be significantly reduced in S+ H/R group(17.28+/-4.75)%(P=0.012 8 vs. H/R group , P=0.003 9 vs. control group). The ratio of AnnexinV and PI double positive cells in H/R group(28.23+/-6.73)% was significantly higher compared to control group(3.53+/-2.83)%(P=0.001 1), which was significantly reduced in S+ H/R group(18.10+/-4.56)%(P=0.037 2 vs. H/R group, P=0.038 3 vs. control group). (2)The ATP level of H9c2 cells in H/R group(49.05+/-10.12)% was significantly lower than in control group 100%(P=0.000 5), which was significantly increased in S+ H/R group(68.67+/-13.32)%(P=0.019 9 vs. H/R group). Confocal microscope showed that red fluorescence was dominant in the control group, red fluorescence was significantly reduced, while green fluorescence was significantly increased in H9c2 cells of H/R group and the fluorescence ratio of red to green in H/R group((37.13+/-8.47)%) was significantly decreased compared to control group (100%, P=0.000 1), fluorescence ratio of red to green was significantly increased in S+ H/R group((63.77+/-12.32)% vs. H/R group, P=0.007 3). (3)The mitochondrial DNA oxidative damage in different groups: there was only few 8-hydroxyguanine (8 OHdG) expression, which marked as green, in control group, and 8-OHdG expression was significantly upregulated in H/R group, moreover, the 8-OHdG was co-localized with mitochondria.The expression of 8-OHdG was significantly lower in S+ H/R group compared to H/R group. Conclusion: Salvianolate can reduce mitochondrial DNA oxidative damage, and protect mitochondrial function, thus inhibit myocardial cell apoptosis and eventually reduce the myocardial H/R-injury in H9c2 cells. PMID- 28100349 TI - [A case of apical hypertrophic cardiomyopathy complicated with apical aneurysm]. PMID- 28100350 TI - [Clinical applications and research advances of optical coherence tomography in guiding percutaneous coronary intervention for bifurcation lesions]. PMID- 28100351 TI - [Research progress on treatment of non-in-stent restenosis coronary artery lesions by drug-eluting balloon]. PMID- 28100352 TI - [Update on the cardiotoxicity of noncardiovascular drugs]. PMID- 28100353 TI - [Research advances of bone regulation in vascular calcification]. PMID- 28100354 TI - [Bronchiectasis: more attention and research needed]. PMID- 28100355 TI - [Present situation and challenges of bronchiectasis in China]. PMID- 28100356 TI - [Review and prospect of tubercluosis prevention and control anually (2016)]. PMID- 28100357 TI - [Hemoptysis in adults with bronchiectasis: correlation with disease severity and exacerbation risk]. AB - Objective: To investigate the association between hemoptysis and disease severity and risks of acute exacerbations in patients with bronchiectasis. Methods: Between September 2012 and January 2014, we recruited 148 patients (56 males, 92 females, mean age: 44.6 years) with clinically stable bronchiectasis, who were classified into hemoptysis group (36 males, 70 females, mean age: 45.6 years) and non-hemoptysis group (20 males, 22 females, mean age: 41.8 years). We inquired the past history, and evaluated chest imaging characteristics, lung function, cough sensitivity assessed using capsaicin cough challenge tests, and airway inflammation. We also performed a 1-year follow-up to evaluate whether patients with hemoptysis would have greater risk of having acute exacerbations. Results: In the hemoptysis group, median 24-hour sputum volume was 20.0 ml, median Bronchiectasis Severity Index (BSI) was 7.0, median bronchiectatic lobes was 4.0, median chest CT score was 7.0, the geometric mean for eliciting 5 coughs following capsaicin cough sensitivity (C5) was 77 MUmol/L, 67 cases (63%) had cystic bronchiectasis and 52 cases (49%) had pulmonary cavity shown on chest CT, and 35 cases (33%) had Pseudomonas aeruginosa colonization. In the non-hemoptysis group, median 24-hour sputum volume was 5.0 ml, median BSI was 4.0, median bronchiectatic lobes was 3.0, median chest CT score was 5.0, 15 cases (36%) had cystic bronchiectasis and 10 cases (24%) had pulmonary cavity, the geometric mean for C5 was 212 MUmol/L, and 4 cases (10%) had Pseudomonas aeruginosa colonization. All the above parameters differed significantly between the hemoptysis and the non-hemoptysis group (P<0.05). In the hemoptysis group, 29 patients with pulmonary cavity (27%) had reported the use of intravenous antibiotics, and 44 cases (42%) had at least one hospitalization within the previous 2 years. In the non-hemoptysis group, 8 cases (19.0%) had reported the use of intravenous antibiotics, and 8 cases (19.0%) reported hospitalization within 2 years. A prior history of hemoptysis was associated with a greater risk of experiencing bronchiectasis exacerbations during follow-up, after adjusting for age, sex, smoking status and BSI (62 cases in the hemoptysis group, 18 cases in the non-hemoptysis group, chi(2)=16.06, P=0.03). In a multivariate model, cystic bronchiectasis was the sole risk factor for hemoptysis; 67 cases which accounted for 63% of patients in the hemoptysis group and 15 cases which accounted for 36% of patients in the non-hemoptysis group, odds ratio: 2.84, 95% confidence interval: 1.00-8.14, P=0.05 . Conclusions: In this study, 72% of bronchiectasis patients had experienced hemoptysis, which was associated with the severity of bronchiectasis. Patients with a prior history of hemoptysis had a greater risk of acute exacerbations during follow-up than those without. PMID- 28100358 TI - [Study on the effect and predictive to bronchiectasis combined with rheumatoid arthritis]. AB - Objective: To explore the clinical characteristics of bronchiectasis(BR)coexisting in patients with rheumatoid arthritis (RA). Methods: One hundred and forty-eight bronchiectasis patients were retrospectively analyzed. These cases were all diagnosed in the Respiratory Department of Shanghai Pulmonary Hospital and Shanghai Gongli Hospital of Pudong New Area during Jan. 2012 to Dec.2015.The patients consisted of 74 males and 74 females, aging from 45 to 79 [mean(65+/-11)] years. In these patients, coexisting rheumatoid arthritis was found in 34 males and 36 females, aging from 45 to 79[mean(68+/-12)] years(RA-BR group). Patients with bronchiectasis alone consisted of 40 males and 38 females, aging from 49 to 76 [mean(63+/-10)] years (BR alone group). Data between the 2 groups of patients were compared, including general clinical features, serum anti-cyclic citrullinated peptide antibodies (anti-CCP), rheumatoid factor (RF), chest high-resolution CT (HRCT), and lung function . FACED scores were used to assess the severity of bronchiectasis. Meanwhile, we analyzed the correlation between anti-CCP and FACED scores in the 2 groups. Results: We observed an increase of serum anti-CCP in RA-BR patients compared with BR alone patients (196+/-68 versus 64+/-26, P<0.05). In addition, FACED scores in RA-BR patients were higher than those in BR patients (5.2+/-1.8 versus 3.1+/-1.4 , P< 0.05). Positive correlations between serum anti-CCP levels and FACED scores (r=0.678, r=0.461, P<0.05) in both RA-BR and BR alone groups were observed in this study. Conclusions: The disease severity scores of RA-BR patients were higher than those of patients with BR alone. Levels of serum anti CCP may act as a predictor for the diagnosis and prognosis of bronchiectasis in patients with RA. PMID- 28100359 TI - [Holmium: yttrium-aluminum-garnet (Ho: YAG) laser lithotripsy in the treatment of broncholithiasis]. AB - Objective: To assess the effectiveness of Ho: YAG Laser in the treatment of broncholithiasis. Methods: We retrospectively reviewed the clinical data of 6 patients who underwent Ho: YAG Laser lithotripsy in Peking University First Hospital during May 2012 to October 2015. 4 females and 2 males, with a median age of 60 years, were enrolled. Among 6 patients, persistent cough(n=2), hemoptysis(n=2), recurrent pneumonia(n=2) were the main clinical symptoms. Broncholiths were found in the left side in 1 patient and right side in 5 patients. 2 broncholiths were located in main bronchus and 4 in segmental bronchus. There were 2 patients with intraluminal broncholiths and 4 with transbranchial broncholiths. All 6 patients received Ho: YAG Laser(0.8-1.2 J pulse energies, 5-10 Hz frequencies, 365 MUm laser fibers) under rigid bronchoscopy in general anesthesia and experienced relief of symptoms. Results: Complete removal of broncholith was accomplished in intraluminal broncholith group and 1 patient in transbracnhial broncholith group, the other 3 transbracnhial broncholiths were partly removed. Complications included perioperative massive hemolysis(n=1), bronchoesophageal fistula(n=1) and postoperative pneumonia (n=2), no long term complications were encounted. Conclusion: The Ho: YAG were associated with acute complications including fistula, perioperative massive hemolysis, infections and no long-term side effects. It represents a safe and effective therapy option for broncholithiasis. PMID- 28100360 TI - [End tidal PCO(2) for evaluation of severity of disease in idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension]. AB - Objective: To explore the difference in end tidal PCO(2) (P(ET)CO(2)) between idiopathic pulmonary arterial hypertension (IPAH) and chronic thromboembolic pulmonary hypertension (CTEPH), and to analyze the correlation between P(ET)CO(2) and the indexes of disease severity in IPAH and CTEPH patients. Methods: Data were retrieved from 68 IPAH patients and 52 CTEPH patients who all had received right-heart catheterization, pulmonary function test and cardiopulmonary exercise testing at Shanghai Pulmonary Hospital from October 2011 to October 2014. In addition, other clinical parameters were also collected. Results: The IPAH group had a significantly higher mPAP, PVR [(60+/-16) mmHg (1 mmHg=0.133 kPa), (13+/-6) Wood U ] than the CTEPH group [(46+/-12) mmHg, (9+/-4) Wood U, t=4.90, 4.83, all P<0.01]. Meanwhile, the IPAH group had a lower percentage of predicted peakVO(2), oxygen pulse [(45+/-15)%, (60+/-22)%] compared with the CTEPH group [(53+/-16)%, (68+/-21)%, t=-2.42, -1.96, all P<0.05]. The value of P(ET)CO(2) at rest, AT, peak in the IPAH patients [(27+/-5), (28+/-7), (25+/-7) mmHg] were higher than those in the CTEPH patients [(24+/-4) mmHg, (23+/-6) mmHg, (21+/-6) mmHg, t=3.22 4.54, all P<0.01]. There was a significantly difference in P(ET)CO(2) at AT and peak between WHO-FC I-II and III-IV subgroups in IPAH (t=2.55, 2.60, all P<0.05) and CTEPH (t=2.39, P<0.05), except for P(ET)CO(2) at peak in the CTEPH patients (t=1.71, P>0.05). A moderately inverse correlation was found between P(ET)CO(2) at AT and NT-proBNP in the IPAH group (r=-0.58, P<0.01), meanwhile P(ET)CO(2) at AT in the CTEPH group was weakly correlated with NT-proBNP (r=-0.34, P<0.05). Conclusions: Compared with the CTEPH patients, the IPAH patients had significantly decreased exercise capacity and increased P(ET)CO(2). P(ET)CO(2) could reflect the disease severity in both IPAH and CTEPH patients, being superior in IPAH than in CTEPH. Furthermore, P(ET)CO(2) at AT might be better than P(ET)CO(2) at peak in reflecting the ventilatory efficiency. PMID- 28100361 TI - [The relationship between nutritional status and oxidative stress markers, pulmonary function in patients with stable chronic obstructive pulmonary disease]. AB - Objective: To investigate the association between the nutritional status of patients with chronic obstructive pulmonary disease (COPD) and the levels of serum oxidative stress markers protein carbonyls (PC), malondialdehyde (MDA), 8 hydroxy-2'-deoxyguanosine (8-OHdG), total antioxidant capacity (TAC) and pulmonary function. Methods: 200 patients with stable COPD (the COPD group) and 100 healthy individuals (the control group) who visited during June 2014 and August 2014 were enrolled in our study. The levels of PC, MDA, 8-OHdG and TAC in serum were detected. Pulmonary function was tested. Nutritional status was assessed by mini nutritional assessment (MNA) that classified the nutrition class. Results: The levels of PC, MDA, and 8-OHdG in serum increased significantly in the COPD group [3.82 (1.79, 6.83) MUg/L, 3.89(2.77, 5.40) MUmol/L and 359.18(259.25, 587.85) ng/L, respectively], and the levels of TAC in serum decreased significantly in COPD group [11.35(4.81, 20.20)U/ml], as compared with the control group [2.29(1.08, 3.26) MUg/L, 3.08(2.32, 4.03) MUmol/L, 311.37(265.47, 374.08) ng/L and 18.81(15.21, 23.19) U/ml, respectively, all P<0.05]. All the nutrition assessment parameters were gradually decreased as nutritional status worsen (all P<0.05). In malnourished (risk) COPD subgroup, the levels of PC and TAC in serum increased significantly [6.10(3.02, 8.18) MUg/L and 13.33(6.07, 23.96) U/ml, respectively] and the FEV(1)% and FEV(1)/FVC index decreased significantly [42.90(34.68, 71.23) and 46.96(38.96, 60.63), respectively] as compared the well-nourished COPD subgroup [3.25(1.61, 5.37) MUg/L, 9.99(4.41, 16.77) U/ml, 69.10(45.95, 89.23) and 53.32(42.13, 63.15), all P<0.05]. Furthermore, we had found that the upper arm muscle circumference, calf circumference and BMI were positively correlated with MNA (r=0.498, 0.587, 0.781, P<0.001), negatively correlated with PC (r=-0.209, -0.195, -0.231, P<0.05) and positively correlated with FEV(1)% (r=0.223, 0.274, 0.350, P<0.05). The upper arm muscle circumference and BMI were positively correlated with FEV(1)/FVC (r=0.166, 0.224, P<0.05). In COPD group, the level of PC in serum and FEV(1)% were important factor in MNA score, and the impacts of FEV(1)% were greater than the level of PC(beta=0.367, -0.304, P<0.001). Conclusion: The protein carbonylation and airflow limitation might be closely related to malnutrition. PMID- 28100362 TI - [Severe obstructive sleep apnea-hypopnea syndrome with dilated cardiomyopathy leading to pulmonary hypertension: case report and literature review]. AB - Objective: To study the relationship between dilated cardiomyopathy and obstructive sleep apnea-hypopnea syndrome (OSAHS) and to evaluate the curative effects of continuous positive airway pressure (CPAP) in OSAHS complicated with dilated cardiomyopathy. Methods: We reported one case with the symptom of exertional dyspnea for 1 year and aggravating for 1 month. The patient finally was diagnosed with severe OSAHS complicated with dilated cardiomyopathy leading to pulmonary hypertension. A systematic literature review was performed for similar published cases in Pubmed, Wanfang and CNKI database, using the keywords (obstructive sleep apnea) OR(OSA) OR(OSAHS) AND(dilated cardiomyopathy OR DCM)from January 1990 to May 2016. Results: Our patient had no significant improvement after receiving initial treatments, including reducing cardiac preload, improving myocardial metabolism, increasing myocardial contractility, and anticoagulants. After the patient was diagnosed as having severe OSAHS by polysomnography(PSG) and treated with CPAP, his symptoms improved remarkably. The enlarged heart became smaller and the patient had no repeated dyspnea at follow up examination. By literature review, we found 4 English original articles and 6 Chinese articles (1 review article, 1 expert note, 1 original article and 3 case reports) on OSAHS complicated by DCM.Four Chinese and 1 English articles reported that the symptoms and parameters of OSAHS with DCM was improved remarkably after treatment with CPAP. Conclusion: For patients with dilated cardiomyopathy which fails to conventional therapy, especially those accompanied by obesity, snoring, daytime sleepiness, morning dry mouth and other related symptoms, PSG should be carried out. Early CPAP therapy could improve symptoms and prognosis of OSAHS associated with DCM. PMID- 28100364 TI - [Assessment of bronchiectasis severity in adults]. PMID- 28100365 TI - [Effectiveness and safety assessment of inhaled antibiotics therapy in adults with bronchiectasis]. PMID- 28100363 TI - [Hyper-IgE syndrome in adulthood: a case report and literature review]. AB - Objective: To describe the clinical features of hyper-IgE syndrome (HIES), with emphasis on refractory pulmonary cystic lesions as the initial presentation in adulthood. Methods: A case of HIES presenting with pulmonary cystic lesions in an adult patient was retrospectively analyzed. We used "hyper-IgE syndrome" as the Chinese keywords, "hyper-IgE syndrome, China" as the English keywords to retrieve the literature from Wanfang database/CNKI database and Pubmed database until April 2016. The clinical data were pooled and analyzed. Results: A 19 year old female patient was admitted to our hospital because of recurrent cough and expectoration as the chief complaint. Physical examination revealed broad nasal bridge and scoliosis, and chest CT showed gradually enlarged and increased cystic lesions. Laboratory studies demonstrated significantly increased blood eosinophils and serum level of total IgE, together with a definite chemotactic dysfunction of neutrophils. A further detection of STAT3 mutation was negative. The diagnosis of HIES was made and antibiotic treatment resulted in disease remission. Literature review found 45 reports including 37 in Chinese and 11 in English. Eight cases of adult HIES were reported, and all the patients were male, aging 18 to 31 years. Prolonged disease course, recurrent infection and formation of cystic lesions in the lungs were important features of HIES. Early diagnosis and treatment with specific antibiotics were important for improving outcome of the patients. Conclusion: Refractory pulmonary cystic lesions can be the initial presentation in adult HIES. Understanding of the clinical characteristics of HIES will be helpful to avoid misdiagnosis and improve prognosis. PMID- 28100366 TI - [Different phenotypes of alveolar macrophages and bronchial asthma]. PMID- 28100367 TI - [Role of pulmonary vein in pulmonary hypertension]. PMID- 28100368 TI - [Progress in precision medicine: a scientific perspective]. AB - Precision medicine is a new strategy for disease prevention and treatment by taking into account differences in genetics, environment and lifestyles among individuals and making precise diseases classification and diagnosis, which can provide patients with personalized, targeted prevention and treatment. Large scale population cohort studies are fundamental for precision medicine research, and could produce best evidence for precision medicine practices. Current criticisms on precision medicine mainly focus on the very small proportion of benefited patients, the neglect of social determinants for health, and the possible waste of limited medical resources. In spite of this, precision medicine is still a most hopeful research area, and would become a health care practice model in the future. PMID- 28100369 TI - [Innovations on technology, management and concept are indispensible for scientific research, prevention and treatment of malignant tumor in China]. AB - Malignant tumor has become the top cause of deaths before the average life expectancy in Chinese population. From the variations in the morbidity rate and mortality rate of malignant tumor in the mainland of China between 2000 and 2011, the primary prevention targeting the risk factors/etiological agents significantly reduced the morbidity rates of gastric cancer, esophageal cancer, and primary liver cancer, therefore reduced the mortality rates of these cancers. However, the contribution of clinical treatments to the mortality reduction was not obviously improved during this period. Importantly, it is necessary to conduct research to identify precancerous lesions and early tumors which are prone to progress to aggressive diseases for the active secondary prevention to avoid over-diagnosis and over-treatment. Multi-center, prospective randomized controlled clinical trials and prognosis evaluation independently carried out by third parts are needed to evaluate the longterm effectiveness of some clinical treatment efficiency for cancers with different histological types. On the basis of a series of population-based studies in China, the prevention and clinical treatments for malignant tumor need innovations on technology, management, and even concept; the mechanisms of "forward placement of strategic pass" for the prevention and control of malignant tumor should be established and improved to reduce the increasing disease burden due to malignant tumor in China. PMID- 28100370 TI - [Associations between airflow obstruction and total and cause-specific mortality in adults in China]. AB - Objective: To examine the prospective associations between airflow obstruction and total and cause-specific mortality. Methods: The study was based on China Kadoorie Biobank, in which 199 099 men and 287 895 women aged 30-79 years at baseline survey were included after excluding those with heart disease, stroke and cancer. The Global Initiative on Obstructive Lung Disease (GOLD) guideline was used to classify airflow obstruction. Cox regression models were used to estimate adjusted HR and 95%CI. Results: During 3 494 079 person-years of follow up between 2004 and 2013 (median 7.2 years), a total of 21 649 people died. Absolute mortality rates were 5.5, 9.9, 13.1, 32.4 and 63.3 deaths per 1 000 person-years for participants who had normal airflow, GOLD-1 to GOLD-4 airflow obstruction, respectively. After adjusting potential confounders, compared with participants with normal lung function, the HRs for death were 0.98 (95%CI: 0.88 1.09), 1.03 (95%CI: 0.97-1.09), 1.62 (95% CI: 1.53-1.73) and 2.83 (95% CI: 2.59 3.10) for those whose airflow obstruction were classified as GOLD-1 to GOLD-4, respectively. The airflow obstruction was also associated with increased risk for deaths due to ischemic heart disease, cerebrovascular disease and chronic obstructive pulmonary disease. Conclusion: Airflow obstruction is associated with total and certain cause-specific mortality, the higher the airflow obstruction degree is, the higher the death risk is. PMID- 28100371 TI - [Changes in genotype prevalence of human papillomavirus over 10-year follow-up of a cervical cancer screening cohort]. AB - Objective: To evaluate the dynamic variation of genotypes distribution of human papillomavirus (HPV) over 10-year follow-up in a cervical cancer screening cohort. Methods: Based on the Shanxi Province Cervical Cancer Screening Study I cohort, we detected HPV genotypes on the well-preserved exfoliated cervical cells from women who were tested HPV positive from year 2005 to year 2014 using reverse linear probe hybridization assay. The changes of prevalence of type-specific HPV over time among the overall population were estimated using linear mixed models. The association between the type-specific HPV and cervical intraepithelial neoplasia grade 2 or worse (CIN2 +) was calculated by linear Chi-square test. Finally, the trends of multiple infections of HPV with the increase of the age were analyzed. Results: During the cervical cancer screening of the overall population from 2005 to 2014, the most common genotypes among the population were HPV16 and 52. The prevalence of HPV16 decreased over time from 4.6% in 2005 to 2.2% in 2010 and 2014 (F=8.125, P<0.001). The prevalence of HPV52 remained pretty stable and HPV33, 51 and 58 slightly decreased then apparently increased. Further stratification analysis by pathological lesions showed the same trend of the HPV prevalence for the histology normal women with the overall population. Of note, for those women with the cervical intraepithelial neoplasia (CIN2 +), the detection rate of HPV16 decreased from 65.22% in 2005 to 41.03% in 2010 and finally to 31.58% in 2014 (chi(2)=4.420, P=0.036) and that of HPV33 substantially increased. No significant variation was found for other types of HPV. Multiple infection rate varied with the growing age of the women. Conclusions: The genotypes prevalence of HPV tended to vary over time during cervical cancer screening in the context of regular screening combining with immediate treatment for those CIN2 + women. HPV16 prevalence significantly decreased over time, which indicated that the variation of type-specific HPV prevalence should be considered when regular cervical cancer screening was organized using HPV technique. PMID- 28100372 TI - [Research on potential interaction between mitochondrial DNA copy number and related factors on risk of hypertension in coal miners]. AB - Objective: To investigate the effects of mitochondrial DNA (mtDNA) copy number in peripheral blood and related factors on the risk of hypertension in coal miners. Methods: A case-control study was conducted in 378 coal miners with hypertension and 325 healthy coal miners recruited from Datong Coal Mine Group. A standard questionnaire was used to collect their general information, such as demographic characteristics, habits and occupational history. Fluorescence quantitative PCR was performed to detect the copy number of mtDNA. Logistic regression model was applied for identifying the related risk factors of hypertension and analyzing the interaction between mtDNA copy number and risk factors. Results: The prevalence of hypertension of high mtDNA copy number was lower than mtDNA copy numberin 0-5.67 group, but the difference was not statistically significant (P=0.414). Alcohol drinking (OR=1.80, 95% CI: 1.26-2.56), family history of hypertension (OR=1.74, 95% CI: 1.20- 2.50), work shifts (OR=0.69, 95% CI: 0.48 0.99), education level (P=0.012) and family monthly income level (P=0.001) were related to the prevalence of hypertension. There were potential interactions between mtDNA copy number and alcohol drinking, family monthly income level, family history of hypertension, respectively. Alcohol drinking was a risk factor for hypertension [1.77 (1.25-2.50)]. Potential interactions between mtDNA copy number and alcohol drinking reduced the risk of hypertension (OR=1.20, 95% CI: 1.07-1.35). Family history of hypertension was a risk factor for hypertension [1.81(1.26-2.59)]. Potential interactions between mtDNA copy number and family history of hypertension reduced the risk of hypertension (OR=1.24, 95%CI: 1.09 1.41). Family monthly income level was a protect factor for hypertension [0.55(0.46-0.66)]. Potential interactions between mtDNA copy number and family monthly income level increased the protection role of hypertension (OR=0.90, 95% CI: 0.86-0.94). Conclusion: mtDNA copy number variation was not significantly associated with the prevalence of hypertension in coal miners, but mtDNA copy number showed multiplication interaction on the prevalence of hypertension with alcohol drinking, family monthly income level as well as family history of hypertension and made their influences weaken. PMID- 28100373 TI - [Epidemiological characteristics of children aged 1-4 years without timely birth dose of hepatitis B vaccine vaccination in China, 2014]. AB - Objective: To evaluate the epidemiological characteristics of the children aged 1 4 years without timely birth dose of hepatitis B vaccine (HepB(1)) vaccination. Methods: Based on the data from 160 disease surveillance points in 31 provinces of China, two-stage cluster random sampling was used to select the target population aged 1-4 years. A standard questionnaire was used to collect the information about the birth date, gender, ethnic group, place of birth, HepB immunization history of the children selected. A blood sample (3 ml) was taken from each subject for HBsAg testing. SAS software (Version 9.4) was used in our study. We analyzed the age, gender, ethnic group, area specific distributions of the children aged 1-4 years without timely HepB(1) vaccination and the influencing factors, and the relationship between the HepB(1) vaccination time and HBsAg prevalence rate. Results: A total of 12 587 children aged 1-4 years were analyzed and the non-timely HepB(1) vaccination rate was 10.12%. The place of birth, ethnic group, urban/rural area, eastern/central/western area, age were the main influencing factor of the non-timely HepB(1) vaccination. The non-timely HepB(1) vaccination rate was higher in 3-4 years old children (11.13%) than in 1 2 years old children (8.97%), in rural area (12.05%) than in urban area (8.19%), in western area (13.41%) than in central area (9.27%) and eastern area (7.72%), in minority ethnic group (18.06%) than in Han ethnic group (8.77%) and in children born outside hospital (57.66%) than in children born in hospital (9.27%). The HBsAg prevalence rate among 1-4 years children was 0.31%. The HBsAg prevalence rate of the children with timely HepB(1) vaccination (0.25%) was lower than that of the children without timely HepB(1) vaccination (0.89%). Conclusions: In China, the HBsAg prevalence rate among 1-4 years children with HepB vaccination decreased to <0.5% and the timely HepB(1) vaccination rate reached to 90%. We should strengthen the timely HepB(1) vaccination for the children in minority ethnic groups, in western area, in rural area as well as those born outside hospitals. PMID- 28100374 TI - [Study of disease burden of chronic hepatitis B and C patients in Shanghai based on Bronfenbrenner' s ecological systems theory: a community-based survey]. AB - Objective: To systemically analyze family burden, quality of life of chronic hepatitis B and C patients in Shanghai and related influencing factors. Methods: A representative sample of chronic hepatitis patients (n=1 478) and their family members (n=1 478) was randomly selected through a multi-stage cluster sampling from 30 communities in 10 districts of Shanghai. One patient and one family member of each family were interviewed using different questionnaires to collect related information. Based on Bronfenbrenner' s ecological systems, psychological measurement, two-level random intercept model and multivariable structural equation model were applied to determine the effects and directions of the factors between life quality of chronic hepatitis patients and family burden. Results: The mean score of quality of life of chronic hepatitis patients in Shanghai was 78.70 +/- 13.25, the score of " specific module" was highest and the score of " social function" was lowest. Additionally, the mean score of burden reported by the family members was 12.62+/-10.74, the score of " financial burden" was highest, and the score of " effect on family member' s health" was lowest. Multivariable structural equation model indicated that eight factors were related with life quality and family burden of patients with chronic hepatitis. Among them, HCV infection, elevated serum alanine aminotransferase level, average monthly cost for patient >3 000 yuan (RMB) and poor health of family members were the direct risk factors for the life quality of the patients as well as family burden. The factor of drinking more than once a week influenced the patients' life quality directly and family burden indirectly. On the contrary, the factors of local household registration, hospitalization and family member's indifferent attitude to hepatitis B vaccination influenced the family burden of the chronic hepatitis patients directly and the life quality of the patients indirectly. Conclusion: The findings could be used in the development of community based management and intervention of chronic hepatitis patients in Shanghai. PMID- 28100375 TI - [Epidemiological characteristics of HBeAg reversion in chronic hepatitis B patients with HBeAg seroconversion in Jiangsu province, 2012-2014]. AB - Objective: To understand characteristics and influencing factors of reversion of HBeAg in chronic hepatitis B patients with HBeAg sero-conversion, and provide epidemiological evidence for the regular management of chronic hepatitis B patients. Methods: From 2012 to 2014, a cohort study was conducted among the chronic hepatitis B patients with sero-conversion of HBeAg in Jiangsu province. Association between participants' demographics, ALT, HBV DNA and incidence of HBeAg reversion was analyzed by Cox regression model. HBV DNA changing trend between patients with HBeAg reversion and patients with persistent HBeAg sero conversion was compared by repeated measure data variance analysis. Results: In 2012, there were 5 068 HBeAg seroconverted chronic hepatitis B patients aged (51.9 +/- 12.8) years enrolled. By 2014, HBeAg had reversed in 121 cases with the rate of 1.3/100 person-years. The probability of HBeAg reversion decreased with the age of the patients. By Cox regression analysis, HBV DNA level was an important influencing factor for the progress of HBeAg reversion. The patients with HBV DNA>=200 000 IU/ml had a higher HBeAg reversion rate DNA (3.8/100 person years) than those with HBV DNA <2 000 IU/ml (1.1 person-years) (HR=3.44, 95% CI: 1.91-6.20, P=0.000). Compared with the persistent HBeAg sero-conversion group, HBV DNA and ALT showed a more dramatic increase in the HBeAg reversion group (P=0.000). Conclusions: There was a certain HBeAg reversion rate in chronic hepatitis B patients with HBeAg sero-conversion. Younger chronic CHB patients with HBeAg sero-conversion and those with higher HBV DNA lever had higher HBeAg reversion rate. Following up and management of chronic CHB patients with HBeAg sero-conversion is important and helpful for the control of hepatitis B. PMID- 28100376 TI - [Related factors for severe liver fibrosis in chronic hepatitis C patients with remunerated blood donation history in Jurong of Jiangsu province]. AB - Objective: The incidence of liver fibrosis in patients with chronic hepatitis C is high. Without effective treatment, it would lead to liver cirrhosis. This study is to identify the related factors for the incidence of liver fibrosis in patients with chronic hepatitis C in order to make early intervention treatment and reduce the case fatality rate. Methods: This cross-sectional survey was conducted in adults aged >=50 years with local residence for more than 5 years in Jurong of Jiangsu province from March to May in 2015, the patients infected with hepatitis C virus through remunerated blood donation were screened and included in the analysis. Descriptive statistical analysis was done to compare the differences in the incidence of liver fibrosis among the patients with different age, sex and education level or co-infected with hepatitis B virus or not. The risk factors for severe liver fibrosis were identified with univariate and multivariate logistic regression analysis. Liver fibrosis was diagnosed by using FIB-4 index method. Results: A total of 719 patients with chronic hepatitis C were surveyed. Severe liver fibrosis developed in 285 of the 719 patients, in whom 21.84% was males. Multivariate logistic regression analysis showed that the patients with higher education level (OR=0.65, 95%CI: 0.47-0.90) and with access of antiviral therapy (OR=0.33, 95%CI: 0.22-0.49) had lower risk for severe liver fibrosis, the patients with high fasting blood glucose level (OR=1.80, 95% CI: 1.19-2.77) and abnormal white blood cell count (OR=2.77, 95% CI: 1.95-3.90) had higher risk for severe liver fibrosis. Conclusions: The incidence of severe liver fibrosis in patients with hepatitis C was affected by many factors. Higher education level and antiviral therapy were the protective factors, but high fasting blood glucose level and abnormal white blood cell count were the risk factors. PMID- 28100377 TI - [Comparison of human papilloma virus infection status between men who have sex with men recruited from gay bathhouses and HIV voluntary counseling and testing clinics respectively in Urumqi]. AB - Objective: To understand the human papilloma virus (HPV) infection status in men who have sex with men (MSM) recruited from gay bathhouses and HIV voluntary counseling and testing (VCT) clinics in Urumqi, Xinjiang Uygur autonomous region, and identify the associated risk factors. Methods: A total of 200 MSM aged >=18 years were recruited by using the " snowballing" sampling method from gay bathhouses and VCT clinics in Urumqi during March-May, 2016. The MSM recruited completed questionnaires after filling in the informed consent form. The information about their demographic characteristics and sexual behaviors were collected, and anal swabs were collected from them for HPV genotyping. Results: The overall HPV infection rate was 54.0%. The HPV infection rate was 66.7%(74/111) in MSM from gay bathhouses and 38.2%(34/89) in MSM from VCT clinics and the high risk type HPV infection rate was 39.6% (44/111) in MSM from gay bathhouses and 14.6% (13/89) in MSM from VCT clinics, the differences were significant (chi(2)=16.112, P<0.05; chi(2)=15.190, P<0.05). Multiple logistic regression analysis indicated that the major risk factors for HPV infection included activity in gay bathhouse (OR=3.732, 95% CI: 1.950-7.141) and anal sexual behavior (OR=2.555, 95%CI: 1.329-4.912). Conclusion: The prevalence of HPV in MSM from gay bathhouses was higher than that in MSM from VCT clinics, indicating that close attention should be paid to the behavior intervention in MSM. PMID- 28100378 TI - [Analysis on mortality of cervical cancer and its temporal trend in women in China, 2006-2012]. AB - Objective: To analyze the mortality of cervical cancer and its temporal trend in women in China between 2006 and 2012. Methods: The cause-of-death data about cervical cancer, which was abstracted from National Disease Surveillance Points and adjusted by special survey for underreporting, was used to analyze the age and area specific crude mortality rates of cervical cancer in China during 2006 2012. The age-standardized mortality rate was calculated by using world standardized population (Segi's). The Joinpoint regression model was used to obtain annual percentage change and 95%CI for assessing the time trend of mortality rate of cervical cancer from 2006 to 2012. Results: In 2012, the crude mortality rate of cervical cancer was 3.15 per 100 000 in women in China. The mortality rate in rural area (3.45/100 000) was higher than that in urban area (2.76/100 000), while the central area had the highest mortality rate of cervical cancer (3.77/100 000) compared with western area (3.23/100 000) and eastern area (2.54/100 000). The Segi's age-standardized mortality rate in eastern area increased by 2.9% (95%CI: 0.8%-5.0%) annually, an increase of 6.0% was observed in age group 30-59 years (95%CI: 1.6%-10.5%). However, the Segi's age standardized mortality rate in central area declined by 4.6% (95%CI: -5.9% - 3.3%), where the declines of 3.2% and 5.7% were observed in age groups 30-59 years and >=60 years (95%CI: - 5.0%-- 1.4% and 95% CI: - 9.3% --2.0%) and respectively. There was no significant change in cervical cancer mortality in western area. The similar trends were observed in the age-standardized mortality rate calculated according to the population of China. Conclusions: The decline of overall mortality rate of cervical cancer tended to stop in China and significant differences still exist among different areas. Our results suggest that the central/western areas and rural areas are still key areas for cervical cancer prevention and control and close attention should be paid to the increase of cervical cancer mortality in women aged 35-59 years in eastern area. It is essential to establish a systematic cervical cancer prevention network with larger population coverage to reduce the deaths caused by cervical cancer. PMID- 28100379 TI - [Cost-effectiveness analysis on colorectal cancer screening program]. AB - Objective: To evaluate the cost-effectiveness of colorectal cancer screening program in different age groups from the view of health economics. Methods: The screening compliance rates, detection rates in different age groups were calculated by using the data from colorectal cancer screening program in Jiashan county, Zhejiang province. The differences in indicator among age groups were analyzed with chi(2) test or trend chi(2) test. The ratios of cost to the number of case were calculated according to cost statistics. Results: The detection rates of immunochemical fecal occult blood test (iFOBT) positivity, advanced adenoma and colorectal cancer and early stage cancer increased with age, while the early diagnosis rates were negatively associated with age. After exclusion the younger counterpart, the cost-effectiveness of individuals aged >50 years could be reduced by 15%-30%. Conclusion: From health economic perspective, it is beneficial to start colorectal cancer screening at age of 50 years to improve the efficiency of the screening. PMID- 28100380 TI - [Cigarette consumer price and affordability in China: results from 2015 China adult survey]. AB - Objective: To analyze the change of cigarette consumption price, and understand the cigarette affordability in China. Methods: A total of 16 800 households were selected through multi-stage stratified cluster sampling. Then IPAQ was used to randomly select one family member to conduct the survey. Questionnaire from Global Tobacco Surveillance System with added country-specific questions was used. Results: Up to 50% of current smokers would buy 20 cigarettes with price of 9.9 yuan (RMB) or less, and 25% of current smokers would not buy 20 cigarettes with price exceed 5.5 yuan (RMB). Only 10% would buy 20 cigarettes with price over 19.9 yuan (RMB). The calculated median monthly expenditure for cigarettes was 181.4 yuan (RMB). From 2010 to 2015, the proportion of annual expenditure for cigarettes in disposable income per capita declined from 10.5% to 8.8% in urban area and from 21.1% to 17.3% in rural area. Conclusion: During 2010-2015, the purchasing power of Chinese smokers increased in both urban area and rural area due to the decrease of cigarette consumption price. PMID- 28100381 TI - [Trend of mortality of congenital malformation in children aged <5 years in Beijing, 2006-2015]. AB - Objective: To investigate the change in mortality of congenital malformation in children aged <5 years in Beijing from 2006 to 2015. Methods: Using the death surveillance data in children aged <5 years in Beijing from 2006 to 2015, which was collected from the real-time surveillance network, we calculated the area and age distributions of the mortality of congenital malformation in children aged <5 years in Beijing. Meanwhile, the variations of age, time and space in the causes of deaths were discussed. Results: The mortality rate of congenital malformation in the children s decreased from 1.9090/00 in 2006 to 0.7030/00 in 2015, the decrease rate was 63.17%. The decrease rate was highest in neonates (71.50%) (chi(2)=57.993, P<0.01). Expect urban area (chi(2)=3.384, P>0.05), the mortality rates of congenital malformation in the children showed a downward trend in outer suburban area and suburban area (chi(2) =40.637 and 50.646, P<0.01). The proportion of the children died of congenital malformation decreased from 32.97% in 2006 to 23.24% in 2015, which mainly occurred in infancy and neonatal period (chi(2)=9.395 and 4.354, P<0.05). The constituent ratios of the children died of neural tube defects, respiratory system abnormalities and other abnormalities decreased significantly (chi(2)=13.478, 7.358, 7.912 and 10.074, P<0.01). The constituent ratios of children died of chromosomal abnormality, multiple malformations and digestive tract abnormality didn' t decreased significantly (P>0.05). In the leading causes of deaths from congenital malformation, the mortality of congenital heart disease, neural tube defects and digestive tract atresia decreased obviously (chi(2)=70.868, 18.431 and 9.225, P<0.01), except biliary atresia (chi(2)= 1.407, P>0.05). There was an obvious area specific difference between the deaths of congenital heart disease and the deaths of neural tube defects, the mortality was higher in outer suburbs than in suburban and urban area (chi(2)=45.783 and 6.649, P<0.05). Conclusion: Although the mortality rate of children with congenital malformation in Beijing has declined year by year, it is still the main cause of deaths in children under 5 years old, and the prevention and control of related diseases should be strengthened. PMID- 28100382 TI - [Epidemiological pattern of abnormal urinary fluoride rates in population with occupational fluoride exposure in Shanghai]. AB - Objective: To investigate the epidemiological features of abnormal urinary fluoride rates in population with occupational exposure, and its relationships with age, work years and gender in Shanghai. Methods: A questionnaire survey was conducted respectively in 4 999 exposed workers and 283 non-exposed people during 2012-2015. Their urine samples were collected in plastic bottles and the fluoride ion selective electrode method was used for urinary fluoride level analysis. Logistic regression model was used to estimate associations between the abnormal rates and demographic/socioeconomic status of the study subjects. Results: In the past 4 years, the abnormal urinary fluoride rates (>=1.6 mg/L) in the population with occupational exposure was about 14.38%, it was about 1.43% in the control groups without occupational exposure. Their geometric mean of urinary fluoride content was 0.95 mg/L and 0.46 mg/L, respectively. The incidences of the abnormal rates in those aged >=50 years and 34-39 years were 19.15% and 22.39%, respectively. The abnormal rate in males was 16.87%, much higher than that in females (6.85%). The abnormal rate had an upward trend along with the increased work years, especially in those with work years of >=20 years. The abnormal rate was 23.28% in those with work years of >=20 years and 13.29% in those with work years of <4 years. The relative risk for abnormal urinary fluoride rates was higher in male group, older age group and longer work year group, the odds ratio was 2.28, 1.10 and 1.13, respectively. Conclusions: Serious challenges exist in occupational health supervision. The relevant national standards should be updated as soon as possible. Males, those aged >50 years, and those with longer work years are the risk groups for intervention measures. More efforts are needed, such as strengthening the innovative application of health examination data and the equalization of basic public health service with comprehensive occupational health supervision programs among off-farm workers in the new medical reform. PMID- 28100383 TI - [HIV antibody detection results in patients seeking medical care in Peking Union Medical College Hospital, 2003-2014]. AB - Objective: To better understand the infection status of HIV in the patients seeking medical care in Peking Union Medical College Hospital. Methods: The HIV detection data of the patients in the hospital from 2003-2014 were collected for a statistical analysis with software SPSS 19.0. Results: A total of 715 421 patients were screened, and 1 012 (0.14%) patients were HIV positive, and HIV infection were confirmed in 776 (0.11%) patients by Western Blot testing. The detection rate of HIV infection increased from 0.05% in 2003 to 0.17% in 2014 (trend chi(2)=66.83 , P=0.000), and the increase during 2012-2014 was obvious. Of the 776 newly diagnosed HIV-infected individuals, 631 (81.31%) were men and 145 (18.69%) were women. The percentage of the males infected with HIV increased from 50.00% to 90.26% (trend chi(2)=58.41, P=0.000). The median age was 36 years (interquartile range: 27-43), and the age group 18-50 years were mostly affected. In the 776 patients infected with HIV, 634 (81.70% ) were infected through sexual contacts, and the proportion of sexual transmissions increased with year (trend chi(2)=126.38, P=0.000). The proportion of infected men who have sex with men (MSM) increased from 0% in 2003 to 53.90% in 2014 (trend chi(2)=11.96, P=0.001), similar to the trend in western countries. The proportion of infected patients who were not married increased from 18.75% to 42.21% (trend chi(2)=43.74, P=0.000). The top three source departments of HIV/AIDS cases were internal medicine (51.03%), emergency room (18.30%) and dermatology (13.53%). The proportion of the HIV/AIDS patients from department of gynecology and obstetrics declined from 18.75% in 2003 to 2.60% in 2014. No HIV/AIDS patients were detected in department of surgery, department of otorhinolaryngology, department of ophthalmology, department of stomatology and health examination center in 2003, but 14 cases (9.10%), 11 cases (7.14%) and 4 cases (2.60%) were detected in these departments respectively in 2014. Conclusion: The HIV detection rate increased with year in Peking Union Medical College Hospital, suggesting the necessity of strengthened HIV test in general hospitals. MSM are the population at high risk, to whom more attention should be paid. PMID- 28100384 TI - [Seasonality of clustering of fever and diarrhea in Beijing, 2009-2015]. AB - Objective: To understand the seasonal distribution of the clustering of fever and diarrhea. Methods: Concentration degree and circular distribution methods were used to analyze the seasonal distribution of the clustering of fever and diarrhea in Beijing from 2009 to 2015. The information were collected from the Infectious Disease Surveillance Information System of Beijing. Results: The M values of the clustering of fever and diarrhea were 0.57 and 0.47. Circular distribution results showed that the clustering of fever and diarrhea angle dispersion index R values were 0.57 and 0.46 respectively, the sample average angle of Rayleigh' s test Z values were 414.14, 148.09 respectively (all P<0.01). The clustering of fever and diarrhea had seasonality. The incidence peak of fever was on October 13, and the epidemic period was during August 13-December 14. The incidence peak of diarrhea was on July 31, and the epidemic period was during May 20-October 11. Conclusion: The clustering of fever had obvious seasonality in Beijing, which mainly occurred in autumn and winter. The cluster of diarrhea had certain seasonality, which mainly occurred in summer and autumn. PMID- 28100385 TI - [Phylogenetic analysis of envelope gene of dengue virus serotype 2 in Guangzhou, 2001-2015]. AB - Objective: To investigate the molecular characteristics of dengue virus serotype 2 (DENV2) in Guangzhou during 2001-2015, and analyze the E gene of the strains isolated, the phylogenetic tree and molecular clock were constructed to know about the evolution of the strains. Methods: The serum samples of the patients were detected by real time PCR, and positive samples were used to isolate dengue virus by using C6/36 cells. The E gene of the isolated strains were sequenced. The phylogenetic tree was constructed by using software Mega 4.0, and the molecular clock was drawn by using software BEASTv1.8.2. Results: Twenty-six dengue virus strains were isolated between 2001 and 2015. They were all clustered into 2 genotypes, i.e. cosmopolitan genotype and Asian genotype I. The strains isolated in Guangzhou shared high homology with Southeast Asian strains. The cosmopolitan genotype was divided into 2 sub-genotype at about 46 and 35 years ago. The substitution rate of dengue virus serotype 2 in Guangzhou was 7.1 * 10( 4) per year per site. Conclusions: There were close relationship between the Guangzhou strains and Southeast Asian strains. Guangzhou was at high risk of imported dengue fever, outbreak of dengue hemorrhagic fever and dengue shock syndrome. There might be two ways of introduction of cosmopolitan genotype. The substitution rate of the strains in Guangzhou was similar to that in the neighbor countries. PMID- 28100387 TI - [Economic burden of esophageal cancer in China from 1996 to 2015: a systematic review]. AB - Objective: To explore existing evidence of economic burden of esophageal cancer in China over the past 20 years. Methods: Based on PubMed, CNKI and Wanfang, literatures published from 1996 to 2015 were retrieved with the key words such as " economic burden" , "cost of illness" and so on. Then the information excerpted from those literatures were analyzed after several exclusionary procedures for non-esophageal cancer related literatures. The information about subjects and data source, methodology, main results were structurally abstracted and then analyzed. Quality assessments were conducted independently by two investigators using an 11-item instrument recommended by the Agency for Healthcare Research and Quality (AHRQ) for cross-sectional studies. All the expenditure data were calculated according to year-specific personal health care consumer price index (CPI) of China, the annual growth rate was calculated according to the average speed of growth. Results: A total of 23 studies (21 individual surveys and 2 population-based surveys) were included in the analysis, in which 12 were published over the past 5 years. Among the 21 individual surveys, 17 were hospital-based and the data were obtained through medical record review, and most of which only considered the direct medical economic burden (including the average overall expenditure per patient, per time and per diem). The median expenditure per patient during 1996-2011 ranged from 7 463 to 37 647 yuan (RMB) and the average growth rate was 7.68%. The median medical expenditure per clinical visit during 1996-2013 ranged from 6 851 to 57 554 yuan (RMB) and the average growth rate was 11.89%. The median medical expenditure per diem during 1996-2010 ranged from 225 to 1 319 yuan (RMB) and the average growth rate was 12.53%. The direct medical expenditure per clinical visit varied greatly with area, which were much higher in Beijing, Shanxi and Hubei. In both individual survey and population-based survey, less data about the direct non-medical expenditure and the influence of indirect expenditure on the economic burden were reported. Conclusion: Less data are available on economic burden of esophageal cancer in China over the past 20 years and the data's comparability are poor, especially in terms of population level or indirect burden. Direct medical expenditure is on the rise, and regional differences. PMID- 28100386 TI - [Effect of extracellular signal-regulated kinas 1/2 expression and HPV16 infection and their interaction in progression of cervical cancerization]. AB - Objective: To investigate the effect of ERK1/2 protein expression and HPV16 infection, as well as their interaction in the cervical carcinogenesis. Methods: A total of 176 patients, including 34 cases with normal cervix (NC), 26 cases with cervical intraepithelial neoplasm I (CIN I), 57 cases with cervical intraepithelial neoplasm II/III (CIN II/III) and 59 cases with cervical squamous cell carcinoma (SCC), were enrolled from Shanxi Tumor Hospital, Shanxi Maternal and Child Health Center, Jincheng Coal General Hospital from September 2013 to March 2014. The information about their demographic characteristics and risk factors associated with cervical cancer was collected with structural questionnaire, and cervical tissue samples were collected from each subject. HPV16 infection was detected by PCR, and phosphorylation of ERK1/2 (p-ERK1/2) protein expression levels were detected by immunohistochemistry. Meanwhile, cervical cancer cell lines Siha (HPV16 positive) and C33A (HPV negative) were treated with ERK inhibitor U0126 in vitro. Cell proliferation was determined by living cell count, cell cycle and apoptosis was detected by flow cytometry. Results: The HPV16 infection rate (trend chi(2)=17.99, P<0.001) and p-ERK1/2 protein high expression (trend chi(2)=10.58, P=0.001) increased gradually along with the severity of cervix lesions. There was an additive interaction between HPV16 infection and p-ERK protein expression in the CIN I, CIN II/III and SCC groups. Cell experiments showed that after ERK inhibition, the proliferation of the two cells were reduced (Siha: t=6.863, P<0.001; C33A: t=7.092, P<0.001) and the apoptosis were increased (Siha: t=-5.201, P=0.006; C33A: t=-4.335, P=0.005). After ERK inhibition, the cell proliferation index of Siha (HPV16 positive) was higher than that of C33A (HPV16 negative) (t =7.066, P<0.001), but the apoptosis rate of Siha was lower than that of C33A (t=-2.431, P=0.057). Conclusions: HPV16 infection and the high expression of p-ERK1/2 could increase the risk of cervical cancer. And there might be synergistic actions between the two factors in the progression of cervical cancer. The effect of ERK1/2 activation to HPV16 infection cells might be more significant in the process of cervical cancer cell proliferation and apoptosis. PMID- 28100388 TI - [Reliability and validity of depression scales of Chinese version: a systematic review]. AB - Objective: Through systematically reviewing the reliability and validity of depression scales of Chinese version in adults in China to evaluate the psychometric properties of depression scales for different groups. Methods: Eligible studies published before 6 May 2016 were retrieved from the following database: CNKI, Wanfang, PubMed and Embase. The HSROC model of the diagnostic test accuracy (DTA) for Meta-analysis was used to calculate the pooled sensitivity and specificity of the PHQ-9. Results: A total of 44 papers evaluating the performance of depression scales were included. Results showed that the reliability and validity of the common depression scales were eligible, including the Beck depression inventory (BDI), the Hamilton depression scale (HAMD), the center epidemiological studies depression scale (CES-D), the patient health questionnaire (PHQ) and the Geriatric depression scale (GDS). The Cronbach' s coefficient of most tools were larger than 0.8, while the test-retest reliability and split-half reliability were larger than 0.7, indicating good internal consistency and stability. The criterion validity, convergent validity, discrimination validity and screening validity were acceptable though different cut-off points were recommended by different studies. The pooled sensitivity of the 11 studies evaluating PHQ-9 was 0.88 (95%CI: 0.85-0.91) while the pooled specificity was 0.89 (95%CI: 0.82-0.94), which demonstrated the applicability of PHQ-9 in screening depression. Conclusion: The reliability and validity of different depression scales of Chinese version are acceptable. The characteristics of different tools and study population should be taken into consideration when choosing a specific scale. PMID- 28100389 TI - [Effect of combination model on fitting cancer mortality and prediction]. AB - Objective: To reduce the cancer burden in the Jinchang cohort and provide evidence for developing cancer prevention strategies and performing effectiveness evaluation in the Jinchang cohort. We are fitting thirteen years of cancer mortality data from the Jinchang cohort by using six kinds of predicting methods to compare relative fitness and to select good predicting methods for the prediction of cancer mortality trends. Methods: The mortality data of cancer in Jinchnag cohort from 2001-2013 were fitted using six kinds of predicting methods: dynamic series, linear regression, exponential smoothing, autoregressive integrated moving average (ARIMA) model, grey model (GM), and Joinpoint regression. Weight coefficients of combination models were calculated by four methods: the arithmetic average method, the variance inverse method, the mean square error inverse method, and the simple weighted average method. Results: The cancer mortality was fitted and compared by using six kinds of forecasting methods; the fitting precision of the Joinpoint linear regression had the highest accuracy (87.64%), followed by linear regression (87.32%), the dynamic series (86.99%), GM (1, 1) (86.25%), exponential smoothing (85.72%) and ARIMA (1, 0, 0) (81.98%), respectively. Prediction accuracy of the combination model derived from GM (1, 1) and linear regression (>99%) was higher than that of the combination model derived from ARIMA (1, 0, 0) and GM (1, 1). The combination model derived from the GM (1, 1) and linear regression, with weight coefficients based on the arithmetic average method and the mean square error inverse method, had the best prediction effect of the four weight calculation methods. Conclusion: Prediction accuracy of the combination model, with accuracy >95%, was higher than that of the single prediction methods. PMID- 28100390 TI - [How to write high-quality epidemiological research paper VI. Strengthening the Reporting of Observational Studies in Epidemiology-Nutritional Epidemiology (STROBE-nut)]. AB - Concerns have been raised about the reporting quality in nutritional epidemiology. Therefore, strengthening the reporting of observational studies in epidemiology-nutritional epidemiology (STROBE-nut) has been proposed by extending the STROBE statement to include additional recommendations on issues related to nutritional epidemiology and dietary assessment, aiming to provide more specific guidelines on how to report observational research in the field. This paper presents a brief introduction to STROBE-nut and also an explanation of the key points in the additional items, with an example illustrating the application of the checklist. PMID- 28100391 TI - [A review of progress in research of effect of air pollutants on fetal growth]. AB - Slow fetal growth is a global public health concern because it might be associated with many diseases later in life. With the progress of technology to measure long-term air pollution exposure. Many epidemiological studies have evaluated the effects of maternal air pollutant exposure on fetal growth. In this paper, we summarize the research progress in this field after the analysis on the related literatures retrieved from the databases of Medline and Web of Science. PMID- 28100392 TI - Replication Study: The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. AB - In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Chroscinski et al., 2015) that described how we intended to replicate selected experiments from the paper "The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors "(Willingham et al., 2012). Here we report the results of those experiments. We found that treatment of immune competent mice bearing orthotopic breast tumors with anti-mouse CD47 antibodies resulted in short-term anemia compared to controls, consistent with the previously described function of CD47 in normal phagocytosis of aging red blood cells and results reported in the original study (Table S4; Willingham et al., 2012). The weight of tumors after 30 days administration of anti-CD47 antibodies or IgG isotype control were not found to be statistically different, whereas the original study reported inhibition of tumor growth with anti-CD47 treatment (Figure 6A,B; Willingham et al., 2012). However, our efforts to replicate this experiment were confounded because spontaneous regression of tumors occurred in several of the mice. Additionally, the excised tumors were scored for inflammatory cell infiltrates. We found IgG and anti-CD47 treated tumors resulted in minimal to moderate lymphocytic infiltrate, while the original study observed sparse lymphocytic infiltrate in IgG-treated tumors and increased inflammatory cell infiltrates in anti-CD47 treated tumors (Figure 6C; Willingham et al., 2012). Furthermore, we observed neutrophilic infiltration was slightly increased in anti-CD47 treated tumors compared to IgG control. Finally, we report a meta-analysis of the result. PMID- 28100393 TI - Melanoma mystery. AB - Biological variability has confounded efforts to confirm the role of PREX2 mutations in melanoma. PMID- 28100394 TI - Replication Study: Melanoma genome sequencing reveals frequent PREX2 mutations. AB - In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Chroscinski et al., 2014) that described how we intended to replicate selected experiments from the paper "Melanoma genome sequencing reveals frequent PREX2 mutations" (Berger et al., 2012). Here we report the results of those experiments. We regenerated cells stably expressing ectopic wild-type and mutant phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2 (PREX2) using the same immortalized human NRASG12D melanocytes as the original study. Evaluation of PREX2 expression in these newly generated stable cells revealed varying levels of expression among the PREX2 isoforms, which was also observed in the stable cells made in the original study (Figure S6A; Berger et al., 2012). Additionally, ectopically expressed PREX2 was found to be at least 5 times above endogenous PREX2 expression. The monitoring of tumor formation of these stable cells in vivo resulted in no statistically significant difference in tumor-free survival driven by PREX2 variants, whereas the original study reported that these PREX2 mutations increased the rate of tumor incidence compared to controls (Figure 3B and S6B; Berger et al., 2012). Surprisingly, the median tumor free survival was 1 week in this replication attempt, while 70% of the control mice were reported to be tumor-free after 9 weeks in the original study. The rapid tumor onset observed in this replication attempt, compared to the original study, makes the detection of accelerated tumor growth in PREX2 expressing NRASG12D melanocytes extremely difficult. Finally, we report meta-analyses for each result. PMID- 28100395 TI - Replication Study: Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. AB - In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Kandela et al., 2015) that described how we intended to replicate selected experiments from the paper "Coadministration of a tumor penetrating peptide enhances the efficacy of cancer drugs" (Sugahara et al., 2010). Here we report the results of those experiments. We found that coadministration with iRGD peptide did not have an impact on permeability of the chemotherapeutic agent doxorubicin (DOX) in a xenograft model of prostate cancer, whereas the original study reported that it increased the penetrance of this cancer drug (Figure 2B; Sugahara et al., 2010). Further, in mice bearing orthotopic 22Rv1 human prostate tumors, we did not find a statistically significant difference in tumor weight for mice treated with DOX and iRGD compared to DOX alone, whereas the original study reported a decrease in tumor weight when DOX was coadministered with iRGD (Figure 2C; Sugahara et al., 2010). In addition, we did not find a statistically significant difference in TUNEL staining in tumor tissue between mice treated with DOX and iRGD compared to DOX alone, while the original study reported an increase in TUNEL positive staining with iRGD coadministration (Figure 2D; Sugahara et al., 2010). Similar to the original study (Supplemental Figure 9A; Sugahara et al., 2010), we did not observe an impact on mouse body weight with DOX and iRGD treatment. Finally, we report meta-analyses for each result. PMID- 28100396 TI - Small molecules remain on target for c-Myc. AB - Targeting the transcription factor c-Myc via one of its coactivator proteins is a promising strategy for cancer therapy. PMID- 28100397 TI - Replication Study: Discovery and preclinical validation of drug indications using compendia of public gene expression data. AB - In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Kandela et al., 2015) that described how we intended to replicate selected experiments from the paper "Discovery and Preclinical Validation of Drug Indications Using Compendia of Public Gene Expression Data" (Sirota et al., 2011). Here we report the results of those experiments. We found that cimetidine treatment in a xenograft model using A549 lung adenocarcinoma cells resulted in decreased tumor volume compared to vehicle control; however, while the effect was in the same direction as the original study (Figure 4C; Sirota et al., 2011), it was not statistically significant. Cimetidine treatment in a xenograft model using ACHN renal cell carcinoma cells did not differ from vehicle control treatment, similar to the original study (Supplemental Figure 1; Sirota et al., 2011). Doxorubicin treatment in a xenograft model using A549 lung adenocarcinoma cells did not result in a statistically significant difference compared to vehicle control despite tumor volume being reduced to levels similar to those reported in the original study (Figure 4C; Sirota et al., 2011). Finally, we report a random effects meta-analysis for each result. These meta analyses show that the inhibition of A549 derived tumors by cimetidine resulted in a statistically significant effect, as did the inhibition of A549 derived tumors by doxorubicin. The effect of cimetidine on ACHN derived tumors was not statistically significant, as predicted. PMID- 28100398 TI - Making sense of replications. AB - The first results from the Reproducibility Project: Cancer Biology suggest that there is scope for improving reproducibility in pre-clinical cancer research. PMID- 28100399 TI - Mixed outcomes for computational predictions. AB - Experimental efforts to validate the output of a computational model that predicts new uses for existing drugs highlights the inherently complex nature of cancer biology. PMID- 28100400 TI - Replication Study: BET bromodomain inhibition as a therapeutic strategy to target c-Myc. AB - In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Kandela et al., 2015) that described how we intended to replicate selected experiments from the paper "BET bromodomain inhibition as a therapeutic strategy to target c-Myc" (Delmore et al., 2011). Here we report the results of those experiments. We found that treatment of human multiple myeloma (MM) cells with the small-molecular inhibitor of BET bromodomains, (+)-JQ1, selectively downregulated MYC transcription, which is similar to what was reported in the original study (Figure 3B; Delmore et al., 2011). Efficacy of (+) JQ1 was evaluated in an orthotopically xenografted model of MM. Overall survival was increased in (+)-JQ1 treated mice compared to vehicle control, similar to the original study (Figure 7E; Delmore et al., 2011). Tumor burden, as determined by bioluminescence, was decreased in (+)-JQ1 treated mice compared to vehicle control; however, while the effect was in the same direction as the original study (Figure 7C-D; Delmore et al., 2011), it was not statistically significant. The opportunity to detect a statistically significant difference was limited though, due to the higher rate of early death in the control group, and increased overall survival in (+)-JQ1 treated mice before the pre-specified tumor burden analysis endpoint. Additionally, we evaluated the (-)-JQ1 enantiomer that is structurally incapable of inhibiting BET bromodomains, which resulted in a minimal impact on MYC transcription, but did not result in a statistically significant difference in tumor burden or survival distributions compared to treatment with (+)-JQ1. Finally, we report meta-analyses for each result. PMID- 28100401 TI - Modelling the long-term evolution of worst-case Arctic oil spills. AB - We present worst-case assessments of contamination in sea ice and surface waters resulting from hypothetical well blowout oil spills at ten sites in the Arctic Ocean basin. Spill extents are estimated by considering Eulerian passive tracers in the surface ocean of the MITgcm (a hydrostatic, coupled ice-ocean model). Oil in sea ice, and contamination resulting from melting of oiled ice, is tracked using an offline Lagrangian scheme. Spills are initialized on November 1st 1980 2010 and tracked for one year. An average spill was transported 1100km and potentially affected 1.1 million km2. The direction and magnitude of simulated oil trajectories are consistent with known large-scale current and sea ice circulation patterns, and trajectories frequently cross international boundaries. The simulated trajectories of oil in sea ice match observed ice drift trajectories well. During the winter oil transport by drifting sea ice is more significant than transport with surface currents. PMID- 28100403 TI - Concordance between Women's Self-Reported Reasons for Cesarean Delivery and Hospital Discharge Records. AB - BACKGROUND: Women's self-reports of whether they had a cesarean delivery are nearly 100% accurate, but there is little extant research on how accurately women self-report reasons for cesarean delivery when asked to recall this information in the postpartum period. OBJECTIVE: We compared women's self-reported reasons for cesarean with their hospital discharge records and examined correlates of variability in agreement between sources. METHODS: Data are from the First Baby Study, a cohort of 3,006 women who gave birth to their first baby between 2009 and 2011. Survey data were linked to hospital discharge records. Among women who delivered by cesarean (n = 846), we assessed the probability that women's self reported reasons for cesarean delivery were confirmed by hospital discharge records (positive predictive value [PPV]), and whether agreement differed by reason for cesarean or by women's characteristics. RESULTS: Overall, 91% of women reported a reason for their cesarean that was present in the discharge data. PPV varied by reason for cesarean, with high PPV for dystocia, macrosomia, and cephalopelvic disproportion (91.1%), and lower PPV for malposition (81.7%). In multivariable models, women with more education and higher family income had higher odds of concordance. CONCLUSIONS: Despite some variation in the probability that women's self-reported reason for cesarean is supported by the hospital discharge record, more than 90% of women reported a reason that was found in their discharge record. Accurate recall of reasons for prior cesarean may help women and clinicians to manage future pregnancies. PMID- 28100404 TI - Gallbladder adenomyomatosis: not always benign. PMID- 28100405 TI - Dynamic Hilbert warping, a new measure of RR-interval signals evaluated in the cognitive load estimation. AB - RR interval (RRI) signals represent the time intervals between successive heart R waves. These signals are influenced by many cognitive and psychological processes. In this study, a new technique based on the combination of empirical mode decomposition and dynamic Hilbert warping (DHW) was proposed to inference cognitive states from measured RRI signals. Moreover, a set of entropic and statistical measures was extracted to characterize the regularity and temporal distribution in the phase spectra and amplitude envelope of the analytic signals. The discriminating capability of the proposed method was studied in 45 healthy subjects. They performed an arithmetic task with five levels of difficulty. The study indicated the importance of phase information in cognitive load estimation (CLE). The new phase characteristics were able to extract hidden information from the RRI signals. The results revealed a striking decrease in DHW value with increasing load level. The entropic measures of analytic signal also showed an increasing trend as the mental load increased. Although, phase information had an ability to discriminate between more distinct levels as well as between more similar ones, amplitude information was effective only in discriminating between more distinct levels. PMID- 28100406 TI - Modeling of path planning and needle steering with path tracking in anatomical soft tissues for minimally invasive surgery. AB - Steerable needles can potentially improve the effectiveness of diagnostic and therapeutic procedures, such as biopsy and cancer treatment, by increasing the targeting accuracy and reaching previously inaccessible targets. A discrete potential field algorithm based on three dimensional (3D) anatomical structures is proposed in this paper to plan the needle path in minimally invasive surgery. A 3D kinematic model of needle steering is formulated using Lie group theory. Model parameters are fitted using experimental data acquired via a 2-degree of freedom robotic device and an ultrasound imaging device. To execute the paths with variable curvatures, the model is incorporated with duty cycled spinning. Empirical formula between needle curvature and duty cycled factor is obtained through insertion experiments. To improve the targeting accuracy, a path tracking algorithm is developed by correcting for the heading error and cross-track error of the needle tip. The targeting error of the simulation is 0.29 mm. We experimentally evaluate the path tracking model and it achieves an average targeting error of 1.15 +/- 0.56 mm in 3D environments with anatomical obstacles. The results of simulation are in agreement with steering experiments, showing that the discrete potential field algorithm and path tracking model have the potential to improve targeting accuracy and advance the therapeutic and diagnostic procedures. PMID- 28100402 TI - The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age. AB - OBJECTIVE: To determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low gestational age (<=28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control). STUDY DESIGN: Caregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in >=3 surveys). RESULTS: Infants (n = 450, late surfactant n = 217, control n = 233) were 25.3 +/- 1.2 weeks' gestation and 713 +/- 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit [RB] 1.28 [95% CI 1.07-1.55]). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89 1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM. CONCLUSION: Treatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580. PMID- 28100407 TI - Pressure ulcer reconstruction in patients with heterotopic ossification after spinal cord injury: A case series and review of literature. AB - Heterotopic ossification (HO) is widely recognized as a common occurrence among patients suffering from traumatic spinal cord injuries (SCI). The exact etiology of HO formation remains unknown. Published medical and surgical management strategies are often plagued with questionable effectiveness and frequent complications. There are minimal publications regarding the management strategies of HO in SCI patients as it pertains to plastic surgery. We present a case series of patients treated at our institution who underwent treatment for pressure ulcers with underlying HO to highlight the vast spectrum of clinical phenotypes present in this population. The pathophysiology, diagnostic tools, methods of prevention, and surgical management of HO are discussed here. We believe that there are two clinically relevant patterns of HO in SCI patients. A neurogenic process that occurs early after injury is usually bilateral and involves uninjured hip joints. Pressure sores that occur are related to poor joint mobility and subsequent development of pressure points. An infection-driven process in which HO development is associated with either pressure sores or septic hip joints is generally unilateral and not always associated with hip contractures. They present different challenges and reconstructive options to plastic surgeons. Although complications such as infection and HO recurrence are common, the functional and psychological benefits of restoring hip flexion are usually worthwhile. PMID- 28100408 TI - Increased cerebrospinal fluid progranulin correlates with interleukin-6 in the acute phase of neuromyelitis optica spectrum disorder. AB - We examined progranulin (PGRN) levels in cerebrospinal fluid (CSF) samples during the acute phase in 15 patients with neuromyelitis optica spectrum disorders (NMOSD) and compared the results with those from 17 patients with multiple sclerosis (MS), 30 patients with other inflammatory neurological diseases (OIND), and 20 non-inflammatory controls (NIC). CSF PGRN levels of NMOSD patients were significantly higher than those of MS patients and NICs. These levels correlated with CSF interleukin-6 levels, CSF cell counts, CSF protein levels, improvements in the Expanded Disability Status Scale score, and affected total spinal cord lesion length in the NMOSD patients. PMID- 28100409 TI - Effect of thymectomy for thymic atrophy in myasthenia gravis: A retrospective study on 93 patients. AB - To clarify the efficacy of thymectomy among myasthenia gravis (MG) patients with and without thymoma. We classified MG patients who underwent thymectomy into 3 groups, such as thymic atrophy group, thymic follicular hyperplasia (TFH) group and thymoma group. We compared the data of clinical features and postoperative prognosis at very short-term, short-term, and medium-term. The clinical course of MG patients with atrophic thymus after thymectomy was even better than those of TFH or thymoma, in this retrospective study. However, we found no significant differences in the comparison of mean dose of prednisolone between the 3 groups at each time point. PMID- 28100410 TI - COMP serum levels: A new non-invasive biomarker of liver fibrosis in patients with chronic viral hepatitis. AB - BACKGROUND & AIMS: Recently we have shown that cartilage oligomeric matrix protein (COMP), a fibrillar collagen assembly regulator, is strongly associated with cirrhosis and hepatocellular carcinoma progression. Therefore, we assessed whether serum COMP levels can be used as a non-invasive fibrosis marker in patients with chronic viral hepatitis (CVH) and compared this marker with standard methods for disease stage assessment [histology, transient elastography (TE), APRI, FIB-4]. METHODS: Sera from 116 CVH patients, 66 HBV [24 female; median age 53(22-76)] and 50 HCV [21 female; median age 48.5(25-69)] were investigated by COMP-ELISA. APRI and FIB-4 score was calculated in all along with TE. Liver biopsy was performed in 61. Patients were divided into two groups (F1/F2 and F3/F4) according to Metavir score. RESULTS: 55/116 (47%) CVH patients were classified in F3/F4-group according to TE [14.3(9.3-75)kPa]. APRI score was >1.5 in 21/116 and FIB-4>3.25 in 20/116. Liver histology revealed 24/61 (39%) patients with significant fibrosis (stage 3-4), while 12/61 (19.7%) had cirrhosis. COMP levels correlated with TE measurements (r=0.5; p<0.001) and APRI score (r=0.23; p<0.02). The diagnostic accuracy of COMP in detecting cirrhosis was as good as TE, APRI and FIB-4 index (AUC 0.884) with sensitivity and specificity of 83.3% and 83.7% (cut-off 11.5U/L). CONCLUSIONS: COMP serum levels performed as well as TE, APRI and FIB4 score in detecting cirrhosis in CVH patients, suggesting COMP as a sensitive non-invasive, easy to perform biomarker of liver fibrosis. Further studies are needed in order to validate our findings in CVH patients. PMID- 28100411 TI - Comparison of mid-term results between conversion total knee arthroplasties following closed wedge high tibial osteotomy and primary total knee arthroplasties: A matched pair study including patellar symptom and position. AB - BACKGROUND: The purpose of this study was to compare mid-term clinical and radiographic results of conversion total knee arthroplasties (TKA) following a closed-wedge high tibial osteotomy (HTO) and primary TKAs. METHODS: A total of 32 conversion TKAs (29 patients) were compared with a matched control group of patients who had undergone primary TKA. The clinical results were evaluated using the Knee Society Knee and Function score, the Western Ontario and McMaster Universities score, patella score, and range of motion (ROM). The radiographic results were evaluated using femorotibial angle, mechanical axis (MA), the method employed by the American Knee Society, joint line height (JLH), the amount of tibial bone resection, and the Insall-Salvati ratio. The clinical and radiographic results of conversion TKAs were compared with primary TKAs. The thickness of the polyethylene insert was also compared. RESULTS: No significant differences were observed in the clinical scores or ROM between two groups. No significant differences were detected in femorotibial angle, MA, and position of the components between two groups. The amount of tibial bone resection and pre operative JLH both were significantly lower in the conversion group than those in the control group, although postoperative JLH and pre and postoperative Insall Salvati ratio did not differ between two groups. No significant difference in the thickness of the polyethylene insert was identified between two groups. CONCLUSIONS: The previous closed-wedge HTO itself had no detrimental effect on the mid-term outcome of the subsequent TKA, including patellar symptom and position. No significant differences in the postoperative joint line and patella height were detected between the conversion and primary TKA groups. PMID- 28100414 TI - Stephen Kuffler. PMID- 28100413 TI - Bipolar Disorder and Dementia: Weighing the Evidence. PMID- 28100412 TI - Virome of US bovine calf serum. AB - Using viral metagenomics we analyzed four bovine serum pools assembled from 715 calves in the United States. Two parvoviruses, bovine parvovirus 2 (BPV2) and a previously uncharacterized parvovirus designated as bosavirus (BosaV), were detected in 3 and 4 pools respectively and their complete coding sequences generated. Based on NS1 protein identity, bosavirus qualifies as a member of a new species in the copiparvovirus genus. Also detected were low number of reads matching ungulate tetraparvovirus 2, bovine hepacivirus, and several papillomaviruses. This study further characterizes the diversity of viruses in calf serum with the potential to infect fetuses and through fetal bovine serum contaminate cell cultures. PMID- 28100415 TI - A 10-year trend of dental treatments under general anesthesia of children in Taipei Veterans General Hospital. AB - BACKGROUND: General anesthesia (GA) as a pediatric dental procedure is a well established method of behavior management. However, studies of pediatric dentistry under GA have mostly focused on handicapped patients, and various retrospective studies in Taiwan have mainly reviewed only a limited number of years. The purpose of the present study was to report trends in pediatric dental treatment performed under GA over the past 10 years. METHODS: A retrospective review of the hospital records of patients receiving dental treatment under GA from 2006 until 2015 was performed. The patients were divided into three age groups: < 3 years, 3-6 years, and > 6 years. A range of information including basic patient characteristics and types of dental treatment was identified and then analyzed. RESULTS: A total of 791 cases (< 3 years old: 65 cases, 3-6 years old: 492, > 6 years old: 235; 549 male, 242 female) were treated under GA. The case number was found to have increased from 94 during 2006-2007 to 238 during 2014-2015, with the increase being especially pronounced among those aged 3-6 years (2006-2007: 49, 2014-2015: 165). The most common treatments (extraction, restoration, and pulp therapy) were associated with multiple dental caries (684, 86.4%). The < 3-years-old group was characterized by the highest decayed, extracted, and filled surface and decayed, missing, and filled surface indices; the highest mean number of treated teeth; and the highest mean number of treated teeth by composite resin fillings. The 3-6-years-old group had the highest number of primary teeth extractions. The > 6-years-old group had the lowest mean number of treated teeth by stainless-steel crowns (SSCs) and fewest cases treated with pulp therapy. From 2011 onwards, the number of primary tooth extractions significantly increased, while in 2013, there was a crossover whereby the SSC count surpassed the composite resin filling count. CONCLUSION: Over the past 10 years, there has been an increased use of GA for pediatric dental treatments, in particular, in cases with multiple dental caries. In addition, there has also been an increasing trend towards extraction of primary teeth and the use of SSCs. PMID- 28100417 TI - Long-range and regional transported size-resolved atmospheric aerosols during summertime in urban Shanghai. AB - In this study, the concentrations of water soluble ions (WSI), organic carbon (OC), and elemental carbon (EC) of size-resolved (0.056-18MUm) atmospheric aerosols were measured in July and August 2015 in Shanghai, China. Backward trajectory model and potential source contribution function (PSCF) model were used to identify the potential source distributions of size-resolved particles and PM1.8-associated atmospheric inorganic and carbonaceous aerosols. The results showed that the average mass concentrations of PM0.1, PM1, and PM1.8 were 21.21, 82.90, and 100.1MUgm-3 in July and 7.00, 29.21, and 35.10MUgm-3 in August, respectively, indicating that the particulate matter pollution was more serious in July than in August in this study due to the strong dependence of the aerosol species on the air mass origins. The trajectory cluster analysis revealed that the air masses originated from heavily industrialized areas including the Pearl River Delta (PRD) region, the Yangtze River Delta (YRD) region and the Beijing Tianjin region were characterised with high OC and SO42- loadings. The results of PSCF showed that the pollution in July was mainly influenced by long-range transport while it was mainly associated to local and intra-regional transport in August. Besides the contributions of anthropogenic sources from YRD and PRD region, ship emissions from the East China Sea also made a great contribution to the high loadings of PM1.8 and PM1.8-associated NO3-, NH4+, and EC in July. SO42- in Shanghai was dominantly ascribed to anthropogenic sources and the high PSCF values for PM1.8-associated SO42- observed in August was mainly due to the ship emissions of Shanghai port, such as Wusong port and Yangshan deep-water port. These results indicated that the particulate pollutants from long-range transported air masses and shipping made a significant contribution to Shanghai's air pollution. PMID- 28100416 TI - A retrospective analysis of the clinical effects of neoadjuvant combination therapy with full-dose gemcitabine and radiation therapy in patients with biliary tract cancer. AB - PURPOSE: This study aims to evaluate survival and the objective response to neoadjuvant combination therapy with gemcitabine and radiation therapy in patients with biliary tract cancer. METHODS: The chemoradiation therapy regimen consisted of 3 cycles of full-dose gemcitabine (1000 mg/m2 at days 1, 8, and 15, every 4 weeks) with 50-60 Gy radiation. We compared 27 patients who received neoadjuvant chemoradiation therapy and 79 patients who were treated without neoadjuvant therapy. Hemi-hepatectomy or pancreatoduodenectomy was planned for all of the patients in the study population. CT-based staging was used to adjust for the pre-treatment characteristics of the patients. RESULTS: After confirming the reproducibility of CT-based staging, we analyzed the survival of the patients. The multivariate analysis showed that the absence of arterial invasion on CT, the absence of lymph node swelling, and neoadjuvant therapy were independent prognostic factors. The three-year recurrence-free survival (RFS) rates in patients treated with and without neoadjuvant therapy were 78% and 58%, respectively (P = 0.0263). The adjusted overall survival (OS) (determined by the inverse probability of treatment weighting method using the inverse propensity score) was improved by neoadjuvant therapy (P = 0.00187); the hazard ratio was 0.3505. CONCLUSIONS: Neoadjuvant chemoradiation therapy might have the potential to improve RFS and OS. REGISTRATION: UMIN-CTR UMIN000015450. PMID- 28100418 TI - Persistent organic pollutants in the Atlantic and southern oceans and oceanic atmosphere. AB - Persistent organic pollutants (POPs) continue to cycle through the atmosphere and hydrosphere despite banned or severely restricted usages. Global scale analyses of POPs are challenging, but knowledge of the current distribution of these compounds is needed to understand the movement and long-term consequences of their global use. In the current study, air and seawater samples were collected Oct. 2007-Jan. 2008 aboard the Icebreaker Oden en route from Goteborg, Sweden to McMurdo Station, Antarctica. Both air and surface seawater samples consistently contained alpha-hexachlorocyclohexane (alpha-HCH), gamma-HCH, hexachlorobenzene (HCB), alpha-Endosulfan, and polychlorinated biphenyls (PCBs). Sample concentrations for most POPs in air were higher in the northern hemisphere with the exception of HCB, which had high gas phase concentrations in the northern and southern latitudes and low concentrations near the equator. South Atlantic and Southern Ocean seawater had a high ratio of alpha-HCH to gamma-HCH, indicating persisting levels from technical grade sources. The Atlantic and Southern Ocean continue to be net sinks for atmospheric alpha-, gamma-HCH, and Endosulfan despite declining usage. PMID- 28100420 TI - Osteoarthritis year in review 2016: mechanics. AB - Inappropriate biomechanics, namely wear-and-tear, has been long believed to be a main cause of osteoarthritis (OA). However, this view is now being re-evaluated, especially when examined alongside mechanobiology and new biomechanical studies. These are multiscale experimental and computational studies focussing on cell- and tissue-level mechanobiology through to organ- and whole-body-level biomechanics, which focuses on the biomechanical and biochemical environment of the joint tissues. This review examined papers from April 2015 to April 2016, with a focus on multiscale experimental and computational biomechanical studies of OA. Assessing the onset or progression of OA at organ- and whole-body-levels, gait analysis, medical imaging and neuromusculoskeletal modelling revealed the extent to which tissue damage changes the view of inappropriate biomechanics. Traditional gait analyses studies reported that conservative treatments can alter joint biomechanics, thereby improving pain and function experienced by those with OA. Results of animal models of OA were consistent with these human studies, showing interactions among bone, cartilage and meniscus biomechanics and the onset and/or progression OA. Going down size scales, experimental and computational studies probed the nanosize biomechanics of molecules, cells and extracellular matrix, and demonstrated how the interactions between biomechanics and morphology affect cartilage dynamic poroelastic behaviour and pathways to OA. Finally, integration of multiscale experimental data and computational models were proposed to predict cartilage extracellular matrix remodelling and the development of OA. Summarising, experimental and computational methods provided a nuanced biomechanical understanding of the sub-cellular, cellular, tissue, organ and whole-body mechanisms involved in OA. PMID- 28100419 TI - Redox dysregulation, immuno-inflammatory alterations and genetic variants of BDNF and MMP-9 in schizophrenia: Pathophysiological and phenotypic implications. AB - BACKGROUND: Although a clear mechanism underlying the pathophysiology of schizophrenia (SZ) remains elusive, oxidative stress, inflammatory syndrome and immune activation have become an attractive hypothesis for explaining the pathophysiology of SZ. Data from prior studies on the role of matrix metalloproteinase 9 (MMP-9) and brain-derived neurotrophic factor (BDNF) single nucleotide polymorphisms (SNPs) in SZ are contradictory. We aimed to investigate whether oxidative stress, inflammatory and immune activation markers as well as MMP-9 levels may be implicated in SZ pathogenesis. The association of MMP-9 and BDNF SNPs with the clinical expression of SZ was examined. SUBJECTS AND METHODS: Ninety-four subjects were recruited, including 44 SZ patients and 50 healthy controls. Serum levels of thiobarbituric acid reactive substances (TBARS), protein carbonyl content (PCC), nitrite, C-reactive protein (CRP), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), Beta-2 microglobulin (Beta2M), complement component 3 (C3), C4 and MMP-9 were measured. The MMP-9 -1562C>T and BDNF196G>A SNPs were genotyped using polymerase chain reaction-restriction fragment length polymorphism assay. Psychopathology was assessed using the positive and negative syndrome scale (PANSS). RESULTS: SZ patients showed significantly higher TBARS, PCC, nitrite, CRP, IL-6, TNF-alpha, Beta2M, C3 and MMP-9 levels than controls. In distinguishing SZ patients from healthy controls, CRP and MMP-9 yielded similar discriminatory performance, and both perform better than IL-6, Beta2M, C3, nitrite, TBARS, PCC, TNF-alpha and C4. The MMP-9 -1562C>T SNP genotypes distribution didn't differ significantly between controls and SZ patients. As compared to controls, SZ patients harbor a significantly higher frequency of the BDNF196GG genotype and a lower frequency of the BDNF196GA/AA genotype. Patients carrying the MMP-9 -1562CC or BDNF196GG genotype revealed a significantly higher PANSS than those carrying MMP-9 -1562CT/TT or BDNF196GA/AA genotype. Male gender and the MMP-9 -1562CC genotype were identified as independent predictive factors for higher PANSS. CONCLUSIONS: Redox dysregulation and alterations in the immuno-inflammatory pathways are major culprits in the pathogenesis of SZ. MMP-9 and BDNF SNPs are associated with the clinical phenotype of SZ and, thus, may be a useful marker predicting the phenotypic expression and prognosis of SZ patients. PMID- 28100421 TI - Osteoarthritis year in review 2016: biology. AB - This review highlights a selection of literature in the area of osteoarthritis biology published between the 2015 and 2016 Osteoarthritis Research Society International (OARSI) World Congress. Highlights were selected from a pubmed search covering cartilage, bone, inflammation and pain. A personal selection was made based, amongst other things, on topics presented during the 2015 conference. This covers circadian rhythm, TGF-beta signaling, autophagy, SIRT6, exercise, lubricin, TLR's, pain and NGF. Furthermore, in this review we have made an effort to connect these seemingly distant topics into one scheme of connections between them, revealing a theoretical big picture underneath. PMID- 28100422 TI - Osteoarthritis year in review 2016: genetics, genomics and epigenetics. AB - The purpose of this narrative review is to provide an overview of last year's publications in the field of genetics, genomics and epigenetics in the osteoarthritis (OA) field. Major themes arising from a Pubmed search on (epi)genetics in OA were identified. In addition, general developments in the fast evolving field of (epi)genetics are reviewed and relevance for the OA field is summarized. In the last 5 years, a number of genome-wide association studies have identified a modest number of genetic loci associated to OA. Continued functional research into these DNA variants is showing putative biological mechanisms underlying these associations. Over the last year, no additional large genome-wide association studies were published, but there clearly remains much to be discovered in the OA genetic field. A lot of research has been done into the epigenetics of OA over the last year. Several genome-wide screens examining the methylome of osteoarthritic cartilage were done. Pathway analysis confirmed deregulation of developmental and extracellular pathways in OA cartilage. Over the last year many microRNAs (miRNAs) have been identified that potentially play important roles in cartilage homeostasis and/or OA process. Continued research will learn whether these identified miRNAs are truly causal and can be used in clinical applications. Many of the epigenetic findings need further confirmation, but they highlight potential novel pathways involved in cartilage biology and OA. PMID- 28100423 TI - Osteoarthritis year in review 2016: clinical. AB - Both epidemiologic and clinical research continues to be performed in osteoarthritis (OA). While epidemiologic studies identify risk factors for incident and progressive disease, clinical studies explore the role of both non pharmacologic and pharmacologic treatments, including oral and intra-articular therapies. We performed a systematic review of the literature using PubMed for the time period between April 1, 2015 to February 22, 2016. Selected publications in the areas of both epidemiology and treatment are reviewed in this article. PMID- 28100424 TI - Adjunctive antidepressants in bipolar depression. PMID- 28100425 TI - Safety and efficacy of adjunctive second-generation antidepressant therapy with a mood stabiliser or an atypical antipsychotic in acute bipolar depression: a systematic review and meta-analysis of randomised placebo-controlled trials. AB - BACKGROUND: Although mania and hypomania define bipolar disorder, depressive episodes are more common and impairing, with few proven treatments. Adjunctive therapy with second-generation antidepressants is widely used to treat acute bipolar depression, but their efficacy and safety remain controversial. METHODS: In this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to Jan 31, 2016, for randomised, double-blind, placebo-controlled trials of second-generation antidepressants adjunctive to a mood stabiliser or an antipsychotic in patients with acute bipolar depression. We extracted data from published reports. The primary outcome was change in clinician-rated depressive symptom score; secondary outcomes were clinical response, clinical remission, treatment-emergent mania or hypomania, and tolerability (using dropout rates as a proxy). We used pooled random-effects models, subgroup comparisons, and meta regression for analyses. We made subgroup comparisons on the basis of mood stabiliser or antipsychotic treatment and did meta-regression examining trial duration. This study is registered with PROSPERO, number CRD#42015016024. FINDINGS: We identified six trials representing 1383 patients with bipolar depression. Second-generation antidepressants were associated with a small but significant improvement in clinician-rated depressive symptom score (standardised mean differences 0.165 [95% CI 0.051-0.278], p=0.004). However, clinical response and remission rates did not differ significantly between patients receiving adjunctive antidepressants and those receiving placebo (1.158 [0.840-1.597], p=0.371 for clinical response; 1.220 [0.874-1.703], p=0.243 for remission). Acute treatment was not associated with an increased risk of treatment-emergent mania or hypomania (0.926 [0.576-1.491], p=0.753), but 52 week extension periods were associated with an increase in risk (1.774 [1.018-3.091], p=0.043). INTERPRETATION: Adjunctive second-generation antidepressants are associated with reduced symptoms of acute bipolar depression, but the magnitude of benefit is small because they do not increase clinical response or remission rates. However, these medications should be used only in the short term because prolonged use is associated with an increased risk of treatment-emergent mania or hypomania. FUNDING: None. PMID- 28100426 TI - Ferumoxytol MRA for transcatheter aortic valve replacement planning with renal insufficiency. AB - BACKGROUND: Computed tomography angiography (CTA) is the test of choice for pre procedure imaging of transcatheter aortic valve replacement (TAVR) candidates. The iodinated contrast required, however, increases the risk of renal dysfunction in patients with pre-existing renal failure. Ferumoxytol is a magnetic resonance imaging (MRI) contrast agent that can be used with renal failure. Its long vascular resonance time allows gated MRA sequences that approach CTA in image quality. We present respiratory and cardiac gated MRA enabled by ferumoxytol that can be post-processed in an analogous fashion to CTA. METHODS: Seven patients with renal failure presenting for TAVR were imaged with respiratory and cardiac gated MRA at 3T using ferumoxtyol for contrast. Aortic annulus, root and peripheral access dimensions were calculated in a fashion identical to that used for CTA. Of these, 6 patients underwent a TAVR procedure and 5 had intraoperative valve assessment with transesophageal echocardiograph (TEE) using standard clinical protocols that employed both two- and three-dimensional techniques. RESULTS: Good correlation between MRA aortic annulus measurements and those from TEE were shown in 5 patients with mean annulus area of 392.4mm2 (290-470 range) versus 374.1mm2 (285-440 range), with a pairwise correlation coefficient of 0.92, p=0.029. All patients received Sapien valve implants (one 20mm, three 23mm, and two 26mm valves). Access decisions were guided by MRA with no complications. Annulus sizing resulted in no greater than trace/mild aortic regurgitation in all patients. CONCLUSIONS: Ferumoxytol MRA is a safe alternative to CTA in patients with renal failure for pre-TAVR analysis of the aortic root and peripheral access. PMID- 28100427 TI - The possible role of propofol in drug-induced torsades de pointes: A real-world single-center analysis. AB - BACKGROUND: Torsades de pointes (TdP) is a polymorphic ventricular tachycardia associated with QT prolongation. Propofol is a sedative-anesthetic with proarrhythmic effects on cardiac myocytes. We performed a retrospective study to determine the incidence of TdP following propofol exposure at Mayo Clinic (Rochester, MN) from 08/11/1998-11/20/2015. METHODS: We queried our database using key search terms to identify patients exposed to propofol who developed TdP perioperatively or during non-surgical sedation. QT intervals were obtained from electrocardiograms (ECGs) performed before propofol exposure and after documented TdP and were corrected using Fridericia and Framingham methods. T wave peak-to end (Tp-e)/QT ratios were also calculated. RESULTS: A total of 628,784 patients received propofol over 17.3years. Of these patients, 21 developed TdP (12, postoperatively; 3, intraoperatively; 6, during sedation). There were 17 patients who were exposed to at least one factor associated with QT-prolongation, including QT-prolonging medications in 8 patients, heart rate <60 beats per minute in 8 patients, potassium <3.5mmol/L in 4 patients, magnesium <1.8mg/dL in 2 patients, and subarachnoid hemorrhage in 2 patients. The number of patients with QTc>500ms using Fridericia correction was significantly higher from baseline following exposure to propofol (1 patient vs 6 patients, P=0.04); however no significant difference was observed with Framingham correction. CONCLUSION: In our study, TdP after propofol administration occurred with an annual incidence of 1.93 per million and was often associated with other risk factors. Nevertheless, propofol should be administered with caution in patients at risk of developing TdP. PMID- 28100428 TI - Heart failure with preserved ejection fraction has a better long-term prognosis than heart failure with reduced ejection fraction in old patients in a 5-year follow-up retrospective study. AB - BACKGROUND: The issue of whether prognosis is similar between heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) remains unresolved. Because of the problem of inconsistency in the diagnostic criteria and because there is currently no lifesaving therapy available for HFpEF, it seems to be the right time to study the outcome of a clearly defined HFpEF compared with HFrEF in contemporary heart failure (HF) therapy. This study investigates 5-year-mortality and its prognostic factors in old patients with HFpEF compared with those with HFrEF. METHODS: This is a retrospective study. Patients hospitalized at Sahlgrenska University Hospital/Ostra for HF were consecutively included between May 2007 and April 2008. Diagnosis were reviewed and re-evaluated for each patient. The outcome measure was all-cause mortality and collected from May 2007 and 2013. RESULTS: Mean age of the study population (n=289) was 79+/-7years. One third of the HF cohort had HFpEF. When adjusted for age HFrEF patients had a 42% higher 5-year mortality than HFpEF. By logistic regression analysis age, female sex, pulmonary disease, renal dysfunction, loop diuretics and aldosterone receptor antagonist were negatively associated with prognosis in HFpEF, whereas angiotensin converting enzyme inhibitors/angiotensin II receptor blockers (ACEi/ARBs) and Statins were positive prognostic factors. In HFrEF age, atrial fibrillation, NT proBNP and loop diuretics were negative predictive factors, while treated hypertension, percutaneous coronary intervention, ACEi/ARBs and beta-blockers were positive factors for survival. CONCLUSION: HFpEF proved to have a better long-term prognosis than HFrEF and a distinct prognostic risk profile. PMID- 28100429 TI - Right ventricular function measured by TAPSE in obese subjects at the time of acute myocardial infarction and 2year outcomes. AB - INTRODUCTION: Obesity is associated with significantly better outcome after acute myocardial infarction (AMI), a phenomenon known as 'obesity paradox'. Tricuspid annular plane systolic excursion (TAPSE) is an echocardiographic measurement of right ventricular (RV) function and has prognostic implications at the time of AMI. METHODS: We examined the difference in RV function among patients admitted with AMI according to obesity status. In a single center cohort analysis of 105 patients admitted between 2010 and 2011 with the diagnosis of AMI. Demographic, anthropometric data and cardiovascular risk factors were prospectively collected. All subjects had echocardiogram within 48h of AMI diagnosis for TAPSE calculations. Subjects were divided into two groups based on their obesity status. RESULTS: Obese subjects had better RV function compared to non-obese, TAPSE: 19+/-6.6 vs. 16+/-4.9mm; p 0.02 at the time of AMI. There was no significant difference in TAPSE between OSA and non-OSA subjects, 19+/-6.3 vs. 17+/-6.2mm; p 0.21. After 2years of follow up, patients with obesity and better RV function were less likely to develop new onset heart failure (HF) with OR 0.30 (95% CI 0.09-0.93; p 0.03) and OR 0.31 (95% CI 0.11-0.76; p 0.007) respectively. CONCLUSION: Obese patients had better RV function measured by TAPSE at the time AMI when compared non-obese patients. Patients with better RV function at the time of AMI were less likely to develop new-onset HF and there was a trend in the obese group to less likely develop new-onset HF after 2year follow up. PMID- 28100430 TI - Three decades later: The fate of the population of patients who underwent the Atriopulmonary Fontan procedure. AB - OBJECTIVE: To review our experience of patients with an atrio-pulmonary Fontan circulation to determine their long-term outcomes. METHODS AND RESULTS: A retrospective analysis of long-term follow-up data using the Australia and New Zealand Fontan Registry was performed. There were 215 patients surviving hospital discharge after an atrio-pulmonary Fontan completion. A total of 163 patients were alive at latest follow-up, with 52 deaths. Twelve patients had required heart transplantation and 95 had Fontan failure (death, transplantation, Fontan takedown, Fontan conversion, severe systemic ventricular dysfunction or NYHA>=3). Twenty-eight year freedom from death, death and transplantation and Fontan failure were 69% (95% CI 61-78%), 64% (95% CI 56-74%) and 45% (95% CI 36-55%) respectively. One hundred and thirty patients developed atrial arrhythmias. Freedom from arrhythmia at 28years post Fontan was 22.9% (95% CI: 15.1-30.8). Development of arrhythmia increased the likelihood of death (HR:2.97, 95%CI 1.50 5.81; p=0.002), death and heart transplantation (HR:3.11, 95%CI 1.64-5.87; p<0.001) and Fontan failure (HR:4.78 95%CI 2.95-7.74; p<0.001). There were 42 patients who had thromboembolic events, of which only 12 were therapeutically anti-coagulated. Two-thirds of the surviving patients (86/126) with an intact atrio-pulmonary Fontan were regularly reviewed. Patients receiving follow-up care with general cardiologists without specialised training were more likely to face Fontan failure than those managed by cardiologists with specialist training in congenital heart disease (HR: 1.94, 95% CI 1.16-3.24; p=0.02). The majority of the surviving patients (81/86) remained physically active and almost two-thirds (54/86) were currently employed. CONCLUSION: Two-thirds of the patients who underwent a classical atrio-pulmonary Fontan are still alive 3 decades later. The majority are affected by the burden of arrhythmias but remain functionally active today. These challenging patients should only receive follow-up care from cardiologists with specialised training. PMID- 28100431 TI - 4CMenB vaccine effectiveness: reasons for optimism. PMID- 28100432 TI - Effectiveness and impact of a reduced infant schedule of 4CMenB vaccine against group B meningococcal disease in England: a national observational cohort study. AB - BACKGROUND: In September, 2015, the UK became the first country to introduce the multicomponent group B meningococcal (MenB) vaccine (4CMenB, Bexsero) into a publicly funded national immunisation programme. A reduced two-dose priming schedule was offered to infants at 2 months and 4 months, alongside an opportunistic catch-up for 3 month and 4 month olds. 4CMenB was predicted to protect against 73-88% of MenB strains. We aimed to assess the effectiveness and impact of 4CMenB in vaccine-eligible infants in England. METHODS: Public Health England (PHE) undertakes enhanced surveillance of meningococcal disease through a combination of clinical, public health, and laboratory reporting. Laboratory confirmed cases of meningococcal disease are followed up with PHE local health protection teams, general practitioners, and hospital clinicians to collect demographic data, vaccination history, clinical presentation, and outcome. For cases diagnosed between Sept 1, 2015, and June 30, 2016, vaccine effectiveness was assessed using the screening method. Impact was assessed by comparing numbers of cases of MenB in vaccine-eligible children to equivalent cohorts in the previous 4 years and to cases in vaccine-ineligible children. FINDINGS: Coverage of 4CMenB in infants eligible for routine vaccination was high, achieving 95.5% for one dose and 88.6% for two doses by 6 months of age. Two-dose vaccine effectiveness was 82.9% (95% CI 24.1-95.2) against all MenB cases, equivalent to a vaccine effectiveness of 94.2% against the highest predicted MenB strain coverage of 88%. Compared with the prevaccine period, there was a 50% incidence rate ratio (IRR) reduction in MenB cases in the vaccine-eligible cohort (37 cases vs average 74 cases; IRR 0.50 [95% CI 0.36-0.71]; p=0.0001), irrespective of the infants' vaccination status or predicted MenB strain coverage. Similar reductions were observed even after adjustment for disease trends in vaccine-eligible and vaccine-ineligible children. INTERPRETATION: The two-dose 4CMenB priming schedule was highly effective in preventing MenB disease in infants. Cases in vaccine eligible infants halved in the first 10 months of the programme. While ongoing national surveillance will continue to monitor the longer-term impact of the programme, these findings represent a step forward in the battle against meningococcal disease and will help reassure that the vaccine protects against this deadly infection. FUNDING: Public Health England. PMID- 28100433 TI - PR1 peptide vaccine in myeloid malignancies. PMID- 28100434 TI - MNX1: a novel prostate cancer oncogene. PMID- 28100435 TI - Suicide in survivors of childhood and young adult cancers. PMID- 28100436 TI - Incidence of breast cancer in women with type 2 diabetes. PMID- 28100437 TI - Finding the right dose of rifampicin, and the right dose of optimism. PMID- 28100439 TI - Considerations for an Access-Centered Design of the Fever Thermometer in Low Resource Settings: A Literature Review. AB - BACKGROUND: The lack of adequate information about fever in low-resource settings, its unreliable self-assessment, and poor diagnostic practices may result in delayed care and under-or-overdiagnosis of diseases such as malaria. The mismatches of existing fever thermometers in the context of use imply that the diagnostic tools and connected services need to be studied further to address the challenges of fever-related illnesses and their diagnostics. OBJECTIVE: This study aims to inform a product-service system approach to design a reliable and accessible fever thermometer and connected services, as well as contribute to the identification of innovative opportunities to improve health care in low-resource settings. METHODS: To determine what factors impede febrile people seeking health care to access adequate fever diagnostics, a literature search was conducted in Google Scholar and PubMed with relevant keywords. Next, these factors were combined with a patient journey model to design a new product-service system for fever diagnostics in low-resource settings. RESULTS: In total, 37 articles were reviewed. The five As framework was used to categorize the identified barriers. The results indicate that there is a poor distribution of reliable fever diagnostic practices among remote communities. This paper speaks to the global public health and design communities. Three complementary considerations are discussed that support the idea of a more holistic approach to the design of fever diagnostics: (1) understanding of the fever diagnostics patient journey, (2) identifying user groups of the thermometers in a specific health care system, and (3) assessing different needs and interests of the different users. CONCLUSIONS: Access to basic, primary health care may be enhanced with better information and technology design made through the involvement of system users. PMID- 28100440 TI - It's About Me: Patients' Experiences of Patient Participation in the Web Behavior Change Program for Activity in Combination With Multimodal Pain Rehabilitation. AB - BACKGROUND: Patients' participation in their health care is recognized as a key component in high-quality health care. Persons with persistent pain are recommended treatments with a cognitive approach from a biopsychosocial explanation of pain, in which a patient's active participation in their rehabilitation is in focus. Web-based interventions for pain management have the potential to increase patient participation by enabling persons to play a more active role in rehabilitation. However, little is known about patients' experiences of patient participation in Web-based interventions in clinical practice. OBJECTIVE: The objective of our study was to explore patients' experiences of patient participation in a Web Behavior Change Program for Activity (Web-BCPA) in combination with multimodal rehabilitation (MMR) among patients with persistent pain in primary health care. METHODS: Qualitative interviews were conducted with 15 women and 4 men, with a mean age of 45 years. Data were analyzed with qualitative content analysis. RESULTS: One theme, "It's about me," and 4 categories, "Take part in a flexible framework of own priority," "Acquire knowledge and insights," "Ways toward change," and "Personal and environmental conditions influencing participation," were developed. Patient participation was depicted as being confirmed in an individualized and structured rehabilitation framework of one's own choice. Being confirmed was fundamental to patient participation in the interaction with the Web-BCPA and with the health care professionals in MMR. To acquire knowledge and insights about pain and their life situation, through self-reflection in the solitary work in the Web-BCPA and through feedback from the health care professionals in MMR, was experienced as patient participation by the participants. Patient participation was described as structured ways to reach their goals of behavior change, which included analyzing resources and restrictions, problem solving, and evaluation. The individual's emotional and cognitive resources and restrictions, as well as health care professionals and significant others' attitudes and behavior influenced patient participation in the rehabilitation. To some extent there were experiences of restrained patient participation through the great content of the Web-BCPA. CONCLUSIONS: Patient participation was satisfactory in the Web-BCPA in combination with MMR. The combined treatment was experienced to increase patient participation in the rehabilitation. Being confirmed through self-identification and finding the content of the Web-BCPA trustworthy was emphasized. Patient participation was experienced as a learning process leading to new knowledge and insights. Higher user control regarding the timing of the Web-BCPA and therapist guidance of the content may further increase patient participation in the combined treatment. PMID- 28100438 TI - High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi arm, multi-stage randomised controlled trial. AB - BACKGROUND: Tuberculosis is the world's leading infectious disease killer. We aimed to identify shorter, safer drug regimens for the treatment of tuberculosis. METHODS: We did a randomised controlled, open-label trial with a multi-arm, multi stage design. The trial was done in seven sites in South Africa and Tanzania, including hospitals, health centres, and clinical trial centres. Patients with newly diagnosed, rifampicin-sensitive, previously untreated pulmonary tuberculosis were randomly assigned in a 1:1:1:1:2 ratio to receive (all orally) either 35 mg/kg rifampicin per day with 15-20 mg/kg ethambutol, 20 mg/kg rifampicin per day with 400 mg moxifloxacin, 20 mg/kg rifampicin per day with 300 mg SQ109, 10 mg/kg rifampicin per day with 300 mg SQ109, or a daily standard control regimen (10 mg/kg rifampicin, 5 mg/kg isoniazid, 25 mg/kg pyrazinamide, and 15-20 mg/kg ethambutol). Experimental treatments were given with oral 5 mg/kg isoniazid and 25 mg/kg pyrazinamide per day for 12 weeks, followed by 14 weeks of 5 mg/kg isoniazid and 10 mg/kg rifampicin per day. Because of the orange discoloration of body fluids with higher doses of rifampicin it was not possible to mask patients and clinicians to treatment allocation. The primary endpoint was time to culture conversion in liquid media within 12 weeks. Patients without evidence of rifampicin resistance on phenotypic test who took at least one dose of study treatment and had one positive culture on liquid or solid media before or within the first 2 weeks of treatment were included in the primary analysis (modified intention to treat). Time-to-event data were analysed using a Cox proportional-hazards regression model and adjusted for minimisation variables. The proportional hazard assumption was tested using Schoelfeld residuals, with threshold p<0.05 for non-proportionality. The trial is registered with ClinicalTrials.gov (NCT01785186). FINDINGS: Between May 7, 2013, and March 25, 2014, we enrolled and randomly assigned 365 patients to different treatment arms (63 to rifampicin 35 mg/kg, isoniazid, pyrazinamide, and ethambutol; 59 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, SQ109; 57 to rifampicin 20 mg/kg, isoniazid, pyrazinamide, and SQ109; 63 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, and moxifloxacin; and 123 to the control arm). Recruitment was stopped early in the arms containing SQ109 since prespecified efficacy thresholds were not met at the planned interim analysis. Time to stable culture conversion in liquid media was faster in the 35 mg/kg rifampicin group than in the control group (median 48 days vs 62 days, adjusted hazard ratio 1.78; 95% CI 1.22-2.58, p=0.003), but not in other experimental arms. There was no difference in any of the groups in time to culture conversion on solid media. 11 patients had treatment failure or recurrent disease during post-treatment follow-up: one in the 35 mg/kg rifampicin arm and none in the moxifloxacin arm. 45 (12%) of 365 patients reported grade 3-5 adverse events, with similar proportions in each arm. INTERPRETATION: A dose of 35 mg/kg rifampicin was safe, reduced the time to culture conversion in liquid media, and could be a promising component of future, shorter regimens. Our adaptive trial design was successfully implemented in a multi-centre, high tuberculosis burden setting, and could speed regimen development at reduced cost. FUNDING: The study was funded by the European and Developing Countries Clinical Trials partnership (EDCTP), the German Ministry for Education and Research (BmBF), and the Medical Research Council UK (MRC). PMID- 28100441 TI - Assessing the Efficacy of an App-Based Method of Family Planning: The Dot Study Protocol. AB - BACKGROUND: Some 222 million women worldwide have unmet needs for contraception; they want to avoid pregnancy, but are not using a contraceptive method, primarily because of concerns about side effects associated with most available methods. Expanding contraceptive options-particularly fertility awareness options that provide women with information about which days during their menstrual cycles they are likely to become pregnant if they have unprotected intercourse-has the potential to reduce unmet need. Making these methods available to women through their mobile phones can facilitate access. Indeed, many fertility awareness applications have been developed for smartphones, some of which are digital platforms for existing methods, requiring women to enter information about fertility signs such as basal body temperature and cervical secretions. Others are algorithms based on (unexplained) calculations of the fertile period of the menstrual cycle. Considering particularly this latter (largely untested) group, it is critical that these apps be subject to the same rigorous research as other contraceptive methods. Dynamic Optimal Timing, available via the Dot app as a free download for iPhone and Android devices, is one such method and the only one that has published the algorithm that forms its basis. It combines historical cycle data with a woman's own personal cycle history, continuing to accrue this information over time to identify her fertile period. While Dot has a theoretical failure rate of only 3 in 100 for preventing pregnancy with perfect use, its effectiveness in typical use has yet to be determined. OBJECTIVE: The study objective is to assess both perfect and typical use to determine the efficacy of the Dot app for pregnancy prevention. METHODS: To determine actual use efficacy, the Institute for Reproductive Health is partnering with Cycle Technologies, which developed the Dot app, to conduct a prospective efficacy trial, following 1200 women over the course of 13 menstrual cycles to assess pregnancy status over time. This paper outlines the protocol for this efficacy trial, following the Standard Protocol Items: Recommendations for Intervention Trials checklist, to provide an overview of the rationale, methodology, and analysis plan. Participants will be asked to provide daily sexual history data and periodically answer surveys administered through a call center or directly on their phone. RESULTS: Funding for the study was provided in 2013 under the United States Agency for International Development Fertility Awareness for Community Transformation project. Recruitment for the study will begin in January of 2017. The study is expected to last approximately 18 months, depending on recruitment. Findings on the study's primary outcomes are expected to be finalized by September 2018. CONCLUSIONS: Reproducibility and transparency, important aspects of all research, are particularly critical in developing new approaches to research design. This protocol outlines the first study to prospectively test both the efficacy (correct use) and effectiveness (actual use) of a pregnancy prevention app. This protocol and the processes it describes reflect the dynamic integration of mobile technologies, a call center, and Health Insurance Portability and Accountability Act-compliant study procedures. Future fertility app studies can build on our approaches to develop methodologies that can contribute to the evidence base around app-based methods of contraception. CLINICALTRIAL: ClinicalTrials.gov NCT02833922; https://clinicaltrials.gov/ct2/show/NCT02833922 (Archived be WebCite at http://www.webcitation.org/6nDkr0e76). PMID- 28100442 TI - Rare Diseases on the Internet: An Assessment of the Quality of Online Information. AB - BACKGROUND: The importance of the Internet as a medium for publishing and sharing health and medical information has increased considerably during the last decade. Nonetheless, comprehensive knowledge and information are scarce and difficult to find, especially for rare diseases. Additionally, the quality of health or medical information about rare diseases is frequently difficult to assess for the patients and their family members. OBJECTIVE: The aim of this study is to assess the quality of information on the Internet about rare diseases. Additionally, the study aims to evaluate if the quality of information on rare diseases varies between different information supplier categories. METHODS: A total of 13 quality criteria for websites providing medical information about rare diseases were transferred to a self-disclosure questionnaire. Identified providers of information on the Internet about rare diseases were invited to fill out the questionnaire. The questionnaire contained questions about the information provider in general (eg, supplier category, information category, language, use of quality certificates, and target group) and about quality aspects that reflect the 13 quality criteria. Differences in subgroup analyses were performed using t tests. RESULTS: We identified 693 websites containing information about rare diseases. A total of 123 questionnaires (17.7%) were completely filled out by the information suppliers. For the remaining identified suppliers (570/693, 82.3%), the questionnaires were filled out by the authors based on the information available on their website. In many cases, the quality of websites was proportionally low. Furthermore, subgroup analysis showed no statistically significant differences between the quality of information provided by support group/patient organization compared to medical institution (P=.19). The quality of information by individuals (patient/relative) was significantly lower compared to information provided by support group/patient organization (P=.001), medical institution (P=.009), and other associations and sponsoring bodies (P=.001) as well. CONCLUSIONS: Overall, the quality of information on the Internet about rare diseases is low. Quality certificates are rarely used and important quality criteria are often not fulfilled completely. Additionally, some information categories are underrepresented (eg, information about psychosocial counseling, social-legal advice, and family planning). Nevertheless, due to the high amount of information provided by support groups, this study shows that these are extremely valuable sources of information for patients suffering from a rare disease and their relatives. PMID- 28100443 TI - Surveillance of antimicrobial use in Dutch long-term care facilities. AB - Objectives: : Residents living in a long-term care facility (LTCF) are more susceptible to infections. Treatment with antimicrobials is sometimes necessary; however, antibiotic use is considered one of the most important drivers of the development of antibiotic resistance. Surveillance data on antibiotic use in these LTCFs are necessary to get more insight into these patterns. The objective of this study was to describe antibiotic use in LTCFs in the Netherlands. Methods: : One hundred and seventy-seven LTCFs in the Netherlands were contacted and asked to participate in a study concerning antibiotic resistance and antibiotic use. Associated pharmacies were asked to provide data about systemic antibiotic use for each participating LTCF location over 1 year. Results on antibiotic use are reported here. Results: : Antibiotic use data from 96 LTCFs were collected from the pharmacies, and 68 of these LTCFs completed additional questionnaires on general characteristics of their location. Mean total use of systemic antimicrobials was 73 DDDs/1000 residents per day (range 2-197 DDDs/1000 residents per day). Co-amoxiclav (23 DDDs/1000 residents/day, range 0-70) was used the most, followed by nitrofurantoin derivatives (12 DDDs/1000 residents/day, range 0-38) and fluoroquinolones (12 DDDs/1000 residents/day, range 0-52). Statistical analysis revealed no significant correlations between the LTCF characteristics and the level of antibiotic use. Conclusions: There was a high use of broad-spectrum antimicrobials, with a large variation in total antibiotic use between individual locations. Further analysis of more in-depth data and possible influencing factors is needed. PMID- 28100444 TI - Successful retreatment of a patient with chronic hepatitis C genotype 2k/1b virus with ombitasvir/paritaprevir/ritonavir plus dasabuvir. PMID- 28100445 TI - APOL1 variants may induce HIV-associated nephropathy during HIV primary infection. PMID- 28100446 TI - Commentaries on Viewpoint: A time for exercise: the exercise window. PMID- 28100447 TI - Last Word on Viewpoint: A time for exercise: the exercise window. PMID- 28100448 TI - Commentaries on Viewpoint: "Tighter fit" theory-physiologists explain why "higher altitude" and jugular occlusion are unlikely to reduce risks for sports concussion and brain injuries. PMID- 28100449 TI - Last Word on Viewpoint: All is fair in altitude and concussions. PMID- 28100450 TI - A 2-Oxoglutarate-Dependent Dioxygenase Mediates the Biosynthesis of Glucoraphasatin in Radish. AB - Glucosinolates (GSLs) are secondary metabolites whose degradation products confer intrinsic flavors and aromas to Brassicaceae vegetables. Several structures of GSLs are known in the Brassicaceae, and the biosynthetic pathway and regulatory networks have been elucidated in Arabidopsis (Arabidopsis thaliana). GSLs are precursors of chemical defense substances against herbivorous pests. Specific GSLs can act as feeding blockers or stimulants, depending on the pest species. Natural selection has led to diversity in the GSL composition even within individual species. However, in radish (Raphanus sativus), glucoraphasatin (4 methylthio-3-butenyl glucosinolate) accounts for more than 90% of the total GSLs, and little compositional variation is observed. Because glucoraphasatin is not contained in other members of the Brassicaceae, like Arabidopsis and cabbage (Brassica oleracea), the biosynthetic pathways for glucoraphasatin remain unclear. In this report, we identified and characterized a gene encoding GLUCORAPHASATIN SYNTHASE 1 (GRS1) by genetic mapping using a mutant that genetically lacks glucoraphasatin. Transgenic Arabidopsis, which overexpressed GRS1 cDNA, accumulated glucoraphasatin in the leaves. GRS1 encodes a 2 oxoglutarate-dependent dioxygenase, and it is abundantly expressed in the leaf. To further investigate the biosynthesis and transportation of GSLs in radish, we grafted a grs1 plant onto a wild-type plant. The grafting experiment revealed a leaf-to-root long-distance glucoraphasatin transport system in radish and showed that the composition of GSLs differed among the organs. Based on these observations, we propose a characteristic biosynthesis pathway for glucoraphasatin in radish. Our results should be useful in metabolite engineering for breeding of high-value vegetables. PMID- 28100452 TI - Development and validation of an electronic frailty index using routine primary care electronic health record data. PMID- 28100451 TI - An Aphid Effector Targets Trafficking Protein VPS52 in a Host-Specific Manner to Promote Virulence. AB - Plant- and animal-feeding insects secrete saliva inside their hosts, containing effectors, which may promote nutrient release and suppress immunity. Although for plant pathogenic microbes it is well established that effectors target host proteins to modulate host cell processes and promote disease, the host cell targets of herbivorous insects remain elusive. Here, we show that the existing plant pathogenic microbe effector paradigm can be extended to herbivorous insects in that effector-target interactions inside host cells modify critical host processes to promote plant susceptibility. We showed that the effector Mp1 from Myzus persicae associates with the host Vacuolar Protein Sorting Associated Protein52 (VPS52). Using natural variants, we provide a strong link between effector virulence activity and association with VPS52, and show that the association is highly specific to Mpersicae-host interactions. Also, coexpression of Mp1, but not Mp1-like variants, specifically with host VPS52s resulted in effector relocalization to vesicle-like structures that associate with prevacuolar compartments. We show that high VPS52 levels negatively impact virulence, and that aphids are able to reduce VPS52 levels during infestation, indicating that VPS52 is an important virulence target. Our work is an important step forward in understanding, at the molecular level, how a major agricultural pest promotes susceptibility during infestation of crop plants. We give evidence that an herbivorous insect employs effectors that interact with host proteins as part of an effective virulence strategy, and that these effectors likely function in a species-specific manner. PMID- 28100455 TI - Obamacare repeal could leave 32 million uninsured and double premiums, report finds. PMID- 28100453 TI - Mechanisms of Vasovagal Syncope in the Young: Reduced Systemic Vascular Resistance Versus Reduced Cardiac Output. AB - BACKGROUND: Syncope is a sudden transient loss of consciousness and postural tone caused by cerebral hypoperfusion. The most common form is vasovagal syncope (VVS). Presyncopal progressive early hypotension in older VVS patients is caused by reduced cardiac output (CO); younger patients have reduced systemic vascular resistance (SVR). Using a priori criteria for reduced CO (?CO) and SVR (?SVR), we studied 48 recurrent young fainters comparing subgroups of VVS with VVS-?CO, VVS ?SVR, and both VVS-?CO&?SVR. METHODS AND RESULTS: Subjects were studied supine and during 70-degrere upright tilt with a Finometer to continuously measure blood pressure, CO, and SVR and impedance plethysmography to estimate thoracic, splanchnic, pelvic, and calf blood volumes, blood flows, and vascular resistances and electrocardiogram to measure heart rate and rhythm. Central blood volume was decreased in all VVS compared to control. VVS-?CO was associated with decreased splanchnic blood flow and increased splanchnic blood pooling compared to control. Seventy-five percent of VVS patients had reduced SVR, including 23% who also had reduced CO. Many VVS-?SVR increased CO during tilt, with no difference in splanchnic pooling, caused by significant increases in splanchnic blood flow and reduced splanchnic resistance. VVS-?CO&?SVR patients had splanchnic pooling comparable to VVS-?CO patients, but SVR comparable to VVS-?SVR. Splanchnic vasodilation was reduced, compared to VVS-?SVR, and venomotor properties were similar to control. Combined splanchnic pooling and reduced SVR produced the earliest faints among the VVS groups. CONCLUSIONS: Both ?CO and ?SVR occur in young VVS patients. ?SVR is predominant in VVS and is caused by impaired splanchnic vasoconstriction. PMID- 28100456 TI - Half of women experience "red flag" event during childbirth, warns report. PMID- 28100454 TI - Gene therapy targeting oligodendrocytes provides therapeutic benefit in a leukodystrophy model. AB - Pelizaeus-Merzbacher-like disease or hypomyelinating leukodystrophy-2 is an autosomal recessively inherited leukodystrophy with childhood onset resulting from mutations in the gene encoding the gap junction protein connexin 47 (Cx47, encoded by GJC2). Cx47 is expressed specifically in oligodendrocytes and is crucial for gap junctional communication throughout the central nervous system. Previous studies confirmed that a cell autonomous loss-of-function mechanism underlies hypomyelinating leukodystrophy-2 and that transgenic oligodendrocyte specific expression of another connexin, Cx32 (GJB1), can restore gap junctions in oligodendrocytes to achieve correction of the pathology in a disease model. To develop an oligodendrocyte-targeted gene therapy, we cloned the GJC2/Cx47 gene under the myelin basic protein promoter and used an adeno-associated viral vector (AAV.MBP.Cx47myc) to deliver the gene to postnatal Day 10 mice via a single intracerebral injection in the internal capsule area. Lasting Cx47 expression specifically in oligodendrocytes was detected in Cx47 single knockout and Cx32/Cx47 double knockout mice up to 12 weeks post-injection, including the corpus callosum and the internal capsule but also in more distant areas of the cerebrum and in the spinal cord. Application of this oligodendrocyte-targeted somatic gene therapy at postnatal Day 10 in groups of double knockout mice, a well characterized model of hypomyelinating leukodystrophy-2, resulted in significant improvement in motor performance and coordination at 1 month of age in treated compared to mock-treated mice, as well as prolonged survival. Furthermore, immunofluorescence and morphological analysis revealed improvement in demyelination, oligodendrocyte apoptosis, inflammation, and astrogliosis, all typical features of this leukodystrophy model in both brain and spinal cord. Functional dye transfer analysis confirmed the re-establishment of oligodendrocyte gap junctional connectivity in treated as opposed to untreated mice. These results provide a significant advance in the development of oligodendrocyte-cell specific gene therapy. Adeno-associated viral vectors can be used to target therapeutic expression of a myelin gene to oligodendrocytes. We show evidence for the first somatic gene therapy approach to treat hypomyelinating leukodystrophy-2 preclinically, providing a potential treatment for this and similar forms of leukodystrophies. PMID- 28100457 TI - Winter pressure leaves surgeons short of training opportunities. PMID- 28100458 TI - James B Williams. PMID- 28100460 TI - Making a song and dance about trachoma. PMID- 28100461 TI - Why would I smile? PMID- 28100459 TI - Clinical and pathological characteristics of HIV- and HHV-8-negative Castleman disease. AB - Castleman disease (CD) comprises 3 poorly understood lymphoproliferative variants sharing several common histopathological features. Unicentric CD (UCD) is localized to a single region of lymph nodes. Multicentric CD (MCD) manifests with systemic inflammatory symptoms and organ dysfunction due to cytokine dysregulation and involves multiple lymph node regions. Human herpesvirus 8 (HHV 8) causes MCD (HHV-8-associated MCD) in immunocompromised individuals, such as HIV-infected patients. However, >50% of MCD cases are HIV and HHV-8 negative (defined as idiopathic [iMCD]). The clinical and biological behavior of CD remains poorly elucidated. Here, we analyzed the clinicopathologic features of 74 patients (43 with UCD and 31 with iMCD) and therapeutic response of 96 patients (43 with UCD and 53 with iMCD) with HIV-/HHV-8-negative CD compared with 51 HIV /HHV-8-positive patients. Systemic inflammatory symptoms and elevated inflammatory factors were more common in iMCD patients than UCD patients. Abnormal bone marrow features were more frequent in iMCD (77.0%) than UCD (45%); the most frequent was plasmacytosis, which was seen in 3% to 30.4% of marrow cells. In the lymph nodes, higher numbers of CD3+ lymphocytes (median, 58.88 +/- 20.57) and lower frequency of CD19+/CD5+ (median, 5.88 +/- 6.52) were observed in iMCD patients compared with UCD patients (median CD3+ cells, 43.19 +/- 17.37; median CD19+/CD5+ cells, 17.37 +/- 15.80). Complete surgical resection is a better option for patients with UCD. Siltuximab had a greater proportion of complete responses and longer progression-free survival (PFS) for iMCD than rituximab. Centricity, histopathological type, and anemia significantly impacted PFS. This study reveals that CD represents a heterogeneous group of diseases with differential immunophenotypic profiling and treatment response. PMID- 28100462 TI - Cervical lung herniation. PMID- 28100463 TI - No asthma is found in third of adults with previous diagnosis. PMID- 28100464 TI - Six-Month Market Exclusivity Extensions To Promote Research Offer Substantial Returns For Many Drug Makers. AB - To incentivize pharmaceutical manufacturers to invest in areas of unmet medical need, policy makers frequently propose extending the market exclusivity period of desired drugs. Some such proposals are modeled after the pediatric exclusivity patent extension program, which since 1997 has provided six additional months of market exclusivity for drugs studied in children. The most recent proposal would encourage rare disease research by providing six months of extended exclusivity for any existing drug that is granted subsequent FDA approval for a new rare disease indication. Yet the economic impact of such proposals is rarely addressed. We found that for the thirteen FDA-approved drugs that gained supplemental approval for a rare disease indication from 2005 through 2010, the median projected cost of clinical trials leading to approval was $29.8 million. If the exclusivity extension had been in place, the median discounted financial gain to manufacturers would have been $94.6 million. Median net returns would have been $82.4 million, with higher returns for drugs with higher annual sales. Extending market exclusivity would provide substantial compensation to many manufacturers, particularly for top-selling products, far in excess of the cost of conducting these trials. Alternative strategies to incentivize the study of approved drugs for rare diseases may offer similar benefits at a lower cost. PMID- 28100465 TI - Prevalence of Masked Hypertension Among US Adults With Nonelevated Clinic Blood Pressure. AB - Masked hypertension (MHT), defined as nonelevated blood pressure (BP) in the clinic setting and elevated BP assessed by ambulatory monitoring, is associated with increased risk of target organ damage, cardiovascular disease, and mortality. Currently, no estimate of MHT prevalence exists for the general US population. After pooling data from the Masked Hypertension Study (n = 811), a cross-sectional clinical investigation of systematic differences between clinic BP and ambulatory BP (ABP) in a community sample of employed adults in the New York City metropolitan area (2005-2012), and the National Health and Nutrition Examination Survey (NHANES; 2005-2010; n = 9,316), an ongoing nationally representative US survey, we used multiple imputation to impute ABP-defined hypertension status for NHANES participants and estimate MHT prevalence among the 139 million US adults with nonelevated clinic BP, no history of overt cardiovascular disease, and no use of antihypertensive medication. The estimated US prevalence of MHT in 2005-2010 was 12.3% of the adult population (95% confidence interval: 10.0, 14.5)-approximately 17.1 million persons aged >=21 years. Consistent with prior research, estimated MHT prevalence was higher among older persons, males, and those with prehypertension or diabetes. To our knowledge, this study provides the first estimate of US MHT prevalence-nearly 1 in 8 adults with nonelevated clinic BP-and suggests that millions of US adults may be misclassified as not having hypertension. PMID- 28100468 TI - Feasibility of sample size calculation for RNA-seq studies. AB - Sample size calculation is a crucial step in study design but is not yet fully established for RNA sequencing (RNA-seq) analyses. To evaluate feasibility and provide guidance, we evaluated RNA-seq sample size tools identified from a systematic search. The focus was on whether real pilot data would be needed for reliable results and on identifying tools that would perform well in scenarios with different levels of biological heterogeneity and fold changes (FCs) between conditions. We used simulations based on real data for tool evaluation. In all settings, the six evaluated tools provided widely different answers, which were strongly affected by FC. Although all tools failed for small FCs, some tools can at least be recommended when closely matching pilot data are available and relatively large FCs are anticipated. PMID- 28100466 TI - Associations of Accelerometer-Measured and Self-Reported Sedentary Time With Leukocyte Telomere Length in Older Women. AB - Few studies have assessed the association of sedentary time with leukocyte telomere length (LTL). In a cross-sectional study conducted in 2012-2013, we examined associations of accelerometer-measured and self-reported sedentary time with LTL in a sample of 1,481 older white and African-American women from the Women's Health Initiative and determined whether associations varied by level of moderate- to vigorous-intensity physical activity (MVPA). The association between sedentary time and LTL was evaluated using multiple linear regression models. Women were aged 79.2 (standard deviation, 6.7) years, on average. Self-reported sedentary time was not associated with LTL. In a model adjusting for demographic characteristics, lifestyle behaviors, and health-related factors, among women at or below the median level of accelerometer-measured MVPA, those in the highest quartile of accelerometer-measured sedentary time had significantly shorter LTL than those in the lowest quartile, with an average difference of 170 base pairs (95% confidence interval: 4, 340). Accelerometer-measured sedentary time was not associated with LTL in women above the median level of MVPA. Findings suggest that, on the basis of accelerometer measurements, higher sedentary time may be associated with shorter LTL among less physically active women. PMID- 28100469 TI - Immunohistochemical Phenotype of Breast Cancer during 25-Year Follow-up of the Royal Marsden Tamoxifen Prevention Trial. AB - The randomized, double-blinded Royal Marsden Tamoxifen Breast Cancer Prevention Trial in healthy high-risk women started in 1986 and is still blinded. Eligible participants (n = 2,471) were randomly assigned to tamoxifen (20 mg/d) or placebo for 8 years. Analysis in 2006 showed a 30% risk reduction of estrogen receptor (ER)-positive invasive breast cancer mostly in the posttreatment period. Biomarker analysis in this population may identify any subgroup-specific preventive effects tamoxifen. After a median follow-up of 18.4 years, 242 patients had developed invasive cancer, 134 on placebo and 108 on tamoxifen. From these, 180 tissue blocks were available and ER, progesterone receptor (PgR), Ki67, HER2, and EGFR were immunohistochemically analyzed. A 32% reduction in ER+ and PgR+ invasive cancers resulted after 8 years of treatment. Quantitative levels of ER and PgR were lower in the tamoxifen-treated group, significantly so for ER (P = 0.001). These lower ER levels were restricted to the posttreatment period (P = 0.018). Among the ER+ group, there was a similar proportional decrease in PgR+ and PgR- tumors by tamoxifen. The median levels of Ki67 were similar in both arms. The numbers of HER2-positive and EGFR-positive cancers were higher in the tamoxifen arm but not significantly so. In conclusion, the preventive effects of tamoxifen result in reduced ER-positive but not ER-negative tumors and reduced ER expression in the ER-positive cases largely confined to the posttreatment period. Overall reductions in PgR expression are explained by lower frequency of ER-positive cases. Impact on Ki67, HER2, and EGFR was modest. Cancer Prev Res; 10(3); 171-6. (c)2017 AACR. PMID- 28100467 TI - An essential role of CBL and CBL-B ubiquitin ligases in mammary stem cell maintenance. AB - The ubiquitin ligases CBL and CBL-B are negative regulators of tyrosine kinase signaling with established roles in the immune system. However, their physiological roles in epithelial tissues are unknown. Here, we used MMTV-Cre mediated Cbl gene deletion on a Cbl-b null background, as well as a tamoxifen inducible mammary stem cell (MaSC)-specific Cbl and Cbl-b double knockout (Cbl/Cbl-b DKO) using Lgr5-EGFP-IRES-CreERT2, to demonstrate a mammary epithelial cell-autonomous requirement of CBL and CBL-B in the maintenance of MaSCs. Using a newly engineered tamoxifen-inducible Cbl and Cbl-b deletion model with a dual fluorescent reporter (Cblflox/flox; Cbl-bflox/flox; Rosa26-CreERT; mT/mG), we show that Cbl/Cbl-b DKO in mammary organoids leads to hyperactivation of AKT-mTOR signaling with depletion of MaSCs. Chemical inhibition of AKT or mTOR rescued MaSCs from Cbl/Cbl-b DKO-induced depletion. Our studies reveal a novel, cell autonomous requirement of CBL and CBL-B in epithelial stem cell maintenance during organ development and remodeling through modulation of mTOR signaling. PMID- 28100470 TI - Vacuum aspiration for induced abortion could be safely and legally performed by nurses and midwives. AB - BACKGROUND: Some 40% of abortions carried out in England and Wales are done by vacuum aspiration. It is widely assumed that, in order to be lawful, these procedures must be performed by doctors. AIM AND DESIGN: This study aimed to provide a detailed reassessment of the relevant law and the clinical evidence that supports this assumption. CONCLUSIONS: A close reading of relevant law reveals that this assumption is unfounded. On the contrary, it would be lawful for appropriately trained nurses or midwives, acting as part of a multidisciplinary team, to carry out vacuum aspiration procedures. This interpretation of the law offers the potential for developing more streamlined, cost-effective abortion services, which would be both safe and highly acceptable to patients. PMID- 28100471 TI - Valve thrombosis following transcatheter aortic valve replacement: significance of blood stasis on the leaflets. AB - OBJECTIVES: Leaflet thrombosis following transcatheter aortic valve replacement (TAVR) and valve-in-valve (ViV) procedures has been increasingly recognized. However, the factors affecting the post-TAVR/ViV thrombosis are not fully understood. This study aimed to investigate the effect of the geometric confinement of transcatheter aortic valve (TAV) on blood residence time (BRT) on the TAV leaflets and in turn on the post-TAVR valve thrombosis. METHODS: Two computational models, representing a surgical bioprosthesis and a TAV, were developed to study the effect of the geometric confinement on BRT on the leaflets in ViV setting/TAVR Intra-annular positioning. 3D flow fields were obtained via a one-way fluid-solid interaction modelling approach validated by experimental testing. BRT was compared between the two models by quantification and statistical analysis of the residence time of randomly distributed particles in close proximity of the leaflets. RESULTS: Significantly longer BRT on the leaflets was observed in the TAV compared to the surgical valve during different stages of the cardiac cycle. During forward flow, the mean value of BRT was found to be 39% higher in the TAV compared to the surgical bioprosthesis ( P < 0.0001). During diastole, specifically from end-systole to mid-diastole and from mid-diastole to the beginning of systole, the amount by which the mean BRT was higher for TAV compared to the surgical valve was 150% and 40%, respectively ( P < 0.0005). CONCLUSIONS: The geometric confinement of TAV by the failed bioprosthesis or the calcified native valve increases the BRT on the TAV leaflets. This may act as a permissive factor in valve thrombosis. PMID- 28100472 TI - Complex congenital fistula between coronary arteries, bronchial arteries, and pulmonary artery assessed with cardiac computed tomography. PMID- 28100474 TI - Regional diaphragm volume displacement is heterogeneous in dogs. AB - Muscle shortening and volume displacement (VD) are critical determinants of the pressure-generating capacity of the diaphragm. The present study was designed to test the hypothesis that diaphragm VD is heterogeneous and that distribution of VD is dependent on regional muscle shortening, posture, and the level of muscle activation. Radioopaque markers were sutured along muscle bundles of the peritoneal surface of the crural, dorsal costal, midcostal, and ventral costal regions of the left hemidiaphragm in four dogs. The markers were followed by biplanar video fluoroscopy during quiet spontaneous breathing, passive inflation to total lung capacity (TLC), and inspiratory efforts against an occluded airway at three lung volumes spanning the vital capacity [functional residual capacity, functional residual capacity + 1/2 inspiratory capacity, and TLC in both the prone and supine postures]. Our data show the ventral costal diaphragm had the largest VD and contributed nearly two times to the total diaphragm VD compared with the dorsal costal portion. In addition, the ventral costal diaphragm contributed nearly half of the total VD in the prone position, whereas it only contributed a quarter of the total VD in the supine postition. During efforts against an occluded airway and during passive inflation to TLC in the supine position, the crural diaphragm displaced volume equivalent to that of the midcostal portion. Regional muscle shortening closely matched regional VD. We conclude that the primary force generator of the diaphragm is primarily dominated by the contribution of the ventral costal region to its VD. PMID- 28100475 TI - Effects of obesity and exercise on testicular leptin signal transduction and testosterone biosynthesis in male mice. AB - To explore the role of the testicular leptin and JAK-STAT[leptin (LEP)-JAK-STAT] pathway in testosterone biosynthesis during juvenile stages and exercise for weight loss, male C57BL/6J mice were randomly divided into normal-diet and high fat diet groups. After 10 wk, mice in the high-fat diet-fed group were further divided randomly into obese control, obese moderate-volume exercise, and obese high-volume exercise groups. Mice in the obese moderate-volume exercise group were provided with 2 h/day, 6 days/wk swimming exercise for 8 wk, and mice in the obese high-volume exercise group underwent twice the amount of daily exercise intervention as the obese moderate-volume exercise group. The results showed that a high-fat diet causes obesity, leptin resistance, inhibition of the testicular LEP-JAK-STAT pathway, decreased mRNA and protein expression of steroidogenic factor-1, steroidogenic acute regulatory protein, and the P-450 side-chain cleavage enzyme, a decrease in the serum testosterone-to-estradiol ratio, and declines in sperm quality parameters. Both moderate and high-volume exercise were able to reduce body fat and increase the mRNA and protein expression of LEP-JAK STAT, but only moderate exercise significantly increased the mRNA and protein expression of steroidogenic factor-1, steroidogenic acute regulatory protein, and P-450 side-chain cleavage enzyme and significantly reversed the serum testosterone-to-estradiol ratio and sperm quality parameters. These findings suggest that by impairing the testicular LEP-JAK-STAT pathway, early-stage obesity inhibits the biosynthesis of testosterone and sexual development and reduces male reproductive potential. Long-term moderate and high-volume exercise can effectively reduce body fat and improve obesity-induced abnormalities in testicular leptin signal transduction, whereas only moderate-volume exercise can reverse the negative impacts of obesity on male reproductive function. PMID- 28100473 TI - Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature. AB - BACKGROUND: Bainbridge-Ropers syndrome (BRPS) is a recently described developmental disorder caused by de novo truncating mutations in the additional sex combs like 3 (ASXL3) gene. To date, there have been fewer than 10 reported patients. OBJECTIVES: Here, we delineate the BRPS phenotype further by describing a series of 12 previously unreported patients identified by the Deciphering Developmental Disorders study. METHODS: Trio-based exome sequencing was performed on all 12 patients included in this study, which found a de novo truncating mutation in ASXL3. Detailed phenotypic information and patient images were collected and summarised as part of this study. RESULTS: By obtaining genotype:phenotype data, we have been able to demonstrate a second mutation cluster region within ASXL3. This report expands the phenotype of older patients with BRPS; common emerging features include severe intellectual disability (11/12), poor/ absent speech (12/12), autistic traits (9/12), distinct face (arched eyebrows, prominent forehead, high-arched palate, hypertelorism and downslanting palpebral fissures), (9/12), hypotonia (11/12) and significant feeding difficulties (9/12) when young. DISCUSSION: Similarities in the patients reported previously in comparison with this cohort included their distinctive craniofacial features, feeding problems, absent/limited speech and intellectual disability. Shared behavioural phenotypes include autistic traits, hand-flapping, rocking, aggressive behaviour and sleep disturbance. CONCLUSIONS: This series expands the phenotypic spectrum of this severe disorder and highlights its surprisingly high frequency. With the advent of advanced genomic screening, we are likely to identify more variants in this gene presenting with a variable phenotype, which this study will explore. PMID- 28100476 TI - Chronic anemic hypoxemia attenuates glucose-stimulated insulin secretion in fetal sheep. AB - Fetal insulin secretion is inhibited by acute hypoxemia. The relationship between prolonged hypoxemia and insulin secretion, however, is less well defined. To test the hypothesis that prolonged fetal hypoxemia impairs insulin secretion, studies were performed in sheep fetuses that were bled to anemic conditions for 9 +/- 0 days (anemic, n = 19) and compared with control fetuses (n = 15). Arterial hematocrit and oxygen content were 34% and 52% lower, respectively, in anemic vs. control fetuses (P < 0.0001). Plasma glucose concentrations were 21% higher in the anemic group (P < 0.05). Plasma norepinephrine and cortisol concentrations increased 70% in the anemic group (P < 0.05). Glucose-, arginine-, and leucine stimulated insulin secretion all were lower (P < 0.05) in anemic fetuses. No differences in pancreatic islet size or beta-cell mass were found. In vitro, isolated islets from anemic fetuses secreted insulin in response to glucose and leucine as well as control fetal islets. These findings indicate a functional islet defect in anemic fetuses, which likely involves direct effects of low oxygen and/or increased norepinephrine on insulin release. In pregnancies complicated by chronic fetal hypoxemia, increasing fetal oxygen concentrations may improve insulin secretion. PMID- 28100478 TI - Adropin acts in the rat paraventricular nucleus to influence neuronal excitability. AB - Adropin is a peptide hormone with cardiovascular and metabolic roles in the periphery, including effects on glucose and lipid homeostasis. Central administration of adropin has been shown to inhibit water intake in rats; however, the site at which central adropin acts has yet to be elucidated. The hypothalamic paraventricular nucleus (PVN), a critical autonomic control center, plays essential roles in the control of fluid balance, energy homeostasis, and cardiovascular regulation, and is, therefore, a potential target for centrally acting adropin. In the present study, we used whole cell patch-clamp techniques to examine the effects of adropin on the excitability of neurons within the PVN. All three neuronal subpopulations (magnocellular, preautonomic, and neuroendocrine) in the PVN were found to be responsive to bath-application of 10 nM adropin, which elicited responses in 68% of cells tested (n = 57/84). The majority of cells (58%) depolarized (5.2 +/- 0.3 mV; n = 49) in response to adropin, whereas the remaining responsive cells (10%) hyperpolarized (-3.4 +/- 0.5 mV; n = 8), effects that were shown to be concentration-dependent. Additionally, responses were maintained in the presence of 1 MUM TTX in 75% of cells tested (n = 9/12), and voltage-clamp analysis revealed that adropin had no effect on the amplitude or frequency of excitatory or inhibitory postsynaptic currents (EPSCs and IPSCs) in PVN neurons, suggesting the peptide exerts direct, postsynaptic actions on these neurons. Collectively, these findings suggest central adropin may exert its physiological effects through direct actions on neurons in the PVN. PMID- 28100477 TI - Inability to replete white adipose tissue during recovery phase of sepsis is associated with increased autophagy, apoptosis, and proteasome activity. AB - Adipose tissue is an important energy depot and endocrine organ, and the degree of adiposity impacts the host response to infection. However, little is known regarding the mechanisms by which white adipose tissue (WAT) is lost acutely and then restored after the resolution of sepsis. Therefore, the signaling pathways governing protein synthesis, autophagy, apoptosis, and the ubiquitin-proteasome were investigated to identify potential mechanisms mediating the acute (24 h) loss of WAT after cecal ligation and puncture as well as the failure to replenish WAT during recovery (day 10). While whole body fat mass was decreased equally in pair-fed control and septic mice at 5 days after cecal ligation and puncture, fat mass remained 35% lower in septic mice at day 10 During sepsis-recovery, protein synthesis in epididymal WAT was increased compared with control values, and this increase was associated with an elevation in eukaryotic translation initiation factor (eIF)2Bepsilon but no change in mammalian target of rapamycin complex 1 activity (eIF4E-binding protein-1 or S6 kinase 1 phosphorylation). Protein breakdown was increased during sepsis-recovery, as evidenced by the elevation in ubiquitin-proteasome activity. Moreover, indexes of autophagy (light chain 3B-II, autophagy-related protein 5/12, and beclin) were increased during sepsis-recovery and associated with increased AMP-activated kinase-dependent Ser555 phosphorylated Unc-51-like autophagy activating kinase-1. Apoptosis was increased, as suggested by the increased cleavage of caspase-3 and poly(ADP ribose) polymerase. These changes were associated with increased inflammasome activity (increased NLR family, pyrin domain containing 3; TMS1; and caspase-1 cleavage) and the endoplasmic reticulum stress response (increased eIF2alpha and activating transcription factor-4) and browning (uncoupling protein-1) in epididymal WAT. Our data suggest that WAT stores remain depleted during recovery from sepsis due to sustained inflammation and elevations in protein and cellular degradation, despite the increase in protein synthesis. PMID- 28100479 TI - Evidence of central sensitisation in those with dry eye symptoms and neuropathic like ocular pain complaints: incomplete response to topical anaesthesia and generalised heightened sensitivity to evoked pain. AB - OBJECTIVE: To evaluate how closely neuropathic-like ocular pain (NOP) symptoms align with a metric of central sensitisation (ie, the presence of persistent ocular pain after topical anaesthetic placement) in individuals with dry eye (DE) symptoms. DESIGN: Cross-sectional study of 224 individuals with DE symptoms seen in the Miami Veterans Affairs eye clinic. An evaluation was performed consisting of questionnaires regarding DE symptoms, NOP descriptors and evoked pain sensitivity testing on the forehead and forearm, followed by a comprehensive ocular surface examination including corneal mechanical sensitivity testing. Subsequent analyses were performed to examine for differences between those with and without ocular pain after topical anaesthetic placement. RESULTS: The mean age was 62 years with 91% being men. DE symptoms and NOP symptoms were higher in subjects with persistent ocular pain after anaesthesia. Most DE signs were not related to persistent pain, with the exception of meibum quality. Individuals with persistent ocular pain also demonstrated greater sensitivity to evoked pain at testing sites on the forehead and forearm. When examining receiver operator characteristic curves considering persistent pain as a gold standard for central sensitisation within the corneal pathway, intensity of ocular pain ratings, Ocular Surface Disease Index scores and sensitivity to light provided the most robust relationships, each with an area under the curve of 0.72. CONCLUSIONS: Individuals with DE symptoms and persistent ocular pain after topical proparacaine (a marker of central sensitisation to pain) more frequently report NOP-like symptoms and demonstrate increased sensitivity to evoked pain. PMID- 28100480 TI - Detection of posterior vortex veins in eyes with pathologic myopia by ultra widefield indocyanine green angiography. AB - AIMS: To analyse the characteristics of posterior vortex veins detected in highly myopic eyes by wide-field indocyanine green angiography (ICGA). METHODS: One hundred and fifty-eight consecutive patients (302 eyes) with high myopia (myopic refractive error >8.0 dioptres (D) or axial length >=26.5 mm) were studied. Wide field ICGA was performed with the Spectralis HRA module. RESULTS: Posterior vortex veins were found in 80 eyes (26%). The prevalence of posterior staphyloma was significantly higher in eyes in which posterior vortex vein was detected than in eyes without posterior vortex vein. The posterior vortex veins were classified into five types according to the site of exit from the eye; around the optic nerve in 28%, in the macular area in 17%, along the border of staphyloma in 6%, along the margin of macular atrophy or large peripapillary conus in 21%, and elsewhere in 28%. In one eye, two posterior vortex veins collected the choroidal venous blood from the entire fundus. CONCLUSIONS: Wide-field ICGA can analyse the characteristic features of choroidal blood outflow system through posterior vortex veins in highly myopic eyes. They may play an important role as routes of choroidal outflow in highly myopic eyes. PMID- 28100481 TI - Safety of anterior chamber paracentesis using a 30-gauge needle integrated with a specially designed disposable pipette. AB - AIMS: To investigate the safety of anterior chamber (AC) paracentesis using a 30 gauge needle integrated with a specially designed disposable pipette. METHODS: In this retrospective observational case-series study, AC paracentesis was performed on 301 eyes of 301 patients between September 2009 and August 2016 at the Department of Ophthalmology, Kyoto Prefectural University of Medicine and the Baptist Eye Institute, Kyoto, Japan. AC paracentesis was performed with the patient placed in the supine position using a 30-gauge needle integrated with a disposable pipette with one hand, and the safety post procedure was then evaluated. RESULTS: The indications for AC paracentesis were virus detection (ie, corneal endotheliitis, anterior infectious uveitis, cytomegalovirus retinitis and acute retinal necrosis) in 264 eyes, bacterial detection (ie, endophthalmitis) in 8 eyes and malignancy (ie, primary intraocular lymphoma, leukaemia and retinoblastoma) in 29 eyes. No serious complications such as infection, hyphema, lens trauma or severe inflammation including hypopyon and AC fibrin formation were observed. CONCLUSIONS: Our findings show that AC paracentesis with a disposable pipette is safe with no severe complications. PMID- 28100482 TI - Mitomycin C-augmented trabeculectomy: subtenon injection versus soaked sponges: a randomised clinical trial. AB - BACKGROUND/AIMS: To compare the efficacy and safety of subtenon injection of mitomycin C (MMC) with that of conventional application of MMC-soaked sponges in trabeculectomy. METHODS: In this multicentre randomised clinical trial, 80 consecutive open-angle glaucoma cases were randomised into two groups; group 1 received a subtenon injection of 0.1 mL of 0.01% MMC, while group 2 received 0.02% MMC-soaked sponges. Primary outcome measure was intraocular pressure (IOP), and secondary outcome measures were endothelial cell count (ECC) changes and bleb morphology according to the Indiana Bleb Appearance Grading Scale. Outcome measures were compared at 1, 3 and 6 months postoperatively. Complete and qualified success was defined as IOP within 6-15 mm Hg without and with medications at month 6, respectively. RESULTS: Mean preoperative IOP was 21.8+/ 5.1 in group 1, which reduced to 10.3+/-3.7 mm Hg at final visit (p<0.001). Corresponding values for group 2 were 21.8+/-5 and 10.8+/-3.5 mm Hg respectively (p<0.001). Complete success was 82.5% in both groups, and qualified success was 0 and 2.5% in groups 1 and 2, respectively. (p=0.316) The blebs tended to be more diffuse, less vascularised and shallower in group 1, at month 6 (p=0.45,<0.001 and <0.007 respectively). ECCs did not change significantly at final visit (p=0.813). CONCLUSIONS: Subtenon injection of MMC is a safe and effective alternative to the conventional soaked sponge method. This method produces more favourable bleb morphology after trabeculectomy. TRIAL REGISTRATION NUMBER: NCT02385370, Post-results. PMID- 28100483 TI - Electrophysiological changes in 12-year-old children born MLP: reduced VEP amplitude in MLP children. AB - AIM: To study the electrophysiological changes in relation to fundus morphology in moderate-to-late preterm (MLP) children with no previous history of retinopathy of prematurity. METHODS: Visual acuity (VA), refraction and fundus variables measured by optical coherence tomography, pattern reversal visual evoked potentials and full-field electroretinography (ff-ERG) were obtained from 22 twelve-year-old MLP children (11 male, 11 female) and 21 full-term controls. RESULTS: There were no significant differences between the MLP and control groups in VA, refraction or optic disc parameters. There was a trend for thinner papillary retinal nerve fibre layer in the MLP group. Visual evoked potential amplitudes (P100) were lower in the MLP group than in controls, that is, right eye p=0.0027, left eye p=0.0037. No differences in latencies were found. After Bonferroni adjustment for multiple testing, no ff-ERG differences were noted between MLP and controls. Lower gestational age was correlated with smaller light adapted 3.0 b-wave amplitudes (p=0.0076, r=0.565). CONCLUSIONS: Our results indicate that moderate premature birth may affect visual evoked potential amplitudes without clear retinal structural changes in MLP children at 12 years of age. PMID- 28100484 TI - ATF6 knockdown decreases apoptosis, arrests the S phase of the cell cycle, and increases steroid hormone production in mouse granulosa cells. AB - Activating transcription factor 6 (ATF6), a sensor protein located in the endoplasmic reticulum (ER) membrane, is an important factor in the ER stress signaling pathway. ER stress is known to be involved in folliculogenesis, follicular growth, and ovulation; however, the physiological function of ATF6 in mouse granulosa cells remains largely unknown. The aim of this study was to assess the role of ATF6 in mouse granulosa cells with respect to apoptosis, the cell cycle, and steroid hormone production, as well as several key genes related to follicular development, via RNA interference, immunohistochemical staining, real-time quantitative PCR, Western blotting, flow cytometry, terminal deoxynucleotidyltransferase-mediated deoxy-UTP nick end labeling (TUNEL) assay, and ELISA. Immunohistochemical staining revealed that ATF6 was extensively distributed in the granulosa cells of various ovarian follicles and oocytes in adult female mice. FSH or LH treatment significantly increased ATF6 protein levels in mouse granulosa cells. In the meantime, a recombinant plasmid was used to deplete ATF6 successfully using short hairpin RNA-mediated interference technology, which was verified at both the mRNA and protein levels. Flow cytometry and TUNEL assay analysis indicated that ATF6 depletion decreased apoptosis and arrested the S phase of the cell cycle in mouse granulosa cells. Consistent with these results, p53, caspase-3, B cell lymphoma 2 (Bcl-2) associated X protein, CCAAT-enhancer-binding protein homologous protein, cyclin A1, cyclin B1, and cyclin D2 mRNA expression decreased, whereas Bcl-2 and glucose regulated protein 78 kDa mRNA expression increased. Interestingly, ATF6 knockdown obviously increased progesterone and estradiol production in mouse granulosa cells. Cytochrome P450 1b1 (Cyp1b1) mRNA levels were downregulated, whereas Cyp11a1, steroidogenic acute regulatory, and Cyp19a1 mRNA levels were upregulated, in keeping with the changes in steroid hormones. Furthermore, ATF6 disruption remarkably increased insulin-like growth factor binding protein4 (Igfbp4) expression and decreased hyaluronan synthase 2 (Has2), prostaglandin endoperoxide synthase 2 (Ptgs2), and prostaglandin F receptor (Ptgfr) expression in mouse granulosa cells, which are proteins crucial for follicular development. But, after treating with tunicamycin, the levels of Has2, Ptgs2, and Ptgfr increased relatively, whereas Igfbp4 expression decreased. Collectively, these results imply that ATF6, as a key player in ER stress signaling, may regulate apoptosis, the cell cycle, steroid hormone synthesis, and other modulators related to folliculogenesis in mouse granulosa cells, which may indirectly be involved in the development, ovulation, and atresia of ovarian follicles by affecting the physiological function of granulosa cells. The present study extends our understanding and provides new insights into the physiological significance of ATF6, a key signal transducer of ER stress, in ovarian granulosa cells. PMID- 28100485 TI - Quantification of growth factor signaling and pathway cross talk by live-cell imaging. AB - Peptide growth factors stimulate cellular responses through activation of their transmembrane receptors. Multiple intracellular signaling cascades are engaged following growth factor-receptor binding, leading to short- and long-term biological effects. Each receptor-activated signaling pathway does not act in isolation but rather interacts at different levels with other pathways to shape signaling networks that are distinctive for each growth factor. To gain insights into the specifics of growth factor-regulated interactions among different signaling cascades, we developed a HeLa cell line stably expressing fluorescent live-cell imaging reporters that are readouts for two major growth factor stimulated pathways, Ras-Raf-Mek-ERK and phosphatidylinositol (PI) 3-kinase-Akt. Incubation of cells with epidermal growth factor (EGF) resulted in rapid, robust, and sustained ERK signaling but shorter-term activation of Akt. In contrast, hepatocyte growth factor induced sustained Akt signaling but weak and short-lived ERK activity, and insulin-like growth factor-I stimulated strong long-term Akt responses but negligible ERK signaling. To address potential interactions between signaling pathways, we employed specific small-molecule inhibitors. In cells incubated with EGF or platelet-derived growth factor-AA, Raf activation and the subsequent stimulation of ERK reduced Akt signaling, whereas Mek inhibition, which blocked ERK activation, enhanced Akt and turned transient effects into sustained responses. Our results reveal that individual growth factors initiate signaling cascades that vary markedly in strength and duration and demonstrate in living cells the dramatic effects of cross talk from Raf and Mek to PI 3-kinase and Akt. Our data further indicate how specific growth factors can encode distinct cellular behaviors by promoting complex interactions among signaling pathways. PMID- 28100487 TI - Doxorubicin-induced nitrosative stress is mitigated by vitamin C via the modulation of nitric oxide synthases. AB - An increase in oxidative stress is suggested to be the main cause in Doxorubicin (Dox)-induced cardiotoxicity. However, there is now evidence that activation of inducible nitric oxide synthase (iNOS) and nitrosative stress are also involved. The role of vitamin C (Vit C) in the regulation of nitric oxide synthase (NOS) and reduction of nitrosative stress in Dox-induced cardiotoxicity is unknown. The present study investigated the effects of Vit C in the mitigation of Dox-induced changes in the levels of nitric oxide (NO), NOS activity, protein expression of NOS isoforms, and nitrosative stress as well as cytokines TNF-alpha and IL-10 in isolated cardiomyocytes. Cardiomyocytes isolated from adult Sprague-Dawley rats were segregated into four groups: 1) control, 2) Vit C (25 uM), 3) Dox (10 uM), and 4) Vit C + Dox. Dox caused a significant increase in the generation of superoxide radical (O2.-), peroxynitrite, and NO, and these effects of Dox were blunted by Vit C. Dox increased the expression of iNOS and altered protein expression as well as activation of endothelial NOS (eNOS). These changes were prevented by Vit C. Dox induced an increase in the ratio of monomeric/dimeric eNOS, promoting the production of O2.-, which was prevented by Vit C by increasing the stability of the dimeric form of eNOS. Vit C protected against the Dox-induced increase in TNFalpha as well as a reduction in IL-10. These results suggest that Vit C provides cardioprotection by reducing oxidative/nitrosative stress and inflammation via a modulation of Dox-induced increase in the NO levels and NOS activity. PMID- 28100486 TI - c-Jun enhances intestinal epithelial restitution after wounding by increasing phospholipase C-gamma1 transcription. AB - c-Jun is an activating protein 1 (AP-1) transcription factor and implicated in many aspects of cellular functions, but its exact role in the regulation of early intestinal epithelial restitution after injury remains largely unknown. Phospholipase C-gamma1 (PLCgamma1) catalyzes hydrolysis of phosphatidylinositol 4,5 biphosphate into the second messenger diacylglycerol and inositol 1,4,5 triphosphate, coordinates Ca2+ store mobilization, and regulates cell migration and proliferation in response to stress. Here we reported that c-Jun upregulates PLCgamma1 expression and enhances PLCgamma1-induced Ca2+ signaling, thus promoting intestinal epithelial restitution after wounding. Ectopically expressed c-Jun increased PLCgamma1 expression at the transcription level, and this stimulation is mediated by directly interacting with AP-1 and CCAAT-enhancer binding protein (C/EBP) binding sites that are located at the proximal region of the rat PLCgamma1 promoter. Increased levels of PLCgamma1 by c-Jun elevated cytosolic free Ca2+ concentration and stimulated intestinal epithelial cell migration over the denuded area after wounding. The c-Jun-mediated PLCgamma1/Ca2+ signal also plays an important role in polyamine-induced cell migration after wounding because increased c-Jun rescued Ca2+ influx and cell migration in polyamine-deficient cells. These findings indicate that c-Jun induces PLCgamma1 expression transcriptionally and enhances rapid epithelial restitution after injury by activating Ca2+ signal. PMID- 28100488 TI - Kinetic analyses of vasculogenesis inform mechanistic studies. AB - Vasculogenesis is a complex process by which endothelial stem and progenitor cells undergo de novo vessel formation. Quantitative assessment of vasculogenesis is a central readout of endothelial progenitor cell functionality. However, current assays lack kinetic measurements. To address this issue, new approaches were developed to quantitatively assess in vitro endothelial colony-forming cell (ECFC) network formation in real time. Eight parameters of network structure were quantified using novel Kinetic Analysis of Vasculogenesis (KAV) software. KAV assessment of structure complexity identified two phases of network formation. This observation guided the development of additional vasculogenic readouts. A tissue cytometry approach was established to quantify the frequency and localization of dividing ECFCs. Additionally, Fiji TrackMate was used to quantify ECFC displacement and speed at the single-cell level during network formation. These novel approaches were then implemented to identify how intrauterine exposure to maternal diabetes mellitus (DM) impairs fetal ECFC vasculogenesis. Fetal ECFCs exposed to maternal DM form fewer initial network structures, which are not stable over time. Correlation analyses demonstrated that ECFC samples with greater division in branches form fewer closed network structures. Additionally, reductions in average ECFC movement over time decrease structural connectivity. Identification of these novel phenotypes utilizing the newly established methodologies provides evidence for the cellular mechanisms contributing to aberrant ECFC vasculogenesis. PMID- 28100489 TI - TALE-induced bHLH transcription factors that activate a pectate lyase contribute to water soaking in bacterial spot of tomato. AB - AvrHah1 [avirulence (avr) gene homologous to avrBs3 and hax2, no. 1] is a transcription activator-like (TAL) effector (TALE) in Xanthomonas gardneri that induces water-soaked disease lesions on fruits and leaves during bacterial spot of tomato. We observe that water from outside the leaf is drawn into the apoplast in X. gardneri-infected, but not X. gardneriDeltaavrHah1 (XgDeltaavrHah1) infected, plants, conferring a dark, water-soaked appearance. The pull of water can facilitate entry of additional bacterial cells into the apoplast. Comparing the transcriptomes of tomato infected with X. gardneri vs. XgDeltaavrHah1 revealed the differential up-regulation of two basic helix-loop-helix (bHLH) transcription factors with predicted effector binding elements (EBEs) for AvrHah1. We mined our RNA-sequencing data for differentially up-regulated genes that could be direct targets of the bHLH transcription factors and therefore indirect targets of AvrHah1. We show that two pectin modification genes, a pectate lyase and pectinesterase, are targets of both bHLH transcription factors. Designer TALEs (dTALEs) for the bHLH transcription factors and the pectate lyase, but not for the pectinesterase, complement water soaking when delivered by XgDeltaavrHah1 By perturbing transcriptional networks and/or modifying the plant cell wall, AvrHah1 may promote water uptake to enhance tissue damage and eventual bacterial egression from the apoplast to the leaf surface. Understanding how disease symptoms develop may be a useful tool for improving the tolerance of crops from damaging disease lesions. PMID- 28100490 TI - Amino-terminal domains of kainate receptors determine the differential dependence on Neto auxiliary subunits for trafficking. AB - The kainate receptor (KAR), a subtype of glutamate receptor, mediates excitatory synaptic responses at a subset of glutamatergic synapses. However, the molecular mechanisms underlying the trafficking of its different subunits are poorly understood. Here we use the CA1 hippocampal pyramidal cell, which lacks KAR mediated synaptic currents, as a null background to determine the minimal requirements for the extrasynaptic and synaptic expression of the GluK2 subunit. We find that the GluK2 receptor itself, in contrast to GluK1, traffics to the neuronal surface and synapse efficiently and the auxiliary subunits Neto1 and Neto2 caused no further enhancement of these two trafficking processes. However, the regulation of GluK2 biophysical properties by Neto proteins is the same as that of GluK1. We further determine that it is the amino-terminal domains (ATDs) of GluK1 and GluK2 that control the strikingly different trafficking properties between these two receptors. Moreover, the ATDs are critical for synaptic expression of heteromeric receptors at mossy fiber-CA3 synapses and also mediate the differential dependence on Neto proteins for surface and synaptic trafficking of GluK1 and GluK2. These results highlight the fundamental differences between the two major KAR subunits and their interplay with Neto auxiliary proteins. PMID- 28100491 TI - Motor control by precisely timed spike patterns. AB - A fundamental problem in neuroscience is understanding how sequences of action potentials ("spikes") encode information about sensory signals and motor outputs. Although traditional theories assume that this information is conveyed by the total number of spikes fired within a specified time interval (spike rate), recent studies have shown that additional information is carried by the millisecond-scale timing patterns of action potentials (spike timing). However, it is unknown whether or how subtle differences in spike timing drive differences in perception or behavior, leaving it unclear whether the information in spike timing actually plays a role in brain function. By examining the activity of individual motor units (the muscle fibers innervated by a single motor neuron) and manipulating patterns of activation of these neurons, we provide both correlative and causal evidence that the nervous system uses millisecond-scale variations in the timing of spikes within multispike patterns to control a vertebrate behavior-namely, respiration in the Bengalese finch, a songbird. These findings suggest that a fundamental assumption of current theories of motor coding requires revision. PMID- 28100492 TI - Dynamic assembly of ultrasoft colloidal networks enables cell invasion within restrictive fibrillar polymers. AB - In regenerative medicine, natural protein-based polymers offer enhanced endogenous bioactivity and potential for seamless integration with tissue, yet form weak hydrogels that lack the physical robustness required for surgical manipulation, making them difficult to apply in practice. The use of higher concentrations of protein, exogenous cross-linkers, and blending synthetic polymers has all been applied to form more mechanically robust networks. Each relies on generating a smaller network mesh size, which increases the elastic modulus and robustness, but critically inhibits cell spreading and migration, hampering tissue regeneration. Here we report two unique observations; first, that colloidal suspensions, at sufficiently high volume fraction (phi), dynamically assemble into a fully percolated 3D network within high-concentration protein polymers. Second, cells appear capable of leveraging these unique domains for highly efficient cell migration throughout the composite construct. In contrast to porogens, the particles in our system remain embedded within the bulk polymer, creating a network of particle-filled tunnels. Whereas this would normally physically restrict cell motility, when the particulate network is created using ultralow cross-linked microgels, the colloidal suspension displays viscous behavior on the same timescale as cell spreading and migration and thus enables efficient cell infiltration of the construct through the colloidal-filled tunnels. PMID- 28100493 TI - Large 14C excursion in 5480 BC indicates an abnormal sun in the mid-Holocene. AB - Radiocarbon content in tree rings can be an excellent proxy of the past incoming cosmic ray intensities to Earth. Although such past cosmic ray variations have been studied by measurements of 14C contents in tree rings with >=10-y time resolution for the Holocene, there are few annual 14C data. There is a little understanding about annual 14C variations in the past, with the exception of a few periods including the AD 774-775 14C excursion where annual measurements have been performed. Here, we report the result of 14C measurements using the bristlecone pine tree rings for the period from 5490 BC to 5411 BC with 1- to 2-y resolution, and a finding of an extraordinarily large 14C increase (200/00) from 5481 BC to 5471 BC (the 5480 BC event). The 14C increase rate of this event is much larger than that of the normal grand solar minima. We propose the possible causes of this event are an unknown phase of grand solar minimum, or a combination of successive solar proton events and a normal grand solar minimum. PMID- 28100494 TI - Quantification of BK Virus Standards by Quantitative Real-Time PCR and Droplet Digital PCR Is Confounded by Multiple Virus Populations in the WHO BKV International Standard. AB - BACKGROUND: The WHO recently released a BK virus (BKV) international standard. This study evaluated the WHO international standard and commercially available BKV standards by quantitative real-time PCR (qPCR) and droplet digital PCR (ddPCR). METHODS: WHO, Exact Diagnostics, Acrometrix, and Zeptometrix BKV standards were tested by qPCR and ddPCR. Two preparations of NIST BKV clones were also tested. Nucleic acid was extracted with the Roche MP96 and MPLC, followed by quantification in duplicate. To resolve discrepancies, we sequenced the WHO and NIST materials. RESULTS: Manufacturers' expected copies/mL were close to WHO IU/mL: linear regression of qPCR data revealed 1.12 Exact copies/IU, 0.76 Acrometrix copies/IU, and 0.70 Zeptometrix copies/IU. For ddPCR, similar concentrations were measured when either the VP1 region or the T region was targeted, and concentrations were almost 2-fold higher when both regions were targeted simultaneously. ddPCR results for the VP1 and T regions were similar for all commercial standards, but targeting the T region of the WHO standard led to a 4-fold lower result than the VP1 region. Next-generation sequencing revealed no primer or probe mismatches. However, large differences in coverage across the WHO standard and junctional reads were observed, indicating subpopulations of the WHO standard with deletions in the T region. CONCLUSIONS: BKV standards showed concordance among providers, but the WHO standard contains subpopulations of viruses with various deletions in the T region. PCR results will vary depending on which region of the WHO standard is targeted. PMID- 28100495 TI - Probe-Free Digital PCR Quantitative Methodology to Measure Donor-Specific Cell Free DNA after Solid-Organ Transplantation. AB - BACKGROUND: Donor-specific cell-free DNA (dscfDNA) is increasingly being considered as a noninvasive biomarker to monitor graft health and diagnose graft rejection after solid-organ transplantation. However, current approaches used to measure dscfDNA can be costly and/or laborious. A probe-free droplet digital PCR (ddPCR) methodology using small deletion/insertion polymorphisms (DIPs) was developed to circumvent these limitations without compromising the quantification of dscfDNA. This method was called PHABRE-PCR (Primer to Hybridize across an Allelic BREakpoint-PCR). The strategic placement of one primer to hybridize across an allelic breakpoint ensured highly specific PCR amplification, which then enabled the absolute quantification of donor-specific alleles by probe-free ddPCR. METHODS: dscfDNA was serially measured in 3 liver transplant recipients. Donor and recipient genomic DNA was first genotyped against a panel of DIPs to identify donor-specific alleles. Alleles that differentiated donor-specific from recipient-specific DNA were then selected to quantify dscfDNA in the recipient plasma. RESULTS: Lack of amplification of nontargeted alleles confirmed that PHABRE-PCR was highly specific. In recipients who underwent transplantation, dscfDNA was increased at day 3, but decreased and plateaued at a low concentration by 2 weeks in the 2 recipients who did not develop any complications. In the third transplant recipient, a marked increase of dscfDNA coincided with an episode of graft rejection. CONCLUSIONS: PHABRE-PCR was able to quantify dscfDNA with high analytical specificity and sensitivity. The implementation of a DIP-based approach permits surveillance of dscfDNA as a potential measure of graft health after solid-organ transplantation. PMID- 28100496 TI - Preexisting Immunity, Not Frailty Phenotype, Predicts Influenza Postvaccination Titers among Older Veterans. AB - Both preexisting immunity to influenza and age have been shown to be correlates of influenza vaccine responses. Frailty, an indicator of functional impairment in older adults, was also shown in one study to predict lower influenza vaccine responses among nonveterans. In the current study, we aimed to determine the associations between frailty, preexisting immunity, and immune responses to influenza vaccine among older veterans. We studied 117 subjects (age range, 62 to 95 years [median age, 81 years]), divided into three cohorts based on the Fried frailty test, i.e., nonfrail (NF) (n = 23 [median age, 68 years]), prefrail (n = 50 [median age, 80 years]), and frail (n = 44 [median age, 82 years]), during the 2010-2011 and 2011-2012 influenza seasons. Subjects received the seasonal trivalent inactivated influenza vaccine, and baseline and postvaccination samples were obtained. Anti-influenza humoral immunity, as measured by hemagglutination inhibition (HI) and microneutralization assays, was measured for influenza B, A(H1N1)pdm09, and A(H3N2) viruses. Postvaccination titers were not different between frail and NF subjects overall in this older subset of veterans. However, preexisting HI titers were strongly correlated with postvaccination titers among all functional status groups. When microneutralization titers were compared, the association between preexisting immunity and vaccine responses varied by frailty status, with the strongest correlation being observed for the NF group. In conclusion, preexisting immunity rather than frailty appeared to predict postvaccination titers in this older veteran cohort. PMID- 28100497 TI - Avian and Human Seasonal Influenza Hemagglutinin Proteins Elicit CD4 T Cell Responses That Are Comparable in Epitope Abundance and Diversity. AB - Avian influenza viruses remain a significant concern due to their pandemic potential. Vaccine trials have suggested that humans respond poorly to avian influenza vaccines relative to seasonal vaccines. It is important to understand, first, if there is a general deficiency in the ability of avian hemagglutinin (HA) proteins to generate immune responses and, if so, what underlies this defect. This question is of particular interest because it has been suggested that in humans, the poor immunogenicity of H7 vaccines may be due to a paucity of CD4 T cell epitopes. Because of the generally high levels of cross-reactive CD4 T cells in humans, it is not possible to compare the inherent immunogenicities of avian and seasonal HA proteins in an unbiased manner. Here, we empirically examine the epitope diversity and abundance of CD4 T cells elicited by seasonal and avian HA proteins. HLA-DR1 and HLA-DR4 transgenic mice were vaccinated with purified HA proteins, and CD4 T cells to specific epitopes were identified and quantified. These studies revealed that the diversity and abundance of CD4 T cells specific for HA do not segregate on the basis of whether the HA was derived from human seasonal or avian influenza viruses. Therefore, we conclude that failure in responses to avian vaccines in humans is likely due to a lack of cross reactive CD4 T cell memory perhaps coupled with competition with or suppression of naive, HA-specific CD4 T cells by memory CD4 T cells specific for more highly conserved proteins. PMID- 28100498 TI - The Predominant CD4+ Th1 Cytokine Elicited to Chlamydia trachomatis Infection in Women Is Tumor Necrosis Factor Alpha and Not Interferon Gamma. AB - Chlamydia trachomatis infection is the most prevalent bacterial sexually transmitted infection and can cause significant reproductive morbidity in women. There is insufficient knowledge of C. trachomatis-specific immune responses in humans, which could be important in guiding vaccine development efforts. In contrast, murine models have clearly demonstrated the essential role of T helper type 1 (Th1) cells, especially interferon gamma (IFN-gamma)-producing CD4+ T cells, in protective immunity to chlamydia. To determine the frequency and magnitude of Th1 cytokine responses elicited to C. trachomatis infection in humans, we stimulated peripheral blood mononuclear cells from 90 chlamydia infected women with C. trachomatis elementary bodies, Pgp3, and major outer membrane protein and measured IFN-gamma-, tumor necrosis factor alpha (TNF-alpha) , and interleukin-2 (IL-2)-producing CD4+ and CD8+ T-cell responses using intracellular cytokine staining. The majority of chlamydia-infected women elicited CD4+ TNF-alpha responses, with frequency and magnitude varying significantly depending on the C. trachomatis antigen used. CD4+ IFN-gamma and IL 2 responses occurred infrequently, as did production of any of the three cytokines by CD8+ T cells. About one-third of TNF-alpha-producing CD4+ T cells coproduced IFN-gamma or IL-2. In summary, the predominant Th1 cytokine response elicited to C. trachomatis infection in women was a CD4+ TNF-alpha response, not CD4+ IFN-gamma, and a subset of the CD4+ TNF-alpha-positive cells produced a second Th1 cytokine. PMID- 28100499 TI - Gremlin1 plays a key role in kidney development and renal fibrosis. AB - Gremlin1 (Grem1), an antagonist of bone morphogenetic proteins, plays a key role in embryogenesis. A highly specific temporospatial gradient of Grem1 and bone morphogenetic protein signaling is critical to normal lung, kidney, and limb development. Grem1 levels are increased in renal fibrotic conditions, including acute kidney injury, diabetic nephropathy, chronic allograft nephropathy, and immune glomerulonephritis. We demonstrate that a small number of grem1-/- whole body knockout mice on a mixed genetic background (8%) are viable, with a single, enlarged left kidney and grossly normal histology. The grem1-/- mice displayed mild renal dysfunction at 4 wk, which recovered by 16 wk. Tubular epithelial cell specific targeted deletion of Grem1 (TEC-grem1-cKO) mice displayed a milder response in the acute injury and recovery phases of the folic acid model. Increases in indexes of kidney damage were smaller in TEC-grem1-cKO than wild type mice. In the recovery phase of the folic acid model, associated with renal fibrosis, TEC-grem1-cKO mice displayed reduced histological damage and an attenuated fibrotic gene response compared with wild-type controls. Together, these data demonstrate that Grem1 expression in the tubular epithelial compartment plays a significant role in the fibrotic response to renal injury in vivo. PMID- 28100501 TI - MDM2 mediates fibroblast activation and renal tubulointerstitial fibrosis via a p53-independent pathway. AB - It is well recognized that murine double minute gene 2 (MDM2) plays a critical role in cell proliferation and inflammatory processes during tumorigenesis. It is also reported that MDM2 is expressed in glomeruli and involved in podocyte injury. However, whether MDM2 is implicated in renal fibrosis remains unclear. Here we investigated the role of MDM2 in tubulointerstitial fibrosis (TIF). By immunohistochemical staining and Western blotting we confirmed that MDM2 is upregulated in the tubulointerstitial compartment in patients with TIF and unilateral urethral obstruction (UUO) mice, which mainly originates from myofibroblasts. Consistently, in vitro MDM2 is increased in TGF-beta1-treated fibroblasts, one of the major sources of collagen-producing myofibroblasts during TIF, along with fibroblast activation. Importantly, genetic deletion of MDM2 significantly attenuates fibroblast activation. We then analyzed the possible downstream signaling of MDM2 during fibroblast activation. p53-dependent pathway is the classic downstream signaling of MDM2, and Nutlin-3 is a small molecular inhibitor of MDM2-p53 interaction. To our surprise, Nutlin-3 could not ameliorate fibroblast activation in vitro and TIF in UUO mice. However, we found that Notch1 signaling is attenuated during fibroblast activation, which could be markedly rescued by MDM2 knockdown. Overexpression of intracellular domain of Notch1 (NICD) by plasmid could obviously minimize fibroblast activation induced by TGF beta1. In addition, the degradation of NICD is strikingly suppressed by PYR-41, an inhibitor of ubiquitin-activating enzyme E1, and proteasome inhibitor MG132. Taken together, our findings provide the first evidence that MDM2 is involved in fibroblast activation and TIF, which associates with Notch1 ubiquitination and proteasome degradation. PMID- 28100500 TI - Mononuclear phagocyte subpopulations in the mouse kidney. AB - Mononuclear phagocytes are the most common cells in the kidney associated with immunity and inflammation. Although the presence of these cells in the kidney has been known for decades, the study of mononuclear phagocytes in the context of kidney function and dysfunction is still at an early stage. The purpose of this review is to summarize the present knowledge regarding classification of these cells in the mouse kidney and to identify relevant questions that would further advance the field and potentially lead to new opportunities for treatment of acute kidney injury and other kidney diseases. PMID- 28100503 TI - Chronic kidney disease promotes chronic inflammation in visceral white adipose tissue. AB - White adipose tissue plays an important role in the development of metabolic disturbance, which is a common feature in patients with chronic kidney disease (CKD). The effect of CKD on white adipose tissue remains poorly appreciated. Here, we evaluated the inflammatory potential of visceral white adipose tissue in a rat model of CKD. The results showed that production of proinflammatory cytokines and infiltration of macrophage in the tissue were increased significantly in CKD rats compared with sham rats. Moreover, the primary adipocytes and stromal vascular fraction under the condition of CKD could trigger the inflammatory response in each other. Free fatty acid induced robust inflammatory response in ex vivo peritoneal-derived macrophages from CKD rats, which was associated with reduced activity of silent information regulator T1 (SIRT1). Improvement of SIRT1 activity by an activator could alleviate free fatty acid-induced inflammatory response in the macrophages and inflammation in the white adipose tissue. Moreover, oxidative stress occurred in the tissue and linked with the reduced activity of SIRT1 in macrophages and enhanced release of free fatty acid in the tissue. We thus identified CKD as a risk factor for chronic inflammation in white adipose tissue. These observations might open up new therapeutic strategies for metabolic disturbance in CKD via the modulation of adipose tissue-related pathways. PMID- 28100502 TI - RACK1 regulates angiotensin II-induced contractions of SHR preglomerular vascular smooth muscle cells. AB - The preglomerular microcirculation of spontaneously hypertensive rats (SHR) is hypersensitive to angiotensin (ANG) II, and studies have shown that this is likely due to enhanced coincident signaling between G protein subunits alphaq (Galphaq; released by ANG II) and betagamma (Gbetagamma; released by Gi-coupled receptors) to active phospholipase C (PLC). Here we investigated the molecular basis for the enhanced coincident signaling between Gbetagamma and Galphaq in SHR preglomerular vascular smooth muscle cells (PGVSMCs). Because receptor for activated C kinase 1 (RACK1; a scaffolding protein) organizes interactions between Gbetagamma, Galphaq, and PLC, we included RACK1 in this investigation. Cell fractionation studies demonstrated increased levels of membrane (but not cytosolic) Gbeta, Galphaq, PLCbeta3, and RACK1 in SHR PGVSMCs compared with Wistar-Kyoto rat PGVSMCs. In SHR PGVSMCs, coimmunoprecipitation demonstrated RACK1 binding to Gbeta and PLCbeta3, but only at cell membranes. Pertussis toxin (which blocks Gbetagamma) and U73122 (which blocks PLC) reduced membrane RACK1; however, RACK1 knockdown (shRNA) did not affect membrane levels of Gbeta, Galphaq, or PLCbeta3 In a novel gel contraction assay, RACK1 knockdown in SHR PGVSMCs attenuated contractions to ANG II and abrogated the ability of neuropeptide Y (which signals via Gbetagamma) to enhance ANG II-induced contractions. We conclude that in SHR PGVSMCs the enlarged pool of Gbetagamma and PLCbeta3 recruits RACK1 to membranes and RACK1 then organizes signaling. Consequently, knockdown of RACK1 prevents coincident signaling between ANG II and the Gi pathway. This is the first study to implicate RACK1 in vascular smooth muscle cell contraction and suggests that RACK1 inhibitors could be effective cardiovascular drugs. PMID- 28100504 TI - A new microscope for the kidney: mathematics. PMID- 28100505 TI - (5R)-5-hydroxytriptolide ameliorates lupus nephritis in MRL/lpr mice by preventing infiltration of immune cells. AB - (5R)-5-hydroxytriptolide (LLDT-8), a triptolide derivative with low toxicity, was previously reported to have strong immunosuppressive effects both in vitro and in vivo, but it remains unknown whether LLDT-8 has a therapy effect on systemic lupus erythematosus. In this study, we aimed to investigate the therapeutic effects of LLDT-8 on lupus nephritis in MRL/lpr mice, a model of systemic lupus erythematosus. Compared with the vehicle group, different clinical parameters were improved upon LLDT-8 treatment as follows: prolonged life span of mice, decreased proteinuria, downregulated blood urea nitrogen and serum creatinine, reduced glomerular IgG deposits, and ameliorated histopathology. A decreased expression of the inflammatory cytokines IFN-gamma, IL-17, IL-6, and TNF-alpha was also observed in the kidney of LLDT-8 treated MRL/lpr mice. Moreover, infiltration of T cells in the kidney was mitigated after LLDT-8 treatment, corresponding with decreased expression of related chemokines IP-10, Mig, and RANTES in the kidney. The proportion of macrophage and neutrophil cells and related chemokines expression was also reduced in kidneys of LLDT-8-treated mice. In the human proximal tubule epithelial cell line and mouse mesangial cell line, consistent with our in vivo experimental results, LLDT-8 suppressed the expression of related chemokines and IL-6. In summary, LLDT-8 has a therapeutic benefit for lupus nephritis via suppressing chemokine expression and inhibiting immune cell infiltration in kidneys of MRL/lpr mice. PMID- 28100506 TI - Twittering on about mental health: is it worth the effort? AB - The medical community disseminates information increasingly using social media. Randomised controlled trials are being conducted in this area to evaluate effectiveness of social media with mixed results so far, but more trials are likely to be published in the coming years. One recent twitter randomised control trial using Cochrane Schizophrenia Group reviews suggests that tweets increase the hits to the target web page by about threefold and time spent on the web page is also increased threefold when referrals come in via twitter. These are early findings and need further replication. Twitter appeals to professionals, entertainers and politicians among others as a means of networking with peers and connecting with the wider public. Twitter, in particular, seems to be well placed for use by the medical community and is effective in promoting messages, updating information, interacting with each other locally and internationally and more so during conferences. Twitter is also increasingly used to disseminate evidence in addition to traditional media such as academic peer-reviewed journals. Caution is required using twitter as inadvertent tweets can lead to censure. Overall, the use of twitter responsibly by the medical community will increase visibility of research findings and ensure up to date evidence is readily accessible. This should open the door for further trials of different social media platforms to evaluate their effectiveness in disseminating accurate high-quality information instantaneously to a global audience. PMID- 28100507 TI - Efficacy of iron-supplement bars to reduce anemia in urban Indian women: a cluster-randomized controlled trial. AB - Background: India's high prevalence of iron-deficiency anemia has largely been attributed to the local diet consisting of nonheme iron, which has lower absorption than that of heme iron.Objective: We assessed the efficacy of the consumption of iron-supplement bars in raising hemoglobin concentrations and hematocrit percentages in anemic (hemoglobin concentration <12 g/dL) Indian women of reproductive age.Design: The Let's be Well Red study was a 90-d, pair-matched, cluster-randomized controlled trial. A total of 361 nonpregnant women (age 18-35 y) were recruited from 10 sites within Mumbai and Navi Mumbai, India. All participants received anemia education and a complete blood count (CBC). Random assignment of anemic participants to intervention and control arms occurred within 5 matched site-pairs. Intervention participants received 1 iron-supplement bar (containing 14 mg Fe)/d for 90 d, whereas control subjects received nothing. CBC tests were given at days 15, 45, and 90. Primary outcomes were 90-d changes from baseline in hemoglobin concentrations and hematocrit percentages. Linear mixed models and generalized estimating equations were used to model continuous and binary outcomes, respectively.Results: Of 179 anemic participants, 136 (76.0%) completed all follow-up assessments (65 intervention and 71 control participants). Baseline characteristics were comparable by arm. Mean hemoglobin and hematocrit increases after 90 d were greater for intervention than for control participants [1.4 g/dL (95% CI: 1.3, 1.6 g/dL) and 2.7% (95% CI: 2.2%, 3.2%), respectively]. The anemia prevalence at 90 d was lower for intervention (29.2%) than for control participants (98.6%) (OR: 0.007; 95% CI: 0.001, 0.04).Conclusions: The daily consumption of an iron-supplement bar leads to increased hemoglobin concentrations and hematocrit percentages and to a lower anemia prevalence in the target population with no reported side effects. This intervention is an attractive option to combat anemia in India. This trial was registered at clinicaltrials.gov as NCT02032615. PMID- 28100508 TI - Challenges in accurately modeling the complexity of human ingestive behavior: the influence of portion size and energy density of food on fMRI food-cue reactivity. PMID- 28100509 TI - Determining the protein needs of "older" persons one meal at a time. PMID- 28100510 TI - The nutritional metabolomics crossroads: how to ensure success for dietary biomarkers. PMID- 28100511 TI - Higher dietary flavonoid intakes are associated with lower objectively measured body composition in women: evidence from discordant monozygotic twins. AB - Background: Although dietary flavonoid intake has been associated with less weight gain, there are limited data on its impact on fat mass, and to our knowledge, the contribution of genetic factors to this relation has not previously been assessed.Objective: We examined the associations between flavonoid intakes and fat mass.Design: In a study of 2734 healthy, female twins aged 18-83 y from the TwinsUK registry, intakes of total flavonoids and 7 subclasses (flavanones, anthocyanins, flavan-3-ols, flavonols, flavones, polymers, and proanthocyanidins) were calculated with the use of food-frequency questionnaires. Measures of dual-energy X-ray absorptiometry-derived fat mass included the limb-to-trunk fat mass ratio (FMR), fat mass index, and central fat mass index.Results: In cross-sectional multivariable analyses, higher intake of anthocyanins, flavonols, and proanthocyanidins were associated with a lower FMR with mean +/- SE differences between extreme quintiles of -0.03 +/- 0.02 (P-trend = 0.02), -0.03 +/- 0.02 (P-trend = 0.03), and -0.05 +/- 0.02 (P-trend < 0.01), respectively. These associations were not markedly changed after further adjustment for fiber and total fruit and vegetable intakes. In monozygotic, intake-discordant twin pairs, twins with higher intakes of flavan-3-ols (n = 154, P = 0.03), flavonols (n = 173, P = 0.03), and proanthocyanidins (n = 172, P < 0.01) had a significantly lower FMR than that of their co-twins with within-pair differences of 3-4%. Furthermore, in confirmatory food-based analyses, twins with higher intakes of flavonol-rich foods (onions, tea, and pears; P = 0.01) and proanthocyanidin-rich foods (apples and cocoa drinks; P = 0.04) and, in younger participants (aged <50 y) only, of anthocyanin-rich foods (berries, pears, grapes, and wine; P = 0.01) had a 3-9% lower FMR than that of their co twins.Conclusions: These data suggest that higher habitual intake of a number of flavonoids, including anthocyanins, flavan-3-ols, flavonols, and proanthocyanidins, are associated with lower fat mass independent of shared genetic and common environmental factors. Intervention trials are needed to further examine the effect of flavonoid-rich foods on body composition. PMID- 28100514 TI - Preoperative alpha-blockade in catecholamine-secreting tumours: fight for it or take flight? PMID- 28100512 TI - Postexercise repletion of muscle energy stores with fructose or glucose in mixed meals. AB - Background: Postexercise nutrition is paramount to the restoration of muscle energy stores by providing carbohydrate and fat as precursors of glycogen and intramyocellular lipid (IMCL) synthesis. Compared with glucose, fructose ingestion results in lower postprandial glucose and higher lactate and triglyceride concentrations. We hypothesized that these differences in substrate concentration would be associated with a different partition of energy stored as IMCLs or glycogen postexercise.Objective: The purpose of this study was to compare the effect of isocaloric liquid mixed meals containing fat, protein, and either fructose or glucose on the repletion of muscle energy stores over 24 h after a strenuous exercise session.Design: Eight male endurance athletes (mean +/ SEM age: 29 +/- 2 y; peak oxygen consumption: 66.8 +/- 1.3 mL . kg-1 . min-1) were studied twice. On each occasion, muscle energy stores were first lowered by a combination of a 3-d controlled diet and prolonged exercise. After assessment of glycogen and IMCL concentrations in vastus muscles, subjects rested for 24 h and ingested mixed meals providing fat and protein together with 4.4 g/kg fructose (the fructose condition; FRU) or glucose (the glucose condition; GLU). Postprandial metabolism was assessed over 6 h, and glycogen and IMCL concentrations were measured again after 24 h. Finally, energy metabolism was evaluated during a subsequent exercise session.Results: FRU and GLU resulted in similar IMCL [+2.4 +/- 0.4 compared with +2.0 +/- 0.6 mmol . kg-1 wet weight . d 1; time * condition (mixed-model analysis): P = 0.45] and muscle glycogen (+10.9 +/- 0.9 compared with +12.3 +/- 1.9 mmol . kg-1 wet weight . d-1; time * condition: P = 0.45) repletion. Fructose consumption in FRU increased postprandial net carbohydrate oxidation and decreased net carbohydrate storage (estimating total, muscle, and liver glycogen synthesis) compared with GLU (+117 +/- 9 compared with +135 +/- 9 g/6 h, respectively; P < 0.01). Compared with GLU, FRU also resulted in lower plasma glucose concentrations and decreased exercise performance the next day.Conclusions: Mixed meals containing fat, protein, and either fructose or glucose elicit similar repletion of IMCLs and muscle glycogen. Under such conditions, fructose lowers whole-body glycogen synthesis and impairs subsequent exercise performance, presumably because of lower hepatic glycogen stores. This trial was registered at clinicaltrials.gov as NCT01866215. PMID- 28100515 TI - Quest to determine the ideal position of the central venous catheter tip. PMID- 28100513 TI - Loss of Ranbp2 in motoneurons causes disruption of nucleocytoplasmic and chemokine signaling, proteostasis of hnRNPH3 and Mmp28, and development of amyotrophic lateral sclerosis-like syndromes. AB - The pathogenic drivers of sporadic and familial motor neuron disease (MND), such amyotrophic lateral sclerosis (ALS), are unknown. MND impairs the Ran GTPase cycle, which controls nucleocytoplasmic transport, ribostasis and proteostasis; however, cause-effect mechanisms of Ran GTPase modulators in motoneuron pathobiology have remained elusive. The cytosolic and peripheral nucleoporin Ranbp2 is a crucial regulator of the Ran GTPase cycle and of the proteostasis of neurological disease-prone substrates, but the roles of Ranbp2 in motoneuron biology and disease remain unknown. This study shows that conditional ablation of Ranbp2 in mouse Thy1 motoneurons causes ALS syndromes with hypoactivity followed by hindlimb paralysis, respiratory distress and, ultimately, death. These phenotypes are accompanied by: a decline in the nerve conduction velocity, free fatty acids and phophatidylcholine of the sciatic nerve; a reduction in the g ratios of sciatic and phrenic nerves; and hypertrophy of motoneurons. Furthermore, Ranbp2 loss disrupts the nucleocytoplasmic partitioning of the import and export nuclear receptors importin beta and exportin 1, respectively, Ran GTPase and histone deacetylase 4. Whole-transcriptome, proteomic and cellular analyses uncovered that the chemokine receptor Cxcr4, its antagonizing ligands Cxcl12 and Cxcl14, and effector, latent and activated Stat3 all undergo early autocrine and proteostatic deregulation, and intracellular sequestration and aggregation as a result of Ranbp2 loss in motoneurons. These effects were accompanied by paracrine and autocrine neuroglial deregulation of hnRNPH3 proteostasis in sciatic nerve and motoneurons, respectively, and post transcriptional downregulation of metalloproteinase 28 in the sciatic nerve. Mechanistically, our results demonstrate that Ranbp2 controls nucleocytoplasmic, chemokine and metalloproteinase 28 signaling, and proteostasis of substrates that are crucial to motoneuronal homeostasis and whose impairments by loss of Ranbp2 drive ALS-like syndromes. PMID- 28100516 TI - Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) in children: a step forward in apnoeic oxygenation, paradigm-shift in ventilation, or both? PMID- 28100517 TI - Indirect admission to intensive care after surgery: what should be considered? PMID- 28100518 TI - Stopping antithrombotics during regional anaesthesia and eye surgery: crying wolf? PMID- 28100519 TI - Paravertebral block in paediatric abdominal surgery-a systematic review and meta analysis of randomized trials. AB - The increased popularity of paravertebral block (PVB) can be attributed to its relative safety and comparable efficacy when compared with epidural analgesia. It has thus been recommended for open cholecystectomy and other less painful surgeries such as inguinal herniorraphy and appendectomy. We performed a systematic review of PVB in paediatric abdominal conditions to assess its clinical efficacy and side effects compared with other analgesic therapies.A search of Medline, Embase, and Web of Science and hand-searching references from inception date to May 2016 was done. Relevant studies were randomized clinical trials in patients 0-18 years old comparing PVB (single shot or continuous catheter) with any comparator and analgesic medication. Pain scores, rescue analgesia and adverse events were compared.The systematic reviews identified six trials enrolling 358 paediatric patients. PVB medications included bupivacaine, ropivacaine, lidocaine, and fentanyl. Surgical procedures included inguinal herniorraphy, cholecystectomy, and appendectomy. The standardized mean difference in early pain scores favoured PVB: 0.85 [95% confidence interval (CI) 0.12-1.58] at 4-6 h and 0.64 (95% CI 0.28-1.00) at 24 h. One study reported a reduced length of stay. Parental [odds ratio (OR) 5.12 (95% CI 2.59-10.1)] and surgeon [OR 6.05 (95% CI 2.25-16.3)] satisfaction were higher in those receiving a PVB. No major complications occurred with a PVB.PVB resulted in minimally improved pain scores for up to 24 h after surgery, reduced rescue analgesia requirements, and increased surgeon and parental satisfaction. PVB is a good alternative to caudal and ilioinguinal block in paediatric abdominal surgery. PMID- 28100520 TI - Evidence basis for using perineural dexmedetomidine to enhance the quality of brachial plexus nerve blocks: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Dexmedetomidine has been proposed as a perineural local anaesthetic (LA) adjunct to prolong peripheral nerve block duration; however, results from our previous meta-analysis in the setting of brachial plexus block (BPB) did not support its use. Many additional randomized trials have since been published. We thus conducted an updated meta-analysis. METHODS: Randomized trials investigating the addition of dexmedetomidine to LA compared with LA alone (Control) in BPB for upper extremity surgery were sought. Sensory and motor block duration, onset times, duration of analgesia, analgesic consumption, pain severity, patient satisfaction, and dexmedetomidine-related side-effects were analysed using random effects modeling. We used ratio-of-means (lower confidence interval [point estimate]) for continuous outcomes. RESULTS: We identified 32 trials (2007 patients), and found that dexmedetomidine prolonged sensory block (at least 57%, P < 0.0001), motor block (at least 58%, P < 0.0001), and analgesia (at least 63%, P < 0.0001) duration. Dexmedetomidine expedited onset for both sensory (at least 40%, P < 0.0001) and motor (at least 39%, P < 0.0001) blocks. Dexmedetomidine also reduced postoperative oral morphine consumption by 10.2mg [-15.3, -5.2] (P < 0.0001), improved pain control, and enhanced satisfaction. In contrast, dexmedetomidine increased odds of bradycardia (3.3 [0.8, 13.5](P = 0.0002)), and hypotension (5.4 [2.7, 11.0] (P < 0.0001)). A 50-60ug dexmedetomidine dose maximized sensory block duration while minimizing haemodynamic side-effects. No patients experienced any neurologic sequelae. Evidence quality for sensory block was high according to the GRADE system. CONCLUSIONS: New evidence now indicates that perineural dexmedetomidine improves BPB onset, quality, and analgesia. However, these benefits should be weighed against increased risks of motor block prolongation and transient bradycardia and hypotension. PMID- 28100521 TI - Perioperative alpha-receptor blockade in phaeochromocytoma surgery: an observational case series. AB - BACKGROUND: Mortality associated with surgery for phaeochromocytoma has dramatically decreased over the last decades. Many factors contributed to the dramatic decline of the mortality rate, and the influence of an alpha-receptor blockade is unclear and has never been tested in a randomized trial. We evaluated intraoperative haemodynamic conditions and the incidence of complications in patients with and without alpha-receptor blockade undergoing surgery for catecholamine producing tumours. METHODS: Haemodynamic conditions and perioperative complications were assessed in 110 patients with (B) and 166 without (N) alpha-receptor blockade. Data were analysed as a consecutive case series of 303 cases and subsequently via propensity score matching, and presented as mean and confidence interval (CI). RESULTS: No difference in maximal intraoperative systolic arterial pressures (B = 178 mm Hg (CI 169-187) vs N = 185 mm Hg (CI 177-193; P = 0.2542) and hypertensive episodes above 250 mm Hg were found (P = 0.7474) for the closed case series. No major complications occurred. Propensity score matching (75 pairs) revealed a significant difference of 17 mm Hg in maximal intraoperative systolic bp for these selected pairs (P = 0.024). CONCLUSIONS: Only a slight difference in mean maximal systolic arterial pressure was detected between patients with or without an alpha-receptor blockade. There was no difference in the incidence of excessive hypertensive episodes between groups and no major complications occurred. The basis for the general recommendation of perioperative alpha- receptor blockade for phaeochromocytoma surgery demands further study. PMID- 28100523 TI - Endothelial dysfunction in the early postoperative period after major colon cancer surgery. AB - BACKGROUND: Evidence suggests that endothelial dysfunction in the early postoperative period promotes myocardial injury after non-cardiac surgery. The aim of this study was to investigate the impact of colon cancer surgery on endothelial function and the association with the l-arginine-nitric oxide pathway postoperatively. METHODS: Patients undergoing elective colon cancer surgery (n = 31) were included in this prospective observational cohort study. Endothelial function, as measured using the reactive hyperaemia index (RHI), was assessed non invasively using digital pulse tonometry. RHI and plasma concentrations of L arginine, asymmetric dimethylarginine (ADMA), dihydrobiopterin and biopterin metabolites, tetrahydrobiopterin (BH4) and total biopterin were measured before surgery, at four h after surgery and at postoperative day one and two. Cardiac troponin I was measured before surgery and once daily on postoperative days one to four. RESULTS: Preoperative RHI was 1.86 (1.64 - 2.11) and decreased significantly during the observation period (linear mixed effects model of serial measurements, P = 0.015). Both L-arginine (P < 0.001) and ADMA (P = 0.024) decreased during the postoperative period. All biopterin metabolites were significantly decreased after surgery. A significant positive correlation was found between logAUC(l-arginine/ADMA) and logAUC(RHI) (P = 0.015) and between logAUC(L-arginine/ADMA) and logAUC(BH4) (P = 0.015). None of the patients had cardiac troponin I elevations. CONCLUSIONS: RHI was attenuated in the first days after colon cancer surgery indicating acute endothelial dysfunction. Endothelial dysfunction correlated with disturbances in the L-arginine - nitric oxide pathway. Our findings provide a rationale for investigating the hypothesized association between acute endothelial dysfunction and cardiovascular complications after non-cardiac surgery. CLINICAL TRIAL REGISTRATION: NCT02344771. PMID- 28100524 TI - Making robust assessments of specialist trainees' workplace performance. AB - BACKGROUND: Workplace-based assessments should provide a reliable measure of trainee performance, but have met with mixed success. We proposed that using an entrustability scale, where supervisors scored trainees on the level of supervision required for the case would improve the utility of compulsory mini clinical evaluation exercise (CEX) assessments in a large anaesthesia training program. METHODS: We analysed mini-CEX scores from all Australian and New Zealand College of Anaesthetists trainees submitted to an online database over a 12-month period. Supervisors' scores were adjusted for the expected supervision requirement for the case for trainees at different stages of training. We used generalisability theory to determine score reliability. RESULTS: 7808 assessments were available for analysis. Supervision requirements decreased significantly (P < 0.05) with increased duration and level of training, supporting validity. We found moderate reliability (G > 0.7) with a feasible number of assessments. Adjusting scores against the expected supervision requirement considerably improved reliability, with G > 0.8 achieved with only nine assessments. Three per cent of trainees generated average mini-CEX scores below the expected standard. CONCLUSIONS: Using an entrustment scoring system, where supervisors score trainees on the level of supervision required, mini-CEX scores demonstrated moderate reliability within a feasible number of assessments, and evidence of validity. When scores were adjusted against an expected standard, underperforming trainees could be identified, and reliability much improved. Taken together with other evidence on trainee ability, the mini-CEX is of sufficient reliability for inclusion in high stakes decisions on trainee progression towards independent specialist practice. PMID- 28100525 TI - Transoesophageal echocardiographic evaluation of central venous catheter positioning using Peres' formula or a radiological landmark-based approach: a prospective randomized single-centre study. AB - BACKGROUND: The lower superior vena cava (SVC), near its junction with the right atrium (RA), is considered the ideal location for the central venous catheter tip to ensure proper function and prevent injuries. We determined catheter insertion depth with a new formula using the sternoclavicular joint and the carina as radiological landmarks, with a 1.5 cm safety margin. The accuracy of tip positioning with the radiological landmark-based technique (R) and Peres' formula (P) was compared using transoesophageal echocardiography. METHODS: Real-time ultrasound-guided central venous catheter insertion was done through the right internal jugular or subclavian vein. Patients were randomly assigned to either the P group (n=93) or the R group (n=95). Optimal catheter tip position was considered to be within 2 cm above and 1 cm below the RA-SVC junction. Catheter tip position, abutment, angle to the vascular wall, and flow stream were evaluated on a bicaval view. RESULTS: The distance from the skin insertion point to the RA-SVC junction and determined depth of catheter insertion were more strongly correlated in the R group [17.4 (1.2) and 16.7 (1.5) cm; r=0.821, P<0.001] than in the P group [17.3 (1.2) and 16.4 (1.1) cm; r=0.517, P<0.001], with z=3.96 (P<0.001). More tips were correctly positioned in the R group than in the P group (74 vs 93%, P=0.001). Abutment, tip angle to the lateral wall >40 degrees , and disrupted flow stream were comparable. CONCLUSIONS: Catheter tip position was more accurate with a radiological landmark-based technique than with Peres' formula. CLINICAL TRIAL REGISTRATION: Clinical Trial Registry of Korea: https://cris.nih.go.kr/cris/index.jsp KCT0001937. PMID- 28100522 TI - Intraoperative dexamethasone does not increase the risk of postoperative wound infection: a propensity score-matched post hoc analysis of the ENIGMA-II trial (EnDEX). AB - BACKGROUND: In a post hoc analysis of the ENIGMA-II trial, we sought to determine whether intraoperative dexamethasone was associated with adverse safety outcomes. METHODS: Inverse probability weighting with estimated propensity scores was used to determine the association of dexamethasone administration with postoperative infection, quality of recovery, and adverse safety outcomes for 5499 of the 7112 non-cardiac surgery subjects enrolled in ENIGMA-II. RESULTS: Dexamethasone was administered to 2178 (40%) of the 5499 subjects included in this analysis and was not associated with wound infection [189 (8.7%) vs 275 (8.3%); propensity score adjusted relative risk (RR) 1.10; 95% confidence interval (CI) 0.89-1.34; P=0.38], severe postoperative nausea and vomiting on day 1 [242 (7.3%) vs 189 (8.7%); propensity score-adjusted RR 1.06; 95% CI 0.86-1.30; P=0.59], quality of recovery score [median 14, interquartile range (IQR) 12-15, vs median 14, IQR 12 16, P=0.10), length of stay in the postanaesthesia care unit [propensity score adjusted median (IQR) 2.0 (1.3, 2.9) vs 1.9 (1.3, 3.1), P=0.60], or the primary outcome of the main trial. Dexamethasone administration was associated with a decrease in fever on days 1-3 [182 (8.4%) vs 488 (14.7%); RR 0.61; 95% CI 0.5 0.74; P<0.001] and shorter lengths of stay in hospital [propensity score-adjusted median (IQR) 5.0 (2.9, 8.2) vs 5.3 (3.1, 9.1), P<0.001]. Neither diabetes mellitus nor surgical wound contamination status altered these outcomes. CONCLUSION: Dexamethasone administration to high-risk non-cardiac surgical patients did not increase the risk of postoperative wound infection or other adverse events up to day 30, and appears to be safe in patients either with or without diabetes mellitus. CLINICAL TRIAL REGISTRATION: NCT00430989. PMID- 28100526 TI - Comparison of different techniques of central venous pressure measurement in mechanically ventilated critically ill patients. AB - BACKGROUND: Several techniques exist for measuring central venous pressure (CVP) but little information is available about the accuracy of each method. The aim of this study was to compare different methods of CVP measurements in mechanically ventilated patients. METHODS: CVP was measured in mechanically ventilated patients without spontaneous breathing using four different techniques: 1) end expiratory CVP measurement at the base of the" c" wave (CVPMEASURED), chosen as the reference method; 2) CVP measurement from the monitor averaging CVP over the cardiac and respiratory cycles (CVPMONITOR); 3) CVP measurement after a transient withdrawing of mechanical ventilation (CVPNADIR); 4) CVP measurement corrected for the transmitted respiratory pressure induced by intrinsic PEEP (calculated CVP: CVPCALCULATED). Bias, precision, limits of agreement, and proportions of outliers (difference > 2 mm Hg) were determined. RESULTS: Among 61 included patients, 103 CVP assessments were performed. CVPMONITOR bias [-0.87 (1.06) mm Hg] was significantly different from those of CVPCALCULATED [1.42 (1.07), P < 0.001 and CVPNADIR (1.04 (1.29), P < 0.001]. The limits of agreement of CVPMONITOR [-2.96 to 1.21 mm Hg] were not significantly different to those of CVPNADIR (-1.49 to 3.57 mm Hg, P = 0.39) and CVPCALCULATED (-0.68 to 3.53 mm Hg, P = 0.31). The proportion of outliers was not significantly different between CVPMONITOR (n = 5, 5%) and CVPNADIR (n = 9, 9%, P = 0.27) but was greater with CVPCALCULATED (n = 16, 15%, P = 0.01). CONCLUSIONS: In mechanically ventilated patients, CVPMONITOR is a reliable method for assessing CVPMEASURED Taking into account transmitted respiratory pressures, CVPCALCULATED had a higher proportion of outliers and precision than CVPNADIR. PMID- 28100527 TI - Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) in children: a randomized controlled trial. AB - BACKGROUND: Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) was introduced to adult anaesthesia to improve the safety of airway management during apnoea before intubation. The objective of our study was to determine whether THRIVE safely prolongs apnoeic oxygenation in children. METHODS: This was a randomized controlled trial in 48 healthy children, with normal airways and cardiorespiratory function, in age groups 0-6 and 7-24 months, 2-5 and 6-10 yr old, presenting for elective surgery or imaging under general anaesthesia. All children were induced with sevoflurane, O2, and N2O, followed by muscle relaxation with rocuronium, and standardized preoxygenation with bag-and mask ventilation. The control arm received jaw support during apnoea, whereas the THRIVE arm received jaw support during apnoea and age-specific flow rates. The primary outcome was to demonstrate that children allocated to THRIVE maintain transcutaneous haemoglobin saturation at least twice as long as the expected age dependent apnoea time in the control group. RESULTS: Both study arms (each n=24) were similar in age and weight. The apnoea time was significantly shorter in the control arm: average 109.2 (95% CI 28.8) s in the control arm and 192 s in the THRIVE arm (0-6 months), 147.3 (95% CI 18.9) and 237 s (7-24 months), 190.5 (95% CI 15.3) and 320 s (2-5 yr), and 260.8 (95% CI 37.5) and 430 s (6-10 yr), respectively. Average transcutaneous haemoglobin saturation remained at 99.6% (95% CI 0.2) during THRIVE. Transcutaneous CO2 increased to a similar extent in both arms, with 2.4 (95% CI 0.5) mm Hg min-1 for the control arm and 2.4 (95% CI 0.4) mm Hg min-1 for the THRIVE arm. CONCLUSION: Transnasal humidified rapid insufflation ventilatory exchange prolongs the safe apnoea time in healthy children but has no effect to improve CO2 clearance. CLINICAL TRIAL REGISTRATION: ACTRN12615001319561. PMID- 28100528 TI - Higher risk of opioid-induced respiratory depression in children with neurodevelopmental disability: a retrospective cohort study of 12 904 patients. AB - BACKGROUND: Children with neurodevelopmental disabilities may be at risk of opioid-induced respiratory depression. We aimed to quantify the risks and effectiveness of morphine nurse-controlled analgesia (morphine-NCA) for postoperative pain in children with neurodevelopmental disabilities. METHODS: We carried out a retrospective cohort study of 12 904 children who received postoperative i.v. morphine-NCA. Subjects were divided into a neurodevelopmental disability group and a control group. Rates of clinical satisfaction, respiratory depression, and serious adverse events were obtained, and statistical analysis, including multilevel logistic regression using Bayesian inference, was performed. RESULTS: Of 12 904 patients, 2390 (19%) had neurodevelopmental disabilities. There were 88 instances of respiratory depression and 52 serious adverse events; there were no opioid-related deaths. The cumulative incidence of respiratory depression in the neurodevelopmental disability group was 1.09% vs 0.59% in the control group [odds ratio 1.8 (98% chance that the true odds ratio was >1)]. A significant interaction between postoperative morphine dose and neurodevelopmental disabilities was observed, with higher risk of respiratory depression with increasing dose. Satisfaction with morphine-NCA was very high overall, although children with neurodevelopmental disabilities were 1% more likely to have infusions rated as fair or poor (3.3 vs 2.1%, chi2P<0.001). CONCLUSIONS: Children with neurodevelopmental disabilities were 1.8 times more likely to suffer respiratory depression, absolute risk difference 0.5%; opioid induced respiratory depression in this group may relate to increased sensitivity to dose-relate respiratory effects of morphine. Morphine-NCA as described was an acceptable technique for children with and without neurodevelopmental disabilities. PMID- 28100529 TI - Children and parental anxiolysis in paediatric ambulatory surgery: a randomized controlled study comparing 0.3 mg kg-1 midazolam to tablet computer based interactive distraction. AB - BACKGROUND: The operating theatre, anaesthesia induction and separation from parents create fear and anxiety in children. Anxiety leads to adverse behavioral changes appearing and sometimes persisting during the postoperative period. Our aim was to compare the effects of midazolam (0.3 mg kg-1: MDZ) for premedication with age-appropriate tablet game apps (TAB) on children anxiety during and after ambulatory surgery. METHODS: A randomized controlled trial was conducted from May 16th, 2013 to March 25th, 2014 at the Children Hospital of Lyon. The primary outcome of this study was the change in m-YPAS score at the time of anaesthetic mask induction. Anxiety was also assessed in the waiting surgical area, at the time of separation with parents and when back in the ambulatory surgery ward. RESULTS: One hundred and eighteen patients aged four-11 yr were recruited, 60 in the TAB Group and 58 in the MDZ Group. Main endpoint was missing for three patients from the MDZ Group. At the time of mask induction, there was no significant difference between MDZ and TAB Group for the m-YPAS score (40.5 (18.6) vs 41.8 (20.7), P = 0.99). There was no significant correlation between m YPAS score and its evolution over the four period of time between subjects. CONCLUSIONS: We were not able to show whether TAB is superior to MDZ to blunt anxiety in children undergoing ambulatory surgery. TAB is a non-pharmacological tool which has the capacity in reducing perioperative stress without any sedative effect in this population. CLINICAL TRIAL REGISTRATION: NCT 02192710. PMID- 28100531 TI - Efficacy of continuous intravenous glucose monitoring in perioperative glycaemic control: a randomized controlled study. PMID- 28100530 TI - Feasibility of measuring memory response to increasing dexmedetomidine sedation in children. AB - BACKGROUND: The memory effect of dexmedetomidine has not been prospectively evaluated in children. We evaluated the feasibility of measuring memory and sedation responses in children during dexmedetomidine sedation for non-painful radiological imaging studies. Secondarily, we quantified changes in memory in relation to the onset of sedation. METHODS: A 10 min bolus of dexmedetomidine (2 mcg kg-1) was given to children as they named simple line drawings every five s. The absence of sedation was identified as any verbal response, regardless of correctness. After recovery, recognition memory was tested with correct Yes/No recognitions (50% novel pictures) and was matched to sedation responses during the bolus period (subsequent memory paradigm). RESULTS: Of 64 accruals, 30 children (mean [SD]6.1 (1.2) yr, eight male) received dexmedetomidine and completed all study tasks. Individual responses were able to be modelled successfully in the 30 children completing all the study tasks, demonstrating feasibility of this approach. Children had 50% probability of verbal response at five min 40 s after infusion start, whereas 50% probability of subsequent recognition memory occurred sooner at four min five s. CONCLUSIONS: Quantifying memory and sedation effects during dexmedetomidine infusion in verbal children was possible and demonstrated that memory function was present until shortly before verbal unresponsiveness occurred. This is the first study to investigate the effect of dexmedetomidine on memory in children. CLINICAL TRIAL REGISTRATION: NCT 02354378. PMID- 28100532 TI - Does benzodiazepine administration affect patient satisfaction: a secondary analysis of the ConCIOUS study. PMID- 28100533 TI - Ketamine inhalation. PMID- 28100534 TI - Direct laryngoscopy training is important for videolaryngoscopy skill acquisition. PMID- 28100535 TI - 'LIVES': a mnemonic for teaching advanced airway management. PMID- 28100537 TI - Preoperative supplementation with fibrinogen concentrate in cardiac surgery. PMID- 28100536 TI - Transparent acrylic protector use for patient positioning and monitoring in robot assisted laparoscopic prostatectomy. PMID- 28100538 TI - Reply. PMID- 28100539 TI - Waist circumference is better than body mass index, but sagittal anterior diameter may be even better. PMID- 28100540 TI - Reply. PMID- 28100544 TI - Oscillatory whole-body vibration improves exercise capacity and physical performance in pulmonary arterial hypertension: a randomised clinical study. AB - OBJECTIVE: In patients with pulmonary arterial hypertension (PAH), supportive therapies may be beneficial in addition to targeted medical treatment. Here, we evaluated the effectiveness and safety of oscillatory whole-body vibration (WBV) in patients on stable PAH therapy. METHODS: Twenty-two patients with PAH (mean PAP>=25 mm Hg and pulmonary arterial wedge pressure (PAWP)<=15 mm Hg) who were in world health organization (WHO)-Functional Class II or III and on stable PAH therapy for>=3 months, were randomised to receive WBV (16 sessions of 1-hour duration within 4 weeks) or to a control group, that subsequently received WBV. Follow-up measures included the 6-min walking distance (6MWD), cardiopulmonary exercise testing (CPET), echocardiography, muscle-power, and health-related quality of life (HRQoL; SF-36 and LPH questionnaires). RESULTS: When compared to the control group, patients receiving WBV exhibited a significant improvement in the primary endpoint, the 6MWD (+35.4+/-10.9 vs -4.4+/-7.6 m), resulting in a net benefit of 39.7+/-7.8 m (p=0.004). WBV was also associated with substantial improvements in CPET variables, muscle power, and HRQoL. The combined analysis of all patients (n=22) indicated significant net improvements versus baseline in the 6MWD (+38.6 m), peakVO2 (+65.7 mL/min), anaerobic threshold (+40.9 mL VO2/min), muscle power (+4.4%), and HRQoL (SF-36 +9.7, LPH -11.5 points) (all p<0.05). WBV was well tolerated in all patients, and no procedure-related severe adverse events (SAEs) occurred. CONCLUSIONS: WBV substantially improves exercise capacity, physical performance, and HRQoL in patients with PAH who are on stable targeted therapy. This methodology may be utilised in structured training programmes, and may be feasible for continuous long-term physical exercise in these patients. TRIAL REGISTRATION NUMBER: NCT01763112; Results. PMID- 28100545 TI - Chronic effects of air pollution on lung function after lung transplantation in the Systems prediction of Chronic Lung Allograft Dysfunction (SysCLAD) study. AB - An irreversible loss in lung function limits the long-term success in lung transplantation. We evaluated the role of chronic exposure to ambient air pollution on lung function levels in lung transplant recipients (LTRs).The lung function of 520 LTRs from the Cohort in Lung Transplantation (COLT) study was measured every 6 months. The levels of air pollutants (nitrogen dioxide (NO2), particulate matter with an aerodynamic cut-off diameter of x um (PMx) and ozone (O3)) at the patients' home address were averaged in the 12 months before each spirometry test. The effects of air pollutants on forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) in % predicted were estimated using mixed linear regressions. We assessed the effect modification of macrolide antibiotics in this relationship.Increased 12-month levels of pollutants were associated with lower levels of FVC % pred (-2.56%, 95% CI -3.86--1.25 for 5 ug.m-3 of PM10; 0.75%, 95% CI -1.38--0.12 for 2 ug.m-3 of PM2.5 and -2.58%, 95% CI -4.63--0.53 for 10 ug.m-3 of NO2). In patients not taking macrolides, the deleterious association between PM and FVC tended to be stronger and PM10 was associated with lower FEV1Our study suggests a deleterious effect of chronic exposure to air pollutants on lung function levels in LTRs, which might be modified with macrolides. PMID- 28100547 TI - How much is too much alcohol in tuberculosis? PMID- 28100548 TI - MST1R mutation as a genetic cause of Lady Windermere syndrome. PMID- 28100546 TI - Accuracy of line probe assays for the diagnosis of pulmonary and multidrug resistant tuberculosis: a systematic review and meta-analysis. AB - Only 25% of multidrug-resistant tuberculosis (MDR-TB) cases are currently diagnosed. Line probe assays (LPAs) enable rapid drug-susceptibility testing for rifampicin (RIF) and isoniazid (INH) resistance and Mycobacterium tuberculosis detection. Genotype MTBDRplusV1 was WHO-endorsed in 2008 but newer LPAs have since been developed.This systematic review evaluated three LPAs: Hain Genotype MTBDRplusV1, MTBDRplusV2 and Nipro NTM+MDRTB. Study quality was assessed with QUADAS-2. Bivariate random-effects meta-analyses were performed for direct and indirect testing. Results for RIF and INH resistance were compared to phenotypic and composite (incorporating sequencing) reference standards. M. tuberculosis detection results were compared to culture.74 unique studies were included. For RIF resistance (21 225 samples), pooled sensitivity and specificity (with 95% confidence intervals) were 96.7% (95.6-97.5%) and 98.8% (98.2-99.2%). For INH resistance (20 954 samples), pooled sensitivity and specificity were 90.2% (88.2 91.9%) and 99.2% (98.7-99.5%). Results were similar for direct and indirect testing and across LPAs. Using a composite reference standard, specificity increased marginally. For M. tuberculosis detection (3451 samples), pooled sensitivity was 94% (89.4-99.4%) for smear-positive specimens and 44% (20.2 71.7%) for smear-negative specimens.In patients with pulmonary TB, LPAs have high sensitivity and specificity for RIF resistance and high specificity and good sensitivity for INH resistance. This meta-analysis provides evidence for policy and practice. PMID- 28100549 TI - Impact of CPAP therapy on health-related quality of life in elderly patients with apnoea-hypopnea syndrome: a systematic review of randomised clinical trials. PMID- 28100550 TI - Additional important research priorities for bronchiectasis in China. PMID- 28100551 TI - Psychometric properties of the St George's Respiratory Questionnaire in patients with idiopathic pulmonary fibrosis. AB - The St George's Respiratory Questionnaire (SGRQ) has been used to measure health related quality of life (HRQoL) in patients with idiopathic pulmonary fibrosis (IPF).This analysis evaluated the psychometric properties of the SGRQ using data from 428 patients with IPF who participated in a 12-month, randomised, placebo controlled phase II trial of nintedanib.Internal consistency (Cronbach's alpha) was 0.91 for SGRQ total and >0.70 for domain scores. Test-retest reliability (intraclass correlation coefficients) was 0.77, 0.77, 0.69 and 0.66 for SGRQ total, activity, impact and symptoms scores, respectively. Construct validity of SGRQ total and domain scores was supported by weak to moderate cross-sectional correlations with the Medical Research Council dyspnoea scale (0.32-0.55), 6-min walk test distance (-0.25- -0.34), percentage predicted forced vital capacity ( 0.11- -0.15) and measures of gas exchange (-0.26-0.03). There was some evidence that the SGRQ total score was sensitive to detecting change.The reliability, construct validity and responsiveness of the SGRQ in patients with IPF suggest that this is an acceptable measure of HRQoL in patients with IPF. PMID- 28100552 TI - Toward understanding patient experience in idiopathic pulmonary fibrosis. PMID- 28100553 TI - Additional important research priorities for bronchiectasis in China. PMID- 28100554 TI - Should we be concerned about air quality as a contributor to poor outcomes in lung transplant recipients? PMID- 28100555 TI - Environmental tobacco smoke exposure among infants, children and young people: now is no time to relax. PMID- 28100556 TI - Poverty, low birthweight and brain size. PMID- 28100557 TI - Dual sensory impairment in special schools in South-Eastern Nigeria. AB - In a cross-sectional study to determine the magnitude of dual sensory impairment (DSI-combined hearing and vision loss) in children in single-disability special education schools, children in schools for the blind and schools for the deaf in four states in South-East Nigeria were examined by an ophthalmologist and otorhinolaryngologist to determine the level of their disability and to identify other disabilities if any. Participants were all students with childhood blindness or childhood deafness. The magnitude and causes of DSI and the burden of undetected DSI were the main outcome measures. A total of 273 students were examined. About 7% of these students had DSI out of which over 60% (12/19) was previously undetected. There was more DSI in the blind schools than in the deaf schools (p=0.003). There is a large burden of undetected DSI in children in special schools in Nigeria. There is a need to create awareness of this problem and advocate appropriate screening, rehabilitative and educational strategies for children who have it. PMID- 28100559 TI - What is involved in medicines management across care boundaries? A qualitative study of healthcare practitioners' experiences in the case of acute kidney injury. AB - OBJECTIVES: To examine the role of individual and collective cognitive work in managing medicines for acute kidney injury (AKI), this being an example of a clinical scenario that crosses the boundaries of care organisations and specialties. DESIGN: Qualitative design, informed by a realist perspective and using semistructured interviews as the data source. The data were analysed using template analysis. SETTING: Primary, secondary and intermediate care in England. PARTICIPANTS: 12 General practitioners, 10 community pharmacists, 7 hospital doctors and 7 hospital pharmacists, all with experience of involvement in preventing or treating AKI. RESULTS: We identified three main themes concerning participants' experiences of managing medicines in AKI. In the first theme, challenges arising from the clinical context, AKI is identified as a technically complex condition to identify and treat, often requiring judgements to be made about renal functioning against the context of the patient's general well-being. In the second theme, challenges arising from the organisational context, the crossing of professional and organisational boundaries is seen to introduce problems for the coordination of clinical activities, for example by disrupting information flows. In the third theme, meeting the challenges, participants identify ways in which they overcome the challenges they face in order to ensure effective medicines management, for example by adapting their work practices and tools. CONCLUSIONS: These themes indicate the critical role of cognitive work on the part of healthcare practitioners, as individuals and as teams, in ensuring effective medicines management during AKI. Our findings suggest that the capabilities underlying this work, for example decision-making, communication and team coordination, should be the focus of training and work design interventions to improve medicines management for AKI or for other conditions. PMID- 28100560 TI - Prevalence, impact and cost of multimorbidity in a cohort of people with chronic pain in Ireland: a study protocol. AB - INTRODUCTION: Multimorbidity (MM) refers to the coexistence of two or more chronic conditions within one person, where no one condition is considered primary. As populations age and healthcare provision improves, MM is becoming increasingly common and poses a challenge to the single morbidity approach to illness management, usually adopted by healthcare systems. Indeed, recent research has shown that 66.2% of the people in primary care in Ireland are living with MM. Healthcare usage and cost is significantly associated with MM, and additional chronic conditions lead to exponential increases in service usage and financial costs, and decreases in physical and mental well-being. Certain conditions, for example, chronic pain, are highly correlated with MM. This study aims to assess the extent, profile, impact and cost of MM among Irish adults with chronic pain. METHODS AND ANALYSIS: Using cluster sampling, participants aged 18 years and over will be recruited from Irish pain clinics and provided an information package and questionnaire asking them to participate in our study at three time points, 1 year apart. The questionnaire will include our specially developed checklist to assess the prevalence and impact of MM, along with validated measures of quality of life, pain, depression and anxiety, and illness perception. Economic data will also be collected, including direct and indirect costs. ETHICS AND DISSEMINATION: Ethical approval has been granted by the Research Ethics Committee of the National University of Ireland, Galway. Dissemination of results will be via journal articles and conference presentations. PMID- 28100561 TI - Investigation of the degree of organisational influence on patient experience scores in acute medical admission units in all acute hospitals in England using multilevel hierarchical regression modelling. AB - OBJECTIVES: Previous studies found that hospital and specialty have limited influence on patient experience scores, and patient level factors are more important. This could be due to heterogeneity of experience delivery across subunits within organisations. We aimed to determine whether organisation level factors have greater impact if scores for the same subspecialty microsystem are analysed in each hospital. SETTING: Acute medical admission units in all NHS Acute Trusts in England. PARTICIPANTS: We analysed patient experience data from the English Adult Inpatient Survey which is administered to 850 patients annually in each acute NHS Trusts in England. We selected all 8753 patients who returned the survey and who were emergency medical admissions and stayed in their admission unit for 1-2 nights, so as to isolate the experience delivered during the acute admission process. PRIMARY AND SECONDARY OUTCOME MEASURES: We used multilevel logistic regression to determine the apportioned influence of host organisation and of organisation level factors (size and teaching status), and patient level factors (demographics, presence of long-term conditions and disabilities). We selected 'being treated with respect and dignity' and 'pain control' as primary outcome parameters. Other Picker Domain question scores were analysed as secondary parameters. RESULTS: The proportion of overall variance attributable at organisational level was small; 0.5% (NS) for respect and dignity, 0.4% (NS) for pain control. Long-standing conditions and consequent disabilities were associated with low scores. Other item scores also showed that most influence was from patient level factors. CONCLUSIONS: When a single microsystem, the acute medical admission process, is isolated, variance in experience scores is mainly explainable by patient level factors with limited organisational level influence. This has implications for the use of generic patient experience surveys for comparison between Trusts and should prompt further research to explore if more discriminant surveys can be developed. PMID- 28100562 TI - Healthcare organisation and delivery for people with dementia and comorbidity: a qualitative study exploring the views of patients, carers and professionals. AB - OBJECTIVES: People living with dementia (PLWD) have a high prevalence of comorbidty. The aim of this study was to explore the impact of dementia on access to non-dementia services and identify ways of improving service delivery for this population. DESIGN: Qualitative study involving interviews and focus groups. Thematic content analysis was informed by theories of continuity of care and access to care. SETTING: Primary and secondary care in the South and North East of England. PARTICIPANTS: PLWD who had 1 of the following comorbidities-diabetes, stroke, vision impairment, their family carers and healthcare professionals (HCPs) in the 3 conditions. RESULTS: We recruited 28 community-dwelling PLWD, 33 family carers and 56 HCPs. Analysis resulted in 3 overarching themes: (1) family carers facilitate access to care and continuity of care, (2) the impact of the severity and presentation of dementia on management of comorbid conditions, (3) communication and collaboration across specialities and services is not dementia aware. We found examples of good practice, but these tended to be about the behaviour of individual practitioners rather than system-based approaches; current systems may unintentionally block access to care for PLWD. CONCLUSIONS: This study suggests that, in order to improve access and continuity for PLWD and comorbidity, a significant change in the organisation of care is required which involves: coproduction of care where professionals, PLWD and family carers work in partnership; recognition of the way a patient's diagnosis of dementia affects the management of other long-term conditions; flexibility in services to ensure they are sensitive to the changing needs of PLWD and their family carers over time; and improved collaboration across specialities and organisations. Research is needed to develop interventions that support partnership working and tailoring of care for PLWD and comorbidity. PMID- 28100563 TI - Effect of socioeconomic disadvantage, remoteness and Indigenous status on hospital usage for Western Australian preterm infants under 12 months of age: a population-based data linkage study. AB - OBJECTIVES: Our primary objective was to determine the incidence of hospital admission and emergency department presentation in Indigenous and non-Indigenous preterm infants aged postdischarge from birth admission to 11 months in Western Australia. Secondary objectives were to assess incidence in the poorest infants from remote areas and to determine the primary causes of hospital usage in preterm infants. DESIGN: Prospective population-based linked data set. SETTING AND PARTICIPANTS: All preterm babies born in Western Australia during 2010 and 2011. MAIN OUTCOME MEASURES: All-cause hospitalisations and emergency department presentations. RESULTS: There were 6.9% (4211/61 254) preterm infants, 13.1% (433/3311) Indigenous preterm infants and 6.5% (3778/57 943) non-Indigenous preterm infants born in Western Australia. Indigenous preterm infants had a higher incidence of hospital admission (adjusted incident rate ratio (aIRR) 1.24, 95% CI 1.08 to 1.42) and emergency department presentation (aIRR 1.71, 95% CI 1.44 to 2.02) compared with non-Indigenous preterm infants. The most disadvantaged preterm infants (7.8/1000 person days) had a greater incidence of emergency presentation compared with the most advantaged infants (3.1/1000 person days) (aIRR 1.61, 95% CI 1.30 to 2.00). The most remote preterm infants (7.8/1000 person days) had a greater incidence of emergency presentation compared with the least remote preterm infants (3.0/1000 person days; aIRR 1.82, 95% CI 1.49 to 2.22). CONCLUSIONS: In Western Australia, preterm infants have high hospital usage in their first year of life. Infants living in disadvantaged areas, remote area infants and Indigenous infants are at increased risk. Our data highlight the need for improved postdischarge care for preterm infants. PMID- 28100564 TI - Ageing and mental health: changes in self-reported health due to physical illness and mental health status with consecutive cross-sectional analyses. AB - OBJECTIVES: It is known that self-reported health (SRH) declines with increasing age and that comorbidity increases with age. We wished to examine how age transfers its effect to SRH through comorbid disease and mental illness and whether these processes remained stable from 1994 until 2008. The hypothesis is that ageing and/or the increased age-related burden of pathology explains the declining SRH. SETTING: The Tromso Study (TS) is a cohort study using a survey approach with repeated physical examinations. It was conducted in the municipality of Tromso, Norway, from 1974 to 2008. PARTICIPANTS: A total of 21 199 women and 19 229 men participated. PRIMARY AND SECONDARY OUTCOME MEASURES: SRH is the outcome of interest. We calculated and compared the effect sizes of age, comorbidity and mental health symptoms using multimediator analysis based on OLS regression. RESULTS: Ageing had a negative impact on SRH, but the total effect of age decreased from 1994 to 2007. We assessed the direct effect of age and then the proportion of indirect age-related effects through physical illness and mental health symptoms on the total effect. The direct effect of age represented 79.3% of the total effect in 1994 and decreased to 58.8% in 2007. Physical illness emerged as an increasingly important factor and increased its influence from 15.7% to 41.2% of the total effect. Age alone had a protective effect on mental health symptoms and this increased (2.5% to 17.3%), but we found a stronger association between mental health symptoms and physical disease in the later waves of the study (increasing from 3.7% to 14.8%). CONCLUSIONS: The results suggest that the effect on SRH of mental health symptoms caused by physical illness is an increasing public health problem. Treatment and care for specific medical conditions must therefore focus more strongly on how these conditions affect the patient's mental health and address these concerns accordingly. PMID- 28100565 TI - Prevalence and clinical impact of recreational drug consumption in people living with HIV on treatment: a cross-sectional study. AB - OBJECTIVES: Drug interactions, poor adherence to medication and high-risk sexual behaviour may occur in individuals with HIV using recreational drugs. Thus, we aimed to assess the prevalence of recreational drugs use and to explore its clinical impact in HIV patients on treatment. METHODS: Observational, cross sectional, study conducted in a 700 bed university hospital, Barcelona, Spain. A total of 208 adults living with HIV on treatment were included. A questionnaire was administered by clinical pharmacists, including evaluation of sociodemographic variables, past 12-month drug consumption, adherence to antiretrovirals (Simplified Medication Adherence Questionnaire) and high-risk sexual behaviour (condomless sex/multiple partners). Additional data were obtained from clinical records. Recreational drug-antiretroviral interactions were checked in reference databases. Prevalence was calculated for 5% precision and 95% CI. Crude and adjusted binary logistic regressions were performed to identify associations between recreational drug use and adherence problems, and between recreational drug use and high-risk sexual behaviour. RESULTS: From the overall sample, 92 participants (44.2%) consumed recreational drugs over the past 1 year. Of these, 44 (48.8%) had used different types of recreational drugs in this period. We detected 11 recreational substances, including sildenafil and nitrites. The most consumed drugs were: cannabis (68.5%), cocaine (45.5%), nitrites (31.5%), sildenafil (28.3) and ecstasy (19.6%). Relevant interactions occurred in 46 (50%) of the individuals consuming drugs. Recreational drug consumption was found to be related to adherence problems with antiretrovirals (OR: 2.51 (95% CI 1.32 to 4.77) p=0.005) and high-risk sexual behaviour (OR: 2.81 (95% CI 1.47 to 5.39) p=0.002). CONCLUSIONS: Recreational drugs are frequently used by HIV patients on treatment. Classical drugs and new substances consumed in sexual context are usual. Recreational drug consumption interferes with several clinical outcomes, including potentially relevant interactions between drugs and antiretrovirals, adherence problems and high-risk sexual behaviour. Thus, there is the urgent need of implementing patient-centred care involving recreational drug consumption. PMID- 28100567 TI - MeCP2 regulated glycogenes contribute to proliferation and apoptosis of gastric cancer cells. AB - Aberrant glycogene and glycan expression is intimately associated with carcinogenesis, invasion, and metastasis of gastric cancer (GC); however the regulatory mechanisms for glycogenes in GC cells remain unclear. Methyl-CpG binding protein 2 (MeCP2) regulates genes by binding to methylated promoters, and in our previous work we found that it is overexpressed in GC cell lines and tissues, functioning as an oncogene. In this study we detected the expression of 212 glycogenes in MeCP2 silenced GC cells versus control using the Agilent Whole Human Genome Microarray and mining the data through bioinformatic analysis. A total of 10 glycogenes exhibited increased expression (FC >= 2, P < 0.05), while 16 showed decreased expression (FC <= 2, P < 0.05) in the MeCP2 silenced cells, which corresponded to down-regulation of Lewis antigens (UEA-I), T/Tn antigens (PNA), and mature N-glycans (PHA-E and PHA-E+L) and up-regulation of lactosylceramide, a precursor oligosaccharide of N-glycans. Examination of the TCGA Gastric Cancer databases demonstrated that nine glycogenes (24.6%) were oppositely regulated by MeCP2 in MeCP2 knockdown BGC-823 cells relative to their expression level in GC tissues, and might be downstream genes of MeCP2. Individual gene analysis suggested that neutral alpha-glucosidase AB (GANAB) knockdown can rescue the effects of MeCP2 overexpression on GC cells. MeCP2 promotes GANAB by binding to the second methylated CpG island (206 bp, -12916 to 13122) of the GANAB promoter. In conclusion, glycogenes can be either up- or down regulated by MeCP2 directly or indirectly to alter the glycopatterning and affect the proliferation and apoptosis of GC cells. PMID- 28100566 TI - Loss of AXIN1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions. AB - In colorectal cancer (CRC), WNT pathway activation by genetic rearrangements of RSPO3 is emerging as a promising target. However, its low prevalence severely limits availability of preclinical models for in-depth characterization. Using a pipeline designed to suppress stroma-derived signal, we find that RSPO3 "outlier" expression in CRC samples highlights translocation and fusion transcript expression. Outlier search in 151 CRC cell lines identified VACO6 and SNU1411 cells as carriers of, respectively, a canonical PTPRK(e1)-RSPO3(e2) fusion and a novel PTPRK(e13)-RSPO3(e2) fusion. Both lines displayed marked in vitro and in vivo sensitivity to WNT blockade by the porcupine inhibitor LGK974, associated with transcriptional and morphological evidence of WNT pathway suppression. Long term treatment of VACO6 cells with LGK974 led to the emergence of a resistant population carrying two frameshift deletions of the WNT pathway inhibitor AXIN1, with consequent protein loss. Suppression of AXIN1 in parental VACO6 cells by RNA interference conferred marked resistance to LGK974. These results provide the first mechanism of secondary resistance to WNT pathway inhibition. PMID- 28100568 TI - Stentriever thrombectomy with distal protection device for carotid free floating thrombus: a technical case report. AB - We report the clinical details, imaging findings and management of a 45-year-old man who presented with recurrent transient ischemic attacks due to carotid free floating thrombus. Free floating thrombus of the carotid artery is a very rare condition with a high risk of distal embolic shower. The optimal treatment options are debatable and include medical management, surgical thrombectomy and endovascular thrombectomy. We describe the use of a stentriever with filter protection in the management of carotid free floating thrombus as a novel treatment option. PMID- 28100569 TI - Multiple pregnancy in a primigravida with uncorrected Pentalogy of Fallot. AB - Pentalogy of Fallot is a cyanotic congenital heart disease that has guarded prognosis without surgical intervention in infancy. Women with uncorrected defects rarely survive into childbearing age and pregnancy in this group is associated with a high rate of perinatal loss. Physiological cardiovascular changes in pregnancy can lead to maternal haemodynamic instability with subsequent adverse cardiac sequelae with or without fetal decompensation. Optimum management and pregnancy outcomes in mother with uncorrected Pentalogy of Fallot and twin pregnancy have not been described in the literature. We describe a successful case of monochorionic diamniotic twin pregnancy in an affected woman who has not undergone surgical repair. Her pregnancy progressed without any adverse cardiopulmonary complications. Her caesarean delivery and postpartum recovery were favourable, with successful birth of two healthy babies at 35.7 weeks. This case emphasises the importance of a multidisciplinary team, especially of obstetricians with expertise in high-risk pregnancies, adult congenital heart disease cardiologists and anaesthesiologist. PMID- 28100570 TI - A rare cause of constrictive pericarditis. AB - A 67-year-old man presented with 3 months of exertional dyspnoea and 1 week of oedema. Examination revealed elevated neck veins, pulsus paradoxus, muffled heart sounds, decreased breath sounds and pedal oedema. Transthoracic echocardiogram (TTE) demonstrated cardiac tamponade, and chest X-ray showed pleural effusion. Pericardiocentesis, thoracocentesis, laboratory investigations and CT did not elucidate an underlying aetiology. Three weeks later, he presented with recurrent cardiac tamponade and pleural effusion. Pericardial window histology was benign. Pleural and pericardial fluids were again unrevealing. Three months later, he presented with worsening congestive heart failure. TTE, cardiac catheterisation and cardiac MRI were consistent with constrictive pericarditis. Preoperative workup did not identify an underlying cause. The patient underwent subtotal pericardiectomy. Intraoperative frozen section indicated malignancy. Pathology confirmed metastatic poorly differentiated signet ring adenocarcinoma of intestinal origin. He died 4 days postoperatively from multiorgan failure. PMID- 28100571 TI - Primary squamous cell carcinoma of the thyroid with complete response to radical radiotherapy and concurrent cisplatin-based chemotherapy. AB - Chemoradiotherapy and/or surgery are both potentially radical treatments for squamous cell carcinomas. Squamous cell carcinomas are considered chemosensitive tumours compared to adenocarcinomas or anaplastic thyroid malignancies. A 76-year old man was found to have T4bN0M0 primary squamous cell carcinoma of the thyroid with encasement of the internal carotid artery. The disease was deemed unresectable. Therefore, he was treated with radical radiotherapy with concurrent cisplatin-based chemotherapy. We discuss herein the aetiology, diagnosis and management of primary squamous cell carcinoma of the thyroid. We demonstrate success of chemoradiotherapy in an unresectable case of a rare and aggressive disease. PMID- 28100572 TI - Pain in the neck. PMID- 28100573 TI - Mucormycosis pulmonary abscess, containment in a patient with uncontrolled diabetes mellitus. AB - A 56-year-old Hispanic male with solo risk factor of uncontrolled diabetes mellitus presented with recurrent haemoptysis. Initial concern was for malignancy with postobstructive pneumonia; however, invasive testing and biopsy confirmed infectious mass of fungal aetiology requiring surgical resection followed by a prolonged course of anti-fungal therapy. Discussion centred on approach to, progression of and course of action in the management of pulmonary abscess due to mucormycosis. PMID- 28100575 TI - Atrophic pityriasis versicolor occurring in a patient with Sjogren's syndrome. AB - Pityriasis versicolor is one of the most frequent epidermal mycotic infections in the world, but its atrophic variant is rarely described. The aetiology of the atrophy is still unknown, and two main hypotheses have been formulated, one suggesting a correlation with long-term use of topical steroids and the other a delayed type hypersensitivity to epicutaneous antigens derived from components of the fungus. Atrophic pityriasis versicolor is a benign disease, but needs to be distinguished from other more severe skin diseases manifesting with cutaneous atrophy. The diagnosis can be easily confirmed by direct microscopic observation of the scales soaked in 15% potassium hydroxide, which reveals the typical 'spaghetti and meatball' appearance, or by a skin biopsy in doubtful cases. Here, we describe a case of extensive atrophic pityriasis versicolor occurring in a woman affected by Sjogren's syndrome which completely resolved after topical antifungal treatment. PMID- 28100574 TI - Clostridium hastiforme bacteraemia secondary to pyometra in a 64-year-old woman. AB - The Gram-negative, rod-shaped, anaerobe bacteria Tissierella praeacuta was first described in 1908 by Tissier. However, during the past decade, Clostridium hastiforme has been recognised as a later synonym of T. praeacuta. C. hastiforme/T. praeacuta has only rarely been described in previous literature as a cause of human infection. We present here a case report of C. hastiforme/T. praeacuta bacteraemia secondary to pyometra in a 64-year-old woman with a history of multiple sclerosis and an intrauterine device inserted three decades earlier. C. hastiforme/T. praeacuta was isolated from blood as well as pus from the site of infection. The patient was cured with a combination of drainage and antibiotic therapy. PMID- 28100576 TI - Perioperative management of a large, late presenting phaeochromocytoma. AB - A 77-year-old man presenting to the emergency department with an acute coronary syndrome was later found to have a phaeochromocytoma. The lateness of this presentation was likely due to the protective alpha blocking effects of long-term terazosin therapy for his prostatism. alpha blockers such as terazosin are a well recognised medical therapy in the perioperative optimisation of phaeochromocytoma because they treat the adrenergic effects of catecholamine release from the tumour such as hypertension. This patient was diagnosed with an ST elevation myocardial infarction (STEMI). A cardiac angiogram showed no evidence of vessel occlusion. A right adrenal mass of 9*8*9 cm was incidentally found and confirmed as a phaeochromocytoma with raised plasma metanephrines and normetanephrines. Following preoperative optimisation and multidisciplinary team involvement, an open right adrenalectomy was performed successfully some months later. PMID- 28100578 TI - Ocular surface squamous neoplasia treated with topical interferon alpha 2b. PMID- 28100577 TI - Late spontaneous decapsulation of the kidney graft in a patient with hepatitis C and treated with sirolimus: possible pathophysiological association in a rare complication. AB - Late decapsulation with fluid collection is a rare complication of renal transplantation with deleterious effects on kidney function. Its physiopathology is unclear but there might be an association with mammalian target of rapamycin (m-TOR) inhibitors, especially in patients with chronic hepatitis C. We report a case of late spontaneous decapsulation 12 years after kidney transplant in a patient infected with hepatitis C under treatment with sirolimus. He underwent marsupialisation of the collection, sirolimus was converted to cyclosporine and hepatitis C treatment was performed with success. This is the first successful case report of late spontaneous decapsulation of the kidney graft in a patient with hepatitis C. PMID- 28100579 TI - Acute mania after levothyroxine replacement for hypothyroid-induced heart block. AB - Psychiatric disturbances can manifest after levothyroxine (LT4) treatment for severe hypothyroidism. We present the case of a young Filipino man with Hashimoto's thyroiditis and high-grade heart block, who was given a full replacement LT4 dose on admission. Twenty-four hours after this dose, he developed manic symptoms, which were addressed with sedatives and neuroleptics with gradual restoration of euthymia the following day. A comprehensive workup did not reveal any findings suggestive of another aetiology for either mania or heart block. We ultimately ascribed the mania as secondary to LT4, and the heart block to hypothyroidism. Although mania is more likely to be precipitated by high starting LT4 doses, reports have shown that symptoms can still arise even at lower doses and with more gradual titration, especially in long-standing hypothyroidism. PMID- 28100581 TI - Diabetes mellitus and the incidence of hearing loss: a cohort study. PMID- 28100582 TI - Bicycle injuries and helmet use: a systematic review and meta-analysis. PMID- 28100580 TI - Venetoclax in Patients with Previously Treated Chronic Lymphocytic Leukemia. AB - Venetoclax is the first BCL2 inhibitor to enter routine clinical practice. It is an orally bioavailable small molecule that binds BCL2 very specifically. Acting as a pharmacologic mimic of the proteins that initiate apoptosis (a so-called BH3 mimetic), venetoclax rapidly induces apoptosis in chronic lymphocytic leukemia (CLL) cells, which express high levels of BCL2 and rely on it to maintain their survival. As a single agent, daily venetoclax treatment induced durable responses in 79% of patients with relapsed or refractory CLL or small lymphocytic lymphoma in a phase I study, including complete remissions in 20% of patients. Its use was approved by the FDA in April 2016 for patients with previously treated del(17p) CLL on the basis of a single-arm phase II trial demonstrating a 79% response rate and an estimated 1-year progression-free survival of 72% with 400 mg/day continuous therapy. This review focuses on venetoclax, its mechanism of action, pharmacology, and clinical trial data and seeks to place it in the context of rapid advances in therapy for patients with relapsed CLL, especially those with del(17p) CLL. Clin Cancer Res; 23(16); 4527-33. (c)2017 AACR. PMID- 28100583 TI - Every participant is a PI. Citizen science and participatory governance in population studies. PMID- 28100584 TI - UMI-tools: modeling sequencing errors in Unique Molecular Identifiers to improve quantification accuracy. AB - Unique Molecular Identifiers (UMIs) are random oligonucleotide barcodes that are increasingly used in high-throughput sequencing experiments. Through a UMI, identical copies arising from distinct molecules can be distinguished from those arising through PCR amplification of the same molecule. However, bioinformatic methods to leverage the information from UMIs have yet to be formalized. In particular, sequencing errors in the UMI sequence are often ignored or else resolved in an ad hoc manner. We show that errors in the UMI sequence are common and introduce network-based methods to account for these errors when identifying PCR duplicates. Using these methods, we demonstrate improved quantification accuracy both under simulated conditions and real iCLIP and single-cell RNA-seq data sets. Reproducibility between iCLIP replicates and single-cell RNA-seq clustering are both improved using our proposed network-based method, demonstrating the value of properly accounting for errors in UMIs. These methods are implemented in the open source UMI-tools software package. PMID- 28100585 TI - Fast and accurate de novo genome assembly from long uncorrected reads. AB - The assembly of long reads from Pacific Biosciences and Oxford Nanopore Technologies typically requires resource-intensive error-correction and consensus generation steps to obtain high-quality assemblies. We show that the error correction step can be omitted and that high-quality consensus sequences can be generated efficiently with a SIMD-accelerated, partial-order alignment-based, stand-alone consensus module called Racon. Based on tests with PacBio and Oxford Nanopore data sets, we show that Racon coupled with miniasm enables consensus genomes with similar or better quality than state-of-the-art methods while being an order of magnitude faster. PMID- 28100586 TI - Axon Termination, Pruning, and Synaptogenesis in the Giant Fiber System of Drosophila melanogaster Is Promoted by Highwire. AB - The ubiquitin ligase Highwire has a conserved role in synapse formation. Here, we show that Highwire coordinates several facets of central synapse formation in the Drosophila melanogaster giant fiber system, including axon termination, axon pruning, and synaptic function. Despite the similarities to the fly neuromuscular junction, the role of Highwire and the underlying signaling pathways are distinct in the fly's giant fiber system. During development, branching of the giant fiber presynaptic terminal occurs and, normally, the transient branches are pruned away. However, in highwire mutants these ectopic branches persist, indicating that Highwire promotes axon pruning. highwire mutants also exhibit defects in synaptic function. Highwire promotes axon pruning and synaptic function cell autonomously by attenuating a mitogen-activated protein kinase pathway including Wallenda, c-Jun N-terminal kinase/Basket, and the transcription factor Jun. We also show a novel role for Highwire in non-cell autonomous promotion of synaptic function from the midline glia. Highwire also regulates axon termination in the giant fibers, as highwire mutant axons exhibit severe overgrowth beyond the pruning defect. This excessive axon growth is increased by manipulating Fos expression in the cells surrounding the giant fiber terminal, suggesting that Fos regulates a trans-synaptic signal that promotes giant fiber axon growth. PMID- 28100587 TI - Efficient Estimation of Realized Kinship from Single Nucleotide Polymorphism Genotypes. AB - Realized kinship is a key statistic in analyses of genetic data involving relatedness of individuals or structure of populations. There are several estimators of kinship that make use of dense SNP genotypes. We introduce a class of estimators, of which some existing estimators are special cases. Within this class, we derive properties of the estimators and determine an optimal estimator. Additionally, we introduce an alternative marker weighting that takes allelic associations [linkage disequilibrium (LD)] into account, and apply this weighting to several estimators. In a simulation study, we show that improved estimators are obtained (1) by optimal weighting of markers, (2) by taking physical contiguity of genome into account, and (3) by weighting on the basis of LD. PMID- 28100588 TI - Involvement of Conserved Amino Acids in the C-Terminal Region of LINE-1 ORF2p in Retrotransposition. AB - Long interspersed element 1 (L1) is the only currently active autonomous retroelement in the human genome. Along with the parasitic SVA and short interspersed element Alu, L1 is the source of DNA damage induced by retrotransposition: a copy-and-paste process that has the potential to disrupt gene function and cause human disease. The retrotransposition process is dependent upon the ORF2 protein (ORF2p). However, it is unknown whether most of the protein is important for retrotransposition. In particular, other than the Cys motif, the C terminus of the protein has not been intensely examined in the context of retrotransposition. Using evolutionary analysis and the Alu retrotransposition assay, we sought to identify additional amino acids in the C terminus important for retrotransposition. Here, we demonstrate that Gal4-tagged and untagged C-terminally truncated ORF2p fragments possess residual potential to drive Alu retrotransposition. Using sight-directed mutagenesis we identify that while the Y1180 amino acid is important for ORF2p- and L1-driven Alu retrotransposition, a mutation at this position improves L1 retrotransposition. Even though the mechanism of the contribution of Y1180 to Alu and L1 mobilization remains unknown, experimental evidence rules out its direct involvement in the ability of the ORF2p reverse transcriptase to generate complementary DNA. Additionally, our data support that ORF2p amino acids 1180 and 1250-1262 may be involved in the reported ORF1p-mediated increase in ORF2p-driven Alu retrotransposition. PMID- 28100589 TI - Meiotic Consequences of Genetic Divergence Across the Murine Pseudoautosomal Region. AB - The production of haploid gametes during meiosis is dependent on the homology driven processes of pairing, synapsis, and recombination. On the mammalian heterogametic sex chromosomes, these key meiotic activities are confined to the pseudoautosomal region (PAR), a short region of near-perfect sequence homology between the X and Y chromosomes. Despite its established importance for meiosis, the PAR is rapidly evolving, raising the question of how proper X/Y segregation is buffered against the accumulation of homology-disrupting mutations. Here, I investigate the interplay of PAR evolution and function in two interfertile house mouse subspecies characterized by structurally divergent PARs, Mus musculus domesticus and M. m. castaneus Using cytogenetic methods to visualize the sex chromosomes at meiosis, I show that intersubspecific F1 hybrids harbor an increased frequency of pachytene spermatocytes with unsynapsed sex chromosomes. This high rate of asynapsis is due, in part, to the premature release of synaptic associations prior to completion of prophase I. Further, I show that when sex chromosomes do synapse in intersubspecific hybrids, recombination is reduced across the paired region. Together, these meiotic defects afflict ~50% of spermatocytes from F1 hybrids and lead to increased apoptosis in meiotically dividing cells. Despite flagrant disruption of the meiotic program, a subset of spermatocytes complete meiosis and intersubspecific F1 males remain fertile. These findings cast light on the meiotic constraints that shape sex chromosome evolution and offer initial clues to resolve the paradox raised by the rapid evolution of this functionally significant locus. PMID- 28100590 TI - Inferring Individual Inbreeding and Demographic History from Segments of Identity by Descent in Ficedula Flycatcher Genome Sequences. AB - Individual inbreeding and historical demography can be estimated by analyzing runs of homozygosity (ROH), which are indicative of chromosomal segments of identity by descent (IBD). Such analyses have so far been rare in natural populations due to limited genomic resources. We analyzed ROH in whole genome sequences from 287 Ficedula flycatchers representing four species, with the objectives of evaluating the causes of genome-wide variation in the abundance of ROH and inferring historical demography. ROH were clearly more abundant in genomic regions with low recombination rate. However, this pattern was substantially weaker when ROH were mapped using genetic rather than physical single nucleotide polymorphism (SNP) coordinates in the genome. Empirical results and simulations suggest that high ROH abundance in regions of low recombination was partly caused by increased power to detect the very long IBD segments typical of regions with a low recombination rate. Simulations also showed that hard selective sweeps (but not soft sweeps or background selection) likely contributed to variation in the abundance of ROH across the genome. Comparisons of the abundance of ROH among several study populations indicated that the Spanish pied flycatcher population had the smallest historical effective population size (Ne) for this species, and that a putatively recently founded island (Baltic) population had the smallest historical Ne among the collared flycatchers. Analysis of pairwise IBD in Baltic collared flycatchers indicated that this population was founded <60 generations ago. This study provides a rare genomic glimpse into demographic history and the mechanisms underlying the genome-wide distribution of ROH. PMID- 28100591 TI - Dynamics and Fate of Beneficial Mutations Under Lineage Contamination by Linked Deleterious Mutations. AB - Beneficial mutations drive adaptive evolution, yet their selective advantage does not ensure their fixation. Haldane's application of single-type branching process theory showed that genetic drift alone could cause the extinction of newly arising beneficial mutations with high probability. With linkage, deleterious mutations will affect the dynamics of beneficial mutations and might further increase their extinction probability. Here, we model the lineage dynamics of a newly arising beneficial mutation as a multitype branching process. Our approach accounts for the combined effects of drift and the stochastic accumulation of linked deleterious mutations, which we call lineage contamination We first study the lineage-contamination phenomenon in isolation, deriving dynamics and survival probabilities (the complement of extinction probabilities) of beneficial lineages. We find that survival probability is zero when [Formula: see text] where U is deleterious mutation rate and [Formula: see text] is the selective advantage of the beneficial mutation in question, and is otherwise depressed below classical predictions by a factor bounded from below by [Formula: see text] We then put the lineage contamination phenomenon into the context of an evolving population by incorporating the effects of background selection. We find that, under the combined effects of lineage contamination and background selection, ensemble survival probability is never zero but is depressed below classical predictions by a factor bounded from below by [Formula: see text] where [Formula: see text] is mean selective advantage of beneficial mutations, and [Formula: see text] This factor, and other bounds derived from it, are independent of the fitness effects of deleterious mutations. At high enough mutation rates, lineage contamination can depress fixation probabilities to values that approach zero. This fact suggests that high mutation rates can, perhaps paradoxically, (1) alleviate competition among beneficial mutations, or (2) potentially even shut down the adaptive process. We derive critical mutation rates above which these two events become likely. PMID- 28100592 TI - Detecting High-Order Epistasis in Nonlinear Genotype-Phenotype Maps. AB - High-order epistasis has been observed in many genotype-phenotype maps. These multi-way interactions between mutations may be useful for dissecting complex traits and could have profound implications for evolution. Alternatively, they could be a statistical artifact. High-order epistasis models assume the effects of mutations should add, when they could in fact multiply or combine in some other nonlinear way. A mismatch in the "scale" of the epistasis model and the scale of the underlying map would lead to spurious epistasis. In this article, we develop an approach to estimate the nonlinear scales of arbitrary genotype phenotype maps. We can then linearize these maps and extract high-order epistasis. We investigated seven experimental genotype-phenotype maps for which high-order epistasis had been reported previously. We find that five of the seven maps exhibited nonlinear scales. Interestingly, even after accounting for nonlinearity, we found statistically significant high-order epistasis in all seven maps. The contributions of high-order epistasis to the total variation ranged from 2.2 to 31.0%, with an average across maps of 12.7%. Our results provide strong evidence for extensive high-order epistasis, even after nonlinear scale is taken into account. Further, we describe a simple method to estimate and account for nonlinearity in genotype-phenotype maps. PMID- 28100593 TI - Clinical implications of DNMT3A mutations in a Southeast Asian cohort of acute myeloid leukaemia patients. AB - AIMS: In recent years, genomic technologies have enabled the identification of mutations in acute myeloid leukaemia (AML). DNMT3A is a recurrently mutated epigenetic modifier gene in AML. To date, the prognostic significance of DNMT3A mutations has not been studied in a Southeast Asian AML population. We sought to investigate the clinical implications of DNMT3A mutations in a Southeast Asian cohort of AML patients. METHODS: DNMT3A mutations were identified using a targeted next-generation sequencing panel in 157 AML patients. We studied the molecular and clinical features of patients with DNMT3A mutations and assessed the prognostic impact of DNMT3A mutations. RESULTS: DNMT3A mutations were found in 33 of 157 (21.0%) AML patients. 114 patients were included for statistical analysis. Pretreatment data revealed that patients with DNMT3A mutations were older (>=60 years old), had a higher white blood cell count at diagnosis, had more adverse cytogenetic risk profiles and were more often associated with NPM1 mutations compared with patients with wild-type DNMT3A. Survival analysis showed that DNMT3A mutations were associated with poorer clinical outcomes. This was especially when associated with NPM1 and FLT3-ITD mutations (AML NPM1/FLT3/DNMT3A ), which are common. The AML NPM1/FLT3/DNMT3A subtype was an independent predictor for poorer overall survival (OS). Other independent risk factors for poorer OS include advanced age at diagnosis and adverse cytogenetic risk stratification. CONCLUSIONS: DNMT3A mutations are associated with an unfavourable clinical outcome in our Southeast Asian AML patient cohort. In particular, AML NPM1/FLT3/DNMT3A patients had the poorest prognosis. PMID- 28100594 TI - Rapid Aminoglycoside NP Test for Rapid Detection of Multiple Aminoglycoside Resistance in Enterobacteriaceae. AB - The rapid aminoglycoside NP (Nordmann/Poirel) test was developed to rapidly identify multiple aminoglycoside (AG) resistance in Enterobacteriaceae It is based on the detection of the glucose metabolism related to enterobacterial growth in the presence of a defined concentration of amikacin plus gentamicin. Formation of acid metabolites was evidenced by a color change (orange to yellow) of the red phenol pH indicator. The rapid aminoglycoside NP test was evaluated by using bacterial colonies of 18 AG-resistant isolates producing 16S rRNA methylases, 20 AG-resistant isolates expressing AG-modifying enzymes (acetyl-, adenyl-, and phosphotransferases), and 10 isolates susceptible to AG. Its sensitivity and specificity were 100% and 97%, respectively, compared to the broth dilution method, which was taken as the gold standard for determining aminoglycoside resistance. The test is inexpensive, rapid (<2 h), and implementable worldwide. PMID- 28100595 TI - Determinants of Viral Oncogene E6-E7 mRNA Overexpression in a Population-Based Large Sample of Women Infected by High-Risk Human Papillomavirus Types. AB - Cervical cancer screening by human papillomavirus (HPV) DNA testing with cytology triage is more effective than cytology testing. Compared to cytology, the HPV DNA test's higher sensitivity, which allows better protection with longer intervals, makes it necessary to triage the women with a positive result to compensate its lower specificity. We are conducting a large randomized clinical trial (New Technologies for Cervical Cancer 2 [NTCC2]) within organized population-based screening programs in Italy using HPV DNA as the primary screening test to evaluate, by the Aptima HPV assay (Hologic), the use of HPV E6-E7 mRNA in a triage test in comparison to cytology. By the end of June 2016, data were available for 35,877 of 38,535 enrolled women, 2,651 (7.4%) of whom were HPV DNA positive. Among the samples obtained, 2,453 samples were tested also by Aptima, and 1,649 (67.2%) gave a positive result. The proportion of mRNA positivity was slightly higher among samples tested for HPV DNA by the Cobas 4800 HPV assay (Roche) than by the Hybrid Capture 2 (HC2) assay (Qiagen). In our setting, the observed E6-E7 mRNA positivity rate, if used as a triage test, would bring a rate of immediate referral to colposcopy of about 4 to 5%. This value is higher than that observed with cytology triage for both immediate and delayed referrals to colposcopy. By showing only a very high sensitivity and thus allowing a longer interval for HPV DNA-positive/HPV mRNA-negative women, a triage by this test might be more efficient than by cytology. PMID- 28100596 TI - Genomic Epidemiology of Penicillin-Nonsusceptible Pneumococci with Nonvaccine Serotypes Causing Invasive Disease in the United States. AB - Conjugate vaccination against seven pneumococcal serotypes (PCV7) reduced disease prevalence due to antibiotic-resistant strains throughout the 2000s. However, diseases caused by resistant nonvaccine type (NVT) strains increased. Some of these emerging strains were derived from vaccine types (VT) that had changed their capsule by recombination. The introduction of a vaccine targeting 13 serotypes (PCV13) in 2010 has led to concern that this scenario will repeat itself. We generated high-quality draft genomes from 265 isolates of NVT pneumococci not susceptible to penicillin (PNSP) in 2009 and compared them with the genomes of 581 isolates from 2012 to 2013 collected by the Active Bacterial Core surveillance (ABCs) of the Centers for Disease Control and Prevention (CDC). Of the seven sequence clusters (SCs) identified, three SCs fell into a single lineage associated with serogroup 23, which had an origin in 1908 as dated by coalescent analysis and included isolates with a divergent 23B capsule locus. Three other SCs represented relatively deep-branching lineages associated with serotypes 35B, 15A, and 15BC. In all cases, the resistant clones originated prior to 2010, indicating that PNSP are at present dominated by descendants of NVT clones present before vaccination. With one exception (15BC/ST3280), these SCs were related to clones identified by the Pneumococcal Molecular Epidemiology Network (PMEN). We conclude that postvaccine diversity in NVT PNSP between 2009 and 2013 was driven mainly by the persistence of preexisting strains rather than through de novo adaptation, with few cases of serotype switching. Future surveillance is essential for documenting the long-term dynamics and resistance of NVT PNSP. PMID- 28100597 TI - Investigation of a Candida guilliermondii Pseudo-outbreak Reveals a Novel Source of Laboratory Contamination. AB - Candida guilliermondii was isolated from sterile specimens with increasing frequency over a several-month period despite a paucity of clinical evidence suggesting true Candida infections. However, a health care-associated outbreak was strongly considered due to growth patterns in the microbiology laboratory that were more consistent with true infection than environmental contamination. Therefore, an extensive investigation was performed to identify its cause. With the exception of one case, patient clinical courses were not consistent with true invasive fungal infections. Furthermore, no epidemiologic link between patients was identified. Rather, extensive environmental sampling revealed C. guilliermondii in an anaerobic holding jar in the clinical microbiology laboratory, where anaerobic plates were prereduced and held before inoculating specimens. C. guilliermondii grows poorly under anaerobic conditions. Thus, we postulate that anaerobic plates became intermittently contaminated. Passaging from intermittently contaminated anaerobic plates to primary quadrants of aerobic media during specimen planting yielded a colonial growth pattern typical for true specimen infection, thus obscuring laboratory contamination. A molecular evaluation of the C. guilliermondii isolates confirmed a common source for pseudo outbreak cases but not for the one true infection. In line with Reason's model of organizational accidents, active and latent errors coincided to contribute to the pseudo-outbreak. These included organism factors (lack of growth in anaerobic conditions obscuring plate contamination), human factors (lack of strict adherence to plating order, leading to only intermittent observation of aerobic plate positivity), and laboratory factors (novel equipment). All of these variables should be considered when evaluating possible laboratory-based pseudo outbreaks. PMID- 28100599 TI - Rapid and Specific Detection of the Escherichia coli Sequence Type 648 Complex within Phylogroup F. AB - The Escherichia coli sequence type 648 complex (STc648) is an emerging lineage within phylogroup F-formerly included within phylogroup D-that is associated with multidrug resistance. Here, we designed and validated a novel multiplex PCR-based assay for STc648 that took advantage of (i) four distinctive single-nucleotide polymorphisms in icd allele 96 and gyrB allele 87, two of the multilocus sequence typing alleles that define ST648; and (ii) the typical absence within STc648 of uidA, an E. coli-specific gene encoding beta-glucuronidase. Within a diverse 212 strain validation set that included 109 STs other than STc648, from phylogroups A, B1, B2, C, D, E, and F, the assay exhibited 100% sensitivity (95% confidence interval [CI], 82% to 100%) and specificity (95% CI, 98% to 100%). It functioned similarly well in two distant laboratories that used boiled lysates or DNAzol purified DNA as the template DNA. Thus, this novel multiplex PCR-based assay should enable any laboratory equipped for diagnostic PCR to rapidly, accurately, and economically screen E. coli isolates for membership in STc648. PMID- 28100598 TI - Molecular and Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry-Based Characterization of Clinically Significant Melanized Fungi in India. AB - Melanized or black fungi are a heterogeneous group of fungi causing cutaneous to systemic diseases with high mortality. These fungi are rarely reported as agents of human infections, primarily due to difficulties in their classical identification. In this study, we examined, using molecular methods and matrix assisted laser desorption ioniazation-time of flight mass spectrometry (MALDI-TOF MS), the diversity of melanized fungi (MF) isolated from patients in 19 medical centers in India. Overall, during a 4-year period, 718 (5.3%) clinical specimens yielded MF. Of these, 72 (10%) isolates had clinical significance and were identified primarily by sequencing the internal transcribed spacer and large subunit (LSU) regions. MF represented 21 genera comprising 29 species, the majority of them belonging to the orders Pleosporales (50%) and Chaetothyriales (22%). Among the 29 fungal species identified in this study, only 6 (20%) species were identified by the MALDI-TOF MS due to the limited commercial database of Bruker Daltonics for MF. However, a 100% identification rate of 20 additional species identified in this study was obtained by constructing an in-house database using 24- to 96-h-old liquid cultures. Further, the CLSI broth microdilution method revealed low MICs for posaconazole (<=1 MUg/ml) and voriconazole (<=2 MUg/ml) in 96% and 95% of isolates, respectively. Skin/subcutaneous and sino-nasal and pulmonary phaeohyphomycosis due to MF were diagnosed in 21.4% (n = 15) and 28.5% (n = 20) of cases. Also, 10% of patients had central nervous system involvement (n = 7), and 3 cases of fungal osteomyelitis due to Cladophialophora bantiana and Corynespora spp. were observed. PMID- 28100600 TI - Suitability of Carbapenem Inactivation Method (CIM) for Detection of IMP Metallo beta-Lactamase-Producing Enterobacteriaceae. PMID- 28100601 TI - Use of Selective Fungal Culture Media Increases Rates of Detection of Fungi in the Respiratory Tract of Cystic Fibrosis Patients. AB - The prevalence of fungi in the respiratory tracts of cystic fibrosis (CF) patients has risen. However, fungal surveillance is not routinely performed in most clinical centers in the United States, which may lead to an underestimation of the true prevalence of the problem. We conducted a prospective study comparing the rates of detection for clinically important fungi (CIF), defined as Aspergillus, Scedosporium, and Trichosporon species and Exophiala dermatitidis, in CF sputa using standard bacterial and selective fungal culture media, including Sabouraud dextrose agar with gentamicin (SDA), inhibitory mold agar (IMA), and brain heart infusion (BHI) agar with chloramphenicol and gentamicin. We described the prevalence of these fungi in an adult CF population. A total of 487 CF respiratory samples were collected from 211 unique participants. CIF were detected in 184 (37.8%) samples. Only 26.1% of CIF-positive samples were detected in bacterial culture medium, whereas greater rates of detection for fungi were found in IMA (65.8%; P < 0.001), in SDA (at 30 degrees C, 64.7%; P = 0.005), and in BHI agar (63.0%; P = 0.001). The prevalences of Aspergillus and Scedosporium species were 40.8% and 5.2%, respectively, which are greater than the nationally reported prevalence numbers of 20.4% and 1.9%. Selective fungal culture media and longer incubation periods yielded higher rates of detection for CIF in CF sputum samples compared with that detected in bacterial culture medium, resulting in an underdetection of fungi by bacterial culture alone. The prevalence of fungi in CF may be better estimated by using selective fungal culture media, and this may translate to important clinical decisions. PMID- 28100602 TI - FIND Tuberculosis Strain Bank: a Resource for Researchers and Developers Working on Tests To Detect Mycobacterium tuberculosis and Related Drug Resistance. AB - The spread of multidrug-resistant (MDR) tuberculosis (TB) and extensively drug resistant (XDR) TB hampers global efforts in the fight against tuberculosis. To enhance the development and evaluation of diagnostic tests quickly and efficiently, well-characterized strains and samples from drug-resistant tuberculosis patients are necessary. In this project, the Foundation for Innovative New Diagnostics (FIND) has focused on the collection, characterization, and storage of such well-characterized reference materials and making them available to researchers and developers. The collection is being conducted at multiple centers in Southeast Asia, South America, Eastern Europe, and soon the sub-Saharan Africa regions. Strains are characterized for their phenotypic resistances and MICs to first-line drugs (FLDs) and second-line drugs (SLDs) using the automated MGIT 960 system following validated procedures and WHO criteria. Analysis of resistance-associated mutations is done by whole-genome sequencing (WGS) using the Illumina NextSeq system. Mycobacterial interspersed repetitive-unit-variable-number tandem-repeat analysis and WGS are used to determine strain lineages. All strains are maintained frozen at -80 degrees C +/- 10 degrees C as distinct mother and daughter lots. All strains are extensively quality assured. The data presented here represent an analysis of the initial part of the collection. Currently, the bank contains 118 unique strains with extracted genomic DNA and matched sputum, serum, and plasma samples and will be expanded to a minimum of 1,000 unique strains over the next 3 years. Analysis of the current strains by phenotypic resistance testing shows 102 (86.4%), 10 (8.5%), and 6 (5.1%) MDR, XDR, and mono/poly resistant strains, respectively. Two of the strains are resistant to all 11 drugs that were phenotypically tested. WGS mutation analysis revealed FLD resistance-associated mutations in the rpoB, katG, inhA, embB, embA, and pncA genes; SLD resistance in the gyrA, gyrB, rrs, eis, and tlyA genes; and ethionamide resistance in the ethA genes. Most important lineages are represented in the bank, and further collections have been initiated to increase geographic and lineage diversity. The bank provides highly characterized and high-quality strains as a resource for researchers and developers in support of the development and evaluation of new diagnostics and drug resistance detection tools. PMID- 28100603 TI - Digestion-Resistant Dextrin Derivatives Are Moderately Digested in the Small Intestine and Contribute More to Energy Production Than Predicted from Large Bowel Fermentation in Rats. AB - Background: Digestion-resistant dextrin derivatives (DRDDs), including resistant maltodextrin (RM), polydextrose, and resistant glucan (RG), have been developed as low-energy foods. However, data on the resistance of DRDDs to small-intestinal digestion are scarce.Objective: We sought to determine the site and extent of DRDD breakdown in the rat intestine and to predict its energy contributions.Methods: In vitro small-intestinal resistance of DRDDs was evaluated by the AOAC method for dietary fiber measurement and by artificial digestion with the use of pancreatic alpha-amylase and brush-boarder membrane vesicles. In vivo small-intestinal resistance of DRDDs was determined from the feces of male ileorectostomized Sprague-Dawley rats fed a control diet or a diet containing one of the DRDDs at 50 g/kg for 9 d (period 1) and then for 10 d (period 2), during which they received 1 g neomycin/L in their drinking water. Separately, male Sprague-Dawley rats were fed the same diets for 4 wk, and the whole-gut recoveries of DRDDs were determined from feces at days 8-10.Results: Small-intestinal resistances determined in vitro by artificial digestion (RM: 70%; polydextrose: 67%; RG: 69%) were lower than those measured by the AOAC method (RM: 92%; polydextrose: 80%; RG: 82%). In the ileorectostomized rats, fecal dry-matter excretions were consistently greater in the DRDDs than in the control. The small-intestinal resistances of the DRDDs were 68%, 58%, and 62% in period 1 and 66%, 61%, and 67% during period 2 for RM, polydextrose, and RG, respectively. The resistances did not differ among the DRDDs at either time. In the normal rats, food intakes and body weight gains did not differ among the groups. The whole-gut recovery of RM (13%) was lower than that of polydextrose (33%) and RG (29%), which did not differ.Conclusions: DRDDs were more digestible in the rat small intestine than the AOAC method. The energy contribution from small-intestine digestibility, not just large-bowel fermentability, must be considered in determining the energy contribution of DRDDs. Whether humans respond similarly needs to be tested. PMID- 28100604 TI - Sufficient Protein Quality of Food Aid Varies with the Physiologic Status of Recipients. AB - Protein quality scores use the amino acid (AA) requirements of a healthy North American child. AA requirements vary with physiologic status. We estimated AA requirements for healthy North American children, children with environmental enteric dysfunction, children recovering from wasting, and children with an acute infection. The protein quality of food aid products was then calculated to determine whether it was sufficient in all these groups, and we found that it may not be adequate for all of them. Physiologic status is important when assessing the protein quality of food aid. Rates of weight gain from 8 published trials treating children with moderate acute malnutrition were abstracted, and protein quality scores from the corresponding food aid products were calculated with the use of the digestible indispensable amino acid score (DIAAS). Two DIAAS values were calculated, one in healthy children aged 1-3 y as a reference population and the other in malnourished children aged 1-3 y as a reference population. These data were used to calculate the best fit regression line between weight gain and protein quality. The slope of the regression line was greater when malnourished children were used as a reference population than when healthy children were used (0.128; 95% CI: 0.118, 0.138 compared with 0.097; 95% CI: 0.090, 0.105 measured in g . kg-1 . d-1 . DIASS U-1). These findings suggest that adjusting AA requirements for physiologic status may more accurately estimate the minimum protein quality of food aid products. PMID- 28100605 TI - Urine 24-Hour Sodium Excretion Decreased between 1953 and 2014 in Japan, but Estimated Intake Still Exceeds the WHO Recommendation. AB - Background: Accurate monitoring of sodium intake is necessary for evaluating strategies used to reduce sodium intake. However, no repeat survey has been conducted in representative populations in Japan to examine trends in sodium intake with the use of 24-h urinary sodium excretion, a standard evaluation method for sodium intake monitoring.Objective: The objective of this study was to examine potential trends in sodium intake by examining previous reports of 24-h urinary sodium excretion in healthy Japanese adult populations.Methods: We systematically searched for reports of 24-h urinary sodium excretion in healthy Japanese adult populations (mean age range: 18-69 y). We searched PubMed and Web of Science for English-language articles and hand-searched 7 Japanese scientific journals for Japanese-language articles. Trends in urinary sodium excretion were examined with the use of weighted linear regression and random-effects meta regression analyses, with adjustment or stratification to address study characteristics (population mean age, percentage of men, and sample size) and study assessment for completeness of urine collection.Results: We identified 68 reports of urinary sodium excretion from 53 articles published from 1953 through 2014 that showed high rates of urinary sodium excretion in healthy Japanese adult populations (weighted mean: 4900 mg/d). The rate of urinary sodium excretion significantly decreased between 1953 and 2014, by 4350 mg/d (P < 0.001); however, the rate of reduction in urinary sodium excretion was variable and decreased with time (P-linear trend <0.001 and P-quadratic trend <0.001). In the random-effects meta-regression analysis of studies that assessed completeness of urine collection with creatinine excretion, no significant relation between urinary sodium excretion and year was observed from 1978 to 2014 (beta = -16, P = 0.40).Conclusion: Despite a decrease in urinary sodium excretion in healthy Japanese adult populations between 1953 and 2014, sodium intake still exceeds the WHO recommendation for adults. This review was registered at PROSPERO as CRD42016035452. PMID- 28100607 TI - Poor Adherence to Ketone Testing in Patients With Type 1 Diabetes. PMID- 28100606 TI - Predictive Hyperglycemia and Hypoglycemia Minimization: In-Home Evaluation of Safety, Feasibility, and Efficacy in Overnight Glucose Control in Type 1 Diabetes. AB - OBJECTIVE: The objective of this study was to determine the safety, feasibility, and efficacy of a predictive hyperglycemia and hypoglycemia minimization (PHHM) system compared with predictive low-glucose insulin suspension (PLGS) alone in overnight glucose control. RESEARCH DESIGN AND METHODS: A 42-night trial was conducted in 30 individuals with type 1 diabetes in the age range 15-45 years. Participants were randomly assigned each night to either PHHM or PLGS and were blinded to the assignment. The system suspended the insulin pump on both the PHHM and PLGS nights for predicted hypoglycemia but delivered correction boluses for predicted hyperglycemia on PHHM nights only. The primary outcome was the percentage of time spent in a sensor glucose range of 70-180 mg/dL during the overnight period. RESULTS: The addition of automated insulin delivery with PHHM increased the time spent in the target range (70-180 mg/dL) from 71 +/- 10% during PLGS nights to 78 +/- 10% during PHHM nights (P < 0.001). The average morning blood glucose concentration improved from 163 +/- 23 mg/dL after PLGS nights to 142 +/- 18 mg/dL after PHHM nights (P < 0.001). Various sensor-measured hypoglycemic outcomes were similar on PLGS and PHHM nights. All participants completed 42 nights with no episodes of severe hypoglycemia, diabetic ketoacidosis, or other study- or device-related adverse events. CONCLUSIONS: The addition of a predictive hyperglycemia minimization component to our existing PLGS system was shown to be safe, feasible, and effective in overnight glucose control. PMID- 28100608 TI - Herpes Simplex Virus 1 UL24 Abrogates the DNA Sensing Signal Pathway by Inhibiting NF-kappaB Activation. AB - Cyclic GMP-AMP synthase (cGAS) is a newly identified DNA sensor that recognizes foreign DNA, including the genome of herpes simplex virus 1 (HSV-1). Upon binding of viral DNA, cGAS produces cyclic GMP-AMP, which interacts with and activates stimulator of interferon genes (STING) to trigger the transcription of antiviral genes such as type I interferons (IFNs), and the production of inflammatory cytokines. HSV-1 UL24 is widely conserved among members of the herpesviruses family and is essential for efficient viral replication. In this study, we found that ectopically expressed UL24 could inhibit cGAS-STING-mediated promoter activation of IFN-beta and interleukin-6 (IL-6), and UL24 also inhibited interferon-stimulatory DNA-mediated IFN-beta and IL-6 production during HSV-1 infection. Furthermore, UL24 selectively blocked nuclear factor kappaB (NF kappaB) but not IFN-regulatory factor 3 promoter activation. Coimmunoprecipitation analysis demonstrated that UL24 bound to the endogenous NF kappaB subunits p65 and p50 in HSV-1-infected cells, and UL24 was also found to bind the Rel homology domains (RHDs) of these subunits. Furthermore, UL24 reduced the tumor necrosis factor alpha (TNF-alpha)-mediated nuclear translocation of p65 and p50. Finally, mutational analysis revealed that the region spanning amino acids (aa) 74 to 134 of UL24 [UL24(74-134)] is responsible for inhibiting cGAS STING-mediated NF-kappaB promoter activity. For the first time, UL24 was shown to play an important role in immune evasion during HSV-1 infection.IMPORTANCE NF kappaB is a critical component of the innate immune response and is strongly induced downstream of most pattern recognition receptors (PRRs), leading to the production of IFN-beta as well as a number of inflammatory chemokines and interleukins. To establish persistent infection, viruses have evolved various mechanisms to counteract the host NF-kappaB pathway. In the present study, for the first time, HSV-1 UL24 was demonstrated to inhibit the activation of NF kappaB in the DNA sensing signal pathway via binding to the RHDs of the NF-kappaB subunits p65 and p50 and abolishing their nuclear translocation. PMID- 28100609 TI - Sterol Binding by the Tombusviral Replication Proteins Is Essential for Replication in Yeast and Plants. AB - Membranous structures derived from various organelles are important for replication of plus-stranded RNA viruses. Although the important roles of co opted host proteins in RNA virus replication have been appreciated for a decade, the equally important functions of cellular lipids in virus replication have been gaining full attention only recently. Previous work with Tomato bushy stunt tombusvirus (TBSV) in model host yeast has revealed essential roles for phosphatidylethanolamine and sterols in viral replication. To further our understanding of the role of sterols in tombusvirus replication, in this work we showed that the TBSV p33 and p92 replication proteins could bind to sterols in vitro The sterol binding by p33 is supported by cholesterol recognition/interaction amino acid consensus (CRAC) and CARC-like sequences within the two transmembrane domains of p33. Mutagenesis of the critical Y amino acids within the CRAC and CARC sequences blocked TBSV replication in yeast and plant cells. We also showed the enrichment of sterols in the detergent-resistant membrane (DRM) fractions obtained from yeast and plant cells replicating TBSV. The DRMs could support viral RNA synthesis on both the endogenous and exogenous templates. A lipidomic approach showed the lack of enhancement of sterol levels in yeast and plant cells replicating TBSV. The data support the notion that the TBSV replication proteins are associated with sterol-rich detergent-resistant membranes in yeast and plant cells. Together, the results obtained in this study and the previously published results support the local enrichment of sterols around the viral replication proteins that is critical for TBSV replication.IMPORTANCE One intriguing aspect of viral infections is their dependence on efficient subcellular assembly platforms serving replication, virion assembly, or virus egress via budding out of infected cells. These assembly platforms might involve sterol-rich membrane microdomains, which are heterogeneous and highly dynamic nanoscale structures usurped by various viruses. Here, we demonstrate that TBSV p33 and p92 replication proteins can bind to sterol in vitro Mutagenesis analysis of p33 within the CRAC and CARC sequences involved in sterol binding shows the important connection between the abilities of p33 to bind to sterol and to support TBSV replication in yeast and plant cells. Together, the results further strengthen the model that cellular sterols are essential as proviral lipids during viral replication. PMID- 28100610 TI - The Measles Virus Receptor SLAMF1 Can Mediate Particle Endocytosis. AB - The signaling lymphocyte activation molecule F1 (SLAMF1) is both a microbial sensor and entry receptor for measles virus (MeV). Herein, we describe a new role for SLAMF1 to mediate MeV endocytosis that is in contrast with the alternative, and generally accepted, model that MeV genome enters cells only after fusion at the cell surface. We demonstrated that MeV engagement of SLAMF1 induces dramatic but transient morphological changes, most prominently in the formation of membrane blebs, which were shown to colocalize with incoming viral particles, and rearrangement of the actin cytoskeleton in infected cells. MeV infection was dependent on these dynamic cytoskeletal changes as well as fluid uptake through a macropinocytosis-like pathway as chemical inhibition of these processes inhibited entry. Moreover, we identified a role for the RhoA-ROCK-myosin II signaling axis in this MeV internalization process, highlighting a novel role for this recently characterized pathway in virus entry. Our study shows that MeV can hijack a microbial sensor normally involved in bacterial phagocytosis to drive endocytosis using a complex pathway that shares features with canonical viral macropinocytosis, phagocytosis, and mechanotransduction. This uptake pathway is specific to SLAMF1-positive cells and occurs within 60 min of viral attachment. Measles virus remains a significant cause of mortality in human populations, and this research sheds new light on the very first steps of infection of this important pathogen.IMPORTANCE Measles is a significant disease in humans and is estimated to have killed over 200 million people since records began. According to current World Health Organization statistics, it still kills over 100,000 people a year, mostly children in the developing world. The causative agent, measles virus, is a small enveloped RNA virus that infects a broad range of cells during infection. In particular, immune cells are infected via interactions between glycoproteins found on the surface of the virus and SLAMF1, the immune cell receptor. In this study, we have investigated the steps governing entry of measles virus into SLAMF1-positive cells and identified endocytic uptake of viral particles. This research will impact our understanding of morbillivirus-related immunosuppression as well as the application of measles virus as an oncolytic therapeutic. PMID- 28100611 TI - The Envelope Gene of Transmitted HIV-1 Resists a Late Interferon Gamma-Induced Block. AB - Type I interferon (IFN) signaling engenders an antiviral state that likely plays an important role in constraining HIV-1 transmission and contributes to defining subsequent AIDS pathogenesis. Type II IFN (IFN-gamma) also induces an antiviral state but is often primarily considered to be an immunomodulatory cytokine. We report that IFN-gamma stimulation can induce an antiviral state that can be both distinct from that of type I interferon and can potently inhibit HIV-1 in primary CD4+ T cells and a number of human cell lines. Strikingly, we find that transmitted/founder (TF) HIV-1 viruses can resist a late block that is induced by type II IFN, and the use of chimeric IFN-gamma-sensitive/resistant viruses indicates that interferon resistance maps to the env gene. Simultaneously, in vitro evolution also revealed that just a single amino acid substitution in the envelope can confer substantial resistance to IFN-mediated inhibition. Thus, the env gene of transmitted HIV-1 confers resistance to a late block that is phenotypically distinct from blocks previously described to be resisted by env and is therefore mediated by unknown IFN-gamma-stimulated factor(s) in human CD4+ T cells and cell lines. This important unidentified block could play a key role in constraining HIV-1 transmission.IMPORTANCE The human immune system can hinder invading pathogens through interferon (IFN) signaling. One consequence of this signaling is that cells enter an antiviral state, increasing the levels of hundreds of defenses that can inhibit the replication and spread of viruses. The majority of HIV-1 infections result from a single virus particle (the transmitted/founder) that makes it past these defenses and colonizes the host. Thus, the founder virus is hypothesized to be a relatively interferon-resistant entity. Here, we show that certain HIV-1 envelope genes have the unanticipated ability to resist specific human defenses mediated by different types of interferons. Strikingly, the envelope gene from a founder HIV-1 virus is far better at evading these defenses than the corresponding gene from a common HIV-1 lab strain. Thus, these defenses could play a role in constraining the transmission of HIV-1 and may select for transmitted viruses that are resistant to this IFN-mediated inhibition. PMID- 28100612 TI - Sex-Dependent Intestinal Replication of an Enteric Virus. AB - Coxsackievirus is an enteric virus that initiates infection in the gastrointestinal tract before disseminating to peripheral tissues to cause disease, but intestinal factors that influence viral replication are understudied. Furthermore, a sex bias for severe sequelae from coxsackievirus infections has been observed in humans. While mouse models mimicking human pathogenesis have been well characterized, many of these experiments use intraperitoneal injection of coxsackievirus to infect mice, bypassing the intestine. In light of recent studies identifying intestinal factors, such as the microbiota, that alter enteric viral replication, we sought to investigate coxsackievirus replication within the intestine. Here, we orally infected mice with coxsackievirus B3 (CVB3) and found that CVB3 replication in the intestine is sex dependent. CVB3 replicated efficiently in the intestine of male mice but not female mice. Additionally, we found that the type I interferon response and sex hormones can alter both viral replication and lethality. Overall, these data suggest that sex and the immune response play a vital role in CVB3 replication in the intestine and should be considered in light of the sex bias observed in human disease.IMPORTANCE Sex bias in severe sequelae from enteric viral infections has been observed. Since viruses have evolved to achieve optimal levels of fitness in their environmental niches, it is imperative to study viruses at the site of initial replication. Here, we used an oral inoculation system for CVB3, which follows the natural route of infection in the gastrointestinal tract. We found that sex can influence the replication of CVB3 in the intestine. Additionally, the type I interferon response and sex hormones alter both CVB3 intestinal replication and lethality. Overall this work highlights the fact that sex should be considered in investigations of enteric viral replication and pathogenesis. PMID- 28100613 TI - Dynamic Modulation of Expression of Lentiviral Restriction Factors in Primary CD4+ T Cells following Simian Immunodeficiency Virus Infection. AB - Although multiple restriction factors have been shown to inhibit HIV/SIV replication, little is known about their expression in vivo Expression of 45 confirmed and putative HIV/SIV restriction factors was analyzed in CD4+ T cells from peripheral blood and the jejunum in rhesus macaques, revealing distinct expression patterns in naive and memory subsets. In both peripheral blood and the jejunum, memory CD4+ T cells expressed higher levels of multiple restriction factors compared to naive cells. However, relative to their expression in peripheral blood CD4+ T cells, jejunal CCR5+ CD4+ T cells exhibited significantly lower expression of multiple restriction factors, including APOBEC3G, MX2, and TRIM25, which may contribute to the exquisite susceptibility of these cells to SIV infection. In vitro stimulation with anti-CD3/CD28 antibodies or type I interferon resulted in upregulation of distinct subsets of multiple restriction factors. After infection of rhesus macaques with SIVmac239, the expression of most confirmed and putative restriction factors substantially increased in all CD4+ T cell memory subsets at the peak of acute infection. Jejunal CCR5+ CD4+ T cells exhibited the highest levels of SIV RNA, corresponding to the lower restriction factor expression in this subset relative to peripheral blood prior to infection. These results illustrate the dynamic modulation of confirmed and putative restriction factor expression by memory differentiation, stimulation, tissue microenvironment and SIV infection and suggest that differential expression of restriction factors may play a key role in modulating the susceptibility of different populations of CD4+ T cells to lentiviral infection.IMPORTANCE Restriction factors are genes that have evolved to provide intrinsic defense against viruses. HIV and simian immunodeficiency virus (SIV) target CD4+ T cells. The baseline level of expression in vivo and degree to which expression of restriction factors is modulated by conditions such as CD4+ T cell differentiation, stimulation, tissue location, or SIV infection are currently poorly understood. We measured the expression of 45 confirmed and putative restriction factors in primary CD4+ T cells from rhesus macaques under various conditions, finding dynamic changes in each state. Most dramatically, in acute SIV infection, the expression of almost all target genes analyzed increased. These are the first measurements of many of these confirmed and putative restriction factors in primary cells or during the early events after SIV infection and suggest that the level of expression of restriction factors may contribute to the differential susceptibility of CD4+ T cells to SIV infection. PMID- 28100615 TI - Rhinovirus C, Asthma, and Cell Surface Expression of Virus Receptor CDHR3. AB - Human rhinoviruses (RVs) of the A, B, and C species are defined agents of the common cold. But more than that, RV-A and RV-C are the dominant causes of hospitalization category infections in young children, especially those with asthma. The use of cadherin-related family member 3 (CDHR3) by RV-C as its cellular receptor creates a direct phenotypic link between human genetics (G versus A alleles cause Cys529 versus Tyr529 protein variants) and the efficiency with which RV-C can infect cells. With a lower cell surface display density, the human-specific Cys529 variant apparently confers partial protection from the severest virus-induced asthma episodes. Selective pressure favoring the Cys529 codon may have coemerged with the evolution of RV-C and helped shape modern human genomes against the virus-susceptible, albeit ancestral Tyr529. PMID- 28100614 TI - Human Rhinovirus Diversity and Evolution: How Strange the Change from Major to Minor. AB - Rhinoviruses are the most common causes of the common cold. Their many distinct lineages fall into "major" and "minor" groups that use different cell surface receptors to enter host cells. Minor-group rhinoviruses are more immunogenic in laboratory studies, although their patterns of transmission and their cold symptoms are broadly similar to those of the major group. Here we present evolutionary evidence that minor-group viruses are also more immunogenic in humans. A key finding is that rates of amino acid substitutions at exposed sites in the capsid proteins VP2, VP3, and VP1 tend to be elevated in minor-group relative to major-group viruses, while rates at buried sites show no consistent differences. A reanalysis of historical virus watch data also indicates a higher immunogenicity of minor-group viruses, consistent with our findings about evolutionary rates at amino acid positions most directly exposed to immune surveillance. The increased immunogenicity and speed of evolution in minor-group lineages may contribute to the very large numbers of rhinovirus serotypes that coexist while differing in virulence.IMPORTANCE Most colds are caused by rhinoviruses (RVs). Those caused by a subset known as the minor-group members of rhinovirus species A (RV-A) are correlated with the inception and aggravation of asthma in at-risk populations. Genetically, minor-group viruses are similar to major-group RV-A, from which they were derived, although they tend to elicit stronger immune responses. Differences in their rates and patterns of molecular evolution should be highly relevant to their epidemiology. All RV-A strains show high rates of amino acid substitutions in the capsid proteins at exposed sites not previously identified as being immunogenic, and this increase is significantly greater in minor-group viruses. These findings will inform future studies of the recently discovered RV-C, which also appears to exacerbate asthma in adults and children. In addition, these findings draw attention to the difficult problem of explaining the long-term coexistence of many serotypes of major- and minor-group RVs. PMID- 28100616 TI - The V3 Loop of HIV-1 Env Determines Viral Susceptibility to IFITM3 Impairment of Viral Infectivity. AB - Interferon-inducible transmembrane proteins (IFITMs) inhibit a broad spectrum of viruses, including HIV-1. IFITM proteins deter HIV-1 entry when expressed in target cells and also impair HIV-1 infectivity when expressed in virus producer cells. However, little is known about how viruses resist IFITM inhibition. In this study, we have investigated the susceptibilities of different primary isolates of HIV-1 to the inhibition of viral infectivity by IFITMs. Our results demonstrate that the infectivity of different HIV-1 primary isolates, including transmitted founder viruses, is diminished by IFITM3 to various levels, with strain AD8-1 exhibiting strong resistance. Further mutagenesis studies revealed that HIV-1 Env, and the V3 loop sequence in particular, determines the extent of inhibition of viral infectivity by IFITM3. IFITM3-sensitive Env proteins are also more susceptible to neutralization by soluble CD4 or the 17b antibody than are IFITM3-resistant Env proteins. Together, data from our study suggest that the propensity of HIV-1 Env to sample CD4-bound-like conformations modulates viral sensitivity to IFITM3 inhibition.IMPORTANCE Results of our study have revealed the key features of the HIV-1 envelope protein that are associated with viral resistance to the IFITM3 protein. IFITM proteins are important effectors in interferon-mediated antiviral defense. A variety of viruses are inhibited by IFITMs at the virus entry step. Although it is known that envelope proteins of several different viruses resist IFITM inhibition, the detailed mechanisms are not fully understood. Taking advantage of the fact that envelope proteins of different HIV-1 strains exhibit different degrees of resistance to IFITM3 and that these HIV-1 envelope proteins share the same domain structure and similar sequences, we performed mutagenesis studies and determined the key role of the V3 loop in this viral resistance phenotype. We were also able to associate viral resistance to IFITM3 inhibition with the susceptibility of HIV-1 to inhibition by soluble CD4 and the 17b antibody that recognizes CD4-binding-induced epitopes. PMID- 28100617 TI - Differences in Glycoprotein Complex Receptor Binding Site Accessibility Prompt Poor Cross-Reactivity of Neutralizing Antibodies between Closely Related Arenaviruses. AB - The glycoprotein complex (GPC) of arenaviruses, composed of stable signal peptide, GP1, and GP2, is the only antigen correlated with antibody-mediated neutralization. However, despite strong cross-reactivity of convalescent antisera between related arenavirus species, weak or no cross-neutralization occurs. Two closely related clade B viruses, Machupo virus (MACV) and Junin virus (JUNV), have nearly identical overall GPC architecture and share a host receptor, transferrin receptor 1 (TfR1). Given structural and functional similarities of the GP1 receptor binding site (RBS) of these viruses and the recent demonstration that the RBS is an important target for neutralizing antibodies, it is not clear how these viruses avoid cross-neutralization. To address this, MACV/JUNV chimeric GPCs were assessed for interaction with a group of alpha-JUNV GPC monoclonal antibodies (MAbs) and mouse antisera against JUNV or MACV GPC. All six MAbs targeted GP1, with those that neutralized JUNV GPC-pseudovirions competing with each other for RBS binding. However, these MAbs were unable to bind to a chimeric GPC composed of JUNV GP1 containing a small disulfide bonded loop (loop 10) unique to MACV GPC, suggesting that this loop may block MAbs interaction with the GP1 RBS. Consistent with this loop causing interference, mouse anti-JUNV GPC antisera that solely neutralized pseudovirions bearing autologous GP1 provided enhanced neutralization of MACV GPC when this loop was removed. Our studies provide evidence that loop 10, which is unique to MACV GP1, is an important impediment to binding of neutralizing antibodies and contributes to the poor cross-neutralization of alpha-JUNV antisera against MACV.IMPORTANCE Multiple New World arenaviruses can cause severe disease in humans, and some geographic overlap exists among these viruses. A vaccine that protects against a broad range of New World arenaviruses is desirable for purposes of simplicity, cost, and broad protection against multiple National Institute of Allergy and Infectious Disease-assigned category A priority pathogens. In this study, we sought to better understand how closely related arenaviruses elude cross-species neutralization by investigating the structural bases of antibody binding and avoidance. In our studies, we found that neutralizing antibodies against two New World arenaviruses, Machupo virus (MACV) and Junin virus (JUNV), bound to the envelope glycoprotein 1 (GP1) with JUNV monoclonal antibodies targeting the receptor binding site (RBS). We further show that altered structures surrounding the RBS pocket in MACV GP1 impede access of JUNV-elicited antibodies. PMID- 28100619 TI - Functional Analysis of Hepatitis C Virus (HCV) Envelope Protein E1 Using a trans Complementation System Reveals a Dual Role of a Putative Fusion Peptide of E1 in both HCV Entry and Morphogenesis. AB - Hepatitis C virus (HCV) is an enveloped RNA virus belonging to the Flaviviridae family. It infects mainly human hepatocytes and causes chronic liver diseases, including cirrhosis and cancer. HCV encodes two envelope proteins, E1 and E2, that form a heterodimer and mediate virus entry. While E2 has been extensively studied, less has been done so for E1, and its role in the HCV life cycle still needs to be elucidated. Here we developed a new cell culture model for HCV infection based on the trans-complementation of E1. Virus production of the HCV genome lacking the E1-encoding sequence can be efficiently rescued by the ectopic expression of E1 in trans The resulting virus, designated HCVDeltaE1, can propagate in packaging cells expressing E1 but results in only single-cycle infection in naive cells. By using the HCVDeltaE1 system, we explored the role of a putative fusion peptide (FP) of E1 in HCV infection. Interestingly, we found that the FP not only contributes to HCV entry, as previously reported, but also may be involved in virus morphogenesis. Finally, we identified amino acid residues in FP that are critical for biological functions of E1. In summary, our work not only provides a new cell culture model for studying HCV but also provides some insights into understanding the role of E1 in the HCV life cycle.IMPORTANCE Hepatitis C virus (HCV), an enveloped RNA virus, encodes two envelope proteins, E1 and E2, that form a heterodimeric complex to mediate virus entry. Compared to E2, the biological functions of E1 in the virus life cycle are not adequately investigated. Here we developed a new cell culture model for single-cycle HCV infection based on the trans-complementation of E1. The HCV genome lacking the E1-encoding sequence can be efficiently rescued for virus production by the ectopic expression of E1 in trans This new model renders a unique system to dissect functional domains and motifs in E1. Using this system, we found that a putative fusion peptide in E1 is a multifunctional structural element contributing to both HCV entry and morphogenesis. Our work has provided a new cell culture model to study HCV and provides insights into understanding the biological roles of E1 in the HCV life cycle. PMID- 28100618 TI - Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody Dependent Cell-Mediated Cytotoxicity Responses. AB - HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cellular-mediated cytotoxicity (ADCC). HIV-1 has evolved sophisticated mechanisms to avoid the exposure of Env ADCC epitopes by downregulating CD4 and by limiting the overall amount of Env on the cell surface. In HIV-1, substitution of large residues such as histidine or tryptophan for serine 375 (S375H/W) in the gp120 Phe 43 cavity, where Phe 43 of CD4 contacts gp120, results in the spontaneous sampling of an Env conformation closer to the CD4-bound state. While residue S375 is well conserved in the majority of group M HIV-1 isolates, CRF01_AE strains have a naturally occurring histidine at this position (H375). Interestingly, CRF01_AE is the predominant circulating strain in Thailand, where the RV144 trial took place. In this trial, which resulted in a modest degree of protection, ADCC responses were identified as being part of the correlate of protection. Here we investigate the influence of the Phe 43 cavity on ADCC responses. Filling this cavity with a histidine or tryptophan residue in Env with a natural serine residue at this position (S375H/W) increased the susceptibility of HIV-1-infected cells to ADCC. Conversely, the replacement of His 375 by a serine residue (H375S) within HIV-1 CRF01_AE decreased the efficiency of the ADCC response. Our results raise the intriguing possibility that the presence of His 375 in the circulating strain where the RV144 trial was held contributed to the observed vaccine efficacy.IMPORTANCE HIV-1-infected cells presenting Env in the CD4-bound conformation on their surface are preferentially targeted by ADCC mediated by HIV positive (HIV+) sera. Here we show that the gp120 Phe 43 cavity modulates the propensity of Env to sample this conformation and therefore affects the susceptibility of infected cells to ADCC. CRF01_AE HIV-1 strains have an unusual Phe 43 cavity-filling His 375 residue, which increases the propensity of Env to sample the CD4-bound conformation, thereby increasing susceptibility to ADCC. PMID- 28100620 TI - Overexpression of Interleukin-7 Extends the Humoral Immune Response Induced by Rabies Vaccination. AB - Rabies continues to present a public health threat in most countries of the world. The most efficient way to prevent and control rabies is to implement vaccination programs for domestic animals. However, traditional inactivated vaccines used in animals are costly and have relatively low efficiency, which impedes their extensive use in developing countries. There is, therefore, an urgent need to develop single-dose and long-lasting rabies vaccines. However, little information is available regarding the mechanisms underlying immunological memory, which can broaden humoral responses following rabies vaccination. In this study, a recombinant rabies virus (RABV) that expressed murine interleukin-7 (IL 7), referred to here as rLBNSE-IL-7, was constructed, and its effectiveness was evaluated in a mouse model. rLBNSE-IL-7 induced higher rates of T follicular helper (Tfh) cells and germinal center (GC) B cells from draining lymph nodes (LNs) than the parent virus rLBNSE. Interestingly, rLBNSE-IL-7 improved the percentages of long-lived memory B cells (Bmem) in the draining LNs and plasma cells (PCs) in the bone marrow (BM) for up to 360 days postimmunization (dpi). As a result of the presence of the long-lived PCs, it also generated prolonged virus neutralizing antibodies (VNAs), resulting in better protection against a lethal challenge than that seen with rLBNSE. Moreover, consistent with the increased numbers of Bmem and PCs after a boost with rLBNSE, rLBNSE-IL-7-immunized mice promptly produced a more potent secondary anti-RABV neutralizing antibody response than rLBNSE-immunized mice. Overall, our data suggest that overexpressing IL-7 improved the induction of long-lasting primary and secondary antibody responses post-RABV immunization.IMPORTANCE Extending humoral immune responses using adjuvants is an important method to develop long-lasting and efficient vaccines against rabies. However, little information is currently available regarding prolonged immunological memory post-RABV vaccination. In this study, a novel rabies vaccine that expressed murine IL-7 was developed. This vaccine enhanced the numbers of Tfh cells and the GC responses, resulting in upregulated quantities of Bmem and PCs. Moreover, we found that the long-lived PCs that were elicited by the IL-7-expressing recombinant virus (rLBNSE-IL-7) were able to sustain VNA levels much longer than those elicited by the parent rLBNSE virus. Upon reexposure to the pathogen, the longevous Bmem, which maintained higher numbers for up to 360 dpi with rLBNSE-IL-7 compared to rLBNSE, could differentiate into antibody-secreting cells, resulting in rapid and potent secondary production of VNAs. These results suggest that the expression of IL-7 is beneficial for induction of potent and long-lasting humoral immune responses. PMID- 28100621 TI - Recombinant Adenoviruses Displaying Matrix 2 Ectodomain Epitopes on Their Fiber Proteins as Universal Influenza Vaccines. AB - Influenza is a zoonotic disease that poses severe threats to public health and the global economy. Reemerging influenza pandemics highlight the demand for universal influenza vaccines. We developed a novel virus platform using extracellular domain IV of the matrix 2 protein (M2e), AdC68-F3M2e, by introducing three conserved M2e epitopes into the HI loop of the chimpanzee adenovirus (AdV) fiber protein. The M2e epitopes were expressed sufficiently on the AdV virion surface without affecting fiber trimerization. Additionally, one recombinant adenovirus, AdC68-F3M2e(H1-H5-H7), induced robust M2e-specific antibody responses in BALB/c mice after two sequential vaccinations and conferred efficient protection against homologous and heterologous influenza virus (IV) challenges. We found that the use of AdV with tandem M2e epitopes in fiber is a potential strategy for influenza prevention.IMPORTANCE Influenza epidemics and pandemics severely threaten public health. Universal influenza vaccines have increasingly attracted interest in recent years. Here, we describe a new strategy that incorporates triple M2e epitopes into the fiber protein of chimpanzee adenovirus 68. We optimized the process of inserting foreign genes into the AdC68 structural protein by one-step isothermal assembly and demonstrated that this 225 bp HI loop insertion could be well tolerated. Furthermore, two doses of adjuvant free fiber-modified AdC68 could confer sufficient protection against homologous and heterologous influenza virus infections in mice. Our results show that AdC68 F3M2e could be pursued as a novel universal influenza vaccine. PMID- 28100623 TI - A Temperature-Sensitive Lesion in the N-Terminal Domain of the Rotavirus Polymerase Affects Its Intracellular Localization and Enzymatic Activity. AB - Temperature-sensitive (ts) mutants of simian rotavirus (RV) strain SA11 have been previously created to investigate the functions of viral proteins during replication. One mutant, SA11-tsC, has a mutation that maps to the gene encoding the VP1 polymerase and shows diminished growth and RNA synthesis at 39 degrees C compared to that at 31 degrees C. In the present study, we sequenced all 11 genes of SA11-tsC, confirming the presence of an L138P mutation in the VP1 N-terminal domain and identifying 52 additional mutations in four other viral proteins (VP4, VP7, NSP1, and NSP2). To investigate whether the L138P mutation induces a ts phenotype in VP1 outside the SA11-tsC genetic context, we employed ectopic expression systems. Specifically, we tested whether the L138P mutation affects the ability of VP1 to localize to viroplasms, which are the sites of RV RNA synthesis, by expressing the mutant form as a green fluorescent protein (GFP) fusion protein (VP1L138P-GFP) (i) in wild-type SA11-infected cells or (ii) in uninfected cells along with viroplasm-forming proteins NSP2 and NSP5. We found that VP1L138P-GFP localized to viroplasms and interacted with NSP2 and/or NSP5 at 31 degrees C but not at 39 degrees C. Next, we tested the enzymatic activity of a recombinant mutant polymerase (rVP1L138P) in vitro and found that it synthesized less RNA at 39 degrees C than at 31 degrees C, as well as less RNA than the control at all temperatures. Together, these results provide a mechanistic basis for the ts phenotype of SA11-tsC and raise important questions about the role of leucine 138 in supporting key protein interactions and the catalytic function of the VP1 polymerase.IMPORTANCE RVs cause diarrhea in the young of many animal species, including humans. Despite their medical and economic importance, gaps in knowledge exist about how these viruses replicate inside host cells. Previously, a mutant simian RV (SA11-tsC) that replicates worse at higher temperatures was identified. This virus has an amino acid mutation in VP1, which is the enzyme responsible for copying the viral RNA genome. The mutation is located in a poorly understood region of the polymerase called the N-terminal domain. In this study, we determined that the mutation reduces the ability of VP1 to properly localize within infected cells at high temperatures, as well as reduced the ability of the enzyme to copy viral RNA in a test tube. The results of this study explain the temperature sensitivity of SA11-tsC and shed new light on functional protein protein interaction sites of VP1. PMID- 28100622 TI - Glycosylation of the Hemagglutinin Protein of H5N1 Influenza Virus Increases Its Virulence in Mice by Exacerbating the Host Immune Response. AB - The highly pathogenic avian influenza (HPAI) H5N1 viruses continue to circulate in nature and threaten public health. Although several viral determinants and host factors that influence the virulence of HPAI H5N1 viruses in mammals have been identified, the detailed molecular mechanism remains poorly defined and requires further clarification. In our previous studies, we characterized two naturally isolated HPAI H5N1 viruses that had similar viral genomes but differed substantially in their lethality in mice. In this study, we explored the molecular determinants and potential mechanism for this difference in virulence. By using reverse genetics, we found that a single amino acid at position 158 of the hemagglutinin (HA) protein substantially affected the systemic replication and pathogenicity of these H5N1 influenza viruses in mice. We further found that the G158N mutation introduced an N-linked glycosylation at positions 158 to 160 of the HA protein and that this N-linked glycosylation enhanced viral productivity in infected mammalian cells and induced stronger host immune and inflammatory responses to viral infection. These findings further our understanding of the determinants of pathogenicity of H5N1 viruses in mammals.IMPORTANCE Highly pathogenic avian influenza (HPAI) H5N1 viruses continue to evolve in nature and threaten human health. Key mutations in the virus hemagglutinin (HA) protein or reassortment with other pandemic viruses endow HPAI H5N1 viruses with the potential for aerosol transmissibility in mammals. A thorough understanding of the pathogenic mechanisms of these viruses will help us to develop more effective control strategies; however, such mechanisms and virulent determinants for H5N1 influenza viruses have not been fully elucidated. In this study, we identified glycosylation at positions 158 to 160 of the HA protein of two naturally occurring H5N1 viruses as an important virulence determinant. This glycosylation event enhanced viral productivity, exacerbated the host response, and thereby contributed to the high pathogenicity of H5N1 virus in mice. PMID- 28100624 TI - Azacytidine Treatment Inhibits the Progression of Herpes Stromal Keratitis by Enhancing Regulatory T Cell Function. AB - Ocular infection with herpes simplex virus 1 (HSV-1) sets off an inflammatory reaction in the cornea which leads to both virus clearance and chronic lesions that are orchestrated by CD4 T cells. Approaches that enhance the function of regulatory T cells (Treg) and dampen effector T cells can be effective to limit stromal keratitis (SK) lesion severity. In this report, we explore the novel approach of inhibiting DNA methyltransferase activity using 5-azacytidine (Aza; a cytosine analog) to limit HSV-1-induced ocular lesions. We show that therapy begun after infection when virus was no longer actively replicating resulted in a pronounced reduction in lesion severity, with markedly diminished numbers of T cells and nonlymphoid inflammatory cells, along with reduced cytokine mediators. The remaining inflammatory reactions had a change in the ratio of CD4 Foxp3+ Treg to effector Th1 CD4 T cells in ocular lesions and lymphoid tissues, with Treg becoming predominant over the effectors. In addition, compared to those from control mice, Treg from Aza-treated mice showed more suppressor activity in vitro and expressed higher levels of activation molecules. Additionally, cells induced in vitro in the presence of Aza showed epigenetic differences in the Treg specific demethylated region (TSDR) of Foxp3 and were more stable when exposed to inflammatory cytokines. Our results show that therapy with Aza is an effective means of controlling a virus-induced inflammatory reaction and may act mainly by the effects on Treg.IMPORTANCE HSV-1 infection has been shown to initiate an inflammatory reaction in the cornea that leads to tissue damage and loss of vision. The inflammatory reaction is orchestrated by gamma interferon (IFN-gamma) secreting Th1 cells, and regulatory T cells play a protective role. Hence, novel therapeutics that can rebalance the ratio of regulatory T cells to effectors are a relevant issue. This study opens up a new avenue in treating HSV-induced SK lesions by increasing the stability and function of regulatory T cells using the DNA methyltransferase inhibitor 5-azacytidine (Aza). Aza increased the function of regulatory T cells, leading to enhanced suppressive activity and diminished lesions. Hence, therapy with Aza, which acts mainly by its effects on Treg, can be an effective means to control virus-induced inflammatory lesions. PMID- 28100626 TI - Effect of Metformin on Metabolites and Relation With Myocardial Infarct Size and Left Ventricular Ejection Fraction After Myocardial Infarction. AB - BACKGROUND: Left ventricular ejection fraction (LVEF) and infarct size (ISZ) are key predictors of long-term survival after myocardial infarction (MI). However, little is known about the biochemical pathways driving LV dysfunction after MI. To identify novel biomarkers predicting post-MI LVEF and ISZ, we performed metabolic profiling in the GIPS-III randomized clinical trial (Glycometabolic Intervention as Adjunct to Primary Percutaneous Intervention in ST Elevation Myocardial Infarction). We also investigated the metabolic footprint of metformin, a drug associated with improved post-MI LV function in experimental studies. METHODS AND RESULTS: Participants were patients with ST-segment-elevated MI who were randomly assigned to receive metformin or placebo for 4 months. Blood samples were obtained on admission, 24 hours post-MI, and 4 months post-MI. A total of 233 metabolite measures were quantified using nuclear magnetic resonance spectrometry. LVEF and ISZ were assessed 4 months post-MI. Twenty-four hours post MI measurements of high-density lipoprotein (HDL) triglycerides (HDL-TG) predicted LVEF (beta=1.90 [95% confidence interval (CI), 0.82 to 2.98]; P=6.4*10 4) and ISZ (beta=-0.41 [95% CI, -0.60 to -0.21]; P=3.2*10-5). In addition, 24 hours post-MI measurements of medium HDL-TG (beta=-0.40 [95% CI, -0.60 to -0.20]; P=6.4*2*10-5), small HDL-TG (beta=-0.34 [95% CI, -0.53 to -0.14]; P=7.3*10-4), and the triglyceride content of very large HDL (beta=-0.38 [95% CI, -0.58 to 0.18]; P=2.7*10-4) were associated with ISZ. After the 4-month treatment, the phospholipid content of very large HDL was lower in metformin than in placebo treated patients (28.89% versus 38.79%; P=7.5*10-5); alanine levels were higher in the metformin group (0.46 versus 0.44 mmol/L; P=2.4*10-4). CONCLUSIONS: HDL triglyceride concentrations predict post-MI LVEF and ISZ. Metformin increases alanine levels and reduces the phospholipid content in very large HDL particles. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov/ct2/show/NCT01217307. Unique Identifier: NCT01217307. PMID- 28100625 TI - The PTPN14 Tumor Suppressor Is a Degradation Target of Human Papillomavirus E7. AB - Activation of signaling pathways ensuring cell growth is essential for the proliferative competence of human papillomavirus (HPV)-infected cells. Tyrosine kinases and phosphatases are key regulators of cellular growth control pathways. A recently identified potential cellular target of HPV E7 is the cytoplasmic protein tyrosine phosphatase PTPN14, which is a potential tumor suppressor and is linked to the control of the Hippo and Wnt/beta-catenin signaling pathways. In this study, we show that the E7 proteins of both high-risk and low-risk mucosal HPV types can interact with PTPN14. This interaction is independent of retinoblastoma protein (pRb) and involves residues in the carboxy-terminal region of E7. We also show that high-risk E7 induces proteasome-mediated degradation of PTPN14 in cells derived from cervical tumors. This degradation appears to be independent of cullin-1 or cullin-2 but most likely involves the UBR4/p600 ubiquitin ligase. The degree to which E7 downregulates PTPN14 would suggest that this interaction is important for the viral life cycle and potentially also for the development of malignancy. In support of this we find that overexpression of PTPN14 decreases the ability of HPV-16 E7 to cooperate with activated EJ-ras in primary cell transformation assays.IMPORTANCE This study links HPV E7 to the deregulation of protein tyrosine phosphatase signaling pathways. PTPN14 is classified as a potential tumor suppressor protein, and here we show that it is very susceptible to HPV E7-induced proteasome-mediated degradation. Intriguingly, this appears to use a mechanism that is different from that employed by E7 to target pRb. Therefore, this study has important implications for our understanding of the molecular basis for E7 function and also sheds important light on the potential role of PTPN14 as a tumor suppressor. PMID- 28100627 TI - Inflammatory Biomarkers Predict Heart Failure Severity and Prognosis in Patients With Heart Failure With Preserved Ejection Fraction: A Holistic Proteomic Approach. AB - BACKGROUND: Underlying mechanisms in heart failure (HF) with preserved ejection fraction remain unknown. We investigated cardiovascular plasma biomarkers in HF with preserved ejection fraction and their correlation to diastolic dysfunction, functional class, pathophysiological processes, and prognosis. METHODS AND RESULTS: In 86 stable patients with HF and EF >=45% in the Karolinska Rennes (KaRen) biomarker substudy, biomarkers were quantified by a multiplex immunoassay. Orthogonal projection to latent structures by partial least square analysis was performed on 87 biomarkers and 240 clinical variables, ranking biomarkers associated with New York Heart Association (NYHA) Functional class and the composite outcome (all-cause mortality and HF hospitalization). Biomarkers significantly correlated with outcome were analyzed by multivariable Cox regression and correlations with echocardiographic measurements performed. The orthogonal partial least square outcome-predicting biomarker pattern was run against the Ingenuity Pathway Analysis (IPA) database, containing annotated data from the public domain. The orthogonal partial least square analyses identified 32 biomarkers correlated with NYHA class and 28 predicting outcomes. Among outcome-predicting biomarkers, growth/differentiation factor-15 was the strongest and an additional 7 were also significant in Cox regression analyses when adjusted for age, sex, and N-terminal probrain natriuretic peptide: adrenomedullin (hazard ratio per log increase 2.53), agouti-related protein; (1.48), chitinase-3-like protein 1 (1.35), C-C motif chemokine 20 (1.35), fatty acid-binding protein (1.33), tumor necrosis factor receptor 1 (2.29), and TNF related apoptosis-inducing ligand (0.34). Twenty-three of them correlated with diastolic dysfunction (E/e') and 5 with left atrial volume index. The IPA suggested that increased inflammation, immune activation with decreased necrosis and apoptosis preceded poor outcome. CONCLUSIONS: In HF with preserved ejection fraction, novel biomarkers of inflammation predict HF severity and prognosis that may complement or even outperform traditional markers, such as N-terminal probrain natriuretic peptide. These findings lend support to a hypothesis implicating global systemic inflammation in HF with preserved ejection fraction. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov; Unique identifier: NCT00774709. PMID- 28100628 TI - External validation of the GREAT score to predict relapse risk in Graves' disease: results from a multicenter, retrospective study with 741 patients. AB - CONTEXT: First-line treatment in Graves' disease is often done with antithyroid agents (ATD), but relapse rates remain high making definite treatment necessary. Predictors for relapse risk help guiding initial treatment decisions. OBJECTIVE: We aimed to externally validate the prognostic accuracy of the recently proposed Graves' Recurrent Events After Therapy (GREAT) score to predict relapse risk in Graves' disease. DESIGN, SETTING AND PARTICIPANTS: We retrospectively analyzed data (2004-2014) of patients with a first episode of Graves' hyperthyroidism from four Swiss endocrine outpatient clinics. MAIN OUTCOME MEASURES: Relapse of hyperthyroidism analyzed by multivariate Cox regression. RESULTS: Of the 741 included patients, 371 experienced a relapse (50.1%) after a mean follow-up of 25.6 months after ATD start. In univariate regression analysis, higher serum free T4, higher thyrotropin-binding inhibitor immunoglobulin (TBII), younger age and larger goiter were associated with higher relapse risk. We found a strong increase in relapse risk with more points in the GREAT score from 33.8% in patients with GREAT class I (0-1 points), 59.4% in class II (2-3 points) with a hazard ratio of 1.79 (95% CI: 1.42-2.27, P < 0.001) and 73.6% in class III (4-6 points) with a hazard ratio of 2.24 (95% CI: 1.64-3.06, P < 0.001). CONCLUSIONS: Based on this retrospective analysis within a large patient population from a multicenter study, the GREAT score shows good external validity and can be used for assessing the risk for relapse in Graves' disease, which influence the initial treatment decisions. PMID- 28100629 TI - Impact of food, alcohol and pH on modified-release hydrocortisone developed to treat congenital adrenal hyperplasia. AB - BACKGROUND: We developed a modified-release hydrocortisone, Chronocort, to replace the cortisol rhythm in patients with congenital adrenal hyperplasia. Food, alcohol and pH affect drug absorption, and it is important to assess their impact when replicating a physiological rhythm. SUBJECTS AND METHODS: In vitro dissolution to study impact of alcohol and pH on Chronocort. A phase 1, three period, cross over study in 18 volunteers to assess the impact of food on Chronocort and to compare bioavailability to immediate-release hydrocortisone. RESULTS: In vitro dissolution of Chronocort was not affected by gastrointestinal pH up to 6.0 nor by an alcohol content up to 20% v/v. Food delayed and reduced the rate of absorption of Chronocort as reflected by a longer Tmax (fed vs fasted: 6.75 h vs 4.5 h, P = 0005) and lower Cmax (549.49 nmol/L vs 708.46 nmol/L, ratio 77% with CI 71-85). Cortisol exposure was similar in fed and fasted state: Geo LSmean ratio (CI) AUC0t for fed/fasted was 108.33% (102.30-114.72%). Cortisol exposure was higher for Chronocort compared to immediate-release hydrocortisone: Geo LSmean ratios (CI) 118.83% (111.58-126.54%); however, derived free cortisol showed cortisol exposure CIs were within 80.0-125.0%: Geo LSmean ratio (CI) for AUC0t 112.73% (105.33-120.65%). CONCLUSIONS: Gastric pH <=6.0 and alcohol do not affect hydrocortisone release from Chronocort. Food delays Chronocort absorption, but cortisol exposure is similar in the fasted and fed state and exposure as assessed by free cortisol is similar between Chronocort and immediate-release hydrocortisone. PMID- 28100630 TI - A multivariable prediction model for pegvisomant dosing: monotherapy and in combination with long-acting somatostatin analogues. AB - BACKGROUND: Effective treatment of acromegaly with pegvisomant (PEGV), a growth hormone receptor antagonist, requires an appropriate dose titration. PEGV doses vary widely among individual patients, and various covariates may affect its dosing and pharmacokinetics. OBJECTIVE: To identify predictors of the PEGV dose required to normalize insulin-like growth factor I (IGF-I) levels during PEGV monotherapy and in combination with long-acting somatostatin analogues (LA-SSAs). DESIGN: Two retrospective cohorts (Rotterdam + Liege Acromegaly Survey (LAS), total n = 188) were meta-analyzed as a form of external replication to study the predictors of PEGV dosing in addition to LA-SSA, the LAS (n = 83) was used to study the predictors of PEGV monotherapy dosing. Multivariable regression models were used to identify predictors of the PEGV dose required to normalize IGF-I levels. RESULTS: For PEGV dosing in combination with LA-SSA, IGF-I levels, weight, height and age, were associated with the PEGV normalization dosage (P <= 0.001, P <= 0.001, P = 0.028 and P = 0.047 respectively). Taken together, these characteristics predicted the PEGV normalization dose correctly in 63.3% of all patients within a range of +/-60 mg/week (21.3% within a range of +/-20 mg/week). For monotherapy, only weight was associated with the PEGV normalization dose (P <= 0.001) and predicted this dosage correctly in 77.1% of all patients within a range of +/-60 mg/week (31.3% within a range of +/-20 mg/week). CONCLUSION: In this study, we show that IGF-I levels, weight, height and age can contribute to define the optimal PEGV dose to normalize IGF-I levels in addition to LA-SSA. For PEGV monotherapy, only the patient's weight was associated with the IGF-I normalization PEGV dosage. PMID- 28100631 TI - Association of triiodothyronine levels with future development of metabolic syndrome in euthyroid middle-aged subjects: a 6-year retrospective longitudinal study. AB - BACKGROUND: Several cross-sectional studies have reported that thyroid hormone levels are associated with cardiovascular risk markers and metabolic syndrome (MetS) even in euthyroid subjects. However, the prognostic role of serum thyroid hormone levels in the risk of incident MetS has not been elucidated. AIM: We aimed to investigate the associations of baseline serum thyroid hormone levels with the development of MetS in healthy subjects. METHODS: This 6-year, cross sectional, longitudinal and follow-up study was conducted in 12 037 euthyroid middle-aged subjects without MetS subjected to comprehensive health examinations. Subjects were grouped according to total triiodothyronine (T3) quartiles. The hazard ratio (HR) for the development of MetS according to T3 quartiles was estimated using Cox proportional hazards model. RESULTS: During the 6-year period, 3544 incident cases of MetS (29%) were identified. The proportion of subjects with incident MetS increased across the T3 quartiles (P for trend <0.001). The HR and 95% confidence interval (CI) for the development of MetS were significantly higher in the highest T3 quartile compared with the lowest T3 quartile even after adjusting for confounding variables including gender, age and smoking (HR: 1.238, 95% CI: 1.128-1.358, P < 0.001). CONCLUSION: In euthyroid middle-aged subjects, serum T3 levels are associated with increased risk for future development of MetS. PMID- 28100632 TI - The role of hepatic trans-arterial chemoembolization in metastatic medullary thyroid carcinoma: a specialist center experience and review of the literature. AB - BACKGROUND: Liver metastases are relatively common in patients with metastatic medullary thyroid carcinoma (MTC), carrying a negative impact on disease prognosis. The options for selective therapy of liver metastases in MTC patients are limited to catheter-guided procedures such as trans-arterial chemoembolization (TACE). Data regarding the effectiveness and safety of this procedure in MTC are limited. AIM: To explore the clinical outcome, survival and safety profile of TACE for liver metastases in a group of MTC patients. METHODS: Retrospective case series of patients treated at a single tertiary University Medical Center from 2005 to 2015. RESULTS: Seven consecutive patients (mean age 64.5 +/- 10.9 years, 5 females) with histologically confirmed MTC with liver metastases were included. Metastatic involvement of the liver was less than 50% of the liver volume in all patients. The median size of the largest liver lesion was 40 +/- 6.9 mm. The patients underwent in total 20 sessions of TACE. Clinical improvement as well as tumor response (PR) were observed in all patients. The median time to tumor progression was 38 months (range 8-126). Three patients were still alive at the end of the follow-up period (a median overall survival rate of 57 +/- 44 months). CONCLUSION: TACE in MTC patients with hepatic metastases is usually well tolerated and induces both clinical improvement and tumor response for prolonged periods of time in the majority of patients. This therapeutic option should always be considered, irrespective of the presence of extrahepatic metastasis. PMID- 28100633 TI - Automated mitotic spindle tracking suggests a link between spindle dynamics, spindle orientation, and anaphase onset in epithelial cells. AB - Proper spindle positioning at anaphase onset is essential for normal tissue organization and function. Here we develop automated spindle-tracking software and apply it to characterize mitotic spindle dynamics in the Xenopus laevis embryonic epithelium. We find that metaphase spindles first undergo a sustained rotation that brings them on-axis with their final orientation. This sustained rotation is followed by a set of striking stereotyped rotational oscillations that bring the spindle into near contact with the cortex and then move it rapidly away from the cortex. These oscillations begin to subside soon before anaphase onset. Metrics extracted from the automatically tracked spindles indicate that final spindle position is determined largely by cell morphology and that spindles consistently center themselves in the XY-plane before anaphase onset. Finally, analysis of the relationship between spindle oscillations and spindle position relative to the cortex reveals an association between cortical contact and anaphase onset. We conclude that metaphase spindles in epithelia engage in a stereotyped "dance," that this dance culminates in proper spindle positioning and orientation, and that completion of the dance is linked to anaphase onset. PMID- 28100634 TI - Cryptochromes regulate IGF-1 production and signaling through control of JAK2 dependent STAT5B phosphorylation. AB - Insulin-like growth factor (IGF) signaling plays an important role in cell growth and proliferation and is implicated in regulation of cancer, metabolism, and aging. Here we report that IGF-1 level in blood and IGF-1 signaling demonstrates circadian rhythms. Circadian control occurs through cryptochromes (CRYs) transcriptional repressors and components of the circadian clock. IGF-1 rhythms are disrupted in Cry-deficient mice, and IGF-1 level is reduced by 80% in these mice, which leads to reduced IGF signaling. In agreement, Cry-deficient mice have reduced body (~30% reduction) and organ size. Down-regulation of IGF-1 upon Cry deficiency correlates with reduced Igf-1 mRNA expression in the liver and skeletal muscles. Igf-1 transcription is regulated through growth hormone induced, JAK2 kinase-mediated phosphorylation of transcriptional factor STAT5B. The phosphorylation of STAT5B on the JAK2-dependent Y699 site is significantly reduced in the liver and skeletal muscles of Cry-deficient mice. At the same time, phosphorylation of JAK2 kinase was not reduced upon Cry deficiency, which places CRY activity downstream from JAK2. Thus CRYs link the circadian clock and JAK-STAT signaling through control of STAT5B phosphorylation, which provides the mechanism for circadian rhythms in IGF signaling in vivo. PMID- 28100635 TI - Phospholipase Lpl1 links lipid droplet function with quality control protein degradation. AB - Protein misfolding is toxic to cells and is believed to underlie many human diseases, including many neurodegenerative diseases. Accordingly, cells have developed stress responses to deal with misfolded proteins. The transcription factor Rpn4 mediates one such response and is best known for regulating the abundance of the proteasome, the complex multisubunit protease that destroys proteins. Here we identify Lpl1 as an unexpected target of the Rpn4 response. Lpl1 is a phospholipase and a component of the lipid droplet. Lpl1 has dual functions: it is required for both efficient proteasome-mediated protein degradation and the dynamic regulation of lipid droplets. Lpl1 shows a synthetic genetic interaction with Hac1, the master regulator of a second proteotoxic stress response, the unfolded protein response (UPR). The UPR has long been known to regulate phospholipid metabolism, and Lpl1's relationship with Hac1 appears to reflect Hac1's role in stimulating phospholipid synthesis under stress. Thus two distinct proteotoxic stress responses control phospholipid metabolism. Furthermore, these results provide a direct link between the lipid droplet and proteasomal protein degradation and suggest that dynamic regulation of lipid droplets is a key aspect of some proteotoxic stress responses. PMID- 28100636 TI - Centriole splitting caused by loss of the centrosomal linker protein C-NAP1 reduces centriolar satellite density and impedes centrosome amplification. AB - Duplication of the centrosomes is a tightly regulated process. Abnormal centrosome numbers can impair cell division and cause changes in how cells migrate. Duplicated centrosomes are held together by a proteinaceous linker made up of rootletin filaments anchored to the centrioles by C-NAP1. This linker is removed in a NEK2A kinase-dependent manner as mitosis begins. To explore C-NAP1 activities in regulating centrosome activities, we used genome editing to ablate it. C-NAP1-null cells were viable and had an increased frequency of premature centriole separation, accompanied by reduced density of the centriolar satellites, with reexpression of C-NAP1 rescuing both phenotypes. We found that the primary cilium, a signaling structure that arises from the mother centriole docked to the cell membrane, was intact in the absence of C-NAP1, although components of the ciliary rootlet were aberrantly localized away from the base of the cilium. C-NAP1-deficient cells were capable of signaling through the cilium, as determined by gene expression analysis after fluid flow-induced shear stress and the relocalization of components of the Hedgehog pathway. Centrosome amplification induced by DNA damage or by PLK4 or CDK2 overexpression was markedly reduced in the absence of C-NAP1. We conclude that centriole splitting reduces the local density of key centriolar precursors to impede overduplication. PMID- 28100640 TI - Outpatient parents' views on shared-decision-making at an Italian children's hospital. AB - Information is lacking on what parents in southern European countries know and how they view clinical shared-decision-making (SDM) for their children. This survey assesses general parental views on SDM and patient-physician SDM relationships in an Italian paediatric outpatients' clinic. In a 3-month cross sectional survey, we enrolled 458 consecutive native and foreign Italian-speaking parents bringing their children to our public hospital for various reasons. Parents completed an anonymous questionnaire exploring their general views on SDM, including what doctor-patient relationship predominates today, and what approach reassures them most. Multivariate logistic regression analysed outcome data from parental questionnaire answers. Results are reported as percentages, odds ratios (OR) and 95% confidence intervals (CI). Multivariate logistic regression showed that 440 parents (96.1%) appreciated SDM, 245 (53.5%) preferred SDM for choosing children's treatment, 126 (27.5%) answered that SDM is the predominant relationship today, and most parents 275 (60.0%) felt reassured by SDM. More native than foreign Italian-speaking parents preferred SDM (97.0 vs 89.7%, OR = 3.8; 95% CI = 1.4-10.8). Highly-educated parents preferred SDM for choosing their child's therapy (57.9 vs 34.1%, OR = 2.7; 95% CI = 1.6-4.4) and this approach reassured them (64.3 vs 41.2%, OR = 2.5; 95% CI = 1.6-4.1). In conclusion, parents bringing children to an Italian outpatient clinic, especially highly-educated parents, wish to be offered SDM and find it reassuring. These findings should encourage paediatricians working in a challenging multicultural environment to change their physician-centred approach and engage parents in tailored SDM strategies. PMID- 28100637 TI - A Zip3-like protein plays a role in crossover formation in the SC-less meiosis of the protist Tetrahymena. AB - When programmed meiotic DNA double-strand breaks (DSBs) undergo recombinational repair, genetic crossovers (COs) may be formed. A certain level of this is required for the faithful segregation of chromosomes, but the majority of DSBs are processed toward a safer alternative, namely noncrossovers (NCOs), via nonreciprocal DNA exchange. At the crossroads between these two DSB fates is the Msh4-Msh5 (MutSgamma) complex, which stabilizes CO-destined recombination intermediates and members of the Zip3/RNF212 family of RING finger proteins, which in turn stabilize MutSgamma. These proteins function in the context of the synaptonemal complex (SC) and mainly act on SC-dependent COs. Here we show that in the SC-less ciliate Tetrahymena, Zhp3 (a protein distantly related to Zip3/RNF212), together with MutSgamma, is responsible for the majority of COs. This activity of Zhp3 suggests an evolutionarily conserved SC-independent strategy for balancing CO:NCO ratios. Moreover, we report a novel meiosis specific protein, Sa15, as an interacting partner of Zhp3. Sa15 forms linear structures in meiotic prophase nuclei to which Zhp3 localizes. Sa15 is required for a wild-type level of CO formation. Its linear organization suggests the existence of an underlying chromosomal axis that serves as a scaffold for Zhp3 and other recombination proteins. PMID- 28100641 TI - New sources of value for health and care in a carbon-constrained world. AB - Background: Due to the climate crisis, it is increasingly evident that countries will have to decarbonize. Healthcare, which has a large carbon footprint and uses vast quantities of resources, will have to undergo significant transformation. In this research, we sought the ideas of leading thinkers in the field, to address the question of how health systems can provide high-quality care in a carbon constrained world. Methods: Semi-structured, qualitative in-depth interviews with 15 healthcare thought leaders from Australia, the UK, the USA and New Zealand. The interviews were transcribed and analysed by matrix display and thematic analysis. Results: 'Green' initiatives such as improving energy efficiency and implementing travel plans will be insufficient to achieve the scale of decarbonization required. According to the thought leaders in our study, it is likely that greater carbon and resource savings will come from thinking much more broadly about innovative models of care and using 'new' sources of 'value' such as 'people' and 'relationships'. Conclusions: Using human resources and human interactions as low-carbon sources of value in healthcare are promising models. PMID- 28100638 TI - Retromer-driven membrane tubulation separates endosomal recycling from Rab7/Ypt7 dependent fusion. AB - Endosomes are the major protein-sorting hubs of the endocytic pathway. They sort proteins destined for degradation into internal vesicles while in parallel recycling receptors via tubular carriers back to the Golgi. Tubule formation depends on the Rab7/Ypt7-interacting retromer complex, consisting of the sorting nexin dimer (SNX-BAR) and the trimeric cargo selection complex (CSC). Fusion of mature endosomes with the lysosome-like vacuole also requires Rab7/Ypt7. Here we solve a major problem in understanding this dual function of endosomal Rab7/Ypt7, using a fully reconstituted system, including purified, full-length yeast SNX-BAR and CSC, whose overall structure we present. We reveal that the membrane-active SNX-BAR complex displaces Ypt7 from cargo-bound CSC during formation of recycling tubules. This explains how a single Rab can coordinate recycling and fusion on endosomes. PMID- 28100639 TI - Munc13-4 functions as a Ca2+ sensor for homotypic secretory granule fusion to generate endosomal exocytic vacuoles. AB - Munc13-4 is a Ca2+-dependent SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor)- and phospholipid-binding protein that localizes to and primes secretory granules (SGs) for Ca2+-evoked secretion in various secretory cells. Studies in mast cell-like RBL-2H3 cells provide direct evidence that Munc13-4 with its two Ca2+-binding C2 domains functions as a Ca2+ sensor for SG exocytosis. Unexpectedly, Ca2+ stimulation also generated large (>2.4 MUm in diameter) Munc13-4+/Rab7+/Rab11+ endosomal vacuoles. Vacuole generation involved the homotypic fusion of Munc13-4+/Rab7+ SGs, followed by a merge with Rab11+ endosomes, and depended on Ca2+ binding to Munc13-4. Munc13-4 promoted the Ca2+ stimulated fusion of VAMP8-containing liposomes with liposomes containing exocytic or endosomal Q-SNAREs and directly interacted with late endosomal SNARE complexes. Thus Munc13-4 is a tethering/priming factor and Ca2+ sensor for both heterotypic SG-plasma membrane and homotypic SG-SG fusion. Total internal reflection fluorescence microscopy imaging revealed that vacuoles were exocytic and mediated secretion of beta-hexosaminidase and cytokines accompanied by Munc13 4 diffusion onto the plasma membrane. The results provide new molecular insights into the mechanism of multigranular compound exocytosis commonly observed in various secretory cells. PMID- 28100643 TI - Fluid shear stress increases transepithelial transport of Ca2+ in ciliated distal convoluted and connecting tubule cells. AB - In kidney, transcellular transport of Ca2+ is mediated by transient receptor potential vanilloid 5 and Na+-Ca2+ exchanger 1 proteins in distal convoluted and connecting tubules (DCTs and CNTs, respectively). It is not yet understood how DCT/CNT cells can adapt to differences in tubular flow rate and, consequently, Ca2+ load. This study aims to elucidate the molecular mechanisms by which DCT/CNT cells sense fluid dynamics to control transepithelial Ca2+ reabsorption and whether their primary cilia play an active role in this process. Mouse primary DCT/CNT cultures were subjected to a physiologic fluid shear stress (FSS) of 0.12 dyn/cm2 Transient receptor potential vanilloid 5 and Na+-Ca2+ exchanger 1 mRNA levels were significantly increased upon FSS exposure compared with static controls. Functional studies with 45Ca2+ demonstrated a significant stimulation of transepithelial Ca2+ transport under FSS compared with static conditions. Primary cilia removal decreased Ca2+ transport in both static and FSS conditions, a finding that correlated with decreased expression of genes involved in transepithelial Ca2+ transport; however, FSS-induced stimulation of Ca2+ transport was still observed. These results indicate that nephron DCT and CNT segments translate FSS into a physiologic response that implicates an increased Ca2+ reabsorption. Moreover, primary cilia influence transepithelial Ca2+ transport in DCTs/CNTs, yet this process is not distinctly coupled to FSS sensing by these organelles.-Mohammed, S. G., Arjona, F. J., Latta, F., Bindels, R. J. M., Roepman, R., Hoenderop, J. G. J. Fluid shear stress increases transepithelial transport of Ca2+ in ciliated distal convoluted and connecting tubule cells. PMID- 28100644 TI - Multicellular hypothesis for the pathogenesis of Alzheimer's disease. AB - Extensive abnormal interactions among microglia, astrocytes, and neurons of the CNS have been observed in proteinopathic neurodegenerative dementias of the elderly. These multicellular interactions are initiated by insoluble tangles of phosphorylated tau protein and plaques of amyloid peptides. Most research has focused on these neurotoxic proteins, but much less is known about the pathogenic roles of the responding resident and recruited neural cells. Principal interactions among the major 3 sets of CNS cells are herein considered at several levels in relation to cellular phenotypic alterations, mechanisms of cellular communication, and extent of involvement in the pathogenesis of Alzheimer's disease and related proteinopathic dementias. It remains to be determined which of these abnormal neurocellular phenomena are primary events and sufficiently contributory to neurodegeneration to be useful targets for therapy of senile dementias.-Goetzl, E. J., Miller, B. L. Multicellular hypothesis for the pathogenesis of Alzheimer's disease. PMID- 28100642 TI - Isoform-specific mechanisms of alpha3beta4*-nicotinic acetylcholine receptor modulation by the prototoxin lynx1. AB - This study investigates-for the first time to our knowledge-the existence and mechanisms of functional interactions between the endogenous mammalian prototoxin, lynx1, and alpha3- and beta4-subunit-containing human nicotinic acetylcholine receptors (alpha3beta4*-nAChRs). Concatenated gene constructs were used to express precisely defined alpha3beta4*-nAChR isoforms (alpha3beta4)2beta4 , (alpha3beta4)2alpha3-, (alpha3beta4)2alpha5(398D)-, and (alpha3beta4)2alpha5(398N)-nAChR in Xenopus oocytes. In the presence or absence of lynx1, alpha3beta4*-nAChR agonist responses were recorded by using 2-electrode voltage clamp and single-channel electrophysiology, whereas radioimmunolabeling measured cell-surface expression. Lynx1 reduced (alpha3beta4)2beta4-nAChR function principally by lowering cell-surface expression, whereas single-channel effects were primarily responsible for reducing (alpha3beta4)2alpha3-nAChR function [decreased unitary conductance (>=50%), altered burst proportions (3 fold reduction in the proportion of long bursts), and enhanced closed dwell times (3- to 6-fold increase)]. Alterations in both cell-surface expression and single channel properties accounted for the reduction in (alpha3beta4)2alpha5-nAChR function that was mediated by lynx1. No effects were observed when alpha3beta4* nAChRs were coexpressed with mutated lynx1 (control). Lynx1 is expressed in the habenulopeduncular tract, where alpha3beta4*-alpha5*-nAChR subtypes are critical contributors to the balance between nicotine aversion and reward. This gives our findings a high likelihood of physiologic significance. The exquisite isoform selectivity of lynx1 interactions provides new insights into the mechanisms and allosteric sites [alpha(-)-interface containing] by which prototoxins can modulate nAChR function.-George, A. A., Bloy, A., Miwa, J. M., Lindstrom, J. M., Lukas, R. J., Whiteaker, P. Isoform-specific mechanisms of alpha3beta4*-nicotinic acetylcholine receptor modulation by the prototoxin lynx1. PMID- 28100646 TI - Targeting the correct target in HCC. PMID- 28100645 TI - Lipoxin A4 stimulates endothelial miR-126-5p expression and its transfer via microvesicles. AB - The proresolution lipid mediator lipoxin (LX)A4 bestows protective bioactions on endothelial cells. We examined the impact of LXA4 on transcellular endothelial signaling via microRNA (miR)-containing microvesicles. We report LXA4 inhibition of MV release by TNF-alpha-treated HUVECs, associated with the down-regulation of 18 miR in endothelial microvesicles (EMVs) and the up-regulation of miR-126-5p, both in HUVECs and in EMVs. LXA4 up-regulated miR-126-5p by ~5-fold in HUVECs and promoted a release of microvesicles (LXA4-EMVs) that enhanced miR-126-5p by ~7 fold in recipient HUVECs. In these cells, LXA4-EMVs abrogated the up-regulation of VCAM-1, induced in recipient HUVECs by EMVs released by untreated or TNF-alpha treated HUVECs. LXA4-EMVs also reduced by ~40% the expression of SPRED1, which we validated as an miR-126-5p target, whereas they stimulated monolayer repair in an in vitro wound assay. This effect was lost when the EMVs were depleted of miR-126 5p. These results provide evidence that changes in miR expression and microvesicle packaging and transfer represent a mechanism of action of LXA4, which may be relevant in vascular biology and inflammation.-Codagnone, M., Recchiuti, A., Lanuti, P., Pierdomenico, A. M., Cianci, E., Patruno, S., Mari, V. C., Simiele, F., Di Tomo, P., Pandolfi, A., Romano, M. Lipoxin A4 stimulates endothelial miR-126-5p expression and its transfer via microvesicles. PMID- 28100647 TI - MarpoDB: An Open Registry for Marchantia Polymorpha Genetic Parts. AB - Marchantia polymorpha is an extant relative of the earliest terrestrial plants and has attracted a substantial interest as a model organism for evolutionary and developmental studies. Given its relatively simple genome, compact gene families, simple morphology, ease of propagation and transformation, M. polymorpha is becoming a promising platform for plant synthetic biology. Modular genetic parts have been essential for development of synthetic biology approaches, so we sought to design an engineering oriented database for M. polymorpha genetic parts where each gene is a stand-alone functional unit. MarpoDB is a database of M. polymorpha genes and genetic parts, which is tailored to become an integral tool for a synthetic biology workflow. Among its features are precompiled cross database querying to InterPro, Pfam signatures and non-redundant Viridiplantae BLAST annotations; BLAST querying to M. polymorpha genes; sequence export in GenBank format; recoding of sequences to the common syntax for type IIS assembly and exchange of DNA parts; and a minimalistic, intuitive and interactive user interface for gene models and sequence exploration. Furthermore, we have implemented user input to encourage feedback, collaboration and exchange between the MarpoDB community. MarpoDB source-code is released on GitHub to promote development of computational tools for synthetic biology. PMID- 28100648 TI - Multiscale Structural Analysis of Plant ER-PM Contact Sites. AB - Membrane contact sites are recognized across eukaryotic systems as important nanostructures. Endoplasmic reticulum (ER)-plasma membrane (PM) contact sites (EPCS) are involved in excitation-contraction coupling, signaling, and plant responses to stress. In this report, we perform a multiscale structural analysis of Arabidopsis EPCS that combines live cell imaging, quantitative transmission electron microscopy (TEM) and electron tomography over a developmental gradient. To place EPCS in the context of the entire cortical ER, we examined green fluorescent protein (GFP)-HDEL in living cells over a developmental gradient, then Synaptotagmin1 (SYT1)-GFP was used as a specific marker of EPCS. In all tissues examined, young, rapidly elongating cells showed lamellar cortical ER and higher density of SYT1-GFP puncta, while in mature cells the cortical ER network was tubular, highly dynamic and had fewer SYT1-labeled puncta. The higher density of EPCS in young cells was verified by quantitative TEM of cryo-fixed tissues. For all cell types, the size of each EPCS had a consistent range in length along the PM from 50 to 300 nm, with microtubules and ribosomes excluded from the EPCS. The structural characterization of EPCS in different plant tissues, and the correlation of EPCS densities over developmental gradients illustrate how ER-PM communication evolves in response to cellular expansion. PMID- 28100649 TI - Incidence of delivery wire recapture failure with the Pipeline Flex device. AB - BACKGROUND: The Pipeline Flex embolization device has several advantages over the first-generation Pipeline embolization device (Covidien, Dublin, Republic of Ireland). Despite these advantages, we have observed frequent difficulty in recapturing the device's delivery wire. OBJECTIVE: To prospectively document the incidence of failure to recapture the delivery wire. METHODS: We tracked our experience in patients undergoing endovascular treatment with a flow-diverting stent for cerebral aneurysms between 1 May and 30 September 2016. Patient and lesion characteristics, device dimensions, and technical outcomes of delivery wire recapture were prospectively recorded for each device. RESULTS: Eighteen devices were deployed in 15 patients by the senior author (FCA) during this period. Failure to recapture the delivery wire occurred in 10 of 18 (56%) cases. No adverse outcomes of delivery wire recapture failure were encountered in this series. CONCLUSIONS: The incidence of delivery wire recapture failure with the Pipeline Flex device is high. Failure to recapture the delivery wire carries a theoretical risk of stent displacement when re-navigating across the device, and endovascular surgeons should be aware of this limitation. Authors are encouraged to report delivery wire recapture failure rates in future clinical series in which the Pipeline Flex device is used. PMID- 28100651 TI - Stabilization of Bacillus circulans xylanase by combinatorial insertional fusion to a thermophilic host protein. AB - High thermostability of an enzyme is critical for its industrial application. While many engineering approaches such as mutagenesis have enhanced enzyme thermostability, they often suffer from reduced enzymatic activity. A thermally stabilized enzyme with unchanged amino acids is preferable for subsequent functional evolution necessary to address other important industrial needs. In the research presented here, we applied insertional fusion to a thermophilic maltodextrin-binding protein from Pyrococcus furiosus (PfMBP) in order to improve the thermal stability of Bacillus circulans xylanase (BCX). Specifically, we used an engineered transposon to construct a combinatorial library of randomly inserted BCX into PfMBP. The library was then subjected to functional screening to identify successful PfMBP-BCX insertion complexes, PfMBP-BCX161 and PfMBP BCX165, displaying substantially improved kinetic stability at elevated temperatures compared to unfused BCX and other controls. Results from subsequent characterizations were consistent with the view that lowered aggregation of BCX and reduced conformational flexibility at the termini was responsible for increased thermal stability. Our stabilizing approach neither sacrificed xylanase activity nor required changes in the BCX amino acid sequence. Overall, the current study demonstrated the benefit of combinatorial insertional fusion to PfMBP as a systematic tool for the creation of enzymatically active and thermostable BCX variants. PMID- 28100650 TI - Transforming growth factor beta suppresses peroxisome proliferator-activated receptor gamma expression via both SMAD binding and novel TGF-beta inhibitory elements. AB - Transforming growth factor beta (TGF-beta) contributes to wound healing and, when dysregulated, to pathological fibrosis. TGF-beta and the anti-fibrotic nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) repress each other's expression, and such PPARgamma down-regulation is prominent in fibrosis and mediated, via previously unknown SMAD-signaling mechanisms. Here, we show that TGF-beta induces the association of SMAD3 with both SMAD4, needed for translocation of the complex into the nucleus, and the essential context sensitive co-repressors E2F4 and p107. The complex mediates TGF-beta-induced repression by binding to regulatory elements in the target promoter. In the PPARG promoter, we found that the SMAD3-SMAD4 complex binds both to a previously unknown consensus TGF-beta inhibitory element (TIE) and also to canonical SMAD binding elements (SBEs). Furthermore, the TIE and SBEs independently mediated the partial repression of PPARG transcription, the first demonstration of a TIE and SBEs functioning within the same promoter. Also, TGF-beta-treated fibroblasts contained SMAD complexes that activated a SMAD target gene in addition to those repressing PPARG transcription, the first finding of such dual activity within the same cell. These findings describe in detail novel mechanisms by which TGF beta represses PPARG transcription, thereby facilitating its own pro-fibrotic activity. PMID- 28100652 TI - Correlation between discharge timings of pairs of motor units reveals the presence but not the proportion of common synaptic input to motor neurons. AB - We investigated whether correlation measures derived from pairs of motor unit (MU) spike trains are reliable indicators of the degree of common synaptic input to motor neurons. Several 50-s isometric contractions of the biceps brachii muscle were performed at different target forces ranging from 10 to 30% of the maximal voluntary contraction relying on force feedback. Forty-eight pairs of MUs were examined at various force levels. Motor unit synchrony was assessed by cross correlation analysis using three indexes: the output correlation as the peak of the cross-histogram (rho) and the number of synchronous spikes per second (CIS) and per trigger (E). Individual analysis of MU pairs revealed that rho, CIS, and E were most often positively associated with discharge rate (87, 85, and 76% of the MU pairs, respectively) and negatively with interspike interval variability (69, 65, and 62% of the MU pairs, respectively). Moreover, the behavior of synchronization indexes with discharge rate (and interspike interval variability) varied greatly among the MU pairs. These results were consistent with theoretical predictions, which showed that the output correlation between pairs of spike trains depends on the statistics of the input current and motor neuron intrinsic properties that differ for different motor neuron pairs. In conclusion, the synchronization between MU firing trains is necessarily caused by the (functional) common input to motor neurons, but it is not possible to infer the degree of shared common input to a pair of motor neurons on the basis of correlation measures of their output spike trains.NEW & NOTEWORTHY The strength of correlation between output spike trains is only poorly associated with the degree of common input to the population of motor neurons. The synchronization between motor unit firing trains is necessarily caused by the (functional) common input to motor neurons, but it is not possible to infer the degree of shared common input to a pair of motor neurons on the basis of correlation measures of their output spike trains. PMID- 28100654 TI - Dissociation between sustained single-neuron spiking and transient beta-LFP oscillations in primate motor cortex. AB - Determining the relationship between single-neuron spiking and transient (20 Hz) beta-local field potential (beta-LFP) oscillations is an important step for understanding the role of these oscillations in motor cortex. We show that whereas motor cortex firing rates and beta spiking rhythmicity remain sustained during steady-state movement preparation periods, beta-LFP oscillations emerge, in contrast, as short transient events. Single-neuron mean firing rates within and outside transient beta-LFP events showed no differences, and no consistent correlation was found between the beta oscillation amplitude and firing rates, as was the case for movement- and visual cue-related beta-LFP suppression. Importantly, well-isolated single units featuring beta-rhythmic spiking (43%, 125/292) showed no apparent or only weak phase coupling with the transient beta LFP oscillations. Similar results were obtained for the population spiking. These findings were common in triple microelectrode array recordings from primary motor (M1), ventral (PMv), and dorsal premotor (PMd) cortices in nonhuman primates during movement preparation. Although beta spiking rhythmicity indicates strong membrane potential fluctuations in the beta band, it does not imply strong phase coupling with beta-LFP oscillations. The observed dissociation points to two different sources of variation in motor cortex beta-LFPs: one that impacts single neuron spiking dynamics and another related to the generation of mesoscopic beta LFP signals. Furthermore, our findings indicate that rhythmic spiking and diverse neuronal firing rates, which encode planned actions during movement preparation, may naturally limit the ability of different neuronal populations to strongly phase-couple to a single dominant oscillation frequency, leading to the observed spiking and beta-LFP dissociation.NEW & NOTEWORTHY We show that whereas motor cortex spiking rates and beta (~20 Hz) spiking rhythmicity remain sustained during steady-state movement preparation periods, beta-local field potential (beta-LFP) oscillations emerge, in contrast, as transient events. Furthermore, the beta-LFP phase at which neurons spike drifts: phase coupling is typically weak or absent. This dissociation points to two sources of variation in the level of motor cortex beta: one that impacts single-neuron spiking and another related to the generation of measured mesoscopic beta-LFPs. PMID- 28100653 TI - Minocycline blocks glial cell activation and ventilatory acclimatization to hypoxia. AB - Ventilatory acclimatization to hypoxia (VAH) is the time-dependent increase in ventilation, which persists upon return to normoxia and involves plasticity in both central nervous system respiratory centers and peripheral chemoreceptors. We investigated the role of glial cells in VAH in male Sprague-Dawley rats using minocycline, an antibiotic that inhibits microglia activation and has anti inflammatory properties, and barometric pressure plethysmography to measure ventilation. Rats received either minocycline (45mg/kg ip daily) or saline beginning 1 day before and during 7 days of chronic hypoxia (CH, PiO2 = 70 Torr). Minocycline had no effect on normoxic control rats or the hypercapnic ventilatory response in CH rats, but minocycline significantly (P < 0.001) decreased ventilation during acute hypoxia in CH rats. However, minocycline administration during only the last 3 days of CH did not reverse VAH. Microglia and astrocyte activation in the nucleus tractus solitarius was quantified from 30 min to 7 days of CH. Microglia showed an active morphology (shorter and fewer branches) after 1 h of hypoxia and returned to the control state (longer filaments and extensive branching) after 4 h of CH. Astrocytes increased glial fibrillary acidic protein antibody immunofluorescent intensity, indicating activation, at both 4 and 24 h of CH. Minocycline had no effect on glia in normoxia but significantly decreased microglia activation at 1 h of CH and astrocyte activation at 24 h of CH. These results support a role for glial cells, providing an early signal for the induction but not maintenance of neural plasticity underlying ventilatory acclimatization to hypoxia.NEW & NOTEWORTHY The signals for neural plasticity in medullary respiratory centers underlying ventilatory acclimatization to chronic hypoxia are unknown. We show that chronic hypoxia activates microglia and subsequently astrocytes. Minocycline, an antibiotic that blocks microglial activation and has anti-inflammatory properties, also blocks astrocyte activation in respiratory centers during chronic hypoxia and ventilatory acclimatization. However, minocycline cannot reverse ventilatory acclimatization after it is established. Hence, glial cells may provide signals that initiate but do not sustain ventilatory acclimatization. PMID- 28100655 TI - Furosemide depresses the presynaptic fiber volley and modifies frequency dependent axonal excitability in rat hippocampus. AB - The loop diuretic furosemide is known to have anticonvulsant effects, believed to be exerted through blockade of glial Na+-K+-2Cl- cotransport causing altered volume regulation in brain tissue. The possibility that direct effects of furosemide on neuronal properties could also be involved is supported by previous observations, but such effects have not been thoroughly investigated. In the present study we show that furosemide has two opposing effects on stimulus induced postsynaptic excitation in the nonepileptic rat hippocampal slice: 1) an enhancement of e-s coupling, which depended on intact GABAA transmission and was partially mimicked by selective blockade of K+-2Cl- cotransport, and 2) a decrement of field excitatory postsynaptic potentials. The balance between these effects varied, depending on the amount of synaptic drive. In addition, the compound action potential (fiber volley) recorded from the stimulated Schaffer collateral axons in stratum radiatum showed a progressive decrease during perfusion of furosemide. This effect was activity-independent, was mimicked by the stilbene derivative DIDS, and could be reproduced on fiber volleys in the alveus. Furosemide also reduced the initial enhancement of the fiber volley observed during trains of high-frequency stimulation (HFS). Results of hyperosmotic expansion of the extracellular volume, with 30 mM sucrose, indicated that both the induction and antagonism of the HFS-induced enhancement were independent of signaling via the extracellular space. Furosemide caused an increased decay of paired-pulse-induced supranormal axonal excitability, which was antagonized by ZD7288. We conclude that furosemide decreases axonal excitability and prevents HFS-induced hyperexcitability via mechanisms downstream of blockage of anion transport, which could include hyperpolarization of axonal membranes.NEW & NOTEWORTHY This study shows that the anion transporter antagonists furosemide and DIDS cause a marked decrease of axonal excitability in rat hippocampal CA1 region and prevent the induction of activity-dependent hyperexcitability in Schaffer collateral axons. The data are consistent with direct effects on axonal membrane properties. We also find that activity dependent enhancement and depression of axonal excitability can be modified independently, suggesting that these events are governed by different underlying processes. PMID- 28100656 TI - Perceptual attraction in tool use: evidence for a reliability-based weighting mechanism. AB - Humans are well able to operate tools whereby their hand movement is linked, via a kinematic transformation, to a spatially distant object moving in a separate plane of motion. An everyday example is controlling a cursor on a computer monitor. Despite these separate reference frames, the perceived positions of the hand and the object were found to be biased toward each other. We propose that this perceptual attraction is based on the principles by which the brain integrates redundant sensory information of single objects or events, known as optimal multisensory integration. That is, 1) sensory information about the hand and the tool are weighted according to their relative reliability (i.e., inverse variances), and 2) the unisensory reliabilities sum up in the integrated estimate. We assessed whether perceptual attraction is consistent with optimal multisensory integration model predictions. We used a cursor-control tool-use task in which we manipulated the relative reliability of the unisensory hand and cursor position estimates. The perceptual biases shifted according to these relative reliabilities, with an additional bias due to contextual factors that were present in experiment 1 but not in experiment 2 The biased position judgments' variances were, however, systematically larger than the predicted optimal variances. Our findings suggest that the perceptual attraction in tool use results from a reliability-based weighting mechanism similar to optimal multisensory integration, but that certain boundary conditions for optimality might not be satisfied.NEW & NOTEWORTHY Kinematic tool use is associated with a perceptual attraction between the spatially separated hand and the effective part of the tool. We provide a formal account for this phenomenon, thereby showing that the process behind it is similar to optimal integration of sensory information relating to single objects. PMID- 28100657 TI - Frequency tuning of synaptic inhibition underlying duration-tuned neurons in the mammalian inferior colliculus. AB - Inhibition plays an important role in creating the temporal response properties of duration-tuned neurons (DTNs) in the mammalian inferior colliculus (IC). Neurophysiological and computational studies indicate that duration selectivity in the IC is created through the convergence of excitatory and inhibitory synaptic inputs offset in time. We used paired-tone stimulation and extracellular recording to measure the frequency tuning of the inhibition acting on DTNs in the IC of the big brown bat (Eptesicus fuscus). We stimulated DTNs with pairs of tones differing in duration, onset time, and frequency. The onset time of a short, best-duration (BD), probe tone set to the best excitatory frequency (BEF) was varied relative to the onset of a longer-duration, nonexcitatory (NE) tone whose frequency was varied. When the NE tone frequency was near or within the cell's excitatory bandwidth (eBW), BD tone-evoked spikes were suppressed by an onset-evoked inhibition. The onset of the spike suppression was independent of stimulus frequency, but both the offset and duration of the suppression decreased as the NE tone frequency departed from the BEF. We measured the inhibitory frequency response area, best inhibitory frequency (BIF), and inhibitory bandwidth (iBW) of each cell. We found that the BIF closely matched the BEF, but the iBW was broader and usually overlapped the eBW measured from the same cell. These data suggest that temporal selectivity of midbrain DTNs is created and preserved by having cells receive an onset-evoked, constant-latency, broadband inhibition that largely overlaps the cell's excitatory receptive field. We conclude by discussing possible neural sources of the inhibition.NEW & NOTEWORTHY Duration-tuned neurons (DTNs) arise from temporally offset excitatory and inhibitory synaptic inputs. We used single-unit recording and paired-tone stimulation to measure the spectral tuning of the inhibitory inputs to DTNs. The onset of inhibition was independent of stimulus frequency; the offset and duration of inhibition systematically decreased as the stimulus departed from the cell's best excitatory frequency. Best inhibitory frequencies matched best excitatory frequencies; however, inhibitory bandwidths were more broadly tuned than excitatory bandwidths. PMID- 28100658 TI - Maps of cone opsin input to mouse V1 and higher visual areas. AB - Studies in the mouse retina have characterized the spatial distribution of an anisotropic ganglion cell and photoreceptor mosaic, which provides a solid foundation to study how the cortex pools from afferent parallel color channels. In particular, the mouse's retinal mosaic exhibits a gradient of wavelength sensitivity along its dorsoventral axis. Cones at the ventral extreme mainly express S opsin, which is sensitive to ultraviolet (UV) wavelengths. Then, moving toward the retina's dorsal extreme, there is a transition to M-opsin dominance. Here, we tested the hypothesis that the retina's opsin gradient is recapitulated in cortical visual areas as a functional map of wavelength sensitivity. We first identified visual areas in each mouse by mapping retinotopy with intrinsic signal imaging (ISI). Next, we measured ISI responses to stimuli along different directions of the S- and M-color plane to quantify the magnitude of S and M input to each location of the retinotopic maps in five visual cortical areas (V1, AL, LM, PM, and RL). The results illustrate a significant change in the S:M-opsin input ratio along the axis of vertical retinotopy that is consistent with the gradient along the dorsoventral axis of the retina. In particular, V1 populations encoding the upper visual field responded to S-opsin contrast with 6.1-fold greater amplitude than to M-opsin contrast. V1 neurons encoding lower fields responded with 4.6-fold greater amplitude to M- than S-opsin contrast. The maps in V1 and higher visual areas (HVAs) underscore the significance of a wavelength sensitivity gradient for guiding the mouse's behavior.NEW & NOTEWORTHY Two elements of this study are particularly novel. For one, it is the first to quantify cone inputs to mouse visual cortex; we have measured cone input in five visual areas. Next, it is the first study to identify a feature map in the mouse visual cortex that is based on well-characterized anisotropy of cones in the retina; we have identified maps of opsin selectivity in five visual areas. PMID- 28100660 TI - Secondary electron effect on electron beam induced charging of SiO2 particle analyzed by electron holography. AB - Charging of a SiO2 particle induced by electron illumination was investigated by changing the illuminated area of the particle and its support film through control of the position of the mask plate inserted in a transmission electron microscope illumination system. The electric fields around the charged SiO2 particle were analyzed using electron holography. The amount of charge was evaluated quantitatively by comparing the reconstructed phase images with the simulated phase images. When the support film was not covered against the incident electron beam, secondary electrons emitted from the conductive support film were attracted to the charged particle, resulting in particle discharge. In contrast, when the support film was completely covered, secondary electrons were not emitted from the film, so that the particle remained positively charged. PMID- 28100661 TI - Weak-beam scanning transmission electron microscopy for quantitative dislocation density measurement in steels. AB - To evaluate dislocations induced by neutron irradiation, we developed a weak-beam scanning transmission electron microscopy (WB-STEM) system by installing a novel beam selector, an annular detector, a high-speed CCD camera and an imaging filter in the camera chamber of a spherical aberration-corrected transmission electron microscope. The capabilities of the WB-STEM with respect to wide-view imaging, real-time diffraction monitoring and multi-contrast imaging are demonstrated using typical reactor pressure vessel steel that had been used in an European nuclear reactor for 30 years as a surveillance test piece with a fluence of 1.09 * 1020 neutrons cm-2. The quantitatively measured size distribution (average loop size = 3.6 +/- 2.1 nm), number density of the dislocation loops (3.6 * 1022 m-3) and dislocation density (7.8 * 1013 m m-3) were carefully compared with the values obtained via conventional weak-beam transmission electron microscopy studies. In addition, cluster analysis using atom probe tomography (APT) further demonstrated the potential of the WB-STEM for correlative electron tomography/APT experiments. PMID- 28100659 TI - A neural locus for spatial-frequency specific saccadic suppression in visual motor neurons of the primate superior colliculus. AB - Saccades cause rapid retinal-image shifts that go perceptually unnoticed several times per second. The mechanisms for saccadic suppression have been controversial, in part because of sparse understanding of neural substrates. In this study we uncovered an unexpectedly specific neural locus for spatial frequency-specific saccadic suppression in the superior colliculus (SC). We first developed a sensitive behavioral measure of suppression in two macaque monkeys, demonstrating selectivity to low spatial frequencies similar to that observed in earlier behavioral studies. We then investigated visual responses in either purely visual SC neurons or anatomically deeper visual motor neurons, which are also involved in saccade generation commands. Surprisingly, visual motor neurons showed the strongest visual suppression, and the suppression was dependent on spatial frequency, as in behavior. Most importantly, suppression selectivity for spatial frequency in visual motor neurons was highly predictive of behavioral suppression effects in each individual animal, with our recorded population explaining up to ~74% of behavioral variance even on completely different experimental sessions. Visual SC neurons had mild suppression, which was unselective for spatial frequency and thus only explained up to ~48% of behavioral variance. In terms of spatial frequency-specific saccadic suppression, our results run contrary to predictions that may be associated with a hypothesized SC saccadic suppression mechanism, in which a motor command in the visual motor and motor neurons is first relayed to the more superficial purely visual neurons, to suppress them and to then potentially be fed back to cortex. Instead, an extraretinal modulatory signal mediating spatial-frequency-specific suppression may already be established in visual motor neurons.NEW & NOTEWORTHY Saccades, which repeatedly realign the line of sight, introduce spurious signals in retinal images that normally go unnoticed. In part, this happens because of perisaccadic suppression of visual sensitivity, which is known to depend on spatial frequency. We discovered that a specific subtype of superior colliculus (SC) neurons demonstrates spatial-frequency-dependent suppression. Curiously, it is the neurons that help mediate the saccadic command itself that exhibit such suppression, and not the purely visual ones. PMID- 28100662 TI - Zika virus causes supernumerary foci with centriolar proteins and impaired spindle positioning. AB - Zika virus (ZIKV) causes congenital microcephaly. Although ZIKV can impair cell cycle progression and provoke apoptosis, which probably contributes to disease aetiology through depletion of neural progenitor cells, additional cellular mechanisms may be important. Here, we investigated whether ZIKV infection alters centrosome number and spindle positioning, because such defects are thought to be at the root of inherited primary autosomal recessive microcephaly (MCPH). In addition to HeLa cells, in which centrosome number and spindle positioning can be well monitored, we analysed retinal epithelial cells (RPE-1), as well as brain derived microglial (CHME-5) and neural progenitor (ReN) cells, using immunofluorescence. We established that ZIKV infection leads to supernumerary foci containing centriolar proteins that in some cases drive multipolar spindle assembly, as well as spindle positioning defects in HeLa, RPE-1 and CHME-5 cells, but not in ReN cells. We uncovered similar phenotypes in HeLa cells upon infection with dengue virus (DENV-2), another flavivirus that does not target brain cells and does not cause microcephaly. We conclude that infection with Flaviviridae can increase centrosome numbers and impair spindle positioning, thus potentially contributing to microcephaly in the case of Zika. PMID- 28100663 TI - Leveraging genome-wide datasets to quantify the functional role of the anti-Shine Dalgarno sequence in regulating translation efficiency. AB - Studies dating back to the 1970s established that sequence complementarity between the anti-Shine-Dalgarno (aSD) sequence on prokaryotic ribosomes and the 5' untranslated region of mRNAs helps to facilitate translation initiation. The optimal location of aSD sequence binding relative to the start codon, the full extents of the aSD sequence and the functional form of the relationship between aSD sequence complementarity and translation efficiency have not been fully resolved. Here, we investigate these relationships by leveraging the sequence diversity of endogenous genes and recently available genome-wide estimates of translation efficiency. We show that-after accounting for predicted mRNA structure-aSD sequence complementarity increases the translation of endogenous mRNAs by roughly 50%. Further, we observe that this relationship is nonlinear, with translation efficiency maximized for mRNAs with intermediate levels of aSD sequence complementarity. The mechanistic insights that we observe are highly robust: we find nearly identical results in multiple datasets spanning three distantly related bacteria. Further, we verify our main conclusions by re analysing a controlled experimental dataset. PMID- 28100664 TI - Rab1 interacts with GOLPH3 and controls Golgi structure and contractile ring constriction during cytokinesis in Drosophila melanogaster. AB - Cytokinesis requires a tight coordination between actomyosin ring constriction and new membrane addition along the ingressing cleavage furrow. However, the molecular mechanisms underlying vesicle trafficking to the equatorial site and how this process is coupled with the dynamics of the contractile apparatus are poorly defined. Here we provide evidence for the requirement of Rab1 during cleavage furrow ingression in cytokinesis. We demonstrate that the gene omelette (omt) encodes the Drosophila orthologue of human Rab1 and is required for successful cytokinesis in both mitotic and meiotic dividing cells of Drosophila melanogaster We show that Rab1 protein colocalizes with the conserved oligomeric Golgi (COG) complex Cog7 subunit and the phosphatidylinositol 4-phosphate effector GOLPH3 at the Golgi stacks. Analysis by transmission electron microscopy and 3D-SIM super-resolution microscopy reveals loss of normal Golgi architecture in omt mutant spermatocytes indicating a role for Rab1 in Golgi formation. In dividing cells, Rab1 enables stabilization and contraction of actomyosin rings. We further demonstrate that GTP-bound Rab1 directly interacts with GOLPH3 and controls its localization at the Golgi and at the cleavage site. We propose that Rab1, by associating with GOLPH3, controls membrane trafficking and contractile ring constriction during cytokinesis. PMID- 28100665 TI - Co-option of bacteriophage lysozyme genes by bivalve genomes. AB - Eukaryotes have occasionally acquired genetic material through horizontal gene transfer (HGT). However, little is known about the evolutionary and functional significance of such acquisitions. Lysozymes are ubiquitous enzymes that degrade bacterial cell walls. Here, we provide evidence that two subclasses of bivalves (Heterodonta and Palaeoheterodonta) acquired a lysozyme gene via HGT, building on earlier findings. Phylogenetic analyses place the bivalve lysozyme genes within the clade of bacteriophage lysozyme genes, indicating that the bivalves acquired the phage-type lysozyme genes from bacteriophages, either directly or through intermediate hosts. These bivalve lysozyme genes underwent dramatic structural changes after their co-option, including intron gain and fusion with other genes. Moreover, evidence suggests that recurrent gene duplication occurred in the bivalve lysozyme genes. Finally, we show the co-opted lysozymes exhibit a capacity for antibacterial action, potentially augmenting the immune function of related bivalves. This represents an intriguing evolutionary strategy in the eukaryote-microbe arms race, in which the genetic materials of bacteriophages are co-opted by eukaryotes, and then used by eukaryotes to combat bacteria, using a shared weapon against a common enemy. PMID- 28100666 TI - T-type Ca2+ channels are required for enhanced sympathetic axon growth by TNFalpha reverse signalling. AB - Tumour necrosis factor receptor 1 (TNFR1)-activated TNFalpha reverse signalling, in which membrane-integrated TNFalpha functions as a receptor for TNFR1, enhances axon growth from developing sympathetic neurons and plays a crucial role in establishing sympathetic innervation. Here, we have investigated the link between TNFalpha reverse signalling and axon growth in cultured sympathetic neurons. TNFR1-activated TNFalpha reverse signalling promotes Ca2+ influx, and highly selective T-type Ca2+ channel inhibitors, but not pharmacological inhibitors of L type, N-type and P/Q-type Ca2+ channels, prevented enhanced axon growth. T-type Ca2+ channel-specific inhibitors eliminated Ca2+ spikes promoted by TNFalpha reverse signalling in axons and prevented enhanced axon growth when applied locally to axons, but not when applied to cell somata. Blocking action potential generation did not affect the effect of TNFalpha reverse signalling on axon growth, suggesting that propagated action potentials are not required for enhanced axon growth. TNFalpha reverse signalling enhanced protein kinase C (PKC) activation, and pharmacological inhibition of PKC prevented the axon growth response. These results suggest that TNFalpha reverse signalling promotes opening of T-type Ca2+ channels along sympathetic axons, which is required for enhanced axon growth. PMID- 28100668 TI - Correction to 'NMJ-morph reveals principal components of synaptic morphology influencing structure-function relationships at the neuromuscular junction'. PMID- 28100667 TI - The control of translational accuracy is a determinant of healthy ageing in yeast. AB - Life requires the maintenance of molecular function in the face of stochastic processes that tend to adversely affect macromolecular integrity. This is particularly relevant during ageing, as many cellular functions decline with age, including growth, mitochondrial function and energy metabolism. Protein synthesis must deliver functional proteins at all times, implying that the effects of protein synthesis errors like amino acid misincorporation and stop-codon read through must be minimized during ageing. Here we show that loss of translational accuracy accelerates the loss of viability in stationary phase yeast. Since reduced translational accuracy also reduces the folding competence of at least some proteins, we hypothesize that negative interactions between translational errors and age-related protein damage together overwhelm the cellular chaperone network. We further show that multiple cellular signalling networks control basal error rates in yeast cells, including a ROS signal controlled by mitochondrial activity, and the Ras pathway. Together, our findings indicate that signalling pathways regulating growth, protein homeostasis and energy metabolism may jointly safeguard accurate protein synthesis during healthy ageing. PMID- 28100669 TI - The Preventive Value of Epidural Calcitonin in Patients with Lower Limb Amputation. AB - Background: Postamputation pain is highly prevalent after limb amputation with neuropathic nature; calcitonin may effectively relieve many neuropathic pain states. Design: Double-blind randomized multicenter study. Setting: Our study hypothesis is to evaluate the preventive value of epidural calcitonin on postoperative pain, grade of phantom pain, and the development of allodynia and hyperalgesia in patients undergoing lower limb amputation. Patients: A cohort of 60 diabetic patients of both genders suffering from vascular insufficiency of one or both lower limbs underwent minor or major lower limb amputation. Patients were divided randomly into two equal groups: an epidural bupivacaine-calcitonin fentanyl (BCF) group and a bupivacaine-fentanyl (BF) group. Methods: Patients were instructed about the use of a 10 cm visual analog scale (VAS). Phantom limb pain was graded using a four-grade scale. Pin-prick hyperalgesia and allodynia were evaluated at one week, one month, three months, and six months after surgery. Results: There were no significant differences between groups regarding patients' characteristics. There was no significant difference in the VAS scale between groups. There was statically significant improvement in the grade of phantom pain in the BCF group at six and 12 months after surgery ( P = 0.033 and 0.001, respectively). A significantly higher number of patients developed allodynia in the BF group at six ( P = 0.039) and 12 ( P = 0.013) months and hyperalgesia at 12 months ( P = 0.025). Conclusion: The preventive use of epidural calcitonin improved the grade of phantom pain and reduced the incidence of allodynia and hyperalgesia in patients undergoing lower limb amputation under combined spinal-epidural anesthesia during one year of follow-up. PMID- 28100671 TI - Fast-Neutron Survey With Compact Plastic Scintillation Detectors. AB - With the rise of the Silicon Photomultiplier (SiPM), it is now practical to build compact scintillation detectors well suited to portable use. A prototype survey meter for fast-neutrons and gamma-rays, based around an EJ-299-34 plastic scintillator with SiPM readout, has been developed and tested. A custom digital pulse processor was used to perform pulse shape discrimination on-the-fly. Ambient dose equivalent H*(10) was calculated by means of two energy-dependent 'G functions'. The sensitivity was calculated to be between 0.10 and 0.22 cps/(uSv/hr) for fast-neutrons with energies above 2.5 MeV. The prototype was used to survey various laboratory radiation fields, with the readings compared with commercial survey meters. The high sensitivity and lightweight nature of this detector makes it promising for rapid survey of the mixed neutron/gamma-ray fields encountered in industry and homeland security. PMID- 28100670 TI - TWO NEW SINGLE-EXPOSURE, MULTI-DETECTOR NEUTRON SPECTROMETERS FOR RADIATION PROTECTION APPLICATIONS IN WORKPLACE MONITORING. AB - This communication describes two new instruments, based on multiple active thermal neutron detectors arranged within a single moderator, that permit to unfold the neutron spectrum (from thermal to hundreds of MeV) and to determine the corresponding integral quantities with only one exposure. This makes them especially advantageous for neutron field characterisation and workplace monitoring in neutron-producing facilities. One of the devices has spherical geometry and nearly isotropic response, the other one has cylindrical symmetry and it is only sensitive to neutrons incident along the cylinder axis. In both cases, active detectors have been specifically developed looking for the criteria of miniaturisation, high sensitivity, linear response and good photon rejection. The calculated response matrix has been validated by experimental irradiations in neutron reference fields with a global uncertainty of 3%. The measurements performed in realistic neutron fields permitted to determine the neutron spectra and the integral quantities, in particular H*(10). PMID- 28100674 TI - Correction. PMID- 28100673 TI - Setting up a clinic to assess children and young people for female genital mutilation. AB - It is now mandatory for health, social care professionals and teachers to report to the police all under-18s where female genital mutilation (FGM) has been disclosed by the child or where physical signs of FGM are seen. Such referrals are likely to result in a request for medical examination. New multiagency statutory guidance sets out instructions for physical examination but provides no details how services should be set-up. This review gives practical guidance learnt from the first year of the UK's only dedicated children's FGM service. PMID- 28100675 TI - Protein synthesis inhibition and GADD34 control IFN-beta heterogeneous expression in response to dsRNA. AB - In innate immune responses, induction of type-I interferons (IFNs) prevents virus spreading while viral replication is delayed by protein synthesis inhibition. We asked how cells perform these apparently contradictory activities. Using single fibroblast monitoring by flow cytometry and mathematical modeling, we demonstrate that type-I IFN production is linked to cell's ability to enter dsRNA-activated PKR-dependent translational arrest and then overcome this inhibition by decreasing eIF2alpha phosphorylation through phosphatase 1c cofactor GADD34 (Ppp1r15a) expression. GADD34 expression, shown here to be dependent on the IRF3 transcription factor, is responsible for a biochemical cycle permitting pulse of IFN synthesis to occur in cells undergoing protein synthesis inhibition. Translation arrest is further demonstrated to be key for anti-viral response by acting synergistically with MAVS activation to amplify TBK1 signaling and IFN beta mRNA transcription, while GADD34-dependent protein synthesis recovery contributes to the heterogeneous expression of IFN observed in dsRNA-activated cells. PMID- 28100676 TI - Gene-body chromatin modification dynamics mediate epigenome differentiation in Arabidopsis. AB - Heterochromatin is marked by methylation of lysine 9 on histone H3 (H3K9me). A puzzling feature of H3K9me is that this modification localizes not only in promoters but also in internal regions (bodies) of silent transcription units. Despite its prevalence, the biological significance of gene-body H3K9me remains enigmatic. Here we show that H3K9me-associated removal of H3K4 monomethylation (H3K4me1) in gene bodies mediates transcriptional silencing. Mutations in an Arabidopsis H3K9 demethylase gene IBM1 induce ectopic H3K9me2 accumulation in gene bodies, with accompanying severe developmental defects. Through suppressor screening of the ibm1-induced developmental defects, we identified the LDL2 gene, which encodes a homolog of conserved H3K4 demethylases. The ldl2 mutation suppressed the developmental defects, without suppressing the ibm1-induced ectopic H3K9me2. The ectopic H3K9me2 mark directed removal of gene-body H3K4me1 and caused transcriptional repression in an LDL2-dependent manner. Furthermore, mutations of H3K9 methylases increased the level of H3K4me1 in the gene bodies of various transposable elements, and this H3K4me1 increase is a prerequisite for their transcriptional derepression. Our results uncover an unexpected role of gene-body H3K9me2/H3K4me1 dynamics as a mediator of heterochromatin silencing and epigenome differentiation. PMID- 28100678 TI - Modulation of Naive CD8 T Cell Response Features by Ligand Density, Affinity, and Continued Signaling via Internalized TCRs. AB - T cell response magnitudes increase with increasing antigenic dosage. However, it is unclear whether ligand density only modulates the proportions of responding ligand-specific T cells or also alters responses at the single cell level. Using brief (3 h) exposure of TCR-transgenic mouse CD8 T cells in vitro to varying densities of cognate peptide-MHC ligand followed by ligand-free culture in IL-2, we found that ligand density determined the frequencies of responding cells but not the expression levels of the early activation marker molecule, CD69. Cells with low glucose uptake capacity and low protein synthesis rates were less ligand sensitive, implicating metabolic competence in the response heterogeneity of CD8 T cell populations. Although most responding cells proliferated, ligand density was associated with time of entry into proliferation and with the extent of cell surface TCR downmodulation. TCR internalization was associated, regardless of the ligand density, with rapidity of c-myc induction, loss of the cell cycle inhibitor p27kip1, metabolic reprogramming, and cell cycle entry. A low affinity peptide ligand behaved, regardless of ligand density, like a low density, high affinity ligand in all these parameters. Inhibition of signaling after ligand exposure selectively delayed proliferation in cells with internalized TCRs. Finally, internalized TCRs continued to signal and genetic modification of TCR internalization and trafficking altered the duration of signaling in a T cell hybridoma. Together, our findings indicate that heterogeneity among responding CD8 T cell populations in their ability to respond to TCR-mediated stimulation and internalize TCRs mediates detection of ligand density or affinity, contributing to graded response magnitudes. PMID- 28100677 TI - Paired Siglec receptors generate opposite inflammatory responses to a human specific pathogen. AB - Paired immune receptors display near-identical extracellular ligand-binding regions but have intracellular sequences with opposing signaling functions. While inhibitory receptors dampen cellular activation by recognizing self-associated molecules, the functions of activating counterparts are less clear. Here, we studied the inhibitory receptor Siglec-11 that shows uniquely human expression in brain microglia and engages endogenous polysialic acid to suppress inflammation. We demonstrated that the human-specific pathogen Escherichia coli K1 uses its polysialic acid capsule as a molecular mimic to engage Siglec-11 and escape killing. In contrast, engagement of the activating counterpart Siglec-16 increases elimination of bacteria. Since mice do not have paired Siglec receptors, we generated a model by replacing the inhibitory domain of mouse Siglec-E with the activating module of Siglec-16. Siglec-E16 enhanced proinflammatory cytokine expression and bacterial killing in macrophages and boosted protection against intravenous bacterial challenge. These data elucidate uniquely human interactions of a pathogen with Siglecs and support the long standing hypothesis that activating counterparts of paired immune receptors evolved as a response to pathogen molecular mimicry of host ligands for inhibitory receptors. PMID- 28100679 TI - Etv5 Regulates IL-10 Production in Th Cells. AB - IL-10 is an immunoregulatory cytokine that has broad effects across the immune system. In Th cell subsets, Th2 cells produce considerable amounts of IL-10. The transcription factors that regulate IL-10 production in Th2 cells are still incompletely described. In this study, we demonstrate that the ETS family transcription factor ETS variant (Etv)5 regulates IL-10 production in Th2 cells. T cell-specific Etv5-deficient and littermate control mice demonstrated that IL 10 production and gene expression were significantly decreased in the absence of Etv5. In an Aspergillus fumigatus extract-induced inflammation model, IL-10 producing CD4+ T cells in bronchoalveolar lavage and lung were significantly decreased in mice that lacked Etv5 in T cells, compared with control mice. We showed that Etv5 directly binds to the Il10 locus conserved noncoding sequence 3 site and that it activates gene expression in a luciferase reporter assay and following retroviral transduction. Etv5 deficiency did not affect the expression of other transcription factors known to be important for expression of IL-10, including Jun family members, GATA3, E4BP4, and IFN regulatory factor 4. However, in the absence of Etv5, binding of these transcription factors to the Il10 locus was dramatically reduced. Ectopic Etv5 expression in Th2 cells that lack Etv5 restored IL-10 production and the binding of IL-10-inducing transcription factors including E4BP4, IFN regulatory factor 4, and GATA3. Taken together, we conclude that Etv5 plays a crucial role in regulating IL-10 production in Th2 cells by facilitating the binding of IL-10-inducing transcription factors at the Il10 locus. PMID- 28100680 TI - Th22 Cells Form a Distinct Th Lineage from Th17 Cells In Vitro with Unique Transcriptional Properties and Tbet-Dependent Th1 Plasticity. AB - Th22 cells are a major source of IL-22 and have been found at sites of infection and in a range of inflammatory diseases. However, their molecular characteristics and functional roles remain largely unknown because of our inability to generate and isolate pure populations. We developed a novel Th22 differentiation assay and generated dual IL-22/IL-17A reporter mice to isolate and compare pure populations of cultured Th22 and Th17 cells. Il17a fate-mapping and transcriptional profiling provide evidence that these Th22 cells have never expressed IL-17A, suggesting that they are potentially a distinct cell lineage from Th17 cells under in vitro culture conditions. Interestingly, Th22 cells also expressed granzymes, IL-13, and increased levels of Tbet. Using transcription factor-deficient cells, we demonstrate that RORgammat and Tbet act as positive and negative regulators of Th22 differentiation, respectively. Furthermore, under Th1 culture conditions in vitro, as well as in an IFN-gamma-rich inflammatory environment in vivo, Th22 cells displayed marked plasticity toward IFN-gamma production. Th22 cells also displayed plasticity under Th2 conditions in vitro by upregulating IL-13 expression. Our work has identified conditions to generate and characterize Th22 cells in vitro. Further, it provides evidence that Th22 cells develop independently of the Th17 lineage, while demonstrating plasticity toward both Th1 and Th2-type cells. PMID- 28100681 TI - LFA-1 Activation in NK Cells and Their Subsets: Influence of Receptors, Maturation, and Cytokine Stimulation. AB - The integrin LFA-1 is essential for efficient activation and for cytotoxicity of NK cells because it initiates the assembly of the immunological synapse and mediates firm adhesion to the target. LFA-1 is also needed to polarize the cytotoxic machinery of the NK cell toward the target cell. The binding affinity and avidity of integrins can be regulated via inside-out signals from other receptors. In this article, we investigate the signals necessary to activate LFA 1 in human NK cells. Our data show that LFA-1 has a low ligand-binding activity in resting human NK cells, but it can be stimulated by triggering activating receptors, such as 2B4 or CD16, or by coactivation of different receptor combinations. Short-term stimulation of freshly isolated NK cells with cytokines, such as IL-15, IL-12, or IL-18, does not activate LFA-1 but increases the responsiveness of the cells to subsequent receptor stimulation. Different NK cell subsets vary in their ability to induce LFA-1 binding activity after activating receptor stimulation. Interestingly, the NK cell subsets that are more mature and possess higher cytotoxic potential also show the highest activation of LFA-1, which correlated with the expression of the small calcium-binding protein S100A4. Our data suggest that regulation of LFA-1 is one reason for the different activity of NK cells during differentiation. PMID- 28100682 TI - Diet-Derived Short Chain Fatty Acids Stimulate Intestinal Epithelial Cells To Induce Mucosal Tolerogenic Dendritic Cells. AB - The gastrointestinal tract is continuously exposed to many environmental factors that influence intestinal epithelial cells and the underlying mucosal immune system. In this article, we demonstrate that dietary fiber and short chain fatty acids (SCFAs) induced the expression of the vitamin A-converting enzyme RALDH1 in intestinal epithelial cells in vivo and in vitro, respectively. Furthermore, our data showed that the expression levels of RALDH1 in small intestinal epithelial cells correlated with the activity of vitamin A-converting enzymes in mesenteric lymph node dendritic cells, along with increased numbers of intestinal regulatory T cells and a higher production of luminal IgA. Moreover, we show that the consumption of dietary fiber can alter the composition of SCFA-producing microbiota and SCFA production in the small intestines. In conclusion, our data illustrate that dietary adjustments affect small intestinal epithelial cells and can be used to modulate the mucosal immune system. PMID- 28100683 TI - Impact of microscopic orbital periosteum invasion in orbital preservation surgery. AB - Objective: The orbital periosteum is considered to be a barrier to tumor spread; however, it is difficult to evaluate microscopic tumor spread during surgery. This study aimed to assess the impact of pathological status in orbital preservation surgery. Methods: We retrospectively analyzed the 3-year local control rate and treatment outcomes of patients with malignant tumors invading the orbit who were treated between 2006 and 2012. Results: In total, 27 patients were reviewed over a median follow-up period of 36 months. Pathologically, 19 had carcinomas and 8 had sarcomas. Treatment was by orbital exenteration in 6 patients and orbital preservation surgery in 21 patients. After orbital preservation surgery, poorer 3-year local control rates were significantly associated with positive surgical margins (negative vs. positive: 91% vs. 41%, P = 0.040) and microscopic orbital periosteum invasion (negative vs. positive: 90% vs. 39%, P = 0.010). These factors were independent risk factors in multivariate analysis. The locations of the positive margin were most common at the horizontal and vertical margins of the orbital periosteum and the posterior margin of the orbital apex. Moreover, in 24% of patients, invasion evaluation by preoperative imaging study was underestimated compared with postoperative microscopic evaluation. Conclusions: The positive surgical margin and microscopic orbital periosteum invasion were the risk factors of orbital recurrence. It is difficult to determine the indications for orbital preservation surgery by preoperative imaging studies because of the unpredictable accurate pathological status before surgery and the limitations of preoperative imaging evaluation. PMID- 28100684 TI - Association between poorly differentiated clusters and efficacy of 5-fluorouracil based adjuvant chemotherapy in stage III colorectal cancer. AB - Objective: Although poorly differentiated cluster has been reported to be a useful grading system for predicting prognosis in colorectal cancer, its relationship to chemotherapy efficacy has not been demonstrated. We aimed to investigate the association between poorly differentiated cluster and the efficacy of 5-fluorouracil-based adjuvant chemotherapy in stage III colorectal cancer. Methods: This retrospective study enrolled 131 patients with stage III colorectal cancer who underwent curative resection: 72 received 5-fluorouracil based adjuvant chemotherapy (chemotherapy group) and 59 did not (surgery-alone group). Poorly differentiated cluster was defined as a cancer cluster of >=5 cancer cells without gland-like structure, and was classified into poorly differentiated cluster G1, G2 and G3 according to the number of clusters. The benefit of 5-fluorouracil-based adjuvant chemotherapy was evaluated based on poorly differentiated cluster grade. Results: Thirty-nine, 40 and 52 patients were classified as poorly differentiated cluster G1, G2 and G3, respectively. Significant differences in the 5-year cumulative recurrence rate and relapse-free survival were observed between poorly differentiated cluster G1/G2 and G3 (26.7% vs. 47.5%, P = 0.010; 66.0% vs. 43.9%, P = 0.004). A comparison of cumulative recurrence rate and relapse-free survival between the chemotherapy and surgery alone groups showed a significant benefit of adjuvant chemotherapy in poorly differentiated cluster G1/G2 patients (cumulative recurrence rate: 17.4% vs. 37.3%, P = 0.035; relapse-free survival: 79.5% vs. 51.9%, P = 0.002), but not in poorly differentiated cluster G3 patients (cumulative recurrence rate: 48.6% vs. 44.8%, P = 0.885; relapse-free survival: 51.4% vs. 32.7%, P = 0.068). Conclusions: In stage III colorectal cancer, poorly differentiated cluster G1/G2 predicts a significant benefit from 5-fluorouracil-based adjuvant chemotherapy, whereas poorly differentiated cluster G3 predicts a poor response to it. PMID- 28100685 TI - Heat stress induces ferroptosis-like cell death in plants. AB - In plants, regulated cell death (RCD) plays critical roles during development and is essential for plant-specific responses to abiotic and biotic stresses. Ferroptosis is an iron-dependent, oxidative, nonapoptotic form of cell death recently described in animal cells. In animal cells, this process can be triggered by depletion of glutathione (GSH) and accumulation of lipid reactive oxygen species (ROS). We investigated whether a similar process could be relevant to cell death in plants. Remarkably, heat shock (HS)-induced RCD, but not reproductive or vascular development, was found to involve a ferroptosis-like cell death process. In root cells, HS triggered an iron-dependent cell death pathway that was characterized by depletion of GSH and ascorbic acid and accumulation of cytosolic and lipid ROS. These results suggest a physiological role for this lethal pathway in response to heat stress in Arabidopsis thaliana The similarity of ferroptosis in animal cells and ferroptosis-like death in plants suggests that oxidative, iron-dependent cell death programs may be evolutionarily ancient. PMID- 28100686 TI - Noncanonical function of DGCR8 controls mESC exit from pluripotency. AB - Mouse embryonic stem cells (mESCs) deficient for DGCR8, a key component of the microprocessor complex, present strong differentiation defects. However, the exact reasons impairing their commitment remain elusive. The analysis of newly generated mutant mESCs revealed that DGCR8 is essential for the exit from the pluripotency state. To dissociate canonical versus noncanonical functions of DGCR8, we complemented the mutant mESCs with a phosphomutant DGCR8, which restored microRNA levels but did not rescue the exit from pluripotency defect. Integration of omics data and RNA immunoprecipitation experiments established DGCR8 as a direct interactor of Tcf7l1 mRNA, a core component of the pluripotency network. Finally, we found that DGCR8 facilitated the splicing of Tcf7l1, an event necessary for the differentiation of mESCs. Our data reveal a new noncanonical function of DGCR8 in the modulation of the alternative splicing of Tcf7l1 mRNA in addition to its established function in microRNA biogenesis. PMID- 28100690 TI - Oxytocin Treatment May Improve Infant Feeding and Social Skills in Prader-Willi Syndrome. PMID- 28100688 TI - The Use of Oxytocin to Improve Feeding and Social Skills in Infants With Prader Willi Syndrome. AB - BACKGROUND AND OBJECTIVES: Patients with Prader-Willi syndrome (PWS) display poor feeding and social skills as infants and fewer hypothalamic oxytocin (OXT) producing neurons were documented in adults. Animal data demonstrated that early treatment with OXT restores sucking after birth. Our aim is to reproduce these data in infants with PWS. METHODS: We conducted a phase 2 escalating dose study of a short course (7 days) of intranasal OXT administration. We enrolled 18 infants with PWS under 6 months old (6 infants in each step) who received 4 IU of OXT either every other day, daily, or twice daily. We investigated the tolerance and the effects on feeding and social skills and changes in circulating ghrelin and brain connectivity by functional MRI. RESULTS: No adverse events were reported. No dose effect was observed. Sucking assessed by the Neonatal Oral Motor Scale was abnormal in all infants at baseline and normalized in 88% after treatment. The scores of Neonatal Oral-Motor Scale and videofluoroscopy of swallowing significantly decreased from 16 to 9 (P < .001) and from 18 to 12.5 (P < .001), respectively. Significant improvements in Clinical Global Impression scale scores, social withdrawal behavior, and mother-infant interactions were observed. We documented a significant increase in acylated ghrelin and connectivity of the right superior orbitofrontal network that correlated with changes in sucking and behavior. CONCLUSIONS: OXT is well tolerated in infants with PWS and improves feeding and social skills. These results open perspectives for early treatment in neurodevelopment diseases with feeding problems. PMID- 28100687 TI - A STRIPAK complex mediates axonal transport of autophagosomes and dense core vesicles through PP2A regulation. AB - Autophagy plays an essential role in the cellular homeostasis of neurons, facilitating the clearance of cellular debris. This clearance process is orchestrated through the assembly, transport, and fusion of autophagosomes with lysosomes for degradation. The motor protein dynein drives autophagosome motility from distal sites of assembly to sites of lysosomal fusion. In this study, we identify the scaffold protein CKA (connector of kinase to AP-1) as essential for autophagosome transport in neurons. Together with other core components of the striatin-interacting phosphatase and kinase (STRIPAK) complex, we show that CKA associates with dynein and directly binds Atg8a, an autophagosomal protein. CKA is a regulatory subunit of PP2A, a component of the STRIPAK complex. We propose that the STRIPAK complex modulates dynein activity. Consistent with this hypothesis, we provide evidence that CKA facilitates axonal transport of dense core vesicles and autophagosomes in a PP2A-dependent fashion. In addition, CKA deficient flies exhibit PP2A-dependent motor coordination defects. CKA function within the STRIPAK complex is crucial to prevent transport defects that may contribute to neurodegeneration. PMID- 28100691 TI - Registry in a tube: multiplexed pools of retrievable parts for genetic design space exploration. PMID- 28100689 TI - Effectiveness and Duration of Protection of One Dose of a Meningococcal Conjugate Vaccine. AB - BACKGROUND: Meningococcal conjugate vaccines were licensed beginning in 2005 on the basis of serologic end points and recommended for use in adolescents. A single dose at age 11 to 12 years was expected to provide protection through late adolescence. We conducted a case-control evaluation of vaccine effectiveness (VE) and duration of protection of a meningococcal (groups A, C, W, and Y) polysaccharide diphtheria toxoid conjugate vaccine (MenACWY-D). METHODS: Cases of culture- or polymerase chain reaction-confirmed serogroup A, C, W, and Y meningococcal disease among adolescents were identified through meningococcal disease surveillance sites in the United States from January 1, 2006, through August 31, 2013. Attempts were made to enroll 4 friend and school controls per case. VE was calculated using the generalized estimating equation, controlling for underlying medical conditions and smoking. RESULTS: Serogroup C accounted for 88 (49%), serogroup Y 80 (44%), and serogroup W 13 (7%) of enrolled cases. Thirty six (20%) cases and 87 (44%) controls received MenACWY-D. The overall VE estimate 0 to 8 years postvaccination was 69% (51% to 80%); VE was 79% (49% to 91%) at <1 year, 69% (44% to 83%) at 1 to <3 years, and 61% (25% to 79%) at 3 to <8 years. VE was 77% (57% to 88%) against serogroup C and 51% (1% to 76%) against serogroup Y. CONCLUSIONS: MenACWY-D was effective in the first year after vaccination but effectiveness waned 3 to <8 years postvaccination. The estimates of VE from this evaluation informed the Advisory Committee on Immunization Practices in its decision to add a booster dose of MenACWY. PMID- 28100694 TI - ADPriboDB: The database of ADP-ribosylated proteins. PMID- 28100692 TI - Insights into the RecQ helicase mechanism revealed by the structure of the helicase domain of human RECQL5. AB - RecQ helicases are important maintainers of genome integrity with distinct roles in almost every cellular process requiring access to DNA. RECQL5 is one of five human RecQ proteins and is particularly versatile in this regard, forming protein complexes with a diverse set of cellular partners in order to coordinate its helicase activity to various processes including replication, recombination and DNA repair. In this study, we have determined crystal structures of the core helicase domain of RECQL5 both with and without the nucleotide ADP in two distinctly different ('Open' and 'Closed') conformations. Small angle X-ray scattering studies show that the 'Open' form of the protein predominates in solution and we discuss implications of this with regards to the RECQL5 mechanism and conformational changes. We have measured the ATPase, helicase and DNA binding properties of various RECQL5 constructs and variants and discuss the role of these regions and residues in the various RECQL5 activities. Finally, we have performed a systematic comparison of the RECQL5 structures with other RecQ family structures and based on these comparisons we have constructed a model for the mechano-chemical cycle of the common catalytic core of these helicases. PMID- 28100693 TI - Viral genome packaging terminase cleaves DNA using the canonical RuvC-like two metal catalysis mechanism. AB - Bacteriophages and large dsDNA viruses encode sophisticated machinery to translocate their DNA into a preformed empty capsid. An essential part of this machine, the large terminase protein, processes viral DNA into constituent units utilizing its nuclease activity. Crystal structures of the large terminase nuclease from the thermophilic bacteriophage G20c show that it is most similar to the RuvC family of the RNase H-like endonucleases. Like RuvC proteins, the nuclease requires either Mn2+, Mg2+ or Co2+ ions for activity, but is inactive with Zn2+ and Ca2+. High resolution crystal structures of complexes with different metals reveal that in the absence of DNA, only one catalytic metal ion is accommodated in the active site. Binding of the second metal ion may be facilitated by conformational variability, which enables the two catalytic aspartic acids to be brought closer to each other. Structural comparison indicates that in common with the RuvC family, the location of the two catalytic metals differs from other members of the RNase H family. In contrast to a recently proposed mechanism, the available data do not support binding of the two metals at an ultra-short interatomic distance. Thus we postulate that viral terminases cleave DNA by the canonical RuvC-like mechanism. PMID- 28100696 TI - The 24th annual Nucleic Acids Research database issue: a look back and upcoming changes. PMID- 28100695 TI - Mapping the affinity landscape of Thrombin-binding aptamers on 2?F-ANA/DNA chimeric G-Quadruplex microarrays. AB - In situ fabricated nucleic acids microarrays are versatile and very high throughput platforms for aptamer optimization and discovery, but the chemical space that can be probed against a given target has largely been confined to DNA, while RNA and non-natural nucleic acid microarrays are still an essentially uncharted territory. 2?-Fluoroarabinonucleic acid (2?F-ANA) is a prime candidate for such use in microarrays. Indeed, 2?F-ANA chemistry is readily amenable to photolithographic microarray synthesis and its potential in high affinity aptamers has been recently discovered. We thus synthesized the first microarrays containing 2?F-ANA and 2?F-ANA/DNA chimeric sequences to fully map the binding affinity landscape of the TBA1 thrombin-binding G-quadruplex aptamer containing all 32 768 possible DNA-to-2?F-ANA mutations. The resulting microarray was screened against thrombin to identify a series of promising 2?F-ANA-modified aptamer candidates with Kds significantly lower than that of the unmodified control and which were found to adopt highly stable, antiparallel-folded G quadruplex structures. The solution structure of the TBA1 aptamer modified with 2?F-ANA at position T3 shows that fluorine substitution preorganizes the dinucleotide loop into the proper conformation for interaction with thrombin. Overall, our work strengthens the potential of 2?F-ANA in aptamer research and further expands non-genomic applications of nucleic acids microarrays. PMID- 28100697 TI - The histone demethylase PHF8 is a molecular safeguard of the IFNgamma response. AB - A precise immune response is essential for cellular homeostasis and animal survival. The paramount importance of its control is reflected by the fact that its non-specific activation leads to inflammatory events that ultimately contribute to the appearance of many chronic diseases. However, the molecular mechanisms preventing non-specific activation and allowing a quick response upon signal activation are not yet fully understood. In this paper we uncover a new function of PHF8 blocking signal independent activation of immune gene promoters. Affinity purifications coupled with mass spectrometry analysis identified SIN3A and HDAC1 corepressors as new PHF8 interacting partners. Further molecular analysis demonstrated that prior to interferon gamma (IFNgamma) stimulation, PHF8 is bound to a subset of IFNgamma-responsive promoters. Through the association with HDAC1 and SIN3A, PHF8 keeps the promoters in a silent state, maintaining low levels of H4K20me1. Upon IFNgamma treatment, PHF8 is phosphorylated by ERK2 and evicted from the promoters, correlating with an increase in H4K20me1 and transcriptional activation. Our data strongly indicate that in addition to its well-characterized function as a coactivator, PHF8 safeguards transcription to allow an accurate immune response. PMID- 28100700 TI - PBrowse: a web-based platform for real-time collaborative exploration of genomic data. AB - Genome browsers are widely used for individually exploring various types of genomic data. A handful of genome browsers offer limited tools for collaboration among multiple users. Here, we describe PBrowse, an integrated real-time collaborative genome browser that enables multiple users to simultaneously view and access genomic data, thereby harnessing the wisdom of the crowd. PBrowse is based on the Dalliance genome browser and has a re-designed user and data management system with novel collaborative functionalities, including real-time collaborative view, track comment and an integrated group chat feature. Through the Distributed Annotation Server protocol, PBrowse can easily access a wide range of publicly available genomic data, such as the ENCODE data sets. We argue that PBrowse represents a paradigm shift from using a genome browser as a static data visualization tool to a platform that enables real-time human-human interaction and knowledge exchange in a collaborative setting. PBrowse is available at http://pbrowse.victorchang.edu.au, and its source code is available via an open source BSD 3 license at http://github.com/VCCRI/PBrowse. PMID- 28100698 TI - Cdc45-induced loading of human RPA onto single-stranded DNA. AB - Cell division cycle protein 45 (Cdc45) is an essential component of the eukaryotic replicative DNA helicase. We found that human Cdc45 forms a complex with the single-stranded DNA (ssDNA) binding protein RPA. Moreover, it actively loads RPA onto nascent ssDNA. Pull-down assays and surface plasmon resonance studies revealed that Cdc45-bound RPA complexed with ssDNA in the 8-10 nucleotide binding mode, but dissociated when RPA covered a 30-mer. Real-time analysis of RPA-ssDNA binding demonstrated that Cdc45 catalytically loaded RPA onto ssDNA. This placement reaction required physical contacts of Cdc45 with the RPA70A subdomain. Our results imply that Cdc45 controlled stabilization of the 8-nt RPA binding mode, the subsequent RPA transition into 30-mer mode and facilitated an ordered binding to ssDNA. We propose that a Cdc45-mediated loading guarantees a seamless deposition of RPA on newly emerging ssDNA at the nascent replication fork. PMID- 28100699 TI - Proteogenomics produces comprehensive and highly accurate protein-coding gene annotation in a complete genome assembly of Malassezia sympodialis. AB - Complete and accurate genome assembly and annotation is a crucial foundation for comparative and functional genomics. Despite this, few complete eukaryotic genomes are available, and genome annotation remains a major challenge. Here, we present a complete genome assembly of the skin commensal yeast Malassezia sympodialis and demonstrate how proteogenomics can substantially improve gene annotation. Through long-read DNA sequencing, we obtained a gap-free genome assembly for M. sympodialis (ATCC 42132), comprising eight nuclear and one mitochondrial chromosome. We also sequenced and assembled four M. sympodialis clinical isolates, and showed their value for understanding Malassezia reproduction by confirming four alternative allele combinations at the two mating type loci. Importantly, we demonstrated how proteomics data could be readily integrated with transcriptomics data in standard annotation tools. This increased the number of annotated protein-coding genes by 14% (from 3612 to 4113), compared to using transcriptomics evidence alone. Manual curation further increased the number of protein-coding genes by 9% (to 4493). All of these genes have RNA-seq evidence and 87% were confirmed by proteomics. The M. sympodialis genome assembly and annotation presented here is at a quality yet achieved only for a few eukaryotic organisms, and constitutes an important reference for future host microbe interaction studies. PMID- 28100701 TI - Self-cytoplasmic DNA upregulates the mutator enzyme APOBEC3A leading to chromosomal DNA damage. AB - Foreign and self-cytoplasmic DNA are recognized by numerous DNA sensor molecules leading to the production of type I interferons. Such DNA agonists should be degraded otherwise cells would be chronically stressed. Most human APOBEC3 cytidine deaminases can initiate catabolism of cytoplasmic mitochondrial DNA. Using the human myeloid cell line THP-1 with an interferon inducible APOBEC3A gene, we show that cytoplasmic DNA triggers interferon alpha and beta production through the RNA polymerase III transcription/RIG-I pathway leading to massive upregulation of APOBEC3A. By catalyzing C->U editing in single stranded DNA fragments, the enzyme prevents them from re-annealing so attenuating the danger signal. The price to pay is chromosomal DNA damage in the form of CG->TA mutations and double stranded DNA breaks which, in the context of chronic inflammation, could drive cells down the path toward cancer. PMID- 28100703 TI - Paternal epigenetic programming: evolving metabolic disease risk. AB - Parental health or exposures can affect the lifetime health outcomes of offspring, independently of inherited genotypes. Such 'epigenetic' effects occur over a broad range of environmental stressors, including defects in parental metabolism. Although maternal metabolic effects are well documented, it has only recently been established that that there is also an independent paternal contribution to long-term metabolic health. Both paternal undernutrition and overnutrition can induce metabolic phenotypes in immediate offspring, and in some cases, the induced phenotype can affect multiple generations, implying inheritance of an acquired trait. The male lineage transmission of metabolic disease risk in these cases implicates a heritable factor carried by sperm. Sperm based transmission provides a tractable system to interrogate heritable epigenetic factors influencing metabolism, and as detailed here, animal models of paternal programming have already provided some significant insights. Here, we review the evidence for paternal programming of metabolism in humans and animal models, and the available evidence on potential underlying mechanisms. Programming by paternal metabolism can be observed in multiple species across animal phyla, suggesting that this phenomenon may have a unique evolutionary significance. PMID- 28100702 TI - Zanthoxylum alkylamides ameliorate protein metabolism disorder in STZ-induced diabetic rats. AB - This study aimed to evaluate the protein metabolism effect of Zanthoxylum alkylamides and to explore the potential mechanism in streptozotocin (STZ) induced diabetic rats. Diabetic rats were orally treated with 2, 4 and 8 mg per kg bw of alkylamides daily for 28 days. Alkylamides decreased the relative weight of the liver and food intake, significantly increased the relative skeletal muscle weight and significantly decreased the blood urea nitrogen levels. Insulin, insulin-like growth factor 1, total protein (TP) and albumin (ALB), globular proteins and ALB proteins/globulin protein levels in serum significantly increased. TP, RNA content and RNA/DNA ratio significantly increased in the skeletal muscle of diabetic rats. Real-time quantitative polymerase chain reaction results indicated that alkylamides significantly increased the mRNA expression of insulin receptor (InR), IGF1 and insulin-like growth factor 1 receptor (IGF1R) in the liver and skeletal muscle. Moreover, the mRNA and protein expression levels of PI3K, PKB and mTOR significantly increased, whereas those of atrogin-1, muscle ring finger 1 and FOXO in the skeletal muscle significantly decreased. Alkylamides may advance protein synthesis by the PI3K/PKB/mTOR signalling pathway and attenuate the catabolism of protein through the ubiquitin proteasome pathway. Therefore, it was possible that alkylamides ameliorate protein metabolism disorders in diabetic rats by activating the mTOR pathway. PMID- 28100705 TI - Fine-Tuning Plant Growth in the Face of Drought. PMID- 28100704 TI - Frequency of abnormal pulmonary computed tomography findings in asylum seeking refugees in Turkey. AB - Background: Lungs are particularly vulnerable to both acute infections, including TB, and chronic diseases such as chronic obstructive pulmonary disease, as well as to malignancies, all of which require particular attention during war times in which health conditions are far from optimal. Methods: This retrospective cross sectional study included 1149 refugees that underwent thoracic computed tomography (CT) for respiratory symptoms between March 2013 and February 2015 in Turkey. Results: At least one positive CT finding was seen in 231 (20.1%) of the patients. The most common findings were chronic pulmonary changes (n=197, 17.2%), followed by findings suggestive of infections (n=39, 3.4%), and mass/nodular lesions (n=16, 1.4%). The rates of the lesions suggestive of active TB and malignancy were 1.0% (n=11) and 0.7% (n=8), respectively. Age 55-64 years was an independent significant predictor for any CT lesion, chronic changes, mass lesions, and lesions suggestive of malignancy. Age>65 years was predictive of any CT lesion and chronic changes. Conclusions: The findings of this study indicate the need for implementation of cost-effective screening strategies in refugees, particularly during war times. Screening for TB would improve disease control among both refugees and the host populations. Middle aged and older individuals, in particular, would benefit from more proactive screening tools and strategies for the early diagnosis of pulmonary malignancies and chronic lung diseases. PMID- 28100707 TI - The RLA1/SMOS1 Transcription Factor Functions with OsBZR1 to Regulate Brassinosteroid Signaling and Rice Architecture. AB - Brassinosteroids (BRs) are plant-specific steroid hormones that control plant growth and development. Recent studies have identified key components of the BR signaling pathway in Arabidopsis thaliana and in rice (Oryza sativa); however, the mechanism of BR signaling in rice, especially downstream of GSK3/SHAGGY-like kinase (GSK2), remains unclear. Here, we identified a BR-insensitive rice mutant, reduced leaf angle1 (rla1), and cloned the corresponding gene. RLA1 was identical to the previously reported SMALL ORGAN SIZE1 (SMOS1), which was cloned from another allele. RLA1/SMOS1 encodes a transcription factor with an APETALA2 DNA binding domain. Genetic analysis indicated that RLA1/SMOS1 functions as a positive regulator in the BR signaling pathway and is required for the function of BRASSINAZOLE-RESISTANT1 (OsBZR1). In addition, RLA1/SMOS1 can interact with OsBZR1 to enhance its transcriptional activity. GSK2 can interact with and phosphorylate RLA1/SMOS1 to reduce its stability. These results demonstrate that RLA1/SMOS1 acts as an integrator of the transcriptional complex directly downstream of GSK2 and plays an essential role in BR signaling and plant development in rice. PMID- 28100708 TI - The Origin of Floral Organ Identity Quartets. AB - The origin of flowers has puzzled plant biologists ever since Darwin referred to their sudden appearance in the fossil record as an abominable mystery. Flowers are considered to be an assembly of protective, attractive, and reproductive male and female leaf-like organs. Their origin cannot be understood by a morphological comparison to gymnosperms, their closest relatives, which develop separate male or female cones. Despite these morphological differences, gymnosperms and angiosperms possess a similar genetic toolbox consisting of phylogenetically related MADS domain proteins. Using ancestral MADS domain protein reconstruction, we trace the evolution of organ identity quartets along the stem lineage of crown angiosperms. We provide evidence that current floral quartets specifying male organ identity, which consist of four types of subunits, evolved from ancestral complexes of two types of subunits through gene duplication and integration of SEPALLATA proteins just before the origin of flowering plants. Our results suggest that protein interaction changes underlying this compositional shift were the result of a gradual and reversible evolutionary trajectory. Modeling shows that such compositional changes may have facilitated the evolution of the perfect, bisexual flower. PMID- 28100706 TI - OsCUL3a Negatively Regulates Cell Death and Immunity by Degrading OsNPR1 in Rice. AB - Cullin3-based RING E3 ubiquitin ligases (CRL3), composed of Cullin3 (CUL3), RBX1, and BTB proteins, are involved in plant immunity, but the function of CUL3 in the process is largely unknown. Here, we show that rice (Oryza sativa) OsCUL3a is important for the regulation of cell death and immunity. The rice lesion mimic mutant oscul3a displays a significant increase in the accumulation of flg22- and chitin-induced reactive oxygen species, and in pathogenesis-related gene expression as well as resistance to Magnaporthe oryzae and Xanthomonas oryzae pv oryzae. We cloned the OsCUL3a gene via a map-based strategy and found that the lesion mimic phenotype of oscul3a is associated with the early termination of OsCUL3a protein. Interaction assays showed that OsCUL3a interacts with both OsRBX1a and OsRBX1b to form a multisubunit CRL in rice. Strikingly, OsCUL3a interacts with and degrades OsNPR1, which acts as a positive regulator of cell death in rice. Accumulation of OsNPR1 protein is greater in the oscul3a mutant than in the wild type. Furthermore, the oscul3a osnpr1 double mutant does not exhibit the lesion mimic phenotype of the oscul3a mutant. Our data demonstrate that OsCUL3a negatively regulates cell death and immunity by degrading OsNPR1 in rice. PMID- 28100710 TI - Tree diversity affects chlorophyll a fluorescence and other leaf traits of tree species in a boreal forest. AB - An assemblage of tree species with different crown properties creates heterogeneous environments at the canopy level. Changes of functional leaf traits are expected, especially those related to light interception and photosynthesis. Chlorophyll a fluorescence (ChlF) properties in dark-adapted leaves, specific leaf area, leaf nitrogen content (N) and carbon isotope composition (delta13C) were measured on Picea abies (L.) H.Karst., Pinus sylvestris L. and Betula pendula Roth. in monospecific and mixed boreal forests in Europe, in order to test whether they were affected by stand species richness and composition. Photosynthetic efficiency, assessed by induced emission of leaf ChlF, was positively influenced in B. pendula by species richness, whereas P. abies showed higher photosynthetic efficiency in monospecific stands. Pinus sylvestris had different responses when it coexisted with P. abies or B. pendula. The presence of B. pendula, but not of P. abies, in the forest had a positive effect on the efficiency of photosynthetic electron transport and N in P. sylvestris needles, and the photosynthetic responses were positively correlated with an increase of leaf delta13C. These effects on P. sylvestris may be related to high light availability at the canopy level due to the less dense canopy of B. pendula. The different light requirements of coexisting species was the most important factor affecting the distribution of foliage in the canopy, driving the physiological responses of the mixed species. Future research directions claim to enhance the informative potential of the methods to analyse the responses of pure and mixed forests to environmental factors, including a broader set of plant species' functional traits and physiological responses. PMID- 28100709 TI - The Arabidopsis RING-Type E3 Ligase TEAR1 Controls Leaf Development by Targeting the TIE1 Transcriptional Repressor for Degradation. AB - The developmental plasticity of leaf size and shape is important for leaf function and plant survival. However, the mechanisms by which plants form diverse leaves in response to environmental conditions are not well understood. Here, we identified TIE1-ASSOCIATED RING-TYPE E3 LIGASE1 (TEAR1) and found that it regulates leaf development by promoting the degradation of TCP INTERACTOR CONTAINING EAR MOTIF PROTEIN1 (TIE1), an important repressor of CINCINNATA (CIN) like TEOSINTE BRANCHED1/CYCLOIDEA/PCF (TCP) transcription factors, which are key for leaf development. TEAR1 contains a typical C3H2C3-type RING domain and has E3 ligase activity. We show that TEAR1 interacts with the TCP repressor TIE1, which is ubiquitinated in vivo and degraded by the 26S proteasome system. We demonstrate that TEAR1 is colocalized with TIE1 in nuclei and negatively regulates TIE1 protein levels. Overexpression of TEAR1 rescued leaf defects caused by TIE1 overexpression, whereas disruption of TEAR1 resulted in leaf phenotypes resembling those caused by TIE1 overexpression or TCP dysfunction. Deficiency in TEAR partially rescued the leaf defects of TCP4 overexpression line and enhanced the wavy leaf phenotypes of jaw-5D We propose that TEAR1 positively regulates CIN-like TCP activity to promote leaf development by mediating the degradation of the TCP repressor TIE1. PMID- 28100711 TI - Effects of structural complexity on within-canopy light environments and leaf traits in a northern mixed deciduous forest. AB - Canopy structure influences forest productivity through its effects on the distribution of radiation and the light-induced changes in leaf physiological traits. Due to the difficulty of accessing and measuring forest canopies, few field-based studies have quantitatively linked these divergent scales of canopy functioning. The objective of our study was to investigate how canopy structure affects light profiles within a forest canopy and whether leaves of mature trees adjust morphologically and biochemically to the light environments characteristic of canopies with different structural complexity. We used a combination of light detection and ranging (LiDAR) data and hemispherical photographs to quantify canopy structure and light environments, respectively, and a telescoping pole to sample leaves. Leaf mass per area (LMA), nitrogen on an area basis (Narea) and chlorophyll on a mass basis (Chlmass) were measured in red maple (Acer rubrum), american beech (Fagus grandifolia), white pine (Pinus strobus), and northern red oak (Quercus rubra) at different heights in plots with similar leaf area index but contrasting canopy complexity (rugosity). We found that more complex canopies had greater porosity and reduced light variability in the midcanopy while total light interception was unchanged relative to less complex canopies. Leaf phenotypes of F. grandifolia, Q. rubra and P. strobus were more sun-acclimated in the midstory of structurally complex canopies while leaf phenotypes of A. rubrum were more shade-acclimated (lower LMA) in the upper canopy of more complex stands, despite no differences in total light interception. Broadleaf species showed further differences in acclimation with increased Narea and reduced Chlmass in leaves with higher LMA, while P. strobus showed no change in Narea and Chlmass with higher LMA. Our results provide new insight on how light distribution and leaf acclimation in mature trees might be altered when natural and anthropogenic disturbances cause structural changes in the canopy. PMID- 28100712 TI - Salt management strategy defines the stem and leaf hydraulic characteristics of six mangrove tree species. AB - Mangroves in hypersaline coastal habitats are under constant high xylem tension and face great risk of hydraulic dysfunction. To investigate the relationships between functional traits and salt management, we measured 20 hydraulic and photosynthetic traits in four salt-adapted (SA) and two non-SA (NSA) mangrove tree species in south China. The SA species included two salt secretors (SSs), Avicennia marina (Forsskal) Vierhapper and Aegiceras corniculatum (L.) Blanco and two salt excluders (SEs), Bruguiera gymnorrhiza (L.) Savigny and Kandelia obovata (L.) Sheue et al. The two NSA species were Hibiscus tiliaceus (L.) and Pongamia pinnata (L.) Merr. Extremely high xylem cavitation resistance, indicated by water potential at 50% loss of xylem conductivity (Psi50; -7.85 MPa), was found in SEs. Lower cavitation resistance was observed in SSs, and may result from incomplete salt removal that reduces the magnitude of xylem tension required to maintain water uptake from the soil. Surprisingly, the NSA species, P. pinnata, had very low Psi50 (-5.44 MPa). Compared with NSAs, SAs had lower photosynthesis, vessel density, hydraulic conductivity and vessel diameter, but higher sapwood density. Eight traits were strongly associated with species' salt management strategies, with predawn water potential (PsiPD) and mean vessel diameter accounting for 95% flow (D95) having the most significant association; D95 separated SAs from NSAs and SEs had the lowest PsiPD. There was significant coupling between hydraulic traits and carbon assimilation traits. Instead of hydraulic safety being compromised by xylem efficiency, mangrove species with higher safety had higher efficiency and greater sapwood density (rhoSapwood), but there was no relationship between rhoSapwood and efficiency. Principal component analysis differentiated the species of the three salt management strategies by loading D, D95 and vessel density on the first axis and loading PsiPD, Psi50 and water potential at 12% loss of xylem conductivity (Psi12), rhoSapwood and quantum yield on the second axis. Our results provide the first comparative characterization of hydraulic and photosynthetic traits among mangroves with different salt management strategies. PMID- 28100716 TI - Carphology. PMID- 28100717 TI - A Country Doctor's Notebook-Mikhail Bulgakov. PMID- 28100714 TI - The dynamics of the pulmonary microbiome during mechanical ventilation in the intensive care unit and the association with occurrence of pneumonia. AB - RATIONALE: Ventilator-associated pneumonia (VAP) is the most common nosocomial infections in patients admitted to the ICU. The adapted island model predicts several changes in the respiratory microbiome during intubation and mechanical ventilation. OBJECTIVES: We hypothesised that mechanical ventilation and antibiotic administration decrease the diversity of the respiratory microbiome and that these changes are more profound in patients who develop VAP. METHODS: Intubated and mechanically ventilated ICU-patients were included. Tracheal aspirates were obtained three times a week. 16S rRNA gene sequencing with the Roche 454 platform was used to measure the composition of the respiratory microbiome. Associations were tested with linear mixed model analysis and principal coordinate analysis. MEASUREMENTS AND MAIN RESULTS: 111 tracheal aspirates were obtained from 35 patients; 11 had VAP, 18 did not have VAP. Six additional patients developed pneumonia within the first 48 hours after intubation. Duration of mechanical ventilation was associated with a decrease in alpha diversity (Shannon index; fixed-effect regression coefficient (beta): -0.03 (95% CI -0.05 to -0.005)), but the administration of antibiotic therapy was not (fixed-effect beta: 0.06; 95% CI -0.17 to 0.30). There was a significant difference in change of beta diversity between patients who developed VAP and control patients for Bray-Curtis distances (p=0.03) and for Manhattan distances (p=0.04). Burkholderia, Bacillales and, to a lesser extent, Pseudomonadales positively correlated with the change in beta diversity. CONCLUSION: Mechanical ventilation, but not antibiotic administration, was associated with changes in the respiratory microbiome. Dysbiosis of microbial communities in the respiratory tract was most profound in patients who developed VAP. PMID- 28100713 TI - AHRR (cg05575921) hypomethylation marks smoking behaviour, morbidity and mortality. AB - RATIONALE AND OBJECTIVES: Self-reported smoking underestimates disease risk. Smoking affects DNA methylation, in particular the cg05575921 site in the aryl hydrocarbon receptor repressor (AHRR) gene. We tested the hypothesis that AHRR cg05575921 hypomethylation is associated with risk of smoking-related morbidity and mortality. METHODS: From the Copenhagen City Heart Study representing the Danish general population, we studied 9234 individuals. Using bisulphite treated leucocyte DNA, AHRR (cg05575921) methylation was measured. Rs1051730 (CHRN3A) genotype was used to evaluate smoking heaviness. Participants were followed for up to 22 years for exacerbations of COPD, event of lung cancer and all-cause mortality. Six-year lung cancer risk was calculated according to the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCOM2012). MEASUREMENTS AND MAIN RESULTS: AHRR (cg05575921) hypomethylation was associated with former and current smoking status, high daily and cumulative smoking, short time since smoking cessation (all p values <7*10-31), and the smoking-related CHRN3A genotype (-0.48% per T-allele, p=0.002). The multifactorially adjusted HRs for the lowest versus highest methylation quintiles were 4.58 (95% CI 2.83 to 7.42) for COPD exacerbations, 4.87 (2.31 to 10.3) for lung cancer and 1.67 (1.48 to 1.88) for all-cause mortality. Finally, among 2576 high-risk smokers eligible for lung cancer screening by CT, observed cumulative incidences of lung cancer after 6 years for individuals in the lowest and highest methylation quintiles were 3.7% and 0.0% (p=2*10-7), whereas predicted PLCOM2012 6-year risks were similar (4.3% and 4.4%, p=0.77). CONCLUSION: AHRR (cg05575921) hypomethylation, a marker of smoking behaviour, provides potentially clinical relevant predictions of future smoking-related morbidity and mortality. PMID- 28100718 TI - ABN News. PMID- 28100719 TI - Testing for departure from uniformity and estimating mean direction for circular data. AB - Although circular data are common in biological studies, the analysis of such data is often more rudimentary than it need be. One of the most common hypotheses tested is whether the data suggest that samples are clustered around a certain specified direction, rather than being uniformly spread across all possible directions. Here, I use data from a recent publication on the compass directions of epiphytes and mistletoes on tree trunks. This is used to demonstrate how with relatively little extra work researchers can improve the rigour of testing such hypotheses, and this improved rigour can lead to biological insights missed by simpler analyses. Specifically, I highlight that a much broader range of null hypotheses can be tested than current practice, and that a range of methods are available for estimating a confidence interval for mean direction. I offer advice on appropriate selection for both tests and parameter estimation methods, and highlight the need to correct for the fact that sample estimates are biased estimates of population parameters for circular data. PMID- 28100720 TI - Audience affects decision-making in a marmoset communication network. AB - An audience can have a profound effect on the dynamics of communicative interactions. As a result, non-human primates often adjust their social decision making strategies depending on the audience composition at a given time. Here we sought to test how the unique vocal behaviour of multiple audience members affected decisions to communicate. To address this issue, we developed a novel experimental paradigm in which common marmosets directly interacted with multiple 'virtual monkeys' (VMs), each of whom represented an individual marmoset with distinct vocal behaviour. This active social signalling paradigm provided subjects an opportunity to interact with and learn about the behaviour of each VM in the network and apply this knowledge in subsequent communicative decisions. We found that subjects' propensity to interact with particular VMs was determined by the behaviour of each VM in the audience and suggests that marmoset social decision-making strategies are highly adaptive to nuances of the immediate communication network. PMID- 28100721 TI - Meta-analysis of timing of endovascular aneurysm treatment in subarachnoid haemorrhage: inconsistent results of early treatment within 1 day. AB - BACKGROUND AND PURPOSE: To systematically review and meta-analyse the data on impact of timing of endovascular treatment in aneurysmal subarachnoid haemorrhage (SAH) to determine if earlier treatment is associated with improved clinical outcomes and reduced case fatality. METHODS: We searched MEDLINE, Cochrane database, EMBASE and Web of Science to identify studies for inclusion. The measures of effect utilised were unadjusted/adjusted ORs. Effect estimates were combined using random effects models for each outcome (poor outcome, case fatality); heterogeneity was assessed using the I2 index. Subgroup and sensitivity analyses were performed to account for heterogeneity and risk of bias. RESULTS: 16 studies met the inclusion criteria. Treatment <1 day was associated with a reduced odds of poor outcome compared with treatment >1 day (OR=0.40 (95% CI 0.28 to 0.56; I2=0%)) but not when compared with treatment at 1 3 days (OR=1.16 (95% CI 0.47 to 2.90; I2=81%)). Treatment at <2 days and at <3 days were associated with similar odds of poor outcome compared with later treatment (OR=1.20 (95% CI 0.70 to 2.05; I2=73%; OR=0.71 (95% CI 0.36 to 1.37; I2=71%)). Early treatment was associated with similar odds of case fatality compared with later treatment, regardless of how early/late treatment were defined (OR=1.80 (95% CI 0.88 to 3.67; I2=34%) for treatment <1 day vs days 1-3; OR=1.71 (95% CI 0.72 to 4.03; I2=54%) for treatment <2 days vs later; OR=0.90 (95% CI 0.31 to 2.68; I2=48%) for treatment <3 days vs later). CONCLUSIONS: In only 1 of the analyses was there a statistically significant result, which favoured treatment <1 day. The inconsistent results and heterogeneity within most analyses highlight the lack of evidence for best timing of endovascular treatment in SAH patients. PMID- 28100724 TI - Transient smartphone blindness: Relevance to misdiagnosis in neurologic practice. PMID- 28100723 TI - A respiratory-gated micro-CT comparison of respiratory patterns in free-breathing and mechanically ventilated rats. AB - In this study, we aim to quantify the differences in lung metrics measured in free-breathing and mechanically ventilated rodents using respiratory-gated micro computed tomography. Healthy male Sprague-Dawley rats were anesthetized with ketamine/xylazine and scanned with a retrospective respiratory gating protocol on a GE Locus Ultra micro-CT scanner. Each animal was scanned while free-breathing, then intubated and mechanically ventilated (MV) and rescanned with a standard ventilation protocol (56 bpm, 8 mL/kg and PEEP of 5 cm H2O) and again with a ventilation protocol that approximates the free-breathing parameters (88 bpm, 2.14 mL/kg and PEEP of 2.5 cm H2O). Images were reconstructed representing inspiration and end expiration with 0.15 mm voxel spacing. Image-based measurements of the lung lengths, airway diameters, lung volume, and air content were compared and used to calculate the functional residual capacity (FRC) and tidal volume. Images acquired during MV appeared darker in the airspaces and the airways appeared larger. Image-based measurements showed an increase in lung volume and air content during standard MV, for both respiratory phases, compared with matched MV and free-breathing. Comparisons of the functional metrics showed an increase in FRC for mechanically ventilated rats, but only the standard MV exhibited a significantly higher tidal volume than free-breathing or matched MV Although standard mechanical ventilation protocols may be useful in promoting consistent respiratory patterns, the amount of air in the lungs is higher than in free-breathing animals. Matching the respiratory patterns with the free-breathing case allowed similar lung morphology and physiology measurements while reducing the variability in the measurements. PMID- 28100726 TI - Decreased intestinal acetylcholinesterase in early Parkinson disease: An 11C donepezil PET study. AB - OBJECTIVE: To investigate systemic levels of acetylcholinesterase in early Parkinson disease (PD) with 11C-donepezil PET, a potential marker of parasympathetic innervation. METHODS: This was a cross-sectional study with 19 patients with early-stage PD (disease duration 1.5 +/- 0.6 years) and 16 age matched controls who had clinical assessments, olfaction tests, and 11C-donepezil PET to measure acetylcholinesterase density in peripheral organs. RESULTS: The patients with PD showed significantly reduced 11C-donepezil uptake in the small intestine (-14%, p = 0.018), colon (-22%, p < 0.001), and kidneys (-14%, p = 0.028). No difference in myocardial or pancreatic acetylcholinesterase levels was seen. CONCLUSION: We found significantly decreased 11C-donepezil signal in the intestine and kidneys of patients with early PD, suggesting that parasympathetic denervation is present early in the disease course. PMID- 28100725 TI - Genome-wide association study identifies MAPT locus influencing human plasma tau levels. AB - OBJECTIVE: To identify genetic loci associated with plasma tau concentrations in healthy elders and individuals with Alzheimer disease. METHODS: Four hundred sixty-three non-Hispanic white individuals exceeding quality control criteria were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI-1) cohort. Association of plasma tau with genetic polymorphisms was performed with a linear regression model. Significant associations were validated in an independent replication cohort consisting of 431 healthy elders or individuals with mild cognitive impairment recruited from the University of California, San Francisco Memory and Aging Center. RESULTS: The minor allele (A) of rs242557 in the microtubule-associated protein tau gene (MAPT) was associated with higher plasma tau levels at genome-wide significance (p = 4.85 * 10-9, empiric family wise error corrected p = 0.0024) in a dose-dependent fashion. This association was also observed in the replication cohort (p = 1.0 * 10-5; joint analysis p = 1.2 * 10-12). Single nucleotide polymorphisms near PARK2 (rs2187213) (p = 6.15 * 10-6), IL2RA (rs7072793, rs7073236) (p = 7.89 * 10-6), and an intergenic locus on 9p21.3 (rs7047280) (p = 8.13 * 10-6) were identified as suggestive loci associated with plasma tau levels. CONCLUSIONS: MAPT H1c haplotype (rs242557) has previously been identified as a genetic risk factor for progressive supranuclear palsy and corticobasal degeneration. The current findings suggest that plasma tau concentration could be an endophenotype for identifying risk for 4-repeat tauopathies in older individuals. PMID- 28100729 TI - Toward quantitative MRI analysis: A smart approach to characterize neonatal white matter injury. PMID- 28100728 TI - Direct cortical stimulation of human posteromedial cortex. AB - BACKGROUND: The posteromedial cortex (PMC) is a collective term for an anatomically heterogeneous area of the brain constituting a core node of the human default mode network (DMN), which is engaged during internally focused subjective cognition such as autobiographical memory. METHODS: We explored the effects of causal perturbations of PMC with direct electric brain stimulation (EBS) during presurgical epilepsy monitoring with intracranial EEG electrodes. RESULTS: Data were collected from 885 stimulations in 25 patients implanted with intracranial electrodes across the PMC. While EBS of regions immediately dorsal or ventral to the PMC reliably produced somatomotor or visual effects, respectively, we found no observable behavioral or subjectively reported effects when sites within the boundaries of PMC were electrically perturbed. In each patient, null effects of PMC stimulation were observed for sites in which intracranial recordings had clearly demonstrated electrophysiologic responses during autobiographical recall. CONCLUSIONS: Direct electric modulation of the human PMC produced null effects when standard functional mapping methods were used. More sophisticated stimulation paradigms (e.g., EBS during experimental cognitive tests) will be required for testing the causal contribution of PMC to human cognition and subjective experience. Nonetheless, our findings suggest that some extant theories of PMC and DMN contribution to human awareness and subjective conscious states require cautious re-examination. PMID- 28100727 TI - Quantitative assessment of white matter injury in preterm neonates: Association with outcomes. AB - OBJECTIVE: To quantitatively assess white matter injury (WMI) volume and location in very preterm neonates, and to examine the association of lesion volume and location with 18-month neurodevelopmental outcomes. METHODS: Volume and location of WMI was quantified on MRI in 216 neonates (median gestational age 27.9 weeks) who had motor, cognitive, and language assessments at 18 months corrected age (CA). Neonates were scanned at 32.1 postmenstrual weeks (median) and 68 (31.5%) had WMI; of 66 survivors, 58 (87.9%) had MRI and 18-month outcomes. WMI was manually segmented and transformed into a common image space, accounting for intersubject anatomical variability. Probability maps describing the likelihood of a lesion predicting adverse 18-month outcomes were developed. RESULTS: WMI occurs in a characteristic topology, with most lesions occurring in the periventricular central region, followed by posterior and frontal regions. Irrespective of lesion location, greater WMI volumes predicted poor motor outcomes (p = 0.001). Lobar regional analysis revealed that greater WMI volumes in frontal, parietal, and temporal lobes have adverse motor outcomes (all, p < 0.05), but only frontal WMI volumes predicted adverse cognitive outcomes (p = 0.002). To account for lesion location and volume, voxel-wise odds ratio (OR) maps demonstrate that frontal lobe lesions predict adverse cognitive and language development, with maximum odds ratios (ORs) of 78.9 and 17.5, respectively, while adverse motor outcomes are predicted by widespread injury, with maximum OR of 63.8. CONCLUSIONS: The predictive value of frontal lobe WMI volume highlights the importance of lesion location when considering the neurodevelopmental significance of WMI. Frontal lobe lesions are of particular concern. PMID- 28100730 TI - Sleep to Remember. AB - Scientific investigation into the possible role of sleep in memory consolidation began with the early studies of Jenkins and Dallenbach (1924). Despite nearly a century of investigation with a waxing and waning of interest, the role of sleep in memory processing remains controversial and elusive. This review provides the historical background for current views and considers the relative contribution of two sleep states, rapid eye movement sleep and slow-wave sleep, to offline memory processing. The sequential hypothesis, until now largely ignored, is discussed, and recent literature supporting this view is reviewed. PMID- 28100732 TI - Acute Stress Shapes Synaptic Inhibition within an Amygdala Microcircuit. PMID- 28100733 TI - Training Microglia to Resist Alzheimer's Disease. PMID- 28100731 TI - Sleep Is for Forgetting. AB - It is possible that one of the essential functions of sleep is to take out the garbage, as it were, erasing and "forgetting" information built up throughout the day that would clutter the synaptic network that defines us. It may also be that this cleanup function of sleep is a general principle of neuroscience, applicable to every creature with a nervous system. PMID- 28100734 TI - Does the Superior Colliculus Control Perceptual Sensitivity or Choice Bias during Attention? Evidence from a Multialternative Decision Framework. AB - : Distinct networks in the forebrain and the midbrain coordinate to control spatial attention. The critical involvement of the superior colliculus (SC)-the central structure in the midbrain network-in visuospatial attention has been shown by four seminal, published studies in monkeys (Macaca mulatta) performing multialternative tasks. However, due to the lack of a mechanistic framework for interpreting behavioral data in such tasks, the nature of the SC's contribution to attention remains unclear. Here we present and validate a novel decision framework for analyzing behavioral data in multialternative attention tasks. We apply this framework to re-examine the behavioral evidence from these published studies. Our model is a multidimensional extension to signal detection theory that distinguishes between two major classes of attentional mechanisms: those that alter the quality of sensory information or "sensitivity," and those that alter the selective gating of sensory information or "choice bias." Model-based simulations and model-based analyses of data from these published studies revealed a converging pattern of results that indicated that choice-bias changes, rather than sensitivity changes, were the primary outcome of SC manipulation. Our results suggest that the SC contributes to attentional performance predominantly by generating a spatial choice bias for stimuli at a selected location, and that this bias operates downstream of forebrain mechanisms that enhance sensitivity. The findings lead to a testable mechanistic framework of how the midbrain and forebrain networks interact to control spatial attention. SIGNIFICANCE STATEMENT: Attention involves the selection of the most relevant information for differential sensory processing and decision making. While the mechanisms by which attention alters sensory encoding (sensitivity control) are well studied, the mechanisms by which attention alters decisional weighting of sensory evidence (choice-bias control) are poorly understood. Here, we introduce a model of multialternative decision making that distinguishes bias from sensitivity effects in attention tasks. With our model, we simulate experimental data from four seminal studies that microstimulated or inactivated a key attention-related midbrain structure, the superior colliculus (SC). We demonstrate that the experimental effects of SC manipulation are entirely consistent with the SC controlling attention by changing choice bias, thereby shedding new light on how the brain mediates attention. PMID- 28100735 TI - Neural Tuning to Numerosity Relates to Perceptual Tuning in 3-6-Year-Old Children. AB - : Neural representations of approximate numerical value, or numerosity, have been observed in the intraparietal sulcus (IPS) in monkeys and humans, including children. Using functional magnetic resonance imaging, we show that children as young as 3-4 years old exhibit neural tuning to cardinal numerosities in the IPS and that their neural responses are accounted for by a model of numerosity coding that has been used to explain neural responses in the adult IPS. We also found that the sensitivity of children's neural tuning to number in the right IPS was comparable to their numerical discrimination sensitivity observed behaviorally, outside of the scanner. Children's neural tuning curves in the right IPS were significantly sharper than in the left IPS, indicating that numerical representations are more precise and mature more rapidly in the right hemisphere than in the left. Further, we show that children's perceptual sensitivity to numerosity can be predicted by the development of their neural sensitivity to numerosity. This research provides novel evidence of developmental continuity in the neural code underlying numerical representation and demonstrates that children's neural sensitivity to numerosity is related to their cognitive development. SIGNIFICANCE STATEMENT: Here we test for the existence of neural tuning to numerosity in the developing brain in the youngest sample of children tested with fMRI to date. Although previous research shows evidence of numerical distance effects in the intraparietal sulcus of the developing brain, those effects could be explained by patterns of neural activity that do not represent neural tuning to numerosity. These data provide the first robust evidence that from as early as 3-4 years of age there is developmental continuity in how the intraparietal sulcus represents the values of numerosities. Moreover, the study goes beyond previous research by examining the relation between neural tuning and perceptual tuning in children. PMID- 28100736 TI - Methyl-CpG-Binding Protein MBD1 Regulates Neuronal Lineage Commitment through Maintaining Adult Neural Stem Cell Identity. AB - : Methyl-CpG-binding domain 1 (MBD1) belongs to a family of methyl-CpG-binding proteins that are epigenetic "readers" linking DNA methylation to transcriptional regulation. MBD1 is expressed in neural stem cells residing in the dentate gyrus of the adult hippocampus (aNSCs) and MBD1 deficiency leads to reduced neuronal differentiation, impaired neurogenesis, learning deficits, and autism-like behaviors in mice; however, the precise function of MBD1 in aNSCs remains unexplored. Here, we show that MBD1 is important for maintaining the integrity and stemness of NSCs, which is critical for their ability to generate neurons. MBD1 deficiency leads to the accumulation of undifferentiated NSCs and impaired transition into the neuronal lineage. Transcriptome analysis of neural stem and progenitor cells isolated directly from the dentate gyrus of MBD1 mutant (KO) and WT mice showed that gene sets related to cell differentiation, particularly astrocyte lineage genes, were upregulated in KO cells. We further demonstrated that, in NSCs, MBD1 binds and represses directly specific genes associated with differentiation. Our results suggest that MBD1 maintains the multipotency of NSCs by restraining the onset of differentiation genes and that untimely expression of these genes in MBD1-deficient stem cells may interfere with normal cell lineage commitment and cause the accumulation of undifferentiated cells. Our data reveal a novel role for MBD1 in stem cell maintenance and provide insight into how epigenetic regulation contributes to adult neurogenesis and the potential impact of its dysregulation. SIGNIFICANCE STATEMENT: Adult neural stem cells (aNSCs) in the hippocampus self-renew and generate neurons throughout life. We show that methyl-CpG-binding domain 1 (MBD1), a DNA methylation "reader," is important for maintaining the integrity of NSCs, which is critical for their neurogenic potency. Our data reveal a novel role for MBD1 in stem cell maintenance and provide insight into how epigenetic regulation preserves the multipotency of stem cells for subsequent differentiation. PMID- 28100737 TI - Selectivity in Postencoding Connectivity with High-Level Visual Cortex Is Associated with Reward-Motivated Memory. AB - : Reward motivation has been demonstrated to enhance declarative memory by facilitating systems-level consolidation. Although high-reward information is often intermixed with lower reward information during an experience, memory for high value information is prioritized. How is this selectivity achieved? One possibility is that postencoding consolidation processes bias memory strengthening to those representations associated with higher reward. To test this hypothesis, we investigated the influence of differential reward motivation on the selectivity of postencoding markers of systems-level memory consolidation. Human participants encoded intermixed, trial-unique memoranda that were associated with either high or low-value during fMRI acquisition. Encoding was interleaved with periods of rest, allowing us to investigate experience-dependent changes in connectivity as they related to later memory. Behaviorally, we found that reward motivation enhanced 24 h associative memory. Analysis of patterns of postencoding connectivity showed that, even though learning trials were intermixed, there was significantly greater connectivity with regions of high level, category-selective visual cortex associated with high-reward trials. Specifically, increased connectivity of category-selective visual cortex with both the VTA and the anterior hippocampus predicted associative memory for high- but not low-reward memories. Critically, these results were independent of encoding-related connectivity and univariate activity measures. Thus, these findings support a model by which the selective stabilization of memories for salient events is supported by postencoding interactions with sensory cortex associated with reward. SIGNIFICANCE STATEMENT: Reward motivation is thought to promote memory by supporting memory consolidation. Yet, little is known as to how brain selects relevant information for subsequent consolidation based on reward. We show that experience-dependent changes in connectivity of both the anterior hippocampus and the VTA with high-level visual cortex selectively predicts memory for high-reward memoranda at a 24 h delay. These findings provide evidence for a novel mechanism guiding the consolidation of memories for valuable events, namely, postencoding interactions between neural systems supporting mesolimbic dopamine activation, episodic memory, and perception. PMID- 28100738 TI - miR-142-3p Is a Key Regulator of IL-1beta-Dependent Synaptopathy in Neuroinflammation. AB - : MicroRNAs (miRNA) play an important role in post-transcriptional gene regulation of several physiological and pathological processes. In multiple sclerosis (MS), a chronic inflammatory and degenerative disease of the CNS, and in its mouse model, the experimental autoimmune encephalomyelitis (EAE), miRNA dysregulation has been mainly related to immune system dysfunction and white matter (WM) pathology. However, little is known about their role in gray matter pathology. Here, we explored miRNA involvement in the inflammation-driven alterations of synaptic structure and function, collectively known as synaptopathy, a neuropathological process contributing to excitotoxic neurodegeneration in MS/EAE. Particularly, we observed that miR-142-3p is increased in the CSF of patients with active MS and in EAE brains. We propose miR 142-3p as a molecular mediator of the IL-1beta-dependent downregulation of the glial glutamate-aspartate transporter (GLAST), which causes an enhancement of the glutamatergic transmission in the EAE cerebellum. The synaptic abnormalities mediated by IL-1beta and the clinical and neuropathological manifestations of EAE disappeared in miR-142 knock-out mice. Furthermore, we observed that in vivo miR 142-3p inhibition, either by a preventive and local treatment or by a therapeutic and systemic strategy, abolished IL-1beta- and GLAST-dependent synaptopathy in EAE wild-type mice. Consistently, miR-142-3p was responsible for the glutamatergic synaptic alterations caused by CSF of patients with MS, and CSF levels of miR-142-3p correlated with prospective MS disease progression. Our findings highlight miR-142-3p as key molecular player in IL-1beta-mediated synaptic dysfunction, possibly leading to excitotoxic damage in both EAE and MS diseases. Inhibition of miR-142-3p could be neuroprotective in MS. SIGNIFICANCE STATEMENT: Current studies suggest the role of glutamate excitotoxicity in the development and progression of multiple sclerosis (MS) and of its mouse model experimental autoimmune encephalomyelitis (EAE). The molecular mechanisms linking inflammation and synaptic alterations in MS/EAE are still unknown. Here, we identified miR-142-3p as a determinant molecular actor in inflammation-dependent synaptopathy typical of both MS and EAE. miR-142-3p was upregulated in the CSF of MS patients and in EAE cerebellum. Inhibition of miR-142-3p, locally in EAE brain and in a MS chimeric ex vivo model, recovered glutamatergic synaptic enhancement typical of EAE/MS. We proved that miR-142-3p promoted the IL-1beta-dependent glutamate dysfunction by targeting glutamate-aspartate transporter (GLAST), a crucial glial transporter involved in glutamate homeostasis. Finally, we suggest miR-142-3p as a negative prognostic factor in patients with relapsing-remitting multiple sclerosis. PMID- 28100739 TI - Action Categories in Lateral Occipitotemporal Cortex Are Organized Along Sociality and Transitivity. AB - : How neural specificity for distinct conceptual knowledge categories arises is central for understanding the organization of semantic memory in the human brain. Although there is a large body of research on the neural processing of distinct object categories, the organization of action categories remains largely unknown. In particular, it is unknown whether different action categories follow a specific topographical organization on the cortical surface analogously to the category-specific organization of object knowledge. Here, we tested whether the neural representation of action knowledge is organized in terms of nonsocial versus social and object-unrelated versus object-related actions (sociality and transitivity, respectively, hereafter). We hypothesized a major distinction of sociality and transitivity along dorsal and ventral lateral occipitotemporal cortex (LOTC), respectively. Using fMRI-based multivoxel pattern analysis, we identified neural representations of action information associated with sociality and transitivity in bilateral LOTC. Representational similarity analysis revealed a dissociation between dorsal and ventral LOTC. We found that action representations in dorsal LOTC are segregated along features of sociality, whereas action representations in ventral LOTC are segregated along features of transitivity. In addition, representations of sociality and transitivity features were found more anteriorly in LOTC than representations of specific subtypes of actions, suggesting a posterior-anterior gradient from concrete to abstract action features. These findings elucidate how the neural representations of perceptually and conceptually diverse actions are organized in distinct subsystems in the LOTC. SIGNIFICANCE STATEMENT: The lateral occipitotemporal cortex (LOTC) is critically involved in the recognition of objects and actions, but our knowledge about the underlying organizing principles is limited. Here, we discovered a dorsal-ventral distinction of actions in LOTC: dorsal LOTC represents actions based on sociality (how much an action is directed to another person) in proximity to person knowledge. In contrast, ventral LOTC represents actions based on transitivity (how much an action involves the interaction with inanimate objects) in proximity to tools/artifacts in ventral LOTC, suggesting a mutually dependent organization of actions and objects. In addition, we found a posterior-to-anterior organization of the LOTC for concrete and abstract representations, respectively. Our findings provide important insights about the organization of actions in LOTC. PMID- 28100740 TI - Epilepsy-Associated KCNQ2 Channels Regulate Multiple Intrinsic Properties of Layer 2/3 Pyramidal Neurons. AB - : KCNQ2 potassium channels are critical for normal brain function, as both loss of-function and gain-of-function KCNQ2 variants can lead to various forms of neonatal epilepsy. Despite recent progress, the full spectrum of consequences as a result of KCNQ2 dysfunction in neocortical pyramidal neurons is still unknown. Here, we report that conditional ablation of Kcnq2 from mouse neocortex leads to hyperexcitability of layer 2/3 (L2/3) pyramidal neurons, exhibiting an increased input resistance and action potential frequency, as well as a reduced medium afterhyperpolarization (mAHP), a conductance partly mediated by KCNQ2 channels. Importantly, we show that introducing the KCNQ2 loss-of-function variant KCNQ2I205V into L2/3 pyramidal neurons using in utero electroporation also results in a hyperexcitable phenotype similar to the conditional knock-out. KCNQ2I205V has a right-shifted conductance-to-voltage relationship, suggesting loss of KCNQ2 channel activity at subthreshold membrane potentials is sufficient to drive large changes in L2/3 pyramidal neuronal excitability even in the presence of an intact mAHP. We also found that the changes in excitability following Kcnq2 ablation are accompanied by alterations at action potential properties, including action potential amplitude in Kcnq2-null neurons. Importantly, partial inhibition of Nav1.6 channels was sufficient to counteract the hyperexcitability of Kcnq2-null neurons. Therefore, our work shows that loss of KCNQ2 channels alters the intrinsic neuronal excitability and action potential properties of L2/3 pyramidal neurons, and identifies Nav1.6 as a new potential molecular target to reduce excitability in patients with KCNQ2 encephalopathy. SIGNIFICANCE STATEMENT: KCNQ2 channels are critical for the development of normal brain function, as KCNQ2 variants could lead to epileptic encephalopathy. However, the role of KCNQ2 channels in regulating the properties of neocortical neurons is largely unexplored. Here, we find that Kcnq2 ablation or loss-of function at subthreshold membrane potentials leads to increased neuronal excitability of neocortical layer 2/3 (L2/3) pyramidal neurons. We also demonstrate that Kcnq2 ablation unexpectedly leads to a larger action potential amplitude. Importantly, we propose the Nav1.6 channel as a new molecular target for patients with KCNQ2 encephalopathy, as partial inhibition of these channels counteracts the increased L2/3 pyramidal neuron hyperexcitability of Kcnq2-null neurons. PMID- 28100741 TI - Control of Spike Transfer at Hippocampal Mossy Fiber Synapses In Vivo by GABAA and GABAB Receptor-Mediated Inhibition. AB - : Despite extensive studies in hippocampal slices and incentive from computational theories, the synaptic mechanisms underlying information transfer at mossy fiber (mf) connections between the dentate gyrus (DG) and CA3 neurons in vivo are still elusive. Here we used an optogenetic approach in mice to selectively target and control the activity of DG granule cells (GCs) while performing whole-cell and juxtacellular recordings of CA3 neurons in vivo In CA3 pyramidal cells (PCs), mf-CA3 synaptic responses consisted predominantly of an IPSP at low stimulation frequency (0.05 Hz). Upon increasing the frequency of stimulation, a biphasic response was observed consisting of a brief mf EPSP followed by an inhibitory response lasting on the order of 100 ms. Spike transfer at DG-CA3 interneurons recorded in the juxtacellular mode was efficient at low presynaptic stimulation frequency and appeared insensitive to an increased frequency of GC activity. Overall, this resulted in a robust and slow feedforward inhibition of spike transfer at mf-CA3 pyramidal cell synapses. Short-term plasticity of EPSPs with increasing frequency of presynaptic activity allowed inhibition to be overcome to reach spike discharge in CA3 PCs. Whereas the activation of GABAA receptors was responsible for the direct inhibition of light evoked spike responses, the slow inhibition of spiking activity required the activation of GABAB receptors in CA3 PCs. The slow inhibitory response defined an optimum frequency of presynaptic activity for spike transfer at ~10 Hz. Altogether these properties define the temporal rules for efficient information transfer at DG-CA3 synaptic connections in the intact circuit. SIGNIFICANCE STATEMENT: Activity-dependent changes in synaptic strength constitute a basic mechanism for memory. Synapses from the dentate gyrus (DG) to the CA3 area of the hippocampus are distinctive for their prominent short-term plasticity, as studied in slices. Plasticity of DG-CA3 connections may assist in the encoding of precise memory in the CA3 network. Here we characterize DG-CA3 synaptic transmission in vivo using targeted optogenetic activation of DG granule cells while recording in whole-cell patch-clamp and juxtacellular configuration from CA3 pyramidal cells and interneurons. We show that, in vivo, short-term plasticity of excitatory inputs to CA3 pyramidal cells combines with robust feedforward inhibition mediated by both GABAA and GABAB receptors to control the efficacy and temporal rules for information transfer at DG-CA3 connections. PMID- 28100742 TI - Visual Sampling Predicts Hippocampal Activity. AB - : Eye movements serve to accumulate information from the visual world, contributing to the formation of coherent memory representations that support cognition and behavior. The hippocampus and the oculomotor network are well connected anatomically through an extensive set of polysynaptic pathways. However, the extent to which visual sampling behavior is related to functional responses in the hippocampus during encoding has not been studied directly in human neuroimaging. In the current study, participants engaged in a face processing task while brain responses were recorded with fMRI and eye movements were monitored simultaneously. The number of gaze fixations that a participant made on a given trial was correlated significantly with hippocampal activation such that more fixations were associated with stronger hippocampal activation. Similar results were also found in the fusiform face area, a face-selective perceptual processing region. Notably, the number of fixations was associated with stronger hippocampal activation when the presented faces were novel, but not when the faces were repeated. Increases in fixations during viewing of novel faces also led to larger repetition-related suppression in the hippocampus, indicating that this fixation-hippocampal relationship may reflect the ongoing development of lasting representations. Together, these results provide novel empirical support for the idea that visual exploration and hippocampal binding processes are inherently linked. SIGNIFICANCE STATEMENT: The hippocampal and oculomotor networks have each been studied extensively for their roles in the binding of information and gaze function, respectively. Despite the evidence that individuals with amnesia whose damage includes the hippocampus show alterations in their eye movement patterns and recent findings that the two systems are anatomically connected, it has not been demonstrated whether visual exploration is related to hippocampal activity in neurologically intact adults. In this combined fMRI-eye-tracking study, we show how hippocampal responses scale with the number of gaze fixations made during viewing of novel, but not repeated, faces. These findings provide new evidence suggesting that the hippocampus plays an important role in the binding of information, as sampled by gaze fixations, during visual exploration. PMID- 28100743 TI - Three Small-Receptive-Field Ganglion Cells in the Mouse Retina Are Distinctly Tuned to Size, Speed, and Object Motion. AB - : Retinal ganglion cells (RGCs) are frequently divided into functional types by their ability to extract and relay specific features from a visual scene, such as the capacity to discern local or global motion, direction of motion, stimulus orientation, contrast or uniformity, or the presence of large or small objects. Here we introduce three previously uncharacterized, nondirection-selective ON-OFF RGC types that represent a distinct set of feature detectors in the mouse retina. The three high-definition (HD) RGCs possess small receptive-field centers and strong surround suppression. They respond selectively to objects of specific sizes, speeds, and types of motion. We present comprehensive morphological characterization of the HD RGCs and physiological recordings of their light responses, receptive-field size and structure, and synaptic mechanisms of surround suppression. We also explore the similarities and differences between the HD RGCs and a well characterized RGC with a comparably small receptive field, the local edge detector, in response to moving objects and textures. We model populations of each RGC type to study how they differ in their performance tracking a moving object. These results, besides introducing three new RGC types that together constitute a substantial fraction of mouse RGCs, provide insights into the role of different circuits in shaping RGC receptive fields and establish a foundation for continued study of the mechanisms of surround suppression and the neural basis of motion detection. SIGNIFICANCE STATEMENT: The output cells of the retina, retinal ganglion cells (RGCs), are a diverse group of ~40 distinct neuron types that are often assigned "feature detection" profiles based on the specific aspects of the visual scene to which they respond. Here we describe, for the first time, morphological and physiological characterization of three new RGC types in the mouse retina, substantially augmenting our understanding of feature selectivity. Experiments and modeling show that while these three "high definition" RGCs share certain receptive-field properties, they also have distinct tuning to the size, speed, and type of motion on the retina, enabling them to occupy different niches in stimulus space. PMID- 28100744 TI - Compensatory Activation of Cannabinoid CB2 Receptor Inhibition of GABA Release in the Rostral Ventromedial Medulla in Inflammatory Pain. AB - : The rostral ventromedial medulla (RVM) is a relay in the descending pain modulatory system and an important site of endocannabinoid modulation of pain. Endocannabinoids inhibit GABA release in the RVM, but it is not known whether this effect persists in chronic pain states. In the present studies, persistent inflammation induced by complete Freund's adjuvant (CFA) increased GABAergic miniature IPSCs (mIPSCs). Endocannabinoid activation of cannabinoid (CB1) receptors known to inhibit presynaptic GABA release was significantly reduced in the RVM of CFA-treated rats compared with naive rats. The reduction in CFA treated rats correlated with decreased CB1 receptor protein expression and function in the RVM. Paradoxically, the nonselective CB1/CB2 receptor agonist WIN55212 inhibited GABAergic mIPSCs in both naive and CFA-treated rats. However, WIN55212 inhibition was reversed by the CB1 receptor antagonist rimonabant in naive rats but not in CFA-treated rats. WIN55212-mediated inhibition in CFA treated rats was blocked by the CB2 receptor-selective antagonist SR144528, indicating that CB2 receptor function in the RVM is increased during persistent inflammation. Consistent with these results, CB2 receptor agonists AM1241 and GW405833 inhibited GABAergic mIPSC frequency only in CFA-treated rats, and the inhibition was reversed with SR144528. When administered alone, SR144528 and another CB2 receptor-selective antagonist AM630 increased mIPSC frequency in the RVM of CFA-treated rats, indicating that CB2 receptors are tonically activated by endocannabinoids. Our data provide evidence that CB2 receptor function emerges in the RVM in persistent inflammation and that selective CB2 receptor agonists may be useful for treatment of persistent inflammatory pain. SIGNIFICANCE STATEMENT: These studies demonstrate that endocannabinoid signaling to CB1 and CB2 receptors in adult rostral ventromedial medulla is altered in persistent inflammation. The emergence of CB2 receptor function in the rostral ventromedial medulla provides additional rationale for the development of CB2 receptor-selective agonists as useful therapeutics for chronic inflammatory pain. PMID- 28100745 TI - Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease. AB - : Neuroinflammation is an important contributor to Alzheimer's disease (AD) pathogenesis, as underscored by the recent identification of immune-related genetic risk factors for AD, including coding variants in the gene TREM2 (triggering receptor expressed on myeloid cells 2). Understanding TREM2 function promises to provide important insights into how neuroinflammation contributes to AD pathology. However, studies so far have produced seemingly conflicting results, with reports that amyloid pathology can be both decreased and increased in TREM2-deficient AD mouse models. In this study, we unify these previous findings by demonstrating that TREM2 deficiency ameliorates amyloid pathology early, but exacerbates it late in disease progression in the APPPS1-21 mouse model of AD. We also demonstrate that TREM2 deficiency decreases plaque associated myeloid cell accumulation by reducing cell proliferation, specifically late in pathology. In addition, TREM2 deficiency reduces myeloid cell internalization of amyloid throughout pathology, but decreases inflammation related gene transcript levels selectively late in disease progression. Together, these results suggest that TREM2 plays distinct functional roles at different stages in AD pathology. SIGNIFICANCE STATEMENT: Alzheimer's disease (AD) is a devastating neurodegenerative disorder and there are currently no effective treatments that modify disease progression. However, the recent identification of genetic risk factors for AD promises to provide new insight into AD biology and possible new therapeutic targets. Among these risk factors, variants in the gene TREM2 (triggering receptor expressed on myeloid cells 2) confer greatly elevated risk for developing the disease. We demonstrate that TREM2 deficiency has opposing effects on AD-related pathologies at early and late stages of disease progression, unifying previous work in the field. In addition, we examine how TREM2 affects the function of the brain immune cell populations in which it is expressed throughout disease progression to understand possible mechanisms underlying its differential impacts on pathology. PMID- 28100746 TI - End-Stopping Predicts Curvature Tuning along the Ventral Stream. AB - : Neurons in primate inferotemporal cortex (IT) are clustered into patches of shared image preferences. Functional imaging has shown that these patches are activated by natural categories (e.g., faces, body parts, and places), artificial categories (numerals, words) and geometric features (curvature and real-world size). These domains develop in the same cortical locations across monkeys and humans, which raises the possibility of common innate mechanisms. Although these commonalities could be high-level template-based categories, it is alternatively possible that the domain locations are constrained by low-level properties such as end-stopping, eccentricity, and the shape of the preferred images. To explore this, we looked for correlations among curvature preference, receptive field (RF) end-stopping, and RF eccentricity in the ventral stream. We recorded from sites in V1, V4, and posterior IT (PIT) from six monkeys using microelectrode arrays. Across all visual areas, we found a tendency for end-stopped sites to prefer curved over straight contours. Further, we found a progression in population curvature preferences along the visual hierarchy, where, on average, V1 sites preferred straight Gabors, V4 sites preferred curved stimuli, and many PIT sites showed a preference for curvature that was concave relative to fixation. Our results provide evidence that high-level functional domains may be mapped according to early rudimentary properties of the visual system. SIGNIFICANCE STATEMENT: The macaque occipitotemporal cortex contains clusters of neurons with preferences for categories such as faces, body parts, and places. One common question is how these clusters (or "domains") acquire their cortical position along the ventral stream. We and other investigators previously established an fMRI-level correlation among these category domains, retinotopy, and curvature preferences: for example, in inferotemporal cortex, face- and curvature preferring domains show a central visual field bias whereas place- and rectilinear-preferring domains show a more peripheral visual field bias. Here, we have found an electrophysiological-level explanation for the correlation among domain preference, curvature, and retinotopy based on neuronal preference for short over long contours, also called end-stopping. PMID- 28100747 TI - Selective Deletion of Sodium Salt Taste during Development Leads to Expanded Terminal Fields of Gustatory Nerves in the Adult Mouse Nucleus of the Solitary Tract. AB - : Neuronal activity plays a key role in the development of sensory circuits in the mammalian brain. In the gustatory system, experimental manipulations now exist, through genetic manipulations of specific taste transduction processes, to examine how specific taste qualities (i.e., basic tastes) impact the functional and structural development of gustatory circuits. Here, we used a mouse knock-out model in which the transduction component used to discriminate sodium salts from other taste stimuli was deleted in taste bud cells throughout development. We used this model to test the hypothesis that the lack of activity elicited by sodium salt taste impacts the terminal field organization of nerves that carry taste information from taste buds to the nucleus of the solitary tract (NST) in the medulla. The glossopharyngeal, chorda tympani, and greater superficial petrosal nerves were labeled to examine their terminal fields in adult control mice and in adult mice in which the alpha-subunit of the epithelial sodium channel was conditionally deleted in taste buds (alphaENaC knockout). The terminal fields of all three nerves in the NST were up to 2.7 times greater in alphaENaC knock-out mice compared with the respective field volumes in control mice. The shapes of the fields were similar between the two groups; however, the density and spread of labels were greater in alphaENaC knock-out mice. Overall, our results show that disruption of the afferent taste signal to sodium salts disrupts the normal age-dependent "pruning" of all terminal fields, which could lead to alterations in sensory coding and taste-related behaviors. SIGNIFICANCE STATEMENT: Neural activity plays a major role in the development of sensory circuits in the mammalian brain. To date, there has been no direct test of whether taste-elicited neural activity has a role in shaping central gustatory circuits. However, recently developed genetic tools now allow an assessment of how specific taste stimuli, in this case sodium salt taste, play a role in the maturation of the terminal fields in the mouse brainstem. We found that the specific deletion of sodium salt taste during development produced terminal fields in adults that were dramatically larger than in control mice, demonstrating for the first time that sodium salt taste-elicited activity is necessary for the normal maturation of gustatory inputs into the brain. PMID- 28100748 TI - Independent Neural Computation of Value from Other People's Confidence. AB - : Expectation of reward can be shaped by the observation of actions and expressions of other people in one's environment. A person's apparent confidence in the likely reward of an action, for instance, makes qualities of their evidence, not observed directly, socially accessible. This strategy is computationally distinguished from associative learning methods that rely on direct observation, by its use of inference from indirect evidence. In twenty three healthy human subjects, we isolated effects of first-hand experience, other people's choices, and the mediating effect of their confidence, on decision making and neural correlates of value within ventromedial prefrontal cortex (vmPFC). Value derived from first-hand experience and other people's choices (regardless of confidence) were indiscriminately represented across vmPFC. However, value computed from agent choices weighted by their associated confidence was represented with specificity for ventromedial area 10. This pattern corresponds to shifts of connectivity and overlapping cognitive processes along a posterior-anterior vmPFC axis. Task behavior and self-reported self reliance for decision-making in other social contexts correlated. The tendency to conform in other social contexts corresponded to increased activation in cortical regions previously shown to respond to social conflict in proportion to subsequent conformity (Campbell-Meiklejohn et al., 2010). The tendency to self monitor predicted a selectively enhanced response to accordance with others in the right temporoparietal junction (rTPJ). The findings anatomically decompose vmPFC value representations according to computational requirements and provide biological insight into the social transmission of preference and reassurance gained from the confidence of others. SIGNIFICANCE STATEMENT: Decades of research have provided evidence that the ventromedial prefrontal cortex (vmPFC) signals the satisfaction we expect from imminent actions. However, we have a surprisingly modest understanding of the organization of value across this substantial and varied region. This study finds that using cues of the reliability of other peoples' knowledge to enhance expectation of personal success generates value correlates that are anatomically distinct from those concurrently computed from direct, personal experience. This suggests that representation of decision values in vmPFC is suborganized according to the underlying computation, consistent with what we know about the anatomical heterogeneity of the region. These results also provide insight into the observational learning process by which someone else's confidence can sway and reassure our choices. PMID- 28100749 TI - Promoted Interaction of C/EBPalpha with Demethylated Cxcr3 Gene Promoter Contributes to Neuropathic Pain in Mice. AB - : DNA methylation has been implicated in the pathogenesis of chronic pain. However, the specific genes regulated by DNA methylation under neuropathic pain condition remain largely unknown. Here we investigated how chemokine receptor CXCR3 is regulated by DNA methylation and how it contributes to neuropathic pain induced by spinal nerve ligation (SNL) in mice. SNL increased Cxcr3 mRNA and protein expression in the neurons of the spinal cord. Meanwhile, the CpG (5' cytosine-phosphate-guanine-3') island in the Cxcr3 gene promoter region was demethylated, and the expression of DNA methyltransferase 3b (DNMT3b) was decreased. SNL also increased the binding of CCAAT (cytidine-cytidine-adenosine adenosine-thymidine)/enhancer binding protein alpha (C/EBPalpha) with Cxcr3 promoter and decreased the binding of DNMT3b with Cxcr3 promoter in the spinal cord. C/EBPalpha expression was increased in spinal neurons after SNL, and inhibition of C/EBPalpha by intrathecal small interfering RNA attenuated SNL induced pain hypersensitivity and reduced Cxcr3 expression. Furthermore, SNL induced mechanical allodynia and heat hyperalgesia were markedly reduced in Cxcr3 /- mice. Spinal inhibition of Cxcr3 by shRNA or CXCR3 antagonist also attenuated established neuropathic pain. Moreover, CXCL10, the ligand of CXCR3, was increased in spinal neurons and astrocytes after SNL. Superfusing spinal cord slices with CXCL10 enhanced spontaneous EPSCs and potentiated NMDA-induced and AMPA-induced currents of lamina II neurons. Finally, intrathecal injection of CXCL10 induced CXCR3-dependent pain hypersensitivity in naive mice. Collectively, our results demonstrated that CXCR3, increased by DNA demethylation and the enhanced interaction with C/EBPalpha, can be activated by CXCL10 to facilitate excitatory synaptic transmission and contribute to the maintenance of neuropathic pain. SIGNIFICANCE STATEMENT: Peripheral nerve injury induces changes of gene expression in the spinal cord that may contribute to the pathogenesis of neuropathic pain. CXCR3 is a chemokine receptor. Whether it is involved in neuropathic pain and how it is regulated after nerve injury remain largely unknown. Our study demonstrates that spinal nerve ligation downregulates the expression of DNMT3b, which may cause demethylation of Cxcr3 gene promoter and facilitate the binding of CCAAT/enhancer binding protein alpha with Cxcr3 promoter and further increase CXCR3 expression in spinal neurons. The upregulated CXCR3 may contribute to neuropathic pain by facilitating central sensitization. Our study reveals an epigenetic mechanism underlying CXCR3 expression and also suggests that targeting the expression or activation of CXCR3 signaling may offer new therapeutics for neuropathic pain. PMID- 28100750 TI - Target-Dependent Compartmentalization of the Corelease of Glutamate and GABA from the Mossy Fibers. AB - : The mossy fibers (MFs) corelease glutamate and GABA onto pyramidal cells of CA3 during development, until the end of the third postnatal week. However, the major target cells of the MF are the interneurons of CA3. Therefore, it has been shown that the interneurons of the hilus and stratum lucidum receive this dual monosynaptic input on MF stimulation. Because the plasticity of glutamatergic transmission from the different terminals of the MF is target specific, we here asked whether the corelease of glutamate and GABA was also subjected to a target dependent compartmentalization. We analyzed the occurrence and plasticity of MF simultaneous glutamatergic-GABAergic signaling onto interneurons of the different strata of CA3 in rats during the third postnatal week. We show the coexistence of time-locked, glutamate receptor and GABA receptor-mediated mono synaptic responses evoked by MF stimulation in interneurons from stratum lucidum and stratum radiatum, but not in interneurons from stratum lacunosum-moleculare. As expected from the transmission of MF origin, MF GABAergic responses were depressed by the activation of metabotropic glutamate receptors. Strikingly, while MF glutamatergic responses underwent LTD, the simultaneous MF GABAergic responses of stratum lucidum interneurons, but not of stratum radiatum interneurons, displayed a Hebbian form of LTP that was mimicked by PKC activation. PKA activation potentiated MF glutamatergic responses of stratum radiatum interneurons, whereas in stratum lucidum interneurons only GABAergic responses were potentiated. We here disclose that the corelease of glutamate and GABA, as well as their plasticity are compartmentalized in a target-dependent manner, showing counterbalanced compensatory plasticity of two neurotransmitters released by different terminals of the same pathway. SIGNIFICANCE STATEMENT: The mossy fibers transiently corelease glutamate and GABA onto pyramidal cells of CA3. We here describe that they can also corelease these amino acids onto interneurons, in a target-dependent manner. Many interneurons in stratum lucidum and stratum radiatum receive both signals, while those in stratum lacunosum moleculare exclusively receive a glutamatergic signal. It is noteworthy that glutamatergic LTD, which is known to exist on stratum lucidum interneurons, coexists in the same pathway with a presynaptic form of GABAergic LTP, while interneurons of stratum radiatum, despite receiving this dual signaling, do not display such plasticity. The GABAergic LTP is mimicked with PKA or PKC activation. We disclose compartmentalized corelease of glutamate and GABA and its differential plasticity from a single pathway onto different interneuron sets. PMID- 28100755 TI - Confidentiality of sexual health patients' information - what has history taught us and where do we stand? PMID- 28100751 TI - Decision-Related Activity in Macaque V2 for Fine Disparity Discrimination Is Not Compatible with Optimal Linear Readout. AB - : Fine judgments of stereoscopic depth rely mainly on relative judgments of depth (relative binocular disparity) between objects, rather than judgments of the distance to where the eyes are fixating (absolute disparity). In macaques, visual area V2 is the earliest site in the visual processing hierarchy for which neurons selective for relative disparity have been observed (Thomas et al., 2002). Here, we found that, in macaques trained to perform a fine disparity discrimination task, disparity-selective neurons in V2 were highly selective for the task, and their activity correlated with the animals' perceptual decisions (unexplained by the stimulus). This may partially explain similar correlations reported in downstream areas. Although compatible with a perceptual role of these neurons for the task, the interpretation of such decision-related activity is complicated by the effects of interneuronal "noise" correlations between sensory neurons. Recent work has developed simple predictions to differentiate decoding schemes (Pitkow et al., 2015) without needing measures of noise correlations, and found that data from early sensory areas were compatible with optimal linear readout of populations with information-limiting correlations. In contrast, our data here deviated significantly from these predictions. We additionally tested this prediction for previously reported results of decision-related activity in V2 for a related task, coarse disparity discrimination (Nienborg and Cumming, 2006), thought to rely on absolute disparity. Although these data followed the predicted pattern, they violated the prediction quantitatively. This suggests that optimal linear decoding of sensory signals is not generally a good predictor of behavior in simple perceptual tasks. SIGNIFICANCE STATEMENT: Activity in sensory neurons that correlates with an animal's decision is widely believed to provide insights into how the brain uses information from sensory neurons. Recent theoretical work developed simple predictions to differentiate decoding schemes, and found support for optimal linear readout of early sensory populations with information-limiting correlations. Here, we observed decision-related activity for neurons in visual area V2 of macaques performing fine disparity discrimination, as yet the earliest site for this task. These findings, and previously reported results from V2 in a different task, deviated from the predictions for optimal linear readout of a population with information-limiting correlations. Our results suggest that optimal linear decoding of early sensory information is not a general decoding strategy used by the brain. PMID- 28100757 TI - Pre-exposure prophylaxis: making history. PMID- 28100752 TI - Differential Vulnerability of CA1 versus CA3 Pyramidal Neurons After Ischemia: Possible Relationship to Sources of Zn2+ Accumulation and Its Entry into and Prolonged Effects on Mitochondria. AB - : Excitotoxic mechanisms contribute to the degeneration of hippocampal pyramidal neurons after recurrent seizures and brain ischemia. However, susceptibility differs, with CA1 neurons degenerating preferentially after global ischemia and CA3 neurons after limbic seizures. Whereas most studies address contributions of excitotoxic Ca2+ entry, it is apparent that Zn2+ also contributes, reflecting accumulation in neurons either after synaptic release and entry through postsynaptic channels or upon mobilization from intracellular Zn2+-binding proteins such as metallothionein-III (MT-III). Using mouse hippocampal slices to study acute oxygen glucose deprivation (OGD)-triggered neurodegeneration, we found evidence for early contributions of excitotoxic Ca2+ and Zn2+ accumulation in both CA1 and CA3, as indicated by the ability of Zn2+ chelators or Ca2+ entry blockers to delay pyramidal neuronal death in both regions. However, using knock out animals (of MT-III and vesicular Zn2+ transporter, ZnT3) and channel blockers revealed substantial differences in relevant Zn2+ sources, with critical contributions of presynaptic release and its permeation through Ca2+- (and Zn2+) permeable AMPA channels in CA3 and Zn2+ mobilization from MT-III predominating in CA1. To assess the consequences of the intracellular Zn2+ accumulation, we used OGD exposures slightly shorter than those causing acute neuronal death; under these conditions, cytosolic Zn2+ rises persisted for 10-30 min after OGD, followed by recovery over ~40-60 min. Furthermore, the recovery appeared to be accompanied by mitochondrial Zn2+ accumulation (via the mitochondrial Ca2+ uniporter MCU) in CA1 but not in CA3 neurons and was markedly diminished in MT III knock-outs, suggesting that it depended upon Zn2+ mobilization from this protein. SIGNIFICANCE STATEMENT: The basis for the differential vulnerabilities of CA1 versus CA3 pyramidal neurons is unclear. The present study of events during and after acute oxygen glucose deprivation highlights a possible important difference, with rapid synaptic entry of Ca2+ and Zn2+ contributing more in CA3, but with delayed and long-lasting accumulation of Zn2+ within mitochondria occurring in CA1 but not CA3 pyramidal neurons. These data may be consistent with observations of prominent mitochondrial dysfunction as a critical early event in the delayed degeneration of CA1 neurons after ischemia and support a hypothesis that mitochondrial Zn2+ accumulation in the early reperfusion period may be a critical and targetable upstream event in the injury cascade. PMID- 28100758 TI - The discovery of Chlamydia trachomatis. PMID- 28100759 TI - Increasing rates of reported chemsex/sexualised recreational drug use in men who have sex with men attending for postexposure prophylaxis for sexual exposure. PMID- 28100760 TI - Street and labour children; special group for elimination of viral hepatitis in Iran. PMID- 28100762 TI - From testing to screening for STIs. PMID- 28100761 TI - The acceptability of self-sampled screening for HPV DNA: a systematic review and meta-analysis. AB - OBJECTIVE: To examine whether or not self-sampled cervical screening for human papillomavirus (HPV) DNA is acceptable and if women prefer self-sampling to clinician-based sampling. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Thirty-seven primary studies obtained through a comprehensive search of six electronic bibliographic databases from 1986 to 2014 and other sources. Search keywords included HPV, screening, DNA testing, vaginal testing, self collected specimen, self-collected sample, self-sampling, self-screening, preferences and acceptability. REVIEW METHODS: Studies eligible for analysis included those that had participants perform self-sampling, evaluated participant acceptance of or preference for self-sampled vaginal HPV DNA and reported data to calculate an effect size. There were no exclusion criteria for publication status or geographical location. Meta-analytic methods were used to quantitatively synthesise effect sizes across studies. RESULTS: The 37 studies included 18 516 female participants from 24 countries across five continents. Overall, there was a high level of acceptability of self-sampling among the participants. Participants reported preference for self-sampling over clinician sampling due to attractive characteristics such as ease and privacy. CONCLUSIONS: The overall acceptability of self-sampled cervical screening, coupled with economic and effective care, provides opportunities for expanding screening services. Importantly, this can provide a creative screening alternative for women who do not participate in traditional cytological screening, and may ultimately reduce health disparities and prevent cervical disease. PMID- 28100763 TI - Clinical round up. PMID- 28100764 TI - Drip 'n Ship Versus Mothership for Endovascular Treatment: Modeling the Best Transportation Options for Optimal Outcomes. AB - BACKGROUND AND PURPOSE: There is uncertainty regarding the best way for patients outside of endovascular-capable or Comprehensive Stroke Centers (CSC) to access endovascular treatment for acute ischemic stroke. The role of the nonendovascular capable Primary Stroke Centers (PSC) that can offer thrombolysis with alteplase but not endovascular treatment is unclear. A key question is whether average benefit is greater with early thrombolysis at the closest PSC before transportation to the CSC (Drip 'n Ship) or with PSC bypass and direct transport to the CSC (Mothership). Ideal transportation options were mapped based on the location of their endovascular-capable CSCs and nonendovascular-capable PSCs. METHODS: Probability models for endovascular treatment were developed from the ESCAPE trial's (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times) decay curves and for alteplase treatment were extracted from the Get With The Guidelines decay curve. The time on-scene, needle-to-door-out time at the PSC, door-to-needle time at the CSC, and door-to-reperfusion time were assumed constant at 25, 20, 30, and 115 minutes, respectively. Emergency medical services transportation times were calculated using Google's Distance Matrix Application Programming Interface interfaced with MATLAB's Mapping Toolbox to create map visualizations. RESULTS: Maps were generated for multiple onset-to-first medical response times and door-to-needle times at the PSCs of 30, 60, and 90. These figures demonstrate the transportation option that yields the better modeled outcome in specific regions. The probability of good outcome is shown. CONCLUSIONS: Drip 'n Ship demonstrates that a PSC that is in close proximity to a CSC remains significant only when the PSC is able to achieve a door-to-needle time of <=30 minutes when the CSC is also efficient. PMID- 28100765 TI - Acute Transient Vestibular Syndrome: Prevalence of Stroke and Efficacy of Bedside Evaluation. AB - BACKGROUND AND PURPOSE: The aim of this study was to determine the prevalence of stroke and efficacy of bedside evaluation in diagnosing stroke in acute transient vestibular syndrome (ATVS). METHODS: We performed a prospective, single-center, observational study that had consecutively recruited 86 patients presenting with ATVS to the emergency department of Pusan National University Yangsan Hospital from January to December 2014. All patients received a constructed evaluation, including HINTS plus (head impulse, nystagmus patterns, test of skew, and finger rubbing) and brain magnetic resonance imagings. Patients without an obvious cause further received perfusion-weighted imaging. Multivariable logistic regression was used to determine clinical parameters to identify stroke in ATVS. RESULTS: The prevalence of stroke was 27% in ATVS. HINTS plus could not be applied to the majority of patients because of the resolution of the vestibular symptoms, and magnetic resonance imagings were falsely negative in 43% of confirmed strokes. Ten patients (12%) showed unilateral cerebellar hypoperfusion on perfusion weighted imaging without an infarction on diffusion-weighted imaging, and 8 of them had a focal stenosis or hypoplasia of the corresponding vertebral artery. The higher risk of stroke in ATVS was found in association with craniocervical pain (odds ratio, 9.6; 95% confidence interval, 2.0-45.2) and focal neurological symptoms/signs (odds ratio, 15.2; 95% confidence interval, 2.5-93.8). CONCLUSIONS: Bedside examination and routine magnetic resonance imagings have a limitation in diagnosing strokes presenting with ATVS, and perfusion imaging may help to identify strokes in ATVS of unknown cause. Associated craniocervical pain and focal neurological symptoms/signs are the useful clues for strokes in ATVS. PMID- 28100766 TI - Comparison of a CHOP-LAsp-based protocol with and without maintenance for canine multicentric lymphoma. AB - The recommendation to treat canine lymphoma with a discontinuous protocol is based on small case numbers and mostly historic controls. This study compares duration of first remission (DFR) and overall survival time (ST) with a discontinuous protocol to the same protocol with maintenance phase. 408 dogs were treated with a CHOP-LAsp (C=cyclophosphamide; H=hydroxydaunorubicin; O=Oncovin; P=prednisolone; LAsp=l-asparaginase)-based 28-week induction protocol. In 75 dogs (cohort 1), this was followed by a maintenance phase consisting of vincristine, chlorambucil and actinomycin-D with a total treatment duration of two years. In the subsequent 333 dogs, therapy was discontinued after induction (cohort 2). Median DFR and ST in cohort 1 were 216 and 375 days and 184 and 304 days in cohort 2. 6-Month, 1-year and 2-year survival rates in cohort 1 were 73 per cent, 50 per cent, 24 per cent and 67 per cent, 39 per cent, 21 per cent in cohort 2. There was no significant difference between the two protocols (P=0.291 for ST, P=0.071 for DFR). On multivariate analysis, corticosteroid pretreatment (P=0.005), thrombocytopenia at diagnosis (P=0.019), stage (P=0.009), substage b at relapse (P<0.001), age (P=0.002) and incomplete or unstable remission necessitating intensification of therapy (P=0.004) were negatively correlated with ST in both groups. This study supports the use of a discontinuous protocol for canine multicentric lymphoma. PMID- 28100767 TI - Effects of season on bull sperm quality in thawed samples in northern Spain. AB - The aim of the present study was to evaluate the possible effects of climate factors on sperm quality of Holstein dairy bulls housed in northern Spain. Semen samples from 11 Holstein dairy bulls were collected and cryopreserved in winter, spring and summer. Sperm quality parameters such as motility, morphology, plasma membrane integrity, acrosome status, mitochondrial membrane potential, DNA fragmentation index and reactive oxygen species were assessed. Samples collected in spring showed higher mean values of total and progressive motility compared with samples collected in winter. Mean values of average path velocity and straight-line velocity were higher in spring than in summer. The proportion of viable spermatozoa was higher in spring than in winter as was the proportion of viable spermatozoa with non-reacted acrosome. The proportion of live cells that were not producing superoxide or hydrogen peroxide was higher in samples collected in spring than in winter. No differences were found in sperm morphology or the DNA fragmentation index among seasons. In conclusion, results suggest that sperm quality of bulls housed in northern Spain is affected by season. Samples collected in spring appear to have better sperm quality than samples collected in other seasons. PMID- 28100768 TI - Control of bovine tuberculosis in a farmed red deer herd in England. AB - This report describes how Mycobacterium bovis infection was controlled and eventually eradicated in a farmed red deer herd in the north of England, following sustained tuberculin skin testing supplemented with serological (antibody) tests over a period of approximately two years. By taking advantage of the anamnestic antibody response produced by the skin test to detect skin test negative, antibody-positive infected individuals, a total of 35 additional animals were identified, including 2 with gross visible lesions typical of bovine tuberculosis (BTB). Without detection and removal, these animals would have posed a continued risk of BTB persistence within the herd and potentially contributed to the spread of infection from deer into wildlife and surrounding cattle farms in an area of low BTB incidence. This case supports the use of ancillary diagnostic serological tests to speed up the resolution of incidents of BTB caused by M bovis in captive deer herds. PMID- 28100769 TI - The Ubiquitin-like with PHD and Ring Finger Domains 1 (UHRF1)/DNA Methyltransferase 1 (DNMT1) Axis Is a Primary Regulator of Cell Senescence. AB - As senescence develops, cells sequentially acquire diverse senescent phenotypes along with simultaneous multistage gene reprogramming. It remains unclear what acts as the key regulator of the collective changes in gene expression at initiation of senescent reprogramming. Here we analyzed time series gene expression profiles obtained in two different senescence models in human diploid fibroblasts: replicative senescence and H2O2-induced senescence. Our results demonstrate that suppression of DNA methyltransferase 1 (DNMT1)-mediated DNA methylation activity was an initial event prior to the display of senescent phenotypes. We identified seven DNMT1-interacting proteins, ubiquitin-like with PHD and ring finger domains 1 (UHRF1), EZH2, CHEK1, SUV39H1, CBX5, PARP1, and HELLS (also known as LSH (lymphoid-specific helicase) 1), as being commonly down regulated at the same time point as DNMT1 in both senescence models. Knockdown experiments revealed that, among the DNMT1-interacting proteins, only UHRF1 knockdown suppressed DNMT1 transcription. However, UHRF1 overexpression alone did not induce DNMT1 expression, indicating that UHRF1 was essential but not sufficient for DNMT1 transcription. Although UHRF1 knockdown effectively induced senescence, this was significantly attenuated by DNMT1 overexpression, clearly implicating the UHRF1/DNMT1 axis in senescence. Bioinformatics analysis further identified WNT5A as a downstream effector of UHRF1/DNMT1-mediated senescence. Senescence-associated hypomethylation was found at base pairs -1569 to -1363 from the transcription start site of the WNT5A gene in senescent human diploid fibroblasts. As expected, WNT5A overexpression induced senescent phenotypes. Overall, our results indicate that decreased UHRF1 expression is a key initial event in the suppression of DNMT1-mediated DNA methylation and in the consequent induction of senescence via increasing WNT5A expression. PMID- 28100770 TI - Control of Amino Acid Homeostasis by a Ubiquitin Ligase-Coactivator Protein Complex. AB - Intercellular amino acid transport is essential for the growth of all multicellular organisms, and its dysregulation is implicated in developmental disorders. By an unknown mechanism, amino acid efflux is stimulated in plants by overexpression of a membrane-localized protein (GLUTAMINE DUMPER 1 (GDU1)) that requires a ubiquitin ligase (LOSS OF GDU 2 (LOG2). Here we further explore the physiological consequences of the interaction between these two proteins. LOG2 ubiquitin ligase activity is necessary for GDU1-dependent tolerance to exogenous amino acids, and LOG2 self-ubiquitination was markedly stimulated by the GDU1 cytosolic domain, suggesting that GDU1 functions as an adaptor or coactivator of amino acid exporter(s). However, other consequences more typical of a ligase substrate relationship are observed: disruption of the LOG2 gene increased the in vivo half-life of GDU1, mass spectrometry confirmed that LOG2 ubiquitinates GDU1 at cytosolic lysines, and GDU1 protein levels decreased upon co-expression with active, but not enzymatically inactive LOG2. Altogether these data indicate LOG2 negatively regulates GDU1 protein accumulation by a mechanism dependent upon cytosolic GDU1 lysines. Although GDU1-lysine substituted protein exhibited diminished in vivo ubiquitination, overexpression of GDU1 lysine mutants still conferred amino acid tolerance in a LOG2-dependent manner, consistent with GDU1 being both a substrate and facilitator of LOG2 function. From these data, we offer a model in which GDU1 activates LOG2 to stimulate amino acid export, a process that could be negatively regulated by GDU1 ubiquitination and LOG2 self ubiquitination. PMID- 28100771 TI - Janus Kinase 2 (JAK2) Dissociates Hepatosteatosis from Hepatocellular Carcinoma in Mice. AB - Hepatocellular carcinoma is an end-stage complication of non-alcoholic fatty liver disease (NAFLD). Inflammation plays a critical role in the progression of non-alcoholic fatty liver disease and the development of hepatocellular carcinoma. However, whether steatosis per se promotes liver cancer, and the molecular mechanisms that control the progression in this disease spectrum remain largely elusive. The Janus kinase signal transducers and activators of transcription (JAK-STAT) pathway mediates signal transduction by numerous cytokines that regulate inflammation and may contribute to hepatocarcinogenesis. Mice with hepatocyte-specific deletion of JAK2 (L-JAK2 KO) develop extensive fatty liver spontaneously. We show here that this simple steatosis was insufficient to drive carcinogenesis. In fact, L-JAK2 KO mice were markedly protected from chemically induced tumor formation. Using the methionine choline deficient dietary model to induce steatohepatitis, we found that steatohepatitis development was completely arrested in L-JAK2 KO mice despite the presence of steatosis, suggesting that JAK2 is the critical factor required for inflammatory progression in the liver. In line with this, L-JAK2 KO mice exhibited attenuated inflammation after chemical carcinogen challenge. This was associated with increased hepatocyte apoptosis without elevated compensatory proliferation, thus thwarting expansion of transformed hepatocytes. Taken together, our findings identify an indispensable role of JAK2 in hepatocarcinogenesis through regulating critical inflammatory pathways. Targeting the JAK-STAT pathway may provide a novel therapeutic option for the treatment of hepatocellular carcinoma. PMID- 28100772 TI - De Novo Sphingolipid Biosynthesis Is Required for Adipocyte Survival and Metabolic Homeostasis. AB - Sphingolipids are a diverse class of essential cellular lipids that function as structural membrane components and as signaling molecules. Cells acquire sphingolipids by both de novo biosynthesis and recycling of exogenous sphingolipids. The individual importance of these pathways for the generation of essential sphingolipids in differentiated cells is not well understood. To investigate the requirement for de novo sphingolipid biosynthesis in adipocytes, a cell type with highly regulated lipid metabolism, we generated mice with an adipocyte-specific deletion of Sptlc1 Sptlc1 is an obligate subunit of serine palmitoyltransferase, the enzyme responsible for the first and rate-limiting step of de novo sphingolipid biosynthesis. These mice, which initially developed adipose tissue, exhibited a striking age-dependent loss of adipose tissue accompanied by evidence of adipocyte death, increased macrophage infiltration, and tissue fibrosis. Adipocyte differentiation was not affected by the Sptlc1 deletion. The mice also had elevated fasting blood glucose, fatty liver, and insulin resistance. Collectively, these data indicate that de novo sphingolipid biosynthesis is required for adipocyte cell viability and normal metabolic function and that reduced de novo sphingolipid biosynthesis within adipocytes is associated with adipocyte death, adipose tissue remodeling, and metabolic dysfunction. PMID- 28100773 TI - Targeted Fcgamma Receptor (FcgammaR)-mediated Clearance by a Biparatopic Bispecific Antibody. AB - Soluble ligands have commonly been targeted by antibody therapeutics for cancers and other diseases. Although monoclonal antibodies targeting such ligands can block their interactions with their cognate receptors, they can also significantly increase the half-life of their ligands by FcRn-mediated antibody recycling, thereby evading ligand renal clearance and requiring increasingly high antibody doses to neutralize the increasing pool of target. To overcome this issue, we generated a bispecific/biparatopic antibody (BiSAb) that targets two different epitopes on IL-6 to block IL-6-mediated signaling. The BiSAb formed large immune complexes with IL-6 that can bind Fcgamma receptors on phagocytic cells and are rapidly internalized. In addition, rapid clearance of the BiSAb.IL 6 complex was observed in mice while the parental antibodies prolonged the serum half-life of IL-6. Intravital imaging of the liver in mice confirmed that the rapid clearance of these large immune complexes was associated with Fcgamma receptor-dependent binding to Kupffer cells in the liver. The approach described here provides a general strategy for therapeutic antibodies with the ability to not only neutralize but also actively drive clearance of their soluble antigens. PMID- 28100775 TI - Cool-associated Tyrosine-phosphorylated Protein 1 Is Required for the Anchorage independent Growth of Cervical Carcinoma Cells by Binding Paxillin and Promoting AKT Activation. AB - Cool-associated tyrosine-phosphorylated protein 1 (Cat-1) is a signaling scaffold as well as an ADP-ribosylation factor-GTPase-activating protein. Although best known for its role in cell migration, we recently showed that the ability of Cat 1 to bind paxillin, a major constituent of focal complexes, is also essential for the anchorage-independent growth of HeLa cervical carcinoma cells. Here we set out to learn more about the underlying mechanism by which Cat-paxillin interactions mediate this effect. We show that knocking down paxillin expression in HeLa cells promotes their ability to form colonies in soft agar, whereas ectopically expressing paxillin in these cells inhibits this transformed growth phenotype. Although knocking down Cat-1 prevents HeLa cells from forming colonies in soft agar, when paxillin is knocked down together with Cat-1, the cells are again able to undergo anchorage-independent growth. These results suggest that the requirement of Cat-1 for this hallmark of cellular transformation is coupled to its ability to bind paxillin and abrogate its actions as a negative regulator of anchorage-independent growth. We further show that knocking down Cat-1 expression in HeLa cells leads to a reduction in Akt activation, which can be reversed by knocking down paxillin. Moreover, expression of constitutively active forms of Akt1 and Akt2 restores the anchorage-independent growth capability of HeLa cells depleted of Cat-1 expression. Together, these findings highlight a novel mechanism whereby interactions between Cat-1 and its binding partner paxillin are necessary to ensure sufficient Akt activation so that cancer cells are able to grow under anchorage-independent conditions. PMID- 28100774 TI - Loss of Cyclin-dependent Kinase 2 in the Pancreas Links Primary beta-Cell Dysfunction to Progressive Depletion of beta-Cell Mass and Diabetes. AB - The failure of pancreatic islet beta-cells is a major contributor to the etiology of type 2 diabetes. beta-Cell dysfunction and declining beta-cell mass are two mechanisms that contribute to this failure, although it is unclear whether they are molecularly linked. Here, we show that the cell cycle regulator, cyclin dependent kinase 2 (CDK2), couples primary beta-cell dysfunction to the progressive deterioration of beta-cell mass in diabetes. Mice with pancreas specific deletion of Cdk2 are glucose-intolerant, primarily due to defects in glucose-stimulated insulin secretion. Accompanying this loss of secretion are defects in beta-cell metabolism and perturbed mitochondrial structure. Persistent insulin secretion defects culminate in progressive deficits in beta-cell proliferation, reduced beta-cell mass, and diabetes. These outcomes may be mediated directly by the loss of CDK2, which binds to and phosphorylates the transcription factor FOXO1 in a glucose-dependent manner. Further, we identified a requirement for CDK2 in the compensatory increases in beta-cell mass that occur in response to age- and diet-induced stress. Thus, CDK2 serves as an important nexus linking primary beta-cell dysfunction to progressive beta-cell mass deterioration in diabetes. PMID- 28100776 TI - Crystallographic Snapshots of Class A beta-Lactamase Catalysis Reveal Structural Changes That Facilitate beta-Lactam Hydrolysis. AB - beta-Lactamases confer resistance to beta-lactam-based antibiotics. There is great interest in understanding their mechanisms to enable the development of beta-lactamase-specific inhibitors. The mechanism of class A beta-lactamases has been studied extensively, revealing Lys-73 and Glu-166 as general bases that assist the catalytic residue Ser-70. However, the specific roles of these two residues within the catalytic cycle remain not fully understood. To help resolve this, we first identified an E166H mutant that is functional but is kinetically slow. We then carried out time-resolved crystallographic study of a full cycle of the catalytic reaction. We obtained structures that represent apo, ES*-acylation, and ES*-deacylation states and analyzed the conformational changes of His-166. The "in" conformation in the apo structure allows His-166 to form a hydrogen bond with Lys-73. The unexpected "flipped-out" conformation of His-166 in the ES* acylation structure was further examined by molecular dynamics simulations, which suggested deprotonated Lys-73 serving as the general base for acylation. The "revert-in" conformation in the ES*-deacylation structure aligns His-166 toward the water molecule that hydrolyzes the acyl adduct. Finally, when the acyl adduct is fully hydrolyzed, His-166 rotates back to the "in" conformation of the apo state, restoring the Lys-73/His-166 interaction. Using His-166 as surrogate, our study identifies distinct conformational changes within the active site during catalysis. We suggest that the native Glu-166 executes similar changes in a less constricted way. Taken together, this structural series improves our understanding of beta-lactam hydrolysis in this important class of enzymes. PMID- 28100778 TI - Structure of the Z Ring-associated Protein, ZapD, Bound to the C-terminal Domain of the Tubulin-like Protein, FtsZ, Suggests Mechanism of Z Ring Stabilization through FtsZ Cross-linking. AB - Cell division in most bacteria is mediated by the tubulin-like FtsZ protein, which polymerizes in a GTP-dependent manner to form the cytokinetic Z ring. A diverse repertoire of FtsZ-binding proteins affects FtsZ localization and polymerization to ensure correct Z ring formation. Many of these proteins bind the C-terminal domain (CTD) of FtsZ, which serves as a hub for FtsZ regulation. FtsZ ring-associated proteins, ZapA-D (Zaps), are important FtsZ regulatory proteins that stabilize FtsZ assembly and enhance Z ring formation by increasing lateral assembly of FtsZ protofilaments, which then form the Z ring. There are no structures of a Zap protein bound to FtsZ; therefore, how these proteins affect FtsZ polymerization has been unclear. Recent data showed ZapD binds specifically to the FtsZ CTD. Thus, to obtain insight into the ZapD-CTD interaction and how it may mediate FtsZ protofilament assembly, we determined the Escherichia coli ZapD FtsZ CTD structure to 2.67 A resolution. The structure shows that the CTD docks within a hydrophobic cleft in the ZapD helical domain and adopts an unusual structure composed of two turns of helix separated by a proline kink. FtsZ CTD residue Phe-377 inserts into the ZapD pocket, anchoring the CTD in place and permitting hydrophobic contacts between FtsZ residues Ile-374, Pro-375, and Leu 378 with ZapD residues Leu-74, Trp-77, Leu-91, and Leu-174. The structural findings were supported by mutagenesis coupled with biochemical and in vivo studies. The combined data suggest that ZapD acts as a molecular cross-linking reagent between FtsZ protofilaments to enhance FtsZ assembly. PMID- 28100777 TI - Structure-Activity Relationship of alpha Mating Pheromone from the Fungal Pathogen Fusarium oxysporum. AB - During sexual development ascomycete fungi produce two types of peptide pheromones termed a and alpha. The alpha pheromone from the budding yeast Saccharomyces cerevisiae, a 13-residue peptide that elicits cell cycle arrest and chemotropic growth, has served as paradigm for the interaction of small peptides with their cognate G protein-coupled receptors. However, no structural information is currently available for alpha pheromones from filamentous ascomycetes, which are significantly shorter and share almost no sequence similarity with the S. cerevisiae homolog. High resolution structure of synthetic alpha-pheromone from the plant pathogenic ascomycete Fusarium oxysporum revealed the presence of a central beta-turn resembling that of its yeast counterpart. Disruption of the-fold by d-alanine substitution of the conserved central Gly6 Gln7 residues or by random sequence scrambling demonstrated a crucial role for this structural determinant in chemoattractant activity. Unexpectedly, the growth inhibitory effect of F. oxysporum alpha-pheromone was independent of the cognate G protein-coupled receptors Ste2 and of the central beta-turn but instead required two conserved Trp1-Cys2 residues at the N terminus. These results indicate that, despite their reduced size, fungal alpha-pheromones contain discrete functional regions with a defined secondary structure that regulate diverse biological processes such as polarity reorientation and cell division. PMID- 28100779 TI - Intramembrane Proteolysis of Astrotactins. AB - Astrotactins are vertebrate-specific membrane proteins implicated in neuron-glia interactions during central nervous system development and in hair follicle polarity during skin development. By studying epitope-tagged derivatives of mouse astrotactin-2 (Astn2) produced in transfected cells, we determined that the amino and carboxyl termini reside in the extracellular space and are initially linked by two transmembrane segments and a single cytoplasmic domain. We further show that Astn2 undergoes proteolytic cleavage in the second transmembrane domain (TM2) and that a disulfide bond holds the resulting two fragments together. Recombinant Astn1 also undergoes TM2 cleavage, as does Astn2 isolated from mouse cerebellum. Astn2 intramembrane proteolysis is insensitive to replacement of TM2 by the transmembrane domain of CD74 or by 21 alanines. However, replacement of TM2 by the transmembrane domain of CD4, the asialoglycoprotein receptor, or the transferrin receptor eliminates intramembrane proteolysis, as does leucine substitution of residues that overlap or are immediately upstream of the cleavage site. Replacement of the transmembrane domain of CD74 or the asialoglycoprotein receptor with Astn2 TM2 leads to the appearance of a carboxyl-terminal fragment consistent with intramembrane proteolysis. These experiments define a highly unusual transmembrane topology for the astrotactins, reveal intramembrane proteolysis as a feature of astrotactin maturation, and constrain the substrate sequences that are permissive for cleavage of one type 2 transmembrane segment. PMID- 28100780 TI - A novel microRNA located in the TrkC gene regulates the Wnt signaling pathway and is differentially expressed in colorectal cancer specimens. AB - Tropomyosin receptor kinase C (TrkC) is involved in cell survival, apoptosis, differentiation, and tumorigenesis. TrkC diverse functions might be attributed to the hypothetical non-coding RNAs embedded within the gene. Using bioinformatics approaches, a novel microRNA named TrkC-miR2 was predicted within the TrkC gene capable of regulating the Wnt pathway. For experimental verification of this microRNA, the predicted TrkC-premir2 sequence was overexpressed in SW480 cells, which led to the detection of two mature TrkC-miR2 isomiRs, and their endogenous forms were detected in human cell lines as well. Later, an independent promoter was deduced for TrkC-miR2 after the treatment of HCT116 cells with 5-azacytidine, which resulted in differential expression of TrkC-miR2 and TrkC host gene. RT quantitative PCR and luciferase assays indicated that the APC2 gene is targeted by TrkC-miR2, and Wnt signaling is up-regulated. Also, Wnt inhibition by using small molecules along with TrkC-miR2 overexpression and TOP/FOP flash assays confirmed the positive effect of TrkC-miR2 on the Wnt pathway. Consistently, TrkC miR2 overexpression promoted SW480 cell survival, which was detected by flow cytometry, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays, and crystal violate analysis. RT-qPCR analysis revealed that TrkC-miR2 is significantly up-regulated (~70 times) in colorectal tumor tissues compared with their normal pairs. Moreover, the TrkC-miR2 expression level discriminated grades of tumor malignancies, which was consistent with its endogenous levels in HCT116, HT29, and SW480 colorectal cancer cell lines. Finally, an opposite expression pattern was observed for TrkC-miR2 and the APC2 gene in colorectal cancer specimens. In conclusion, here we introduce TrkC-miR2 as a novel regulator of Wnt signaling, which might be a candidate oncogenic colorectal cancer biomarker. PMID- 28100781 TI - Biogenesis of a Mitochondrial Outer Membrane Protein in Trypanosoma brucei: TARGETING SIGNAL AND DEPENDENCE ON A UNIQUE BIOGENESIS FACTOR. AB - The mitochondrial outer membrane (OM) contains single and multiple membrane spanning proteins that need to contain signals that ensure correct targeting and insertion into the OM. The biogenesis of such proteins has so far essentially only been studied in yeast and related organisms. Here we show that POMP10, an OM protein of the early diverging protozoan Trypanosoma brucei, is signal-anchored. Transgenic cells expressing variants of POMP10 fused to GFP demonstrate that the N-terminal membrane-spanning domain flanked by a few positively charged or neutral residues is both necessary and sufficient for mitochondrial targeting. Carbonate extraction experiments indicate that although the presence of neutral instead of positively charged residues did not interfere with POMP10 localization, it weakened its interaction with the OM. Expression of GFP-tagged POMP10 in inducible RNAi cell lines shows that its mitochondrial localization depends on pATOM36 but does not require Sam50 or ATOM40, the trypanosomal analogue of the Tom40 import pore. pATOM36 is a kinetoplastid-specific OM protein that has previously been implicated in the assembly of OM proteins and in mitochondrial DNA inheritance. In summary, our results show that although the features of the targeting signal in signal-anchored proteins are widely conserved, the protein machinery that mediates their biogenesis is not. PMID- 28100782 TI - Triphosphate Reorientation of the Incoming Nucleotide as a Fidelity Checkpoint in Viral RNA-dependent RNA Polymerases. AB - The nucleotide incorporation fidelity of the viral RNA-dependent RNA polymerase (RdRp) is important for maintaining functional genetic information but, at the same time, is also important for generating sufficient genetic diversity to escape the bottlenecks of the host's antiviral response. We have previously shown that the structural dynamics of the motif D loop are closely related to nucleotide discrimination. Previous studies have also suggested that there is a reorientation of the triphosphate of the incoming nucleotide, which is essential before nucleophilic attack from the primer RNA 3'-hydroxyl. Here, we have used 31P NMR with poliovirus RdRp to show that the binding environment of the triphosphate is different when correct versus incorrect nucleotide binds. We also show that amino acid substitutions at residues known to interact with the triphosphate can alter the binding orientation/environment of the nucleotide, sometimes lead to protein conformational changes, and lead to substantial changes in RdRp fidelity. The analyses of other fidelity variants also show that changes in the triphosphate binding environment are not always accompanied by changes in the structural dynamics of the motif D loop or other regions known to be important for RdRp fidelity, including motif B. Altogether, our studies suggest that the conformational changes in motifs B and D, and the nucleoside triphosphate reorientation represent separable, "tunable" fidelity checkpoints. PMID- 28100783 TI - Dual Functional Roles of Molecular Beacon as a MicroRNA Detector and Inhibitor. AB - MicroRNAs are essential in many cellular processes. The ability to detect microRNAs is important for understanding its function and biogenesis. This study is aimed at using a molecular beacon to detect miR-430 in developing zebrafish embryos as a proof of principle. miR-430 is crucial for the clearance of maternal mRNA during maternal zygotic transition in embryonic development. Despite its known function, the temporal and spatial expression of miR-430 remains unclear. We used various imaging techniques, including laser scanning confocal microscopy, spinning disk, and lightsheet microscopy, to study the localization of miR-430 and any developmental defects possibly caused by the molecular beacon. Our results show that miR-430 is expressed early in development and is localized in distinct cytoplasmic granules where its target mRNA can be detected. We also show that the designed molecular beacon can inhibit the function of miR-430 and cause developmental defect in the brain, notochord, heart, and kidney, depending on the delivery site within the embryo, suggesting that miR-430 plays a diverse role in embryonic morphogenesis. When compared with morpholino, molecular beacon is 2 orders of magnitude more potent in inhibiting miR-430. Thus, our results reveal that in addition to being used as a valuable tool for the detection of microRNAs in vivo, molecular beacons can also be employed to inhibit microRNAs in a specific manner. PMID- 28100784 TI - Mitochondrial O-GlcNAc Transferase (mOGT) Regulates Mitochondrial Structure, Function, and Survival in HeLa Cells. AB - O-Linked N-acetylglucosamine transferase (OGT) catalyzes O-GlcNAcylation of target proteins and regulates numerous biological processes. OGT is encoded by a single gene that yields nucleocytosolic and mitochondrial isoforms. To date, the role of the mitochondrial isoform of OGT (mOGT) remains largely unknown. Using high throughput proteomics, we identified 84 candidate mitochondrial glycoproteins, of which 44 are novel. Notably, two of the candidate glycoproteins identified (cytochrome oxidase 2 (COX2) and NADH:ubiquinone oxidoreductase core subunit 4 (MT-ND4)) are encoded by mitochondrial DNA. Using siRNA in HeLa cells, we found that reducing endogenous mOGT expression leads to alterations in mitochondrial structure and function, including Drp1-dependent mitochondrial fragmentation, reduction in mitochondrial membrane potential, and a significant loss of mitochondrial content in the absence of mitochondrial ROS. These defects are associated with a compensatory increase in oxidative phosphorylation per mitochondrion. mOGT is also critical for cell survival; siRNA-mediated knockdown of endogenous mOGT protected cells against toxicity mediated by rotenone, a complex I inhibitor. Conversely, reduced expression of both nucleocytoplasmic (ncOGT) and mitochondrial (mOGT) OGT isoforms is associated with increased mitochondrial respiration and elevated glycolysis, suggesting that ncOGT is a negative regulator of cellular bioenergetics. Last, we determined that mOGT is probably involved in the glycosylation of a restricted set of mitochondrial targets. We identified four proteins implicated in mitochondrial biogenesis and metabolism regulation as candidate substrates of mOGT, including leucine-rich PPR containing protein and mitochondrial aconitate hydratase. Our findings suggest that mOGT is catalytically active in vivo and supports mitochondrial structure, health, and survival, whereas ncOGT predominantly regulates cellular bioenergetics. PMID- 28100785 TI - Protein Kinase C Controls Binding of Igo/ENSA Proteins to Protein Phosphatase 2A in Budding Yeast. AB - Protein phosphatase 2A (PP2A) plays important roles in controlling mitosis in all eukaryotic cells. The form of PP2A that controls mitosis is associated with a conserved regulatory subunit that is called B55 in vertebrates and Cdc55 in budding yeast. The activity of this form of PP2A can be inhibited by binding of conserved Igo/ENSA proteins. Although the mechanisms that activate Igo/ENSA to bind and inhibit PP2A are well understood, little is known about how Igo/Ensa are inactivated. Here, we have analyzed regulation of Igo/ENSA in the context of a checkpoint pathway that links mitotic entry to membrane growth in budding yeast. Protein kinase C (Pkc1) relays signals in the pathway by activating PP2ACdc55 We discovered that constitutively active Pkc1 can drive cells through a mitotic checkpoint arrest, which suggests that Pkc1-dependent activation of PP2ACdc55 plays a critical role in checkpoint signaling. We therefore used mass spectrometry to determine how Pkc1 modifies the PP2ACdc55 complex. This revealed that Pkc1 induces changes in the phosphorylation of multiple subunits of the complex, as well as dissociation of Igo/ENSA. Pkc1 directly phosphorylates Cdc55 and Igo/ENSA, and phosphorylation site mapping and mutagenesis indicate that phosphorylation of Cdc55 contributes to Igo/ENSA dissociation. Association of Igo2 with PP2ACdc55 is regulated during the cell cycle, yet mutation of Pkc1 dependent phosphorylation sites on Cdc55 and Igo2 did not cause defects in mitotic progression. Together, the data suggest that Pkc1 controls PP2ACdc55 by multiple overlapping mechanisms. PMID- 28100786 TI - Inositol Depletion Induced by Acute Treatment of the Bipolar Disorder Drug Valproate Increases Levels of Phytosphingosine. AB - Bipolar disorder (BD) is a severe psychiatric illness affecting ~1% of the world population. Valproate (VPA) and lithium, widely used for the treatment of BD, are not universally effective. These drugs have been shown to cause inositol depletion, but translating this observation to a specific therapeutic mechanism has been difficult, hampering the development of more effective therapies. We have shown previously in yeast that chronic VPA treatment induces the unfolded protein response due to increasing ceramide levels. To gain insight into the mechanisms activated during acute VPA treatment, we performed a genome-wide expression study in yeast treated with VPA for 30 min. We observed increased mRNA and protein levels of RSB1, which encodes an exporter of long chain bases dihydrosphingosine (DHS) and phytosphingosine (PHS), and further saw that VPA increased sensitivity of an rsb1Delta mutant to PHS, suggesting that VPA increases long chain base levels. Consistent with this, PHS levels were elevated in wild type and, to a greater extent, in rsb1Delta cells. Expression of ORM genes (negative regulators of PHS synthesis) and of fatty acid elongase genes FEN1 and SUR4 were decreased, and expression of YOR1 (exporter of PHS-1P) and DPL1 (lyase that degrades DHS-1P and PHS-1P) was increased. These effects were more pronounced in medium lacking inositol, and were mirrored by inositol starvation of an ino1Delta mutant. These findings provide a metabolic explanation as to how VPA-mediated inositol depletion causes increased synthesis of PHS and further support the therapeutic relevance of inositol depletion as a bipolar disorder treatment. PMID- 28100787 TI - Polymorphic Variants of Human Protein l-Isoaspartyl Methyltransferase Affect Catalytic Activity, Aggregation, and Thermal Stability: IMPLICATIONS FOR THE ETIOLOGY OF NEUROLOGICAL DISORDERS AND COGNITIVE AGING. AB - Protein l-isoaspartyl methyltransferase (PIMT/PCMT1), a product of the human pcmt1 gene, catalyzes repair of abnormal l-isoaspartyl linkages in age-damaged proteins. Pcmt1 knock-out mice exhibit a profound neuropathology and die 30-60 days postnatal from an epileptic seizure. Here we express 15 reported variants of human PIMT and characterize them with regard to their enzymatic activity, thermal stability, and propensity to aggregation. One mutation, R36C, renders PIMT completely inactive, whereas two others, A7P and I58V, exhibit activity that is 80-100% higher than wild type. G175R is highly prone to aggregation and has greatly reduced activity. R17S and R17H show markedly enhanced sensitivity to thermal denaturation. Based on previous studies of moderate PIMT variation in humans and mice, we predict that heterozygosity for R36C, G175R, R17S, and R17H will prove detrimental to cognitive function and successful aging, whereas homozygosity (if it ever occurs) will lead to severe neurological problems in the young. PMID- 28100788 TI - Genomic Infectious Disease Epidemiology in Partially Sampled and Ongoing Outbreaks. AB - Genomic data are increasingly being used to understand infectious disease epidemiology. Isolates from a given outbreak are sequenced, and the patterns of shared variation are used to infer which isolates within the outbreak are most closely related to each other. Unfortunately, the phylogenetic trees typically used to represent this variation are not directly informative about who infected whom-a phylogenetic tree is not a transmission tree. However, a transmission tree can be inferred from a phylogeny while accounting for within-host genetic diversity by coloring the branches of a phylogeny according to which host those branches were in. Here we extend this approach and show that it can be applied to partially sampled and ongoing outbreaks. This requires computing the correct probability of an observed transmission tree and we herein demonstrate how to do this for a large class of epidemiological models. We also demonstrate how the branch coloring approach can incorporate a variable number of unique colors to represent unsampled intermediates in transmission chains. The resulting algorithm is a reversible jump Monte-Carlo Markov Chain, which we apply to both simulated data and real data from an outbreak of tuberculosis. By accounting for unsampled cases and an outbreak which may not have reached its end, our method is uniquely suited to use in a public health environment during real-time outbreak investigations. We implemented this transmission tree inference methodology in an R package called TransPhylo, which is freely available from https://github.com/xavierdidelot/TransPhylo. PMID- 28100789 TI - Complex Evolutionary History of the Mammalian Histone H1.1-H1.5 Gene Family. AB - H1 is involved in chromatin higher-order structure and gene regulation. H1 has a tripartite structure. The central domain is stably folded in solution, while the N- and C-terminal domains are intrinsically disordered. The terminal domains are encoded by DNA of low sequence complexity, and are thus prone to short insertions/deletions (indels). We have examined the evolution of the H1.1-H1.5 gene family from 27 mammalian species. Multiple sequence alignment has revealed a strong preferential conservation of the number and position of basic residues among paralogs, suggesting that overall H1 basicity is under a strong purifying selection. The presence of a conserved pattern of indels, ancestral to the splitting of mammalian orders, in the N- and C-terminal domains of the paralogs, suggests that slippage may have favored the rapid divergence of the subtypes and that purifying selection has maintained this pattern because it is associated with function. Evolutionary analyses have found evidences of positive selection events in H1.1, both before and after the radiation of mammalian orders. Positive selection ancestral to mammalian radiation involved changes at specific sites that may have contributed to the low relative affinity of H1.1 for chromatin. More recent episodes of positive selection were detected at codon positions encoding amino acids of the C-terminal domain of H1.1, which may modulate the folding of the CTD. The detection of putative recombination points in H1.1-H1.5 subtypes suggests that this process may has been involved in the acquisition of the tripartite H1 structure. PMID- 28100791 TI - The Reliability and Stability of an Inferred Phylogenetic Tree from Empirical Data. AB - The reliability of a phylogenetic tree obtained from empirical data is usually measured by the bootstrap probability (Pb) of interior branches of the tree. If the bootstrap probability is high for most branches, the tree is considered to be reliable. If some interior branches show relatively low bootstrap probabilities, we are not sure that the inferred tree is really reliable. Here, we propose another quantity measuring the reliability of the tree called the stability of a subtree. This quantity refers to the probability of obtaining a subtree (Ps) of an inferred tree obtained. We then show that if the tree is to be reliable, both Pb and Ps must be high. We also show that Ps is given by a bootstrap probability of the subtree with the closest outgroup sequence, and computer program RESTA for computing the Pb and Ps values will be presented. PMID- 28100792 TI - Evolutionary History of the Asian Horned Frogs (Megophryinae): Integrative Approaches to Timetree Dating in the Absence of a Fossil Record. AB - Molecular dating studies typically need fossils to calibrate the analyses. Unfortunately, the fossil record is extremely poor or presently nonexistent for many species groups, rendering such dating analysis difficult. One such group is the Asian horned frogs (Megophryinae). Sampling all generic nomina, we combined a novel ~5 kb dataset composed of four nuclear and three mitochondrial gene fragments to produce a robust phylogeny, with an extensive external morphological study to produce a working taxonomy for the group. Expanding the molecular dataset to include out-groups of fossil-represented ancestral anuran families, we compared the priorless RelTime dating method with the widely used prior-based Bayesian timetree method, MCMCtree, utilizing a novel combination of fossil priors for anuran phylogenetic dating. The phylogeny was then subjected to ancestral phylogeographic analyses, and dating estimates were compared with likely biogeographic vicariant events. Phylogenetic analyses demonstrated that previously proposed systematic hypotheses were incorrect due to the paraphyly of genera. Molecular phylogenetic, morphological, and timetree results support the recognition of Megophryinae as a single genus, Megophrys, with a subgenus level classification. Timetree results using RelTime better corresponded with the known fossil record for the out-group anuran tree. For the priorless in-group, it also outperformed MCMCtree when node date estimates were compared with likely influential historical biogeographic events, providing novel insights into the evolutionary history of this pan-Asian anuran group. Given a relatively small molecular dataset, and limited prior knowledge, this study demonstrates that the computationally rapid RelTime dating tool may outperform more popular and complex prior reliant timetree methodologies. PMID- 28100801 TI - The fallacy of the average: on the ubiquity, utility and continuing novelty of Jensen's inequality. AB - Biologists often cope with variation in physiological, environmental and ecological processes by measuring how living systems perform under average conditions. However, performance at average conditions is seldom equal to average performance across a range of conditions. This basic property of nonlinear averaging - known as 'Jensen's inequality' or 'the fallacy of the average' - has important implications for all of biology. For instance, a burgeoning awareness of Jensen's inequality has improved our ability to predict how plants and animals will respond to a warmer and more variable future climate. But for many biologists, the fallacy of the average is still a novel concept. Here, I highlight the importance of Jensen's inequality, provide a simple graphical approach to understanding its effects, and explore its consequences at atomic, molecular, organismal and ecological levels. PMID- 28100790 TI - Genome-Wide Analysis in Brazilians Reveals Highly Differentiated Native American Genome Regions. AB - Despite its population, geographic size, and emerging economic importance, disproportionately little genome-scale research exists into genetic factors that predispose Brazilians to disease, or the population genetics of risk. After identification of suitable proxy populations and careful analysis of tri continental admixture in 1,538 North-Eastern Brazilians to estimate individual ancestry and ancestral allele frequencies, we computed 400,000 genome-wide locus specific branch length (LSBL) Fst statistics of Brazilian Amerindian ancestry compared to European and African; and a similar set of differentiation statistics for their Amerindian component compared with the closest Asian 1000 Genomes population (surprisingly, Bengalis in Bangladesh). After ranking SNPs by these statistics, we identified the top 10 highly differentiated SNPs in five genome regions in the LSBL tests of Brazilian Amerindian ancestry compared to European and African; and the top 10 SNPs in eight regions comparing their Amerindian component to the closest Asian 1000 Genomes population. We found SNPs within or proximal to the genes CIITA (rs6498115), SMC6 (rs1834619), and KLHL29 (rs2288697) were most differentiated in the Amerindian-specific branch, while SNPs in the genes ADAMTS9 (rs7631391), DOCK2 (rs77594147), SLC28A1 (rs28649017), ARHGAP5 (rs7151991), and CIITA (rs45601437) were most highly differentiated in the Asian comparison. These genes are known to influence immune function, metabolic and anthropometry traits, and embryonic development. These analyses have identified candidate genes for selection within Amerindian ancestry, and by comparison of the two analyses, those for which the differentiation may have arisen during the migration from Asia to the Americas. PMID- 28100802 TI - Hydrodynamic detection and localization of artificial flatfish breathing currents by harbour seals (Phoca vitulina). AB - Harbour seals are known to be opportunistic feeders, whose diet consists mainly of pelagic and benthic fish, such as flatfish. As flatfish are often cryptic and do not produce noise, we hypothesized that harbour seals are able to detect and localize flatfish using their hydrodynamic sensory system (vibrissae), as fish emit water currents through their gill openings (breathing currents). To test this hypothesis, we created an experimental platform where an artificial breathing current was emitted through one of eight different openings. Three seals were trained to search for the active opening and station there for 5 s. Half of the trials were conducted with the seal blindfolded with an eye mask. In blindfolded and non-blindfolded trials, all seals performed significantly better than chance. The seals crossed the artificial breathing current (being emitted into the water column at an angle of 45 deg to the ground) from different directions. There was no difference in performance when the seals approached from in front, from behind or from the side. All seals responded to the artificial breathing currents by directly moving their snout towards the opening from which the hydrodynamic stimulus was emitted. Thus, they were also able to extract directional information from the hydrodynamic stimulus. Hydrodynamic background noise and the swimming speed of the seals were also considered in this study as these are aggravating factors that seals in the wild have to face during foraging. By creating near-natural conditions, we show that harbour seals have the ability to detect a so-far overlooked type of stimulus. PMID- 28100803 TI - A new cue for torpor induction: charcoal, ash and smoke. AB - Recent work has shown that the use of torpor for energy conservation increases after forest fires in heterothermic mammals, probably in response to the reduction of food. However, the specific environmental cues for this increased torpor expression remain unknown. It is possible that smoke and the novel substrate of charcoal and ash act as signals for an impending period of starvation requiring torpor. We therefore tested the hypothesis that the combined cues of smoke, a charcoal/ash substrate and food shortage will enhance torpor expression in a small forest-dwelling marsupial, the yellow-footed antechinus (Antechinus flavipes), because like other animals that live in fire-prone habitats they must effectively respond to fires to ensure survival. Activity and body temperature patterns of individuals in outdoor aviaries were measured under natural environmental conditions. All individuals were strictly nocturnal, but diurnal activity was observed shortly after smoke exposure. Overall, torpor in females was longer and deeper than that in males. Interestingly, while both males and females increased daily torpor duration during food restriction by >2-fold as anticipated, a combination of food restriction and smoke exposure on a charcoal/ash substrate further increased daily torpor duration by ~2-fold in both sexes. These data show that this combination of cues for torpor induction is stronger than food shortage on its own. Our study provides significant new information on how a small forest-dwelling mammal responds to fire cues during and immediately after a fire and identifies a new, not previously recognised, regulatory mechanism for thermal biology in mammals. PMID- 28100804 TI - Role of the different eyes in the visual odometry in the wolf spider Lycosa tarantula (Araneae, Lycosidae). AB - The wolf spider Lycosa tarantula returns home by means of path integration. Previous studies demonstrated: (i) that the angular component of the outbound run is measured using a polarized-light compass associated with the anterior median eyes; (ii) changes in direction of the substratum are detected by the anterior lateral eyes (ALEs); and (iii) in relation to the linear component of the outbound run, an increase of optic flow, in either the lateral or ventral fields of view, caused spiders to search for the burrow at a point nearer to the goal. However, the role of the secondary eyes [ALEs, posterior lateral eyes (PLEs) and posterior median eyes (PMEs)] in the perception of this optic flow and the importance of them for gauging the distance walked is still unknown. In this study, lateral or ventral gratings of wavelength lambda=1 cm were used, with two groups of spiders in each setup: (1) PLEs+PMEs covered and (2) ALEs covered. The largest reduction in the distance walked to return to the burrow was observed with the ventral grating/ALEs covered. These results show the importance of the previously neglected ALEs for the visual behavior of these spiders. The possibility of gathering information for locomotion from the three pairs of secondary eyes in the mushroom bodies is discussed. PMID- 28100805 TI - Differences in mobility at the range edge of an expanding invasive population of Xenopus laevis in the west of France. AB - Theoretical models predict that spatial sorting at the range edge of expanding populations should favor individuals with increased mobility relative to individuals at the center of the range. Despite the fact that empirical evidence for the evolution of locomotor performance at the range edge is rare, data on cane toads support this model. However, whether this can be generalized to other species remains largely unknown. Here, we provide data on locomotor stamina and limb morphology in individuals from two sites: one from the center and one from the periphery of an expanding population of the clawed frog Xenopus laevis in France where it was introduced about 30 years ago. Additionally, we provide data on the morphology of frogs from two additional sites to test whether the observed differences can be generalized across the range of this species in France. Given the known sexual size dimorphism in this species, we also test for differences between the sexes in locomotor performance and morphology. Our results show significant sexual dimorphism in stamina and morphology, with males having longer legs and greater stamina than females. Moreover, in accordance with the predictions from theoretical models, individuals from the range edge had a greater stamina. This difference in locomotor performance is likely to be driven by the significantly longer limb segments observed in animals in both sites sampled in different areas along the range edge. Our data have implications for conservation because spatial sorting on the range edge may lead to an accelerated increase in the spread of this invasive species in France. PMID- 28100806 TI - The lateral line confers evolutionarily derived sleep loss in the Mexican cavefish. AB - Sleep is an essential behavior exhibited by nearly all animals, and disruption of this process is associated with an array of physiological and behavioral deficits. Sleep is defined by changes in sensory gating that reduce sensory input to the brain, but little is known about the neural basis for interactions between sleep and sensory processing. Blind Mexican cavefish comprise an extant surface dwelling form and 29 cave morphs that have independently evolved increased numbers of mechanoreceptive lateral line neuromasts and convergent evolution of sleep loss. Ablation of the lateral line enhanced sleep in the Pachon cavefish population, suggesting that heightened sensory input underlies evolutionarily derived sleep loss. Targeted lateral line ablation and behavioral analysis localized the wake-promoting neuromasts in Pachon cavefish to superficial neuromasts of the trunk and cranial regions. Strikingly, lateral line ablation did not affect sleep in four other cavefish populations, suggesting that distinct neural mechanisms regulate the evolution of sleep loss in independently derived cavefish populations. Cavefish are subject to seasonal changes in food availability, raising the possibility that sensory modulation of sleep is influenced by metabolic state. We found that starvation promotes sleep in Pachon cavefish, and is not enhanced by lateral line ablation, suggesting that functional interactions occur between sensory and metabolic regulation of sleep. Taken together, these findings support a model where sensory processing contributes to evolutionarily derived changes in sleep that are modulated in accordance with food availability. PMID- 28100807 TI - Cost minimisation analysis of thermometry in two different hospital systems. AB - INTRODUCTION: Temperature monitoring can be accomplished by various methods, including oral (OT), rectal (RT), axillary (AT), tympanic membrane (TMT) and temporal artery (TAT) thermometry, with varying amounts of cost incurred by healthcare systems. METHODS: The potential thermometry cost savings in two hospital systems-University Hospital Centre Zagreb (UHCZ), which uses TMT (device Covidien Genius 2) and University of Michigan Hospitals (UMH), which relies on OT, RT and AT (device Welch Allyn suretemp plus 692)-were analysed to evaluate institution-wide TAT (device Exergen TAT-5000) implementation. Two scenarios were developed: scenario 1, comparing costs for a period of 1, 3 and 5 years; scenario 2, calculation of the number of measurements per device for TAT to be cost effective. RESULTS: At UHCZ, use of TAT would bring budget savings regardless of the number of devices per bed and the number of years observed. Savings would range from US$0.08 million (one device per bed, impact for 1 year) to US$1.8 million (one device per 10 beds, impact for 5 years). At UMH, use of TAT would lead to budget savings if one device per 10 beds were acquired, but only over a period of 3 or 5 years. Other TAT scenarios were associated with budget costs at UMH even after a period of 5 years. CONCLUSIONS: Sensitivity analyses showed that the price of current consumables had the highest impact on the model in both hospital settings, with TAT up to 10 times cheaper in that regard over TMT at UHCZ, potentially leading to considerable budget savings within a year of hospital-wide implementation. PMID- 28100808 TI - Correction for Lund et al., HIV-1-Neutralizing IgA Detected in Genital Secretions of Highly HIV-1-Exposed Seronegative Women on Oral Preexposure Prophylaxis. PMID- 28100809 TI - Classic Spotlight, 1971 to 1973: Articles of Significant Interest Selected from the Journal of Virology Archives by the Editors. PMID- 28100811 TI - The molecular speciation of soil-transmitted helminth eggs collected from school children across six endemic countries. AB - BACKGROUND: The diagnosis of soil-transmitted helminths (STHs; Ascaris, Trichuris and hookworms) is traditionally based on the demonstration of eggs in stool using microscopic techniques. While molecular techniques are more appropriate to speciate STH species they are seldom applied. In this study we speciated STH eggs from stool using molecular techniques to gain insights into the distribution of both human and animal STH species in the human host. METHODS: We speciated 207 STH egg isolates from stool collected during the baseline survey of six drug efficacy trials conducted in Brazil, Cambodia, Cameroon, Ethiopia, Tanzania and Vietnam applying a PCR - restriction fragment length polymorphisms based approach. RESULTS: DNA of Ascaris was detected in 71 (34.3%) samples, of which all were identified as the human roundworm Ascaris lumbricoides. In 87 (42.0%) samples, DNA of Trichuris spp. was found and further speciation demonstrated the presence of the human Trichuris trichiura (100%) and the canine Trichuris vulpis (n=7; 8.0%; in Cameroon only). Hookworms were identified in 104 (50.2%) samples, with Necator americanus (n=73; 70.2%) being the predominant species followed by Ancylostoma duodenale (n=40; 38.5%). CONCLUSIONS: Our study indicates that STH infections in humans are predominantly caused by human STH species. They also suggest that zoonotic transmission occurs on a local scale. PMID- 28100812 TI - Problems with equating thermal preference with 'emotional fever' and sentience: comment on 'Fish can show emotional fever: stress-induced hyperthermia in zebrafish' by Rey et al. (2015). PMID- 28100813 TI - Coral calcifying fluid pH is modulated by seawater carbonate chemistry not solely seawater pH. AB - Reef coral calcification depends on regulation of pH in the internal calcifying fluid (CF) in which the coral skeleton forms. However, little is known about calcifying fluid pH (pHCF) regulation, despite its importance in determining the response of corals to ocean acidification. Here, we investigate pHCF in the coral Stylophora pistillata in seawater maintained at constant pH with manipulated carbonate chemistry to alter dissolved inorganic carbon (DIC) concentration, and therefore total alkalinity (AT). We also investigate the intracellular pH of calcifying cells, photosynthesis, respiration and calcification rates under the same conditions. Our results show that despite constant pH in the surrounding seawater, pHCF is sensitive to shifts in carbonate chemistry associated with changes in [DIC] and [AT], revealing that seawater pH is not the sole driver of pHCF Notably, when we synthesize our results with published data, we identify linear relationships of pHCF with the seawater [DIC]/[H+] ratio, [AT]/ [H+] ratio and [[Formula: see text]]. Our findings contribute new insights into the mechanisms determining the sensitivity of coral calcification to changes in seawater carbonate chemistry, which are needed for predicting effects of environmental change on coral reefs and for robust interpretations of isotopic palaeoenvironmental records in coral skeletons. PMID- 28100815 TI - Stress induced hyperthermia in zebrafish: a reply to Key et al. PMID- 28100814 TI - Predicting behavioural responses to novel organisms: state-dependent detection theory. AB - Human activity alters natural habitats for many species. Understanding variation in animals' behavioural responses to these changing environments is critical. We show how signal detection theory can be used within a wider framework of state dependent modelling to predict behavioural responses to a major environmental change: novel, exotic species. We allow thresholds for action to be a function of reserves, and demonstrate how optimal thresholds can be calculated. We term this framework 'state-dependent detection theory' (SDDT). We focus on behavioural and fitness outcomes when animals continue to use formerly adaptive thresholds following environmental change. In a simple example, we show that exposure to novel animals which appear dangerous-but are actually safe-(e.g. ecotourists) can have catastrophic consequences for 'prey' (organisms that respond as if the new organisms are predators), significantly increasing mortality even when the novel species is not predatory. SDDT also reveals that the effect on reproduction can be greater than the effect on lifespan. We investigate factors that influence the effect of novel organisms, and address the potential for behavioural adjustments (via evolution or learning) to recover otherwise reduced fitness. Although effects of environmental change are often difficult to predict, we suggest that SDDT provides a useful route ahead. PMID- 28100816 TI - Diets derived from maize monoculture cause maternal infanticides in the endangered European hamster due to a vitamin B3 deficiency. AB - From 1735 to 1940, maize-based diets led to the death of hundreds of thousands of people from pellagra, a complex disease caused by tryptophan and vitamin B3 deficiencies. The current cereal monoculture trend restricts farmland animals to similarly monotonous diets. However, few studies have distinguished the effects of crop nutritional properties on the reproduction of these species from those of other detrimental factors such as pesticide toxicity or agricultural ploughing. This study shows that maize-based diets cause high rates of maternal infanticides in the European hamster, a farmland species on the verge of extinction in Western Europe. Vitamin B3 supplementation is shown to effectively restore reproductive success in maize-fed females. This study pinpoints how nutritional deficiencies caused by maize monoculture could affect farmland animal reproduction and hence their fitness. PMID- 28100817 TI - Mechanical sensitivity and the dynamics of evolutionary rate shifts in biomechanical systems. AB - The influence of biophysical relationships on rates of morphological evolution is a cornerstone of evolutionary theory. Mechanical sensitivity-the correlation strength between mechanical output and the system's underlying morphological components-is thought to impact the evolutionary dynamics of form-function relationships, yet has rarely been examined. Here, we compare the evolutionary rates of the mechanical components of the four-bar linkage system in the raptorial appendage of mantis shrimp (Order Stomatopoda). This system's mechanical output (kinematic transmission (KT)) is highly sensitive to variation in its output link, and less sensitive to its input and coupler links. We found that differential mechanical sensitivity is associated with variation in evolutionary rate: KT and the output link exhibit faster rates of evolution than the input and coupler links to which KT is less sensitive. Furthermore, for KT and, to a lesser extent, the output link, rates of evolution were faster in 'spearing' stomatopods than 'smashers', indicating that mechanical sensitivity may influence trait-dependent diversification. Our results suggest that mechanical sensitivity can impact morphological evolution and guide the process of phenotypic diversification. The connection between mechanical sensitivity and evolutionary rates provides a window into the interaction between physical rules and the evolutionary dynamics of morphological diversification. PMID- 28100818 TI - Lowland biotic attrition revisited: body size and variation among climate change 'winners' and 'losers'. AB - The responses of lowland tropical communities to climate change will critically influence global biodiversity but remain poorly understood. If species in these systems are unable to tolerate warming, the communities-currently the most diverse on Earth-may become depauperate ('biotic attrition'). In response to temperature changes, animals can adjust their distribution in space or their activity in time, but these two components of the niche are seldom considered together. We assessed the spatio-temporal niches of rainforest mammal species in Borneo across gradients in elevation and temperature. Most species are not predicted to experience changes in spatio-temporal niche availability, even under pessimistic warming scenarios. Responses to temperature are not predictable by phylogeny but do appear to be trait-based, being much more variable in smaller bodied taxa. General circulation models and weather station data suggest unprecedentedly high midday temperatures later in the century; predicted responses to this warming among small-bodied species range from 9% losses to 6% gains in spatio-temporal niche availability, while larger species have close to 0% predicted change. Body mass may therefore be a key ecological trait influencing the identity of climate change winners and losers. Mammal species composition will probably change in some areas as temperatures rise, but full scale biotic attrition this century appears unlikely. PMID- 28100819 TI - Vertically transmitted rhabdoviruses are found across three insect families and have dynamic interactions with their hosts. AB - A small number of free-living viruses have been found to be obligately vertically transmitted, but it remains uncertain how widespread vertically transmitted viruses are and how quickly they can spread through host populations. Recent metagenomic studies have found several insects to be infected with sigma viruses (Rhabdoviridae). Here, we report that sigma viruses that infect Mediterranean fruit flies (Ceratitis capitata), Drosophila immigrans, and speckled wood butterflies (Pararge aegeria) are all vertically transmitted. We find patterns of vertical transmission that are consistent with those seen in Drosophila sigma viruses, with high rates of maternal transmission, and lower rates of paternal transmission. This mode of transmission allows them to spread rapidly in populations, and using viral sequence data we found the viruses in D. immigrans and C. capitata had both recently swept through host populations. The viruses were common in nature, with mean prevalences of 12% in C. capitata, 38% in D. immigrans and 74% in P. aegeria We conclude that vertically transmitted rhabdoviruses may be widespread in a broad range of insect taxa, and that these viruses can have dynamic interactions with their hosts. PMID- 28100820 TI - Support for the reproductive ground plan hypothesis in a solitary bee: links between sucrose response and reproductive status. AB - In social bees, foraging behaviour is correlated with reproductive status and sucrose sensitivity via endocrine pathways. This association led to the hypothesis that division of labour in social insect societies is derived from an ancestral ground plan that functions to synchronize dietary preferences with reproductive needs in solitary insects. However, the relationship between these traits is unknown for solitary bees, which represent the ancestral state of social bees. We used the proboscis extension response assay to measure sucrose response among reproductive females of the solitary alkali bee (Nomia melanderi) as a function of acute juvenile hormone (JH) treatments and reproductive physiology. We also tested long-term effects of JH on reproductive development in newly emerged females. JH did not have short-term effects on reproductive physiology or sucrose response, but did have significant long-term effects on ovary and Dufour's gland development. Dufour's gland size, not ovary development, was a significant predictor of sucrose response. This provides support for the reproductive ground plan hypothesis, because the Dufour's gland has conserved reproductive functions in bees. Differing results from this study and honeybees suggest independent origins of division of labour may have evolved via co-option of different components of a conserved ground plan. PMID- 28100821 TI - Tail regeneration after autotomy revives survival: a case from a long-term monitored lizard population under avian predation. AB - Caudal autotomy in lizards has intrigued scientists for more than 100 years. Because of the relative lack of literature under natural conditions, the complicated association among field autotomy rate, real predation pressure, the long-term cost of tail loss, and the benefit of regeneration remains equivocal. In this study, we conducted a 7-year capture-mark-recapture (CMR) programme with a wild population of a sexually dichromatic lizard, Takydromus viridipunctatus We used autotomy indexes and a contemporary bird census mega-dataset of four predatory birds as predictors to examine the association between tail loss and predation pressure. We further estimated the survival cost of tail loss and alleviation by regeneration under natural conditions through CMR modelling. We found that large and small avian predators affect lizard survival through the following two routes: the larger-sized cattle egret causes direct mortality while the smaller shrikes and kestrels are the major causes of autotomy. Following autotomy, the survival rate of tailless individuals over the next month was significantly lower than that of tailed individuals, especially males during the breeding season, which showed a decline of greater than 30%. This sex-related difference further demonstrated the importance of reproductive costs for males in this sexually dichromatic species. However, the risk of mortality returned to baseline after the tails were fully grown. This study indicates the benefit of tail regeneration under natural conditions, which increases our understanding of the cost-benefit dynamics of caudal autotomy and further explains the maintenance of this trait as an evolutionarily beneficial adaption to long-term predator-prey interactions. PMID- 28100822 TI - Conditional fetal and infant killing by male baboons. AB - Sexually selected feticide-the death of infants in utero as a result of male behaviour-has only rarely been described or analysed, although it is presumed to be favoured by the same selective pressures that favour sexually selected infanticide. To test this hypothesis, we measured the frequency of feticide and infanticide by male baboons of the Amboseli basin in Kenya, and examined which characteristics of a male and his environment made him more likely to commit feticide and/or infanticide. We found a dramatic increase in fetal and infant death rates, but no increase in death rates of 1- to 2-year-old individuals, following the immigration of males who stood to benefit from feticide and infanticide. Specifically, fetal and infant death rates were highest following immigrations in which: (i) the immigrant male rapidly attained high rank, (ii) that male remained consistently resident in the group for at least three months, (iii) food availability and social group range overlap was relatively low and (iv) relatively many pregnant females and/or dependent infants were present. Together, these results provide strong evidence for the existence of both sexually selected feticide and infanticide in our population, and they indicate that feticide and infanticide are conditional male behavioural strategies employed under particular circumstances. PMID- 28100823 TI - Conspicuous plumage colours are highly variable. AB - Elaborate ornamental traits are often under directional selection for greater elaboration, which in theory should deplete underlying genetic variation. Despite this, many ornamental traits appear to remain highly variable and how this essential variation is maintained is a key question in evolutionary biology. One way to address this question is to compare differences in intraspecific variability across different types of traits to determine whether high levels of variation are associated with specific trait characteristics. Here we assess intraspecific variation in more than 100 plumage colours across 55 bird species to test whether colour variability is linked to their level of elaboration (indicated by degree of sexual dichromatism and conspicuousness) or their condition dependence (indicated by mechanism of colour production). Conspicuous colours had the highest levels of variation and conspicuousness was the strongest predictor of variability, with high explanatory power. After accounting for this, there were no significant effects of sexual dichromatism or mechanisms of colour production. Conspicuous colours may entail higher production costs or may be more sensitive to disruptions during production. Alternatively, high variability could also be related to increased perceptual difficulties inherent to discriminating highly elaborate colours. Such psychophysical effects may constrain the exaggeration of animal colours. PMID- 28100824 TI - Asthma-COPD overlap syndrome showed more exacerbations however lower mortality than COPD. AB - Background: Asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is a new determinate syndrome whose exact characteristics remain unclear. Aim: The objective of this study is to find more difference between ACOS and COPD. Design: A retrospective study of ACOS and COPD in Chinese. Methods: Data from 65 patients with ACOS and 65 patients with COPD were retrospectively collected and analyzed. The basis of this study was to compare the two groups while ruling out differences in age, sex and smoking history. Results: Patients with ACOS tended to have earlier ages of onset, longer durations of symptoms, better nutritional status, higher single-breath diffusing capacity of carbon monoxide (DLCO) %predicted and airway resistance %predicted, more exacerbations in the preceding 12 months and shorter lengths of hospitalization. DLCO %predicted, airway resistance %predicted, and length of hospitalization were the variables most significantly associated with the presence of ACOS in patients with COPD. ROC correlating airway resistance %predicted value and current ACOS showed an optimal cutoff of airway resistance %predicted of over 296.6. During follow-up (median: 45 months; interquartile range: 6-82 months), 16 patient deaths were recorded (3 patients with ACOS). The risk remained significantly higher in patients with COPD alone than in patients with ACOS (HR 3.932; 95% CI 1.083-19.755; P = 0.046). Conclusion: Patients with ACOS were more likely to have better prognoses and lower mortality than those with COPD alone, though with greater exacerbation frequency. PMID- 28100825 TI - Understanding the cognitive experience of death and the near-death experience. PMID- 28100826 TI - Biomechanical properties of wheat grains: the implications on milling. AB - Millennia of continuous innovation have driven ever increasing efficiency in the milling process. Mechanically characterizing wheat grains and discerning the structure and function of the wheat bran layers can contribute to continuing innovation. We present novel shear force and puncture force testing regimes to characterize different wheat grain cultivars. The forces endured by wheat grains during the milling process can be quantified, enabling us to measure the impact of commonly applied grain pretreatments, such as microwave heating, extended tempering, enzyme and hormone treatments on grains of different 'hardness'. Using these methods, we demonstrate the importance of short tempering phases prior to milling and identify ways in which our methods can detect differences in the maximum force, energy and breaking behaviours of hard and soft grain types. We also demonstrate for the first time, endosperm weakening in wheat, through hormone stratification on single bran layers. The modern milling process is highly refined, meaning that small, cultivar specific, adjustments can result in large increases in downstream profits. We believe that methods such as these, which enable rapid testing of milling pretreatments and material properties can help to drive an innovation process that has been core to our industrial efforts since prehistory. PMID- 28100827 TI - Insights into resource consumption, cross-feeding, system collapse, stability and biodiversity from an artificial ecosystem. AB - Community ecosystems at very different levels of biological organization often have similar properties. Coexistence of multiple species, cross-feeding, biodiversity and fluctuating population dynamics are just a few of the properties that arise in a range of ecological settings. Here we develop a bottom-up model of consumer-resource interactions, in the form of an artificial ecosystem 'number soup', which reflects basic properties of many bacterial and other community ecologies. We demonstrate four key properties of the number soup model: (i) communities self-organize so that all available resources are fully consumed; (ii) reciprocal cross-feeding is a common evolutionary outcome, which evolves in a number of stages, and many transitional species are involved; (iii) the evolved ecosystems are often 'robust yet fragile', with keystone species required to prevent the whole system from collapsing; (iv) non-equilibrium dynamics and chaotic patterns are general properties, readily generating rich biodiversity. These properties have been observed in empirical ecosystems, ranging from bacteria to rainforests. Establishing similar properties in an evolutionary model as simple as the number soup suggests that these four properties are ubiquitous features of all community ecosystems, and raises questions about how we interpret ecosystem structure in the context of natural selection. PMID- 28100828 TI - An integrated modelling framework for neural circuits with multiple neuromodulators. AB - Neuromodulators are endogenous neurochemicals that regulate biophysical and biochemical processes, which control brain function and behaviour, and are often the targets of neuropharmacological drugs. Neuromodulator effects are generally complex partly owing to the involvement of broad innervation, co-release of neuromodulators, complex intra- and extrasynaptic mechanism, existence of multiple receptor subtypes and high interconnectivity within the brain. In this work, we propose an efficient yet sufficiently realistic computational neural modelling framework to study some of these complex behaviours. Specifically, we propose a novel dynamical neural circuit model that integrates the effective neuromodulator-induced currents based on various experimental data (e.g. electrophysiology, neuropharmacology and voltammetry). The model can incorporate multiple interacting brain regions, including neuromodulator sources, simulate efficiently and easily extendable to large-scale brain models, e.g. for neuroimaging purposes. As an example, we model a network of mutually interacting neural populations in the lateral hypothalamus, dorsal raphe nucleus and locus coeruleus, which are major sources of neuromodulator orexin/hypocretin, serotonin and norepinephrine/noradrenaline, respectively, and which play significant roles in regulating many physiological functions. We demonstrate that such a model can provide predictions of systemic drug effects of the popular antidepressants (e.g. reuptake inhibitors), neuromodulator antagonists or their combinations. Finally, we developed user-friendly graphical user interface software for model simulation and visualization for both fundamental sciences and pharmacological studies. PMID- 28100829 TI - A mathematical model of tumour angiogenesis: growth, regression and regrowth. AB - Cancerous tumours have the ability to recruit new blood vessels through a process called angiogenesis. By stimulating vascular growth, tumours get connected to the circulatory system, receive nutrients and open a way to colonize distant organs. Tumour-induced vascular networks become unstable in the absence of tumour angiogenic factors (TAFs). They may undergo alternating stages of growth, regression and regrowth. Following a phase-field methodology, we propose a model of tumour angiogenesis that reproduces the aforementioned features and highlights the importance of vascular regression and regrowth. In contrast with previous theories which focus on vessel remodelling due to the absence of flow, we model an alternative regression mechanism based on the dependency of tumour-induced vascular networks on TAFs. The model captures capillaries at full scale, the plastic dynamics of tumour-induced vessel networks at long time scales, and shows the key role played by filopodia during angiogenesis. The predictions of our model are in agreement with in vivo experiments and may prove useful for the design of antiangiogenic therapies. PMID- 28100830 TI - Neural bases of recommendations differ according to social network structure. AB - Ideas spread across social networks, but not everyone is equally positioned to be a successful recommender. Do individuals with more opportunities to connect otherwise unconnected others-high information brokers-use their brains differently than low information brokers when making recommendations? We test the hypothesis that those with more opportunities for information brokerage may use brain systems implicated in considering the thoughts, perspectives, and mental states of others (i.e. 'mentalizing') more when spreading ideas. We used social network analysis to quantify individuals' opportunities for information brokerage. This served as a predictor of activity within meta-analytically defined neural regions associated with mentalizing (dorsomedial prefrontal cortex, temporal parietal junction, medial prefrontal cortex, /posterior cingulate cortex, middle temporal gyrus) as participants received feedback about peer opinions of mobile game apps. Higher information brokers exhibited more activity in this mentalizing network when receiving divergent peer feedback and updating their recommendation. These data support the idea that those in different network positions may use their brains differently to perform social tasks. Different social network positions might provide more opportunities to engage specific psychological processes. Or those who tend to engage such processes more may place themselves in systematically different network positions. These data highlight the value of integrating levels of analysis, from brain networks to social networks. PMID- 28100835 TI - Good to the last "emulsified" drop. AB - Nanoliter scale droplets sealed and encapsulated in solid PEFE polymer shells are combined with graphical coding to advance droplet microfluidics. PMID- 28100832 TI - Reporter gene imaging of targeted T cell immunotherapy in recurrent glioma. AB - High-grade gliomas are aggressive cancers that often become rapidly fatal. Immunotherapy using CD8+ cytotoxic T lymphocytes (CTLs), engineered to express both herpes simplex virus type 1 thymidine kinase (HSV1-TK) and interleukin-13 (IL-13) zetakine chimeric antigen receptor (CAR), is a treatment strategy with considerable potential. To optimize this and related immunotherapies, it would be helpful to monitor CTL viability and trafficking to glioma cells. We show that noninvasive positron emission tomography (PET) imaging with 9-[4-[18F]fluoro-3 (hydroxymethyl)butyl]guanine ([18F]FHBG) can track HSV1-tk reporter gene expression present in CAR-engineered CTLs. [18F]FHBG imaging was safe and enabled the longitudinal imaging of T cells stably transfected with a PET reporter gene in patients. Further optimization of this imaging approach for monitoring in vivo cell trafficking should greatly benefit various cell-based therapies for cancer. PMID- 28100836 TI - A sterile animal model for neuroinflammation? AB - MRI-guided pulsed focused ultrasound combined with systemic infusion of contrast agent microbubbles induces local neuroinflammation in the rat. PMID- 28100834 TI - Soft robotic sleeve supports heart function. AB - There is much interest in form-fitting, low-modulus, implantable devices or soft robots that can mimic or assist in complex biological functions such as the contraction of heart muscle. We present a soft robotic sleeve that is implanted around the heart and actively compresses and twists to act as a cardiac ventricular assist device. The sleeve does not contact blood, obviating the need for anticoagulation therapy or blood thinners, and reduces complications with current ventricular assist devices, such as clotting and infection. Our approach used a biologically inspired design to orient individual contracting elements or actuators in a layered helical and circumferential fashion, mimicking the orientation of the outer two muscle layers of the mammalian heart. The resulting implantable soft robot mimicked the form and function of the native heart, with a stiffness value of the same order of magnitude as that of the heart tissue. We demonstrated feasibility of this soft sleeve device for supporting heart function in a porcine model of acute heart failure. The soft robotic sleeve can be customized to patient-specific needs and may have the potential to act as a bridge to transplant for patients with heart failure. PMID- 28100831 TI - Coexistence of potent HIV-1 broadly neutralizing antibodies and antibody sensitive viruses in a viremic controller. AB - Some HIV-1-infected patients develop broad and potent HIV-1 neutralizing antibodies (bNAbs) that when passively transferred to mice or macaques can treat or prevent infection. However, bNAbs typically fail to neutralize coexisting autologous viruses due to antibody-mediated selection against sensitive viral strains. We describe an HIV-1 controller expressing HLA-B57*01 and HLA-B27*05 who maintained low viral loads for 30 years after infection and developed broad and potent serologic activity against HIV-1. Neutralization was attributed to three different bNAbs targeting nonoverlapping sites on the HIV-1 envelope trimer (Env). One of the three, BG18, an antibody directed against the glycan-V3 portion of Env, is the most potent member of this class reported to date and, as revealed by crystallography and electron microscopy, recognizes HIV-1 Env in a manner that is distinct from other bNAbs in this class. Single-genome sequencing of HIV-1 from serum samples obtained over a period of 9 years showed a diverse group of circulating viruses, 88.5% (31 of 35) of which remained sensitive to at least one of the temporally coincident autologous bNAbs and the individual's serum. Thus, bNAb-sensitive strains of HIV-1 coexist with potent neutralizing antibodies that target the virus and may contribute to control in this individual. When administered as a mix, the three bNAbs controlled viremia in HIV-1YU2-infected humanized mice. Our finding suggests that combinations of bNAbs may contribute to control of HIV-1 infection. PMID- 28100837 TI - ERAD-icating mutant insulin promotes functional insulin secretion. AB - Overexpression of a chaperone protein liberates functional insulin from a misfolded mutant partner to improve insulin secretion. PMID- 28100838 TI - CAR T cells engage in anticancer martial arts. AB - A clever redesign of the chimeric antigen receptor T cell concept turns a cancer mediated immunosuppressive cytokine into a growth signal. PMID- 28100840 TI - Sialic acids in squamous cell carcinoma of the head and neck. AB - Altered glycosylation is a universal characteristic of cancer cells, and various types of glycan structures are well-known markers of tumor progression and invasion. The present article discusses this aspect of the role of sialic acid, biosynthesis of sialylglycoconjugates and the genetic basis of its disorder, as well as the effects and the correlation between altered sialylation and clinical prognosis in head and neck squamous cell carcinoma (HNSCC). Only a few studies concerning the level of sialic acid in head and neck tumors have been conducted so far. The conclusions of the published reports dedicated to that problem confirm the presence of elevated levels of total sialic acid in these tumors. The authors do not always agree with the level of free or associated form of sialic acid correlated with tumor size, severity of the condition, and lymph nodes. Comparing the progress that has been made in the diagnosis and treatment of other cancers thanks to extensive work on the role of sialic acids, we come to the conclusion that only further detailed studies of this subject in relation to HNSCC are able to answer the question whether the extent of glycoforms of sialic acid may act as a tumor marker or target of immunotherapy. PMID- 28100833 TI - Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies. AB - Cytolytic CD8 T cells play a crucial role in the control and elimination of virus infected cells and are a major focus of HIV cure efforts. However, it has been shown that HIV-specific CD8 T cells are infrequently found within germinal centers (GCs), a predominant site of active and latent HIV infection. We demonstrate that HIV infection induces marked changes in the phenotype, frequency, and localization of CD8 T cells within the lymph node (LN). Significantly increased frequencies of CD8 T cells in the B cell follicles and GCs were found in LNs from treated and untreated HIV-infected individuals. This profile was associated with persistent local immune activation but did not appear to be directly related to local viral replication. Follicular CD8 (fCD8) T cells, despite compromised cytokine polyfunctionality, showed good cytolytic potential characterized by high ex vivo expression of granzyme B and perforin. We used an anti-HIV/anti-CD3 bispecific antibody in a redirected killing assay and found that fCD8 T cells had better killing activity than did non-fCD8 T cells. Our results indicate that CD8 T cells with potent cytolytic activity are recruited to GCs during HIV infection and, if appropriately redirected to kill HIV-infected cells, could be an effective component of an HIV cure strategy. PMID- 28100842 TI - Prognostic value of thymidine kinase activity in patients with chronic lymphocytic leukemia. AB - Thymidine kinase (TK) activity is a marker of biological activity that allows the indolent and aggressive forms of chronic lymphocytic leukemia (CLL) to be distinguished. The aims of the study were to determine the relationship between TK activity and clinical status and prognosis, as well as to compare its activity with that of other prognostic and predictive factors. TK activity was measured in patient sera at the time of diagnosis using the DiviTum method, with the mean value being 439 Du/L. A correlation was found between TK activity and risk of disease progression (p=0.045). The optimal discriminative value of TK activity in the prediction of CLL progression was found to be 600 Du/L. TK activity significantly differed between the patients who achieved complete remission and those who only partially responded to therapy. In 93% of patients without any response to treatment and 18 out of 20 patients with progressive disease, TK activity over 600 Du/L was noted. In addition, all of the 10 patients with 17p13 deletion displayed TK activity of over 600 Du/L (p=0.0004). High TK activity also correlated with elevated levels of LDH (p=0.001) and beta2-microglobulin (p=0.03) in the study group. The results of the study indicated the importance of TK activity as a prognostic factor in patients with CLL. PMID- 28100841 TI - Cannabinoids - a new weapon against cancer? AB - Cannabis has been cultivated by man since Neolithic times. It was used, among others for fiber and rope production, recreational purposes and as an excellent therapeutic agent. The isolation and characterization of the structure of one of the main active ingredients of cannabis - Delta9 - tetrahydrocannabinol as well the discovery of its cannabinoid binding receptors CB1 and CB2, has been a milestone in the study of the possibilities of the uses of Cannabis sativa and related products in modern medicine. Many scientific studies indicate the potential use of cannabinoids in the fight against cancer. Experiments carried out on cell lines in vitro and on animal models in vivo have shown that phytocannabinoids, endocannabinoids, synthetic cannabinoids and their analogues can lead to inhibition of the growth of many tumor types, exerting cytostatic and cytotoxic neoplastic effect on cells thereby negatively influencing neo angiogenesis and the ability of cells to metastasize. The main molecular mechanism leading to inhibition of proliferation of cancer cells by cannabinoids is apoptosis. Studies have shown, however, that the process of apoptosis in cells, treated with recannabinoids, is a consequence of induction of endoplasmic reticulum stress and autophagy. On the other hand, in the cellular context and dosage dependence, cannabinoids may enhance the proliferation of tumor cells by suppressing the immune system or by activating mitogenic factors. Leading from this there is a an obvious need to further explore cannabinoid associated molecular pathways making it possible to develop safe therapeutic drug agents for patients in the future. PMID- 28100839 TI - Tyrosine kinase blocking collagen IV-derived peptide suppresses ocular neovascularization and vascular leakage. AB - Vascular endothelial growth factor (VEGF)-neutralizing proteins provide benefit in several retinal and choroidal vascular diseases, but some patients still experience suboptimal outcomes, and the need for frequent intraocular injections is a barrier to good outcomes. A mimetic peptide derived from collagen IV, AXT107, suppressed subretinal neovascularization (NV) in two mouse models predictive of effects in neovascular age-related macular degeneration (NVAMD) and inhibited retinal NV in a model predictive of effects in ischemic retinopathies. A combination of AXT107 and the current treatment aflibercept suppressed subretinal NV better than either agent alone. Furthermore, AXT107 caused regression of choroidal NV. AXT107 reduced the VEGF-induced vascular leakage that underlies macular edema in ischemic retinopathies and NVAMD. In rabbit eyes, which are closer to the size of human eyes, intraocular injection of AXT107 significantly reduced VEGF-induced vascular leakage by 86% at 1 month and 70% at 2 months; aflibercept significantly reduced leakage by 69% at 1 month and did not reduce leakage at 2 months, demonstrating the longer effectiveness of AXT107. AXT107 reduced ligand-induced phosphorylation of multiple receptors: VEGFR2, c Met, and PDGFRbeta. Optimal signaling through these receptors requires complex formation with beta3 integrin, which was reduced by AXT107 binding to alphavbeta3 AXT107 also reduced total VEGFR2 levels by increasing internalization, ubiquitination, and degradation. This biomimetic peptide is a sustained, multitargeted therapy that may provide advantages over intraocular injections of specific VEGF-neutralizing proteins. PMID- 28100843 TI - Pathophysiology and molecular basis of selected metabolic abnormalities in Huntington's disease. AB - Huntington's disease (HD) is an incurable, devastating neurodegenerative disease with a known genetic background and autosomally dominant inheritance pattern. HTT gene mutation (mHTT) is associated with polymorphic fragment elongation above 35 repeats of the CAG triplet. The mHTT product is an altered protein with a poly-Q elongated fragment, with the highest expression determined in the central nervous system (CNS) and with differentiated expression outside the CNS. A drastic loss of striatal and deeper layers of the cerebral cortex neurons was determined in the CNS, but muscle and body weight mass loss with dysfunction of many organs was also observed. HD symptoms include neurological disturbances, such as choreal movements with dystonia, speech and swallowing impairments, and additionally a variety of psychiatric and behavioral symptoms with cognitive decline have been described. They are the result of disturbances of several cellular pathways related to signal transmission, mitochondrial dysfunction and energy metabolism impairment shown by gene and protein expression and alteration of their functions. Impairment of energy processes demonstrated by a decrease of ATP production and increase of oxidative stress markers was determined in- and outside of the CNS in glycolysis, the Krebs cycle and the electron transport chain. A correlation between the increase of energy metabolism impairment level and the increase in number of CAG repeats in HTT has often been described. The energy metabolism study is an initial stage of sensitive biomarkers and a new therapeutic investigative option for early application in order to inhibit pathological processes in HD. Identification of pathological changes outside the CNS requires a reevaluation of diagnostic and therapeutic rules in HD. PMID- 28100844 TI - Phospholipids and products of their hydrolysis as dietary preventive factors for civilization diseases. AB - The results of numerous epidemiological studies indicate that phospholipids play an important role in the prevention of chronic diseases faced by contemporary society. Firstly, these compounds are responsible for the proper functioning of cell membranes, by ensuring liquidity and permeability, which is pivotal for normal activity of membrane proteins, including receptors. These mechanisms are at the core of prevention of cancer, autoimmune or neurological disorders. Secondly, structure and properties of phospholipids cause that they are highly available source of biologically active fatty acids. Thirdly, also products of endogenous hydrolysis of phospholipids exhibit biological activity. These include lysophospholipids formed as a result of disconnecting free fatty acid from glycerophospholipids in the reaction catalyzed by phospholipase A, phosphatidic acid and hydrophilic subunits released by the activity of phospholipase D. The bioactive products of hydrolysis also include ceramides liberated from phosphosphingolipids after removal of a hydrophilic unit catalyzed by sphingomyelinase. Phospholipids are supplied to the human body with food. A high content of phospholipids is characteristic for egg yolk, liver, pork and poultry, as well as some soy products. Particularly beneficial are phospholipids derived from seafood because they are a rich source of essential fatty acids of the n-3 family. PMID- 28100846 TI - Regulatory lymphocytes in thyroid orbitopathy and autoimmune thyroid diseases. AB - Thyroid orbitopathy (OT), as an organ-specific autoimmune disease, is a result of immune dysregulation leading to loss of control over inflammation directed against self-antigens. The source of the autoreactive lymphocytes is the impairment of central tolerance as well as their induction on the periphery by modified or sequestered by that time antigens. Active suppression by the various subpopulations of regulatory lymphocytes (Lreg) acts as a counterbalance to the proinflammatory factors and is aimed at dampening pathological reaction. Thereby, qualitative or quantitative shortfalls of Lreg play a critical role in the development of autoimmune diseases. Giving direction to Lreg-based therapy and restoring the dynamic balance seem to be of crucial importance, especially in diseases such as OT, where the causative self-antigen is not yet unequivocally elucidated. Technical difficulties with isolation and assessment of Lreg function in vitro as well as lack of unification of research protocols make the findings non-comparable, inconclusive and sometimes even conflicting. Lack of a Tregs' (regulatory T cells) specific set of surface markers makes the demethylation status analysis of TSDR (Treg specific demethylated region) FOXP3 (forkhead box P3) locus the most reliable method of their quantification. Despite numerous discrepancies between research findings, most of them point to Lreg's pivotal role in immune disturbances, which form the basis of OT and autoimmune thyroid diseases (AITD). PMID- 28100845 TI - Role of prometastatic factors in gastric cancer development. AB - The second half of the 20th century has seen a sharp worldwide decline in both the incidence and mortality of gastric cancer. Despite this, gastric cancer is the most common cause of mortality in the world. It is closely related to the commonly asymptomatic course at the beginning and delayed diagnosis. Approximately 90-97% of stomach cancers are adenocarcinomas, which may be subdivided histologically into two categories - intestinal type, and diffuse type. Cancer metastasis is a complex multi-step process that is closely associated with tumor phenotype. The most important steps in the metastasis process are proteolytic activity, migration, adhesion, proliferation, and neovascularization. In this review we focus on mechanisms regulating gastric cancer metastasis. PMID- 28100847 TI - Genetic background of aberrant thermogenin expression (UCP1) in obesity leading to metabolic syndrome. AB - Cardiovascular and metabolic disturbances individually and interdependently lead to chronic pathological conditions observed in cardio-metabolic diseases (CMDs). In Europe, the morbidity and mortality caused by cardiovascular disease are the highest among all diseases. Therefore, it seems important to search for new and alternative therapies for obesity, which is the main cause of type 2 diabetes (T2D) and cardiovascular disease (CD). Great attention has been paid to the role of brown adipose tissue in fat burning and the possibility of transformation of the white adipose tissue to cells with brown adipose tissue function as a potential form of treatment of obesity. The best-characterized marker of brown adipose tissue is uncoupling protein 1 (UCP1), which has the ability to dissipate energy as heat in the process called non-shivering thermogenesis. Numerous studies have shown that altered expression of this protein can lead to disturbances in fat metabolism. One possible reason for the aberrant expression of UCP1 may be inherited variations in the gene encoding that protein. Therefore, several studies investigating the role of polymorphisms in the gene encoding UCP1 in susceptibility to obesity or metabolic syndrome have been performed. Here we summarize the results of studies describing the associations between the UCP1 gene polymorphisms A-3826G, A-1766G, Met229Leu and Ala64Thr and polymorphism Trp64Arg in the beta3-AR gene, their correlations and their associations with the occurrence of metabolic syndrome. PMID- 28100848 TI - Influence of 28-O-propynoylbetulin on proliferation and apoptosis of melanotic and amelanotic human melanoma cells. AB - INTRODUCTION: A relatively new approach in treatment of malignant melanoma is the use of betulin and its synthetic derivatives that have anticancer properties. The aim of the study was to determine the effect of an acetylenic derivative of betulin, 28-O-propynoylbetulin, on cell growth and apoptosis induction in human melanotic and amelanotic melanoma cells. MATERIALS AND METHODS: The A2058 and C32 cell lines were incubated with 28-O-propynoylbetulin (working solutions from 0.1 to 10 MUg/ml). To evaluate cell proliferation, a sulforhodamine B based assay was conducted. In order to elucidate the early stages of apoptosis in both melanoma cell lines, caspase-3 activity was evaluated. RESULTS: The administration of 28-O propynoylbetulin at a concentration equal to or less than 1 MUg/ml did not cause a statistically significant change in the cell proliferation in either melanoma cell line (compared to control, p>0.05). Higher concentrations of the compound (3 and 10 MUg/ml) inhibited the cell growth (in comparison to control, p<0.05). These results corresponded with caspase-3 activity results that revealed an increase of enzyme activity after 24-hour incubation with 3 and 10 MUg/ml of the compound (compared to control, p<0.05). DISCUSSION: The study revealed that 28-O propynoylbetulin may have diverse effects on melanoma cells and could be a strong inhibitor of cell growth (C32 cells) or exert a more potent proapoptotic effect (A2058 cells). These findings support the possibility of the use of EB5 in different antimelanoma approaches. PMID- 28100849 TI - The role genes encoding of killer cell immunoglobulin-like receptors (KIRs) and their ligands in susceptibility to and progression of HIV infection. AB - NK cells are a part of the innate antiviral response. Their activity is regulated by signals from the surface receptors. Some of them, known as killer cell immunoglobulin-like receptors (KIRs), determine the quality and intensity of the immunological response, together with their ligands (HLA class I). KIR genes are very polymorphic, and this is reflected in the NK activity modulation. The stimulation of NK cells, especially in the early stages of the infection, can reduce the transmission of HIV or slow down the progression of infection. The varied KIR/HLA repertoire is a limiting factor for the risk of HIV infection and disease progression. Such diversity enables optimal regulation of NK cells and maintenance of the balance between activation to eliminate infected cells and inhibition. The control of NK cell activity via KIR3DL1/3DS1 and HLA-Bw4 (especially Bw4-80I) seems to be very important in the HIV context. With a few exceptions, it leads to a reduction of susceptibility to HIV infection and better viremia control, and slows down depletion of CD4+ T cells. Incompatibility of sexual partners for KIRs and HLA may oblige NK cells from the exposed partner to reject incoming cells from the HIV-positive partner. The presence of the inhibitory KIR, in the absence of its ligand, results in a lower threshold of NK cell activation, which reduces the chance of infection. The presence of an inhibitory receptor with a low affinity to the ligand (KIR2DL3+HLA-C1) is associated with lower susceptibility, and the effective NK cell inhibition (KIR2DL2+HLA-C1) results in increased susceptibility to HIV infection. The advantage of activating KIRs, especially in the presence of their ligands, is associated with higher cytolytic abilities, and thus reduced risk of HIV infection. If the virus is not eliminated in an early stage of infection, massive activation of NK is unfavorable due to the excessive stimulation of the immune system. PMID- 28100850 TI - Molecular characteristic and physiological role of DOPA-decarboxylase. AB - The enzyme DOPA decarboxylase (aromatic-L-amino-acid decarboxylase, DDC) plays an important role in the dopaminergic system and participates in the uptake and decarboxylation of amine precursors in the peripheral tissues. Apart from catecholamines, DDC catalyses the biosynthesis of serotonin and trace amines. It has been shown that the DDC amino acid sequence is highly evolutionarily conserved across many species. The activity of holoenzyme is regulated by stimulation/blockade of membrane receptors, phosphorylation of serine residues, and DDC interaction with regulatory proteins. A single gene codes for DDC both in neuronal and non-neuronal tissue, but synthesized isoforms of mRNA differ in the 5' UTR and in the presence of alternative exons. Tissue-specific expression of the DDC gene is controlled by two spatially distinct promoters - neuronal and non neuronal. Several consensus sequences recognized by the HNF and POU family proteins have been mapped in the neuronal DDC promoter. Since DDC is located close to the imprinted gene cluster, its expression can be subjected to tightly controlled epigenetic regulation. Perturbations in DDC expression result in a range of neurodegenerative and psychiatric disorders and correlate with neoplasia. Apart from the above issues, the role of DDC in prostate cancer, bipolar affective disorder, Parkinson's disease and DDC deficiency is discussed in our review. Moreover, novel and prospective clinical treatments based on gene therapy and stem cells for the diseases mentioned above are described. PMID- 28100851 TI - Effects of Propofol on Oxidative Stress Parameters in Selected Parts of the Brain in a Rat Model of Parkinson Disease. AB - INTRODUCTION: Propofol is an intravenous sedative-hypnotic agent that is commonly used to induce and maintain general anaesthesia. This drug has antioxidant properties, which are partly caused by a phenolic structure similar to alpha tocopherol. The present study aimed to evaluate the effect of propofol on the level of oxidative stress biomarkers in the frontal cortex, striatum, thalamus, hippocampus and cerebellum in rats with experimental Parkinson's disease (PD). MATERIAL/METHODS: The experiment was performed on 24 male Wistar rats assigned to the following groups: 1 - control; 2 - PD; 3 - PD with propofol. The dopaminergic systems were damaged with 6-hydroxydopamine (6-OHDA) administered to each lateral ventricle (2x15 MUg/5 MUl). 60 mg/kg of propofol was later given to the 8-week old rats intraperitoneally. The activities of superoxide dismutase (SOD) and its enzymes Cu/ZnSOD and MnSOD, together with the malondialdehyde (MDA) concentration, total oxidative status (TOS) and total antioxidant capacity (TAC), were measured. RESULTS: In the 2nd group, a significant increase in MDA concentration in the striatum, hippocampus and thalamus, and an increase of TOS in the striatum, thalamus and cerebellum were noted, along with a TAC decrease in the cortex, striatum and thalamus. Propofol caused a significant decrease in MDA levels in the cortex, striatum, hippocampus and thalamus, and a decrease in TOS levels in the cortex, striatum and cerebellum, with increased TAC in all evaluated structures. CONCLUSIONS: A shortage of natural antioxidants is observed in PD, along with an increase in pro-oxidants in many brain areas. Propofol inhibits oxidative stress in the brain, which shows its neuroprotective properties against oxidative damage. PMID- 28100852 TI - Allergenicity of milk of different animal species in relation to human milk. AB - Protein content in cow milk (with over 20 proteins, and peptides may also occur as a result of enzymatic hydrolysis) ranges from 2.5% to 4.2% and is about 1.5-2 times higher than in human milk. Its most important allergens are considered to be beta-lactoglobulin (absent in human milk) and alphas1-casein. The most similar in composition to human milk is horse and donkey milk. It contains considerably more whey proteins (35-50%) than cow milk (about 20%), and the concentration of the most allergenic casein fraction alphas1 is 1.5-2.5 g/l. In comparison, the content of alphas1-casein in cow milk is about 10 g/l. beta-lactoglobulin present in donkey milk is a monomer, while in milk of ruminants it is a dimer. Like human milk, it contains a substantial amount of lactose (about 7%), which determines its flavour and facilitates calcium absorption. The high lysozyme content (about 1 g/l) gives it antibacterial properties (compared to trace amounts in ruminants). Camel milk is also more digestible and induces fewer allergic reactions, because it lacks beta-lactoglobulin, and its beta-casein has a different structure. It also contains (compared to cow milk) more antibacterial substances such as lysozyme, lactoferrin and immunoglobulins, and furthermore the number of immunoglobulins is compatible with human ones. Goat milk components have a higher degree of assimilability as compared to cow milk. Its main protein is beta-casein, with total protein content depending on the alphas1-casein genetic variant. Goats with the '0' variant do not synthesize this allergenic protein. Clinical and immunochemical studies indicate, however, that it cannot be a substitute for cow milk without the risk of an anaphylactic reaction. PMID- 28100853 TI - Antioxidant and antimicrobial properties of bioactive phytochemicals from cranberry. AB - In the rational human diet, the important role of fruits and vegetables, which are a source of bioactive phytochemicals, is emphasized. Among fruits particular attention, due to a number of documented health-promoting properties, is focused on cranberry. This fruit is characterized by the high content of antioxidant phenolic compounds, which may support the natural antioxidant defense system of the body in the prevention of damage caused by oxidative stress induced by reactive oxygen species (ROS). Therefore, cranberry is suggested for the prevention of civilization diseases such as atherosclerosis, hypertension and cancer, whose etiology is associated directly with oxidative stress. The health promoting potential of cranberry is also associated with its antibacterial activity resulting from the presence of proanthocyanidins (PAC) type A with documented anti-adherence properties. The best-established medical applications of cranberry fruits are prevention and treatment of bacterial infections of the urinary tract (UTI), infections of gastric mucosa, and infections of the oral cavity. Due to the widespread use of cranberry and pharmaceutical preparations containing PACs in treating UTI, it is very important to evaluate the absorption, bioavailability and metabolism of these compounds in the human body. PMID- 28100854 TI - The role of cancer stem cells in pathogenesis of colorectal cancer. AB - Colorectal cancer (CRC) is the third most commonly diagnosed cancer, accounting for about 10% of total adult malignancies worldwide. The majority of CRC cases are diagnosed at the late stage; thus the investigation of the pathogenesis of early-stage disease and its detection could prevent formation of metastasis, a leading cause of death. This review highlights the recent progress in the understanding of the development of cancer stem cells (CSCs) in the colon epithelium and mechanisms of their proliferation. Moreover, we describe the role of the CSCs in resistance to chemotherapy and formation of metastases. We present evidence for the importance of the interactions between CSCs and their environment in the propagation of the disease. It is hoped that further studies of colorectal cancer CSCs could be helpful in the early detection and improved therapy of this neoplasm. PMID- 28100855 TI - Trace elements as an activator of antioxidant enzymes. AB - Oxidative stress is a state of impaired balance between the formation of free radicals and antioxidant capacity of the body. It causes many defects of the body, e.g. lipid peroxidation, DNA and protein damage. In order to prevent the effects of oxidative stress, the organism has developed defence mechanisms. These mechanisms capture and inhibit the formation of free radicals and also chelate ion metals that catalyse free radical reactions. Trace elements are components of antioxidant enzymes involved in antioxidant mechanisms. Selenium, as a selenocysteine, is a component of the active site of glutathione peroxidase (GPx). The main function of GPx is neutralization of hydrogen peroxide (H2O2) and organic peroxide (LOOH). Furthermore, selenium is a structural part of a large group of selenoproteins that are necessary for proper functioning of the body. Manganese, copper and zinc are a part of the group of superoxide dismutase enzymes (MnSOD, Cu/ZnSOD), which catalyse the superoxide anion dismutation into hydrogen peroxide and oxygen. Formed hydrogen peroxide is decomposed into water and oxygen by catalase or glutathione peroxidase. An integral component of catalase (CAT) is iron ions. The concentration of these trace elements has a significant influence on the activity of antioxidant enzymes, and thus on defence against oxidative stress. Even a small change in the level of trace elements in the tissue causes a disturbance in their metabolism, leading to the occurrence of many diseases. PMID- 28100856 TI - [Deep Brain Stimulation for Parkinson Disease:Mechanisms and New Technology]. PMID- 28100857 TI - [Clinical Features and Findings in Patients with Unruptured Intracranial Aneurysms Aged >=80 Years]. AB - OBJECTIVE: It is difficult to decide whether to treat unruptured intracranial aneurysm(UIA)in elderly patients aged >=80 years because they have potentially shorter life expectancy and risks related to treatment. Here, we report the results of the treatment of patients aged >=80 years. METHODS: A retrospective review was performed in patients who underwent surgical or endovascular treatment between April 2012 and December 2015 at our institution. RESULTS: Between April 2012 and December 2015 we treated 130 UIA patients who presented with 145 aneurysms and 12 patients who presented with 14 aneurysms, who were aged >=80 years. One patient was male and the others were female. Their mean age was 81.9 years(range: 80-88 years). The aneurysms included ICA aneurysms(n=6), ACA aneurysms(n=1), MCA aneurysms(n=4), and BA aneurysms(n=3). The maximum sizes of the aneurysms were <=5mm(n=3), 5-10mm(n=8), and >=10mm(n=3). The reasons for treatment were as follows: symptomatic aneurysms(n=2), strong desire of the patient to treat their aneurysms(n=4), high risk of rupture because of the morphology of the aneurysm(n=4), concomitant presentation with a ruptured aneurysm(n=1), and recurrence after coil embolization(n=1). In the endovascular treatment we used dual anti-platelet drugs in all cases and a stent device in 3 cases. In all cases, we used general anesthesia. There were no complications during the operations or ischemic or hemorrhagic events after surgery. We identified subcutaneous hematoma at the puncture site in 2 cases. The modified Rankin Scale(mRS)score of no patient worsened compared to their preoperative mRS score. The average length of hospital stay was 31 days. In comparison with patients aged <=79 years, there was no significant worsening of the mRS score. In patients aged >=80 years, the length of their hospital stay was longer than that of younger patients. CONCLUSION: While caution is warranted when treating UIA patients aged >=80 years, our findings for the treatment of aged patients were noteworthy. This treatment is meritorious if the indications are well considered and an experienced physician performs the operation. However, there are problems associated with using anti-platelet drugs in elderly patients. PMID- 28100858 TI - [Semi-quantitative Assessment of Tinnitus Before and After Endovascular Treatment for Intracranial Dural Arteriovenous Fistula:Usefulness of the Tinnitus Handicap Inventory(THI)Score]. AB - Intracranial dural arteriovenous fistulas(dAVFs)cause pulsatile tinnitus that can easily impair the individual's quality of life. In this study, we aimed to assess the usefulness of the semi-quantitative Tinnitus Handicap Inventory(THI)score before and after endovascular treatment in patients with intracranial dAVF by determining the relationship between the severity of pulsatile tinnitus, radiographic findings, and the effect of treatment. This study included a total of 14 sides in 13 patients who underwent endovascular therapy for pulsatile tinnitus due to intracranial dAVFs between March 2014 and September 2015. Using THI scores, the severity of pulsatile tinnitus was semi-quantitatively evaluated before and within 7 days after transarterial or transvenous embolization. Pre treatment THI score was 37.9+/-24.0, ranging from 5 to 82. Transarterial or transvenous embolization significantly decreased THI score to 8.8+/-16.1(p<0.01). The average THI improvement(%)was 78.9+/-31.1% and significantly correlated with treatment results. Thus, THI improvement(%)was significantly lesser in patients with partial embolization than in those with near-total or complete embolization. These findings strongly suggest that THI score is quite useful in the semi quantitative evaluation of the effects of endovascular therapy in patients with intracranial dAVF. PMID- 28100859 TI - [Cotton-Dam Wash Cytology:A Technique for Diagnosis and Prevention of Dissemination during Resection of Metastatic Brain Tumors]. AB - The management of brain metastases has been important in neurosurgical oncology. Resection of a brain metastasis carries an increased risk of leptomeningeal dissemination than other treatment modalities such as irradiation or pharmacotherapy. We have utilized intraoperative wash cytology of cotton patties covering the brain surface. The cytology information contributes to making a decision of postoperative whole brain radiation. We named the method as "cotton dam", that serves as a check and catch of neoplastic cells on the brain surface during resection surgery. PMID- 28100860 TI - [A Pediatric Case of Intractable Cerebrospinal Fluid Leakage after Implantation of an Intrathecal Baclofen Pump]. AB - Intrathecal baclofen(ITB)infusion can offer a useful treatment for severe spasticity;however, numerous complications have been reported. We report a pediatric case in which intractable cerebrospinal fluid(CSF)leakage associated with several inconvenient symptoms arose after implantation of the ITB pump system. A 10-year-old girl with spastic quadriparesis and athetoid cerebral palsy underwent implantation of an ITB delivery system. After discharge, she presented with fluid collection surrounding the pump in the abdomen. The volume of fluid increased and was percutaneously aspirated every other week. However, conservative management failed to relieve fluid collection, which was suspected to be due to CSF leakage. She underwent additional purse-string suture of the point inserted catheter insertion in the back, epidural blood patch, and subfascial implantation of an anchor. However, none of these therapies proved effective. Progressive enlargement of the accumulated fluid was observed. Furthermore, symptoms of ITB withdrawal appeared. Lumbar-peritoneal shunting was performed, and the subcutaneous fluid collection was relieved postoperatively. The course after shunting was uneventful;hence, the dose of baclofen was stabilized. No recurrence of fluid collection was encountered for two years. Intractable CSF leakage was thought to be caused by wasting, occult hydrocephalus, and twisted movements. This case indicates that care is required in the management of CSF leakage after ITB pump implantation. PMID- 28100861 TI - [A Case of Intracranial Localized Castleman's Disease Mimicking Convexity Meningioma]. AB - A 68-year-old man presented with abnormal behavior and Todd's paralysis on the right side after having taken a bath. Computed tomography and magnetic resonance imaging revealed a tumor mimicking convexity meningioma that had a perifocal edema, although its mass was not very large. The patient underwent surgery, and full recovery was achieved following a total removal of the lesion. Pathohistological examination demonstrated an intermediate type of Castleman's disease. The final diagnosis was intracranial localized Castleman's disease because the results of the full physical examination and laboratory analyses were normal. Castleman's disease is a rare lymphoproliferative disorder of unknown etiology. Moreover, intracranial involvement is very rare. In cases of intracranial meningeal tumors with perifocal edema, we should take this disease into consideration in the differential diagnosis. PMID- 28100862 TI - [Bone Flap Resorption after Cranioplasty in Pediatric Patients:Report of 2 Cases]. AB - Aseptic bone flap resorption, a rare complication after cranioplasty following decompressive craniectomy, is more likely to develop in children. We experienced two cases of aseptic bone flap resorption and identified potential pathophysiological mechanisms through histological findings. In the first case, an 11-year-old girl underwent decompressive craniectomy due to brain swelling with contusion. An autologous bone flap was cryopreserved for four months. Twenty five months after cranioplasty with autologous bone flap, aseptic bone flap resorption was observed, and cranioplasty was performed with ceramic bone. Most of the histological findings in this case showed mature osseous tissue, while some showed osteoclasts and new bone formation due to endochondral ossification. In the second case, a 10-year-old girl underwent frontal craniectomy and removal of contusional hematoma. Fourteen months after cranioplasty with autologous bone flap, aseptic bone flap resorption was observed, and cranioplasty was performed with ceramic bone paste. The progression of bone flap resorption was not recognized for 12 months. In these cases, new bone formation was not necessarily linked to pathological bone flap resorption. It is supposed that the balance between bone destruction and new bone formation was disrupted by unknown factors. PMID- 28100863 TI - [Utility of Intraoperative Catheter Myelography during Intrathecal Baclofen Pump Implantation:Report of 2 Cases]. AB - We report two patients in whom the intrathecal baclofen(ITB)catheter was located in the subdural space, although we had confirmed good outflow of spinal fluid from the spinal catheter. Patient 1 was a woman in her 30s with spastic quadriplegia due to subarachnoid hemorrhage. An ITB pump was implanted, and a good outflow of spinal fluid from the spinal catheter was observed during the surgery. Postoperatively, her spasticity did not improve. Catheter myelography revealed that the spinal catheter was located in the subdural space. Using intraoperative catheter myelography, we corrected the position of the catheter. Patient 2 was a man in his 20s diagnosed with adrenoleukodystrophy. An ITB therapy was performed to improve his spastic gait. Intraoperative catheter myelography showed that the spinal catheter was located in the subdural space, although there was good outflow of spinal fluid from the catheter. Our experience suggests that the outflow of spinal fluid alone should not be used to determine the location of the spinal catheter. Intraoperative catheter myelography is useful for the correct placement of the spinal catheter in the subarachnoid space. PMID- 28100864 TI - [Pre- and Intra-Operative Supporting Technology for Brain Tumors(3)Surgical Approaches and Strategies for Third Ventricle Tumors]. PMID- 28100865 TI - Investigation of the 5q33.3 longevity locus and age-related phenotypes. AB - A large meta-analysis recently found the 5q33.3 locus to be associated with survival to >= 90 years and lower all-cause mortality, thus suggesting it as a third human longevity locus alongside APOE and FOXO3A. The 5q33.3 locus has previously been associated with blood pressure regulation and cardiovascular diseases in middle-aged individuals. However, part of the influence on mortality appears to be independent of cardiovascular phenotypes, and the role of the 5q33.3 locus in longevity and survival is therefore still partly unknown. We investigated the association between the longevity-associated variant rs2149954 on chromosome 5q33.3 and age-related phenotypes in two cohorts of 1,588 and 1,271 long-lived individuals (mean ages 93.1 and 95.9 years, respectively) as well as in 700 middle-aged and 677 elderly individuals (mean ages 52.5 and 78.7 years). Altogether, nominally significant associations between the rs2149954 minor allele and a decreased risk of heart attack and heart failure as well as increased physical functioning were found in the long-lived individuals. In the middle-aged and elderly individuals, rs2149954 minor allele carriers had a lower risk of hypertension. Our results thereby confirm a role of the 5q33.3 locus in cardiovascular health and, interestingly, they also suggest a role in physical functioning. PMID- 28100866 TI - Development of Intra-knee Joint Sustained-Release Gel Formulation and Evaluation of Its Pharmacological Efficiency in Rats. AB - In the development of a drug for intra-articular administration, a sustained release formulation is desirable since it is difficult to sustain the effects of conventional injections due to fast drug leakage from the joint cavity. In this study, we prepared sustained release gel formulations for intra-articular administration containing indocyanine green (ICG) as a model drug to follow its fate after intra-articular administration in rats with in-vivo imaging system (IVIS). ICG administered as an aqueous solution leaked from the joint cavity in a short time and was excreted out of the body within a day. On the other hand, ICG in the sustained-release formulations was retained and released in the joint cavity for a week. Next, we prepared a sustained-release formulation with hyaluronic acid (HA) as the gel base containing a pain-relief drug (Drug A). We had administered it and other formulations into the rat knee where we injected bradykinin to evaluate their walking distance after 1 and 3 d. The effect of an aqueous solution of Drug A disappeared on day 3. The HA gel formulation without Drug A was more effective than the aqueous solution. The HA gel formulation with Drug A was the most effective; the walking distance was about 85% of the baseline on day 3. This study showed that the gel formulations were effective to sustain the release of a drug in the knee joint, and that the combination of a pain relief drug with HA gel was effective to improve the mobility of the acute pain model rats. PMID- 28100867 TI - Effects of Pre- and Post-Administration of Vitamin A on the Growth of Refractory Cancers in Xenograft Mice. AB - Vitamin A is an essential nutrient that is obtained from the daily diet. The major forms of vitamin A in the body consist of retinol, retinal, retinoic acid (RA), and retinyl esters. Retinal is fundamental for vision and RA is used in clinical therapy of human acute promyelocytic leukemia. The actions of retinol and retinyl palmitate (RP) are not known well. Recently, we found that retinol is a potent anti-proliferative agent against human refractory cancers, including gallbladder cancer, being more effective than RA, while RP was inactive. In the current study, we determined serum retinol concentrations in xenograft mice bearing tumors derived from four refractory cancer cell lines. We also examined the effects of vitamin A on proliferation of human gallbladder cancer cells in vivo. Serum retinol concentrations were significantly lower in xenograft mice with tumors derived from various refractory cancer cell lines as compared with control mice. The growth of tumors was inhibited with increasing serum retinol concentrations obtained post-administration of RP. In addition, pre administration of RP increased serum retinol concentrations and suppressed tumor growth. These results indicate that administration of RP can maintain retinol concentrations in the body and that this might suppress cancer cell growth and attachment. The regulation of vitamin A concentration in the body, which is critical biomarker of health, could be beneficial for cancer prevention and therapy. PMID- 28100869 TI - Gonadotoropin actions on spermatogenesis and hormonal therapies for spermatogenic disorders [Review]. AB - Microdissection testicular sperm extraction and intracytoplasmic sperm injection have made it possible for men with non-obstructive azoospermia (NOA) to conceive a child. A majority of men cannot produce sperm because spermatogenesis per se is believed to be "irreversibly" disturbed. For these men, it has been thought that any hormonal therapy will be ineffective. Further understandings of endocrinological regulation of spermatogenesis are needed and LH or FSH receptor knock out (KO) mice have revealed the roles of gonadotropin separately. Spermatogenesis has been shown to shift during evolution from FSH to LH dominance because LH receptor KO causes infertility while FSH receptor KO does not. High concentrations of intratesticular testosterone secreted from Leydig cells, ranging from 100- to 1,000-fold higher than in the systemic circulation, has pivotal roles during spermatogenesis. This is especially important during spermiogenesis, a post-meiotic step for progression from round to elongating spermatids. Sertoli cells are the target of FSH and have numerous androgen receptors, indicating that Sertoli cells are regulated by FSH and the paracrine functions of testosterone. In combination with Leydig cell-derived growth factors, particularly epidermal growth factor-like growth factors, Sertoli cells support spermatogenesis, especially at proximal levels of spermatogenesis (e.g., spermatogonial proliferation). Taken together, the current knowledge from human studies indicating that testosterone optimization by clomiphene, hCG and/or aromatase inhibitors and high dose hCG/FSH treatment can, at least in part, improve spermatogenesis in NOA. Accordingly hormonal therapy may open a therapeutic window for sperm production in selected patients. PMID- 28100868 TI - Growth Inhibition of Refractory Human Gallbladder Cancer Cells by Retinol, and Its Mechanism of Action. AB - Among the constituents of the essential nutrient vitamin A, retinol is a potent suppressor of refractory cancer cell growth linked to tumor progression, showing greater efficacy than retinoic acid (RA). However, the mechanisms of retinol action on human refractory cancer are not known well. In the current study, we examined the actions of retinol on proliferation of human gallbladder cancer NOZ C-1 cells. Retinol and RA inhibited the proliferation of human NOZ C-1 cells in dose-dependent manner, while RA was less potent than retinol. Cell incorporation of RA was approximately two-fold higher than retinol and was not correlated with anti-proliferative activity. Retinol did not affect caspase-3 activity or mRNA expression of Bax and Bcl-2, which are associated with apoptosis. In addition, protein expression of phosphorylated extracellular signal-regulated kinase (p ERK)/ERK and p-Akt/Akt were not significantly changed by retinol treatment. In contrast, retinol treatment significantly increased the mRNA expression of endoplasmic reticulum (ER) stress factors (heme oxygenase 1 (HMOX1), CCAAT/enhancer-binding protein homologous protein (CHOP), 78 kDa glucose regulated protein (GRP78), and DnaJ (Hsp40) homolog, subfamily B, member 9 (DNAJB9)). Furthermore, the number of cells in the G0/G1 phase was increased, while the number of cells in the S phase were decreased by retinol treatment. Retinol increased expression of the autophagy-associated protein, LC3-II. These results indicate that retinol is a potent suppressor of gallbladder cancer cell growth by mechanisms that involve ER stress, which results in autophagy and cell cycle delay. This suggests that retinol might be useful for anticancer prevention and therapy in the clinic. PMID- 28100870 TI - Impact on Clinical Outcomes of Periodic Leg Movements During Sleep in Hospitalized Patients Following Acute Decompensated Heart Failure. AB - BACKGROUND: Periodic leg movements during sleep (PLM) are characterized by regularly recurring movement of the legs during sleep. Although PLM is common and a predictor of death in patients with chronic heart failure, the clinical significance of PLM in hospitalized patients with a reduced left ventricular ejection fraction (LVEF) following acute decompensated heart failure (ADHF) remains unknown.Methods and Results:After initial improvement of acute signs and symptoms of ADHF, 94 consecutive patients with reduced LVEF who underwent polysomnography were enrolled. They were divided into 2 groups based on the presence or absence of severe PLM defined as PLM index >=30. The risks for clinical events, composite of all-cause death and rehospitalization, were assessed using a stepwise multivariable Cox proportional model including variables showing P<0.10 in univariate analyses. Severe PLM was observed in 21 patients (22%). At a median follow-up of 5.2 months, 30 patients experienced clinical events (32%). In the multivariable analysis, the presence of severe PLM was significantly associated with increasing clinical events (hazard ratio, 2.16; 95% confidence interval, 1.03-4.54; P=0.042) independent of hemoglobin level and the severity of sleep-disordered breathing. CONCLUSIONS: In hospitalized patients with systolic dysfunction following ADHF, severe PLM was prevalent and significantly associated with increased risk of death and/or rehospitalization. PMID- 28100871 TI - In vivo direct reprogramming of liver cells to insulin producing cells by virus free overexpression of defined factors. AB - Direct reprogramming of autologous cells from diabetes patients to insulin producing cells is a new method for pancreatic cell replacement therapy. At present, transdifferentiation among mature cells is achieved mainly by introducing foreign genes into the starting tissue with viral vector, but there are potentical safety problems. In the present study, we delivered plasmids carrying Pdx1, Neurog3 and MafA genes (PNM) into mouse hepatocytes by hydrodynamics tail vein injection, investigated islet beta cells markers in transfected cells from protein and mRNA level, and then observed the long-term control of blood glucose in diabetic mice. We found that hepatocytes could be directly reprogrammed into insulin-producing cells after PNM gene transfection by non-viral hydrodynamics injection, and fasting blood glucose was reduced to normal, and lasted until 100 days after transfection. Intraperitoneal glucose tolerance test (IPGTT) showed that glucose regulation ability was improved gradually and the serum insulin level approached to the level of normal mice with time. Insulin-positive cells were found in the liver tissue, and the expression of various islet beta-cell-specific genes were detected at the mRNA level, including islet mature marker gene Ucn3. In conclusion, we provide a new approach for the treatment of diabetes by in vivo direct reprogramming of liver cells to insulin producing cells through non-viral methods. PMID- 28100872 TI - Serum Monokine Induced by Gamma Interferon Is Associated With Severity of Coronary Artery Disease. AB - The immune system may play important roles in the pathogenesis of cardiovascular disease. T-cell mediated immune responses in human progression of atherosclerotic disease and hypertension have recently been revealed, but the significance of T cell specific chemokines in coronary artery heart disease has not been confirmed. In our study, we sought to examine the association between serum levels of the monokine induced by gamma interferon (MIG)/CXCL9 and the severity of coronary artery disease. We studied 117 patients with coronary heart disease and 80 patients with no coronary heart disease. The severity of coronary artery disease was assessed via coronary artery angiography and the Gensini score was calculated. Clinical and biochemical indices, including serum levels of MIG, CD40L, and IFN-gamma were analyzed in all subjects. Finally, we found there was a significant correlation between serum MIG levels and the severity of coronary artery disease, quantified by the Gensini score (r = 0.122, P = 0.009). Furthermore, multivariate regression analysis revealed that serum MIG levels were independently associated with the severity of coronary artery disease, quantified by the Gensini score (beta = 0.100, P = 0.021). Our findings could indicate the potential clinical implication of MIG with respect to early coronary artery atherosclerosis in humans. PMID- 28100874 TI - Efficacy of Multidetector Computed Tomography to Predict Periprocedural Myocardial Injury After Percutaneous Coronary Intervention for Chronic Total Occlusion. AB - Specific signatures of culprit lesions detected on multidetector computed tomography (MDCT) were identified as predictors of periprocedural myocardial injury (PMI) after percutaneous coronary intervention (PCI) in patients with stable angina; PMI has been shown to be associated with a worse prognosis. We investigated the association between preprocedural culprit lesion characteristics, assessed by MDCT, and PMI after PCI for chronic total occlusion (CTO). From three medical centers, 81 patients who underwent pre-PCI MDCT and CTO PCI, and systematic cardiac troponin (cTn) sampling before and after PCI, were included. Patients were divided into two groups according to the presence or absence of post-PCI cTn elevation. Patient characteristics, MDCT findings, and procedural variables were compared between the two groups. Procedure success was observed in 65 patients (80.2%) and was not associated with PMI. The incidence of PMI was higher in patients treated with the retrograde versus the antegrade approach. On MDCT, lesion length and the presence of the napkin-ring sign were significantly associated with PMI. Multivariate analysis revealed that the lesion length (odds ratio [OR]: 1.04; 95% confidence interval [CI]: 1.01-1.08; P < 0.05), napkin-ring sign (OR: 5.41; 95% CI: 1.01-29.0; P < 0.05), and retrograde approach (OR: 4.78; 95% CI: 1.28-15.4; P < 0.05) were significant predictors of PMI. PMI is not uncommon in patients undergoing elective CTO PCI, regardless of procedure success or failure. Pre-PCI MDCT may help identify patients at high risk for PMI after CTO PCI. PMID- 28100873 TI - microRNA-10a Targets T-box 5 to Inhibit the Development of Cardiac Hypertrophy. AB - The mechanism of cardiac hypertrophy involving microRNAs (miRNAs) is attracting increasing attention. Our study aimed to investigate the role of miR-10a in cardiac hypertrophy development and the underlying regulatory mechanism.Transverse abdominal aortic constriction (TAAC) surgery was performed to establish a cardiac hypertrophy rat model, and angiotensin II (AngII) was used to induce cardiac hypertrophy in cultured neonatal rat cardiomyocytes. Expression of T-box 5 (TBX5) and miR-10a was altered by cell transfection of siRNA or miRNA mimic/inhibitor. Leucine incorporation assay, histological and cytological examination, quantitative real-time PCR (qRT-PCR), and Western blot were performed to detect the effects of miR-10a and TBX5 on cardiac hypertrophy. Dual luciferase reporter assay was conducted to verify the regulation of TBX5 by miR 10a.miR-10a was down-regulated, and TBX5 was up-regulated in the rat model and AngII-stimulated cardiomyocytes. miR-10a inhibited TBX5 expression by directly targeting the binding site in Tbx5 3'UTR. Overexpression of miR-10a in AngII treated cardiomyocytes decreased relative cell area, and significantly reduced the mRNA levels of natriuretic peptide A (Nppa), myosin heavy chain 7 cardiac muscle beta (Myh7), and leucine incorporation (P < 0.01 or P < 0.001). Knockdown of Tbx5 had similar effects on AngII-induced cardiomyocytes.Our findings indicate that miR-10a may inhibit cardiac hypertrophy via targeting Tbx5. Thus, miR-10a provides promising therapeutic strategies for the treatment of cardiac hypertrophy. PMID- 28100875 TI - The Role of Thiol/Disulphide Homeostasis in Anthracycline Associated Cardiac Toxicity. AB - The aim of the present study was to evaluate whether the baseline thiol/disulfide state can predict the occurrence of anthracycline induced cardiac toxicity. A total of 186 cancer patients receiving anthracycline (doxorubicin)-based chemotherapy were enrolled. All patients underwent 2-dimensional (2D) speckle tracking echocardiography (STE) to determine their left ventricular ejection fraction (LVEF) and blood samples for measuring thiol forms were obtained before treatment and 4 weeks after completion of the chemotherapy. The mean dose of doxorubicin exposure was 255 +/- 39.2 mg/m2. Baseline native thiol was found to be lower whereas baseline disulfide and the disulfide/total thiol ratio were found to be higher in patients who had a decrease in LVEF after anthracycline therapy. Also, the amount of decrease in LVEF was well correlated with the delta value of the thiol forms. Logistic regression analysis revealed that changes in BNP and global longitudinal strain (GLS), baseline level of native thiol, disulfide, and the disulfide/total thiol ratio were strong predictors for a decrease in LVEF.The thiol/disulfide pathway may be a factor for predicting chemotherapy-induced cardiac toxicity as one of the oxidative stress mechanisms. PMID- 28100876 TI - Primary Percutaneous Coronary Intervention Followed by Valve Surgery for Acute Coronary Syndrome at Left Main Trunk Complicated With Severe Aortic Stenosis. AB - An 89-year-old woman appeared to have acute coronary syndrome at the left main trunk (LMT) complicated with severe aortic stenosis, moderate-severe mitral regurgitation, depressed left ventricular (LV) function, and multivessel disease. Because of sustained hypotension even under intra-aortic balloon pumping support during emergency coronary angiograhy, we performed primary percutaneous coronary intervention solely for the LMT lesion using a bare metal stent, leading to recovery from the shock state. On the second hospital day, based on our heart team consensus, we performed aortic valve replacement and coronary artery bypass grafting surgery, and added edge-to-edge repair (Alfieri stitch) of the mitral valve, resulting in complete revascularization and dramatically improved LV function. PMID- 28100877 TI - Transcatheter Aortic Valve Implantation With Different Valve Designs for Severe Device Landing Zone Calcification. AB - Severe device landing zone calcification (DLZ-CA) predicted paravalvular leak (PVL) and post-dilatation (PD) after transcatheter aortic valve implantation (TAVI). The aim of this study was to determine the influence of DLZ-CA on PVL or PD rates after SAPIEN XT (XT) versus CoreValve (CV).We analyzed patients undergoing TAVI who had severe DLZ-CA. Severe DLZ-CA defined the upper left ventricular outflow tract calcification; the cross-sectional region 2 mm inferior to the annular plane. PVL was evaluated at 30days using transthoracic echocardiography. Overall, 133 patients had XT-TAVI and the remaining 41 patients had CV-TAVI. Two patients had annulus injury in the XT group (oversizing 20.2% and 20.5% for two XT cases). PD was less frequently performed in the XT group (34.1% versus 12.8%; P = 0.002), but PVL rates were similar between both groups (42.1% versus 41.5% for the XT and CV groups, respectively; P = 0.94). Importantly, excessive oversizing or the degree of filling volume was not associated with decreased PVL after XT-TAVI (P = non-significant for all). On multivariate analysis, CV-TAVI was found to be one of the independent predictors of need for PD (Odds ratio 3.63, 95% confidence interval 1.55 to 8.53, P = 0.003).In the setting of severe DLZ-CA, XT and CV have similar rates of PVL but XT had less need for PD. Excessive oversizing with XT carries a risk of root injury which could be further increased by DLZ-CA. PMID- 28100878 TI - Should Aortic Valve Calcification be Checked Before Percutaneous Coronary Intervention? PMID- 28100879 TI - Association Between Prior Aspirin Use and Morphological Features of Culprit Lesions at First Presentation of Acute Coronary Syndrome Assessed by Optical Coherence Tomography. AB - BACKGROUND: The effect of prior use of aspirin (ASA) on the onset of acute coronary syndrome (ACS) has not been clarified. This study used optical coherence tomography (OCT) to investigate the morphological features of culprit lesions of ACS in patients with prior ASA use.Methods and Results:In total, 442 patients with their first ACS episode undergoing OCT for the culprit lesions were investigated. Clinical characteristics, OCT findings, and adverse events at 30 days were compared between patients with prior ASA use and ASA-naive patients (non-ASA). 67 patients (15.2%) had received ASA at presentation. The ASA group was older, had higher frequency of dyslipidemia and hypertension, and lower renal function than the non-ASA group. Non-ST-elevation ACS was more prevalent in the ASA than in the non-ASA group (79.1 vs. 53.6%, P<0.001). Propensity score matching yielded 49 patients in both groups. OCT revealed less frequent thrombi in the ASA than in the non-ASA group in both the entire (37.3 vs. 75.2%, P<0.001) and score-matched cohorts (38.8 vs. 75.5%, P<0.001), whereas no significant difference was observed in plaque characteristics. Rate of adverse events did not differ between the ASA and the non-ASA groups in the matched cohort. CONCLUSIONS: With a first ACS presentation, patients with prior ASA use were more likely to present with non-ST-elevation ACS with less frequent intraluminal thrombi, but no significant difference in underlying plaque characteristics or clinical course. PMID- 28100880 TI - Significant Association of Serum Adiponectin and Creatine Kinase-MB Levels in ST Segment Elevation Myocardial Infarction. AB - AIMS: Adiponectin, an adipocyte-specific secretory protein, abundantly exists in the blood stream while its concentration paradoxically decreases in obesity. Hypoadiponectinemia is one of risks of cardiovascular diseases. However, impact of serum adiponectin concentration on acute ischemic myocardial damages has not been fully clarified. The present study investigated the association of serum adiponectin and creatine kinase (CK)-MB levels in subjects with ST-segment elevation myocardial infarction (STEMI). METHODS: This study is a physician initiated observational study and is also registered with the University Hospital Medical Information Network (Number: UMIN 000014418). Patients were admitted to Senri Critical Care Medical Center, given a diagnosis of STEMI, and treated by primary percutaneous coronary intervention (PCI). Finally, 49 patients were enrolled and the association of serum adiponectin, CK-MB, and clinical features were mainly analyzed. RESULTS: Serum adiponectin levels decreased rapidly and reached the bottom at 24 hours after recanalization. Such reduction of serum adiponectin was inversely correlated with the area under the curve (AUC) of serum CK-MB (p=0.013). Serum adiponectin concentrations were inversely correlated with AUC of serum CK-MB. In multivariate analysis, serum adiponectin concentration on admission (p=0.002) and collateral (p=0.037) were significantly and independently correlated with serum AUC of CK-MB. CONCLUSION: Serum AUC of CK-MB in STEMI subjects was significantly associated with serum adiponectin concentration on admission and reduction of serum adiponectin levels from baseline to bottom. The present study may provide a possibility that serum adiponectin levels at acute phase are useful in the prediction for prognosis after PCI-treated STEMI subjects. PMID- 28100882 TI - Efficient Fractionation and Analysis of Fatty Acids and their Salts in Fat, Oil and Grease (FOG) Deposits. AB - A fractionation methodology of fat, oil and grease (FOG) deposits was developed based on the insolubility of fatty acid salts in dichloromethane (DCM) and the relatively high solubility of fatty acids and triglycerides in DCM. Using this method, coupled with spectral analysis, it was shown that fatty acids rather than fatty acid salts were the predominant species in FOG deposits obtained from three metropolitan locations in the United States and that fatty acid triglycerides were either not detected or were present in very small concentrations. This solubility-based fractionation approach also revealed the presence of nitrogen containing compounds that had not been previously detected in FOG deposits including peptides and (or) proteins. The comparison of the ratios of stearic acid salts to stearic acid versus the ratio of palmitic acid salts to palmitic acid in FOG deposits may indicate that the initial step in FOG deposit formation is the preferential precipitation of stearic acid salts. PMID- 28100883 TI - Soy Protein Isolate Suppresses Lipodystrophy-induced Hepatic Lipid Accumulation in Model Mice. AB - Lipodystrophies are acquired and genetic disorders characterized by the complete or partial absence of body fat with a line of metabolic disorders, including hepatic steatosis. Because soy protein isolate (SPI) has been reported to reduce cholesterol and triglyceride levels in animals and humans, we explored the effect of SPI on the pathophysiology of hepatic lipid accumutaion in a diet-induced lipodystrophy model mice. Four weeks of the lipodystrophy model diet induced hepatic lipid accumulation concomitant with marked deficiencies of adipose tissue and serum adipocytokines in mice. However, supplementing the lipodystrophy model diet with SPI could alleviate the hepatic lipid acculation without affecting the lipoatrophic effect of the diet. Enhanced lipogenesis is the principal mechanism of hepatic steatosis in this model, but SPI supplementation significantly attenuated the increase in enzyme activity and/or mRNA expression. Additionally, SPI supplementation upregulated the hepatic mRNA expression of an enzyme involved in cholesterol catabolism. In conclusion, our results indicate the possibility of dietary SPI to attenuate lipodystorophy-induced hepatic steatosis through the direct reduction of hepatic lipogenesis without affecting adipocytokine production. PMID- 28100881 TI - Transporters for the Intestinal Absorption of Cholesterol, Vitamin E, and Vitamin K. AB - Humans cannot synthesize fat-soluble vitamins such as vitamin E and vitamin K. For this reason, they must be obtained from the diet via intestinal absorption. As the deficiency or excess of these vitamins has been reported to cause several types of diseases and disorders in humans, the intestinal absorption of these nutrients must be properly regulated to ensure good health. However, the mechanism of their intestinal absorption remains poorly understood. Recent studies on cholesterol using genome-edited mice, genome-wide association approaches, gene mutation analyses, and the development of cholesterol absorption inhibitors have revealed that several membrane proteins play crucial roles in the intestinal absorption of cholesterol. Surprisingly, detailed analyses of these cholesterol transporters have revealed that they can also transport vitamin E and vitamin K, providing clues to uncover the molecular mechanisms underlying the intestinal absorption of these fat-soluble vitamins. In this review, we focus on the membrane proteins (Niemann-Pick C1 like 1, scavenger receptor class B type I, cluster of differentiation 36, and ATP-binding cassette transporter A1) that are (potentially) involved in the intestinal absorption of cholesterol, vitamin E, and vitamin K and discuss their physiological and pharmacological importance. We also discuss the related uncertainties that need to be explored in future studies. PMID- 28100884 TI - Stabilization of Neem Oil Biodiesel with Corn Silk Extract during Long-term Storage. AB - The current study aimed to evaluate the antioxidant efficiency of different extracts of corn silk. In addition, the impact of corn silk extract on oxidative stability of neem biodiesel during storage was studied. The highest phenolics, DPPH radical scavenging and reducing power activities were recorded for methanol water extract. The longest oxidation stability (10 h) was observed for biodiesel samples blended with 1000 ppm of corn silk extract (CSE). At the end of storage period the induction time of biodiesel samples mixed with 1000 ppm of CSE or butylated hydroxytoluene (BHT) were about 6.72 and 5.63 times as high as in biodiesel samples without antioxidants. Biodiesel samples blended with 1000 ppm of CSE had the lowest acidity at the end of storage period. Peroxide value of biodiesel samples containing 1000 ppm of CSE was about 4.28 times as low as in control sample without antioxidants. PMID- 28100885 TI - Quantitative Analysis of the Distribution of cis-Eicosenoic Acid Positional Isomers in Marine Fishes from the Indian Ocean. AB - This study investigated the occurrence and distribution of cis-eicosenoic acid (c 20:1) positional isomers in fishes from the Indian Ocean and compared to those from the Pacific and Atlantic Ocean. Lipids were extracted from the edible part of the fish and then methylated. The eicosenoic acid methyl ester fraction was separated from total fatty acid methyl esters by reversed-phase HPLC and quantitatively analyzed using a GC-FID fitted with the SLB-IL111 highly polar GC column. c14-20:1 was used as an internal standard. The results indicated that the highest levels of c-20:1 positional isomers were found in fishes from the Pacific Ocean (saury, 166.95+/-12.4 mg/g of oil), followed by the Atlantic Ocean (capelin, 162.7+/-3.5 mg/g of oil), and lastly in fishes from the Indian Ocean (goatfish, 34.39 mg/g of oil). With only a few exceptions, the most abundant 20:1 positional isomer found in fishes of the Indian and Atlantic Ocean was the c11 20:1 isomer (>50%) followed by the c13-20:1 isomer (<25%). Unusually, the c7-20:1 isomer was predominantly found in a few fishes such as the tooth ponyfish, longface emperor, and commerson's sole. The c9, c5, and c15-20:1 isomers were the least occurring in fishes from the Indian and Atlantic Ocean. In contrast, the c9 20:1 isomer was the principal isomer identified in fishes from the Pacific Ocean. The results revealed that the content and distribution of c-20:1 positional isomers varied among fishes in different oceans. The data presented in the current study are the first to report on the distribution of c-20:1 positional isomers in fishes from the Indian Ocean. PMID- 28100886 TI - Characterization of Volatile Compounds with HS-SPME from Oxidized n-3 PUFA Rich Oils via Rancimat Tests. AB - Algae oil and fish oil are n-3 PUFA mainstream commercial products. The various sources for the stability of n-3 PUFA oxidation are influenced by the fatty acid composition, extraction and refined processing. In this study, the oil stability index (OSI) occurs within 2.3 to 7.6 hours with three different n-3 PUFA rich oil. To set the OSI in the Rancimat test as the oil stability limit and observed various degrees of oxidation (0, 25, 50, 75, 100 and 125%). The volatile oxidation compounds were analyzed via headspace-solid phase microextraction (HS SPME) and GC/MS. We detected 51 volatile compound variations during the oxidation, which were composed of aldehydes, hydrocarbons, cyclic compounds, alcohols, benzene compounds, ketones, furans, ester and pyrrolidine. The off flavor characteristics can be strongly influenced by the synergy effects of volatile oxidation compounds. Chemometric analysis (PCA and AHC) was applied to identify the sensitive oxidation marker compounds, which included a (E,E)-2,4 heptadienal appropriate marker, via lipid oxidation in the n-3 PUFA rich oil. PMID- 28100887 TI - Production of a Health-Beneficial Food Emulsifier by Enzymatic Partial Hydrolysis of Phospholipids Obtained from the Head of Autumn Chum Salmon. AB - Phospholipids and their partial hydrolysates, namely lysophospholipids (LPLs), have been widely used in food, pharmaceutical, and cosmetic products as highly efficient emulsifiers. This study was conducted to produce docosahexaenoic acid (DHA)-esterified LPLs by enzymatic modification of phospholipids obtained from the head of autumn chum salmon (Oncorhynchus keta). The emulsifying properties of the obtained LPLs were also evaluated. Two different types of substrates of salmon head phospholipids were prepared via silica gel and cold acetone precipitation. Enzymatic partial hydrolysis was carried out using immobilized phospholipase A1 (PLA1) and Lipozyme RM IM. Results showed that the increase in DHA in the LPLs was much higher in the silica-separated phospholipids than in the acetone-precipitated phospholipids. When silica-separated phospholipids were used as the substrate, the DHA content of the LPLs increased from 23.1% to 40.6% and 42.6% after 8 h of partial hydrolysis with Lipozyme RM IM and immobilized PLA1, respectively. The yield of the LPLs was comparatively higher in the Lipozyme RM IM than in the immobilized PLA1 hydrolysis reaction. The critical micelle concentration values of the LPLs and purified lysophosphatidylcholine (LPC) were 100 mg/L and 5 mg/L, respectively. The surface tension values of the LPLs and LPC were reduced to 30.0 mN/m and 30.5 mN/m, respectively. The hydrophilic-lipophilic balance of the LPLs and LPC were 6.0 and 9.4, respectively. Based on the emulsifying properties observed, we conclude that LPLs derived from the phospholipids of salmon head lipids could be used as a health-beneficial emulsifier in the food industry. PMID- 28100888 TI - beta hydroxybutyrate levels in serum and cerebrospinal fluid under ketone body metabolism in rats. AB - A high-fat, low-carbohydrate diet (KD) or calorie restriction in the form of every-other-day fasting (EODF) results in ketone body metabolism with an increasing beta-hydroxybutyrate (betaOHB) level. Previous studies have supported that a KD and EODF have a neuroprotective effect. However, the betaOHB levels in the cerebrospinal fluid (CSF) resulting from a KD and EODF remain unknown. The aim of this study was to detect betaOHB levels in rats fed a KD, EODF diet, and every-other-day ketogenic diet (EODKD) and to compare the serum betaOHB level with the CSF betaOHB level. Twenty-four male Sprague-Dawley rats were randomly divided into KD, EODF, EODKD, and standard diet (SD) groups. A customized food with a ratio of carbohydrates to fats of 1:4 was used in the KD and EODKD groups. The betaOHB level was measured using ELISA kits in 200 ul serum and 100 ul CSF samples for each rat after feeding for 2 weeks. The KD, EODF, and EODKD resulted in a significant increase in betaOHB levels in both the serum and CSF. The betaOHB levels in the EODKD group were the highest. The CSF betaOHB level was, on average, 69% of the serum betaOHB level. There was a positive correlation between the overall betaOHB levels in serum and that in cerebrospinal fluid. This study demonstrated that the KD, EODF, and EODKD resulted in ketone body metabolism, as the betaOHB levels increased significantly compared with those resulting from the standard diet. Our results suggested that the serum betaOHB level was an indicator of the CSF betaOHB level, and that the EODKD was an effective diet to enhance ketogenic metabolism. PMID- 28100889 TI - Cotransfer of regulatory T cells improve the therapeutic effectiveness of mesenchymal stem cells in treating a colitis mouse model. AB - Inflammatory bowel disease (IBD) is a severe inflammatory condition in the colon. To date, clinical solutions for this disease have been limited. Mesenchymal stem cells (MSCs), multipotential cells with immune regulation and anti-inflammatory functions, have been applied to treatment of IBD. However, the therapeutic effectiveness of MSCs still needs to be improved. Here, we were interested in whether regulatory T cells (Tregs) could enhance the immune regulation function of MSCs in treatment of mouse colitis. We generated a dextran sulfate sodium (DSS)-induced IBD mouse model. Combined cell therapy with both MSCs and Tregs was able to help increase body weight and preserve a better colon morphology compared with single cell therapy with MSCs or Tregs alone. Further studies demonstrated that combined cell therapy could reduce pro-inflammatory cytokines such as TNF alpha,IL-10, IFN-gamma, IL-17A, IL-1beta and at the same time promote CD3+ T cells apoptosis. In conclusion, our study indicates that combined cell therapy could prevent the development of colitis in a mouse model, which may lead to a new effective therapeutic approach for treatment of human IBD. PMID- 28100890 TI - Research progress on the direct antiviral drugs for hepatitis C virus. AB - Hepatitis C, caused by the hepatitis C virus (HCV) that attacks the liver and leads to inflammation, is a severe threat to human health. Pegylated interferon alpha (INF-alpha) and ribavirin based therapy was once the standard therapy for HCV infection. However, it is suboptimal in efficacy and poorly tolerated in some patients. In the last five years, four classes of direct antiviral drugs (NAAs) that target non-structural proteins (NS) of the virus including NS3/NS4A, NS5A, and NS5B have been developed and opened a new era in HCV treatment as they are more effective and tolerable than the INF-alpha and ribavirin combination regimen. Importantly, the newly introduced multiple NAAs combination therapy makes it possible to eradicate all genotypes of HCV. We review recent progress on the research and development of DAAs in the present article. PMID- 28100891 TI - Reverse Right Ventricular Remodeling After Lung Transplantation in Patients With Pulmonary Arterial Hypertension Under Combination Therapy of Targeted Medical Drugs. AB - BACKGROUND: Patients with pulmonary arterial hypertension (PAH) are currently treated with combination therapy of PAH-targeted drugs. Reverse right ventricular (RV) remodeling after lung transplantation (LTx) in patients with end-stage PAH despite combination therapy of PAH-targeted drugs has not been fully elucidated.Methods and Results:A total of 136 patients, including 32 with PAH, underwent LTx from 1998 to 2014. We enrolled 12 consecutive patients with PAH treated with combination therapy of PAH-targeted drugs who underwent LTx and retrospectively analyzed the temporal and serial changes in hemodynamics and echocardiography before LTx and at 3 and 12 months after LTx. Before LTx, the RV was markedly dilated with substantially reduced RV fractional area change (RVFAC). At 3 months after LTx, pulmonary artery pressure, pulmonary vascular resistance and RV stroke work index were significantly decreased, while left ventricular stroke work index was increased. RV size assessed by echocardiography also significantly decreased and RVFAC improved. At 12 months after LTx, RVFAC was further increased and RV wall thickness was decreased significantly. CONCLUSIONS: Although severe RV dysfunction and dilation were observed in patients with end-stage PAH despite combination therapy of PAH-targeted drugs, RV function and morphology were improved after reduction of RV pressure load by LTx. PMID- 28100892 TI - Association between participation in social activity and physical fitness in community-dwelling older Japanese adults. AB - Purpose This study aimed to examine the relationship between participation in social activity and both, composite and individual measures of physical fitness in community-dwelling older adults.Methods This study was conducted using baseline data from the Sasaguri Genkimon Study (SGS), a longitudinal cohort study conducted in 2011. Participants were 1,365 community-dwelling men and women aged 65 years or above, who did not require certified nursing care and who resided in Sasaguri, a town located east of the Fukuoka metropolitan area. Participation in social activity was assessed by asking participants whether they engaged in any of eight social activities. Physical fitness tests assessed participants' handgrip strength and knee extension strength as measures of muscle strength, and their one-leg standing time, 5-m maximum gait speed, and 5-repetition sit-to stand rate as measures of their physical performance. Multiple linear regression and logistic regression analyses were conducted to assess the relationship between participation in social activity and each measure of physical fitness, adjusting for sex; age; body mass index; socioeconomic status; solitary living; exercise, habitual drinking and smoking; accelerometer-measured, moderate-to vigorous physical activity; cognitive function; instrumental activities of daily living; distress; social network; and comorbidities.Results A total of 83.6% of the participants were engaged in at least one social activity. After adjusting for potential confounders, engagement in social activity was positively associated with a higher composite physical fitness score, faster gait speed and 5-repetition sit-to-stand rate, and longer one-leg standing time (P=0.008, P=0.030, P=0.034, and P=0.009, respectively).Conclusion Participation in social activity was significantly associated with physical fitness, specifically those related to locomotive function. These associations were independent of various confounders including socioeconomic status, and comorbidities. PMID- 28100894 TI - Initiatives for community building in an urban semi-marginal village: Progress of the Ajinadai Lively Project and future challenges. AB - Objectives We launched and engaged in the "Ajinadai Lively Project" to examine the ideal state of community building in an urban semi-marginal village. In addition to discussing its progress and describing the activities, we examine future challenges.Methods (1) We gathered existing resources, conducted a district survey and focus group interview, and investigated the community's health issues. (2) We conducted a workshop with local residents and formulated an action plan. (3) We conducted a health volunteer training class to foster community leaders. (4) Local residents interacted with students through nursing school practice and student volunteer activities.Results The health issues in the community were as follows: (1) Few connections existed between residents across generations, and no framework for mutual assistance was established. (2) Many solitary elderly people and elderly households existed, and we found many instances of elderly-to-elderly care and social withdrawal of elderly people. (3) Many slopes and staircases existed, which made mobility difficult for elderly people. Based on these results, we encouraged the state to pursue quality of life as "A community where people connect and help one another across generations" as well as "A healthy community where people greet one another." We also established health, behavioral, and environmental goals. The health volunteer training class became an impetus for residents to realize the necessity of not only protecting their own health, but also encouraging others and the whole community to get involved.Conclusion While the health volunteer training class did not initiate autonomous activity, it increased the motivation of residents themselves for community building. Performing continuous evaluations and offering support for autonomous activity is important in the future. PMID- 28100893 TI - Nutritional status and dietary intake among pregnant women in relation to pre pregnancy body mass index in Japan. AB - Objective The present study examined nutritional status and dietary intake of pregnant women in Japan in relation to pre-pregnancy body mass index (BMI).Methods Participants included 141 Japanese women with singleton pregnancies, from the outpatient department of the S hospital, Gunma prefecture, Japan. Two-day food records, dietary assessment questionnaires, and clinical records were obtained at 20 weeks gestation. Nine patients were excluded from the study due to morning sickness. The remaining 132 participants were divided into 3 groups according to pre-pregnancy BMI: underweight, normal weight, and overweight. Nutritional status and dietary intake were analyzed in relation to BMI using the chi-square test, Fisher's exact test, Kruskal-Wallis test, one-way analysis of variance, and analysis of covariance with adjustment for age, employment status, and total energy intake.Results Women who were underweight before pregnancy were more frequently working full-time than normal weight and overweight women. Underweight women were also more frequently anemic (P=0.038, underweight 39.3%, normal weight 24.7%, overweight 0%) and had lower mean hemoglobin (Hb) (P=0.021, underweight 11.3 g/dL, normal weight 11.6 g/dL, overweight 12.1 g/dL) and hematocrit (Hct) levels (P=0.025, underweight 33.7%, normal weight 34.3%, overweight 36.0%). Their dietary intake of protein, iron, magnesium, and folic acid was lower than that of normal weight and overweight women. Their meals tended to include fewer meat, fish, egg, and soybean dishes (underweight, mean of 4.7 servings per day; normal weight, 6.1 servings; overweight, 6.1 servings).Conclusion Pregnant women who were underweight before pregnancy had increased risk of anemia as well as reduced Hb and Hct levels. They had lower dietary intake of protein, iron and folic acid compared to women in the other BMI categories. Anemia and these nutrient deficiencies are known risk factors for low birth weight. Our findings suggest the importance of providing underweight pregnant women with support to improve dietary intake during their pregnancy, especially to increase intake of protein and iron through consumption of fish and meat dishes. PMID- 28100895 TI - A study on the non smoking recommendation in medical guidelines. PMID- 28100896 TI - Investigating the effect of traditional Persian music on ECG signals in young women using wavelet transform and neural networks. AB - OBJECTIVE: In the past few decades, several studies have reported the physiological effects of listening to music. The physiological effects of different music types on different people are different. In the present study, we aimed to examine the effects of listening to traditional Persian music on electrocardiogram (ECG) signals in young women. METHODS: Twenty-two healthy females participated in this study. ECG signals were recorded under two conditions: rest and music. For each ECG signal, 20 morphological and wavelet based features were selected. Artificial neural network (ANN) and probabilistic neural network (PNN) classifiers were used for the classification of ECG signals during and before listening to music. RESULTS: Collected data were separated into two data sets: train and test. Classification accuracies of 88% and 97% were achieved in train data sets using ANN and PNN, respectively. In addition, the test data set was employed for evaluating the classifiers, and classification rates of 84% and 93% were obtained using ANN and PNN, respectively. CONCLUSION: The present study investigated the effect of music on ECG signals based on wavelet transform and morphological features. The results obtained here can provide a good understanding on the effects of music on ECG signals to researchers. PMID- 28100897 TI - X indening oral liquid improves cardiac function of rats with chronic cardiac failure via TGF-beta1/Smad3 and p38 MAPK pathway. AB - OBJECTIVE: Xindening oral liquid (Xin) is a widely used traditional Chinese medicine for the treatment of chronic heart failure (CHF). However, the exact mechanisms related to its therapeutic effects against CHF remain unclear. In the present study, we investigate the effects of Xin on cardiac function in CHF rats and the possible mechanisms involved. METHODS: Transverse aortic constriction (TAC) was conducted to induce a CHF rat model in this study. Sixty male Wistar rats were randomly assigned to six groups 28 days after TAC: sham; CHF model; Xin at concentrations of 5 ml/kg, 10 mL/kg, and 20 mL/kg; and QiLi 0.6 g/kg. After four weeks, the rats were treated with Xin (5, 10, or 20 mL/kg/d) for six weeks consecutively. At the end of the study, the cardiac function, heart weight index (HWI) and left ventricular mass index (LVMI), serum level of LDH, B-type natriuretic peptide (BNP), cTnI and CK-MB, and collagen volume fraction were studied. The expression of transforming growth factor-beta1 (TGF-beta1), drosophila mothers against decapentaplegic protein 3 (Smad3), and p38 mitogen activated protein kinase (p38 MAPK) were detected. RESULTS: The results showed that Xin treatment significantly improved cardiac function but decreased the serum level of LDH, BNP, cTnI, and CKMB of CHF rats. In addition, it reduced the HWI, LVMI, and collagen volume fraction compared with the model group. Xin treatment significantly improved cardiac function and attenuated cardiac fibrosis by suppressing the p38 MAPK and TGF-beta1/Smad3 signaling pathway in CHF rats. CONCLUSION: These results suggested that Xin might be a promising complementary treatment for CHF. More detailed experimental studies will be carried out in our subsequent research. PMID- 28100898 TI - New oral anticoagulants-TURKey (NOAC-TURK): Multicenter cross-sectional study. AB - OBJECTIVE: New oral anticoagulants (NOACs) are increasingly used both for prevention of stroke in non-valvular atrial fibrillation (NVAF) and the treatment of venous thromboembolism (VTE). In this study, we aimed to evaluate the current patterns of NOACs treatment in Turkey. Moreover, demographic and clinical parameters and bleeding and/or embolic events under NOACs treatment were analyzed. METHODS: The New Oral Anticoagulants-TURKey (NOAC-TURK) study was designed as a multicenter cross-sectional study. A total of 2,862 patients from 21 different centers of Turkey under the treatment of NOACs for at least three months were included in this study. Demographic, clinical, and laboratory characteristics of study participants with their medications used were obtained through the NOAC-TURK survey database. Additional necessary medical records were obtained from electronic health records of participating centers. RESULTS: Of the 2. 862 patients, 1.131 (39.5%) were male and the mean age was 70.3+/-10.2 years. Hypertension was found as the most frequent comorbidity (81%). The most common indication for NOACs was permanent atrial fibrillation (83.3%). NOACs were mainly preferred because of inadequate therapeutic range or overdose during warfarin usage. The most frequent complication was bleeding (n=217, 7.6%), and major bleeding was observed in 1.1% of the patients. Embolic events were observed in 37 patients (1.3%). Rivaroxaban and dabigatran were both more preferred than apixaban. Almost half of the patients (47.6%) were using lower doses of NOACs, which is definitely much more than expected. CONCLUSION: The NOAC-TURK study showed an important overview of the current NOACs treatment regimens in Turkey. Although embolic and bleeding complications were lower than or similar to previous studies, increased utilization of low-dose NOACs in this study should be considered carefully. According to the results of this study, NOACs treatment should be guided through CHA2DS2-VASc and HASBLED scores to ensure more benefit and less adverse effects in NVAF patients. PMID- 28100899 TI - Effectiveness of computed tomography attenuation values in characterization of pericardial effusion. AB - OBJECTIVE: The aim of this study was to evaluate the effectiveness of computed tomography (CT) attenuation values in the characterization of pericardial effusion. METHODS: This study consisted of 96 patients with pericardial effusion who underwent pericardiocentesis. For further diagnostic evaluation of pericardial effusion, all the patients were assessed by thorax CT. CT attenuation values were measured from at least 5 different areas of pericardial fluid by specifying the largest region of interest. The average of these measurements was computed and considered as the CT attenuation value of the patient. The patients were classified into two groups: patients with transudative pericardial effusion and those with exudative pericardial effusion. RESULTS: CT attenuation values were significantly higher in patients with exudative pericardial effusion than in those with transudative pericardial effusion [14.85+/-10.7 Hounsfield unit (HU) vs. 1.13+/-4.3 HU, p<0.001]. CT attenuation values had a close correlation with the pericardial fluid albumin (r=0.829), protein (r=0.752), and LDH (r=0.708) levels; WBC count (r=0.564); protein ratio (r=0.739); and LDH ratio (r=0.689) as well as the albumin gradient (r=-0.725). A cut-off value of 4.7 HU had 80% sensitivity and 87.7% specificity for the identification of exudative pericardial effusion. In addition, a cut-off value of 6.5 HU had 71.4% sensitivity and 72.3% specificity for the prediction of cardiac tamponade. CONCLUSION: In patients with pericardial effusion, CT attenuation values seem to be correlated with the characterization parameters of the fluid and may distinguish exudative pericardial effusion from transudative pericardial effusion. This parameter was also found to be a predictor of cardiac tamponade. CT attenuation values can be a useful tool in the clinical evaluation of patients with pericardial effusion. PMID- 28100900 TI - Paeonia lactiflora Inhibits Cell Wall Synthesis and Triggers Membrane Depolarization in Candida albicans. AB - Fungal cell walls and cell membranes are the main targets of antifungals. In this study, we report on the antifungal activity of an ethanol extract from Paeonia lactiflora against Candida albicans, showing that the antifungal activity is associated with the synergistic actions of preventing cell wall synthesis, enabling membrane depolarization, and compromising permeability. First, it was shown that the ethanol extract from P. lactiflora was involved in damaging the integrity of cell walls in C. albicans. In isotonic media, cell bursts of C. albicans by the P. lactiflora ethanol extract could be restored, and the minimum inhibitory concentration (MIC) of the P. lactiflora ethanol extract against C. albicans cells increased 4-fold. In addition, synthesis of (1,3)-beta-D-glucan polymer was inhibited by 87% and 83% following treatment of C. albicans microsomes with the P. lactiflora ethanol extract at their 1* MIC and 2* MIC, respectively. Second, the ethanol extract from P. lactiflora influenced the function of C. albicans cell membranes. C. albicans cells treated with the P. lactiflora ethanol extract formed red aggregates by staining with a membrane impermeable dye, propidium iodide. Membrane depolarization manifested as increased fluorescence intensity by staining P. lactiflora-treated C. albicans cells with a membrane-potential marker, DiBAC4(3) ((bis-1,3-dibutylbarbituric acid) trimethine oxonol). Membrane permeability was assessed by crystal violet assay, and C. albicans cells treated with the P. lactiflora ethanol extract exhibited significant uptake of crystal violet in a concentration-dependent manner. The findings suggest that P. lactiflora ethanol extract is a viable and effective candidate for the development of new antifungal agents to treat Candida associated diseases. PMID- 28100901 TI - Pancreas Transplant with Duodeno-Duodenostomy and Caval Drainage Using a Diamond Patch Graft: A Single-Center Experience. AB - BACKGROUND The surgical technique used in pancreas transplant is essential for patient safety and graft survival, and problems exist with conventional strategies. When enteric exocrine drainage is performed, there is no method of immunologic monitoring other than direct graft pancreas biopsy. The most common cause of early graft failure is graft thrombosis, and adequate preventive and treatment strategies are unclear. To overcome these disadvantages, we suggest a modified surgical technique. MATERIAL AND METHODS Eleven patients underwent pancreas transplant with our modified technique. The modified surgical techniques are as follows: 1) graft duodenum was anastomosed with recipient duodenum to enable endoscopic immunological monitoring, and 2) the inferior vena cava was chosen for vascular anastomosis and a diamond-shaped patch was applied to prevent graft thrombosis. RESULTS No patient mortality or graft failure occurred. One case of partial thrombosis of the graft portal vein occurred, which did not affect graft condition, and resolved after heparin treatment. All patients were cured from diabetes mellitus. There were no cases of pancreatic rejection, but 2 cases of graft duodenal rejection occurred, which were adequately treated with steroid therapy. CONCLUSIONS This modified surgical technique for pancreas transplant represents a feasible method for preventing thrombosis and allows for direct graft monitoring through endoscopy. PMID- 28100903 TI - Rhodoccocus Equi Pneumonia and Paradoxical Immune Reconstitution Inflammatory Syndrome in a Patient with Acquired Immune Deficiency Syndrome (AIDS). AB - BACKGROUND Pulmonary infections are a major cause of mortality and morbidity in patients infected with human immunodeficiency virus (HIV) and can progress rapidly to respiratory failure and death without appropriate therapy. Herein, we present a rare case of an advanced HIV infection and Rhodoccocus equi (R. equi) pneumonia in a young male who had severe paradoxical immune reconstitution inflammatory syndrome (IRIS). CASE REPORT A 47-year-old nonsmoking Hispanic man with advanced HIV infection presented with severe acute necrotizing pneumonia secondary to R. equi. Although his initial response to antimicrobial therapy was optimal, he became symptomatic again in spite of continuation of antibiotics as he developed severe paradoxical IRIS 3 weeks after starting a new highly active anti-retroviral therapy (HAART). CONCLUSIONS The diagnosis of IRIS remains challenging because of the wide variations in the clinical presentation and etiologies. In spite of its rarity as an opportunistic pathogen, we recommend that R. equi, an intracellular pathogen, be included in the differential list of pathogens associated with IRIS. PMID- 28100902 TI - Prognostic Role of Neutrophil-to-Lymphocyte Ratio in Locally Advanced Rectal Cancer Treated with Neoadjuvant Chemoradiotherapy. AB - BACKGROUND Increasing evidence suggests that cancer-associated inflammation is associated with poorer outcomes. The neutrophil-to-lymphocyte ratio (NLR), considered as a systemic inflammation marker, is thought to predict prognoses in colorectal cancer. In this study, we explored the association between the NLR and prognoses following neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). MATERIAL AND METHODS From February 2002 to December 2012, a group of 202 patients diagnosed with LARC and receiving neoadjuvant CRT followed by radical surgery was included in our retrospective study. The associations between the pre-CRT NLR and clinicopathological characteristics, as well as the predictive value of pre-CRT NLR against survival outcomes, were analyzed. RESULTS The average NLR was 2.7+/-1.5 (median 2.4, range 0.6-12.8). There were 63 (31.2%) patients with NLR >=3.0, and 139 (68.8%) patients with NLR <3.0. Correlation analyses showed that no clinicopathological characteristics except age were associated with NLR. We did not find an association between NLR and survival outcomes. In multivariate Cox model analyses, the R1/R2 resection, lymph node ratio >=0.1, and perineural/lymphovascular invasion were independently associated with worse disease-free survival and overall survival. CONCLUSIONS In our cohort, the NLR did not correlate with survival outcomes in LARC patients undergoing neoadjuvant CRT. The prognostic value of NLR should be validated in large-scale prospective studies. PMID- 28100904 TI - Kidney cancer in 2016: The evolution of anti-angiogenic therapy for kidney cancer. PMID- 28100905 TI - Renal transplantation in 2016: Novel approaches to improve recipient and allograft outcomes. PMID- 28100906 TI - Glomerular disease in 2016: New advances in the treatment of glomerular disease. PMID- 28100907 TI - Critical care nephrology in 2016: Managing organ dysfunction in critical care. PMID- 28100908 TI - Genetics of kidney disease in 2016: Ingenious tactics to unravel complex kidney disease genetics. PMID- 28100909 TI - Impact of pretransplant induction therapy on autologous stem cell transplantation for patients with newly diagnosed POEMS syndrome. AB - POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) is a rare plasma cell dyscrasia sometimes treated with a haematopoietic cell autotransplant. We analyzed data from 138 subjects with newly diagnosed POEMS syndrome receiving a autotransplant at our center. Thirty-two subjects with severe end-organ dysfunction ineligible for immediate autotransplant received pretransplant therapy, which made a subsequent autotransplant feasible. Pretransplant therapy resulted in vascular endothelial growth factor (VEGF) remissions in 15 (47%). Thirty-three transplant recipients (24%) had early posttransplant complications. Risk factors for these complications identified through multivariate analysis included age >50 years (odds ratio (OR) 2.79, 95% confidence interval (CI) 1.09-7.14; P=0.033), time from symptom onset to transplant >5 years (OR 4.71, 95% CI 1.10-20.18; P=0.037) and pleural effusion (OR 3.39, 95% CI 1.26-9.12; P=0.016). Subjects receiving pretransplant therapy had fewer early complications than those who did not (OR 0.17, 95% CI 0.04-0.71; P=0.015), especially in subjects with a VEGF remission (OR 0.05, 95% CI 0.01-0.49; P=0.010). Autotransplants resulted in hematological remission in 60 (50%), VEGF remissions in 76 (72%) and improvements in other organ functions (65-90%). The 5-year progression-free survival (PFS) and overall survival were 76% (95% CI 64-84%) and 94% (95% CI 87-97%), respectively. Hematological (5-year PFS 83 vs 66%, P=0.008), VEGF (5-year PFS 79 vs 57%, P=0.021) remissions and especially both (5-year PFS 95 vs 61%, P=0.004) were associated with better PFS. PMID- 28100910 TI - A novel sequence variant in SFRP4 causing Pyle disease. AB - Pyle disease (PYL) is an extremely rare disorder of irregular development of long bone. Recently, homozygous mutations in secreted frizzled-related protein 4 gene (SFRP4) gene were found to underlie this condition. Sequencing of coding regions of SFRP4 gene from an 11-year-old female with PYL was performed. A novel homozygous nonsense variant, c.183C>G (p.Y61*) was observed. Segregation analysis in the patient revealed a germline mutation, resulting in reduced protein formation. This is the second report from a fourth affected family with a SFRP4 mutation causing PYL disease. PMID- 28100911 TI - Variants on chromosome 4q21 near PKD2 and SIBLINGs are associated with dental caries. AB - A recent genome-wide association study (GWAS) for dental caries nominated the chromosomal region 4q21 near ABCG2, PKD2 and the SIBLING (small integrin-binding ligand N-linked glycoprotein) gene family. In this investigation, we followed up and fine-mapped this region using a tag-SNP (single-nucleotide polymorphism) approach in 13 age- and race-stratified samples from 6 independent studies (N=4089). Participants were assessed for dental caries via intraoral examination and 49 tag-SNPs were genotyped capturing much of the variation in the 4q21 locus. Linear models were used to test for genetic association, while adjusting for sex, age and components of ancestry. SNPs in and near PKD2 showed significant evidence of association in individual samples of black adults (rs17013735, P-value=0.0009) and white adults (rs11938025; P-value=0.0005; rs2725270, P-value=0.003). Meta analyses across black adult samples recapitulated the association with rs17013735 (P-value=0.003), which occurs at low frequency in non-African populations, possibly explaining the race specificity of the effect. In addition to race specific associations, we also observed evidence of gene-by-fluoride exposure interaction effects in white adults for SNP rs2725233 upstream of PKD2 (P=0.002). Our results show evidence of regional replication, though no single variant clearly accounted for the original GWAS signal. Therefore, while we interpret our results as strengthening the hypothesis that chromosome 4q21 may impact dental caries, additional work is needed. PMID- 28100913 TI - Genome-wide association study using the ethnicity-specific Japonica array: identification of new susceptibility loci for cold medicine-related Stevens Johnson syndrome with severe ocular complications. AB - A genome-wide association study (GWAS) for cold medicine-related Stevens-Johnson syndrome (CM-SJS) with severe ocular complications (SOC) was performed in a Japanese population. A recently developed ethnicity-specific array with genome wide imputation that was based on the whole-genome sequences of 1070 unrelated Japanese individuals was used. Validation analysis with additional samples from Japanese individuals and replication analysis using samples from Korean individuals identified two new susceptibility loci on chromosomes 15 and 16. This study might suggest the usefulness of GWAS using the ethnicity-specific array and genome-wide imputation based on large-scale whole-genome sequences. Our findings contribute to the understanding of genetic predisposition to CM-SJS with SOC. PMID- 28100912 TI - Cryptic splice activation but not exon skipping is observed in minigene assays of dystrophin c.9361+1G>A mutation identified by NGS. AB - Next-generation sequencing (NGS) discloses nucleotide changes in the genome. Mutations at splicing regulatory elements are expected to cause splicing errors, such as exon skipping, cryptic splice site activation, partial exon loss or intron retention. In dystrophinopathy patients, prediction of splicing outcomes is essential to determine the phenotype: either severe Duchenne or mild Becker muscular dystrophy, based on the reading frame rule. In a Vietnamese patient, NGS identified a c.9361+1G>A mutation in the dystrophin gene and an additional DNA variation of A>G at +117 bases in intron 64. To ascertain the consequences of these DNA changes on dystrophin splicing, minigene constructs were prepared inserting dystrophin exon 64 plus various lengths of intron 64. Exon 64 skipping was observed in the minigene construct with 160 nucleotide (nt) of intron 64 sequence with both c.9361+1A and +117G. In contrast, minigene constructs with larger flanking intronic domains resulted in cryptic splice site activation rather than exon skipping. Meanwhile, the cryptic splice site activation was induced even in +117G when intron 64 was elongated to 272 nt and longer. It was expected that cryptic splice site activation is an in vivo splicing outcome. PMID- 28100915 TI - Whole-exome sequencing study reveals common copy number variants in protocadherin genes associated with childhood obesity in Koreans. AB - Recently, the prevalence of childhood obesity has significantly increased in industrialized countries, including Korea, and now controlling obesity is becoming an economic burden. However, knowledge of the risk factors associated with obesity is still limited. In this study, we aimed to discover additional obesity-associated loci in children. To achieve this, we conducted an exome-wide association analysis of copy number variation (CNV) using whole-exome sequencing (WES) data from a total of 102 cases and 86 controls. We newly identified a CNV locus that overlapped two protocadherin genes, PCDHB7 and PCDHB8, which are brain function-related genes (P-value=6.40 * 10-4, odds ratio=2.2189). A subsequent replication analysis using WES data from 203 obese and 291 normal weight children showed that this CNV region satisfied the genome-wide significance standard (Fisher's combined P-value=3.76 * 10-5). Moreover, correlation test using 199 additional samples supported significant association between CNV and increased body mass index. This region also showed a meaningful association with 273 cases and 2596 controls in adult samples. Our findings suggest that differences in the common CNV region at 5q31.3 may have an impact on the pathophysiology of obesity. PMID- 28100916 TI - Twenty-four-hour urinary sodium and potassium excretion and associated factors in Japanese secondary school students: methodological issues that can lead to misinterpretation. PMID- 28100914 TI - TET-mediated hydroxymethylcytosine at the Ppargamma locus is required for initiation of adipogenic differentiation. AB - BACKGROUND/OBJECTIVES: Adipose tissue is one of the main organs regulating energy homeostasis via energy storage as well as endocrine function. The adipocyte cell number is largely determined by adipogenesis. While the molecular mechanism of adipogenesis has been extensively studied, its role in dynamic DNA methylation plasticity remains unclear. Recently, it has been shown that Tet methylcytosine dioxygenase (TET) is catalytically capable of oxidizing DNA 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5-hmC) toward a complete removal of the methylated cytosine. We investigate whether expression of the Tet genes and production of hydroxymethylcytosine are required for preadipocyte differentiation. SUBJECTS/METHODS: Murine 3T3-L1 preadipocytes were used to evaluate the role of Tet1 and Tet2 genes during adipogenesis. Changes in adipogenic ability and in epigenetic status were analyzed, with and without interfering Tet1 and Tet2 expression using small interfering RNA (siRNA). The adipogenesis was evaluated by Oil-Red-O staining and induced expression of adipogenic genes using quantitative polymerase chain reaction (qPCR). Levels of 5 hmC and 5-mC were measured by MassARRAY, immunoprecipitation and GC mass spectrometry at specific loci as well as globally. RESULTS: Both Tet1 and Tet2 genes were upregulated in a time-dependent manner, accompanied by increased expression of hallmark adipogenic genes such as Ppargamma and Fabp4 (P<0.05). The TET upregulation led to reduced DNA methylation and elevated hydroxymethylcytosine, both globally and specifically at the Ppargamma locus (P<0.05 and P<0.01, respectively). Knockdown of Tet1 and Tet2 blocked adipogenesis (P<0.01) by repression of Ppargamma expression (P<0.05). In particular, Tet2 knockdown repressed conversion of 5-mC to 5-hmC at the Ppargamma locus (P<0.01). Moreover, vitamin C treatment enhanced adipogenesis (P<0.05), while fumarate treatment inhibited it (P<0.01) by modulating TET activities. CONCLUSIONS: TET proteins, particularly TET2, were required for adipogenesis by modulating DNA methylation at the Ppargamma locus, subsequently by inducing Ppargamma gene expression. PMID- 28100917 TI - Systolic blood pressure amplification and waveform calibration. PMID- 28100918 TI - Cardioprotective effects of SGLT2 inhibitors are possibly associated with normalization of the circadian rhythm of blood pressure. AB - Improvement in cardiovascular (CV) morbidity and mortality in the EMPA-REG OUTCOME study provides new insight into the therapeutic use of sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes. Although SGLT2 inhibitors have several pleiotropic effects, the underlying mechanism responsible for their cardioprotective effects remains undetermined. In this regard, the absence of a nocturnal fall in blood pressure (BP), that is, non dipping BP, is a common phenomenon in type 2 diabetes and has a crucial role in the pathogenesis of CV morbidity and mortality. In most clinical trials, SGLT2 inhibitors reduce both systolic BP (~3-5 mm Hg) and diastolic BP (~2 mm Hg) in patients with type 2 diabetes. In addition, recent clinical and animal studies have revealed that SGLT2 inhibitors enable the change in BP circadian rhythm from a non-dipper to a dipper type, which is possibly associated with the improvement in CV outcomes in patients with type 2 diabetes. In this review, recent data on the effect of SGLT2 inhibitors on the circadian rhythm of BP will be summarized. The possible underlying mechanisms responsible for the SGLT2 inhibitor-induced improvement in the circadian rhythm of BP will also be discussed. PMID- 28100919 TI - Preventive effect of Eucommia leaf extract on aortic media hypertrophy in Wistar Kyoto rats fed a high-fat diet. AB - Eucommia ulmoides Oliver leaf extract (ELE) has been shown to have anti hypertensive and anti-obesity effects in rats that are fed a high-fat diet (HFD). To explore the effects of chronic administration of ELE on body weight, blood pressure and aortic media thickness, 7-week-old male Wistar-Kyoto (WKY) rats were orally administered a normal diet, a 30% HFD, or a 5% ELE plus HFD ad libitum for 10 weeks. The HFD treatment caused mild obesity and hypertension in the normotensive rats, while rats receiving both ELE and the HFD had significantly lower body weights, less visceral and perirenal fat, lower blood pressure and thinner aortic media than the control rats receiving the HFD only. The plasma adiponectin/leptin ratio also improved in ELE-treated rats. Although plasma leptin levels were elevated in all HFD rats, adiponectin levels increased only in the ELE-treated rats. Anti-hypertensive and anti-obesity effects may be caused by the geniposidic acid (GEA) and/or asperuloside present in ELE. These findings suggest that chronic ELE administration prevents aortic media hypertrophy in early-stage obesity with hypertension. Long-term administration of ELE might inhibit the development of arteriosclerosis. PMID- 28100920 TI - Within-country variation of salt intake assessed via urinary excretion in Japan: a multilevel analysis in all 47 prefectures. AB - Salt intake in Japan remains high; therefore, exploring within-country variation in salt intake and its cause is an important step in the establishment of salt reduction strategies. However, no nationwide evaluation of this variation has been conducted by urinalysis. We aimed to clarify whether within-country variation in salt intake exists in Japan after adjusting for individual characteristics. Healthy men (n=1027) and women (n=1046) aged 20-69 years were recruited from all 47 prefectures of Japan. Twenty-four-hour sodium excretion was estimated using three spot urine samples collected on three nonconsecutive days. The study area was categorized into 12 regions defined by the National Health and Nutrition Survey Japan. Within-country variation in sodium excretion was estimated as a population (region)-level variance using a multilevel model with random intercepts, with adjustment for individual biological, socioeconomic and dietary characteristics. Estimated 24 h sodium excretion was 204.8 mmol per day in men and 155.7 mmol per day in women. Sodium excretion was high in the Northeastern region. However, population-level variance was extremely small after adjusting for individual characteristics (0.8 and 2% of overall variance in men and women, respectively) compared with individual-level variance (99.2 and 98% of overall variance in men and women, respectively). Among individual characteristics, greater body mass index, living with a spouse and high miso-soup intake were associated with high sodium excretion in both sexes. Within-country variation in salt intake in Japan was extremely small compared with individual level variation. Salt reduction strategies for Japan should be comprehensive and should not address the small within-country differences in intake. PMID- 28100921 TI - Clinical significance of 'cardiometabolic memory': a systematic review of randomized controlled trials. AB - 'Cardiometabolic memory' has been proposed based on clinical evidence to explain how, even after the cessation of a clinical trial, the superiority of one treatment over the outcome persists. To understand the cardiometabolic memory phenomenon, we performed a systematic review of randomized controlled trials (RCTs) using PubMed in August 2016. The search terms 'randomized controlled trial', 'post-trial follow-up' and 'diabetes, hypertension or dyslipidemia' were used, and articles published after the year 2000 were searched. We judged the memory phenomenon to be positive when the cardiovascular outcome at the end of the post-trial follow-up period in the intervention group was significantly superior even though the favorable control of a risk factor (blood glucose, blood pressure or lipid level) during the trial period was lost after the cessation of the intervention. Among 907 articles retrieved in the initial screening, 21 articles were judged as describing a positive memory phenomenon. Eight, six and seven of the articles concerned diabetes, hypertension and dyslipidemia, respectively. Transient intensive glucose lowering rather easily induced memory for the suppression of diabetic microangiopathies, while memory for the suppression of macroangiopathies tended to be first evident in the post-trial follow-up period. Transient intensive blood pressure lowering was generally effective in the formation of memory for the suppression of cardiovascular events and had an especially strong impact on risk reduction of chronic heart failure. Transient intensive LDL cholesterol lowering clearly had a long-term beneficial effect on risk reduction of cardiovascular events. Our systematic review revealed the clinical relevance of cardiometabolic memory. PMID- 28100922 TI - The effects of missed doses of amlodipine and losartan on blood pressure in older hypertensive patients. AB - This randomized, double-blind, parallel-group, multicenter study compared the efficacy of amlodipine and losartan in an older hypertensive population, focusing on therapeutic coverage in the case of missed doses. Following a 4-week, single blind, placebo washout period, 211 patients were randomly assigned to receive either 5 mg of amlodipine once daily or 50 mg of losartan once daily. Doses were doubled after 6 weeks of treatment if the diastolic blood pressure exceeded 90 mm Hg. After the 12-week treatment period, patients received the placebo for 2 days (drug holiday) to simulate two missed doses of antihypertensive medication. Twenty-four-hour ambulatory blood pressure monitoring was conducted at the end of the placebo washout period (baseline), upon completion of the 12-week treatment period (steady state), and after the 2-day drug holiday. Amlodipine was more effective than losartan in reducing patients' 24-h ambulatory blood pressure at the steady-state sampling time. The increases in 24-h blood pressure during the drug holiday averaged 6+/-2/2+/-1 mm Hg (P<0.0001) in the amlodipine group and 3+/-2/2+/-1 mm Hg (P<0.0001) in the losartan group. The rise in systolic pressure was greater in patients on amlodipine than in those on losartan (P<0.0001). For diastolic pressure, the changes did not differ. Owing to the lower pressure during treatment, patients in the amlodipine group remained at a significantly lower blood pressure level after the 2-day drug holiday. Amlodipine was more effective than losartan in lowering blood pressure and in maintaining blood pressure control after two missed doses, and the difference was most significant for systolic blood pressure. PMID- 28100924 TI - Rheumatoid arthritis: Nicotine exacerbates arthritis. PMID- 28100923 TI - Reductions in central arterial compliance with age are related to sympathetic vasoconstrictor nerve activity in healthy men. AB - The compliance of large elastic arteries in the cardiothoracic circulation declines, whereas sympathetic nervous system activity increases markedly with advancing age in adult humans. We tested the hypothesis that the reduction in compliance of the large elastic arteries with age is associated with elevations in sympathetic tone to vascular smooth muscle in 16 young and 17 older adults. Carotid arterial compliance (via ultrasonography) was 45% lower in healthy older compared with young men (P<0.001), and was inversely related to sympathetic nerve activity (via microneurography) (r=-0.51; P<0.005). Statistically correcting for sympathetic nerve activity abolished the age-related difference in arterial compliance (P=0.35). Our results suggest that increases in the sympathetic tone of vascular smooth muscle may have a mechanistic role in the age-related reduction in large artery compliance. PMID- 28100925 TI - Systemic lupus erythematosus: New pathway blocks disease in lupus-prone mice. PMID- 28100926 TI - Are coarse-grained models apt to detect protein thermal stability? The case of OPEP force field. AB - We present the first investigation of the kinetic and thermodynamic stability of two homologous thermophilic and mesophilic proteins based on the coarse-grained model OPEP. The object of our investigation is a pair of G-domains of relatively large size, 200 amino acids each, with an experimental stability gap of about 40 K. The OPEP force field is able to maintain stable the fold of these relatively large proteins within the hundrend-nanosecond time scale without including external constraints. This makes possible to characterize the conformational landscape of the folded protein as well as to explore the unfolding. In agreement with all-atom simulations used as a reference, we show that the conformational landscape of the thermophilic protein is characterized by a larger number of substates with slower dynamics on the network of states and more resilient to temperature increase. Moreover, we verify the stability gap between the two proteins using replica-exchange simulations and estimate a difference between the melting temperatures of about 23 K, in fair agreement with experiment. The detailed investigation of the unfolding thermodynamics, allows to gain insight into the mechanism underlying the enhanced stability of the thermophile relating it to a smaller heat capacity of unfolding. PMID- 28100927 TI - Resolution of morphology-based taxonomic delusions: Acrocordiella, Basiseptospora, Blogiascospora, Clypeosphaeria, Hymenopleella, Lepteutypa, Pseudapiospora, Requienella, Seiridium and Strickeria. AB - Fresh material, type studies and molecular phylogeny were used to clarify phylogenetic relationships of the nine genera Acrocordiella, Blogiascospora, Clypeosphaeria, Hymenopleella, Lepteutypa, Pseudapiospora, Requienella, Seiridium and Strickeria. At first sight, some of these genera do not seem to have much in common, but all were found to belong to the Xylariales, based on their generic types. Thus, the most peculiar finding is the phylogenetic affinity of the genera Acrocordiella, Requienella and Strickeria, which had been classified in the Dothideomycetes or Eurotiomycetes, to the Xylariales. Acrocordiella and Requienella are closely related but distinct genera of the Requienellaceae. Although their ascospores are similar to those of Lepteutypa, phylogenetic analyses do not reveal a particularly close relationship. The generic type of Lepteutypa, L. fuckelii, belongs to the Amphisphaeriaceae. Lepteutypa sambuci is newly described. Hymenopleella is recognised as phylogenetically distinct from Lepteutypa, and Hymenopleella hippophaeicola is proposed as new name for its generic type, Sphaeria (= Lepteutypa) hippophaes. Clypeosphaeria uniseptata is combined in Lepteutypa. No asexual morphs have been detected in species of Lepteutypa. Pseudomassaria fallax, unrelated to the generic type, P. chondrospora, is transferred to the new genus Basiseptospora, the genus Pseudapiospora is revived for P. corni, and Pseudomassaria carolinensis is combined in Beltraniella (Beltraniaceae). The family Clypeosphaeriaceae is discontinued, because the generic type of Clypeosphaeria, C. mamillana, is a member of the Xylariaceae. The genus Seiridium, of which the sexual morph Blogiascospora is confirmed, is unrelated to Lepteutypa, as is Lepteutypa cupressi. The taxonomy of the cypress canker agents is discussed. The family Sporocadaceae is revived for a large clade of the Xylariales that contains Hymenopleella, Seiridium and Strickeria among a number of other genera. Neotypes are proposed for Massaria fuckelii and Sphaeria hippophaes. Didymella vexata, Seiridium marginatum, Sphaeria corni, Sphaeria hippophaes, Sphaeria seminuda are epitypified, Apiosporina fallax, Massaria occulta, Sphaeria mamillana and Strickeria kochii are lecto- and epitypified. We also provide DNA data for Broomella vitalbae, Cainia desmazieri and Creosphaeria sassafras. PMID- 28100929 TI - Quantitative computed tomography analysis of the airways in patients with cystic fibrosis using automated software: correlation with spirometry in the evaluation of severity. AB - OBJECTIVE: To perform a quantitative analysis of the airways using automated software, in computed tomography images of patients with cystic fibrosis, correlating the results with spirometric findings. MATERIALS AND METHODS: Thirty four patients with cystic fibrosis were studied-20 males and 14 females; mean age 18 +/- 9 years-divided into two groups according to the spirometry findings: group I (n = 21), without severe airflow obstruction (forced expiratory volume in first second [FEV1] > 50% predicted), and group II (n = 13), with severe obstruction (FEV1 <= 50% predicted). The following tracheobronchial tree parameters were obtained automatically: bronchial diameter, area, thickness, and wall attenuation. RESULTS: On average, 52 bronchi per patient were studied. The number of bronchi analyzed was higher in group II. The correlation with spirometry findings, especially between the relative wall thickness of third to eighth bronchial generation and predicted FEV1, was better in group I. CONCLUSION: Quantitative analysis of the airways by computed tomography can be useful for assessing disease severity in cystic fibrosis patients. In patients with severe airflow obstruction, the number of bronchi studied by the method is higher, indicating more bronchiectasis. In patients without severe obstruction, the relative bronchial wall thickness showed a good correlation with the predicted FEV1. PMID- 28100928 TI - Mass Spectrometry: A Technique of Many Faces. AB - Protein complexes form the critical foundation for a wide range of biological process, however understanding the intricate details of their activities is often challenging. In this review we describe how mass spectrometry plays a key role in the analysis of protein assemblies and the cellular pathways which they are involved in. Specifically, we discuss how the versatility of mass spectrometric approaches provides unprecedented information on multiple levels. We demonstrate this on the ubiquitin-proteasome proteolytic pathway, a process that is responsible for protein turnover. We follow the various steps of this degradation route and illustrate the different mass spectrometry workflows that were applied for elucidating molecular information. Overall, this review aims to stimulate the integrated use of multiple mass spectrometry approaches for analyzing complex biological systems. PMID- 28100930 TI - Radiological findings in megaesophagus secondary to Chagas disease: chest X-ray and esophagogram. AB - OBJECTIVE: To identify and classify the radiographic patterns of megaesophagus in Chagas disease, as seen on esophagograms and chest X-rays. MATERIALS AND METHODS: This was a prospective study of 35 patients diagnosed with esophageal disease via manometry. The changes found on esophagograms were stratified according to Rezende's classification, divided into four categories (grades I through IV) determined by the degree of dilatation and impairement of esophageal motility. We subsequently correlated that ranking with the chest X-ray findings: gastric air bubble; air-fluid level; and mediastinal widening. RESULTS: Among the 35 patients, the esophageal disease was classified as grade I in 9 (25.7%), grade II in 3 (8.6%), grade III in 19 (54.3%), and grade IV in 4 (11.4%). None of the patients with grade I esophageal disease showed changes on chest X-rays. In two of the three patients with grade II disease, there was no gastric air-bubble, although there were no other findings in any of the grade II patients. Of the 19 patients with grade III disease, 15 had abnormal findings on X-rays. All four patients with grade IV disease showed abnormalities. CONCLUSION: The use of Rezende's classification is feasible, encompassing findings ranging from the subtle changes that characterize the initial phases of esophageal disease to the complete akinesia seen in dolicomegaesophagus. Chest X-ray findings are more common in patients with advanced stages of the disease and indicate the degree of esophageal involvement in Chagas disease. PMID- 28100931 TI - The value of anterior displacement of the abdominal aorta in diagnosing neuroblastoma in children. AB - OBJECTIVE: To determine the value of anterior displacement of the abdominal aorta, when present at any level or only at the level of the adrenal gland, contralateral to the mass, in diagnosing neuroblastoma on computed tomography or magnetic resonance imaging in children up to 7 years of age. MATERIALS AND METHODS: Imaging examinations of 66 patients were classified by consensus as for the presence of anterior aorta displacement and were compared with the pathology report. RESULTS: We found anterior abdominal aorta displacement in 26 (39.39%) of the 66 patients evaluated. Among those 26 patients, we identified neuroblastoma in 22 (84.62%), nephroblastoma in 3 (11.54%), and Burkitt lymphoma in 1 (3.85%). The positive predictive value was 84.62%, and the specificity was 88.24%. The displacement of the aorta was at the adrenal level, contralateral to the mass, in 14 cases, all of which were attributed to neuroblastoma. CONCLUSION: When the abdominal aorta is displaced at the level of the adrenal gland, contralateral to the mass, it can be said that the diagnosis is neuroblastoma, whereas abdominal aorta displacement occurring at other abdominal levels has a positive predictive value for neuroblastoma of approximately 85%. PMID- 28100932 TI - Defecography by digital radiography: experience in clinical practice. AB - OBJECTIVE: The objective of this study was to profile patients who undergo defecography, by age and gender, as well as to describe the main imaging and diagnostic findings in this population. MATERIALS AND METHODS: This was a retrospective, descriptive study of 39 patients, conducted between January 2012 and February 2014. The patients were evaluated in terms of age, gender, and diagnosis. They were stratified by age, and continuous variables are expressed as mean +/- standard deviation. All possible quantitative defecography variables were evaluated, including rectal evacuation, perineal descent, and measures of the anal canal. RESULTS: The majority (95%) of the patients were female. Patient ages ranged from 18 to 82 years (mean age, 52 +/- 13 years): 10 patients were under 40 years of age; 18 were between 40 and 60 years of age; and 11 were over 60 years of age. All 39 of the patients evaluated had abnormal radiological findings. The most prevalent diagnoses were rectocele (in 77%) and enterocele (in 38%). Less prevalent diagnoses were vaginal prolapse, uterine prolapse, and Meckel's diverticulum (in 2%, for all). CONCLUSION: Although defecography is performed more often in women, both genders can benefit from the test. Defecography can be performed in order to detect complex disorders such as uterine and rectal prolapse, as well as to detect basic clinical conditions such as rectocele or enterocele. PMID- 28100933 TI - Growth of Heterostegina depressa under natural and laboratory conditions. AB - The use of micro-computed tomography (MUCT) provides a unique opportunity to look inside the shells of larger benthic foraminifera to investigate their structure by measuring linear and volumetric parameters. For this study, gamonts/schizonts and agamonts of the species Heterostegina depressa d'Orbigny were examined by MUCT; each single chamber's volume was digitally measured. This approach enables cell growth to be recognised in terms of chamber volume sequence, which progressively increases until reproduction occurs. This sequence represents the ontogeny of the foraminiferal cell and has been used here to investigate controlling factors potentially affecting the process of chamber formation. This is manifested as instantaneous or periodic deviations of the realised chamber volumes derived from modelled growth functions. The results obtained on naturally grown specimens show oscillations in chamber volumes which can be modelled by sums of sinusoidal functions. A set of functions with similar periods in all investigated specimens points to lunar and tidal cycles. To determine whether such cyclic signals are genuine and not the effects of a theoretical model, the same analysis was conducted on specimens held in a closed laboratory facility, as they should not be affected by natural environmental effects. Surprisingly, similar cyclicities were observed in such samples. However, a solely genetic origin of these cycles couldn't be verified either. Therefore, detailed analysis on the phase equality of these growth oscillations have been done. This approach is pivotal for proving that the oscillatory patterns discovered in LBF are indeed genuine signals, and on how chamber growth might be influenced by tidal currents or lunar months. PMID- 28100934 TI - Association of Insulin Resistance with Glucose and Lipid Metabolism: Ethnic Heterogeneity in Far Western China. AB - Objective. To study the relationships between IR and glucose and lipid metabolism in far western China and these relationships' ethnic heterogeneity. Methods. From the baseline survey, 419 Uygur cases, 331 Kazak cases, and 220 Han cases were randomly selected, resulting in a total of 970 cases for study. FINS concentration was measured by radioimmunoassay. Results. (1) In the Kazak population, IR was correlated with hyperglycemia; high levels of TC, TG, and LDL C; and low levels of HDL-C and abdominal obesity (all P < 0.05). (2) In the Uygur population, the influence of IR on hyperglycemia and abdominal obesity was the greatest. In the Kazak population, IR was associated with hyperglycemia most closely. In the Han population, IR may have had an impact on the incidence of low HDL-C levels. (3) After adjusting for sex, age, smoking status, and alcohol consumption, IR was still associated with anomalies in the metabolism of the Uygur, Kazak, and Han populations. Conclusion. IR was involved in the process of glucose and lipid metabolism, and its degree of involvement differed among the ethnicities studied. We could consider reducing the occurrence of abnormal glucose and lipid metabolism by controlling IR and aiming to reduce the prevalence of metabolic syndrome and related diseases. PMID- 28100935 TI - Dalbergioidin Ameliorates Doxorubicin-Induced Renal Fibrosis by Suppressing the TGF-beta Signal Pathway. AB - We investigated the effect of Dalbergioidin (DAL), a well-known natural product extracted from Uraria crinita, on doxorubicin- (DXR-) induced renal fibrosis in mice. The mice were pretreated for 7 days with DAL followed by a single injection of DXR (10 mg/kg) via the tail vein. Renal function was analyzed 5 weeks after DXR treatment. DXR caused nephrotoxicity. The symptoms of nephrotic syndrome were greatly improved after DAL treatment. The indices of renal fibrosis, the phosphorylation of Smad3, and the expression of alpha-smooth muscle actin (alpha SMA), fibronectin, collagen III (Col III), E-cadherin, TGF-beta, and Smad7 in response to DXR were all similarly modified by DAL. The present findings suggest that DAL improved the markers for kidney damage investigated in this model of DXR induced experimental nephrotoxicity. PMID- 28100936 TI - Chitosan Modulates Inflammatory Responses in Rats Infected with Enterotoxigenic Escherichia coli. AB - This study aims to investigate the effects of dietary chitosan (COS) on gastrointestinal pathogen resistance in mice model. For two weeks, a control group of ICR mice received a basal diet whilst the intervention group received the basal diet supplemented with 300 mg/kg COS. After two weeks, the mice fed the supplemented diet had a lower body weight. Then enterotoxigenic Escherichia coli (E. coli) was administered to the mice through oral gavage, with each mouse receiving 108 CFU. At day 7 after infection, the bacterial load in the jejunum and faeces was significantly lower in the COS group than that in the control group. Moreover, the mRNA and protein levels of IL-1beta, IL-6, IL-17, IL-18, and TNF-alpha were significantly lower in the group of mice receiving the COS diet; also the jejunal production of toll-like receptor-4 (TLR-4) was suppressed in the COS group. These results indicate the intervention influenced inflammation and controlled E. coli infection. PMID- 28100937 TI - Why the Resistance: Minimally Invasive Pancreaticoduodenectomy-Saving the Patient from Tigers. PMID- 28100938 TI - Public Perceptions of Plastic Surgery Practice in Brazil. AB - The perception of medical specialists by the public has a significant effect on health-care decisions, research funding allocation, and implantation of educational measures. The purpose of this survey was to assess the public's perception of the field of plastic surgery practice. General public members (n = 1290) completed a survey where they matched nine specialties with 28 plastic surgery-related scenarios. Response patterns were distributed as "plastic surgeon alone," "plastic surgeon combined with other specialists," or "no plastic surgeon." Sociodemographic data and previous plastic surgery contact were also collected. "Plastic surgeon alone" was identified as an expert by more than 70 % of respondents in four (40 %) aesthetic-related scenarios and in one (5.5 %) general/reconstructive-related scenario. "Plastic surgeon alone" was significantly (all p < 0.05) more recognized as an expert than other response patterns in all aesthetic-related scenarios, except for botulinum toxin for facial wrinkles. There was a significant (all p < 0.05) poor understanding of the role of plastic surgeons in facial fracture surgery, facial paralysis management, chest wall surgery, hand surgery-related scenarios, and tumor surgery-related scenarios. Age, health-care professional, education level, and prior plastic surgery contact were significant (all p < 0.05) determinants of "plastic surgeon" as a response pattern, according to bivariate analysis and multiple linear regression analysis. The public has a poor understanding of the broad field of plastic surgery practice. Therefore, improved public education about the scope of plastic surgery is needed. PMID- 28100939 TI - Management of Liver Trauma in Minia University Hospital, Egypt. AB - The aim of this study is to present the outcome of operative and non-operative management of patients with liver injury treated in a single institution depending on imaging. This study was conducted at the Causality Unit of Minia University Hospital, and included 60 patients with hepatic trauma from March 2012 to January 2013. In our study, males represent 80 % while females represent 20 % of the traumatized patients. The peak age for trauma found was 11-30 years. Blunt trauma is the most common cause of liver injury as it was the cause in 48 patients (80 %). Firearm injuries are the most common cause of penetrating trauma (60 %) followed by stab injuries (40 %). More than one half of our patients (34 out of 60) were treated with non-operative management (NOM) with a high success rate. The operative procedures done were suture hepatorrhaphy (20 cases), non anatomical resection in one case, anatomical resection in one case, and damage control therapy using pads in two cases. In another two cases, nothing was done as subcapsular hematoma had resolved. Minia University Hospital is a big tertiary Hospital in Egypt at which blunt liver trauma is more common than penetrating liver trauma. Surgery is no longer the only option available. It has been reserved for extensive lesions with condition of hemodynamic instability or for the treatment of the complications. NOM is an effective treatment modality in most cases. PMID- 28100940 TI - Surgery in Pancreatic Necrosis-Challenges and Outcomes in an Industrial Hospital. AB - Twenty-seven cases of pancreatic necrosis were admitted and treated at our hospital from Jan 2010 till Jan 2015. Eight of these patients (29 %) underwent pancreatic necrosectomy. Of a total number of 957 patients admitted for acute pancreatitis, 27 patients (3 %) were diagnosed to have necrotizing pancreatitis. Of the 8 patients operated on, 5 patients (62.5 %) were treated successfully. The 3 patients who died had 3 organ (renal, respiratory and cardiovascular) failures. Nineteen patients of pancreatic necrosis responded to medical management and were successfully treated. PMID- 28100941 TI - Outcomes of Laparoscopy Combined with Enhanced Recovery Pathway for Reversal of Hartmann's Procedure. AB - The objective of this study is to discuss the security and feasibility of the laparoscopic reversal of Hartmann's procedure (LRHP) on the concept of enhanced recovery after surgery (ERAS). The clinical data of 42 patients who underwent laparoscopic reversal of Hartmann's procedure was retrospectively analyzed, and the operative time, blood loss, intraoperative and postoperative complications, conversion to open surgery, postoperative hospital stay, and so on were observed. Twenty-nine patients (69.00 % of the study pool) received complete postoperative recovery courses as prescribed by enhanced recovery program (ERP). The postoperative length of stay (LOS) in the hospital was 5.6 (3-16 days). The overall and major (grades III to V) postoperative morbidities were 33.3 % (n = 14) and 4.8 % (n = 2), respectively. Our preliminary results showed that using the laparoscopic technology in reversal of Hartmann's colostomy on the concept of ERP is safe and feasible. Patients with intra- or postoperative complications were found to have statistically significant associations with greater risk of ERP failure. PMID- 28100942 TI - Potential Benefits of Rib Fracture Fixation in Patients with Flail Chest and Multiple Non-flail Rib Fractures. AB - The purpose of this study is to evaluate the potential benefits of rib fracture fixation in patients with flail chest and multiple non-flail rib fractures versus conventional treatment modalities. A retrospective reviewed study compared 86 cases which received surgical treatment between June 2009 and May 2013 to 76 cases which received conservative treatment between January 2006 and May 2009. The patients were divided into the flail chest (n = 38) and multiple non-flail rib fracture groups (n = 124). In the flail chest group, the mechanical ventilation time, ICU monitoring time, tracheostomies, thoracic deformity, and impaired pulmonary function and return to full-time employment were compared. In the multiple non-flail rib fracture group, fracture healing, visual analog scale (VAS) pain score, inpatient length of stay, atelectatic, pulmonary complications, and normal activity-returning time were compared. Patients in the flail chest operative fixation group had significantly shorter ICU stay, decreased ventilator requirements, fewer tracheostomies, less thoracic deformity and impaired pulmonary function, and more returned to full-time employment. Patients in the multiple non-flail rib fracture operative fixation had shorter hospital stay, less pain, earlier return to normal activity, more fracture healing, less atelectasis, and fewer pulmonary infections. This study demonstrates the potential benefits of surgical stabilization of flail chest and multiple non flail rib fractures with plate fixation. When compared with conventional conservative management, operatively managed patients demonstrated improved clinical outcomes. PMID- 28100943 TI - Comparison of the Clinical Outcome and Complications in Laparoscopic Hernia Repair of Inguinal Hernia With Mesh Fixation Using Fibrin Glue vs Tacker. AB - Although laparoscopic repair offers a quick and less morbid way of treating hernias, complications like hematoma, seroma, neuralgia, recurrence, mesh infection, hydrocele, etc. are known. The present study was undertaken to compare various clinical outcomes between mesh fixation using fibrin glue and mesh fixation with tacker in a 3-months follow-up. One hundred patients aged 18 to 60 years having inguinal hernia admitted in Poona Hospital and Research Centre, Pune, between October 2012 and November 2014 for laparoscopic hernia surgery and ready to participate in this study were included. All of them underwent laparoscopic repair of hernia by total extra peritoneal (TEP) method following sample surgical protocol in all of them except for method of mesh fixation. Mean time calculated from insertion of the first trocar to beginning of skin suturing was 54.9 min in tacker group and 50.3 min in fibrin glue group with no statistically significant difference between the two. The incidence of urinary retention was significantly higher in tacker (34 %) as compared to fibrin glue (12 %) group. Incidence of hematoma was significantly higher in tacker group in 15-day follow-up, but there was no significant difference in hematoma formation at hernial sites in both groups after 15 days of follow-up. The incidence of neuralgia was significantly higher in the tacker group (24 %) compared with the fibrin glue group (2 %). Significantly, more number of people in the fibrin glue group 68 and 90 %, respectively, returned to work during 15 and 30 days follow-up as compared to the tacker group 46 and 64 %. Fibrin glue can be considered as an alternative to tacker for mesh fixation. PMID- 28100944 TI - Ostomy in Nontraumatic Conditions: Our Experience and Review of the Literature. AB - A number of nontraumatic acute abdomen can result in peritonitis leading to sepsis. In emergent conditions, various procedures like segmentary colectomy and/or subtotal colectomy with anastomosis, Hartmann's procedure, transverse colectomy, and/or expandable metallic stent (SEMS) placement can be performed, considering the status of the patient and the facilitaties of the institution. In our study, we examined the cases diagnosed as acute abdomen without the history of trauma, which had lead to a procedure requiring colostomy. We retrospectively analysed 105 cases of nontraumatic acute abdomen, resulted in a procedure requiring colostomy. American Society of Anesthesiologists (ASA) scoring and Mannheim Peritonitis Index (MPI) were used in the evaluation of the risk of mortality and morbidity. There were colonic perforations of rectosigmoid tumor in 66 cases (62.8 %), sigmoid volvulus in 10 cases (9.5 %), colonic anastomotic leakage in 9 cases (8.5 %), intestinal adhesions in 8 cases (7.6 %), mesenteric ischemia in 5 cases (4.7 %), gynecological diseases in 3 cases (2.85 %), strangulated hernias in 3 (2.85 %), and Ogilvie syndrome in 1 case (0.95 %). Rate of morbidity was found to be 25.7 %, while mortality occurred in 2.8 % of the cases. Cases with mortality and morbidity had ASA scores above two and MPI scores above 23. Anastomotic leakage was the only reason of mortality. In nontraumatic occasions, the management and prognosis of cases with peritonitis, general status of the patients play major roles. The prognosis rates of morbidity and mortality can be highly predicted when ASA and MPI scores are evaluated together. PMID- 28100945 TI - Study of 433 Operated Cases of Thoracic Trauma. AB - Patients with thoracic trauma constitute one third of all the trauma cases. Of traumatic patients, 20-25 % die because of thoracic trauma. Our aim was to compare our clinical experience and the results with the related literature. Four hundred thirty-three patients, who underwent surgical interventions due to thoracic trauma, were evaluated. The latest form of treatment applied were taken as the criteria for the quantitative detection of patients. Continuous variables were expressed as mean +/- standard deviation, while categorical variables were explained as number and percentage. The significance of the analysis results was evaluated using Fisher's exact test. p values <0.05 were considered as significant. Penetrating injuries were found in 258 (59 %) of the patients, and blunt trauma was identified in 175 (41 %). Depending on the trauma, pneumothorax was discovered in 130 patients (30.02 %), hemothorax in 117 (27.02 %), hemopneumothorax in 61 (14.08 %), pulmonary contusion in 110 (45 %), pneumomediastinum in 14 (3.23 %), and pericardial tamponade in 1 patient (0.23 %). It was demonstrated that 385 of 433 patients examined in the study underwent tube thoracostomy, 41 were treated with thoracotomy, while 6 of them underwent video-assisted thoracoscopic surgery (VATS), and 1 underwent sternotomy. No correlation was observed between mortality, morbidity, and gender and type of trauma and location of trauma (p > 0.05). However, statistically significant correlation was found between mortaxlity, morbidity, and the presence of concomitant injuries, the duration between injury and admission being more than 1 h (p < 0.05). Urgent intervention, early diagnosis, and fast transport are vital for patients with thoracic injuries. PMID- 28100946 TI - Management of Young Patients with Temporomandibular Joint Ankylosis-a Surgical and Anesthetic Challenge. AB - Temporomandibular joint ankylosis is a unique disease where fracture of the mandibular condyle or any other cause leading to ankylosis of the joint can lead to multiple problems if not detected and treated early. If affected in early years of life, it may cause facial dysmorphism, restricted mouth opening, and difficulty in eating, speech, and sleep. Early surgery and physiotherapy can restore the joint function to a great extent. Anesthetizing a pediatric patient with this disorder is a definite challenge which needs expertise in difficult airway management. PMID- 28100947 TI - Solitary Splenic Metastasis from a Mucinous Adenocarcinoma of the Cecum. A Case Report. AB - Reports of cases of splenic metastasis are very rare, even more so when they are derived from a mucinous adenocarcinoma of the cecum. The most common presentation of a solitary splenic metastasis is from lung primary tumors, endometrium, ovary, cervix, stomach, colon, breast, bladder, and skin. We report the case of an 84 year-old woman with a solitary splenic metastasis from a mucinous adenocarcinoma of the cecum. Until this work, only 18 cases of solitary splenic metastases from colorectal carcinomas have been described in the literature. PMID- 28100948 TI - Malignant Proliferating Trichilemmal Tumour of the Scalp with Intra-Cranial Extension and Lung Metastasis-a Case Report. AB - Malignant proliferating trichilemmal tumour (MPTT) is a rare cutaneous tumour predominantly affecting the scalp, eyelids, neck and face of elderly women. It is a large, solitary, multilobulated lesion that may arise within a pilar cyst. These tumours are largely benign, often cystic and are characterized by trichilemmal keratinisation. However at times, the tumour has an aggressive clinical course and a propensity for distant metastasis. We report a case of a 29 year-old male who presented with a scalp swelling. Histology revealed malignant proliferating trichilemmal tumour of scalp. CT thorax showed multiple nodules in both lungs suggestive of lung metastasis. The patient underwent palliative radiotherapy and chemotherapy and expired 2 months after palliation. To the best of our knowledge, malignant proliferating trichilemmal tumour of the scalp with intra-cranial extension and lung metastasis is a rare condition, and only a handful of cases are reported till date. We report a case of malignant proliferating trichilemmal tumour of the scalp with intra-cranial extension and lung metastasis with relevant discussion at the same time. PMID- 28100949 TI - Rosai-Dorfman Disease Presenting with Recurrent, Unilateral Submandibular Lymph Adenitis: a Case Report. AB - Rosai-Dorfman Disease (RDD) is a rare disease of unknown aetiology, initially described as a separate entity in 1969 by Rosai and Dorfman. We describe here a case of RDD presenting with acute, recurrent lymphadenitis and massive lymphadenopathy. The patient's good response to the antibiotics was a false pointer towards infective pathology. The repeated fine needle aspiration cytology was inconclusive or suggested nonspecific reactive hyperplasia. The excision biopsy confirmed the diagnosis of RDD and was supported by immune-histochemistry for S-100 antigen. No other lymph node group was involved clinically or radiologically. The patient was treated with long-term antibiotic and low-dose predenisolone. The residual lymph node mass was excised after 3 months of first surgery. The patient is on regular follow-up for last 2 years and no recurrence has been reported. PMID- 28100950 TI - Primary Breast T Cell Lymphoma Involving Nipple-Areolar Complex in a Young Patient. AB - We present a rare case of recurrent primary breast lymphoma involving the nipple areolar complex and review literature on primary breast lymphoma, its clinical presentation and management. It is diagnosed by histopathology. It needs multimodality management protocols. PMID- 28100951 TI - An Unusual Cause of Duodenal Obstruction: Persimmon Phytobezoar. AB - Duodenal phytobezoar, an unusual cause of acute duodenal obstruction, is rarely seen. The most common cause of this type of bezoar is persimmon. It frequently arises from underlying gastrointestinal tract pathologies (gastric surgery, etc.). Here, we report the case of a 66-year-old man who had undergone distal gastrectomy with Billroth I reconstruction for gastric cancer and experienced severe epigastric discomfort, abdominal pain, and vomiting for a few days. The abdominal computed tomography scan showed a large-sized mass in the horizontal portion of the duodenum. On following endoscopic examination, a large phytobezoar was revealed in the duodenum. He was treated with endoscopic fragmentation combined with nasogastric Coca-Cola. The patient tolerated the procedure well and resumed a normal oral diet 3 days later. PMID- 28100952 TI - Gangrene of the Hand Following a Haemodialysis Access: Lessons to be Learnt. AB - Renal replacement therapy is a "way of life" for patients with chronic kidney disease (CKD), and haemodialysis forms their "lifeline". Haemodialysis access, via a small surgery, to anastomose an artery and a vein in the arm or forearm, is the universally accepted standard of care. However, even this minor surgical intervention can lead to devastating complications without adequate pre-operative evaluation and apt intra-operative decision making. The following article pictorically exemplifies the most dreaded complication of a gangrenous hand as well as highlights the lessons to be learnt, in order to avoid this infirmity. PMID- 28100953 TI - Some Stones Are Precious-Extraluminal Appendicoliths. AB - Appendicoliths are commonly implicated in the etiopathogenesis of acute appendicitis. Extraluminal appendicoliths are not uncommon and are frequently encountered with ruptured appendicitis. The present image scenario focuses on the importance of identifying and subsequently retrieval of these extraluminal appendicoliths to prevent long-term complications, including intra-abdominal abscess. PMID- 28100954 TI - Even Handed Future of Surgery-Ambidextrous, Serious Gamers with Innate Left Hand Laterality. PMID- 28100955 TI - Gastric Mucormycosis Presenting as Gastrocolic Fistula: a Rare Entity. PMID- 28100956 TI - The Influence of Pain Severity and Interference on Satisfaction with Pain Management among Middle-Aged and Older Adults. AB - Background. Health outcomes are often contingent on how effective the individual is able to manage existent illness-related symptoms. This is all the more relevant among chronic pain patients. Objective. This study aimed to identify indicators of pain treatment satisfaction among middle-aged and older adults (N = 150) receiving outpatient treatment from a comprehensive cancer center. Methods. Patients were surveyed on questions assessing pain treatment satisfaction, pain severity, and additional social characteristics. Results. Descriptive data showed that middle-aged adults reported more pain locations, greater pain severity, and less satisfaction with pain treatment. A multivariate model was specified, showing older adults being more satisfied with their pain treatment. For the middle-aged adults, treatment satisfaction was generally lower with greater pain severity. This counters that for the older adults, where treatment satisfaction remained consistent despite increased levels of pain severity. Conclusion. These findings address an important issue regarding how pain is experienced across the life course. This suggests that general assumptions cannot be made about the health outcomes of older adults. Beyond the descriptive definitions of pain, there remains the need to develop models that account for determinants that may account for the pain experience among a diverse adult population. PMID- 28100957 TI - Conditions for success in introducing telemedicine in diabetes foot care: a qualitative inquiry. AB - BACKGROUND: The uptake of various telehealth technologies to deliver health care services at a distance is expanding; however more knowledge is needed to help understand vital components for success in using telehealth in different work settings. This study was part of a larger trial designed to investigate the effect of an interactive telemedicine platform. The platform consisted of a web based ulcer record linked to a mobile phone to provide care for people with diabetic foot ulcers in outpatient clinics in specialist hospital care in collaboration with primary health care. The aim of this qualitative study was to identify perceptions of health care professionals in different working settings with respect to facilitators to engagement and participation in the application of telemedicine. METHODS: Ten focus groups were conducted with health care professionals and leaders in Western Norway between January 2014 and June 2015 using Interpretive Description, an applied qualitative research strategy. RESULTS: Four key conditions for success in using telemedicine as a new technology in diabetes foot care were identified: technology and training that were user-friendly; having a telemedicine champion in the work setting; the support of committed and responsible leaders; and effective communication channels at the organizational level. CONCLUSIONS: Successful larger scale implementation of telemedicine must involve consideration of complex contextual and organizational factors associated with different work settings. This form of new care technology in diabetes foot care often involves health care professionals working across different settings with different management systems and organizational cultures. Therefore, attention to the distinct needs of each staff group seems an essential condition for effective implementation. PMID- 28100958 TI - Routine dyspnea assessment and documentation: Nurses' experience yields wide acceptance. AB - BACKGROUND: Dyspnea (breathing discomfort) is a common and distressing symptom. Routine assessment and documentation can improve management and relieve suffering. A major barrier to routine dyspnea documentation is the concern that it will have a deleterious effect on nursing workflow and that it will not be readily accepted by nurses. Nurses at our institution recently began to assess and document dyspnea on all medical-surgical patients upon admission and once per shift throughout their hospitalization. A year after dyspnea measurement was implemented we explored nurses' approach to dyspnea assessment, their perception of patient response, and their perception of the utility and burden of dyspnea measurement. METHODS: We obtained feedback from nurses using a three-part assessment of practice: 1) a series of recorded focus group interviews with nurses, 2) a time-motion observation of nurses performing routine dyspnea and pain assessment, and 3) a randomized, anonymous on-line survey based, in part, on issues raised in focus groups. RESULTS: Ninety-four percent of the nurses surveyed reported administering the dyspnea assessment is "easy" or "very easy". None of the nurses reported that assessing dyspnea negatively impacted workflow and many reported that it positively improved their practice by increasing their awareness. Our time-motion data showed dyspnea assessment and documentation takes well less than a minute. Nurses endorsed the importance of routine measurement and agreed that most patients were able to provide a meaningful rating of their dyspnea. Nurses found the patient report very useful, and used it in conjunction with observed signs to respond to changes in a patient's condition. CONCLUSIONS: In this study, we have demonstrated that routine dyspnea assessment and documentation was widely accepted by the nurses at our institution. Our nurses fully incorporated routine dyspnea assessment and documentation into their practice and felt that it improved patient-centered care. PMID- 28100959 TI - Hydrogen-rich saline attenuates eosinophil activation in a guinea pig model of allergic rhinitis via reducing oxidative stress. AB - BACKGROUND: It is well considered that reactive oxygen species (ROS) plays a prominent causative role in the development of allergic rhinitis (AR), and eosinophils cells as important allergic inflammatory cells contribute to elevating oxidative stress. Hydrogen, emerging as a novel antioxidant, has been proven effective in selectively reducing ROS in animals models of oxidative damage. We herein aim to verify protective effects of hydrogen on eosinophils cells in guinea pigs models of AR. METHODS: Thirty two guinea pigs were random divided into four groups, and AR model was established through ovalbumin sensitization. The guinea pigs were injected with hydrogen-rich saline (Normal HRS and AR-HRS group) or normal saline (control and AR group). The frequencies of sneezing and scratching were recorded. The IgE level, blood eosinophil count and eosinophil cationic protein (ECP) level in serum were measured. The serum malondialdehyde (MDA) and superoxide dismutase (SOD) assays were also measured to evaluate oxidative stress. The expression levels of eotaxin mRNA and protein in the nasal mucosa were also determined by real-time RT-PCR, Western blot and immunofluorescence. RESULTS: HRS reduced the ROS and MDA levels and increased SOD level in guinea pigs of AR-HRS group accompanied with decreased frequency of sneezing and scratches. Meanwhile, there was a decline of the number of eosinophils cells in blood and of thelevel of ECP in serum in the AR-HRS group. HRS also significantly decreased the expression of eotaxin in nasal mucosa. CONCLUSION: HRS may play a protective role in attenuating allergic inflammation, and suppressing the increase and activation of eosinophils in AR possibly through antioxidation effect of hydrogen. PMID- 28100960 TI - A survey of thrombosis experts evaluating practices and opinions regarding venous thromboprophylaxis in patients post major abdominal surgery. AB - BACKGROUND: Patients undergoing major abdominal surgery are at high risk for developing venous thromboembolism in the post-operative period. Current evidence based guidelines recommend routine pharmacological venous thromboembolism prophylaxis in patient at moderate to high risk post major abdominal surgery. However, the type of agent, dose and duration of thromboprophylaxis remain unclear. We sought to survey current clinical practice and assess for potential clinical equipoise regarding pharmacological thromboprophylaxis post major abdominal surgery. METHODS: An electronic survey targeting thrombosis expert members of Thrombosis Canada was conducted. RESULTS: The total response rate was 52.3% (45/86). All thrombosis experts recommended pharmacological thromboprophylaxis for high risk patients post major abdominal surgery. Over 68% of the thrombosis experts recommended thromboprophylaxis during hospitalization only. The majority of the participants recommended using LMWH (85.9%) over UFH (10.1%). Approximately a third of the surveyed thrombosis experts estimated the incidence of overall VTE at 7 to 10 days post-operatively in patients who do not receive thromboprophylaxis post major abdominal surgery to be between 4 and 6%. A total of 55.3% of the thrombosis experts estimated the incidence of PE to be between 0.5 and 1.0% for the same patient population. The risk of major bleeding episode was estimated to be between 0.5 and 1% in patients receiving 7 to 10 days of pharmacological thromboprophylaxis in the post-operative period by a majority of the thrombosis experts (68.4%). However, approximately 80% of thrombosis experts believed that there is still some clinical equipoise around the use of thromboprophylaxis post discharge (up to 7 to 10 days) in high risk adult patients post major abdominal surgery. CONCLUSIONS: Thrombosis experts recommend LMWH prophylaxis post major abdominal surgery. There is still, however, significant clinical equipoise regarding the duration of thromboprophylaxis (hospitalization only vs. total to 7-10 days). The result of the survey might not be generalizable to non-academic centers and to other countries. PMID- 28100962 TI - CTLS-2016 and the Formation of a Pan-European Professional Society through the Lens of an ABRF Founding Member. PMID- 28100963 TI - Rebirth Certificate. PMID- 28100961 TI - Auxin Extraction and Purification Based on Recombinant Aux/IAA Proteins. AB - BACKGROUND: Indole-3-acetic acid (IAA) extraction and purification are of great importance in auxin research, which is a hot topic in the plant growth and development field. Solid-phase extraction (SPE) is frequently used for IAA extraction and purification. However, no IAA-specific SPE columns are commercially available at the moment. Therefore, the development of IAA-specific recognition materials and IAA extraction and purification methods will help researchers meet the need for more precise analytical methods for research on phytohormones. RESULTS: Since the AUXIN RESISTANT/INDOLE-3-ACETIC ACID INDUCIBLE (Aux/IAA) proteins show higher specific binding capability with auxin, recombinant IAA1, IAA7 and IAA28 proteins were used as sorbents to develop an IAA extraction and purification method. A GST tag was used to solidify the recombinant protein in a column. Aux/IAA proteins solidified in a column have successfully trapped trace IAA in aqueous solutions. The IAA7 protein showed higher IAA binding capability than the other proteins tested. In addition, expression of the IAA7 protein in Drosophila Schneider 2 (S2) cells produced better levels of binding than IAA7 expressed in E. coli. CONCLUSION: This work validated the potential of Aux/IAA proteins to extract and purify IAA from crude plant extracts once we refined the techniques for these processes. PMID- 28100964 TI - Comparative Efficacy of Nebivolol and Metoprolol to Prevent Tachycardia-Induced Cardiomyopathy in a Porcine Model. AB - Chronic tachycardia is a well-known cause of nonischemic cardiomyopathy. We hypothesized that nebivolol, a beta-blocker with nitric oxide activity, would be superior to a pure beta-blocker in preventing tachycardia-induced cardiomyopathy in a porcine model. Fifteen healthy Yucatan pigs were randomly assigned to receive nebivolol, metoprolol, or placebo once a day. All pigs underwent dual chamber pacemaker implantation. The medication was started the day after the pacemaker implantation. On day 7 after implantation, each pacemaker was set at atrioventricular pace (rate, 170 beats/min), and the pigs were observed for another 7 weeks. Transthoracic echocardiograms, serum catecholamine levels, and blood chemistry data were obtained at baseline and at the end of the study. At the end of week 8, the pigs were euthanized, and complete histopathologic studies were performed. All the pigs developed left ventricular cardiomyopathy but remained hemodynamically stable and survived to the end of the study. The mean left ventricular ejection fraction decreased from baseline by 34%, 20%, and 20% in the nebivolol, metoprolol, and placebo groups, respectively. These changes did not differ significantly among the 3 groups (P =0.51). Histopathologic analysis revealed mild left ventricular perivascular fibrosis with cardiomyocyte hypertrophy in 14 of the 15 pigs. Both nebivolol and metoprolol failed to prevent cardiomyopathy in our animal model of persistent tachycardia and a high catecholamine state. PMID- 28100965 TI - Aspirin Resistance Predicts Adverse Cardiovascular Events in Patients with Symptomatic Peripheral Artery Disease. AB - Antiplatelet therapy reduces the risk of myocardial infarction, stroke, and vascular death in patients who have symptomatic peripheral artery disease. However, a subset of patients who take aspirin continues to have recurrent cardiovascular events. There are few data on cardiovascular outcomes in patients with peripheral artery disease who manifest aspirin resistance. Patients with peripheral artery disease on long-term aspirin therapy (>=4 wk) were tested for aspirin responsiveness by means of the VerifyNow Aspirin Assay. The mean follow up duration was 22.6 +/- 8.3 months. The primary endpoint was a composite of death, myocardial infarction, or ischemic stroke. Secondary endpoints were the incidence of vascular interventions (surgical or percutaneous), or of amputation or gangrene caused by vascular disease. Of the 120 patients enrolled in the study, 31 (25.8%) were aspirin-resistant and 89 (74.2%) were aspirin-responsive. The primary endpoint occurred in 10 (32.3%) patients in the aspirin-resistant group and in 13 (14.6%) patients in the aspirin-responsive group (hazard ratio=2.48; 95% confidence interval, 1.08-5.66; P=0.03). There was no significant difference in the secondary outcome of revascularization or tissue loss. By multivariate analysis, aspirin resistance and history of chronic kidney disease were the only independent predictors of long-term adverse cardiovascular events. Aspirin resistance is highly prevalent in patients with symptomatic peripheral artery disease and is an independent predictor of adverse cardiovascular risk. Whether intervening in these patients with additional antiplatelet therapies would improve outcomes needs to be explored. PMID- 28100966 TI - Total Arch versus Hemiarch Replacement for Type A Acute Aortic Dissection: A Single-Center Experience. AB - We retrospectively evaluated early and intermediate outcomes of aortic arch surgery in patients with type A acute aortic dissection (AAD), investigating the effect of arch surgery extension on postoperative results. From January 2006 through July 2013, 201 patients with type A AAD underwent urgent corrective surgery at our institution. Of the 92 patients chosen for this study, 59 underwent hemiarch replacement (hemiarch group), and 33 underwent total arch replacement (total arch group) in conjunction with ascending aorta replacement. The operative mortality rate was 22%. Total arch replacement was associated with a 33% risk of operative death, versus 15% for hemiarch (P=0.044). Multivariable analysis found these independent predictors of operative death: age (odds ratio [OR]=1.13/yr; 95% confidence interval [CI], 1.04-1.23; P=0.002), body mass index >30 kg/m2 (OR=9.9; 95% CI, 1.28-19; P=0.028), postoperative low cardiac output (OR=10.6; 95% CI, 1.18-25; P=0.035), and total arch replacement (OR=8.8; 95% CI, 1.39-15; P=0.021) The mean overall 5-year survival rate was 59.3% +/- 5.5%, and mean 5-year freedom from distal reintervention was 95.4% +/- 3.2% (P=NS). In type A AAD, aortic arch surgery is still associated with high operative mortality rates; hemiarch replacement can be performed more safely than total arch replacement. Rates of distal aortic reoperation were not different between the 2 surgical strategies. PMID- 28100967 TI - Anesthetic Management in Radiofrequency Catheter Ablation of Ventricular Tachycardia. AB - Radiofrequency catheter ablation is increasingly being used to treat patients who have ventricular tachycardia, and anesthesiologists frequently manage their perioperative care. This narrative review is intended to familiarize anesthesiologists with preprocedural, intraprocedural, and postprocedural implications of this ablation. Ventricular tachycardia typically arises from structural heart disease, most often from scar tissue after myocardial infarction. Many patients thus affected will benefit from radiofrequency catheter ablation in the electrophysiology laboratory to ablate the foci of arrhythmogenesis. The pathophysiology of ventricular tachycardia is complex, as are the technical aspects of mapping and ablating these arrhythmias. Patients often have substantial comorbidities and tenuous hemodynamic status, necessitating pharmacologic and mechanical cardiopulmonary support. General anesthesia and monitored anesthesia care, when used for sedation during ablation, can lead to drug interactions and side effects in the presence of ventricular tachycardia, so anesthesiologists should also be aware of potential perioperative complications. We discuss variables that can help anesthesiologists safely guide patients through the challenges of radiofrequency catheter ablation of ventricular tachycardia. PMID- 28100968 TI - Direct Measurement of Left Atrial Pressure during Routine Transradial Catheterization. AB - Left atrial pressure indicates the left ventricular filling pressure in patients who have systolic or diastolic left ventricular dysfunction or valvular heart disease. The use of indirect surrogate methods to determine left atrial pressure has been essential in the modern evaluation and treatment of cardiovascular disease because of the difficulty and inherent risks associated with direct methods (typically the transseptal approach). One method that has been widely used to determine left atrial pressure indirectly is Swan-Ganz catheterization, in which a balloon-flotation technique is applied to measure pulmonary capillary wedge pressure; however, this approach has been associated with several limitations and potential risks. Measuring left ventricular end-diastolic pressure has also been widely used as a simple means to estimate filling pressures but remains a surrogate for the gold standard of directly measuring left atrial pressure. We describe a simple, low-risk method to directly measure left atrial pressure that involves the use of standard coronary catheterization techniques during a transradial procedure. PMID- 28100969 TI - Proarrhythmic Antiarrhythmic. PMID- 28100971 TI - Tricuspid Valve Replacement in an HIV-Infected Patient with Severe Tricuspid Regurgitation Secondary to Remote Endocarditis. AB - Surgical intervention for severe tricuspid regurgitation secondary to remote infective endocarditis has been infrequent, especially in patients also infected with the human immunodeficiency virus (HIV). We describe the case of a 62-year old HIV-positive man, with a 24-year history of endocarditis caused by intravenous heroin use, who presented with severe tricuspid regurgitation. The patient was initially asymptomatic, was taking antiretroviral medications, and had a satisfactory CD4 count and an undetectable viral load, so we decided to manage the regurgitation conservatively. Two years later, he presented with biventricular heart failure and dyspnea. After surgical tricuspid valve replacement, his condition improved substantially. This case illustrates that HIV infected patients with complex medical conditions can successfully undergo cardiac surgery. PMID- 28100972 TI - Unrepaired Tetralogy of Fallot with Absent Pulmonary Valve in a Mildly Symptomatic 16-Year-Old Boy. AB - Absent pulmonary valve is a rare and severe variant seen in only 3% to 6% of patients with tetralogy of Fallot. Fetuses with this combined condition who survive through birth typically need intervention in infancy or early childhood because of respiratory distress, heart failure, or failure to thrive. We describe the unusual case of a mildly symptomatic 16-year-old boy with these conditions who underwent successful primary repair. Our search of the medical literature yielded fewer than 5 cases of tetralogy of Fallot with absent pulmonary valve (or variants with an absent left pulmonary artery) and survival without repair into later adolescence or adulthood. PMID- 28100970 TI - Sickle Cell Disease with Cyanotic Congenital Heart Disease: Long-Term Outcomes in 5 Children. AB - Sickle cell disease is a risk factor for cerebrovascular accidents in the pediatric population. This risk is compounded by hypoxemia. Cyanotic congenital heart disease can expose patients to prolonged hypoxemia. To our knowledge, the long-term outcome of patients who have combined sickle cell and cyanotic congenital heart disease has not been reported. We retrospectively reviewed patient records at our institution and identified 5 patients (3 girls and 2 boys) who had both conditions. Their outcomes were uniformly poor: 4 died (age range, 12 mo-17 yr); 3 had documented cerebrovascular accidents; and 3 developed ventricular dysfunction. The surviving patient had developmental delays. On the basis of this series, we suggest mitigating hypoxemia, and thus the risk of stroke, in patients who have sickle cell disease and cyanotic congenital heart disease. Potential therapies include chronic blood transfusions, hydroxyurea, earlier surgical correction to reduce the duration of hypoxemia, and heart or bone marrow transplantation. PMID- 28100974 TI - Percutaneous Embolectomy of Serpentine Thrombus from the Right Atrium in a 51 Year-Old Man. AB - Treatment of large, fresh thrombi in the vascular system can be challenging. AngioVac, a cardiopulmonary pump system, has been used to remove large thrombi and even some tumors by a percutaneous route. We report here a case of a 51-year old man who presented with a large thrombus (7.5 * 1.5 cm) in his inferior vena cava, extending into his right atrium and right ventricle. Because the surgical risk was high, we attempted percutaneous embolectomy via the AngioVac aspiration system. We also review the literature concerning this emerging technique. PMID- 28100973 TI - Endovascular Treatment of Superior Vena Cava Syndrome via Balloon-in-Balloon Catheter Technique with a Palmaz Stent. AB - Superior vena cava syndrome is a well-known disease entity that carries substantial rates of morbidity and mortality. Although most cases of superior vena cava syndrome are secondary to a malignant process, additional causes (such as mediastinal fibrosis, pacemaker lead implantation, or central venous catheter placement) have been reported. Multiple treatment options include percutaneous transluminal angioplasty, stent implantation, thrombolysis, mechanical thrombectomy, and venous grafting. We present a case of superior vena cava syndrome in a symptomatic 30-year-old woman who obtained complete relief of obstruction and marked symptomatic improvement through venoplasty and stenting, aided by our use of a balloon-in-balloon catheter system. PMID- 28100975 TI - Management of a Mycotic Thoracoabdominal Aortic Aneurysm Involving the Celiac Artery. AB - A mycotic aneurysm that also involves the visceral arteries is a life-threatening condition. Surgical management typically consists of debridement and in situ repair with a Dacron graft and reimplantation of the involved visceral branches. We report a rare case of a mycotic saccular thoracoabdominal aortic aneurysm involving the celiac artery, with Streptococcus pneumoniae as the responsible organism. Successful repair of the aneurysm and concomitant revascularization of the celiac artery were achieved. PMID- 28100976 TI - Ventricular Tachycardia in Fabry Disease Detected in a 50-Year-Old Woman during 14-Day Continuous Cardiac Monitoring. AB - Fabry disease is an X-linked lysosomal storage disorder. Female carriers were long thought to be asymptomatic; however, research has revealed the opposite. Cardiac conditions are the chief causes of death in women with Fabry disease. Although ventricular tachycardia has been reported in male patients with Fabry disease, it is not thought to be a frequent finding in females. We describe the case of a 50-year-old woman in whom we used 14-day continuous electrocardiographic monitoring to identify nonsustained ventricular tachycardia, after electrocardiograms and 24-hour Holter monitoring failed to detect the arrhythmia. A permanent implantable cardioverter-defibrillator relieved the patient's symptoms. We discuss why this case supports the need for more extensive electrophysiologic evaluation in women who have Fabry disease. PMID- 28100977 TI - Preserving a Well-Functioning 33-Year-Old Starr-Edwards Aortic Prosthesis in Repeat Aortic Root Aneurysm Repair. AB - We report the case of a 61-year-old obese male patient in whom we found a well functioning 33-year-old Starr-Edwards aortic prosthesis during repeat aortic surgery. Rather than explant the prosthesis, we remodeled the aortic root, almost completely removing the aortic sinuses and leaving only a pillar of aortic tissue around the coronary ostia. The proximal end of a Hemashield tube-graft was then scalloped to accommodate the remaining aortic tissue. The patient's heart function was excellent after his weaning from cardiopulmonary bypass. Simplifying the repeat aortic root repair, by preserving a well-functioning Starr-Edwards valve, might lead to a better outcome in similar cases. We also discuss other instances of this valve's durability. PMID- 28100978 TI - Inflammation and Rupture of a Congenital Pericardial Cyst Manifesting Itself as an Acute Chest Pain Syndrome. AB - We present the case of a 63-year-old woman with a remote history of supraventricular tachycardia and hyperlipidemia, who presented with recurrent episodes of acute-onset chest pain. An electrocardiogram showed no evidence of acute coronary syndrome. A chest radiograph revealed a prominent right-sided heart border. A suspected congenital pericardial cyst was identified on a computed tomographic chest scan, and stranding was noted around the cyst. The patient was treated with nonsteroidal anti-inflammatory drugs, and the pain initially abated. Another flare-up was treated similarly. Cardiac magnetic resonance imaging was then performed after symptoms had resolved, and no evidence of the cyst was seen. The suspected cause of the patient's chest pain was acute inflammation of a congenital pericardial cyst with subsequent rupture and resolution of symptoms. PMID- 28100979 TI - Late Cardiac Rupture after Amplatzer Septal Occluder Implantation. AB - Transcatheter device implantation has become an attractive alternative to surgery in the closure of atrial septal defects in selected patients. However, it can lead to early and late sequelae, some of them life threatening. For example, 79 days before her admission to our emergency department with sudden-onset respiratory distress and respiratory arrest (leading to cardiac tamponade and rupture), a 22-year-old woman had undergone percutaneous closure of an atrial septal defect. We describe the damage and its treatment. Although the adverse effects of transcatheter device implantation are rare, physicians should know that these events can be life threatening. Further data are needed to prevent such sequelae and to design new devices. It is of utmost importance that patients and their family members be informed both of possible sequelae and of life-saving interventions to be administered at early diagnosis. PMID- 28100980 TI - Accessory Mitral Valve Leaflet Causing Severe Left Ventricular Outflow Tract Obstruction in a Preterm Neonate with a Partial Atrioventricular Septal Defect. AB - Atrioventricular septal defects represent a class of congenital cardiac malformations that vary in presentation and management strategy depending upon the severity of the particular lesions present. We present the case of a premature neonate who had a partial atrioventricular septal defect and an accessory mitral (or left atrioventricular) valve leaflet. The latter caused severe left ventricular outflow tract obstruction and severely depressed left ventricular function. We found only one other report of this atrioventricular valve abnormality in association with atrioventricular septal defect. To our knowledge, our patient (at a body weight of 1,800 g) is the smallest to survive corrective surgery of an accessory mitral valve leaflet with severe left ventricular outflow tract obstruction. In addition to our patient's case, we discuss the relevant medical literature. PMID- 28100981 TI - Isolated Left Subclavian Artery, Complete Atrioventricular Block, and Tricuspid Atresia in a Neonate. AB - Isolated left subclavian artery is one of the rarer aortic arch anomalies. It has been associated with other congenital heart diseases, typically tetralogy of Fallot, double-outlet right ventricle, and atrial and ventricular septal defects. Its significant clinical implications include a left-to-right shunt from the vertebrobasilar system, which causes pulmonary overcirculation and subclavian steal. We present an unusual case of a premature infant who was diagnosed prenatally with congenital complete atrioventricular block and tricuspid atresia and was found to have an isolated left subclavian artery postnatally. The patient underwent implantation of a permanent single-chamber epicardial pacing system. To our knowledge, this combination of lesions has not been reported-and in our case, it influenced our surgical planning. PMID- 28100982 TI - Bilateral Lower-Extremity Edema Caused by Iliopsoas Bursal Distention after Hip Arthroplasty. AB - Lower-extremity edema is encountered by internists, nephrologists, vascular specialists, and many others. We report a case of an elderly woman who presented with a painful, swollen left leg. Without a clear diagnosis, she had been taking diuretics for the past 8 years for swelling in both legs. After extensive investigation, we found that her lower-extremity edema was due to bilateral iliopsoas bursal distention secondary to degeneration of her hip prostheses. Chronic breakdown of the polyethylene component of the hip prostheses had led to a communication between the artificial joints and the iliopsoas bursae. With the aid of ultrasonographic guidance, she underwent drainage, followed by clinical and radiographic improvement. Although case reports have described leg swelling arising from extravascular compression by enlarged iliopsoas bursae, we think that this is the first case of clinically significant bilateral lower-extremity edema arising from that cause. More important than the novelty is the inappropriate use of diuretics to treat lower-extremity edema without first establishing a diagnosis. PMID- 28100983 TI - A "Malignant" Arrhythmia: Cardiac Metastasis and Ventricular Tachycardia. PMID- 28100984 TI - Intraoperative Transesophageal Echocardiography Accurately Identifies Sinus of Valsalva Aneurysm in a 27-Year-Old Man. PMID- 28100985 TI - Patient Lives Almost 50 Years after Aortic Valve Replacement with a Starr-Edwards Caged-Ball Valve. PMID- 28100986 TI - Evaluating Coronary-Cameral Fistulas. PMID- 28100989 TI - The toxicity and enzyme activity of a chlorine and sulfate containing aeruginosin isolated from a non-microcystin-producing Planktothrix strain. AB - The toxicity of six different Planktothrix strains was examined in acute toxicity assays with the crustacean Thamnocephalus platyurus. The presence of toxicity in two strains could be explained by the occurrence of microcystins. The other four Planktothrix strains were not able to produce microcystins due to different mutations in the microcystin synthetase (mcy) gene cluster. In these strains, toxicity was attributed to the presence of chlorine and sulfate containing compounds. The main representative, called aeruginosin 828A, of such a compound in the Planktothrix strain 91/1 was isolated, and structure elucidation by 2D-NMR and MS methods revealed the presence of phenyllactic acid (Pla), chloroleucine (Cleu), 2-carboxy-6-(4'-sulfo-xylosyl)-octahydroindole (Choi), and 3-aminoethyl-1 N-amidino-Delta-3-pyrroline (Aeap) residues. Aeruginosin 828A was found to be toxic for Thamnocephalus platyurus with a LC50 value of 22.4 uM, which is only slightly higher than the toxicity found for microcystins. Additionally, very potent inhibition values for thrombin (IC50 = 21.8 nM) and for trypsin (IC50 = 112 nM) have been determined for aeruginosin 828A. These data support the hypothesis that aeruginosins containing chlorine and sulfate groups, which were found in microcystin-deficient Planktothrix strains, can be considered as another class of toxins. PMID- 28100988 TI - Simultaneous analyses of N-linked and O-linked glycans of ovarian cancer cells using solid-phase chemoenzymatic method. AB - BACKGROUND: Glycans play critical roles in a number of biological activities. Two common types of glycans, N-linked and O-linked, have been extensively analyzed in the last decades. N-glycans are typically released from glycoproteins by enzymes, while O-glycans are released from glycoproteins by chemical methods. It is important to identify and quantify both N- and O-linked glycans of glycoproteins to determine the changes of glycans. METHODS: The effort has been dedicated to study glycans from ovarian cancer cells treated with O-linked glycosylation inhibitor qualitatively and quantitatively. We used a solid-phase chemoenzymatic approach to systematically identify and quantify N-glycans and O-glycans in the ovarian cancer cells. It consists of three steps: (1) immobilization of proteins from cells and derivatization of glycans to protect sialic acids; (2) release of N-glycans by PNGase F and quantification of N-glycans by isobaric tags; (3) release and quantification of O-glycans by beta-elimination in the presence of 1 phenyl-3-methyl-5-pyrazolone (PMP). RESULTS: We used ovarian cancer cell lines to study effect of O-linked glycosylation inhibitor on protein glycosylation. Results suggested that the inhibition of O-linked glycosylation reduced the levels of O-glycans. Interestingly, it appeared to increase N-glycan level in a lower dose of the O-linked glycosylation inhibitor. The sequential release and analyses of N-linked and O-linked glycans using chemoenzymatic approach are a platform for studying N-glycans and O-glycans in complex biological samples. CONCLUSION: The solid-phase chemoenzymatic method was used to analyze both N linked and O-linked glycans sequentially released from the ovarian cancer cells. The biological studies on O-linked glycosylation inhibition indicate the effects of O-glycosylation inhibition to glycan changes in both O-linked and N-linked glycan expression. PMID- 28100990 TI - Drug-Induced Liver Injury Associated with Complementary and Alternative Medicines. AB - A 24-year-old man was admitted due to acute hepatitis with unknown etiology. After his condition and laboratory data gradually improved with conservative therapy, he was discharged 1 month later. Two months after his discharge, however, liver dysfunction reappeared. After his mother accidentally revealed that he took complementary and alternative medicine, discontinuation of the therapy caused his condition to improve. Finally, he was diagnosed with a recurrent drug-induced liver injury associated with Japanese complementary and alternative medicine. It is important to take the medical history in detail and consider complementary and alternative medicine as a cause of liver disease. PMID- 28100991 TI - Sphincter of Oddi Dysfunction: A Perplexing Presentation. AB - Sphincter of Oddi dysfunction is caused by stenosis or dyskinesia of the sphincter of Oddi, leading to blockage of bile drainage from the common bile duct. We present the case of a 16-year-old female with chronic abdominal pain who underwent laparoscopic cholecystectomy for cholelithiasis but continued to experience abdominal pain, nausea, and vomiting along with persistently elevated ALT and AST levels. Postoperative abdominal ultrasound was nondiagnostic. Esophagogastroduodenoscopy showed mild reflux esophagitis and mild chronic Helicobacter pylori-negative gastritis. Omeprazole was started, but it did not decrease the frequency and severity of the abdominal symptoms. Magnetic resonance cholangiopancreatography did not reveal any pathology. Endoscopic retrograde cholangiopancreatography with manometry confirmed an elevated biliary sphincter pressure. Biliary sphincterotomy was performed, and the symptoms improved. PMID- 28100992 TI - Multiple Magnetic Foreign Bodies Causing Severe Digestive Tract Injuries in a Child. AB - Foreign body (FB) ingestion is a common emergency as well as a major cause of accidental injury and represents a severe public health problem in childhood, especially in infants. Most cases of FB ingestion reported in children aged between 6 months and 3 years depend primarily on the fact that young children are more likely to explore objects using their mouth and are not able to distinguish edible objects from nonedible ones, their teeth are physiologically lacking, and they have poor swallowing coordination. Although, sometimes it can cause serious complications, FB ingestion generally has a low mortality rate. However, accidental ingestion of magnetic toys, as a rare kind of FB mostly encountered in children, has now become more common due to the increased availability of objects and toys with magnetic elements. The majority of magnetic FB traverse the gastrointestinal (GI) system spontaneously without complication, but in rare cases may cause severe damages to the GI tract due to its special pathogenesis [Kay and Wyllie: Curr Gastroenterol Rep 2005;7: 212-218]. Ingestion of multiple magnets may be related to increased morbidity resulting in a delay of recognition of FB injury that can lead to serious complications and require surgical resolution. PMID- 28100993 TI - CDC Group EO-4 and Candida tropicalis Peritonitis in a Patient on Peritoneal Dialysis after Upper Endoscopy, Colonoscopy and Coil Embolization of the Gastroduodenal Artery. AB - Peritoneal dialysis (PD) is an excellent form of renal replacement therapy for many patients with end-stage renal disease (ESRD). Over 10,000 patients receive PD in the United States [United States Renal Data System: 2015 USRDS Annual Data Report: Epidemiology of Kidney Disease in the United States, 2015]. PD has superior outcomes compared to hemodialysis in the first 2 years of ESRD [Sinnakirouchenan and Holley: Adv Chronic Kidney Dis 2011;18: 428-432]. However, peritonitis is a known complication and may result in significant morbidity and necessitate transition to hemodialysis, which increases medical costs [Holley and Piraino: Semin Dial 1990;3: 245-248]. We report the first case of a PD patient who underwent endoscopy, colonoscopy and CT angiogram with coil embolization for gastrointestinal bleeding without antibiotic prophylaxis and subsequently developed CDC group EO-4 organism and fungal peritonitis. PMID- 28100994 TI - Reocclusion after Self-Expandable Metallic Stent Placement for Relieving Malignant Colorectal Obstruction as a Palliative Treatment. AB - Self-expandable metallic stent (SEMS) placement has been practiced in several hospitals in Japan, including ours, since January 2012. Here, we report the case of an 82-year-old Japanese man who presented to the hospital with a 1-week history of right hypochondrial pain. Computed tomography (CT) findings indicated colorectal cancer. The laboratory findings on admission indicated severe anemia (red blood cell count, 426 * 104/MUL; hemoglobin, 7.9 g/dL). We performed SEMS placement because the patient refused to undergo surgery. He did not attend any of the scheduled follow-up visits after SEMS placement. However, a year and a half after the SEMS placement, the patient attended the hospital because of difficulty in passing stool. A plain abdominal CT scan showed bowel reobstruction due to the ascending colon cancer after SEMS placement. We performed an emergency operation, ascending colostomy, on the same day. Colorectal stent placement may be a good treatment option for patients who refuse to undergo conventional therapeutic treatments or in those with unresectable colorectal cancer. Patients should be carefully followed up every few months after SEMS placement because of the risk of reocclusion. PMID- 28100995 TI - A Rare Case of Intraductal Papillary Mucinous Neoplasm of the Biliary Duct in a Patient with Prostate Adenocarcinoma. AB - Intraductal papillary mucinous neoplasms (IPMNs) are mucin-producing papillary neoplasms of the pancreatic or biliary ductal system that exhibit variable cellular atypia and cause ductal dilation. There are few reported cases of IPMN arising from the biliary tree in the literature. It has a higher propensity to undergo malignant transformation compared to IPMN arising from the pancreatic duct. An 80-year-old male underwent cross-sectional tomography (CT) imaging of the abdomen for evaluation of prostate adenocarcinoma, which revealed an incidental 2.3 * 2.7 cm soft tissue mass centered at the porta hepatis with diffuse dilatation of the left intrahepatic biliary ductal system and mild prominence of the right intrahepatic ductal system. Endoscopic ultrasound showed 2 adjacent hilar masses involving the common hepatic duct and the left hepatic duct with protrusion of the tissue into the lumen of the duct and upstream ductal dilatation. Endoscopic retrograde cholangiopancreatography revealed a large filling defect in the common hepatic duct extending into the left hepatic duct. A large amount of clot and soft tissue with a fish-egg appearance was retrieved. The patient underwent left hepatic lobectomy, radical resection of the common hepatic duct with Roux-en-Y hepaticojejunostomy to the right hepatic duct. Histopathological examination of the resected specimen revealed intraductal papillary mucinous neoplasm with diffuse high-grade dysplasia. Follow-up CT scan of the abdomen 2 months after the surgery was negative for any masses. PMID- 28100996 TI - Intrapancreatic Accessory Spleen: A Diagnosis Not to Forget! AB - A 69-year-old male patient was incidentally diagnosed with a 5-mm lesion in the pancreatic tail by endoscopic ultrasound (EUS). After contrast-enhanced EUS and EUS-elastography, all imaging features were highly suggestive of a benign pancreatic solid lesion such as an intrapancreatic accessory spleen (IPAS) or a benign neuroendocrine tumor. Interposition of the splenic artery precluded EUS guided fine-needle aspiration (FNA). When an asymptomatic pancreatic mass is detected, IPAS diagnosis should be considered, and, if EUS-FNA is infeasible, contrast-enhanced EUS and EUS-elastography are useful tools to differentiate a pancreatic benign lesion as IPAS from a malignancy, with avoidance of unnecessary surgery. PMID- 28100997 TI - A Rare Cause of Dysphagia to Remember: Calcific Tendinitis of the Longus Colli Muscle. AB - Longus colli tendinitis (LCT) is an acute inflammatory condition with symptoms typically consisting of acute neck pain and stiffness with or without dysphagia. Once more severe etiologies for these symptoms are ruled out, this self-limiting condition usually resolves spontaneously with nonsteroidal anti-inflammatory drugs and corticosteroids. We present a case of LCT that presented as acute neck pain, dysphagia, and odynophagia that rapidly resolved once diagnosed and treated with anti-inflammatory agents. Though exceedingly rare, LCT must be considered in the differential diagnosis of acute neck pain, dysphagia, and odynophagia when more common etiologies do not correlate with the clinical presentation. PMID- 28100998 TI - A Man with Pancreatic Head Mass Lesion on Endoscopic Ultrasound and Granuloma on Cytopathology. AB - Primary pancreatic lymphoma is an unlikely malignancy accounting for less than 0.5% of pancreatic tumors. Clinical presentation is often nonspecific and may be clinically misdiagnosed as pancreatic adenocarcinoma. Here we present an Iranian case of primary pancreatic lymphoma in a 47-year-old male suffering from jaundice and 20% weight loss. Endoscopic ultrasound revealed a mixed echoic mass lesion at the head of pancreas. The patient underwent endoscopic ultrasound-guided fine needle aspiration of solid pancreatic mass and histopathologic diagnosis revealed granuloma. Computed tomography-guided core needle biopsy was performed and eventually histological examination showed granuloma that was coherent with the diagnosis of primary pancreatic lymphoma. Primary pancreatic lymphoma is a rare entity presenting with nonspecific symptoms, laboratory and radiological findings. Computed tomography results in combination with clinical and radiological studies generally provide guidance for appropriate investigation. PMID- 28100999 TI - Colorectal Cancer Associated with Streptococcus anginosus Bacteremia and Liver Abscesses. AB - Streptococcus anginosus is part of the normal flora of the human gastrointestinal tract. Their ability to cause abscesses is very unique and sets them apart from the rest of the streptococci groups. While an association of group D streptococcus bacteremia and endocarditis with colorectal carcinoma is well established, S. anginosus infections are rarely implicated with colonic malignancy. We present a case of a 62-year-old male who presented to the hospital with fatigue and generalized abdominal pain. Computed tomography of the abdomen revealed multiple liver abscesses and rectal thickening. Blood cultures were found to grow S. anginosus bacteria. Colonoscopy revealed a rectal mass which was later confirmed to be rectal adenocarcinoma. This case presents an association between S. anginosus bacteremia and presence of colorectal cancer which has been highlighted in only a few case reports in literature. This should prompt clinicians to screen for colorectal cancer in patients with S. anginosus bacteremia. PMID- 28101001 TI - A Motion-Based Feature for Event-Based Pattern Recognition. AB - This paper introduces an event-based luminance-free feature from the output of asynchronous event-based neuromorphic retinas. The feature consists in mapping the distribution of the optical flow along the contours of the moving objects in the visual scene into a matrix. Asynchronous event-based neuromorphic retinas are composed of autonomous pixels, each of them asynchronously generating "spiking" events that encode relative changes in pixels' illumination at high temporal resolutions. The optical flow is computed at each event, and is integrated locally or globally in a speed and direction coordinate frame based grid, using speed-tuned temporal kernels. The latter ensures that the resulting feature equitably represents the distribution of the normal motion along the current moving edges, whatever their respective dynamics. The usefulness and the generality of the proposed feature are demonstrated in pattern recognition applications: local corner detection and global gesture recognition. PMID- 28101000 TI - 2-Chloroethanol Induced Upregulation of Matrix Metalloproteinase-2 in Primary Cultured Rat Astrocytes Via MAPK Signal Pathways. AB - This study was to explore the mechanisms underlying 1,2-dichloroethane (1,2-DCE) induced brain edema by focusing on alteration of matrix metalloproteinase-2 (MMP 2) in rat astrocytes induced by 2-chloroethanol (2-CE), an intermediate metabolite of 1,2-DCE in vivo. Protein and mRNA levels of MMP-2, and the phosphorylated protein levels of p38 MAPK (p-p38), extracellular signal regulated protein kinase (p-ERK1/2) and c-Jun N-terminal kinase (p-JNK1/2) in astrocytes were examined by immunostaining, western blot or real-time RT-PCR analysis. Findings from this study disclosed that protein levels of MMP-2 were upregulated by 2-CE in astrocytes. Meanwhile, protein levels of p-p38, p-ERK1/2 and p-JNK1/2 were also increased apparently in the cells treated with 2-CE. Moreover, pretreatment of astrocytes with SB202190 (inhibitor of p38 MAPK), U0126 (inhibitor of ERK1/2) or SP600125 (inhibitor of JNK1/2) could suppress the upregulated expression of p-p38, p-ERK1/2, and p-JNK1/2. In response to suppressed protein levels of p-p38 and p-JNK1/2, the protein levels of MMP-2 also decreased significantly, indicating that activation of MAPK signal pathways were involved in the mechanisms underlying 2-CE-induced upregulation of MMP-2 expression. PMID- 28101002 TI - An Evolutionary Hypothesis of Binary Opposition in Functional Incompatibility about Habenular Asymmetry in Vertebrates. AB - Many vertebrates have asymmetrical circuits in the nervous system. There are two types of circuit asymmetry. Asymmetrical circuits in sensory and/or motor systems are usually related to lateralized behaviors. It has been hypothesized that spatial asymmetry in the environment and/or social interactions has led to the evolution of asymmetrical circuits by natural selection. There are also asymmetrical circuits that are not related to lateralized behaviors. These circuits lie outside of the sensory and motor systems. A typical example is found in the habenula (Hb), which has long been known to be asymmetrical in many vertebrates, but has no remarkable relationship to lateralized behaviors. Instead, the Hb is a hub wherein information conveyed to the unilateral Hb is relayed to diverging bilateral nuclei, which is unlikely to lead to lateralized behavior. Until now, there has been no hypothesis regarding the evolution of Hb asymmetry. Here, we propose a new hypothesis that binary opposition in functional incompatibility applies selection pressure on the habenular circuit and leads to asymmetry. Segregation of the incompatible functions on either side of the habenula is likely to enhance information processing ability via creating shorter circuits and reducing the cost of circuit duplication, resulting in benefits for survival. In zebrafish and mice, different evolutionary strategies are thought to be involved in Hb asymmetry. In zebrafish, which use a strategy of structurally fixed asymmetry, the asymmetrical dorsal Hb leads to constant behavioral choices in binary opposition. In contrast, in mice, which use a strategy of functionally flexible lateralization, the symmetrical lateral Hb is functionally lateralized. This makes it possible to process complicated information and to come to variable behavioral choices, depending on the specific situation. These strategies are thought to be selected for and preserved by evolution under selection pressures of rigidity and flexibility of sociability in zebrafish and mice, respectively, as they are beneficial for survival. This hypothesis is highly valuable because it explains how the Hb evolved differently in terms of asymmetry and lateralization among different species. In addition, one can propose possible experiments for the verification of this hypothesis in future research. PMID- 28101003 TI - Endoplasmic Reticulum Protein Quality Control Failure in Myelin Disorders. AB - Reaching the correct three-dimensional structure is crucial for the proper function of a protein. The endoplasmic reticulum (ER) is the organelle where secreted and transmembrane proteins are synthesized and folded. To guarantee high fidelity of protein synthesis and maturation in the ER, cells have evolved ER protein quality control (ERQC) systems, which assist protein folding and promptly degrade aberrant gene products. Only correctly folded proteins that pass ERQC checkpoints are allowed to exit the ER and reach their final destination. Misfolded glycoproteins are detected and targeted for degradation by the proteasome in a process known as endoplasmic reticulum-associated degradation (ERAD). The excess of unstructured proteins in the ER triggers an adaptive signal transduction pathway, called unfolded protein response (UPR), which in turn potentiates ERQC activities in order to reduce the levels of aberrant molecules. When the situation cannot be restored, the UPR drives cells to apoptosis. Myelin forming cells of the central and peripheral nervous system (oligodendrocytes and Schwann cells) synthesize a large amount of myelin proteins and lipids and therefore are particularly susceptible to ERQC failure. Indeed, deficits in ERQC and activation of ER stress/UPR have been implicated in several myelin disorders, such as Pelizaeus-Merzbacher and Krabbe leucodystrophies, vanishing white matter disease and Charcot-Marie-Tooth neuropathies. Here we discuss recent evidence underlying the importance of proper ERQC functions in genetic disorders of myelinating glia. PMID- 28101004 TI - Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease. AB - The identification and cloning of the two major cannabinoid (CB1 and CB2) receptors together with the discovery of their endogenous ligands in the late 80s and early 90s, resulted in a major effort aimed at understanding the mechanisms and physiological roles of the endocannabinoid system (ECS). Due to its expression and localization in the central nervous system (CNS), the CB1 receptor together with its endogenous ligands (endocannabinoids (eCB)) and the enzymes involved in their synthesis and degradation, has been implicated in multiple pathophysiological events ranging from memory deficits to neurodegenerative disorders among others. In this review, we will provide a general overview of the ECS with emphasis on the CB1 receptor in health and disease. We will describe our current understanding of the complex aspects of receptor signaling and trafficking, including the non-canonical signaling pathways such as those mediated by beta-arrestins within the context of functional selectivity and ligand bias. Finally, we will highlight some of the disorders in which CB1 receptors have been implicated. Significant knowledge has been achieved over the last 30 years. However, much more research is still needed to fully understand the complex roles of the ECS, particularly in vivo and to unlock its true potential as a source of therapeutic targets. PMID- 28101006 TI - Inverse Relationship between Basal Pacemaker Neuron Activity and Aversive Long Term Memory Formation in Lymnaea stagnalis. AB - Learning and memory formation are essential physiological functions. While quiescent neurons have long been the focus of investigations into the mechanisms of memory formation, there is increasing evidence that spontaneously active neurons also play key roles in this process and possess distinct rules of activity-dependent plasticity. In this study, we used a well-defined aversive learning model of aerial respiration in the mollusk Lymnaea stagnalis (L. stagnalis) to study the role of basal firing activity of the respiratory pacemaker neuron Right Pedal Dorsal 1 (RPeD1) as a determinant of aversive long term memory (LTM) formation. We investigated the relationship between basal aerial respiration behavior and RPeD1 firing activity, and examined aversive LTM formation and neuronal plasticity in animals exhibiting different basal aerial respiration behavior. We report that animals with higher basal aerial respiration behavior exhibited early responses to operant conditioning and better aversive LTM formation. Early behavioral response to the conditioning procedure was associated with biphasic enhancements in the membrane potential, spontaneous firing activity and gain of firing response, with an early phase spanning the first 2 h after conditioning and a late phase that is observed at 24 h. Taken together, we provide the first evidence suggesting that lower neuronal activity at the time of learning may be correlated with better memory formation in spontaneously active neurons. Our findings provide new insights into the diversity of cellular rules of plasticity underlying memory formation. PMID- 28101008 TI - Knockout of Lysosomal Enzyme-Targeting Gene Causes Abnormalities in Mouse Pup Isolation Calls. AB - Humans lacking a working copy of the GNPTAB gene suffer from the metabolic disease Mucolipidosis type II (MLII). MLII symptoms include mental retardation, skeletal deformities and cartilage defects as well as a speech delay with most subjects unable to utter single words (Otomo et al., 2009; Cathey et al., 2010; Leroy et al., 2012). Here we asked whether mice lacking a copy of Gnptab gene exhibited vocal abnormities. We recorded ultrasonic vocalizations from 5 to 8 day old mice separated from their mother and littermates. Although Gnptab-/- pups emitted a similar number of calls, several features of the calls were different from their wild type littermates. Gnptab-/- mice showed a decrease in the length of calls, an increase in the intra-bout pause duration, significantly fewer pitch jumps with smaller mean size, and an increase in the number of isolated calls. In addition, Gnptab-/- mice vocalizations had less power, particularly in the higher frequencies. Gnptab+/- mouse vocalizations did not appear to be affected. We then attempted to classify these recordings using these features to determine the genotype of the animal. We were able to correctly identify 87% of the recordings as either Gnptab-/- or Gnptab+/+ pup, significantly better than chance, demonstrating that genotype is a strong predictor of vocalization phenotype. These data show that deletion of genes in the lysosomal enzyme targeting pathway affect mouse pup isolation calls. PMID- 28101007 TI - Regulation of Spontaneous Propagating Waves in the Embryonic Mouse Brainstem. AB - Spontaneous activity (SA) modulates many aspects of neural development, including neuronal phenotype, axon path-finding and synaptic connectivity. In the embryonic mouse brainstem, SA initially is recorded in isolated cells at embryonic day (E) 9.5, and 48 h later takes the form of propagating waves. The majority of these waves originate from one midline initiation zone (InZ), which is situated within the developing serotonergic raphe. InZ cells express a t-type calcium channel, are depolarized, and have high membrane resistance, the combination of which allows spontaneous depolarization. Propagating events require signaling at metabotropic 5-HT receptors; a possible source could be 5-HT released by newly differentiating 5-HT neurons. At E11.5, waves propagate throughout the hindbrain, with some events crossing into the midbrain. At E12.5, lateral cells (further than 150 MUm from the midline) up-regulate expression of a K channel that increases resting conductance and hyperpolarizes them, preventing the propagation of waves laterally. At the same stage, cells in the isthmus up-regulate t-type calcium channels, permitting more events to cross into the midbrain, some of which form recurring loops of activity that are able to keep intracellular calcium levels high for many minutes. At E13.5, caudal hindbrain cells hyperpolarize utilizing the same K conductance, and 24 h later, at E14.5, the InZ hyperpolarizes and no longer undergoes spontaneous events. Thus, 5-HT receptor dependent propagating waves in the embryonic brainstem are generated and propagated by regulation of membrane conductance. We discuss these mechanisms, and the possible role of this SA in neuronal development. PMID- 28101009 TI - Commentary: Knowledge Acquisition during Exam Preparation Improves Memory and Modulates Memory Formation. PMID- 28101005 TI - The Therapeutic Potential of Targeting Substance P/NK-1R Interactions in Inflammatory CNS Disorders. AB - The inflammatory responses of resident central nervous system (CNS) cells are now known to play a critical role in the initiation and progression of an array of infectious and sterile neuroinflammatory disorders such as meningitis, encephalitis, Parkinson's disease, Alzheimer's disease and multiple sclerosis (MS). Regulating glial inflammatory responses in a timely manner is therefore critical in preserving normal CNS functions. The neuropeptide substance P is produced at high levels within the CNS and its selective receptor, the neurokinin 1 receptor (NK-1R), is abundantly expressed by neurons and is present on glial cell types including microglia and astrocytes. In addition to its functions as a neurotransmitter in the perception of pain and its essential role in gut motility, this tachykinin is widely recognized to exacerbate inflammation at peripheral sites including the skin, gastrointestinal tract and the lungs. Recently, a number of studies have identified a role for substance P and NK-1R interactions in neuroinflammation and described the ability of this neuropeptide to alter the immune functions of activated microglia and astrocytes. In this review article, we describe the expression of substance P and its receptor by resident CNS cells, and we discuss the ability of this neuropeptide to exacerbate the inflammatory responses of glia and immune cells that are recruited to the brain during neurodegenerative diseases. In addition, we discuss the available data indicating that the NK-1R-mediated augmentation of such responses appears to be detrimental during microbial infection and some sterile neurodegenerative disorders, and propose the repurposed use of NK-1R antagonists, of a type that are currently approved as anti-emetic and anti-anxiolytic agents, as an adjunct therapy to ameliorate the inflammatory CNS damage in these conditions. PMID- 28101010 TI - Monetary, Food, and Social Rewards Induce Similar Pavlovian-to-Instrumental Transfer Effects. AB - Multiple types of reward, such as money, food or social approval, are capable of driving behavior. However, most previous investigations have only focused on one of these reward classes in isolation, as such it is not clear whether different reward classes have a unique influence on instrumental responding or whether the subjective value of the reward, rather than the reward type per se, is most important in driving behavior. Here, we investigate behavior using a well established reward paradigm, Pavlovian-to-instrumental transfer (PIT), and three different reward types: monetary, food and social rewards. The subjective value of each reward type was matched using a modified Becker-DeGroot-Marschak (BDM) auction where subjective reward value was expressed through physical effort using a bimanual grip force task. We measured the influence of reward-associated stimuli on how participants distributed forces between hands when reaching a target effort range on the screen bimanually and on how much time participants spent in this target range. Participants spent significantly more time in the target range (15% +/- 2% maximal voluntary contraction) when a stimulus was presented that was associated with a reward used during instrumental conditioning or Pavlovian conditioning compared to a stimulus associated with a neutral outcome (i.e., general PIT). The strength of the PIT effect was modulated by subjective value (i.e., individuals who showed a stronger PIT effect rated the value of rewards more highly), but not by reward type, demonstrating that stimuli of all reward types were able to act as appetitive reinforcers and influenced instrumental responding, when matched to the same subjective reward value. This is the first demonstration that individually matched monetary, food and social rewards are equally effective as appetitive reinforcers in PIT. These findings strengthen the hypotheses that the subjective value is crucial for how much reward-associated stimuli influence behavior. PMID- 28101011 TI - Response Inhibition Is Facilitated by a Change to Red Over Green in the Stop Signal Paradigm. AB - Actions are informed by the complex interactions of response execution and inhibition networks. These networks integrate sensory information with internal states and behavioral goals to produce an appropriate action or to update an ongoing action. Recent investigations have shown that, behaviorally, attention is captured through a hierarchy of colors. These studies showed how the color hierarchy affected visual processing. To determine whether the color hierarchy can be extended to higher level executive functions such as response execution and inhibition, we conducted several experiments using the stop-signal task (SST). In the first experiment, we modified the classic paradigm so that the go signals could vary in task-irrelevant color, with an auditory stop signal. We found that the task-irrelevant color of the go signals did not differentially affect response times. In the second experiment we determined that making the color of the go signal relevant for response selection still did not affect reaction times(RTs) and, thus, execution. In the third experiment, we modified the paradigm so that the stop signal was a task relevant change in color of the go signal. The mean RT to the red stop signal was approximately 25 ms faster than to the green stop signal. In other words, red stop signals facilitated response inhibition more than green stop signals, however, there was no comparative facilitation of response execution. These findings suggest that response inhibition, but not execution, networks are sensitive to differences in color salience. They also suggest that the color hierarchy is based on attentional networks and not simply on early sensory processing. PMID- 28101014 TI - Different Effects of Implicit and Explicit Motor Sequence Learning on Latency of Motor Evoked Potential Evoked by Transcranial Magnetic Stimulation on the Primary Motor Cortex. AB - Motor training induces plastic changes in the primary motor cortex (M1). However, it is unclear whether and how the latency of motor-evoked potentials (MEP) and MEP amplitude are affected by implicit and/or explicit motor learning. Here, we investigated the changes in M1 excitability and MEP latency induced by implicit and explicit motor learning. The subjects performed a serial reaction time task (SRTT) with their five fingers. In this task, visual cues were lit up sequentially along with a predetermined order. Through training, the subjects learned the order of sequence implicitly and explicitly. Before and after the SRTT, we recorded MEP at 25 stimulation points around the hot spot for the flexor pollicis brevis (FPB) muscle. Although no changes in MEP amplitude were observed in either session, we found increases in MEP latency and changes in histogram of MEP latency after implicit learning. Our results suggest that reorganization across the motor cortices occurs during the acquisition of implicit knowledge. In contrast, acquisition of explicit knowledge does not appear to induce the reorganization based on the measures we recorded. The fact that the above mentioned increases in MEP latency occurred without any alterations in MEP amplitude suggests that learning has different effects on different physiological signals. In conclusion, our results propose that analyzing a combination of some indices of M1 excitability, such as MEP amplitude and MEP latency, is encouraged in order to understand plasticity across motor cortices. PMID- 28101012 TI - Morphological and Functional Differences between Athletes and Novices in Cortical Neuronal Networks. AB - The cortical structural and functional differences in athletes and novices were investigated with a cross-sectional paradigm. We measured the gray matter volumes and resting-state functional connectivity in 21 basketball players and 21 novices with magnetic resonance imaging (MRI) techniques. It was found that gray matter volume in the left anterior insula (AI), inferior frontal gyrus (IFG), inferior parietal lobule (IPL) and right anterior cingulate cortex (ACC), precuneus is greater in basketball players than that in novices. These five brain regions were selected as the seed regions for testing the resting-state functional connectivity in the second experiment. We found higher functional connectivity in default mode network, salience network and executive control network in basketball players compared to novices. We conclude that the morphology and functional connectivity in cortical neuronal networks in athletes and novices are different. PMID- 28101013 TI - Effects of Muscle Fatigue, Creep, and Musculoskeletal Pain on Neuromuscular Responses to Unexpected Perturbation of the Trunk: A Systematic Review. AB - Introduction: Trunk neuromuscular responses have been shown to adapt under the influence of muscle fatigue, as well as spinal tissue creep or even with the presence of low back pain (LBP). Despite a large number of studies exploring how these external perturbations affect the spinal stability, characteristics of such adaptations remains unclear. Aim: The purpose of this systematic review was to assess the quality of evidence of studies investigating trunk neuromuscular responses to unexpected trunk perturbation. More specifically, the targeted neuromuscular responses were trunk muscle activity reflex and trunk kinematics under the influence of muscle fatigue, spinal creep, and musculoskeletal pain. Methods: A research of the literature was conducted in Pubmed, Embase, and Sport Discus databases using terms related to trunk neuromuscular reflex responses, measured by electromyography (baseline activity, reflex latency, and reflex amplitude) and/or trunk kinematic, in context of unexpected external perturbation. Moreover, independent variables must be either trunk muscle fatigue or spinal tissue creep or LBP. All included articles were scored for their electromyography methodology based on the "Surface Electromyography for the Non Invasive Assessment of Muscles (SENIAM)" and the "International Society of Electrophysiology and Kinesiology (ISEK)" recommendations whereas overall quality of articles was scored using a specific quality checklist modified from the Quality Index. Meta-analysis was performed on reflex latency variable. Results: A final set of 29 articles underwent quality assessments. The mean quality score was 79%. No effect of muscle fatigue on erector spinae reflex latency following an unexpected perturbation, nor any other distinctive effects was found for back muscle fatigue and reflex parameters. As for spinal tissue creep effects, no alteration was found for any of the trunk reflex variables. Finally, the meta analysis revealed an increased erector spinae reflex latency in patients with chronic LBP in comparison with healthy controls following an unexpected trunk perturbation. Conclusion: The literature provides some evidence with regard to trunk adaptions in a context of spinal instability. However, most of the evidence was inconclusive due to a high methodological heterogeneity between the studies. PMID- 28101015 TI - M2-Polarized Macrophages Compose Lupus Vulgaris Arising from a Bacillus Calmette Guerin Vaccination Site. AB - Since bacillus Calmette-Guerin (BCG) is an attenuated strain of Mycobacterium bovis, lupus vulgaris (LV) is reported as one of the rare complications after BCG vaccination, correlating with immunosuppression in the lesional skin. In this report, we describe a case of LV arising from the BCG vaccination site 22 years after vaccination. Interestingly, in the present case, granuloma cells were composed of M2-polarized macrophages. Our case might explain the contribution of M2-polarized macrophages to the biology of LV arising from a BCG vaccination site. PMID- 28101016 TI - Cellulitis in a Liver Transplant Patient as an Initial Manifestation of Disseminated Cryptococcal Disease. AB - A 50-year-old male underwent liver transplantation due to cryptogenic cirrhosis and was admitted with severe pain in the left leg as well as phlogosis. Amoxicillin/clavulanic acid was prescribed, assuming bullous erysipelas. Among the tests performed, the latex agglutination test for the Cryptococcus sp. antigen was positive, and in both the blood culture and blister culture Cryptococcus sp. was isolated. Daily fluconazole was started. Even though liposomal amphotericin B has been started on the fifth day of hospitalization, the patient progressed to death. PMID- 28101017 TI - Efficacy of a Film-Forming Medical Device Containing Piroxicam and Sun Filters in the Treatment of Multiple Actinic Keratosis Lesions in a Subject with a History of Kaposi Sarcoma. AB - Actinic keratosis (AK) is considered a premalignant form of skin cancer due to chronic sun exposure. In addition, human papilloma virus (HPV) has been advocated a role in the pathogenesis of this clinical condition. HPV proteins (mainly E6 and E7) seem to act synergistically with ultraviolet (UV) radiation in reducing the defensive mechanisms of keratinocyte apoptosis after UV damage. Data regarding the involvement of other viruses, i.e. human herpes viruses (HHV), in the pathogenesis of AK are so far controversial. HHV8 is considered the infective agent involved in the development of Kaposi sarcoma. Some experimental data have shown that AK lesions carry HHV8 in more than 30% of the bioptic samples. Topical piroxicam was shown to be effective in the treatment of AK. In addition, the molecule shows antiviral action against HPV and HHV8. Here, we report the efficacy of a medical device containing a film-forming substance (polyvinyl alcohol), chemical and physical sun filters (SPF 50+), and 0.8% piroxicam (ActixicamTM, Difa Cooper; ACTX) in the treatment of multiple scalp AK lesions, unresponsive to other treatments, in a subject with Kaposi sarcoma and a history of severe contact dermatitis. The subject presented with severe involvement of the scalp, with multiple hypertrophic AK lesions. Previous lesion-directed and field-targeted treatments have not been effective. The subject was treated with ACTX applied twice daily on the affected scalp. Relevant clinical improvement was observed as soon as 1 month of therapy. Complete clinical resolution of all scalp lesions was observed after 3 months of treatment. The product was well tolerated. PMID- 28101018 TI - Remarkable Improvement of Nail Changes in Alopecia Areata Universalis with 10 Months of Treatment with Tofacitinib: A Case Report. AB - Alopecia areata (AA) is a chronic, autoimmune disease. The main symptom is massive hair loss, localized or diffuse, in the scalp and the whole body. However, nails may also be involved, and brittleness, fragility and pitting can be signs of nail dystrophy in AA patients. Here, we report the case of a male patient with AA refractory to various treatments, including oral, topical and intralesional corticosteroids, immunosuppressants, cyclosporin and PUVA (oxoralen plus ultraviolet light), all interrupted due to side effects. The patient's nails had erythematous blotches (striated lunulae) with regular and superficial pitting as well as fragility (trachyonychia), and he could no longer play the guitar because of these symptoms. With patient consent, we introduced tofacitinib (5 mg twice daily), which resulted in remarkable improvements not only regarding hair regrowth but also nail changes, with function recovery within 10 months. PMID- 28101019 TI - A Case of Therapy-Resistant Folliculitis due to Adrenal Insufficiency? AB - A report on a 40-year-old patient with recalcitrant, suppurative folliculitis is presented. After years of unsuccessful treatment with conventional therapies, the patient was diagnosed with adrenal insufficiency with a low level of circulating cortisol. A few weeks after the patient was subjected to substitution therapy with hydrocortisone, his folliculitis resolved. We discuss the role of plasma cortisol level in the pathogenesis of folliculitis. PMID- 28101020 TI - Late Onset of Acute Urticaria after Bee Stings. AB - Here we report the cases of five patients with a late onset of acute urticaria after a bee sting. The ages of the five Japanese patients ranged from 33 to 86 years (median: 61). All patients had no history of an allergic reaction to bee stings. The onset of urticaria was 6-14 days (median: 10) after a bee sting. Although four of the patients did not describe experiencing a bee sting at their presentation, the subsequent examination detected anti-bee-specific IgE antibodies. So, we think a history of a bee sting should thus be part of the medical interview sheet for patients with acute urticaria, and an examination of IgE for bees may help prevent a severe bee-related anaphylactic reaction in the future. PMID- 28101021 TI - Late-Onset Multiple Self-Healing Squamous Epithelioma Ferguson-Smith Recurrence Induced by Radiotherapy. AB - We report the case of a woman in her 60s with confirmed multiple self-healing squamous epitheliomas (MSSE) Ferguson-Smith. After recurrences following surgery and radiotherapy, the patient was successfully treated with minimal surgical intervention combined with intralesional injections of triamcinolone acetate. The histological comparison between mature and regressed keratoacanthomas (KA) revealed an increased inflammatory infiltrate with numerous plasmacytoid dendritic cells in the regressed KA in comparison to the mature one, speaking in favor of an inflammation-mediated regression process. Corticosteroids injection in MSSE may have paradoxical effects with action on the proliferation phase rather than the inflammatory regression phase of the KA. Our case confirms previous reports showing that radiotherapy may exacerbate MSSE and should be avoided. Intralesional triamcinolone acetate injection is a safe and easy to use method also effective for multiple lesions. Our case underlines the difference between squamous cell carcinoma and KA, responding differently to therapies like imiquimod or radiotherapy. PMID- 28101022 TI - Necrobiotic Xanthogranuloma in a Patient with Multiple Myeloma. AB - An 82-year-old woman presented with a 9-month history of multiple, well-defined skin lesions on her neck and upper chest, progressively increasing in size. Histological examination of a skin biopsy showed a regular epidermis. In the dermis, granulomatous changes with central necrobiosis were found which extended focally into the subcutaneous fat. The necrobiotic areas were surrounded by Touton cells and foreign-body giant cells. Laboratory analysis revealed leucopenia. Serum electrophoresis and immunofixation disclosed the presence of an IgG-lambda paraprotein. Bone marrow aspiration cytology showed 20% plasmatic cells. The skeletal X-ray revealed frontal and occipital osteolytic skull lesions as well as pubic osteolysis. Urinalysis was unremarkable without proteinuria. Based on the clinical, laboratory, and histological findings, necrobiotic xanthogranuloma in association with multiple myeloma was diagnosed. The patient was treated with bortezomib combined with oral dexamethasone. Follow-up at week 13 revealed the complete disappearance of the IgG paraproteinemia. However, the skin lesions remained unchanged. Therefore, bortezomib treatment was discontinued, and systemic corticosteroids were continued at a higher dosage. After the steroid treatment, the lesions markedly flattened. PMID- 28101023 TI - Pyoderma Gangrenosum and Erythema Nodosum Revealing Takayasu's Arteritis. AB - We report a Caucasian female who presented with simultaneous erythema nodosum and pyoderma gangrenosum due to underlying Takayasu's arteritis. Takayasu's arteritis is a chronic large vessel vasculitis of unknown cause. The disease has a worldwide distribution but is most commonly seen in Asian populations. There is a strong predilection for young females. The clinical presentation is variable, but mostly derives from stenosis or occlusion of affected arteries, resulting in claudication and ischemia. Skin manifestations are observed in up to 28% of patients with Takayasu's arteritis, with erythema nodosum reported more frequently in Caucasians. Pyoderma gangrenosum is more common in Asian patients. This report demonstrates the importance to exclude Takayasu's arteritis in patients with such skin lesions. PMID- 28101024 TI - Bazex Syndrome in Lung Squamous Cell Carcinoma: High Expression of Epidermal Growth Factor Receptor in Lesional Keratinocytes with Th2 Immune Shift. AB - An 82-year-old Japanese man was referred for detailed examination of hyperkeratotic erythematous plaques on his palms and soles for 6 months. Two weeks before his first visit, he had undergone lung lobectomy for right lung squamous cell carcinoma (SCC). Laboratory findings showed elevations of eosinophil counts, serum IgE, thymus and activation-regulated chemokine, SCC antigen, and soluble interleukin-2 receptor levels. Histological results of a skin biopsy involving the left palm showed psoriasiform dermatitis. Before lung lobectomy, the hyperkeratotic erythematous plaques on the palms and soles and the erythemas on the trunk and extremities were difficult to treat with topical steroids. After lobectomy, the skin symptoms dramatically and rapidly subsided with topical steroids. Therefore, we diagnosed Bazex syndrome (BS), also known as acrokeratosis paraneoplastica, as a paraneoplastic cutaneous disease in lung SCC. The mild eosinophilia subsided and levels of SCC antigen, IgE, and soluble interleukin-2 receptor were reduced. BS is a paraneoplastic cutaneous disease characterized by acral psoriasiform lesions associated with an underlying neoplasm. In a previous report, a shift to the Th2 immune condition was found in patients with non-small cell lung cancer, as shown in our patient. Epidermal growth factor receptor (EGFR) is also known as tumor growth factor-alpha receptor; it is increased in psoriatic keratinocytes. In our case, EGFR expression increased in lesional keratinocytes 2 weeks after surgery and decreased 4 weeks after surgery. We speculate that a shift to Th2 immune reactions in lung SCC may be the pathogenesis of BS, whereby lesional keratinocytes highly express EGFR in parallel with disease activity. PMID- 28101025 TI - Giant Basal Cell Carcinomas Arising on the Bilateral Forearms of a Patient: A Case Report and Review of Nonsurgical Treatment Options. AB - Giant basal cell carcinomas (GBCCs) are large basal cell carcinomas (BCCs; <5 cm) with a greater propensity to invade and metastasize than standard BCCs. The presence of 2 GBCCs in a single individual is rare. We present the case of a 71 year-old Caucasian male with bilateral GBCCs on the dorsal forearms, measuring 130 cm2 and 24 cm2, respectively, that developed over a 21-year period. Over this period, the patient treated the tumors with herbal remedies. Histologic evaluation showed a conventional nodular BCC for both tumors. Computed tomography and magnetic resonance imaging revealed a T4N0M0 stage for the larger lesion. Surgical excision and grafting and reconstruction were offered, but he declined. This case highlights a shared belief in holistic treatments and rejection of Western medical interventions that are common among many patients with GBCC. Studies reporting nonsurgical treatments for GBCCs, including radiotherapy, vismodegib, topical imiquimod, and acitretin are reviewed. PMID- 28101026 TI - Transdifferentiation of Small Cell Carcinoma of the Urinary Bladder from Urothelial Carcinoma after Transurethral Resection of a Bladder Tumor, Intravesical Bacillus Calmette-Guerin Instillation, and Chemotherapy: A Case Report. AB - A 73-year-old male underwent transurethral resection of a bladder tumor in August 2010 and April 2011. Pathological examination revealed urothelial carcinoma. After the surgery, chemotherapy and intravesical Bacillus Calmette-Guerin instillation were performed. In September 2014, he once again underwent transurethral resection of the bladder tumor for recurrence, and was again diagnosed with urothelial carcinoma, pT2, by pathological examination. After neoadjuvant chemotherapy, radical cystectomy for tumor recurrence was performed. Pathological examination at this time revealed small cell carcinoma, pT3N0. It is rare for urothelial carcinoma to change to small cell carcinoma, and the mechanism and cause of this change are still unknown. In this case report, we discuss what causes small cell carcinoma of the urinary bladder and review the literature regarding its origin. PMID- 28101027 TI - Bilateral Facial Nerve Paralysis as First Presentation of Lung Cancer. AB - Leptomeningeal carcinomatosis is rare, and its precise incidence is unknown. It is associated with a wide spectrum of solid and hematological malignancies. To complicate its diagnosis, the clinical presentation of leptomeningeal carcinomatosis can be variable. We report a case of a 38-year-old male with bilateral facial nerve paralysis as first presentation of lung adenocarcinoma. To our knowledge, this is the only case describing bilateral facial nerve palsy as the first and only manifestation of lung adenocarcinoma. PMID- 28101028 TI - A Scary Onset of a Rare and Aggressive Type of Primary Breast Sarcoma: A Case Report. AB - Primary breast sarcoma, arising from connective tissue within the breast, is extremely rare, accounting for less than 1% of all primary breast malignancies and no more than 5% of all sarcomas. The rarity of this pathology limits most studies to case reports and small retrospective studies, which has led to a lack of consensus on the clinical management. We report a clinical case of a 52-year old woman, perimenopausal, previously healthy, with regular breast surveillance, who presented with a large (>20 cm) and rapidly expanding hypervascularized tumor of the left breast developed over 10 days, with a very thin preulcerative skin over the last 4 days. There was no systemic dissemination. The patient was submitted to total mastectomy and excision of axillary adenopathy. The tumor was diagnosed histologically as malignant phyllodes tumor associated with areas of high-grade sarcoma. Due to rapid growth and aggressive histological characteristics, adjuvant chemotherapy and radiotherapy were performed. There is a lot of evidence that tumors larger than 5 cm are associated with a poor prognosis. Despite the poor prognosis associated with this aggressive entity, the patient had no recurrence during 5 years of follow-up. We review the relevant literature about primary breast sarcomas. PMID- 28101029 TI - Ductal Adenocarcinoma of the Prostate: A Case Report. AB - Ductal adenocarcinoma is an unusual variant of adenocarcinoma of the prostate. A 73-year-old male was referred to our hospital for the further examination of an elevated prostate-specific antigen level of 23.4 ng/mL. Radical prostatectomy (RP) was performed based on the diagnosis obtained by a prostate needle biopsy. The RP specimen revealed ductal adenocarcinoma of the prostate with positive capsular penetration. We herein report a rare case of ductal adenocarcinoma of the prostate. PMID- 28101030 TI - Mucoepidermoid Carcinoma of the Breast Found during Treatment of Lymphoma. AB - A 71-year-old woman, previously treated for malignant lymphoma, was admitted to our hospital with a tumor in the right breast. The tumor size was 2.0 cm in diameter, and the borderline was unclear. The core needle biopsy material revealed an invasive adenocarcinoma with metaplastic change. Right mastectomy and sentinel lymph node biopsy was performed. Histologically, the tumor was composed of mucus-secreting, epidermoid, and intermediate cells. These findings confirmed the diagnosis as mucoepidermoid carcinoma (MEC) of the breast. MEC is more frequently observed in the salivary glands and occurs rarely in the breast, with an incidence of approximately 0.3% of all breast cancers. Because of the rarity of the disease, the clinicopathological features and clinical outcome have not been fully investigated. The relationship between MEC of the breast and lymphoma are unclear. Here we report a rare case of MEC of the breast. PMID- 28101031 TI - Alectinib-Induced Erythema Multiforme and Successful Rechallenge with Alectinib in a Patient with Anaplastic Lymphoma Kinase-Rearranged Lung Cancer. AB - BACKGROUND: Alectinib is an oral drug developed for the treatment of patients with fusion gene encoding echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK)-rearranged non-small cell lung cancer (NSCLC). Here, we present the case of a patient treated with alectinib who developed a hypersensitivity reaction with successful rechallenge treatment. CASE PRESENTATION: A 39-year-old woman who was a passive smoker was referred to Osaka City University Hospital for the evaluation of a skin event caused by treatment for NSCLC with the fusion gene EML4-ALK. The skin reaction was observed on the anterior chest, upper arms, and ear auricles on day 11 of treatment with oral alectinib. The skin event presented as widely distributed erythematous macules that were confluent, indicating a severe and life-threatening form. The skin lesions started to resolve after the initiation of treatment with 40 mg prednisolone. After regrowth of the tumor, she received a rechallenge program for alectinib for 2 weeks; thereafter, alectinib treatment was successfully reinitiated. CONCLUSION: To the best of our knowledge, we present the first case in which alectinib, which binds to the adenosine triphosphate site of EML4-ALK, induced erythema multiforme. Moreover, successful readministration of alectinib through our rechallenge program has not been reported so far. PMID- 28101032 TI - Debilitating Skin Toxicity Associated with Pembrolizumab Therapy in an 81-Year Old Female with Malignant Melanoma. AB - Frequently described immune-mediated adverse effects of immune therapy include dermatological complications, hepatitis, colitis, pneumonitis, and endocrinopathies. As utilization of pembrolizumab and related agents continues to expand both in the available indications as well as duration of exposure, there remains a significant potential to uncover previously undescribed adverse events. From a dermatological standpoint, 39% of patients receiving pembrolizumab therapy experience some form of skin-related drug toxicity [Naidoo et al.: Ann Oncol 2015;26: 2375-2391]. We describe a case of pembrolizumab-induced disabling autoimmune ectodermal toxicity. PMID- 28101033 TI - Maximizing the Benefit-Cost Ratio of Anthracyclines in Metastatic Breast Cancer: Case Report of a Patient with a Complete Response to High-Dose Doxorubicin. AB - Despite the clinical efficacy of anthracycline agents such as doxorubicin, dose limiting cardiac toxicities significantly limit their long-term use. Here, we present the case of a 33-year-old female patient with extensive metastatic ER+/PR+/HER2- mucinous adenocarcinoma of the breast, who was started on doxorubicin/cyclophosphamide therapy after progressing on paclitaxel and ovarian suppressor goserelin with aromatase inhibitor exemestane. The patient was comanaged by cardiology, who carefully monitored measures of cardiac function, including EKGs, serial echocardiograms, and profiling of lipids, troponin, and pro-BNP every 2 months. The patient was treated with the cardioprotective agent dexrazoxane, and changes in cardiac markers [e.g. decreases in ejection fraction (EF)] were immediately addressed by therapeutic intervention with the ACE inhibitor lisinopril and beta-blocker metoprolol. The patient had a complete response to doxorubicin therapy, with a cumulative dose of 1,350 mg/m2, which is significantly above the recommended limits, and to our knowledge, the highest dose reported in literature. Two and a half years after the last doxorubicin cycle, the patient is asymptomatic with no cardiotoxicity and an excellent quality of life. This case highlights the importance of careful monitoring and management of doxorubicin-mediated cardiotoxicity, and that higher cumulative doses of anthracyclines can be considered in patients with ongoing clinical benefit. PMID- 28101034 TI - A Case of Poorly Differentiated Large-Cell Neuroendocrine Carcinoma of the Cecum: A Rare Malignancy, with Review of the Literature. AB - Poorly differentiated neuroendocrine carcinomas (NECs) are rare tumors that can arise anywhere along the gastrointestinal tract. They often present in advanced stage and portend a poor prognosis when compared to adenocarcinomas of the same stage. Characterization of these tumors is best accomplished with tissue biopsy, as peripheral tumor markers commonly used in NECs are of little utility. Therapeutic strategies often involve chemotherapeutic regimens that have been used to treat small-cell lung cancer. Recent studies have shown that programmed death-ligand 1 (PD-L1) expression within poorly differentiated NECs is a poor prognostic indicator. However, PD-L1 expression may represent a possible target for immunotherapy drugs, often called checkpoint inhibitors, such as anti-PD-1 inhibitors. PMID- 28101035 TI - Early Motor Fluctuations in a Patient with Striatonigral Degeneration. AB - We report a 44-year-old female with striatonigral degeneration (SND) who showed wearing-off oscillations after 4 months of levodopa treatment. The patient presented with asymmetric left-side dominant rigidity, and levodopa was effective at first. However, she began to show wearing-off oscillations of motor symptoms, which gradually worsened thereafter. Fluid-attenuated inversion recovery sequence magnetic resonance imaging (MRI) showed linear lateral putamen hyperintensities, and positron emission tomography (PET) studies using 18F-fluorodopa (FD) and 11C N-methylspiperon (NMSP) showed a marked decrease of radioactivity in the right putamen, especially in the posterior putamen. The results of MRI and 2 PET studies with FD and NMSP were well consistent with the diagnosis of SND. PMID- 28101036 TI - Anti-N-Methyl-D-Aspartate Receptor Encephalitis in HIV Infection. AB - Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a rare condition characterized by emotional and behavioral disturbances, dyskinesias, and extrapyramidal signs. It occurs in young women of reproductive age and is classically described as a paraneoplastic phenomenon. We present a 36-year-old, HIV-positive female who was admitted to the hospital in an acute confusional state, with a stiff posture, periods of motor agitation, and myoclonic jerks of the hands. Her mental state progressively deteriorated. Without evidence of infection, the presence of anti-NMDAR antibodies both in serum and cerebrospinal fluid clinched the diagnosis of autoimmune encephalitis. No evidence of neoplastic disease was found, and the beneficial response to immunosuppressive therapy was exceptional. This is the first report of anti-NMDAR encephalitis in an HIV-infected individual, reminding us that autoimmune encephalitis should be included in the differential diagnosis of a young patient presenting in an acute confusional state. PMID- 28101037 TI - Successful Restoration of Visual Acuity with an Extended Range of Vision Intraocular Lens after Multifocal Laser Ablation. AB - As our baby boomer population is aging and developing cataracts, so are our post LASIK patients. These patients underwent LASIK surgery as they wished to be spectacle-free and are hoping to remain so after intraocular lens (IOL) surgery. Unfortunately, very little information is available regarding the suitability of presbyopia correcting IOLs for post-LASIK patients. This case represents successful implantation of an extended range of vision IOL in a 59-year-old patient who underwent multifocal ablation excimer laser surgery 12 years before. Emmetropia was targeted for the dominant eye and -0.5 D for the fellow eye. The 13 month follow-up after bilateral implantation of the TECNIS Symfony IOL revealed an uncorrected visual acuity of 20/25 for distance, 20/20 for intermediate and 20/16 for near. The patient is very happy and did not report any visual symptoms when asked. This successful case should encourage surgeons to consider implanting an extended range of vision IOLs in post-LASIK patients. PMID- 28101038 TI - Successful Management in a Case of Traumatic Retinal Detachment due to Open Globe Injury Using Microincisional Vitrectomy. AB - BACKGROUND: Retinal detachment (RD) following ocular trauma often results in guarded visual prognosis and sometimes leads to loss of the eye. With the advent of microincisional vitrectomy surgery and the development of surgical techniques, the management of ocular trauma has been transformed. CASE PRESENTATION: A 34 year-old man sustained an open globe injury from fragmented glass at work. He received primary repair and another follow-up surgery 9 days later, including vitrectomy, silicone oil tamponade, and lensectomy for RD and traumatic cataract at another medical center. However, his retina was totally detached and completely curled up in a roll with choroid on display when he was seen by us 1 month later. He was managed with vigilant and patient peeling and unfolding of the retina using a 23-gauge forceps and silicone oil tamponade, and achieved anatomical success and preservation of his eye at 6-month follow-up. CONCLUSIONS: This report demonstrates that even in cases which appear to be hopeless at presentation, the surgeon's perseverance and surgical technique can salvage an eye that may otherwise be phthisical. It also encourages retinal surgeons to use microincisional vitrectomy to manage severe traumatic RD. PMID- 28101039 TI - Multifocal Toric Intraocular Lens for Traumatic Cataract in a Child. AB - A child suffering from traumatic cataract and corneal astigmatism of 2.14 D had a phacoemulsification operation and implantation of a ReSTOR Toric intraocular lens (IOL) to correct the astigmatism. The primary outcome measurements were the uncorrected distance visual acuity (UDVA), uncorrected near vision at 40 cm, intraocular pressure, spherical equivalent refraction, residual astigmatism, corneal astigmatism, presence of unusual optical phenomena, and use of spectacles. At 7 months postoperatively, UDVA was maintained between 16/20 and 24/20, near vision was between J1 and J3, residual spherical refraction was 0 0.37 D, and residual refractive cylinder was between 0 and 0.67 D. A multifocal toric IOL can provide the possibility of satisfactory vision for both distant and near conditions without the use of spectacles to meet children's needs when studying and doing sports. Additionally, binocular vision can be reconstructed. This intervention, therefore, seems to be a satisfactory alternative. PMID- 28101040 TI - High Rate of Early Posterior Capsule Opacification following Femtosecond Laser Assisted Cataract Surgery. AB - PURPOSE: To compare the rates of rapid posterior capsule opacification (PCO) formation in the first 3 months following femtosecond laser-assisted cataract surgery (FLACS) to manual anterior capsulorhexis. METHODS: Retrospective review of 29 cases of FLACS, comparing the rates of PCO in the first 3 months following surgery to 50 consecutive cases of manual anterior capsulorhexis. RESULTS: Seven of the 29 FLACS cases developed PCO requiring capsulotomy at 3 months, while none of the control cases required a capsulotomy over the same time period (p < 0.05). CONCLUSION: There is an increased incidence of early-onset PCO following the use of femtosecond laser in cataract surgery that is otherwise unfounded in manual capsulorhexis. This suggests that the use of a femtosecond laser could increase the risk of this novel postoperative complication. PMID- 28101042 TI - Use of Internal Limiting Membrane Autograft in Primary Vitrectomy for Rhegmatogenous Retinal Detachment. AB - During a pars plana vitrectomy, an unplanned retinotomy in the raphe was performed in a 55-year-old female patient with rhegmatogenous retinal detachment and proliferative vitreoretinopathy. Since diathermy and laser therapy were not available at that moment, it was decided to peel off a small graft of the internal limiting membrane adjacent to the retinotomy site which had been previously stained with Brilliant Blue G. The graft was displaced under perfluorocarbon fluids and placed inside the retinotomy. Three weeks after surgery, the apparent closure of the retinotomy was observed clinically. PMID- 28101041 TI - Endophthalmitis following 27-Gauge Pars Plana Vitrectomy for Vitreous Floaters. AB - PURPOSE: To report a case of Staphylococcus epidermidis endophthalmitis following 27-gauge pars plana vitrectomy for symptomatic vitreous floaters. METHODS: The clinical course and imaging findings, including fundus optomap, and spectral domain optical coherence tomography of a 24-year-old male patient were documented. RESULTS: The patient, with a preoperative best-corrected visual acuity (BCVA) of 1.0, developed endophthalmitis following 27-gauge pars plana vitrectomy for symptomatic vitreous floaters. After a series of treatments, including emergent vitreous tap and silicone oil injection, antibiotic treatment, and silicone oil removal, the patient regained a BCVA of 0.6. CONCLUSION: Although rare, the potential risk of endophthalmitis should be explicitly discussed with patients considering surgical intervention for vitreous floaters. PMID- 28101043 TI - Effects of Disseminated Mycobacterial Infection on Age-Related Macular Degeneration. AB - Our patient, in the 7th decade of life, presented with worsening blurry vision over 3 weeks. The pertinent history included nonexudative age-related macular degeneration, recent pulmonary mycobacterial infection, and autoimmune pancreatitis. The patient had decreased visual acuity in both eyes; the remaining findings of our examination were relatively benign. The diagnosis of bilateral exudative age-related macular degeneration was aided by ocular imaging. Not only were exudative changes confirmed, but one modality suggested an underlying occult choroiditis, which presumably fueled a local inflammatory drive leading to evolution of the disease. Given the choroiditis developed in the setting of a recent Mycobacterium chelonae infection, dissemination of the organism must be considered a potential culprit. Additionally, a chronic inflammatory state perhaps played a simultaneous immunologic role. We feel the proposed pathogenic mechanism outlined sufficiently accounts for the rare event, that is, development of subacute bilateral exudative maculopathy. The patient responded well to bilateral intravitreal aflibercept injections. After 1 month, visual acuity was found to be near baseline and ocular imaging showed significant resolution of the exudative changes. An additional follow-up 3 months after confirmed similar stability. This case required thorough investigation of seemingly unrelated components within the patient's history. We stress the importance of obtaining appropriate documentation from fellow health care teams when suspicious clinical presentations arise. During our investigation, we identified cryptic retinal lesions by way of angiography - leading us to recommend usage of such methods in complex cases. We also summarize the implemented aflibercept course and the favorable response to such treatment. PMID- 28101044 TI - Heads-Up Macular Surgery with a 27-Gauge Microincision Vitrectomy System and Minimal Illumination. AB - OBJECTIVE: We combined heads-up 3-dimensional (3D) 27-gauge microincision vitrectomy surgery (27GMIVS) with a very low-intensity illumination system. METHODS: This study was based on a retrospective, interventional case series of 6 eyes of 6 patients with macular disease. All patients underwent heads-up 3D 27GMIVS and the power of the intraocular illuminator was set to its minimum level, 1% (approximately 0.1 lm), throughout the surgery. RESULTS: We found that the procedure was easy when the heads-up 3D system was used, but not through the eyepiece of a microscope. All surgeries were successfully finished without any complications. Postoperative visual acuity was restored or maintained in all eyes during the follow-up period. CONCLUSION: Heads-up, 3D system-assisted 27GMIVS with minimal illumination enabled excellent intraoperative visualization of retinal tissues, caused minimal phototoxicity to the macular retinal cells, and might therefore represent the next step in the development of an ideal, minimally invasive method of treating macular disease. PMID- 28101045 TI - ExPRESS Mini-Shunt as a Treatment Alternative for Medically Uncontrolled Steroid Induced Glaucoma in a Pediatric Patient. AB - This case report illustrates the use of ExPRESS mini-shunt in a pediatric glaucoma patient. We describe the management of steroid-induced glaucoma with ExPRESS mini-shunt in a 9-year-old boy with allergic keratoconjunctivitis. The intraocular pressure of both of his eyes was uncontrolled with medical and laser treatment. Both eyes were treated with ExPRESS mini-shunt and mitomycin-C. Transient overfiltration with postoperative hypotony occurred in both eyes and resolved after 2 weeks. One year postoperatively, intraocular pressure was maintained below 21 mm Hg without medication in 1 eye. Bleb needling with mitomycin-C was done to maintain filtration. The fellow eye received cataract extraction but developed bleb failure a few months afterwards. The intraocular pressure was controlled medically. To conclude, ExPRESS mini-shunt is a new surgical option in selected patients. Bleb failure developed after cataract extraction. Postoperative inflammation should be minimized. Patient selection, such as those with stable ocular condition, is important to increase surgical success. PMID- 28101047 TI - Acute Anterior Uveitis in a Patient Taking Fingolimod (FTY720) for Multiple Sclerosis. AB - Fingolimod is an oral sphingosine-1-phosphate (S1P) receptor modulator and the first oral therapy for relapsing-remitting multiple sclerosis. Its use has been complicated by a low rate of cystoid macular edema usually in the first 3 months after commencement of the medication. We report the case of a 34-year-old male with relapsing-remitting multiple sclerosis, who developed acute anterior uveitis on day 5 of fingolimod treatment. He responded to appropriate treatment and cessation of drug, but developed low-grade chronic anterior uveitis without cystoid macular edema. We discuss possible mechanisms of uveitis onset in this group of patients. Urgent ophthalmological review is recommended for patients receiving fingolimod therapy who develop a red, painful eye, which may occur within 5 days of fingolimod treatment initiation. PMID- 28101046 TI - A Case of Proliferative Retinopathy Complicated with Tuberous Sclerosis Treated by Vitreous Surgery. AB - We report a case of proliferative retinopathy complicated with retinal hamartoma in a tuberous sclerosis patient. This study involved a 16-year-old female patient who was diagnosed as having tuberous sclerosis at birth. Ophthalmic examination revealed retinal hamartoma surrounding the optic disc in both eyes. Vitreous surgery involving a vitrectomy and resection of the proliferative membranes was performed for proliferative retinopathy in her right eye. Postoperative fundus findings showed improvement and decreased exudative changes. The proliferative and exudative changes appeared to be due to the retinal hamartoma, and vitreous surgery proved effective in this case. PMID- 28101048 TI - Five-Port Combined Limbal and Pars Plana Vitrectomy for Infectious Endophthalmitis. AB - Pars plana vitrectomy for acute infectious endophthalmitis can be challenging due to severe inflammation in the anterior chamber creating significant media opacity. We describe a surgical technique combining limbal based vitrectomy and pars plana vitrectomy to manage acute infectious endophthalmitis. Limbal based vitrectomy facilitates removal of anterior chamber fibrin and inflammatory membranes for safe and optimal posterior pars plana vitrectomy. PMID- 28101049 TI - Tuberculous Subretinal Abscess in a Non-HIV Patient with Miliary Tuberculosis. AB - This case report describes the features of a tuberculous subretinal abscess in a non-HIV patient. It includes the characterization of the lesion with spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence examination. SD-OCT and autofluorescence imaging showed external retinal involvement during development of the tuberculous subretinal abscess. Patients with tuberculous lesions need a multidisciplinary approach, since the disease may involve any part of the body. In this case in particular, incidental findings at computed tomography scan led to the detection of this rare ocular manifestation of tuberculous disease. PMID- 28101050 TI - Sustained Obesity and Depressive Symptoms over 6 Years: Race by Gender Differences in the Health and Retirement Study. AB - Background: Although obesity and physical activity influence psychosocial well being, these effects may vary based on race, gender, and their intersection. Using 6-year follow-up data of a nationally representative sample of adults over age of 50 in the United States, this study aimed to explore race by gender differences in additive effects of sustained high body mass index (BMI) and physical activity on sustained depressive symptoms (CES-D) and self-rated health (SRH). Methods: Data came from waves 7, 8, and 10 (2004-2010) of the Health and Retirement Study (HRS), an ongoing national cohort started in 1992. The study enrolled a representative sample of Americans (n = 19,280) over the age of 50. Latent factors were used to calculate sustained high BMI and physical activity (predictors) and sustained poor SRH and high depressive symptoms (outcomes) based on measurements in 2004, 2006, and 2010. Age, education, and income were confounders. Multi-group structural equation modeling (SEM) was used to test the additive effects of BMI and physical activity on depressive symptoms and SRH, where the groups were defined based on race by gender. Results: Group differences were apparent in the direction and significance of the association between sustained high BMI and depressive symptoms. The association between sustained high BMI and depressive symptoms was positive and significant for White women (B = 0.03, p = 0.007) and non-significant for White men (B = -0.03, p = 0.062), Black men (B = -0.02, p = 0.564) and Black women (B = 0.03, p = 0.110). No group differences were found in the paths from sustained physical activity to depressive symptoms, or from physical activity or BMI to SRH. Conclusion: Sustained high BMI and high depressive symptoms after age 50 are positively associated only for White women. As the association between sustained health problems such as depression and obesity are not universal across race and gender groups, clinical and public health interventions and programs that simultaneously target multiple health problems may have differential effects across race by gender groups. PMID- 28101051 TI - Robust Detection of Impaired Resting State Functional Connectivity Networks in Alzheimer's Disease Using Elastic Net Regularized Regression. AB - The large number of multicollinear regional features that are provided by resting state (rs) fMRI data requires robust feature selection to uncover consistent networks of functional disconnection in Alzheimer's disease (AD). Here, we compared elastic net regularized and classical stepwise logistic regression in respect to consistency of feature selection and diagnostic accuracy using rs-fMRI data from four centers of the "German resting-state initiative for diagnostic biomarkers" (psymri.org), comprising 53 AD patients and 118 age and sex matched healthy controls. Using all possible pairs of correlations between the time series of rs-fMRI signal from 84 functionally defined brain regions as the initial set of predictor variables, we calculated accuracy of group discrimination and consistency of feature selection with bootstrap cross validation. Mean areas under the receiver operating characteristic curves as measure of diagnostic accuracy were 0.70 in unregularized and 0.80 in regularized regression. Elastic net regression was insensitive to scanner effects and recovered a consistent network of functional connectivity decline in AD that encompassed parts of the dorsal default mode as well as brain regions involved in attention, executive control, and language processing. Stepwise logistic regression found no consistent network of AD related functional connectivity decline. Regularized regression has high potential to increase diagnostic accuracy and consistency of feature selection from multicollinear functional neuroimaging data in AD. Our findings suggest an extended network of functional alterations in AD, but the diagnostic accuracy of rs-fMRI in this multicenter setting did not reach the benchmark defined for a useful biomarker of AD. PMID- 28101052 TI - Correlations of Ventricular Enlargement with Rheologically Active Surfactant Proteins in Cerebrospinal Fluid. AB - Purpose: Surfactant proteins (SPs) are involved in the regulation of rheological properties of body fluids. Concentrations of SPs are altered in the cerebrospinal fluid (CSF) of hydrocephalus patients. The common hallmark of hydrocephalus is enlargement of the brain ventricles. The relationship of both phenomena has not yet been investigated. The aim of this study was to evaluate the association between SP concentrations in the CSF and enlargement of the brain ventricles. Procedures: Ninty-six individuals (41 healthy subjects and 55 hydrocephalus patients) were included in this retrospective analysis. CSF specimens were analyzed for SP-A, SP-B, SP-C and SP-D concentrations by use of enzyme linked immunosorbent assays (ELISA). Ventricular enlargement was quantified in T2 weighted (T2w) magnetic resonance imaging (MRI) sections using an uni-dimensional (Evans' Index) and a two-dimensional approach (lateral ventricles area index, LVAI). Results: CSF-SP concentrations (mean +/- standard deviation in ng/ml) were as follows: SP-A 0.71 +/- 0.58, SP-B 0.18 +/- 0.43, SP-C 0.89 +/- 0.77 and SP-D 7.4 +/- 5.4. Calculated values of Evans' Index were 0.37 +/- 0.11, a calculation of LVAI resulted in 0.18 +/- 0.15 (each mean +/- standard deviation). Significant correlations were identified for Evans' Index with SP-A (r = 0.388, p < 0.001) and SP-C (r = 0.392, p < 0.001), LVAI with SP-A (r = 0.352, p = 0.001), SP-C (r = 0.471, p < 0.001) and SP-D (r = 0.233, p = 0.025). Furthermore, SP-C showed a clear inverse correlation with age (r = -0.357, p = 0.011). Conclusion: The present study confirmed significant correlations between SPs A, C and D in the CSF with enlargement of the inner CSF spaces. In conclusion, SPs clearly play an important role for CSF rheology. CSF rheology is profoundly altered in hydrocephalic diseases, however, diagnosis and therapy of hydrocephalic conditions are still almost exclusively based on ventricular enlargement. Until now it was unclear, whether the stage of the disease, as represented by the extent of ventricular dilatation, is somehow related to the changes of SP levels in the CSF. Our study is the first to provide evidence that increasing ventriculomegaly is accompanied by enhanced changes of rheologically active compounds in the CSF and therefore introduces completely new aspects for hydrocephalus testing and conservative therapeutic approaches. PMID- 28101053 TI - Frontal Structural Neural Correlates of Working Memory Performance in Older Adults. AB - Working memory is an executive memory process that allows transitional information to be held and manipulated temporarily in memory stores before being forgotten or encoded into long-term memory. Working memory is necessary for everyday decision-making and problem solving, making it a fundamental process in the daily lives of older adults. Working memory relies heavily on frontal lobe structures and is known to decline with age. The current study aimed to determine the neural correlates of decreased working memory performance in the frontal lobes by comparing cortical thickness and cortical surface area from two demographically matched groups of healthy older adults, free from cognitive impairment, with high versus low N-Back working memory performance (N = 56; average age = 70.29 +/- 10.64). High-resolution structural T1-weighted images (1 mm isotropic voxels) were obtained on a 3T Philips MRI scanner. When compared to high performers, low performers exhibited significantly decreased cortical surface area in three frontal lobe regions lateralized to the right hemisphere: medial orbital frontal gyrus, inferior frontal gyrus, and superior frontal gyrus (FDR p < 0.05). There were no significant differences in cortical thickness between groups, a proxy for neurodegenerative tissue loss. Our results suggest that decreases in cortical surface area (a proxy for brain structural integrity) in right frontal regions may underlie age-related decline of working memory function. PMID- 28101054 TI - Protease-Activated Receptor 2 Promotes Pro-Atherogenic Effects through Transactivation of the VEGF Receptor 2 in Human Vascular Smooth Muscle Cells. AB - Background: Obesity is associated with impaired vascular function. In the cardiovascular system, protease-activated receptor 2 (PAR2) exerts multiple functions such as the control of the vascular tone. In pathological conditions, PAR2 is related to vascular inflammation. However, little is known about the impact of obesity on PAR2 in the vasculature. Therefore, we explored the role of PAR2 as a potential link between obesity and cardiovascular diseases. Methods: C57BL/6 mice were fed with either a chow or a 60% high fat diet for 24 weeks prior to isolation of aortas. Furthermore, human coronary artery endothelial cells (HCAEC) and human coronary smooth muscle cells (HCSMC) were treated with conditioned medium obtained from in vitro differentiated primary human adipocytes. To investigate receptor interaction vascular endothelial growth factor receptor 2 (VEGFR2) was blocked by exposure to calcium dobesilate and a VEGFR2 neutralization antibody, before treatment with PAR2 activating peptide. Student's t-test or one-way were used to determine statistical significance. Results: Both, high fat diet and exposure to conditioned medium increased PAR2 expression in aortas and human vascular cells, respectively. In HCSMC, conditioned medium elicited proliferation as well as cyclooxygenase 2 induction, which was suppressed by the PAR2 antagonist GB83. Specific activation of PAR2 by the PAR2 activating peptide induced proliferation and cyclooxygenase 2 expression which were abolished by blocking the VEGFR2. Additionally, treatment of HCSMC with the PAR2 activating peptide triggered VEGFR2 phosphorylation. Conclusion: Under obesogenic conditions, where circulating levels of pro-inflammatory adipokines are elevated, PAR2 arises as an important player linking obesity related adipose tissue inflammation to atherogenesis. We show for the first time that the underlying mechanisms of these pro-atherogenic effects involve a potential transactivation of the VEGFR2 by PAR2. PMID- 28101055 TI - Inferring the Impact of Regulatory Mechanisms that Underpin CD8+ T Cell Control of B16 Tumor Growth In vivo Using Mechanistic Models and Simulation. AB - A major barrier for broadening the efficacy of immunotherapies for cancer is identifying key mechanisms that limit the efficacy of tumor infiltrating lymphocytes. Yet, identifying these mechanisms using human samples and mouse models for cancer remains a challenge. While interactions between cancer and the immune system are dynamic and non-linear, identifying the relative roles that biological components play in regulating anti-tumor immunity commonly relies on human intuition alone, which can be limited by cognitive biases. To assist natural intuition, modeling and simulation play an emerging role in identifying therapeutic mechanisms. To illustrate the approach, we developed a multi-scale mechanistic model to describe the control of tumor growth by a primary response of CD8+ T cells against defined tumor antigens using the B16 C57Bl/6 mouse model for malignant melanoma. The mechanistic model was calibrated to data obtained following adenovirus-based immunization and validated to data obtained following adoptive transfer of transgenic CD8+ T cells. More importantly, we use simulation to test whether the postulated network topology, that is the modeled biological components and their associated interactions, is sufficient to capture the observed anti-tumor immune response. Given the available data, the simulation results also provided a statistical basis for quantifying the relative importance of different mechanisms that underpin CD8+ T cell control of B16F10 growth. By identifying conditions where the postulated network topology is incomplete, we illustrate how this approach can be used as part of an iterative design-build test cycle to expand the predictive power of the model. PMID- 28101058 TI - Genetic Variation in the Histamine Production, Response, and Degradation Pathway Is Associated with Histamine Pharmacodynamic Response in Children with Asthma. AB - Introduction: There is growing knowledge of the wide ranging effects of histamine throughout the body therefore it is important to better understand the effects of this amine in patients with asthma. We aimed to explore the association between histamine pharmacodynamic (PD) response and genetic variation in the histamine pathway in children with asthma. Methods: Histamine Iontophoresis with Laser Doppler Monitoring (HILD) was performed in children with asthma and estimates for area under the effect curve (AUEC), maximal response over baseline (Emax), and time of Emax (Tmax) were calculated using non-compartmental analysis and non linear mixed-effects model with a linked effect PK/PD model. DNA isolation and genotyping were performed among participants to detect known single nucleotide polymorphisms (SNPs) (n = 10) among genes (HDC, HNMT, ABP1, HRH1, HRH4) within the histamine pathway. General linear model was used to identify associations between histamine related genetic variants and measured histamine PD response parameters. Results: Genotyping and HILD response profiles were completed for 163 children. ABP1 47 C/T, ABP1 4107, and HNMT-1639 C/Twere associated with Emax (ABP1 47 CC genotype mean Emax 167.21 vs. CT/TT genotype mean Emax 139.20, p = 0.04; ABP1 4107 CC genotype mean Emax 141.72 vs. CG/GG genotype mean Emax 156.09, p = 0.005; HNMT-1639 CC genotype mean Emax 132.62 vs. CT/TT genotype mean Emax 155.3, p = 0.02). In a stratified analysis among African American children only, ABP1 and HNMT SNPs were also associated with PD response; HRH4 413 CC genotype was associated with lower Emax, p = 0.009. Conclusions: We show for the first time that histamine pathway genetic variation is associated with measureable changes in histamine response in children with asthma. The variability in histamine response and impact of histamine pathway genotype is important to further explore in patients with asthma so as to improve disease phenotyping leading to more personalized treatments. PMID- 28101057 TI - Pomegranate Extract Enhances Endothelium-Dependent Coronary Relaxation in Isolated Perfused Hearts from Spontaneously Hypertensive Ovariectomized Rats. AB - Decline in estrogen levels promotes endothelial dysfunction and, consequently, the most prevalent cardiovascular diseases in menopausal women. The use of natural therapies such as pomegranate can change these results. Pomegranate [Punica granatum L. (Punicaceae)] is widely used as a phytotherapeutic agent worldwide, including in Brazil. We hypothesized that treatment with pomegranate hydroalcoholic extract (PHE) would improve coronary vascular reactivity and cardiovascular parameters. At the beginning of treatment, spontaneously hypertensive female rats were divided into Sham and ovariectomized (OVX) groups, which received pomegranate extract (PHE) (250 mg/kg) or filtered water (V) for 30 days by gavage. Systolic blood pressure was measured by tail plethysmography. After euthanasia, the heart was removed and coronary vascular reactivity was assessed by Langendorff retrograde perfusion technique. A dose-response curve for bradykinin was performed, followed by L-NAME inhibition. The protein expression of p-eNOS Ser1177, p-eNOS Thr495, total eNOS, p-AKT Ser473, total AKT, SOD-2, and catalase was quantified by Western blotting. The detection of coronary superoxide was performed using the protocol of dihydroethidium (DHE) staining Plasma nitrite measurement was analyzed by Griess method. Systolic blood pressure increased in both Sham-V and OVX-V groups, whereas it was reduced after treatment in Sham-PHE and OVX-PHE groups. The baseline coronary perfusion pressure was reduced in the Sham-PHE group. The relaxation was significantly higher in the treated group, and L-NAME attenuated the relaxation in all groups. The treatment has not changed p eNOS (Ser1177), total eNOS, p-AKT (Ser473) and total AKT in any groups. However, in Sham and OVX group the treatment reduced the p-eNOS (Thr495) and SOD-2. The ovariectomy promoted an increasing in the superoxide anion levels and the treatment was able to prevent this elevation and reducing oxidative stress. Moreover, the treatment prevented the decreasing in plasmatic nitrite. We observed a reduction in total cholesterol and LDL in the Sham-PHE group. The treatment with PHE enhances the endothelium-dependent coronary relaxation and improves cardiovascular parameters, which suggests a therapeutic role of PHE. PMID- 28101056 TI - Cerebral Gluconeogenesis and Diseases. AB - The gluconeogenesis pathway, which has been known to normally present in the liver, kidney, intestine, or muscle, has four irreversible steps catalyzed by the enzymes: pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1,6 bisphosphatase, and glucose 6-phosphatase. Studies have also demonstrated evidence that gluconeogenesis exists in brain astrocytes but no convincing data have yet been found in neurons. Astrocytes exhibit significant 6-phosphofructo-2 kinase/fructose-2,6-bisphosphatase-3 activity, a key mechanism for regulating glycolysis and gluconeogenesis. Astrocytes are unique in that they use glycolysis to produce lactate, which is then shuttled into neurons and used as gluconeogenic precursors for reduction. This gluconeogenesis pathway found in astrocytes is becoming more recognized as an important alternative glucose source for neurons, specifically in ischemic stroke and brain tumor. Further studies are needed to discover how the gluconeogenesis pathway is controlled in the brain, which may lead to the development of therapeutic targets to control energy levels and cellular survival in ischemic stroke patients, or inhibit gluconeogenesis in brain tumors to promote malignant cell death and tumor regression. While there are extensive studies on the mechanisms of cerebral glycolysis in ischemic stroke and brain tumors, studies on cerebral gluconeogenesis are limited. Here, we review studies done to date regarding gluconeogenesis to evaluate whether this metabolic pathway is beneficial or detrimental to the brain under these pathological conditions. PMID- 28101060 TI - Protein Fragmentation As a Regulatory Mechanism: Insights from Two Different Ca2+ Channels, RyR1 and IP3R. PMID- 28101059 TI - The Role of the Cytoskeleton and Myosin-Vc in the Targeting of KCa3.1 to the Basolateral Membrane of Polarized Epithelial Cells. AB - Understanding the targeting of KCa3.1 to the basolateral membrane (BLM) of polarized epithelial cells is still emerging. Here, we examined the role of the cytoskeleton (microtubules and microfilaments) and Myosin-Vc (Myo-Vc) in the targeting of KCa3.1 in Fischer rat thyroid epithelial cells. We used a pharmacological approach with immunoblot (for the BLM expression of KCa3.1), Ussing chamber (functional BLM expression of KCa3.1) and siRNA experiments. The actin cytoskeleton inhibitors cytochalasin D (10 MUM, 5 h) and latrunculin A (10 MUM, 5 h) reduced the targeting of KCa3.1 to the BLM by 88 +/- 4 and 70 +/- 5%, respectively. Colchicine (10 MUM, 5 h) a microtubule inhibitor reduced targeting of KCa3.1 to the BLM by 63 +/- 7% and decreased 1-EBIO-stimulated KCa3.1 K+ current by 46 +/- 18%, compared with control cells. ML9 (10 MUM, 5 h), an inhibitor of myosin light chain kinase, decreased targeting of the channel by 83 +/- 2% and reduced K+ current by 54 +/- 8% compared to control cells. Inhibiting Myo-V with 2,3-butanedione monoxime (10 mM, 5 h) reduced targeting of the channel to the BLM by 58 +/- 5% and decreased the stimulated current of KCa3.1 by 48 +/- 12% compared with control cells. Finally, using siRNA for Myo-Vc, we demonstrated that knockdown of Myo-Vc reduced the BLM expression of KCa3.1 by 44 +/- 7% and KCa3.1 K+ current by 1.04 +/- 0.14 MUA compared with control cells. These data suggest that the microtubule and microfilament cytoskeleton and Myo-Vc are critical for the targeting of KCa3.1. PMID- 28101061 TI - The Influence of Gender and Anthropometry on Haemodynamic Status at Rest and in Response to Graded Incremental Head-Up Tilt in Young, Healthy Adults. AB - The body's ability to rapidly and appropriately regulate blood pressure in response to changing physiological demand is a key feature of a healthy cardiovascular system. Passively tilting the body, thereby changing central blood volume, is a well-recognized and controlled method of evaluating this ability. However, such studies usually involve single tilt angles, or intermittent tilting separated by supine, resting periods; valuable information concerning the adaptive capacity of the regulatory systems involved is therefore currently lacking. Furthermore, despite increasing recognition that men and women differ in the magnitude of their haemodynamic response to such stimuli, little is known about the degree to which gender differences in body composition and anthropometry influence these regulatory pathways, or indeed if these differences are apparent in response to graded, incremental tilting. In the present study we measured, in 23 young, healthy adults (13 men, 10 women), the continuous beat-to beat haemodynamic response to graded, incremental tilting (0 degrees , 20 degrees , 40 degrees , 60 degrees , and back to 40 degrees ) with each tilt angle lasting 16 min. On average, we observed increases in heart rate (+41%), blood pressure (+10%), and total peripheral resistance (+16%) in response to tilting. However, whilst men showed an immediate decrease in cardiac output upon tilting (-8.9%) cardiac output in women did not change significantly from supine values. Interestingly, the decrease in stroke volume observed in women was significantly less than that observed in men (-22 vs. -36%, p < 0.05); although the present study could not determine if this difference was due to gender per se or due to differences in body size (in particular height) between the two gender groups. Such disparities in the magnitude of autonomic response may indicate (in the case of our gradual incremental tilt procedure) a better buffering capacity to progressive changes in central blood volume in women; which warrants further investigation, particularly in light of the well-recognized differences in cardiovascular disease risk between men and women. PMID- 28101062 TI - Elastase-Induced Parenchymal Disruption and Airway Hyper Responsiveness in Mouse Precision Cut Lung Slices: Toward an Ex vivo COPD Model. AB - Background: COPD is a progressive lung disease characterized by emphysema and enhanced bronchoconstriction. Current treatments focused on bronchodilation can delay disease progression to some extent, but recovery or normalization of loss of lung function is impossible. Therefore, novel therapeutic targets are needed. The importance of the parenchyma in airway narrowing is increasingly recognized. In COPD, the parenchyma and extracellular matrix are altered, possibly affecting airway mechanics and enhancing bronchoconstriction. Our aim was to set up a comprehensive ex vivo Precision Cut Lung Slice (PCLS) model with a pathophysiology resembling that of COPD and integrate multiple readouts in order to study the relationship between parenchyma, airway functionality, and lung repair processes. Methods: Lungs of C57Bl/6J mice were sliced and treated ex vivo with elastase (2.5 MUg/ml) or H2O2 (200 MUM) for 16 h. Following treatment, parenchymal structure, airway narrowing, and gene expression levels of alveolar Type I and II cell repair were assessed. Results: Following elastase, but not H2O2 treatment, slices showed a significant increase in mean linear intercept (Lmi), reflective of emphysema. Only elastase-treated slices showed disorganization of elastin and collagen fibers. In addition, elastase treatment lowered both alveolar Type I and II marker expression, whereas H2O2 stimulation lowered alveolar Type I marker expression only. Furthermore, elastase-treated slices showed enhanced methacholine-induced airway narrowing as reflected by increased pEC50 (5.87 at basal vs. 6.50 after elastase treatment) and Emax values (47.96 vs. 67.30%), and impaired chloroquine-induced airway opening. The increase in pEC50 correlated with an increase in mean Lmi. Conclusion: Using this model, we show that structural disruption of elastin fibers leads to impaired alveolar repair, disruption of the parenchymal compartment, and altered airway biomechanics, enhancing airway contraction. This finding may have implications for COPD, as the amount of elastin fiber and parenchymal tissue disruption is associated with disease severity. Therefore, we suggest that PCLS can be used to model certain aspects of COPD pathophysiology and that the parenchymal tissue damage observed in COPD contributes to lung function decline by disrupting airway biomechanics. Targeting the parenchymal compartment may therefore be a promising therapeutic target in the treatment of COPD. PMID- 28101063 TI - Living at a Geographically Higher Elevation Is Associated with Lower Risk of Metabolic Syndrome: Prospective Analysis of the SUN Cohort. AB - Living in a geographically higher altitude affects oxygen availability. The possible connection between environmental factors and the development of metabolic syndrome (MetS) feature is not fully understood, being the available epidemiological evidence still very limited. The aim of the present study was to evaluate the longitudinal association between altitude and incidence of MetS and each of its components in a prospective Spanish cohort, The Seguimiento Universidad de Navarra (SUN) project. Our study included 6860 highly educated subjects (university graduates) free from any MetS criteria at baseline. The altitude of residence was imputed with the postal code of each individual subject residence according to the data of the Spanish National Cartographic Institute and participants were categorized into tertiles. MetS was defined according to the harmonized definition. Cox proportional hazards models were used to assess the association between the altitude of residence and the risk of MetS during follow-up. After a median follow-up period of 10 years, 462 incident cases of MetS were identified. When adjusting for potential confounders, subjects in the highest category of altitude (>456 m) exhibited a significantly lower risk of developing MetS compared to those in the lowest tertile (<122 m) of altitude of residence [Model 2: Hazard ratio = 0.75 (95% Confidence interval: 0.58-0.97); p for trend = 0.029]. Living at geographically higher altitude was associated with a lower risk of developing MetS in the SUN project. Our findings suggest that geographical elevation may be an important factor linked to metabolic diseases. PMID- 28101065 TI - Non-linearities in Theory-of-Mind Development. AB - Research on Theory-of-Mind (ToM) has mainly focused on ages of core ToM development. This article follows a quantitative approach focusing on the level of ToM understanding on a measurement scale, the ToM Storybooks, in 324 typically developing children between 3 and 11 years of age. It deals with the eventual occurrence of developmental non-linearities in ToM functioning, using smoothing techniques, dynamic growth model building and additional indicators, namely moving skewness, moving growth rate changes and moving variability. The ToM sum scores showed an overall developmental trend that leveled off toward the age of 10 years. Within this overall trend two non-linearities in the group-based change pattern were found: a plateau at the age of around 56 months and a dip at the age of 72-78 months. These temporary regressions in ToM sum-score were accompanied by a decrease in growth rate and variability, and a change in skewness of the ToM data, all suggesting a developmental shift in ToM understanding. The temporary decreases also occurred in the different ToM sub-scores and most clearly so in the core ToM component of beliefs. It was also found that girls had an earlier growth spurt than boys and that the underlying developmental path was more salient in girls than in boys. The consequences of these findings are discussed from various theoretical points of view, with an emphasis on a dynamic systems interpretation of the underlying developmental paths. PMID- 28101066 TI - Cognitive Behavioral Group Therapy Reduces Stress and Improves the Quality of Life in Patients with Parkinson's Disease. AB - Objective: The aim of this study is to compare a cognitive behavioral group therapy (CBT) with a health enhancement program (HEP) for stress reduction and the impact on quality of life (QoL) in patients with Parkinson's disease (PD). Method: Thirty patients with PD participated in the study: 16 received CBT including stress-reducing elements and 14 took part in a HEP. The two groups did not differ significantly in their baseline demographic characteristics. The patients in both groups underwent weekly sessions of 2 h duration for 9 weeks. The Parkinson's Disease Questionnaire with 39 items (PDQ-39), the Burden Questionnaire for Parkinson's Disease (translated from the original German: Belastungsfragebogen fur Parkinsonpatienten (BELA) and the Disease-Related Questionnaire [Fragebogen zur krankheitsbezogenen Kommunikation (FKK)] were used for assessment. Ratings were completed at baseline and after 9 weeks (immediately after the last treatment session). Results: The patients in the CBT group achieved significantly better BELA, FKK and PDQ-39 scores (p < 0.05). Subscale analysis revealed that the scores on the BELA subscales "emotional well-being" and "somatic motor function" contributed significantly to stress reduction (p < 0.05). The FKK revealed significant improvement in social skills in the CBT group (p < 0.05). Conclusion: Cognitive Behavioral Group Therapy appears to be an effective way for patients with PD to lessen stress and improve their quality of life. PMID- 28101067 TI - Using a Mixed IRT Model to Assess the Scale Usage in the Measurement of Job Satisfaction. AB - This study investigated the adequacy of a rating scale with a large number of response categories that is often used in panel surveys for assessing diverse aspects of job satisfaction. An inappropriate scale usage is indicative of overstraining respondents and of diminished psychometric scale quality. The mixed Item Response Theory (IRT) approach for polytomous data allows exploring heterogeneous patterns of inappropriate scale usage in form of avoided categories and response styles. In this study, panel data of employees (n = 7036) on five aspects of job satisfaction measured on an 11-point rating scale within the "Household, Income and Labor Dynamics in Australia" (wave 2001) were analyzed. A three-class solution of the restricted mixed generalized partial credit model fit the data best. The results showed that in no class the 11-point scale was appropriately used but that the number of categories used was reduced in all three classes. Respondents of the large class (40%) appropriately differentiate between up to six categories. The two smaller classes (33 and 27%) avoid even more categories and show some kind of extreme response style. Furthermore, classes differ in socio-demographic and job-related factors. In conclusion, a two to six-point scale without the middle point might be more adequate for assessing job satisfaction. PMID- 28101064 TI - Resting-State Functional Connectivity in Autism Spectrum Disorders: A Review. AB - Ongoing debate exists within the resting-state functional MRI (fMRI) literature over how intrinsic connectivity is altered in the autistic brain, with reports of general over-connectivity, under-connectivity, and/or a combination of both. Classifying autism using brain connectivity is complicated by the heterogeneous nature of the condition, allowing for the possibility of widely variable connectivity patterns among individuals with the disorder. Further differences in reported results may be attributable to the age and sex of participants included, designs of the resting-state scan, and to the analysis technique used to evaluate the data. This review systematically examines the resting-state fMRI autism literature to date and compares studies in an attempt to draw overall conclusions that are presently challenging. We also propose future direction for rs-fMRI use to categorize individuals with autism spectrum disorder, serve as a possible diagnostic tool, and best utilize data-sharing initiatives. PMID- 28101068 TI - Heterogeneity of Developmental Dyscalculia: Cases with Different Deficit Profiles. AB - Developmental Dyscalculia (DD) has long been thought to be a monolithic learning disorder that can be attributed to a specific neurocognitive dysfunction. However, recent research has increasingly recognized the heterogeneity of DD, where DD can be differentiated into subtypes in which the underlying cognitive deficits and neural dysfunctions may differ. The aim was to further understand the heterogeneity of developmental dyscalculia (DD) from a cognitive psychological perspective. Utilizing four children (8-9 year-old) we administered a comprehensive cognitive test battery that shed light on the cognitive behavioral profile of each child. The children were compared against norm groups of aged-matched peers. Performance was then contrasted against predominant hypotheses of DD, which would also give insight into candidate neurocognitive correlates. Despite showing similar mathematical deficits, these children showed remarkable interindividual variability regarding cognitive profile and deficits. Two cases were consistent with the approximate number system deficit account and also the general magnitude-processing deficit account. These cases showed indications of having domain-general deficits as well. One case had an access deficit in combination with a general cognitive deficit. One case suffered from general cognitive deficits only. The results showed that DD cannot be attributed to a single explanatory factor. These findings support a multiple deficits account of DD and suggest that some cases have multiple deficits, whereas other cases have a single deficit. We discuss a previously proposed distinction between primary DD and secondary DD, and suggest hypotheses of dysfunctional neurocognitive correlates responsible for the displayed deficits. PMID- 28101069 TI - Novel Metaphors Comprehension in a Child with High-Functioning Autism Spectrum Disorder: A Study on Assessment and Treatment. AB - Until the first decade of the current millennium, the literature on metaphor comprehension highlighted typical difficulties in children with high-functioning Autism Spectrum Disorder (ASD). More recently, some scholars have devised special programs for enhancing the capability of understanding metaphors in these children. This article presents a case study based on a treatment aiming at enhancing novel metaphor comprehension in a high-functioning child with ASD. M.M., a pseudoacronym for an 8;10 year-old boy, diagnosed with high-functioning ASD, was first assessed with a metaphor comprehension test. This testing (at time T0) highlighted a rigid refusal of metaphors and a marked tendency toward literal interpretation. A baseline treatment (8 sessions of 45-60 min each, twice a week) was implemented, based on a series of recognition, denomination and emotion comprehension activities. M.M.'s metaphor comprehension was assessed a second time (T1), followed by the experimental treatment (same duration and frequency as the first one), specifically focused on metaphor comprehension. Finally, a third assessment of metaphor comprehension took place (T2), followed by a last assessment 4 months later (follow-up, T3). The comparison between the performances at the metaphor comprehension test across the four assessments, from T0 to T3, showed that the baseline treatment produced no effect at all, whereas a significant improvement appeared at T2, just after the experimental treatment, later confirmed at the follow up. Both quantitative and qualitative results showed an evident improvement in the way M.M. handled the semantic issues posed by the metaphors of the test, in line with the strategies he was taught during the treatment. PMID- 28101070 TI - Psychotherapy with a 3-Year-Old Child: The Role of Play in the Unfolding Process. AB - Few studies have investigated the outcomes and process of psychodynamic psychotherapies with children. Among the limited number of studies, some only paid attention to play and verbal production, as they are fundamental aspects in assessing the psychotherapy process. This paper focuses on an empirical investigation of a 3-year, once-a-week psychodynamic psychotherapy carried out with a 3-year-old girl. A process-outcome design was implemented to evaluate play and verbal discourse in in the initial, middle, and final parts of 30 psychotherapy sessions. Repeated measurements of standardized play categories (the Play Category System and the Affect in Play Scale-Preschool version) and verbal discourse (Verbal Production) were analyzed. To increase the clinical validity of the study, data from the assessment phase and vignettes from the sessions were reported to deepen the patient's picture during the unfolding therapy process. Parent reports before and after the therapy were also included. Empirically measured changes in play and verbal production were fundamental in evaluating the young patient's psychotherapy process. Verbal production and discourse ability progressively increased and took the place of play, which instead became more symbolic. Developmental issues as well as psychotherapy's influence on the patient's change, were discussed in relation to the role of play in enhancing the development of verbal dialog and the expression of the child's emotions, needs, and desires. PMID- 28101071 TI - Optimism and Hope in Chronic Disease: A Systematic Review. AB - There is a growing recognition that positive psychological functioning (which includes constructs such as optimism and hope) influences health. However, the understanding of these underlying mechanisms in relation to health is limited. Therefore, this review sought to identify what the scientific literature says about the influence of optimism and hope on chronic disease treatment. A search was conducted in the PsycINFO, Scopus, Pubmed, and Web of Science databases using the indexing terms optimism, hope, chronic diseases, randomized controlled trial, and treatment between 1998 and 2015. In the articles, we identified the most studied diseases in context, the assessment instruments used, the participant characteristics investigated, the results found, and the publication dates. From our analysis of the articles that met our inclusion criteria, it appears that the study of these constructs is recent and there is evidence that individuals with greater optimism and hope seek to engage in healthier behaviors, regardless of their clinical status, and that this contributes to chronic disease treatment. More research is needed so that targeted interventions can be carried out effectively in chronic disease treatment. PMID- 28101072 TI - The Freedom to Pursue Happiness: Belief in Free Will Predicts Life Satisfaction and Positive Affect among Chinese Adolescents. AB - A small amount of research has examined the association between the belief in free will and subjective well-being (SWB) among Western laypersons from individualist cultures. However, no study has examined this association among participants from collectivist cultures (e.g., Eastern Asian cultures). Therefore, in this study, we explored this association among two large, independent cohorts of Chinese adolescents (N1 = 1,660; N2 = 639; high school students). The belief in free will was measured by a self-reported questionnaire (Cohorts 1 and 2) and a two-alternative forced choice question regarding the existence of free will (Cohort 2). SWB included cognitive well-being (life satisfaction) and affective well-being (positive and negative affect) in both cohorts. Data analyses indicated that a stronger belief in free will was consistently associated with higher life satisfaction and positive affect in both cohorts. Our investigation provides evidence supporting the cultural generality of the positive effects of believing in free will on SWB. PMID- 28101074 TI - Options for Prospective Meta-Analysis and Introduction of Registration-Based Prospective Meta-Analysis. PMID- 28101073 TI - Cross-Representational Interactions: Interface and Overlap Mechanisms. AB - A crucial question facing cognitive science concerns the nature of conceptual representations as well as the constraints on the interactions between them. One specific question we address in this paper is what makes cross-representational interplay possible? We offer two distinct theoretical scenarios: according to the first scenario, co-activated knowledge representations interact with the help of an interface established between them via congruent activation in a mediating third-party general cognitive mechanism, e.g., attention. According to the second scenario, co-activated knowledge representations interact due to an overlap between their features, for example when they share a magnitude component. First, we make a case for cross-representational interplay based on grounded and situated theories of cognition. Second, we discuss interface-based interactions between distinct (i.e., non-overlapping) knowledge representations. Third, we discuss how co-activated representations may share their architecture via partial overlap. Finally, we outline constraints regarding the flexibility of these proposed mechanisms. PMID- 28101075 TI - Commentary: From 'sense of number' to 'sense of magnitude' - The role of continuous magnitudes in numerical cognition. PMID- 28101076 TI - Psychological Detachment Mediating the Daily Relationship between Workload and Marital Satisfaction. AB - Scholars already demonstrated that psychologically detaching from work after workhours can diminish or avoid the negative effects of job demands on employees' well-being. In this study, we examined a curvilinear relationship between workload and psychological detachment. Moreover, we investigated the moderating influence of an employee's work-home segmentation preference on the relation between detachment and marital satisfaction. In addition, we applied and extended the stressor-detachment model by examining detachment as a mediator of the relation between workload and marital satisfaction. A total of 136 employees participated in our daily diary survey study during 10 consecutive working days. The results of the Bayesian 2-level path analyses revealed a negative linear and curvilinear relationship between workload and psychological detachment on a daily basis. Daily detachment positively related to marital satisfaction, with one's preference to segment work from home reinforcing this relationship. Moreover, psychological detachment fully mediated the daily relationship between workload and marital satisfaction. Implications for practice and suggestions for future research are discussed. PMID- 28101077 TI - Joint Action: Mental Representations, Shared Information and General Mechanisms for Coordinating with Others. AB - In joint action, multiple people coordinate their actions to perform a task together. This often requires precise temporal and spatial coordination. How do co-actors achieve this? How do they coordinate their actions toward a shared task goal? Here, we provide an overview of the mental representations involved in joint action, discuss how co-actors share sensorimotor information and what general mechanisms support coordination with others. By deliberately extending the review to aspects such as the cultural context in which a joint action takes place, we pay tribute to the complex and variable nature of this social phenomenon. PMID- 28101078 TI - Fat Tissue Accretion in Children and Adolescents: Interplay between Food Responsiveness, Gender, and the Home Availability of Snacks. AB - The appetitive trait "food responsiveness" is assumed to be a risk factor for adiposity gain primarily in obesogenic environments. So far, the reported results are inconsistent in school-aged children, possibly because these studies did not take into account important moderators such as gender and the food-environment. In order to better inform caregivers, clinicians and the developers of targeted obesity-prevention interventions on the conditions in which food responsiveness precedes adiposity gain, the current study investigated if this relationship is stronger in girls and in children exposed to a higher home availability of energy dense snacks. Age- and sex-independent Fat and Lean Mass Index z-scores were computed based on air-displacement plethysmography at baseline and after 2 years in a community sample of 129 children (48.8% boys) aged 7.5-14 years at baseline. Parents reported at baseline on children's food responsiveness and the home availability of energy-dense snacks. Food responsiveness was a significant predictor of increases in Fat Mass Index z-scores over 2 years in girls but not boys. The home availability of energy-dense snacks did not significantly moderate the relation of food responsiveness with Fat Mass Index z-score changes. The results suggest that food responsiveness precedes accelerated fat tissue accretion in girls, and may inform targeted obesity-prevention interventions. Further, future research should investigate to which food-environmental parameters children high in food responsiveness mainly respond. PMID- 28101080 TI - Soil Microbiome Is More Heterogeneous in Organic Than in Conventional Farming System. AB - Organic farming system and sustainable management of soil pathogens aim at reducing the use of agricultural chemicals in order to improve ecosystem health. Despite the essential role of microbial communities in agro-ecosystems, we still have limited understanding of the complex response of microbial diversity and composition to organic and conventional farming systems and to alternative methods for controlling plant pathogens. In this study we assessed the microbial community structure, diversity and richness using 16S rRNA gene next generation sequences and report that conventional and organic farming systems had major influence on soil microbial diversity and community composition while the effects of the soil health treatments (sustainable alternatives for chemical control) in both farming systems were of smaller magnitude. Organically managed system increased taxonomic and phylogenetic richness, diversity and heterogeneity of the soil microbiota when compared with conventional farming system. The composition of microbial communities, but not the diversity nor heterogeneity, were altered by soil health treatments. Soil health treatments exhibited an overrepresentation of specific microbial taxa which are known to be involved in soil suppressiveness to pathogens (plant-parasitic nematodes and soil-borne fungi). Our results provide a comprehensive survey on the response of microbial communities to different agricultural systems and to soil treatments for controlling plant pathogens and give novel insights to improve the sustainability of agro ecosystems by means of beneficial microorganisms. PMID- 28101081 TI - Antibacterial Activity and Mechanism of Action of Black Pepper Essential Oil on Meat-Borne Escherichia coli. AB - The aim of this study was to investigate the antibacterial activity of black pepper essential oil (BPEO) on Escherichia coli, further evaluate the potential mechanism of action. Results showed that the minimum inhibition concentration (MIC) of BPEO was 1.0 MUL/mL. The diameter of inhibition zone values were with range from 17.12 to 26.13 mm. 2 * MIC treatments had lower membrane potential and shorter kill-time than 1 * MIC, while control had the highest values. E. coli treated with BPEO became deformed, pitted, shriveled, adhesive, and broken. 2 * MIC exhibited the greatest electric conductivity at 1, 3, 5, 7, 9, 11, and 13 h, leaked DNA materials at 4, 8, 12, 16, 20, 24, and 28 h, proteins at 4, 6, 8, 10, 12, 14, and 16 h, potassium ion at 0, 0.5, 1, 1.5, and 2 h, phosphate ion at 0.5, 1, 1.5, and 2 h and ATP (P < 0.05); 1 * MIC had higher values than control. BPEO led to the leakage, disorder and death by breaking cell membrane. This study suggested that the BPEO has potential as the natural antibacterial agent in meat industry. PMID- 28101079 TI - A Disease Model of Muscle Necrosis Caused by Aeromonas dhakensis Infection in Caenorhabditis elegans. AB - A variety of bacterial infections cause muscle necrosis in humans. Caenorhabditis elegans has epidermis and bands of muscle that resemble soft-tissue structures in mammals and humans. Here, we developed a muscle necrosis model caused by Aeromonas dhakensis infection in C. elegans. Our data showed that A. dhakensis infected and killed C. elegans rapidly. Characteristic muscle damage in C. elegans induced by A. dhakensis was demonstrated in vivo. Relative expression levels of host necrosis-associated genes, asp-3, asp-4, and crt-1 increased significantly after A. dhakensis infection. The RNAi sensitive NL2099 rrf-3 (pk1426) worms with knockdown of necrosis genes of crt-1 and asp-4 by RNAi showed prolonged survival after A. dhakensis infection. Specifically knockdown of crt-1 and asp-4 by RNAi in WM118 worms, which restricted RNAi only to the muscle cells, conferred significant resistance to A. dhakensis infection. In contrast, the severity of muscle damage and toxicity produced by the A. dhakensis hemolysin deletion mutant is attenuated. In another example, shiga-like toxin-producing enterohemorrhagic E. coli (EHEC) known to elicit toxicity to C. elegans with concomitant enteropathogenicty, did not cause muscle necrosis as A. dhakensis did. Taken together, these results show that Aeromonas infection induces muscle necrosis and rapid death of infected C. elegans, which are similar to muscle necrosis in humans, and then validate the value of the C. elegans model with A. dhakensis infection in studying Aeromonas pathogenicity. PMID- 28101082 TI - Improved Culture Medium (TiKa) for Mycobacterium avium Subspecies Paratuberculosis (MAP) Matches qPCR Sensitivity and Reveals Significant Proportions of Non-viable MAP in Lymphoid Tissue of Vaccinated MAP Challenged Animals. AB - The quantitative detection of viable pathogen load is an important tool in determining the degree of infection in animals and contamination of foodstuffs. Current conventional culture methods are limited in their ability to determine these levels in Mycobacterium avium subspecies paratuberculosis (MAP) due to slow growth, clumping and low recoverability issues. The principle goal of this study was to evaluate a novel culturing process (TiKa) with unique ability to stimulate MAP growth from low sample loads and dilutions. We demonstrate it was able to stimulate a mean 29-fold increase in recoverability and an improved sensitivity of up to three logs when compared with conventional culture. Using TiKa culture, MAP clumping was minimal and produced visible colonies in half the time required by standard culture methods. Parallel quantitative evaluation of the TiKa culture approach and qPCR on MAP loads in tissue and gut mucosal samples from a MAP vaccine-challenge study, showed good correlations between colony counts (cfu) and qPCR derived genome equivalents (Geq) over a large range of loads with a 30% greater sensitivity for TiKa culture approach at low loads (two logs). Furthermore, the relative fold changes in Geq and cfu from the TiKa culture approach suggests that non-mucosal tissue loads from MAP infected animals contained a reduced proportion of non-viable MAP (mean 19-fold) which was reduced significantly further (mean 190-fold) in vaccinated "reactor" calves. This study shows TiKa culture equates well with qPCR and provides important evidence that accuracy in estimating viable MAP load using DNA tests alone may vary significantly between samples of mucosal and lymphatic origin. PMID- 28101083 TI - The Role of Microbes in the Nutrition of Detritivorous Invertebrates: A Stoichiometric Analysis. AB - Detritus represents an important pool in the global carbon cycle, providing a food source for detritivorous invertebrates that are conspicuous components of almost all ecosystems. Our knowledge of how these organisms meet their nutritional demands on a diet that is typically comprised of refractory, carbon rich compounds nevertheless remains incomplete. "Trophic upgrading" of detritus by the attached microbial community (enhancement of zooplankton diet by the inclusion of heterotrophic protozoans) represents a potential source of nutrition for detritivores as both bacteria and their flagellated protistan predators are capable of biosynthesizing essential micronutrients such as polyunsaturated fatty acids (PUFAs). There is however a trade-off because although microbes enhance the substrate in terms of its micronutrient content, the quantity of organic carbon is diminished though metabolic losses as energy passes through the microbial food web. Here, we develop a simple stoichiometric model to examine this trade-off in the nutrition of detritivorous copepods inhabiting the mesopelagic zone of the ocean, focusing on their requirements for carbon and an essential PUFA, docosahexaenoic acid (DHA). Results indicate that feeding on microbes may be a highly favorable strategy for these invertebrates, although the potential for carbon to become limiting when consuming a microbial diet exists because of the inefficiencies of trophic transfer within the microbial food web. Our study highlights the need for improved knowledge at the detritus-microbe-metazoan interface, including interactions between the physiology and ecology of the associated organisms. PMID- 28101084 TI - A Novel Multi-domain High Molecular, Salt-Stable Alkaline Xylanase from Alkalibacterium sp. SL3. AB - A novel multi-domain high molecular xylanase coding gene (xynSL3) was cloned from Alkalibacterium sp. SL3, an alkaliphilic bacterial strain isolated from the sediment of soda lake Dabusu. The deduced XynSL3 is composed of a putative signal peptide, three tandem domains of carbohydrate binding module (CBM) family 22, a catalytic domain of glycosyl hydrolase (GH) family 10 and a domain of CBM9. XynSL3 shares the highest identity of 66% to a hypothetical protein from Alkalibacterium sp. AK22 and has low identities (33-45%) with other functionally characterized xylanases. The gene xynSL3 was expressed heterologously in Escherichia coli and the recombinant enzyme demonstrated some particular characteristics. Purified recombinant XynSL3 (rXynSL3) was highly active and stable over the neutral and alkaline pH ranges from 7.0 to 12.0, with maximum activity at pH 9.0 and around 45% activity at pH 12.0. It had an apparent temperature optimum of 55 degrees C and was stable at 50 degrees C. The rXynSL3 was highly halotolerant, retaining more than 60% activity with 3 M NaCl and was stable at up to a 4 M concentration of NaCl. The hydrolysis products of rXynSL3 from corncob xylan were mainly xylobiose and xylotetraose. The activity of rXynSL3 was enhanced by Ca2+ and it has strong resistance to sodium dodecyl sulfate (SDS). This multi-domain, alkaline and salt-tolerant enzyme has great potential for basic research and industrial applications such as the biobleaching of paper pulp and production of xylo-oligosaccharides (XOS). PMID- 28101085 TI - The Identification of Intrinsic Chloramphenicol and Tetracycline Resistance Genes in Members of the Bacillus cereus Group (sensu lato). AB - Bacillus toyonensis strain BCT-7112T (NCIMB 14858T) has been widely used as an additive in animal nutrition for more than 30 years without reports of adverse toxigenic effects. However, this strain is resistant to chloramphenicol and tetracycline and it is generally considered inadvisable to introduce into the food chain resistance determinants capable of being transferred to other bacterial strains, thereby adding to the pool of such determinants in the gastro enteric systems of livestock species. We therefore characterized the resistance phenotypes of this strain and its close relatives to determine whether they were of recent origin, and therefore likely to be transmissible. To this end we identified the genes responsible for chloramphenicol (catQ) and tetracycline (tetM) resistance and confirmed the presence of homologs in other members of the B. toyonensis taxonomic unit. Unexpectedly, closely related strains encoding these genes did not exhibit chloramphenicol and tetracycline resistance phenotypes. To understand the differences in the behaviors, we cloned and expressed the genes, together with their upstream regulatory regions, into Bacillus subtilis. The data showed that the genes encoded functional proteins, but were expressed inefficiently from their native promoters. B. toyonensis is a taxonomic unit member of the Bacillus cereus group (sensu lato). We therefore extended the analysis to determine the extent to which homologous chloramphenicol and tetracycline resistance genes were present in other species within this group. This analysis revealed that homologous genes were present in nearly all representative species within the B. cereus group (sensu lato). The absence of known transposition elements and the observations that they are found at the same genomic locations, indicates that these chloramphenicol and tetracycline resistance genes are of ancient origin and intrinsic to this taxonomic group, rather than recent acquisitions. In this context we discuss definitions of what are and are not intrinsic genes, an issue that is of fundamental importance to both Regulatory Authorities, and the animal feed and related industries. PMID- 28101086 TI - Characterization of Gut Microbiome Dynamics in Developing Pekin Ducks and Impact of Management System. AB - Little to no research has been conducted on the gut microbiome of the Pekin duck, yet over 24.5 million ducks are raised for human consumption each year in the United States alone. Knowledge of the microbiome could lead to an understanding of the effects of growing conditions such as the use of prebiotics, probiotics, and enzymes in feeding practices, the use of antibiotics, and the sources of pathogenic bacteria in diseased ducks. In order to characterize changes in the caecal microbiome that occur as ducks develop through a typical industry grow-out period, a 16S rRNA community analysis of caecal contents collected over a 6-week period was conducted using a next generation sequencing approach. Transitions in the composition of the caecal microbiome occurred throughout the lifespan, with a large shift during days 4 through 10 posthatch. Two major phyla of bacteria were found to be present within the caeca of aviary raised ducks, with the relative abundance of each phylum varying by age of the duck. Proteobacteria is dominant for the first 3 days of age, and Firmicutes increases and dominates beginning at day 4. Barn raised ducks contained a significant population of Bacteroidetes in addition to Proteobacteria and Firmicutes at later developmental time points, though this phylum was absent in aviary raised ducks. Genera containing pathogens of anseriformes most often found in industry settings were either absent or found as normal parts of the caecal microbial populations. The high level differences in phylum abundance highlight the importance of well-designed sampling strategies for microbiome based studies. Results showed clear distinctions between Pekin Duck caecal contents and those of Broiler Chickens and Turkey in a qualitative comparison. These data provide a reference point for studies of the Pekin Duck through industry grow-out ages, provide a foundation for understanding the types of bacteria that promote health, and may lead to improved methods to increase yields and decrease instances of disease in agricultural production processes. PMID- 28101087 TI - Rice Stripe Mosaic Virus, a Novel Cytorhabdovirus Infecting Rice via Leafhopper Transmission. AB - A new rice viral disease exhibiting distinct symptoms-yellow stripes, mosaic and twisted tips on leaves-was found in China. Electron microscopy of infected leaf cells revealed the presence of bacilliform virions and electron-translucent granular-fibrillar viroplasm in the cytoplasm. The enveloped viral particles were 300 to 375 nm long and 45 to 55 nm wide. The leafhopper Recilia dorsalis was able to transmit the virus to rice seedlings, which subsequently exhibited symptoms similar to those observed in fields. The complete genome of the virus was obtained by small-RNA deep sequencing and reverse transcription-PCR product sequencing. The anti-genome contains seven open reading frames (ORFs). The deduced amino acids of ORF1, ORF5, and ORF7 are, respectively, homologous to the nucleocapsid protein (N), glycoprotein (G), and large polymerase protein (L) of known rhabdoviruses. The predicted product of ORF2 is identified as a phosphoprotein (P) based on its multiple potential phosphorylation sites and 12.6 to 21.0% amino acid (aa) identities with the P proteins of plant rhabdoviruses. The product of ORF4 is presumed to be the viral matrix (M) protein for it shares 10.3 to 14.3% aa identities with those of other rhabdoviruses. The above five products were confirmed as the viral structural proteins by SDS-PAGE and aa sequencing analyses of purified virus preparation. ORF3 and ORF6 are considered to encode two nonstructural proteins with unknown functions. Phylogenetic analysis based on protein N, G, and L amino acid sequences indicated that the isolated virus, which we have tentatively named Rice stripe mosaic virus (RSMV), is a new species in the genus Cytorhabdovirus. To our knowledge, RSMV is the only cytorhabdovirus naturally infecting rice and the first reported leafhopper transmitted cytorhabdovirus. Our surveys of rice fields indicate that RSMV occurs frequently in Guangdong Province, China. Although the disease incidence is low at present, it might become serious with the vector insect population increasing. PMID- 28101088 TI - Laser Capture Microdissection Protocol for Xylem Tissues of Woody Plants. AB - Laser capture microdissection (LCM) enables precise dissection and collection of individual cell types from complex tissues. When applied to plant cells, and especially to woody tissues, LCM requires extensive optimization to overcome such factors as rigid cell walls, large central vacuoles, intercellular spaces, and technical issues with thickness and flatness of the sections. Here we present an optimized protocol for the laser-assisted microdissection of developing xylem from mature trees: a gymnosperm (Norway spruce, Picea abies) and an angiosperm (aspen, Populus tremula) tree. Different cell types of spruce and aspen wood (i.e., ray cells, tracheary elements, and fibers) were successfully microdissected from tangential, cross and radial cryosections of the current year's growth ring. Two approaches were applied to achieve satisfactory flatness and anatomical integrity of the spruce and aspen specimens. The commonly used membrane slides were ineffective as a mounting surface for the wood cryosections. Instead, in the present protocol we use glass slides, and introduce a glass slide sandwich assembly for the preparation of aspen sections. To ascertain that not only the anatomical integrity of the plant tissue, but also the molecular features were not compromised during the whole LCM procedure, good quality total RNA could be extracted from the microdissected cells. This showed the efficiency of the protocol and established that our methodology can be integrated in transcriptome analyses to elucidate cell-specific molecular events regulating wood formation in trees. PMID- 28101089 TI - Identification and Analysis of MS5d: A Gene That Affects Double-Strand Break (DSB) Repair during Meiosis I in Brassica napus Microsporocytes. AB - Here, we report the identification of the Brassica-specific gene MS5d, which is responsible for male sterility in Brassica napus. The MS5d gene is highly expressed in the microsporocyte and encodes a protein that localizes to the nucleus. Light microscopy analyses have demonstrated that the MS5d gene affects microsporocyte meiosis in the thermosensitive genic male sterility line TE5A. Sequence comparisons and genetic complementation revealed a C-to-T transition in MS5d, encoding a Leu-to-Phe (L281F) substitution and causing abnormal male meiosis in TE5A. These findings suggest arrested meiotic chromosome dynamics at pachytene. Furthermore, immunofluorescence analyses showed that double-strand break (DSB) formation and axial elements were normal but that DSB repair and spindle behavior were aberrant in TE5A meiocytes. Collectively, our results indicate that MS5d likely encodes a protein required for chromosomal DSB repair at early stages of meiosis in B. napus. PMID- 28101091 TI - Conservation of Indigenous Vegetables from a Hotspot in Tropical Asia: What Did We Learn from Vavilov? PMID- 28101090 TI - Transcriptome Analysis of Chilling-Imbibed Embryo Revealed Membrane Recovery Related Genes in Maize. AB - The delayed seed germination and poor seedling growth caused by imbibitional chilling injury was common phenomenon in maize seedling establishment. In this study, RNA sequencing technology was used to comprehensively investigate the gene expressions in chilling-imbibed maize embryo and to reveal the underlying mechanism of chilling injury at molecular level. Imbibed seeds for 2 h at 5 degrees C (LT2) were selected and transcriptomic comparative analysis was performed. Among 327 DEGs indentified between dry seed (CK0) and LT2, 15 specific genes with plasma membrane (PM) relevant functions belonging to lipid metabolism, stress, signaling and transport were characterized, and most of them showed down regulation pattern under chilling stress. When transferred to 25 degrees C for recovery (LT3), remarkable changes occurred in maize embryo. There were 873 DEGs including many PM related genes being identified between LT2 and LT3, some of which showing significant increase after 1 h recovery. Moreover, 15 genes encoding intracellular vesicular trafficking proteins were found to be exclusively differential expressed at recovery stage. It suggested that the intracellular vesicle trafficking might be essential for PM recovery through PM turnover. Furthermore, transcriptome analyses on imbibed embryos under normal condition (25 degrees C) were also made as a contrast. A total of 651 DEGs were identified to mainly involved in protein metabolism, transcriptional regulation, signaling, and energy productions. Overall, the RNA-Seq results provided us a deep knowledge of imbibitional chilling injury on plasma membrane and a new view on PM repaired mechanism during early seed imbibition at transcriptional level. The DEGs identified in this work would be useful references in future seed germination research. PMID- 28101092 TI - Frameshift Mutation Confers Function as Virulence Factor to Leucine-Rich Repeat Protein from Acidovorax avenae. AB - Many plant pathogens inject type III (T3SS) effectors into host cells to suppress host immunity and promote successful infection. The bacterial pathogen Acidovorax avenae causes brown stripe symptom in many species of monocotyledonous plants; however, individual strains of each pathogen infect only one host species. T3SS deleted mutants of A. avenae K1 (virulent to rice) or N1141 (virulent to finger millet) caused no symptom in each host plant, suggesting that T3SS effectors are involved in the symptom formation. To identify T3SS effectors as virulence factors, we performed whole-genome and predictive analyses. Although the nucleotide sequence of the novel leucine-rich repeat protein (Lrp) gene of N1141 had high sequence identity with K1 Lrp, the amino acid sequences of the encoded proteins were quite different due to a 1-bp insertion within the K1 Lrp gene. An Lrp-deleted K1 strain (KDeltaLrp) did not cause brown stripe symptom in rice (host plant for K1); by contrast, the analogous mutation in N1141 (NDeltaLrp) did not interfere with infection of finger millet. In addition, NDeltaLrp retained the ability to induce effector-triggered immunity (ETI), including hypersensitive response cell death and expression of ETI-related genes. These data indicated that K1 Lrp functions as a virulence factor in rice, whereas N1141 Lrp does not play a similar role in finger millet. Yeast two-hybrid screening revealed that K1 Lrp interacts with oryzain alpha, a pathogenesis-related protein of the cysteine protease family, whereas N1141 Lrp, which contains LRR domains, does not. This specific interaction between K1 Lrp and oryzain alpha was confirmed by Bimolecular fluorescence complementation assay in rice cells. Thus, K1 Lrp protein may have acquired its function as virulence factor in rice due to a frameshift mutation. PMID- 28101093 TI - Evaluation of the SeedCounter, A Mobile Application for Grain Phenotyping. AB - Grain morphometry in cereals is an important step in selecting new high-yielding plants. Manual assessment of parameters such as the number of grains per ear and grain size is laborious. One solution to this problem is image-based analysis that can be performed using a desktop PC. Furthermore, the effectiveness of analysis performed in the field can be improved through the use of mobile devices. In this paper, we propose a method for the automated evaluation of phenotypic parameters of grains using mobile devices running the Android operational system. The experimental results show that this approach is efficient and sufficiently accurate for the large-scale analysis of phenotypic characteristics in wheat grains. Evaluation of our application under six different lighting conditions and three mobile devices demonstrated that the lighting of the paper has significant influence on the accuracy of our method, unlike the smartphone type. PMID- 28101094 TI - RNA-Guided Cas9-Induced Mutagenesis in Tobacco Followed by Efficient Genetic Fixation in Doubled Haploid Plants. AB - Customizable endonucleases are providing an effective tool for genome engineering. The resulting primary transgenic individuals (T0) are typically heterozygous and/or chimeric with respect to any mutations induced. To generate genetically fixed mutants, they are conventionally allowed to self-pollinate, a procedure which segregates individuals into mutant heterozygotes/homozygotes and wild types. The chances of recovering homozygous mutants among the progeny depend not only on meiotic segregation but also on the frequency of mutated germline cells in the chimeric mother plant. In Nicotiana species, the heritability of Cas9-induced mutations has not been demonstrated yet. RNA-guided Cas9 endonuclease-mediated mutagenesis was targeted to the green fluorescent protein (GFP) gene harbored by a transgenic tobacco line. Upon retransformation using a GFP-specific guide RNA/Cas9 construct, the T0 plants were allowed to either self pollinate, or were propagated via regeneration from in vitro cultured embryogenic pollen which give rise to haploid/doubled haploid plants or from leaf explants that form plants vegetatively. Single or multiple mutations were detected in 80% of the T0 plants. About half of these mutations proved heritable via selfing. Regeneration from in vitro cultured embryogenic pollen allowed for homozygous mutants to be produced more efficiently than via sexual reproduction. Consequently, embryogenic pollen culture provides a convenient method to rapidly generate a variety of genetically fixed mutants following site-directed mutagenesis. The recovery of a mutation not found among sexually produced and analyzed progeny was shown to be achievable through vegetative plant propagation in vitro, which eventually resulted in heritability when the somatic clones were selfed. In addition, some in-frame mutations were associated with functional attenuation of the target gene rather than its full knock-out. The generation of mutants with compromised rather than abolished gene functionality holds promise for future approaches to the conclusive functional validation of genes which are indispensible for the plant. PMID- 28101095 TI - Ascorbate Alleviates Fe Deficiency-Induced Stress in Cotton (Gossypium hirsutum) by Modulating ABA Levels. AB - Fe deficiency causes significant losses to crop productivity and quality. To understand better the mechanisms of plant responses to Fe deficiency, we used an in vitro cotton ovule culture system. We found that Fe deficiency suppressed the development of ovules and fibers, and led to tissue browning. RNA-seq analysis showed that the myo-inositol and galacturonic acid pathways were activated and cytosolic APX (ascorbate peroxidase) was suppressed in Fe-deficient treated fibers, which increased ASC (ascorbate) concentrations to prevent tissue browning. Suppression of cytosolic APX by RNAi in cotton increased ASC contents and delayed tissue browning by maintaining ferric reduction activity under Fe deficient conditions. Meanwhile, APX RNAi line also exhibited the activation of expression of iron-regulated transporter (IRT1) and ferric reductase-oxidase2 (FRO2) to adapt to Fe deficiency. Abscisic acid (ABA) levels were significantly decreased in Fe-deficient treated ovules and fibers, while the upregulated expression of ABA biosynthesis genes and suppression of ABA degradation genes in Fe-deficient ovules slowed down the decreased of ABA in cytosolic APX suppressed lines to delay the tissue browning. Moreover, the application of ABA in Fe deficient medium suppressed the development of tissue browning and completely restored the ferric reduction activity. In addition, ABA 8'-hydroxylase gene (GhABAH1) overexpressed cotton has a decreased level of ABA and shows more sensitivity to Fe deficiency. Based on the results, we speculate that ASC could improve the tolerance to Fe deficiency through activating Fe uptake and maintaining ABA levels in cotton ovules and fibers, which in turn reduces symptom formation. PMID- 28101096 TI - New Candidate Genes Affecting Rice Grain Appearance and Milling Quality Detected by Genome-Wide and Gene-Based Association Analyses. AB - Appearance and milling quality are two crucial properties of rice grains affecting its market acceptability. Understanding the genetic base of rice grain quality could considerably improve the high quality breeding. Here, we carried out an association analysis to identify QTL affecting nine rice grain appearance and milling quality traits using a diverse panel of 258 accessions selected from 3K Rice Genome Project and evaluated in two environments Sanya and Shenzhen. Genome-wide association analyses using 22,488 high quality SNPs identified 72 QTL affecting the nine traits. Combined gene-based association and haplotype analyses plus functional annotation allowed us to shortlist 19 candidate genes for seven important QTL regions affecting the grain quality traits, including two cloned genes (GS3 and TUD), two fine mapped QTL (qGRL7.1 and qPGWC7) and three newly identified QTL (qGL3.4, qGW1.1, and qGW10.2). The most likely candidate gene(s) for each important QTL were also discussed. This research demonstrated the superior power to shortlist candidate genes affecting complex phenotypes by the strategy of combined GWAS, gene-based association and haplotype analyses. The identified candidate genes provided valuable sources for future functional characterization and genetic improvement of rice appearance and milling quality. PMID- 28101097 TI - C1 Metabolism Inhibition and Nitrogen Deprivation Trigger Triacylglycerol Accumulation in Arabidopsis thaliana Cell Cultures and Highlight a Role of NPC in Phosphatidylcholine-to-Triacylglycerol Pathway. AB - Triacylglycerol (TAG) accumulation often occurs in growth limiting conditions such as nutrient deprivations. We analyzed and compared the lipid contents of Arabidopsis cells grown under two conditions that inhibited growth as a way to study interactions between membrane and storage lipids. In order to inhibit C1 metabolism, the first condition utilized methotrexate (MTX), a drug that inhibits methyl transfer reactions and potentially reduces Pi-choline synthesis, the polar head of phosphatidylcholine (PC). MTX-treated cells displayed a 10- to 15-fold increase in TAG compared to that found in control cells. This corresponded to a net increase of lipids as the total amount of membrane glycerolipids was minimally affected. Under this condition, PC homeostasis appeared tightly regulated and not strictly dependent on the rate of Pi-choline synthesis. The second condition we investigated involved nitrogen deprivation. Here, we observed a 40-fold increase of TAG. In these cells, the overall lipid content remained unchanged, but membrane lipids decreased by a factor of two suggesting a reduction of the membrane network and a rerouting of membrane lipids to storage lipids. Under all conditions, fatty acid (FA) analyses showed that the FA composition of TAG was comparable to that in PC, but different from that in acyl CoA, suggesting that TAG accumulation involved PC-derived DAG moieties. In agreement, analyses by qPCR of genes coding for TAG synthesis showed a strong increase of non-specific phospholipase C (NPC) expressions, and experiments using labeled (fluorescent) PC indicated higher rates of PC-to-TAG conversion under both situations. These results highlight a role for NPC in plant cell oil production. PMID- 28101098 TI - Phylogenetic and Taxonomic Status Analyses of the Abaso Section from Multiple Nuclear Genes and Plastid Fragments Reveal New Insights into the North America Origin of Populus (Salicaceae). AB - Although, the Abaso section is widely accepted as an independent section, the taxonomic status of Populus mexicana (section Abaso) has not yet been resolved due to the limited availability markers and/or the lack of P. mexicana specimens in previous studies. Thirty-one poplar species that represent six sections of the Populus genus were sampled, and 23 single-copy nuclear DNA and 34 chloroplast fragments were sequenced. The present study obtained two updated phylogenies of Populus. We found that monophyly of the genus Populus is strongly supported by nuclear and plastid gene, which is consistent with previous studies. P. mexicana, diverged first in the nuclear DNA tree, which occupied the basal position, implying that the section Abaso may be the most ancestral lineage in extant populous species. Given that the short branches and low statistical support for the divergence of sections Abaso and Turanga, this observation probably indicated that a rapid radiation evolution following the early split of the genus Populus. In the plastid tree, P. mexicana clustered with modern-day species of section Tacamahaca in the plastid tree. Based on cytoplasmic and single-copy nuclear marker sequences, we hypothesized that chloroplast capture resulted in the inconsistent position of P. mexicana between the phylogenetic trees. Given the first unequivocal records of poplar fossils from the Eocene with similar leaf morphology to the extant P. mexicana and the phylogenetic positions of P. mexicana in our study, we support the hypothesis that the Populus genus originated in North America, which will provide new insights to the development of the origin of Populus species. PMID- 28101099 TI - Magnetic Resonance Volumetry: Prediction of Subjective Memory Complaints and Mild Cognitive Impairment, and Associations with Genetic and Cardiovascular Risk Factors. AB - BACKGROUND/AIMS: Subjective memory complaints (SMC) are strong predictors of mild cognitive impairment (MCI) and subsequent Alzheimer's disease. Our aims were to see if fully automated cerebral MR volume measurements could distinguish subjects with SMC and MCI from controls, and if probable parental late-onset Alzheimer's disease (LOAD), apolipoprotein E epsilon4 genotype, total plasma homocysteine, and cardiovascular risk factors were associated with MR volumetric findings. METHODS: 198 stroke-free subjects comprised the control (n = 58), the SMC (n = 25) and the MCI (n = 115) groups. Analysis of covariance and receiver operating characteristic curve was used to see if MR volumetry distinguished subjects with SMC and MCI from controls. RESULTS: Subjects with SMC and MCI had significantly larger lateral ventricles and smaller hippocampal volumes than controls. The area under the curve in subjects with SMC and MCI compared to that of controls was less than 0.68 for all volumes of intracranial structures. There was an interaction between sex and probable parental LOAD for hippocampal volume, with a significant association between probable parental LOAD and hippocampal volume in women. CONCLUSIONS: Fully automated MR volumetry can distinguish subjects with SMC and MCI from controls in a general population, but insufficiently to assume a clear clinical role. Research on sporadic LOAD might benefit from a sex-specific search for genetic risk factors. PMID- 28101100 TI - The Utility of the Mini-Addenbrooke's Cognitive Examination as a Screen for Cognitive Impairment in Elderly Patients with Chronic Kidney Disease and Diabetes. AB - BACKGROUND/AIMS: We tested the utility of the Mini-Addenbrooke's Cognitive Examination (M-ACE) in a cohort of older adults with chronic kidney disease (CKD) and diabetes. METHOD: The M-ACE was administered to 112 CKD and diabetes patients attending a nephrology clinic. Cognitive impairment was based upon patient, informant, and case review, neuropsychological assessment, and application of criteria for mild cognitive impairment (MCI) and the Diagnostic and Statistical Manual of Mental Disorders, fifth edition for dementia. The M-ACE was also compared to the Mini-Mental State Examination (MMSE). RESULTS: Upon assessment, 52 patients had normal cognitive function, 33 had MCI, and 27 had dementia. The area under the receiver operating curve for the M-ACE was 0.96 (95% CI 0.95 1.00). The sensitivity and specificity for a dementia diagnosis were 0.96 and 0.84 at the cut point <25 and 0.70 and 1.00 at the cut point <21. Mean M-ACE scores differed significantly between normal, demented, and MCI groups (p < 0.001), and compared to the MMSE, the M-ACE did not suffer from ceiling effects. CONCLUSION: The M-ACE is an easily administered test with good sensitivity and specificity to capture and assist in the diagnosis of MCI or dementia in patients with CKD and diabetes. PMID- 28101102 TI - Brain-Derived Neurotrophic Factor Serum Levels and Hippocampal Volume in Mild Cognitive Impairment and Dementia due to Alzheimer Disease. AB - BACKGROUND/AIMS: Hippocampal atrophy is a recognized biomarker of Alzheimer disease (AD) pathology. Serum brain-derived neurotrophic factor (BDNF) reduction has been associated with neurodegeneration. We aimed to evaluate BDNF serum levels and hippocampal volume in clinical AD (dementia and mild cognitive impairment [MCI]). METHODS: Participants were 10 patients with MCI and 13 with dementia due to AD as well as 10 healthy controls. BDNF serum levels were determined by ELISA and volumetric measures with NeuroQuant(r). RESULTS: MCI and dementia patients presented lower BDNF serum levels than healthy participants; dementia patients presented a smaller hippocampal volume than MCI patients and healthy participants. DISCUSSION: The findings support that the decrease in BDNF might start before the establishment of neuronal injury expressed by the hippocampal reduction. PMID- 28101101 TI - Predictive Factors of Rapid Cognitive Decline in Patients with Alzheimer Disease. AB - AIM: To determine predictive factors associated with rapid cognitive decline (RCD) in elderly patients suffering from Alzheimer disease (AD). METHODS: Patients suffering from mild to moderate AD were included. RCD was defined as the loss of at least 3 points on the Mini-Mental State Examination (MMSE) over 12 months. Factors associated with RCD were identified by logistic regression. RESULTS: Among 123 patients included, 61 were followed up until 12 months. RCD occurred in 46% of patients (n = 28). Polymedication (p < 0.0001), the fact that the caregiver was the child or spouse of the patient (p < 0.0001) and autonomy for washing (p < 0.0001) were protective factors against RCD, while the presence of caregiver burden (p < 0.0001) was shown to be a risk factor for RCD. CONCLUSION: Early detection of the RCD risk in AD patients could make it possible to anticipate the patient's medical needs and adjust the care plan for caregiver burden. PMID- 28101103 TI - Albumin Binding Function: The Potential Earliest Indicator for Liver Function Damage. AB - Background. Currently there is no indicator that can evaluate actual liver lesion for early stages of viral hepatitis, nonalcoholic fatty liver disease (NAFLD), and cirrhosis. Aim of this study was to investigate if albumin binding function could better reflect liver function in these liver diseases. Methods. An observational study was performed on 193 patients with early NAFLD, viral hepatitis, and cirrhosis. Cirrhosis patients were separated according to Child Pugh score into A, B, and C subgroup. Albumin metal ion binding capacity (Ischemia-modified albumin transformed, IMAT) and fatty acid binding capacity (total binding sites, TBS) were detected. Results. Both IMAT and TBS were significantly decreased in patients with NAFLD and early hepatitis. In hepatitis group, they declined prior to changes of liver enzymes. IMAT was significantly higher in cirrhosis Child-Pugh class A group than hepatitis patients and decreased in Child-Pugh class B and class C patients. Both IMAT/albumin and TBS/albumin decreased significantly in hepatitis and NAFLD group patients. Conclusions. This is the first study to discover changes of albumin metal ion and fatty acid binding capacities prior to conventional biomarkers for liver damage in early stage of liver diseases. They may become potential earliest sensitive indicators for liver function evaluation. PMID- 28101104 TI - Application of Long-Range Surface Plasmon Resonance for ABO Blood Typing. AB - In this study, we demonstrate a long-range surface plasmon resonance (LR-SPR) biosensor for the detection of whole cell by captured antigens A and B on the surface of red blood cells (RBCs) as a model. The LR-SPR sensor chip consists of high-refractive index glass, a Cytop film layer, and a thin gold (Au) film, which makes the evanescent field intensity and the penetration depth longer than conventional SPR. Therefore, the LR-SPR biosensor has improved capability for detecting large analytes, such as RBCs. The antibodies specific to blood group A and group B (Anti-A and Anti-B) are covalently immobilized on a grafting self assembled monolayer (SAM)/Au surface on the biosensor. For blood typing, RBC samples can be detected by the LR-SPR biosensor through a change in the refractive index. We determined that the results of blood typing using the LR-SPR biosensor are consistent with the results obtained from the agglutination test. We obtained the lowest detection limits of 1.58 * 105 cells/ml for RBC-A and 3.83 * 105 cells/ml for RBC-B, indicating that the LR-SPR chip has a higher sensitivity than conventional SPR biosensors (3.3 * 108 cells/ml). The surface of the biosensor can be efficiently regenerated using 20 mM NaOH. In summary, as the LR-SPR technique is sensitive and has a simple experimental setup, it can easily be applied for ABO blood group typing. PMID- 28101105 TI - Oral Administration of Lactobacillus plantarum 299v Reduces Cortisol Levels in Human Saliva during Examination Induced Stress: A Randomized, Double-Blind Controlled Trial. AB - Objective. To clarify the effect of Lactobacillus plantarum 299v on the salivary cortisol and salivary IgA levels in young adults under examination stress. Design. Forty-one students with an upcoming academic exam were included in a randomized double-blind, placebo-controlled study. The probiotic bacteria or the placebo product was administered in capsules once a day during 14 days. Saliva was collected and a perceived stress test was filled out at each sampling occasion. Saliva was collected for cortisol analysis by Electrochemiluminescence Immunoassay (ECLI) and salivary IgA was analysed by Enzyme-Linked Immunosorbent Assay (ELISA). Abundance of lactobacilli was evaluated by cultivation of saliva on selective medium and identification of L. plantarum 299v was done on randomly selected colonies by a random amplification of polymorphic DNA (RAPD) typing. Results. A significant difference in cortisol levels was found between the treatment group and the placebo group (P < 0.05), together with a significant increase in levels of lactobacilli in the treatment group compared with the placebo group (P < 0.001). No significant changes were found for salivary IgA. Conclusion. A probiotic bacterium with ability to reduce symptoms of irritable bowel syndrome (IBS) prohibited increased levels of the stress marker cortisol during the examination period. The registration number of the study is NCT02974894, and the study is registered at ClinicalTrials.gov. PMID- 28101106 TI - Multiport Combined Endoscopic Approach to Nonembolized Juvenile Nasopharyngeal Angiofibroma with Parapharyngeal Extension: An Emerging Concept. AB - Background. Surgical approaches to the parapharyngeal space (PPS) are challenging by virtue of deep location and neurovascular content. Juvenile Nasopharyngeal Angiofibroma (JNA) is a formidable hypervascular tumor that involves multiple compartments with increase in size. In tumors with extension to parapharyngeal space, the endonasal approach was observed to be inadequate. Combined Endoscopic Endonasal Approaches and Endoscopic Transoral Surgery (EEA-ETOS) approach has provided a customized alternative of multicorridor approach to access JNA for its safe and efficient resection. Methods. The study demonstrates a case series of patients of JNA with prestyloid parapharyngeal space extension operated by endoscopic endonasal and endoscopic transoral approach for tumor excision. Results. The multiport EEA-ETOS approach was used to provide wide exposure to access JNA in parapharyngeal space. No major complications were observed. No conversion to external approach was required. Postoperative morbidity was low and postoperative scans showed no residual tumor. A one-year follow-up was maintained and there was no evidence of disease recurrence. Conclusion. Although preliminary, our experience demonstrates safety and efficacy of multiport approach in providing access to multiple compartments, facilitating total excision of JNA in selected cases. PMID- 28101107 TI - Comparison of Human Papillomavirus Detection in Urine and Cervical Samples Using High-Risk HPV DNA Testing in Northern Thailand. AB - Objective. To evaluate the performance of high-risk human papillomavirus (HPV) DNA testing in urine samples compared to that of cervical sample testing in Northern Thailand. Methods. Paired urine and cervical samples were collected during the follow-up of women with a previous positive HPV test. HPV testing was performed using the Cobas 4800 HPV Test. Linear Array assay was used for genotyping in selected cases. Results. Paired urine and cervical samples were obtained from 168 women. Of 123 paired samples with valid results, agreement in the detection of high-risk HPV DNA was present in 106 cases (86.2%), with a kappa statistic of 0.65 (substantial agreement). Using the cervical HPV results as a reference, the sensitivity of urine HPV testing was 68.6% (24/35) and the specificity 93.2% (82/88). For the detection of histologic high-grade squamous intraepithelial lesion or worse (HSIL+), the sensitivity of urine HPV testing was 80.0% (4/5) and the specificity 78.0% (92/118). Conclusion. Although urine HPV testing had a rather low sensitivity for HPV detection, its sensitivity for histologic HSIL+ detection was high. For clinical use of urine HPV testing, standardization of specimen collection and processing techniques or application of a more sensitive test, especially in the detection of HPV52 and HPV58, is necessary. PMID- 28101108 TI - Chondrosarcomatous Differentiation in a Large Malignant Melanoma of the Scalp. AB - Background. Divergent differentiation in malignant melanoma is a rare phenomenon, which can lead to delayed diagnosis or misdiagnosis, impacting upon patient treatment and outcome, as well as the understanding of tumour behaviour. Case. We present the case of a large long-standing tumour on the scalp of a 72-year-old female patient, which when excised and examined histologically was revealed to be a nodular malignant melanoma displaying chondrosarcomatous differentiation. Foci suggestive of lentigo maligna were also present. Rapid metastatic spread of the tumour was observed shortly after the primary resection. Discussion. To our knowledge, this is the first reported case in the literature of chondrosarcomatous differentiation in a lentigo maligna melanoma. The clinical and histopathological details and images of this case are presented alongside a discussion regarding such tumours and patterns of similar tumour behaviour. PMID- 28101110 TI - The Best Age for Pregnancy and Undue Pressures. AB - In western countries we assist at the paradox that fertility is socially discouraged by a mindset that depicts fertility as a resource to exploit as late as possible. So, couples have high expectative about the advantages of delayed parenthood, but they are scarcely informed about its risks. Scientific data suggests to anticipate the first pregnancy, but social pressures impose to wait, though delayed childbearing can provoke sterility and a greater gap between generations. The best age to become parents should be autonomously decided by a couple, under the condition of being a free informed choice and not a social imposition, but currently this is not guaranteed to western women and men. PMID- 28101109 TI - Isolation of an ES-Derived Cardiovascular Multipotent Cell Population Based on VE Cadherin Promoter Activity. AB - Embryonic Stem (ES) or induced Pluripotent Stem (iPS) cells are important sources for cardiomyocyte generation, targeted for regenerative therapies. Several in vitro protocols are currently utilized for their differentiation, but the value of cell-based approaches remains unclear. Here, we characterized a cardiovascular progenitor population derived during ES differentiation, after selection based on VE-cadherin promoter (Pvec) activity. ESCs were genetically modified with an episomal vector, allowing the expression of puromycin resistance gene, under Pvec activity. Puromycin-surviving cells displayed cardiac and endothelial progenitor cells characteristics. Expansion and self-renewal of this cardiac and endothelial dual-progenitor population (CEDP) were achieved by Wnt/beta-catenin pathway activation. CEDPs express early cardiac developmental stage-specific markers but not markers of differentiated cardiomyocytes. Similarly, CEDPs express endothelial markers. However, CEDPs can undergo differentiation predominantly to cTnT+ (~47%) and VE-cadherin+ (~28%) cells. Transplantation of CEDPs in the left heart ventricle of adult rats showed that CEDPs-derived cells survive and differentiate in vivo for at least 14 days after transplantation. A novel, dual progenitor population was isolated during ESCs differentiation, based on Pvec activity. This lineage can self-renew, permitting its maintenance as a source of cardiovascular progenitor cells and constitutes a useful source for regenerative approaches. PMID- 28101111 TI - A Randomized Trial to Evaluate the Effect of Local Endometrial Injury on the Clinical Pregnancy Rate of Frozen Embryo Transfer Cycles in Patients With Repeated Implantation Failure. AB - Objective: Repeated implantation failure (RIF) is a condition in which the embryos implantation decreases in the endometrium. So, our aim was to evaluate the effect of local endometrial injury on embryo transfer results. Materials and methods: In this simple randomized clinical trial (RCT), a total of 120 patients were selected. The participants were less than 40 years old, and they are in their minimum two cycles of vitro fertilization (IVF). Patients were divided randomly into two groups of LEI (Local endometrial injury) and a control group (n = 60 in each group). The first group had four small endometrial injuries from anterior, posterior, and lateral uterus walls which were obtained from people who were in 21th day of their previous IVF cycle. The second group was the patients who have not received any intervention. Results: The experimental and control patients were matched in the following factors. Regarding the clinical pregnancy rate, there was no significant difference noted between the experimental and the control group. Conclusion: Local endometrial injury in a preceding cycle does not increase the clinical pregnancy rate in the subsequent FET cycle of patients with repeated implantation failure. PMID- 28101112 TI - Effect of Training Preparation for Childbirth on Fear of Normal Vaginal Delivery and Choosing the Type of Delivery Among Pregnant Women in Hamadan, Iran: A Randomized Controlled Trial. AB - Objective: To examine effect of an educational program on pregnant women's fear of normal vaginal delivery. Fear of natural childbirth during pregnancy may increase the risk of caesarean section. Educational programs may be effective in reducing women fear of natural childbirth. Materials and methods: This randomized controlled trial conducted from September 2012 to January 2013 in Hamadan, Iran. One hundred fifty eligible women were randomly assigned to group "A" (Intervention group, n = 75) or group "B" (Control group, n = 75). Women in group A, participated in an antenatal educations program for physiologic childbirth in 8 two-hour sessions. A self-designed questionnaire was used to examine women's fear of natural childbirth. Data were analyzed with SPSS.16 software. Results: Baseline characteristics of women were similar in both groups. After intervention the mean fear score in group A compared to group B was significantly reduced (51.7 +/- 22.4 vs. 58.7 +/- 21.7) (p = 0.007). Physiologic delivery was the first choice of type of child birth after training in pregnant women in group A (58.7%). But delivery in physiologic form had lowest rate in group A (8%). Conclusion: Results of present study showed that educational program could be serving as an important tool in reducing women fear from natural childbirth and in choosing of physiologic birth. And for delivery as a physiological, education and counseling of pregnant women, doctors and midwives are required. PMID- 28101113 TI - Evaluating the Effectiveness of Pubertal Preparedness Program in Terms of Knowledge and Attitude Regarding Pubertal Changes Among Pre-Adolescent Girls. AB - Objective: To compare the knowledge and attitude regarding pubertal changes among pre - adolescent girls before and after the pubertal preparedness program (PPP) in experimental and comparison group. Materials and methods: A Quasi experimental (non- equivalent comparison group pretest posttest) design was adopted with 104pre-adolescentgirls (52 in each experimental and comparison group) of age 12 14years, selected by purposive sampling from two different Government schools of Ambala District. Knowledge and attitude was assessed using structured knowledge questionnaire (KR-20 = 0.74) and 5 point likert scale (Cronbach's alpha = 0.79) respectively. On the same day of pretest, PPP was administered and on 12th day FAQs reinforcement session was held only for experimental group. After 28 days, posttest was taken. Results: The computed t value of pretest of knowledge and attitude scores of pre-adolescent girls (1.97), (1.95) respectively in experimental and comparison group was found non-significant at 0.05 level of significance which shows that both group didn't differ significantly in their knowledge and attitude before the administration of intervention. Findings of unpaired 't' value of posttest knowledge and attitude scores of pre-adolescent girls (19.77), (17.17) respectively in experimental and comparison group were found significant at 0.05 level of significance, Thus knowledge and attitude of pre-adolescent girls were improved with PPP and FAQs session. Conclusion: Pubertal preparedness program and FAQs reinforcement session are effective in enhancing knowledge and developing favorable attitude among pre-adolescent girls. PMID- 28101114 TI - Dietary and Socio-Demographic Determinants of Serum Persistent Organic Pollutants (POPs) Levels in Pregnant Women in Tehran. AB - Objective: To determine the levels of Polychlorinated biphenyls (PCBs) and Polybrominateddiphenyl ethers (PBDEs) as persistent organic pollutants (POPs) in serum of primiparous women at the third trimester of pregnancy and identify the main determinants of POPs levels such as socio-demographic, lifestyle, and diet in Tehran. Materials and methods: One- hundred eighty five serum samples from two simultaneous case-control studies were collected from September 2013 until August 2015.Ten most abundant PCB congeners (International Union of Pure and Applied Chemistry (IUPAC) congeners 28, 52, 74, 99, 101, 118, 138, 153, 180 and 187) as well as eight PBDE congeners (IUPAC congeners 28, 47, 99, 100, 153, 154, 183 and 209)were analyzed by Gas Chromatography Mass Spectrometry (GC/MS). Multiple linear regression analysis was conducted to explain the relationship between total PCBs and total BPDEs and most detected congeners and some determinants, separately. Results: The mean (SD) age of the participating women was 27.82 +/- 5.24 years. The geometric mean (SD) of total PCBs was 2.42 +/- 2.26 and total PBDEs was 1.28 +/- 1.41 ng/g lipid. Only the PCB 138, PCB 153 and PBDE 153 were detected in 100% of samples. We observed a significant relationship between the time of being indoors and total PBDEs (P = 0.03). Passive smoking was significantly associated with PCB 153 (P = 0.049). The results of the linear regression analysis showed the negative and weak association (P-value < 0.05) between diet (egg and fat and oil consumption) and POPs in this population. Conclusion: It seems the most common route of exposure to PBDEs in our population is indoor pollutants. Meanwhile inhalation of smoke from environment is a route of exposure to PCB 153. Further study is needed to evaluate the effects of socio demographics and especially dietary intake on POPs level. PMID- 28101115 TI - Marital Satisfaction and Its Influencing Factors in Fertile and Infertile Women. AB - Objective: To determine marital satisfaction and its influencing factors among fertile and infertile women in Shahroud. Materials and methods: In this comparative study, 1528 participants (511 infertile and1017 fertile women) were evaluated using Enrich Marital Satisfaction Scale. Data were analyzed using chi square and t-test. Results: A total of 1402 participants (78.7%) had high marital satisfaction. The results show that no significant differences exist between marital satisfaction, marital communication, conflict resolution and idealistic distortion in fertile and infertile women. However, a significant difference was observed between marital satisfaction, and job, spouse's job and income in fertile and infertile groups, but the place of residence, education, spouse's education and fertility status showed no significant difference. Conclusion: Results showed that infertility does not reduce marital satisfaction. Since marital satisfaction is moderate in both groups, sex education for people bound to marry and sexual counseling for couples can lead to improved sexual satisfaction. PMID- 28101116 TI - Journey to Motherhood in the First Year After Child Birth. AB - Objective: Child bearing is a period of psychological challenges that must be viewed in a social context. This study reports the maternal transition from the perspective of Iranian first-time mothers in the first year after childbirth. Materials and methods: Qualitative method was chosen for explanation of mothers' individual experiences of motherhood.26 first-time mothers (aged 18-35 years old with various socio-economic status) who had delivered between 0-1 year prior to the interviews participated in the study.Data were collected through in-depth semi-structured interviews and interview transcripts were analyzed using the constant comparison method. Results: The core category was called "Regaining advanced balance." There were several themes within this category: "internal conflicts", "encounter and interaction" and "internalization". They felt unpreparedness, lack of control over their lives, incomplete maternal feelings and unstable relation to their husbands and others. Within the first postpartum days and weeks a sort of attachment develops between mother and child as the mother starts to attain a better understanding of maternal feelings; she begins to accept the child as an independent identity and reconstructs herself. As the attachment to child deepens, the mother feels control over the affairs. She realizes a kind of development and integration in herself which specifically stems from becoming a mother and attempts to strengthen family bonds. Conclusion: Through the expression of new mothers' experiences toward motherhood, healthcare providers can reach a better perception of the emotional and psychological changes as well as the various aspects of mothers' acceptance of their maternal role and helps a better preparation and presentation of effective training programs for mothers and families. PMID- 28101117 TI - Maternal Mortality Ratio and Causes of Death in IRI Between 2009 and 2012. AB - Objective: The Maternal Mortality Ratio is an important health indicator. We presented the distribution and causes of maternal mortality in Islamic Republic of Iran. Materials and methods: After provision of an electronic Registry system for date entry, a descriptive-retrospective data collection had been performed for all maternal Deaths in March 2009- March 2012. All maternal deaths and their demographic characteristic were identified by using medical registries, death certificates, and relevant codes according to International Classification of Diseases (ICD-9) during pregnancy, labor, and 42 days after parturition. Results: During 3 years, there were 5094317 deliveries and 941 maternal deaths (MMR of 18.5 per 1000000 live births). We had access to pertained data of 896 cases (95.2%) for review in our study. Of 896 reported deaths, 549 were classified as direct, 302 as indirect and 45 as unknown. Hemorrhage was the most common cause of maternal mortality, followed by Preeclampsia, Eclampsia and sepsis. Among all indirect causes, cardio -vascular diseases were responsible for 10% of maternal deaths, followed by thromboembolism, HTN and renal diseases. Conclusion: Although maternal mortality ratio in IRI could be comparable with the developed countries but its pattern is following developing countries and with this study we had provided reliable data for other prospective studies. PMID- 28101118 TI - Neuroprotective Effect of Paeonol Mediates Anti-Inflammation via Suppressing Toll Like Receptor 2 and Toll-Like Receptor 4 Signaling Pathways in Cerebral Ischemia Reperfusion Injured Rats. AB - Paeonol is a phenolic compound derived from Paeonia suffruticosa Andrews (MC) and P. lactiflora Pall (PL). Paeonol can reduce cerebral infarction volume and improve neurological deficits through antioxidative and anti-inflammatory effects. However, the anti-inflammatory pathway of paeonol remains unclear. This study investigated the relationship between anti-inflammatory responses of paeonol and signaling pathways of TLR2 and TLR4 in cerebral infarct. We established the cerebral ischemia-reperfusion model in Sprague Dawley rats by occluding right middle cerebral artery for 60 min, followed by reperfusion for 24 h. The neurological deficit score was examined, and the brains of the rats were removed for cerebral infarction volume and immunohistochemistry (IHC) analysis. The infarction volume and neurological deficits were lower in the paeonol group (pretreatment with paeonol; 20 mg/kg i.p.) than in the control group (without paeonol treatment). The IHC analysis revealed that the number of TLR2-, TLR4-, Iba1-, NF-kappaB- (P50-), and IL-1beta-immunoreactive cells and TUNEL-positive cells was significantly lower in the paeonol group; however, the number of TNF alpha-immunoreactive cells did not differ between the paeonol and control groups. The paeonol reveals some neuroprotective effects in the model of ischemia, which could be due to the reduction of many proinflammatory receptors/mediators, although the mechanisms are not clear. PMID- 28101119 TI - In Vitro Antiproliferative and Antioxidant Effects of Extracts from Rubus caesius Leaves and Their Quality Evaluation. AB - The present study was performed to evaluate the effect of different extracts and subfractions from Rubus caesius leaves on two human colon cancer cell lines obtained from two stages of the disease progression lines HT29 and SW948. Tested samples inhibited the viability of cells, both HT29 and SW948 lines, in a concentration-dependent manner. The most active was the ethyl acetate fraction which, applied at the highest concentration (250 MUg/mL), decreased the viability of cells (HT29 and SW948) below 66%. The extracts and subfractions were also investigated for antioxidant activities on DPPH and FRAP assays. All extracts, with the exception of water extract at a dose of 250 MUg/mL, almost totally reduced DPPH. The highest Fe3+ ion reduction was shown for the diethyl and ethyl acetate fractions. It was more than 6.5 times higher (at a dose 250 MUg/mL) as compared to the control. The LC-MS studies of the analysed preparations showed that all samples contain a wide variety of polyphenolics, among which ellagitannins turned out to be the main constituents with dominant ellagic acid, sanguiin H-6, and flavonol derivatives. PMID- 28101120 TI - Phytochemical and Antinociceptive, Anti-Inflammatory, and Antioxidant Studies of Smilax larvata (Smilacaceae). AB - The tea of aerial parts of Smilax larvata Griseb. (Smilacaceae) has been ethnopharmacologically used in Southern Brazil due to its anti-inflammatory action. In this study, ethanolic and organic extracts from aerial parts of S. larvata were phytochemically and pharmacologically characterized. The phytochemical analysis of EtOAc extract of S. larvata revealed the presence of three flavonoids, drabanemoroside, kaempferol 3-O-alpha-L-rhamnopyranosyl(1->2) alpha-L-rhamnopyranoside, and kaempferol, the first two being isolated for the first time in this genus, two phenolic compounds p-hydroxybenzoic acid and p coumaric acid, and alkaloids. In vitro assays demonstrated a potential antioxidant property of SLG. The treatment with SLG induced a significant reduction of the formalin-evoked flinches in rats, an effect reversed by opioid antagonist naloxone. Treatment with SLG also induced a significant increase in the hot plate latency and a decrease of intestinal motility by 45%. No effect was observed over nociceptive responses induced by a TRPA1 agonist mustard oil or over acetic acid-induced writhing in mice. Together, our data suggested that SLG has an in vivo antinociceptive effect, which seems to be associated with the opioid system activation. These findings support previous claims of medical use of Smilax larvata in the treatment of pain conditions. PMID- 28101121 TI - Embryology of the VNO and associated structures in the grass snake Natrix natrix (Squamata: Naticinae): a 3D perspective. AB - BACKGROUND: Snakes are considered to be vomerolfaction specialists. They are members of one of the most diverse groups of vertebrates, Squamata. The vomeronasal organ and the associated structures (such as the lacrimal duct, choanal groove, lamina transversalis anterior and cupola Jacobsoni) of adult lizards and snakes have received much anatomical, histological, physiological and behavioural attention. However, only limited embryological investigation into these structures, constrained to some anatomical or cellular studies and brief surveys, has been carried out thus far. The purpose of this study was, first, to examine the embryonic development of the vomeronasal organ and the associated structures in the grass snake (Natrix natrix), using three-dimensional reconstructions based on histological studies, and, second, to compare the obtained results with those presented in known publications on other snakes and lizards. RESULTS: Five major developmental processes were taken into consideration in this study: separation of the vomeronasal organ from the nasal cavity and its specialization, development of the mushroom body, formation of the lacrimal duct, development of the cupola Jacobsoni and its relation to the vomeronasal nerve, and specialization of the sensory epithelium. Our visualizations showed the VNO in relation to the nasal cavity, choanal groove, lacrimal duct and cupola Jacobsoni at different embryonic stages. We confirmed that the choanal groove disappears gradually, which indicates that this structure is absent in adult grass snakes. On our histological sections, we observed a gradual growth in the height of the columns of the vomeronasal sensory epithelium and widening of the spaces between them. CONCLUSIONS: The main ophidian taxa (Scolecophidia, Henophidia and Caenophidia), just like other squamate clades, seem to be evolutionarily conservative at some levels with respect to the VNO and associated structures morphology. Thus, it was possible to homologize certain embryonic levels of the anatomical and histological complexity, observed in the grass snake, with adult conditions of certain groups of Squamata. This may reflect evolutionary shift in Squamata from visually oriented predators to vomerolfaction specialists. Our descriptions offer material useful for future comparative studies of Squamata, both at their anatomical and histological levels. PMID- 28101122 TI - Start early! Does social instability during the pre- and early postnatal development prepare male wild cavies for social challenge later in life? AB - BACKGROUND: The social environment the mother experiences during pregnancy and lactation can powerfully influence the offspring's behavioural profile. Our previous studies in wild cavies show that two different social environments during pregnancy and lactation bring about different behavioural strategies of male offspring later in life: An unstable social environment leads to a behavioural camouflage strategy, hypothesised to be beneficial at times of socially challenging situations. A stable social environment during early phases of life, however, leads to an early reproduction strategy, expected to be more successful at times of social stability. In the present study, we observed the behavioural strategies of the two types of males in direct comparison in a socially challenging situation: Two adolescent males were placed simultaneously in an unknown social group consisting of one adult male and two females in a semi naturalistic environment. Cortisol as well as testosterone concentrations and activity levels were compared. Furthermore, paternities were analysed after the males reached sexual maturity. We hypothesised that sons showing a behavioural camouflage strategy are better adapted to cope with this socially challenging situation compared to those displaying an early reproduction strategy. RESULTS: At the beginning of the experiment, no differences in plasma cortisol concentrations between the males were found, both showed a highly significant increase due to the challenging situation. From day 5 until the end of the experiment (duration = 40 days) sons showing an early reproduction strategy had significantly higher plasma cortisol concentrations compared with those showing a behavioural camouflage strategy. Plasma testosterone concentrations did not differ significantly. Activity levels decreased significantly over time independently of the male's behavioural strategy. Both types of males did not sire offspring during the observation period. CONCLUSION: Higher cortisol values from day 5 until the end of the experiment in sons showing an early reproduction strategy indicate higher levels of stress in these males compared to those displaying a camouflage strategy. We conclude that the modulation of the males behavioural strategy due to an unstable social environment during early development facilitates the endocrine adaptation to a comparable social situation later in life. PMID- 28101123 TI - Regulatory landscape of AGE-RAGE-oxidative stress axis and its modulation by PPARgamma activation in high fructose diet-induced metabolic syndrome. AB - BACKGROUND: The AGE-RAGE-oxidative stress (AROS) axis is involved in the onset and progression of metabolic syndrome induced by a high-fructose diet (HFD). PPARgamma activation is known to modulate metabolic syndrome; however a systems level investigation looking at the protective effects of PPARgamma activation as related to the AROS axis has not been performed. The aim of this work is to simultaneously characterize multiple molecular parameters within the AROS axis, using samples taken from different body fluids and tissues of a rat model of HFD induced metabolic syndrome, in the presence or absence of a PPARgamma agonist, Rosiglitazone (RGZ). METHODS: Rats were fed with 60% HFD for the first half of the treatment duration (21 days) then continued with either HFD alone or HFD plus RGZ for the second half. RESULTS: Rats receiving HFD alone showed metabolic syndrome manifestations including hypertension, dyslipidemia, increased glucose levels and insulin resistance, as well as abnormal kidney and inflammatory parameters. Systolic blood pressure, plasma triglyceride and glucose levels, plasma creatinine, and albuminuria were significantly improved in the presence of RGZ. The following molecular parameters of the AROS axis were significantly upregulated in our rat model: carboxymethyl lysine (CML) in urine and liver; carboxyethyl lysine (CEL) in urine; advanced glycation end products (AGEs) in plasma; receptor for advanced glycation end products (RAGE) in liver and kidney; advanced oxidation protein products (AOPP) in plasma; and 4-hydroxynonenal (HNE) in plasma, liver, and kidney. Conversely, with RGZ administration, the upregulation of AOPP and AGEs in plasma, CML and CEL in urine, RAGE in liver as well as HNE in plasma and liver was significantly counteracted/prevented. CONCLUSIONS: Our data demonstrate (i) the systems-level regulatory landscape of HFD-induced metabolic syndrome involving multiple molecular parameters, including HNE, AGEs and their receptor RAGE, and (ii) attenuation of metabolic syndrome by PPARgamma modulation. PMID- 28101124 TI - Reduced up-regulation of the nitric oxide pathway and impaired endothelial and smooth muscle functions in the female type 2 diabetic goto-kakizaki rat heart. AB - BACKGROUND: Type 2 diabetes is associated with greater relative risk of cardiovascular diseases in women than in men, which is not well understood. Consequently, we have investigated if male and female displayed differences in cardiac function, energy metabolism, and endothelial function which could contribute to increased cardiovascular complications in type 2 diabetic female. METHODS: Male and female Control and type 2 diabetic Goto-Kakizaki (GK) isolated rat hearts were perfused during 28 min with a physiological buffer before freeze clamping for biochemical assays. High energy phosphate compounds and intracellular pH were followed using 31P magnetic resonance spectroscopy with simultaneous measurement of contractile function. Nitric oxide (NO) pathway and endothelium-dependent and independent vasodilatations were measured as indexes of endothelial function. Results were analyzed via two-way ANOVA, p < 0.05 was considered as statistically significant. RESULTS: Myocardial function was impaired in male and female diabetic versus Control groups (p < 0.05) without modification of energy metabolism. Coronary flow was decreased in both diabetic versus Control groups but to a higher extent in female GK versus male GK rat hearts (p < 0.05). NO production was up-regulated in diabetic groups but to a less extent in female GK rat hearts (p < 0.05). Endothelium-dependent and independent vasodilatations were impaired in female GK rat compared with male GK (p < 0.05) and female Control (p < 0.05) rat hearts. CONCLUSIONS: We reported here an endothelial damage characterized by a reduced up-regulation of the NO pathway and impaired endothelial and smooth muscle functions, and coronary flow rates in the female GK rat hearts while energy metabolism was normal. Whether these results are related to the higher risk of cardiovascular complications among type 2 diabetic female needs to be further elicited in the future. PMID- 28101126 TI - Characterisation of microbial communities within aggressive prostate cancer tissues. AB - BACKGROUND: An infectious aetiology for prostate cancer has been conjectured for decades but the evidence gained from questionnaire-based and sero-epidemiological studies is weak and inconsistent, and a causal association with any infectious agent is not established. We describe and evaluate the application of new technology to detect bacterial and viral agents in high-grade prostate cancer tissues. The potential of targeted 16S rRNA gene sequencing and total RNA sequencing was evaluated in terms of its utility to characterise microbial communities within high-grade prostate tumours. METHODS: Two different Massively Parallel Sequencing (MPS) approaches were applied. First, to capture and enrich for possible bacterial species, targeted-MPS of the V2-V3 hypervariable regions of the 16S rRNA gene was performed on DNA extracted from 20 snap-frozen prostate tissue cores from ten "aggressive" prostate cancer cases. Second, total RNA extracted from the same prostate tissue samples was also sequenced to capture the sequence profile of both bacterial and viral transcripts present. RESULTS: Overall, 16S rRNA sequencing identified Enterobacteriaceae species common to all samples and P. acnes in 95% of analyzed samples. Total RNA sequencing detected endogenous retroviruses providing proof of concept but there was no evidence of bacterial or viral transcripts suggesting active infection, although it does not rule out a previous 'hit and run' scenario. CONCLUSIONS: As these new investigative methods and protocols become more refined, MPS approaches may be found to have significant utility in identifying potential pathogens involved in disease aetiology. Further studies, specifically designed to detect associations between the disease phenotype and aetiological agents, are required. PMID- 28101125 TI - Preventive transarterial embolization in upper nonvariceal gastrointestinal bleeding. AB - BACKGROUND: Transarterial embolization (TAE) is a therapeutic option for patients with a high risk of recurrent bleeding after endoscopic haemostasis. The aim of our prospective study was a preliminary assessment of the safety, efficacy, and clinical outcomes following preventive TAE in patients with non-variceal acute upper gastrointestinal bleeding (NVUGIB) with a high risk of recurrent bleeding after endoscopic haemostasis. METHODS: Preventive visceral angiography and TAE were performed after endoscopic haemostasis on patients with NVUGIB who were at a high risk of recurrent bleeding (PE+ group). The comparison group consisted of similar patients who only underwent endoscopic haemostasis, without preventive TAE (PE- group). The technical success of preventive TAE, the completeness of haemostasis, the incidence of rebleeding and the need for surgical intervention and the main outcomes were compared between the groups. RESULTS: The PE+ group consisted of 25 patients, and the PE- group of 50 patients, similar in age (median age 66 vs. 63 years), gender and comorbid conditions. The ulcer size at endoscopy was not significantly different (median of 152 mm vs. 127 mm). The most frequent were Forest II type ulcers, 44% in both groups. The distribution of the Forest grade was even. The median haemoglobin on admission was 8, 2 g/dl vs. 8,7 g/dl, p = 0,482, erythrocyte count was 2,7 * 1012/L vs. 2,9 * 1012/L, p = 0,727. The shock index and Rockall scores were similar, as well as and transfusion - on average, four units of packed red blood cells for the majority of patients in both groups, however, significantly more fresh frozen plasma was transfused in the PE- group, p = 0,013. The rebleeding rate was similar, while surgical treatment was needed notably more often in the PE- group, 8% vs. 35% accordingly, p = 0,012. The median ICU stay was 3 days, hospital stay - 6 days vs. 9 days, p = 0.079. The overall mortality reached 20%; in the PE+ group it was 4%, not reaching a statistically significant difference. CONCLUSION: Preventive TAE is a feasible, safe and effective minimally invasive type of haemostasis decreasing the risk of repeated bleeding and preparing the patient for the definitive surgical intervention when indicated. PMID- 28101127 TI - Mental health and trauma in asylum seekers landing in Sicily in 2015: a descriptive study of neglected invisible wounds. AB - BACKGROUND: In 2015, Italy was the second most common point of entry for asylum seekers into Europe after Greece. The vast majority embarked from war-torn Libya; 80,000 people claimed asylum that year. Their medical conditions were assessed on arrival but their mental health needs were not addressed in any way, despite the likelihood of serious trauma before and during migration. Medecins sans Frontieres (MSF), in agreement with the Italian Ministry of Health, provided mental health (MH) assessment and care for recently-landed asylum seekers in Sicily. This study documents mental health conditions, potentially traumatic events and post-migratory living difficulties experienced by asylum seekers in the MSF programme in 2014-15. METHODS: All asylum seekers transiting the 15 MSF supported centres were invited to a psycho-educational session. A team of psychologists and cultural mediators then provided assessment and care for those identified with MH conditions. Potentially traumatic events experienced before and during the journey, as well as post-migratory living difficulties, were recorded. All those diagnosed with MH conditions from October 2014 to December 2015 were included in the study. RESULTS: Among 385 individuals who presented themselves for a MH screening during the study period, 193 (50%) were identified and diagnosed with MH conditions. Most were young, West African males who had left their home-countries more than a year prior to arrival. The most common MH conditions were post traumatic stress disorder (31%) and depression (20%). Potentially traumatic events were experienced frequently in the home country (60%) and during migration (89%). Being in a combat situation or at risk of death, having witnessed violence or death and having been in detention were the main traumas. Lack of activities, worries about home, loneliness and fear of being sent home were the main difficulties at the AS centres. CONCLUSION: MH conditions, potentially traumatic events and post-migratory living difficulties are commonly experienced by recently-arrived ASs, this study suggests that mental health and psychosocial support and improved living circumstances should be integrated into European medical and social services provided by authorities in order to fulfil their humanitarian responsibility and reduce the burden of assimilation on receiving countries. PMID- 28101128 TI - Simultaneous determination of newly developed antiviral agents in pharmaceutical formulations by HPLC-DAD. AB - BACKGROUND: Ombitasvir/paritaprevir/ritonavir/dasabuvir (Viekira Pak(r)) are the newest medicines approved for use in the treatment of hepatitis C virus (HCV) and are available in tablet form as an oral combination. Specifically, these agents are indicated in the treatment of HCV in patients with genotype 1 infection. Due to the therapeutic importance and increased use of Viekira Pak, proper methods for its determination in bulk and pharmaceutical formulations must be developed. RESULTS: The present study describes the development and validation of a simple, rapid, selective and economical reverse phase high performance liquid chromatography-diode array detection (HPLC-DAD) method for the simultaneous determination of paritaprevir (PAR), ombitasvir (OMB), dasabuvir(DAS) and ritonavir (RIT) in bulk and pharmaceutical preparations. The proposed method was carried out using an RPC18 column (150 * 4.5 mm, 3.5 MU), with a mobile phase consisting of 10 mM phosphate buffer (pH 7)and acetonitrile (35:65, v/v) at a flow rate of 1 ml/min and a detection wavelength of 254 nm. Sorafenib (SOR) was selected as the internal standard to ensure that the quantitative performance was high. The method was validated based on its specificity, linearity, limit of detection, limit of quantitation, accuracy, precision, robustness and stability. The calibration curves for PAR, DAS, RIT and OMB were linear at 2.5-60, 1.25-30, 1.7-40 and 0.42-10 MUg/ml, respectively, and all of the correlation coefficients were >0.999. CONCLUSIONS: The proposed method was successfully applied for the determination of ombitasvir/paritaprevir/ritonavir/dasabuvirin tablets, without interference from the excipient peaks. Hence, the method can be applied for the routine quality control analysis of the studied drugs, either in bulk or dosed forms.Graphical abstractSimultaneous estimation of newly developed antiviral agents in pharmaceutical formulations by HPLC-DAD method. PMID- 28101130 TI - Silica-titania xerogel doped with Mo,P-heteropoly compounds for solid phase spectrophotometric determination of ascorbic acid in fruit juices, pharmaceuticals, and synthetic urine. AB - BACKGROUND: Ascorbic acid is one of the most important vitamins to monitor in dietary sources (juices and vitamins) and biological liquids. RESULTS: Silica and silica-titania xerogels doped with Mo,P-heteropoly compounds (HPC) have been synthesized varying titanium(IV) and HPC content in sol. Their surface area and porosity have been studied with nitrogen adsorption and scanning electron microscopy, their elemental composition has been studied with energy-dispersive X ray analysis. The redox properties of the sensor material with sufficient porosity and maximal HPC content have been studied with potentiometry and solid phase spectrophotometry and it has been used for solid phase spectrophotometric determination of ascorbic acid. The proposed method is characterized by good selectivity, simple probe pretreatment and broad analytical range (2-200 mg/L, LOD 0.7 mg/L) and has been applied to the analysis of fruit juices, vitamin tablets, and synthetic urine. CONCLUSIONS: New sensor material has been used for simple and selective solid phase spectrophotometric procedure of ascorbic acid determination in fruit juices, vitamin tablets, and synthetic urine.Graphical abstractWe synthesized several silica-titania xerogels doped with Mo,P-heteropoly compounds, studied their properties, and designed the sensor material for solid phase spectrophotometric determination of ascorbic acid in fruit juices, pharmaceuticals, and synthetic urine. PMID- 28101129 TI - A traditional poly herbal medicine "Le Pana Guliya" induces apoptosis in HepG2 and HeLa cells but not in CC1 cells: an in vitro assessment. AB - "Le Pana Guliya" (LPG) is a polyherbal formulation which is used to treat different types of cancers in traditional medicine. In this study we describe in vitro efficacy and mechanism of action of LPG on two cancer cell lines (HepG2 and HeLa) compared with a normal cell line CC1. The MTT, LDH assays and protein synthesis were used to study antiproliferative activity of LPG while NO synthesis and GSH content were assayed to determine the oxidative stress exerted by LPG. Rhodamine 123 staining, caspase 3 activity, DNA fragmentation and microscopic examination of cells stained with ethidium bromide/acridine orange were used to identify the apoptosis mechanisms associated with LPG. The LPG showed the most potent antiproliferative effect against the proliferation of HepG2 and HeLa cells with an EC50 value of 2.72 +/- 1.36 and 19.03 +/- 2.63 ug/mL for MTT assay after 24 h treatment respectively. In contrast, CC1 cells showed an EC50 value of 213.07 +/- 7.71 ug/mL. Similar results were observed for LDH release. A dose dependent decrease in protein synthesis was shown in both cancer cell types compared to CC1 cells. The reduction of GSH content and elevation of cell survival with exogenous GSH prove that the LPG act via induction of oxidative stress. LPG also stimulates the production of NO and mediates oxidative stress. Rhodamine 123 assay shows the mitochondrial involvement in cell death by depletion of Deltapsi inducing downstream events in apoptosis. This results in increase in caspase-3 activity eventually DNA fragmentation and LPG induced apoptotic cell death. In conclusion the present study suggested that the LPG exerted an anticancer activity via oxidative stress dependent apoptosis. Therefore present study provides the scientific proof of the traditional knowledge in using LPG as an anticancer agent. PMID- 28101131 TI - Using flow technologies to direct the synthesis and assembly of materials in solution. AB - In the pursuit of materials with structure-related function, directing the assembly of materials is paramount. The resultant structure can be controlled by ordering of reactants, spatial confinement and control over the reaction/crystallisation times and stoichiometries. These conditions can be administered through the use of flow technologies as evidenced by the growing widespread application of microfluidics for the production of nanomaterials; the function of which is often dictated or circumscribed by size. In this review a range of flow technologies is explored for use in the control of self-assembled systems: including techniques for reagent ordering, mixing control and high throughput optimisation. The examples given encompass organic, inorganic and biological systems and focus on control of shape, function, composition and size.Graphical abstract. PMID- 28101132 TI - What are "good outcomes" in public mental health settings? A qualitative exploration of clients' and therapists' experiences. AB - BACKGROUND: The mental health field sees a surge of interest in Routine Outcome Monitoring, mandated by a wish to help better those not-on-track to recovery. What constitutes positive outcomes for these patients is not fully understood. AIMS: To contribute knowledge into what constitutes meaningful outcome concepts in the experiences of patients with long and complex mental health suffering and treatment, and the clinicians who work to help them. METHODS: A qualitative in depth study of 50 participants' experiences. Data are collected through focus groups and individual interviews, and analyzed using a team based structured thematic analytic approach. RESULTS: We found an overarching theme of outcome as an ongoing process of recovery, with the four constituent themes: (1) strengthening approach patterns for new coping; (2) embodying change reflected by others; (3) using new understandings developed in dialogue; and (4) integrating collaborative acceptance. CONCLUSIONS: We discuss our findings in light of existing empirical studies and different recovery concepts, and suggest that if outcomes monitoring is to become an integral part of routine practice, it might be beneficial to integrate an understanding of outcomes as ongoing processes of recovery within mental health suffering into these systems. PMID- 28101134 TI - Single cell isolation process with laser induced forward transfer. AB - BACKGROUND: A viable single cell is crucial for studies of single cell biology. In this paper, laser-induced forward transfer (LIFT) was used to isolate individual cell with a closed chamber designed to avoid contamination and maintain humidity. Hela cells were used to study the impact of laser pulse energy, laser spot size, sacrificed layer thickness and working distance. The size distribution, number and proliferation ratio of separated cells were statistically evaluated. Glycerol was used to increase the viscosity of the medium and alginate were introduced to soften the landing process. RESULTS: The role of laser pulse energy, the spot size and the thickness of titanium in energy absorption in LIFT process was theoretically analyzed with Lambert-Beer and a thermal conductive model. After comprehensive analysis, mechanical damage was found to be the dominant factor affecting the size and proliferation ratio of the isolated cells. An orthogonal experiment was conducted, and the optimal conditions were determined as: laser pulse energy, 9 MUJ; spot size, 60 MUm; thickness of titanium, 12 nm; working distance, 700 MUm;, glycerol, 2% and alginate depth, greater than 1 MUm. With these conditions, along with continuous incubation, a single cell could be transferred by the LIFT with one shot, with limited effect on cell size and viability. CONCLUSION: LIFT conducted in a closed chamber under optimized condition is a promising method for reliably isolating single cells. PMID- 28101133 TI - Temperament and character traits in female adolescents with nonsuicidal self injury disorder with and without comorbid borderline personality disorder. AB - BACKGROUND: Temperament and character traits of adolescents with nonsuicidal self injury disorder (NSSI) might differentiate those- with and without comorbid borderline personality disorder (BPD). METHODS: Participants were 57 female adolescents with NSSI disorder without BPD (NSSI - BPD), 14 adolescents with NSSI disorder and BPD (NSSI + BPD), 32 clinical controls (CC), and 64 nonclinical controls (NC). Temperament and character traits were assessed with the Junior Temperament and Character Inventory, and impulsivity with the Barratt Impulsiveness Scale and a Go/NoGo task. RESULTS: Adolescents with NSSI disorder scored significantly higher on novelty seeking and harm avoidance and lower on persistence, self-directedness, and cooperativeness than CC. The NSSI + BPD group scored even higher than the NSSI - BPD group on novelty seeking and harm avoidance and lower on persistence and cooperativeness (d >= 0.72). Adolescents with NSSI reported higher levels of impulsivity than the CC and NC group. However, this difference was not found in a Go/NoGo task. CONCLUSIONS: The results provide further evidence for a distinct diagnostic entity of NSSI disorder. PMID- 28101135 TI - Towards the 10-year milestone of Journal of Biological Engineering. AB - October 10th, 2016 marked the 9th anniversary for the Journal of Biological Engineering (JBE), the official journal of Institute of Biological Engineering (IBE), published by BioMed Central. We are entering into the 10th year of its exciting and productive history. In this editorial, a brief history of JBE is summarized, along with a series of analyses on average number of citations, breakdown of topical subjects, geographical representations and so forth for all published articles in JBE. Future prospects and new directions of JBE are also described in this editorial. PMID- 28101137 TI - Validation of questionnaire on the Spiritual Needs Assessment for Patients (SNAP) questionnaire in Brazilian Portuguese. AB - OBJECTIVES: Spirituality is related to the care and the quality of life of cancer patients. Thus, it is very important to assess their needs. The objective of this study was the translation and cultural adjustment of the Spiritual Needs Assessment for Patients (SNAP) questionnaire to the Brazilian Portuguese language. METHODOLOGY: The translation and cultural adjustment of the SNAP questionnaire involved six stages: backtranslation, revision of backtranslation, translation to the original language and adjustments, pre-test on ten patients, and test and retest with 30 patients after three weeks. Adult patients, with a solid tumour and literate with a minimum of four years schooling were included. For analysis and consistency we used the calculation of the Cronbach alpha coefficient and the Pearson linear correlation. RESULTS: The final questionnaire had some language and content adjustments compared to the original version in English. The correlation analysis of each item with the total score of the questionnaire showed coefficients above 0.99. The calculation of the Cronbach alpha coefficient was 0.9. The calculation of the Pearson linear correlation with the test and retest of the questionnaire was equal to 0.95. CONCLUSION: The SNAP questionnaire translated into Brazilian Portuguese is adequately reliable and consistent. This instrument allows adequate access to spiritual needs and can help patient care. PMID- 28101136 TI - Hepatic metastasis of thymoma: case report and immunohistochemical study. AB - Thymomas are rare tumours characterised by their slow growth and capacity to invade directly by contiguity. While distant dissemination is infrequent, all sub types of thymoma have the capacity to metastasise to extrathoracic organs. We present here the case of a female patient with a liver mass discovered 13 years after the removal of a mediastinal thymoma and after ten years from thyroidectomy for papillary carcinoma. The histopathological study showed that the lesion contained an epithelial component, which was immunohistochemically positive for pankeratin. It was accompanied by numerous small lymphocytes testing positive for TdT, CD3, CD4, CD5, CD8, CD99, and CD43. The result was consistent with hepatic metastatic thymoma sub-type B1, according to the World Health Organisation classification (WHO). Our case highlights the importance of morphological and immunohistological examinations in the differential diagnosis of visceral masses in patients with a history of thymoma. Given the infrequency of its metastasis and the increased risk of developing other primary tumours that these patients have, these studies play a significant role. PMID- 28101138 TI - Research engagement among black men with prostate cancer. AB - BACKGROUND: Black men are three times more likely to develop prostate cancer (PCa) and often present with more aggressive disease. Nevertheless, black men are consistently underrepresented in research studies. We aimed to get more insight into the reasons for this reduced recruitment, as it is important for future research to include results that are also applicable to black men with PCa. METHODS: Two focus groups (n = 10 and n = 6) of black males currently under treatment for PCa at Guys Hospital, London, UK were held to gather information regarding the understanding of and exposure to research, as well as the barriers and facilitators for recruitment into research studies. RESULTS: Barriers to recruitment included; mistrust of researchers, lack of understanding of the research process and the mechanisms of PCa and a reliance on herbal medicine. Suggested facilitators for recruitment improvement included thorough explanations of the research process, media advertisement and word of mouth. Financial incentives were also discussed but received mixed reception. CONCLUSION: We uncovered a number of barriers to recruitment of black men with PCa into research and accompanying strategies for improving involvement. Many are consistent with the literature, emphasising that current efforts have not been successful in ameliorating the concerns of the black community. Beliefs in herbal medicine and aversion to financial incentives appear to be novel themes, and so further insight into these issues could prove beneficial. PMID- 28101139 TI - Solitary thyroid metastasis from colon cancer: a rare case report. AB - Malignant metastases to the thyroid are rare and are even rarer from a colorectal primary. As these metastases are often asymptomatic, they are usually discovered incidentally on imaging performed as follow-up for the primary tumour. In this report, we present a case of metastatic sigmoid adenocarcinoma to the thyroid diagnosed and treated at our institution. PMID- 28101140 TI - Radiation-induced breast angiosarcoma: a case report. AB - Radiation-induced breast angiosarcoma is a severe but rare late complication in the breast-preserving management of breast cancer through surgery and radiotherapy [1]. Often the initial diagnosis of this entity is complex given its relatively anodyne nature and usually being present in the form of typically multifocal reddish-purple papular skin lesions [2]. Because of the low incidence of this tumour, there is a limited number of studies regarding its optimal therapeutic management [3]. The preferred treatment is aggressive surgical removal and the prognosis is poor with an overall survival rate of 12-20% at five years [4]. PMID- 28101141 TI - The principles of cancer staging. AB - The anatomic disease extent or tumour stage of a cancer at diagnosis as a determinant of prognosis is discussed. The importance of cancer stage in individual patient prognosis and determination of treatment is reviewed as well as its value in research and cancer control activities. The conflict between the need for stability of cancer stage definitions over time and the need to evolve with advances in medicine are examined. The ecancer elearning modules on Cancer Stage are introduced. PMID- 28101142 TI - Exploring accessibility of pretreated poplar cell walls by measuring dynamics of fluorescent probes. AB - BACKGROUND: The lignocellulosic cell wall network is resistant to enzymatic degradation due to the complex chemical and structural features. Pretreatments are thus commonly used to overcome natural recalcitrance of lignocellulose. Characterization of their impact on architecture requires combinatory approaches. However, the accessibility of the lignocellulosic cell walls still needs further insights to provide relevant information. RESULTS: Poplar specimens were pretreated using different conditions. Chemical, spectral, microscopic and immunolabeling analysis revealed that poplar cell walls were more altered by sodium chlorite-acetic acid and hydrothermal pretreatments but weakly modified by soaking in aqueous ammonium. In order to evaluate the accessibility of the pretreated poplar samples, two fluorescent probes (rhodamine B-isothiocyanate dextrans of 20 and 70 kDa) were selected, and their mobility was measured by using the fluorescence recovery after photobleaching (FRAP) technique in a full factorial experiment. The mobility of the probes was dependent on the pretreatment type, the cell wall localization (secondary cell wall and cell corner middle lamella) and the probe size. Overall, combinatory analysis of pretreated poplar samples showed that even the partial removal of hemicellulose contributed to facilitate the accessibility to the fluorescent probes. On the contrary, nearly complete removal of lignin was detrimental to accessibility due to the possible cellulose-hemicellulose collapse. CONCLUSIONS: Evaluation of plant cell wall accessibility through FRAP measurement brings further insights into the impact of physicochemical pretreatments on lignocellulosic samples in combination with chemical and histochemical analysis. This technique thus represents a relevant approach to better understand the effect of pretreatments on lignocellulose architecture, while considering different limitations as non specific interactions and enzyme efficiency. PMID- 28101143 TI - Clinical aspects of pancreatogenic diabetes secondary to hereditary pancreatitis. AB - BACKGROUND: Hereditary pancreatitis is a rare inherited form of pancreatitis, characterized by recurrent episodes of acute pancreatitis with early onset and/or chronic pancreatitis, and presenting brittle diabetes, composed of episodes of nonketotic hyperglycemia and severe hypoglycemia. The existing literature regarding this form of diabetes is scarce. In this report, clinical features of pancreatogenic diabetes secondary to hereditary pancreatitis are presented along with recommendations for appropriate medical treatment. RESULTS: Clinical data from five patients of a family with pancreatogenic diabetes secondary to hereditary pancreatitis were analyzed. The average time between hereditary pancreatitis and diabetes diagnosis was 80 +/- 24 months (range: 60-180 months) with a mean age of 25.6 +/- 14.7 years (range: 8-42 years), four patients used antidiabetic agents for 46 +/- 45 months and all progressed to insulin therapy with a mean dose of 0.71 +/- 0.63 IU/kg (range: 0.3-1.76 IU/kg). The glycemic control had a high variability with average capillary blood glucose of 217.00 +/- 69.44 mg/dl (range: 145-306 mg/dl) and the average HbA1c was 9.9 +/- 1.9% (range: 7.6-11.6%). No ketoacidosis episodes occurred and there were several episodes of hospitalization for severe hypoglycemia. CONCLUSIONS: Diabetes mellitus secondary to hereditary pancreatitis presents with early onset, diverse clinical presentation and with extremely labile glycemic control. Diabetes treatment varies according to the presentation and insulin is frequently necessary for glycemic control. PMID- 28101144 TI - Histopathological findings in systemic sclerosis-related myopathy: fibrosis and microangiopathy with lack of cellular inflammation. AB - OBJECTIVES: The objective of this study was to identify specific histopathological features of skeletal muscle involvement in systemic sclerosis (SSc) patients. METHODS: A total of 35 out of 112 SSc-patients (32%, including 81% female and 68% diffuse scleroderma) presenting clinical, biological and electromyographic (EMG) features of muscle weakness, were included. Patients underwent vastus lateralis biopsy, assessed for individual pathologic features including fibrosis [type I collagen (Coll-I), transforming growth factor beta (TGF-beta)], microangiopathy [cluster of differentiation 31 (CD31), pro angiogenic vascular endothelial growth factor A (VEGF-A), anti-angiogenic VEGF A165b], immune/ inflammatory response [CD4, CD8, CD20, human leucocyte antigens ABC (HLA-ABC)], and membranolytic attack complex (MAC). SSc biopsies were compared with biopsies of (n = 35) idiopathic inflammatory myopathies (IIMs) and to (n = 35) noninflammatory myopathies (NIMs). Ultrastructural abnormalities of SSc myopathy were also analyzed by transmission electron microscopy (TEM). RESULTS: Fibrosis in SSc myopathy (81%) is higher compared with IIM (32%, p < 0.05) and with NIM (18%, p < 0.05). Vascular involvement is dominant in SSc muscle (92%), and in IIM (78%) compared with NIM (21%, p < 0.05). In particular, CD31 shows loss of endomysial vessels in SSc myopathy compared with IIM (p < 0.05) and with NIM (p < 0.01). VEGF-A is downregulated in SSc myopathy compared with IIM (p < 0.05) and NIM (p < 0.05). Conversely, VEGF-A165b is upregulated in SSc myopathy. The SSc immune/inflammatory response suggested humoral process with majority (85%) HLA-ABC fibral neoexpression and complement deposits on endomysial capillaries MAC, compared with IIM (p < 0.05), characterized by CD4+/CD8+/B-cell infiltrate, and NIM (p < 0.05). TEM analysis showed SSc vascular alterations consisting of thickening and lamination of basement membrane and endothelial cell 'swelling' coupled to endomysial/perimysial fibrosis. CONCLUSIONS: Fibrosis, microangiopathy and humoral immunity are predominant in SSc myopathy, even if it is difficult to identify specific histopathological hallmarks of muscle involvement in SSc, since they could be present also in other (IIM/NIM) myopathies. PMID- 28101145 TI - Impact of physical activity and mechanical loading on biomarkers typically used in osteoarthritis assessment: current concepts and knowledge gaps. AB - There is an ongoing need to develop prognostic and diagnostic biomarkers for osteoarthritis (OA). Understanding how biomarkers change in response to physical activity may be vital for understanding if a patient has a joint that is failing to adapt to a given loading stimulus. The purpose of this review is to describe how biomarker changes after joint loading may help detect early OA and determine prognosis. This may help to inform and more specifically target interventions and clinical trials. We conducted a critical review of the relevant literature that was published to January 2016. There is extensive OA biomarker research, specifically basal biomarker concentrations; however, there is limited research surrounding biomarker response to load. Some of this limited research includes the response of minimal biomarkers reflecting bone, synovium, inflammatory, and cartilage responses to load. Biomarker changes occur in bone and cartilage in response to a variety of activities and are influenced by variables such as body weight, load, vibration, and activity time. Biomarker responses to loading tasks may serve as a measure of overall joint health and be predictive of structural changes. Biomarkers adapt to training over time, and this may indicate a need for a gradual return to physical activity after an injury to allow time for joint tissues to adapt to load. Biomarker responses to physical activity may be monitored to determine appropriate loading levels and safety for return to activity. PMID- 28101147 TI - A double gallbladder with a common bile duct stone treated by laparoscopy accompanied by choledochoscopy via the cystic duct: A case report. AB - A double gallbladder is a rare congenital malformation. The present study describes a case of double gallbladder with secondary common bile duct stones. By way of laparoscopic choledochoscopy, the exploration and removal of a common bile duct stone was performed through the cystic duct. The process involved a primary suture of the cystic duct and was performed without using a T-tube, and completed a surgical removal of the gallbladder. The present case was successfully treated by laparoscopic surgery. From a review of previous studies published in the English language, this study, to the best of our knowledge, is the first report of such a case. Therefore, laparoscopic dissection is safe for the removal of a double gallbladder and for exploration of the common duct by choledochoscopy. PMID- 28101146 TI - Bone health in HIV and hepatitis B or C infections. AB - Chronic infections with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) add to age-dependent bone loss and may contribute to lower bone strength in the elderly. In this review, we report recent highlights on the epidemiology of bone fragility in chronic viral infections with HIV, HCV and HBV, its physiopathology and discuss the interference of antiviral therapies with bone metabolism. Chronic infections influence bone through the interactions between risk factors for bone fragility and falls (which are highly prevalent in infected patients), virus activity and antiviral drugs. HIV-infected patients are at increased risk of fracture and the risk is higher in cases of co-infection with HIV and untreated chronic viral hepatitis. In HIV patients, the majority of bone loss occurs during virus activity and at initiation of antiretroviral therapy (ART). However, long-term elderly HIV-infected patients on successful ART display bone microstructure alterations only partially captured by dual energy X-ray absorptiometry (DXA). Bone loss is associated with an increase of bone resorption, reflecting the upregulation of the receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) pathways via a crosstalk between virus activity, inflammation and the immune system. The use of some antiviral drugs, such as tenofovir (controlling both HBV and HIV infections) or protease inhibitors, may be associated with higher bone toxicity. The reduction of tenofovir plasma concentrations with the implementation of tenofovir alafenamide (TAF) attenuates bone mineral density (BMD) loss but it remains unknown whether it will contribute to reducing fracture risk in long-term HIV-treated patients. Moreover, to what extent the new direct-acting agents for treatment of HCV, including nucleotide inhibitors and protease inhibitors, may affect bone health similarly as ART in HIV should be investigated. PMID- 28101148 TI - Cell therapy for cerebral hemorrhage: Five year follow-up report. AB - The aim of the study was to examine treatment of cerebral hemorrhages with bone marrow or human umbilical cord-derived mesenchymal stem cells (BMSCs or Hu-MSCs) and conventional surgical approaches, and determine and compare the effectiveness, feasibility, safety and reproducibility of each method. A retrospective analysis was performed on a cohort of cell-treated cerebral hemorrhage patients from October 1, 2007 to October 1, 2009. A total of 24 patients, all of whom received conventional surgical treatment, were classified as follows: i) The control group consisted of 8 patients who received only hematoma removal surgery, ii) the autologous group consisted of 7 patients who received additional autologous bone marrow mononuclear cell transplantation, and iii) the allograft group consisted of 9 patients who received additional umbilical cord mononuclear cell transplantation. After conventional hematoma removal surgery and X-ray supervision within 24 h and at 7 days, neurological disability and function tests were completed 3, 6, 12, 36 and 60 months later. The T-cell marker plasma levels were analyzed after 60 months. The results showed that, at approximately 3.5 months after graft the hematomas in all the groups were completely reabsorbed as observed on computed tomography scans. However, the functional outcomes in the cell-transplanted groups were better than in the control group after 5 years. While the National Institutes of Health Stroke Scale, modified Rankin score and modified Barthel index scores were simliar in the cell-transplanted groups, patients in the allograft group had better outcomes than those in the autologous graft group starting at 3 months and until the end of the follow-up period. The serum levels of T-cell markers CD4, CD56 and human leukocyte antigen-DR in the allograft group showed no signs of immunogenic graft complications and there were no significant differences in T-cell subtypes among the patient groups. The results of the present study suggest that, treatment of cerebral hemorrhage patients can be safely and effectively accomplished using Hu MSC grafting and larger clinical trials should be considered in the future. PMID- 28101149 TI - Effects of nano tantalum implants on inducing osteoblast proliferation and differentiation. AB - In the present study, we examined the effects of nano tantalum (Ta) dental implants on inducing osteoblast proliferation and differentiation. The MG-63 osteoblasts were divided into 3 groups after recovery, passage and storage: i) Osteoblast culturing group (control group); ii) osteoblast and titanium (Ti) implant co-culturing group (Ti group); and iii) osteoblast and Ta implant co culturing group (Ta group). After 7 days, a scanning electron microscope was used to observe the growth status, number and morphological changes of the cells on the surfaces of the materials. An MTT assay was used to detect cell proliferation after culturing for 1, 3 and 7 days. ELISA assay was used to detect the levels of alkaline phosphatase (ALP) after 1, 3 and 7 days. Western blot analysis was used to detect the expression levels of collagen type I (Col-1) and osteocalcin after 1, 3 and 7 days. There was significant cell spreading on the surfaces of Ti and of Ta after 7 days, flat and with many pseudopodia. Additionally, there were more cell components in the Ta group. Concurrently, cell proliferation in the Ti and Ta groups increased. There was also an increase in the level of ALP and the expression level of Col-1 over time. The indexes of the Ta group were more apparent than those of the Ti group at each time-point, and the differences were statistically significant (p<0.05). In conclusion, compared with Ti implants, Ta implants induced more osteoblast proliferation and differentiation. PMID- 28101150 TI - Promising effects of Chinese traditional treatment for child typhoid complicated by myocarditis. AB - The clinical effects were compared and analyzed of traditional Chinese medicine (TCM) 'Ling Gui Long Mu soup' combined with the conventional Western medications in treating child typhoid complicated by myocarditis. From July, 2010 to May, 2014, 54 children suffering from typhoid complicated by myocarditis were enrolled in the present study. The patients were divided into the observation and control groups (n=27 cases per group) according to the random number table. Patients in the observation group were treated with basic Western medicine combined with TCM 'Ling Gui Long Mu soup' while patients in the control group were treated only with Western medicine. We analyzed the final curative effects in the two groups. The total effective rate in the observation group was significantly higher than that of the control group and the difference was statistically significant (P<0.05). The improvement rate of the syndrome in the TCM observation group was significantly higher than that in the control group and the difference was statistically significant (P<0.05). Although the C-reactive protein (CRP) and creatinine kinase-MB (CK-MB) levels in the two groups were decreased following the treatment, CRP and CK-MB levels in the observation group were further reduced, and the difference was statistically significant (P<0.05). In conclusion, for child typhoid complicated by myocarditis, TCM 'Ling Gui Long Mu soup' significantly improved the clinical efficiency of the treatment and improved the syndrome. Therefore, 'Ling Gui Long Mu soup' is useful in clinical practice. PMID- 28101151 TI - Effect of general anesthesia on serum beta-amyloid protein and regional cerebral oxygen saturation of elderly patients after subtotal gastrectomy. AB - The aim of the present study was to investigate the influence of general anesthesia on serum beta-amyloid protein (Abeta) and regional cerebral oxygen saturation (rSO2) of elderly patients after subtotal gastrectomy. From June, 2014 to December, 2015, among 168 patients undergoing subtotal gastrectomy, the Mini Mental State Examination and Montreal Cognitive Assessment was administered the day prior to surgery and the second and ninth days after the operation. In addition, we administered the tests to 168 healthy adult volunteers (healthy controls) who were treated in our hospital medical center in the same period. Near-infrared spectroscopy technology was used for continuous monitoring of the intraoperative rSO2, and the mean of intraoperative rSO2 was then calculated. Of the 168 patients, 28 developed postoperative cognitive dysfunction (POCD) and the remaining 140 patients were normal (control). The ELISA method was used to test the expression levels of serum Abeta in the three groups and statistical analyses were conducted. Serum Abeta level in the POCD group was significantly higher than that in the control and healthy control groups, and the difference was statistically significant (P<0.05). The rSO2 level in the patients with POCD was significantly lower than the control group (P<0.05). The correlation analysis with Abeta as an independent variable and other factors as dependent variables revealed that the serum Abeta level negatively correlated with rSO2 (r=-1.6749, P<0.05). The combined Abeta and rSO2 may be useful for the diagnosis and prevention of POCD after subtotal gastrectomy under general anesthesia. PMID- 28101152 TI - The association between HERG gene expression and cardiac arrhythmia disease in children. AB - We explored the possible link between the expression of HERG gene and cardiomyopathy in children. From April 2013 to April 2015, 73 children with cardiac arrhythmia who were treated were enrolled in the present study to serve as the observation group. At the same time, 76 normal individuals were also enrolled as the control group. HERG expression level in the observation group was compared with the control group. To determine the level of HERG gene expression we used fluorescent directional PCR, enzyme immunoassay and western blot analysis. The results showed that HERG mRNA level in the observation group was significantly higher than that of the control group. The level of HERG protein in the observation group was significantly higher as well. In the observation group, HERG expression gradually increased with time during the course of the disease. This result suggested that HERG gene expression was associated with the severity of cardiac arrhythmia in children. HERG expression may be the cause of deterioration in cardiomyopathy. The results have provided a theoretical and practical basis for the diagnosis and treatment of children cardiomyopathy. Thus, we established a correlation between HERG expression and cardiac arrhythmia in children. PMID- 28101153 TI - Upregulated effects of miR-7 in methicillin-resistant Staphylococcus aureus. AB - The aim of the study was to investigate the characteristic function of the upregulated effects of miR-7 in methicillin-resistant Staphylococcus aureus (MRSA). After separating the MRSA in clinic, the expression of miR-7 mRNA was tested by reverse transcription polymerase chain reaction. The overexpression, inhibition of miR-7, and control group were established by plasmid in vitro. Following transfection of the bacterial strain, the effect of beta-lactam antibiotics in minimum inhibitory concentration (MIC) was observed using the microporous dilution method, and antibacterial effects in vitro were observed using the dynamic growth curve method. The expression of miR-7 in sensitive MRSA was upregulated distinctly, with significant difference (P<0.05). MIC and the number of bacteria in the miR-7 overexpression group significantly increased while the inhibition group decreased prominently, with significant difference (P<0.05). The control and null plasmid groups revealed no significant difference. In conclusion, miR-7 upregulated the antimicrobial activity of MRSA, and the intervention of its expression may become a possible antibacterial target. PMID- 28101154 TI - Minimally invasive open nephrectomy on children with multicystic dysplastic kidney. AB - The aim of the study was to summarize the preliminary experience of minimally invasive open nephrectomy operation on children with multicystic dysplastic kidney (MCDK). A retrospective review was performed on the clinical materials of the 15 children that had accepted consecutive minimally invasive open nephrectomies during the previous 2 years. The enrolled children were diagnosed with unilateral MCDK under computed tomography, emission computerized tomography and ultrasound and no anomaly in the contralateral functioning kidney was found. Of the 15 children, 12 were boys and 3 were girls, with 5 cases on the right and 10 cases on the left. Operations were completed at the retroperitoneal space in order to open an incision on the waists and ribs of the children, the length of which ranged from 1.5 to 2.0 cm (average 1.7 cm). The age of the children at operation ranged from 3 months to 5.6 years old, with an average of 2.4 years old. Surgery lasted for 30-50 min, with an average of 34.6 min. The estimated blood loss of each child was <5 ml. After operation, prophylactic intravenous antibiotics were administered for 2-4 days to prevent infection. All of the operations proved very successful. Following surgery the children were hospitalized for 2-4 days for observation, with an average of 2.8 days. No complications occurred during the follow-up period. In conclusion, minimally invasive open nephrectomy is effective for children with MCDK. The procedure is superior with regard to operative time, cosmesis, and length of stay. It is a safe and effective treatment choice for patietns with MCDK and can be easily performed on children. PMID- 28101155 TI - The 5-HT2A receptor potassium-chloride cotransporter 2 signaling pathway in a rat incision pain model. AB - Postoperative pain is a critical problem in clinical pain administration. Due to the unclear formation mechanism of postoperative pain, the treatment of postoperative pain is still in the symptomatic treatment stage and lacking satisfactory analgesic effect. Postoperative pain can be simulated by using a rat incision pain model. We observed changes in pain-related behavior of rats affected by the 5-hydroxytryptamine 2A receptor (5-HT2AR) agonist, TCB-2, and antagonist, ketanserin, through intrathecal delivery. The transcription and translation level of potassium-chloride cotransporter 2 (KCC2) in the spinal cord was also measured to investigate the role of the 5-HT2AR-KCC2 pathway in the mechanism of incision pain. Compared with the control group, rats in the incision pain group had decreased mechanical withdrawal threshold (MWT), with significant differences on day 1-7 after surgery, and significant decreases in thermal withdrawal latency (TWL) on days 1, 2, 3 and 6 (P<0.05). Compared with the incision + dimethyl sulfoxide (DMSO) group, MWT and TWL decreased in the incision + ketanserin group on day 1 and 2 (P<0.05). There was no significant difference detected in TWL of incision + TCB-2 group on day 1, while MWT increased significantly compared to the incision + DMSO group (P<0.05). Furthermore, the transcription and translation levels of KCC2 in the incision + ketanserin group decreased significantly in comparison to the incision + DMSO group (P<0.05), while an increase was detected in the incision + TCB-2 group (P<0.05). MWT and TWL decreased in the incision pain rats, accompanied with a decreased transcription and translation level of KCC2. Intrathecal delivery of the 5-HT2AR agonist, TCB-2, alleviated the decreased WMT and inhibited the decreased transcription and translation level of KCC2, while intrathecal delivery of the 5 HT2AR antagonist, ketanserin, aggravated the decreased WMT and transcription and translation levels of KCC2, suggesting the involement of the 5-HT2AR-KCC2 pathway in the formation mechanism of incision pain in rats. PMID- 28101156 TI - Clinical and microbiological profile of babies born with risk of neonatal sepsis. AB - The aim of the present study was to evaluate the effects of antibiotics on the condition of babies born with risk of neonatal sepsis. From March, 2014 to February, 2015, 200 neonates born with risk factors of septicemia in the Neonatal Intensive Care Unit at Xuzhou Central Hospital, were enrolled in the present study. Venous blood samples were collected within 6 h of birth using aseptic technique. Part of the blood specimens were cultured using BACTEC PEDS PLUS/F Culture Vials. Subsequently, the subcultures were prepared from each presumptive positive vial and bacterial isolates were identified. The remaining portion was used to measure the level of C-reactive protein (CRP) and total leukocyte count (TLC). The result showed that 32% of neonates were infected, of whom, 21.9% had Staphylococcus aureus, 21.9% had Acinetobacter Baumanni, and 12.5% had Klebsiella pneumoniae. Additionally, Staphylococcus epidermis, Enteroccus spp., Pseudomonas aeruginosa and E. coli was isolated from 9.4, 7.8, 6.3 and 4.7% of neonates, respectively. The neonates enrolled in the present study had >=1 risk factor for neonatal sepsis, and the average number of risk factors was 1.95 per neonate. Neonates (39.1%) with positive blood culture results, had a CRP level >0.8 mg/dl, and 12.5% was shown to have an abnormal increase in their leukocyte counts. The association between leukocyte counts and blood culture results was not statistically significant. Of the neonates with positive blood cultures 45.3% died within 7 days after birth, while there was no mortality among those with negative culture results. The results indicate that in the presence of risk factors for sepsis, irrespective of clinical features of septicemia, neonatal sepsis screening should be performed. Rational and appropriate use of antibiotics may minimize the emergence of multidrug resistant bacteria in neonatal units. PMID- 28101157 TI - Functional analysis of keratinocyte and fibroblast gene expression in skin and keloid scar tissue based on deviation analysis of dynamic capabilities. AB - The aim of the present study was to select key genes that are associated with fibroblasts and keratinocytes during keloid scar progression and development. The gene expression profile of GSE44270, which includes 32 samples, was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) in case samples compared with control samples were screened using the Limma R package followed by hierarchical clustering analysis. Protein-protein interaction (PPI) networks of the total selected DEGs were constructed using Cytoscape. Moreover, the Gene Ontology biological processes and significant Kyoto Encyclopedia of Genes and Genomes pathways of the total selected DEGs were enriched using the Database for Annotation, Visualization and Integrated Discovery. Significant pathways that may be associated with keloid scar were analyzed using deviation analysis of dynamic capabilities. There were 658 DEGs in fibroblast keloid vs. normal, 112 DEGs in fibroblast non-lesion vs. normal, 439 DEGs in fibroblast keloid vs. non-lesion, 523 DEGs in keratocyte keloid vs. normal, 186 DEGs in keratocyte non-lesion vs. normal, and 963 DEGs in keratocyte keloid vs. non-lesion groups. HOXA9, BMP4, CDKN1A and SMAD2 in fibroblasts, and HOXA7, MCM8, PSMA4 and PSMB2 in keratinocytes were key genes in the PPI networks. Moreover, the amino sugar and nucleotide sugar metabolism pathway, cell cycle, and extracellular matrix (ECM)-receptor interaction pathway were significant pathways. This study suggests that several key genes (BMP4, HOXA9, SMAD2, CDKN1A, HOXA7, PSMA4 and PSMB2) that participate in some significant pathways (cell cycle and ECM-receptor interaction pathways) may be potential therapeutic targets for keloid scars. PMID- 28101159 TI - Clinical effects of FURL and PCNL with holmium laser for the treatment of kidney stones. AB - In the present study, the clinical effects of flexible ureteroscopy lithotripsy (FURL) and percutaneous nephrolithotomy (PCNL) for the treatment of kidney stones of <=2 cm was studied. Seventy-two patients with kidney stones were randomly divided into the FURL group (n=39) under ureteroscope lithotripsy with holmium laser and PCNL group (n=33) under PCNL with holmium laser and compared their clinical effects. At 3 months after the operation, the stone removal rate of the FURL group was significantly higher than that of the PCNL group. The subgroup analysis revealed that the difference in the lower kidney calyx was more obvious (P<0.05) while the difference in the complex kidney stones was not statistically significant (P>0.05). The incidence of complications of the FURL group was significantly lower than that of the PCNL group (P<0.05). The operation time and recurrence rate of the FURL group were significantly less than that of the PCNL group (P<0.05). Differences regarding the creatinine and urea nitrogen levels before operation, and 3 and 7 days after the operation between the two groups were not statistically significant (P>0.05). Additionally, 3 and 7 days after operation, the cystatin C levels of the FURL group were significantly higher than those of the PCNL group, and the KIM-1 levels were significantly lower than the PCNL group (P<0.05). In conclusion, compared with PCNL with holmium laser, FURL with holmium laser was more safe and effective in treating kidney stones <=2 cm. Therefore, the method is worthy of wide application in clinic. PMID- 28101158 TI - Prevalence of carbapenemases among high-level aminoglycoside-resistant Acinetobacter baumannii isolates in a university hospital in China. AB - The prevalence of aminoglycoside resistant enzymes has previously been reported and extended-spectrum beta-lactamase among Acinetobacter baumannii. To track the risk of multidrug-resistant A. baumannii, the present study aimed to determine the prevalence of carbapenemases in high-level aminoglycoside resistant A. baumannii over two years. A total of 118 strains of A. baumannii were consecutively collected in the First Affiliated Hospital of Chengdu Medical College, Chengdu, China. These isolates were investigated on the genetic basis of their resistance to aminoglycosides. The results showed that 75 (63.56%) isolates were high-level resistant to aminoglycosides, including gentamicin and amikacin (minimum inhibitory concentration, >=256 ug/ml). Aminoglycoside-resistant genes ant(2")-Ia, aac(6')-Ib, aph(3')-Ia, aac(3)-Ia, aac(3)-IIa, armA, rmtA, rmtB, rmtC, rmtD, rmtE, rmtF, rmtG, rmtH and npmA, and carbapenem-resistant genes blaOXA-23, blaOXA-24, blaOXA-51, blaOXA-58, blaSIM, blaIMP, blaNDM-1 and blaKPC, were analyzed using polymerase chain reaction. The positive rate of ant(2")-Ia, aac(6')-Ib, aph(3')-Ia, aac(3)-Ia and aac(3)-IIa was 66.95, 69.49, 42.37, 39.83 and 14.41%, respectively. armA was present in 72.0% (54/75) of A. baumannii isolates with high-level resistance to aminoglycosides. The remaining nine 16S ribosomal RNA methlyase genes (rmtA, rmtB, rmtC, rmtD, rmtE, rmtF, rmtG, rmtH and npmA) and aminoglycoside-modifying enzyme gene aac(6')-Ib-cr were not detected. Among the 54 armA-positive isolates, the prevalence of the carbapenem resistant blaOXA-23 and blaOXA-51 genes was 79.63 and 100%, respectively. armA, ant(2")-Ia and aac(6')-Ib were positive in 43 isolates. The results of multilocus sequence typing revealed 31 sequence types (STs) in all clinical strains. Among these STs, the high-level aminoglycoside-resistant A. baumannii ST92, which mostly harbored blaOXA-23, was the predominant clone (29/75). In conclusion, A. baumannii harboring carbapenemases and aminoglycoside-resistant enzymes are extremely prevalent in western China, emphasizing the need to adopt surveillance programs to solve the therapeutic challenges that this presents. PMID- 28101160 TI - Facile mechanical shaking method is an improved isolation approach for islet preparation and transplantation. AB - Successful islet isolation is crucial for islet transplantation and cell treatment for type 1 diabetes. Current isolation methods are able to obtain 500 1,000 islets per rat, which results in a waste of >=50% of total islets. In the present study, a facile mechanical shaking method for improving islet yield (up to 1,500 per rat) was developed and summarized, which was demonstrated to be more effective than the existing well-established stationary method. The present results showed that isolated islets have a maximum yield of 1,326+/-152 when shaking for 15 min for the fully-cannulated pancreas. For both fully-cannulated and half-cannulated pancreas in the presence of rat DNAse inhibitor, the optimal shaking time was amended to 20 min with a further increased yield of 1,344+/-134 and 1,286+/-124 islets, respectively. Furthermore, the majority of the isolated islets were morphologically intact with a well-defined surface and almost no central necrotic zone, which suggested that the condition of islets obtained via the mechanical shaking method was consistent with the stationary method. Islet size distribution was also calculated and it was demonstrated that islets from the stationary method exhibited the same size distribution as the non-cannulated group, which had more larger islets than the fully-cannulated and half-cannulated groups isolated via the shaking method. In addition, the results of glucose challenge showed that the refraction index of each group was >2.5, which indicated the well-preserved function of isolated islets. Furthermore, the transplanted islets exhibited a therapeutic effect after 1 day of transplantation; however, they failed to control blood glucose levels after ~7 days of transplantation. In conclusion, these results demonstrated that the facile mechanical shaking method may markedly improve the yield of rat islet isolation, and in vitro and in vivo investigation demonstrated the well-preserved function of isolated islets in the control of blood glucose. Therefore, the facile mechanical shaking method may be an alternative improved procedure to obtain higher islet yield for islet preparation and transplantation in the treatment of type 1 diabetes. PMID- 28101161 TI - Clinical effect of hydrocolloid dressings in prevention and treatment of infant diaper rash. AB - The aim of the study was to investigate the application of hydrocolloid dressings in the prevention and treatment of infant diaper rash. A total of 210 infants with diaper rash were included in the study and randomized into 3 groups of 70 infants. Infants in group A received hydrocolloid dressings and individualized nursing; infants in group B received mupirocin plaster and topical application of pearl powder as well as routine nursing; and infants in group C received zinc oxide plaster and routine nursing. The clinical efficacy, incidence of adverse events, time to resolution of diaper rash, hospitalization duration, mean cost and satisfaction of nursing were compared between the 3 groups. After 1 cycle of treatment and nursing, the difference in the healing rate of mild diaper rash between groups A, B and C was significant (P<0.05), with the best healing rate in group A. Differences in the healing rate of grade I and II diaper rash between groups A, B and C was significant (P<0.05), with the best healing rate in group A. The incidence of adverse events in infants between groups A, B and C were significantly different (P<0.05), with the lowest incidence in group A (2.9%). The time to resolution of diaper rash, hospitalization duration and cost in infants were not significantly different (P<0.05). The satisfaction rate of nursing for the parents of groups A, B and C was 98.6, 87.1 and 80.0%, respectively (P<0.05). Hydrocolloid dressings combined with individualized nursing may prevent and treat infant diaper rash effectively, decrease the incidence of adverse reactions significantly, shorten time to resolution of diaper rash and hospitalization duration, reduce mean hospitalization cost, improve parent satisfaction and promote nursing-patient harmony. Thus, this method of treatment was worthy of clinical application. PMID- 28101162 TI - Correlation between high perfusion syndrome and stent restenosis after stent implantation. AB - The present study was conducted to determine the correlation between high perfusion syndrome and stent restenosis after cerebral vascular stent implantation. A total of 146 patients diagnosed with cerebral vascular stenosis and stent implantation were selected. A total of 55 cases (37.67%) of cerebral hyperperfusion syndrome patients were diagnosed by xenon-enhanced computer tomography (Xe-CT) examination and clinical symptoms within 3 days after surgery and were chosen as the observation group. A total of 91 cases were selected as the control group. After treatment, blood flow of the anterior cerebral artery, middle cerebral artery, posterior cerebral artery, anterior border zone, posterior border zone and the inner border zone of the two groups increased, with values in the observation group increasing more significantly, and the differences were statistically significant (P<0.05). The rate of restenosis and target lesion diameter one month and one year after operation in the observation group were significantly higher than those in the control group (P<0.05). Multivariate logistic regression analysis showed that the mean systolic blood pressure (mSBP), mean diastolic blood pressure (mDBP), stenosis rate of cerebral vascular diameter and high perfusion syndrome were independent risk factors for restenosis (P<0.05). The application of Xe-CT examination is important for early diagnosis of hyperperfusion syndrome. Hyperperfusion syndrome and the occurrence of stent restenosis are closely related. mSBP, mDBP, cerebral blood vessel diameter stenosis rate and high perfusion comprehensive syndrome are the independent risk factors of restenosis. PMID- 28101163 TI - Expression of adrenomedullin in rats after spinal cord injury and intervention effect of recombinant human erythropoietin. AB - The expression of adrenomedullin (ADM) in injured tissue of rat spinal cord was observed and the effect of recombinant human erythropoietin was analyzed. A total of 45 Sprague-Dawley rats were selected and divided into 3 equal groups including, a sham-operation group in which rats received an excision of vertebral plate; a spinal cord injury model group and a recombinant human erythropoietin group in which rats with spinal cord injury received a caudal vein injection of 300 units recombinant human erythropoietin after injury. Hematoxylin and eosin staining was performed to observe the spinal cord injury conditions. Immunohistochemical staining was performed to observe the expression of ADM. Pathologic changes in the group of recombinant human erythropoietin at various times were significantly less severe than those in the group of spinal cord injury model. The expression of ADM was increased particularly in the group of recombinant human erythropoietin (P<0.01). The improved Tarlov scores of the group of spinal cord injury model and the group of recombinant human erythropoietin were lower than those of the sham-operation group at 3, 6 and 9 days (P<0.01). Thus, the recombinant human erythropoietin is capable of alleviating the secondary injury of spinal cord. One of the mechanisms may be achieved by promoting the increase of ADM expression. PMID- 28101164 TI - Paeoniflorin attenuates hippocampal damage in a rat model of vascular dementia. AB - Paeoniflorn (PF), the principal bioactive component of Paeoniae radix prescribed in traditional Chinese medicine, possesses a wide range of biological effects and exhibits neuroprotective effects in numerous diseases. Previous studies have demonstrated that PF significantly attenuates memory impairment in rats with vascular dementia (VD). In the present study, a bilateral common carotid artery occlusion (BCCAO) rat model was used to explore the underlying mechanisms of PF. The expression levels of neuron-specific enolase (NSE), S100beta, B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein, cytochrome c and brain-derived neurotrophic factor (BDNF) in the hippocampus were measured by western blot analysis. The results showed that administration of PF for 28 days significantly decreased the expression levels of NSE and S100beta, both sensitive markers for brain damage, in vascular dementia (VD) model rats. In addition, PF inhibited the initiation of apoptotic cell death and attenuated the decreased expression levels of BDNF induced by bilateral common carotid artery occlusion. These data confirm the neuroprotective effects of PF on VD and provide a novel insight into the long term use of PF as a potential treatment in the stages of early cognitive impairment in VD. PMID- 28101165 TI - Functions of microRNA-143 in the apoptosis, invasion and migration of nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is a common cancer characterized by poor prognosis in areas of Southern China where it is endemic. microRNAs (miRNAs) are a class of naturally occurring small noncoding RNAs, some of which contribute to the initiation and development of cancer. The current study was designed to examine the expression level of miR-143 in NPC tissues. The potential functional targets of miR-143 involved in tumor apoptosis, invasion and migration were also investigated. Reverse transcription-quantitative polymerase chain reaction was used to evaluate the expression levels of miR-143 in clinical NPC specimens. Western blotting was used to explore the expression levels of extracellular signal regulated kinase (ERK)-5, Kirsten rat sarcoma viral oncogene homolog (KRAS), caspase 3 and B-cell lymphoma 2 (Bcl-2) in CNE-2Z cells following transfection with miR-143. Significantly decreased expression levels of miR-143 were observed in NPC tissues in comparison with matched normal nasopharyngeal tissues. Moreover, negative associations of miR-143 with tumor invasion depth, as well as lymph node metastasis were found. The enforced expression of miR-143 induced NPC cell apoptosis in addition to the suppression of growth, migration and invasion. The functions of miR-143 in NPC are mediated, at least in part, by the inhibition of ERK-5 activity and promotion of caspase 3 and KRAS expression. These findings suggest that miR-143 may function as a tumor suppressor in the development and progression of NPC. PMID- 28101166 TI - Hsp70 inducer, 17-allylamino-demethoxygeldanamycin, provides neuroprotection via anti-inflammatory effects in a rat model of traumatic brain injury. AB - Traumatic brain injury (TBI) is the predominant cause of mortality in young adults and children living in China. TBI induces inflammatory responses; in addition, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 are important pro-inflammatory cytokines. Considering the observation that Hsp-70 overexpression can exert neuroprotection, identifying a drug that is able to induce the upregulation of Hsp70 has the potential to be a promising therapy for the treatment of neurological diseases. Thus, the present study assessed the clinical effectiveness of an anticancer drug and Hsp70 activator, 17 allylamino-demethoxygeldanamycin (17-AAG), to evaluate its potential as a treatment for patients with TBI. The aim of present study was to determine the neuroprotective effects of 17-AAG following trauma and to investigate the underlying mechanisms of action. To establish rat models, rats were subjected to a controlled cortical impact injury and randomly divided into vehicle or 17-AAG groups. In the 17-AAG group, rats were administered with an intraperitoneal injection of 17-AAG (80 mg/kg) immediately following the establishment of TBI. The motor function was measured using Neurologic Severity Score, and neuronal death was evaluated using immunofluorescence. The expression levels of GLT-1, Bcl 2 and Hsp-70 were detected by western blot analysis and the expression levels of inflammatory cytokines were quantified using ELISA. The present study determined that 17-AAG significantly reduced brain edema and motor neurological deficits (P<0.05), in addition to increasing neuronal survival. The aforementioned findings are associated with a downregulation of the expression levels of pro inflammatory cytokines TNF-alpha, IL-1beta and IL-6. Conversely, no significant changes of glutamate transporter-1 expression were observed. The present results suggest that 17-AAG treatment may provide a neuroprotective effect by reducing inflammation following TBI. PMID- 28101167 TI - Protective approaches against myocardial ischemia reperfusion injury. AB - Myocardial ischemia-reperfusion is the leading cause for the events of cardiovascular disease, and is considered as a major contributor to the morbidity and mortality associated with coronary occlusion. The myocardial damage caused by ischemia-reperfusion injury constitutes the primary pathological manifestation of coronary artery disease. It results from the interaction between the substances that accumulate during ischemia and those that are delivered on reperfusion. The level of this damage can range from a small insult resulting in limited myocardial damage to a large injury culminating in myocyte death. Importantly, major ischemia-reperfusion injury to the heart can result in permanent disability or death. Given the worldwide prevalence of coronary artery disease, developing a strategy to provide cardioprotection against ischemia-reperfusion-induced damage is of great importance. Currently, the treatment of reperfusion injury following ischemia is primarily supportive, since no specific target-oriented therapy has been validated thus far. Nevertheless, therapeutic approaches to protect against myocardial ischemia-reperfusion injury remain an active area of investigation given the detrimental effects of this phenomenon. PMID- 28101168 TI - CT-guided 125I seed implantation for inoperable retroperitoneal sarcoma: A technique for delivery of local tumor brachytherapy. AB - Radical surgery is currently the first treatment of choice for retroperitoneal soft tissue sarcoma (RSTS). However, the prognosis of RSTS remains poor due to ineffective local control and a high incidence of metastasis after surgical resection. Brachytherapy has been shown to safely provide local radiotherapy for numerous types of cancer when used alone or in combination with surgical resection, but has not been well characterized in the management of RSTS. The aim of this study was to evaluate CT-guided 125I seed implantation for local control and pain relief in the treatment of inoperable RSTS. A total of 23 patients with RSTS were treated with 125I implantation. Pain was assessed using a visual analog scale. Other endpoints were evaluated via computed tomography scan or phone call/e-mail records. The occurrence of complications was assessed preoperatively (baseline) and during postoperatively follow-up or until patient succumbed. All patients were successfully treated with 125I implantation. A mean number of 70.87 radioactive seeds were applied in each patient. During the follow-up, two patients were unaccounted for, local recurrence occurred in three patients, five succumbed and complications were observed in sixteen. The patient's VAS score changed from 7.4 preoperatively to 7.6, 2.3, 2.0, 1.2, 1.5, 1.4 and 2.5 at 24 h, 1, 3, 6, 12, 24 and 36 months after the procedure, respectively. Good local control and significant pain relief after 125I seed implantation was observed in patients with inoperable RSTS. Thus, the present results suggest that this method could be an effective treatment option for patients with inoperable RSTS. PMID- 28101170 TI - Extramedullary hematopoiesis: A report of two cases. AB - Extramedullary hematopoiesis (EMH) is defined as hematopoiesis occurring in organs outside of the bone marrow. The present report describes two cases of thalassemic patients with paraspinal medullary hematopoiesis and analyzes the clinical manifestations, imaging, pathology, diagnosis and treatment of EMH. In addition, a supplementary review of previously published cases is provided along with a review of the related literature. Computed tomography (CT) of the first case revealed multiple paraspinal masses, and the largest was 6.2*8.0 cm in diameter. Likewise, CT of the second patient revealed multiple paraspinal masses in the bottom of the left thoracic cavity, and the largest was measured 10.1*10.5 cm. The two cases underwent surgical biopsy and the findings were compatible with a diagnosis of EMH. In conclusion, EMH is a compatible and rare disease, and should be distinguished from other neoplasms. EMH must considered when masses with characteristic radiologic appearance are detected in patients with thalassemia intermedia. PMID- 28101171 TI - Effect of glucocorticoid on cytokines TLR9 and TLR7 in peripheral blood for patients with uveitis. AB - The effect of glucocorticoid on cytokines Toll-like receptor (TLR)9 and TLR7 in peripheral blood of patients with uveitis was explored. Forty-six patients with uveitis admitted to our hospital from April 2014 to April 2015 were selected as the research observational group. Thirty-five able-bodied individuals in the same period were selected as the control group. To treat uveitis, the observational group was injected with glucocorticoid (1-2 mg/kg/day) daily, while the control group did not receive any treatment. The quantity of expression of peripheral blood cytokines TLR9 and TLR7 were detected by the methods of fluorescence quantitative PCR, enzyme-linked immunosorbent assay and western blotting. The content of peripheral blood TLR9 and TLR7 (0.21+/-0.01, 0.19+/-0.01) decreased significantly (P<0.05) in observational group after glucocorticoid treatment. Compared with data of control group (0.21+/-0.01, 0.19+/-0.01), TLR9 and TLR7 content in peripheral blood after glucocorticoid treatment on the patients with uveitis from observation group (0.19+/-0.01, 0.17+/-0.01) did not show any significant difference, for correlation between TLR9 and TLR7 in observation group before and after treatment. It was observed that the cytokine content of TLR9 was associated with TLR7 positively (r=0.653, P=0.012). In conclusion, glucocorticoid can improve uveitis by reducing the content of cytokines TLR9 and TLR7 in peripheral blood. PMID- 28101169 TI - Role of Wnt/beta-catenin, Wnt/c-Jun N-terminal kinase and Wnt/Ca2+ pathways in cisplatin-induced chemoresistance in ovarian cancer. AB - The aim of the present study was to explore the expression of Wnt signaling proteins beta-catenin, c-Jun N-terminal kinase (JNK) and Ca2+/calmodulin dependent protein kinase II (CaMKII) in ovarian cancer cells, and assess the correlation between this expression and cisplatin-induced chemoresistance. SKOV3 ovarian carcinoma cells and SKOV3/DDP (cisplatin resistant) cells were treated with cisplatin in the absence or presence of a Wnt signaling activator (CHIR 99021, glycogen synthase kinase 3beta inhibitor) or inhibitor (XAV-939, tankyrase inhibitor). Following incubation for 48 h, cell viability, proliferation and cytotoxicity were measured using a sensitive colorimetric cell counting kit. Expression levels of beta-catenin, JNK and CaMKII were detected by western blot and immunofluorescence staining. The results of the current study identified that beta-catenin and JNK expression levels were significantly higher (P<0.01 and P<0.05 respectively), while CaMKII expression was lower (P>0.05), in SKOV3/DDP cells compared with SKOV3 cells. Moreover, following treatment with 20 uM cisplatin, reduced expression of beta-catenin and JNK (P<0.05 and P<0.01 respectively), and increased expression of CaMKII (P<0.01), was observed in SKOV3 and SKOV3/DPP cell lines. Furthermore, inhibition of beta-catenin signaling by XAV-939 effectively reversed cisplatin chemoresistance in SKOV3/DDP cells. Similarly, XAV-939 downregulated JNK expression (P<0.001), but upregulated CaMKII expression (P<0.001), in SKOV3/DDP cells. In conclusion, abnormal activation of Wnt/beta-catenin and Wnt/JNK signaling pathways in ovarian cancer cells promotes cisplatin resistance, while the Wnt/Ca2+ signaling pathway reduces cisplatin resistance. This indicates that beta-catenin, JNK and CaMKII are potential therapeutic targets in chemoresistant ovarian cancers. PMID- 28101172 TI - Adenosine triphosphate stress 99mTc-methoxyisobutylisonitrile gated myocardial perfusion imaging efficacy in diagnosing stent restenosis following coronary stent implantation. AB - Coronary stent restenosis rate following implantation is considerably high. The adenosine stress gated myocardial perfusion imaging (G-MPI) method has been widely used in the diagnosis, risk stratification and prognosis evaluation of coronary heart disease; however, the high cost of adenosine limits its clinical application. The aim of the present study was to investigate the efficacy of adenosine triphosphate (ATP) stress 99mTc-methoxyisobutylisonitrile (99mTc-MIBI) G-MPI for diagnosis in-stent restenosis following coronary stent implantation. Data from 66 patients with typical angina pectoris symptoms who had undergone percutaneous coronary stent implantation >3 months prior to participation in the study were analyzed. All the patients underwent ATP stress 99mTc-MIBI G-MPI and coronary artery angiography as the criterion diagnostic standard within 1 month. The sensitivity, specificity, and accuracy of ATP stress 99mTc-MIBI G-MPI in the assessment of in-stent restenosis were calculated. In addition, Fisher's exact probability methods were used to compare differences between experimental groups. Among 66 patients with a total of 99 implanted coronary arterial branches, 39 patients (59%) with 45 coronary arteries (45%) presented in-stent restenosis. The diagnostic sensitivity, specificity, accuracy, positive predictive and negative predictive value of ATP stress 99mTc-MIBI G-MPI for assessing stent restenosis in all patients were 85, 89, 86, 92 and 80%, respectively. Similarly, these values in patients with myocardial infarction were 79, 88, 83, 88 and 78%, respectively, while in patients without myocardial infarction the values were 90, 91, 90, 95 and 83%, respectively. Therefore, the diagnostic efficacy of ATP stress 99mTc MIBI G-MPI in patients without myocardial infarction was higher compared with those with myocardial infarction; however, no significant difference was observed between the two groups. Furthermore, the sensitivity, specificity and accuracy for diagnosing LAD stent restenosis were higher compared with LCX and RCA stent restenosis, but with no significant differences observed (P>0.05). The present results indicated that ATP stress 99mTc-MIBI G-MPI had a high clinical application value for diagnosing in-stent restenosis following coronary stent implantation as a non-invasive examination tool, with the advantages of safety and low cost. PMID- 28101173 TI - Particularly interesting Cys-His-rich protein is highly expressed in human intracranial aneurysms and resists aneurysmal rupture. AB - Particularly interesting Cys-His-rich protein (PINCH) has several biological functions in cancer development, invasion and metastasis in malignant cells, and the expression of PINCH is upregulated in several cancer types, including breast cancer, gastric adenocarcinoma and rectal cancer. However, the contribution of PINCH to human cerebral aneurysms remains largely unknown. Therefore, the significance of PINCH expression in cerebral aneurysm growth and rupture was examined in the present study. The protein expression levels of alpha-smooth muscle actin, osteopontin (OPN), matrix metalloproteinase (MMP) 9 and PINCH were evaluated using immunohistochemistry and western blot analyses. The results demonstrate that the protein expression levels of OPN, MMP9 and PINCH in the unruptured intracranial aneurysm (UA) and ruptured intracranial aneurysm (RA) groups were markedly higher than those of the control group, whereas OPN and PINCH expression levels were decreased in the RA group compared to those of the UA group. In addition, there was a strong correlation between PINCH and tumor size (r=0.650 and P=0.0026), as well as between PINCH and OPN (r=0.639 and P=0.0033) in the unruptured cerebral aneurysms. However, the correlation between PINCH and tumor size (r=0.450 and P=0.1393) and between PINCH and OPN (r=0.366 and P=0.2426) revealed no obvious difference in the ruptured cerebral aneurysms. In conclusion, PINCH was highly expressed in the UAs, which may be a critical factor for preventing aneurysmal rupture. Moreover, PINCH may facilitate intracranial aneurysm progression, at least partially, through the activation of extracellular signal-regulated kinase signaling and the suppression of c-Jun N terminal kinase signaling. PMID- 28101174 TI - Protective effects of resveratrol on autologous nucleus pulposus model of radiculopathy. AB - Nucleus pulposus (NP) has been suggested to trigger an autoimmune response if exposed to the immune system, which plays a key role in neuropathic pain. Therefore, appropriate suppression of inflammation is a key factor for treating the radiculopathy caused by intervertebral disk (IVD) degeneration. Resveratrol, a key component of red wine, has been suggested to exhibit anti-inflammatory properties in vitro and in vivo. However, the effects of resveratrol on NP mediated pain in vivo have not been studied. The aim of the present study was to investigate whether resveratrol may be useful in treating NP-mediated pain in an autologous NP model of radiculopathy. A total of 36 adult male Sprague-Dawley rats were allocated randomly into sham (group I), saline-treated (group II) and resveratrol-treated (group III) groups. Animal behavior in response to non noxious mechanical stimulation with von Frey filaments was compared at days 0 (baseline), 3, 7, 14 and 21 following surgery. The expression of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL 1) were assessed at days 7 and 14. The data showed that resveratrol exhibited an anti-inflammatory effect on the expression of proinflammatory cytokines. Compared with group II, the expression of TNF-alpha and IL-1 was significantly decreased at each time point in group III. In addition, resveratrol significantly reduced pain behavior triggered by the application of NP tissue on the dorsal root ganglion for up to 14 days. These data suggest that resveratrol has potential for the treatment of NP-mediated pain, indicating a potential clinical application. PMID- 28101175 TI - Effect of miR-146a and miR-155 on cardiac xenotransplantation. AB - The aim of the present study was to investigate the expression levels of miR-146a and miR-155 in a cardiac xenograft model treated with the immunosuppressant FK506, and to construct lentiviral vectors to further study the roles of miR-146a and miR-155 in cardiac xenotransplantation. Expression levels of miR-146a and miR 155 were examined by quantitative polymerase chain reaction analysis and protein expression of RelA, which is a member of the nuclear factor-kappaB family, was examined by western blot analysis. Pre-miR-146a and pre-miR-155 fragments were designed and synthesized according to MiRBase and were cloned into the plasmid pCDH1-MCS1-EF1-copGFP. Recombinant plasmids were identified by enzyme digestion and sequencing. Survival time of cardiac grafts in the FK506 treatment group was significantly increased in comparison with the control group (P<0.05). In addition, the histopathological grading results were significantly decreased in the treatment group (P<0.05). A significant decrease in RelA protein expression levels was observed in the treatment group (P<0.05), along with a significant increase in miR-146a expression levels (P<0.05) and a significant decrease in miR 155 expression levels (P<0.05). Digestion and sequencing findings demonstrated that the insertion of miRNA into the plasmid pCDH1-MCS1-EF1-copGFP conformed with the pre-miRNAs, and the lentiviral vectors were concentrated to a titer of 5*107 IFU/ml. These findings demonstrated that FK506 is able to inhibit the rejection effect in a mouse-to-rat cardiac xenotransplantation model. FK506 treatment altered the expression levels of miR-146a and miR-155, indicating that they may have an important role in regulating the immune response to the rejection effect. miR-146a and miR-155 lentiviral vectors were successfully constructed for further experiments both in vitro and in vivo. PMID- 28101176 TI - Anticancer effects of valproic acid on oral squamous cell carcinoma via SUMOylation in vivo and in vitro. AB - Aberrant histone deacetylase (HDAC) has a key role in the neoplastic process associated with the epigenetic patterns of tumor-related genes. The present study was performed to investigate the effects and determine the mechanism of action of the HDAC inhibitor, valproic acid (VPA), on the CAL27 cell line derived from oral squamous cell carcinoma (OSCC). The effects of VPA on the viability of CAL27 cells were investigated using MTT assays. Alterations in the cell cycle and apoptosis were also examined using propidium iodide (PI) and Annexin V-PI assays, and were subequently analyzed by flow cytometry. Small ubiquitin-related modifier (SUMO)-related genes were evaluated by reverse transcription-quantitative polymerase chain reaction analysis. In addition, the effects of VPA were assessed using a xenograft model in vivo. The present results demonstrated significant dose-dependent inhibition of cell viability following VPA treatment. Treatment with VPA increased the distribution of CAL27 cells in the G1 phase and reduced cells in the S phase, and significantly increased the expression levels of SUMO1 and SUMO2 (P<0.01). Using a xenograft model, the mean tumor volume in VPA-treated animals was demonstrated to be significantly reduced, and the rate of apoptosis was significantly increased, as compared with the control animals. These results suggested that VPA may regulate SUMOylation, producing an anticancer effect in vivo. Further investigation into the role of VPA in tumorigenesis may identify novel therapeutic targets for OSCC. PMID- 28101177 TI - Analysis on mechanism of ATP-sensitive K+ channel opener natakalim improving congestive heart failure after myocardial infarction. AB - The action mechanism of natakalim, a novel ATP-sensitive potassium channel opener, was studied in ameliorating the congestive heart failure (CHF) after myocardial infarction. A total of 25 healthy Wistar male rats (age, 10 weeks; average weight, 300 g) were selected, and the CHF models after acute myocardial infarction (AMI) were prepared by ligation of left anterior descending branch. They were randomly divided into the sham operation group, the model group and the groups of 1, 3 and 9 mg/kg/day natakalims. Each group had 5 mice that were sacrificed after 8 weeks. We compared left ventricular end-diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), left ventricular mass index, myocardial cell cross-sectional area, myocardial collagen content, plasma endothelin-1 (ET 1) and endothelial nitric oxide synthase (eNOS) levels. Compared with the sham operation, the LVEDD and NT-proBNP in the model group and each natakalim group were elevated. LVEF decreased significantly, while the left ventricular mass index, myocardial cell cross-sectional area, myocardial collagen content, plasma ET-1 and eNOS levels increased. Natakalim intervention improved the above changes and the improvement effect of 3 mg/kg/day group was the highest. The mechanism of natakalim against the endothelin system can be explained by the fact that inhibiting ET-1 synthesis can reduce the ET-1 levels in circulation leading to the release of NO and PGI2. Inhibition of the vasoconstriction effect of ET-1 can improve the hemodynamics of high-load status and ameliorate the cardiac systolic and diastolic functions. In conclusion, natakalim can improve the ventricular remodeling of CHF after AMI, and 3 mg/kg/day was the most effective dose. PMID- 28101179 TI - Study of the functional mechanisms of osteopontin and chemokine-like factor 1 in the development and progression of abdominal aortic aneurysms in rats. AB - The aim of the study was to investigate the functional mechanisms of osteopontin (Opn) and chemokine-like factor 1 (Cklf1) during the development and progression of abdominal aortic aneurysms (AAA) in rats. Healthy adult Sprague-Dawley rats (n=30) were randomly divided into the AAA, control and sham groups (10 rats/group) and experimental rat models of AAA were generated by enzyme perfusion in abdominal aorta for 30 min. The AAA formation was assessed by measuring the aortal diameter and hematoxylin and eosin staining as well as specific staining to detect the structural changes of the aorta and inflammatory cell infiltration. Immunohistochemistry, western blot analysis and statistical analysis were also performed to examine the expression levels of Opn, Cklf1 and matrix metalloproteinase (MMP)-2 in the arterial tissue. Rat models of AAA were successfully established by protease perfusion. After perfusion, the diameter expansion rate of abdominal aorta was significantly higher (P<0.01) compared to controls, elastin present at the middle layer was significantly reduced and inflammatory cell infiltration was significantly higher in AAA rats. The expression of Opn, Cklf1 and MMP-2 in the AAA group was significantly increased compared to the control group (P<0.05) as revealed by immunohistochemical staining. The western blot analysis revealed that, the expression levels of Opn, Cklf1 and MMP-2 in the AAA group were significantly higher than the sham and control groups (P<0.01). We also found that the expression of Opn and MMP-2 was positively correlated. In conclusion, in rat models of AAA, Opn and Cklf1 function synergistically to upregulate the expression of MMP-2, causing accelerated degradation of extracellular matrix and eventually leading to the development and progression of AAA. PMID- 28101178 TI - Endothelium-dependent vasodilation effects of Panax notoginseng and its main components are mediated by nitric oxide and cyclooxygenase pathways. AB - Panax notoginseng, a traditional Chinese herbal medicine, has been used for the treatment of cardiovascular diseases. The main bioactive components of this species are Panax notoginseng saponins (PNS). The present study aimed to investigate the effects of PNS and five of its main components (ginsenosides Rg1, Re, Rb1 and Rd, and notoginsenoside R1) on rat aorta rings pre-contracted with norepinephrine (NE) and to determine the underlying mechanism of action. Isolated aorta rings (with or without intact endothelium) from adult male Wistar rats were stimulated with NE to induce vasoconstriction, and subsequently treated with different concentrations of PNS and its five main components (Rg1, Re, Rb1, R1 and Rd) separately. This procedure was repeated after pre-incubation with the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and the cyclooxygenase (COX) inhibitor indomethacin (INDO), in order to elucidate the mechanism of action of PNS and its components. The results demonstrated that PNS and the components Rg1, Re, Rb1 and R1, but not Rd, induced vessel relaxation in a concentration-dependent manner when the endothelium lining was intact. NO synthase inhibitor L-NAME and guanylate cyclase inhibitor ODQ attenuated the diastolic effects of PNS, Rg1, Re, Rb1 and R1 in aortic rings with intact endothelium. By contrast, INDO, a known COX inhibitor weakened the vasodilation effects of PNS, Re and Rb1 but demonstrated no effect on Rg1 and R1. In conclusion, PNS and two of its main components (Re and Rb1) exert vasodilating effects through the NO and COX pathways. PMID- 28101180 TI - Acute renal injury induced by valacyclovir hydrochloride: A case report. AB - Acyclovir has been a frequently used antiviral agent in the clinical treatment of leukemia, acute encephalitis, malignant tumor and herpes simplex. The adverse effects of this drug have been widely described in clinical practice. In the present study, a case of a 35-year-old female patient diagnosed with herpes simplex, who developed acute renal injury following treatment with valacyclovir hydrochloride, is described. Kidney biopsy, light microscopy and laboratory examination were performed, and all findings revealed the signs of evident vacuolar degeneration of capillary endothelial and renal tubular epithelial cells, erythrocyte aggregation in partial renal tubule and microvilli exfoliation from epithelial cells. Renal interstitial edema was clearly identified. The clinical evidence observed from this female patient indicated that renal functions should be closely monitored during valacyclovir hydrochloride administration. A variety of effective measures, such as hydration, alkalizing urine, promoting the discharge of medication and the use of antagonists are recommended following the administration of antiviral agents. PMID- 28101181 TI - MicroRNA-351 inhibits denervation-induced muscle atrophy by targeting TRAF6. AB - MicroRNAs (miRs) have been observed to be involved in the modulation of various physiopathological processes. However, the impacts of miRNAs on muscle atrophy have not been fully investigated. In the present study, the results demonstrated that miR-351 was differentially expressed in the tibialis anterior (TA) muscle at various times following sciatic nerve transection, and the time-dependent expression profile of miR-351 was inversely correlated with that of tumor necrosis factor receptor-associated factor 6 (TRAF6) at the mRNA and protein levels. The dual luciferase reporter assay indicated that miR-351 was able to significantly downregulate the expression levels of TRAF6 by directly targeting the 3'-untranslated region of TRAF6. Overexpression of miR-351 inhibited a significant decrease in the wet weight ratio or cross-sectional area of the TA muscle following sciatic nerve transection. Western blot analysis indicated that the protein expression levels of TRAF6, muscle ring-finger protein 1 (MuRF1) and muscle atrophy F-box (MAFBx) in denervated TA muscles were suppressed by overexpression of miR-351. These results demonstrate that miR-351 inhibits denervation-induced atrophy of TA muscles following sciatic nerve transection at least partially through negative regulation of TRAF6 as well as MuRF1 and MAFBx, the two downstream signaling molecules of TRAF6. PMID- 28101182 TI - Protective effect of taraxasterol against rheumatoid arthritis by the modulation of inflammatory responses in mice. AB - Taraxasterol is an effective component of dandelion that has anti-inflammatory effects in vivo and in vitro. The present study was performed to explore whether taraxasterol exhibits a protective effect against rheumatoid arthritis through the modulation of inflammatory responses in mice. Eight-week-old CCR9-deficient mice were injected with a collagen II monoclonal antibody cocktail to create a rheumatoid arthritis model. In the experimental group, arthritic model mice were treated with 10 mg/kg taraxasterol once per day for 5 days. Treatment with taraxasterol significantly increased the pain thresholds and reduced the clinical arthritic scores of the mice in the experimental group compared with those of the model group. Furthermore, treatment with taraxasterol significantly suppressed tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and nuclear factor kappaB protein expression levels compared with those in the rheumatoid arthritis model mice. Taraxasterol treatment also significantly reduced nitric oxide, prostaglandin E2 and cyclooxygenase-2 levels compared with those in the rheumatoid arthritis model group. These observations indicate that the protective effect of taraxasterol against rheumatoid arthritis is mediated via the modulation of inflammatory responses in mice. PMID- 28101184 TI - Anti-inflammatory effects of luteolin on experimental autoimmune thyroiditis in mice. AB - Hashimoto's thyroiditis (HT) is the most common organ-specific autoimmune disease and is believed to be a predominately T cell-mediated autoimmunity. Signal transducer and activator of transcription (STAT)3 is a crucial transcription factor of T cell-mediated immunity, with key roles in the proliferation and migration of T helper (Th) cells, differentiation of Th cells into Th17 cells, and the balance between Treg cells and Th17 cells. Flavonoid luteolin has been shown to markedly inhibit Tyr705 activation/phosphorylation of STAT3 and exert anti-inflammatory effects in multiple sclerosis. In the present study, the effect of luteolin on experimental autoimmune thyroiditis (EAT) was analyzed in C57BL/6 mice. Hematoxylin and eosin examination showed that luteolin attenuated lymphocytic infiltration and follicle destruction in thyroid glands. Immunohistochemistry results demonstrated that luteolin significantly reduced the phosphorylation of STAT3 within the thyroid. An in vitro study was carried out in a RAW264.7 macrophage cell line. Western blot findings demonstrated that luteolin significantly inhibited interferon-gamma-induced increases in cyclooxygenase 2, phosphorylated STAT1 and phosphorylated STAT3 expression levels and the secretion of the proinflammatory cytokine tumor necrosis factor-alpha in supernatants. The present findings indicated that luteolin may exert potent anti-inflammatory effects on murine EAT, which may provide a novel therapeutic medication strategy for the early intervention of HT. PMID- 28101185 TI - Hypokalemic myopathy in primary aldosteronism: A case report. AB - Primary aldosteronism (PA) is a rare disorder. The majority of patients with PA present with typical features and are easily diagnosed. This disorder is usually diagnosed with hypokalemia, hypertension or an adrenal mass. However, patients with atypical symptoms may present a challenge for diagnosis and treatment. In the present study, a case of PA is described that presented with hypokalemic myopathy simulating polymyositis. The patient was a 44-year-old woman who presented with weakness and difficulty walking. The patient was initially suspected to have PM and was treated with methylprednisolone. The patient was found to have hypokalemia which persisted despite high-dose supplementation of potassium. Adrenal computed tomography revealed a right adrenal mass. Surgical adrenalectomy was conducted. The final pathological diagnosis was benign adrenocortical adenoma. The serum tests remained normal and the patient's symptoms were resolved during the 8-month follow-up. PMID- 28101183 TI - Protective effect of berberine against oxidative stress-induced apoptosis in rat bone marrow-derived mesenchymal stem cells. AB - Bone marrow-derived mesenchymal stem cells (BMSCs) have the potential to be used for the treatment of delayed union, nonunion or persistent bone defects in MSC based cell therapy. However, implantation of BMSCs into the fracture site is confronted with apoptosis on account of harsh conditions and oxidative stress. In the present study, the anti-apoptotic effects of berberine (BBR) on BMSCs subjected to hydrogen peroxide (H2O2) are investigated, and the potential underlying mechanisms are explored. Oxidative injury was induced by exposure to H2O2, and cell viability was assessed using a cell counting kit-8 assay. The apoptosis of BMSCs was measured by Hoechst 33258 and Annexin V-fluorescein isothiocyanate/propidium iodide assay. Reactive oxygen species staining and superoxide dismutase (SOD) assay were applied to assess the anti-oxidative effect of BBR. Finally, western blot was performed to measure the expression levels of phosphorylated (p)-Akt, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax) and cleaved caspase-3. In the present study, it was identified that BBR remarkably attenuated H2O2-induced apoptotic cell death via quenching ROS production and increasing SOD activity. Further studies indicated that BBR can reduce apoptosis by upregulating the expression level of p-Akt and Bcl-2, and downregulating the expression levels of Bax and cleaved caspase-3. Taken together, the results of the present study demonstrate that pretreatment with BBR could alleviate H2O2-induced apoptosis in rat BMSCs in vitro. PMID- 28101186 TI - Comparative analysis of signaling pathways in peripheral blood from patients with Kashin-Beck disease and osteoarthritis. AB - The aim of the present study was to investigate the early diagnostic biomarkers of Kashin-Beck disease (KBD), and to compare the common signaling pathways of peripheral mononuclear cells between patients with KBD and those with osteoarthritis (OA). A total of 20 and 12 peripheral blood samples were separately collected from KBD patients and normal control subjects, respectively, in an endemic area according to the diagnosis criteria. Total RNAs were extracted and gene expression levels were determined using an Agilent whole genome expression microarrays. The gene expression data of OA were obtained from GEO published database. Significant different pathways between KBD and OA were analyzed using Ingenuity Pathway Analysis software. A total of 82 differentially expressed genes, 51 significant different signaling pathways and five significant biological functions were identified in KBD patient samples, while 89, 50 and five significantly different genes, pathways and functions were identified in OA. Nine common significant pathways and five common differentially expressed genes were identified between the KBD and OA. Nine common significant pathways and five common differentially expressed genes were found between the two diseases. The present results suggest that there are similarities in vascular microcirculation, immunoreactions and cell apoptosis between KBD and OA, which may contribute to the early diagnosis and pathogenetic study of KBD. PMID- 28101187 TI - Severe pneumonia due to infection with Candida krusei in a case of suspected Middle East respiratory syndrome: A case report and literature review. AB - Candida krusei (C. krusei) pneumonia is a rare infection that is frequently associated with a poor outcome. The present study reports an unusual case of C. krusei pneumonia that was initially suspected to be a Middle East respiratory syndrome (MERS) case. A 64-year-old Saudi Arabian male patient was admitted to our hospital with complaints of cough and dyspnea that persisted for 6 days. The patient presented fever (oral temperature, 38.5 degrees C) and slight tachypnea (25 respirations/min). A chest computerized tomography demonstrated unclear lung fields, diffuse pathological changes in the two lungs and multiple lymphadenectasis in the retrocaval and para-aortic arch area. The patient received 95-98% oxygen (6 l/min) for 24 h, as well as sulbactam sodium/cefoperazone sodium (1:1) injection (3.0 g) every 12 h, oral oseltamivir capsules (75 mg/time) twice a day, medaron injection (80 mg/time) and 750 ml fluid infusion; however, he succumbed to the disease on day 2 after admission. The infection was diagnosed by sputum smear and culture subsequent to patient mortality. A sputum smear showed a large fungal infection and sputum culture revealed the presence of C. krusei infection. Serum procalcitonin concentrations were 4.73 ug/l and 7.23 ug/l on days 2 and 3 after admission, respectively. In conclusion, the diagnosis of Candida pneumonia should be strongly considered in the presence of growth of Candida from a sputum culture and based on a suggestive computed tomography image. Tumescent diaphragmatic lymph nodes may also be an important symptom of Candida pneumonia. Treatment should be initiated immediately to improve tissue oxygenation, restore cardiovascular function and improve other organ functions. PMID- 28101188 TI - miR-125a-3p targetedly regulates GIT1 expression to inhibit osteoblastic proliferation and differentiation. AB - Osteoblasts are a prerequisite for osteogenesis and bone formation, and play a key role in metabolic balance, growth, development and wound repair. G protein coupled receptor kinase interacting protein 1 (GIT1) and a series of miRNAs are known to have important effects in the growth and migration of osteoblasts, but little is known about micro RNAs (miRNAs) targeting GIT1. The present study found that miR-125a-3p has matching sites on GIT1. In the osteoblastic differentiation process of human bone marrow-derived mesenchymal stem cells (HMSCs), the expression of miR-125a-3p was suppressed compared with that in non differentiating (HMSCs) while the expression of GIT1 showed a gradual and significant increase. Thus, miR-125a-3p expression was negatively correlated with the expression of GIT1. Following the transfection of human osteoblasts with miR 125a-3p mimics and inhibitors, respectively, the effect on GIT1 expression was opposite to the change of miR-125a-3p expression. In addition, the impact of miR 125a-3p and GIT1 on osteoblastic proliferation and differentiation was detected, and the results indicated that miR-125a-3p targetedly regulated GIT1 expression to inhibit osteoblastic proliferation and differentiation. These findings may provide a theoretical basis for clarifying the physiological and pathological role of miRNAs in osteoblast differentiation and maturation processes, and for the physiological and pathological investigation of bone. PMID- 28101189 TI - Inhibition of cytoskeletal protein carbonylation may protect against oxidative damage in traumatic brain injury. AB - Oxidative stress is the principal factor in traumatic brain injury (TBI) that initiates protracted neuronal dysfunction and remodeling. Cytoskeletal proteins are known to be carbonylated under oxidative stress; however, the complex molecular and cellular mechanisms of cytoskeletal protein carbonylation remain poorly understood. In the present study, the expression levels of glutathione (GSH) and thiobarbituric acid reactive substances (TBARS) were investigated in PC12 cells treated with H2O2. Western blot analysis was used to monitor the carbonylation levels of beta-actin and beta-tubulin. The results indicated that oxidative stress was increased in PC12 cells that were treated with H2O2 for 24 or 48 h. In addition, increased carbonylation levels of beta-actin and beta tubulin were detected in H2O2-treated cells. However, these carbonylation levels were reduced by pretreatment with aminoguanidine, a type of reactive carbonyl species chelating agent, and a similar trend was observed following overexpression of proteasome beta5 via transgenic technology. In conclusion, the present study results suggested that the development of TBI may cause carbonylation of cytoskeletal proteins, which would then undermine the stability of cytoskeletal proteins. Thus, the development of TBI may be improved via the inhibition of cytoskeletal protein carbonylation. PMID- 28101190 TI - ROR2 inhibits the proliferation of gastric carcinoma cells via activation of non canonical Wnt signaling. AB - Gastric carcinoma is one of the most common human cancers and has a poor prognosis. Receptor tyrosine kinase-like orphan receptor 2 (ROR2), which is a non canonical receptor of the Wnt signaling pathway, has been reported to be deregulated in numerous types of human cancers, including gastric carcinoma. However, the exact role of ROR2 in the regulation of the malignant phenotypes of gastric carcinoma, as well as the underlying molecular mechanism, remains largely unclear. The present study demonstrated that ROR2 was recurrently downregulated in gastric carcinoma tissues, as compared with their matched adjacent normal tissues. Furthermore, the expression levels of ROR2 were reduced in several common gastric carcinoma cell lines, as compared with normal gastric epithelial cells. Gastric carcinoma cells were transfected with ROR2 plasmids, and it was demonstrated that restoration of ROR2 expression significantly inhibited the proliferation and induced the apoptosis of gastric carcinoma cells by a Wnt5a independent mechanism. In addition, it was observed that ROR2-overexpressing cells accumulated in the G0/G1 phase; thus suggesting that overexpression of ROR2 induced cell cycle arrest at the G0/G1 phase. An investigation of the underlying mechanism demonstrated that activation of the non-canonical Wnt signaling pathway inhibited canonical Wnt signal transduction, as demonstrated by the decreased level of beta-catenin in nuclei, as well as the reduced expression levels of c Myc. The results of the present study indicated a tumor suppressive role for ROR2 in gastric carcinoma growth in vitro, and suggested that ROR2 may be used as a molecular target for the treatment of gastric carcinoma. PMID- 28101191 TI - MicroRNA-212 suppresses the proliferation and migration of osteosarcoma cells by targeting forkhead box protein A1. AB - MicroRNAs (miRNAs) are a class of small non-coding RNAs that function as critical gene regulators by targeting the 3' untranslated region (UTR) of mRNA, causing translational repression or mRNA degradation. Deregulation of specific miRNAs, including miR-212, has been identified in patients with osteosarcoma. However, the underlying mechanism is yet to be fully elucidated. The present study aimed to reveal the regulatory mechanism of miR-212 in osteosarcoma cell viability and migration. Quantitative polymerase chain reaction data revealed that miR-212 was significantly downregulated in osteosarcoma tissues compared with normal bone tissues. miR-212 was also downregulated in osteosarcoma cell lines compared with normal osteoblast cell lines. Overexpression of miR-212 significantly suppressed the viability and migration of human osteosarcoma MG-63 and Saos-2 cell lines. In addition, forkhead box protein A1 (FOXA1), an oncogene in osteosarcoma, was predicted to be a putative target of miR-212 by bioinformatical analysis. Furthermore, luciferase reporter assay data confirmed that miR-212 could directly bind to the seed sequences within the 3'UTR of FOXA1 mRNA, and miR-212 negatively mediated the protein levels of FOXA1 in osteosarcoma MG-63 and Saos-2 cells. Moreover, knockdown of FOXA1 also led to a significant decrease in the viability and migration of osteosarcoma MG-63 and Saos-2 cells and the expression levels of FOXA1 were significantly upregulated in osteosarcoma tissues and cell lines. These data suggest that miR-212 inhibits the viability and migration of osteosarcoma cells by targeting FOXA1. Accordingly, miR-212 may become a potential candidate for osteosarcoma therapy. PMID- 28101192 TI - C-peptide exhibits a late induction effect on matrix metallopeptidase-9 in high glucose-stimulated rat mesangial cells. AB - Insufficient matrix metalloproteinase (MMP)-9 and MMP-2 is considered to be a contributor of extracellular matrix (ECM) accumulation in diabetic nephropathy (DN). C-peptide can reverse fibrosis, thus exerting a beneficial effect on DN. Whether C-peptide induces MMP-9 and MMP-2 to reverse ECM accumulation is not clear. In the present study, in order to determine ECM metabolism, rat mesangial cells were treated with high glucose (HG) and C-peptide intervention, then the early and late effects of C-peptide on HG-affected MMP-9 and MMP-2 were evaluated. Firstly, it was confirmed that HG mainly suppressed MMP-9 expression levels. Furthermore, C-peptide treatment induced MMP-9 expression at 6 h and suppressed it at 24 h, revealing the early dual effects of C-peptide on MMP-9 expression. Subsequently, significant increase in MMP-9 expression at 72, 96 and 120 h C-peptide treatment was observed. These changes in MMP-9 protein content confirmed its expression changes following late C-peptide treatment. Furthermore, at 96 and 120 h C-peptide treatment reversed the HG-inhibited MMP-9 secretion, further indicating the late induction effect of C-peptide on MMP-9. The present results demonstrated that C-peptide exerted a late induction effect on MMP-9 in HG-stimulated rat mesangial cells, which may be associated with the underlying mechanism of C-peptide's reversal effects on DN. PMID- 28101193 TI - 18F-FLT and 18F-FDG PET-CT imaging in the evaluation of early therapeutic effects of chemotherapy on Walker 256 tumor-bearing rats. AB - The present study aimed to evaluate the early therapeutic effects of chemotherapy on Walker 256 tumor-bearing Wistar rats via F-18-fluoro-3'-deoxy-3'-L fluorothymidine (18F-FLT) and F-18-fluoro-deoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) imaging. Walker 256 tumor bearing Wistar rats were subjected to 18F-FLT and 18F-FDG PET-CT imaging prior to and 24 and 48 h after epirubicin chemotherapy. 18F-FLT and 18F-FDG uptake [tumor/muscle (T/M)], the percentage of injected dose per gram (% ID/g), and the Ki-67 labeling index (LI-Ki-67) were quantitatively determined for each rat prior to and following epirubicin chemotherapy. The correlation between % ID/g and tumor LI-Ki-67 was analyzed. Both 18F-FLT and 18F-FDG tumor uptake decreased significantly at 24 and 48 h after chemotherapy (P<0.01 and P<0.05, respectively). LI-Ki-67 also significantly reduced 24 and 48 h after chemotherapy (P<0.001). Furthermore, 18F-FLT and 18F-FDG T/M tumor uptake correlated positively with LI-Ki-67 before and after chemotherapy (r=0.842 and 0.813, respectively). During the early post-chemotherapy stage, 18F-FLT and 18F-FDG uptake in Walker 256 tumors reduced significantly, which correlated positively with the tumor cell proliferative activity. PMID- 28101195 TI - Combinations in multimodality treatments and clinical outcomes during cancer. AB - Combination approach could be easily considered as the future of therapeutics in all pathological states including cancer. Scientists are trying different combinations in order to determine synergism among different therapeutics which ultimately helps in the improved and more efficient management of the affected patients. Combination of multi-chemotherapeutic agents, or multi-drug therapy, may be the most commonly used strategy for cancer treatment. Monotherapy causes drug resistance and loses its response in patients after several cycles of treatment. While combining different anticancer drugs together for cancer treatment, as in the case of the cocktail therapy for HIV, not only overcomes the drug resistance but also leads to a synergistic effect, therefore showing prolonged survival for patients. The present review article is focused on different combinations in use for better efficiency of therapeutics against cancer. We searched the electronic database PubMed for pre-clinical as well as clinical controlled trials reporting diagnostic as well as therapeutic advances of various combinations in cancer. It was observed clearly that combination approach is better in various aspects including increase in efficacy, specificity and decline in the unwanted side effects. PMID- 28101194 TI - Inhibition of NEDD8 and FAT10 ligase activities through the degrading enzyme NEDD8 ultimate buster 1: A potential anticancer approach. AB - The capabilities of tumour cells to survive through deregulated cell cycles and evade apoptosis are hallmarks of cancer. The ubiquitin-like proteins (UBL) proteasome system is important in regulating cell cycles via signaling proteins. Deregulation of the proteasomal system can lead to uncontrolled cell proliferation. The Skp, Cullin, F-box containing complex (SCF complex) is the predominant E3 ubiquitin ligase, and has diverse substrates. The ubiquitin ligase activity of the SCF complexes requires the conjugation of neural precursor cell expressed, developmentally down-regulated 8 (NEDD8) to cullin proteins. A tumour suppressor and degrading enzyme named NEDD8 ultimate buster 1 (NUB1) is able to recruit HLA-F-adjacent transcript 10 (FAT10)- and NEDD8-conjugated proteins for proteasomal degradation. Ubiquitination is associated with neddylation and FAT10ylation. Although validating the targets of UBLs, including ubiquitin, NEDD8 and FAT10, is challenging, understanding the biological significance of such substrates is an exciting research prospect. This present review discusses the interplay of these UBLs, as well as highlighting their inhibition through NUB1. Knowledge of the mechanisms by which NUB1 is able to downregulate the ubiquitin cascade via NEDD8 conjugation and the FAT10 pathway is essential. This will provide insights into potential cancer therapy that could be used to selectively suppress cancer growth. PMID- 28101196 TI - Denosumab treatment of inoperable or locally advanced giant cell tumor of bone. AB - Giant cell tumor of bone (GCTB) is an osteolytic, locally aggressive tumor that rarely metastasizes and typically occurs in the bones. At present, the primary treatment for GCTB is curettage with local adjuvants. Giant cells express receptor activator of nuclear factor-kappaB ligand (RANKL). Denosumab, a RANKL inhibitor appears to present an effective therapeutic option in advanced cases of GCTB. The aim of the present study was to confirm the efficacy of denosumab in large group of patients with locally advanced GCTB. A total of 35 patients with histologically confirmed GCTB that were treated with denosumab with no participation in clinical trials between May 2013 and September 2015 were included in the present study. Denosumab treatment was administered until complete tumor resection was feasible or tumor progression or unacceptable toxicity had occurred. The mean denosumab treatment duration was 7.4 months. A total of 17 patients received surgery following denosumab treatment: 11 patients underwent wide en bloc resection with prosthesis implantation in 10 cases and 6 patients were treated with intralesional curettage. Tumor progression was observed in 2 patients that underwent intralesional curettage without prosthesis implantation. In addition, tumor progression was observed during denosumab treatment in 2 patients that had previously undergone radiotherapy. The overall 1 year progression-free survival rate was 92.8%. Thus, for patients with advanced, unresectable, progressive or symptomatic pretreated GCTB, denosumab provides a therapeutic option not previously available, which has become the standard therapy in multidisciplinary management of GCTB. PMID- 28101197 TI - Multiple large xanthomas: A case report. AB - A 23-year-old male patient presented with multiple large masses in his elbows, buttocks, knees, Achilles tendons, feet, shoulders and hands. The large masses in the elbows and buttocks measured ~6*5*5 cm and ~7*5*4 cm, respectively. The patient presented with an elevated level of low-density lipoprotein cholesterol, and had been previously diagnosed with homozygous familial hypercholesterolemia (FH) and multiple xanthomas. Local surgical excisions were performed to remove the massive xanthomas from the elbows and buttocks, and histological analysis of the surgical specimens confirmed the previous diagnosis of homozygous FH (HoFH). The aim of the present study was to report a rare case of HoFH coinciding with multiple, large and widely-distributed xanthomas and to discuss the clinical characteristics, in order to provide a better understanding of xanthomas and FH. PMID- 28101198 TI - Elevated expression of Nrf2 mediates multidrug resistance in CD133+ head and neck squamous cell carcinoma stem cells. AB - Enhanced expression of the ATP-binding cassette (ABC) transporter protein ABC sub family G member 2 (ABCG2) in cancer stem cells (CSCs) plays a major role in chemotherapeutic drug efflux, which results in therapy failure and tumor relapse. In addition to downregulating apoptosis in CSCs, it has been reported that the transcriptional upregulation of the redox sensing factor Nrf2 is involved in the upregulation of ABCG2 expression and consequent chemoresistance. The current study investigated the presence of cancer stem-like side population (SP) cells from head and neck squamous cell carcinoma (HNSCC) samples, and evaluated the Nrf2 expression profile and multidrug resistance properties of HNSCC stem cells. Fluorescence-activated cell sorting was used for SP cells detection, while reverse transcription-polymerase chain reaction was used for the analysis of Nrf2 expression. The present study identified ~2.1% SP cells present in HNSCC specimens, which were positive for cluster of differentiation (CD)133 expression and displayed significantly elevated messenger RNA expression of Nrf2, compared with non-SP cells. These data suggest that the ABC transporter ABCG2 is highly upregulated in SP cells, and this results in multidrug resistance. In addition, these CD133+ cells underwent rapid proliferation and exhibited high self-renewal and tumorigenic properties. Taken together, the present findings suggest that elevated expression of Nrf2 mediated drug resistance in HNSCC CSCs, which may be one of the causative factors for cancer treatment failure. Therefore, novel anti cancer drugs that downregulate the Nrf2 signaling pathway could effectively improve the treatment and survival rate of patients with HNSCC. PMID- 28101199 TI - Ultrastructural changes during lung carcinogenesis-modulation by curcumin and quercetin. AB - The aim of the present study was to examine the effectiveness of curcumin and quercetin in modulating ultrastructural changes during lung carcinogenesis. A total of 24 male laka mice were divided into the normal control, benzo[a]pyrene (BP)-treated, BP+curcumin-treated, BP+quercetin- treated, and BP+curcumin+quercetin-treated groups (n=6 per group). Lung carcinogenesis was induced by a single intraperitoneal injection of BP [100 mg/kg of body weight (b.wt.)]. Curcumin was supplemented to mice at a dose level of 60 mg/kg of b.wt. in drinking water and quercetin was given at a dose level of 40 mg/kg of b.wt. in drinking water. The ultrastructure of BP-treated mice revealed disruptions in cellular integrity together with nuclear deformation and premature mitochondrial aging. Notably, supplementation with phytochemicals individually resulted in improvement of the ultra-histoarchitecture of BP-treated mice although the improvement was much greater with combined supplementation of phytochemicals. Furthermore, BP treatment revealed alterations in lung histoarchitecture, which, however, were improved appreciably following combined supplementation with curcumin and quercetin. The results of the present study show that, combined supplementation with curcumin and quercetin effectively preserved the histoarchitecture as well as ultra-histoarchitecture during BP-induced lung carcinogenesis in mice. PMID- 28101200 TI - Special AT-rich DNA-binding protein-1 expression is associated with liver cancer metastasis. AB - To aim of the present study was to investigate the association between special AT rich DNA-binding protein-1 (SATB1) expression and liver cancer metastasis. SATB1 mRNA and protein expression in hepatocellular carcinoma tissues was analyzed by immunohistochemistry, and in two hepatocellular cancer cell lines, MHCC-97H (high metastatic potential) and HepG2 (low metastatic potential), by reverse transcription-polymerase chain reaction and western blot analysis. Transwell migration and wound-healing assays were also performed to investigate the metastasis of liver cancer following upregulation or silencing of SATB1 expression. The results revealed that SATB1 expression was significantly higher in hepatocellular carcinoma tissues compared with carcinoma-adjacent tissues. Furthermore, SATB1 expression was correlated with tumor size, differentiation degree, hemorrhage and/or necrosis, invasion and/or metastases and TNM stage. Both the mRNA and protein expression of SATB1 was higher in MHCC-97H cells than HepG2 cells. In addition, the migration capability of MHCC-97H cells was decreased after SATB1 silencing, whereas the migration capability of HepG2 cells was increased after SATB1 upregulation. SATB1 expression was demonstrated to be positively correlated with liver cancer metastasis. These results indicate that liver cancer metastasis is regulated by SATB1 expression. Thus, immunohistochemical SATB1 expression may present an independent risk factor for the metastasis of liver cancer. PMID- 28101201 TI - Diosmetin inhibits cell proliferation and induces apoptosis by regulating autophagy via the mammalian target of rapamycin pathway in hepatocellular carcinoma HepG2 cells. AB - Hepatocellular carcinoma (HCC), which is a type of malignant tumor, is the fifth most common cancer in men and ninth in women worldwide. The aim of the present study was to investigate the antitumor effect of diosmetin (DIOS) in hepatocellular carcinoma HepG2 cells. The proliferation, apoptosis and autophagy rates of HepG2 cells were measured following treatment with DIOS. The effects of DIOS treatment on HepG2 cell proliferation and apoptosis rates were analyzed using MTT assays and Annexin V staining, respectively. The effect of DIOS treatment on autophagy levels was assessed using transmission electron microscopy, green fluorescent protein (GFP)-microtubule-associated protein 1 light chain (LC3) transfection and LysoTracker Red staining. Furthermore, bafilomycin A1 (BA1), an autophagy inhibitor, was used to assess the association between DIOS and cell autophagy, proliferation and apoptosis. In addition, the expression of autophagy-related proteins [mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinase, P70S6K, phosphoinositide-dependent kinase-1, extracellular signal-regulated kinase, 5'-AMP-activated protein kinase and Akt] and apoptosis-related proteins [B-cell lymphoma (Bcl)-2-associated X protein, Bak, p53, Bcl-2 and caspase-3] were analyzed by western blotting. The results revealed that DIOS significantly inhibited proliferation (P<0.01) and induced apoptosis (P<0.001) in HepG2 cells. It was also demonstrated that DIOS triggered autophagy by regulating the mTOR pathway in HepG2 cells. Notably, following treatment of HepG2 cells with the autophagy inhibitor, BA1, the expression of apoptosis-related proteins, including Bax, Bak and p53, were significantly decreased (P<0.05), and cell viability was recovered to a certain extent. In conclusion, DIOS inhibits cell proliferation and induces apoptosis in HepG2 cells via regulation of the mTOR pathway. Thus, the results of the current study indicate that DIOS may present a potential therapeutic agent for HCC treatment. PMID- 28101202 TI - Cadherin-11 expression is upregulated in invasive human breast cancer. AB - Loss of expression of cadherin-11 protein is correlated with a loss of epithelial phenotype and a gain in tumor cell proliferation and invasion. It has been hypothesized that cadherin-11 may be a molecular marker for a more aggressive subtype of breast cancer. The present study examined the expression of the mesenchymal gene/protein cadherin-11 in malignant, benign and healthy breast cancer samples. A paraffin-embedded tissue microarray of both malignant and benign/healthy breast tumor was used. Clinicopathological parameters, including age, grading, tumor size, hormone receptors and HER2 receptors status were obtained from patient medical records. Expression of cadherin-11 was analyzed using the monoclonal mouse anti cadherin-11 IgG2B clone. Total RNA was extracted from each breast cancer sample and subjected to semi-quantitative RT-PCR analysis for cadherin-11. Cadherin-11 was detected in 80/82 malignant breast cancer samples and in 33/70 non-malignant tissue samples. Cadherin-11 expression was observed to be predominantly localized to the membrane of tumor cells. When compared to healthy breast tissue biopsies, both cadherin-11 mRNA and protein were demonstrated to be significantly overexpressed in breast carcinoma (P=0.040 and P<0.0001, respectively). Within malignant tumors, however, protein expression was not identified to be associated with other clinicopathological parameters. Our results indicate that cadherin-11 expression is upregulated in malignant human breast cancer. PMID- 28101203 TI - Short-term effect analysis of radiofrequency ablation combined chemotherapy on middle and late period non-small cell lung cancer. AB - In this study, we investigated the effect of radiofrequency ablation (RFA) combined chemotherapy on middle and late period non-small cell lung cancer (NSCLC). In total, 85 cases of middle and late period NSCLC patients were selected, and were randomly divided into the RFA combined chemotherapy group, RFA treatment group and chemotherapy group. After treatment, the three groups were followed up for computed tomography (CT) scan, and were analyzed for the effect of RFA combined chemotherapy on middle and late period NSCLC. It was found that CT value of RFA combined chemotherapy group decreased significantly compared to before surgery (P<0.05). The CT value of the RFA group decreased significantly compared to before surgery (P<0.05). The CT value of chemotherapy group was not significantly changed compared to before surgery (P>0.05). The postoperative CT value of the RFA combined chemotherapy group and RFA group was smaller compared to that of the chemotherapy group (P<0.05). Effective rate [complete response (CR) + partial response (PR)] of RFA combined chemotherapy group was significantly higher than that of the EFA and chemotherapy groups (P<0.05). Effective rate (CR+PR) of the RFA group was significantly higher than that of the chemotherapy group (P<0.05). By contrast, the progressive rate (P) of RFA combined chemotherapy group was significantly lower than that of the RFA and chemotherapy groups (P<0.05). In conclusion, RFA combined chemotherapy has obvious effect on middle and late period NSCLC, and is safe and feasible. PMID- 28101204 TI - Downregulation of miR-221/222 by a microRNA sponge promotes apoptosis in oral squamous cell carcinoma cells through upregulation of PTEN. AB - MicroRNA-221 and microRNA-222 (miR-221/222) have been identified as oncogenes and confirmed to be overexpressed in various types of cancer. However, the regulation mechanism of miR-221/222 in oral squamous cell carcinoma (OSCC) remains to be fully elucidated. Previously, an miR-221/222 sponge was successfully constructed and its effect on the downregulation of miR-221/222 expression was investigated. In the present study, the dual luciferase reporter assay revealed a phosphatase and tensin homolog (PTEN) deletion on chromosome 10 to be a target gene of miR 221/222. It was also demonstrated that miR-221/222 suppression by transfection with an miR-221/222 sponge in vitro resulted in upregulation of PTEN. Notably, the proliferation and invasiveness of the miR-221/222 sponge-transfected cells was significantly inhibited, while apoptosis was promoted, when determined by Cell Counting Kit-8, Transwell assays and flow cytometry. The results of the present study prove that miR-221/222 may downregulate the expression of PTEN in OSCC cells and function as oncogenes, providing a novel insight into the underlying mechanism of OSCC tumorigenesis. The present study suggests that upregulating the expression of PTEN by downregulation of miR-221/222 may be a potential treatment for OSCC. PMID- 28101206 TI - Primary chondrosarcoma of the thyroid cartilage: Surgery-based management of a rare case. AB - In this study, we present a case of a 52-year-old male with a chondrosarcoma of the left lamina of the thyroid cartilage. Pre-operative evaluations detected typical calcifications and delineated the extent of the tumor. The patient underwent a total laryngectomy to ensure the complete resection of the tumor. The tumor was histopathologically found to consist of chondrocytes in a hyaline cartilage matrix. The patient's post-operative course has been successful apart from the permanent tracheostomy. Herien, we discuss the methods and rationales for the diagnosis and management of and recovery from this rare tumor, and also provide a review of the literature. PMID- 28101205 TI - Impact of microsatellite status on chemotherapy for colorectal cancer patients with KRAS or BRAF mutation. AB - KRAS and BRAF mutations are frequently detected in cases of colorectal cancer (CRC). The microsatellite status of patients with CRC and mutated KRAS/BRAF is important when determining cancer therapy. In the present study, the microsatellite status and genetic polymorphisms of KRAS (codons 12 and 13) and BRAF (V600E) were characterized in CRC tissue. The mismatch repair activity and oncogenic potential of KRAS were assessed by immunoblots from two KRAS-mutated CRC cell lines, SW480 and HCT116, with different microsatellite statuses, following treatment with 5-fluorouracil (5-FU) and oxaliplatin. Of all the 205 patients with CRC enrolled in the present study, 31.2% (64 of 205) had a KRAS or BRAF mutation, and 79.7% (51 of 64) of these patients with a KRAS/BRAF mutation exhibited microsatellite stability (MSS), indicating that microsatellite status is correlated with KRAS/BRAF mutation (P=0.027). A higher proportion (39.0%, 41 of 105) of elderly patients (>=62.6 years) had mutated KRAS or BRAF than younger patients (<62.6 years; 23.0%, 23 of 100; P=0.013). In the subgroup of 154 patients with MSS, patients without the KRAS or BRAF mutation (n=110) had longer disease-specific survival rates (58.8+/-9.4%) than patients with KRAS or BRAF mutations (n=44; 50.6+/-11.0%; P=0.043). Cytoplasmic KRAS levels decreased whereas nuclear MutS protein homolog 2 (MSH2) levels increased slightly in CRC HCT116 cells that were microsatellite instable, following treatment with 76.9 uM 5-FU for 2 days. In microsatellite stable SW480 cells, MSH2 levels markedly increased in the nucleus following 150 uM oxaliplatin treatment for 3 days. However, no significant change was observed regarding KRAS distribution in these cells. The results of the present study suggest that it is important to identify patients with CRC who may benefit from adjuvant chemotherapy with 5-FU or oxaliplatin, particularly CRC patients with MSS and mutated KRAS or BRAF, who have poorer overall survival rates than patients with microsatellite instability. Knowledge of the microsatellite status of patients and whether they harbor KRAS or BRAF mutations may enable more effective therapeutic strategies to be developed. Further prospective studies are required to validate the findings of the current study. PMID- 28101207 TI - Structure-function analysis of DNA helicase HELQ: A new diagnostic marker in ovarian cancer. AB - It has been previously reported that a deficiency of the helicase, POLQ-like (HELQ) gene increases the risk of ovarian cancer. The present study aimed to explore the structure-function association of HELQ and discuss the effect of molecular structure on the occurrence of tumors. ExPASy tools were employed to analyze the physicochemical properties and secondary structure of the genes. PHYRE2 Protein Fold Recognition Server was used to construct the three dimensional model and find the ligand-binding sites of HELQ. In addition, the potential functions corresponding to these structures were excavated by comparing and analyzing protein domains. The HELQ protein is located in the cytoplasm (56.5%) and nucleus (21.7%). HELQ has 4 conserved domains, consisting of DEXDc, HELICc, HHH_5 and PRK02362, which contain the adenosine triphosphate (ATP) binding site, nucleotide binding region and putative Mg2+ binding site. In the secondary structure, it was found that HELQ was mainly composed of alpha helix (46.68%) and random coils (43.05%), with only 10.26% extended strand. According to 3DLigandSite Server, the ligand binding sites appeared in ILE333, LYS335, TYR337, SER362, LEU367, LYS397, GLN340, GLY363, GLY364 and ASN678 of the amino acid sequence. Among the functional protein association networks, regulator of telomere elongation helicase 1, family with sequence similarity 175 member A, small ubiquitin-like modifier 1, DNA polymerase nu and coiled-coil domain containing 158 were involved and co-expressed with HELQ. PredictProtein analysis indicated that the dominant functions of HELQ were ATP-dependent helicase activity and participation in the DNA repair process. Characteristics of the HELQ protein were obtained by bioinformatics analysis, based on which the role of HELQ in DNA replication, DNA repair and maintenance of genomic stability was explored. It was concluded that modulation the function of HELQ helicase may be used in the treatment of ovarian cancer. PMID- 28101208 TI - Effect of bovine dialyzable leukocyte extract on induction of cell differentiation and death in K562 human chronic myelogenous leukemia cells. AB - Differentiation induction therapy is an attractive approach in leukemia treatment due to the fact that in blast crisis stage, leukemic cells lose their differentiation capacity. Therefore, it has been proposed as a therapeutic strategy to induce terminal differentiation of leukemic blast cells into a specific lineage, leading to prevention of high proliferation rates. The aim of the present study was to demonstrate the potential of cell differentiation and death induced by bovine dialyzable leukocyte extract (bDLE) in the K562 cell line. For this purpose K562 and MOLT-3 human leukemic cell lines and primary human monocytes and murine peritoneal macrophages were exposed to bDLE, phorbol myristate acetate (PMA) and dimethyl sulfoxide for 96 h, and the viability, proliferation and cell cycle were evaluated. To determine the lineage that led to cell differentiation, Romanowsky staining was performed to observe the morphological changes following the treatments, and the expression of the surface markers cluster of differentiation (CD)14+, CD68+, CD163+ and CD42a+, as well as the phagocytic activity, and the production of nitric oxide (NO) (assessed by colorimetric assay), cytokines [interleukin (IL)-1beta, IL-6, IL-8 and tumor necrosis factor-alpha] and chemokines [chemokine (C-C motif) ligand (CCL)2, CCL5 and chemokine (C-X-C motif) ligand 8] in cell supernatants was assessed by flow cytometry. The results of the present study reveal that high doses of bDLE increase the cell death in K562 and MOLT-3 lines, without affecting the viability of human monocytes and murine peritoneal macrophages. Furthermore, low doses of bDLE induce differentiation in K562 cells towards a monocyte/macrophage lineage with an M2 phenotype, and induced moderately upregulated expression of CD42+, a megakaryocytic marker. Cell cycle arrest in the S and G2/M phases was observed in bDLE-treated K562 cells, which demonstrated similar phagocytic activity, NO levels and cytokine and chemokine production to that of PMA-treated cells. The present study demonstrates that bDLE exhibits an antileukemia effect, suggesting that it may be an effective candidate for leukemia treatment. PMID- 28101210 TI - UBE2T silencing suppresses proliferation and induces cell cycle arrest and apoptosis in bladder cancer cells. AB - Ubiquitin-conjugating enzyme E2T (UBE2T), a member of the ubiquitin-conjugating E2 family in the ubiquitin-proteasome pathway, has been reported to be overexpressed in certain tumor types and to have an important role in the Fanconi anemia pathway. In the present study, the expression of UBE2T and its association with bladder cancer were investigated; to the best of our knowledge, this has not been reported previously. Immunohistochemistry and western blot analysis demonstrated that UBE2T was significantly upregulated in bladder cancer tissues and cell lines compared with adjacent normal bladder tissues and a normal human urinary tract epithelial cell line, respectively. UBE2T was detectable in the nuclei and cytoplasm of cancer cells, exhibiting stronger expression in the nuclei. A UBE2T-siRNA-expressing lentivirus was constructed and used to infect human bladder cancer 5637 cells, in order to examine the role of UBE2T in bladder cancer cell growth in vitro. The knockdown of UBE2T significantly decreased bladder cancer cell proliferation and colony formation. Furthermore, UBE2T silencing induced cell cycle arrest at G2/M phase and increased cell apoptosis. Therefore, UBE2T serves an important role in the growth of bladder cancer cells, and may be considered as a potential biomarker and therapeutic target for bladder cancer. PMID- 28101209 TI - Significance of interstitial tumor-associated macrophages in the progression of lung adenocarcinoma. AB - Stepwise progression from adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) to lepidic predominant adenocarcinoma (LPA) was proposed by various scholars. Interstitial tumor-associated macrophages (TAMs) and various potential chemokines involved in the progression from AIS/MIA to LPA were hypothesized. In the present study, immunohistochemistry or immunofluorescent double staining was used to detect the expression of the TAMs marker cluster of differentiation (CD) 68, tumor-derived colony-stimulating factor (CSF)-1, interleukin (IL)-6, matrix metalloproteinase (MMP)-2, E-cadherin and Snail in lung adenocarcinoma specimens, including AIS/MIA, LPA and other types. It was observed that infiltrating TAMs were negatively associated with the prognosis of patients, and that the infiltration degree of interstitial TAMs was higher in LPA than that in AIS/MIA. In addition, E-cadherin, Snail and MMP-2 expression were significantly correlated with the infiltration degree of TAMs. Survival analysis revealed that co-expression of CD68, CSF-1 and IL-6 was an independent prognostic factor. Stratified analysis demonstrated that, in AIS/MIA patients, there was a statistically significant difference between the number of TAMs (TAMs <=25 and TAMs >25) in the CD68+CSF-1+IL-6+ group compared with other groups (including CD68+CSF-1-IL-6-, CD68+CSF-1+IL-6-, CD68+CSF-1-IL-6+ and CD68- groups). By contrast, in patients with TAMs >25 and in patients with positive CD68, CSF-1 and IL-6 expression, the survival rates were not significantly different between AIS/MIA and LPA. These results suggested that co-expression of TAMs marker CD68, CSF-1 and IL-6 may be a valuable independent prognostic predictor in lung adenocarcinoma. TAMs may facilitate AIS/MIA progression to LPA, which may be closely associated with the induction of the epithelial-mesenchymal transition. PMID- 28101211 TI - Receptor FGFRL1 acts as a tumor suppressor in nude mice when overexpressed in HEK 293 Tet-On cells. AB - Fibroblast growth factor receptor-like 1 (FGFRL1) is a transmembrane receptor that interacts with heparin and FGF ligands. In contrast to the classical FGF receptors, FGFR1 to FGFR4, it does not appear to affect cell growth and proliferation. In the present study, an inducible gene expression system was utilized in combination with a xenograft tumor model to investigate the effects of FGFRL1 on cell adhesion and tumor formation. It was determined that recombinant FGFRL1 promotes the adhesion of HEK 293 Tet-On(r) cells in vitro. Moreover, when such cells are induced to express FGFRL1DeltaC they aggregate into huge clusters. If injected into nude mice, the cells form large tumors. Notably, this tumor growth is completely inhibited when the expression of FGFRL1 is induced. The forced expression of FGFRL1 in the tumor tissue may restore contact inhibition, thereby preventing growth of the cells in nude mice. The results of the present study demonstrate that FGFRL1 acts as a tumor suppressor similar to numerous other cell adhesion proteins. It is therefore likely that FGFRL1 functions as a regular cell-cell adhesion protein. PMID- 28101212 TI - Effect of oxaliplatin combined with polyenephosphatidylcholine on the proliferation of human gastric cancer SGC-7901 cells. AB - Oxaliplatin (L-OHP) is a platinum compound that is widely used to treat certain solid tumors, including gastric tumors. L-OHP is an effective anti-cancer treatment; however, its usage increases the probability of patients developing hepatic injury with inflammation, referred to as chemotherapy-associated steatohepatitis. The present study aimed to evaluate the outcome of L-OHP treatment combined with polyenephosphatidylcholine (PPC), a major component of essential phospholipids used to treat steatohepatitis, on SGC-7901 gastric cancer cell proliferation. This would help to determine whether combination therapy with L-OHP and PPC is clinically beneficial for patients with gastric cancer. The viability of SGC-7901 cells was verified by an MTT assay; flow cytometry was used to analyze the cell cycle and rates of cell apoptosis; oxidation-related indicators were measured by spectrophotometry, and the expression of cell cycle- and apoptosis-related proteins was determined by western blotting. The results demonstrated that L-OHP significantly inhibited SGC-7901 cell growth in a dose- and time-dependent manner (F=194.193, P<0.01 and F=12.428, P=0.01, respectively). Furthermore, PPC stimulated the growth of SGC-7901 cells and greatly promoted their apoptosis induced by L-OHP, which was supported by the upregulation of cytochrome c and the downstream activation of caspases 3 and 9. Finally, following treatment with a combination of PPC and L-OHP, the expression of cyclins D1 and E was downregulated; however, PPC did not alter the production of reactive oxygen species caused by L-OHP (P=0.88). The present study determined that the combination of L-OHP and PPC exerts a synergistic anti-tumor effect, suggesting that L-OHP and PPC combination therapy may be used as a treatment for patients with gastric cancer that reduces the side effects of L-OHP without inhibiting its efficacy. PMID- 28101213 TI - Osteopontin improves adhesion and migration of human primary renal cortical epithelial cells during wound healing. AB - The aim of the present study was to investigate the effect of osteopontin (OPN) on adhesion and migration in human primary renal cortical epithelial cells during wound healing and Transwell assays. MTT assay was used to examine the cell viability and western blot analysis was used to examine the expression of cytoskeletal proteins and cell adhesion molecules. The results showed that overexpression of OPN had positive effects on the viability, proliferation, adhesion and migration of the human primary renal cortical epithelial cells. In addition, the integrity of the cell membrane and cytoskeleton of the epithelial cells was negatively affected by knockdown of OPN expression. The Transwell migration and a wound healing assays performed using OPN-knockdown cells suggested that OPN had a significant impact on cell migration (P=0.0421) and wound healing (P=0.0333). Therefore, OPN may be a potential target for the therapeutic modulation of skin repair to improve the healing rate and quality of wound healing. PMID- 28101214 TI - PARP-1 may be involved in angiogenesis in epithelial ovarian cancer. AB - Poly (ADP-ribose) polymerase 1 (PARP-1) is involved in DNA repair and has been implicated in chemoresistance. The present study investigated whether PARP-1 promotes angiogenesis in ovarian cancer. PARP-1 and vascular endothelial growth factor A (VEGF-A) expression and CD34+ microvascular density (MVD) were assessed using immunohistochemistry in 60 human epithelial ovarian cancer specimens. PARP 1 was stably knocked-down in SKOV3 cells using a specific small interfering RNA (siRNA); angiogenic capacity was assessed using the human umbilical vein endothelial cell (HUVEC) tubule formation assay; and PARP-1 and VEGF-A expression were examined by reverse transcription-quantitative polymerase chain reaction, western blotting and ELISA. PARP-1 was found to be expressed in 73.3% (44/60) of the human epithelial ovarian cancer specimens and was significantly associated with VEGF-A, MVD, tumor size, histological grade and lymphatic metastasis (P<0.05). Compared with cells transfected with a negative control siRNA, knockdown of PARP-1 significantly suppressed the ability of SKOV3 cell conditioned media to promote HUVEC tubule formation on Matrigel in vitro. Knockdown of PARP-1 in SKOV3 cells also significantly reduced VEGF-A mRNA and protein expression and secretion. In summary, PARP-1 is overexpressed and may enhance angiogenesis in epithelial ovarian cancer by upregulating VEGF-A. PMID- 28101215 TI - Rottlerin-induced autophagy leads to apoptosis in bladder cancer cells. AB - It has been well-established that apoptosis contributes to cancer cell death; however, the role of autophagy in cancer cell death remains unclear. The aim of the present study was to investigate the effects of rottlerin, a traditional Indian medicine, on cell growth inhibition and autophagy in EJ human bladder carcinoma cells in vitro. Cell viability, measured by MTT assay, was found to be suppressed in a dose- and time-dependent manner. In addition, apoptosis was significantly increased in cells treated with rottlerin, as indicated by increased annexin V-fluorescein isothiocyanate/propidium iodide staining and changes in the cell cycle distribution that indicated blockage at G1 phase. Rottlerin treatment also enhanced the activation of autophagy, with increased expression of microtubule-associated protein 1 light chain 3 (LC3)-II and the appearance of autophagosomes. The increased level of LC3-II and autophagosomes suggests that autophagy may contribute to apoptosis in these cells. In addition, no apparent alterations in the levels of pro-caspase-3, cleaved caspase-3, total poly (ADP ribose) polymerase (PARP) and cleaved-PARP were observed in cells treated with rottlerin, which indicates that caspases may not serve a key role during the process of apoptosis induced by rottlerin. Therefore, the results of the present study indicate that rottlerin promotes apoptosis and arrests the cell cycle in EJ cells, which may be caused by autophagy activation. PMID- 28101216 TI - Epidermal growth factor receptor mutation enhances expression of vascular endothelial growth factor in lung cancer. AB - Epidermal growth factor receptor (EGFR) activation has been demonstrated to have a critical role in tumor angiogenesis. In the present study, the correlation between EGFR mutations and vascular endothelial growth factor (VEGF) was investigated in lung cancer cell lines and non-small-cell lung cancer (NSCLC) tumor tissues. VEGF levels were significantly increased in culture medium of lung cancer cells and NSCLC tissues with EGFR mutations (H1650 vs. A549, P=0.0399; H1975 vs. A549, P<0.0001). Stable lung cancer cell lines expressing mutant (exon 19 deletion, E746-A750; exon 21 missense mutation, L858R) and wild-type EGFR genes were established. Significantly increased expression of VEGF and stronger inhibitory effects of gefitinib to VEGF expression were observed in exon 19 deletion stable lung cancer cells (exon 19 deletion vs. wild-type EGFR, P=0.0005). The results of the present study may provide an insight into the association of mutant EGFR and VEGF expression in lung cancer, and may assist with further development of targeted therapy for NSCLC in the future. PMID- 28101217 TI - Safety and effectiveness of percutaneous radiofrequency ablation in early stage renal cell carcinoma. AB - The purpose of this study was to analyze the safety and effectiveness of percutaneous radiofrequency ablation (RFA) in early stage renal cell carcinoma. A total of 76 patients suffering from early stage renal cell carcinoma were selected and randomly assigned into the observation group (41 cases) or the control group (35 cases). Percutaneous RFA was used in the observation group, while retroperitoneoscopic radical operation of renal cell carcinoma was used in the control group, and the operative effects were compared. In the observation group, operation time, blood loss during operation, length of stay and incidence rate of complications were lower than those in control group (P<0.05). For both groups, serum C-reactive protein, interleukin-6 and T lymphocyte counts at 1, 2 and 3 days after operation were all increased; however, the control group had significantly greater increase for all the time points (P<0.05). For total effective rates, tumour-free survival times and survival rates, there were no statistically significant differences between the two groups (P>0.05). Percutaneous RFA has a reduced size of operation wound and a quick postoperative recovery time in the treatment of early stage renal cell carcinoma. It results in less inflammation and immunity-based injuries in the body and achieves the same clinical outcomes as retroperitoneoscopic radical operation of renal cell carcinoma. PMID- 28101218 TI - Bevacizumab, pemetrexed and carboplatin in first-line treatment of non-small cell lung cancer patients: Focus on patients with brain metastases. AB - Data concerning bevacizumab plus pemetrexed plus carboplatin as first-line treatment for patients with non-squamous non-small cell lung cancer (NSCLC) with or without brain metastases (BM) are lacking. The present study analyzed the efficacy and safety of this combination as induction therapy, followed by maintenance therapy with bevacizumab plus pemetrexed in non-squamous NSCLC patients with or without BM. Treatment-naive patients with advanced non-squamous NSCLC and an Eastern Cooperative Oncology Group performance status score of 0-2 were eligible. Treatment consisted of carboplatin (area under the curve of 5), pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg) every 3 weeks for 6 cycles. Responders and patients with stable disease received maintenance therapy with bevacizumab plus pemetrexed until disease progression, which was evaluated every 3 cycles, or unacceptable toxicity. Kaplan-Meier median progression-free survival (PFS) and overall survival (OS) times were the primary endpoints, and safety was the secondary endpoint. In total, 39 patients, aged 44-78 years (median, 60 years), were treated; 11 (28.2%) of whom presented with BM. The majority of patients (56.4%) completed 6 cycles of induction therapy, and 26 patients continued on to maintenance therapy. The median PFS time was 8.2 months [95% confidence interval (CI), 7.05-9.35] and the median OS time was 14.0 months (95% CI, 8.46-19.54). Median PFS and OS times did not differ significantly between patients with or without BM (log rank (Mantel-Cox): PFS, P=0.748 and OS, P=0.447). The majority of patients (76.9%) did not experience adverse events during treatment. Overall, bevacizumab plus pemetrexed plus carboplatin as induction therapy, followed by bevacizumab plus pemetrexed as maintenance therapy was effective and well tolerated in advanced NSCLC, whether brain metastases were present or not. PMID- 28101219 TI - N-terminal truncated carboxypeptidase E expression is associated with poor prognosis of lung adenocarcinoma. AB - Lung cancer is a malignant tumor with high morbidity and mortality rates. To date, no suitable molecular diagnostic tool to predict disease recurrence and metastasis has been identified. The current study aimed to evaluate the potential of N-terminal truncated carboxypeptidase E (CPEDeltaN) to predict the recurrence and metastasis of lung adenocarcinoma. Western blotting revealed the co expression of CPE and CPEDeltaN in the surgically collected pathological and pericarcinoma tissues tissues of 62.1% (59/95) lung adenocarcinoma patients. The full length CPE protein was predominantly expressed in pericarcinoma tissues and CPEDeltaN expression was identified in the pericarcinoma normal tissues of only 5.26% (5/95) patients. The 3-year postoperative recurrence and metastasis rates were significantly higher in patients with positive CPEDeltaN expression than in patients with negative CPEDeltaN expression (P=0.009). Furthermore, the overall survival rate of patients with predominant nuclear CPE expression was lower than that of patients with predominant cytoplasmic CPE expression (46.3 vs. 64.7%); however, no statistically significant difference was identified (P=0.125). Thus, the results of the current study indicated that CPEDeltaN may present a novel molecular biomarker for predicting recurrence and metastasis of lung adenocarcinoma, which may aid with stratifying patients by risk and thus, may facilitate individualized therapy. PMID- 28101221 TI - A complex translocation (3;17;15) in acute promyelocytic leukemia confirmed by fluorescence in situ hybridization. AB - Acute promyelocytic leukemia (APL) is typified by t(15;17)(q22;q21), generating the promyelocytic leukemia (PML) gene at 15q22 with the retinoic acid alpha receptor (RARA) gene at 17q21. The PML-RARA fusion gene is believed to play a vital role in leukemogenesis. A sizeable minority of patients with complex variants of APL have been reported. The present study reports the case of a 33 year-old male with APL carrying a potential complex translocation. The initial symptom was bleeding gums. Chromosomal analysis of the bone marrow cells revealed an atypical 17q aberration. Fluorescence in situ hybridization further indicated that 92% of analyzed cells were positive for the PML-RARA fusion gene. The patient experienced complete remission following treatment with arsenic trioxide and chemotherapy. The atypical translocations in acute promyelocytic leukemia require further investigation. PMID- 28101220 TI - Antitumor effect of forbesione isolated from Garcinia hanburyi on cholangiocarcinoma in vitro and in vivo. AB - Cholangiocarcinoma (CCA) is a malignancy with no effective therapy and poor prognosis. Forbesione, a caged xanthone isolated from Garcinia hanburyi, has been reported to inhibit proliferation and to induce apoptosis in human CCA cell lines. The present study aimed to further explore the potential anticancer properties of forbesione by testing its effects against the hamster CCA cell line Ham-1 in vitro and in vivo. It was observed that forbesione inhibited the growth of Ham-1 cells in vitro and suppressed Ham-1 growth as allograft in hamsters by inducing cell cycle arrest at the S phase. This was mediated by decreasing the protein expression of cyclin E, cyclin A and cyclin-dependent kinase 2. In addition, increased expression of p21 and p27 was detected, which could possibly explain the reduced expression of proliferating cell nuclear antigen and of the bile duct cell marker cytokeratin 19 observed in forbesione-treated Ham-1 cells in vitro and in tumor tissues of forbesione-treated hamsters. Furthermore, forbesione induced apoptosis through multiple pathways. The death receptor pathway was activated by increased expression of Fas, Fas-associated death domain and activated caspase-3, along with decreased expression of procaspase-8 and procaspase-3. The mitochondrial pathway was driven by increased expression of B cell lymphoma (Bcl)-2-like protein 4, activated caspase-9 and inhibitor of kappaB alpha, along with decreased expression of Bcl-2, survivin, procaspase-9 and nuclear factor-kappaB/p65. The endoplasmic reticulum pathway was stimulated by increased expression of activated caspase-12 and decreased expression of procaspase-12. No side effects or toxicity were observed in forbesione-treated hamsters. Thus, forbesione is a potential drug candidate for cancer therapy that deserves further investigation. PMID- 28101222 TI - FRAT1 expression regulates proliferation in colon cancer cells. AB - Colorectal cancer is one of the most common gastric malignancies worldwide. However, the underlying mechanism of colon cancer development and valuable indicators of the disease remain unclear. In this study, the expression of frequently rearranged in advanced T-cell lymphomas 1 (FRAT1) in colon cancer was investigated and the association between FRAT1 expression and biological properties of tumors was analyzed. A total of 147 colon cancer tissue samples and adjacent normal tissues were collected between January 2013 and June 2014. The FRAT1 gene and protein expression levels were analyzed in tissues with different TNM and pathological stages. Small hairpin RNAs (shRNAs) containing the human FRAT1 gene were constructed and transfected into colon cancer HT-29 cells. The proliferation and migration of the cells was also analyzed in relation to a reduction in FRAT1 expression. In colon cancer tissues, the expression of FRAT1 was significantly higher when compared with adjacent tissues. In addition, FRAT1 expression was found to positively correlate with the degree of tumor malignancy, and this difference was determined to be statistically significant (P<0.05). Following shRNA transfection in HT-29 cells to decrease the expression of FRAT1, the proliferation and migration of the HT-29 cells decreased (due to conversion of the shRNA into small interfering RNA). These results indicate that in colon cancer, FRAT1 may present a novel tool for analyzing the tumor progression and may be a novel therapeutic target for the treatment of colon cancer. PMID- 28101223 TI - Modulatory effect of luteolin on redox homeostasis and inflammatory cytokines in a mouse model of liver cancer. AB - Liver cancer is one of the leading causes of cancer-associated mortality worldwide. Due to changes in lifestyle and daily exposure to various chemicals, which may lead to chemical intoxication, liver cancer has become a prominent disease in humans. Chemical-induced carcinogenesis in experimental animals has become a reliable model for the investigation of liver cancer-associated biological alterations that may mimic human hepatic cancer. Liver cancer in BALB/c mice was induced by administering diethylnitrosamine (DN) in drinking water for 6 weeks. Luteolin (LUT) is a flavone that is found in the leaves of the majority of spice-associated plants. In the present study, 20 ug/kg of body weight LUT was administered intraperitoneally every alternate day to treat the DN induced liver cancer in mice. LUT improved the host system by modifying the levels of alpha-fetoprotein, enzymatic antioxidants, such as superoxide dismutase and catalase, marker enzymes, such as AST and ALT, and lipid peroxides in the plasma or liver tissue. LUT also reduced the levels of glutathione and the inflammatory cytokines interleukin-2 and interferon-gamma in the plasma or liver tissue. These findings augmented the treatment against liver cancer and supported the effective anticancer activity of LUT against DN-induced liver carcinogenesis in mice. PMID- 28101224 TI - Impact of chromosome 17q deletion in the primary lesion of colorectal cancer on liver metastasis. AB - Colorectal cancer is a prevalent malignancy worldwide, and investigations are required to elucidate the underlying carcinogenic mechanisms. Amongst these mechanisms, de novo carcinogenesis and the adenoma to carcinoma sequence, are the most understood. Metastasis of colorectal cancer to the liver often results in fatality, therefore, it is important for any associated risk factors to be identified. Regarding the treatment of the disease, it is important to manage not only the primary colorectal tumor, but also the liver metastases. Previously, through gene variation analysis, chromosomal loss has been indicated to serve an important role in liver metastasis. Such analysis may aid in the prediction of liver metastasis risk, alongside individual responses to treatment, thus improving the management of colorectal cancer. In the present study, we aimed to clarify a cause of the liver metastasis of colorectal cancer using comparative genomic hybridization analysis. A total of 116 frozen samples were analyzed from patients with advanced colorectal cancer that underwent surgery from 2004 to 2011. The present study analyzed mutations within tumor suppressor genes non metastatic gene 23 (NM23), deleted in colorectal carcinoma (DCC) and deleted in pancreatic carcinoma, locus 4 (DPC4), which are located on chromosomes 17 and 18 and have all been reported to affect liver metastasis of colorectal cancer. The association between chromosomal abnormalities (duplication and deletion) and liver metastasis of colorectal cancer was evaluated using comparative genomic hybridization. Cluster analysis indicated that the group of patients lacking the long arm of chromosome 17 demonstrated the highest rate of liver metastasis. No significant association was observed between the frequency of liver metastases for synchronous and heterochronous colorectal cancer cases and gene variation (P=0.206). However, when these liver metastasis cases were divided into the synchronous and heterochronous types, the ratio of each was significantly different between gene variation groups, classified by the existence of the 17q deletion (P=0.023). These results indicate that the deletion of 17q may act as a predictive marker of liver metastasis in postoperative states. PMID- 28101225 TI - Monocytic myeloid-derived suppressor cells as a potent suppressor of tumor immunity in non-small cell lung cancer. AB - Immunotherapy is a promising therapeutic option for patients with non-small cell lung cancer (NSCLC) who do not qualify for surgery. In patients with advanced NSCLC, systemic immune suppression is frequently observed, therefore, researchers are investigating the tumor microenvironment for less invasive and more effective methods of treating lung cancer. Monocytic myeloid-derived suppressor cells (Mo MDSCs) are potent suppressors of tumor immunity; therefore, this population may significantly impede the application of immunotherapy to treat cancer. The present study evaluated the distribution of Mo-MDSCs and monocytes/macrophages in the peripheral blood, lymph nodes and tumor tissue of patients with NSCLC. Furthermore, the profiles of cytokines produced by these cell populations, including interleukin (IL)-1beta, IL-12/23p40, IL-10, transforming growth factor beta (TGF-beta) and tumor necrosis factor (TNF), were compared. The cell populations and the expression of cytokines were assessed by flow cytometry after 4 h in culture with mitogens and Brefeldin A. Mo-MDSCs were more numerous than monocytes/macrophages in all tissues and their prevalence was highest in the peripheral blood; they expressed higher levels of TGF-beta than monocytes/macrophages in all tissues and expression of TGF-beta produced by Mo MDSCs was higher in the blood than in lymph nodes and tumor tissues. A higher percentage of monocytes/macrophages was observed in lymph nodes and tumor tissues than in blood. CD14+HLA-DR+ cells also produced more IL-10 in lymph nodes than Mo MDSCs and more IL-1beta and TNF in all tissues. A higher prevalence of cluster of differentiation 14+ human leukocyte antigen-D related+ cells secreting IL-1beta, TNF and IL-12/23p40 was observed in peripheral blood. Thus, the results of the current study support the statement that Mo-MDSCs and monocytes/macrophages participate in NSCLC induced immunosuppression, and is consistent with previous research into associations between the TGF-beta signaling pathway and tumor cell invasion, motility and metastasis. The study also demonstrated that Mo-MDSCs promote tumor growth through their immunosuppressive activity. In addition, the profile of cytokines expressed by monocytes/macrophages suggests that this cell population may be associated with metastasis formation and angiogenesis promotion in patients with NSCLC. PMID- 28101226 TI - Evaluation of plasma microRNA levels to predict insensitivity of patients with advanced lung adenocarcinomas to pemetrexed and platinum. AB - Pemetrexed combined with platinum is a first-line therapy used to treat patients with advanced non-small cell lung cancer (NSCLC) that exhibit negative or unknown epidermal growth factor receptor (EGFR) mutational status or anaplastic lymphoma kinase (ALK) rearrangements. Lung adenocarcinoma (LAC) is the primary type of NSCLC. In order to prevent overtreatment, it is necessary to identify patients with LAC who may not benefit from certain chemotherapies. Patients recruited in the present study (n=129) were diagnosed with advanced LAC and received first line pemetrexed and platinum-based chemotherapy. A microRNA (miR) microarray was used to screen the plasma miR expression profiles in a screening set of eight patients prior to and following treatment. Specifically, plasma miR-25, miR-21, miR-27b, miR-326, miR-483-5p and miR-920 were selected for reverse transcription quantitative polymerase chain reaction analysis in a training set (n=44) prior to treatment. The screening and training set patients were all non-smokers with no prior history of serious or chronic disease. The ??Cq values of these miRs were compared between the group that showed benefit from pemetrexed and platinum treatment and the group that did not. Consequently, the ??Cq values of miR-25, miR-21, miR-27b and miR-326 were further determined in a validation set (n=77). The results of the present study demonstrate that plasma expression levels of miR 25, miR-21, miR-27b and miR-326, in the training and validation sets prior to treatment, were significantly different between the benefit and non-benefit groups (P<=0.001). The expression of miR-25, miR-21, miR-27b and miR-326 was upregulated in the non-benefit group and this elevation was positively correlated with decreased progression-free survival (PFS; P<=0.001). In addition, the predictive power of each miR was evaluated through receiver operating characteristic curves, in which miR-25 exhibited the highest degree of accuracy (area under the curve, 0.926; 95% confidence interval, 0.881-0.971). These results indicate that overexpression of plasma miR-25, miR-21, miR-27b and miR 326, prior to treatment, in patients with advanced LAC is predictive of non benefit from first-line pemetrexed and platinum-based chemotherapy, and is associated with decreased PFS. Among these four miRs, miR-25 exhibited the highest degree of accuracy in predicting insensitivity, suggesting it is the most promising biomarker. PMID- 28101227 TI - Downregulation of mir-23b in plasma is associated with poor prognosis in patients with colorectal cancer. AB - MicroRNAs (miRNAs) are short, non-coding RNA molecules that act as regulators of gene expression. Circulating blood miRNAs have potential as cancer biomarkers. The main objective of the present study was to assess the effect of miRNA-23b (miR-23b) expression in plasma on the diagnosis and prognosis of colorectal cancer (CRC). Reverse transcription-quantitative polymerase chain reaction (PCR) was used to measure miR-23b expression levels, and methylation-specific PCR was used to test the promoter methylation status. Subsequently, the expression level of miR-23b in plasma samples was compared between CRC patients and healthy control individuals. The miR-23b expression levels were significantly lower in CRC cells and primary CRC tissues than in nonmalignant colorectal tissues (P<0.001). It was also shown that miR-23b expression is downregulated by promoter methylation and can be restored by demethylation agent treatment. miR-23b was significantly decreased in plasma samples from CRC patients compared with the healthy control individuals (P<0.001). The value of the area under the receiver operating characteristic curve was 0.842 (sensitivity, 84.38%; specificity, 77.08%; 95% confidence interval, 0.763-0.922). Low plasma miR-23b expression was significantly associated with clinical stage, tumor depth, distant metastasis and tumor recurrence. CRC patients with low miR-23b expression in plasma exhibited a shorter recurrence-free survival time and poorer overall survival rate. The present results suggested that the downregulation of miR-23b in the plasma has the potential to be a diagnostic and prognostic biomarker in CRC. PMID- 28101228 TI - Increased expression of PDIA3 and its association with cancer cell proliferation and poor prognosis in hepatocellular carcinoma. AB - The prognosis of hepatocellular carcinoma (HCC) is unfavorable following complete tumor resection. The aim of the present study was to identify a molecule able to predict HCC prognosis through comprehensive protein profiling and to elucidate its clinicopathological significance. Comprehensive protein profiling of HCC was performed by liquid chromatography-tandem mass spectrometry. Through the bioinformatic analysis of proteins expressed differentially in HCC and non-HCC tissues, protein disulfide-isomerase A3 (PDIA3) was identified as a candidate for the prediction of prognosis. PDIA3 expression was subsequently examined in 86 cases of HCC by immunostaining and associations between PDIA3 expression levels and clinicopathological characteristics were evaluated. The Ki-67 index and apoptotic cell death of carcinoma cells were examined by immunostaining and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay in 24 cases. The results demonstrated that PDIA3 was expressed in all 86 HCC cases; 56 HCC cases (65%) exhibited high expression of PDIA3 and 30 (35%) exhibited low expression. The disease-free and overall survival times of HCC patients with high PDIA3 expression were significantly shorter than in HCC patients with low expression. Furthermore, increased expression of PDIA3 was associated with an elevated Ki-67 index, indicating increased cancer cell proliferation and a reduction in apoptotic cell death. Taken together, these results suggest that PDIA3 expression is associated with tumor proliferation and decreased apoptosis in HCC, and that increased expression of PDIA3 predicts poor prognosis. PDIA3 may therefore be a key molecule in the development of novel targeting therapies for patients with HCC. PMID- 28101229 TI - Retrospective analysis of breast cancer prognosis among young and older women in a Brazilian cohort of 738 patients, 1985-2002. AB - Invasive breast cancer (BC) is infrequent among women aged <=40 years, however, the disease outlook in these younger patients is generally worse than among older women. The present study aimed to compare socio-demographic, clinical and pathological characteristics, and their association with long-term survival, between two random cohorts of young (<=40 years) and older (50-69 years) Brazilian patients with BC. The cohort comprised of 738 randomly selected women who were diagnosed with BC at Barretos Cancer Hospital, Pio XII Foundation (Barretos, Brazil) between January 1985 and December 2002; the patients included young women (n=376) and older women (n=362). The current analysis suggested that BC in young women is associated with numerous pathological features of aggressiveness. Second cancer and bilateral BC were independent predictors of a poor outcome in the younger group. Furthermore, C-erB-2 was positively correlated with poor outcome in the older group, whereas estrogen receptor status and TNM stage were associated with disease prognosis in both groups. The overall survival rates of the two age groups were similar except when analyzed according the treatment period (1997-2002). Although patients aged <=40 years harbored tumors with more aggressive clinicopathological characteristics, these characteristics were not independent predictors of overall survival. The present study indicates that medical advances associated with prevention of breast cancer may improve screening programs, which may therefore increase early diagnosis and subsequently lower mortality rates. PMID- 28101230 TI - Effect of IL-17 in the development of colon cancer in mice. AB - Cytokine therapy is commonly used for tumor immunotherapy. Although early studies focused directly on the tumor, current investigations are more attentive of the tumor microenvironment. Various immune cells and related cytokines in the tumor microenvironment play an important role in the occurrence and development of tumor. Interleukin (IL)-17 is the characteristic cytokine produced by Th17 cells. IL-17 has been associated with various immune responses. The results of previous studies showed that IL-17 can significantly reduce the size of transplanted tumors in tumor-bearing mice, albeit it has no effect on the survival time of mice. By investigating the effect of IL-17 in the number and distribution of lymphocyte infiltration in tumor tissues, the expression of cytokines and transcription factors associated with the subsets of CD4+T cells in tumor tissues, the distribution of subsets of spleen lymphocyte in tumor-bearing mice, a preliminary investigation of the possible antitumor mechanism of IL-17 was performed. In conclusion, the antitumor effect of IL-17 gene transfection in the colon cancer of mice may be associated with the mechanisms whereby IL-17 gene transfection can change the distribution of different subsets of spleen lymphocytes in mice. IL-17 gene transfection can increase the number of lymphocyte infiltration in tumor tissues. IL-17 gene transfection can promote the high expression of interferon-gamma in tumor tissue, while reducing the expression of IL-10 and IL-13 factors, thus exerting an antitumor effect. PMID- 28101232 TI - Feasibility and application of single-hole video-assisted thoracoscope in pulmonary peripheral tumors. AB - The feasibility and clinical application of single-hole video-assisted thoracoscope in pulmonary peripheral tumors was examined. From March, 2011 to March, 2015, we retrospectively analyzed the clinical data obtained from 32 patients with pulmonary peripheral tumor that received single-hole thoracoscopic surgery. We completed the surgery via a 1.5-cm incision on the seventh or eighth rib in midaxillary line as the observation hole, and a 4.0-5.0-cm incision in the lateral margin of pectoralis major in the fourth or fifth rib in midaxillary line as the operation hole. All the patients had completed the tumor-reductive surgery under single-hole thoracoscope successfully. None required second operation hole or needed a transfer to thoracotomy. Operation time was 40-100 min with an average of 65.78+/-15.87 min. Intraoperative blood loss was 20-100 ml, with an average of 47.19+/-26.91 ml. Post-operative chest drainage time was 3-6 days, with an average of 4.22+/-0.87 days. Hospitalization time after operation was 5-7 days, with an average hospitalization time of 5.97+/-0.82 days. No patient received a second surgery for pulmonary leak or bleeding and no patient had any complication. All the cases recovered without any problem. In conclusion, for patients with pulmonary peripheral tumor, single-hole video-assisted thoracoscope could further reduce their surgical trauma. The operation was safe and feasible and worthy of wide application. PMID- 28101231 TI - The biological significance of methylome differences in human papilloma virus associated head and neck cancer. AB - In recent years, studies have suggested that promoter methylation in human papilloma virus (HPV) positive head and neck squamous cell carcinoma (HNSCC) has a mechanistic role and has the potential to improve patient survival. The present study aimed to replicate key molecular findings from previous analyses of the methylomes of HPV positive and HPV negative HNSCC in an independent cohort, to assess the reliability of differentially methylated markers in HPV-associated tumors. HPV was measured using real-time quantitative PCR and the biological significance of methylation differences was assessed by Ingenuity Pathway Analysis (IPA). Using an identical experimental design of a 450K methylation platform, 7 of the 11 genes were detected to be significantly differentially methylated and all 11 genes were either hypo- or hypermethylated, which was in agreement with the results of a previous study. IPA's enriched networks analysis identified one network with msh homeobox 2 (MSX2) as a central node. Locally dense interactions between genes in networks tend to reflect significant biology; therefore MSX2 was selected as an important gene. Sequestration in the top four canonical pathways was noted for 5-hydroxytryptamine receptor 1E (serotonin signaling), collapsin response mediator protein 1 (semaphorin signaling) and paired like homeodomain 2 (bone morphogenic protein and transforming growth factor-beta signaling). Placement of 9 of the 11 genes in highly ranked pathways and bionetworks identified key biological processes to further emphasize differences between HNSCC HPV positive and negative pathogenesis. PMID- 28101234 TI - Dysregulation of MALAT1 and miR-619-5p as a prognostic indicator in advanced colorectal carcinoma. AB - The present study aimed to detect the expression of metastasis associated lung adenocarcinoma transcript 1 (MALAT1) and microRNA (miR)-619-5p in colorectal carcinoma (CRC), and to evaluate the significance of MALAT1 and miR-619-5p expression in the clinical diagnosis and prognosis of CRC. Quantitative polymerase chain reaction was used to detect MALAT1 and miR-619-5p expression in 120 colorectal carcinoma and 120 adjacent normal tissue samples. The expression levels of MALAT1 and miR-619-5p were significantly different between colorectal carcinoma and adjacent normal tissues (P<0.05). MALAT1 exhibited an average 2.52 fold increase in colorectal adenoma when compared with adjacent normal tissues, while miR-619-5p exhibited an average 5.79-fold decrease in colorectal adenoma when compared with adjacent normal tissues. There was a significant difference between the MALAT1 expression in CRC tissues obtained from men and women (P=0.027), and in tumor-node-metastasis (TNM) stage II and stage III lesions (P=0.019). MALAT1 expression was associated with lymphovascular invasion (P=0.047) and perineural invasion (P=0.012). In addition, miR-619-5p expression was also significantly different between men and women (P=0.032), and between TNM stage II and stage III lesions (P=0.012). miR-619-5p expression was also associated with lymphovascular invasion (P=0.023) and perineural invasion (P=0.009). Patients with high expression of MALAT1 and low expression of miR-619 5p demonstrated significantly shorter disease-free survival (DFS) (P=0.002) and overall survival (OS) times (P=0.004) compared with patients with low MALAT1 expression and high miR-619-5p expression. Patients with perineural invasion demonstrated significantly shorter DFS (P=0.001) and OS times (P=0.003) compared with patients without perineural invasion. In addition, there was a negative correlation between MALAT1 expression and miR-619-5p expression (r=-0.415, P=0.004) in CRC tissues. In conclusion, MALAT1 and miR-619-5p have potential for the molecular diagnosis of CRC patients, and combined assaying of MALAT1 and miR 619-5p may improve the accuracy of the diagnosis of CRC and act as a good prognostic indicator in CRC patients. PMID- 28101233 TI - Lipid raft localization of epidermal growth factor receptor alters matrix metalloproteinase-1 expression in SiHa cells via the MAPK/ERK signaling pathway. AB - Matrix metalloproteinase-1 (MMP-1) has been identified as an important participant in tumor invasion, metastasis and angiogenesis. The purpose of the present study was to investigate the effects of epidermal growth factor receptor (EGFR) localization to lipid rafts on signaling pathways involved in the regulation of MMP-1 expression in SiHa cells, a cervical cancer cell line. EGFR activation by EGF specifically induced MMP-1 expression at both the messenger RNA and protein levels. Additionally, it was observed that EGFR localized to lipid rafts, and that the redistribution of EGFR induced by lipid raft disruption strengthened EGF-induced MMP-1 expression. MMP-1 induction was blocked by the mitogen-activated protein kinase (MAPK) kinase inhibitors PD98059 and U0126. Our results suggested that lipid rafts provide a platform to inhibit EGFR regulation of MMP-1 in SiHa cells through the MAPK/extracellular signal-regulated kinase signaling pathway. PMID- 28101236 TI - Identification of proteins associated with pediatric bilateral Wilms tumor. AB - Wilms tumor (WT) is the most common cancer that primarily develops in abdominal solid organ of children. It has no incipient symptom, and the most frequent symptoms are a painless, palpable abdominal mass. Proteomics technology was used to select the differentially expressed proteins of bilateral Wilms tumor (BWT). Ten serum samples of children with BWT were chosen, 20 serum samples of children with unilateral WT (UWT) and 20 serum samples of healthy children were selected, and proteomics technology was used to detect and collect data. Using bioinformatics, the data were analyzed and 10 difference peaks were obtained (P<0.01). Non-linear support vector machine was used to classify and to select the composite pattern with the highest Youdens index, and one differentially expressed protein with m/z of 5,648 kDa was obtained. A significantly high expression in children with BWT was obtained, and the expression intensity was also significantly (3,889.36+/-1,796.83) higher for children with BWT compared to those with UWT (2,886.81+/-1,404.65) and healthy children (432.21+/-730.42). Matrix-assisted laser desorption ionization/time-of-flight ionization/time-of flight mass spectrometry was used for identification of the peak, and the peak was further identified as apolipoprotein C-III (APO C-III) by western blot analysis. In conclusion, to the best of our knowledge, a differentially expressed protein of APO C-III of BWT was obtained through proteomics technology for the first time, and it is expected to be a new marker for the early diagnosis and prognosis of BWT. PMID- 28101235 TI - Protective effect of selenium against cisplatin-induced nasopharyngeal cancer in male albino rats. AB - The present study evaluated the protective effect of selenium against cisplatin induced nasopharyngeal cancer in the cardiac tissue of adult rats. Male Wistar rats were divided into 4 groups of 6 rats each. Different combinations of selenium and cisplatin were administered for 45 days, following which the animals were sacrificed and the nasopharyngeal tissue was surgically removed. Lipid peroxidation, reduced glutathione, and the antioxidant enzymes superoxide dismutase (SOD), catalase and lactate dehydrogenase (LDH) were measured. Apoptotic-related gene (p53, bax and caspase 3) mRNA expression was determined using quantitative polymerase chain reaction. Caspase 3 activity was also measured in all the groups. The results demonstrated that selenium significantly reduced the levels of malondialdehyde. The levels of glutathione, SOD, LDH and catalase significantly increased following selenium treatment. Relative mRNA expression (p53, bax and caspase 3) was significantly reduced in the cisplatin treated rats, but it significantly increased following selenium treatment. The anticancer activity of selenium was also investigated in HK1cells. Fluorescence and confocal microscopy were used to analyze apoptosis and reactive oxygen species. The protective effect of selenium was also evident through caspase 3 activity, which significantly increased following selenium treatment. Taken together, these results indicate that selenium may be beneficial against cisplatin-induced nasopharyngeal cancer. PMID- 28101237 TI - Heat shock factor 2 is associated with the occurrence of lung cancer by enhancing the expression of heat shock proteins. AB - Cancer is the leading cause of morbidity and mortality worldwide, particularly lung cancer. Heat shock proteins and their upstream heat shock factors are involved in the occurrence of cancer and have been widely researched. However, the role of heat shock factor 2 (HSF2) in lung cancer remains unclear. In the present study, expression levels of HSF2 in lung cancer tissues from 50 lung cancer patients were detected by reverse transcription quantitative polymerase chain reaction, and 76% (38/50) were upregulated compared with the matched normal tissues. This suggested possible involvement of HSF2 in lung cancer. To additionally investigate the role of HSF2 in lung cancer occurrence, a plasmid encoding HSF2 was constructed. HSF2 was over expressed in normal lung epithelial BEAS-2B cells and lung cancer A549 cells. The results showed that HSF2 overexpression promoted cell proliferation and cell migration in BEAS-2B and A549 cells. Additional experiments showed that the HSF2-induced cell proliferation and cell migration were dependent on induction of HSPs, particularly HSP27 and HSP90, as co-transfection of HSP27 small interfering RNA (siRNA) or HSP90 siRNA attenuated HSF2-induced cell growth and migration. In conclusion, the present study showed that HSF2 is aberrantly expressed in lung cancer, and it may be an upstream regulator of HSPs, which may strongly affect cell growth and cell migration. Additional studies are required to explain the detailed mechanism between lung cancer, HSF2, HSPs and other possible signaling pathways. PMID- 28101238 TI - Diosmetin triggers cell apoptosis by activation of the p53/Bcl-2 pathway and inactivation of the Notch3/NF-kappaB pathway in HepG2 cells. AB - Diosmetin (DIOS), a flavonoid compound, is abundant in Citrus limon. Emerging studies have shown that DIOS is an effective compound implicated in multiple types of cancer. However, whether DIOS serves a role in hepatocellular carcinoma (HCC) is still obscure. HepG2 cells were used in the present study, and it was observed that DIOS exhibited antitumor activity against liver cancer cells. Western blotting was performed to evaluate cell apoptosis and survival-associated proteins, and the results demonstrated that DIOS treatment resulted in the activation of the p53-dependent apoptosis pathway. Our results revealed that DIOS caused inhibition of the nuclear factor (NF)-kappaB signaling pathway and downregulation of Notch3 receptor. Furthermore, by using small hairpin RNA Notch3, it was confirmed that DIOS inhibited the NF-kappaB signaling pathway by inactivation of Notch3. In conclusion, the present results demonstrated that DIOS triggered cell apoptosis by activation of the p53 signaling pathway and inhibited the NF-kappaB cell survival pathway by downregulation of Notch3 receptor expression. DIOS is a potential agent for prevention of HCC. PMID- 28101239 TI - Naphthazarin suppresses cell proliferation and induces apoptosis in human colorectal cancer cells via the B-cell lymphoma 2/B-cell associated X protein signaling pathway. AB - Colorectal cancer is the most common gastrointestinal cancer in the USA. Naphthazarin, one of the naturally available 1,4-naphthoquinone derivatives, is a natural bioactive molecule that exhibits an antitumor effect. To the best of our knowledge, this is the first study to investigate the anticancer effect of naphthazarin on cell proliferation and apoptosis in human SW480 colorectal cancer cells. In the present study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays were performed to assess the effect of napthazarin on cell proliferation and cytotoxicity of SW430 cells, respectively. In addition, an Annexin V-fluorescein isothiocyanate/propidium iodide apoptosis assay and 4',6-diamidino-2-phenylindole staining were used to analyze cell and nuclei apoptosis of SW480 cells, respectively, following treatment with naphthazarin. Poly (ADP-ribose) polymerase (PARP), B-cell lymphoma 2 (Bcl-2) and B-cell associated X protein (Bax) protein expression was analyzed by western blot. Furthermore, caspase-3 activation was analyzed using a commercial kit. The results revealed that naphthazarin exhibited cell growth inhibition, an increase in cytotoxicity and apoptosis induction in SW480 cells, which was associated with activation of the Bax/Bcl-2 signaling pathway and cleaved caspase-3 activation. However, no significant differences in PARP expression were identified following treatment with naphthazarin in SW480 cells. Taken together, these results suggest that naphthazarin decreased cell viability and induced apoptosis of SW480 cells, indicating that naphthazarin may present a potential therapeutic agent for human colorectal cancer treatment. PMID- 28101240 TI - Downregulation of Annexin A1 is correlated with radioresistance in nasopharyngeal carcinoma. AB - Radiotherapy is the primary treatment for nasopharyngeal carcinoma (NPC), but radioresistance often remains an obstacle to successful treatment. In our previous study, it was demonstrated that Annexin A1 (ANXA1) was involved in the p53-mediated radioresponse in NPC cells, which suggested that it may be associated with radioresistance in NPC; however, the role of ANXA1 in NPC radioresistance is unknown. In the present study, CNE2 cells were stably transfected with pLKO.1-ANXA1-small hairpin (sh)RNAs to investigate the effects of ANXA1 on the radiosensitivity of NPC. CNE2 cells transfected with pLKO.1 were used as the control. The radiosensitivities of the cells in vitro were analyzed using the clonogenic survival assay, cell growth analysis, flow cytometry and Hoechst 33258 staining. ANXA1 downregulation significantly enhanced clonogenic survival and cell growth following treatment of CNE2 cells with ionizing radiation (IR), increased the number of cells in the S phase and decreased IR induced apoptosis. These results suggested that the radiosensitivity of CNE2 cells transfected with ANXA1-specific shRNA was significantly lower compared with the control cells. Therefore, ANXA1 downregulation may be involved in the radioresistance of NPC, and ANXA1 may be considered a novel biomarker for predicting NPC response to radiotherapy. PMID- 28101241 TI - Potential role of melastatin-related transient receptor potential cation channel subfamily M gene expression in the pathogenesis of urinary bladder cancer. AB - Urinary bladder cancer is one of the most common malignancies of the urinary tract. Ion channels and calcium homeostasis are involved in almost all basic cellular mechanisms. The transient receptor potential cation channel subfamily M (TRPM) takes its name from the melastatin protein, which is classified as potential tumor suppressor. To the best of our knowledge, there have been no previous studies in the literature investigating the role of these ion channels in bladder cancer. The present study aimed to determine whether bladder cancer is associated with mRNA expression levels of TRPM ion channel genes, and whether there is the potential to conduct further studies to establish novel treatment modalities. The present study included a total of 47 subjects, of whom 40 were bladder cancer patients and 7 were controls. Following the histopathological evaluation for bladder carcinoma, the mRNA and protein expression of TRPM were examined by reverse transcription-quantitative polymerase chain reaction (RT qPCR) and immunohistochemistry in tumor and normal tissues, in order to determine whether there is a difference in the expression of these channels in tumor and normal tissues. Immunoreactivity for TRPM2, TRPM4, TRPM7 and TRPM8 was observed in epithelial bladder cells in the two groups. RT-qPCR revealed a significant increase in TRPM7 expression in bladder cancer tissue compared to the controls (healthy bladder tissue), whereas no differences in TRPM2 or TRPM4 expression levels were observed. There were significant reductions in the expression levels of TRPM5 and TRPM8 in bladder cancer tissues. In the present study, the effects of TRP ion channels on the formation of bladder cancer was investigated. This study is instructive for TRPM2, TRPM4, TRPM5, TRPM7 and TRPM8 and their therapeutic role in bladder cancer. The results support the fact that these gens can be novel targets and can also be tested for during the treatment of bladder cancer. PMID- 28101244 TI - Celery extract inhibits mouse CYP2A5 and human CYP2A6 activities via different mechanisms. AB - Human cytochrome P450 (CYP) 2A6 participates in the metabolism of nicotine and precarcinogens, thus the deliberate inhibition of CYP2A6 may reduce cigarette consumption and therefore reduce the risk of developing the types of cancer associated with smoking. The inhibitory effects and mechanisms of celery (Apium graveolens) extract on mouse CYP2A5 and human CYP2A6 activity remain unclear. These effects were investigated in mouse and human liver microsomes using coumarin 7-hydroxylation in a probe reaction. Celery extract reduced CYP2A5 and CYP2A6 activities in vitro in a dose-dependent manner. In vivo experiments also showed that celery extract markedly decreased CYP2A5 activity. The inhibition of celery extract on CYP2A5 was time- and nicotinamide adenine dinucleotide phosphate (NADPH)-independent, and was markedly reduced by ultracentrifugation. Additionally, the inhibition of celery extract on CYP2A6 was time and NADPH dependent. Levels of inhibition were characterized by a Ki, the measure of the tightness of bonds between the enzyme and its inhibitor, of 266.4 ug/ml for CYP2A5, and a Ki of 1,018 ug/ml and Kinact of 0.3/min for CYP2A6. Kinact is the maximal rate of enzyme inactivation at a saturating concentration of inhibitor. The coumarin derivative 5-methoxypsoralen present in celery extract did not solely to the inhibition of CYP2A5/6 activity. In conclusion, celery extract inhibited the levels of mouse CYP2A5 and human CYP2A6 activity via different mechanisms: Mixed competitive inhibition for CYP2A5 and mechanism-based inhibition for CYP2A6. PMID- 28101242 TI - Screening and analysis of breast cancer genes regulated by the human mammary microenvironment in a humanized mouse model. AB - Tumor microenvironments play critical regulatory roles in tumor growth. Although mouse cancer models have contributed to the understanding of human tumor biology, the effectiveness of mouse cancer models is limited by the inability of the models to accurately present humanized tumor microenvironments. Previously, a humanized breast cancer model in severe combined immunodeficiency mice was established, in which human breast cancer tissue was implanted subcutaneously, followed by injection of human breast cancer cells. It was demonstrated that breast cancer cells showed improved growth in the human mammary microenvironment compared with a conventional subcutaneous mouse model. In the present study, the novel mouse model and microarray technology was used to analyze changes in the expression of genes in breast cancer cells that are regulated by the human mammary microenvironment. Humanized breast and conventional subcutaneous mouse models were established, and orthotopic tumor cells were obtained from orthotopic tumor masses by primary culture. An expression microarray using Illumina HumanHT 12 v4 Expression BeadChip and database analyses were performed to investigate changes in gene expression between tumors from each microenvironment. A total of 94 genes were differentially expressed between the primary cells cultured from the humanized and conventional mouse models. Significant upregulation of genes that promote cell proliferation and metastasis or inhibit apoptosis, such as SH3 domain binding protein 5 (BTK-associated), sodium/chloride cotransporter 3 and periostin, osteoblast specific factor, and genes that promote angiogenesis, such as KIAA1618, was also noted. Other genes that restrain cell proliferation and accelerate cell apoptosis, including tripartite motif containing TRIM36 and NES1, were downregulated. The present results revealed differences in various aspects of tumor growth and metabolism between the two model groups and indicated the functional changes specific to the human mammary microenvironment. PMID- 28101243 TI - miR-199a-5p regulates HIF-1alpha and OSGIN2 and its expression is correlated to soft-tissue sarcoma patients' outcome. AB - Soft tissue sarcomas are a heterogeneous group of malignant neoplasms of mesenchymal origin. Partly due to hypoxia, an aggressive and radioresistant phenotype frequently develops, resulting in poorer patient outcome. microRNAs (miRNAs) are tiny, non-coding regulators of gene expression and in situations of cellular stress situations may predict clinical progression and patient outcome. In the present study, hypoxia-associated miR-199a-5p expression in 96 soft tissue sarcoma samples was analysed by reverse transcription-quantitative polymerase chain reaction and associations between miR-199a-5p expression and patient clinicopathological characteristics and survival were measured. Additionally, luciferase reporter assays analyzed the post-transcriptional regulation of hypoxia-associated genes hypoxia-inducible factor 1alpha (HIF-1alpha), oxidative stress induced growth inhibitor 2 (OSGIN2) and vascular endothelial growth factor (VEGF) by miR-199a-5p. Survival analyses indicated that low expression of miR 199a-5p was significantly correlated with poorer tumor-specific survival (univariate Cox's-Regression analyses; relative risk=1.92, P=0.029). Furthermore, it was demonstrated that the 3'UTR of HIF-1alpha and OSGIN2 genes were regulated by miR-199a-5p in-vitro, although the 3'UTR of VEGF was not. To the best of our knowledge, this is the first report demonstrating the regulation of the 3'untranslated region of the OSGIN2 gene by miR-199a-5p and a significant correlation between low miR-199a-5p expression and a poor outcome of patients with soft tissue sarcoma. PMID- 28101245 TI - APOBEC3B expression in human leptomeninges and meningiomas. AB - Nucleic acid-editing enzymes of the apolipoprotein B mRNA-editing enzyme (APOBEC) family have been associated with somatic mutation in cancer. However, the role of APOBEC catalytic subunit 3B (APOBEC3B) editing in the pathogenesis of base substitutions in meningiomas is unknown. In the present study, the expression of APOBEC3B was examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analyses in five fetal and one adult human leptomeninges and 38 meningiomas. Genomic DNA was sequenced using the Illumina Tru-Seq Cancer Panel. Three meningioma primary cultures were also established and treated with cerebrospinal fluid form patients without neurological disease or platelet-derived growth factor-BB (PDGF-BB), prior to evaluation of APOBEC3B expression. By western blotting, APOBEC3B was revealed to be present in 100% of the fetal leptomeninges, and in 88% of World Health Organization grade I, 100% of grade II and 83% of grade III meningiomas tested, but was not different between grades. RT-qPCR revealed no difference in the mRNA expression of APOBEC3B between grades. Sequencing revealed no elevated levels of the C>T mutations that are characteristic of APOBEC3B editing of genomic DNA. Treatment with cerebrospinal fluid and PDGF-BB had no effect on APOBEC3B protein expression in the leptomeningeal or meningioma cells. These findings suggest that the mutations associated with increased APOBEC3B expression may not be central to the pathogenesis of meningiomas. PMID- 28101246 TI - Detection of microRNA-200b may predict the inhibitory effect of gefitinib on non small cell lung cancer and its potential mechanism. AB - The present study aimed to investigate the association and underlying mechanisms between microRNA-200b level and the inhibitory effect of gefitinib on non-small cell lung cancer. In total, 100 patients (43 males and 57 females; median age, 63 years) with advanced non-small cell lung cancer (NSCLC) were selected. All patients were administered with gefitinib orally (250 mg/day) and the effect of gefitinib was evaluated according to the Response Evaluation Criteria in Solid Tumors guidelines. Tumor tissue and plasma samples were collected prior to and subsequent to therapy. The microRNA-200b levels in tissues and plasma were determined by quantitative polymerase chain reaction (PCR). A549 cells were cultured in vitro and transfected with microRNA-200b mimic. Using Cell Counting Kit-8 assay, the proliferation inhibition detected was induced by 0.1 uM gefitinib in transfected or non-transfected A549 cells. Cell apoptosis and cell cycle progression were analyzed by flow cytometry and the migration of cells was observed by Transwell assay. In addition, mRNA and protein levels of insulin-like growth factor 1 receptor (IGF-1R), protein kinase B (AKT) and extracellular signal-related kinase (ERK), together with the phosphorylation of AKT and ERK in A549 cells, were determined by quantitative PCR and western blot analysis, respectively. The microRNA-200b levels in gefitinib-insensitive patients were decreased compared with gefitinib-sensitive patients. Transfection with microRNA 200b mimic increased the gefitinib induced proliferation inhibition, apoptosis and cell cycle arrest in A549 cells. Also, transfection with microRNA-200b mimic increased the migration inhibitory effect of gefitinib on A549 cells. Decreased IGF-1R expression together with reduced phosphorylation of AKT and ERK were observed following transfection of A549 cells with the microRNA 200b mimic. In conclusion, detection of microRNA-200b may predict the inhibitory effect of gefitinib on NSCLC. Upregulation of microRNA-200b led to the elevated sensitivity of glioma cells to gefitinib, and this effect may be explained as microRNA-200b being able to inhibit the expression of IGF-1R, thereby reducing the activation of downstream phosphoinositide 3-kinase/AKT and mitogen-activated protein kinase signaling pathways. PMID- 28101247 TI - Clinical characteristics of infant neuroblastoma and a summary of treatment outcome. AB - Neuroblastoma (NB) is the most common malignant solid tumor in the peripheral nervous system in infants and young children, with a high degree of malignancy. The clinical characteristics and prognosis of NB in infants are unique. The present study retrospectively analyzed the prognosis of infant NB cases that underwent different treatments. In total, 16 infant NB cases (10 male and 6 female) who were treated between February 2007 and August 2013 in Beijing Tongren Hospital (Beijing, China), were enrolled in the study. They were diagnosed by pathology, medical imaging and serology methods. These 16 patients were subjected to comprehensive treatment, including chemotherapy, surgery, autologous peripheral blood stem cell transplantation (APBSCT) and radiation therapy. The age distribution and clinical stages were: 5 cases (31.25%) at <=3 months (4 cases at stage 4s and 1 case at stage 4); 2 cases (12.5%) at 3-6 months (both at stage 4s); and 9 cases (56.25%) at 6-12 months (2 cases at stage 4s, 6 cases at stage 4 and 1 case at stage 3). Subsequent to treatment, nicotinic acid esterase (NSE) levels in the patient's serum significantly decreased. The NSE levels in 12 cases (75%) dropped to the reference value (0-15.2 ng/dl). All the NB infants at stages 4s and 3 were treated by surgery and chemotherapy (100%; 9/9). The 5 NB infants at stage 4 were treated by chemotherapy and surgery. For the 2 NB infants who experienced recurrence or whose condition was partially relieved after conventional therapy, APBSCT therapy was applied. At the last follow-up in September 2014, 13 cases (81.25%) presented with a complete response, 2 cases (12.50%) with a partial response and 1 case (6.25%) with recurrence after transplantation (progressive disease). In conclusion, infant NB cases are sensitive to chemotherapy, particularly the cases at stage 4s, which occur with a higher incidence, but with a better clinical response and prognosis after treatment. PMID- 28101248 TI - Expression of cancerous inhibitor of protein phosphatase 2A in human triple negative breast cancer correlates with tumor survival, invasion and autophagy. AB - Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently characterized oncoprotein which is involved in the progression of several human malignancies. The present study aimed to investigate its biological function in human triple negative breast cancer (TNBC). The expression of CIP2A in TNBC cells was examined and it was observed that CIP2A was elevated in the TNBC cell line compared with poorly invasive breast cancer cells. CIP2A depletion in TNBC cell lines inhibited proliferation, and induced apoptosis and autophagy. In addition, CIP2A depletion inhibited invasion and migration of TNBC cells. Furthermore, CIP2A depletion downregulated Akt/mTOR/P70S6K phosphorylation. These results validate the role of CIP2A as a invasion-associated oncoprotein and established CIP2A as a promising therapeutic target of TNBC. PMID- 28101249 TI - 3-Bromopyruvate inhibits human gastric cancer tumor growth in nude mice via the inhibition of glycolysis. AB - [This retracts the article DOI: 10.3892/ol.2014.2779.]. PMID- 28101251 TI - Antifungal and anthelmintic activity of novel benzofuran derivatives containing thiazolo benzimidazole nucleus: an in vitro evaluation. AB - A novel series of thiazolo[3,2-a]benzimidazole derivatives containing benzofuran nucleus (5a-l) have been synthesized. The key intermediate, substituted benzimidazol-sulfanyl benzofuran ethanone (3a-d) was prepared by refluxing the mixture of substituted 2-acetyl benzofuran and substituted 2 mercaptobenzimidazole in acetic acid. The cyclisation of compounds (3a-d) using polyphosphoric acid furnished the corresponding 6-substituted benzofuran thiazolo[3,2-a]benzimidazoles (4a-d). Further, the cyclized compounds (4a-d) were subjected for Mannich reaction to give corresponding Mannich bases (5a-l). All newly synthesized compounds were screened for antifungal and anthelmintic activity. Amongst the tested compounds, 4b and 4d exhibited potential antifungal activity. From the anthelmintic activity data, it was found that the compounds 3a, 3b and 5i were found to be more effective against the tested earthworm Pheretima posthuma. In correlation to anthelmintic activity, the selected compounds were subjected for molecular docking studies and the compounds 3a and 5i have emerged as active anthelmintic agents with maximum binding affinity (-3.7 and -5.4 kcal/mol). PMID- 28101252 TI - Identification of proteins from wild cardoon flowers (Cynara cardunculus L.) by a proteomic approach. AB - Proteomic approach was applied to identify total proteins, particularly the enzymatic content, from wild cardoon flowers. As the selection of an appropriate sample preparation method is the key for getting reliable results, two different extraction/precipitation methods (trichloroacetic acid and phenol/ammonium acetate) were tested on fresh and lyophilized flowers. After two-dimensional electrophoresis (2D-E) separations, a better protein pattern was obtained after phenol extraction from lyophilized flowers. Only 46 % of the total analyzed spots resulted in a protein identification by mass spectrometry MALDI-TOF. Four proteases (cardosins A, E, G, and H), which have become a subject of great interest in dairy technology, were identified. They presented molecular weights and isoelectric points very close and high levels of homology between matched peptides sequences. The absence of the other cardosins (B, C, D, and F) could be an advantage, as it reduces the excessive proteolytic activity that causes bitter flavors and texture defects, during cheese making. PMID- 28101254 TI - JOCB Bulletin. PMID- 28101250 TI - Is phosphatidylglycerol essential for terrestrial life? AB - Lipids are of increasing importance in understanding biological systems. Lipids carrying an anionic charge are noted in particular for their electrostatic interactions with both proteins and divalent cations. However, the biological, analytical, chemical and biophysical data of such species are rarely considered together, limiting our ability to assess the true role of such lipids in vivo. In this review, evidence from a range of studies about the lipid phosphatidylglycerol is considered. This evidence supports the conclusions that this lipid is ubiquitous in living systems and generally of low abundance but probably fundamental for terrestrial life. Possible reasons for this are discussed and further questions posed. PMID- 28101253 TI - 2-(chromon-3-yl)imidazole derivatives as potential antimicrobial agents: synthesis, biological evaluation and molecular docking studies. AB - A series of novel 2-(chromon-3-yl)-4,5-diphenyl-1H-imidazoles (4a-h) were synthesized by one pot condensation of substituted 3-formylchromones (1a-h), benzil (2) and ammonium acetate (3) in refluxing acetic acid at 110 degrees C under N2 atmosphere. Allylation of compounds 4a-h with allyl bromide in the presence of fused K2CO3 furnished N-allyl-2-(chromon-3-yl)-4,5-diphenyl-1H imidazoles (6a-h). The synthesized compounds were characterized spectroscopically and evaluated for in vitro antimicrobial activity against various pathogenic bacterial and fungal strains by disc diffusion method. Compounds bearing electron withdrawing substituents such as bromo (4f) showed significant inhibitory activity against S. cerevisiae (MIC 1.4 MUg/ml) and 4g containing chloro substituent, displayed more inhibitory potential against C. albicans (MIC 1.5), as compared to the standard drugs. Compounds 6a and 4c exhibit remarkable inhibitory potential against B. subtilis with MIC 0.98 and 1.23, respectively. The time kill assay for active compound 6a was performed by viable cell count (VCC) method to elucidate the microbicidal nature of 2-(chromon-3-yl)imidazoles. A molecular docking study of most active compounds with target 'lanosterol 14alpha-demethylase' (CYP51) was performed to unravel the mode of antifungal action. PMID- 28101255 TI - The Microbiology Effect: A Call for Education Research. PMID- 28101256 TI - Build the Future of Science Communication in Developing Countries through Systematic Training of Young Scientists. PMID- 28101257 TI - The Necessity of Prerequisite Undergraduate Microbiology Courses for Pre-Allied Health Professionals. PMID- 28101258 TI - Publishing, Objectivity, and Prestige. PMID- 28101259 TI - The Science Teaching Fellows Program: A Model for Online Faculty Development of Early Career Scientists Interested in Teaching. AB - The American Society for Microbiology (ASM) has a history of providing a wide range of faculty development opportunities. Recently, ASM developed the Science Teaching Fellows Program (STF) for early career biologists and postdoctoral students to explore student-centered teaching and develop the skills needed to succeed in positions that have a significant teaching component. Participants were selected to STF through a competitive application process. The STF program consisted of a series of six webinars. In preparation for each webinar, participants completed a pre-webinar assignment. After each webinar, fellows practiced what they learned by completing a post-webinar assignment. In a survey used to assess the impact of STF, participants reported greater knowledge of the webinar-based instructional topics and a sense of being part of an educational community and were more confident about varied teaching methods. PMID- 28101260 TI - Tracking the Resolution of Student Misconceptions about the Central Dogma of Molecular Biology. AB - The goal of our study was to track changes in student understanding of the central dogma of molecular biology before and after taking a genetics course. Concept maps require the ability to synthesize new information into existing knowledge frameworks, and so the hypothesis guiding this study was that student performance on concept maps reveals specific central dogma misconceptions gained, lost, and retained by students. Students in a genetics course completed pre- and posttest concept mapping tasks using terms related to the central dogma. Student maps increased in complexity and validity, indicating learning gains in both content and complexity of understanding. Changes in each of the 351 possible connections in the mapping task were tracked for each student. Our students did not retain much about the central dogma from their introductory biology courses, but they did move to more advanced levels of understanding by the end of the genetics course. The information they retained from their introductory courses focused on structural components (e.g., protein is made of amino acids) and not on overall mechanistic components (e.g., DNA comes before RNA, the ribosome makes protein). Students made the greatest gains in connections related to transcription, and they resolved the most prior misconceptions about translation. These concept-mapping tasks revealed that students are able to correct prior misconceptions about the central dogma during an intermediate-level genetics course. From these results, educators can design new classroom interventions to target those aspects of this foundational principle with which students have the most trouble. PMID- 28101261 TI - External and Internal Barriers to Studying Can Affect Student Success and Retention in a Diverse Classroom. AB - Although a majority of under-represented minority (URM) students begin their postsecondary education at community colleges, little is known about barriers to success and retention for transfer-bound science students. This study focuses on some of the barriers that affect these students' ability to study adequately for a community college "gateway" course. It tests whether instructors' expectations of study time were realistic for community college students and whether students reported facing external barriers, such as job and family responsibilities, or internal barriers to studying, such as lack of motivational, cognitive, and metacognitive abilities, all of which have been shown to impact academic success and retention. It also tests whether students who faced such barriers were less likely to succeed in and complete the course, as well as whether time spent studying was related to course success. The findings reported here show that community college students do not have enough available time to study and that external and internal barriers are both prevalent among these students. In addition, students who faced such barriers are more likely to fail or drop the class. Results also show that study time is positively correlated with retention, but not performance, as well as with some motivational, cognitive, and metacognitive dimensions of self-regulated learning. These findings lead to new questions, including whether student success in a community college class is associated with the use of cognitive and metacognitive learning strategies for students with no prior degrees, and whether increased course structure may improve success for college students with lower self-regulated abilities. PMID- 28101262 TI - The Use of Group Activities in Introductory Biology Supports Learning Gains and Uniquely Benefits High-Achieving Students. AB - This study describes the implementation and effectiveness of small-group active engagement (GAE) exercises in an introductory biology course (BSCI207) taught in a large auditorium setting. BSCI207 (Principles of Biology III-Organismal Biology) is the third introductory core course for Biological Sciences majors. In fall 2014, the instructors redesigned one section to include GAE activities to supplement lecture content. One section (n = 198) employed three lectures per week. The other section (n = 136) replaced one lecture per week with a GAE class. We explored the benefits and challenges associated with implementing GAE exercises and their relative effectiveness for unique student groups (e.g., minority students, high- and low-grade point average [GPA] students). Our findings show that undergraduates in the GAE class exhibited greater improvement in learning outcomes than undergraduates in the traditional class. Findings also indicate that high-achieving students experienced the greatest benefit from GAE activities. Some at-risk student groups (e.g., two-year transfer students) showed comparably low learning gains in the course, despite the additional support that may have been afforded by active learning. Collectively, these findings provide valuable feedback that may assist other instructors who wish to revise their courses and recommendations for institutions regarding prerequisite coursework approval policies. PMID- 28101263 TI - Team-Based Learning in a Pipeline Course in Medical Microbiology for Under Represented Student Populations in Medicine Improves Learning of Microbiology Concepts. AB - As part of an undergraduate pipeline program at our institution for students from underrepresented minorities in medicine backgrounds, we created an intensive four week medical microbiology course. Team-based learning (TBL) was implemented in this course to enhance student learning of course content. Three different student cohorts participated in the study, and there were no significant differences in their prior academic achievement based on their undergraduate grade point average (GPA) and pre-course examination scores. Teaching techniques included engaged lectures using an audience response system, TBL, and guided self directed learning. We hypothesized that more active learning exercises, irrespective of the amount of lecture time, would help students master course content. In year 2 as compared with year 1, TBL exercises were decreased from six to three with a concomitant increase in lecture time, while in year 3, TBL exercises were increased from three to six while maintaining the same amount of lecture time as in year 2. As we hypothesized, there was significant (p < 0.01) improvement in performance on the post-course examination in years 1 and 3 compared with year 2, when only three TBL exercises were used. In contrast to the students' perceptions that more lecture time enhances learning of course content, our findings suggest that active learning strategies, such as TBL, are more effective than engaged lectures in improving student understanding of course content, as measured by post-course examination performance. Introduction of TBL in pipeline program courses may help achieve better student learning outcomes. PMID- 28101264 TI - Ripped from the Headlines: Using Current Events and Deliberative Democracy to Improve Student Performance in and Perceptions of Nonmajors Biology Courses. AB - Despite the importance of scientific literacy, many foundational science courses are plagued by low student engagement and performance. In an attempt to improve student outcomes, an introductory biology course for nonscience majors was redesigned to present the course content within the framework of current events and deliberative democratic exercises. During each instructional unit of the redesigned course, students were presented with a highly publicized policy question rooted in biological principles and currently facing lawmakers. Working in diverse groups, students sought out the information that was needed to reach an educated, rationalized decision. This approach models civic engagement and demonstrates the real-life importance of science to nonscience majors. The outcomes from two semesters in which the redesign were taught were compared with sections of the course taught using traditional pedagogies. When compared with other versions of the same course, presenting the course content within a deliberative democratic framework proved to be superior for increasing students' knowledge gains and improving students' perceptions of biology and its relevance to their everyday lives. These findings establish deliberative democracy as an effective pedagogical strategy for nonmajors biology. PMID- 28101265 TI - Prevalence and Persistence of Misconceptions in Tree Thinking. AB - Darwin described evolution as "descent with modification." Descent, however, is not an explicit focus of most evolution instruction and often leaves deeply held misconceptions to dominate student understanding of common ancestry and species relatedness. Evolutionary trees are ways of visually depicting descent by illustrating the relationships between species and groups of species. The ability to properly interpret and use evolutionary trees has become known as "tree thinking." We used a 20-question assessment to measure misconceptions in tree thinking and compare the proportion of students who hold these misconceptions in an introductory biology course with students in two higher-level courses including a senior level biology course. We found that misconceptions related to reading the graphic (reading the tips and node counting) were variably influenced across time with reading the tips decreasing and node counting increasing in prevalence. On the other hand, misconceptions related to the fundamental underpinnings of evolutionary theory (ladder thinking and similarity equals relatedness) proved resistant to change during a typical undergraduate study of biology. A possible new misconception relating to the length of the branches in an evolutionary tree is described. Understanding the prevalence and persistence of misconceptions informs educators as to which misconceptions should be targeted in their courses. PMID- 28101266 TI - How to Assess Your CURE: A Practical Guide for Instructors of Course-Based Undergraduate Research Experiences. AB - Integrating research experiences into undergraduate life sciences curricula in the form of course-based undergraduate research experiences (CUREs) can meet national calls for education reform by giving students the chance to "do science." In this article, we provide a step-by-step practical guide to help instructors assess their CUREs using best practices in assessment. We recommend that instructors first identify their anticipated CURE learning outcomes, then work to identify an assessment instrument that aligns to those learning outcomes and critically evaluate the results from their course assessment. To aid instructors in becoming aware of what instruments have been developed, we have also synthesized a table of "off-the-shelf" assessment instruments that instructors could use to assess their own CUREs. However, we acknowledge that each CURE is unique and instructors may expect specific learning outcomes that cannot be assessed using existing assessment instruments, so we recommend that instructors consider developing their own assessments that are tightly aligned to the context of their CURE. PMID- 28101267 TI - Bioart and Bildung-Wetware: Art, Agency, Animation, an Exhibition as Case Study. AB - Recent events in the field of biology have further unfixed the definition of life. The negotiability of "life" is at the center of the exhibition "Wetware: Art, Agency, Animation" at the Beall Center for Art + Technology at the University of California, Irvine. The exhibition includes art by nine international artists working in the avant-garde area of contemporary art called "bioart." This article is devoted to the unique educational space opened through the practice of bioart, focusing on how the exhibition brings the scientific question "What is life?" to a public audience. Bildung, a term that translates as education but encompasses exploration and growth, is based on the holistic unity of science and art and is used here to show that neither science nor art sacrifices legitimacy or distinction within bioart. Art can suggest design and be useful; science can point to abstraction and be poetic. Bioart inspires a chain of curiosity about the form, materials, media that artists use to probe, shape, direct, and display scientific processes and concepts. PMID- 28101268 TI - Traditional Versus Online Biology Courses: Connecting Course Design and Student Learning in an Online Setting. AB - Online courses are a large and growing part of the undergraduate education landscape, but many biology instructors are skeptical about the effectiveness of online instruction. We reviewed studies comparing the effectiveness of online and face-to-face (F2F) undergraduate biology courses. Five studies compared student performance in multiple course sections at community colleges, while eight were smaller scale and compared student performance in particular biology courses at a variety of types of institutions. Of the larger-scale studies, two found that students in F2F sections outperformed students in online sections, and three found no significant difference; it should be noted, however, that these studies reported little information about course design. Of the eight smaller scale studies, six found no significant difference in student performance between the F2F and online sections, while two found that the online sections outperformed the F2F sections. In alignment with general findings about online teaching and learning, these results suggest that well-designed online biology courses can be effective at promoting student learning. Three recommendations for effective online instruction in biology are given: the inclusion of an online orientation to acclimate students to the online classroom; student-instructor and student student interactions facilitated through synchronous and asynchronous communication; and elements that prompt student reflection and self-assessment. We conclude that well-designed online biology courses can be as effective as their traditional counterparts, but that more research is needed to elucidate specific course elements and structures that can maximize online students' learning of key biology skills and concepts. PMID- 28101269 TI - Metagenomic Approaches to Identify Novel Organisms from the Soil Environment in a Classroom Setting. AB - Molecular Microbial Metagenomics is a research-based undergraduate course developed at Georgia State University. This semester-long course provides hands on research experience in the area of microbial diversity and introduces molecular approaches to study diversity. Students are part of an ongoing research project that uses metagenomic approaches to isolate clones containing 16S ribosomal ribonucleic acid (rRNA) genes from a soil metagenomic library. These approaches not only provide a measure of microbial diversity in the sample but may also allow discovery of novel organisms. Metagenomic approaches differ from the traditional culturing methods in that they use molecular analysis of community deoxyribonucleic acid (DNA) instead of culturing individual organisms. Groups of students select a batch of 100 clones from a metagenomic library. Using universal primers to amplify 16S rRNA genes from the pool of DNA isolated from 100 clones, and a stepwise process of elimination, each group isolates individual clones containing 16S rRNA genes within their batch of 100 clones. The amplified 16S rRNA genes are sequenced and analyzed using bioinformatics tools to determine whether the rRNA gene belongs to a novel organism. This course provides avenues for active learning and enhances students' conceptual understanding of microbial diversity. Average scores on six assessment methods used during field testing indicated that success in achieving different learning objectives varied between 84% and 95%, with 65% of the students demonstrating complete grasp of the project based on the end-of-project lab report. The authentic research experience obtained in this course is also expected to result in more undergraduates choosing research-based graduate programs or careers. PMID- 28101270 TI - Using Online Active-Learning Techniques to Convey Time Compensated Sun Compass Orientation in the Eastern North American Monarch. AB - A common tool that animals use to navigate in a constant direction is known as "time compensated sun compass orientation." This is a process by which animals use the position of the sun along with information from their internal circadian clocks to determine and maintain a directional heading. Many circadian scientists and educators use this process as an example of how the internal circadian clock can directly influence animal behavior. However, many students have difficulty grasping this biological process due to its multivariable nature. We have created an online module that uses the principles of active learning to facilitate student comprehension of this process. Our module contains instructional videos, practice problems and an interactive diagram. We implemented the module in an undergraduate biological clocks class at Vanderbilt University, where its use significantly improved students' understanding of time compensated sun compass orientation as well as their ability to solve complex problems involving principles associated with this process. PMID- 28101271 TI - The Impact of an Interactive Statistics Module on Novices' Development of Scientific Process Skills and Attitudes in a First-Semester Research Foundations Course. AB - Evidence suggests that incorporating quantitative reasoning exercises into existent curricular frameworks within the science, technology, engineering, and mathematics (STEM) disciplines is essential for novices' development of conceptual understanding and process skills in these domains. Despite this being the case, such studies acknowledge that students often experience difficulty in applying mathematics in the context of scientific problems. To address this concern, the present study sought to explore the impact of active demonstrations and critical reading exercises on novices' comprehension of basic statistical concepts, including hypothesis testing, experimental design, and interpretation of research findings. Students first engaged in a highly interactive height activity that served to intuitively illustrate normal distribution, mean, standard deviation, and sample selection criteria. To enforce practical applications of standard deviation and p-value, student teams were subsequently assigned a figure from a peer-reviewed primary research article and instructed to evaluate the trustworthiness of the data. At the conclusion of this exercise, students presented their evaluations to the class for open discussion and commentary. Quantitative assessment of pre- and post-module survey data indicated a statistically significant increase both in students' scientific reasoning and process skills and in their self-reported confidence in understanding the statistical concepts presented in the module. Furthermore, data indicated that the majority of students (>85%) found the module both interesting and helpful in nature. Future studies will seek to develop additional, novel exercises within this area and to evaluate the impact of such modules across a variety of STEM and non-STEM contexts. PMID- 28101272 TI - Isolation and Characterization of Agrobacterium Strains from Soil: A Laboratory Capstone Experience. AB - In this investigation, the students' goal was to isolate and characterize Agrobacterium strains from soil. Following selection and enrichment on 1A-t medium, putative Agrobacterium isolates were characterized by Gram stain reaction and biochemical tests. Isolates were further evaluated using polymerase chain reaction (PCR) with different primer sets designed to amplify specific regions of bacterial deoxyribonucleic acid (DNA). Primer sets included AGRH to identify isolates that were members of the Rhizobiaceae, BIOVAR1 primers to identify members of Agrobacterium biovar group I, and a third set, VIRG, to determine presence of virG (only present in pathogenic Agrobacterium strains). During the investigation, students applied previously learned techniques including serial dilution, use of selective/differential media, staining protocols, biochemical analysis, molecular analysis via PCR, and electrophoresis. Students also gained practical experience using photo documentation to record data for an eventual mock journal publication of the capstone laboratory experience. Pre- and post evaluation of class content knowledge related to the techniques, protocols, and learning objectives of these laboratories revealed significant learning gains in the content areas of Agrobacterium-plant interactions (p <= 0.001) and molecular biology (p <= 0.01). The capstone journal assignment served as the assessment tool to evaluate mastery and application of laboratory technique, the ability to accurately collect and evaluate data, and critical thinking skills associated with experimental troubleshooting and extrapolation. Analysis of journal reports following the capstone experience showed significant improvement in assignment scores (p <= 0.0001) and attainment of capstone experience learning outcomes. PMID- 28101273 TI - Who Scared the Cat? A Molecular Crime Scene Investigation Laboratory Exercise. AB - This introductory laboratory exercise gives first-year life science majors or nonmajors an opportunity to gain knowledge and experience in basic bioinformatics and molecular biology laboratory techniques and analysis in the context of a mock crime scene investigation. In this laboratory, students determine if a human (Lady) or dog (Kona) committed the fictional crime of scaring a cat. Students begin by performing in silico PCR using provided dog- and human-specific PCR primers to determine the sequences to be amplified and predict PCR amplicon sizes. They then BLAST (Basic Local Alignment Search Tool) the in silico PCR results to confirm that the PCR primers are designed to amplify genomic fragments of the cardiac actin gene in both dogs and humans. Finally, they use DNA quantification techniques, PCR, and agarose gel electrophoresis to identify the culprit and they confirm results by analyzing Sanger sequencing. Student learning gains were demonstrated by successful execution of the lab and by analysis and interpretation of data in the completion of laboratory reports. The student learning gains were also demonstrated by increased performance on a post laboratory assessment compared to the pre-assessment. A post-activity assessment also revealed that students perceived gains in the skills and conceptual knowledge associated with the student learning outcomes. Finally, assessment of this introductory molecular biology and bio-informatics activity reveals that it allows first-year students to develop higher-order data analysis and interpretation skills. PMID- 28101274 TI - Enhancing Scientific Literacy in the Undergraduate Cell Biology Laboratory Classroom. AB - This paper describes the implementation of the Scientific Literacy in Cell Biology (SLCB) curriculum in an undergraduate biology laboratory course. The SLCB curriculum incorporated the reading and discussion of primary literature into hands-on and collaborative practical experiences. It was implemented in five stages over an 11-week period, during which students were also introduced to the theory and practice of common cell biology techniques. We report on the effectiveness of the course, as measured by pre- and post-course survey data probing students' content knowledge and their level of familiarity, confidence, and experience with different skills pertaining to analyzing (reading, interpreting, and discussing) primary literature. In the spring 2015 semester, 287 (72%) of the 396 students who were enrolled in the laboratory completed both the pre- and post-course survey. The average score on the content questions of the post-course survey was significantly higher (p < 0.0001) than the average score on the pre-course survey. Students reported that they gained greater familiarity, experience, and confidence in the skills that were measured. Our findings may aid in reforming higher-education science laboratory courses to better promote writing, reading, data processing, and presentation skills. Journal of Microbiology & Biology Education. PMID- 28101275 TI - Improvement in Student Data Analysis Skills after Out-of-Class Assignments. PMID- 28101276 TI - A Model for a Course-Based Undergraduate Research Experience (CURE) in a Field Setting. PMID- 28101277 TI - Designing an Audiocast Assignment: A Primary-Literature-Based Approach that Promotes Student Learning of Cell and Molecular Biology through Conversations with Scientist Authors. PMID- 28101278 TI - Looking through the Lens: Adapting and Modifying Photovoice Projects for Active Learning and Engagement in Biology. PMID- 28101279 TI - A Cost-Effective Approach to Producing Animated Infographics for Immunology Teaching. PMID- 28101280 TI - Video Lecture Capture Technology Helps Students Study without Affecting Attendance in Large Microbiology Lecture Courses. PMID- 28101281 TI - Using the Improvisational "Yes, and..." Approach as a Review Technique in the Student-Centered Biology Classroom. PMID- 28101282 TI - Quantitative Modeling of Membrane Transport and Anisogamy by Small Groups Within a Large-Enrollment Organismal Biology Course. PMID- 28101283 TI - Group Active Engagements Using Quantitative Modeling of Physiology Concepts in Large-Enrollment Biology Classes. PMID- 28101284 TI - Exploring Catalase and Invertase Activity Using Sodium Alginate-Encapsulated Yeast (Yeast Spheres). PMID- 28101287 TI - Microbiology Instruction Using Current Foodborne Outbreak Resources. PMID- 28101285 TI - Twitter as a Tool for Teaching and Communicating Microbiology: The #microMOOCSEM Initiative. PMID- 28101288 TI - Correction Notice: Perspectives in Marine Citizen Science. AB - [This corrects the article on p. 56 in vol. 17, PMID: 27047591.]. PMID- 28101289 TI - Nasal Septal Agenesis and Attenuated Lower and Upper Lateral Cartilages in a 5 Year-Old Child: A Sporadic Finding. AB - Introduction: Cartilaginous nasal septal agenesis is a rare finding. In fact, just one case has been reported to have congenital agenesis of all nasal cartilages in a 6-year-old child by Bakhshaee et al. The literature review shows another case that was reported by Ozek et al in Turkey, where they reported a case of total nasal agenesis that was associated with Tessier no. 30. We could not find a similar case in the literature where only agenesis of the nasal cartilaginous septum was present. Methods/Case Report: This is a case report of a 5-year-old child presenting to our clinic with agenesis of his nasal septum and attenuation of the upper and lower lateral cartilages. His parents were seeking a corrective procedure to improve the shape of his nose. He was a male child with a right unilateral cleft lip and palate that were corrected surgically in 2009 (lip repair) and 2010 (palate repair), respectively. Results: On postoperative week 3, the patient's mother brought him to the emergency department with a history of falling on his face while playing at home. Examination revealed swelling of the nose but no breathing difficulties. He still had an acceptable augmented nose but with sings of deviation and collapse. Discussion: We report this case to find an answer to how such cases can be approached in the future in terms of the surgical intervention required and to study the options of redoing such cases. PMID- 28101290 TI - Artery-Only Ear Replantation in a Child: A Case Report With Daily Photographic Documentation. AB - Objective: Ear replantation poses a significant technical challenge even for the skilled microsurgeon. Many ear amputations result from avulsion and thus have damaged and often diminutive vessels with a paucity of veins. Artery-only replantation is an option for ear salvage, but little is published on the clinical course and appearance after this procedure. Methods: A subtotal ear replantation was performed on a 10-year-old boy without a venous anastomosis. Leech therapy was used to manage venous congestion postoperatively, and daily photography was performed to document the clinical course. Results: Postoperative venous congestion was successfully managed with leech therapy. Four days after the replantation, arterial thrombosis occurred that required a take back and salvage with an interposition vein graft for arterial repair. Native venous drainage and arterial revascularization from skin edges were evident by postoperative day 12, and leeches were discontinued on day 14. The patient required debridement of the posterior ear and superior helix necrotic skin, with burying of the upper portion of the ear in a superior auricular skin flap. The ear was subsequently released from the head, and the exposed portions were covered successfully with a full-thickness skin graft. Conclusions: While arterial and venous anastomoses should always be attempted, arterial-only ear replantation can provide excellent results when venous congestion is properly managed. Daily photography can be a useful tool to monitor subtle skin color changes that may indicate native venous drainage and arterial revascularization. PMID- 28101291 TI - What Is It? A Rare Presentation of a Meningioma. AB - Introduction: Primary extracranial meningiomas are rare manifestations of a central nervous system tumor. This article presents a case study of a soft-tissue primary extracranial tumor in the temporal region that was initially diagnosed as melanoma at an outside institution and whose definitive diagnosis proved difficult prior to successful excision. Methods: Temporal muscle biopsy, ultrasound-guided biopsy, and computed tomography were conducted at an outside institution prior to the patient's presentation to our care. Upon presenting to our institution a positron emission tomographic scan was then conducted prior to excision. After excision, the mass was sent to pathology and further immunohistochemistry was conducted. To ensure the mass was completely excised, magnetic resonance imaging was performed after its removal. Results: A 3 * 3-cm mass was excised in its entirety from the patient's temporal region and sent to pathology for immunohistochemistry and mutation testing. It proved to have the most common mutation for a primary extracranial meningioma, a neurofibromatosis type 2 frameshift. Conclusion: The presentation of a primary extracranial meningioma in the temporal region is a rare finding. Because of its slow-growing nature and generally asymptomatic presentation, it can be misdiagnosed. Utilization of radiological imaging is essential both pre- and postoperatively in order for its identification and complete excision. PMID- 28101292 TI - Is allergic sensitization relevant in severe asthma? Which allergens may be culprit? AB - Severe asthma is a major health concern. The allergic (IgE-mediated) form of asthma is well known from a pathogenic viewpoint. We searched the available literature to identify which allergens are most frequently associated with severe, refractory or life threatening asthma. According to the results, molds, pet dander, cockroach and ragweed were more frequently responsible for severe asthma. Thunderstorm asthma, in addition, represents a special association between allergic sensitization and an external climatic factor. A detailed knowledge of the most harmful allergens is mandatory for an appropriate diagnostic and preventive approach. PMID- 28101293 TI - Establishing the prevalence of low vitamin D in non-immunoglobulin-E mediated gastrointestinal food allergic children in a tertiary centre. AB - BACKGROUND: There is no data on the prevalence of vitamin D deficiency in children with non-immunoglobulin-E (IgE) mediated gastrointestinal food allergy. The aims of our study were to understand the prevalence of vitamin D insufficiency and deficiency in children with non-IgE mediated gastrointestinal food allergy and identify predisposing factors. METHODS: This was a retrospective study which looked at data from Great Ormond Street Hospital from January 2002 to September 2015. Children 0-18 years old with a confirmed diagnosis of non-IgE mediated gastrointestinal food allergy who had a vitamin D level measured during the course of their disease were included. Low vitamin D levels were defined as <50 nmol/L; insufficient levels were defined as 25-50 nmol/L and deficient levels as <25 nmol/L. Patient characteristics and clinical factors were also recorded. RESULTS: Ninety-two patients met the study criteria; 49% were female and median age was 10 years 2 months [IQR: 4 years 8 months to 13 years 7 months]. Of the cohort, 26% (24/92) had low vitamin D levels; 16% had insufficient vitamin D levels and 10% had vitamin D deficiency. Gender (p = 0.043) and age (p = 0.035) were significantly associated with low vitamin D levels. Twelve percent of children who were on an amino acid formula (AAF) had low vitamin D compared to 31% of children who were not (p = 0.06). No other clinical factors were found to be significantly associated with low vitamin D levels. CONCLUSIONS: Children with non-IgE mediated gastrointestinal food allergy are at risk of vitamin D insufficiency and deficiency. Further prospective studies need to be performed in all children with non-IgE mediated gastrointestinal food allergies. TRIAL REGISTRATION: The study was registered with the GOSH Research & Development department as a retrospective case note review. The Health Research Authority confirmed that NHS Research and Ethics Committee approval was not required; thus there is no trial registration number. PMID- 28101294 TI - Erratum to: Risk and safety requirements for diagnostic and therapeutic procedures in allergology: World Allergy Organization Statement. AB - [This corrects the article DOI: 10.1186/s40413-016-0122-3.]. PMID- 28101295 TI - Change in Free Radical and Antioxidant Enzyme Levels in the Patients Undergoing Open Heart Surgery with Cardiopulmonary Bypass. AB - Objective. The purpose of this study is to determine the changes in oxidative damage and antioxidant parameters in open heart surgeries with cardiopulmonary bypass (CPB) in preoperative and early postoperative periods. Methods. A total of three consecutive arterial blood samples were obtained from the patients in the study group, in preoperative, early postoperative, and postoperative periods, respectively. Oxidative damage indicator (MDA) and antioxidant indicators (GPx, GSH, CAT, and SOD) were examined. Results. A statistically significant increase was observed in MDA level in postoperative period compared to preoperative and early postoperative periods. GSH levels and CAT activities increased significantly in early postoperative and postoperative periods. Analyses revealed an increase in GPx and SOD enzyme activities only in the postoperative period. Conclusion. Even though the increase in MDA level was suppressed by the increased GSH level and CAT activity like in early postoperative period, efficiency can be brought for the increases in insufficient significant antioxidant parameters in postoperative period by administering antioxidant supplements to the patients and thus the increase in MDA in postoperative period can be significantly suppressed. PMID- 28101299 TI - Redox-Activated Signal Transduction Pathways Mediating Cellular Functions in Inflammation, Differentiation, Degeneration, Transformation, and Death. PMID- 28101296 TI - Naturally Occurring Nrf2 Activators: Potential in Treatment of Liver Injury. AB - Oxidative stress plays a major role in acute and chronic liver injury. In hepatocytes, oxidative stress frequently triggers antioxidant response by activating nuclear erythroid 2-related factor 2 (Nrf2), a transcription factor, which upregulates various cytoprotective genes. Thus, Nrf2 is considered a potential therapeutic target to halt liver injury. Several studies indicate that activation of Nrf2 signaling pathway ameliorates liver injury. The hepatoprotective potential of naturally occurring compounds has been investigated in various models of liver injuries. In this review, we comprehensively appraise various phytochemicals that have been assessed for their potential to halt acute and chronic liver injury by enhancing the activation of Nrf2 and have the potential for use in humans. PMID- 28101297 TI - CD36/Sirtuin 1 Axis Impairment Contributes to Hepatic Steatosis in ACE2-Deficient Mice. AB - Background and Aims. Angiotensin converting enzyme 2 (ACE2) is an important component of the renin-angiotensin system. Since angiotensin peptides have been shown to be involved in hepatic steatosis, we aimed to evaluate the hepatic lipid profile in ACE2-deficient (ACE2-/y) mice. Methods. Male C57BL/6 and ACE2-/y mice were analyzed at the age of 3 and 6 months for alterations in the lipid profiles of plasma, faeces, and liver and for hepatic steatosis. Results. ACE2-/y mice showed lower body weight and white adipose tissue at all ages investigated. Moreover, these mice had lower levels of cholesterol, triglycerides, and nonesterified fatty acids in plasma. Strikingly, ACE2-/y mice showed high deposition of lipids in the liver. Expression of CD36, a protein involved in the uptake of triglycerides in liver, was increased in ACE2-/y mice. Concurrently, these mice exhibited an increase in hepatic oxidative stress, evidenced by increased lipid peroxidation and expression of uncoupling protein 2, and downregulation of sirtuin 1. ACE2-/y mice also showed impairments in glucose metabolism and insulin signaling in the liver. Conclusions. Deletion of ACE2 causes CD36/sirtuin 1 axis impairment and thereby interferes with lipid homeostasis, leading to lipodystrophy and steatosis. PMID- 28101298 TI - Ginkgo Biloba Ameliorates Subfertility Induced by Testicular Ischemia/Reperfusion Injury in Adult Wistar Rats: A Possible New Mitochondrial Mechanism. AB - Testicular torsion, a surgical emergency, could affect the endocrine and exocrine testicular functions. This study demonstrates histopathological and physiological effects of testicular ischemia/perfusion (I/R) injury and the possible protective effects of Ginkgo biloba treatment. Fifty adult male Wistar rats, 180-200 gm, were randomly divided into sham-operated, Gingko biloba supplemented, ischemia only, I/R, and Gingko biloba treated I/R groups. Overnight fasted rats were anaesthetized by Pentobarbital; I/R was performed by left testis 720 degrees rotation in I/R and treated I/R groups. Orchiectomy was performed for histopathological studies and detection of mitochondrial NAD+. Determination of free testosterone, FSH, TNF-alpha, and IL1-beta in plasma was performed. Plasma free testosterone was significantly decreased, while plasma FSH, TNF-alpha, IL 1beta, and testicular mitochondrial NAD+ were significantly increased in I/R group compared to control group. These parameters were reversed in Gingko biloba treated I/R group compared to I/R group. I/R caused marked testicular damage and increased APAF-1 in the apoptotic cells which were reversed by Ginkgo biloba treatment. It could be concluded that I/R caused subfertility induced by apoptosis and oxidative stress manifested by the elevated testicular mitochondrial NAD+, which is considered a new possible mechanism. Also, testicular injury could be reduced by Gingko biloba administration alone. PMID- 28101300 TI - The Peroxidation of Leukocytes Index Ratio Reveals the Prooxidant Effect of Green Tea Extract. AB - Despite tea increased plasma nonenzymatic antioxidant capacity, the European Food Safety Administration (EFSA) denied claims related to tea and its protection from oxidative damage. Furthermore, the Supplement Information Expert Committee (DSI EC) expressed some doubts on the safety of green tea extract (GTE). We performed a pilot study in order to evaluate the effect of a single dose of two capsules of a GTE supplement (200 mg * 2) on the peroxidation of leukocytes index ratio (PLIR) in relation to uric acid (UA) and ferric reducing antioxidant potential (FRAP), as well as the sample size to reach statistical significance. GTE induced a prooxidant effect on leukocytes, whereas FRAP did not change, in agreement with the EFSA and the DSI EC conclusions. Besides, our results confirm the primary role of UA in the antioxidant defences. The ratio based calculation of the PLIR reduced the sample size to reach statistical significance, compared to the resistance to an exogenous oxidative stress and to the functional capacity of oxidative burst. Therefore, PLIR could be a sensitive marker of redox status. PMID- 28101301 TI - NUCLEI SEGMENTATION VIA SPARSITY CONSTRAINED CONVOLUTIONAL REGRESSION. AB - Automated profiling of nuclear architecture, in histology sections, can potentially help predict the clinical outcomes. However, the task is challenging as a result of nuclear pleomorphism and cellular states (e.g., cell fate, cell cycle), which are compounded by the batch effect (e.g., variations in fixation and staining). Present methods, for nuclear segmentation, are based on human designed features that may not effectively capture intrinsic nuclear architecture. In this paper, we propose a novel approach, called sparsity constrained convolutional regression (SCCR), for nuclei segmentation. Specifically, given raw image patches and the corresponding annotated binary masks, our algorithm jointly learns a bank of convolutional filters and a sparse linear regressor, where the former is used for feature extraction, and the latter aims to produce a likelihood for each pixel being nuclear region or background. During classification, the pixel label is simply determined by a thresholding operation applied on the likelihood map. The method has been evaluated using the benchmark dataset collected from The Cancer Genome Atlas (TCGA). Experimental results demonstrate that our method outperforms traditional nuclei segmentation algorithms and is able to achieve competitive performance compared to the state of-the-art algorithm built upon human-designed features with biological prior knowledge. PMID- 28101303 TI - Efficacy of multiple biliary stenting for refractory benign biliary strictures due to chronic calcifying pancreatitis. AB - AIM: To investigate endoscopic therapy efficacy for refractory benign biliary strictures (BBS) with multiple biliary stenting and clarify predictors. METHODS: Ten consecutive patients with stones in the pancreatic head and BBS due to chronic pancreatitis who underwent endoscopic therapy were evaluated. Endoscopic insertion of a single stent failed in all patients. We used plastic stents (7F, 8.5F, and 10F) and increased stents at intervals of 2 or 3 mo. Stents were removed approximately 1 year after initial stenting. BBS and common bile duct (CBD) diameter were evaluated using cholangiography. Patients were followed for >= 6 mo after therapy, interviewed for cholestasis symptoms, and underwent liver function testing every visit. Patients with complete and incomplete stricture dilations were compared. RESULTS: Endoscopic therapy was completed in 8 (80%) patients, whereas 2 (20%) patients could not continue therapy because of severe acute cholangitis and abdominal abscess, respectively. The mean number of stents was 4.1 +/- 1.2. In two (20%) patients, BBS did not improve; thus, a biliary stent was inserted. BBS improved in six (60%) patients. CBD diameter improved more significantly in the complete group than in the incomplete group (6.1 +/- 1.8 mm vs 13.7 +/- 2.2 mm, respectively, P = 0.010). Stricture length was significantly associated with complete stricture dilation (complete group; 20.5 +/- 3.0 mm, incomplete group; 29.0 +/- 5.1 mm, P = 0.011). Acute cholangitis did not recur during the mean follow-up period of 20.6 +/- 7.3 mo. CONCLUSION: Sequential endoscopic insertion of multiple stents is effective for refractory BBS caused by chronic calcifying pancreatitis. BBS length calculation can improve patient selection procedure for therapy. PMID- 28101302 TI - Robot-assisted laparoscopic gastrectomy for gastric cancer. AB - Phase III evidence in the shape of a series of randomized controlled trials and meta-analyses has shown that laparoscopic gastrectomy is safe and gives better short-term results with respect to the traditional open technique for early-stage gastric cancer. In fact, in the East laparoscopic gastrectomy has become routine for early-stage gastric cancer. In contrast, the treatment of advanced gastric cancer through a minimally invasive way is still a debated issue, mostly due to worries about its oncological efficacy and the difficulty of carrying out an extended lymphadenectomy and intestinal reconstruction after total gastrectomy laparoscopically. Over the last ten years the introduction of robotic surgery has implied overcoming some intrinsic drawbacks found to be present in the conventional laparoscopic procedure. Robot-assisted gastrectomy with D2 lymphadenectomy has been shown to be safe and feasible for the treatment of gastric cancer patients. But unfortunately, most available studies investigating the robotic gastrectomy for gastric cancer compared to laparoscopic and open technique are so far retrospective and there have not been phase III trials. In the present review we looked at scientific evidence available today regarding the new high-tech surgical robotic approach, and we attempted to bring to light the real advantages of robot-assisted gastrectomy compared to the traditional laparoscopic and open technique for the treatment of gastric cancer. PMID- 28101304 TI - Gastric antral webs in adults: A case series characterizing their clinical presentation and management in the modern endoscopic era. AB - AIM: To investigate the current management of gastric antral webs (GAWs) among adults and identify optimal endoscopic and/or surgical management for these patients. METHODS: We reviewed our endoscopy database seeking to identify patients in whom a GAW was visualized among 24640 esophagogastroduodenoscopies (EGD) over a seven-year period (2006-2013) at a single tertiary care center. The diagnosis of GAW was suspected during EGD if aperture size of the antrum did not vary with peristalsis or if a "double bulb" sign was present on upper gastrointestinal series. Confirmation of the diagnosis was made by demonstrating a normal pylorus distal to the GAW. RESULTS: We identified 34 patients who met our inclusion criteria (incidence 0.14%). Of these, five patients presented with gastric outlet obstruction (GOO), four of whom underwent repeated sequential balloon dilations and/or needle-knife incisions with steroid injection for alleviation of GOO. The other 29 patients were incidentally found to have a non obstructing GAW. Age at diagnosis ranged from 30-87 years. Non-obstructing GAWs are mostly incidental findings. The most frequently observed symptom prompting endoscopic work-up was refractory gastroesophageal reflux (n = 24, 70.6%) followed by abdominal pain (n = 11, 33.4%), nausea and vomiting (n = 9, 26.5%), dysphagia (n = 6, 17.6%), unexplained weight loss, (n = 4, 11.8%), early satiety (n = 4, 11.8%), and melena of unclear etiology (n = 3, 8.82%). Four of five GOO patients were treated with balloon dilation (n = 4), four-quadrant needle-knife incision (n = 3), and triamcinolone injection (n = 2). Three of these patients required repeat intervention. One patient had a significant complication of perforation after needle-knife incision. CONCLUSION: Endoscopic intervention for GAW using balloon dilation or needle-knife incision is generally safe and effective in relieving symptoms, however repeat treatment may be needed and a risk of perforation exists with thermal therapies. PMID- 28101305 TI - Recurrence of choledocholithiasis following endoscopic bile duct clearance: Long term results and factors associated with recurrent bile duct stones. AB - AIM: To evaluate the rate of recurrence of symptomatic choledocholithiasis and identify factors associated with the recurrence of bile duct stones in patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic sphincterotomy (EST) for bile duct stone disease. METHODS: All patients who underwent ERCP and EST for bile duct stone disease and had their bile duct cleared from 1/1/2005 until 31/12/2008 was enrolled. All symptomatic recurrences during the study period (until 31/12/2015) were recorded. Clinical and laboratory data potentially associated with common bile duct (CBD) stone recurrence were retrospectively retrieved from patients' files. RESULTS: A total of 495 patients were included. Sixty seven (67) out of 495 patients (13.5%) presented with recurrent symptomatic choledocholithiasis after 35.28 +/- 16.9 mo while twenty two (22) of these patients (32.8%) experienced a second recurrence after 35.19 +/- 23.2 mo. Factors associated with recurrence were size (diameter) of the largest CBD stone found at first presentation (10.2 +/- 6.9 mm vs 7.2 +/- 4.1 mm, P = 0.024), diameter of the CBD at the first examination (15.5 +/- 6.3 mm vs 12.0 +/- 4.6 mm, P = 0.005), use of mechanical lithotripsy (ML) (P = 0.04) and presence of difficult lithiasis (P = 0.04). Periampullary diverticula showed a trend towards significance (P = 0.066). On the contrary, number of stones, angulation of the CBD, number of ERCP sessions required to clear the CBD at first presentation, more than one ERCP session needed to clear the bile duct initially and a gallbladder in situ did not influence recurrence. CONCLUSION: Bile duct stone recurrence is a possible late complication following endoscopic stone extraction and CBD clearance. It appears to be associated with anatomical parameters (CBD diameter) and stone characteristics (stone size, use of ML, difficult lithiasis) at first presentation. PMID- 28101306 TI - Essential role of small bowel capsule endoscopy in reclassification of colonic inflammatory bowel disease type unclassified. AB - AIM: To evaluate the role of small bowel capsule endoscopy (SBCE) on the reclassification of colonic inflammatory bowel disease type unclassified (IBDU). METHODS: We performed a multicenter, retrospective study including patients with IBDU undergoing SBCE, between 2002 and 2014. SBCE studies were reviewed and the inflammatory activity was evaluated by determining the Lewis score (LS). Inflammatory activity was considered significant and consistent with Crohn's disease (CD) when the LS >= 135. The definitive diagnosis during follow-up (minimum 12 mo following SBCE) was based on the combination of clinical, analytical, imaging, endoscopic and histological elements. RESULTS: Thirty-six patients were included, 21 females (58%) with mean age at diagnosis of 33 +/- 13 (15-64) years. The mean follow-up time after the SBCE was 52 +/- 41 (12-156) mo. The SBCE revealed findings consistent with significant inflammatory activity in the small bowel (LS >= 135) in 9 patients (25%); in all of them the diagnosis of CD was confirmed during follow-up. In 27 patients (75%), the SBCE revealed no significant inflammatory activity (LS < 135); among these patients, the diagnosis of Ulcerative Colitis (UC) was established in 16 cases (59.3%), CD in 1 case (3.7%) and 10 patients (37%) maintained a diagnosis of IBDU during follow-up. A LS >= 135 at SBCE had a sensitivity = 90%, specificity = 100%, positive predictive value = 100% and negative predictive value = 94% for the diagnosis of CD. CONCLUSION: SBCE proved to be fundamental in the reclassification of patients with IBDU. Absence of significant inflammatory activity in the small intestine allowed exclusion of CD in 94% of cases. PMID- 28101307 TI - Review and Recommendations on Management of Adult Female Thalassemia Patients with Hypogonadism based on Literature Review and Experience of ICET-A Network Specialists. AB - BACKGROUND: Multi-transfused thalassemia major (TM) patients frequently develop severe endocrine complications, mainly due to iron overload, anemia, and chronic liver disease, which require prompt diagnosis, treatment and follow-up by specialists. The most common endocrine complication documented is hypogonadotropic hypogonadism which increases with age and associated comorbidities. It is thus important for physicians to have a clear understanding of the pathophysiology and management of this disorder. Also to be aware of the side effects, contraindications and monitoring of sex steroid therapy. In this paper, practical ICET-A recommendations for the management of hypogonadism in adult females with TM are addressed. METHODS: In March 2015, the Coordinator of the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) conducted a two-step survey to assess the attitudes and practices of doctors in the ICET-A network taking care of adult female TM patients with hypogonadism. They were clinically characterized by the absence of pubertal development or discontinuation or regression of the maturation of secondary sex characteristics, and biochemically by persistent low FSH, LH and estradiol levels. Recently a supplementary survey on adult female hypogonadism in TM was undertaken within the ICET-A network. RESULTS: The completed questionnaires were returned by 16 of 27 specialists (59.2%) following 590 female TM patients over the age of 18 years; 315 patients (53.3%) had hypogonadism, and only 245 (74.6%) were on hormone replacement therapy (HRT). Contraceptive oral pills (COC) were the first treatment choice in 11 centers (68.7%). A wide range of COCs was used with different progestin contents. In general, the patients' compliance to treatment was reported as good in 81.2 % of centers. The frequency of required tests for follow-up HRT, in addition to the regular check-up for thalassemia, was variable in the participating centers. CONCLUSIONS: Doctors taking care of TM patients should have sound knowledge of the pathophysiology of hypogonadism in adult females with TM. They should know the potential effects of HRT including advantages and disadvantages of estrogen and progestins. Moreover, they should keep in consideration the emotional needs of these patients dreaming of attaining a full pubertal development. PMID- 28101310 TI - Effectiveness and Safety of Sitagliptin in Patients with Beta-thalassaemia Major and Diabetes Mellitus: A Case Series. AB - Sitagliptin, a modern antidiabetic agent which is weight neutral and associated with low rate of hypoglycaemias, is being increasingly used in type 2 diabetes mellitus (DM). However, there is a paucity of data about its efficacy and safety in beta-thalassaemia major (beta-TM). This retrospective case series of five patients (mean age of 45 years) is the first study evaluating the use of sitagliptin in patients with beta-TM and DM. Four patients responded well to sitagliptin, as evidenced by a decrease in fructosamine by 77 and 96MUmol/L (equivalent reduction in HbA1c of 1.5% and 1.9%) observed in two patients and reduction in the frequency of hypoglycaemia without worsening glycaemic control in two others. One patient did not respond to sitagliptin. No patients reported significant side effects. This study provides evidence that sitagliptin may be considered, with caution, for use in patients with beta-TM and DM, under the close monitoring of a Diabetologist. PMID- 28101309 TI - Patients with Haemoglobinopathies and Chronic Hepatitis C: A Real Difficult to Treat Population in 2016? AB - BACKGROUND & OBJECTIVES: In the past, patients with haemoglobinopathies were at high risk of acquiring hepatitis C virus (HCV) due to multiple transfusions before HCV screening. In these patients, the coexistence of haemochromatosis and chronic hepatitis C (CHC) often leads to more severe liver disease. We assessed the HCV prevalence, clinical characteristics and outcome in this setting with particular attention to the response to treatment including therapies with the new direct acting antivirals (DAAs). METHODS: The medical records of 81 consecutive patients followed the last 15 years were reviewed retrospectively. RESULTS: 43/81 (53%) patients were anti-HCV positive including 31/43 (72.1%) with CHC (HCV-RNA positive; age 25+/-7 years; 45.2% with genotype 1b; 19.4% cirrhotics; baseline ferritin 887 ng/ml; range: 81-10.820). Thirty patients received IFN-based therapy with or without ribavirin with sustained virological response (SVR) in 14/30 (46.7%). Eleven patients (9 non-responders to IFN-based therapies, one in relapse and one naive) received treatment with DAAs (SVR: 100%). 3/11 patients increased their transfusion needs while 1/11 reported mild arthralgias. No drug-drug interactions between DAAs and chelation agents were observed as attested by the stability of ferritin levels during treatment. CONCLUSIONS: More than 1/3 of patients with haemoglobinopathies suffered from CHC. Response rates to IFN-based treatment seem to be similar to other patients with CHC, while most importantly, treatment with DAAs was excellent and safe even in difficult to treat patients (most null responders with severe fibrosis) suggesting that this group of HCV patients should no longer be regarded as a difficult to treat. PMID- 28101308 TI - Antibacterial Resistance in Patients with Hematopoietic Stem Cell Transplantation. AB - Recipients of hematopoietic stem cell transplantation (HSCT) are at substantial risk of bacterial, fungal, viral, and parasitic infections depending on the time elapsed since transplantation, presence of graft-versus-host disease (GVHD), and the degree of immunosuppression. Infectious complications in HSCT recipients are associated with high morbidity and mortality. Bacterial infections constitute the major cause of infectious complications, especially in the early post-transplant period. The emergence of antibacterial resistance complicates the management of bacterial infections in this patient group. Multidrug-resistant bacterial infections in this group of patients have attracted considerable interest and may lead to significant morbidity and mortality. Empirical antibacterial therapy in patients with HSCT and febrile neutropenia has a critical role for survival and should be based on local epidemiology. This review attempts to provide an overview of risk factors and epidemiology of emerging resistant bacterial infections and their management in HSCT recipients. PMID- 28101311 TI - A Hospital-Based Retrospective Comparative Study of Complications, Outcomes, Clinical and Laboratory Parameters of Malaria with and without Neurological Involvement. AB - BACKGROUND & OBJECTIVES: Classically associated with Plasmodium (P.) falciparum, neurological complications in severe malaria is associated with increased morbidity and mortality. However, reports implicate the long considered benign P. vivax for causing severe malaria as well. We aimed to analyse the cerebral complications in malaria, and study if there is a species-related difference in the presentation and outcomes. METHODS: We retrospectively compared patients with malaria hospitalised from 2009-15, with (n=105) and without (n=1155) neurological involvement regarding outcomes, complications, demographic attributes, clinical features, and laboratory parameters. Subsequently, the same parameters were studied in those with cerebral malaria due to mono-infections of P. vivax or P. falciparum and their co-infection. RESULTS: Cerebral malaria was observed in 8.3% (58/696), 7.4% (38/513) and 17.6% (6/51) of P. vivax, P. falciparum and combined plasmodial infections respectively. Those with cerebral malaria had significantly (p<0.05) longer hospitalisation, delayed defervescence, required mechanical ventilatory support and dialysis despite comparable levels of azotemia and renal insufficiency, and adverse outcomes compared to non-cerebral malaria. Severe thrombocytopenia, respiratory distress and mechanical ventilation were significantly (p<0.05) associated with P. vivax cerebral malaria. CONCLUSIONS: The plasmodial species are comparable in clinical and laboratory parameters and outcomes in cerebral malaria in isolation and combination (p>0.05). P. vivax is emerging as the predominant cause of cerebral malaria, and its virulence is comparable to P. falciparum. PMID- 28101312 TI - Cryoglobulin Test and Cryoglobulinemia Hepatitis C-Virus Related. AB - Cryoglobulins are immunoglobulins that precipitate in serum at temperatures below 37 degrees C and resolubilize upon warming. The clinical syndrome of cryoglobulinemia usually includes purpura, weakness, and arthralgia, but the underlying disease may also contribute other symptoms. Blood samples for cryoglobulin are collected, transported, clotted and spun at 37 degrees C, before the precipitate is allowed to form when serum is stored at 4 degrees C in a Wintrobe tube for at least seven days. The most critical and confounding factor affecting the cryoglobulin test is when the preanalytical phase is not fully completed at 37 degrees C. The easiest way to quantify cryoglobulins is the cryocrit estimate. However, this approach has low accuracy and sensitivity. Furthermore, the precipitate should be resolubilized by warming to confirm that it is truly formed of cryoglobulins. The characterization of cryoglobulins requires the precipitate is several times washed, before performing immunofixation, a technique by which cryoglobulins can be classified depending on the characteristics of the detected immunoglobulins. These features imply a pathogenic role of these molecules which are consequently associated with a wide range of symptoms and manifestations. According to the Brouet classification, Cryoglobulins are grouped into three types by the immunochemical properties of immunoglobulins in the cryoprecipitate. The aim of this paper is to review the major aspects of cryoglobulinemia and the laboratory techniques used to detect and characterize cryoglobulins, taking into consideration the presence and consequences of cryoglobulinemia in Hepatitis C Virus (HCV) infection. PMID- 28101313 TI - A Young Adult with Unintended Acute Intravenous Iron Intoxication Treated with Oral Chelation: The Use of Liver Ferriscan for Diagnosing and Monitoring Tissue Iron Load. AB - Acute iron intoxication (FeI) in humans has not been adequately studied. The manifestation of FeI, defined as a serum iron concentration >300 MUg/dL (55 MUmol/L) within 12 hours of ingestion, include various symptoms appearing in progressive stages. Systemic toxicity is expected with an intake of 60 mg/kg. A 27-year-old female nurse presented with unintended acute intravenous iron intoxication (FeI) a week after self-injecting herself with 20 ampoules of IV iron (4,000 mg elemental iron, 60 mg/kg). She had stable vital signs and mild hepatic tenderness. Hepatic MRI (Ferriscan(r)) showed a moderate/severe liver iron content (LIC: 9 mg/g dry tissue). Her hemogram, electrolytes, hepatic and renal functions were normal. Based on the high dose of iron received and her elevated LIC, chelation therapy was advised. She accepted only oral therapy and was started on deferasirox at a dose of 30 mg/kg daily. This oral chelation proved to be effective in clearing her hepatic iron overload after six months (LIC: 2 mg/g dry tissue), without side effects. This case also proved the value of Ferriscan(r) in diagnosing the degree of hepatic FeI and monitoring therapy to achieve a safe level of LIC. PMID- 28101314 TI - Is There a Role for Minimal Residual Disease Monitoring in Follicular Lymphoma in the Chemo-Immunotherapy Era? AB - After 25 years, evaluation of minimal residual disease (MRD) in follicular lymphoma (FL) has become a standardized technique frequently integrated into clinical trials for its consistent and independent prognostic significance. Achievement of a sustained MRD negativity is a marker of treatment sensibility that has been associated with excellent clinical outcome in terms of clinical response and progression-free survival, independently from the employed therapy. However, no survival advantages has been reported for MRD negative patients and despite the compelling results of clinical trials, MRD evaluation has currently no role in clinical practice. Ongoing clinical trials will help in clarifying the potential setting in which MRD monitoring may have a routine clinical application i.e. allowing de-escalation of standard maintenance therapy in very low risk patients. In this review the clinical implications of MRD monitoring in Rituximab era are discussed in light of the current treatment paradigms most aimed at reducing toxicities, and the response definition that now routinely integrates PET scan. PMID- 28101315 TI - VCAM-1 and ICAM-1 Serum Levels as Markers of Relapse in Visceral Leishmaniasis. PMID- 28101316 TI - Defining Invasive Fungal Infection Risk in Hematological Malignancies: A New Tool for Clinical Practice. PMID- 28101318 TI - Prevalence and correlates of antipsychotic polypharmacy among outpatients with schizophrenia attending a tertiary psychiatric facility in Nigeria. AB - BACKGROUND: The study aimed to determine the prevalence, pattern and correlates of antipsychotic polypharmacy (APP) among outpatients with schizophrenia attending a tertiary psychiatric facility in Nigeria. METHOD: A cross-sectional study of 250 patients with schizophrenia attending the outpatient clinic of a regional tertiary psychiatric facility in Nigeria was undertaken. They were administered a sociodemographic questionnaire, the Positive and Negative Syndrome Scale (PANSS), the Global Assessment of Functioning (GAF) scale and the Liverpool University Side Effects Rating Scale (LUNSERS). RESULTS: Of the 250 subjects interviewed, 176 (70.4%) were on APP. APP was significantly associated with higher prescribed chlorpromazine equivalent doses of antipsychotics (p < 0.001), increased frequency of dosing (p < 0.001), negative symptoms (p < 0.01), poorer functioning (p = 0.04) and greater side-effect burden (p = 0.04). CONCLUSION: The APP rate reported from this study is high. Clinicians should be mindful of its impact on dosage and side-effect profiles as APP use is associated with negative symptoms and poor psychosocial functioning. PMID- 28101317 TI - Corticotropin-releasing factor overexpression in mice abrogates sex differences in body weight, visceral fat, and food intake response to a fast and alters levels of feeding regulatory hormones. AB - BACKGROUND: Corticotropin-releasing factor overexpressing (CRF-OE) male mice showed an inhibited feeding response to a fast, and lower plasma acyl ghrelin and Fos expression in the arcuate nucleus compared to wild-type (WT) mice. We investigated whether hormones and hypothalamic feeding signals are impaired in CRF-OE mice and the influence of sex. METHODS: Male and female CRF-OE mice and WT littermates (4-6 months old) fed ad libitum or overnight fasted were assessed for body, adrenal glands and perigonadal fat weights, food intake, plasma hormones, blood glucose, and mRNA hypothalamic signals. RESULTS: Under fed conditions, compared to WT, CRF-OE mice have increased adrenal glands and perigonadal fat weight, plasma corticosterone, leptin and insulin, and hypothalamic leptin receptor and decreased plasma acyl ghrelin. Compared to male, female WT mice have lower body and perigonadal fat and plasma leptin but higher adrenal glands weights. CRF-OE mice lost these sex differences except for the adrenals. Male CRF OE and WT mice did not differ in hypothalamic expression of neuropeptide Y (NPY) and proopiomelanocortin (POMC), while female CRF-OE compared to female WT and male CRF-OE had higher NPY mRNA levels. After fasting, female WT mice lost more body weight and ate more food than male WT, while CRF-OE mice had reduced body weight loss and inhibited food intake without sex difference. In male WT mice, fasting reduced plasma insulin and leptin and increased acyl ghrelin and corticosterone while female WT showed only a rise in corticosterone. In CRF-OE mice, fasting reduced insulin while leptin, acyl ghrelin and corticosterone were unchanged with no sex difference. Fasting blood glucose was higher in CRF-OE with female > male. In WT mice, fasting increased hypothalamic NPY expression in both sexes and decreased POMC only in males, while in CRF-OE mice, NPY did not change, and POMC decreased in males and increased in females. CONCLUSIONS: These data indicate that CRF-OE mice have abnormal basal and fasting circulating hormones and hypothalamic feeding-related signals. CRF-OE also abolishes the sex difference in body weight, abdominal fat, and fasting-induced feeding and changes in plasma levels of leptin and acyl ghrelin. PMID- 28101319 TI - The Nursing Assessment of Medication Acceptance: the reliability and validity of a schizophrenia medication adherence scale. AB - BACKGROUND: Many patients with schizophrenia have low medication adherence. There is, however, no objective assessment scale that can be used by nurses or caregiver specialists. The Nursing Assessment of Medication Acceptance (NAMA) was developed to assess patients' medication adherence. The aim of this study was to examine the validity and reliability of the NAMA in patients with schizophrenia. METHODS: A total of 121 Japanese patients with schizophrenia were enrolled. All patients underwent evaluation using the NAMA and the Drug Attitude Inventory (DAI 10). Reliability was investigated using a test-retest method and a parallel-test method. To determine the test-retest reliability of the NAMA, we tested 101 schizophrenia patients twice, with the second assessment 2-4 weeks after the date of the first assessment. For validity verification, standard-related validity and the degree of concordance with the DAI-10 scores were measured. RESULTS: The Cronbach's alpha value of the NAMA in schizophrenia was 0.88. The test-retest correlation coefficients were all between 0.53-0.74. The total scores and all subscores for the NAMA were significantly correlated, and the NAMA total scores were significantly correlated with the DAI-10 total scores. CONCLUSIONS: The NAMA shows good reliability and validity in measuring medication adherence in schizophrenia. PMID- 28101320 TI - Variation in dose and plasma level of lamotrigine in patients discharged from a mental health trust. AB - BACKGROUND: The objectives of this study were to investigate the dose of lamotrigine when prescribed with an enzyme inhibitor or enzyme inducer in patients discharged from a mental health trust and to determine the corresponding lamotrigine plasma concentrations and the factors that may affect these. METHODS: All patients discharged on lamotrigine between October 2007 and September 2012 were identified using the pharmacy dispensing database. We recorded demographic details, lamotrigine dose and plasma levels and coprescribed medication. RESULTS: During the designated period, 187 patients were discharged on lamotrigine of whom 117 had their plasma levels recorded. The mean lamotrigine daily dose was 226.1 mg (range 12.5-800 mg) and the mean plasma level 5.9 mg/l (range 0.8-18.1 mg/l). Gender, ethnicity, diagnosis and smoking status had no significant effect on dose or plasma levels. Patients taking an enzyme-inducing drug (n = 6) had significantly lower plasma levels [mean (SD) 3.40 (1.54) mg/l] than those not taking enzyme inducers [n = 111; 6.03 (3.13) mg/l; p = 0.043]. Patients taking an enzyme-inhibiting drug (n = 23) had significantly higher levels [7.47 (3.99) mg/l] than those not taking an inhibitor [n = 94; 5.52 (2.75) mg/l; p = 0.035]. No significant difference was found between the doses of lamotrigine in patients taking an enzyme inhibitor and those not taking one (p = 0.376). No significant difference was found between the doses of lamotrigine in patients taking an enzyme-inducing drug and those not taking any (p = 0.574). CONCLUSIONS: Current dosing recommendations indicate that lamotrigine doses should be halved in individuals taking enzyme inhibitors and doubled in those on enzyme inducers. In our survey these recommendations were rarely followed with the consequence that patients received too high or too low a dose of lamotrigine, respectively. PMID- 28101321 TI - Switching away from pipotiazine palmitate: a naturalistic study. AB - BACKGROUND: In March 2015, pipotiazine palmitate depot antipsychotic was globally withdrawn due to the shortage of its active ingredient. Thus, all patients receiving this medication had to be switched to an alternative antipsychotic drug. In this study we set to evaluate the process of switching away from pipotiazine palmitate within our clinical service, and its impact on hospitalization. METHODS: Demographic and clinical data on patients who were receiving pipotiazine palmitate in Northamptonshire at the time of its withdrawal were anonymously extracted from their electronic records and analyzed using descriptive statistics. RESULTS: A total of 17 patients were switched away from pipotiazine palmitate at the time of its withdrawal, all of whom had a prior history of nonadherence with oral treatment. A total of 14 patients were switched to another depot antipsychotic drug, while three patients chose an oral alternative which they subsequently discontinued resulting in relapse and hospitalization. There was a five-fold increase in mean hospitalization among patients who completed a year after the switch. CONCLUSION: Switching away from pipotiazine palmitate was associated with significant clinical deterioration in patients who switched to an oral antipsychotic, whereas most patients who switched to another depot treatment maintained stability. Clinicians should exercise caution when switching patients with schizophrenia away from depot antipsychotic drugs, especially in cases of patients with a history of treatment nonadherence who prefer to switch to oral antipsychotics. PMID- 28101322 TI - Brexpiprazole and cariprazine: distinguishing two new atypical antipsychotics from the original dopamine stabilizer aripiprazole. AB - BACKGROUND: Brexpiprazole and cariprazine are the latest US Food and Drug Administration approved atypical antipsychotics available in the United States. Both function as partial agonists of the dopamine-2 receptor (D2R), a mechanism of action shared with aripiprazole. However, all three differ in their affinities for the D2R as well as for serotonin receptors (5-HTRs). This paper seeks to delineate these pharmacodynamic and clinical differences amongst the three dopamine partial agonist atypical antipsychotic drugs. METHODS: PubMed and clinicaltrials.gov searches were used to generate preclinical and clinical evidence for review. Data derived from animal models and human subjects were used to provide insight on clinical mechanisms and adverse effect potentials. Clinical trial data were reviewed to compare clinical efficacy and adverse effects. RESULTS: Efficacies among the three drugs are comparable for their shared indications. Side-effect profile and underlying pharmacodynamic mechanism of action for each drug may differ. CONCLUSION: Partial agonism of the D2R is a similarity of the three drugs reviewed. Each drug varies in affinity for both the D2R and a diverse group of 5-HTRs, generating a distinct profile of clinical indications and adverse effects for each. PMID- 28101323 TI - Gabapentin treatment in clozapine-induced restless legs syndrome: two cases and a review of the literature. AB - Restless legs syndrome (RLS) is a neuro-sensorimotor disorder affecting 2-4% of adults. It is characterized by intense urges to move the legs, associated with unpleasant sensory disturbances in the legs occurring at rest and manifests mostly in the evening and night, relieved by movement. Diagnosis is primarily based on clinical presentation and the consensus criteria for the diagnosis have been established. Antipsychotics, the dopamine antagonists, have been reported to induce RLS. Dopamine agonists, the effective first-line treatment of RLS, carry the risk of inducing or worsening psychosis. Many nondopaminergic agents including antiepileptic medications have also been used in the treatment of primary RLS. In this report we describe clozapine-induced RLS in two patients with schizophrenia and its successful treatment with gabapentin, a nondopaminergic agent. In addition, we have reviewed the available literature on clozapine-induced RLS and its management. PMID- 28101324 TI - Oxytocin for frontotemporal dementia: a systematic review. AB - BACKGROUND: The aim of this systematic review is to identify published randomized controlled trials (RCTs) that evaluated the use of oxytocin in individuals with frontotemporal dementia (FTD). METHODS: A literature search was conducted of PubMed, MEDLINE, EMBASE, PsycINFO and Cochrane collaboration databases for RCTs in any language that evaluated the use of oxytocin in individuals with FTD. Bibliographic databases of published articles were also searched for additional studies. RESULTS: A total of two RCTs that evaluated the use of oxytocin in individuals with FTD were identified. In one study, the use of oxytocin in individuals with FTD produced a reduction in identification of negative facial expressions (anger and fear) which can be hypothesized to improve trust and increase cooperation in these individuals. Both studies noted oxytocin was well tolerated and showed short term benefits on behavioral symptoms in individuals with FTD. CONCLUSIONS: Oxytocin appears to improve social aspects of cognition and behavioral symptoms in individuals with FTD and is well tolerated. However, positive data from larger and longer duration RCTs are needed before the routine use of oxytocin in individuals with FTD can be recommended. PMID- 28101325 TI - Role of psilocybin in the treatment of depression. AB - Psilocybin is a naturally occurring alkaloid, pharmacologically similar to the classic hallucinogen lysergic acid diethylamide (LSD). Although primarily used as a recreational drug or an entheogen in particular cultural settings, recent population based studies have shown that it does not lead to serious physical or mental health problems or dependent use. In view of recent work demonstrating psilocybin's potential to increase subjective sense of wellbeing and because of its novel mechanism of 5-HT2A serotonin receptor agonism, it is being explored for possible therapeutic utility in mood and anxiety disorders. PMID- 28101326 TI - Microhomology-mediated end joining: new players join the team. AB - DNA double-strand breaks (DSBs) are the most deleterious type of DNA damage in cells arising from endogenous and exogenous attacks on the genomic DNA. Timely and properly repair of DSBs is important for genomic integrity and survival. MMEJ is an error-prone repair mechanism for DSBs, which relies on exposed microhomologous sequence flanking broken junction to fix DSBs in a Ku- and ligase IV-independent manner. Recently, significant progress has been made in MMEJ mechanism study. In this review, we will summarize its biochemical activities of several newly identified MMEJ factors and their biological significance. PMID- 28101327 TI - Hsa-let-7c-5p augments enterovirus 71 replication through viral subversion of cell signaling in rhabdomyosarcoma cells. AB - BACKGROUND: Human enterovirus 71 (EV71) causes severe hand, foot and mouse disease, accompanied by neurological complications. During the interaction between EV71 and the host, the virus subverts host cell machinery for its own replication. However, the roles of microRNAs (miRNAs) in this process remain obscure. RESULTS: In this study, we found that the miRNA hsa-let-7c-5p was significantly upregulated in EV71-infected rhabdomyosarcoma cells. The overexpression of hsa-let-7c-5p promoted replication of the virus, and the hsa let-7c-5p inhibitor suppressed viral replication. Furthermore, hsa-let-7c-5p targeted mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) and inhibited its expression. Interestingly, downregulation of MAP4K4 expression led to an increase in EV71 replication. In addition, MAP4K4 knockdown or transfection with the hsa-let-7c-5p mimic led to activation of the c-Jun NH2-terminal kinase (JNK) signaling pathway, whereas the hsa-let-7c-5p inhibitor inhibited activation of this pathway. Moreover, EV71 infection promoted JNK pathway activation to facilitate viral replication. CONCLUSIONS: Our data suggested that hsa-let-7c-5p facilitated EV71 replication by inhibiting MAP4K4 expression, which might be related to subversion of the JNK pathway by the virus. These results may shed light on a novel mechanism underlying the defense of EV71 against cellular responses. In addition, these findings may facilitate the development of new antiviral strategies for use in future therapies. PMID- 28101328 TI - Perceived health status in a comparative perspective: Methodological limitations and policy implications for Israel. AB - BACKGROUND: The perceived health status indicator included in the OECD Health Statistics suffers from severe methodological limitations related to data collection. Furthermore, this indicator is also included in the OECD's Better Life Index, thus distorting the total health score of some OECD countries, among them Israel. The purpose of this paper is to explore the erroneous use of OECD health data in Israel and to warn of its implications. METHODS: Analysis of data from the OECD Health Database, Better Life Index and the Israeli Central Bureau of Statistics, review of media reports and governmental documents concerning health measures, conversations and correspondence held with officials in the relevant organizations. RESULTS: OECD's perceived health status outcomes for Israel are biased upwards, resulting also in an upward bias of the Israeli overall health grade in the Better Life Index. This is due to the methodological differences between the OECD's standard survey questionnaire and the Israeli one. Yet, erroneous comparisons constantly appear in governmental documents and media reports, presenting health status in Israel in an excessive positive light. CONCLUSIONS: Data from the OECD Health Statistics and the Better Life Index are reaching policy makers and the public in a manner that potentially distorts professional and political discourse on health. This may lead to a decrease in the resources allocated to health based on a flawed comparison. In the long run, and no less serious, the systematic imprecision may detract from the reliability of authority reports in the eyes of the public. Caution is essential in dealing with health indices and international comparisons. The OECD and relevant national agencies should invest greater efforts in the consolidation of definitions and methodologies. PMID- 28101329 TI - Association between sports type and overuse injuries of extremities in adults: a systematic review. AB - BACKGROUND: Sports injuries are often described as overuse or traumatic. Little is known about the frequency of overuse injuries and, in particular, if they vary between different types of sporting activities. PURPOSE: To identify any differences between sports in relation to diagnoses of overuse injuries of the extremities (OIE) and anatomical areas most likely to be injured in adults and to compare these findings with those reported in youngsters, as identified in a previous review. METHODS: A search was made in May 2015 and again in April 2016 in PubMed, SportDiscus, PsycInfo, and Web of Sciences. Search terms were " overuse injuries OR cumulative trauma disorders OR musculoskeletal injuries " AND " extremity OR limb " AND " physical activity OR sport OR risk factor OR exercises ". Inclusion criteria were: 1) prospective, or cross-sectional study design; 2) at least 1/3 of the population should be >= 19 years; 3) articles must clearly state if reported cases were classified as traumatic or overuse injuries in relation to a particular sports type, 4) sample size >50, and 5) articles must not deal with specific occupational subpopulations nor with clinical populations. A blinded systematic review was conducted and results reported per anatomical site of injury and diagnosis for the different sports. RESULTS: In all, 10 of 1435 identified articles were included, studying soccer, beach-volleyball and triathlon. In general, the incidence estimates were low, never above 2.0/1000 h of practice, similar to results seen in children/adolescents. The incidence estimates and the diagnoses of OIE were given only in 4 articles on soccer, making comparisons between sports impossible. As in children/adolescents, the lower limb is more often affected than the upper but contrary to young people the injured site in adults is more often the knee and above, and there were also differences in the diagnoses for the two age groups. CONCLUSION: The literature does not permit to identify clearly the difference in the incidence of OIE for different sports showing that more but well-designed surveillance studies are needed. PMID- 27928499 TI - Whole genome resequencing of a laboratory-adapted Drosophila melanogaster. AB - As part of a study into the molecular genetics of sexually dimorphic complex traits, we used high-throughput sequencing to obtain data on genomic variation in an outbred laboratory-adapted fruit fly ( Drosophila melanogaster) population. We successfully resequenced the whole genome of 220 hemiclonal females that were heterozygous for the same Berkeley reference line genome (BDGP6/dm6), and a unique haplotype from the outbred base population (LH M). The use of a static and known genetic background enabled us to obtain sequences from whole-genome phased haplotypes. We used a BWA-Picard-GATK pipeline for mapping sequence reads to the dm6 reference genome assembly, at a median depth-of coverage of 31X, and have made the resulting data publicly-available in the NCBI Short Read Archive (Accession number SRP058502). We used Haplotype Caller to discover and genotype 1,726,931 small genomic variants (SNPs and indels, <200bp). Additionally we detected and genotyped 167 large structural variants (1-100Kb in size) using GenomeStrip/2.0. Sequence and genotype data are publicly-available at the corresponding NCBI databases: Short Read Archive, dbSNP and dbVar (BioProject PRJNA282591). We have also released the unfiltered genotype data, and the code and logs for data processing and summary statistics ( https://zenodo.org/communities/sussex_drosophila_sequencing/). PMID- 27928499 TI - Whole genome resequencing of a laboratory-adapted Drosophila melanogaster population sample. AB - As part of a study into the molecular genetics of sexually dimorphic complex traits, we used high-throughput sequencing to obtain data on genomic variation in an outbred laboratory-adapted fruit fly ( Drosophila melanogaster) population. We successfully resequenced the whole genome of 220 hemiclonal females that were heterozygous for the same Berkeley reference line genome (BDGP6/dm6), and a unique haplotype from the outbred base population (LH M). The use of a static and known genetic background enabled us to obtain sequences from whole-genome phased haplotypes. We used a BWA-Picard-GATK pipeline for mapping sequence reads to the dm6 reference genome assembly, at a median depth-of coverage of 31X, and have made the resulting data publicly-available in the NCBI Short Read Archive (Accession number SRP058502). We used Haplotype Caller to discover and genotype 1,726,931 small genomic variants (SNPs and indels, <200bp). Additionally we detected and genotyped 167 large structural variants (1-100Kb in size) using GenomeStrip/2.0. Sequence and genotype data are publicly-available at the corresponding NCBI databases: Short Read Archive, dbSNP and dbVar (BioProject PRJNA282591). We have also released the unfiltered genotype data, and the code and logs for data processing and summary statistics ( https://zenodo.org/communities/sussex_drosophila_sequencing/). PMID- 28003882 TI - Evolutionary relations and population differentiation of Acipenser gueldenstaedtii Brandt, Acipenser persicus Borodin, and Acipenser baerii Brandt. AB - Russian ( Acipenser gueldenstaedtii), Persian ( A. persicus) and Siberian ( A. baerii) sturgeons are closely related 'Ponto-Caspian' species. Investigation of their population structure is an important problem, the solution of which determines measures for conservation of these species. According to previous studies, 'baerii-like' mitochondrial genotypes were found in the Caspian Sea among 35% of Russian sturgeon specimens, but were not found in Persian sturgeons. This confirms genetic isolation of the Persian sturgeon from the Russian sturgeon in the Caspian Sea. However, in order to clarify the relationships of these species it is necessary to analyze nuclear DNA markers. The amplified fragment length polymorphism (method) allows estimating interpopulation and interspecific genetic distances using nuclear DNA markers. In the present study, four samples were compared: Persian sturgeons from the South Caspian Sea, Russian sturgeons from the Caspian Sea and the Sea of Azov, and Siberian sturgeons from the Ob' River, which are close to the latter two species, but are also clearly morphologically and genetically distinct from them. For the amplified fragment length polymorphism (AFLP) method, eight pairs of selective primers were used. The analysis revealed that the Siberian sturgeon has formed a separate branch from the overall Persian-Russian sturgeons cluster, which was an expected result. In addition, the results showed that the Caspian Russian sturgeon is closer to the Persian sturgeon from the Caspian Sea than to the Russian Sturgeon from the Sea of Azov. The present DNA marker data confirm that despite the genetic isolation of the Persian sturgeon from the Russian sturgeon in the Caspian Sea, the Persian sturgeon is a young species. PMID- 28101334 TI - Implementation of short incubation MALDI-TOF MS identification from positive blood cultures in routine diagnostics and effects on empiric antimicrobial therapy. AB - BACKGROUND: Results of blood culture (BC) diagnostics should be swiftly available to guide treatment of critically ill patients. Conventional BC diagnostics usually performs species identification of microorganisms from mature solid medium colonies. Species identification might be speed up by using matrix assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) of biomass from shortly incubated solid media. METHODS: This single-center analysis compared the applicability of MALDI-TOF-based species identification from shortly incubated cultures in laboratory routine vs. conventional diagnostics and assessed its effects of on empiric antibiotic therapy. RESULTS: Median time between detection of BCs as "positive" by incubators and further processing (e.g. microscopy) was 6 h 21 min. Median time between microscopy and result reporting to the ward was 15 min. Including 193 BCs, MALDI-TOF from shortly incubated biomass resulted in significantly faster (p > 0.001) species identification. Species results became available for clinicians after a median of 188 min (231 min for Gram-positive bacteria, 151 min for Gram-negative bacteria) compared to 909 min (n = 192 BCs) when conventional diagnostics was used. For 152/179 bacteremia episodes (85%) empiric antibiotic therapy had already been started when the microscopy result was reported to the ward; microscopy led to changes of therapies in 14/179 (8%). In contrast, reporting the bacterial species (without antibiogram) resulted in therapeutic adjustments in 36/179 (20%). Evaluating these changes revealed improved therapies in 26/36 cases (72%). CONCLUSIONS: Species identification by MALDI-TOF MS from shortly incubated subcultures resulted in adjustments of empiric antibiotic therapies and might improve the clinical outcome of septic patients. PMID- 28101333 TI - Behaviour change interventions to influence antimicrobial prescribing: a cross sectional analysis of reports from UK state-of-the-art scientific conferences. AB - BACKGROUND: To improve the quality of antimicrobial stewardship (AMS) interventions the application of behavioural sciences supported by multidisciplinary collaboration has been recommended. We analysed major UK scientific research conferences to investigate AMS behaviour change intervention reporting. METHODS: Leading UK 2015 scientific conference abstracts for 30 clinical specialties were identified and interrogated. All AMS and/or antimicrobial resistance(AMR) abstracts were identified using validated search criteria. Abstracts were independently reviewed by four researchers with reported behavioural interventions classified using a behaviour change taxonomy. RESULTS: Conferences ran for 110 days with >57,000 delegates. 311/12,313(2.5%) AMS-AMR abstracts (oral and poster) were identified. 118/311(40%) were presented at the UK's infectious diseases/microbiology conference. 56/311(18%) AMS-AMR abstracts described behaviour change interventions. These were identified across 12/30(40%) conferences. The commonest abstract reporting behaviour change interventions were quality improvement projects [44/56 (79%)]. In total 71 unique behaviour change functions were identified. Policy categories; "guidelines" (16/71) and "service provision" (11/71) were the most frequently reported. Intervention functions; "education" (6/71), "persuasion" (7/71), and "enablement" (9/71) were also common. Only infection and primary care conferences reported studies that contained multiple behaviour change interventions. The remaining 10 specialties tended to report a narrow range of interventions focusing on "guidelines" and "enablement". CONCLUSION: Despite the benefits of behaviour change interventions on antimicrobial prescribing, very few AMS-AMR studies reported implementing them in 2015. AMS interventions must focus on promoting behaviour change towards antimicrobial prescribing. Greater focus must be placed on non-infection specialties to engage with the issue of behaviour change towards antimicrobial use. PMID- 28101335 TI - Novel SNPs in IL-17F and IL-17A genes associated with somatic cell count in Chinese Holstein and Inner-Mongolia Sanhe cattle. AB - BACKGROUND: Bovine mastitis is the most common and costly disease of lactating cattle worldwide. Apart from milk somatic cell count (SCC) and somatic cell score (SCS), serum cytokines such as interleukin-17 (IL-17) and interleukin-4 (IL-4) may also be potential indicators for bovine mastitis. The present study was designed to investigate the effects of single nucleotide polymorphisms (SNPs) in bovine IL-17F and IL-17A genes on SCC, SCS and serum cytokines in Chinese Holstein and Inner-Mongolia Sanhe cattle, and to compare the mRNA expression variations of the cows with different genotypes. RESULTS: A total of 464 lactating cows (337 Holstein and 127 Inner-Mongolia Sanhe cattle) were screened for SNPs identification and the data were analyzed using fixed effects of herd, parity, season and year of calving by general linear model procedure. The results revealed that SNP g.24392436C > T in IL-17F and SNP g.24345410A > G in IL-17A showed significant effects on SCC and IL-4 in Holstein (n = 337) and on IL-17 and IL-4 in Sanhe cattle (n = 127). The homozygous GG genotype of SNP g.24345410A > G had significantly higher mRNA expression compared with the heterozygous AG genotype. CONCLUSIONS: The results indicate that IL-17F and IL-17A could be powerful candidate genes of mastitis resistance and the significant SNPs might be useful genetic markers against mastitis in both dairy and dual purpose cattle. PMID- 28101336 TI - Regulatory elements and transcriptional control of chicken vasa homologue (CVH) promoter in chicken primordial germ cells. AB - BACKGROUND: Primordial germ cells (PGCs), the precursors of functional gametes, have distinct characteristics and exhibit several unique molecular mechanisms to maintain pluripotency and germness in comparison to somatic cells. They express germ cell-specific RNA binding proteins (RBPs) by modulating tissue-specific cis- and trans-regulatory elements. Studies on gene structures of chicken vasa homologue (CVH), a chicken RNA binding protein, involved in temporal and spatial regulation are thus important not only for understanding the molecular mechanisms that regulate germ cell fate, but also for practical applications of primordial germ cells. However, very limited studies are available on regulatory elements that control germ cell-specific expression in chicken. Therefore, we investigated the intricate regulatory mechanism(s) that governs transcriptional control of CVH. RESULTS: We constructed green fluorescence protein (GFP) or luciferase reporter vectors containing the various 5' flanking regions of CVH gene. From the 5' deletion and fragmented assays in chicken PGCs, we have identified a CVH promoter that locates at -316 to +275 base pair fragment with the highest luciferase activity. Additionally, we confirmed for the first time that the 5' untranslated region (UTR) containing intron 1 is required for promoter activity of the CVH gene in chicken PGCs. Furthermore, using a transcription factor binding prediction, transcriptome analysis and siRNA-mediated knockdown, we have identified that a set of transcription factors play a role in the PGC-specific CVH gene expression. CONCLUSIONS: These results demonstrate that cis-elements and transcription factors localizing in the 5' flanking region including the 5' UTR and an intron are important for transcriptional regulation of the CVH gene in chicken PGCs. Finally, this information will contribute to research studies in areas of reproductive biology, constructing of germ cell-specific synthetic promoter for tracing primordial germ cells as well as understanding the transcriptional regulation for maintaining germness in PGCs. PMID- 28101337 TI - Adipocyte lipolysis links obesity to breast cancer growth: adipocyte-derived fatty acids drive breast cancer cell proliferation and migration. AB - BACKGROUND: Obesity is associated with increased recurrence and reduced survival of breast cancer. Adipocytes constitute a significant component of breast tissue, yet their role in provisioning metabolic substrates to support breast cancer progression is poorly understood. RESULTS: Here, we show that co-culture of breast cancer cells with adipocytes revealed cancer cell-stimulated depletion of adipocyte triacylglycerol. Adipocyte-derived free fatty acids were transferred to breast cancer cells, driving fatty acid metabolism via increased CPT1A and electron transport chain complex protein levels, resulting in increased proliferation and migration. Notably, fatty acid transfer to breast cancer cells was enhanced from "obese" adipocytes, concomitant with increased stimulation of cancer cell proliferation and migration. This adipocyte-stimulated breast cancer cell proliferation was dependent on lipolytic processes since HSL/ATGL knockdown attenuated cancer cell responses. CONCLUSIONS: These findings highlight a novel and potentially important role for adipocyte lipolysis in the provision of metabolic substrates to breast cancer cells, thereby supporting cancer progression. PMID- 28101338 TI - Critical role of calpain in inflammation. AB - Calpains are a family of cysteine proteases, implicated in a wide range of cellular calcium-regulated functions. Evidence from previous studies using an inhibitor of calpain indicates that calpain activation is involved in the process of numerous inflammation-associated diseases. As a result of in-depth studies, calpains have been proposed to influence the process of inflammation via a variety of mechanisms. The aim of the present study is to provide an overview of recent reports regarding the role of calpain in the process of inflammation, including regulation of immune cell migration, modulation of the activation of inflammatory mediators, degradation of certain associated proteins and induction of cell apoptosis. Understanding these mechanisms may contribute to the investigation of novel therapeutic targets for inflammation-associated diseases. PMID- 28101339 TI - Pre-treatment with simvastatin prevents the induction of diet-induced atherosclerosis in a rabbit model. AB - The aim of the present study was to investigate the potential antiatherosclerotic activities of simvastatin in rabbits. Twenty-two, male, New Zealand rabbits were divided into the following groups: Control group (group C); cholesterol group (group A), in which the rabbits were fed a commercial rabbit chow supplemented with 0.5% w/w cholesterol for 8 weeks and then fed with normal chow for an additional 8 weeks; and a treatment group (group B), in which the rabbits initially received standard commercial rabbit chow along with being administered simvastatin for 8 weeks, following which they consumed a high-cholesterol diet for a further 8 weeks. The rabbits pre-treated with simvastatin presented significantly lower serum cholesterol and low-density lipoprotein cholesterol levels when compared with the non simvastatin-treated cholesterol-fed animals. Furthermore, none of the rabbits in the simvastatin group presented with atherosclerotic lesions in the aorta. Thus, simvastatin was demonstrated to exhibit preventive properties against the formation of atherosclerosis in the atherosclerosis model in the current study, predominantly via its hypolipidemic activity. PMID- 28101341 TI - Influence of high-altitude hypoxic environments on the survival of cochlear hair cells and spiral ganglion neurons in rats. AB - The aim of the present study was to observe the histological changes in the peripheral auditory system in rats at different time-points after relocating from low altitude to high altitude (3,600 m). The general physical condition of the rats was observed and cochlear tissue samples were obtained every month. The morphology and survival of the cochlear hair cells (HCs) were observed using cochlear surface preparation at 1, 30, 90, 120, 150 and 180 days after moving to the plateau area. Changes in spiral ganglion neurons (SGNs) were detected at different time-points using immunofluorescence technology on frozen sections. No obvious morphological changes were observed in the cochlear HCs within 1-3 months of the rats moving to the plateau area, and there was little loss of outer HCs (OHCs) at 3 months. Cell swelling, dislocation and loss of cochlear OHCs were apparent at 4 months, and the losses of cochlear OHCs and inner HCs (IHCs) were 54 and 39%, respectively at 6 months. The loss of SGNs was observed at 3 months, and there was a loss of 28-35% of SGNs during 3-6 months. Thus, a high-altitude hypoxic environment influenced the cochlear HCs in rats after moving to the plateau area in a time-dependent manner. The damage to SGNs occurred earlier than the HCs, although SGN damage was not aggravated with time. Furthermore, compared with cochlear HCs, cochlear SGNs were identified to be markedly more sensitive to hypoxia, and exerted an adaptive mechanism to protect neurons from hypoxia. PMID- 28101340 TI - Pseudo-continuous arterial spin labeling imaging of cerebral blood perfusion asymmetry in drug-naive patients with first-episode major depression. AB - Many previous studies have reported that regional cerebral blood flow (rCBF) aberrations may be one of the pathological characteristics of depression and rCBF has demonstrated a certain degree of asymmetry. However, studies investigating the cerebral blood perfusion asymmetry changes of drug-naive patients experiencing their first episode of major depression using pseudo-continuous arterial spin labeling (pCASL) are rare. Ten drug-naive patients experiencing their first major depression episode and 15 healthy volunteers were enrolled in the current study. A novel pCASL method was applied to whole brain MRI scans of all of the samples. The Statistics Parameter Mapping and Relative Expression Software Tool software packages were used for the pre-processing and statistical analysis of the two sets of images, and the differences in the cerebral blood perfusion at the whole brain level were compared between the two groups. Compared with the healthy control group, the cerebral perfusion of the depression patients showed an asymmetric pattern. Decreased cerebral blood perfusion regions were primarily located in the left hemisphere, specifically in the left temporal lobe, frontal lobe and cingulate cortex [P<0.05 and cluster size >=30 with false discovery rate (FDR) correction]. Simultaneously, increased perfusion regions were predominantly located in the right hemisphere, specifically in the right cerebellum, thalamus, frontal lobe and anterior cingulate cortex (P<0.05 and cluster size >=30, with FDR correction). Thus, pCASL may characterize the alterations in cerebral blood perfusion of patients with depression. PMID- 28101342 TI - Pharmacodynamic analysis of target-controlled infusion of propofol in patients with hepatic insufficiency. AB - The effect of liver dysfunction on target-controlled infusion (TCI) of propofol remains poorly documented. The pharmacodynamic performance of propofol TCI was evaluated in a cohort of Chinese patients with hepatic insufficiency. Fifty-three patients with hepatic insufficiency were enrolled in the current prospective, observational study. Anesthesia was induced with propofol via TCI to a plasma concentration of 3 ug/ml. Following loss of consciousness (LOC), fentanyl and cisatracurium were administered. Pharmacodynamic parameters were recorded during TCI, including time to LOC, bispectral index (BIS), heart rate (HR) and blood pressure. Patients were divided into two groups based on model of end stage liver disease (MELD) score: Those with a MELD score of <=9 and those with a MELD score of >=10. BIS, mean arterial pressure and HR were demonstrated to vary according to time, but were not affected by liver dysfunction. Hypotension was prominent in patients with a MELD score of >=10 30 min after induction. The proportion of bradycardia and hypotension at the other time points was not significantly different between MELD scores of <=9 and >=10. Notably, no bradycardia was observed in MELD of >=10. Thus, bradycardia and hypotension was observed in patients with hepatic insufficiency over time, although patients with different severities of hepatic insufficiency did not present with different depths of anesthesia. TCI of propofol to 3 ug/ml may be not suitable for patients with hepatic insufficiency, particularly those with severe liver dysfunction. Predictive concentrations (Cp) of TCI propofol requires further investigation and adjustment in patients with hepatic insufficiency (trial registration no. ChiCTR OCH-12002255). PMID- 28101344 TI - Evaluation of pharmacological relaxation effect of the natural product naringin on in vitro cultured airway smooth muscle cells and in vivo ovalbumin-induced asthma Balb/c mice. AB - Asthma has become a common chronic respiratory disease worldwide and its prevalence is predicted to continue increasing in the next decade, particularly in developing countries. A key component in asthma therapy is to alleviate the excessive bronchial airway narrowing ultimately due to airway smooth muscle contraction, which is often facilitated by a smooth muscle relaxant, such as the beta2-adrenergic agonists. Recently, bitter taste receptor (TAS2R) agonists, including saccharin and chloroquine, have been found to potently relax the airway smooth muscle cells (ASMCs) via intracellular Ca2+ signaling. This inspires a great interest in screening the vast resource of natural bitter substances for potential bronchodilatory drugs. In the present study, the relaxation effect of naringin, a compound extracted from common grapefruit, on ASMCs cultured in vitro or bronchial airways of Balb/c mice in vivo was evaluated. The results demonstrated that, when exposed to increasing doses of naringin (0.125, 0.25, 0.5 and 1.0 mM), the traction force generated by the cultured ASMCs decreased progressively, while the intracellular calcium flux signaling in the ASMCs increased. When inhaled at increasing doses (15, 30 and 60 ug), naringin also dose-dependently reduced the bronchial airway resistance of the normal and ovalbumin-induced asthma Balb/c mice in response to challenge with methacholine. In conclusion, these findings indicate that naringin was able to effectively relax murine ASMCs in vitro and in vivo, thus suggesting that it is a promising drug agent to be further investigated in the development of novel bronchodilators for the treatment of asthma. PMID- 28101343 TI - Effect of 1,25(OH)2D3 on transdifferentiation of rat renal tubular epithelial cells induced by high glucose. AB - Deficiency in vitamin D and its active metabolite is a characteristic of chronic kidney diseases (CKDs). Previous studies have reported that 1alpha,25 dihydroxyvitamin D3 [1,25(OH)2D3], the active form of vitamin D, can attenuate renal interstitial fibrosis. The present study aimed to explore the effect of 1,25(OH)2D3 on the transdifferentiation of NRK-52E rat renal tubular epithelial cells (RTECs) induced by high glucose, as well as the expression of vitamin D receptor (VDR) and production of angiotensin (Ang) II. Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses were performed to detect the protein and mRNA expression of alpha-smooth muscle actin (alpha-SMA), E-cadherin and VDR. Furthermore, the production of Ang II was analyzed by enzyme-linked immunosorbent assay (ELISA). Treatment with high glucose decreased E-cadherin and VDR, while increasing alpha-SMA and Ang II, and of note, these changes were attenuated by 1,25(OH)2D3 in a dose-dependent manner. In conclusion, the present study revealed that 1,25(OH)2D3 inhibits high glucose induced transdifferentiation of rat RTECs in a dose-dependent manner, which may be associated with the downregulation of Ang II and upregulation of VDR. PMID- 28101345 TI - beta-cell function prior to liver transplantation contributes to post-operative diabetes. AB - Liver cirrhosis and diabetes mellitus (DM) are closely associated. The present study aimed to determine whether liver transplantation (LT) may prevent/cure DM in patients with cirrhosis and whether the degree of glucose tolerance prior to transplantation is associated with the onset of DM after transplantation. Seventy three patients who received a living donor LT at Nagasaki University Hospital (Nagasaki, Japan) between November 2005 and December 2012 were recruited. Among them, patients were considered diabetic if they had been prescribed diabetes medications or had impaired glucose tolerance, as evidenced by an oral glucose tolerance test (OGTT). Patients were followed up until December 31, 2013 to evaluate glucose tolerance. Patients who had developed DM 2 years after transplantation were found to be older and the incidence of diabetes prior to transplantation (n=73) was higher than in those who did not. Multivariate analysis revealed that DM requiring treatment prior to transplantation was the only independent factor for DM developed at 2 years after transplantation. OGTT results showed that in patients with poor insulin sensitivity indices prior to transplantation (n=45), improvements were seen at 2 years after transplantation, while beta-cell function and insulinogenic index had decreased, which may have been the cause of DM after transplantation. In conclusion, the pre-operative beta cell function determined by an OGTT may be a useful predictive tool for the recurrence of DM after LT. PMID- 28101346 TI - A case study of bofutsushosan-induced pulmonary injury in a patient: Case report. AB - Bofutsushosan, a herbal (traditional Kampo) medicine, is administered to obese patients in North-East Asia. Bofutsushosan has been reported to exert various anti-obesity effects by stimulating the adipose tissue. The present study describes the case of a patient who developed a severe pulmonary injury that was potentially associated with bofutsushosan therapy. A 52-year-old woman was admitted to Mito Medical Center, University of Tsukuba, Mito Kyodo General Hospital (Mito, Japan) due to progressive dyspnea. Two months previously, bofutsushosan had been newly prescribed for her obesity. Bilateral ground-glass opacities and progressive respiratory deterioration suggested respiratory failure due to a therapeutic agent-induced lung injury. With discontinuation of bofutsushosan and the administration of a corticosteroid, an improvement in her respiratory condition was achieved, although sequelae remained in certain areas of the lungs. Resumption of other therapeutic agents did not reinduce the lung injury. Therefore, a diagnosis of bofutsushosan-induced lung injury was made. Although bofutsushosan-induced lung injury is particularly rare, clinicians should consider it when bofutsushosan is used. PMID- 28101347 TI - Clinical presentation and management of uveal melanoma. AB - Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. The majority of the patients are Caucasian (97.8%) and aged 50-80 years. Choroidal melanoma is the predominant type (86.3%). The clinical presentation may range from no symptoms over various types of visual disturbances to visual loss. Examination includes slit-lamp biomicroscopy, indirect ophthalmoscopy and diagnostic testing, such as B-scan ultrasonography. A number of patients with posterior UM are treated with plaque radiation therapy or enucleation. At present, targeted therapy includes inhibitors of the mitogen-activated protein kinase/mitogen-activated protein kinase kinase signaling pathway. UM disseminates hematogenously, with a high propensity for metastasis to the liver, which the most common site (93% of the cases). While UM is uncommon, a significant proportion of affected patients succumb to this disease and new treatment options to improve patient survival are required. PMID- 28101349 TI - Clear cell carcinoma of the lower uterine segment: A case report. AB - Uterine carcinoma of the lower uterine segment (LUS) is a rare tumor that accounts for 3-3.5% of cases of uterine malignant cancer. The tumor arises from the lower region of the uterine body through the upper region of the cervix. The present study reported a case of clear cell carcinoma that originated from the LUS. A 50-year-old woman visited a local hospital due to irregular vaginal bleeding. She was suspected to have a uterine tumor and was referred to Tachikawa Hospital (Tokyo, Japan). Transvaginal ultrasound and magnetic resonance imaging revealed a uterine tumor from the lower region of the uterine body through the upper region of the cervix. Endocervical curettage revealed clear cell carcinoma. Based on a diagnosis of clear cell carcinoma of the LUS, radical hysterectomy was performed with bilateral salpingo-oophorectomy, paraaortic lymph node dissection and omentectomy. Macroscopically, the tumor was limited to the lower region of the uterine body through the upper region of the cervix in the resected uterus. Histopathological findings indicated no tumors in the uterine corpus and uterine cervix, but clear cell carcinoma was observed in the LUS epithelium. At the 1 year follow-up, the patient remained free of local recurrence and metastasis. To the best of our knowledge, clear cell carcinoma of the LUS has not previously been reported. More cases are required to clarify the pathology. PMID- 28101348 TI - Evans blue-mediated white-light detection of non-muscle-invasive bladder cancer: A preclinical feasibility and safety study using a rat bladder urothelial cell carcinoma model. AB - Photodynamic diagnosis (PDD) improves the detection of non-muscle-invasive bladder cancer (NMIBC). However, white-light (WL) cystoscopy remains the technique routinely used in urological clinics. A more cost-effective but equally performant alternative to PDD may encompass the use of an intense tumoritropic dye in combination with WL cystoscopy. Using a preclinical setting, we investigated the practical aspects of the use of Evans blue (EB) dye for the possible future detection of NMIBC using WL cystoscopy. A solution of 1 and 5 mM EB was instilled into healthy and AY-27 tumor-bearing rat bladders. The bladders were then rapidly dissected and the inner walls were inspected for EB using WL stereomicroscopy. EB present in the bladders and the plasma was also quantified using high performance liquid chromatography. To assess the effects of repeated instillations on normal rat bladders, EB was instilled for 7 consecutive days, after which time the bladder wall was investigated histologically. To gain insight into the mechanisms underlying the selective accumulation of EB in malignant urothelium, RNA sequencing of urothelial tissue and subsequent comparative analysis were performed, with a specific focus on cell adhesion. The concentrations of EB were substantially higher in malignant bladders compared with those in healthy bladders, matching the blue staining of the inner bladder wall observed by stereomicroscopy. EB was equally present in the plasma of healthy and tumor-bearing subjects, although at low concentrations. Importantly, EB did not cause any abnormalities in the urothelium after 7 days of repeated instillation in normal rats. RNA sequencing of the urothelium indicated an abnormal expression of several genes related to cell adhesion in malignant urothelium compared with the normal urothelium. Our findings may be important for future clinical developments in the field of diagnostics for bladder cancer. Implementing the more cost-effective protocol of EB instillations in combination with WL cystoscopy may offer a benefit to patients as well as the healthcare system. PMID- 28101350 TI - TP53 mutation is associated with a poor clinical outcome for non-small cell lung cancer: Evidence from a meta-analysis. AB - A number of studies have examined the association between tumor protein 53 (TP53) mutations and the clinical outcome in patients with non-small-cell lung cancer (NSCLC), although these have yielded conflicting results. In the present study, electronic databases updated to September 2015 were searched to find relevant studies. A meta-analysis was performed on the eligible studies, which quantitatively evaluated the association between the TP53 mutations and the survival of patients with NSCLC. Subgroup and sensitivity analyses were performed. A total of 19 studies that involved a total of 6,084 patients with NSCLC were included. When the TP53 mutation group (n=1,406) was compared with the wild-type group (lacking TP53 mutations; n=1,965), the wild-type group was associated with a significantly higher overall survival rate [hazard ratio (HR), 1.26; 95% confidence interval (CI) 1.12-1.41, P<0.0001]. Significant benefits of overall survival in the wild-type group were found in the subgroup involving patients with NSCLC in the early stages, including the I/II phases (HR, 1.93, 95% CI, 1.17-3.19, P=0.01; heterogeneity, I2=0.0%, P=0.976) and patients with adenocarcinoma (HR, 3.06; 95% CI, 1.66-5.62, P<0.0001; heterogeneity: I2=0.0%, P=0.976). This meta-analysis has indicated that TP53 gene alteration may be an indicator of a poor prognosis in patients with NSCLC. Furthermore, the results also suggested that the role of TP53 mutations may differ according to different pathological types and clinical stages. The presence of these mutations may define a subset of patients with NSCLC appropriate for investigational therapeutic strategies. PMID- 28101351 TI - Pro-inflammatory effect of a traditional Chinese medicine formula with potent anti-cancer activity in vitro impedes tumor inhibitory potential in vivo. AB - Medicinal formulas are a part of the complex discipline of traditional Chinese medicine that has been used for centuries in China and East Asia. These formulas predominantly consist of the extracts isolated from herbal plants, animal parts and medicinal minerals. The present study aimed to investigate the impact of 150 formulas, used as non-prescription drugs in China, on the treatment of cancer. A formula was identified, C54, commonly used to treat sore throats, which exhibited marked growth inhibition in vitro, associated with cell cycle arrest and apoptosis. Cytotoxicity was, in part, due to the ability of C54 to inhibit the expression and function of the transcription factor, Fli-1, leading to marked inhibition of leukemic cell growth in tissue culture. However, when injected into a model of leukemia initiated by Fli-1 activation, C54 only exhibited a limited tumor inhibition. C54 also did not suppress xenograft growth of the breast cancer cell line, MDA-MB-231, orthopedically transplanted into the mammary fat pad of severe combined immunodeficiency (SCID) mice. Notably, splenomegaly and accumulation of inflammatory CD11b+/Gr1+ monocytes were observed in the tumors and spleens of C54-treated mice. As inflammation is known to accelerate tumor progression, this immune response may counteract the cell-autonomous effect of C54, and account for its limited tumor inhibitory effect in vivo. Combining C54 with an anti-inflammatory drug may improve the potency of C54 for treatment of certain cancers. The present study has highlighted the complexity of Chinese medicinal compounds and the need to thoroughly analyze their systemic effects at high concentrations in vivo. PMID- 28101352 TI - Shear wave elastography and contrast-enhanced ultrasonography in the diagnosis of thyroid malignant nodules. AB - The aim of the present study was to evaluate the value of shear wave elastography (SWE) and contrast-enhanced ultrasonography (CEUS) in the diagnosis of thyroid malignant nodules. A total of 253 patients with 319 thyroid nodules were subjected to two-dimensional ultrasound (2DUS) and CEUS examinations prior to thyroidectomy between March, 2014 and December, 2015. Young's modulus value for each nodule on 2DUS and CEUS images were recorded. The sensitivity, specificity and accuracy of 2DUS, SWE and CEUS in the diagnosis of thyroid malignant nodules were assessed. The results demonstrated that, of the 319 nodules that were pathologically confirmed, 183 were malignant and 136 were benign. The area under the receiver operating characteristic curve as a result of SWE diagnosis was 0.77. When the threshold of the Young's modulus value was >=27.65 kPa in the diagnosis of malignant thyroid nodules, SWE exhibited a sensitivity of 84.55% (115/136), a specificity of 84.15% (154/183) and an accuracy of 84.32% (269/319). US contrast imaging of malignant thyroid nodules revealed a major tendency for early hypoenhancement and hypoenhancement. CEUS exhibited a sensitivity of 87.5% (119/136), a specificity of 86.33% (158/183) and an accuracy of 86.83% (277/319) in the diagnosis of malignant thyroid nodules. Compared with 2DUS, SWE, CEUS and their combined use exhibited statistically significant differences in the diagnosis of thyroid malignant nodules in terms of sensitivity, specificity and accuracy (chi2=9.220,15.310 and 40.296, respectively; P=0.000); SWE or CEUS did not differ significantly in the diagnosis of thyroid malignant nodules in terms of sensitivity, specificity or accuracy (chi2=0.737;P=0.542); Compared with the use of SWE or CEUS alone, their combination exhibited statistically significant differences in the diagnosis of malignant thyroid nodules in terms of sensitivity, specificity and accuracy (chi2=12.264 and 6.939, respectively; P=0.000,0.005). In conclusion, the high accuracy of the combined use of SWE and CEUS in the diagnosis of malignant thyroid nodules is of great clinical value. PMID- 28101353 TI - Clinical characteristics and treatment of 69 patients with extranodal natural killer T-cell lymphoma. AB - This study was conducted to retrospectively analyze the clinical characteristics and survival of patients with extranodal natural killer-T cell lymphoma (ENKL) and compare different treatment regimens. The univariate analysis demonstrated that survival was worse for patients with extranasal primary tumors, Eastern Cooperative Oncology Group performance status (ECOG PS) scores of >=2, International Prognostic Index (IPI) scores of 3-5, Ann Arbor stage III and IV disease, B symptoms, lymph node involvement and absence of radiotherapy. The Cox analysis demonstrated that ECOG PS score, stage, IPI, presence of B symptoms and radiotherapy were independent prognostic factors for overall survival (OS). The effect of diverse therapies on survival was then analyzed, and it was found that the 5-year survival rate of patients receiving chemoradiotherapy differed significantly from that of patients who received chemotherapy alone [hazard ratio (HR)=0.347, P=0.0203], but did not differ significantly from the survival of patients treated with radiotherapy alone (HR=1.534, P=0.6371). A subgroup analysis revealed a difference between the radiotherapy and non-radiotherapy groups for patients with extranasal-type stage III/IV disease. It was concluded that ECOG score, stage, IPI, presence of B symptoms and radiotherapy were independent prognostic factors for OS in patients with ENKL. The addition of radiotherapy achieved better outcomes compared with chemotherapy alone, but no difference was observed between chemoradiotherapy and radiotherapy. Patients with advanced-stage disease may also benefit from radiotherapy. PMID- 28101354 TI - Histological complete response in a patient with advanced biliary tract cancer treated by gemcitabine/cisplatin/S-1 combination chemotherapy: A case report. AB - A 68-year-old woman was referred to our hospital with increased levels of biliary enzymes. On imaging, the patient was diagnosed with unresectable intrahepatic biliary tract cancer (BTC) with invasion of the portal vein and para-aortic lymph node metastasis (cT3N1M1, cStage IVb) and underwent endoscopic biliary drainage for the biliary stricture prior to therapy. The patient was subsequently enrolled in a phase III randomized trial (UMIN000014371/NCT02182778) and randomly assigned to receive gemcitabine/cisplatin/S-1 (GCS) combination therapy intravenously at doses of 1,000 or 25 mg/m2 on day 1 and orally twice daily at a dose of 80 mg/m2 on days 1-7 every 2 weeks. After 12 cycles of scheduled therapy without uncontrollable adverse effects, the patient achieved a good partial response with chemotherapy. Computed tomography (CT) revealed a marked reduction of the primary and metastatic lesions. In addition,18F-fluorodeoxyglucose-positron emission tomography/CT revealed diminishing abnormal uptake and no macroscopic evidence of factors adversely affecting tumor resectability. Therefore, the patient underwent extended right hepatic lobectomy, lymph node dissection and left hepaticojejunostomy. Finally, histological examination of the resected tissues revealed no residual cancer cells, suggesting a pathologically complete response. We herein present the case of a patient with intrahepatic BTC who achieved a pathologically complete response following combination chemotherapy with GCS. PMID- 28101355 TI - Undifferentiated carcinoma of the gallbladder with endothelial differentiation: A case report and literature review. AB - Undifferentiated carcinoma of the gallbladder is a rare cancer type with a poor prognosis. The present study described a case of undifferentiated gallbladder carcinoma of the spindle- and giant-cell type, according to the 2010 World Health Organization classification. Hematoxylin and eosin staining revealed that the tumor consisted of dense interlacing bundles of spindle-shaped cells. No evidence of cartilaginous, osseous or rhabdomyosarcomatous differentiation was observed. Immunohistochemical staining revealed that spindle- and polygonal-shaped cells of the undifferentiated carcinoma were positive for cytokeratin AE1/3, vimentin and vascular endothelial growth factor. Furthermore, numerous spindle-shaped cells were positive for cluster of differentiation (CD)34 and CD31, and certain spindle shaped cells were positive for Factor VIII. These results suggested classification of the present case as 'undifferentiated gallbladder carcinoma with endothelial differentiation'. PMID- 28101356 TI - A case report of primary cutaneous natural killer/T-cell lymphoma. AB - Primary cutaneous extranodal natural killer/T-cell lymphoma, nasal type (ENKL-NT) is a relatively rare disease associated with aggressive tumor-cell behavior and poor prognosis. Progress in immunohistochemistry has improved the identification of ENKL-NT. The present case study reported on a 64-year-old female patient presenting with several red nodular lesions on the neck developed over four months. Cutaneous biopsy revealed these cells were positive for CD3, CD56, CD5, CD8 and negative for CD2, CD34, CD7, CD20 and Granzyme B. A computed tomography scan and bone marrow biopsy did not show any abnormalities and a diagnosis of primary cutaneous ENKL-NT was made. After treatment with chemotherapy regimens comprising cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), followed by high-dose treatment with methotrexate, dexamethasone, ifosfamide, etoposide and L-asparaginasum (SMILE), the patient succumbed to the disease. The present study exemplified that immunohistochemical analysis as well as the recognition of atypical lymphoid cells showing angiocentricity is crucial for the correct diagnosis of ENKL-NT. The prognosis of primary cutaneous ENKL-NT remains poor. As the CHOP regimen is not completely effective, high-dose chemotherapy, such as the SMILE regimen, is required. PMID- 28101357 TI - Treatment of synchronous adenocarcinoma and lymphoma of the stomach: A case report. AB - Gastric cancer is one of the leading causes of cancer-related mortality worldwide. The majority of gastric cancers are diagnosed at an advanced or metastatic stage, with a 5-year survival rate of ~5-20% and a median overall survival of <1 year. Synchronous occurrence of gastric adenocarcinoma and lymphoma is rare, and thus far there is no consensus regarding their management. We herein describe a case of synchronous gastric adenocarcinoma and diffuse large B-cell lymphoma in a patient with chronic hepatitis B and the treatment strategy. A literature review with the most up-to-date treatment options and their application in similar situations was also performed. PMID- 28101359 TI - Effect of combined treatment with micelle-incorporated cisplatin (NC-6004) and S 1 on human gastric cancer xenografts. AB - Combination therapy with S-1 and cisplatin (CDDP) is the standard chemotherapy for advanced gastric cancer in Japan; however, its administration requires hospitalization for hydration to prevent nephrotoxicity from CDDP. By contrast, NC-6004 appears to reduce the renal toxicity of CDDP and may be used on an outpatient basis. Thus, the effects of combined treatment with S-1 and NC-6004 were compared with those of S-1 and CDDP in a human gastric cancer model. In vitro cytotoxic effects were investigated in 44As3Luc, MKN45 and MKN74 human gastric cancer cell lines. The effects of NC-6004 and 5-fluorouracil (5-FU) were compared with the effects of CDDP and 5-FU using the combination index method. The in vivo antitumor effects of S-1/NC-6004 and S-1/CDDP were evaluated in mice bearing 44As3Luc xenografts. Both combinations exhibited synergistic activity in MKN45 and MKN74 cells and additive effects in 44As3Luc cells. Moreover, the in vivo antitumor effects did not differ between the S-1/NC-6004 and S-1/CDDP treatment groups. However, a significantly lower body weight loss was observed in S-1/NC-6004-treated mice compared with the S-1/CDDP-treated mice. Our data warrant a clinical evaluation of S-1/NC-6004 combination therapy. PMID- 28101358 TI - Novel predictive biomarkers for cervical cancer prognosis. AB - High hypoxic, glycolytic and acidosis metabolisms characterize cervical cancer tumors and have been described to be involved in chemoradioresistance mechanisms. Based on these observations, the present study assessed four selected novel biomarkers on the prognosis of locally advanced cervical carcinoma. A total of 66 patients with stage IIB/IIIB cervical cancer were retrospectively included. The protein expression levels of glucose transporter 1 (GLUT1), carbonic anhydrase 9 (CAIX) and hexokinase 1 (HKII) were investigated by immunohistochemistry on tumor biopsies, hemoglobin was measured and the disease outcome was monitored. A total of 53 patients (80.3%) presented a complete response. For these patients, the protein expression levels of GLUT1, CAIX and HKII were overexpressed. A significant difference was observed (P=0.0127) for hemoglobin levels (<=11 g/dl) in responsive compared with non-responsive patients. The expression of GLUT1 is associated with a lower rate of both overall and disease-free survival, with a trend of decreased risk of 1.1x and 1.5x, respectively. Co-expression of GLUT1 and HKII is associated with a decreased trend risk of 1.6x for overall survival. Patients with hemoglobin levels <=11 g/dl had a 4.3-fold risk (P=0.02) in decreasing both to the rate of overall and disease-free survival. The presence of anemic hypoxia (hemoglobin <=11 g/dl) and the expression of GLUT1 and/or HKII influence treatment response and are associated with a lower overall and disease free survival. The present results demonstrated that these biomarkers may be used as predictive markers and suggested that these metabolic pathways can be used as potential novel therapeutic targets. PMID- 28101360 TI - Successful treatment of anti-NMDA receptor encephalitis with a prompt ovarian tumour removal and prolonged course of plasmapheresis: A case report. AB - Anti-N-methyl-d-aspartate-receptor (NMDAR) encephalitis is an uncommon autoimmune disorder with a wide spectrum of neuropsychiatric symptoms. There is a great requirement to emphasize the importance of a multidisciplinary team approach in the process of diagnosis and treatment of the potentially fatal condition, including psychiatrists, neurologists, gynaecologists and intensivists. Physicians must be aware that psychiatric and neurological disorders, which are typical features for NMDAR encephalitis in young women with ovarian tumours, may progress into status epilepticus and respiratory insufficiency. This disease can only be successfully treated with prompt surgical intervention and an early implementation of a wide array of immunosuppressive therapies. Optimal timing of initiation of therapeutic plasma exchange, as well as duration of treatment necessary to achieve desirable outcomes in patients with NMDAR remains unknown. The present case report aims to raise awareness about the importance of early implementation of this potentially life-saving therapy and continuing the treatment courses until full subsidence of symptoms. PMID- 28101362 TI - Erratum: Sialoblastoma of the cheek: A case report and review of the literature. AB - [This corrects the article DOI: 10.3892/mco.2016.840.]. PMID- 28101361 TI - Bronchoscopic resection of bronchial angiolipoma: A rare case report. AB - Angiolipoma is a rare benign tumor that most commonly occurs in the extremities and trunk. Angiolipomas originating in the bronchial tree are extremely rare. To the best of our knowledge, only one such case, confined to the bronchus intermedius, has been reported to date. The present study describes the case of an asymptomatic 74-year-old man with a yellowish round mass incidentally discovered at the orifice of the right lower bronchus during a routine health check. The tumor originated from the membranous part of the right inferior bronchus. Using a high-frequency electric snare and argon plasma coagulation under general anesthesia, successful bronchoscopic resection of the tumor was performed. At 15 months after the surgery, the patient remained recurrence- and symptom-free. PMID- 28101364 TI - Hemodynamic effects of electrical muscle stimulation in the prophylaxis of deep vein thrombosis for intensive care unit patients: a randomized trial. AB - BACKGROUND: Deep vein thrombosis (DVT) is a major complication in critical care. There are various methods of prophylaxis, but none of them fully prevent DVT, and each method has adverse effects. Electrical muscle stimulation (EMS) could be a new effective approach to prevent DVT in intensive care unit (ICU) patients. We hypothesized that EMS increases the venous flow of the lower limbs and has a prophylactic effect against the formation of DVT. METHODS: This study included 26 patients admitted to a single ICU. We enrolled patients who could not move themselves due to spinal cord injury, head injury, central nervous system abnormalities, and sedation for mechanical ventilation. The patients were randomly allocated to either the EMS group or the control group. Patients in the EMS group received 30-min sessions of EMS applied to the bilateral lower extremities on arbitrary days within 14 days after admission. The control patients received no EMS. The peak flow velocity and diameter of the popliteal vein (Pop.V) and common femoral vein (CFV) were measured by ultrasound and then the volumes of venous flow were calculated using a formula. RESULTS: There were no statistically significant differences in patient characteristics between the two groups except for the mortality rate. In the EMS group, the median and interquartile range (IQR, 25th-75th percentile) of velocities of the Pop.V and CFV were higher during EMS compared with at rest: 10.6 (8.0-14.8) vs 24.5 (15.1 37.8) cm/s and 17.0 (12.3-23.8) vs 24.3 (17.0-33.0) cm/s, respectively (p < 0.05). The median (IQR) of volumes of venous flow of the Pop.V and CFV at rest and during EMS were 4.2 (2.7-7.2) vs 8.6 (5.4-16.1) cm3/s and 12.9 (9.7-21.4) vs 20.8 (12.3-34.1) cm3/s, respectively (p < 0.05). There were no major complications related to EMS. CONCLUSIONS: EMS increased the venous flow of the lower limbs. EMS could be one potential method for venous thromboprophylaxis. TRIAL REGISTRATION: UMIN000013642. PMID- 28101365 TI - Comments to Role of upper airway ultrasound in airway management. AB - Tracheal ultrasound can be an alternative diagnostic tool in airway management, besides traditional confirmatory methods such as capnography and auscultation. The standard image is a hyperechoic air-mucosa (A-M) interface with a reverberation artifact posteriorly (comet-tail artifact). If the second A-M interface appears, which we call a "double-tract sign," esophageal intubation is considered. PMID- 28101363 TI - Hormonal, chemical and thermal inhibition of spermatogenesis: contribution of French teams to international data with the aim of developing male contraception in France. AB - Since the 1970s, international research on male contraception has been actively pursued. Hormonal and non-hormonal methods (thermal, chemical) have been tested, leading to clinical trials of interest to thousands of men and couples. The results showed that it was possible to develop methods of male contraception that inhibited spermatogenesis with good contraceptive efficacy. However, their side effects (mainly loss of libido), poorly accepted modes of administration, and the high frequency of poor responders prevented their widespread use. Based on earlier initiatives, new avenues were explored and significant progress was achieved, allowing the reasoned use of male contraception. For 40 years, several French teams have played an important role in this research. The aim of this paper is to outline the history and the progress of the experimental and clinical works of these teams who addressed hormonal, chemical and thermal approaches to male contraception. These approaches have led to a better comprehension of spermatogenesis that could be useful in fields other than male contraception: effects of toxic compounds, fertility preservation. PMID- 28101367 TI - Contribution of point and small-scaled sources to the PM10 emission using positive matrix factorization model. AB - BACKGROUND: The positive matrix factorization is a powerful environmental analysis technique which has been successfully utilized to assess air-born particulate matter source contribution. The new version of this model (PMF5) has two additional estimation error methods and some other useful advantages compared to the previous versions. In the present study, the capability of PMF5 for identification and contribution of small size particle source to the ambient particulate matter was evaluated. METHODS: The study area is surrounded by three industrial complexes and 2 locations of dumped tailing soils of mining activities and related manufactures. Ambient particulate matter were sampled at 2 sites in the urban area of Zanjan (Iran) and 196 collected samples were analyzed for 15 chemical elements. RESULTS: At downtown, the identified factors (and their contributions to particulate matter) were: soil particles (40.36%), fuel combustion and traffic (26.8%), tailing soils (lead and zinc) (21.32%), and nickel and industrial emission(5.7%). The identified factors at residential site of studied area (and their contributions to particulate matter) were general industrial emission (28.2%), tailing soils (lead and zinc) (39.2%), soil (25.8%), cadmium and general pollutants (6.7%). CONCLUSION: The results of modeled data by PMF 5 indicated that the applied model could identify the dumps of tailing soils as a separated factor. The other particulate matter sources in the studied area were traffic, fuel combustion, soil particles and industrial pollutants. PMID- 28101366 TI - Weighting Criteria and Prioritizing of Heat stress indices in surface mining using a Delphi Technique and Fuzzy AHP-TOPSIS Method. AB - BACKGROUND: Heat stress as a physical harmful agent can increase the risk of health and safety problems in different workplaces such as mining. Although there are different indices to assess the heat stress imposed on workers, choosing the best index for a specific workplace is so important. Since various criteria affect an index applicability, extracting the most effective ones and determining their weights help to prioritize the existing indices and select the optimal index. METHODS: In order to achieve this aim, present study compared some heat stress indices using effective methods. The viewpoints of occupational health experts and the qualitative Delphi methods were used to extract the most important criteria. Then, the weights of 11 selected criteria were determined by Fuzzy Analytic Hierarchy Process. Finally, fuzzy TOPSIS technique was applied for choosing the most suitable heat stress index. RESULTS: According to result, simplicity, reliability, being low cost, and comprehensiveness were the most determinative criteria for a heat stress index. Based on these criteria and their weights, the existing indices were prioritized. Eventually, wet bulb glob temperature appropriated the first priority and it was proposed as an applicable index for evaluating the heat stress at outdoor hot environments such as surface mines. CONCLUSIONS: The use of these strong methods allows introducing the most simple, precise, and applicable tool for evaluation the heat stress in hot environments. It seems that WBGT acts as an appropriate index for assessing the heat stress in mining activities at outdoors. PMID- 28101369 TI - A single gene controls leaf background color in caladium (Araceae) and is tightly linked to genes for leaf main vein color, spotting and rugosity. AB - Modern cultivated caladiums (Caladium*hortulanum) are grown for their long lasting and colorful leaves. Understanding the mode of inheritance for caladium leaf characteristics is critical for plant breeders to select appropriate parents, predict progeny performance, estimate breeding population sizes needed, and increase breeding efficiencies. This study was conducted to determine the mode of inheritance of two leaf background colors (lemon and green) in caladium and to understand their relationships with four other important leaf characteristics including leaf shape, main vein color, spotting, and rugosity. Seven caladium cultivars and three breeding lines were used as parents in 19 crosses, and their progeny were phenotyped for segregation of leaf traits. Results showed that the two leaf background colors are controlled by a single nuclear locus, with two alleles, LEM and lem, which control the dominant lemon and the recessive green leaf background color, respectively. The lemon-colored cultivar 'Miss Muffet' and breeding lines UF-52 and UF-53 have a heterozygous genotype LEMlem. Chi-square tests showed that the leaf background color locus LEM is independent from the leaf shape locus F, but is tightly linked to three loci (S, V and RLF) controlling leaf spotting, main vein color, and rugosity in caladium. A linkage map that consists of four loci controlling major caladium leaf characteristics and extends ~15 cM was developed based on the observed recombination frequencies. This is the first report on the mode of inheritance of leaf background colors in caladium and in the Araceae family. The information gained in this study will be very useful for caladium breeding and study of the inheritance of leaf colors in other ornamental aroids, an important group of ornamental plants in the world. PMID- 28101368 TI - Polymorphisms in the canine monoamine oxidase a (MAOA) gene: identification and variation among five broad dog breed groups. AB - BACKGROUND: In humans, reduced activity of the enzyme monoamine oxidase type A (MAOA) due to genetic polymorphisms within the MAOA gene leads to increased brain neurotransmitter levels associated with aggression. In order to study MAOA genetic diversity in dogs, we designed a preliminary study whose objectives were to identify novel alleles in functionally important regions of the canine MAOA gene, and to investigate whether the frequencies of these polymorphisms varied between five broad breed groups (ancient, herding, mastiff, modern European, and mountain). Fifty dogs representing these five breed groups were sequenced. RESULTS: A total of eleven polymorphisms were found. Seven were single nucleotide polymorphisms (SNPs; two exonic, two intronic and three in the promoter), while four were repeat intronic variations. The most polymorphic loci were repeat regions in introns 1, 2 (7 alleles) and 10 (3 alleles), while the exonic and the promoter regions were highly conserved. Comparison of the allele frequencies of certain microsatellite polymorphisms among the breed groups indicated a decreasing or increasing trend in the number of repeats at different microsatellite loci, as well as the highest genetic diversity for the ancient breeds and the lowest for the most recent mountain breeds, perhaps attributable to canine domestication and recent breed formation. While a specific promoter SNP (-212A > G) is rare in the dog, it is the major allele in wolves. Replacement of this ancestral allele in domestic dogs may lead to the deletion of heat shock factor binding sites on the MAOA promoter. CONCLUSIONS: Dogs exhibit significant variation in certain intronic regions of the MAOA gene, while the coding and promoter regions are well-conserved. Distinct genetic differences were observed between breed groups. Further studies are now required to establish whether such polymorphisms are associated in any way with MAOA level and canine behaviour including aggression. PMID- 28101370 TI - Recurrent ovarian Sertoli-Leydig cell tumor in a child with Peutz-Jeghers syndrome. AB - We present a female child with Peutz-Jeghers syndrome (PJS) with a recurrent ovarian Sertoli-Leydig cell tumor (SLCT). SLCTs are relatively rare sex cord neoplasms that can occur in PJS. The patient was an African-American female who first presented at the age of 3 years with precocious puberty, and then at the age of 17 years with abdominal pain and irregular menses. In each case, she had resection of the mass, which included oophorectomy. To our knowledge, this is the first reported case in a child with PJS to have a recurrent ovarian SLCT. PMID- 28101371 TI - A novel PLP1 mutation F240L identified in a patient with connatal type Pelizaeus Merzbacher disease. AB - Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive hypomyelination disorder caused by mutations in the proteolipid protein 1 gene (PLP1) located on chromosome Xq22. A male patient showed severe developmental delay, pendular nystagmus and laryngeal wheezing. The auditory brain stem response showed only the first wave and brain magnetic resonance imaging showed white matter hypomyelination, suggesting typical PMD. A novel PLP1 mutation, F240L, which was inherited from his mother, was identified. PMID- 28101372 TI - Lessons I have learned from my patients: everyday life with primary orthostatic tremor. AB - BACKGROUND: Primary orthostatic tremor is a rare disorder that is still under diagnosed or misdiagnosed. Motor symptoms are fairly characteristics but the real impact on the patient's every day life and quality of life is under-estimated. The "how my patients taught me" format describes the impact on the patients' every day life with their own words, which is rarely done. CASE PRESENTATION: A 46 year old lady was diagnosed primary orthostatic tremor (POT) based on the cardinal symptoms: feelings of instability, leg tremor and fear of falling in the standing position, improvement with walking and disappearance while sitting, frequency of Tremor in the 13-18Hz range, normal neurological examination. She gives illustrative examples of her disability in every day life activity (shower, public transportation, shopping). She reports how she felt stigmatized by her "invisible disorder". As a consequence, she developed anxiety depression and social phobia. All these troubles are unknown or under recognized by doctors and family. CONCLUSIONS: We review the clinical signs of POT that may help to increase the awareness of doctors and improve the diagnosis accuracy, based on the motor symptoms and description of the every day life disability, as reported by the patient. Non-motor symptoms (including somatic concerns, anxiety, depression, and social phobia) should be better considered in POT as they have a major impact on quality of life. Pharmacological treatments (clonazepam, gabapentin) may be helpful but have a limited effect over the years as the patients experience a worsening of their condition. On the long term follow-up, there are still unmet needs in POT, and new therapeutic avenues may be based on the pathophysiology by modulating the cerebello-thalamo-cortical network. PMID- 28101373 TI - Optimizing maternal and neonatal outcomes with postpartum contraception: impact on breastfeeding and birth spacing. AB - Postpartum contraception is important to prevent unintended pregnancies. Assisting women in achieving recommended inter-pregnancy intervals is a significant maternal-child health concern. Short inter-pregnancy intervals are associated with negative perinatal, neonatal, infant, and maternal health outcomes. More than 30% of women experience inter-pregnancy intervals of less than 18 months in the United States. Provision of any contraceptive method after giving birth is associated with improved inter-pregnancy intervals. However, concerns about the impact of hormonal contraceptives on breastfeeding and infant health have limited recommendations for such methods and have led to discrepant recommendations by organizations such as the World Health Organization and the U.S. Centers for Disease Control and Prevention. In this review, we discuss current recommendations for the use of hormonal contraception in the postpartum period. We also discuss details of the lactational amenorrhea method and effects of hormonal contraception on breastfeeding. Given the paucity of high quality evidence on the impact on hormonal contraception on breastfeeding outcomes, and the strong evidence for improved health outcomes with achievement of recommended birth spacing intervals, the real risk of unintended pregnancy and its consequences must not be neglected for fear of theoretical neonatal risks. Women should establish desired hormonal contraception before the risk of pregnancy resumes. With optimization of postpartum contraception provision, we will step closer toward a healthcare system with fewer unintended pregnancies and improved birth outcomes. PMID- 28101374 TI - Arginine methylation of USP9X promotes its interaction with TDRD3 and its anti apoptotic activities in breast cancer cells. AB - The Tudor domain-containing proteins are characterized by their specific interactions with methylated protein motifs, including methyl-arginines and methyl-lysines. The Tudor domain-containing protein 3 (TDRD3) is one of the major methyl-arginine effector molecules that recognizes methylated arginine residues on histones and the C-terminal domain of RNA polymerase II, and activates transcription. However, majority of the cellular TDRD3 localizes to the cytoplasm and its functions there are still elusive. Here, we have identified ubiquitin specific protease 9 X-linked (USP9X) as a TDRD3-interacting protein by GST (glutathione S-transferase) pull-down and co-immunoprecipitation. Detailed characterization suggests that the interaction between TDRD3 and USP9X is mediated through the Tudor domain of TDRD3 and the arginine methylation of USP9X. This interaction plays a critical role in TDRD3 protein stability, as knockdown of USP9X expression leads to increased TDRD3 ubiquitination. We also found that USP9X co-localizes with TDRD3 in cytoplasmic stress granules and this localization is diminished in Tdrd3-null mouse embryonic fibroblast cells, suggesting that TDRD3 is essential for USP9X stress granule localization. Furthermore, we found that one of the USP9X de-ubiquitination targets, myeloid cell leukemia protein 1, is regulated by TDRD3, indicating that TDRD3 potentially regulates USP9X de-ubiquitinase activity. Finally, we show that knockdown of TDRD3 expression sensitizes breast cancer cells to chemotherapeutic drug-induced apoptosis, likely due to its regulation of USP9X. This study provides a novel candidate strategy for targeting apoptosis pathways in cancer therapy. PMID- 28101375 TI - Aurora-A promotes the establishment of spindle assembly checkpoint by priming the Haspin-Aurora-B feedback loop in late G2 phase. AB - Aurora-A kinase functions mainly in centrosome maturation, separation and spindle formation. It has also been found to be amplified or overexpressed in a range of solid tumors, which is linked with tumor progression and poor prognosis. Importantly, Aurora-A inhibitors are being studied in a number of ongoing clinical trials. However, whether and how Aurora-A has a role in the regulation of the mitotic checkpoint is controversial. Additionally, the function of nuclear accumulated Aurora-A in late G2 phase is not clear. Here we show that knockout, inhibition or blockade of the nuclear entry of Aurora-A severely decreased the centromere localization of Aurora-B and the phosphorylation of histone H3 threonine 3 (H3T3-ph) mediated by the kinase Haspin in late G2 phase. We further reveal that nuclear-accumulated Aurora-A phosphorylates Haspin at multiple sites at its N-terminus and that this promotes H3T3-ph and the rapid recruitment to the centromere of the chromosomal passenger complex. In addition, Aurora-A facilitates the association of Aurora-B with their common substrates: Haspin and Plk1. Notably, these functions of Aurora-A are mostly independent of Plk1. Thus we demonstrate that, in late G2 and prophase, Aurora-A phosphorylates Haspin to trigger the Haspin-H3T3-ph-Aurora-B positive feedback loop that supports the timely establishment of the chromosomal passenger complex and the mitotic checkpoint before spindle assembly. PMID- 28101377 TI - Erratum: A unified molecular mechanism for the regulation of acetyl-CoA carboxylase by phosphorylation. AB - [This corrects the article DOI: 10.1038/celldisc.2016.44.]. PMID- 28101378 TI - Changes of the Macular Ganglion Cell-Inner Plexiform Layer Thickness after Cataract Surgery in Glaucoma Patients. AB - Purpose. To investigate the effect of uneventful cataract surgery on macular ganglion cell-inner plexiform layer (mGC-IPL) thickness in glaucoma patients. Methods. This retrospective study included 65 eyes of 65 subjects who underwent uneventful cataract surgery, including 13 glaucoma eyes and 52 normal eyes. Using spectral domain optical coherence tomography, the mGC-IPL thickness was measured and compared between glaucoma and normal eyes preoperatively as well as 1 month and 3 months postoperatively. Linear regression analysis was used to determine the factors associated with postoperative change in mGC-IPL thickness. Results. The mean mGC-IPL significantly increased in both groups 1 month and 3 months after surgery (all P values equal to or less than 0.001). The postoperative changes between groups were not significantly different (P = 0.171). In the multivariate regression analysis, preoperative mGC-IPL thickness showed a significant association with the change of average mGC-IPL thickness 1 month and 3 months after surgery (all P values < 0.001). Conclusions. The mean mGC-IPL thickness was increased after cataract surgery, and the postoperative mGC-IPL thickness changes were associated with preoperative mGC-IPL thickness in both groups and axial length in normal eye. The effects of cataract surgery on mean mGC-IPL thickness were not different in glaucomatous and normal eyes. PMID- 28101376 TI - ATPase activity tightly regulates RecA nucleofilaments to promote homologous recombination. AB - Homologous recombination (HR), catalyzed in an evolutionarily conserved manner by active RecA/Rad51 nucleofilaments, maintains genomic integrity and promotes biological evolution and diversity. The structures of RecA/Rad51 nucleofilaments provide information critical for the entire HR process. By exploiting a unique capillary electrophoresis-laser-induced fluorescence polarization assay, we have discovered an active form of RecA nucleofilament, stimulated by ATP hydrolysis, that contains mainly unbound nucleotide sites. This finding was confirmed by a nuclease protection assay and electron microscopy (EM) imaging. We further found that these RecA-unsaturated filaments promote strand exchange in vitro and HR in vivo. RecA mutants (P67D and P67E), which only form RecA-unsaturated nucleofilaments, were able to mediate HR in vitro and in vivo, but mutants favoring the formation of the saturated nucleofilaments failed to support HR. We thus present a new model for RecA-mediated HR in which RecA utilizes its intrinsic DNA binding-dependent ATPase activity to remodel the nucleofilaments to a less saturated form and thereby promote HR. PMID- 28101379 TI - The Effect of Eighteen-Month Metformin Treatment in Obese Adolescents: Comparison of Results Obtained in Daily Practice with Results from a Clinical Trial. AB - Background. In a recent randomized controlled trial (RCT) in obese adolescents, 18 month-treatment with metformin versus placebo was reported to lead to stabilisation of the BMI. This study aimed to compare the effect of metformin on BMI in obese adolescents in daily practice versus results obtained in an RCT. Methods. Obese adolescents treated off label with metformin in daily practice in an outpatient clinic with a follow-up of >=18 months were identified. Anthropometric and biochemical data were collected at baseline and at 18 months. Patients treated with metformin for 18 months in an RCT were used for comparison. BMI was compared between the two groups. Results. Nineteen patients (median age 14.3 (interquartile range 11.7-15.7) years, BMI 31.3 (28.8-33.8) kg/m2) treated in daily practice were compared to 23 patients receiving metformin in the RCT (age 13.6 (12.6-15.3) years, BMI 29.8 (28.1-34.5) kg/m2). BMI change after 18 months was -0.36 (-2.10-1.58) versus +0.22 (-2.87-1.27) kg/m2 for the two groups, respectively. In the multivariable model, BMI change was not statistically significantly different between the two groups (p = 0.61). Conclusion. Treatment with metformin in obese adolescents in daily practice resulted in a comparable change in BMI as observed in an RCT. This trial is registered with ClinicalTrials.gov number: NCT01487993. PMID- 28101380 TI - Perinatal Risks Associated with Early Vanishing Twin Syndrome following Transfer of Cleavage- or Blastocyst-Stage Embryos. AB - Objective. To investigate whether the perinatal risks associated with early vanishing twin (VT) syndrome differ between cleavage- or blastocyst-stage embryo transfers (ET) in fresh in vitro fertilization (IVF) cycles. Methods. Retrospective, single-center, cohort study of IVF cycles with fresh cleavage- or blastocyst-stage ETs resulting in a live singleton birth. The incidence of preterm birth (PTB), low birth weight (LBW), and very low birth weight (VLBW) was compared between cleavage- and blastocyst-stage ET cycles complicated by early VT. Results. 7241 patients had live singleton births. Early VT was observed in 709/6134 (11.6%) and 70/1107 (6.32%) patients undergoing cleavage-stage and blastocyst-stage ETs, respectively. Patients in the blastocyst-stage group were younger compared to the cleavage-stage group. The cleavage-stage group had a similar birth weight compared to the blastocyst-stage group. There was no difference in the incidence of PTB (9.87% versus 8.57%), LBW (11.1% versus 11.4%), or VLBW (1.13 versus 1.43%) when comparing the cleavage-stage early VT and blastocyst-stage early VT groups, even after adjustment with logistic regression. Conclusions. Our study highlights that the adverse perinatal risks of PTB, LBW, and VLBW associated with early VT syndrome are similar in patients undergoing cleavage-stage or blastocyst-stage ETs during fresh IVF cycles. PMID- 28101382 TI - Complete Resolution of Tumor Burden of Primary Cardiac Non-Hodgkin's Lymphoma. AB - Primary cardiac tumors are a rare set of benign and malignant neoplasms found in the heart or pericardium. We describe a patient presenting with nonspecific symptoms and ultimately diagnosed with primary cardiac non-Hodgkin's lymphoma (PCL). Our patient had extensive tumor in the right ventricle, which extended into the right atrium and right ventricular outflow tract. The tumor also encased the right coronary artery, which manifested as ischemic changes on EKG and cardiac MRI. The patient was treated with chemotherapy and achieved complete remission, with dramatic and full resolution of the mass on repeat echocardiography in nine weeks. More studies are needed to understand the optimal management and prognosis of patients with PCL. PMID- 28101381 TI - Loss of Myh14 Increases Susceptibility to Noise-Induced Hearing Loss in CBA/CaJ Mice. AB - MYH14 is a member of the myosin family, which has been implicated in many motile processes such as ion-channel gating, organelle translocation, and the cytoskeleton rearrangement. Mutations in MYH14 lead to a DFNA4-type hearing impairment. Further evidence also shows that MYH14 is a candidate noise-induced hearing loss (NIHL) susceptible gene. However, the specific roles of MYH14 in auditory function and NIHL are not fully understood. In the present study, we used CRISPR/Cas9 technology to establish a Myh14 knockout mice line in CBA/CaJ background (now referred to as Myh14-/- mice) and clarify the role of MYH14 in the cochlea and NIHL. We found that Myh14-/- mice did not exhibit significant hearing loss until five months of age. In addition, Myh14-/- mice were more vulnerable to high intensity noise compared to control mice. More significant outer hair cell loss was observed in Myh14-/- mice than in wild type controls after acoustic trauma. Our findings suggest that Myh14 may play a beneficial role in the protection of the cochlea after acoustic overstimulation in CBA/CaJ mice. PMID- 28101383 TI - Fibrous Dysplasia versus Juvenile Ossifying Fibroma: A Dilemma. AB - Fibrous dysplasia (FD) is a condition characterized by excessive proliferation of bone forming mesenchymal cells which can affect one bone (monostotic type) or multiple bones (polyostotic type). It is predominantly noticed in adolescents and young adults. Fibrous dysplasia affecting the jaws is an uncommon condition. The most commonly affected facial bone is the maxilla, with facial asymmetry being the chief complaint. The lesion in many instances is confused with ossifying fibroma (OF). Diagnosis of these two lesions has to be done based on clinical, radiographic, and microscopic findings. Here, we present a case of fibrous dysplasia of maxilla in a nine-year-old boy mimicking juvenile ossifying fibroma. PMID- 28101384 TI - Acrokeratosis Paraneoplastica Associated with Cervical Squamous Cell Carcinoma. AB - Background. Acrokeratosis paraneoplastica, or Bazex syndrome, is a paraneoplastic syndrome characterized by cutaneous psoriasiform lesions with associated acral erythema and scale, as well as nail changes, including onycholysis and ungual dystrophy. Its most advanced, severe form involves the trunk, elbows, and knees. It is typically associated with upper aerodigestive tract malignancies in males. Rare cases associated with gynecological cancers have been reported, including uterine adenocarcinoma, as well as ovarian and vulvar squamous cell carcinomas. Cutaneous manifestations often precede cancer diagnosis. In most reported cases, skin changes resolve when the underlying malignancy is adequately treated. Main Observations. We present the case of a 56-year-old female diagnosed with acrokeratosis paraneoplastica following the discovery of FIGO stage IIB cervical squamous cell carcinoma (SCC). Scaling, hyperpigmentation, xerosis, and fissuring were noted on the patient's hands, feet, legs, arms, and lower back. Pitting was noted on her fingernails. Her cervical cancer was successfully treated with chemoradiotherapy, after which her cutaneous lesions persisted for two months before resolving. Conclusions. The presentation of acrokeratosis paraneoplastica in this context is atypical. Reports of associations with gynecological cancers, as in our patient's case, are exceedingly rare. PMID- 28101385 TI - Kawasaki Shock Syndrome in a 12-Year-Old Girl Mimicking Septic Shock. AB - Kawasaki disease is diagnosed when fever lasts for more than 5 days with the presence of four out of five of the following clinical features: bilateral conjunctival congestion, changes in the lips and oral cavity, polymorphous exanthem, changes in peripheral extremities, and acute nonpurulent cervical lymphadenopathy (Nakamura et al., 2012). The average age of onset is 2 years and 90% of patients are below 5 years of age. Boys are more affected than girls (Cox and Sallis, 2009). This case report describes an adolescent female who was initially managed as having septic shock and subsequently found to have Kawasaki shock syndrome. PMID- 28101387 TI - Identification of Dietzia spp. from Cardiac Tissue by 16S rRNA PCR in a Patient with Culture-Negative Device-Associated Endocarditis: A Case Report and Review of the Literature. AB - The genus Dietzia was recently distinguished from other actinomycetes such as Rhodococcus. While these organisms are known to be distributed widely in the environment, over the past decade several novel species have been described and isolated from human clinical specimens. Here we describe the identification of Dietzia natronolimnaea/D. cercidiphylli by PCR amplification and sequencing of the 16S rRNA encoding gene from cardiac tissue in a patient with culture-negative device-associated endocarditis. PMID- 28101386 TI - A Rare Manifestation of Tuberculosis Presenting in the United States. AB - A 64-year-old Bangladeshi female presented to her primary care physician with a tender right breast lump that had been present for 4-5 days along with subjective fevers and malaise. Initial biopsy revealed granulomas, but Ziehl-Neelsen and Gram stain were negative for TB so antibiotics were prescribed for abscess until culture came positive for tuberculosis. She was started on triple therapy for extrapulmonary tuberculosis, an exceedingly rare presentation that requires high clinical suspicion in the Western world. PMID- 28101388 TI - Bilateral Moyamoya Disease in a 2-Year-Old Pakistani Male Treated with Bilateral Encephaloduroarteriosynangiosis: A Positive Outcome. AB - Background. We present a rare case of bilateral moyamoya disease presenting as multiple strokes and neurological deficits, treated with the neurosurgical procedure, encephaloduroarteriosynangiosis (EDAS), in a 2-year-old male Pakistani minor. A positive outcome was achieved and the patient recovered fully. Case Summary. Our patient presented with a history of seizures and multiple episodes of hemiparesis (on and off weakness) at the age of 2 years. He had a delayed speech development and could not speak more than a few words. He had a slight slurring of speech too. He was diagnosed with bilateral moyamoya disease on Computed Tomography Angiography (CTA). Bilateral EDAS was done in the same year, after which his symptoms improved and patient had moderate functional recovery. Conclusion. A rare disease, moyamoya has been left unexplored in Pakistan; physicians and surgeons when dealing with cases in the pediatric population presenting with symptoms of stroke, signs of generalized weakness, and seizures should consider moyamoya disease as a possibility. Furthermore, this case demonstrates the effectiveness of EDAS procedure for the treatment of moyamoya disease. PMID- 28101389 TI - Superior Patellar Dislocation Misdiagnosed as Patellar Tendon Rupture: The Value of Ultrasonography. AB - Superior dislocation of the patella with intact patellar tendon is a rare condition. Most cases in literatures were diagnosed by clinical examination and plain radiography; however there are many cases that were misdiagnosed as patellar tendon rupture. In this case, we demonstrate the use of ultrasound for diagnosis of superior dislocation of the patella in the emergency department. We also include a literature review of similar cases and discuss the advantages of different types of imaging for diagnosis in this condition. PMID- 28101390 TI - A Method of Using a Pelvic C-Clamp for Intraoperative Reduction of a Zone 3 Sacral Fracture. AB - It is challenging to properly reduce pelvic ring injuries that involve a zone 3 sacral fracture. Several open and closed reduction methods have been described. Percutaneous reductions are challenging, and improper reductions can have poor long-term outcomes. The pelvic C-clamp is a tool designed to provide emergency stabilization to patients suffering from c-type pelvic ring injuries. We describe a case in which a patient's open book pelvic ring injury with a zone three sacral fracture is reduced intraoperatively with the use of a pelvic C-clamp and stabilized with transsacral screws. PMID- 28101391 TI - Functional and Aesthetic Tragal Reconstruction in the Age of Mobile Electronic Devices. AB - We present a method to create a tragus using the patient's conchal cartilage. It is a simplified, single-stage technique with well-hidden incisions, yet it maintains the rigidity of a natural tragus. This patient did not have a history of radiation to the area, which may compromise healing with this technique. The cosmetic importance of the tragus has been described, but its functionality in accommodating modern technology has not been previously discussed. The main treatment goal for this patient was to gain the ability to wear earphones (clinical question/level of evidence: therapeutic, V). PMID- 28101392 TI - Acupuncture in the Treatment of a Female Patient Suffering from Chronic Schizophrenia and Sleep Disorders. AB - Background. The use of acupuncture in the treatment of sleep disorders in patients with chronic schizophrenia is investigated. Case Presentation. We report the case of a 44-year-old female outpatient of German origin who had been suffering from long-term schizophrenia and sleep disorders. The patient was treated with manual acupuncture weekly for 12 weeks, and a psychological assessment was performed before, immediately after, and three months after the acupuncture treatment period. In addition, actiwatch data were collected for 14 days both before and after the acupuncture treatment period. Conclusion. Acupuncture treatment led to a decrease in general psychopathology, less severe sleep problems, and markedly improved cognitive functioning (working memory) in the patient; however, the positive and the negative symptoms remained stable. The actiwatch data revealed a beneficial effect of acupuncture, showing better sleep latency, a trend towards better sleep efficiency, and a decrease in the number of minutes that the patient was awake during the night after acupuncture treatment. In sum, this study showed that acupuncture might be beneficial in the treatment of sleep disorders in patients suffering from chronic schizophrenia, but future, large, randomized (placebo), controlled, clinical trials are needed in order to replicate the present preliminary findings. PMID- 28101393 TI - Unusual Presentation of Tuberculous Thyroid Abscess in a Background of Hashimoto's Thyroiditis in a Chronic Hepatitis B Carrier. AB - Tuberculosis of thyroid gland is a very rare disease. It has variable presentations and may be sometimes associated with autoimmune thyroiditis. We report a case of 45-year-old male, with left sided painless neck swelling, with a purulent discharging sinus over it associated with night sweats and loss of appetite. Thyroid imaging disclosed heterogeneous enhancement of left lobe of thyroid gland with internal vascularity and coarse calcifications. Core needle biopsy revealed caseous necrosis and AFB positivity. Patient had thyroid peroxidase antibody and thyroglobulin antibody positivity and the rest of thyroid function tests were normal. Patient had positive Mantoux test, hepatitis B surface Ag, and low viral DNA. The patient was diagnosed as being a case of tuberculous abscess of thyroid gland and was put on antitubercular therapy for 2 months. Patient subsequently underwent left hemithyroidectomy when there was no response. Histopathological examination revealed tuberculosis of thyroid gland. A final diagnosis of tuberculous abscess of thyroid gland in a background of Hashimoto's thyroiditis in a chronic HBV carrier was made. Therefore, although rare tuberculosis of thyroid should be kept in mind as a differential diagnosis of thyroid swelling. PMID- 28101394 TI - Ancient Schwannoma of the Cauda Equina: Our Experience and Review of the Literature. AB - Ancient schwannomas (AS) are exceedingly rare variant of common schwannomas (CS). Only two cases involving the cauda equina region have been previously reported in literature. AS are typically associated with a higher histological degree of degenerative changes (Antoni B areas). It is of peculiar importance, according to our opinion, to outline that, because of their extremely slow growth (which explains the increase of the degenerative changes in respect to the CS) and their typical soft consistency in respect to their standard counterparts, AS usually imply an even better prognosis. PMID- 28101395 TI - Superior Mesenteric Artery Syndrome: A Case Report of Two Surgical Options, Duodenal Derotation and Duodenojejunostomy. AB - Superior mesenteric artery (SMA) syndrome is a rare cause of duodenal obstruction and its management is usually conservative with nasojejunal feeding. The pathophysiology entails the loss of the fat pad between the superior mesenteric artery and the abdominal aorta. This reduces the angle between the two vessels to less than 20 degrees with the resultant compression of the third part of the duodenum. The surgical management is usually a laparoscopic duodenojejunostomy. The two cases in our series had two different surgical procedures with good outcomes in both patients. The surgical management of each patient should be determined on its own merits irrespective of the standard of care. PMID- 28101396 TI - New Insights into the Effects of Several Environmental Parameters on the Relative Fitness of a Numerically Dominant Class of Evolved Niche Specialist. AB - Adaptive radiation in bacteria has been investigated using Wrinkly Spreaders (WS), a morphotype which colonises the air-liquid (A-L) interface of static microcosms by biofilm formation with a significant fitness advantage over competitors growing lower down in the O2-limited liquid column. Here, we investigate several environmental parameters which impact the ecological opportunity that the Wrinkly Spreaders exploit in this model system. Manipulation of surface area/volume ratios suggests that the size of the WS niche was not as important as the ability to dominate the A-L interface and restrict competitor growth. The value of this niche to the Wrinkly Spreaders, as determined by competitive fitness assays, was found to increase as O2 flux to the A-L interface was reduced, confirming that competition for O2 was the main driver of WS fitness. The effect of O2 on fitness was also found to be dependent on the availability of nutrients, reflecting the need to take up both for optimal growth. Finally, the meniscus trap, a high-O2 region formed by the interaction of the A-L interface with the vial walls, was also important for fitness during the early stages of biofilm formation. These findings reveal the complexity of this seemingly simple model system and illustrate how changes in environmental physicality alter ecological opportunity and the fitness of the adaptive morphotype. PMID- 28101397 TI - Statistical parametric mapping of stimuli evoked changes in total blood flow velocity in the mouse cortex obtained with extended-focus optical coherence microscopy. AB - Functional magnetic resonance (fMRI) imaging is the current gold-standard in neuroimaging. fMRI exploits local changes in blood oxygenation to map neuronal activity over the entire brain. However, its spatial resolution is currently limited to a few hundreds of microns. Here we use extended-focus optical coherence microscopy (xfOCM) to quantitatively measure changes in blood flow velocity during functional hyperaemia at high spatio-temporal resolution in the somatosensory cortex of mice. As optical coherence microscopy acquires hundreds of depth slices simultaneously, blood flow velocity measurements can be performed over several vessels in parallel. We present the proof-of-principle of an optimised statistical parametric mapping framework to analyse quantitative blood flow timetraces acquired with xfOCM using the general linear model. We demonstrate the feasibility of generating maps of cortical hemodynamic reactivity at the capillary level with optical coherence microscopy. To validate our method, we exploited 3 stimulation paradigms, covering different temporal dynamics and stimulated limbs, and demonstrated its repeatability over 2 trials, separated by a week. PMID- 28101398 TI - Wide-field retinal optical coherence tomography with wavefront sensorless adaptive optics for enhanced imaging of targeted regions. AB - The peripheral retina of the human eye offers a unique opportunity for assessment and monitoring of ocular diseases. We have developed a novel wide-field (>70 degrees ) optical coherence tomography system (WF-OCT) equipped with wavefront sensorless adaptive optics (WSAO) for enhancing the visualization of smaller (<25 degrees ) targeted regions in the peripheral retina. We iterated the WSAO algorithm at the speed of individual OCT B-scans (~20 ms) by using raw spectral interferograms to calculate the optimization metric. Our WSAO approach with a 3 mm beam diameter permitted primarily low- but also high- order peripheral wavefront correction in less than 10 seconds. In preliminary imaging studies in five normal human subjects, we quantified statistically significant changes with WSAO correction, corresponding to a 10.4% improvement in average pixel brightness (signal) and 7.0% improvement in high frequency content (resolution) when visualizing 1 mm (~3.5 degrees ) B-scans of the peripheral (>23 degrees ) retina. We demonstrated the ability of our WF-OCT system to acquire non wavefront corrected wide-field images rapidly, which could then be used to locate regions of interest, zoom into targeted features, and visualize the same region at different time points. A pilot clinical study was conducted on seven healthy volunteers and two subjects with prodromal Alzheimer's disease which illustrated the capability to image Drusen-like pathologies as far as 32.5 degrees from the fovea in un-averaged volume scans. This work suggests that the proposed combination of WF-OCT and WSAO may find applications in the diagnosis and treatment of ocular, and potentially neurodegenerative, diseases of the peripheral retina, including diabetes and Alzheimer's disease. PMID- 28101400 TI - Choriocapillaris evaluation in choroideremia using optical coherence tomography angiography. AB - The choriocapillaris plays an important role in supporting the metabolic demands of the retina. Studies of the choriocapillaris in disease states with optical coherence tomography angiography (OCTA) have proven insightful. However, image artifacts complicate the identification and quantification of the choriocapillaris in degenerative diseases such as choroideremia. Here, we demonstrate a supervised machine learning approach to detect intact choriocapillaris based on training with results from an expert grader. We trained a random forest classifier to evaluate en face structural OCT and OCTA information along with spatial image features. Evaluation of the trained classifier using previously unseen data showed good agreement with manual grading. PMID- 28101399 TI - Stimulus-evoked outer segment changes occur before the hyperpolarization of retinal photoreceptors. AB - Transient retinal phototropism (TRP) has been predominantly observed in rod photoreceptors activated by oblique visible light stimulation. Dynamic confocal microscopy and optical coherence tomography (OCT) have revealed rod outer segment (ROS) movement as the physical source of TRP. However, the physiological source of ROS movement is still not well understood. In this study, concurrent near infrared imaging of TRP and electroretinogram (ERG) measurement of retinal electrophysiology revealed that ROS movement occurs before the onset of the ERG a wave, which is known to reflect the hyperpolarization of retinal photoreceptors. Moreover, substitution of normal superfusing medium with low-sodium medium reversibly blocked the photoreceptor ERG a-wave, but largely preserved the stimulus-evoked ROS movements. Our experimental results and theoretical analysis indicate that early, disc-based stages of the phototransduction cascade, which occur before the hyperpolarization of retinal photoreceptors, contribute to the TRP associated ROS movement. PMID- 28101401 TI - Human heart failure biomarker immunosensor based on excessively tilted fiber gratings. AB - A label-free immunosensor platform based on excessively tilted fiber gratings (Ex TFGs) was developed for highly specific and fast detection of human N-terminal pro-B-type natriuretic peptide (NT-proBNP), which is considered a powerful biomarker for prognosis and risk stratification of heart failure (HF). High purity anti-NT-proBNP monoclonal antibodies (MAbs) prepared in our laboratory were immobilized on fiber surface through the staphylococcal protein A (SPA) method for subsequent specific binding of the targeted NT-proBNP. Utilizing fiber optic grating demodulation system (FOGDS), immunoassays were carried out in vitro by monitoring the resonance wavelength shift of Ex-TFG biosensor with immobilized anti-NT-proBNP MAbs. Lowest detectable concentration of ~0.5ng/mL for NT-proBNP was obtained, and average sensitivity for NT-proBNP at a concentration range of 0~1.0 ng/mL was approximately 45.967 pm/(ng/mL). Several human serum samples were assessed by the proposed Ex-TFG biomarker sensor, with high specificity for NT proBNP, indicating potential application in early diagnosing patients with acute HF symptoms. PMID- 28101402 TI - Identification and removal of laser-induced noise in photoacoustic imaging using singular value decomposition. AB - Singular value decomposition (SVD) was used to identify and remove laser-induced noise in photoacoustic images acquired with a clinical ultrasound scanner. This noise, which was prominent in the radiofrequency data acquired in parallel from multiple transducer elements, was induced by the excitation light source. It was modelled by truncating the SVD matrices so that only the first few largest singular value components were retained, and subtracted prior to image reconstruction. The dependency of the signal amplitude and the number of the largest singular value components used for noise modeling was investigated for different photoacoustic source geometries. Validation was performed with simulated data and measured noise, and with photoacoustic images acquired from the human forearm and finger in vivo using L14-5/38 and L40-8/12 linear array clinical imaging probes. The use of only one singular value component was found to be sufficient to achieve near-complete removal of laser-induced noise from reconstructed images. This method has strong potential to increase image quality for a wide range of photoacoustic imaging systems with parallel data acquisition. PMID- 28101404 TI - Model for indirect laser surgery. AB - We present a theoretical model for laser cutting of biological tissue by a strongly heated fiber tip with a highly absorbing coating. A significant dependence of the cutting speed and cutting depth on the inclination angle of the scalpel to the surface when scattering exceeds absorption in the biological tissue is shown. Experimental evidences of this effect are presented. In the experiment, we used silica fiber with coating made of carbon and silicon organic varnish, the 0.97-um wavelength laser and porcine skin. The additional opportunity to increase the efficiency of cutting by deposition of the absorbing layer on the tissue surface is considered. PMID- 28101403 TI - Quantitative assessment of hemodynamic and structural characteristics of in vivo brain tissue using total diffuse reflectance spectrum measured in a non-contact fashion. AB - Here we present a new methodology that investigates the intrinsic structural and hemodynamic characteristics of in vivo brain tissue, in a non-contact fashion, and can be easily incorporated in an intra-operative environment. Within this methodology, relative total diffuse reflectance spectra (RTD(lambda)) were acquired from targets using a hybrid spectroscopy imaging system. A spectral interpretation algorithm was subsequently applied to RTD(lambda) to retrieve optical properties related to the compositional and structural characteristics of each target. Estimation errors of the proposed methodology were computationally evaluated using a Monte Carlo simulation model for photon migration under various conditions. It was discovered that this new methodology could handle moderate noise and achieve very high accuracy, but only if the refractive index of the target is known. The accuracy of the technique was also validated using a series of tissue phantom studies, and consistent and accurate estimates of MUs'(lambda)/MUa(lambda) were obtained from all the phantoms tested. Finally, a small-scale animal study was conducted to demonstrate the clinical utility of the reported method, wherein a forepaw stimulation model was utilized to induce transient hemodynamic responses in somatosensory cortices. With this approach, significant stimulation-related changes (p < 0.001) in cortical hemodynamic and structural characteristics were successfully measured. PMID- 28101405 TI - Deep tissue photoacoustic computed tomography with a fast and compact laser system. AB - Photoacoustic computed tomography (PACT) holds great promise for biomedical imaging, but wide-spread implementation is impeded by the bulkiness of flash-lamp pumped laser systems, which typically weigh between 50 - 200 kg, require continuous water cooling, and operate at a low repetition rate. Here, we demonstrate that compact lasers based on emerging diode technologies are well suited for preclinical and clinical PACT. The diode-pumped laser used in this study had a miniature footprint (13 * 14 * 7 cm3), weighed only 1.6 kg, and outputted up to 80 mJ per pulse at 1064 nm. In vitro, the laser system readily provided over 4 cm PACT depth in chicken breast tissue. In vivo, in addition to high resolution, non-invasive brain imaging in living mice, the system can operate at 50 Hz, which enabled high-speed cross-sectional imaging of murine cardiac and respiratory function. The system also provided high quality, high frame rate, and non-invasive three-dimensional mapping of arm, palm, and breast vasculature at multi centimeter depths in living human subjects, demonstrating the clinical viability of compact lasers for PACT. PMID- 28101406 TI - Design and characterization of a combined OCT and wide field imaging falloposcope for ovarian cancer detection. AB - Early detection of ovarian cancer is only achieved in around 20% of women due to lack of effective screening. We propose a method for surveillance of high risk women based on a microendoscope introduced transvaginally to image the fallopian tubes and ovaries. This requires extreme miniaturization of the optics and catheter sheath. We describe the design of a falloposcope that combines optical coherence tomography (OCT) and wide field imaging into a sub-1 mm diameter package. We characterize the systems and show that they provide contrast on ex vivo samples of ovary and fallopian tube. In addition, we show the mechanical performance of the endoscope in an anatomically correct model of the female reproductive tract. PMID- 28101407 TI - Intraluminal laser speckle rheology using an omni-directional viewing catheter. AB - A number of disease conditions in luminal organs are associated with alterations in tissue mechanical properties. Here, we report a new omni-directional viewing Laser Speckle Rheology (LSR) catheter for mapping the mechanical properties of luminal organs without the need for rotational motion. The LSR catheter incorporates multiple illumination fibers, an optical fiber bundle and a multi faceted mirror to permit omni-directional viewing of the luminal wall. By retracting the catheter using a motor-drive assembly, cylindrical maps of tissue mechanical properties are reconstructed. Evaluation conducted in a test phantom with circumferentially-varying mechanical properties demonstrates the capability of the LSR catheter for the accurate mechanical assessment of luminal organs. PMID- 28101408 TI - In vivo visualization and ex vivo quantification of experimental myocardial infarction by indocyanine green fluorescence imaging. AB - The fluorophore indocyanine green accumulates in areas of ischemia-reperfusion injury due to an increase in vascular permeability and extravasation of the dye. The aim of the study was to validate an indocyanine green-based technique of in vivo visualization of myocardial infarction. A further aim was to quantify infarct size ex vivo and compare this technique with the standard triphenyltetrazolium chloride staining. Wistar rats were subjected to regional myocardial ischemia (30 minutes) followed by reperfusion (n = 7). Indocyanine green (0.25 mg/mL in 1 mL of normal saline) was infused intravenously for 10 minutes starting from the 25th minute of ischemia. Video registration in the near infrared fluorescence was performed. Epicardial fluorescence of indocyanine green corresponded to the injured area after 30 minutes of reperfusion. Infarct size was similar when determined ex vivo using traditional triphenyltetrazolium chloride assay and indocyanine green fluorescent labeling. Intravital visualization of irreversible injury can be done directly by fluorescence on the surface of the heart. This technique may also be an alternative for ex vivo measurements of infarct size. PMID- 28101409 TI - Assessment of corneal properties based on statistical modeling of OCT speckle. AB - A new approach to assess the properties of the corneal micro-structure in vivo based on the statistical modeling of speckle obtained from Optical Coherence Tomography (OCT) is presented. A number of statistical models were proposed to fit the corneal speckle data obtained from OCT raw image. Short-term changes in corneal properties were studied by inducing corneal swelling whereas age-related changes were observed analyzing data of sixty-five subjects aged between twenty four and seventy-three years. Generalized Gamma distribution has shown to be the best model, in terms of the Akaike's Information Criterion, to fit the OCT corneal speckle. Its parameters have shown statistically significant differences (Kruskal-Wallis, p < 0.001) for short and age-related corneal changes. In addition, it was observed that age-related changes influence the corneal biomechanical behaviour when corneal swelling is induced. This study shows that Generalized Gamma distribution can be utilized to modeling corneal speckle in OCT in vivo providing complementary quantified information where micro-structure of corneal tissue is of essence. PMID- 28101410 TI - Modulation of cardiomyocyte activity using pulsed laser irradiated gold nanoparticles. AB - Can photothermal gold nanoparticle mediated laser manipulation be applied to induce cardiac contraction? Based on our previous work, we present a novel concept of cell stimulation. A 532 nm picosecond laser was employed to heat gold nanoparticles on cardiomyocytes. This leads to calcium oscillations in the HL-1 cardiomyocyte cell line. As calcium is connected to the contractility, we aimed to alter the contraction rate of native and stem cell derived cardiomyocytes. A contraction rate increase was particularly observed in calcium containing buffer with neonatal rat cardiomyocytes. Consequently, the study provides conceptual ideas for a light based, nanoparticle mediated stimulation system. PMID- 28101412 TI - Visualization of micro-capillaries using optical coherence tomography angiography with and without adaptive optics. AB - The purpose of this work is to investigate the benefits of adaptive optics (AO) technology for optical coherence tomography angiography (OCTA). OCTA has shown great potential in non-invasively enhancing the contrast of vessels and small capillaries. Especially the capability of the technique to visualize capillaries with a lateral extension that is below the transverse resolution of the system opens unique opportunities in diagnosing retinal vascular diseases. However, there are some limitations of this technology such as shadowing and projection artifacts caused by overlying vasculature or the inability to determine the true extension of a vessel. Thus, the evaluation of the vascular structure and density based on OCTA alone can be misleading. In this paper we compare the performance of AO-OCT, AO-OCTA and OCTA for imaging retinal vasculature. The improved transverse resolution and the reduced depth of focus of AO-OCT and AO-OCTA greatly reduce shadowing artifacts allowing for a better differentiation and segmentation of different vasculature layers of the inner retina. The comparison is done on images recorded in healthy volunteers and in diabetic patients with distinct pathologies of the retinal microvasculature. PMID- 28101414 TI - Anti-confocal assessment of middle ear inflammation. AB - To improve the diagnostic prediction of recurrence of otitis media with effusion after surgery, an anti-confocal system combined with spectroscopic measurements is proposed to reject unwanted signals from the eardrum and assess the blood content. The anti-confocal system was experimentally evaluated on both optical middle ear phantom and human skin. Results showed effective rejection of signals from the eardrum using a central stop replacing the confocal pinhole, while still detecting signals from the middle ear mucosa. The system is sensitive to changes in blood content, but scattering and absorption characteristics of the eardrum can distort the measurement. Confocal detection of eardrum properties was shown to be a promising approach to correct measurements. PMID- 28101413 TI - Significant and sustaining elevation of blood oxygen induced by Chinese cupping therapy as assessed by near-infrared spectroscopy. AB - Cupping therapy has been used in traditional Chinese medicine for thousands of years to relieve muscle pain/tendency/fatigue and to cure or reduce symbols of other diseases. However, its therapeutic effect is sparsely interpreted in the language of modern physiology. To objectively evaluate its therapeutic effect, we focused on dry cupping treatment and utilized near-infrared spectroscopy (NIRS) to assess the concentration change in oxy-hemoglobin ([HbO2]), deoxy-hemoglobin ([Hb]), and blood volume in the course of cupping therapy over 13 volunteers on the infraspinatus muscle, where is usually applied for shoulder pains. Both a prominent drop in [Hb] and a significant elevation in [HbO2] in the tissue surrounding the cupping site were observed during both cupping and post treatment, manifesting the enhancement of oxygen uptake. This resulting promotion indicates potential positive therapeutic effect of cupping therapy in hemodynamics for facilitating muscular functions. PMID- 28101411 TI - Simultaneous multimodal ophthalmic imaging using swept-source spectrally encoded scanning laser ophthalmoscopy and optical coherence tomography. AB - Scanning laser ophthalmoscopy (SLO) benefits diagnostic imaging and therapeutic guidance by allowing for high-speed en face imaging of retinal structures. When combined with optical coherence tomography (OCT), SLO enables real-time aiming and retinal tracking and provides complementary information for post-acquisition volumetric co-registration, bulk motion compensation, and averaging. However, multimodality SLO-OCT systems generally require dedicated light sources, scanners, relay optics, detectors, and additional digitization and synchronization electronics, which increase system complexity. Here, we present a multimodal ophthalmic imaging system using swept-source spectrally encoded scanning laser ophthalmoscopy and optical coherence tomography (SS-SESLO-OCT) for in vivo human retinal imaging. SESLO reduces the complexity of en face imaging systems by multiplexing spatial positions as a function of wavelength. SESLO image quality benefited from single-mode illumination and multimode collection through a prototype double-clad fiber coupler, which optimized scattered light throughput and reduce speckle contrast while maintaining lateral resolution. Using a shared 1060 nm swept-source, shared scanner and imaging optics, and a shared dual-channel high-speed digitizer, we acquired inherently co-registered en face retinal images and OCT cross-sections simultaneously at 200 frames-per second. PMID- 28101416 TI - Light field otoscope design for 3D in vivo imaging of the middle ear. AB - We present a light field digital otoscope designed to measure three-dimensional shape of the tympanic membrane. This paper describes the optical and anatomical considerations we used to develop the prototype, along with the simulation and experimental measurements of vignetting, field curvature, and lateral resolution. Using an experimental evaluation procedure, we have determined depth accuracy and depth precision of our system to be 0.05-0.07 mm and 0.21-0.44 mm, respectively. To demonstrate the application of our light field otoscope, we present the first three-dimensional reconstructions of tympanic membranes in normal and otitis media conditions, acquired from children who participated in a feasibility study at the Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center. PMID- 28101417 TI - Investigation of terahertz radiation influence on rat glial cells. AB - We studied an influence of continuous terahertz (THz) radiation (0.12 - 0.18 THz, average power density of 3.2 mW/cm2) on a rat glial cell line. A dose-dependent cytotoxic effect of THz radiation is demonstrated. After 1 minute of THz radiation exposure a relative number of apoptotic cells increased in 1.5 times, after 3 minutes it doubled. This result confirms the concept of biological hazard of intense THz radiation. Diagnostic applications of THz radiation can be restricted by the radiation power density and exposure time. PMID- 28101415 TI - Endoscopic sensing of alveolar pH. AB - Previously unobtainable measurements of alveolar pH were obtained using an endoscope-deployable optrode. The pH sensing was achieved using functionalized gold nanoshell sensors and surface enhanced Raman spectroscopy (SERS). The optrode consisted of an asymmetric dual-core optical fiber designed for spatially separating the optical pump delivery and signal collection, in order to circumvent the unwanted Raman signal generated within the fiber. Using this approach, we demonstrate a ~100-fold increase in SERS signal-to-fiber background ratio, and demonstrate multiple site pH sensing with a measurement accuracy of +/ 0.07 pH units in the respiratory acini of an ex vivo ovine lung model. We also demonstrate that alveolar pH changes in response to ventilation. PMID- 28101418 TI - Multi-surface segmentation of OCT images with AMD using sparse high order potentials. AB - In age-related macular degeneration (AMD), the quantification of drusen is important because it is correlated with the evolution of the disease to an advanced stage. Therefore, we propose an algorithm based on a multi-surface framework for the segmentation of the limiting boundaries of drusen: the inner boundary of the retinal pigment epithelium + drusen complex (IRPEDC) and the Bruch's membrane (BM). Several segmentation methods have been considerably successful in segmenting retinal layers of healthy retinas in optical coherence tomography (OCT) images. These methods are successful because they incorporate prior information and regularization. Nonetheless, these factors tend to hinder the segmentation for diseased retinas. The proposed algorithm takes into account the presence of drusen and geographic atrophy (GA) related to AMD by excluding prior information and regularization just valid for healthy regions. However, even with this algorithm, prior information and regularization still cause the oversmoothing of drusen in some locations. Thus, we propose the integration of local shape prior in the form of a sparse high order potentials (SHOPs) into the algorithm to reduce the oversmoothing of drusen. The proposed algorithm was evaluated in a public database. The mean unsigned errors, relative to the average of two experts, for the inner limiting membrane (ILM), IRPEDC and BM were 2.94+/ 2.69, 5.53+/-5.66 and 4.00+/-4.00 um, respectively. Drusen areas measurements were evaluated, relative to the average of two expert graders, by the mean absolute area difference and overlap ratio, which were 1579.7 +/- 2106.8 um2 and 0.78 +/- 0.11, respectively. PMID- 28101419 TI - Posterior rat eye during acute intraocular pressure elevation studied using polarization sensitive optical coherence tomography. AB - Polarization sensitive optical coherence tomography (PS-OCT) operating at 840 nm with axial resolution of 3.8 um in tissue was used for investigating the posterior rat eye during an acute intraocular pressure (IOP) increase experiment. IOP was elevated in the eyes of anesthetized Sprague Dawley rats by cannulation of the anterior chamber. Three dimensional PS-OCT data sets were acquired at IOP levels between 14 mmHg and 105 mmHg. Maps of scleral birefringence, retinal nerve fiber layer (RNFL) retardation and relative RNFL/retina reflectivity were generated in the peripapillary area and quantitatively analyzed. All investigated parameters showed a substantial correlation with IOP. In the low IOP range of 14 45 mmHg only scleral birefringence showed statistically significant correlation. The polarization changes observed in the PS-OCT imaging study presented in this work suggest that birefringence of the sclera may be a promising IOP-related parameter to investigate. PMID- 28101420 TI - Compact diode laser source for multiphoton biological imaging. AB - We demonstrate a compact, pulsed diode laser source suitable for multiphoton microscopy of biological samples. The center wavelength is 976 nm, near the peak of the two-photon cross section of common fluorescent markers such as genetically encoded green and yellow fluorescent proteins. The laser repetition rate is electrically tunable between 66.67 kHz and 10 MHz, with 2.3 ps pulse duration and peak powers >1 kW. The laser components are fiber-coupled and scalable to a compact package. We demonstrate >600 MUm depth penetration in brain tissue, limited by laser power. PMID- 28101421 TI - Structural and functional human retinal imaging with a fiber-based visible light OCT ophthalmoscope. AB - The design of a multi-functional fiber-based Optical Coherence Tomography (OCT) system for human retinal imaging with < 2 micron axial resolution in tissue is described. A detailed noise characterization of two supercontinuum light sources with different pulse repetition rates is presented. The higher repetition rate and lower noise source is found to enable a sensitivity of 96 dB with 0.15 mW light power at the cornea and a 98 microsecond exposure time. Using a broadband (560 +/- 50 nm), 90/10, fused single-mode fiber coupler designed for visible wavelengths, the sample arm is integrated into an ophthalmoscope platform, similar to current clinical OCT systems. To demonstrate the instrument's range of operation, in vivo structural retinal imaging is also shown at 0.15 mW exposure with 10,000 and 70,000 axial scans per second (the latter comparable to commercial OCT systems), and at 0.03 mW exposure and 10,000 axial scans per second (below maximum permissible continuous exposure levels). Lastly, in vivo spectroscopic imaging of anatomy, saturation, and hemoglobin content in the human retina is also demonstrated. PMID- 28101422 TI - Low-cost hand-held probe for depth-resolved low-coherence interferometry. AB - We report on the development of a low-cost hand-held low-coherence interferometric imaging system based on the principle of linear optical coherence tomography (Linear OCT), a technique which was first proposed in the early 2000s as a simpler alternative to the conventional time-domain and Fourier-domain OCT. A bench-top implementation of the proposed technique is first presented and validated. The axial resolution, SNR, and sensitivity roll-of of the system was estimated to be 5.2 MUm and 80 dB, and 3.7 dB over a depth of 0.15 mm, respectively. After validating the bench-top system, two hand-held probe implementations for contact-based imaging and in vivo human tympanic membrane imaging are presented. The performance of the proposed system was compared with a research-grade state-of-the-art Fourier-domain low coherence interferometry (LCI) system by imaging several biological and non-biological samples. The results of this study suggest that the proposed system might be a suitable choice for applications where imaging depth and SNR can be traded for lower cost and simpler optical design. PMID- 28101423 TI - Assessing the effects of riboflavin/UV-A crosslinking on porcine corneal mechanical anisotropy with optical coherence elastography. AB - In this work we utilize optical coherence elastography (OCE) to assess the effects of UV-A/riboflavin corneal collagen crosslinking (CXL) on the mechanical anisotropy of in situ porcine corneas at various intraocular pressures (IOP). There was a distinct meridian of increased Young's modulus in all samples, and the mechanical anisotropy increased as a function of IOP and also after CXL. The presented noncontact OCE technique was able to quantify the Young's modulus and elastic anisotropy of the cornea and their changes as a function of IOP and CXL, opening new avenues of research for evaluating the effects of CXL on corneal biomechanical properties. PMID- 28101424 TI - Detection and classification of three-class initial dips from prefrontal cortex. AB - In this paper, the use of initial dips using functional near-infrared spectroscopy (fNIRS) for brain-computer interface (BCI) is investigated. Features and window sizes for detecting initial dips are also discussed. Three mental tasks including mental arithmetic, mental counting, and puzzle solving are performed in obtaining fNIRS signals from the prefrontal cortex. Vector-based phase analysis method combined with a threshold circle, as a decision criterion, are used to detect the initial dips. Eight healthy subjects participate in experiment. Linear discriminant analysis is used as a classifier. To classify initial dips, five features (signal mean, peak value, signal slope, skewness, and kurtosis) of oxy-hemoglobin (HbO) and four different window sizes (0~1, 0~1.5, 0~2, and 0~2.5 sec) are examined. It is shown that a combination of signal mean and peak value and a time period of 0~2.5 sec provide the best average classification accuracy of 57.5% for three classes. To further validate the result, three-class classification using the conventional hemodynamic response (HR) is also performed, in which two features (signal mean and signal slope) and 2~7 sec window size have yielded the average classification accuracy of 65.9%. This reveals that fNIRS-based BCI using initial dip detection can reduce the command generation time from 7 sec to 2.5 sec while the classification accuracy is a bit sacrificed from 65.9% to 57.5% for three mental tasks. Further improvement can be made by using deoxy hemoglobin signals in coping with the slow HR problem. PMID- 28101425 TI - Study of in vitro RBCs membrane elasticity with AOD scanning optical tweezers. AB - The elasticity of red cell membrane is a critical physiological index for the activity of RBC. Study of the inherent mechanism for RBCs membrane elasticity transformation is attention-getting all along. This paper proposes an optimized measurement method of erythrocytes membrane shear modulus incorporating acousto optic deflector (AOD) scanning optical tweezers system. By use of this method, both membrane shear moduli and sizes of RBCs with different in vitro times were determined. The experimental results reveal that the RBCs membrane elasticity and size decline with in vitro time extension. In addition, semi quantitative measurements of S-nitrosothiol content in blood using fluorescent spectrometry during in vitro storage show that RBCs membrane elasticity change is positively associated with the S-nitrosylation level of blood. The analysis considered that the diminished activity of the nitric oxide synthase makes the S-nitrosylation of in vitro blood weaker gradually. The main reason for worse elasticity of the in vitro RBCs is that S-nitrosylation effect of spectrin fades. These results will provide a guideline for further study of in vitro cells activity and other clinical applications. PMID- 28101426 TI - Asymmetric split H-shape nanoantennas for molecular sensing. AB - In this paper we report on a very sensitive biosensor based on gold asymmetric nanoantennas that are capable of enhancing the molecular resonances of C-H bonds. The nanoantennas are arranged as arrays of asymmetric-split H-shape (ASH) structures, tuned to produce plasmonic resonances with reflectance double peaks within the mid-infrared vibrational resonances of C-H bonds for the assay of deposited films of the molecule 17beta-estradiol (E2), used as an analyte. Measurements and numerical simulations of the reflectance spectra have enabled an estimated enhancement factor on the order of 105 to be obtained for a thin film of E2 on the ASH array. A high sensitivity value of 2335 nm/RIU was achieved, together with a figure of merit of approximately 8. Our experimental results were corroborated using numerical simulations for the C-H stretch vibrational resonances from the analyte, superimposed on the plasmonic resonances of the ASH nanoantennas. PMID- 28101428 TI - Wide field and highly sensitive angiography based on optical coherence tomography with akinetic swept source. AB - Wide-field vascular visualization in bulk tissue that is of uneven surface is challenging due to the relatively short ranging distance and significant sensitivity fall-off for most current optical coherence tomography angiography (OCTA) systems. We report a long ranging and ultra-wide-field OCTA (UW-OCTA) system based on an akinetic swept laser. The narrow instantaneous linewidth of the swept source with its high phase stability, combined with high-speed detection in the system enable us to achieve long ranging (up to 46 mm) and almost negligible system sensitivity fall-off. To illustrate these advantages, we compare the basic system performances between conventional spectral domain OCTA and UW-OCTA systems and their functional imaging of microvascular networks in living tissues. In addition, we show that the UW-OCTA is capable of different depth-ranging of cerebral blood flow within entire brain in mice, and providing unprecedented blood perfusion map of human finger in vivo. We believe that the UW OCTA system has promises to augment the existing clinical practice and explore new biomedical applications for OCT imaging. PMID- 28101427 TI - Dynamic imaging and quantitative analysis of cranial neural tube closure in the mouse embryo using optical coherence tomography. AB - Neural tube closure is a critical feature of central nervous system morphogenesis during embryonic development. Failure of this process leads to neural tube defects, one of the most common forms of human congenital defects. Although molecular and genetic studies in model organisms have provided insights into the genes and proteins that are required for normal neural tube development, complications associated with live imaging of neural tube closure in mammals limit efficient morphological analyses. Here, we report the use of optical coherence tomography (OCT) for dynamic imaging and quantitative assessment of cranial neural tube closure in live mouse embryos in culture. Through time-lapse imaging, we captured two neural tube closure mechanisms in different cranial regions, zipper-like closure of the hindbrain region and button-like closure of the midbrain region. We also used OCT imaging for phenotypic characterization of a neural tube defect in a mouse mutant. These results suggest that the described approach is a useful tool for live dynamic analysis of normal neural tube closure and neural tube defects in the mouse model. PMID- 28101429 TI - Chronic wide-field imaging of brain hemodynamics in behaving animals. AB - Chronically monitoring cerebral activities in awake and freely moving status is very important in physiological and pathological studies. We present a novel standalone micro-imager for monitoring the cerebral blood flow (CBF) and total hemoglobin (HbT) activities in freely moving animals using the laser speckle contrast imaging (LSCI) and optical intrinsic signal (OIS) methods. A new cranial window method, using contact lens and wide field optics, is also proposed to achieve the chronic and wide-field imaging of rat's cerebral cortex. The hemodynamic activities of rats' cortex were measured for the first time without restriction of cables or fibers in awake and behaving animals. Chronic imaging showed the increase of CBF and HbT in motor cortex when the rats were climbing on the cage wall. Interestingly, the CBF activation of supplying vessel was smaller than that of parenchyma. Furthermore, after the climbing, CBF demonstrated fully return to the baseline while HbT showed a delayed recovery. The standalone micro imager technology provides new possibilities of brain imaging in cognitive neuroscience studies. PMID- 28101430 TI - Projection method for improving signal to noise ratio of localized surface plasmon resonance biosensors. AB - This paper presents a simple and accurate method (the projection method) to improve the signal to noise ratio of localized surface plasmon resonance (LSPR). The nanostructures presented in the paper can be readily fabricated by nanoimprint lithography. The finite difference time domain method is used to simulate the structures and generate a reference matrix for the method. The results are validated against experimental data and the proposed method is compared against several other recently published signal processing techniques. We also apply the projection method to biotin-streptavidin binding experimental data and determine the limit of detection (LoD). The method improves the signal to noise ratio (SNR) by one order of magnitude, and hence decreases the limit of detection when compared to the direct measurement of the transmission-dip. The projection method outperforms the established methods in terms of accuracy and achieves the best combination of signal to noise ratio and limit of detection. PMID- 28101431 TI - Non-invasive terahertz imaging of tissue water content for flap viability assessment. AB - Accurate and early prediction of tissue viability is the most significant determinant of tissue flap survival in reconstructive surgery. Perturbation in tissue water content (TWC) is a generic component of the tissue response to such surgeries, and, therefore, may be an important diagnostic target for assessing the extent of flap viability in vivo. We have previously shown that reflective terahertz (THz) imaging, a non-ionizing technique, can generate spatially resolved maps of TWC in superficial soft tissues, such as cornea and wounds, on the order of minutes. Herein, we report the first in vivo pilot study to investigate the utility of reflective THz TWC imaging for early assessment of skin flap viability. We obtained longitudinal visible and reflective THz imagery comparing 3 bipedicled flaps (i.e. survival model) and 3 fully excised flaps (i.e. failure model) in the dorsal skin of rats over a postoperative period of 7 days. While visual differences between both models manifested 48 hr after surgery, statistically significant (p < 0.05, independent t-test) local differences in TWC contrast were evident in THz flap image sets as early as 24 hr. Excised flaps, histologically confirmed as necrotic, demonstrated a significant, yet localized, reduction in TWC in the flap region compared to non traumatized skin. In contrast, bipedicled flaps, histologically verified as viable, displayed mostly uniform, unperturbed TWC across the flap tissue. These results indicate the practical potential of THz TWC sensing to accurately predict flap failure 24 hours earlier than clinical examination. PMID- 28101432 TI - Atypical hemolytic uremic syndrome in first trimester pregnancy successfully treated with eculizumab. AB - BACKGROUND: Atypical hemolytic uremic syndrome is a rare disorder which is known to cause acute thrombotic microangiopathy during pregnancy with poor maternal and fetal outcomes. Atypical hemolytic uremic syndrome is caused mostly by dysregulation of alternative complement pathway secondary to genetic mutations. Most of the cases reported have been in the post-partum period. We report a rare case of a patient who presents with thrombotic microangiopathy in the first trimester of her eleventh pregnancy and was successfully treated with eculizumab. CASE PRESENTATION: A 30-year-old woman presented at 10 weeks of gestation with hypertension, hemolytic anemia, thrombocytopenia, and acute kidney injury, consistent with thrombotic microangiopathy. She was managed initially with daily plasmapheresis. However, her kidney function did not recover, requiring hemodialysis. ADAMTS13 activity was later found to be within normal limit, hence diagnosis of atypical hemolytic uremic syndrome was strongly considered at that time and she was immediately treated with anti-C5 humanized monoclonal antibody (eculizumab). The patient responded well (resolution of thrombotic microangiopathy and recovery of renal function) to eculizumab, with continued remission after discharge and successfully delivered a healthy baby at term without any peripartum complications. CONCLUSION: Early recognition of atypical hemolytic uremic syndrome is often difficult as several other conditions also manifest as thrombotic microangiopathy during pregnancy, causing delay in initiating appropriate treatment. Our case suggests that treatment of atypical hemolytic uremic syndrome in early trimester of pregnancy with eculizumab results in good outcome to mother and fetus. PMID- 28101434 TI - An expanded nuclear phylogenomic PCR toolkit for Sapindales. AB - PREMISE OF THE STUDY: We tested PCR amplification of 91 low-copy nuclear gene loci in taxa from Sapindales using primers developed for Bursera simaruba (Burseraceae). METHODS AND RESULTS: Cross-amplification of these markers among 10 taxa tested was related to their phylogenetic distance from B. simaruba. On average, each Sapindalean taxon yielded product for 53 gene regions (range: 16 90). Arabidopsis thaliana (Brassicales), by contrast, yielded product for two. Single representatives of Anacardiaceae and Rutacaeae yielded 34 and 26 products, respectively. Twenty-six primer pairs worked for all Burseraceae species tested if highly divergent Aucoumea klaineana is excluded, and eight of these amplified product in every Sapindalean taxon. CONCLUSIONS: Our study demonstrates that customized primers for Bursera can amplify product in a range of Sapindalean taxa. This collection of primer pairs, therefore, is a valuable addition to the toolkit for nuclear phylogenomic analyses of Sapindales and warrants further investigation. PMID- 28101433 TI - Use of sonic tomography to detect and quantify wood decay in living trees. AB - PREMISE OF THE STUDY: Field methodology and image analysis protocols using acoustic tomography were developed and evaluated as a tool to estimate the amount of internal decay and damage of living trees, with special attention to tropical rainforest trees with irregular trunk shapes. METHODS AND RESULTS: Living trunks of a diversity of tree species in tropical rainforests in the Republic of Panama were scanned using an Argus Electronic PiCUS 3 Sonic Tomograph and evaluated for the amount and patterns of internal decay. A protocol using ImageJ analysis software was used to quantify the proportions of intact and compromised wood. The protocols provide replicable estimates of internal decay and cavities for trees of varying shapes, wood density, and bark thickness. CONCLUSIONS: Sonic tomography, coupled with image analysis, provides an efficient, noninvasive approach to evaluate decay patterns and structural integrity of even irregularly shaped living trees. PMID- 28101435 TI - Microsatellite markers for Nuphar japonica (Nymphaeaceae), an aquatic plant in the agricultural ecosystem of Japan. AB - PREMISE OF THE STUDY: Nuphar species (Nymphaeaceae) are representative aquatic plants in irrigation ponds in Japanese agricultural ecosystems. We developed 15 polymorphic microsatellite markers for N. japonica and confirmed their utility for its close relatives N. oguraensis var. akiensis and N. *saijoensis, which originated from natural hybridization between N. japonica and N. oguraensis. METHODS AND RESULTS: Genetic variation was characterized in 15 polymorphic loci in three populations of N. japonica. The average number of alleles per locus was 3.47 (range = 2-9; n = 32), and the average expected heterozygosity per locus was 0.84 (range = 0.5-1.0); 11 loci were amplified in N. oguraensis var. akiensis and 15 in N. *saijoensis. CONCLUSIONS: The polymorphic microsatellite markers developed in this study will be useful for investigating the levels of genetic diversity within remnant populations of Nuphar taxa and could provide a valuable tool for conservation genetics of these taxa. PMID- 28101436 TI - Development and characterization of microsatellite primers in the endangered Mediterranean shrub Ziziphus lotus (Rhamnaceae). AB - PREMISE OF THE STUDY: Microsatellite primers were developed to characterize and evaluate patterns of genetic diversity and structure in the endangered Mediterranean shrub Ziziphus lotus (Rhamnaceae). METHODS AND RESULTS: Twenty microsatellite primers were developed for Z. lotus, of which 14 were polymorphic. We evaluated microsatellite polymorphism in 97 specimens from 18 Spanish and seven Moroccan populations. Between two and eight alleles were found per locus, and the average number of alleles was 5.54. Observed heterozygosity and expected heterozygosity ranged from 0.08 to 0.90 and from 0.08 to 0.82, respectively. Nine of these primers also amplified microsatellite loci in Z. jujuba. CONCLUSIONS: The microsatellite markers described here will be useful in studies on genetic variation, population genetic structure, and gene flow in the fragmented habitat of this species. These markers are a valuable resource for designing appropriate conservation measures for the species in the Mediterranean range. PMID- 28101437 TI - Characterization of 16 microsatellite markers for the Oreinotinus clade of Viburnum (Adoxaceae). AB - PREMISE OF THE STUDY: Microsatellite loci were isolated from four species of Viburnum (Adoxaceae) to study population structure and assess species boundaries among morphologically similar South American Viburnum species of the Oreinotinus clade. METHODS AND RESULTS: Using a microsatellite-enriched library and mining next-generation sequence data, 16 microsatellites were developed. Each locus was tested on two populations of V. triphyllum and one population of V. pichinchense. For nuclear loci, one to 13 alleles were recovered, expected heterozygosity ranged from 0 to 0.8975, Simpson diversity index ranged from 0.0167 to 1.000, and Shannon diversity index ranged from 0 to 2.3670 in a given population. For the mitochondrial locus, three to six alleles were recovered and unbiased haploid diversity values ranged from 0.756 to 0.853 in a given population. CONCLUSIONS: The 16 microsatellite loci developed for the Oreinotinus clade (Viburnum, Adoxaceae) will inform investigations of population structure and species boundaries within this group. PMID- 28101438 TI - Development and characterization of EST-SSR markers for Artocarpus hypargyreus (Moraceae). AB - PREMISE OF THE STUDY: Polymorphic microsatellite markers were developed for Artocarpus hypargyreus (Moraceae), a threatened species endemic to China, to investigate the genetic diversity and structure of the species. METHODS AND RESULTS: Based on the transcriptome data of A. hypargyreus, 63 primer pairs were preliminarily designed and tested, of which 34 were successfully amplified and 10 displayed clear polymorphisms across the 67 individuals from four populations of A. hypargyreus. The results showed the number of alleles per locus ranged from three to 10, and the observed heterozygosity and expected heterozygosity per locus varied from 0.000 to 0.706 and from 0.328 to 0.807, respectively. CONCLUSIONS: These microsatellite markers will be useful in exploring genetic diversity and structure of A. hypargyreus. Furthermore, most loci were successfully cross-amplified in A. nitidus and A. heterophyllus, indicating that they will be of great value for genetic study across this genus. PMID- 28101439 TI - Development of highly variable microsatellite markers for the tetraploid Silene stellata (Caryophyllaceae). AB - PREMISE OF THE STUDY: We designed and tested microsatellite markers for the North American native species Silene stellata (Caryophyllaceae) to investigate its population genetic structure and identify selection on floral design through male reproductive success. METHODS AND RESULTS: A total of 153 candidate microsatellite loci were isolated based on next-generation sequencing. We identified 18 polymorphic microsatellite loci in three populations of S. stellata, with di- or trinucleotide repeats. Genotyping results showed the number of alleles per locus ranged from six to 45 and expected heterozygosity ranged from 0.511 to 0.951. Five of these loci were successfully amplified in S. virginica and S. caroliniana and were also polymorphic. CONCLUSIONS: The microsatellite markers reported here provide a valuable tool for paternity analysis in S. stellata. They will also be useful for investigating the population genetic structures of S. stellata and related species. PMID- 28101440 TI - High Spatial Resolution Laser Desorption/Ionization Mass Spectrometry Imaging of Organic Layers in an Organic Light-Emitting Diode. AB - To improve the durability of organic materials in electronic devices, an analytical method that can obtain information about the molecular structure directly from specific areas on a device is desired. For this purpose, laser desorption/ionization mass spectrometry imaging (LDI-MSI) is one of the most promising methods. The high spatial resolution stigmatic LDI-MSI with MULTUM-IMG2 in the direct analysis of organic light-emitting diodes was shown to obtain a detailed mass image of organic material in the degraded area after air exposure. The mass image was observed to have a noticeably improved spatial resolution over typical X-ray photoelectron spectroscopy, generally used technique in analysis of electronic devices. A prospective m/z was successfully deduced from the high spatial resolution MSI data. Additionally, mass resolution and accuracy using a spiral-orbit TOF mass spectrometer, SpiralTOF, were also investigated. The monoisotopic mass for the main component, N,N'-di-1-naphthalenyl-N,N'-diphenyl 1,1'-biphenyl-4,4'-diamine (m/z 588), was measured with a mass resolution of approximately 80,000 and a mass error of about 5 mDa using an external calibrant. This high mass resolution and accuracy data successfully deduced a possible elemental composition of partially remained material in the degraded area, C36H24, which was determined as anthracene, 9-[1,1'-biphenyl]-4-yl-10-(2 naphthalenyl) by combining structural information with high-energy CID data. The high spatial resolution of 1 MUm in LDI-MSI along with high mass resolution and accuracy could be useful in obtaining molecular structure information directly from specific areas on a device, and is expected to contribute to the evolution of electrical device durability. PMID- 28101441 TI - Reduced Sampling Size with Nanopipette for Tapping-Mode Scanning Probe Electrospray Ionization Mass Spectrometry Imaging. AB - Mass spectrometry imaging (MSI) with ambient sampling and ionization can rapidly and easily capture the distribution of chemical components in a solid sample. Because the spatial resolution of MSI is limited by the size of the sampling area, reducing sampling size is an important goal for high resolution MSI. Here, we report the first use of a nanopipette for sampling and ionization by tapping mode scanning probe electrospray ionization (t-SPESI). The spot size of the sampling area of a dye molecular film on a glass substrate was decreased to 6 MUm on average by using a nanopipette. On the other hand, ionization efficiency increased with decreasing solvent flow rate. Our results indicate the compatibility between a reduced sampling area and the ionization efficiency using a nanopipette. MSI of micropatterns of ink on a glass and a polymer substrate were also demonstrated. PMID- 28101442 TI - Determination of Optimal Vapor Pressure Data by the Second and Third Law Methods. AB - Though equilibrium vapor pressures are utilized to determine thermodynamic properties of not only gaseous species but also condensed phases, the obtained data often disagree by a factor of 100 and more. A new data analysis method is proposed using the so-called second and third law procedures to improve accuracy of vapor pressure measurements. It was found from examination of vapor pressures of cesium metaborate and silver that the analysis of the difference between the second and third law values can result in determination of an optimal data set. Since the new thermodynamic method does not require special techniques and or experiences in dealing with measured data, it is reliable and versatile to improve the accuracy of vapor pressure evaluation. PMID- 28101443 TI - National physical activity surveillance: Users of wearable activity monitors as a potential data source. AB - The objective of this study was to assess usage patterns of wearable activity monitors among US adults and how user characteristics might influence physical activity estimates from this type of sample. We analyzed data on 3367 respondents to the 2015 HealthStyles survey, an annual consumer mail panel survey conducted on a nationwide sample. Approximately 1 in 8 respondents (12.5%) reported currently using a wearable activity monitor. Current use varied by sex, age, and education level. Use increased with physical activity level from 4.3% for inactive adults to 17.4% for active adults. Overall, 49.9% of all adults met the aerobic physical activity guideline, while this prevalence was 69.5% among current activity monitor users. Our findings suggest that current users of wearable activity monitors are not representative of the overall US population. Estimates of physical activity levels using data from wearable activity monitors users may be an overestimate and therefore data from users alone may have a limited role in physical activity surveillance. PMID- 28101444 TI - Accelerometer data treatment for adolescents: Fitting a piece of the puzzle. AB - This study aimed to assess the differences in participant retention and associations between physical activity and key variables when a range of accelerometer data inclusion criteria are employed. Data were drawn from 204 adolescents of Pacific Island heritage (survey, body composition, 7-day accelerometry) and their parents (date of birth, socioeconomic status) between October 2014 and February 2016 in Auckland, New Zealand. Data wear time criteria for inclusion were as follows: A) > = 10 h/weekday or > = 8 h weekend day, > = 5 days (at least one weekend day); B) > = 10 h/weekday or > = 8 h weekend day, > = 4 days; C) > = 7 h/day, > = 3 days; D) > = 10 h/day, > = 1 day. Overall, 49%, 62%, 88%, and 96% of participants met the criteria, respectively. Adjusted odds of meeting each criterion were examined using a multivariable logistic regression model. Almost 50% of participants were excluded by the most stringent inclusion criteria. Increased body fat percentage and proportion of time in moderate-to vigorous activity were associated with decreased odds of meeting Criterions A and B. This research contributes to a growing understanding of the impact of differing accelerometer reduction approaches to sample retention and bias in adolescent physical activity research. PMID- 28101445 TI - Comparison of percutaneous vertebroplasty with and without interventional tumor removal for spinal metastatic tumor without epidural involvement. AB - AIM: To evaluate the efficacy of percutaneous vertebroplasty (PVP) combined with interventional tumor removal (ITR) in providing pain relief, reducing disability, and improving functional performance in patients with malignant vertebral compression fractures without epidural involvement. METHODS: Patients with malignant vertebral compression fractures (n=58) were treated with either PVP+ITR (n=31, group A) or PVP alone (n=27, group B). A 14 G needle was inserted into the vertebral body, and the tract was sequentially dilated with working cannulae. When the last working cannula had reached the distal pedicle of vertebral arch, ITR was performed with a marrow nucleus rongeurs inserted through the working cannula. Finally, cement was injected into the excavated vertebral body. Patients were followed up at 1, 3, and 6 months after the procedure, and every 6 months thereafter. RESULTS: The overall excellent and good pain relief rate during follow-ups was significantly better in group A than in group B (94% vs.56%; p=0.002). The average VAS, ODI, and KPS scores at 3 months, 6 months, 1-year, and >1 year were all significantly lower in group A than in group B (p<0.05). The mean cement filling volume and the stability of the treated vertebrae were significantly higher in group A than in group B (p<0.05). CONCLUSIONS: The combination of PVP+ITR is a safe and effective procedure, capable of providing significantly greater pain relief and vertebral stability than PVP alone in patients with malignant vertebral compression fractures. PMID- 28101446 TI - Hypertonicity: Clinical entities, manifestations and treatment. AB - Hypertonicity causes severe clinical manifestations and is associated with mortality and severe short-term and long-term neurological sequelae. The main clinical syndromes of hypertonicity are hypernatremia and hyperglycemia. Hypernatremia results from relative excess of body sodium over body water. Loss of water in excess of intake, gain of sodium salts in excess of losses or a combination of the two are the main mechanisms of hypernatremia. Hypernatremia can be hypervolemic, euvolemic or hypovolemic. The management of hypernatremia addresses both a quantitative replacement of water and, if present, sodium deficit, and correction of the underlying pathophysiologic process that led to hypernatremia. Hypertonicity in hyperglycemia has two components, solute gain secondary to glucose accumulation in the extracellular compartment and water loss through hyperglycemic osmotic diuresis in excess of the losses of sodium and potassium. Differentiating between these two components of hypertonicity has major therapeutic implications because the first component will be reversed simply by normalization of serum glucose concentration while the second component will require hypotonic fluid replacement. An estimate of the magnitude of the relative water deficit secondary to osmotic diuresis is obtained by the corrected sodium concentration, which represents a calculated value of the serum sodium concentration that would result from reduction of the serum glucose concentration to a normal level. PMID- 28101447 TI - Functional coupling of V-ATPase and CLC-5. AB - Dent's disease is an X-linked renal tubulopathy characterized by low molecular weight proteinuria, hypercalciuria and progressive renal failure. Disease aetiology is associated with mutations in the CLCN5 gene coding for the electrogenic 2Cl-/H+ antiporter chloride channel 5 (CLC-5), which is expressed in the apical endosomes of renal proximal tubules with the vacuolar type H+-ATPase (V-ATPase). Initially identified as a member of the CLC family of Cl- channels, CLC-5 was presumed to provide Cl- shunt into the endosomal lumen to dissipate H+ accumulation by V-ATPase, thereby facilitating efficient endosomal acidification. However, recent findings showing that CLC-5 is in fact not a Cl- channel but a 2Cl-/H+ antiporter challenged this classical shunt model, leading to a renewed and intense debate on its physiological roles. Cl- accumulation via CLC-5 is predicted to play a critical role in endocytosis, as illustrated in mice carrying an artificial Cl- channel mutation E211A that developed defective endocytosis but normal endosomal acidification. Conversely, a recent functional analysis of a newly identified disease-causing Cl- channel mutation E211Q in a patient with typical Dent's disease confirmed the functional coupling between V-ATPase and CLC 5 in endosomal acidification, lending support to the classical shunt model. In this editorial, we will address the current recognition of the physiological role of CLC-5 with a specific focus on the functional coupling of V-ATPase and CLC-5. PMID- 28101448 TI - Acetylsalicylic acid interferes with embryonic kidney growth and development by a prostaglandin-independent mechanism. AB - AIM: To evaluate the effects of the non-selective, non-steroidal anti inflammatory drug (NSAID) acetylsalicylic acid (ASA), on ex vivo embryonic kidney growth and development. METHODS: Pairs of fetal mouse kidneys at embryonic day 12.5 were cultured ex vivo in increasing concentrations of ASA (0.04-0.4 mg/mL) for up to 7 d. One organ from each pair was grown in control media and was used as the internal control for the experimental contralateral organ. In some experiments, organs were treated with ASA for 48 h and then transferred either to control media alone or control media containing 10 MUmol/L prostaglandin E2 (PGE2) for a further 5 d. Fetal kidneys were additionally obtained from prostaglandin synthase 2 homozygous null or heterozygous (PTGS2-/- and PTGS2-/+) embryos and grown in culture. Kidney cross-sectional area was used to determine treatment effects on kidney growth. Whole-mount labelling to fluorescently detect laminin enabled crude determination of epithelial branching using confocal microscopy. RESULTS: Increasing ASA concentration (0.1, 0.2 and 0.4 mg/mL) significantly inhibited metanephric growth (P < 0.05). After 7 d of culture, exposure to 0.2 mg/mL and 0.4 mg/mL reduced organ size to 53% and 23% of control organ size respectively (P < 0.01). Addition of 10 MUmol/L PGE2 to culture media after exposure to 0.2 mg/mL ASA for 48 h resulted in a return of growth area to control levels. Application of control media alone after cessation of ASA exposure showed no benefit on kidney growth. Despite the apparent recovery of growth area with 10 MUmol/L PGE2, no obvious renal tubular structures were formed. The number of epithelial tips generated after 48 h exposure to ASA was reduced by 40% (0.2 mg/mL; P < 0.05) and 47% (0.4 mg/mL; P < 0.01). Finally, growth of PTGS2-/- and PTGS2+/- kidneys in organ culture showed no differences, indicating that PTGS2 derived PGE2 may at best have a minor role. CONCLUSION: ASA reduces early renal growth and development but the role of prostaglandins in this may be minor. PMID- 28101450 TI - Hyponatremic hypertensive syndrome - a retrospective cohort study. AB - AIM: To ascertain the frequency of hyponatremic hypertensive syndrome (HHS) in a cohort of children with hypertensive emergency in a tertiary pediatric hospital. METHODS: A retrospective review was undertaken among children with hypertensive emergency admitted in our tertiary children hospital between June 2014 and December 2015 with an aim to identify any children with HHS. Three children with HHS were identified during this period. RESULTS: The 3 patients with HHS presented with hypertensive emergency. They were initially managed with Labetalol infusion and thereafter switched to oral anti-hypertensives (combination of Nifedipine sustained release, Hydralazine and Beta Blocker). All 3 were diagnosed to have unilateral renal artery stenosis. One child was lost to follow up, whereas the other 2 underwent renal angioplasty which was followed with normalization of blood pressure. CONCLUSION: Despite activation of renin angiotensin axis secondary to renal artery stenosis, these groups of children have significant hyponatremia. Renal re-vascularisation produces excellent results in most of them. PMID- 28101451 TI - Laparoscopic vs open donor nephrectomy: Lessons learnt from single academic center experience. AB - AIM: To compare laparoscopic and open living donor nephrectomy, based on the results from a single center during a decade. METHODS: This is a retrospective review of all living donor nephrectomies performed at the Massachusetts General Hospital, Harvard Medical School, Boston, between 1/1998 - 12/2009. Overall there were 490 living donors, with 279 undergoing laparoscopic living donor nephrectomy (LLDN) and 211 undergoing open donor nephrectomy (OLDN). Demographic data, operating room time, the effect of the learning curve, the number of conversions from laparoscopic to open surgery, donor preoperative glomerular filtration rate and creatinine (Cr), donor and recipient postoperative Cr, delayed graft function and donor complications were analyzed. Statistical analysis was performed. RESULTS: Overall there was no statistically significant difference between the LLDN and the OLDN groups regarding operating time, donor preoperative renal function, donor and recipient postoperative kidney function, delayed graft function or the incidence of major complications. When the last 100 laparoscopic cases were analyzed, there was a statistically significant difference regarding operating time in favor of the LLDN, pointing out the importance of the learning curve. Furthermore, another significant difference between the two groups was the decreased length of stay for the LLDN (2.87 d for LLDN vs 3.6 d for OLDN). CONCLUSION: Recognizing the importance of the learning curve, this paper provides evidence that LLDN has a safety profile comparable to OLDN and decreased length of stay for the donor. PMID- 28101449 TI - Immunohistochemical expression of intrarenal renin angiotensin system components in response to tempol in rats fed a high salt diet. AB - AIM: To determine the effect of tempol in normal rats fed high salt on arterial pressure and the balance between antagonist components of the renal renin angiotensin system. METHODS: Sprague-Dawley rats were fed with 8% NaCl high-salt (HS) or 0.4% NaCl (normal-salt, NS) diet for 3 wk, with or without tempol (T) (1 mmol/L, administered in drinking water). Mean arterial pressure (MAP), glomerular filtration rate (GFR), and urinary sodium excretion (UVNa) were measured. We evaluated angiotensin II (Ang II), angiotensin 1-7 (Ang 1-7), angiotensin converting enzyme 2 (ACE2), mas receptor (MasR), angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptor (AT2R) in renal tissues by immunohistochemistry. RESULTS: The intake of high sodium produced a slight but significant increase in MAP and differentially regulated components of the renal renin-angiotensin system (RAS). This included an increase in Ang II and AT1R, and decrease in ACE-2 staining intensity using immunohistochemistry. Antioxidant supplementation with tempol increased natriuresis and GFR, prevented changes in blood pressure and reversed the imbalance of renal RAS components. This includes a decrease in Ang II and AT1R, as increase in AT2, ACE2, Ang (1-7) and MasR staining intensity using immunohistochemistry. In addition, the natriuretic effects of tempol were observed in NS-T group, which showed an increased staining intensity of AT2, ACE2, Ang (1-7) and MasR. CONCLUSION: These findings suggest that a high salt diet leads to changes in the homeostasis and balance between opposing components of the renal RAS in hypertension to favour an increase in Ang II. Chronic antioxidant supplementation can modulate the balance between the natriuretic and antinatriuretic components of the renal RAS. PMID- 28101452 TI - Severe hyperkalemia following blood transfusions: Is there a link? AB - Patients with gastrointestinal bleeding often require large volume blood transfusion. Among the various side effects of blood transfusion, the increase of potassium levels is a serious one which is often overlooked. We report a case of severe hyperkalemia in a patient with gastric bleeding after large volume transfusion of packed red blood cells. The patient had hyperkalemia at baseline associated with his receiving medication as well as acute renal failure following hypovolemia. The baseline hyperkalemia was further aggravated after massive transfusions of packed red blood cells in a short period of time. The associated pathogenetic mechanisms resulting in the increase of potassium levels are presented. A number of risk factors which increase the risk of hyperkalemia after blood transfusion are discussed. Moreover, appropriate management strategies for the prevention of blood transfusion associated hyperkalemia are also presented. Physicians should always keep in mind the possibility of hyperkalemia in cases of blood transfusion. PMID- 28101453 TI - FGF23 and inflammation. AB - Systemic inflammation is a recognized feature in chronic kidney disease (CKD). The role of systemic inflammation in the pathogenesis of vascular calcification was recently settled. FGF23 was recently accused as a direct stimulus of systemic inflammation. This finding explains the strong association of FGF23 to vascular calcification and increased mortality among CKD. PMID- 28101454 TI - Vitamins, Are They Safe? AB - The consumption of a daily multivitamin among people all over the world is dramatically increasing in recent years. Most of the people believe that if vitamins are not effective, at least they are safe. However, the long term health consequences of vitamins consumption are unknown. This study aimed to assess the side effects and possible harmful and detrimental properties of vitamins and to discuss whether vitamins can be used as safe health products or dietary supplements. We performed a MEDLINE/PubMed, EMBASE, Scopus and Google Scholar search and assessed reference lists of the included studies which were published from 1993 through 2015. The studies, with an emphasis on RCTs (randomized controlled clinical trials), were reviewed. As some vitamins such as fat-soluble vitamins (vitamin A, vitamin D, vitamin E), and also some of the water-soluble vitamins like folic acid may cause adverse events and some like vitamin C is widely taken assuming that it has so many benefits and no harm, we included relevant studies with negative or undesired results regarding the effect of these vitamins on health. Our recommendation is that taking high-dose supplements of vitamins A, E, D, C, and folic acid is not always effective for prevention of disease, and it can even be harmful to the health. PMID- 28101455 TI - Pharmaceutical Cocrystals: Regulatory and Strategic Aspects, Design and Development. AB - Cocrystal is a concept of the supramolecular chemistry which is gaining the extensive interest of researchers from pharmaceutical and chemical sciences and of drug regulatory agencies. The prominent reason of which is its ability to modify physicochemical properties of active pharmaceutical ingredients. During the development of the pharmaceutical product, formulators have to optimize the physicochemical properties of active pharmaceutical ingredients. Pharmaceutical cocrystals can be employed to improve vital physicochemical characteristics of a drug, including solubility, dissolution, bioavailability and stability of pharmaceutical compounds while maintaining its therapeutic activity. It is advantageous being a green synthesis approach for production of pharmaceutical compounds. The formation polymorphic forms, solvates, hydrates and salts of cocrystals during the synthesis reported in the literature which can be a potential issue in the development of pharmaceutical cocrystals. The approaches like hydrogen bonding rules, solubility parameters, screening through the CSD database or thermodynamic characteristics can be utilized for the rational design of cocrystals and selection of coformers for synthesis multi-component cocrystals. Considering the significance of pharmaceutical cocrystals pharmaceutical regulatory authorities in the United States and Europe issued guidance documents which may be helpful for pharmaceutical product registration in these regions. In this article, we deal with the design, synthesis, strategic aspects and characteristics of cocrystals along perspectives on its regulatory and intellectual property considerations. PMID- 28101457 TI - Therapeutic Effects of Omega-3 Fatty Acids on Chronic Kidney Disease-Associated Pruritus: a Literature Review. AB - Uremic pruritus remains one of the most tormenting, frequent and potentially disabling problem in chronic kidney disease (CKD) patients. However, an area of substantial etiological interest with relation to uremic pruritus is the essential fatty acids deficiency. So we performed a literature review to elucidate the efficacy of omega-3 fatty acids on uremic pruritus. This review evaluated all of the studies published in English language, focusing on the clinical effects of omega-3 fatty acids on uremic pruritus. The literature review was conducted in December 2015 and carried out by searching Scopus, Medline, Cochrane central register of controlled trials, and Cochrane database of systematic reviews. The search terms were "kidney injury", "kidney failure", "chronic kidney disease", "end-stage renal disease", "dialysis", "hemodialysis", "peritoneal dialysis", "pruritus", "itch", "skin problems", "fish oil", "omega 3", "n-3 fatty acids", "polyunsaturated fatty acids", "docosahexaenoic acid", and "eicosapentaenoic acid". Four small studies investigating potential benefits of omega-3 fatty acids on symptoms of uremic pruritus were found. Among them, three small randomized controlled trials have shown a significant improvement in pruritus symptoms (evaluated by a standard questionnaire) in CKD patients who took omega-3 supplement compared to omega-6, omega-9, and placebo supplementation. Despite numerous limitations of the studies, it is worth noting that even minor reduction in itching symptoms may be clinically significant for CKD patients. Therefore, and considering multiple health benefits of omega-3 fatty acids in advanced CKD and negligible risk profile, omega-3 intake can wisely be applied to CKD patients with uremic pruritus. PMID- 28101458 TI - Cationic Liposomes Modified with Polyallylamine as a Gene Carrier: Preparation, Characterization and Transfection Efficiency Evaluation. AB - Purpose: Cationic polymers and cationic liposomes have shown to be effective non viral gene delivery vectors. In this study, we tried to improve the transfection efficiency by employing the advantages of both. Methods: For this purpose, modified polyallylamines (PAAs) were synthesized. These modifications were done through the reaction of PAA (15 KDa) with acrylate and 6-bromoalkanoic acid derivatives. Liposomes comprising of these cationic polymers and cationic lipid were prepared and extruded through polycarbonate filters to obtain desired size. Liposome-DNA nanocomplexes were prepared in three carrier to plasmid (C/P) ratios. Size, zeta potential and DNA condensation ability of each complex were characterized separately and finally transfection efficiency and cytotoxicity of prepared vectors were evaluated in Neuro2A cell line. Results: The results showed that mean particle size of all these nanocomplexes was lower than 266 nm with surface charge of 22.0 to 33.9 mV. Almost the same condensation pattern was observed in all vectors and complete condensation was occurred at C/P ratio of 1.5. The lipoplexes containing modified PAA 15 kDa with 10% hexyl acrylate showed the highest transfection efficacy and lowest cytotoxicity in C/P ratio of 0.5. Conclusion: In some cases nanocomplexes consisting of cationic liposome and modified PAA showed better transfection activity and lower cytotoxicity compared to PAA. PMID- 28101456 TI - Overview of Albumin and Its Purification Methods. AB - As the most frequent plasma protein, albumin constitutes more than 50% of the serum proteins in healthy individuals. It has a key role in oncotic pressure maintenance and it is known as a versatile protein carrier for transportation of various endogenous and exogenous ligands. Reduced amounts of albumin in the body will lead to different kinds of diseases such as hypovolemia and hypoproteinemia. It also has various indications in shocks, burns, cardiopulmonary bypass, acute liver failure and etc. Further applications in research consist of cell culture supplement, drug delivery carrier and protein/drug stabilizer. So, the demand for albumin increased annually worldwide. Due to different applications of albumin, many efforts have been accomplished to achieve albumin during a long period of time. In this review, an overview of serum albumin and different purification methods are summarized. PMID- 28101459 TI - Venlafaxine-Induced Cytotoxicity Towards Isolated Rat Hepatocytes Involves Oxidative Stress and Mitochondrial/Lysosomal Dysfunction. AB - Purpose: Depression is a public disorder worldwide. Despite the widespread use of venlafaxine in the treatment of depression, it has been associated with the incidence of toxicities. Hence, the goal of the current investigation was to evaluate the mechanisms of venlafaxine-induced cell death in the model of the freshly isolated rat hepatocytes. Methods: Collagenase-perfused rat hepatocytes were treated with venlafaxine and other agents. Cell damage, reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial membrane potential decline, lysosomal damage, glutathione (GSH) level were analyzed. Moreover, rat liver mitochondria were isolated through differential centrifugation to assess respiratory chain functionality. Results: Our results demonstrated that venlafaxine could induce ROS formation followed by lipid peroxidation, cellular GSH content depletion, elevated GSSG level, loss of lysosmal membrane integrity, MMP collapse and finally cell death in a concentration-dependent manner. N-acetyl cysteine, taurine and quercetine significantly decreased the aforementioned venlafaxine-induced cellular events. Also, radical scavenger (butylatedhydroxytoluene and alpha-tocopherol), CYP2E1 inhibitor (4 methylpyrazole), lysosomotropic agents (methylamine and chloroquine), ATP generators (L-gluthamine and fructose) and mitochondrial pore sealing agents (trifluoperazine and L-carnitine) considerably reduced cytotoxicity, ROS generation and lysosomal leakage following venlafaxine treatment. Mitochondrion dysfunction was concomitant with the blockade of the electron transfer complexes II and IV of the mitochondrial respiratory system. Conclusion: Therefore, our data indicate that venlafaxine induces oxidative stress towards hepatocytes and our findings provide evidence to propose that mitochondria and lysosomes are of the primary targets in venlafaxine-mediated cell damage. PMID- 28101460 TI - Captopril and Valsartan May Improve Cognitive Function Through Potentiation of the Brain Antioxidant Defense System and Attenuation of Oxidative/Nitrosative Damage in STZ-Induced Dementia in Rat. AB - Purpose: Previous findings have shown the crucial roles of brain renin angiotensin system (RAS) in pathogenesis of Alzheimer's disease (AD). Since RAS inhibitors may have beneficial effects on dementia and cognitive function in elderly people, the aim of present study was to examine the neuroprotective actions of captopril and valsartan on memory function and neuronal damage in experimental model of AD. Methods: Adult forty male Wistar rats (220-280g) were randomly divided into 5 groups; Control, Vehicle, Alzheimer and treatment groups. AD was induced by the injections of streptozotocin (3mg/kg, bilateral intracerebroventricular) at days 1&3. Treated rats received orally captopril (50mg/kg/day) and valsartan (30mg/kg/day). Memory function and histological assessments were done at termination of experiment. Finally, superoxide dismutase (SOD) and catalase (CAT) activities as well as malondialdehyde (MDA) and NOx contents were determined. Results: There was a significant increase in the mean value of latency in Alzheimer group (66%). Captopril and valsartan considerably decreased this value in both treatment groups (45% and 72%, respectively). In Alzheimer group the activities of brain's SOD and CAT reduced (40% and 47%, respectively) in accompany with an increase in MDA and NOx contents (49% and 50%, respectively). Captopril and valsartan significantly increased the activities of brain's SOD and CAT concomitant reduction in MDA and NOx contents. Also, histopathological damages noticeably decreased in both treatment groups. Conclusion: Our findings indicate that RAS inhibition by using captopril and valsartan potentiates the antioxidant defense system of brain and reduces oxidative/nitrosative stress in accompany with neuronal damage during AD. PMID- 28101462 TI - Identification and Molecular Characterization of Genes Coding Pharmaceutically Important Enzymes from Halo-Thermo Tolerant Bacillus. AB - Purpose: Robust pharmaceutical and industrial enzymes from extremophile microorganisms are main source of enzymes with tremendous stability under harsh conditions which make them potential tools for commercial and biotechnological applications. Methods: The genome of a Gram-positive halo-thermotolerant Bacillus sp. SL1, new isolate from Saline Lake, was investigated for the presence of genes coding for potentially pharmaceutical enzymes. We determined gene sequences for the enzymes laccase (CotA), l-asparaginase (ansA3, ansA1), glutamate-specific endopeptidase (blaSE), l-arabinose isomerase (araA2), endo-1,4-beta mannosidase (gmuG), glutaminase (glsA), pectate lyase (pelA), cellulase (bglC1), aldehyde dehydrogenase (ycbD) and allantoinases (pucH) in the genome of Bacillus sp. SL1. Results: Based on the DNA sequence alignment results, six of the studied enzymes of Bacillus sp. SL-1 showed 100% similarity at the nucleotide level to the same genes of B. licheniformis 14580 demonstrating extensive organizational relationship between these two strains. Despite high similarities between the B. licheniformis and Bacillus sp. SL-1 genomes, there are minor differences in the sequences of some enzyme. Approximately 30% of the enzyme sequences revealed more than 99% identity with some variations in nucleotides leading to amino acid substitution in protein sequences. Conclusion: Molecular characterization of this new isolate provides useful information regarding evolutionary relationship between B. subtilis and B. licheniformis species. Since, the most industrial processes are often performed in harsh conditions, enzymes from such halo thermotolerant bacteria may provide economically and industrially appealing biocatalysts to be used under specific physicochemical situations in medical, pharmaceutical, chemical and other industries. PMID- 28101461 TI - Acute and Subchronic Toxicity Study of the Median Septum of Juglans regia in Wistar Rats. AB - Purpose: Median septum of Juglans regia L. (Juglandaceae) with anti-diabetic effects has been used in Iranian traditional medicine. The present study estimates both oral acute and subchronic toxicities. Methods: In the oral acute toxicity study, female Wistar rats were treated with doses of 10, 100, 1000, 1600, 2900 and 5000 mg/ kg of the Juglans regia septum of methanol extract (JRSME), and were monitored for 14 days. In subchronic study, JRSME was administered by gavage at dose of 1000 mg/kg daily in Wistar rats for 28 days. Antioxidant status and biochemical examinations were fulfilled, and the vital organs were subjected to pathological analyses. Results: The extract did not produce any toxic signs or deaths; the medium lethal dose must be higher than 5000 mg/kg. In subchronic study, No significant morphological and histopathological changes were observed in the studied tissues. There was a significant increase in serum malondialdehyde (MDA) level in treated group compared to control after 4 weeks of JRSME intake. The treatment of rats resulted in a significant reduction of serum urea level (p<0.05), kidney's xanthine dehydrogenase (XDH) activity (p<0.001) and elevation of aldehyde oxidase (AO) activity (p<0.05) in kidney. In the treated group, the mean diameter of glomerulus and proximal urine tube epithelium stature was slightly greater than control group. A significant increase in serum MDA level is subject for further studies. Conclusion: This study showed that the extract has no acute or subacute adverse effects with dose of 1000 mg/kg. The administration of JRSME may improve kidney structure and function and help in treatment of some chronic diseases. PMID- 28101463 TI - Development of a Novel Human Single Chain Antibody Against EGFRVIII Antigen by Phage Display Technology. AB - Purpose: EGFRvIII as the most common mutant variant of the epidermal growth factor receptor is resulting from deletion of exons 2-7 in the coding sequence and junction of exons 1 and 8 through a novel glycine residue. EGFRvIII is highly expressed in glioblastoma, carcinoma of the breast, ovary, and lung but not in normal cells. The aim of the present study was identification of a novel single chain antibody against EGFRvIII as a promising target for cancer therapy. Methods: In this study, a synthetic peptide corresponding to EGFRvIII protein was used for screening a naive human scFv phage library. A novel five-round selection strategy was used for enrichment of rare specific clones. Results: After five rounds of screening, six positive scFv clones against EGFRvIII were selected using monoclonal phage ELISA, among them, only three clones had expected size in PCR reaction. The specific interaction of two of the scFv clones with EGFRvIII was confirmed by indirect ELISA. One phage clone with higher affinity in scFv ELISA was purified for further analysis. The purity of the produced scFv antibody was confirmed using SDS-PAGE and Western blotting analyses. Conclusion: In the present study, a human anti- EGFRvIII scFv with high affinity was first identified from a scFv phage library. This study can be the groundwork for developing more effective diagnostic and therapeutic agents against EGFRvIII expressing cancers. PMID- 28101465 TI - Nanostructured Lipid Carrier for Topical Application of N-Acetyl Glucosamine. AB - : Purpose: Hyperpigmentation occurs when melanin is overproduced in certain spots on the skin and is one of the most challenging skin conditions to treat. Although it is usually harmless, for cosmetic reasons, it is dreadfully bothersome to those who undergo it. It was reported that N-acetyl-glucosamine (NAGA) prevents melanin synthesis and alters the expression of numerous genes related to pigmentation. In spite of these advantages, NAGA cannot be employed in topical formulations due to its extremely polar characteristics. Nanoparticles, especially lipid-based ones, have been introduced as an efficient carrier for dermal drug delivery. Methods: The aim of the present study was to load adequate hydrophilic NAGA to the lipophilic nanostructured lipid carriers (NLCs) for potential dermal application. METHODS: NAGA-loaded NLCs were formulated, using hot homogenization technique, and the characteristics of the optimized formulation were analyzed by laser light scattering, X-ray diffraction, and scanning electron microscopy methods. Loading capacity percentage and in vitro release study were carried out by applying a validated HPLC method. The optimum formulation was utilized for the in vivo skin lightening evaluations in healthy volunteers. Results: NAGA-loaded NLCs demonstrated promising results (the size of 190 nm, narrow size distribution, loading capacity of 9%, and appropriate NAGA release profile) suitable for dermal delivery. XRD results exhibited a dramatic reduction in the crystalline structure of encapsulated NAGA. Dermoscopy images indicated a considerable decline in melanin distribution pattern in the majority of the cases treated with NAGA-loaded NLCs. Conclusion: Thus, this study has opened new horizons for the potential use of lipid based nanoparticles in the managing of hyperpigmentation. PMID- 28101464 TI - Anti-Inflammatory and Antibothropic Properties of Jatropha Elliptica, a Plant from Brazilian Cerrado Biome. AB - Purpose: The aim of this study was to evaluate the antibothropic and anti inflammatory properties of J. elliptica.Methods: Phytochemical screening and thin layer chromatography (TLC) assays were performed on J. elliptica hydroalcoholic extract (TE) in order to observe its main constituents. The antibothropic activity of TE was evaluated by the in vitro neuromuscular blockade caused by Bothrops jararacussu venom (Bjssu), in a mouse phrenic nerve-diaphragm model (PND). A quantitative histological study was carried out to observe a possible protection of TE against the venom myotoxicity. The anti-inflammatory activity was also evaluated in two models, Bjssu-induced paw edema, and carrageenan induced neutrophils migration in the peritoneal cavity. Results: TLC analysis revealed several compounds in TE, such as saponins, alkaloids, and phenolic constituents. TE was able to neutralize the blockade and the myotoxicity induced by venom, when it was pre-incubated for 30 min with venom. In addition, it showed anti-inflammatory activity, inducing less neutrophils migration and reducing paw edema. Conclusion:J. elliptica showed both antibothropic and anti-inflammatory properties. PMID- 28101466 TI - Characterization of the Effect of Drug-Drug Interaction on Protein Binding in Concurrent Administration of Sulfamethoxazol and Diclofenac Sodium Using Bovine Serum Albumin. AB - Purpose: This project was aimed to determine the effect of concurrent administration of sulfamethoxazole and diclofenac sodium. Methods: Equilibrium dialysis method was adopted to study different protein binding aspects of sulfamethoxazole and diclofenac sodium. Results: Sulfamethoxazole showed two types of association constants; high affinity constant 29.0+/-0.20*106 M-1 with lower number of binding sites of 0.7+/-1 and low affinity constant 1.13+/ 0.20*106 M-1 with higher number of binding sites of 3.45+/-1 at pH 7.4 and 40 degrees C temperature. Diclofenac sodium showed high affinity constant 33.66+/ 0.20*106 M-1 with lower number of binding sites of 1.01+/-1 and low affinity constant 1.72+/-0.20*106 M-1 with higher number of binding sites of 6.40+/-1 at the same condition. Site specific probe displacement data implied that site-I, warfarin sodium site, was the high affinity site, while site-II, diazepam site, was the low affinity site for these drugs. During concurrent administration, sulfamethoxazole increased the free concentration of diclofenac sodium from 17.5+/-0.14% to 70.0+/-0.014% in absence and from 22.5+/-0.07% to 83.0+/-0.014% in presence of site-I specific probe. Diclofenac sodium also increased the free concentration of sulfamethoxazole from 2.8+/-0.07% to 52.0+/-0.14% and from 8.5+/ 0.014% to 64.4+/-0.07% in absence and presence of site-I specific probe respectively. Conclusion: The study revealed that the concurrent administration of sulfamethoxazole and diclofenac sodium may result drug concentration alteration in blood. PMID- 28101467 TI - Some Qualitative and Rheological Properties of Virgin Olive Oil- Apple Vinegar Salad Dressing Stabilized With Xanthan Gum. AB - Purpose: Lipid oxidation and rheological properties are the main qualitative parameters determined in food emulsions. Salad dressings are food emulsions important in our daily diet, but conventional salad dressings have high amounts of cholesterol and saturated fatty acids because of egg yolk in their formulations. There are many studies on the modification of salad dressing formulations to replace egg yolk and saturated fats. The present study describes new formulation of salad dressing with olive oil and apple vinegar to produce a functional food product. Methods: This study investigated the qualitative properties, oxidative stability, rheological behavior and microstructure of the salad dressing without egg yolk. Oil-in-water emulsions were prepared with virgin olive oil and apple vinegar stabilized with various percentages of xanthan (T1: 0.25%, T2: 0.5%. T3: 0.75%). Samples were stored at refrigerator for 90 days and experiments were performed at production day and during storage. Results: The obtained results showed that peroxide value was increased for all samples during storage, but it was at an acceptable level. Fatty acid changes were not significant during storage. Droplet size was reduced by increasing xanthan gum. T2 had the best rheological properties during storage. Generally, T2 and T3 had higher scores and were more acceptable in organoleptic assay. Conclusion: Obtained results showed that T2 had suitable qualitative and rheological properties and can be a proper egg yolk free salad dressing to introduce to the market. PMID- 28101468 TI - Agglomeration of Celecoxib by Quasi Emulsion Solvent Diffusion Method: Effect of Stabilizer. AB - Purpose: The quasi-emulsion solvent diffusion (QESD) has evolved into an effective technique to manufacture agglomerates of API crystals. Although, the proposed technique showed benefits, such as cost effectiveness, that is considerably sensitive to the choice of a stabilizer, which agonizes from a absence of systemic understanding in this field. In the present study, the combination of different solvents and stabilizers were compared to investigate any connections between the solvents and stabilizers. Methods: Agglomerates of celecoxib were prepared by QESD method using four different stabilizers (Tween 80, HPMC, PVP and SLS) and three different solvents (methyl acetate, ethyl acetate and isopropyl acetate). The solid state of obtained particles was investigated by differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) spectroscopy. The agglomerated were also evaluated in term of production yield, distribution of particles and dissolution behavior. Results: The results showed that the effectiveness of stabilizer in terms of particle size and particle size distribution is specific to each solvent candidate. A stabilizer with a lower HLB value is preferred which actually increased its effectiveness with the solvent candidates with higher lipophilicity. HPMC appeared to be the most versatile stabilizer because it showed a better stabilizing effect compared to other stabilizers in all solvents used. Conclusion: This study demonstrated that the efficiency of stabilizers in forming the celecoxib agglomerates by QESD was influenced by the HLB of the stabilizer and lipophilicity of the solvents. PMID- 28101469 TI - Concurrent Inflammation Augments Antimalarial Drugs-Induced Liver Injury in Rats. AB - Purpose: Accumulating evidence suggests that drug exposure during a modest inflammation induced by bacterial lipopolysaccharide (LPS) might increase the risk of drug-induced liver injury. The current investigation was designed to test if antimalarial drugs hepatotoxicity is augmented in LPS-treated animals. Methods: Rats were pre-treated with LPS (100 ug/kg, i.p). Afterward, non hepatotoxic doses of amodiaquine (25, 50 and 100 mg/kg, oral) and chloroquine (25, 50 and 100 mg/kg, oral) were administered. Results: Interestingly, liver injury was evident only in animals treated with both drug and LPS as estimated by pathological changes in serum biochemistry (ALT, AST, LDH, and TNF-alpha), and liver tissue (severe hepatitis, endotheliitis, and sinusoidal congestion). An increase in liver myeloperoxidase enzyme activity, lipid peroxidation, and protein carbonylation, along with tissue glutathione depletion were also detected in LPS and drug co-treated animals. Conclusion: Antimalarial drugs rendered hepatotoxic in animals undergoing a modest inflammation. These results indicate a synergistic liver injury from co-exposure to antimalarial drugs and inflammation. PMID- 28101470 TI - Protective Roles of N-acetyl Cysteine and/or Taurine against Sumatriptan-Induced Hepatotoxicity. AB - Purpose: Triptans are the drug category mostly prescribed for abortive treatment of migraine. Most recent cases of liver toxicity induced by triptans have been described, but the mechanisms of liver toxicity of these medications have not been clear. Methods: In the present study, we obtained LC50 using dose-response curve and investigated cell viability, free radical generation, lipid peroxide production, mitochondrial injury, lysosomal membrane damage and the cellular glutathione level as toxicity markers as well as the beneficial effects of taurine and/or N-acetyl cysteine in the sumatriptan-treated rat parenchymal hepatocytes using accelerated method of cytotoxicity mechanism screening. Results: It was revealed that liver toxicity induced by sumatriptan in in freshly isolated parenchymal hepatocytes is dose-dependent. Sumatriptan caused significant free radical generation followed by lipid peroxide formation, mitochondrial injury as well as lysosomal damage. Moreover, sumatriptan reduced cellular glutathione content. Taurine and N-acetyl cysteine were able to protect hepatocytes against sumatriptan-induced harmful effects. Conclusion: It is concluded that sumatriptan causes oxidative stress in hepatocytes and the decreased hepatocytes glutathione has a key role in the sumatriptan-induced harmful effects. Also, N-acetyl cysteine and/or taurine could be used as treatments in sumatriptan-induced side effects. PMID- 28101471 TI - Association of Vitamin D Deficiency and Thyroid Function in Postmenopausal Women. AB - Pupose: Although there are reports of vitamin D (VitD) insufficiency in immune mediated hypothyroidism, an association between VitD and thyroid-stimulating hormone (TSH) levels has yet to be shown. We aim to examine VitD and TSH levels among postmenopausal women, as both conditions are more prevalent in elderly women. Methods: The clinic records of postmenopausal women during their routine maintenance visits were reviewed. All patients were examined for the symptoms related to thyroid function and osteoporosis. Participants were divided into three subgroups according to their TSH levels (below <0.5 mIU/L, 0.51-4.0 mIU/L and >4.0 mIU/L). Patient characteristics and VitD levels were compared between these subgroups. Multivariate linear regression model was constructed using serum VitD and serum TSH as the dependent variables to identify factors independently associated with these laboratory values. Results: Two-hundred and nighty nine postmenopausal women were included. Average age was 62.2+/-7.5 years old. VitD was insufficient (10-30 ng/mL) in 12.0% and deficient (<10 ng/mL) in 60.9% of the participants. In 11.3%, TSH was low and in 7.6% of women, TSH was high, while the remaining 80.1%, had normal TSH levels. Subjects with low TSH had significantly higher VitD concentrations (34.2+/-29.1 ng/mL) compared to the other two groups (P-value: 0.039). In multivariate regression analysis, TSH was not a contributing factor, as age was the only significant predictor of VitD levels. Meanwhile, no predictor (including age and VitD) was identified for TSH levels in linear regression analysis. Conclusion: Age was the only independent predictor of serum VitD in this study population. Though suppressed TSH was associated with higher VitD levels, the association was not linear between TSH and VitD in postmenopausal women. PMID- 28101472 TI - The Effects of Hypoxia on U937 Cell Line in Mesenchymal Stem Cells Co-Culture System. AB - Purpose: Mesenchymal Stem Cells (MSCs) are the most important members of Bone Marrow (BM) milieu. MSCs affect different kinds of cells, particularly malignant cells of hematologic malignancies, but the effects of MSCs are unclear exactly. Here we analyzed the effects of derived Umbilical Cord Blood-MSCs on proliferation, cell death and some surface markers of U937 cell line in a Co culture system with MSCs. Methods: Here we designed Co-culture systems as a model of BM milieu. We cultured U937 cells on UCB-MSCs and MSCs Conditioned Medium (C.M) driven and then treated U937 cells with optimum concentration of chloride cobalt (CoCl2) as a hypoxia-mimetic agent. In addition, we applied suitable concentrations of H2O2 to induce cell death. Proliferation rate, cell death rate and some surface markers of hypoxic U937 cells were analyzed by MTT assay, flow cytometry and Real Time-PCR were flown respectively. Results: UCB-MSCs showed supportive effects on U937 proliferation rate in normoxia and hypoxia. Lethal effect of H2O2 suppressed in the presence of UCB-MSCs in hypoxia and normoxia. Among CD11a, CD14, CD49d, CD54 and CD116 markers, CD49d was down regulated in presence of UCB-MSCs and CD116 was up regulated in hypoxia. Other markers didn't show any significant changes. Conclusion: This work provides evidences that MSCs play critical roles in U937 cells biology. These observations shed new light on MSCs roles and demonstrated that MSCs should be regarded as an important member of BM milieu in several clinical applications such as BM transplantation prognosis and treatment of hematologic malignancies. PMID- 28101473 TI - Purification and Characterization of Bovine Serum Albumin Using Chromatographic Method. AB - Purpose: Albumin is an abundant protein of blood and has many biopharmaceutical applications. The aim of this study was to purify bovine serum albumin (BSA) using produced rabbit anti-BSA antibody. Methods: The polyclonal antibody was produced against the BSA in rabbits. Then, the pure BSA was injected to three white New Zealand rabbits. ELISA test was done to evaluate antibody production. After antibody purification,the purified antibody was attached to CNBr-activated sepharose and finally it was used for purification of albumin from bovine serum. Western blotting analysis was used for functional assessment of immunoaffinity purified BSA. Results: The titer of anti-bovine albumin determined by ELISA was obtained 1: 256000. The SDS-PAGE showed up to 98% purity of isolated BSA and western blotting confirmed the BSA functionality. Purified bovine serum albumin by affinity chromatography showed a single band with molecular weight of 66 KDa. Conclusion: Affinity chromatography using produced rabbit anti-BSA antibody would be an economical and safe method for purification of BSA. PMID- 28101474 TI - The Laboratory Diagnosis of Autoimmune Encephalitis. AB - Autoimmune encephalitis is a group of encephalitis syndromes that cause altered mentality, memory decline, or seizures in association with the presence of serum and cerebrospinal fluid (CSF) autoantibodies (auto-Abs). An early diagnosis enables early treatments. The detection of auto-Abs is a confirmatory diagnosis. Tissue-based assay, cell-based immunoassay, and immunoblotting are used to detect various autoantibodies. The CSF test for the presence of antibodies is important because it is more sensitive and reflects disease activity in many autoimmune encephalitis, although antibody tests can be negative even in the presence of autoimmune encephalitis. EEG is often abnormal, but nonspecific. A unilateral or bilateral medial temporal T2 high signal is a common finding in MRI. Fludeoxyglucose-positron emission tomography is sometimes useful for diagnosis in patients with normal MRI. PMID- 28101475 TI - Anticonvulsive Effects of Licofelone on Status Epilepticus Induced by Lithium pilocarpine in Wistar Rats: a Role for Inducible Nitric Oxide Synthase. AB - BACKGROUND AND PURPOSE: Status epilepticus (SE) is a neurological disorder with high prevalence and mortality rates, requiring immediate intervention. Licofelone is a cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibitor, which its effectiveness to treat osteoarthritis has been approved. Increasing evidence suggests an involvement of COX and LOX enzymes in epileptic disorders. Thus, in the present study we investigate possible effects of licofelone on prevention and termination of SE. We also evaluated whether the nitrergic system could participate in this effect of licofelone. METHODS: We have utilized lithium pilocarpine model of SE in adult Wistar rats to assess the potential effect of licofelone on seizure susceptibility. Licofelone was administered 1 h before pilocarpine. To evaluate probable role of nitric oxide (NO) system, L-arginine (60 mg/kg, i.p.), as a NO precursor; L-NAME (15 mg/kg, i.p.), as a non-selective nitric oxide synthase (NOS) inhibitor; aminoguanidine (100 mg/kg, i.p.), as an inducible NOS (iNOS) inhibitor and 7-nitroindazole (60 mg/kg, i.p.), as a neuronal NOS inhibitor were injected 15 min before licofelone. Also, licofelone and diazepam 10 mg/kg were administered 30 minutes after onset of SE. RESULTS: Pre-treatment with licofelone at the dosage of 10 mg/kg, significantly prevented the onset of SE in all subjects (p < 0.001). L-arginine significantly inverted this anticonvulsant effect (p < 0.05). However, L-NAME and aminoguanidine, potentiated the anticonvulsant effect of licofelone (p < 0.05, p < 0.01). Licofelone could not terminate seizures after onset which was terminated by diazepam. CONCLUSIONS: Our findings showed that anticonvulsive effects of licofelone on SE could be mediated by iNOS. Also, we suggest that COX/5-LOX activation is possibly required in the initial stage of onset but SE recruits extra excitatory pathways with prolongation. PMID- 28101476 TI - Psychometric Properties of the Persian Version of the Quality of Life in Epilepsy Inventory in the Later Life. AB - BACKGROUND AND PURPOSE: The reports indicate on the incidence of seizure disorder about 1.5 per cent of the normal elderly population. The Quality of Life in Epilepsy Inventory (QOLIE-31) has been pervasive simple tool to screen seizure in the busy neurophysiological settings and monitoring. It was constructed as self administered tool in two formats, 89 and 31-items. To the reliability and validity of the QOLIE-31 across older adults in the southwest Iran and discuss its role in the detection of health-related quality of elderly patients with epilepsy. METHODS: About 73 older adults (mean age = 66.3 +/- 1.71) were sampled from the eight hospitals and caring centres. They replied to the QOLIE-31. External and criterion validity was calculated by correlation to the SF-36 questionnaire, to check and validate the epilepsy specific dimensions. The QOLIE 31 includes seven subscales: overall quality of life, seizure worry, emotional well-being, energy/fatigue, cognitive, medication effects, and social function. RESULTS: There was significant difference within sample groups regarding main variables (p < 0.05). The coefficients of Cronbach's alpha (alpha= 0.76), convergent validity (0.81), divergent validity (-0.21), external validity with overall score of SF-36 (0.87), and criterion validity (0.78) were estimated, which were significant at p < 0.01. The exploratory factor analysis demonstrated that the QOLIE-31 is organized into six factors, which clarifies 92 per cent of the scale's variance. Second-order confirmatory factor analysis pointed out that the factor is well matched up onto a principal factor. Consequently, the 6 factors model was well appropriate for the data by the fit index techniques for adjusting the scale (AGFI = 0.94, GFI = 0.96, RMSEA = 0.003, IFI = 0.90, NFI = 0.95, CFI = 0.95). CONCLUSIONS: The results pointed to the well-adjusted reliability and psychometric properties of the QOLIE-31 and its usefulness for the relevant studies as well. PMID- 28101478 TI - Focal Epileptogenic Lesions in Adult Patients with Epilepsy and Generalized Epileptiform Discharges. AB - BACKGROUND AND PURPOSE: There are reports of successful resective epilepsy surgery for pediatric patients with epilepsy and generalized epileptiform discharges when they had focal epileptogenic lesions identified by MRI. However, there is limited information regarding adult patients with epilepsy who have both generalized epileptiform discharges and focal epileptogenic lesions. METHODS: To investigate the incidence and characteristics of adult patients who have both generalized epileptiform discharges and potentially epileptogenic lesions, we retrospectively analyzed data of clinical features and results of EEG and MRI of all patients with adult-onset epilepsy in a tertiary referral hospital. RESULTS: While 1315 patients were classified as having partial seizures, 207 patients were classified as having generalized seizures. Five of 207 patients (2.4%) with generalized seizures had potentially epileptogenic lesions. All the epileptogenic lesions were congenital or acquired during early life, such as focal cortical dysplasia, dysembryoplastic neuroepithelial tumor, and cerebromalacic change because of perinatal injury. CONCLUSIONS: The presence of epileptogenic lesions in adult patients with generalized epileptiform discharges may be an incidental finding, but it has been suggested that some adult-onset epilepsy with generalized epileptiform discharges may actually have focal onset, which may have significant clinical implications for the choice of appropriate treatment. PMID- 28101477 TI - Change of Patient Selection Strategy and Improved Surgical Outcome in MRI negative Neocortical Epilepsy. AB - BACKGROUND AND PURPOSE: It is crucial to make selection strategy to identify surgical candidates among medically refractory MRI-negative neocortical epilepsy patients. In our previous study, we suggested two or more concordance between noninvasive studies (EEG, ictal scalp EEG, interictal FDG-PET, and SPECT) as a new patient selection strategy for MRI-negative neocortical epilepsy surgery. The objective of this study was to evaluate the surgical outcomes of MRI-negative neocortical epilepsy patients before and after the implementation of a new selection strategy. METHODS: From 1995 to 2011, we included 153 consecutive MRI negative neocortical epilepsy patients who received focal resection and had a follow-up period of at least 2 years. These patients were divided into two groups according to their date of surgery (before and after July 2002). The old group consisted of 89 patients and the new one consisted of 53 patients. Clinical characteristics, presurgical evaluations, and pathology were reviewed. RESULTS: The new patient selection strategy led to a significant increase in the concordance between two or more modalities. The improvement in surgical outcome after 2002 was significant (seizure-free outcome, 47.2% vs. 75.5%; p = 0.001). Concordance between two or more presurgical evaluations and localizing PET were related to a seizure-free outcome in a multivariate analysis. CONCLUSIONS: After a change in surgical strategy to select patients with two or more concordance between noninvasive studies, the seizure-free outcome improved up to 75.5%. MRI negative neocortical epilepsy patients with two or more concordance between noninvasive studies seem to be good candidates for epilepsy surgery. PMID- 28101479 TI - Excessive Daytime Sleepiness and Sleep Disorders in a Population of Patients with Epilepsy: a Case-Control Study. AB - BACKGROUND AND PURPOSE: There are several primary causes for excessive daytime sleepiness (EDS) and sleep disorders in patients with epilepsy. Up to now, studies in the literature report conflicting data in terms of both prevalence and aetiology. The aim of our study was therefore to evaluate the prevalence of EDS and some sleep disorders in a population of patients with epilepsy treated with no more than two antiepileptic drugs (AEDs). We also investigated the role of the depression of mood as a variable that can negatively affect EDS. METHODS: We prospectively and consecutively recruited 99 patients with a diagnosis of epilepsy, sleep disorders and EDS, belonging to the Centre for Epilepsy of the Department of Experimental Biomedicine and Clinical Neurosciences of the University of Palermo. 61.6% of patients recruited were suffering from focal epilepsy, and 38.3% from generalized epilepsy. 68.6% were undertaking monotherapy and 27.2% were drug resistant. Patients were matched for sex and age (+/- 5 years) with 96 non epileptic controls recruited from high school students, college students, relatives and friends of the medical team that conducted the study. EDS was found in 11.1% of patients with epilepsy. Clinical evaluation of sleep disorders was performed using validated questionnaires to investigate excessive daytime sleepiness (EDS), insomnia, Restless Legs Syndrome (RLS) and Obstructive Sleep Apnoea Syndrome (OSAS). In a second phase of the study, 43 of the investigated patients and 34 controls - after giving their consent - underwent a polysomnographic examination by "Compumedics Somte". RESULTS: Our study shows a statistically significant difference between cases and controls with regard to the prevalence of RLS (p = 0.022) and severity of OSAS with an increased risk in moderate-severe forms of epilepsy (odd ratio [OR] 2.5) most significantly associated with male gender (p = 0.04) and focal epilepsy (OR 3.8) with PSG seizures (0.02). Moreover, a statistically significant difference was demonstrated about mood disorders (p = 0.001) among patients with epilepsy and non epileptic controls. Sleepiness in patients with epilepsy seems to be particularly related to both the depression of mood (p = 0.01) and the presence of OSAS (p = 0.03), as well as to a higher mean age (p = 0.006) and a longer duration of illness (p = 0.04). CONCLUSIONS: Our results confirm that drowsiness trouble frequently complained by patients with epilepsy, is particularly related not only to the presence of OSAS but also to the depression of mood. PMID- 28101480 TI - Spectrum of Cutaneous Adverse Reactions to Levetiracetam and Human Leukocyte Antigen Typing in North-Indian Patients. AB - BACKGROUND AND PURPOSE: Aromatic antiepileptic drugs are frequently implicated for cutaneous adverse drug reactions (cADRs); there are case-reports of even severe reactions like drug reaction eosinophilia and systemic symptoms (DRESS) and Stevens Johnson syndrome (SJS)-toxic epidermal necrolysis with Levetiracetam (LEV). Certain human leukocyte antigen (HLA)-alleles have strong association with cADRs due to specific drugs - HLA-B*15:02 and HLA-A*31:01 in Carbamazepine (CBZ) related SJS in Han-Chinese and European populations, respectively. Here, the spectrum of cADRs to LEV was studied, and HLA-typing in patients with cADRs due to LEV and some who were LEV-tolerant was performed, in an attempt to find an association between HLA and such reactions. METHODS: 589 patients taking LEV were screened for skin reactions, and eight patients with LEV-related cADRs and 25 LEV tolerant controls were recruited - all 33 of North Indian ethnicity, their HLA-A, B, DRB1 genotyping done. Statistical analysis was done to compare carrier-rates and allele-frequencies of HLA-alleles between cases and controls (and healthy population, where necessary) for alleles occurring more than two times in either group. RESULTS: Out of 589 patients on LEV screened, there were 8 cases of cADR: 5 with maculopapular exanthema (MPE), 2 of SJS, and 1 with DRESS. Although HLA A*33:01 was seen to occur more in MPE cases as compared to tolerant controls, the difference was not statistically significant (odds ratio [OR] 6.00, 95% confidence interval [CI] 0.30-116.6; p = 0.31). HLA A*11:01 and 24:02 were found to occur more in LEV-tolerant controls than in cases (OR 0.23 [95% CI 0.02-2.36, p = 0.33] and 1.00 [95% CI 0.09-11.02, p = 1.00] respectively). CONCLUSIONS: Cutaneous reactions to LEV are very unusual, and their association with HLA in North-Indian population was not statistically significant. PMID- 28101481 TI - Evaluation of Ictal Consciousness in Temporal and Extra Temporal Epilepsy: Observations from a Tertiary Care Hospital in India. AB - BACKGROUND AND PURPOSE: Differences in consciousness during seizures depend on the location of the seizure onset. METHODS: The present study evaluates ictal consciousness using the ictal consciousness inventory (ICI) in drug refractory mesial temporal (MTLE), neocortical temporal (NTLE) and extra temporal epilepsy (ETLE). This was a cross sectional cohort study with 45 patients with mesial temporal epilepsy, 47 with extra temporal and 11 patients with neocortical temporal epilepsy. The ICI a 20 item questionnaire was used to calculate the scores for level (L, question 1-10) and content (C, question 11-20) of consciousness. RESULTS: The patients in mesial temporal group had higher ICI-L scores, p = 0.0129 as compared to the extra temporal group, but no difference was observed in the content of consciousness. The ICI-L and C scores were not different in the mesial temporal and the neocortical temporal group (p = 0.53 and 0.65) respectively. CONCLUSIONS: Patients with mesial temporal epilepsy had a higher level of consciousness than the extra temporal group but there was no difference in the content. Also there was no difference in the level and content of consciousness between mesial and the neocortical temporal group. PMID- 28101482 TI - Cefepime-Induced Non-Convulsive Status Epilepticus in a Patient with Normal Renal Function. AB - Cefepime-induced encephalopathy including nonconvulsive status epilepticus has been known to develop in the patients with renal impairment. However, we report a 74-year-old woman with normal renal function who developed stuporous mental status during cefepime administration. Electroencephalogram (EEG) revealed 2 Hz rhythmic sharp-and-waves continuously, which suggested nonconvulsive status epilepticus (NCSE). After cefepime discontinuation, clinical symptoms recovered gradually and EEG findings showed only background slowing without epileptiform discharges. Cefepime-induced NCSE could be developed even in the patients with normal renal function, when they are elderly. Therefore, clinicians should be aware of the possibility of cefepime-induced NCSE when prescribing cefepime even to the patients with normal renal function. PMID- 28101484 TI - CADASIL Initially Presented with a Seizure. AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disease of the cerebral small blood vessels characterized by recurrent ischemic strokes, migraine, and progressive cognitive impairment. In patients with CADASIL, in whom subcortical white matter structures are typically involved, epileptic seizures have been rarely reported as an initial clinical symptom. We describe a patient genetically confirmed as having CADASIL who initially presented with a seizure. PMID- 28101483 TI - Intermittent Theta Slowings in Contralateral Side of Weakness after Sleep Deprivation on Spot EEG in Sporadic Hemiplegic Migraine. AB - Hemiplegic migraine (HM) is an uncommon type of migraine which is classified into sporadic and familial subtype. The noticed electroencephalogram (EEG) findings during HM attack are diffuse slowing contralateral to the weakened limb, but are usually normal in asymptomatic states. A 52-year-old woman who suffered from headache accompanying right arm weakness and aphasic symptoms admitted to our hospital. She underwent total five times of EEG including 2 times before admission. Only the last EEG exam after 24 hours of sleep deprivation (SD) showed intermittent slowing and higher amplitude of positive occipital sharp transients (POSTs) on the left parieto-occipital area. Here, we report a case with HM who revealed abnormal EEG findings after SD, which was not observed in the routine EEG study without SD. PMID- 28101485 TI - Minimizing the Health Effects of the Nuclear Accident in Fukushima on Thyroids. AB - RESULTS OF THE SCREENING OF THYROIDS: Because of the March 2011 nuclear accident in Fukushima, Japan, the Fukushima Prefecture initiated a thyroid ultrasound examination program. The first cycle of examinations on all children (more than 300,000) of the Fukushima Prefecture identified 116 patients as having malignant or suspected malignant thyroid nodules, and in the second cycle 59 new cases were identified. According to the available data, the thyroid cancers found by the screening are unlikely to be due to radiation, but the possibility cannot be excluded. URGENT MEASURES: The current thyroid ultrasound examination program has been detecting thyroid cancers, regardless of the cause, in all children in the Fukushima Prefecture. Fukushima Prefecture is already taking measures against thyroid cancer, even if an increase occurs in radiation-induced thyroid cancer in Fukushima Prefecture. Therefore, the urgent challenge is how to treat children with thyroid cancer found by the screening. FUTURE DIRECTIONS OF THE MEASURES: At the end of each cycle, the findings must be carefully discussed with experts around the world and among stakeholders in Fukushima, and a consensus must be reached regarding whether the current program will be continued or needs improvement. In addition, the survey should be improved as an epidemiological follow-up research program. Before starting this, a consensus must be reached with the inhabitants with regard to carrying out epidemiological research for several decades. Dialogue absolutely must continue among all stakeholders to determine how best to formulate a program to deal with urgent matters and to determine the next stage of any epidemiological research. PMID- 28101486 TI - Immunohistochemical Expression of Estrogen Receptor-alpha and Progesterone Receptor in Patients with Papillary Thyroid Cancer. AB - BACKGROUND: Papillary thyroid cancer (PTC) prevalence is nearly 3 times higher in females than in males. This gender difference suggests that growth and progression of PTC might be influenced by female sex hormones. OBJECTIVES: To analyze the expression of both estrogen receptor (ER)-alpha and progesterone receptor (PR) by immunohistochemistry in 203 PTC patients. METHODS: ER-alpha and PR expression was evaluated in paraffin-embedded tumor tissue samples of 45 males and 158 females followed up for 7.2 +/- 3.7 years. RESULTS: ER-alpha was expressed in 52 (25.6%) patients (41 females and 11 males) and PR in 94 (46.3%) patients (75 females and 19 males). ER-alpha and PR were coexpressed in 31 (15.3%) patients (27 females and 4 males). ER-alpha expression correlated significantly with tumor size in the whole sample (ER-alpha positive 22.8 +/- 11.8 mm vs. ER-alpha negative 15.1 +/- 12.4 mm; p = 0.02) and in the subgroup of women (ER-alpha positive 18.8 +/- 12.8 mm vs. ER-alpha negative 14.9 +/- 12.3 mm; p = 0.048). In addition, ER-alpha expression significantly correlated with remission of the disease. In fact, of the 192 patients followed up, 50/153 (32.7%) disease-free patients were ER-alpha positive, in contrast to only 3/39 (7.7%) with evidence of disease persistence/recurrence (chi2 = 8.5, p = 0.0036). PR expression was not associated with any of the parameters analyzed. CONCLUSIONS: The present study confirmed recent data indicating that ER-alpha and PR expression is a common finding in thyroid tumor tissue. However, in contrast to previous reports, we observed an association between ER-alpha expression and a more favorable outcome in PTC patients. PMID- 28101487 TI - Immunoglobulin G4-Related Thyroid Diseases. AB - Immunoglobulin G4-related disease (IgG4-RD) is a new disease category involving many organ systems, including the endocrine system in general and the thyroid in particular. Since an initial association was made between hypothyroidism and autoimmune (IgG4-related) pancreatitis, more forms of IgG4-related thyroid disease (IgG4-RTD) have been recognized. Four subcategories of IgG4-RTD have so far been identified: Riedel thyroiditis (RT), fibrosing variant of Hashimoto thyroiditis (FVHT), IgG4-related Hashimoto thyroiditis, and Graves disease with elevated IgG4 levels. Although a male predominance is seen for IgG4-RD in general, RT and FVHT have a female preponderance. The pathogenesis of IgG4-RD is not completely understood; however, genetic factors, antigen-antibody reactions, and an allergic phenomenon have been described. Diagnosis of IgG4-RD requires a combination of clinical features, serological evidence, and histological features. Histology is the mainstay of diagnosis, with IgG4 immunostaining. Although serum IgG4 levels are usually elevated in IgG4-RD, raised serum IgG4 is neither necessary nor adequate for diagnosis. Imaging supports the diagnosis and is a useful tool in disease monitoring. Management of IgG4-RTD is both medical and surgical. Steroids are the first-line treatment and may produce a swift response. Tamoxifen and rituximab are second-line agents used in steroid resistant patients. Surgical debulking is carried out in RT solely as a procedure to relieve obstruction. Other endocrine associations described with IgG4-RD are hypophysitis and Hashimoto encephalopathy. IgG4-RTD is an uncommon disease entity, and prompt diagnosis and treatment can improve outcomes. PMID- 28101488 TI - Thyroid Function and High-Sensitivity C-Reactive Protein in Cross-Sectional Results from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil): Effect of Adiposity and Insulin Resistance. AB - BACKGROUND: Subclinical hypothyroidism (SCH) is associated with an increased cardiovascular risk, but little information is available about its association with high-sensitivity C-reactive protein (hs-CRP). OBJECTIVES: This study aims to analyze the association between SCH and hs-CRP using baseline data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). METHODS: The study has a cross-sectional design. We included subjects with normal thyroid function (thyroid-stimulating hormone, TSH, 0.4-4.0 MUIU/ml and normal free thyroxine, fT4, 10.3-24.45 pmol/l) and SCH (TSH >4.0 MUIU/ml and normal fT4) who were evaluated for hs-CRP. We excluded individuals on medications that affect thyroid function and those who had prevalent cardiovascular disease. Multivariate linear regression evaluated hs-CRP and TSH as continuous variables, and logistic regression models assessed hs-CRP >=19.05 nmol/l as the dependent variable and crescent quintiles of TSH as the independent variables adjusted for demographic and cardiovascular risk factors. RESULTS: We included 12,284 subjects with a median age of 50 years (interquartile range = 45-57); 6,408 (52.2%) were female, 11,589 (94.3%) were euthyroid, and 695 (5.7%) had SCH. Bivariate analyses of participants stratified into quintiles of TSH revealed differences according to hs-CRP but not the Framingham risk score. The fifth quintile of TSH was not associated with elevated hs-CRP, odds ratio = 1.11 (95% confidence interval = 0.98-1.26), p = 0.102, in a fully adjusted logistic model, also consistent with the linear model (beta = 0.024, p = 0.145). CONCLUSIONS: TSH is not associated with hs-CRP. Obesity and insulin resistance are very important confounders in the study of the association between SCH and hs-CRP. PMID- 28101489 TI - Correction of Hypothyroidism Leads to Change in Lean Body Mass without Altering Insulin Resistance. AB - BACKGROUND: Hypothyroidism is associated with insulin resistance, dyslipidemia, and abnormal body composition. This study assessed changes in body composition and insulin resistance after thyroxine (T4) replacement in overt hypothyroidism. METHODS: In this prospective longitudinal study carried out in a tertiary care center, adult nondiabetic patients with overt hypothyroidism were rendered euthyroid on T4. Anthropometry including skinfold thickness (SFT) at the triceps and subscapularis was recorded. Patients underwent testing for fasting plasma glucose, creatinine, serum insulin, T4, thyrotropin (TSH) and body composition analysis by dual-energy X-ray absorptiometry (DEXA) both before and at 2 months after restoration to the euthyroid state. RESULTS: Twenty-seven patients (20 female and 7 male) aged 35.3 +/- 11.0 years (min-max: 17-59 years) with overt hypothyroidism were recruited. Serum T4 at the time of recruitment was 48.9 +/- 24.6 nmol/l (normal range = 64.4-142 nmol/l). All patients had TSH >=50 uIU/l. Following treatment, there was a mean body weight reduction of 1.7 kg (p = 0.01). Waist circumference as well as triceps and subscapularis SFT decreased significantly (p < 0.001). There was no change in fat mass (FM), percentage of fat (%FM) or bone mineral content in any of the specified regions or in the body as a whole. In contrast, mean lean body mass (LBM) decreased significantly by 0.8 kg (p < 0.01) in the trunk and 1.3 kg (p < 0.01) in the whole body. Insulin resistance and level of glycemia were not affected by treatment with T4. CONCLUSION: LBM decreases significantly without affecting FM after correction of hypothyroidism. Insulin resistance was not influenced by T4 treatment. PMID- 28101490 TI - Periodic Granulocyte Count Measuring Is Useful for Detecting Asymptomatic Agranulocytosis in Antithyroid Drug-Treated Patients with Graves' Disease. AB - OBJECTIVE: Finding agranulocytosis (AG) at an early stage is important to improve outcome, but periodic granulocyte count monitoring is not generally recommended for patients with Graves' disease, because AG develops suddenly. METHOD: At the Kuma Hospital, Graves' patients under antithyroid drug (ATD) treatment in an outpatient clinic have a granulocyte count examination during each visit, and if it is <1,000/MUl, a warning is immediately sent to the patient's physician. We evaluated the usefulness of this system. RESULTS: We investigated 25 AG and 33 granulocytopenia (GP) cases over a recent 5-year period, excluding patients who developed AG or GP at another hospital and were referred to us for treatment. Among the 25 AG patients, 16 patients (64%; 9 asymptomatic and 7 very mild symptomatic cases) were discovered by the periodic granulocyte count examination at an outpatient clinic. The remaining 9 patients visited the Kuma Hospital or other hospitals because of infection symptoms. Most of the AG patients were given granulocyte colony-stimulating factor injections immediately and were admitted if a prompt increase in granulocytes could not be obtained. The final treatments for Graves' disease were 131I-radioisotope therapy (19 patients), thyroidectomy (2 patients), inorganic iodine (1 patient), or another ATD (1 patient). Among the 33 GP patients, 31 (94%), including 20 asymptomatic cases, were discovered during periodic granulocyte count monitoring. Most of them stopped ATD, and other treatments for Graves' disease were selected. CONCLUSION: Periodic monitoring of granulocyte counts is useful for identifying AG and GP patients with no or minimum infection symptoms. PMID- 28101491 TI - Can the American Thyroid Association Risk of Recurrence Predict Radioiodine Refractory Disease in Differentiated Thyroid Cancer? AB - OBJECTIVE: The aim of this study was to compare the TNM staging system and the American Thyroid Association (ATA) recurrence risk classification in predicting radioiodine refractory disease (RRD) in differentiated thyroid cancer (DTC) and to analyze the correlation of stimulated thyroglobulin (Tg) levels and rate of Tg elevation with the standardized uptake value on 18F-fludeoxyglucose (FDG) PET/CT scan. METHODS: RRD was indicated through the retrospective analysis of consecutive 18F-FDG PET/CT scans in DTC with stimulated Tg >10 ng/ml and negative 131I NaI whole-body scans (WBS). Tg elevation velocity was compared to the likelihood of a positive scan. The ATA recurrence risk and TNM staging system were compared to see which of them better predicted the subsequent development of RRD. RESULTS: Fifty-eight of 636 subjects developed RRD: 52 papillary and 6 follicular thyroid cancer. The median time between diagnosis and a negative WBS was 24 months (range 12-240). RRD developed in 11 low-risk, 32 intermediate-risk and 15 high-risk patients. A better response to therapy was seen in the low-risk versus the intermediate- and high-risk groups. 18F-FDG PET/CT scans had a diagnostic accuracy of 94.8%, sensitivity of 97.7%, specificity of 85.7%, positive predictive value of 95.6% and negative predictive value of 92%. There was no correlation between the Tg level or rate of rise and a positive scan. Overall, PET-CT upstaged 18 (31%) cases, leading to a change in management in 20 (35%) cases. CONCLUSION: The TNM and ATA staging systems show no significant difference in predicting the development of RRD. RRD is less likely in stage I, II and low-risk patients. There is no correlation between the level or rate of Tg rise and a positive 18F-FDG PET/CT scan. PMID- 28101493 TI - An Invitation to Join the Consortium on Thyroid and Pregnancy. PMID- 28101492 TI - Trends and Predictors of Chemotherapy Use among Thyroid Cancer Patients in the National Cancer Database (2004-2013). AB - BACKGROUND/AIM: Beginning in 2011, the Food and Drug Administration (FDA) approved the use of multikinase inhibitors (MKIs) for medullary thyroid cancers (MTCs), and in 2013 MKIs were approved for metastatic differentiated thyroid cancers (DTCs). However, little is known about the use of chemotherapy in thyroid cancer patients. Thus, the goal of our study was to describe patterns of chemotherapy use, including MKIs, among DTC and MTC patients in the National Cancer Database (NCDB). METHODS: Chemotherapy use, along with other treatment types (surgery and radiation), was assessed between 2004 and 2013. The primary predictor was the year of diagnosis (2004-2010 and 2011-2013), based on the FDA's approval of chemotherapy for MTC (2011). Baseline use of MKIs in DTCs in 2013 was also examined. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% CI of receipt of chemotherapy. RESULTS: Overall, 199,654 patients were included in our analytic sample with 194,667 nonmetastatic DTCs, 1,633 metastatic DTCs, and 3,354 MTCs. Among MTCs, chemotherapy use significantly increased from 3.1% in 2004-2010 to 5.0% in 2011-2013 (p = 0.018) in unadjusted and adjusted (OR = 1.54, 95% CI: 1.00, 2.36) analyses. In metastatic DTCs, 4.9% of patients received chemotherapy in 2013, which was not significantly higher than in previous years (p = 0.755). CONCLUSIONS: Overall, chemotherapy use among MTCs increased marginally following the FDA's approval of MKIs in 2011, although their use remains very low. MKIs were infrequently used in metastatic DTCs in 2013. Future studies examining patterns of chemotherapy in thyroid cancer patients are warranted. PMID- 28101494 TI - Origin of Thyroid C Cells: Clinical Interpretation. PMID- 28101495 TI - Medullary Thyroid Carcinoma - Distinction towards Neuroectodermal Tumours: Reply to the Letter by Paschou and Vryonidou. PMID- 28101496 TI - Medication-related osteonecrosis of the jaw: a preliminary retrospective study of 130 patients with multiple myeloma. AB - BACKGROUND: Multiple myeloma (MM) is characterized by a neoplastic proliferation of plasma cells primarily in the bone marrow. Bisphosphonates (BP) are used as supportive therapy in the management of MM. This study aimed to analyze the incidence, risk factors, and clinical outcomes of medication-related necrosis of the jaw (MRONJ) in MM patients. METHODS: One hundred thirty MM patients who had previous dental evaluations were retrospectively reviewed. Based on several findings, we applied the staging and treatment strategies on MRONJ. We analyzed gender, age, type of BP, incidence, and local etiological factors and assessed the relationship between these factors and the clinical findings at the first oral examination. RESULTS: MRONJ was found in nine male patients (6.9%). The mean patient age was 62.2 years. The median BP administration time was 19 months. Seven patients were treated with a combination of IV zoledronate and pamidronate, and two patients received single-agent therapy. The lesions were predominantly located in the mandible (n = 8), and the most common predisposing dental factor was a history of prior extraction (n = 6). Half of the MRONJ were related to diseases found on the initial dental screen. Patients with MRONJ were treated with infection control and antibiotic therapy. When comparing between the MRONJ stage and each factor (sign, location, etiologic factor, BP type, treatment, and outcome), there were no significant differences between stages, except for between the stage and sign (with or without purulence). CONCLUSIONS: For prevention of MRONJ, we recommend routine dental examinations and treatment prior to starting BP therapy. PMID- 28101497 TI - The factors that influence postoperative stability of the dental implants in posterior edentulous maxilla. AB - BACKGROUND: All clinicians are aware of the difficulty of installing a dental implant in posterior maxilla because of proximate position of maxillary sinus, insufficient bone width, and lower bone density. This study is to examine which factors will make the implantation in the posterior maxilla more difficult, and which factors will affect the postoperative implant stability in this region. METHODS: Five hundred seventy-three fixtures on the maxilla posterior were included for this study from all the patients who underwent an installation of the dental implant fixture from January 2010 to December 2014 at the Department of Oral and Maxillofacial Surgery in Pusan National University Dental Hospital (Yangsan, Korea). The postoperative implant stability quotient (ISQ) value, fixture diameter and length, presence of either bone graft or sinus lift, and graft material were included in the reviewed factors. The width and height of the bone bed was assessed via preoperative cone beam CT image analysis. The postoperative ISQ value was taken just before loading by using the OsstellTM mentor(r) (Integration Diagnostics AB, Gothenburg, Sweden). The t test and ANOVA methods were used in the statistical analysis of the data. RESULTS: Mean ISQ of all the included data was 79.22. Higher initial bone height, larger fixture diameter, and longer fixture length were factors that influence the implant stability on the posterior edentulous maxilla. On the other hand, the initial bone width, bone graft and sinus elevation procedure, graft material, and approach method for sinus elevation showed no significant impact associated with the implant stability on the posterior edentulous maxilla. CONCLUSIONS: It is recommended to install the fixtures accurately in a larger diameter and longer length by performing bone graft and sinus elevation. PMID- 28101498 TI - Hepatitis B Stigma and Knowledge among Vietnamese in Ho Chi Minh City and Chicago. AB - Stigma regarding viral hepatitis and liver disease has psychological and social consequences including causing negative self-image, disrupting relationships, and providing a barrier to prevention, testing, and treatment. The aim of this study was to characterize and compare HBV knowledge and stigma in Vietnamese in Ho Chi Minh City and Chicago and to begin to evaluate the cultural context of HBV stigma. Methods. A written survey including knowledge questions and a validated HBV stigma questionnaire was distributed to Vietnamese in Ho Chi Minh City and Chicago. 842 surveys from Ho Chi Minh City and 170 from Chicago were analyzed. Results. Vietnamese living in Chicago had better understanding of HBV transmission and that HBV can cause chronic infection and liver cancer. Vietnamese in Chicago had higher stigma scores on a broad range of items including guilt and shame about HBV and were more likely to feel that persons with HBV can bring harm to others and should be isolated. Conclusions. Vietnamese in Ho Chi Minh City and Chicago have knowledge deficits about HBV, particularly regarding modes of transmission. Persons in Ho Chi Minh City expressed lower levels of HBV stigma than Vietnamese living in Chicago, likely reflecting changing cultural attitudes in Vietnam. Culturally appropriate educational initiatives are needed to address the problem of HBV stigma. PMID- 28101500 TI - Corrigendum: Spleen-Dependent Immune Protection Elicited by CpG Adjuvanted Reticulocyte-Derived Exosomes from Malaria Infection Is Associated with Changes in T Cell Subsets' Distribution. AB - [This corrects the article on p. 131 in vol. 4, PMID: 27900319.]. PMID- 28101499 TI - Plasma Membrane Targeting of Endogenous NKCC2 in COS7 Cells Bypasses Functional Golgi Cisternae and Complex N-Glycosylation. AB - Na+K+2Cl- co-transporters (NKCCs) effect the electroneutral movement of Na+-K+ and 2Cl- ions across the plasma membrane of vertebrate cells. There are two known NKCC isoforms, NKCC1 (Slc12a2) and NKCC2 (Slc12a1). NKCC1 is a ubiquitously expressed transporter involved in cell volume regulation, Cl- homeostasis and epithelial salt secretion, whereas NKCC2 is abundantly expressed in kidney epithelial cells of the thick ascending loop of Henle, where it plays key roles in NaCl reabsorption and electrolyte homeostasis. Although NKCC1 and NKCC2 co transport the same ions with identical stoichiometry, NKCC1 actively co transports water whereas NKCC2 does not. There is growing evidence showing that NKCC2 is expressed outside the kidney, but its function in extra-renal tissues remains unknown. The present study shows molecular and functional evidence of endogenous NKCC2 expression in COS7 cells, a widely used mammalian cell model. Endogenous NKCC2 is primarily found in recycling endosomes, Golgi cisternae, Golgi-derived vesicles, and to a lesser extent in the endoplasmic reticulum. Unlike NKCC1, NKCC2 is minimally hybrid/complex N-glycosylated under basal conditions and yet it is trafficked to the plasma membrane region of hyper osmotically challenged cells through mechanisms that require minimal complex N glycosylation or functional Golgi cisternae. Control COS7 cells exposed to slightly hyperosmotic (~6.7%) solutions for 16 h were not shrunken, suggesting that either one or both NKCC1 and NKCC2 may participate in cell volume recovery. However, NKCC2 targeted to the plasma membrane region or transient over expression of NKCC2 failed to rescue NKCC1 in COS7 cells where NKCC1 had been silenced. Further, COS7 cells in which NKCC1, but not NKCC2, was silenced exhibited reduced cell size compared to control cells. Altogether, these results suggest that NKCC2 does not participate in cell volume recovery and therefore, NKCC1 and NKCC2 are functionally different Na+K+2Cl- co-transporters. PMID- 28101501 TI - Classical Presentation of Acute Pyelonephritis in a Case of Brucellosis. AB - Although Brucella species is known to affect almost all organs in humans, renal involvement presenting as acute pyelonephritis remains a rare entity in brucellosis. We report the case of a female patient who presented with symptoms of fever with chills, right loin pain and dysuria in the emergency room. Blood cultures drawn at the time of admission grew Brucella spp., but no organisms were isolated from urine culture although urinalysis data was indicative of urinary tract infection. Empiric therapy with piperacillin/tazobactam plus gentamicin relieved her symptoms. However, the treatment was switched to doxycycline plus rifampicin once the blood culture result was obtained. PMID- 28101502 TI - Pregnant Woman with Atypical Hemolytic Uremic Syndrome Delivered a Healthy Newborn under Eculizumab Treatment. AB - Pregnancy-associated thrombotic microangiopathy is a very rare condition; however, it significantly increases fetal or maternal morbidity and mortality. Pregnancy may trigger atypical hemolytic uremic syndrome (aHUS) or thrombotic thrombocytopenic purpura. The risk for pregnancy-associated aHUS is highest during the second pregnancy. The outcome is usually poor with 50-60% mortality; renal dysfunction and hypertension are the rule in those who survive the acute episode. After the development of complement regulation mechanisms and aHUS pathogenesis, eculizumab has been widely used as a first-line treatment in aHUS. Eculizumab has been produced to minimize immunogenicity and Fc-mediated functions, including recruitment of inflammatory cells and complement activation, and using eculizumab in first-line treatment improves kidney function. Recent studies showed that early diagnosis and rapid use of eculizumab in first-line treatment improve outcomes. We demonstrate a case with pregnancy-triggered aHUS occurring in the second trimester, who was successfully treated and delivered a healthy baby under eculizumab treatment. PMID- 28101503 TI - Detection of QTLs for Yield Heterosis in Rice Using a RIL Population and Its Testcross Population. AB - Analysis of the genetic basis of yield heterosis in rice was conducted by quantitative trait locus mapping using a set of 204 recombinant inbred lines (RILs), its testcross population, and mid-parent heterosis dataset (HMP). A total of 39 QTLs for six yield traits were detected, of which three were detected in all the datasets, ten were common to the RIL and testcross populations, six were common to the testcross and HMP, and 17, 2, and 1 were detected for RILs, testcrosses, and HMP, respectively. When a QTL was detected in both the RIL and testcross populations, the difference between TQ and IR24 and that between Zh9A/TQ and Zh9A/IR24 were always in the same direction, providing the potential to increase the yield of hybrids by increasing the yield of parental lines. Genetic action mode of the 39 QTLs was inferred by comparing their performances in RILs, testcrosses, and HMP. The genetic modes were additive for 17 QTLs, dominance for 12 QTLs, and overdominance for 10 QTLs. These results suggest that dominance and overdominance are the most important contributor to yield heterosis in rice, in which the accumulative effects of yield components play an important role. PMID- 28101504 TI - Voltage-Dependent Inactivation of MscS Occurs Independently of the Positively Charged Residues in the Transmembrane Domain. AB - MscS (mechanosensitive channel of small conductance) is ubiquitously found among bacteria and plays a major role in avoiding cell lysis upon rapid osmotic downshock. The gating of MscS is modulated by voltage, but little is known about how MscS senses membrane potential. Three arginine residues (Arg-46, Arg-54, and Arg-74) in the transmembrane (TM) domain are possible to respond to voltage judging from the MscS structure. To examine whether these residues are involved in the voltage dependence of MscS, we neutralized the charge of each residue by substituting with asparagine (R46N, R54N, and R74N). Mechanical threshold for the opening of the expressed wild-type MscS and asparagine mutants did not change with voltage in the range from -40 to +100 mV. By contrast, inactivation process of wild-type MscS was strongly affected by voltage. The wild-type MscS inactivated at +60 to +80 mV but not at -60 to +40 mV. The voltage dependence of the inactivation rate of all mutants tested, that is, R46N, R54N, R74N, and R46N/R74N MscS, was almost indistinguishable from that of the wild-type MscS. These findings indicate that the voltage dependence of the inactivation occurs independently of the positive charges of R46, R54, and R74. PMID- 28101505 TI - Gaps in the Continuum of HIV Care: Long Pretreatment Waiting Time between HIV Diagnosis and Antiretroviral Therapy Initiation Leads to Poor Treatment Adherence and Outcomes. AB - Background. Criteria for antiretroviral treatment (ART) were adjusted to enable early HIV treatment for people living HIV/AIDS (PLHIV) in China in recent years. This study aims to determine how pretreatment waiting time after HIV confirmation affects subsequent adherence and outcomes over the course of treatment. Methods. A retrospective observational cohort study was conducted using treatment data from PLHIV in Yuxi, China, between January 2004 and December 2015. Results. Of 1,663 participants, 348 were delayed testers and mostly initiated treatment within 28 days. In comparison, 1,315 were nondelayed testers and the median pretreatment waiting time was 599 days, but it significantly declined over the study period. Pretreatment CD4 T-cell count drop (every 100 cells/mm3) contributed slowly in CD4 recovery after treatment initiation (8% less, P < 0.01) and increased the risk of poor treatment adherence by 15% (ARR = 1.15, 1.08 1.25). Every 100 days of extensive pretreatment waiting time increased rates of loss to follow-up by 20% (ARR = 1.20, 1.07-1.29) and mortality rate by 11% (ARR = 1.11, 1.06-1.21), based on multivariable Cox regression. Conclusion. Long pretreatment waiting time in PLHIV can lead to higher risk of poor treatment adherence and HIV-related mortality. Current treatment guidelines should be updated to provide ART promptly. PMID- 28101508 TI - Animal Models of Human Pathology 2016. PMID- 28101507 TI - Assessing the Contribution of the Oscillatory Potentials to the Genesis of the Photopic ERG with the Discrete Wavelet Transform. AB - The electroretinogram (ERG) is composed of slow (i.e., a-, b-waves) and fast (i.e., oscillatory potentials: OPs) components. OPs have been shown to be preferably affected in some diseases (such as diabetic retinopathy), while the a- and b-waves remain relatively intact. The purpose of this study was to determine the contribution of OPs to the building of the ERG and to examine whether a signal mostly composed of OPs could also exist. DWT analyses were performed on photopic ERGs (flash intensities: -2.23 to 2.64 log cd.s.m-2 in 21 steps) obtained from normal subjects (n = 40) and patients (n = 21) affected with a retinopathy. In controls, the %OP value (i.e., OPs energy/ERG energy) is stimulus and amplitude-independent (range: 56.6-61.6%; CV = 6.3%). In contrast, the %OPs measured from the ERGs of our patients varied significantly more (range: 35.4% 89.2%; p < 0.05) depending on the pathology, some presenting with ERGs that are almost solely composed of OPs. In conclusion, patients may present with a wide range of %OP values. Findings herein also support the hypothesis that, in certain conditions, the photopic ERG can be mostly composed of high-frequency components. PMID- 28101506 TI - Functional Characterization of the N-Terminal C2 Domain from Arabidopsis thaliana Phospholipase Dalpha and Dbeta. AB - Most of plant phospholipases D (PLD) exhibit a C2-lipid binding domain of around 130 amino acid residues at their N-terminal region, involved in their Ca2+ dependent membrane binding. In this study, we expressed and partially purified catalytically active PLDalpha from Arabidopsis thaliana (AtPLDalpha) in the yeast Pichia pastoris. The N-terminal amino acid sequence of the recombinant AtPLDalpha was found to be NVEETIGV and thus to lack the first 35 amino acid belonging to the C2 domain, as found in other recombinant or plant purified PLDs. To investigate the impact of such a cleavage on the functionality of C2 domains, we expressed, in E. coli, purified, and refolded the mature-like form of the C2 domain of the AtPLDalpha along with its equivalent C2 domain of the AtPLDbeta, for the sake of comparison. Using Forster Resonance Energy Transfer and dot-blot assays, both C2 domains were shown to bind phosphatidylglycerol in a Ca2+ independent manner while phosphatidic acid and phosphatidylserine binding were found to be enhanced in the presence of Ca2+. Amino acid sequence alignment and molecular modeling of both C2 domains with known C2 domain structures revealed the presence of a novel Ca2+-binding site within the C2 domain of AtPLDalpha. PMID- 28101509 TI - Expression Profile of Long Noncoding RNAs in Human Earlobe Keloids: A Microarray Analysis. AB - Background. Long noncoding RNAs (lncRNAs) play key roles in a wide range of biological processes and their deregulation results in human disease, including keloids. Earlobe keloid is a type of pathological skin scar, and the molecular pathogenesis of this disease remains largely unknown. Methods. In this study, microarray analysis was used to determine the expression profiles of lncRNAs and mRNAs between 3 pairs of earlobe keloid and normal specimens. Gene Ontology (GO) categories and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to identify the main functions of the differentially expressed genes and earlobe keloid-related pathways. Results. A total of 2068 lncRNAs and 1511 mRNAs were differentially expressed between earlobe keloid and normal tissues. Among them, 1290 lncRNAs and 1092 mRNAs were upregulated, and 778 lncRNAs and 419 mRNAs were downregulated. Pathway analysis revealed that 24 pathways were correlated to the upregulated transcripts, while 11 pathways were associated with the downregulated transcripts. Conclusion. We characterized the expression profiles of lncRNA and mRNA in earlobe keloids and suggest that lncRNAs may serve as diagnostic biomarkers for the therapy of earlobe keloid. PMID- 28101511 TI - Video-Assisted Thoracoscopic Surgery and Minimal Access Spinal Surgery Compared in Anterior Thoracic or Thoracolumbar Junctional Spinal Reconstruction: A Case Control Study and Review of the Literature. AB - There are no published reports that compare the outcomes of video-assisted thoracoscopic surgery (VATS) and minimal access spinal surgery (MASS) in anterior spinal reconstruction. We conducted a retrospective case-control study in a single center and systematically reviewed the literature to compare the efficacy and safety of VATS and MASS in anterior thoracic (T) and thoracolumbar junctional (TLJ) spinal reconstruction. From 1995 to 2012, there were 111 VATS patients and 76 MASS patients treated at our hospital. VATS patients had significantly (p < 0.001) longer operating times and significantly (p < 0.022) higher thoracotomy conversion rates. We reviewed 6 VATS articles and 10 MASS articles, in which there were 625 VATS patients and 399 MASS patients. We recorded clinical complications and a thoracotomy conversion rate from our cases and the selected articles. The incidence of approach-related complications was significantly (p = 0.021) higher in VATS patients. The conversion rate was 2% in VATS patients and 0% in MASS patients (p = 0.001). In conclusion, MASS is associated with reduction in operating time, approach-related complications, and the thoracotomy conversion rate. PMID- 28101512 TI - Analysis of Carbon Fiber Reinforced PEEK Hinge Mechanism Articulation Components in a Rotating Hinge Knee Design: A Comparison of In Vitro and Retrieval Findings. AB - Carbon fiber reinforced poly-ether-ether-ketone (CFR-PEEK) represents a promising alternative material for bushings in total knee replacements, after early clinical failures of polyethylene in this application. The objective of the present study was to evaluate the damage modes and the extent of damage observed on CFR-PEEK hinge mechanism articulation components after in vivo service in a rotating hinge knee (RHK) system and to compare the results with corresponding components subjected to in vitro wear tests. Key question was if there were any similarities or differences between in vivo and in vitro damage characteristics. Twelve retrieved RHK systems after an average of 34.9 months in vivo underwent wear damage analysis with focus on the four integrated CFR-PEEK components and distinction between different damage modes and classification with a scoring system. The analysis included visual examination, scanning electron microscopy, and energy dispersive X-ray spectroscopy, as well as surface roughness and profile measurements. The main wear damage modes were comparable between retrieved and in vitro specimens (n = 3), whereby the size of affected area on the retrieved components showed a higher variation. Overall, the retrieved specimens seemed to be slightly heavier damaged which was probably attributable to the more complex loading and kinematic conditions in vivo. PMID- 28101510 TI - Roles of pRB in the Regulation of Nucleosome and Chromatin Structures. AB - Retinoblastoma protein (pRB) interacts with E2F and other protein factors to play a pivotal role in regulating the expression of target genes that induce cell cycle arrest, apoptosis, and differentiation. pRB controls the local promoter activity and has the ability to change the structure of nucleosomes and/or chromosomes via histone modification, epigenetic changes, chromatin remodeling, and chromosome organization. Functional inactivation of pRB perturbs these cellular events and causes dysregulated cell growth and chromosome instability, which are hallmarks of cancer cells. The role of pRB in regulation of nucleosome/chromatin structures has been shown to link to tumor suppression. This review focuses on the ability of pRB to control nucleosome/chromatin structures via physical interactions with histone modifiers and chromatin factors and describes cancer therapies based on targeting these protein factors. PMID- 28101513 TI - Comparison of Sexual Knowledge, Attitude, and Behavior between Female Chinese College Students from Urban Areas and Rural Areas: A Hidden Challenge for HIV/AIDS Control in China. AB - Currently, research in sexual behavior and awareness in female Chinese college students (FCCSs) is limited, particularly regarding the difference and the influencing factors between students from rural areas and urban areas. To fill the gap in available data, a cross-sectional study using anonymous questionnaires was conducted among 3193 female students from six universities located in Beijing, Shanghai, and Guangzhou, China, from February to June, 2013. Of the 2669 respondents, 20.6% and 20.9% of the students from urban and rural areas, respectively, reported being sexually experienced. The proportion of students who received safe-sex education prior to entering university from rural areas (22.4%, 134/598) was lower (P < 0.0001) than the proportion from urban areas (41.8%, 865/2071). Sexual behavior has become increasingly common among FCCSs, including high-risk sexual behavior such as unprotected commercial sex. However, knowledge concerning human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) transmission and the risks is insufficient, particularly for those from rural areas, which is a challenge for HIV/AIDS control in China. The Chinese government should establish more specific HIV/AIDS prevention policies for Chinese young women, strengthen sex education, and continue to perform relevant research. PMID- 28101514 TI - [18F]FDG Uptake in the Aortic Wall Smooth Muscle of Atherosclerotic Plaques in the Simian Atherosclerosis Model. AB - Atherosclerosis is a self-sustaining inflammatory fibroproliferative disease that progresses in discrete stages and involves a number of cell types and effector molecules. Recently, [18F]fluoro-2-deoxy-D-glucose- ([18F]FDG-) positron emission tomography (PET) has been suggested as a tool to evaluate atherosclerotic plaques by detecting accumulated macrophages associated with inflammation progress. However, at the cellular level, it remains unknown whether only macrophages exhibit high uptake of [18F]FDG. To identify the cellular origin of [18F]FDG uptake in atherosclerotic plaques, we developed a simian atherosclerosis model and performed PET and ex vivo macro- and micro-autoradiography (ARG). Increased [18F]FDG uptake in the aortic wall was observed in high-cholesterol diet-treated monkeys and WHHL rabbits. Macro-ARG of [18F]FDG in aortic sections showed that [18F]FDG was accumulated in the media and intima in the simian model as similar to that in WHHL rabbits. Combined analysis of micro-ARG with immunohistochemistry in the simian atherosclerosis model revealed that most cellular [18F]FDG uptake observed in the media was derived not only from the infiltrated macrophages in atherosclerotic plaques but also from the smooth muscle cells (SMCs) of the aortic wall in atherosclerotic lesions. PMID- 28101518 TI - Is It Time to Include CT "Reverse Halo Sign" and qPCR Targeting Mucorales in Serum to EORTC-MSG Criteria for the Diagnosis of Pulmonary Mucormycosis in Leukemia Patients? AB - In 23 leukemia patients with proven (n = 17) or possible (n = 6) pulmonary mucormycosis (PM), the presence of reversed halo sign on computed tomography was strongly associated with the positivity of quantitative polymerase chain reaction assays targeting Mucorales in the serum, confirming the value of these two tools for the diagnosis of PM in this setting. PMID- 28101519 TI - Delayed tacrolimus leukoencephalopathy, a rare and reversible cause of dementia. PMID- 28101516 TI - Postocclusive Hyperemia Measured with Laser Doppler Flowmetry and Transcutaneous Oxygen Tension in the Diagnosis of Primary Raynaud's Phenomenon: A Prospective, Controlled Study. AB - The aim of this study was to measure the sensitivity and specificity of transcutaneous oxygen tension and postocclusive hyperemia testing using laser Doppler flowmetry in patients with primary Raynaud's phenomenon. One hundred patients and one hundred controls were included in the study. Baseline microvascular blood flow and then time to peak flow following occlusion were measured using laser Doppler flowmetry. Afterwards, the transcutaneous oxygen tension was recorded. The sensitivities of baseline microvascular blood flow, postocclusive time to peak flow, and transcutaneous oxygen tension were 79%, 79%, and 77%, respectively. The postocclusive time peak flow had a superior specificity of 90% and area under the curve of 0.92 as compared to 66% and 0.80 for baseline microvascular flow and 64% and 0.76 for transcutaneous oxygen tension. Time to postocclusive peak blood flow measured by laser Doppler flowmetry is a highly accurate test for differentiating patients with primary Raynaud's phenomenon from healthy controls. PMID- 28101520 TI - An observational study of alemtuzumab following fingolimod for multiple sclerosis. AB - OBJECTIVE: To describe a series of patients with relapsing multiple sclerosis (MS) who experienced significant and unexpected disease activity within the first 12 months after switching from fingolimod to alemtuzumab. METHODS: Patients with relapsing MS treated sequentially with fingolimod then alemtuzumab who experienced significant subsequent disease activity were identified by personal communication with 6 different European neuroscience centers. RESULTS: Nine patients were identified. Median disease duration to alemtuzumab treatment was 94 (39-215) months and follow-up from time of first alemtuzumab cycle 20 (14-21) months. Following first alemtuzumab infusion cycle, 8 patients were identified by at least 1 clinical relapse and radiologic disease activity and 1 by significant radiologic disease activity alone. CONCLUSIONS: We acknowledge the potential for ascertainment bias; however, these cases may illustrate an important cause of reduced efficacy of alemtuzumab in a vulnerable group of patients with MS most in need of disease control. We suggest that significant and unexpected subsequent disease activity after alemtuzumab induction results from prolonged sequestration of autoreactive lymphocytes following fingolimod withdrawal, allowing these cells to be concealed from the usual biological effect of alemtuzumab. Subsequent lymphocyte egress then provokes disease reactivation. Further animal studies and clinical trials are required to confirm these phenomena and in the meantime careful consideration should be given to mode of action of individual therapies and sequential treatment effects in MS when designing personalized treatment regimens. PMID- 28101521 TI - Anti-Inflammatory Effects of Protein Kinase Inhibitor Pyrrol Derivate. AB - In our previous studies we showed antitumor and anti-inflammatory activities of protein kinases inhibitor pyrrol derivate 1-(4-Cl-benzyl)-3-Cl-4-(CF3-fenylamino) 1H-pyrrol-2,5-dione (MI-1) on rat colon cancer model. Therefore anti-inflammatory effect of MI-1 on rat acetic acid induced ulcerative colitis (UC) model was aimed to be discovered. The anti-inflammatory effects of MI-1 (2.7 mg/kg daily) compared to reference drug Prednisolone (0.7 mg/kg daily) after 14-day usage were evaluated on macro- and light microscopy levels and expressed in 21-grade scale. Redox status of bowel mucosa was also estimated. It was shown that in UC group the grade of total injury (GTI) was equal to 9.6 (GTIcontrol = 0). Increase of malonic dialdehyde (MDA) by 89% and protein carbonyl groups (PCG) by 60% and decrease of superoxide dismutase (SOD) by 40% were also observed. Prednisolone decreased GTI to 3 and leveled SOD activity, but MDA and PCG remained higher than control ones by 52% and 42%, respectively. MI-1 restored colon mucosa integrity and decreased mucosa inflammation down to GTI = 0.5 and leveled PCG and SOD. Thus, MI-1 possessed anti-inflammatory properties, which were more expressed that Prednisolone ones, as well as normalized mucosa redox balance, and so has a prospect for correction of inflammatory processes. PMID- 28101517 TI - The Role of HMGB1 in the Pathogenesis of Type 2 Diabetes. AB - Significance. With an alarming increase in recent years, diabetes mellitus has become a global challenge. Despite advances in treatment of diabetes mellitus, currently, medications available are unable to control the progression of diabetes and its complications. Growing evidence suggests that inflammation is an important pathogenic mediator in the development of diabetes mellitus. The perspectives including suggestions for new therapies involving the shift from metabolic stress to inflammation should be taken into account. Critical Issues. High-mobility group box 1 (HMGB1), a nonhistone nuclear protein regulating gene expression, was rediscovered as an endogenous danger signal molecule to trigger inflammatory responses when released into extracellular milieu in the late 1990s. Given the similarities of inflammatory response in the development of T2D, we will discuss the potential implication of HMGB1 in the pathogenesis of T2D. Importantly, we will summarize and renovate the role of HMGB1 and HMGB1-mediated inflammatory pathways in adipose tissue inflammation, insulin resistance, and islet dysfunction. Future Directions. HMGB1 and its downstream receptors RAGE and TLRs may serve as potential antidiabetic targets. Current and forthcoming projects in this territory will pave the way for prospective approaches targeting the center of HMGB1-mediated inflammation to improve T2D and its complications. PMID- 28101522 TI - What Influences Where They Give Birth? Determinants of Place of Delivery among Women in Rural Ghana. AB - Background. There is a paucity of empirical literature in Ghana on rural areas and their utilisation of health facilities. The study examined the effects of the sociodemographics of rural women on place of delivery in the country. Methods. The paper made use of data from the 2014 Ghana Demographic and Health Survey. Women from rural areas who had given birth within five years prior to the survey were included in the analysis. Descriptive analyses and binary logistic regression were used to analyse the data. Results. Wealth, maternal education, ecological zone, getting money for treatment, ethnicity, partner's education, parity, and distance to a health facility were found as the determinants of place of delivery among women in rural Ghana. Women in the richest wealth quintile were three times (OR = 3.04, 95% CI = 0.35-26.4) more likely to deliver at a health facility than the poorest women. Conclusions. It behoves the relevant stakeholders including the Ghana Health Service and the Ministry of Health to pay attention to the wealth status, maternal education, ecological zone, ethnicity, partner's education, parity, and distance in their planning regarding delivery care in rural Ghana. PMID- 28101515 TI - Signaling Pathways in Cardiac Myocyte Apoptosis. AB - Cardiovascular diseases, the number 1 cause of death worldwide, are frequently associated with apoptotic death of cardiac myocytes. Since cardiomyocyte apoptosis is a highly regulated process, pharmacological intervention of apoptosis pathways may represent a promising therapeutic strategy for a number of cardiovascular diseases and disorders including myocardial infarction, ischemia/reperfusion injury, chemotherapy cardiotoxicity, and end-stage heart failure. Despite rapid growth of our knowledge in apoptosis signaling pathways, a clinically applicable treatment targeting this cellular process is currently unavailable. To help identify potential innovative directions for future research, it is necessary to have a full understanding of the apoptotic pathways currently known to be functional in cardiac myocytes. Here, we summarize recent progress in the regulation of cardiomyocyte apoptosis by multiple signaling molecules and pathways, with a focus on the involvement of these pathways in the pathogenesis of heart disease. In addition, we provide an update regarding bench to bedside translation of this knowledge and discuss unanswered questions that need further investigation. PMID- 28101523 TI - Spatial Mnemonic Encoding: Theta Power Decreases and Medial Temporal Lobe BOLD Increases Co-Occur during the Usage of the Method of Loci. AB - The method of loci is one, if not the most, efficient mnemonic encoding strategy. This spatial mnemonic combines the core cognitive processes commonly linked to medial temporal lobe (MTL) activity: spatial and associative memory processes. During such processes, fMRI studies consistently demonstrate MTL activity, while electrophysiological studies have emphasized the important role of theta oscillations (3-8 Hz) in the MTL. However, it is still unknown whether increases or decreases in theta power co-occur with increased BOLD signal in the MTL during memory encoding. To investigate this question, we recorded EEG and fMRI separately, while human participants used the spatial method of loci or the pegword method, a similarly associative but nonspatial mnemonic. The more effective spatial mnemonic induced a pronounced theta power decrease source localized to the left MTL compared with the nonspatial associative mnemonic strategy. This effect was mirrored by BOLD signal increases in the MTL. Successful encoding, irrespective of the strategy used, elicited decreases in left temporal theta power and increases in MTL BOLD activity. This pattern of results suggests a negative relationship between theta power and BOLD signal changes in the MTL during memory encoding and spatial processing. The findings extend the well known negative relation of alpha/beta oscillations and BOLD signals in the cortex to theta oscillations in the MTL. PMID- 28101524 TI - The Role of Dopamine in Anticipatory Pursuit Eye Movements: Insights from Genetic Polymorphisms in Healthy Adults. AB - There is a long history of eye movement research in patients with psychiatric diseases for which dysfunctions of neurotransmission are considered to be the major pathologic mechanism. However, neuromodulation of oculomotor control is still hardly understood. We aimed to investigate in particular the impact of dopamine on smooth pursuit eye movements. Systematic variability in dopaminergic transmission due to genetic polymorphisms in healthy subjects offers a noninvasive opportunity to determine functional associations. We measured smooth pursuit in 110 healthy subjects genotyped for two well-documented polymorphisms, the COMT Val158Met polymorphism and the SLC6A3 3'-UTR-VNTR polymorphism. Pursuit paradigms were chosen to particularly assess the ability of the pursuit system to initiate tracking when target motion onset is blanked, reflecting the impact of extraretinal signals. In contrast, when following a fully visible target sensory, retinal signals are available. Our results highlight the crucial functional role of dopamine for anticipatory, but not for sensory-driven, pursuit processes. We found the COMT Val158Met polymorphism specifically associated with anticipatory pursuit parameters, emphasizing the dominant impact of prefrontal dopamine activity on complex oculomotor control. In contrast, modulation of striatal dopamine activity by the SLC6A3 3'-UTR-VNTR polymorphism had no significant functional effect. Though often neglected so far, individual differences in healthy subjects provide a promising approach to uncovering functional mechanisms and can be used as a bridge to understanding deficits in patients. PMID- 28101526 TI - Rapamycin-Resistant mTOR Activity Is Required for Sensory Axon Regeneration Induced by a Conditioning Lesion. AB - Neuronal mammalian target of rapamycin (mTOR) activity is a critical determinant of the intrinsic regenerative ability of mature neurons in the adult central nervous system (CNS). However, whether its action also applies to peripheral nervous system (PNS) neurons after injury remains elusive. To address this issue unambiguously, we used genetic approaches to determine the role of mTOR signaling in sensory axon regeneration in mice. We showed that deleting mTOR in dorsal root ganglion (DRG) neurons suppressed the axon regeneration induced by conditioning lesions. To establish whether the impact of mTOR on axon regeneration results from functions of mTOR complex 1 (mTORC1) or 2 (mTORC2), two distinct kinase complexes, we ablated either Raptor or Rictor in DRG neurons. We found that suppressing mTORC1 signaling dramatically decreased the conditioning lesion effect. In addition, an injury to the peripheral branch boosts mTOR activity in DRG neurons that cannot be completely inhibited by rapamycin, a widely used mTOR specific inhibitor. Unexpectedly, examining several conditioning lesion-induced pro-regenerative pathways revealed that Raptor deletion but not rapamycin suppressed Stat3 activity in neurons. Therefore, our results demonstrate that crosstalk between mTOR and Stat3 signaling mediates the conditioning lesion effect and provide genetic evidence that rapamycin-resistant mTOR activity contributes to the intrinsic axon growth capacity in adult sensory neurons after injury. PMID- 28101528 TI - Discriminating Valid from Spurious Indices of Phase-Amplitude Coupling. AB - Recently there has been a strong interest in cross-frequency coupling, the interaction between neuronal oscillations in different frequency bands. In particular, measures quantifying the coupling between the phase of slow oscillations and the amplitude of fast oscillations have been applied to a wide range of data recorded from animals and humans. Some of the measures applied to detect phase-amplitude coupling have been criticized for being sensitive to nonsinusoidal properties of the oscillations and thus spuriously indicate the presence of coupling. While such instances of spurious identification of coupling have been observed, in this commentary we give concrete examples illustrating cases when the identification of cross-frequency coupling can be trusted. These examples are based on control analyses and empirical observations rather than signal-processing tools. Finally, we provide concrete advice on how to determine when measures of phase-amplitude coupling can be considered trustworthy. PMID- 28101525 TI - Untangling Basal Ganglia Network Dynamics and Function: Role of Dopamine Depletion and Inhibition Investigated in a Spiking Network Model. AB - The basal ganglia are a crucial brain system for behavioral selection, and their function is disturbed in Parkinson's disease (PD), where neurons exhibit inappropriate synchronization and oscillations. We present a spiking neural model of basal ganglia including plausible details on synaptic dynamics, connectivity patterns, neuron behavior, and dopamine effects. Recordings of neuronal activity in the subthalamic nucleus and Type A (TA; arkypallidal) and Type I (TI; prototypical) neurons in globus pallidus externa were used to validate the model. Simulation experiments predict that both local inhibition in striatum and the existence of an indirect pathway are important for basal ganglia to function properly over a large range of cortical drives. The dopamine depletion-induced increase of AMPA efficacy in corticostriatal synapses to medium spiny neurons (MSNs) with dopamine receptor D2 synapses (CTX-MSN D2) and the reduction of MSN lateral connectivity (MSN-MSN) were found to contribute significantly to the enhanced synchrony and oscillations seen in PD. Additionally, reversing the dopamine depletion-induced changes to CTX-MSN D1, CTX-MSN D2, TA-MSN, and MSN-MSN couplings could improve or restore basal ganglia action selection ability. In summary, we found multiple changes of parameters for synaptic efficacy and neural excitability that could improve action selection ability and at the same time reduce oscillations. Identification of such targets could potentially generate ideas for treatments of PD and increase our understanding of the relation between network dynamics and network function. PMID- 28101527 TI - Regulation of Physical Microglia-Neuron Interactions by Fractalkine Signaling after Status Epilepticus. AB - Microglia, the resident immune cells of the brain, perform elaborate surveillance in which they physically interact with neuronal elements. A novel form of microglia-neuron interaction named microglial process convergence (MPC) toward neuronal axons and dendrites has recently been described. However, the molecular regulators and pathological relevance of MPC have not been explored. Here, using high-resolution two-photon imaging in vivo and ex vivo, we observed a dramatic increase in MPCs after kainic acid- or pilocarpine-induced experimental seizures that was reconstituted after glutamate treatment in slices from mice. Interestingly, a deficiency of the fractalkine receptor (CX3CR1) decreased MPCs, whereas fractalkine (CX3CL1) treatment increased MPCs, suggesting that fractalkine signaling is a critical regulator of these microglia-neuron interactions. Furthermore, we found that interleukin-1beta was necessary and sufficient to trigger CX3CR1-dependent MPCs. Finally, we show that a deficiency in fractalkine signaling corresponds with increased seizure phenotypes. Together, our results identify the neuroglial CX3CL1-CX3CR1 communication axis as a modulator of potentially neuroprotective microglia-neuron physical interactions during conditions of neuronal hyperactivity. PMID- 28101531 TI - Osteopontin Is a Blood Biomarker for Microglial Activation and Brain Injury in Experimental Hypoxic-Ischemic Encephalopathy. AB - Clinical management of neonatal hypoxic-ischemic encephalopathy (HIE) suffers from the lack of reliable surrogate marker tests. Proteomic analysis may identify such biomarkers in blood, but there has been no proof-of-principle evidence to support this approach. Here we performed in-gel trypsin digestion of plasma proteins from four groups of 10-d-old mice [untouched and 24 h after low-dose lipopolysaccharide (LPS) exposure, hypoxia-ischemia (HI), or LPS/HI injury; n = 3 in each group) followed by liquid chromatography-tandem mass spectrometry and bioinformatics analysis to search for HI- and LPS/HI-associated brain injury biomarkers. This analysis suggested the induction of plasma osteopontin (OPN) by HI and LPS/HI, but not by sham and injury-free LPS exposure. Immunoblot confirmed post-HI induction of OPN protein in brain and blood, whereas Opn mRNA was induced in brain but not in blood. This disparity suggests brain-derived plasma OPN after HI injury. Similarly, immunostaining showed the expression of OPN by Iba1+ microglia/macrophages in HI-injured brains. Further, intracerebroventricular injection of LPS activated microglia and up-regulated plasma OPN protein. Importantly, the induction of plasma OPN after HI was greater than that of matrix metalloproteinase 9 or glial fibrillary acid protein. Plasma OPN levels at 48 h post-HI also parallel the severity of brain damage at 7-d recovery. Together, these results suggest that OPN may be a prognostic blood biomarker in HIE through monitoring brain microglial activation. PMID- 28101530 TI - Integrative Analysis of Disease Signatures Shows Inflammation Disrupts Juvenile Experience-Dependent Cortical Plasticity. AB - Throughout childhood and adolescence, periods of heightened neuroplasticity are critical for the development of healthy brain function and behavior. Given the high prevalence of neurodevelopmental disorders, such as autism, identifying disruptors of developmental plasticity represents an essential step for developing strategies for prevention and intervention. Applying a novel computational approach that systematically assessed connections between 436 transcriptional signatures of disease and multiple signatures of neuroplasticity, we identified inflammation as a common pathological process central to a diverse set of diseases predicted to dysregulate plasticity signatures. We tested the hypothesis that inflammation disrupts developmental cortical plasticity in vivo using the mouse ocular dominance model of experience-dependent plasticity in primary visual cortex. We found that the administration of systemic lipopolysaccharide suppressed plasticity during juvenile critical period with accompanying transcriptional changes in a particular set of molecular regulators within primary visual cortex. These findings suggest that inflammation may have unrecognized adverse consequences on the postnatal developmental trajectory and indicate that treating inflammation may reduce the burden of neurodevelopmental disorders. PMID- 28101529 TI - Cortico-Cortical Connections of Primary Sensory Areas and Associated Symptoms in Migraine. AB - Migraine is a recurring, episodic neurological disorder characterized by headache, nausea, vomiting, and sensory disturbances. These events are thought to arise from the activation and sensitization of neurons along the trigemino vascular pathway. From animal studies, it is known that thalamocortical projections play an important role in the transmission of nociceptive signals from the meninges to the cortex. However, little is currently known about the potential involvement of cortico-cortical feedback projections from higher-order multisensory areas and/or feedforward projections from principle primary sensory areas or subcortical structures. In a large cohort of human migraine patients (N = 40) and matched healthy control subjects (N = 40), we used resting-state intrinsic functional connectivity to examine the cortical networks associated with the three main sensory perceptual modalities of vision, audition, and somatosensation. Specifically, we sought to explore the complexity of the sensory networks as they converge and become functionally coupled in multimodal systems. We also compared self-reported retrospective migraine symptoms in the same patients, examining the prevalence of sensory symptoms across the different phases of the migraine cycle. Our results show widespread and persistent disturbances in the perceptions of multiple sensory modalities. Consistent with this observation, we discovered that primary sensory areas maintain local functional connectivity but express impaired long-range connections to higher order association areas (including regions of the default mode and salience network). We speculate that cortico-cortical interactions are necessary for the integration of information within and across the sensory modalities and, thus, could play an important role in the initiation of migraine and/or the development of its associated symptoms. PMID- 28101532 TI - Overexpression of Brain-Derived Neurotrophic Factor Protects Large Retinal Ganglion Cells After Optic Nerve Crush in Mice. AB - Brain-derived neurotrophic factor (BDNF), a neurotrophin essential for neuron survival and function, plays an important role in neuroprotection during neurodegenerative diseases. In this study, we examined whether a modest increase of retinal BDNF promotes retinal ganglion cell (RGC) survival after acute injury of the optic nerve in mice. We adopted an inducible Cre-recombinase transgenic system to up-regulate BDNF in the mouse retina and then examined RGC survival after optic nerve crush by in vivo imaging. We focused on one subtype of RGC with large soma expressing yellow fluorescent protein transgene that accounts for ~11% of the total SMI-32-positive RGCs. The median survival time of this subgroup of SMI-32 cells was 1 week after nerve injury in control mice but 2 weeks when BDNF was up-regulated. Interestingly, we found that the survival time for RGCs taken as a whole was 2 weeks, suggesting that these large-soma RGCs are especially vulnerable to optic nerve crush injury. We also studied changes in axon number using confocal imaging, confirming first the progressive loss reported previously for wild-type mice and demonstrating that BDNF up-regulation extended axon survival. Together, our results demonstrate that the time course of RGC loss induced by optic nerve injury is type specific and that overexpression of BDNF prolongs the survival of one subgroup of SMI-32-positive RGCs. PMID- 28101533 TI - Experimental Design and Data Analysis Issues Contribute to Inconsistent Results of C-Bouton Changes in Amyotrophic Lateral Sclerosis. AB - The possible presence of pathological changes in cholinergic synaptic inputs [cholinergic boutons (C-boutons)] is a contentious topic within the ALS field. Conflicting data reported on this issue makes it difficult to assess the roles of these synaptic inputs in ALS. Our objective was to determine whether the reported changes are truly statistically and biologically significant and why replication is problematic. This is an urgent question, as C-boutons are an important regulator of spinal motoneuron excitability, and pathological changes in motoneuron excitability are present throughout disease progression. Using male mice of the SOD1-G93A high-expresser transgenic (G93A) mouse model of ALS, we examined C-boutons on spinal motoneurons. We performed histological analysis at high statistical power, which showed no difference in C-bouton size in G93A versus wild-type motoneurons throughout disease progression. In an attempt to examine the underlying reasons for our failure to replicate reported changes, we performed further histological analyses using several variations on experimental design and data analysis that were reported in the ALS literature. This analysis showed that factors related to experimental design, such as grouping unit, sampling strategy, and blinding status, potentially contribute to the discrepancy in published data on C-bouton size changes. Next, we systematically analyzed the impact of study design variability and potential bias on reported results from experimental and preclinical studies of ALS. Strikingly, we found that practices such as blinding and power analysis are not systematically reported in the ALS field. Protocols to standardize experimental design and minimize bias are thus critical to advancing the ALS field. PMID- 28101534 TI - Pathogenicity Determinants of the Human Malaria Parasite Plasmodium falciparum Have Ancient Origins. AB - Plasmodium falciparum, the most deadly of the human malaria parasites, is a member of the Laverania subgenus that also infects African Great Apes. The virulence of P. falciparum is related to cytoadhesion of infected erythrocytes in microvasculature, but the origin of dangerous parasite adhesion traits is poorly understood. To investigate the evolutionary history of the P. falciparum cytoadhesion pathogenicity determinant, we studied adhesion domains from the chimpanzee malaria parasite P. reichenowi. We demonstrate that the P. reichenowi var gene repertoire encodes cysteine-rich interdomain region (CIDR) domains which bind human CD36 and endothelial protein C receptor (EPCR) with the same levels of affinity and at binding sites similar to those bound by P. falciparum. Moreover, P. reichenowi domains interfere with the protective function of the activated protein C-EPCR pathway on endothelial cells, a presumptive virulence trait in humans. These findings provide evidence for ancient evolutionary origins of two key cytoadhesion properties of P. falciparum that contribute to human infection and pathogenicity. IMPORTANCE Cytoadhesion of P. falciparum-infected erythrocytes in the microcirculation is a major virulence determinant. P. falciparum is descended from a subgenus of parasites that also infect chimpanzees and gorillas and exhibits strict host species specificity. Despite their high genetic similarity to P. falciparum, it is unknown whether ape parasites encode adhesion properties similar to those of P. falciparum or are as virulent in their natural hosts. Consequently, it has been unclear when virulent adhesion traits arose in P. falciparum and how long they have been present in the parasite population. It is also unknown whether cytoadhesive interactions pose a barrier to cross-species transmission. We show that parasite domains from the chimpanzee malaria parasite P. reichenowi bind human receptors with specificity similar to that of P. falciparum. Our findings suggest that parasite adhesion traits associated with both mild and severe malaria have much earlier origins than previously appreciated and have important implications for virulence evolution in a major human pathogen. PMID- 28101536 TI - Host Range Restriction of Insect-Specific Flaviviruses Occurs at Several Levels of the Viral Life Cycle. AB - The genus Flavivirus contains emerging arthropod-borne viruses (arboviruses) infecting vertebrates, as well as insect-specific viruses (ISVs) (i.e., viruses whose host range is restricted to insects). ISVs are evolutionary precursors to arboviruses. Knowledge of the nature of the ISV infection block in vertebrates could identify functions necessary for the expansion of the host range toward vertebrates. Mapping of host restrictions by complementation of ISV and arbovirus genome functions could generate knowledge critical to predicting arbovirus emergence. Here we isolated a novel flavivirus, termed Nienokoue virus (NIEV), from mosquitoes sampled in Cote d'Ivoire. NIEV groups with insect-specific flaviviruses (ISFs) in phylogeny and grows in insect cells but not in vertebrate cells. We generated an infectious NIEV cDNA clone and a NIEV reporter replicon to study growth restrictions of NIEV in comparison to yellow fever virus (YFV), for which the same tools are available. Efficient RNA replication of the NIEV reporter replicon was observed in insect cells but not in vertebrate cells. Initial translation of the input replicon RNA in vertebrate cells was functional, but RNA replication did not occur. Chimeric YFV carrying the envelope proteins of NIEV was recovered via electroporation in C6/36 insect cells but did not infect vertebrate cells, indicating a block at the level of entry. Since the YF/NIEV chimera readily produced infectious particles in insect cells but not in vertebrate cells despite efficient RNA replication, restriction is also determined at the level of assembly/release. Taking the results together, the ability of ISF to infect vertebrates is blocked at several levels, including attachment/entry and RNA replication as well as assembly/release. IMPORTANCE Most viruses of the genus Flavivirus, e.g., YFV and dengue virus, are mosquito borne and transmitted to vertebrates during blood feeding of mosquitoes. Within the last decade, an increasing number of viruses with a host range exclusively restricted to insects in close relationship to the vertebrate-pathogenic flaviviruses were discovered in mosquitoes. To identify barriers that could block the arboviral vertebrate tropism, we set out to identify the steps at which the ISF replication cycle fails in vertebrates. Our studies revealed blocks at several levels, suggesting that flavivirus host range expansion from insects to vertebrates was a complex process that involved overcoming multiple barriers. PMID- 28101535 TI - The Case for Adopting the "Species Complex" Nomenclature for the Etiologic Agents of Cryptococcosis. AB - Cryptococcosis is a potentially lethal disease of humans/animals caused by Cryptococcus neoformans and Cryptococcus gattii. Distinction between the two species is based on phenotypic and genotypic characteristics. Recently, it was proposed that C. neoformans be divided into two species and C. gattii into five species based on a phylogenetic analysis of 115 isolates. While this proposal adds to the knowledge about the genetic diversity and population structure of cryptococcosis agents, the published genotypes of 2,606 strains have already revealed more genetic diversity than is encompassed by seven species. Naming every clade as a separate species at this juncture will lead to continuing nomenclatural instability. In the absence of biological differences between clades and no consensus about how DNA sequence alone can delineate a species, we recommend using "Cryptococcus neoformans species complex" and "C. gattii species complex" as a practical intermediate step, rather than creating more species. This strategy recognizes genetic diversity without creating confusion. PMID- 28101537 TI - Interventional Photoacoustic Imaging of the Human Placenta with Ultrasonic Tracking for Minimally Invasive Fetal Surgeries. AB - Image guidance plays a central role in minimally invasive fetal surgery such as photocoagulation of inter-twin placental anastomosing vessels to treat twin-to twin transfusion syndrome (TTTS). Fetoscopic guidance provides insufficient sensitivity for imaging the vasculature that lies beneath the fetal placental surface due to strong light scattering in biological tissues. Incomplete photocoagulation of anastamoses is associated with postoperative complications and higher perinatal mortality. In this study, we investigated the use of multi spectral photoacoustic (PA) imaging for better visualization of the placental vasculature. Excitation light was delivered with an optical fiber with dimensions that are compatible with the working channel of a fetoscope. Imaging was performed on an ex vivo normal term human placenta collected at Caesarean section birth. The photoacoustically-generated ultrasound signals were received by an external clinical linear array ultrasound imaging probe. A vein under illumination on the fetal placenta surface was visualized with PA imaging, and good correspondence was obtained between the measured PA spectrum and the optical absorption spectrum of deoxygenated blood. The delivery fiber had an attached fiber optic ultrasound sensor positioned directly adjacent to it, so that its spatial position could be tracked by receiving transmissions from the ultrasound imaging probe. This study provides strong indications that PA imaging in combination with ultrasonic tracking could be useful for detecting the human placental vasculature during minimally invasive fetal surgery. PMID- 28101538 TI - Recent advances in engineering microparticles and their nascent utilization in biomedical delivery and diagnostic applications. AB - Complex microparticles (MPs) bearing unique characteristics such as well-tailored sizes, various morphologies, and multi-compartments have been attempted to be produced by many researchers in the past decades. However, a conventionally used method of fabricating MPs, emulsion polymerization, has a limitation in achieving the aforementioned characteristics and several approaches such as the microfluidics-assisted (droplet-based microfluidics and flow lithography-based microfluidics), electrohydrodynamics (EHD)-based, centrifugation-based, and template-based methods have been recently suggested to overcome this limitation. The outstanding features of complex MPs engineered through these suggested methods have provided new opportunities for MPs to be applied in a wider range of applications including cell carriers, drug delivery agents, active pigments for display, microsensors, interface stabilizers, and catalyst substrates. Overall, the engineered MPs expose their potential particularly in the field of biomedical engineering as the increased complexity in the engineered MPs fulfills well the requirements of the high-end applications. This review outlines the current trends of newly developed techniques used for engineered MPs fabrication and focuses on the current state of engineered MPs in biomedical applications. PMID- 28101539 TI - Regioselective magnesiation of N-heterocyclic molecules: securing insecure cyclic anions by a beta-diketiminate-magnesium clamp. AB - Using a specially designed magnesium metallating manifold, combining kinetically activated TMP amide base with a sterically amplified beta-diketiminate ligand, this study has established a new regioselective strategy for magnesiation of challenging N-heterocyclic molecules. The broad scope of the approach is illustrated through reactions of pyrazine, triazoles and substituted pyridines by isolation and structural elucidation of their magnesiated intermediates. PMID- 28101540 TI - Lactols in an asymmetric aldol-desymmetrization sequence: access to tetrahydro-4H furo[2,3-b]pyran-2-one and tetrahydro-4H-furo[2,3-b]furan-2-one derivatives. AB - An asymmetric aldol-desymmetrization sequence was developed which provided highly efficient access to important bicyclic oxygen-containing scaffolds with multiple chiral centers and one is a quaternary stereogenic center containing a free hydroxy group. Moreover, starting from racemic precursors, the final products were obtained as two separable diastereomers by flash chromatography. Several other heterocycles could also be easily generated with this strategy. PMID- 28101541 TI - Inner salt-shaped small molecular photosensitizer with extremely enhanced two photon absorption for mitochondrial-targeted photodynamic therapy. AB - Herein, we experimentally and theoretically demonstrate an unprecedentedly enhanced two-photon absorption in a small organic molecule by a simple introduction of an inner salt-shaped structure. Moreover, such an inner salt shaped small molecule also exhibits superior singlet oxygen quantum yield and fascinating structure-inherent mitochondrial-targeting ability for highly efficient two-photon photodynamic therapy via a mitochondrial apoptosis pathway. PMID- 28101542 TI - Revisiting secondary interactions in neighboring group participation, exemplified by reactivity changes of iminylium intermediates. AB - Neighboring group participation is defined as the action of a substituent to stabilize a transition state or an intermediate by forming a bond or a partial bond with the reaction center. In addition to the primary interaction with the nearest neighboring group, secondary interactions involving another neighboring group(s) could also occur in principle. Here, we revisit this issue by examining the influence of secondary interactions on the stability and reactivity of the putative iminylium cation intermediates, formed by N-O bond cleavage of 1 tetralone oxime systems. A direct observation of a peri-bromo-iminylium intermediate in solution supported the involvement of iminylium cations and the stabilizing effect of secondary interactions arising from a distal tandem substituent. Both experimental and computational findings support the idea that secondary interactions of a tandem-neighboring group on the primary peri heteroatom (Br, Cl, and O(Me))-iminylium bonding interaction, i.e., a weak halogen bonding interaction (ester (nitro) oxygen-halogen bonding) and an unprecedented hydrogen bonding interaction between a nitro oxygen atom and a CH3O hydrogen atom, are crucial determinants of the reaction pathway, leading to either overwhelmingly selective syn-migration of the oxime functionality or covalent bond formation under acid-catalyzed Beckmann rearrangement conditions. PMID- 28101543 TI - The recent development of efficient Earth-abundant transition-metal nanocatalysts. AB - Whereas noble metal compounds have long been central in catalysis, Earth-abundant metal-based catalysts have in the same time remained undeveloped. Yet the efficacy of Earth-abundant metal catalysts was already shown at the very beginning of the 20th century with the Fe-catalyzed Haber-Bosch process of ammonia synthesis and later in the Fischer-Tropsch reaction. Nanoscience has revolutionized the world of catalysis since it was observed that very small Au nanoparticles (NPs) and other noble metal NPs are extraordinarily efficient. Therefore the development of Earth-abundant metals NPs is more recent, but it has appeared necessary due to their "greenness". This review highlights catalysis by NPs of Earth-abundant transition metals that include Mn, Fe, Co, Ni, Cu, early transition metals (Ti, V, Cr, Zr, Nb and W) and their nanocomposites with emphasis on basic principles and literature reported during the last 5 years. A very large spectrum of catalytic reactions has been successfully disclosed, and catalysis has been examined for each metal starting with zero-valent metal NPs followed by oxides and other nanocomposites. The last section highlights the catalytic activities of bi- and trimetallic NPs. Indeed this later family is very promising and simultaneously benefits from increased stability, efficiency and selectivity, compared to monometallic NPs, due to synergistic substrate activation. PMID- 28101544 TI - Tetrathienyl-functionalized red- and NIR-absorbing BODIPY dyes appending various peripheral substituents. AB - A series of boron-dipyrromethene dyes (BODIPYs) 4a-g with different thienyl moieties at 2,3,5,6-positions of the BODIPY core were synthesized by the Stille cross-coupling reaction. The new compounds were characterized by 1H NMR, 13C NMR, HRMS, and IR spectroscopy. The single crystal structure of compound 4e was obtained by X-ray crystallography. The optical and electrochemical properties of these dyes were studied by UV/Vis spectroscopy, fluorescence spectroscopy, and cyclic voltammetry. The DFT calculation of the frontier molecular orbitals of these dyes corroborates the observed effects of peripheral substituents on the optical and redox properties. These results reveal a good tunability of the optical and electronic properties of these BODIPYs by varying the peripheral groups at the alpha-positions of thienyl moieties, which leads to the absorption and emission reaching the NIR region. PMID- 28101545 TI - Direct N-H/alpha,alpha,beta,beta-C(sp3)-H functionalization of piperidine via an azomethine ylide route: synthesis of spirooxindoles bearing 3-substituted oxindoles. AB - A protocol for the direct functionalization of N-H/alpha,alpha,beta,beta-C(sp3)-H of piperidine without any metal or external oxidants is reported. This reaction is promoted by 4-(trifluoromethyl)benzoic acid via an azomethine ylide intermediate. This is a simple method for the synthesis of spirooxindoles bearing 3-substituted oxindole moieties. PMID- 28101546 TI - Regioselective switching approach for the synthesis of alpha and delta carboline derivatives. AB - A metal-free protocol for accessing both alpha and delta-carboline derivatives, starting from a common indolylchalcone oxime ester precursor is reported. The reaction involves mild conditions and uses a regiodivergent approach. DDQ is used as a switching agent in selectively generating alpha and delta-carboline derivatives in good to moderate yields. PMID- 28101547 TI - In situ generation and reactions of p-(trifluoromethyl)benzyl electrophiles: an efficient access to p-(trifluoromethyl)benzyl compounds. AB - A new three-component reaction, namely condensation-anti-Michael addition aromatization, enabling the construction of benzylic compounds is disclosed. This reaction can not only act as an alternative approach to regioselective Csp2-H trifluoromethylation of arenes through an "aromatic to be" strategy, but also provides a simple, convenient, step-economic, and practical strategy for the in situ generation of electrophilic p-(trifluoromethyl)benzyl species under extremely mild conditions. PMID- 28101548 TI - Taco complex-templated highly regio- and stereo-selective photodimerization of a coumarin-containing crown ether. AB - Preorientation of the terminal coumarins of a crown ether with the assistance of taco-type host-guest complex formation promotes regio- and stereo-selectivity of coumarin photodimerization to give only the syn head-to-tail coumarin isomer. PMID- 28101549 TI - Palladium(ii)-catalyzed direct O-alkenylation of 2-arylquinazolinones with N tosylhydrazones: an efficient route to O-alkenylquinazolines. AB - An efficient Pd(ii)-catalyzed direct O-alkenylation of 2-arylquinazolinones with simple ketone-derived N-tosylhydrazones is reported. In this reaction, O alkenylquinazolines were obtained in good yields, with excellent functional group tolerance. Pd-carbene migratory insertion is proposed as the key step in the reaction mechanism. PMID- 28101550 TI - Photoredox-catalysed redox-neutral trifluoromethylation of vinyl azides for the synthesis of alpha-trifluoromethylated ketones. AB - A redox-neutral, mild, and simple protocol is developed for the synthesis of alpha-trifluoromethylated ketones from vinyl azides under transition-metal-free conditions. In the presence of organic photoredox catalyst N-methyl-9-mesityl acridinium and sodium trifluoromethanesulfinate, a broad range of substituted vinyl azides were found to react smoothly upon visible-light irradiation, readily furnishing the corresponding products in satisfied yields. PMID- 28101551 TI - Diels-Alder trapping of in situ generated dienes from 3,4-dihydro-2H-pyran with p quinone catalysed by p-toluenesulfonic acid. AB - This comprehensive study portrays that p-toluenesulfonic acid is a more efficient catalyst for the reaction between p-quinones and 3,4-dihydro-2H-pyran, than the Lewis acids. The products were accomplished by the Diels-Alder cycloaddition reaction and their mechanistic pathways have been formulated. The impact of C2 and C2,5 substituents of the p-quinones on the cycloaddition reaction has been explored. Remarkably, it is the first report to explore this kind of in situ generated diene for the Diels-Alder cycloaddition reaction. PMID- 28101552 TI - A photo-auxiliary approach - enabling excited state classical phototransformations with metal free visible light irradiation. AB - Most traditional photoreactions require UV light to yield the desired product. To address this issue, photoreaction of hydrazide based chromophores was evaluated with visible light using a metal free photocatalyst to afford photoproducts in high yields. This hydrazide functionality itself may be removed/modified after the photoreaction, highlighting its role as a "photo-auxiliary". A preliminary mechanistic model based on photophysical experiments is provided to highlight the generality of the strategy. PMID- 28101553 TI - Nucleophilic ring-opening reactions of trans-2-aroyl-3-aryl-cyclopropane-1,1 dicarboxylates with hydrazines. AB - trans-2-Aroyl-3-aryl-cyclopropane-1,1-dicarboxylates when treated with arylhydrazines in refluxing EtOH gave dihydropyrazoles, whereas with hydrazines in refluxing AcOH, they formed cyclopropane-fused pyridazinones. Although in both cases the corresponding hydrazones are formed initially, the former case involves a subsequent 5-exo-tet nucleophilic ring-opening, and the later, a 6-exo-trig nucleophilic attack by the other hydrazone nitrogen. The products are obtained in moderate to excellent yields with complete regio-and diastereoselectivity. PMID- 28101554 TI - Correction: Facile functionalization at the C4 position of pyrimidine nucleosides via amide group activation with (benzotriazol-1 yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and biological evaluations of the products. AB - Correction for 'Facile functionalization at the C4 position of pyrimidine nucleosides via amide group activation with (benzotriazol-1 yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and biological evaluations of the products' by Hari K. Akula, et al., Org. Biomol. Chem., 2017, DOI: 10.1039/c6ob02334g. PMID- 28101555 TI - Predictors for living at home after geriatric inpatient rehabilitation: A prospective cohort study. AB - OBJECTIVE: To evaluate patient characteristics predicting living at home after geriatric rehabilitation. DESIGN: Prospective cohort study. PATIENTS: A total of 210 patients aged 65 years or older receiving inpatient rehabilitation. METHODS: Candidate predictors evaluated during rehabilitation were: age, vulnerability (Vulnerable Elders Survey), multimorbidity (Cumulative Illness Rating Scale), cognition (Mini-Mental State Examination), depression (Hospital Anxiety and Depression Scale), living alone, previous independence in activities of daily living, fall risk, and mobility at discharge (Timed Up and Go test). Multiple imputation data-sets, bivariate and multiple regression were used to build a predictive model for living at home, which was evaluated at 3-month follow-up. RESULTS: A total of 210 patients (mean age 76.0 years, 46.2% women) were included in the study. Of these, 87.6% had been admitted to geriatric rehabilitation directly from acute hospital care. Follow-up was complete in 75.2% of patients. The strongest predictor for living at home was better mobility at discharge (Timed Up and Go test < 20 s), followed by lower multimorbidity, better cognition, and not living alone. In bivariate regression, living at home was also associated with age, fall risk, vulnerability, depression, and previous independence in activities of daily living. CONCLUSION: Mobility is the most important predictive factor for living at home after geriatric rehabilitation. Assessment and training of mobility are therefore key aspects in geriatric rehabilitation. PMID- 28101556 TI - Time for food - training physiatrists in nutritional prescription. AB - INTRODUCTION: Sub-optimal nutrition is a leading factor in all-cause mortality, the preponderance of non-communicable chronic diseases, and various health conditions that are treated by physiatrists, such as stroke and musculoske-letal disorders. Furthermore, patients with chronic pain have a high prevalence of nutritional deficiencies, and malnutrition has been associated with limited rehabilitation outcomes in elderly patients with hospital-associated deconditioning. Thus, physiatrists may find it valuable to include nutrition in their patient services. However, discussion of nutritional counselling in the physiatry literature is rare. OBJECTIVE: To inform physiatrists about including nutritional counselling as part of the treatment they provide. METHODS: The paper reviews recommended communication skills, behavioural change strategies, and opportunities for inter-professional collaboration. Further resources to educate physiatrists both in nutritional prescription and in improving their own personal health behaviours are provided. CONCLUSION: Training physiatrists to address nutrition is a step-wise process, described here. PMID- 28101557 TI - High incidence of falls and fall-related injuries in wheelchair users with spinal cord injury: A prospective study of risk indicators. AB - OBJECTIVE: To identify risk indicators for, and incidence of, recurrent falls and fall-related injuries in wheelchair users with traumatic spinal cord injury. DESIGN: Prospective multi-centre study. SUBJECTS: One hundred and forty-nine wheelchair users with spinal cord injury attending follow-up in Sweden and Norway. METHODS: Inclusion criteria: wheelchair users >= 18 years old with traumatic spinal cord injury >= 1 year post-injury. EXCLUSION CRITERIA: individuals with motor complete injuries above C5. Falls were prospectively reported by text message every second week for one year and were followed-up by telephone interviews. Outcomes were: fall incidence, risk indicators for recurrent (> 2) falls and fall-related injuries. Independent variables were: demographic data, quality of life, risk willingness, functional independence, and exercise habits. RESULTS: Of the total sample (n = 149), 96 (64%) participants fell, 45 (32%) fell recurrently, 50 (34%) were injured, and 7 (5%) severely injured. Multivariate logistic regression analysis showed that reporting recurrent falls the previous year increased the odds ratio (OR) of recurrent falls (OR 10.2, p < 0.001). Higher quality of life reduced the OR of fall-related injuries (OR 0.86, p = 0.037). CONCLUSION: Previous recurrent falls was a strong predictor of future falls. The incidence of falls, recurrent falls and fall related injuries was high. Hence, prevention of falls and fall-related injuries is important. PMID- 28101558 TI - Do pain characteristics guide selection for multimodal pain rehabilitation? AB - OBJECTIVE: To determine whether self-reported pain measures are associated with selection for multimodal or multidisciplinary rehabilitation (MMR) and whether this selection is influenced by sex. DESIGN: Cross-sectional cohort study. SUBJECTS: A total of 1,226 women and 464 men with chronic pain conditions from 2 university hospitals. METHODS: Drawing from the Swedish Quality Registry for Pain Rehabilitation (SQRP), data on pain, psychological symptoms, function, health, and activity/participation were collected. Multiple logistic regression was used to investigate association of pain measures with selection for MMR (no/yes) after multidisciplinary assessment. Covariates were: age, educational level, anxiety, depression, working status, and several pain measures. RESULTS: High pain intensity in the previous week (odds ratio (OR) 0.92; 95% confidence interval (CI) 0.86-0.99) and high pain severity (Multidimensional Pain Inventory) (OR 0.83; 95% CI 0.74-0.95) were negatively associated with selection for MMR, whereas higher number of pain quadrants was positively associated with selection for MMR. Similar results were obtained for women, but none of the measures was predictive for men. CONCLUSION: This practice-based study showed that higher scores on self-reported pain were not associated with selection for MMR, and in women there was a negative association for higher pain intensity and pain severity. Thus, other factors than pain determine whether patients are selected for MMR. PMID- 28101559 TI - Cannabis use in persons with traumatic spinal cord injury in Denmark. AB - OBJECTIVE: To evaluate recreational and medical cannabis use in individuals with traumatic spinal cord injury, including reasons and predictors for use, perceived benefits and negative consequences. DESIGN: Cross-sectional survey in Denmark. METHODS: A 35-item questionnaire was sent to 1,101 patients with spinal cord injury who had been in contact with a rehabilitation centre between 1990 and 2012. RESULTS: A total of 537 participants completed the questionnaire. Of these, 36% had tried cannabis at least once and 9% were current users. Of current users, 79% had started to use cannabis before their spinal cord injury. The main reason for use was pleasure, but 65% used cannabis partly for spinal cord injury-related consequences and 59% reported at least good effect on pain and spasticity. Negative consequences of use were primarily inertia and feeling quiet/subdued. Lower age, living in rural areas/larger cities, tobacco-smoking, high alcohol intake and higher muscle stiffness were significantly associated with cannabis use. Those who had never tried cannabis reported that they would mainly use cannabis to alleviate pain and spasticity if it were legalized. CONCLUSION: Cannabis use is more frequent among individuals with spinal cord injury in Denmark than among the general population. High muscle stiffness and various demographic characteristics (lower age, living in rural areas/larger cities, tobacco-smoking and high alcohol intake) were associated with cannabis use. Most participants had started using cannabis before their spinal cord injury. There was considerable overlap between recreational and disability-related use. PMID- 28101560 TI - Effectiveness of two vocational rehabilitation programmes in women with long-term sick leave due to pain syndrome or mental illness: 1-year follow-up of a randomized controlled trial. AB - OBJECTIVE: Mental illness and chronic pain are common reasons for long-term sick leave, typically more so for women. This study investigated the effects on return to work of 2 vocational rehabilitation programmes. METHODS: In this randomized controlled study, 308 women were allocated to treatment with acceptance and commitment therapy, to multidisciplinary assessment and individualized rehabilitation interventions, or to a control group. Return-to-work at 12 months was assessed as: (i) returning to health insurance; (ii) number of reimbursed health insurance days during follow-up; (iii) self-reported change in working hours; (iv) a composite measure of self-reported change in work-related engagement. RESULTS: The mean age of the Swedish study population was 48.5 years (standard deviation (SD) 6.3 years) and the mean time on sick leave 7.5 years (SD 3.2 years). There were no significant differences in reimbursed days or returning to the health insurance at 12 months. The multidisciplinary assessment and individualized rehabilitation interventions group, compared with control, reported a significant increase in working hours per week, as well as a significant increase in work-related engagement. CONCLUSION: Multidisciplinary assessments and individual rehabilitation interventions may improve the chance of return-to-work in women with long-term sick leave due to pain condition or mental illness. PMID- 28101561 TI - Wheelchair donation in a low-resources setting: Utilization, challenges and benefits of wheelchairs provided through a specialized seating programme in Haiti. AB - OBJECTIVE: To describe a 6-month follow-up of a specialized paediatric wheelchair and seating programme in Haiti. DESIGN: Descriptive design using a structured survey and open-ended questions. METHODS: Concurrent with a seating and wheelchair programme conducted in northern Haiti, beneficiaries and their families were introduced to the study, and 86 of 91 consented to future contact. A survey was developed with input from international and local partners, and administered by face-to-face or telephone interviews. Donated wheelchairs were assessed in 5 categories: wheelchair utilization, maintenance, fit, environmental access, and perceived benefits of wheelchair use. RESULTS: A total of 57 beneficiaries (age range < 2-31 years) were located 6 months after receiving their custom-fit wheelchair and consented to the survey. All respondents still had the wheelchair, 70.2% were using it a minimum of 3-5 days/week, 17.5% were using it < 3 days/week and 12.3% were not using it at all. Primary reasons for not using the wheelchair were that it was broken, uncomfortable, or difficult to transport. The commonly reported benefits were improved mobility, independence, participation and social interaction. CONCLUSION: The majority of people who received customized wheelchairs continued to use their equipment 6 months later, with predominantly beneficial outcomes. In future seating initiatives in low resource settings, efforts to optimize equipment durability and training of local technicians should be supported and evaluated. PMID- 28101562 TI - Effects of wheelchair propulsion on neuropathic pain and resting electroencephalography after spinal cord injury. AB - OBJECTIVES: To investigate the effects of wheelchair propulsion on neuropathic pain and to examine resting electroencephalography pre- and post-wheelchair propulsion after spinal cord injury. DESIGN: Cross-sectional study. PARTICIPANTS: Eleven individuals with spinal cord injury and pain and 10 healthy controls. METHODS: Single-session 15-min wheelchair propulsion and measurement of resting electroence-phalography. Effects of wheelchair propulsion were investigated using numerical rating scale (NRS) for neuropathic pain and short-form Profile of Mood States-Brief for mood. Peak alpha frequency on electroencephalography was calculated in 4 regions of interest; frontal, central, parietal and occipital areas. These outcomes were compared between pre- and post-wheelchair propulsion. RESULTS: Ten participants with spinal cord injury and all healthy controls completed the wheelchair propulsion exercise. NRS scores and negative mood were significantly improved following the wheelchair propulsion exercise. Pre wheelchair propulsion, parietal and occipital peak alpha frequencies were significantly lower in the spinal cord injury group compared with the healthy controls group. Post-wheelchair propulsion, central peak alpha frequency increased in the spinal cord injury group. CONCLUSION: Wheelchair propulsion exercise temporarily decreased neuropathic pain intensity, improved negative mood, and modified alpha activity in spinal cord injury. PMID- 28101563 TI - World Health Organisation Global Disability Action Plan 2014-2021: Challenges and perspectives for physical medicine and rehabilitation in Pakistan. AB - OBJECTIVE: To provide an update on disability and outline potential barriers and facilitators for implementation of the World Health Organization Global Disability Action Plan (GDAP) in Pakistan. METHODS: A 6-day workshop at the Armed Forces Institute of Rehabilitation Medicine, Islamabad facilitated by rehabilitation staff from Royal Melbourne Hospital, Australia. Local healthcare professionals (n = 33) from medical rehabilitation facilities identified challenges in service provision, education and attitudes/approaches to people with disabilities, using consensus agreement for objectives listed in the GDAP. RESULTS: Respondents agreed on the following challenges in implementing the GDAP: shortage of skilled work-force, fragmented healthcare system, poor coordination between acute and subacute healthcare sectors, limited health services infrastructure and funding, lack of disability data, poor legislation, lack of guidelines and accreditation standards, limited awareness/knowledge of disability, socio-cultural perceptions and geo-topographical issues. The main facilitators included: need for governing/leadership bodies, engagement of healthcare professionals and institutions using a multi-sectoral approach, new partnerships and strategic collaboration, provision of financial and technical assistance, future policy direction, research and development. CONCLUSION: The barriers to implementing the GDAP identified here highlight the emerging priorities and challenges in the development of rehabilitation medicine and GDAP implementation in a developing country. The GDAP summary actions were useful planning tools to improve access and strengthen rehabilitation services. PMID- 28101564 TI - Changes in body composition after spasticity treatment with intrathecal baclofen. AB - OBJECTIVE: To assess changes in body composition, body weight and resting metabolic rate in patients who received intrathecal baclofen therapy for spasticity. DESIGN: Prospective, longitudinal, quasi-experimental, with a pre/post design. PATIENTS: Twelve patients with spasticity, fulfilling study criteria, and due for pump implantation for intrathecal baclofen therapy, completed the study. METHODS: Data were obtained before, 6 months and 12 months after commencement of intrathecal baclofen therapy as regards body composition (by skinfold calliper), body weight, and resting metabolic rate (by resting oxygen consumption). Spasticity was assessed according to the Modified Ashworth Scale (MAS) and Penn Spasm Frequency Scale (PSFS). RESULTS: A reduction in spasticity according to MAS occurred. Mean fat body mass increased and mean lean body mass decreased. Mean body weight showed a non-significant increase and resting metabolic rate a non-significant decrease. CONCLUSION: This explorative study indicates that unfavourable changes in body composition might occur after intrathecal baclofen therapy. Since obesity and increased fat body mass contribute to an increased cardiovascular risk, these findings may indicate a need for initiation of countermeasures, e.g. increased physical activity and/or dietary measures, in conjunction with intrathecal baclofen therapy. Further studies, including larger study samples and control groups, are needed to corroborate these findings. PMID- 28101565 TI - Use of neuromuscular electrical stimulation to preserve the thickness of abdominal and chest muscles of critically ill patients: A randomized clinical trial. AB - OBJECTIVE: To evaluate and compare the effects of neuromuscular electrical stimulation combined with conventional physical therapy on muscle thickness in critically ill patients. DESIGN: Double-blind, randomized controlled trial. PATIENTS: Twenty-five patients participated in the study. METHODS: Patients on mechanical ventilation for 24-48 h were randomized to an intervention group (neuromuscular electrical stimulation + conventional physical therapy) or a conventional group (sham neuromuscular electrical stimulation + conventional physical therapy). Primary outcome was thickness of the rectus abdominis and chest muscles, determined on cross-sectional ultrasound images before and after the intervention. RESULTS: Eleven patients were included in the intervention group and 14 in the conventional group. After neuromuscular electrical stimulation, rectus abdominis muscle thickness and chest muscle thickness were preserved in the intervention group, whereas there was a significant reduction in thickness in the conventional group, with a significant difference between groups. There was a significant difference between groups in length of stay in the intensive care unit, with shorter length of stay in the intervention group. CONCLUSION: There was no change in rectus abdominis and chest muscle thickness in the intervention group. A significant decrease was found in these measures in the conventional group. PMID- 28101566 TI - Effect of physical activity in the first five days after cardiac surgery. AB - OBJECTIVES: To quantify physiotherapist-supervised and independent physical activity undertaken from the first to the fifth day after cardiac surgery (POD1 to POD5), and to relate the amount of physical activity undertaken with hospital stay and postoperative physiological functional capacity on POD6. METHODS: Physiotherapist-supervised and independent physical activity were monitored in 83 adult patients undergoing cardiac surgery, using a bi-axial accelerometer and skin sensors that measured, galvanic skin response and body temperature. Patients completed a 6-min walk test (6MWT) on POD6. Step count and physical activity intensity (METs; metbolic equivalents) were the main outcome measures. RESULTS: Males exhibited significantly higher physiotherapist-supervised and independent physical activity step counts and time >= 3 METS (p < 0.0001). The 6MWT distance on POD6 was greater in men (mean 393 m, standard deviation (SD) 108 m) than women (mean 300 m, SD 121 m) (p = 0.005). Mean length of stay in hospital was 9 days (SD 3 days) and was negatively correlated with overall physiotherapist-supervised (R = -0.70), independent physical activity step counts (R = -0.62), and combined physiotherapist-supervised (R = -0.65) and independent (R = -0.43) physical activity time >= 3 METs. CONCLUSION: Physiotherapist-supervised activity fosters improvements in postoperative physiological functional capacity and reduces length of stay in hospital following cardiac surgery. PMID- 28101567 TI - Influence of arm crank ergometry on development of lymphedema in breast cancer patients after axillary dissection: A randomized controlled trail. AB - OBJECTIVE: To investigate the safety and efficacy of arm crank ergometry in breast cancer patients after axillary lymph node dissection, with regard to changes in bioelectrical impedance analysis, arm circumference, muscular strength, quality of life and fatigue. DESIGN: Randomized controlled clinical intervention trial. SUBJECTS: Forty-nine patients with breast cancer after axillary lymph node dissection. METHODS: Arm crank ergometer training twice weekly was compared with usual care over 12 weeks. RESULTS: The arm crank ergometer group improved significantly in terms of lean body mass and skeletal muscle mass, and showed a significant decrease in body fat. In the arm crank ergometer group, as well as the usual care group, a significant increase in armpit circumference was detected during the training period. The magnitude of the gain was higher in the usual care group. For all other measured regions of the arm a significant decrease in circumference was seen in both groups. Muscular strength of the upper extremity increased significantly in both groups, with a greater improvement in the arm crank ergometer group. In both groups a non significant trend towards improvement in quality of life was observed. The arm crank ergometer group showed significant improvements in physical functioning, general fatigue and physical fatigue. CONCLUSION: These results confirm the feasibility of arm crank ergometer training after axillary lymph node dissection and highlight improvements in strength, quality of life and reduced arm symptoms with this training. PMID- 28101568 TI - Puerarin inhibits M2 polarization and metastasis of tumor-associated macrophages from NSCLC xenograft model via inactivating MEK/ERK 1/2 pathway. AB - Non-small cell lung carcinoma (NSCLC) metastasis is responsible for most of cancer-related mortality. The tumor associated macrophages (TAMs) are known to be crucial cells in lung cancer and are usually divided into two antagonistic types, M1 and M2. Puerarin has a wide spectrum of pharmacological properties. The present study explores puerarin on macrophage polarization and metastasis of NSCLC. The results demonstrated that puerarin inhibited tumor growth and tumor volumes in NSCLC xenograft model, increased M1 markers [CD197+, inducible nitric oxide synthase (iNOS)+, CD40+)] and reduced M2 markers (CD206+, Arg-1+ and CD163+). Besides, puerarin elevated the level of pro-inflammatory cytokine interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha and interleukin (IL) 12, decreased the expression of pro-tumor cytokines IL-10, IL-4 and transforming growth factor (TGF)-beta. To explore whether puerarin directly acts on macrophages, we purified macrophages from NSCLC model, the results showed that puerarin inhibited macrophages polarized to M2 phenotype and did not require the auxiliary of other cells. In addition, puerarin suppressed the invasion and migration of NSCLC macrophages, restrained the expression of angiogenesis factors. Puerarin also inhibited the activation of mitogen-activated extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) 1/2 pathway through inhibition of ERK nucleus translocation. Finally, IL-4 induced M2 macrophage polarization and metastasis were partially offset by puerarin through inactivating the MEK/ERK 1/2 pathway. Taken together, this study validated that puerarin is able to skew macrophage populations back to M1 subsets to stimulate antitumor effects and suggests puerarin is a negative metastatic regulator of NSCLC. PMID- 28101569 TI - Resveratrol inhibits adventitial fibroblast proliferation and induces cell apoptosis through the SIRT1 pathway. AB - Atherosclerosis is one of the most important causes of cardiovascular disease and studies have showed that adventitial fibroblasts, which are considered to be the most common cell type of the vascular adventitia, are involved in the development of early atherosclerotic plaques. Resveratrol is a plant polyphenolic compound confirmed to have anti-atherosclerotic and cardioprotective effects. The aim of the present study was to investigate the effects of resveratrol on adventitial fibroblasts in vitro and to clarify the underlying mechanism. Adventitial fibroblasts were isolated from the thoracic aorta of 8-week-old SPF Sprague Dawley rats. Following pre-treatment with different concentrations of resveratrol, cell viability, DNA synthesis ability, cell apoptosis and cell migration ability were assessed in vitro. Through transfection with small interfering (si)RNA targeting sirtuin 1 (SIRT1), the role of the SIRT1 pathway in these processes was evaluated. Western blot analysis was used to assess the protein expression of SIRT1. It was demonstrated that resveratrol inhibited the cell viability, DNA synthesis and migratory ability of the adventitial fibroblasts, and induced cell apoptosis in a concentration-dependent manner in vitro. These effects were partly through the SIRT1 pathways. siRNA targeting SIRT1 successfully reversed the antiproliferative, antimigratory and pro apoptotic effects of resveratrol on adventitial fibroblasts. In conclusion, the data showed that resveratrol inhibited cell viability, DNA synthesis and cell migration, and induced cell apoptosis in the rat adventitial fibroblasts in vitro through the SIRT1 signaling pathway. As the activation and migration of adventitial fibroblasts contributes to the early development of atherosclerosis, this may be a mechanism underlying the anti-atherosclerotic effect of resveratrol. PMID- 28101570 TI - Inhibition of TLR4 protects rat islets against lipopolysaccharide-induced dysfunction. AB - Oxidative stress leads to dysfunction in pancreatic cells, causing a reduction in insulin secretion following exposure to glucose. Toll-like receptor 4 (TLR4) may be activated by exposure to lipopolysaccharide (LPS) stress. TLR4 may mediate the initiation of inflammatory and immune defense responses; however, the importance of the LPS/TLR4 interaction in apoptosis induced by oxidative stress in pancreatic beta cells remains to be elucidated. The present study aimed to investigate the importance of TLR4 during LPS-induced oxidative stress, apoptosis and dysfunction of insulin secretion in isolated islets of rats. LPS-induced stimulation of TLR4 increased the production of reactive oxygen species and promoted apoptosis by upregulating the expression levels of caspase-3, poly ADP ribose polymerase and altering the expression ratio of B-cell lymphoma-2 (Bcl 2)/Bcl-2 associated X protein. Additionally, the insulin secretion of islets cells was reduced. Anti-TLR4 antibody and a knockdown of TLR4 by TLR4-short hairpin RNA were used to inhibit TLR4 activity, which may reverse LPS-induced events. The present study determined that in islets exposed to LPS oxidative stress, dysfunction may be partly mediated via the TLR4 pathway. Inhibition of TLR4 may prevent dysfunction of rat islets due to oxidative stress. The present study revealed that targeting the LPS/TLR4 signaling pathway and antioxidant therapy may be a novel treatment for the severely septic patients with hyperglycemia stress. PMID- 28101572 TI - Insulin induction instigates cell proliferation and metastasis in human colorectal cancer cells. AB - The progression of colorectal cancer has been reported to have a positive correlation with the combination of hyperglycemia and hyperinsulinemia in diabetic patients, leading to a lower survival rate. However, how insulin acts on colorectal cancer remains not well understood. The purpose of this study was to explore the effect of insulin on colon cancer cell proliferation and its underlying molecular signaling as well as the impact of insulin-induced in vitro metastasis. Our results showed that insulin markedly promoted cell proliferation, migration and anchorage-independent growth in human colon cancer HCT-116 cells. Insulin-regulated insulin receptors (IRs) stimulate insulin receptor substrate 1 (IRS-1) and interact with the downstream signals, causing a rise in HCT-116 cell proliferation. Moreover, insulin significantly induced the migration ability of HCT-116 cells. The metastatic ability of matrix metalloproteinase-2 (MMP-2) mRNA and activity was activated by insulin. Overall, insulin-triggered cell proliferation and metastatic effects on colorectal cancer cells are mediated by IRS-1 and downstream molecules and by increasing phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) signaling. Therefore, insulin induction might have the potential to induce colorectal cancer progression in diabetes patients. PMID- 28101571 TI - Upregulation of miR-146a by YY1 depletion correlates with delayed progression of prostate cancer. AB - Previously published studies explained that the excessive expression of miR-146a influences the prostate cancer (PCa) cells in terms of apoptosis, progression, and viability. Although miR-146a acts as a tumor suppressor, current knowledge on the molecular mechanisms that controls its expression in PCa is limited. In this study, gene set enrichment analysis (GSEA) showed negatively enriched expression of miR-146a target gene sets and positively enriched expression of gene sets suppressed by the enhancer of zeste homolog 2 (EZH2) after YY1 depletion in PCa cells. The current results demonstrated that the miR-146a levels in PCa tissues with high Gleason scores (>7) are significantly lower than those in PCa tissues with low Gleason scores (<=7), which were initially observed in the clinical specimens. An inverse relationship between YY1 and miR-146a expression was also observed. Experiments indicated the decrease in cell viability, proliferation, and promoting apoptosis after YY1 depletion, while through inhibiting miR-146a could alleviate the negative effect brought by YY1 depletion. We detected the reversed adjustment of YY1 to accommodate miR-146a transcriptions. On the basis of YY1 depletion, we determined that the expression of miR-146a increased after EZH2 knockdown. We validated the combination of YY1 and its interaction with EZH2 at the miR-146a promoter binding site, thereby prohibiting the transcriptional activity of miR-146a in PCa cells. Our results suggested that YY1 depletion repressed PCa cell viability and proliferation and induced apoptosis at least in a miR-146a-assisted manner. PMID- 28101573 TI - Combining doxorubicin with a phenolic extract from flaxseed oil: Evaluation of the effect on two breast cancer cell lines. AB - Breast cancer is one of the most frequently diagnosed forms of cancer and different treatments are used to block its progression. However, it still represents a very common cause of death in women. Doxorubicin (Dox) is reported as an effective agent in breast cancer treatment nonetheless it induces many side effects. For this reason, many laboratories are engaged in understanding how it is possible to decrease the drug concentration, considering that one of the possible solutions is to use drug synergy, combining it with natural substances. Recently we showed that a phenolic extract from flaxseed (FS) oil, named PEFSO, induced on MCF-7 cell line an increase of apoptosis with related modification of G0/G1 phase cell cycle, and the activation of signaling and pro-oxidant pathways. In this study we present data on the combined effect of Dox and PEFSO on two different breast cancer cell lines to define the conditions to use lower doses of this chemotherapeutic agent. We report the data relating to the ability of this mixture to induce cytotoxicity and apoptosis, cell cycle modification, mitochondrial membrane depolarization and activation of extrinsic and/or intrinsic apoptotic pathway. PMID- 28101574 TI - NEK2 serves as a prognostic biomarker for hepatocellular carcinoma. AB - Never in mitosis gene A (NIMA)-related kinase 2 (NEK2) is a microtubule associated protein that regulates spindle assembly in human cells and is overexpressed in various malignancies. However, the role of NEK2 in hepatocellular carcinoma (HCC) remains undetermined. We performed RNA-seq of the HCC cell line SMMC-7721 and the normal liver cell line HL-7702 using the Ion Proton System. NEK2 expression was detected using quantitative reverse transcription polymerase chain reaction in two cell lines and 5 matched HCC and adjacent non-tumorous liver tissues. The correlation between survival and NEK2 expression was analyzed in 359 patients with HCC using RNASeqV2 data available from The Cancer Genome Atlas (TCGA) website (https://tcga data.nci.nih.gov/tcga/). The expression of NEK2, phospho-AKT and MMP-2 was evaluated by immunohistochemistry in 63 cases of HCC and matched adjacent non tumorous liver tissues. Relationships between protein expression and clinicopathological parameters were assessed, and the correlations between NEK2 with phospho-AKT and MMP-2 expressions were evaluated. A total of 610 differentially expressed genes (DEGs) were revealed in the transcriptome comparison, 297 of which were upregulated and 313 were downregulated in HCC. NEK2, as the most obviously different DEG in cells and tissues from the RNA-seq data, was listed as an HCC candidate biomarker for further verification. NEK2 was overexpressed in HCC cells and tissues (P=0.002, P=0.013) and HCC patients with a high expression of NEK2 had a poor prognosis (P=0.0145). Clinical analysis indicated that the overexpression of NEK2 in HCC was significantly correlated with diolame complete (P<0.001), tumor nodule number (P=0.012) and recurrence (P=0.004). NEK2 expression was positively correlated with the expression of phospho-AKT (r=0.883, P<0.01) and MMP-2 (r=0.781, P<0.01). Overexpression of NEK2 was associated with clinicopathological characteristics and poor patient outcomes, suggesting that NEK2 serves as a prognostic biomarker for HCC. Alteration of NEK2 protein levels may contribute to invasion and metastasis of HCC, which may occur through activation of AKT signaling and promotion of MMP-2 expression. PMID- 28101575 TI - Identification of potential targets for differentiation in human leukemia cells induced by diallyl disulfide. AB - Diallyl disulfide (DADS) is a primary component of garlic, which has chemopreventive potential. We previously found that moderate doses (15-120 uM) of DADS induced apoptosis and G2/M phase cell cycle arrest. In this study, we observed the effect of low doses (8 uM) of DADS on human leukemia HL-60 cells. We found that DADS could inhibit proliferation, migration and invasion in HL-60 cells, and arrested cells at G0/G1 stage. Then, cell differentiation was displayed by morphologic observation, NBT reduction activity and CD11b evaluation of cytometric flow. It showed that DADS induced differentiation, reduced the ability of NBT and increased CD11b expression. Likewise, DADS inhibited xenograft tumor growth and induced differentiation in vivo. In order to make sure how DADS induced differentiation, we compared the protein expression profile of DADS treated cells with that of untreated control. Using high resolution mass spectrometry, we identified 18 differentially expressed proteins after treatment with DADS, including four upregulated and 14 downregulated proteins. RT-PCR and western blot assay showed that DJ-1, cofilin 1, RhoGDP dissociation inhibitor 2 (RhoGDI2), Calreticulin (CTR) and PCNA were decreased by DADS. These data suggest that the effects of DADS on leukemia may be due to multiple targets for intervention. PMID- 28101576 TI - Multiple effects of ellagic acid on human colorectal carcinoma cells identified by gene expression profile analysis. AB - Colorectal carcinoma (CRC) is the third most commonly diagnosed cancer in the world. Phytochemicals have become a research hotspot in recent years as cancer prevention and treatment agents due to their low toxicity and limited side effects. Ellagic acid (EA), a natural phenolic constituent, displays various biological activities, including anticancer effects. However, the detailed anticancer mechanisms of EA remain unclear. In the present study, we found that EA inhibited the growth of HCT-116 colon cancer cells. Moreover, we identified differentially expressed genes (DEGs) by microarray profiling of HCT-116 cells treated with EA. A total of 857 DEGs (363 upregulated and 494 downregulated) were identified with a >1.5-fold change in expression after treatment with EA for 72 h. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that a large number of cellular functions were modified by EA including proliferation, apoptosis, cell cycle and angiogenesis. Interaction network analysis using DEGs provided details of their interactions and predicted the key target pathways of EA. To verify the result of cDNA microarray, 10 selected DEGs related to proliferation, apoptosis or cell cycle were further confirmed by real-time RT-PCR. Based on microarray data, we identified several crucial functions of EA. These results provide important new data for EA in anti CRC research. PMID- 28101577 TI - Viscumins functionally modulate cell motility-associated gene expression. AB - In Europe extracts from Viscum album L., the European white-berry mistletoe, are widely used as a complementary cancer therapy. Viscumins (mistletoe lectins, ML) have been scrutinized as important active components of mistletoe and exhibit a variety of anticancer effects such as stimulation of the immune system, induction of cytotoxicity, reduction of tumor cell motility as well as changes in the expression of genes associated with cancer development and progression. By microarray expression analysis, quantitative RT-PCR and RT-PCR based validation of microarray data we demonstrate for the Viscum album extract Iscador Qu and for the lectins Aviscumine and ML-1 that in glioma cells these drugs differentially modulate the expression of genes involved in the regulation of cell migration and invasion, including processes modulating cell architecture and cell adhesion. A variety of differentially expressed genes in ML treated cells are associated with the transforming growth factor (TGF)-beta signaling pathway or are targets of TGF beta. ML treatment downregulated the expression of TGF-beta itself, of the TGF beta receptor II (TGFBR2), of the TGF-beta intracellular signal transducer protein SMAD2, and of matrix-metalloproteinases (MMP) MMP-2 and MMP-14. Even if the changes in gene expression differ between Aviscumine, Iscador Qu and ML-1, the overall regulation of motility associated gene expression by all drugs showed functional effects since tumor cell motility was reduced in a ML-dependent manner. Therefore, ML containing compounds might provide clinical benefit as adjuvant therapeutics in the treatment of patients with invasively growing tumors such as glioblastomas. PMID- 28101578 TI - A 22q11.2 amplification in the region encoding microRNA-650 correlates with the epithelial to mesenchymal transition in breast cancer primary cultures of Mexican patients. AB - Breast cancer ranks first in incidence and mortality in working age women. Cancer initiation and progression relies on accumulation of genetic and epigenetic aberrations that alter cellular processes, among them, epithelial to mesenchymal transition (EMT) denotes particularly aggressive neoplasias given its capacity to invade and metastasize. Several microRNAs (miRNA) have been found able to regulate gene expression at the core of EMT. In this study, the Affymetrix CytoScan HD array was used to analyze three different primary tumor cell isolates from Mexican breast cancer patients. We found an amplification in band 22q11.2 shared by the three samples, in the region that encodes miRNA-650. Overexpression of this miRNA has been associated with downregulation of tumor suppressors ING4 and NDRG2, which have been implicated in cancer progression. Using the Pathway Linker platform the ING4 and NDRG2 interaction networks showed a significant association with signaling pathways commonly deregulated in cancer. Also, several studies support their participation in the EMT. Supporting the latter, we found that the three primary isolates were E-cadherin negative, vimentin positive, presented a cancer stem cell-like phenotype CD44+CD24-/low and were invasive in Transwell invasion assays. This evidence suggests that the gain of region 22q11.2 contributes to trigger EMT. This is the first evidence linking miR-650 and breast cancer. PMID- 28101579 TI - Role of tRNA selenocysteine 1 associated protein 1 in the proliferation and apoptosis of cardiomyocyte-like H9c2 cells. AB - Transfer RNA selenocysteine 1 associated protein 1 (Trnau1ap) serves an essential role in the synthesis of selenoproteins, which have critical functions in numerous biological processes. Selenium deficiency results in a variety of diseases, including cardiac disease. However, the mechanisms underlying myocardial injury induced by selenium deficiency remain unclear. The present study examined the effects of Trnau1ap under- and overexpression in cardiomyocyte like H9c2 cells, by transfection with small interfering RNA and an overexpression plasmid, respectively. Expression levels of glutathione peroxidase, thioredoxin reductase and selenoprotein K were decreased in Trnau1ap-underexpressing cells, and increased in Trnau1ap-overexpressing cells. Using MTT, proliferating cell nuclear antigen, annexin V and caspase-3 activity assays, it was demonstrated that reducing Trnau1ap expression levels inhibited the proliferation of H9c2 cells and induced apoptosis. Conversely, increasing Trnau1ap expression levels promoted cell growth. Western blot analysis revealed that the phosphoinositide 3 kinase/protein kinase B signaling pathway was activated in Trnau1ap underexpressing cells. Furthermore, the apoptotic pathway was activated in these cells, evidenced by relatively greater expression levels of B-cell lymphoma (Bcl 2)-associated X protein and reduced expression levels of Bcl-2. Taken together, these findings suggest that Trnau1ap serves a key role in the proliferation and apoptosis of H9c2 cells. The present study provides insight into the underlying mechanisms of myocardial injury induced by selenium deficiency. PMID- 28101580 TI - Crude extract and solvent fractions of Calystegia soldanella induce G1 and S phase arrest of the cell cycle in HepG2 cells. AB - The representative halophyte Calystegia soldanella (L) Roem. et Schult is a perennial vine herb that grows in coastal dunes throughout South Korea as well as in other regions around the world. This plant has long been used as an edible and medicinal herb to cure rheumatic arthritis, sore throat, dropsy, and scurvy. Some studies have also shown that this plant species exhibits various biological activities. However, there are few studies on cytotoxicity induced by C. soldanella treatment in HepG2 human hepatocellular carcinoma cells. In this study, we investigated the viability of HepG2 cells following treatment with crude extracts and four solvent-partitioned fractions of C. soldanella. Of the crude extract and four solvent fractions tested, treatment with the 85% aqueous methanol (aq. MeOH) fraction resulted in the greatest inhibition of HepG2 cell proliferation. Flow cytometry showed that the 85% aq. MeOH fraction induced a G0/G1 and S phase arrest of the cell cycle progression. The 85% aq. MeOH fraction arrested HepG2 cells at the G0/G1 phase in a concentration-dependent manner, and resulted in decreased expression of cyclin D1, cyclin E, cyclin-dependent kinase (CDK)2, CDK4, CDK6, p21, and p27. Additionally, the 85% aq. MeOH fraction treatment also arrested HepG2 cells in the S phase, with decreased expression of cyclin A, CDK2, and CDC25A. Also, treatment with this fraction reduced the expression of retinoblastoma (RB) protein and the transcription factor E2F. These results suggest that the 85% aq. MeOH fraction exhibits potential anticancer activity in HepG2 cells by inducing G0/G1 and S phase arrest of the cell cycle. PMID- 28101581 TI - The protein arginine methyltransferase 5 promotes malignant phenotype of hepatocellular carcinoma cells and is associated with adverse patient outcomes after curative hepatectomy. AB - The prognosis of advanced hepatocellular carcinoma (HCC) is dismal. Novel molecular targets for diagnosis and therapy is urgently required. This study evaluated expression and functions of the protein arginine methyltransferase 5 (PRMT5) in HCC. Using HCC cell lines, the expression levels of PRMT5 mRNA were determined using the quantitative real-time reverse-transcription polymerase chain reaction, and the effect of a small interfering PRMT5-siRNA on cell phenotype was evaluated. Further, PRMT5 expression was determined in 144 pairs of resected liver tissues to evaluate its clinical significance. Regardless of their differentiated phenotypes, nine HCC cell lines expressed different levels of PRMT5 mRNA. Inhibition of PRMT5 expression significantly decreased the proliferation, invasion, and migration of HCC cell lines. Although the level of PRMT5 mRNA was not influenced by patient's background liver status, it was significantly higher in HCC tissues than in the corresponding noncancerous tissues. High levels of PRMT5 mRNA in HCC tissues were significantly associated with advanced disease stage and adverse prognosis. In conclusion, our results indicate that PRMT5 may act as a putative oncogene in HCC and that the levels of PRMT5 mRNA represent a promising prognostic marker and a potential target of molecular therapy for HCC. PMID- 28101583 TI - Integrated analysis of microRNA and transcription factor reveals important regulators and regulatory motifs in adult B-cell acute lymphoblastic leukemia. AB - B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological malignancy and a leading cause of cancer-related mortality in children and young adults. The molecular mechanisms involved in the regulation of its gene expression has yet to be fully elucidated. In the present study, we performed large scale expression profiling of microRNA (miRNA) and transcription factor (TF) by Illumina deep-sequencing and TF array technology, respectively, and identified 291 differentially expressed miRNAs and 201 differentially expressed TFs in adult B-ALL samples relative to their controls. After integrating expression profile data with computational prediction of miRNA and TF targets from different databases, we construct a comprehensive miRNA-TF regulatory network specifically for adult B-ALL. Network function analysis revealed 25 significantly enriched pathways, four pathways are well-known to be involved in B ALL, such as PI3K-Akt signaling pathway, Jak-STAT signaling pathway, Ras signaling pathway and cell cycle pathway. By analyzing the network topology, we identified 28 hub miRNAs and 19 hub TFs in the network, and found nine potential B-ALL regulators among these hub nodes. We also constructed a Jak-STAT signaling sub-network for B-ALL. Based on the sub-network analysis and literature survey, we proposed a cellular model to discuss MYC/miR-15a-5p/FLT3 feed-forward loop (FFL) with Jak-STAT signaling pathway in B-ALL. These findings enhance our understanding of this disease at the molecular level, as well as provide putative therapeutic targets for B-ALL. PMID- 28101582 TI - AURKA, DLGAP5, TPX2, KIF11 and CKAP5: Five specific mitosis-associated genes correlate with poor prognosis for non-small cell lung cancer patients. AB - The growth of a tumor depends to a certain extent on an increase in mitotic events. Key steps during mitosis are the regulated assembly of the spindle apparatus and the separation of the sister chromatids. The microtubule-associated protein Aurora kinase A phosphorylates DLGAP5 in order to correctly segregate the chromatids. Its activity and recruitment to the spindle apparatus is regulated by TPX2. KIF11 and CKAP5 control the correct arrangement of the microtubules and prevent their degradation. In the present study, we investigated the role of these five molecules in non-small cell lung cancer (NSCLC). We analyzed the expression of the five genes in a large cohort of NSCLC patients (n=362) by quantitative real-time PCR. Each of the genes was highly overexpressed in the tumor tissues compared to corresponding normal lung tissue. The correlation of the expression of the individual genes depended on the histology. An increased expression of AURKA, DLGAP5, TPX2, KIF11 and CKAP5 was associated with poor overall survival (P=0.001-0.065). AURKA was a significant prognostic marker using multivariate analyses (P=0.006). Immunofluorescence studies demonstrated that the five mitosis-associated proteins co-localized with the spindle apparatus during cell division. Taken together, our data demonstrate that the expression of the mitosis-associated genes AURKA, DLGAP5, TPX2, KIF11 and CKAP5 is associated with the prognosis of NSCLC patients. PMID- 28101584 TI - Myeloprotective effects of C-type natriuretic peptide on cisplatin-induced bone marrow granulocytopenia in mice. AB - PURPOSE: Cisplatin is an effective chemotherapeutic agent used to treat a variety of malignant tumors. The major toxicity associated with cisplatin treatment is granulocytopenia. C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, protects against toxicity in many organs, including the heart, blood vessels, lung, and kidney. The objective of this study was to investigate the myeloprotective effects of CNP in a mouse model of cisplatin-induced granulocytopenia. METHODS: The mice were divided into two groups: cisplatin with vehicle and cisplatin with CNP. CNP (2.5 MUg/kg/min via osmotic pump, subcutaneously) or vehicle administration was started two day before cisplatin injection, and continued until the mice were killed. At 0, 2, 4, 8, and 14 days after cisplatin injection (16 mg/kg, intraperitoneally as a single dose), we counted total and living cells and granulocyte/macrophage colony-forming units (CFU-GM) in bone marrow. In addition, at 0, 1, 2, and 4 days after cisplatin injection, we measured mRNA levels of CXC chemokine receptor 4 (CXCR4) and chemokine CXC ligand 12 (CXCL12) in bone marrow. RESULTS: CNP significantly attenuated the reduction in bone marrow nucleated cell count and CFU-GM in bone marrow at 4 days after cisplatin injection. Four days after cisplatin injection, CNP significantly decreased the CXCR4 mRNA level in bone marrow, but had no effect on the level of CXCL12 mRNA. CONCLUSIONS: CNP exerts myeloprotective effects in cisplatin-induced granulocytopenia and decreases CXCR4 expression. PMID- 28101586 TI - Bone cultures from war-wounded civilians in the Middle East: a surgical prospective. AB - PURPOSE: Hidden infections in a reconstructive surgery program are frequently underestimated. METHODS: A retrospective study was undertaken of 1,891 civilian war-wounded patients from Iraq, Syria, Yemen and Gaza treated in Amman from August 2006 to January 2016. One thousand three hundred and fifty-three underwent surgical interventions for previous bone injury and had systematic bone cultures. RESULTS: Among patients (167) without any clinical, biological or radiological signs of infection, 46% demonstrated infection based on bone cultures. We conclude that bone culture should become a prerequisite for any reconstruction in such contexts. PMID- 28101585 TI - Whole pelvis radiotherapy for pathological node-positive prostate cancer : Oncological outcome and prognostic factors. AB - PURPOSE: The goal of this work was to investigate the oncological outcome of whole pelvis radiotherapy (wpRT) in pathologic pelvic lymph node-positive (pN1) prostate cancer (PCa), evaluate the location of relapse, and identify potential prognostic factors. PATIENTS AND METHODS: All patients undergoing pelvic lymph node dissection (PLND) since the year 2000 at a single tertiary care center were evaluated. A total of 154 patients with pN1 PCa were treated with wpRT (39 in an adjuvant setting) and 2-3 years of androgen deprivation therapy (ADT). Kaplan Meier analysis was performed to estimate biochemical recurrence-free survival (bRFS), clinical progression-free survival (cPFS), and prostate cancer-specific survival (CSS). Uni- and multivariate regression analyses were performed to identify prognostic factors. RESULTS: Estimated bRFS was 67%, cPFS was 71%, and CSS was 96% at 5 years. Median follow-up was 55 months (interquartile range 25 87). Multivariate analysis identified having only 1 positive lymph node, a shorter time between diagnosis and PLND, and older age as independent favorable prognostic factors for biochemical and clinical recurrence. The number of positive lymph nodes was prognostic for CSS (hazard ratio [HR] 1.34, 95% confidence interval 1.17-1.54) and OS (HR 1.22, 95% confidence interval 1.10 1.36). Bone metastases were the most frequent location of PCa relapse (n = 32, 64%). CONCLUSIONS: Patients with pN1 PCa treated with wpRT and 2-3 years ADT have an encouraging 5-year CSS. Understaging of the disease extent may be the most important enemy in definitive pN1 PCa treatment. PMID- 28101587 TI - Factors Limiting Formation of Community Forestry Enterprises in the Southern Mixteca Region of Oaxaca, Mexico. AB - Many studies have considered community-based forestry enterprises to be the best option for development of rural Mexican communities with forests. While some of Mexico's rural communities with forests receive significant economic and social benefits from having a community forestry enterprise, the majority have not formed such enterprises. The purpose of this article is to identify and describe factors limiting the formation of community forestry enterprise in rural communities with temperate forests in the Southern Mixteca region of Oaxaca, Mexico. The study involved fieldwork, surveys applied to Community Board members, and maps developed from satellite images in order to calculate the forested surface area. It was found that the majority of Southern Mixteca communities lack the natural and social conditions necessary for developing community forestry enterprise; in this region, commercial forestry is limited due to insufficient precipitation, scarcity of land or timber species, community members' wariness of commercial timber extraction projects, ineffective local governance, lack of capital, and certain cultural beliefs. Only three of the 25 communities surveyed have a community forestry enterprise; however, several communities have developed other ways of profiting from their forests, including pine resin extraction, payment for environmental services (PES), sale of spring water, and ecotourism. We conclude that community forestry enterprise are not the only option for rural communities to generate income from their forests; in recent years a variety of forest-related economic opportunities have arisen which are less demanding of communities' physical and social resources. PMID- 28101588 TI - Factors Controlling Sediment Load in The Central Anatolia Region of Turkey: Ankara River Basin. AB - Better understanding of the factors controlling sediment load at a catchment scale can facilitate estimation of soil erosion and sediment transport rates. The research summarized here enhances understanding of correlations between potential control variables on suspended sediment loads. The Soil and Water Assessment Tool was used to simulate flow and sediment at the Ankara River basin. Multivariable regression analysis and principal component analysis were then performed between sediment load and controlling variables. The physical variables were either directly derived from a Digital Elevation Model or from field maps or computed using established equations. Mean observed sediment rate is 6697 ton/year and mean sediment yield is 21 ton/y/km2 from the gage. Soil and Water Assessment Tool satisfactorily simulated observed sediment load with Nash-Sutcliffe efficiency, relative error, and coefficient of determination (R2) values of 0.81, -1.55, and 0.93, respectively in the catchment. Therefore, parameter values from the physically based model were applied to the multivariable regression analysis as well as principal component analysis. The results indicate that stream flow, drainage area, and channel width explain most of the variability in sediment load among the catchments. The implications of the results, efficient siltation management practices in the catchment should be performed to stream flow, drainage area, and channel width. PMID- 28101589 TI - [Intramedullary nailing in diaphyseal clavicle fractures using minimally invasive percutaneous reduction]. AB - OBJECTIVE: Closed reduction and intramedullary nailing is common in diaphyseal clavicle fractures. The aim of this report is to demonstrate a surgical method with minimally invasive percutaneous reduction in cases where closed reduction fails. The procedure is associated with good cosmetic results. INDICATIONS: Percutaneous reduction using two reduction forceps enables intramedullary nailing without an open procedure. CONTRAINDICATIONS: Open, multifragmented or non dislocated fractures, oblique fractures due to postoperative dislocation or shortening risk, fracture having potential to become compound fractures, neurovascular complications, pseudoarthroses. SURGICAL TECHNIQUE: The patient is in beach-chair position. After an incision, the nail is entered from medial, two reduction forceps are mounted percutaneously at the lateral and medial fragment. After reduction the nail is pushed forward into the lateral fragment. Thereby, the fracture hematoma is not disturbed for the most part. POSTOPERATIVE MANAGEMENT: Early functional rehabilitation with maximal abduction and anteversion of 90 degrees for 6 weeks. RESULTS: Anatomic reduction can be achieved with mild cosmetic impairment. PMID- 28101590 TI - [Minimally invasive treatment of intra-articular calcaneal fractures with the 2 point distractor]. AB - OBJECTIVE: Open treatment of calcaneus fractures often has an increased risk of wound healing. Minimally invasive treatment with small incisions reduces complications. INDICATIONS: Calcaneal fractures with malalignment/comminution >1 2 mm; broadening, varus alignment of the calcaneal length axis or shortening; emergency surgery for open fractures or compartment syndrome. CONTRAINDICATIONS: Local or general contraindications. SURGICAL TECHNIQUE: Standardised positioning; restoration of length/axis with 2-point distractor under fluoroscopic control. Fragment reduction via small incisions. Fixation with 7.3 mm cannulated screws and 4.0 mm sustentaculum screws. POSTOPERATIVE MANAGEMENT: Cast-free and no weight bearing for 6 weeks; then weight bearing in a heel off-loading shoe for another 6 weeks with physiotherapy; if needed postoperative cast until soft tissue consolidation. RESULTS: Of 212 calcaneal fractures, 182 were treated with this technique. Wound healing complication rate was 2.7%; 4.7% of patients required secondary arthrodesis of the subtalar joint. PMID- 28101599 TI - ? PMID- 28101592 TI - Long-term safety and outcome of fludarabine, cyclophosphamide and mitoxantrone (FCM) regimen in previously untreated patients with advanced follicular lymphoma: 12 years follow-up of a phase 2 trial. AB - Fludarabine combinations are very affective in follicular lymphoma (FL) with high rates of complete response and prolonged survival. However, late toxicities could be a concern. The aim of the present study was to analyze the long-term impact on survival, relapse and late toxicities of a trial of treatment with fludarabine, mitoxantrone and cyclophosphamide (FCM regimen) for untreated patients with advanced stage FL. One hundred and twenty patients enrolled in a phase 2 trial of treatment with FCM regimen between 2000 and 2003 were evaluated. After a median follow-up of 12 years, 52 patients eventually relapsed/progressed with 10 year progression-free survival (PFS) of 46 %. Ten patients showed histological transformation to aggressive lymphoma with a risk of transformation of 2 and 9 % at 5 and 10 years, respectively. Three patients developed therapy-related myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) and seven solid neoplasms with an overall risk of 3 and 8 % at 5 and 10 years, respectively. Twenty-six patients eventually died during the follow-up. Overall survival at 10 years was 83 %. In conclusion, FCM regimen allows excellent long-lasting response in previously untreated patients with FL. The incidence of late events including histological transformation and secondary neoplasia is low but not negligible. PMID- 28101602 TI - The "O" sign. PMID- 28101593 TI - Diffuse phalangeal signal abnormality on magnetic resonance imaging: phalangeal microgeodic disease. AB - BACKGROUND: Phalangeal microgeodic disease is a rare and benign self-limited condition involving the phalanges, often in the setting of cold exposure, with characteristic MR imaging abnormalities. Radiographic case descriptions are predominantly from Asia and Europe, with only seven cases using MR to characterize phalangeal microgeodic disease. OBJECTIVE: In this study we describe the MR imaging appearance of unusual and striking phalangeal signal abnormality compatible with phalangeal microgeodic disease at our institution in North America. MATERIALS AND METHODS: We retrospectively reviewed cases presenting at our institution with unusual or unexplained phalangeal signal abnormalities between 2001 and 2014. We reviewed the MR imaging appearances in conjunction with radiographs and any other available imaging investigations. RESULTS: Of 189 examinations reviewed during the study period, 8 imaging studies in 6 patients met the study inclusion criteria. Signal abnormality was present in 57 of 112 phalanges (51%), frequently involving the distal phalanges (70%, 28 of 40), followed by the middle phalanges (56%, 18 of 32) and the proximal phalanges (28%, 11 of 40). The pattern of involvement was most commonly diaphysis (38%), followed by metaphysis (32%) and epiphysis (30%). The extent of MR signal abnormality was greater than that suspected based on clinical presentation or on radiographs. CONCLUSION: The presence of unexplained diffuse characteristic marrow involvement of multiple painful phalanges on MR images, often in the setting of cold exposure, should raise the possibility of phalangeal microgeodic disease. Consideration of this diagnosis based on MR findings would lead to a more conservative management and avoid unnecessary invasive diagnostic procedures. PMID- 28101591 TI - Functions of Cancer-Derived Extracellular Vesicles in Immunosuppression. AB - Extracellular vesicles, including exosomes, constitute an important element of intercellular communication by carrying a variety of molecules from producer to target cells. The transport of mRNA and miRNA can directly modulate gene expression in the target cells. The miRNA content in exosomes is characteristic for the cell from which the vesicles were derived enabling the usage of exosomes as biomarkers for the diagnosis various diseases, including cancer. Cancer derived exosomes support the survival and progression of tumors in many ways and also contribute to the neutralization of the anti-cancer immune response. Exosomes participate in all known mechanisms by which cancer evades the immune system. They influence the differentiation and activation of immune suppressor cells, they modulate antigen presentation, and are able to induce T-cell apoptosis. Although cancer-derived exosomes mainly suppress the immune system and facilitate tumor progression, they are also important sources of tumor antigens with potential clinical application in stimulating immune responses. This review summarizes how exosomes assist cancer to escape immune recognition and to acquire control over the immune system. PMID- 28101603 TI - Biodegradation of Aldrin and Dieldrin by the White-Rot Fungus Pleurotus ostreatus. AB - Aldrin and its metabolite dieldrin are persistent organic pollutants that contaminate soil in many parts of the world. Given the potential hazards associated with these pollutants, an efficient degradation method is required. In this study, we investigated the ability of Pleurotus ostreatus to transform aldrin as well as dieldrin in pure liquid cultures. This fungus completely eliminated aldrin in potato dextrose broth (PDB) medium during a 14-day incubation period. Dieldrin was detected as the main metabolite, and 9 hydroxylaldrin and 9-hydroxyldieldrin were less abundant metabolites. The proposed route of aldrin biotransformation is initial metabolism by epoxidation, followed by hydroxylation. The fungus was also capable of degrading dieldrin, a recalcitrant metabolite of aldrin. Approximately 3, 9, and 18% of dieldrin were eliminated by P. ostreatus in low-nitrogen, high-nitrogen, and PDB media, respectively, during a 14-day incubation period. 9-Dihydroxydieldrin was detected as a metabolite in the PDB culture, suggesting that the hydroxylation reaction occurred in the epoxide ring. These results indicate that P. ostreatus has potential applications in the transformation of aldrin as well as dieldrin. PMID- 28101604 TI - A users' guide to the 2016 Surviving Sepsis Guidelines. PMID- 28101606 TI - Practice guidelines as implementation science: the journal editors' perspective. PMID- 28101607 TI - A Backwards Step for Pilonidal Sinus Flap Surgery? PMID- 28101608 TI - Prognostic Impact of Further Treatments on Distant Metastasis in Patients with Minimally Invasive Follicular Thyroid Carcinoma: Verification Using Inverse Probability of Treatment Weighting. PMID- 28101609 TI - Patient Preparation for Transitions of Surgical Care: Is Failing to Prepare Surgical Patients Preparing Them to Fail? AB - BACKGROUND: Transitions of care before and after surgery are critical for patient preparation. We sought to determine whether the degree of exposure to health information resources before and after surgery increases preparedness and decreases hospital readmission. METHODS: A national Web-based, cross-sectional survey was conducted of 1917 patients and caregivers who had a recent surgical encounter. Health information resources used before and after surgery were correlated with patient level of preparedness. We also evaluated the association between preparedness and hospital readmission. RESULTS: Compared to unprepared patients, those who felt prepared were most likely to be given multiple health information resources before surgery (92 vs. 77%, p < 0.001) and before leaving the hospital (91 vs. 69%, p = 0.02). Feeling prepared was positively correlated with the number of resources provided to patients by their surgical team and used before surgery and before leaving the hospital (p < 0.05, both). 30-day readmission was significantly lower among patients who felt prepared either before (7% prepared vs. 22% not prepared, p = <0.001) or after surgery (9% prepared vs. 23% not prepared, p < 0.001). CONCLUSIONS: Patients with access to more health information resources during transitions before and after surgery feel better prepared and have lower rates of 30-day readmission. PMID- 28101610 TI - Queries and Comments on the Current Role of "Selective Parathyroid Venous Sampling in Patients with Persistent or Recurrent Primary Hyperparathyroidism and Negative, Equivocal or Discordant Noninvasive Imaging". PMID- 28101611 TI - Pilonidal Disease Surgery Needs More Off-Midline Closure Education: Reply. PMID- 28101612 TI - Abolishment of N-glycan mannosylphosphorylation in glyco-engineered Saccharomyces cerevisiae by double disruption of MNN4 and MNN14 genes. AB - Mannosylphosphorylated glycans are found only in fungi, including yeast, and the elimination of mannosylphosphates from glycans is a prerequisite for yeast glyco engineering to produce human-compatible glycoproteins. In Saccharomyces cerevisiae, MNN4 and MNN6 genes are known to play roles in mannosylphosphorylation, but disruption of these genes does not completely remove the mannosylphosphates in N-glycans. This study was performed to find unknown key gene(s) involved in N-glycan mannosylphosphorylation in S. cerevisiae. For this purpose, each of one MNN4 and five MNN6 homologous genes were deleted from the och1Deltamnn1Deltamnn4Deltamnn6Delta strain, which lacks yeast-specific hyper mannosylation and the immunogenic alpha(1,3)-mannose structure. N-glycan profile analysis of cell wall mannoproteins and a secretory recombinant protein produced in mutants showed that the MNN14 gene, an MNN4 paralog with unknown function, is essential for N-glycan mannosylphosphorylation. Double disruption of MNN4 and MNN14 genes was enough to eliminate N-glycan mannosylphosphorylation. Our results suggest that the S. cerevisiae och1Deltamnn1Deltamnn4Deltamnn14Delta strain, in which all yeast-specific N-glycan structures including mannosylphosphorylation are abolished, may have promise as a useful platform for glyco-engineering to produce therapeutic glycoproteins with human-compatible N-glycans. PMID- 28101613 TI - Estimation of Anaerobic Debromination Rate Constants of PBDE Pathways Using an Anaerobic Dehalogenation Model. AB - This study aims to estimate anaerobic debromination rate constants (km) of PBDE pathways using previously reported laboratory soil data. km values of pathways are estimated by modifying a previously developed model as Anaerobic Dehalogenation Model. Debromination activities published in the literature in terms of bromine substitutions as well as specific microorganisms and their combinations are used for identification of pathways. The range of estimated km values is between 0.0003 and 0.0241 d-1. The median and maximum of km values are found to be comparable to the few available biologically confirmed rate constants published in the literature. The estimated km values can be used as input to numerical fate and transport models for a better and more detailed investigation of the fate of individual PBDEs in contaminated sediments. Various remediation scenarios such as monitored natural attenuation or bioremediation with bioaugmentation can be handled in a more quantitative manner with the help of km estimated in this study. PMID- 28101615 TI - Erratum to: Chemoembolization of Neuroendocrine Liver Metastases Using Streptozocin and Tris-acryl Microspheres: Embozar (EMBOsphere + ZAnosaR) Study. PMID- 28101614 TI - [Dermatological topical and systemic therapy during pregnancy]. AB - During pregnancy, a successful and safe therapeutic management of patients is possible to lower the burden of disease. Often topical therapy in combination with intensive basic skin care is sufficient. Drug therapies may also be used, most often for systemic diseases such as autoimmune diseases or psoriasis. An early change in therapy is also key during planned pregnancies so that treatments can be switched, adjusted, reduced or closely monitored. Another point to consider is to keep drug dosing as low as possible (without occlusion in local therapy) or short termed (with the exception of autoimmune or malignant diseases). An interdisciplinary collaboration between obstetrics and gynecology/rheumatology/internal medicine/dermatology as well as pharmacologists is of utmost importance. PMID- 28101616 TI - Successful Retrieval of an Embolized Vascular Closure Device (Angio-Seal(r)) After Peripheral Angioplasty. AB - A 55-year-old male with peripheral arterial disease underwent angioplasty of the right lower limb arteries via antegrade femoral access. Angio-Seal(r) closure device was used to treat the puncture site, whereby the intravascular sealing anchor accidentally embolized into the malleolar region of the right posterior tibial artery. Successful retrieval of the anchor was accomplished by a SpiderFX embolic protection device. This technique may be a useful approach to retrieve embolized foreign bodies via endovascular access. PMID- 28101617 TI - A New CT-Guided Modified Trocar Technique for Drainage of Difficult Locations Abscesses. AB - PURPOSE: Computed tomography (CT) is commonly used to guide drainage of deep seated abdominal fluid collections. However, in some cases, these collections seem to be inaccessible due to surrounding organs or their being in difficult locations. The aim of this study is to describe a modified Trocar technique to drain collections in difficult locations, especially those in the subphrenic space, without passing through intervening organs. MATERIALS AND METHODS: This retrospective case series study describes seven inpatients who underwent CT guided drainage using a modified Trocar technique for abscesses that are difficult to access percutaneously. All patients provided written informed consent prior to the procedure. After placement of a 12-14F catheter inside the peritoneum, the Trocar stylet was removed so that the tip of the catheter became blunt and flexible to avoid injury to organs and structures in the catheter route, and the catheter was slowly advanced towards the collection using CT guidance and tactile sensation. After reaching the target, the stylet was reintroduced to enter the abscess wall. RESULTS: All procedures were performed using an anterior abdominal wall access with adequate catheter positioning and resulted in clinical status improvement in the days after the drainage. No complications related to the procedure were identified in any of the patients. CONCLUSIONS: The modified Trocar technique for percutaneous CT-guided drainage of abdominal abscesses may be feasible for lesions that are difficult to access with conventional methods. PMID- 28101618 TI - [Neurological and psychiatric journals during the Third Reich : National socialistic and racist contents]. AB - The aim of this study was to investigate scientific articles in three German journals for national socialist and racist contents. The three journals evaluated for the period of the Third Reich were the Der Nervenarzt, Deutsche Zeitschrift fur Nervenheilkunde and the Archiv fur Psychiatrie und Nervenkrankheiten. The specialist disciplines of neurology and psychiatry were united in the year 1935 and Ernst Rudin, a neurological geneticist, was appointed as president (Reichsleiter) of the society. The universal idea of a degenerative development, which was believed to exert a negative influence on public health, was widely accepted in this time period; therefore, in some articles measures were called for, such as termination of pregnancy, sterilization and castration of diseased people and also of criminals. National socialist ideals became part of articles on nervous diseases, works of art of the mentally ill and suicidal tendencies. The recruitment of volunteers and informed consent for participation in human experiments were not described in scientific publications. PMID- 28101619 TI - [All-rounder vitamin D?] AB - BACKGROUND: Many indications are discussed for vitamin D substitution, such as osteoporosis, autoimmune diseases, cancer and psychiatric diseases. Also discussed is the fact that the majority of the German population suffer from a vitamin D deficiency. OBJECTIVE: Review of the study results for these individual diseases and a critical analysis of the currently established therapeutic reference range, which defines a vitamin D deficiency. MATERIAL AND METHODS: A literature search was carried out in the statements of the German Society for Nutrition, in scientific publications and journals. RESULTS: The study results on prevention and therapy of various diseases with vitamin D show inconsistent results. Well-established indications are the prevention of rickets in babies and the supportive therapy for osteoporosis. The currently established reference range for the definition of a vitamin D deficiency came from studies where vitamin D deficiency was correlated to an increase in parathyroid hormone. Different laboratories use different methods for measurement of vitamin D levels. CONCLUSION: More studies are needed to clarify the role of vitamin D in the prevention and treatment of various diseases. Another problem is that different laboratories do not use the same measurement methods to determine vitamin D and the use of different methods leads to widely varying results which cannot be compared. Therefore, a standardization of the methods would be desirable. PMID- 28101620 TI - [Home-based telerehabilitation after stroke]. AB - The use of modern information and telecommunication technologies enables telerehabilitation of neurological deficits in the domestic environment. The current state of studies on rehabilitative teletherapy for improvement of motor function and mobility deficits due to stroke is reviewed. Two neurolinguistic proof of concept studies investigating the efficacy of online interactive telespeech therapy are reported, which compared virtual screen to screen interactive telerehabilitation of aphasia after stroke and dysarthrophonia in Parkinson's disease to conventional face to face rehabilitation. The results of the studies indicate that the neurological rehabilitation of motor and communicative deficits in the domestic environment of patients by means of teletherapy is just as efficient as conventional rehabilitation. Under home-based telerehabilitation patient transfer becomes unnecessary. Rehabilitative Teletherapy is a posthospital component of a cross-sector supply chain for patients with handicaps or impairments due to stroke and other neurological diseases. PMID- 28101621 TI - [Cardiogenic shock]. PMID- 28101622 TI - [Use of vasopressors and inotropics in cardiogenic shock]. AB - Vasoactive drugs and inotropic agents are important for the hemodynamic management of cardiogenic shock. In this article the use of different vasoactive and ionotropic drugs in cardiogenic shock is presented. Hemodynamic management during cardiogenic shock occurs after initial moderate volume delivery by dobutamine to increase inotropism. If adequate perfusion pressures are not achieved norepinephrine is administered. If a sufficient increase in cardiac performance can still not be achieved by the treatment, administration of levosimendan or phosphodiesterase (PDE) inhibitors may be necessary. Levosimendan is superior to PDE inhibitors for patients in cardiogenic shock. The aim of hemodynamic management in cardiogenic shock is to allow the transient use of inotropics and vasopressors in the lowest necessary dose and only as long as necessary. The daily question is whether the dose can be reduced or in the case of deterioration whether the use of an extracorporeal circulatory support system should be considered. There are currently no available data on mortality that demonstrate the benefit of hemodynamic monitoring using target criteria. The advantage, however, results from the economic use of inotropics and vasopressors by certain target criteria. PMID- 28101623 TI - [102 patients with suspected myocarditis : Clinical presentation, diagnostics, therapy and prognosis]. AB - INTRODUCTION: Myocarditis is a disease which is difficult to diagnose and which includes a risk of the development of dilated cardiomyopathy and sudden cardiac death. METHODS AND PATIENTS: In this study 102 patients were included from the time period 2003-2013 after diagnosis or suspected diagnosis of myocarditis in the department of internal medicine at the University Hospital Halle (Saale). RESULTS: Of the study participants 77.5% were male and the average age was 35.5 +/- 14.1 years. The symptoms reported by the patients were angina in 46.1%, dyspnea in 38.2%, performance deterioration in 29.4%, palpitations in 9.8% and syncope in 8.8%. In 45.1% of patients, symptoms were preceded by a respiratory infection. All patients underwent an echocardiogram and in 36.5% it was possible to demonstrate a regional wall motion abnormality and in 20.4% a pericardial effusion. A myocardial biopsy was performed in 15.6% of the patients. The presence of cardiotropic viruses was investigated in 37.3% of patients but was detected in only 5.9%. Cardiac magnetic resonance imaging (MRI) was performed in 82 patients of whom 33.3% showed a late enhancement and 11.9% a wall movement disorder. In this study four patients, all male, died and three suffered recurrent myocarditis. CONCLUSION: This study showed the wide range of symptoms in myocarditis. Myocarditis is rarely severely manifested and in this study the mortality was 3.9%. For further optimization of the diagnostic and treatment algorithms, prospective, randomized studies would be desirable. PMID- 28101625 TI - Is cardiac CT capable to distinguish between myocardial fibrosis and inflammation? PMID- 28101624 TI - The safety and efficacy of cardiac contractility modulation in heart failure : A meta-analysis of clinical trials. AB - BACKGROUND: Cardiac contractility modulation (CCM) has developed as a promising treatment device for heart failure (HF). This meta-analysis aimed at systematically reviewing the latest available published trials to provide evidence on the safety and efficacy of CCM in patients with HF. METHODS: We searched the Cochrane Central Resister of Controlled Trials, PubMed, and EMBASE in May 2016 to identify eligible clinical trials comparing CCM with sham treatment or with usual care. All-cause mortality, all-cause hospitalization, and serious cardiopulmonary adverse effects were considered to be the primary outcomes of interest in evaluating the safety of CCM for patients with HF. Peak oxygen consumption and 6-min walk tests were performed as the second outcomes of interest to assess efficacy. Risk ratio (RR), standard mean difference (SMD), and 95% confidence intervals (CIs) were calculated. RESULTS: Four studies enrolling 723 participants were included. Compared with the control arm, CCM did not significantly improve all-cause mortality or all-cause hospitalizations. No differences were observed for adverse effects of CCM, possibly due to the low number of studies. By contrast, CCM significantly improved peak oxygen consumption (standard mean difference 0.233, 95% CI, 0.065-0.401 ml/kg/min, p = 0.006) and the 6-min walk test distance (standard mean difference 0.924, 95% CI, 0.001-0.334 m, p = 0.049). CONCLUSION: In our meta-analysis of published clinic trials we found that CCM did not lower the risk of severe cardiovascular adverse events; however, it was associated with remarkable improvements in functional cardiopulmonary capacity. Therefore, CCM may serve as an alternative option for patients with advanced HF. PMID- 28101626 TI - [Pneumonia]. PMID- 28101627 TI - ? PMID- 28101605 TI - Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. AB - OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012". DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality. PMID- 28101629 TI - Treatment of Ribbing disease with 5-year follow-up and literature review. AB - Ribbing disease, or multiple diaphyseal sclerosis, is a rare diaphyseal sclerosis of unknown etiology. Patients with this pathology usually present with asymmetric pain limited to the lower extremities. Though all efforts are made to relieve the progressive pain associated with Ribbing disease, no medical or surgical treatments have been established yet. In this case report, we followed up a Ribbing case with sclerotic bone fenestration for 5 years. The radiological changes and the clinical effects are described, and the different Ribbing treatments are then briefly reviewed. PMID- 28101628 TI - Rho kinase inhibitor fasudil mitigates high-cholesterol diet-induced hypercholesterolemia and vascular damage. AB - The current study was designed to investigate the potential beneficial therapeutic outcome of Rho kinase inhibitor (fasudil) against hypercholesterolemia-induced myocardial and vascular injury in rabbits together with diet modification. Sixteen male rabbits were randomly divided into four groups: normal control group which received standard rabbit chow, hypercholesterolemic control group, and treated groups which received cholesterol rich rabbit chow (1.5% cholesterol) for 8 weeks. Treated groups received either fasudil (100 mg/kg/day) or rosuvastatin (2.5 mg/kg/day) starting from the ninth week for further 4 weeks with interruption of the cholesterol-rich chow. Biochemical assessment of serum cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and myocardial oxidative/antioxidant biomarkers malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH), besides biochemical assessment of serum nitric oxide (NO), creatine kinase (CK), and lactate dehydrogenase (LDH) activities and serum total antioxidant capacity (TAC), was conducted. Serum vascular cell adhesion molecule 1 (VCAM-1) and serum Rho-associated protein kinase 1 (ROCK-1) were also evaluated along with histopathological examination of aorta specimens. Fasudil administration significantly decreased serum cholesterol, triglyceride (TG), and LDL and significantly increased serum HDL, with concomitant decrease in serum CK and LDH activities, NO, and restoration of serum TAC. Myocardial MDA significantly declined; SOD activity and GSH contents were restored. Serum ROCK-1 and VCAM-1 levels significantly declined as well. Vascular improvement was confirmed with histopathological examination, which revealed normal aortic intema with the absence of atheromas. Fasudil has promising anti-atherogenic activity mediated primarily via alleviation of hypercholesterolemia-induced oxidative stress and modulation of inflammatory response. PMID- 28101630 TI - Association between sleep apnea and low bone mass in adults: a systematic review and meta-analysis. AB - : We performed a systematic review of the literature to assess the association between sleep apnea and bone metabolism diseases including osteoporosis in adult population. Results from clinical trials suggest that the association between sleep apnea and low bone mass in adults is possible. INTRODUCTION: This study aimed to synthesize existing evidence on the potential association between sleep apnea and low bone mass in adults. METHODS: Electronic searches of five databases were performed. The inclusion criteria consisted of studies in humans that assessed potential associations between sleep apnea and bone metabolic diseases in an adult population. For diagnosis of sleep apnea overnight polysomnography, home polygraphy, or validated records from healthcare databases were considered. Reduced bone density, osteoporosis, serum/urinary levels for markers of bone formation and resorption, or risk of fractures caused without history of trauma were considered indicators of low bone mass. A random-effects model meta-analysis was applied when possible. RESULTS: Of the 963 relevant references, 12 studies met our inclusion criteria and were assessed to be of medium to low bias. Nine out of 12 studies reported an association between sleep apnea and low bone mass (increased bone resorption markers, reduced bone density, and higher risk of osteoporosis). Two studies did not report a significant association, whereas one study reported an increase of bone density in sleep apnea patients compared to non-sleep apnea patients. Meta-analysis of 2 studies (n = 112,258 patients) showed that sleep apnea was a significant risk factor for osteoporosis (odds ratio (OR), 1.92; 95%CI, 1.24 to 2.97; I2 = 66%); females only had an OR of 2.56 (95% CI, 1.96 to 3.34; I2 = 0%) while the OR in males was 2.03 (95% CI, 1.24 to 3.35; I2 = 38%). CONCLUSIONS: An association between sleep apnea and low bone mass in adults is plausible, but supporting evidence has a risk of bias and is inconsistent. PMID- 28101633 TI - Erratum to: A FAS-ligand variant associated with autoimmune lymphoproliferative syndrome in cats. PMID- 28101632 TI - A discrete-time model for population persistence in habitats with time-varying sizes. AB - In this paper, we use periodic and stochastic integrodifference models to study the persistence of a single-species population in a habitat with temporally varying sizes. We extend a persistence metric for integral operators on bounded domains to that of integral operators on unbounded domains. Using this metric in the periodic model, we present new perspectives of the critical habitat size problem in the case of dynamically changing habitat sizes. Specifically, we extend the concept of critical habitat size to that of lower minimal limit size in a period-2 scenario, and prove the existence of the lower minimal limit size. For the stochastic model, we point out the importance of considering multiple time scales in the temporal variability of the habitat size. The models are relevant to biological scenarios such as seasonal variability of wetland habitat sizes under precipitation variability. PMID- 28101631 TI - Lumbar and sacral pedicle screw placement using a template does not improve the midterm pain and disability outcome in comparison with free-hand method. AB - BACKGROUND: The free-hand technique carries a higher risk of pedicle weakening and neurovascular injuries in comparison with pedicle screw placement using a drill guide. Due to this evidence and because of some variances in the surgical method, different outcome can be expected. The objective of the study was to evaluate the disability, the back and leg pain before and at least 3 years after the surgery between examined groups. MATERIALS AND METHODS: Eleven patients in drill guide and 13 in control group were randomly assigned for vertebral fusion in the lumbar and first sacral regions. Pre- and post-operative CT scans, Oswestry disability index (ODI) and visual analogue scale (VAS) for back and leg pain were taken. Post-operative evaluations of cortex perforation and statistical analysis between studied groups have been performed. RESULTS: Seventy-two screws were inserted in each group. All patients completed a 3-year follow-up. Comparing groups, there was no statistical significant difference in VAS and ODI before or after surgery. Cortex perforation incidence in drill guide group was 6 and in free-hand group 29 (p < 0.05). In each group, pain and disability were significantly lower as before the procedure. CONCLUSIONS: The application of a drill guide template for pedicle screw placement is not more effective in reducing pain and disability after midterm follow-up in comparison with the free hand technique. However, it reduces the cortex perforation incidence. Concerning this evidence, a drill guide is still an additional tool that could in the future potentially compete with other screw placement techniques. PMID- 28101634 TI - Is the arthroscopic suture bridge technique suitable for full-thickness rotator cuff tears of any size? AB - PURPOSE: The purpose of this study was to compare functional outcomes and tendon integrity between the suture bridge and modified tension band techniques for arthroscopic rotator cuff repair. METHODS: A consecutive series of 128 patients who underwent the modified tension band (MTB group; 69 patients) and suture bridge (SB group; 59 patients) techniques were enrolled. The pain visual analogue scale (VAS), Constant, and American Shoulder and Elbow Surgeons (ASES) scores were determined preoperatively and at the final follow-up. Rotator cuff hypotrophy was quantified by calculating the occupation ratio (OR). Rotator cuff integrity and the global fatty degeneration index were determined by using magnetic resonance imaging at 6 months postoperatively. RESULTS: The average VAS, Constant, and ASES scores improved significantly at the final follow-up in both groups (p < 0.05 for all scores). The retear rate of small-to-medium tears was similar in the modified tension band and suture bridge groups (7.0 vs. 6.8%, respectively; p = n.s.). The retear rate of large-to-massive tears was significantly lower in the suture bridge group than in the modified tension band group (33.3 vs. 70%; p = 0.035). Fatty infiltration (postoperative global fatty degeneration index, p = 0.022) and muscle hypotrophy (postoperative OR, p = 0.038) outcomes were significantly better with the suture bridge technique. CONCLUSION: The retear rate was lower with the suture bridge technique in the case of large-to-massive rotator cuff tears. Additionally, significant improvements in hypotrophy and fatty infiltration of the rotator cuff were obtained with the suture bridge technique, possibly resulting in better anatomical outcomes. The suture bridge technique was a more effective method for the repair of rotator cuff tears of all sizes as compared to the modified tension band technique. LEVEL OF EVIDENCE: Retrospective Cohort Design, Treatment Study, level III. PMID- 28101635 TI - Trait assembly in grasslands depends on habitat history and spatial scale. AB - During the past century, grasslands in Europe have undergone marked changes in land-use, leading to a decline in plant diversity both at local and regional scales, thus possibly also affecting the mechanisms of species sorting into local communities. We studied plant species assembly in grasslands with differing habitat history and hypothesised that trait divergence prevails in historical grasslands due to niche differentiation and trait convergence prevails in more dynamic grasslands due to competitive exclusion and dispersal limitation. We tested these hypotheses in 35 grassland complexes in Estonia, containing neighbouring grassland habitats with different land-use histories: continuously managed open historical grassland, currently overgrown former grassland and young developing grassland. We assessed species assembly patterns in each grassland type for finer scale-a 2 * 2 m plot scale from a local community pool and for broader scale-a local community from the habitat species pool for that grassland stage and observed changes in trait means at finer scale. We found that grasslands with long management history are assembled differently from former grasslands or young developing grasslands. In historical grasslands, divergence or random patterns prevailed at finer scale species assembly while in former or developing grasslands, mostly convergence patterns prevailed. With increasing scale convergence patterns become more prevalent in all grassland types. We conclude that land-use history is an important factor to consider when assessing grassland functional trait assembly, particularly at small scales. Understanding the mechanisms behind species assembly and their relationship with land-use history is vital for habitat conservation and restoration. PMID- 28101636 TI - A slow opportunist: physiological and growth responses of an obligate understory plant to patch cut harvesting. AB - Understory light environments change rapidly following timber harvest, and while many understory species utilize and benefit from the additional light, this response is not ubiquitous in shade-obligate species. I examined the effects of patch cut timber harvest on the physiology and growth of an obligate forest understory species to determine if disturbances via timber harvest are physiological stressors or whether such disturbances provide physiological benefits and growth increases in understory species. Forest canopy structure, along with photosynthesis, respiration, water use efficiency, stomatal conductance, and growth rates of American ginseng were quantified one summer before and two summers after patch cut timber harvest. Survival following timber harvest was lower than that observed at undisturbed populations; however, growth of survivors increased post-harvesting, with growth increasing as a function of canopy openness. Light response curves as well as photosynthesis and respiration rates indicated that plants were not well acclimated to higher light levels in the growing season after timber harvest, but rather to two growing seasons after harvest. Relative growth rate formed a positive linear relationship with maximum photosynthesis following timber harvest. My study suggests that ginseng is a "slow opportunist", because while it benefits from sudden light increases, acclimation lags at least one growing season behind canopy changes. American ginseng is surprisingly resilient in the face of a discrete environmental shift and may benefit from forest management strategies that mimic the natural disturbance regimes common in mature forests throughout its range. PMID- 28101637 TI - Refractory skin lesion, hypertension and acute kidney injury in a young boy: Questions. PMID- 28101638 TI - Refractory skin lesion, hypertension, and acute kidney injury in a young boy: Answers. PMID- 28101639 TI - Laparoscopic hysteropexy: 10 years' experience. AB - INTRODUCTION AND HYPOTHESIS: Uterine prolapse is common and has traditionally been treated by vaginal hysterectomy. Increasingly, women are seeking uterine preserving alternatives. Laparoscopic hysteropexy offers resuspension of the uterus using polypropylene mesh. We report on 10 years' experience with this technique. METHODS: All hysteropexy procedures in our unit since 2006 were reviewed. Primary outcome was safety of hysteropexy, as assessed by intraoperative and major postoperative complications. Secondary outcomes were measures of feasibility, including operating time, length of stay, conversion to alternative procedures, change in point C, patient satisfaction, and repeat apical prolapse surgery. RESULTS: Data were available for 507 women. Complications were rare (1.8%) with no evidence of any mesh exposure. Mean operating time was 62.5 min and median length of stay 2 nights. In 17 patients (3.4%), hysteropexy was abandoned. There was a mean change in point C of 7.9 cm and 93.8% of patients felt that their prolapse was "very much" or "much" better. Of these women, 2.8% have had repeat apical surgery. CONCLUSIONS: To our knowledge, this is the largest series to date, describing 10 years' experience with laparoscopic hysteropexy. The surgical technique appears to be safe, with low complication rates, which supports the choice of appropriately selected women to opt for uterine preservation surgery as an alternative to hysterectomy for the management of uterine prolapse. PMID- 28101640 TI - Labia minora hypertrophy: causes, impact on women's health, and treatment options. AB - INTRODUCTION AND HYPOTHESIS: We provide a review of the literature about the onset and development of hypertrophy of the labia minora, together with some expert opinions on the appropriateness of labiaplasty. METHODS: We searched PubMed and used popular search engines, with a greater emphasis on the physiology and hormone-mediated metabolism of these structures, and less emphasis on their surgical treatment. RESULTS: We describe major embryological, cytological, and biochemical features of this anatomical part and summarize the clinical aspects of its hypertrophy, evaluating types of discomfort reported by women and the medical treatments available. Also, based on what is known about the artificial elongation and spontaneous hypertrophy of the inner labia, we illustrate and discuss the main biological factors that may trigger this medical condition. There are not enough data identifying a clear inheritance of inner labia hypertrophy in the absence of other pathological conditions; instead, we found indirect evidence for an association with transient episodes of local inflammation either before birth or during puberty. We also analyze the role played by estrogen receptors and other factors with regard to the onset of this condition and highlight the importance of their timing in determining the size of women's labia minora. Remarkably, most cases of enlarged labia minora should be considered as outliers that are within the physiological range of size variation described for these structures. CONCLUSIONS: We generally advise against surgical treatment of labia minora, especially in young, pre-pubertal girls, unless specific medical conditions are also present and/or the psychological impact on the patient is deemed particularly negative. PMID- 28101641 TI - Volumetric growth rates of meningioma and its correlation with histological diagnosis and clinical outcome: a systematic review. AB - INTRODUCTION: Tumour growth has been used to successfully predict progression free survival in low-grade glioma. This systematic review sought to establish the evidence base regarding the correlation of volumetric growth rates with histological diagnosis and potential to predict clinical outcome in patients with meningioma. METHODS: This systematic review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Databases were searched for full text English articles analysing volumetric growth rates in patients with a meningioma. RESULTS: Four retrospective cohort studies were accepted, demonstrating limited evidence of significantly different tumour doubling rates and shapes of growth curves between benign and atypical meningiomas. Heterogeneity of patient characteristics and timing of volumetric assessment, both pre- and post-operatively, limited pooled analysis of the data. No studies performed statistical analysis to demonstrate the clinical utility of growth rates in predicting clinical outcome. CONCLUSION: This systematic review provides limited evidence in support of the use of volumetric growth rates in meningioma to predict histological diagnosis and clinical outcome to guide future monitoring and treatment. PMID- 28101642 TI - Late sodium current and intracellular ionic homeostasis in acute ischemia. AB - Blockade of the late Na+ current (I NaL) protects from ischemia/reperfusion damage; nevertheless, information on changes in I NaL during acute ischemia and their effect on intracellular milieu is missing. I NaL, cytosolic Na+ and Ca2+ activities (Nacyt, Cacyt) were measured in isolated rat ventricular myocytes during 7 min of simulated ischemia (ISC); in all the conditions tested, effects consistently exerted by ranolazine (RAN) and tetrodotoxin (TTX) were interpreted as due to I NaL blockade. The results indicate that I NaL was enhanced during ISC in spite of changes in action potential (AP) contour; I NaL significantly contributed to Nacyt rise, but only marginally to Cacyt rise. The impact of I NaL on Cacyt was markedly enhanced by blockade of the sarcolemmal(s) Na+/Ca2+ exchanger (NCX) and was due to the presence of (Na+-sensitive) Ca2+ efflux through mitochondrial NCX (mNCX). sNCX blockade increased Cacyt and decreased Nacyt, thus indicating that, throughout ISC, sNCX operated in the forward mode, in spite of the substantial Nacyt increment. Thus, a robust Ca2+ source, other than sNCX and including mitochondria, contributed to Cacyt during ISC. Most, but not all, of RAN effects were shared by TTX. (1) The paradigm that attributes Cacyt accumulation during acute ischemia to decrease/reversal of sNCX transport may not be of general applicability; (2) I NaL is enhanced during ISC, when the effect of Nacyt on mitochondrial Ca2+ transport may substantially contribute to I NaL impact on Cacyt; (3) RAN may act mostly, but not exclusively, through I NaL blockade during ISC. PMID- 28101643 TI - Polymorphisms in genes encoding miR-155 and miR-146a are associated with protection to type 1 diabetes mellitus. AB - AIMS: Type 1 diabetes mellitus (T1DM) is characterized by severe autoimmune destruction of pancreatic beta-cells. The triggering of autoimmunity against beta cells is probably caused by a combination of environmental and genetic risk factors. Even though much is known about the genetic of T1DM, more information is needed to completely unravel this tangled disease. MicroRNAs (miRNAs) are a class of small noncoding RNAs molecules that negatively regulate gene expression by inducing target mRNA cleavage or by inhibiting protein translation. Abnormal miRNA expressions have been described in autoimmune diseases and T1DM. Polymorphisms in genes codifying miRNAs may alter the expression of the corresponding miRNA and, thus, confer susceptibility for a given disease. Therefore, the aim of this study was to investigate whether polymorphisms in genes encoding miR-155, miR-146a, and miR-375 are associated with T1DM. METHODS: Frequencies of the miRNA-146a rs2910164, miRNA-155 rs767649 and miRNA-375 rs6715345 polymorphisms were analyzed in 490 T1DM patients and in 469 nondiabetic subjects. RESULTS: The miR-146a rs2910164 and miR-155 rs767649 polymorphisms were associated with protection for T1DM, and the strongest association was observed for the dominant model [odds ratio (OR) = 0.557 95% CI 0.355-0.874 and OR = 0.508, 95% CI 0.265-0.973, respectively, after adjustment for age, ethnicity, and risk HLA loci]. However, miR-375 rs6715345 frequencies did not differ between cases and controls. CONCLUSION: MiR-146a rs2910164 and miR-155 rs767649 polymorphisms were associated with protection for T1DM. PMID- 28101644 TI - Comparative evaluation of phototrophic microtiter plate cultivation against laboratory-scale photobioreactors. AB - Extended cultivation times, rendering phototrophic bioprocess development time inefficient, resulted in the recent development of micro-photobioreactors enabling accelerated process development. However, especially for laboratory photobioreactors, only little is known concerning the influence of design on process performance. Thus, the aim of the present investigation was to evaluate the scalability of a microtiter plate-based parallelized micro-photobioreactor against a representative set of established laboratory photobioreactors. Lipid production by Chlorella vulgaris was used as a model system. During exponential growth, the microtiter plate cultures achieved maximal growth rates of ca. 1.44 +/- 0.02 day-1 being in good agreement with the larger systems. Moreover, cultures in the micro-photobioreactor could be kept in the exponential phase up to the highest biomass concentrations most probably due to the beneficial light supply at this scale. Compared to the shake flask and test tube cultures, microtiter plate cultivation achieved an equivalent biomass yield, lipid content, and lipid fingerprint. In contrast, the flat-panel process resulted only in marginal productivity due to insufficient light supply. Thus, microtiter plates showed good scalability to the investigated laboratory photobioreactors as overall differences were rather small taking the differing scales into account. PMID- 28101645 TI - Forensic parameters of 19 X-STR polymorphisms in two Chinese populations. AB - Application of X-STRs as complements of autosomal STR application in the forensic genetics has become a tendency for kinship testing, especially in deficiency paternity cases. Recently, a novel kit of 19 X-STR loci was developed, which permitted the analysis of 19 STR in the same PCR reaction, and these markers can be clustered into seven groups for the physical linkage. The objective of this study was to evaluate the allele and haplotype diversity of 19 X-STR loci in the Uygur (n = 220) and Tibetan nationality (n = 270) and to estimate the usefulness for complex kinship analysis. In the Tibetan and Uygur populations, a total of alleles of all loci were 188 and 212, with the allele frequencies ranged from 0.0037 to 0.5593 and from 0.0045 to 0.5409, respectively. Compared with previous studies, DXS10135 was the most polymorphic locus in the two population groups, whereas the least variant locus was DXS10164 in the Uygur population and DXS7423 in the Tibetan nationality. Haplotype diversity obtained in this investigation was greater than 0.9 across all LGs. This study indicated the new kit could be used as a supplementary tool in kinship testing in China. In addition, the data sets can be used as supplementary national X-STR references to enlarge the database. PMID- 28101646 TI - Pedigree-based relationship inference from complex DNA mixtures. AB - We present a general method for analysing DNA mixtures involving relatives that accounts for dropout and drop-in, mutations, silent alleles and population substructure. Whether the aim is to identify the contributors to a mixture who may be related, or to determine the relationship between individuals based on a DNA mixture, both types of problems can be handled by the method and software presented here. We focus on the latter scenario, motivated by non-invasive prenatal paternity testing where the profile of the child is available only in the form of a mixture with the mother's profile. Relationships are represented by pedigrees and can include kinship between more than two individuals. The software is freely available as a graphical user interface in the R package relMix. PMID- 28101647 TI - A real-time PCR approach to identify anthelmintic-resistant nematodes in sheep farms. AB - Resistance to fenbendazole, ivermectin, and moxidectin was explored by a fecal egg count reduction test in four meat sheep flocks in southwestern France where anthelmintic resistance was suspected. The FECR test results of the present study confirmed the presence of benzimidazole resistance in three out of the four farms and the presence of ivermectin resistance in one flock. In addition, a suspicion of moxidectin resistance was shown in this latter farm. Both conventional morphological and molecular identifications were performed on larval cultures before and after the treatment in the studied farms. A high positive correlation was found between the number of larvae counted under binocular microscope and the number of larvae estimated by the qPCR analysis (R 2 = 0.88) and a high Cohen's Kappa value (0.91) in the detection of strongylid larvae in larval cultures. According to qPCR results, Trichostrongylus species demonstrated high levels of BZ resistance and Teladorsagia circumcincta was involved in the IVM resistance in one farm. The molecular procedures used in this study have the potential to be beneficial for anthelmintic resistance surveillance in sheep industry. PMID- 28101648 TI - The limits of boundaries: unpacking localization and cognitive mapping relative to a boundary. AB - Previous research (Zhou, Mou, Journal of Experimental Psychology: Learning, Memory and Cognition 42(8):1316-1323, 2016) showed that learning individual locations relative to a single landmark, compared to learning relative to a boundary, led to more accurate inferences of inter-object spatial relations (cognitive mapping of multiple locations). Following our past findings, the current study investigated whether the larger number of reference points provided by a homogeneous circular boundary, as well as less accessible knowledge of direct spatial relations among the multiple reference points, would lead to less effective cognitive mapping relative to the boundary. Accordingly, we manipulated (a) the number of primary reference points (one segment drawn from a circular boundary, four such segments, vs. the complete boundary) available when participants were localizing four objects sequentially (Experiment 1) and (b) the extendedness of each of the four segments (Experiment 2). The results showed that cognitive mapping was the least accurate in the whole boundary condition. However, expanding each of the four segments did not affect the accuracy of cognitive mapping until the four were connected to form a continuous boundary. These findings indicate that when encoding locations relative to a homogeneous boundary, participants segmented the boundary into differentiated pieces and subsequently chose the most informative local part (i.e., the segment closest in distance to one location) as the primary reference point for a particular location. During this process, direct spatial relations among the reference points were likely not attended to. These findings suggest that people might encode and represent bounded space in a fragmented fashion when localizing within a homogeneous boundary. PMID- 28101653 TI - Effect of timing of collection of salivary metabolomic biomarkers on oral cancer detection. AB - The aim of this study is to evaluate the effect of duration after meals for saliva collections for oral cancer detection using metabolomics. Saliva samples were collected from oral cancer patients (n = 22) and controls (n = 44). Saliva from cancer patients was collected 12 h after dinner, and 1.5 and 3.5 h after breakfast. Control subjects fasted >1.5 h prior to saliva collection. Hydrophilic metabolites were analyzed using capillary electrophoresis mass spectrometry. Levels of 51 metabolites differed significantly in controls vs. oral cancer patients at the 12-h fasting time point (P < 0.05). Fifteen and ten metabolites differed significantly at the 1.5- and 3.5-h time points, respectively. The area of under receiver operating characteristic curve for discriminating oral cancer patients from controls was greatest at the 12-h fasting time point. The collection time after meals affects levels of salivary metabolites for oral cancer screening. The 12-h fasting after dinner time point is optimal. This study contributes to design of saliva collection protocols for metabolomics-based biomarker discovery. PMID- 28101652 TI - Alteration of metabolomic markers of amino-acid metabolism in piglets with in feed antibiotics. AB - In-feed antibiotics have been used to promote growth in piglets, but its impact on metabolomics profiles associated with host metabolism is largely unknown. In this study, to test the hypothesis that antibiotic treatment may affect metabolite composition both in the gut and host biofluids, metabolomics profiles were analyzed in antibiotic-treated piglets. Piglets were fed a corn-soy basal diet with or without in-feed antibiotics from postnatal day 7 to day 42. The serum biochemical parameters, metabolomics profiles of the serum, urine, and jejunal digesta, and indicators of microbial metabolism (short-chain fatty acids and biogenic amines) were analyzed. Compared to the control group, antibiotics treatment did not have significant effects on serum biochemical parameters except that it increased (P < 0.05) the concentration of urea. Antibiotics treatment increased the relative concentrations of metabolites involved in amino-acid metabolism in the serum, while decreased the relative concentrations of most amino acids in the jejunal content. Antibiotics reduced urinary 2-ketoisocaproate and hippurate. Furthermore, antibiotics decreased (P < 0.05) the concentrations of propionate and butyrate in the feces. Antibiotics significantly affected the concentrations of biogenic amines, which are derived from microbial amino-acid metabolism. The three major amines, putrescine, cadaverine, and spermidine, were all increased (P < 0.05) in the large intestine of antibiotics-treated piglets. These results identified the phenomena that in-feed antibiotics may have significant impact on the metabolomic markers of amino-acid metabolism in piglets. PMID- 28101650 TI - Speech disorders in Parkinson's disease: early diagnostics and effects of medication and brain stimulation. AB - Hypokinetic dysarthria (HD) occurs in 90% of Parkinson's disease (PD) patients. It manifests specifically in the areas of articulation, phonation, prosody, speech fluency, and faciokinesis. We aimed to systematically review papers on HD in PD with a special focus on (1) early PD diagnosis and monitoring of the disease progression using acoustic voice and speech analysis, and (2) functional imaging studies exploring neural correlates of HD in PD, and (3) clinical studies using acoustic analysis to evaluate effects of dopaminergic medication and brain stimulation. A systematic literature search of articles written in English before March 2016 was conducted in the Web of Science, PubMed, SpringerLink, and IEEE Xplore databases using and combining specific relevant keywords. Articles were categorized into three groups: (1) articles focused on neural correlates of HD in PD using functional imaging (n = 13); (2) articles dealing with the acoustic analysis of HD in PD (n = 52); and (3) articles concerning specifically dopaminergic and brain stimulation-related effects as assessed by acoustic analysis (n = 31); the groups were then reviewed. We identified 14 combinations of speech tasks and acoustic features that can be recommended for use in describing the main features of HD in PD. While only a few acoustic parameters correlate with limb motor symptoms and can be partially relieved by dopaminergic medication, HD in PD seems to be mainly related to non-dopaminergic deficits and associated particularly with non-motor symptoms. Future studies should combine non-invasive brain stimulation with voice behavior approaches to achieve the best treatment effects by enhancing auditory-motor integration. PMID- 28101651 TI - Eslicarbazepine acetate: its effectiveness as adjunctive therapy in clinical trials and open studies. AB - Eslicarbazepine acetate (ESL) is a once-daily antiepileptic drug that is approved as adjunctive therapy in adults with focal-onset seizures. Following oral administration, ESL is rapidly metabolized to its active metabolite, eslicarbazepine, which acts primarily by enhancing slow inactivation of voltage gated sodium channels. The efficacy and safety/tolerability of ESL in the adjunctive setting were established in a comprehensive Phase III program (n = 1702 randomized patients) and this evidence has been supported by several open studies (n = 864). ESL treatment has demonstrated improvements in health-related quality of life, in both randomized clinical trials and open studies. ESL has also been shown to be usually well tolerated and efficacious when used in the adjunctive setting in elderly patients. The effectiveness of ESL as the only add on to antiepileptic drug monotherapy has been demonstrated in a multinational study (n = 219), subgroup analyses of which have also shown it to be efficacious and generally well tolerated in patients who had previously not responded to carbamazepine therapy. Open studies have also demonstrated improvements in tolerability in patients switched overnight from oxcarbazepine to ESL. Due to differences in pharmacokinetics, pharmacodynamics, and metabolism, there may be clinical situations in which it is appropriate to consider switching patients from oxcarbazepine or carbamazepine to ESL. PMID- 28101654 TI - Cell viability and shock wave amplitudes in the endothelium of porcine cornea exposed to ultrashort laser pulses. AB - PURPOSE: Some forms of keratoplasty assisted by ultrashort-pulse lasers require performing laser cuts close to the endothelium, which requires the knowledge of "safe" values concerning incision depth and pulse energy preserving endothelial cell viability. Our study aims to determine the thresholds for cell death in porcine corneas exposed to ultrashort laser pulses, in terms of laser pulse energy and nearness of the impacts to the endothelium. METHODS: Using a laboratory laser set-up, lamellar cuts were induced while varying pulse energies and distances from the endothelium. A fluorescent staining protocol was used to determine the percentage of surviving endothelial cells. Numerical simulations of the Euler equations for compressible fluids provided pressure level and axial and radial pressure gradient estimates at the endothelium. RESULTS: Ninety percent of the endothelial cells survived when using 16.5 MUJ pulses no closer than 200 MUm to the endothelium, or pulses not exceeding 2 MUJ at a distance of 50 MUm. The comparison of the observed percentage of surviving cells with the estimates of the shock wave amplitudes and gradients generated by the laser pulses yielded cell death thresholds at amplitudes in the megapascal range, or gradients of the order of 108 Pa/m. CONCLUSIONS: Our results provide limits in terms of pulse energy and distance of the incision from the endothelium within which endothelial cell viability is preserved. Current forms of corneal laser surgery are compatible with these limits. However, these limits will need to be considered for the development of future laser routines working in close proximity to the endothelium. PMID- 28101655 TI - Percutaneous vertebral augmentation in fragility fractures-indications and limitations. AB - INTRODUCTION: There is still no general consensus about the management of osteoporotic vertebral fractures. Recommendations depend on type of fracture, grade of instability, bone quality, and general conditions of the patient. Spontaneous fractures may be considered to be treated different compared to cases with high-velocity trauma. METHODS: According to the DVO, patients without trauma should first be treated conservatively. However, there is no more strict time protocol of 3 or 6 week conservative treatment before operations may be indicated. Surgical criteria are not yet distinctly defined. For highly unstable fractures (type B and C according to the AO Spine Classification), posterior instrumentation with cement augmented screws and as long construct, respectively, is adequate. Current literature has been analysed for diagnostic and therapeutic protocols. RESULTS: There is no clear operative concept for burst fractures and classic osteoporotic fractures with dynamic ongoing sintering. Percutaneous vertebral augmentation showed to prevent the fractures from ongoing kyphotic deformity and the patients from painful immobilization. Indications and results of classical vertebroplasty and kyphoplasty have been discussed intensively in the literature. Further development included special injection techniques, cements with different viscosities and stenting systems to reach more stable constructs and avoid typical complications, such as cement extrusion. CONCLUSIONS: This review reports upon indications and limitations of percutaneous vertebral augmentation and the potential development of classifications and therapeutic algorithms. PMID- 28101649 TI - Molecular mechanism of sarcopenia and cachexia: recent research advances. AB - Skeletal muscle provides a fundamental basis for human function, enabling locomotion and respiration. Muscle loss occurs as a consequence of several chronic diseases (cachexia) and normal aging (sarcopenia). Although many negative regulators (atrogin-1, muscle ring finger-1, nuclear factor-kappaB (NF-kappaB), myostatin, etc.) have been proposed to enhance protein degradation during both sarcopenia and cachexia, the adaptation of these mediators markedly differs within both conditions. Sarcopenia and cachectic muscles have been demonstrated to be abundant in myostatin-linked molecules. The ubiquitin-proteasome system (UPS) is activated during rapid atrophy model (cancer cachexia), but few mediators of the UPS change during sarcopenia. NF-kappaB signaling is activated in cachectic, but not in sarcopenic, muscle. Recent studies have indicated the age-related defect of autophagy signaling in skeletal muscle, whereas autophagic activation occurs in cachectic muscle. This review provides recent research advances dealing with molecular mediators modulating muscle mass in both sarcopenia and cachexia. PMID- 28101656 TI - Off-label use of antimicrobials in neonates in a tertiary children's hospital. AB - PURPOSE: Off-label (OL) use of drugs for hospitalized children is very common. OL use occurs especially in the youngest patients, neonates. This study focused on the OL use of antimicrobials in neonates. To our knowledge, only few studies have focused on the prevalence of OL use of antimicrobials in neonates. METHODS: We investigated the OL use of antimicrobials in neonates in a tertiary children's hospital. First, we investigated what were the most consumed OL antimicrobials in defined daily doses according to hospital's registry data from neonatal intensive care unit (NICU) during 2009-2014. Second, we conducted a targeted retrospective study of premature neonates (400-2000 g) with blood culture-positive infections and receiving antimicrobial therapy between 2005 and 2014 (N = 282). The data were obtained from the electronic patient records and from the hospital's electronic infection registry. Statistical analysis was conducted by using a univariate logistic regression model fitted for OL usage. RESULTS: In NICU, 35% (7/20) of antimicrobials used were OL. Eighteen percent (51/282) of premature neonates with blood culture-positive infections received at least one antimicrobial OL. The most commonly used OL antimicrobials in neonates were meropenem 88% (45/51), rifampicin 18% (9/51), and ciprofloxacin 8% (4/51). The odds for OL use were significantly higher the smaller the neonate birth weight was. An increase in birth weight was found to statistically significantly decrease the probability of OL usage (odds ratio = 0.85 for 100 g increase in birth weight, p value <0.001). CONCLUSION: More studies in neonates on especially dosing and pharmacokinetics of antimicrobials are urgently needed. PMID- 28101658 TI - Naso-intestinal tube is more effective in treating postoperative ileus than naso gastric tube in elderly colorectal cancer patients. AB - OBJECTIVE: The objective of this study was to compare the effect of naso intestinal tube and naso-gastric tube in relieving postoperative ileus in elderly patients with colorectal cancer. METHODS: Patients (n = 46) with ileus symptom following radical surgery for treating colorectal cancer were placed with either naso-intestinal tube at duodenum or conventional naso-gastric tube. Then, their waist perimeter, intra abdominal pressure, maximum diameter in bowls, length of time to pass flatus or passage of bowel movement or to return to diet, length of hospital stay, daily drainage, serum levels of lactic acid, hemoglobin, and creatinine as well were compared. RESULTS: Naso-intestinal tube placement is more effective than naso-gastric tube in relieving intra abdominal pressures, reducing maximum bowl diameter and waist circumference, correcting serum lactic acid levels, alleviating analgesia dependence, regaining serum albumin level, increasing drainage and shortening the time of length of hospital stay, passing flatus or faces, and time to return to diet. CONCLUSION: Naso-intestinal tube is effective in treating POI and shows advantage over conventional naso-gastric tube insertion. PMID- 28101657 TI - Levodopa/carbidopa microtablets in Parkinson's disease: a study of pharmacokinetics and blinded motor assessment. AB - BACKGROUND: Motor function assessments with rating scales in relation to the pharmacokinetics of levodopa may increase the understanding of how to individualize and fine-tune treatments. OBJECTIVES: This study aimed to investigate the pharmacokinetic profiles of levodopa-carbidopa and the motor function following a single-dose microtablet administration in Parkinson's disease. METHODS: This was a single-center, open-label, single-dose study in 19 patients experiencing motor fluctuations. Patients received 150% of their individual levodopa equivalent morning dose in levodopa-carbidopa microtablets. Blood samples were collected at pre-specified time points. Patients were video recorded and motor function was assessed with six UPDRS part III motor items, dyskinesia score, and the treatment response scale (TRS), rated by three blinded movement disorder specialists. RESULTS: AUC0-4/dose and C max/dose for levodopa was found to be higher in Parkinson's disease patients compared with healthy subjects from a previous study, (p = 0.0008 and p = 0.026, respectively). The mean time to maximum improvement in sum of six UPDRS items score was 78 min (+/ 59) (n = 16), and the mean time to TRS score maximum effect was 54 min (+/-51) (n = 15). Mean time to onset of dyskinesia was 41 min (+/-38) (n = 13). CONCLUSIONS: In the PD population, following levodopa/carbidopa microtablet administration in fasting state, the Cmax and AUC0-4/dose were found to be higher compared with results from a previous study in young, healthy subjects. A large between subject variability in response and duration of effect was observed, highlighting the importance of a continuous and individual assessment of motor function in order to optimize treatment effect. PMID- 28101661 TI - Erratum to: Home Monitoring Program Reduces Mortality in High-Risk Sociodemographic Single-Ventricle Patients. PMID- 28101660 TI - PocketECG: A New Noninvasive Method for Continuous and Real-Time ECG Monitoring Initial Results in Children and Adolescents. AB - Long-term ECG is widely used in diagnosis and assessment of many cardiac symptoms which may be caused by dangerous arrhythmias that sometimes can be difficult to document. The PocketECG system is a new technological solution for a long-term, noninvasive, continuous and real-time ECG monitoring that provides automatic diagnosis of dysrhythmias. ECG data transmission occurs over a mobile network. The goal of this study was to assess the reliability of long-term ECG recordings acquired with the PocketECG system. One hundred and fifteen patients (43 girls and 72 boys) of an average age of 15.5 +/- 2.5 years were examined at the Department of Cardiology at the Children's Memorial Health Institute. Two simultaneous 24-h ECG recordings were conducted: one with a Holter monitor and one with the PocketECG system. A linear correlation was demonstrated between the two methods with regard to the recorded QRS complexes [H = 1173.0 (-1946.40; 4838.50) + PocketECG*0.98 (0.94; 1.02)]. Mean diurnal heart rhythms were comparable (p > 0.05) despite the fact that the slowest and the fastest rates were different. The rate of detection for ventricular, supraventricular dysrhythmias and pauses in ventricular rhythm were comparable in both methods. The PocketECG system for continuous and real-time ECG recording is a reliable method for the assessment of heart rhythm and dysrhythmias in children and adolescents. PMID- 28101662 TI - Strategies to Prevent Cast Formation in Patients with Plastic Bronchitis Undergoing Heart Transplantation. AB - Plastic bronchitis, a rare complication after Fontan palliation, carries a high morbidity and mortality risk. Heart transplantation is an effective treatment option, but casts may occur in the early post-operative period. We present a case series detailing peri-operative management strategies to minimize morbidity and mortality related to plastic bronchitis in patients undergoing heart transplantation. Patient 1 received no treatment pre-, intra-, or post-transplant for prevention of bronchial casts and developed severe respiratory acidosis 18 h following transplant. Emergent bronchoscopy was performed and a large obstructive cast was removed. The patient recovered and received inhaled tissue plasminogen activator (tPA) for 5 days. Patient 2 received inhaled tPA before, during, and for 5 days after transplantation and no bronchial casts developed. Patient 3 underwent intraoperative bronchoscopy just prior to implantation revealing no casts. The patient underwent non-urgent, preemptive bronchoscopy on post transplant days 1, 3, and 4, removing several partially obstructive bronchial blood clots/casts, with no casts thereafter. Heart transplantation results in eventual resolution of plastic bronchitis. Residual bronchial casts can still be problematic in the peri-operative period. Airway clearance with inhaled tPA or bronchoscopy may prevent the need for prolonged mechanical ventilation and reduce post-operative morbidity in this unique population. PMID- 28101663 TI - History of Fiberoptic Endoscopic Evaluation of Swallowing for Evaluation and Management of Pharyngeal Dysphagia: Changes over the Years. PMID- 28101664 TI - History and Evolution of the Barium Swallow for Evaluation of the Pharynx and Esophagus. AB - This article reviews the history of the barium swallow from its early role in radiology to its current status as an important diagnostic test in modern radiology practice. Though a variety of diagnostic procedures can be performed to evaluate patients with dysphagia or other pharyngeal or esophageal symptoms, the barium study has evolved into a readily available, non-invasive, and cost effective technique that can facilitate the selection of additional diagnostic tests and guide decisions about medical, endoscopic, or surgical management. This article focuses on the evolution of fluoroscopic equipment, radiography, and contrast media for evaluating the pharynx and esophagus, the importance of understanding pharyngoesophageal relationships, and major advances that have occurred in the radiologic diagnosis of select esophageal diseases, including gastroesophageal reflux disease, infectious esophagitis, eosinophilic esophagitis, esophageal carcinoma, and esophageal motility disorders. PMID- 28101665 TI - Feasibility and Psychometric Properties of the Adjusted DSWAL-QoL Questionnaire for Dysphagic Patients with Additional Language and/or Cognitive Impairment: Part I. AB - The Swallowing Quality-of-Life questionnaire (SWAL-QoL) is considered the gold standard for assessing health-related quality of life in people with dysphagia. However, many dysphagic patients struggle to complete this questionnaire because of additional functional sequelae such as language impairment and cognitive disorders. In this study, we sought to develop an adjusted Dutch version of the SWAL-QoL (aDSWALQoL) and to evaluate its psychometric properties and feasibility compared with the original questionnaire. We developed the aDSWAL-QoL based on recommendations from previous literature. The feasibility, internal consistency, test-retest reliability, and criterion validity of the aDSWAL-QoL were evaluated in 78 dysphagic patients, among whom 43 had additional language and/or cognitive impairments (DysLC). Statistical analyses were performed using SPSS 20.0. The aDSWAL-QoL had a higher degree of feasibility for the DysLC group. We obtained high Cronbach's alpha coefficients for total scale and for almost all subscales. Total aDSWAL-QoL scores showed excellent testretest agreement and good criterion validity with respect to the DSWAL-QoL. Almost all subscales showed significantly moderate to good test-retest agreement and criterion validity. However, the psychometric properties of the 'Food selection' subscale were inadequate. The aDSWAL-QoL is a feasible, reliable, and valid tool for use with DysLC patients. Conversion of the aDSWAL-QoL into an audio computer-assisted self-administered format should be investigated. The construct validity of the aDSWAL-QoL will be evaluated in a separate report. PMID- 28101666 TI - History of the Use of Esophageal Stent in Management of Dysphagia and Its Improvement Over the Years. AB - The art and science of using stents to treat dysphagia and seal fistula, leaks and perforations has been evolving. Lessons learnt from the deficiencies of previous models led to several improvements making stent deployment easier, and with some designs, it was also possible to remove the stents if needed. With these improvements, besides malignant dysphagia, newer indications for using stents emerged. Unfortunately, despite several decades of evolution, as yet, there is no perfect stent that "fits all." This article is an overview of how this evolution process happened and where we are currently with using stents to manage patients with dysphagia and with other esophageal disorders. PMID- 28101667 TI - Impact of an arbuscular mycorrhizal fungus versus a mixed microbial inoculum on the transcriptome reprogramming of grapevine roots. AB - Grapevine, cultivated for both fruit and beverage production, represents one of the most economically important fruit crops worldwide. With the aim of better understanding how grape roots respond to beneficial microbes, a transcriptome sequencing experiment has been performed to evaluate the impact of a single arbuscular mycorrhizal (AM) fungal species (Funneliformis mosseae) versus a mixed inoculum containing a bacterial and fungal consortium, including different AM species, on Richter 110 rootstock. Results showed that the impact of a single AM fungus and of a complex microbial inoculum on the grapevine transcriptome differed. After 3 months, roots exclusively were colonized after the F. mosseae treatment and several AM marker genes were found to be upregulated. The mixed inoculum led only to traces of colonization by AM fungi, but elicited an important transcriptional regulation. Additionally, the expression of genes belonging to categories such as nutrient transport, transcription factors, and cell wall-related genes was significantly altered in both treatments, but the exact genes affected differed in the two conditions. These findings advance our understanding about the impact of soil beneficial microbes on the root system of a woody plant, also offering the basis for novel approaches in grapevine cultivation. PMID- 28101668 TI - Results of a population-based-assessment: we need better communication and more profound patient involvement. AB - BACKGROUND: In Austria several regulations were published in order to support initiatives to increase patient safety. Since then, many patient safety projects were implemented in Austrian hospitals; therefore, it was the aim of the current survey to examine the perceptions of Austrian citizens with respect to topics relevant to patient safety. METHODS: Between 8 and 22 October 2015 a qualitative cross-sectional telephone interview study was performed. A sample of citizens above 14 years of age was randomly drawn. The survey contained 6 questions. In each of the nine states of Austria, a representative number of citizens were interviewed. RESULTS: In total 1021(female: 52.3%) telephone interviews were performed and 249 (24.7%) citizens stated that trust/confidence in patient safety is very high, 571 (55.9%) assessed the reputation of a hospital as very important and 739 (72.4%) stated that a detailed explanation of the treatment as well as information on associated risk factors and possibilities of further treatments is very important. Of the respondents 722 (70.7%) stated that patient safety measures in a given hospital are very important, 807 (79.0%) stated that it is important to be informed about patient safety measures and 547 (53.6%) stated that if something did not satisfactorily function they would complain to the hospital. Significant differences occurred for states with and without university hospitals. CONCLUSION: The results of the survey give cause for concern as the majority of interviewed citizens have medium or low trust/confidence in patient safety. Furthermore, more than two-thirds of Austrian citizens revealed that detailed explanation of treatment, information on associated risk factors, information about patient safety measures to predict medical errors and information about patient safety measures which are in place in a hospital are very important. The study showed that patient safety is an important topic for Austrian citizens and they want to be informed and involved. The study also indicated the need to promote patient safety aspects and to decrease the number of people who are not confident concerning patient safety in Austrian hospitals. PMID- 28101669 TI - Outcomes and trends of peripartum maternal admission to the intensive care unit. AB - BACKGROUND: The number of pregnant women with severe comorbidities is increasing. The aim of the present study was to analyze outcomes and determine trends in women who required peripartum admission to the intensive care unit (ICU). METHODS: In this retrospective study, we identified all women who were admitted to the ICU between the second trimester of pregnancy and 6 weeks postpartum. Women with ICU admission between 2011 and 2014 were assigned to the study group, whereas those admitted between 1996 and 2003 were assigned to the historical group. Comorbidities, characteristics, outcomes, and treatment efforts were assessed. Descriptive analysis, Fisher's exact test, unpaired Student's t-test and one-way ANOVA were performed. RESULTS: We identified 238 cases, including 135 (56.7%) in the study group and 103 (43.3%) in the historical group. In 83 (34.9%) women, deterioration of the pre-existing medical condition was causal for ICU admission. Overall, preterm delivery and mean gestational age were 81.5% and 31.6 +/- 6.2 weeks, respectively. In comparison to the historical group, women of the study group were older (p = 0.005), more frequently presented with multiple comorbidities (p = 0.003), pre-existing conditions (p < 0.001), and congenital heart disease (p = 0.012). Moreover, they had a shorter length of stay at the ICU than those of the historical group (p = 0.02). CONCLUSIONS: Peripartum ICU admissions are increasing in frequency. As maternal characteristics are changing, adequate risk stratification with multidisciplinary care are essential, and access to intermediate care units would be preferable for patients with short term admission. PMID- 28101671 TI - ? PMID- 28101672 TI - ? PMID- 28101673 TI - ? PMID- 28101670 TI - Recombination correlates with synaptonemal complex length and chromatin loop size in bovids-insights into mammalian meiotic chromosomal organization. AB - Homologous chromosomes exchange genetic information through recombination during meiosis, a process that increases genetic diversity, and is fundamental to sexual reproduction. In an attempt to shed light on the dynamics of mammalian recombination and its implications for genome organization, we have studied the recombination characteristics of 112 individuals belonging to 28 different species in the family Bovidae. In particular, we analyzed the distribution of RAD51 and MLH1 foci during the meiotic prophase I that serve, respectively, as proxies for double-strand breaks (DSBs) which form in early stages of meiosis and for crossovers. In addition, synaptonemal complex length and meiotic DNA loop size were estimated to explore how genome organization determines DSBs and crossover patterns. We show that although the number of meiotic DSBs per cell and recombination rates observed vary between individuals of the same species, these are correlated with diploid number as well as with synaptonemal complex and DNA loop sizes. Our results illustrate that genome packaging, DSB frequencies, and crossover rates tend to be correlated, while meiotic chromosomal axis length and DNA loop size are inversely correlated in mammals. Moreover, axis length, DSB frequency, and crossover frequencies all covary, suggesting that these correlations are established in the early stages of meiosis. PMID- 28101674 TI - Posterior tail development in the salamander Eurycea cirrigera: exploring cellular dynamics across life stages. AB - During embryogenesis, the body axis elongates and specializes. In vertebrate groups such as salamanders and lizards, elongation of the posterior body axis (tail) continues throughout life. This phenomenon of post-embryonic tail elongation via addition of vertebrae has remained largely unexplored, and little is known about the underlying developmental mechanisms that promote vertebral addition. Our research investigated tail elongation across life stages in a non model salamander species, Eurycea cirrigera (Plethodontidae). Post-embryonic addition of segments suggests that the tail tip retains some aspects of embryonic cell/tissue organization and gene expression throughout the life cycle. We describe cell and tissue differentiation and segmentation of the posterior tail using serial histology and expression of the axial tissue markers, MF-20 and Pax6. Embryonic expression patterns of HoxA13 and C13 are shown with in situ hybridization. Tissue sections reveal that the posterior spinal cord forms via cavitation and precedes development of the underlying cartilaginous rod after embryogenesis. Post-embryonic tail elongation occurs in the absence of somites and mesenchymal cells lateral to the midline express MF-20. Pax6 expression was observed only in the spinal cord and some mesenchymal cells of adult Eurycea tails. Distinct temporal and spatial patterns of posterior Hox13 gene expression were observed throughout embryogenesis. Overall, important insights to cell organization, differentiation, and posterior Hox gene expression may be gained from this work. We suggest that further work on gene expression in the elongating adult tail could shed light on mechanisms that link continual axial elongation with regeneration. PMID- 28101675 TI - Operative planning aid for optimal endoscopic third ventriculostomy entry points in pediatric cases. AB - OBJECT: Endoscopic third ventriculostomy (ETV) uses anatomical spaces of the ventricular system to reach the third ventricle floor and create an alternative pathway for cerebrospinal fluid flow. Optimal ETV trajectories have been previously proposed in the literature, designed to grant access to the third ventricle floor without a displacement of eloquent periventricular structures. However, in hydrocephalus, there is a significant variability to the configuration of the ventricular system, implying that the optimal ETV trajectory and cranial entry point needs to be planned on a case-by-case basis. In the current study, we created a mathematical model, which tailors the optimal ETV entry point to the individual case by incorporating the ventricle dimensions. METHODS: We retrospectively reviewed the imaging of 30 consecutive pediatric patients with varying degrees of ventriculomegaly. Three dimensional radioanatomical models were created using preoperative MRI scans to simulate the optimal ETV trajectory and entry point for each case. The surface location of cranial entry points for individual ETV trajectories was recorded as Cartesian coordinates centered at Bregma. The distance from the Bregma in the coronal plane represented as "x", and the distance from the coronal suture in the sagittal plane represented as "y". The correlation between the ventricle dimensions and the x, y coordinates were tested using linear regression models. RESULTS: The distance of the optimal ETV entry point from the Bregma in the coronal plane ("x") and from the coronal suture in the sagittal plane ("y") correlated well with the frontal horn ratio (FHR). The coordinates for x and y were fitted along the following linear equations: x = 85.8 FHR-13.3 (r 2 = 0.84, p < 0.001) and y = -69.6 FHR + 16.7 (r 2 = 0.83, p < 0.001). CONCLUSION: The surface location of the optimal cranial ETV entry point correlates well with the ventricle size. We provide the first model that can be used as a surgical planning aid for a case specific ETV entry site with the incorporation of the ventricle size. PMID- 28101676 TI - Patterns of statin initiation and continuation in patients with breast or colorectal cancer, towards end-of-life. AB - PURPOSE: Cross-sectional studies show that statins, used in cardiovascular disease prevention, are often discontinued approaching death. Studies investigating associations between statin exposure and cancer outcomes, not accounting for these exposure changes, are prone to reverse causation bias. The aim of this study was to describe longitudinally the changes in statin initiation and continuation prior to death in patients with breast or colorectal cancer, thus establishing an appropriate exposure lag time. METHODS: This study was carried out using linked cancer registry and prescribing data. We identified patients who died of their cancer (cases) and cancer survivors were used as controls. The probability of initiating or continuing statin use was estimated up to 5 years prior to death (or index date). Conditional binomial models were used to estimate relative risks and risk differences for associations between approaching cancer death and statin use. RESULTS: Compared to controls, the probability of continued statin use in breast cancer cases was significantly lower 3 months prior to death (RR 0.86 95% CI 0.79, 0.94). Similarly, in colorectal cancer cases, the probability of continued statin use was significantly lower 3 months prior to colorectal cancer death (RR 0.77 95% CI 0.68, 0.88). CONCLUSION: A significant proportion of patients will cease statin treatment in the months prior to a colorectal or breast cancer death. PMID- 28101677 TI - Emesis and nausea related to single agent trabectedin in ovarian cancer patients: a sub-study of the MITO15 project. AB - The MITO 15 was a prospective, single-arm trial, evaluating trabectedin monotherapy in patients with recurrent ovarian cancer (OC) who were BRCA mutation carriers or had a BRCAness phenotype. It is largely reported that trabectedin may induce nausea and vomiting but the real emetogenic potential of the drug, in the different schedules, has never been fully described; furthermore, OC patients are known to have an enhanced risk of developing nausea and vomiting due to female gender, abdominal spreading of the disease, and major surgery experienced by most of them. We thought to carry on a sub-study in the MITO 15 context focused on chemotherapy-induced nausea and vomiting (CINV) associated with trabectedin single agent. For all patients enrolled in the trial, we evaluated the antiemetic regimen at the first cycle, acute and delayed CINV, any rescue therapy, any change in the prophylactic antiemetic regimen, and the potential relationship between dexamethasone dosage and incidence of CINV. Overall, our findings were consistent with literature and confirmed that trabectedin can be classified as moderately emetogenic. We observed slightly higher rates of both nausea and vomiting compared to previous experiences with trabectedin monotherapy, probably due to intrinsic features of our population: all females and suffering from ovarian cancer. It seems that in preventing acute CINV, the combination of three drugs was more effective than the doublet; however, the difference did not reach statistical significance; further studies are required to verify such hypothesis. Given the extreme heterogeneity of the antiemetic regimens used, it appears that a standard antiemetic protocol does not exist and more specific guidelines for clinicians are needed. PMID- 28101678 TI - Breast carcinoma subtypes show different patterns of metastatic behavior. AB - The aim of our retrospective study was to analyze patterns of subtype specific metastatic spread and to identify the time course of distant metastases. A consecutive series of 490 patients with breast cancer who underwent surgery and postoperative treatment at Semmelweis University, Hungary, and diagnosed between the years 2000 and 2007 was identified from the archives of the 2nd Department of Pathology, Hungary. Molecular subtypes were defined based on the 2011 St. Gallen recommendations. Statistical analysis was performed with SPSS Statistics for Windows, Version 22.0. Distant metastasis free survival (DMFS) was defined as the time elapsed between the first pathological diagnosis of the tumor and the first distant metastasis detection. Distant metastases were detected in 124 patients. Mean time to develop metastasis was 29 months (range 0-127 months). The longest DMFS was observed in the Luminal A (LUMA) subtype (mean 39 months) whereas the shortest was seen in the HER2-positive (HER2+) subtype (mean 21 months; p = 0.012). We confirmed that HER2+ tumors carry a higher risk for distant metastases (42.1%). LUMA-associated metastases were found to be solitary in 59% of cases, whereas HER2+ tumors showed multiple metastases in 79.2% of cases. LUMA tumors showed a preference for bone-only metastasis as compared with HER2+ and triple negative breast cancer (TNBC) cases, which exhibited a higher rate of brain metastasis. The most frequent second metastatic sites of hormone receptor (HR) positive tumors were the lung and liver, whereas the brain was the most affected organ in HR-negative (HR-) cases. Tumor subtypes differ in DMFS and in pattern of distant metastases. HER2+ tumors featured the most aggressive clinical course. Further identification of subtype-specific factors influencing prognosis might have an impact on clinical care and decision-making. PMID- 28101679 TI - Inhibitory effect of saliva on osteoclastogenesis in vitro requires toll-like receptor 4 signaling. AB - OBJECTIVES: Saliva can suppress osteoclastogenesis, but the underlying mechanism has not been discovered yet. Considering that endotoxins suppress osteoclastogenesis in bone marrow cultures and that saliva contains endotoxins, it was reasonable to hypothesize that the impact of saliva on osteoclastogenesis requires toll-like receptor 4 signaling. MATERIAL AND METHODS: To test this hypothesis, we blocked toll-like receptor 4 signaling with TAK-242 in the presence of saliva in murine bone marrow cultures. Osteoclastogenesis was evaluated based on gene expression analysis and histochemical staining for tartrate-resistant acid phosphatase. Resorption was performed on dentine. RESULTS: We report that TAK-242 reversed the inhibitory effect of fresh sterile saliva on the formation of multinucleated cells that stained positive for tartrate-resistant acid phosphatase. In line with this finding, TAK-242 increased the expression of the osteoclast functional genes cathepsin K, calcitonin receptor, and tartrate-resistant acid phosphatase in the presence of saliva. TAK 242 also supported the expression of NFATc1, the master regulator of osteoclastogenesis, as well as DC-STAMP and Atp6v0d2, both being cell fusion genes. In support of the hypothesis, depletion of saliva from endotoxin partially reversed the inhibitory effect on osteoclastogenesis. Moreover, salivary pellicle on plastic and titanium did not affect osteoclastogenesis. CONCLUSION: Inhibition of toll-like receptor 4 signaling revealed that saliva can contribute to innate immunity by preventing hematopoietic progenitors to become osteoclasts. CLINICAL RELEVANCE: Saliva can activate pattern recognition receptor signaling through endotoxins and other stress factors, indicating the demand for macrophages rather than for osteoclasts. PMID- 28101680 TI - Application of tissue-engineered bone grafts for alveolar cleft osteoplasty in a rodent model. AB - OBJECTIVES: The clinical standard for alveolar cleft osteoplasty is augmentation with autologous bone being available in limited amounts and might be associated with donor site morbidity. The aim of the present study was the creation of tissue-engineered bone grafts and their in vivo evaluation regarding their potential to promote osteogenesis in an alveolar cleft model. MATERIALS AND METHODS: Artificial bone defects with a diameter of 3.3 mm were created surgically in the palate of 84 adult Lewis rats. Four experimental groups (n = 21) were examined: bovine hydroxyl apatite/collagen (bHA) without cells, bHA with undifferentiated mesenchymal stromal cells (MSC), bHA with osteogenically differentiated MSC. In a control group, the defect remained empty. After 6, 9 and 12 weeks, the remaining defect volume was assessed by cone beam computed tomography. Histologically, the remaining defect width and percentage of bone formation was quantified. RESULTS: After 12 weeks, the remaining defect width was 60.1% for bHA, 74.7% for bHA with undifferentiated MSC and 81.8% for bHA with osteogenically differentiated MSC. For the control group, the remaining defect width measured 46.2% which was a statistically significant difference (p < 0.001). CONCLUSIONS: The study design was suitable to evaluate tissue-engineered bone grafts prior to a clinical application. In this experimental set-up with the described maxillary defect, no promoting influence on bone formation of bone grafts containing bHA could be confirmed. CLINICAL RELEVANCE: The creation of a sufficient tissue-engineered bone graft for alveolar cleft osteoplasty could preserve patients from donor site morbidity. PMID- 28101683 TI - Allergy, Histamine and Antihistamines. AB - This chapter concentrates on the role in allergic disease of histamine acting on H1-receptors. It is clear that allergy has its roots in the primary parasite rejection response in which mast cell-derived histamine creates an immediate hostile environment and eosinophils are recruited for killing. This pattern is seen in allergic rhinitis where the early events of mucus production and nasal itching are primarily histamine mediated whereas nasal blockage is secondary to eosinophil infiltration and activation. In asthma, the role of histamine is less clear. Urticaria is characterized by mast cell driven pruritic wheal and flare type skin reactions that usually persist for less than 24 h. Although the events leading to mast cell degranulation have been unclear for many years, it is now becoming evident that urticaria has an autoimmune basis. Finally, the properties of first- and second-generation H1-antihistamines and their role in allergic is discussed. PMID- 28101682 TI - Synthesis, spectral and extended spectrum beta-lactamase studies of transition metal tetraaza macrocyclic complexes. AB - Urinary tract infections commonly occur in humans due to microbial pathogens invading the urinary tract, which can bring about a range of clinical symptoms and potentially fatal sequelae. The present study is aimed at addressing the development of a new antimicrobial agent against extended spectrum beta lactamase (ESBL) producing E. coli bacteria. We have synthesised some biologically potent (NNNN) donor macrocycles (L 1 = dibenzo[f,n]dipyrido[3,4-b:4',3' j][1,4,9,12]tetraazacyclohexadecine-6,11,18,23(5H,12H, 7H, 24H)-tetraone, and L 2 = 6,12,19,25-tetraoxo-4,6,11,12,16,18,23,24-octahydrotetrabenzo [b,g,k,p][1,5,10,14]tetra azacyclooctadecine-2,13-dicarboxylic acid) and their Ti and Zr metal complexes in alcoholic media using microwave protocol. Macrocyclic ligands were synthesised by incorporating of 3,5-diaminobenzoic acid, phthalic acid and 3,4-diaminopyridine in 1:1:1 molar ratio. The macrocyclic ligands and their metal complexes have been characterised by elemental analysis, conductance measurement, magnetic measurement and their structure configurations have been determined by various spectroscopic (FTIR, 1H/13C NMR, UV-Vis, LC-MS mass, XRD and TGA) techniques. [ZrL2Cl2]Cl2 metal complex shows excellent antibacterial activity against ESBLs. A zone of inhibition and minimum inhibitory concentration was determined by McFarland and the dilution method, respectively. The spectral studies confirm the binding sites of the nitrogen atom of the macrocycles. An octahedral geometry has been assigned to the metal complexes based on the findings. PMID- 28101681 TI - Extended liver venous deprivation before major hepatectomy induces marked and very rapid increase in future liver remnant function. AB - OBJECTIVE: The aim of this study was to assess the safety and efficacy of extended liver venous deprivation (eLVD), i.e. combination of right portal vein embolisation and right (accessory right) and middle hepatic vein embolisation before major hepatectomy for future remnant liver (FRL) functional increase. METHODS: eLVD was performed in non-cirrhotic patients referred for major hepatectomy in a context of small FRL (baseline FRL <25% of the total liver volume or FRL function <2.69%/min/m2). All patients underwent 99mTc-mebrofenin hepatobiliary scintigraphy (HBS) and computed tomographic evaluations. RESULTS: Ten consecutive patients underwent eLVD before surgery for liver metastases (n = 8), Klatskin tumour (n = 1) and gallbladder carcinoma (n = 1). FRL function increased by 64.3% (range = 28.1-107.5%) at day 21. In patients with serial measurements, maximum FRL function was at day 7 (+65.7 +/- 16%). The FRL volume increased by +53.4% at 7 days (+25 +/- 8 cc/day). Thirty-one days (range = 22-45 days) after eLVD, 9/10 patients were resected. No post-hepatectomy liver failure was reported. Two grade II and one grade III complications (Dindo-Clavien classification) occurred. No patient died with-in 90 days following surgery. CONCLUSIONS: eLVD is safe and provides a marked and very rapid increase in liver function, unprecedented for an interventional radiology procedure. KEY POINTS: * eLVD is safe * eLVD provides a marked and very rapid increase in liver function * After eLVD, the FRL-F increased by 64.3% (28.1-107.5%) at day 21 * After eLVD, the maximum FRL-F was obtained at day 7 (+65.7 +/- 16%) * After eLVD, the FRL volume increased by +53.4% at 7 days (+25 +/- 8 cc/day). PMID- 28101684 TI - p53 Replacement Therapy for Cancer. AB - Tumor suppressor gene (TSG) replacement therapy that involves various delivery systems is emerging as a promising antitumor strategy because malignant tumors develop through genetic alterations in TSGs. The most potent therapeutic TSG for tumor suppression is the multifunctional transcription factor p53 gene that regulates diverse cellular phenomena such as cell cycle arrest, senescence, apoptosis, and autophagy. Since the p53 gene is frequently inactivated by aberrant genetic regulation in human cancers, p53 replacement therapy is widely and frequently used as a potent antitumor strategy to restore wild-type p53 function in the p53-inactivated tumors. This chapter focuses on four types of p53 transfer systems: cationic liposome-DNA plasmid complexes, a replication deficient adenovirus vector, a replication-competent adenovirus vector, and a protein transduction system. Moreover, we discuss recent advances in our understanding of the molecular basis of the p53-mediated cell death signaling pathway and therapeutic methods for enhancing tumor cell death and induction of bystander effects within tumor tissues in p53 replacement therapy. Exploration of the molecular mechanism underlying the p53-mediated tumor-suppressive network system and development of an effective strategy for enhancing p53-mediated cell death signaling pathways would lead to an improvement in the clinical outcome of patients with p53-inactivated cancers. PMID- 28101685 TI - Retroviral Vectors for Cancer Gene Therapy. AB - Advances in molecular technologies have led to the discovery of many disease related genetic mutations as well as elucidation of aberrant gene and protein expression patterns in several human diseases, including cancer. This information has driven the development of novel therapeutic strategies, such as the utilization of small molecules to target specific cellular pathways and the use of retroviral vectors to retarget immune cells to recognize and eliminate tumor cells. Retroviral-mediated gene transfer has allowed efficient production of T cells engineered with chimeric antigen receptors (CARs), which have demonstrated marked success in the treatment of hematological malignancies. As a safety point, these modified cells can be outfitted with suicide genes. Customized gene editing tools, such as clustered regularly interspaced short palindromic repeats-CRISPR associated nucleases (CRISPR-Cas9), zinc-finger nucleases (ZFNs), or TAL-effector nucleases (TALENs), may also be combined with retroviral delivery to specifically delete oncogenes, inactivate oncogenic signaling pathways, or deliver wild-type genes. Additionally, the feasibility of retroviral gene transfer strategies to protect the hematopoietic stem cells (HSC) from the dose-limiting toxic effects of chemotherapy and radiotherapy was demonstrated. While some of these approaches have yet to be translated into clinical application, the potential implications for improved cellular replacement therapies to enhance and/or support the current treatment modalities are enormous. PMID- 28101686 TI - Minicircle-Based Engineering of Chimeric Antigen Receptor (CAR) T Cells. AB - Plasmid DNA is being used as a pharmaceutical agent in vaccination, as well as a basic substance and starting material in gene and cell therapy, and viral vector production. Since the uncontrolled expression of backbone sequences present in such plasmids and the dissemination of antibiotic resistance genes may have profound detrimental effects, an important goal in vector development was to produce supercoiled DNA lacking bacterial backbone sequences: Minicircle (MC) DNA. The Sleeping Beauty (SB) transposon system is a non-viral gene delivery platform enabling a close-to-random profile of genomic integration. In combination, the MC platform greatly enhances SB transposition and transgene integration resulting in higher numbers of stably modified target cells. We have recently developed a strategy for MC-based SB transposition of chimeric antigen receptor (CAR) transgenes that enable improved transposition rates compared to conventional plasmids and rapid manufacturing of therapeutic CAR T cell doses (Monjezi et al. 2016). This advance enables manufacturing CAR T cells in a virus free process that relies on SB-mediated transposition from MC DNA to accomplish gene-transfer. Advantages of this approach include a strong safety profile due to the nature of the MC itself and the genomic insertion pattern of MC-derived CAR transposons. In addition, stable transposition and high-level CAR transgene expression, as well as easy and reproducible handling, make MCs a preferred vector source for gene-transfer in advanced cellular and gene therapy. In this chapter, we will review our experience in MC-based CAR T cell engineering and discuss our recent advances in MC manufacturing to accelerate both pre-clinical and clinical implementation. PMID- 28101688 TI - mRNA Cancer Vaccines. AB - mRNA cancer vaccines are a relatively new class of vaccines, which combine the potential of mRNA to encode for almost any protein with an excellent safety profile and a flexible production process. The most straightforward use of mRNA vaccines in oncologic settings is the immunization of patients with mRNA vaccines encoding tumor-associated antigens (TAAs). This is exemplified by the RNActive(r) technology, which induces balanced humoral and cellular immune responses in animal models and is currently evaluated in several clinical trials for oncologic indications. A second application of mRNA vaccines is the production of personalized vaccines. This is possible because mRNA vaccines are produced by a generic process, which can be used to quickly produce mRNA vaccines targeting patient-specific neoantigens that are identified by analyzing the tumor exome. Apart from being used directly to vaccinate patients, mRNAs can also be used in cellular therapies to transfect patient-derived cells in vitro and infuse the manipulated cells back into the patient. One such application is the transfection of patient-derived dendritic cells (DCs) with mRNAs encoding TAAs, which leads to the presentation of TAA-derived peptides on the DCs and an activation of antigen specific T cells in vivo. A second application is the transfection of patient derived T cells with mRNAs encoding chimeric antigen receptors, which allows the T cells to directly recognize a specific antigen expressed on the tumor. In this chapter, we will review preclinical and clinical data for the different approaches. PMID- 28101687 TI - Noncoding RNA for Cancer Gene Therapy. AB - Gene therapy is a prospective strategy to modulate gene expression level in specific cells to treat human inherited diseases, cancers, and acquired disorders. A subset of noncoding RNAs, microRNAs (miRNAs) and small interference RNAs (siRNAs), compose an important class of widely used effectors for gene therapy, especially in cancer treatment. Functioning through the RNA interference (RNAi) mechanism, miRNA and siRNA show potent ability in silencing oncogenic factors for cancer gene therapy. For a better understanding of this field, we reviewed the mechanism and biological function, the principles of design and synthesis, and the delivery strategies of noncoding RNAs with clinical potentials in cancer gene therapy. PMID- 28101689 TI - Gene Therapeutic Approaches to Overcome ABCB1-Mediated Drug Resistance. AB - Multidrug resistance (MDR) to pharmaceutical active agents is a common clinical problem in patients suffering from cancer. MDR is often mediated by over expression of trans-membrane xenobiotic transport molecules belonging to the superfamily of ATP-binding cassette (ABC)-transporters. This protein family includes the classical MDR-associated transporter ABCB1 (MDR1/P-gp). Inhibition of ABC-transporters by low molecular weight compounds in cancer patients has been extensively investigated in clinical trials, but the results have been disappointing. Thus, in the last decades alternative experimental therapeutic strategies for overcoming MDR were under extensive investigation. These include gene therapeutic approaches applying antisense-, ribozyme-, RNA interference-, and CRISPR/Cas9-based techniques. Various delivery strategies were used to reverse MDR in different tumor models in vitro and in vivo. Results and conclusions of these gene therapeutic studies will be discussed. PMID- 28101690 TI - Bacterial Toxins for Oncoleaking Suicidal Cancer Gene Therapy. AB - For suicide gene therapy, initially prodrug-converting enzymes (gene-directed enzyme-producing therapy, GDEPT) were employed to intracellularly metabolize non toxic prodrugs into toxic compounds, leading to the effective suicidal killing of the transfected tumor cells. In this regard, the suicide gene therapy has demonstrated its potential for efficient tumor eradication. Numerous suicide genes of viral or bacterial origin were isolated, characterized, and extensively tested in vitro and in vivo, demonstrating their therapeutic potential even in clinical trials to treat cancers of different entities. Apart from this, growing efforts are made to generate more targeted and more effective suicide gene systems for cancer gene therapy. In this regard, bacterial toxins are an alternative to the classical GDEPT strategy, which add to the broad spectrum of different suicide approaches. In this context, lytic bacterial toxins, such as streptolysin O (SLO) or the claudin-targeted Clostridium perfringens enterotoxin (CPE) represent attractive new types of suicide oncoleaking genes. They permit as pore-forming proteins rapid and also selective toxicity toward a broad range of cancers. In this chapter, we describe the generation and use of SLO as well as of CPE-based gene therapies for the effective tumor cell eradication as promising, novel suicide gene approach particularly for treatment of therapy refractory tumors. PMID- 28101691 TI - Use of Bacteria in Cancer Therapy. AB - Cancer is one of the most dreaded diseases in humans and most common cause of death in twenty-first century. New cancer therapies are urgently required because of the existing pharmacological side effects of the conventional chemotherapy, radiation, or surgery. Newer modalities such as cancer vaccines and biological therapies are proving very helpful in the treatment of cancer along with the conventional therapies. The success of these novel cancer therapies is attributed to their lesser toxicity and the specific killing of the cancer cells. Bacterial therapy for cancer has been recognized a century ago. Live, attenuated, or genetically modified obligate or facultative anaerobic bacterial species exhibit the inherent property of colonizing the tumors and are capable of multiplying selectively inside the tumors, thereby inhibiting cancerous growths. The bacteria and their spores are used in the target specific therapies, delivering the prodrugs and the various proteins to the tumors. Albeit bacterial treatment of cancer is providing new perspective in the treatment of disease, the use of microorganisms to target tumors has certain confinements. The biosafety, genetic instability and the confounded interaction of the bacteria with treatment drugs, requires the more noteworthy consideration regarding the use of this novel treatment in the cancer treatment. PMID- 28101694 TI - Relationship Between Phenotypic and Genotypic Characteristics of Trichophyton mentagrophytes Strains Isolated from Patients with Dermatophytosis. AB - According to epidemiological, clinical and mycological criteria, it has long been admitted that the Trichophyton mentagrophytes species includes two varieties: a zoophilic variety (var. mentagrophytes) and an anthropophilic variety (var. interdigitale) that involve the upper and the lower part of the body, respectively. The further application of molecular techniques to the characterization of dermatophyte strains showed that this classification is unreliable. The aim of our study was to assess the usefulness of PCR-RFLP (restriction fragment length polymorphism) and sequencing in the characterization of T. mentagrophytes strains taken from Tunisian patients. The study was carried out in 2008 in the laboratory of Parasitology-Mycology of Farhat Hached University Hospital, Sousse, Tunisia. A total of 133 strains were isolated from 133 patients addressed to the laboratory for dermatological lesions very evocative of dermatomycosis. Eighty strains were isolated from lesions located on the lower part of the body (onychomycosis, tinea pedis) and 53 strains from the upper part of the body (tinea capitis, tinea corporis). All strains were submitted to mycological examination (direct microscopic examination and culture on Sabouraud medium) and further investigated by using RFLP analysis of the PCR amplified ITS1-5.8 s-ITS2 region of the ribosomal DNA and the MvaI restriction enzyme. In addition, 62 strains were further submitted to a sequencing of the ITS1-5.8 s-ITS2 region. On the basis of mycological criteria, all strains were diagnosed as T. mentagrophytes. All strains produced the same RFLP pattern and were identified as T. mentagrophytes interdigitale regardless of the location of lesions. Out of the 62 sequenced strains, 16 were found anthropophilic and 46 were zoophilic. In conclusion, all strains provisionally diagnosed as T. mentagrophytes on the basis of mycological criteria were shown to belong to T. interdigitale by using PCR-RFLP and sequencing irrespective of the site of lesions. The predominance of zoophilic strains needs further investigation. PMID- 28101695 TI - The Spatial Release of Cognitive Load in Cocktail Party Is Determined by the Relative Levels of the Talkers. AB - In a multi-talker situation, spatial separation between talkers reduces cognitive processing load: this is the "spatial release of cognitive load". The present study investigated the role played by the relative levels of the talkers on this spatial release of cognitive load. During the experiment, participants had to report the speech emitted by a target talker in the presence of a concurrent masker talker. The spatial separation (0 degrees and 120 degrees angular distance in azimuth) and the relative levels of the talkers (adverse, intermediate, and favorable target-to-masker ratio) were manipulated. The cognitive load was assessed with a prefrontal functional near-infrared spectroscopy. Data from 14 young normal-hearing listeners revealed that the target-to-masker ratio had a direct impact on the spatial release of cognitive load. Spatial separation significantly reduced the prefrontal activity only for the intermediate target-to-masker ratio and had no effect on prefrontal activity for the favorable and the adverse target-to-masker ratios. Therefore, the relative levels of the talkers might be a key point to determine the spatial release of cognitive load and more specifically the prefrontal activity induced by spatial cues in multi-talker situations. PMID- 28101692 TI - The assembly and function of perinuclear actin cap in migrating cells. AB - Stress fibers are actin bundles encompassing actin filaments, actin-crosslinking, and actin-associated proteins that represent the major contractile system in the cell. Different types of stress fibers assemble in adherent cells, and they are central to diverse cellular processes including establishment of the cell shape, morphogenesis, cell polarization, and migration. Stress fibers display specific cellular organization and localization, with ventral fibers present at the basal side, and dorsal fibers and transverse actin arcs rising at the cell front from the ventral to the dorsal side and toward the nucleus. Perinuclear actin cap fibers are a specific subtype of stress fibers that rise from the leading edge above the nucleus and terminate at the cell rear forming a dome-like structure. Perinuclear actin cap fibers are fixed at three points: both ends are anchored in focal adhesions, while the central part is physically attached to the nucleus and nuclear lamina through the linker of nucleoskeleton and cytoskeleton (LINC) complex. Here, we discuss recent work that provides new insights into the mechanism of assembly and the function of these actin stress fibers that directly link extracellular matrix and focal adhesions with the nuclear envelope. PMID- 28101698 TI - 6th Educational Meeting "Colorectal Cancer" : Republic of San Marino, 5-6 December, 2016 Presidents: Filippo La Torre, Giovanni Milito. PMID- 28101696 TI - Role of the Helix in Talin F3 Domain (F3 Helix) in Talin-Mediated Integrin Activation. AB - Increases in ligand binding to cellular integrins (activation) play an important role in platelet and leukocyte function. Talin is necessary in vivo and sufficient in vitro for integrin alphaIIbbeta3 activation. The precise mechanisms by which talin activates integrin are still being elucidated. In particular, talin undergoes conformational changes (around the F3 helix) and inserts the F3 helix into lipid bilayer; however, the connection between this lipid-inserting mechanism of talin and talin's capacity to activate integrin has never been explored before. In this work, we used rational mutagenesis, modeled cell systems, and structural modeling to study the potential role of membrane-induced talin conformational changes in talin-mediated integrin activation. Mutations of the residues critical for talin F3 helix to insert into membrane completely abolished talin-mediated integrin activation without affecting the binding of talin to integrins. Furthermore, mutations of the lipid-binding sequences in talin F3 helix significantly reduced the capacity of talin to activate integrin. Our results suggest that the F3 helix may contribute to talin-mediated integrin activation. PMID- 28101697 TI - Predictors of the Usefulness of Corticosteroids for Cancer-Related Fatigue in End of-Life Patients. AB - BACKGROUND AND OBJECTIVES: Although some studies have examined the use of corticosteroids, their effectiveness in treating cancer-related fatigue (CRF) has yet to be established. Therefore, this retrospective study attempted to identify factors that would predict the usefulness of corticosteroids in treating CRF. METHODS: We examined 87 hospitalized end-of-life cancer patients who were given betamethasone for relief of CRF at our hospital between January 2008 and January 2014. We evaluated the effect of betamethasone at 3 days after administration and performed a multivariate logistic regression analysis designed to identify predictive factors for the usefulness of corticosteroids. Threshold measurements were examined using a receiver operating characteristic (ROC) curve. RESULTS: This analysis identified the initial daily dose of betamethasone [odds ratio (OR) = 1.662], days from the start date of betamethasone administration to the date of death (OR = 1.05), administration of fentanyl (OR = 0.206) and age (OR = 1.055) as significant factors related to the effect of betamethasone. ROC curve analysis of the effect of the betamethasone showed that the threshold for the initial daily dose of betamethasone was above 4 mg, the threshold for the days from the start date of the betamethasone administration to the date of death was above 16 days and the threshold for age was above 60 years old. CONCLUSION: The initial daily dose of betamethasone, days from the start date of the betamethasone administration to the date of death, non-administration of fentanyl and advanced age were shown to be predictive factors for the usefulness of corticosteroids for CRF in end-of-life patients. PMID- 28101699 TI - Humanity at the Edge: The Moral Laboratory of Feeding Precarious Lives. AB - At the heart of anthropology and the social sciences lies a notion of human existence according to which humans and animals share the basic need for food, but only humans have the capacity for morality. Based on fieldwork in a pig laboratory, a neonatal intensive care unit (NICU), and a dementia nursing home, we follow practices of feeding precarious lives lacking most markers of human personhood, including the exercise of moral judgment. Despite the absence of such markers, laboratory researchers and caregivers in these three sites do not abstain from engaging in questions about the moral status of the piglets, infants, and people with dementia in their care. They continually negotiate how their charges belong to the human collectivity and thereby challenge the notion of 'the human' that is foundational to anthropology. Combining analytical approaches that do not operate with a fixed boundary between human and animal value and agency with approaches that focus on human experience and virtue ethics, we argue that 'the human' at stake in the moral laboratory of feeding precarious lives puts 'the human' in anthropology at disposal for moral experimentation. PMID- 28101700 TI - Predicting brain metastases for non-small cell lung cancer based on magnetic resonance imaging. AB - In this study the relationship between brain structure and brain metastases (BM) occurrence was analyzed. A model for predicting the time of BM onset in patients with non-small cell lung cancer (NSCLC) was proposed. Twenty patients were used to develop the model, whereas the remaining 69 were used for independent validation and verification of the model. Magnetic resonance images were segmented into cerebrospinal fluid, gray matter (GM), and white matter using voxel-based morphometry. Automatic anatomic labeling template was used to extract 116 brain regions from the GM volume. The elapsed time between the MRI acquisitions and BM diagnosed was analyzed using the least absolute shrinkage and selection operator method. The model was validated using the leave-one-out cross validation (LOOCV) and permutation test. The GM volume of the extracted 11 regions of interest increased with the progression of BM from NSCLC. LOOCV test on the model indicated that the measured and predicted BM onset were highly correlated (r = 0.834, P = 0.0000). For the 69 independent validating patients, accuracy, sensitivity, and specificity of the model for predicting BM occurrence were 70, 75, and 66%, respectively, in 6 months and 74, 82, and 60%, respectively, in 1 year. The extracted brain GM volumes and interval times for BM occurrence were correlated. The established model based on MRI data may reliably predict BM in 6 months or 1 year. Further studies with larger sample size are needed to validate the findings in a clinical setting. PMID- 28101701 TI - Early postoperative tumor progression predicts clinical outcome in glioblastoma implication for clinical trials. AB - Molecular markers define the diagnosis of glioblastoma in the new WHO classification of 2016, challenging neuro-oncology centers to provide timely treatment initiation. The aim of this study was to determine whether a time delay to treatment initiation was accompanied by signs of early tumor progression in an MRI before the start of radiotherapy, and, if so, whether this influences the survival of glioblastoma patients. Images from 61 patients with early post surgery MRI and a second MRI just before the start of radiotherapy were examined retrospectively for signs of early tumor progression. Survival information was analyzed using the Kaplan-Meier method, and a Cox multivariate analysis was performed to identify independent variables for survival prediction. 59 percent of patients showed signs of early tumor progression after a mean time of 24.1 days from the early post-surgery MRI to the start of radiotherapy. Compared to the group without signs of early tumor progression, which had a mean time of 23.3 days (p = 0.685, Student's t test), progression free survival was reduced from 320 to 185 days (HR 2.3; CI 95% 1.3-4.0; p = 0.0042, log-rank test) and overall survival from 778 to 329 days (HR 2.9; CI 95% 1.6-5.1; p = 0.0005). A multivariate Cox regression analysis revealed that the Karnofsky performance score, O-6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, and signs of early tumor progression are prognostic markers of overall survival. Early tumor progression at the start of radiotherapy is associated with a worse prognosis for glioblastoma patients. A standardized baseline MRI might allow for better patient stratification. PMID- 28101702 TI - Bone Marrow Very Small Embryonic-Like Stem Cells: New Generation of Autologous Cell Therapy Soon Ready for Prime Time? AB - Very small embryonic-like stem cells (VSELs) are major pluripotent stem cells described in human and mouse. In this issue of Stem Cell Reviews and Reports, Shaikh and colleagues show in a valuable work that mouse bone marrow collected after 5FU treatment contains VSELs able to undergo in vitro multi-lineage differentiation into cells from all three germ layers and also in germ and hematopoietic cells. These findings are robust since no confounding factor such as feeder cell fusion with VSELs can occur here. This paper allows one to better appreciate bone marrow-VSELs differentiation potential and opens new perspectives for autologous cell therapy. Furthermore, it might help explaining lots of contradictive data from the past 20 years, in particular related to ability of bone marrow cells to differentiate into cardiomyocytes. PMID- 28101703 TI - Differences in Cortical Sources of the Event-Related P3 Potential Between Young and Old Participants Indicate Frontal Compensation. AB - The event-related P3 potential, as elicited in auditory signal detection tasks, originates from neural activity of multiple cortical structures and presumably reflects an overlap of several cognitive processes. The fact that the P3 is affected by aging makes it a potential metric for age-related cognitive change. The P3 in older participants is thought to encompass frontal compensatory activity in addition to task-related processes. The current study investigates this by decomposing the P3 using group independent component analysis (ICA). Independent components (IC) of young and old participants were compared in order to investigate the effects of aging. Exact low-resolution tomography analysis (eLORETA) was used to compare current source densities between young and old participants for the P3-ICs to localize differences in cortical source activity for every IC. One of the P3-related ICs reflected a different constellation of cortical generators in older participants compared to younger participants, suggesting that this P3-IC reflects shifts in neural activations and compensatory processes with aging. This P3-IC was localized to the orbitofrontal/temporal, and the medio-parietal regions. For this IC, older participants showed more frontal activation and less parietal activation as measured on the scalp. The differences in cortical sources were localized in the precentral gyrus and the parahippocampal gyrus. This finding might reflect compensatory activity recruited from these cortical sources during a signal detection task. PMID- 28101704 TI - Molecular cloning and gene/protein expression of FAT/CD36 from grass carp (Ctenopharyngodon idella) and the regulation of its expression by dietary energy. AB - Fatty acid translocase/cluster of differentiation 36 (FAT/CD36) functions as a membrane long-chain fatty acid transporter in various tissues in land animals. Not much is known about the CD36 molecule in teleost fish. Therefore, we studied CD36 in grass carp (Ctenopharyngodon idella, ciCD36). The full-length complementary DNA sequence of ciCD36 was 1976 bp, with an ORF of 468 amino acids, which had high sequence similarity to the CD36 of common carp. The messenger RNA (mRNA) expression of ciCD36 was high in the intestine, heart, liver, visceral tissue, and brain, but absent in the kidney. The protein expression of ciCD36 was high in the brain, intestine, liver, heart, muscle, eye, visceral tissue, gonad, and gill, but not in the kidney. Four groups of grass carp (16 tanks) were fed three times daily to satiation with 17.2 kJ gross energy/g diet (control, CON), 19.4 kJ gross energy/g diet (more energy supplied by proteins, HP), 19.9 kJ gross energy/g diet (more energy supplied by fat, HF), and 19.1 kJ gross energy/g diet (more energy supplied by carbohydrate, HC) for 11 weeks, respectively. At the end of the feeding experiment, the fish were fasted for 48 h, and the brain, heart, intestine, and liver were sampled and designated as the 0-h samples. The fish were then fed a single meal of the above four diets, and these tissues were collected at 8- and 24-h intervals after refeeding to analyze ciCD36 mRNA and protein expression levels. The results showed that at the transcriptional and translational levels, ciCD36 expression was significantly affected by refeeding time and the different diets (P < 0.05), and the regulation of its transcription in different tissues varied. At the translational level, the protein expression levels decreased in the CON and HC groups, and increased in the HP and HF groups after refeeding. The results indicated that ciCD36 has a modulatory role in the adaptation to dietary high energy in grass carp. Translational regulation might be responsible for the observed variations in ciCD36 expression. PMID- 28101705 TI - Tyrosine Kinase Inhibitors and Proton Pump Inhibitors: An Evaluation of Treatment Options. AB - Tyrosine kinase inhibitors (TKIs) have rapidly become an established factor in oncology, and have been shown to be effective in a wide variety of solid and hematologic malignancies. Use of the oral administration route of TKIs offers flexibility and is convenient for the patient; however, despite these advantages, the oral route of administration also causes a highly relevant new problem. Acid inhibitory drugs, such as proton pump inhibitors (PPIs), increase the intragastric pH, which may subsequently decrease TKI solubility, bioavailability, and treatment efficacy. Clear and practical advice on how to manage PPI use during TKI therapy is currently not available in the literature. Since PPIs are extensively used during TKI therapy, prescribers are presented with a big dilemma as to whether or not to continue the combined treatment, resulting in patients possibly being deprived of optimal therapy. When all pharmacological characteristics and data of either TKIs and PPIs are considered, practical and safe advice on how to manage this drug combination can be given. PMID- 28101706 TI - Comparative assessment of LECA and Spartina maritima to remove emerging organic contaminants from wastewater. AB - The present work aimed to evaluate the capacity of constructed wetlands (CWs) to remove three emerging organic contaminants with different physicochemical properties: caffeine (CAF), oxybenzone (MBPh), and triclosan (TCS). The simulated CWs were set up with a matrix of light expanded clay aggregates (LECA) and planted with Spartina maritima, a salt marsh plant. Controlled experiments were carried out in microcosms using deionized water and wastewater collected at a wastewater treatment plant (WWTP), with different contaminant mass ranges, for 3, 7, and 14 days. The effects of variables were tested isolatedly and together (LECA and/or S. maritima). The presence of LECA and/or S. maritima has shown higher removal (around 61-97%) of lipophilic compounds (MBPh and TCS) than the hydrophilic compound (CAF; around 19-85%). This was attributed to the fact that hydrophilic compounds are dissolved in the water column, whereas the lipophilic ones suffer sorption processes promoting their removal by plant roots and/or LECA. In the control (only wastewater), a decrease in the three contaminant levels was observed. Adsorption and bio/rhizoremediation are the strongest hypothesis to explain the decrease in contaminants in the tested conditions. PMID- 28101707 TI - Distributions and ecological risk assessment of estrogens and bisphenol A in an arid and semiarid area in northwest China. AB - Free estrogens (estrone, E1; 17beta-estradiol, 17beta-E2; estriol, E3; and 17alpha-ethinylestradiol, EE2), their corresponding sulfate and glucuronide conjugates, and bisphenol A (BPA) were investigated in water and sediments in the Fen River catchment, an arid and semiarid area in northwest China. E1 and BPA were frequently detected in the wet and dry sampling seasons. In addition to the sulfate conjugates, other conjugated estrogens were not detected in water and sediments. The concentrations of these compounds in water generally increased from upstream to downstream. The concentrations in water samples of most sites were higher in the wet season than those in the dry season, but concentrations in sediments of most sites were higher in the dry season than those in the wet season. The distributions of these compounds in sediments were positively correlated with the total organic carbon (TOC) contents of sediments (0.3 < R 2 < 0.6, p < 0.01) and concentrations in water (0.25 < R 2 < 0.50, p < 0.01). In this catchment, E1 was the main contributor to endocrine disrupting risk. The surface water in most of the tributaries and the sewage in the drainage channels were at risk. The pore waters of sediments were at risk at most sampling sites. PMID- 28101708 TI - Characterization of interaction between amino acids and fulvic-like organic matter by fluorescence spectroscopy combining thermodynamic calculation. AB - Dissolved organic matter (DOM), as a very fine colloidal suspension, could inevitably affect the transformation process of dissolved organic nitrogen (DON) in drinking water treatment. Tryptophan and tyrosine were used as representatives of DON to investigate the interactions between amino acids and fulvic-like components of fluorescent DOM using titration experiments. The fluorescence intensity decreased significantly with the increasing fulvic acid (FA) concentration, suggesting that FA could greatly quench the intrinsic fluorescence of amino acids such as tryptophan and tyrosine. The absolute spectrum peaks of amino acids (AA) were changed in the presence of FA, possibly being resulted from non-covalent interactions between amino acids and FA. The specific hydrogen bonding and van der Waals forces played dominant roles in the interactions according to the results of theoretical analysis and thermodynamic calculation. The distance between donor and acceptor was 1.25 and 1.14 nm for the FA-tyrosine and FA-tryptophan system, indicating the energy transfer from tyrosine or tryptophan to FA. The association constant (K) decreased with the increase of temperature and pH value, while the change of ionic strength had no obvious influence on K value. PMID- 28101709 TI - Distributed mixed-integer fuzzy hierarchical programming for municipal solid waste management. Part I: System identification and methodology development. AB - Due to the existence of complexities of heterogeneities, hierarchy, discreteness, and interactions in municipal solid waste management (MSWM) systems such as Beijing, China, a series of socio-economic and eco-environmental problems may emerge or worsen and result in irredeemable damages in the following decades. Meanwhile, existing studies, especially ones focusing on MSWM in Beijing, could hardly reflect these complexities in system simulations and provide reliable decision support for management practices. Thus, a framework of distributed mixed integer fuzzy hierarchical programming (DMIFHP) is developed in this study for MSWM under these complexities. Beijing is selected as a representative case. The Beijing MSWM system is comprehensively analyzed in many aspects such as socio economic conditions, natural conditions, spatial heterogeneities, treatment facilities, and system complexities, building a solid foundation for system simulation and optimization. Correspondingly, the MSWM system in Beijing is discretized as 235 grids to reflect spatial heterogeneity. A DMIFHP model which is a nonlinear programming problem is constructed to parameterize the Beijing MSWM system. To enable scientific solving of it, a solution algorithm is proposed based on coupling of fuzzy programming and mixed-integer linear programming. Innovations and advantages of the DMIFHP framework are discussed. The optimal MSWM schemes and mechanism revelations will be discussed in another companion paper due to length limitation. PMID- 28101710 TI - Effect of different sulfadimidine addition methods on its degradation behaviour in swine manure. AB - Sulfadimidine (SM2) is commonly used in the swine industry and enters the environment via faeces. In recent years, advances in the ecotoxicology of SM2 have become a popular research interest with two common research methods including swine manure collection from swine fed with a diet containing SM2 and directly adding SM2. The purpose of this experiment was to compare SM2 degradation behaviour in pig manure with two different SM2 addition methods. The results showed that the degradation half-lives of SM2 in manure from SM2-fed swine treatment were 33.2 and 32.0 days at the initial addition level of SM2 at 32.1 and 64.3 mg/kg, respectively. This was significantly longer than that in manure directly adding SM2 treatment with the half-lives of 21.4 and 14.8 days. The metabolite of SM2 N4-acetyl-sulfamethazine occurred in manure from SM2-fed swine treatment but was not detected in directly adding SM2 treatment. The pH in manure from SM2-fed swine treatment was significantly lower than that in directly adding SM2 treatment, but the values of organic carbon, total nitrogen, and electrical conductivity in manure from SM2-fed swine treatment were significantly higher than those in manure directly adding SM2 treatment. Meanwhile, although the copy number of bacteria had no significant difference between two treatments, there was a significant difference in bacteria diversity. Results of the present study demonstrated that the presence of the metabolites, chemical property, and microbial diversity might be the reason for different SM2 degradation behaviours on different addition methods. Thus, the method using manure with SM2 collected from swine could obtain more accurate results for the ecotoxicological study of SM2. PMID- 28101711 TI - Catalytic performance of graphene-bimetallic composite for heterogeneous oxidation of acid orange 7 from aqueous solution. AB - In this study, reduced graphene oxide (rGO) embedded with bimetallic nanoparticles of cobalt-manganese oxide (CoMn2O4) was fabricated by hydrothermal treatment. The obtained product was characterized and applied for the heterogeneous activation of peroxymonosulfate (PMS) to degrade acid orange 7 (AO7). The characterization results revealed that 10-20 nm nanosized CoMn2O4 was homogenously decorated on the surface of rGO. The effect of different CoMn2O4 loadings showed that catalyst with a CoMn2O4 contents higher than 20% performs stronger capability for catalytic degradation of AO7 compared to pure CoMn2O4. In a system containing 4 mM PMS and 0.05 g/L 50% CoMn2O4/rGO, 100% conversion of AO7 (70 mg/L) and 43% mineralization could be achieved within 12 and 60 min, respectively. Recycling experiment along with XRD data demonstrates good stability of the catalyst for five successive runs. Inhibition confirmation results suggest that surface-bound SO4*- and HO* radicals both played a key role in degradation of AO7. Therefore, this material demonstrates a very efficient catalytic performance for the degradation of organic dyes. PMID- 28101712 TI - Herbicides and trace metals in urban waters in Melbourne, Australia (2011-12): concentrations and potential impact. AB - Urban stormwater samples were collected from five aquatic systems in Melbourne, Australia, on six occasions between October 2011 and March 2012 and tested for 30 herbicides and 14 trace metals. Nineteen different herbicides were observed in one or more water samples from the five sites; chemicals observed at more than 40% of sites were simazine (100%), MCPA (83%), diuron (63%) and atrazine (53%). Using the toxicity unit (TU) concept to assess potential risk to aquatic ecosystems, none of the detected herbicides were considered to pose an individual, group or collective short-term risk to fish or zooplankton in the waters studied. However, 13 herbicides had TU values suggesting they might have posed an individual risk to primary producers at the time of sampling. Water quality guideline levels were exceeded on many occasions for Cd, Cu, Cr, Pb and Zn. Similarly, RQmed and RQmax exceeded 1 for Cd, Cr, Cu, Mn, Ni, Pb, V and Zn. Almost all the metals screened exceeded a log10TU of -3 for every trophic level, suggesting that there may have been some impact on aquatic organisms in the studied waterbodies. Our data indicate that Melbourne's urban aquatic environments may be being impacted by approved domestic, industrial and sporting application of herbicides and that stormwater quality needs to be carefully assessed prior to reuse. Further research is required to understand the performance of different urban stormwater wetland designs in removing pesticides and trace metals. Applying the precautionary principle to herbicide regulation is important to ensure there is more research and assessment of the long-term 'performance' standard of all herbicides and throughout their 'life cycle'. Implementing such an approach will also ensure government, regulators, decision makers, researchers, policy makers and industry have the best possible information available to improve the management of chemicals, from manufacture to use. PMID- 28101713 TI - Macro- and Microelement Content and Other Properties of Chaenomeles japonica L. Fruit and Protective Effects of Its Aqueous Extract on Hepatocyte Metabolism. AB - This growing interest in the cultivation of Japanese quince Chaenomeles japonica L. results from the potentially beneficial properties of its fruit. Fresh fruits are very firm and too acidic to eat raw, but their bioactive components, distinctive aroma, and high amount of dietary fiber make the fruits well suited for industrial processing. However, not all the properties of the fruit have been investigated. For example, there are no comprehensive reports about the mineral content or potentially harmful effects on liver metabolism. Hence, the purpose of our study was to examine fresh Japanese quince fruit in terms of (1) ascorbic acid, oxalate, fiber, macro- and micronutrients, dry matter, extract, total acidity, antioxidant activity, and phenolic compound levels; and (2) the effect of its extract on in vitro hepatocyte metabolism, measured by the concentration of lipid peroxides (LPO) and reactive oxygen species (ROS) and the severity of apoptosis and necrosis. The fruit of C. japonica had high levels of macro- and microelements, ascorbic acid, phenolic compounds, fiber, and low oxalate levels. Our analysis of macro- and microelements showed that the average content of Fe was 0.516 mg/g, Cu 0.146 mg/g, Zn 0.546 mg/g, Mg 16.729 mg/g, and Ca 22.920 mg/g of fresh fruit. A characteristic feature of the fresh fruit of C. japonica is a high level of polyphenols, which-combined with a high content of vitamin C-affect their high antioxidant potential. In the tested hepatocyte cultures incubated with extract of the Japanese quince, we observed a significant decrease in the concentration of lipid peroxides compared to the control. There were also no signs of increased formation of ROS in the mitochondria of hepatocytes incubated with the extract of quince. Malondialdehyde was strongly negatively correlated with the concentration of Japanese quince extract, which indicates the hepatoprotective properties of Japanese quince. In addition, our analysis of confocal microscopy images showed that the hepatocytes incubated with the extract of Japanese quince at any concentration did not show any signs of apoptosis or necrosis. The aqueous extract of quince fruit has antioxidative and antiapoptotic hepatocytes, thus exerting a hepatoprotective effect. PMID- 28101714 TI - Assessment of Zinc Status in School-Age Children from Rural Areas in China Nutrition and Health Survey 2002 and 2012. AB - Zinc is an essential trace element for growth and development in children, but zinc deficiency is a serious nutritional problem worldwide. Our study aimed to assess the zinc status of school-age children living in rural areas of China and to examine the change of zinc status based on the China Nutrition and Health Survey 2002 and 2012. We used the probability proportional to size sampling method for subject selection, and a total of 3407 school-age children were included in this study. Zinc status was assessed by three items of indicators recommended by the World Health Organization (WHO), the United Nations Children's Fund (UNICEF), the International Atomic Energy Agency (IAEA), and the International Zinc Nutrition Consultative Group (IZiNCG). The concentration of serum zinc was 718.2 MUg/L, and 44.4% of children being zinc deficiency in 2002, while 846.8 MUg/L and 10.4% in 2012. Zinc intake was 7.8 mg/day with a 7.6% inadequate zinc intake in 2002, together with 6.9 mg/day and 38.2% in 2012. Height-for-age Z score was -1.06 and 19.1% of children being stunting in 2002, as well as -0.15 and 6.8% in 2012. In conclusion, the zinc status of school-age children living in rural areas of China has been significantly improved in addition to zinc intake over the past 10 years. However, the zinc deficiency still observed in poor rural areas of China in 2012. In addition, we suggested that the zinc bioavailability should be taken into account when assessing zinc status in population. PMID- 28101715 TI - Cortex- and Amygdala-Dependent Learning and Nicotinic Acetylcholine Receptor Gene Expression is Severely Impaired in Mice Orally Treated with AlCl3. AB - Recent industrialization has increased human exposure to bio-available aluminum (Al). If more Al enters the brain than leaves, Al concentration will rise in the brain leading to neurodegenerative disorders. The aim of the present study was to determine Al concentration, neurodegeneration, and nicotinic acetylcholine receptor (nAChR) gene expression in the cortex and amygdala after oral ingestion of Al salt. The effect of Al on cortex- and amygdala-dependent learning and memory functions was also assessed. Mice were given AlCl3 (250 mg/kg) in drinking water for 42 days. nAChR gene expression was determined in the cortex and amygdala. The mice were subjected to behavior tests (fear conditioning, fear extinction, and open field), to assess memory deficits. The acquisition of fear memory in the fear conditioning test remained unaffected due to the Al administration. However, fear extinction (which is a new learning) was severely impaired. The behavioral analysis in the open field test showed greater anxiety and less adaptability to the new environment in Al-treated animals. High Al concentration and severe neurodegeneration in the cortex were observed following Al treatment while a slight, non-significant elevation in Al concentration was observed in the amygdala of Al-treated animals. The analysis of nAChR gene expression via RT-PCR showed a significant reduction in expression of alpha7, alpha4, and beta2 nAChR genes in the cortex of Al-treated animals, while in the amygdala, the level of the alpha4 nAChR gene remained unaltered. Oral Al ingestion causes neuropathological changes and suppresses expression of nAChR genes that lead to deficits in learning and higher anxiety in Al-treated animals. PMID- 28101716 TI - Circulating activated protein C in thrombophilia carriers. PMID- 28101718 TI - Poisoning Through Pediatric Skin: Cases from the Literature. AB - Poisoning through pediatric skin leading to acute systemic symptoms is a relatively uncommonly reported phenomenon. Systemic toxicity through the skin typically occurs by direct contact between therapeutic or non-therapeutic topical agents and the skin. Though uncommon, poisoning through pediatric skin can have significant consequences and must be recognized so the offending agent may be discontinued and appropriate treatment initiated. We performed a literature search for all article types between 1950 and April 2016 to provide a single source of detectable cases of acute toxicity in pediatric patients due to percutaneous exposure. This literature review discusses relevant pediatric skin physiology along with reports of poisoning events that resulted in systemic signs and symptoms and even death to provide a comprehensive report on causes of pediatric poisoning through the skin. PMID- 28101717 TI - Trace metals accumulation in soil irrigated with polluted water and assessment of human health risk from vegetable consumption in Bangladesh. AB - Trace metals accumulation in soil irrigated with polluted water and human health risk from vegetable consumption was assessed based on the data available in the literature on metals pollution of water, soil, sediment and vegetables from the cites of Bangladesh. The quantitative data on metal concentrations, their contamination levels and their pollution sources have not been systematically gathered and studied so far. The data on metal concentrations, sources, contamination levels, sample collection and analytical tools used were collected, compared and discussed. The USEPA-recommended method for health risk assessment was used to estimate human risk from vegetable consumption. Concentrations of metals in water were highly variable, and the mean concentrations of Cd, Cr, Cu and As in water were found to be higher than the FAO irrigation water quality standard. In most cases, mean concentrations of metals in soil were higher than the Bangladesh background value. Based on geoaccumulation index (I geo) values, soils of Dhaka city are considered as highly contaminated. The I geo shows Cd, As, Cu, Ni, Pb and Cr contamination of agricultural soils and sediments of the cities all over the Bangladesh. Polluted water irrigation and agrochemicals are identified as dominant sources of metals in agricultural soils. Vegetable contamination by metals poses both non-carcinogenic and carcinogenic risks to the public. Based on the results of the pollution and health risk assessments, Cd, As, Cr, Cu, Pb and Ni are identified as the priority control metals and the Dhaka city is recommended as the priority control city. This study provides quantitative evidence demonstrating the critical need for strengthened wastewater discharge regulations in order to protect residents from heavy metal discharges into the environment. PMID- 28101719 TI - In Patients with a Soft Pancreas, a Thick Parenchyma, a Small Duct, and Fatty Infiltration Are Significant Risks for Pancreatic Fistula After Pancreaticoduodenectomy. AB - BACKGROUND: This study sought to characterize soft and hard pancreatic textures radiologically and histologically, and to identify specific risks in a soft pancreas associated with postoperative pancreatic fistula (POPF) formation after pancreaticoduodenectomy (PD). METHODS: Consecutive 145 patients who underwent PD at a single institution between January 2010 and May 2013 were studied. Pancreatic consistency was intraoperatively judged as soft or hard. Pancreatic configuration was assessed using preoperative CT. Histologic components of the pancreatic stump were evaluated using a morphometric analysis. Clinicopathologic parameters were then analyzed for the risk of clinically relevant POPF. RESULTS: Compared with patients with a hard pancreas (n = 66), those with a soft pancreas (n = 79) had a smaller main pancreatic duct (MPD) diameter and a larger parenchymal thickness on CT, had a smaller fibrosis ratio and a larger lobular ratio histologically, and developed clinically relevant POPF more frequently (P < 0.001 for all). In patients with a soft pancreas, an MPD diameter <2 mm, a parenchymal thickness >=10 mm, a lobular ratio <75%, and a fat ratio >=20% were independently associated with clinically relevant POPF (P < 0.010 for all). CONCLUSION: In patients with a soft pancreas, a thick parenchyma, a small MPD, and fatty infiltration were strongly associated with clinically relevant POPF after PD. PMID- 28101720 TI - Enhanced Recovery after Surgery Programs for Liver Resection: a Meta-analysis. AB - BACKGROUND AND AIMS: Due to the limited number of high-quality randomized controlled trials on enhanced recovery after surgery for hepatectomy, previous reviews have not been sufficiently comprehensive. Our objectives were to evaluate and compare the safety and efficacy of enhanced recovery after surgery programs and traditional care in patients undergoing open or laparoscopic surgery and to assess the optimized items for hepatectomy. METHODS: We searched the PubMed, Embase, and the Cochrane Library databases for all the relevant studies regardless of study design. We assessed the methodological quality of the included studies and excluded studies of poor quality. We performed a meta analysis using RevMan 5.3 software. RESULTS: In total, 19 original studies with 2575 patients, including four randomized controlled trials and 15 non-randomized controlled trials, were analyzed. The meta-analysis demonstrated that enhanced recovery after surgery programs could reduce morbidity, hospital stays and cost, blood loss, and time to bowel function recovery for both open and laparoscopic surgery without increasing mortality, readmission rate, or transfusion rate. Twelve items were essential for liver surgery. CONCLUSIONS: Enhanced recovery after surgery programs for hepatectomy are feasible and efficient. Further studies should optimize perioperative outcomes for liver surgery. PMID- 28101722 TI - The Effect of Antibiotic-Coated Sutures on the Incidence of Surgical Site Infections in Abdominal Closures: a Meta-Analysis. AB - OBJECTIVE: This meta-analysis aims to determine if antibiotic-impregnated sutures for abdominal fascial closure prevent postoperative surgical site infections (SSIs), hernias, and/or dehiscence. METHODS: MEDLINE and EMBASE databases (1946 2016) were searched. Randomized controlled trials comparing antibiotic impregnated sutures to standard sutures for abdominal closure were eligible. Risk of bias was evaluated using the Cochrane Handbooks definitions. RESULTS: Four hundred fifty articles were reviewed; five eligible studies (N = 3117) were identified. All studies routinely used prophylactic antibiotics. Overall risk of SSI in the antibiotic-impregnated suture group was 10.4 vs. 13.0% in the control group. Pooled data showed no difference in SSI between suture types (odds ratio 0.79, 95% CI 0.57-1.09, P = 0.15, I 2 = 44%). There was no evidence of subgroup effect by suture material (polydioxanone vs. polyglactin 910; P = 0.19) or by comparing colorectal surgery studies to others (P = 0.67). There was a high risk of bias in two studies, one for high loss to follow-up and one for not using an intent-to-treat analysis. CONCLUSION: Our meta-analysis is the most comprehensive review on the utility of antibiotic-impregnated sutures in abdominal surgery to prevent SSI. We found no evidence to support routine use of these sutures. PMID- 28101721 TI - Quantitative Assessment of Visceral Obesity and Postoperative Colon Cancer Outcomes. AB - BACKGROUND: Quantitative computed tomography (CT) assessment of visceral adiposity may be superior to body mass index (BMI) as a predictor of surgical morbidity. We sought to examine the association of CT measures of obesity and BMI with short-term postoperative outcomes in colon cancer patients. METHODS: In this retrospective study, 110 patients treated with colectomy for stage I-III colon cancer were classified as obese or non-obese by preoperative CT-based measures of adiposity or BMI [obese: BMI >= 30 kg/m2, visceral fat area (VFA) to subcutaneous fat area ratio (V/S) >=0.4, and VFA > 100 cm2]. Postoperative morbidity and mortality rates were compared. RESULTS: Obese patients, by V/S and VFA but not BMI, were more likely to be male and have preexisting hypertension and diabetes. The overall complication rate was 25.5%, and there were no mortalities. Obese patients by VFA (with a trend for V/S but not BMI) were more likely to develop postoperative complications as compared to patients classified as non-obese: VFA (30.5 vs.10.7%, p = 0.03), V/S (29.2 vs. 9.5%, p = 0.05), and BMI (32.4 vs. 21.9%, p = 0.23). CONCLUSIONS: Elevated visceral obesity quantified by CT is associated with the presence of key metabolic comorbidities and increased postoperative morbidity and may be superior to BMI for risk stratification. PMID- 28101723 TI - Role of high-resolution computerized tomography chest in identifying tubercular etiology in patients diagnosed as Eales' disease. AB - BACKGROUND: The high resolution computerized tomography of chest is an important diagnostic imaging tool to identify any pulmonary tubercular lesion. It's role in Eales' disease to identify any possible association with pulomonary tuberculosis has not been studied earlier. So, this study was conducted to assess the role of high resolution computerized tomography (HRCT) chest in identifying tuberculous etiology in Eales' disease. RESULTS: It was a retrospective study conducted at a tertiary care eye hospital in South India between January 2009 and October 2014 were included. A total of 29 diagnosed cases of Eales' (24 male and 5 female) were included in the study. These patients were followed up for a mean period of 739.75 days. Out of them, 13 (44.8%) had bilateral and 16 (55.2%) had unilateral ocular involvement. Eight cases (34.5%) patients had vitreous inflammation. Mantoux test was positive in 12 (41.4%) cases and chest x-ray suggestive of TB was present in four cases (13.8%). QuantiFERON TB gold was positive in 15 (51.7%) and HRCT chest suggestive of TB was positive in 15 (51.7%) case. Out of 15 Eales' cases with positive HRCT scan suggestive of TB, the commonly noted lesions were calcified nodules 34.5%, mediastinal hilar lymphadenopathy 13.8%, parenchymal soft tissue lesions in 3.4%. Five (17.2%) cases underwent pars plana vitrectomy for non resolving vitreous hemorrhage and one case underwent retinal attachment surgery with encirclage. Six patients were started on 9 months regimen of ATT by the chest physician. Final visual outcome improved in 17(40.5%) eyes, maintained in 21(50%) eyes but vision deterioration in 7(16.7%) eyes. CONCLUSIONS: HRCT chest is an important diagnostic tool to rule out pulmonary tuberculosis in Eales' disease. PMID- 28101724 TI - Drug-Drug Multicomponent Solid Forms: Cocrystal, Coamorphous and Eutectic of Three Poorly Soluble Antihypertensive Drugs Using Mechanochemical Approach. AB - The present study deals with the application of mechanochemical approach for the preparation of drug-drug multicomponent solid forms of three poorly soluble antihypertensive drugs (telmisartan, irbesartan and hydrochlorothiazide) using atenolol as a coformer. The resultant solid forms comprise of cocrystal (telmisartan-atenolol), coamorphous (irbesartan-atenolol) and eutectic (hydrochlorothiazide-atenolol). The study emphasizes that solid-state transformation of drug molecules into new forms is a result of the change in structural patterns, diminishing of dimers and creating new facile hydrogen bonding network based on structural resemblance. The propensity for heteromeric or homomeric interaction between two different drugs resulted into diverse solid forms (cocrystal/coamorphous/eutectics) and become one of the interesting aspects of this research work. Evaluation of these solid forms revealed an increase in solubility and dissolution leading to better antihypertensive activity in deoxycorticosterone acetate (DOCA) salt-induced animal model. Thus, development of these drug-drug multicomponent solid forms is a promising and viable approach to addressing the issue of poor solubility and could be of considerable interest in dual drug therapy for the treatment of hypertension. PMID- 28101725 TI - Sustained-Release Delivery System of a Slow Hydrogen Sulfide Donor, GYY 4137, for Potential Application in Glaucoma. AB - Hydrogen sulfide (H2S) targets both underlying factors in glaucoma pathogenesis by reducing elevated intraocular pressure (IOP) and providing retinal neuroprotection, whereas the current clinical approaches targets only reducing IOP. Therefore, H2S could be a potential superior candidate for glaucoma pharmacotherapy. However, H2S could be toxic in a concentration greater than 200 MUM and its donors are unstable in water. Therefore, this study investigated the preparation and characterization of a non-aqueous in situ gelling sustained release delivery system for H2S donors. The delivery system was prepared by dissolving GYY 4137, a H2S donor, in poly lactide-co-glycolide polymer (PLGA) (Resomer(r) RG 502H) solution prepared by dissolving polymer in a mixture of benzyl alcohol and benzyl benzoate in a ratio of 7:3, respectively. The GYY 4137 formulation was characterized for syringeability/injectability, change in pH and tonicity, moisture content, GYY 4137 degradation, and toxicity using rheometer, pH and osmometer, Karl Fisher titrimeter, NMR spectrometer, and Y79 retinoblastoma cells, respectively. The formulation was easily syringeable and injectable as evidenced by rheological data (plastic flow pattern with 43.89 +/- 3.21 cP viscosity and 1.12 +/- 0.15 Pa yield value). The pH, tonicity, and moisture content values were within acceptable range. NMR spectroscopy indicated presence of 4-methoxyphenylphosphonic acid (GYY 4137 degradation product). The GYY 4137 formulation did not show any significant (p < 0.05) toxicity except the solvent mixture. A sustained release of H2S was observed up to 72 h. The in situ gel forming PLGA-based system can be manipulated to achieve sustained release of H2S from its donor GYY 4137. PMID- 28101726 TI - Development of Timolol-Loaded Galactosylated Chitosan Nanoparticles and Evaluation of Their Potential for Ocular Drug Delivery. AB - This study was conducted to develop timolol maleate (TM)-loaded galactosylated chitosan (GC) nanoparticles (NPs) (TM-GC-NPs) followed by optimization via a four level and three-factor Box-Behnken statistical experimental design. The optimized nanoparticles showed a particle size of 213.3 +/- 6.83 nm with entrapment efficiency of 38.58 +/- 1.31% and drug loading of 17.72 +/- 0.28%. The NPs were characterized with respect to zeta potential, pH, surface morphology, and differential scanning calorimetry (DSC). The determination of the oil-water partition coefficient demonstrated that the TM-GC-NPs had a high liposolubility at pH 6 as compared to timolol-loaded chitosan nanoparticles (TM-CS-NPs) and commercial TM eye drops. The in vitro release study indicated that TM-GC-NPs had a sustained release effect compared with the commercial TM eye drops. Ocular tolerance was studied by the hen's egg chorioallantoic membrane (HET-CAM) assay and the formulation was non-irritant and could be used for ophthalmic drug delivery. The in vitro transcorneal permeation study and confocal microscopy showed enhanced penetration, and retention in the cornea was achieved with TM-GC NPs compared with the TM-CS-NPs and TM eye drops. Preocular retention study indicated that the retention of TM-GC-NPs was significantly longer than that of TM eye drops. The in vivo pharmacodynamic study suggested TM-GC-NPs had a better intraocular pressure (IOP) lowering efficacy and a prolonged working time compared to commercial TM eye drops (P <= 0.05). The optimized TM-GC-NPs could be prepared successfully promising their use as an ocular delivery system. PMID- 28101727 TI - Reliable prediction of adsorption isotherms via genetic algorithm molecular simulation. AB - Conventional molecular simulation techniques such as grand canonical Monte Carlo (GCMC) strictly rely on purely random search inside the simulation box for predicting the adsorption isotherms. This blind search is usually extremely time demanding for providing a faithful approximation of the real isotherm and in some cases may lead to non-optimal solutions. A novel approach is presented in this article which does not use any of the classical steps of the standard GCMC method, such as displacement, insertation, and removal. The new approach is based on the well-known genetic algorithm to find the optimal configuration for adsorption of any adsorbate on a structured adsorbent under prevailing pressure and temperature. The proposed approach considers the molecular simulation problem as a global optimization challenge. A detailed flow chart of our so-called genetic algorithm molecular simulation (GAMS) method is presented, which is entirely different from traditions molecular simulation approaches. Three real case studies (for adsorption of CO2 and H2 over various zeolites) are borrowed from literature to clearly illustrate the superior performances of the proposed method over the standard GCMC technique. For the present method, the average absolute values of percentage errors are around 11% (RHO-H2), 5% (CHA-CO2), and 16% (BEA-CO2), while they were about 70%, 15%, and 40% for the standard GCMC technique, respectively. PMID- 28101728 TI - Implementation of an evidence-based biobehavioral treatment for cancer patients. AB - One aim of dissemination and implementation (DI) research is to study the translation of evidence-based treatments (EBTs) from the research environments of their development and testing to broader communities where they are needed. There are few behavioral medicine DI studies and none in cancer survivorship. A determinant model (Setting, Therapist, Education, imPlementation, and Sustainability (STEPS)) was used to conceptualize DI of mental health treatment and frame a longitudinal study of implementation of a behavioral medicine EBT-a biobehavioral intervention (BBI) for cancer patients. Using effective dissemination strategies, therapists were trained in the BBI and followed to determine if implementation occurred. Participants (N = 108) were psychologists, social workers, and other oncology mental health providers from diverse settings to whom the BBI had been disseminated. BBI trainers then provided 6 months of support for implementation (e.g., monthly conference calls). Therapists reported number of patients treated, with or without the BBI, at 2, 4, and 6 months; use of support strategies was tracked. Generalized linear mixed models show that the proportion of patients treated with BBI ranged from 58 to 68%, with a 2% increase across follow-ups. Therapist and setting characteristics did not predict usage. Implementation of a behavioral medicine EBT provides a "real-world" demonstration of a BBI moved from the research setting to diverse communities. As the first study in cancer, it is an encouraging example of training and supporting mental health providers to deliver evidence-based psychological treatment and finding their success in doing so. PMID- 28101730 TI - Concepts for Studying Urban Environmental Justice. AB - PURPOSE OF REVIEW: This paper offers research frameworks for understanding and acting to address urban environmental justice. Urban neighborhoods tend to concentrate and colocate vulnerable people and toxic environments. Cities are also where the poor and people of color tend to be disproportionately exposed to environmental hazards, such as air pollution, lead in paint and water, and polluting industries. RECENT FINDINGS: Researchers and government agencies are increasingly recognizing the need to document cumulative exposures that the urban poor and people of color experience in addition to environmental hazards. These "toxic stressors" can exacerbate the health impacts of pollution exposures and include such social and economic factors as discrimination, racism, linguistic isolation, and political exclusion. Urban environmental justice research can benefit from a structural racism approach, which requires documenting the historical decisions, institutions, and policies that contribute to today's cumulative exposures. Key research frameworks and methods utilizing this approach for urban environmental justice include community-based participatory research, measuring cumulative stressors, and community-based asset and hazard mapping. PMID- 28101731 TI - Trompe l'oeil electrocardiogram. PMID- 28101729 TI - Air Pollution and Successful Aging: Recent Evidence and New Perspectives. AB - PURPOSE OF REVIEW: Worldwide demographic changes occurring in a relatively short period have led to a growing interest in the determinants of aging "successfully" and how to promote a healthier old age. As environmental exposures such as ambient air pollution are believed to play a role in the process of aging, they might represent one of the pathways turning potential successful agers to unsuccessful agers. We aimed to critically review the current epidemiological evidence of the associations between chronic exposure to ambient air pollution and several key determinants of unsuccessful aging and to identify specific populations of unsuccessful agers that are potentially more vulnerable to air pollution's health effects. RECENT FINDINGS: Epidemiologic evidence supports the association between air pollution and increased risk for several major chronic diseases, cognitive impairment, frailty, and decreased longevity-all important determinants of unsuccessful aging-as well as evidence for higher vulnerability among frail populations. However, several methodological shortcomings, including possible publication bias, lack of use of an adequate indicator of unsuccessful aging, limitations in exposure assessment, and residual confounding particularly due to socioeconomic status, hinder inference of causal relationship at this stage. Future studies should use constructs such as frailty index to estimate successful aging, as well as integrate time activity patterns into the exposure assessment metric. Additionally, studies in low- and middle-income countries are needed. PMID- 28101732 TI - The analysis of knee joint loading during drop landing from different heights and under different instruction sets in healthy males. AB - BACKGROUND: Mechanical loading during exercise has been shown to promote tissue remodeling. Safe and accessible exercise may be beneficial to populations at risk of diminished bone and joint health. We examined the effect of drop height and instruction on knee loading during a drop-landing task and proposed a task that makes use of drop heights that may be appropriate for rehabilitation purposes and functional in daily life to examine transient knee joint loads. METHODS: Twenty males (22.0 +/- 2.8 years) performed drop landings from 22 cm (low) and 44 cm (high) heights, each under three instructions: "land naturally" (natural), "softly" (soft), and "stiffly" (stiff). Knee compression force and external flexion moment were estimated using three-dimensional inverse dynamics and normalized to body mass. RESULTS: Peak knee compression force was larger (p < 0.001) for high (17.8 +/- 0.63 N/kg) than low (14.8 +/- 0.61 N/kg) heights. There was an increase (p < 0.001) in the knee compression force across soft (11.8 +/- 0.40 N/kg), natural (17.0 +/- 0.62 N/kg), and stiff (20.2 +/- 0.67 N/kg) instructions. Peak knee flexion moment in high-natural (2.12 +/- 0.08 Nm/kg) was larger (p < 0.001) than in high-soft (1.88 +/- 0.08 Nm/kg), but lower than in high-stiff (2.23 +/- 0.08 Nm/kg). No differences in peak knee flexion moment were observed across instructions for the low height. CONCLUSIONS: We propose a drop landing task that creates a scalable increase in knee compression loading. The absence of increased knee flexion moment with drop from the low height, compared to high, suggests that individuals could perform the task without incremental risk of knee injury. This task could be used in future studies to examine the effect of acute bouts of mechanical loading on bone and cartilage metabolism. PMID- 28101733 TI - 3D absorbed dose distribution estimated by Monte Carlo simulation in radionuclide therapy with a monoclonal antibody targeting synovial sarcoma. AB - BACKROUND: Radiolabeled OTSA101, a monoclonal antibody targeting synovial sarcoma (SS) developed by OncoTherapy Science, was used to treat relapsing SS metastases following a theranostic procedure: in case of significant 111In-OTSA101 tumor uptake and favorable biodistribution, patient was randomly treated with 370/1110 MBq 90Y-OTSA101. Monte Carlo-based 3D dosimetry integrating time-activity curves in VOI was performed on 111In-OTSA101 repeated SPECT/CT. Estimated absorbed doses (AD) in normal tissues were compared to biological side effects and to the admitted maximal tolerated absorbed dose (MTD) in normal organs. Results in the tumors were also compared to disease evolution. RESULTS: Biodistribution and tracer quantification were analyzed on repeated SPECT/CT acquisitions performed after injection of 111In-OTSA101 in 19/20 included patients. SPECT images were warped to a common coordinates system with deformable registration. Volumes of interest (VOI) for various lesions and normal tissues were drawn on the first CT acquisition and reported to all the SPECT images. Tracer quantification and residence time of 111In-OTSA101 in VOI were used to evaluate the estimated absorbed doses per MBq of 90Y-OTSA101 by means of Monte Carlo simulations (GATE). A visual scale analysis was applied to assess tumor uptake (grades 0 to 4) and results were compared to the automated quantification. Results were then compared to biological side effects reported in the selected patients treated with 90Y OTSA101 but also to disease response to treatment. After screening, 8/20 patients were treated with 370 or 1110 MBq 90Y-OTSA101. All demonstrated medullary toxicity, only one presented with transient grade 3 liver toxicity due to disease progression, and two patients presented with transient grade 1 renal toxicity. Median absorbed doses were the highest in the liver (median, 0.64 cGy/MBq; [0.27 1.07]) being far lower than the 20 Gy liver MTD, and the lowest in bone marrow (median, 0.09 cGy/MBq; [0.02 -0.18]) being closer to the 2 Gy bone marrow MTD. Most of the patients demonstrated progressive disease on RECIST criteria during patient follow-up. 111In-OTSA101 tumors tracer uptake visually appeared highly heterogeneous in inter- and intra-patient analyses, independently of tumor sizes, with variable kinetics. The majority of visual grades corresponded to the automated computed ones. Estimated absorbed doses in the 95 supra-centimetric selected lesions ranged from 0.01 to 0.71 cGy per injected MBq (median, 0.22 cGy/MBq). The maximal tumor AD obtained was 11.5 Gy. CONCLUSIONS: 3D dosimetry results can explain the observed toxicity and tumors response. Despite an intense visual 111In-OTSA101 liver uptake, liver toxicity was not the dose limiting factor conversely to bone marrow toxicity. Even though tumors 111In-OTSA101 avidity was visually obvious for treated patients, the low estimated tumors AD obtained by 3D dosimetry explain the lack of tumor response. PMID- 28101735 TI - Urethral carcinoma in situ: recognition and management. AB - PURPOSE: Urethral carcinoma in situ (CIS) is an uncommon malignancy that is poorly described in the published literature and is often under-recognized in the clinical setting. This short case series reports some challenges associated with the recognition and management of this disease. METHODS: A retrospective chart review was done over a 12-year period of patients presenting with urethral cancer to the Johns Hopkins Hospital. Four patients were identified with CIS of the anterior urethra, and their demographic and clinical data were recorded. RESULTS: Three patients presented with meatal lesions that were initially treated as infectious/inflammatory diseases before diagnoses of malignancy were determined following lesion biopsy. The fourth patient presented with painless hematuria and had a cystoscopy and biopsy of urethral polyps. All patients were treated surgically by sequential distal urethrectomy and various reconstructive procedures. Concurrent lymph node dissections were undertaken in two patients who had clinical or radiologic evidence of lymphadenopathy. One patient had persistent disease even after aggressive urethral resection, and he succumbed to his illness 2 years later. CONCLUSION: This is the largest series of urethral CIS, a disease with potentially serious consequences. A high index of suspicion should be maintained when evaluating and managing these patients. PMID- 28101736 TI - Diagnostic validity of ICDAS and DIAGNOdent combined: an in vitro study in pre cavitated lesions. AB - In a continuous process such as caries, it is important to possess criteria or instruments that allow the lesions to be diagnosed at early stages so that preventive or interceptive treatments can be applied before cavitation takes place. The present study seeks to assess the diagnostic efficacy of the International Caries Detection and Assessment System (ICDAS II) criteria and the DIAGNOdent laser fluorescence (LF) pen in occlusal caries lesions, using histological sections as the gold standard. Sixty-four permanent teeth were examined by two researchers who previously performed and calibrated both the ICDAS II criteria and the use of DIAGNOdent pen. The teeth were then cut into sections and observed under an optical microscope. The sensitivity values were 0.82 (ICDAS II) and 0.85 (LF). The specificity values were 1.00 (ICDAS II) and 0.53 (LF). The intraexaminer reproducibility was 0.892 for ICDAS II and 0.912 for the DIAGNOdent, so it was high for both diagnostic methods. However, the DIAGNOdent pen showed greater sensitivity and the ICDAS criteria more specificity. It was concluded that both methods are efficacious individually but combining the two is recommended to improve the diagnosis. PMID- 28101737 TI - Spatholobus suberectus Dunn. constituents inhibit sortase A and Staphylococcus aureus cell clumping to fibrinogen. AB - Sortases are a family of Gram-positive transpeptidases responsible for anchoring surface protein virulence factors to the peptidoglycan cell wall layer. In Staphylococcus aureus (S. aureus), deletion of sortase isoform results in a significant reduction in virulence and infection potential. Twenty flavonoids were isolated from the stem of the folk medicinal plant Spatholobus suberectus Dunn. These compounds were tested against S. aureus-derived sortase A (SrtA), a key transpeptidase for bacterial virulence. Among these active flavonoids, 7 hydroxy-6-methoxy-flavanone (3) and formononetin (10) were identified as compounds with promising SrtA inhibitory activity. These compounds also exhibited inhibitory activity against S. aureus cell clumping to fibrinogen. The suppression of cell-clumping activity indicates the potential of these compounds in the treatment of S. aureus infections via the inhibition of SrtA. PMID- 28101738 TI - Synthesis of novel oleanolic acid and ursolic acid in C-28 position derivatives as potential anticancer agents. AB - A series of nitrogen-containing derivatives of oleanolic acid and ursolic acid were prepared by a modification at C-28 position via esterification with 2 hydroxyacetic acid followed by amidation with amines, such as piperazine, N methylpiperazine, and alkane-1, 2-diamines, alkane-1, 4-diamines, alkane-1, 6 diamines. In vitro antiproliferative activities of the compounds prepared towards MCF-7, Hela and A549 cell lines were evaluated by a MTT method to show that OA 5a, OA-5b, OA-5c and UA-5a showed somewhat improved antiproliferative activities against MCF-7, Hela and A549 cells comparing to that of the positive control, gefitinib. PMID- 28101739 TI - Inhalation dose due to radon, thoron, and progenies in dwellings of a hill station. AB - The general public spends a major portion of their time in an indoor environment and hence receives a considerable amount of radiation. Knowledge about indoor radiation is important in order to arrive at the actual effective dose received by residents. The indoor radon, thoron, and progeny concentrations observed in the present study were found to vary with seasons of a given year. The highest and lowest indoor average radon, thoron, and progeny levels were observed during winter and summer seasons, respectively. The concentrations of indoor radon, thoron, and progenies were found to vary with the type of houses. The highest 222Rn, 220Rn, and progeny concentrations were observed in mud houses and the lowest values were recorded in wooden houses. The indoor 222Rn concentration correlated well with concentration of its grandparent 238U in underlying soil with a correlation coefficient of 0.87. The correlation between indoor 220Rn and 232Th in the underlying soil was found to be 0.64. The estimated effective doses received by the general public in the present study due to indoor radon and thoron were 1.49 +/- 0.49 and 1.30 +/- 0.53 mSv/year, respectively. The annual effective doses due to radon and thoron progenies were estimated as 0.76 +/- 0.27 and 0.47 +/- 0.23 mSv/year, respectively. The contributions from 222Rn, 220Rn, and corresponding progenies to the annual effective doses received were 37, 32, 19, and 12%, respectively. The general public living in the study area receives an inhalation dose of 4.02 mSv/year due to indoor radon, thoron, and progenies, which were found to be less than the action limit of ICRP 2009. PMID- 28101734 TI - Chondroitin sulfates and their binding molecules in the central nervous system. AB - Chondroitin sulfate (CS) is the most abundant glycosaminoglycan (GAG) in the central nervous system (CNS) matrix. Its sulfation and epimerization patterns give rise to different forms of CS, which enables it to interact specifically and with a significant affinity with various signalling molecules in the matrix including growth factors, receptors and guidance molecules. These interactions control numerous biological and pathological processes, during development and in adulthood. In this review, we describe the specific interactions of different families of proteins involved in various physiological and cognitive mechanisms with CSs in CNS matrix. A better understanding of these interactions could promote a development of inhibitors to treat neurodegenerative diseases. PMID- 28101740 TI - Improving Parameter Inference from FRAP Data: an Analysis Motivated by Pattern Formation in the Drosophila Wing Disc. AB - Fluorescence recovery after photobleaching (FRAP) is used to obtain quantitative information about molecular diffusion and binding kinetics at both cell and tissue levels of organization. FRAP models have been proposed to estimate the diffusion coefficients and binding kinetic parameters of species for a variety of biological systems and experimental settings. However, it is not clear what the connection among the diverse parameter estimates from different models of the same system is, whether the assumptions made in the model are appropriate, and what the qualities of the estimates are. Here we propose a new approach to investigate the discrepancies between parameters estimated from different models. We use a theoretical model to simulate the dynamics of a FRAP experiment and generate the data that are used in various recovery models to estimate the corresponding parameters. By postulating a recovery model identical to the theoretical model, we first establish that the appropriate choice of observation time can significantly improve the quality of estimates, especially when the diffusion and binding kinetics are not well balanced, in a sense made precise later. Secondly, we find that changing the balance between diffusion and binding kinetics by changing the size of the bleaching region, which gives rise to different FRAP curves, provides a priori knowledge of diffusion and binding kinetics, which is important for model formulation. We also show that the use of the spatial information in FRAP provides better parameter estimation. By varying the recovery model from a fixed theoretical model, we show that a simplified recovery model can adequately describe the FRAP process in some circumstances and establish the relationship between parameters in the theoretical model and those in the recovery model. We then analyze an example in which the data are generated with a model of intermediate complexity and the parameters are estimated using models of greater or less complexity, and show how sensitivity analysis can be used to improve FRAP model formulation. Lastly, we show how sophisticated global sensitivity analysis can be used to detect over-fitting when using a model that is too complex. PMID- 28101741 TI - Anti-hyperuricemic effect of taxifolin in cultured hepatocytes and model mice. AB - Hyperuricemia is recognized as an important risk factor for gout. High dietary intake of purine-rich foods such as meats and sea foods increases uric acid (UA) levels in the blood. Taxifolin present in Siberian larch and strawberries has been reported to possess health promoting activities including anti-oxidant effect. In this study, we examined anti-hyperuricemic effect of taxifolin in both cultured hepatocytes and hyperuricemic model mice. In cultured AML12 hepatocytes, taxifolin significantly suppressed UA production dose- and time-dependently. In mice with hyperuricemia induced by concurrent administration of guanosine-5' monophosphate and inosine-5'-monophosphate, oral administration of taxifolin suppressed the increases in plasma and liver UA levels. In addition, it also suppressed hepatic xanthine oxidase (XO) activity. Thus, anti-hyperuricemic effect of taxifolin could be explained, at least partly, by suppressing UA production via inhibition of XO activity in the liver. These results suggest that taxifolin possesses a potent hypouricemic effect and it could be a potential candidate for an anti-hyperuricemic phytochemical. PMID- 28101742 TI - Melatonin as an Agent for Cardioprotection in Patients with ST-Elevation Myocardial Infarction and Short Ischaemic Time. PMID- 28101743 TI - Imaging of cardiac sympathetic activity in heart failure: Not out of the woods yet. PMID- 28101744 TI - Cardiovascular testing in patients with postural orthostatic tachycardia syndrome and Ehlers-Danlos syndrome type III. PMID- 28101746 TI - Music Preferences, Friendship, and Externalizing Behavior in Early Adolescence: A SIENA Examination of the Music Marker Theory Using the SNARE Study. AB - Music Marker Theory posits that music is relevant for the structuring of peer groups and that rock, urban, or dance music preferences relate to externalizing behavior. The present study tested these hypotheses, by investigating the role of music preference similarity in friendship selection and the development of externalizing behavior, while taking the effects of friends' externalizing behavior into account. Data were used from the first three waves of the SNARE (Social Network Analysis of Risk behavior in Early adolescence) study (N = 1144; 50% boys; M age = 12.7; SD = 0.47), including students who entered the first-year of secondary school. Two hypotheses were tested. First, adolescents were expected to select friends based both on a similarity in externalizing behavior and music genre preference. Second, a preference for rock, urban, or dance, music types was expected to predict the development of externalizing behavior, even when taking friends' influence on externalizing behavior into account. Stochastic Actor-Based Modeling indicated that adolescents select their friends based on both externalizing behavior and highbrow music preference. Moreover, both friends' externalizing behavior and a preference for dance music predicted the development of externalizing behavior. Intervention programs might focus on adolescents with dance music preferences. PMID- 28101745 TI - Emotional Awareness in Depressive and Anxiety Symptoms in Youth: A Meta-Analytic Review. AB - Emotion regulation is assumed to play an important role in depressive and anxiety symptoms in youth. However, the role of core components of emotion regulation, such as emotional awareness, is not well understood so far. Thus this meta analysis aimed to examine the relationship between depressive and anxiety symptoms with emotional awareness in youth. A systematic literature search (PsycINFO, Medline, Google Scholar) identified 21 studies, from which 34 effect sizes were extracted. Results from random effects models showed that difficulties in emotional awareness were significantly correlated with a medium effect size for each, depressive and anxiety symptoms separately, and for their combined effects (overall outcome). Additionally, further analyses revealed that age was a significant moderator of the relationship between emotional awareness with depressive and anxiety symptoms, with younger samples (mean age <= 12 years) showing a stronger association between difficulties in emotional awareness and depressive and anxiety symptoms as compared to older samples (mean age > 12 years). The results suggest that emotional awareness may be of relevance for depressive and anxiety symptoms in youth. Future work is required to examine longitudinal developments, moderators, and mediators in multi-method approaches. Moreover, children and adolescents may benefit from interventions that aim to enhance emotional awareness. PMID- 28101747 TI - Adolescents' Conflict Management Styles with Mothers: Longitudinal Associations with Parenting and Reactance. AB - Adolescents' conflict management styles with parents are assumed to have an important impact on the quality of the parent-adolescent relationship and on adolescents' psychosocial development. Longitudinal research investigating possible determinants of these conflict management skills is scarce. The parenting context and adolescents' tendency to reject maternal authority are expected to shape adolescents' conflict management styles. Therefore, the present three-wave longitudinal study focuses on how parenting and adolescents' reactance relates to adolescents' conflict management styles and conflict frequency with mothers over time, and whether reactance may also explain the associations between parenting and certain conflict variables. We addressed these research questions by using a hybrid cross-lagged panel model with parenting as a latent variable (i.e., supportive parenting) and the other variables as manifest variables. Supportive parenting was measured by four well-known parenting dimensions: autonomy support, responsiveness, psychological control, and harsh control. Four conflict styles were investigated: positive problem solving, withdrawal, conflict engagement, and compliance. Questionnaires were completed by 812 adolescents at three annual waves (52% girls at Time 1). Supportive parenting was associated with fewer conflicts, more positive problem solving, and less compliance and reactance over time. Reactance was associated with more conflicts, conflict engagement and withdrawal, and less compliance. We did not find evidence for the mediating role of reactance in the over-time associations between parenting and adolescents' conflict management and frequency. Both parenting and reactance appeared important and unique determinants for adolescents' conflict management styles and frequency. PMID- 28101748 TI - Romantic Attachment, Conflict Resolution Styles, and Teen Dating Violence Victimization. AB - Although research on dating violence has increased in the last decades, little is known about the role of romantic attachment and conflict resolution in understanding victimization by an intimate partner among adolescents. This study examined the relationships between insecure attachment styles, destructive conflict resolution strategies, self-reported and perceived in the partner, and psychological and physical victimization by a dating partner in 1298 adolescents (49% girls). Anxious attachment was related to both forms of victimization via self-reported conflict engagement and conflict engagement attributed to the partner among boys and girls. Moreover, both insecure attachment styles were also indirectly linked to victimization via self-reported withdrawal and conflict engagement perceived in the partner, but only among boys. The implications of the findings for promoting constructive communication patterns among adolescents for handling their relationship conflicts are discussed. PMID- 28101749 TI - Twenty-seven Years of Cerebral Pyruvate Recycling. AB - Cerebral pyruvate recycling is a metabolic pathway deriving carbon skeletons and reducing equivalents from mitochondrial oxaloacetate and malate, to the synthesis of mitochondrial and cytosolic pyruvate, lactate and alanine. The pathway allows both, to provide the tricarboxylic acid cycle with pyruvate molecules produced from alternative substrates to glucose and, to generate reducing equivalents necessary for the operation of NADPH requiring processes. At the cellular level, pyruvate recycling involves the activity of malic enzyme, or the combined activities of phosphoenolpyruvate carboxykinase and pyruvate kinase, as well as of those transporters of the inner mitochondrial membrane exchanging the corresponding intermediates. Its cellular localization between the neuronal or astrocytic compartments of the in vivo brain has been controversial, with evidences favoring either a primarily neuronal or glial localizations, more recently accepted to occur in both environments. This review provides a brief history on the detection and characterization of the pathway, its relations with the early developments of cerebral high resolution 13C NMR, and its potential neuroprotective functions under hypoglycemic conditions or ischemic redox stress. PMID- 28101751 TI - Fatal disseminated neonatal herpes simplex virus type 1 infection in neonates in a forensic setting. PMID- 28101750 TI - Mortuary operations following mass fatality natural disasters: a review. AB - This is a critical review to discuss the best practice approaches to mortuary operations in preparation for and the response to natural, mass fatality, disaster events, as identified by a review of published articles. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) Statement guided the identification of potential articles to use in this critical review. Subsequent searches were also conducted to identify articles relating to heat wave, and flood mortality. All identified peer-reviewed studies published in English which discussed the preparation and response of mortuaries to mass fatality natural disasters occurring in developed countries were included. Using the PRISMA-P method of identifying articles, 18 articles were selected for inclusion in this review. Although there are numerous articles which describe the mortuary response to mass fatality incidents, few articles analyzed the response, or discussed the roles which supported and enabled the organization to undertake the task of identifying disaster victims. It is thus difficult to determine objectively if the actions and activities outlined in the articles represent best practice. PMID- 28101752 TI - The impact of hydrocortisone treatment on neutrophil gelatinase-associated lipocalin release in porcine endotoxemic shock. AB - BACKGROUND: A key feature of sepsis is systemic inflammatory activation that could be counteracted by steroids. In this experimental model of systemic inflammation, we sought to investigate whether septic neutrophil activation, evaluated by the plasma levels of neutrophil gelatinase-associated protein (NGAL), is modulated by the timing of hydrocortisone treatment. METHODS: Sixteen anesthetized pigs were allocated to one of four equally sized groups. Three of these groups received endotoxin at 2 MUg * kg-1 * h-1 for 6 h so as to induce endotoxemic shock. Hydrocortisone (5 mg * kg-1) was administered intravenously before endotoxemic challenge, or at the onset of endotoxemic shock. Endotoxemic pigs not receiving hydrocortisone and non-endotoxemic pigs served as control groups. Physiologic variables, hematology, and biochemistry, including plasma NGAL, were measured repeatedly. RESULTS: Hydrocortisone treatment prior to endotoxemia attenuated some inflammatory, hematological, circulatory, and metabolic manifestations of shock (i.e., higher white blood cell count, higher mean arterial pressure, lower heart rate and mean pulmonary arterial pressure, higher left ventricular stroke work index, higher base excess). Endotoxemic shock increased plasma NGAL (p < 0.001). In pigs given hydrocortisone before the endotoxin infusion, plasma NGAL was lower as compared to those given hydrocortisone at endotoxemic shock (p < 0.05). Plasma NGAL levels correlated inversely to neutrophil granulocyte counts (rho = -0.65) but not to urine output (rho = -0.10) at the end of the experiment. CONCLUSIONS: The increase in plasma NGAL is counteracted by hydrocortisone administration prior to endotoxemia; concomitantly, this treatment was associated with less expressed circulatory derangement. Urine NGAL did not differ between the groups, suggesting that the NGAL response was not primarily related to kidney injury. PMID- 28101753 TI - Effect and safety of paroxetine combined with zolpidem in treatment of primary insomnia. AB - PURPOSE: Primary insomnia is a persistent and recurrent disorder as well as a risk factor for depression. The aim of this study was to determine whether the zolpidem combined with paroxetine would be effective in the treatment of patients with primary insomnia. METHODS: Ninety patients meeting DSM-IV criteria for primary insomnia were randomly assigned to 8 weeks of treatment with zolpidem combined with paroxetine (the combined treatment group, n = 45) or zolpidem combined with placebo (the control group, n = 45). Patients were assessed with the Pittsburgh Sleep Quality Index (PSQI), polysomnography (PSG), and the Treatment Emergent Symptom Scale (TESS). RESULTS: Compared with the control group, the combined treatment group was more significantly improved on wake time after sleep onset (WASO), total sleep time (TST), sleep efficiency (SE), and total PSQI scores, but not the sleep onset latency (SOL). CONCLUSIONS: Eight weeks of the zolpidem combined with paroxetine treatment to patients with primary insomnia is more effective than zolpidem treatment only in sleep maintenance and early morning awakenings. PMID- 28101754 TI - Editor's Spotlight/Take 5: What Does a Shoulder MRI Cost the Consumer? PMID- 28101756 TI - Your Best Life: Dealing with Loss. PMID- 28101755 TI - Does N-terminal Pro-brain Type Natriuretic Peptide Predict Cardiac Complications After Hip Fracture Surgery? AB - BACKGROUND: Elderly patients with hip fracture are at risk for cardiac complications. N-terminal pro-brain type natriuretic peptide (NT-proBNP) has been shown to predict cardiac complications in surgical patients; however, to our knowledge, only two studies have evaluated the utility of this test in patients with hip fracture. We believe it is important to assess a more accurate cutoff value of NT-proBNP with exclusion of patients with renal failure. QUESTIONS/PURPOSES: To assess the association between preoperative NT-proBNP and cardiac complications after hip fracture surgery. METHODS: We performed 450 surgical procedures in patients with hip fractures between January 2011 and December 2014. Exclusion criteria were renal dysfunction and inadequate laboratory tests. The final study population consisted of 328 patients (mean age, 83 years; 80% women). Preoperatively, measurement of NT-proBNP level was performed. The primary endpoint was the occurrence of cardiac complications within 14 days after surgery based on a chart review. The predictive value of NT proBNP was assessed using multivariate logistic regression analysis, controlling for relevant confounding variables such as age, gender, body weight, and renal function; we also performed receiver operating characteristic (ROC) curve analysis. Postoperative cardiac complications were encountered in 7% of patients (24 of 328). RESULTS: The median preoperative NT-proBNP level was higher in patients with complications than in those without (1090 [interquartile range, 614 3191 pg/mL] vs 283 pg/mL [interquartile range, 137-507 pg/mL], p < 0.001). The cutoff level of NT-proBNP determined by ROC curve analysis was 600 pg/mL, with a sensitivity, specificity, positive predictive value, and negative predictive value of 79%, 81%, 25%, and 98%, respectively, and the area under the ROC curve was 0.87 (95% CI, 0.80-0.94; p < 0.001). After controlling for potentially relevant confounding variables, we found a preoperative NT-proBNP greater than 600 pg/mL was associated with an increased risk of cardiac complications (odds ratio, 13; 95% CI, 4-38; p < 0.001) compared with those with NT-proBNP less than 600 pg/mL. CONCLUSIONS: Preoperative NT-proBNP greater than 600 pg/mL is independently associated with postoperative cardiac complications in patients with hip fracture without renal dysfunction. NT-proBNP measurement provides additional information and is clinically useful for predicting cardiac complications during the early phase after hip fracture surgery. Future studies might develop a simple index for prediction of postoperative cardiac complication including cutoff values of NT-proBNP. LEVEL OF EVIDENCE: Level III, diagnostic study. PMID- 28101758 TI - Applying Collaborative Learning and Quality Improvement to Public Health: Lessons from the Collaborative Improvement and Innovation Network (CoIIN) to Reduce Infant Mortality. AB - OBJECTIVES: Infant mortality remains a significant public health problem in the U.S. The Collaborative Improvement & Innovation Network (CoIIN) model is an innovative approach, using the science of quality improvement and collaborative learning, which was applied across 13 Southern states in Public Health Regions IV and VI to reduce infant mortality and improve birth outcomes. We provide an in depth discussion of the history, development, implementation, and adaptation of the model based on the experience of the original CoIIN organizers and participants. In addition to the political genesis and functional components of the initiative, 8 key lessons related to staffing, planning, and implementing future CoIINs are described in detail. METHODS: This paper reports the findings from a process evaluation of the model. Data on the states' progress toward reducing infant mortality and improving birth outcomes were collected through a survey in the final months of a 24-month implementation period, as well as through ongoing team communications. RESULTS: The peer-to-peer exchange and platform for collaborative learning, as well as the sharing of data across the states, were major strengths and form the foundation for future CoIIN efforts. A lasting legacy of the initiative is the unique application and sharing of provisional "real time" data to inform "real time" decision-making. CONCLUSION: The CoIIN model of collaborative learning, QI, and innovation offers a promising approach to strengthening partnerships within and across states, bolstering data systems to inform and track progress more rapidly, and ultimately accelerating improvement toward healthier communities, States, and the Nation as a whole. PMID- 28101757 TI - Final report of KSCC0803: feasibility study of capecitabine as adjuvant chemotherapy for stage III colon cancer in Japan. AB - BACKGROUND: The impact of oral capecitabine as adjuvant chemotherapy for Japanese patients with resected colon cancer was unclear. We previously planned and conducted a prospective feasibility study (KSCC0803) and reported on the safety of oral capecitabine as adjuvant chemotherapy for Japanese patients with resected stage III colon cancer. The purpose of the current study was to assess the survival results from that study. METHODS: The study subjects were Japanese patients with resected stage III colon cancer. The protocol adjuvant regimen consisted of oral capecitabine 1250 mg/m2 twice daily on days 1-14 of a 3-week cycle for a total of eight cycles. The 3- and 5-year disease free survival (DFS) rates and overall survival (OS) rates were analyzed in the eligible cohort. RESULTS: Ninety-seven patients were registered between September 2008 and August 2009 and treated with the protocol regimen. The median follow-up time was 60.7 months. The 3- and 5-year DFS rates were 71.2% [95% confidence interval (CI): 61.7-79.8%] and 69.7% (95% CI: 59.4-77.8%), respectively. The 3- and 5-year OS rates were 92.6% (95% CI: 85.2-96.4%) and 84.5% (95% CI: 75.1-90.5%), respectively. CONCLUSIONS: The survival results in this study are in line with those of previously reported, reliable, studies. The safety and tolerability of the protocol regimen have already been confirmed. Oral capecitabine is acceptable as adjuvant chemotherapy for Japanese patients with resected stage III colon cancer. PMID- 28101759 TI - Trends in Modification of Smoking Behaviors Among Pregnant Women in West Virginia. AB - Background Rates of smoking among pregnant women in West Virginia are higher than national prenatal smoking rates. Recent research has pointed to the benefit of smoking reduction among a sample of pregnant women who participated in a clinical study in West Virginia. The purpose of the current study is to examine trends associated with reduced smoking exposure among a representative sample of pregnant women in the state. Method Secondary data analysis was conducted using de-identified weighted PRAMS 2005-2010 data from West Virginia examining factors associated with favorable change in prenatal smoking behavior, either quitting or reducing smoking in pregnancy. Results Multivariable analyses results demonstrate that pregnant women are more likely to engage in a favorable smoking behavior change if they were younger (<35 years of age), were primiparous, and had a higher level of education. Discussion Findings from the study identified factors that contribute to women's likelihood of quitting or reducing smoking in pregnancy in West Virginia. Health care providers and policy makers should consider these factors in implementing approaches that will be effective in promoting smoking cessation and reduction among pregnant women in the state thereby reducing prenatal smoking exposure. Conclusion Population-based research has been used to identify factors associated with smoking cessation or reduction that can be used to develop appropriate and effective approaches to modifying health behaviors in specific populations. PMID- 28101760 TI - A CAD of fully automated colonic polyp detection for contrasted and non contrasted CT scans. AB - PURPOSE: Computer-aided detection (CAD) systems are developed to help radiologists detect colonic polyps over CT scans. It is possible to reduce the detection time and increase the detection accuracy rates by using CAD systems. In this paper, we aimed to develop a fully integrated CAD system for automated detection of polyps that yields a high polyp detection rate with a reasonable number of false positives. METHODS: The proposed CAD system is a multistage implementation whose main components are: automatic colon segmentation, candidate detection, feature extraction and classification. The first element of the algorithm includes a discrete segmentation for both air and fluid regions. Colon air regions were determined based on adaptive thresholding, and the volume/length measure was used to detect air regions. To extract the colon-fluid regions, a rule-based connectivity test was used to detect the regions belong to the colon. Potential polyp candidates were detected based on the 3D Laplacian of Gaussian filter. The geometrical features were used to reduce false-positive detections. A 2D projection image was generated to extract discriminative features as the inputs of an artificial neural network classifier. RESULTS: Our CAD system performs at 100% sensitivity for polyps larger than 9 mm, 95.83% sensitivity for polyps 6-10 mm and 85.71% sensitivity for polyps smaller than 6 mm with 5.3 false positives per dataset. Also, clinically relevant polyps ([Formula: see text]6 mm) were identified with 96.67% sensitivity at 1.12 FP/dataset. CONCLUSIONS: To the best of our knowledge, the novel polyp candidate detection system which determines polyp candidates with LoG filters is one of the main contributions. We also propose a new 2D projection image calculation scheme to determine the distinctive features. We believe that our CAD system is highly effective for assisting radiologist interpreting CT. PMID- 28101761 TI - The SG13S114 polymorphism of the ALOX5AP gene is associated with ischemic stroke in Europeans: a meta-analysis of 8062 subjects. AB - The association between ALOX5AP SG13S114 polymorphism and ischemic stroke (IS) susceptibility has extensively been investigated, especially in white populations; however, the results were inconclusive. Here, we perform a meta analysis to clarify the effect of SG13S114 variant on the IS risk in Europeans. The Web of Science, PubMed, EMBASE, and Medline were searched up to August 1st, 2016. Data were extracted and the odd ratios (ORs) and 95% confidence intervals (CIs) were calculated by a fixed-effects or random-effects model. In total, 8 case control studies involved 8062 subjects were finally included in this meta analysis. We observed a significantly decreased IS risk in persons carrying an A allele at the SG13S114 polymorphism compared with those with a T allele (A vs T, OR = 0.856, 95% CI = 0.797-0.919, p < 0.001). In addition, the results of sensitivity and cumulative meta-analysis indicated the robustness of our results. In addition, the publication bias was not detected using the funnel plot and Egger's tests. In summary, the present meta-analysis suggested that the A allele at the ALOX5AP SG13S114 polymorphism is a protective factor for the IS in the Europeans. In addition, further studies with large sample size are needed to validate the association, as well as in other ethnic groups. PMID- 28101762 TI - Neuropsychological assessment in migraine patients: a descriptive review on cognitive implications. AB - Migraine is considered a disabling disorder with highly prevalence in population. Recent studies report that migraine patients have a cognitive decline associated to structural brain alterations. We search on PubMed and Web of Science databases and screening references of included studies and review articles for additional citations. From 519 studies identified, only 16 met the inclusion criteria. All studies were conducted on 1479 migraineurs (190 non-migraine headache and 11,978 controls subject) and examined the association between migraine and cognitive impairment. The results are discordant. Indeed, while cognitive deficits during the attack of migraine are now recognized, only few studies confirmed the presence of cognitive impairment in migraine patients. Given the prevalence of migraine in the population (especially among women), and the early age of the population, an association between migraine and cognitive impairment could have substantial public health implications. Future studies should determine if specific migraine characteristics, for example, attack frequency, may impact the association between migraine and cognitive decline. PMID- 28101763 TI - MiR-126 Affects Brain-Heart Interaction after Cerebral Ischemic Stroke. AB - Cardiovascular diseases are approximately three times higher in patients with neurological deficits than in patients without neurological deficits. MicroRNA 126 (MiR-126) facilitates vascular remodeling and decreases fibrosis and is emerging as an important factor in the pathogenesis of cardiovascular diseases and cerebral stroke. In this study, we tested the hypothesis that decreased miR 126 after ischemic stroke may play an important role in regulating cardiac function. Wild-type (WT), specific conditional-knockout endothelial cell miR-126 (miR-126EC-/-), and miR-126 knockout control (miR-126fl/fl) mice were subjected to distal middle cerebral artery occlusion (dMCAo) (n = 10/group). Cardiac hemodynamics and function were measured using transthoracic Doppler echocardiography. Mice were sacrificed at 28 days after dMCAo. WT mice subjected to stroke exhibited significantly decreased cardiac ejection fraction and increased myocyte hypertrophy, fibrosis as well as increased heart inflammation, infiltrating macrophages, and oxidative stress compared to non-stroke animals. Stroke significantly decreased serum and heart miR-126 expression and increased miR-126 target genes, vascular cell adhesion protein-1, and monocyte chemotactic protein-1 gene, and protein expression in the heart compared to non-stroke mice. MiR-126EC-/- mice exhibited significantly decreased cardiac function and increased cardiomyocyte hypertrophy, fibrosis, and inflammatory factor expression after stroke compared to miR-126fl/fl stroke mice. Exosomes derived from endothelial cells of miR-126EC-/- (miR-126EC-/-EC-Exo) mice exhibited significantly decreased miR-126 expression than exosomes derived from miR 126fl/fl (miR-126fl/fl-EC-Exo) mice. Treatment of cardiomyocytes subjected to oxygen glucose deprivation with miR-126fl/fl-EC-Exo exhibited significantly decreased hypertrophy than with miR-126EC-/-EC-Exo treatment. Ischemic stroke directly induces cardiac dysfunction. Decreasing miR-126 expression may contribute to cardiac dysfunction after stroke in mice. PMID- 28101764 TI - Diazepam in the Treatment of Moderate to Severe Alcohol Withdrawal. AB - Benzodiazepines ameliorate or prevent the symptoms and complications of moderate to severe alcohol withdrawal, which can include autonomic hyperactivity, agitation, combativeness, hallucinations, seizures, delirium, and death. The benzodiazepines most commonly used for this purpose are lorazepam, chlordiazepoxide, oxazepam, and diazepam. It is widely asserted that no member of this group is superior to the others for treatment of alcohol withdrawal. However, of these, diazepam has the shortest time to peak effect, which facilitates both rapid control of symptoms and accurate titration to avoid over sedation. Furthermore, diazepam and its active metabolite, desmethyldiazepam, have the longest elimination half-lives, so their levels decrease in a gradual, self-tapering manner, resulting in a smoother withdrawal, i.e., a lower incidence and severity of both breakthrough symptoms and rebound phenomena, including a possibly decreased seizure risk. Importantly, the fear of increased risk of over sedation with diazepam compared with other benzodiazepines is based on a misunderstanding of its pharmacokinetics and is unfounded. Similarly, the notion that diazepam should be avoided in patients with liver disease and elderly patients to avoid prolonged over-sedation is based on no more than conjecture. In fact, there is clinical evidence that diazepam is safe for the treatment of alcohol withdrawal in these patients when administered using a simple symptom based approach. There is one instance in which diazepam should not be used: when intramuscular administration is the only option, the lipophilicity of diazepam can result in slow absorption-either lorazepam or, when rapid control of symptoms is required, midazolam should be used. The comparative pharmacokinetics of the benzodiazepines used in the treatment of alcohol withdrawal together with a comprehensive review of the literature on their use strongly suggest that diazepam should be the preferred benzodiazepine for the treatment of patients experiencing moderate to severe alcohol withdrawal under most circumstances. PMID- 28101767 TI - Being Human. PMID- 28101765 TI - Tolerability and Safety of Commonly Used Antiepileptic Drugs in Adolescents and Adults: A Clinician's Overview. AB - This paper discusses the issues surrounding the tolerability and safety of the commonly used antiepileptic drugs (AEDs) in adolescents and adults. The content includes dose-related adverse effects, idiosyncratic reactions, behavioural and psychiatric comorbidities, chronic problems, enzyme induction and teratogenesis. Twenty-one AEDs are discussed in chronological order of their introduction into the UK, starting with phenobarbital and ending with brivaracetam. Wherever possible, advice is given on anticipating, recognising and managing these issues and thereby improving the lives of people with epilepsy, most of whom will need to take one or more of these agents for life. Avoidance of side effects will increase the possibility of achieving and maintaining long-term seizure freedom. Alternatively, adverse events from AEDs will substantially reduce quality of life and often result in higher healthcare costs. PMID- 28101768 TI - Gender Diversity in Childhood: A Human Right. PMID- 28101769 TI - Childhood absence epilepsy and benign epilepsy with centro-temporal spikes: a narrative review analysis. AB - BACKGROUND: Recent studies have shown a possible coexistence of absence seizures with other forms of epilepsy. The purpose of this study was to ascertain the possible contemporary or subsequent presence of childhood absence epilepsy (CAE) and benign epilepsy with centro-temporal spikes (BECTS) in pediatric epileptic patients. DATA SOURCES: A PubMed systematic search indexed for MEDLINE, PubMed and EMBASE was undertaken to identify studies in children including articles written between 1996 and 2015. Retrospective studies, meta-analysis and case reports were included. The list of references of all the relevant articles was also studied. The date of our last search was December 2015. RESULTS: Review of the literature revealed 19 cases, 8 females and 11 males, reporting a consecutive or contemporary coexistence of CAE and BECTS within the same patients. Patient's age ranged between 4 and 12 years. Three out of 19 patients presented concomitant features of both syndromes, whereas 16 patients experienced the two syndromes at different times. CONCLUSIONS: BECTS and CAE may be pathophysiologically related, and the two epileptic phenotypes may indicate a neurobiological continuum. Further studies are needed to elucidate a probable genetic or functional link between partial and primarily generalized electro-clinical patterns in idiopathic childhood epilepsies. PMID- 28101770 TI - Factors controlling fetal echocardiography determine the diagnostic accuracy of isolated ventricular septal defect. AB - BACKGROUND: Fetal echocardiography (FECG) is a key screening tool for prenatal cardiac abnormalities. Herein, we examined the ultrasonic factors determining prenatal ultrasonic diagnosis of isolated ventricular septal defect (IVSD). METHODS: The diagnostic role of ultrasonic factors was investigated in patients in middle or late pregnancy, diagnosed with IVSD by FECG and confirmed using postnatal echocardiography. RESULTS: One hundred and six patients with IVSD were enrolled; the majority had perimembranous VSD. The combined imaging mode of 2 dimentional-echocardiography (2DE) and color doppler flow imaging (CDFI) showed the highest rate (56.6%) of IVSD detection, while CDFIwas more efficient than 2DE (32.1% vs. 11.3%). The single-view mode was more efficient than multiple-view mode (75.5% vs. 24.5%). The highest efficient mode to detect IVSD was achieved using combined imaging mode on the single view of the left ventricular outflow tract view (LVOTV) (28.3%). FECG correctly classified 71.7% of fetal IVSD. There was a significant difference of accuracy rate in classifying IVSD among the three different imaging modes (chi 2=7.141, P<0.05). The single imaging mode of CDFIand the mode of CDFIcombined with 2DE correctly classified 75.9% and 75.0% of fetal IVSD, respectively. LVOTV was the most accurate view of fetal IVSD classification (85.2%; chi 2=15.782, P<0.05). There was no difference in accuracies of IVSD classification among multiple-view modes (chi 2=2.343, P>0.05) or between single view mode and multiple-view mode (chi 2=0.32, P>0.05). CONCLUSION: Single LVOTV in CDFIor CDFIcombined with 2DE of FECG were the most effective diagnostic modes for fetal IVSD diagnosis. PMID- 28101766 TI - Crossing the Blood-Brain Barrier: Recent Advances in Drug Delivery to the Brain. AB - CNS disorders are on the rise despite advancements in our understanding of their pathophysiological mechanisms. A major hurdle to the treatment of these disorders is the blood-brain barrier (BBB), which serves as an arduous janitor to protect the brain. Many drugs are being discovered for CNS disorders, which, however fail to enter the market because of their inability to cross the BBB. This is a pronounced challenge for the pharmaceutical fraternity. Hence, in addition to the discovery of novel entities and drug candidates, scientists are also developing new formulations of existing drugs for brain targeting. Several approaches have been investigated to allow therapeutics to cross the BBB. As the molecular structure of the BBB is better elucidated, several key approaches for brain targeting include physiological transport mechanisms such as adsorptive-mediated transcytosis, inhibition of active efflux pumps, receptor-mediated transport, cell-mediated endocytosis, and the use of peptide vectors. Drug-delivery approaches comprise delivery from microspheres, biodegradable wafers, and colloidal drug-carrier systems (e.g., liposomes, nanoparticles, nanogels, dendrimers, micelles, nanoemulsions, polymersomes, exosomes, and quantum dots). The current review discusses the latest advancements in these approaches, with a major focus on articles published in 2015 and 2016. In addition, we also cover the alternative delivery routes, such as intranasal and convection-enhanced diffusion methods, and disruption of the BBB for brain targeting. PMID- 28101771 TI - Impact of relocation and environmental cleaning on reducing the incidence of healthcare-associated infection in NICU. AB - BACKGROUND: Hospital environment remains a risk for healthcare-associated infections (HAIs). This was a prospective study to evaluate the comprehensive impact of relocating a neonatal intensive care unit (NICU) to a new facility and improved environmental cleaning practice on the presence of methicillin-resistant Staphylococcus aureus (MRSA) on inanimate surfaces and the incident rate of HAIs. METHODS: New environmental cleaning measures were adopted after the NICU was moved to a new and better-designed location. The effect of moving and the new environmental cleaning practice was investigated by comparing the positive number of MRSA on ward surfaces and the incidence density of HAIs between the baseline and intervention periods. RESULTS: Only 2.5% of environmental surfaces were positive for MRSA in the intervention period compared to 44.0% in the baseline period (P<0.001). Likewise, the total incident rate of HAIs declined from 16.8 per 1000 cot-days to 10.0 per 1000 cot-days (P<0.001). CONCLUSION: The comprehensive measures of relocating the NICU to a new facility design with improved environmental cleaning practice are effective and significantly reduce the incidence of HAIs. PMID- 28101772 TI - Zinc deficiency in the pediatric age group is common but underevaluated. AB - BACKGROUND: Subclinical micronutrient deficiencies have been gradually becoming more important as a public health problem and drawing attention of the health authorities. Today it has been known that detecting and treating people having deficiency symptoms alone is no longer sufficient. It is important to detect and prevent any deficiency before it displays clinical manifestations. Zinc deficiency is one of the most widespread micronutrient deficiencies. In this study, we aimed to evaluate the zinc status and the associated factors in healthy school-age children. METHODS: The study was carried out in schools in Altindag, the district of Ankara. A total of 1063 healthy children, 585 girls and 478 boys, aged 5-16 years were included in the study. Serum zinc, high-sensitivity C reactive protein levels and white blood cell count were measured. A serum zinc level <65 MUg/dL was considered as subclinical zinc deficiency for children <10 years of age. For children >=10 years of age the cutoffs for serum zinc concentration were set at 66 MUg/dL for females and 70 MUg/dL for males. A questionnaire was developed to collect socioeconomic and demographic information of the participants. RESULTS: The prevalence of subclinical zinc deficiency in children attending the study was detected to be 27.8%. This high ratio showed zinc deficiency was an important health problem in the Altindag district of Ankara, Turkey. CONCLUSIONS: Evaluating the indicators of zinc deficiency such as serum zinc concentration, dietary zinc intake and stunting prevalence, this study is the most comprehensive epidemiological study performed in children in Turkey. This study reveals the high prevalence of subclinical zinc deficiency and indicates that zinc deficiency is a public health concern for the study population. PMID- 28101773 TI - What is the appropriate strategy for diagnosing NAFLD using ultrasonography in obese children? AB - BACKGROUND: The aim of this study is to identify obese children who are candidates for a potential diagnosis of non-alcoholic fatty liver disease (NAFLD). METHODS: We enrolled 242 obese children (122 boys and 120 girls) aged 7 16 years who were examined with abdominal ultrasonography in our pediatric obesity clinic. We compared patients in the normal group with those in the NAFLD group (mild disease, moderate to severe disease) and identified the optimal anthropometric parameters among height, weight, body mass index (BMI), waist circumference, hip circumference, waist to height ratio (WHtR), and waist to hip ratio to predict NAFLD using a receiver operating characteristic curve analysis. We also investigated risk factors associated with NAFLD for the anthropometric parameters and the biochemical model using logistic regression. RESULTS: The high and low-risk groups for hepatic steatosis relative to a WHtR of 0.56 as the standard point showed significant differences in hepatic steatosis severity grade (P<0.001), BMI (P=0.004), hip circumference (P=0.090), aspartate aminotransferase (P<0.001), alanine aminotransferase (P<0.001), triglycerides (P=0.001), and the triglyceride to high-density lipoprotein (HDL) cholesterol ratio (P=0.006). Risk factors for hepatic steatosis on logistic regression analysis were male sex (odds ratio: 3.68, 95% confidence interval: 1.76-7.70), WHtR >0.56 (2.25, 1.05-4.81), and waist circumference >90th percentile (20.22, 9.21-44.36) in the anthropometric parameter model and elevated alanine aminotransferase levels (boys >25.8 U/L, girls >22.1 U/L) (6.93, 2.52-19.03), hypertriglyceridemia (>110 mg/dL) (3.80, 1.23-11.75), and triglyceride to HDL cholesterol ratio >3 (9.23, 2.95 8.83) in the biochemical parameter model. CONCLUSION: A diagnostic approach to hepatic steatosis is recommended as part of the proper screening and stratification of risk factors in obese children. WHtR is a simple and convenient method of effectively identifying obese children who are candidates for hepatic steatosis screening. PMID- 28101774 TI - Newborn screening for remethylation disorders and vitamin B12 deficiency evaluation of new strategies in cohorts from Qatar and Germany. AB - BACKGROUND: Newborn screening is a precondition for early diagnosis and successful treatment of remethylation disorders and classical homocystinuria (cystathionine-beta-synthase deficiency). Newborn screening for classical homocystinuria using total homocysteine measurement in dried blood spots has been very successfully performed for many years for newborns from Qatar. METHODS: A new optimized newborn screening strategy for remethylation disorders and homocystinuria was developed and evaluated for newborns from Qatar using total homocysteine measurement as first-tier and methionine, methionine-phenylalanine ratio and propionylcarnitine as second-tiers. Proposed cut-offs were also retrospectively evaluated in newborn screening samples of 12 patients with remethylation disorders and vitamin B12 deficiency from Qatar and Germany. RESULTS: Over a 12 months period, the proposed strategy led to a decrease in the recall rate in homocysteine screening for Qatar from 1.09% to 0.68%, while allowing for additional systematic inclusion of remethylation disorders and vitamin B12 deficiency into the screening panel for Qatar. In the evaluated period the applied strategy would have detected all patients with classical homocystinuria identified by the previous strategy and in addition 5 children with maternal nutritional vitamin B12 deficiency and one patient with an isolated remethylation disorder. Additional retrospective evaluation of newborn screening samples of 12 patients from Germany and Qatar with remethlyation disorders or vitamin B12 deficiency showed that all of these patients would have been detected by the cut-offs used in the proposed new strategy. In addition, an adapted strategy for Germany using methionine, methionine-phenylalanine-ratio and propionylcarnitine as first-tier, and homocysteine as a second-tier test was also positively evaluated retrospectively. CONCLUSIONS: The proposed strategy for samples from Qatar allows inclusion of remethylation disorders and vitamin B12 deficiency in the screening panel, while lowering the recall rate. An adapted second-tier strategy is presented for screening in Germany and will be prospectively evaluated over the next years in a pilot project named "Newborn Screening 2020". PMID- 28101775 TI - Clinical experience in the treatment of children who swallowed multiple magnetic foreign bodies: A report of five cases. AB - BACKGROUND: Several clinical reports have been published on complications resulting from swallowing multiple magnetic foreign bodies. This study aimed to summarize the clinical experience of managing children who swallowed multiple magnetic foreign bodies. METHODS: We reviewed the clinical records of five children who swallowed multiple magnetic foreign bodies and were admitted to our hospital during June 2012 to June 2014. Details of the patients' presentation, imaging studies, complications and treatment were recorded. RESULTS: All five children suffered from gastrointestinal perforation and intestinal obstruction. The magnetic foreign bodies caused local bowel wall tissue ischemia necrosis and perforation as well as other complications associated with fistula formation. The magnets were finally removed by laparotomy surgery. CONCLUSION: If magnetic foreign bodies cannot be removed by endoscopy, an operation is suggested as soon as possible to avoid serious complications. PMID- 28101777 TI - Comorbidities in Down syndrome livebirths and health care intervention: an initial experience from the birth defects registry in Southern Thailand. AB - BACKGROUND: Down syndrome (DS) is the most common chromosomal disorder causing mental retardation with a worldwide average prevalence of 1-2 cases per 1000 births. This study aimed to determine the comorbidities associated with DS and the coverage of health care services and developmental interventions for DS livebirths in Southern Thailand. METHODS: A total of 149 livebirth DS infants, recruited through the prospective birth defects registry system during 2009-2013 in 3 provinces in Southern Thailand, were regularly followed-up every 3-6 months. The data collection form included the infants' demographic data, associated congenital anomalies, and developmental interventions. RESULTS: The DS infants were born at an average gestational age of 38.5+/-2.3 weeks with average birth weight of 2760+/-478 g, length 48.5+/-2.2 cm, and head circumference 32.7+/-1.2 cm. Congenital heart diseases, gastrointestinal defects and congenital hypothyroidism were found in 43.0%, 6.7%, and 12.1% of the cases, respectively. The percentage of DS infants who received developmental interventions in this current study were significantly greater than in a previous study covering the years 1992-2002: early stimulation program 90.0% vs. 65.6% (P<0.01), and speech training program 74.8% vs. 38.9% (P<0.01), respectively, and the infants in our study began intervention programs significantly earlier, 0.58+/-0.39 years vs. 1.69+/-0.66 years, respectively. CONCLUSIONS: Congenital heart disease was the most common comorbidity associated with DS. The coverage of health care services and developmental interventions for DS children has generally improved in Southern Thailand. One hundred percent coverage of health services and interventions for children with special needs is expected in the near future. PMID- 28101776 TI - Plyometric exercise and bone health in children and adolescents: a systematic review. AB - BACKGROUND: Many jumping interventions have been performed in children and adolescents in order to improve bone-related variables and thus, ensure a healthy bone development during these periods and later in life. This systematic review aims to summarize and update present knowledge regarding the effects that jumping interventions may have on bone mass, structure and metabolism in order to ascertain the efficacy and durability (duration of the effects caused by the intervention) of the interventions. DATA SOURCES: Identification of studies was performed by searching in the database MEDLINE/PubMed and SportDiscus. Additional studies were identified by contacting clinical experts and searching bibliographies and abstracts. Search terms included "bone and bones", "jump*", "weight-bearing", "resistance training" and "school intervention". The search was conducted up to October 2014. Only studies that had performed a specific jumping intervention in under 18-year olds and had measured bone mass were included. Independent extraction of articles was done by 2 authors using predefined data fields. RESULTS: A total of 26 studies were included in this review. Twenty-four studies found positive results as subjects included in the intervention groups showed higher bone mineral density, bone mineral content and bone structure improvements than controls. Only two studies found no effects on bone mass after a 10-week and 9-month intervention. Moreover, those studies that evaluated the durability of the effects found that some of the increases in the intervention groups were maintained after several years. CONCLUSIONS: Jumping interventions during childhood and adolescence improve bone mineral content, density and structural properties without side effects. These type of interventions should be therefore implemented when possible in order to increase bone mass in early stages of life, which may have a direct preventive effect on bone diseases like osteoporosis later in life. PMID- 28101778 TI - Eight novel MUT loss-of-function missense mutations in Chinese patients with isolated methylmalonic academia. AB - BACKGROUND: Isolated methylmalonic acidemia is a rare autosomal recessive metabolic disorder mostly caused by mutations in the methylmalonyl coenzyme A mutase (MCM) gene (MUT). This study aimed to verify whether missense mutations in MUT in Chinese patients affect the stability and enzymatic activity of MCM. METHODS: Eight Chinese patients were identified with novel mutations. Plasmids carrying the wild-type and mutated MUT cDNA were constructed and transfected into HEK293T cells for functional analyses. The expression and activity of MCM were determined by western blot and ultra-performance liquid chromatography, respectively. RESULTS: All patients had high levels of blood propionylcarnitine and urinary methylmalonyl acid. By the end of the study, two patients were lost to follow-up, three died, and three survived with mental retardation. Compared to the wild-type protein, the expression levels of all missense mutations of in vitro MCM protein were decreased (P<0.05) except those for I597R, and the MCM activity of the mutations was reduced in a permissive assay. CONCLUSIONS: The missense mutations L140P, A141T, G161V, W309G, I505T, Q514K, I597R and G723D affected the stability and enzymatic activity of MCM, indicating that they had a disease-causing capacity. PMID- 28101779 TI - Randomized controlled trial of topical EMLA and vapocoolant spray for reducing pain during wDPT vaccination. AB - BACKGROUND: Intramuscular vaccination is among the most common source of iatrogenic pain in infants. Vapocoolant sprays are rapid-acting alternative to topical anesthetics. They provide transient anesthesia via evaporation induced skin cooling, and reduce pain due to vaccine injection in children and adults. The objective was to compare the synergistic analgesic effect of eutectic mixture of local anesthetics (EMLA) with breastfeeding (EB group) and vapocoolant spay with breastfeeding (VB group) to that of only breastfeeding (BO group) during whole cell diptheria, pertussis and tetanus (wDPT) vaccination. METHODS: A double blind randomized controlled trial was done to include infants up to 3 months of age who came for their first wDPT vaccination. The primary outcome variable was the duration of cry after vaccination. Secondary outcome variables were Modified Facial Coding Score, Neonatal Infant Pain Scale and latency of onset of cry. RESULTS: Of the 201 eligible participants, 111 babies were excluded and remaining 90 babies were randomized into three groups of thirty each. The groups did not differ significantly in baseline characteristics. Median (interquartile range, IQR) of duration of cry was lesser [35.86 (21.07-107.75) seconds] in babies receiving EMLA cream with breast feeding (EB group) and in babies receiving vapocoolant spray with breast feeding (VB group) [32.58 (21.25-106.21) seconds] as compared to babies receiving only breast feeding (BO group) [67.5 (27.6-180) seconds] (P=0.147). Difference in median (IQR) of latency of cry was not statistically significant. Modified Facial Coding Score and Neonatal Infant Pain Scale at 1 minute and 3 minutes was significantly lower in the EB and VB group, as compared to the BO group (P<0.05). CONCLUSION: Addition of topical EMLA application or vapocoolant spray to breastfeeding during wDPT vaccination does not reduce duration of cry in infants up to 3 months of age. However, they are able to show reduction in pain score and further studies are warranted to assess their efficacy as pain relief measures in infants and children. PMID- 28101780 TI - Update of the spectrum of mucopolysaccharidoses type III in Tunisia: identification of three novel mutations and in silico structural analysis of the missense mutations. AB - BACKGROUND: Mucopolysaccharidoses type III (MPS III) are a group of autosomal recessive lysosomal storage diseases, caused by mutations in genes that code for enzymes involved in the lysosomal degradation of heparan sulphate: heparan sulfate sulfamidase (SGSH), alpha-Nacetylglucosaminidase (NAGLU), heparan sulfate acetyl-CoA: alpha-glucosaminide N-acetyltransferase (HGSNAT), and N acetylglucosamine-6-sulfatase (GNS). METHODS: In this study, we have performed the molecular analysis of the SGSH, NAGLU and HGSNAT genes in 10 patients from 6 different MPS III Tunisian families. RESULTS: In the SGSH gene, two mutations were identified: one novel (p.D477N) and one already described (p.Q365X). In the NAGLU gene, two novel mutations were discovered (p.L550P and p.E153X). For the novel missense mutations found in these two genes we performed an in silico structural analysis and the results were consistent with the clinical course of the patients harboring those mutations. Finally, in HGSNAT gene, we found the splicesite mutation c.234+1G>A that had already been reported as relatively frequent in MPS IIIC patients from countries surrounding the basin of the Mediterranean sea. Its presence in two Tunisian MPS IIIC families points to the hypothesis of its peri Mediterranean origin. With the exception of the c.234+1G>A mutation, that was identified in two unrelated MPS IIIC families, the other identified mutations were family-specific and were always found in homozygosity in the patients studied, thus reflecting the existence of consanguinity in MPS III Tunisian families. CONCLUSIONS: Three novel mutations are reported here, further contributing to the knowledge of the molecular basis of these diseases. The results of this study will allow carrier detection in affected families and prenatal molecular diagnosis, leading to an improvement in genetic counseling. PMID- 28101781 TI - Seeking Medical Information Using Mobile Apps and the Internet: Are Family Caregivers Different from the General Public? AB - Family caregivers play an important role to care cancer patients since they exchange medical information with health care providers. However, relatively little is known about how family caregivers seek medical information using mobile apps and the Internet. We examined factors associated with medical information seeking by using mobile apps and the Internet among family caregivers and the general public using data from the 2014 Health Information National Trends Survey 4 Cycle 1. The study sample consisted of 2425 family caregivers and 1252 non family caregivers (the general public). Guided by Comprehensive Model of Information Seeking (CMIS), we examined related factors' impact on two outcome variables for medical information seeking: mobile apps use and Internet use with multivariate logistic regression analyses. We found that online medical information seeking is different between family caregivers and the general public. Overall, the use of the Internet for medical information seeking is more common among family caregivers, while the use of mobile apps is less common among family caregivers compared with the general public. Married family caregivers were less likely to use mobile apps, while family caregivers who would trust cancer information were more likely to use the Internet for medical information seeking as compared to the general public. Medical information seeking behavior among family caregivers can be an important predictor of both their health and the health of their cancer patients. Future research should explore the low usage of mobile health applications among family caregiver population. PMID- 28101782 TI - The antineoplastic drug, trastuzumab, dysregulates metabolism in iPSC-derived cardiomyocytes. AB - BACKGROUND: The targeted ERBB2 therapy, trastuzumab, has had a tremendous impact on management of patients with HER2+ breast cancer, leading to development and increased use of further HER2 targeted therapies. The major clinical side effect is cardiotoxicity but the mechanism is largely unknown. On the basis that gene expression is known to be altered in multiple models of heart failure, we examined differential gene expression of iPSC-derived cardiomyocytes treated at day 11 with the ERBB2 targeted monoclonal antibody, trastuzumab for 48 h and the small molecule tyrosine kinase inhibitor of EGFR and ERBB2. RESULTS: Transcriptome sequencing was performed on four replicates from each group (48 h untreated, 48 h trastuzumab and 48 h lapatinib) and differential gene expression analyses were performed on each treatment group relative to untreated cardiomyocytes. 517 and 1358 genes were differentially expressed, p < 0.05, respectively in cardiomyocytes treated with trastuzumab and lapatinib. Gene ontology analyses revealed in cardiomyocytes treated with trastuzumab, significant down-regulation of genes involved in small molecule metabolism (p = 3.22 * 10-9) and cholesterol (p = 0.01) and sterol (p = 0.03) processing. We next measured glucose uptake and lactate production in iPSC-derived cardiomyocytes 13 days post-plating, treated with trastuzumab up to 96 h. We observed significantly decreased glucose uptake from the media of iPSC-derived cardiomyocytes treated with trastuzumab as early as 24 h (p = 0.001) and consistently up to 96 h (p = 0.03). CONCLUSIONS: Our study suggests dysregulation of cardiac gene expression and metabolism as key elements of ERBB2 signaling that could potentially be early biomarkers of cardiotoxicity. PMID- 28101783 TI - Tissue is the issue and tissue competition. Re-biopsy for mutation T790: where and why? AB - Lung cancer is still the leading cause of death among all cancers. During the last 15 years, pharmacogenomics of lung cancer have established targeted therapy with tyrosine kinase inhibitors (TKIs) for epidermal growth factor receptor (EGFR) positive patients in adenocarcinoma or mixed adenosquamus lung cancer patients. However; while novel drugs are released in the market, at the same time novel mutations are observed after tyrosine kinase inhibitor administration. Recently the novel mutation T790 was observed and is highly prevalent in patients already treated with a TKI. A new drug targeting this mutation is already on the market, however; the most important factor for successful treatment in these patients, is adequate tissue re-sampling so that novel mutations can be detected. PMID- 28101784 TI - Dental implants and grafting success remain high despite large variations in maxillary sinus mucosal thickening. AB - BACKGROUND: Although mucosal thickening is the most common radiographic finding observed regarding sinus pathology, the knowledge regarding its clinical significance on the outcomes of dental implants and grafting in the maxillary sinuses is still limited. We hypothesized that mucosal thickening would not alter the predictability for sinus floor augmentation and dental implant placement. The purpose of this retrospective study was to evaluate the outcomes of dental implant placement in sinus-augmented areas with preexisting sinus mucosal thickening. METHODS: This study involved the review of cone-beam computed tomographic (CBCT) scans taken on patients that underwent both maxillary sinus elevation with grafting and implant placement at the University of Michigan School of Dentistry from 2004 to 2014. Cases with documented radiographic and clinical follow-up were included. The data analyses revealed the following. RESULTS: A total of 29 CBCT scans met the inclusion criteria for evaluation, and 93.1% of them had maxillary sinus mucosal/tissue thickening. Specifically, 6.9% of cases exhibited no thickening, 6.9% had minimal thickening (1-2 mm), 20.7% of cases had moderate thickening (2-5 mm), and 65.5% had severe thickening (>5 mm). We propose these categorical measurements of tissue thickening as a new "mucosal thickening index." The tissue thickening did not vary based on gender, age, or smoking status, nor did it relate to the underlying alveolar ridge height. However, patients with a history of periodontal diseases demonstrated a significant association with mucosal thickening (p = 0.0043). These data indicate that there is high implant and grafting success rate (100%) in the maxillary sinus despite large and varied physiologic sinus mucosal/tissue thickening. CONCLUSIONS: Based on study findings, this research will help guide dental practitioners regarding cases that exhibit mucosal thickening. These data support the concept that physiologic mucosal thickening in varied ranges is not associated with implant or grafting failure in the maxillary sinus. PMID- 28101787 TI - A Recombinant Highly Thermostable beta-Mannanase (ReTMan26) from Thermophilic Bacillus subtilis (TBS2) Expressed in Pichia pastoris and Its pH and Temperature Stability. AB - A gene encoding a highly thermostable beta-mannanase from a thermophilic Bacillus subtilis (TBS2) was successfully expressed in Pichia pastoris. The maximum activity of the recombinant thermostable beta-mannanase (ReTMan26) was 5435 U/mL, which was obtained by high-density, fed-batch cultivation after 168-h induction with methanol in a 50-L bioreactor. The protein yield reached 3.29 mg/mL, and the protein had a molecular weight of ~42 kDa. After fermentation, ReTMan26 was purified using a 10-kDa cut-off membrane and Sephadex G-75 column. The pH and temperature optima of purified ReTMan26 were pH 6.0 and 60 degrees C, respectively, and the enzyme was stable at pH 2.0-8.0 and was active at 20-100 degrees C. HPLC analysis of the products of locust bean gum hydrolysis showed that the mannan-oligosaccharide content was 62.5%. ReTMan26 retained 58.6% of its maximum activity after treatment at 100 degrees C for 10 min, which was higher than any other beta-mannanase reported up to now, suggesting its potential for industrial applications. PMID- 28101788 TI - Embling Production in Althaea officinalis L., Through Somatic Embryogenesis and Their Appraisal via Histological and Scanning Electron Microscopical Studies. AB - In vitro propagation of a medicinally important plant, Althaea officinalis, has been achieved through somatic embryogenesis. Somatic embryos (globular to torpedo shaped embryos) were induced on Murashige and Skoog's (MS) medium augmented with various concentrations of 2,4-dichlorophenoxyacetic acid (2,4-D, 5.0, 10.0, 15.0, 20.0, and 25.0) alone or combined with N6-benzylaminopurine (BA, 0.1, 0.5, 1.0, 1.5, and 2.0 MUM). These were directly formed from the cut ends and subsequently spread on the whole surface of internodal explants. For embryo maturation, torpedo embryos were transferred on a medium containing different levels of BA (0.1, 0.5, or 1.0 MUM) and abscisic acid (ABA) (0.5, 1.0, or 1.5 MUM) or alpha naphthalene acetic acid (NAA) (0.1, 0.5 or 1.0 MUM). Among the different concentrations tested, 0.5 MUM BA along with 1.0 MUM ABA was found most effective, on which a highest yield (58.0%) with an optimum number (35.0) of mature embryos (cotyledonary stage) was observed after 2 weeks of transfer. Germination of cotyledonary embryos into plantlets with 68% were observed on 1/2 MS medium. Histological and scanning electron microscopical (SEM) studies proved that the regenerated structures were somatic embryos and not shoot primordia. Plants grew vigorously when transferred to a greenhouse. PMID- 28101786 TI - Evaluation of T Regulatory Lymphocytes Transcription Factors in HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) Patients. AB - HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an aggressive neurological disease. The CD4+CD25+ T cell population plays pivotal roles in the maintenance of immunological tolerance and prevention of such autoimmune diseases. In the current study, proviral load (PVL), factor forkhead box p3 (Foxp3), and glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) gene expression and regulatory T cells (Tregs) counts of 21 HAM/TSP patients and 16 HTLV-1 healthy carriers (ACs) were measured using real time PCR, TaqMan method, and flow cytometry. The demographic, history of disease, and severity of myelopathy were assessed by a checklist and the Osame motor disability score (OMDS). The mean OMDS for HAM/TSP was 4.82 +/- 2.37 which had no significant correlation with Treg count or the expression of Foxp3, GITR, and PVL. The CD4+CD25+ cell counts had no significant differences between HAM/TSP and ACs. Findings revealed a higher PVL in HAM/TSPs (313.36 copies/104) compared to ACs (144.93 copies/104, p = 0.035). The Foxp3 and GITR mRNA levels were lower in HAM/TSP patients (11.78 and 13.80, respectively) than those in healthy carriers (18.44 and 21.00, p = 0.041 and 0.03, respectively). There was a significant correlation between Treg frequency and Foxp3 gene expression (R = 0.67, p = 0.006) and GITR and Foxp3 (R = 0.84, p = 0.042) in HAM/TSP patients. Furthermore, the transcription factors have strong correlations with CD4+CD25+ T cell frequencies. These findings suggest that HTLV-1 infection can modify the expression of main functional transcription factors, FOXP3 and GITR, which may lead to immune response deterioration of Tregs and consequently HAM/TSP manifestation. PMID- 28101785 TI - Acinetobacter baumannii bacteraemia in patients with haematological malignancy: a multicentre retrospective study from the Infection Working Party of Jiangsu Society of Hematology. AB - Acinetobacter baumannii (Ab) bacteraemia in patients with haematological malignancies is fatal but rarely reported. We explored the clinical characteristics, drug resistances and prognostic factors in these patients. This multicentre, retrospective study was conducted at the department of haematology wards of 18 tertiary hospitals in China from January 2014 to June 2015. The total clinical isolates from every source were collected from patients with haematological malignancy. Haematological malignancy patients diagnosed with Ab bacteraemia were analysed. During the study period, 40 patients with Ab bacteraemia were identified, accounting for 2.9% (40/1358) of bacteraemia cases, of which 25 (62.5%) had acute leukaemia (AL) and 27 (67.5%) had neutropaenia. Compared with non-neutropaenic patients, neutropaenic patients showed higher Acute Physiology and Chronic Health Evaluation (APACHE) scores and 30-day mortality rates (p < 0.05). The in vitro antibiotic susceptibility of Ab to colistin was highest, at 100%, followed by that of tigecycline (91.30%) and amikacin (75.86%). Compared with the patients who had carbapenem-susceptible Ab infections, patients infected with carbapenem-resistant Ab (CRAB) had significantly longer hospital stays and were more likely to have had exposure to carbapenem before bacteraemia (p < 0.05). The 30-day mortality rate was 32.5%. CRAB, neutropaenia, higher APACHE score, Pitt bacteraemia score and inappropriate initial antimicrobial therapy were significantly associated with 30-day mortality. Multivariable analysis showed that APACHE score and CRAB were independent predictors of 30-day mortality. Haematologic patients with AL and febrile neutropaenia were at high risk of Ab bacteraemia. More attention should be paid to CRAB, which is an independent risk factor for mortality in haematological malignancy patients with Ab bacteraemia. PMID- 28101789 TI - Prevalence and Predictors of Uncircumcised, Kenyan Men's Desire for Circumcision for Their Infant Sons. AB - Men are key decision makers for their son's circumcision, so understanding their beliefs is important for the uptake of early infant male circumcision in countries in sub-Saharan Africa that have high HIV prevalence. We analyzed men's preferences for circumcising their sons using data from a population representative survey of 1501 uncircumcised men aged 25-49 years in western Kenya. Most men (59%) reported they would "definitely" want their son circumcised if a son was born to them within the next year. However, only 25% intended to become circumcised themselves. In multivariable Poisson regression models to estimate prevalence ratios, key predictors of the desire to circumcise their sons included knowledge that circumcision reduces HIV acquisition, having a supportive partner, discussing circumcision with the partner, altruism, and intention to be circumcised himself. Focusing on partner dynamics may have the greatest capacity to increase demand since 55% had not talked to their partner about circumcision. PMID- 28101790 TI - Perspectives of People with a Chronic Disease on Participating in Work: A Focus Group Study. AB - Purpose To explore solutions that people with a chronic disease use to overcome difficulties they experience regarding participating in work, and the support they require to identify or implement these solutions. Methods Focus groups were held to explore solutions and support requirements of people with a chronic disease. Participants were recruited through a research institution's patient panel, a patient federation and personal networks. Analysis was conducted by means of open and selective coding, using the MAXQDA software package. Results Five focus groups were held with 19 participants with different chronic diseases. Solutions that were identified included learning to accept and cope with the disease, which is frequently supported by family and friends. Disclosing the disease to employers and colleagues, identifying active ways to help with duties, and implementing adaptations to the work environment were all effective solutions with the help, empathy and understanding of people in the work environment. Solutions mostly supported by patient associations included providing sufficient information about the disease, relevant help and protective legal regulations regarding work participation. Finally, health professionals could support solutions such as incorporating periods of rest, promoting self-efficacy and gaining insight into an individual's ability to participate in work. Conclusions People with a chronic disease suggested various solutions that can help overcome difficulties surrounding participating in work. Support from friends and family, patient associations, employers, colleagues and occupational health professionals is needed to help identify and implement suitable solutions. PMID- 28101791 TI - Strategies to Reduce 30-Day Readmissions in Patients with Cirrhosis. AB - PURPOSE OF REVIEW: Approximately, one quarter of patients discharged after a hospitalization for decompensated cirrhosis will be readmitted within 30 days. These readmissions have been associated with increased morbidity and mortality, can be financially harmful to the health system, and may be partially preventable. This review summarizes the literature on readmissions, providing clinicians with tools for risk prediction and a taxonomy for preventative interventions. RECENT FINDINGS: Readmission strategies can be categorized according to complexity (simple versus complex) and specificity (focused versus broad). The literature thus far provides the following generalizable inferences: 1) Interventions should be integrated in the clinical workflow, 2) default options are more powerful than voluntary actions, 3) knowledge improvement should focus on the front line clinicians, 4) process improvements do not always translate into better outcomes, and 5) any successful intervention must include viable alternatives to hospitalization. A growing body of literature provides concrete and actionable guidance for interventions to reduce readmissions in patients with cirrhosis. PMID- 28101792 TI - Medical Management of Diabesity: Do We Have Realistic Targets? AB - PURPOSE OF REVIEW: The global prevalence of "diabesity"-diabetes related to obesity-is increasing steadily over the past few decades because of the obesity epidemic. Although bariatric surgery is an effective treatment option for patients with diabesity, its limited availability, invasiveness, relatively high costs and the potential for surgical and postsurgical complications restrict its widespread use. Therefore, medical management is the only option for a majority of patients with diabesity. Diabetes control with several anti-diabetic agents, including insulin, causes weight gain with probability of worsening diabesity. Rational use of anti-diabetic medications with weight loss potential in varying combinations may help to address this key issue for long-term management of diabesity. There is no consensus on such an approach from different professional bodies like American Diabetes Association, European Association for Study of Diabetes, or International Diabetes Federation. We attempt to discuss the key issues and realistic targets for diabesity management in this paper. RECENT FINDINGS: Rational use of anti-diabetic combinations can mitigate worsening of diabesity to some extent while managing patients. Retrospective studies showed that combination therapy with glucagon-like peptide-1 (GLP-1) receptor agonists and sodium glucose co-transporter 2 (SGLT-2) inhibitors, when administered along with other anti-diabetic medications, offer the best therapeutic benefit in the medical management of diabesity. Different combinations of other anti-diabetic drugs with minimum weight gain potential were also found useful. Because of insufficient evidence based on prospective randomised controlled trials (RCTs), future research should focus on evolving the appropriate rational drug combinations for the medical management of diabesity. PMID- 28101794 TI - Diabetic Foot Infections: an Update in Diagnosis and Management. AB - Foot infections are a common problem in patients with diabetes and a risk factor for limb amputation. They occur as a result of skin ulceration, which facilitates penetration of pathogens to deeper tissues. The diagnosis of infection is clinical. Aerobic gram-positive cocci are the most common pathogens. Ulcers which are chronic, preceded by administration of antibiotics and hospitalization or complicated by severe infection are polymicrobial. Antibiotic therapy is initially empiric based on the severity of the infection. Definitive therapy is modified according to the results of the microbiological culture and the response to empiric treatment. The optimal duration of antibiotic therapy ranges from 1-2 weeks for mild infections to 2-4 weeks and even longer for severe infections and osteomyelitis. Surgical consultation should be sought for infections complicated with abscesses, necrotizing fasciitis or osteomyelitis. With appropriate care, infection resolves in about 80-90% of non-limb threatening and in about 60% of severe infections. PMID- 28101793 TI - Substance Use Disorders among Patients with Type 2 Diabetes: a Dangerous but Understudied Combination. AB - PURPOSE OF REVIEW: This paper reviews research on substance use and disorders (SUDs) among adults with diabetes. It describes epidemiological data on SUDs in persons with type 2 diabetes, overviews effects of substance use on diabetes outcomes, and discusses treatments for SUDs in patients with diabetes. RECENT FINDINGS: Rates of current smoking range from 10 to 26% and alcohol use disorders are 0-5%. Rates of illicit SUDs are 3-4%, but there are no population-based studies using nationally representative samples. Smoking increases the risk for long-term diabetes complications and premature death. Alcohol and illicit drug use can also impact long-term diabetes complications by impairing glucose homeostasis and adversely influencing self-management behaviors. There is mixed evidence about psychosocial smoking cessation interventions in adults with diabetes and little on alcohol and illicit SUD interventions. Limited data exist on pharmacotherapies for SUDs in this population, but a recent study suggests that varenicline is safe and effective for treating smoking in patients with diabetes. Substance use is an understudied problem in type 2 diabetes, and addressing substance use holds potential for improving outcomes. Additional large population-based epidemiological studies in those with type 2 diabetes are needed, particularly for alcohol and illicit SUDs. Longitudinal studies should be conducted to better understand the time course of diabetes onset and outcomes in relation to SUDs. Randomized controlled trials are needed to assess safety and efficacy of promising psychosocial and pharmacological interventions. PMID- 28101796 TI - Letter to the editor: "Should we perform elective inguinal hernia repair in the elderly?" by Wu J. J. et al. (Hernia. 2016 Jul 20. [Epub ahead of print]). PMID- 28101795 TI - Locally advanced pancreatic cancer successfully treated by distal pancreatectomy with celiac axis resection (DP-CAR) after S-1 with radiation therapy followed by gemcitabine/nab-paclitaxel therapy: a case report. AB - BACKGROUND: The prognosis for pancreatic cancer remains dismal because many patients are diagnosed with unresectable cancer at the initial diagnosis. Recently, conversion surgery was reported as an effective treatment for initially unresectable pancreatic cancer with a favorable response to non-surgical treatment lasting over 240 days. Here, we describe a case of locally advanced pancreatic cancer (LAPC) successfully resected after treatment with S-1 and radiation followed by gemcitabine/nab-paclitaxel therapy. CASE PRESENTATION: A 73 year-old man with LAPC was referred to our hospital. Computed tomography findings revealed a 2.5-cm mass in the pancreatic body that had invaded the celiac artery, common hepatic artery, and splenic artery. Superior mesenteric artery (SMA) encasement was not observed, but tumor abutment over 180 degrees with the main tumor was detected. Staging laparoscopy showed no findings of distant metastasis, and washing cytology revealed no malignancy. He was diagnosed with unresectable pancreatic cancer. Treatment with S-1 with radiation therapy followed by gemcitabine with nab-paclitaxel was performed. Six months after the initial treatment, the tumor size had decreased to 1.2 cm, and encasement of the main artery was diminished. Though abutment to the main artery, including the SMA, was still detected, distal pancreatectomy with celiac artery resection was performed. The histopathological findings around the celiac artery revealed fibrous changes with an Evans classification of grade IIb. There was no residual cancer at the periphery; thus, R0 resection was achieved. The patient has been healthy and without recurrence for more than 12 months since the initial treatment. CONCLUSIONS: Gemcitabine/nab-paclitaxel therapy revealed high response rate for metastasic pancreatic cancer (PC), but the effect for LAPC proposing conversion surgery was not well discussed. In this case, we achieve R0 resection combined with chemoradiation therapy and gemcitabine/nab-paclitaxel therapy. This regimen was also effective for LAPC and may be used to increase the population of conversion surgery by its high response rate. PMID- 28101797 TI - Ni(II) and Zn(II) Complexes Containing Alkynyl Functionalized Salicylaldimine Ligand and Heterocyclic Coligand: Synthesis, Characterization and Luminescence Properties. AB - Some nickel(II) and zinc(II) complexes of the type [Ni(L)(phen/bipy)]X (1a-6a) and [Zn(L) (phen/bipy)]X (1b-6b) (where L = 2-{(E)-[(4 trimethylsilylethynylphenyl)imino]methyl}-4-(4-nitro phenylethynyl)phenol; phen = 1, 10-phenanthroline, bipy = 2, 2'-bipyridine; X = ClO4-, BF4-, PF6-) have been prepared and characterized on the basis of elemental analyses, FTIR, 1H NMR and mass spectral studies. The molecular structure of L was determined by single crystal X-ray diffraction studies. The electrochemical behaviour of the Ni(II) complexes indicate that the phen complexes appears at more positive potential as compared to those for bipy complexes, as a consequence of its strong pi-acidic character. TGA was carried out to study the thermal behavior of the complexes. Room temperature luminescence is observed for all complexes corresponds to pi -> pi* ILCT transition. The size of the counter anion and heterocyclic coligands phen and bipy shows marked effect on emission properties of the complexes. PMID- 28101798 TI - miR-10b, miR-26a, miR-146a And miR-153 Expression in Triple Negative Vs Non Triple Negative Breast Cancer: Potential Biomarkers. AB - MicroRNAs (miRNAs) are small non-coding RNAs composed of 18-25 nucleotides that can post-transcriptionally regulate gene expression and have key regulatory roles in cancer, acting as both oncogenes and tumor suppressors. About 1000 genes in humans encode miRNAs, which account for approximately 3% of the human genome, and up to 30% of human protein coding genes may be regulated by miRNAs. The objective of this article is to evaluate the expression profile of four miRNAs previously implicated in triple negative breast cancer: miR-10b, miR-26a, miR-146a and miR 153, and to determine their possible interaction in triple negative and non triple negative breast cancer based on clinical outcome and the expression of BRCA1. 24 triple-negative and 13 non triple negative breast cancer cases, were studied by q-RT-PCR and immunohistochemistry to determine the expression of the four studied miRNAs and the BRCA1 protein, respectively. We observed that the BRCA1 protein was absent in 62.5% of the triple negative cases. Besides, the miR 146a and miR-26a were over expressed in triple negative breast cancer. These two miRNAs, miR-10b and miR-153 were significantly associated to lymph node metastases occurrence in triple negative breast carcinoma. All the analyzed microRNAs were not associated with the expression of BRCA1 in our conditions. Our work provides evidence that miR-146a, miR-26a, miR-10b and miR-153 could be defined as biomarkers in triple negative breast cancer to predict lymph node metastases (LNM). PMID- 28101799 TI - Antitumor Efficacy of SLPI Promoter-Controlled Expression of Artificial microRNA Targeting EGFR in a Squamous Cell Carcinoma Cell Line. AB - The purpose of this study was to develop a recombinant adenovirus with secretory leukoprotease inhibitor (SLPI) promoter-controlled expression for gene therapy of squamous cell carcinoma (SCC). An artificial microRNA targeting epidermal growth factor receptor (EGFR) was designed, and used to construct a replication defective recombinant adenovirus with SLPI promoter-controlled expression. The silencing efficiency of this vector (Ad-SLPI-EGFRamiR) was detected in Hep-2 cells. Western blotting showed that the expression of 170 kD EGFR was significantly reduced in Hep-2 cells 72 h after infection with Ad-SLPI-EGFRamiR. At a multiplicity of infection (MOI) of 200 pfu/cell, proliferation of Hep-2 cells was highly inhibited by Ad-SLPI-EGFRamiR (inhibition rate: ~70%). The apoptosis rate of Hep-2 cells at 72 h after infection with Ad-SLPI-EGFRamiR at a MOI 35 pfu/cell was 32.8%. The adenovirus constructed was able to specifically inhibit the growth of SCC cells in vitro. PMID- 28101800 TI - Is the Genetic Background of Co-Stimulatory CD28/CTLA-4 Pathway the Risk Factor for Prostate Cancer? AB - The impairment of immunological surveillance caused by aberrant T cell activation can lead to an inadequate anti-tumor response. Therefore, deregulation in co stimulatory pathway might be associated with cancer susceptibility. Here we undertook a prospective study to investigate whether genetic variations in gene encoding molecule CD28 and CTLA-4 playing pivotal role in regulating adoptive immune response can influence susceptibility to prostate cancer. Single nucleotide polymorphisms (SNPs) in CTLA-4 and CD28 genes were genotyped in 301 prostate cancer (PCa) patients and 301 controls. The distributions of the genotypes and haplotypes in the CTLA-4/CD28 SNPs were similar in both studied groups. However, the overrepresentation of carriers of CTLA-4c.49A>G[A] allele and carriers of CTLA-4g.319C>T[T] allele in PCa as compared to controls was observed (p = 0.082 and p = 0.13, respectively). The risk of disease was higher (OR 1.78) for carriers of both susceptibility alleles as compared to carriers of protective genotypes (p = 0.03). The CTLA-4c.49A>G and CTLA-4g.319C>T SNPs might be considered as low risk susceptibility locus for PCa. PMID- 28101801 TI - Identification of Changes in the Human Papilloma Virus 16 (HPV16) Genome During Early Dissemination of Cervical Cancer Cells May Complement Histological Diagnosis of Lymph Node Metastasis. AB - Cancer of the uterine cervix (CACX) is one of the most common carcinoma affecting women worldwide. During treatment, histologically lymph node (LN) metastasis and presence of HPV DNA in blood plasma act as a major prognostic factor. Despite the lack of apparent LN involvement, some early-invasive CACX patients have shown recurrences and poor survival. This is suggestive of undetected early dissemination of cancer cells characterized by presence of HPV DNA in histologically non-metastatic LNs which finally progresses into histologically visible metastasis. This present study investigated the status and origin of HPV genome during early dissemination by molecular analysis in primary tumor (PT), histologically non-metastatic pelvic lymph nodes (LNs) and blood plasma (BP) of same patient. First, CACX patients showing signs of early dissemination was identified by detection of HPV in PT (n = 22) and their corresponding histologically non-metastatic pelvic LNs (n = 45) and BP (n = 18) followed by typing of HPV16/18. This was followed by comparative analysis of the physical, copy number and methylation (enhancer/early/late) status of HPV16 genome present in LNs and BP with that of PT. Our study revealed for the first time that the HPV16 genome were frequently present in the integrated form though the copy number was low in both non-metastatic LNs and BP. However, the methylation pattern of PT was discordant with that of corresponding LNs and BP in majority of the cases. Critical assessment of HPV16 profiles established that the presence of hrHPV may be due to the early dissemination of PT cells having significant pathological implications. PMID- 28101803 TI - Lung retransplantation in an adult 13 years after single lobar transplant in childhood. AB - Single living-donor lobar lung transplantation provides acceptable results for critically ill children; however, an additional lung transplantation may be required in the future as the recipient grows. We describe a case of successful lung retransplantation in a grown-up patient after single lobar lung transplantation in childhood. A 23-year-old man underwent bilateral cadaveric lung retransplantation for chronic lung allograft dysfunction 13 years after right single living-donor lobar transplantation for idiopathic pulmonary arterial hypertension performed at the age of 10 years. The postoperative course was uneventful. The patient had received growth hormone therapy at a local hospital for 3 years until the development of chronic lung allograft dysfunction after the initial transplantation. Pediatric recipients undergoing single living-donor lobar lung transplantation should be cautiously followed for potential retransplantation. PMID- 28101802 TI - COLD-PCR Technologies in the Area of Personalized Medicine: Methodology and Applications. AB - Somatic mutations bear great promise for use as biomarkers for personalized medicine, but are often present only in low abundance in biological material and are therefore difficult to detect. Many assays for mutation analysis in cancer related genes (hotspots) have been developed to improve diagnosis, prognosis, prediction of drug resistance, and monitoring of the response to treatment. Two major approaches have been developed: mutation-specific amplification methods and methods that enrich and detect mutations without prior knowledge on the exact location and identity of the mutation. CO-amplification at Lower Denaturation temperature Polymerase Chain Reaction (COLD-PCR) methods such as full-, fast-, ice- (improved and complete enrichment), enhanced-ice, and temperature-tolerant COLD-PCR make use of a critical temperature in the polymerase chain reaction to selectively denature wild-type-mutant heteroduplexes, allowing the enrichment of rare mutations. Mutations can subsequently be identified using a variety of laboratory technologies such as high-resolution melting, digital polymerase chain reaction, pyrosequencing, Sanger sequencing, or next-generation sequencing. COLD PCR methods are sensitive, specific, and accurate if appropriately optimized and have a short time to results. A large variety of clinical samples (tumor DNA, circulating cell-free DNA, circulating cell-free fetal DNA, and circulating tumor cells) have been studied using COLD-PCR in many different applications including the detection of genetic changes in cancer and infectious diseases, non-invasive prenatal diagnosis, detection of microorganisms, or DNA methylation analysis. In this review, we describe in detail the different COLD-PCR approaches, highlighting their specificities, advantages, and inconveniences and demonstrating their use in different fields of biological and biomedical research. PMID- 28101805 TI - Ketogenic diet in pyruvate dehydrogenase complex deficiency: short- and long-term outcomes. AB - OBJECTIVES: Our aime was to study the short- and long-term effects of ketogenic diet on the disease course and disease-related outcomes in patients with pyruvate dehydrogenase complex deficiency, the metabolic factors implicated in treatment outcomes, and potential safety and compliance issues. METHODS: Pediatric patients diagnosed with pyruvate dehydrogenase complex deficiency in Sweden and treated with ketogenic diet were evaluated. Study assessments at specific time points included developmental and neurocognitive testing, patient log books, and investigator and parental questionnaires. A systematic literature review was also performed. RESULTS: Nineteen patients were assessed, the majority having prenatal disease onset. Patients were treated with ketogenic diet for a median of 2.9 years. All patients alive at the time of data registration at a median age of 6 years. The treatment had a positive effect mainly in the areas of epilepsy, ataxia, sleep disturbance, speech/language development, social functioning, and frequency of hospitalizations. It was also safe-except in one patient who discontinued because of acute pancreatitis. The median plasma concentration of ketone bodies (3-hydroxybutyric acid) was 3.3 mmol/l. Poor dietary compliance was associated with relapsing ataxia and stagnation of motor and neurocognitive development. Results of neurocognitive testing are reported for 12 of 19 patients. CONCLUSION: Ketogenic diet was an effective and safe treatment for the majority of patients. Treatment effect was mainly determined by disease phenotype and attainment and maintenance of ketosis. PMID- 28101804 TI - White matter hyperintensities correlate to cognition and fiber tract integrity in older adults with HIV. AB - Our aim was to examine the clinical relevance of white matter hyperintensities (WMH) in HIV. We used an automated approach to quantify WMH volume in HIV seropositive (HIV+; n = 65) and HIV seronegative (HIV-; n = 29) adults over age 60. We compared WMH volumes between HIV+ and HIV- groups in cross-sectional and multiple time-point analyses. We also assessed correlations between WMH volumes and cardiovascular, HIV severity, cognitive scores, and diffusion tensor imaging variables. Serostatus groups did not differ in WMH volume, but HIV+ participants had less cerebral white matter (mean: 470.95 [43.24] vs. 497.63 [49.42] mL, p = 0.010). The distribution of WMH volume was skewed in HIV+ with a high proportion (23%) falling above the 95th percentile of WMH volume defined by the HIV- group. Serostatus groups had similar amount of WMH volume growth over time. Total WMH volume directly correlated with measures of hypertension and inversely correlated with measures of global cognition, particularly in executive functioning, and psychomotor speed. Greater WMH volume was associated with poorer brain integrity measured from diffusion tensor imaging (DTI) in the corpus callosum and sagittal stratum. In this group of HIV+ individuals over 60, WMH burden was associated with cardiovascular risk and both worse diffusion MRI and cognition. The median total burden did not differ by serostatus; however, a subset of HIV+ individuals had high WMH burden. PMID- 28101806 TI - Purification and characterization of glutamate decarboxylase from Enterococcus raffinosus TCCC11660. AB - Glutamate decarboxylase (GAD) is the sole enzyme that synthesizes gamma aminobutyric acid through the irreversible decarboxylation of L-glutamate. In this study, the purification and characterization of an unreported GAD from a novel strain of Enterococcus raffinosus TCCC11660 were investigated. The native GAD from E. raffinosus TCCC11660 was purified 32.3-fold with a recovery rate of 8.3%, using ultrafiltration and ammonium sulfate precipitation, followed by ion exchange and size-exclusion chromatography. The apparent molecular weight of purified GAD, as determined by SDS-PAGE and size-exclusion chromatography was 55 and 110 kDa, respectively, suggesting that GAD exists as a dimer of identical subunits in solution. In the best sodium citrate buffer, metal ions of Mo6+ and Mg2+ had positive effects, while Cu2+, Fe2+, Zn2+ and Co2+ showed significant adverse effects on enzyme activity. The optimum pH and temperature of GAD were determined to be 4.6 and 45 degrees C, while the K m and V max values for the sole L-glutamate substrate were 5.26 and 3.45 MUmol L-1 min-1, respectively. PMID- 28101807 TI - Direct bioethanol production from wheat straw using xylose/glucose co fermentation by co-culture of two recombinant yeasts. AB - To achieve a cost-effective bioconversion of lignocellulosic materials, a novel xylose/glucose co-fermentation process by co-culture of cellulose-utilizing recombinant Saccharomyces cerevisiae (S. cerevisiae) and xylan-utilizing recombinant Pichia pastoris (P. pastoris) was developed, in which ethanol was produced directly from wheat straw without additional hydrolytic enzymes. Recombinant S. cerevisiae coexpressing three types of cellulase and recombinant P. pastoris coexpressing two types of xylanase were constructed, respectively. All cellulases and xylanases were successfully expressed and similar extracellular activity was demonstrated. The maximum ethanol concentration of 32.6 g L-1 with the yield 0.42 g g-1 was achieved from wheat straw corresponding to 100 g L-1 of total sugar after 80 h co-fermentation, which corresponds to 82.6% of the theoretical yield. These results demonstrate that the direct and efficient ethanol production from lignocellulosic materials is accomplished by simultaneous saccharification (cellulose and hemicellulose) and co-fermentation (glucose and xylose) with the co-culture of the two recombinant yeasts. PMID- 28101808 TI - Construction of engineered Saccharomyces cerevisiae strain to improve that whole cell biocatalytic production of melibiose from raffinose. AB - There are excessive by-products in the biocatalysis process of this whole-cell biocatalytic production of melibiose from raffinose with current Saccharomyces cerevisiae strains. To solve this problem, we constructed engineered strains based on a liquor yeast (S. cerevisiae) via gene deletion (mel1 gene), heterologous integration (fsy1 or/and ffzi1 gene from Candida magnoliae), and gene overexpression (gcr1 gene). Functional verification showed that deletion of the mel1 gene led to elimination of the reactions catalyzed by alpha galactosidase, as well as elimination of the degradation of melibiose and the formation of galactose by-product. Insertion of the fsy1 or/and ffzi1 gene and overexpression of the gcr1 gene could contribute to fructose transport for enhancing the biopurification rate of the fructose by-product. Compared with the wild-type strain, the optimal engineered strain of MP8 (Deltamel1::fsy1 cm ::ffzi1 cm ::gcr1 sc ) had improved about 30% on yield, 31% on productivity, and 36% on purity of the melibiose product. PMID- 28101809 TI - Sequential Exposure of Bortezomib and Vorinostat is Synergistic in Multiple Myeloma Cells. AB - PURPOSE: To examine the combination of bortezomib and vorinostat in multiple myeloma cells (U266) and xenografts, and to assess the nature of their potential interactions with semi-mechanistic pharmacodynamic models and biomarkers. METHODS: U266 proliferation was examined for a range of bortezomib and vorinostat exposure times and concentrations (alone and in combination). A non-competitive interaction model was used with interaction parameters that reflect the nature of drug interactions after simultaneous and sequential exposures. p21 and cleaved PARP were measured using immunoblotting to assess critical biomarker dynamics. For xenografts, data were extracted from literature and modeled with a PK/PD model with an interaction parameter. RESULTS: Estimated model parameters for simultaneous in vitro and xenograft treatments suggested additive drug effects. The sequence of bortezomib preincubation for 24 hours, followed by vorinostat for 24 hours, resulted in an estimated interaction term significantly less than 1, suggesting synergistic effects. p21 and cleaved PARP were also up-regulated the greatest in this sequence. CONCLUSIONS: Semi-mechanistic pharmacodynamic modeling suggests synergistic pharmacodynamic interactions for the sequential administration of bortezomib followed by vorinostat. Increased p21 and cleaved PARP expression can potentially explain mechanisms of their enhanced effects, which require further PK/PD systems analysis to suggest an optimal dosing regimen. PMID- 28101810 TI - Increased incidence of autoimmune thyroid disorders in patients with psoriatic arthritis: a longitudinal follow-up study. AB - Contrasting results have been reported about the prevalence of thyroid autoimmunity (AT) and dysfunction (TD) in patients with psoriatic arthritis (PsA). In this study, we pointed to evaluate the incidence of new cases of clinical and subclinical TD in a broad group of patients with PsA versus a control group, matched by age and gender belonging to the same geographic area. PsA patients with TD were excluded firstly, and new cases of thyroid disorders were evaluated in 97 PsA patients and 97 matched controls, who had comparable iodine intake (median follow-up of 74 months in PsA versus 92 in controls). A raised rate of new cases of hypothyroidism, TD, positive antithyroid peroxidase (AbTPO) antibodies, and appearance of a small hypoechoic thyroid pattern in PsA, especially in female gender, compared to controls has been evidenced. Risk factors in female gender for the development of TD are thyroid-stimulating hormone (TSH) within the normal range but at the higher limit, positive AbTPO, and small thyroid volume. To sum up, thyroid function follow-up and suitable treatments should be performed regularly in female patients at high risk (TSH within the normal range but at the higher limit, positive AbTPO, hypoechoic and small thyroid). PMID- 28101812 TI - Cognitive and emotional demands of black humour processing: the role of intelligence, aggressiveness and mood. AB - Humour processing is a complex information-processing task that is dependent on cognitive and emotional aspects which presumably influence frame-shifting and conceptual blending, mental operations that underlie humour processing. The aim of the current study was to find distinctive groups of subjects with respect to black humour processing, intellectual capacities, mood disturbance and aggressiveness. A total of 156 adults rated black humour cartoons and conducted measurements of verbal and nonverbal intelligence, mood disturbance and aggressiveness. Cluster analysis yields three groups comprising following properties: (1) moderate black humour preference and moderate comprehension; average nonverbal and verbal intelligence; low mood disturbance and moderate aggressiveness; (2) low black humour preference and moderate comprehension; average nonverbal and verbal intelligence, high mood disturbance and high aggressiveness; and (3) high black humour preference and high comprehension; high nonverbal and verbal intelligence; no mood disturbance and low aggressiveness. Age and gender do not differ significantly, differences in education level can be found. Black humour preference and comprehension are positively associated with higher verbal and nonverbal intelligence as well as higher levels of education. Emotional instability and higher aggressiveness apparently lead to decreased levels of pleasure when dealing with black humour. These results support the hypothesis that humour processing involves cognitive as well as affective components and suggest that these variables influence the execution of frame shifting and conceptual blending in the course of humour processing. PMID- 28101814 TI - Arbutus andrachne L. Reverses Sleep Deprivation-Induced Memory Impairments in Rats. AB - Sleep deprivation (SD) is associated with cognitive deficits. It was found to affect the hippocampus region of the brain by impairing memory formation. This impairment is suggested to be caused by elevation in oxidative stress in the body, including the brain during SD. It was hypothesized that the methanolic extract of the fruits of Arbutus andrachne L. (Ericaceae) will prevent chronic SD induced impairment of hippocampal memory via its antioxidative properties. The methanolic extract of the fruits of A. andrachne was evaluated for its beneficial properties to reverse SD-induced cognitive impairment in rats. Animals were sleep deprived for 8 weeks using a multiple platform model. The extract was administered i.p. at three doses (50, 200, and 500 mg/kg). Behavioral studies were conducted to test the spatial learning and memory using radial arm water maze (RAWM). In addition, the hippocampus was dissected to analyze the following oxidative stress markers: glutathione (GSH), oxidized glutathione (GSSG), GSH/GSSG, glutathione peroxidase (GPx), and catalase. Chronic SD impaired short- and long-term memories (P < 0.05). Treatment of animals with A. andrachne fruit extract at all doses prevented long-term memory impairment induced by SD while such treatment prevented short-term memory impairment only at 200 and 500 mg/kg dose levels. Moreover, A. andrachne fruit extract normalized the reduction in the hippocampus GSH/GSSG ratio and activity of GPx, and catalase (P < 0.05) induced by chronic sleep deprivation. Chronic sleep deprivation impaired both short- and long-term memory formation, while methanolic extract of A. andrachne fruits reversed this impairment, probably through normalizing oxidative stress in the hippocampus. PMID- 28101811 TI - The distribution and function of human memory T cell subsets in lung cancer. AB - The distribution and function of T lymphocytes in human lung cancer remain limited. In this study, we investigated the properties of human T cell subsets in the blood of non-small cell lung cancer (NSCLC) patients. We found a relatively normal level of CD4+ subsets in the blood of NSCLC patients, but CD8+ effector T cells increased and CD8+ effector memory cells declined compared to the healthy donors. To further analyze their properties, we stimulated the peripheral blood mononuclear cells (PBMCs) of NSCLC patients by mitogens to examine cytokine production. Our data suggest that both CD4+ and CD8+ naive cells in NSCLC patients significantly reduced IFN-gamma and TNF-alpha production. Additionally, fewer CD8+ effector cells produced IFN-gamma and TNF-alpha in NSCLC patients than in healthy subjects. Moreover, similar results were observed for CD4+ or CD8+ memory cells in NSCLC patients for the production of IFN-gamma, TNF-alpha, and IL 17. Therefore, our results strongly suggest that the function of CD4+ and CD8+ T lymphocytes in NSCLC patients is compromised or dysregulated. The development of vaccines and antitumor immunotherapy may be essential for the treatment of lung cancer patients. PMID- 28101816 TI - Retraction note to: Brassica RNA binding protein ERD4 is involved in conferring salt, drought tolerance and enhancing plant growth in Arabidopsis. PMID- 28101813 TI - A Multi-US City Assessment of Awareness and Uptake of Pre-exposure Prophylaxis (PrEP) for HIV Prevention Among Black Men and Transgender Women Who Have Sex with Men. AB - The HIV epidemic among Black men and transgender women who have sex with men (BMTW) demands an urgent public health response. HIV point prevalence among this population ranges from 25 to 43%-a rate far exceeding any other group. Pre exposure prophylaxis (PrEP) for HIV prevention is a very promising prevention tool; however, its full potential to slow the epidemic has yet to be realized. For the current study, random time-location sampling at Black Gay Pride Events was used to collect data from N = 1274 BMTW, from five US cities, reporting HIV negative/unknown status. In-field HIV testing was also provided to participants. Participants were assessed on awareness and use of PrEP, health care factors, HIV testing history, psychosocial variables, and sex behaviors. About one third of participants were aware of PrEP (39%), and a small percentage of participants were users of PrEP (4.6%). In multivariable analyses, being in a relationship, testing for HIV in the past 6 months, and others being aware of one's sexuality were positively associated with PrEP awareness. Higher levels of internalized homophobia and greater numbers of female sex partners were positively associated with PrEP use, while education and condom use were negatively associated. Based on study findings, messaging and uptake of PrEP needs greater expansion and requires novel approaches for scale-up. Improving linkage to HIV testing services is likely critical for engaging BMTW with PrEP. The potential for PrEP to slow the HIV epidemic is high; however, we must strengthen efforts to ensure universal availability and uptake. PMID- 28101815 TI - Developing a Crowdsourcing Approach and Tool for Pharmacovigilance Education Material Delivery. AB - The number of pharmacovigilance professionals worldwide is increasing with a high staff turnover. There is a constant stream of new colleagues with an interest or need to learn about the discipline. Consequently, there is an increasing need for training in pharmacovigilance. An important step towards this has been made through developing and publishing the World Health Organization (WHO) International Society of Pharmacovigilance (ISoP) Pharmacovigilance Curriculum. Using the Pharmacovigilance Curriculum effectively, it should be supplemented by providing comprehensive training material from various sources, and making the Pharmacovigilance Curriculum attractive and a high-utility product. We describe a pilot of the development and initial evaluation of a crowdsourcing tool for the provision of pharmacovigilance education material. Pharmacovigilance experts shared links to their material to sections of relevance in the hierarchy and a small group of organisations conducted an initial testing. In this pilot, we have shown the usability of such a web-based tool. The strengths of this approach include the potential for a routine 'democratic' approach to sharing educational material to a wider community and an openness for access. PMID- 28101817 TI - Seeing is Engaging: Vlogs as a Tool for Patient Engagement. PMID- 28101818 TI - Autophagy is a regulator of TRAIL-induced apoptosis in NSCLC A549 cells. AB - Autophagy, a catabolic process by which cytoplasmic components are degraded in lysosomes, plays an important role in the maintenance of cellular homeostasis. Dysregulation of autophagy is associated with several diseases. However, few studies have addressed the role of autophagy in the lung, and its role in lung diseases remains unclear. In the present study, we examined the effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on autophagy in A549 cells and explored the underlying mechanisms. We showed that TRAIL promoted autophagosome formation, as detected by the levels of LC3-II, and its effect on promoting autophagy was dependent on the expression of the autophagy related genes (ATGs) Atg5, Atg7, and beclin-1. TRAIL-induced ATG expression was attenuated by JNK silencing or treatment with the JNK inhibitor SP600125, indicating the involvement of the JNK pathway. Crosstalk between autophagy and apoptosis was demonstrated by silencing the autophagy related genes Atg5, Atg7, and beclin-1, and the dependence of TRAIL-induced apoptosis on autophagy-related gene expression. Taken together, our results indicate that TRAIL promotes autophagy in A549 cells via a mechanism involving the modulation of ATG expression through the JNK pathway. Inhibition of autophagy enhanced TRAIL induced cell proliferative inhibition and apoptosis in A549 cells. PMID- 28101821 TI - Prevalence and Characteristics of Patients with Suspected Inherited Renal Cell Cancer: Application of the ACMG/NSGC Genetic Referral Guidelines to Patient Cohorts. AB - Patients with suspected hereditary renal cell cancer (RCC) are under-referred for genetic evaluation. Characterizing the prevalence and characteristics of suspected inherited RCC is a crucial step toward advancing personalized, genetically-based cancer risk management for patients and their families. To evaluate the prevalence and characteristics of suspected inherited RCC syndromes based on consensus criteria, we performed a cross-sectional analysis of patients with a diagnosis of RCC in SEER (2001-2011, n = 105,754) and in our institutional cancer registry (2004-2013, n = 998). Consensus criteria for referral of patients with RCC for genetic evaluation from the American College of Medical Genetics and Genomics and National Society of Genetic Counselors (ACMG/NSGC) were applied to the two cohorts. The associations between meeting referral criteria with demographic characteristics were assessed with chi-square tests. Overall, 24.0 % of the SEER cohort and 33.7 % of our institutional cohort met ACMG/NSGC referral criteria for genetic counseling. While white patients more commonly met early onset clear cell RCC criteria, black patients met papillary RCC criteria at twice the rate of whites in both cohorts (p < 0.0001). As many as 1 in 5 individuals with RCC meet referral criteria for genetic evaluation based on newly emerging guidelines, with differences in pathology noted by race. Prospective genetic testing studies utilizing emerging referral guidelines should help to refine the genetic spectrum of inherited kidney cancer. This study supports efforts to increase awareness of referral of patients with RCC for genetic counseling particularly among urologic providers. PMID- 28101820 TI - Insulin/insulin-like growth factor-1 signalling (IIS) based regulation of lifespan across species. AB - An organism's well-being is facilitated by numerous molecular and biochemical pathways that ensure homeostasis within cells and tissues. Aging causes a gradual let-down in the maintenance of homeostasis due to various endogenous and environmental challenges, leading to amassing of damages, functional deterioration of different tissues and vulnerability to ailments. Nutrient sensing pathways that maintain glucose homeostasis in body are involved in regulation of aging. Insulin/insulin-like growth factor-1 (IGF-1) signalling (IIS) pathway was the first nutrient sensing pathway discovered to affect the aging process. This pathway is highly conserved and the most studied among different organisms. Epigenetic machineries that include DNA and histone modifying enzymes and various non-coding RNAs have been identified as important contributors to nutrition-related longevity and aging control. In this report, we present the homology and differences in IIS pathway of various organisms including worm, fly, rodent and human. We also discuss how epigenome remodelling, chromatin based strategies, small and long non-coding RNA are involved to regulate multiple steps of aging or age-related insulin homeostasis. Enhanced study of the role of IIS pathway and epigenetic mechanisms that regulate aging may facilitate progressive prevention and treatment of human age-related diseases. PMID- 28101819 TI - High Central Aortic Rather than Brachial Blood Pressure is Associated with Carotid Wall Remodeling and Increased Arterial Stiffness in Childhood. AB - INTRODUCTION: In adults, central blood pressure (cBP) is reported to associate target organ damages (TODs) rather than peripheral blood pressure (pBP). However, data regarding the association of pre-clinical TODs with cBP and pBP in pediatric populations are scarce. AIM: To evaluate in children and adolescents the importance of cBP and pBP levels, in terms of their association with hemodynamic and vascular changes. METHODS: 315 subjects [age (mean/range) 12/8-18 years] were included. MEASUREMENTS: pBP (oscillometry, Omron-HEM433INT and Mobil-O-Graph), cBP levels and waveforms (oscillometry, Mobil-O-Graph; applanation tonometry, SphygmoCor), aortic wave reflection-related parameters, carotid intima-media thickness (CIMT) and carotid (elastic modulus, stiffness-index) and aortic stiffness (carotid-femoral pulse wave velocity, PWV). Four groups were defined considering pBP and cBP percentiles (th): cBP >=90th, cBP <90th, pBP >=90th, pBP <90th. In each group, haemodynamic and vascular parameters were compared for subgroups defined considering the level of the remaining blood pressure (cBP or pBP). Subgroups were matched for anthropometric and cardiovascular risk factors (propensity matching-score). RESULTS: Subjects with high cBP showed a worse cardiovascular risk profile in addition to worse peripheral hemodynamic conditions. The CIMT, carotid and aortic stiffness levels were also higher in those subjects. CIMT and carotid stiffness remained statistically higher when subjects were matched for pBP and other cardiovascular risk factors. There were no differences in arterial properties when subjects were analyzed (compared) considering similar pBP levels, during normal and high cBP conditions. CONCLUSION: Compared with pBP, the cBP levels show a greater association with vascular alterations (high CIMT and arterial stiffness), in children and adolescents. PMID- 28101822 TI - Lupinus albus Conglutin Gamma Modifies the Gene Expressions of Enzymes Involved in Glucose Hepatic Production In Vivo. AB - Lupinus albus seeds contain conglutin gamma (Cgamma) protein, which exerts a hypoglycemic effect and positively modifies proteins involved in glucose homeostasis. Cgamma could potentially be used to manage patients with impaired glucose metabolism, but there remains a need to evaluate its effects on hepatic glucose production. The present study aimed to analyze G6pc, Fbp1, and Pck1 gene expressions in two experimental animal models of impaired glucose metabolism. We also evaluated hepatic and renal tissue integrity following Cgamma treatment. To generate an insulin resistance model, male Wistar rats were provided 30% sucrose solution ad libitum for 20 weeks. To generate a type 2 diabetes model (STZ), five day-old rats were intraperitoneally injected with streptozotocin (150 mg/kg). Each animal model was randomized into three subgroups that received the following oral treatments daily for one week: 0.9% w/v NaCl (vehicle; IR-Ctrl and STZ Ctrl); metformin 300 mg/kg (IR-Met and STZ-Met); and Cgamma 150 mg/kg (IR-Cgamma and STZ-Cgamma). Biochemical parameters were assessed pre- and post-treatment using colorimetric or enzymatic methods. We also performed histological analysis of hepatic and renal tissue. G6pc, Fbp1, and Pck1 gene expressions were quantified using real-time PCR. No histological changes were observed in any group. Post-treatment G6pc gene expression was decreased in the IR-Cgamma and STZ Cgamma groups. Post-treatment Fbp1 and Pck1 gene expressions were reduced in the IR-Cgamma group but increased in STZ-Cgamma animals. Overall, these findings suggest that Cgamma is involved in reducing hepatic glucose production, mainly through G6pc inhibition in impaired glucose metabolism disorders. PMID- 28101823 TI - Biological Activities of Asteraceae (Achillea millefolium and Calendula officinalis) and Lamiaceae (Melissa officinalis and Origanum majorana) Plant Extracts. AB - Asteraceae (Achillea millefolium and Calendula officinalis) and Lamiaceae (Melissa officinalis and Origanum majorana) extracts were obtained by applying two sequential extraction processes: supercritical fluid extraction with carbon dioxide, followed by ultrasonic assisted extraction using green solvents (ethanol and ethanol:water 50:50). The extracts were analyzed in terms of the total content of phenolic compounds and the content of flavonoids; the volatile oil composition of supercritical extracts was analyzed by gas chromatography and the antioxidant capacity and cell toxicity was determined. Lamiaceae plant extracts presented higher content of phenolics (and flavonoids) than Asteraceae extracts. Regardless of the species studied, the supercritical extracts presented the lowest antioxidant activity and the ethanol:water extracts offered the largest, following the order Origanum majorana > Melissa officinalis ~ Achillea millefolium > Calendula officinalis. However, concerning the effect on cell toxicity, Asteraceae (especially Achillea millefolium) supercritical extracts were significantly more efficient despite being the less active as an antioxidant agent. These results indicate that the effect on cell viability is not related to the antioxidant activity of the extracts. PMID- 28101824 TI - Empirically derived weights for GMS capitation payments to General Practitioners. AB - AIM: Unlike other weighted capitation schemes used in Irish health service financing and in health systems internationally, the GMS capitation payments scheme for General Practitioners lacks transparency in both the data used and the model employed. In this study, evidence-based weights were generated and compared to current payment weights. METHODS: Four datasets on GP utilisation were interrogated. RESULTS: Evidence-based weights indicated that over 70s had higher payments per consultation than other groups. Considerable intra-age band differences in capitation payment were detected. DISCUSSION AND CONCLUSION: The results suggest that there is a need for a comprehensive review of the current payments system. Current age bands should be narrowed. The implications for the efficiency and equity of general practice in Ireland are discussed. PMID- 28101826 TI - Sagittal band, boutonniere, and pulley injuries in the athlete. AB - PURPOSE OF REVIEW: While hand injuries occur frequently in the athletic population, sagittal band ruptures, boutonniere deformities, and pulley ruptures are infrequently encountered. These injuries represent diagnostic challenges and can result in significant impairment. Early recognition with appropriate treatment is necessary to maximize recovery and minimize return to athletic competition. This review will focus on the underlying mechanism, pathophysiology of injury, diagnosis, and treatment of each of these injuries. RECENT FINDINGS: With respect to sagittal band ruptures, boutonniere deformities, and pulley ruptures, the recent literature has been limited in scope. For sagittal band injuries, current efforts have focused on alternative techniques for sagittal band reconstruction. Little progress has been made in recent years with respect to boutonniere injuries in the athletic population; prevention of fixed deformities remains the backbone of treatment. The exact contribution from individual and combined pulley injuries in the creation of bowstringing remains controversial. Recent anatomical studies have failed to definitively answer the question of what degree of rupture is necessary to create symptomatic bowstringing. Favorable outcomes, with respect to both preventing bowstringing and returning to full athletic participation, have been newly reported following pulley reconstruction in rock climbers. Due to the infrequent nature of sagittal band ruptures, boutonniere deformities, and pulley ruptures, current treatment is mostly guided by historically established methods, limited case series, and case reports. Nonsurgical treatment remains the mainstay for most injuries and, if employed early, often precludes the need for surgery. Further anatomical and clinical research, including outcome studies, is necessary in guiding treatment algorithms. PMID- 28101825 TI - Neurosarcoidosis: clinical presentations and changing treatment patterns in an Irish Caucasian population. AB - BACKGROUND: The clinical manifestations of neurosarcoidosis are highly variable and it should be considered as a potential differential diagnosis in any neurological presentation. AIM: This study was designed to describe the clinical, diagnostic, and treatment patterns and functional outcome in a Caucasian neurosarcoidosis population. DESIGN: A retrospective analysis was performed on prospectively recorded data in patients attending our neurology clinic between 2008 and 2014 with a diagnosis of definite or probable neurosarcoidosis according to Zajiek criteria. METHODS: Detailed clinical features, baseline demographic data, results of investigations, treatment type and duration, and clinical outcomes were collated. RESULTS: Eleven patients were identified (55% men) with mean age 39 years (range 21-63). Four had a prior history of systemic sarcoidosis leading to earlier diagnosis (6.7 vs 13.1 months). Six were found to have evidence of systemic sarcoidosis on further investigation and one was biopsy proven isolated neurosarcoidosis. The commonest site of CNS involvement was the cranial nerves (64%), and headache (45%) was the most frequent presenting symptom. MRI abnormalities included leptomeningeal enhancement, white matter lesions, acute arteritis, spinal cord lesion, and cauda equina enhancement. The commonest CSF finding was raised protein (n = 6) and a lymphocytic pleocytosis (n = 7). Serum ACE was only elevated in three cases. Ten patients were treated with both corticosteroids and steroid-sparing agents 8 of whom went into remission. CONCLUSIONS: This series highlights the diverse nature of neurosarcoidosis. Early introduction of aggressive therapy with corticosteroids and steroid-sparing agents appears to improve clinical outcome. PMID- 28101827 TI - Scapholunate and perilunate injuries in the athlete. AB - PURPOSE OF THE REVIEW: Scapholunate and perilunate injuries can be difficult to diagnose and treat in the athlete. In this review article, we present the mechanism of injury, evaluation, management, and outcomes of treatment for these injuries. RECENT FINDINGS: Acute repair of dynamic scapholunate ligament injuries remains the gold standard, but judicious use of a wrist splint can be considered for the elite athlete who is in season. The treatment of static scapholunate ligament injury remains controversial. Newer SL reconstructive techniques that aim to restore scapholunate function without compromising wrist mobility as much as tenodesis procedures show promise in athlete patients. Acute injuries to the scapholunate ligament are best treated aggressively in order to prevent the sequelae of wrist arthritis associated with long-standing ligamentous injury. Acute repair is favored. Reconstructive surgical procedures to manage chronic scapholunate injury remain inferior to acute repair. The treatment of lunotriquetral ligament injuries is not well defined. PMID- 28101829 TI - Autism Spectrum Disorders - Diagnosis and Management. AB - Autism Spectrum Disorder (ASD) is a neuro-developmental disorder commonly seen in children. It is characterized by age inappropriate, impaired social communication and the presence of stereotypic behavior. This disorder is hypothesized to result from cerebral dysfunction arising from a complex interaction between genetic, epigenetic and environmental factors. ASD should be suspected in children failing ASD specific screening tests, in the presence of red flags in social, language and/or play domains, in children with developmental or language delay, abnormal behavior, poor school performance or in those who are at high risk. Comprehensive assessment comprises of a step-wise approach that includes taking a detailed history, performing a holistic examination and observing the child closely in relation to play, social interaction and behavior. Diagnosis is established by application of the diagnostic criteria for ASD of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM V). The degree of severity, intellectual and language impairment and presence of other illnesses should be specified. Functional assessment identifies an individual's strengths and weaknesses. All these are important to formulate a customized intervention plan along with the family. The goal is to build up skills enabling optimal and as far as possible normal functioning while simultaneously reducing maladaptive behavior. This is achieved by a multi-disciplinary team comprising of various personnel experienced in tackling issues in ASD related to their respective areas of expertise. Intervention is primarily non-pharmacological, based on behavioral modification strategies. Drugs are only indicated in the reduction of target symptoms refractory to behavioral intervention. Although there is no cure, timely and appropriate intervention can improve the quality of life significantly. PMID- 28101828 TI - Current trends in the diagnosis and management of syndesmotic injury. AB - Ideal management of the various presentations of syndesmotic injury remains controversial to this day. High quality evidentiary science on this topic is rare, and numerous existing studies continue to contradict one another. The primary reasons for these discrepancies are that previous studies have failed to (1) properly distinguish between isolated (non-fractured) and non-isolated injuries, (2) accurately define stable from unstable injuries, and (3) sufficiently differentiate between acute and chronic injuries. The purpose of this review is to summarize today's body of literature regarding diagnosis and management of syndesmotic injury and discuss current trends and important future directions to optimize care of this very heterogeneous population. PMID- 28101830 TI - Getting ahead of yourself: Parafoveal word expectancy modulates the N400 during sentence reading. AB - An important question in the reading literature regards the nature of the semantic information readers can extract from the parafovea (i.e., the next word in a sentence). Recent eye-tracking findings have found a semantic parafoveal preview benefit under many circumstances, and findings from event-related brain potentials (ERPs) also suggest that readers can at least detect semantic anomalies parafoveally (Barber, Van der Meij, & Kutas, Psychophysiology, 50(1), 48-59, 2013). We use ERPs to ask whether fine-grained aspects of semantic expectancy can affect the N400 elicited by a word appearing in the parafovea. In an RSVP-with-flankers paradigm, sentences were presented word by word, flanked 2 degrees bilaterally by the previous and upcoming words. Stimuli consisted of high constraint sentences that were identical up to the target word, which could be expected, unexpected but plausible, or anomalous, as well as low constraint sentences that were always completed with the most expected ending. Findings revealed an N400 effect to the target word when it appeared in the parafovea, which was graded with respect to the target's expectancy and congruency within the sentence context. Furthermore, when targets appeared at central fixation, this graded congruency effect was mitigated, suggesting that the semantic information gleaned from parafoveal vision functionally changes the semantic processing of those words when foveated. PMID- 28101831 TI - Psychometric properties of the Portuguese version of the Yale Food Addiction Scale. AB - PURPOSE: Rising rates of obesity have been recently associated to the novel concept of food addiction (FA). The Yale Food Addiction Scale (YFAS) is the most widely used measure for examining FA (1) and analysis of its reliability and validity is expected to facilitate empirical research on the construct. Here, we tested the psychometric properties of a Portuguese version of the YFAS (P-YFAS), establishing its factor structure, reliability and construct validity. METHODS: Data were obtained from 468 Portuguese individuals, 278 sampled from non-clinical populations, and 190 among obese candidates for weight-loss surgery. A battery of self-report measures of eating behavior was applied. RESULTS: Confirmatory factor analysis verified a one-factor structure with acceptable fit, with item analysis suggesting the need to eliminate item 24 from the P-YFAS. Internal consistency (KR-20 = .82) and test-retest stability were adequate. Correlation analyses supported convergent and divergent validity of the P-YFAS, particularly in the clinical sample. Both FA symptom count and diagnosis, according to the P-YFAS, adequately discriminated between samples, with classification of FA met by 2.5 and 25.8% of the participants in the non-clinical and clinical samples, respectively. CONCLUSIONS: These findings reinforce the use of P-YFAS in non clinical and clinical populations. Future directions for extending YFAS validation are discussed. PMID- 28101832 TI - Serum uric acid levels contribute to new renal damage in systemic lupus erythematosus patients. AB - This study aims to determine whether uric acid levels contribute to new renal damage in systemic lupus erythematosus (SLE) patients. This prospective study was conducted in consecutive patients seen since 2012. Patients had a baseline visit and follow-up visits every 6 months. Patients with >=2 visits were included; those with end-stage renal disease (regardless of dialysis or transplantation) were excluded. Renal damage was ascertained using the SLICC/ACR damage index (SDI). Univariable and multivariable Cox-regression models were performed to determine the risk of new renal damage. Uric acid was included as a continuous and dichotomous (per receiving operating characteristic curve) variable. Multivariable models were adjusted for age at diagnosis, disease duration, socioeconomic status, SLEDAI, SDI, serum creatinine, baseline use of prednisone, antimalarials, and immunosuppressive drugs. One hundred and eighty-six patients were evaluated; their mean (SD) age at diagnosis was 36.8 (13.7) years; nearly all patients were mestizo. Disease duration was 7.7 (6.8) years. Follow-up time was 2.3 (1.1) years. The SLEDAI was 5.2 (4.3) and the SDI 0.8 (1.1). Uric acid levels were 4.5 (1.3) mg/dl. During follow-up, 16 (8.6%) patients developed at least one new point in the renal domain of the SDI. In multivariable analyses, uric acid levels (continuous and dichotomous) at baseline predicted the development of new renal damage (HR 3.21 (1.39-7.42), p 0.006; HR 18.28 (2.80 119.48), p 0.002; respectively). Higher uric acid levels contribute to the development of new renal damage in SLE patients independent of other well-known risk factors for such occurrence. PMID- 28101833 TI - Gout treatment: survey of Brazilian rheumatology residents. AB - To assess the current practices in gout management among Brazilian rheumatology residents. We performed a cross-sectional online survey among all the rheumatology residents and those rheumatologists who had just completed their training (post-residency (PR)) regarding their approach to gout management. Results were compared with the 2012 American College of Rheumatology (ACR) gout guidelines and with the responses of a previous survey with a representative sample of practicing Brazilian rheumatologists (RHE). We received 224 responses (83%) from 271 subjects. Among all respondents, the first-choice treatment for gout flares was the combination of a nonsteroidal anti-inflammatory drug + colchicine for otherwise healthy patients. A target serum urate <6 mg/dL for patients without tophi was reported by >75%. Less than 70% reported starting allopurinol at low doses (<=100 mg/day) for patients with normal renal function and <50% reported maintaining urate-lowering therapy indefinitely for patients without tophi. Among residents and PR, the residency stage was the main predictor of concordance with the ACR guidelines, with PR achieving the greatest rates. Reported practices were commonly concordant with the 2012 ACR gout guidelines, especially among PR. However, some important aspects of gout management need improvement. These results will guide the development of a physician education program to improve the management of gout patients in Brazil. PMID- 28101834 TI - Management of acute skin toxicity with Hypericum perforatum and neem oil during platinum-based concurrent chemo-radiation in head and neck cancer patients. AB - Acute skin toxicity is a frequent finding during combined radiotherapy and chemotherapy in head and neck cancer patients. Its timely and appropriate management is crucial for both oncological results and patient's global quality of life. We herein report clinical data on the use of Hypericum perforatum and neem oil in the treatment of acute skin toxicity during concurrent chemo radiation for head and neck cancer. A consecutive series of 50 head and neck cancer patients undergoing concomitant radio-chemotherapy with weekly cisplatin was analyzed. Treatment with Hypericum perforatum and neem oil was started in case of G2 acute skin toxicity according to the RTOG/EORTC scoring scale and continued during the whole treatment course and thereafter until complete recovery. The maximum detected acute skin toxicity included Grade 2 events in 62% of cases and G3 in 32% during treatment and G2 and G3 scores in 52 and 8%, respectively, at the end of chemo-radiation. Grade 2 toxicity was mainly observed during weeks 4-5, while G3 during weeks 5-6. Median times spent with G2 or G3 toxicity were 23.5 and 14 days. Patients with G3 toxicity were reconverted to a G2 profile in 80% of cases, while those with a G2 score had a decrease to G1 in 58% of cases. Time between maximum acute skin toxicity and complete skin recovery was 30 days. Mean worst pain score evaluated with the Numerical Rating Scale-11 was 6.9 during treatment and 4.5 at the end of chemo-radiotherapy. Hypericum perforatum and neem oil proved to be a safe and effective option in the management of acute skin toxicity in head and neck cancer patients submitted to chemo-radiation with weekly cisplatin. Further studies with a control group and patient-reported outcomes are needed to confirm this hypothesis. PMID- 28101836 TI - A Review of Clinical Outcomes Associated with Two Meropenem Dosing Strategies. AB - Meropenem is a carbapenem antibiotic that exhibits time-dependent bactericidal activity, traditionally dosed intravenously at 1 g every 8 h. In order to maximize its pharmacodynamic activity and reduce costs, an alternative regimen employed by many institutions is 500 mg every 6 h. The objective of this review was to summarize and evaluate published literature comparing clinical outcomes associated with these two meropenem dosing regimens. The literature was searched up to October 2016 using the MEDLINE, EMBASE, and Google Scholar databases. Three retrospective cohort studies were identified that compared clinical outcomes in general infectious disease patients (two studies) and patients with febrile neutropenia (one study). All studies reported no difference in clinical outcomes (clinical success, time to defervescence, sign or symptom resolution, length of stay, mortality, need for other antibiotics, and seizure rates). One study reported reduced economic costs with the alternative dosing. Interpretation of findings was primarily limited by small sample sizes and generalizability. Based on the data reviewed, the alternative dosing regimen of meropenem 500 mg intravenously every 6 h could be considered a therapeutic option. Future studies are needed to confirm the findings of this review, especially in high-risk populations such as immunocompromised patients or those with severe infections. PMID- 28101835 TI - Relationships Between Perceived Family Gambling and Peer Gambling and Adolescent Problem Gambling and Binge-Drinking. AB - The study systematically examined the relative relationships between perceived family and peer gambling and adolescent at-risk/problem gambling and binge drinking. It also determined the likelihood of at-risk/problem gambling and binge drinking as a function of the number of different social groups with perceived gambling. A multi-site high-school survey assessed gambling, alcohol use, presence of perceived excessive peer gambling (peer excess-PE), and family gambling prompting concern (family concern-FC) in 2750 high-school students. Adolescents were separately stratified into: (1) low-risk, at-risk, and problem/pathological gambling groups; and, (2) non-binge-drinking, low-frequency binge-drinking, and high-frequency-binge-drinking groups. Multinomial logistic regression showed that relative to each other, FC and PE were associated with greater likelihoods of at-risk and problem/pathological gambling. However, only FC was associated with binge-drinking. Logistic regression revealed that adolescents who endorsed either FC or PE alone, compared to no endorsement, were more likely to have at-risk and problem/pathological gambling, relative to low risk gambling. Adolescents who endorsed both FC and PE, compared to PE alone, were more likely to have problem/pathological gambling relative to low-risk and at-risk gambling. Relative to non-binge-drinking adolescents, those who endorsed both FC and PE were more likely to have low- and high-frequency-binge-drinking compared to FC alone or PE alone, respectively. Family and peer gambling individually contribute to adolescent at-risk/problem gambling and binge drinking. Strategies that target adolescents as well as their closely affiliated family and peer members may be an important step towards prevention of harm associated levels of gambling and alcohol use in youths. PMID- 28101837 TI - Drug Exposure and the Risk of Microscopic Colitis: A Critical Update. AB - A variety of luminal antigens, including a wide range of drugs, have been associated with the still little-known pathophysiology of microscopic colitis (MC), with variable evidence suggesting causality. This article aims to review the aspects related to drugs as potential triggers of MC; to discuss the most commonly identified associations between drugs and MC; and to analyze the limitations of the studies currently available. A literature search was performed in PubMed combining the search terms 'drug exposure', 'drug consumption', and 'risk factors' with 'microscopic colitis', 'lymphocytic colitis', and 'collagenous colitis', with no language restrictions. Reference lists of retrieved documents were also reviewed. A handful of case-control studies have demonstrated significant associations between some commonly used drugs and a higher risk of developing MC. No universally accepted criteria for establishing cause-effect relationships in adverse reactions to drugs are available, but several methods that can be applied to MC, can provide degrees of the likelihood of an association. A high probability imputation in the development of MC as a drug adverse effect has only been demonstrated for individual cases by applying chronological (challenge, de-challenge, and relapse with re-challenge) and semiological criteria. Several case-control studies have shown significant associations between exposure to drugs and MC, but the variability in their design, the reference populations used, and the definitions for drug exposure considered require specific analyses. It can be concluded that drug exposure and MC as a likely cause-effect relationship has only been described for a handful of drugs and in individual cases. PMID- 28101840 TI - Stereoselective Conversion of Ketoprofen in Men Versus Women from Two Different Oral Dosage Formulations: Observations and Introspection of the Pharmacokinetic Data. PMID- 28101838 TI - Renal consequences of preterm birth. AB - BACKGROUND: The developmental origin of health and disease concept identifies the brain, cardiovascular, liver, and kidney systems as targets of fetal adverse programming with adult consequences. As the limits of viability in premature infants have been pushed to lower gestational ages, the long-term impact of prematurity on kidneys still remains a significant burden during hospital stay and beyond. OBJECTIVES: The purpose of this study is to summarize available evidence, mechanisms, and short- and long-term renal consequences of prematurity and identify nephroprotective strategies and areas of uncertainty. RESULTS: Kidney size and nephron number are known to be reduced in surviving premature infants due to disruption of organogenesis at a crucial developmental time point. Inflammation, hyperoxia, and antiangiogenic factors play a role in epigenetic conditioning with potential life-long consequences. Additional kidney injury from hypoperfusion and nephrotoxicity results in structural and functional changes over time which are often unnoticed. Nephropathy of prematurity and acute kidney injury confound glomerular and tubular maturation of preterm kidneys. Kidney protective strategies may ameliorate growth failure and suboptimal neurodevelopmental outcomes in the short term. In later life, subclinical chronic renal disease may progress, even in asymptomatic survivors. CONCLUSION: Awareness of renal implications of therapeutic interventions and renal conservation efforts may lead to a variety of short and long-term benefits. Adequate monitoring and supplementation of microelement losses, gathering improved data on renal handling, and exploration of new avenues such as reliable markers of injury and new therapeutic strategies in contemporary populations, as well as long-term follow-up of renal function, is warranted. PMID- 28101841 TI - Influence of Sex and Food on the Bioavailability and the R-to-S Conversion of Ketoprofen Stereoisomers in Humans. PMID- 28101839 TI - Surgical Treatment of Ischemic Mitral Regurgitation: Valve Repair Versus Replacement. AB - PURPOSE OF REVIEW: Ischemic mitral regurgitation (MR), which occurs in about 20 30% patients with a prior myocardial infarction, is associated with worsening heart failure and an increase in cardiovascular mortality. It should be treated surgically if certain hemodynamic severity criteria are met and in patients who continue to experience symptoms of heart failure despite optimal medical therapy. However, current guidelines do not suggest which of the available approaches to mitral valve surgery-mitral valve (MV) repair or replacement (MVR) is superior for this indication. While MV repair is reported to confer improved survival, MVR may provide higher rates of freedom from recurrent MR. This article attempts to provide the reader with a comprehensive review and comparison of current techniques of mitral valve surgery in patients with severe ischemic MR. RECENT FINDINGS: The first randomized trial to compare MV repair versus MVR in patients with severe ischemic MR, the Cardiothoracic Surgical Trials Network (CTSN) trial, was recently concluded and reported no significant difference in the primary outcome of left ventricular end systolic volume index between the two approaches at either 1- or 2-year follow-ups. Data comparing approaches of MV repair and MVR for ischemic MR is largely limited to small, non-randomized retrospective trials. The only randomized trial data to examine this issue suggested no difference in mortality with either MVR or MV repair; however, MVR was shown to be consistently associated with higher rates of MR recurrence. Certain echocardiographic features have been reported to predict poor outcomes with MVR and may help refine the selection of the surgical approach in the individual patient. PMID- 28101842 TI - Violence Exposure Subtypes Differentially Mediate the Relation between Callous Unemotional Traits and Adolescent Delinquency. AB - Research with children and adolescents has established a link between callous unemotional (CU) traits and delinquency, as well as a link between violence exposure (witnessing and direct victimization) and diverse negative and antisocial outcomes. Little attention has been paid to investigating the association among CU traits, violence exposure, and various forms of delinquency. Using a sample of 753 adolescents (male =58%; African American =46%), the current study aimed to elucidate the mediating role of violence exposure (measured in grades 7, 8, 10, 11) on the relationship between CU traits measured in grade 7 and later delinquency (i.e., property, violent, drug, and sexual) assessed in grade 12. Total violence exposure (witnessing and direct victimization) mediated the association between CU traits and all forms of delinquency. When looking at witnessing and direct victimization separately, however, only witnessing violence mediated the relationship between CU traits and all forms of delinquency. These results highlight the importance of violence exposure in the CU-delinquency link, and showed the differential roles of indirect and direct forms of violence exposure on the association. Witnessing and direct victimization may involve different underlying mechanisms influencing developmental outcomes in youth. These findings have important implications for understanding developmental models of violence exposure, CU traits, and delinquency, as well as interventions for youth who have experienced both indirect and direct forms of violence. PMID- 28101843 TI - Postprandial GLP-2 Levels Are Increased After Biliopancreatic Diversion in Diabetic Individuals with Class I Obesity: a Prospective Study. AB - BACKGROUND: Biliopancreatic diversion (BPD) is a predominantly malabsorptive procedure. Glucagon-like peptide 2 (GLP-2) plays predominantly trophic effects on the gut. A significant increase in GLP-2 after BPD in rats was previously observed, but there are no studies investigating the effect of BPD in GLP-2 levels in humans. OBJECTIVE: The aim of this study is to evaluate the influence of BPD on the release of GLP-2. METHODS: This is a prospective cohort study that evaluated diabetic individuals with class I obesity which underwent BPD (Scopinaro operation) and were followed up for 12 months. Of 12 individuals, four did not comply with the proposed follow-up and were excluded from the analysis. GLP-2 levels were determined by means of an enzyme-linked immunosorbent assay (ELISA), and we collected serial lab samples through a standard meal tolerance test (MTT) in the immediate preoperative period and 12 months after surgery. RESULTS: During standard MTT, we observed significant increases of GLP-2 levels from 15 to 60 min (respectively, at 15 min, 5.7 +/- 3.4 versus 12.4 +/- 4.3, p = 0.029; 30 min, 6 +/- 3.5 versus 14.6 +/- 3.9; p = 0.004; 45 min, 5.6 +/- 4.1 versus 12.6 +/- 5.2, p = 0.013; 60 min, 5.8 +/- 2.9 versus 10.6 +/- 5.6, p = 0.022); then it began to gradually decrease to levels close to the basal. DISCUSSION: Our findings have confirmed that there is a significant increase in GLP-2 levels after BPD in humans. GLP-2 plays a number of roles which may be adaptive, compensatory, and beneficial in the context of BPD. The clinical implications of this finding remain to be completely understood. PMID- 28101844 TI - Prediction of Diabetes Remission at Long Term Following Biliopancreatic Diversion. AB - IMPORTANCE: In obese patients with type 2 diabetes (T2DM), the marked weight loss following bariatric surgery is accompanied in a consistent number of cases by T2DM resolution or control. The clinical need of preoperative parameters reliable in predicting a positive metabolic outcome at long term following the operation has then emerged. OBSERVATION: A cohort of 135 consecutive T2DM patients with a wide range of body mass index (BMI) at more than 5 years following biliopancreatic diversion (BPD) was considered. The 5-year-T2DM resolution, defined as glycosylated hemoglobin (HbA1C) lower than 6.5% without antidiabetic therapy, was related to demographic, anthropometric, and biochemical findings prior to the operation. The long-term metabolic outcome was positively related to baseline BMI values and negatively with the preoperative use of insulin. CONCLUSION: BMI and insulin therapy at the time of surgery are associated with the probability of T2DM long lasting remission and could be used as solid predictors before surgery. In the overweight and non morbidly obese diabetic patients, bariatric surgery is less efficient in determining long term T2DM resolution than in their morbid obese counterparts. PMID- 28101846 TI - CDK11p58 Promotes Microglia Activation via Inducing Cyclin D3 Nuclear Localization. AB - Microglia activation has been implicated in the pathogenesis of many neurological diseases. These reactive microglia are capable of producing a variety of proinflammatory mediators and potentially neurotoxic compounds. The increase of cell number and expression of CD11b are the main features of activated microglia. In this study, we examined the suppressive effects of CDK11p58 on microglia activation induced by lipopolysaccharide (LPS) in vitro. We found that in the activated microglia, the expression of CDK11p58 increased and the overexpression of CDK11p58 could reduce the increased proliferation and CD11b expression in LPS activated microglia. Such suppressive effects might be resulted from the interaction with cyclin D3 which promoted CDK11p58 nuclear localization. Our results suggested that CDK11p58 acted to regulate microglia activation through CDK11p58 and cyclin D3 interaction. PMID- 28101845 TI - Feasibility, Acceptability and Preliminary Treatment Outcomes in a School-Based CBT Intervention Program for Adolescents with ASD and Anxiety in Singapore. AB - Adolescents with autism spectrum disorder (ASD) are at high risk for anxiety difficulties and disorders. Clinic-based cognitive behavioral therapy (CBT) is effective; however, few published school-based CBT programs for youth with ASD exist. In this study, the Facing Your Fears CBT protocol was adapted for delivery and piloted within a school setting by non-clinicians, with culturally appropriate adaptations. 44 13-15 aged youth with ASD from 22 mainstream schools in Singapore participated. Feasibility, acceptability and preliminary treatment outcomes were examined. Decreases in youth and parent reported anxiety symptoms were reported. Staff and parents found the program useful. Stakeholder support was important for implementation. Initial findings reflect the importance of carefully bridging research-to-practice for youth with ASD and anxiety. PMID- 28101848 TI - Open access to scientific articles: a review of benefits and challenges. AB - The Internet has fundamentally changed the publishing of scholarly peer reviewed journals, and the way readers find and access articles. Digital access is nowadays the norm, in particular for researchers. The Internet has enabled a totally new business model, Open Access (OA), in which an article is openly available in full text for anyone with Internet access. This article reviews the different options to achieve this, whether by journals changing their revenue structures from subscription to publishing charges, or authors utilizing a number of options for posting OA versions of article manuscripts in repositories. It also discusses the regrettable emergence of "predatory" publishers, who spam academics, and make money by promising them rapid publication with only the semblance of peer review. The situation is further discussed from the viewpoints of different stakeholders, including academics as authors and readers, practicing physicians and the general public. PMID- 28101847 TI - Off-Target Anti-Inflammatory Activity of the P2X7 Receptor Antagonist AZ11645373. AB - We have found that a well-characterized P2X7 receptor antagonist AZ11645373 blocked production of pro-inflammatory chemokine IL-8 in endothelial cells treated with OxPAPC. The effect was not due to toxicity of AZ11645373 as documented by cellular metabolic activity assay. The mechanism of inhibition by AZ11645373 was apparently independent of the P2X7 receptor because this receptor was not involved in induction of IL-8 under our experimental conditions. In support of this notion, two P2X7 agonists ATP and BzATP did not upregulate IL-8. On the other hand, a chemically different P2X7 receptor antagonist A740003 did not inhibit OxPAPC-induced production of IL-8. The inhibitory action of AZ11645373 was observed at the level of IL-8 protein and messenger RNA (mRNA) induction. Furthermore, AZ11645373 inhibited induction of mRNA encoding for COX-2 (PTGS2) suggesting that its anti-inflammatory potential is not limited to suppression of IL-8 production. In addition to inhibiting stimulation by OxPAPC, AZ11645373 suppressed induction of IL-8 by TNFalpha and LPS. To summarize, AZ11645373 inhibits in a P2X7-independent manner action of chemically different inflammatory agonists such as OxPLs, LPS, and TNFalpha. Thus, AZ11645373 may be especially effective for treatment of inflammatory disorders due to a beneficial combination of P2X7 receptor-dependent effects (inhibition of inflammasome activation, antinociceptive effects) with P2X7-independent general anti inflammatory action described in this paper. PMID- 28101849 TI - Mechanistic Study of the Gas-Phase In-Source Hofmann Elimination of Doubly Quaternized Cinchona-Alkaloid Based Phase-Transfer Catalysts by (+)-Electrospray Ionization/Tandem Mass Spectrometry. AB - An unusual in-source fragmentation pattern observed for 14 doubly quaternized cinchona alkaloid-based phase-transfer catalysts (PTC) was studied using (+)-ESI high resolution mass spectrometry. Loss of the substituted benzyl cation (R1 or R2) was found to be the major product ion [M2+ - R1+ or R2+]+ in MS spectra of all PTC compounds. A Hofmann elimination product ion [M - H]+ was also observed. Only a small amount of the doubly charged M2+ ions were observed in the MS spectra, likely due to strong Columbic repulsion between the two quaternary ammonium cations in the gas phase. The positive voltage in the MS inlet but not the ESI probe was found to induce this extensive fragmentation for all PTC diboromo-salts. Compound 1 was used as an example to illustrate the proposed in source fragmentation mechanism. The mechanism of formation of the Hofmann elimination product ion [M - H]+ was further investigated using HRMS/MS, H/D exchange, and DFT calculations. The proposed formation of 2b as the major Hofmann elimination product ion was supported both by HRMS/MS and DFT calculations. Formation of product ion 2b through a concerted unimolecular Ei elimination pathway is proposed rather than a bimolecular E2 elimination pathway for common solution Hofmann eliminations. Graphical Abstract ?. PMID- 28101850 TI - Assessment of regional pulmonary blood flow using 68Ga-DOTA PET. AB - BACKGROUND: In vivo determination of regional pulmonary blood flow (PBF) is a valuable tool for the evaluation of many lung diseases. In this study, the use of 68Ga-DOTA PET for the in vivo quantitative determination of regional PBF is proposed. This methodology was implemented and tested in healthy pigs and validated using fluorescent microspheres. The study was performed on young large white pigs (n = 4). To assess the reproducibility and consistency of the method, three PET scans were obtained for each animal. Each radiotracer injection was performed simultaneously to the injection of fluorescent microspheres. PBF images were generated applying a two-compartment exchange model over the dynamic PET images. PET and microspheres values were compared by regression analysis and Bland-Altman plot. RESULTS: The capability of the proposed technique to produce 3D regional PBF images was demonstrated. The correlation evaluation between 68Ga DOTA PET and microspheres showed a good and significant correlation (r = 0.74, P < 0.001). CONCLUSIONS: Assessment of PBF with the proposed technique allows combining the high quantitative accuracy of PET imaging with the use of 68Ga/68Ge generators. Thus, 68Ga-DOTA PET emerges as a potential inexpensive method for measuring PBF in clinical settings with an extended use. PMID- 28101852 TI - Synthesis of Carbonates from Alcohols and CO2. AB - Alcohols are ubiquitous compounds in nature that offer modular building blocks for synthetic chemistry. Here we discuss the most recent development of different classes of alcohols and their coupling chemistry with carbon dioxide as to afford linear and cyclic carbonates, the challenges associated with their formation, and the potential of this chemistry to revive a waste carbon feed stock. PMID- 28101851 TI - Importance of Radioactive Labelling to Elucidate Inositol Polyphosphate Signalling. AB - Inositol polyphosphates, in their water-soluble or lipid-bound forms, represent a large and multifaceted family of signalling molecules. Some inositol polyphosphates are well recognised as defining important signal transduction pathways, as in the case of the calcium release factor Ins(1,4,5)P3, generated by receptor activation-induced hydrolysis of the lipid PtdIns(4,5)P2 by phospholipase C. The birth of inositol polyphosphate research would not have occurred without the use of radioactive phosphate tracers that enabled the discovery of the "PI response". Radioactive labels, mainly of phosphorus but also carbon and hydrogen (tritium), have been instrumental in the development of this research field and the establishment of the inositol polyphosphates as one of the most important networks of regulatory molecules present in eukaryotic cells. Advancements in microscopy and mass spectrometry and the development of colorimetric assays have facilitated inositol polyphosphate research, but have not eliminated the need for radioactive experimental approaches. In fact, such experiments have become easier with the cloning of the inositol polyphosphate kinases, enabling the systematic labelling of specific positions of the inositol ring with radioactive phosphate. This approach has been valuable for elucidating their metabolic pathways and identifying specific and novel functions for inositol polyphosphates. For example, the synthesis of radiolabelled inositol pyrophosphates has allowed the discovery of a new protein post-translational modification. Therefore, radioactive tracers have played and will continue to play an important role in dissecting the many complex aspects of inositol polyphosphate physiology. In this review we aim to highlight the historical importance of radioactivity in inositol polyphosphate research, as well as its modern usage. PMID- 28101853 TI - Investigation on the Effects of the Formation of a Silver "Flower-Like Structure" on Graphene. AB - In this report, we experimentally investigate the formation of "flower-like silver structures" on graphene. Using an electrochemical deposition technique with deposition times of 2.5 and 5 min, agglomerations of silver nanoparticles (AgNPs) were deposited on the graphene surfaces, causing the formation of "flower like structures" on the graphene substrate. Localized surface plasmon resonance (LSPR) was observed in the interaction between the structures and the graphene substrate. The morphology of the samples was observed using a field-emission scanning electron microscope (FESEM) and Raman spectroscopy. Thereafter, the potential of the flower-like Ag microstructures on graphene for use in Raman spectroscopic applications was examined. The signal showed a highest intensity value after a deposition time of 5 min, as portrayed by the intense local electromagnetic fields. For a better understanding, the CST Microwave Studio software, based on the finite element method (FEM), was applied to simulate the absorption characteristics of the structures on the graphene substrate. The absorption peak was redshifted due to the increment of the nanoparticle size. PMID- 28101854 TI - Impurity Location-Dependent Relaxation Dynamics of Cu:CdS Quantum Dots. AB - Various types of 2% Cu-incorporated CdS (Cu:CdS) quantum dots (QDs) with very similar sizes have been prepared via a water soluble colloidal method. The locations of Cu impurities in CdS host nanocrystals have been controlled by adopting three different synthetic ways of doping, exchange, and adsorption to understand the impurity location-dependent relaxation dynamics of charge carriers. The oxidation state of incorporated Cu impurities has been found to be +1 and the band-gap energy of Cu:CdS QDs decreases as Cu2S forms at the surfaces of CdS QDs. Broad and red-shifted emission with a large Stokes shift has been observed for Cu:CdS QDs as newly produced Cu-related defects become luminescent centers. The energetically favored hole trapping of thiol molecules, as well as the local environment, inhibits the radiative recombination processes of Cu:CdS QDs, thus resulting in low photoluminescence. Upon excitation, an electron is promoted to the conduction band, leaving a hole on the valence band. The hole is transferred to the Cu+ d-state, changing Cu+ into Cu2+, which then participates in radiative recombination with an electron. Electrons in the conduction band are ensnared into shallow-trap sites within 52 ns. The electrons can be further captured on the time scale of 260 ns into deep-trap sites, where electrons recombine with holes in 820 ns. Our in-depth analysis of carrier relaxation has shown that the possibilities of both nonradiative recombination and energy transfer to Cu impurities become high when Cu ions are located at the surface of CdS QDs. PMID- 28101855 TI - Improving Morphological Quality and Uniformity of Hydrothermally Grown ZnO Nanowires by Surface Activation of Catalyst Layer. AB - This paper presents a study about the dependence of the hydrothermal growth of ZnO nanowires (NWs) with the passivation level of the active surface of the Au catalyst layer. The hydrothermal method has many potential applications because of its low processing temperature, feasibility, and low cost. However, when a gold thin film is utilized as the seed material, the grown NWs often lack morphological homogeneity; their distribution is not uniform and the reproducibility of the growth is low. We hypothesize that the state or condition of the active surface of the Au catalyst layer has a critical effect on the uniformity of the NWs. Inspired by traditional electrochemistry experiments, in which Au electrodes are typically activated before the measurements, we demonstrate that such activation is a simple way to effectively assist and enhance NW growth. In addition, several cleaning processes are examined to find one that yields NWs with optimal quality, density, and vertical alignment. We find cyclic voltammetry measurements to be a reliable indicator of the seed-layer quality for subsequent NW growth. Therefore, we propose the use of this technique as a standard procedure prior to the hydrothermal synthesis of ZnO NWs to control the growth reproducibility and to allow high-yield wafer-level processing. PMID- 28101857 TI - Fibrous Protein Structures: Hierarchy, History and Heroes. AB - During the 1930s and 1940s the technique of X-ray diffraction was applied widely by William Astbury and his colleagues to a number of naturally-occurring fibrous materials. On the basis of the diffraction patterns obtained, he observed that the structure of each of the fibres was dominated by one of a small number of different types of molecular conformation. One group of fibres, known as the k-m e-f group of proteins (keratin - myosin - epidermin - fibrinogen), gave rise to diffraction characteristics that became known as the alpha-pattern. Others, such as those from a number of silks, gave rise to a different pattern - the beta pattern, while connective tissues yielded a third unique set of diffraction characteristics. At the time of Astbury's work, the structures of these materials were unknown, though the spacings of the main X-ray reflections gave an idea of the axial repeats and the lateral packing distances. In a breakthrough in the early 1950s, the basic structures of all of these fibrous proteins were determined. It was found that the long protein chains, composed of strings of amino acids, could be folded up in a systematic manner to generate a limited number of structures that were consistent with the X-ray data. The most important of these were known as the alpha-helix, the beta-sheet, and the collagen triple helix. These studies provided information about the basic building blocks of all proteins, both fibrous and globular. They did not, however, provide detailed information about how these molecules packed together in three-dimensions to generate the fibres found in vivo. A number of possible packing arrangements were subsequently deduced from the X-ray diffraction and other data, but it is only in the last few years, through the continued improvements of electron microscopy, that the packing details within some fibrous proteins can now be seen directly. Here we outline briefly some of the milestones in fibrous protein structure determination, the role of the amino acid sequences and how new techniques, including electron microscopy, are helping to define fibrous protein structures in three-dimensions. We also introduce the idea that, from the known sequence characteristics of different fibrous proteins, new molecules can be designed and synthesized, thereby generating new biological materials with specific structural properties. Some of these, for example, are planned for use in drug delivery systems. Along the way we also introduce the various Chapters of the book, where individual fibrous proteins are discussed in detail. PMID- 28101856 TI - Relationship of long-term prognosis to MMP and TIMP polymorphisms in patients after ST elevation myocardial infarction. AB - The influence of polymorphisms in the large group of MMP and TIMP genes on clinical outcomes in patients after ST elevation myocardial infarction (STEMI) treated with primary PCI was analysed. In total, 550 consecutive Caucasian patients with STEMI were included in the present study, with a median of 32 months. We analysed 19 polymorphisms in the genes coding MMP and TIMP genes. The MMP-1 -519A/G and -422A/T polymorphisms are associated with combined endpoint after myocardial infarction. The hazard ratio for AT variant of MMP-1 -422A/T was 1.75 (p < 0.001); the variants with at least one A allele of MMP-1 -519A/G have less risk of combined endpoint. The TT variants of -1562C/T MMP-9 and at least one T allele of +92C/T MMP-13 were considered in a trend to affect disease progression and long-term survival after myocardial infarction. According to reclassification analysis NRI and IDI, long-term risk stratification using MMP-1 422A/T and -519A/G polymorphisms gives additional information to the commonly used GRACE risk score. Patient stratification after myocardial infraction (MI) according to risk genotypes of MMP-1 polymorphisms could have important clinical implications for identification of patients at risk and therapeutic strategies. PMID- 28101858 TI - Coiled-Coil Design: Updated and Upgraded. AB - alpha-Helical coiled coils are ubiquitous protein-folding and protein-interaction domains in which two or more alpha-helical chains come together to form bundles. Through a combination of bioinformatics analysis of many thousands of natural coiled-coil sequences and structures, plus empirical protein engineering and design studies, there is now a deep understanding of the sequence-to-structure relationships for this class of protein architecture. This has led to considerable success in rational design and what might be termed in biro de novo design of simple coiled coils, which include homo- and hetero-meric parallel dimers, trimers and tetramers. In turn, these provide a toolkit for directing the assembly of both natural proteins and more complex designs in protein engineering, materials science and synthetic biology. Moving on, the increased and improved use of computational design is allowing access to coiled-coil structures that are rare or even not observed in nature, for example alpha helical barrels, which comprise five or more alpha-helices and have central channels into which different functions may be ported. This chapter reviews all of these advances, outlining improvements in our knowledge of the fundamentals of coiled-coil folding and assembly, and highlighting new coiled coil-based materials and applications that this new understanding is opening up. Despite considerable progress, however, challenges remain in coiled-coil design, and the next decade promises to be as productive and exciting as the last. PMID- 28101859 TI - Functional and Structural Roles of Coiled Coils. AB - Coiled coils appear in countless structural contexts, as appendages to small proteins, as parts of multi-domain proteins, and as building blocks of filaments. Although their structure is unpretentious and their basic properties are understood in great detail, the spectrum of functional properties they provide in different proteins has become increasingly complex. This chapter aims to depict this functional spectrum, to identify common themes and their molecular basis, with an emphasis on new insights gained into dynamic aspects. PMID- 28101860 TI - The Structure and Topology of alpha-Helical Coiled Coils. AB - alpha-Helical coiled coils constitute one of the most diverse folds yet described. They range in length over two orders of magnitude; they form rods, segmented ropes, barrels, funnels, sheets, spirals, and rings, which encompass anywhere from two to more than 20 helices in parallel or antiparallel orientation; they assume different helix crossing angles, degrees of supercoiling, and packing geometries. This structural diversity supports a wide range of biological functions, allowing them to form mechanically rigid structures, provide levers for molecular motors, project domains across large distances, mediate oligomerization, transduce conformational changes and facilitate the transport of other molecules. Unlike almost any other protein fold known to us, their structure can be computed from parametric equations, making them an ideal model system for rational protein design. Here we outline the principles by which coiled coils are structured, review the determinants of their folding and stability, and present an overview of their diverse architectures. PMID- 28101861 TI - Structural Transition of Trichocyte Keratin Intermediate Filaments During Development in the Hair Follicle. AB - The intermediate filaments (IF) in trichocyte (hard alpha-) keratin are unique amongst the various classes of IF in having not one but two topologically distinct structures. The first is formed at an early stage of hair development in a reducing environment within the cells in the lower part of the follicle. The second structure occurs at a later stage of hair development in the upper part of the follicle, where there is a transition to an oxidizing environment. Crosslinking studies reveal that molecular slippage occurs within the IF upon oxidation and that this results in many cysteine residues lying in near axial alignment, thereby facilitating disulphide bond formation. The disulphide bonds so formed stabilize the assembly of IF molecules and convert the keratin fibre into a tough, resilient and insoluble structure suitable for its function in vivo as a thermo-regulator and a protector of the animal against its external environment. PMID- 28101862 TI - Crystallographic Studies of Intermediate Filament Proteins. AB - Intermediate filaments (IFs), together with microtubules and actin microfilaments, are the three main cytoskeletal components in metazoan cells. IFs are formed by a distinct protein family, which is made up of 70 members in humans. Most IF proteins are tissue- or organelle-specific, which includes lamins, the IF proteins of the nucleus. The building block of IFs is an elongated dimer, which consists of a central alpha-helical 'rod' domain flanked by flexible N- and C-terminal domains. The conserved rod domain is the 'signature feature' of the IF family. Bioinformatics analysis reveals that the rod domain of all IF proteins contains three alpha-helical segments of largely conserved length, interconnected by linkers. Moreover, there is a conserved pattern of hydrophobic repeats within each segment, which includes heptads and hendecads. This defines the presence of both left-handed and almost parallel coiled-coil regions along the rod length. Using X-ray crystallography on multiple overlapping fragments of IF proteins, the atomic structure of the nearly complete rod domain has been determined. Here, we discuss some specific challenges of this procedure, such as crystallization and diffraction data phasing by molecular replacement. Further insights into the structure of the coiled coil and the terminal domains have been obtained using electron paramagnetic resonance measurements on the full-length protein, with spin labels attached at specific positions. This atomic resolution information, as well as further interesting findings, such as the variation of the coiled-coil stability along the rod length, provide clues towards interpreting the data on IF assembly, collected by a range of methods. However, a full description of this process at the molecular level is not yet at hand. PMID- 28101863 TI - Lessons from Animal Models of Cytoplasmic Intermediate Filament Proteins. AB - Cytoplasmic intermediate filaments (IFs) represent a major cytoskeletal network contributing to cell shape, adhesion and migration as well as to tissue resilience and renewal in numerous bilaterians, including mammals. The observation that IFs are dispensable in cultured mammalian cells, but cause tissue-specific, life-threatening disorders, has pushed the need to investigate their function in vivo. In keeping with human disease, the deletion or mutation of murine IF genes resulted in highly specific pathologies. Epidermal keratins, together with desmin, are essential to protect corresponding tissues against mechanical force but also participate in stabilizing cell adhesion and in inflammatory signalling. Surprisingly, other IF proteins contribute to tissue integrity to a much lesser extent than anticipated, pointing towards their role in stress situations. In support, the overexpression of small chaperones or the interference with inflammatory signalling in several settings has been shown to rescue severe tissue pathologies that resulted from the expression of mutant IF proteins. It stills remains an open issue whether the wide range of IF disorders share similar pathomechanisms. Moreover, we lack an understanding how IF proteins participate in signalling processes. Now, with a large number of mouse models in hand, the next challenge will be to develop organotypic cell culture models to dissect pathomechanisms at the molecular level, to employ Crispr/Cas-mediated genome engineering to optimize models and, finally, to combine available animal models with medicinal chemistry for the development of molecular therapies. PMID- 28101864 TI - Filamentous Structure of Hard beta-Keratins in the Epidermal Appendages of Birds and Reptiles. AB - The structures of avian and reptilian epidermal appendages, such as feathers, claws and scales, have been modelled using X-ray diffraction and electron microscopy data, combined with sequence analyses. In most cases, a family of closely related molecules makes up the bulk of the appendage, and each of these molecules contains a central beta-rich 34-residue segment, which has been identified as the principal component of the framework of the 3.4 nm diameter filaments. The N- and C-terminal segments form the matrix component of the filament/matrix complex. The 34-residue beta-rich central domains occur in pairs, related by either a parallel dyad or a perpendicular dyad axis, and form a beta sandwich stabilized by apolar interactions. They are also twisted in a right handed manner. In feather, the filaments are packed into small sheets and it is possible to determine their likely orientation within the sheets from the low angle X-ray diffraction data. The physical properties of the various epidermal appendages can be related to the amino acid sequence and composition of defined molecular segments characteristic of the chains concerned. PMID- 28101865 TI - Tropomyosin Structure, Function, and Interactions: A Dynamic Regulator. AB - Tropomyosin is the archetypal-coiled coil, yet studies of its structure and function have proven it to be a dynamic regulator of actin filament function in muscle and non-muscle cells. Here we review aspects of its structure that deviate from canonical leucine zipper coiled coils that allow tropomyosin to bind to actin, regulate myosin, and interact directly and indirectly with actin-binding proteins. Four genes encode tropomyosins in vertebrates, with additional diversity that results from alternate promoters and alternatively spliced exons. At the same time that periodic motifs for binding actin and regulating myosin are conserved, isoform-specific domains allow for specific interaction with myosins and actin filament regulatory proteins, including troponin. Tropomyosin can be viewed as a universal regulator of the actin cytoskeleton that specifies actin filaments for cellular and intracellular functions. PMID- 28101866 TI - Titin and Nebulin in Thick and Thin Filament Length Regulation. AB - In this review we discuss the history and the current state of ideas related to the mechanism of size regulation of the thick (myosin) and thin (actin) filaments in vertebrate striated muscles. Various hypotheses have been considered during of more than half century of research, recently mostly involving titin and nebulin acting as templates or 'molecular rulers', terminating exact assembly. These two giant, single-polypeptide, filamentous proteins are bound in situ along the thick and thin filaments, respectively, with an almost perfect match in the respective lengths and structural periodicities. However, evidence still questions the possibility that the proteins function as templates, or scaffolds, on which the thin and thick filaments could be assembled. In addition, the progress in muscle research during the last decades highlighted a number of other factors that could potentially be involved in the mechanism of length regulation: molecular chaperones that may guide folding and assembly of actin and myosin; capping proteins that can influence the rates of assembly-disassembly of the myofilaments; Ca2+ transients that can activate or deactivate protein interactions, etc. The entire mechanism of sarcomere assembly appears complex and highly dynamic. This mechanism is also capable of producing filaments of about the correct size without titin and nebulin. What then is the role of these proteins? Evidence points to titin and nebulin stabilizing structures of the respective filaments. This stabilizing effect, based on linear proteins of a fixed size, implies that titin and nebulin are indeed molecular rulers of the filaments. Although the proteins may not function as templates in the assembly of the filaments, they measure and stabilize exactly the same size of the functionally important for the muscles segments in each of the respective filaments. PMID- 28101867 TI - Myosin and Actin Filaments in Muscle: Structures and Interactions. AB - In the last decade, improvements in electron microscopy and image processing have permitted significantly higher resolutions to be achieved (sometimes <1 nm) when studying isolated actin and myosin filaments. In the case of actin filaments the changing structure when troponin binds calcium ions can be followed using electron microscopy and single particle analysis to reveal what happens on each of the seven non-equivalent pseudo-repeats of the tropomyosin alpha-helical coiled-coil. In the case of the known family of myosin filaments not only are the myosin head arrangements under relaxing conditions being defined, but the latest analysis, also using single particle methods, is starting to reveal the way that the alpha-helical coiled-coil myosin rods are packed to give the filament backbones. PMID- 28101868 TI - Dystrophin and Spectrin, Two Highly Dissimilar Sisters of the Same Family. AB - Dystrophin and Spectrin are two proteins essential for the organization of the cytoskeleton and for the stabilization of membrane cells. The comparison of these two sister proteins, and with the dystrophin homologue utrophin, enables us to emphasise that, despite a similar topology with common subdomains and a common structural basis of a three-helix coiled-coil, they show a large range of dissimilarities in terms of genetics, cell expression and higher level structural organisation. Interactions with cellular partners, including proteins and membrane phospholipids, also show both strikingly similar and very different behaviours. The differences between dystrophin and spectrin are also illustrated by the large variety of pathological anomalies emerging from the dysfunction or the absence of these proteins, showing that they are keystones in their function of providing a scaffold that sustains cell structure. PMID- 28101870 TI - Fibrillar Collagens. AB - Fibrillar collagens (types I, II, III, V, XI, XXIV and XXVII) constitute a sub group within the collagen family (of which there are 28 types in humans) whose functions are to provide three-dimensional frameworks for tissues and organs. These networks confer mechanical strength as well as signalling and organizing functions through binding to cellular receptors and other components of the extracellular matrix (ECM). Here we describe the structure and assembly of fibrillar collagens, and their procollagen precursors, from the molecular to the tissue level. We show how the structure of the collagen triple-helix is influenced by the amino acid sequence, hydrogen bonding and post-translational modifications, such as prolyl 4-hydroxylation. The numerous steps in the biosynthesis of the fibrillar collagens are reviewed with particular attention to the role of prolyl 3-hydroxylation, collagen chaperones, trimerization of procollagen chains and proteolytic maturation. The multiple steps controlling fibril assembly are then discussed with a focus on the cellular control of this process in vivo. Our current understanding of the molecular packing in collagen fibrils, from different tissues, is then summarized on the basis of data from X ray diffraction and electron microscopy. These results provide structural insights into how collagen fibrils interact with cell receptors, other fibrillar and non-fibrillar collagens and other ECM components, as well as enzymes involved in cross-linking and degradation. PMID- 28101871 TI - Recombinant Structural Proteins and Their Use in Future Materials. AB - Recombinant proteins are polymers that offer the materials engineer absolute control over chain length and composition: key attributes required for design of advanced polymeric materials. Through this control, these polymers can be encoded to contain information that enables them to respond as the environment changes. However, despite their promise, protein-based materials are under-represented in materials science. In this chapter we investigate why this is and describe recent efforts to address this. We discuss constraints limiting rational design of structural proteins for advanced materials; advantages and disadvantages of different recombinant expression platforms; and, methods to fabricate proteins into solid-state materials. Finally, we describe the silk proteins used in our laboratory as templates for information-containing polymers. PMID- 28101872 TI - Properties of Engineered and Fabricated Silks. AB - Silk is a protein-based material which is predominantly produced by insects and spiders. Hundreds of millions of years of evolution have enabled these animals to utilize different, highly adapted silk types in a broad variety of applications. Silk occurs in several morphologies, such as sticky glue or in the shape of fibers and can, depending on the application by the respective animal, dissipate a high mechanical energy, resist heat and radiation, maintain functionality when submerged in water and withstand microbial settling. Hence, it's unsurprising that silk piqued human interest a long time ago, which catalyzed the domestication of silkworms for the production of silk to be used in textiles. Recently, scientific progress has enabled the development of analytic tools to gain profound insights into the characteristics of silk proteins. Based on these investigations, the biotechnological production of artificial and engineered silk has been accomplished, which allows the production of a sufficient amount of silk materials for several industrial applications. This chapter provides a review on the biotechnological production of various silk proteins from different species, as well as on the processing techniques to fabricate application-oriented material morphologies. PMID- 28101873 TI - Biomaterials Made from Coiled-Coil Peptides. AB - The development of biomaterials designed for specific applications is an important objective in personalized medicine. While the breadth and prominence of biomaterials have increased exponentially over the past decades, critical challenges remain to be addressed, particularly in the development of biomaterials that exhibit highly specific functions. These functional properties are often encoded within the molecular structure of the component molecules. Proteins, as a consequence of their structural specificity, represent useful substrates for the construction of functional biomaterials through rational design. This chapter provides an in-depth survey of biomaterials constructed from coiled-coils, one of the best-understood protein structural motifs. We discuss the utility of this structurally diverse and functionally tunable class of proteins for the creation of novel biomaterials. This discussion illustrates the progress that has been made in the development of coiled-coil biomaterials by showcasing studies that bridge the gap between the academic science and potential technological impact. PMID- 28101874 TI - Bioengineered Collagens. AB - There is a great deal of interest in obtaining recombinant collagen as an alternative source of material for biomedical applications and as an approach for obtaining basic structural and biological information. However, application of recombinant technology to collagen presents challenges, most notably the need for post-translational hydroxylation of prolines for triple-helix stability. Full length recombinant human collagens have been successfully expressed in cell lines, yeast, and several plant systems, while collagen fragments have been expressed in E. coli. In addition, bacterial collagen-like proteins can be expressed in high yields in E. coli and easily manipulated to incorporate biologically active sequences from human collagens. These expression systems allow manipulation of biologically active sequences within collagen, which has furthered our understanding of the relationships between collagen sequences, structure and function. Here, recombinant studies on collagen interactions with cell receptors, extracellular matrix proteins, and matrix metalloproteinases are reviewed, and discussed in terms of their potential biomaterial and biomedical applications. PMID- 28101875 TI - Sustanon induces dose-independent hypertrophy and satellite cell proliferation in slow oxidative fibers of avian skeletal muscle. AB - Sustanon is a well-known anabolic drug that is used to treat hypogonadism and restore muscle mass and bone density. As research to date has been limited to its effects in glycolytic fibers, this study aimed to investigate the dose-related effects of Sustanon on the oxidative fibers of avian skeletal muscle. Adult female chickens were randomly divided into 4 groups: control (C), received a dose of 100 MUl normal saline per injection; and Sustanon-1, -2, and -3 (S1, S2, and S3), that received a dose of 12.5, 25, or 50 mg/kg Sustanon per injection, respectively. Each bird received 4 injections at weekly intervals (1 injection/week). Robust histochemical and immunofluorescent techniques along with morphometric analyses were applied to determine the oxidative activity and morphological variations of the oxidative muscle fibers in all groups. Sustanon treated groups exhibited significant increases in fiber size and numbers of satellite cells and myonuclei compared to the control group. However, no significant variations were found between Sustanon-treated groups in the aforementioned indices. In conclusion, Sustanon induced oxidative fiber hypertrophy that was associated with satellite cell proliferation and myonuclear accretion in avian skeletal muscle. Furthermore, the effects of Sustanon appeared to be dose-independent. PMID- 28101876 TI - Extraction of actionable information from crowdsourced disaster data. AB - Natural disasters cause enormous damage to countries all over the world. To deal with these common problems, different activities are required for disaster management at each phase of the crisis. There are three groups of activities as follows: (1) make sense of the situation and determine how best to deal with it, (2) deploy the necessary resources, and (3) harmonize as many parties as possible, using the most effective communication channels. Current technological improvements and developments now enable people to act as real-time information sources. As a result, inundation with crowdsourced data poses a real challenge for a disaster manager. The problem is how to extract the valuable information from a gigantic data pool in the shortest possible time so that the information is still useful and actionable. This research proposed an actionable-data extraction process to deal with the challenge. Twitter was selected as a test case because messages posted on Twitter are publicly available. Hashtag, an easy and very efficient technique, was also used to differentiate information. A quantitative approach to extract useful information from the tweets was supported and verified by interviews with disaster managers from many leading organizations in Thailand to understand their missions. The information classifications extracted from the collected tweets were first performed manually, and then the tweets were used to train a machine learning algorithm to classify future tweets. One particularly useful, significant, and primary section was the request for help category. The support vector machine algorithm was used to validate the results from the extraction process of 13,696 sample tweets, with over 74 percent accuracy. The results confirmed that the machine learning technique could significantly and practically assist with disaster management by dealing with crowdsourced data. PMID- 28101878 TI - Bootstrapping disaster: The challenge of growing and maintaining a cross-sector collaborative network. AB - This article examines the interaction of nonprofit and private actors with the traditional bureaucratic structures of government in central Pennsylvania&s recovery from hurricane Irene and tropical storm Lee. That effort relied heavily on private and nonprofit organizations as drivers of the response and recovery. The author maps the organizations involved in the recovery effort and explores the impact of the recovery effort on those organizations. A social network analysis was conducted and complemented with follow-up interviews with key actors. The network analysis reveals weak communication between sectors and a reliance on nonprofits to deliver services; interviews uncover the challenges of intersectoral collaboration. The author addresses the successes and limitations of the means by which a network of nonprofit efforts were coordinated with federal and state relief efforts and draw lessons for improving future practices. The author finds that this case deviates from theory in several ways that complicated community response and recovery. In particular, the challenges of developing and maintaining a recovery network while simultaneously delivering services placed great strain on several organizations, as well as on the fledgling network as a whole. PMID- 28101877 TI - Using a call center to coordinate Zika virus testing-New York City, 2016. AB - BACKGROUND: After local testing criteria for Zika virus expanded to include asymptomatic pregnant women who traveled to areas with active Zika virus transmission while pregnant, the New York City (NYC) Department of Health and Mental Hygiene (DOHMH) experienced a surge in test requests and subsequent testing delays due to factors such as incorrectly completed laboratory requisition forms. The authors describe how DOHMH addressed these issues by establishing the Zika Testing Call Center (ZTCC). METHODS: Using a case study approach, the authors illustrate how DOHMH leveraged protocols, equipment, and other resources used previously during DOHMH&s Ebola emergency response to meet NYC's urgent Zika virus testing needs. To request Zika virus testing, providers call the ZTCC; if patients meet testing criteria, the ZTCC collects data necessary to complete requisition forms and sends the forms back to providers. The ZTCC also provides guidance on specimens needed for Zika virus testing. Providers submit completed requisition forms and appropriate specimens to DOHMH for testing. RESULTS: During March 21 through July 21, 2016, testing for 3,866 patients was coordinated through the ZTCC. CONCLUSION: The ZTCC exemplifies how a health department, using previous emergency response experiences, can quickly address local testing needs for an emerging infectious disease. PMID- 28101879 TI - Private sector involvement in times of armed conflict: What are the constraints for trading medical equipment? AB - OBJECTIVE: Today, healthcare facilities are highly dependent on the private sector to keep their medical equipment functioning. Moreover, private sector involvement becomes particularly important for the supply of spare parts and consumables. However, in times of armed conflict, the capacity of the corporate world appears to be seriously hindered. Subsequently, this study researches the influence of armed conflict on the private medical equipment sector. DESIGN: This study follows a qualitative approach by conducting 19 interviews with representatives of the corporate world in an active conflict zone. A semistructured interview guide, consisting of 10 questions, was used to examine the constraints of this sector. RESULTS: The results reveal that the lack of skilled personnel, complicated importation procedures, and a decrease in financial capacity are the major constraints faced by private companies dealing in medical equipment in conflict zones. CONCLUSIONS: Even when no official sanctions and embargoes for medical items exist, constraints for trading medical equipment are clearly recognizable. Countries at war would benefit from a centralized structure that deals with the importation procedures for medical items, to assist local companies in their purchasing procedures. A high degree of adaption is needed to continue operating, despite the emerging constraints of armed conflict. Future studies might research the constraints for manufacturers outside the conflict to export medical items to the country of war. PMID- 28101869 TI - Fibrin Formation, Structure and Properties. AB - Fibrinogen and fibrin are essential for hemostasis and are major factors in thrombosis, wound healing, and several other biological functions and pathological conditions. The X-ray crystallographic structure of major parts of fibrin(ogen), together with computational reconstructions of missing portions and numerous biochemical and biophysical studies, have provided a wealth of data to interpret molecular mechanisms of fibrin formation, its organization, and properties. On cleavage of fibrinopeptides by thrombin, fibrinogen is converted to fibrin monomers, which interact via knobs exposed by fibrinopeptide removal in the central region, with holes always exposed at the ends of the molecules. The resulting half-staggered, double-stranded oligomers lengthen into protofibrils, which aggregate laterally to make fibers, which then branch to yield a three dimensional network. Much is now known about the structural origins of clot mechanical properties, including changes in fiber orientation, stretching and buckling, and forced unfolding of molecular domains. Studies of congenital fibrinogen variants and post-translational modifications have increased our understanding of the structure and functions of fibrin(ogen). The fibrinolytic system, with the zymogen plasminogen binding to fibrin together with tissue-type plasminogen activator to promote activation to the active proteolytic enzyme, plasmin, results in digestion of fibrin at specific lysine residues. In spite of a great increase in our knowledge of all these interconnected processes, much about the molecular mechanisms of the biological functions of fibrin(ogen) remains unknown, including some basic aspects of clotting, fibrinolysis, and molecular origins of fibrin mechanical properties. Even less is known concerning more complex (patho)physiological implications of fibrinogen and fibrin. PMID- 28101880 TI - Family emergency plan and preparedness among medical practitioners in Zaria, Nigeria. AB - BACKGROUND: There has been an increase in the incidence of disasters in many parts of the world. Similarly, Nigeria has witnessed a recent increase of man made disaster events such as plane crash, fire incidents, flood, and building collapse, including bomb blast orchestrated by terrorists that often create emergency situations. Therefore, the aim of the study was to evaluate family emergency plan and preparedness among medical practitioners in Zaria. METHODS: This was a cross-sectional descriptive study (May-July, 2013) of medical practitioners in Zaria, Nigeria. The structured questionnaire sought the socio demographic features of the respondents, the availability of emergency gate(s) in the house, education of safety measures within and outside the house, well-known located shut-off devices for gases, electricity, and water in the house, and written document/policy in the event of disaster. Also, planned orientations/drills/sensitizations, whether there is contact information of family members and supporting agencies. RESULTS: Majority of the respondents were male 56 (80.0 percent) and fall within the age group of 46-50 years (20.0 percent). Only 8.6 percent admitted having an unwritten policy on emergency management in their houses. Similarly, only 8.6 percent do create time to teach their family members on emergency management. Only 27 (38.6 percent) had emergency supplies kits and among this group, water appears to be the most essential component that the respondents had paid attention to, leaving out special items. The communication plans of respondents to likely supportive services/agencies during disaster showed that majority had contact address or have affirmative plans for hospital and ambulance services than for radio and television stations. CONCLUSION: Family emergency plans and preparedness among medical practitioners in Zaria are extremely low. There is a gap between knowledge of what need to be done to enhance preparedness and internalizing preparedness recommendations in the study area. PMID- 28101881 TI - Using a novel technology for disaster staff notification. AB - Notification of backup staff and determining their ability to augment frontline staff is a major component of any disaster plan. However, the communication and organization of this effort has many challenges. These include communication system overload, the disaster setting, disrupted transportation, and staffing impacts on normal operations. An optimal disaster notification system must have the ability to be modified to include all hazards and the unique environment in which the plan is being made. This article highlights a unique disaster staff notification system using a novel technology, an outside administrator, and a multilayer system of redundant communication. PMID- 28101882 TI - Measuring communication and participation in children with speech and language disorders. PMID- 28101883 TI - myTREEHOUSE Self-Concept Assessment: preliminary psychometric analysis of a new self-concept assessment for children with cerebral palsy. AB - AIM: To evaluate the preliminary validity and reliability of the myTREEHOUSE Self Concept Assessment for children with cerebral palsy (CP) aged 8 to 12 years. METHOD: The myTREEHOUSE Self-Concept Assessment includes 26 items divided into eight domains, assessed across three Performance Perspectives (Personal, Social, and Perceived) and an additional Importance Rating. Face and content validity was assessed by semi-structured interviews with seven expert professionals regarding the assessment construct, content, and clinical utility. Reliability was assessed with 50 children aged 8 to 12 years with CP (29 males, 21 females; mean age 10y 2mo; Gross Motor Function Classification System [GMFCS] level I=35, II=8, III=5, IV=1; mean Wechsler Intelligence Scale for Children - Fourth Edition [WISC IV]=104), whose data was used to calculate internal consistency of the scale, and a subset of 35 children (20 males, 15 females; mean age 10y 5mo; GMFCS level I=26, II=4, III=4, IV=1; mean WISC-IV=103) who participated in test-retest reliability within 14 to 28 days. RESULTS: Face and content validity was supported by positive expert feedback, with only minor adjustments suggested to clarify the wording of some items. After these amendments, strong internal consistency (Cronbach's alpha 0.84-0.91) and moderate to good test-retest reliability (intraclass correlation coefficient 0.64-0.75) was found for each component. INTERPRETATION: The myTREEHOUSE Self-Concept Assessment is a valid and reliable assessment of self-concept for children with CP aged 8 to 12 years. PMID- 28101884 TI - Lung microdialysis study of florfenicol in pigs after single intramuscular administration. AB - For most bacterial lung infections, the concentration of unbound antimicrobial agent in lung interstitial fluid has been considered as the gold standard for estimating the antibacterial efficacy. In this study, the pharmacokinetics of florfenicol (FF) in porcine lung interstitial fluid was investigated after single intramuscular administration at two different doses (20 and 50 mg/kg). Twelve pigs underwent thoracotomy under general anesthesia. Then, the CMA/30 probe was implanted into the lung and perfused at 1 MUL/min. The microdialysis (MD) samples were collected on a preset schedule and analyzed by high-performance liquid chromatography (HPLC). Noncompartmental pharmacokinetic analysis was performed. FF exhibited rapid distribution and slow elimination in porcine lung interstitial fluid. The main pharmacokinetic parameters at 20 and 50 mg/kg were 4.88 +/- 0.54 and 10.36 +/- 2.52 MUg/mL for the maximum concentration (Cmax ), 3.25 +/- 0.32 and 3.50 +/- 0.27 h for the time to Cmax (Tmax ), 9.47 +/- 6.84 and 7.75 +/- 3.23 h for the half-life (t1/2 ), 0.10 +/- 0.06 and 0.10 +/- 0.04 1/h for the terminal elimination rate constant (lambdaz ), 13.85 +/- 7.97 and 11.42 +/- 2.79 h for the mean residence time (MRT), 37.77 +/- 8.13 and 71.15 +/- 16.99 h.MUg/mL for the area under the curve from time 0 to 18.25 h (AUC0-18.25 ), and 51.18 +/- 20.11 and 88.78 +/- 27.58 h.MUg/mL for the area under the curve from time 0 to infinity (AUC0-infinity ), respectively. PMID- 28101885 TI - What is the true in vitro potency of oxytetracycline for the pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida? AB - The pharmacodynamics of oxytetracycline was determined for pig respiratory tract pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida. Indices of potency were determined for the following: (i) two matrices, broth and pig serum; (ii) five overlapping sets of twofold dilutions; and (iii) a high strength starting culture. For A. pleuropneumoniae, minimum inhibitory concentration (MIC) was similar for the two matrices, but for P. multocida, differences were marked and significantly different. MIC and minimum bactericidal concentration (MBC) serum: broth ratios for A. pleuropneumoniae were 0.83:1 and 1.22:1, respectively, and corresponding values for P. multocida were 22.0:1 and 7.34:1. For mutant prevention concentration (MPC) serum: broth ratios were 0.79:1 (A. pleuropneumoniae) and 20.9:1 (P. multocida). These ratios were corrected for serum protein binding to yield fraction unbound (fu) serum: broth MIC ratios of 0.24:1 (A. pleuropneumoniae) and 6.30:1 (P. multocida). Corresponding fu serum: broth ratios for MPC were almost identical, 0.23:1 and 6.08:1. These corrections for protein binding did not account for potency differences between serum and broth for either species; based on fu serum MICs, potency in serum was approximately fourfold greater than predicted for A. pleuropneumoniae and sixfold smaller than predicted for P. multocida. For both broth and serum and both bacterial species, MICs were also dependent on initial inoculum strength. The killing action of oxytetracycline had the characteristics of codependency for both A. pleuropneumoniae and P. multocida in both growth media. The in vitro potency of oxytetracycline in pig serum is likely to be closer to the in vivo plasma/serum concentration required for efficacy than potency estimated in broths. PMID- 28101888 TI - Editorial Comment to 'Predictors of successful trial without catheter following acute urinary retention in benign prostatic enlargement: A single centre, multivariate analysis' (Manuscript ID: NAU-16-0436.R1). PMID- 28101886 TI - Incident alopecia areata and vitiligo in adult women with atopic dermatitis: Nurses' Health Study 2. AB - We aimed to determine the risk of alopecia areata (AA) and vitiligo associated with atopic dermatitis (AD) in a large cohort of US women, the Nurses' Health Study 2. We used logistic regression to calculate age- and multivariate-adjusted odds ratios to determine the risk of incident AA and vitiligo associated with AD diagnosed in or before 2009. A total of 87 406 and 87 447 participants were included in the AA and vitiligo analyses, respectively. A history of AD in 2009 was reported in 11% of participants. There were 147 incident cases of AA and 98 incident cases of vitiligo over 2 years of follow-up. AD was associated with increased risk of developing AA (OR 1.80, 95% CI 1.18-2.76) and vitiligo (OR 2.14, 95% CI 1.29-3.54) in multivariate models. In this study of US women, AD was associated with increased risk of incident vitiligo and AA in adulthood. PMID- 28101887 TI - Abiraterone or Enzalutamide in Advanced Castration-Resistant Prostate Cancer: An Indirect Comparison. AB - BACKGROUND: To perform a comparative effectiveness analyses between enzalutamide and abiraterone acetate in both the pre-docetaxel and post-docetaxel settings based on published phase III randomized trials. METHODS: The primary measure of efficacy was the posterior probability that enzalutamide outperforms abiraterone acetate (AA) with prednisone in terms of overall survival (OS) on average. Indirect meta-estimates were generated from four randomized studies in the context of a Bayesian hierarchical model with study-specific efficacy estimates meta-analyzed on the log scale. RESULTS: We found weak evidence that enzalutamide outperforms AA with prednisone in terms of OS in the pre-docetaxel and post docetaxel settings. However, we found strong evidence that enzalutamide outperforms AA with prednisone in terms of radiographic PFS, time until PSA progression, and PSA response rate in both the pre- and post-docetaxel settings. Rates of grade 3 or worse adverse events were broadly similar between treatment (enzalutamide or AA) and control arms (placebo or placebo with prednisone) in all included randomized studies. CONCLUSIONS: There is strong evidence that enzalutamide outperforms AA with prednisone in terms of radiographic PFS and PSA progression and PSA response rate but not OS in the pre and post-docetaxel settings. These results may further guide clinicians in making treatment recommendations for patients with advanced prostate cancer. Prostate 77: 639-646, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28101889 TI - Predictors of successful trial without catheter following acute urinary retention in benign prostatic enlargement: A single centre, multivariate analysis. AB - OBJECTIVE: To evaluate the parameters which predict the success or failure of trial without catheter (TWOC) for acute urine retention (AUR). MATERIALS AND METHODS: Medical records of 2 188 patients presenting with first episode of AUR were analyzed. All patients underwent catheterization and were started on alpha blocker followed by TWOC. Age, baseline American urological association (AUA) score, prostate volume (PV), residual volume of urine (RV) and intravesical prostatic protrusion (IPP), prostate specific antigen (PSA) were recorded. RESULTS: TWOC was successful in 737 patients (33.7%) and failed in 1 451 patients (66.3%). Patients with successful TWOC had lower mean age, PV, IPP, RV, AUA score, and PSA than those with failed TWOC. On multivariate analysis, the significant independent predictors were IPP, age, AUA score, PV, and RV at odds ratios of 3.11, 1.84, 1.78, 1.53, and 1.23, respectively. From ROC curve, IPP had cut off value of 9 mm and detected success of TWOC with sensitivity (S) of 91% and failure with specificity (s) of 90%. Similarly, cut off value of 64 years for age (S:86%, s:87%), 20 for AUA symptom score (S:83%, s:81%), 56 cc for PV (S:80%, s:74%) and 750 mL for RV (S:71%, s:68%) were obtained. CONCLUSION: Age, baseline AUA score, IPP, PV, and RV independently predict the outcome of TWOC. Patients with IPP > 9 mm, age > 65 years, baseline AUA score > 20, PV > 56 cc, or RV > 750 mL have less probability of successful TWOC in AUR and can be considered for immediate surgery following an episode of AUR. PMID- 28101891 TI - Different expression of leptin and IGF1 in the adult and prepubertal testis in dogs. AB - Leptin (Lep) and insulin-like growth factor 1 (IGF1) are implicated in the regulation of testicular function, but in dogs, our knowledge is limited to the possible role of the IGF1 system in testicular tumours. In this study, we aimed to describe and compare gene expression and protein localization of Lep, IGF1 and their receptors (LepR and IGF1R, respectively) in the testis of healthy adult and prepubertal dogs. Testes were collected from sexually healthy mature (n = 7) and from 8-week-old dogs (n = 7). Relative gene expression of Lep, LepR, IGF1 and IGF1R was determined by semi-quantitative real-time (TaqMan) PCR and cellular distribution in the testis by immunohistochemistry. Statistical analysis was carried out with Student's t test. Lep and LepR mRNA concentration was similar between the two groups, but IGF1 and IGF1R gene expression was significantly higher in the 8-week-old pups. Protein localization and the intensity of signals differed by age. In adults, Lep and LepR immunoreactivity was detected in spermatocytes and spermatids. Leydig cells showed sporadic, weak Lep staining. In prepubertal animals, intense Lep signals were present in Leydig and Sertoli cells, and LepR was found in Leydig cells. IGF1 and IGF1R protein was expressed in spermatogonia of the mature testis; IGF1 signals in Leydig cells seemed stronger than IGF1R. In the pups, IGF1 and IGF1R staining was detected in Leydig cells and in gonocytes. Sertoli cells showed weak IGF1 and sporadic, weak IGF1R signals. In conclusion, Lep and IGF1 may support spermatogenesis in adult dogs and mediate Leydig cell function. In the immature testis, they may promote development of Sertoli and Leydig cells and gonocytes. PMID- 28101892 TI - An assessment of differential reinforcement procedures for learners with autism spectrum disorder. AB - Differential reinforcement procedures may promote unprompted correct responding, resulting in a quicker transfer of stimulus control than nondifferential reinforcement. Recent studies that have compared reinforcement arrangements have found that the most effective arrangement may differ across participants. The current study conducted an assessment of differential reinforcement arrangements (i.e., quality, schedule, and magnitude) and nondifferential reinforcement to identify the most effective arrangement for each participant. The assessment phase showed that the quality arrangement was the most efficient for all participants during auditory-visual matching. Next, a validation phase was conducted to evaluate whether the assessment would predict the most effective arrangement across multiple skills. The results from the assessment phase were validated for all participants for the same skill. However, the results were only validated for one participant during the other skills (i.e., tact and intraverbal). The results are discussed in light of previous research and future areas of research. PMID- 28101890 TI - G-CSF mobilized peripheral blood stem cell collection for allogeneic transplantation in healthy donors: Analysis of factors affecting yield. AB - Mobilized PBSC are the main source for allogeneic HSCT. We aimed to evaluate factors that affect CD34+ cell yield including the donor's age, gender, BSA, processed blood volume and the method of G-CSF dose calculation. Data from 170 healthy donors were analyzed. The concentration of CD34+ cells in the peripheral blood (PB) and the processed volume of blood were significantly correlated to CD34+ cells yield (P < .00005 and P < .001, respectively). The G-CSF dose per m2 was significantly correlated to the concentration of CD34+ cells in the PB (P = .0003) and in the product (P = .01). Smaller BSA and less processed volume were found among female donors, who were given lesser G-CSF dose per m2 , and showed lower yield compared to men. However, multivariate analysis of the yield showed that only the concentration of CD34+ cells in the PB and the processed volume remained independent significant. PMID- 28101893 TI - The genus Anthopsis and its phylogenetic position in Chaetothyriales. AB - The genus Anthopsis was introduced for a black fungus with peculiar, inverted phialides and triangular conidia. The genus accommodates, in addition to the type species Anthopsis deltoidea, which once was reported as a cause of human phaeohyphomycosis, two further taxa: A. catenata and A. microspora. Current taxonomy is mainly based on microscopic structures of phialides. To assess the phylogenetic position of the genus, sequences of the internal transcribed spacer region and partial LSU rDNA were obtained for Anthopsis spp. and compared with sequences from public databases. Phylogenetic analyses based on both loci were used to assess the evolutionary relationships of Anthopsis spp. at the family and ordinal levels. Anthopsis s.str. was found to cluster in Chaetothyriales, while A. catenata proved to be of helotialean affinity. Thermotolerance and morphology of each species were recorded. PMID- 28101894 TI - Sleep quality and body mass index: a co-twin study. AB - There is a consistent relationship between body mass index and sleep quality. However, the directionality and possible confounding factors of this relationship are unclear. Our aim is to confirm the association between sleep quality and body mass index, independent of possible genetic confounding, as well as to provide some indirect inferences about the directionality of this association. The co twin study design was used to analyse the body mass index-sleep relationship in a sample of 2150 twins. We selected two parallel sub-samples of twins discordant for body mass index (n = 430 pairs), or discordant for sleep quality (n = 316 pairs). Sleep quality and body mass index showed an inverse relationship (b = 0.056, P = 0.032) in the global sample. When twins discordant for body mass index were selected, this association maintained a similar effect size and statistical significance, at all levels of the case-control analysis (all discordant pairs b = 0.173, P < 0.001; dizygotic twins b = 0.174, P = 0.002; monozygotic twins b = 0.173, P = 0.050). Nevertheless, when twin pairs were selected on the basis of their discordance for sleep quality, the association between body mass index and sleep quality appeared weaker and lost significance (b = 0.021, P = 0.508). The analyses including only dizygotic (b = 0.028, P = 0.526) or monozygotic (b = 0.001, P = 0.984) pairs produced similar non-significant results. Our results confirm the relationship between sleep quality and body mass index, even after applying high levels of control, including genetic factors. Moreover, this study suggests a possible directionality of this relationship, such that sleep quality would strongly affect body mass index, while the opposite would be less robust and consistent in non-clinical samples. PMID- 28101895 TI - On the rarity of dioecy in flowering plants. AB - Dioecy, the coexistence of separate male and female individuals in a population, is a rare but phylogenetically widespread sexual system in flowering plants. While research has concentrated on why and how dioecy evolves from hermaphroditism, the question of why dioecy is rare, despite repeated transitions to it, has received much less attention. Previous phylogenetic and theoretical studies have suggested that dioecy might be an evolutionary dead end. However, recent research indicates that the phylogenetic support for this hypothesis is attributable to a methodological bias and that there is no evidence for reduced diversification in dioecious angiosperms. The relative rarity of dioecy thus remains a puzzle. Here, we review evidence for the hypothesis that dioecy might be rare not because it is an evolutionary dead end, but rather because it easily reverts to hermaphroditism. We review what is known about transitions between hermaphroditism and dioecy, and conclude that there is an important need to consider more widely the possibility of transitions away from dioecy, both from an empirical and a theoretical point of view, and by combining tools from molecular evolution and insights from ecology. PMID- 28101897 TI - Missed nursing care as an 'art form': The contradictions of nurses as carers. AB - This article draws on the free-text commentaries from trans-Tasman studies that used the MISSCARE questionnaire to explore the reasons why nurses miss care. In this paper, we examine the idea that nurses perpetuate a self-effacing approach to care, at the expense of patient care and professional accountability, using what they describe as the art of nursing to frame their claims of both nursing care and missed nursing care. We use historical dialogue alongside a paradigmatic analysis to examine why nurses allow themselves to continue working within settings that put their professional/personal selves aside in an attempt to deliver care within constraints that make completing care an impossible task. The findings suggest an ambivalence and conflict confront nurses attempting to provide care within the New Public Management environment. This can be seen in the tensions that draw a line between care as an art, and care as a financial target, juxtaposed with the inherent clash of values arising from the way nursing care is conceptualised within two contradictory paradigms. PMID- 28101896 TI - Adaptation of genetically monomorphic bacteria: evolution of copper resistance through multiple horizontal gene transfers of complex and versatile mobile genetic elements. AB - Copper-based antimicrobial compounds are widely used to control plant bacterial pathogens. Pathogens have adapted in response to this selective pressure. Xanthomonas citri pv. citri, a major citrus pathogen causing Asiatic citrus canker, was first reported to carry plasmid-encoded copper resistance in Argentina. This phenotype was conferred by the copLAB gene system. The emergence of resistant strains has since been reported in Reunion and Martinique. Using microsatellite-based genotyping and copLAB PCR, we demonstrated that the genetic structure of the copper-resistant strains from these three regions was made up of two distant clusters and varied for the detection of copLAB amplicons. In order to investigate this pattern more closely, we sequenced six copper-resistant X. citri pv. citri strains from Argentina, Martinique and Reunion, together with reference copper-resistant Xanthomonas and Stenotrophomonas strains using long read sequencing technology. Genes involved in copper resistance were found to be strain dependent with the novel identification in X. citri pv. citri of copABCD and a cus heavy metal efflux resistance-nodulation-division system. The genes providing the adaptive trait were part of a mobile genetic element similar to Tn3 like transposons and included in a conjugative plasmid. This indicates the system's great versatility. The mining of all available bacterial genomes suggested that, within the bacterial community, the spread of copper resistance associated with mobile elements and their plasmid environments was primarily restricted to the Xanthomonadaceae family. PMID- 28101898 TI - Prediction of excited-state properties of oligoacene crystals using polarizable continuum model-tuned range-separated hybrid functional approach. AB - A methodology combining the polarizable continuum model and optimally-tuned range separated (RS) hybrid functional was proposed for the quantitative characterization of the excited-state properties in oligoacene (from anthracene to hexacene) crystals. We show that it provides lowest vertical singlet and triplet excitation energies, singlet-triplet gap, and exciton binding energies in very good agreement with the available experimental data. We further find that it significantly outperforms its non-tuned RS counterpart and the widely used B3LYP functional, and even many-body perturbation theory within the GW approximation (based on a PBE starting point). Hence, this approach provides an easily applicable and computationally efficient tool to study the excited-state properties of organic solids of complexity. (c) 2017 Wiley Periodicals, Inc. PMID- 28101899 TI - Recommendations for the use of sensor-augmented pumps with predictive low-glucose suspend features in children: The importance of education. AB - Sensor-augmented pumps, which consist of a pump and a continuous glucose monitoring system, offer considerable therapeutic opportunities, despite requiring close attention in the early phase of their use. The aim of this paper is to provide recommendations on the use of a predictive low glucose management (PLGM) system (Minimed 640GTM, Medtronic, Northridge, CA, USA) in adolescents with type 1 diabetes either at the start of therapy or during follow-up. Sound clinical recommendations on PLGM are of increasing importance since several recent papers have reported significant clinical improvements in patients with PLGM, especially in adults. These recommendations are based on the experience of a group of pediatric endocrinologists who collaborated to closely and intensively study the on-boarding of adolescent patients with type 1 diabetes on automated systems to gain first-hand experience and peer-to-peer insights in a unique free living environment. The suggestions provided here are indicative, so can be adapted to the individual realities and experiences of different diabetes centers. However, we believe that close adherence to the proposed scheme is likely to increase the chances of improving the clinical and metabolic outcomes of patients treated with this therapy. PMID- 28101900 TI - Bronchial thermoplasty in severe asthma in Australia. AB - BACKGROUND: Bronchial thermoplasty (BT) is an approved bronchoscopic intervention for the treatment of severe asthma. However, limited published experience exists outside of clinical trials regarding patient selection and outcomes achieved. AIMS: To evaluate the effectiveness and safety of BT in patients with severe asthma encountered in clinical practice. METHODS: This is a retrospective analysis of the first 'real world' data from Australia. The following outcomes were measured prior to, and 6 months following BT: spirometry, Asthma Control Questionnaire-5 (ACQ-5) score, reliever and preventer medication use and exacerbation history. RESULTS: Twenty patients were treated from June 2014 to December 2015 at three university teaching hospitals. All subjects met the European Respiratory Society/American Thoracic Society definition of severe asthma. Mean pre-bronchodilator forced expiratory volume in 1 s was 62.8 +/- 16.6% predicted (range: 33-95%). All patients were being treated with high dose inhaled corticosteroids, long-acting beta2 agonists and long-acting muscarinic antagonists. Ten patients (50%) were taking maintenance oral prednisolone. Most subjects also required at least one of montelukast (65%), omalizumab (30%) and methotrexate (20%). ACQ-5 improved from 3.6 +/- 1.1 at baseline to 1.6 +/- 1.2 at 6 months, P < 0.001. Short-acting reliever use decreased from a median of 8.0 0.25 puffs/day, P < 0.001, and exacerbations requiring corticosteroids also significantly reduced. Five of 10 patients completely discontinued maintenance oral corticosteroids. Ten patients with a baseline forced expiratory volume in 1 s of <60% predicted significantly improved from 49.2 +/- 9.6% to 61.8 +/- 17.6%, P < 0.05. Only two procedures required hospitalisation beyond the planned overnight admission. CONCLUSION: BT is a safe procedure which can achieve clinical improvement in those with uncontrolled symptoms and severe airflow obstruction. PMID- 28101901 TI - Cyto-genotoxicity and oxidative stress in common carp (Cyprinus carpio) exposed to a mixture of ibuprofen and diclofenac. AB - Thirty million people worldwide consume each day nonsteroidal anti-inflammatory drugs (NSAIDs), a heterogeneous group of pharmaceuticals used for its analgesic, antipyretic, and anti-inflammatory properties. Recent studies report high NSAID concentrations in wastewater treatment plant effluents, in surface, ground, and drinking water, and in sediments. NSAIDs are also known to induce toxicity on aquatic organisms. However, toxicity in natural ecosystems is not usually the result of exposure to a single substance but to a mixture of toxic agents, yet only a few studies have evaluated the toxicity of mixtures. The aim of this study was to evaluate the toxicity induced by diclofenac (DCF), ibuprofen (IBP), and their mixture on a species of commercial interest, the common carp Cyprinus carpio. The median lethal concentration of IBP and DCF was determined, and oxidative stress was evaluated using the following biomarkers: lipid peroxidation and activity of the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase. Cyto-genotoxicity was evaluated by micronucleus test, comet assay, and the specific activity of caspase-3. Results show that DCF, IBP, and a mixture of these pharmaceuticals induced free radical production, oxidative stress and cyto-genotoxicity in tissues of C. carpio. However, a greater effect was elicited by the mixture than by either pharmaceutical alone in some biomarkers evaluated, particularly in gill. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1637-1650, 2017. PMID- 28101902 TI - Global exploration of isomers and isomerization channels on the quantum chemical potential energy surface of H3 CNO3. AB - Global exploration of isomers and isomerization channels on the quantum chemical potential energy surface (PES) is performed for H3 CNO3 using the Scaled Hypersphere Search-Anharmonic Downward Distortion Following (SHS-ADDF) method. The molecular formula of H3 CNO3 includes functional groups of CH3 , OH, NH2 , COOH, NO, NO2 , and NO3 , which are very important in connection with amino acids and NOx. Geometrical structures and interconversion pathways are disclosed after 18719781 force calculations and 534726 Hessian calculations at the level of B3LYP/6-31G(d). The explored results are confirmed to be valid, especially for the important lower energy regions, by re-optimization at the higher level of B3LYP/6-311++G(d,p). A global reaction route-mapping using SHS-ADDF demonstrates the entire view and undeveloped landscapes on PES of H3 CNO3 . Typical compounds of H3 CNO3 , aminoxy formic acid, hydroxycarbamic acid, aminoperformic acid, hydroxymethyl nitrite, nitromethanol, methyl nitrate, methyl peroxynitrite, and dioxaziridine, are well separated from others by very high energy-barriers. The stable-most conformer of H3 CNO3 is difficult to be determined, because of seven structures existing with nearly the same energies within 5.7 kJ/mol at the level of CCSD(T)/aug-cc-pVTZ. (c) 2017 Wiley Periodicals, Inc. PMID- 28101904 TI - Functional analysis of the circadian clock gene timeless in Tribolium castaneum. AB - Circadian rhythms are endogenous oscillations with a period of about 24 h driven by a circadian clock. So far, variable oscillators have been found in insects. To explore the circadian clock of Tribolium castaneum, we cloned the clock gene timeless (Tctimeless). Its open reading frame is 3240 bp in length and consists of 10 exons. Tctimeless is highly expressed in the late pupal stage. Tissue specific expression analysis in late adult stages revealed high expression of Tctimeless in the head, epidermis, fat body and accessory glands. Silencing of Tctimeless by RNA interference (RNAi) at the late larval stages caused a failure to initiate eclosion. Tctimeless knockdown in late pupal stages led to a gender independent decline in egg production and progeny survival. As a core clock gene, Tctimeless exhibited one expression peak in the middle of the circadian day. Knockdown of Tctimeless disrupted daily expression patterns of Tccycle, Tcclock, Tcperiod and itself, while Tctimeless and Tcperiod expression patterns over the circadian day were also perturbed when Tccycle or Tcclock is suppressed by RNAi. This study identified a complex transcriptional relationship among circadian clock genes in T. castaneum. PMID- 28101903 TI - Development and characterization of anti-glycopeptide monoclonal antibodies against human podoplanin, using glycan-deficient cell lines generated by CRISPR/Cas9 and TALEN. AB - Human podoplanin (hPDPN), which binds to C-type lectin-like receptor-2 (CLEC-2), is involved in platelet aggregation and cancer metastasis. The expression of hPDPN in cancer cells or cancer-associated fibroblasts indicates poor prognosis. Human lymphatic endothelial cells, lung-type I alveolar cells, and renal glomerular epithelial cells express hPDPN. Although numerous monoclonal antibodies (mAbs) against hPDPN are available, they recognize peptide epitopes of hPDPN. Here, we generated a novel anti-hPDPN mAb, LpMab-21. To characterize the hPDPN epitope recognized by the LpMab-21, we established glycan-deficient CHO-S and HEK-293T cell lines, using the CRISPR/Cas9 or TALEN. Flow cytometric analysis revealed that the minimum hPDPN epitope, in which sialic acid is linked to Thr76, recognized by LpMab-21 is Thr76-Arg79. LpMab-21 detected hPDPN expression in glioblastoma, oral squamous carcinoma, and seminoma cells as well as in normal lymphatic endothelial cells. However, LpMab-21 did not react with renal glomerular epithelial cells or lung type I alveolar cells, indicating that sialylation of hPDPN Thr76 is cell-type-specific. LpMab-21 combined with other anti-hPDPN antibodies that recognize different epitopes may therefore be useful for determining the physiological function of sialylated hPDPN. PMID- 28101905 TI - Mapping the road from childhood adversity to personality disorder: The role of unresolved states of mind. AB - Childhood adversity has been found to be an important aetiological factor in the development of personality disorder (PD) in several studies. However, the role of disorganized attachment with unresolved mental states for traumatic experiences requires further investigation. This study explores the relationship between childhood adversities, unresolved states of mind, PD diagnosis and psychiatric distress. Two hundred forty-five adult participants, 124 from a clinical PD group and 121 non-psychiatric controls were assessed using the Structured Clinical Interview for DSM-IV, the Cassel Baseline Questionnaire, the Symptom Checklist-90 R and the Adult Attachment Interview, in order to ascertain presence of PD, childhood adversity, level of psychiatric distress and unresolved states of mind. Within the overall unresolved (U-overall) attachment category, a distinction was made between unresolved for abuse (U-abuse) and unresolved for loss (U-loss). The results indicated that childhood adversity was significantly associated with unresolved states of mind, as well as with overall PD diagnosis, paranoid PD, borderline PD, avoidant PD and psychiatric distress. Mediation analyses confirmed that U-overall and U-loss were significant mediators between childhood adversity and PD diagnoses, but surprisingly, U-abuse was not a significant mediator. The strength, limitations and clinical implications of the findings are discussed. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28101906 TI - Areolar Metastases of Skin Malignant Melanoma - Report of a Unique Case. PMID- 28101908 TI - Recurrent Rearrangements of Human Amylase Genes Create Multiple Independent CNV Series. AB - The human amylase gene cluster includes the human salivary (AMY1) and pancreatic amylase genes (AMY2A and AMY2B), and is a highly variable and dynamic region of the genome. Copy number variation (CNV) of AMY1 has been implicated in human dietary adaptation, and in population association with obesity, but neither of these findings has been independently replicated. Despite these functional implications, the structural genomic basis of CNV has only been defined in detail very recently. In this work, we use high-resolution analysis of copy number, and analysis of segregation in trios, to define new, independent allelic series of amylase CNVs in sub-Saharan Africans, including a series of higher-order expansions of a unit consisting of one copy each of AMY1, AMY2A, and AMY2B. We use fiber-FISH (fluorescence in situ hybridization) to define unexpected complexity in the accompanying rearrangements. These findings demonstrate recurrent involvement of the amylase gene region in genomic instability, involving at least five independent rearrangements of the pancreatic amylase genes (AMY2A and AMY2B). Structural features shared by fundamentally distinct lineages strongly suggest that the common ancestral state for the human amylase cluster contained more than one, and probably three, copies of AMY1. PMID- 28101907 TI - Increased Arf/p53 activity in stem cells, aging and cancer. AB - Arf/p53 pathway protects the cells against DNA damage induced by acute stress. This characteristic is the responsible for its tumor suppressor activity. Moreover, it regulates the chronic type of stress associated with aging. This is the basis of its anti-aging activity. Indeed, increased gene dosage of Arf/p53 displays elongated longevity and delayed aging. At a cellular level, it has been recently shown that increased dosage of Arf/p53 delays age-associated stem cell exhaustion and the subsequent decline in tissue homeostasis and regeneration. However, p53 can also promote aging if constitutively activated. In this context, p53 reduces tissue regeneration, which correlates with premature exhaustion of stem cells. We discuss here the current evidence linking the Arf/p53 pathway to the processes of aging and cancer through stem cell regulation. PMID- 28101909 TI - Efficient transdifferentiation of human dermal fibroblasts into skeletal muscle. AB - Skeletal muscle holds significant regenerative potential but is incapable of restoring tissue loss caused by severe injury, congenital defects or tumour ablation. Consequently, skeletal muscle models are being developed to study human pathophysiology and regeneration. Their physiological accuracy, however, is hampered by the lack of an easily accessible human cell source that is readily expandable and capable of efficient differentiation. MYOD1, a master gene regulator, induces transdifferentiation of a variety of cell types into skeletal muscle, although inefficiently in human cells. Here we used MYOD1 to establish its capacity to induce skeletal muscle transdifferentiation of human dermal fibroblasts under baseline conditions. We found significant transdifferentiation improvement via transforming growth factor-beta/activin signalling inhibition, canonical WNT signalling activation, receptor tyrosine kinase binding and collagen type I utilization. Mechanistically, manipulation of individual signalling pathways modulated the transdifferentiation process via myoblast proliferation, lowering the transdifferentiation threshold and inducing cell fusion. Overall, we used transdifferentiation to achieve the robust derivation of human skeletal myotubes and have described the signalling pathways and mechanisms regulating this process. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28101910 TI - A practical approach to vaccination of patients with autoimmune inflammatory rheumatic diseases in Australia. AB - Autoimmune inflammatory rheumatic diseases (AIIRD), such as rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis are often complicated by infection, which results in significant morbidity and mortality. The increased risk of infection is probably due to a combination of immunosuppressive effects of the AIIRD, comorbidities and the use of immunosuppressive conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) and more recently, targeted synthetic DMARDs and biologic DMARDs that block specific pro inflammatory enzymes, cytokines or cell types. The use of these various DMARDs has revolutionised the treatment of AIIRD. This has led to a marked improvement in quality of life for AIIRD patients, who often now travel for prolonged periods. Many infections are preventable with vaccination. However, as protective immune responses induced by vaccination may be impaired by immunosuppression, where possible, vaccination may need to be performed prior to initiation of immunosuppression. Vaccination status should also be reviewed when planning overseas travel. Limited data regarding vaccine efficacy in patients with AIIRD make prescriptive guidelines difficult. However, a vaccination history should be part of the initial work-up in all AIIRD patients. Those caring for AIIRD patients should regularly consider vaccination to prevent infection within the practicalities of routine clinical practice. PMID- 28101911 TI - Comparison of CBV, BEAM and BEAC high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation in non-Hodgkin lymphoma: Efficacy and toxicity. AB - AIM: Limited data are available to guide the choice of conditioning regimen before autologous hematopoietic stem cell transplantation (AHSCT) for patients with lymphoma. METHODS: We analyzed 129 non-Hodgkin lymphoma patients who underwent AHSCT from 1996 to 2013 using the most common regimens: CBV (cyclophosphamide, carmustine and etoposide; n = 16), BEAM (carmustine, etoposide, cytarabine and melphalan; n = 36) and BEAC (carmustine, etoposide, cytarabine and cyclophosphamide; n = 77). RESULTS: At a median follow-up of 42.5 months, the estimated 5-year overall survival for the CBV, BEAM and BEAC groups was 68.8%, 77.8% and 81.8%, respectively (P = 0.584). The estimated 5-year progression-free survival in the CBV group (43.8%) was relatively inferior to the BEAM (66.7%) and BEAC (67.5%) groups, but the differences were not significant (P = 0.403). Grade 2 or higher mucositis, diarrhea and fever were relatively more common in the BEAM group (P < 0.05). No differences were observed in the time to hematopoietic recovery and the duration of hospitalization. The amount of transfused platelet was significantly less in the CBV. CONCLUSION: CBV, BEAM and BEAC regimens are all optional high-dose chemotherapy before AHSCT for NHL patients. PMID- 28101913 TI - Nasopharyngeal colonization with Streptococcus pneumoniae triggers dendritic cell dependent antibody responses against invasive disease in mice. AB - Nasopharyngeal colonization with Streptococcus pneumoniae (Spn) is an important precondition for the development of pneumococcal pneumonia. At the same time, nasopharyngeal colonization with Spn has been shown to mount adaptive immune responses against Spn in mice and humans. Cellular responses of the nasopharyngeal compartment, including the nasal-associated lymphoid tissue, to pneumococcal colonization and their importance for developing adaptive immune responses are poorly defined. We show that nasopharyngeal colonization with S. pneumoniae led to substantial expansion of dendritic cells (DCs) both in nasopharyngeal tissue and nasal-associated lymphoid tissue of mice. Depletion of DCs achieved by either diphtheria toxin (DT) treatment of chimeric zDC+/DTR mice, or by use of FMS-like tyrosine kinase 3 ligand (Flt3L) KO mice exhibiting congenitally reduced DC pool sizes, significantly diminished antibody responses after colonization with Spn, along with impaired protective immunity against invasive pneumococcal disease. Collectively, the data show that classical DCs contribute to pneumococcal colonization induced adaptive immune responses against invasive pneumococcal disease in two different mouse models. These data may be useful for future nasopharyngeal vaccination strategies against pneumococcal diseases in humans. PMID- 28101914 TI - Prenatal Stress Exposure Generates Higher Early Survival and Smaller Size without Impacting Developmental Rate in a Pacific Salmon. AB - Prenatal exposure to elevated glucocorticoids can act as a signal of environmental stress, resulting in modifications to offspring phenotype. While "negative" phenotypic effects (i.e., smaller size, slower growth) are often reported, recent research coupling phenotype with other fitness-related traits has suggested positive impacts of prenatal stress. Using captive Chinook salmon (Oncorhynchus tshawytscha), we treated eggs with biologically relevant cortisol levels-low (300 ng mL-1 ), high (1,000 ng mL-1 ), or control (0 ng mL-1 )-to examine the early-life impacts of maternally transferred stress hormones on offspring. Specifically, we measured early survival, rate of development, and multiple measures of morphology. Low and high cortisol dosing of eggs resulted in significantly higher survival compared to controls (37% and 24% higher, respectively). Fish reared from high dose eggs were structurally smaller compared to control fish, but despite this variation in structural size, exposure to elevated cortisol did not impact developmental rate. These results demonstrate that elevations in egg cortisol can positively influence offspring fitness through an increase in early survival while also altering phenotype at a critical life-history stage. Overall, these results suggest that exposure to prenatal stress may not always produce apparently negative impacts on offspring fitness and further proposes that complex phenotypic responses should be examined in relevant environmental conditions. PMID- 28101915 TI - Early medieval stone-lined graves in Southern Germany: analysis of an emerging noble class. AB - OBJECTIVES: Stone-lined graves, which first appear in Bavarian territory during the 7th century AD, are assumed to be tombs of emerging nobility. While previous research on stone-lined grave goods supports their status as elite burials, an important factor defining nobility-kinship-has not been examined so far. MATERIALS AND METHODS: Morphological analysis of the commingled skeletal remains of 21 individuals from three archaeological sites was carried out. Radiocarbon dating was conducted on these individuals to gain information on usage intervals of these graves. To test whether stone-lined graves can be considered family graves, analyses of mitochondrial HVR I, Y-chromosomal and autosomal STRs were carried out. RESULTS: Morphological examination revealed a surplus of males buried in stone-lined graves and radiocarbon dating points to usage of the tombs for several generations. According to aDNA analysis, kinship can be assumed both between and within stone-lined graves. DISCUSSION: Taken together, these results hint at burials of family members with high social status being inhumed at the same site, in some cases even the same grave, for several generations. They also suggest, for the first time, that an early medieval linear cemetery was structured according to biological kinship. PMID- 28101917 TI - Imaging in gynecological disease (12): clinical and ultrasound features of invasive and non-invasive malignant serous ovarian tumors. AB - OBJECTIVES: To describe clinical and ultrasound features of different subclasses of malignant serous ovarian tumors according to the World Health Organization 2014 classification. METHODS: Patients with a histological diagnosis of borderline tumor (BOT), non-invasive and invasive low-grade serous carcinoma (LGSC) and high-grade serous carcinoma (HGSC), who had undergone preoperative ultrasound examination, were retrospectively identified from two ultrasound centers. The masses were described using the terms of the International Ovarian Tumor Analysis Group. RESULTS: Sixty-four (15.8%) women had a serous BOT, 11 (2.7%) a non-invasive LGSC, 31 (7.6%) an invasive LGSC and 300 (73.9%) had a HGSC. The vast majority of BOTs (82.3%) and non-invasive LGSCs (90.9%) were Stage I according to the International Federation of Gynecology and Obstetrics (FIGO) classification scheme, whereas most invasive LGSCs (74.2%) and HGSCs (74.0%) were FIGO Stage III. On ultrasound examination, most borderline lesions were described as unilocular-solid (54.7%) or as multilocular-solid (29.7%) cysts. Papillary projections were present in 52 (81.3%) BOTs. Most non-invasive LGSCs (63.6%) were multilocular-solid cysts and 81.8% had papillary projections. Invasive LGSCs were multilocular-solid cysts in 54.8% of cases, and papillary projections were present in 32.3% of lesions. HGSCs were multilocular-solid (32.7%) or solid (64.0%) masses, with papillary projections in only 7% of cases. CONCLUSIONS: Papillary projections were the most typical ultrasound feature of non-invasive (borderline and low-grade) malignant serous tumors, while the presence of solid components but few, if any, papillations was the most representative feature of invasive (low-grade and high-grade) serous tumors. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28101916 TI - Perceptions of cancer of unknown primary site: a national survey of Australian medical oncologists. AB - BACKGROUND: Despite being the sixth most common cause of cancer death in Australia, cancer of unknown primary (CUP) site remains poorly understood. AIMS: To describe practices relating to the diagnosis, investigation, classification, communication and management of CUP among medical oncologists. METHODS: We invited all members of the Medical Oncology Group of Australia to participate in a national, anonymous online survey about CUP. The survey collected data regarding diagnosis acceptance, diagnostic tests, treatment protocols and communication practices around the diagnosis of CUP. RESULTS: Three hundred and two oncologists were invited and 86 (28%) completed the survey. Eighty (93%) respondents were directly involved in the assessment of patients with CUP. Eighty five (99%) respondents were prepared to make a diagnosis of CUP if, after appropriate diagnostic tests, the primary location could not be ascertained. Eighty-three percent would assign a primary site to obtain Pharmaceutical Benefits Schedule funding of medical therapy. Sixty-two percent did not have a specific treatment protocol designed for CUP. The majority of oncologists used serum tumour markers and computed tomography scans in the initial work-up, while 43% indicated they would use a positron emission tomography scan in the majority of cases. The majority would arrange mammography in female patients. Thematic analysis of responses to open-ended questions about how CUP is described identified little consistency in the language being used. CONCLUSION: The approach to diagnosis, investigation and management of CUP by medical oncologists in Australia is variable. Many preferred to estimate the primary site and treat accordingly. Pharmaceutical Benefits Schedule restrictions may encourage the practice of 'best guessing'. PMID- 28101918 TI - Plastic temporal bones. PMID- 28101919 TI - Lost in markers? Time for phenomics and phenomapping in dilated cardiomyopathy. PMID- 28101920 TI - Quantitative proteomic analysis of HIV-1 Tat-induced dysregulation in SH-SY5Y neuroblastoma cells. AB - Despite affecting up to 70% of HIV-positive patients and being the leading cause of dementia in patients under 40 years, the molecular mechanisms involved in the onset of HIV-associated neurocognitive disorders (HAND) are not well understood. To address this, we performed SILAC-based quantitative proteomic analysis on HIV Tat treated SH-SY5Y neuroblastoma cells. Isolated protein was fractionated by SDS PAGE and analyzed by nLC-MS/MS on an Orbitrap Velos. Using MaxQuant, we identified and quantified 3077 unique protein groups, of which 407 were differentially regulated. After applying an additional standard deviation-based cutoff, 29 of these were identified as highly significantly and stably dysregulated. GO term analysis shows dysregulation in both protein translation machinery as well as cytoskeletal regulation that have both been implicated in other dementias. In addition, several key cytoskeletal regulatory proteins such as ARHGEF17, the Rho GTPase, SHROOM3, and CMRP1 are downregulated. Together, these data demonstrate that HIV-Tat can dysregulate neuronal cytoskeletal regulatory proteins that could lead to the major HAND clinical manifestation synapse loss. PMID- 28101921 TI - Effects of shifts in food reinforcement context on rats' consumption of concurrently available water or sucrose solution. AB - The purpose of this study was to investigate the effects of signaled transitions from relatively rich to lean conditions of food reinforcement on drinking concurrently available water or sucrose-sweetened water in rats. Past research demonstrated that these negative incentive shifts produce behavioral disruption in the form of extended pausing on fixed-ratio schedules. Four male Long-Evans rats operated on a two-component multiple fixed-ratio fixed-ratio schedule. In one manipulation, the ratio was held constant and the components arranged either a large six-pellet reinforcer (rich) or small one-pellet reinforcer (lean). In a second manipulation, the components both produced a one-pellet reinforcer but differed in terms of the ratio requirement, with the rich and lean conditions corresponding to relatively small and large ratios. In both manipulations, components were pseudorandomly presented to arrange four transitions signaled by retractable levers: lean-to-lean, lean-to-rich, rich-to-rich, and rich-to-lean (the negative incentive shift). During experimental conditions, a bottle with lickometer was inserted in the chamber, providing concurrent access either to tap water or a 10% sucrose solution. The negative incentive shift produced considerably more drinking than the other transitions in all rats during both manipulations. The level of drinking was not polydipsic; rather, it appears that the negative incentive shift enhanced the value of concurrently available reinforcers relative to food reinforcement. PMID- 28101923 TI - How suboptimal is suboptimal choice? AB - In a frequently used suboptimal-choice procedure pigeons choose between an alternative that delivers three food pellets with p = 1.0 and an alternative that delivers ten pellets with p = 0.2. Because pigeons reliably choose the probabilistic (suboptimal) alternative, the procedure has been proposed as a nonhuman analog of human gambling. The present experiments were conducted to evaluate two potential threats to the validity of this procedure. Experiments 1 and 2 evaluated if pigeons obtained food at a lower unit price (i.e., pecks per pellet) on the suboptimal alternative than on the optimal alternative. When pigeons worked under this suboptimal procedure they all preferred the suboptimal alternative despite some pigeons paying a higher price for food on that alternative. In Experiment 2, when the unit price ratio more closely approximated the inverse of the expected value ratio, pigeons continued to prefer the suboptimal alternative despite its economic suboptimality. Experiment 3 evaluated if, in accord with the string-theory of gambling, the valuation of the suboptimal alternative was increased when pigeons misattributed a subset of the suboptimal no-food trials to the optimal alternative. When trial sequences were arranged to minimize these possible attribution errors, pigeons still preferred the suboptimal alternative. These data remove two threats to the validity of the suboptimal choice procedure; threats that would have suggested that suboptimal choice reflects economic maximization. PMID- 28101922 TI - A second type of magnitude effect: Reinforcer magnitude differentiates delay discounting between substance users and controls. AB - Basic research on delay discounting, examining preference for smaller-sooner or larger-later reinforcers, has demonstrated a variety of findings of considerable generality. One of these, the magnitude effect, is the observation that individuals tend to exhibit greater preference for the immediate with smaller magnitude reinforcers. Delay discounting has also proved to be a useful marker of addiction, as demonstrated by the highly replicated finding of greater discounting rates in substance users compared to controls. However, some research on delay discounting rates in substance users, particularly research examining discounting of small-magnitude reinforcers, has not found significant differences compared to controls. Here, we hypothesize that the magnitude effect could produce ceiling effects at small magnitudes, thus obscuring differences in delay discounting between groups. We examined differences in discounting between high risk substance users and controls over a broad range of magnitudes of monetary amounts ($0.10, $1.00, $10.00, $100.00, and $1000.00) in 116 Amazon Mechanical Turk workers. We found no significant differences in discounting rates between users and controls at the smallest reinforcer magnitudes ($0.10 and $1.00) and further found that differences became more pronounced as magnitudes increased. These results provide an understanding of a second form of the magnitude effect: That is, differences in discounting between populations can become more evident as a function of reinforcer magnitude. PMID- 28101924 TI - Effects of differential rates of alternative reinforcement on resurgence of human behavior. AB - Despite the success of exposure-based psychotherapies in anxiety treatment, relapse remains problematic. Resurgence, the return of previously eliminated behavior following the elimination of an alternative source of reinforcement, is a promising model of operant relapse. Nonhuman resurgence research has shown that higher rates of alternative reinforcement result in faster, more comprehensive suppression of target behavior, but also in greater resurgence when alternative reinforcement is eliminated. This study investigated rich and lean rates of alternative reinforcement on response suppression and resurgence in typically developing humans. In Phase 1, three groups (Rich, n = 18; Lean, n = 18; Control, n = 10) acquired the target response. In Phase 2, target responding was extinguished and alternative reinforcement delivered on RI 1 s, RI 3 s, and extinction schedules, respectively. Resurgence was assessed during Phase 3 under extinction conditions for all groups. Target responding was suppressed most thoroughly in Rich and partially in Lean. Target responding resurged in the Rich and Lean groups, but not in the Control group. Between groups, resurgence was more pronounced in the Rich group than the Lean and Control groups. Clinical implications of these findings, including care on the part of clinicians when identifying alternative sources of reinforcement, are discussed. PMID- 28101926 TI - Alan Baron: A pioneer in translational science. PMID- 28101925 TI - "Watch out!": Effects of instructed threat and avoidance on human free-operant approach-avoidance behavior. AB - Approach-avoidance paradigms create a competition between appetitive and aversive contingencies and are widely used in nonhuman research on anxiety. Here, we examined how instructions about threat and avoidance impact control by competing contingencies over human approach-avoidance behavior. Additionally, Experiment 1 examined the effects of threat magnitude (money loss amount) and avoidance cost (fixed ratio requirements), whereas Experiment 2 examined the effects of threat information (available, unavailable and inaccurate) on approach-avoidance. During the task, approach responding was modeled by reinforcing responding with money on a FR schedule. By performing an observing response, participants produced an escalating "threat meter". Instructions stated that the threat meter levels displayed the current probability of losing money, when in fact loss only occurred when the level reached the maximum. Instructions also stated pressing an avoidance button lowered the threat level. Overall, instructions produced cycles of approach and avoidance responding with transitions from approach to avoidance when threat was high and transitions back to approach after avoidance reduced threat. Experiment 1 revealed increasing avoidance cost, but not threat magnitude, shifted approach-avoidance transitions to higher threat levels and increased anxiety ratings, but did not influence the frequency of approach avoidance cycles. Experiment 2 revealed when threat level information was available or absent earnings were high, but earnings decreased when inaccurate threat information was incompatible with contingencies. Our findings build on prior nonhuman and human approach-avoidance research by highlighting how instructed threat and avoidance can impact human AA behavior and self-reported anxiety. PMID- 28101927 TI - Comparing positive and negative reinforcement: A fantasy experiment. AB - We propose quantitative experimental approaches to the question of whether positive and negative reinforcement are functionally different, and discuss scientific and ethical concerns that would arise if these approaches were pursued. PMID- 28101928 TI - Are positive and negative reinforcement "different"? Insights from a free-operant differential outcomes effect. AB - Although theoretical discussions typically assume that positive and negative reinforcement differ, the literature contains little unambiguous evidence that they produce differential behavioral effects. To test whether the two types of consequences control behavior differently, we pitted money-gain positive reinforcement and money-loss-avoidance negative reinforcement, scheduled through identically programmed variable-cycle schedules, against each other in concurrent schedules. Contingencies of response-produced feedback, normally different in positive and negative reinforcement, were made symmetrical. Steeper matching slopes were produced compared to a baseline consisting of all positive reinforcement. This free-operant differential outcomes effect supports the notion that that stimulus-presentation positive reinforcement and stimulus-elimination negative reinforcement are functionally "different." However, a control experiment showed that the feedback asymmetry of more traditional positive and negative reinforcement schedules also is sufficient to create a "difference" when the type of consequence is held constant. We offer these findings as a small step in meeting the very large challenge of moving negative reinforcement theory beyond decades of relative quiescence. PMID- 28101929 TI - Dysgeusia and health-related quality of life of cancer patients receiving chemotherapy: A cross-sectional study. AB - The aim of the study was to evaluate taste disorders in patients receiving chemotherapy and to assess the impact of dysgeusia on patients' health-related quality of life (HRQOL). A total of 289 patients with a diagnosis of malignant solid or haematological cancer undergoing chemotherapy completed a questionnaire assessing dysgeusia and HRQOL. Sixty-four per cent of patients developed dysgeusia after and during chemotherapy. A statistically significant correlation was found between type of cancer and dysgeusia (p = .012), moreover a statistically significant association was found between type of chemotherapy and occurrence of dysgeusia (p = .031). Patients with dysgeusia had a worse overall HRQOL than those who did not have dysgeusia, and the association between HRQOL and dysgeusia was also statistically significant (p = .003). Patients with dysgeusia had a higher probability of having a worse HRQOL (p = .002). In line with previous studies, we observed a significant correlation between chemotherapy and dysgeusia. Furthermore, this study found that cancer patients with dysgeusia have a lower quality of life. In particular the domains "role," "social aspect," "nausea-vomiting" and "appetite" are most influenced by dysgeusia. Improving the communication and information to patients considered at higher risk of developing dysgeusia can have a positive impact on patients' quality of life. PMID- 28101930 TI - Effect of humidity and temperature on the survival of Listeria monocytogenes on surfaces. AB - : Listeria monocytogenes is a pathogenic bacterium, with human disease and infection linked to dairy products, seafood, ready-to-eat meat and raw & undercooked meats. Stainless steel is the most common food preparation surface and therefore, it is important to understand how food storage conditions such as surface materials, temperature and relative humidity can affect survival of L. monocytogenes. In this study, survival of L. monocytogenes on stainless steel was investigated at three temperatures (4, 10 and 21 degrees C), each approx. 11, 50 and 85% humidity. Results indicate that the lower the temperature, the more cells were recovered in all three humidity environments, while medium humidity enhances survival, irrespective of temperature. Lower humidity decreases recovery at all temperatures. These data support the guidance noted above that humidity control is important, and that lower humidity environments are less likely to support retention of viable L. monocytogenes on a stainless steel surface. SIGNIFICANCE AND IMPACT OF THE STUDY: Understanding survival of potential food-borne pathogens is essential for the safe production and preparation of food. While it has long been 'common knowledge' that relative humidity can affect the growth and survival of micro-organisms, this study systematically describes the survival of L. monocytogenes on stainless steel under varying humidity and temperatures for the first time. The outcomes from this paper will allow those involved with food manufacture and preparation to make informed judgement on environmental conditions relating to humidity control, which is lacking in the food standards guidelines. PMID- 28101932 TI - Amino Acid Profiling of Zinc Resistant Prostate Cancer Cell Lines: Associations With Cancer Progression. AB - BACKGROUND: Failure in intracellular zinc accumulation is a key process in prostate carcinogenesis. Nevertheless, epidemiological studies of zinc administration have provided contradicting results. In order to examine the impact of the artificial intracellular increase of zinc(II) ions on prostate cancer metabolism, PNT1A, 22Rv1, and PC-3 prostatic cell lines-depicting different stages of cancer progression-and their zinc-resistant counterparts were used. To determine "benign" and "malignant" metabolic profiles, amino acid patterns, gene expression, and antioxidant capacity of these cell lines were assessed. METHODS: Amino acid profiles were examined using an ion-exchange liquid chromatography. Intracellular zinc content was measured by atomic absorption spectrometry. Metallothionein was quantified using differential pulse voltammetry. The content of reduced glutathione was determined using high performance liquid chromatography coupled with an electrochemical detector. Cellular antioxidant capacity was determined by the ABTS test and gene expression analysis was performed by qRT-PCR. RESULTS AND CONCLUSIONS: Long-term zinc treatment was shown to reroute cell metabolism from benign to more malignant type. Long-term application of high concentration of zinc(II) significantly enhanced cisplatin resistance, invasiveness, cellular antioxidant capacity, synthesis of glutathione, and expression of treatment resistance- and stemness associated genes (SOX2, POU5F1, BIRC5). Tumorous cell lines universally displayed high accumulation of aspartate and sarcosine and depletion of essential amino acids. Increased aspartate/threonine, aspartate/methionine, and sarcosine/serine ratios were associated with cancer phenotype with high levels of sensitivity and specificity. Prostate 77: 604-616, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28101933 TI - Associations of common variants in the SLC16A11, TCF7L2, and ABCA1 genes with pediatric-onset type 2 diabetes and related glycemic traits in families: A case control and case-parent trio study. AB - BACKGROUND: There is evidence of associations of single-nucleotide polymorphisms (SNPs) with type 2 diabetes (T2D) and related glycemic traits in adults, but there is a little information about such associations in youths. OBJECTIVE: The aim of this study was to evaluate the associations of SNPs in the TCF7L2, SLC16A11, and ABCA1 genes with T2D and related glycemic traits in Mexican children and adolescents. SUBJECTS: A total of 99 families with children with T2D (n = 327) and 83 families with children without the disease (n = 212). METHODS: The associations between SNPs of TCF7L2 (rs7903146 and rs12255372), SLC16A11 (rs13342232), and ABCA1 (rs9282541) with T2D were analyzed. We also evaluated the effects of SNPs on quantitatively related glycemic traits after adjusting for age, sex, and the presence of overweight or obesity. RESULTS: The G allele of SLC16A1 /rs13342232 was associated with T2D in adults (adjusted odds ratio [ORadj] = 1.89; 95% confidence interval [CI]: 1.18; 3.06) and children (ORadj = 1.94; 95% CI: 1.25; 3.00). In addition, the combined analysis of case-control and case-parent trio was also significant (OR = 1.43; 95% CI: 1.12; 1.74). After adjusting for known confounding factors, we found a significant association between TCF7L2/rs122555372 and C-peptide (beta = -0.76, P = .005) in patients with diabetes and between fasting glucose (beta = 2.05, P = .039) and homeostatic model assessment of beta-cell function (beta = -32.14, P = .025) levels in individuals without diabetes. CONCLUSIONS: The results suggest that SLC16A1 /rs13342232 might be involved in the risk of pediatric-onset T2D in Mexican families. Moreover, TCF7L2/rs122555372 was associated with pancreatic reserve in patients with T2D and with fasting glucose and beta-cell function in individuals without diabetes. PMID- 28101935 TI - Effect of cholesterol-loaded cyclodextrins on cryosurvival of dog spermatozoa. AB - Cryopreservation affects integrity of cholesterol and phospholipids in the plasma membrane of sperm leading to decreased fertility of frozen-thawed semen. Cholesterol-loaded cyclodextrins (CLC) have been shown to improve post-thaw semen quality in various species. The aim of this study was to investigate the optimal concentration of CLC for better post-thaw semen quality in dogs. Semen collection, through digital manipulation, was conducted once a week in four adult German shepherd dogs (n = 20 ejaculates; five ejaculates/dog). Semen samples with mass motility>3 (0: without movement; 5: fast progressive movement), motility >70% and concentration >200 * 106 /ml were pooled and processed in Tris-citrate extender containing 0, 1, 2 or 3 mg of CLC. The post-thaw quality was assessed on the basis of percentage motility, morphological abnormalities, live/dead ratio and plasma membrane, acrosome and DNA integrity, evaluated using anova and further analysed by Tukey's range test, if applicable. The addition of CLC showed an overall improvement in post-thaw semen quality. Among various treatment groups, and when compared to the control, the percentages of motile (55.5%), viable (65%), plasma membrane intact (56.7%), acrosome intact (49.2%) and DNA intact (98%) spermatozoa were significantly higher in 2 mg/ml CLC group (p < .05). It is concluded that incorporation of cholesterol in semen extender results in a beneficial increase in post-thaw semen quality in dogs. PMID- 28101934 TI - Detection of neonatal unit clusters of Candida parapsilosis fungaemia by microsatellite genotyping: Results from laboratory-based sentinel surveillance, South Africa, 2009-2010. AB - Neonatal candidaemia is a common, deadly and costly hospital-associated disease. To determine the genetic diversity of Candida parapsilosis causing fungaemia in South African neonatal intensive care units (NICUs). From February 2009 through to August 2010, cases of candidaemia were reported through laboratory-based surveillance. C. parapsilosis isolates from neonatal cases were submitted for identification by internal transcribed spacer (ITS) region sequencing, antifungal susceptibility testing and microsatellite genotyping. Cluster analysis was performed using Unweighted Pair Group Method with Arithmetic Mean (UPGMA). Of 1671 cases with a viable Candida isolate, 393 (24%) occurred among neonates. Isolates from 143 neonatal cases were confirmed as C. parapsilosis sensu stricto. Many isolates were resistant to fluconazole (77/143; 54%) and voriconazole (20/143; 14%). Of 79 closely-related genotypes, 18 were represented by >=2 isolates; 61 genotypes had a single isolate each. Seven clusters, comprised of 82 isolates, were identified at five hospitals in three provinces. Isolates belonging to certain clusters were significantly more likely to be fluconazole resistant: all cluster 7 isolates and the majority of cluster 4 (78%), 5 (89%) and 6 (67%) isolates (P<.001). Candida parapsilosis-associated candidaemia in public-sector NICUs was caused by closely related genotypes and there was molecular evidence of undetected outbreaks as well as intra-hospital transmission. PMID- 28101937 TI - Methods of anorectal manometry vary widely in clinical practice: Results from an international survey. AB - BACKGROUND: Ano-rectal manometry (ARM) is the most commonly performed investigation for assessment of anorectal dysfunction. Its use is supported by expert consensus documents and international guidelines. Variation in technology, data acquisition, and analysis affect results and clinical interpretation. This study examined variation in ARM between institutions to establish the status of current practice. METHODS: A 50-item web-based questionnaire assessing analysis and interpretation of ARM was distributed by the International Anorectal Physiology Working Group via societies representing practitioners that perform ARM. Study methodology and performance characteristics between institutions were compared. KEY RESULTS: One hundred and seven complete responses were included from 30 countries. Seventy-nine (74%) institutions performed at least two studies per week. Forty-nine centers (47%) applied conventional ARM (<=8 pressure sensors) and 57 (53%) high-resolution ARM (HR-ARM). Specialist centers were most likely to use HR-ARM compared to regional hospitals and office-based practice (63% vs 37%). Most conventional ARM systems used water-perfused technology (34/49); solid-state hardware was more frequently used in centers performing HR ARM (44/57). All centers evaluated rest and squeeze. There was marked variation in the methods used to report results of maneuvers. No two centers had identical protocols for patient preparation, setup, study, and data interpretation, and no center fully complied with published guidelines. CONCLUSIONS & INFERENCES: There is significant discrepancy in methods for data acquisition, analysis, and interpretation of ARM. This is likely to impact clinical interpretation, transfer of data between institutions, and research collaboration. There is a need for expert international co-operation to standardize ARM. PMID- 28101936 TI - Quantitative iTRAQ-based proteomic analysis of rice grains to assess high night temperature stress. AB - Rice yield and quality are adversely affected by increasing global surface temperature, and are strongly attributed to high night temperature (HNT) than high daytime temperature. However, the molecular mechanism underlying the heat tolerant characteristics of rice remains unclear. In the present study, we compared the proteomes of heat-tolerant and -sensitive lines of rice at early milky stage using an iTRAQ method. We have identified 38 differentially expressed proteins between the two lines, of which 32 proteins have been functionally annotated in NCBI and/or the UniProt database. These proteins were then classified into seven functional subgroups, which include signal transduction, transcript regulation, oxidation, defense response, transport, energy metabolism, and biosynthesis. Further analysis indicated that HNT stress could disrupt the redox equilibrium of plant cells, which in turn triggers the calcium-dependent protein kinase and COP9 signalosome, thereby regulating downstream genes/proteins that are involved in the HNT response. The candidate proteins may provide genetic resources for the improvement of heat-tolerant characteristics in rice, and the proposed model for signal transduction and transcriptional regulation may facilitate in the elucidation of the molecular mechanism underlying the response to HNT stress in rice. PMID- 28101939 TI - Care planning: a neoliberal three card trick. PMID- 28101938 TI - The second Team Haemophilia Education Meeting, 2016, Frankfurt, Germany. AB - The first Team Haemophilia Education (THE) Meeting was held on 7-8 May 2015 in Amsterdam, The Netherlands. It aimed to promote the optimal care of patients with haemophilia through education of the multidisciplinary treatment team. This was achieved by reviewing the latest developments in haemophilia management, considering how these can be implemented in the clinic to improve patient care and providing a platform for networking and debate for all haemophilia treatment team members. The second THE Meeting was held on 19-20 May in Frankfurt, Germany, and participants included doctors, nurses, physiotherapists, patient representatives and data management staff from 20 different countries. Topics covered the role of the multidisciplinary team in delivering the best haemophilia care, challenges in the management of haemophilia across Europe, available clotting factor treatments, future treatments and the use of genetics in advising carriers of haemophilia. This report is a summary of the key developments in haemophilia care presented by various investigators and healthcare professionals at THE Meeting 2016. PMID- 28101940 TI - Chronic nasal exposure to nanoparticulate TiO2 causes pulmonary tumorigenesis in male mice. AB - Chronic inhalation bioassays in rodents are used to assess pulmonary carcinogenicity for purposes of hazard identification and potentially for risk characterization. Numerous studies have been confirmed that exposure to titanium dioxide nanoparticles (TiO2 NPs) may result in chronic pulmonary inflammation in both mice and rats. However, very few studies have focused on the pulmonary tumorigenesis. In this study, to examine whether chronic TiO2 NP exposure induce tumorigenesis in the lung, forty mice (each group) were nasally exposed to 1.25, 2.5, and 5 mg/kg body weight TiO2 NPs for nine consecutive months, lung pathology was then evaluated, and the biochemical function parameters in bronchoalveolar lavage (BAL) and tumor markers in the serum were investigated using an ELISA method. We observed that nasal exposure to TiO2 NPs caused infiltration of inflammatory cells, tumorigenesis in the lung, and accompanied by significant increases of lactate dehydrogenase, alkaline phosphatase, and total protein levels in BLAF, significant increases in tumor markers including cytokeratin 19, neuron-specific enolase, carcinoembryonic antigen, squamous cell carcinoma antigen, and cancer antigen-125 in the serum. It implies that chronic inhaled TiO2 NPs may increase possibility of pulmonary tumor formation for human. Therefore, the production and application of TiO2 NPs should be paid more attention. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1651-1657, 2017. PMID- 28101942 TI - The use of hemodynamic support in massive pulmonary embolism. AB - Massive pulmonary embolism is life threatening and can present as cardiogenic shock and cardiac arrest. We report a case of a 47-year-old male who arrested during his postoperative hospitalization and was found to have a massive pulmonary embolism with bilateral involvement of the pulmonary arteries. Given his profound shock and right ventricular failure, an Impella RP was used to stabilize his acute right ventricular failure while percutaneous embolectomy and thrombolysis was used to treat the pulmonary embolism. The patient underwent the procedure successfully with reduction in vasopressors and thrombus burden and recovery of right ventricular function. (c) 2017 Wiley Periodicals, Inc. PMID- 28101941 TI - Key messages for communicating information about BRCA1 and BRCA2 to women with breast or ovarian cancer: Consensus across health professionals and service users. AB - BACKGROUND: Genetic testing of cancer predisposing genes will increasingly be needed in oncology clinics to target cancer treatment. This Delphi study aimed to identify areas of agreement and disagreement between genetics and oncology health professionals and service users about the key messages required by women with breast/ovarian cancer who undergo BRCA1/BRCA2 genetic testing and the optimal timing of communicating key messages. METHODS: Participants were 16 expert health professionals specialising in oncology/genetics and 16 service users with breast/ovarian cancer and a pathogenic BRCA1/BRCA2 variant. Online questionnaires containing 53 inductively developed information messages were circulated to the groups separately. Participants rated each message as key/not key on a Likert scale and suggested additional messages. Questionnaires were modified according to the feedback and up to 3 rounds were circulated. Consensus was reached when there was >=75% agreement. RESULTS: Thirty key messages were agreed by both groups with 7 of the key messages agreed by >=95% of participants: dominant inheritance, the availability of predictive testing, the importance of pretest discussion, increased risk of breast and ovarian cancer, and the option of risk reducing mastectomy and bilateral salpingo-oophorectomy. Both groups agreed that key messages should be communicated before genetic testing and once a pathogenic variant has been identified. CONCLUSIONS: There was a high level of agreement within and between the groups about the information requirements of women with breast/ovarian cancer about BRCA1/BRCA2. These key messages will be helpful in developing new approaches to the delivery of information as genetic testing becomes further integrated into mainstream oncology services. PMID- 28101943 TI - Stability of color in Spanish-style green table olives pasteurized and stored in plastic containers. AB - BACKGROUND: There is an increasing interest in the use of pasteurizable plastic packaging by the olive industry. In order to investigate the change from traditional glass or varnished can containers to plastic packaging, the proper plastic material that is compatible with fermented olives while maintaining color quality during pasteurization treatment and storage must be selected. This work is focused on color stability in two distinct pasteurizable plastic containers with different oxygen permeability. RESULTS: In PET + MDPE/EVOH (polyethylene terephthalate + medium-density polyethylene/ethylene vinyl alcohol) pouches, pasteurization provoked severe browning which drastically decreased their color shelf life (<6 weeks). However, this browning did not occur in the unpasteurized product without preservatives owing to the presence of microorganisms. In AlOx coated PET + MDPE (aluminum oxide coating on polyethylene terephthalate + medium density polyethylene) pouches, color changes were small or negligible throughout storage, especially if ascorbic acid was added to the packing solution (shelf life > 6.5 months). CONCLUSION: The plastic material had a significant effect on the retention of color of the pasteurized product. The use of AlOx-coated PET + MDPE pouches could be an alternative to traditional packaging for the pasteurization and storage of Spanish-style green olives from a color quality standpoint. (c) 2017 Society of Chemical Industry. PMID- 28101944 TI - Biomechanical implications of walking with indigenous footwear. AB - OBJECTIVES: This study investigates biomechanical implications of walking with indigenous "Kolhapuri" footwear compared to barefoot walking among a population of South Indians. MATERIALS AND METHODS: Ten healthy adults from South India walked barefoot and indigenously shod at voluntary speed on an artificial substrate. The experiment was repeated outside, on a natural substrate. Data were collected from (1) a heel-mounted 3D-accelerometer recording peak impact at heel contact, (2) an ankle-mounted 3D-goniometer (plantar/dorsiflexion and inversion/eversion), and (3) sEMG electrodes at the m. tibialis anterior and the m. gastrocnemius medialis. RESULTS: Data show that the effect of indigenous footwear on the measured variables, compared to barefoot walking, is relatively small and consistent between substrates (even though subjects walked faster on the natural substrate). Walking barefoot, compared to shod walking yields higher impact accelerations, but the differences are small and only significant for the artificial substrate. The main rotations of the ankle joint are mostly similar between conditions. Only the shod condition shows a faster ankle rotation over the rapid eversion motion on the natural substrate. Maximal dorsiflexion in late stance differs between the footwear conditions on an artificial substrate, with the shod condition involving a less dorsiflexed ankle, and the plantar flexion at toe-off is more extreme when shod. Overall the activity pattern of the external foot muscles is similar. DISCUSSION: The indigenous footwear studied (Kolhapuri) seems to alter foot biomechanics only in a subtle way. While offering some degree of protection, walking in this type of footwear resembles barefoot gait and this type of indigenous footwear might be considered "minimal". PMID- 28101945 TI - Epidermal growth factor receptor (EGFR)-MAPK-nuclear factor(NF)-kappaB-IL8: A possible mechanism of particulate matter(PM) 2.5-induced lung toxicity. AB - Airway inflammation plays a central role in the pathophysiology of diverse pulmonary diseases. In this study, we investigated whether exposure to particulate matter (PM) 2.5, a PM with an aerodynamic diameter of less than 2.5 um, enhances inflammation-related toxicity in the human respiratory system through activation of the epidermal growth factor receptor (EGFR) signaling pathway. Through cytokine antibody array analysis of two extracts of PM2.5 [water (W-PM2.5 ) and organic (O-PM2.5 ) soluble extracts] exposed to A549 (human alveolar epithelial cell), we identified eight cytokines changed their expression with W-PM2.5 and three cytokines with O-PM2.5 . Among them, epidermal growth factor (EGF) was commonly up-regulated by W-PM2.5 and O-PM2.5 . Then, in both groups, we can identify the increase in EGF receptor protein levels. Likewise, increases in the phosphorylation of ERK1/2 MAP kinase and acetylation of nuclear factor(NF)-kappaB were detected. We also detected an increase in IL-8 that was related to inflammatory response. And using the erlotinib as an inhibitor of EGFR, we identified the erlotinib impaired the phosphorylation of EGFR, ERK1/2, acetylation of NF-kappaB proteins and decreased IL-8. Furthermore, at in vivo model, we were able to identify similar patterns. These results suggest that PM2.5 may contribute to an abnormality in the human respiratory system through EGFR, MAP kinase, NF-kappaB, and IL-8 induced toxicity signaling. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1628-1636, 2017. PMID- 28101947 TI - Combined surgical therapy of advanced peri-implantitis evaluating two methods of surface decontamination: a 7-year follow-up observation. AB - OBJECTIVES: To assess the long-term outcomes (>4 years) following combined surgical resective/regenerative therapy of advanced peri-implantitis lesions using two surface decontamination methods. MATERIAL & METHODS: Fifteen patients (n = 15 combined supra- and intrabony defects) completed a follow-up observation period of 7 years. The treatment procedure included access flap surgery, granulation tissue removal and implantoplasty at buccally and supracrestally exposed implant parts, and a randomly assigned decontamination of the unmodified intrabony implant surface areas using either (i) an Er:YAG laser (ERL) or (ii) plastic curettes + cotton pellets + sterile saline (CPS). Intrabony defects were filled using a natural bone mineral and covered by a native collagen membrane. RESULTS: At 7 years, both ERL and CPS were associated with similar mean bleeding on probing reductions (CPS: 89.99 +/- 11.65% versus ERL: 86.66 +/- 18.26%) and clinical attachment level gains (CPS: 2.76 +/- 1.92 mm versus ERL: 2.06 +/- 2.52 mm). CONCLUSION: Combined surgical resective/regenerative therapy of advanced peri-implantitis was effective on the long-term, but not influenced by the initial method of surface decontamination. PMID- 28101946 TI - Repeat hepatectomy is independently associated with favorable long-term outcome in patients with colorectal liver metastases. AB - Up to three-quarters of patients undergoing liver resection for colorectal liver metastases (CRLM) develop intrahepatic recurrence. Repeat hepatic resection appears to provide the optimal chance of cure for these patients. The aim of this study was to analyze short- and long-term outcomes following index and repeat hepatectomy for CRLM. Clinicopathological data were obtained from a prospectively maintained database. Perioperative variables and outcomes were compared using the Chi-squared test. Variables associated with long-term survival following index and second hepatectomy were identified by Cox regression analyses. Over the study period, 488 patients underwent hepatic resection for CRLM, with 71 patients undergoing repeat hepatectomy. There was no significant difference in rates of morbidity (P = 0.135), major morbidity (P = 0.638), or mortality (P = 0.623) when index and second hepatectomy were compared. Performance of repeat hepatectomy was independently associated with increased overall and cancer-specific survival following index hepatectomy. Short disease-free interval between index and second hepatectomy, number of liver metastases >1, and resection of extrahepatic disease were independently associated with shortened survival following repeat resection. Repeat hepatectomy for recurrent CRLM offers short-term outcomes equivalent to those of patients undergoing index hepatectomy, while being independently associated with improved long-term patient survival. PMID- 28101948 TI - Influence of the marine feeding area on the muscle and egg fatty-acid composition of Atlantic salmon Salmo salar spawners estimated from the scale stable isotopes. AB - Fatty acids in muscle tissue and eggs of female Atlantic salmon Salmo salar spawners were analysed to evaluate the dietary quality of their final feeding areas in the Baltic Sea. The final likely feeding area was identified by comparing stable carbon and nitrogen isotope composition of the outermost growth region (final annulus) of scales of returned S. salar with that of reference S. salar caught from different feeding areas. Some overlap of stable-isotope reference values among the three areas, in addition to prespawning fasting, decreased the ability of muscle tri-acylglycerols to discriminate the final likely feeding area and the area's dietary quality. Among three long-chained polyunsaturated fatty acids, docosahexaenoic acid (DHA; 22:6n-3), eicosapentaenoic acid (EPA; 20:5n-3) and arachidonic acid (ARA; 20:4n-6), the proportions of ARA in total lipids of spawning S. salar muscle and eggs showed a significant negative correlation with increasing probability of S. salar having returned from the Baltic Sea main basin (i.e. the Baltic Sea proper). The results suggest that ARA in muscle and eggs is the best dietary indicator for dietary characteristics of final marine feeding area dietary characteristics among S. salar in the Baltic Sea. PMID- 28101949 TI - Highly Active Three-Dimensional NiFe/Cu2 O Nanowires/Cu Foam Electrode for Water Oxidation. AB - Water splitting is of paramount importance for exploiting renewable energy conversion and -storage systems, but is greatly hindered by the kinetically sluggish oxygen evolution reaction (OER). In this work, a three-dimensional, highly efficient, and durable NiFe/Cu2 O nanowires/Cu foam anode (NiFe/Cu2 O NWs/CF) for water oxidation in 1.0 m KOH was developed. The obtained electrode exhibited a current density of 10 mA cm-2 at a uniquely low overpotential of eta=215 mV. The average specific current density (js ) was estimated, on the basis of the electrocatalytically active surface area, to be 0.163 mA cm-2 at eta=310 mV. The electrode also displayed a low Tafel slope of 42 mV decade-1 . Moreover, the NiFe/Cu2 O NWs/CF electrode could maintain a steady current density of 100 mA cm-2 for 50 h at an overpotential of eta=260 mV. The outstanding electrochemical performance of the electrode for the OER was attributed to the high conductivity of the Cu foam and the specific structure of the electrode with a large interfacial area. PMID- 28101950 TI - Molecular binding of toxic phenothiazinium derivatives, azures to bovine serum albumin: A comparative spectroscopic, calorimetric, and in silico study. AB - In this paper, the comparative binding behavior of antimalarial drug azure A, azure B and azure C with bovine serum albumin (BSA) has been studied. The interaction has been confirmed by multispectroscopic (UV, fluorescence, Fourier transform infrared (FT-IR), and circular dichroism) and molecular docking techniques. The experimental results show that azure B has the highest BSA binding affinity followed by azure A and azure C. The experimental evidence of binding showed a static quenching mechanism in the interaction azures with BSA. The isothermal titration calorimetry result reveals that the binding was exothermic with positive entropy contribution in each case. The thermodynamic parameters DeltaH, DeltaG, and DeltaS at 25 degrees C were calculated, which indicates that the weak van der Waals forces and hydrogen bonding rather than the hydrophobic effect played an important role in the interaction. According to the theory of Forster nonradiative energy transfer, the distance (r) between the donor (BSA) and acceptor azures found to be <7 nm in all the case. The circular dichroism and FT-IR studies show that the content of alpha-helix structure has increased for the azures-BSA system. Overall, experimental studies characterize the interaction dynamics and energetics of the binding of three toxic analogs towards the physiologically relevant serum albumins. We hope, the outcome of this work will be most helpful for synthesizing a new type of phenothiazinium derivatives of the better therapeutic application. PMID- 28101951 TI - Rigidity and flexibility in the tetrasaccharide linker of proteoglycans from atomic-resolution molecular simulation. AB - Proteoglycans (PGs) are covalent conjugates between protein and carbohydrate (glycosaminoglycans). Certain classes of glycosaminoglycans such as chondroitin sulfate/dermatan sulfate and heparan sulfate utilize a specific tetrasaccharide linker for attachment to the protein component: GlcAbeta1-3Galbeta1-3Galbeta1 4Xylbeta1-O-Ser. Toward understanding the conformational preferences of this linker, the present work used all-atom explicit-solvent molecular dynamics (MD) simulations combined with Adaptive Biasing Force (ABF) sampling to determine high resolution, high-precision conformational free energy maps DeltaG(phi, psi) for each glycosidic linkage between constituent disaccharides, including the variant where GlcA is substituted with IdoA. These linkages are characterized by single, predominant (> 97% occupancy), and broad (45 degrees * 60 degrees for DeltaG(phi, psi) < 1 kcal/mol) free-energy minima, while the Xyl-Ser linkage has two such minima similar in free-energy, and additional flexibility from the Ser sidechain dihedral. Conformational analysis of microsecond-scale standard MD on the complete tetrasaccharide-O-Ser conjugate is consistent with ABF data, suggesting (phi, psi) probabilities are independent of the linker context, and that the tetrasaccharide acts as a relatively rigid unit whereas significant conformational heterogeneity exists with respect to rotation about bonds connecting Xyl to Ser. (c) 2017 Wiley Periodicals, Inc. PMID- 28101952 TI - Classical biochemistry reveals the complexity of the mitochondrial protein import system. PMID- 28101955 TI - Prescription Drug Monitoring Programs Produce a Limited Impact on Painkiller Prescribing in Medicare Part D. AB - OBJECTIVE: To measure the impact of prescription drug monitoring programs (PDMPs) on prescribing of opioid and nonopioid painkillers. DATA SOURCE: 2010-2013 physician-level Medicare Part D prescribing data released by the Centers for Medicare and Medicaid Services and Propublica. STUDY DESIGN: Using difference-in differences models with physician-level fixed effects, the study compares prescribing in states with and without PDMPs for opioid and nonopioid analgesics, oxycodone, hydrocodone, and opioids by controlled substances Schedules II-IV. PRINCIPAL FINDINGS: Prescription drug monitoring programs were associated with a 5.2 percent decrease in days supply prescribed per physician for oxycodone in addition to smaller reductions for hydrocodone and opioids overall (2.8 percent and 2 percent, respectively) and a small increase in prescribing for Schedule IV opioids. PDMPs were not associated with changes for nonopioid analgesics or other opioids in Schedules II and III. The effects of PDMPs were negated in states where statutes explicitly did not require use of the PDMP. CONCLUSIONS: Prescription drug monitoring programs have a modest effect targeted at the high profile drug oxycodone among the Medicare Part D population and an even smaller effect for hydrocodone and opioids in general. The findings suggest some substitution toward lower schedule opioids. Substantially addressing the widespread opioid abuse problem will require enhancing existing PDMPs or implementing new policies. PMID- 28101956 TI - AGGREGATES: Finding structures in simulation results of solutions. AB - Molecular Dynamic and Monte-Carlo simulations are widely used to investigate the structure and physical properties of solids and liquids at a molecular level. Tools to extract the most relevant information from the obtained results are, however, in considerable demand. One such tool, the program AGGREGATES, is described in this work. Based on distance criteria, the program searches trajectory files for the presence of molecular clusters and computes several statistical and shape properties for these structures. Tools designed to investigate the local organization and the molecular conformations in the clusters are also available. Among these, it is introduced a new approach to perform a First Shell Analysis, by looking for the presence of atomic contacts between molecules. These elements are particularly useful to obtain information on molecular assembly processes (such as the nucleation of crystals or colloidal particles) or to investigate polymorphism in organic compounds. The program features are illustrated here through the investigation of the 4' hydroxyacetophenone + ethanol system. (c) 2017 Wiley Periodicals, Inc. PMID- 28101954 TI - Task-sharing with nurses to enhance access to HIV treatment in Cote d'Ivoire. AB - OBJECTIVE: We report the first national programme in Cote d'Ivoire to evaluate the feasibility of nurse-led HIV care as a model of task-sharing with nurses to increase coverage and decentralisation of HIV services. METHODS: Twenty-six public HIV facilities implemented either a nurse-with-onsite-physician or a nurse with-visiting-physician model of HIV task-sharing. Routinely collected patient data were reviewed to analyse patient characteristics of those enrolling in care and initiating antiretroviral therapy (ART). Retention, loss to programme and death were compared across facility-level characteristics. RESULTS: A total of 1224 patients enrolled in HIV care, with 666 initiating ART, from January 2012 to May 2013 (median follow-up 13 months). The majority (94%) were adults >=15 years. Fourteen facilities provided ART initiation for the first time during the pilot period; 20 facilities were primary level. Nurse-led care with a visiting physician was provided in 14 of the primary-level facilities. Nurse-led ART care with an onsite physician was provided in all secondary-level facilities and six of the primary-level facilities. During the pilot, 567 (85%) of patients were retained, 28 (4.2%) died, 47 (7.1%) were lost to follow-up, and 24 (3.6%) transferred. Five deaths (10.9%) were recorded among children as compared to 23 deaths (3.7%) among adults (P = 0.037). There were no differences in retention by model of nurse-led ART care. CONCLUSION: Task-sharing of HIV care and ART initiation with nurses in Cote d'Ivoire is feasible. This pilot illustrates two models of nurse-led HIV care and has informed national policy on nurse-led HIV care in Cote d'Ivoire. PMID- 28101953 TI - Associations between participation in family activities and adolescent school problems. AB - INTRODUCTION: Adolescent risk outcomes related to school issues are widespread, with about 20% parents reporting poor school engagement amongst their youth. Previous literature suggests that adolescents who report strong bonds with their parents are often identified as being less likely to engage in risky behaviours, such as substance use. The current study sought to examine the association between the frequencies of selected family activities and school problems amongst adolescents after adjustments for family connectedness and other characteristics. METHODS: Data were drawn from the National Longitudinal Survey of Youth, 1997. Of the 8984 youth interviewed, 3855 also had a sibling interviewed who met the selection criteria. School problem outcomes measured were suspension occurrence, poor grades and highest grade completed low for age. Independent variables of interest were self-reported frequency of family dinner, fun and religious activities in a typical week. Multivariable logistic models were estimated for each outcome, and multivariable linear probability models were estimated adjusting for family fixed effects. RESULTS: Adjusting for family connectedness, there were significant associations between certain family activities and adolescent school problem measures. However, these results did not remain significant in models with family fixed effects, suggesting that associations could be driven by family-level confounders. DISCUSSION: This study did not find strong evidence of a protective relationship between family activities and school problems. Therefore, it suggested that programme and policymakers be cautious in overstating the importance of family activities in preventing adolescent risk outcomes until true causal relationships can be determined. PMID- 28101957 TI - Summer co-existence of small-sized cyprinid and percid individuals in natural and impounded stretches of a lowland river: food niche partitioning among fishes. AB - Due to changes of discharge regime downstream of a dam reservoir, an alluvial natural stretch of the Warta River changed to a macrophyte-dominated ecosystem. Large patches of submersed, aquatic macrophytes appeared in summer and their effect is analysed in this study. These patches contained enriched macroinvertebrate assemblages (epiphyton and benthos) and they were refuge for both zooplankton and young fishes released from the reservoir. Despite these altered conditions in this stretch, roach Rutilus rutilus, perch Perca fluviatilis and ruffe Gymnocephalus cernua dominated, as they did in the natural backwater. Fishes were sampled every 2 weeks from June to August, together with their food resources to assess the partitioning of the diet among small individuals of the three species in both stretches (the natural and affected ones). The aim of the analysis was to answer how animal food associated with water plants was partitioned between the species. In both stretches, G. cernua were primarily benthivorous, but epiphytic fauna, zooplankton and large-sized benthic chironomid larvae replaced lack of many large, benthic insects in the tailwater. Levins' food breath index decreased from 0.36 in the backwater to 0.29 in the tailwater. An opposite trend was observed for P. fluviatilis occurring among macrophytes. Perca fluviatilis were competitors of R. rutilus and took food not only in or on the river bed, but also in the water column. They ate zooplankton and epiphytic fauna and Levins' index increased from 0.32 to 0.44 in the tailwater. Rutilus rutilus fed on adult insects, algae and plant fragments in the natural stretch. In the tailwater, these food types were chiefly complemented by zooplankton. Despite this, the niche breadth of R. rutilus was similar at the two sites. Abundance of food associated with the macrophytes appeared to facilitate cohabitation in the abundant fish populations, but P. fluviatilis appeared to benefit the most in the altered river stretch. PMID- 28101958 TI - A review of maternal alloimmunisation to Rh D in Northern Ireland. AB - OBJECTIVES: To estimate the current incidence of maternal sensitisation to Rhesus (Rh) D in Northern Ireland, examine adherence to recommendations for administration of anti-D immunoglobulin and identify potential causes for all cases of anti-D alloimmunisation sensitisation from January 2010 to September 2015. BACKGROUND: Post-partum anti-D immunoglobulin administered to Rh D-negative women and routine antenatal anti-D prophylaxis have greatly reduced the incidence of haemolytic disease of the fetus and newborn due to immune anti-D. Despite these measures, anti-D alloimmunisation sensitisation continues to occur, albeit much less frequently than in the past. METHODS/MATERIALS: This was a retrospective review of new sensitisations to Rh D detected in antenatal records between January 2010 and September 2015 in Northern Ireland. A review of patient notes and laboratory data was carried out to examine adherence to standards and identify potential causes of sensitisation. RESULTS: A total of 67 new sensitisations to Rh D were identified over a 69-month period, and the sensitisation rate for the full calendar years 2010-2014 was 0.310%. Only 4% of cases appear to have been preventable, with two cases involving failure to adhere to guidelines. CONCLUSION: A total 96% of sensitisations occurred despite full compliance with guidelines. In a large proportion, sensitisation occurred following delivery (51%). A change in practice in Northern Ireland is under consideration to increase the dose of anti-D immunoglobulin given following delivery from 500 to 1500 U in an attempt to reduce these sensitisations. PMID- 28101959 TI - Comprehensive Analysis of Transcript Changes Associated With Allograft Rejection: Combining Universal and Selective Features. AB - We annotated the top transcripts associated with kidney transplant rejection by p value, either universal for all rejection or selective for T cell-mediated rejection (TCMR) or antibody-mediated rejection (ABMR; ClinicalTrials.gov NCT01299168). We used eight class-comparison algorithms to interrogate microarray results from 703 biopsies, 205 with rejection. The positive comparators were all rejection, TCMR, or ABMR; the negative comparators varied from normal biopsies to all nonrejecting biopsies, including other diseases. The universal algorithm, rejection versus all nonrejection, identified transcripts mainly inducible by interferon gamma. Selectivity for ABMR or TCMR required the other rejection class as well as nonrejection biopsies in the comparator to avoid selecting universal transcripts. Direct comparison of ABMR versus TCMR yielded only transcripts related to TCMR, the stronger signal. Transcripts highly associated with rejection were never completely specific for rejection: Many were increased in biopsies without rejection, reflecting sharing between rejection and injury induced innate immunity. Union of the top 200 transcripts from universal and selective algorithms yielded 454 transcripts that permitted unsupervised analysis of biopsies in principal component analysis: PC1 was rejection, and PC2 was separation of TCMR from ABMR. Appreciating rejection-associated molecular changes requires a diverse case mix, accurate histologic classification (including C4d negative ABMR), and both selective and universal algorithms. PMID- 28101960 TI - Effects of Antegrade Accessory Pathway Conduction on QRS Terminal Vector in Patients with Preexcitation Syndrome. AB - BACKGROUND: Ventricle preexcitation through accessory pathway changes QRS initial vector, and manifests as delta wave on electrocardiogram (ECG). However, QRS terminal vector can also be affected. METHODS: A total of 158 patients who had single accessory pathway (AP) with antegrade conduction capacity were included and divided into two groups according to the ECG with or without delta wave. Note that 150 patients had delta wave (overt AP group) on ECG; classical preexcitation syndrome was diagnosed before radiofrequency ablation. Eight patients had no delta wave on ECG (unapparent AP group); preexcitation was induced by transesophageal atrial pacing. ECGs and intracardiac electrogram (IEGM) before and after ablation and during atrioventricular reentrant tachycardia were analyzed. RESULTS: (1) In the overt AP group: QRS terminal vector amplitude and polarity changes were observed in all the 150 patients, and were related to AP location and delta wave polarity. (2) In the unapparent AP group: QRS terminal vector changes were found in two out of eight patients, and the initial activation of ventricle myocardium via AP on IEGM was almost simultaneous with the onset of QRS complex on ECG. CONCLUSIONS: It is not only the QRS initial vector, but also the QRS terminal vector that can be changed by the antegrade accessory pathway conduction in patients with preexcitation syndrome. The change of QRS terminal vector is valuable for the diagnosis of atypical preexcitation. PMID- 28101961 TI - Antibody formation towards porcine tissue in patients implanted with crosslinked heart valves is directed to antigenic tissue proteins and alphaGal epitopes and is reduced in healthy vegetarian subjects. AB - BACKGROUND: Glutaraldehyde-fixed porcine heart valves (ga-pV) are one of the most frequently used substitutes for insufficient aortic and pulmonary heart valves which, however, degenerate after 10-15 years. Yet, xeno-immunogenicity of ga-pV in humans including identification of immunogens still needs to be investigated. We here determined the immunogenicity of ga-pV in patients with respect to antibody formation, identity of immunogens and potential options to reduce antibody levels. METHODS: Levels of tissue-specific and anti-alphaGal antibodies were determined retrospectively in patients who received ga-pV for 51 months (n=4), 25 months (n=6) or 5 months (n=4) and compared to age-matched untreated subjects (n=10) or younger subjects with or without vegetarian diet (n=12/15). Immunogenic proteins were investigated by Western blot approaches. RESULTS: Tissue-specific antibodies in patients were elevated after 5 (1.73-fold) and 25 (1.46-fold, both P<.0001) months but not after 51 months, whereas anti-Gal antibodies were induced 4.75-fold and 3.66-fold after 5 and 25 months (both P<.0001) and still were significantly elevated after 51 months (2.85-fold, P<.05). Western blots of porcine valve extracts with and without enzymatic deglycosylation revealed strong specific staining at ~65 and ~140 kDa by patient sera in either group which were identified by 2D Western blots and mass spectrometry as serum albumin and collagen 6A1. Vegetarian diet reduced significantly (0.63-fold, P<.01) the level of pre-formed alphaGal but not of tissue-specific antibodies. CONCLUSION: Immune response in patients towards ga-pV is induced by the porcine proteins albumin and collagen 6A1 as well as alphaGal epitopes, which seemed to be more sustained. In contrast, in healthy young subjects pre-formed anti-Gal antibodies were reduced by a meat-free nutrition. PMID- 28101962 TI - The peopling of the Americas and the origin of the Beringian occupation model. AB - The current model for peopling of the Americas involves divergence from an ancestral Asian population followed by a period of population isolation and genetic diversification in Beringia, and finally, a rapid expansion into and throughout the Americas. Studies in the 1970s sought to characterize the biological relationships between different indigenous populations and first proposed an occupation of Beringia. More recent studies using molecular genetic markers often neglect to reference early works that laid the groundwork for current colonization models. We address this matter, and briefly summarize the literature and technological advances that contributed to our current understanding of the peopling of the Americas. Furthermore, we argue that describing the process of peopling of the Americas as "migrations from Asia" minimizes the significant genetic diversification that occurred outside of Asia, and offends indigenous Americans by discounting their origin narratives and land rights. Rather than referring to the indigenous peoples of the Americas as "migrants" or "immigrants," we recommend consistency in the language used to describe all post-glacial expansions of people into Asia, Europe and the Americas. PMID- 28101963 TI - Extreme biophysics: Enzymes under pressure. AB - A critical question about piezophilic (pressure-loving) microbes is how their constituent molecules maintain function under high pressure. Here, factors are examined that may lead to the increased activity under pressure in dihydrofolate reductase from the piezophilic Moritella profunda compared to the homologous enzyme from the mesophilic Escherichia coli. Molecular dynamics simulations are performed at various temperatures and pressures to examine how pressure affects the flexibility of the enzymes from these two microbes, since both stability and flexibility are necessary for enzyme activity. The results suggest that collective motions on the 10-ns timescale are responsible for the flexibility necessary for "corresponding states" activity at the growth conditions of the parent organism. In addition, the results suggest that while the lower stability of many enzymes from deep-sea microbes may be an adaptation for greater flexibility at low temperatures, high pressure may enhance their adaptation to low temperatures. (c) 2017 Wiley Periodicals, Inc. PMID- 28101964 TI - Patient outcome after implant of a cardioverter defibrillator in the 'real world': the key role of co-morbidities. PMID- 28101965 TI - A multi-hit hypothesis of bullous pemphigoid and associated neurological disease: Is HLA-DQB1*03:01, a potential link between immune privileged antigen exposure and epitope spreading? AB - Bullous pemphigoid (BP) is the most common autoimmune blistering disease and is linked to IgG recognition of 2 hemidesmosomal antigens, that is, BP230 (BP antigen 1) and BP180 (BP antigen 2, collagen XVII). The association of BP with other systemic diseases, particularly neurocognitive diseases, provides a potential clue in the underlying pathogenesis of BP. The role of HLA-DQB1*03:01 binding to the immunogenic portion of BP180 provides a potential mechanism by which exposure to neuronal collagen BP180 may lead to cutaneous disease. In our proposed multi-hit hypothesis, patients with underlying neuronal disease are exposed to previously sequestered self-antigen, most importantly BP180. Patients with the HLA-DQB1*03:01 allele show an increased T-cell avidity to several epitopes of BP180, particularly the BP180-NC16a domain. Thus, they have a genetic susceptibility to developing BP upon exposure to the target antigen. In a patient with dysregulation of Th1/Th2 balance, anergy is lost and T-cells are subsequently primed resulting in the development of functional autoimmunity against the BP180-NC16a domain leading to clinically overt disease. PMID- 28101966 TI - The free energy of locking a ring: Changing a deoxyribonucleoside to a locked nucleic acid. AB - Locked nucleic acid (LNA), a modified nucleoside which contains a bridging group across the ribose ring, improves the stability of DNA/RNA duplexes significantly, and therefore is of interest in biotechnology and gene therapy applications. In this study, we investigate the free energy change between LNA and DNA nucleosides. The transformation requires the breaking of the bridging group across the ribose ring, a problematic transformation in free energy calculations. To address this, we have developed a 3-step (easy to implement) and a 1-step protocol (more efficient, but more complicated to setup), for single and dual topologies in classical molecular dynamics simulations, using the Bennett Acceptance Ratio method to calculate the free energy. We validate the approach on the solvation free energy difference for the nucleosides thymidine, cytosine, and 5-methyl-cytosine. (c) 2017 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc. PMID- 28101968 TI - Defined daily doses (DDD) do not accurately reflect opioid doses used in contemporary chronic pain treatment. AB - OBJECTIVE: To assess how well the defined daily dose (DDD) metric reflects opioid utilisation among chronic non-cancer pain patients. DESIGN: Descriptive, cross sectional study, utilising a 7-day medication diary. SETTING: Community-based treatment settings, Australia. SUBJECTS: A sample of 1101 people prescribed opioids for chronic non-cancer pain. METHODS: Opioid dose data was collected via a self-completed 7-day medication diary capturing names, strengths and doses of each medication taken in the past week. Median daily dose was calculated for each opioid. Comparisons were made to the World Health Organization's (WHO) DDD metric. RESULTS: WHO DDDs ranged from 0.6 to 7.1 times the median opioid doses used by the sample. For transdermal fentanyl and oral hydromorphone, the median dose was comparable with the DDD. The DDD for methadone was 0.6 times lower than the median doses used by this sample of chronic pain patients. In contrast, the DDD for oxycodone and transdermal buprenorphine, the most commonly used strong opioids for chronic pain in Australia, was two to seven times higher than actual doses used. CONCLUSIONS: For many opioids, there are key differences between the actual doses used in clinical practice and the WHO's DDDs. The interpretation of opioid utilisation studies using population-level DDDs may be limited, and a recalibration of the DDD for many opioids or the reporting of opioid utilisation in oral morphine equivalent doses is recommended. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28101969 TI - Low trabecular bone density in recent sedentary modern humans. AB - OBJECTIVES: Research on a limited number of samples suggests that trabecular bone density (i.e., bone volume fraction, BVF) within specific articulations is lower among more sedentary Holocene agricultural populations compared with Holocene foragers, implying that activity levels have a significant effect on trabecular BVF. However, it is unclear to what extent BVF differs among groups with varying activity levels and how general this phenomenon is across multiple limb articulations. Here, we test two hypotheses that: (i) sedentary populations have lower BVF compared with active populations across limb articulations; and (ii) these declines are more uniform in the lower limb (because of its more direct relationship to mobility), and more variable in the upper limb. MATERIALS AND METHODS: We estimated BVF in seven lower and upper limb articulations of five Holocene population samples with subsistence strategies spanning from foraging through horticultural to industrial using pQCT (peripheral Quantitative Computed Tomography). RESULTS: Both hypotheses are largely supported. First, the most active groups have significantly greater BVF in most limb elements compared with more sedentary groups. Second, all sedentary groups have relatively similar (and lower) BVF in the lower limb but show more variation in upper limb articulations. CONCLUSIONS: These results suggest that a decline in activity levels associated with the adoption of agriculture and industrialization significantly contributed to the reduction in BVF in recent modern humans, but specific behavioral changes, particularly in the upper limb, also affected these patterns. PMID- 28101971 TI - Quality of patient-centred care: Medical oncology patients' perceptions and characteristics associated with quality of care. PMID- 28101970 TI - Neuropeptide Y resists excess loss of fat by lipolysis in calorie-restricted mice: a trait potential for the life-extending effect of calorie restriction. AB - Neuropeptide Y (NPY) is an orexigenic peptide that plays an essential role in caloric restriction (CR)-mediated lifespan extension. However, the mechanisms underlying the NPY-mediated effects in CR are poorly defined. Here, we report that NPY deficiency in male mice during CR increases mortality in association with lipodystrophy. NPY-/- mice displayed a rapid decrease in body weight and fat mass, as well as increased lipolysis during CR. These alterations in fat regulation were inhibited by the lipolysis inhibitor, acipimox, a treatment associated with reduced mortality. The lipolytic/thermogenic signaling, beta3 adrenergic receptor/hormone sensitive lipase, was markedly activated in white adipose tissue of NPY-/- mice compared with that of NPY+/+ mice, and thermogenesis was controlled by NPY under negative energy balance. These results demonstrate the critical role of NPY in the regulation of lipid metabolic homeostasis and survival via control of lipolysis and thermogenesis in a state of negative energy balance. PMID- 28101972 TI - An evaluation of the quality of evidence available to inform current bone conducting hearing device national policy. AB - OBJECTIVES: In 2016, NHS England published the commissioning policy on Bone Conducting Hearing Devices (BCHDs). This policy was informed by updated evidence on the clinical and cost-effectiveness of BCHDs as well as by the 2013 Bone Anchored Hearing Aid (BAHA) policy. Commissioning policies set the criteria for service delivery and therefore have a major impact on the care received by patients. It is important that stakeholders have a good appreciation of the available evidence informing policy, as this will promote engagement both with the policy and with future research leading on from the policy. In this article, we provide stakeholders with a transparent and pragmatic assessment of the quality of the body of evidence available to inform current BCHD national policy. METHOD: (i) A systematic review of the literature on BCHDs published since the development of the 2013 policy was performed in September 2016, adhering to PRISMA recommendations. The search terms used were as follows bone conduction; bone conducting; bone anchor; BAHA; Bone Anchored Hearing Aid; Bone Conducting Hearing Device; BCHD; Bone Conducting Hearing Implant; BCHI; Sophono; Bonebridge; Soundbite; Ponto; Hearing aid; implant; device; hearing device. Publications that could inform current BCHD policy were included. The quality of included articles was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. (ii) The quality of evidence referenced by the 2013 BAHA policy was assessed using the GRADE system. RESULTS: (i) Of the 2576 publications on BCHDs identified by the systematic search, 39 met the inclusion criteria for further analysis. Using the GRADE criteria, the quality of evidence was classified as of 'very low quality'. (ii) The 2013 BAHA policy was informed by 14 references. The GRADE system classifies the quality of evidence that informed the policy as of 'very low quality'. CONCLUSIONS: The GRADE system defines the body of evidence available to inform current national BCHD policy as of 'very low quality'. There is an urgent need for high-quality research to help make informed policy decisions about the care of patients with hearing loss. An (inter)national registry of BCHDs could address this need. PMID- 28101974 TI - Etiquette, competence, and professionalism: the profile of the 'ideal pediatric anesthesiologist'. PMID- 28101973 TI - Heparin cross-linked collagen sponge scaffolds improve functional regeneration of rat tracheal epithelium. AB - Tracheal epithelial cells maintain airway homeostasis by mediating mucociliary clearance. Following tracheal reconstruction, timely epithelial regeneration is required to prevent respiratory compromise and infectious diseases. To achieve rapid tracheal epithelial regeneration, a heparin cross-linked collagen sponge containing fibroblast growth factor-2 (FGF-2) was prepared as a graft for tracheal reconstruction. The heparin cross-linked sponge exhibited a high FGF-2 retaining capacity, and tracheal epithelial and mesenchymal cells cultured in this sponge containing FGF-2 showed high proliferative capacities. Subsequently, heparin-free collagen sponge scaffolds (C/F scaffold) and collagen sponge scaffolds cross-linked with 10 MUg/ml heparin retained FGF-2 (C/H10/F scaffold), and were transplanted into rats with tracheal defects. Invasion of both epithelial and non-epithelial cells was greater in rats treated with the C/H10/F scaffold at 1 week post-transplantation than in rats treated with the C/F scaffold. Moreover, at 2 weeks after transplantation, improved cilia formation was observed in the C/H10/F scaffold group, with higher motility and more potent posterior-anterior flow generation than in the C/F scaffold group. These results suggest that heparin improves functional regeneration of tracheal epithelium. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28101975 TI - Novel approach to supine positioning for infants with spinal neural tube defects. PMID- 28101976 TI - A reflection on professionalism. PMID- 28101967 TI - Host-related factors explaining interindividual variability of carotenoid bioavailability and tissue concentrations in humans. AB - Carotenoid dietary intake and their endogenous levels have been associated with a decreased risk of several chronic diseases. There are indications that carotenoid bioavailability depends, in addition to the food matrix, on host factors. These include diseases (e.g. colitis), life-style habits (e.g. smoking), gender and age, as well as genetic variations including single nucleotide polymorphisms that govern carotenoid metabolism. These are expected to explain interindividual differences that contribute to carotenoid uptake, distribution, metabolism and excretion, and therefore possibly also their association with disease risk. For instance, digestion enzymes fostering micellization (PNLIP, CES), expression of uptake/efflux transporters (SR-BI, CD36, NPC1L1), cleavage enzymes (BCO1/2), intracellular transporters (FABP2), secretion into chylomicrons (APOB, MTTP), carotenoid metabolism in the blood and liver (LPL, APO C/E, LDLR), and distribution to target tissues such as adipose tissue or macula (GSTP1, StARD3) depend on the activity of these proteins. In addition, human microbiota, e.g. via altering bile-acid concentrations, may play a role in carotenoid bioavailability. In order to comprehend individual, variable responses to these compounds, an improved knowledge on intra-/interindividual factors determining carotenoid bioavailability, including tissue distribution, is required. Here, we highlight the current knowledge on factors that may explain such intra-/interindividual differences. PMID- 28101977 TI - Distribution of sciatic nerve division in children: a prospective observational study using an ultrasound device. PMID- 28101978 TI - Hyperthermia during a laparoscopic procedure. PMID- 28101979 TI - Could acupuncture be an adequate alternative to dexamethasone in pediatric tonsillectomy? PMID- 28101980 TI - Reply to Xin, Juan; Zhang, Yabing; Zhou, Xiaoshuang; Liu, Bin, regarding their comment 'Acupuncture may be an effective supplement treatment for dexamethasone in pediatric tonsillectomy'. PMID- 28101981 TI - Are children with Cornelia de Lange syndrome at risk for malignant hyperthermia? PMID- 28101982 TI - Reply to Monteleone, Matthew; Teng, Howard, regarding their comment 'Dexmedetomidine as an adjuvant to the infant spinal anesthestic'. PMID- 28101984 TI - In this issue: February 2017. PMID- 28101983 TI - Working to define professionalism in pediatric anesthesiology: a qualitative study of domains of the expert pediatric anesthesiologist as valued by interdisciplinary stakeholders. AB - BACKGROUND: Unprofessional behavior is a significant problem throughout graduate medical education programs and medical centers. Some authors have suggested that professionalism curricula should be focused toward faculty, not trainees, to interrupt the modeling of unprofessionalism. Developing such curricula requires a needs assessment and is challenging given data indicating that the definition of professionalism varies based on medical specialty. Thus, a specialty-specific definition of professionalism is needed as a first step in any curriculum development. AIM: The aim of this study was to define professionalism in pediatric anesthesiology. METHODS: This is a qualitative study using focus groups for data collection and a grounded theory approach for analysis. Four relevant stakeholder groups, pediatric surgeons and endoscopists, perioperative nurses, pediatric anesthesiologists, and parents of children who had undergone surgery at our facility, were recruited for participation. De-identified transcripts were analyzed and coded to derive major domains and component themes relevant to the definition of professionalism for pediatric anesthesiology. Member checking with participants from our stakeholder groups was used to validate thematic development and increase the trustworthiness of our findings. RESULTS: Focus group participants included 20 individuals, 14 of whom were female. Analysis of transcripts identified 11 major domains across the four groups: Patient Ownership, Specialty Expertise, Continuous Team Improvement, Expressive Communication, Active Listening, Care Coordination, Medical Hierarchy, Leadership, Teamwork, Personality Traits, and Physical Image. The data uncovered several controversies for future study. CONCLUSION: A composite of these 11 domains may give a more complete image of what surgical and nursing colleagues, patient families, and anesthesiologist partners expect of the pediatric anesthesiologist. Despite some overlap and interdependence between domains, this research may contribute to the creation of future educational curricula and provides domains for evaluation of professionalism in pediatric anesthesiology. PMID- 28101985 TI - Time-dependent density functional theory study on direction-dependent electron and hole transfer processes in molecular systems. AB - We report on real-time time-dependent density functional theory calculations on direction-dependent electron and hole transfer processes in molecular systems. As a model system, we focus on alpha-sulfur. It is shown that time scale of the electron transfer process from a negatively charged S8 molecule to a neighboring neutral monomer is comparable to that of a strong infrared-active molecular vibrations of the dimer with one negatively charged monomer. This results in a strong coupling between the electrons and the nuclei motion which eventually leads to S8 ring opening before the electron transfer process is completed. The open-ring structure is found to be stable. The similar infrared-active peak in the case of hole transfer, however, is shown to be very weak and hence no significant scattering by the nuclei is possible. The presented approach to study the charge transfer processes in sulfur has direct applications in the increasingly growing research field of charge transport in molecular systems. (c) 2017 Wiley Periodicals, Inc. PMID- 28101986 TI - Size-Dependent Activity of Palladium Nanoparticles: Efficient Conversion of CO2 into Formate at Low Overpotentials. AB - Remarkable size-dependent activity of palladium nanoparticles (PdNPs) towards formate production is evident at very low overpotentials (-0.1 to -0.5 V vs. RHE). Size-selective PdNPs, chemically synthesized at sizes of 3.8-10.7 nm, effected an electrochemical CO2 reduction reaction in aqueous 0.5 m NaHCO3 . The faradaic efficiency of formate production (FEformate ) on 3.8 nm PdNPs exceeded 86 % at E=-0.1 V versus RHE, whereas on 6.5 nm PdNPs an even higher FEformate of 98 % was observed. However, FEformate decreased for larger PdNPs. The superior efficiency towards formate production at low overpotentials is rationalized in terms of a changed catalytic pathway through PdH phases. The observed maximum in the formate efficiency for a mean particle size of about 6.5 nm is discussed in terms of counterbalancing the size-dependent effects of a competing CO2 reduction reaction and a parasitic hydrogen evolution reaction. Production rates of formate are also remarkably high at -0.3 V versus RHE with 539.9 and 452.3 ppm h-1 mgPd 1 for the 6.5 and 3.8 nm PdNPs, respectively. PMID- 28101987 TI - Delivery Outcomes of Patients with Acute Migraine in Pregnancy: A Retrospective Study. AB - OBJECTIVE: To describe labor and delivery outcomes in pregnant patients presenting to the hospital setting with an acute severe migraine headache attack earlier in the same gestation. METHODS: We retrospectively reviewed pregnancy and delivery records from a database of consecutive inpatient neurology consultations for acute headache in pregnant women over a 5 year period. RESULTS: We identified 86 pregnant women with acute migraine. The mean age was 29.3 (+/-6.4) years. Nearly half had migraine with aura (35/86 [40.7%]), 12.8% (12/86) had chronic migraine, and 31.4% (27/86) presented in status migrainosus. Complication rates included 54.7%([41/75], 95% CI 29.87, 52.13) for at least one adverse outcome, 28.0% ([21/75], 95% CI 11.78, 30.22) for preterm delivery, 21.3% ([16/75], 95% CI 7.7, 24.3) for preeclampsia, 30.6% ([23/75] 95% CI 13.48, 32.52) for cesarean delivery, and 18.7% ([14/75] 95% CI 6.15, 21.85) for low birthweight. CONCLUSIONS: Pregnant women seeking treatment for acute migraine headache experienced a higher rate of preterm delivery, preeclampsia, and low birthweight but a lower rate of cesarean delivery than the local and general populations. More than half (54.7% [41/75] 95% CI 29.87, 52.13) of the study patients experienced some type of adverse birth outcome, suggesting that pregnancies in migraine patients presenting to an acute care setting may benefit from more intense surveillance. PMID- 28101988 TI - Toxicity assessment of zero valent iron nanoparticles on Artemia salina. AB - The present study deals with the toxicity assessment of two differently synthesized zero valent iron nanoparticles (nZVI, chemical and biological) as well as Fe2+ ions on Artemia salina at three different initial concentrations of 1, 10, and 100 mg/L of these particles. The assessment was done till 96 h at time intervals of 24 h. EC50 value was calculated to evaluate the 50% mortality of Artemia salina at all exposure time durations. Between chemically and biologically synthesized nZVI nanoparticles, insignificant differences in the level of mortality were demonstrated. At even 24 h, Fe2+ ion imparted complete lethality at the highest exposure concentration (100 mg/L). To understand intracellular oxidative stress because of zero valent iron nanoparticles, ROS estimation, SOD activity, GSH activity, and catalase activity was performed which demonstrated that ionic form of iron is quite lethal at high concentrations as compared with the same concentration of nZVI exposure. Lower concentrations of nZVI were more toxic as compared with the ionic form and was in order of CS-nZVI > BS-nZVI > Fe2+ . Cell membrane damage and bio-uptake of nanoparticles were also evaluated for all three concentrations of BS-nZVI, CS-nZVI, and Fe2+ using adult Artemia salina in marine water; both of which supported the observations made in toxicity assessment. This study can be further explored to exploit Artemia salina as a model organism and a biomarker in an nZVI prone aquatic system to detect toxic levels of these nanoparticles. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1617-1627, 2017. PMID- 28101989 TI - Diagnosis of Peste des Petits Ruminants in Wild and Domestic Animals in Xinjiang, China, 2013-2016. AB - Peste des petits ruminants viruses (PPRVs) re-emerged in China at the end of 2013 and then spread rapidly into 22 provinces through movement of live goats and sheep. In this study, 96 samples of domestic animals and 13 samples of wildlife were analysed for the presence of PPRV infection by ELISA or RT-PCR. Of 96 samples from sheep and goats, 91 were PPRV positive, whereas all of the 13 samples from three wild species, Capra ibex (Capra ibex sibirica), argali (Ovis ammon) and Goitered gazelle (Gazella subgutturosa), were found to be positive. Five wildlife-origin isolates from the above samples were identified as the lineage IV by a multiple alignment of the partial sequences in N gene. PMID- 28101990 TI - A Single Center Study of 1,179 Heart Transplant Patients-Factors Affecting Pacemaker Implantation. AB - BACKGROUND: After around 10% of heart transplant patients require pacemaker implantation. The bradyarrhythmias causing pacemaker requirement include sinus node dysfunction (SND) and atrioventricular block (AVB). This study sought to define clinical predictors for pacemaker requirement as well as identify differences in the patient groups developing SND and AVB. METHODS: Our operative database was used to collect retrospective recipient, donor, and operative data of all patients receiving orthotopic heart transplants between 1981 and 2016. RESULTS: In the 35-year period 1,179 transplants were performed (mean recipient age 45.5 +/- 0.5 years, 20.4% female, 90.6% biatrial technique) with bradyarrhythmias requiring pacemaker implantation developing in 135 patients (11.5%). Independent risk factors were prolonged operative time 340 minutes versus 313 minutes (P = 0.027) and a biatrial anastomosis (P = 0.036). Ischemia time, cardiopulmonary bypass time, aortic cross clamp time, and reperfusion time all had no significant effect on pacemaker implantation rates. Similarly, whether the transplant was a reoperation, a retransplant, or performed after primary assist implantation had no effects on pacemaker implantation rates. There was no survival difference between the paced and nonpaced groups. The donor age was higher in the patients who developed AVB as the indication for pacemaker implantation (43 vs 34 years, P = 0.031). Patients with AVB had longer aortic cross clamp times and developed the arrhythmia later than those who developed SND. CONCLUSIONS: Use of the bicaval instead of the biatrial technique and shortened operative times should reduce pacemaker requirement after heart transplantation. Survival is not affected by this complication. PMID- 28101993 TI - Repetitive Transcranial Magnetic Stimulation for Phantom Limb Pain: Probably Effective but Understudied. PMID- 28101994 TI - A Personal Evaluation of Changing Social Contracts in Medicine: Reflections of Medicine in the Media. PMID- 28101991 TI - Clinically Distinct Phenotypes of Canavan Disease Correlate with Residual Aspartoacylase Enzyme Activity. AB - We describe 14 patients with 12 novel missense mutations in ASPA, the gene causing Canavan disease (CD). We developed a method to study the effect of these 12 variants on the function of aspartoacylase-the hydrolysis of N-acetyl-l aspartic acid (NAA) to aspartate and acetate. The wild-type ASPA open reading frame (ORF) and the ORFs containing each of the variants were transfected into HEK293 cells. Enzyme activity was determined by incubating cell lysates with NAA and measuring the released aspartic acid by LC-MS/MS. Clinical data were obtained for 11 patients by means of questionnaires. Four patients presented with a non typical clinical picture or with the milder form of CD, whereas seven presented with severe CD. The mutations found in the mild patients corresponded to the variants with the highest residual enzyme activities, suggesting that this assay can help evaluate unknown variants found in patients with atypical presentation. We have detected a correlation between clinical presentation, enzyme activity, and genotype for CD. PMID- 28101995 TI - Cholinergic signaling in myelination. AB - There is a long history of research on acetylcholine (ACh) function in myelinating glia, but a resurgence of interest recently as a result of the therapeutic potential of manipulating ACh signaling to promote remyelination, and the broader interest in neurotransmitter signaling in activity-dependent myelination. Myelinating glia express all the major types of muscarinic and nicotinic ACh receptors at different stages of development, and acetylcholinesterase and butyrylcholinesterase are highly expressed in white matter. This review traces the history of research on ACh signaling in Schwann cells, oligodendrocytes, and in the myelin sheath, and summarizes current knowledge on the intracellular signaling and functional consequences of ACh signaling in myelinating glia. Implications of ACh in diseases, such as Alzheimer's disease, multiple sclerosis, and white matter toxicity caused by pesticides are considered, together with an outline of major questions for future research. GLIA 2017;65:687-698. PMID- 28101996 TI - Aquatic therapy for people with persistent knee pain: A feasibility study. PMID- 28101998 TI - 58TH ANNUAL MEETING & EXHIBITION. PMID- 28101997 TI - The ecology of anemia: Anemia prevalence and correlated factors in adult indigenous women in Argentina. AB - OBJECTIVES: The Toba/Qom of Namqom are an indigenous community native to the Gran Chaco region of northern Argentina. Historically seminomadic foragers, the diet of peri-urban community members has rapidly changed from high-protein, high-fiber to hypercaloric, processed. This study aims to understand the impact of this nutritional transition on aspects of women's health by exploring the relationship between prevalence of anemia and current diet composition, place of birth, and reproductive history. METHODS: We measured the capillary hemoglobin (Hb) levels of 153 adult women. Each participant was also given two interviews characterizing reproductive history and a 24-hour food recall. RESULTS: The average Hb level was 12.6 g/dL (range 5.8-15.7 g/dL). In our sample, 28% of participants were anemic and 31% were borderline anemic. Iron and vitamin C consumption were negatively associated with Hb levels. Body mass index was marginally associated with Hb levels. Being born in a peri-urban setting, a proxy for early Westernized diet was associated with higher risk of anemia, suggesting developmental experience may play a role. Pregnant and lactating women had lower Hb levels than menstruating and menopausal women. Age, height, parity, and age at first pregnancy were not found to be statistically significant predictors of anemia. CONCLUSIONS: Iron deficiency represents a serious health concern for women, particularly pregnant ones. Our results suggest that both past and current nutritional ecology variables may be associated with the risk of anemia. These findings inform public health interventions, since reproductive history may be more difficult to modify than current diet. PMID- 28101999 TI - Congratulations. PMID- 28102000 TI - Bone regeneration in minipigs via calcium phosphate cement scaffold delivering autologous bone marrow mesenchymal stem cells and platelet-rich plasma. AB - Macroporous calcium phosphate cement (CPC) with stem cell seeding is promising for bone regeneration. The objective of this study was to investigate the effects of co-delivering autologous bone marrow mesenchymal stem cells (BMSCs) and autologous platelet-rich plasma (PRP) in CPC scaffold for bone regeneration in minipigs for the first time. Twelve female adult Tibet minipigs (12-18 months old) were used. A cylindrical defect with 10 mm height and 8 mm diameter was prepared at the femoral condyle. Two bone defects were created in each minipig, one at each side of the femoral condyle. Three constructs were tested: (1) CPC scaffold (CPC control); (2) CPC seeded with BMSCs (CPC-BMSC); (3) CPC seeded with BMSCs and PRP (CPC-BMSC-PRP). Two time points were tested: 6 and 12 weeks (n = 4). Good integration of implant with surrounding tissues was observed in all groups. At 12 weeks, the CPC-BMSC-PRP group had significantly less residual CPC remaining in the defect than the CPC-BMSC group and the CPC control (p < 0.05). The residual CPC volume for the CPC-BMSC-PRP group was half that of the CPC control. New bone formation for CPC-BMSC-PRP was more than two-fold that of the CPC control (p < 0.05). CPC-BMSC-PRP had new blood vessel density that was nearly two-fold that of the CPC control (p < 0.05). In conclusion, CPC scaffold with autologous BMSC-PRP doubled the new bone regeneration and blood vessel density in minipigs compared with the CPC control. In the present study, the new macroporous CPC system with co-delivered BMSC-PRP has been shown to promote scaffold resorption and bone regeneration in large defects. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28102002 TI - Pseudoherpetic transient acantholytic dermatosis (Grover disease): case series and review of the literature. AB - A total of 3 cases of pseudoherpetic transient acantholytic dermatosis (Grover disease) are presented, followed by a brief review of prior reports. All 3 patients were above the age of 60 and presented with a pruritic eruption composed of papules with or without vesicles distributed on the trunk. For all 3 patients, the clinical differential diagnosis included drug eruption but did not include Grover disease; in 1 patient, the clinical impression included herpesvirus infection. Similar histologic and immunohistochemical findings were demonstrated in all 3 cases. Intraepidermal vesicles with acantholysis, multinucleation and hypereosinophilic keratinocytes mimicking necrosis raised the possibility of herpesvirus infection. However, the focality of the process at scanning magnification, absence of true cytopathic effect despite multinucleation, and identification of dyskeratosis rather than true necrosis all permitted for morphologic distinction as pseudoherpetic change. Immunohistochemistry, negative for herpes simplex virus and varicella zoster virus antigens, also distinguished pseudoherpetic change in these patients from a true herpesvirus infection. This series highlights an uncommon histologic variant of a common disorder and describes morphologic and immunohistochemical findings to facilitate its distinction from true herpesvirus infection. PMID- 28102001 TI - Evaluation of the hybrid resolution PACE model for the study of folding, insertion, and pore formation of membrane associated peptides. AB - The PACE force field presents an attractive model for conducting molecular dynamics simulations of membrane-protein systems. PACE is a hybrid model, in which lipids and solvents are coarse-grained consistent with the MARTINI mapping, while proteins are described by a united atom model. However, given PACE is linked to MARTINI, which is widely used to study membranes, the behavior of proteins interacting with membranes has only been limitedly examined in PACE. In this study, PACE is used to examine the behavior of several peptides in membrane environments, namely WALP peptides, melittin and influenza hemagglutinin fusion peptide (HAfp). Overall, we find PACE provides an improvement over MARTINI for modeling helical peptides, based on the membrane insertion energetics for WALP16 and more realistic melittin pore dynamics. Our studies on HAfp, which forms a helical hairpin structure, do not show the hairpin structure to be stable, which may point toward a deficiency in the model. (c) 2017 Wiley Periodicals, Inc. PMID- 28102003 TI - Intervention quality is not routinely assessed in Cochrane systematic reviews of radiation therapy interventions. AB - INTRODUCTION: The aim of this study was to maximise the benefits from clinical trials involving technological interventions such as radiation therapy. High compliance to the quality assurance protocols is crucial. We assessed whether the quality of radiation therapy intervention was evaluated in Cochrane systematic reviews. METHODS: We searched 416 published Cochrane systematic reviews and identified 67 Cochrane systematic reviews that investigated radiation therapy or radiotherapy as an intervention. For each systematic review, either quality assurance or quality control for the intervention was identified by a description of such processes in the published systematic reviews. RESULTS: Of the 67 Cochrane systematic reviews studied, only two mentioned quality assurance or quality control. CONCLUSIONS: Our findings revealed that 65 of 67 (97%) Cochrane systematic reviews of radiation therapy interventions failed to consider the quality of the intervention. We suggest that advice about the evaluation of intervention quality be added to author support materials. PMID- 28102004 TI - Prevalence and causes of hearing impairment in Fundong Health District, North West Cameroon. AB - OBJECTIVE: To estimate the prevalence and causes of hearing impairment in Fundong Health District, North-West Cameroon. METHODS: We selected 51 clusters of 80 people (all ages) through probability proportionate to size sampling. Initial hearing screening was undertaken through an otoacoustic emission (OAE) test. Participants aged 4+ years who failed this test in both ears or for whom an OAE reading could not be taken underwent a manual pure-tone audiometry (PTA) screening. Cases of hearing impairment were defined as those with pure-tone average >=41 dBHL in adults and >=35 dBHL in children in the better ear, or children under age 4 who failed the OAE test in both ears. Each case with hearing loss was examined by an ear, nose and throat nurse who indicated the main likely cause. RESULTS: We examined 3567 (86.9%) of 4104 eligible people. The overall prevalence of hearing impairment was 3.6% (95% confidence interval [CI]: 2.8 4.6). The prevalence was low in people aged 0-17 (1.1%, 0.7-1.8%) and 18-49 (1.1%, 0.5-2.6%) and then rose sharply in people aged 50+ (14.8%, 11.7-19.1%). Among cases, the majority were classified as moderate (76%), followed by severe (15%) and profound (9%). More than one-third of cases of hearing impairment were classified as unknown (37%) or conductive (37%) causes, while sensorineural causes were less common (26%). CONCLUSIONS: Prevalence of hearing impairment in North-West Cameroon is in line with the WHO estimate for sub-Saharan Africa. The majority of cases with known causes are treatable, with impacted wax playing a major role. PMID- 28102006 TI - Prozone Effect Can Be Specific to Single Antigen Bead Kit Manufacturers. PMID- 28102005 TI - Blind prediction of deleterious amino acid variations with SNPs&GO. AB - SNPs&GO is a machine learning method for predicting the association of single amino acid variations (SAVs) to disease, considering protein functional annotation. The method is a binary classifier that implements a support vector machine algorithm to discriminate between disease-related and neutral SAVs. SNPs&GO combines information from protein sequence with functional annotation encoded by gene ontology (GO) terms. Tested in sequence mode on more than 38,000 SAVs from the SwissVar dataset, our method reached 81% overall accuracy and an area under the receiving operating characteristic curve of 0.88 with low false positive rate. In almost all the editions of the Critical Assessment of Genome Interpretation (CAGI) experiments, SNPs&GO ranked among the most accurate algorithms for predicting the effect of SAVs. In this paper, we summarize the best results obtained by SNPs&GO on disease-related variations of four CAGI challenges relative to the following genes: CHEK2 (CAGI 2010), RAD50 (CAGI 2011), p16-INK (CAGI 2013), and NAGLU (CAGI 2016). Result evaluation provides insights about the accuracy of our algorithm and the relevance of GO terms in annotating the effect of the variants. It also helps to define good practices for the detection of deleterious SAVs. PMID- 28102007 TI - Effects of Diet Restriction and Diet Complexity on Life History Strategies in Side-Blotched Lizards (Uta stansburiana). AB - Organisms must balance energy invested into self-maintenance, reproduction, and somatic growth over their lifetime. In this study, the effects of diet restriction and diet complexity on side-blotched lizards (Uta stansburiana) were analyzed. Thirty male lizards, housed in the laboratory, were fed either an ad libitum or a restricted diet for 18 days (phase 1). Individuals from both treatments were then assigned to a diet of the same quantity of food that was either simple (only crickets) or complex (crickets, cockroaches, waxworms, and mealworms) for 35 days (phase 2). We evaluated (1) how diet restriction affected life history strategies and (2) how diet complexity affected recovery from diet restriction as measured at the end of phase 2 by body mass, snout-vent length, calculated body condition score, wound healing, tail regrowth, bacterial killing ability, oxidative stress, and plasma testosterone and corticosterone concentrations. Lizards without diet restriction allocated more energy to self maintenance (i.e., maintaining higher body condition scores, healing wounds more quickly) than lizards with diet restriction. Lizards with diet restriction had higher plasma testosterone concentrations and larger increases in snout-vent lengths than those fed ad libitum, which may reflect allocations toward reproduction and somatic growth. A complex diet resulted in better body condition and faster tail regrowth than a simple diet, suggesting that a complex diet enhanced recovery from diet restriction, although long-term life history choices remained unaltered. Finally, lizards on a complex diet consumed substantially less food while maintaining higher body condition, suggesting that key nutrients may be lacking from a simple diet. PMID- 28102008 TI - Gender-Associated Mitochondrial DNA Heteroplasmy in Somatic Tissues of the Endangered Freshwater Mussel Unio crassus (Bivalvia: Unionidae): Implications for Sex Identification and Phylogeographical Studies. AB - Some bivalve species possess two independent mitochondrial DNA lineages: maternally (F-type) and paternally (M-type) inherited. This phenomenon is called doubly uniparental inheritance. It is generally agreed that F-type mtDNA is typically present in female somatic and gonadal tissues as well as in male somatic tissues, whereas the M-type mtDNA occurs only in male germ line and gonadal tissue. In the present study, the mtDNA heteroplasmy (for both F and M genomes) in male somatic tissues of Unio crassus (Philipsson, 1788), species threatened with extinction, has been confirmed. Taking advantage from the presence of Mcox1 marker only in male somatic tissues, we developed a new method of sex identification in this endangered species, using nondestructive tissue sampling. Probability of correct sex identification was estimated at 97.5%. The present study is the first report on gender-associated mitochondrial DNA heteroplasmy in male somatic tissues of thick-shelled river mussel and first approach to U. crassus sex identification at molecular level. Our study also confirmed the utility of paternally inherited Mcox1 gene fragment as a complementary molecular tool for resolving phylogeographical relationships among populations of thick-shelled river mussel. PMID- 28102009 TI - Detection of Equine Herpesvirus (EHV) -1, -2, -4 and -5 in Ethiopian Equids with and without Respiratory Problems and Genetic Characterization of EHV-2 and EHV-5 Strains. AB - Infections with equine herpesviruses (EHVs) are widespread in equine populations worldwide. Whereas both EHV-1 and EHV-4 produce well-documented respiratory syndromes in equids, the contribution of EHV-2 and EHV-5 to disease of the respiratory tract is still enigmatic. This study describes the detection and genetic characterization of EHVs from equids with and without clinical respiratory disease. Virus-specific PCRs were used to detect EHV-1, -2, -4 and 5. From the total of 160 equids with respiratory disease, EHV-5 was detected at the highest prevalence (23.1%), followed by EHV-2 (20.0%), EHV-4 (8.1%) and EHV-1 (7.5%). Concurrent infections with EHV-2 and EHV-5 were recorded from nine (5.2%) diseased horses. Of the total of 111 clinically healthy equids, EHV-1 and EHV-4 were never detected whereas EHV-2 and EHV-5 were found in 8 (7.2%) and 18 (16.2%) horses, respectively. A significantly higher proportion of EHV-2-infected equids was observed in the respiratory disease group (32/160, 20.0%; P = 0.005) compared to those without disease (8/111; 7.2%). EHV-2-positive equids were three times more likely to display clinical signs of respiratory disease than EHV-2-negative equids (OR 3.22, 95% CI: 1.42-7.28). For EHV-5, the observed difference was not statistically significant (P = 0.166). The phylogenetic analysis of the gB gene revealed that the Ethiopian EHV-2 and EHV-5 strains had a remarkable genetic diversity, with a nucleotide sequence identity among each other that ranged from 94.0 to 99.4% and 95.1 to 100%, respectively. Moreover, the nucleotide sequence identity of EHV-2 and EHV-5 with isolates from other countries acquired from GenBank ranged from 92.9 to 99.1% and 95.1 to 99.5%, respectively. Our results suggest that besides EHV-1 and EHV-4, EHV-2 is likely to be an important contributor either to induce or predispose equids to respiratory disease. However, more work is needed to better understand the contribution of EHV-2 in the establishment of respiratory disease. PMID- 28102010 TI - A muscular imprint on the anterolateral surface of the proximal femurs of the Krapina Neandertal collection. AB - OBJECTIVES: The purpose of this study is to report and interpret a feature on the anterolateral surface of the proximal femurs of the Krapina hominid collection that we briefly described in 2006 (Periodicum Biologorum, 108, 319-329). MATERIALS AND METHODS: We recorded the presence or absence of the feature in all the proximal femurs of the Krapina collection (six specimens recordable) and in 622 modern human adult femurs. RESULTS: The feature consists in a series of crests delimitating three raised or depressed areas. This feature has been found in three out of four adult Neandertal femurs observable. The two observable subadult Neandertal femurs do not show this character. None of the modern femurs displayed the feature. CONCLUSION: We interpret this feature as a muscular imprint, probably representing the m. vastus intermedius origin and discuss a possible interpretation. We did not find any other references for such imprint in the existing literature regarding the Neandertal femurs. PMID- 28102011 TI - Local myogenic pulp-derived cell injection enhances craniofacial muscle regeneration in vivo. AB - OBJECTIVES: To enhance myogenic differentiation in pulp cells isolated from extracted premolars by epigenetic modification using a DNA demethylation agent, 5 aza-2'-deoxycytidine (5-Aza), and to evaluate the potent stimulatory effect of 5 Aza-treated pulp cell injection for craniofacial muscle regeneration in vivo. SETTING AND SAMPLE POPULATION: Pulp cells were isolated from premolars extracted for orthodontic purposes from four adults (age range, 18-22.1 years). MATERIAL AND METHODS: Levels of myogenic differentiation and functional contraction response in vitro were compared between pulp cells with or without pre-treatment of 5-Aza. Changes in muscle regeneration in response to green fluorescent protein (GFP)-labelled myogenic pulp cell injection in vivo were evaluated using a cardiotoxin (CTX)-induced muscle injury model of the gastrocnemius as well as the masseter muscle in mice. RESULTS: Pre-treatment of 5-Aza in pulp cells stimulated myotube formation, myogenic differentiation in terms of desmin and myogenin expression, and the level of collagen gel contraction. The local injection of 5 Aza pre-treated myogenic pulp cells was engrafted into the host tissue and indicated signs of enhanced muscle regeneration in both the gastrocnemius and the masseter muscles. CONCLUSION: The epigenetic modification of pulp cells from extracted premolars and the local injection of myogenic pulp cells may stimulate craniofacial muscles regeneration in vivo. PMID- 28102012 TI - Visual perception of faces with unilateral and bilateral cleft lip and palate: An Eye-Tracking Study. AB - OBJECTIVES: To test the hypotheses that there are differences between orthodontists, individuals with cleft lip and palate (CLP) and laypersons in the visual perception of faces with unilateral (UCLP) and bilateral cleft lip and palate (BCLP), the faces with UCLP and BCLP are visually perceived differently and the hierarchy of visual attention changes when viewing individuals with CLP. SETTING AND SAMPLE POPULATION: Department of Orthodontics and Experimental Psychology at Ege University, Izmir. Sixty images (faces with a social smile and at rest) of 30 volunteers (unaffected controls, UCLP, BCLP) were viewed by 80 participants: orthodontists, individuals with CLP and laypersons. MATERIALS AND METHODS: Eye fixations on four areas of interest were quantified: eyes, nose, upper lip and lower lip-chin. Time to first fixation, fixation before, fixation count and fixation duration parameters were analysed. RESULTS: Orthodontists fixated on the upper-lip area more often than laypersons or individuals with CLP (F2.144 =8.47, P=.00, eta2=.19 in faces at rest). The upper-lip area received more fixations (F2.144 =21.93, P=.00, eta2=.23) and longer fixation durations (F2.144 =28.86, P=.00, eta2=.27) from all participants who gazed on faces with UCLP and a social smile. CONCLUSION: The hypotheses of the study were supported. Orthodontists and laypersons focused more attention on the upper lip and eyes in the resting position, respectively. The upper-lip area of the BCLP images captured more attention at rest. PMID- 28102013 TI - The effect of potassium diclofenac and dexamethasone on MMP-1 gene transcript levels during experimental tooth movement in rats. AB - OBJECTIVES: The aim of this study was to analyze MMP-1 transcript levels in periodontal tissues of rats that underwent orthodontic treatment using potassium diclofenac and dexamethasone at different stages of tooth movement. SETTING AND SAMPLE POPULATION: The sample comprised of ninety male Wistar rats. MATERIAL AND METHODS: A closed nickel-titanium coil spring was used to apply a force of 50 cN to move the maxillary right first molars mesially. One group received daily doses of 0.9% saline solution, the second group received daily doses of 5 mg/kg potassium diclofenac, and the third group received daily doses of 0.5 mg/kg dexamethasone. Tooth movement was observed on days 0, 1, 3, 7, and 14. MMP-1 transcript levels were evaluated by real-time polymerase chain reaction and the results were compared between groups by three-way ANOVA, with a significance level of 0.05. RESULTS: Transcript levels increased in groups that received the coil spring treatment on all days of the experiment. MMP-1 expression was found to be decreased in groups treated with potassium diclofenac and dexamethasone compared to that in the control group, on days 1, 3, 5, and 7. CONCLUSIONS: The application of orthodontic forces significantly increased MMP-1 transcript levels. The use of anti-inflammatory drugs may have an inhibitory effect on MMP-1 expression. PMID- 28102014 TI - Phonetic analysis during treatment with rapid maxillary expander. AB - OBJECTIVES: To investigate possible changes and/or device-related impairments in phonetic habits produced by rapid maxillary expansion (RME). MATERIALS AND METHODS: Thirty-five patients scheduled for RME were divided into two groups: Group A (banded two-arm Hyrax) and Group B (banded four-arm Hyrax). Speech samples were collected at six time points, before, during and after RME removal. Acoustical analysis was performed using PRAAT and BioVoice analysis tools. Ten volunteers completed a questionnaire on the acceptability of patient's speech. Maxillary dimensions and palatal volume were measured on dental casts before and after expansion using a digital gauge. RESULTS: Voice analysis showed an increase in the peak frequency of fricative consonants (/s/,/?/) after expansion, whereas there was no change of formant frequencies of palatal consonants (/n/,/y/). Vowel /i/ displayed a lowering of the first formant frequency, and an increase in the second and third formant frequencies. After bonding, Group B showed both a greater reduction in the peak frequency of fricatives and a greater increase in the formant frequencies of palatal consonants than Group A. CONCLUSION: Rapid maxillary expansion causes a slight phonetic change in the acoustical parameters of both consonants and vowels. The two-arm Hyrax caused less speech impairment than the four-arm Hyrax during the treatment. PMID- 28102016 TI - Mechanical and barrier properties of maize starch-gelatin composite films: effects of amylose content. AB - BACKGROUND: In order to obtain new reinforcing bio-fillers to improve the physicochemical properties of gelatin-based films, three types of maize starch, waxy maize starch (Ap), normal starch (Ns) and high-amylose starch (Al), were incorporated into gelatin film and the resulting film properties were investigated, focusing on the impact of amylose content. RESULTS: The thickness, opacity and roughness of gelatin film increased depending on the amylose content along with the starch concentration. The effects of the three starches on the mechanical properties of gelatin film were governed by amylose content, starch concentration as well as environmental relative humidity (RH). At 75% RH, the presence of Al and Ns in the gelatin matrix increased the film strength but decreased its elongation, while Ap exhibited an inverse effect. Starch addition decreased the oxygen permeability of the film, with the lowest value at 20% Al and Ns. All starches, notably at 30% content, led to a decrease in the water vapor permeability of the film at 90% RH, especially Ns starch. Furthermore, the starches improved the thermal stability of the film to some extent. Fourier transform infrared spectra indicated that some weak intermolecular interactions such as hydrogen bonding occurred between gelatin and starch. Moreover, a high degree of B-type crystallinity of starch was characterized in Gel-Al film by X ray diffraction. CONCLUSION: Tailoring the properties of gelatin film by the incorporation of different types of maize starch provides the potential to extend its applications in edible food packaging. (c) 2017 Society of Chemical Industry. PMID- 28102015 TI - Circulating Antioxidant Levels and Risk of Prostate Cancer by TMPRSS2:ERG. AB - BACKGROUND: Few studies have considered etiological differences across molecular subtypes of prostate cancer, despite potential to improve opportunities for precision prevention of a disease for which modifiable risk factors have remained elusive. Factors that lead to DNA double-strand breaks, such as oxidative stress, may promote the formation of the TMPRSS2:ERG gene fusion in prostate cancer. We tested the hypothesis that increasing levels of pre-diagnostic circulating antioxidants, which may reduce oxidative stress, are associated with lower risk of developing TMPRSS2:ERG positive prostate cancer. METHODS: We conducted a nested case-control study, including 370 cases and 2,470 controls, to evaluate associations between pre-diagnostic alpha- and beta-carotene, alpha- and gamma tocopherol, beta-cryptoxanthin, lutein, lycopene, retinol, and selenium with the risk of prostate cancer by ERG protein expression status (a marker of TMPRSS2:ERG). Multivariable unconditional polytomous logistic regression was used to calculate odds ratios and 95% confidence intervals. RESULTS: We did not find any of the antioxidants to be significantly associated with the risk of prostate cancer according to ERG status. CONCLUSIONS: The results do not support the hypothesis that circulating pre-diagnostic antioxidant levels protect against developing TMPRSS2:ERG positive prostate cancer. Additional studies are needed to explore mechanisms for the development of TMPRSS2:ERG positive disease. Prostate 77: 647-653, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28102017 TI - Priming the stump in peripheral nerve injury (Commentary on Zhang et al. (2017)). PMID- 28102018 TI - Microwave-Assisted Rapid Synthesis of Self-Assembled T-Nb2 O5 Nanowires for High Energy Hybrid Supercapacitors. AB - Recently ion-intercalation hybrid supercapacitors, with high energy density at high power density, have been widely investigated to meet ever-increasing practical demands. Here, a unique hybrid supercapacitor has been designed and fabricated using self-assembled orthorhombic-phase niobium oxide@carbon (T-Nb2 O5 @C) nanowires as an anode and commercially available activated carbon as a cathode. The 3D-interconnected T-Nb2 O5 @C nanowires have been synthesized through a highly efficient microwave-solvothermal method, combined with subsequent thermal treatment. The experimental parameters (e.g., time and temperature) can be easily programmed, and the synthesis time can be significantly shortened, thus enabling the buildup of abundant recipes for the engineering of scaled-up production. The Li-ion intercalation pseudocapacitance electrode, made from the as-formed self-assembled T-Nb2 O5 @C nanowires, shows excellent charge storage and transfer capability. When assembled into a hybrid supercapacitor with a cathode of activated carbon, a high energy density of 60.6 Wh kg-1 and a high power density of 8.5 kW kg-1 with outstanding stability are achieved. In virtue of easy optimization and programmability of the synthetic strategy, and the remarkable electrochemical performance, the self-assembled T Nb2 O5 @C nanowires offer a promising anode for asymmetric hybrid supercapacitors. PMID- 28102019 TI - Shrimp tropomyosin retains antibody reactivity after exposure to acidic condition. AB - BACKGROUND: Although shrimp can be found in certain high acid food matrices, the allergenic capacity of shrimp tropomyosin exposed to low pH condition has not been fully clarified. Thus, a model marinade comprising white vinegar adjusted to different pH was used to determine the effects of acid-induced denaturation on the immunoreactivity of tropomyosin. RESULTS: Whole shrimp experienced either swelling or shrinkage after marination depending on the vinegar pH and the final muscle pH. The extractability of soluble myofibrillar proteins was reduced significantly among shrimp marinated in vinegar at pH 1.0-3.5, and a substantial amount of tropomyosin was retained in the insoluble pellets. Consequently, the immunoglobulin E (IgE)-binding capacity of tropomyosin was significantly lower in the soluble protein fraction of shrimp marinated at pH 1.0-3.5 compared with samples marinated at pH 4.8 and control. However, tropomyosin in the insoluble protein fraction of all marinated shrimp showed strong IgE-binding capacity at all marinating conditions. CONCLUSION: Thus, tropomyosin in shrimp exposed to low pH condition retained its allergenic capacity owing to the conservation of its linear epitopes. Analysis of the insoluble protein fraction was crucial for the accurate determination of the effect of low pH condition on the immunoreactivity of this allergen. (c) 2017 Society of Chemical Industry. PMID- 28102020 TI - Families' experiences of involvement in care planning in mental health services: an integrative literature review. AB - : WHAT IS KNOWN ON THE SUBJECT?: Current policy advocates for the participation of family carers in care planning. Caring for a person with a mental illness requires a significant commitment from families to support their relative's recovery. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: The evidence of family involvement in care planning is generally fraught with conflicting experiences related to different requirements between mental health professionals, families and service users. Confidentiality remains contentious at a practice level in terms of information sharing and decision-making. There is a requirement and need for a shared understanding around care planning between families and mental health professionals. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: The provision of written information pertaining to families regarding confidentiality is required at service level. Educational workshops concerning care planning and treatment options should be provided for service users, families and mental health professionals. Further research into effective service-wide strategies that explore with families how their engagement can be positively fostered in mental health services is warranted. ABSTRACT: Introduction Mental health service policy stipulates that family carers be involved in care planning. Aim To identify families' experiences of care planning involvement in adult mental health services. Method An integrative review where electronic databases and grey literature were searched for papers published between 01 January 2005 and 10 February 2016. Results Fifteen papers met the inclusion criteria. Thematic analysis generated three themes: (1) families' experience of collaboration, (2) families' perceptions of professionals and (3) families' impressions of the care planning process. Collaborative decision-making is not regularly experienced by families with an 'us' and 'them' divide, perpetuated by a lack of communication, confidentiality constraints and a claim of 'insider knowledge' of service users. When involved, families perceive care planning to be uncoordinated and that their lived experiences are not always appreciated. Discussion Families need to be valued, empowered and engaged in care planning and the partnership distance be addressed. Accommodating the views of family, service user and professionals is preferable but not always possible. Our findings suggest that the key element for professionals is to value all 'insider knowledge' where possible. Implications for Practice Services should develop written information on confidentiality for families and facilitate open communication concerning their involvement in care planning. PMID- 28102021 TI - High prevalence of diabetes and anthropometric heterogeneity among tuberculosis patients in Pakistan. AB - BACKGROUND: In Pakistan, the prevalence of diabetes (DM) among adults is 6.9% and expected to double by 2040. DM may facilitate transmission and halter the elimination of tuberculosis (TB). We aimed to determine the prevalence of DM among patients with TB in Pakistan, and to investigate anthropometric biochemical and haemodynamic associations between TB patients with and without DM. METHODS: We conducted a cross-sectional study at Gulab Devi Chest Hospital in Lahore, Punjab. A total of 3027 newly diagnosed smear-positive TB patients >=25 years of age were screened for DM by HbA1c regardless of previous DM history. RESULTS: The prevalence of screen-detected DM and known DM among the TB participants was 13.5% and 26.1%, respectively, resulting in a combined DM prevalence of 39.6%. Most participants were male (64.4%). Using bivariate analyses, participants with DM were significantly older (49.8 vs. 40.6 years) with higher haemoglobin (men, 12.1 vs. 11.8 g/dl, women 11.5 vs. 10.7 g/dl), body mass index (21.0 vs. 17.6 kg/m2 ) and waist-hip ratio (men, 0.87 vs. 0.81, women, 0.87 vs. 0.79) (all P < 0.05) than participants without DM. Stratifying by screen-detected and known DM, these differences remained significant when using multivariate analysis. CONCLUSION: We report a high prevalence of DM among patients with TB who may be anthropometrically and biochemically distinct from TB patients without DM, and this heterogeneity further transcends the different DM groups. PMID- 28102022 TI - The Flavonoid 7,4'-Dihydroxyflavone Prevents Dexamethasone Paradoxical Adverse Effect on Eotaxin Production by Human Fibroblasts. AB - Eotaxin/CCL-11 is a major chemoattractant that contributes to eosinophilic inflammation in asthma. Glucocorticoids inhibit inflammation, but long-time exposure may cause paradoxical adverse effects by augmenting eotaxin/CCL 11production. The aim of this study was to determine if 7,4'-dihydroxyflavone (7,4'-DHF), the eotaxin/CCL11 inhibitor isolated from Glycyrrhiza uralensis, reduces in vitro eotaxin production induced by long-time dexamethasone (Dex) exposure, and if so, to elucidate the mechanisms of this inhibition. Human lung fibroblast-1 cells were used to identify the potency of 7,4'-DHF compared with other compounds from G. uralensis, to compare 7,4'-DHF with Dex on eotaxin production following 24-h short-time culture and 72-h longer-time (LT) culture, and to determine the effects of the 7,4'-DHF on Dex LT culture augmented eotaxin production and molecule mechanisms. 7,4'-DHF was the most potent eotaxin/CCL-11 inhibitor among the ten compounds and provided continued suppression. In contrast to short-time culture, Dex LT culture increased constitutively, and IL-4/TNF alpha stimulated eotaxin/CCL11 production by human lung fibroblast-1 cells. This adverse effect was abrogated by 7,4'-DHF co-culture. 7,4'-DHF significantly inhibited Dex LT culture augmentation of p-STAT6 and impaired HDAC2 expression. This study demonstrated that 7,4'-DHF has the ability to consistently suppress eotaxin production and prevent Dex-paradoxical adverse effects on eotaxin production. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28102023 TI - 6-Gingerol-rich fraction prevents disruption of histomorphometry and marker enzymes of testicular function in carbendazim-treated rats. AB - Previous investigations demonstrated that 6-gingerol-rich fraction (6-GRF) prevented testicular toxicity via inhibition of oxidative stress and endocrine disruption in CBZ-treated rats. The influence of 6-GRF on alterations in histomorphometry and marker enzymes of testicular function in CBZ-treated rats which hitherto has not been reported was investigated in this study. The animals were orally administered either CBZ (50 mg/kg) alone or in combination with 6-GRF (50, 100 and 200 mg/kg) for 14 consecutive days. Histomorphormetric analysis demonstrated that 6-GRF significantly prevented CBZ-mediated increase in the organo-somatic index of the testes and seminiferous tubular diameter as well as the reduction in epithelium height and tubular length of testes in the rats. Similarly, 6-GRF ameliorated CBZ-induced disruption in the epithelium height as well as in the proportion of tubule and interstitium of the epididymis the treated rats. Furthermore, 6-GRF prevented CBZ-mediated increase in testicular acid phosphatase activity and the decrease in testicular alkaline phosphatase, aminotransferases, glucose-6-phosphate dehydrogenase and lactate dehydrogenase activities. Moreover, 6-GRF ameliorated CBZ-induced reduction in the testicular and epididymal sperm count and sperm motility in the treated rats. Conclusively, 6-GRF enhances key functional enzymes involve in spermatogenesis and maintains histo-architecture of testes and epididymis in CBZ-treated rats. PMID- 28102024 TI - Generating Antigen-Specific Regulatory T Cells in the Fast Lane. PMID- 28102025 TI - The Direct Referral to Endovascular Center criteria: a proposal for pre-hospital evaluation of acute stroke in the Madrid Stroke Network. AB - BACKGROUND AND PURPOSE: For patients with acute ischaemic stroke due to large vessel occlusion, it has recently been shown that mechanical thrombectomy (MT) with stent retrievers is better than medical treatment alone. However, few hospitals can provide MT 24 h/day 365 days/year, and it remains unclear whether selected patients with acute stroke should be directly transferred to the nearest MT-providing hospital to prevent treatment delays. Clinical scales such as Rapid Arterial Occlusion Evaluation (RACE) have been developed to predict large-vessel occlusion at a pre-hospital level, but their predictive value for MT is low. We propose new criteria to identify patients eligible for MT, with higher accuracy. METHODS: The Direct Referral to Endovascular Center criteria were defined based on a retrospective cohort of 317 patients admitted to a stroke center. The association of age, sex, RACE scale score and blood pressure with the likelihood of receiving MT were analyzed. Cut-off points with the highest association were thereafter evaluated in a prospective cohort of 153 patients from nine stroke units comprising the Madrid Stroke Network. RESULTS: Patients with a RACE scale score >= 5, systolic blood pressure <190 mmHg and age <81 years showed a significantly higher probability of undergoing MT (odds ratio, 33.38; 95% confidence interval, 12-92.9). This outcome was confirmed in the prospective cohort, with 68% sensitivity, 84% specificity, 42% positive and 94% negative predictive values for MT, ruling out 83% of hemorrhagic strokes. CONCLUSIONS: The Direct Referral to Endovascular Center criteria could be useful for identifying patients suitable for MT. PMID- 28102026 TI - Piperine, a Pungent Alkaloid from Black Pepper, Inhibits B Lymphocyte Activation and Effector Functions. AB - Piperine has several well-documented anti-inflammatory properties; however, little is known regarding its effect on humoral immunity. In this study, we describe the immunosuppressive effect of piperine on B lymphocytes, which are integral to the humoral immune response. Mouse B cells were cultured in the absence or presence of non-cytotoxic concentrations (25, 50, and 100 MUM) of piperine during T-dependent or T-independent stimulation. Piperine inhibited B cell proliferation by causing G0/G1 phase cell cycle arrest in association with reduced expression of cyclin D2 and D3. The inhibitory effect of piperine was not mediated through transient receptor potential vanilloid-1 ion channel (TRPV1) because piperine also inhibited the proliferation of B cells from TRPV1-deficient mice. Expression of class II major histocompatibility complex molecules and costimulatory CD40 and CD86 on B lymphocytes was reduced in the presence of piperine, as was B cell-mediated antigen presentation to syngeneic T cells. In addition, piperine inhibited B cell synthesis of interleukin (IL)-6 and IL-10 cytokines, as well as IgM, IgG2b, and IgG3 immunoglobulins. The inhibitory effect of piperine on B lymphocyte activation and effector function warrants further investigation for possible application in the treatment of pathologies related to inappropriate humoral immune responses. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28102027 TI - Patient engagement in HIV care and treatment in Zambia, 2004-2014. AB - OBJECTIVE: To describe engagement along the HIV continuum of care using a large network of clinics in Zambia. METHODS: We employed a practical framework to describe retention along the HIV treatment cascade, using routinely collected clinical data available in resource-constrained settings. We included health facilities in four Zambian provinces with more than 300 enrolled patients over the age of 5 years. We described attrition at each step, from HIV enrolment to 720 days after ART initiation. The population was further stratified by year of enrolment to describe temporal trends in patient engagement. RESULTS: From January 2004 to December 2014, 444 439 individuals over the age of 5 years sought HIV care at 75 eligible health facilities. Among those enrolled into HIV care, 82.1% (95% confidence interval [CI]: 79.4-84.5%) were fully assessed for ART eligibility within 180 days of enrolment and 63.6% (95% CI: 61.7-65.3) were found to be eligible for ART based on the HIV treatment guidelines at the time. Of those patients eligible for ART, 81.1% (95% CI: 79.5-82.7%) initiated ART within 180 days. Patient retention in ART programme was 81.2% (95% CI: 80.4-81.9%) at 90 days, 70.0% (95% CI: 68.7-71.2%) at 360 days and 61.6% (95% CI: 60.0-63.2%) at 720 days. We noted a steady decline in proportions assessed for ART eligibility and deemed eligible for ART in the time frame. Proportions that started ART and remained in care remained relatively consistent. CONCLUSION: We describe a simple approach for assessing patient engagement after enrolment into HIV care. Using limited types of data routinely available, we demonstrate an important and replicable approach to monitoring programmes in resource-constrained settings. PMID- 28102029 TI - Biochemical markers to predict internal browning disorders in 'Rocha' pear during storage under high CO2. AB - BACKGROUND: The aim of this study was to identify biochemical markers to predict internal browning disorders (IBD) in 'Rocha' pear. Fruits from five orchards were stored for 45 days under cold air followed by 100 days in browning-inducing controlled atmosphere (CA) conditions (1 kPa O2 + 10 kPa CO2 ). RESULTS: Relationships between concentrations of ethanol (EtOH), acetaldehyde (AcDH) and ascorbic acid (AA), activities of peroxidase (POX) and polyphenoloxidase (PPO) and IBD incidence were established. The partial least square (PLS) model using the most promising markers, EtOH and AcDH, explained 89% of the variance in IBD incidence, whereas the univariate models based on the same markers explained between 89 and 94%. In contrast, the models based on AA levels and AA depletion rate only explained 57 and 82% of the variance in IBD incidence respectively. Model validation confirmed the robustness of EtOH for the prediction (R2 = 0.91, RMSE = 11.1) and allowed proposing a threshold level of 30 uL EtOH L-1 above which IBD may occur. Using this threshold value, the storage time limit associated with the occurrence of the first IBD symptoms was predicted with an acceptable RMSE of 9 days. CONCLUSION: This work clearly identifies biochemical IBD markers for 'Rocha' pear and shows that dynamic changes in ethanol concentration during the beginning of storage may be used to predict IBD development. Therefore the results presented herein represent a major step forward in the prediction of IBD in 'Rocha' pear. (c) 2017 Society of Chemical Industry. PMID- 28102028 TI - The involvement of MsmK in pathogenesis of the Streptococcus suis serotype 2. AB - Streptococcus suis serotype 2 (SS2) is an important swine and human pathogen that causes global economic and public health problems. Virulent S. suis strains successfully maintain high bacterial concentrations in host blood and rapidly adapt to challenging environments within hosts. Successful survival in hosts is a major factor influencing the pathogenesis of SS2. We have previously identified that SS2 colonization in mouse brain is possibly affected by the ATPase, MsmK of carbohydrate ATP-binding cassette (ABC) transporters because of carbohydrate utilization. In this study, the chain length of the msmK deletion mutant was longer than that of the wild type, and the former was significantly more susceptible than the latter when theses strains were exposed to mouse blood both in vivo and in vitro. The hemolytic activity of the mutant strain was decreased. Although the adhesion of the mutant to HEp-2 cell lines was enhanced, the deletion of msmK impaired the abilities of SS2 to resist phagocytosis and survive severe stress conditions. MsmK contributed to the survival and adaptation of SS2 in host bloodstream. Therefore, MsmK was identified as a multifunctional component that not only contributed to carbohydrate utilization but also participated in SS2 pathogenesis. PMID- 28102031 TI - Dual nano-sized contrast agents in PET/MRI: a systematic review. AB - Nowadays molecular imaging plays a vital role in achieving a successful targeted and personalized treatment. Hence, the approach of combining two or more medical imaging modalities was developed. The objective of this review is to systematically compare recent dual contrast agents in Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI) and in some cases Single photon emission computed tomography (SPECT)/MRI in terms of some their characteristics, such as tumor uptake, and reticuloendothelial system uptake (especially liver) and their relaxivity rates for early detection of primary cancer tumor. To the best of our knowledge, this is the first systematic and integrated overview of this field. Two reviewers individually directed the systematic review search using PubMed, MEDLINE and Google Scholar. Two other reviewers directed quality assessment, using the criteria checklist from the CAMARADES (Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies) tool, and differences were resolved by consensus. After reviewing all 49 studies, we concluded that a size range of 20-200 nm can be used for molecular imaging, although it is better to try to achieve as small a size as it is possible. Also, small nanoparticles with a hydrophilic coating and positive charge are suitable as a T2 contrast agent. According to our selected data, the most successful dual probes in terms of high targeting were with an average size of 40 nm, PEGylated using peptides as a biomarker and radiolabeled with copper 64 and gallium 68. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28102030 TI - Impact of Sodium-Glucose Cotransporter 2 Inhibitors on Nonglycemic Outcomes in Patients with Type 2 Diabetes. AB - The efficacy of the sodium-glucose cotransporter 2 (SGLT2) inhibitors canagliflozin, dapagliflozin, and empagliflozin in reducing hyperglycemia in patients with type 2 diabetes is well documented. In addition, positive effects have been observed with these agents on nonglycemic variables, such as reductions in body weight and blood pressure, which may confer additional health benefits. SGLT2 inhibitors are also associated with evidence of renal-protecting benefits. Furthermore, during the landmark Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) trial, a substantial reduction in major adverse cardiovascular outcomes was demonstrated with empagliflozin therapy. In view of the complex pathogenesis of cardiovascular disease in patients with diabetes, a pharmacologic intervention for type 2 diabetes that produces a multifaceted reduction in cardiovascular disease risk, separate from glycemic control alone, would be advantageous. Although SGLT2 inhibitors are generally well tolerated, they are associated with an increased risk of genital mycotic infections, as well as the potential risk for serious adverse events such as dehydration, development of diabetic ketoacidosis, serious urinary tract infections, and bone fractures. The findings of ongoing research will help to determine the magnitude and clinical importance of these adverse events and whether the findings of EMPA-REG OUTCOME represent a class effect for SGLT2 inhibition or are specific to empagliflozin and will further elucidate the future role of SGLT2 inhibitors in the individualized management of patients with type 2 diabetes. In this article, we discuss the nonglycemic outcomes associated with SGLT2 inhibitor therapy in patients with type 2 diabetes as well as the clinical implications of these agents. PMID- 28102033 TI - Ten novel MHC-DPB1 alleles identified in Tibetan macaque (Macaca thibetana). AB - Ten novel MHC-DPB1 alleles of Tibetan macaque, were identified by cloning and sequencing. PMID- 28102032 TI - Nonpromoter methylation of the CDKN2A gene with active transcription is associated with improved locoregional control in laryngeal squamous cell carcinoma. AB - We previously reported a novel association between CDKN2A nonpromoter methylation and transcription (ARF/INK4a) in human papillomavirus associated oropharyngeal tumors. In this study we assessed whether nonpromoter CDKN2A methylation in laryngeal squamous cell carcinomas (LXSCC) conferred a similar association with transcription that predicted patient outcome. We compared DNA methylation and ARF/INK4a RNA expression levels for the CDKN2A locus using the Illumina HumanMethylation27 beadchip and RT-PCR in 43 LXSCC tumor samples collected from a prospective study of head and neck cancer patients treated at Montefiore Medical Center (MMC). Validation was performed using RNAseq data on 111 LXSCC tumor samples from the Cancer Genome Atlas (TCGA). The clinical relevance of combined nonpromoter CDKN2A methylation and transcription was assessed by multivariate Cox regression for locoregional recurrence on a subset of 69 LXSCC patients with complete clinicopathologic data from the MMC and TCGA cohorts. We found evidence of CDKN2A nonpromoter hypermethylation in a third of LXSCC from our MMC cohort, which was significantly associated with increased ARF and INK4a RNA expression (Wilcoxon rank-sum, P = 0.007 and 0.003, respectively). A similar association was confirmed in TCGA samples (Wilcoxon rank-sum test P < 0.0001 for ARF and INK4a). Patients with CDKN2A hypermethylation or high ARF/INK4a expression were significantly less likely to develop a locoregional recurrence compared to those with neither of the features, independent of other clinicopatholgic risk factors (adjusted hazard ratio=0.21, 95% confidence interval:0.05-0.81). These results support the conclusion that CDKN2A nonpromoter methylation is associated with increased ARF and INK4a RNA expression, and improved locoregional control in LXSCC. PMID- 28102034 TI - Common and well-documented HLA alleles over all of Europe and within European sub regions: A catalogue from the European Federation for Immunogenetics. AB - BACKGROUND: A catalogue of common and well-documented (CWD) human leukocyte antigen (HLA), previously established by the American Society for Histocompatibility and Immunogenetics (ASHI), is widely used as indicator for typing ambiguities to be resolved in tissue transplantation or for checking the universality of any HLA allele in the world. However, European population samples, which are characterized by a substantial level of genetic variation, are underrepresented in the ASHI catalogue. Therefore, the Population Genetics Working Group of the European Federation for Immunogenetics (EFI) has facilitated data collection for an European CWD catalogue. MATERIALS AND METHODS: To this end, 2nd-field HLA-A, -B, -C,- DRB1,- DQA1,- DQB1 and -DPB1 data of 77 to 121 European population samples (21 571-3 966 984 individuals) from 3 large databases, HLA-net/Gene[VA], allelefrequencies.net and DKMS, were analysed. RESULTS: The total number of CWD alleles is similar in the EFI (N = 1048) and ASHI (N = 1031) catalogues, but the former counts less common (N = 236 vs 377) and more well-documented (N = 812 vs 654) alleles than the latter, possibly reflecting differences in sample numbers and sizes. Interestingly, approximately half of the CWD alleles reported by EFI were not reported by ASHI and vice-versa, underlining the distinct features of the two catalogues. Also, although 78 common alleles are widely distributed across Europe, some alleles are only common within specific sub-regions, showing regional variability. CONCLUSION: Although the definition of CWD alleles itself is affected by different parameters, calling for current updates of the list, the EFI CWD catalogue provides new insights into European population genetics and will be a very useful tool for tissue-typing laboratories in and beyond Europe. PMID- 28102035 TI - Description of the novel KIR2DL1*034 allele Identified from a southern Chinese Han individual. AB - The novel KIR2DL1*034 allele differs from the closest allele KIR2DL1*00302 by a single missense mutation. PMID- 28102036 TI - Combining one-step Sanger sequencing with phasing probe hybridization for HLA class I typing yields rapid, G-group resolution predicting 99% of unique full length protein sequences. AB - BACKGROUND: Sanger-based DNA sequencing of exons 2+3 of HLA class I alleles from a heterozygote frequently results in two or more alternative genotypes. This study was undertaken to reduce the time and effort required to produce a single high resolution HLA genotype. MATERIALS AND METHODS: Samples were typed in parallel by Sanger sequencing and oligonucleotide probe hybridization. This workflow, together with optimization of analysis software, was tested and refined during the typing of over 42,000 volunteers for an unrelated hematopoietic progenitor cell donor registry. Next generation DNA sequencing (NGS) was applied to over 1000 of these samples to identify the alleles present within the G group designations. RESULTS: Single genotypes at G level resolution were obtained for over 95% of the loci without additional assays. The vast majority of alleles identified (>99%) were the primary allele giving the G groups their name. Only 0.7% of the alleles identified encoded protein variants that were not detected by a focus on the antigen recognition domain (ARD)-encoding exons. CONCLUSION: Our combined method routinely provides biologically relevant typing resolution at the level of the ARD. It can be applied to both single samples or to large volume typing supporting either bone marrow or solid organ transplantation using technologies currently available in many HLA laboratories. PMID- 28102038 TI - EDTA is superior to DTT treatment for overcoming the prozone effect in HLA antibody testing. AB - A limitation of solid-phase human leukocyte antigen (HLA) antibody assays is the falsely low/negative result of samples with high-titer antibodies, a phenomenon known as the prozone effect. Here we compared the efficacy of ethylenediaminetetraacetic acid (EDTA) and dithiothreitol (DTT) treatment of serum samples in overcoming the prozone effect. A total of 21 serum samples were treated with either EDTA or DTT before HLA single antigen bead assay. The efficacy of prozone effect reversal, compared with untreated samples, was examined on fourfold, serially diluted samples, from neat to 1:256, using PBS as diluent. EDTA reversed the prozone effect in all tested samples, with an efficiency of greater than 84%, estimated by the ratio of undiluted sample mean fluorescence intensity (MFI) to peak MFI, for any given dilution. In contrast, the efficiency of DTT treatment was as low as 47%. These results show superior prozone effect reversal with EDTA treatment, compared with DTT. PMID- 28102037 TI - In celebration of Ruggero Ceppellini: HLA in transplantation. AB - The availability of hematopoietic cell transplantation as curative therapy for blood disorders has been dramatically improved through a better understanding of the human leukocyte antigen (HLA) barrier. Although a fully compatible unrelated donor is preferable, transplantation from donors with a limited degree of HLA mismatching is associated with acceptable outcomes in many cases. Research on the limits of HLA mismatching, and the features that define permissible HLA mismatches will continue to enable transplantation to be more broadly available to patients in need. PMID- 28102040 TI - Identification of the novel HLA-B*39:01:01:04 allele in a Chinese individual by sequence-based typing. AB - The new HLA-B*39:01:01:04 allele differs from HLA-B*39:01:01 by a C -> T substitution in intron 1. PMID- 28102039 TI - A dispermic chimerism detected in a Taiwanese potential unrelated hematopoietic stem cell donor. AB - Chimerism is defined as the presence of 2 or more than 1 genetically distinct cell populations in an organism. Dispermic chimeras are derived from the fertilization of 1 or 2 matured nuclei by 2 sperms. We here report detection of a healthy and phenotypically normal female with normal ABO red blood cell typing in whom dispermic chimerism was suspected after 3 alleles were identified at multiple human leukocyte antigen (HLA) loci using molecular HLA analysis. Molecular HLA typing showed the donor to have 3 HLA-A, -B, -C, -DRB1, -DQB1 and DPB1 alleles in blood, saliva and nail samples. In addition, 3 of her 9 short tandem repeat loci also showed to have 3 distinct alleles in blood, nail and saliva specimens. In all investigations, the third alleles were attributed to a dual paternal contribution. This case represents a dispermic chimerism, with 2 paternal and 1 maternal haplotypes variably distributed throughout body tissues in a healthy and phenotypically normal female without abnormalities in erythrocyte ABO blood group. The origin of this chimerism is probably due to the fertilization of a single egg and its polar body, or a parthenogenetic egg, by 2 sperms. PMID- 28102041 TI - A new HLA-B*55 allele, B*55:83N with a stop codon in exon 4 generated by a point mutation, identified in a Chinese individual. AB - The new allele HLA-B*55:83N differs from HLA-B*55:02:01:01 by a single nucleotide. PMID- 28102042 TI - Identification of a 10/10 matched donor for patients with an uncommon haplotype is unlikely. AB - BACKGROUND: Despite over 6 million subjects contributing to the National Marrow Donor Program human leukocyte antigen (HLA) haplotype frequency reference data (HFD), haplotypes cannot be predicted from the HLA assignments of some patients searching for an unrelated donor (URD) in the Be The Match Registry(r). We aimed to determine the incidence of these patient searches and whether haplotypes lacking from the HFD can be found among the low-resolution typed URD pool. MATERIALS AND METHODS: New NMDP searches with uncommon patient haplotypes (UPH), defined as a lack of haplotype pairs in any single ethnic group in the HFD based upon HLA-A~C~B~DRB1~DQB1, were identified. Each search had up to 20 potential 10/10 or 8/8 URDs typed to determine the likelihood of an allele match. RESULTS: The incidence of patient searches without haplotype pairs in a single ethnic group in the HFD was 1.2% (N=144 out of 12,172) and a majority of these patients (117; 81%) had one uncommon haplotype previously uncharacterized in the HFD. Non White patients had the highest incidence of UPH. Importantly, no patients with UPH had a 10/10 URD identified. The transplant rate among UPH patients was 15%, and a majority of these patients utilized cord blood units as their transplant stem cell source. CONCLUSION: Therefore, the HLA HFD that informs the HapLogic matching algorithm is thorough as UPH patient searches were infrequent. Since such patients are highly unlikely to have a fully 10/10 matched URD identified, this study supports the identification of alternative stem cell sources including cord blood or a mismatched URD early in the search process. PMID- 28102043 TI - Identification of a novel HLA-B*40 allele, HLA-B*40:332, in a Korean individual. AB - HLA-B*40:332 differs from B*40:01:02 by 1 nucleotide difference at nucleotide position 439. PMID- 28102046 TI - Association of moyamoya disease with thyroid autoantibodies and thyroid function. PMID- 28102047 TI - Adequate tacrolimus concentration for myasthenia gravis treatment. AB - BACKGROUND AND PURPOSE: A single, oral dose of 3 mg/day tacrolimus, approved for myasthenia gravis (MG) treatment in Japan, was shown to reduce steroid dose and anti-acetylcholine receptor (AChR) antibody titers as well as to improve MG symptoms. However, no studies have investigated the association between tacrolimus concentration and its clinical efficacy in MG. In this study, we aimed to determine the optimal tacrolimus concentration for MG treatment. METHODS: The trough tacrolimus concentration in 51 patients with MG (positive for anti-AChR antibody, n = 48; negative for anti-AChR and anti-muscle-specific tyrosine kinase antibodies, n = 3) who received 3 mg/day tacrolimus for more than 1 year was measured using a chemiluminescent enzyme immunoassay. The clinical characteristics of patients with MG as well as the dose of prednisolone used before and after tacrolimus treatment were evaluated retrospectively. RESULTS: The median trough tacrolimus concentration was 5.4 (range, 2.9-7.6) ng/mL, which was correlated with 'minimal manifestation or better status' (P = 0.0190, r = 0.3273) and the reduction in anti-AChR antibody 1 year after tacrolimus initiation (P = 0.0170, r = 0.3465). When the cut-off value for tacrolimus was defined as 4.8 ng/mL using a receiver operating characteristic curve, patients with adequate tacrolimus concentration (>=4.8 ng/mL) showed more reduction in anti-AChR antibody titers and more improvement in MG-related activities in daily life scores. More patients with adequate tacrolimus concentration achieved 'minimal manifestation or better status' compared with those with low tacrolimus concentration. CONCLUSIONS: An adequate tacrolimus concentration is required for better MG prognosis. PMID- 28102048 TI - Proteinuria as an important marker in the evaluation of the efficacy and safety of systemic thrombolysis in patients with acute ischaemic stroke. PMID- 28102045 TI - Inflammatory profile discriminates clinical subtypes in LRRK2-associated Parkinson's disease. AB - BACKGROUND AND PURPOSE: The presentation of Parkinson's disease patients with mutations in the LRRK2 gene (PDLRRK2 ) is highly variable, suggesting a strong influence of modifying factors. In this context, inflammation is a potential candidate inducing clinical subtypes. METHODS: An extensive battery of peripheral inflammatory markers was measured in human serum in a multicentre cohort of 142 PDLRRK2 patients from the MJFF LRRK2 Consortium, stratified by three different subtypes as recently proposed for idiopathic Parkinson's disease: diffuse/malignant, intermediate and mainly pure motor. RESULTS: Patients classified as diffuse/malignant presented with the highest levels of the pro inflammatory proteins interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP 1) and macrophage inflammatory protein 1-beta (MIP-1-beta) paralleled by high levels of the neurotrophic protein brain-derived neurotrophic factor (BDNF). It was also possible to distinguish the clinical subtypes based on their inflammatory profile by using discriminant and area under the receiver operating characteristic curve analysis. CONCLUSIONS: Inflammation seems to be associated with the presence of a specific clinical subtype in PDLRRK2 that is characterized by a broad and more severely affected spectrum of motor and non-motor symptoms. The pro-inflammatory metabolites IL-8, MCP-1 and MIP-1-beta as well as BDNF are interesting candidates to be included in biomarker panels that aim to differentiate subtypes in PDLRRK2 and predict progression. PMID- 28102049 TI - Declining incidence of intracerebral hemorrhage. PMID- 28102050 TI - Amiodarone-induced gait unsteadiness is revealed to be bilateral vestibulopathy. PMID- 28102053 TI - Size of Inhaled Corticosteroid and Small Airway Inflammation in Asthma. PMID- 28102051 TI - T-cell immunoglobulin mucin 3 blockade drives an antitumor immune response in head and neck cancer. AB - T-cell immunoglobulin mucin 3 (TIM3) contributes to immune suppression during progression of many cancers, but the precise role of TIM3 in head and neck squamous cell carcinoma (HNSCC) is not clearly understood. In this study, we report that TIM3 expression was significantly up-regulated in patients with HNSCC and associated with lymph node metastasis. Additionally, TIM3 expression was increased in patients with recurrent HNSCC and patients with preradiotherapy or prechemotherapy. We also characterized CD8+ T cells and CD11b+ CD33+ myeloid derived suppressor cells (MDSCs) in human HNSCC, and found that their expression was positively correlated with TIM3 expression. To determine the underlying mechanism of TIM3 in immune response during HNSCC progression, we utilized the Tgfbr1/Pten 2cKO HNSCC mouse model with TIM3 overexpression. Treatment with anti TIM3 monoclonal antibody effectively suppressed tumor growth through restoring effector T-cell function by targeting CD4+ TIM3+ cells and CD8+ TIM3+ cells and decreasing MDSCs. Our findings demonstrate TIM3 expression in patients with HNSCC and suggest anti-TIM3 immunotherapy as a novel therapeutic approach for effective treatment of HNSCC. PMID- 28102052 TI - Increasing incidence of invasive and in situ cervical adenocarcinoma in the Netherlands during 2004-2013. AB - In the developed world, the incidence of cervical squamous cell carcinoma has decreased, however, the incidence of adenocarcinoma in situ (AIS) and invasive adenocarcinoma increased, predominantly in young females. The goal of this study was to evaluate the most recent incidence rates of AIS, adenocarcinoma, and squamous cell carcinoma of the uterine cervix in the Netherlands in 2004-2013. By using Dutch national pathology and cancer registries, we calculated European standardized incidence rates (ESR) and estimated annual percentage changes (EAPC) for AIS during 2004-2013 and for invasive cervical carcinomas during 1989-2013. For AIS, presence or absence of concomitant cervical intraepithelial neoplasia (CIN) was explored. The estimated annual percentage change (EAPC) of squamous cell carcinoma decreased significantly in 1989-2013, predominantly in 1989-2003. The EAPC of invasive adenocarcinoma decreased in 1989-2003, but remained stable in 2004-2013. The EAPC of AIS increased significantly, predominantly in women of 25-39 years old. Of these AIS cases, 58.9% had concomitant CIN and AIS with concomitant CIN showed a significantly higher EAPC compared to AIS without CIN. Our conclusion is that despite a nationwide screening program for cancer of the uterine cervix, the incidence of adenocarcinoma in the Netherlands remained stable during 2004-2013 and the incidence of adenocarcinoma in situ increased. This was most predominant in cases with concomitant CIN and in younger females. The incidence of squamous cell carcinoma decreased in the same timeframe. PMID- 28102054 TI - Extracellular Vesicles, a Key Mediator to Link Environmental Microbiota to Airway Immunity. AB - Asthma is considered the hallmark of chronic airway inflammation, in which several inflammatory cells of the innate and adaptive immune system act together. The disease is thought to be caused by a combination of genetic and environmental factors; however, precise mechanisms for airway inflammation remain unclear. The human microbiota provides an increasingly favored explanation for inflammatory diseases; an altered microbiota composition has been shown to regulate immune responses. However, given the complexity of the microbiota, additional research is needed to elucidate its role in the development of disease. One of the candidate molecules that link microbiota to disease is the extracellular vesicles (EVs). EVs are secreted by diverse cell types and they possess the pathophysiological function of delivering signals between bacteria and host. We discuss the role of the microbiota in the development of asthma through releasing EVs. PMID- 28102055 TI - Role of Regulatory Cells in Oral Tolerance. AB - The immune system is continuously exposed to great amounts of different antigens from both food and intestinal microbes. Immune tolerance to these antigens is very important for intestinal and systemic immune homeostasis. Oral tolerance is a specific type of peripheral tolerance induced by exposure to antigen via the oral route. Investigations on the role of intestinal immune system in preventing hypersensitivity reactions to innocuous dietary and microbial antigens have been intensively performed during the last 2 decades. In this review article, we discuss how food allergens are recognized by the intestinal immune system and draw attention to the role of regulatory T (Treg) and B (Breg) cells in the establishment of oral tolerance and tolerogenic features of intestinal dendritic cells. We also emphasize the potential role of tonsils in oral tolerance induction because of their anatomical location, cellular composition, and possible usage to develop novel ways of specific immunotherapy for the treatment of allergic diseases. PMID- 28102056 TI - Asthma-Related Outcomes in Patients Initiating Extrafine Ciclesonide or Fine Particle Inhaled Corticosteroids. AB - PURPOSE: Extrafine-particle inhaled corticosteroids (ICS) have greater small airway deposition than standard fine-particle ICS. We sought to compare asthma related outcomes after patients initiated extrafine-particle ciclesonide or fine particle ICS (fluticasone propionate or non-extrafine beclomethasone). METHODS: This historical, matched cohort study included patients aged 12-60 years prescribed their first ICS as ciclesonide or fine-particle ICS. The 2 cohorts were matched 1:1 for key demographic and clinical characteristics over the baseline year. Co-primary endpoints were 1-year severe exacerbation rates, risk domain asthma control, and overall asthma control; secondary endpoints included therapy change. RESULTS: Each cohort included 1,244 patients (median age 45 years; 65% women). Patients in the ciclesonide cohort were comparable to those in the fine-particle ICS cohort apart from higher baseline prevalence of hospitalization, gastroesophageal reflux disease, and rhinitis. Median (interquartile range) prescribed doses of ciclesonide and fine-particle ICS were 160 (160-160) MUg/day and 500 (250-500) MUg/day, respectively (P<0.001). During the outcome year, patients prescribed ciclesonide experienced lower severe exacerbation rates (adjusted rate ratio [95% CI], 0.69 [0.53-0.89]), and higher odds of risk-domain asthma control (adjusted odds ratio [95% CI], 1.62 [1.27 2.06]) and of overall asthma control (2.08 [1.68-2.57]) than those prescribed fine-particle ICS. The odds of therapy change were 0.70 (0.59-0.83) with ciclesonide. CONCLUSIONS: In this matched cohort analysis, we observed that initiation of ICS with ciclesonide was associated with better 1-year asthma outcomes and fewer changes to therapy, despite data suggesting more difficult-to control asthma. The median prescribed dose of ciclesonide was one-third that of fine-particle ICS. PMID- 28102057 TI - Periostin in Exhaled Breath Condensate and in Serum of Asthmatic Patients: Relationship to Upper and Lower Airway Disease. AB - PURPOSE: Periostin is considered a biomarker for eosinophilic airway inflammation and have been associated with NSAID-Exacerbated Respiratory Disease (NERD) and chronic rhinosinusitis (CRS). In this study, we aimed to evaluate periostin in exhaled breath condensate (EBC) and in serum of patients with various asthma phenotypes. METHODS: The study included 40 asthmatic patients (22 with NERD) and 17 healthy controls. All the procedures (questionnaire, spirometry, FeNO, nasal swabs, EBC collecting, and blood sampling) were performed on the same day. Periostin concentrations were measured using an ELISA kit. RESULTS: Periostin was detected in EBC from 37 of 40 asthmatics and in 16 from 17 of controls. The concentration of periostin in EBC did not differ between the study groups and was not associated with NERD or asthma severity. However, the EBC periostin was significantly higher in asthmatics with CRS as compared to those without (3.1 vs 2 ng/mL, P=0.046). Patients with positive bacterial culture from nasal swabs had higher EBC periostin concentrations than those without (3.2 vs 2.1 ng/mL; P=0.046). The mean serum periostin level was higher in asthmatics with a 1-year history of exacerbation than in those without (3.2 vs 2.3 ng/mL, P=0.045). Asthmatics with skin manifestation of NSAIDs hypersensitivity had higher serum periostin levels as compared to those without (3.5 vs 2.3 ng/mL; P=0.03). CONCLUSIONS: EBC periostin levels seem to reflect intensity of upper airway disease in asthmatics, while serum levels of periostin are associated with asthma activity (exacerbations or FeNO) or NERD subphenotypes. PMID- 28102058 TI - Neonatal Immune State Is Influenced by Maternal Allergic Rhinitis and Associated With Regulatory T cells. AB - PURPOSE: Maternal influences contribute to the origin of allergic diseases, but the mechanisms are not clear. The current literature prompted the role of epigenetics in the development of allergic diseases. We sought to investigate the roles of regulatory T (Treg) cells and Forkhead box p3 (Foxp3) DNA methylation in the process of maternal transmission of allergic rhinitis (AR) susceptibility. METHODS: BALB/c female mice (AR mother) were sensitized by intraperitoneal injection of Dermatophagoides pteronyssinus (Der p) 1 on day 1 and 7. Then they mated with normal male mice on day 8. From day 21 to 28, the female mice were intranasal challenged with Der p 1 continuously. The normal controls were given with normal saline in the same way. On postnatal day 3, Female mice and their offspring were sacrificed to detect their histopathology in nasal mucosae, cytokines in sera of mother and spleen homogenates of offspring, Treg cells count, Foxp3 mRNA expressions, and Foxp3 DNA methylation levels in spleens. RESULTS: Compared with the normal controls, neonatal offspring of Der p 1 stimulated female mice (AR offspring) showed the elevation of interleukin (IL)-4 (P<0.01) and IL-17 (P<0.01), the submission of IL-10 (P<0.01) in spleen homogenates. Further, Treg cells count in AR offspring decreased remarkably compared with the normal offspring (P<0.01). Though the difference of Foxp3 DNA methylation level between AR offspring and normal control offspring was not obvious, correlation analysis demonstrated that there was significantly positive correlation between Foxp3 DNA methylation level of mother and that of offspring (r=0.803, P<0.01). CONCLUSIONS: Under the influence of Maternal AR, their neonatal offspring develop into T-helper type 2 (Th2) dominant immune state, which is closely associated with the recession of Treg cells. Foxp3 DNA methylation may be a mechanism responsible for that maternal effect but still need more studies to ensure. PMID- 28102060 TI - Usefulness of House Dust Mite Nasal Provocation Test in Asthma. AB - PURPOSE: We previously reported that the skin prick test was sensitive and the serum specific immunoglobulin E test was specific for predicting positive airway responses to house dust mites (HDMs) in patients with asthma. Because the nose and bronchus are one airway, the nasal provocation test would be more specific for predicting the bronchial responses to HDM than the skin test. METHODS: The allergy skin prick test and nasal and bronchial provocation tests using HDM (Dermatophagoides farinae) were performed in 41 young men (age, 19-28 years) who wanted military certification for asthma. The nasal responses to HDM was scored according to the severity of rhinorrhea, sneezing, and nose itching. RESULTS: The prevalence of a positive skin prick test to HDM did not significantly differ between patients with (n=24) and without (n=17) an early airway reaction (EAR; 79.2% vs 70.6%, P=0.534). However, the prevalence of a positive nasal test was significantly higher in the airway responders than in the others (37.5% vs 0%, P=0.005). The concordance of a positive response to the nasal test (kappa=0.332, P=0.004) but not to the skin prick test (kappa=0.091, P=0.529) was significant with an EAR. The diagnostic sensitivity of the nasal test (37.5%) was lower than that of the skin prick test (79.2%), but the specificity was higher (100% vs 29.4%). CONCLUSIONS: The skin prick test is more sensitive, whereas the nasal test is more specific and accurate, for predicting an EAR to HDM in patients with asthma. PMID- 28102059 TI - Vgamma1+ gammadeltaT Cells Are Correlated With Increasing Expression of Eosinophil Cationic Protein and Metalloproteinase-7 in Chronic Rhinosinusitis With Nasal Polyps Inducing the Formation of Edema. AB - PURPOSE: We have found that expression of gammadeltaT cells is increased in pathological mucosa of chronic rhinosinusitis with nasal polyps (CRSwNP) compared with normal nasal mucosa. This increase is correlated with the infiltration of eosinophils in CRSwNP. Here, we investigated the expression of gammadeltaT cells, inflammation and tissue remodeling factors as well as their probable relationships in different types of chronic rhinosinusitis (CRS) in China. METHODS: A total of 76 surgical tissue samples that included 43 CRSwNP samples (15 eosinophilic and 28 non-eosinophilic), 17 CRS samples without nasal polyps (CRSsNP), and 16 controls were obtained. Quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to measure the mRNA expression levels of Vgamma1+ gammadeltaT cells, Vgamma4+ gammadeltaT cells, eosinophil cationic protein (ECP), interleukin (IL)-8, transforming growth factor (TGF)-beta2, metalloproteinase (MMP)-7, tissue inhibitor of metalloproteinase (TIMP)-4 and hypoxia-inducible factor (HIF)-1alpha. Enzyme linked immunosorbent assay (ELISA) was used to measure the protein level of ECP and MMP-7 in CRSwNP. The eosinophils were counted and the level of edema was analyzed with HE staining. RESULTS: The mRNA expression levels of the Vgamma1 subset, ECP and MMP-7 were significantly increased in CRSwNP with histological characteristics of eosinophilic infiltration and edema. The expression of the Vgamma1 gene in CRSwNP correlated positively with the expression of both ECP and MMP-7. No significant decreases in the mRNA expression levels of TGF-beta2, TIMP-4 or HIF-1alpha were observed in the CRSwNP samples. The expression levels of Vgamma1 gene, ECP and MMP-7 were significantly increased in eosinophilic CRSwNP compared to non-eosinophilic CRSwNP. CONCLUSIONS: Our results suggest the associations between Vgamma1+ gammadeltaT cells, ECP and MMP-7 in CRSwNP, indicating that Vgamma1+ gammadeltaT cells can induce the eosinophilic inflammation, which has a further effect on the formation of edema. PMID- 28102062 TI - The Role of IL-17 in a Lipopolysaccharide-Induced Rhinitis Model. AB - PURPOSE: Lipopolysaccharide (LPS) is a cell wall component of Gram-negative bacteria and important for pro-inflammatory mediators. This study aimed to establish a rhinitis model using ovalbumin (OVA) and LPS in order to evaluate the role of interleukin (IL)-17 in the pathogenesis of an LPS-induced non eosionophilic rhinitis model. METHODS: Mice were divided into 4 groups and each group consisted of 10 mice (negative control group, allergic rhinitis model group, 1-MUg LPS treatment group, and 10-MUg LPS treatment group). BALB/c mice were sensitized with OVA and 1 or 10 MUg of LPS, and challenged intranasally with OVA. Multiple parameters of rhinitis were also evaluated to establish the LPS induced rhinitis model. IL-17 knockout mice were used to check if the LPS-induced rhinitis model were dependent on IL-17. Eosinophil and neutrophil infiltration, and mRNA and protein expression profiles of cytokine in nasal mucosa or spleen cell culture were evaluated using molecular, biochemical, histopathological, and immunohistological methods. RESULTS: In the LPS-induced rhinitis model, neutrophil infiltration increased in the nasal mucosa, and systemic and nasal IL 17 and interferon-gamma (IFN-gamma) levels also increased as compared with the OVA-induced allergic rhinitis model. These findings were LPS-dose-dependent. In IL-17 knockout mice, those phenotypes (neutrophil infiltration, IL-17, and IFN gamma) were reversed, showing IL-17 dependency of LPS-induced rhinitis. The expression of vascular endothelial growth factor (VEGF), an important mediator for inflammation and angiogenesis, decreased in IL-17 knockout mice, showing the relationship between IL-17 and VEGF. CONCLUSIONS: This study established an LPS induced rhinitis model dependent on IL-17, characterized by neutrophil infiltration and increased expression of IL-17. PMID- 28102061 TI - Clinical Diversity of Atopic Dermatitis: A Review of 5,000 Patients at a Single Institute. AB - PURPOSE: Atopic dermatitis (AD) is a chronic eczematous dermatitis that has a high prevalence and diverse clinical features. Although several hypotheses about its multifactorial pathogenesis have been suggested, the cause is not yet fully understood. A better understanding of the clinical features may helpful inelucidating the pathogenesis of AD. METHODS: This retrospective study analyzed the questionnaires, medical charts, and laboratory examination results of 5,000 patients diagnosed with AD at a single tertiary hospital in Korea. RESULTS: The demographics, allergic comorbidities, family history, severity, and treatment experiences of the patients were analyzed. Most of the patients were adults, 76.3% of whom were classified as havingan extrinsic type of AD. The mean eczema area and severity index (EASI) score was found to be 13.68, and adult patients were found to have higher severity than the other age groups. The anatomical involvements were different among the age groups, with more involvements of the head and neck in adults. The patients reported seasonal changes and stress as the factors that aggravated their symptoms the most. Topical steroids and oral cyclosporine were the most used medications at our clinic, whereas 10.1% of the patients underwent allergen-specific immunotherapy. CONCLUSIONS: This analysis of 5,000 patients would lead to a better understanding of various subtypes and diverse clinical features of AD in Koreans. Distinct characteristics were observed among different age groups; thus, treatment strategies may need to be differentiated accordingly. PMID- 28102063 TI - Sputum Inflammatory Mediators Are Increased in Aspergillus fumigatus Culture Positive Asthmatics. AB - Aspergillus fumigatus sensitization and culture in asthma are associated with disease severity and lung function impairment, but their relationship with airway inflammation is poorly understood. We investigated the profile of 24 sputum inflammatory mediators in A. fumigatus culture-positive or-negative moderate-to severe asthmatics. Fifty-two subjects were recruited from a single center. A. fumigatus was cultured from 19 asthmatics. Asthma control, symptom score, lung function, and sputum cell count were not significantly different between the asthmatics with and without a positive A. fumigatus culture. All of the sputum mediators were numerically increased in subjects with a positive versus negative sputum A. fumigatus culture. Sputum TNF-R2 was significantly elevated (P=0.03) and the mediator that best distinguished A. fumigatus culture-positive from culture-negative subjects (receiver-operator characteristic area under the curve 0.66 [95% CI: 0.51 to 0.82, P=0.045]). A. fumigates-positive culture in moderate to-severe asthma is associated with increased inflammatory sputum mediators. PMID- 28102064 TI - Fixed Food Eruption Caused by Actinidia arguta (Hardy Kiwi): A Case Report and Literature Review. AB - Fixed drug eruption (FDE) is a common hypersensitivity reaction characterized by recurrent, well-circumscribed, erythematous patches that arise at the same site as a result of systemic drug exposure. However, fixed food eruption (FFE), a lesion triggered by food ingestion, is a rare allergy that was first defined in 1996. Based on their anti-inflammatory and anti-oxidant properties, the fruit and leaves of Actinidia arguta, the hardy kiwi, are widely consumed across Korea, Japan, and China. This report describes the first case of FFE caused by hardy kiwi leaves, known as Daraesun in Korean, confirmed by oral provocation tests and skin biopsy. PMID- 28102065 TI - Comment on "Long-Term Effects of Diesel Exhaust Particles on Airway Inflammation and Remodeling in a Mouse Model" by Kim et al. PMID- 28102066 TI - Erratum: In Vitro Evaluation of Allergen Potencies of Commercial House Dust Mite Sublingual Immunotherapy Reagents. AB - This corrects the article on p. 124 in vol. 7, PMID: 25729619. PMID- 28102067 TI - Thy3A and Thy3B nodules: is surgery the best treatment? PMID- 28102068 TI - Robust Guar Gum/Cellulose Nanofibrils Multilayer Films with Good Barrier Properties. AB - The pursuit of sustainable functional materials requires development of materials based on renewable resources and efficient fabrication methods. Hereby, we fabricated all-polysaccharides multilayer films using cationic guar gum (CGG) and anionic cellulose nanofibrils (i.e., TEMPO-oxidized cellulose nanofibrils, TOCNs) through a layer-by-layer casting method. This technique is based on alternate depositions of oppositely charged water-based CGG and TOCNs onto laminated films. The resultant polyelectrolyte multilayer films were transparent, ductile, and strong. More importantly, the self-standing films exhibited excellent gas (water vapor and oxygen) and oil barrier performances. Another outstanding feature of these resultant films was their resistance to various organic solvents including methanol, acetone, N,N-dimethylacetamide (DMAc) and tetrahydrofuran (THF). The proposed film fabrication process is environmentally benign, cost-effective, and easy to scale-up. The developed CGG/TOCNs multilayer films can be used as a renewable material for industrial applications such as packaging. PMID- 28102069 TI - Tuning the Morphologies of MnO/C Hybrids by Space Constraint Assembly of Mn-MOFs for High Performance Li Ion Batteries. AB - Morphology controllable fabrication of electrode materials is of great significance but is still a major challenge for constructing advanced Li ion batteries. Herein, we propose a novel space constraint assembly approach to tune the morphology of Mn(terephthalic acid) (PTA)-MOF, in which benzonic acid was employed as a modulator to adjust the available MOF assembly directions. As a result, Mn(PTA)-MOFs with microquadrangulars, microflakes, and spindle-like microrods morphologies have been achieved. MnO/C hybrids with preserved morphologies were further obtained by self-sacrificial and thermal transformation of Mn(PTA)-MOFs. As anodes for Li ion batteries, these morphologies showed great influence on the electrochemical properties. Owing to the abundant porous structure and unique architecture, the MnO/C spindle-like microrods demonstrated superior electrochemical properties with a high reversible capacity of 1165 mAh g 1 at 0.3 A g-1, excellent rate capability of 580 mAh g-1 at 3 A g-1, and no considerable capacity loss after 200 cycles at 1 A g-1. This strategy could be extended to engineering the morphology of other MOF-derived functional materials in various structure-dependent applications. PMID- 28102070 TI - Well-Ordered Oxygen-Deficient CoMoO4 and Fe2O3 Nanoplate Arrays on 3D Graphene Foam: Toward Flexible Asymmetric Supercapacitors with Enhanced Capacitive Properties. AB - In this work, we report the development of well-ordered hydrogenated CoMoO4 (H CoMoO4) and hydrogenated Fe2O3 (H-Fe2O3) nanoplate arrays on 3D graphene foam (GF) and explore their practice application as binder-free electrodes in assembling flexible all-solid-state asymmetric supercapacitor (ASC) devices. Our results show that the monolithic 3D porous GF prepared by solution casting method using Ni foam template possesses large surface area, superior electrical conductivity, and sufficient surface functional groups, which not only facilitate in situ growth of CoMoO4 and Fe2O3 nanoplates but also contribute the double layer capacitance of the resultant supercapacitor. The well-ordered pseudocapacitive metal oxide nanoplate arrays standing up on 3D GF scaffold can provide efficient space and shorten the length for electrolyte diffusion from the outer to the inner region of the electrode material for Faradaic energy storage. Furthermore, one of our major findings is that the introduction of oxygen vacancies in CoMoO4 and Fe2O3 nanoplates by hydrogenation treatment can increase their electronic conductivity as well as improve their donor density and surface properties, which gives rise to a substantially improved electrochemical performance. Benefiting from the synergistic contributions of different components in the nanohybrid electrode, the resultant flexible ASC device with GF/H-CoMoO4 as the positive electrode and GF/H-Fe2O3 as the negative electrode achieves a wide operation voltage of 1.5 V and a maximum volumetric specific capacitance of 3.6 F cm-3, which is two times larger than that of the Ni/GF/CoMoO4//Ni/GF/Fe2O3 device (1.8 F cm-3), and the rate capability is up to 70% as the current density increases from 2 to 200 mA cm-3. Moreover, the Ni/GF/H CoMoO4//Ni/GF/H-Fe2O3 device also exhibits a high energy density of 1.13 mWh cm-3 and a high power density of 150 mW cm-3, good mechanical flexibility with the decrease in capacitance of less than 4% after being bent inward to different angles and inward to 90 degrees 200 times, and good cycling stability of 93.1% capacitance retention after 5000 cycles. PMID- 28102071 TI - Temperature-Induced Misfolding in Prion Protein: Evidence of Multiple Partially Disordered States Stabilized by Non-Native Hydrogen Bonds. AB - The structural basis of pathways of misfolding of a cellular prion (PrPC) into the toxic scrapie form (PrPSC) and identification of possible intermediates (e.g., PrP*) still eludes us. In this work, we have used a cumulative ~65 MUs of replica exchange molecular dynamics simulation data to construct the conformational free energy landscapes and capture the structural and thermodynamic characteristics associated with various stages of the thermal denaturation process in human prion protein. The temperature-dependent free energy surfaces consist of multiple metastable states stabilized by non-native contacts and hydrogen bonds, thus rendering the protein prone to misfolding. We have been able to identify metastable conformational states with high beta content (~30-40%) and low alpha-content (~10-20%) that might be precursors of PrPSC oligomer formation. These conformations also involve participation of the unstructured N-terminal domain, and its role in misfolding has been investigated. All the misfolded or partially unfolded states are quite compact in nature despite having large deviations from the native structure. Although the number of native contacts decreases dramatically at higher temperatures, the radius of gyration and number of intraprotein hydrogen bonds and contacts remain relatively unchanged, leading to stabilization of the misfolded conformations by non-native interactions. Our results are in good agreement with the established view that the C-terminal regions of the second and third helices (H2 and H3, respectively) of mammal prions might be the Achilles heels of their stability, while separation of B1-H1-B2 and H2-H3 domains seems to play a key role, as well. PMID- 28102072 TI - Ultrafast Dischargeable LiMn2O4 Thin-Film Electrodes with Pseudocapacitive Properties for Microbatteries. AB - LiMn2O4 (LMO) thin films are deposited on Si-based substrates with Pt current collector via multi-layer pulsed-laser-deposition technique. The LMO thin films feature unique kinetics that yield outstanding electrochemical cycling performance in an aqueous environment. At extremely high current densities of up to 1880 MUA cm-2 (~ 348 C), a reversible capacity of 2.6 MUAh cm-2 is reached. Furthermore, the electrochemical cycling remains very stable for over 3500 cycles with a remarkable capacity retention of 99.996% per cycle. We provide evidence of significant nondiffusion-controlled, pseudocapacitive-like storage contribution of the LMO electrode. PMID- 28102074 TI - Growth of a Large-Area, Free-Standing, Highly Conductive and Fully Foldable Silver Film with Inverted Pyramids for Wearable Electronics Applications. AB - A promising new concept is the application of flexible and foldable conductive film or paper for wearable electronics, in which silver nanowires, carbon nanotubes, and graphene are primarily used as conductive materials. However, their insufficient nanostructure contacts lead to poor electrical conductivity and mechanical fracture. Here, we demonstrate a simple and innovative strategy for fabricating a free-standing silver film with inverted pyramids by replicating pyramids on a textured silicon wafer under a hydrothermal reaction. In this unique structure, the inverted pyramids on the film surface can provide sufficient buffer space for a mechanically foldable and unfoldable cushion, and the continuous film ensures an uninterrupted electron transport pathway. As a result, the silver film with inverted pyramids can exhibit extremely high conductivity, with a sheet resistance as low as 2.55 * 10-3 Omega/sq, corresponding to an electrical conductivity of 4.2 * 105 S cm-1 for a 9.2-MUm thick film (67.7% of bulk silver's conductivity). Surprisingly, this film has outstanding mechanical folding stability, with less than a 0.5% deviation from the initial resistance after 35,000 repetitive folding and unfolding cycles when tested at the folding site. The film is free-standing, thin, flexible, foldable, and suitable for cutting and patterned growth, which makes it suitable for wearable electronics, showing a much wider range of applications than substrate based ones. PMID- 28102073 TI - Estimates of Health Impacts and Radiative Forcing in Winter Haze in Eastern China through Constraints of Surface PM2.5 Predictions. AB - The Gridpoint Statistical Interpolation (GSI) Three-Dimensional Variational (3DVAR) data assimilation system is extended to treat the MOSAIC aerosol model in WRF-Chem, and to be capable of assimilating surface PM2.5 concentrations. The coupled GSI-WRF-Chem system is applied to reproduce aerosol levels over China during an extremely polluted winter month, January 2013. After assimilating surface PM2.5 concentrations, the correlation coefficients between observations and model results averaged over the assimilated sites are improved from 0.67 to 0.94. At nonassimilated sites, improvements (higher correlation coefficients and lower mean bias errors (MBE) and root-mean-square errors (RMSE)) are also found in PM2.5, PM10, and AOD predictions. Using the constrained aerosol fields, we estimate that the PM2.5 concentrations in January 2013 might have caused 7550 premature deaths in Jing-Jin-Ji areas, which are 2% higher than the estimates using unconstrained aerosol fields. We also estimate that the daytime monthly mean anthropogenic aerosol radiative forcing (ARF) to be -29.9W/m2 at the surface, 27.0W/m2 inside the atmosphere, and -2.9W/m2 at the top of the atmosphere. Our estimates update the previously reported overestimations along Yangtze River region and underestimations in North China. This GSI-WRF-Chem system would also be potentially useful for air quality forecasting in China. PMID- 28102075 TI - Molecular Features of Humic Acids and Fulvic Acids from Contrasting Environments. AB - Insight in the molecular structure of humic acid (HA) and fulvic acid (FA) can contribute to identify relationships between their molecular properties, and further our quantitative abilities to model important organic matter functions such as metal complexation and association with mineral surfaces. Pyrolysis gas chromatography/mass spectrometry (Py-GC-MS) is used to compare the molecular composition of HA and FA. A systematic comparison was obtained by using samples from different environmental sources, including solid and aqueous samples from both natural and waste sources. The chemical signature of the pyrolysates was highly variable and no significant difference between HA and FA was found for major chemical groups, that is, carbohydrates, phenols, benzenes, and lignin phenols, together accounting for 62-96% of all quantified pyrolysis products. However, factor analysis showed that within each sample, FAs consistently differed from corresponding HAs in a larger contribution from mono- and polyaromatic hydrocarbons and heterocyclic hydrocarbons, together accounting for 3.9-44.5% of the quantified pyrolysis products. This consistent difference between FAs and corresponding HAs, suggests that their binding properties may, in addition to the carboxyl and phenolic groups, be influenced by the molecular architecture. Py-GC-MS may thus contribute to identify relationships between HA and FA binding- and molecular-properties. PMID- 28102077 TI - Boosting Hot-Electron Generation: Exciton Dissociation at the Order-Disorder Interfaces in Polymeric Photocatalysts. AB - Excitonic effects, arising from the Coulomb interactions between photogenerated electrons and holes, dominate the optical excitation properties of semiconductors, whereas their influences on photocatalytic processes have seldom been discussed. In view of the competitive generation of excitons and hot carriers, exciton dissociation is proposed as an alternative strategy for hot carrier harvesting in photocatalysts. Herein, by taking heptazine-based melon as an example, we verified that enhanced hot-carrier generation could be obtained in semicrystalline polymeric photocatalysts, which is ascribed to the accelerated exciton dissociation at the abundant order-disorder interfaces. Moreover, driven by the accompanying electron injection toward ordered chains and hole blocking in disordered chains, semicrystalline heptazine-based melon showed an ~7-fold promotion in electron concentration with respect to its pristine counterpart. Benefiting from these, the semicrystalline sample exhibited dramatic enhancements in electron-involved photocatalytic processes, such as superoxide radical production and selective alcohol oxidation. This work brightens excitonic aspects for the design of advanced photocatalysts. PMID- 28102078 TI - Peptide Selection for Targeted Protein Quantitation. AB - Targeted proteomics methods in their different flavors rely on the use of a few peptides as proxies for protein quantitation, which need to be specified either prior to or after data acquisition. However, in contrast with discovery methods that use all identified peptides for a given protein to estimate its abundance, targeted proteomics methods are limited in the number of peptides that are used for protein quantitation. Because only a few peptides per protein are acquired or extracted in targeted experiments, the selection of peptides that are used for targeted protein quantitation becomes crucial. Several rules have been proposed to guide peptide selection for targeted proteomics studies, which have generally been based on the amino acidic composition of the peptide sequences. However, the compliance of these rules does not imply that not-conformed peptides are not reproducibly generated nor do they guarantee that the selected peptides correctly represent the behavior of the protein abundance under different conditions. PMID- 28102079 TI - Medium-Sized Cyclic Ethers via Stevens [1,2]-Shift of Mixed Monothioacetal Derived Sulfonium Ylides: Application to Formal Synthesis of (+)-Laurencin. AB - A novel approach to medium-sized cyclic ethers was devised using a Stevens [1,2] shift of a sulfonium ylide derived from a readily accessible six-membered mixed monothioacetal precursor. The concise and efficient transformation offers a surprising degree of chirality transfer with observed retention of stereochemical configuration on the anomeric migrating carbon and has been applied as the key step in an enantioselective formal synthesis of (+)-laurencin. PMID- 28102076 TI - Kinobead and Single-Shot LC-MS Profiling Identifies Selective PKD Inhibitors. AB - ATP-competitive protein kinase inhibitors are important research tools and therapeutic agents. Because there are >500 human kinases that contain highly conserved active sites, the development of selective inhibitors is extremely challenging. Methods to rapidly and efficiently profile kinase inhibitor targets in cell lysates are urgently needed to discover selective compounds and to elucidate the mechanisms of action for polypharmacological inhibitors. Here, we describe a protocol for microgram-scale chemoproteomic profiling of ATP competitive kinase inhibitors using kinobeads. We employed a gel-free in situ digestion protocol coupled to nanoflow liquid chromatography-mass spectrometry to profile ~200 kinases in single analytical runs using as little as 5 MUL of kinobeads and 300 MUg of protein. With our kinobead reagents, we obtained broad coverage of the kinome, monitoring the relative expression levels of 312 kinases in a diverse panel of 11 cancer cell lines. Further, we profiled a set of pyrrolopyrimidine- and pyrazolopyrimidine-based kinase inhibitors in competition binding experiments with label-free quantification, leading to the discovery of a novel selective and potent inhibitor of protein kinase D (PKD) 1, 2, and 3. Our protocol is useful for rapid and sensitive profiling of kinase expression levels and ATP-competitive kinase inhibitor selectivity in native proteomes. PMID- 28102080 TI - N-Oleoylglycine-Induced Hyperphagia Is Associated with the Activation of Agouti Related Protein (AgRP) Neuron by Cannabinoid Receptor Type 1 (CB1R). AB - N-Acyl amino acids (NAAAs) are conjugate products of fatty acids and amino acids, which are available in animal-derived food. We compared the effects of N arachidonoylglycine (NAGly), N-arachidonoylserine (NASer), and N-oleoylglycine (OLGly) on in vivo food intake and in vitro [Ca2+]i of Agouti-related protein (AgRP) neurons to identify the role of these compounds in energy homeostasis. Hypothalamic neuropeptide expression and anxiety behavior in response to OLGly were also tested. To further identify the underlying mechanism of OLGly on food intake, we first detected the expression level of potential OLGly receptors. The cannabinoid receptor type 1 (CB1R) antagonist was cotreated with OLGly to analyze the activation of AgRP neuron, including [Ca2+]i, expression levels of PKA, CREB, and c-Fos, and neuropeptide secretion. Results demonstrated that only OLGly (intrapertioneal injection of 6 mg/kg) can induce hyperphagia without changing the expression of hypothalamic neuropeptides and anxiety-like behavior. Moreover, 20 MUM OLGly robustly enhances [Ca2+]i, c-Fos protein expression in AgRP neuron, and AgRP content in the culture medium. OLGly-induced activation of AgRP neuron was completely abolished by the CB1R-specific antagonist, AM251. In summary, this study is the first to demonstrate the association of OLGly-induced hyperphagia with activation of the AgRP neuron by CB1R. These findings open avenues for investigation and application of OLGly to modulate energy homeostasis. PMID- 28102082 TI - Characterization of the Molecular Mechanisms Underlying the Chronic Phase of Stroke in a Cynomolgus Monkey Model of Induced Cerebral Ischemia. AB - Stroke is one of the main causes of mortality and long-term disability worldwide. The pathophysiological mechanisms underlying this disease are not well understood, particularly in the chronic phase after the initial ischemic episode. In this study, a Macaca fascicularis stroke model consisting of two sample groups, as determined by MRI-quantified infarct volumes as a measure of the stroke severity 28 days after the ischemic episode, was evaluated using qualitative and quantitative proteomics analyses. By using multiple online multidimensional liquid chromatography platforms, 8790 nonredundant proteins were identified that condensed to 5223 protein groups at 1% global false discovery rate (FDR). After the application of a conservative criterion (5% local FDR), 4906 protein groups were identified from the analysis of cerebral cortex. Of the 2068 quantified proteins, differential proteomic analyses revealed that 31 and 23 were dysregulated in the elevated- and low-infarct-volume groups, respectively. Neurogenesis, synaptogenesis, and inflammation featured prominently as the cellular processes associated with these dysregulated proteins. Protein interaction network analysis revealed that the dysregulated proteins for inflammation and neurogenesis were highly connected, suggesting potential cross talk between these processes in modulating the cytoskeletal structure and dynamics in the chronic phase poststroke. Elucidating the long-term consequences of brain tissue injuries from a cellular prospective, as well as the molecular mechanisms that are involved, would provide a basis for the development of new potentially neurorestorative therapies. PMID- 28102081 TI - Deep Coverage of Global Protein Expression and Phosphorylation in Breast Tumor Cell Lines Using TMT 10-plex Isobaric Labeling. AB - Labeling peptides with isobaric tags is a popular strategy in quantitative bottom up proteomics. In this study, we labeled six breast tumor cell lysates (1.34 mg proteins per channel) using 10-plex tandem mass tag reagents and analyzed the samples on a Q Exactive HF Quadrupole-Orbitrap mass spectrometer. We identified a total of 8,706 proteins and 28,186 phosphopeptides, including 7,394 proteins and 23,739 phosphosites common to all channels. The majority of technical replicates correlated with a R2 >= 0.98, indicating minimum variability was introduced after labeling. Unsupervised hierarchical clustering of phosphopeptide data sets successfully classified the breast tumor samples into Her2 (epidermal growth factor receptor 2) positive and Her2 negative groups, whereas mRNA abundance did not. The tyrosine phosphorylation levels of receptor tyrosine kinases, phosphoinositide-3-kinase, protein kinase C delta, and Src homology 2, among others, were significantly higher in the Her2 positive than the Her2 negative group. Despite ratio compression in MS2-based experiments, we demonstrated the ratios calculated using an MS2 method are highly correlated (R2 > 0.65) with ratios obtained using MS3-based quantitation (using a Thermo Orbitrap Fusion mass spectrometer) with reduced ratio suppression. Given the deep coverage of global and phosphoproteomes, our data show that MS2-based quantitation using TMT can be successfully used for large-scale multiplexed quantitative proteomics. PMID- 28102083 TI - Development and characterization of morin hydrate loaded microemulsion for the management of Alzheimer's disease. AB - The aim of this study is to prepare and characterize intranasal delivery of morin hydrate loaded microemulsion for the management of Alzheimer's diseases. After intranasal delivery, brain and blood drug concentrations were found to be higher for optimized morin hydrate loaded microemulsion as compared to plain morin hydrate. Significant (P < 0.05) reduction in assessed pharmacodynamic parameters was observed after intranasal administration of morin hydrate loaded microemulsion as compared to sham control group. Daily chronic treatment with morin loaded microemulsion till the 21st day significantly increased the memory in wistar rats with STZ-induced dementia. PMID- 28102085 TI - 2008-2009 Conferences. PMID- 28102084 TI - Long-bone properties and development are affected by caponisation and breed in Polish fowls. AB - 1. The aim of the study was to investigate the effects of caponisation on bone development of males of two native breeds in Poland. 2. The weight, length and cross-sectional area of tibiae and femora were measured, densitometric measurements and tests of strength were determined and dimensions were calculated. 3. Breed and caponisation did not influence bone weight and length. Higher mechanical strength of the femur was found in entire males, mainly in the Polbar breed. Tibial strength was reduced in capons of the Green Partridge breed. Maximum elastic strength was greater in the Polbar, irrespective of caponisation. Bone cross-sectional area was influenced by breed, while caponisation reduced femoral bone mineral density in both breeds. 4. Caponisation thus increased growth rate but had adverse effects on bone development. 5. Caponisation had fewer negative effects in the Polbar than in the Greenleg Partridge. PMID- 28102087 TI - Relationship quality of persons with obstructive sleep apnoea syndrome. AB - In the field of sleep disorders, the quality of couple relationship is arousing increasing attention, given its implications for quality of life and treatment adherence. The aim of the present study was to evaluate relationship quality in a sample of treated or untreated patients with Obstructive Sleep Apnoea Syndrome. Eighty-seven patients were recruited in a hospital-based Centre for Sleep Medicine. Subjects were administered the Dyadic Adjustment Scale (DAS) to evaluate relationship quality, and the Epworth Sleepiness Scale (ESS). Apnoea hypopnoea indexes (AHI) were collected through nocturnal polysomnography or home testing with a portable monitoring device. Although the DAS average scores were similar to local normative values, relationship quality was significantly lower in the untreated patients when compared with the ones treated. The ESS scores showed a negative correlation with many DAS scores, whereas no significant correlation emerged for AHI. Such data suggest a significant impact of perceived sleep apnoea symptoms on marital satisfaction, even though in the absence of striking differences between the whole sample and the general population. PMID- 28102088 TI - Hyperandrogenism in a postmenopausal woman: a rare case of ectopic adrenal cortical gland. AB - Most frequent causes of androgenic manifestation are Cushing's syndrome, PCO, benign and malignant androgen-secreting non adrenal tumors and iatrogenic hirsutism. Hyperplasia or neoplasms of ectopic adrenocortical gland are rare. We report a case of a 63-year old female with hirsutism and alopecia. Laboratory data highlighted increased levels of androgens. Diagnostic imaging revealed normal morphology of adrenocortical gland and ovaries. In view of the clinical picture and suspected diagnosis of extra-adrenal cause, she underwent bilateral salpingo-oophorectomy. Histologic examination showed an ectopic adrenal gland with adenoma in the ovarian and peri-ovarian tissue. At six months of follow up, the patients has no sign of hyperandrogenism. In case of hyperandrogenism in postmenopausal women and in the absence of the adrenocortical gland abnormality, ovarian origin should be considered in the differential diagnosis. PMID- 28102090 TI - Upper extremity movement reliability and validity of the Kinect version 2. AB - PURPOSE: Studies have shown that marker-less motion detection systems, such as the first generation Kinect (Kinect 1), have good reliability and potential for clinical application. Studies of the second generation Kinect (Kinect 2) have shown a large range of accuracy relative to balance and joint localization; however, few studies have investigated the validity and reliability of the Kinect 2 for upper extremity motion. This investigation compared reliability and validity among the Kinect 1, Kinect 2 and a video motion capture (VMC) system for upper extremity movements. DESIGN: One healthy, adult male performed six upper extremity movements during two separate sessions. All movements were recorded on the Kinect 1, Kinect 2 and VMC simultaneously. Data were analyzed using MATLAB (Natick, MA), Microsoft Excel (Redmond, WA), and SPSS (Armonk, NY). RESULTS: Results indicated good reliability for both Kinects within a day; results between days were inconclusive for both devices due to the inability to exactly repeat the desired movements. Range of motion (ROM) magnitudes for both Kinects were different from the VMC, yet patterns of motion were very highly correlated for both devices. CONCLUSION: Simple transformations of Kinect data could bring magnitudes in line with those of the VMC, allowing the Kinects to be used in a clinical setting. Implications for Rehabilitation The clinical implications of the investigation support the notion that the Kinects could be used in the clinical setting if an understanding of their limitations exists. Using the Kinects to make assessments with a given data collection session is acceptable. Using the Kinects to make comparisons across different days such as before or after an intervention should be approached with caution. The Kinect 2 provides a more cost effective option compared to the VMC. Additionally, the Kinect is more portable, requires less time to set-up, and takes up less space, thus increasing its overall usability compared to the VMC. PMID- 28102089 TI - Disulfiram moderately restores impaired hepatic redox status of rats subchronically exposed to cadmium. AB - Examination of cadmium (Cd) toxicity and disulfiram (DSF) effect on liver was focused on oxidative stress (OS), bioelements status, morphological and functional changes. Male Wistar rats were intraperitoneally treated with 1 mg CdCl2/kg BW/day; orally with 178.5 mg DSF/kg BW/day for 1, 3, 10 and 21 days; and co-exposed from 22nd to 42nd day. The co-exposure nearly restored previously suppressed total superoxide dismutase (SOD), catalase (CAT) and increased glutathione peroxidase (GPx) activities; increased previously reduced glutathione reductase (GR) and total glutathione-S-transferase (GST) activities; reduced previously increased superoxide anion radical (O2.-) and malondialdehyde (MDA) levels; increased zinc (Zn) and iron (Fe), and decreased copper (Cu) (yet above control value), while magnesium (Mg) was not affected; and decreased serum alanine aminotransferases (ALT) levels. Histopathological examination showed signs of inflammation process as previously demonstrated by exposure to Cd. Overall, we ascertained partial liver redox status improvement, compared with the formerly Cd-induced impact. PMID- 28102091 TI - Obesity-related insulin resistance in adolescents: a systematic review and meta analysis of observational studies. AB - Insulin resistance is common among obese adolescents; however, the extent of this problem is not clear. We conducted a systematic review of PubMed-Medline, CINAHL, The Web of Science, EMBASE and Scopus for observational studies evaluating components defining insulin resistance (insulin, C-peptide and homeostatic model assessment-insulin resistance [HOMA-IR]) in obese adolescents (12-18 years) versus non-obese adolescents. Our systematic review and meta-analysis followed the PRISMA guidelines. Data were combined using a random-effects model and summary statistics were calculated using the mean differences (MDs). 31 studies were included (n = 8655). In 26 studies, fasting insulin levels were higher in obese adolescents when compared to non-obese adolescents (MD = 64.11 pmol/L, 95%CI 49.48-78.75, p < 0.00001). In three studies, fasting C-peptide levels were higher in obese adolescents when compared to non-obese adolescents (MD = 0.29 nmol/L, 95%CI 0.22-0.36, p < 0.00001). In 24 studies, HOMA-IR values were higher in obese adolescents when compared to non-obese adolescents (MD = 2.22, 95%CI 1.78-2.67, p < 0.00001). Heterogeneity of effects among studies was moderate to high. Subgroup analyses showed similar results to the main analyses. Circulating insulin and C-peptide levels and HOMA-IR values were significantly higher in obese adolescents compared to those non-obese. PMID- 28102092 TI - Survival of ileal pouch anal anastomosis constructed after colectomy or secondary to a previous ileorectal anastomosis in ulcerative colitis patients: a population based cohort study. AB - OBJECTIVES: Ileorectal anastomosis (IRA) affects bowel function, sexual function and reproduction less negatively than ileal pouch anal anastomosis (IPAA), the standard reconstruction after colectomy for ulcerative colitis (UC). In younger UC patients, IRA may have a role postponing pelvic surgery and IPAA. The aim of the present study was to investigate the survival of IPAA secondary to IRA compared to IPAA as primary reconstruction, as this has not previously been studied in UC. PATIENTS AND METHODS: All patients with UC diagnosis between 1960 and 2010 in Sweden were identified from the National Patient Registry. From this cohort, colectomized patients reconstructed with primary IPAA and patients reconstructed with IPAA secondary to IRA were identified. The survival of the IPAA was followed up until pouch failure, defined as pouchectomy and ileostomy or a diverting ileostomy alone. RESULTS: Out of 63,796 patients, 1796 were reconstructed with IPAA, either primarily (n = 1720) or secondary to a previous IRA (n = 76). There were no demographic differences between the groups, including length of follow-up (median 12.6 (IQR 6.7-16.6) years and 10.0 (IQR 3.5-15.9) years, respectively). Failure of the IPAA occurred in 103 (6.0%) patients with primary and in 6 (8%) patients after secondary IPAA (P = 0.38 log-rank). The 10 year pouch survival was 94% (95% CI 93-96) for primary IPAA and 92% (81-97) for secondary. CONCLUSIONS: Patients choosing IRA as primary reconstruction do not have an increased risk of failure of a later secondary IPAA in comparison with patients with primary IPAA. PMID- 28102093 TI - Cardiovascular safety and benefits of GLP-1 receptor agonists. AB - INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) constitute a class of drugs for the treatment of type 2 diabetes, and currently, six different GLP-1RAs are approved. Besides improving glycemic control, the GLP 1RAs have other beneficial effects such as weight loss and a low risk of hypoglycemia. Treatment with the GLP-1RA lixisenatide has been shown to be safe in patients with type 2 diabetes and recent acute coronary syndrome. Furthermore, liraglutide and semaglutide have been shown to reduce cardiovascular (CV) disease (CVD) risk in type 2 diabetes patients with established and/or high risk of CVD. The CV safety of the remaining GLP-1RAs in type 2 diabetes patients with established and/or high risk of CVD remains uncertain, but ongoing CV outcome trials (CVOTs) will elucidate this within a few years. Areas covered: The aim of this review is to provide an overview of the existing GLP-1RAs with a particular focus on their clinical effects on CV risk factors and their CV safety and benefits. Expert opinion: Data on the CV risks and benefits associated with GLP 1RA treatment in patients with type 2 diabetes and high risk of CVD are emerging and look promising (especially for liraglutide and semaglutide). Data from ongoing CVOTs will be crucial for the positioning of the individual GLP-1RAs in the treatment of patients with type 2 diabetes and high risk of CVD. However, the long-term CV safety and the potential of GLP-1RAs to prevent CVD in type 2 diabetes patients with less risk of CVD (e.g. newly diagnosed patients) remain uncertain. PMID- 28102094 TI - Tolerability of the oral fluoropyrimidine S-1 after hand-foot syndrome-related discontinuation of capecitabine in western cancer patients. PMID- 28102095 TI - Significance of the ionized calcium measurement to assess calcium status in osteopenic/osteoporosis postmenopausal outpatients. AB - INTRODUCTION: Evaluation of calcium status is important in the osteoporotic risk assessment. Although guidelines indicate total calcium (tCa) as first-line measurement, directly measured ionized calcium (m-iCa), considered as the gold standard, is more and more often required. Aim of this study is to evaluate the agreement between m-iCa, tCa and iCa calculated from a formula based on total calcium and albumin (c-iCa) in osteopenic/osteoporotic postmenopausal outpatients. METHODS: A total of 140 postmenopausal outpatients, 41 osteopenic (OPN) and 99 osteoporotic (OP) were enrolled. Levels of tCa, m-iCa, c-iCa, total protein and albumin, vitamin D (25-OHD), parathyroid hormone 1-84 (PTH), bone alkaline phosphatase, osteocalcin and serum collagen type 1 cross-linked C telopeptide (CTX) were also measured. RESULTS: There were no statistically significant differences between OPN and OP groups regarding values of tCa, m-iCa, and c-iCa, 25-OHD and PTH. However, OP women had lower levels of CTX (p < 0.05). A significant direct correlation between m-iCa and tCa (r = 0.60, p < 0.001) and c-iCa (r = 0.61, p < 0.001) was found. Women with isolated hyper-m-iCa had similar DEXA parameter levels respect to the other patients. However, one patient with confirmed primary hyperparathyroidism presented hyper-m-iCa versus normal tCa and c-iCa values. CONCLUSIONS: The use of tCa could be sufficient to characterize the calcium status in postmenopausal outpatients, but reflexive calcium testing strategy for m-iCa test is necessary to women presenting the low or high extremes of tCa levels, or in women with suspected PHPT. PMID- 28102096 TI - Cutoff score evaluation of undergraduate dental curriculum. AB - BACKGROUND AND OBJECTIVES: Exams at the Faculty of Dentistry (KAUFD) are usually constructed to match King Abdulaziz University (KAU) policy of a fixed 60% cutoff score, though they have never been tested or evaluated. The purpose of this study was to validate the cutoff scores of three final fifth-year written exams of the undergraduate Endodontic course to assess whether they were similar to KAU regulation using the Angoff rating method. DESIGN AND SETTINGS: This study was conducted between May 2014 and February 2015 at the Faculty of Dentistry, King Abdulaziz University. METHODS: Using the Angoff rating method, three final fifth year undergraduate Endodontic written exams were evaluated by four senior faculty members. RESULTS: The cutoff scores for exams 1, 2 and 3 were 57.4%, 62.9% and 63.1%, respectively. Adjusting the exams' cut off scores would cause changes in some students' results. CONCLUSIONS: Although the cutoff scores for all exams were close to 60%, slight deviation from the accepted cutoff score could definitely affect the students' results. Therefore, all exams should be validated before being given to students to certify that the cutoff score is credible and defensible. PMID- 28102097 TI - Familiar auditory sensory training in chronic traumatic brain injury: a case study. AB - PURPOSE: The evaluation and treatment for patients with prolonged periods of seriously impaired consciousness following traumatic brain injury (TBI), such as a vegetative or minimally conscious state, poses considerable challenges, particularly in the chronic phases of recovery. METHOD: This blinded crossover study explored the effects of familiar auditory sensory training (FAST) compared with a sham stimulation in a patient seven years post severe TBI. Baseline data were collected over 4 weeks to account for variability in status with neurobehavioral measures, including the Disorders of Consciousness scale (DOCS), Coma Near Coma scale (CNC), and Consciousness Screening Algorithm. Pre stimulation neurophysiological assessments were completed as well, namely Brainstem Auditory Evoked Potentials (BAEP) and Somatosensory Evoked Potentials (SSEP). RESULTS: Results revealed that a significant improvement in the DOCS neurobehavioral findings after FAST, which was not maintained during the sham. BAEP findings also improved with maintenance of these improvements following sham stimulation as evidenced by repeat testing. CONCLUSIONS: The results emphasize the importance for continued evaluation and treatment of individuals in chronic states of seriously impaired consciousness with a variety of tools. Further study of auditory stimulation as a passive treatment paradigm for this population is warranted. Implications for Rehabilitation Clinicians should be equipped with treatment options to enhance neurobehavioral improvements when traditional treatment methods fail to deliver or maintain functional behavioral changes. Routine assessment is crucial to detect subtle changes in neurobehavioral function even in chronic states of disordered consciousness and determine potential preserved cognitive abilities that may not be evident due to unreliable motor responses given motoric impairments. Familiar Auditory Stimulation Training (FAST) is an ideal passive stimulation that can be supplied by families, allied health clinicians and nursing staff of all levels. PMID- 28102099 TI - 30th Anniversary of the National Nursing Research Roundtable. PMID- 28102098 TI - A Randomized Double-Blind Placebo-Controlled Trial of Fruit and Vegetable Concentrates on Intermediate Biomarkers in Head and Neck Cancer. AB - BACKGROUND: Head and neck cancer (HNC) patients are at an increased risk for developing second primary tumors (SPTs). Diets rich in fruits and vegetables (FVs) may lower HNC risk. FV concentrates may offer a potential alternative to increasing FV intake. METHODS: We conducted a randomized, double-blind, placebo controlled trial to evaluate whether Juice PLUS+ (JP; a commercial product with multiple FV concentrates) has an effect on p27 and Ki-67, biomarkers associated with the risk of SPTs. During 2004-2008, we randomized 134 HNC patients to 12 weeks of JP (n = 72) or placebo (n = 62). Oral cavity mucosal biopsies and whole blood were obtained at baseline and after 12 weeks. All participants were given the opportunity to receive JP for 5 years following the end of the intervention period, and they were followed yearly for the development of SPTs. RESULTS: After 12 weeks, patients on JP had significantly higher serum alpha-carotene ( P = .009), beta-carotene ( P < .0001), and lutein ( P = .003) but did not differ significantly in p27 ( P = .23) or Ki-67 ( P = .95). JP use following the initial 12-week trial was not significantly associated with SPT prevention. CONCLUSIONS: Despite increased serum micronutrient levels, our results do not suggest a clinical benefit of JP in HNC patients. Future studies should focus on longer intervention periods and/or modified supplement formulations with demonstrated chemopreventive properties. PMID- 28102100 TI - A systematic review: the influence of real time feedback on wheelchair propulsion biomechanics. AB - BACKGROUND: Clinical guidelines recommend that, in order to minimize upper limb injury risk, wheelchair users adopt a semi-circular pattern with a slow cadence and a large push arc. OBJECTIVES: To examine whether real time feedback can be used to influence manual wheelchair propulsion biomechanics. REVIEW METHODS: Clinical trials and case series comparing the use of real time feedback against no feedback were included. A general review was performed and methodological quality assessed by two independent practitioners using the Downs and Black checklist. The review was completed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. RESULTS: Six papers met the inclusion criteria. Selected studies involved 123 participants and analysed the effect of visual and, in one case, haptic feedback. Across the studies it was shown that participants were able to achieve significant changes in propulsion biomechanics, when provided with real time feedback. However, the effect of targeting a single propulsion variable might lead to unwanted alterations in other parameters. Methodological assessment identified weaknesses in external validity. CONCLUSIONS: Visual feedback could be used to consistently increase push arc and decrease push rate, and may be the best focus for feedback training. Further investigation is required to assess such intervention during outdoor propulsion. Implications for Rehabilitation Upper limb pain and injuries are common secondary disorders that negatively affect wheelchair users' physical activity and quality of life. Clinical guidelines suggest that manual wheelchair users should aim to propel with a semi-circular pattern with low a push rate and large push arc in the range in order to minimise upper limbs' loading. Real time visual and haptic feedback are effective tools for improving propulsion biomechanics in both complete novices and experienced manual wheelchair users. PMID- 28102101 TI - Thyroid in pregnancy: From physiology to screening. AB - Thyroid hormones are crucial for the growth and maturation of many target tissues, especially the brain and skeleton. During critical periods in the first trimester of pregnancy, maternal thyroxine is essential for fetal development as it supplies thyroid hormone-dependent tissues. The ontogeny of mature thyroid function involves organogenesis, and maturation of the hypothalamus, pituitary and the thyroid gland; and it is almost complete by the 12th-14th gestational week. In case of maternal hypothyroidism, substitution with levothyroxine must be started in early pregnancy. After the 14th gestational week, fetal brain development may already be irreversibly affected by lack of thyroid hormones. The prevalence of manifest hypothyroidism in pregnancy is about 0.3-0.5%. The prevalence of subclinical hypothyroidism varies between 4 and 17%, strongly depending on the definition of the upper TSH cutoff limit. Hyperthyroidism occurs in 0.1-1% of all pregnancies. Positivity for antibodies against thyroid peroxidase (TPOAb) is common in women of childbearing age with an incidence rate of 5.1-12.4%. TPOAb-positivity may be regarded as a manifestation of a general autoimmune state which may alter the fertilization and implantation processes or cause early missed abortions. Women positive for TPOAb are at a significant risk of developing hypothyroidism during pregnancy and postpartum. Laboratory diagnosis of thyroid dysfunction during pregnancy is based upon serum TSH concentration. TSH in pregnancy is physiologically lower than the non-pregnant population. Results of multiple international studies point toward creation of trimester-specific reference intervals for TSH in pregnancy. Screening for hypothyroidism in pregnancy is controversial and its implementation varies from country to country. Currently, the case-finding approach of screening high-risk women is preferred in most countries to universal screening. However, numerous studies have shown that one-third to one-half of women with thyroid disorders escape the case-finding approach. Moreover, the universal screening has been shown to be more cost-effective. Screening for thyroid disorders in pregnancy should include assessment of both TSH and TPOAb, regardless of the screening approach. This review summarizes the current knowledge on physiology of thyroid hormones in pregnancy, causes of maternal thyroid dysfunction and its effects on pregnancy course and fetal development. We discuss the question of case-finding versus universal screening strategies and we display an overview of the analytical methods and their reference intervals in the assessment of thyroid function and thyroid autoimmunity in pregnancy. Finally, we present our results supporting the implementation of universal screening. PMID- 28102104 TI - Fasting urinary calcium to creatinine ratio for the evaluation of calcium nephrolithiasis in adults. PMID- 28102102 TI - Impact of Thoracic Endovascular Aortic Repair on Pulsatile Circumferential and Longitudinal Strain in Patients With Aneurysm. AB - PURPOSE: To quantify both pulsatile longitudinal and circumferential aortic strains before and after thoracic endovascular aortic repair (TEVAR), potentially clarifying TEVAR-related complications. METHODS: This retrospective study assessed the impact of TEVAR on pulsatile aortic strains through custom developed software and cardiac-gated computed tomography imaging of 8 thoracic aneurysm patients (mean age 71.0+/-8.2 years; 6 men) performed before TEVAR and during follow-up (median 0.1 months, interquartile range 0.1-5.8). Lengths of the ascending aorta, the aortic arch, and the descending aorta were measured. Diameters and areas were computed at the sinotubular junction, brachiocephalic trunk, left subclavian artery, and the celiac trunk. Pulsatile longitudinal and circumferential strains were quantified as systolic increments of length and circumference divided by the corresponding diastolic values. RESULTS: Average pulsatile longitudinal strain ranged from 1.4% to 7.1%, was highest in the arch (p<0.001), and increased after TEVAR by 77% in the arch (7.1%+/-2.5% vs 12.5%+/ 5.1%, p=0.04) and by 69% in the ascending aorta (5.6+/-2.3% vs 9.4+/-4.4%, p=0.06). Average pulsatile circumferential strain ranged from 3.6% to 5.0% before TEVAR and did not differ significantly throughout the thoracic aorta; there was a nonsignificant increase after TEVAR at the unstented sinotubular junction (5.0%+/ 1.4% vs 6.3%+/-1.0%, p=0.18), with a significant increase at the celiac trunk (3.6%+/-1.8% vs 6.2%+/-1.8%, p=0.02). Pulsatile circumferential strains within stented segments were deemed unreliable due to image artifacts. CONCLUSION: TEVAR was associated with an increase of pulsatile longitudinal strains (in the arch) and circumferential strains (at the celiac trunk) in unstented aortic segments. These observations suggest increased pulsatile wall stress after TEVAR in segments adjacent to the device, which may contribute to the understanding of stent-graft-related complications such as retrograde dissection, aneurysm formation, and rupture. PMID- 28102105 TI - Pitching form determines probabilistic structure of errors in pitch location. AB - According to recent motor control studies, it is important to know probabilistic structure of his/her own motor errors to choose an optimal motor plan (i.e., where you aim at) to maximise the expected gain. In this study, we questioned if pitching form determines the probabilistic structure of pitching errors in baseball pitchers. Eighteen collegiate baseball pitchers with various pitching forms including right- and left-handed overarm, sidearm and underarm throwers threw 100 pitches aiming at a target located 90 cm above the ground. Two dimensional distribution of pitch location was fitted by using bivariate normal distribution and 95% confidence ellipse was calculated. In order to quantify the pitching form, the direction of the throwing arm trajectory in frontal plane was calculated. The direction of the long axis was dependent on each participant's pitching form (e.g., right overarm pitchers pitched along a right-up-left-down ellipse and left overarm pitchers pitched along a left-up-right-down ellipse). This was confirmed by circular correlation analysis (P = 0.98). These results suggest that different mechanisms, potentially errors in pitching mechanics and errors in ball release timing, might contribute to errors along the long axis and those along the short axis. PMID- 28102106 TI - Comparison of disability and quality of life between patients with pediatric and adult onset paraplegia. AB - OBJECTIVE: To investigate the factors that affect disability and quality of life in patients with spinal cord injuries (SCIs) and to compare the degree of disability and quality of life in patients with SCI according to over and under 18 years of age when their injury occurred. DESIGN: Cohort study. SETTING: Two academic hospitals in Istanbul, Turkey. PARTICIPANTS: Forty patients with SCI were included in this study. Group 1 included 20 patients with SCI who were younger than 18 years of age when their injury occurred, Group 2 included 20 patients who were older than 18 years of age when their injury occurred. OUTCOME MEASURES: Patients' demographics, duration of SCI and degree of disability were assessed using the Craig Handicap Assessment and Reporting Technique (CHART). Quality of life was assessed using the World Health Organization Quality of Life Scale Short Form (WHOQOL-Bref). Depression was assessed using the Beck Depression Inventory (BDI). RESULTS: Although there was no significant difference between the BDI scores and CHART scores of the two groups, environment domain scores in the WHOQOL-Bref were significantly higher in Group 2 than in Group 1 (P<0.05). No significant correlation was found between age of SCI onset, disease duration, ASIA scores, depression scores, total CHART scores for all patients. CONCLUSION: Adaptation to environment was significantly better in those who suffered SCI during adulthood than in pediatric patients with SCI. Disability level was not associated with age of disease onset, disease duration, neurological status, depression level. PMID- 28102107 TI - Occupational, dietary, and other risk factors for myelodysplastic syndromes in Western Greece. AB - PURPOSE: We have observed an increasing incidence of myelodysplastic syndromes (MDS) in the geographic area of Western Greece during the past two decades. The objective of this study was to investigate potential risk factors for the manifestation of MDS in this area of Greece. METHODS: A hospital-based case control study was conducted in the public hospitals of the region. Participants were interviewed based on a questionnaire regarding demographics, occupational exposures, smoking, alcohol consumption, dietary, and domestic factors. RESULTS: A total of 228 individuals (126 cases, 102 controls) were recruited in this study. Univariate analysis showed that risk of MDS was associated with a family history of hematologic malignancy or solid tumor, exposure to pesticides, insecticides, herbicides, increased weekly intake of meat and eggs, and increased alcohol intake, whereas fruit intake had a protective effect. Analysis by pesticide ingredient showed a weak association of exposure to paraquat and glyphosate with the occurrence of MDS. Multivariate analysis showed that independent risk factors for the manifestation of MDS were family history of solid tumor (OR 2.47, 95% CI 1.32-4.65), meat intake for >=5 days/week (OR 2.67, 95% CI 1.05-6.80) and exposure to pesticides (OR 3.25, 95% CI 1.73-6.11). CONCLUSIONS: Exposure to pesticides is a major risk factor of MDS in Western Greece. Family history of solid tumor and increased meat intake also appear to play a role in the pathogenesis of MDS. Public health authorities should implement policies to advise and protect farmers from the harmful effects of agrochemicals. Emphasis should also be given to health promotion advice including healthy eating. PMID- 28102108 TI - Readiness to change as a moderator of therapy outcome in patients with somatoform disorders. AB - OBJECTIVE: A considerable amount of patients with somatoform disorders do not benefit from psychotherapy as much as expected. Our aim was to explore whether readiness to change moderates the relationship between the intensity of symptoms and therapy outcome in the early stages of psychotherapy. METHOD: 144 patients with somatoform disorders received an outpatient cognitive-behavioural intervention. Symptom intensity was measured with the Screening for Somatoform Disorders (SOMS-7). For readiness to change, a German modification of the Pain Stages of Change Questionnaire (PSOCQ) was used, which comprises four subscales (FF-STABS). Regression analyses were carried out, with baseline symptoms and the readiness to change subscales as predictors and symptom reduction as the outcome variable. RESULTS: Moderation analyses revealed significant interaction effects between baseline symptoms and the precontemplation subscale, as well as between baseline symptoms and the action subscale. For preparation and maintenance, no significant interaction effects were found. CONCLUSIONS: The results suggest that readiness to change is a variable that can be used to differentiate between patients, with low precontemplation and action scores indicating a better chance for positive outcome, even with high initial impairment. Rather than using readiness to change sum scores, the sub-aspects of this construct should be the subject of future research. PMID- 28102109 TI - Epigenetic regulation of RGS2 (Regulator of G-protein signaling 2) in chemoresistant ovarian cancer cells. AB - Regulator of G-protein signaling 2 (RGS2) is a GTPase-activating protein functioning as an inhibitor of G-protein coupled receptors (GPCRs). RGS2 dysregulation was implicated in solid tumour development and RGS2 downregulation has been reported in prostate and ovarian cancer progression. However, the molecular mechanism by which RGS2 expression is suppressed in ovarian cancer remains unknown. The expression and epigenetic regulation of RGS2 in chemosensitive and chemoresistant ovarian cancer cells were determined by qRT-PCR and chromatin immunoprecipitation assays, respectively. In the present study, the molecular mechanisms contributing to the loss of RGS2 expression were determined in ovarian cancer. The data indicated that suppression of RGS2 gene in chemoresistant ovarian cancer cells, in part, due to accumulation of histone deacetylases (HDACs) and DNA methyltransferase I (DNMT1) at the promoter region of RGS2. Inhibition of HDACs or DNMTs significantly increases RGS2 expression. These results suggest that epigenetic changes in histone modifications and DNA methylation may contribute to the loss of RGS2 expression in chemoresistant ovarian cancer cells. The results further suggest that class I HDACs and DNMT1 contribute to the suppression of RGS2 during acquired chemoresistance and support growing evidence that inhibition of HDACs/DNMTs represents novel therapeutic approaches to overcome ovarian cancer chemoresistance. PMID- 28102110 TI - Evaluation of the antidepressant- and anxiolytic-like effects of a hydrophilic extract from the green seaweed Ulva sp. in rats. AB - OBJECTIVES: The green seaweed Ulva sp. contains a large amount of ulvans, a family of sulphated polysaccharides. The present study was designed to investigate in rats the antidepressant- and anxiolytic-like effects of a hydrophilic extract of Ulva sp. (MSP) containing about 45% of ulvans. METHODS: After a 14-day administration of MSP at doses of 10, 20 and 40 mg/kg/day, 48 and 60 male adult Wistar rats were respectively tested in the elevated plus-maze (EPM) and the forced swimming test (FST). In the FST, MSP effects were compared to the reference antidepressant drug imipramine (IMI) (10 mg/kg/day). Acute and sub-chronic toxicities of the extract were also assessed in male and female rats following OECD guidelines. RESULTS: MSP treatment did not modify anxiety-related behaviour in the EPM. In contrast, MSP induced a dose-dependent reduction of immobility behaviour in the FST. At the highest tested dose of 40 mg/kg, MSP displayed a significant antidepressant-like effect similar to IMI. MSP did not modify the exploratory behaviour of rats in the open field test and did not produce any toxic effect. DISCUSSION: MSP may potentially represent a good adjunct or alternative to existing antidepressant therapeutics. Further studies are necessary to confirm the mechanism of action of MSP and its modulation of brain functioning. PMID- 28102111 TI - Applying relationship anecdotes paradigm interviews to study client-therapist relationship narratives: Core conflictual relationship theme analyses. AB - OBJECTIVE: We describe client-therapist relational narratives collected in relationship anecdotes paradigm (RAP) interviews during psychotherapy and the application of the core conflictual relationship theme (CCRT) method. Changes in clients' and therapists' CCRT in relation to each other are examined and associations between their CCRTs and self-reported ruptures and repairs are explored. METHOD: Sixty-seven clients and 27 therapists underwent RAP interviews and completed self-report rupture and repair items at early, middle, and late psychodynamic psychotherapy. Client-therapist relationship narratives were rated on the CCRT and the relational interplay within dyads was explored qualitatively. RESULTS: CCRT changes from early to late therapy showed that with time clients perceived the therapist (RO) and the self (RS) more positively, and the therapist perceived the self (RS) less negatively. Some associations were found between tension in the session and clients' and therapists' negative RO and RS. Therapists' reports of alliance repairs were associated with positive RO and RS. CONCLUSIONS: Relational narratives that clients and therapists tell in RAP interviews about meaningful interactions between them, enhance our understanding of clients' and therapists' inner experiences during interpersonal dances in the therapeutic relationship. Limitations and directions for future research are discussed, and implications for training are suggested. PMID- 28102112 TI - Dutiful daughters: HIV/AIDS, moral pragmatics, female citizenship and structural violence among Devadasis in northern Karnataka, India. AB - Decades of research have documented how sex workers worldwide, particularly female sex workers (FSWs), shoulder a disproportionate burden of the HIV epidemic. In India, although a substantial progress has been made in controlling the epidemic, its prevalence among FSWs and the Devadasis (also called traditional sex workers) in northern Karnataka is still significantly high. On the other hand, much of the HIV prevention research has focused on their mapping and size estimation, typologies, bio-behavioural surveillance, condom use and other prevention technologies. In this article, drawing on critical theoretical perspectives, secondary historical sources and in-depth interviews, we unravel wider social, cultural and political economic complexities surrounding the lives of Devadasis, and specifically illuminate the moral pragmatics that shed light on their entry into sex trade and vulnerability to HIV. Findings from this research are extremely important since while much is known about Devadasis in social sciences and humanities, relatively little is known about the complexities of their lives within public health discourses related to HIV. Our work has direct implications for ongoing HIV prevention and health promotion efforts in the region and beyond. PMID- 28102113 TI - Comparison of the effects on dynamic balance and aerobic capacity between objective and subjective methods of high-intensity robot-assisted gait training in chronic stroke patients: a randomized controlled trial. AB - BACKGROUND: Robot-assisted gait training (RAGT) is effective for improving dynamic balance and aerobic capacity, but previous RAGT method does not set suitable training intensity. Recently, high-intensity treadmill gait training at 70% of heart rate reserve (HRR) was used for improving aerobic capacity and dynamic balance. PURPOSE: This study was designed to compare the effectiveness between objective and subjective methods of high-intensity RAGT for improving dynamic balance and aerobic capacity in chronic stroke. METHODS: Subjects were randomly allocated into experimental (n = 17) and control (n = 17) groups. The experimental group underwent high-intensity RAGT at 70% of HRR, whereas the control group underwent high-intensity RAGT at an RPE of 15. Both groups received their assigned training for 30 min per session, 3 days per week for 6 weeks. All subjects also received an additional 30 min of conventional physical therapy. Before and after each of the 18 sessions, the dynamic balance and aerobic capacity of all subjects were evaluated by a blinded examiner. RESULTS: After training, Berg Balance Scale (BBS) and Timed Up and Go Test scores, VO2max, and VO2max/kg were significantly increased in both groups (p < 0.05). These variables in experimental group were significantly greater than control group. However, the BBS score was not significantly different between both groups. All subjects completed high-intensity RAGT. No adverse effect of training was observed in both groups. CONCLUSION: High-intensity RAGT at 70% of HRR significantly improved dynamic balance and aerobic capacity more than RAGT at RPE of 15. These results suggest that high-intensity RAGT at 70% of HRR is safe and effective for improving dynamic balance and aerobic capacity in chronic stroke. PMID- 28102114 TI - GIW and InCoB are advancing bioinformatics in the Asia-Pacific. AB - GIW/InCoB2015 the joint 26th International Conference on Genome Informatics (GIW) and 14th International Conference on Bioinformatics (InCoB) held in Tokyo, September 9-11, 2015 was attended by over 200 delegates. Fifty-one out of 89 oral presentations were based on research articles accepted for publication in four BMC journal supplements and three other journals. Sixteen articles in this supplement and six articles in the BMC Systems Biology GIW/InCoB2015 Supplement are covered by this introduction. The topics range from genome informatics, protein structure informatics, image analysis to biological networks and biomarker discovery. PMID- 28102116 TI - The Role of Participant Responsiveness on a Socio-Emotional Learning Program. AB - The present study set out to evaluate participant responsiveness, one of the main dimensions of implementation quality, in a Socio-Emotional Learning after-school program using Educational Dance activities, Experiencing Emotions, and also to understand its influence on program outcomes. The sample involved 98 middle school Portuguese pupils, 53 of whom participated in the program and 45 in after school control sessions. Outcome measures included pre-test and post-test questionnaires of pupils' socio-emotional skills, well-being and school engagement. A self-report item measured pupils' satisfaction at the end of the program, and a checklist measuring attendance and homework completion was filled in by the facilitator at each session of the program and control condition. Results revealed (1) high levels of pupils' satisfaction and attendance, and a medium-high level of homework completion towards the program; (2) that pupils' higher attendance rate in the program predicted higher results in the self management (p = .04, d = .57; p = .003, d = .87) and social awareness (p = .04, d = .59) SEL domains, emotional (p = .02, d = .67) and psychological (p = .009, d = .76) well-being and school engagement (p = .04, d = .56); (3) that pupils' higher rate of homework completion in the program predicted higher results in the relationship skills SEL area (p = .04, d = .59) and in school engagement (p = .005, d = 1.50); (4) that pupils' from the control condition higher rates of homework completion also predicted better school engagement (p = .006, d = .88). Implications for research and practice are discussed. PMID- 28102117 TI - Efficacy of an Intervention Program to Improve Employability of University Students. AB - In the current socioeconomic situation, the need to improve employability of potential workers is especially relevant. The aim of this study was to evaluate the efficacy of an intervention program focusing on improving employability of university students. To do this, a two-group study was designed: one group undertook the intervention program and the other group were used for comparison. Two measurements were taken at different times (pre-intervention and post intervention). The sample consisted of 271 university students. The results show that the group that underwent the intervention program improved their perceived employability F(1, 269) = 17.49, p < .001; eta2 = .06, openness to learning F(1, 269) = 4.24, p < .05; eta2 = .02, self-efficacy for labor market insertion F(1, 269) = 75.70, p < .001; eta2 = .22 and for teamwork F(1, 269) = 39.43, p < .001; eta2 = .13, and their knowledge of employment resources F(1, 269) = 512.89, p < .001; eta2 = .66 compared to the group that did not. Furthermore, there was a high level of satisfaction of participants with the intervention program. PMID- 28102118 TI - Myeloid Cells in Asthma. AB - Asthma is a heterogeneous chronic inflammatory disorder of the airways, and not surprisingly, many myeloid cells play a crucial role in pathogenesis. Antigen presenting dendritic cells are the first to recognize the allergens, pollutants, and viruses that are implicated in asthma pathogenesis, and subsequently initiate the adaptive immune response by migrating to lymph nodes. Eosinophils are the hallmark of type 2 inflammation, releasing toxic compounds in the airways and contributing to airway remodeling. Mast cells and basophils control both the early- and late-phase allergic response and contribute to alterations in smooth muscle reactivity. Finally, relatively little is known about neutrophils and macrophages in this disease. Although many of these myeloid cells respond well to treatment with inhaled steroids, there is now an increasing armamentarium of targeted biologicals that can specifically eliminate only one myeloid cell population, like eosinophils. It is only with those new tools that we will be able to fully understand the role of myeloid cells in chronic asthma in humans. PMID- 28102119 TI - Glutathione and Glutathione Transferase Omega 1 as Key Posttranslational Regulators in Macrophages. AB - Macrophage activation during phagocytosis or by pattern recognition receptors, such as Toll-like receptor 4, leads to the accumulation of reactive oxygen species (ROS). ROS act as a microbicidal defense mechanism, promoting clearance of infection, allowing for resolution of inflammation. Overproduction of ROS, however, overwhelms our cellular antioxidant defense system, promoting oxidation of protein machinery, leading to macrophage dysregulation and pathophysiology of chronic inflammatory conditions, such as atherosclerosis. Here we will describe the role of the antioxidant tripeptide glutathione (GSH). Until recently, the binding of GSH, termed glutathionylation, was only considered to maintain the integrity of cellular components, limiting the damaging effects of an aberrant oxidative environment. GSH can, however, have positive and negative regulatory effects on protein function in macrophages. GSH regulates protein secretion, driving tumor necrosis factor alpha release, hypoxia-inducible factor-1alpha stability, STAT3 phosphorylation, and caspase-1 activation in macrophages. GSH also plays a role in host defense against Listeria monocytogenes, modifying the key virulence protein PrfA in infected macrophages. We will also discuss glutathione transferase omega 1, a deglutathionylating enzyme recently shown to play a role in many aspects of macrophage activity, including metabolism, NF kappaB activation, and cell survival pathways. Glutathionylation is emerging as a key regulatory event in macrophage biology that might be susceptible to therapeutic targeting. PMID- 28102120 TI - Intestinal Mononuclear Phagocytes in Health and Disease. AB - The intestine is the tissue of the body with the highest constitutive exposure to foreign antigen and is also a common entry portal for many local and systemic pathogens. Therefore, the local immune system has the unenviable task of balancing efficient responses to dangerous pathogens with tolerance toward beneficial microbiota and food antigens. As in most tissues, the decision between tolerance and immunity is critically governed by the activity of local myeloid cells. However, the unique challenges posed by the intestinal environment have necessitated the development of several specialized mononuclear phagocyte populations with distinct phenotypic and functional characteristics that have vital roles in maintaining barrier function and immune homeostasis in the intestine. Intestinal mononuclear phagocyte populations, comprising dendritic cells and macrophages, are crucial for raising appropriate active immune responses against ingested pathogens. Recent technical advances, including microsurgical approaches allowing collection of cells migrating in intestinal lymph, intravital microscopy, and novel gene-targeting approaches, have led to clearer distinctions between mononuclear phagocyte populations in intestinal tissue. In this review, we present an overview of the various subpopulations of intestinal mononuclear phagocytes and discuss their phenotypic and functional characteristics. We also outline their roles in host protection from infection and their regulatory functions in maintaining immune tolerance toward beneficial intestinal antigens. PMID- 28102115 TI - Can probiotics modulate human disease by impacting intestinal barrier function? AB - Intestinal barrier integrity is a prerequisite for homeostasis of mucosal function, which is balanced to maximise absorptive capacity, while maintaining efficient defensive reactions against chemical and microbial challenges. Evidence is mounting that disruption of epithelial barrier integrity is one of the major aetiological factors associated with several gastrointestinal diseases, including infection by pathogens, obesity and diabetes, necrotising enterocolitis, irritable bowel syndrome and inflammatory bowel disease. The notion that specific probiotic bacterial strains can affect barrier integrity fuelled research in which in vitro cell lines, animal models and clinical trials are used to assess whether probiotics can revert the diseased state back to homeostasis and health. This review catalogues and categorises the lines of evidence available in literature for the role of probiotics in epithelial integrity and, consequently, their beneficial effect for the reduction of gastrointestinal disease symptoms. PMID- 28102122 TI - Advances in Myeloid-Like Cell Origins and Functions in the Model Organism Drosophila melanogaster. AB - Drosophila has long served as a valuable model for deciphering many biological processes, including immune responses. Indeed, the genetic tractability of this organism is particularly suited for large-scale analyses. Studies performed during the last 3 decades have proven that the signaling pathways that regulate the innate immune response are conserved between Drosophila and mammals. This review summarizes the recent advances on Drosophila hematopoiesis and immune cellular responses, with a particular emphasis on phagocytosis. PMID- 28102123 TI - Health in India, 2017. PMID- 28102124 TI - Clinical guidance for bronchiolitis. PMID- 28102125 TI - ACA repeal and the AMA. PMID- 28102126 TI - Mentoring clinical trainees: a need for high touch. PMID- 28102121 TI - Inflammasomes in Myeloid Cells: Warriors Within. AB - The inflammasome is a large multimeric protein complex comprising an effector protein that demonstrates specificity for a variety of activators or ligands; an adaptor molecule; and procaspase-1, which is converted to caspase-1 upon inflammasome activation. Inflammasomes are expressed primarily by myeloid cells and are located within the cell. The macromolecular inflammasome structure can be visualized by cryo-electron microscopy. This complex has been found to play a role in a variety of disease models in mice, and several have been genetically linked to human diseases. In most cases, the effector protein is a member of the NLR (nucleotide-binding domain leucine-rich repeat-containing) or NOD (nucleotide oligomerization domain)-like receptor protein family. However, other effectors have also been described, with the most notable being AIM-2 (absent in melanoma 2), which recognizes DNA to elicit inflammasome function. This review will focus on the role of the inflammasome in myeloid cells and its role in health and disease. PMID- 28102127 TI - Can Myanmar's older people lead the way to universal health coverage? PMID- 28102128 TI - Offline: The possible impossibility of universal health coverage. PMID- 28102129 TI - Experts confident of Congressional funding for US Cures Act. PMID- 28102130 TI - New research centre focuses on conflict in the Middle East. PMID- 28102131 TI - Profile: Swiss School of Public Health, Zurich, Switzerland. PMID- 28102132 TI - Mental illness in Han Kang's The Vegetarian. PMID- 28102133 TI - Zika rash and increased risk of congenital brain abnormalities. PMID- 28102134 TI - Zika virus: are we going too far? PMID- 28102135 TI - The possibility of vascular care for prevention of dementia. PMID- 28102136 TI - Zika rash and increased risk of congenital brain abnormalities - Authors' reply. PMID- 28102137 TI - Hypertension control and cardiovascular disease. PMID- 28102138 TI - Hypertension control and cardiovascular disease. PMID- 28102140 TI - Effect of staffing on improving newborn health. PMID- 28102139 TI - Hypertension control and cardiovascular disease - Authors' reply. PMID- 28102141 TI - Department of error. PMID- 28102142 TI - Genetics of common forms of epilepsy. PMID- 28102143 TI - Corrections. PMID- 28102144 TI - Mechanical thrombectomy after intravenous thrombolysis for acute ischaemic stroke. PMID- 28102145 TI - Mechanical thrombectomy after intravenous thrombolysis for acute ischaemic stroke. PMID- 28102146 TI - Severe B-cell-mediated CNS disease secondary to alemtuzumab therapy. PMID- 28102147 TI - Mechanical thrombectomy after intravenous thrombolysis for acute ischaemic stroke - Authors' reply. PMID- 28102149 TI - Jeff Carroll. PMID- 28102148 TI - Neurological inspiration in Beckett's Waiting for Godot. PMID- 28102151 TI - Pleiotropic genetic effects influencing sleep and neurological disorders. AB - Research evidence increasingly points to the large impact of sleep disturbances on public health. Many aspects of sleep are heritable and genes influencing traits such as timing, EEG characteristics, sleep duration, and response to sleep loss have been identified. Notably, large-scale genome-wide analyses have implicated numerous genes with small effects on sleep timing. Additionally, there has been considerable progress in the identification of genes influencing risk for some neurological sleep disorders. For restless legs syndrome, implicated variants are typically in genes associated with neuronal development. By contrast, genes conferring risk for narcolepsy function in the immune system. Many genetic variants associated with sleep disorders are also implicated in neurological disorders in which sleep abnormalities are common; for example, variation in genes involved in synaptic homoeostasis are implicated in autism spectrum disorder and sleep-wake control. Further investigation into pleiotropic roles of genes influencing both sleep and neurological disorders could lead to new treatment strategies for a variety of sleep disturbances. PMID- 28102152 TI - Solanezumab: too late in mild Alzheimer's disease? PMID- 28102153 TI - Manual Therapy in the Treatment of Idiopathic Scoliosis. Analysis of Current Knowledge. AB - BACKGROUND: Apart from the recommended specific physiotherapy, the treatment of idiopathic scoliosis (IS) also incorporates non-specific manual therapy (NMT). The aim of this paper is to assess the efficacy of NMT (manual therapy, chiropractic, osteopathy) used in the treatment of children and adolescents with IS. MATERIAL AND METHODS: The study analysed systematic reviews (Analysis 1) and other recent scientific publications (Analysis 2). Analysis 1 encompassed papers on the use of NMT in patients with IS. Works concerning specific physiotherapy (SP) or bracing (B) and other types of scoliosis were excluded from the analysis. Inclusion criteria for Analysis 2 were: treatment with NMT; subjects aged 10-18 years with IS. The following types of papers were excluded: works analysing NMT combined with SP or B, reports concerning adult pa tients, analyses of single cases and publications included in Analysis 1. RESULTS: Analysis 1: six systematic reviews contained 6 papers on the efficacy of NMT in the treatment of IS. The results of these studies are contradictory, ranging from Cobb angle reduction to no treatment effects whatsoever. The papers analysed are characterised by poor methodological quality: small group sizes, incomplete descriptions of the study groups, no follow-up and no control groups. Analysis 2: in total, 217 papers were found. None of them met the criteria set for the analysis. CONCLUSIONS: 1. Few papers verifying the efficacy of manual therapy, chiropractic and osteopathy in the treatment of idiopathic scoliosis have been published to date. 2. The majority are experimental studies with poor methodology or observational case studies. 3. At present, the efficacy of non-specific manual therapy in the treatment of patients with idiopathic scoliosis cannot be reliably evaluated. 4. It is necessary to conduct further research based on appropriate methods (prospective, rando mi s ed, controlled studies) in order to reliably assess the usefulness of non-specific manual therapy in the treatment of idiopathic scoliosis. PMID- 28102150 TI - Ultra-rare genetic variation in common epilepsies: a case-control sequencing study. AB - BACKGROUND: Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. METHODS: We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. FINDINGS: We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2.3, 95% CI 1.7-3.2, p=9.1 * 10-8; familial non-acquired focal epilepsy 3.6, 2.7-4.9, p=1.1 * 10-17). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein coding genes (p=5.8 * 10-8) that were lower than expected from a random sampling of genes. INTERPRETATION: We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future. FUNDING: National Institute of Neurological Disorders and Stroke (NINDS), and Epilepsy Research UK. PMID- 28102154 TI - Effectiveness of Treatment of Idiopathic Scoliosis by SpineCor Dynamic Bracing with Special Physiotherapy Programme in SpineCor System. AB - BACKGROUND: The SpineCor dynamic brace for the treatment of idiopathic scoliosis is designed to maintain the correct position of the spine and a new movement strategy for 20 hours per day. The SpineCor exercise system intensifies and complements the brace treatment. This study evaluated the effectiveness of a comprehensive treatment of idiopathic scoliosis involving the SpineCor system. MATERIAL AND METHODS: The study assessed a group of 40 patients (38 girls and 2 boys) with idiopathic scoliosis treated with the SpineCor brace. The average age at beginning of treatment was 13.1 yrs (10-15). Minimum treatment time was 18 months. 28 participants met the SRS criteria. Angles of the curve before and after bracing based on imaging studies were measured at the beginning and end of the treatment, analyzed and compared. Rehabilitation focused on teaching active corrective movement throughout the brace treatment. A control group was formed of 33 patients, including 21 meeting the SRS criteria, who used the SpineCor dynamic brace but did not participate in the associated exercise programme. RESULTS: Among patients from the exercise group who met the SRS criteria, 25% demonstrated reduced curve angles, 35.7% demonstrated curve progression and 39.3% showed stabilization (no change). Among patients meeting the SRS criteria from the control group, a decrease in curve angle was observed in 14.3% of the patients, curve progression in 57.1% and stabilization in 28.6%. CONCLUSIONS: 1. The addition of a dedicated physiotherapy programme to SpineCor dynamic bracing improves the chances of obtaining a positive outcome. 2. It is necessary to further analyse the course of the comprehensive treatment, also with regard to other types of braces and kinesiotherapy programmes. PMID- 28102155 TI - Surgical Treatment of Radial Head Fractures: Outcomes and Complications. AB - BACKGROUND: Appropriate treatment of radial head fractures remains an area of disputes and controversy. The present paper aims to assess the outcomes of surgical fixation of these injuries and identify the most common complications. MATERIAL AND METHODS: The medical records of 63 patients (25 women and 38 men) treated in 2011 -2014 were analysed retrospectively. The treatment outcomes were assessed according to the Broberg and Morrey rating system and the QuickDASH score. RESULTS: Of 21 patients with isolated fractures, all those with Type 2 fractures demonstrated excellent outcomes. In the group with Type 3 fractures, 11 patients showed satisfactory and 4 unsatisfactory outcomes. Of 19 patients with a fracture combined with elbow dislocation, all those with Type 2 fractures achieved excellent results while in the group with Type 3 fractures 8 patients had satisfactory and 4 had unsatisfactory outcomes. 23 patients were diagnosed with Hotchkiss' terrible triad; 7 of them had sustained Type 2 fractures and showed satisfactory outcomes while those with Type 3 fractures demonstrated 12 satisfactory and 4 unsatisfactory results. Complications included limited elbow mobility (59% of the patients), pain (52.9%), lower muscle strength (35.3%), posttraumatic arthrosis (29.4%), heterotopic ossification (11.8%) and nonunion (1.5%). Eleven patients required repeat surgery. CONCLUSIONS: 1. Today's materials used for the fixation of fracture fragments allow for a stable fixation of almost any fracture of the radial head. 2. As long as fixation of a given radial head fracture is technically possible, open reduction and internal fixation should be attempted. 3. If fixation is impossible, radial head replacement should be a method of choice. PMID- 28102156 TI - Quality of Life in Pediatric Patients with Avascular Necrosis of the Femoral Head. AB - BACKGROUND: The aim of the present study was to evaluate health-related quality of life in pediatric patients with avascular necrosis of the femoral head. MATERIAL AND METHODS: A comparative study was conducted involving 32 children and adolescents in "ONFH Group" (subjects with a diagnosis of ONFH) and 44 in "Comparison Group" (asymptomatic children), both aged between 8 and 18. Clinical and sociodemographic data were obtained along with PedsQL 4.0 questionnaires to evaluate the quality of life in the age-ranges studied. RESULTS: The two groups were similar as regards sociodemographic characteristics. Comparison of the quality of life total scores demonstrated significant differences between the ONFH group and the comparison group (58.86+/-16.54 versus 82.08+/-9.51), and this also occurred in all the domains analyzed. The predictors that showed correlation with the quality of life were: presence of necrosis, age, time of diagnosis, radiographic classification, Charnley score, educational level, previous surgeries, and previous infections. CONCLUSION: Our data confirm the hypothesis that pediatric patients with ONFH demonstrate a lower quality of life than healthy children in all the domains evaluated, especially with regard to the physical aspect. PMID- 28102157 TI - Sexual Dimorphism of Acetabular Anatomy Based on Three-dimensional Computed Tomography Image of Pelvises. AB - BACKGROUND: The study aimed to compare sex differences in the morphology and spatial orientation of pelvic acetabula to advance the understanding of hip anatomy. MATERIAL AND METHODS: The study was based on three-dimensional reconstructions of computed tomography images of 50 female and 50 male acetabula. The images were used for spatial analysis of hip acetabula relative to the base of the sacral bone as the plane of reference. Statistical analysis was performed to compare angles relevant to the actual axis of the acetabulum (inclination angle, anteversion angle, tilt angle) as well as the volume and inner surface area of the acetabulum. RESULTS: Both the inclination and tilt angles of the acetabulum did not differ significantly between the groups, the respective values being: 68.61 degrees and 26.53 degrees in females and 70.56 degrees and 30.19 degrees in males (p>0.05). The anteversion angle was significantly larger for female acetabula (38.27 degrees compared to 32.05 degrees in men, with p=0.0008), while the volume and the inner surface area were significantly smaller in women (p=0.0007 and 0.0001 respectively). CONCLUSIONS: 1. Acetabular orientation is sex-specific, with female acetabula being more forward-oriented than those of men. 2. The volume and inner surface area of acetabula also differ between the sexes, being smaller in women. 3. Regardless of the plane of reference, sexual dimorphism of the acetabulum is constant. 4. Awareness of the above sex-dependent differences is necessary for preoperative planning before orthopaedic surgeries (such as hip arthroplasty or operative treatment of FAI). PMID- 28102158 TI - Use of Trabecular Titanium Implants for Primary Hip Arthroplasty. AB - BACKGROUND: Total hip arthroplasty is an increasingly common procedure. The large number of cases inevitably includes patients who require filling of their acetabular defect even in their primary surgery. The use of a utogenous grafts and allografts as well as resistance rings requires patients to avoid loading the limb for a long time to enable implant integration. This disadvantage may be partially eliminated by using trabecular titanium implants. The aim of this paper is to present the outcomes of the use of trabecular titanium implants in primary hip arthroplasty. MATERIAL AND METHODS: The study embraced 23 patients (18 women and 5 men) whose primary hip arthroplasty was performed in the Cracow Centre of Rehabilitation and Orthopaedics in the period 2010-2015 and involved placement of a trabecular titanium implant. RESULTS: Medium-term follow-up revealed improvement according to the modified and traditional Harris Hip Score and reduction in pain according to VAS. Loosening of the implant or infection were not recorded. The use of trabecular titanium allowed for reducing the amount of bone grafts used. CONCLUSIONS: 1. Reconstruction of acetabular defects with trabecular titanium implants may be used in primary hip arthroplasty to produce good clinical and radiographic outcomes. 2. The use of trabecular titanium implants allows for reducing the amount of bone grafts necessary to fill the acetabular defect and enables immediate partial loading of the limb. PMID- 28102159 TI - X-rays for Acute Knee Injuries: Pre- and Post- Pittsburgh Decision Rules Implementation. A District General Hospital Experience. AB - BACKGROUND: We wanted to assess the number of unnecessary radiographs done for acute knee injury patients and the accuracy of the Pittsburgh decision rules. MATERIAL AND METHODS: A retrospective observational study was done to look at the acute knee injury patients presented to a district general hospital Accident and Emergency Department from August 2011 till August 2013. We assessed the following parameters: sex, age, mechanism of injury, weight-bearing status and incidence of fractures in patients subjected to plain radiograph. A prospective study was then done from April 2014- August 2014 following implementation of the Pittsburgh decision rules. RESULTS: 24% of the patients had knee X-ray, compared to 72.12% in the first cycle. 36.8% had fracture, compared to 6.1% first cycle, with 66.7 % reduction in x-rays. Pittsburgh decision rules sensitivity was 100% and specificity 85.3%, positive predictive value 45.8% and accuracy 87%. CONCLUSIONS: 1. The Pittsburgh decision rules is highly sensitive, specific and accurate in determining the need of X-ray in acute knee Injuries. 2. We found that the Pittsburgh decision rules performs well in our hospital, which coincides with previously published literature. PMID- 28102160 TI - Assessment of Selected Factors Influencing the Development of Stiffness after Total Knee Arthroplasty. AB - BACKGROUND: Surgical treatment of idiopathic degenerative disease of the knee joint with total arthroplasty is aimed at reducing concomitant pain and improving the limited range of motion. This paper aims to assess the influence of pain intensity and range of motion on the presence of knee joint stiffness after primary total arthroplasty. MATERIAL AND METHODS: 59 male and female patients were divided into two groups based on the presence (G1) or absence (G2) of stiffness in the operated knee joint at 3 months post-operatively. Patients completed a questionnaire evaluating the following: sex, age, BMI, pain intensity in a VAS scale and the range of motion of the operated knee joint. The functional status was assessed with the WOMAC score. RESULTS: Mean age was 68.20 +/- 7.02 years in Group 1 (23 women, 7 men) and 67.66 +/- 7.47 years in Group 2 (20 women, 9 men). In the first examination, mean active flexion range of motion (ROM) of the operated knee joint was 98.00 degrees +/- 10.39 degrees in Group 1 and 92.07 degrees +/- 12.14 degrees in Group 2; in the second examination, it was 88.83 degrees +/- 4.68 degrees in Group 1 and 90.69 degrees +/- 6.23 degrees in Group 2 (p<0.05). The total WOMAC score was 51.13 +/- 13.48 in Group 1 and 51.28 +/- 15.32 in Group 2 in the first examination and 18.50 +/- 9.38 in Group 1 and 13.17 +/- 9.02 in Group 2 (p<0.05) in the second examination. CONCLUSIONS: 1. Pain and range of motion in the operated joint may need to be taken into consideration as factors in the development of stiffness in the early post operative period after primary total knee arthroplasty. 2. There is a need for further research on the problem of knee joint stiffness in the early post operative period. PMID- 28102161 TI - Orthotopic Autologous Chondrocyte Grafting as a Method of Treatment of Growth Plate Damage in Rabbits. AB - BACKGROUND: With the continuous advances in the therapy of joint cartilage injury, some of those classification systems are also being used for evaluating the quality of regenerating cartilage. Histo lo gi cal assessment of joint cartilage is a very important component in the staging of osteoarthritis and tracing therapeutic outcomes. We performed a histological assessment of regenerating growth plate in a group of New Zealand white rabbits as a component of autologous chondrocyte therapy for growth plate damage. MATERIAL AND METHODS: We studied a group of 14 five-week-old in-bred white rabbits. We used a tre phine needle to harvest growth plate from the medial fourth of tibial width. The mean duration of the procedure was 25 minutes (range: 12-37 minutes). We conducted a total of 25 growth plate harvesting procedures. In 21 cases, we placed a drainage tube at the site of the defect for 22 days. After removing the tube, we introduced a cartilago-fibrinous construct containing cultured autologous chondrocytes into 14 defects, while 4 defects were left intact. Three growth plates represented non-intervention controls. RESULTS: Our analysis showed satisfactory graft morphology and integration; absence of inflammatory res ponse and fair restitution of growth plate architecture. CONCLUSIONS: 1. Growth plate damage can lead to the development of an angular deformity as a result of im paired longitudinal bone growth; 2. Autologous chondrocyte grafting is a good method of treatment for growth plate damage; 3. A weakness of autologous chondrocyte grafting is the relatively long time of chondrocyte culturing. PMID- 28102162 TI - Biomechanical Causes of Fracture Non-union after Diaphyseal Forearm Fracture Fixation: an in Silico Analysis. Case Study. AB - : Non-union of forearm bone shaft fractures remains, in some cases, a major clinical problem. The aim of this study was to assess the biomechanical causes of non-union in a patient with diaphyseal forearm fractures fixated with LCP plates. The paper describes the case of a 35-year-old male who developed a non-union as a result of destabilisation of the fixation. The case was analysed with an in silico analysis of the removed fixation device. CONCLUSION: To sum up, we believe that the case described in this paper confirms the limitations to the use of LCP reconstruction plates in patients with well-developed musculature, even in the case of repeat fixation, when good adjustment of the plate well to the axis of the bone appears necessary. It is possible to use an orthosis, first a locking one and then one that limits pronation during further treatment of a partially healed fracture, but, as this case shows, it is not a fully reliable method of preventing complications. PMID- 28102163 TI - Does Mobility of the Elderly with Hip Fractures Improve at One Year Following Surgery? A 5-year Prospective Survey. AB - BACKGROUND: Hip fracture and its consequences are one of the major causes of morbidity and disability in the elderly. The purpose of this study was to collect epidemiologic data and assess the daily activities and walking ability of patients 3 months and 1 year following surgery because of a hip fracture. MATERIAL AND METHODS: We prospectively obtained data of all consecutive patients more than 50 years of age with any type of hip fracture from 2008 to 2013. After excluding pathologic fractures, hip fracture dislocations, non-surgically treated cases, and dead patients, functional status of the subjects at 3 months and 1 year after surgery was evaluated using a 10-degree scale of pain, modified Barthel index of daily activity, and independent walking ability. RESULTS: In total, 1015 cases were enrolled. Mean age was 75.6 year with a female to male ratio of 1.33. Left-sided hip fractures were seen in 51.7 % of cases. Intertrochanteric fractures were the most common type (72.1 %), followed by femoral neck (24.0 %) and subtrochanteric fractures (3.9 %). At both 3-month and 1-year follow-up visits, 562 subjects (317 women and 245 men) completed the questionnaires. Activities of daily living and independent walking ability were improved significantly at 1 year and the improvements were statistically superior to the results obtained at 3 months (p-value < 0.001 for both variables). CONCLUSION: By continuing rehabilitation of elderly patients with surgically treated hip fractures for one year, improvement in activities of life and walking independence can be expected even if they have a poor result after the first 3 months of rehabilitation. PMID- 28102164 TI - Results of Total Cementless Hip Joint Arthroplasty with Taperloc Stem. AB - BACKGROUND: The aim of this paper is to present the results of hip joint arthroplasty with the use of the Taperloc stem. MATERIAL AND METHODS: The study group consisted of 117 patients (75 women and 42 men) who underwent 121 hip joint arthroplasties with Taperloc stems. Mean age of the patients at surgery was 53.8 years (range: 2475 years). Mean follow-up period was 159.5 months. RESULTS: Pre operative Merle d'Aubigne-Postel scores (modified by Charnley) of the study group were poor in all patients. Mean post-operative improvement was 6.6 points. Excellent results were obtained in 86 cases, good in 19, fair in 9 and poor in 7 cases. Poor results were always associated with implant component loosening: 5 cases of acetabular cup loosening, 1 case of a loosened stem and 1 septic loosening of the entire endoprosthesis. In six cases (4.9%), patients developed heterotopic ossification. According to the Kaplan-Meier estimator, 10 years' survival probability was 94.21% for the whole endoprosthesis and 98.34% for the stem alone. CONCLUSIONS: 1. Our follow-up data covering a mean period of over 13 years showed that the use of the Ta-perloc stem substantially reduces hip pain and results in a good lasting clinical outcome. 2. With good surgical technique and in the absence of complications, the risk of aseptic loosening is minimal. PMID- 28102165 TI - Occupational Activity in Patients 10 Years after Hip Replacement Surgery. AB - BACKGROUND: Advanced hip osteoarthritis requires total joint replacement surgery to improve daily activity, including occupational activity. The purpose of this study was to evaluate employment status among patients 10 years after hip replacement surgery. MATERIAL AND METHODS: A total of 63 patients who underwent total hip replacement surgery at the Department of Orthopedics and Traumatology between 2003 and 2005 were enrolled in the study. At the time of the study (2014), all patients from the study group were of working age. Ultimately, 32 patients participated in the study. Each participant completed a questionnaire with questions about the place of residence, age, type of endoprosthesis, employment status, type of work performed, reason for arthroplasty, postoperative course of rehabilitation and subjective health status. Functional capacity was evaluated using Harris' 100-point scale. RESULTS: 88% of the respondents had been employed prior to surgery, compared to only 46% one year after surgery and only 40% at 10 years after surgery. A positive outcome was that 17% of the respondents receiving a disability pension prior to surgery were able to return to work after surgery. CONCLUSIONS: 1. Hip replacement surgery may affect the employment status of patients. 2. The most significant factors influencing cessation of work were a high BMI, living in a rural environment and being female. PMID- 28102166 TI - Stress Fractures of Tibia Treated with Ilizarov External Fixator. AB - BACKGROUND: Stress fractures are the result of cyclic loading of the bone, which gradually becomes damaged. Most often they are treated by rest or plaster cast and, in rare cases, by internal fixation. There is little published data on initial reposition followed by stabilization with the Ilizarov apparatus in such fractures. MATERIAL AND METHODS: Six patients were treated with an external fixator according to the Ilizarov method for a stress fracture of the tibia between 2007 and 2015. Three patients were initially treated conservatively. Due to increasing tibial deformation, they were qualified for surgical treatment with external stabilization. In the other patients, surgery was the first-line treatment. All patients demonstrated risk factors for a stress fracture. After the surgery, they fully loaded the operated limb. RESULTS: No patient developed malunion, nonunion, infection or venous thrombosis. The average time from the first operation to the removal of the external fixator was 19 weeks. Radiographic and clinical outcomes were satisfactory in all patients. CONCLUSION: 1. The Ilizarov method allows for successful stabilization of stress fractures of the tibia. 2. It may be a good alternative to internal stabilization, especially in patients with multiple comorbidities which affect bone quality and may impair soft tissue healing. PMID- 28102167 TI - Assessment and Comparison of the Efficacy of Rehabilitation Conducted at a Sanatorium and in an Outpatient Facility in Patients with Low Back Pain. Pilot Study. AB - BACKGROUND: Low back pain is nowadays believed to be one of the most serious and common health problems and is even often classified as a disease of civilisation. Prevention and treatment of such conditions is very important, particularly taking into consideration the fact that they are increasingly common in young people. Low back pain is effectively prevented and treated with rehabilitation. The aim of this paper was to assess and compare rehabilitation procedures performed in patients with low back pain in the sanatorium setting and on an outpatient basis. MATERIAL AND METHODS: The study was conducted in a group of 80 patients. Half of these patients were treated as outpatients and the other half underwent treatment at a sanatorium. Outcomes in all patients were assessed with physical tests and a survey. RESULTS: 1. The study showed that sanatorium-based rehabilitation is more beneficial with respect to decreasing pain and is associated with a decrease in the number of patients taking analgesics and a higher percentage of patients taking up physical activity after the treatment. 2. Supplementing traditional rehabilitation with natural methods used at a sanatorium leads to better treatment outcomes. PMID- 28102168 TI - Brachial Plexus Root Avulsion Injury with Occipital Condyle Fractures. Case Study. AB - Avulsion injuries of the brachial plexus with occipital condyle fractures are very rare and usually result from motor vehicle accidents. This paper presents an analysis of the case of a 24-year-old male patient who sustained both these injuries in a car accident. Computed tomography revealed a fracture of the right occipital condyle and a magnetic resonance scan showed spinal nerve disruption at the C3-C7 level on the left. The patient underwent conservative treatment. PMID- 28102169 TI - Hip joint arthroplasty in pubic symphysis separation in the course of congenital bladder exstrophy - study of two cases. AB - Congenital bladder exstrophy is a severe congenital malformation identified in one out of 30,000-50,000 live newborns and seen more often in girls. Some patients develop osteoarthritis of the hip joints which requires total hip arthroplasty. Reports of such cases are very rare in the world literature, which prompted us to present two cases treated at our Department and analyse their early outcomes. Our experience so far has been rather modest but the results encourage considering total hip arthroplasty in the treatment of hip osteoarthritis in future patients with pubic symphysis separation in the course of congenital bladder exstrophy. PMID- 28102170 TI - Complication of a Femoral Fracture Treated by Intramedullary Nailing - Numerical Analysis of a Clinical Case. AB - The aim of this paper is to conduct a numerical analysis of a case of femoral fracture treated by intramedullary nailing and confirm the conditions which led to the formation of a pseudarthrosis at the fracture site. A low-energy femoral fracture was treated by placing a ChFN System intramedullary nail with a derotation pin. Using the finite element method, a bone-implant system was generated which made it possible to observe the displacement area and strains in the region of the fracture gap. The calculations were conducted for 3 variants of the model, using a titanium nail (10 mm and 12 mm) and a steel one (10 mm). Analysis of strain distribution indicated that the highest strain values occur in the fracture gap and that they are higher when a titanium alloy is used (0-17% vs 0-11%). Interfragmentary movements caused by an imposed load were also higher when a titanium alloy implant was used. Strain analysis showed that the percentage of elements in the gap area which are potentially able to grow bone tissue is higher when a steel implant is used. It is possible to indicate sites where unfavourable fracture gap healing will take place, which may lead to the development of a pseudarthrosis. The use of a steel implant increases the probability of obtaining stable bone union. PMID- 28102171 TI - Lumbar Disc Herniation Causing Cauda Equina Syndrome in a Paediatric Patient. A Case Report. AB - Lumbar disc disease occurs mainly in the adult population. A disc prolapse in the paediatric population is very rare. Cauda equine syndrome resulting from compression of the cauda equina is a rare syndrome and is one of the few spinal surgical emergencies. Here we present a 13-year-old boy with pain in the lumbar region radiating bilaterally to the lower limbs, with asymmetrical weakness of lower the limbs, perianal hypoaesthesia and urinary retention. MRI of lumbar spine confirmed disc protrusion at the L3-L4 level with severe spinal canal stenosis. Patient was treated with microdiscectomy at the L3-L4 level. Postoperatively, his neurological deficit disappeared gradually. Although very rare, lumbar disc prolapse in the paediatric age group can lead to cauda equina syndrome. Early diagnosis and treatment can prevent life-long disability. PMID- 28102172 TI - Dr. Jozef Aleksiewicz Activity in Support of the Development of Orthopedics and Rehabilitation in Iwonicz-Zdroj (1921-1957). AB - Based on source materials in the possession of Jozef Aleksiewicz family (typescripts, manuscripts, photographs, other documents) and articles published in professional medical journals and newspapers, the authors present the contribution of Dr. J. Aleksiewicz to the development of orthopedics and rehabilitation in Iwonicz-Zdroj. In May 1921, he was appointed Surgeon General of the Spa Commission in Iwonicz-Zdroj. After holding several scholarly trips abroad in 1925 to sanatoriums treating cases of osteo-articular tuberculosis, he commenced the construction of "Sanato", a modern sanatorium. Opened in 1930, it was the only center in Poland treating osteo-articular tuberculosis in a spa setting. It was the first orthopedic rehabilitation center in what is now Podkarpackie Voivodship offering diagnostic work-up, surgery and conservative treatment of osteo-articular tuberculosis in children. Modelled on the best Western centers, Dr. Aleksiewicz widely employed physical methods, such as Swedish therapeutic gymnastics, mechanotherapy, massage, physical therapy and hydrotherapy. PMID- 28102173 TI - In vitro evaluation of the antibacterial and osteogenic activity promoted by selenium-doped calcium phosphate coatings. AB - Selenium is an essential trace element present in 25 selenoenzymes, playing critical roles in a variety of physiological processes, such as anti-oxidative defense and the modulation of cell proliferation and differentiation. This paper characterizes selenium-doped calcium phosphate coatings and evaluates their effects on the osteogenic activity, the proliferation of osteosarcoma cells and biofilm formation. To do so, the structure and elemental composition of the obtained coatings were analyzed, in addition to their thicknesses, and they were compared to pure calcium phosphate coatings. Moreover, the dose-effect ratio of two coatings with the lower (0.6 at%) and the higher (2.7 at%) selenium content was studied in terms of osteogenic, anti-biofilm and cancerous anti-proliferative properties. The results showed the incorporation of selenium in the form of selenite groups into the hydroxyapatite structure, with a similar crystalline pattern to the latter and increased roughness of the coatings. The calcium phosphate coatings with 2.7 at% of selenium resulted in significant osteogenic activity (p < 0.01) of healthy pre-osteoblasts (MC3T3-E1) over long periods of incubation, a significant anti-proliferative effect (p < 0.01) on cancerous osteoblasts (MG63) in a preliminary study, and anti-biofilm properties (p < 0.01) against Staphylococcus epidermidis and Staphylococcus aureus bacterial strains, which are responsible for most infections after orthopedic surgeries. PMID- 28102174 TI - Modeling dynamics of mutants in heterogeneous stem cell niche. AB - Studying the stem cell (SC) niche architecture is a crucial step for investigating the process of oncogenesis and obtaining an effective stem cell therapy for various cancers. Recently, it has been observed that there are two groups of SCs in the SC niche collaborating with each other to maintain tissue homeostasis: border stem cells (BSCs), which are responsible in controlling the number of non-stem cells as well as stem cells, and central stem cells (CeSCs), which regulate the SC niche. Here, we develop a bi-compartmental stochastic model for the SC niche to study the spread of mutants within the niche. The analytic calculations and numeric simulations, which are in perfect agreement, reveal that in order to delay the spread of mutants in the SC niche, a small but non-zero number of SC proliferations must occur in the CeSC compartment. Moreover, the migration of BSCs to CeSCs delays the spread of mutants. Furthermore, the fixation probability of mutants in the SC niche is independent of types of SC division as long as all SCs do not divide fully asymmetrically. Additionally, the progeny of CeSCs have a much higher chance than the progeny of BSCs to take over the entire niche.